PMID- 12592601
TI  - [Selfexpandable metal stent for the treatment of a large anastomotic
      insufficiency after esophageal resection].
AB  - Mediastinal anastomotic leaks are still catastrophic events following surgical
      procedures and are still a therapeutic challenge. A variety of conservative and
      surgical procedures have been proposed for the management of this conditions. An
      aggressive surgical approach is associated with considerable morbidity and
      lethality. A conservative approach is indicated only in a few selected patients
      with minimal anastomotic leaks. With advances in minimally invasive techniques,
      interventional endoscopic procedures have become an established therapeutic
      approach in the treatment of anastomotic insufficiencies. Our case report
      demonstrates that transesophageal placement of a selfexpandable metal stent in
      combination with interventional drainage of the paraesophageal space is a safe
      and effective procedure in the management of a mediastinal anastomotic leaks.

PMID- 12592602
TI  - [W.D.H.A. Syndrome due to occult neuroendocrine malignancy with concomitant liver
      metastases].
AB  - In June 1999, a 62-year-old man is hospitalised to evaluate the sonographic
      suspicion of liver metastases. The biopsy of the liver shows a malignant
      neuroendocrine tumour. Further diagnostic investigation including gastroscopy,
      colonoscopy, enteroclysis, thoracal and abdominal CT and somatostatin-receptor
      scintigraphy does not localise the primary tumour. In the absence of clinical
      symptoms a wait and see procedure with clinical and imaging controls at regular
      intervals is arranged. Beginning in spring of 2001--nearly two years after the
      initial diagnosis--the patient suffers from progredient diarrhoea and weight loss
      leading to hospitalisation in September 2001. The existence of secretory
      diarrhoea, hypokalaemia and hypercalcaemia arouses suspicion of vipoma. This is
      proven by a remarkably elevated plasma concentration of vasoactive intestinal
      peptide (VIP). Once more, an accurate investigation is started but no primary
      tumour can be discovered despite extensive liver metastases. A vipoma is a rare
      differential diagnosis of secretory diarrhoea. This case report describes the
      remarkable constellation of liver metastases of a malignant neuroendocrine
      neoplasm without a primary tumour and the clinical presentation of a W.D.H.A.
      syndrome (watery diarrhoea, hypokalaemia and hypo- or achlorhydria). Despite
      extensive disease, therapy with octreotide and prednisolone provides a good
      clinical response.

PMID- 12592605
TI  - Improving the prediction of complex diseases by testing for multiple disease
      susceptibility genes.
AB  - Studies have argued that genetic testing will provide limited information for
      predicting the probability of common diseases, because of the incomplete
      penetrance of genotypes and the low magnitude of associated risks for the general
      population. Such studies, however, have usually examined the effect of one gene
      at time. We argue that disease prediction for common multifactorial diseases is
      greatly improved by considering multiple predisposing genetic and environmental
      factors concurrently, provided that the model correctly reflects the underlying
      disease etiology. We show how likelihood ratios can be used to combine
      information from several genetic tests to compute the probability of developing a
      multifactorial disease. To show how concurrent use of multiple genetic tests
      improves the prediction of a multifactorial disease, we compute likelihood ratios
      by logistic regression with simulated case-control data for a hypothetical
      disease influenced by multiple genetic and environmental risk factors. As a
      practical example, we also apply this approach to venous thrombosis, a
      multifactorial disease influenced by multiple genetic and nongenetic risk
      factors. Under reasonable conditions, the concurrent use of multiple genetic
      tests markedly improves prediction of disease. For example, the concurrent use of
      a panel of three genetic tests (factor V Leiden, prothrombin variant G20210A, and
      protein C deficiency) increases the positive predictive value of testing for
      venous thrombosis at least eightfold. Multiplex genetic testing has the potential
      to improve the clinical validity of predictive testing for common multifactorial
      diseases.

PMID- 12592606
TI  - Informative missingness in genetic association studies: case-parent designs.
AB  - We consider the effect of informative missingness on association tests that use
      parental genotypes as controls and that allow for missing parental data. Parental
      data can be informatively missing when the probability of a parent being
      available for study is related to that parent's genotype; when this occurs, the
      distribution of genotypes among observed parents is not representative of the
      distribution of genotypes among the missing parents. Many previously proposed
      procedures that allow for missing parental data assume that these distributions
      are the same. We propose association tests that behave well when parental data
      are informatively missing, under the assumption that, for a given trio of
      paternal, maternal, and affected offspring genotypes, the genotypes of the
      parents and the sex of the missing parents, but not the genotype of the affected
      offspring, can affect parental missingness. (This same assumption is required for
      validity of an analysis that ignores incomplete parent-offspring trios.) We use
      simulations to compare our approach with previously proposed procedures, and we
      show that if even small amounts of informative missingness are not taken into
      account, they can have large, deleterious effects on the performance of tests.

PMID- 12592608
TI  - The genetic legacy of the Mongols.
AB  - We have identified a Y-chromosomal lineage with several unusual features. It was
      found in 16 populations throughout a large region of Asia, stretching from the
      Pacific to the Caspian Sea, and was present at high frequency: approximately 8%
      of the men in this region carry it, and it thus makes up approximately 0.5% of
      the world total. The pattern of variation within the lineage suggested that it
      originated in Mongolia approximately 1,000 years ago. Such a rapid spread cannot
      have occurred by chance; it must have been a result of selection. The lineage is
      carried by likely male-line descendants of Genghis Khan, and we therefore propose
      that it has spread by a novel form of social selection resulting from their
      behavior.

PMID- 12592607
TI  - Mutations in genes encoding fast-twitch contractile proteins cause distal
      arthrogryposis syndromes.
AB  - The distal arthrogryposes (DAs) are a group of disorders characterized by
      multiple congenital contractures of the limbs. We previously mapped a locus for
      DA type 2B (DA2B), the most common of the DAs, to chromosome 11. We now report
      that DA2B is caused by mutations in TNNI2 that are predicted to disrupt the
      carboxy-terminal domain of an isoform of troponin I (TnI) specific to the
      troponin-tropomyosin (Tc-Tm) complex of fast-twitch myofibers. Because the DAs
      are genetically heterogeneous, we sought additional candidate genes by examining
      modifiers of mutant Drosophila isoforms of TnI. One of these modifiers, Tm2,
      encodes tropomyosin, another component of the Tc-Tm complex. A human homologue of
      Tm2, TPM2, encodes beta-tropomyosin and maps to the critical interval of DA type
      1 (DA1). We discovered that DA1 is caused by substitution of a highly conserved
      amino acid residue in beta-tropomyosin. These findings suggest that DAs, in
      general, may be caused by mutations in genes encoding proteins of the contractile
      apparatus specific to fast-twitch myofibers. This provides a new opportunity to
      directly study the etiology and pathogenesis of multiple-congenital-contracture
      syndromes.

PMID- 12592609
TI  - Extracellular matrix protein expression during mouse detrusor development.
AB  - BACKGROUND/PURPOSE: Extracellular matrix proteins are implicated in regulating
      cell proliferation and differentiation. The authors systematically analysed the
      expression of elastin; collagen types I, III, IV; laminin; and fibronectin during
      mouse detrusor muscle development, a period during which downregulation of
      detrusor proliferation and increasing smooth muscle differentiation is known to
      occur. METHODS: Embryonic days 14 (E14) and 18 (E18), and postnatal day 1 (D1)
      and week 6 (6wk) were examined, a period spanning the inception of the bladder to
      postnatal maturity. Immunohistochemistry of whole bladders was used to
      immunolocalise protein expression, and Western blot of dissected detrusor layers
      was used to semiquantify soluble protein expression. RESULTS: All proteins were
      detected at all 4 stages. Statistically significant increases were documented for
      elastin (E14 to 6wk), collagen type I (E18 to 6wk), collagen type III (D1 to 6wk)
      and laminin (E14 to 6wk). Fibronectin levels were relatively high up to D1, after
      which levels declined significantly. Collagen type IV levels decreased
      significantly (E18 to 6wk). CONCLUSIONS: The authors postulate that changing
      levels of laminin and fibronectin have opposing effects on the transition from
      proliferating primitive mesenchymal cells to differentiated detrusor muscle.
      Furthermore, changes in collagen type III and elastin may be important for
      bladder compliance.

PMID- 12592610
TI  - Surgical complications of pancreatectomy for persistent hyperinsulinaemic
      hypoglycaemia of infancy.
AB  - PURPOSE: The aim of this study was to review the surgical complications of
      pancreatectomy for persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI).
      METHODS: A retrospective review was conducted of patients undergoing
      pancreatectomy for PHHI in one institution over the past 13 years. RESULTS: The
      records of 48 patients were reviewed; the age at operation ranged from 10 days to
      30 months (median, 8 weeks). Weight at operation ranged from 1.97 to 11.4 kg
      (median, 5.2 kg). There were no deaths. Intraoperative complications comprised
      bleeding in 7, (major in 2), splenic injury in one, bile duct injury in 2 (1
      oversewn, 1 choledochoduodenostomy), and 1 small bowel injury. Postoperatively, 5
      children underwent choledochoduodenostomy: 2 for biliary leak and 3 for delayed
      bile duct stricture. Other postoperative complications included wound infection
      (n = 3), prolonged ileus (n = 1) and adhesion obstruction (n = 1), and wound
      leakage (n = 1). Renal failure developed in one child owing to acute tubular
      necrosis. Nine patients required further pancreatic resection because of
      continued hypoglycaemia. Three patients continued to require medication for
      hyperinsulinism despite surgery, 20 required insulin, and 13 required pancreatic
      enzyme replacement at the time of the last review. CONCLUSIONS: Pancreatectomy
      resulted in resolution of hyperinsulinism in 45 of 48 patients. Sixteen patients
      required no further surgery or medication. Pancreatectomy for PHHI may be
      associated with major intra and postoperative morbidity.

PMID- 12592611
TI  - Early perfluorodecalin lung distension in infants with congenital diaphragmatic
      hernia.
AB  - BACKGROUND/PURPOSE: Pulmonary hypoplasia contributes to mortality in infants with
      severe congenital diaphragmatic hernia (CDH). Accelerated postnatal lung growth
      with perfluorocarbon lung distension has been demonstrated in animals. The
      authors present a study measuring perfluorodecalin distension in neonates with
      severe CDH on extracorporeal membrane oxygenation (ECMO) support. METHODS: Six
      consecutive neonates with CDH requiring ECMO support were recruited. The lungs
      were filled with perfluorodecalin, and continuous positive airway pressure was
      applied for 6 to 10 days (mean, 7.7 days +/- 0.7). The perfluorodecalin was
      exchanged 4 times a day. Radiographic lung projections were measured, and from 2
      dimensional measurements an estimated lung volume was calculated using the ECMO
      cannula as reference. RESULTS: Perfluorodecalin instillation started soon after
      starting ECMO support (mean, 13.5 +/- 5.3 hours). The volume required to fill the
      lungs increased significantly (P <.02). The radiographic dimension of the
      affected lung increased significantly (mean percentage increase, 272%; P <.02).
      The contralateral lung dimension also increased (mean percentage increase 51%; P
      <.02). CDH repair was undertaken on ECMO in all cases. All patients survived
      (follow-up, 3 to 42 months). CONCLUSIONS: This protocol of early perfluorodecalin
      lung distension in infants with severe CDH on ECMO support resulted in
      significant radiographic lung enlargement. Clinical outcomes are encouraging.
      Possible mechanisms include alveolar recruitment, alveolar dilatation, and
      accelerated postnatal lung growth.

PMID- 12592612
TI  - Isolation and culture of adult and fetal rabbit bladder smooth muscle cells and
      their interaction with biopolymers.
AB  - PURPOSE: The aim of this study was to test the feasibility of isolation and
      culture of adult and fetal rabbit bladder smooth muscle cells (SMCs) and
      comparison of their interactions with different types of biodegradable
      biopolymers in cell culture. METHODS: Bladder SMCs isolated from adult and fetus
      rabbits were identified by immunostaining for smooth muscle alpha-actin and
      myosin. Growth kinetics of SMCs were estimated using population doubling time
      (PDT) and thymidine labeling index (TLI). Poly (D, L-lactide-co-glycolide; PLGA)
      copolymers were synthesized at 85:15 and 75:25 monomer ratios. The porous
      scaffolds prepared from these polymers were seeded with SMCs. The study compared
      the effectiveness of adsorbing fibronectin and fetal calf serum (FCS) on these
      biopolymers. The cells grown on these polymers were quantified using a neutral
      red uptake assay. RESULTS: Over 90% of the 2 cell populations stained positive
      for SMC marker proteins. Fetal SMCs were seen to emerge from the tissue after 3
      to 4 days, whereas adult SMCs were seen after 5 to 6 days. However, estimated PDT
      of fetal and adult SMCs was 85.2 and 54.5 hours, respectively, and TLI of adult
      SMCs was also higher than with fetal SMCs. Proliferation on 75:25 PLGA was better
      than for 85:15 and for both biopolymers; adsorption of FCS significantly affected
      cell attachment relative to fibronectin. CONCLUSIONS: Although fetal SMCs were
      shown to emerge from explants early after seeding onto dishes, doubling time and
      S-phase fraction of adult bladder SMCs were markedly higher than of fetal derived
      cells. Adsorption of serum proteins significantly enhances the attachment of both
      fetal and adult SMCs to biopolymers.

PMID- 12592613
TI  - New perspective for the management of near-total or total intestinal
      aganglionosis in infants.
AB  - BACKGROUND/PURPOSE: Extensive intestinal aganglionosis is rare. The diagnosis and
      treatment are known to be difficult and it had been considered to be fatal. The
      aim of this study was to review our experience with children with extensive
      intestinal aganglionosis. METHODS: Retrospective analysis was conducted in
      patients referred to the intestinal transplantation unit since 1993. Presentation
      and outcome were analysed looking at 2 groups who had either undergone previous
      subtotal intestinal resection (group I) or no or limited resection (group II).
      RESULTS: Eight children were selected (3 patients in group I and 5 in group II).
      Group I was remarkable in that patients all were referred early in age with
      progressing liver failure. Parents of one patient refused to accept
      transplantation as treatment, and he died one month later. Two noncirrhotic
      patients were maintained in the parenteral nutrition programme and currently
      progress well with enteral feedings. The other 5 patients underwent transplant,
      and 4 of 5 are alive after transplantation with a mean follow-up of 22.2 months
      (range 0.4 to 63.6). CONCLUSIONS: Subtotal resection of intestine at the time of
      diagnosis must be avoided. Conservative management with parenteral nutrition may
      be associated with long-term good outcome. Small bowel transplant may open new
      perspective in the management of patients with end-stage liver disease.

PMID- 12592614
TI  - Role of Sonic hedgehog in the development of the trachea and oesophagus.
AB  - BACKGROUND/PURPOSE: The secreted glycoprotein, Sonic hedgehog (Shh) plays an
      important patterning role in the development of many organ systems. The authors
      aimed to study the temporal and spatial pattern of expression of Shh and its
      receptor Ptc1 during the development of the anterior foregut and to test the
      hypothesis that the Shh expression pattern is disturbed during the development of
      oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) in Adriamycin
      treated mouse embryos. METHODS: Saline and Adriamycin-treated (4 mg/kg) CBA/Ca
      embryos were harvested between embryonic days (E) 10.5 and 12.5, and Shh and Ptc1
      expression was studied by whole-mount and section in situ hybridisation using
      digoxygenin-labelled riboprobes. RESULTS: At E10.5, saline-treated embryos had an
      undivided foregut in which the ventrally placed prospective tracheal epithelium
      was positive for Shh, whereas the dorsal part was negative. At E11.5, this
      pattern had reversed with the separated trachea becoming negative and the
      oesophagus gaining expression of Shh. Ptc1 was expressed in the mesoderm adjacent
      to Shh expressing endoderm at both stages. Affected Adriamycin-treated embryos
      had an undivided foregut at E11.5, the epithelium of which showed diffuse Shh
      staining that lacked the dorso-ventral patterning seen in controls. CONCLUSIONS:
      The reversal in the dorso-ventral pattern of Shh expression during the narrow
      embryologic window in which tracheo-oesophageal separation is initiated suggests
      that Shh may play an important role in this process. Transient disturbance of
      this pattern may underlie the abnormal organogenesis in the Adriamycin model.

PMID- 12592615
TI  - Body temperature and heat production in suckling rat endotoxaemia: beneficial
      effects of glutamine.
AB  - BACKGROUND/PURPOSE: Sepsis is an important cause of neonatal mortality. The aim
      of the study was to investigate the metabolism of endotoxic neonatal rats and the
      potential beneficial effect of glutamine. METHODS: Suckling rats received
      intraperitoneal saline (control; C), endotoxin (300 microg/g LPS; E),
      saline+glutamine (2 mmol/g; CG), endotoxin+glutamine (EG), saline+leucine (2
      mmol/g; CL) or endotoxin+leucine (EL). Sepsis score (0-8) and rectal temperature
      were monitored. Hypothermia was defined as rectal temperature less than 32
      degrees C. Oxygen consumption (VO2, mL/kg/h), a determinant of heat production,
      was measured by indirect calorimetry. Data (mean +/- SEM) were compared by
      analysis of variance (ANOVA), paired t test or Fisher's Exact test. RESULTS:
      Endotoxic (E) rats had significantly lower VO2 than C rats from 90 minutes
      postinjection to the end of the experiment, 210 minutes (VO2 from 150 to 210
      minutes: C 671 +/- 45; E 429 +/- 36, P <.0004; n = 8; paired t test). VO2 of CL
      or CG rats was elevated between 90 and 210 minutes compared with control, but
      significantly (P <.01) only in the L group (C 706 +/- 31; CG 871 +/- 63; CL 984
      +/- 31; n = 7-9, ANOVA). VO2 was significantly higher (P <.05) in EG rats than E
      rats (E 460 +/- 29; EG 654 +/- 68; n = 9-10). In the EL group, VO2 was raised but
      was not significantly different from E (E 460 +/- 29; EL 637 +/- 52; n = 8-10).
      EG rats were significantly less hypothermic between 90 and 210 minutes (58 of 132
      measurements) compared with E (95 of 147; P =.0007, Fisher's Exact test), whereas
      the EL group were similarly hypothermic (74 of 120) to E (P =.7). Sepsis score
      was significantly lower in the EG group than both E and EL groups (E 4.9 +/- 0.3;
      EG 3.6 +/- 0.3; EL 5.0 +/- 0.3; n = 40; P <.01; ANOVA). CONCLUSIONS: Neonatal
      endotoxaemia lowers VO2, heat production, and body temperature. Glutamine and
      leucine both cause nutrient-induced thermogenesis in control animals and restore
      VO2 of endotoxic animals. Glutamine additionally increases rectal temperature,
      reduces incidence of hypothermia, and improves clinical signs of endotoxic rats.
      This suggests that glutamine may be beneficial for nutrition in neonatal sepsis.

PMID- 12592616
TI  - Evolution of a percutaneous fetoscopic access system for single-port tracheal
      occlusion.
AB  - BACKGROUND/PURPOSE: Prenatal tracheal occlusion currently is being assessed as a
      treatment modality for congenital diaphragmatic hernia (CDH). The development of
      a totally percutaneous fetoscopic access system would help avoid the need for
      maternal laparotomy and reduce the morbidity rate of fetal surgical procedures
      for the mother. Laparoscopic radial expansion sheaths and Seldinger technique
      based vascular catheters both have been advocated as means of achieving amniotic
      cavity access. The authors have investigated these 2 systems in an attempt to
      develop a reliable method for achieving safe percutaneous fetoscopic access and
      present the first successful attempt to deploy an intratracheal balloon using an
      entirely percutaneous approach through a single port in an ovine model. METHODS:
      A number of prototype systems were evaluated sequentially over a 3-year period in
      an ovine model: (1) the radially expanding InnerDyne step port system, (2) a new
      rigid cannula with a bulbous/sharp end preloaded onto the radially expanding
      InnerDyne port, (3) a conical removable addition to the rigid cannula in 2, (4) a
      modified bulbous/sharp ended cannula incorporating a circumferential protective
      insert, (5) a rigid split sheath with the radially expanding port placed through
      the lumen of the split sheath, (6) a flexible introducer and dilator with the
      split sheath (used in the Seldinger placement of central lines), and (7) a 2
      needle approach using a superelastic shape-memory alloy Nickel-Titanium wire with
      the flexible dilator and sheath, incorporating a side perfusion port. For balloon
      tracheal occlusion, live anaesthetized time-mated pregnant ewes were used at 110
      days' gestation. Tracheobronchoscopy was achieved using a 3-mm 0 degrees
      telescope, and the cutaneotracheal tract was secured by a 3.3-mm sheath
      incorporating a side-perfusion port. The rigid telescope was replaced by a
      flexible choledochoscope preloaded with a silicone balloon. The balloon was
      deployed 2 cm above the carina proximal to the right upper lobe bronchus.
      RESULTS: The many problems encountered in the evolution of the preferred system
      related mainly to separation and tenting of the chorioamniotic membranes in the
      ovine uterus and inconsistent access to the fetal parts of interest. Each
      resulted in significant modifications to our approach. Furthermore, the use of
      rigid access devices commonly caused fetal injury. Successful access to the
      intrauterine cavity and cannulation of the trachea was achieved consistently with
      minimal trauma, irrespective of fetal position by method 7. Multiple port
      placement allowed visualization of the entry of all components of the system
      confirming minimal chorioamniotic membrane separation and tenting. Single port
      tracheal occlusion was undertaken first on 6 cadavers before being performed
      successfully on 3 live anaesthetized ewes. Fetoscopic access and cannulation of
      the trachea was achieved consistently in all live animals irrespective of fetal
      position. CONCLUSIONS: This modified Seldinger technique using the unique
      properties of the memory-shaped alloy wire for initial uterine access offers a
      safe method for the percutaneous placement of fetoscopic ports in the ovine model
      for prenatal intervention. Successful placement of a tracheal balloon entirely
      through a single percutaneously placed port represents a further advance in
      prenatal therapy for CDH.

PMID- 12592617
TI  - New technique for fixation of Broviac catheters.
AB  - Broviac catheters are in common use for administration of parenteral nutrition,
      cancer chemotherapy, and antibiotic therapy within the paediatric population.
      Inadvertent dislodgement of these catheters is common during the initial weeks
      before the Dacron cuff is anchored by the ingrowth of fibrous tissue. The authors
      describe a technique in which an internal fixation suture is placed to prevent
      dislodgement or migration.

PMID- 12592618
TI  - Quality of life after gastric transposition for oesophageal atresia.
AB  - BACKGROUND/PURPOSE: A small proportion of infants born with oesophageal atresia
      in which the gap between the 2 ends of the oesophagus is too great for an end-to
      end anastomosis will require oesophageal replacement. Since 1981 the author's
      procedure of choice for oesophageal replacement has been gastric transposition.
      The long-term functional outcome appears to be satisfactory, but the quality of
      life of these patients has not been investigated formally. This report assesses
      the health-related quality of life (QOL) of 2 groups of patients born with
      oesophageal atresia who have undergone gastric transposition. METHODS: The study
      group comprised 28 patients aged 2 to 22 years who resided in England. Group 1 (n
      = 13), comprised patients who had undergone cervical oesophagostomy and
      gastrostomy without attempt at oesophageal anastomosis; group 2 (n = 15),
      comprised patients who had undergone previous attempts at reconstruction or
      replacement. QOL was assessed using modified versions of the Gastrointestinal
      Quality Of Life Index (GIQLI). RESULTS: QOL scores based on patients' responses
      showed no significant differences between the groups (124 v 119). However, the
      disease-specific symptom scores showed that patients in group 1 experienced fewer
      symptoms compared with those in group 2. Additionally, based on parental
      responses, patients in group 1 had higher QOL scores than those in group 2. QOL
      scores for patients aged 2 to 4 years (n = 5) did not differ between the groups
      (81 v 92, not significant). CONCLUSIONS: The quality of life for patients with
      oesophageal atresia undergoing gastric transposition was generally unimpaired by
      any side effects of gastric transposition. Patients undergoing gastric
      transposition as a primary procedure experienced fewer disease-specific symptoms
      in the medium term compared with patients who had undergone previous unsuccessful
      attempts at reconstruction or replacement of their oesophagus.

PMID- 12592619
TI  - Thoracic outlet syndrome in paediatrics: clinical presentation, surgical
      treatment, and outcome in a series of eight children.
AB  - BACKGROUND/PURPOSE: This report reviews the clinical presentation, surgical
      treatment, and outcome of 8 children treated for the thoracic outlet syndrome
      (TOS) during the last 3 years. METHODS: From 1998 through 2001 31 patients were
      admitted to our Vascular Surgery Unit with TOS. Eight of them (25.8%) were in the
      paediatric age group, 8 to 16 years (mean, 13 years). No sex prevalence was
      found. The presenting symptoms were neurologic in 2 patients (25%) and secondary
      to venous flow impairment in 6 (75%). At phlebography, venous thrombosis was seen
      in 2 cases, and functional intermittent obstruction was seen in 4. Seven patients
      underwent decompressive surgical partial resection of the first rib with
      transaxillary or supraclavicular access. One patient was treated conservatively.
      RESULTS: There were no major postoperative complications. Mean hospital stay was
      2.7 days. In no patient were there signs of recurrence after a mean follow-up of
      18 months (range, 3 to 36 months). CONCLUSIONS: In the authors' experience TOS in
      paediatric patients occurs with the same symptoms and thrombotic complications as
      in adults. The same surgical strategy adopted in adult patients is advisable for
      affected children.

PMID- 12592620
TI  - HIV-positive African children with rectal fistulae.
AB  - BACKGROUND/PURPOSE: Human immunodeficiency virus (HIV) disease is an increasingly
      common infection in children in sub-Sahara Africa. Rectal fistulation is one such
      condition with which these patients present to the paediatric surgeon. This
      appeared to be an exclusively female condition until 2 male patients were treated
      recently. METHODS: A 6-year (1996 through 2001) retrospective study found 39
      children presenting with HIV-related rectal fistulae. Thirty-seven girls were
      seen with rectovaginal fistulae (RVF), and there is supportive documentation
      showing an increase in this condition throughout Southern Africa. Until now, boys
      have not been described with this condition. The author presents 2 boys who
      complete this spectrum of HIV-related acquired rectal fistulae. RESULTS: All
      patients were found to have rectal fistula at the dentate line. In girls it
      varied in size from pin-point to 5 mm diameter, tracking anteriorly into the
      vagina. When closure of the fistula was attempted, it broke down. The 2 boys had
      a large fistula, which tracked to the prostatic urethra on the right of the
      verumontanum. The first patient underwent a successful repair. The second patient
      had a "Y"-shaped fistula based at the dentate line, with the second limb passing
      into the bladder. The parents refused further treatment and took the child home.
      CONCLUSIONS: HIV disease affects increasing numbers of children. A spectrum of
      rectal fistulae now has been seen in both girls and boys. These acquired rectal
      fistulae arise at the dentate line in both genders. Girls with these fistulae are
      seen more commonly, presenting with RVF. The closure of a fistula has only been
      successful in one boy.

PMID- 12592621
TI  - After the honeymoon--medium-term outcome of antegrade continence enema procedure.
AB  - PURPOSE: The aim of this study was to determine medium-term outcomes of the
      antegrade continence enema (ACE) procedure. METHODS: A retrospective casenote
      review plus telephone questionnaire was conducted. The study was performed at a
      regional paediatric surgical centre. The subjects were consecutive children
      undergoing the ACE procedure over a 5 year period. Main outcome measures were use
      of the ACE; reversal rates; complications, ease of use, effectiveness, and
      satisfaction scores. Data are expressed as median (range). RESULTS: Thirty-two
      (52%) of 62 children undergoing the ACE procedure were girls. The age at the time
      of operation was 11.5 (3.8 to 17.6) years. Underlying diagnoses included spina
      bifida (n = 31), anorectal malformations (n = 15), slow-transit constipation (n =
      9), Hirschsprung's disease (n = 2), sacral agenesis (n = 2), and trauma/tumour (n
      = 2). Median follow-up was 5.4 (3.25 to 8.25) years. Eleven of 62 (18%) children
      were no longer using the ACE (n = 5) or had it surgically reversed (n = 6; 14.1
      +/- 9.3 months postprocedure). Reasons for disuse/reversal were lack of
      effectiveness (n = 4), complications (n = 2), noncompliance (n = 3), independent
      continence (n = 1), and pain (n = 1). Five (8%) children currently have a
      colostomy. Gender (P =.31; Fisher's Exact), age (Pearson), and underlying
      diagnoses (P =.07, Chi2) were not predictors of failure. Overall, stomal stenosis
      was the most common complication, affecting 26 of 62 (41%) children. Of 32
      questionnaire respondents to linear scores, ease of use was rated as 2 (0 to 8,
      0, very easy; 10, very difficult), discomfort on use as 3 (0 to 9; 0, no pain;
      10, very painful), overall satisfaction as 9 (0 to 10; 0, completely
      dissatisfied; 10, completely satisfied). Eighty-four percent were completely
      continent or had soiling less than once a month. There was a significant
      correlation between the level of continence and satisfaction with the procedure
      (P =.04; Pearson). CONCLUSIONS: The ACE procedure offers significant benefits to
      some children with incontinence or intractable constipation. However, it is not
      universally successful, and other continence promoting strategies may need to be
      considered.

PMID- 12592622
TI  - Preoperative enterocolitis is associated with poorer long-term bowel function
      after Soave-Boley endorectal pull-through for Hirschsprung's disease.
AB  - BACKGROUND/PURPOSE: The purpose of the investigation was to apply a
      semiquantitative scoring system for bowel function to patients who had undergone
      endorectal pull-through (ERPT) for Hirschsprung's disease (HD) and to use this to
      analyse the clinical factors relating to functional outcome. METHODS: The case
      note details of 63 patients undergoing ERPT for HD were reviewed. A questionnaire
      using a semiquantitative scoring system for 6 aspects of bowel function was sent
      to parents of 55 patients. The total functional score (TFS) for each patient was
      calculated, and a statistical analysis was performed to determine which clinical
      factors were significantly related to bowel functional outcome. RESULTS: Fifty
      (91%) of the parents returned the questionnaire. TFS was "good" in 45%, "fair" in
      33% and "poor" in 22%. There was a statistically significant difference in the
      scores of those who had preoperative Hirschsprung's associated enterocolitis
      (HAEC) TFS = 8.0 and those who did not, TFS 12.7 (P <.01) The sex of the patient,
      length of aganglionic segment, timing of ERPT (early/late), staging of ERPT (1 or
      2), presence/absence of anastomotic stricture, and presence or absence of Down's
      syndrome did not statistically significantly affect TFS. CONCLUSIONS:
      Preoperative HAEC was the most important factor in relation to functional outcome
      after ERPT for HD. The reason remains unclear.

PMID- 12592623
TI  - Immunocolocalization of the heme oxygenase-2 and interstitial cells of Cajal in
      normal and aganglionic colon.
AB  - PURPOSE: Interstitial cells of Cajal (ICCs) are pacemaker cells that play an
      important role in the control of gut motility. Carbon monoxide (CO) has been
      proposed as an endogenous messenger molecule between ICC and smooth muscle cells
      in the gastrointestinal tract (GIT). Heme oxygenase-2 (HO-2) is the main
      physiologic mechanism for generating CO in human cells. The aim of this study was
      to investigate the immunocolocalization of the HO-2 and ICCs in normal and
      aganglionic bowel of Hirschsprung's disease (HD). METHODS: Full-thickness
      specimens were obtained from aganglionic colon during pull-through operation from
      10 patients diagnosed as having HD. Normal control large bowel specimens were
      collected from 4 patients during bladder augmentation procedures. Double
      immunostaining was carried out using c-kit and HO-2 antibodies.
      Immunolocalization was detected by means of confocal laser scanning microscopy.
      RESULTS: HO-2 immunoreactivity (IR) was found in many ICCs present around the
      myenteric plexus, within the longitudinal and circular muscle layers and at the
      innermost part of the circular muscle layer in normal colon. In the aganglionic
      colon there was absence of HO-2 IR in the sparsely found ICCs. In the
      transitional zone of HD bowel the colocalization of HO-2 IR and ICCs was much
      reduced compared with controls. CONCLUSIONS: The results of this study provide
      the first evidence for the presence of HO-2 immunoreactivity in the ICCs in
      normal human colon and absence of HO-2 immunoreactivity in sparsely appearing
      ICCs in the bowel of HD patients. The lack of HO-2 in the ICCs in the bowel of HD
      patients may result in impaired intracellular communication between ICCs and SMCs
      causing motility dysfunction.

PMID- 12592624
TI  - Fate of the pouch in 151 pediatric patients after ileal pouch anal anastomosis.
AB  - BACKGROUND/PURPOSE: Ileal pouch anal anastomosis (IPAA) offers many pediatric
      patients a surgical cure for mucosal ulcerative colitis (MUC) with preservation
      of anal continence. However, some patients incur serious problems after surgery
      including chronic pouchitis and pouch failure. The goal of this study is to
      identify clinical and pathologic factors that are associated with an adverse
      outcome of IPAA. METHODS: A retrospective analysis of outcome was performed in
      151 consecutive patients < or = 21 years of age who underwent IPAA with a mean
      follow-up of 7.24 years (range, 2 to 15 years). Patients were categorized into 4
      outcome groups: A, no pouchitis; B, mild, acute pouchitis; C, chronic refractory
      pouchitis; and D, pouch failure. Pairwise comparisons were used to test the
      association between the groups and clinical and pathologic variables including
      age, sex, duration of symptoms, perianal disease, colonoscopic histology,
      terminal ileitis, operation type, staged versus unstaged IPAA, colonic specimen
      histology, early postoperative complications defined as less than 31 days
      postsurgery, late postoperative complications defined as 31 or more days
      postsurgery, and pouch fistulae. Crohn's disease as a definitive diagnosis and
      indeterminant colitis, a histologic diagnosis, also were tested for association
      with the above variables and outcome groups. RESULTS: One hundred and fifty-one
      pediatric patients underwent IPAA utilizing mucosectomy and hand-sewn S or J (n =
      44) and stapled J or S-W anastomosis (n = 107) with 0% mortality rate and outcome
      as follows: group A, n = 54; group B, n = 73; group C, n = 11; group D, n = 13.
      Variables strongly associated with poor outcome, groups C and D, were duration of
      symptoms (P =.03), perianal disease (P =.03), late complications (P <.001), pouch
      fistulae (P <.001), and Crohn's disease (P <.0001). Furthermore, Crohn's disease
      was associated strongly with female gender (P =.01), perianal disease (P =.004),
      early (P =.006) and late (P <.001) complications, and pouch fistula (P <.001).
      The findings of indeterminant colitis, terminal ileitis, and early postoperative
      complications did not show significant differences between the 4 outcome groups.
      CONCLUSIONS: Crohn's disease appears to be an important determinant of
      postoperative complications, chronic pouchitis, and pouch failure and occurred in
      15% of the authors' patients after IPAA. Indeterminant colitis and the
      intraoperative findings of terminal ileitis are not associated with Crohn's
      disease or adverse outcome after IPAA in pediatric patients. Operation type and
      stage do not alter the clinical course after IPAA in pediatric patients.

PMID- 12592625
TI  - Small bowel allografts maintained by administration of bombesin while under
      immunosuppression.
AB  - BACKGROUND/PURPOSE: The aim of this study was to determine if Bombesin (BBS)
      could help maintain the mucosal villus state in small bowel allografts without
      inducing acute rejection under immunosuppression. METHODS: Allogeneic small bowel
      transplantation was performed heterotopically in rats (n = 12). All rats received
      daily administration of FK506 from postoperative day 0 to day 28. On
      postoperative day 14, rats were divided into 2 groups of 6 rats each, and
      administered BBS or normal saline as a control. After 2 weeks of treatment, the
      rats were killed, and the graft mucosal villus state was evaluated by H&E
      staining, and crypt cell proliferation analysis was performed using
      immunohistochemistry with proliferative cell nuclear antigen (PCNA). RESULTS:
      Villi were thin, and villus blunting was marked in the control group. The BBS
      group showed that the villi of the grafts were well maintained, and the volume of
      the lamina propria mucosa was adequately preserved. The PCNA labeling index of
      crypt cells in the control group was 40.06 +/- 3.36 (mean +/- SD) and that in the
      BBS group was 61.02 +/- 4.27. There was a significant difference (P <.001)
      between the 2 groups. CONCLUSIONS: BBS maintained allograft epithelial cells and
      the volume of the lamina propria intestinal mucosa, stimulating proliferation of
      crypt cells under immunosuppression without inducing acute rejection.

PMID- 12592626
TI  - Hypothermia throughout intestinal ischaemia-reperfusion injury attenuates lung
      neutrophil infiltration.
AB  - BACKGROUND/PURPOSE: Secondary organ damage to the lungs is an important
      consequence of intestinal ischaemia reperfusion (IIR) injury. Moderate
      hypothermia ameliorates gut necrosis and liver energy failure after IIR but
      potential beneficial effects on lung neutrophil infiltration after reperfusion of
      ischaemic bowel have not been investigated. METHODS: Adult Sprague-Dawley rats
      underwent 60 minutes intestinal ischaemia followed by 120 minutes of reperfusion.
      The animals were maintained at either normothermia (36 degrees to 38 degrees C)
      or moderate hypothermia (30 degrees to 32 degrees C). Four groups were studied:
      (A) sham normothermia; (B) IIR normothermia; (C) sham hypothermia; and (D) IIR
      hypothermia. Lungs and terminal ileum were removed for measurement of
      myeloperoxidase activity (a marker of neutrophil infiltration). Results are
      expressed as milliunits per milligrams protein, mean +/- SEM, and one-way
      analysis of variance (ANOVA) with Tukey post-test was used for group comparisons.
      RESULTS: Lungs: IIR at normothermia significantly increased lung neutrophil
      infiltration assessed by myeloperoxidase activity compared with sham-operated
      controls (normothermia sham 4.6 +/- 1.0, n = 8; normothermia IIR 37.7 +/- 13.8, n
      = 8; P =.011). Moderate hypothermia during IIR significantly attenuated lung
      neutrophil infiltration (7.2 +/- 2.1, n = 9) compared with normothermia IIR (P
      =.016) such that myeloperoxidase activity was similar to that found in sham
      normothermia (4.6 +/- 1.0, n = 8) and sham hypothermia (3.1 +/- 1.3, n = 8).
      Intestine: Gut myeloperoxidase activity was 0.9 +/- 0.5 in sham normothermia (n =
      9) and 2.3 +/- 0.6 after normothermic IIR (n = 8). After IIR at hypothermia gut
      myeloperoxidase activity (0.5 +/- 0.2; n = 8) was significantly less than
      normothermic IIR (P =.035) and higher than sham hypothermia (0.2 +/- 0.1, n = 9;
      P =.01). CONCLUSIONS: These results indicate that moderate hypothermia may
      prevent damage to another distant organ, ie the lungs, by preventing recruitment
      of neutrophils. This may be of benefit in decreasing distal organ damage in
      diseases in which intestinal ischaemia-reperfusion is implicated in the
      pathogenesis.

PMID- 12592627
TI  - Keratinocyte growth factor decreases total parenteral nutrition-induced apoptosis
      in mouse intestinal epithelium via Bcl-2.
AB  - BACKGROUND/PURPOSE: Total parenteral nutrition (TPN) induces epithelial cell (EC)
      apoptosis. Keratinocyte Growth Factor (KGF) increases EC-growth; however, little
      is known of its effect on apoptosis. This study aims to determine if mRNA
      expression of Bcl-2 proteins (major mediators of epithelial cell apoptosis) is
      altered with TPN, and if KGF-administration influences Bcl-2 family expression.
      METHODS: C57BL/6J mice (n = 6 per group) received oral feeding (control), TPN
      (TPN), or TPN plus intravenous KGF daily (TPN + KGF). After 7 days, intestine was
      harvested and EC isolated. Apoptosis was identified using flow cytometry. EC mRNA
      expression of Bcl-2 family members was measured by reverse transcriptase
      polymerase chain reaction; Bcl-2 protein level was measured by immunoblot
      analysis. RESULTS: EC apoptotic rates were: control, 14.4% +/- 5.1%; TPN, 29.4%
      +/- 11.3%; KGF, 17.2% +/- 5.6%. Pro-apoptotic Bcl-2 proteins changed minimally
      with TPN or KGF; however, the antiapoptotic protein Bcl-2 changed significantly:
      control, 0.78 +/- 0.24; TPN, 0.10 +/- 0.13; KGF, 0.76 +/- 0.36. EC Bcl-2 protein
      levels were: control, 0.16 +/- 0.13; TPN 0.18 +/- 0.16; and TPN + KGF 0.47 +/-
      0.19. CONCLUSIONS: TPN-induced apoptosis decreased Bcl-2 mRNA expression. KGF
      decreased EC apoptosis and increased Bcl-2 expression. Modalities to increase
      endogenous KGF, or KGF-administration may have benefit in patients on TPN.

PMID- 12592628
TI  - Peritoneal macrophage activity after laparoscopy or laparotomy.
AB  - BACKGROUND/PURPOSE: The beneficial effect of laparoscopy on the immune system
      seems not to be present at the peritoneal level at which the local immunity
      appears to be impaired by CO2. The aim of this study was to investigate the
      peritoneal macrophages (MPhis) activity after laparoscopy and laparotomy.
      METHODS: Thirty rats (300 to 350 g) were used and divided into 3 groups. In the
      laparotomy group, the peritoneum was opened and the abdominal wall exposed to air
      for 60'. In the laparoscopy group, pneumoperitoneum was created and maintained at
      4 to 6 mm Hg for 60'. In the control group, anaesthesia was maintained for 60'
      without any other manipulations. Twenty-four hours after operation, peritoneal
      MPhis were harvested and cultured. The authors investigated nitrite/nitrate (NOx)
      production as well as the message for the inducible nitric oxide (iNOS), with the
      reverse transcriptase polymerase chain reaction under basal condition and after
      Lipopolysaccharide (LPS) stimulation. RESULTS: Basal MPhi NOx release was
      significantly higher after laparoscopy than either after laparotomy or control.
      LPS stimulation produced a strong increase in NOx production in laparotomy MPhis
      and control MPhis. In contrast, the increase in NOx production was markedly
      reduced in MPhi harvested after laparoscopy. Similar results were obtained for
      macrophage mRNA for iNOS; indeed, the increase in iNOS mRNA after LPS stimulation
      was blunted severely in MPhi from laparoscopy group. CONCLUSIONS: MPhis after
      laparoscopy display an higher basal immune performance. After a second insult
      (LPS), they display a state of tolerance or desensitisation (blunted NOx
      production and reduced mRNA expression). This observation could have important
      implications in considering laparoscopy in patients with malignancy or sepsis.

PMID- 12592629
TI  - Experience with thoracoscopic lobectomy in infants and children.
AB  - PURPOSE: This study evaluates the safety and efficacy of thoracoscopic lobectomy
      in infants and children. METHODS: From January 1995 to May 2002, 45 patients
      underwent video-assisted thoracoscopic lobe resection. Ages ranged from 2 days to
      18 years and weights from 2.8 to 78 kg. Preoperative diagnosis included
      sequestration/congenital adenomatoid malformation (n = 28), severe bronchiectasis
      (n = 12), congenital lobar emphysema (n = 3), and malignancy (n = 2). RESULTS:
      Forty-three of 45 procedures were completed thoracoscopically. Operating times
      ranged from 35 minutes to 210 minutes (average, 125 minutes). There were 6 upper,
      one middle, and 38 lower lobe resections. There was one intraoperative
      complication (2.4%) requiring conversion to an open thoracotomy. Chest tubes were
      left in 38 of 45 patients for 1 to 3 days. Hospital stay ranged from 1 to 5 days
      (average 2.4). CONCLUSIONS: Thoracoscopic lung resection is a safe and
      efficacious technique. It helps avoid the inherent morbidity of a major
      thoracotomy incision and is associated with the same decrease in postoperative
      pain, recovery, and hospital stay as seen in minimally invasive procedures.

PMID- 12592630
TI  - Carbon dioxide elimination during laparoscopy in children is age dependent.
AB  - The absorption of carbon dioxide (CO2) used for positive pressure
      pneumoperitoneum may lead to an increased CO2 load. CO2 elimination during
      laparoscopy has not been investigated previously in paediatrics. The aim of this
      study was to characterise the pattern of CO2 elimination during laparoscopic
      surgery in infants and children. METHODS: Twenty children undergoing laparoscopy
      and 19 children undergoing laparotomy for elective abdominal operations were
      studied. Pneumoperitoneum was achieved using insufflation of unheated CO2. CO2
      elimination (metabolically produced + absorbed; milliliters per kilogram per
      minute) was measured minute by minute during the operation by indirect
      calorimetry. End-tidal CO2 (kPa) was recorded every 10 minutes. The above
      variables were assessed before CO2 insufflation, during pneumoperitoneum, and
      after desufflation. RESULTS: Before insufflation, CO2 elimination was 4.6 +/- 0.3
      ml/kg/min and increased after 15 minutes of pneumoperitoneum to 5.2 +/- 0.3 (P
      <.001). Post desufflation, CO2 elimination decreased toward preinsufflation
      values, but did not return to baseline by the end of operation (5.8 +/- 0.3; P
      <.001). End-tidal CO2 was 4.7 +/- 0.2 preinsufflation, peaked at 1 hour (5.3 +/-
      0.2; P <.001) and subsequently decreased in response to ventilatory adjustments.
      The total amount of CO2 insufflated was positively correlated with patient age
      (r2 = 0.27; P <.01). CO2 elimination was age related, as indicated by multilevel
      model analysis and by negative correlations between maximum increase in CO2
      elimination and both age (r2 = 0.27; P <.01) and weight (r2 = 0.29; P <.01).
      These data suggest that the younger or smaller the child, the larger the increase
      in CO2 elimination. Seven patients (35%) responded to desufflation with a sharp
      transient increase in CO2 elimination, which did not appear to be related to
      patient age, length of pneumoperitoneum, abdominal pressure, or type of
      operation. CONCLUSIONS: During pneumoperitoneum, younger children absorb
      proportionately more CO2 than older individuals. The short-lived increase in CO2
      elimination postdesufflation may be related to an increase in venous return from
      the lower limbs after release of the abdominal pressure. These findings suggest
      that small children warrant close monitoring during laparoscopy and during the
      immediate postoperative period.

PMID- 12592631
TI  - Single cannula technique and robotic telescopic assistance in infants and
      children who require laparoscopic Nissen fundoplication.
AB  - BACKGROUND/PURPOSE: Laparoscopic Nissen fundoplication (LNF) is being utilized
      more extensively in the management of symptomatic gastroesophageal reflux disease
      in infants and children. The traditional approach utilizes 5 3- to 5-mm cannulas
      for telescope and instrument access to the peritoneal cavity. The purpose of this
      study is to report the technique and document the results using a single 5-mm
      umbilical cannula for LNF, stab incisions for placement of the instruments, and
      robotic telescope assistance. METHODS: From November 1999 through March 2002, 154
      patients underwent LNF by the senior author for pathologic gastroesophageal
      reflux disease. All operations were performed with a single 5-mm umbilical
      cannula through which a 4- or 5-mm telescope was placed for operative
      visualization. Four stab incisions were made through the upper/lateral abdominal
      wall under direct visualization avoiding the epigastric vessels. Through these
      stab incisions, instruments were inserted into the peritoneal cavity. The maximum
      insufflation pressure was 15 mm Hg in all cases. The ability to perform the
      procedure in the absence of additional operative cannula placement, complications
      during instrument insertion, the ability to maintain adequate pneumoperitoneum,
      the patient's age, weight, operating time, and the addition of a gastrostomy were
      recorded. RESULTS: All but one of the 154 LNFs were completed successfully using
      this technique. The mean age at operation and mean operating time was 23.9 months
      (range, 3 weeks to 180 months) and 91 minutes (31 to 160 minutes), respectively.
      Patients weight ranged from 2.4 to 57 kg (mean, 10.4 kg). Gastrostomies were
      placed in 52 cases. There were no complications associated with the stab
      incisions or insertion of the operative instruments through the abdominal wall.
      Pneumoperitoneum was maintained adequately in all cases. CONCLUSIONS: LNF can be
      performed safely and effectively with a single umbilical cannula. We recommend
      its use for pediatric patients who require LNF.

PMID- 12592632
TI  - Is primary endoscopic puncture of ureterocele a long-term effective procedure?
AB  - BACKGROUND/PURPOSE: For more than a decade, endoscopic puncture of ureterocele
      has been recommended as an initial and, in the majority of the patients, as a
      definitive procedure. This study evaluates the long-term effectiveness of primary
      endoscopic puncture of ureterocele. METHODS: Over the last 18 years (1984 through
      2001), 52 patients (median age 3 months) underwent primary endoscopic puncture of
      ureterocele. The median follow-up was 9 years (6 months to 18 years). Antenatal
      ultrasound scan detected hydronephrosis and led to the postnatal diagnosis of
      ureterocele in 12 (23%) children, whereas in the remaining 40 (77%) children the
      diagnosis was made on investigation for urinary tract infection (UTI). The
      ureterocele presented as a part of renal duplication in 48 (92%) patients and a
      single system in 4 (8%). Forty-four (92%) of the patients with duplication
      presented with non- or poorly functioning upper poles. Vesicoureteric reflux
      (VUR) was seen in the lower moiety of the ipsilateral kidney in 31 and in 18 of
      the contralateral kidney comprising 49 renal refluxing units (RRU). RESULTS:
      Complete decompression of the ureterocele was achieved in 48 (92%) patients after
      the first endoscopic puncture. Four (8%) patients required a second puncture of
      ureterocele. Nine (17%) of the 52 patients underwent nephrectomy for a
      nonfunctioning kidney. Ten (19%) patients required upper pole partial nephrectomy
      owing to nonfunctioning upper pole. Twenty-nine (59%) of the 49 RRU showed
      spontaneous resolution of VUR. Sixteen (33%) RRU underwent endoscopic correction
      of VUR. One required ureteric reimplantation. The remaining 4 (8%) are maintained
      on prophylactic antibiotics. Five (10%) patients had VUR in the upper pole
      moieties after ureterocele puncture. CONCLUSIONS: Our data suggest that primary
      endoscopic puncture of ureteroceles is a simple, long-term, effective, and safe
      procedure avoiding complete reconstruction in the majority of the patients.

PMID- 12592633
TI  - The adolescent varicocele: the crucial role of hormonal tests in selecting
      patients with testicular dysfunction.
AB  - BACKGROUND/PURPOSE: Early identification and treatment of varicocele during
      adolescence may reduce the risk of infertility. Prophylactic surgery on all
      adolescents with varicocele would be unnecessary surgery on a high percentage of
      them. Suggested guidelines for early intervention have included testicular volume
      loss and abnormality in the hormonal integrity of the hypothalamic-pituitary
      testicular axes. Previous studies have documented no correlation between
      testicular volume loss and abnormal response to GnRH test. The role of these 2
      prognostic factors in predicting semen abnormalities in this age group never has
      been investigated, so far. In the current study we correlated hormonal tests and
      orchidometry to semen analysis in a selected group of adolescents. METHODS:
      Adolescents with varicocele and Tanner stage V underwent semen analysis, Prader
      orchidometry, and hormonal tests (basal LH and FSH [bLH and bFSH], testosterone
      [T], LH and FSH after GnRH stimulation test [sLH and sFSH]). According to semen
      analysis (in relation to Oval Motility Index) patients were divided into 2
      groups: group A, adolescents with pathologic semen and group B, adolescents with
      normal semen. Hormonal tests and testicular volumes (in those with left
      unilateral varicocele) were compared between the 2 groups. Statistical analysis
      was performed using Mann-Whitney U test and Student's t test. RESULTS: Of 76
      patients, 20 (Group A) had a pathologic semen analysis. Levels of bLH, bFSH, sFSH
      were significantly higher in group A compared with group B (56 with normal
      semen). sLH was higher in group A, but the difference was not statistically
      significant. T levels were not different between the 2 groups. Of 68 patients who
      had left unilateral varicocele and no previous inguinal--scrotal surgery 14 had
      pathologic semen analysis. There was no statistically significant difference
      between the 2 groups for any of the orchidometric parameters investigated.
      CONCLUSIONS: The evaluation of testicular volumes during physical examination for
      varicocele in Tanner stage V adolescents is not predictive for testicular
      dysfunction. LH and FSH dosages with or without GnRH stimulation test can
      identify those subjects at risk for infertility, and their use should be
      encouraged for selecting patients who need surgical correction.

PMID- 12592634
TI  - Surgical management and genotype/phenotype correlations in WT1 gene-related
      diseases (Drash, Frasier syndromes).
AB  - BACKGROUND/PURPOSE: The WT1 gene plays a role in urogenital and gonadal
      development. Germline mutations of this gene have been observed in patients with
      Drash or Frasier syndrome (Sd). The purpose of this report is to compare
      phenotype and genotype of these patients. METHODS: Retrospective study of 12
      patients treated since 1980 for WT1 gene-related disorders was conducted.
      RESULTS: End-stage renal disease (ESRD) occurred in 9 patients, mostly because of
      diffuse mesangial sclerosis (DMS) or focal and segmental glomerular sclerosis
      (FSGS). Seven patients underwent kidney transplantation, and 2 died. Eleven
      tumors occurred: 8 Wilms' tumors, one soft tissue tumor, one bladder papilloma,
      and one gonadoblastoma. Wilms' tumors occurred at a younger age than expected.
      Eight patients had a 46,XY karyotype. One of these XY patients had female
      phenotype (Frasier syndrome); she was raised as a girl with bilateral
      gonadectomy. Seven XY patients had ambiguous phenotype; 4 have been raised as
      boys and 3 as girls. Four patients had a 46,XX karyotype; they had female
      genitalia and were raised as girls. WT1 gene analysis was performed in 10
      patients and showed heterozygous germline mutations in exon 9 (n = 6), intron 9
      (n = 1), exon 3 (n = 1), exon 4 (n = 1), or exon 7 (n = 1). CONCLUSIONS: ESRD was
      secondary to DMS when exon 9 was mutated, and secondary to FSGS when intron 9 was
      mutated. When exon 3, 4, and 7 were mutated, no nephropathy has been observed.
      Wilms' tumors occurred with any kind of WT1 mutation except intron 9. Abnormal
      sexual differentiation has been observed in all XY patients with WT1 mutation,
      and the most profound inversion of phenotype was observed with mutation in intron
      9. Correlation between phenotype and genotype provides better understanding of
      the role of WT1, and can help the surgeon in the management of these patients.

PMID- 12592635
TI  - Megatherapy with hematopoietic stem cell rescue as a preoperative treatment in
      unresectable pediatric malignancies.
AB  - BACKGROUND/PURPOSE: To improve the quality of life and prognosis of the patients
      with advanced pediatric malignant tumors, the authors have used megatherapy (MT)
      with hematopoietic stem cell transplantation (SCT) before surgery. To elucidate
      the impact of preoperative MT on the treatments of pediatric advanced
      malignancies, the authors reviewed the timing of surgery, preoperative condition,
      postoperative recovery, and outcome. METHODS: Between 1991 and 2001, 24 children
      with malignant tumors received MT with SCT before surgery, and 19 tumors were
      resected after SCT. These tumors included 12 neuroblastomas, 2 hepatic tumors, 2
      peripheral primitive neuroectodermal tumors, one rhabdomyosarcoma, one Wilms'
      tumor, and one yolk sac tumor. RESULTS: The mean duration of white blood cell
      (WBC) recovery (>1,000/mm3) and platelet recovery (>50,000/mm3) after SCT was
      17.1 and 42.5 days, respectively. Distant metastases were controlled in 9 of 15
      cases. The tumors were resected completely in 14 cases (73.7%), and complete
      remission (CR) was achieved after surgery in 9 cases (47.4%). There was no
      postoperative complication or remarkable functional impairment. At 7 months to 7
      years after diagnosis, 9 patients are alive without disease, one with disease, 6
      have died of recurrent tumor, and 2 have died of chemotherapy-associated
      complications. CONCLUSIONS: The current study suggested that MT with SCT before
      surgical resection contributes to increase in resectability and achieving CR. In
      the treatment of advanced pediatric malignancies, especially in the case of
      unresectable tumor, preoperative MT with SCT should be considered.

PMID- 12592636
TI  - Hepatoblastoma in children of extremely low birth weight: a report from a single
      perinatal center.
AB  - BACKGROUND/PURPOSE: The incidence of hepatoblastoma (HB) in children of low birth
      weight is increasing. In the authors' institute, 5 infants of extremely low birth
      weight (ELBW) were found to have HB. The purpose of this study was to identify
      the characteristics of these infants to elucidate the pathogenesis of HB arising
      in ELBW infants. METHODS: Birth weight (BW) ranged from 554 to 750 g (mean, 654
      g) and gestational age from 23 to 29 weeks (mean, 25.8 weeks). Medical records of
      the 5 patients were reviewed, and perinatal treatments were compared with those
      of ELBW infants without HB. RESULTS: One patient with intraabdominal hemorrhage
      had emergency operation, which was followed by early postoperative death. The
      parents of one child refused treatment because of associated severe anomalies. He
      died of the growing tumor 4 months after diagnosis. The remaining 3 patients had
      radical operation performed after intraarterial chemoembolization and systemic
      chemotherapy. One died of hepatic failure 7 months after operation. Two are alive
      5 and 9 months after operation. The incidence of HB among ELBW infants was
      estimated to be about 0.5% in our institute. The mean durations of mechanical
      ventilation, oxygen inhalation, and hospitalization during the neonatal periods
      in cases of HB were significantly longer than those in BW matched control infants
      (P <.01). CONCLUSIONS: ELBW children have a high risk for HB. In follow-up of
      ELBW infants, serum alpha-fetoprotein or abdominal ultrasonography may be useful
      to detect early HB. The children with HB received perinatal treatments for a
      significantly longer time, which suggests that perinatal intensive and long-term
      medical treatments may be involved in the tumorigenesis in the highly sensitive
      immature liver.

PMID- 12592637
TI  - Surgical infants on total parenteral nutrition have impaired cytokine responses
      to microbial challenge.
AB  - BACKGROUND/PURPOSE: Cytokines are essential for the prevention of microbial
      infections. Total parenteral nutrition (TPN) in infancy is associated with an
      increased risk of infection, and this could be related to altered cytokine
      production. The aim of the study was to determine if cytokine production is
      altered in monocytes from surgical infants receiving TPN. METHODS: There were 3
      study groups: (a) infants receiving TPN, (b) enterally fed healthy control
      infants, and (c) enterally fed healthy control adults. Blood samples were
      incubated with either Escherichia coli LPS, Staphylococcus epidermidis, or with
      medium alone. Flow cytometry was used to measure monocyte intracellular cytokine:
      tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta. RESULTS: After
      LPS stimulation, the percent of monocytes producing TNF-alpha and IL-6 were lower
      in infants on TPN than both control infants and adults. This was most apparent
      for TNF-alpha. The difference for IL-1beta was significant only between infant on
      TPN and control adults. When blood was stimulated with S. epidermidis, all 3
      cytokines were significantly lower in the TPN group compared with control adults.
      However, the differences between infants on TPN and infant controls only reached
      statistical significance for IL-6. CONCLUSIONS: The inflammatory response to
      bacterial challenge is impaired in infants on TPN compared with enterally fed
      infants or adults. The pattern of this response may be dependent on the nature of
      the microbial challenge. Our results indicate that the susceptibility of TPN-fed
      surgical infants to bacterial infections may in part be caused by impaired
      cytokine responses after bacterial invasion.

PMID- 12592640
TI  - The changing world demography of type 2 diabetes.
AB  - In recent years it has been estimated that the current global prevalence of type
      2 diabetes amounts to about 150 million patients. Projections suggest that by the
      year 2025 the number of prevalent patients in the world will reach approximately
      300 million. It is assumed that the increase in the number of patients will be
      most pronounced in nations currently undergoing socio-economic development
      including increasing urbanization. The technique used to provide these estimates
      is based on results from available, contemporary survey results, combined with
      expected future trends in demographic indicators. We suggest that the currently
      available methods for the estimation of the future global burden of type 2
      diabetes mellitus yield underestimates. Further modifications and validity tests
      of the modelling techniques are necessary in order to develop a reliable
      instrument to globally monitor the effects of the struggle against the diabetes
      problem.

PMID- 12592641
TI  - A new look at viruses in type 1 diabetes.
AB  - Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells.
      Genetic factors are believed to be a major component for the development of T1D,
      but the concordance rate for the development of diabetes in identical twins is
      only about 40%, suggesting that nongenetic factors play an important role in the
      expression of the disease. Viruses are one environmental factor that is
      implicated in the pathogenesis of T1D. To date, 14 different viruses have been
      reported to be associated with the development of T1D in humans and animal
      models. Viruses may be involved in the pathogenesis of T1D in at least two
      distinct ways: by inducing beta cell-specific autoimmunity, with or without
      infection of the beta cells, [e.g. Kilham rat virus (KRV)] and by cytolytic
      infection and destruction of the beta cells (e.g. encephalomyocarditis virus in
      mice). With respect to virus-mediated autoimmunity, retrovirus, reovirus, KRV,
      bovine viral diarrhoea-mucosal disease virus, mumps virus, rubella virus,
      cytomegalovirus and Epstein-Barr virus (EBV) are discussed. With respect to the
      destruction of beta cells by cytolytic infection, encephalomyocarditis virus,
      mengovirus and Coxsackie B viruses are discussed. In addition, a review of
      transgenic animal models for virus-induced autoimmune diabetes is included,
      particularly with regard to lymphocytic choriomeningitis virus, influenza viral
      proteins and the Epstein-Barr viral receptor. Finally, the prevention of
      autoimmune diabetes by infection of viruses such as lymphocytic choriomeningitis
      virus is discussed.

PMID- 12592642
TI  - Gene expression profiling in islet biology and diabetes research.
AB  - Following the sequencing of most of the human and mouse genomes, the next task
      for physicians and scientists will be to assess the relative levels of expression
      of these genes during development, following exposure to various nutritional and
      pharmacological conditions, and in disease states such as diabetes and related
      metabolic disorders. This review provides an overview of the various
      methodologies available for monitoring global gene expression. Use of cDNA
      libraries, Expressed Sequence Tag (EST) sequencing projects and databases,
      differential display (DD), serial analysis of gene expression (SAGE), subtractive
      cloning, and both cDNA and oligo microarrays are discussed, along with their
      merits and limitations. The Endocrine Pancreas Consortium
      http://www.cbil.upenn.edu/EPConDB/ has constructed mouse and human cDNA libraries
      from adult and various stages of embryonic development of endocrine pancreas.
      Over 100,000 ESTs have been deposited in public databases, and each clone is
      available through the IMAGE Consortium. A guide to Internet access is provided
      for future investigation.

PMID- 12592643
TI  - Effect of enalapril and losartan on the events that precede diabetic nephropathy
      in rats.
AB  - BACKGROUND: Mesangial cell proliferation, phenotype change, and increased
      transforming growth factor-beta (TGF-beta) precede mesangial expansion in
      diabetic rats. Experiments using mesangial cell culture have shown that
      angiotensin II increases TGF-beta production by these cells. The aim of the
      present study was to investigate the effect of enalapril and losartan on the
      events that precede diabetic nephropathy in rats. It was also analyzed if the
      determination of urinary TGF-beta could be a mean for the evaluation of
      therapeutic efficacy in this disease. METHODS: Eighty-two female Wistar rats were
      made diabetic by intravenous injection of streptozotocin diluted in citrate
      buffer, and citrate buffer alone was injected into the control group (N = 34).
      Ten days later, the right kidney was removed. Thirty diabetic rats were treated
      with enalapril, DMN + E, in drinking water (20 mg/L) and 24 with losartan, DMN +
      L (50 mg/L). Urinary TGF-beta was determined 90 days after STZ or buffer
      injection, the animals were killed, and the kidneys were removed for histological
      and immunohistochemical studies. RESULTS: The immunostaining for TGF-beta and
      fibronectin in the cortical tubulointerstitium and glomeruli was higher in
      untreated diabetic rats (p < 0.001). Treatment with enalapril or losartan reduced
      this increase. The urinary TGF-beta excretion (pg/mg urinary creatinine) was 48.6
      +/- 5.9 in control animals, 603.9 +/- 80.41 in untreated diabetic rats, 279.3 +/-
      47.0 in diabetic rats treated with enalapril, and 243.7 +/- 40.0 in rats treated
      with losartan. CONCLUSIONS: We concluded that enalapril or losartan treatment can
      modify events that precede diabetic nephropathy by reducing TGF-beta and
      fibronectin expression in glomeruli and tubulointerstitium as well as urinary TGF
      beta content.

PMID- 12592644
TI  - Humoral and cellular immune responses to proinsulin in adults with newly
      diagnosed type 1 diabetes.
AB  - BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by
      immunity against pancreatic islet-derived proteins. The object of this study was
      to measure antibody and T-cell responses against proinsulin (PI), an islet
      derived protein, and to map its dominant T-cell epitopes. METHODS: Antibody
      responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein
      tyrosine phosphatase IA-2 and islet-cell antigen were measured in 116 newly
      diagnosed diabetic subjects aged 16 to 40 years. T-cell proliferative responses
      to proinsulin and proinsulin peptides were measured in 33 of these diabetic
      subjects and in 21 healthy control subjects. RESULTS: 22% of diabetic subjects
      but no control subjects expressed antibodies to proinsulin. A strong correlation
      existed between antibody levels to proinsulin and insulin within diabetic
      subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects
      displayed T-cell responses to proinsulin. There was no correlation between
      antibody and T-cell responses to proinsulin within subjects. Amino acid region 56
      to 72 was identified as the major T-cell epitope of proinsulin, though
      significant responses to region 14 to 37 were also present. CONCLUSION: Elevated
      proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important
      autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin
      protein was not detected, two dominant T-cell epitopes of proinsulin were
      identified that span the C-peptide and insulin junctions. Immunity to proinsulin
      was lower than that reported for childhood-onset type 1 diabetes and we propose
      that, like insulin, proinsulin may be targeted less frequently in adulthood.

PMID- 12592645
TI  - Ascorbic acid supplementation restores defective leukocyte-endothelial
      interaction in alloxan-diabetic rats.
AB  - BACKGROUND: Defective leukocyte-endothelial interactions are observed in
      experimental diabetes and may reduce the capacity to mount an adequate
      inflammatory response. The present study investigated the effect of ascorbic
      acid, an inhibitor of free radical and glycated protein formation as well as an
      aldose reductase inhibitor, on leukocyte-endothelial interaction in alloxan
      diabetic rats. METHODS: Rats were rendered diabetic by alloxan injection (40
      mg/kg; iv). After 30 days, diabetic and nondiabetic controls were supplemented
      for 12 days with ascorbic acid (50 or 200 mg/kg/day) or received saline by
      gavage. The number of rollers, stickers after zymosan-activated plasma (10%) or
      leukotriene B(4) (1 microM) applied topically, and migrated cells after local
      injection of carrageenan (100 microg) were determined in the venules of the
      internal spermatic fascia by intravital microscopy. Erythrocyte velocity and wall
      shear rate were determined as well. Reactive oxygen species formation by
      endothelial cells was measured in vivo by the same technique. Immunocytochemistry
      for ICAM-1 detection on the endothelium of the venules of the internal spermatic
      fascia was carried out in cross sections of the whole testis of the animals.
      RESULTS: The reduced number of rollers, stickers and migrated cells, as well as
      the higher production of reactive oxygen species by endothelial cells in diabetic
      rats was corrected by ascorbic acid supplementation. The low immunoreactivity for
      ICAM-1 in the venules of diabetic rats was improved by ascorbic acid
      supplementation. Ascorbic acid supplementation did not interfere with erythrocyte
      velocity or wall shear stress. Ascorbic acid administered to control rats did not
      alter the parameters studied above. CONCLUSION: We conclude that ascorbic acid
      improves leukocyte-endothelial interaction in diabetic rats at least in part by
      restoring the expression of ICAM-1 in the venules of diabetic rats.

PMID- 12592647
TI  - Current literature in diabetes.

PMID- 12592646
TI  - The prevalence of coeliac disease in Libyan children with type 1 diabetes
      mellitus.
AB  - BACKGROUND: Diagnosis of atypical and silent forms of coeliac disease (CD) is
      important because of its serious complications. Increased prevalence of coeliac
      disease worldwide in individuals with type 1 diabetes mellitus (DM) was
      described. There are no data on the prevalence of CD in the Libyan population and
      Libyan DM patients. The aim of this study was to test the occurrence of CD
      related markers in a group of Libyan children with DM. METHODS: A cohort of 234
      Libyan children with DM (121 males and 113 females) aged between 2 and 25 years
      and 50 healthy school children were screened for CD using the enzyme-linked
      immunosorbent assay (ELISA) for IgA and IgG antigliadin (AGA), anti-tissue
      transglutaminase (tTG), and anticalreticulin antibodies. An IgA antiendomysial
      antibody (EmA) was determined by immunofluorescence. RESULTS: Fifty patients
      (21.3%) were positive for IgA- and/or IgG-AGA, tTG, and anticalreticulin
      antibodies. Nineteen of these patients were EmA positive and seven were EmA
      negative. From the EmA negative patients we found that five sera with IgA
      deficiency had high IgG class in antigliadin, anti-tissue transglutaminase, and
      anticalreticulin antibodies. All these patients underwent intestinal biopsy.
      Twenty-four had clear histological (atrophy) evidence of CD including the EmA
      negative patients with IgA deficiency; prevalence of CD in this study was thus
      10.3%. CONCLUSION: The prevalence of CD in diabetic children in Libya was found
      to be higher than in several European countries. Serological markers are useful
      for identifying DM patients who should undergo a small intestinal biopsy.

PMID- 12592648
TI  - [The nasosinus inverted papilloma with intracranial extension].
AB  - OBJECTIVE: To study the treatment of inverted papilloma (NIP) with intracranial
      extension. METHOD: Nine patients of NIP all suffered from the operation. Six
      patients with anterior skull base erosion suffered from large tumor resections
      via combined craniofacial and cranial approach. Three patients suffered from
      small tumor resections via transfrontal and transethmoidal sinus approach. The
      defects of basicranial bone and dura were repaired at the same time. Five
      patients were found the tissue canceration in the postoperation. RESULT: In 7
      patients followed-up from 3 to 13 years, no one has recurrenced. CONCLUSION: The
      canceration probability of NIP with intracranial extension should be sufficiently
      considered. The tumor resection via combined craniofacial approach or
      transfrontal approach must be based on the tumor size and extension, and removed
      completely.

PMID- 12592649
TI  - [Endoscopic sinus surgery for recurrent sinusitis and nasal polyps].
AB  - OBJECTIVE: To study the treatment methods of improving the operative effect and
      reducing the complications of chronic sinusitis and nasal polyps. METHOD: Two
      hundred and eighty cases with chronic sinusitis and nasal polyps were performed
      with endoscopic sinus surgery. RESULT: The long-term follow-up was performed at 6
      and 12 months after operation, the results showed that the total effective rate
      were 85.75% (the cure rate was 58.2%; the improvement rate was 27.5%) and 81.4%
      (the cure rate was 54.6%; the improvement rate was 26.8%) respectively, the
      complication rate was 9.3%. CONCLUSION: Correct operation choices, preoperative
      and postoperative combing treatment and excellent surgical skills are keys of
      improving the operative effect and reducing the complications.

PMID- 12592650
TI  - [The effect of managements of middle turbinate on nasal airway resistance in
      endoscopic sinus surgery].
AB  - OBJECTIVE: To study the influence of different managements of middle turbinate on
      nasal airway resistance(NAR) and nasal airflow sensation. METHOD: Patients were
      divided into three groups: total resection group (32 patients/sides), partial
      resection group (37 patients/sides) and total reservation group (34
      patients/sides). The NAR and nasal airflow sensation were measured with anterior
      rhinomanometer and visual analogue scale test (VAS) respectively. RESULT: The NAR
      and VAS scores decreased significantly after operation (P < 0.01). But there was
      no significant difference between these three groups(P > 0.05). CONCLUSION: The
      different managements of middle turbinate have no significant influence on NAR
      and nasal airflow sensation.

PMID- 12592651
TI  - [The observation of clinical efficacy of combined modality therapy in 58 cases of
      perennial allergic rhinitis].
AB  - OBJECTIVE: To study the effect of combined modality therapy on perennial allergic
      rhinitis (PAR). METHOD: Fifty-eight cases of PAR received a 4-weeks treatment
      with combined beclomethasone dipropionate nasal spray (BDP), cetirizine
      hydrochloride, ethmoidal nerve radiofrequency treatment, and half-dose combined
      BDP, cetirizine hydrochlonde was used for improving the recurrence symptoms in
      one year follow-up. RESULT: The overall effective (excellent/good) rate was
      94.83% (excellent 72.41%, good 22.41%). The recurrence rate was 51.72%, but
      symptoms of 27 recurrence cases were lighter than pre-treatment. All treatments
      were well tolerated, and no serious adverse events occurred. CONCLUSION: The
      reasonable combined modality therapy is aimed at the complicated pathogenesis of
      PAR, and the curative effect is satisfactory, so it is a good way to treat PAR.

PMID- 12592653
TI  - [The effects of endoscopic nasal surgery on the function of eustachian tube].
AB  - OBJECTIVE: To observe the effects of endoscopic nasal surgery on the function of
      eustachian tube. METHOD: The tympanometric pressure, static compliance and
      gradient of tympanogram were measured for sinuses and turbinate group (10 cases)
      and nasal septum group (10 cases) at 1, 3, 5 and 10 days after operation by using
      audiometer acoustic impedance. RESULT: The peak pressure of tympanogram of two
      groups were droped obviously 1-3 days after operation. In sinuses and turbinate
      group, it droped from -85.5 dapa to -148.0 dapa (at 1 day) and -139.0 dapa at 3
      days, compared to the pre-operation, the differences were significantly (P <
      0.01). In nasal septum group, it droped from -51.0 dapa to -111.5 dapa at 1 day
      and -96.0 dapa at 3 days, compared to the pre-operation, the differences were
      also significantly (P < 0.01). The level of static compliance, gradient were no
      significantly difference between before and after operation (P > 0.05).
      CONCLUSION: The eustachian tube of patients of two groups were blocked at the
      early stage of post-operation. The treatment of active anti-infection, promptly
      cleaning of nasal cavity, relexing the pressure of nasal cavity as soon as
      possible, all of this can reduce the effect of operation on the function of
      eustachian tube.

PMID- 12592652
TI  - [Clinical observation of allergic fungal sinusitis].
AB  - OBJECTIVE: To study the diagnosis and treatment of allergic fungal sinusitis
      (AFS). METHOD: Eight cases of AFS were analysed. The cardinal symptom is the
      symptom of allergic rhinitis and bone erosion of sinus. All cases were treated
      with the endoscopic sinus surgery, steroids and topical antifungal therapy.
      RESULT: In follow-up of 13 months to 40 months, no recurrence occured with 6
      cases, recurrence with 2 cases then were given the same treatment again and are
      in follow-up now. CONCLUSION: The cardinal symptom of AFS is the symptom of
      allergic rhinitis and bone erosion of sinus. The comprehensive treatment with the
      endoscopic sinus surgery, steroids and topical antifungal therapy is needed. AFS
      is easily recurrent. The long-term follow-up is very important.

PMID- 12592654
TI  - [Surgery of infratemporal fossa tumors].
AB  - OBJECTIVE: To investigate the effects of surgical approach on tumor with advanced
      infratemporal fossa. METHOD: Four different kinds of surgical approaches were
      selected and used according to preoperative clinical and radiographic findings
      and its invading structures. RESULT: The survival rate according to Kaplan-meire
      showed that the two years survival rate for benign tumor were 100%, but malignant
      tumor were 47.1%. CONCLUSION: Surgery of the infratemporal fossa tumors appears
      to be safe and complete removal of the tumor invading lateral skull bone and its
      surrounding structures is necessary. The adjuvant chemotherapy and radiotherapy
      are worth while procedure for postoperative of malignant tumors.

PMID- 12592655
TI  - [Endoscopic sinus surgery, clinical observation with 165 cases].
AB  - OBJECTIVE: To observe the long-term curative effect of endoscopic sinus
      surgery(ESS). METHOD: 165 cases (276 sides) of chronic sinusitis and nasal polyps
      were treated with ESS, and following up survey 1 year post-operatively. RESULT:
      It was found that 107 cases were cured (64.8%), 43 cases achieved symptomatic
      relief (26.1%), 15 cases remained failure (9.1%), and the effective rate was
      90.9%, mainly operative complication was adhesion of nasal cavity. CONCLUSION:
      The curative effect of ESS was successful. It is effective to use reasonable
      concentration hemostasin to hemostasia, it is very important to treat middle
      turbinate precisely, and regularly follow-up could reduce operation
      complications.

PMID- 12592656
TI  - [The effect of postoperative nasal cavity adhesion on the long-term results of
      endoscopic sinus surgery].
AB  - OBJECTIVE: To observe the effect of postoperative nasal cavity adhesion on the
      long-term results of endoscopic sinus surgery. METHOD: From October, 1994 to
      September 1998, 845 patients with sinusitis and polyps under gone endoscopic
      sinus surgery in our hospital. There were 132 cases with unilateral lesion and
      713 cases with bilateral lesion, total of 1558 lateral lesions. All the lesions
      were classified according to the Haikou (1997) typing and staging system of
      sinusitis. All the cases were follow-up over 1 year. RESULT: According to the
      Haikou cure criterion, 1280 sides were cured one year after operation. The total
      cure rate was 82.2%. The cure rates of type I, type II stage 1, type II stage 2,
      type II stage 3 and type III patients were 91%, 98.9%, 82.8%, 75% and 61.2%
      respectively. Total of 278 sides were failure. 151 sides of them had nasal cavity
      adhesion (54.3%). The types of the nasal cavity adhesion were middle turbinate
      adhesion to the lateral wall of the middle meatus, to the inferior turbinate and
      to the nasal septum. CONCLUSION: The postoperative nasal cavity adhesion was the
      main factor which can cause the failure of the endoscopic sinus surgery. The
      middle turbinate played an important role in preventing nasal cavity adhesion.

PMID- 12592657
TI  - [The utility of peak nasal inspiratory flow rate for clinical practice].
AB  - OBJECTIVE: To find out whether peak nasal inspiratory flow rate (PnIFR) of one
      side nose can indicate nasal patency. METHOD: PnIFR was measured using RHAT-301
      wind rate meter (Qinghuatongfang Incorporated Company). One hundred subjects were
      recruited. We measured PnIFR of every side of nose of all subjects before and
      after using 3% ephedrine and registered the grade of patients' complaint of nasal
      obstruction. RESULT: PnIFR in normal male and in normal female are different;
      PnIFR in normal and in patients are different; The grade of patients' complaint
      of nasal obstruction is correlated with PnIFR; PnIFR in patients before and after
      using ephedrine are different. CONCLUSION: PnIFR of one side nose can indicate
      the severity of nasal obstruction; RHAT-301 flow meter is convenient to measure
      PnIFR for clinical practice, and PnIFR of one side nose can indicate nasal
      patency; PnIFR of one side nose can indicate the effect of drugs on nasal airway
      resistance (NAR).

PMID- 12592658
TI  - [The value of nasal endoscopy in the surgery of the nasal inverted papillomas].
AB  - OBJECTIVE: To investigate the value of nasal endoscopy in the surgery of the
      nasal inverted papillomas. METHOD: 29 patients with nasal inverted papilloma, 15
      cases of them were applied nasal endoscopic surgery (nasal endoscopic surgery
      group), 14 cases were applied nasal lateral incision surgery(nasal lateral
      incision group), and compared the results of the two surgery. RESULT: Follow-up
      1.8 years. COMPLICATIONS: nasal endoscopic surgery group(1 case) was obviously
      lower than nasal lateral incision group(5 cases), P < 0.01; The hospitalization
      time: nasal endoscopic surgery group(13.1 d) was obviously short than nasal
      lateral incision group(20.4 d), P < 0.01; The volume of blood during surgery(I-II
      stage): nasal endoscopic surgery group(175 ml) was obviously lower than nasal
      lateral incision group(525 ml), P < 0.01; CONCLUSION: The nasal endoscopy was a
      better method for treating I-II stage nasal inverted papilloma, and the major
      advantage is an incision of the face can be avoided. As to III-IV stage disease,
      should be carefully selected endoscopic surgery. Nasal lateral incision surgery
      still was a safe and reliable therapeutic method.

PMID- 12592659
TI  - [Observation of the therapeutic effect of intranasal endoscopic repair on
      cerebrospinal fluid rhinorrhea].
AB  - OBJECTIVE: To observe the therapeutic effect of intranasal endoscopic repair on
      cerebrospinal fluid (CSF) rhinorrhea. METHOD: Messerklinger operative technique
      was followed. The affected uncinate process, ethmoid bulla was resected. The
      ethmoid sinus was open and the anterior skull base exposed. 0 degree, 30 degrees
      endoscope and suction were used to help localize fistula. RESULT: 10 cases were
      successfully repaired during the first attempt. Follow-up for four months to one
      year found no recurrence and not any complication. CONCLUSION: Intranasal
      endoscopic repair of CSF rhinorrhea could afford excellent view, facilitate
      precise tissue graft placement and better recovery.

PMID- 12592660
TI  - [Analysis of vertical partial laryngectomy for carcinoma of the larynx].
AB  - OBJECTIVE: To evaluate the effect of vertical partial laryngectomy in the
      treatment of laryngocarcinoma. METHOD: 50 patients who underwent vertical partial
      laryngectomy from 1979 to 1997 were retrospectively reviewed. The reconstruction
      methods for the laryngeal defect were the pedicle muscular flap, skin graft,
      cervical skin flap, hypopharyngeal mucous membrane flap and outer perichondrium
      of the thyroid cartilage etc. RESULT: Postoperative decannulation rate was 98.0%.
      The overall 3-, 5- and 10-year survival rates were 89.6%, 82.9%, 66.7%
      respectively. Among all the deaths, 4 died of recurrence of laryngocarcinoma, 1
      distant metastasis, 1 other carcinoma and 5 intercurrent disease. CONCLUSION:
      Vertical partial laryngectomy is effective in treating laryngocarcinoma.
      Anesthesia, resecting limits and the reconstruction methods for the laryngeal
      defect also affect the curative results.

PMID- 12592661
TI  - [Prevention and treatment for aspiration of tracheaesophageal shunt phonatory
      opening].
AB  - OBJECTIVE: Estimating the curative effective of the brim shape epiglottis plasty.
      METHOD: A pedical cricoid cartilage flap has been built as well as the epiglottis
      after total laryngectomy, a downward concave face of the brim shape epiglottis
      above the phonatory opening from the posterior wall of the trachea and the
      anterior wall of the esophagus was made. RESULT: Of 26 cases undergoing this
      operation, 21/26 patients have not happened food aspiration, 2/26 cases died due
      to recurrence of the carcinoma, 3/26 cases missing connection following 2.0-5.0
      years. CONCLUSION: We consider this method not only avoided aspiration of the
      food but also is advantageous to the function of speech and swallowing in
      different degree.

PMID- 12592662
TI  - [Selective resection of the carotid artery for the treatment of carotid body
      tumor].
AB  - OBJECTIVE: Selecting carotid tumors and preventing the fatal bleeding of
      intraoperation. METHOD: The carotid compression test and inspection of
      angiography with transcranial Doppler sonography and keeping intraoperative awake
      after relieving pain anesthetization. RESULT: Ten cases of carotid artery were
      occluded for 2 hours within operation, and 4 carotids were resected and 6 carotid
      body tumor were peeled and their carotid were reserved. No neurological problems
      were encountered in the 10 patients for 5 years. CONCLUSION: Our experience
      proved that the carotid compression test and inspection of angiography with
      transcranial Doppler sonography and keeping intraoperative awake after relieving
      pain anesthetization can help to supervise the selective carotid resection.

PMID- 12592663
TI  - [Molecular biological study of aloe vera in the treatment of experimental
      allergic rhinitis in rat].
AB  - OBJECTIVE: To study the therapeutic mechanism of aloe vera in allergic rhinitis
      (AR). METHOD: Ovalbumin sensitized white rat used as animal models of AR were
      treated intranasally with aloe vera. At the end of treatment, the differences in
      the behavior science were observed; the changes in the nasal mucosa were studied
      by pathological; IL-2, IL-4 mRNA in the nasal mucosa and spleen were used to do
      reverse transcriptive polymerase chain reaction (RT-PCR). RESULT: The behavior
      science score of positive controls (8.42 +/- 1.06) was higher than the
      experimental group (2.02 +/- 0.42) and normal controls (0); inflammatory
      reactions in the experimental group nasal mucosa were remarkably relieved; the
      mean expression level of IL-2 mRNA in the experimental group was higher
      significantly than positive controls (P < 0.01); but that of IL-4 mRNA was lower
      evidently (P < 0.01). CONCLUSION: The aloe vera are suggested to be involved in
      the differentiation of CD4+ lymphocytes, by means of regulating the expression of
      Th1 and Th2 cytokines. The results suggests that local aloe vera treatment was a
      selective and non-traumatic method to treat the allergic rhinitis.

PMID- 12592664
TI  - [Animal experimental study of effects of long-term triamcinolone acetonide
      acetate nasal spray on the nasal mucosa].
AB  - OBJECTIVE: To explore the effects of triamcinolone acetonide acetate nasal spray
      on the animal's nasal mucosa. METHOD: Animals were divided into three groups:
      group one for high dosage; group two for low dosage; group three for control.
      Animals were given the high dosage of triamcinolone acetonide acetate nasal spray
      (880 micrograms), low dosage of triamcinolone acetonide acetate nasal (220
      micrograms), 0.9% saline solution spray for each nasal cavity for two months.
      Before and after drug spraying, the examination of nasal mucosa and the blood
      routine were made, and the middle and inferior turbinate were removed for light
      and electron microscopic examination. RESULT: No differences of blood routine and
      nasal mucosa can be seen among the three groups, and the light and electron
      microscopic examination also. CONCLUSION: No harmful effects of triamcinolone
      acetonide acetate nasal spray on the nasal mucosa for long time using can be seen
      on the animal's experiment.

PMID- 12592665
TI  - Oxidative stress, mitochondrial dysfunction, and epilepsy.
AB  - Epilepsy is a common and heterogeneous neurological disorder arising from
      biochemical and molecular events that are incompletely understood. To effectively
      manage epilepsies, it is important to understand the mechanisms underlying both
      seizure-induced brain damage as well as seizure initiation. Oxidative stress is
      emerging as a mechanism that may play an important role in the etiology of
      seizure-induced neuronal death. Conversely, epileptic seizures are a common
      occurrence in mitochondrial diseases arising from defects in oxidative
      phosphorylation. This review focuses on the emerging role of oxidative stress and
      mitochondrial dysfunction both as a consequence and cause of epileptic seizures.

PMID- 12592666
TI  - Roles of protein kinase C delta in the accumulation of P53 and the induction of
      apoptosis in H2O2-treated bovine endothelial cells.
AB  - To clarify the signaling pathways of oxidative stress-induced apoptosis in bovine
      aortic endothelial cells (BAEC), we treated cells with 1 mM H2O2 and investigated
      the roles of protein kinase C delta (PKC delta) and Ca2+ in the accumulation of
      p53 associated with apoptosis. The treatment of cells with H2O2 caused the
      accumulation of p53, which was inhibited by rottlerin (a PKC delta inhibitor) but
      not by BAPTA-AM (an intracellular Ca2+ chelator). PKC delta itself was activated
      through the phosphorylation at tyrosine residues. H2O2 induced the release of
      cytochrome c and the activation of caspases 3 and 9, and these apoptotic signals
      were inhibited by rottlerin and BAPTA-AM. These results suggest that PKC delta
      contributes to the accumulation of p53 and that Ca2+ plays a role in downstream
      signals of p53 leading to apoptosis in H2O2-treated BAEC.

PMID- 12592667
TI  - Reduced serum hydroxyl radical scavenging activity in erythropoietin therapy
      resistant renal anemia.
AB  - Relation between anemia resistant to recombinant human erythropoietin (rHuEPO)
      therapy and the oxidative stress in hemodialysis (HD) patients was investigated.
      Stable HD patients who had consistent hemoglobin concentrations on a constant
      dose of rHuEPO were studied. Patients were excluded if there were factors that
      might affect hemopoiesis or administration of antioxidant supplements. Patients
      were classified into three groups: High (9000 U/week), Low (1500-4500 U/week) and
      No rHuEPO group. Thiobarbituric acid reactive substances (TBARS) of sera and
      erythrocyte were examined. Serum superoxide and hydroxyl radical scavenging
      activities were measured using electron spin resonance. TBARS in the erythrocyte
      was higher in High rHuEPO group compared with No rHuEPO group, though the serum
      TBARS were similar. A diminution of serum hydroxyl radical scavenging activity
      was observed in High rHuEPO group. Hydroxyl radical signal intensity showed a
      strong correlation with the serum ferritin in High rHuEPO group, although
      ferritin concentrations were not different among the 3 groups. Superoxide
      scavenging activity showed no differences. These results indicate that increased
      lipid peroxidation in erythrocyte, raised by decreased serum hydroxyl radical
      scavenging activity, is one cause of rHuEPO resistant anemia. Serum ferritin may
      be involved in this hydroxyl radical production.

PMID- 12592668
TI  - Immunohistochemical artifact for nitrotyrosine in eosinophils or eosinophil
      containing tissue.
AB  - Immunohistochemical artifacts for nitrotyrosine were investigated in eosinophils
      with regard to fixatives. Immunoreactivity for nitrotyrosine was revealed in
      separated eosinophils and in gastric mucosa fixed with periodate, lysine
      paraformaldehyde (PLP). The increase in immunoreactivity by PLP was due to
      periodate itself, a component of PLP. Nitrotyrosine formed by peroxidase using
      NO2- and H2O2 or by peroxynitrite was not completely inhibited by 100 mM
      dithionite but the immunoreactivity for nitrotyrosine antibodies by PLP was
      completely inhibited by 5.7 mM dithionite. Although untreated eosinophils or
      ovalbumin (OVA) did not show protein tyrosine nitration in a standard Western
      blot, the treatment of the blotted membrane with PLP increased the reactivities
      of proteins from eosinophils with anti-nitrotyrosine antibodies. The increase in
      immunoreactivity of OVA with anti-nitrotyrosine antibodies by PLP did not change
      with pre-treatment with dithionite but was abolished by treatment with dithionite
      after PLP fixation. In HPLC assays, periodate did not generate nitrotyrosine from
      L-tyrosine and aminotyrosine. These results suggest that the treatment of
      eosinophils or eosinophil-containing tissues with PLP fixative augments the
      immunoreactivity of nitrotyrosine antibodies with eosinophils due to the
      formation of epitopes similar to nitrotyrosine by an oxidation reaction of
      periodate, which evokes an artifact in nitrotyrosine immunohistochemistry.

PMID- 12592669
TI  - Antioxidant action of 2,2,4,6-tetra-substituted 2,3-dihydro-5-hydroxybenzofuran
      against lipid peroxidation: effects of substituents and side chain.
AB  - With increasing evidence suggesting the involvement of oxidative stress in
      various disorders and diseases, the role of antioxidants in vivo has received
      much attention. 2,3-Dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran
      (BO-653) was designed, synthesized and has been evaluated as a novel
      antiatherogenic drug. In order to further understand the action of BO-653 and
      also radical-scavenging antioxidants in general, the dynamics of inhibition of
      oxidation by BO-653 were compared with those of the related compounds, 2,3
      dihydro-5-hydroxy-2,2-dimethyl-4,6-di-tert-butylbenzofuran (BOB), 2,3-dihydro-5
      hydroxy-2,2,4,6-tetramethylbenzofuran (BOM), alpha-tocopherol and 2,2,5,7,8
      pentamethyl-6-chromanol (PMC), aiming specifically at elucidating the effects of
      substituents and side chain length of the phenolic antioxidants. These five
      antioxidants exerted substantially the same reactivities toward radicals and
      antioxidant capacities against lipid peroxidation in organic solution. When
      compared with di-methyl side chains, the di-pentyl side chains of BO-653 reduced
      its inter-membrane mobility but exerted less significant effect than the phytyl
      side chain of alpha-tocopherol on the efficacy of radical scavenging within the
      membranes. Di-tert-butyl groups at both ortho-positions made BO-653 and BOB more
      lipophilic than di-methyl substituents and reduced markedly the reactivity toward
      Cu(II) and also the synergistic interaction with ascorbate. The results of the
      present study together with those of the previous work on the effect of
      substituents on the stabilities of aryloxyl radicals suggest that tert-butyl
      group is more favorable than methyl group as the substituent at the ortho
      positions and that di-pentyl side chains may be superior to a phytyl side chain.

PMID- 12592670
TI  - Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen
      peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42.
AB  - Several substances related to the neurodegenerative diseases of Alzheimer and
      Parkinson, such as hydrogen peroxide, tumor necrosis factor alpha, dopamine and
      beta-amyloid peptide 1-42, have been shown to induce apoptosis in tumoral cell
      lines and rat neurons but not in human neurons. Moreover, the role of
      mitochondria (membrane potential) during neuronal apoptosis is still a matter of
      debate. We present here, for the first time, in cultured human cortical neurons
      that the DNA fragmentation induced by these substances was preceded by a decrease
      of the mitochondrial membrane potential. We have also examined the antiapoptotic
      effect of the antioxidants glutathione, N-acetyl-cysteine and ascorbic acid. All
      these antioxidants inhibited the apoptosis induced by hydrogen peroxide, tumor
      necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, since they were
      able to inhibit completely the mitochondrial membrane potential depolarization
      and the DNA fragmentation.

PMID- 12592671
TI  - Oxidation of Cu, Zn-superoxide dismutase by the myeloperoxidase/hydrogen
      peroxide/chloride system: functional and structural effects.
AB  - This study investigated the functional and structural effects of bovine Cu, Zn
      superoxide dismutase (Cu, Zn-SOD) oxidation by the myeloperoxidase (MPO)/hydrogen
      peroxide (H2O2)/chloride system and reagent hypochlorous acid (HOCl). Exposure to
      HOCl led to a fast inactivation accompanied by structural alterations. The
      residual SOD activity depended on the reactants concentration ratio and on the
      exposure time. The concomitant high consumption of HOCl indicated the presence of
      multiple targets on the protein. As assessed by SDS/PAGE, HOCl caused the
      dissociation of the protein into protomers at 16 kDa stable to both SDS and
      reducing conditions. Results from isoelectric focusing gels showed that exposure
      to HOCl induced the formation of modified protein derivatives, with a more acidic
      net electric charge than the parent molecule, consistent with the presence of
      additional ions observed in the electrospray ionization mass spectra. The
      reaction of protein with HOCl resulted in changes in protein conformation as
      assessed by the UV fluorescence and oxidation of the unique methionine and
      tyrosine, chlorination of several lysines with formation of chloramines. There
      was no significant formation of dityrosine and carbonyl groups. Exposure to high
      levels of HOCl resulted in complete enzyme inactivation, loss of additional
      lysine, histidine and arginine residues and coincident detection of weakly bound
      zinc and copper using 4-pyridylazaresorcinol. Collectively, the results suggest
      that the decrease of the dismutase activity is probably related to both
      dissociation into protomers and unfolding due to extensive oxidative
      modifications of amino acids.

PMID- 12592672
TI  - Interactions of flavonoids with iron and copper ions: a mechanism for their
      antioxidant activity.
AB  - The metal chelating properties of flavonoids suggest that they may play a role in
      metal-overload diseases and in all oxidative stress conditions involving a
      transition metal ion. A detailed study has been made of the ability of flavonoids
      to chelate iron (including Fe3+) and copper ions and its dependence of structure
      and pH. The acid medium may be important in some pathological conditions. In
      addition, the ability of flavonoids to reduce iron and copper ions and their
      activity-structure relationships were also investigated. To fulfill these
      objectives, flavones (apigenin, luteolin, kaempferol, quercetin, myricetin and
      rutin), isoflavones (daidzein and genistein), flavanones (taxifolin, naringenin
      and naringin) and a flavanol (catechin) were investigated. All flavonoids studied
      show higher reducing capacity for copper ions than for iron ions. The flavonoids
      with better Fe3+ reducing activity are those with a 2,3-double bond and
      possessing both the catechol group in the B-ring and the 3-hydroxyl group. The
      copper reducing activity seems to depend largely on the number of hydroxyl
      groups. The chelation studies were carried out by means of ultraviolet
      spectroscopy and electrospray ionisation mass spectrometry. Only flavones and the
      flavanol catechin interact with metal ions. At pH 7.4 and pH 5.5 all flavones
      studied appear to chelate Cu2+ at the same site, probably between the 5-hydroxyl
      and the 4-oxo groups. Myricetin and quercetin, however, at pH 7.4, appear to
      chelate Cu2+ additionally at the ortho-catechol group, the chelating site for
      catechin with Cu2+ at pH 7.4. Chelation studies of Fe3+ to flavonoids were
      investigated only at pH 5.5. Only myricetin and quercetin interact strongly with
      Fe3+, complexation probably occurring again between the 5-hydroxyl and the 4-oxo
      groups. Their behaviour can be explained by their ability to reduce Fe3+ at pH
      5.5, suggesting that flavonoids reduce Fe3+ to Fe2+ before association.

PMID- 12592673
TI  - Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide
      induced testicular gametogenic and steroidogenic disorders: a correlative
      approach to oxidative stress.
AB  - The present study was undertaken to find out the adverse effects of
      cyclophosphamide on testicular activities along with testicular oxidative stress
      at its therapeutic dose and the protective effects of alpha-tocopherol succinate
      on testicular dysfunctions induced by cyclophosphamide in mature albino rats. A
      significant diminution in the activities of testicular delta 5, 3 beta
      hydroxysteroid dehydrogenase (HSD) and 17 beta-hydroxysteroid dehydrogenase (HSD)
      along with significant reduction in the plasma level of testosterone and number
      of spermatogonia-A (ASg), preleptotene spermatocytes (pLSc), midpachytene
      spermatocytes (mPSc) and step 7 spermatids (7Sd) at stage VII of spermatogenic
      cycle were observed following cyclophosphamide treatment. Oxidative stress was
      also noted in testis, which was enlightened by significant elevation in the level
      of malondialdehyde (MDA) and conjugated dienes along with significant reduction
      in the activities of testicular peroxidase and catalase. Co-administration of
      alpha-tocopherol succinate in cyclophosphamide-treated rats resulted a
      significant restoration of all the above-mentioned parameters to the control
      level. The results of our experiment suggest that cyclophosphamide treatment at
      its clinical dose is associated with antigonadal activities as well as induction
      of oxidative stress in gonad that can be ameliorated significantly by alpha
      tocopherol succinate co-administration. So, our data have some potential clinical
      implications.

PMID- 12592674
TI  - Structure-antioxidant activity relationships of flavonoids: a re-examination.
AB  - The antioxidant and prooxidant activities of flavonoids belonging to several
      classes were studied to establish their structure-activity relationships against
      different oxidants. Special attention was paid to the flavonoids quercetin
      (flavone), taxifolin (flavanone) and catechin (flavanol), which possess different
      basic structures but the same hydroxylation pattern (3,5,7,3'4'-OH). It was found
      that these three flavonoids exhibited comparable antioxidant activities against
      different oxidants leading to the conclusion that the presence of ortho-catechol
      group (3',4'-OH) in the B-ring is determinant for a high antioxidant capacity.
      The flavone kaempferol (3,5,7,4'-OH), however, in spite of bearing no catechol
      group, also presents a high antioxidant activity against some oxidants. This fact
      can be attributed to the presence of both 2,3-double bond and the 3-hydroxyl
      group, meaning that the basic structure of flavonoids becomes important when the
      antioxidant activity of B-ring is small.

PMID- 12592675
TI  - The metabolism of dietary polyphenols and the relevance to circulating levels of
      conjugated metabolites.
AB  - Berry extracts rich in anthocyanins have been linked to protective effects
      including the modulation of age-related neurological dysfunction and the
      improvement of the resistance of red blood cells against oxidative stress in
      vitro. In this study the bioavailability, metabolism and elimination of
      polyphenols from blackcurrant juice, rich in anthocyanins, flavonols, and
      hydroxycinnamates, were investigated. The four major native anthocyanidin
      glycosides of blackcurrant juice, delphinidin-3-glucoside, delphinidin-3
      rutinoside, cyanidin-3-glucoside and cyanidin-3-rutinoside, were detected and
      identified in low amounts by HPLC and LC-MS in plasma and urine post-ingestion.
      Elimination of the anthocyanins was fast (maximum excretion after 1 h) and plasma
      levels (0-128.6 nmol/l) and total urinary exretion (0.07-1.35 mg; 0.007-0.133% of
      the dose ingested) were low. Most significantly, of the hydroxycinnamates,
      conjugated and free ferulic, isoferulic, p-coumaric, sinapic and vanillic acids
      were identified in plasma and urine, using GC-MS techniques. Quercetin and
      kaempferol (as glucuronides) and the proposed colonic metabolite of quercetin, 3
      hydroxyphenylacetic acid, were detectable in a minority of subjects. Increased
      daily urinary hippuric, 4-hydroxyhippuric and 3-hydroxyhippuric acid levels were
      also observed post-ingestion in all volunteers.

PMID- 12592676
TI  - [Revisiting my course in learning traditional Chinese medicine].

PMID- 12592677
TI  - [Measurement for peri-menopausal stage].

PMID- 12592678
TI  - [Effect of yangjing zhongyu decoction on expression of insulin-like growth factor
      II and its receptor in endometrium of women with unexplained infertility].
AB  - OBJECTIVE: To investigate the effect of Yangjing Zhongyu Decoction (YJZYD) on
      expression of insulin-like growth factor II (IGF-II) and its receptor II (IGF-II
      R) in endometrium of women with unexplained infertility, and the relationship of
      which with the receptibility of endometrium to ovum implantation. METHODS:
      Reverse transcription-polymerase chain reaction (RT-PCR) assay was used to detect
      quantitatively the expression of IGF-II and IGF-II R in 22 women with unexplained
      infertility before and after YJZYD treatment during mid-luteal phase. RESULTS:
      The levels of IGF-II and IGF-II R before treatment were 0.794 +/- 0.453 and 0.725
      +/- 0.354 (in grey level, the same below) respectively, which were significantly
      increased in the same phase after treatment, reaching 1.202 +/- 0.551 and 1.045
      +/- 0.581 respectively (P < 0.01 and P < 0.05). Correlation analysis showed the
      level of IGF-II mRNA was positively correlated with the level of IGF-II mRNA
      either before or after treatment. CONCLUSION: YJZYD could enhance the expression
      of IGF-II and IGF-II R in the endometrium during mid-luteal phase, promote the
      differentiation of endometrium and increase its reception to ovum implantation.

PMID- 12592679
TI  - [Clinical study on relationship between memory quotient, estrogen and Chinese
      nourishing kidney herbs in perimenopausal women].
AB  - OBJECTIVE: To explore the memory quotient and hormone level in women with
      perimenopausal syndrome and healthy women in perimenopausal period, and the
      effect of estrogen and Chinese nourishing Kidney herbs (CNKH) on memory. METHODS:
      Fifty-six women of perimenopausal syndrome were treated with estrogen (n = 24)
      and CNKH (n = 32) respectively. The changes of memory and estrogen level before
      and after treatment were determined and compared with those in healthy women.
      RESULTS: The memory quotient (MQ) and estrogen level increased and follicule
      stimulating hormone (FSH) level decreased significantly after treatment in both
      groups (P < 0.01), these parameters approached to those in healthy women. The
      difference of therapeutic effect between the two treated group was insignificant
      (P > 0.05). CONCLUSION: The decrease of memory is related to the lowering of
      estrogen level, CNKH could improve the brain function and enhance memory.

PMID- 12592680
TI  - [Efficacy observation in treating patients with postmenopausal coronary heart
      disease by bushen peiyuan principle].
AB  - OBJECTIVE: To observe the effect of Bushen Peiyuan Principle (BSPY, a TCM
      principle for tonifying Kidney and nourishing primordial energy) in treating
      patients with postmenopausal coronary heart disease (PCHD) instead of hormone
      treatment. METHODS: Twenty-five healthy women, who were monepaused for over 5
      years but without CHD complication were allocated in Group A, 25 patients with
      PCHD complication suffered from estrogen contraindications such as embolism,
      hysteromyoma and mammary adenoma, were arranged in Group B, and 25 patients of
      PCHD without above-mentioned complications were divided into Group C. Group B and
      C was treated with BSPY and hormone replacement therapy respectively, and the
      drugs for hypolipidemics were withdrawn 1 month before the study. All the
      patients were observed for 3.5 months, with their blood levels of estradiol (E2)
      and lipids determined before and after treatment. RESULTS: Before treatment, the
      level of E2 in the two treated groups was lower than that in the normal group
      significantly (P < 0.01), and the parameters of blood lipids were abnormal in
      them. These abnormalities were improved after treatment significantly (P < 0.05
      or P < 0.01). The level of E2 raised significantly (P < 0.01) after treatment in
      patients of Group C, with withdrawal vaginal bleeding presented in 90% of less
      than 56 years in age. In the Group B after treatment, level of E2 showed a slight
      rising and withdrawal vaginal bleeding was not found but with improvement of
      symptoms and signs better than that in Group C. CONCLUSION: Using BSPY in
      treating PCHD displayed significant adjustment on disturbance of blood lipid
      spectrum and improvement on clinical manifestations. As compared with the
      therapeutic effect of hormone replacement therapy, the risk of carcinogenesis
      caused by endometrial hyperplasia could be avoided because the blood level of E2
      is only slightly increased by BSPY.

PMID- 12592681
TI  - [Effect of hejie decoction on T-cell receptor V beta 7 gene expression in
      patients of chronic hepatitis B].
AB  - OBJECTIVE: To explore the therapeutic effect of Hejie Decoction (HJD) in treating
      chronic hepatitis B and its relationship with T-cell receptor V beta 7 (TCRV beta
      7) gene expression. METHODS: Forty-five patients of chronic hepatitis B were
      randomly divided into two groups. The 30 patients in the treated group were
      treated by HJD, and the 15 patients in the control group were treated by
      conventional western medicine. The therapeutic effect and changes of TCRV beta 7
      gene expression after treatment were observed. RESULTS: After 6 months treatment,
      the ALT level in the two groups were obviously decreased (P < 0.01). No
      significant difference was shown in comparison of the total effective rate
      between the two groups but it did show in comparison of markedly effective rate
      between them. TCRV beta 7 expression was detected in 5 patients of the treated
      group, and HBV-DNA and HBeAg in the 5 patients were all negatively converted.
      While in the control group, no one had TCRV beta 7 expression detected, either no
      one with negative conversion of HBV-DNA and HBeAg. TCRV beta 7 could not be
      detected in all the patients whose HBV-DNA and HBeAg hasn't negatively converted,
      though their liver function could be normalized. CONCLUSION: HJD might have the
      effect of regulation on TCRV beta 7 expression, it possibly is the important way
      for HBV replication inhibition and virucidal action of HJD.

PMID- 12592682
TI  - [Observation on effect of yugan granule in treating patients of chronic hepatitis
      B with basic core promoter mutant hepatitis B virus].
AB  - OBJECTIVE: To observe the effect of Yugan Granule (YGG) in treating patients of
      chronic hepatitis B infected with basic core promoter (BCP) mutant HBV. METHODS:
      BCP mutation was detected by microwell liquid hybridization combined with enzyme
      linked immunosorbent assay (ELISA) and 46 patients were confirmed to be the
      mutant positive (Group A), and 69 the mutant negative (Group B). All patients
      were treated by YGG and the clinical symptoms and laboratory parameters before
      and after treatment were observed. RESULTS: The scores of symptoms and serum
      levels of alanine transaminase (ALT) and total bilirubin (TBil) were decreased
      markedly in both groups after treatment. The HBeAg negative conversion rate in
      Group A was 60%, obviously higher than that in Group B (30%, P < 0.05), while HBV
      DNA negative conversion rate between the two groups had the insignificant
      difference. The overall efficacy was similar in the two groups. CONCLUSION: YGG
      could remarkably alleviate the symptoms, reduce serum levels of ALT and TBil, and
      showed the effect of anti-HBV with the same efficacy both to BCP mutant and wild
      strain HBV infected patients.

PMID- 12592683
TI  - [Clinical observation on dusuqing in treating senile bacterial pneumonia].
AB  - OBJECTIVE: To evaluate the clinical effect of Dusuqing (DSQ) in treating senile
      bacterial pneumonia and to explore its possible mechanism. METHODS: Patients were
      randomly divided into two groups, the treated group treated with conventional
      western therapy (CWT) and the combined treated group treated with CWT plus DSQ
      respectively. The changes of serum cytokines, interleukin-2 (IL-2) and tumor
      necrosis factor-alpha (TNF-alpha), before and after treatment were observed.
      RESULTS: In the 33 patients of the combined treated group, the total effective
      rate being 93.9%. While in the 31 patients of treated group, the total effective
      rate being 83.9%. The difference of the total effective rate between the two
      groups was significant (P < 0.05). The scores of principal symptoms, secondary
      symptoms and total scores were all obviously lowered in both groups, particularly
      in the combined treated group. The peripheral blood IL-2 level was lower and TNF
      alpha higher in senile patients than those in healthy aged subjects respectively.
      All the two parameters approached normal level in the combined treated group but
      with insignificant change in the CWT treated group. CONCLUSION: DSQ showed
      obvious effect in treating senile bacterial pneumonia. The mechanism might be
      related with the lowering of inflammatory cytokines such as oversecreted TNF
      alpha, as well as the improvement of immune function (elevation of IL-2) of
      organism.

PMID- 12592684
TI  - [Study on influence of acupunctural signal on energy metabolism of human brain by
      positron emission tomography].
AB  - OBJECTIVE: To study the biologic process of energy metabolism in brain during
      acupuncture using positron emission tomography (PET) with 18F-2-desoxyglucose
      (18FDG) for further elucidation of the relationship between acupunctural signal
      and nerve system. METHODS: Electroacupuncture (EA) was applied on right lateral
      of a healthy volunteer and paralytic limbs of 4 patients with cerebral infarction
      at acupoints L14, LI11, ST36 and SP6 using Hans acupoint-nerve stimulator. PET
      imaging was conducted on the healthy subject or patients with the same posture
      before and during EA with GE Advance II PET system. RESULTS: PET showed that in
      the healthy subject, before EA, the glucose metabolism (GM) in bilateral cerebral
      cortex, bilateral thalamus, basal nuclei and cerebellum was almost symmetrical,
      but during EA, the GM in contralateral thalamus, contralateral frontal lobe and
      parietal lobe (motor and sensory area) increased obviously. While in the patients
      before EA, the GM in the infarcted area was significantly lower than that in the
      non-infarcted area, as compared with that observed with CT and MRI, it showed a
      similar figure but with bigger abnormal area. During EA, GM in the infarcted area
      increased with apparent reduction of size. Increased GM of focal area, widened
      cerebral cortex and decreased edematous area were shown in patients with larger
      infarction area. Quantitative analysis revealed evident change in local/total
      ratio of glucose and increase of GM change rate. CONCLUSION: (1) EA on limb
      acupoints of healthy subject could induce obvious increase of regional GM in
      brain and contralateral thalamus, contralateral frontal lobe and parietal lobe
      (motor and sensory area). (2) EA on acupoints of paralytic limbs could cause
      increase of GM in contralateral thalamus, contralateral frontal lobe and parietal
      lobe. Besides, GM also increased in the area with lowered GM before EA,
      accompanied with shrinkage or disappearance of lesion. (3) Acupuncture could
      evoke the function of brain cells and raise the GM in them.

PMID- 12592685
TI  - [Comparative study of electro-acupuncture and maprotiline in treating
      depression].
AB  - OBJECTIVE: To compare the effect of electro-acupuncture (EA) and maprotiline
      (Map) in treating depression. METHODS: Thirty patients of depression were treated
      with EA and 31 patients with Map orally taken respectively. The therapeutic
      effect and side-effect were evaluated by measurement of Hamilton Depression
      Rating Scale (HAMD), Self-Rating Scale for Depression (SDS), Self-Rating Scale
      for Anxiety (SAS), Clinical Global Impression Scale (CGI) and Asberg Rating Scale
      for side-effects (ARS) before treatment and on the day 14, 28 and 42 of the
      therapeutic course. RESULTS: After treatment, the scores of HAMD and SDS lowered
      significantly (P < 0.01) than before treatment, and with insignificant difference
      between the group (P > 0.05). For patients with somatic syndrome, the HAMD score
      decrease rate was obviously higher in the Map group than that in the EA group.
      However, for the patients with anxiety somatization syndrome, the score of SAS,
      ARS in the EA group were significantly lower than those in the Map group (P <
      0.05). Moreover, the efficacy index was higher in the EA group (P < 0.01).
      CONCLUSION: Both EA and Map are effective in treating depression.

PMID- 12592686
TI  - [Clinical study on effect of Astragalus in efficacy enhancing and toxicity
      reducing of chemotherapy in patients of malignant tumor].
AB  - OBJECTIVE: To observe the effect of Astragalus membranaceus efficacy enhancing
      and toxicity reducing on chemotherapy in patients of malignant tumor. METHODS:
      One hundred and twenty tumor patients were randomly divided into the treated
      group and the control group. Both groups were treated with chemotherapy, but to
      the treated group, Astragalus injection was given additionally by intravenous
      dripping, 20 ml in 250 ml of normal saline once per day for 21 days as one course
      and 4 courses were given successively. RESULTS: Compared with the control group,
      the treated group showed a lower progressive incidence, lesser decrease of
      peripheral WBC and platelet count (P < 0.05), accompanied with CD8 significantly
      lowered (P < 0.05), CD4/CD8 ratio significantly increased (P < 0.01), IgG and IgM
      levels raised (P < 0.05) and Karnofsky scores elevated more than those in the
      control group. IgA level was unchanged in both groups. CONCLUSION: Astragalus
      injection supplemented with chemotherapy could inhibit the development of tumor,
      decrease the toxic-adverse effect of chemotherapy, elevate the immune function of
      organism and improve the quality of life in patients.

PMID- 12592687
TI  - [Effect of naoyi'an on basic fibroblastic growth factor mRNA expression and tumor
      necrosis factor protein expression in brain of rats following intracerebral
      hemorrhage].
AB  - OBJECTIVE: To investigate the effect of Naoyi'an granule (NYAG) on basic
      fibroblastic growth factor (bFGF) mRNA expression and tumor necrosis factor (TNF)
      protein expression following intracerebral hemorrhage and provide the theoretical
      evidence of NYAG in treating intracerebral hemorrhage and promoting the
      rehabilitation of neural function. METHODS: Model rats of intracerebral
      hemorrhage induced by infusion of collagenase VII into the caudate-putamen were
      used to determine the related parameters of behavior scores (BS), Northern blot,
      Western blot assay and optical density (OD) scanning in the model and the model
      treated with NYAG. And the data got from the two groups were compared. RESULTS:
      BS in the model group began to lower 24 hrs after modeling and a significant
      decrease was shown 7 days later, while in the NYAG group, it decreased
      significantly three days after modeling, the difference between the two groups
      was significant (P < 0.05). Levels of bFGF mRNA expression and TNF protein
      expression increased after modeling, it reached the peak in three days and began
      to decrease gradually in seven days in both groups. However, the level in the
      NYAG group was higher than that in the model group in various times of the
      experimental process. CONCLUSION: NYAG could enhance the bFGF expression and
      suppress the TNF expression so as to improve the behavior deficit in treating
      intracerebral hemorrhage, which may be one of the main mechanisms of NYAG for
      promoting the rehabilitation of neural function.

PMID- 12592688
TI  - [Study on preventive effect of buyang huanwu decoction on cardiomyocyte apoptosis
      induced by hypoxia-reoxygenation in rats].
AB  - OBJECTIVE: To observe the preventive effect of rats' serum containing Buyang
      Huanwu Decoction (BYHWD) on cultured cardiomyocyte apoptosis of neonatal rat
      induced by means of 24 hrs hypoxia and 4 hrs reoxygenation, and to investigate
      its mechanism concerned with nitric oxide (NO). METHODS: Myocyte apoptosis was
      detected by flow cytometry and ELISA with Annexin V-PI double labeled method. The
      lactate dehydrogenase (LDH) releasing level was measured with ultraviolet
      spectrophotometer. The NO concentration was determined by modified Yu method and
      the concentration of thiobarbituric acid response substance (TBARS) was tested by
      Ohkawa method. RESULTS: BYHWD contained rats' serum could significantly prevent
      cardiomyocyte from apoptosis induced by hypoxia and reoxygenation. After hypoxia
      reoxygenation, the NO, LDH and TBARS levels in the supernatant of cultured liquid
      treated with BYHWD were significantly lower than those in non-treated cultured
      liquid, the effect of BYHWD was dose-dependent. CONCLUSION: BYHWD can prevent
      cardiomyocytes from apoptosis induced by hypoxia and reoxygenation, its mechanism
      might be related with oxygen free radical and NO scavenging produced during the
      hypoxia-reoxygenation process.

PMID- 12592689
TI  - [Effects of electroacupuncture on laminin expression after spinal cord injury in
      rats].
AB  - OBJECTIVE: To observe the effects of electro-acupuncture (EA) on laminin (LN)
      expression related to the nerve fibers regeneration and development in the
      microenvironment after rats' spinal cord injury (SCI). METHODS: The SCI model of
      rats was established by the modified Allen's method to injure the 12th thoracic
      vertebra of animal. Experimental rats were divided into 4 groups, the sham group
      (no SCI and treatment), control group (with SCI and no treatment), hormone group
      (with SCI and dexamethasone) and EA group (with SCI and EA). LN expression was
      assessed by Western Blot assay at various time points, week 1, 2 and 4. RESULTS:
      The LN expression in EA group increased significantly at week 1, and remained
      constantly at week 2-4 with a tendency of gradually increasing. The LN expression
      in the hormone group elevated with obvious expression at week 2, and remained
      constantly also, with its expression up-regulated at week 2-4. The LN expression
      presented in both the EA group and the hormone group earlier than that in the
      control group, and the level of LN expression of EA group was higher than that in
      other two groups. CONCLUSION: EA could promote the production and secretion of LN
      expression, so it may have active beneficial leading effects on potentially
      regeneration capacity of the central nervous system.

PMID- 12592690
TI  - [Experimental study on effect of jiangya maijing liquid on spontaneous
      hypertension rats fed with high lipid diet].
AB  - OBJECTIVE: To observe and identify the effect of Jiangya Maijing Liquid (JYMJL)
      on spontaneous hypertension rats (SHR) fed with high lipid diet in antagonizing
      hypertension and hyperlipidemia and improving pathological changes of kidney.
      METHODS: Forty-two SHR were divided into 5 groups, except Group A, the Groups B-E
      were fed with high lipid diet, and Group C, D and E was treated with JYMJL,
      western drug and Niuhuang Jiangya pill respectively. Besides, Group F was set up
      for control with normal rats fed by normal diet. The changes of blood pressure
      (BP), biological indices and renal pathology were observed in the 14 weeks'
      period of observation. RESULTS: (1) BP raised significantly in Group A and B, it
      became stable in Group C from the 5th week on and was lower than the BP in other
      groups (P < 0.01). BP in Group F was not changed; (2) The highest level of nitric
      oxide (NO) was shown in Group F, and that in Group B and E was lower than that in
      Group C and D; (3) Level of cholesterol was lower in Group A and F than that in
      Group C, D and E (P < 0.01), and that in Group C was lower than that in Group B
      and E (P < 0.01 and P < 0.05 respectively); (4) Pathologic examination on kidney
      showed that no change was found in Group F, the most severe change was shown in
      Group B among Group B-E, and the improvement after treatment in Group C was
      better than that in group B (P < 0.01). CONCLUSION: (1) Condition of disease in
      rats with hypertension complicated with hyperlipidemia was more severe than that
      with simple hypertension; (2) JYMJL could restrain the developing of hypertension
      in SHR, the mechanism may be related with the raising of NO; (3) JYMJL has effect
      of lowering blood lipid; (4) JYMJL has kidney protective effect, it could
      alleviate the pathological changes in kidney by way of lowering BP and blood
      lipid.

PMID- 12592691
TI  - [Study on effect of electrical stimulus on repairing of astrocytes and neurons in
      rehabilitation after middle cerebral artery occlusion in rats].
AB  - OBJECTIVE: To explore the mechanism of rehabilitation after middle cerebral
      artery occlusion (MCAO). METHODS: MCAO model was reproduced with two-kidney, two
      clip renovascular hypertensive rats stroke-prone (RHRSP), which were divided into
      two groups, the treated group (treated with electric stimulus) and the control
      group (untreated model) randomly. The rehabilitation of rats was evaluated by
      balance beam walking test. The ultrastructural changes of neurons and astrocytes,
      expressions of glial fibrillary acidic protein (GFAP)-positive cells,
      neurofilament (NF) protein, and cerebral capillary dilatation M-associated
      protein-2 (MAP2), as well as the neurons apoptosis and the number of dilatation
      of cerebral capillary in the margin of infarcted area were observed by the end of
      1st, 3rd, 6th and 9th week after modeling. RESULTS: The motor function of
      paralysed limbs recovered better in the treated group than that in the control
      group by the end of 3-9th week after MCAO, the expression of GFAP-positive cells
      in astrocytes and NF, MAP2 in neurons as well as the number of cerebral capillary
      dilatation at the margin of infarcted area were higher than those in the control
      group (P < 0.05). CONCLUSION: Electric stimulation treatment could improve the
      recovery of motor function of paralyzed limbs. It might be due to the effect of
      electric stimulus in increasing astrocytes proliferation, reinforcing activity of
      neurons and evoking the dilatation of cerebral capillary.

PMID- 12592692
TI  - [Effect of lugu Ganoderma lucidum on low-density lipoprotein oxidation and
      monocyte adhesion to endothelium].
AB  - OBJECTIVE: To study the effect of Lugu Ganoderma Lucidum (LGL) on low-density
      lipoprotein (LDL) oxidation and monocyte adhesion to endothelium (AdM-E) induced
      by oxydative LDL and advanced glycosylation endproducts (AGE) by using serum
      pharmacological technique. METHODS: LDL oxidation was determined by measuring the
      thiobarbituric acid reactive substances in the supernatants, and AdM-E was
      determined by measuring myeloperoxidase activity of adherent monocyte. RESULTS:
      Serum derived from rats 0.5 hrs, 1 hr, 2 hrs, 3 hrs after LGL administering 0.12
      g/kg once and 0.5 hrs, 1 hr after LGL administering twice showed no significant
      effect on LDL oxidation, but the serum from rats 2 hrs, 3 hrs after LGL 0.12 g/kg
      administering twice or from rats after 10 successive days LGL administering in
      dose of 0.12 g/kg, 0.24 g/kg and 0.72 g/kg, all could lower the LDL oxidation (P
      < 0.05). Besides, the serum from rats with 10 days LGL administering of all
      dosages also could inhibit AdM-E induced by AGE (P < 0.05), and those of 0.24
      g/kg and 0.72 g/kg could inhibit AdM-E induced by oxydative LDL (P < 0.05).
      CONCLUSION: LGL could decrease LDL oxidation and AdM-E induced by AGE or
      oxydative LDL.

PMID- 12592693
TI  - [Clinical observation on the anti-liver fibrosis treatment by diammonion
      glycyrrhizinate injection combined with salvia].

PMID- 12592694
TI  - [Observation on clinical, treatment of cervical erosion with combined therapy of
      baqfukang foaming agent and tissue freezing by microwave].

PMID- 12592695
TI  - [Clinical observation of congestive heart failure treated by integrated
      traditional Chinese and Western medicine].

PMID- 12592696
TI  - [Comparative study on treatment of severe hepatitis by Western medicine and by
      TCM].

PMID- 12592697
TI  - [Thought on TMC study of pregnant hypertension syndrome].

PMID- 12592698
TI  - [Exploration on application of nanophase drug carrier system in Chinese drug
      form].

PMID- 12592699
TI  - [The characteristics and application of Chinese preparation for emergent aid of
      angina pectoris].

PMID- 12592700
TI  - [Minutes of the first session of national conference on andropathy].

PMID- 12592701
TI  - [New English translation of three-yin and three-yang of TCM].

PMID- 12592702
TI  - Bioinformatics and cytogenetics of unusual Drosophila melanogaster X-chromosome
      morphology.

PMID- 12592703
TI  - Genomic structure of the human UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase gene.
AB  - The UDP-GlcNAc:dolichol-P GlcNAc-1-P transferase catalyzes the first and
      committed step in the dolichol cycle, thus playing a fundamental role in the
      pathway for protein N-glycosylation. The structure of the GlcNAc-1-P transferase
      gene has been previously elucidated in mouse and hamster. Moreover, the human
      cDNA has been cloned. Using sequence database tools, we deduced the genomic
      structure of the human GlcNAc-1-P transferase gene, which was experimentally
      confirmed by sequence analysis. The gene is composed of 9 exons and spans 5.5 kb.
      All splice acceptor and donor sites conform to the canonical AG/GT rule. The 5'
      end of the gene is different from previously reported, as, consequently, the N
      terminal of the encoded protein, which is predicted to be 408 amino acids long.
      The transcription start site, determined by 5' RACE, occurs 180 nucleotides
      upstream of the translation initiation codon. Several potential transcription
      regulatory motifs, such as Sp-1, E4TF1 and ATF binding sites, were identified in
      the 5'-flanking region. A polyadenylation signal is located 466 bp downstream of
      the stop codon. The genomic organization of the gene is similar to that of the
      corresponding mouse and hamster genes, though extensive homology is restricted to
      the coding regions. Analysis of a panel of radiation hybrids led to the
      assignment of the GlcNAc-1-P transferase gene to chromosome 11, at 4.19 cR from
      NIB361, according to the location of the homologous sequences in the database at
      11q23.

PMID- 12592704
TI  - Genomic cloning and promoter analysis of a mouse anion exchanger 3 (AE3) gene.
AB  - The brain and cardiac isoforms of anion exchanger 3 (AE3) are considered to use
      their own promoters for their expression. However, little is known as to how the
      alternative transcription initiation is regulated. As a first step for
      elucidating the regulation, we obtained a genomic gene of mouse AE3. The 19-kbp
      clone contains about 6 kbp of 5' flanking region, 23 exons, and 22 introns. We
      have sequenced the whole region including introns and determined the intron-exon
      boundaries. Six amino acids are different from those deduced from the reported
      mouse AE3 cDNA. We measured a promoter activity of the 5' flanking region of the
      exon 1 for a brain type isoform and that of the exon C1 for a cardiac type
      isoform. The upstream region of the exon C1 indeed showed a promoter activity in
      rat cardiomyoblastic H9C2 cells, rat pheochromocyotoma PC12 cells, and human HeLa
      cells whereas the 5' flanking region of the exon 1 does not in HeLa cells,
      suggesting that the promoter for the cardiac type is rather ubiquitously active.

PMID- 12592705
TI  - Molecular cloning, nucleotide sequence and presence of multiple functional
      polyadenylation signals in the 3'-untranslated region of equine dopamine beta
      hydroxylase cDNA.
AB  - Complementary DNA (cDNA) encoding equine dopamine beta-hydroxylase (DBH) was
      amplified with a combination of reverse transcription-polymerase chain reaction
      (RT-PCR) and rapid amplification of cDNA ends (RACE) method, and their nucleotide
      sequences (Accession No. AB029430: the DDBJ nucleotide sequence database) was
      determined. A total of 3842 bp cDNA sequence was consisted with 5 bp of 5'
      flanking untranslated sequence, 1833 bp of open reading frame encoding 610 amino
      acids, and 2004 bp of 3' flanking untranslated sequence. The deduced amino acid
      sequence of equine DBH was very similar to the known mammalian DBH sequences. The
      similarity between amino acid sequence of equine DBH to sequences of bovine,
      human, rat and mouse DBH were 86.3, 84.6, 82.2 and 81.2%, respectively. Northern
      blot analysis and in situ hybridization revealed three different sizes of mRNA
      expressions in equine adrenal medulla tissue. Then we found three putative
      polyadenylation signal sites in the 3' flanking untranslated sequence. These
      results indicate that alternative use of three polyadenylation sites generates
      the equine DBH mRNA that have different sizes of 3' flanking untranslated region.
      These results may provide further evidence for understanding DBH molecule and
      clues for the equine DBH gene analysis.

PMID- 12592706
TI  - Characterization of the platelet-derived growth factor receptor alpha and c-kit
      genes in the pufferfish Fugu rubripes.
AB  - The receptor tyrosine kinase type III subfamily includes the PDGF receptors
      (alpha and beta), c-kit and the colony stimulating factor 1 receptor (CSF1R). The
      similar genomic organization of the genes encoding these receptors and the
      observation that in mammals, the genes for PDGFR alpha and PDGFR beta are
      tandemly linked with the c-kit and CSF1R genes, respectively, suggest that these
      genes arose from an ancestral receptor tyrosine kinase gene. We have previously
      cloned two copies each of the PDGFR beta and CSF1R genes from the pufferfish,
      Fugu rubripes, and shown that they are tandemly linked. We have now cloned the
      Fugu PDGFR alpha and c-kit genes and show that they are also tandemly linked. The
      intergenic region between the two genes in the Fugu (13 kb) and humans (350 kb)
      contains a conserved 59 bp element, which may play a role in regulation. The Fugu
      PDGFR alpha gene is transcribed from two promoters giving rise to alternate
      transcripts.

PMID- 12592707
TI  - Cloning and sequence analysis of a mitochondrial gene cluster encoding cytochrome
      C oxidase subunit III from Trichoderma pseudokoningii.
AB  - A mitochondrial gene cluster encoding cytochrome c oxidase subunit III (COX3), an
      ORF (called ORF250) similar to NADH dehydrogenase subunit VI (ND6), ten tRNA
      molecules, partial rRNA small subunit and rRNA large subunit from Trichoderma
      pseudokoningii S38 was cloned and sequenced. These genes are tandemly clustered
      on the mitochondrial genome of Trichoderma pseudokoningii S38. Phylogenetic
      analysis showed that cytochrome C oxidase subunits III exhibited high degree of
      similarity to sequences from Hypocrea jecorina, Verticillium lecanii, Podospora
      anserine, Neurospora crassa and Magnaporthe grisea (99, 90, 84, 82 and 79%
      identity, respectively). Prediction of transmembrane helices revealed that COX3
      was a transmembrane protein. Northern dot blot analysis showed that the
      cytochrome c oxidase subunits III gene we had cloned is actively transcribed in
      the T. pseudokoningii mitochondria.

PMID- 12592708
TI  - The zebrafish thrombospondin 3 and 4 genes (thbs3 and thbs4): cDNA and protein
      structure.
AB  - The cDNA sequences of the zebrafish thrombospondin 3 gene (thbs3) and
      thrombospondin 4 gene (thbs4) have been determined, and the encoded amino acid
      sequences (Thbs3 and Thbs4) have been analyzed. Thbs3 cDNA specifies a protein of
      962 amino acid residues (MW 105,787), while Thbs4 cDNA specifies a protein of 949
      residues (MW 103,989). Both proteins are highly acidic with Asp + Glu contents of
      15.8% (Thbs3) and 16.9% (Thbs4). The acidic amino acids are clustered in the
      region of the Type III repeats and part of the C-terminal domain. The presence of
      signal peptides indicates that Thbs3 and Thbs4 function as secreted,
      extracellular proteins. The two polypeptides contain homologous sequences with
      two cysteines that are likely to form interchain disulfide bonds. Potential
      glycosylation sites were identified, five for Thbs3 and three for Thbs4. The
      polypeptides share the domain structure characteristic of the thrombospondin
      3/thrombospondin 4/COMP subgroup of thrombospondin proteins. This domain
      structure consists of an amino-terminal thrombospondin N-terminal-like domain
      (TSPN domain), four Type II (EGF-like) repeats, seven Type III (calcium-binding)
      repeats, and a carboxyl terminal region. In aligning the Thbs3 and Thbs4 domain
      sequences with those of other thrombospondins, a gradient of sequence homology is
      observed that increases from N-terminus to C-terminus.

PMID- 12592709
TI  - Cloning and characterization of the genes coding for antigen 85A, 85B and 85C of
      Mycobacterium avium subsp. paratuberculosis.
AB  - Three genes encoding the secreted proteins (antigen 85-A, B, and C) of
      Mycobacterium avium subsp. paratuberculosis were cloned, sequenced and studied.
      The complete sequences of these three 85-complex proteins revealed their
      similarity with 85-complex proteins of other mycobacterial species. Specifically,
      these sequences showed 99% homology with M. avium 85-complex protein sequences.
      The multiple homology analysis of these sequences revealed that variations occur
      at only certain amino acid positions and this is true with all other 85-complex
      protein sequences of mycobacteria. However, the proposed three conserved regions
      involved in fibronectin binding in other mycobacteria were observed in N-terminal
      regions 85A, B and C of M. avium subsp. paratuberculosis.

PMID- 12592710
TI  - Cloning and molecular characterization of the salt-regulated jojoba ScRab cDNA
      encoding a small GTP-binding protein.
AB  - Salt stress results in a massive change in gene expression. An 837 bp cDNA
      designated ScRab was cloned from shoot cultures of the salt tolerant jojoba
      (Simmondsia chinesis). The cloned cDNA encodes a full length 200 amino acid long
      polypeptide that bears high homology to the Rab subfamily of small GTP binding
      proteins, particularly, the Rab5 subfamily. ScRab expression is reduced in shoots
      grown in the presence of salt compared to shoots from non-stressed cultures. His6
      tagged ScRAB protein was expressed in E. coli, and purified to homogeneity. The
      purified protein bound radiolabelled GTP. The unlabelled guanine nucleotides GTP,
      GTP gamma S and GDP but not ATP, CTP or UTP competed with GTP binding.

PMID- 12592711
TI  - Cloning and characterization of a novel human alcohol dehydrogenase gene
      (ADHFe1).
AB  - There are three types of NAD(P)(+)-dependent alcohol dehydrogenase: "medium
      chain" zinc-containing enzymes, "short-chain" zinc-lacking enzymes and iron
      activated enzymes. Although the medium-chain family and the short-chain family
      have been characterized in human, the iron-activated alcohol dehydrogenase family
      seems to exist only in microbial organisms. We have now cloned and characterized
      an iron-activated alcohol dehydrogenase gene, Fe-containing alcohol dehydrogenase
      1 (ADHFe1) in human. The cDNA was isolated from the human fetal brain cDNA
      library. It contains a long open reading frame, which is not homologous with the
      other alcohol dehydrogenases isoenzymes characterized in human. The hypothetical
      alcohol dehydrogenase does, however, show strong homology to the iron-activated
      alcohol dehydrogenases from microbial organisms. Northern blotting analysis only
      detected expression in adult liver tissue. At least two different splicing
      variants were screened by PCR using the multiple tissue cDNA panels as templates.

PMID- 12592712
TI  - Cloning and characterization of the novel isoforms for PGF2 alpha receptor in the
      bovine corpus luteum.
AB  - The cDNA clones for five novel isoforms of prostaglandin (PG) F2 alpha receptor
      (FP) were isolated from the bovine corpus luteal cDNA library. The sequence
      analysis revealed that each FP isoform, respectively, encodes 325 (alpha), 326
      (beta), 339 (gamma), 293 (delta), and 298 (epsilon) amino acid proteins, carrying
      the specific carboxyl tails (C-tails) caused by alternative mRNA splicing.
      Depending on the splicing sites, FP isoforms can be classified into two types.
      The FP-alpha, FP-beta, and FP-gamma belong to the same group (Type I), which has
      common amino acid sequences with the exception of each specific 4th intracellular
      C-tail, while FP-delta and FP-epsilon are classified into the second group (Type
      II), which has a truncated structure lacking transmembrane domain VII and an
      intracellular C-tail. The RT-PCR analysis indicated that the mRNAs for these
      isoforms are expressed at the same time with that of FP in the bovine corpus
      luteum during the estrous cycle and pregnancy.

PMID- 12592713
TI  - How hygiene can help you retire.

PMID- 12592714
TI  - A new approach to restoring root-end cavity preparation in surgical endodontic
      procedures--a scanning electron microscopy study.
AB  - While many different restorative materials are now available for filling root-end
      preparations in surgical endodontic therapy, each one has drawbacks. The current
      study suggests that a flowable composite resin, cured by a high-power curing
      light in 10 seconds, may be the material of choice. The significance of coating
      the resected root surface with a dentin-bonding agent is also discussed.

PMID- 12592715
TI  - Complications associated with diabetes mellitus after guided tissue regeneration-
      a case report revisited.
AB  - Twelve to fourteen million individuals suffer from diabetes mellitus (DM), though
      the disease is undiagnosed in a large number of these people. Dentists must be
      aware of the signs and symptoms of DM so they can better manage the treatment of
      whatever dental therapy their patients with diabetes require. DM has been
      reclassified into type 1 and type 2, based on the individual's insulin
      requirements. The diabetic patient may present with, or develop, advanced
      periodontal disease, which may be more difficult to control because of metabolic
      status and commitment to dental care. This article includes a description of a
      type 2 diabetic who reportedly was well controlled, yet experienced complications
      after guided tissue regeneration. The postsurgical results were acceptable and
      the patient remained stable during supportive periodontal therapy. However, she
      became noncompliant with her dental care and converted from a type 2 to a type 1
      diabetic with poor control. The case illustrates the rapid progression of
      periodontal disease in a side that had been successfully treated. It also
      discusses the interrelationships between diabetes and periodontal disease.

PMID- 12592716
TI  - Year in review.

PMID- 12592717
TI  - Desperately seeking: an educational program to integrate entrepreneurship with
      clinical dentistry.

PMID- 12592718
TI  - The sandwich technique and strip crowns: an esthetic restoration for primary
      incisors.
AB  - The restoration of carious, fractured, or discolored primary incisors is
      rewarding to dentists because it gives them the satisfaction of knowing they have
      restored the smile and self-confidence of a growing child. However, restoring
      primary teeth can be a strenuous task because of the difficulty in keeping these
      patients' teeth dry and the uncooperative behavior of the child that sometimes
      occurs. Dentists are always seeking procedures that are esthetic, easy to use,
      and relatively quick to complete. This article describes a relatively easy
      technique that produces a beautiful outcome in a comparatively short time. The
      author has used this procedure on hundreds of children for more than 20 years,
      modifying the approach as appropriate when new methods and materials become
      available.

PMID- 12592720
TI  - Self-etching adhesives: new science or just a trend?

PMID- 12592719
TI  - The modified laminar impression.

PMID- 12592721
TI  - Perspectives. Medicaid: same-old, same-old or a new, not-so-brave world?

PMID- 12592722
TI  - XML and HIPAA: the data wave of the future? Web-enable your data to strategically
      position your organization for future e-health initiatives.

PMID- 12592723
TI  - LIS and the enterprise. Lab information systems play a pivotal role in patient
      care, and IT systems have evolved to meet current-day users' needs.

PMID- 12592724
TI  - Pain-free CPOE. Following the right protocol is a critical step for encouraging
      physician adoption.

PMID- 12592725
TI  - In record time: diary of an EMR installation. Georgia pediatric practice
      discovers that not only is eight enough, it's the perfect number of weeks
      necessary for implementing an EMR.

PMID- 12592726
TI  - What works. Living large. A small HMO implements a managed care information
      system that enables it to compete with large rivals.

PMID- 12592727
TI  - What works. Headache relief. Outsourcing credentialing for a busy physician
      practice brings improvement.

PMID- 12592728
TI  - A million a month. Pennsylvania health system customizes software not only to
      strengthen claims processing, but also to improve its payment posting process.

PMID- 12592729
TI  - CRM builds market share. Arkansas health system uses CRM and target marketing to
      grow its business.

PMID- 12592730
TI  - A technology for all seasons. South Carolina hospital uses bar code scanning
      throughout the enterprise,  in clinical and nonclinical settings, for increased
      efficiency and quality.

PMID- 12592732
TI  - Laboratory information systems hotlist.

PMID- 12592731
TI  - Getting paid the first time. North Carolina specialty practice gains from claims
      and coding software.

PMID- 12592733
TI  - Healthcare's last mile: linking disparate information systems.

PMID- 12592734
TI  - It's my bag! Public health nursing across Nebraska.

PMID- 12592735
TI  - Nebraska Center for Nursing: 2002 update.

PMID- 12592736
TI  - Nebraska Nursing Leadership Group.

PMID- 12592737
TI  - Specialty vs. discipline--the dilemma.

PMID- 12592738
TI  - Esthetic diagnosis by the numbers.

PMID- 12592739
TI  - Smoking cessation activities in Texas: the role of dentists.

PMID- 12592740
TI  - New drugs and product approvals from 2001.

PMID- 12592741
TI  - Oral and maxillofacial pathology case of the month. Dentin dysplasia type I.

PMID- 12592742
TI  - Acetaminophen levels 4 and 7 hours after 2000 and 3000 mg single doses in healthy
      adults.
AB  - PURPOSE: Therapeutic acetaminophen levels are not achieved at currently
      recommended doses. The purpose of this study is to determine acetaminophen levels
      in healthy adults after taking a single dose well in excess of the recommended
      dose. METHODS: 24 healthy adults received single 2 or 3 gram acetaminophen doses.
      Serum acetaminophen levels were drawn at 4 and 7 hours after the dose. RESULTS:
      The 2 gram doses (6 subjects) ranged from 23 to 40 mg/kg of body weight. The 3
      gram single doses (18 subjects) ranged from 38 to 69 mg/kg of body weight. Mean 4
      hour acetaminophen levels for 2 and 3 gram doses were 8.8 (SD 3.6, range 3-13)
      and 21.8 (SD 6.5, range 6-32) mcg/ml, respectively. Mean 7-hour acetaminophen
      levels for 2 and 3 gram doses were 1.5 (SD 1.4, range 0-3) and 7.7 (SD 4.6, range
      0-17) mcg/ml, respectively. CONCLUSIONS: Dosing by weight (i.e., mg/kg) appears
      to provide a more predictable dose-response relationship. Optimal adult dosing
      appears to be somewhere in the 20 to 30 mg/kg range based on the premise that the
      4 hour level is a trough level that should be in the low therapeutic range.

PMID- 12592743
TI  - Healthy people in Hawaii?: an overview of ethnic health disparities in Hawaii for
      the Healthy People 2010 initiative targeted health concerns.
AB  - Significant health disparities exist between ethnic groups in the United States.
      The authors reviewed literature examining the epidemiology of health disparities
      in Hawaii's multiethnic population. One of the primary goals of the Healthy
      People 2010 initiative is to eliminate health disparities, specifically cancer,
      cardiovascular disease, diabetes, infant mortality, child and adult immunizations
      and HIV/AIDS. However, the research on ethnic health disparities is fragmented,
      especially in Asian/Pacific Islanders. Unclear definitions of ethnicity (i.e.,
      self-report, mixed ethnicity, etc) and aggregated study populations (i.e.,
      combining multiple ethnic groups into one category) obscure the true health
      status of ethnic minorities in Hawaii. This paper presents an overview of the
      state of the literature on Hawaii ethnic health disparities.

PMID- 12592744
TI  - MD/PHD program at the John A. Burns School of Medicine.

PMID- 12592745
TI  - Highlights of recent cancer incidence data in Hawaii.

PMID- 12592747
TI  - South Africa: HIV/AIDS education, support and care.

PMID- 12592749
TI  - Peak nursing bodies call on government for urgent action on nursing crisis.

PMID- 12592748
TI  - The business planning framework--nursing resources.

PMID- 12592750
TI  - Radiation safety--dispelling some of the myths.

PMID- 12592751
TI  - Nurses. Worth looking after--a winning campaign.

PMID- 12592752
TI  - Exposure to blood borne viruses--sharps and needlestick injuries.

PMID- 12592753
TI  - Retractable needle and syringe technology initiative.

PMID- 12592754
TI  - All super funds are not the same.

PMID- 12592755
TI  - Advocating for equality in mental health coverage.

PMID- 12592756
TI  - The successful interview. How to market yourself for career advancement.

PMID- 12592757
TI  - Tips on taking the NCLEX exam.

PMID- 12592758
TI  - The joys and challenges of school nursing.

PMID- 12592759
TI  - How to create a job winning resume.

PMID- 12592760
TI  - Classic Creutzfeldt-Jakob disease recommendations for the operating room.

PMID- 12592762
TI  - Waiting for Romanow.

PMID- 12592761
TI  - Determining the cost-effectiveness of the Registered Nurse First Assistant: the
      research link.
AB  - As monetary constraints in health care increase, stakeholders search for avenues
      to ensure cost-effective care provision. In the perioperative environment one
      such avenue involves the group of health care providers supporting surgeons and
      patients during surgery--the surgical assistant. In Canada, general practice
      physicians predominantly fill this role. Another viable option promoted as a cost
      effective alternative to the physician assistant is the Registered Nurse First
      Assistant (RNFA). The relationship between RNFA cost-effectiveness and role
      implementation and reimbursement is explored in this article. The importance of
      formally determining the cost-effectiveness of the RNFA through the utilization
      and development of research is presented.

PMID- 12592763
TI  - Codman Award paper. Family concerns and responses following a severe traumatic
      brain injury: a grounded theory study.
AB  - The focus of this paper is to present an inductively derived substantive theory,
      "Negotiating Uncertainty". The theory details the most salient concerns of
      families who had a close relative who had suffered a severe TBI and how they
      dealt with the experience during the uncertain trajectory of illness that
      followed coma. This study was conducted in two acute care neurosurgical units in
      Level 1 trauma facilities in Toronto, Canada, using the grounded theory research
      method. There were a total of 36 participants in the study: 11 individuals who
      were injured and 25 close family members. Supporting data is provided to permit
      the reader to hear the issues of family members first-hand and to evaluate the
      recommendations for practice, education, and research.

PMID- 12592764
TI  - [The status of academic focus in nursing education in Germany].

PMID- 12592765
TI  - [Living with a chronic progressive form of multiple sclerosis--a balance act].
AB  - There are only a few studies in the German speaking countries available which
      address the subject of the experience of chronically ill people during the course
      of their illness. Therefore it was the intent of this present study to find
      answers for central nurse science issues: How do people who suffer from a
      chronically progressive course of multiple sclerosis experience the downward
      trajectory? Which strategies do they develop in order to integrate the disease
      into their lives? In what ways does the scientific paradigm of medicine influence
      the perceptions of the illness and the life with it? After an analysis of the
      national and international state of nursing research follows a description of the
      methodology of the Grounded Theory and the individual examination steps of the
      study. The second part examines some essentials of the study. The results show
      that the trajectory is characterized by four phases. At first the ill person
      concentrates on the social discussion of the pathogenesis and the medical
      paradigma. But with physical experiences, exchange with other affected people and
      acquired information, those concerned develop a very case-specific knowledge.
      Often disillusioned by the medication strategies, based on the experience that
      their subjectivity and their individuality are not taken into account, they
      increasingly disapprove the deficit-oriented perspective of the professionals.
      They develop distinctly self-caring potentialities. To identify and support this
      self-care potentialities should be the very core of nursing.

PMID- 12592767
TI  - [Experience of patients in the intensive care unit. A qualitative study].
AB  - How patients experience their stay in the Intensive Care Unit is often not
      discernible externally. The patients are frequently sedated and in such a life
      threatening condition that they cannot express their experiences in this
      situation. Observation of the patients during their stay in ICU lends little to
      understanding their experiences. What one perceives from the outside can differ
      greatly from that which the patients experience themselves. Therefore, in this
      study, the patients were interviewed about their experiences several weeks to
      months after their release from the hospital. In this way, the patients could
      describe their perceptions from their own perspectives and thus be better
      understood. For this purpose the methodology of narrative interview was chosen so
      that the former patients could talk freely about what they experienced during
      their stay in ICU. Two of the interviews were completely analysed sequentially.
      The remaining interviews were used for purposes of comparison. The results of
      this study are the dimensions, which describe the experiences of patients in
      Intensive Care Units. The first dimension describes the experience of losses of
      memory, orientation impairment, and dreams. These experiences are closely related
      to outside influences, which could help to reconstruct the lost time and regain
      orientation, for example the reports of relatives. The second dimension
      represents how ill or healthy the patients considered themselves, and how much
      understanding they showed for their being treated in the ICU. The third
      dimension, which can be considered of overriding importance, outlines the
      patients' trust in relatives, the nursing staff and doctors.

PMID- 12592766
TI  - [Developing and establishing an expanded and more comprehensive HIV/AIDS nursing
      practice].
AB  - Developing and establishing an advanced nursing practice is an essential step
      toward future-oriented nursing care. An action research process was initiated to
      establish advanced nursing practice at the HIV clinic of the outpatient
      department at the University Hospital Basel with the goal to offer advanced
      nursing care to patients. Participatory action research allows generating
      knowledge about a social system while at the same time tempts to promote social
      change. The most important goal is to constantly analyse, improve, and evaluate
      nursing care for patients and family caregivers. Advanced nursing practice in
      HIV/AIDS is based on solid knowledge regarding the illness and current therapies.
      Central concepts are caring, clinical experiences, evidence based practice, and
      patient preferences. Through a systematic step-by-step process, the nurses at the
      HIV clinic are being better educated and more experienced in these concepts. An
      essential aspect of advanced nursing practice is the specialization of each nurse
      in a self selected topic within HIV/AIDS care. These nurses now offer new
      services such as medication management and adherence support, health maintenance
      and prevention, and symptom management. This ongoing process of learning while
      establishing advanced nursing practice in HIV/AIDS, enables the nurses to face
      future changes in health care in a proactive way.

PMID- 12592769
TI  - Advancing nursing practice--opportunities and directions.

PMID- 12592768
TI  - [Predictive validity of the original and expanded Norton Scale in geriatric
      nursing].
AB  - Prevention of pressure sores is a central task of nursing. For ethical and
      economic reasons correct assessment of the risk of pressure sores is a
      prerequisite of adequate prevention of pressure sores. In Germany the Norton
      scale is one of the most widespread tools for assessing the risk of pressure
      sores. For practical purposes the original translated version of the Norton scale
      is in use, as well as an extended modified version. Validity and reliability of
      these two versions are in the early stages of examination in Germany. The present
      descriptive longitudinal study aims at determining the predictive value of both
      versions of the Norton scale in nursing homes. In a convenience sample of 146
      individuals from five nursing homes residents from the age of 60 were assessed by
      professional nursing staff with the aid of both versions of the Norton scale at
      weekly intervals. Simultaneously the skin status was recorded on both sampling
      days. The results exhibit high values of sensitivity (91%-95%) and low
      specificity (6.2%-20.6%) in both scales. Both scales tend to overrate the risk of
      pressure sores. The values indicate that the original Norton scale assesses the
      residents free of pressure sores better than its extended version. Because of the
      convenience-sample the results are not representative and apply only to the
      investigated setting and population. The predictive validity of the original and
      modified version of the Norton scale is insufficiently verified, so there is
      great need of further investigation of the validity of the two versions.
      Application of assessment scales in nursing should be supplemented by
      professional expertise of the nursing staff to counterbalance assessment errors
      of the tools.

PMID- 12592770
TI  - More on Nightingale.

PMID- 12592771
TI  - The expanded role of the critical care nurse: a review of the current position.
AB  - The advanced practice role of the registered nurse is a topic that is currently
      being debated both nationally and internationally. This paper examines the
      literature as it relates to role expansion within nursing in general and more
      specifically to critical care nurses. The role of the critical care nurse is
      changing and this has occurred as a result of historical evolution, the use of
      increasing technology, the blurring of medical and nursing roles and current
      workforce shortages. The literature reviewed identifies some of the factors that
      have propelled this process and examines the use of terminology as it relates to
      advanced practice roles and their titles. Finally, the attributes and educational
      preparation required to perform at an increased level are examined.

PMID- 12592772
TI  - The need for a new advanced nursing practice role for Australian adult critical
      care settings.
AB  - The current deficit of knowledge related to advanced nursing practice in
      Australian adult critical care settings presents a barrier to future role
      development. This paper reports the findings of one theme identified by a
      research study that explored issues related to the potential for a new advanced
      nursing practice role for these settings. The qualitative approach of focus group
      methodology was used to collect data from a purposive sample of regional
      Queensland critical care nurses (n = 26). Thematic content analysis of the data
      identified concepts that progressively contributed to five major themes. This
      paper will report the findings related to the theme that there is a need for a
      new advanced nursing practice role for adult critical care settings. Participants
      perceived that nurses are already practising at advanced levels that may
      predetermine a new role. There was believed to be a need for recognition of and
      legal sanction for critical care nurses' present practices that extend beyond the
      current scope of nursing practice. Participants proposed that critical care
      nurses may be more competent than inexperienced medical personnel in this
      environment and participants wanted consistent levels of autonomy for advanced
      practices. The current career structure was seen to be a failure and many
      participants perceived the lack of opportunities for critical care nurses to
      advance up the clinical career pathway as problematic in recruitment and
      retention issues. The findings of this study provide new information that makes
      an important contribution to further exploration of advanced nursing practice
      role development for Australian adult critical care settings.

PMID- 12592773
TI  - Chest x-ray quiz. The likely problem is a light middle lobe
      consolidation/atelectasis from pneumonia.

PMID- 12592774
TI  - Tachycardia's toll: tachycardia induced cardiomyopathy--a case study.
AB  - Cardiac arrhythmias are a well known cause of mortality for patients with heart
      disease. However, sinus tachycardia is a more unusual arrhythmia which can lead
      to serious heart damage or death. Even young patients with structurally normal
      hearts may become gravely ill. This case study outlines the condition of sinus
      tachycardia, and associated changes in heart function, altered cellular structure
      of the myocardium and compensatory mechanisms in the body. Treatment modalities,
      including electro-physiological studies and drug therapies to moderate the
      tachycardia and myocardial oxygen demand of the heart, are discussed. Fourteen
      year old 'Ben' was previously a well, active and outgoing youth who suddenly
      became critically ill. He endured weeks of hospitalisation, numerous serious
      complications including Torsade de pointes arrhythmia, Cheyne-Stokes
      respirations, nausea and dizziness during this acute phase. Despite challenges,
      Ben's severely compromised heart muscle recovered at a remarkable rate.

PMID- 12592775
TI  - The impact of breastmilk on infant and child health.
AB  - Infant-formula-feeding is inferior to breastfeeding because human milk provides
      specific and non-specific factors that have long-term consequences for early
      metabolism and the development of disease. Human milk enhances the immature
      immunologic system of the neonate and strengthens host defense mechanisms against
      infective and other foreign agents. Some mechanisms that explain active
      stimulation of the infant's immune system by breastfeeding are the bioactive
      factors in human milk such as hormones, growth factors and colony stimulating
      factors, as well as specific nutrients. Human milk may reduce the incidence of
      disease in infancy because mammalian evolution promotes a survival advantage. In
      addition, factors in milk promote gastrointestinal mucosal maturation, decrease
      the incidence of infection, alter gut microflora, and have immunomodulatory and
      anti-inflammatory functions. Hormones, growth factors and cytokines in human milk
      may modulate the development of disease. Furthermore breastfed babies have
      reduced exposure to foreign dietary antigen. Following the termination of
      breastfeeding, there is evidence of ongoing protection against illness due to
      protective influences on the immune system mediated via human milk. Industry
      continues to attempt to improve infant formula with the addition of compounds
      such as fatty acids, oligosaccharides, nucleotides and lactoferrin. However,
      human milk has such far-reaching effects on the infant's immune response that
      optimal development depends heavily on its provision. All mothers should be
      encouraged and supported to continue breastfeeding for six months and beyond in
      order to promote the good health of their infants.

PMID- 12592776
TI  - Breastfeeding intentions and outcomes of adolescent mothers in the Starting Out
      program.
AB  - Studies of adolescent mothers have shown that they have a lower rate of
      breastfeeding than older mothers. This study explores the breastfeeding
      intentions and outcomes of adolescents attending the Starting Out program of
      UnitingCare Connections. Starting Out is a community-based program for pregnant
      and parenting young women up to the age of 25 years. The program offers young
      women counselling, antenatal support and education, supported accommodation,
      outreach support, and information. Antenatal support and education are an
      important part of the service offered to pregnant young women at Starting Out. Of
      the pregnant young women in the study 97.6% said they wanted to breastfeed, with
      82.8% breastfeeding on discharge from hospital. However, the number of young
      women still breastfeeding at three and six months fell to levels lower than these
      rates for older women. Furthermore, 48.5% of the young women breastfed for a
      shorter period than they intended to breastfeed. The factors influencing these
      results are discussed. Although young women are less likely to breastfeed than
      older women, this study has shown that the Starting Out program has had positive
      breastfeeding outcomes for young women who were involved in the antenatal
      classes.

PMID- 12592777
TI  - A descriptive survey of data collection in breastfeeding services at Victorian
      maternity hospitals.
AB  - An increasing number of breastfeeding clinics have been established in Victoria,
      Australia since 1994. The aim of this study was to identify hospital
      breastfeeding clinics in the state of Victoria and to examine their methods of
      data collection. A further aim was to investigate the feasibility of developing a
      standard, minimum data-set or attendance registration form for breastfeeding
      clinics. A postal questionnaire was sent to 82 Victorian maternity hospitals in
      September 2000. The response rate was 93% (76/82); 81% (62/76) indicated a need
      for a standard form. The 37 hospitals (49%) that provide a breastfeeding clinic
      collect a variable amount of information from their clients. Thirteen
      breastfeeding clinics are provided by maternity hospitals with over 1000 births
      annually, and they see an average of nine women per week (range 2-18). The
      collection of standard information would enable a comprehensive description of
      individual breastfeeding clinic services and comparison between service
      providers. This could act as the starting point for evaluating breastfeeding
      clinic service accessibility, profile of usage and the impact on breastfeeding
      outcomes.

PMID- 12592778
TI  - [Revista Brasileira de Enfermagem: 70 years].

PMID- 12592779
TI  - [Problems of educational programs in health: strategies of diabetics].
AB  - The present paper had as objective to reflect on the health education process
      faced by the diabetic person when confronted with prohibitions and limitations
      imposed by the disease and health professionals. As framework, the paper relied
      on Michell Maffesoli's Comprehensive Sociology which, through the study of daily
      life, reveals that the human being uses transgressions and double games to escape
      the rules imposed by society. To silence, to keep secret, not to dialogue, seems
      to be strategies that reflect our way of doing health education.

PMID- 12592780
TI  - [The mental patient and the psychiatric institution: the voice of the silenced].
AB  - A systematized observation of human behavior towards madness induced personal
      questions on what mental patients had to say about their own life dynamics. The
      perspective of these people, regarding the concept of insanity, is the subject of
      this study. This descriptive and qualitative investigation has two objectives.
      The first is the description of the speech of mental patients in relation to
      insanity. The second objective is the analysis of their perception of the
      psychiatric process. Results obtained through semi-structured interviews showed
      that the great majority of the patients do not consider themselves mentally ill.
      They approach madness as stereotypy, aggressiveness, mendicancy and absence of
      reasoning. Although they admitted being different, they did not consider
      themselves mentally ill.

PMID- 12592781
TI  - [Impaired physical mobility in elderly: related factors and defining
      characteristics].
AB  - The present exploratory study aims at estimating the occurrence of the Nursing
      Diagnosis "Impaired Physical Mobility' in elderly who live in a home institution
      in the city of Goiania, Goias. The study was carried out from December 1999 to
      February 2000. The collection of data was done through interviews, observations,
      physical exam and information obtained from the professionals who assisted the
      elderly. Sixty patients ranging from 60 to 105 years were the subjects of this
      study. Results showed 100% of the elderly were impaired regarding physical
      mobility. This impairment was generally related to muscular-skeletal-weakness
      (76.7%), reduced muscle resistance and strength (61.7%), neuro-muscular weakness
      (55%), besides perceptional or cognitive damage (53.3%). The most frequent
      defining characteristics were: decreased flexibility (96.7%), jeopardized
      articulations (96.7%), and inability to move in a physical environment (83.3%).

PMID- 12592782
TI  - [Death according to the social representations of health professionals].
AB  - The purpose of this investigation was to acknowledge and to analyze death
      according to the social representation of health professionals. The research was
      carried out with professionals that renders assistance to the women in the
      gestation-puerperal period. The technique of content analysis was chosen, but
      data analysis was also anchored in social representations. From the narratives of
      the subjects interviewed, death emerged as an empirical category with a social
      representation denominated as "terrible". Death, as it enters the scene, both in
      hospital or ambulatory settings, is apprehended in different ways by health
      professionals: as a terrible phase of life that is difficult to be accepted, as a
      conflict over the purpose of one's profession, as a way of seeking for mistakes
      in the procedure carried out in order to justify it, and, at this moment,
      professionals experience feelings of insecurity, incapacity, embarrassment,
      guilt, anguish, suffering and pain.

PMID- 12592783
TI  - [Production profile of a scientific journal: Revista Latino-americana de
      Enfermagem].
AB  - This article presents the production disseminated by Revista Latino-Americana de
      Enfermagem from 1993 to September 2001, the destination of the manuscripts
      submitted for publication and the description of the major problems detected by
      the editors and reviewers concerning manuscript evaluation. In spite of the
      problems detected, most of the manuscripts elaborated by nurse researchers were
      considered to be good quality and to have significantly contributed to nursing
      development. The problem that has been pointed out aims at warning authors with
      regard to some aspects that must be observed before submitting manuscripts to a
      journal for publication.

PMID- 12592784
TI  - [Program designed for the parents of babies at risk: contribution to the training
      of the nursing student].
AB  - The present study is related to the academic education of nursing students who
      participated in a public service program designed for parents of high-risk
      newborns assisted in neonatal units. It is a descriptive study that has as its
      objective to analyze the contribution of such professional experience for those
      students. The subjects of this investigation were nursing students aged 18 to 22
      years old. These students performed ludic, educational and leisure activities
      with parents of high-risk newborns assisted in a university school in the city of
      Ribeirao Preto. Data were collected by means of a questionnaires through which
      the subjects reported their experience in the project (advantages, disadvantages
      and contributions to their education). The answers were analyzed through the
      thematic analysis technique. Results showed that the program expanded students'
      view concerning nursing care and hospital care (beyond disease). It also improved
      interpersonal relationships; promoted the development of skills and the
      acquisition of knowledge and values. Thus contributing to students academic
      education and creativity.

PMID- 12592785
TI  - [Usefulness and significance of King's theory of goal attainment].
AB  - The present research focuses on the analysis model of three theories: Meleis
      Theory, Goal Achievement Theory (King, 1981) and on a study by Silveira. Its
      objective is to analyze the usefulness and social significance of King's Theory.
      After a comprehensive reading of the theories mentioned, the excerpt "Theory
      Criticism" was selected from Melei's model to serve as the analytical support.
      The study "To be naked in the intensive therapy unit: perceptions and an
      encounter" (Silveira, 1996), which has as its theoretical framework the theories
      mentioned above, was chosen. Through critical analysis, and based on the
      interaction of those constructs, we concluded that: King's Theory is useful in
      research because it propitiates perception and interpretation of objective
      subjective data from concrete reality. Its social significance is related to the
      application of the theory by representatives of several social segments. It
      encourages re-socialization of people and groups aiming at a more humane and
      solidary world.

PMID- 12592786
TI  - [Validation of the meaning of terms identified in the CIPESC project for the axis
      focus of nursing practice of ICNP].
AB  - This work aims at continuing the contribution of Brazilian nursing in the
      elaboration of ICNPa, which is being constructed by the coordination of ICN. It
      has two main objectives which are: 1) the definition of the terms identified in
      the CIPESC project and classified in the axis focus of nursing practice of the
      Nursing Phenomena Classification of ICNPa-Beta Version; 2) the validation of
      these definitions within a group of judges composed of professionals who were
      previously involved in the execution of the CIPESC project, or who were teachers
      or nurse assistants in the area of community health nursing. The process was
      carried out in two phases, considering that the definitions that had a 0.80 rate
      of Agreement (RA) within the group of judges were validated. Ninety-nine
      definitions of the terms were validated: 26 attained a RA equal to 1.00; 56
      attained a RA between 0.90-0.99 and, 17 attained a RA between 0.80 an 0.89. The
      definition of one term was not validated.

PMID- 12592787
TI  - [The customer's rights as an ethics matter].
AB  - Despite the technological progress in the health field, the symmetrical
      relationships between customers, health professionals and institutions has not
      achieved an acceptable level. This research presents a theoretical discussion on
      ethics and customer rights matters in the daily nursing service. It approaches
      the asymmetry of the relationship between health professionals and customers; the
      exchange of knowledge as a possibility of reducing this asymmetry; the users the
      of health service as consumers; bioethic and its principles; the questioning of
      daily practice as essential to ethics. It emphasizes the importance of reflection
      on the part of nurses in relation to ethic problems, in order to commit these
      professionals with the social transformations.

PMID- 12592788
TI  - [Research assisting nursing practice: a philosophical view].
AB  - The authors of the present article reflect on the difficulties of nursing
      research and its relation with its practice, which is based on the philosophy of
      praxis. Initially, there is a discussion on the relationship between theory and
      praxis from a philosophical perspective. The authors make a resumed review of
      nursing knowledge in the last century. Finally, they present the dialectic of
      interactions as a possibility of advancing beyond the territories of the
      dialectic of work. According to the authors, complex areas of knowledge related
      to health/illness/care cannot be exclusively studied by formal sciences or
      exclusively by biological and social sciences. They believe that a consistent
      epistemological project has to consider a third area that would include the
      dialectic of reasoning and the dialectic of representations.

PMID- 12592789
TI  - [A gender reading about the (re)inauguration of a female practice: from England
      to Brazil].
AB  - It is a gender reading of Florence Nightingale's main work, "Notes on Nursing:
      what is and what isn't", a book which brings together the principles and
      essential elements of modern nursing, professionalized in England in the second
      half of the XIX century and the way the profession was constituted in Brazil, as
      explicited in the work of Glete de Alcantara: "Modern nursing as a professional
      category: obstacles to its expansion in Brazilian society", the first nursing
      dissertation produced in the country, in 1963. It verified that in both
      situations the specificities of the nursing profession intermixes with that of
      the female working world.

PMID- 12592790
TI  - [The nurse as a healer of the mental patient: report of an experience].
AB  - The present paper reports the experience of a nurse who starts a process for
      recuperating the social benefits of a group of intern patients in the Psychiatry
      Institute of Santa Catarina in Sao Jose (SC). Many of the social benefits were
      taken away from these patients without their approval, and were spent, most of
      the time, by their legal curators.

PMID- 12592791
TI  - [Didactic psychodrama: strategy for the humanization of work relations].
AB  - The aim of this study is to analyze the use of pedagogical psychodrama as a
      strategy for reflecting on the humanization of health care. Five meetings were
      held from May to June 2000. In these meetings the following themes were
      developed: context of work in emergencies; updating of the personal and
      professional, individual and group reference, and acknowledgement of users. In
      view of the need of rethinking humanization in emergency care, we consider that
      the psychodrama approach alerted health professionals for the necessary
      commitment and responsibility in their work.

PMID- 12592792
TI  - The management of high-risk melanoma: staging, treatment, and nursing issues.
AB  - The incidence of malignant melanoma continues to increase. Treatment of high-risk
      disease requires a rigorous course of therapy. Nurses who care for these patients
      must understand the disease and its therapy to adequately prepare patients for
      treatment. The diagnosis, staging, treatment, and symptom management for high
      risk melanoma are reviewed.

PMID- 12592793
TI  - The necessary elements of a dermatologic history and physical evaluation.
AB  - The skin reflects the internal well-being of the body and can develop
      manifestations of systemic illness. The nurse's ability to recognize and
      accurately describe lesions can lead to prompt diagnosis and treatment of
      conditions, helping the patient to avoid discomfort, systemic illness, or death.
      To accurately describe skin findings, the nurse should know the names and
      defining characteristics of certain primary lesions.

PMID- 12592794
TI  - Smallpox vaccine revisited.
AB  - Smallpox is a serious contagious disease which is back in the public eye. Yet,
      most health care providers are unprepared for its return. Nurses will be key
      health care professionals in a smallpox outbreak or vaccination program.

PMID- 12592795
TI  - Developing a skin care pathway for pediatrics.
AB  - Pressure ulcers can be an expensive complication for children undergoing
      orthopedic corrections, contributing to admissions solely for treating skin
      breakdown. Developing a skin care pathway has increased reporting, improved
      patient teaching, and standardized wound care. The basic principles used in
      developing a skin care pathway are reviewed.

PMID- 12592796
TI  - Actinic keratoses and skin cancer.
AB  - The "Clinical Snapshot" series provides a concise examination of a clinical
      presentation including history, treatment, patient education, and nursing
      measures. Using the format here, you are invited to submit your "Clinical
      Snapshot" to Dermatology Nursing.

PMID- 12592797
TI  - Cutaneous angiosarcoma.
AB  - The "Clinical Snapshot" series provides a concise examination of a clinical
      presentation including history, treatment, patient education, and nursing
      measures. Using the format here, you are invited to submit your "Clinical
      Snapshot" to Dermatology Nursing.

PMID- 12592798
TI  - What's your assessment?
AB  - The "What's Your Assessment?" series includes a short case presentation and
      differential diagnosis. It is followed by a discussion of the disease or
      condition and the rationale used in each step of the assessment.

PMID- 12592799
TI  - Actions have consequences. Cochlear implants: an update.

PMID- 12592800
TI  - Deaf and hard of hearing Americans' instant messaging and e-mail use: a national
      survey.
AB  - An online survey of 884 deaf and hard of hearing adults asked about their current
      and past use of communication technologies, notably TTY, telecommunications relay
      services, e-mail, and instant messaging (IM). Results showed that respondents
      were using e-mail and IM far more than TTY and relay services. The study
      participants virtually all had e-mail and IM at home. In fact, about one quarter
      had a high-speed ("broadband") connection at home. While the vast majority also
      had and used e-mail at work, just 1 in 3 had IM at his or her place of
      employment. The findings have several implications. Most important for educators
      is that strong reading and writing skills are essential if adults who are deaf or
      hard of hearing are to take advantage of today's communications technologies.
      Another conclusion is that some workers who are deaf or hard of hearing appear to
      face discrimination in employment because office policies forbid the use of a
      highly effective reasonable accommodation, instant messaging.

PMID- 12592801
TI  - Assessing the employment and independence of people who are deaf and low
      functioning.
AB  - There is much variation in functional level among people who are deaf and low
      functioning. The present study focused on the work and independent living status
      of people who are deaf and have varying levels of low functioning. Each study
      participant attended a comprehensive rehabilitation facility. Information was
      collected through personal interviews. Not all interviewees were employed at the
      time of the interview, but the majority lived on their own. Those interviewees
      who worked were, on the whole, happy with their jobs. Workplace accommodations
      were virtually nonexistent, while home accommodations included television closed
      captioning, TTYs, and alarm clocks with visual or vibrating signals. Suggestions
      and guidelines are given on areas in which people who are deaf and low
      functioning may need services beyond job placement.

PMID- 12592802
TI  - Phonemic awareness and reading ability: an investigation with young readers who
      are deaf.
AB  - The study examined the relationship between phonemic awareness and reading
      ability in students who are deaf. The research questions were: (a) What is the
      relationship between phonemic awareness and reading ability in students who are
      deaf? (b) Does phonemic awareness facilitate the reading development of these
      students? Participants were 29 children of primary school age enrolled in a
      residential school for students who are deaf. The dependent variable, reading
      ability, was measured by a retelling task. The independent variables were age,
      language ability, and phonemic awareness. Language ability was determined through
      expert analysis of participant interviews. Phonemic awareness was measured with a
      word-to-word matching task. Descriptive techniques and multiple regression
      analysis were employed to analyze the data. Results indicated that reading
      ability was significantly correlated to language ability, but not to phonemic
      awareness. Phonemic awareness did not contribute to any of the variance in
      reading ability. The study results call into question the role of phonemic
      awareness as a prerequisite for reading development.

PMID- 12592803
TI  - The effectiveness of an intervention program on hearing aid maintenance for
      teenagers and their teachers.
AB  - The impact of an intervention program on hearing aid functioning and maintenance
      was evaluated. The program targeted 29 teenagers who wore hearing aids, and 7 of
      their teachers. Using an A-B-A paradigm, the researcher monitored student and
      clinician reports on the hearing aids' functioning over a 12-week period that
      began before intervention and concluded 3 weeks after intervention ended. Pretest
      and posttest student and teacher questionnaires tapped these two groups'
      knowledge and attitudes concerning hearing aids. The 6-week intervention
      comprised theoretical and practical instruction in hearing aid maintenance. The
      number of functioning hearing aids increased significantly following
      intervention, and continued to increase even after intervention ended. The gap
      between student and clinician reports on the functional status of the hearing
      aids was widest in the study's first stage and narrowest--indeed, negligible--in
      the third. The questionnaire results indicated that both students and teachers
      acquired new knowledge. The study findings underscore the need for intervention
      programs in hearing aid maintenance and their benefits to adolescent students and
      their teachers.

PMID- 12592805
TI  - [Helicobacter pylori--a challenge for medicine].

PMID- 12592804
TI  - Metacognitive ability from a theory-of-mind perspective: a cross-cultural study
      of students with and without hearing loss.
AB  - Theory of Mind (see, e.g., Bartsch & Estes, 1996) is a concept that can help
      educators understand how students think about their state of mind and that of
      others involved in various life situations. To examine the impact of culture and
      the impact of hearing loss on metacognition as explained by Theory of Mind, two
      samples of students with and without hearing losses who were from two different
      cultures were compared on their ability to choose pictures representing their
      perspectives on specific life situations. The two groups did not differ in their
      metacognitive interpretations of the experiences when they were from the same
      culture, although students from different cultures did differ, indicating that
      culture may have a greater impact on metacognition as explained by Theory of Mind
      than hearing loss. Data collected in the present study affirmed previous research
      showing that students with hearing losses could make metacognitive decisions
      about life situations just as ably as their hearing peers from the same culture.

PMID- 12592806
TI  - [Helicobacter pylori--introduction and review of research].
AB  - The discovery of Helicobacter pylori has revolutionized the pathophysiological
      and clinical approach to gastric and duodenal ulcer. Since the first paper
      identifying H. pylori was published only 17 years ago, it has been found out that
      this bacterium causes probably the commonest human infection. Numerous papers
      published so far have confirmed causal relationship between H. pylori infection
      and gastritis, duodenal ulcer, gastric ulcer and gastric cancer. If any recent
      achievement in the world of medicine is to be called revolutionary, then it is
      the discovery of the role of a spiral bacterium in the etiopathogenesis of
      gastritis, gastric ulcer, duodenal ulcer and gastric cancer. The discovery of the
      role of Helicobacter pylori has entirely changed our views and approach to the
      treatment of patients with stomach disorders. Not only do these discoveries
      change our actions, but above all our way of thinking. Almost routine diagnostics
      and treatment of gastritis, gastric ulcer or cancer has been replaced by studies
      in epidemiology, isolation and eradication of a single bacterium.

PMID- 12592807
TI  - [Epidemiology of Helicobacter pylori infection].
AB  - About 50% of adults in the developed and 80-90% in the developing countries are
      estimated to be infected by Helicobacter pylori. Being 68% nationally, this rate
      is higher in the northern continental parts of Croatia, which also have higher
      gastric cancer rates. Low socio-economic status, poor living conditions in
      childhood (the age when Helicobacter pylori is typically acquired), and exposure
      to the stomach content of an infected person are risk factors for Helicobacter
      pylori. Most of the infected are symptomless, with 10 to 20% subsequently
      developing the disease, and this mainly from peptic ulcer, asymptomatic chronic
      gastritis and chronic dyspepsia. Less than 5/10,000 become affected with
      adenocarcinoma, MALT lymphoma or primary non-Hodgkin's gastric lymphoma.
      Helicobacter pylori is under intensive study for possible association with other
      diseases. As transmission route of the infection is still unclear, any mechanism
      allowing the bacteria entry into a non-infected individual's stomach is probably
      a possibility. In addition to improved socio-economic status, eradication or
      vaccination may be contributors to the reduction in the number of the infected.

PMID- 12592808
TI  - [Helicobacter pylori--bacterial characteristics].
AB  - Helicobacter pylori lives in the gastric mucosa of about half of world
      population. H. pylori is a gram-negative, microaerophilic, facultatively
      acidophilic rod, very sensitive to drying and usual disinfectants. H. pylori
      strains show great genetic variability, the main mechanism of this phenomenon
      being in vivo genetic recombination. The principal virulence factors are:
      vacuolating cytotoxin, enzyme urease, motility, adhesive molecules on the cell
      surface, catalase and superoxide-dysmutase, receptor for human lactoferin and
      factors which promote proinflammatory cytokine secretion. Strains of H. pylori
      are sensitive to ampicillin and tetracycline; resistance to macrolide antibiotics
      is 7-15% in different parts of the world, and to metronidazole is 7-50% or even
      more. Because in vitro sensitivity of H. pylori is the most important factor for
      successful therapy, it is necessary to monitor this sensitivity continuously in a
      particular area.

PMID- 12592809
TI  - [Hormonal regulation of gastric secretion and Helicobacter pylori].
AB  - Helicobacter pylori has been recognized as one of the most important factors that
      lead to chronic changes in the gastric mucosa. These changes have either direct
      or indirect impact on various intestinal hormones (gastrin, somatostatin,
      bombensin, cholecystokinin...) which regulate gastric secretion. Gastric
      secretion enhancement is mostly caused by higher concentration of serum gastrin.
      The mechanism in which the Helicobacter pylori infection influences the
      regulation of gastrin and other intestinal hormones is yet to be discovered. It
      is known that eradication of the Helicobacter pylori infection decreases serum
      gastrin concentration, thus decreasing gastric secretion and inflammatory changes
      of the gastric mucosa.

PMID- 12592810
TI  - [Diagnosis of Helicobacter pylori infection].
AB  - The diagnostics of Helicobacter pylori infection is now one of the most important
      aspects of the diagnosis of various gastroduodenal diseases. New data have shown
      that Helicobacter pylori is a causative agent of peptic ulcer disease and an
      important factor in cancer development. Numerous diagnostic tests are now
      available. They can be divided into two groups: invasive and noninvasive tests.
      All invasive test methods are based on endoscopic examination during which biopsy
      specimens are obtained for direct (histological analysis, isolation) or indirect
      (urease test) diagnosis of Helicobacter pylori infection. Noninasive methods
      reveal the presence of Helicobacter pylori by measuring the activity of urease
      (urea breath test), then by confirming the presence of antibodies in the serum or
      saliva of the infected person or by confirming the presence of Helicobacter
      pylori antigens in the feces.

PMID- 12592811
TI  - [Helicobacter pylori--bacteriologic diagnosis and antibiotic sensitivity tests].
AB  - Bacteriological diagnosis of Helicobacter pylori consists of culture from gastric
      biopsies, gastric juice, faeces and from specimens obtained from oral cavity,
      antigen stool assay and molecular diagnostic methods. In routine work culture is
      done from gastric biopsies. Other specimens are usually cultivated for research
      purposes. Culture constitutes the most specific way to establish the diagnosis of
      H. pylori infection. One of the major advantages of culture is that it allows
      sensitivity testing to drugs used in therapy. Culture also allows
      characterisation of H. pylori. Antigen stoll assay is a non-invasive diagnostic
      procedure, which should be evaluated. Molecular methods have confirmed their
      potential for epidemiological research and for the detection of resistant H.
      pylori, especially for macrolides. The clinical settings, local availability and
      economic considerations should guide use of bacteriological diagnostic methods.

PMID- 12592812
TI  - [Serodiagnosis of Helicobacter pylori infection].
AB  - Infection with Helicobacter pylori induces antibodies, but these are not able to
      eradicate the bacterium from the gastric mucosa. Enzyme linked immunosorbent
      assay is the laboratory based method and most commonly used to measure
      qualitatively and quantitatively anti-Helicobacter pylori antibodies of different
      immunoglobulin classes in almost all infected patients. Quantitative serological
      tests are useful in the follow-up of eradication therapy. Serology is the method
      of choice in population studies and in the retrospective analysis of stored serum
      samples to study the natural course of this chronic infection.

PMID- 12592813
TI  - [The urea breath test].
AB  - Helicobacter pylori is infective cause of peptic ulcer and a risk factor for
      gastric carcinoma. The discovery of the bacterial ed to importance of finding a
      new reliable and inexpensive diagnostic method for detection of infection before
      and after eradication therapy. Urea breath test is isotope based test. It has
      become the most specific and sensitive method in detection of Helicobacter pylori
      infection, therefore many other isotope based tests become popular in diagnostic
      of gastrointestinal diseases. Because of its simplicity and no need in using
      endoscopy in the procedure it is very popular in primary diagnosis and in
      controlling eradication. It is successfully used in diagnostics of Helicobacter
      pylori and bacteria eradication success testing, where it is one of most reliable
      diagnostic methods.

PMID- 12592814
TI  - [The rapid urease test].
AB  - Today there are many methods in diagnostics of Helicobacter pylori infection.
      They are divided in two major groups based on using of endoscopy (invasive and
      non-invasive methods). Helicobacter pylori bacteria are specific because of
      having very big amounts of urease enzyme that divides urea on NH3 and CO2 which
      enables environment suitable for survival. Rapid ureas test is based on detecting
      of the enzyme activity. Because of its simplicity and high sensitivity and
      specificity it belongs to methods that are used in every day practice in
      endoscopic laboratories.

PMID- 12592815
TI  - [Morphology of gastritis and Helicobacter pylori infection].
AB  - Helicobacter pylori infection almost invariably results in chronic gastritis. The
      Sydney System (1990) emphasised the importance of combining topographical,
      morphological and etiological aspects in attempt to make clinical useful
      diagnosis of chronic gastritis. The aims of revised Sydney System in Houston
      (1994), Texas, were to improve terminology of chronic gastritis emphasising
      distinction between nonatrophic and atrophic gastritis, and in addition to
      determinate special forms of gastritis. The special forms of gastritis were
      described and diagnostic criteria were provided. Principles and grading of
      histological division of Sydney System were only slightly modified, grading being
      improved by the provision of a visual scale. Endoscopy and histological findings
      of 1062 patients from University Hospital Merkur were compared to evaluate the
      value of endoscopic division of Sydney System, and the modified grading proposed
      by Houston classification. There was no correlation between endoscopic and
      histological findings. Localisation of inflammatory cells was either 1)
      superficial or 2) diffuse in the mucosa, respectively. In Helicobacter pylori
      positive patients the most common finding was chronic active gastritis, and in
      Helicobacter pylori negative superficial and inactive chronic gastritis.

PMID- 12592816
TI  - [Gastric ulcer and Helicobacter pylori infection].
AB  - Helicobacter pylori infection and the use of non-steroidal anti-inflammatory
      drugs (NSAID) are considered to be the two major risk factors implicated in the
      development of gastric ulcer. Helicobacter pylori infection related chronic
      gastritis is known to be the underlying condition which may lead to gastric
      ulcer. Development of gastric ulcer as the consequence of underlying chronic
      gastritis is caused by many factors. Treating Helicobacter pylori infection
      entails the healing of gastric ulcer, it concomitantly prevents recurrences and
      complications of gastric ulcer, primarily bleeding, and changes the natural
      course of gastric ulcer disease. Continuation of antisecretory maintenance
      treatment beyond ulcus healing and eradication of Helicobacter pylori infection
      is only indicated in risk groups. Patients with gastric ulcer caused by NSAID use
      are managed with antisecretory therapy.

PMID- 12592817
TI  - [Duodenal ulcer and Helicobacter pylori infection].
AB  - The research accomplishment of Australian investigators Marshall and Warren,
      published in 1983, has entirely changed our understanding of ulcer genesis and
      proposed a new strategy in diagnostics and therapy of peptic ulcer disease. The
      key etiopathogenetic role of Helicobacter pylori has been recognised. Marshall
      confirmed on himself that Helicobacter pylori, as an infectious agent, fulfilled
      all Koch's postulates. The bacterial infection caused the mucosal inflammatory
      changes in his stomach which were rapidly resolved by antibiotics. During later
      clinical and experimental investigations the association of Helicobacter pylori
      and peptic ulcer has also been proved. Etiopathogenetic influence of Helicobacter
      pylori infection on duodenal ulcer development is nowadays very well known.
      Diagnostic guidelines, the modes of treatment and clinical management of these
      patients are mostly precisely defined. In this article, besides the general
      review of modern knowledge about Helicobacter pylori infection concerning
      epidemiology, etiopathogenesis, diagnostics and duodenal ulcer therapy, we are
      going to present also our results in the management of the large group of
      patients with duodenal peptic ulcer or ulcer scars.

PMID- 12592818
TI  - [Gastroesophageal reflux disease and Helicobacter pylori infection].
AB  - Gastroesophageal reflux disease (GERD) is one of the common diseases of the upper
      gastrointestinal system. It is present in the whole world population, especially
      frequent in the developed countries. It evolves from pathological reflux which
      exposes the esophagus to the gastric contents which must overcome esophageal
      defense system. Many factors have been found to be involved in the pathogenesis
      of GERD; the most important one is the relaxation of the lower esophageal
      sphincter. Intensity of the disease is proportional to the amount of gastric
      contents refluxing from the stomach and the duration of esophageal exposure to
      this contents. GERD is currently in the spotlight because of its special
      significance in the development of very specific disease in the lower part of the
      esophagus--Barrett's esophagus, as well as esophageal adenocarcinoma which has
      lately been increasing in prevalence. Today, unrecognized and inadequately cured
      GERD is known to be a high risk factor for adenocarcinoma of the esophagus. In
      recent years the relation between GERD and Helicobacter pylori infection has been
      the topic of investigation by many prominent researchers. Therapy of GERD is
      based on inhibition of acid secretion. There are many different therapeutic
      agents available, however, proton pump inhibitors (PPI) are considered to be the
      most effective in the treatment of this disease.

PMID- 12592819
TI  - [Helicobacter pylori and malignant diseases of the stomach].
AB  - The association between Helicobacter pylori infection and gastric malignancies,
      cancer and MALT lymphoma, has been suggested through several lines of evidence
      during the last decade. Although unresolved issues still cast doubts on the real
      weight of these association, in the sequence of events that leads to gastric
      cancer or lymphoma, Helicobacter pylori appears to play a prominent role in the
      very initial steps as causative agent of chronic gastritis. The subsequent events
      in the sequence--atrophy, intestinal metaplasia, dysplasia and cancer are
      multifactorial involving environmental agents, host response and characteristics
      of the bacterial strain itself. Recognition of the causal role of Helicobacter
      pylori infection in the cancer induction theoretically presents tools for its
      prevention. The ongoing studies will show in the future whether eradication or
      prevention of infection are followed by a reduction in risk of cancer. Lymphomas
      arising from gastric mucosa-associated lymphoid tissue (MALT) may be a clonal
      evolution starting from the infection. In low-grade gastric MALT lymphoma cure of
      the infection induces complete remission in the majority of patients. Longer
      follow-up investigations are necessary to determine if remissions indicate a cure
      of the disease.

PMID- 12592820
TI  - [Non-ulcer dyspepsia and Helicobacter pylori infection].
AB  - In this article we reviewed experiences in approach and procedure with dyspepsia,
      with special accent on non-ulcer dyspepsia and Helicobacter pylori infection.
      Dyspepsia makes around 50% of gastroenterology cases. In 20% of cases it is
      caused by peptic ulcer disease and in 50% of cases non-ulcer dyspepsia. Around
      50% of non-ulcer dyspepsia is followed by coexistent Helicobacter pylori positive
      gastritis. Dyspepsia followed by alarming symptoms in patients who are over 55
      years old or in patients who are using NSAID indicated urgent endoscopic
      procedure--gastroscopy. In other patients non-invasive testing on Helicobacter
      pylori infection is recommended where eradication therapy should be applied in
      Helicobacter pylori positive and empirical cure by antisecreting drugs or
      prokinetics in Helicobacter pylori negative patients. Final gastroscopic
      evaluation is indicated after unsuccessful therapy. Ceasing of non-ulcer
      dyspeptic symptoms could be predicted in 20% of patients with cured Helicobacter
      pylori infection.

PMID- 12592821
TI  - [Extra-gastrointestinal tract diseases and Helicobacter pylori infection].
AB  - Helicobacter pylori infection is linked to conditions of the upper
      gastrointestinal tract, including peptic ulcer and gastric adenocarcinoma na MALT
      lymphoma. It has also been associated with wide variety of extragastric and non
      gastrointestinal conditions. However, the evidence in support of Helicobacter
      pylori infection as a cause of the non-gastrointestinal tract diseases is not
      widely understood. We reviewed the medical literature in regard to putative
      association of Helicobacter pylori infection and non-gastrointestinal tract
      condition, notably cardiovascular, autoimmune and dermatological diseases. The
      majority of published papers examining the potential causal relationship were
      case-control studies, cross-sectional and cohort studies while only a few recent
      articles that did not confirm the evidence of causal relationship represent well
      designed population-based prospective studies. The lack of clear evidence for
      etiopathogenetic associations of Helicobacter pylori infection and non
      gastrointestinal tract conditions should focus our attention on appropriate
      testing and treatment of Helicobacter pylori infection in patients with
      conditions that are of proven association such as peptic ulcer disease.

PMID- 12592822
TI  - [Specific aspects of Helicobacter pylori infection in childhood].
AB  - Helicobacter pylori, like most enteric infections, usually is acquired in
      childhood, and is carried for lifetime in the majority of infected individuals.
      While the infection results in chronic inflammation of gastric mucosa in all
      infected persons, some individuals will subsequently develop duodenal ulcer, and
      in some the disease can progress to dysplasia and carcinoma. On the other hand,
      duodenal ulcer and gastric cancer are not the problems associated with childhood
      age, and H. pylori associated gastritis does not appear to be the cause of any
      symptoms in children. However, there are data about the increased risk for
      developing malignant gastric disorders especially if the infection was long
      lasting, i.e. was acquired in childhood. The aim of this article is to present
      the specificity of the infection of Helicobactery pylori in childhood, regarding
      the epidemiology, clinical presentation, diagnostic procedures and the treatment.

PMID- 12592823
TI  - [Helicobacter pylori--overview of therapy].
AB  - The clinical significance of Helicobacter pylori infection in the
      etiopathogenesis of many gastroduodenal disorders, especially peptic ulcer
      disease and current awareness of the benefits of its eradication has entirely
      changed the current treatment of these diseases. Eradication was already defined
      as the disappearance of Helicobacter pylori from the gastric mucosa (finding
      negativization) confirmed at least 4 weeks (or later) after completed antibiotic
      eradication therapy. The regimen has to be simple, cheap and tolerable so that
      the patient could carry it out completely and as easy as possible (good
      compliance is required). The success of Helicobacter pylori eradication,
      evaluated by the strict "intention-to-treat" criteria, has to be higher than 80%.
      Current modern therapy should be triple and not longer than 7 days. One of three
      proton pump inhibitors is recommended as the antisecretory component (omeprazole,
      pantoprazole or lansoprazole). Two of three following antibiotis is added to this
      therapy: metronidazole/tinidazole, clarithromycin or amoxicillin. Treatment
      failure and growing number of antimicrobial resistant Helicobacter pylori strains
      require new ways of therapy and more effective drugs. Our results of 7-, 10- and
      14-day therapy consisting of omeprazole, amoxicillin and metronidazole are poorer
      than those of drug combination including clarithromycin instead of amoxicillin.
      The results of Clinical Hospital "Merkur" showed that combination of amoxicillin,
      metronidazole and pantoprazole was more effective than the same combination with
      omeprazole, and the opposite was true for metronidazole and azithromycin combined
      with omeprazole and pantoprazole, respectively. The results of other medical
      centers prescribing the same eradication protocols were completely different. The
      differences are probably caused by poor patient compliance.

PMID- 12592824
TI  - [A vaccine against Helicobacter pylori infection].
AB  - Oral immunization with the urease of Helicobacter pylori was shown to induce
      protection against Helicobacter felis in mice. The first identification of a
      protective antigen (urease) was followed by the identification of the protective
      antigens, such as the heat-shock protein (HspA) and the vacuolating cytotoxin
      VacA. The final selection of the antigens to be used in a vaccine depends on the
      conservation of these antigens among Helicobacter pylori strains, their role as
      virulence factors and conservation of their immunogenic properties when expressed
      as recombinant proteins. Furthermore, therapeutic immunizations were also
      effective in eradication of Helicobacter from chronically infected animals. These
      encouraging results imply that immunization may also be useful in the therapy of
      Helicobacter pylori infection in humans. In this review, preliminary data and
      directions for future research on Helicobacter vaccines are described.

PMID- 12592825
TI  - No shortage of excuses. Nurses worry that health care industry will use staffing
      crisis to replace RNs.

PMID- 12592826
TI  - Republican-controlled Congress presents challenges for nursing issues. ANA-PAC
      succeeds in getting pro-nurse candidates elected.

PMID- 12592827
TI  - Know your rights. ANA's Bill of Rights arms nurses with critical information.

PMID- 12592828
TI  - Using calcium sulfate as a graft enhancer and membrane barrier. [Interview].

PMID- 12592829
TI  - Neighborhood disorder, individual protective factors, and the risk of adolescent
      delinquency.
AB  - Traditionally, violent and delinquent behaviors have been addressed by the
      criminal justice system, with the focus being secondary and tertiary
      interventions. During the last decade, the focus on violence as a public health
      issue has increased. The purpose of this research was to examine how individual
      protective factors for adolescent delinquency varied according to neighborhood
      quality. The researcher conducted a secondary data analysis, using data from the
      National Youth Survey A total of 1,621 adolescents comprised the sample. The
      majority of the respondents participated in some type of delinquent behavior,
      with more Blacks reporting participation in violent behaviors. There was a
      positive relationship between academic history and no participation in delinquent
      behavior. The regression model for violent delinquency accounted for 10% of the
      variance in the disordered neighborhoods. Primary prevention efforts, commonly
      used by public health nurses, should be aimed at eliminating risk factors such as
      those found in disordered neighborhoods.

PMID- 12592830
TI  - Spiritual expressions in the caring environment of adult day care centers.
AB  - Adult day care, an increasingly important community-based service for adults who
      need supervision and assistance with basic needs, is particularly important for
      African-American families in whom the placement of family members in institutions
      has traditionally been viewed as an unacceptable option. Actual utilization of
      adult day care services depends on the creation of a caring milieu in the
      centers, and one important element is the opportunity for spiritual expression. A
      recent ethnographic study explored factors influencing care expressions, patterns
      and practices in two adult day care centers with predominantly African-American
      clients and staff. The study findings included unique examples of indigenous
      spiritual expressions that had evolved in the cultural milieu of the centers, and
      provided the basis for recommended strategies to incorporate spirituality in
      adult day care and other clinical settings.

PMID- 12592831
TI  - Concerns of hospice patient caregivers.
AB  - This descriptive study examined the needs and concerns of caregivers who provide
      care for patients at home, and who are also receiving hospice home care. Services
      that caregivers need to provide this care was also identified. The settings were
      two Midwestern, suburban hospices. Thirty-three caregivers participated. Nine
      participants were males and 24 were female. Ages ranged from 20 through 80 years.
      Caregivers completed a 28-item semi-structured questionnaire developed by the
      researchers. Demographic information and caregiver problems with symptom
      management, time spent giving care, hospice services utilized, other sources of
      support and assistance were assessed. Open-ended items asked about caregivers'
      stress levels and about problems that were not resolved by hospice. The study
      found that the distressing symptoms caregivers found most difficult to manage
      were constipation, confusion, and anorexia. Caregivers identified lack of
      mobility and loss of bladder control most frequently as unmanageable symptoms. A
      majority of respondents identified the hospice nurse as their main source of
      information regarding care and resource needs and often cited the nurse as a
      source of emotional support. Sixty-four percent reported that they provided care
      12-24 hours per day with some respite from family members. Results of the study
      indicate that caregivers spend a large amount time with the hospice patients
      despite use of hospice services and assistance from family members. This can lead
      to high stress levels and exhaustion. There is a need for more respite care for
      caregivers. Hospice provides caregivers with needed support, both emotional and
      with the care itself.

PMID- 12592832
TI  - Childhood obesity reduction by school based programs.
AB  - Childhood obesity has become one of the most common health problems facing
      children in America. Results from the Third National Health and Nutrition
      Examination Survey reveal that ethnic minority children in the United States are
      at particular risk for development of cardiovascular disease due to their
      disproportionate levels of obesity. In treating childhood obesity among ethnic
      minorities, practitioners need to be mindful of the cultural norms surrounding
      body size. Additional concerns that must be addressed include the effects of
      target marketing of unhealthy foods toward ethnic minorities and environmental
      deterrents to outside physical activities, to name a few. Strategies given to
      address the problem of childhood obesity among ethnic minorities include,
      increasing the child's physical activity, reducing television viewing and the
      adoption and maintenance of healthy lifestyle practices for the entire family.

PMID- 12592833
TI  - Cultural competence: an evolutionary perspective.
AB  - PROBLEM: The need for conceptual clarity, which is essential for effective
      communication related to cultural competence. Practice, education,
      administration, and research are identified. METHODS: Rodgers' (2000) method of
      concept analysis. FINDINGS: Attributes of cultural competence were identified as
      cultural awareness, cultural knowledge, cultural understanding, cultural
      sensitivity, and cultural skill. CONCLUSIONS: Cultural competence can best be
      identified as a nonlinear dynamic process that is never ending and ever
      expanding. It is built on increases in knowledge and skill development related to
      its attributes.

PMID- 12592834
TI  - Concept analysis of comfort.
AB  - TOPIC: The concept of comfort, although used frequently and throughout the
      nursing literature, has not been clearly or consistently defined. PURPOSE: To
      clarify the meaning of comfort by employing the systematic approach of an
      evolutionary concept-analysis method. SOURCES: Books, journals, professional
      organization position statements, electronic searches. CONCLUSIONS: A clear
      definition and meaning of comfort is needed, and thus the ability to use this
      concept empirically in order to further nursing knowledge development.

PMID- 12592835
TI  - Critique of transcultural practices in end-of-life clinical nursing practice.
AB  - TOPIC: Transcultural nursing practices for terminally ill patients. PURPOSE: To
      examine several criticisms of transcultural nursing theory in end-of-life care.
      SOURCES: Published literature and interviews with nurses. CONCLUSIONS: Nurses
      often encounter barriers that impede their ability to provide ideal end-of-life
      care.

PMID- 12592836
TI  - Reflections on practice: why choose nursing?

PMID- 12592837
TI  - The NCLEX examination: getting the correct answers.

PMID- 12592838
TI  - CDC releases guidelines for hand hygiene.

PMID- 12592839
TI  - ARNP licensure in Florida.

PMID- 12592840
TI  - Highlighting the Eleanor Bindrim scholarship.

PMID- 12592841
TI  - Making healthcare safer for all.

PMID- 12592842
TI  - Bioethics focus group survey results.

PMID- 12592843
TI  - FIU school of nursing is recipient of Harvey cardiology patient simulator.

PMID- 12592844
TI  - UF nursing researchers to study Florida's public health role in STD control and
      prevention.

PMID- 12592845
TI  - The impact factor of scientific journals.

PMID- 12592846
TI  - Case management: evolution of the concept in the 80's and 90's.
AB  - Case Management is a term that is present in almost every American health care
      situation. It is mostly used to coordinate community services with satisfactory
      results for the patient within a certain period of time, with limited resources.
      Through time, it has been used for different purposes. The goal of this study was
      to show the historical evolution of case management as expressed by the American
      nursing literature, in the 80's and 90's, according to its use, meaning, and
      application, and following a theoretical framework for concept analysis. The data
      was extracted from two journals: "Nursing Management" and "Journal of Nursing
      Administration". The publications showed case management portrayed as a process
      that serves a common goal; where quality and cost of care were the prevalent and
      influential elements along time, and its practice focusing in a given population
      defined as of high risk and high cost for health care.

PMID- 12592847
TI  - [Profile of nurses who work in the care of pregnant, parturient, and puerperal
      women at institutions in Sorocaba/SP (1999)].
AB  - This study aimed at verifying the institutions where pregnant, parturient and
      puerperal women were given care. It also aimed at identifying the nurses who
      participate in such caregiving, the activities performed and the problems faced
      by them and their level of satisfaction at work. Seventy-four nurses were
      interviewed in the 35 institutions found in Sorocaba, of whom 27% were
      specialists and 28% were qualified obstetricians. The others had not been trained
      in that area. The major problems reported were the lack of skills to perform
      prenatal nursing consultations, shortage of staff and materials and the
      accumulation of. Seventy-three percent of the interviewees reported to be
      satisfied in relation to their jobs.

PMID- 12592848
TI  - [Women in labor and obstetrics team: difficult art of communication].
AB  - This study aimed at describing how communication is established between
      professionals assisting low-risk childbirth and women experiencing the
      parturition process. The results obtained from participant observation and
      interviews with the puerperae showed that the quality of communication is
      impaired and there is the prevalence of non-therapeutic communication. Technicism
      dominates and is permeated by a low level of perception and sensitivity with
      regard to the actual needs of women in labor. The management of labor and
      childbirth was most often the simple execution of technical procedures.

PMID- 12592849
TI  - [Follow up of obstetric nurses graduated from training and specialization courses
      in obstetric nursing at the nursing school of the University of Sao Paulo].
AB  - The purpose of this study was to show the prevalence of characteristics in former
      students from the Specialization Course on Obstetric Nursing of the University of
      Sao Paulo College of Nursing, Brazil. The population consisted of 92 former
      students who graduated in 1980 to 1985, of whom 50% worked in the field of
      obstetric nursing. Of these, 73.2% were clinical nurses and 26.8% were university
      faculty. Concerning those who no longer performed in that field, 76.0% did so
      after graduation and 24.0% never worked in the area. Regarding professional
      satisfaction, 71.7% reported to be satisfied and 28.3% were dissatisfied. The
      reasons given for stopping working in that area suggest very important points to
      be analyzed professional representation entities as well as by those who are
      responsible for the education of these professionals.

PMID- 12592850
TI  - [Health profile of workers at a teaching health center].
AB  - The purpose of this study was to describe the health profile of the 184 workers
      employed in a Teaching Health Center in the city of Ribeirao Preto from the
      viewpoint of Health Promotion, using Blum's Epidemiological Model and the risk
      factors related to chronic-degenerative diseases. A descriptive study was carried
      out using a structured interview. The authors of the study concluded that the
      workers were mainly females at the age range of 35 to 39 years with a college
      degree. The results showed that 61.9% were overweight or obese; hypertension was
      detected in 33.1%; 41 (22.3%) had blood pressure above normal levels and obesity
      was present in more than half of the individuals with altered blood pressure. The
      data enabled the authors to explore the presence of self-created risks for
      chronic-degenerative diseases, to identify factors related to health promotion
      and disease prevention as well as to reflect about workers' self-care and self
      responsibility concerning their health, aiming at the quality of life they will
      enjoy as a result of the demographic and epidemiological transition that we are
      currently experiencing.

PMID- 12592851
TI  - [Authoritarianism and benevolence towards mental illness: study with beginning a
      nursing program].
AB  - Students beginning a nursing program tend to show negative attitudes towards
      mental health patientsm as does the general population. This study aimed at
      studying these students' authoritarianism and benevolence towards mental patients
      utilizing the opinion scale about the mental illness. The results indicated that
      the students showed authoritarianism towards mental patients with a tendency to
      protective behavior, which enabled the conclusion that these aspects must be
      considered in the elaboration of the course programs in this area in order to
      lead them to more therapeutic conducts in the future.

PMID- 12592853
TI  - [Medication errors and consequences for nursing professionals and clients: an
      exploratory study].
AB  - The purpose of this study was to analyzed the consequences for the patients and
      professionals involved in medication. The author adopted as the methodological
      reference the Critical Incident Technique modificated. The study was developed at
      a University Hospital at the state of Sao Paulo, Brazil. Data were collected
      through interviews with 7 nurses, 4 nursing technicians and 23nursing
      auxillaries. The analysis enabled the identification consequences for the patient
      and consequences for the professional involved.

PMID- 12592852
TI  - [Developing people: teaching strategies to promote self-knowledge in nursing
      education].
AB  - This is a study elaborated on the basis of the course Mental Health-I, about the
      nurse formation through self-knowledge motivation. The goals were, to reflect
      about self-knowledge as a tool in the nurse formation and to analyze didactic
      strategies to facilitate its development. The data was collected during the
      course using written registers, self-evaluation and course evaluation. Results
      showed that the student has the opportunity to develop her/his self-knowledge
      given that some teaching techniques stimulate the contact with personal issues,
      facilitating the discovery of potentiality for the professional practice. We
      concluded that the course has been playing a fundamental role in the nurse
      education.

PMID- 12592854
TI  - [Evaluation of the adaptation process in elderly patients with arterial
      hypertension].
AB  - We objectified to evaluate the adaptive process of an old-aged person who carries
      arterial hypertension, establishing nursing diagnoses and implementing nursing
      actions. The study stages were developed at home, being used for the data
      collection an Roy's model based instrument. After the behaviors and stimulus
      evaluation, six diagnoses were elaborated: restricted mobility, gait, and/or
      coordination; impairment of a primary sense; sleep deprivation; low self-esteem;
      role transition and loneliness. We concluded that the nursing goals and
      interventions were important, once that allowed in a general way, the ineffective
      responses substitution for adaptive ones.

PMID- 12592855
TI  - [The "To Live in Cascavel" project: analysis of the information flow].
AB  - This study estimated and evaluated the time period (in days) concerning the flow
      of Live Birth Declarations (DNV) for high-risk newborns assisted by the Project
      "Living in Cascavel"-Parana, Brazil, from 1996 to 1998, according to organization
      sites (hospital, epidemiological surveiliance service, basic health unit). Three
      hundred and three declarations were analyzed, and in order to analyze the flow
      time of the DNVs, 95% confidence intervals were constructed for the medium
      population times (in days). Results showed that the DNVs took 25 to 30 days to
      flow from the hospital until the moment when the home visit occurred. The care to
      high-risk newborns must take place in the shortest possible time; therefore, the
      flow time of DNVs found in this study, from birth until the home visit, may
      hinder the achievement of one of the objectives proposed by the project in
      question, which is the reduction of infant morbi-mortality in the municipality.

PMID- 12592856
TI  - [Complications and incidents associated with arm edema in the first 3 months
      after mastectomy].
AB  - This study aimed at identifying complications, intercurrences and the appearance
      of edema following breast cancer surgery as well as factors that could predispose
      to arm lymphedema on the operated side. It is a descriptive and prospective study
      based on a quantitative approach. The subjects consisted of 17 women submitted to
      unilateral mastectomy in a University Hospital. Data were collected by means of a
      weekly post-operative follow-up of each patient for a period of three months.
      Edema was detected in 11 women, nine of which were in mild level and two in
      moderate level. It must be emphasized that even mild-level edema could become
      severe if not treated appropriately. Among the women with edema, complications,
      intercurrences and other variables were observed. The results revealed the
      importance of nurse follow up during the mastectomy post-operative period as well
      as the need for better staff training for patient guidance aiming at edema
      prevention.

PMID- 12592857
TI  - [Children and adolescents with chronic disease: living with changes].
AB  - This study concerns descriptive and exploratory, with aimed at apprehending by
      means of interviews the experiences of children and adolescents with a chronic
      disease, as it is felt by them. The results show that the lives of children and
      adolescents are changed by frequent hospitalizations and by the limitations
      imposed by the disease, which causes alterations particularly in their schooling
      process. Considering that children and adolescents experience complex feelings
      and situations in the everyday routine of living with a chronic disease, it is
      important that health care professionals learn about such needs and incorporate
      them to care planning, aiming at providing effective intervention in order to
      promote growth and development.

PMID- 12592858
TI  - [Circumstances of the formalization of the nursing assistant course in Brazil:
      studying between the lines the 775/49 law].
AB  - The objective of this study is to discuss the circunstances that determined the
      incorporation of nursing assistant course at the law number 775/49. Thus we tried
      to understand the brasilian scene and the politics of hospital health during the
      period of president Dutra's government and the hospital conditions at that time.
      The laws and edicts about nursing between 1945 and 1949 are fundamental sources,
      documents from CD/EEAN/UFRJ and nurses deposition about this question. The first
      documents analised showed nursin staff insufficiency and the conflict between
      nurses wish to maintain a high level education and the responsability to supply
      the demand of nursing personal. The law officialized a course what informaly
      already existed.

PMID- 12592859
TI  - [Scientific production about occupational accidents with needle-stick devices
      among nursing workers].
AB  - This study has the purpose to identify methodological approaches used in research
      articles published in the last 16 years by periodicals indexed to the Lilacs and
      Medline databases. The authors searched for studies on occupational accidents
      with needlestick materials in order to identify the facts that predispose this
      kind of accidents among nursing workers. Fifty-five articles were analyzed of
      which thirty-nine were international and sixteen were national. The most
      frequently used methodological approaches were field description, action research
      and bibliographic research. Among the factors that predispose this kind of
      accident in various countries, the inadequate practice of recapping needles and
      inadequate material disposal can be distinguished.

PMID- 12592860
TI  - [Revisiting early weaning through history].
AB  - The basic action of health requests addressed strategy as taking consciousness to
      the importance of the breastfeeding. The breastfeeding history shows a hiatus as
      the people worked with precocious wean. The aim of this study was revisit
      precocious wean through historical breastfeeding clipping. Bibliographical
      revision methodology was used. The samples consisted by books, monographs,
      thesis, dissertations, texts published in scientific magazines were consulted and
      scientific article was captured through Internet in the period from 1978 to 1998,
      that portray histories from mythological time to the most current centuries. The
      revision pointed that weans is built partner-culturally. The woman to maintain
      the maternal breast-feeding needs not only support family and social but also
      government support.

PMID- 12592861
TI  - [Professional image and identity in the building of nursing knowledge].
AB  - Based on a historic qualitative study, using documental analyse we searched for
      the dispersions in the construction of knowledge in the articles of the Anais do
      Congresso Brasileiro de Enfermagem, from 1977 through 1987. The dispersions
      emerged as categories that repeat themselves as subjects of note or as smaller
      punctuation. Our analyze converged into two main categories: professional image
      and professional identity. These categories took the shape of a complex and
      dynamic network, in which there were two explicit sub-categories: professional
      status and professional role.

PMID- 12592862
TI  - [Setting up a new teaching proposal on the nursing course at the University of
      Londrina].
AB  - The article had as its main goal to outline the history of the Nursing Curriculum
      of the State University of Londrina since its begining in 1972 until the present
      Curriculum, started in January 2000. The studying is based on a bibliographic
      research and the result has enabled us to outline all the changing process of the
      curriculum considering the professors disquiet and the work market demands. The
      studying, after substantiating all the curriculum changes, has contributed to
      better understand the pedagogical proposal that form the present integrated
      Curriculum of the Nursing Course of the State University of Londrina.

PMID- 12592863
TI  - Philip A. Newbold, FACHE, president and CEO, Memorial Hospital and Health System,
      South Bend, Indiana. Interview by Kyle L. Grazier.

PMID- 12592864
TI  - New ways of thinking about career success.

PMID- 12592865
TI  - Strategic positioning: where does your organization stand?

PMID- 12592866
TI  - The roles of senior management in quality improvement efforts: what are the key
      components?
AB  - With increasing attention directed at quality problems and medical errors in
      healthcare organizations, the ability of senior management to promote and sustain
      effective quality improvement efforts is paramount to their organizational
      success. We sought to define key roles and activities that comprise senior
      managers' involvement in improvement efforts directed at physicians' prescription
      of beta-blockers after acute myocardial infarction (AMI). We also developed a
      taxonomy to organize the diverse roles and activities of managers in quality
      improvement efforts and proposed key elements that might be most central to
      successful improvement efforts. Results are based on a qualitative study of 8
      hospitals across the country and included in-depth interviews with 45 clinical
      and administrative staff from these hospitals. The findings help identify a
      checklist that senior managers may use to assess their own and others'
      participation in quality improvement efforts in their institutions. By
      reinforcing their current involvement or by identifying potential gaps in their
      involvement in quality improvement efforts, practitioners may enhance their
      effectiveness in promoting and sustaining quality in clinical care.

PMID- 12592867
TI  - The long-term costs of career interruptions.
AB  - This article is based on a study that analyzed the long-term salary implications
      of career choices made by healthcare administrators. The study used a cohort of
      graduates from a single health administration program; these individuals had
      comparable levels of human capital at the outset of their careers. We estimated
      the effect of periods of part-time employment and job interruptions--voluntary
      and involuntary--on long-term salary progression. We also estimated the impact of
      other career choices, such as membership in a professional organization or the
      decision to relocate. After controlling for these choices, we estimated the
      residual effect of gender on salary. We found that voluntary interruptions had a
      greater effect on long-term salary growth than did involuntary interruptions of
      the same length or periods of part-time employment. Individuals evaluating
      options for balancing career and family constraints should understand the long
      term cost of choosing a career interruption rather than part-time employment
      during periods of heightened responsibilities outside the workplace. Healthcare
      administrators should also be educated about the positive association between
      professional memberships and career advancement to make informed decisions about
      participation in such organizations. Surprisingly, after controlling for all
      choice variables, gender had no measurable effect on long-term salary growth.
      Half of those who indicated a voluntary interruption for dependent care reasons
      preferred part-time or flexible-hour work if it had been available. These results
      suggest that a pool of healthcare administrators might compete for positions if
      more part-time opportunities were available.

PMID- 12592869
TI  - The development of a customer excellence master plan.

PMID- 12592868
TI  - Understanding organizational designs of primary care practices.
AB  - During the past decade, many hospitals experienced difficulty integrating primary
      care practices into their health systems. We hypothesized that this difficulty
      may be, in part, a result of limited understanding of practice organizational
      designs. The structure and function of practices have not been well studied. In
      this article, we answer the following questions: Are practices all the same, or
      do variations in their organizational design exist? Do hospital designs predict
      the designs of affiliated practices? If variation exists, what are the management
      implications? Eighteen family practices, including nine affiliated with five
      separate hospital systems, were studied using an in-depth comparative case study
      design. A content analysis of the rich descriptive data from these cases
      indicates that a great variety exists in the organizational design of primary
      care practices, and this variety appears to be influenced by the initial
      conditions under which the practice was organized. Hospital system design in and
      of itself did not predict the design of affiliated practices. In fact, both
      affiliated and independent practices exhibited a range of design characteristics,
      some of which did not fit traditional models. Hospital systems that allowed
      greater flexibility of practice organizational designs were more effective at
      integrating and managing practices. Practices response to environmental change
      was greater when practice autonomy was highest. These findings suggest that a
      science of practice organizational design separate from that of hospitals is
      needed to help explain the success and failure of practices within health systems
      and to provide information for planning practice change.

PMID- 12592870
TI  - Using benchmarking to manage your laboratory.
AB  - How does your cost per test compare with the competition? Does your productivity
      measure up? Benchmarking data provide the answers, but you may not realize just
      how far the information can go. In times of budget cuts, comparing your
      laboratory operations with the best performers can be crucial. The Virginia
      Commonwealth University Health System (VCUHS) Pathology Department in Richmond,
      Virginia, demonstrated that benchmarking is more than a paper exercise. It
      literally saved the laboratory. The keys were clarification, consistency, and
      communication.

PMID- 12592871
TI  - Integration of a statewide public hospital laboratory system.
AB  - Louisiana operates one of the largest public hospital and clinic systems in the
      nation, consisting of nine geographically dispersed hospitals, providing a full
      range of medical care to approximately 1 million low-income and indigent
      citizens. For many years, these hospitals were under the auspices of the State
      Department of Hospitals. In 1997, just at the end of a multi-million-dollar
      procurement project to install laboratory information systems at several of the
      sites, governance of the nine hospitals was transferred formally to Louisiana
      State University (LSU) under a new branch, the LSU Health Care Services Division.
      As a result of Y2K issues at several sites not originally included in the
      procurement, the LIS installation had to be expanded while facing a very critical
      implementation deadline. This article describes the procedural and organizational
      strategies used to successfully accomplish a major project of reorganization and
      systemic integration of nine geographically distant and disparate public hospital
      laboratories while simultaneously installing a new networked LIS at all sites
      within a relatively short span of 3 years.

PMID- 12592872
TI  - Career development: enhancing your networking skills.
AB  - Can you walk into a room full of strangers and chat easily, get to know people,
      and let them get to know you? Networking is not just a job search strategy; it is
      a critical professional career development enrichment strategy that can help you
      build your knowledge and expertise. When you need help, do you have a network of
      available people or do you know how to develop a network to assist you?
      Networking sounds easy and we tend to think it should come naturally. However,
      networking is a learned skill that just about everyone struggles with at some
      time or another (1). This article provides a how- to network process, summarized
      in Table 1, that will enhance your career development.

PMID- 12592873
TI  - Use of needle safety devices by clinical laboratories in North Carolina
      hospitals.
AB  - Laboratories across the U.S. have implemented needle safety devices to varying
      degrees and are making efforts to comply with the most recent legislation in this
      area, The Needlestick Safety and Prevention Act. A survey was conducted among
      hospital clinical laboratories in North Carolina, with a 70% response rate. Of 86
      responding laboratories that offered either inpatient and/or outpatient
      phlebotomy, 88% reported currently using safety devices, and only two of the
      nonusers indicated no plans for adoption of such devices. The most commonly
      reported types of venipuncture safety devices in use or being adopted were the
      modified vacuum-tube holder for either one-handed needle release or needle
      retraction and sheathing, followed by needle clips. Despite studies demonstrating
      reduced needlestick rates and cost savings with use of needle safety devices,
      respondents' concerns included added cost, staff dissatisfaction with devices
      because they were cumbersome, and being uncertain that the devices would reduce
      needlesticks.

PMID- 12592874
TI  - The challenging journey of CLS/MLS student recruitment.
AB  - Clinical laboratory science/medical laboratory science (CLS/MLS) programs
      struggle for student applicants. At the same time, the health-care industry
      suffers from a shortage of qualified laboratory scientists. This article
      addresses the University of Utah's (U of U) Medical Laboratory Science program
      efforts to increase student enrollment. Student applicants were needed
      desperately. The Director of Medical Laboratory Science Education appointed a 0.5
      FTE person to manage student recruitment and academic advisement. Immediately, we
      took a "shotgun" approach to promote and attract qualified students, followed by
      specific exploratory methods to examine students' motivations in applying to the
      U of U MLS program. Recently, we conducted a national study of university-based
      CLS/MLS programs to research what motivates students' enrollment in CLS/MLS
      programs. We found that the most important motivational factors for a student's
      choice of a CLS/MLS program are 1) based on geographical location, 2) influenced
      by family and friends in making their decision, 3) viewing the laboratory
      profession as a stepping stone to other professions, and 4) their college
      advisor, the most relevant information source for these students. The U of U MLS
      program markets locally and encourages family and friends to spread the word
      about the profession. We remain visible to college advisors and find new
      opportunities to expose the profession to high school students.

PMID- 12592875
TI  - Mystery patient insight into clinical laboratory service.
AB  - Gone are the days when most patients tolerated impersonal service from their
      physicians and health-care providers in general. Every day, customer and patient
      satisfaction becomes more critical to a health-care provider's success and
      survival. Open communications, Internet-informed patients, and aggressive watch
      groups reveal those health-care providers who consistently deliver poor service.
      Most health-care providers employ patient satisfaction surveys to monitor their
      level of service; however, written and telephone surveys seldom provide the
      surveyor the insight necessary to provide differentiating service because of a
      large illiteracy rate and fear of reprisal. Toward this end, a well-trained
      mystery patients offers the health-care provider greater insight into how service
      is dispensed to its customers and patients. This article offers an aggregate of
      mystery patient insights into delivering clinical laboratory services both in
      hospital and medical practice environments, supported with insightful information
      into creating winning service strategies.

PMID- 12592876
TI  - Systems thinking and managing complexity, Part One.

PMID- 12592877
TI  - The institutional review board and investigator conflicts of interest.

PMID- 12592878
TI  - Common cent$ 10: the magnificent seven.

PMID- 12592879
TI  - Clearing the air: the selection, location, and use of hoods.

PMID- 12592880
TI  - Monitoring low molecular weight heparins.
AB  - Low molecular weight heparin (LMWH) is used in the treatment of various
      thrombotic disorders. The clinical indications, pharmacology, and complications
      of therapy are reviewed. The indications for the need for monitoring include
      renal failure, obesity, pregnancy, and pediatric use. Monitoring focuses on the
      anti-Xa properties of LMWH. The two major assay types, chronometric (clotting)
      and chromogenic (amidolytic), are reviewed and compared.

PMID- 12592881
TI  - Mentoring 102: the power of the clear answer.

PMID- 12592882
TI  - Meeting the challenges of compliance.

PMID- 12592883
TI  - Juggling the management of multiple departments successfully.

PMID- 12592884
TI  - Planning and training are keys to successful evacuations.

PMID- 12592885
TI  - The fire ant wars. Nature and science in the pesticide controversies of the late
      twentieth century.
AB  - This essay uses an approach borrowed from environmental history to investigate
      the interaction of science and nature in a late twentieth-century controversy.
      This debate, over the proper response to fire ants that had been imported into
      the American South accidentally and then spread across the region, pitted Rachel
      Carson and loosely federated groups of conservationists, scientists, and citizens
      against the U.S. Department of Agriculture. The analysis falls into three
      sections: an examination of the natural history of the ants; an examination of
      the views of the competing factions; and an examination of how those views,
      transformed into action, affected the natural world. Both sides saw the ants in
      terms of a constellation of beliefs about the relationship between nature,
      science, and democracy. As various ideas were put into play, they interacted with
      the natural history of the insects in unexpected ways--and with consequences for
      the cultural authority of the antagonists. Combining insights from the history of
      science and environmental history helps explain how scientists gain and lose
      cultural authority and, more fundamentally, allows for an examination of how
      nature can be integrated into the history of science.

PMID- 12592886
TI  - Blood, politics, and social science. Richard Titmuss and the Institute of
      Economic Affairs, 1957-1973.
AB  - Long before his last book, The Gift Relationship: From Human Blood to Social
      Policy, was published in early 1971, Richard M. Titmuss (1907-1973), a professor
      of social administration at the London School of Economics, had been a major
      figure in the debates over the welfare state. The Gift Relationship was the
      culmination of an eventful relationship with the Institute of Economic Affairs, a
      think tank that advocated the extension of rational pricing to social services.
      By arguing that the British system of blood procurement and distribution, based
      on free giving within the National Health Service, was more efficient than the
      partly commercialized American system, Titmuss intended to signal the dangers of
      the increasing commercialization of society. What made for the impact of his
      book, however, was not merely its argument that transfusion-transmitted
      infections were much more common with paid than with voluntary donors, but also
      its reflections on what it is that holds a society together. And here Titmuss
      argued that a "socialist" social policy, by encouraging the sense of community,
      played a central role. The eclecticism of Titmuss's work, together with its
      strong ethical and political flavor, makes it a rich and original account of the
      "social" at a time when heated debated over social policy, both in Britain and in
      the United States, raised the question of the division of labor among the social
      sciences.

PMID- 12592890
TI  - Drive-thru-flu.

PMID- 12592891
TI  - Thoughts on the nursing shortage.

PMID- 12592892
TI  - Treatment of pain in women who have elective abdominal hysterectomies.

PMID- 12592893
TI  - Response to proposed BOME midwifery rules published 10/7/02 for public hearing on
      the rules.

PMID- 12592894
TI  - [Physiotherapy in correction of proatherogenic shifts in long-term administration
      of beta-blockers and thiazide diuretics].
AB  - A physiotherapeutic complex (laser therapy, dry carbon dioxide and iodine-bromine
      baths) addition to a course treatment with beta-blockers and thiazide diuretics
      produced positive changes in the levels of triglicerides, total cholesterol, beta
      and alpha-cholesterol, lipid peroxidation in patients with proatherogenic shifts
      in the lipid spectrum and lipid peroxidation system secondary to long-term
      therapy with beta-blockers and thiazide diuretics, and therefore can be used for
      partial correction and prevention of the above shifts.

PMID- 12592895
TI  - [Basic etiological factors, pathogenetic mechanisms, and clinical forms of
      meteopathic reactions].
AB  - The paper reviews basic etiological factors of meteopathic reactions, presents a
      scheme of pathogenetic mechanisms of the development and clinical classification.
      Meteopathic reactions are attributed to the following causing factors:
      atmospheric electromagnetic impacts ("storms"), change of thermobaric situation
      ("hypoxic weather for "spastic"), weather situation of the intermediate type.
      Pathogenetic mechanisms of meteopathic reactions provoke the following
      developments: electromagnetic impacts irritate the cells of afferent nervous
      ends, weather hypoxic conditions aggravate lack of oxygen of affected organs and
      tissues, spasm of vascular smooth muscles worsens transport of oxygen to organs
      and tissues causing capillary-trophic insufficiency. Clinically, meteopathic
      reactions run latently or manifest as aggrevation of preexisting diseases. Hence,
      meteopathic reactions are divided into cerebral, cardial, respiratory,
      peripheral, abdominal (visceral) and combined; mild, moderate and severe.

PMID- 12592896
TI  - [Effect of general carbon dioxide baths and physical exercise on parameters of 24
      hour monitoring of EKG and cardiac rhythm variability in postmyocardial
      infarction patients].
AB  - Myocardial infarction survivors took general carbon dioxide baths and/or did
      therapeutic exercises. Compared to controls, all these patients experienced a
      significantly less number and duration of episodes of ST-segment ischemic
      depressions detected at 24-h ECG monitoring while significant differences by
      cardiac rhythm variability before and after the treatment were not registered
      though the test group showed the trend to normalization of the heart rhythm.

PMID- 12592897
TI  - [Peloid interference therapy of patients with chronic obstructive bronchitis in
      health resort].

PMID- 12592898
TI  - [Exercise therapy in rehabilitation of patients with pulmonary tuberculosis
      before and after surgical treatment].

PMID- 12592899
TI  - [Preventive use of ozone, short waves, and laser therapy alone and in combination
      in early postoperative period after dental implantation].

PMID- 12592900
TI  - [Effect of drinking mineral water on hormonal regulation of glucose homeostasis
      after mastectomy for breast cancer].
AB  - Glycohomeostasis was studied in patients operated for breast cancer, healthy
      controls and ulcer patients before and after gastric resection (each group
      consisted of 12-15 examinees). Patients with duodenal ulcer had insulin
      hypersection including early phase reaction. Gastric resection decreases
      insulinemia in an early phase of reaction to oral glucose test. In postmastectomy
      patients insulinemia is 2-3 times higher than that in duodenal ulcer patients and
      5 times higher than that in healthy subjects. Besides hyperinsulinemia, they had
      insulin resistance and impaired carbohydrate tolerance. A course intake of
      mineral water raised tissue sensitivity to insulin at early stages of glucose
      test and lowered basal level of insulin and hydrocortisone.

PMID- 12592901
TI  - [Interference therapy in combined treatment of patients with chronic nonspecific
      salpingoophoritis].
AB  - Neurotropic interference therapy (NIT) was studied as monotherapy and in
      combination with iodine-bromide water in 50 patients with chronic nonspecific
      salpingoophoritis. NIT was found effective in the above disease as it improved
      clinical picture, reproductive function, psychoemotional condition of the
      patients. The addition of iodine-bromide water to NIT potentiates and prolongs
      neurotropic, endocrine, analgetic and anti-inflammatory effects of NIT.

PMID- 12592902
TI  - [Acute salpingoophoritis: early intensive UHF-therapy].
AB  - The placebo-controlled trial of effectiveness of early intensive UHF therapy in
      107 females at reproductive age with acute salpin-goophoritis has demonstrated
      high clinical and local immunomodulating effects of intensive UHF therapy (460
      MHz, 3 procedures a day) in combination with adequate antibacterial treatment
      used as early as hospitalization day 1.

PMID- 12592903
TI  - [Local hypothermia in combined treatment of acute inflammatory diseases of
      uterine appendages].

PMID- 12592904
TI  - [Pain perception and psychological status of patients suffering from spinal
      osteochondrosis with pain syndrome].
AB  - 132 patients suffering from spinal osteochondrosis with pain syndrome were
      examined for pain perception and psychological status. Pain intensity in such
      patients showed association with hypochondriac and anxiodepressive disorders
      combination with rigidity and development of fixations. Deterioration of life
      quality correlated with severity of pain syndrome and such features as
      unsatisfaction, tension, anxiety, rigidity, fixation of attention on personal
      feelings, pessimistic outlook, low stress resistance. Psychological
      characteristics and quality of life depended on gender and location of
      vertebrogenic pain syndrome.

PMID- 12592905
TI  - [Resonance response of cell-tissue structures to impulse frequency of infrared
      laser radiation of low intensity (experimental study)].
AB  - A morphological evaluation of the results of transcutaneous radiation of male
      mice with infra-red impulse laser beam for 10 min (10,100, 1000, 10,000 Hz) 5
      min, 3 and 24 hours after the procedure has confirmed the existence of
      "resonance" frequencies for different types of endocrine cells and has shown that
      the response depends not only on the dose of infrared low-intensity laser
      radiation. Thus, account for resonance frequencies is one of perspective
      approaches to optimization of laser therapy which may raise effectiveness and
      safety of laser exposure.

PMID- 12592906
TI  - [Experimental assessment of the effect of low mineralized chloride sodium silica
      mineral water from Ketskinskoe deposit and water extract of therapeutic mud from
      Paratunskoe deposit].

PMID- 12592907
TI  - [Ecological assessment of low mineralized peloids of the Samara region and humin
      peloid preparations].

PMID- 12592908
TI  - [Physiotherapeutic methods and elements of exercise treatment in rehabilitation
      of patients after liver transplantation in early postoperative period
      (preliminary results)].

PMID- 12592909
TI  - [Rehabilitation of children and adolescents with diabetes mellitus in sanatoria
      for children with parents].

PMID- 12592910
TI  - [Effect of exercise therapy on microcirculation in children with atopic
      dermatitis].

PMID- 12592911
TI  - [Health resort factors in rehabilitation of children living in polluted
      environment].

PMID- 12592912
TI  - [Horseback riding therapy in development of motor skills in infantile cerebral
      palsy].

PMID- 12592913
TI  - [Morphofunctional features of movement of invalids with amputated legs in
      volleyball playing in sitting position].

PMID- 12592914
TI  - [Combined treatment of patients with neuroendocrine dysfunction of the urinary
      bladder].

PMID- 12592915
TI  - What does HIPAA really mean?

PMID- 12592916
TI  - Validity and reliability of a dental operator posture assessment instrument
      (PAI).
AB  - PURPOSE: Basic operating posture is considered an important occupational health
      issue for oral health care clinicians. It is generally agreed that the physical
      posture of the operator, while providing care, should be such that all muscles
      are in a relaxed, well-balanced, and neutral position. Postures outside of this
      neutral position are likely to cause musculoskeletal discomfort. To date, the
      range of the neutral operator position has not been well-defined; nor have any
      specific instruments been identified that can quantitatively or semi
      quantitatively assess dental operator posture. This paper reports on the
      development of an instrument that can be used to semi-quantitatively evaluate
      postural components. METHODS: During the first phase of the study, an expert
      panel defined the basic parameters for acceptable, compromised, and harmful
      operator postures and established face validity of a posture assessment
      instrument (PAI). During the second phase, the PAI was tested for reliability
      using generalizability theory. Four raters tested the instrument for reliability.
      RESULTS: Overall, total PAI scores were similar amongst three of the raters, with
      the fourth rater's scores being slightly greater than the other three. The main
      effect of the rater on individual postural components was moderate, indicating
      that rater variance contributed to 11.9% of total variance. CONCLUSIONS: The PAI
      measures posture as it occurs and will have numerous applications when evaluating
      operator performance in the dental and dental hygiene education setting. Also,
      the PAI will prove useful when examining the effects of operator posture and
      musculoskeletal disorders.

PMID- 12592917
TI  - Effects of occupational ultrasonic noise exposure on hearing of dental
      hygienists: a pilot study.
AB  - PURPOSE: The purpose of this case-control study was to determine whether long
      term ultrasonic noise exposure via the dental office environment is related to
      dental hygienists' hearing status. METHODS: Registered dental hygienists (N =
      698) who live in the Hampton Roads areas of Virginia were mailed a Dental Hygiene
      Work History Questionnaire to determine who would meet the inclusion criteria and
      would be willing to participate in the study. Consenting subjects were
      categorized into one of two groups, according to ultrasonic scaler usage rate,
      and matched on age. Persons with known hearing loss due to infection, disease, or
      congenital defect were excluded from the study. The final sample consisted of 20
      dental hygienists with a high ultrasonic usage rate and a matched group of 20
      dental hygienists who had a low ultrasonic usage rate. Once the groups were
      formed, a certified audiologist tested subjects' hearing in each ear via the pure
      tone audiometer. Audiometric data were analyzed using the analysis of variance
      for repeated measures procedure to determine if degree of ultrasonic scaler noise
      exposure in the dental office environment was significantly related to hearing
      status in these dental hygienists. RESULTS: Results revealed that the right and
      left ears were not statistically different in the hearing threshold levels,
      regardless of group status. However, there was a significant difference in the
      high ultrasonic usage group and the low ultrasonic usage group at the 3000 Hz. No
      differences were found at the frequencies of 500, 1000, 2000, 4000, 6000, and
      8000 Hz. CONCLUSIONS: Based on these outcomes, the ultrasonic scaler is not
      considered to have a negative effect on the hearing of dental hygienists at 500,
      1000, 2000, 4000, 6000, and 8000 Hz, but may be related to hearing loss at 3000
      Hz. Ultrasonic noise may in fact be affecting dental hygienists' hearing at 3000
      Hz, but loss of hearing observed at the higher frequencies may be attributed to
      other unidentified factors present in both groups.

PMID- 12592918
TI  - Evidence-based prevention, management, and monitoring of dental caries.
AB  - Dental caries, not unlike periodontal diseases, is now recognized as an
      infectious, transmissible, multifactorial disease of bacterial origin. Current
      evidence-based emphasis is on the need to recognize a carious lesion in its
      earliest stage before demineralization has produced a cavitated lesion that
      requires restoration by a dentist. As a result of current understanding of caries
      control, the dental hygienist's role as a prevention specialist is to determine
      the dental caries risk factors for patients of all ages and to introduce
      remineralization strategies into the patient's dental hygiene care plan.
      Conservative strategies of a concentrated program include initial infection
      control with a chlorhexidine rinse; extra daily fluoride exposures; placement of
      pit and fissure sealants where indicated; control of sucrose exposures; use of
      sugar substitutes, particularly xylitol-containing sugar-free chewing gum; and an
      emphasis on a daily bacterial plaque removal routine. Evidence supports the
      management and monitoring of dental caries. Caries risk level must be reevaluated
      at each maintenance appointment. Appropriate in-office strategies to preserve
      tooth structure should be carried out and followed by applicable home regimens
      that are based on need, not age.

PMID- 12592919
TI  - Xylitol for caries prevention.
AB  - Xyitol is a naturally occurring sweetener which is essentially not fermentable by
      the caries-inducive oral microflora. When tested as a sucrose replacer, or even
      as a small dietary addition, systematic xylitol use leads to impressive
      reductions in caries incidence. Xylitol is compatible and complementary with all
      current oral hygiene recommendations. The appealing sensory and functional
      properties of xylitol facilitate a wide array of applications that promote oral
      health.

PMID- 12592920
TI  - The transtheoretical model: an approach to behavioral change.
AB  - PURPOSE: Facilitating change in the behavior of clients to encourage effective
      and consistent oral self-care behaviors has been a main focus in the delivery of
      dental hygiene care. The Transtheoretical Model proposes that individuals
      progress through a series of stages when intentionally changing a behavior.
      Individuals utilize stage specific processes of change. The level of decisional
      balance and self-efficacy of an individual impact progression through the stages.
      This paper reviews the development of the Transtheoretical Model, presents a
      description of the model, and provides suggested applications for dental hygiene
      practice.

PMID- 12592921
TI  - Understanding and managing dentin hypersensitivity.
AB  - Dental hygienists frequently encounter clients who present with one or several
      sensitive teeth. These clients often rely on the dental hygienist to help
      determine the cause and to provide supportive treatment to relieve their
      discomfort. Therefore, it is essential for dental hygienists to fully understand
      the complexity of dentin sensitivity, be well informed about treatment
      approaches, and have an appreciation of the difficulties inherent in designing
      and conducting clinical hypersensitivity trials. Difficulties in designing
      hypersensitivity research have precluded a definitive answer concerning a best
      treatment approach. The purpose of this course is to present dental hygienists
      with current information about the pain of sensitive teeth and the associated
      differential diagnosis. The theory of pain transmission, etiology of dentin
      sensitivity, professional and self-care treatment modalities, and natural
      remission of tooth sensitivity will be discussed. Tooth and pulp biology will be
      reviewed as a means of explaining treatment and management approaches. At
      completion of this course, as measured by a post-test, participants with be
      prepared to apply the knowledge gained to their evidence-based practice to
      positively impact the oral health of their clients.

PMID- 12592922
TI  - [UltrasonIc diagnosis of inflammation of the umbilical cord structures,
      persistent urachus and umbilical hernia in calves].
AB  - The umbilical stalk, vein, arteries, urachal region, liver and urinary bladder in
      35 calves with the clinical suspect of umbilical disease were examined
      ultrasonographically with a 3.5 and 5 MHz convex scanner and a 7.5, 10 and 13 MHz
      linear scanner (Esaote AU5, Esaote, Florenz). Extra- and intraabdominal umbilical
      structures could be evaluated well by ultrasonography. An exact description of
      the extent of the disease and of the involvement of other structures, as the
      liver or the urinary bladder, was made possible by ultrasonography. Complications
      during surgery could be reduced and in the case of a poor prognosis the calves
      were euthanatized to prevent costs for the owner.

PMID- 12592923
TI  - [Electronic quantification of traction force during use of a mechanical calving
      aid in bovine parturition].
AB  - In this study, a specially developed computer-controlled system was used to
      obtain a continuous measurement of the forces that arise when using a mechanical
      calving aid. By this means, potentiograms for twenty-four births in cows using a
      tractive device were obtained (fourteen primiparae with an average age of twenty
      eight months; ten pluriparae with an average age of fifty-four months; breeds:
      thirteen RB, eleven SB). A modern mechanical calving device with a locking
      mechanism was used as an aid in the extraction process. In births with use of
      light tractive force (approx. 50 kp), extraction took between 41 and +/- 21
      seconds. Moderately heavy tractive force (approx. 80-100 kp) was applied in
      extractions taking 86 to +/- 22 seconds, whereas heavy tractive force (etwa 100
      120 kp) was used in extractions lasting between 268 and +/- 117 seconds. The
      highest levels measured for brief applications of force were between 130 and 140
      kp. Single strains of up to 150 kp were reached. Injuries in the soft birth canal
      were ascertained in 29.2% of the births. Such injuries were discerned more often
      in primiparae than in the pluriparae. The lacerations were merely superficial and
      caused no further after-effects. There were no limb injuries in the calves. For
      the use of mechanical calving aids the use of chains with exact markings should
      ensure that the limbs are fixated at equal lengths. Furthermore, every device
      should be equipped with a locking mechanism (150 kp) to prevent the use of too
      much force. This also prevents misjudgment of the birth situation concerning
      fetus size and the dimensions of the mother cow's pelvis.

PMID- 12592924
TI  - Tachydyspnea in an infant chimpanzee.
AB  - Reports on intensive care and invasive treatments of primates are scarce.
      Generally, there is little knowledge and experience in regard to resuscitation,
      cardiac support and ventilation support especially in small infants of primate
      species. We therefore report on our experience with respect to the successful
      treatment of a former small-for-date chimpanzee infant with severe
      cardiorespiratory distress due to pneumonia inflicted by an unknown infective
      agent. Treatment was primarily with analgosedation, oxygen application and
      dobutamine infusions. Cooperation of neonatologists and veterinarians is
      recommended for treatment of young primates.

PMID- 12592925
TI  - [Epidemiological model development using BSE as an example--observations from a
      statistical viewpoint].
AB  - Since first BSE cases in cattle born in Germany were recognized, questions have
      been raised concerning the future development of the disease and the
      epidemiological dynamics of BSE, and, consequently, modelling approaches that
      might answer these questions. The database for such modelling efforts is formed
      by BSE incidence numbers or incidence rates, broken down by age at onset of
      clinical disease, and by time of onset or time of birth, respectively, from
      available information gathered for suspect and confirmed BSE cases. To describe
      such data, statistical age-period-cohort-models and two
      epidemiologically/biologically oriented modelling approaches are discussed: the
      so-called three-factor-model used by the Central Veterinary Laboratory of the
      British Ministry for Agriculture, Fisheries and Food (MAFF) (now Department of
      the Environment and Rural Affairs (DEFRA)), and a back-calculation-model
      developed by a working group at the University of Oxford. Resulting model
      calculations are supposed to serve several purposes, including a prediction of
      future BSE incidence numbers, and, especially based on the "Oxford"-model, a back
      calculation of the epidemic of BSE infections from the epidemic of clinically
      diseased BSE cases. Analysis of these approaches reveals some problems even to
      identify unique age, period, or birth cohort effects. An additional estimation of
      epidemiological components of BSE, for example the frequency distribution of
      incubation times, has to rely on further assumptions that cannot be validated by
      the model fit as such. Therefore, modelling results should be interpreted with
      caution. However, the limitations demonstrated by this discussion emphasize the
      need for specific studies to investigate certain aspects of the BSE epidemic, for
      example the distribution of times from infection to disease onset, and for the
      centralised collection of valid and detailed population data for cattle.

PMID- 12592926
TI  - Molecular genetic and expression analysis of alpha-tocopherol transfer protein
      mRNA in German shepherd dogs with degenerative myelopathy.
AB  - Degenerative Myelopathy (DM) is a progressive neurological disorder of the spinal
      cord preferentially occurring in German shepherd dogs. The pathogenesis of the
      disease is unknown. However, there are indications that vitamin E deficiency may
      be involved in the pathogenesis of DM. Therefore, we analyzed the expression and
      the nucleotide sequence of the canine alpha-tocopherol transfer protein (alpha
      Ttp) of German shepherd dogs with DM in order to determine whether a deficiency
      or a defect of the alpha Ttp could be a primary factor in the pathogenesis of DM,
      as found in human patients with Ataxia with vitamin E deficiency (AVED). The cDNA
      of the coding region of the canine alpha Ttp-mRNA was generated from total liver
      RNA using RT-PCR and 5' RACE technique. We determined the sequence of 707 out of
      834 base pairs or 84.8% of the canine alpha Ttp coding region. Sequence
      comparison of canine alpha Ttp between affected and control dogs revealed no
      differences in either nucleotide or predicted amino acid sequence. Using Northern
      blot analysis alpha Ttp-mRNA expression was solely found in the liver of the
      dogs, rats and humans, while various other organs showed no alpha Ttp-mRNA
      expression. No significant differences in expression levels of canine alpha Ttp
      mRNA were found between DM and control dogs. Our data suggest that the canine
      alpha Ttp gene is unlikely to be involved in the pathogenesis of DM in German
      shepherd dogs.

PMID- 12592927
TI  - Inhibitory effect of different enterocins against fecal bacterial isolates.
AB  - Anti-microbial activity of five different enterocins produced by ruminal and
      environmental enterococci against fecal bacterial isolates was tested. The
      majority of all 61 strains (80.4%) were inhibited by all enterocins used. The
      remaining strains were inhibited at least by one enterocin. The highest activity,
      51,200 arbitrary units per ml-1 (AU ml-1) was measured when crude extracts of
      enterocin V24 (CE V24) were used against enterococci. CE AL41 and EK13 showed an
      activity of 25,600 AU ml-1. The lowest activity was obtained with Enterocin CE
      EC24 (100-400 AU ml-1). Crude extract of enterocin CCM4231 inhibited the
      indicator strains with an activity ranging from 100 up to 6400 AU ml-1, which is
      in accordance with our previous results. It further indicates the probable use of
      enterocins or its producers in environmental biotechnology with the aim to
      increase the effectiveness of sanitation of animal excrements after standard
      treatment.

PMID- 12592928
TI  - [Helminth infection in cattle from Schleswig-Holstein (Germany) after one grazing
      season].
AB  - Fifteen Holstein-Friesian bulls which grazed together for one season (April to
      November) in Schleswig-Holstein were necropsied after housing for 2 to 6 weeks.
      The approximately 12-month old bulls weighed 378 to 491 kg at slaughter and did
      not receive any anthelmintic on pasture. The most prevalent species of the
      gastrointestinal tract was Ostertagia ostertagi (prevalence; geometric mean worm
      count; minimum-maximum) (100%; 1,355; 130-4,590) followed by Cooperia (C.)
      oncophora (86.7%; 343; 20-14,800), Oesophagostomum (Oe.) radiatum (86.7%; 3.7; 1
      42), Trichostrongylus axei (80%; 65; 50-910), C. punctata (73.3%; 14.8; 10-140),
      Trichuris (T.) discolor (73.3%; 4.8; 1-108) and Skrjabinagia lyrata (60%; 8.5; 18
      260) which were recorded in more than half of the animals. Less frequently, C.
      surnabada (46.7%; 18; 10-4025), T. skrjabini (33.3%; 0.7; 2-14), Nematodirus
      helvetianus (13.3%; 0.5; 20-30), Spiculopteragia bohmi (6.7%; 0.2; [26]),
      Capillaria bovis (6.7%; 0.2; [10]) and Oe. venulosum (6.7%; 0.2; [9]) were
      recovered. Inhibited fourth-stage larvae of the Ostertagiinae were recovered from
      the abomasal mucosae of all bulls (100%; 13,159; 5,800-56,950). The abomasum
      harboured the highest worm burden followed by the small intestine and large
      intestine (geometric means): 15,565, 461 and 10 nematodes, respectively.
      Inhibited fourth-stage larvae amounted to 90% of the abomasal Ostertagiinae.
      Dictyocaulus viviparus was recorded in 73.3% of the animals with a geometric mean
      count of 12.8 (1-822 per animal).

PMID- 12592929
TI  - [Palaeoparasitological analysis of guinea pig mummies of the Chiribaya culture,
      Moquegua Valley, Peru].
AB  - During several excavations of archeological sites in the Moquegua Valley,
      Southern Peru, various guinea pig mummies (Cavia aperea f. porcellus) have been
      discovered. They belong to the Chiribaya Culture (900-1100 AD). The outstanding
      preservation of the mummified animals gave rise to the idea of a
      paleoparasitological analysis. In the fur, numerous well preserved ectoparasites
      (lice, fleas, mites) could be recovered. Generally, ectoparasite remains are
      rarely found among archeological material. This is the first account of an
      extensive ectoparasitological analysis of animal mummies in Peru. A modified
      technique for recovery and preservation of the ectoparasites has been developed.

PMID- 12592931
TI  - Occurrence of Salmonellae in retail raw chicken products in Ethiopia.
AB  - A cross-sectional study was undertaken to determine the presence and prevalence
      of salmonellae in retail raw chicken meat and giblets (gizzard and liver) in
      supermarkets in Addis Ababa (Ethiopia). A total of 301 samples (244 chicken meat,
      32 gizzards and 25 livers) were collected from 22 randomly selected supermarkets
      and examined for the presence of Salmonella. For the isolation and identification
      of salmonellae, the technique recommended by the International Organization for
      Standardization (ISO 6579, 1998) was used. Salmonellae were detected from 54
      (17.9%) of the 301 samples examined. Chicken meat and giblet samples in 68.2%
      (15/22) of the supermarkets were contaminated with salmonellae. The contamination
      level of Salmonella was higher in chicken giblets as compared to chicken meat,
      which were respectively 12.3%, 53.1% and 28.0% in chicken meat, gizzard and liver
      samples. Out of the 54 Salmonella isolates, nine different serotypes were
      identified: Salmonella Braenderup (31.5%), S. Anatum (25.9%), S. Saintpaul
      (14.8%), S. Uganda (11.1%), S. Haifa, S. Group B, S. Rough form and S.
      Typhimurium (each 3.7%) and S. Virchow (1.8%). The high level of Salmonella
      contamination of chicken meat and giblets observed in the present study indicated
      the need in an improvement in the microbiological quality of retail chicken in
      Ethiopia.

PMID- 12592930
TI  - Effect of dolomite, magnesium oxide (MgO) and chalk (CaCO3) on in vitro
      fermentation of amorphous and crystalline cellulose and meadow hay using inoculum
      from sheep.
AB  - Some minerals can influence some biochemical parameters of rumen fermentation.
      The objective of this experiment was to determine the effect of different amounts
      (0.1, 0.25 and 0.5 g) of dolomite and to compare the effect of dolomite,
      magnesium oxide (MgO) and chalk (CaCO3) upon the end products of rumen
      fermentation in vitro. Amorphous and crystalline cellulose as well as meadow hay
      were used as substrates and incubated with buffered rumen fluid in sealed
      fermentation bottles. In dependence on the amount of dolomite and the kind of
      substrate an inhibitory effect of dolomite on methane production was evident.
      Significant differences of methane production were found between the controls,
      crystalline cellulose and meadow hay with 0.5 g of dolomite. An increase of total
      gas production was observed for cellulose with both 0.25 and 0.5 g of dolomite
      and also for meadow hay with 0.5 g of dolomite. It can be concluded that there
      was a remarkable effect of dolomite on methane production and also a slight
      effect of magnesium oxide and chalk as compared to the effect of dolomite on the
      fermentation parameters of incubated substrates.

PMID- 12592932
TI  - Virulence of Mycoplasma synoviae strains in experimentally infected broiler
      chickens.
AB  - Seven field isolates of German origin and the type strain WVU 1853 of Mycoplasma
      synoviae (MS) were experimentally investigated for their virulence in mycoplasma
      free broiler chickens. Two groups of birds were inoculated at 6 days of age with
      each isolate, one group into the thoracic air sac and the other group
      intravenously and all surviving birds were examined at necropsy 17 days post
      inoculation (pi). Groups of negative control birds received sterile Frey's broth
      medium by intravenous and intra-air sac inoculation, respectively. Variation in
      virulence was evaluated on the basis of significant differences in incidence,
      severity and extend of MS-induced airsacculitis and synovitis as well as
      isolation rates of MS especially from parenchymous organs. All the strains tested
      were pathogenic but varied in their virulence for broiler chickens. Based on
      differences of the virulence, the isolates were classified to the categories:
      (1.) highly virulent, (2.) virulent, (3.) moderately virulent and (4.) slightly
      virulent. (1) Strains WVU 1853 and 246-91 induced a systemic disease associated
      with multiple synovitis and bilateral airsacculitis (2) Strains 93-92 and 151-77
      induced bilateral airsacculitis similar to WVU 1853 and 246-91 but rarely a
      systemic disease after exposure by intra-thoracic airsac inoculation. (3) In
      comparison, strains 27-79, 76-93 and 513-83 caused less frequently airsacculitis
      and even if, then only at the side of intra-airsac exposure. (4) Strain 91-93 has
      been found to differ significantly from all the other isolates in its capacity to
      produce disease independently from the inoculation route. After intravenous
      inoculation, findings gave no indications for strains with selective tropism to
      the epithelial membranes of the lower respiratory tract or to those of the
      joints, tendon sheaths and bursae. However, the presented data of the experiments
      suggest that the MS strains tested differ in their potential capacity to invade
      systemically and produce acute septicaemia.

PMID- 12592933
TI  - [Prevalence of herd specific factors and limb disorders, and their associations
      in intensive swine production].
AB  - A longitudinal observational study in 180 pig breeding herds was performed to
      calculate prevalences of herd specific factors as well as typical limb disorders
      and to estimate their associations in a 2-step regression analysis. Regarding
      herd size, genetics, feeding and weight gain herds were distributed almost equal.
      The population density and the hygiene status were considered proper in most
      herds. In the farrowing units partially slatted floors of metal or plastic with
      slats > 9 mm, in the weaning units fully slatted floors of plastic, and in the
      rearing units fully slatted floors of concrete were most common. Less than 6% of
      the farms housed their pigs on solid concrete with straw bedding. Herd
      prevalences of fault floors varied between 18 and 43%. As a herd health problem
      (morbidity > 25%) claw hematomas and limb abrasions in just 1-week old piglets,
      overgrown claws and bursa swellings in weaned pigs, and bursa swellings in
      rearing pigs were wide spread. Leg deformations by osteopathy or arthritis
      occurred only sporadically. In the risk analysis claw hematomas of piglets were
      associated with slatted floors, particulary with slats < 10 mm. Abrasions were
      associated with concrete and rough floor surfaces at all. Overgrown claws and
      bursa swellings in weaned and in rearing pigs were associated with damaged,
      slippery or rough floor surfaces. Other associations were not detected. The
      quality of floor might be more important than the type of housing.

PMID- 12592934
TI  - AISAC: the international ministry. International Federation of Catholic Health
      Care Associations.

PMID- 12592935
TI  - Developing leaders for 2010.

PMID- 12592936
TI  - Boosting organ donation among Hispanics.

PMID- 12592937
TI  - A new year of opportunities.

PMID- 12592938
TI  - The communitarian tradition. The church's social teaching guides our ministry
      toward collaboration, not individualism.

PMID- 12592939
TI  - Genetics and confidentiality.

PMID- 12592940
TI  - The challenge and heart of chaplaincy. Recent decades have brought a host of
      changes to the health care chaplain's role.

PMID- 12592941
TI  - Becoming a physician executive. To be effective leaders, clinicians must first
      adopt a new mind-set.

PMID- 12592942
TI  - Removing bias from health care. Studies show that women and African Americans
      often get inferior care.

PMID- 12592943
TI  - Nine axioms for success in mergers. Health care leaders must take great care with
      the cultural factors involved.

PMID- 12592944
TI  - Measuring mission integration. A new tool examines mission integration from a
      historical perspective.

PMID- 12592945
TI  - Being environmentally responsible. Group purchasing practices can help hospitals
      protect the environment.

PMID- 12592946
TI  - Parish nursing programs. Through them, faith communities are reclaiming a role in
      healing.

PMID- 12592947
TI  - Oh, what a month!

PMID- 12592948
TI  - Health Value Added (HVA): linking strategy, performance, and measurement in
      healthcare organizations.
AB  - This paper describes "Health Value Added"--an innovative model that links
      performance measurement to strategy in health maintenance organizations. The HVA
      model was developed by Maccabi Healthcare Services, Israel's second largest HMO,
      with the aim of focusing all its activities on providing high quality care within
      budgetary and regulatory constraints. HVA draws upon theory and practice from
      strategic management and performance measurement in order to assess an HMO's
      ability to improve the health of its members. The model consists of four
      interrelated levels--mission, goals, systems, and resources--and builds on the
      existence of advanced computerized information systems that make comprehensive
      measurements available to decision makers in real time. HVA enables management to
      evaluate overall organizational performance as well as the performance of semi
      autonomous units. In simple terms, the sophisticated use of performance measures
      can help healthcare organizations obtain more health for the same money.

PMID- 12592949
TI  - Results of lumbar disk prosthesis after a follow-up period of 48 months.
AB  - BACKGROUND: Damage to the intervertebral disk is usually corrected by means of a
      prosthesis. OBJECTIVES: To report the outcome of the artificial lumbar disk
      replacement with the Charite SB III disk prosthesis in 20 patients after a 48
      month follow-up. METHODS: The 20 patients were evaluated clinically and
      radiographically during this period. Preoperative diagnosis included degenerative
      diskopathy in 17 patients and failed posterior conventional diskectomy in 3. The
      prosthesis was implanted at one level in 17 patients and bi-level implantation
      was performed in the other 3 patients. RESULTS: Eighty percent of patients
      reported satisfactory to very good results. Poor results were reported by four
      patients, one of whom underwent posterolateral fusion and another is waiting for
      the same operation. There were two dislocations of the prosthesis followed by
      immediate revision surgery. CONCLUSIONS: Contraindications for surgery appear to
      be the principal cause of failure rather than the prosthesis itself.

PMID- 12592950
TI  - Improvement in mitral regurgitation after aortic valve replacement.
AB  - BACKGROUND: Concomitant mitral valve regurgitation is often present in patients
      with aortic stenosis. The additional MV replacement is associated with high
      operative risk. Previous studies have shown an amelioration of MV regurgitation
      after aortic valve replacement but most of the patient groups were heterogenous.
      OBJECTIVES: To determine whether AV replacement for aortic stenosis has any
      effect on MV regurgitation. METHODS: We reviewed two-dimensional echocardiography
      and color flow Doppler assessment of both aortic stenosis and MV regurgitation
      severity in 30 patients. Patients with previous MV surgery, organic MV disease,
      occlusive carotid artery disease, ejection fraction < 50%, and coexisting
      significant AV regurgitation were excluded. Preoperatively, MV regurgitation was
      mild in 23 patients (77%) and moderate in 7 (23%); in no patient was the
      condition severe. All patients had severe atrial stenosis (peak average aortic
      gradient 86 +/- 22 mmHg in the mild MV regurgitation group and 83 +/- 26 mmHg in
      the moderate group). The patients were divided into two groups according to the
      severity of MV regurgitation (associated mild, and moderate). Group 2, with
      moderate MV regurgitation, was the most problematic in terms of decision making
      for concomitant MV surgery. Therefore, additional assessment of several
      parameters was required. RESULTS: There was a significant decrease in MV
      regurgitation area (7.6 +/- 1.9 vs. 3.0 +/- 1.2 cm2, P < or = 0.012) and percent
      (28 +/- 5% vs. 12 +/- 6%, P < or = 0.001) between pre- and postoperative
      evaluation. Thus, the severity of the condition in all patients with moderate MV
      regurgitation decreased after AV replacement; in the mild group it remained
      unchanged in 53% or improved in 47%. There was no association between the
      preoperative gradient on the aortic valve and the degree of MV regurgitation.
      CONCLUSIONS: In our population of patients with severe atrial stenosis there were
      no patients with coexisting severe MV regurgitation. The decision to repair or
      replace a severely leaking mitral valve is an easy one, as in mild MV
      regurgitation. The clinical problem often presents in patients with severe aortic
      stenosis and moderate MV regurgitation. We believe that additional MV surgery is
      not necessary, at least in patients with preserved left ventricular function and
      without organic MV disease.

PMID- 12592951
TI  - Natural history of moderate mitral valve stenosis.
AB  - BACKGROUND: With the introduction of surgery and percutaneous balloon
      valvuloplasty for relieving severe mitral stenosis the natural history of the
      disease has markedly altered. OBJECTIVES: To determine the natural history of the
      disease in patients with moderate mitral valve stenosis. METHODS: Demographic,
      clinical and echocardiographic data were evaluated in 36 patients with moderate
      mitral stenosis during a follow-up of 71 +/- 15 months. RESULTS: The 36 patients
      comprised 32 women and 4 men with a mean age of 43.7 +/- 12.2 years; 28 were
      Jewish and 8 were of Arab origin. During follow-up, there was a significant
      decrease in mitral valve area, with an increase in mean mitral valve gradient and
      score. Mean loss of mitral valve area was 0.04 +/- 0.11 cm 2/year. No correlation
      was found between disease progression and age, past mitral valve commissurotomy,
      baseline mean gradient or mitral valve score. Larger baseline mitral valve area
      (P = 0.007) and Arab origin (P = 0.03) had an independent correlation to loss of
      mitral valve area. Fifteen patients (42%) did not demonstrate any loss in mitral
      valve area during the follow-up period. CONCLUSIONS: The rate of mitral valve
      narrowing in patients with moderate mitral stenosis is variable and cannot be
      predicted by patient's age, past commissurotomy, valve score or gradient.
      Secondly, larger baseline mitral valve area and Arab origin showed an independent
      correlation to loss of mitral valve area; and finally, in many patients valve
      area did not change over a long observation period.

PMID- 12592952
TI  - Nitric oxide inhalation and high frequency oscillatory ventilation for hypoxemic
      respiratory failure in infants.
AB  - BACKGROUND: High frequency oscillatory ventilation has proved valuable in
      recruiting and sustaining lung volume; the combined treatment may augment nitric
      oxide delivery to target vessels. NO therapy lowers pulmonary resistance and
      improves oxygenation. OBJECTIVE: To retrospectively review data on changes in
      oxygenation-indicated by arterial/alveolar PO2 ratio, oxygenation index, and
      outcome--in a cohort of 10 infants with hypoxemic respiratory failure in whom
      nitric oxide inhalation was instituted in a compassionate-use protocol after
      deteriorated oxygenation. METHODS: NO inhalation was administered at a range of
      0.12-122 days of life using the SensorMedics system in 10 infants who developed
      hypoxemic respiratory failure associated with a variety of lung diseases while on
      HFOV. RESULTS: The infants' birthweight was 1,717 +/- 1,167 g and their
      gestational age 31.1 +/- 6.5 weeks. Mean exposure to NO inhalation was 14.2 days
      and ranged from 3-59 days. Oxygenation index decreased from 39.3 +/- 13.2 to 12.7
      +/- 6.9 (P < 0.0002) after NO therapy. Despite an initial prompt response to NO
      inhalation, two patients died of progressive intractable respiratory failure and
      one term infant died of extrapulmonary complications (hypoxic ischemic
      encephalopathy grade III and multiorgan failure). CONCLUSION: Our results
      indicate that the combined treatment of HFOV and NO inhalation is superior to
      HFOV alone for improving oxygenation in a selected cohort of infants ventilated
      for a variety of lung diseases.

PMID- 12592953
TI  - Agents of non-gonococcal urethritis in males attending an Israeli clinic for
      sexually transmitted diseases.
AB  - BACKGROUND: Non-gonococcal urethritis is the most common clinical diagnosis in
      men seeking care at clinics for sexually transmitted diseases. OBJECTIVE: To
      identify the pathogens involved in NGU among males attending an Israeli STD
      clinic. METHODS: During 19 months spanning September 1996 to July 1998 we
      investigated a cohort of 238 male patients attending the Bnai Zion Medical Center
      STD clinic with a clinical presentation of urethritis. Intraurethral swab
      specimens were tested for Neisseria gonorrhea, Ureaplasma urealyticum, Mycoplasma
      hominis, and Trichomonas vaginalis by culture and for herpes simplex virus by
      antigen detection. First voiding urine for C. trachomatis was done by polymerase
      chain reaction. The specific seropositivities of HSV types 1 and 2 were tested by
      enzyme-linked immunosorbent assay. RESULTS: From among 238 males with dysuria or
      urethral discharge an etiology for urethritis was found for 71 (29.8%). N.
      gonorrhea was recovered in only three men (4.2%). In the remaining 68 NGU
      patients Chlamydia trachomatis (35/68, 51.5%) and U. urealyticum (31/68, 45.6%)
      were the most common infecting and co-infecting pathogens (P < 0.0001). M.
      hominis and T. vaginalis were found in 9/68 (13.2%), and 1 patient, respectively.
      HSV was recovered from the urethra in 7/68 males (10.3%)--3 with HSV-1, 2 with
      HSV-2, and 2 were seronegative for HSV. None of these males had genital lesions.
      Although a single etiologic agent was identified in 45/68 infected men (66.2%),
      co-infection was common: 2 organisms in 15 (22%) and 3 organisms in 8 (11.8%).
      CONCLUSION: C. trachomatis and U. urealyticum were the most common infecting and
      co-infecting pathogens in this cohort of men with NGU. Unrecognized genital HSV
      infections are common in males attending our STD clinic, and symptomatic shedding
      of HSV occurs without genital lesions. Still, the microbial etiology in this
      group remains unclear in many patients despite careful microbiologic evaluation.

PMID- 12592954
TI  - Computed tomography-guided core needle biopsy for bone and soft tissue tumors.
AB  - BACKGROUND: Imaging-guided core needle biopsy is a well-established technique for
      the diagnosis of bone and soft tissue tumors and tumor-like lesions in
      specialized orthopedic oncology centers. OBJECTIVE: To present our results of
      computed tomography-guided core needle biopsy with assessment of the accuracy of
      the technique. METHODS: Between July 1998 and October 2000, 215 CT-guided core
      needle biopsies were performed and histologically examined in the Unit of Bone
      and Soft Tissue Pathology, Tel Aviv Sourasky Medical Center. There were 80 soft
      tissue and 135 bony lesions. All biopsies were performed by the same radiologist
      and the histologic examination by the same pathologist. To assess the accuracy of
      the procedure, we compared the diagnosis at biopsy with the diagnosis after
      definitive surgery (when available). RESULTS: Bone core needle biopsy (n = 135)
      showed malignancy in 89 cases (primary or recurrent bone sarcoma, lymphoma,
      myeloma, metastatic carcinoma or melanoma). There were 29 benign lesions. In 17
      cases the result was inconclusive and an open incisional biopsy was performed. Of
      the 80 soft tissue biopsies, 35 were malignant (25 soft tissue sarcomas, 6
      lymphomas, 4 metastatic carcinomas); 40 were benign (myositis ossificans,
      neurofibroma, desmoid tumor, schwannoma, hematoma and others), and 5 were
      inconclusive and followed by an open incisional biopsy. The core needle biopsy
      histologic diagnosis was compared with that of the definitive surgery and the
      diagnostic accuracy was 90%. Only three samples initially diagnosed as benign
      turned out to be malignant. No significant complications occurred during the
      procedures. CONCLUSIONS: CT-guided CNB of musculoskeletal lesions is a safe and
      effective procedure that assures sufficient and proper material for histologic
      examination. The accuracy of this method in our center was 90%. Tumor sampling is
      extremely important, especially in soft tissue sarcomas, and cores should be
      taken in different directions, including areas of necrosis. The processing is
      quick, especially for bone CNB, and diagnosis can be achieved within 24 hours.
      The material undergoes excellent fixation and the immunostains are reliable.

PMID- 12592955
TI  - Awareness of personal healthcare and menopause in menopausal women in Israel.
AB  - BACKGROUND: Menopause affects women's health and well-being, but their knowledge
      of proper care and maintenance is uncertain. OBJECTIVE: To assess the attitude
      and approach of the healthy, low risk, postmenopausal population in Israel to
      personal healthcare and menopause. METHODS: The study population comprised 500
      menopausal women attending community outpatient primary care clinics. All women
      completed a 20-item questionnaire covering personal healthcare habits, lifestyle,
      knowledge about menopause, and attitude and approach to menopause and use of
      hormone replacement therapy. RESULTS: The patients' mean body mass index was 25.8
      +/- 4.1 kg/m2; more than half the women were overweight, 28% engaged in regular
      sports activity, and 11.2% smoked; 74% had a positive attitude towards their age;
      60% underwent yearly screening mammography; 74% had had Pap smear, and 86% had
      lipid profile measurements during the last year; self-examination of the breast
      was regularly performed by only 49%. HRT is currently being used by 27% and had
      been used in the past by another 16%. The primary reasons for stopping therapy
      were irregular bleeding in 38% and apparent ineffectiveness in 35%. There was a
      positive significant correlation between level of education and both undergoing
      regular medical screening and engaging in regular sports activity. HRT current
      utilization was negatively associated with age and being a housewife.
      CONCLUSIONS: A relatively high percentage of the study population safeguards its
      health and regularly uses HRT. We believe that stronger efforts are needed in
      Israel to promote good healthcare habits and positive attitudes toward menopause
      and HRT use.

PMID- 12592956
TI  - Domestic abuse in pregnancy: results from a phone survey in northern Israel.
AB  - BACKGROUND: Domestic violence is considered a major risk factor in pregnancy.
      OBJECTIVES: To assess the prevalence of different kinds of abuse (physical,
      psychological, sexual) of pregnant as compared to non-pregnant women, and to
      identify demographic risk factors for physical abuse that characterize the woman
      and her partner. METHODS: A cross-sectional survey was conducted in 270 women
      seeking gynecologic care at women health centers in northern Israel. Information
      was collected by means of a standardized questionnaire administered via phone,
      and addressing demographic data, interaction with the partner, and reporting of
      physical abuse. All information was obtained from the respondents (including
      information about her partner). RESULTS: Four abuse scores were computed: severe
      physical attack, minor physical attack, psychological abuse, and sexual coercion.
      Psychological abuse was found to be the most prevalent (24%), followed by minor
      and severe physical attack (17% and 8.1%, respectively), and sexual coercion
      (5.6%). Physical attacks related to pregnancy (directed at the abdomen) occurred
      in 5.4% of the pregnant women. There was no significant difference in the
      prevalence of the different types of abuse between pregnant and non-pregnant
      women. Physical attack was associated with socioeconomic status, work status, and
      degree of religiosity. CONCLUSION: Pregnant women were at a similar risk for
      abuse as non-pregnant women in all abuse categories. Predictors for abuse-
      socioeconomic status and religiosity--were reviewed primarily in a cultural
      context.

PMID- 12592957
TI  - Questions and answers about autoimmunity and the smallpox vaccine.

PMID- 12592958
TI  - SWOT analysis: strengths, weaknesses, opportunities and threats of the Israeli
      Smallpox Revaccination Program.
AB  - During September 2002, Israel began its current revaccination program against
      smallpox, targeting previously vaccinated "first responders" among medical and
      emergency workers. In order to identify the potential strengths and weaknesses of
      this program and the conditions under which critical decisions were reached, we
      conducted a SWOT analysis of the current Israeli revaccination program, designed
      to identify its intrinsic strengths and weaknesses, as well as opportunities for
      its success and threats against it. SWOT analysis--a practical tool for the study
      of public health policy decisions and the social and political contexts in which
      they are reached--revealed clear and substantial strengths and weaknesses of the
      current smallpox revaccination program, intrinsic to the vaccine itself. A number
      of threats were identified that may jeopardize the success of the current
      program, chief among them the appearance of severe complications of vaccination.
      Our finding of a lack of a generation of knowledge on smallpox vaccination
      highlights the need for improved physician education and dissipation of
      misconceptions that are prevalent in the public today.

PMID- 12592959
TI  - Regulation of lung edema clearance by dopamine.
AB  - In the kidney, dopamine inhibits Na,K-ATPase, which results in natriuresis
      because less Na+ is reabsorbed by the proximal and distal tubules. In contrast,
      dopamine stimulates Na,K-ATPase activity in the alveolar epithelium, leading to
      increased alveolar fluid reabsorption. Importantly, dopamine increases alveolar
      fluid reabsorption not only in normal alveolar epithelium but also in models of
      lung injury. Dopamine short-term regulation of alveolar epithelial Na,K-ATPase
      occurs via D1 receptor activation, protein kinase C and protein phosphatase 2A
      pathways, leading to increased Na,K-ATPase activity by recruiting sodium pumps
      from the intracellular compartment to the basolateral membranes. Conversely, D2
      receptor activation by long-term dopamine regulates (approximately 24 hours)
      alveolar epithelial Na,K-ATPase via the MAPK pathway, [figure: see text] which
      results in de novo synthesis of Na,K-ATPase proteins. Conceivably, by increasing
      Na,K-ATPase activity and promoting alveolar fluid reabsorption, dopamine can be
      of clinical relevance for the treatment of patients with acute hypoxemic
      respiratory failure due to pulmonary edema.

PMID- 12592960
TI  - Corticosteroids in sepsis: a new concept for an old drug.
AB  - Sepsis is an inflammatory syndrome caused by infection. Consequently, anti
      inflammatory therapy in sepsis has been a subject of extensive research, and
      corticosteroids have long been used to treat severe infections. However, studies
      conducted in the 1980s failed to demonstrate any beneficial effects of high dose,
      short-term steroid therapy in sepsis and this therapy was therefore abandoned in
      the last decade. Recently, a new concept has emerged with more promising results-
      low dose, long-term hydrocortisone therapy- and this approach is now being
      evaluated in the treatment of septic shock. It is supported by the observation
      that many sepsis patients have relative adrenal insufficiency. Moreover, the anti
      inflammatory effects of steroids and their ability to improve reactivity to
      catecholamines further contribute to their effects in sepsis. Large randomized
      clinical trials will be required to determine the exact role of corticosteroids
      in septic shock.

PMID- 12592961
TI  - Possible beneficial effects of soy protein on the vascular endothelium in
      postmenopausal women--future directions.

PMID- 12592962
TI  - Artificial intervertebral disk.

PMID- 12592963
TI  - Accent echoing: a newly described imitation phenomenon of psychosis?

PMID- 12592964
TI  - Unusual manifestations of Hodgkin's disease.

PMID- 12592965
TI  - Ablation therapy of tachycardia-related cardiomyopathy.

PMID- 12592966
TI  - Elongation of long bones for short stature in patients with hypophosphatemic
      rickets.

PMID- 12592967
TI  - Update on asthma.

PMID- 12592968
TI  - Omental cake in a male.

PMID- 12592969
TI  - Coexisting chondrocalcinosis, osteoarthritis and popliteal cyst.

PMID- 12592970
TI  - Bilateral posterior segment intraocular hemorrhage after heparin therapy in a
      diabetic patient.

PMID- 12592971
TI  - AHNA participates in nursing summit on complementary and integrative care.

PMID- 12592972
TI  - Aromatherapy for health professionals.

PMID- 12592973
TI  - Resolving arthritis, allergies, & immune compromising disorders with the JMT
      technique.

PMID- 12592974
TI  - Reiki: a gift and a skill anyone can learn.

PMID- 12592975
TI  - Calling Dr. Root.

PMID- 12592976
TI  - Alpha Omega Alpha: encouraging excellence in medicine for more than a century.

PMID- 12592977
TI  - Public health and medicine: synergistic science and conflicting cultures.

PMID- 12592978
TI  - Rewriting the body: the origins of anatomical dissection in ancient Greece.

PMID- 12592979
TI  - The orbit of my eye.

PMID- 12592980
TI  - American pharmaceutical prices.

PMID- 12592981
TI  - The Canadians are killing us.

PMID- 12592982
TI  - Re: "Solutions must be the answer".

PMID- 12592983
TI  - Re: "Solutions must be the answer".

PMID- 12592984
TI  - Re: "Solutions must be the answer".

PMID- 12592985
TI  - Re: "Solutions must be the answer".

PMID- 12592986
TI  - Rationing health care.

PMID- 12592987
TI  - Prevention and control of schistosomiasis and soil-transmitted helminthiasis.
AB  - This report contains the recommendations of a WHO Expert Committee convened to
      consider the prevention and control of schistosomiasis and soil-transmitted
      helminth infections. Although these infections remain major public health
      concerns in many parts of the world, particularly in the poorest developing
      countries, cost-effective solutions are both available and deliverable. The
      report reviews the burden of disease, its impact on both health and development,
      the substantial benefits of treatment, and the safety, efficacy and ease of
      administration of available anthelminthic drugs. Similarities in the population
      at risk and in the tools required to combat the problems have prompted moves
      towards a combined approach to the control of schistosomiasis and soil
      transmitted helminthiasis. Such an approach relies largely on epidemiological
      surveillance, health education, improvements in hygiene and sanitation, and-
      above all--regular treatment of high-risk groups, particularly school-age
      children. The report focuses on how these various elements can be achieved,
      emphasizing the potential of the school system for drug delivery and health
      education and the opportunities for integration of control activities with
      existing health programmes. It also stresses that the cost of recommended
      anthelminthic drugs has now fallen to a level at which it should no longer deter
      Member States from making treatment widely available in endemic areas. The
      recommendations of the Expert Committee provide clear and strategic guidance on
      the implementation of control measures and on ensuring their sustainability.

PMID- 12592988
TI  - Evaluation of certain veterinary drug residues in food.
AB  - This report presents the conclusions of a Joint FAO/WHO Expert Committee convened
      to evaluate the safety of residues of certain veterinary drugs in food and to
      recommend maximum levels for such residues in food. The first part of the report
      considers risk assessment principles and presents the views of the Committee on
      the FAO/WHO Project to update principles and methods for the risk assessment of
      chemicals in food. Summaries follow of the Committee's evaluations of
      toxicological and residue data on a variety of veterinary drugs: three
      anthelminthic agents (doramectin, ivermectin and tiabendazole), seven
      antimicrobial agents (cefuroxime, dihydrostreptomycin and streptomycin,
      lincomycin, neomycin, oxytetracycline and thiamphenicol), four insecticides
      (cyhalothrin, cypermethrin and alpha-cypermethrin, and phoxim) and one production
      aid (melengestrol acetate). Annexed to the report is a summary of the Committee's
      recommendations on these drugs, including Acceptable Daily Intakes and Maximum
      Residue Limits and further information required.

PMID- 12592989
TI  - A pilot study on observations on CD4 & CD8 counts in healthy HIV seronegative
      individuals.
AB  - BACKGROUND & OBJECTIVES: CD4 T lymphocyte count is used to measure the
      progression of HIV infection and is recommended as part of the standard care of
      HIV infected person. Information on reference CD4 counts and CD4:CD8 ratio in
      healthy individuals is lacking in India. Therefore the present study was
      undertaken to obtain base-line data on CD4 counts and CD4:CD8 ratio of healthy
      population from north India and to assess the feasibility of using the values as
      reference in an extended larger study. METHODS: In this pilot study 84 HIV
      negative healthy volunteers (56 males, 28 females) in the age group of 20-59 yr
      and who were willing to participate in the study were enrolled after proper
      counseling. Blood specimens were collected from each subject and processed for
      anti-HIV antibodies for exclusion of HIV. CD4 and CD8 counts of the samples were
      performed by fluorescence activated cell sorting (FACS). RESULTS: The mean +/- SD
      of the absolute numbers of CD4 and CD8 lymphocytes/microliter was 763.6 +/- 226
      and 547.5 +/- 190 in males and 797.9 +/- 263 and 567.7 +/- 250 in females. The
      range of the CD4 and CD8 counts was 365-1328 and 264-991 in males and 415-1257
      and 224-1126 in females respectively. The mean +/- SD of the CD4:CD8 ratio was
      1.47 +/- 0.42 in males and 1.52 +/- 0.45 in females. INTERPRETATION & CONCLUSION:
      The results of this study showed that there is wide variability in CD4 count in
      our population, as is seen in studies reported from other parts of India. A large
      multicentric study could define the normal range for CD4 and CD8 counts and
      CD4:CD8 ratio in the Indian population.

PMID- 12592990
TI  - Profile of asymptomatic chronic HBV infection in India.
AB  - BACKGROUND & OBJECTIVES: In India, horizontal transmission in early childhood has
      been shown to be a significant mode of transmission of hepatitis B virus (HBV).
      This prospective, cross-sectional study was undertaken to study the biochemical,
      serological and histological profile of incidentally detected asymptomatic HBsAg
      positive subjects (IDAHS) picked up at a tertiary care referral centre. METHODS:
      In 157 (M:F::123:34) HBsAg positive subjects, clinical, biochemical, virological
      and histological assessment was done. The histological activity index (HAI) of >
      3 was considered as chronic hepatitis. Serum was tested for HBsAg, HBeAg, HBeAb,
      HBV DNA and alanine transaminase (ALT). RESULTS: Seventy (45%) subjects were
      HBeAg and 83 (53%) anti-HBe positive. While 71 per cent of the subjects with
      elevated ALT had an HAI > 3, only 36 per cent with normal ALT showed significant
      histological changes (P < 0.001). Significant histopathological lesions in the
      liver biopsy were seen in 92 (59%) subjects, with moderate to severe lesions in
      14. IDAHS who were HBeAg +ve were more likely to have significant histological
      lesion than those who were anti-HBe +ve (P < 0.01). In the anti-HBe +ve group, 35
      of 57 (61%) subjects for whom HBV-DNA was available, were HBV-DNA positive. Anti
      HBe+ve, HBV-DNA+ ve IDAHS with elevated ALT were more likely to have chronic
      hepatitis vis-a-vis those subjects in this group who had a normal ALT (P <
      0.001). INTERPRETATION & CONCLUSION: ALT is a reliable discriminant of
      significant histological lesion in IDAHS. The relatively young mean age of Anti
      HBe +ve IDAHS suggests an early age of infection and hence, early seroconversion
      or mutant virus infection in this cohort. A significant proportion of these IDAHS
      have HBV-DNA positivity and HAI > 3. Our results clearly demonstrate ongoing
      liver disease in asymptomatic, so-called "HBV carriers". We propose that the term
      hepatitis B 'carrier' should be abandoned and replaced by 'chronic HBV
      infection'.

PMID- 12592991
TI  - Prevalence of Chlamydia trachomatis & herpes simplex virus in males with
      urethritis & females with cervicitis attending STD clinic.
AB  - BACKGROUND & OBJECTIVES: Cervicitis and urethritis due to Chlamydia trachomatis
      are common sexually transmitted diseases. However, there is a paucity of
      information on urethritis and mucopurulent cervicitis due to herpes simplex virus
      (HSV) from India. We used polymerase chain reaction (PCR) to find out the
      prevalence of C. trachomatis and HSV associated urethritis in males and
      mucopurulent cervicitis in females attending a sexually transmitted diseases
      (STD) clinic. METHODS: Twenty five endocervical swabs from 25 women with
      mucopurulent cervicitis and 75 urethral swabs from 72 males with urethritis were
      processed for the detection of C. trachomatis and HSV by antigen detection by
      fluorescent antibody test (FAT), culture and PCR. RESULTS: Among the 25 women,
      one (4.0%) was positive for C. trachomatis and 3 (12.0%) were positive for HSV by
      PCR. FAT and culture were negative. Nine (12.0%) of the 75 urethral swabs were
      positive for C. trachomatis and 5 (6.6%) were positive for HSV by PCR. Among the
      9 positive by PCR for C. trachomatis, 3 (4.0%) were positive by FAT. Cultures for
      both organisms were negative. INTERPRETATION & CONCLUSION: Endocervicitis and
      male urethritis due to C. trachomatis and HSV are not uncommon among high-risk
      individuals. The diagnosis could be established mainly by PCR.

PMID- 12592992
TI  - BCG vaccination reaction in low birth weight infants.
AB  - BACKGROUND & OBJECTIVES: About 30 per cent newborns (preterm and term) weigh <
      2500 g at birth. The immunological system is less mature in low birth weight
      (LBW) babies compared to term and normal birth weight (NBW) babies. Bacille
      Calmettee Guerin (BCG) vaccine is given at birth under the national immunization
      programme. There is a paucity of information on the immunogenicity of BCG vaccine
      in preterm and LBW babies. It was, therefore, proposed to study the reaction of
      BCG vaccination in LBW, preterm and normal birth weight newborns. METHODS: A
      total of 143 newborns (90 term and 53 preterm; of these 78 were LBW) received
      during March to September 1998, 0.1 ml of BCG vaccine (Danish 1331 strain)
      intradermally on the left arm just above the insertion of the deltoid muscle
      within 7 days of life. At the same time trivalent oral polio vaccine was
      administered as per the national immunization programme. These babies were
      followed up in the immunization clinic at 4, 6, 8, 10 and 12 +/- 1 wk to observe
      reactions at the BCG vaccination site. RESULTS: After 4 wk reaction at the
      vaccination site was significantly (P < 0.001) delayed in preterm babies as
      compared to term infants, and in the LBW babies (P < 0.05) as compared to NBW
      babies. The reaction at the site of vaccination was not found to be different at
      6, 8, 10, 12 wk. BCG scar was seen in 47.5 per cent infants (45.4% in < 2500 g
      birth weight and 50% in > or = 2500 g birth weight infants) at 12 wk. But 33
      (42.3%) LBW and 24 (36.9%) NBW infants also showed papule, pustule, ulceration or
      scab at the BCG vaccination site. INTERPRETATION & CONCLUSION: The BCG reaction
      was seen in the sequential order from papule to scar formation. No significant
      difference was seen in the scar formation in infants studied with varying
      gestation and birth weights after 12 wk of BCG vaccination. Fifty seven (40.4%)
      babies still showed different stages of BCG reaction at 12 wk. BCG vaccine along
      with OPV administered in early neonatal life showed successful BCG reaction in
      95.5 per cent infants.

PMID- 12592993
TI  - Typhidot test to detect IgG & IgM antibodies in typhoid fever.
AB  - BACKGROUND & OBJECTIVES: As typhoid fever is endemic in India, there is a
      continuing search for a simple test which can be carried out in small
      laboratories for an early and rapid diagnosis. We have evaluated the Typhidot
      test for this purpose. METHODS: The Typhidot test was carried out on coded sera
      according to the manufacturer's instructions. The test was performed on 30 Widal
      positive sera, 30 sera from blood culture positive patients, 60 Widal negative
      sera and 30 samples from patients whose blood culture grew Gram negative bacilli
      (GNB) other than Salmonella Typhi. RESULTS: Typhidot test was positive for both
      IgG and IgM in 39 samples, IgM alone in 24 and IgG alone in 2. Of the 30 culture
      positive samples, 27 were positive by Typhidot. The Typhidot test gave a
      sensitivity of 100 per cent and specificity of 80 per cent when bacteraemic
      patients were analysed. INTERPRETATION & CONCLUSION: The Typhidot is easy to
      perform, and requires no special equipment or training of staff for
      interpretation of results. It will be a useful complementary test to blood
      culture and the Widal test in the diagnosis of typhoid fever.

PMID- 12592994
TI  - Phenotypic & genotypic variants of Pseudomonas aeruginosa isolated from children
      with cystic fibrosis in India.
AB  - BACKGROUND & OBJECTIVES: Pseudomonas aeruginosa is the leading cause of morbidity
      and mortality in patients with cystic fibrosis (CF). With increase in the
      chronicity of the disease, there is a diversification of the organism into
      different colony morphological types. The antimicrobial susceptibility of the
      organism varies with its colony morphology. The present work was carried out to
      study the different morphotypes of P. aeruginosa isolated from patients of cystic
      fibrosis. METHODS: We studied 38 children with CF attending the Paediatric Chest
      Clinic at the All India Institute of Medical Sciences, New Delhi, India during
      October 2000-January 2001 who were regularly followed up at the clinic. Patients
      were divided into 2 groups, Group 1 included all patients chronically infected
      with P. aeruginosa and Group 2 included patients who were infrequently colonized
      with this organism. Different colony morphological types of P. aeruginosa on
      culture media were identified. They were characterized by phenotypic methods
      using antibiograms and genotypic methods using enterobacterial repetitive
      intergenic consensus (ERIC) polymerase chain reaction and PCR-ribotyping.
      RESULTS: Fourteen of the 38 patients were colonized at least once with P.
      aeruginosa. Eight patients belonged to Group 1 and 42 isolates were obtained from
      these patients. Group 2 had 6 patients and 9 isolates were obtained from them.
      All patients in Group 1 harboured different colony morphotypes (Types 1-6) while
      all 6 patients in Group 2 showed a single type of colony morphology (Type 1). The
      isolates from Group 1 patients showed higher antimicrobial resistance as compared
      to Group 2 patients. Molecular typing of the isolates revealed 10 ERIC-PCR
      patterns and 2 PCR-ribotyping patterns among Group 1 and 2 ERIC-PCR and 1 PCR
      ribotyping pattern among patients of Group 2. INTERPRETATION & CONCLUSION: The
      frequency of different morphotypes of P. aeruginosa and antibiotic resistance was
      higher among Group 1 patients. On molecular typing, more than one genotype was
      isolated from Group 1 patients while only one genotype was isolated from patients
      in Group 2. We conclude that at a given time, chronically infected patients can
      be colonized by phenotypically and genotypically distinct strains of P.
      aeruginosa which has an implication in the management of these patients.

PMID- 12592995
TI  - Treatment and posttreatment dentoalveolar changes following intrusion of
      mandibular molars with application of a skeletal anchorage system (SAS) for open
      bite correction.
AB  - The skeletal anchorage system (SAS) consists of titanium anchor plates and
      monocortical screws that are temporarily implanted in either the maxilla or the
      mandible as absolute orthodontic anchorage. With SAS, anterior open bite can be
      improved by the counterclockwise rotation of the mandible, accompanied by the
      intrusion of molars. The present study was designed to evaluate treatment and
      posttreatment dentoalveolar changes following the intrusion of mandibular molars.
      Nine adult open bite patients (7 women and 2 men) successfully treated with SAS
      were included in the following study. The amount of intrusion, relapse, and
      dentoalveolar changes were measured on cephalometric radiographs, panoramic
      radiographs, and dental casts. The results of this study were as follows: (1) the
      average amount of intrusion of the mandibular first and second molars was 1.7 mm
      and 2.8 mm, respectively; (2) the average relapse rates were 27.2% at the first
      molars and 30.3% at the second molars; (3) there were no significant changes in
      crestal bone heights, clinical crown length, or root length; and (4)
      counterclockwise rotation of the mandible and decrease of anterior facial height
      were observed during treatment. Thus, it was concluded that SAS would be a valid
      modality to intrude mandibular molars for correction of open bite.

PMID- 12592996
TI  - Indications and procedures for segmental dentoalveolar osteotomy: a review of 13
      patients.
AB  - The authors evaluated the surgical area, indications, and procedures for
      segmental dentoalveolar osteotomy carried out on 16 jaws in 13 patients treated
      at the Department of Oral and Maxillofacial Surgery, Kobe University Graduate
      School of Medicine, between 1990 and 2001. Osteotomy was indicated mainly in
      cases where tooth repositioning by orthodontic treatment was limited, where
      social conditions (e.g., age, time, finances) precluded orthodontic treatment, or
      where revision of orthodontic or surgical treatment was required. In cases of
      maxillary anterior segmental dentoalveolar osteotomy, the modified Wunderer
      method was used, where after an incision was made in the palatal mucosa, a
      mucoperiosteal flap was abraded as much as possible until the area of the
      osteotomy on the palatal side could be visualized. In maxillary posterior
      segmental dentoalveolar osteotomy, the operation was carried out in 2 stages
      because of the risk of necrosis of the bone fragments. In the first stage, an
      osteotomy was carried out on the vestibular side, since the vestibular gingival
      pedicle was intact. In the second stage, 3 weeks later, another osteotomy was
      performed after the palatal mucoperiosteal flap was abraded to visualize the area
      of the osteotomy as well as that of the maxillary anterior segmental
      dentoalveolar osteotomy.

PMID- 12592997
TI  - A stent fabricated on a selectively colored stereolithographic model for
      placement of orthodontic mini-implants.
AB  - The purpose of this report is to present a new method for placing orthodontic
      mini-implants using a stent fabricated on a selectively colored
      stereolithographic model. A stent was fabricated that incorporated a guide groove
      drilled in accordance with the planned direction of the mini-implant. Tooth
      crowns, gingiva, tooth roots, and the maxillary sinuses were clearly identified
      in the stereolithographic model. As a result, the stent could be fabricated while
      taking into account the anatomic characteristics of both the bone interior and
      the dental surface. A stent fabricated on the selectively colored
      stereolithographic model is suggested to be a promising device for guiding
      placement of orthodontic mini-implants adjacent to the tooth roots and the
      maxillary sinuses.

PMID- 12592998
TI  - The sagittal mandibular osteotomy under local anesthesia and intravenous
      sedation: four years of multicenter experience.
AB  - Today many surgical procedures involving head and neck areas can be performed
      under local anesthesia and intravenous sedation. The authors add to this list the
      sagittal osteotomies of the mandibular rami, thereby avoiding the need for
      general anesthesia and a hospital stay. The authors designed a protocol to be
      followed in a multicenter study (Milan and Barcelona) and applied it in 35
      clinical cases with Class II malocclusion. The surgical procedure was performed
      with the Monitored Anesthesia Care technique, a combination of regional
      anesthesia and intravenous sedation. The results were good in all the clinical
      cases; skeletal correction of Class II was achieved in all patients and there
      were no intraoperative or postoperative complications. The major advantage of
      this technique is the functional control of the temporomandibular joint, which
      avoids displacements caused by gravity and the muscular relaxation commonly seen
      under general anesthesia. Furthermore, this protocol allows a reduction in costs,
      duration of surgery, and patient morbidity and convalescence. When this technique
      is accepted without hesitation, all Class II patients with only mandibular
      deficiency deformity may be treated in the most suitable way, thus providing the
      most satisfactory outcomes for the patient, orthodontist, and surgeon.

PMID- 12592999
TI  - Three cases of anterior maxillary osteotomy under orotracheal intubation.
AB  - Anterior maxillary osteotomy is frequently applied to skeletal Class II cases
      with maxillary protrusion. In addition to the anteroposterior problem, these
      cases are often accompanied with a long midfacial appearance and display of
      incisors and gingiva during smiling. In the application of anterior maxillary
      osteotomy to such patients, it is necessary to move the anterior maxillary
      segments upward as well as backward. Since the upward movement occasionally
      interferes with the intranasal endotracheal tube, orotracheal intubation is
      recommended for the operation. Recently, the use of a resin replica of the
      mandibular dental arch was introduced to place the anterior maxillary segment
      correctly in the planned position and to obtain the correct occlusion. This
      article reports on 3 maxillary protrusive skeletal Class II patients with deep
      overbites and vertical esthetic problems treated by this method. The treatment
      results show that all 3 patients exhibited large upward and backward movements of
      the anterior maxillary segments and desirable facial profiles, with a reduction
      of the deep overbites after the treatment. This case report demonstrates that the
      anterior maxillary osteotomy under orotracheal intubation with the use of a resin
      replica is a useful method to treat maxillary protrusive skeletal Class II
      patients with a large alveolar height.

PMID- 12593000
TI  - The long-term clinical morbidity of mandibular step osteotomy.
AB  - The objectives of this retrospective study were to assess the clinical
      applications of mandibular step osteotomy (MSO) and to evaluate its long-term
      clinical morbidities. A total of 152 patients with MSO performed between 1990 and
      1999 were assessed. Forty-two patients were successfully recalled through
      questionnaires and clinical parameters for clinical evaluation, which included
      (1) tooth sensibility; (2) periodontal status; (3) neurosensory deficit in terms
      of light-touch threshold, 2-point discrimination, and pain threshold; and (4)
      temporomandibular joint function. The patients were finally asked about their
      overall satisfaction with the surgical treatment. The result revealed that MSO
      was commonly indicated for the correction of mandibular hyperplasia. Clinical
      assessments showed that 2.75% of the teeth assessed had negative pulpal response,
      3.9% showed mildly increased probing depth, and another 3.9% showed gingival
      recession. Neurosensory assessment revealed that 31% of the operating sites had
      an increased light-touch threshold, 4.8% had heightened 2-point discrimination,
      and 9% had an elevated pain threshold. Also, 9.7% of the patients showed reduced
      mouth opening and 17% had mild tenderness of masticatory muscles. Of all the
      patients assessed, 12% were not satisfied with the orthognathic treatment. The
      reasons included relapse, residual asymmetry, and persistent paresthesia.

PMID- 12593001
TI  - Osteogenic distraction and orthognathic surgery to correct sequelae of ankylosis
      of the temporomandibular joint: a case report.
AB  - A 17-year-old female patient presented with sequelae to ankylosis of the
      temporomandibular joint, which included vertical maxillary protrusion, anterior
      open bite, labial incompetence, micrognathia, undefined neck angle, facial
      asymmetry, Class II molar relationship, and Class III canine relationship. She
      presented with the following cephalometric and soft tissue data: SNA angle = 78
      degrees, SNB angle = 70 degrees, incisor-nasion-point A = 11 degrees, incisor
      nasion-point B = 33 degrees, Frankfort-mandibular plane angle = 43 degrees,
      occlusal plane = 25 degrees, subnasale-stomion = 20 mm, stomion superius-stomion
      inferius = 9 mm, stomion inferius-soft tissue menton = 30 mm, neck angle = 144
      degrees, and chin projection = 10 mm. Orthognathic surgery and mandibular
      osteogenic distraction were employed, specifically Le Fort I osteotomy to
      decrease a vertical excess of 12 mm, augmentation genioplasty of 17 mm, and
      bilateral extraoral distractors of bidirectional vector for a 14-mm augmentation
      of the mandible. The result was satisfactory with minimal adverse complications.

PMID- 12593002
TI  - Costs of surgical-orthodontic treatment in community hospital care: an analysis
      of the different phases of treatment.
AB  - To determine the distribution of costs and various influencing factors in the
      entire process of surgical-orthodontic treatment in community hospital care, a
      retrospective study was carried out. The records and radiographs of 99 community
      hospital patients operated on between 1994 and 2001 were included. Cost analysis
      data were gathered from 4 phases of treatment: the orthodontics, the surgical
      outpatient assessments, the surgery/surgeries, and the inpatient period. The
      results showed that the surgical phases together are responsible for roughly 61%
      of the costs, 28% of which were attributed to the surgical operation itself.
      Orthodontics made up approximately 39% of the total costs, with an average of 26
      visits. The average total costs of all treatments were US $6,206 +/- 912.
      Patients that could be operated on with bilateral sagittal split ramus osteotomy
      of the mandible only had the lowest costs, and those who required bimaxillary
      osteotomies had the highest costs. Of the several clinical and cephalometric
      measurements made in this study, only skeletal open bite and orthodontic space
      closure after tooth extraction were found to affect the costs. It can be
      concluded that surgical-orthodontic treatment is a rather expensive way to
      correct dentofacial malocclusions due to the high costs of the surgical phase.
      Skeletal open bite constituted the most costly entity, while malocclusion
      resulting from mandibular deformity was the cheapest.

PMID- 12593003
TI  - Blood transfusions in bimaxillary orthognathic surgery: are they necessary?
AB  - Excessive blood loss is one of the major complications of orthognathic surgery.
      Numerous strategies, including hypotensive anesthetic techniques and blood
      transfusion, have been developed to deal with the blood loss. Blood for
      transfusions can be obtained from banked blood or from autologous donation. In
      this study, the authors looked at 2 groups of patients who had bimaxillary
      orthognathic surgery. One group included patients who had autodonated blood
      (group 1) and who were operated on between 1991 and 1993, and the other patients
      did not autodonate and were operated on between 1998 and 2000 (group 2). It was
      found that fewer than 50% of patients in group 1 were transfused, and none of the
      group 2 patients were. A protocol to lessen blood loss that should obviate the
      need for blood transfusion is proposed. It is concluded that blood transfusion
      should no longer be a consideration during routine bimaxillary orthognathic
      surgery.

PMID- 12593004
TI  - Three-dimensional imaging in orthognathic surgery: the clinical application of a
      new method.
AB  - Many 3-dimensional (3D) techniques have been utilized to register and analyze the
      face in 3 dimensions, but each system has its own merits and disadvantages. C3D
      is a relatively new 3D imaging system that was developed to capture the 3D
      geometry of the face. Landmark identification on 3D facial models is facilitated
      by a software-based facial analysis tool developed by the authors. The
      reproducibility of landmark identification was high for 20 of the chosen points
      (standard deviations of repeated placements of landmarks around their centroids
      were 0.5 mm or less). The method is useful in studying facial soft tissue changes
      following orthognathic surgery and other types of facial surgery, as well as
      assessing facial soft tissue growth and development of the craniofacial complex.

PMID- 12593005
TI  - 3D stereophotogrammetric image superimposition onto 3D CT scan images: the future
      of orthognathic surgery. A pilot study.
AB  - The aim of this study was to register and assess the accuracy of the
      superimposition method of a 3-dimensional (3D) soft tissue stereophotogrammetric
      image (C3D image) and a 3D image of the underlying skeletal tissue acquired by 3D
      spiral computerized tomography (CT). The study was conducted on a model head, in
      which an intact human skull was embedded with an overlying latex mask that
      reproduced anatomic features of a human face. Ten artificial radiopaque landmarks
      were secured to the surface of the latex mask. A stereophotogrammetric image of
      the mask and a 3D spiral CT image of the model head were captured. The C3D image
      and the CT images were registered for superimposition by 3 different methods:
      Procrustes superimposition using artificial landmarks, Procrustes analysis using
      anatomic landmarks, and partial Procrustes analysis using anatomic landmarks and
      then registration completion by HICP (a modified Iterative Closest Point
      algorithm) using a specified region of both images. The results showed that
      Procrustes superimposition using the artificial landmarks produced an error of
      superimposition on the order of 10 mm. Procrustes analysis using anatomic
      landmarks produced an error in the order of 2 mm. Partial Procrustes analysis
      using anatomic landmarks followed by HICP produced a superimposition accuracy of
      between 1.25 and 1.5 mm. It was concluded that a stereophotogrammetric and a 3D
      spiral CT scan image can be superimposed with an accuracy of between 1.25 and 1.5
      mm using partial Procrustes analysis based on anatomic landmarks and then
      registration completion by HICP.

PMID- 12593006
TI  - Computer prediction of hard tissue profiles in orthognathic surgery.
AB  - The purpose of this retrospective study was to analyze the accuracy of computer
      predictions by CASSOS (Computer-Assisted Simulation System for Orthognathic
      Surgery) 2001 software (2000 SoftEnable, Technology). Forty adult patients who
      had undergone orthognathic surgery were evaluated. Pre- and postsurgical lateral
      cephalographs were scanned into the computer, and 71 landmarks for each
      cephalograph were digitized. Digitization error was assessed from repeated
      digitizations. A customized cephalometric analysis consisting of 14 measurements
      was used in this study. Predicted and actual postsurgical hard tissue landmarks
      were compared using the Student t test. Results showed good correlation between
      repeated digitization for all measurements. There were no statistically
      significant differences in 10 of the 14 measurements. The differences that were
      statistically significant were in angular measurements for SNA angle, upper
      incisor to maxillary plane angle (U1-MxP), interincisal angle (U1-L1), and upper
      incisor to anterior cranial base angle (U1-SN). The greatest mean difference
      measured was the interincisal angle (U1-L1) which, although statistically
      significant, was clinically insignificant. This investigation showed that CASSOS
      2001 software provides accurate hard tissue prediction for orthognathic surgical
      procedures.

PMID- 12593007
TI  - [Inhibition of tonic contraction of smooth muscle: a new approach to achieve
      erection dysfunction].
AB  - It has shown that vasoconstriction in the cavernosal circulation is mediated by
      the RhoA/Rho-kinase calcium sensitization pathway. Inhibition of Rho-kinase
      activity in cavernosal smooth muscle with Y-27632 resulted in an erectile
      response marked by elevated intracavernosal pressure (ICP) without a significant
      change in men arterial pressure (MAP). To explain how erection can occurred in
      the presence of this strong vasoconstrictive signal, we have hypothesized that
      nitric oxide (NO) induces vasodilation leading to erection by directly inhibiting
      activity of the RhoA/Rho-kinase pathway, thereby reducing vasoconstriction.
      Administration of Y-27632 restored erectile function in rat models of
      hypogonadism and hypertension, suggesting that Rho-kinase inhibition may have
      potential clinical value. In addition, our results show that topical application
      of Y-27632 may be an effective mode of treatment for erectile dysfunction.

PMID- 12593008
TI  - [Discussion of correlative factors and risk in patients with diabetic erectile
      dysfunction].
AB  - OBJECTIVES: To probe into the pathogenesis, prevention and treatment way of
      diabetic erectile dysfunction (DED). METHODS: The age, course, blood pressure,
      history of drink and smoke, relationship with DED were investigated in 126 DED
      patients of 320 diabetes mellitus. RESULTS: The prevalence of DED in male
      diabetic patients was 39.4% (126/320). It was found by the analysis of Logistic
      regression that the values of OR rise to 1.8467, 1.2614, 1.4508, 1.3212, 1.2065,
      5.3464 (P < 0.01), along with adding of 5 years in course, 10 years in ages, 2%
      in HbA1C, 4 kPa in systolic blood pressure, positive history of smoking and
      drinking respectively. CONCLUSIONS: Drinking is the most dangerous factor among
      all risk factors for occurrence of DED. It is very important to control blood
      pressure well, and to give up tobacco and drink in preventing occurrence of DED.

PMID- 12593009
TI  - [Influence of dibutyryl cyclic adenosine monophosphate on motility of sperm].
AB  - OBJECTIVES: To investigate the influence of cAMP/PKA signal transduction on human
      sperm motility, and to study the effect of dibutyryl cyclic adenosine
      monophosphate dibutyryl cyclic adenosine monophosphate (dbcAMP) on human sperm
      motility in vitro. METHODS: Sperm aseptically obtained by masturbation and
      prepared by swim-up technique from 10 healthy fertile men were incubated with
      different concentrations of dbcAMP. Measurement of mobility were carried out at
      20, 30, and 60 min in all specimens. RESULTS: The sperm treated with dbcAMP
      showed a significant increase in sperm progressive motility and the percentage of
      motile cells. The effect seemed enhanced with the increasing of dbcAMP
      concentration. VSL and VCL were not affected by dbcAMP. CONCLUSIONS: dbcAMP can
      activate the mobility of human sperm in vitro.

PMID- 12593010
TI  - [Diagnostic approaches of neurogenic erectile dysfunction].
AB  - OBJECTIVES: To discuss the diagnostic approaches of neurogenic erectile
      dysfunction(ED), and to improve the diagnostic efficacy. METHODS: Two hundred and
      one patients with ED were evaluated by physical examination, IIEF-5,
      intracavernous injection, colour duplex ultrasonography and bulbocavernosus
      reflex latency, respectively. RESULTS: Among those ED patients, 173, 201, 106, 57
      and 27 cases had undergone above-mentioned examines, 13 neurogenic ED and 188
      miscellaneous(and unknown-causes) ED were diagnosed. CONCLUSIONS: Neurogenic
      erectile dysfunction is a common disorder, the diagnostic approaches should be
      based on patient's situation.

PMID- 12593011
TI  - [Isolation and identification of spermatids in semen of male infertile patients].
AB  - OBJECTIVES: To develop a method by which large and purified populations of
      spermatids can be isolated in semen of male infertile patients. METHODS: A total
      of fifteen ejaculates containing cellular elements from infertile patients with
      various andrological pathologies were obtained after a 24-hour abstinence. A
      modified discontinuous Percoll gradient (15%, 22%, 30%, 40%, 50%, 60%)
      centrifugation method was used to isolate the spermatids. After centrifugation at
      2,000 r/min for 30 min at 18 degrees C, the single Percoll fractions were
      separated and analyzed in order to select the one with the greatest purity of
      spermatid. The germinal cells in each isolated fraction were counted using a
      Macro sperm counting chamber, then the contents of spermatids were determined by
      morphology (Wright-Giemsa staining method) and flow cytometry (FCM) analysis,
      while the contaminated leukocytes were assessed by anti-CD45 immunocytochemistry.
      RESULTS: After Percoll centrifuged, six single fractions were obtained.
      Morphology and FCM analysis showed that the 22% fraction contained mostly
      spermatids [(91.85 +/- 5.18)%, P < 0.005] and the mean density in this fraction
      was (1.010 +/- 0.786) x 10(5)/ml. While in the 30% fraction, various immature
      spermatogenic cells including spermatids were present and leukocytes mostly
      presented in the 60% fraction. CONCLUSIONS: A large population of relatively
      purified spermatids can be isolated from the ejaculates of infertile patients by
      using this modified discontinuous Percoll gradient centrifugation method.

PMID- 12593012
TI  - [Effects of chlorotriptolide and triptonide on chromosome aberration and
      micronuclei of bone marrow cell in male rats].
AB  - OBJECTIVES: To observe the effects of chlorotriptolide (T4) and triptonide (T7)
      on the chromosome aberration and micronuclei rates of bone marrow cell in male SD
      rats. METHODS: Antifertility doses of T4[80 micrograms/(kg.d)] or T7[317
      micrograms/(kg.d)] were given to male rats per OS for 10 weeks. Bone marrow
      slides were then prepared and compared with the controls. RESULTS: The chromosome
      aberration and micronuclei rates were not significantly different from those of
      the controls (P > 0.05). CONCLUSIONS: The results were in accordance with our
      previous reports about the effects of T4 and T7 on the chromosome aberration and
      micronuclei rates of rat spermatogenic cells. At the antifertility doses, T4 and
      T7 did not show a mutagenic effect.

PMID- 12593013
TI  - [Comparison of PSAD and PSAD-TZ value in prostatic hyperplasia and prostatic
      cancer].
AB  - OBJECTIVES: To compare PSAD, PSAD-TZ, PSA, FPSA/TPSA detection used in diagnosis
      of prostatic hyperplasia(BPH) and prostatic cancer(PCa). METHODS: Fourty-three
      cases of BPH and twenty cases of PCa with PSA < 20 micrograms/L were chosen, then
      compared PSA, PSAD, FPSA/TPSA, PSAD-TZ between BPH and PCa. RESULTS: The mean PSA
      in BPH and PCa is (10.47 +/- 6.25) microgram/L and (13.92 +/- 3.20) microgram/L
      respectively with no statistic difference (P > 0.05). The mean PSAD in BPH and
      PCa is (0.15 +/- 0.12) microgram/L and (0.24 +/- 0.13) microgram/L respectively
      with statistic difference (P < 0.05). The mean FPSA/TPSA in BPH and PCa is (0.58
      +/- 0.42) microgram/L and (0.26 +/- 0.17) microgram/L respectively with statistic
      difference (P < 0.05). The mean PSA-TZ in BPH and PCa is (0.26 +/- 0.22) and
      (0.51 +/- 0.28) respectively with obviously statistic difference (P < 0.01).
      CONCLUSIONS: The results suggest PSAD, FPSA/TPSA, especially PSAD-TZ could be
      used to distinguish BPH and PCa.

PMID- 12593014
TI  - [The apoptosis in damaged testicular tissue caused by varicocele].
AB  - OBJECTIVES: To investigate the effects of experimental varicocele on apoptosis of
      spermatogenic cells in rats. METHODS: Experimental varicocele was induced by
      partial ligation of the left renal vein in Wistar rat. Apoptosis cells were
      detected by in situ terminal deoxynucleotityl transferase-mediated dTUP nick end
      labeling(TUNEL) technique. RESULTS: There was certain proportion of apoptosis
      cells in spermatogenic cells in control group rats. The incidence of apoptosis
      increased remarkably in experimental group, the testicular growth was slower than
      that in control group. CONCLUSIONS: The apoptosis of spermatogenic cells caused
      by varicocele may play an important role in leading to subfertility.

PMID- 12593015
TI  - [Detection of DNA damage of human sperm using single cell electrophoresis].
AB  - OBJECTIVES: To detect the sperm DNA damage and to evaluate its significance in
      male reproductive using single cell gel electrophoresis (SCGE). METHODS: Four
      hundred and eighteen sperm samples were analysed using the computer assisted
      analysis system and SCGE. The sperms samples were divided into five grades
      according to the extent of the sperm nuclear DNA damage. RESULTS: 1. When the
      sperm density is less than 20 x 10(6)/ml, the occurence of grade II and III are
      increased significantly; 2. In the unmotile grade d sperm the occurence of grade
      I comet amounts was 5.39%, the occurence of grade II and III was remarkably
      increased. There was a evidently variance between the grade d and grade a + b
      sperm. CONCLUSIONS: SCGE can be used to detect the sperm DNA breakage and to
      evaluate the sperm quality and damage.

PMID- 12593016
TI  - [Discussion of new classification of epididymal malformation in cryptorchidism of
      children].
AB  - OBJECTIVES: To discuss the new classification of epididymal malformation in
      cryptorchidism. METHODS: One hundred and fifty-three boys who were two to four
      year old underwent orchidopexy for cryptorchidism and 144 hydroceles who were two
      to eight year old were enrolled into control. Based on the observation of the
      status between testis and epididymia, the length of epididymis and the
      configuration of epididymis as well as spermaduct, we divided epididymal
      malformations in cryptorchidism into three types. Type I: obstruction of sperm
      transport, including I A, I B and I C; Type II: possible obstruction of sperm
      transport, defined by II A and II B; Type III: no obstruction of sperm transport,
      classified into III A and III B. RESULTS: There were 47 (23.4%) out of 201
      undescended testes with malformation of epididymides and 16 (10.3%) out of 155
      testes in the control(P < 0.05). 11 of 48 cases of bilateral cryptorchidism had
      the same malformations, with 2 cases of type IB, 2 of IC, 1 of II A, 4 of III A
      and 2 of IV B underwent orchidopexy or orchiectomy. CONCLUSIONS: These data
      showed that the incidence of epididymal abnormalities in cryptorchidism was
      higher than that in the hydroceles and it's not essential to have orchiectomy
      unlimitedly to serious epididymal abnormalities.

PMID- 12593017
TI  - [A review of operative treatment of hypospadias in twelve years].
AB  - OBJECTIVES: To evaluate the relationship between the operative methods and the
      therapeutic results of the patients with hypospadias. METHODS: Nine operative
      types and different tissue materials taken in hypospadias operations in the past
      12 years were retrospectively analyzed. RESULTS: The operative types and tissue
      materials had significantly effects on the therapeutic results besides the
      clinical experience of the operators. The cure rates of Tunneltron Urethroplasty,
      Preputial island flap urethroplasty and Bladder mucosa graft urethroplasty were
      86.4%, 83.3% and 83.0% respectively. CONCLUSIONS: All the nine types and
      different tissue materials of Hypospadias operations have its own advantages and
      disadvantages. They are worth further study and improvement.

PMID- 12593018
TI  - [Effect of aging on male sexual function in 93 patients using international index
      of erectile function].
AB  - OBJECTIVES: To investigate the influence of aging on male sexual function.
      METHODS: The study selected 93 ED patients, aged from 23 to 64, who responded to
      the International Index of Erectile Function (IIEF) questionnaire. The
      questionnaire includes 15 items related to male sexual activity, which are
      organized into 5 domains, namely, erectile function (EF), orgasmic function (OF),
      sexual desire (SD), intercourse satisfaction (IS) and overall satisfaction (OS).
      For statistical analysis, ANOVA with DUNCAN test was conducted, and statistical
      significance was set at P < 0.05. Some other risk factors of ED such as
      hypertension, diabetes etc. had been excluded. RESULTS: According to the age, the
      subjects were divided into 5 groups. With age increasing, the proportion of
      moderate and severe in each group increased from 16.17% to 57.14%, whereas EF
      score decreased from (19.50 +/- 4.64) to (15.27 +/- 5.64), OF score decreased
      from (6.93 +/- 2.86) to (5.62 +/- 2.94), SD score decreased from (6.33 +/- 1.63)
      to (4.50 +/- 2.94), IS score decreased from (10.17 +/- 1.94) to (6.93 +/- 2.90),
      OS score decreased from (5.00 +/- 0.89) to (3.15 +/- 1.84). The tendency took on
      linearity (P < 0.01). Aging was negatively correlated to above mentioned scores
      (r = 0.98, P < 0.01). CONCLUSION: Aging could be thought as a risk factor of ED,
      which is negatively correlated with male's EF, OF, IS, OS and SD scores,
      furthermore. IIEF questionnaire is a useful tool assessing epidemiology of ED.

PMID- 12593019
TI  - [Comparative study of transurethral electrovaporization of prostate versus
      transurethral resection of prostate on benign prostatic hyperplasia].
AB  - OBJECTIVES: To compare the efficacy of transurethral electrovaporization of
      prostate (TUVP) with transurethral resection of prostate (TURP). METHODS: 206
      patients with symptomatic benign prostatic hyperplasia (BPH) whose prostatic
      sizes were all less than 60 grams were randomly divided into two groups. 97 cases
      were treated by TUVP while the other 109 cases were treated by TURP. The patients
      who underwent either TUVP or TURP were followed up for 12-34 months with an
      average of 20 months postoperatively. RESULTS: Both groups showed the significant
      decline in the mean IPSS (international prostatic symptom score) (P < 0.01), the
      mean PVR (Postovoiding Residual Volume) (P < 0.01), while increase in mean Qmax
      (Peak uroflow rate) (P < 0.01) in 12 months, 24 months after the operation. There
      were significant differences in the mean duration of operation or catheterization
      postoperatively (P < 0.05). The main complications of post-operation in the two
      groups were stress incontinence, TUR syndrome, urethral stricture, secondary
      bleeding. CONCLUSIONS: Both TUVP and TURP are effective treatment for the patient
      with BPH whose prostatic size is less than 60 grams. TUVP spends shorter time of
      the operation and postoperative catheterization than that of TURP.

PMID- 12593020
TI  - [One-stage repair of hypospadias using pedicled penis and scrotal septal
      symphysis skin flap].
AB  - OBJECTIVES: To evaluate the clinical application of one-stage repair of
      hypospadias using pedicled penis and scrotal septal symphysis skin flap. METHODS:
      One hundred and forty-nine cases of hypopadias were treated with the skin flap
      and followed up. RESULTS: After the operation, one hundred and twenty-two cases
      of patients obtained satisfactory outcomes, twenty-seven cases happened urethral
      leakage and preputial uredema were observed, and three cases suffered from
      urethral-skin fistula. CONCLUSIONS: This technique was an optimal choice to penis
      hypospadias, Penoscrotal hypospadias and light-duty scrotal hypospadias. It was
      simple and convenient and could prevent infection but manage of drain must be
      done postoperatively.

PMID- 12593021
TI  - [Microsurgical inguinal varicocelectomy with delivery of testis].
AB  - OBJECTIVES: To investigate the effect of microsurgical inguinal varicocelectomy
      with delivery of testis. METHODS: We use microsurgical inguinal varicocelectomy
      with delivery of testis to treat 48 patients with varicocele. RESULTS: After six
      months the 30 patients' sperm concentration and motility were significantly
      improved. 6 infertile patient's wives were pregnant. All patients did not have
      the complications such as recurrence, testis trophy and hydrocele. CONCLUSIONS:
      This method has advantages such as less recurrence, less complication and more
      effective.

PMID- 12593022
TI  - [The role of transforming growth factor beta superfamily in male germ cell
      development].
AB  - Transforming growth factor beta (TGF beta) superfamily can regulate the
      development of primordial germ cell (PGC) and gonocyte. TGF beta, bone
      morphogenetic protein (BMP), activin, inhibin, and anti-Mullerian hormone (AMH),
      all of which belong to the TGF beta superfamily, can play important roles in male
      germ cell development. Their downstream signaling molecules, Smads proteins are
      involved in the signal transduction pathway. In addition, TGF beta and AMH
      contribute to the apoptosis during development. Understanding this effect will
      help to elucidate the molecular mechanism of the early development of male
      reproductive system and the pathogenesis of testicular cancer.

PMID- 12593023
TI  - [Current opinion in vasculogenic erectile dysfunction].
AB  - Diagnosis of vasculogenic erectile dysfunction (ED), which can not based on
      single method, is the key for the successive surgical treatment.
      Revascularization is a safe, effective method to treat arteriogenic ED. The key
      for successive treatment is to select the most suitable patients and to avoid any
      risk factors for the surgical candidates, especially for those revascularization
      as the only therapeutic method. The high failure rate in surgery of ED is due to
      venous leakage which has led to these techniques being abandoned by almost all
      urologist. Newly appeared methods with little or no damage are welcome by the
      patients with vasculogenic ED, and the better results can be achieved by the
      combination of general treatment.

PMID- 12593024
TI  - [Influence of male genital bacterial infection on sperm function].
AB  - Male infertility is related to urogenital tract bacterial infection. The
      significance of bacteriosperimia for male infertility has been paid attention in
      recent years. Asymptomatic bacteriosperm may play an important role. However,
      litter is known about the adverse influence of some uropathogenic bacteria on
      sperm function. The article reviewed some uropathogenic bacteria in male
      urogential tract and several pathomechanisms of effect bacteria on sperm
      function.

PMID- 12593025
TI  - [Progress on Y chromosome microdeletions and male infertility].
AB  - About 10%-15% of azoospermic and 5%-10% of severely oligozoospermic men with
      idiopathic infertility have Yq microdeletions which could be transmitted to their
      male offspring by means of ICSI. We review present studies about Yq
      microdeletions including incidence, region, correlations between genotype and
      phenotype, the mechanism of Yq deletions and try to further understand the cause
      of male infertility as well as provide a new way for diagnosis and therapy.

PMID- 12593026
TI  - [Progresses on macrophages of male reproductive tract].
AB  - The review summarized the recent progress on macrophages of male reproductive
      tract and the action of macrophages on male reproductive physiology and
      pathology. The close correlation and effect between testicular macrophages and
      Leydig cells, Sertoli cells, germ cells, hypothalamic-pituitary-gonadal axis were
      introduced, respectively. At the same time, it pointed out the changes of
      macrophages' morphology and function in immune orchitis, and their regulation on
      the development of orchitis. So the complex immune regulation network in testes
      and testicular macrophages playing an important role on spermatogenesis and the
      stableness of spermatogenetic microenvironment in testes were further
      illuminated, which can provide theoretical basis for clinic therapy.

PMID- 12593027
TI  - [Community acquired pneumonia].

PMID- 12593028
TI  - [Pneumococcal pneumonia with bacteremia in adults: a descriptive study from the
      north-west of Spain].
AB  - OBJECTIVE: Analysis of adults patients (> 15 years of age) with Bacteremic
      Pneumococcal Pneumonia (BPP), in the Hospital Complex of Pontevedra. MATERIAL AND
      METHODS: 83 cases of BPP were studied in the last 6 years (1995-2000). RESULTS:
      There were 57 men and 26 women. The overall mean age was 56 year-old; in those
      smaller than 40 years, there was 60% infected by the HIV. The patients' two
      thirds, had > 1 predisposing condition, highlighted: the cigarette smoking, the
      alcoholism and the HIV infection. The typical clinical presentation of
      pneumococcal pneumonia, we find it in 73%. The calculation of the pneumonia
      severity index (PSI, Fine et al.), it framed half of the patients in the group of
      low risk of mortality. The resistance to the penicillin in the isolations, was of
      31%. The initial antibiotic treatment was modified, in 11% of the cases. The
      fatal cases (10%) had: superior age to 65 years, presence of mental confusion, a
      bigger hypoxemia and hypercapnia, admission in the ICU, atypical presentation,
      existence of pleural effusion and a PSI bigger than 140. CONCLUSIONS: The patient
      with BPP in our area, presents some similar clinical characteristics to those
      described in other series; the half is included in the group of low risk of
      mortality. Apart from other factors already well-known, a superior PSI at 140, is
      related directly with the mortality.

PMID- 12593029
TI  - [Levofloxacin versus beta-lactamic therapy in community acquired pneumonia that
      requires hospitalization].
AB  - OBJECTIVE: To compare the effectiveness and security of levofloxacin treatment in
      front betalactamic therapy in patient with community-acquired pneumonia that
      require hospitalization (CAPH). PATIENT AND METHODS: A prospective and randomized
      study along a year from 49 patients diagnosed of (CAPH) that were admitted in the
      Internal Medicine Service. The patients were assigned randomly to receive.-I:
      cefotaxime or ceftriaxone, II: amoxicillin/clavulanate (both could be associated
      or not with a macrolide) or III: levofloxacin. It was accomplished Rx. thorax to
      7-10 days, to the month and, other reviews if was necessary. RESULTS: 29 cases
      were in standard therapy (I or II) and 20 cases received levofloxacin therapy.
      Male 84%, half age 70.9 years old, 57% with moderate or severe underlying
      disease, and 55% with approaches of initial severity criteria. In 47% of the
      cases we arrived to etiologic diagnosis, in the third of the cases were BGN. The
      cure took place in 94% of the patients and 2 patients died (5%). No differences
      were observed regarding demographic characteristics, underlying disease and
      severity. No differences were detected in: the secondary effects, complications,
      hospital stay or, mean stay or percentage of cures. The necessity to prolong the
      therapy was bigger in the standard group in front of the group tried with
      levofloxacin (52% vs. 15%, p:0.02). CONCLUSIONS: In bigger population and with
      initial severity the treatment with levofloxacin can be a valid alternative to
      the standard therapy.

PMID- 12593030
TI  - [Hypophysio-adrenal axis in patients with chronic alcoholism].
AB  - OBJECTIVES: To study the situation of the hypophyso-adrenal axis in patients with
      chronic alcoholism. METHOD: 24 patients with chronic alcoholism admitted in our
      Institution with acute delirium were studied. Cortisol am and pm und (ACTH
      levels, along with hemogram with Wintrobe indexes, patelets number,
      triglicerides, total and HDL cholesterol, transaminases, alkaline phosphatase and
      gammaglutamyltranspeptidase were measured in serum. RESULTS: The mean values of
      ACTH am were 41.2 pcg/ml (normal values 10-80 pcg/ml), of plasma cortisol am 22
      mcg/ml (normal values 10-24 mcg/ml) and plasmo cortisol pm 12.3 mcg/ml (normal
      values 5-12 mcg/ml). CONCLUSIONS: The amount of alcohol consumed by alcoholic
      patients ist not comparable to that used in animal models, which induced adrenal
      hyperfunction. Blood ACTH and cortisol levels are not useful as indirect markers
      of alcoholism. The Wintrobe indexes and serum gammaglutamyltranspeptidase levels
      are more useful for that purpose.

PMID- 12593031
TI  - [Primary cardiac lymphoma: presentation of two cases in immunocompetent
      patients].
AB  - BACKGROUND: Primary cardiac lymphomas (PCL) are extremely rare in immunocompetent
      patients. Their pathogenesis seems obscure and a few studies which have sought
      Epstein Barr virus (EBV) agree that this is generally not demonstrable. CASES:
      Two cases of cardiac lymphoma have been described. In both cases, as usually
      occurs, the histological diagnosis was performed after post-mortem examination.
      Histological examinations revealed a B large cell lymphoma in both patients.
      Autopsy material from both cases showed an inflammatory focus distant from the
      tumoral mass. EBERs and LMP for EBV were negative. CONCLUSIONS: PCLs are often
      fast-growing tumours with a highly unfavorable prognosis. Epstein-Barr virus
      appears to play no role in the development of this malignant condition.

PMID- 12593032
TI  - [Pulmonary Sarcoidosis associated to crescentic glomerulonephritis: a case
      report].
AB  - Sarcoidosis is a chronic disorder of unknown etiology, characteristically by the
      presence of the typical noncaseating sarcoid granuloma. Any tissues can be
      affected, but the organ most frequently affected is the lung being more unusual
      in other organs. Primary glomerular involvement in sarcoidosis is unfrequent. The
      disorder most commonly associated is membranous glomerulonephritis. Rapidly
      progressive crescentic glomerulonephritis have been very scarcely reported. We
      report a case of rapidly progressive glomerulonephritis with crescents added to a
      previous membranous glomerulonephritis with the histological finding of an
      interstitial granuloma, which was clinically apparent in the context of a
      normocalcemic sarcoidosis, diagnosed as lung sarcoidosis two years before.

PMID- 12593033
TI  - [Bronchobiliary fistulae between a liver hydatid cyst and the middle lobe of the
      right lung].
AB  - We report a case of bronchobiliary fistula between a liver hydatid cyst and the
      middle lobe of the right lung. It is also reviewed the etiology, pathogenesis,
      clinical features, diagnosis and treatment of bronchobiliary fistulas.

PMID- 12593034
TI  - [Role of Clostridium difficile infection in the relapse of ulcerative colitis].
AB  - A case of nosocomial diarrhea by Clostridium difficile in an older woman with an
      old history of increasing stool frequency, is reported. Colonoscopy and biopsy
      was performed due to an incomplete response to vancomicyn, and the diagnosis of
      underlying ulcerative colitis was made. The incidence of Clostridium difficile
      infection associated with the relapse of ulcerative colitis is nearly 10%. In
      patients with ulcerative colitis, macroscopic pseudomembranes and the usual
      predisposing factors for Clostridium difficile infection, usually, are not
      present. It seems to exist a significant correlation between the severity of the
      relapse and Clostridium difficile. The specific treatment of the pseudomembranous
      colitis, in the majority of the cases, is sufficient for a correct control of
      relapse of ulcerative colitis.

PMID- 12593035
TI  - [Clinical benefits of tiotropium, a new anticholinergic bronchodilator].
AB  - Bronchodilators are, at the present time, the mainstay of symptomatic therapy in
      patients with chronic obstructive pulmonary disease (COPD). Anticholinergics are
      the first steep in the clinical management of these patients although its short
      half life constitutes a serious limitation in patients with persistent symptoms.
      However, there have been some important developments on this area. Tiotropium
      bromide, used once daily shows several clinical advantages when it is compared
      with ipratropium bromide or with long acting beta-2 agonists. This suggests than
      tiotropium bromide could be in coming years one of the first options for the
      treatment of COPD.

PMID- 12593036
TI  - [Diagnostic-therapeutic management of parathyroid carcinoma].
AB  - Parathyroid carcinoma is an uncommon endocrine malignancy, with difficult
      diagnosis. There are several presenting clinical and biochemical features that
      suggest it: much higher serum calcium and PTH levels than parathyroid adenomas,
      symptoms of severe hypercalcemia, the classical target organs affected and a
      palpable neck mass. Pathologic findings, local invasion, lymph node and distant
      metastases prove the diagnosis. Initial surgical therapy (en bloc dissection) is
      the only chance for cure it. The management of recurrent and/or metastatic
      parathyroid carcinoma is also surgical, resulting in significant palliation from
      hypercalcemia, whereas radiation therapy and chemotherapy are not helpful.
      Bisphosphonates (drugs that inhibit bone resorption) control acute and chronic
      hypercalcemia when surgery is not effective or possible. Preoperative
      localization studies (cervical ultrasound, CT scan, MRI and sestamibi scan) are
      useful in patients with recurrent or persistent parathyroid cancer.

PMID- 12593037
TI  - [Rudolph Virchow in the I centenary of his death].

PMID- 12593038
TI  - [Iron protein-succinylate in the treatment of adult iron-deficiency anemia].

PMID- 12593039
TI  - [Psoas hematoma].

PMID- 12593040
TI  - [A 77 years old patient with relapsing pleural effusion].

PMID- 12593041
TI  - [Utility of D-dimer in the diagnosis of pulmonary thromboembolism in the
      emergency service].

PMID- 12593042
TI  - [Constriction of the visual field by vigabatrin].

PMID- 12593043
TI  - [Aortic endocarditis caused by Salmonella sp. in an HIV infected woman].

PMID- 12593044
TI  - [Deep venous thrombosis and cancer: diagnosis].

PMID- 12593045
TI  - [Acute alopecia associated to empyema caused by actinomyces].

PMID- 12593046
TI  - SSM's CARE PATHWAYS boost patient compliance, lower readmission rates.

PMID- 12593047
TI  - Hospital achieves 90% compliance with pathways.

PMID- 12593048
TI  - Pathways to success: standardizing care throughout a diverse health care system.

PMID- 12593049
TI  - Providers customize form for giving notice of rights.

PMID- 12593050
TI  - Using data management for CM populations.

PMID- 12593051
TI  - 'Storytelling' by staff, patients brings issues to life, aids change.
AB  - Storytelling captures group's interest and personalizes key issues. Organizations
      such as the National Institutes of Health and the Institute for Healthcare
      Improvement have gotten on the storytelling bandwagon. Technique has a virtually
      unlimited range of potential applications.

PMID- 12593052
TI  - Ventilator education program reduces VAP.
AB  - Episodes are slashed 57.6%, more than $400,000 was saved. Multidisciplinary task
      forces draw up new policies, procedures. Program is mandatory for respiratory
      care practitioners.

PMID- 12593053
TI  - QIOs go beyond typical quality initiative.
AB  - An opportunity for improving performance and systems of care is to be identified.
      Three quality improvement organizations are to address a total of 10 different
      clinical areas. A eries of quality indicators will be used to inform decision
      making.

PMID- 12593054
TI  - Are patients' DNR orders overinterpreted?
AB  - Physicians sometimes refrain from other life-saving procedures. Physicians should
      openly discuss goals of therapy with patients. Educators must provide physicians
      with skills needed for such situations.

PMID- 12593055
TI  - Surgical gloves. How do you change yours?
AB  - Surgical gloves are frequently changed intraoperatively, and different techniques
      exist. We surveyed surgeons and scrub staff in our hospital and prospectively
      compared contamination between two glove changing techniques. We questioned 25
      surgeons and 25 scrub staff regarding their intra-operative glove changing
      technique. Twenty scrub staff performed a standard 'surgical scrub', following
      which aliquots of fluorescent powder were applied symmetrically to each forearm
      prior to donning gown and gloves. Subjects were randomised to group 1-open
      technique (OT) followed by closed technique (CT), or group 2-CT followed by OT.
      Following unassisted glove change, glove and hand contamination was assessed.

PMID- 12593056
TI  - Creutzfeldt-Jakob disease-the perioperative connection.

PMID- 12593057
TI  - Are perioperative nurses really patient advocates?

PMID- 12593058
TI  - The importance of research in nursing practice.

PMID- 12593059
TI  - A year in Whangarei.

PMID- 12593060
TI  - Adventures in perioperative Africa.

PMID- 12593061
TI  - Improving oxygenation when conventional ventilation fails: a case study.
AB  - Long periods of significant hypoxia do not disqualify a patient from becoming an
      organ donor. As the management of organ donor patients becomes more complex,
      recovery coordinators often have to change their thinking and resort to
      nonconventional means of management. This case study presents a hypoxic donor and
      how using pressure-control inverse ratio ventilation improved oxygenation in this
      donor. Before changing ventilator modes, the transplant surgeons were concerned
      about the long periods of hypoxia the patient had experienced during her
      hospitalization. After making the change, improving oxygenation, and
      demonstrating an improved oxygen state, 4 organs were recovered and subsequently
      transplanted. All the recovered organs functioned immediately after
      transplantation without any signs of poor performance. Although this treatment
      modality is not available at every institution, it can be used to improve
      oxygenation problems in organ donors.

PMID- 12593062
TI  - Education related to organ donation and transplantation in undergraduate nursing
      schools: 1993 versus 2000.
AB  - PURPOSE: To evaluate the change in the amount and type of content related to
      organ donation and transplantation in US nursing schools from 1993 to 2000.
      METHODS: A survey of 700 nursing schools was conducted in 2000, and its results
      were compared with results of a similar survey conducted in 1993. Three hundred
      fifty schools (53.3%) completed the 2000 survey, and 426 (61%) completed the 1993
      survey. RESULTS: Although the amount of time dedicated to donation (P = .82) and
      transplantation (P = .26) issues did not change significantly, the number and
      types of topics presented, such as minority concerns and cultural issues,
      increased significantly. There was also a significant increase (P = .002) in
      faculty ratings of whether it is important to expose new graduates to this
      content. A significant increase was also observed in the number of schools that
      reported that organ procurement professionals presented such content to students
      (31% to 42%, P = .006). CONCLUSION: Although the amount of time spent on these
      issues has not increased, the number of topics that are now included in the
      nursing curriculum has increased. In 2000, nursing faculty perceived such content
      as more important to include in the school's curriculum than in 1993. This change
      in perception may be a first step in creating a nursing workforce that is
      knowledgeable about organ donation and transplantation.

PMID- 12593063
TI  - A simple technique for aortic cannulation in organ donors with advanced aortic
      disease.
AB  - Cannulation of the abdominal aorta in organ donors with advanced arteriosclerotic
      disease or extensive trauma may be problematic owing to difficulty in securing a
      watertight tie around the diseased aorta, the danger of creating a false
      passageway in the aorta, and the risk of breaking off plaque particles that can
      advance into the arteries of donated organs. Cannulation problems can be avoided
      in these challenging donors by using a simplified technique for cannulation of
      the thoracic aorta in which a Foley catheter is passed down around the aortic
      arch, the balloon is inflated, and cool flushing is initiated.

PMID- 12593064
TI  - Ethics and regulation in organ procurement research.
AB  - This article explores the role of ethics and regulation in human research
      conducted by organ procurement agencies; basic ethical principles for human
      research are outlined. Organ procurement agencies are not required to observe
      federal regulations; however, voluntary adherence will ensure that procurement
      research is conducted according to current standards of ethical practice.
      Although most organ procurement research will qualify for exempt status, this
      determination should be made by an institutional review board. Even if studies
      qualify for exempt status, there is a moral presumption that informed consent
      should be sought, unless certain narrow conditions for waiver of consent are
      satisfied. Finally, when future research utilizing organ procurement records is
      anticipated, procurement coordinators should provide sufficiently detailed
      information to families about such plans to permit their advance informed consent
      to research activities.

PMID- 12593065
TI  - Increasing the quantity of lungs for transplantation using high-frequency chest
      wall oscillation: a proposal.
AB  - The use of chest physiotherapy in donor patient management occupies an
      established place in most lung procurement protocols. Although its merits remain
      controversial and uncorroborated by direct data, some studies support the
      efficacy of chest physiotherapy in a variety of pulmonary patient populations.
      Comparative studies have shown that an airway clearance technology utilizing high
      frequency chest wall oscillation clears pulmonary secretions as well as or better
      than chest physiotherapy, but has few of its contraindications and disadvantages.
      The implementation of high-frequency chest wall oscillation as part of the donor
      lung procurement protocol may increase rates of successful lung recovery by
      providing effective clearance of obstructing pulmonary secretions containing
      destructive by-products of inflammation and entrapped pathogens. High-frequency
      chest wall oscillation may also improve arterial blood gas values, a critical
      factor in increasing lung procurement rates. Although speculative, the benefits
      of high-frequency chest wall oscillation on donor lungs might improve perfusion
      and oxygenation of other organs for possible transplantation.

PMID- 12593066
TI  - Donor Action program in the Emilia-Romagna region of Italy.
AB  - CONTEXT: The high demand for organs for transplantation necessitates enhancement
      of organ procurement activity worldwide. OBJECTIVE: To detect critical areas in
      the organ donation process and to assess whether careful monitoring of deaths in
      each intensive care unit could improve rates of identification of brain death.
      DESIGN: Records of patients who died in intensive care units in the Emilia
      Romagna region between July 1, 1998 and June 30, 2000 were reviewed through the
      Donor Action program. RESULTS: Of the 2469 patients who died during the period
      studied, 1010 (40.9%) had severe brain damage, as indicated by a score of 3 on
      the Glasgow coma scale. A total of 857 patients with severe brain damage who had
      spent more than 6 hours in the intensive care unit (34.7% of all deaths) were
      considered as potential donors. Signs of brain death were observed in 383 (44.7%)
      of the 857 patients who died. Rates of identification of brain death increased
      from 36% to 55% during the study period. CONCLUSION: Considering that the
      characteristics of the study population had not changed, we believe that the
      Donor Action program was an important factor leading to the observed improvement
      in identification of brain death.

PMID- 12593067
TI  - Attitudes of potential candidates for heart and heart-lung transplantation to
      xenotransplantation.
AB  - CONTEXT AND OBJECTIVES: Whether the fact that a transplanted organ is non-human
      would affect acceptance levels among potential recipients of heart and heart-lung
      xenografts has not been determined. Studies in renal patients have produced
      contradictory results. Furthermore, no previous studies have examined the
      attitudes toward xenotransplantation among the chief caregivers of potential
      transplant recipients. PARTICIPANTS AND MEASURES: Fifty-nine patients and 54
      caregivers responded to a questionnaire that requested their views on
      xenotransplantation, the source and level of their knowledge about
      xenotransplantation, and the perceived costs and benefits of this intervention.
      Patients' and caregivers' attitudes to animal experimentation and killing animals
      for human benefit were also assessed by using a specifically designed attitude
      questionnaire. RESULTS: Fifty-six percent of patients and 48% of caregivers were
      unsure about xenotransplantation. Seventy-nine percent of patients and 85% of
      caregivers indicated that they had received little or no information about
      xenotransplantation, and what information they had received was from nonmedical
      sources. Availability of organs was the main perceived benefit (36% of patients
      and 40% of caregivers) and ethical and moral issues were the main perceived cost
      (20% of patients and 25% of caregivers). Overall patients and caregivers were in
      agreement with animal experimentation and killing animals for human benefit.
      CONCLUSIONS: Potential heart and heart-lung recipients and their caregivers have
      limited information about xenotransplantation and are currently unsure about the
      acceptability of this procedure. Although this uncertainty may be due to their
      lack of information about this intervention, it may also reflect concerns about
      the morality of breeding animals solely to provide organs for transplantation.

PMID- 12593068
TI  - Level of awareness about transplantation, brain death and cadaveric organ
      donation in hospital staff in India.
AB  - A questionnaire was distributed in a group of randomly selected hospital staff to
      ascertain the level and factors associated with awareness regarding organ
      transplantation, brain death, and cadaveric organ donation. Between October and
      December 2000, a total of 166 paramedical (nurses, technologists, medical
      physicists) and 100 nonmedical (administrative, clerical, engineering, social
      scientists, and miscellaneous) staff of a tertiary referral academic hospital in
      northern India received this questionnaire. Ninety-seven percent had good to
      excellent awareness about transplantation, 17.3% of the hospital staff thought
      that brain death was a reversible process, and 59.4% had misconceptions about the
      retrieval of cadaveric organs. A significant positive correlation (r = 0.147, P =
      .01) was observed between the awareness of transplantation, brain death, and
      organ donation. A significant association was also observed between the workplace
      (operating room and intensive care unit vs other areas) and awareness of
      transplantation (P = .048), and brain death and organ donation (P = .030).

PMID- 12593069
TI  - Life satisfaction among kidney transplant recipients: demographic and biological
      factors.
AB  - PURPOSE: The Transplant Learning Center is a program providing education and
      support for solid-organ transplant recipients taking cyclosporine (Neoral or
      Sandimmune). One goal of the program is to improve patients' quality of life,
      which may be influenced by demographic and biological factors, and in turn
      influences adherence to prescribed medication regimens. We analyzed the results
      from the initial survey of enrollees to better understand life satisfaction and
      to test the validity and reliability of the satisfaction scale used in the
      program. METHOD: Patients enter the program through self-selection: all enrollees
      who received a kidney transplant were included in this analysis. Satisfaction was
      measured using the Life Satisfaction Index, which includes 8 questions about
      aspects of satisfaction with the patient's life. Associations between the Life
      Satisfaction Index and demographic factors, comorbid medical conditions, adverse
      effects of immunosuppressants, and medication compliance were examined. RESULTS:
      All 3676 kidney transplant recipients who completed the initial survey were
      included. Mean satisfaction scores were highest in persons who were older than 64
      years, men, and those who were married. Satisfaction scores were positively
      correlated with education and income. Mean satisfaction score was significantly
      lower among persons with medical comorbidities, persons who reported that adverse
      effects of medications were more frequent, and persons who reported noncompliance
      with their medication regimen. CONCLUSION: The Life Satisfaction Index is a
      transplant-specific measure of health-related quality of life that can be used to
      help detect areas of potential concern in the clinical management of kidney
      transplant recipients.

PMID- 12593070
TI  - Prevalence of cardiovascular risk factors before kidney transplantation.
AB  - CONTEXT: Assessing the prevalence of cardiovascular risk factors is an essential
      step in developing risk profiles and individualizing interventions to reduce the
      cardiovascular morbidity and mortality of kidney transplant recipients.
      OBJECTIVE: To examine the prevalence of pretransplant modifiable, potentially
      modifiable, and nonmodifiable cardiovascular risk factors in patients who
      received kidney transplants between January 1, 1994, and December 31, 1996.
      DESIGN: An exploratory, retrospective nested case-control design was employed to
      assess pretransplant cardiovascular risk factors in kidney transplant recipients
      with documented posttransplant cardiovascular events (n = 12) and kidney
      transplant recipients with no documented posttransplant cardiovascular events (n
      = 66). Data were analyzed using frequencies, unpaired t tests, and chi 2
      analyses. RESULTS: Significantly higher means of body mass index values greater
      than 25 kg/m2 (32.3 +/- 5.8 kg/m2 vs 28.8 +/- 3.4 kg/m2) and serum total
      cholesterol levels greater than 200 mg/dL (254.5 +/- 5.7 mg/dL vs 242.3 +/- 39.3
      mg/dL) were noted in patients with documented cardiovascular events compared to
      those with no documented cardiovascular events, respectively. Diabetes was more
      prevalent in patients with documented cardiovascular events (33%); these patients
      were also predominantly African American men who had a higher prevalence of
      family and personal histories of cardiovascular disease (17% and 33%).

PMID- 12593071
TI  - Loss of the imagined past: an emotional obstacle to medical compliance in kidney
      transplant recipients.
AB  - Among kidney transplant recipients, the concepts of grief and bereavement have
      been considered in terms of graft rejection, side effects of drugs, or death of
      the donor. However, our research suggests that even after a successful kidney
      transplantation, patients may present with feelings of bereavement, grief, or low
      mood, which may appear paradoxical because they have just received a much desired
      transplant. This sense of bereavement should be considered in terms of an
      imagined past, which may help to understand the patient's current mood changes
      and medical noncompliance. In the case report presented here, we have used the
      concept of systemic integrative psychotherapy to analyze change in a patient's
      life. Based on our research, we suggest that feelings of bereavement and grief
      are generated as patients come to terms with their past, which has been
      irretrievably lost to chronic illness, and contemplate their future. Feelings of
      grief and bereavement in the posttransplant period may be due to the loss of an
      imagined past, and must be differentiated from the bereavement the patient feels
      for the donor and the donor family. These feeling of loss, if not resolved, may
      lead to social isolation and medical noncompliance.

PMID- 12593072
TI  - Graft expression of p38 and tumor necrosis factor-alpha in heart transplantation
      in rats.
AB  - OBJECTIVES: To investigate the expression of p38 mitogen-activated protein kinase
      and its relationship with myocardial apoptosis and tumor necrosis factor-alpha
      during acute cardiac allograft rejection and to study the effects of tacrolimus
      on the expression of the kinase. METHODS: Rats were divided into 3 groups:
      isograft (Lewis heart to Lewis rat; control group), allograft (Brown Norway heart
      to Lewis rat), and tacrolimus-treated allograft (Brown Norway heart to tacrolimus
      treated Lewis rat). Grafts were collected 1, 3, 5, and 7 days after
      transplantation for determination of histopathological features, apoptosis of
      cardiac cells (by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick
      labeling), number of cells positive for both p38 and CD8 (by laser scanning
      confocal imaging), and expression of the kinase (by Western immunoblotting) and
      tumor necrosis factor-alpha (by reverse-transcriptase polymerase chain reaction).
      RESULTS: Compared with isografts from the control group, grafts from the
      untreated allograft group had significantly more apoptotic cells, greater
      expression of tumor necrosis factor-alpha and p38 mitogen-activated protein
      kinase, and more CD8-p38 double-positive cells at 5 and 7 days (P < .05). The
      increases were prevented by treatment with tacrolimus. CONCLUSIONS: The findings
      that the number of apoptotic cells, the number of CD8-p38 double-positive cells,
      the expression of tumor necrosis factor-alpha and p38 mitogen-activated protein
      kinase all increased during the same period in the allografts in
      nonimmunosuppressed recipients suggests that intragraft expression of p38 would
      be associated with the rejection in acute cardiac allograft rejection. Tacrolimus
      may alleviate rejection partly by inhibiting p38 mitogen-activated protein
      kinase.

PMID- 12593073
TI  - North American Transplant Coordinators Organization Public Policy statement.
      Living donor transplantation.

PMID- 12593074
TI  - [Strategies, culture, originality, priority of nursing research].

PMID- 12593075
TI  - [Evaluation of 2 tools for measuring the risk of falls among patients].
AB  - To select a risk assessment tool to predict which elderly inpatients will fall,
      two widely used risk assessment scales (Conley and Stratify) were compared to
      evaluate their sensibility and specificity. A sample of 2651 patients were
      included in the survey (1620 evaluated with the Conley; 1181 with the Stratify
      and 173 with both scales). One hundred and 33 patients fell during the hospital
      stay (5% of the sample but 1% of all the hospital admissions). Both scales show
      low values of sensibility (0.69 Conley and 0.20 Stratify) or specificity (0.41
      Conley and 0.87 Stratify) with a likely hood ratio of 1.18 and 1.55 respectively.
      Neither scale is more predictive for stratifying at risk patients. The Conley
      scale is more sensible in discriminating at risk patients but its use must be
      accompanied by the clinical assessment of the patients.

PMID- 12593076
TI  - [Retrospective survey on falls among hospitalized patients].
AB  - Patients' falls are a frequent event, especially for hospitalised patients, with
      a substantial impact on their health and healthcare costs. In the Careggi
      Hospital (Florence) the reports of patients' falls were analysed to provide real
      life based information on the problem and to explore the possibility of
      preventive planning. During the year 2000, 359 patients (0.44% of all admitted
      patients) suffered an event of fall. Medical wards and wards with stroke patients
      show the higher incidence of falls (0.71% and 0.66% of all admitted patients
      respectively). The larger majority of patients who fall (68.2%) were over 65
      years and almost half (46.7%) of the falls occurred during the night shift. Up to
      79% of patients reported some consequences but only 3.6% of them reported major
      consequences requiring a prognosis > 10 days. The preventive strategies adopted
      are described.

PMID- 12593077
TI  - [Perception of stress factors among patients admitted to an intensive care unit].
AB  - A descriptive study was conducted to identify stress factors for patients
      admitted to an Intensive Care Cardiac Surgery Unit of a Northern Italy hospital
      (Trento). Stress factors were identified according to the opinion of nurses and
      patients and differences in perceptions were explored. Patients and nurses were
      asked to rank the main stress factors from a list of 30 and to rate each over a
      scale of 4 points from 1 to 4 (1 not at all and 4 very stressful). Data were
      collected from the end of September to the end of October 2001. Patients rate as
      more stressful the presence of endotracheal tube (as well as the associated
      point) the impossibility to communicate, suctioning manoeuvres, pain in general.
      Nurses rate as more stressful for the patients the endotracheal tube, the
      suctioning manoeuvre, the worries for the outcome of the heart surgery and the
      impossibility to communicate pain. No statistically significant differences were
      observed for the more important stress factors, but nurses tend to overestimate
      the stress related to factors rated as least important by the patients.

PMID- 12593078
TI  - [Yom Kippur in Sabra].
AB  - The Sabra and Chatila are slaughter are recalled in the memory of jewish-american
      nurse that, after 20 years, comes back to the places were she witnessed the
      massacre made by the israeli army. The choice to be there on the occasion of the
      30th anniversary, to pray and remember, to honour the victims and meet those
      survived, and refugees, still waiting to return to their native land.

PMID- 12593079
TI  - [The impact of nurses shortage].

PMID- 12593080
TI  - [Prevention of falls among elderly people: comparison of guidelines].

PMID- 12593082
TI  - [The challenges of democracy].

PMID- 12593081
TI  - [What is a real therapeutic advance].

PMID- 12593083
TI  - [The incredible "yes" of Mary].

PMID- 12593084
TI  - General prescribing principles. Choosing a drug: 2.

PMID- 12593085
TI  - At-risk nursing staff must test negative for diseases.

PMID- 12593086
TI  - Partners in crime.

PMID- 12593087
TI  - Lone dangers.

PMID- 12593088
TI  - Risky business.

PMID- 12593089
TI  - A sense of belongings.

PMID- 12593090
TI  - Freedom on the front line.

PMID- 12593091
TI  - Ahead of the game.

PMID- 12593092
TI  - Physical health care in medium secure services.
AB  - BACKGROUND: The physical healthcare needs of patients in medium secure units
      (MSUs) are often overlooked. The authors of this article audited patients in one
      forensic MSU to establish the extent of the problem and patients' desire to lead
      a healthy lifestyle. CONCLUSION: Fifty six patients were questioned using semi
      structured interviews. The number of patients who smoke was found to be
      disproportionately high (84 per cent) compared to the general UK population (27
      per cent). The authors also found a correlation between length of stay on the
      unit and increase in body mass index. The authors describe measures taken to
      promote the physical wellbeing of patients in the unit.

PMID- 12593095
TI  - Shape and size of teeth of dogs and cats-relevance to studies of plaque and
      calculus accumulation.
AB  - Crown width, height and buccal surface areas were measured on heads or skulls of
      four dogs and four cats, and were compared with similar measurements on models of
      human dentition. Buccal surface area variability was greater in dogs and cats
      than in humans, and teeth of cats were smaller. Horizontal (gingival and occlusal
      halves) and vertical (mesial, middle, and distal thirds) buccal surface area
      variability was also greater in canine and feline teeth compared with human
      teeth. This increased variability suggests the need for testing of reliability
      and repeatability of scoring when using plaque and calculus indices based on
      horizontal or vertical segmentation. Buccal surface area variability between
      teeth also prompts questioning the validity of equal weighting of smaller,
      irregularly-shaped teeth when calculating a mean mouth score. Whether equal or
      more reliable results would be obtained from scores of whole teeth in comparison
      with segmentation indices used currently has yet to be determined.

PMID- 12593093
TI  - Attitudes to long-term care in multiple sclerosis.
AB  - At a recent conference workshop, a group of specialist nurses examined their
      attitudes towards individuals with multiple sclerosis moving into long-term care.
      This article summarises how the group members examined their attitudes, the
      literature reviewed and what was learnt by sharing experiences. It also suggests
      how nurses could promote positive attitudes towards, and ease, the transition of
      patients into long-term residential care.

PMID- 12593094
TI  - Nursing the breathless patient.
AB  - In this article, Clare Bennett provides an overview and update of respiratory
      assessment and symptom management. The causes and symptoms of breathlessness are
      discussed, along with assessment methods and nursing interventions.

PMID- 12593096
TI  - Physical ergonomics in veterinary dentistry.
AB  - Ergonomics is the application of a body of knowledge addressing the interactions
      between man and the total working environment, such as atmosphere, heat, light
      and sound, as well as all tools and equipment of the workplace. Work related
      musculoskeletal injuries, caused by poor posture, have been discussed in human
      dentistry for several years. Veterinary dentistry, as a relatively new specialty
      within veterinary medicine, should address the ergonomics of poor posture without
      further delay to prevent work-related injuries. The generalist, as well as the
      specialist and their technicians, are subject to various neck and back disorders
      if proper ergonomic recommendations are not followed. This review article
      highlights basic ergonomic design principles for illumination and posture in
      veterinary dentistry.

PMID- 12593097
TI  - Effect of a dental chew on dental substrates and gingivitis in cats.
AB  - The use of special diets or dietary adjuncts, although not eliminating the need
      for regular professional therapy, may serve to improve gingival health during the
      interval between professional oral health assessments and intervention. This
      study was performed to determine the effect of a dental chew on dental hygiene
      and gingival health in cats. The accumulation of dental substrates and the
      development of gingivitis were assessed in cats fed either a dry diet only or a
      dry diet supplemented with dental chews. A two-period, crossover design was used
      with the test phase lasting 4-weeks. Results indicated that the daily addition of
      dental chews to a dry diet was effective in reducing plaque and calculus
      accumulation on tooth surfaces in cats, as well as reducing the severity of
      gingivitis.

PMID- 12593098
TI  - Pulp canal obliteration in a dog.

PMID- 12593099
TI  - Surgical extraction of the maxillary fourth premolar tooth in the dog.

PMID- 12593100
TI  - [Nursing diagnosis for patients with neurogenic bladder].
AB  - This article proposes to deepen the nursing knowledge about patients with urinary
      disorder associated with neurogenic bladder, starting from a bibliographic review
      in order to establish interventions that can help in the treatment and
      implementation of adequate measures of care and comfort of those situations. It
      describes the etiology, classification, exams, medical diagnosis, alternatives to
      treatment and complications from the pathology giving a greater understanding of
      that disorder. It explains the actions of nursing assistance on such cases.

PMID- 12593101
TI  - [Students' perception on health education in hospital practice].
AB  - In the present study, we identified, through students' view, methodological ways
      of working with health education in hospital curricular practice and the
      importance of trying to change the future of health in the country. This
      descriptive and qualitative research involved 66 undergraduate students of a
      nursing school of a private university located on the metropolitan area of Porto
      Alegre. The results showed that the students realize the importance of education
      for health and that this education should be carried out through orientation on
      the bedside and/or in groups taking into consideration each patient's
      individuality.

PMID- 12593102
TI  - [Women's perceptions on risk pregnancy and family implications].
AB  - This study aimed to identify the women's perceptions of risk pregnancies and to
      investigate its implications to the families. The data was collected through a
      qualitative approach, using semi-structured interviews during the months of March
      and April of 1999. Five pregnant women were interviewed at the Obstetric Clinic
      of the University Hospital Julio Muller in Cuiaba/MT. It was found that the women
      sometimes experience confused and contradictory feelings, since the "myth of
      motherhood and maternal love" is still very strong in our society. It was
      observed that the involvement and support of the family during a risky pregnancy
      are very important to the pregnant woman.

PMID- 12593103
TI  - [Work reality and the construction process of the nurse's identity].
AB  - This study tries to understand the relation between the reality of the nurse's
      everyday work and the construction process of this identity, using Agnes Heller's
      sociological theory of everyday life as the main reference. The possibilities of
      the worker's expression and fulfillment occur through objective and subjective
      elements of job reality which comes upon the worker as people who put order and
      tension in their everyday job; these job determinants imprint and produce
      impacts, giving sense to the work quality and constructing concrete possibilities
      to the worker to manifest him/herself as Whole being, guiding the construction of
      his/her identity.

PMID- 12593104
TI  - [Reasons for discontinuing intravenous therapy associated with the time of in
      situ permanence of peripheral venous devices].
AB  - This study aimed to relate the reasons for interrupting intravenous therapy and
      the time of in-situ permanence of venous devices. The results obtained showed
      that in 38 of the 75 punctures performed, the reason to interrupt the venous
      therapy took place after the end of the therapy and that time of in-situ
      permanence of peripheral devices varied from 24 to 48 hours. In 15 punctures, in
      which infiltration was the reason for interruption, the time of permanence was
      shorter than 24 hours. It is believed that the data gathered in this
      investigation should be analyzed by nursing professionals, aiming to enhance new
      educational programs in services related to intravenous therapy.

PMID- 12593105
TI  - [The intensive care nurse and care focused on the family: a proposal for
      sensitivity].
AB  - The aim of this work was to sensitize the nurses of the an intensive care unit,
      through continued education, to the importance of planning the care of the
      critical clients in partnership with them and their families. By doing so we
      meant to amplify the humanization and to bring Public Health System prerogatives
      closer to nursing practice. The nurses attended a workshop and from their reports
      emerged some categories of analysis that at some moments show resistance to
      modify the present practice and at other moments, the desire to transform the
      reality they live in, sensitizing them to the thematic.

PMID- 12593106
TI  - [The CIPESC-Brazil Project: characterization of nursing in Porto Alegre].
AB  - This paper was written using data collected to characterize the labor force of
      nursing and its developed practices on a major project called "Project of
      Classification of Nursing Practices in Collective Health in Brazil". The study
      took place at the Sanitary Districts V and VI of Porto Alegre. The data was
      collected in 1998, through the application of two forms. They were completed by
      28 nurses, 6 nursing technicians, and 101 nursing aids. The results show that
      nurses develop administrative activities, while nursing technicians and nursing
      aids support medical actions, those activities being considered insufficient to
      the development of the Nursing Practice in Collective Health.

PMID- 12593107
TI  - [From classical management to contemporary management: understanding new concepts
      to empower nursing management].
AB  - This theoretical work aimed to study Hospital Administration, focusing on Nursing
      Management. The author points out contemporary administration concepts, and leads
      us to think over how those new models of management (already in use in some
      institutions known as pioneers on this area) may have influence on the Nursing
      Management practice inserted on the context. The author concludes that Nursing is
      going through a transition moment, breaking paradigms, trying to get over
      Classical Administration beliefs and searching for flexible, humanized and shared
      ways to manage Nursing Care.

PMID- 12593108
TI  - [Delivery: a violent act against the newborn?].
AB  - The institutionalization and technological interventions of birth have made it an
      event that belongs to the health team and not to the mother, family and the
      child, interfering on the attachment bounds of parents and baby. This paper
      discusses on a theoretical-reflexive perspective the fact that the event of birth
      has been an act of violence against the newborn. It analyses the current
      conceptions and practices of the institutionalized process of birth and also
      emphasizes that the newborn must be considered a human being with rights. To meet
      the needs and expectations of the newborn's relatives should be the goal of
      health teams to humanize delivery and birth. Also, the fact of giving adequate
      attention to mother/baby and family relations will contribute to a better
      emotional life quality of future generations.

PMID- 12593109
TI  - [Skin care in newborns].
AB  - This article is based on brief recent revision of the scientific literature about
      the care with the skin of the newborn. The text deals with the anatomo-physiology
      aspects of the skin culminating with the specific care of the skin of newborn in
      Neonatal Intensive Care Unit. Considering the highest risk of the pre-term
      newborn to acquire infections, a special nursing care is proposed regarding the
      skin function as a protective barrier of the organism.

PMID- 12593110
TI  - [Recovering reformist practices of psychiatric care and mental health in Rio
      Grande do Sul].
AB  - This article rescues the practices of reformulation of the psychiatric assistance
      in Rio Grande do Sul, Brazil. The influence of the reformists' movements like the
      institutional psychotherapy, the therapeutic community, the sector psychiatry,
      the preventive psychiatry and the democratic psychiatry are recovered.

PMID- 12593111
TI  - [Analysis of Watson's curative factors at an emergency unit].
AB  - The objective of this study was to analyze the development of Jean Watson's ten
      carative factors in the process of caring with clients and their families in an
      emergency unit of a general hospital in Florianopolis. It was based on the
      convergent-assistance research design, and developed with 91 clients, from
      September 3 to November 30, 2001. The development of Watson's ten carative
      factors in the process of caring was effective in the emergency unity
      contributing to an approach more humanized and with greater quality when compared
      to another which emphasizes only the biological dimension.

PMID- 12593112
TI  - [Unveiling meanings of the first in-bed patient bathing to students at a school
      of nursing assistants].
AB  - The present study aims to unveiling the meanings of first inbed patient bathing
      for students of a school of nursing assistants. The present study had a
      qualitative design and counted with a phenomenological-hermeneutic approach.
      Study participants were six students. Data collection was carried out through a
      semi-structured interview; and discourse analysis was done with a hermeneutic
      approach (RICOUER, 1990; MOTTA, 1997; CROSSETTI, 1997). Topics unveiled were both
      the act of facing a new situation and inbed bathing as a moment of providing
      healthcare. We believe that the understanding of these meanings is essential for
      the planning of healthcare teaching, helping students to overcome difficulties
      during inbed bathing.

PMID- 12593113
TI  - [The family and the transformation of psychiatric care: views that coincide or go
      against each other].
AB  - This paper aimed to consider about how the family is seen on the transformation
      process of the psychiatric care and how the family responds to this expectation.
      It was developed from literature review about the subject with emphasis given to
      the papers about the families of popular classes. It was noticed that the family
      is on focus of the Mental Health professionals, both to be helped as well as to
      help fulfill the changes expected on this care field. Nevertheless, not always
      enough support is given in a way that enable them to walk on this direction, so
      that a closer approach is necessary between those social actors.

PMID- 12593114
TI  - [Coma and its impact on the process of being and living: implications for nursing
      care].
AB  - This is a hermeneutic phenomenological study based on the Van Manen's framework,
      that aimed to distinguish the meanings of the experiences lived in the state of
      coma and its impact on the being and living process. It was developed with four
      participants, three males and one female. Based on the analysis of the
      information three themes were identified: the unexpected as reality; the
      singularity of the modified states of consciousness, and the transformation of
      the being and living process. The coma emerged as an unexpected and unique
      process, permeated by different and modified states of consciousness; and
      possibly the unconsciousness as a state of inner life; and having a great impact
      on the life process of the participants. Finally we addressed some implications
      for the nursing care.

PMID- 12593115
TI  - [Living and being health in human aging contextualized through oral history].
AB  - This is a qualitative study with a focus on aging in the healthy living process,
      through the Thematic Oral History. Eight interviews were conducted with elderly
      people, four of them belonging to the UNIVIDA extension project at UNIVALI and
      the other to the SESC elderly group-Florianopolis (SC). The spiritual dimensions,
      of gender, work, esthetics and the art of aging emerged from the narratives,
      allowing to contextualize the healthy aging process. This group of elderly people
      managed to break stereotypes or prejudices existing in our society, becoming
      agents of the changing mentality process.

PMID- 12593116
TI  - [Implementation of a school health listener: experience report].
AB  - During the year of 2000, in a Junior High School of Porto Alegre, a health
      listener service was introduced aiming to ease the path of the school community
      to information and to answer their health needs. The activities were based on
      three axes: Developing Adults Capabilities, Assistance and Education. Those
      activities focused on health and tried to approach different subjects according
      to the school community needs. Through this work, we support the importance of
      developing workshops and nursing consultations as efficient ways to bring
      education and health to the community.

PMID- 12593117
TI  - [Experience with a group in nursing care for diabetics].
AB  - With the implementation of a diabetic group, the objective of this paper is to
      analyze the importance of this activity as a nurse's work tool and to evaluate it
      from the user's point-of-view. It is an experience report based on the
      information from the participating observation and the registrations in a field
      diary. It focuses the interpersonal relations, the understanding level of the
      received information, the diabetics' feelings and expectations. It was noticed
      that the human relationship and the experiences exchange based on cooperation
      contribute to the efficiency in the diabetes treatment.

PMID- 12593118
TI  - Don't forget to ask: using focus groups to assess outcome.

PMID- 12593119
TI  - Making the grade.

PMID- 12593120
TI  - Evaluation of the STRATIFY falls prediction tool on a geriatric unit.
AB  - Accurate prediction of fall-prone hospitalized older adults may be integral to
      reducing falls. The STRATIFY, a simple 5-point falls prediction tool, was
      prospectively validated on a Geriatric Assessment and Rehabilitation Unit as a
      one-time initial predictor of patients likely to fall. Sensitivity and
      specificity were lower than in the original British study. Introducing risk
      assessments validated elsewhere on a patient care unit or on a hospital-wide
      scale requires caution.

PMID- 12593121
TI  - A balanced scorecard approach for nursing report card development.
AB  - In this article we describe the process used to introduce and structure a nursing
      perspective as part of a balanced scorecard framework within a provincial
      hospital performance report. Results of a critical literature review and
      consultative process with key informants are outlined. Nurse-sensitive indicators
      emerged in the areas of system integration and change, clinical utilization and
      outcomes, patient satisfaction, and financial performance.

PMID- 12593122
TI  - Resource utilization in home health chronic obstructive pulmonary disease
      management.
AB  - Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death
      in this country, with a total annual cost of approximately $23 billion. This
      study examined the impact on total resource utilization when a pulmonary
      specialty team manages the in-home healthcare of the patient suffering from
      advanced COPD. Following implementation of the pulmonary specialty team, the use
      of hospital, emergency department, and skilled nursing facility resources
      decreased while home healthcare resource use increased. The overall costs were
      reduced on average by more than $13,000 per patient.

PMID- 12593123
TI  - Documentation of preventive education and screening for osteoporosis.
AB  - The purpose of this study was to identify provider documentation practices
      related to osteoporosis prevention and screening for women aged 40 to 65 years
      and to determine whether documentation practices differ by type of provider. The
      setting was an obstetric/gynecologic clinic of a large metropolitan health
      maintenance organization in Minnesota. One hundred fifty medical records were
      reviewed for documentation addressing calcium intake, vitamin D intake, exercise,
      hormone replacement therapy (HRT), and bone mineral densitometry. A statistically
      significant difference was found between physicians and advanced practice nurses
      in the documentation of vitamin D and HRT as osteoporosis prevention strategies.
      The results of this study suggest a need for increased awareness on the part of
      providers about the importance of their comprehensive documentation of counseling
      and education interventions as one strategy to promote positive outcomes such as
      osteoporosis prevention.

PMID- 12593124
TI  - Incidence of postoperative complications among coronary artery bypass patients
      with and without hypertension.
AB  - Patients (n = 3301) undergoing first-time elective coronary artery bypass
      surgery, between 1994 and 2000, with or without hypertension were compared for
      the incidence of postoperative complications. Fifty-five leg infections were
      documented (overall incidence 1.7%). Hypertension patients had a significantly
      increased risk of leg infections (2.45% versus 0.46%). A 10-year increase in age
      was associated with a 44% increased risk of leg infections (odds ratio = 1.44;
      95% confidence interval = 1.09, 1.91). Hypertension patients also had a greater
      risk of stroke and prolonged ventilation time but not of postoperative mortality.

PMID- 12593125
TI  - Multidimensional construct of health-related quality of life for Chinese dialysis
      patients.
AB  - Quality of life is a term frequently used but seldom well defined in nursing
      research. The lack of a consistent definition and measures to assess the various
      quality of life dimensions makes it difficult to compare research findings across
      multiple studies. The aim of this article was to identify the factors that
      constitute quality of life as perceived by Chinese dialysis patients in Hong
      Kong.

PMID- 12593126
TI  - Approach to imaging the patient with neck pain.
AB  - Neck pain is a common complaint of patients seeking care in the outpatient
      setting, and the cases seen vary widely in severity and cause. A careful history
      and physical exam, followed by appropriate imaging studies, are essential for the
      orderly work-up and management of neck pain in the ambulatory patient. Available
      imaging studies include plain film radiography, computed tomography (CT),
      magnetic resonance, and CT myelography. The general considerations necessary to
      select the appropriate imaging study are discussed for a broad spectrum of common
      disorders.

PMID- 12593127
TI  - Susceptibility contrast and arterial spin labeled perfusion MRI in
      cerebrovascular disease.
AB  - PURPOSE: To directly compare dynamic susceptibility contrast (DSC) and continuous
      arterial spin labeled (CASL) magnetic resonance (MR) perfusion techniques in
      patients with known cerebrovascular disease, with the goals of identifying
      possible pitfalls in interpretation and determining potential for a complementary
      role in this setting. METHODS: DSC and CASL MR perfusion studies were performed
      and compared in 11 patients with acute and/or chronic cerebrovascular disease.
      Using an automated segmentation technique, Pearson correlation coefficients were
      generated for CASL perfusion measurements compared to DSC perfusion maps (time-to
      peak [TTP], relative cerebral blood volume [rCBV], cerebral blood flow [rCBF],
      and mean transit time [MTT]) by hemisphere and vascular territory. RESULTS: TTP
      maps obtained using DSC perfusion MR correlated best both subjectively and
      objectively with CASL perfusion MR measurements when all patients studied were
      considered. If patients with a major transit delay were excluded, DSC rCBF
      correlated best with CASL CBF measurements. CONCLUSION: There may be a
      complementary role for CASL and DSC perfusion MR methods in cerebrovascular
      disease, especially in the setting of a marked transit delay.

PMID- 12593128
TI  - Residual flow signals predict complete recanalization in stroke patients treated
      with TPA.
AB  - BACKGROUND: Residual blood flow around thrombus prior to treatment predicts
      success of coronary thrombolysis. The authors aimed to correlate the presence of
      residual flow signals in the middle cerebral artery (MCA) with completeness of
      recanalization after intravenous tissue plasminogen activator (TPA). METHODS: The
      authors studied consecutive patients treated with intravenous TPA therapy who had
      a proximal MCA occlusion on pretreatment transcranial Doppler (TCD). Patients
      were continuously monitored for 2 hours after TPA bolus. Absent residual flow
      signals correspond to the thrombolysis in brain ischemia (TIBI) 0 grade, and the
      presence of residual flow signals was determined as TIBI 1-3 flow grades.
      Complete recanalization was defined as flow improvement to TIBI grades 4-5.
      RESULTS: Seventy-five patients with a proximal MCA occlusion had median pre-bolus
      NIHSS 16 (85% with > or = 10 points). TPA bolus was given at 141 +/- 56 minutes
      (median 120 minutes). Complete recanalization was observed in 25 (33%), partial
      in 23 (31%), and no early recanalization was seen in 27 (36%) patients within 2
      hours after TPA bolus. Only 19% with absent residual flow signals (TIBI grade 0,
      n = 26) on pretreatment TCD had complete early recanalization. If pretreatment
      TCD showed the presence of any residual flow (TIBI 1-3, n = 49), 41% had complete
      recanalization within 2 hours of TPA bolus (P = .03). CONCLUSIONS: Patients with
      detectable residual flow signals before IV TPA bolus are twice as likely to have
      early complete recanalization. Those with no detectable residual flow signals
      have less than 20% chance for complete early recanalization with intravenous TPA
      and may be candidates for intra-arterial therapies.

PMID- 12593129
TI  - Transcranial Doppler markers of diffusion-perfusion mismatch.
AB  - BACKGROUND AND PURPOSE: During the evaluation of acute ischemic stroke with
      diffusion- and perfusion-weighted magnetic resonance imaging (DWI and PWI,
      respectively), the presence of salvageable brain tissue is suggested by the
      occurrence of a perfusion-diffusion "mismatch." DWI and PWI, however, are not
      universally available and have inherent inconveniences, which justify a search
      for practical diagnostic alternatives. The purpose of this study is to
      investigate whether there are transcranial Doppler (TCD) markers of mismatch.
      METHODS: Retrospective analysis of 22 patients with acute ischemic stroke
      affecting the middle cerebral artery (MCA) territory, who had a TCD performed
      within 24 hours of magnetic resonance imaging (MRI) with DWI and PWI. RESULTS:
      MRI and TCD were performed on average 10.8 +/- 9.2 hours apart. Time from symptom
      onset to MRI and TCD completion were 1.6 +/- 1.6 and 2 +/- 1.9 days,
      respectively. MCA and intracranial internal carotid artery (ICA) cerebral blood
      flow velocity (CBFV) asymmetry, together with a large ICA-to-MCA gradient, were
      associated with the presence of mismatch. The combined use of 2 TCD parameters
      (MCA CBFV asymmetry of > or = 30% and ICA-to-MCA gradient > or = 20 cm/sec) had a
      sensitivity of 75%, specificity of 80%, positive predictive value of 82%, and
      negative predictive value of 73% at detecting mismatch cases. CONCLUSIONS:
      Diffusion-perfusion mismatch appears to be associated with interhemispheric
      asymmetry between MCA and ICA CBFVs, and a large CBFV gradient between the ICA
      and MCA on the affected side. Prospective studies are required to verify these
      observations and to determine whether TCD can be used to follow patients with
      mismatch.

PMID- 12593130
TI  - Neurovascular coupling remains unaffected during normal aging.
AB  - BACKGROUND AND PURPOSE: During normal aging, the cerebral autoregulation
      mechanism and the CO2-induced cerebral reserve capacity remain unaffected. This
      led to the suggestion of a wide compensatory range of mechanisms responsible for
      the cerebral blood flow regulation. The authors investigated the neurovascular
      coupling mechanism for age-related changes. Because several authors criticized
      the comparison between higher and younger age groups, the current authors
      restricted their study on volunteers between 10 and 60 years. METHODS: Twenty
      healthy volunteers in the age group of 10 to 20, 20 to 40, and 40 to 60 each
      without cerebrovascular risk factors were enrolled in this study; they were aged
      16.3 +/- 3.4 SD years (9 boys), 32.7 +/- 2.3 SD years (9 men), and 53.1 +/- 5.3
      SD years (10 men). A functional transcranial Doppler test was performed using a
      visual stimulation paradigm. The resultant flow velocity changes in the posterior
      cerebral artery were analyzed using a control system approach. Resting flow
      velocity and each of the control system parameters, which were time delay,
      attenuation, natural frequency, rate time, and gain, were compared between groups
      statistically. RESULTS: Control system parameters remained statistically
      unchanged between groups, whereas the resting flow velocity decreased
      significantly by age. CONCLUSIONS: The neurovascular coupling mechanism seems to
      be unaffected by moderate aging as estimated by Doppler parameters.
      Vasoregulative dysfunction in patients at vascular risk is more likely to be
      caused by the risk factor rather than by age.

PMID- 12593131
TI  - The role of transcranial Doppler in symptomatic striatocapsular small deep
      infarction.
AB  - BACKGROUND AND PURPOSE: The transcranial Doppler (TCD) findings in symptomatic
      small deep infarction are not well known. The aim of this study was to evaluate
      the role of TCD in striatocapsular small deep infarctions (SSDIs). METHODS: The
      cerebral angiography and TCD findings were analyzed on 100 patients with
      symptomatic cerebral infarcts on the middle cerebral artery (MCA) territory. The
      sensitivity, specificity, and accuracy of TCD in detecting the MCA lesions were
      compared between lacunar group (the patients with lacunar syndrome and SSDIs on
      magnetic resonance image) and nonlacunar group. RESULTS: Thirty-eight patients
      were classified as the lacunar group, whereas 62 patients as the nonlacunar
      group. On angiography, occlusive lesion of MCA was found in 18 of the lacunar
      group and 24 patients of the nonlacunar group. The degree of MCA stenosis was
      higher in the nonlacunar group (80.8% +/- 21.2%) than the lacunar group (60.4% +/
      21.6%). The accuracy of TCD for the detection of MCA stenosis was not different
      between the groups. However, the sensitivity of TCD in the lacunar group was
      lower (72%) than in the nonlacunar group (88%), and it might have been due to the
      difference in the degree of MCA stenosis among the groups. CONCLUSION: Occlusive
      lesions of the MCA should be considered as a potential cause of SSDIs. In this
      respect, TCD may be used for screening candidates for conventional angiography in
      those patients. High rate of mild-degree stenosis of MCA in patients with SSDIs,
      however, caused a risk for missing such stenosis on TCD.

PMID- 12593132
TI  - Outcome in children with significantly abnormal cerebral blood flow detected by
      Doppler ultrasonography: focus on the survivors.
AB  - BACKGROUND AND PURPOSE: The Doppler waveform patterns of loss of diastolic flow,
      appearance of retrograde diastolic flow, or no detectable flow in the cerebral
      arteries suggest significantly abnormal cerebral blood flow (CBF). A
      retrospective study was performed to show that significantly abnormal CBF alone,
      without clinical criteria, is not necessarily specific to brain death in the
      young pediatric population. PATIENTS AND METHODS: Forty-seven pediatric patients,
      from newborn to 4 years of age, were found to have significantly abnormal CBF,
      including 7 patients with loss of diastolic flow, 28 with retrograde diastolic
      flow, and 23 with no detectable cerebral flow on serial Doppler sonographic
      examinations. Their clinical data and sonographic results were collected and
      analyzed. RESULTS: Forty-two patients died, a few of whom had only transient
      improvement of cerebral flow. All of the patients with no detectable cerebral
      flow expired. Five patients survived with or without sequelae. Their underlying
      conditions that caused increased intracranial pressure were treated by medical
      and/or surgical intervention, and diastolic reversal of CBF corrected within 1
      day in all 5. CONCLUSIONS: Although no detectable flow is a lethal sign,
      pediatric patients with loss or reversal of diastolic flow may survive with
      prompt and effective treatment. Using Doppler ultrasound to diagnose cerebral
      circulatory arrest should be done with caution in pediatric patients.

PMID- 12593133
TI  - Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue
      syndrome.
AB  - BACKGROUND AND PURPOSE: During head-up tilt (HUT), patients with chronic fatigue
      syndrome (CFS) have higher rates of neurally mediated hypotension (NMH) and
      postural tachycardia syndrome (POTS) than healthy controls. The authors studied
      whether patients with CFS were also more likely to have abnormal cerebral blood
      flow velocity (CBFV) compared with controls in response to orthostatic stress.
      METHODS: Transcranial Doppler monitoring of middle cerebral artery (MCA) CBFV was
      performed during 3-stage HUT prospectively in 26 patients with CFS and 23 healthy
      controls. At the same time, continuous monitoring of arterial blood pressure
      (BP), heart rate (HR), endtidal CO2 (ET-CO2) were performed. Results are reported
      as mean +/- SD. RESULTS: NMH developed in 21 patients with CFS and in 14 controls
      (P = .22). POTS was present in 9 CFS patients and 7 controls (P = .76). Supine HR
      was higher in CFS patients, but all other hemodynamics and CBFV measures were
      similar at baseline. The median time to hypotension did not differ, but the
      median time to onset of orthostatic symptoms was shorter in those with CFS (P <
      .001). The CBFV did not differ between groups in the supine posture, at 1 or 5
      minutes after upright tilt, at 5 or 1 minute before the end of the test, or at
      termination of the test. Mean CBFV fell at termination of tilt testing in those
      with CFS and controls. ET-CO2 was lower at termination of the test in those with
      CFS versus controls (P = .002). CONCLUSIONS: The results of this study are not
      consistent with the hypothesis that patients with CFS have a distinctive pattern
      of MCA CBFV changes in response to orthostatic stress.

PMID- 12593134
TI  - Residual hippocampal atrophy in asphyxiated term neonates.
AB  - BACKGROUND AND PURPOSE: Previous studies have shown the hippocampus and basal
      ganglia to be highly sensitive to hypoxic-ischemic insult. The authors' aim was
      to evaluate the long-term effects of perinatal asphyxia (PA) on the hippocampus
      and caudate nucleus in a group of participants born at term and who met the
      criteria for hypoxic-ischemic encephalopathy (HIE). Additionally, the authors
      looked for damage in other brain regions using voxel-based morphometry (VBM).
      METHODS: The sample consisted of 13 participants (8 boys and 5 girls) with a mean
      age at study of 16.23 years (+/- 2.89) with antecedents of perinatal asphyxia,
      diagnosed as moderate hypoxic-ischemic encephalopathy. A group of 13 healthy
      adolescents matched for age, sex, educational level, and social background were
      recruited as a comparison group. MR scans were acquired on a 1.5T Signa (General
      Electric, Milwaukee, WI) to evaluate hippocampal and caudate volumes and to
      perform VBM analysis. Finally, Rey's Auditory Verbal Learning Test was
      administered to evaluate verbal long-term memory. RESULTS: HIE participants were
      found to have bilateral hippocampal atrophy (P = .015) and gray matter damage in
      temporal and frontal lobes. The caudate nucleus showed no atrophic changes in PA
      participants, and VBM analysis did not reveal other consistent brain
      abnormalities. Verbal long-term memory was slightly worse in HIE participants.
      CONCLUSIONS: These findings indicate that PA produces hippocampal and other
      nonspecific long-term damage, which cannot be compensated for by plasticity
      mechanisms. However, this damage does not preclude normal development and
      scholarship.

PMID- 12593135
TI  - MRI findings of hemolytic uremic syndrome with encephalopathy: widespread
      symmetrical distribution.
AB  - The authors report the magnetic resonance imaging (MRI) findings in a 22-year-old
      woman with hemolytic uremic syndrome and encephalopathy secondary to verotoxin
      producing Escherichia coli. Multiple lesions in the midbrain, cerebellum,
      occipital lobe, and basal ganglia showed high signal intensity on T2-weighted
      images with widespread symmetrical distribution. Most of these findings showed
      remarkable reduction on MRI images obtained 70 days after the onset. It is
      suggested that edema induced by local breakdown of blood-brain barrier might play
      an important role in the patient.

PMID- 12593136
TI  - Diffusion-weighted magnetic resonance imaging abnormalities in Bartonella
      encephalopathy.
AB  - The authors describe 2 patients with new-onset, refractory status epilepticus and
      serological evidence for Bartonella infection. Brain magnetic resonance imaging
      (MRI) in patient 1 showed transient diffusion abnormalities in the posterior
      (pulvinar) thalami. In patient 2, brain MRI showed several enhancing cortical
      lesions, of which one lesion was bright on diffusion-weighted imaging (DWI). In
      patients with unexplained, refractory seizures, the presence of DWI abnormalities
      warrants a search for unusual infectious or inflammatory disorders, like
      Bartonella encephalitis.

PMID- 12593137
TI  - Ipsilateral hemiplegia in a lateral medullary infarct--Opalski's syndrome.
AB  - A 42-year-old man was admitted complaining of the sudden onset of headache,
      vomiting, vertigo, and gait disturbance. The authors found hemiparesis of his
      right limbs, right Homer's syndrome, and decreased pain and temperature sensation
      of his right face and left limbs. Diffusion-weighted imaging (DWI) showed an
      acute small infarct located on the right side of the lateral lower medulla. This
      is the first report of Opalski's syndrome with lower medullary infarction
      detected by DWI.

PMID- 12593138
TI  - Trancranial Doppler monitoring of response to therapy for meningovascular
      syphilis.
AB  - Meningovascular syphilis is now quite uncommon, but there have been increasing
      reports in patients immunocompromised with human immunodeficiency virus. The
      response of syphilis affecting the central nervous system to antibiotic therapy
      remains a challenge. This is an even greater challenge in patients who have
      underlying compromise of the immune system. The authors present a 46-year-old
      male with recurrent stroke who was found to have cerebrospinal fluid compatible
      with syphilitic involvement of the central nervous system and a cerebral
      arteriogram, which revealed focal narrowing of the right middle cerebral artery.
      The baseline transcranial Doppler study demonstrated increased mean and peak flow
      velocity within the right middle cerebral artery. Despite a 10-day course of
      intravenous penicillin, with substantial improvement in the cerebrospinal fluid
      results, this flow velocity elevation persisted, in a remarkably consistent
      pattern, over a 4-month follow-up period. Thus, the involved vessel remained
      patent following treatment, but no clear resolution of the stenotic lesion was
      observed.

PMID- 12593139
TI  - 5 resolutions for a happy 2003.

PMID- 12593140
TI  - Providing leadership in rural health care: the evolving role of virtual teams in
      managing projects.

PMID- 12593141
TI  - Physicians factored into new JCAHO accreditation process.

PMID- 12593142
TI  - Viewpoint: report cards are here to stay.

PMID- 12593143
TI  - Member presents plan to improve board exam pass rate.

PMID- 12593144
TI  - Testing your diagnostic skills. Case no. 1. Herpes zoster.

PMID- 12593145
TI  - Testing your diagnostic skills. Case no.2. Ameloblastic fibro-odontoma.

PMID- 12593146
TI  - Negative talk affects colleagues, patients, profession.

PMID- 12593147
TI  - [Health of the working population in the Russian Federation].
AB  - The article covers topical problem concerning health state of workers in various
      economic branches.

PMID- 12593148
TI  - [Scientific principles of sanitary and hygienic basis of chemical weapons
      demolishment].
AB  - The authors designed a set of instructions and methodic documents and universal
      methodology for sanitary and hygienic follow-up in establishments running
      chemical weapons demolishment. Those instructions and methodology are aimed to
      safety of workers and general population.

PMID- 12593149
TI  - [Effects of peak levels and number of noise impulses on hearing among forge
      hammering workers].
AB  - The work was aimed (1) to compare actual and expected values of hearing loss in
      forge hammering workers, using risk evaluation patterns based on impulse noise
      measurements, and (2) to simulate harmful hearing changes caused by impulse
      noise. Study of exposure to noise and hearing loss covered forge hammering
      workers in 2 major blacksmith workshops of automobile enterprise, where
      equivalent levels of acoustic pressure (104 and 106 dB) were equal, but peak
      levels and impalse degrees reliably differed. Hearing thresholds for 2 selected
      groups of workers (97 and 235 subjects) were evaluated. When compared, actual and
      expected values of hearing loss calculated according to ISO standard appeared
      different with excess of 1 dB and 3 dB for the workers in shops 1 and 2
      respectively. Excessive hearing loss corresponds to noise exposure increased by
      3.5 years. Hearing loss in the workers subjected to less impulsive noise were
      readily forecasted by ISO standard 1999-1990. Hearing loss in the workers
      subjected to more impulsive noise were in reliable correlation with combination
      of peak level and impulses number.

PMID- 12593150
TI  - [Occupational medicine in Latvia].
AB  - New system of occupational medicine in Latvia is under development already for 10
      years. The biggest efforts have been invested in creation of legal basis
      harmonized to the legislation of EU and extensive training of specialists. The
      State Labour Inspectorate was established, the Institute of Occupational and
      Environmental Health and other medical institutions have been reorganised. A new
      system of information is under construction; as well as new hygienic standards
      are being elaborated.

PMID- 12593151
TI  - [State of nonspecific anti-infection resistance among medical personnel].
AB  - The authors compared nonspecific anti-infectious resistance among medical
      staffers varying in speciality. Skin microflora parameters and salivary lysozyme
      content appeared to be considerably lower in obstetric staffers and in State
      sanitary and epidemiologic supervision officers than in general population.

PMID- 12593152
TI  - [Advantages of periodic medical examinations of asbestos plant workers at the
      Occupational Center].
AB  - The article deals with results of periodic medical examination conducted in
      Regional Occupational Center MONICI for 90 subjects working in apparatus workshop
      of asbestos ware plant. Data presented are results of thorough evaluation of
      respiration biomechanics through electronic spirometry and body plethysmography,
      serum activity of interstitial alveolomucin 3EG5 and oncologic markers CA-125 and
      CA-15.3.

PMID- 12593153
TI  - [Activities of the Health Center providing health care for Nuclear Power Station
      workers and for nearby residents].
AB  - The authors evaluate relationships of parameters describing activities of Health
      center and selected according to "discrete correlation galaxies" method with
      characteristics of health state of population covered by the center. The article
      contains mathematic models that could be a basis for forecasting changes of
      health state characteristics under variation of Health center activity
      parameters.

PMID- 12593154
TI  - [Method evaluating heat isolation for individual device suit designed to protect
      workers from coldness].
AB  - Based on results of personal research and of foreign studies, the authors present
      a method to calculate heat isolation for individual protective means set
      necessary for human heat state preservation in real working conditions. The
      method includes surface temperature measurements with consideration of cooling
      degree and energy consumption, calculation of separate elements of heat balance
      and density of "net" heat flow in correlation with cooling duration. Calculating
      heat isolation, the authors considered influence of wind speed on its value and
      air-resistance of outer clothing.

PMID- 12593155
TI  - [Value of immunomodulators in complex treatment of occupational bronchopulmonary
      diseases].

PMID- 12593156
TI  - [State of oxidative metabolism of erythrocytes and neutrophils in patients with
      vibration disease associated with pneumoconiosis].

PMID- 12593157
TI  - [Psychological characteristics of a group of enrollees -- future nautical
      specialists].
AB  - Nautical speciality poses specific requirements to mental health. Therefore,
      methods for early detection of pathopsychologic changes are widely used at
      preliminary and periodic medical examinations of seamen. The article covers
      necessity of mandatory psychophysiologic selection for enrollees to nautical
      educational institutions.

PMID- 12593158
TI  - [The Charter of the All-Russia public organization "The Russian Association of
      Phthisiatrists].

PMID- 12593159
TI  - [Penitentiary medicine on its way to reforms].

PMID- 12593160
TI  - [Social aspects in tuberculosis among mental patients].
AB  - A total of 206 patients with pulmonary tuberculosis and mental disorders from the
      Kirov Region were examined in 1997-1998. The results were compared with those
      obtained in 154 control patients with pulmonary tuberculosis without mental
      disorders. In both group males fell ill with tuberculosis in the prime of their
      life whereas females did at their old age. Males with mental disorders are more
      susceptible to tuberculosis than mentally healthy patients. In contrast, females
      with mental disorders are much less susceptible to tuberculosis than mentally
      healthy patients. Women of reproductive age are the least prone to tuberculosis
      particularly in the presence of mental disorders. The authors proposes to
      continue studies of the causes of female resistance to tuberculous infection, the
      specific features of the hormonal background in women having mental disorders and
      whether estrogens may be used in the therapy of tuberculosis.

PMID- 12593161
TI  - [Methods of the detection of non-bacterial tuberculosis and its clinical and X
      ray characteristics in children and adolescents].
AB  - Abacillary tuberculosis is presented by all clinical forms among which
      tuberculosis of intrathoracic lymph nodes, infiltrative and focal pulmonary
      tuberculosis are common. Abacillary tuberculous processes are restrictive: the
      involvement of 1-2 segments of the lung is observed in 95% of cases, that of 1-2
      groups of intrathoracic lymph nodes is in 87.5%. Detection rates are 36% at
      tuberculin diagnosis, 30% at fluorography, and 14% on examination of those in
      contact with a patient with tuberculosis. Abacillary tuberculosis is
      asymptomatic. Its major clinical (intoxication and pulmonary) syndromes are
      commonly mild in 97.8%. The clinical manifestations of the disease are somewhat
      more pronounced in patients with infiltrative pulmonary tuberculosis.

PMID- 12593162
TI  - [Atelectasis in the clinical picture of intrathoracic tuberculosis].
AB  - The authors examined 85 patients with intrathoracic tuberculosis in whom the
      tuberculous process had been complicated by tuberculosis of the bronchi with
      their developed obstruction and as a result of atelectasis. Then the atelectasis
      affected area became fibrotic. It was found that with the developed atelectasis,
      there was a persistent cession of bacterial isolation occurred, closure of decay
      cavities in the lung tissue, resolution of fresh focal and infiltrative changes.
      The presence of scarring bronchial stenosis and fibrotic atelectasis suggests of
      a full clinical recovery from intrathoracic tuberculosis.

PMID- 12593163
TI  - [Tuberculous spondylitis syndrome].
AB  - The authors conducted a comprehensive study of 482 patients with suspected
      tuberculous spondylitis. The commonest diagnostic signs of some spinal diseases,
      similar to the clinical ones, were defined on clinical, X-ray, laboratory, and
      thermographic findings. This enabled a differentially diagnostic syndrome
      including 58 signs to be developed. The proposed syndrome is to facilitate the
      differential diagnosis of tuberculous spondylitis from spinal tumors,
      degenerative and dystrophic processes, and nonspecific osteomyelitis of the
      vertebral column.

PMID- 12593164
TI  - [Long-term results of prolonged treatment in patients with fibrosing alveolitis
      (prophylactic medical examination)].
AB  - The results of a long-term (5-10 year) follow-up were studied in 109 patients
      with alveolitis, including 89 with EAA and 20 with IFA. A variety of treatments
      were applied. The predominant treatments were hormonal therapy supplemented by
      plasmapheresis, physiotherapy, oxygen therapy, etc. A follow-up of patients with
      alveolitis was made by 3 groups. Group 1 was compensated--Stage 0; Group 2,
      subcompensated--Stage II; Group 3, decompensated--Stage III. The control periods
      and scope of examinations were defined for each group. The Regulations governing
      the prophylactic medical examination of patients with alveolitis were worked out.
      Among patients with EAA, good results, such as improvement and stabilization of
      the process, were observed in 34.8% of cases, poor results, such as recurrences
      were in 53.6%, death rates were 3%. Among patients with IFA, good results were
      achieved in 15% of cases, recurrences and progression were in 10 and 30.7%,
      respectively, death rates were 40%.

PMID- 12593165
TI  - [Genetic monitoring of tuberculous infection severity in mice with complementary
      inheritance of resistance].
AB  - When infected with a high dose of Mycobacterium tuberculosis H37Rv intravenously,
      1/St and C57BL/6 inbred mice display a similarly high degree of the severity of
      progressive disease characterized by short-term survival rates and a rapid body
      weight loss. Noteworthy, F1 hybrids between these two strains are exceptionally
      resistant to M. tuberculosis-triggered disease and survive about 4-fold longer
      than the either parental strain. The results of a segregation genetic analysis
      performed in this study suggest that mice of either strain carry a homozygous
      recessive allele at a single genetic locus which determines a high susceptibility
      to the disease regardless of a locus expressed in the other parental strain.
      Genetic complementation between these two apparently non-linked loci provides the
      expression of the resistant phenotype in F1 hybrids. Correspondence between these
      loci and the previously mapped QTLs in TB control remains to be established.
      There was a high correlation between the two complex phenotypes that characterize
      the severity of experimental tuberculosis, that is the rate of postinfection body
      weight loss and time to death in this experimental model.

PMID- 12593166
TI  - [Prospects in the search for new biological agents to prevent tuberculosis].
AB  - Six biological specimens, including BCG obtained from Mycobacterium tuberculosis
      or animal tissues in accordance with an original procedure were studied. Their
      protective efficiency in tuberculosis infection was evaluated by the magnitude of
      allergic reactions and by pathological tissue changes 5 months after animal
      immunization and infection. The drug PKP-3 was found to be most effective and its
      further study is promising.

PMID- 12593167
TI  - [Virulence of Mycobacteria tuberculosis].
AB  - The virulence of 43 Mycobacteria tuberculosis strains isolated from 21 patients
      with new cases of pulmonary tuberculosis and from 20 patients with chronic
      destructive pulmonary tuberculosis (CDPT) was studied in non-inbred albino mice.
      Twenty four (56%) and 19 (44%) M. tuberculosis strains belonged to the Beijing
      and individual genotypes, respectively. The virulence of isolates from the new
      cases of pulmonary tuberculosis was higher than that from CDPT patients. The M.
      tuberculosis strains studied showed no correlation between the virulence,
      viability, and affiliation to a certain genotype. However, there was a lower rate
      of decreased virulence in multidrug-resistant strains of the Beijing genotype
      than in the isolates of individual genotypes. This is likely to be a factor of
      the high transmissible capacity of M. tuberculosis strains of the Beijing family.

PMID- 12593169
TI  - [The Anniversary Session on "Current Problems in Phthisiology" dedicated to the
      80th anniversary the Central Scientific Research Institute of Tuberculosis at the
      Russian Academy of Medical Sciences and to the 75th anniversary from the birth of
      academician Khomenko A.G].

PMID- 12593168
TI  - [The role of Chlamydia pneumoniae infection in the pathology of respiratory
      organs].

PMID- 12593171
TI  - [The formation of pulmonary and extrapulmonary risk groups].

PMID- 12593172
TI  - [Methods of functional rehabilitation of patients after lung surgery].

PMID- 12593173
TI  - [The MMW Drug Prize 2002: Prize for a new classic with innovation potential].

PMID- 12593174
TI  - [Inhalation therapy: techniques and use of devices--main mistakes].
AB  - Inhalation therapy is the main route of drug administration in patients with
      obstructive pulmonary diseases. The efficacy of inhalation therapy depends on
      several factors including the individual choice of the device, its correct use,
      and patients' compliance. Metered-dose inhalers and dry-powder inhalers require
      completely different inhalation maneuvers. Poor inhalation technique is
      associated with poorer disease control. Appropriate education when prescribing
      inhalation devices and evaluation of inhalation technique are of overwhelming
      importance.

PMID- 12593175
TI  - [Milestones in inhalation therapy of airway diseases].
AB  - Inhalation is the preferred route for the application of drugs in the management
      of airway diseases. Therefore it was aimed at developing drugs suitable for
      inhalation. An important step was the introduction of the short- and long-acting
      beta 2-agonists and of a new generation of anticholinergics with longer duration
      of action. Most important was the development of inhaled glucocorticoids allowing
      good asthma control without relevant side effects even in a long run.
      Furthermore, the devices for drug application have been improved, and CFCs were
      substituted by HFAs.

PMID- 12593176
TI  - [State of the art of the inhalation therapy of asthma].
AB  - The current concept of asthma pathogenesis is that a characteristic chronic
      inflammatory process involving the airway wall causes the development of airflow
      limitation and increased responsiveness, thereby predisposing the airways to
      narrow in response to a variety of specific (allergic) or unspecific stimuli.
      Medications for asthma are used to reverse and prevent symptoms and airflow
      limitation and include controllers and relievers. The major advantage of
      delivering drugs directly into the airways via inhalation is that high
      concentrations can be delivered more effectively to the airways, and systemic
      side effects are avoided or minimized. Bronchodilators with or without anti
      inflammatory substances are used as basic therapeutic approach in these patients.
      The stepwise approach to therapy recommends that the number/type and frequency of
      medications are increased with increasing asthma severity by adding systemic
      medications to existing inhalation therapy (step III-IV in asthma management
      guidelines). Combination therapy using a long acting beta 2-agonist and a
      glucocorticosteroid resulted in higher lung function improvement, and was
      superior in reduction of exacerbation rates compared with an inhaled
      glucocorticosteroid alone. Hence, the development of a fixed combination
      containing both substances in one device is a logic consequence, and thus,
      simplifying asthma therapy.

PMID- 12593178
TI  - [Effects of patient education in asthma and COPD--what is provable?].
AB  - In international and national guidelines patient education is recommended as an
      integral part of an effective management for both, asthma and COPD, respectively.
      The evaluation of numerous structured education programs for adult asthmatics
      revealed an increase of quality of life of the educated patients, reduced
      morbidity with less asthmatic attacks, a decrease of emergency visits, sick leave
      days and hospitalizations due to asthma. On the basis of cost/benefit analysis
      cost effectiveness could be demonstrated for education programs for asthmatics.
      On the basis of education programs in COPD including self-management, in a
      randomized controlled study an improvement of the patient's ability to react to
      exacerbations could be shown, thus reducing the morbidity by the disease. Further
      controlled studies of the effects of patient education on morbidity, mortality
      and cost effectiveness are necessary to establish the role of structured
      education programs in the treatment of COPD with sufficient validity.

PMID- 12593177
TI  - [Do we need inhalative steroids in chronic COPD patients?].
AB  - The use of inhaled steroids in the management of chronic obstructive pulmonary
      disease (COPD) is controversially discussed. Neither the optimistic view of the
      90s nor the current pessimistic view on these substances seems to be justified.
      It becomes apparent that a more differentiated approach, depending on the
      clinical situation and the cellular composition in the airways, is necessary.
      Patients with severe inflammation, poor lung function, and frequent exacerbations
      seem to benefit more from inhaled steroids. Patients in early stages of the
      disease with occasional symptoms only, and patients predominantly suffering from
      emphysema than from bronchitis seem to have no benefit from this treatment
      option. Special attention should be turned to mixed types with asthma-like
      symptoms. The combination of inhaled long-acting beta 2-mimetics and steroids
      seems to be of advantage; for a final judgment, however, the results of ongoing
      clinical trials have to be awaited.

PMID- 12593179
TI  - [Exercise-induced asthma].
AB  - Physical exercise and, in particular, sport activities put strain on the
      respiratory system due to increased. Though healthy subjects undergo a light
      distension of the respiratory passages, those with bronchial hyperreactivity
      experience a decrease of lung function. The main triggers responsible are the
      relative cooling down, drying up and--compared to healthy subjects--overfast
      airway rewarming. Though, for this reason, basically every asthma patient can
      expect to suffer the effects of exercise-induced asthma, the solution is not in
      overprotection and the avoidance of all physical effort. Thanks to dosed,
      physical activity training programs, any asthmatic can be included in school
      sports or, as an adult, take part in sports and leisure activities, even at an
      above-average level.

PMID- 12593180
TI  - Health missions a la carte.

PMID- 12593181
TI  - Today's technology improves the shade-matching problems of yesterday.

PMID- 12593182
TI  - Laser root canal therapy.
AB  - BACKGROUND: In January 2002, the Food and Drug Administration approved the Er,Cr,
      YSGG laser for complete endodontic therapy. CASE DESCRIPTION: The author presents
      a case of a 45-year-old male requiring interceptive endodontic therapy of tooth
      #21 for the fabrication of an overdenture. The YSGG laser was used for access,
      debridement, and shaping of the canal. CLINICAL IMPLICATIONS: The YSGG laser is
      the first-ever approved by the FDA for complete endodontic therapy. Laser therapy
      may provide clinical improvements in pain control and disinfection during
      endodontic therapy.

PMID- 12593183
TI  - Digital photography and imaging can enhance practice in several ways.

PMID- 12593184
TI  - Collecting copays and deductibles.

PMID- 12593185
TI  - Mediastinal granuloma complicating histoplasmosis.
AB  - Histoplasmosis is common in the Ohio Valley and is mostly asymptomatic. However,
      in a fraction of patients, significant clinical illness and complications can
      occur for which treatment options are limited. We describe a case of a young
      woman with mediastinal granuloma resulting from Histoplasmosis. A brief
      discussion of the disease and its management follows.

PMID- 12593186
TI  - The burden of lung cancer in Kentucky.
AB  - Lung cancer incidence and mortality rates in Kentucky greatly surpass those of
      other states and the nation as a whole. Not only is this one of the most common
      cancers, with 3800 newly diagnosed cases per year in the Commonwealth, it is also
      one of the most fatal. And, unlike many other types of cancer, it is highly
      preventable, as about 90% are caused by cigarette smoking. In this paper we
      present lung cancer rates across different groups and trends of the disease over
      time. We also discuss comparative statistics related to stage at which lung and
      other major cancers are diagnosed and their survival patterns. Smoking data from
      the Behavioral Risk Factor Surveillance System are presented and compared across
      different states in relation to lung cancer occurrence. Finally, both lung cancer
      and smoking trends within Kentucky are compared, showing how both are
      substantially higher in the Appalachian region of the state.

PMID- 12593187
TI  - Motorcycle helmets and head injuries in Kentucky, 1995-2000.
AB  - Motorcycle crashes are common occurrences in Kentucky, and often result in injury
      or death. The use of motorcycle helmets may improve injury outcomes. Data
      collected from University of Louisville Hospital trauma center were used to
      investigate the association between motorcycle helmet use and traumatic brain
      injuries (TBI), severe head injuries, and acute care hospital charges. Multiple
      logistic and linear regression models were used for analysis. Motorcycle drivers
      who did not wear helmets were more likely to incur a TBI (OR = 4.33, 95% CI: 2.60
      7.20), severe head injuries (OR = 4.36, 95% CI: 2.58-7.37), and higher acute care
      hospital charges (beta = $26,618, 95% CI: $8670-$44,565). Kentucky's failure to
      require mandatory helmet use may increase incidence of TBI and severe head
      injuries among motorcyclists, and cost state government millions of dollars to
      pay for care for uninsured or Medicaid patients.

PMID- 12593188
TI  - The obesity epidemic and physician responsibility.

PMID- 12593189
TI  - Underage drinking: a prescription for disaster.

PMID- 12593190
TI  - [Development of GI-II tinted infiltration glass and determination of its
      properties].
AB  - OBJECTIVE: Glass is the weak phase in the glass-alumina composite, and it plays a
      key role in determining the physical, mechanical and optical properties. The
      purpose of this study was to explore the fabrication arts of GI-II tinted
      infiltration glass and determine its properties. METHODS: The thermal properties
      of the glass were tested on a TMA2940 thermal analyzer with heating rate of 5
      degrees C/min and temperature range of 25-750 degrees C. The bar-shaped specimens
      were prepared with the size of 25 mm x 5 mm x 2 mm and their flexural strengths
      and elastic modulus with 3-point bending test were measured. The Vicker's
      hardness and indentation fracture toughness were also determined. The refractive
      index and changes of chemical constituents were tested by means of V prismatic
      refractometer and 2910 DTA analyzer. RESULTS: The results showed that the thermal
      expansion coefficient, Tg and Tf, refractive index, 3-point bending flexural
      strength, bending elastic modulus, Vicker's hardness, indentation fracture
      toughness and density were 6.997 x 10(-6) degrees C-1 (25-500 degrees C), 635
      degrees C and 650 degrees C, 1.64 MPa, 96.27 MPa, 31.16 GPa, 5.534 GPa, 1.05
      MN.m1/2, and 3.214 g/cm3 respectively. Though certain heat processing conditions
      did result in micro-crystalline in the glass, it remained stable under routine
      glass infiltration firing cycles. CONCLUSION: GI-II tinted infiltration glass had
      favorable physical, mechanical properties and good thermal stability.

PMID- 12593191
TI  - [The biological effects of recombinant human bone morphogenetic protein 2 on
      human periodontal ligament fibroblasts].
AB  - OBJECTIVE: The purpose of this study is to study the biological effects of
      recombinant human bone morphogenetic protein 2 (rhBMP2) on human periodontal
      ligament fibroblasts (HPDLFs). METHODS: Human periodontal ligament fibroblasts
      were primary cultured and detected the different doses of rhBMP2 on their
      proliferation, alkaline phosphatase (ALP) activity, osteocalcin (OC) synthesis
      and formation of the mineralized nodules. RESULTS: rhBMP2 (0.25-2 mg/ml) had no
      remarkable effect on the proliferation of HPDLFs. The ALP activity, OC synthesis
      and formation of the mineralized nodules of HPDLFs were significantly stimulated
      by 0.5-2 mg/ml rhBMP2. CONCLUSION: The effects of rhBMP2 on HPDLFs are dose
      dependent. Not only can rhBMP2 stimulate the expression but also promote the
      maturation of osteoblastic phenotype of HPDLFs.

PMID- 12593192
TI  - [A study of tarnish induced by Streptococcus sobrinus serotype g on Co-Cr, Ni-Cr
      and casting titanium alloys].
AB  - OBJECTIVE: The objective of this study was to investigate the tarnish induced by
      Streptococcus sobrinus serotype g on Co-Cr, Ni-Cr and casting titanium alloys.
      METHODS: Co-Cr, Ni-Co and casting titanium alloys were respectively machined into
      a size of 10 mm x 10 mm x 1 mm in tablets, and totally 90 specimens with 30 of
      each were prepared for the test. The 30 specimens of each alloy were randomly and
      equally divided into three subgroups, including the blank control group, the
      media control group and the inoculated media group. Under the aerobic condition,
      the surfaces of the sucrose agar media were inoculated with Streptococcus
      sobrinus serotype g. The labeled sterile specimens were placed on the surface of
      the media for 10 weeks. The specimens were changed to a new sucrose media with
      bacteria each week. The specimens were removed after 10 weeks of incubation,
      immersed in 0.05% glutaraldehyde solution to eliminate AaY4, rinsed with
      distilled water. After 2 weeks, the specimens were removed and observed visually
      or examined by MINOLTA CR-100 color apparatus. RESULTS: Compared with the blank
      control, the control media without bacteria did not influence the alloy specimens
      (P > 0.05). Streptococcus sobrinus serotype g caused tarnish on specimens. There
      was significant difference between the control media group and the blank control
      group with inoculated media group on all the specimens (P < 0.05). CONCLUSION:
      Streptococcus sobrinus serotype g affects the color of Co-Cr, Ni-Cr and casting
      titanium alloys, but the color does not change from yellow-green range to red
      yellow range.

PMID- 12593193
TI  - [Effects of the mechanical stress on the proliferation and function of osteoblast
      like cells in vitro].
AB  - OBJECTIVE: The aim of this study was to investigate the effects of the mechanical
      stress on the proliferation and function of osteoblast-like cells (UMR106) of
      rats, and further to explore the mechanism of remodeling of periodontium from an
      angle of mechanics. METHODS: The flow cytometry and MTT method was used to
      examine the number of osteoblasts-like cells and their proliferation and
      metabolic enzymic activity 6 h, 12 h, 18 h, 24 h, 30 h, and 36 h after the top
      bottom axial stress (225 x g) was exerted on the UMR106 in vitro. RESULTS: The
      difference of cell phase fraction and function between the experimental group and
      the control group were of great significance (P < 0.01). The maximum SPF
      increasing and functional decreasing appeared 12 h after the appliance of the
      stress, and all indexes were no significantly different between the two groups 24
      h after the stress was supplied. Forward light scatter had no remarkable
      alteration. CONCLUSION: The top-bottom axial stress (225 x g) could inevitably
      influence the proliferation and function of osteoblast-like cells without
      pathological damage occurred.

PMID- 12593194
TI  - [A study of rebuild of a three-dimensional anatomic model of mandibles].
AB  - OBJECTIVE: The aim of this study was to rebuild the anatomic structures of the
      mandibular bone and the canal, and to testify the reliability of the rebuilt
      model. METHODS: 15 mandibular bones with teeth are chosen, and a three
      dimensional model was built with the method of CT. The slices vertical to the
      compensating curve were made in every dental position. Then the authors collected
      the data of alveoli and mandibular canal in every slice. The same work was done
      to the bone specimen, and then comparative analysis was done. RESULTS: The
      wideness of the alveoli and 10 mm bellow increased from mesial to distal
      position. It was the same of the alveoli from the top to the bottom. The
      mandibular canal lied in the inner and inferior side of the mandibular body.
      There was no significant difference in data collected with these two methods.
      CONCLUSION: Different types of dental implants should be chosen according to the
      anatomic characteristic of the mandibular bone in every dental position before
      the operation to avoid complications. And a reliable, accurate and direct method
      of planning an implant operation is to rebuild a three-dimensional model.

PMID- 12593195
TI  - [Application of carotid artery reconstruction in head neck malignancy].
AB  - OBJECTIVE: The purpose of this study was to establish an ideal operation method
      to deal with head and neck carcinomas of late stage and involving the carotid.
      METHODS: A total of four metastasized head neck carcinomas involving the carotid
      arteries were included in this clinical trial. The primary tumors of the four
      cases tumors were carcinomas of tongue, esophagus, laryngeal and parotid glands.
      All four cases were examined by means of TCD, DSA, SPECT to confirm good
      compatibility of brain blood circulation before operations. The bony petrous
      sections of carotid arteries were drawn off after the exposure of the bone tissue
      for exterior skull. A by-pass was set up by inserting a shunt tube between the
      common carotid and the infernal carotid artery. The extended tumor resection was
      carried out involving the resection of the carotid artery. The artery was
      reconstructed with saphena magna vein transplantation in one case, and replaced
      by artificial vessels in two cases. Tissue defects were repaired by pedicle PMMF.
      RESULTS: The B-typed ultrasound and TCD examination two weeks to six months post
      operatively showed the four cases revealed good condition of transplanted carotid
      arteries, except one case occurred Honer's syndrome, but there was no central
      nerve's symptom or complication in the other three cases. CONCLUSION: This
      operation method could provide a good chance of survival by curettage of later
      staged head neck tumors. The authors recommend reconstruction of carotid artery
      in the operation treatment of malignant head neck carcinomas during late stages.

PMID- 12593196
TI  - [A retrospective study of clinical manifestation and human papilloma virus
      detection of oral condyloma acuminate in children].
AB  - OBJECTIVE: The aim of this study is to study genotype, transmission, clinical and
      pathological characteristics, and prognosis of oral condyloma acuminate (CA) in
      children. METHODS: The authors retrospected the clinical characteristics and
      slices of HE staining of six cases which have been diagnosed as oral CA and,
      performed inmunohistochemistry (IHC) and in situ hybridization (ISH) analysis to
      detect the DNA of human papilloma virus in 5 cases. RESULTS: Oral CA often
      happened in the hard or soft plates of children of two-year-old. Most of them
      came from the families had been infected by human papilloma virus (HPV).
      Histological examination demonstrated that koilocytes were common in the upper
      spinous and corneal layers. HPV was detected in all cases. HPV16/18-E6 antigen
      was positive in 4 of 5 cases examined. The result of ISH only show one case was
      HPV6- and HPV11-positive, and the other case was HPV-positive, but HPV could not
      be detected when recurring. CONCLUSION: The pathogen leading to oral condyloma
      acuminate (CA) and the transmission way of children may be different from that of
      adults.

PMID- 12593197
TI  - [The effectiveness and reliability of skin paddles of free fibula flaps in
      reconstruction of maxillofacial defects].
AB  - OBJECTIVE: The paper reviewed the effectiveness and reliability of skin paddles
      of free fibula flaps in the reconstruction of maxillofacial defects. METHODS:
      Fifty-five consecutive free fibula osteocutaneous flap transfers performed from
      June 21, 1999 to October 31, 2000 were reviewed. The skin paddles of each flap
      were analyzed in terms of surgical design, blood supply, size, reconstruction
      location, and survival. RESULTS: Fifty-seven skin paddles were used for the 55
      free fibula flaps (double skin paddles for 2 flaps), 37 were nurtured by one
      perforator, 18 by two and two by 3 perforators. Twenty-eight skin paddles were
      used for intraoral reconstruction, 7 for extraoral reconstruction, 1 for both
      intraoral and extraoral reconstruction, 2 for soft tissue augmentation, and the
      remaining 19 were simply used as window for monitoring the blood flow of fibula
      flap. One free fibula flap with one skin paddle was lost because of venous
      thrombosis, and the other 54 flaps survived completely, with 100% survival of 56
      skin paddles. CONCLUSION: The skin paddle of free fibula flap is safe and
      reliable. It can be used for all kinds of soft tissue reconstruction, as well as
      window for monitoring the blood flow of fibula flap after operation.

PMID- 12593198
TI  - [Observation of vasoactive intestinal polypeptide in patients with trigeminal
      neuralgia: a 16-cases report].
AB  - OBJECTIVE: The aim of this study was to observe whether vasoactive intestinal
      polypeptide (VIP) participated in the attack of trigeminal neuralgia, and to
      understand further its pathogenetic mechanism. METHODS: Sixteen patients were
      studied. During the attacks the venous blood was sampled from both the external
      jugular vein and cubital fossa vein ipsilateral to the pain, and after operations
      the venous blood from the external jugular vein was sampled again, the external
      jugular vein blood of eleven normal volunteers was collected as the control.
      Plasma levels of VIP were determined using sensitive radioimmunoassays. RESULTS:
      During the attacks of trigeminal neuralgia the levels of VIP in the external
      jugular vein blood were significantly higher than that in the cubital fossa vein
      blood, postoperative external jugular vein blood and the external jugular vein
      blood of normal volunteers. CONCLUSION: VIP indeed participates in the attack of
      trigeminal neuralgia in the local region, the role of VIP may be relating to
      enhancing the effects of substance P in local neurogenic inflammation.

PMID- 12593199
TI  - [Soft tissue changes of patients with skeletal class II malocclusion after
      orthodontic and surgical treatments].
AB  - OBJECTIVE: One of the prime concerns of both the orthodontist and the oral
      surgeon must be the final soft tissue profile and the esthetic appearance of the
      patient. The purpose of this study was to evaluate the amount, direction, and
      predictability of the soft tissue changes associated with simultaneous skeletal
      changes. METHODS: The authors analyzed the recent 22 cases with skeletal class II
      maloclusion in Orthodontic Department, College of Stomatology, West China
      University of Medical Sciences with 7 male and 15 female from 20 to 30 years old.
      Each patient was taken standardized lateral cephalograms before the treatment and
      6-12 months after the treatment. A total of 16 hard and soft tissue landmarks
      were evaluated in both horizontal and vertical directions. RESULTS: In the
      horizontal directions, the soft tissue maxillary landmarks (superior labial
      sulcus, labrale superius, and upper lip stomion) moved posterior with a range of
      2.17 to 2.33 mm. The strongest correlations were found between the posterior
      movement of the upper incisal edge and the three soft tissue parameters: superior
      labial sulcus r = 0.78, labrale superius r = 0.81, upper lip stomion r = 0.75.
      The soft/hard tissue ratios of the mandible anterior movement is 0.83:1 between
      inferior labial sulcus and B point, and 0.95:1 for Pog' to Pog. In the vertical
      directions, all the soft tissue mandible landmarks (Pog', inferior labial sulcus,
      labrale inferius, lower lip stomion) moved upward more than 2 mm. And the
      soft/hard tissue ratio is from 1.07:1 to 1.34:1. CONCLUSION: The combined
      orthodontic and surgical treatment is an efficient way to cure skeletal class II
      malocclusion. All the patients regained satisfactory face appearance and profile.
      Although the soft tissue movement is less than the hard tissue in both jaws in
      the horizontal direction, the vertical movement of the mandibular soft tissue is
      greater than that of the underlying hard tissue.

PMID- 12593200
TI  - [Fracture strength of custom-fabricated celay all-ceramic post and core].
AB  - OBJECTIVE: The purpose of this study is to compare the fracture strengths of
      custom-fabricated Celay all-ceramic post-core, custom cast metal post-core, and
      prefabricated stainless steel post (Parapost) plus composite resin core with or
      without a 2.0 mm dentine ferrule. METHODS: A total of 60 recently extracted human
      maxillary central incisors were endodontically treated and divided into five
      groups of 12. They were given the following treatments: Group A: Celay ceramic
      post-core with 2.0 mm dentine ferrule, Group B: Celay ceramic post-core with no
      dentine ferrule, Group C: cast metal post-core with 2.0 mm dentine ferrule, Group
      D: cast metal post-core with no dentine ferrule, and Group E: prefabricated post
      and composite core with 2.0 mm dentine ferrule. All specimens were stored at 100%
      humidity at room temperature for 30 days before testing. Each specimen was in a
      special jig at a 45 degrees angle to the long axis and subjected to a load on MTS
      810 universal material testing machine until failure, with crosshead speed of
      0.02 cm/min. Analysis of variance followed by the Newman-Keuls pairwise multiple
      comparison test was used to compare the results of the groups tested. RESULTS:
      There was a statistically significant difference between five groups (P < 0.01).
      Celay ceramic post-core with 2.0 mm dentine ferrule (758.35 N +/- 119.26 N) and
      cast metal post-core with 2.0 mm dentine ferrule (756.63 N +/- 166.22 N) had a
      significantly larger mean failure threshold for fracture than the other three
      groups which had no significant difference between each other. There was a
      statistically significant difference between the fracture resistance of Celay
      post-core restored teeth with and without 2.0 mm dentine ferrule. CONCLUSION: The
      custom-fabricated Celay post-core could be a choice for clinical use in
      endodontically treated tooth when the final restoration is an all-ceramic crown
      and the preparation has a 2.0 mm dentine ferrule.

PMID- 12593201
TI  - [A clinical study on immediate implantation of particulate hydroxylapatite
      artificial bone after teeth extraction].
AB  - OBJECTIVE: The aim of this study is to investigate the effect and complication of
      immediate implantation of particulate hydroxylapatite artificial bone after teeth
      extraction. METHODS: Particulate hydroxylapatite artificial bone was implanted
      into 65 extraction sockets after teeth extraction. All patients were followed up
      until 3 months after the operation. They are examined with clinical examination
      and X-ray examination to observe the effect and complication of the implantation
      operation. RESULTS: The wound healed well in all cases without any complication.
      Compared to the alveolar ridge before teeth extraction, and the height of the
      alveolar ridge after teeth extraction didn't decrease. CONCLUSION: Implantation
      of particulate hydroxylapatite artificial bone after teeth extraction could
      maintain the height of the alveolar ridge and reduce the complication of teeth
      extraction. It would be helpful for the following prosthetic restoration. The
      immediate implantation of artificial bone is therefore needed further study.

PMID- 12593202
TI  - [McNamara cephalmetric analysis of the 67 chengdu adolescents with normal
      occlusions].
AB  - OBJECTIVE: The purpose of this study was to obtain the normal value of McNamura
      analysis for Chengdu adolescents with normal occlusion of early permanent
      dentition. METHODS: McNamara analysis was conducted on the basis of the lateral
      cephalograms of 67 Chengdu adolescents with normal occlusions, and the obtained
      data was compared with that of Shanghai adolescents and McNamara. RESULTS: There
      was no difference in the normal value of McNamara analysis between male and
      female Chengdu adolescents. The Comparative results between Chengdu and Shanghai
      adolescents indicated significantly larger values of Shanghai adolescents in
      effective middle facial lengths, mandibular lengths and lower anterior facial
      heights. The vertical distances from the upper incisor to point A and, from the
      lower incisor to A-Po line of Chengdu adolescents were larger than those of white
      adolescents. CONCLUSION: There is significantly difference in values of normal
      occlusions of McNamara analysis among different regions and different races.

PMID- 12593203
TI  - [The association between IL-1 gene polymorphisms and susceptibility to severe
      periodontitis].
AB  - OBJECTIVE: The purpose of this study was to investigate the relationship between
      IL-1 gene polymorphisms and susceptibility to severe periodonitis in Chinese of
      the Han Nationality. METHODS: DNA samples with buccal swabs were collected from
      30 patients with severe adult periodontitis (AP), 20 patients with rapid
      progressive periodontitis (RPP) and 94 healthy control (HC) individuals.
      Polymorphisms in the IL-1 gene cluster were analyzed with PCR-RFLP. RESULTS: It
      was found that the frequency of IL-1B + 3953/Taq I allele 2 was significantly
      higher in severe AP patients (OR = 6.8, P < 0.05) and RPP patients (OR = 9.6, P <
      0.05) than in healthy controls, and the frequency of IL-1RN intron II/VNTR allele
      2 was significantly higher in the group of severe AP patients (OR = 6.3, P <
      0.05) than in the group of healthy controls. CONCLUSION: IL-1B + 3953/Taq I
      allele 2 and IL-1RN nitrol IL/VNTR allele 2 are genetic indicators of
      susceptibility to severe AP and RPP, and both AP and RPP are genetic
      heterogeneous.

PMID- 12593204
TI  - [Suppression effect of human tumor necrosis factor-alpha gene transfection on
      tongue carcinoma cells].
AB  - OBJECTIVE: The aim of this study was to investigate suppression effects of the
      transfection of human tumor necrosis factor-alpha (hTNF-alpha) gene on tongue
      carcinoma cells. METHODS: The shuttle plasmid containing hTNF-alpha gene was
      extracted and purified, then it was transferred into Tca8113 tongue carcinoma
      cells with cationic liposome DOSPER. The control group was only given equivalent
      liposomes, except the plasmid. After culturing for 24, 48, 72 and 96 hours, the
      expression of hTNF-alpha gene in Tca8113 cells was analysed by ELISA and, the
      survival rate of transferred cells was assayed by MTT enzymatic labeling
      technique. RESULTS: The transferred Tca8113 cells displayed significantly
      overexpression of hTNF-alpha (P < 0.05). The survival rate of the transferred
      Tca8113 cells was decreased significantly (P < 0.05). CONCLUSION: Transfection of
      hTNF-alpha gene in vitro mediated by cationic liposomes can induce the
      overexpression of hTNF-alpha and inhibit the growth of tongue carcinoma cells.

PMID- 12593205
TI  - [Synergistic effects of human tumor necrosis factor-alpha gene transfection and
      interferon-gamma on the growth of tongue carcinoma cells].
AB  - OBJECTIVE: The purpose of this study is to investigate the synergistic effects of
      human tumor necrosis factor-alpha (hTNF-alpha) transfection and interferon-gamma
      (IFN-gamma) on the growth of tongue carcinoma cells. METHODS: The cultured
      Tca8113 tongue carcinoma cells was divided into 2 groups, one group was
      transferred with hTNF-alpha gene. Each of the 2 groups was then divided into 5
      subgroups, and the subgroups were added IFN-gamma until the final IFN-gamma
      concentrations respectively were 0, 10, 100, and 1000 U/ml. After culturing for
      48 hours, the survival rates of the all groups of cells were assayed by MTT
      enzymatic labeling technique, and the expression of hTNF-alpha in Tca8113 cells
      was observed with immunocytochemistry. RESULTS: IFN-gamma did not affect the
      growth of Tca8113 cells without hTNF-alpha, however, the transfection of hTNF
      alpha with the above different concentrations of IFN-gamma synergistically
      inhibited the growth of Tca8113 cells, the concentrations of IFN-gamma were
      positively correlated with the inhibition effects (r = 0.733, P < 0.01), the
      transferred Tca8113 cells displayed remarkable overexpression of hTNF-alpha,
      compared with the non-transferred. CONCLUSION: IFN-gamma can enhance the
      inhibition of hTNF-alpha transfection on the tongue carcinoma cells.

PMID- 12593206
TI  - [Preparation of nanometer powders of dental alumina ceramics].
AB  - OBJECTIVE: The purpose of this study was to explore the preparation method of
      nanometer powders of dental alumina ceramics. METHODS: The effects of
      concentration of inorganic precursors, pH value, calcination temperature and
      ageing time on the synthesizing process, phase composition and microstructure of
      the materials were studied. Aluminium nitrate with concentrations of 0.03 mol/L,
      0.05 mol/L, 0.1 mol/L and 0.2 mol/L were used as inorganic precursors to prepare
      alumina powders via sol-gel method. Ammonia water was added into the solutions to
      adjust the pH values to 5, 9 and 11. The dried gel was then calcined under
      different temperatures, from 950 degrees C to 1200 degrees C. The prepared
      alumina powders were studied by using X-ray diffraction (XRD), and scanning
      electron microscope (SEM). RESULTS: The alumina powder which was prepared with
      0.1 mol/L aluminium nitrate, pH 9, and calcined at 1200 degrees C for 10 min
      showed good physical characteristics. The diameter of final powder was about 70
      nm. CONCLUSION: With the proper preparation condition, weakly agglomerated
      powders of alumina in nanometer particle size could be obtained.

PMID- 12593207
TI  - [Construction of the pyruvate oxidase gene deficiency variant strain of
      Streptococcus oralis].
AB  - OBJECTIVE: The purpose of this study is to construct a pyruvate oxidase gene
      deficiency variant strain of Streptococcus oralis (S. oralis). METHODS: The sopox
      gene, which was got using polymerase chain reaction (PCR), and the 130-basepair
      segment of which was cut down with endonuclease BamHI, and transferred into S.
      oralis (ATCC10557) by using electrotransformation. The authors obtained a variant
      strain of S. oralis, and then the catalase activity of the first culture and 3-4
      subcultures was examined. RESULTS: The authors obtained a pyruvate oxidase gene
      deficiency variant strain of S. orlis. The catalase activity examination showed
      that the ability of producing H2 O2 of the variant strain of S. orlis declined,
      whose catalase activity was between those of the positive control (ATCC10557) and
      the negative control (Escherichia coli, JM109). But the produced H2 O2 quantity
      of their subcultures was less than that of the negative control. CONCLUSION: The
      construction of the pyruvate oxidase gene deficiency variant strain of
      Streptococcus oralis is successful.

PMID- 12593208
TI  - [The prevalence of permanent caries in adolescent in Sichuan province].
AB  - OBJECTIVE: The aim of this survey was to obtain some information of the
      prevalence of dental caries in the youth aged 12, 15 and 18 years of Sichuan
      province. METHODS: Based on WHO and national oral health survey standards, dental
      caries prevalence and treatment needs were investigated randomly in selected
      young individuals of Sichuan province in 1995. RESULTS: The prevalent rates of
      caries of 12-, 15-, and 18-year-old adolescents were 28.47% and 36.40% and 39.54%
      respectively. The mean DMFT of 12-, 15- and 18-year-old were 0.52, 0.81, and
      0.99. There are more pit and fissure caries than smooth caries in the young of 12
      year-old than those of 15- and 18-year-old. CONCLUSION: Despite improvement can
      be seen in adolescents' oral health in Sichuan, there remains a proportion of
      active untreated decays. Some simple prevention programs are needed to stabilize
      the caries.

PMID- 12593209
TI  - [10 years nursing care needs elite professionals: changed times].

PMID- 12593210
TI  - [Nursing Day at the Breisgau-Hochschwarzwald Helios Clinics. Transition nursing-
      a model].

PMID- 12593211
TI  - [Nursing concept for preventing thrombosis: responsibility of nursing].

PMID- 12593212
TI  - [Therapy in HIV infection: HAART: possibilities and limits].

PMID- 12593213
TI  - [Nursing of AIDS patients--retrospect and prospects: fear--habituation-
      indifference].

PMID- 12593214
TI  - [Specialized nursing duty at the Frankfurt AIDS service: "Patients are still
      dying"].

PMID- 12593215
TI  - [Nursing theories in changing times: seeking the key to reality].

PMID- 12593216
TI  - [Defining the needs of others: half full or half empty?--A question of dialogue].

PMID- 12593217
TI  - [Nursing concept model of capabilities and existential life experiences.
      Concentrating on capabilities].

PMID- 12593218
TI  - [Therapeutic domino-world in the general practice test: the patient as partner].

PMID- 12593219
TI  - ["Difficult" patients: a question of relationship].

PMID- 12593220
TI  - [The Burford model for reflective nursing practice: more than a guide].

PMID- 12593221
TI  - [Ending work relationships: the law protects workers and employers].

PMID- 12593222
TI  - [Human Rights Day 10 December: nurses against arbitrary punishment and capital
      punishment].

PMID- 12593223
TI  - [As AIDS nursing specialist in developing countries: steps over a thousand
      hills].

PMID- 12593224
TI  - [Learning in nursing care: the circle completes itself].

PMID- 12593226
TI  - Just say yes--to certification.

PMID- 12593225
TI  - [Documentation system for improved processing of theory and practice].

PMID- 12593227
TI  - Meeting the challenge of the new millennium: caring for culturally diverse
      patients.
AB  - The world is shrinking, and as a consequence, the United States is changing
      rapidly. In this new environment, health care providers must navigate a new
      cultural terrain and develop new skills to provide appropriate care for patients
      from increasingly diverse backgrounds. The new millennium demographic data of the
      United States and the essential elements of cultural assessment are necessary to
      understand how patient care should be approached in an increasingly diverse
      population.

PMID- 12593228
TI  - Relationship of a pelvic floor rehabilitation program for urinary incontinence to
      Orem's Self-Care Deficit Theory of Nursing: Part 1.
AB  - Urinary incontinence is considered a significant social problem affecting many
      individuals' quality of life. Nursing theory is a set of concepts or propositions
      derived from philosophical beliefs about the phenomena of interest to the
      discipline. The ability to use theory to guide nursing practice brings reasoning
      and logic to professional nursing practice. Orem's Self-Care Deficit Theory of
      Nursing gets to the heart of what nursing is and how continence nursing care can
      be offered and delivered as a broadly inclusive professional, rather than
      narrowly procedural, practice offering individual care targeting the self-care
      agent (client) rather than the medical diagnosis.

PMID- 12593229
TI  - Applying Orem's Self-Care Deficit Theory of Nursing to continence care: Part 2.
AB  - Theory based nursing practice provides a framework for initiation of the research
      process. Orem's Self-Care Deficit Theory of Nursing clearly relates and can be
      easily applied to continence care. Orem's Theory guides nursing practice with
      theoretical concepts and goal setting providing a foundation upon which nurses
      can question the practice and expand the avenue for nursing research.

PMID- 12593230
TI  - The role of ketorolac tromethamine in a clinical care pathway for men undergoing
      radical retropubic prostatectomy.
AB  - The use of ketorolac in managing postoperative pain after a variety of surgical
      procedures has potential advantages over the use of narcotic analgesics alone.
      The purpose of this study was to determine whether the addition of ketorolac
      influenced the time to resumption of a full diet, hospital discharge, and
      postoperative complication rates, compared to a group of patients receiving only
      narcotic analgesics whose postoperative management was otherwise similar. The
      group receiving ketorolac had an earlier return to full diet than those receiving
      narcotics alone. Similarly, the median length of hospital stay was shorter in the
      ketorolac group then the group treated with narcotics alone. The inclusion of
      ketorolac in the postoperative pain management of patients after radical
      retropubic prostatectomy appears to be a safe and effective strategy.

PMID- 12593231
TI  - Zoledronic acid (Zometa): bisphosphonate for prostate cancer/bone metastases.

PMID- 12593232
TI  - Sensate focus and its role in treating sexual dysfunction.

PMID- 12593233
TI  - Osteoporosis--Part II: Dietary and/or supplemental calcium and vitamin D.
AB  - Osteoporosis is a significant problem in women and men. As osteoporosis has
      garnered more attention there seems to be more attention than ever placed on the
      potential benefits of calcium and vitamin D. Health professionals need to inform
      patients that there are numerous healthy dietary sources of calcium and vitamin
      D. Several forms of calcium supplements are commercially available today and
      health professionals need to understand the similarities and differences between
      them. Calcium and vitamin D in moderation also have an excellent safety profile
      and may actually have benefits far beyond osteoporosis therapy.

PMID- 12593234
TI  - An insight into the role of the clinical trials coordinator.

PMID- 12593235
TI  - Nursing in the aftermath of disaster.

PMID- 12593236
TI  - Confronting the nursing shortage.

PMID- 12593237
TI  - Exploring the role of the nurse practitioner.

PMID- 12593242
TI  - Developing critical appraisal skills using a review of the evidence for
      postpartum debriefing.

PMID- 12593243
TI  - The impact of childbirth experiences on women's sense of self: a review of the
      literature.
AB  - This paper presents a review of the literature that informed research undertaken
      to determine what features of childbirth have a positive effect on women's sense
      of self. The literature looked at control: of women or with women, trusting
      relationships, balancing self-empathy, self understanding through an instinctual
      response, altered concious states, childbirth and mother/baby relationships.

PMID- 12593244
TI  - Postnatal unhappiness: who should direct support?
AB  - Depression following childbirth is a common, distressing but frequently
      underreported disorder. It involves a spectrum of symptoms, some of which may be
      self-limiting, while others can have major mental health implications in the post
      partum period. A range of health professionals, including midwives and mental
      health nurses, come into contact with women who suffer from postnatal depression;
      however, there is often little attempt made to integrate maternity and mental
      health care approaches. More collaborative frameworks of care are vital if health
      professionals are to adequately meet the needs of 'unhappy' women in the
      postnatal period.

PMID- 12593245
TI  - Is there an association between maternal hypotension and poor pregnancy outcome?:
      a review of contemporary literature.
AB  - This literature review highlights that research about the effect of maternal
      hypotension in pregnancy has either concentrated on an acute hypotensive episode,
      or looked at the influence of persistent maternal hypotension on fetal growth
      and/or premature birth. Whilst there is some German literature no published
      English study has specifically examined the possible significance of chronic
      maternal hypotension on the risk of stillbirth. There is, therefore, a
      significant gap in the research in this area.

PMID- 12593246
TI  - The nursing shortage revisited.

PMID- 12593247
TI  - Strategies for addressing the nursing crisis.

PMID- 12593248
TI  - Using methotrexate to treat placenta accreta.

PMID- 12593249
TI  - New recommendations on SERMS.

PMID- 12593250
TI  - No FDA approval for silicone implants.

PMID- 12593251
TI  - Relief for menstruation-related migraines.

PMID- 12593252
TI  - Young women's breast health needs.

PMID- 12593253
TI  - Debunking infertility myths.

PMID- 12593254
TI  - Injectable Lunelle contraceptive being recalled.

PMID- 12593255
TI  - Pervasive plastic. Exploring the health risks of this omnipresent product.

PMID- 12593257
TI  - Stomach-sleeping increases SIDS risk.

PMID- 12593256
TI  - Endometriosis sufferers risk other diseases. Surveys explore etiology, long-term
      effects in women.

PMID- 12593258
TI  - Placing pulse oximetry sensors.

PMID- 12593259
TI  - When joy becomes grief. Screening tools for postpartum depression.

PMID- 12593260
TI  - Maternal hyponatremia.

PMID- 12593261
TI  - Sexuality & older women. Exploring issues while promoting health.

PMID- 12593262
TI  - HRT & the World Wide Web. Helping patients find good information on the web.

PMID- 12593263
TI  - Where I come from we don't talk about that. Exploring sexuality & culture among
      blacks, Asians and Hispanics.

PMID- 12593264
TI  - Health disparities and culture--moving beyond the beginning.

PMID- 12593265
TI  - Shrouded in secrecy: breaking the news of HIV infection to Ghanaian women.
AB  - The purpose of this research was to examine the experience of HIV-positive
      Ghanaian women and to identify factors that influenced their vulnerability to
      infection. The study was carried out in Ghana from January to May 1999 using
      participatory action research. In-depth interviews and focus groups with 31 HIV
      positive women, 5 HIV-positive men, 8 nurses, 10 professionals, and 2 traditional
      healers were used to collect the data. The need for secrecy in "breaking the
      news" emerged as an important theme. Secrecy affected the women's access to
      treatment and to financial and emotional support from families. The secrecy
      surrounding breaking the news of HIV infection is one manifestation of AIDS
      stigma in Ghana. Encouraging disclosure within a trusting and supportive
      environment may be one strategy to diffuse AIDS stigma in Ghana. Educational
      interventions to eliminate AIDS stigma among health care professionals, including
      nurses, are required in Ghana.

PMID- 12593266
TI  - The use of advance directives in a population of Asian Indian Hindus.
AB  - Advance directives are a way to communicate the kind of care that people desire
      at the end of life. Recent research shows that ethnic minorities have been found
      to complete advance directives significantly less often than Caucasians, and no
      information was available regarding advance directives in the Asian Indian
      population. To address this shortcoming, this descriptive exploratory design
      sampled a community sample of 45 Asian Indian Hindus. Being female and having an
      individualistic decision-making style were significantly positively correlated
      with advance directive completion. Having strong religious affiliation and a
      family decision-making style were significantly negatively correlated with
      advance directive completion. The results of this study provide needed
      information regarding the Asian Indian population and how Hinduism affects
      advance directives.

PMID- 12593267
TI  - Home care nurses: a study of the occurrence of culturally competent care.
AB  - The purpose of this study is to describe how home care nurses orient to and
      manage cultural issues during patient visits. Fourteen home care nurse-patient
      dyads were observed. Interviews were then conducted with nurses. Nurses and the
      home care agencies for which they worked engaged in practices aimed at minimizing
      patients' cultural practices and beliefs. A correspondence with how nurses
      oriented to patients' cultures and how cultural issues were managed during
      encounters was observed. Overwhelmingly, nurses and home care agencies used
      strategies to avoid dealing with patients' "different" cultural backgrounds. Work
      needs to be done to begin integrating theory and practice regarding culturally
      competent health care.

PMID- 12593268
TI  - Gendered nursing education and practice in Iran.
AB  - Through qualitative ethnographic methods, the researcher gendered nursing
      education and practice among human nursing students and faculty. Interaction with
      nursing students and faculty occurred in a familiar turf using the native
      language in interviews and on field observations. Settings included classrooms,
      skills laboratory, faculty offices, clinical areas, and informants' homes. Formal
      and informal interviews, observations, and printed materials provided useful data
      to reach consistent common patterns. Thematic analysis and triangulation of data
      identified gender variations in care and compassion, spirituality, economic
      motives, and practice preference. Integrated experiences of pre-Islamic period
      were used to describe the current developments of gendered nursing education and
      practice in the Islamic Republic of Iran. Study of gendered nursing education and
      practice brings attention to the cultural significance of gender issues. This
      body of knowledge will benefit American nurses and educators by increasing their
      cultural understanding of gender.

PMID- 12593269
TI  - Perspectives on healing foot ulcers by Yaquis with diabetes.
AB  - The purpose of this pilot study was to describe the perspectives of 4 Yaqui
      Native Americans with diabetes regarding biomedical and traditional methods for
      healing foot ulcers. Leininger's sunrise model provided the conceptual framework
      for this study. Analysis of ethnographic data produced four cultural themes: (a)
      Belief in God is expressed in prayers for healing, (b) the way to keep healthy is
      to take care of oneself, (c) foot ulcer is a modern illness that takes time to
      heal, and (d) support is important to survive a difficult journey. Understanding
      cultural beliefs, perceptions, and healing practices of Yaqui individuals with
      foot ulcers may provide health care providers with a broader scope for providing
      culturally competent care.

PMID- 12593270
TI  - Literacy for health: an interdisciplinary model.
AB  - Traditionally, many literacy and health education programs have had difficulty in
      significantly affecting vulnerable priority populations. The materials used were
      largely generalized for one language, one level of literacy, and one culture. A
      multidiscipline review of literature discusses the relationship between literacy,
      health, and culture and provides rationale for the interdisciplinary literacy for
      health model. The model's synthesis of anthropology, linguistics, literacy,
      nursing, and community partnership guides development of culturally and
      linguistically appropriate materials for successful adoption and diffusion within
      a priority population. In Nepal, the model is being used in the Mugom first
      language literacy project among a group of remote Tibetan Buddhist peoples.

PMID- 12593272
TI  - Native American humor: implications for transcultural care.
AB  - Humor is a ubiquitous element in human interactions. It smoothes relationships,
      enhances communication, and assists with management of emotions. It plays a
      significant role in health care relationships. Humor is an important feature of
      Native American culture. If non-Native nurses and caregivers are to deliver
      culturally competent care, they would do well to familiarize themselves with the
      benefits that humor has to offer as well as the pitfalls they may encounter.

PMID- 12593271
TI  - A research-based didactic model for education to promote culturally competent
      nursing care in Sweden.
AB  - As Sweden changes toward a multicultural society, scientific knowledge of
      transcultural nursing care becomes increasingly important. Earlier studies in
      Swedish nursing education have demonstrated a lack of knowledge base in
      transcultural nursing. Through an extensive review of the literature, a didactic
      model was developed to help facilitate the establishment of this body of
      knowledge in transcultural nursing. The article demonstrates how the model
      applies the content and structure of Leininger's theory of culture care diversity
      and universality and ethnonursing method in a 3-year nursing program in theory as
      well as clinical education. The model includes a written guide for faculty
      members, with references to scientific articles and documents to be used.

PMID- 12593273
TI  - Identifying underserved ethnic populations within a community: the first step in
      eliminating health care disparities among racial and ethnic minorities.
AB  - As set forth by the United States Department of Health and Human Services in
      Healthy People 2010, the primary goal of the national health promotion and
      disease prevention plan is to eliminate the health care disparities among racial
      and ethnic groups. This disparity is due, in part, to unequal health access.
      However, equal access to health care alone would not eliminate the difference.
      The health care provided must be culturally competent to be effective. Before
      providers can effectively begin strategizing ways to provide culturally sensitive
      health care for the people they serve, they first need to identify the groups of
      people in their service areas. A clinical example will be used to demonstrate
      public health nursing's role in accessing and advocating for uncounted
      populations as a fundamental beginning for eliminating disparity in health care
      delivery.

PMID- 12593274
TI  - Plans confirm that most nurses will be excluded from HIV tests.

PMID- 12593275
TI  - Smoking can sometimes have therapeutic value.

PMID- 12593276
TI  - Is the primary care and hospital divide outdated?

PMID- 12593277
TI  - Children living in poverty deserve a healthy start.

PMID- 12593278
TI  - Breaking the fall.

PMID- 12593279
TI  - Bereavement: helping a patient with a learning disability to cope.
AB  - Our case study is of a 55-year-old man who has a moderate learning disability. He
      has been diagnosed as having bipolar disorder and is currently in remission. At
      Christmas six years ago while Dave Croft was on home leave from an NHS unit, his
      father died suddenly. His mother, acting in what she felt were Mr Croft's best
      interests, arranged the funeral and did not inform her son until after the
      ceremony had taken place. Mr Croft appeared to have adjusted to his loss, until
      November 2001 when he became increasingly upset and agitated at the mention of
      death. A multidisciplinary team approach and the use of a 'life event book'
      helped Mr Croft come to terms with his bereavement and allowed staff at the unit
      to put a strategy in place to help him prepare for future family bereavements.

PMID- 12593280
TI  - What you need to know about.... Gastric ulcers.

PMID- 12593281
TI  - Oral hygiene.

PMID- 12593282
TI  - Diabetes: signs, symptoms and making a diagnosis.
AB  - There are two principal classes of diabetes-type 1 and type 2. Type 1 is an
      autoimmune disease and is treated with insulin. Type 2 can often be controlled by
      diet initially, but hypoglycaemic agents and insulin may be needed at some stage
      in order to maintain satisfactory glycaemic control. Diabetes affects people of
      all ages and all ethnic groups. Having diabetes will affect many aspects of a
      person's lifestyle, therefore professional psychological support is usually
      necessary at some time.

PMID- 12593283
TI  - Raising awareness and detection of testicular cancer in young men.
AB  - Testicular cancer mainly affects men in their reproductive years and its
      incidence in the UK is rising. Although it is curable if treated early, many men
      are not aware of the symptoms associated with the disease. Until recently, there
      have been few campaigns to raise men's awareness of their health in general or
      their awareness of testicular cancer in particular. This project's aim was to
      evaluate the understanding that young men in the West Midlands had of testicular
      cancer and methods for its detection.

PMID- 12593284
TI  - Sweet smell of success.

PMID- 12593285
TI  - Fertile ground.

PMID- 12593286
TI  - A guide to assisted conception.

PMID- 12593287
TI  - Manual evacuation of faeces.
AB  - Controversy surrounds the manual evacuation of faeces by nurses, and many are
      confused about their professional and legal responsibilities when asked to
      undertake this procedure. The argument that it is a well established and
      successful procedure is supported by many professionals, but there is very little
      documented evidence of its effectiveness as a method of bowel management.

PMID- 12593288
TI  - Drinking water in schools.
AB  - Children do not drink enough during the school day--and the resulting dehydration
      contributes to continence problems (Box 1). One important part of treating these
      problems is an adequate and regular fluid intake during the day (Haines et al,
      2000). However, it is not uncommon for pupils to go six or seven hours without a
      single drink, and those who do drink usually drink less than they need (Almond,
      1993; Haines et al, 2000).

PMID- 12593289
TI  - Utilising frequency volume charts.
AB  - Frequency and nocturia are common lower urinary tract symptoms associated with a
      variety of organic pathologies as well as with life style and psychological
      factors.

PMID- 12593290
TI  - Pelvic floor muscle exercises.
AB  - The ICS Standardisation Committee (Abrams et al, 2002) defines the symptom of
      stress urinary incontinence as the complaint of involuntary leakage on effort or
      exertion, or on sneezing or coughing. Genuine stress incontinence (now known as
      urodynamically proven stress incontinence) is the involuntary loss of urine
      occurring when, in the absence of a detrusor contraction, the intravesical
      pressure exceeds the maximal urethral pressure. These definitions tend to look at
      the urinary mechanism in isolation, and many clinicians now advocate that a more
      holistic view should be taken of this problem.

PMID- 12593291
TI  - Washable products for women.

PMID- 12593292
TI  - Provision of absorbent garments.

PMID- 12593293
TI  - A job less ordinary.

PMID- 12593294
TI  - Putting evidence in perspective.

PMID- 12593295
TI  - Immediate implantation with provisionalization: from literature to clinical
      implications.
AB  - Numerous studies have confirmed the predictability of dental implants used for
      the replacement of a single missing tooth. Successful application of this
      surgical protocol is still technique sensitive and should be executed only by
      experienced restorative teams. Factors such as implant stability, implant design,
      immediate loading, provisionalization, and various others have a direct influence
      on the result of this procedure. This article reviews current literature on
      immediate implant placement and provides clinical guidelines aimed at improving
      the use of this technique in daily restorative practice.

PMID- 12593297
TI  - The pediculated connective tissue graft: a technique for improving unaesthetic
      implant restorations.
AB  - Clinicians are often faced with the treatment of complex aesthetic dilemmas
      around implants, which can be caused by improper fixture placement and inadequate
      soft tissue management. Even the most aesthetic porcelain crown restoration will
      have an undesirable appearance if the soft tissue architecture is deficient.
      Although some implant fixtures may need to be trephined and the site grafted and
      retreated, this is a long process and may have an unpredictable outcome. One
      alternative is to attempt soft tissue augmentation around the unaesthetic
      restoration. Cases will be used to demonstrate the use of the pediculated
      connective tissue graft to augment deficiencies in soft tissue around previously
      restored implants in the maxillary aesthetic zone.

PMID- 12593296
TI  - Post placement and cementation: Part 1.
AB  - Premolars can be considered as a separate entity in the category of root canal
      treated teeth that will receive a full-coverage restoration. Their unique
      morphology and their susceptibility to high occlusal load, as well as
      contemporary preparation guidelines that advocate a wide shoulder finish line
      design will necessitate the placement of a post in the majority of premolars.
      Although some of the remaining thin walls will be eliminated during preparation,
      their removal is not recommended prior to the buildup procedure. Any remaining
      wall structure can provide additional ferrule and serve as an anti-rotation
      mechanism.

PMID- 12593298
TI  - Correcting disclusion utilizing pressed ceramic restorations.

PMID- 12593299
TI  - Endorse, not use.

PMID- 12593300
TI  - Preprosthetic extraoral verification for implant-supported restorations.

PMID- 12593301
TI  - A novel surgical approach to marginal soft tissue recessions: two-year results of
      11 case studies.
AB  - This article describes a surgical procedure used to achieve gingival coverage in
      denuded roots in mandibular canines. The first surgical stage involves an
      apically displaced partial-thickness flap in the area adjacent to the recession.
      A laterally displaced graft is then employed to cover the recession. Although the
      technique involves a two-stage surgery, a palatal graft is not required and the
      surgical procedure only affects one site. This article also presents the clinical
      results 24 months after the second-stage surgery in 11 deep and wide recessions
      affecting misaligned mandibular canines.

PMID- 12593302
TI  - Are your team members motivated?

PMID- 12593303
TI  - The amazing rubber dam.

PMID- 12593305
TI  - Research approaches: likenesses and differences.

PMID- 12593304
TI  - Staged sinus augmentation using a crestal core elevation procedure and modified
      osteotomes to minimize membrane perforation.
AB  - Staged sinus floor elevation allows predictable implant placement in the severely
      deficient posterior maxilla. An alternative to the most commonly used lateral
      window approach involves the apical displacement of crestal core(s) using
      osteotomes and a composite graft. Crestal core elevation (CCE) incorporates
      specially designed osteotomes to minimize the incidence of membrane perforation
      and placement of a barrier membrane over the core osteotomy. This article
      presents the technique and instrumentation, as well as documentation of 43
      patients demonstrating the efficacy of this modality.

PMID- 12593306
TI  - Dimensions of scholarship and the advancement of nursing science: articulating a
      vision.
AB  - Nursing science, if defined as only the works emanating from the totality and
      simultaneity paradigms, cannot be said to have had a transformed nursing
      practice. Indeed, general acceptance of nursing theory as that which guides
      inquiry, education, and practice in nursing has not been achieved. In this
      column, the author calls for a more inclusive conceptualization of nursing
      science, beyond the acknowledged intradisciplinary paradigms. Nursing is posited
      as a human science with multiple paradigms, and two new paradigms are proposed.
      Finally, the author calls for an educational renaissance in nursing and
      establishment of a more scholarly trajectory toward entry into the profession.

PMID- 12593307
TI  - Response to Rawnsley's column: a theoretician's perspective.

PMID- 12593308
TI  - Questions commonly asked about research.

PMID- 12593309
TI  - Structuring meaning through new languaging: going beyond the ethics of caring.

PMID- 12593310
TI  - Teaching-learning within a futures context.

PMID- 12593311
TI  - The unfolding: scenario planning in nursing.
AB  - An interdisciplinary consortium organized a group to explore the meaning and the
      future of nursing in South Dakota using scenario planning. This column provides a
      general description of the four scenarios that emerged, some observations about
      how they might evolve, comments on their implications, and first-person stories,
      as told by fictitious residents. The process of scenario planning is connected to
      nursing science by explicating how five lessons of scenario planning are linked
      with Parse's human becoming concepts of creative imagining, glimpsing the
      paradoxical, and affirming personal becoming.

PMID- 12593313
TI  - Caring as being in nursing: unique or ubiquitous.
AB  - The purpose of this column is to explore ambiguities concerning the concept of
      caring as being in nursing and to consider if caring is unique to nursing or
      ubiquitous, present not only within other health disciplines, but as a potential
      choice for each person. Clarification is sought through an exploration of four
      pathways for thinking about caring as being--artistic endeavors, moving beyond
      self in caring relationships and spirituality, creating caring environments
      through caring-healing consciousness, and soulful caring consciousness. It is
      proposed that caring as being is an essential, but not necessarily unique,
      knowledge source within nursing.

PMID- 12593314
TI  - The nurse theorists: 21st century updates--Martha E. Rogers. Interview by
      Jacqueline Fawcett.

PMID- 12593315
TI  - A comparison of three views of spirituality in oncology nursing.
AB  - This article compares three views of spirituality with specific consideration for
      persons who live with cancer. These views represent theological, psychological,
      and nursing perspectives. Three dimensions of theologically inspired spirituality
      are discussed: institutional religious approaches, intellectual questioning, and
      mystical experiences. The authors review numerous psychological perspectives on
      the topic of spirituality, particularly from the analytic, humanistic, and
      existential schools of thought. A human becoming nursing theory perspective is
      also offered. The authors, who were friends, one a nurse and the other a person
      with cancer, suggest that nurses, who are able to offer true presence from a
      place of hope and fulfilled-emptiness, bear witness to persons in a way that can
      help them transfigure the experience of living with cancer.

PMID- 12593316
TI  - The biobehavioral effects of gentle human touch on preterm infants.
AB  - This study examined the physiological and behavioral effects of a gentle human
      touch nursing intervention on medically fragile preterm infants (27 to 32 weeks
      gestational age). The Roy adaptation model of nursing was the framework for the
      study. The results of this study suggest that the immediate and short-term
      effects of a gentle human touch nursing intervention were not aversive or
      stressful to preterm infants of 27 to 32 weeks gestational age; furthermore, the
      findings document several positive, beneficial behavioral effects of the
      intervention on preterm infants and indicate this type of touching may be
      appropriate for infants in the neonatal intensive care unit.

PMID- 12593317
TI  - Evaluation of education materials using Orem's self-care deficit theory.
AB  - This article presents Orem's self-care deficit nursing theory as the conceptual
      framework in the development, design, selection, and evaluation of appropriate
      written patient education materials for patients with low literacy skills. The
      model, which includes essential evaluation factors used in literacy research,
      offers nurses and other professionals a more comprehensive means to judge the
      suitability of health information and instructional materials. Nurses have a
      critical role in educating consumers and their families and for providing
      patients with useful information that will influence their decision-making and
      participation in care.

PMID- 12593318
TI  - Grief is more than tears.
AB  - Much has been written in the professional and popular literature about grief. The
      multiplicity of sources for information about the phenomenon often leads to
      confusion regarding terminology and process. In addition, assessment and
      intervention methods show the phenomenon as unidimensional despite evidence to
      the contrary. Because nursing routinely deals with grief, it is important that a
      framework be developed to help understand the process and guide appropriate
      interventions. The Neuman systems model is particularly well suited as a
      framework because concepts found in the model are similar to descriptions of the
      concept of grief. An analysis of the grief concept using the Neuman model is
      presented, with perinatal grief presented as an example.

PMID- 12593319
TI  - The many facets of caring.

PMID- 12593320
TI  - A study of yangsaeng and dietary practices among Korean women.
AB  - The purpose of this study was to explore the meaning and nature of the yangsaeng
      experience, a caring intervention, through the dietary practices among a group of
      Korean women. The participants were 14 generally healthy women between 30 and 74
      years of age who were attending a class for homemakers or members of a women's
      club. A phenomenological method was used to analyze the interview data. Ten
      essential themes emerged. The themes can be applied in developing Korean nursing
      caring interventions for facilitating dietary yangsaeng among Korean women. These
      are based on understanding of Korean culture rather than being dawn from Western
      concepts of nutrition and health promotion.

PMID- 12593321
TI  - Learning to practice the discipline of nursing.

PMID- 12593322
TI  - Cognitive theories as reinforcement history surrogates: the case of likelihood
      ratio models of human recognition memory.
AB  - B. F. Skinner (1977) once argued that cognitive theories are essentially
      surrogates for the organism's (usually unknown) reinforcement history. In this
      article, we argue that this notion applies rather directly to a class of
      likelihood ratio models of human recognition memory. The point is not that such
      models are fundamentally flawed or that they are not useful and should be
      abandoned. Instead, the point is that the role of reinforcement history in
      shaping memory decisions could help to explain what otherwise must be explained
      by assuming that subjects are inexplicably endowed with the relevant
      distributional information and computational abilities. To the degree that a role
      for an organism's reinforcement history is appreciated, the importance of animal
      memory research in understanding human memory comes into clearer focus. As
      Skinner was also fond of pointing out, it is only in the animal laboratory that
      an organism's history of reinforcement can be precisely controlled and its
      effects on behavior clearly understood.

PMID- 12593323
TI  - The pigeon's discrimination of visual entropy: a logarithmic function.
AB  - We taught 8 pigeons to discriminate 16-icon arrays that differed in their visual
      variability or "entropy" to see whether the relationship between entropy and
      discriminative behavior is linear (in which equivalent differences in entropy
      should produce equivalent changes in behavior) or logarithmic (in which higher
      entropy values should be less discriminable from one another than lower entropy
      values). Pigeons received a go/no-go task in which the lower entropy arrays were
      reinforced for one group and the higher entropy arrays were reinforced for a
      second group. The superior discrimination of the second group was predicted by a
      theoretical analysis in which excitatory and inhibitory stimulus generalization
      gradients fall along a logarithmic, but not a linear scale. Reanalysis of
      previously published data also yielded results consistent with a logarithmic
      relationship between entropy and discriminative behavior.

PMID- 12593324
TI  - On the determinants of induction in responding for sucrose when food pellet
      reinforcement is upcoming.
AB  - Rats' rates of leverpressing for low-concentration liquid-sucrose reinforcers in
      the first half of an experimental session increase when food pellet, rather than
      sucrose, reinforcers will be available in the second half. Experiment 1
      determined that this induction effect was the outcome of food pellet
      reinforcement's increasing response rates, not of continued sucrose
      reinforcement's decreasing them. Experiments 2 and 3 showed that induction was
      primarily controlled by the conditions of reinforcement in the current session,
      not by those in the previous one. Experiment 4 showed little evidence that the
      induction was the outcome of Pavlovian processes. These results suggest that
      induction may occur because of processes operating at the level of the entire
      session. They also provide a link to a seemingly related area of study: contrast
      effects. Some of the results are consistent with what is known about contrast
      effects, but there are also several, yet unexplained differences.

PMID- 12593325
TI  - Learned suppression of photopositive tendencies in Drosophila melanogaster.
AB  - A task was designed to teach individual flies to avoid a lighted area after they
      had displayed an initial preference for it. The flies walked in a T-maze and
      chose between a lighted and a darkened alley leading, respectively, to a lighted
      and a darkened vial. Flies that were photopositive on a first trial were
      subjected to an aversive stimulus (a filter paper inserted into the lighted vial
      and wetted with a quinine solution), and they performed 16 training trials; they
      learned to avoid the lighted vial. The flies trained with water instead of
      quinine in the lighted vial still display avoidance of the lighted vial, but to a
      lesser extent. The flies trained with a dry filter paper in the lighted vial did
      not show any increase in avoidance during training. Like the flies trained with
      no quinine at all, those trained to avoid the lighted vial under a partial
      reinforcement condition (one half of the trials with quinine, the other half with
      a dry vial) did not master the task. Finally, removal of the quinine after an
      avoidance acquisition criterion was reached resulted in an extinction process.

PMID- 12593326
TI  - How does the ecological foraging behavior of desert kangaroo rats (Dipodomys
      deserti) relate to their behavior on radial mazes?
AB  - Experiment 1 showed that laboratory-reared desert kangaroo rats, like domestic
      Norway rats, efficiently search for food on a radial arm maze (RAM) by avoiding
      revisiting arms within a trial. By placing an RAM on the floor so the animals
      could approach food from any direction, Experiment 2 tested whether efficient
      search by kangaroo rats was based on tactics of distance minimizing, central
      place foraging, trail following, or meandering. In contrast to the dominant trail
      following tactic of domestic Norway rats (Hoffman, Timberlake, Leffel, & Gont,
      1999), kangaroo rats tended to distance minimize, whether maze arms were present
      or not. Experiment 3 indicated that kangaroo rats treated a floor configuration
      of eight food cups as two patches of four, based on beeline travel between
      patches and meandering within them. We conclude that similar performance in an
      elevated RAM by different species can be based on different tactics, and we
      suggest that a laboratory apparatus can be used to cast light on niche-related
      mechanisms.

PMID- 12593328
TI  - No evidence for overshadowing or facilitation of spatial pattern learning by
      visual cues.
AB  - Two experiments were conducted to examine the effects of redundant and relevant
      visual cues on spatial pattern learning. Rats searched for hidden food items on
      the tops of poles that formed a square (Experiment 1) or a checkerboard
      (Experiment 2) pattern. The experimental groups were trained with visual cues
      that specified the locations of the baited poles. All groups were tested without
      visual cues so that any overshadowing or facilitation of spatial pattern learning
      by visual cues could be detected. Spatial choices were controlled by the spatial
      pattern and by the visual cues in both experiments. However, there was no
      evidence of overshadowing or facilitation of spatial pattern learning by visual
      cues in either experiment. The results are consistent with the idea that the
      representation of the spatial pattern that guides choices is not controlled by
      the same learning processes as those that produce associations between visual
      cues and food locations.

PMID- 12593327
TI  - Postinjection suppression of drinking is modified by the presence of conditioned
      contextual cues: implications for both anticipatory and posttreatment nausea in
      humans.
AB  - In three experiments, we set out to determine whether the response of rats to an
      injection of LiCl would be modified by the presence of an environmental context
      that had previously been paired with LiCl. Experiment 1 confirmed that one
      feature of the malaise produced by LiCl is a reduced tendency to consume an
      otherwise palatable flavor. Experiment 2 showed that the size of this response
      was enhanced if it was measured in the presence of a conditioned context. In
      Experiment 3, we investigated the possibility that the postinjection response
      could be modified by an overshadowing treatment given during the conditioning
      phase. The significance of these findings for the understanding of chemotherapy
      induced nausea in the clinical population is discussed.

PMID- 12593329
TI  - Superlatent inhibition and spontaneous recovery: differential effects of pre- and
      postconditioning CS-alone presentations after long delays in different contexts.
AB  - In two pairs of three-stage conditioned taste aversion experiments, we examined
      the effects of delay interval (1 or 21 days) between the second and third stages,
      and of context in which the animals spent the delay (same as or different from
      the context of the other stages) on latent inhibition (LI) and spontaneous
      recovery following extinction. In the LI experiments (Experiments 1A and 1B), the
      first stage comprised nonreinforced presentations to saccharin or to water. In
      the second stage, rats were conditioned by saccharin paired with LiCl. In the
      extinction experiments (Experiments 2A and 2B), the order of the stages was
      reversed. For all experiments, Stage 3, the test stage, consisted of three
      presentations of saccharin alone. There was a super-LI effect in the saccharin
      preexposed group that spent the 21-day delay in the different context (Experiment
      1A). When the delay was spent in the same context, there was no difference in the
      amount of LI between the short- and long-delay groups (Experiment 1B).
      Conversely, there was a spontaneous recovery effect in the long-delay/same
      context group (Experiment 2B), but not in the long-delay/different-context group
      (Experiment 2A). The pattern of results, incompatible with current explanations
      of delay-induced changes in memory performance, was interpreted in terms of an
      interaction between the delay conditions (same or different delay context), which
      modulate the extinction of previously acquired context-CS-nothing associations
      (during CS-alone presentations), and primacy effects.

PMID- 12593330
TI  - Representation of time in time-place learning.
AB  - Ordinal, interval, and circadian mechanisms of solving a time-place task were
      tested. Rats searched for food twice in the morning and once in the afternoon
      (Group AB-C, n = 5) or once in the morning and twice in the afternoon (Group A
      BC, n = 5) in a box with four food troughs. The location of the food depended on
      the time of day in a 12:12-h light:dark cycle. Acquisition was documented by food
      site inspections at the correct locations prior to food availability. On
      nonrewarded probes, the time of the middle search (B) was shifted late (for Group
      AB-C) or early (for Group A-BC). The rats visited Location B at chance, contrary
      to an ordinal mechanism. When the posttesting meal and light-dark transitions
      were omitted, the rats visited correct locations with impaired performance but at
      above-chance levels on nonrewarded probes. The results are consistent with
      interval and circadian representations of time.

PMID- 12593331
TI  - Behavioral expression of learned fear in rats is appropriate to their age at
      training, not their age at testing.
AB  - Recent research has shown that learned fear emerges in a response-specific
      sequence. For example, an odor conditioned stimulus (CS) previously paired with
      shock elicits behavioral expressions of fear like avoidance at a younger age than
      it elicits other behavioral expressions of fear like potentiation of the startle
      response (Richardson, Paxinos, & Lee, 2000). In the present study, the question
      of whether learned fear is expressed in a manner appropriate to the animal's age
      at training or its age at testing was explored in three experiments, all using a
      within-subjects design. The results suggest that learned fear is expressed in a
      manner appropriate to the rat's age at training, not its age at testing. The
      Discussion section focuses on the implications of these findings for (1) the
      developmental analysis of memory and (2) the idea that an aversive CS elicits a
      central state of fear.

PMID- 12593332
TI  - Data archiving for animal cognition research: report of an NIMH workshop.
AB  - In July 2001, the National Institute of Mental Health sponsored a workshop titled
      "Data Archiving for Animal Cognition Research." Participants included scientists
      as well as experts in archiving, publishing, policy, and law. As is described in
      this report, the workshop resulted in a set of conclusions and recommendations
      concerning (A) the impact of data archiving on research, (B) how to incorporate
      data archiving into research practice, (C) contents of data archives, (D)
      technical and archival standards, and (E) organizational, financing, and policy
      issues. The animal cognition research community is encouraged to begin now to
      establish archives, deposit data and related materials, and make use of archived
      materials in new scientific projects.

PMID- 12593333
TI  - Point-counterpoint. Regulated staffing ratios. Not "if" but "how". Nurse to
      patient ratios do not work.

PMID- 12593335
TI  - Nurse executives' values and leadership behaviors. Conflict or coexistence?
AB  - Nurse leaders struggle to provide for the delivery of humanistic and holistic
      healthcare that is consistent with nursing values in a changing economic
      environment. There is concern that nurse executives find it increasingly
      difficult to reconcile the differences between organizational economics and their
      personal and professional identities. The purpose of this study was to examine
      the relationship between nurse executives' perceived personal and organizational
      value congruence and their leadership behaviors (i.e., transformational,
      transactional, and laissez-faire). Four hundred and eleven nurse executives
      employed by American Hospital Association hospitals located east of the
      Mississippi participated in the study. Findings provide insight into the values
      held by nurse executives, personal and organizational value congruence and
      conflict perceived by nurse executives, and the leadership behaviors used by
      nurse executives. For example, the findings indicate there is a moderate degree
      of value congruence between nurse executives' personal and organizational values;
      however, the degree to which specific values are important is significantly
      different. Nurse executives report that they most often engage in
      transformational leadership behaviors, but there was no relationship between
      their leadership behavior and the degree of personal and organizational value
      congruence. Implications for nursing and nursing research are discussed.

PMID- 12593336
TI  - Web journaling. Using informational technology to teach reflective practice.
AB  - Reflection is a process by which we think about experiences and relieve them. Web
      journaling is a tool that gives students opportunities to use reflection when
      they are away from the immediate clinical environment. Through such reflection
      the student's personal knowledge that informs their practice is revealed. The
      revelation of personal knowledge is key to structuring subsequent faculty
      guidance. The web journal is a vehicle for student/faculty dialogue aimed at
      expanding both the faculty's responses to students' learning needs and the
      students' responses to persons in their care. Questions formulated in the
      dialogue direct the student's web-based search for new information. Faculty
      guidance subsequently focuses on the student's decisions regarding the use of
      information to direct clinical practice. Web journaling done over several nursing
      courses reinforces a model of learning, which is increasingly more deliberative
      and intentional. Web journaling may contribute to the development of practice
      throughout a nursing career because it becomes a way for self-directed learning.

PMID- 12593337
TI  - A positive experience connecting thought and action.
AB  - Boyer (1991) suggests that the challenge for nursing education is to provide
      doctoral students more opportunities to see connections between thought and
      action. One way to meet those needs is through an intership experience.

PMID- 12593338
TI  - Exploring the culture of an ICU. The imperative for facilitative leadership.
AB  - This article presents findings of a study conducted in an Australian Intensive
      Care Unit (ICU). The authors were invited by staff of the unit to provide
      education to them to improve their experience of the workplace. Attempts to
      determine what staff would see as useful professional development activity,
      however, revealed an inability to specify their professional development needs.
      Exploration of the workplace situation with all nurses in the unit revealed that
      issues related to the workplace culture--the impact of a changing health care
      contexts on ICU nurses, a lack of collegial support, and a lack of preperation
      for the roles of ICU nurses--resulted in increased tension in the workplace and
      heightened job dissatisfaction. The article provides a discussion of these issues
      and suggests that while all who work in ICU are accountable for their
      interaction, those employed as educators have both a right and a responsibility
      to undertake a leadership role in the workplace. It is argued that the current
      role of educators in demonstrating procedures and equipment, assessing clinical
      competence of those new to the area, and supporting students who participate in
      accredited ICU training does not embrace the potential role of ICU educators to
      facilitate a change in unit culture and behavior.

PMID- 12593339
TI  - Pediatric nursing nurse practitioner focus group report.

PMID- 12593340
TI  - Caring for children and adolescents with autism who require challenging
      procedures.
AB  - Providing nursing care for children with autism or autistic spectrum disorders
      (ASD) can be challenging. As part of a larger study of 62 children with autism
      ages 3-8 years (Coplan et al., 2001; Levy et al., 2001) that required difficult
      procedures, strategies were developed for providing care that incorporated
      theories and knowledge from the disciplines of nursing, child development,
      psychology, applied behavior analysis, and pain management. Applications of these
      strategies are illustrated through the process of a physical exam, phlebotomy,
      and intravenous (IV) insertion during a health care visit. The nurse can develop
      a plan of care to achieve the goals of the visit and optimize the quality of the
      care for the child and family. Interventions presented can be individualized to
      each child.

PMID- 12593341
TI  - Differences in stress and coping for mothers and fathers of children with
      Asperger's syndrome and nonverbal learning disorders.
AB  - Research conducted on families of children with disabilities shows that family
      cohesion and positive family outcomes are influenced by how mothers and fathers
      cope with raising their child with disabilities. This study was designed to
      examine stress and coping differences between mothers and fathers (n = 103) of
      children with Asperger's syndrome (AS) and nonverbal learning disorders (NLD). A
      repeated measure design was used to compare how mothers and fathers cope with
      caring for a particular child to control for differences in the severity and
      nature of the disability across children. Few studies that compare mothers and
      fathers do so at the couple level. Responses indicated that mothers had higher
      rates of stress related to family problems and pessimism about their child's
      future, higher rates of antidepressant use, and higher rates of therapy use than
      did fathers. Mothers found some coping strategies more helpful than fathers did.
      Maternal education and child's age also were related to some stress and coping
      variables. Implications for nurses and future research are discussed.

PMID- 12593342
TI  - Social interactions of children with autism in father-child and mother-child play
      sessions.
AB  - Autism, or the broader category of autistic spectrum disorder (ASD), is a complex
      developmental disability characterized by qualitative impairments in social
      interaction and communication and restricted repetitive patterns of behavior.
      Specific aims of the investigation reported here were to (a) compare autistic
      child behaviors in clinic versus home settings, (b) compare father and mother
      behaviors in clinic versus home settings, and (c) characterize interactions of
      fathers with their autistic children and compare these with mother-child
      interactions. While results indicated that there were no statistically
      significant group differences between child behaviors in clinic versus home
      settings or in father versus mother behaviors, there was wide behavioral
      variability in each setting and differences when comparing individual cases.
      These findings are consistent with the clinical impression that autism is a
      syndrome with various symptom configurations and individual differences in
      behaviors.

PMID- 12593343
TI  - Media violence: advice for parents.
AB  - By the time they reach age 18, American children will have seen 16,000 simulated
      murders and 200,000 acts of violence (American Psychiatric Association, 1998).
      Media violence can be hazardous to children's health, and studies point
      overwhelmingly to a causal connection between media violence and aggressive
      attitudes, values and behaviors in some children (Congressional Public Health
      Summit, 2000). Through education in clinics, schools, and primary care offices,
      pediatric nurses can minimize the impact of media violence. They can obtain
      comprehensive media histories on children and families. They can teach children
      and parents about the effects of media violence and advise them how to avoid
      exposure. Nurses can also encourage the entertainment industry to exercise more
      responsibility in the ways they entertain children.

PMID- 12593344
TI  - Making the grade with asthma, allergies, and anaphylaxis.
AB  - For some students with asthma, allergies, or anaphylaxis, school attendance can
      be risky. School administrators and educators are ill prepared to address medical
      challenges of students with chronic illness. Yet, the number of school nurses
      employed in the United States and the nurse-student ratio is uncertain. An
      unknown number of schools restrict children's rights to carry prescribed
      lifesaving medications while at or traveling to and from school or on field
      trips. Additionally, school indoor air quality is often poor and adversely
      affects students' health. Nurses are natural educators and advocates. Both of
      these roles are instrumental in empowering families to ensure the health of their
      children with asthma and allergies while in school.

PMID- 12593345
TI  - Managing early childhood obesity in the primary care setting: a behavior
      modification approach.
AB  - The purpose of this article is to encourage primary care pediatric nurses to
      begin behavioral-based obesity treatment efforts as early as the preschool years.
      By examining the critical periods for obesity development and how the formation
      of food and activity behaviors interacts with those critical periods during the
      preschool years, the value of initiating early obesity treatment will be
      highlighted. Furthermore, the theory of behavior modification is presented and
      core principles are applied to early childhood weight management efforts.

PMID- 12593346
TI  - Ventricular tachycardia in a neonate.

PMID- 12593347
TI  - The effects of a cochlear implant on the family of a hearing-impaired child.
AB  - PURPOSE: The purpose of this study was to evaluate the effects of a cochlear
      implant on the family of a hearing-impaired child. A single family was
      interviewed to answer these research questions: How does the family adapt
      initially to hearing impairment?, What are the family's concerns before, during,
      and after the implantation?, and How does the family accept and adjust to the
      outcomes of the procedure? METHODS: Immediate family members (mother, father, and
      child) of the child receiving a cochlear implant were interviewed individually
      three times: before, during, and after implantation using an investigator
      designed interview guide. The child's behavior was also observed during a speech
      therapy session before and after completion of the implantation. FINDINGS: The
      findings reflect several common themes concerning ambivalence, excitement, fear,
      anxiety, impatience, and transformation. CONCLUSIONS: The family choosing
      cochlear implantation progressed through several phases of adaptive responses
      from before to after the procedure. Implications for nurses working with families
      during this process are identified.

PMID- 12593348
TI  - Experiencing neonatal death: an ambivalent transition into motherhood.
AB  - OBJECTIVE: To illuminate the lived experience of women facing the threat of
      lossing their newborn child and then experiencing the reality of their infant's
      death. STUDY DESIGN: Sixteen women were interviewed approximately 2 years after
      the death of their infant using a hermeneutic phenomenological approach.
      FINDINGS: The main theme was ambivalent transition into motherhood. The women
      went through the whole life-span of their infant during a very short time. The
      women's narratives were interpreted as broken expectations, total confusion,
      reality awareness, consciously leave-taking, and elusive grief. CONCLUSIONS:
      Women need the opportunity to evolve their own patterns and rhythms in the
      ambivalent transition from expected motherhood to experiencing neonatal dying and
      death. Knowledge about the individuality of this process may assist nurses in
      improving the quality of care.

PMID- 12593349
TI  - Effects of trauma and war on children.

PMID- 12593350
TI  - Learning disabilities: a diagnosis ignored by nurses.

PMID- 12593351
TI  - Needless tests.

PMID- 12593352
TI  - Impact of genetic diseases in Rhode Island.

PMID- 12593353
TI  - Recent advances in maternal serum screening for Down syndrome.
AB  - For the past 15 years, addition of serum markers to screening for Down syndrome
      has enhanced the ability to identify affected pregnancies. During the 1990s,
      incremental improvements in screening have been tested and implemented, first
      with the addition of a fourth biochemical marker, inhibin A, to second trimester
      screening protocols, and second with the development of combined first trimester
      serum and ultrasound screening. With the new century, we are on the verge of a
      major breakthrough in the performance of prenatal screening for Down syndrome,
      with the opportunity to spare almost all pregnant women the risk of amniocentesis
      and CVS, yet attain levels of detection approaching 90%.

PMID- 12593354
TI  - Prenatal screening for cystic fibrosis.

PMID- 12593355
TI  - Early hearing screening, detection and intervention (EHDI) in Rhode Island.
AB  - Currently, professionals and parents are working collaboratively to refine and
      develop a seamless and effective system for screening, detection, intervention,
      and education in Rhode Island.

PMID- 12593356
TI  - Genetic evaluation and counseling for craniofacial anomalies.

PMID- 12593357
TI  - Genetic counseling for adult-onset conditions.

PMID- 12593358
TI  - Quality measurement and quality reporting in Rhode Island: an update.

PMID- 12593359
TI  - Health risks among Rhode Island high school students, 2001.

PMID- 12593361
TI  - Gutsy language.

PMID- 12593360
TI  - Osteoporosis across the lifespan.

PMID- 12593362
TI  - Antitrust suit by St. Luke's surgicenter unsuccessful. Surgery Center of Hammond
      v. the Hospital Service District No. 1 of Tangipahoa.

PMID- 12593363
TI  - Critic of operation of public facility protected by First Amendment. Springer v.
      Henry.

PMID- 12593364
TI  - OIG's special advisory--offering gifts and other inducements to beneficiaries.

PMID- 12593365
TI  - Streamlining the preoperative process for the open heart surgery patient.
AB  - A comprehensive preadmission process for open heart surgery patients sets the
      stage for preventing post-operative complications and improves patient outcomes.
      Due to the complexity and expense of open heart surgery, it is essential for
      every organization to ensure that patients are adequately assessed, well educated
      and prepared both clinically and psychologically for the event. Establishing a
      seamless preoperative process that anticipates all patient and clinical needs
      helps achieve program goals and outcomes, reduces costly delays and improves
      patient and family satisfaction. Organizations should invest the time to
      guarantee that these processes are smooth and efficient.

PMID- 12593366
TI  - Employee recognition brings excellence to the forefront.

PMID- 12593367
TI  - The secrets we keep: privacy and the common good.

PMID- 12593368
TI  - Pre-access processing models.

PMID- 12593369
TI  - A new vision for healthcare delivery.

PMID- 12593370
TI  - Application of attribute control charts to risk-adjusted data for monitoring and
      improving health care performance.
AB  - This article proposes a new class of control charts that may be used for
      monitoring and improving the quality of care. Unlike conventional control charts
      that rely on observed performance data, these charts use risk-adjusted data in
      addition to the observed data. The resulting time-ordered charts are capable of
      reducing time-to-time variation that may stem from uncontrollable changes in
      patient mix over time. Depending on how observed and risk-adjusted data are
      combined, proposed charts are categorized under the framework of either additive
      or multiplicative models. Risk-adjusted rates are obtained using multivariate
      logistic regression models. It was found that the risk-adjusted control charts
      could be effective in reducing biases that arise from variation in patient mix.
      These charts can potentially achieve higher sensitivity and specificity compared
      with ordinary control charts.

PMID- 12593371
TI  - A collaborative model for hospital-based cardiovascular secondary prevention.
AB  - This article presents a collaborative model for hospital-based cardiovascular
      secondary prevention. The model employs a stake holder consortium to provide
      hospitals with a unified approach to improve care and conform to regulatory
      requirements. Hospital teams use a Web-based tool that embeds data collection in
      the process of care and supports rapid cycle improvement. Recognition of
      participation and achievement by the American Heart Association helps to obtain
      administrative support for the program.

PMID- 12593372
TI  - Reducing the incidence of nosocomial pneumonia in cardiovascular surgery
      patients.
AB  - Outcomes management provides a mechanism to foster development of patient-driven
      services through revision of practice and measurement of outcomes. Because
      nosocomial pneumonia is the most common hospital-acquired infection in intensive
      care units, reducing the rate of nosocomial pneumonia became on area of intense
      scrutiny at our institution. This article shares an outcome initiative that
      focused on reducing the incidence of nosocomial pneumonia in a hospital setting.
      Strategies used such as multidisciplinary team formation, case/control study,
      quality improvement activities, risk tool development, and protocol
      implementation, are discussed. Process and outcome data are provided to
      demonstrate the initiative's positive impact. The benefits of this outcome effort
      are easily identified and well-illustrated. The backbone of the initiative-
      proactive identification of problems and the methodical, reasoned search for
      answers--is universally applicable.

PMID- 12593373
TI  - Influencing physician performance.
AB  - For physicians to change their behavior, they must internalize the need for
      change. One way to do this is to get the physicians to agree to the improvement.
      In this study, surgeons were asked to agree that documentation is important. When
      surgeons who agreed that documentation is important were compared with those who
      did not express agreement, those who agreed were more likely to provide the
      required clinical documentation. Furthermore, they showed improvement in their
      percentage of cases with the required documentation when compared to themselves
      over time. Simple strategies such as asking for a private commitment to change
      can enhance competency with documentation requirements.

PMID- 12593374
TI  - St. John Health System and patient safety.
AB  - The first Institute of Medicine (IOM) report refocused the whole health
      profession on patient safety. The goals described in this article were the result
      of the St. John Health System doing the same. We believe that a comprehensive
      approach rather than just focusing on adverse drug events was important. This
      refocusing has been for the most part uniform and identical throughout the
      system. This article describes how, based on the literature supporting the first
      IOM report, St. John Health System developed a comprehensive approach to
      improving patient safety and how that was implemented in our 8 hospital system
      with independent medical staffs.

PMID- 12593375
TI  - Ancillary services in the health care industry: is Six Sigma reasonable?
AB  - Within the naval medical center construct, the disparate disciplines encompassed
      within ancillary services lend themselves to formal quality analysis and process
      improvement. This analysis uses the Six Sigma approach. Error rates were
      investigated and calculated for various processes within ancillary services at
      Naval Medical Center, San Diego. These were translated into the common metric of
      defects per million opportunities (DPMO). DPMO rates vary between 21.5 and
      420,000. These correspond to Sigma values from 1.7 to approaching 6. Rates vary
      with biological complexity of the system and the degree of automation available.
      Some ancillary services translate well into a Six Sigma schema. Systems with high
      potential patient risk if performed poorly and those amenable to second checking
      and computer oversight may be candidates for such optimization. This should be
      undertaken in a local environment conducive to individual error reporting, and in
      a corporate environment with the will and funding to support the transition.

PMID- 12593376
TI  - Citizens' role in health services: satisfaction behavior: Kano's model, Part 1.
AB  - When it comes to consumer satisfaction, there is a lack of consensus over the
      importance of the role of consumers in connection with the quality of services.
      Widely different points of view exist, ranging from a defense of consumer
      satisfaction as the ultimate measure of service quality, to its treatment as a
      commercial issue or as one that merely has to do with image. This first article
      (part 1 of 2, also in this issue) describes and illustrates Kano's explicative
      model of how consumer satisfaction behaves and briefly analyzes the main
      characteristics, advantages, and limitations of the different methods used to
      assess consumer satisfaction.

PMID- 12593377
TI  - Citizens' role in health services: satisfaction behavior: Kano's model, Part 2.
AB  - Kano's approach, besides providing a theoretical model for the behavior of
      consumer satisfaction, makes it possible to convert theory into practice by
      creating instruments (questionnaires) designed to study consumer preferences and
      to find out how a given service feature or attribute will behave in terms of
      consumer satisfaction. In the second part of this article (part 1 is also in this
      issue), we describe the technical aspects of developing and using this type of
      questionnaire and the implications of applying Kano's model.

PMID- 12593378
TI  - Interview with L. Edward Byrant, Jr. Interview by Jean Gayton Carroll.

PMID- 12593379
TI  - New bureau director emphasizes steadfast commitment to underserved populations,
      accountability. Interview by Richard Seaton.

PMID- 12593380
TI  - FDA approves rapid HIV test.

PMID- 12593381
TI  - Report from the Sixth International Congress on Drug Therapy in HIV. What's a
      conference about?

PMID- 12593382
TI  - Who gets treatment and...side effects.

PMID- 12593383
TI  - Protection from nuke side effects.

PMID- 12593384
TI  - What helps adherence to therapy?

PMID- 12593385
TI  - Rub-on vaccine study planned.

PMID- 12593386
TI  - Cancer risk falls in some HAART users.

PMID- 12593387
TI  - Syphilis--the great masquerader.

PMID- 12593388
TI  - Is hepatitis C virus going to become a major STD?

PMID- 12593389
TI  - [Suspected contrast medium concentration in dynamic MR-mammography. Post
      traumatic fracture of the ribs].

PMID- 12593390
TI  - [Functional magnetic resonance tomography (fMRI). 2: Data analysis and
      applications].

PMID- 12593391
TI  - [140th anniversary of the founding of the Czech Medical Society in Prague. The
      Carolinium, 9-10 June 2002].

PMID- 12593394
TI  - The meaning of "S".

PMID- 12593395
TI  - Should anti-epileptic drugs be used for preventing seizures after acute traumatic
      brain injury?

PMID- 12593396
TI  - Primary care errors more frequently result from administrative problems than
      clinical ones, study finds.

PMID- 12593397
TI  - Clinical quiz: cat scratch disease.

PMID- 12593398
TI  - Use of guidelines in a CCU reduces routine use of certain diagnostic tests.

PMID- 12593399
TI  - Weekend, Monday and Friday ICU admissions have increased risk of mortality.

PMID- 12593400
TI  - Kids' asthma management program increases use of guideline-recommended drugs.

PMID- 12593401
TI  - Novel surgical and pharmacological approaches to chronic cholestasis in children:
      partial external biliary diversion for intractable pruritus and xanthomas in
      Alagille Syndrome.

PMID- 12593402
TI  - A prospective, randomized, trial of therapy for extrahepatic portal hypertension!

PMID- 12593403
TI  - Rapid method for the fractionation of nuclear proteins and their complexes by
      batch elution from hydroxyapatite.
AB  - A new procedure for the separation and purification of nuclear proteins and their
      complexes by batch elution from hydroxyapatite is presented. This method allows
      to isolate such proteins with different basic character faster and more
      efficiently than procedures using column chromatography, while showing high
      selectivity, sensitivity, simplicity, mild conditions of purification,
      reproducibility and protein stability.

PMID- 12593404
TI  - David M. Maurice, PhD (1922-2002).

PMID- 12593405
TI  - DentEd Evolves. Global Congress in Dental Education. Prague, Czech Republic.
      March 2001.

PMID- 12593406
TI  - The Madras lunatic asylum in the early nineteenth century.
AB  - Early clarification of authority structures in regard to asylum management and
      curtailment of petty corruption were important features in the development of the
      Madras Lunatic Asylum. Although the development of the Madras Asylum in the early
      nineteenth century had been relatively free of controversy in comparison to the
      institutions in Bengal, it possessed some distinct features. It was finally
      closed down almost exactly a century after its inauguration, and its inmates were
      moved to new premises.

PMID- 12593407
TI  - The importance of properly preparing the OR.

PMID- 12593408
TI  - Universalism in medicine through the ages.
AB  - Since man was formed in the divine likeness, God being considered as the source
      of all truth and goodness, mankind must possess this inherent goodness. It is
      however, this inherent goodness reflected in the healing activities of mankind
      which every culture and race has given witness to in all periods of time. This
      developing in different cultures in different ways throughout the world as a
      thread of continuity linking the brilliant discoveries of the medical sciences of
      our own time with that has gone before.

PMID- 12593409
TI  - Further thoughts on the Trinity America plant closing.

PMID- 12593410
TI  - Lung cancer screening debate.

PMID- 12593411
TI  - Ophthalmic drug products for over-the-counter human use; final monograph;
      technical amendment. Final rule; technical amendment.
AB  - The Food and Drug Administration (FDA) is amending the regulation that
      established conditions under which over-the-counter (OTC) ophthalmic drug
      products are generally recognized as safe and effective and not misbranded. This
      amendment clarifies the active ingredient in OTC eyewash drug products and the
      labeling of the active ingredient and its purpose. This final rule is part of
      FDA's ongoing review of OTC drug products.

PMID- 12593412
TI  - [Conspicuous papillomatous conjunctival and mucosal proliferation. Acanthosis
      nigricans maligna as paraneoplastic syndrome in urothelial carcinoma].

PMID- 12593413
TI  - [Persistent iritis 6 months after cataract surgery. Residual lens nucleus after
      cataract operation in  the chamber angle].

PMID- 12593414
TI  - [Off-label use in oncology. Quackery or progress?].

PMID- 12593415
TI  - [Principles of general ultrasonographic practice. Its use in jaundice].

PMID- 12593416
TI  - Clinical application of positron emission tomography for diagnosis of dementia.
AB  - Clinical applications of PET studies for dementia are reviewed in this paper. At
      the mild and moderate stages of Alzheimer's disease (AD), glucose metabolism is
      reduced not only in the parietotemporal region but also in the posterior
      cingulate and precuneus. At the advanced stage of AD, there is also a metabolic
      reduction in the frontal region. In AD patients, glucose metabolism is relatively
      preserved in the pons, sensorimotor cortices, primary visual cortices, basal
      ganglia, thalamus and cerebellum. In patients with dementia with Lewy bodies,
      glucose metabolism in the primary visual cortices is reduced, and this reduction
      appears to be associated with the reduction pattern in AD patients. In patients
      with frontotemporal dementia, reduced metabolism in the frontotemporal region is
      the main feature of this disease, but reduced metabolism in the basal ganglia,
      and/or parietal metabolic reduction can be associated with the frontotemporal
      reduction. When corticobasal degeneration is associated with dementia, the
      reduction pattern of dementia is similar to the reduction pattern in AD and the
      hallmarks of diagnosing corticobasal degeneration associated with dementia are a
      reduced metabolism in the primary sensorimotor region and/or basal ganglia and an
      asymmetric reduction in the two hemispheres. FDG-PET is a very useful tool for
      the diagnosis of early AD and for the differential diagnosis of dementia. I also
      describe clinical applications of PET for the diagnosis of dementia in Japan.

PMID- 12593417
TI  - Technetium-99m HMPAO brain SPECT in children with attention deficit hyperactivity
      disorder.
AB  - Attention deficit hyperactivity disorder (ADHD) is a developmental,
      neurobehavioral syndrome with an onset in childhood. The aim of this study was to
      investigate the existence of regional perfusion changes in ADHD by means of Tc
      99m HMPAO brain SPECT. Thirteen children with a diagnosis of ADHD and 7 healthy,
      age-matched controls were included in this study. Hypoperfusion was observed on
      the right temporal cortex in 9, and on the left temporal cortex in 3 children.
      The distribution of the lesions showed right lateral temporal cortex involvement
      in 3, right medial temporal cortex in 9 and left medial temporal cortex in 8
      children. Asymmetric perfusion was seen on the caudate nucleus in 4, on the
      thalamus in 3 and on the frontal cortex in 6 children. There was a significant
      difference between children with ADHD and controls in right medial temporal
      cortex: cerebellum and right lateral temporal cortex: cerebellum ratios.
      Hypoperfusion in the right medial temporal cortex was significantly and inversely
      correlated with Du Paul teachers' questionnaire rating scale (r = -0.71, p =
      0.006). It has been postulated that difficulty in self regulating response to
      stimuli in ADHD is mediated by underfunctioning of the orbital frontal cortex and
      subsequent connection to the limbic system. Decreased temporal cortex perfusion
      may dysfunction of the limbic system or the orbito-frontal-limbic axis.

PMID- 12593418
TI  - Quantitative study of the difference in pulmonary perfusion in different
      respiratory phases in healthy volunteers.
AB  - OBJECTIVE: The purpose of this study is to investigate the physiological
      pulmonary perfusion pattern in different respiratory phases by calculating the
      normalized volume center of perfusion intensity. METHODS: Four nonsmoking
      volunteers underwent single photon emission computed tomography (SPECT) of
      maximum inspiration and expiration after the injection of Tc-99m-MAA in each
      respiratory phase at a week's interval. Quantitative analysis by calculating the
      normalized volume center of perfusion intensity was performed. RESULTS:
      Quantitative measurement of the normalized volume center of perfusion intensity
      showed that the percentage averages of ventrodorsal (Y) shift in maximum
      respiration were 16% (left) and 15% (right) in the upper part, 15% (left) and 14%
      (right) in the middle part, 17% (left) and 18% (right) in the lower part, 18%
      (left) and 16% (right) in each total lung. These readings indicated that the
      normalized center of pulmonary perfusion activity at maximum expiration moved in
      the ventral direction in contrast to that at maximum inspiration. In horizontal
      (X) and craniocaudal (Z) directions, the shift in the normalized center of
      pulmonary perfusion activity at maximum expiration indicated no agreement in
      movement direction. CONCLUSION: The normalized center of the pulmonary perfusion
      activity in maximum expiration moved in the ventral direction compared to that in
      maximum inspiration. This phenomenon might be caused by the increase in
      physiological intrathoracic pressure and by a definite reserve of pulmonary
      perfusion.

PMID- 12593419
TI  - The single-plasma-sample method for determining the glomerular filtration rate
      with Tc-99m-diethylenetriamine pentaacetic acid in childhood and adolescence: is
      it age-dependent?
AB  - The aim of this study is to assess the accuracy of the pre-existing single-plasma
      sample method (SPSM) to measure the glomerular filtration rate (GFR) with Tc-99m
      diethylenetriamine pentaacetic acid (Tc-99m-DTPA) in children and adolescents. In
      addition, the age-independent SPSM is evaluated with two algorithms (Bubeck and
      Russell) applied for Tc-99m-mercaptoacetyltriglycine (Tc-99m-MAG3) SPSM. PATIENTS
      AND METHODS: The study was performed on 14 patients (12 men and 2 women; age
      range 3 to 19 yr) with renal diseases. Tc-99m-DTPA (5 MBq/kg) was injected
      intravenously and thereafter blood samples were taken at 5, 15, 60, 90, 120, 150
      and 180 min via the indwelling tube. Radioactivity in the injection syringe and
      plasma was measured by means of a double-well single-plastic scintillation
      counter. The "true" GFR as a reference was determined by two methods: 1) 2
      exponential curve fitting 7 samples (GFR7) and 2) 1-exponential curve fitting 3
      samples between 90 and 150 min (GFR3) in a slow clearance phase. The GFR7 and
      GFR3 were searched for to the clearance (GFR1) estimated from a plasma
      concentration at various sample times by means of 3 equations designed for
      children (Groth & Aasted, Ham-I and -II) and 3 for adults (Christensen & Groth,
      Jacobsson, Itoh). RESULTS: All the SPSM showed close correlations (r > 0.95) with
      the reference methods. Among them, Jacobsson's equation at sample time = 120 min
      tended to be the most accurate (r = 0.9826, RMSE = 7.8 ml/min)). On the other
      hand, Ham-I's equation at sample time = 120 min was the most accurate, when it
      was referred to GFR3 in correction for overestimation (r = 0.9951, RMSE = 4.60
      ml/min). The Bubeck and Russells' algorithms showed that the regression equation
      between the GFR7 and the estimates was different in 2 groups of adults (49 cases)
      and children/adolescents. CONCLUSION: Our study indicates that Jacobsson's and
      Christensen & Groth's equations designed for adults are also applicable in
      determining the GFR with Tc-99m-DTPA in children and adolescents. The algorithms
      applied for age-independent SPSM with Tc-99m-MAG3 appears to be applicable to
      SPSM with Tc-99m-DTPA in children, adolescents and adults, but the single age
      independent equation with Tc-99m-DTPA will need further investigations.

PMID- 12593420
TI  - Present diagnostic strategies for acute pulmonary thromboembolism; results of a
      questionnaire in a retrospective trial conducted by the Respiratory Nuclear
      Medicine Working Group of the Japanese Society of Nuclear Medicine.
AB  - The aim of this study is to re-evaluate and clarify the diagnostic role of
      ventilation/perfusion lung scintigraphy in Japan, now that single-detector-row
      helical CT and multidetector-row CT are available in clinical practice. The
      Respiratory Nuclear Medicine Working Group of the Japanese Society of Nuclear
      Medicine distributed a questionnaire to institutions in Japan equipped with
      scintillation cameras as of September 2001. Of 1,222 institutions, 239 returned
      effective answers (19.6%). The most frequent combination for initial diagnosis of
      acute pulmonary thromboembolism was chest radiography, perfusion lung
      scintigraphy, and contrast-enhanced CT (111 institutions, 46.4%). The
      questionnaire revealed that the validity and usage of perfusion lung scintigraphy
      and those of contrast-enhanced CT were equivalent in the present clinical
      situation. On the other hand, the diagnostic value of ventilation lung
      scintigraphy in suspected pulmonary thromboembolism has not been established in
      Japan. Even though contrast-enhanced CT is widely used in Japan, perfusion lung
      scintigraphy is still required to determine disease severity and monitor its
      progress.

PMID- 12593421
TI  - High-tension electrical injury to the heart as assessed by radionuclide imaging.
AB  - To evaluate cardiac complications associated with electrical injury, 7 patients
      with high-tension electrical injury (6,600 V alternating current) underwent 201Tl
      and 123I-metaiodobenzylguanidine (MIBG) imaging in addition to conventional
      electrocardiographic and echocardiographic assessments. Electrocardiography
      showed transient atrial fibrillation, second degree atrioventricular block, ST
      segment depression, and sinus bradycardia in each patient. Echocardiography
      showed mild hypokinesis of the anterior wall in only 2 patients, but 201Tl and
      123I-MIBG myocardial scintigraphy showed an abnormal scan image in 6/7 and 5/6
      patients, respectively. Decreased radionuclide accumulation was seen primarily in
      areas extending from the anterior wall to the septum. Decreased radionuclide
      accumulation was smaller in extent and milder in degree in 123I. MIBG than in
      201Tl imaging. These results suggest that even in patients without definite
      evidence of severe cardiac complications in conventional examinations,
      radionuclide imaging detects significant damage due to high-tension electrical
      injury, in which sympathetic nerve dysfunction might be milder than myocardial
      cell damage.

PMID- 12593422
TI  - Ischemic "memory image" in acute myocardial infarction of 123I-BMIPP after
      reperfusion therapy: a comparison with 99mTc-pyrophosphate and 201Tl dual-isotope
      SPECT.
AB  - Ischemic "memory image" is a phenomenon of 123I-15-(p-iodophenyl)-3-(R,S)
      methylpentadecanoic acid (BMIPP) in which an area at risk of acute myocardial
      infarction (AMI), could be detected as a defect in a couple of weeks even after
      successful reperfusion therapy. The purpose of this study was to clarify the
      incidence of the ischemic "memory image" of 123I-BMIPP in patients with AMI by
      comparing 99mTc-PYP and 201Tl dual-isotope SPECT. Materials consisted of 14
      patients with successfully reperfused AMI and 20 patients with old myocardial
      infarction (OMI). All AMI patients underwent PYP/Tl dual-isotope SPECT within 1
      week after the onset of AMI, and BMIPP SPECT was performed within 1 week after
      the PYP/Tl dual-isotope SPECT. The extent and severity of the defect of BMIPP and
      Tl were visually scored into four grades: 0 = no defect to 3 = large or severe
      defect. These scores were compared. PYP positive AMI lesions were concordant with
      BMIPP defects (13/14). In AMI, both the extent and severity scores of BMIPP were
      higher than 201Tl (p < 0.001). Differences (BMIPP - Tl) of extent and severity
      scores were greater in AMI than in OMI (p < 0.001). In conclusion, the ischemic
      "memory image" obtained by means of the BMIPP is a common phenomenon (13/14) in
      AMI, and helpful in evaluating the area at risk.

PMID- 12593423
TI  - Noninvasive identification of myocardial sympathetic and metabolic abnormalities
      in a patient with restrictive cardiomyopathy--in comparison with perfusion
      imaging.
AB  - A 42-year-old man had the insidious onset of heart failure, and was diagnosed as
      having restrictive cardiomyopathy. Doppler echocardiography study showed short
      deceleration time of the E wave and short isovolumic relaxation time on
      transmitral Doppler flow. He underwent Tl-201, I-123 beta-methyl-iodophenyl
      pentadecanoic acid (BMIPP) and I-123-metaiodobenzylguanidine (MIBG) cardiac
      scintigraphy. Tl-201 studies showed normal uptake in the left ventricle
      indicating normal blood perfusion. I-123 BMIPP and I-123 MIBG showed reduced
      uptake in the inferior segment of the myocardium, indicating impairment of fatty
      acid metabolism and sympathetic abnormalities.

PMID- 12593424
TI  - Increasing myocardial 123I-BMIPP uptake in non-ischemic area in a patient with
      acute myocardial ischemia.
AB  - The subject was a 65-year-old woman with chest pain. An electrocardiogram
      revealed T-wave-inversion in leads III, aVF, V1-V5. 99mTc-tetrofosmin myocardial
      SPECT showed mildly reduced uptake in the anteroseptal wall and the apex. These
      findings suggested acute myocardial ischemia. Coronary angiography did not show
      any stenotic lesions, but diffuse coronary ectasia was noted in three vessels.
      Coronary flow velocity was remarkably reduced on coronary angiography. Epicardial
      coronary spasm was not provoked by ergonovine loading test. Left ventriculography
      showed diffuse hypokinesis. 123I-BMIPP myocardial SPECT showed mildly reduced
      uptake in the anteroseptal wall and the apex on the early images. But 4-hour
      delayed images showed an increase of 8% in myocardial 123I-BMIPP uptake. We
      treated this patient with ticlopidine and nicorandil. After drug therapy her
      symptoms and left ventriculography improved. 123I-BMIPP myocardial SPECT findings
      on the early images improved, whereas delayed images showed a decrease of 28% in
      myocardial 123I-BMIPP uptake after two weeks and 36% after four weeks. These
      dynamic changes in 123I-BMIPP findings might be a reflection of myocardial fatty
      acid metabolism in patients with acute myocardial ischemia. Delayed 123I-BMIPP
      myocardial SPECT images are useful for the assessment of fatty acid metabolism.

PMID- 12593425
TI  - Quantitative lung perfusion scintigraphy and detection of intrapulmonary shunt in
      liver cirrhosis.
AB  - OBJECTIVE: Frequent association between liver cirrhosis and hypoxemia has been
      well documented. It is mostly attributable to intrapulmonary shunt due to
      dilation of pulmonary vasculature. We performed quantitative lung perfusion
      scintigraphy to detect an intrapulmonary shunt in cirrhosis patients. METHODS:
      Prior to injection, Tc-99m MAA was applied to thin layer chromatography for
      quality control. Three cirrhosis patients who had hypoxemia were examined as well
      as 11 control subjects. After i.v. injection of Tc-99m MAA, whole body anterior
      and posterior images were taken at 5 min in patients with cirrhosis and at 8 time
      points up to 60 min in control subjects. Regions of interest were placed at the
      bilateral lungs and the whole body, and pulmonary accumulation was calculated.
      RESULTS: All the control subjects demonstrated more than 90% of radioactivity in
      the lungs until 20 min. In contrast, all the patients showed values less than 80%
      at 5 min. In the cirrhosis patients with hypoxemia, the presence of
      intrapulmonary shunt was confirmed on quantitative lung perfusion scan. In
      control subjects, pulmonary accumulation of Tc-99m MAA dropped as a function of
      time and became less than 90% after 30 min. CONCLUSION: The timing of
      measurements is essential in evaluating intrapulmonary shunt.

PMID- 12593426
TI  - What is the diagnosis? Addison's disease caused by tuberculosis.

PMID- 12593427
TI  - Semper Paratus.

PMID- 12593428
TI  - Comparison of inter- and intra-chromosomal aberrations in blood samples exposed
      to different dose rates of gamma radiation.
AB  - Peripheral blood samples obtained from a normal healthy volunteer were exposed in
      vitro to gamma radiation with various doses at different dose rates of 1.0, 0.1
      and 0.0014 Gy min(-1). The exposed samples were analysed for different
      chromosomal aberrations such as dicentrics (DC), centric rings (CR) and double
      minutes (DM). The ratio of DC chromosomes (inter) to the total number of centric
      rings (CR) and double-minutes (DM) (CR + DM = intra) were analysed for all the
      three dose rates. The study showed that the frequency of inter-arm chromosomal
      aberrations was more then three times higher than that observed with intra-arm
      chromosomal aberrations in samples exposed at a dose rate of 1.0 and 0.1 Gy min (
      1). However, the frequency of inter- and intra-arm chromosomal aberrations were
      almost same (ratio 1:1) in samples exposed at a dose rate of 0.0014 Gy min(-1).
      This paper discusses the usefulness of the ratio of inter- and intra-arm
      chromosome aberration in finding out whether the sample was exposed to high or
      low dose rate radiation.

PMID- 12593429
TI  - Bayesian estimation of dose thresholds.
AB  - An example is described of Bayesian estimation of radiation absorbed dose
      thresholds (subsequently simply referred to as dose thresholds) using a specific
      parametric model applied to a data set on mice exposed to 60Co gamma rays and
      fission neutrons. A Weibull based relative risk model with a dose threshold
      parameter was used to analyse, as an example, lung cancer mortality and determine
      the posterior density for the threshold dose after single exposures to 60Co gamma
      rays or fission neutrons from the JANUS reactor at Argonne National Laboratory.
      The data consisted of survival, censoring times and cause of death information
      for male B6CF1 unexposed and exposed mice. The 60Co gamma whole-body doses for
      the two exposed groups were 0.86 and 1.37 Gy. The neutron whole-body doses were
      0.19 and 0.38 Gy. Marginal posterior densities for the dose thresholds for
      neutron and gamma radiation were calculated with numerical integration and found
      to have quite different shapes. The density of the threshold for 60Co is unimodal
      with a mode at about 0.50 Gy. The threshold density for fission neutrons declines
      monotonically from a maximum value at zero with increasing doses. The posterior
      densities for all other parameters were similar for the two radiation types.

PMID- 12593430
TI  - Measurement of the neutron detection sensitivity of a liquid in metastable
      states.
AB  - A device able to trap a liquid droplet in a host liquid in a metastable
      (superheated) state was developed for a better understanding of the operational
      principles and for an extension of the application of superheated drop detectors
      (SDDs). Droplets of trans-2-butene in a metastable state were exposed to Am-Be
      neutrons and evaporation of the droplets was observed. By measuring lifetime
      distributions of irradiated droplets, neutron sensitivities were derived from the
      distributions. The sensitivities were compared with calculations and experiments
      performed by using superheated emulsions. Results are discussed related to the
      model of radiation induced vaporisation on which the operational principles of
      superheated emulsions were based. The experiments in this study showed that the
      device developed could be applied to measure radiation sensitivities of different
      kinds of liquids for different kinds of radiations without any special detector
      preparation.

PMID- 12593431
TI  - Analyses of absorbed dose to tooth enamel against external photon exposure.
AB  - Absorbed dose to tooth enamel was examined against external photon exposure by
      measurements with thermoluminescence dosemeters (TLDs) and Monte Carlo
      calculations. TLDs were placed in a realistic physical phantom to measure dose to
      the teeth region in a head. A voxel-type phantom was constructed from computed
      tomography (CT) images of the physical phantom. Monte Carlo calculations with
      this voxel-type phantom were performed to analyse the results of the experiments.
      The data obtained were compared to the enamel doses, which were calculated with a
      modified MIRD-type phantom and already given in a previous paper. It was
      confirmed that the data derived with the MIRD-type phantom are applicable for
      retrospective individual dose assessments by electron spin resonance (ESR)
      dosimetry using teeth for the photon energy region above 300 keV. The analysis,
      however, indicated that the configuration of the head can affect the enamel dose
      relative to external exposure to photons with energy below 100 keV.

PMID- 12593432
TI  - Methodology for evaluation of possible consequences of accidental atmospheric
      releases of hazardous matter.
AB  - Sites exist with high levels of risk of accidental atmospheric releases. These
      releases can be hazardous nuclear, chemical, and biological matter. Such
      accidents may occur during transport of waste, or they may be due to natural
      hazards, human errors, terror acts or various operations at high risk.
      Considering the operation of lifting and transport of the sunken Kursk nuclear
      submarine as an example, a methodology for risk assessment is described. This
      methodology includes two approaches: (1) probabilistic analysis of possible
      atmospheric transport pathways using trajectory modelling, and (2) evaluation of
      possible contamination and consequences using real-time operational atmospheric
      dispersion modelling. The first approach can be applied in advance of an
      operation during the preparation stage, the second in real time during the
      operation stage. For the cases considered in this study, the results of
      trajectory modelling are supported by the operational dispersion modelling, i.e.,
      the westerly flow is dominant during fall occurring 79% of the time. Hence,
      September-October 2001 was more appropriate for the lifting and transport of the
      Kursk nuclear submarine in comparison with summer months, when atmospheric
      transport toward the populated regions of the Kola and Scandinavian Peninsulas
      was dominant. The suggested methodology may be applied to any potentially
      dangerous object involving a risk of atmospheric release of hazardous material of
      nuclear, chemical or biological nature.

PMID- 12593433
TI  - An overview of doses to patients and irradiation conditions of diagnostic chest x
      ray examinations carried out in hospitals of the City of Sao Paulo, Brazil.
AB  - Recently the Brazilian health organisation published information conceming the
      number of hospitals, details of radiological equipment and frequency of medical
      examinations in the country. The information concerning the city of Sao Paulo is
      compiled here, complemented by a survey of absorbed doses to patients undergoing
      the most frequent examination: chest radiographs (postero-anterior (PA) and
      lateral (LAT) projections), as well as the physical parameters employed (tube
      voltage, current-time product, focus-film distance, field size). To collect the
      data, a sample of 12 hospitals (a representative sample of the 199 located in the
      city) was chosen, totalling 27 X ray machines. An anthropomorphic phantom was
      irradiated to simulate the patient. Absorbed doses were determined with
      thermoluminescence dosemeters placed in the phantom, externally and internally.
      Mean values of entrance surface dose (ESD) for PA and LAT projections were 0.22
      mGy (from 0.07 to 0.61 mGy) and 0.98 mGy (from (1.30 to 4.01 mGy), respectively.
      The average organ doses per complete examination (PA and LAT) were 0.15 and 0.24
      mGy to thyroid and lung, respectively. The thyroid was thus in the primary beam
      in many cases. The large variation in the ESD and organ doses indicates that much
      can be done in order to reduce the patient doses by adequate changes of physical
      parameters, without loss of image quality.

PMID- 12593434
TI  - Radiation doses to patients undergoing coronary angiography and percutaneous
      transluminal coronary angioplasty.
AB  - A detailed study of radiation doses received by 168 patients who underwent
      coronary angiography (CAG) and 102 patients who underwent percutaneous
      transluminal coronary angioplasty (PTCA) in two Greek hospitals is presented.
      Radiation dose was measured in terms of dose-area product (DAP). The contribution
      of fluoroscopy and cineradiography to the total DAP was examined separately for
      each radiological projection used in both procedures. Effective dose and doses to
      various organs were estimated with the help of the ODS-60 software. Total DAP was
      found to correlate linearly to fluoroscopy time and cine film length. Mean DAP
      values were found to be 80.8 +/- 28.0 Gy cm2 for CAG and 86.2 +/- 65.6 Gy cm2 for
      PTCAs, whereas the estimated mean values of effective dose were 20.9 +/- 7.5 and
      23.2 +/- 18.1 mSv respectively. DAP to effective dose conversion coefficients
      were estimated to be 0.26 mSv/Gy cm2 for CAG and 0.27 mSv/Gy cm2 for PTCAs.

PMID- 12593435
TI  - Neonatal doses from X ray examinations by birth weight in a neonatal intensive
      care unit.
AB  - The aim of this study was to investigate the frequency and type of X ray
      examinations performed on neonates classified according to their birth weight in
      a neonatal intensive care unit (NICU). In this study, the radiology records of
      2408 neonates who were admitted to the NICU of Oita Prefectural Hospital between
      January 1994 and September 1999 were investigated. This study revealed that the
      neonates with earlier gestational ages and lower birth weights required longer
      NICU stays and more frequent X ray examinations made using a mobile X ray unit.
      The average number of X ray examinations performed on neonates of less than 750 g
      birth weight was 26 films per neonate. In regard to computed tomography and
      fluoroscopy, no significant relationship was found between the birth weight and
      number of X rays. This study revealed that the entrance-surface dose per neonate
      was dependent upon the birth weight, while the maximum dose was not dependent
      upon the birth weight. The average neonatal dose in the NICU was predominantly
      from computed tomography and fluoroscopy. The individual dose varied widely among
      neonates.

PMID- 12593436
TI  - The estimation of absorbed doses received by a victim of a Chinese radiation
      accident.
AB  - The aim of this work was to estimate absorbed doses received by a victim of the
      radiation accident with a 60Co source in Henan province, China. With a Monte
      Carlo stochastic simulation method, an estimation method for doses to the
      radiation accident victim was made. It utilised a mathematical model of adult man
      (MIRD) and a relative applied computer program was developed. By means of the
      simulated conditions of the accident, the absorbed doses to the victim's main
      organ and total body doses were estimated. The results estimated by our Monte
      Carlo method are close to those of experimental simulation measurement of the
      accident. With its convenience and rapidity, this method will be valuable for
      radiation dose reconstruction for victims in radiation accidents.

PMID- 12593437
TI  - Occupational doses during the injection of contrast media in paediatric CT
      procedures.
AB  - The administration of intravenous contrast media by hand or power injection in
      paediatric computed tomography (CT) procedures is carried out at King Faisal
      Specialist Hospital and Research Centre for chest, abdomen and torso diagnostic
      examinations. Some procedures require the CT unit to commence patient scanning
      during the injection of the last volume of the contrast medium. During the
      injection, even if the nurse is wearing a 0.5 mm lead equivalent protective
      apron, the head region and the hand are likely to receive high doses. This study
      was therefore made to assess the head and extremity doses to the nurses during CT
      procedures where typical exposure parameters of 200 to 220 mA s and 120 kVp were
      used. Thermoluminescence dosemeters were deployed for three consecutive months in
      two CT rooms. A total of 96 procedures were performed during this period and they
      were included in this study. Scattered radiation measurements were done at
      different locations where the nurse may be positioned. Results showed that the
      average dose to the head region and the hands per paediatric case were 50 microSv
      and 80 microSv respectively. This study investigated the factors that affect the
      dose and found them to be the length of stay inside the room, type of CT
      examination. exposure parameters and location of the nurse.

PMID- 12593438
TI  - Comments on 'The ICRP and dosimetry: Tlachoctb (Glasnost) redux' (editorial) by
      R. H. Thomas, J. C. McDonald and E. P. Goldfinch.

PMID- 12593439
TI  - Primary carcinoma of the fallopian tube in a 88 years old woman: review of the
      literature.
AB  - A woman of 88 years old with primary carcinoma of the fallopian tube, the oldest
      patient reported in the English literature according to the best of our
      knowledge, was presented. After debulking surgery four courses of chemotherapy
      including paclitaxel and carboplatin was performed. The patient was free of
      disease during two years follow-up.

PMID- 12593440
TI  - The rheumatological prodrome: an unusual inaugural manifestation of acute
      myeloblastic leukemia.
AB  - Uncommon patterns of presentation of acute leukemia pose diagnostic problems. A
      rheumatological prodrome in acute myeloblastic leukemia is very rare. We describe
      one such patient who had a normal haemogram. Bone marrow examination done later
      revealed acute myeloblastic leukemia. The case is discussed with reference to
      literature.

PMID- 12593441
TI  - Acute abdomen in patients receiving chemotherapy.
AB  - OBJECTIVE: To assess the incidence of acute abdomen in patients receiving
      chemotherapy and to evaluate the factors affecting the clinical decision-making.
      MATERIAL AND METHODS: Retrospective analysis of surgical oncology references for
      the patients developing acute abdomen while receiving chemotherapy was carried
      out. A surgical oncologist reviewed each referral and a full work-up was carried
      out. Surgical interventions were carried out as and when deemed necessary.
      Response to treatment, whether surgical or conservative, was used as main outcome
      variable. RESULTS: Mean age of the patients was 37 years (7-58 years). Half of
      the patients were receiving chemotherapy for lymphoproliferative disorders, 13
      for haematological malignancies and 3 for ovarian cancer. Clinical diagnosis was
      of acute appendicitis in 13, paralytic ileus in 9, typhilitis in 3 and intestinal
      perforation in 2, acute intestinal obstruction in 3, and obstructed hernia and
      intussception in one each. Six patients underwent surgery. Two patients expired
      postoperatively of progressive septicaemia and multi-system organ failure.
      CONCLUSION: Evaluation of cancer patients on chemotherapy is difficult.
      Tenderness, presence of peritoneal signs and absence of exaggerated bowel sounds
      are most important clinical signs, however they may be blunted by progressive
      neutropenia or corticosteroid administration. Decision to operate, should be made
      with extreme caution as mortality and morbidity after surgery is high.

PMID- 12593442
TI  - Demonstration of Epstein-Barr virus antibodies in serum of patients with
      nasopharyngeal carcinoma.
AB  - A total of eighty six blood samples (17, 19 & 50 of nasopharyngeal carcinoma,
      oesophageal cancer and normal healthy control respectively) were collected from
      Naga Hospital, Kohima, Nagaland and B. Barooah Cancer Institute, Guwahati, Assam
      and were processed for the detection of EBV-IgG antibody using Elisa test. The
      results showed that EBV positivity is higher among NPC patients as compared to
      oesophageal carcinoma patients and/or healthy control. The data also indicated
      that EBV antibody titre is significantly higher among NPC cases as compared to
      control.

PMID- 12593443
TI  - Superficial temporal artery based flaps for reconstruction following resection of
      head and neck cancer.
AB  - Head and neck cancers account for over twenty five percent of all cancers in the
      Indian subcontinent. Most of them are treated primarily with radiation therapy.
      Reconstruction following resection of post radiation residue or recurrent disease
      requires well vascularised, thin, pliable and easy to do flaps which could be
      used for reconstructing mucosal and cutaneous defects simultaneously to achieve a
      well healed wound with maximum function and cosmesis. Short of the microvascular
      technique the temperoparietal fasciocutaneous island or temperoparietal fascial
      flaps based on the superficial temporal vessels come closest to fulfilling these
      requirements.

PMID- 12593444
TI  - Metaplastic carcinomas of the breast (light microscopic and immunohistochemical
      features).
AB  - Metaplastic carcinomas of the breast are uncommon tumors that contain other
      cellular components besides the glandular component. These carcinomas have a poor
      prognosis as compared to breast carcinomas without metaplasia. It is, therefore,
      important to recognise the metaplastic components. The study was conducted over a
      three year period. All breast carcinomas received during this period in the
      department of pathology were analysed for areas of metaplastic carcinomas. The
      light microscopic features, special stains as well as the immunohistochemical
      markers of metaplastic carcinomas are highlighted in this paper.

PMID- 12593445
TI  - Immunophenotypic subsets in acute lymphoblastic leukemia from a single centre in
      North India: correlation with outcome to induction chemotherapy.
AB  - The poorer outcome of Indian patients with acute lymphoid leukemia (ALL) has been
      observed in earlier studies. However, little data is available on their
      immunophenotypic characteristics. The aim of the present study was thus to
      characterize the immunophenotypic subsets of Indian ALL patients and correlate
      with outcome at the end of induction chemotherapy. Immunophenotyping of 45
      childhood and 25 adult ALL patients was performed by dual colour flow cytometry
      using a panel of B-lineage, T-lineage and Myeloid lineage specific monoclonal
      antibodies. Eighty and 17% of childhood and 92% and none of adults were B-lineage
      and T-lineage ALL, respectively. Aberrant myeloid marker expression was seen in
      11% and 28% of childhood and adult groups, respectively. B-lineage ALL with
      aberrant T-lineage marker expression was observed in 4.4% and 8% of childhood and
      adult groups, respectively. Two each induction failures were observed in both
      childhood and adult groups. All of these were associated with aberrant expression
      of myeloid and/or T-lineage markers on B-lineage ALL. Aberrant expression of
      markers was associated with poorer outcome to induction chemotherapy in both
      childhood and adult ALL patients.

PMID- 12593446
TI  - Cervical intraepithelial neoplasia and human papilloma virus infection in renal
      transplant recipients.
AB  - An association between human papilloma virus (HPV) infection and cervical
      intraepithelial neoplasia has been well established Renal transplant recipients
      on long term immunosuppression are prone to viral infection. It is possible that
      there may be an increased prevalence of papilloma virus infection and associated
      cervical intraepithelial neoplasia in these women. Prospective study of 42 renal
      transplant recipients and 41 age and parity matched controls was undertaken to
      determine whether HPV infection and cervical intraepithelial neoplasia (CIN)
      occurred more often in renal allograft recipients and to assess the relative
      risk. All women underwent Pap smear, colposcopy, histological examination of
      biopsy specimen and polymerase chain reaction for HPV 16. Cytology did not pick
      up HPV infection in any of the women. Colposcopy revealed HPV infection in 15 and
      CIN in 14 women in the immunosuppressed group and HPV in 7 and CIN in 5 women in
      control group. Histological evidence of HPV was found in 24 and CIN in 10 women
      in immunosuppressed group and HPV infection in 13 and CIN in 3 women in control
      group, giving an odds ratio of 6.1. More women in the immunosuppressed group had
      CIN of higher degree as well. PCR revealed infection by HPV 16 in 17 cases and 14
      controls giving an odds ratio of 1.3. Therefore renal allograft recipients on
      immunosuppression should be screened by colposcopy and directed biopsy at regular
      intervals.

PMID- 12593447
TI  - Urodynamic profile after Wertheim's hysterectomy.
AB  - Wertheim 's hysterectomy is likely to cause damage to innervation and anatomical
      support of the lower urinary tract. Urodynamic assessment was done in twenty
      patients of histopathologically proven cancer cervix who were about to undergo
      Wertheim's hysterectomy. The study was performed preoperatively, in the immediate
      postoperative period and six weeks after surgery. Urodynamic study included
      uroflowmetry, cystometry and urethral pressure profile. Urinary symptoms were
      also corelated with the urodynamic profile. It was concluded that the bladder was
      hypertonic in the immediate postoperative period and urethral closure pressures
      were low. Some regeneration of damaged nerve fibres was found to occur during the
      6-8 weeks after surgery resulting in some improvement in sensory and motor
      functions of the bladder Post operatively continuous catheter drainage appeared
      to be the most important part of management of hypertonic bladder and the
      duration was individualised on the basis of urodynamic investigations.

PMID- 12593448
TI  - Study of events leading cellular senescence to human mammary epithelial cancer
      cells in vitro.
AB  - Role of various growth regulatory factors in inducing senescence in cultured HMEC
      cells have been investigated in ten cases of breast cancer. The histological
      grade of tumour cells is found to play significant role in controlling the
      proliferation and phenotypic charateristics of cultured HMEC cells during primary
      culture and also number of subsequent passages resulting in complete cellular
      senescence in them. Effects of conditioned media (CM) collected from primary and
      senescent cultures of these HMEC cells had also been studied on proliferation of
      their own HMEC cells used as target cells, to evaluate the role of various
      autocrine growth factors produced by them. Significant increase in proliferation
      of target cells was noticed on their exposure to CM from senescent cultures,
      while cessation of their proliferation was found on their exposure to CM from
      senscent cultures, suggesting that HMEC cells produce growth promoting factors
      during primary culture and growth inhibitory factors on subsequent passages,
      responsible for inducing features of cellular senescence in them. The role of
      epidermal growth factors (EGF) and transforming growth factors (TGF) alpha and
      beta as autocrine factors in inducing senescence of cultured HMEC cells were also
      investigated. Deletion of EGF from growth media initially caused decreased
      proliferation to target HMEC cells, followed by improvement in their
      proliferation. Supplementation of growth media by TGF-alpha induced significant
      increase in proliferation of target cells. Addition of epidermal growth factors
      receptor (EGFR) antibody to cells exposed to media devoid of EGF and media
      supplemented with TGF-alpha showed marked suppression of proliferation of target
      cells. The morphologic and phenotypic characteristics of target HMEC cells
      exposed to TGF-alpha were also found similar to those HMEC cells grown during
      primary culture, suggesting autocrine production of EGF and TGF-alpha by cultured
      HMEC cells during primary culture. Supplementation of TGF-beta to growth media
      induced marked suppression of proliferation to target cells along with
      morphologic and phenotypic features of terminal differntiation or senescence.
      Exposure of senescent cells to media supplemented with EGF and TGF-alpha could
      not induce their proliferation. This suggest that HMEC cells on subsequent
      passages undergo some genetic and phenotypic alterations resulting in production
      of growth inhibitory factor like TGF-beta which induces cessation of their
      proliferation alone with features of senescence.

PMID- 12593449
TI  - Management of chyle fistulae following surgery in the neck.
AB  - Chyle fistulae are seen in less than twenty percent of cases following head and
      neck surgery. At the Cancer Institute, Madras, India, chyle leaks were seen in 19
      patients between 1990 and 1999. The leak subsided spontaneously in sixteen
      patients on conservative management. The neck was re-explored in three patient.
      The thoracic duct was ligated in one and the wound packed in two. Conservative
      management in the form of aspirations and strapping is more likely to succeed
      when the volume of drainage is low or decresing over time and the surgical
      incision and skin flaps remain healthy. Rightsided leaks and late appearing
      fistulae are also likely to close on conservative management. Dietary
      modifications may help in this process. Re-exploration of the neck would be
      required when conservative management fails. Early exploration would be advised
      when the drainage is large or does not decrease over a few days or if there is a
      tendency to wound breakdown. A thorough knowledge of the anatomy of lymphatic
      pathways from the thorax and abdomen, identification of the thoracic duct during
      surgery and detection and ligature of all lymphatic leaks intraoperatively using
      a trendelenburg position and valsalva maneuver will help reduce the occurrence of
      this problem.

PMID- 12593450
TI  - Discordant findings of Iodine-131 scintiscan and chest radiogram in carcinoma of
      thyroid patients.
AB  - Since 1987, 560 patients have been treated in our department for carcinoma of
      thyroid with radioactive Iodine-131. Recently, we have come across a patient with
      bilateral pulmonary concentration of Iodine-131, that is visualised on Iodine-131
      whole body scintiscan, whereas chest radiogram was negative. Respectively, the
      files of 560 patients of carcinoma of thyroid were analysed. It is found, out of
      560 patients treated, 16 patients, had pulmonary concentration of Iodine-131. The
      chest radiogram was normal in six out of these 16 patients. Details of both chest
      radiogram and scintiscans are presented in this study.

PMID- 12593451
TI  - Population based survival from prostate cancer in Mumbai (Bombay), India.
AB  - Survival from cancer reflects the aggressiveness of the disease, the
      effectiveness of treatment and host factors such as age. Population based
      survival reflects the effectiveness of the overall cancer control strategy in the
      region. Here we report the survival experience of 740 prostate cancer patients
      registered by the Mumbai (Bombay) Cancer Registry during 1987-1991. There have
      been very few reports on survival from cancer in India, mainly because of poor
      patient follow up and inadequate system of registration of death. This has been
      largely overcome in this study by means of matching with death certificate of
      Municipal Corporation, telephone and postal enquiries and active follow up
      through visits of homes of patients. Scrutiny of medical record was also carried
      out whenever it was possible. Thus information on survival status as on January
      1, 1997 was available for 602 patients (82%). The observed survival was 35.1% and
      the corresponding relative survival was 41.6%. The clinical extent of disease,
      treatment given and age of the patient were independent predictors of survival.
      The observed survival was 49.2% for localised disease, 23.5% for direct extention
      and regional node involvement and 12.7% for distant metastatis patients.

PMID- 12593452
TI  - Mesenteric fibromatosis: a report of three cases and literature review.
AB  - Fibromatosis is a group of relatively uncommon benign diseases showing
      proliferation of fibrous tissues and is liable to be confused with fibrosarcoma,
      thereby causing diagnostic as well as therapeutic dilemmas. Even after the
      correct diagnosis is made, one is not sure about the most effective treatment is
      in a given setting. Surgery seems to provide the best results but is not feasible
      at many times due to the extent of the disease, hence the need for non-surgical
      modalities for unresectable and incompletely resected tumors. Mesenteric
      fibromatosis is one of the rarer forms of fibromatosis. Three such cases are
      being presented here with a brief review of the literature.

PMID- 12593453
TI  - Papillary cystadenocarcinoma arising in a paratubal mesothelial cyst of the
      mesosalpinx--a case report.
AB  - Primary carcinoma arising from a paratubal cyst in the mesosalpinx in uncommon.
      Serous tumors of low malignant potential outnumber invasive carcinomas, which are
      often of endometrioid type. Only five cases of serous papillary
      cystadenocarcinoma with capsular invasion have been documented. We report a case
      of invasive papillary cystadenocarcinoma arising in a large paratubal cyst of the
      mesosalpinx, in an infertile woman. Possible hormonal basis, its link to serous
      borderline and malignant tumors of the peritoneum, and value of pre/intra
      operative cyst fluid cytology are discussed. Lack of definitive management
      protocols, prognostic indicators and possible consequences are briefly reviewed.

PMID- 12593454
TI  - Acute erythroleukemia (AML-M6)--a study of clinicohematological, morphological
      and dysplastic features in 10 cases.
AB  - Acute erythroleukemia is a relatively rare form of acute myelogenous leukemia. In
      the present study we analysed ten cases of acute erythroleukemia. All the
      patients were anemic and nine were thrombocytopenic at the time of diagnosis.
      Peripheral blood showed blasts in nine cases. Dyserythropoiesis was seen in all
      the cases whereas dysmegakaryopoiesis was seen in five cases. Dysplasia in the
      granulocytic series was seen in five cases. Based on the overall features this
      study concludes that acute erythroleukemia is associated with dysplasia of
      variable degree.

PMID- 12593455
TI  - Genetics and molecular biology of rhythms in Drosophila and other insects.
AB  - Application of generic variants (Sections II-IV, VI, and IX) and molecular
      manipulations of rhythm-related genes (Sections V-X) have been used extensively
      to investigate features of insect chronobiology that might not have been
      experimentally accessible otherwise. Most such tests of mutants and molecular
      genetic xperiments have been performed in Drosophila melanogaster. Results from
      applying visual-system variants have revealed that environmental inputs to the
      circadian clock in adult flies are mediated by external photoreceptive structures
      (Section II) and also by direct light reception chat occurs in certain brain
      neurons (Section IX). The relevant light-absorbing molecuLes are rhodopsins and
      "blue-receptive" cryptochrome (Sections II and IX). Variations in temperature are
      another clock input (Section IV), as has been analyzed in part by use of
      molecular techniques and transgenes involving factors functioning near the heart
      of the circadian clock (Section VIII). At that location within the fly's
      chronobiological system, approximately a half-dozen-perhaps up to as many as 10
      clock genes encode functions that act and interact to form the circadian
      pacemaker (Sections III and V). This entity functions in part by transcriptional
      control of certain clock genes' expressions, which result in the production of
      key proteins that feed back negatively to regulate their own mRNA production.
      This occurs in part by interactions of such proteins with others that function as
      transcriptional activators (Section V). The implied feedback loop operates such
      that there are daily variations in the abundances of products put out by about
      one-half of the core clock genes. Thus, the normal expression of these genes
      defines circadian rhythms of their own, paralleling the effects of mutations at
      the corresponding genetic loci (Section III), which are to disrupt or apparently
      eliminate clock functioning. The fluctuations in the abundance of gene products
      are controlled transciptionally and posttranscriptionally. These clock mechanisms
      are being analyzed in ways that are increasingly complex and occasionally
      obscure; not all panels of this picture are comprehensive or clear, including
      problems revolving round the biological meaning or a given features of all this
      molecular cycling (Section V). Among the complexities and puzzles that have
      recently arisen, phenomena that stand out are posttranslational modifications of
      certain proteins that are circadianly regulated and regulating; these biochemical
      events form an ancillary component of the clock mechanism, as revealed in part by
      genetic identification of Factors (Section III) that turned out to encode protein
      kinases whose substrates include other pacemaking polypeptides (Section V).
      Outputs from insect circadian clocks have been long defined on formalistic and in
      some cases concrete criteria, related to revealed rhythms such as periodic
      eclosion and daily fluctuations of locomotion (Sections II and III). Based on the
      reasoning that if clock genes can regulate circadian cyclings of their own
      products, they can do the same for genes that function along output pathways;
      thus clock-regulated genes have been identified in part by virtue of their
      products' oscillations (Section X). Those studied most intensively have their
      expression influenced by circadian-pacemaker mutations. The clock-regulated genes
      discovered on molecular criteria have in some instances been analyzed further in
      their mutant forms and found to affect certain features of overt whole-organismal
      rhythmicity (Sections IV and X). Insect chronogenetics touches in part on
      naturally occurring gene variations that affect biological rhythmicity or (in
      some cases) have otherwise informed investigators about certain features of the
      organism's rhythm system (Section VII). Such animals include at least a dozen
      insect species other than D. melanogaster in which rhythm variants have been
      encountered (although usually not looked for systematically). The
      chronobiological "system" in the fruit fly might better be graced with a plural
      appellation because there is a myriad of temporally related phenomena that have
      come under the sway of one kind of putative rhythm variant or the other (Section
      IV). These phenotypes, which range well beyond the bedrock eclosion and locomotor
      circadian rhythms, unfortunately lead to the creation of a laundry list of
      underanalyzed or occult phenomena that may or may not be inherently real, whether
      or not they might be meaningfully defective under the influence of a given
      chronogenetic variant. However, such mutants seem to lend themselves to the
      interrogation of a wide variety of time-based attributes-those that fall within
      the experimental confines of conventionally appreciated circadian rhythms
      (Sections II, III, VI, and X); and others that consist of 24-hr or nondaily
      cycles defined by many kinds of biological, physiological, or biochemical
      parameters (Section IV).

PMID- 12593456
TI  - Efficacy of methylphenidate in patients with cerebral palsy and attention-deficit
      hyperactivity disorder (ADHD).
AB  - Our objective was to study the short-term efficacy and safety of methylphenidate
      in patients with the dual diagnosis of cerebral palsy and attention-deficit
      hyperactivity disorder (ADHD). Twenty-nine patients (8.0 +/- 4.0 years old) with
      cerebral palsy and ADHD completed the study. In a prospective, crossover, double
      blind paradigm, patients were treated with methylphenidate or placebo, each for 4
      weeks. Parents and teachers completed a modified Abbreviated Conners' Rating
      Scale at the beginning of the study and the end of the first and second months of
      treatment with methylphenidate or placebo. Parents were contacted weekly to
      report side effects. Methylphenidate treatment, as assessed by teachers' ratings,
      resulted in a significant improvement in ADHD symptomatology (t = 2.29, df = 27,
      P < .05); however, a trend for improvement was noted only on the parents'
      ratings. After the conclusion of the study, 12 patients continued methylphenidate
      for 20 +/- 10 months. Side effects were minimal, with the exception of transient
      hallucinations in one patient. In children with cerebral palsy and ADHD,
      methylphenidate is effective, rendering it a valuable adjunct to their overall
      medical therapy.

PMID- 12593457
TI  - Atypical brain activation of reading processes in children with developmental
      dyslexia.
AB  - Brain activation differences of reading-related processes between dyslexic and
      normal reading children were localized with functional magnetic resonance imaging
      (MRI). The children performed tasks that varied in visuospatial, orthographic,
      phonologic, and semantic processing demands. Enhanced activation of the left
      extrastriate cortex was found during all tasks in the dyslexic group. During
      orthographic processing, dyslexic children predominantly showed activation in the
      right prefrontal cortex, as also occurred during the visuo-spatial task. Normal
      readers also showed activation in the left prefrontal cortex. Dyslexic readers
      showed less activation of both the temporal and the prefrontal cortex during
      phonologic processing. The results suggest that dyslexic readers fail to use
      brain areas that are normally specialized in language processing, but rather use
      areas that underlie visuospatial processing.

PMID- 12593458
TI  - Sleep-wake patterns in children with intrauterine growth retardation.
AB  - The purpose of this study was to characterize the sleep patterns of children with
      intrauterine growth retardation, known to be at risk for neurodevelopmental
      disorders, and seek a possible correlation with behavior, concentration, and
      attention problems. The sleep patterns of 26 children with intrauterine growth
      retardation aged 4 to 7 years were compared with those of 47 control children
      using activity monitors (actigraphs). In addition, data were collected from the
      parents regarding sleep habits, behavior, concentration, and attention. Children
      with intrauterine growth retardation aged 4 to 7 years were found to have a
      tendency toward poorer quality of sleep than their matched controls. This
      inclination was statistically significant only for one sleep measure, the true
      sleep time. A tendency toward increased fragmentation of sleep, prolonged waking,
      and decreased sleep efficiency, although not statistically significant in this
      study, was demonstrated. Our results showed that 58% of the children with
      intrauterine growth retardation, compared with 40% of the children in the control
      group, could be defined as "poor sleepers" (sleep efficiency lower than 90% or
      three or more waking episodes per night). This disturbed sleep profile is
      probably an integral part of the neurodevelopmental profile typical of these at
      risk children. No significant correlations were found between sleep quality and
      behavior, concentration, and attention problems.

PMID- 12593459
TI  - Caudate nucleus volume asymmetry predicts attention-deficit hyperactivity
      disorder (ADHD) symptomatology in children.
AB  - Clinical diagnosis of attention-deficit hyperactivity disorder (ADHD) is based on
      evaluation of behavioral functioning in three domains: inattentiveness,
      hyperactivity, and impulsivity. Caudate and frontal lobe function figures
      prominently in several neuroanatomic models of attentional functioning. Studies
      comparing children with and without ADHD have found differences in the size and
      symmetry of the caudate nuclei. Using multiple regression, we tested the
      hypothesis that caudate volume symmetry (log left minus log right caudate volume)
      measured from serial sagittal magnetic resonance images in a sample of
      nonreferred children (12 girls/15 boys, 7.0 to 16.6 years, 81 to 129 IQ) would
      predict the cumulative severity of parent-reported ADHD diagnostic behaviors
      beyond variance predicted by age, sex, and level of internalizing problems as
      measured by the Child Behavior Checklist. No child had been previously diagnosed
      with ADHD, although one child was found to meet diagnostic criteria based on the
      rating scale used for the study. The degree of caudate asymmetry significantly
      predicted cumulative severity ratings of inattentive behaviors (P = .015),
      uniquely accounting for 17.1% of the variance in inattention symptomatology over
      demographic variables and internalizing problems, which collectively predicted
      28.9% of the variance. Caudate asymmetry uniquely accounted for only 4.3% of the
      variance in cumulative severity ratings of hyperactive/impulsive symptomatology
      over demographic variables and internalizing problems that collectively predicted
      21.2% of the variance. A greater degree of right to left caudate volume asymmetry
      predicted subclinical inattentive behaviors in a sample of nonreferred children.
      This finding is congruent with neuroanatomic models of attention emphasizing
      lateralized alteration in prefrontal/striatal systems. The results support the
      view that clinical ADHD is the extreme of a behavioral continuum that extends
      into the normal population.

PMID- 12593460
TI  - Practical aspects of conducting large-scale functional magnetic resonance imaging
      studies in children.
AB  - The potential benefits of functional magnetic resonance imaging (MRI) for the
      investigation of normal development have been limited by difficulties in its use
      with children. We describe the practical aspects, including failure rates,
      involved in conducting large-scale functional MRI studies with normal children.
      Two hundred and nine healthy children between the ages of 5 and 18 years
      participated in a functional MRI study of language development. Reliable
      activation maps were obtained across the age range. Younger children had
      significantly higher failure rates than older children and adolescents. It is
      concluded that it is feasible to conduct large-scale functional MRI studies of
      children as young as 5 years old. These findings can be used by other research
      groups to guide study design and plans for recruitment of young subjects.

PMID- 12593461
TI  - Lesion burden and cognitive morbidity in children with sickle cell disease.
AB  - The effect of increased tissue injury in children with sickle cell disease and
      silent cerebral infarcts is not known. We determined the relationship between the
      extent of injury and IQ scores in children with silent cerebral infarcts.
      Participants were 27 children with sickle cell disease who had received magnetic
      resonance imaging (MRI). Children were divided into three groups: group 1, small
      lesion volume (n = 9, < 6.8 cm3); group 2, large lesion volume (n = 9; > 6.8
      cm3); and group 3, no cerebral infarcts (n = 9). The Wechsler Full-Scale IQ was
      significantly lower for group 2 (mean = 76.1) when compared with group 1 (mean =
      87.7) or group 3 (mean = 89.9). In children with silent cerebral infarcts, large
      tissue loss is associated with lower Wechsler Full-Scale IQ and small tissue loss
      is associated with no apparent change in IQ compared with children with no
      cerebral infarcts. The progressive accumulation of silent infarcts may lead to
      poorer intellectual functioning.

PMID- 12593462
TI  - Clinical and diagnostic profile of agenesis of the corpus callosum.
AB  - This study reports the clinical profile, etiologies identified, and outcomes for
      a consecutive series of children with partial or complete agenesis of the corpus
      callosum. Children with agenesis of the corpus callosum were identified in a
      comprehensive computerized database of all patients seen in a single pediatric
      neurology practice over an 11-year interval. Medical records were then
      systematically reviewed. Twenty-four children with agenesis of the corpus
      callosum were identified of a total of 6911 children in the database (0.35%).
      Fifteen were male (62.5%); 9 (37.5%) had presented antenatally, 6 (25%)
      neonatally, and 9 (37.5%) postneonatally. Eight (33.3%) were microcephalic, 12
      (50%) were dysmorphic, 11 (45.8%) had coexisting epilepsy, and 9 (37.5%) had a
      cerebral palsy variant. Investigations revealed an etiology in 11 (45.8%): 3
      chromosomal abnormality, 3 metabolic disorder, 3 cerebral dysgenesis, and 2
      genetic syndromes (Aicardi, Andermann). Outcomes identified included normal or
      mild developmental delay in 7 (29.2%) and moderate-severe developmental delay in
      the remaining 17 (70.8%). Factors predictive of successful etiologic
      determination on bivariate analysis included moderate-severe developmental delay
      or associated cerebral dysgenesis. Factors predictive of eventual developmental
      outcome included microcephaly, coexisting epilepsy, cerebral palsy, or cerebral
      dysgenesis. A spectrum of clinical presentations, underlying etiology, and
      developmental outcome is thus apparent in children with agenesis of the corpus
      callosum. An underlying etiology can be identified in slightly less than half of
      cases, and a normal or mildly delayed outcome is apparent in slightly less than a
      third. Factors predictive of identifying an underlying etiology or eventual
      outcome can be identified.

PMID- 12593463
TI  - Atypical benign epilepsy of childhood with rolandic spikes: features of a subset
      requiring more than one medication for seizure control.
AB  - The objective of this study was to compare the clinical and
      electroencephalographic features of two groups of children with benign epilepsy
      of childhood with rolandic spikes: those in whom seizure control was attained
      either without the use of medication or with a single medication (group 1) and
      those requiring two medications for seizure control (group 2). A consecutive
      series of children with benign epilepsy of childhood with rolandic spikes was
      identified in a single pediatric neurology practice. Medical charts were then
      systematically retrospectively reviewed. A total of 66 children with benign
      epilepsy of childhood with rolandic spikes was identified; 52 (78.8%) required
      either no medication (n = 7) or a single medication (n = 45) for seizure control,
      whereas 14 (21.2%) required two medications. The two groups did not differ with
      respect to gender, age of onset, type (generalized or partial) of initial
      seizure, or whether EEG abnormalities were unilateral or bilateral. They did
      differ significantly with respect to the mean number of seizures experienced
      prior to initiating treatment (group 1, 2.06, versus group 2, 4.36; t = 3.40, P =
      .005). In those treated (n = 59), the initial medication selected (carbamazepine
      versus noncarbamazepine) in the two groups was significantly different: group 1,
      40 (carbamazepine)/45, versus group 2, 9 (carbamazepine)/14; chi2 = 4.59; P =
      .03. The difference in frequency between the two groups of associated comorbid
      conditions (tics, attention-deficit hyperactivity disorder [ADHD], learning
      disability) almost reached the threshold of statistical significance: group 1,
      7/52, versus group 2, 5/14 (chi2 = 3.67, P = .06). A subset of children with
      benign epilepsy of childhood with rolandic spikes may require more than one
      medication for effective seizure control. This subset experiences more seizures
      prior to the initiation of treatment, is more likely to be treated initially with
      a noncarbamazepine medication, and tends to have a higher frequency of associated
      conditions.

PMID- 12593464
TI  - Congenital microcephaly in two infants with the factor V Leiden mutation.
AB  - Two infants with congenital microcephaly associated with the factor V Leiden
      mutation are described. In both cases, brain magnetic resonance imaging (MRI)
      revealed cerebral atrophy and porencephalic cystic lesions, which were probably
      attributable to prenatal cerebral vascular events. These findings suggest that
      assessment for this mutation is an important part of the evaluation of infants
      with unexplained congenital microcephaly, especially in cases with infarcts
      and/or porencephalic cysts on brain MRI.

PMID- 12593465
TI  - Eight-year study of childhood status epilepticus: midazolam infusion in
      management and outcome.
AB  - Sixty-eight children 2 months to 14 years of age were admitted with status
      epilepticus to Sultan Qaboos University Hospital from November 1993 to December
      2001. Thirty-eight children (55.9%) had refractory status epilepticus and 30
      (44.1%) had established status epilepticus. The children with refractory status
      epilepticus had received intravenous or per rectal diazepam and intravenous
      phenytoin/phenobarbital (either or both) before continuous infusion of midazolam
      was given. Fifty-one children received continuous midazolam infusion. In 38
      children with refractory status epilepticus, the midazolam infusion was given in
      addition to the long-acting antiepilepsy drug, whereas 13 (18.8%) children needed
      only midazolam to control the established status epilepticus. Seventeen (25%)
      children were controlled with phenytoin sodium alone. Midazolam was given 0.15
      mg/kg/minute initially as bolus in 1 minute, followed by 1 to 7 microg/kg/minute
      as continuous infusion. The status could not be controlled in one child (1.5%)
      suffering from neurodegenerative disease. Two children needed mechanical
      ventilation following prolonged apnea after diazepam administration in one and
      diazepam plus phenobarbital in the other. No metabolic derangements or compromise
      of vital functions was noted on midazolam infusion. All children made a complete
      recovery. There was one death related to meningoencephalitis.

PMID- 12593466
TI  - Ex vivo high-resolution magnetic resonance imaging of the brain in Joubert's
      syndrome.
AB  - This study employs ex vivo high-resolution magnetic resonance imaging (MRI) to
      examine anatomic structures in an intact brain of a child with Joubert's
      syndrome. Several of the specific hindbrain malformations associated with
      Joubert's syndrome are well resolved with ex vivo MRI, including the "molar tooth
      sign," which arises from enlarged and maloriented superior cerebellar peduncles,
      hypoplastic vermis, and deepening of the interpeduncular fossa. Superior
      resolution was achieved compared with that of in vivo MRI and included
      visualization of the inferior olives. One high-resolution study also showed that
      the decreased width of the brainstem isthmus is probably caused by failure of
      superior cerebellar peduncles to cross the midline at that level. The results of
      this study suggest that high-resolution MRI may be useful in screening the
      brainstem for malformations that can be studied histologically in a much more
      targeted fashion.

PMID- 12593467
TI  - Carbamazepine versus sulthiame in treating benign childhood epilepsy with
      centrotemporal spikes.
AB  - We compared the therapeutic efficacy of carbamazepine versus sulthiame in
      patients with benign childhood epilepsy with centrotemporal spikes. Drug efficacy
      was evaluated only in those patients who initiated treatment with any drug after
      at least three seizures. Thirty-eight patients who received carbamazepine and 18
      patients who received sulthiame were included in the analysis. Cessation of
      seizures was observed in 73.6% of the former and in 66.7% of the latter (P = not
      significant). Five of eight patients who were switched to sulthiame after failing
      carbamazepine became seizure free, whereas none of the three patients who failed
      sulthiame became seizure free after being switched to carbamazepine. The rate of
      drug discontinuation owing to adverse reaction was 15% in carbamazepine and 14.3%
      in sulthiame. Normalization of interictal epileptiform activity on
      electroencephalography was seen more often following treatment with sulthiame
      (71%) than with carbamazepine (42%) (P = not significant). No significant
      differences between these two medications were found in the treatment of benign
      childhood epilepsy with centrotemporal spikes in this small patient sample.

PMID- 12593468
TI  - In memoriam. Warren A. Weinberg (1934-2002).

PMID- 12593470
TI  - Apolipoprotein CIII and highly active antiretroviral therapy (HAART)-induced
      hypertriglyceridemia.

PMID- 12593469
TI  - C-peptide and autoimmune markers in diabetes.
AB  - Autoimmune markers such as islet cell antibodies (ICA), glutamic acid
      decarboxylase antibodies (GADA) and islet antigen-2 antibodies (IA-2A) are found
      in high frequencies among type 1 patients and especially among younger patients.
      Presence of these autoantibodies confirms the destructive process of the beta
      cells associated with immune-mediated type 1 diabetes. Type 2 diabetes is
      characterised by peripheral insulin resistance and a relative deficiency in
      insulin production. However, when autoimmune markers are analysed these are found
      in about 10% of patients clinically classified as type 2 diabetes, indicating
      that the frequency of type 1 diabetes is underestimated. GADA is the most
      frequent marker both among patients clinically classified as type 1 and type 2.
      GADA is also highly predictive for insulin treatment in patients not classified
      as type 1 diabetes. C-peptide is the best marker of the endogenous insulin
      production. Sampling of C-peptide is preferably done in the non-fasting condition
      since these values differentiate better between autoimmune and non-autoimmune
      diabetes. The presence of autoimmune markers at diagnosis predicts a course of
      further deteriorating beta cell function, whereas absence of autoimmune markers
      predicts stable beta cell function for the first two years in adults. Presence of
      GADA and in particular in high levels are prognostic for a low beta cell function
      within the next few years after diagnosis. Positivity only for ICA indicates a
      more preserved beta cell function for the first three years compared to
      positivity for other autoimmune markers.

PMID- 12593471
TI  - Clinical evaluation of the Elecsys CA 15-3 test in breast cancer patients.
AB  - The aim of the present study was to evaluate the clinical performance of the CA
      15-3 assay on Elecsys systems in an international multicenter study (11 centers).
      A total of 1326 single samples (272 apparently healthy individuals, 34 pregnant
      women, 308 benign diseases, 273 cancers other than breast, 439 breast cancer) and
      538 serial samples of 98 breast cancer patients during follow-up were analyzed.
      95% of values in healthy individuals were below 25 kU/L, and 88% in benign breast
      diseases, respectively. In malignant breast disease at primary diagnosis the
      value distribution of Elecsys CA 15-3, sensitivity at 95% specificity, as well as
      the areas under the curve in ROC analysis were clearly correlated to tumor
      stages: UICC I to IV 88 to 25% of values < 25 kU/L, sensitivity 7 to 78%, areas
      under the curve 0.53 to 0.94. During follow-up, sensitivity/specificity for
      detection of recurrences were 90%/71%. In metastatic disease clinical
      progression/response to therapy were indicated in 91%/78% of patients at a
      specificity of 92%/78%. The findings indicate that the Elecsys CA 15-3 assay is
      very suitable in routine work for detection of recurrences as well as for therapy
      control in metastatic breast cancer.

PMID- 12593472
TI  - Detection of Bence Jones myeloma and monitoring of myeloma chemotherapy using
      immunoassays specific for free immunoglobulin light chains.

PMID- 12593473
TI  - Effect of nutrient supplementation on serum homocysteine, iron and proteins in
      psychogeriatric patients.
AB  - In a longitudinal follow-up study the effect of pharmaceutical supplementation of
      nutrients (folate, vitamin B12, B6, B1, C, iron and proteins) was established in
      25 psychogeriatric patients (subject group). A reference group of 30 apparently
      healthy elderly subjects was used for comparison and statistical evaluation. At
      the time of hospitalization percentages concerning the incidence of decreased
      serum concentrations reflecting an inappropriate nutrient state in the subject
      group amounted to 28% for vitamin B12, 20% for folate, 36% for iron, 12% for
      transferrin and 56% for albumin concentrations. Increased plasma concentrations
      of homocysteine combined with decreased folate concentrations were found in 16%
      of the psychogeriatric patients. If compared with the initial results at
      admission, after three weeks of nutrient supplementation the vitamin B12 and
      folate serum concentrations were increased. Results for serum iron concentrations
      remained below the reference range interval in 5 of the 25 subjects reflecting
      iron deficiency. Initially decreased serum transferrin concentrations did not
      return to the reference range. Serum albumin levels still further decreased after
      admission to the hospital, resulting after three weeks in albumin concentrations
      below the reference range for 68% of the subjects. It is concluded that
      supplementation of folate and vitamin B12 lowered homocysteine plasma
      concentrations successfully. Supplementation of protein nutrients is not
      appropriate in order to restore disturbances of protein metabolism. Persisting
      low concentrations of proteins in serum are indicative of irreversible decreased
      synthesis.

PMID- 12593474
TI  - Pro-gastrin-releasing peptide (ProGRP) and neuron specific enolase (NSE) in
      therapy control of patients with small-cell lung cancer.
AB  - In small-cell lung cancer patients tumor markers were used for disease
      monitoring. The goal of this study was to identify diagnostic efficiency in the
      detection of tumor behavior in small-cell lung cancer patients by using a
      relatively new tumor marker, ProGRP, in comparison to the established marker NSE.
      34 consecutive small-cell lung cancer (SCLC) patients were included in this
      prospective study. The changes of the blood levels of ProGRP and NSE were
      compared to the clinical evaluation. Clinical monitoring was evaluated according
      to the standard criteria of the WHO. 19 patients had remission, 8 stable disease
      and 7 tumor progression under therapy. NSE and ProGRP were measured in sera
      before and after treatment with polychemotherapy. After tumor remission the NSE
      but also the ProGRP levels decreased significantly under treatment (p=0.0001
      resp. p=0.0180). As suspected, pre- and post-treatment marker concentrations did
      not differ significantly in patients with stable disease. In progressive small
      cell lung cancer patients an increase of ProGRP and NSE was detectable. Overall,
      a decrease of NSE was seen in 18 (95%) of all responders, while an increase
      during progression could be detected in 6 (86%) of the patients. Because 6
      patients in remission showed an increase in ProGRP concentrations, the
      corresponding data are 68% in responders and also 86% in progressive SCLC
      patients. In conclusion, ProGRP was helpful as a diagnostic aid for therapy
      control in small-cell lung cancer patients. A long-term follow-up indicated that
      ProGRP can be used to monitor disease either with tumor regression under therapy
      as well as detection of subsequent progression. ProGRP could be well suited to
      complete thepresent diagnostic panel for lung cancer.

PMID- 12593475
TI  - Rhodotorula species fungemia: a threat to the immunocompromised host.
AB  - Members of the genus Rhodotorula, family Cryptococcaceae, are common airborne
      fungi showing remarkable ubiquity. In the recent past they were considered
      nonvirulent saprophytes. However, during the last two decades they have emerged
      as opportunistic pathogens in immunocompromised patients. A review of the English
      literature covering the period 1960-2001 disclosed 47 reported cases of
      Rhodotorula spp fungemia. The great majority of these infections has been
      reported after 1990, were catheter-related, and diagnosed in patients with
      cancer. The treatment of Rhodotorula fungemia remains controversial. Resolution
      of coexistent neutropenia is essential for recovery. Removal of the central
      venous catheter is usually sufficient and treatment with systenic antifungals may
      not be required. If catheter removal is undesirable or impossible or when the
      infection persists, treatment with amphotericin B is the treatment of choice.
      Rhodotorula is a fungus with a low virulence and fatality rate. Hence, most
      patients with Rhodotorula fungemia reported in the literature survived with or
      without administration of antifungal agents.

PMID- 12593476
TI  - Effects of exercise on the secondary blood markers commonly used to suspect
      erythropoietin doping.
AB  - Numerous trials have reported that some haematological and biochemical parameters
      could be put together and be used to detect and fight recombinant erythropoietin
      doping. Unfortunately, none of the studies mentioned the necessity of taking pre
      analytical precautions to avoid possible suspicious results coming from major
      plasma volume changes caused notably by dehydration. Therefore we studied the
      behaviour of the most common secondary blood markers before and after a strenuous
      physical activity to find out how reliable these parameters were. The soluble
      transferrin receptor and the haemoglobin concentrations as well as the
      haematocrit level increased significantly after effort, whereas the plasma EPO
      concentration and the reticulocyte count remained constant. On the other hand, if
      the values were corrected for haemoconcentration, the soluble transferrin
      receptor concentration remained stable.

PMID- 12593477
TI  - The relationship between RANTES and mast cells recruitment in the surroundings of
      intrahepatic implanted tumors.
AB  - OBJECTIVE: To explore the relationship between the RANTES, TGFbeta1 and amount of
      mast cells (MC) surrounding the implanted tumors. METHOD: Pieces of Walker 256
      carcinosarcoma were implanted in the liver of 40 male Wistar rats and the formed
      intrahepatic implanted tumors were then divided into 3 groups: group without MC
      infiltration, group with little MC infiltration and group with MC infiltration; 8
      normal rats served as control group. The sera of rats in the different groups
      were tested by ELISA to find the serum RANTES content of the tumor bearing rats,
      then the chemotactic activity of the serum RANTES of different tumor bearing
      groups vs peritoneal MC of normal rats was tested by the microBoyden chamber.
      RESULTS: The MC amount of the tumor bearing rats was quite different, some of
      them showed a significantly increased amount. The groups with more MC
      infiltration showed a higher RANTES content in the sera and a stronger
      chemotactic activity vs MC. CONCLUSION: The RANTES was an effective chemotactic
      factor to MC. The serum concentration of RANTES of the tumor bearing rats is
      related to the difference of the MC amount surrounding the tumor.

PMID- 12593478
TI  - Filter multiplexing by use of spatial Code Division Multiple Access approach.
AB  - The increasing popularity of optical communication has also brought a demand for
      a broader bandwidth. The trend, naturally, was to implement methods from
      traditional electronic communication. One of the most effective traditional
      methods is Code Division Multiple Access. In this research, we suggest the use of
      this approach for spatial coding applied to images. The approach is to multiplex
      several filters into one plane while keeping their mutual orthogonality. It is
      shown that if the filters are limited by their bandwidth, the output of all the
      filters can be sampled in the original image resolution and fully recovered
      through an all-optical setup. The theoretical analysis of such a setup is
      verified in an experimental demonstration.

PMID- 12593479
TI  - Holographic edge-illuminated polymer Bragg gratings for dense wavelength division
      optical filters at 1550 nm.
AB  - We discuss the use of holographic photopolymer materials for use as dense
      wavelength division multiplexing filters in the C-band of the optical
      communication spectrum. An edge-illuminated hologram configuration is described
      that effectively extends the grating length to achieve narrow band filters
      operating near 1550 nm in photopolymers that are 100-200-microm thick. This
      configuration enables the formation of apodized and cascaded filter systems.
      Rouard's method is used to examine the properties of both apodization and
      cascaded gratings and indicates the potential for narrow spectral bandwidths (<
      0.2 nm) and high side-lobe suppression (<-- 30 dB). Initial experimental results
      with a commercially available photopolymer are provided that verify narrowband
      spectral-transmittance properties (< 0.6 nm) and the ability to apodize the index
      profile. The primary limitation of the design is the absorption of existing
      photopolymer materials. Optimizing the polymer chemistry for filter design at
      1550 nm may solve this problem.

PMID- 12593480
TI  - Fabrication of micro optics on coreless fiber segments.
AB  - Fabrication of micro optics for fiber optics applications is a challenge due to
      their size and the issues associated with alignment of the optics to single-mode
      fibers. This study summarizes a method for fabricating diffractive optical
      elements on the ends of coreless fiber segments for passive alignment to single
      mode fibers. Results are presented for passively aligned diffractive lens
      elements used for both collimation and beam shaping.

PMID- 12593481
TI  - Comment: Influence of illuminating beyond the object support on Zernike-type
      phase contrast filtering.
AB  - In this comment, we clarify some serious misinterpretations that can arise from
      an uncritical use of the results presented in [Appl. Opt. 41, 2607, (2002)]. In
      particular, we point out that their suggestion of using "illumination beyond the
      object support" for measuring phase disturbances can result in distorted or
      strongly inaccurate interference patterns. We also point out that Llave and
      Castillo have misinterpreted our previous work describing the effect of phase
      object fill factor on the output interference patterns, which is in fact one of
      the key factors considered in the generalized phase contrast (GPC) method. Unlike
      the Zernike method, the GPC method results in an optimized visualization of the
      phase disturbance by the achievement of a matching condition between the applied
      filter and the spatial average of a given phase disturbance, thereby implying the
      optimal use of fill factor information.

PMID- 12593482
TI  - Subtraction digital holography.
AB  - Overlapping of the desired (first-order) and undesired (zero-order) terms
      originating from the recorded primary-fringe patterns in digital holography is a
      problem without a real-time solution. We propose a procedure for suppressing the
      zero-order disturbance that is realizable in real time. The procedure is based on
      the stochastic change of the speckles in the primary-fringe patterns and on the
      subtraction of two such subsequent patterns. The theoretical description of the
      procedure is given and experimental results presented.

PMID- 12593483
TI  - Silver halide sensitized gelatin process effects in holographic lenses recorded
      on Slavich PFG-01 plates.
AB  - In this work we study the feasibility of using silver halide sensitized gelatin
      based on PFG-01 (Slavich) emulsions to construct uniaxial compound lenses. This
      processing is able to introduce variations in the thickness and refractive index
      of the emulsion. We prove that these changes are not sufficient to provide the
      observed variations in Bragg conditions in the reconstruction and that a shear
      type effect must exist to explain the performance of processed emulsions. We
      study the characteristics of a compound lens, obtaining acceptable image quality,
      good resolution, and the typical field limitation of volume holographic elements.

PMID- 12593484
TI  - Scale-invariant recognition of three-dimensional objects by use of a quasi
      correlator.
AB  - A method of scale-invariant recognition of three-dimensional (3-D) objects is
      presented. Several images of the observed scene are recorded under white-light
      illumination from several different points of view and compressed into a single
      complex two-dimensional matrix. After filtering with a single scale-invariant
      filter, the resultant function is then coded into a computer-generated hologram
      (CGH). When this CGH is coherently illuminated, a correlation space is
      reconstructed in which light peaks indicate the existence and location of true
      targets in the tested 3-D scene. The light peaks are detectable for different
      sizes of the true objects, as long as they are within the invariance range of the
      filter. Experimental results in a complete electro-optical system are presented,
      and comparisons with other systems are investigated by use of computer
      simulation.

PMID- 12593485
TI  - Fourier-synthesis custom-coherence illuminator for extreme ultraviolet microfield
      lithography.
AB  - Scanning illumination systems provide for a powerful and flexible means for
      controlling illumination coherence properties. Here we present a scanning Fourier
      synthesis illuminator that enables microfield extreme ultraviolet lithography to
      be performed on an intrinsically coherent synchrotron undulator beamline. The
      effectiveness of the system is demonstrated through a variety of print
      experiments, including the use of resolution enhancing coherence functions that
      enable the printing of 50-nm line-space features by use of a lithographic optic
      with a numerical aperture of 0.1 and an operational wavelength of 13.4 nm.

PMID- 12593486
TI  - Digital holography of particle fields: reconstruction by use of complex
      amplitude.
AB  - Digital holography appears to be a strong contender as the next-generation
      technology for holographic diagnostics of particle fields and holographic
      particle image velocimetry for flow field measurement. With the digital
      holographic approach, holograms are directly recorded by a digital camera and
      reconstructed numerically. This not only eliminates wet chemical processing and
      mechanical scanning, but also enables the use of complex amplitude information
      inaccessible by optical reconstruction, thereby allowing flexible reconstruction
      algorithms to achieve optimization of specific information. However, owing to the
      inherently low pixel resolution of solid-state imaging sensors, digital
      holography gives poor depth resolution for images, a problem that severely
      impairs the usefulness of digital holography especially in densely populated
      particle fields. This paper describes a technique that significantly improves
      particle axial-location accuracy by exploring the reconstructed complex amplitude
      information, compared with other numerical reconstruction schemes that merely
      mimic traditional optical reconstruction. This novel method allows accurate
      extraction of particle locations from forward-scattering particle holograms even
      at high particle loadings.

PMID- 12593487
TI  - Reconstruction of deforming aortas in two-photon autofluorescence image
      sequences.
AB  - Information loss may occur frequently in the imaging of living tissues by using
      two-photon fluorescence microscopy due to the intensive deformation of the
      tissue. A landmark-based optical flow interpolation scheme is proposed for image
      reconstruction of living aorta walls in two-photon autofluorescence image
      sequences. Landmarks are extracted and evaluated by an active contour-based aorta
      model, and are aligned and reconstructed by use of a hierarchical algorithm. The
      accuracy of the calculation of optical flow is improved by applying landmark
      based image warping. Experimental results show that the proposed scheme
      outperforms commonly used optical flow interpolation techniques for the
      reconstruction of intensively deforming tissues.

PMID- 12593488
TI  - Density implications of shift compensation postprocessing in holographic storage
      systems.
AB  - We investigate the effect of data page misregistration, and its subsequent
      correction in postprocessing, on the storage density of holographic data storage
      systems. A numerical simulation is used to obtain the bit-error rate as a
      function of hologram aperture, page misregistration, pixel fill factors, and
      Gaussian additive intensity noise. Postprocessing of simulated data pages is
      performed by a nonlinear pixel shift compensation algorithm [Opt. Lett. 26, 542
      (2001)]. The performance of this algorithm is analyzed in the presence of noise
      by determining the achievable areal density. The impact of inaccurate
      measurements of page misregistration is also investigated. Results show that the
      shift-compensation algorithm can provide almost complete immunity to page
      misregistration, although at some penalty to the baseline areal density offered
      by a system with zero tolerance to misalignment.

PMID- 12593489
TI  - Low-density parity-check codes for volume holographic memory systems.
AB  - We investigate the application of low-density parity-check (LDPC) codes in volume
      holographic memory (VHM) systems. We show that a carefully designed irregular
      LDPC code has a very good performance in VHM systems. We optimize high-rate LDPC
      codes for the nonuniform error pattern in holographic memories to reduce the bit
      error rate extensively. The prior knowledge of noise distribution is used for
      designing as well as decoding the LDPC codes. We show that these codes have a
      superior performance to that of Reed-Solomon (RS) codes and regular LDPC
      counterparts. Our simulation shows that we can increase the maximum storage
      capacity of holographic memories by more than 50 percent if we use irregular LDPC
      codes with soft-decision decoding instead of conventionally employed RS codes
      with hard-decision decoding. The performance of these LDPC codes is close to the
      information theoretic capacity.

PMID- 12593490
TI  - The LONFLIT4-Concorde--Sigvaris Traveno Stockings in Long Flights (EcoTraS)
      Study: a randomized trial.
AB  - The LONFLIT1/2 studies have established that in high-risk subjects after long ( >
      10 hours) flights the incidence of deep venous thrombosis (DVT) may be between 4%
      and 6%. The LONFLIT4 study was aimed at evaluating the control of edema and DVT
      prevention in low-medium-risk subjects. In this study prophylaxis of edema with
      specific travel stockings was evaluated in 2 separate studies involving flights
      lasting 7 hours and 10-12 hours. Part I. Subjects at low-medium risk for DVT were
      contacted; 55 subjects were excluded for several nonmedical, travel-related
      problems or inconvenient evaluation time; the remaining 211 were randomized into
      2 groups to evaluate prophylaxis with elastic stockings in 7-8-hour, long-haul
      flights. The control group had no prophylaxis; the treatment group used below
      knee, Sigvaris Traveno elastic stockings (Ganzoni, Switzerland, producing 12-18
      mm Hg of pressure at the ankle). Color duplex scanning was used to evaluate the
      possible presence of DVT; edema/swelling were evaluated with a composite score
      including the presence of edema (with an edema tester), variations in ankle
      circumference and leg volumetry, subjective swelling, and discomfort (scale
      ranging from 0 to 10). RESULTS: Of the 103 included subjects in the stockings
      group and 108 in the control group (total 211), 195 subjects completed the study.
      Dropouts (16) were due to low compliance or traveling and connection problems.
      Age, sex distribution, and risk factors distributions were comparable in the 2
      groups. Stockings Group: Of 97 subjects none had DVT or superficial thromboses.
      CONTROL GROUP: Of 98 subjects none had thrombosis. The level of edema at
      inclusion was comparable in the 2 groups of subjects. After flights there was an
      average score of 6.4 (1.3) in the control group, while in the stockings group the
      score was on average 2.4 (SD 1), 2.6 times lower than in the control group (p <
      0.05). In the control group 83% of the subjects had an evident increase in ankle
      circumference and volume that was visible at inspection and associated with
      discomfort. The control of edema with stockings was clear, considering both
      parametric data (circumference and volume) and nonparametric (analogue scale
      lines) measurements. Part II. In this part of the study 200 subjects at low
      medium risk for DVT were contacted; 35 subjects were excluded for several
      nonmedical, travel-related problems or inconvenient evaluation time; the
      remaining 165 were randomized into 2 groups to evaluate prevention in flights
      lasting between 11 and 12 hours. The control group had no prophylaxis; the
      treatment group used Traveno stockings. Of the 83 included subjects in the
      stockings group and 82 in the control group (total 165), 146 subjects completed
      the study. Dropouts were due to low compliance or connection problems. Age/sex
      distribution were comparable. Of 75 subjects completing the study in the
      stockings group and 71 in the control group, none had thrombosis. The average
      level of edema at inclusion was comparable in the 2 groups (1.1). After the
      flight there was a score of 8.9 (2) in controls; in the stockings group the score
      was 2.56 (1.3) (p < 0.05). The control of edema and swelling with stockings even
      after 11 hours of flight was clear, considering both parametric (circumference,
      volume) and nonparametric (analogue scale lines) measurements. The tolerability
      of the stockings was very good and there were no complaints or side effects. In
      conclusion Sigvaris Traveno stockings are very effective in controlling edema in
      long-haul flights.

PMID- 12593491
TI  - Vascular disorders preceding diagnosis of cancer: distinguishing the causal
      relationship based on Bradford-Hill guidelines.
AB  - The literature investigating the association between vascular disorders and
      malignant neoplasms does not comprehensively review the full spectrum of vascular
      disorders associated with cancer, or provide proof that cancer is an etiologic
      factor in the development of these disorders. This paper investigates the causal
      role of cancer in the pathogenesis of vascular disorders, based on the Bradford
      Hill criteria of causation. The Medline database was searched for articles on
      vascular disorders preceding the diagnosis of cancer (VDPCD). Included in the
      analysis were vascular disorders caused either by direct tumoral involvement of
      vessels or by paraneoplastic mechanisms. Vascular disorders caused by adverse
      reactions to anticancer therapy were excluded from analysis. Seven categories of
      VDPCDs were recognized: venous thromboembolism, arterial thrombosis and embolism,
      nonbacterial thrombotic endocarditis, migratory superficial thrombophlebitis,
      vasculitis, thrombotic microangiopathy, and leukothrombosis. To establish
      causality of the association between VDPCDs and malignancy, the degree of
      fulfillment of the Bradford-Hill criteria was assessed. A strong association was
      found in the literature between venous thromboembolism and cancer (OR 2.3-14.9
      and SIR 1.3-4.4). Consistency and temporality of the association were confirmed
      in all VDPCD variants. Seven Bradford-Hill criteria were fulfilled for cancer
      associated with venous thromboembolism, six criteria for superficial phlebitis
      and cancer, and five criteria for each of the other VDPCDs. In conclusion, these
      data support the causal role of cancer in the pathogenesis of all seven
      categories of VDPCDs. Recognition of such a causal link between cancer and
      various vascular disorders may promote an earlier cancer diagnosis.

PMID- 12593492
TI  - The assessment of deep vein thromboses for therapeutic trials.
AB  - In the current paper, we provide recommendations for the assessment of deep vein
      thromboses for the purpose of therapeutic trials evaluating antithrombotic drugs
      in the prevention of deep venous thrombosis. We have reviewed recently published
      articles on diagnostic and therapeutic studies, and we have evaluated methods of
      assessments. Ascending venography has been considered as the reference test for
      the confirmation of DVT. A roentgenographic image is subsequently available for
      review and allows classification by blinded, objective observers. However,
      venography poses substantial clinical and methodological limitations,
      particularly in the setting of systematic screening for all patients enrolled in
      a randomized clinical trial. Compression ultrasonography may replace venography
      for systematic screening of DVT in clinical trials, provided that specific
      methodological details are specified in the protocol and are fulfilled to ensure
      high and comparable sensitivity and specificity from all participating centers.
      This non-invasive technique has virtually no contraindications, and therefore
      more patients can be enrolled and evaluated. Furthermore, the compression
      ultrasonograph can be videotaped for central reading. Compression ultrasonography
      has already been adopted as the principal method for evaluating DVT in several
      ongoing large scale prevention trials with the approval of major drug agencies.

PMID- 12593493
TI  - Effects of policosanol and lovastatin in patients with intermittent claudication:
      a double-blind comparative pilot study.
AB  - Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects.
      The present study was undertaken to compare the effects of policosanol and
      lovastatin on patients with moderately severe intermittent claudication. The
      study had a 4-week baseline step, followed by a 20-week double blinded,
      randomized treatment period. Twenty-eight patients who met study entry criteria
      were randomized to policosanol 10 mg or lovastatin 20 mg tablets once daily.
      Walking distances in a treadmill (constant speed 3.2 km/hr, slope 10 degrees,
      temperature 25 degrees C) were assessed before and after 20 weeks of treatment.
      Both groups were similar at randomization. Compared with baseline, policosanol
      increased significantly (p < 0.01) the initial claudication distance (ICD) from
      160.39 +/- 15.82 m to 211.31 +/- 21.48 m (+33.7%) and the absolute claudication
      distance (ACD) (p < 0.001) from 236.39 +/- 25.44 m to 288.09 +/- 28.47 m
      (+24.3%); meanwhile both variables remained unchanged after lovastatin therapy.
      Changes in ICD and ACD were significantly larger in the policosanol than in the
      lovastatin group (p < 0.01). Policosanol, but not lovastatin, significantly
      increased (p < 0.05) the ankle/arm index, although between-group differences were
      not significant. The frequency of patients reporting improvement on quality of
      life domains was greater in the policosanol than in the lovastatin group.
      Policosanol significantly (p < 0.001) lowered total cholesterol (TC) and low
      density lipoprotein-cholesterol (LDL-C) by 17.5% and 31.0%, respectively, and
      meanwhile increased (p < 0.01) high-density lipoprotein-cholesterol (HDL-C)
      levels by 31.5%. Lovastatin reduced (p < 0.01) TC (18.0%), LDL-C (22.6%), and (p
      < 0.05) triglycerides (9.8%). In addition, policosanol, but not lovastatin,
      moderately, but significantly, reduced (p < 0.05) fibrinogen levels, so that
      final values and percent changes in both groups were different (p < 0.01).
      Treatments were well tolerated. Only 1 lovastatin patient withdrew from the study
      because of a nonfatal myocardial infarction. Five lovastatin patients, but none
      from the policosanol group, experienced 6 adverse events (AE) (p < 0.01). The
      present results indicate that policosanol, but not lovastatin, is a suitable
      alternative to manage patients with intermittent claudication because of
      pleiotropic properties beyond its cholesterol-lowering effects.

PMID- 12593494
TI  - Toe pressure measurements compared to ankle artery pressure measurements.
AB  - The Trans-Atlantic Inter-Society Consensus (TASC)-recommended absolute toe
      pressure is < 30-50 mm Hg for definition of chronic critical limb ischemia (CLI).
      Toe pressures can be measured by different techniques. The authors analyzed the
      clinical use of the Doppler technique and an automatic device with optical
      sensors and estimated their value in documentation of chronic critical limb
      ischemia compared to ankle artery pressures. Three different investigations were
      performed: (1) In 16 healthy subjects the digital artery pressures were measured
      by using 3 different optical sensors (transmission, reflection, and
      microcirculation sensor) and compared to the systolic brachial pressure. (2) In
      50 patients with and without peripheral arterial occlusive disease the toe
      pressures at digits 1 and 2 of both feet were determined by Doppler technique (8
      MHz) and by optical sensors (cuff width constant 1.5 cm) and were compared to the
      ankle artery pressure determined by Doppler technique. (3) In 175 patients the
      toe pressures were measured at 1 toe and the ankle artery pressures were
      determined. In this group they estimated the clinical use of the toe pressure in
      regard to the definition of CLI (toe pressure < 50 mm Hg) compared to the ankle
      pressure < 70 mm Hg. The digital artery pressures measured with the different
      optical sensors, and the systolic brachial pressures were not significantly
      different and the correlation coefficients were around 0.7. In 21 of 50 patients
      the toe pressure at D1 and D2 could not be measured by Doppler technique because
      with the applied cuff no Doppler signal could be detected at the tip of the toe,
      but in 24 of these 29 patients the optical measurement was possible. Mean toe
      pressures at D1 were 108 +/- 45 mm Hg and D2 102 +/- 45 mm Hg, which were
      statistically not different. The correlation coefficient for the highest ankle
      artery pressure and the highest toe pressure determined by the Doppler technique
      was 0.389; for the highest ankle artery pressure and the toe pressure measured by
      the optical sensors it was 0.369, and for the toe pressures measured by Doppler
      technique and the optical sensors it was 0.506. Defining systolic ankle artery
      pressure < or = 50 to 70 mm Hg as the golden standard for CLI, the sensitivity of
      optical toe pressure measurement for the detection of CLI was 8%, the specificity
      was 96%, the positive predictive value 12%, and the negative predictive value was
      94%. Independent of technique the absolute systolic toe pressures did not
      correlate with the absolute systolic ankle pressures. The optical measurement was
      more suitable for toe pressure measurement because it could be used in 90% of all
      patients. All in all, toe pressure measurements are more useful to exclude CLI
      than to prove it.

PMID- 12593495
TI  - Ischemic preconditioning detected by treadmill exercise tests in patients with
      stable angina.
AB  - The aim of this study was to explore the ischemic preconditioning (IP) phenomenon
      in patients with chronic stable angina (SA) by using treadmill exercise tests
      (TETs). Twenty-nine patients with SA were divided into 2 groups: group A (n = 15)
      and group B (n = 14). There was no difference between the 2 groups in both
      clinical characteristics and extent of coronary stenosis. Group A was subjected
      to 2 TETs at a 10-minute interval, but group B had a 60-minute interval according
      to Bruce protocol. The occurrence and time of chest pain, maximal value, duration
      of ST segment depression, and arrhythmias that occurred during TETs were analyzed
      for differences in the 2 tests in the 2 groups. In group A, 9 patients (60.0%)
      complained of chest pain in the first test, whereas only 4 (26.7%) did in the
      second test (p < 0.01); The time of occurrence of chest pain during exercise was
      1.88 +/- 0.2 min in the first test, 2.3 +/- 0.4 min in the second test (p <
      0.05); The maximal value of ST segment depression decreased from 0.21 +/- 0.09 mV
      in the first test to 0.14 +/- 0.05 mV in the second (p < 0.01); the duration of
      ST segment depression decreased from 7.12 +/- 0.9 min in the first test to 4.42
      +/- 0.3 min in the second (p < 0.01). The incidence of arrhythmia decreased from
      40.0% in the first test to 13.3% in the second (p < 0.05). However, no
      significant difference was observed in the multiple parameters, mentioned above,
      in group B. In conclusion, the first ischemic event could induce the IP
      phenomenon and protect the heart from more serious damage at a 10-minute
      interval. However, this effect disappeared when the second test was done at a 60
      minute interval.

PMID- 12593496
TI  - The epsilon 2 and 4 alleles of apolipoprotein E and ischemic vascular events in
      the Greek population--implications for the interpretation of similar studies.
AB  - The authors investigated whether apolipoprotein (apo) E polymorphism has an
      allelic and/or genotypic impact on the risk of an ischemic vascular event (IVE)
      in Greek patients with cardiovascular diseases (CVD). They compared apo E
      polymorphisms in 1) a group of 165 patients with IVE [IVE(+)], of whom 107 had
      survived a myocardial infarction and 58 an ischemic stroke; 2) a group of 165
      patients, matched with the first group for age and gender, with angiographically
      confirmed coronary artery disease but without IVE [IVE(-)]; 3) a group of 240
      healthy younger individuals with no family history of CVD. The apo epsilon2
      allele was 5.2-fold less frequent in the IVE(+) group compared to the IVE(-)
      group (1.2% vs 6.2%, p = 0.001). The frequency of the epsilon2 allele in healthy
      subjects was 8.1%, which is 6.7-fold higher than in the IVE(+) group (p < 0.001),
      and more than twice as high compared to all CVD patients (p = 0.001). No
      significant differences in epsilon4 allele frequencies were observed between
      IVE(+) and IVE(-) patients (9.8% vs 8.4%) or between patients with CVD and
      healthy subjects (9.1% vs 10.2%). The epsilon4 allele was not associated with an
      increased risk for CVD or IVE. In contrast, an inverse and beneficial association
      of the epsilon2 allele with IVE was observed among Greek patients with CVD. These
      results suggest that the epsilon4 and epsilon2 alleles have a variable
      significance in terms of predicting the risk of vascular events in different
      populations. Therefore, it is important to carry out "local" studies.

PMID- 12593497
TI  - Apolipoprotein E polymorphism and atherosclerosis.
AB  - The relationship between apolipoprotein (apo) E and vascular disease has been the
      subject of a considerable amount of research. However, this relationship is far
      from clearly defined. This deficiency appears to be due to a multitude of
      factors. Among these are differences in ethnicity, age (and possibly gender),
      diagnostic criteria, and environmental factors (eg, diet and smoking) that have
      contributed to the contradictory findings. Several diseases and their treatment
      may also influence this relationship. There are also documented interactions
      between apo E genotypes and other genes or vascular risk factors. One possible
      clinically relevant application of identifying the apo E genotype could be to
      assess the response to a particular drug treatment. It may also be that apo E
      polymorphism will become a good predictor of vascular death (eg, from myocardial
      infarction or stroke) rather than an indicator of the risk of developing vascular
      disease but without an acute ischemic event. More research is required to define
      the place of apo E genotyping in the management of vascular disease in its
      various forms. Whatever the future brings, the evaluation of apo E genotypes will
      need to be rapid, cheap, and technically undemanding before this investigation
      becomes widely available and clinically relevant.

PMID- 12593499
TI  - Apoptosis and histopathologic changes in diffuse coronary atherosclerosis.
AB  - The aims of the study were to investigate the histopathologic characteristics of
      atherosclerotic lesions and to evaluate the role of apoptosis or programmed cell
      death in diffuse coronary atherosclerosis. The study included 59 patients who
      underwent coronary artery bypass grafting coupled with coronary endarterectomy
      because of diffuse coronary atherosclerosis. Histopathologic analysis of
      endarterectomy sequesters showed atheroma with confluent extracellular lipid core
      type IV lesions in 13 cases (22%); atheroma with lipid core and a cap of
      fibromuscular layers-type V lesions in 9 cases (15.3%); predominantly calcified
      fibrous tissue-type VII lesions in 13 cases (22%); and predominantly fibrous
      tissue-type VIII lesions in 24 cases (40.7%). TUNEL-positive cells were observed
      in 4 endarterectomy sequesters (6.8%) of subjects with diffuse coronary
      atherosclerosis. TUNEL-positive cells were demonstrated in the area of
      mononuclear infiltrates as well as in the vessel wall. The percentage of TUNEL
      positive cells in mononuclear infiltrates was 0.5%. Intense mononuclear
      infiltrates in tunica intima were found in 50% of sequesters, and they consisted
      of macrophages (40%), T-lymphocytes (17%), and B-lymphocytes (14%). In the area
      of infiltrates the proportion of MIB-1-positive cells was 2.7%, which was higher
      than in the intima outside the area of infiltrates (0.5%). In conclusion,
      apoptosis, which is confined to mononuclear infiltrates, is most likely involved
      in the development of diffuse coronary atherosclerosis; however, the percentage
      of apoptotic cells was low (0.5%). A higher proportion of apoptotic cells in the
      area of infiltrates compared to the rest of the intima was associated with a
      higher proportion of MIB-1-positive cells. Atherosclerotic lesions in diffuse
      coronary atherosclerosis were advanced, with a predominance of type VII to VIII
      lesions.

PMID- 12593498
TI  - Increased immunoglobulin E response in acute coronary syndromes.
AB  - The role of inflammation and mast cell activation has been implicated in
      atherosclerotic plaque destabilization and rupture. To investigate the role of
      immunoglobulin E (IgE) in acute coronary syndrome, a prospective clinical study
      was conducted in patients with acute myocardial infarction (AMI), unstable angina
      pectoris (UAP), stable angina pectoris (SAP), and healthy controls. IgE levels
      were serially measured and compared in consecutive patients with AMI (n = 16) and
      UAP (n = 14) on days 1, 3, 7, 21 after admission and 3 months later and only once
      in stable angina pectoris (n = 15) and healthy controls (n = 14). In addition,
      blood eosinophil and basophil levels on admission were measured in all groups and
      compared. Initial IgE levels determined at admission in patients with AMI, UAP,
      and SAP were significantly higher than levels in the control group (p = 0.002).
      Initial high IgE level in AMI on day 1 increased to a peak by day 7 (p = 0.024),
      then gradually decreased by day 21 and at 3 months (p = 0.052). High IgE level in
      UAP persisted by day 7 and gradually decreased by day 21 and 3 months (p = 0.037
      and p = 0.018, respectively). Blood eosinophil count on admission was
      significantly higher in UAP than in the control group (p = 0.005). Basophil
      levels of both AMI and UAP groups on admission were found to be elevated as
      opposed to control group (p = 0.02 and p = 0.012, respectively). This study
      demonstrates that the level of IgE significantly increased during the acute phase
      of acute coronary syndromes and gradually decreased, supporting the role of acute
      inflammatory response and mast cell involvement in plaque rupture.

PMID- 12593500
TI  - Extent and severity of atherosclerotic vascular disease in patients undergoing
      coronary angiography--the Kuwait Vascular Study.
AB  - Only a few angiographic studies have correlated the presence and severity of
      coronary artery disease with atherosclerosis in other arteries. The presence of
      disease in more than 1 area clearly has important implications on management. One
      hundred and seventy eight patients had angiographic evaluation of their
      peripheral arteries and abdominal aorta after routine diagnostic coronary
      angiography. The extent and severity of vascular disease was correlated with
      those of coronary artery disease. Of the 178 patients, 73.6% were men (mean age
      +/- sd was 52.93 +/- 10.12 years). Hypercholesterolemia (59%), systemic
      hypertension (56.7%) and diabetes mellitus (50.6%) were the major risk factors.
      Triple-vessel coronary artery disease was present in 48.9%, and 13.5% had normal
      coronaries. A new atherosclerotic vascular disease score, which reflects the
      presence and severity of atherosclerotic vascular disease elsewhere, was seen to
      correlate significantly with the extent of coronary artery disease. Of particular
      interest was the involvement of the first part of the vertebral artery in 41.6%
      of patients. The combined involvement of the abdominal aorta, renal artery, and
      iliac artery segments (together referred to as the lower body segment) was seen
      almost exclusively in those with 2- or 3-vessel coronary artery disease. Also
      there was a direct correlation between the extent of coronary artery disease and
      the score in the lower body segment as opposed to the upper body segment
      (subclavian, vertebral, and internal mammary arteries). The presence of
      atherosclerotic vascular disease correlated with the severity of coronary artery
      disease, particularly in respect to disease in the lower body segment. Thus early
      detection of such disease in the iliac or femoral arteries has a potential for
      early diagnosis of significant coronary artery disease.

PMID- 12593501
TI  - Minimally invasive mitral valve surgery: from Port Access to fully robotic
      assisted surgery.
AB  - Currently, there is a growing interest in minimally invasive cardiac surgery, and
      despite early criticisms, it has become the preferred method of mitral valve
      repair and replacement in many institutions worldwide with excellent results. The
      interest in performing cardiac valve operations through minimal incisions was
      stimulated by Port Access technology and has evolved to include robotically
      assisted video-enhanced valve surgery. Robotic assistance has led to shorter
      operating times and represents an ideal tool to prepare for fully robotic
      assisted cardiac procedures. This report will highlight minimally invasive mitral
      valve surgery with its evolution from Port Access techniques to fully robotic
      assisted surgery. The nuances, strengths, and shortcomings, as well as the
      potential to enhance the valvular procedure, the promise to reduce hospital stay,
      earlier return to normal activity, less pain, better cosmesis, and the rethinking
      of surgical dogma that wide surgical exposure is essential for such complex
      intracardiac surgery are discussed.

PMID- 12593502
TI  - Acute myocardial infarction in a 16-year-old male--a case report.
AB  - Acute myocardial infarction in the teenage years of life is a rare phenomenon. It
      is more rare in patients who have no risk factors or comorbid conditions and
      normal coronary arteries. Evaluation requires extensive investigation into the
      various risk factors that may be involved as well as the performance of invasive
      and noninvasive cardiovascular studies. A case of acute myocardial infarction in
      a teenage boy without familial, inherent, or extraneous risk factors is
      presented.

PMID- 12593503
TI  - Right ventricular foreign body: percutaneous transvenous retrieval of a
      Greenfield filter from the right ventricle--a case report.
AB  - A 55-year-old man suffered head injury during a motor vehicle accident. He
      underwent a prophylactic inferior vena cava Greenfield filter placement. The
      filter migrated and lodged in the right ventricle at the level of the tricuspid
      valve. Successful percutaneous, transvenous retrieval of the Greenfield filter
      from the right ventricle was carried out.

PMID- 12593504
TI  - Delayed embolization of Amplatzer septal occluder device: an unknown entity--a
      case report.
AB  - A case of delayed embolization of Amplatzer septal occluder, occurring at 2 weeks
      postimplantation in a 10-year-old girl with an oval-shaped secundum atrial septal
      defect is reported. The structurally intact device dislodged into the left atrium
      owing to reversal of transatrial pressure gradients and embolized to the left
      ventricular outflow tract from where it was retrieved surgically.

PMID- 12593505
TI  - Unusual electrocardiographic presentation of an isolated right ventricular
      myocardial infarction secondary to thrombotic occlusion of a non-dominant right
      coronary artery--a case report and brief review of literature.
AB  - Isolated right ventricular infarction is an extremely rare phenomenon. Its
      electrocardiographic (ECG) features may be misinterpreted or even missed if not
      suspected. A case of an isolated right ventricular myocardial infarction is
      presented, recognized by ST-segment elevation in a single precordial lead, such
      as V1, aided thereafter by right precordial ECG changes. Immediate coronary
      angiography revealed proximal occlusion of a small non-dominant right coronary
      artery. Coronary intervention as well as infusion of intravenous normal saline
      solution and pressor agent for hypotension provided symptomatic relief, and
      subsequent recovery from this potentially life-threatening, but rare condition.
      Routine 12-lead ECG done approximately 12 hours after the admission showed
      extension of ST segment elevation from V1 trough V3 without any ST-segment
      elevation in inferior leads. This case demonstrates that there might be a very
      unusual ECG appearance in the setting of an isolated right ventricular myocardial
      infarction and can be missed if not immediately suspected. Isolated right
      ventricular myocardial infarction may be difficult to recognize, requiring both a
      high index of clinical suspicion for its presence, as well as careful evaluation
      of unusual ECG features of the disease entity.

PMID- 12593506
TI  - Arterial embolism to the upper extremity in a patient with factor V Leiden
      mutation (APC resistance)--a case report and review of the literature.
AB  - Factor V Leiden mutation has emerged as one of the leading abnormalities in
      inherited blood coagulation disorders, resulting in a markedly increased risk for
      deep leg vein thrombosis. A 24-year-old woman presented with acute onset of
      critical ischemia of her left thumb and index finger. Intraarterial angiography
      revealed an embolus in the distal radial artery and a thrombotic occlusion of the
      digital artery of the thumb and index finger. Immediate therapy encompassed a
      selective surgical embolectomy of the distal radial artery followed by a local
      intraarterial lysis that was continued for 3 days. Additionally, therapeutic
      anticoagulation and vasodilating drugs (prostaglandin E) were administered.
      Within 2 days, capillary refill reappeared and the initial loss of sensory
      function at the tip of the thumb and index finger diminished. A screening test
      for thrombophilic disorders led to the diagnosis of a heterozygous mutation of
      factor V (Leiden mutation). Arterial thromboembolic events of factor V Leiden
      mutation are rare and have to date been described only in the supraaortic and
      coronary circulation. Therefore, the arterial embolism to the left hand presented
      in this report constitutes a rarity that could be successfully salvaged by the
      combined use of a vascular surgical procedure and intensified medical management.

PMID- 12593507
TI  - Coronary stent implantation in patients with a single coronary artery--a report
      of 3 cases.
AB  - An isolated single coronary artery is a rare congenital anomaly and a cause of
      cardiac ischemia, congestive heart failure, and sudden cardiac death. Reported
      here are 3 cases of single coronary artery with acute myocardial infarction in
      which coronary stenting was performed. Also reported are the coronary blood flow
      patterns of the right coronary artery arising from the single left coronary
      artery.

PMID- 12593508
TI  - Variation in the life history pattern of Tetranychus urticae (Acari:
      Tetranychidae) after selection for dispersal.
AB  - The spider mite Tetranychus urticae shows variation in its dispersal capacity
      (i.e., the leaf quality at which a female decides to disperse). We were able to
      artificially select mites that had either a high or a low dispersal capacity,
      indicating that this trait was genetically controlled. We then compared
      correlated responses to this selection. Mites with a genetically high dispersal
      capacity ('HD' strains) had a higher diapause incidence and a lower performance
      compared to mites with a low dispersal capacity ('LD' strains). A possible effect
      of random genetic drift during the selection was negligible. Our results suggest
      that differential dispersal capacity is associated with contrasting life history
      patterns as a result of natural selection.

PMID- 12593509
TI  - Importance of ambient saturation deficits in an epizootic of the fungus
      Neozygites floridana in cassava green mites (Mononychellus tanajoa).
AB  - The mite-pathogenic fungus Neozygites floridana Fisher (Entomophthorales:
      Neozygitaceae) is considered to have potential for the biological control of the
      cassava green mite, Mononychellus tanajoa (Bondar). However, its activity is
      sporadic and laboratory data suggest a strong dependence on night-time saturation
      deficits for transmission. We report on an epizootic of this fungus in a mite
      population in northeastern Brazil. During the epizootic, host populations
      appeared to he limited by a combination of the pathogen and a predatory mite
      Neoseiulus idaeus (Acari: Phytoseiidae). When temperatures increased, the
      epizootic finished and the host population began to grow. Abiotic conditions
      could not explain the variation in host mortality following pickup of infective
      propagules in this epizootic. However, night-time saturation did help to explain
      the variation in transmission from infective cadavers to newly killed hosts. This
      supports laboratory observations that horizontal transmission between hosts is
      determined mainly by saturation deficits, while the process of infection is
      little affected by abiotic conditions. A further field observation was the near
      absence of resting spores in dead mites (ca. 0.1% of cadavers), suggesting that
      the pathogen population was unsuccessful in producing inoculum to infect future
      M. tanajoa populations. The implications are that this pathogen will only be
      effective as a biological control agent in periods of high relative humidity, and
      establishment in new areas may be limited by resting spore formation.

PMID- 12593510
TI  - Plant feeding by a predatory mite inhabiting cassava.
AB  - Plant feeding by arthropod predators may strongly affect the dynamics of bi-and
      tri-trophic interactions. We tested whether a predatory mite, Typhlodromalus
      aripo, feeds upon its host plant, cassava. This predator species is an effective
      biological control agent of Monoychellus tanajoa (the cassava green mite or CGM)
      a herbivorous mite specific to cassava. We developed a technique to detect plant
      feeding, based on the use of a systemic insecticide. We found that T. aripo feeds
      upon plant-borne material, while other predatory mite species, Neoseiulus idaeus
      and Phytoseiulus persimilis, do not. Subsequently, we measured survival of
      juveniles and adult females of T. aripo and N. idaeus, both cassava-inhabiting
      predator species, on cassava leaf discs. Survival of T. aripo was higher than
      that of N. idaeus. Thus, T. aripo was able to withstand longer periods of prey
      scarcity. Because CGM populations fluctuate yearly and are heterogeneously
      distributed within plants, plant feeding may facilitate the persistence of
      populations of T. aripo in cassava fields and its control of CGM outbreaks.

PMID- 12593511
TI  - Prey-related odor preference of the predatory mites Typhlodromalus manihoti and
      Typhlodromalus aripo (Acari: Phytoseiidae).
AB  - Typhlodromalus manihoti and Typhlodromalus aripo are exotic predators of the
      cassava green mite Mononychellus tanajoa in Africa. In an earlier paper, we
      showed that the two predators were attracted to odors from M. tanajoa-infested
      cassava leaves. In addition to the key prey species, M. tanajoa, two alternative
      prey mite species, Oligonychus gossypii and Tetranychus urticae also occur in the
      cassava agroecosystem. Here, we used a Y-tube olfactometer to determine the
      attraction of the predators to odors from O. gossypii- or T. urticae-infested
      cassava leaves and their prey-related odor preference. T. aripo but not T.
      manihoti was slightly attracted to odors from O. gossypii-infested leaves. Both
      predator species showed a stronger response to odors from cassava leaves infested
      by M. tanajoa over odors from cassava leaves infested by O. gossypii. Neither
      predator species was attracted to odors from T. urticae-infested leaves and the
      predators preferred the odors from M. tanajoa-infested leaves over those from T.
      urticae-infested leaves. When O. gossypii was present together with M. tanajoa on
      the same leaves or on different sets of leaves offered together as an odor source
      the two predators were attracted. In contrast, after mixing non-attractive odors
      from T. urticae-infested leaves with attractive odors from M. tanajoa-infested
      leaves, neither T. aripo nor T. manihoti was attracted. Ecological advantages and
      disadvantages of the predators' behavior and possible implications for biological
      control of M. tanajoa are discussed.

PMID- 12593512
TI  - Phytoseiid predators suppress populations of Bemisia tabaci on cucumber plants
      with alternative food.
AB  - Phytoseiids are known to attack whiteflies, but it is an open question whether
      they can be used for biological control of these pest insects. Preselection
      experiments in the laboratory showed that two out of five phytoseiid species
      tested, Euseius scutalis and Typhlodromips swirskii, stood out in terms of their
      ability to develop and reproduce on a diet of Bemisia tabaci immatures. In this
      paper, we show that both predators are able to suppress whitefly populations on
      isolated cucumber plants in a greenhouse. Predatory mites were released 2 weeks
      in advance of the release of B. tabaci. To enable their survival and promote
      their population growth, they were provided weekly with alternative food, that
      is, Typha sp. pollen. A few weeks after whitefly introduction, the numbers of
      adult whiteflies on plants with predators were consistently lower than on plants
      without predators, where B. tabaci populations grew exponentially. After 9 weeks,
      this amounted to a 16- to 21-fold difference in adult whitefly population size.
      This shows that the two phytoseiid species are promising biocontrol agents of B.
      tabaci on greenhouse cucumber.

PMID- 12593513
TI  - Complete mitochondrial DNA sequence of the important honey bee pest, Varroa
      destructor (Acari: Varroidae).
AB  - Mites in the genus Varroa are the primary parasites of honey bees on several
      continents. Genetic analyses based on Varroa mitochondrial DNA have played a
      central role in establishing Varroa taxonomy and dispersal. Here we present the
      complete mitochondrial sequence of the important honey bee pest Varroa
      destructor. This species has a relatively compact mitochondrial genome (15,218
      bp). The order of genes encoding proteins is identical to that of most
      arthropods. Ten of 22 transfer RNAs are in different locations relative to hard
      ticks, and the 12S ribosomal RNA subunit is inverted and separated from the 16S
      rRNA by a novel non-coding region, a trait not yet seen in other arthropods. We
      describe a dispersed set of 45 oligonucleotide primers that can be used to
      address genetic questions in Varroa. A subset of these primers should be useful
      for taxonomic and phylogenetic studies in other mites and ticks.

PMID- 12593514
TI  - Reproduction of Varroa destructor in worker brood of Africanized honey bees (Apis
      mellifera).
AB  - Reproduction and population growth of Varroa destructor was studied in ten
      naturally infested, Africanized honey bee (AHB) (Apis mellifera) colonies in
      Yucatan, Mexico. Between February 1997 and January 1998 monthly records of the
      amount of pollen, honey, sealed worker and drone brood were recorded. In
      addition, mite infestation levels of adult bees and worker brood and the
      fecundity of the mites reproducing in worker cells were determined. The mean
      number of sealed worker brood cells (10,070 +/- 1,790) remained fairly constant
      over the experimental period in each colony. However, the presence and amount of
      sealed drone brood was very variable. One colony had drone brood for 10 months
      and another for only 1 month. Both the mean infestation level of worker brood
      (18.1 +/- 8.4%) and adult bees (3.5 +/- 1.3%) remained fairly constant over the
      study period and did not increase rapidly as is normally observed in European
      honey bees. In fact, the estimated mean number of mites fell from 3,500 in
      February 1997 to 2,380 in January 1998. In May 2000 the mean mite population in
      the study colonies was still only 1,821 mites. The fertility level of mites in
      this study was much higher (83-96%) than in AHB in Brazil (25-57%). and similar
      to that found in EHB (76-94%). Mite fertility remained high throughout the entire
      study and was not influenced by the amount of pollen, honey or worker brood in
      the colonies.

PMID- 12593515
TI  - A laboratory evaluation of a regulated airflow through wheat at four combinations
      of temperature and humidity on the productivity of three species of stored
      product mites.
AB  - Aeration is a promising alternative to the use of pesticides for the control of
      storage insects by cooling bulk grain, but its effectiveness against mite pests
      is neither fully understood nor optimised. For this reason, the productivity of
      three species of storage mites, Acarus siro, Lepidoglyphus destructor and
      Tyrophagus longior, was studied in a laboratory-based experiment at four
      combinations of temperature and humidity (10 degrees C and 70% RH, 10 degrees C
      and 80% RH, 20 degrees C and 70% RH, 20 degrees C and 80% RH) with and without an
      airflow (at 10 m3/h/tonne, equalling 2.5 1/s/tonne, in tubes containing 15 g of
      grain). This is the first time that a study has examined the three principal
      components of aeration separately from each other. The effect of these factors
      was different for each species. For A. siro, temperature was the most important
      factor, while airflow and humidity were of similar but lesser importance. For T.
      longior, temperature was more important than humidity, while the reverse was true
      for L. destructor. For these two species, airflow was the least important factor.
      The airflow decreased the productivity of L. destructor and T. longior but
      increased the productivity of A. siro. This increase in productivity confirms
      that, in practice, prevention of mite infestations, in particular A. siro, will
      require storage of grain at low temperature, relative humidity and moisture
      content.

PMID- 12593516
TI  - Microanatomical and microbiological characteristics of the quiescent state of
      Scutovertex minutus (Acari: Oribatida).
AB  - Both adults and juveniles of the oribatid mite Scutovertex minutus
      (Scutoverticidae) may enter an immobile quiescent state under extreme dry
      conditions. The microanatomy of the alimentary tract, contents of parenchyma
      tissue and internal extraintestinal microbial communities were observed in these
      states. The quiescent state lasted at least 10 days and was generally
      characterized by an empty gut, guanine deposition and, in adults, by the
      resorption of spermatids or oocytes and eggs. The homogenate of mites was
      sterile, without microorganisms. The reverse processes were recorded two hours
      after remoistening: the mites started to move again and accompanying histological
      changes were shown.

PMID- 12593517
TI  - Ixodid ticks feeding on humans in South Africa: with notes on preferred hosts,
      geographic distribution, seasonal occurrence and transmission of pathogens.
AB  - This paper records the identities of 558 ixodid ticks feeding on 194 humans in
      South Africa. These ticks belonged to 20 species in six genera and those most
      frequently encountered were AmblYomma hebraeum, Haemaphysalis leachi, Hyalomma
      marginatum rufipes, Hyalomma truncatum, Rhipicephalus appendiculatus,
      Rhipicephalus gertrudae and Rhipicephalus simus. With the exception of the larvae
      of R. appendiculatus, the incidents of these ticks feeding on humans correlated
      well with their seasonal occurrences on preferred hosts. Ticks were also
      collected at monthly intervals, for 14 consecutive months, from the clothing of a
      game-guard providing protection for field-workers engaged in the collection, by
      means of flannel strips, of free-living ticks from the vegetation of four
      localities in the southern region of the Kruger National Park. In addition, with
      the exception of 3 months when the particular worker was absent, ticks that fed
      on one of the field-workers were collected over the same 14-month period. A total
      of 54,429 free-living ticks belonging to 14 species and six genera were collected
      from the vegetation at the four localities during this time and 3751 ticks
      belonging to 11 species and six genera from the clothing of the game-guard. The
      larvae of A. hebraeum and Boophilus decoloratus were the most numerous of the
      immature ticks, and H. leachi and R. simus of the adults on both the vegetation
      and the guard's clothing. Ticks fed on the field-worker on six occasions and 14
      were collected, all of which were A. hebraeum larvae.

PMID- 12593518
TI  - The effect of feeding status on sexual attractiveness of Ixodes ricinus (Acari:
      Ixodidae) females.
AB  - Sexual attractiveness of unengorged, semiengorged and fully engorged females of
      both field and laboratory populations of Ixodes ricinus was studied under
      laboratory conditions by means of a computerised video tracking system. A male
      and a female were allowed to walk freely in a glass arena during 1 h and their
      behavioural interactions were observed. Obtained results revealed that the
      feeding status of L. ricinus females affects their sexual attractiveness. The
      highest attractiveness was observed in engorged females, the lowest in unengorged
      females of the field population. Copulation occurred in all experimental groups
      with the highest frequency observed in the unengorged virgin laboratory females.
      Despite engorged females being highly attractive for males on distance, the
      frequency of copulation was low. Differences between field and laboratory
      populations were found in both behavioural parameters and frequency of
      copulation.

PMID- 12593519
TI  - Mating, male Ixodes scapularis express several genes including those with
      sequence similarity to immunoglobulin-binding proteins and metalloproteases.
AB  - We created a cDNA library from mating, male Ixodes scapularis ticks and screened
      the library with a subtracted probe to eliminate genes common to feeding female
      and mating male I. scapularis ticks. A total of seven unique cDNAs were
      identified in this screen. One cDNA had sequence similarity to the IGBP-MC gene
      from Rhipicephalus appendiculatus, and another cDNA potentially encodes a protein
      with similarity to metalloproteases. RT-PCR, using RNA isolated from male and
      female I. scapularis ticks, confirmed that these genes are expressed in male, but
      not female ticks. The remaining five cDNAs did not match any sequences in the
      GenBank database.

PMID- 12593520
TI  - Introduction. Nebulized beclometasone dipropionate therapy in asthma.

PMID- 12593521
TI  - Comparison of the bioavailability and systemic effects of beclometasone
      dipropionate suspension for nebulization and beclometasone dipropionate via a
      metered-dose inhaler after single-dose administration in healthy male volunteers.
AB  - Pharmacokinetic properties of a drug, and selection and correct usage of an
      appropriate delivery device, are factors that can affect the outcome of inhaled
      therapyThe use of nebulization can overcome problems that are associated with
      other delivery systems used for inhalation therapyThe objective of this open,
      randomized, single-dose study was to compare the systemic exposure and safety of
      beclometasone dipropionate (BDP) suspension for nebulization with BDP via metered
      dose inhaler (MDI) in healthy subjects. Following a run-in period to assess basal
      24-h serum cortisol levels and cortisol urinary excretion, 12 healthy males were
      administered BDP 1,600 microg given via MDI and were then randomized to receive a
      single dose of either 1,600 microg (n = 6) or 3,200 microg BDP (n = 6) suspension
      for nebulization given via a nebulizer Results with respect to systemic exposure
      to beclometasone-17-monopropionate (B17MP) (the active metabolite of BDP) and
      systemic effects on the hypothalamic-pituitary-adrenal (HPA) axis were determined
      by evaluation of a number of pharmacokinetic parameters for plasma B17MP and
      serum and urinary cortisol, respectively. A statistically significantly greater
      peak plasma concentration (Cmax) of B17MP was reported with BDP via MDI (1,587 pg
      ml(-1)) compared with BDP 1,600 microg (455 pg ml(-1)) and BDP 3,200 microg
      suspensions for nebulization (758 pg ml(-1)), and was achieved more rapidly
      (Tmax) (1.3 h, 3 h, and 2.5 h, respectively). In addition, elimination half-life
      (t 1/2(el)) was statistically significantly shorter with BDP via MDI (4.6 h) than
      with both dosages of BDP suspensions for nebulization (7.4 h and 6.3 h with 1600
      microg and 3,200 microg, respectively), as was mean residence time (MRT) (5.4 h,
      11.1 h, and 10.0 h, respectively). Total systemic exposure to B17MP (as
      determined by the area under the concentration-time curve: AUCinfinity) was
      comparable for BDP via MDI (6,883 pg ml(-1) h(-1)) and BDP 3,200 microg
      suspension for nebulization (8,201 pg ml(-1) h(-1)), but significantly greater
      than with BDP 1,600 microg suspension for nebulization (4,870 pg ml(-1); P < 0.05
      vs BDP via MDI). All treatments were well tolerated, and no significant
      differences were found between them with respect to the serum or urinary cortisol
      pharmacokinetic parameters assessed. In conclusion, the results of this study
      demonstrate that BDP suspension for nebulization 3,200 microg given via a
      nebulizer and BDP 1,600 microg given via an MDI are equivalent in terms of
      systemic exposure to B17MP and systemic effects on the HPA axis, with BDP
      suspension for nebulization having a potentially more prolonged activity. It
      confirms that use of a double dose of BDP suspension for nebulization
      administered by nebulizer compared with BDP given via metered-dose inhalation is
      justified and poses no risk with regard to safety.

PMID- 12593522
TI  - The response of two different dosages of beclometasone dipropionate suspension
      for nebulization versus a standard dose of beclometasone dipropionate via a
      metered-dose inhaler on bronchoprovocation testing in adults with asthma.
AB  - The objective of this double-blind, randomized, placebo-controlled, parallel
      group study was to compare the pharmacodynamic effects and safety of
      beclometasone dipropionate (BDP) given by nebulization or metered-dose inhalation
      in adult patients with asthma. Following a 1-week run-in period, 40 patients,
      aged 18-60 years, with intermittent bronchial asthma were randomized to one of
      four treatment groups for 3 weeks (n = 10 in each group): beclometasone
      dipropionate (BDP) suspension for nebulization 1,600 microg day(-1) b.i.d. via a
      nebulizer, BDP suspension for nebulization 3,200 microg day(-1) b.i.d. via a
      nebulizer, BDP 800 microg day(-1) b.i.d. via a metered-dose inhaler (MDI) plus
      spacer, or placebo. At study end, comparable effects were reported for all active
      treatment groups on the primary pharmacodynamic endpoint of FEV1 in response to
      methacholine bronchial provocation testing, with a statistically significant
      improvement shown in the BDP 3,200 microg day(-1) suspension for nebulization
      group compared with pre-treatment for other parameters, including FEV1 and peak
      expiratory flow rates. All treatments were comparable. All treatments were
      equally well tolerated. No significant effects on cortisol levels were reported
      in any of the treatment groups.

PMID- 12593523
TI  - Comparison of the efficacy and safety of beclometasone dipropionate suspension
      for nebulization and beclometasone dipropionate via a metered-dose inhaler in
      paediatric patients with moderate to severe exacerbation of asthma.
AB  - Nebulization simplifies the administration of effective inhaled medications to
      young asthmatics who experience hand-to-lung co-ordination problems and
      inspiratory difficulties associated with metered-dose and dry-powder inhalers,
      respectively. The objective of this double-blind, double-dummy multicentre,
      randomized, parallel-group study was to compare the efficacy and safety of
      corticosteroids given by nebulization or metered-dose inhalation in paediatric
      patients with exacerbation of asthma. Following a 24-h run-in period, 151
      patients, aged 6-16years, with moderate to severe exacerbation of asthma were
      randomized to one of two treatment groups for 4 weeks: beclometasone dipropionate
      (BDP) suspension for nebulization 1,600 microg day(-1) b.i.d. given via a
      nebulizer (n = 75), or BDP spray 800 microg day(-1) b.i.d. given via a metered
      dose inhaler (MDI) plus spacer (BDP MDI) (n = 76). Superimposable and
      statistically significant improvements over baseline were noted at study end for
      the two treatment groups in the various efficacy parameters evaluated (pulmonary
      function tests, asthma symptoms scores, and the use of rescue salbutamol). The
      primary efficacy endpoint was the morning pulmonary expiratory flow rate (PEFR).
      In the BDP nebulization group, mean morning PEFR increased statistically
      significantly from 233.2 +/- 86.31 min(-1) to 322.0 +/- 101.81 min(-1), while in
      the BDP MDI group the increase was from 222.9 +/- 87.31 min(-1) to 314.9 +/-
      96.61 min(-1). Moreover, an additional 4-week treatment period at half doses,
      completed by 26 patients, demonstrated that improvements were maintained or
      further enhanced. The two treatments were equally well tolerated. A total of 25
      and 26 patients in the BDP nebulization and BDP MDI groups, respectively reported
      adverse events during the treatment period, and these were generally mild. In
      conclusion, the results of this study demonstrate that BDP suspension for
      nebulization 1,600 microg day(-1) given via a nebulizer and BDP spray 800 microg
      day(-1) given via an MDI plus spacer are equally effective, with an acceptable
      safety and tolerability profile, when used in paediatric patients with moderate
      to severe asthma exacerbation.

PMID- 12593524
TI  - Comparison of the efficacy and safety of high doses of beclometasone dipropionate
      suspension for nebulization and beclometasone dipropionate via a metered-dose
      inhaler in steroid-dependent adults with moderate to severe asthma.
AB  - Nebulization for the administration of high doses of inhaled corticosteroids can
      benefit steroid-dependent asthmatics. The objective of this double-blind, double
      dummy, multicentre, randomized, parallel-group study was to compare the efficacy
      and safety of high-dose corticosteroids given by nebulization or metered-dose
      inhalation in adult patients with asthma. Following a 2-week run-in period, 124
      patients, aged 18-70 years, with moderate to severe asthma treated with high-dose
      inhaled steroids were randomized to one of two treatment groups for 12 weeks:
      beclometasone dipropionate (BDP) suspension for nebulization 3,000-4,000
      microgday(-1) b.i.d. given via a nebulizer (n = 63), or BDP spray 1,500-2000
      microgday(-1) b.i.d. given via a metered-dose inhaler (MDI) plus spacer (BDP MDI)
      (n = 61). Comparable improvements over baseline, which were statistically
      significant in most cases, were reported at study end for the two treatment
      groups in the various efficacy parameters evaluated (pulmonary function tests,
      clinical symptoms scores, and the use of rescue salbutamol). The primary efficacy
      endpoint was morning pulmonary expiratory flow rate (PEFR). For the intent-to
      treat population, in the BDP nebulization group mean morning PEFR increased
      statistically significantly from 308.7 +/- 107.81 min(-1) to 3 19.2 +/- 104.01
      min(-1) while in the BDP MDI group the increase was from 301.5 +/- 94.71 min(-1)
      to 309.3 +/- 86.71 min(-1). The two treatments were equally well tolerated.A
      total of 19 patients in each group reported adverse events during the treatment
      period, and these were generally mild-moderate in severity. In conclusion, the
      results of this study demonstrate that BDP suspension for nebulization 3,000
      4,000 microg day(-1) given via a nebulizer and BDP spray 1,500-2,000 microg day(
      1) given via an MDI plus spacer are equally effective, with an acceptable safety
      and tolerability profile, when used in steroid-dependent adult patients with
      moderate to severe asthma.

PMID- 12593525
TI  - Comparison of the efficacy and safety of nebulized beclometasone dipropionate and
      budesonide in severe persistent childhood asthma.
AB  - Inhaled steroids are recommended for long-term control of asthma, but their use
      may be limited in young children because of difficulties in using the associated
      inhaler device. The use of nebulizers may help to overcome this issue, without
      compromising therapeutic efficacy or safety. This 14-week, multicentre,
      randomized, controlled, open-label, parallel-group study compared the efficacy
      and safety of nebulized corticosteroids in paediatric patients (aged 6 months to
      6 years) with severe persistent asthma. Beclometasone dipropionate (BDP) 800
      microgday(-1) suspension for nebulization and budesonide (BUD) 750 microg day(-1)
      given by nebulization in a twice-daily regimen, and when used in addition to the
      usual maintenance therapy, resulted in comparable clinical efficacy across all
      parameters. The primary efficacy endpoint was the number of patients who did not
      experience any major exacerbation, this being 40.4% and 51.7% in the BDP and BUD
      groups respectively in the ITT population (P = 0.28), and the mean number of
      global exacerbations (major plus minor) decreased respectively by -37.5% in the
      BDP group and -23.3% in the BUD group. Both treatments were also associated with
      marked reductions in the number of nights with wheezing and the number of days of
      oral steroid use. Moreover, the two treatment groups had a similar adverse-event
      incidence and profile. Only 11 adverse events were reported, and no serious
      adverse events were related to treatment. Urinary cortisol and the time course of
      height and weight were unaffected by both treatments, and BDP was confirmed to
      have a neutral effect on bone metabolism. In conclusion, this study demonstrates
      that both BDP 800 microg day(-1) suspension for nebulization and BUD 750
      microgday(-1) administered by nebulization are effective, with an acceptable
      safety profile, for treatment of severe persistent asthma in infants and young
      children.

PMID- 12593526
TI  - Comparison of the efficacy of beclometasone dipropionate and fluticasone
      propionate suspensions for nebulization in adult patients with persistent asthma.
AB  - The use of nebulization for the administration of inhaled steroids plays an
      important role in asthma patients who are unable to use pressurized aerosol or
      dry-powder inhalers effectively. Moreover, the type of nebulizer used may affect
      how much drug is delivered to the lungs. The objective of this multinational,
      multicentre, randomized, active-controlled, parallel-group study was to compare
      the efficacy and safety of nebulized corticosteroids in adult patients with
      chronic asthma. Following a 1-week placebo run-in period, 205 patients, aged 18
      65 years, with moderate persistent asthma were randomized to one of two treatment
      groups for 12 weeks: beclometasone dipropionate (BDP) suspension for nebulization
      2,400 microg day(-1) b.i.d. (n = 103), or fluticasone propionate (FP) suspension
      for nebulization 2,000 microg day(-1) b.i.d. (n = 102), both administered by a
      jet nebulizer Comparable efficacy in controlling asthma was demonstrated by the
      two treatments at study end, as evident when evaluating various efficacy
      parameters (pulmonary function tests, asthma exacerbations and symptoms, and the
      use of rescue salbutamol). The primary efficacy endpoint was the variation in the
      pulmonary expiratory flow (PEF) at treatment end over the baseline visit. For the
      intent-to-treat population, in the BDP group mean PEF values increased
      statistically significantly from 5.2 +/- 1.31 s(-1) to 5.7 +/- 1.61 s(-1), while
      in the FP group the increase was from 5.2 +/- 1.21 s(-1) to 5.8 +/- 1.81 s(-1).
      Mean PEF values as per cent of predicted also increased in a statistically
      significant way, from 71% to 77.1 % in the BDP group, and from 70.1% to 76.9% in
      the FP group. The two treatments were equally well tolerated.A total of 23 and 32
      patients in the BDP and FP groups, respectively, reported adverse events during
      the treatment period, and these were generally mild. In conclusion, the results
      of this study demonstrate that BDP 2,400 microg day(-1) and FP 2,000 microg day(
      1), both suspensions for nebulization administered via a jet nebulizer, are
      equally effective, with an acceptable safety and tolerability profile, when used
      in adult patients with moderate persistent asthma.

PMID- 12593527
TI  - Conclusion. Nebulized beclometasone dipropionate therapy in asthma.

PMID- 12593528
TI  - L-AP4, a potent agonist of group III metabotropic glutamate receptor, decreases
      central action of angiotensin II.
AB  - The study was designed to investigate the role of the activation of class III
      metabotropic glutamate receptors (mGluRs) in the behavioral activity of
      angiotensin II (AngII). The experiments were performed on adult male Wistar rats.
      Stimulation of group III mGluRs was evoked by icv injection of agonist, L-2-amino
      4-phosphonobutyric acid (L-AP4) (5 microl of 80 mM solution of L-AP4). Fifteen
      minutes later, the animals were given icv solution containing 1 nmol of AngII.
      Memory motivated affectively was evaluated by passive avoidance and active
      avoidance responses (CARs). Moreover, the speculative influence of the treatment
      on motor activity was tested in open field. We observed that both compounds did
      not have significant influence on motor activity of rats in open field test. L
      AP4 given alone had no influence on acquisition, consolidation and recall of
      passive avoidance responses. Examination of influence of L-AP4 on the acquisition
      and extinction of CAR proved that this compound decreased acquisition of CARs,
      while it did not alter extinction of these responses. AngII, as repeatedly shown
      before, greatly increased passive avoidance latency, rate of acquisition of CARs
      and decreased they extinction. Pretreatment of rats with L-AP4 prevented all
      above behavioral effects of the AngII administration.

PMID- 12593529
TI  - Muscimol changes hypoxia-induced impairment of behavior in rats.
AB  - Muscimol, a selective agonist of GABA-A receptors, causes changes in behavioral
      activity. Hypoxia interferes with the GABAergic system and with the functions of
      GABA-A receptors. We used muscimol in Wistar rats to estimate its influence on
      locomotor activity in the open field test as well as on the processes of
      consolidation and retrieval, evaluated in the test of passive conditioned
      reflexes. Anxiolytic activity was examined in the elevated "plus" maze in
      physiological state and after hypoxia-induced amnesia. Following intraperitoneal
      administration of muscimol (1 mg/kg, ip), the animals showed a decrease in
      motility, in retrieval of skill reflexes and in a number of entries into open and
      closed arms in the elevated plus "maze". In animals exposed to hypoxia, we
      observed reduced motility in the open field, inhibition of retrieval and
      consolidation of passive conditioned reflexes, shortened time of sojourn in open
      arms and decreased number of entries into open and closed arms. In the group of
      animals which underwent hypoxia and then received muscimol, we observed no effect
      of hypoxia on muscimol activity in the open field test, except rearing when
      muscimol action was significantly reduced. Muscimol improved consolidation but
      not retrieval in comparison with the hypoxic saline-treated group of rats. In the
      elevated "plus" maze test, treatment of rats with muscimol after hypoxia
      significantly prolonged the time spent in open arms and increased the number of
      entries into open arms, while shortened the time spent in closed arms. In
      conclusion, muscimol in hypoxia-exposed group of rats exerted beneficial effect
      on consolidation in passive avoidance situation and exerted anxiolytic activity.
      Changes in the activity of muscimol under hypoxia may have significant clinical
      implications.

PMID- 12593530
TI  - Hypoxic pulmonary vasoconstriction in isolated blood-perfused rat lung;
      modulation by thromboxane A2, platelet-activating factor, cysteinyl leukotrienes
      and endothelin-1.
AB  - Recent evidence suggests that hypoxic pulmonary vasoconstriction (HPV) is
      mediated by hypoxia-induced closure of voltage-gated potassium channels in
      pulmonary vascular smooth muscle cells. It is also claimed that various
      vasoconstrictor mediators such as thromboxane A2 (TXA2), platelet activating
      factor (PAF), cysteinyl leukotrienes (cys-LTs) or endothelin-1 (ET-1) contribute
      to HPV. Their role, however, has not been unequivocally accepted. On the
      contrary, it is well known that endothelium-derived nitric oxide negatively
      modulates HPV. Since NO counteracts action of vasoconstrictor mediators, we
      tested the hypothesis that modulatory role of TXA2 PAF, cys-LTs and ET-1 in HPV
      would become apparent in absence of endogenous NO. For that purpose we assessed
      contribution of these mediators to HPV in the isolated blood-perfused rat lung
      pretreated with a non-selective NOS inhibitor, L-NAME. HPV, which was greatly
      augmented by L-NAME (300 microM) alone, was inhibited neither by a TXA2 synthase
      inhibitor (Camonagrel, 300 pM), nor by a PAF receptor antagonist (WEB 2170, 100
      microM), nor by an inhibitor of five-lipooxygenase-activating protein (MK 886, 10
      microM), nor by a non-selective ET-1 receptor antagonist (LU 302872, 30 pM). In
      summary, in isolated blood-perfused rat lung, TXA2, PAF, cys-LTs and ET-1 seem
      not to be involved in HPV, whereas we confirm the dominant role of endogenous NO
      in blunting HPV.

PMID- 12593532
TI  - Influence of diethyldithiocarbamate on the activity of ecto-ATPase in lymphocytes
      of rats: ex vivo studies.
AB  - Influence of diethyldithiocarbamate (DTC) on the activity of ecto-ATPase (plasma
      membrane-bound enzyme participating in a cascade of reactions leading to the
      formation of adenosine--a modulator of inflammation) was examined on the
      lymphocytes isolated from the spleen of rats with inflammation. DTC was
      administered at doses of 4 mg/kg and 290 mg/kg using two modes of administration.
      It has been observed that: a) an inflammation caused an increase in ecto-ATPase
      activity in both subpopulations of lymphocytes; in the case of B-lymphocytes, the
      maximum of activity occurred 48 h and in the case of T-lymophocytes, 72 h after
      the injection of carrageenin; b) a single injection of DTC at both doses, 24 h
      before or 24 h after carrageenin injection caused a decrease in ecto-ATPase
      activity in B-lymphocytes and its increase in T-lymphocytes throughout the whole
      measurement period, which was not observed when DTG was administered only after
      provocation of inflammation; c) administration of a high dose of DTC together
      with equimolar doses of disulfiram and CS2 led to a decrease in ecto-ATPase
      activity and 5 '-nucleotidase level in B-lymphocytes, which is bound to the
      former enzyme; d) in in vitro studies, both populations of lymphocytes isolated
      from the rats treated with a four-fold dose of DTC showed higher resistance of
      ecto-ATPase to inhibitors of the enzyme and antagonists of type P2 purinoceptors.

PMID- 12593531
TI  - Mechanisms of delayed preconditioning with A1 adenosine receptor activation in
      porcine coronary smooth muscle cells.
AB  - This study examined the hypothesis that the activation of A1 adenosine receptor
      (A1AR) induces delayed cellular protection (DCP) in porcine coronary smooth
      muscle cells (PCSMC). The following groups of cultured PCSMC, subjected to
      simulated ischemia (SI) at 20 h were studied: (a) SI: with ischemia alone; (b)
      A1AR agonist chloro-N6-cyclopentyl adenosine (CCPA: CCPA (1 microM) alone; (c)
      CCPA + PKC inhibitor chelerythrine chloride (CCL): CCPA and 1 microM CCL; (d)
      CCPA + iNOS inhibitor S-methylthiourea (SMT): CCPA and 100 nM SMT; (e) CCPA +
      KATP channel blocker Glibenclamide (Glb): CCPA and 50 microM Glb; (f) CCPA +
      mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD): CCPA and 100 microM
      of 5-HD; (g) CCPA + A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX):
      CCPA and 1 microM DPCPX. The release of LDH into the medium as well as the amount
      of LDH remaining in the cells was used as a marker of cellular injury and cell
      viability. Up-regulation of A1AR, epsilon-PKC, iNOS and HSP 72i was detected
      through Westem blot analysis. The cellular resistance (%LDH remaining in the
      cells) acquired by PCSMC due to CCPA (59.42 +/- 1.57) was significantly blocked
      by CCL: 39.30 +/- 2.03; SMT: 41.37 +/- 1.98; Glb: 47.24 +/- 1.31; 5-HD: 47.69 +/-
      1.40 and DPCPX: 42.92 +/- 0.79. CCPA increased the expression of A1AR (1.30
      fold), epsilon-PKC (1.20 fold), iNOS (1.50 fold), and HSP 72i (1.70 fold)
      compared to the controls. CCPA-induced up-regulation of A1AR, epsilon-PKC, iNOS,
      HSP 72i, and the opening of both mitochondrial and sarcolemmal KATP channels may
      possibly participate in signaling cascade. Our study suggests that A1AR
      activation up-regulates iNOS, HSP 72i via epsilon-PKC signaling pathway to
      activate both mitochondrial and sarcolemmal KATP channels for cellular protection
      against SI in the cultured PCSMC.

PMID- 12593533
TI  - Effects of combination of cyclosporine with losartan or enalapril on kidney
      function in uremic rats.
AB  - Long-term treatment with cyclosporine in solid organ transplantation has been
      shown to be associated with the development of hypertension and nephrotoxicity.
      Angiotensin-converting enzyme inhibitors have well-known nephroprotective
      properties and may prevent cyclosporine A (CYA)-induced hypertension. Angiotensin
      receptor 1 antagonists have similar properties. The purpose of this study was to
      investigate if losartan or enalapril could be administered with CYA to reduce its
      nephrotoxic effect in uremic rats. The studies were performed on the following
      groups of rats: group I--control; group II--control rats + losartan; group III-
      control rats + CYA; group IV uremic rats; group V--uremic rats + losartan; group
      VI--uremic rats + CYA; group VII--uremic rats + losartan + CYA, group VIII-
      control rats + enalapril; group IX--control rats + enalapril + CYA; group X -
      uremic rats + enalapril; group XI--uremic rats + enalapril + CYA. Pretreatment
      with CYA, losartan or enalapril in uremic rats resulted in a significant increase
      in urea and creatinine levels and a decrease in hematocrit. The same effect was
      observed when uremic rats were given CYA + losartan or CYA + enalapril.
      Pretreatment with losartan was associated with the increase in the level of CYA
      much higher than with CYA treatment alone. Similarly, pretreatment with enalapril
      resulted in a significant increase in CYA concentration in both groups of rats
      given CYA: uremic and non-uremic. Results of our study show that the treatment
      with cyclosporine and a combination of losartan or enalapril results in an
      increase in creatinine and urea levels and a decrease in hematocrit. Therefore,
      physicians should exercise caution, when they give losartan and enalapril to
      kidney allograft recipients treated with cyclosporine, particularly with impaired
      allograft function.

PMID- 12593534
TI  - Effect of capsaicin on ion transport in the caecum of rabbits.
AB  - Effect of capsaicin, a stimulator of C-fibres, on ion transport in the caecum of
      rabbits was studied using electrophysiological methods, designed to evaluate
      ionic currents occurring in epithelial tissues. The experiments consisted in
      measuring transepithelial electrical potential difference (dPD) of an isolated
      fragment of rabbit's caecum, placed in a Ussing apparatus. The ion transport was
      modified through incubation in Ringer solution, supplemented with amiloride,
      bumetanide, and capsaicin. Capsaicin was also administered with peristalting
      pump. The experiments demonstrated that the inhibition of sodium ions transport
      caused by incubation with amiloride and incubation with capsaicin slowed down
      mechanical reaction to electrical potential difference. On the other hand,
      immediately after the administration, the capsaicin effect on C-fibres modified
      electrophysiological reaction of the caecum to mechanical stimulation.
      Physiological and pharmacological experiments reveal that a component dependent
      on activation of C-fibres contributes to the reaction of ion transport activation
      following mechanical stimulation.

PMID- 12593535
TI  - Modulation by cationic amphiphilic drugs of serine base-exchange, phosholipase d
      and intracellular calcium homeostasis in glioma C6 cells.
AB  - We aimed to assess the effect of three drugs belonging to amphiphilic cations,
      imipramine, amitriptyline and propranolol, on lipid synthesis and intracellular
      calcium homeostasis in glioma C6 cells. Antidepressants, imipramine and
      amitriptyline, had a stimulatory effect on [14C]serine incorporation into
      phosphatidylserine. Similar effect was induced by propranolol, antidysrhythmic
      drug and an antagonist of beta-adrenergic receptor, but not by isoproterenol, a
      selective agonist of this receptor. Stimulation of serine base-exchange activity
      by amphiphilic cations occured at concentration as low as 5-25 microM that may be
      reached during clinical treatment. At much higher concentration (250 microM),
      those drugs also stimulated phospholipase D-mediated synthesis of
      [14C]phosphatidylethanol and blocked phorbol ester-induced, protein kinase C
      dependent phospholipase D activity. The latter effect already occurred at low (25
      microM) concentration of drugs. We have also shown that treatment of the cells
      with amphiphilic cations (1 mM) produced only a weak increase in the
      intracellular Ca2+ concentration and did not affect Ca2+ release from the
      intracellular stores evoked by nucleotide receptor agonists, ATP and ADP. In
      contrast, this treatment strongly diminished an unspecific leak of Ca2+ from the
      endoplasmic reticulum caused by thapsigargin and ionomycin. Mianserin, which is
      not cationic amphiphilic drug, did not affect phosphatidylserine synthesis and
      phospholipase D activity and produced heterogenous and chaotic Ca2+ responses.
      Our results suggest that imipramine, amitriptyline and propranolol may modulate
      lipid synthesis and intracellular calcium signaling independently of their action
      on membrane receptors, most probably by modification of the physicochemical
      properties of cell membranes.

PMID- 12593536
TI  - Distribution of allelic variants of functional C3435T polymorphism of drug
      transporter MDR1 gene in a sample of Polish population.
AB  - P-glycoprotein (P-gp), the protein product of MDR1 gene, is an important factor
      regulating the bioavailability of many therapeutics. Recently, the C3435T
      polymorphism of MDR1 was correlated to altered expression and function of P-gp in
      normal tissues. In this study, polymerase chain reaction-restriction fragment
      length polymorphism (PCR-RFLP) assay was applied to assess C3435T MDR1
      polymorphism in 122 healthy individuals of Slavic origin from the population of
      central Poland (Lodz and surrounding areas). The detected genotype variant
      frequencies were as follows: CC in 42%, CT in 41%, and TT in 17% of the tested
      subjects (C-allele frequency was 0.62). The frequency of the C-allele is similar
      to Japanese population and significantly higher than in Caucasians from Western
      Europe. The results of this study give basis for large-scale C3435T MDR1 genotype
      phenotype correlation investigations in Polish population that may be useful to
      individualize therapy of cancer, HIV-1 infection and some other diseases.

PMID- 12593537
TI  - Influence of midazolam on pharmacokinetics of verapamil in rabbits.
AB  - Calcium channel blockers can get involved in pharmacological interactions when
      used concomitantly with other drugs. Previous reports indicate a differential
      influence of various general anesthetics on verapamil pharmacokinetics. A
      tendency of a faster transfer of verapamil from the central compartment to the
      tissue compartment was found to be associated with a slower drug return from the
      tissue at the given verapamil doses during thiopental or propofol anesthesia.
      Thus, an increased storage of verapamil in tissue compartment and prolongation of
      the drug action may occur due to those interactions. The aim of the study was to
      investigate the influence of midazolam on the plasma concentrations and
      pharmacokinetic parameters of verapamil after intravenous bolus administration in
      rabbits during 2 h of observation. Verapamil and midazolam were administered
      intravenously at a dose of 0.2 mg/kg. Verapamil levels in plasma were determined
      by radioanalysis using [3H]verapamil. Levels of verapamil were determined in
      plasma at 5, 10, 15, 30, 45, 90 and 120 min after the administration, and plasma
      disappearance was analyzed according to the non-compartmental and 2-compartmental
      model. After administration of midazolam together with verapamil, a decrease in
      verapamil concentration in plasma was seen, with an increased verapamil transfer
      to the tissue compartment, increased steady state distribution volume and
      shortened residency time of the drug in the plasma.

PMID- 12593538
TI  - Significant variations of responsiveness of rat gut smooth muscles to glutamate.
AB  - Our four-year study, conducted on isolated rat stomach and rectum strips from
      adult rats of the same brood in five series, demonstrated for the first time
      notable variations of the responsiveness of the gut smooth muscles to glutamate,
      the findings that point to strong variability of glutamate contractile action
      which could lead to inconsistencies and should be taken into account in the
      future research.

PMID- 12593539
TI  - Azathioprine-induced fatal macrocytic anemia in rabbits.
AB  - Azathioprine (AZA) is used clinically sometimes at high doses for short-term
      therapy to treat acute rejection of kidney allograft or to desensitize
      hypersensitive patients to it. The delayed consequences of this approach had not
      been well investigated. Therefore, in this study we have investigated the delayed
      consequences of high-dose short-term AZA administration in rabbits. Our results
      showed that oral administration of AZA (10 mg/kg/day) to rabbits for two weeks
      induced reversible thrombocytosis and delayed fatal macrocytic anemia. Moreover,
      neither the hemoglobin level nor the white blood cell count was affected by AZA.
      The solvent of AZA had no effect on blood cell counts and hemoglobin levels. We
      can conclude that although high-dose AZA therapy may not induce immediate and
      significant changes in blood picture, delayed fatal macrocytosis may occur.

PMID- 12593540
TI  - Sib 1893 possesses pro- and anticonvulsant activity in the electroshock seizure
      threshold test in mice.
AB  - SIB 1893, a non-competitive antagonist of group I metabotropic glutamate receptor
      subtype 5, administered at the doses ranging between 0.5-2 mg/kg markedly lowered
      the electroconvulsive threshold, whereas if applied at the higher dose of 40
      mg/kg, it significantly raised the threshold for electroconvulsions in mice,
      exhibiting both pro- and anticonvulsive properties in this test.

PMID- 12593541
TI  - Electroconvulsions elevate the levels of lipid peroxidation products in mice.
AB  - The objective of this study was to determine whether electroconvulsions lead to
      excessive lipid peroxidation. The concentrations of the conjugated dienes (CD)
      and malonyl dialdehyde (MDA) in the homogenates of the brains after seizures
      induced with 25 mA current (MES) measured immediately after seizures were
      significantly higher in comparison with the control brains. There were no
      significant differences between control group and animals treated with multiple
      MES. Significant rise in CD concentrations was also observed at 1 h following
      MES. The results indicate that electroconvulsions may lead to the increased
      formation of lipid peroxidation products.

PMID- 12593542
TI  - Observations on the early results of treatment of recurrent respiratory
      papillomatosis using cidofovir.
AB  - OBJECTIVE: To document the response of two patients with severe recurrent
      laryngeal papillomatosis following treatment with intralesional cidofovir in
      conjunction with carbon-dioxide laser evaporation. SETTING: Tertiary referral
      centre. METHODS: Retrospective review of treatment of two patients followed up
      over a 12-month period. INTERVENTION: Microlaryngoscopy and carbon-dioxide laser
      evaporation of lesions followed by intralesional injection of cidofovir. OUTCOME
      MEASURES: Photodocumentation and descriptive statistical representation of
      intervals between endoscopic treatment. The disease was staged according to
      severity on endoscopy. RESULTS: Initially, both patients showed a marked
      improvement of disease. However, the disease relapsed to a significant extent.
      Overall, there was no demonstrable change in the frequency of required
      endoscopies despite subjective improvement of the airway. CONCLUSION: Cidofovir
      may be of some benefit in the management of recurrent respiratory papillomatosis,
      but further studies are still required.

PMID- 12593543
TI  - Type III tympanoplasties: the Sherbrooke experience.
AB  - OBJECTIVES: To review short- and longer-term results of type III tympanoplasties
      as performed by the senior author and to compare these results with those
      reported in the literature. METHOD: Retrospective review of 96 type III
      tympanoplasties, with and without mastoidectomy, performed between April 1996 and
      August 2000. RESULTS: At a mean of 384 days postoperatively, 57.3% of patients
      had an air-bone gap of less than 20 dB. The average postoperative gap is 21.4 dB.
      Gap closure is best at 2000 Hz, with an average drop of 51% from initial value,
      compared with 34%, 39%, and 18% at 500, 1000, and 4000 Hz, respectively.
      CONCLUSION: Our results are similar to those published previously. We emphasize
      the improvement at 2000 Hz, which is an important frequency for speech
      discrimination. It would be interesting to see if it correlates with an
      improvement in quality of life.

PMID- 12593544
TI  - Use of allogenic dermis for radial forearm free flap donor site coverage.
AB  - OBJECTIVE: The radial forearm free flap has become the method of choice for
      reconstruction of head and neck defects following oncologic ablation. Harvesting
      of a radial forearm free flap leaves a donor site defect. This is most commonly
      closed with a split-thickness skin graft. Morbidity, most commonly owing to a
      lack of graft take over the tendons, can be quite high. Recently, an acellular
      matrix (Alloderm) has been advocated to decrease complications at the radial
      forearm donor site, as well as obviate taking a split-thickness skin graft from
      the thigh. MATERIAL AND METHODS: Tertiary referral academic centre. Retrospective
      chart review of 15 patients. Five patients received allogenic dermis, 10 patients
      received split-thickness skin grafting to the radial forearm donor site. RESULTS:
      Patients with allogenic dermis took between 12 and 16 weeks to heal completely.
      Patients undergoing split-thickness skin graft were completely healed within 4 to
      6 weeks. Cosmesis was judged to be marginally better in the allogenic dermis
      group. Allogenic dermis placement had a greater impact on hand function owing to
      prolonged healing, whereas patients with split-thickness skin graft required
      wound care at the thigh for a 2- to 3-week period owing to the harvesting of the
      skin graft. CONCLUSIONS: Allogenic dermis may be a viable alternative to split
      thickness skin grafting and radial forearm free flap donor sites. Prolonged
      healing with subsequent increased health care services use needs to be addressed.

PMID- 12593545
TI  - Nasopharyngeal angiofibroma.
AB  - OBJECTIVE: To study the clinical profile of nasopharyngeal angiofibromas, various
      surgical approaches, and the outcome of surgery. DESIGN: The retrospective study
      was carried out in 110 consecutive cases of nasopharyngeal angiofibroma over a
      period of 25 years. SETTING: A hospital-based study. METHODS: In 65 patients, a
      transpalatal approach was used, and in 38 patients, a lateral rhinotomy approach
      was used. The tumour was removed by external ethmoidectomy in 2 cases and in by
      transnasal approach in 3 cases. A modification of the transpalatal approach was
      also designed. MAIN OUTCOME MEASURES: Patients were regularly followed up for any
      recurrence for 2 to 5 years. RESULTS: Of 118 operated cases, in 33 patients,
      recurrence was observed. Four cases had to be operated three times and one case
      four times. All of the recurrences were observed within 2 years. CONCLUSIONS:
      Angiofibroma, a disease of adolescent males, arises from either the lateral wall
      or the roof of the nasopharynx. Patients usually present at the late stage of the
      disease. Surgery is the treatment of choice. No single approach is applicable to
      all cases. However, most of the tumours are excisable by a lateral rhinotomy
      approach, with less chance of recurrence. The modified transpalatal approach
      provides excellent exposure. Recurrence occurs within 2 years.

PMID- 12593546
TI  - Parotid gland tumours in 255 consecutive patients: Mount Sinai Hospital's quality
      assurance review.
AB  - Parotid neoplasms represent a diverse group of tumours found in the head and
      neck. Complications following parotidectomy, including Frey's syndrome, facial
      nerve paralysis, sialoceles, and parotid fistulae, have been well documented. A
      retrospective review of 255 patients treated surgically for parotid masses over
      an 8-year period at Mount Sinai Hospital in Toronto was reviewed as part of a
      quality assurance program. The sensitivity, specificity, and predictive values
      for fine-needle aspiration cytology were analyzed. The incidence of benign and
      malignant lesions is presented. The complications following parotidectomy are
      reviewed and in our series are consistent with the figures published in the
      literature.

PMID- 12593547
TI  - Excessive noise levels in the neonatal ICU: potential effects on auditory system
      development.
AB  - OBJECTIVE: Several recent studies have found exceedingly high noise levels in the
      neonatal intensive care unit (NICU) and in incubators. The purpose of this study
      was to perform a detailed noise assessment in a Canadian NICU. METHODS: A noise
      level meter was used to evaluate ambient noise levels in three rooms of the NICU
      and to compare those levels with measurements taken inside an occupied incubator.
      RESULTS: Mean hourly noise levels measured inside the incubator (61 dB) were
      significantly higher than those measured outside (55 dB). Ambient noise levels
      were also significantly higher in rooms where staff activity was greatest (59
      dB). In addition, peak noise levels in excess of 120 dB were found. CONCLUSION:
      These findings are consistent with those of previous studies and suggest that
      noise levels in the NICU are excessive. Furthermore, staff activity is a
      significant contributor. The suggestion that noise in the NICU is detrimental to
      both auditory and central nervous system development is discussed and
      intervention strategies are recommended.

PMID- 12593548
TI  - Nasopharyngeal carcinoma volume measurements determined with computed tomography:
      study of intraobserver and interobserver variability.
AB  - OBJECTIVE: To investigate the intraobserver and interobserver variability of
      computed tomography-based volume measurements of nasopharyngeal carcinoma.
      DESIGN: Prospective study. SETTING: Tertiary care centre. METHODS: The primary
      tumour volume of 13 nasopharyngeal carcinomas was repeatedly measured by two
      trained observers independently in two different sessions, using the summation of
      area technique. MAIN OUTCOME MEASURES: Mean tumour volume and its standard
      deviation were calculated for each tumour. Statistical analysis was done with
      multivariate analysis, linear regression, and a two-way analysis of variance
      (ANOVA) random effects model. RESULTS: The coefficient of variation was less than
      20% in 11 volume measurements, but a large discrepancy between observers was
      noted in two tumours with involvement of the paranasal sinuses. A good linear
      correlation was found between mean tumour volume and its standard deviation:
      standard deviation = 0.26 volume - 2.48 (r = .80). When the two tumours with a
      large coefficient of variation were excluded, the two-way ANOVA random effects
      model revealed that both the interobserver (p = .83) and the intraobserver (p =
      .90) effect are not statistically significant; interobserver variability was the
      major component of total variability (71.0%). CONCLUSIONS: Total variability in
      the computed tomography-based measurement of nasopharyngeal carcinoma volume is
      small by having the measurements done by a trained observer, except in tumours
      with involvement of the paranasal sinuses.

PMID- 12593549
TI  - Cell kinetics of human nasal septal chondrocytes in vitro: importance for
      cartilage grafting in otolaryngology.
AB  - In the field of reconstructive plastic surgery, grafts of autologous cartilage
      are sometimes used to replace damaged or pathologic tissues, particularly in the
      nose, ear, and trachea. However, this procedure is difficult to apply, especially
      because of the scarcity of donor sites. In this study, we have cultured and
      characterized human chondrocytes from human nasal septal cartilage biopsies. The
      proliferative activity was evaluated by incorporation of 3H-thymidine into
      deoxyribonucleic acid (DNA) both under normal culture conditions and with
      different growth factors and serum concentrations. Identification of chondrocytes
      in culture was performed with immunohistochemistry and production of matrix with
      specific histochemical indicators. We observed a significant increase of cell
      kinetics of differentiated chondrocytes, embedded with intense metachromatic
      matrix, in the presence of transforming growth factor beta, and low
      concentrations of fetal calf serum. Therefore, in suitable conditions, human
      chondrocytes obtained even from small specimens can produce in vitro considerable
      quantities of pure autologous cartilaginous tissue within a few days. This newly
      formed cartilage can be used as a grafting material in reconstructive surgery,
      particularly in otolaryngology.

PMID- 12593550
TI  - Can electrocochleography in Meniere's disease be noninvasive?
AB  - OBJECTIVES: To evaluate and compare the results of extratympanic and
      transtympanic electrocochleography (ECochg) in clinically diagnosed cases of
      Meniere's disease and controls. DESIGN: Prospective study on 20 clinically
      diagnosed cases of Meniere's disease and 20 age- and sex-matched controls.
      SETTING: Department of Otolaryngology, Head and Neck Surgery, Postgraduate
      Institute of Medical Education and Research, Chandigarh, India. METHODS:
      Electrocochleography was performed by a transtympanic method using a stainless
      steel needle electrode kept on the promontory and by an extratympanic method
      whereby the needle electrode was inserted into bony canal skin. MAIN OUTCOME
      MEASURES: The various parameters compared were summation potential latency and
      amplitude, action potential latency and amplitude, and ratio of summation to
      action potential amplitude (SP/AP). RESULTS: A significant difference in
      summation to action potential amplitude ratio (SP/AP) between cases and controls
      was obtained by both methods. Using 0.29 as a cutoff for SP/AP, the transtympanic
      method yielded a sensitivity of 100% and a specificity of 90%, whereas the
      extratympanic method showed corresponding values of 90% and 80%, respectively.
      CONCLUSION: Contrary to previous studies, extratympanic ECochg is shown to be an
      efficacious and a less invasive test as compared with the transtympanic method
      and can be easily performed in clinical practice.

PMID- 12593551
TI  - Exudative laryngeal diseases of Reinke's space: a clinicohistopathological
      framing.
AB  - OBJECTIVE: To establish the relationship between the macroscopic and histologic
      diagnosis of nodules, polyps, and Reinke's edema of the true vocal folds and to
      propose a clearer clinical definition of them in the hope of settling the
      difference of opinion between otolaryngologists and pathologists. DESIGN:
      Retrospective study SETTING: Otolaryngology Department of "La Sapienza"
      University of Rome. METHODS: The pathologic reports of 203 patients subjected to
      direct laryngoscopy were studied. MAIN OUTCOME MEASURES: Examination of the
      histologic specimen of the epithelium and the chorion. RESULTS: Microscopic
      examination revealed a high percentage of normal epithelium both for nodules
      (33.79%) and polyps (40.65%). No dysplasia was observed, whereas dysplasia was
      present in 10 cases of Reinke's edema (7 laryngeal intraepithelial neoplasia 1
      and 3 laryngeal intraepithelial neoplasia II). Five different stages of
      histologic progression resulted from the examination of the chorion in both
      nodules and polyps. CONCLUSIONS: Our suggestion is to consider polyps as "older"
      lesions and nodules as "younger" lesions. A polyp may be defined as an abnormal
      unilateral growth of vocal folds, a nodule as a bilateral growth situated between
      the anterior and medium third of the vocal fold, and Reinke's edema as a
      bilateral wound that extends to the whole of the true vocal fold.

PMID- 12593552
TI  - Motion sickness and vestibular hypersensitivity.
AB  - OBJECTIVE: Motion sickness is poorly understood, although it has been recognized
      for years as debilitating. Vestibular function is required for motion sickness to
      occur, but motion sickness can also be brought on without body motion. The aim of
      this study was to see if there was a correlation between caloric response and
      motion sickness susceptibility. DESIGN: One experiment was a prospective study
      carried out on 200 patients. A second prospective study was carried out on 121
      patients. SETTING: Patients referred to our tertiary/quaternary care dizziness
      clinic. METHODS: In experiment 1, caloric scores in patients were correlated with
      symptoms of motion sickness as established by responses to a simple question. In
      experiment 2, caloric scores were correlated with symptomatic responses to
      caloric testing itself. MAIN OUTCOME MEASURES: Caloric responses of the best ear
      were measured according to standardized caloric evaluation methods. RESULTS:
      There was no correlation between motion sickness and caloric scores. There was a
      significant difference in caloric scores between patients made symptomatic by
      calorics and those who were not. CONCLUSIONS: The autonomic response seen in some
      patients is not triggered by a specific level of semicircular canal response (as
      measured by caloric testing). We hypothesize that (similar to space motion
      sickness) the trigger is a signal differential that arises between semicircular
      canals and otoliths and that some patients are unable to suppress this response.
      These patients often suffer motion sickness on a long-term basis.

PMID- 12593553
TI  - Long-term outcome after Griggs tracheostomy.
AB  - OBJECTIVE: The purpose of this study was to evaluate laryngotracheal stenoses in
      the long-term outcome after percutaneous tracheostomy. METHODS: Between 1997 and
      2000, 162 patients were tracheostomized during their postoperative stay at the
      intensive care unit of the Department of Cardiac Surgery, University of
      Heidelberg. Thirty-eight of 80 long-term surviving patients (mean follow-up: 22
      months, range: 7-50 months) gave their informed consent to follow-up
      laryngotracheoscopy. By using this technique, we localized the tracheostomy site,
      evaluated the laryngotracheal morphology, and quantified laryngotracheal stenosis
      planimetrically. RESULTS: Clinically relevant stenoses were found in one patient.
      Another patient had undergone surgical revision of the percutaneous dilatational
      tracheostomy (PDT) prior to our examination. The endoscopic examination revealed
      that 89.5% (34/38) of the patients exhibited tracheal stenosis, less than 25%
      without clinical symptoms. Despite endoscopic guidance during PDT, the location
      of the puncture site was found to vary greatly. Cricoidal lesions were identified
      in 15 patients. In only 12 patients (31.6%), the PDT had been placed at the
      optimal location between the first and the second tracheal ring. In these
      patients, we found the lowest rate of tracheal stenosis in tracheotomies without
      fractured tracheal rings. CONCLUSION: Since clinically relevant tracheal stenosis
      has been found to depend mainly on the puncture site of the PDT and tracheal
      fractures during PDT, we want to emphasize the importance of adequate endoscopic
      guidance during and the careful performance of the PDT. Further follow-up studies
      are necessary to improve and ensure the quality of PDT techniques.

PMID- 12593554
TI  - Wegener's granulomatosis of the orbit.

PMID- 12593555
TI  - Leiomyosarcoma of the larynx: case report with pathologic and surgical
      considerations.

PMID- 12593556
TI  - Fish bone migration through the thyroid gland in the neck.

PMID- 12593557
TI  - Biochip array technology for simultaneous multianalyte analysis--an integrated
      laboratory system.

PMID- 12593558
TI  - Histological analysis of cystic tumour like lesions of central nervous system.
AB  - True cysts of the central nervous system (CNS) are rare lesions. A retrospective
      study of patients with symptomatic non-neoplastic cystic lesions of CNS operated
      in the Department of Neurosurgery, G.B. Pant Hospital, New Delhi between Jan 1994
      and Feb 2001 was conducted. Parasitic cysts, cystic transformation of
      hemmorhages, vascular malformations and cystic tumours were excluded from the
      study. A total of 109 cases were reviewed. There were 34, 27, 17, 16, 8, 3 and 2
      cases of epidermoid, arachnoid, dermoid, colloid, neurenteric, Rathke's and
      ependymal cysts and 1 case each of choroid plexus and glial cysts. The clinical
      presentations, locations, incidence and pathogenesis of these cysts is discussed.

PMID- 12593560
TI  - Fine needle aspiration cytology of head and neck masses.
AB  - Fine needle aspiration cytology (FNAC) was done on 150 patients with swelling in
      the head and neck region, during the period of 18 months from July 1994 to
      December 1995. Of these, 55 patients underwent surgery permitting a correlation
      between the histopathological diagnosis based on permanent paraffin sections and
      the diagnosis made by FNAC in order to evaluate FNAC in terms of accuracy along
      with its complications and limitations. The overall accuracy in the 55 cases
      evaluated was 92.73% with sensitivity of 90.91% and specificity of 93.18%. It was
      confirmed that FNAC is a highly diagnostic procedure for assessing swellings in
      the head and neck region. The method is simple, safe and economical.

PMID- 12593559
TI  - Study of fungal and bacterial infections of the diabetic foot.
AB  - Microbiological study for aerobic organisms, anaerobic organisms and fungi from
      105 cases of diabetic foot ulcers was carried out to determine the aetiological
      agents and their antibiograms. Out of 265 microbial isolates obtained, 160 were
      aerobes, 50 anaerobes and 55 fungal strains. Polymicrobial infection was observed
      in 73 (69.5%) cases. The most frequently isolated aerobic microorganisms were
      Staphylococcus aureus and Pseudomonas aeruginosa. Among the anaerobes Bacteroides
      melaninogenicus and Bacteroides fragilis were most common. Candida species were
      preponderant among the fungal isolates. Antimicrobial sensitivity pattern of the
      isolates is discussed in detail.

PMID- 12593561
TI  - UreC PCR based diagnosis of Helicobacter pylori infection and detection of cag A
      gene in gastric biopsies.
AB  - Polymerase chain reaction assay using ureC gene specific primers for the
      detection of Helicobacter pylori in gastric biopsy specimens from 116 dyspeptic
      patients was compared with other routine invasive diagnostic methods (culture,
      rapid urease test [RUT] and histology). In parallel, gastric biospy specimens
      from 54 patients and their corresponding Helicobacter pylori isolates were
      subjected to PCR with cagA targeting primers using standard protocols.
      Helicobacter pylori were detected in 53%, 43%, 48% and 50% of patients by PCR,
      RUT, culture and histological examination respectively. Based on histology and
      culture positive and at least three test positive result, 44 (37%), 46 (39%) and
      26 (22%), and 56 (48%), 52 (44%) and 8 (6%) patients were classified as
      Helicobacter pylori positive, negative and indeterminate respectively. The
      sensitivity and specificity of PCR assay was the highest-95% and 100% when
      compared with both culture and histology positive, and at least any three
      positive results respectively. The result of cagA positivity in 54 gastric biopsy
      specimens and their corresponding Helicobacter pylori isolates were identical; 18
      of 20 (90%) duodenal ulcer patients and 23 of 28 (82%) patients with chronic
      gastritis and 2 (40%) of 5 patients with portal hypertension and one gastric
      biopsy specimens from gastric cancer patients were found to be cagA positive. PCR
      based method to detect Helicobacter pylori and the virulence gene cag A directly
      from gastric biopsy specimens appears to be promising and can curtail the lengthy
      process of culture-based approaches. The procedure proved to be rapid and
      reliable and could be utilized for diagnostic purposes.

PMID- 12593562
TI  - The renal pathology in children dying with hepatic cirrhosis.
AB  - The aim of this analysis was to observe the pathologic changes in the kidney in
      23 children dying of cirrhosis, including five children with renal failure.
      Besides these pathologic changes, glomerular cellularity and arteriolar wall
      thickness of these patients were compared with 18 age matched autopsy controls
      dying of nonhepatic and nonrenal causes. Histologic examination of the kidneys in
      these cirrhotic children showed significant tubular changes in five patients,
      diffuse glomerulosclerosis in five, only one child had membranous glomerulopathy
      or glomerulonephritis and one cirrhotic with serum hepatitis B surface antigen
      positivity had polyarteritis nodosa. No statistically significant changes were
      observed in the glomerular cellularity and the arteriolar wall thickness in these
      cirrhotic children as compared to the controls. However, medial proliferation and
      hyaline arteriolosclerosis were observed in four cirrhotic children. Tubular bile
      casts and nephrocalcinosis were the sole lesions causing renal failure in two
      cases. A combination of glomerulosclerosis, cast formation and arteriolosclerosis
      was seen in the remaining three patients. Thus the kidney showed a spectrum of
      pathology in pediatric cirrhosis. The tubular lesions causing renal failure
      represent acute treatable lesions whereas glomerulosclerosis and arteriosclerosis
      stand for a more chronic and less reversible renal damage.

PMID- 12593563
TI  - Fine needle aspiration cytology of soft tissue tumours in correlation with
      histopathology.
AB  - FNAC of soft tissue tumours was done in 67 patients. The findings were compared
      with histopathologic findings. Overall diagnostic accuracy was 93.33% for all
      lesions 93.93% for malignant mesenchymal tumours 93.33% for benign mesenchymal
      tumours and 100% for metastatic lesions. FNAC of soft tissue tumours provided
      acceptable diagnostic accuracy when supported by appropriate clinical and other
      diagnostic data.

PMID- 12593564
TI  - Covert bacteriuria in nephrotic syndrome.
AB  - Prevalence of covert bacteriuria in patients of nephrotic syndrome admitted for
      kidney biopsy was studied in 205 patients. Age ranged from 10 years to 65 years.
      148 patients were male and 57 were female. Prevalence of covert bacteriuria was
      found in 38 patients (18.53%). In bacteriuric patients 30 were male, 8 were
      female. Escherichia coli was the commonest organism grown in bacteriuric patients
      (30 or 78.9%). Serum albumin was low and 24-hour urinary protein excretion was
      high in bacteriuric patients in comparison to abacteriuric patients. In
      bacteriuric patients membranous nephropathy was the commonest histopathological
      finding present in 15 patients (39.47%).

PMID- 12593565
TI  - OSPE in pathology.
AB  - Undergraduate medical education is currently undergoing extensive re-evaluation
      with new core educational objectives being defined. Consequently, new exam
      systems have also been designed to test the objectives. Objective structured
      practical examination (OSPE) is one of them. We conducted OSPE in a regular batch
      of 64 students. The batch was divided into 4 groups, one group taking the
      conventional practical exam and the other groups OSPE with minor variations.
      Different aspects were compared and analyzed and we found that OSPE was more
      objective, measured practical skills better, had a wide discrimination index and
      eliminated examiner bias. The questionnaire given to the students revealed a high
      acceptance rate among them.

PMID- 12593566
TI  - Tumoural cysticercosis.
AB  - The unusual occurrence of very large cysticerci presenting as tumour-like lesions
      prompted this search of the pathology records of a south Indian hospital, to find
      similar cases. The maximum diameter of 187 consecutively diagnosed extraneural
      cysticerci, was recorded and those cases exceeding the mean by two standard
      deviations reviewed. Six biopsies showing cysticerci with a maximum diameter
      ranging from 4 to 11 cm, were identified, and hospital records and all
      pathological material available, were reexamined. The clinical differential
      diagnosis included benign and malignant tumours, hydatid cyst and haematoma. All
      the cysts were confirmed to be cysticerci, but species diagnosis was not possible
      by examining archival material. In an appropriate geographical setting, large
      cysticerci should form part of the differential diagnosis of cystic tumour-like
      lesions. An attemp can then be made, while the specimen is still fresh, to
      identify the species.

PMID- 12593567
TI  - Acanthamoeba adherence to soft contact lens and human corneal stroma.
AB  - In the present study, the adhesibility of Acanthamoeba castellani trophozoites
      and cysts to hydrogel contact lenses and to human cornea was investigated.
      Segments of unworn contact lenses were prepared (120 segments in total). In
      addition, 8 corneal buttons were obtained from 8 enucleated eyes. And each cornea
      cut into 8 radial segments. To these lens and corneal segments, 1.2 x 106/ml and
      1.3 x 106/ml of cysts and trophozoites respectively were added under varying
      conditions. The adhesion was checked at 0, 3 and 24 hours after the exposure.
      Adhesion analysis showed that the trophozoites adhered equally well to lens or
      cornea. There is an increase in the number of trophozoites adhering to contact
      lenses as well as cornea. This difference is more significant for contact lenses.
      Washing of contact lenses significantly decreased the adherence of the
      trophozoites after 3 hours of incubation. When the comparison of adhesion was
      done between the unwashed worn and unwashed unworn contact lenses, it was
      observed that there was a significant difference in adherence to new lenses where
      the adherence was much lower. The study shows that washing of contact lenses does
      decrease the chances of colonization by Acantamoeba catellani and also that older
      lenses have higher chances of getting colonized probably due to the occurrence of
      scratches et. on the surface which may help in colonization.

PMID- 12593568
TI  - Faecal lactoferrin assay as an adjunct to Clostridium difficile diarrhoea.
AB  - Inflammation is the hallmark of Clostridium difficile associated diarrhoea and
      lactoferrin is produced by inflammatory cells. The aim of this study was to find
      out whether faecal lactoferrin latex agglutination (FLLA) assay done
      simultaneously with Clostridium difficile toxin (CDT) assay would help in the
      diagnosis of C. difficile infection in paediatric patients. One hundred and fifty
      faecal samples were obtained from paediatric group of patients. Both FLLA and CDT
      assays were done in conjunction on these samples. The data were expressed by
      descriptive statistics. One hundred and nineteen patients received antibiotics
      while 31 did not receive it. Of the former group 89 (74.8%) had diarrhoea while
      30 (25.2%) did not have it. No significant relationship (p=0.287) was seen
      between antibiotic usage and occurrence of diarrhoea. However, CDT positivity was
      seen to be influenced by prior antibiotic usage as 51 (42.9%) patients receiving
      antibiotics were CDT positive when compared to 4 (7.3%) of those who did not
      receive antibiotics (p=0.002). A highly statistically significant (p<0.001)
      relationship was seen between CDT and FLLA positivity. FLLA appears to be an
      useful adjunct for C. difficile associated intestinal diseases in children when
      both the tests are done simultaneously and when other enteropathogens causing
      inflammatory diarrhoeas are ruled out.

PMID- 12593569
TI  - Role of IgM specific indirect immunofluorescence assay in diagnosing an outbreak
      of leptospirosis.
AB  - The study was conducted during a suspected epidemic of leptospirosis in
      Maharashtra. A total of 13 acute phase blood samples, collected at 5-6 days from
      the onset of symptoms, and 10 convalescent phase samples, colected at around 20
      days from the onset of symptoms were obtained from 13 patients. Sera were
      separated and the samples were subjected to Microagglutination Test (MAT) and IgM
      Indirect Immunofluorescence assay (IFA) to detect antibodies against leptospira.
      In the acute phase sera, only one sample was positive by MAT while seven were
      positive by IFA. In the convalescent samples, six were positive by MAT and seven
      were positive by IFA. IFA is a rapid test and can be used for early diagnosis of
      leptospirosis.

PMID- 12593570
TI  - Characterization, antibiotic susceptibility pattern and detection of beta
      lactamases in Enterococci.
AB  - One hundred strains of Enterococci obtained from various clinical specimens over
      a period of six months were speciated of which 56 were E. faecalis and 44 were E.
      faecium. Antimicrobial susceptibility pattern showed 90% of them were resistant
      to penicillin and 20% of them were resistant to vancomycin. Comparative
      evaluation of Beta-lactamase production by iodometric method and cloverleaf
      method showed that the latter was cost effective and easy to perform for routine
      use.

PMID- 12593571
TI  - Ultrastructural morphology of Helicobacter pylori in post vagotomy dyspepsia.
AB  - 31 patients of peptic ulcer (PU) treated in the past by vagotomy with
      Gastrojejunostomy (GJ)/pyloroplasty, later presented with dyspesia. These
      postvagotomy dyspeptic patients were investigated. Antral and corpus endoscopic
      biopsies were taken to evaluate for Helicobacter pylori (Hp) infection by inhouse
      rapid urease test (RUT), histopathological examination and scanning electron
      microscopy (SEM). Dyspepsia score was done in both pre and post treatment phase.
      Hp positive patients were randomised to receive anti H. pylori therapy. Hp
      eradication was recorded by repeat RUT and endoscopic biopsy followed by SEM.
      Coccoid form of Hp were detected in 76.92% cases of vagotomy with
      gastrojejunostomy (GJ) and coccobacillary forms of Hp were seen in 75% cases of
      pyloroplasty. After treatment with anti Hp therapy coccoid forms persisted in
      69.23% of GJ cases, whereas 22% of pyloroplasty cases showed coccoid
      transformation. Anti Hp therapy did not reveal any statistically significant
      improvement in 'Dyspepsia Score' in GJ group, whereas it improved significantly
      in pyloroplasty group (p=0.002).

PMID- 12593572
TI  - Histiocytic necrotizing lymphadenitis (Kikuchi Fujimoto Disease)--a report of
      four cases.
AB  - Four cases of histiocytic necrotizing lymphadenitis without granulocytic
      infiltration (Kikuchi-Fujimoto Disease) are described. All the cases were seen in
      young women who presented with cervical lymphadenopathy with mild or no fever.
      Histology of the lymphnode revealed paracortical necrotizing lesions with
      abundant karyorrhexis. Neutrophils were conspicuous by their absence. Diagnosis
      of Kikuchi-Fujimoto disease was considered after ruling out connective tissue
      disorders. Three of the four cases that were followed up showed a self-limiting
      course. It is important to differentiate this rare cause of febrile disease with
      enlargement of lymphnodes, from other causes of febrile disease with enlargement
      of lymphnodes, from other causes of lymphadenopathy, especially lymphoma.

PMID- 12593573
TI  - Primary breast sarcomas--report of two cases.
AB  - Two (2) primary breast sarcomas out of 110 primary breast malignancies from
      N.R.S. Medical College, Kolkata are being reported. Primary Breast Sarcomas are
      classified into five (5) broad groups with their representative features. Our two
      cases are classified as fibrosarcoma and malignant haemangioendothelioma and
      their features are documented. Because of its rarity, we are presenting this case
      with brief review of literature.

PMID- 12593574
TI  - Papillary cystic tumor of pancreas--report of two cases.
AB  - Two cases of Papillary cystic tumor of pancreas--one metastasizing to lymph node
      and the other non-metastasizing are reported for their rare occurrence. Both
      occurred in young females and presented with heaviness and pain in the left
      hypochondrium with palpable mass. On radiological examination, mass was arising
      from tail of pancreas and had typical gross features. The histological findings
      seen in metastasizing tumor were capsular invasion, infiltration to surrounding
      pancreatic tissue and vascular invasion with metastasis to lymph node. Difference
      in nuclear grade or mitosis was not observed. Adjuvant chemotherapy was given for
      metastasizing tumor and patient is symptom free after 56 month. Non-metastasizing
      case is well after 15 months.

PMID- 12593575
TI  - Choroid plexus papilloma of the fourth ventricle.
AB  - A 14 year old girl presented with a 6 months' history of headache with vomiting,
      ataxia and cerebellar signs. CT and MRI revealed obstructive hydrocephalus
      secondary to a large fourth ventricular mass which enhanced markedly on contrast
      administration. Histopathology of the resected mass revealed papillary structures
      lined by cuboidal cells confirming choroid plexus papilloma.

PMID- 12593576
TI  - Malignant melanoma metastatic to bone marrow.
AB  - Bone marrow aspiration and biopsy is a useful means of detecting systemic
      involvement in patients with non haematological malignancy. Metastases of
      malignant melanoma may be detected in the bone marrow in a small percentage of
      patients. Two cases of malignant melanoma, with metastasis to marrow at the time
      of presentation, are described. In one case, bone marrow was the first site where
      the malignancy was identified. Subsequent investigations revealed an anal
      melanoma. In the second case, the patient had widespread dissemination from a
      tonsillar melanoma to many organs of the body, including bone marrow.

PMID- 12593577
TI  - Extensive squamous metaplasia in nodular goiter--a diagnostic dilemma in the fine
      needle aspiration (FNA) cytology--a case report.
AB  - Metaplastic changes are commonly found at widespread locations occurring in both
      reactive and neoplastic conditions. They can simulate tumors histologically.
      Squamous metaplasia is rarely seen in areas of fibrosis and inflammation
      secondary to hemorrhage in nodular goiters. If it is extensive with associated
      degenerative changes and present clinically in the form of a nodule,
      cytopathologist must take care to differentiate this from primary or metastatic
      squamous cell carcinoma or even anaplastic carcinoma.

PMID- 12593578
TI  - Mucinous carcinoma of rectosigmoid in a 15-year-old child: a case report.
AB  - A 15-year-old girl with Duke's B mucinous carcinoma of the rectosigmoid was
      treated with surgical resection and adjuvant chemotherapy. The patient is alive
      and has been disease-free for 15 months. Colorectal carcinoma is extremely rare
      in children and adolescents. Adenocarcinoma of colon is a virulent disease in
      children and has a poor prognosis. This is because of the poor histological
      characteristics and difficulty in diagnosis.

PMID- 12593579
TI  - Inflammatory fibroid polyp of the jejunum presenting as intussusception.
AB  - Inflammatory fibroid polyp (IFP) of jejunnum is a rare nonneoplastic lesion of
      gastrointestinal tract. We report a case of a 45-year-old man presenting with
      small bowel obstruction due to jejuno-jejunal intussusception of an inflammatory
      fibroid polyp. To the best of our knowledges, this is the eighth reported case
      with such a presentation in English medical literature. Segmental resection of
      the jejunum was performed and histopathology confirmed the diagnosis.

PMID- 12593580
TI  - Hepatitis G virus (HGV): current perspectives.
AB  - Five viruses are usually associated with hepatitis in humans: A-E. In addition to
      these viruses as aetiological agents of hepatitis, there remain a number of
      patients with hepatitis in whom no virus could be identified. It was therefore
      postulated that there may be other agents which may be causing hepatitis.
      Recently, two viruses have been associated with hepatitis: hepatitis G virus
      (HGV), and transfusion transmissible virus (TTV). Hepatitis G virus (HGV) is a
      single stranded RNA virus which represents a newly discovered virus belonging to
      the flavivirus family. HGV is distinct from hepatitis C virus (HCV) and the newly
      discovered GBV-A and GBV-B agents, while GBV-C represents an isolate of HGV. The
      structure of the HGV genome resembles that of HCV. HGV replicates in peripheral
      blood cells, while replication in liver cells has not been observed till date.
      Diagnosis of HGV infection is mainly by use of polymerase chain reaction (PCR),
      as serological techniques are still being developed. Epidemiological data
      indicate that the virus is prevalent throughout the world, including India and is
      transmitted via blood/blood products, sexually and vertically from infected
      mothers to children. The relationship between infection with the virus and
      presence of liver pathology is controversial and has not been proven beyond
      doubt, as majority of patients with HGV have no detectable evidence of disease.

PMID- 12593581
TI  - Cyber-pathology: an introduction to Internet.

PMID- 12593582
TI  - Facts about artefacts in diagnostic pathology.
AB  - Literal meaning of artefact given by 'Oxford Advanced Learner Dictionary' is 'a
      thing made by people'. In medical science 'the fact' is not true; but we observe
      routinely is called artefact. We face various types of artefacts in daily
      reporting of pathology specimen. Many times artefacts hinder the actual
      diagnosis. The artefacts i. e. fixation artefact, processing artefact, staining
      artefact, mounting artefact, air bubbles etc. can cause difficulty in diagnosis
      and a pathologist should be trained to identify those artefacts.

PMID- 12593583
TI  - Age-dependent rates of infection of cassava green mites by a fungal pathogen in
      Brazil.
AB  - Age-specific effects of invertebrate pathogens on their hosts can greatly
      influence the population dynamics in such interactions. Explanations for such
      differences are usually sought within differing intrinsic susceptibilities of the
      host life stages but we present data which indicate that host size, behaviour and
      life history may be the overriding factors determining age-specific effects of a
      fungal pathogen, Neozygitesfloridana (Entomophthorales: Neozygitaceae) on spider
      mites (Mononychellus tanajoa Bondar, Acari: Tetranychidae). Epizootics of N.
      floridana in spider mites are characterised by much greater relative mortality of
      adult females compared with other life stages (ca. 99%), despite similar
      physiological susceptibilities. We present empirical data that demonstrate
      encounter rates of mites with N. floridana increasing with life stage during an
      epizootic on cassava in northeastern Brazil. Estimates of the size, walking
      speeds and patterns, and life history of different life stages (and adult sexes)
      were used to calculate expected relative encounter rates which were found not to
      be different from the observed values (although not testable for larvae). This
      helps explain the different apparent susceptibility of host life stages in the
      field. Given the low ecological susceptibility of younger life stages to this
      pathogen, we predict that the interaction time between host and pathogen,
      determined by climatic conditions, will be critical in determining the degree of
      host population control in an epizootic. We further hypothesise that such
      variation in ecological susceptibility to pathogens can generate selection
      pressures on basic host traits, contributing to the sessile nature of many
      microarthropods.

PMID- 12593584
TI  - Characterization of resistance to clofentezine in populations of European red
      mite from orchards in Ontario.
AB  - Resistance to clofentezine was identified in four populations of the European red
      mite, Panonychus ulmi (Koch), from apple orchards in Ontario after ca. 5 years
      use. Resistance was expressed at high levels (> 2000-fold at the LC 50) to
      clofentezine in a population selected in the laboratory. This population was
      resistant to hexythiazox and to the organotin compounds cyhexatin and fenbutatin
      oxide. However, a population selected with fenbutatin-oxide did not show cross
      resistance to clofentezine. The clofentezine-resistant population was not
      resistant to pyridaben, propargite or dicofol. The synergists, piperonyl butoxide
      and DEF, were ineffective in overcoming the resistance. Resistance to
      clofentezine declined rapidly in a mixed population (most resistance was lost in
      fewer than three generations). There were several fitness factors (fewer
      eggs/female, longer egg stage, longer development time for males) associated with
      the resistant population which may have contributed to the loss of resistant
      phenotypes. However, in a second test in which selection was removed from a
      resistant population, resistance persisted for at least 10 generations.
      Observations on field populations indicated that resistance persisted for at
      least two seasons.

PMID- 12593585
TI  - Effect of acaricide resistance on reproductive ability of the honey bee mite
      Varroa destructor.
AB  - The reproduction of pyrethroid-resistant Varroa destructor mite, a brood parasite
      of honey bees, was observed in Weslaco, Texas, and the results compared with
      known susceptible mite populations from other studies. Seven Apis mellifera
      colonies that had mite populations resistant to the acaricide Apistan were used.
      Pyrethroid-resistance was confirmed when only 17% rather than 90% of mites
      confined in dishes containing Apistan died after 12 h of exposure. The average
      number of eggs laid by resistant mites invading worker and drone cells was 4.4
      and 5.4 respectively. This is similar to the number of eggs laid by susceptible
      mites in worker (4.4-4.8) or drone (4.7-5.5) cells. Also the average number of
      fertilised V. destructor female mites produced by resistant mites in worker (1.0)
      and drone (2.1) cells were similar to the number produced by susceptible mites in
      worker (0.9) and drone (1.9-2.2) cells. In addition, no major differences between
      the resistant and susceptible mite populations were observed in either worker or
      drone cells when six different reproductive categories and offspring mortality
      rates were compared. Therefore, it appears that there is little or no
      reproductive fitness cost associated with pyrethroid resistance in V. destructor
      in Texas.

PMID- 12593586
TI  - Geographic variation in diapause response of adult Rhipicephalus appendiculatus
      ticks.
AB  - Diapause in adults of the African brown ear tick Rhipicephalus appendiculatus is
      dependent on latitude and stock origin. Lower latitude populations, that is,
      those nearer the equator, show no diapause response to long or short day
      exposure. Diapause response to short daylengths is found in higher latitude
      populations, further south, and increases with increasing latitude. Nearly all
      individuals in the southen most population, used in this study, enter diapause
      under short and long day exposure which implies that the onset of diapause in
      this population is obligatory. Diapause termination in higher latitude
      populations is induced by increasing photoperiod, further north, but still south
      of the equator, diapause is terminated by ageing. The differences in diapausing
      behaviour of the different populations are discussed in relation to their
      climatic conditions.

PMID- 12593587
TI  - The role of 2,6-dichlorophenol as sex pheromone of the tropical horse tick
      Anocentor nitens (Acari: Ixodidae).
AB  - The objective of this study was to evaluate the role of 2,6-dichlorophenol (2,6
      DCP) as sex pheromone of Anocentor nitens. Sex pheromones were extracted by
      submerging 150 female fed for 6 days in hexane (3 ml) for two hours and
      sonicating them for 15 min. The extract was analyzed by GC-MS employing the
      Single Ion Monitoring (SIM) method. Identification of 2,6-DCP was based on the
      comparison of mass spectra with a computer search using the NIST library and by
      matching the mass spectrum of the peak at the retention time of 2,6-DCP from
      extracts and the synthetic product. In an olfactometer, males were released at
      2.5 cm from females, control rubber septa and impregnated rubber septa with
      increasing concentrations of 2,6-DCP (50, 500 and 5000 ng). A higher percentage
      of orientation and higher frequencies of angles between 0 degrees and 10 degrees
      were observed for males tested with females than with controls. Attraction of
      males to dummies impregnated with 2,6-DCP was observed with highest response
      (100%) at 50 ng. There was a gradual decrease of responsiveness of males with
      increasing concentration of 2,6-DCP (70 to 75%). This compound stimulated a
      behavior of mounting and ventral positioning of A. nitens males at the lowest 2,6
      DCP concentration whereas dummies impregnated with 2.6-DCP higher than 50 ng
      concentration inhibited these behaviors. Therefore, we can conclude that 2.6-DCP
      can elicit the complete behavior sequence of orientation, location, mounting and
      ventral positioning behaviors and plays a role as an attractant and, as a
      mounting sex pheromone in A. nitens.

PMID- 12593588
TI  - Disaggregation of aggregated platelets by savignygrin, a alphaIIbeta3 antagonist
      from Ornithodoros savignyi.
AB  - Ticks control their host's hemostatic system by secretion of bioactive components
      during feeding that inhibit blood coagulation and platelet aggregation.
      Dissolution of platelets that have already aggregated can enhance control over
      the hemostatic system. It has been shown that disaggregation of aggregated
      platelets by the enzyme apyrase was accompanied by a shape change from the
      aggregated spherical form back to the discoid form associated with un-activated
      platelets. The present study concerns the disaggregation effect of the alpha
      IIb/beta3 antagonist, savignygrin. Aggregated platelets that were disaggregated
      by savignygrin and platelets pre-incubated with savignygrin before activation
      with ADP, retained a spherical form similar to platelets disaggregated by the
      fibrinogenolytic enzyme plasmin. The number of pseudopods were however, markedly
      reduced suggesting a disruption of the focal adhesion points that act as a
      localization point of alpha IIb/beta3. These results are concurrent with
      targeting of alpha IIb/beta3 and dissociation of fibrinogen from its receptor,
      once aggregation has taken place. This is the second mediator of platelet
      disaggregation found in soft ticks and suggests that disaggregation of aggregated
      platelets might play an important part in the anti-hemostatic strategy of ticks.

PMID- 12593589
TI  - Partial strategic tick control within a herd of European breed cattle in the
      state of Rio Grande do Sul, southern Brazil.
AB  - A trial is described, in the state of Rio Grande do Sul, southern Brazil, as one
      of a series suggested to investigate the effects of strategic but selective
      acaricide treatments of cattle within herds against Boophilus microplus. They are
      aimed at considering the repercussions of farmer attempts at immediate reductions
      in acaricide costs and the potential for creation of 'refugia' of untreated
      ticks. Half (Group 1) of a small experimental herd of European breed heifers were
      treated strategically against ticks, three times during the late spring-early
      summer and twice during autumn (southern hemisphere), with an injectable
      avermectin endectocide, designed to act directly against the first and third
      generations of parasitic B. microplus per 'cattle tick year' at this site,
      respectively. The consequent levels of infestations on all of the member cattle
      in their common pasture were monitored. Group 1 showed low to zero tick counts
      during the 28-day treatment interval periods and up to ca. 14 days after the last
      of such a series. Treated cattle, however, became re-infested outside of these
      periods and to levels that would be considered as unacceptable by farmers in the
      state. The untreated cattle (Group 2) showed infestations at generally higher
      levels, than their contemporaries, within and outside of the treatment periods.
      There were thus ample sources of larvae in the pasture, derived principally from
      falling, untreated engorged female ticks, re-infesting both the treated and
      untreated cattle. Advantages of maintaining chemically untreated cattle ticks
      within a herd, compared to their disadvantages as contaminants to classical
      strategic control procedures, merit re-evaluation, especially in relation to the
      recent, world-wide resurgence of acaricide resistance in B. microplus.

PMID- 12593590
TI  - Long-term results of guided tissue regeneration therapy in the treatment of class
      II furcation defects: a randomized clinical trial.
AB  - BACKGROUND: The purpose of this study was to evaluate the results after guided
      tissue regeneration (GTR) using a bioabsorbable membrane in Class II furcation
      defects in mandibular molars over a 24-month period. METHODS: Nine patients with
      2 comparable Class II furcation defects were included. The defects in each
      patient were randomly assigned to either test (GTR) or control (open flap
      debridement) group. Clinical measurements and standardized radiographs were taken
      at baseline, and at 6, 12, 18, and 24 months. The radiographs were analyzed by
      subtraction radiography. RESULTS: There were significant probing depth reductions
      for both test and control groups (P < 0.007, P < 0.0005, respectively); however
      the differences between groups were not significant at any examination. The intra
      group and inter-group differences in the vertical clinical attachment level gain
      were not significant (P > 0.05). Over 24 months, a significant horizontal
      clinical attachment level gain was observed in the test group compared to control
      (P<0.03). In the test group, 2 sites showed complete closure, one was converted
      to Class I, and one tooth was lost due to root resorption. In the control group,
      2 defects progressed to Class III over 24 months. At 6 months, the test group
      showed 0.14 mm of bone loss while the control group showed 0.86 mm of bone gain
      (P = 0.035). The inter-group differences were not significant at 12, 18, and 24
      months. A significant bone height gain was observed in the test group at 24
      months when compared to the values obtained after 6 months (P = 0.015).
      CONCLUSION: GTR may provide a greater horizontal clinical attachment level gain
      with the possibility of complete closure of some defects and stability over time.

PMID- 12593591
TI  - Defect-determined regenerative options for treating periodontal intrabony defects
      in baboons.
AB  - BACKGROUND: In an effort to regenerate periodontal intrabony defects, the healing
      potential of the defect should determine what therapeutic modalities and
      materials are employed. The purpose of this study was to compare regenerative
      outcomes in baboon intrabony defects that were contained versus non-contained,
      using various regenerative therapies. METHODS: Nine adult baboons (Papio anubis)
      in good health were treated. Eighty-six interproximal, intrabony defects were
      surgically created: 43 contained by 3 walls of bone; 43 non-contained with a
      missing buccal wall. Chronicity and plaque accumulation were encouraged with wire
      ligature placement for 8 weeks. After ligature removal, scaling, and a 2- to 4
      week healing period, the defects were treated with the following therapies:
      collagen membrane (GTR), human demineralized freeze-dried bone (DFDB) grafting
      (BG), combined therapy (GTR + BG) and a DFDB-glycoprotein sponge matrix (MAT).
      Clinical healing responses were evaluated in 58 sites by changes in soft tissue
      (recession, probing, clinical attachment) and hard tissue (resorption, defect
      fill) parameters 6 months post-treatment. Histologic evaluation (defect
      regeneration, connective tissue attachment, epithelial migration) was done on 26
      sites. RESULTS: For contained defects, no real significant clinical (ANOVA) or
      histologic differences existed among treatments. However, for non-contained
      defects, combined therapy (GTR + BG) demonstrated clinically significant (P < or
      = 0.05, ANOVA) and histologically superior healing results over the other
      therapies tested. CONCLUSION: These results confirm a defect morphology directed
      rationale for periodontal intrabony therapy.

PMID- 12593592
TI  - Clinical and microbiologic study of periodontitis associated with Kindler
      syndrome.
AB  - BACKGROUND: Little is known about the onset and prevalence of periodontal disease
      in patients with the rare Kindler syndrome, a genodermatological disorder. This
      study investigated the level of clinical periodontal attachment in relation to
      age and presence of putative periodontopathogenic bacteria in individuals with
      Kindler syndrome. METHODS: Eighteen individuals diagnosed with Kindler syndrome
      and 13 control subjects, aged 4 to 37 years, from rural Panama received a limited
      clinical periodontal examination. Subgingival samples were collected for
      identification of putative periodontal pathogens by polymerase chain reaction.
      RESULTS: Mild to severe gingivitis was a common finding in all adults of the
      study population. Seventy-two percent (13/18) of the Kindler patients and 46%
      (6/13) of the control subjects showed mild to severe periodontal disease (P =
      0.001, chi-square test). The onset of periodontitis was earlier and the
      progression occurred at a faster rate in the Kindler group. There was a strong
      correlation (r = 0.83) between the level of attachment loss and age in the
      Kindler group and a weaker correlation (r = 0.66) in the control group. The
      appearance of gingival tissues suggested atypical periodontitis with spontaneous
      bleeding and fragile, often desquamative, gingiva. In periodontitis patients,
      Porphyromonas gingivallis and Diallster pneumosintes tended to occur more
      frequently in control individuals compared to those with Kindler syndrome.
      CONCLUSIONS: In the Kindler group, periodontitis had an onset in early teenage
      years and progressed more rapidly compared to non-Kindler individuals of the same
      geographic and ethnic group. Clinical and microbiological findings suggest
      atypical periodontitis in Kindler patients. We propose to include Kindler
      syndrome in the category of medical disorders predisposing to destructive
      periodontal disease.

PMID- 12593593
TI  - The relationship between volatile sulfur compounds and major halitosis-inducing
      factors.
AB  - BACKGROUND: Although tongue coating and periodontal conditions have been reported
      to be major halitosis-inducing factors, the relationship between volatile sulfur
      compounds (VSC) and these 2 major factors is not yet fully understood. The aim of
      this study was to investigate the relationship of VSC concentrations to tongue
      coating and periodontal health. METHODS: Forty subjects (mean age 33.3 years,
      range 14 to 64 years) were enrolled in this study. Gas chromatography was
      performed to analyze each VSC component from the mouth air sampled prior to
      tongue scraping, after tongue scraping, and after a subsequent prophylaxis on the
      interdental spaces. RESULTS: CH3SH was the most malodorous component among the 3
      major VSC from the mouth air. The high CH3SH group showed a significantly higher
      organoleptic rating (P < 0.01), gingival index (P < 0.01), bleeding index (P <
      0.01), probing depth (P < 0.05), and VSC concentrations prior to tongue scraping
      (P < 0.01), except for the amount of tongue coating, compared to the low CH3SH
      group. All VSC concentrations were vastly reduced by tongue scraping in both
      groups, and the remaining contents were nearly all removed by the subsequent
      prophylaxis. The VSC contents produced by the tongue coating played a major role
      [H2S: 76%; CH3SH: 52%; (CH3)2S: 55%] in the low CH3SH group. In the high CH3SH
      group which had poor periodontal health, the tongue coating still played a major
      role [H2S: 67%; CH3SH: 59%; (CH3)2S: 48%], but the interdental spaces also
      contributed to VSC production [H2S: 26%; CH3SH: 32%; (CH3)2S; 36%]. CONCLUSIONS:
      The tongue coating was demonstrated to be a primary halitosis-inducing factor.
      Periodontal health was also shown to contribute to VSC production.

PMID- 12593594
TI  - Human monoclonal antibody inhibits Porphyromonas gingivalis hemagglutinin
      activity.
AB  - BACKGROUND: Porphyromonas gingivalis has been implicated as an important pathogen
      in the development of chronic periodontitis, and its colonization of subgingival
      sites is critical in the pathogenic process. One potential virulence factor,
      hemagglutinin, may mediate bacteria attachment onto and penetration into host
      cells, as well as agglutinate and lyse erythrocytes to intake heme, an absolute
      requirement for growth. We previously cloned the gene encoding the 130 kDa
      hemagglutinin domain (130k HMGD) and identified its functional domain. The
      construction of a human monoclonal antibody that is capable of inhibiting the
      hemagglutinating ability is significant and important toward the development of
      passive immunotherapy. METHODS: Human lymphocytes isolated from a donor, who had
      high antibody titer against the recombinant 130k HMGD (r130k HMGD), were
      immortalized by Epstein-Barr virus, and specific antibody-producing B cells were
      established by panning using the r130k HMGD. RESULTS: The constructed HuMAb
      HMGD1, IgG subclass, recognized the r130k HMGD as well as the 43 and 49 kDa major
      bands in P. gingivalis cells and vesicles. The HuMAb-HMGD1 significantly
      inhibited hemagglutinating activity of P. gingivalis vesicles in a dose-dependent
      manner. Furthermore, the HuMAb-HMGD1 recognized the synthetic peptide,
      EGSNEFAPVQNLTGSSVG, which contains the functional domain of 130k HMGD.
      CONCLUSION: The newly constructed HuMAb-HMGD1 may prove to be useful for the
      development of passive immunization against periodontal diseases caused by P.
      gingivalis infection, pending the results of fertility study in disease mode.

PMID- 12593595
TI  - The influence of alendronate on bone formation and resorption in a rat ectopic
      bone development model.
AB  - BACKGROUND: Most bone grafting techniques that include bone marrow, alloplastic
      materials, and extracellular bone matrix produce new bone mass, filling bone
      defects unpredictably. In most cases, the new bone undergoes resorption due to
      low local strains, resulting in significant bone loss. Recently, it was shown
      that alendronate and other bisphosphonates reduce bone loss when administered
      systemically or locally. The aim of this study was to investigate whether
      alendronate is effective on bone formation or bone resorption. METHODS: A total
      of 64 rats were divided into 2 main groups. In all the rats, fresh bone marrow
      removed from DA young rats was placed into demineralized rat femur cylinders
      (DBMC) and implanted into subcutaneous sites of host DA rats, to form new bone.
      Group A served as an alendronate treatment group, and group B served as a non
      treated control. Group A received 100 microl of 1.5 mg/ml alendronate solution at
      1, 2, and 3 weeks (group A1) and at 3, 4, and 5 weeks (group A2). At designated
      times, the rats were sacrificed, and the implanted DBMC was dissected out of the
      thorax and processed for histological and microradiography image analysis.
      RESULTS: Alendronate given at 1, 2, and 3 weeks (during the bone formation phase)
      did not increase the amount of bone or the visual bone density in comparison to
      the time-matched control, after 4 and 8 weeks. When alendronate was injected at
      3, 4, and 5 weeks, the bone mass increased by 70% and by 166% after 6 and 10
      weeks, respectively, in comparison to the untreated control. The visual bone
      density in group A2 was maintained at the level of 140 +/- 15 at 6 weeks and 152
      +/- 15 at 10 weeks. The matched, non-treated control group B2 was significantly
      lower, 106 +/- 20 and 108 +/- 15, respectively. The histological sections showed
      that alendronate treatment at 3, 4, and 5 weeks maintained the normal appearance
      of the ossicle at 6 and 10 weeks in comparison to the osteopenic bone appearance
      in the matched controls. CONCLUSIONS: This study suggests that alendronate is
      effective in inhibiting bone loss, but ineffective during the bone formation
      phase. We suggest, therefore, that alendronate should be administered in
      procedures where bone resorption is expected.

PMID- 12593596
TI  - Cyclosporin A-induced gingival overgrowth in renal transplant patients.
AB  - BACKGROUND: The incidence of gingival overgrowth (GO) associated with the use of
      cyclosporin A (CsA) is controversial. In the present study, we determined the
      incidence of GO in Brazilian renal transplant patients treated with CsA and the
      possible associations between periodontal and pharmacological variables. METHODS:
      The test group consisted of 20 renal transplant patients, and the control group
      included 20 non-transplant patients. Periodontal conditions were evaluated based
      on the plaque index (PI), gingival index (GI), probing depth (PD), and the rate
      of gingival overgrowth, together with pharmacological variables (daily CsA dose
      and duration of treatment). RESULTS: A significant difference in PI (P < 0.0001)
      and PD (P < 0.0001) was observed between groups, while GI (P = 0.15) did not
      differ significantly. Using the Pearson correlation coefficient, a significant
      correlation was observed not only between GI (P < 0.001; r = 0.8141) and GO, but
      also for PD (P < 0.001; r = 0.866) and GO. The other correlations were not
      statistically significant. CONCLUSIONS: We conclude that GO induced by CsA may
      vary according to the individual sensitivity of each patient and may or may not
      be correlated with other local factors (periodontal variables).

PMID- 12593597
TI  - Effects of selective cyclooxygenase-2 inhibition on gingival tissue levels of
      prostaglandin E2 and prostaglandin F2alpha and clinical parameters of chronic
      periodontitis.
AB  - BACKGROUND: The purpose of the present study was to evaluate the effect of a
      relatively selective cyclooxygenase (COX)-2 inhibitor (nimesulide) and non
      selective COX-1/COX-2 inhibitor (naproxen) used as an adjunct to non-surgical
      (scaling and root planing [SRP]) periodontal therapy in chronic periodontitis
      patients on the gingival tissue (GT) levels of prostaglandin (PG)E2 and
      PGF2alpha. METHODS: Thirty patients with chronic periodontitis were divided into
      3 groups of 10 each. One group received 100 mg of nimesulide; one received 275 mg
      of naproxen sodium; and the third group received placebo tablets in a 2 x 1
      regimen for 10 days as an adjunct to SRP. GT samples were obtained before drug
      intake and on day 10. Plaque index (PI) and papillary bleeding index (PBI) scores
      were recorded at baseline, day 10, and at 3 months; probing depth (PD) and
      clinical attachment level (CAL) were recorded at baseline and at 3 months. The
      levels of PGE2 were detected using an enzyme immunoassay (EIA), and the levels of
      PGF2alpha were analyzed by radioimmunoassay (RIA). Differences among and within
      the groups were assessed using non-parametric statistical analysis. Ten
      periodontally healthy individuals served as controls. RESULTS: All 3 groups
      showed statistically significant reductions in PBI and PI on day 10 and at 3
      months (P < 0.02), and in PD and CAL at 3 months (P < 0.02, P < 0.05,
      respectively). In the naproxen group, GT PGE2 levels exhibited a significant
      decrease (P < 0.05). However, the decrease of GT PGE2 levels in the nimesulide
      group was insignificant (P > 0.05), while a significant increase was observed in
      the placebo group (P < 0.05) on day 10. Both the nimesulide and naproxen groups
      showed a significant decrease (P<0.05) in PGF2alpha level, while the placebo
      group showed a significant increase (P<0.05). CONCLUSIONS: Nimesulides,
      relatively selective COX-2 inhibitors, may have additional inhibitory effects on
      GT PGF2alpha levels in the first week following non-surgical periodontal
      treatment. However, nimesulide has an insignificant effect on reducing PGE2
      levels in gingival tissue. The determination of GT levels of COX-1 and COX-2
      enzymes as well as PGE2 and PGF2alpha in long-term studies may provide further
      support for the adjunctive use of selective COX-2 inhibitors in treatment of
      chronic periodontitis.

PMID- 12593598
TI  - New directions in dentistry--the role of the National Institute of Dental and
      Craniofacial Research.

PMID- 12593599
TI  - Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings
      from localized aggressive periodontitis.
AB  - Neutrophils play a major role in the host response against invading
      periodontopathogenic microorganisms. Localized aggressive periodontitis (LAgP) is
      associated with various functional abnormalities of neutrophils. Based on the
      recent findings, LAgP neutrophils are not "hypofunctional" or "deficient." They
      are "hyperfunctional," and their amplified activity is responsible for the tissue
      destruction in periodontal disease. Several signal transduction abnormalities are
      associated with elevated neutrophil function in LAgP. There is a strong
      correlation between defective chemotaxis and decreased intracellular Ca2+ levels;
      total calcium-dependent protein Kinase C (PKC) activity of neutrophils is
      significantly lower than healthy subjects; and there is a marked increase in
      diacylglycerol (DAG) accompanied by a pronounced decrease in DAG kinase activity.
      In a separate set of experiments on the involvement of the inducible
      cyclooxygenase isoform (COX-2) and the role of novel lipid mediators in the
      pathogenesis of periodontal disease, crevicular fluid samples from LAgP patients
      were found to contain prostaglandin E2 (PGE2) and 5-LO-derived products,
      leukotriene B4 (LTB4), and the biosynthesis interaction product, lipoxin LXA4.
      Neutrophils from peripheral blood of LAgP patients, but not from healthy
      volunteers, also generated LXA4, suggesting that this immunomodulatory molecule
      may have a role in periodontal disease. Lipoxin generation and its relationship
      to PGE2 and LTB4 can be visualized as an important marker for the pathogenesis of
      periodontal disease. Thus, major advances in our understanding of the role of the
      neutrophil in host defense against periodontal organisms have been made through
      studies of LAgP. LAgP is used as an example of a severe periodontal disease that
      is related to abnormal neutrophil function. In this model, it appears that a
      hyperresponsiveness of the neutrophil, due to cell priming/predisposition,
      results in enhanced tissue damage.

PMID- 12593600
TI  - Neurotrophins in cultured cells from periodontal tissues.
AB  - We review the basic functions of neurotrophins and their receptors and discuss
      the expression and functions of neurotrophins and their specific receptors based
      on recent data using cultured cells from human periodontal tissues.
      Neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor
      (BDNF), and neurotrophin-3 (NT-3) play crucial roles in the differentiation and
      survival of neural cells. Neurotrophins activate 2 different receptor classes:
      the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA,
      TrkB, and TrkC) and the p75 receptor, a member of the tumor necrosis factor
      receptor superfamily. Neurotrophins regulate both cell death and cell survival
      through activations of Trk receptors and/or p75 neurotrophin receptor. It has
      been reported that neurotrophins are also produced from non-neuronal cells, such
      as leukocytes, osteoblasts, or fibroblasts, and act in many other ways on non
      neuronal cells. Neurotrophin expression during bone fracture healing is
      especially interesting, and neurotrophins are now implicated in hard tissue
      regeneration. It is well known that neurotrophins and their receptors are
      expressed in tooth development. Recent studies have found that neurotrophins and
      Trk receptors are expressed in mouse osteoblastic cell lines. Human periodontal
      ligament cells, human gingival fibroblasts, and human gingival keratinocytes
      expressed mRNA for NGF and TrkA. The secretion of bioactive NGF peptides from
      human periodontal ligament cells and human gingival keratinocytes was confirmed
      by bioassay using PC12 cells (rat adrenal pheochromocytoma cells). The expression
      of NGF and TrkA.mRNA was regulated by interleukin (IL)-1beta. NGF increased DNA
      synthesis and expressions of mRNA for bone-related proteins, alkaline
      phosphatase, and osteopontin in human periodontal ligament cells. Neurotrophins
      and Trk receptors expressed in human periodontal tissue may contribute to
      regeneration as well as innervation of periodontal tissue through local autocrine
      and paracrine pathways. Recent data suggest that some functions of neurotrophins
      and Trk receptors relate to periodontal disease and periodontal tissue
      regeneration. However, in vivo studies will be required to clarify the roles of
      neurotrophins and their receptors, including p75, in periodontal disease and
      periodontal tissue regeneration.

PMID- 12593601
TI  - Interactions of Porphyromonas gingivalis with host cells: implications for
      cardiovascular diseases.
AB  - BACKGROUND: Recent epidemiological studies have suggested a contribution of
      periodontitis in atherosclerotic diseases. Two mechanisms have been proposed to
      explain such a connection involving general inflammatory responses and/or
      specific effects of periodontal bacteria on host tissues. METHODS: The role of
      the periodontopathogen Porphyromonas gingivalis as a potential contributor to
      atherosclerosis has been investigated in model systems using human umbilical vein
      endothelial cells (HUVEC) and murine J774 macrophage cell cultures. RESULTS: P.
      gingivalis 381 was demonstrated to induce foam cell formation in J774 macrophage
      cell cultures in the presence of low-density lipoproteins. The active bacterial
      component involved in this process appears to be lipopolysaccharide. This effect
      was not limited to these organisms as several other Gram-positive and Gram
      negative oral bacteria exhibited the same property. In addition, in a more
      specific manner, P. gingivalis induced monocyte chemoattractant protein-1
      secretion in HUVEC cultures. CONCLUSIONS: The fimbriae of strain 381 are
      important, but are not required, for this inductive effect. Taken together, these
      results suggest a potential role for P. gingivalis in several steps involved in
      atherosclerotic lesion formation.

PMID- 12593602
TI  - Molecular interaction of Porphyromonas gingivalis with host cells: implication
      for the microbial pathogenesis of periodontal disease.
AB  - Porphyromonas gingivalis is a predominant periodontal pathogen, which expresses a
      number of potential virulence factors involved in the pathogenesis of
      periodontitis. Among them, fimbriae are a critical factor to mediate the
      bacterial interaction with host tissues, which promotes the bacterial adhesion to
      and invasion of the targeted sites. Fimbriae are capable of binding to human
      salivary components, commensal bacteria, and a variety of host cells including
      macrophages, epithelial cells, and fibroblasts. Human extracellular matrix (ECM)
      proteins such as vitronectin and fibronectin play important roles in cellular
      signal transduction via binding to receptor integrins. Fimbriae showed
      significant binding affinity to ECM proteins and clearly inhibited the molecular
      interactions between vitronectin/fibronectin and their receptor alphavbeta3 and
      alpha5beta1 integrins overexpressed on Chinese hamster ovary (CHO) cell strain.
      P. gingivalis fimbriae are likely to interrupt the cellular signaling via ECM
      proteins/integrins in periodontal regions. Fimbriae are also thought to be
      critically important in invasive events of the organism to host cells. The fimA
      genes, encoding FimA (a subunit of fimbriae), of P. gingivalis strains are
      classified into 5 types, I to V. Recent clinical investigations demonstrated the
      close relationship between the organisms with type II fimA and periodontitis
      development. Recombinant FimA (rFimA) proteins of types I to V were generated to
      compare their adhesion/invasion abilities to human gingival fibroblasts (HGF) and
      a human epithelial cell line (HEp-2 cells), respectively. There were no
      significant differences in the adhesion ability of microspheres (MS) coated with
      these rFimAs to HGF; however, the adhesion of type II rFimA-MS to HEp-2 cells was
      significantly greater than that of other rFimA types. It was also observed that
      the type II rFimA-MS markedly invaded the epithelial cells and accumulated around
      the nuclei. Collectively, these findings suggest that fimbriae of P. gingivalis,
      especially type II, are involved in the initiation and progression of human
      periodontitis.

PMID- 12593603
TI  - Periodontal disease and diabetes mellitus: the role of tumor necrosis factor
      alpha in a 2-way relationship.
AB  - It is generally accepted that obesity is associated with many other multiple-risk
      factor syndromes such as hypertension, hyperlipidemia, type 2 diabetes mellitus,
      and periodontal disease. The number of obese people is increasing rapidly in both
      western and eastern countries. Adipocytes in the adipose tissues of obese people
      produce large quantities of biologically active molecules such as leptin, an
      important molecule regulating energy expenditure and body weight. Therefore,
      adipocyte-derived active molecules, named adipocytokines, are candidate molecules
      accounting for the close association between obesity and other multiple-risk
      factor syndromes. The proinflammatory cytokine tumor necrosis factor-alpha (TNF
      alpha) is produced by adipocytes, and its blood concentration is elevated in
      obese patients and declines with weight loss. Studies have demonstrated that TNF
      alpha suppresses insulin action via its specific receptor; hence, it exacerbates
      insulin resistance. In addition to adipocytes, monocytes/macrophages produce
      large quantities of TNF-alpha. Thus, TNF-alpha, produced from monocytic cells due
      to inflammatory diseases, may have an additive influence on insulin sensitivity
      to adipocyte-derived TNF-alpha. Here, we hypothesized that 1) TNF-alpha produced
      by the adipose tissues of obese patients acts as a risk factor for periodontal
      inflammation, and 2) TNF-alpha produced due to periodontal inflammation may be an
      additional important factor influencing insulin sensitivity in both obese and
      type 2 diabetic patients. We believe that this interaction is a possible
      mechanism accounting for a 2-way relationship between type 2 diabetes and
      periodontal disease.

PMID- 12593604
TI  - Perspective of cytokine regulation for periodontal treatment: fibroblast biology.
AB  - Efforts to understand the pathogenesis of periodontal diseases have been underway
      for decades. Studies of immunological aspects in addition to the structural
      components of gingival fibroblasts showed that the fibroblasts actively
      participate in immune and inflammatory events in periodontal diseases. Future
      strategies for the prevention and treatment of periodontal diseases should
      biologically regulate fibroblast activities. These cells are surrounded by
      monocyte-derived proinflammatory cytokines such as interleukin-1 beta (IL-1beta),
      tumor necrosis factor-alpha (TNF-alpha), and lymphocyte-derived interleukin-6 (IL
      6) in inflamed gingival tissue. Recent anti-cytokine therapy for inflammatory
      diseases including rheumatoid arthritis aimed to inhibit the binding of cytokines
      to targeted cells such as fibroblasts and condrocytes. IL-1beta and TNF-alpha are
      thought to be therapeutic targets because these cytokines are essential for the
      initiation of inflammatory immune reactions and are produced for prolonged
      periods in inflammatory diseases. IL-6 is also a target, because it is abundantly
      present in inflammatory lesions and activates fibroblasts in the presence of
      soluble IL-6 receptor. In addition, these cytokines accelerate gingival
      fibroblasts to produce collagenolytic enzymes, resulting in tissue destruction.
      Soluble receptors for IL-1beta and TNF-alpha are suggested to be candidates for
      therapeutic molecules, but soluble receptor for IL-6 is suggested to be a factor
      stimulating fibroblast. This paper will review the utilization of soluble
      receptors specific to inflammatory cytokines which potentially stimulate
      fibroblasts to regulate biological events involved in the pathogenesis of
      periodontal diseases.

PMID- 12593605
TI  - The role of gingipains in the pathogenesis of periodontal disease.
AB  - Gingipains are trypsin-like cysteine proteinases produced by Porphyromonas
      gingivalis, a major causative bacterium of adult periodontitis. HRgpA (95 kDa)
      and RgpB (50 kDa), products of 2 distinct but related genes, rgpA and rgpB,
      respectively, are specific for Arg-Xaa peptide bonds. Kgp, a product of the kgp
      gene, is specific for Lys-Xaa bonds. HRgpA and Kgp are non-covalent complexes
      containing separate catalytic and adhesion/ hemagglutinin domains, while RgpB has
      only a catalytic domain with a primary structure essentially identical to that of
      the catalytic subunit of HRgp. HRgpA and RgpB induce vascular permeability
      enhancement through activation of the kallikrein/kinin pathway and activate the
      blood coagulation system, which, respectively, are potentially associated with
      gingival crevicular fluid production and progression of inflammation leading to
      alveolar bone loss in the periodontitis site. Kgp is the most potent
      fibrinogen/fibrin degrading enzyme of the 3 gingipains in human plasma and is
      involved in the bleeding tendency at the diseased gingiva. HRgpA activates
      coagulation factors and degrades fibrinogen/fibrin more efficiently than RgpB due
      to the adhesion/hemagglutinin domains, which have affinity for phospholipids and
      fibrinogen. Gingipains degrade macrophage CD14, thus inhibiting activation of the
      leukocytes through the lipopolysaccharide (LPS) receptor, and thereby
      facilitating sustained colonization of P. gingivalis. Gingipains play a role in
      bacterial housekeeping and infection, including amino acid uptake from host
      proteins and fimbriae maturation. Based on the important activities of gingipains
      in the bacterial infection and the pathogenesis of periodontitis, the bacterial
      proteinases can be targets for periodontal disease therapy. Immunization with
      RgpB, HRgpA, or a portion of HRgpA catalytic domain attenuated P. gingivalis
      induced disorders in mice. In addition, a trypsin-like proteinase inhibitor
      retarded P. gingivalis growth specifically. Gingipains are potent virulence
      factors of P. gingivalis, and are likely to be associated with the development of
      periodontitis. It is, therefore, suggested that gingipain inhibition by
      vaccination and gingipain-specific inhibitors is a useful therapy for adult
      periodontitis caused by P. gingivalis infection.

PMID- 12593606
TI  - Characterization of biologically active cell surface components of a periodontal
      pathogen. The roles of major and minor fimbriae of Porphyromonas gingivalis.
AB  - BACKGROUND: We previously reported that the presence of 2 different types of
      fimbriae expressed on the cell surface of Porphyromonas gingivalis ATCC 33277.
      The initial event in most infectious diseases involves adhesion of pathogens to
      host tissues and subsequent invasion by the pathogens. To define the role of
      fimbriae in Porphyromonas gingivalis adherence to and invasion of epithelial
      cells, we have constructed fimbrial mutants. The involvement of P. gingivalis
      fimbriae in the invasion process and alveolar bone resorption in rats was
      examined. METHODS: Inactivated mutants of 41-K fimbrillin gene (fimA) and/or the
      67-K fimbrillin gene (mfa1) were constructed by a homologous recombination
      technique and compared among fimA mutant (MPG1), mfa1 mutant (MPG67), and double
      knockout mutant (MPG4167). Adherence and invasion of P. gingivalis was assessed
      in human oral epithelial KB cells. We used a rat model to examine the role of
      each type of fimbriae in alveolar bone loss by oral infection. RESULTS: The
      adherence and invasion levels of the mutants were lower than the wild-type
      strain. The bone loss of rats infected with the MPG1 was higher than that of
      those infected with MPG67. Moreover, the bone loss of rats infected with the
      double knockout mutant was significantly decreased compared to that of rats
      infected with the wild-type strain. CONCLUSIONS: Data from this study suggest
      that not only the 41-K fimbrial protein, but also the 67-K fimbrial protein, play
      important roles in the pathogenesis of periodontal disease.

PMID- 12593607
TI  - Ecological and immunopathological implications of oral bacteria in Helicobacter
      pylori-infected disease.
AB  - Increasing evidence has linked colonization by Helicobacter pylori with the
      development of gastritis and peptic ulcer disease. H. pylori resides primarily in
      the gastric mucosa without invading the gastric epithelium, causing persistent
      mild gastric inflammation. There are many reports examining the relationship
      between colonization by microorganisms in the stomach and oral cavity. We found
      that some oral bacteria are able to trap H. pylori cells, but oral bacteria
      inhibit H. pylori growth in vitro. In cases where H. pylori was detected in oral
      cavity samples, including oral cancer surface samples, we suggested that this
      species had colonized the stomach and were present in the oral cavity only as a
      transient organism. We demonstrated that periodontopathic Campylobacter rectus
      strains posses proteinaceous antigens, including heat shock proteins that share
      antigenicity with antigens of H. pylori strains. These cross-reactive antigens
      between H. pylori and C. rectus may be related to the induction of
      immunopathological responses in periodontal tissues and the stomach. We concluded
      that H. pylori could not survive in the human oral cavity; however, there would
      be an interrelationship between periodontal disease due to C rectus and stomach
      diseases due to H. pylori.

PMID- 12593608
TI  - High prevalence of Helicobacter pylori detected by PCR in the oral cavities of
      periodontitis patients.
AB  - BACKGROUND: Helicobacter pylori has been associated with the development of
      peptic ulcers and gastric cancer. Although it may be transmitted through the oral
      cavity, it is unknown whether the oral cavity acts as a permanent reservoir for
      this bacterium. The purpose of this study was to use nested polymerase chain
      reaction (PCR) to clarify whether the oral cavity acts as a reservoir for H.
      pylori. METHODS: The existence of H. pylori in the oral cavity was determined by
      nested PCR in 57 subjects and by culture method in 18 subjects. The presence of
      periodontopathic bacteria was also determined by 16S rRNA-based PCR method.
      RESULTS: Although H. pylori was rarely detected in the oral cavity by culture
      technique, it was frequently detected (35.1%) by nested PCR in the oral cavity,
      especially among periodontitis patients who had the bacterium in the
      gastrointestinal tract (46.4%). Among the subjects who harbored H. pylori in the
      stomach or duodenum, 41.2% of patients with periodontal pockets > or = 4 mm and
      9.1% of subjects without pockets showed H. pylori in dental plaque, although a
      statistically significant difference was not observed. One patient who had
      periodontal pockets retained H. pylori in the oral cavity even after eradication
      of the bacterium from the stomach and duodenum. Most (8/10) of the patients who
      had H. pylori in dental plaque harbored Bacteroides forsythus in their oral
      cavities. CONCLUSION: Close attention should be given to periodontitis patients
      who harbor H. pylori in the oral cavity.

PMID- 12593609
TI  - Functional magnetic resonance imaging and control over the biceps muscle after
      intercostal-musculocutaneous nerve transfer.
AB  - OBJECT: Recent progress in the understanding of cerebral plastic changes that
      occur after an intercostal nerve (ICN)-musculocutaneous nerve (MCN) transfer
      motivated a study with functional magnetic resonance (fMR) imaging to map
      reorganization in the primary motor cortex. METHODS: Eleven patients with
      traumatic root avulsions of the brachial plexus were studied. Nine patients
      underwent ICN-MCN transfer to restore biceps function and two patients were
      studied prior to surgery. The biceps muscle recovered well in seven patients who
      had undergone surgery and remained paralytic in the other two patients. Maps of
      neural activity within the motor cortex were generated for both arms in each
      patient by using fMR imaging, and the active pixels were counted. The motor task
      consisted of biceps muscle contraction. Patients with a paralytic biceps were
      asked to contract this muscle virtually. The location and intensity of motor
      activation of the seven surgically treated arms that required good biceps muscle
      function were compared with those of the four arms with a paralytic biceps and
      with activity obtained in the contralateral hemisphere regulating the control
      arms. Activity could be induced in the seven surgically treated patients whose
      biceps muscles had regained function and was localized within the primary motor
      area. In contrast, activity could not be induced in the four patients whose
      biceps muscles were paralytic. Neither the number of active pixels nor the mean
      value of their activations differed between the seven arms with good biceps
      function and control arms. The weighted center of gravity of the distribution of
      activity also did not appear to differ. CONCLUSIONS: Reactivation of the neural
      input activity for volitional biceps control after ICN-MCN transfer, as reflected
      on fMR images, is induced by successful biceps muscle reinnervation. In addition,
      the restored input activity does not differ from the normal activity regulating
      biceps contraction and, therefore, has MCN acceptor qualities. After ICN-MCN
      transfer, cerebral activity cannot reach the biceps muscle following the normal
      nervous system pathway. The presence of a common input response between
      corticospinal neurons of the ICN donor and the MCN acceptor seems crucial to
      obtain a functional result after transfer. It may even be the case that a common
      input response between donor and acceptor needs to be present in all types of
      nerve transfer to become functionally effective.

PMID- 12593610
TI  - Use of proton magnetic resonance spectroscopy of the brain to differentiate
      gliomatosis cerebri from low-grade glioma.
AB  - OBJECT: Gliomatosis cerebri (GC), a rare entity characterized by a widespread
      infiltration of brain by tumor, lacks objective and quantitative diagnostic
      criteria. Single-voxel spectroscopy and chemical shift imaging (two-dimensional
      proton magnetic resonance [MR] spectroscopy) were performed using both short (20-
      or 22-msec) and long (135-msec) echo times in nine patients suffering from GC,
      nine patients with low-grade gliomas (LGGs), and 25 healthy volunteers to
      establish the precise metabolic pattern of this uncommon brain neoplasm. METHODS:
      The gliomatosis infiltration was characterized by markedly elevated levels of
      creatine-phosphocreatine (Cr) and mvo-inositol (Ins), a reduced level of N-acetyl
      aspartate (NAA), and a moderately elevated level of choline-containing compounds
      (Cho). This pattern differs strikingly from LGGs, which are characterized by
      elevated levels of Cho and Ins, markedly reduced levels of NAA, and low-to-normal
      Cr concentrations. Although the distinction between GC and LGG, based on
      histological and MR imaging criteria, is a matter of debate, MR spectroscopy
      produces valuable information for the differentiation between these two entities
      and, hence, the choice of therapeutic strategy. It also provides new insight into
      the pathophysiology of GC because elevated Cr and Ins levels may be related to
      proliferation of glial elements or, more probably, activation of normal glia.
      Elevated levels of Cho reflect cellular proliferation and reduced NAA corresponds
      to reversible neuronal injury and/or focal invasion by the tumor process.
      CONCLUSIONS: Owing to the unfavorable clinical outcome associated with GC
      compared with that associated with LGG, the findings of this study illustrate the
      diagnostic and prognostic value of proton MR spectroscopy in the characterization
      of infiltrating gliomas.

PMID- 12593611
TI  - Influence of shunt type on ventricular volume changes in children with
      hydrocephalus.
AB  - OBJECT: The goal of this study was twofold: to investigate the change in
      ventricular volume in children with hydrocephalus in response to shunt placement
      and to assess the effects of two different valve types (Medium Pressure [MP]
      cylindrical valve and Delta [model 1.5] valve). METHODS: Ventricular volume was
      measured using segmentation techniques on computerized tomography scans and
      magnetic resonance images obtained in 40 children with hydrocephalus who ranged
      in age from 4 days to 16 years. Imaging was performed preoperatively and at 5
      days and 3, 6, and 12 months postoperatively. The results were compared with
      measurements obtained in 71 healthy children ranging in age from 1 month to 15
      years. Each ventricular volume that was measured was divided by the corresponding
      sex and age-related mean normal volume to calculate the "x normal" ventricular
      volume, indicating how many times larger than normal the ventricle was. The mean
      preoperative ventricular volume was 232 cm3 (range 50-992 cm3). The mean
      postoperative volumes were 147, 102, 68, and 61 cm3 at 5 days and at 3, 6, and 12
      months posttreatment, respectively. The mean preoperative x normal ventricular
      volume was 14.5 (range 2.2-141.7), and the mean postoperative x normal volumes
      were 7.9, 5.6, 3.5, and 2.9 at 5 days and 3, 6, and 12 months postimplantation,
      respectively. The rate of volume reduction was consistently higher in patients
      who received the MP valve in comparison with those who received the Delta valve,
      both for new shunt insertions and for shunt revisions. The difference between the
      two valve groups did not reach statistical significance. Two patients in whom
      ventricular volumes increased during the study period experienced shunt
      obstruction at a later time. CONCLUSIONS: Preoperative ventricular volume in
      children with hydrocephalus can be up to 14 times greater than normal. In
      response to shunt placement, the ventricular volume continues to fall during the
      first 6 months after operation. The effect is more profound in children who
      receive the MP valve than in those who receive the Delta valve, although in this
      study the authors did not demonstrate statistical significance in the difference
      between the two valves. Nevertheless, this may indicate that the MP valve
      produces overdrainage in comparison with the Delta valve, even within the first
      few months after insertion. There is some indication that sequential ventricular
      volume measurement may be used to identify impending shunt failure.

PMID- 12593612
TI  - Lack of benefit of endoscopic ventriculoperitoneal shunt insertion: a multicenter
      randomized trial.
AB  - OBJECT: Endoscopically assisted ventricular catheter placement has been reported
      to reduce shunt failure in uncontrolled series. The authors investigated the
      efficacy of this procedure in a prospective multicenter randomized trial.
      METHODS: Children younger than 18 years old who were scheduled for their first
      ventriculoperitoneal (VP) shunt placement were randomized to undergo endoscopic
      or nonendoscopic insertion of a ventricular catheter. Eligibility and primary
      outcome (shunt failure) were decided in a blinded fashion. An intention-to-treat
      analysis was performed. The sample size offered 80% power to detect a 10 to 15%
      absolute reduction in the 1-year shunt failure rate. The authors studied 393
      patients from 16 pediatric neurosurgery centers between May 1996 and November
      1999. Median patient age at shunt insertion was 89 days. The baseline
      characteristics of patients within each group were similar: 54% of patients
      treated with endoscopy were male and 55% of patients treated without endoscopy
      were male; 30% of patients treated with and 26% of those without endoscopy had
      myelomeningocele; a differential pressure valve was used in 51% of patients with
      and 49% of those treated without endoscopy; a Delta valve was inserted in 38% of
      patients in each group; and a Sigma valve was placed in 9% of patients treated
      with and 12% of those treated without endoscopy. Median surgical time lasted 40
      minutes in the group treated with and 35 minutes in the group treated without
      endoscopy. Ventricular catheters, which during surgery were thought to be
      situated away from the choroid plexus, were demonstrated to be in it on
      postoperative imaging in 67% of patients who had undergone endoscopic insertion
      and 61% of those who had undergone nonendoscopic shunt placements. The incidence
      of shunt failure at 1 year was 42% in the endoscopic insertion group and 34% in
      the nonendoscopic group. The time to first shunt failure was not different
      between the two groups (log rank = 2.92, p = 0.09). CONCLUSIONS: Endoscopic
      insertion of the initial VP shunt in children suffering from hydrocephalus did
      not reduce the incidence of shunt failure.

PMID- 12593613
TI  - Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin.
AB  - OBJECT: The goal of this study was to ascertain the long-term effectiveness and
      safety of intrathecal baclofen (ITB) in the treatment of spasticity of cerebral
      origin in children and young adults. METHODS: A prospective, multicenter study
      was conducted in 68 patients who had been enrolled in the initial evaluation of
      ITB therapy and were willing to participate in long-term surveillance. Seventy
      three percent of the patients were younger than 16 years of age at the time of
      study entry. The patients were examined at least every 3 months and were observed
      for an average of 70 months. At each follow-up visit, spasticity in the upper and
      lower extremities was evaluated by applying Ashworth scores. All adverse events
      and complications were recorded on standardized data forms. Spasticity in both
      upper and lower extremities decreased significantly (p < 0.005) and remained
      decreased up to 10 years. The dosage of ITB increased from a mean of 157
      microg/day 3 months after pump insertion to 300 microg/day at 2 years
      postimplantation, and remained relatively stable thereafter. There were no
      significant differences in ITB dosage in children of different ages. Adverse
      events potentially related to ITB therapy occurred in 50% of patients within 2
      months after pump insertion and in 50% of patients thereafter; hypotonia and
      lethargy were the two most common adverse events. The most common complications
      of surgery were catheter-related problems (31%), seromas (24%), and cerebrospinal
      fluid leaks (15%). CONCLUSIONS: Intrathecal baclofen provides effective long-term
      treatment of spasticity of cerebral origin and its effects do not appear to
      diminish with time. This therapy is frequently associated with adverse side
      effects that usually can be alleviated by adjustments in dosage.

PMID- 12593614
TI  - Recovery from mild concussion in high school athletes.
AB  - OBJECT: A computerized neuropsychological test battery was conducted to evaluate
      memory dysfunction and self-reporting of symptoms in a group of high school
      athletes who had suffered concussion. METHODS: Neuropsychological performance
      prior to and following concussion was compared with the test performance of an
      age-matched control group. Potentially important diagnostic markers of concussion
      severity are discussed and linked to recovery within the 1st week of injury.
      CONCLUSIONS: High school athletes who had suffered mild concussion demonstrated
      significant declines in memory processes relative to a noninjured control group.
      Statistically significant differences between preseason and postinjury memory
      test results were still evident in the concussion group at 4 and 7 days
      postinjury. Self-reported neurological symptoms such as headache, dizziness, and
      nausea resolved by Day 4. Duration of on-field mental status changes such as
      retrograde amnesia and posttraumatic confusion was related to the presence of
      memory impairment at 36 hours and 4 and 7 days postinjury and was also related to
      slower resolution of self-reported symptoms. The results of this study suggest
      that caution should be exercised in returning high school athletes to the playing
      field following concussion. On-field mental status changes appear to have
      prognostic utility and should be taken into account when making return-to-play
      decisions following concussion. Athletes who exhibit on-field mental status
      changes for more than 5 minutes have longer-lasting postconcussion symptoms and
      memory decline.

PMID- 12593615
TI  - Apolipoprotein E polymorphism and outcome after closed traumatic brain injury:
      influence of ethnic and regional differences.
AB  - OBJECT: The presence of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele is
      reported to be associated with poor outcome after traumatic brain injury (TBI).
      This study was performed to determine if the presence of the APOE-epsilon4 allele
      influenced outcome in a cohort of black patients with TBI who had homogeneous
      neuropathological findings. METHODS: Venous blood was collected at the time of
      admission to determine the APOE genotype in black Zulu-speaking patients who
      presented with traumatic cerebral contusions. The frequency of the APOE-epsilon4
      allele's appearance was correlated with outcome at a minimum of 6 months of
      follow up. Univariate and multivariate analyses were performed to determine
      independent risk factors and to control for confounding factors. In 110 black
      Zulu-speaking patients with traumatic cerebral contusions, genotypes for APOE
      were analyzed. Eleven of 45 (24.4%) with the APOE-epsilon4 allele experienced a
      poor outcome, compared with 10 (15.4%) of 65 without this allele (p = 0.34). Both
      patients with homozygous APOE-epsilon4 alleles experienced a good outcome
      (Glasgow Outcome Score 5). Univariate and multivariate analysis revealed no
      significant relationship in patients with the APOE-epsilon4 allele with regard to
      age, admission Glasgow Comas Scale score, contusion volume, type of neurosurgical
      management, and outcome. The risk of a poor outcome was, however, greater in
      patients with the APOE-epsilon4 allele (relative risk 1.59; 95% confidence
      interval 0.74-3.42). CONCLUSIONS: The authors recorded no relationship between
      APOE-epsilon4 allele status and outcome after TBI in black patients. Given the
      high regional susceptibility to the APOE gene, further studies, possibly even
      community-based investigations and studies conducted in other geographic areas,
      are probably warranted.

PMID- 12593616
TI  - Brachial plexus injury: factors affecting functional outcome in spinal accessory
      nerve transfer for the restoration of elbow flexion.
AB  - OBJECT: Between 1994 and 1998, 44 nerve transfers were performed using a graft
      between a branch of the accessory nerve and musculocutaneous nerve to restore the
      flexion of the arm in patients with traumatic brachial plexus injuries. A
      retrospective study was conducted, including statistical evaluation of the
      following pre- and intraoperative parameters in 39 patients: 1) time interval
      between injury and surgery; and 2) length of the nerve graft used to connect the
      accessory and musculocutaneous nerves. METHODS: The postoperative follow-up
      interval ranged from 23 to 84 months, with a mean +/- standard deviation of 36 +/
      13 months. Reinnervation of the biceps muscle was achieved in 72% of the
      patients. Reinnervation of the musculocutaneous nerve was demonstrated in 86% of
      the patients who had undergone surgery within the first 6 months after injury, in
      65% of the patients who had undergone surgery between 7 and 12 months after
      injury, and in only 50% of the patients who had undergone surgery 12 months after
      injury. A statistical comparison of the different preoperative time intervals (0
      6 months compared with 7-12 months) showed a significantly better outcome in
      patients treated with early surgery (p < 0.05). An analysis of the impact of the
      length of the interposed nerve grafts revealed a statistically significant better
      outcome in patients with grafts 12 cm or shorter compared with that in patients
      with grafts longer than 12 cm (p < 0.005). CONCLUSIONS: Together, these results
      demonstrated that outcome in patients who undergo accessory to musculocutaneous
      nerve neurotization for restoration of elbow flexion following brachial plexus
      injury is greatly dependent on the time interval between trauma and surgery and
      on the length of the nerve graft used.

PMID- 12593617
TI  - Nerve transfers to the biceps and brachialis branches to improve elbow flexion
      strength after brachial plexus injuries.
AB  - OBJECT: In this study the authors evaluated the outcome in patients with brachial
      plexus injuries who underwent nerve transfers to the biceps and the brachialis
      branches of the musculocutaneous nerve. METHODS: The charts of eight patients who
      underwent an ulnar nerve fascicle transfer to the biceps branch of the
      musculocutaneous nerve and a separate transfer to the brachialis branch were
      retrospectively reviewed. Outcome was assessed using the Medical Research Council
      (MRC) grade to classify elbow flexion strength in conjunction with
      electromyography (EMG). The mean patient age was 26.4 years (range 16-45 years)
      and the mean time from injury to surgery was 3.8 months (range 2.5-7.5 months).
      Recovery of elbow flexion was MRC Grade 4 in five patients, and Grade 4+ in
      three. Reinnervation of both the biceps and brachialis muscles was confirmed on
      EMG studies. Ulnar nerve function was not downgraded in any patient. CONCLUSIONS:
      The use of nerve transfers to reinnervate the biceps and brachialis muscle
      provides excellent elbow flexion strength in patients with brachial plexus nerve
      injuries.

PMID- 12593618
TI  - Symptomatic vasospasm and outcomes following aneurysmal subarachnoid hemorrhage:
      a comparison between surgical repair and endovascular coil occlusion.
AB  - OBJECT: The authors studied patients with aneurysmal subarachnoid hemorrhage
      (SAH) to determine whether the incidence of symptomatic vasospasm or overall
      clinical outcomes differed between patients treated with craniotomy and clip
      application and those treated by endovascular coil occlusion. METHODS: The
      authors reviewed 415 consecutive patients with aneurysmal SAH who had been
      treated with either craniotomy and clip application or endovascular coil
      occlusion at a single institution between 1990 and 2000. Three hundred thirty
      nine patients underwent surgical clip application procedures, whereas 76 patients
      underwent endovascular coil occlusion. Symptomatic vasospasm occurred in 39% of
      patients treated with clip application, 30% of patients treated with endovascular
      coil occlusion, and 37% of patients overall. Compared with patients treated with
      clip application, patients treated with endovascular coil occlusion were more
      likely to suffer acute hydrocephalus (50 compared with 34%, p = 0.008) and were
      more likely to harbor aneurysms in the posterior circulation (53 compared with
      20%, p < 0.001). Logistic regression models controlling for patient age,
      admission World Federation of Neurosurgical Societies (WFNS) grade, acute
      hydrocephalus, aneurysm location, and day of treatment revealed that, among
      patients with an admission WFNS grade of I to III, endovascular coil occlusion
      carried a lower risk of symptomatic vasospasm (odds ratio [OR] 0.34, 95%
      confidence interval [CI] 0.14-0.8) and death or permanent neurological deficit
      due to vasospasm (OR 0.28, 95% CI 0.08-1) compared with craniotomy and clip
      application. Similar models revealed no difference in the likelihood of a Glasgow
      Outcome Scale score of 3 or less at the longest follow-up review (median 6
      months) between treatment groups (OR 0.58, 95% CI 0.28-1.21). CONCLUSIONS:
      Patients with better clinical grades (WFNS Grades I-III) at hospital admission
      were less likely to suffer symptomatic vasospasm when treated by endovascular
      coil occlusion, compared with craniotomy and clip application. Nevertheless,
      there was no significant difference in overall outcome at the longest follow-up
      examination between the two treatment groups.

PMID- 12593619
TI  - Diurnal and seasonal variations in the onset of primary intracerebral hemorrhage
      in individuals living in Izumo City, Japan.
AB  - OBJECT: Little is known about the temporal patterns of primary intracerebral
      hemorrhage (ICH) among the general population. The aim of this study was to
      examine diurnal and seasonal variations in the onset of ICH in a community-based
      series. METHODS: The study population consisted of 350 patients who presented
      with primary ICH for the first time and were treated between 1991 and 1998 in
      Izumo City, Japan. Among the entire patient population, the onset of hemorrhage
      was rarely observed during the night and a peak was observed in the late
      afternoon. In men 69 years of age or younger, the onset of ICH exhibited a
      bimodal distribution, with an initial high peak between 8:00 and 10:00 a.m. and a
      second, lower peak between 6:00 and 8:00 p.m. In contrast, in men 70 years of age
      or older and in women regardless of age, only a single evening peak, between
      approximately 6:00 and 10:00 p.m., was found, and no morning peak was observed.
      For the entire patient population (for both sexes), and for men alone, seasonal
      variations--a peak in winter and a trough in summer-were significant for all age
      groups combined. This factor was significant for patients 69 years of age or
      younger, during the daytime hours (8:00 a.m.-8:00 p.m.), and for patients with
      untreated hypertension; however, it was not significant for patients 70 years of
      age or older, during nighttime hours (10:00 p.m.-8:00 a.m.), or for treated
      hypertensive and normotensive patients. In women, no significant seasonal
      patterns were found, regardless of patient age, time of day at onset of ICH, or
      the presence of risk factors. Seasonal variations were statistically significant
      for patients with hematomas larger than 5 ml, but not for those with hematomas 5
      ml or smaller. CONCLUSIONS: Temporal distributions in the onset of ICH seem to be
      influenced by patient sex and age. The seasonal patterns of ICH occurrence may
      result mainly from changes that occur during the daytime, and may also be
      modified by the presence of untreated hypertension and by the volume of the
      hematoma.

PMID- 12593620
TI  - Salvage retreatment after failure of radiosurgery in patients with arteriovenous
      malformations.
AB  - OBJECT: The goal of this study was to evaluate the outcomes of patients who
      underwent repeated radiosurgery to treat a residual intracranial arteriovenous
      malformation (AVM) after an initial radiosurgical treatment failure. METHODS: The
      authors reviewed the cases of 52 patients who underwent repeated radiosurgery for
      residual AVM at the University of Florida between December 1991 and June 1998. In
      each case, residual arteriovenous shunting persisted longer than 36 months after
      the initial treatment; the mean interval between the first and second treatment
      was 41 months. Each AVM nidus was measured at the time of the original treatment
      and again at the time of retreatment, and the dosimetric parameters of the two
      treatments were compared. After retreatment, patients were followed up and their
      outcomes were evaluated according to a standard posttreatment protocol for
      radiosurgery for AVMs. The mean original lesion volume was 13.8 cm3 and the mean
      volume at retreatment was 4.7 cm3, for an average volume reduction of 66% after
      the initial treatment failure. Only two AVMs (3.8%) failed to demonstrate size
      reduction after the primary treatment. The median doses on initial and repeated
      treatment were 12.5 and 15 Gy, respectively. Five patients were lost to follow up
      and five refused neuroimaging follow up. One patient died of a hemorrhage shortly
      after retreatment. Of the remaining 41 patients, 24 had evidence of cure, 15 on
      angiographic studies and nine on magnetic resonance (MR) images. Seventeen had
      evidence of treatment failure, 10 on angiographic studies and seven on MR images.
      By angiographic criteria alone, the cure rate after retreatment was 60%, whereas
      according to angiographic and MR imaging results, the cure rate was 59%.
      CONCLUSIONS: Although initial radiosurgical treatment failed to obliterate the
      AVM in these 52 patients, it did produce a substantial therapeutic effect (volume
      reduction). This size reduction commonly allowed higher doses to be delivered
      during radiosurgical retreatment. The results show rates of angiographically
      confirmed cure comparable to primary treatment and a low incidence of
      complications, indicating that salvage radiosurgical retreatment is a safe and
      effective therapy in cases of failed AVM radiosurgery.

PMID- 12593622
TI  - Endonasal transsphenoidal approach for pituitary adenomas and other sellar
      lesions: an assessment of efficacy, safety, and patient impressions.
AB  - OBJECT: The direct endonasal approach performed with the aid of an operating
      microscope for removal of pituitary tumors has the potential advantage over the
      traditional sublabial route of minimizing postoperative rhinological
      complications, yet maintaining a high degree of efficacy and safety. To assess
      the effectiveness of this procedure, tumor remission rates and surgical
      complications were documented, and patients' postoperative complaints were
      recorded using a questionnaire. METHODS: One hundred consecutive patients
      underwent 109 endonasal operations for tumor removal. At a median follow-up
      period of 16 months (range 3-45 months), surgical remission rates were as
      follows: in 40 patients with endocrine-inactive macroadenomas, 95% for
      noninvasive and 40% for invasive tumors; in the 20 patients with prolactinomas,
      75% for prolactinomas with an initial prolactin (PRL) level lower than 200 ng/ml,
      33% for those with a PRL level between 200 and 600 ng/ml, and 0% for those with a
      PRL level higher than 1400 ng/ml; in the 15 patients with Cushing disease, 73%
      for microadenomas and 25% for macroadenomas; in the 10 patients with acromegaly,
      75% for microadenomas and 50% for macroadenomas; in the five patients with Rathke
      cleft cysts, 80%; and in the five patients with craniopharyngiomas, 40%. There
      were seven major surgical complications and no operative deaths. Among the 78
      patients who completed questionnaires (response rate 89%), the most common
      complaints concerned nasal packing (39%), removal of packing (36%), and mouth
      breathing (35%). At 3 months or longer after surgery, patients quantified
      sinonasal problems as follows: for facial pain, no problem in 83% and severe
      difficulty in 4%; for nasal congestion, no problem in 74%, and severe difficulty
      in 3%; for decreased nasal airflow, no problem in 77% and severe difficulty in
      4%; for decreased sense of smell, no problem in 73% and severe difficulty in 4%;
      and for upper-lip numbness, no problem in 87% and severe difficulty in 1%. Twelve
      (86%) of 14 patients who had undergone sublabial surgery previously preferred the
      endonasal approach in terms of pain and ease of recovery. CONCLUSIONS: The direct
      endonasal route for pituitary tumor removal has efficacy and complication rates
      comparable to those of the sublabial route. Patients generally recover rapidly
      from this minimally invasive procedure and have no or minimal sinonasal
      complaints. For patients requiring a repeated operation, the endonasal route
      appears to be less painful and easier to recover from than the sublabial route.
      Given the minimal nasal mucosal dissection required and the frequent patient
      complaints related to nasal packing, use of packing is no longer used for this
      procedure.

PMID- 12593621
TI  - Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long
      term outcomes and prognostic factors influencing survival and local tumor
      control.
AB  - OBJECT: Renal cell carcinoma is a leading cause of death from cancer and its
      incidence is increasing. In many patients with renal cell cancer, metastasis to
      the brain develops at some time during the course of the disease. Corticosteroid
      therapy, radiotherapy, and resection have been the mainstays of treatment.
      Nonetheless, the median survival in patients with renal cell carcinoma metastasis
      is approximately 3 to 6 months. In this study the authors examined the efficacy
      of gamma knife surgery in treating renal cell carcinoma metastases to the brain
      and evaluated factors affecting long-term survival. METHODS: The authors
      conducted a retrospective review of 69 patients undergoing stereotactic
      radiosurgery for a total of 146 renal cell cancer metastases. Clinical and
      radiographic data encompassing a 14-year treatment interval were collected.
      Multivariate analyses were used to determine significant prognostic factors
      influencing survival. The overall median length of survival was 15 months (range
      1-65 months) from the diagnosis of brain metastasis. After radiosurgery, the
      median survival was 13 months in patients without and 5 months in those with
      active extracranial disease. In a multivariate analysis, factors significantly
      affecting the rate of survival included the following: 1) younger patient age (p
      = 0.0076); 2) preoperative Karnofsky Performance Scale score (p = 0.0012); 3)
      time from initial cancer diagnosis to brain metastasis diagnosis (p = 0.0017); 4)
      treatment dose to the tumor margin (p = 0.0252); 5) maximal treatment dose (p =
      0.0127); and 6) treatment isodose (p = 0.0354). Prior tumor resection,
      chemotherapy, immunotherapy, or whole-brain radiation therapy did not correlate
      with extended survival. Postradiosurgical imaging of the brain demonstrated that
      63% of the metastases had decreased, 33% remained stable, and 4% eventually
      increased in size. Two patients (2.9%) later underwent a craniotomy and resection
      for a tumor refractory to radiosurgery or a new symptomatic metastasis. Eighty
      three percent of patients died of progression of extracranial disease.
      CONCLUSIONS: Stereotactic radiosurgery for treatment of renal cell carcinoma
      metastases to the brain provides effective local tumor control in approximately
      96% of patients and a median length of survival of 15 months. Early detection of
      brain metastases, aggressive treatment of systemic disease, and a therapeutic
      strategy including radiosurgery can offer patients an extended survival.

PMID- 12593623
TI  - Growth pattern and rate in residual nonfunctioning pituitary adenomas:
      correlations among tumor volume doubling time, patient age, and MIB-1 index.
AB  - OBJECT: Surgical cure can be achieved in pituitary adenomas when they are
      completely removed. It is controversial whether postoperative radiation therapy
      should be given to prevent recurrence, and whether an early reoperation should be
      performed for residual adenomas, because we have little information about the
      natural history of postoperative residual adenomas. METHODS: The residual tumor
      volume was serially measured in 40 nonfunctioning pituitary adenomas (NFPAs) and
      the tumor volume doubling time (TVDT) was calculated. Correlations between the
      patients' age, tumor volume, log TVDT, and MIB-1 index were examined. Other
      factors including the patient's sex, cavernous sinus (CS) invasion by the tumor,
      or presence of an intratumoral cyst were analyzed to assess their influence on
      the TVDT. Values are expressed as the means +/- standard deviations. Thirty-eight
      adenomas increased in volume and two decreased during a follow-up period ranging
      from 4 to 141 months (mean 52.5 months). Exponentially linear tumor growth was
      observed in the 38 growing adenomas regardless of the residual tumor volume, with
      the TVDT ranging from 506 to 5378 days (mean 1836 days). The patients' age was
      57.1 +/- 15.7 years (range 15-79 years), the tumor volume at the beginning of the
      magnetic resonance imaging observation period was 2.5 +/- 2.2 cm3 (range 0.07
      14.5 cm3), and the MIB-1 index was 0.73 +/- 0.68% (range 0.1-2.9%). There was a
      correlation between the log TVDT and patient age (R = 0.73), an inverse
      correlation between the log TVDT and MIB-1 index (r = -0.49), and an inverse
      correlation between the MIB-1 index and patient age (r = -0.61). A significant
      difference (p = 0.0001) was noted between the TVDT (1,106 days) in the 19
      patients younger than 61 years of age and the TVDT (2566 days) in the 19 patients
      who were 61 years of age or older. There was also a significant difference (p =
      0.0002) between the age (50.8 +/- 15.3 years) of the patients with rapidly
      growing tumors (TVDT < 1,836 days, 24 patients) and the age (69.1 +/- 7.6 years)
      of the patients with slowly growing tumors (TVDT> 1836 days, 14 patients). Other
      factors including the patients' sex, CS invasion, and intratumoral cyst formation
      did not affect the TVDT of residual NFPAs. CONCLUSIONS: The tumor growth rate of
      residual NFPAs is strongly influenced by the patient's age. The TVDT in elderly
      patients is much longer than that previously reported. Treatment strategies that
      take into consideration the natural history of residual adenomas should be
      established especially in the elderly population.

PMID- 12593624
TI  - Surgical handling characteristics of an ethylene vinyl alcohol copolymer compared
      with N-butyl cyanoacrylate used for embolization of vessels in an arteriovenous
      malformation resection model in swine.
AB  - OBJECT: There have been significant improvements in neurovascular technology and
      implants over the past decade. One such material, N-butyl cyanoacrylate (NBCA),
      is now commercially available for cerebral arteriovenous malformation (AVM)
      embolization in the US. An ethylene vinyl alcohol copolymer preparation, Onyx,
      which is currently being evaluated, is approved for use outside North America.
      Although reports indicate that Onyx may be superior to NBCA from an endovascular
      perspective, little information exists about its surgical handling
      characteristics. The purpose of this study was to compare the surgical handling
      characteristics of Onyx-treated vessels with those of NBCA-embolized vessels in
      an AVM resection model. METHODS: Fourteen pigs (two groups of seven) were
      anesthetized. A femoral artery was cannulated, followed by selective
      catheterization of the ascending pharyngeal arteries. Nidal rete mirabile (RM)
      embolizations were performed using either 6% Onyx or 20% NBCA. After
      angiographically confirmed obliteration of flow in the right RM, microsurgical
      resection of this structure was performed. Surgical handling characteristics of
      the embolized RM were rated on a scale of 1 to 5 and blood loss was recorded.
      Different surgeons performed the embolizations and resections. The surgeon who
      performed resections was blinded to the embolization agent used, and the data
      analysis was also performed in a blinded fashion. The surgical handling scores
      were superior (p < 0.05) in the Onyx-treated group. Although there was also less
      blood loss in this group, the difference was not significant. Subjectively, the
      surgeon who performed the resections believed that Onyx was softer and handled
      better than NBCA. CONCLUSIONS: Onyx, which may offer endovascular advantages,
      also seems to provide benefits for the surgeon.

PMID- 12593625
TI  - Effects of human amniotic fluid on peripheral nerve scarring and regeneration in
      rats.
AB  - OBJECT: Peripheral nerve repair surgery is still replete with challenges. Despite
      technical improvements in microsurgery, classic methods of nerve repair have
      failed to provide satisfactory results. The purpose of this study was to
      investigate the effects of amniotic fluid from humans on peripheral nerve
      scarring and regeneration in rats. METHODS: Forty adult Sprague-Dawley rats were
      used in this study. After the right sciatic nerve in each rat was transected and
      repaired using an epineural suture procedure, the nerves were divided into two
      groups according to the solution applied around the repair site: experimental
      group, 0.3 ml human amniotic fluid (HAF); and control group, 0.3 ml saline.
      Macroscopic and histological evaluations of peripheral nerve scarring were
      performed 4 weeks postsurgery. Nerves treated with HAF demonstrated a significant
      reduction in the amount of scar tissue surrounding the repair site (p < 0.05). No
      evidence of a reaction against HAF was noted. Functional nerve regeneration was
      measured once every 2 weeks by using a sciatic function index until 12 weeks
      postsurgery. Functional recovery in nerves treated with amniotic fluid occurred
      significantly faster than that in nerves treated with saline (p < 0.05).
      Peripheral nerve regeneration was evaluated histomorphologically at 12 weeks
      postsurgery. Nerves treated with amniotic fluid showed significant improvement
      with respect to the indices of fiber maturation (p < 0.05). CONCLUSIONS:
      Preliminary data show that HAF enhances peripheral nerve regeneration. The
      preventive effect of HAF on epineural scarring and the rich content of
      neurotrophic and neurite-promoting factors possibly contribute to this result.

PMID- 12593626
TI  - Molecular response of human glioblastoma multiforme cells to ionizing radiation:
      cell cycle arrest, modulation of the expression of cyclin-dependent kinase
      inhibitors, and autophagy.
AB  - OBJECT: Ionizing radiation is the gold-standard adjuvant treatment for
      glioblastoma multiforme (GBM), the most aggressive primary brain tumor. The
      mechanisms underlying neoplastic glial cell growth inhibition after
      administration of ionizing radiation, however, remain largely unknown. In this
      report, the authors characterize the response of GBM cells to ionizing radiation
      and elucidate factors that correlate with the radiosensitivity of these tumors.
      METHODS: Six human GBM cell lines were subjected to increasing doses of
      radiation. Each demonstrated a dose-dependent suppression of cell proliferation.
      In the most radiosensitive cell line, the authors demonstrated a transient
      increase in the expression of the cyclin-dependent kinase inhibitors (CDKIs) p21
      and p27, which corresponded with a G1 cell-cycle arrest. In contrast, the most
      radioresistant cell line demonstrated a decrease in p21 and p27 expression
      levels, which correlated with a failure to arrest. Apoptosis did not occur in any
      cell line following irradiation. Instead, autophagic cell changes were observed
      following administration of radiation, regardless of the relative
      radiosensitivity of the cell line. CONCLUSIONS: These findings elucidate some of
      the molecular responses of GBMs to irradiation and suggest novel targets for
      future therapy.

PMID- 12593627
TI  - Cytotoxicity in glioma cells due to interleukin-12 and interleukin-18-stimulated
      macrophages mediated by interferon-gamma-regulated nitric oxide.
AB  - OBJECT: Interleukin (IL)-12 and IL-18 synergistically mediate antitumor responses
      through the production of interferon-gamma (IFNgamma) by T and natural killer
      (NK) cells. Recently, it has been reported that macrophages stimulated with these
      cytokines also produce IFNgamma, which led the authors to investigate the
      antiglioma activity of macrophages stimulated by the combination of these
      cytokines in vitro. METHODS: Dish-adherent peritoneal exudate cells, which had
      been elicited in thioglycollate broth as a source of macrophages, were used in
      the experiment. The murine glioma cell lines VM-glioma and 203G were labeled with
      [3H]thymidine for a cytotoxicity assay of macrophages. In response to the
      combined stimulation by IL-12 and IL-18, macrophages expressed potent cytotoxic
      activity against glioma cells in association with increasing production of
      IFNgamma and nitric oxide (NO). Inhibitors of NO abrogated the cytotoxic activity
      of the macrophages, which had been induced by IL-12 and IL-18, despite the
      increase in IFNgamma production. Neutralization of IFNgamma or use of macrophages
      obtained from IFNgamma gene-knockout mice markedly reduced not only cytotoxic
      activity, but also NO production. Depletion of T and NK cells from the macrophage
      population, which was achieved using antibody plus complement treatment, slightly
      reduced macrophage activities, suggesting that these are the main effector cells,
      although T and NK cells may partially participate in this cytotoxicity.
      CONCLUSIONS: Macrophages stimulated with IL-12 and IL-18 produced IFNgamma and
      NO, which in turn mediated the antiglioma response. Therefore, macrophages as
      well as T and NK cells play an important role in antitumor responses stimulated
      by IL-12 and IL-18.

PMID- 12593628
TI  - Neuroprotection by the stable nitroxide 3-carbamoyl-proxyl during reperfusion in
      a rat model of transient focal ischemia.
AB  - OBJECT: Nitroxides mimic superoxide dismutase (SOD) biochemically and may prevent
      free radical oxidative injury in settings in which endogenous SOD is overwhelmed.
      The authors have previously shown the efficacy of a nitroxide, Tempol, in
      reducing stroke infarct size. Of the nitroxides, 3-carbamoyl-proxyl (3-CP) is
      especially promising for clinical use, because it does not cause hypotension in
      animals. Its efficacy in brain ischemia, however, is untested. The goal of this
      study was to ascertain whether 3-CP would reduce brain damage in a rat ischemia
      reperfusion model. METHODS: The authors performed a blinded, dose-response study
      of the effect of different amounts of 3-CP (1, 10, and 100 mg/kg) on infarct size
      at 24 hours after focal ischemia and reperfusion. The 3-CP was given
      intravenously during reperfusion, which followed 1 hour of reversible ischemia
      induced by a thread placed intraluminally in the middle cerebral artery of rats.
      Brain infarcts, measured with 2,3,5-triphenyltetrazolium chloride staining in six
      3-CP groups, were compared with those measured in controls (animals given an
      equal volume of saline). Edema-corrected infarct sizes (mean +/- standard
      deviation) were as follows: 146 +/- 64 mm3 in controls; 107 +/- 18 mm3 in rats
      given 1 mg/kg 3-CP; 40 +/- 20 mm3 in those given 10 mg/kg 3-CP; and 44 +/- 17 mm3
      in those given 100 mg/kg 3-CP. A statistically significant reduction in infarct
      size was achieved in the 10- and 100-mg/kg 3-CP-treated groups (p < 0.01). A
      reduction in infarct size was also seen in the 1 mg/kg 3-CP-treated group, but
      this did not reach statistical significance. The authors observed no effects of 3
      CP on blood pressure or brain temperature. CONCLUSIONS: Given at reperfusion, 3
      CP significantly decreases brain infarct size at doses of 10 and 100 mg/kg
      without causing hypotension. The authors found that 3-CP is well suited for
      further laboratory and clinical use in brain ischemia and reperfusion.

PMID- 12593629
TI  - Reduced brain infarct volume and improved neurological outcome by inhibition of
      the NR2B subunit of NMDA receptors by using CP101,606-27 alone and in combination
      with rt-PA in a thromboembolic stroke model in rats.
AB  - OBJECT: A novel postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors,
      CP-101,606-27 may attenuate the effects of focal ischemia. In current
      experiments, the authors investigated its neuroprotective effect alone and in
      combination with recombinant tissue plasminogen activator (rt-PA) in
      thromboembolic focal cerebral ischemia in rats. METHODS: Forty-eight male Wistar
      rats underwent embolization of the right middle cerebral artery to produce focal
      cerebral ischemia. After random division into six groups (eight rats in each
      group), animals received: vehicle; low-dose (LD) CP-101, 606-27, 14.4 mg/kg; high
      dose (HD) CP- 101,606-27, 28.8 mg/kg; rt-PA, 10 mg/kg; low-dose combination (LDC)
      CP- 101,606-27, 14.4 mg/kg plus rt-PA, 10 mg/kg; or high-dose combination (HDC)
      CP- 101,606-27, 28.8 mg/kg plus rt-PA, 10 mg/kg) 2 hours after induction of
      embolic stroke. Animals were killed 48 hours after the onset of focal ischemia.
      Brain infarction volume, neurobehavioral outcome, poststroke seizure activity,
      poststroke mortality, and intracranial hemorrhage incidence were observed and
      evaluated. Compared with vehicle-treated animals (39.4 +/- 8.6%) 2 hours
      posttreatment with CP-101,606-27 or rt-PA or in combination a significant
      reduction in the percentage of brain infarct volume was seen (LD CP-101,606-27:
      20.8 +/- 14.3%, p < 0.05; HD CP-101,606-27: 10.9 +/- 3.2%, p < 0.001; rt-PA: 21.1
      +/- 7.3%, p < 0.05; LDC, 18.6 +/- 11.5%, p < 0.05; and HDC: 15.2 +/- 10.1%, p <
      0.05; compared with control: 39.4 +/- 8.6%). Combination of CP-101,606-27 with rt
      PA did not show a significantly enhanced neuroprotective effect. Except for the
      control and LDC treatment groups, neurobehavioral outcome was significantly
      improved 24 hours after embolic stroke in animals in all other active therapeutic
      groups receiving CP-101,606-27 or rt-PA or in combination. The authors also
      observed that treatment with HD CP-101,606-27 decreased poststroke seizure
      activity. CONCLUSIONS: The data in this study suggested that postischemia
      treatment with CP-101,606-27 is neuroprotective in the current stroke model;
      however, the authors also note that although rt-PA may offer modest protection
      when used alone, combination with CP-101,606-27 did not appear to enhance its
      effects.

PMID- 12593630
TI  - Distinctions between pituicytoma and ordinary pilocytic astrocytoma. Case report.
AB  - The authors present a rare case of pituicytoma. A dynamic magnetic resonance
      study performed after Gd injection revealed a markedly, homogeneously enhanced,
      early-phase pituitary lesion in a 32-year-old woman with a 1-year history of
      amenorrhea. The tumor bled easily during transsphenoidal resection. The lesion
      consisted of plump spindle cells and lacked Rosenthal fibers and granular bodies,
      and thus was different from ordinary pilocytic astrocytoma or any other form of
      this tumor. Although pituicytoma is often confused with pilocytic astrocytoma
      when it appears in the sellar region, these two kinds of gliomas should be
      distinguished on the basis of histological differences.

PMID- 12593631
TI  - Continued growth of and increased symptoms from a thrombosed giant aneurysm of
      the vertebral artery after complete endovascular occlusion and trapping: the role
      of vasa vasorum. Case report.
AB  - A 58-year-old woman harboring a partially thrombosed giant aneurysm of the
      vertebral artery (VA) presented with lower cranial nerve palsies and cerebellar
      ataxia. The authors initially attempted to reduce the mass effect by obliterating
      the lumen of the aneurysm as well as by trapping of the parent artery with coils.
      Although there was no angiographically demonstrated evidence of filling, the
      aneurysm continued to enlarge. Magnetic resonance imaging revealed a marked
      enhancement around the packed coils close to the neck of the aneurysm.
      Aneurysmectomy and removal of the coils were performed and resulted in an almost
      complete cure of the patient's symptoms. Interestingly, at the time of resection,
      a marked development of vasa vasorum on the occluded VA and the neck of the
      aneurysm was noted. When the occluded VA was cut, there was blood oozing through
      the coils packed within its lumen on the side where the aneurysm lay.
      Histological examination showed the presence of inflammatory cells and
      neovascularization of a partially organized thrombus around the packed coils in
      both the aneurysm and occluded VA. The proliferation of vasa vasorum was also
      recognized histologically. This unique case provides insight into the growth
      mechanisms of a partially thrombosed giant aneurysm after an apparently complete
      occlusion by endovascular treatment, especially the role of vaso vasorum on the
      occluded parent artery in the dynamic process of neovascularization in the
      incomplete organization of thrombus around the packed coils.

PMID- 12593632
TI  - Disappearance of self-mutilating behavior in a patient with lesch-nyhan syndrome
      after bilateral chronic stimulation of the globus pallidus internus. Case report.
AB  - Lesch-Nyhan syndrome (LNS) is an X-linked hereditary disorder caused by a
      deficiency of hypoxanthine-guanine phosphoribosyltransferase. Patients with this
      syndrome are characterized by hyperuricemia, self-mutilation, developmental
      retardation, and movement disorders such as spasticity and dystonia. The authors
      performed bilateral chronic stimulation of the globus pallidus internus for
      control of dystonic movements in a 19-year-old man with LNS. His self-mutilating
      behavior unexpectedly disappeared after chronic stimulation. This is the first
      case of LNS that has been successfully treated with deep brain stimulation. The
      findings indicate that neurobehavioral features of this syndrome are either
      mediated in the basal ganglia pathways or secondary to the dystonia.

PMID- 12593633
TI  - Brown tumors of the skull base. Case report and review of the literature.
AB  - The natural history of brown tumor of the skull base, a rare and benign
      condition, has not been adequately documented, particularly after nonsurgical
      treatment and over a long follow-up period. The authors report a case of brown
      tumor of the ethmoidal sinus, documenting its clinical, neuroimaging, and
      pathological features with long-term follow-up results, and review previous
      reports on this disorder.

PMID- 12593634
TI  - Delayed stenosis following placement of a polyethylene terephthalate endograft in
      the cervical carotid artery. Report of three cases.
AB  - Three patients with carotid artery (CA) pseudoaneurysms were treated using four
      polyethylene terephthalate endografts (Wallgraft endoprostheses). Two patients
      received a single graft and one patient with bilateral pseudoaneurysms received
      two grafts. Complete occlusion of the pseudoaneurysm with patency of the arterial
      lumen was achieved following endograft placement in all patients. The clinical
      follow-up interval ranged from 12 to 18 months and included angiography or
      ultrasonography studies or both. One patient experienced neurological symptoms,
      and in-graft stenosis ranging from 50 to 100% occurred in three of the four
      grafts. Although the Wallgraft endoprosthesis produced good initial results for
      the treatment of cervical CA pseudoaneurysms, as demonstrated on radiography, it
      was associated with a high rate of stenosis or occlusion in all three patients.

PMID- 12593635
TI  - Significance of a small bulge on the basilar artery in patients with
      perimesencephalic nonaneurysmal subarachnoid hemorrhage. Report of two cases.
AB  - Perimesencephalic nonaneurysmal subarachnoid hemorrhage (SAH) is a distinct type
      of hemorrhage with a characteristic bleeding pattern and an excellent clinical
      outcome. The cause of this benign form of SAH remains unknown. The authors report
      on two cases of perimesencephalic nonaneurysmal SAH in which a small bulge on the
      basilar artery (BA) was demonstrated on three-dimensional rotational angiography
      studies. Based on data from these cases, one may infer that the lesion on the BA
      is responsible for the SAH. The possible pathogenesis is discussed.

PMID- 12593636
TI  - Endoscopically aided retroperitoneal placement of a lumboperitoneal shunt.
      Technical note.
AB  - The authors developed a method for retroperitoneal placement of a lumboperitoneal
      (LP) shunt with the aid of endoscopic monitoring. To perform this procedure, the
      patient is positioned laterally, the retroperitoneum is entered and dilated with
      a balloon through a small incision in the flank, and the space is maintained with
      CO2 insufflation. A peritoneal catheter is introduced into the cavity from the
      lumbar incision, through which the spinal catheter has been inserted. With the
      aid of a percutaneous nephroscope inserted in the cavity, the peritoneum is
      opened with endoscopically guided forceps through the manipulation channel. The
      shunt tube is then inserted into the pelvic peritoneum with the same forceps.
      Only two small skin incisions are needed for this method, and the shunt system is
      shorter compared with the conventional LP setup, which may lessen the risk of
      obstruction. This method is advantageous in patients who have undergone previous
      abdominal surgery, because it provides access to the peritoneum without concern
      for the presence of peritoneal adhesions.

PMID- 12593637
TI  - Multiple cerebral aneurysms and a dural arteriovenous fistula in a patient with
      polyarteritis nodosa. Case illustration.

PMID- 12593638
TI  - Hemispherotomy techniques.

PMID- 12593639
TI  - Intracranial anastomosis.

PMID- 12593640
TI  - Predicting recovery.

PMID- 12593641
TI  - Lumbar drain.

PMID- 12593642
TI  - Early aneurysm surgery.

PMID- 12593643
TI  - Immobilized artificial membrane HPLC in drug research.

PMID- 12593644
TI  - Design and synthesis of the potent, orally available, brain-penetrable
      arylpyrazole class of neuropeptide Y5 receptor antagonists.
AB  - Novel arylpyrazole derivatives were synthesized and evaluated as neuropeptide Y
      (NPY) Y5 receptor antagonists. Compound (-)-7, which features a novel chiral 2,3
      dihydro-1H-cyclopenta[a]naphthalene moiety, showed good binding affinity and
      antagonistic activity for the Y5 receptor. After intracerebroventricular
      administration in SD rats, (-)-7 significantly inhibited food intake that was
      induced by the centrally administered Y5-preferring agonist, bovine pancreatic
      polypeptide, but had only a negligible effect on NPY-induced feeding.

PMID- 12593645
TI  - In vitro and in vivo characterization of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3
      yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt, a potent and selective NPY5
      receptor antagonist.
AB  - To investigate the anorectic potential of NPY5 receptor antagonists, we have
      profiled the in vitro and in vivo properties of 3-[2-[6-(2-tert
      butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt (1).
      This compound was found to have excellent NPY5 receptor affinity and selectivity,
      potent functional antagonism, and good peripheral and central nervous system
      exposure in rats. This compound attenuated bovine pancreatic polypeptide induced
      food intake in rats but failed to demonstrate anorectic activity in rodent
      natural feeding models.

PMID- 12593646
TI  - Synthesis and biological evaluation of novel cyclosporin a analogues: potential
      soft drugs for the treatment of autoimmune diseases.
AB  - Cyclosporin A is effective in the treatment of asthma patients, but its chronic
      use is limited by toxicity. Novel cyclosporin A analogues were synthesized
      utilizing the olefin metathesis reaction and evaluated in a calcineurin A
      inhibition assay. The novel analogues demonstrated activity comparable to
      activity of the parent molecule and are potential soft drugs.

PMID- 12593647
TI  - 2,6-Dimethyltyrosine analogues of a stereodiversified ligand library: highly
      potent, selective, non-peptidic mu opioid receptor agonists.
AB  - We recently reported the use of an exhaustively stereodiversified library based
      on endomorphin-2 (1) to discover mu opioid receptor (MOR) ligands of type 2-4.
      Here, we report the synthesis and evaluation of 2,6-dimethyltyrosine analogues 5
      10. These analogues showed improved affinity for MOR relative to 2-4. In the
      cases of 5 and 6, we synthesized and evaluated five stereoisomers of each,
      thereby discovering stereoisomers with unexpected potency, selectivity, and
      efficacy. These results illustrate the utility of acyclic, stereodiverse
      libraries.

PMID- 12593648
TI  - Discovery of an orally efficacious inhibitor of coagulation factor Xa which
      incorporates a neutral P1 ligand.
AB  - The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are
      described. Structure-activity data suggesting that this class of inhibitors does
      not bind in the canonical mode were confirmed by an X-ray crystal structure
      showing the neutral haloaromatic bound in the S(1) subsite. The most potent
      azaindole, 33 (RPR209685), is selective against related serine proteases and
      attains higher levels of exposure upon oral dosing than comparable benzamidines
      and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of
      thrombosis.

PMID- 12593649
TI  - Molecular structures of human factor Xa complexed with ketopiperazine inhibitors:
      preference for a neutral group in the S1 pocket.
AB  - The structures of the noncovalent complex of human factor Xa (fXa) with four non
      peptide inhibitors containing a central sulfonylpiperazinone scaffold have been
      determined to about 2.1 A resolution. Highly potent fXa inhibitors containing
      both neutral groups such as chlorobenzothiophene or chlorothiophene and basic
      groups such as benzamidine were shown to interact in the S1 pocket through the
      neutral group whereas the S4 pocket is occupied by the basic moiety. The scaffold
      comprising the sulfonyl keto piperazine moiety might play a pivotal role in the
      orientation of substituents, since there is a strong hydrogen bond between Gly219
      of fXa and the carbonyl oxygen of the piperazine. This unique "reverse" binding
      mode is heretofore unreported in fXa and shows that electrostatic interactions in
      the S1 subsite are not an absolute requirement to maintain high affinity.
      Selectivity against other serine proteases can be readily explained in light of
      these structural results. It has opened up new prospects for designing fXa
      inhibitors with increased oral bioavailability.

PMID- 12593650
TI  - Tricyclic indole-2-carboxylic acids: highly in vivo active and selective
      antagonists for the glycine binding site of the NMDA receptor.
AB  - A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and
      evaluated by the radioligand binding assay and the anticonvulsant effects in the
      mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a,
      3f, and 3g which had certain zwitterionic anilides showed high affinity to the
      NMDA-glycine binding site. The absolute configuration of 3S-(-)-4 was confirmed
      by X-ray crystallographic analysis. In particular, 3g (SM-31900) was found to be
      a highly active glycine antagonist for both in vitro and in vivo assays (K(i) =
      1.0 +/- 0.1 nM, ED(50) = 2.3 mg/kg, iv) and also showed high selectivity for the
      glycine site. In addition, 3g was soluble enough in aqueous media (>10 mg/mL at
      pH 7.4) to use for medications by intravenous injection.

PMID- 12593651
TI  - Synthesis and structure-affinity relationships of novel N-(1-ethyl-4
      methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides with potent serotonin 5
      HT3 and dopamine D2 receptor antagonistic activity.
AB  - A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6
      yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were
      prepared and evaluated for their binding affinity for the dopamine D(2) and
      serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane,
      respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar
      binding affinity for the serotonin 5-HT(3) receptor along with moderate to high
      binding affinity for the dopamine D(2) receptor. Introduction of the more
      lipophilic bromine atom and methylamino group at the 5- and 6-positions of the
      pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor
      while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result
      of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine
      3-carboxamide 53 was selected as the most promising product showing a high
      binding affinity for both receptors. Compound 53 affinity for the dopamine D(2)
      and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide
      (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM
      vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change
      in the pharmacological profile with (R)-53 exhibiting a strong affinity for both
      the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53
      had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine
      D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed
      the existence of two energically stable conformers just like two mirror images.
      This may account for (R)-53 high affinity for both the dopamine D(2) and
      serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent
      antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors
      in vivo tests and dose-dependently inhibited both the incidence and frequency of
      emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50)
      values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of
      this pharmacological profile, (R)-53 is now under further investigation as a
      potential broad antiemetic agent.

PMID- 12593652
TI  - Non-peptide angiotensin II receptor antagonists: chemical feature based
      pharmacophore identification.
AB  - Chemical feature based pharmacophore models were elaborated for angiotensin II
      receptor subtype 1 (AT(1)) antagonists using both a quantitative and a
      qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The
      training sets for quantitative model generation consisted of 25 selective AT(1)
      antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM.
      Additionally, a qualitative pharmacophore hypothesis was derived from
      multiconformational structure models of the two highly active AT(1) antagonists
      4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative
      model, the best pharmacophore hypothesis consisted of a five-features model
      (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a
      hydrogen bond acceptor, a negative ionizable function, and an aromatic plane
      function). The best qualitative model consisted of seven features (Hypo2: 11
      points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable
      function, and two hydrophobic functions). The obtained pharmacophore models were
      validated on a wide set of test molecules. They were shown to be able to identify
      a range of highly potent AT(1) antagonists, among those a number of recently
      launched drugs and some candidates presently undergoing clinical tests and/or
      development phases. The results of our study provide confidence for the utility
      of the selected chemical feature based pharmacophore models to retrieve
      structurally diverse compounds with desired biological activity by virtual
      screening.

PMID- 12593653
TI  - Synthesis and dopamine receptor modulating activity of 3-substituted gamma-lactam
      peptidomimetics of L-prolyl-L-leucyl-glycinamide.
AB  - gamma-Lactam peptidomimetic 2 of Pro-Leu-Gly-NH(2) (PLG) was substituted at the 3
      position with isobutyl, butyl, and benzyl moieties to give the PLG
      peptidomimetics 3-5, respectively. These compounds were synthesized to test the
      hypothesis that attaching a hydrophobic moiety to the lactam ring to mimic the
      isobutyl side chain of the leucyl residue of PLG would increase the dopamine
      receptor modulating activity of such peptidomimetics. These peptidomimetics were
      tested for their ability to enhance the binding of [(3)H]-N-propylnorapomorphine
      to dopamine receptors isolated from bovine striatal membranes. The rank order of
      effectiveness of the 3-substituent was benzyl > n-butyl > isobutyl > H.

PMID- 12593654
TI  - Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity
      in Plasmodium falciparum-infected cultured human erythrocytes.
AB  - A series of protease inhibitors targeted at the malarial enzymes plasmepsin I and
      II, and encompassing a basic hydroxyethylamine transition state isostere
      scaffold, was prepared. The substituents in the P1' position were varied and the
      biological activities expressed in K(i)-values ranged from 60 to >2000 nM. A more
      than 4-fold selectivity for either of the plasmepsins could be achieved. All of
      the active compounds exhibited high preference for the plasmepsins over cathepsin
      D, the most closely related human protease. A few active compounds were shown to
      inhibit parasite growth in cultured infected human erythrocytes. An ED(50) value
      as low as 1.6 microM was observed for one of the inhibitors despite K(i) values
      of 115 nM (Plm I) and 121 nM (Plm II).

PMID- 12593655
TI  - Antiinflammatory, gastrosparing, and antiplatelet properties of new NO-donor
      esters of aspirin.
AB  - A new series of NSAIDs in which aspirin is joined by an ester linkage to furoxan
      moieties, with different ability to release NO, were synthesized and tested for
      NO-releasing, antiinflammatory, antiaggregatory, and ulcerogenic properties.
      Related furazan derivatives, aspirin, its propyl ester, and its gamma
      nitrooxypropyl ester were taken as references. All the products described present
      an antiinflammatory trend, maximized in derivatives 12, 16, and 17, they are
      devoid of acute gastrotoxicity, principally due to their ester nature, and show
      an antiplatelet activity primarily determined by their ability to release NO.
      They do not behave as aspirin prodrugs in human serum.

PMID- 12593656
TI  - Antileishmanial ring-substituted ether phospholipids.
AB  - Three series of ring-substituted ether phospholipids were synthesized carrying
      N,N,N-trimethylammonium, N-methylpiperidino, or N-methylmorpholino headgroups.
      The first series is substituted by 2-cyclohexyloxyethyl or 2-(4
      alkylidenecyclohexyloxy)ethyl groups, the second series by cyclohexylidenealkyl
      or adamantylidenealkyl moieties, and the third series by 2-aryloxyethyl or 6
      aryloxyhexyl groups in the alkyl portion of the molecule. The antileishmanial
      activity of the new compounds was evaluated in vitro against the promastigote
      forms of L. donovani and L. infantum using an MTT (3-(4,5-dimethylthiazol-2yl)
      2,5-diphenyltetrazolium bromide)-based microassay as a marker of cell viability.
      Analogues 12, 15, 24, 30, 32, 41, 43, and 45 were more potent than the control
      compound miltefosine (hexadecylphosphocholine) against both L. donovani and L.
      infantum while, derivatives 13 and 42 were equipotent to miltefosine. Analogues
      16, 17, 19, 20 were more potent than miltefosine against L. infantumand compounds
      27, 31, 44 were more active than miltefosine against L. donovani. Differential
      scanning calorimetry (DSC) was used to probe the role of individual ether
      phospholipids on the physicochemical properties of model membranes. The DSC scans
      showed that the active compounds have a more profound effect on the thermotropic
      properties of model membrane bilayers than the less active ones.

PMID- 12593657
TI  - Design, synthesis, SAR, and molecular modeling studies of acylthiocarbamates: a
      novel series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors
      structurally related to phenethylthiazolylthiourea derivatives.
AB  - A novel series of potent, selective HIV-1 N-acylthiocarbamate (ATC) nonnucleoside
      reverse transcriptase inhibitors (NNRTIs) is described. The title compounds were
      synthesized through a highly convergent, one-pot procedure. In cell-based assays,
      the lead compound (17c) prevented the HIV-1 multiplication with an EC(50) of 8
      microM. The lead optimization strategy was developed by single or multiple
      modifications of the three molecular portions, in which 17c was notionally
      divided. Molecular modeling studies led to the synthesis of O-(2
      phthalimidoethyl)-N-(p-substituted phenyl)-N-acylthiocarbamates, which showed in
      vitro activities against HIV-1 in the low nanomolar range. Nevertheless, the
      title compounds retained low potency against HIV-1 strains carrying mutations
      (K103R, Y181C, and K103N/Y181C) responsible for NNRTI resistance. The
      hypothetical docking model of RT/17c and RT/25c, derived from X-ray
      crystallographic structure of a PETT derivative in complex with HIV-1 RT,
      revealed that the model structures of ATCs do not approximate the NNRTI butterfly
      like conformation. Analysis of these hypotetical complexes helps to rationalize
      some SARs and resistance data.

PMID- 12593658
TI  - S-acyl-2-thioethyl aryl phosphotriester derivatives of AZT: synthesis, antiviral
      activity, and stability study.
AB  - The synthesis, antiviral activity, and stability study of phosphotriester
      derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing modified l-tyrosinyl
      residues are reported. These compounds were obtained via phosphoramidite (P(III))
      chemistry from the appropriate aryl precursors. All the derivatives were
      evaluated for their in vitro anti-HIV activity, and they appeared to be potent
      inhibitors of HIV-1 replication in various cell culture experiments, with EC(50)
      values between the micro- and nanomolar range, especially in thymidine kinase
      deficient (TK(-)) cells, showing their ability to act as mononucleotide prodrugs.
      The proposed decomposition process of these mixed mononucleoside aryl
      phosphotriesters successively involves an esterase and a phosphodiesterase
      hydrolysis.

PMID- 12593659
TI  - Synthesis and biological effects of novel 2-amino-3-naphthoylthiophenes as
      allosteric enhancers of the A1 adenosine receptor.
AB  - The current study describes the synthesis and biological evaluation of a novel
      series of 2-amino-3-naphthoylthiophenes, with variable modifications at the 4-
      and 5-position of the thiophene as well as the naphthoyl ring. Allosteric
      enhancer activity was measured in several ways: (1) evaluating the effect on
      forskolin-stimulated cAMP accumulation in the presence of an A(1)-adenosine
      agonist (CPA) in Chinese hamster ovary (CHO) cells expressing the cloned human
      A(1)-adenosine receptor (hA(1)AR); (2) ability of these compounds to displace the
      binding of [(3)H]DPCPX, [(3)H]ZM 241385, and [(3)H]MRE 3008F20 to the ligand
      binding site of CHO cells expressing the hA(1), hA(2A), and hA(3) adenosine
      receptors, respectively; (3) effect on the binding of [(3)H]CCPA to membranes
      from CHO cells expressing hA(1)AR, to rat brain and human cortex membrane
      preparations containing native adenosine A(1) receptors; (4) kinetics of the
      dissociation of [(3)H]CCPA from CHO-hA1 membranes. The pharmacological assays
      compared the various activities to that of the reference compound PD 81,723
      (compound 1). Several compounds appeared to be better than PD 81,723 to enhance
      the effect of CPA (and thus reduce cAMP content) in the CHO:hA(1) assay. The
      effect of these compounds at a concentration of 10 microM was slightly greater
      than that of the same concentration of the PD 81,723 and substantially greater
      than that of PD 81,723 when responses to 1 microM of each compound were compared.
      These include compounds 23, 25-29, 31-34, 38, 39, 43, and 58.
      Cycloalkylthiophenes tended to be more potent then their 4,5-dimethyl analogues,
      and in the series of cycloalkylthiophenes, tetrahydrobenzo[b]thiophene
      derivatives appeared to be more potent than the dihydrocyclopentadien[b]thiophene
      counterparts. Some of the most potent compounds were tested at a concentration of
      10 microM for their affinity as competitors to the antagonist binding site of CHO
      cells expressing hA(1), hA(2A), and hA(3) adenosine receptors. None inhibited
      binding at the hA(2A)AR, but most of them inhibited binding to the hA(1)AR to
      varying extents (0-19%) as well as to the hA(3)AR to a substantial degree (0
      57%). At a concentration of 10 microM, the compounds 31, 34, 37, 38, and 39 were
      more active than PD 81,723 to increase the binding of [(3)H]CCPA to CHO:hA(1),
      human brain and rat cortex membranes. Compound 37 was the most active compound
      increasing the binding to CHO:hA(1), human brain, and rat cortex membranes by
      149, 43, and 27%, respectively (51, 15, and 22%, respectively, for PD 81,723). A
      good correlation was found between the increments [(3)H]CCPA binding to A(1)
      receptors expressed in different systems. Unlike the effect on agonist binding,
      the tested compounds did not increase the binding of the antagonist [(3)H]DPCPX
      on hCHO-A(1) membranes. Ligand dissociation studies revealed that two compounds
      (22 and 39) were more potent than 1 to slow the dissociation of [(3)H]CCPA from
      CHO:hA(1)AR membranes. No clear-cut structure-activity relationship can be
      observed based on data from the functional assay, but we have identified several
      compounds, in particular 37 and 39, which appeared to be more potent than 1 and
      that may be selected for further development.

PMID- 12593660
TI  - Design of novel chimeric melanotropin-deltorphin analogues. Discovery of the
      first potent human melanocortin 1 receptor antagonist.
AB  - A number of novel alpha-melanotropin (alpha-MSH) analogues have been designed,
      synthesized, and assayed for bioactivity at the melanocortin-1 (MC1) receptor
      from Xenopus frog skin, and selected potent analogues were examined at
      recombinant human MC1, MC3, and MC4 receptors expressed in human embryonic kidney
      (HEK) cells. These ligands were designed from Deltorphin-II, by a new hybrid
      approach, which incorporates the hydrophobic tail and the address sequence of
      Deltorphin-II (Glu-Val-Val-Gly-NH(2)) and key pharmacophore elements of
      melanotropins. Some of the ligands designed, c[Xxx-Yyy-Zzz-Arg-Trp-Glu]-Val-Val
      Gly-NH(2) [XXX = nothing, Gly, beta-Ala, gamma-Abu, 6-Ahx; YYY = His, His(3-Bom),
      (S)-cyclopentylglycine (Cpg); ZZZ = Phe, d-Phe; d-Nal(2')], show high potency at
      melanocortin receptors. One ligand, GXH-32B-c[beta-Ala-His-d-Nal(2')-Arg-Trp-Glu]
      Val-Val-Gly-NH(2), the most potent of the chimeric analogues tested, displayed
      agonist activity at each of the MC receptor subtypes analyzed, with an EC(50) of
      2 nM at the amphibian MC1 receptor. In contrast, GXH-38B-c[Gly-Cpg-d-Nal(2')-Arg
      Trp-Glu]-Val-Val-Gly-NH(2) (Cpg = cyclopentyl glycine) was an antagonist with a
      IC(50) of 43 nM at the amphibian receptor, and among the human subtypes tested,
      was the most potent at the MC1 receptor subtype where it also acted as an
      antagonist (K(i) = 53 nM), which is the first potent antagonist discovered for
      the human MC1 receptor. These results provide strong evidence supporting our
      hypothesis that ligand scaffolds for different G-protein coupled receptors
      (GPCRs) can be used to design ligands for other GPCRs and to design more potent
      ligands to treat diseases associated with the human MC1 receptor.

PMID- 12593661
TI  - Development of potential antitumor agents. Synthesis and biological evaluation of
      a new set of sulfonamide derivatives as histone deacetylase inhibitors.
AB  - A series of sulfonamide hydroxamic acids and anilides have been synthesized and
      studied as histone deacetylase (HDAC) inhibitors that can induce hyperacetylation
      of histones in human cancer cells. The inhibition of HDAC activity represents a
      novel approach for intervening in cell cycle regulation. The lead candidates were
      screened in a panel of human tumor and normal cell lines. They selectively
      inhibit proliferation, cause cell cycle blocks, and induce apoptosis in human
      cancer cells but not in normal cells. The structure-activity relationships, the
      antiproliferative activity, and the in vivo efficacy are described.

PMID- 12593662
TI  - Synthesis and flow cytometric evaluation of novel 1,2,3,4-tetrahydroisoquinoline
      conformationally constrained analogues of nitrobenzylmercaptopurine riboside
      (NBMPR) designed for probing its conformation when bound to the es nucleoside
      transporter.
AB  - Novel regioisomers of conformationally constrained analogues of the potent es
      nucleoside transporter ligand, nitrobenzylmercaptopurine riboside (NBMPR),
      designed for probing its bound (bioactive) conformation, were synthesized and
      evaluated as es transporter ligands by flow cytometry. Purine 6-position 5, 6, 7,
      or 8-nitro-1,2,3,4-tetrahydroisoquinolylpurine ribosides, in which the
      nitrobenzyl moiety in NBMPR has been locked into the nitro-1,2,3,4
      tetrahydroisoquinoline system, were synthesized by reaction of the appropriate
      nitro-1,2,3,4-tetrahydroisoquinoline with 6-chloropurine riboside. Flow cytometry
      was performed using 5-(SAENTA)-X8-fluorescein as the competitive ligand. A high
      degree of variation in the es transporter binding capacity of the target
      compounds was observed, with the K(i) values ranging from 0.45 nM for the most
      tightly bound compound (4) to 300 nM for the least tightly bound compound (5).
      The K(i) of NBMPR was 0.70 nM, a little higher than that of compound 4. Compound
      4 is the isomer that has the nitro group in the best orientation at the es
      transporter binding site compared to the other three compounds, 2, 3, and 5.

PMID- 12593664
TI  - Novel alpha-melanocyte stimulating hormone peptide analogues with high
      candidacidal activity.
AB  - alpha-Melanocyte stimulating hormone (alpha-MSH) is an endogenous linear
      tridecapeptide with potent antiinflammatory effects. We recently demonstrated
      that alpha-MSH and its C-terminal sequence Lys-Pro-Val (alpha-MSH (11-13)) have
      antimicrobial effects against two major and representative pathogens:
      Staphylococcus aureus and Candida albicans. In an attempt to improve the
      candidacidal activity of alpha-MSH and to better understand the peptide structure
      antifungal activity relations, we designed and synthesized novel peptide
      analogues. Because previous data suggested that antimicrobial effects of alpha
      MSH were receptor-mediated, we chose to focus on the sequence alpha-MSH (6-13),
      which contains the invariant core sequence His-Phe-Arg-Trp (6-9) that is
      important for binding to the known melanocortin receptors and also contains the
      sequence Lys-Pro-Val (11-13) that is known to be important for antimicrobial
      activity. In this structure-activity study, we discovered several compounds that
      have greater candidacidal activity than alpha-MSH. The peptide [d-Nal-7,Phe-12]
      alpha-MSH (6-13) was the most potent of the analogues tested. The present results
      are very encouraging because they show the great potential of these peptides as a
      truly novel class of candidacidal compounds.

PMID- 12593663
TI  - Syntheses and opioid receptor binding affinities of 8-amino-2,6-methano-3
      benzazocines.
AB  - 8-Amino-2,6-methano-3-benzazocine derivatives have been made using Pd-catalyzed
      amination procedures, and their affinities for opioid receptors were assessed.
      The 8-amino group was hypothesized to be a replacement for the prototypic 8-OH
      substituent for 2,6-methano-3-benzazocines and related opiates. This OH group is
      generally required for binding yet is implicated in unfavorable pharmacokinetic
      characteristics such as low oral bioavailability and rapid clearance via O
      glucuronidation. The core structures in which the 8-OH group was replaced were
      cyclazocine and its enantiomers, ethylketocyclazocine and its enantiomers,
      ketocyclazocine, and Mr2034. Many new analogues had high affinity for opioid
      receptors with several in the subnanomolar range. Highest affinity was seen in
      analogues with secondary 8-(hetero)arylamino appendages. Binding to opioid
      receptors was enantioselective with the (2R,6R,11R)-configuration preferred and
      high selectivity for mu and kappa over delta opioid receptors was observed within
      the series. Several derivatives were shown to have intrinsic opioid-receptor
      mediated activity in [(35)S]GTPgammaS assays.

PMID- 12593665
TI  - Structure-activity relationships of dimethindene derivatives as new M2-selective
      muscarinic receptor antagonists.
AB  - A series of 2,3-disubstituted indenes, which are analogues of the widely used
      histamine H(1) receptor antagonist dimethindene, have been synthesized and
      studied as muscarinic and histamine receptor antagonists. The affinities of these
      compounds for the five human muscarinic receptor subtypes (M(1)-M(5)) and for
      human histamine H(1) receptors were determined in radioligand binding studies
      using membranes from transfected Chinese hamster ovary (CHO) cells and [(3)H]N
      methylscopolamine ([(3)H]NMS). The results demonstrate that the diisopropyl
      analogue 19 has a similar high affinity as (S)-dimethindene at M(2) receptors
      ((S)-dimethindene: pK(i) = 7.52; (-)-19: pK(i) = 7.37) with an improved
      selectivity pattern ((S)-dimethindene: M(2)/M(1) = 6-fold, M(2)/M(3) = 5-fold,
      M(2)/M(4) = 10-fold, M(2)/M(5) = 25-fold; (-)-19: M(2)/M(1) = 36-fold, M(2)/M(3)
      = 96-fold, M(2)/M(4) = 42-fold, M(2)/M(5) = 275-fold). In addition, compound (-)
      19 showed 35-fold lower affinity at histamine H(1) receptors (pK(i) = 5.61) than
      (S)-dimethindene (pK(i) = 7.16). Another interesting compound is the fluoroethyl
      derivative 20 (pK(i)/M(2) = 7.49), which also exhibits a higher M(2) selectivity
      (M(2)/M(1) = 19-fold; M(2)/M(3) = 22-fold; M(2)/M(4) = 13-fold; M(2)/M(5) = 62
      fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high
      affinity for histamine H(1) receptors (pK(i) = 8.14). The compound with the
      highest affinity for M(2) receptors (pK(i) = 7.91), the dimethylaminomethylene
      analogue 31, displayed only a small preference for M(2) receptors. In conclusion,
      compound (-)-19 might be useful to test the hypothesis that blockade of
      muscarinic M(2) receptors in the brain is a viable mechanism by which to produce
      improved cognition. This second-generation dimethindene analogue might also be
      the starting point for the development of M(2)-selective muscarinic antagonists
      useful for quantifying M(2) receptors in the central nervous system with positron
      emission tomography imaging.

PMID- 12593666
TI  - Structure-activity relationship study and drug profile of N-(4
      fluorophenylsulfonyl)-L-valyl-L-leucinal (SJA6017) as a potent calpain inhibitor.
AB  - Novel N-arylsulfonyldipeptidyl aldehyde derivatives were prepared by DMSO
      oxidation from the corresponding dipeptide alcohol, and their potencies as
      calpain inhibitors were evaluated in vitro. Among them, N-(4
      fluorophenylsulfonyl)-l-valyl-l-leucinal (8, SJA6017) potently inhibited
      calpains. 8 also inhibited cathepsin B and L but did not inhibit other cysteine
      proteases (interleukin 1beta-converting enzyme), serine proteases (trypsin,
      chymotrypsin, thrombin, factor VIIa, factor Xa), or proteasome. Preliminary
      cytotoxicity studies of 8 exhibited a relatively safe profile.

PMID- 12593667
TI  - Three-dimensional structure of the ligand-binding core of GluR2 in complex with
      the agonist (S)-ATPA: implications for receptor subunit selectivity.
AB  - Two X-ray structures of the GluR2 ligand-binding core in complex with (S)-2-amino
      3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid ((S)-ATPA) have been
      determined with and without Zn(2+) ions. (S)-ATPA induces a domain closure of ca.
      21 degrees compared to the apo form. The tert-butyl moiety of (S)-ATPA is buried
      in a partially hydrophobic pocket and forces the ligand into the glutamate-like
      binding mode. The structures provide new insight into the molecular basis of
      agonist selectivity between AMPA and kainate receptors.

PMID- 12593668
TI  - Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel
      selective CDK1 inhibitors with P-glycoprotein modulating properties.
AB  - The first series of synthetic 1-aza-9-oxafluorenes with cytostatic activities in
      the micromolar range was evaluated as cyclin-dependent kinase (CDK1) inhibitors.
      Activity was found to be selective in comparison to the inhibition of other
      kinases within the CDK family. Compounds were shown to inhibit the membrane
      efflux pump P-glycoprotein responsible for multidrug resistance in cancer cells.
      First structure-activity relationships are discussed.

PMID- 12593669
TI  - Cell alkalosis elevates cytosolic Ca2+ in rabbit resident alveolar macrophages.
AB  - Disruption of cellular acid-base status alters the host defence functions of
      alveolar macrophages (m phi). These pH effects might be mediated by pH-sensitive
      changes in the signalling pathways of the effector functions of m phi. The
      present study examined the effects of intracellular pH (pH(i)) on the free
      cytosolic calcium concentration ([Ca(2+)](i)), an important second messenger for
      cell functions. [Ca(2+)](i) and pH(i) of rabbit resident alveolar m phi were
      measured using fluorescent dyes. With extracellular pH (pH(o)) of 7.4, the steady
      state pH(i) and [Ca(2+)](i) were approx. 7.14 and 123 nM respectively. Incubation
      at pH(o) 6.8 caused a sustained cytosolic acidosis, but did not affect
      [Ca(2+)](i). Likewise, [Ca(2+)](i) was unchanged when m phi at pH(o) 7.4 were
      acidified using bafilomycin A(1) or sodium propionate. In contrast, [Ca(2+)](i)
      was markedly sensitive to cytosolic alkalosis. Exposure to NH(4)Cl at pH(o) 7.4
      caused transient increases in both pH(i) and [Ca(2+)](i). The Ca(2+) response was
      mediated by release of intracellular Ca(2+) from thapsigargin-sensitive stores
      and was potentiated by capacitative entry of extracellular Ca(2+). Incubation at
      high pH(o) values (>7.4) produced sustained increases in pH(i) and [Ca(2+)](i).
      The sustained elevation of [Ca(2+)](i) was consistent with pH-sensitive
      inhibition of plasma-membrane Ca(2+)-ATPase. The response to high pH(o) was
      unaffected by blockade of L-type or receptor-operated Ca(2+) channels with
      nifedipine or SKF-96365, and was independent of extracellular Na(+). The findings
      indicate that pH impacts cytosolic Ca(2+) homoeostasis at multiple levels. The
      data suggest that cellular acid-base status can influence Ca(2+)-dependent
      signalling events in resident alveolar m phi, especially during alkaline
      disruptions of pH(i).

PMID- 12593671
TI  - Regulation of TG-interacting factor by transforming growth factor-beta.
AB  - TG-interacting factor (TGIF) is a transcriptional co-repressor that directly
      associates with Smad (Sma- and Mad-related protein) proteins and inhibits Smad
      mediated transcriptional activation. By using Affymetrix (Santa Clara, CA,
      U.S.A.) oligonucleotide microarray analysis, we found that TGIF mRNA level was
      elevated by transforming-growth-factor-beta (TGF-beta) treatment in a human T
      cell line, HuT78. Subsequent reverse-transcription PCR assays indicated that TGF
      beta1 and activin were able to induce a rapid and transient increase in the level
      of TGIF in both HuT78 and HepG2 hepatoma cells. To analyse whether or not the
      regulation of TGIF mRNA occurs at the transcriptional level, a 2.4 kb human TGIF
      promoter was isolated. A primer extension assay was performed to localize the
      putative transcription initiation site of the promoter. When transiently
      expressed in HepG2 cells, this promoter was stimulated by TGF-beta1 and activin
      treatment in a time-dependent manner. A series of deletion mutants of the TGIF
      promoter were also generated to further characterize the TGF-beta responsive
      region of the promoter. In addition, expression of TGIF was able to cause a dose
      dependent inhibition of TGF-beta and activin signalling. Taken together, these
      experiments indicated that TGIF is a novel transcriptional target of TGF-beta and
      activin signalling and is likely involved in a negative feedback loop to
      desensitize TGF-beta/activin action.

PMID- 12593670
TI  - Negative regulation of gp130 signalling mediated through tyrosine-757 is not
      dependent on the recruitment of SHP2.
AB  - Cytokines of the interleukin-6 family utilize the shared cytokine receptor gp130
      in the formation of active signalling complexes. Tyrosine-757 (Y757) on this
      receptor is critical for negative regulation of gp130-mediated signalling. Two
      signalling regulators, suppressor of cytokine signalling 3 (SOCS3) and Src
      homology 2 domain-containing tyrosine phosphatase-2 (SHP2), are recruited to Y757
      following receptor activation; however, the relative contribution made by each of
      these in down-regulating gp130 signalling is not known. In the present study, we
      show the design of a mutant gp130 receptor that can recruit SHP2, but not SOCS3.
      This receptor maintains the critical Y757 residue, but contains mutations in
      other surrounding residues which are also important for interactions with the Src
      homology 2 domains of SOCS3 and SHP2. Cells transfected with a chimaeric receptor
      containing the SHP2-selective gp130 intracellular domain showed an enhanced
      response to cytokine stimulation, which was similar to that shown by a chimaeric
      gp130 receptor mutant carrying a Y757F point mutation that failed to recruit
      either SOCS3 or SHP2. These results demonstrate that the recruitment of SHP2
      alone is not sufficient for Y757-dependent negative regulation of gp130
      signalling and that this activity must therefore be dependent on SOCS3.

PMID- 12593672
TI  - Molecular characterization of a male-specific glycosyl hydrolase, Lma-p72,
      secreted on to the abdominal surface of the Madeira cockroach Leucophaea maderae
      (Blaberidae, Oxyhaloinae).
AB  - The epicuticular surface protein Lma-p72 is specific to the abdominal secretions
      of Leucophaea maderae (Madeira cockroach) adult males. Natural Lma-p72 was
      purified and the complete cDNA sequence determined by reverse-transcription PCR
      using primers based on Edman degradation fragments. Northern blot and in situ
      hybridization analyses showed that Lma-p72 was expressed in the tergal and
      sternal glands. Sequence alignment indicates that Lma-p72 is closely related to
      the family 1 glycosyl hydrolases (EC 3.2.1). Native Lma-p72 was proved to be
      active in the abdominal secretions and exhibit a beta-galactosidase-like
      activity. However, weak specificity with respect to the C-4 configuration of the
      substrate was observed. Two main hypotheses were proposed concerning the function
      of this enzyme: Lma-p72 could hydrolyse oligosaccharides from the male abdominal
      secretions, making them more phagostimulatory for the female during the
      precopulatory behaviour. The protein could also cleave a pheromone-sugar
      conjugate to release the pheromonal compounds on to the cuticular surface. Such a
      sugar conjugate could be a transport form. Data from the first in vivo inhibition
      tests indicate that a glycosidase could be directly involved in the production
      process of some pheromonal compounds in L. maderae males.

PMID- 12593673
TI  - Mannose metabolism is required for mycobacterial growth.
AB  - Mycobacteria are the causative agents of tuberculosis and several other
      significant diseases in humans. All species of mycobacteria synthesize abundant
      cell-wall mannolipids (phosphatidylinositol mannosides, lipoarabinomannan), a
      cytoplasmic methylmannose polysaccharide and O-mannosylated glycoproteins. To
      investigate whether these molecules are essential for mycobacterial growth, we
      have generated a Mycobacterium smegmatis mannose auxotroph by targeted deletion
      of the gene encoding phosphomannose isomerase (PMI). The PMI deletion mutant
      displayed a mild hyperseptation phenotype, but grew normally in media containing
      an exogenous source of mannose. When this mutant was suspended in media without
      mannose, ongoing synthesis of both the mannolipids and methylmannose
      polysaccharides was halted and the hyperseptation phenotype became more
      pronounced. These changes preceded a dramatic loss of viability after 10 h in
      mannose-free media. Mannose starvation did not lead to detectable changes in cell
      wall ultrastructure or permeability to hydrophobic drugs, or to changes in the
      rate of biosynthesis of other plasma-membrane or wall-associated phospholipids.
      These results show that mannose metabolism is required for growth of M. smegmatis
      and that one or more mannose-containing molecules may play a role in regulating
      septation and cell division in these bacteria.

PMID- 12593674
TI  - A new method for purification of human plasma retinol-binding protein and
      transthyretin.
AB  - Retinol is transported in the blood bound to a specific carrier protein called
      retinol-binding protein (RBP), which in turn binds to another protein,
      transthyretin (TTR), a homotetrameric, thyroid-hormone-transporting protein.
      Binding of TTR increases the apparent molecular mass of RBP and thereby prevents
      glomerular filtration of RBP. Owing to their rapid turnover rates, plasma
      concentrations of these proteins are sensitive indicators and valuable diagnostic
      markers of vitamin A nutrition, protein energy malnutrition, infection and renal
      tubule function. Previously RBP and TTR were purified by using different
      procedures, either from plasma or from pathological urine of humans. In general
      the procedure for purification of RBP and TTR is laborious, and extensive sample
      recycling is necessary for purification in appreciable amounts. In the present
      study, we have purified RBP using a simple method, which involves (NH(4))(2)SO(4)
      fractionation followed by sequential gel filtration under native conditions and 6
      M urea. TTR, which was eluted in 60 kDa fractions during urea/Sephadex G-100
      chromatography, was further purified to homogeneity using a combination of two
      dye-affinity chromatographic steps on Reactive Yellow and Cibacron Blue coupled
      to agarose columns. SDS/PAGE and immunoblotting, apart from typical UV absorption
      and fluorescent properties of RBP, were used for characterizing the purified RBP
      and TTR. Furthermore, the purified RBP and TTR were found to be functional from
      mutual binding monitored by fluorescence quenching.

PMID- 12593675
TI  - Thermal stabilization of trypsin by enzymic modification with beta-cyclodextrin
      derivatives.
AB  - Streptoverticillum sp. transglutaminase was used as catalyst for the attachment
      of several beta-cyclodextrin derivatives to the glutamine residues in bovine
      pancreatic trypsin. The modifying agents used were mono-6-ethylenediamino-6-deoxy
      beta-cyclodextrin, mono-6-propylenediamino-6-deoxy-beta-cyclodextrin, mono-6
      butylenediamino-6-deoxy-beta-cyclodextrin and mono-6-hexylenediamino-6-deoxy-beta
      cyclodextrin. The transformed trypsin preparations contained about 3 mol of
      oligosaccharides/mol of protein. The specific esterolytic activity of trypsin was
      increased by about 4-21% after conjugation. The K (m) values for cyclodextrin
      trypsin complexes represented about 58-87% of that corresponding to the native
      enzyme. The optimum temperature for esterolytic activity of trypsin was increased
      by about 5-10 degrees C after enzymic modification with the cyclodextrin
      derivatives. The thermostability was increased by 16 degrees C for the modified
      trypsin. Thermal inactivation at different temperatures ranging from 45 to 60
      degrees C was markedly increased for the oligosaccharide-trypsin complexes. This
      modification also protected the enzyme against autolysis at alkaline pH.

PMID- 12593676
TI  - Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in
      human pregnancy.
AB  - BACKGROUND: It is known that during normal pregnancy and after immunotherapy
      blocking antibodies are developed, these antibodies inhibit mixed lymphocyte
      reaction and are also anti-mitogenic in nature. Mixed lymphocyte reaction
      blocking antibodies are specific to the husband's lymphocytes. In the present
      study an attempt has been made to characterize the mixed lymphocyte reaction
      blocking antibodies in normal pregnancy and in women with recurrent spontaneous
      abortion after immunotherapy. METHODS: Serum was obtained from women of different
      gestational windows of pregnancy (Ist, IInd, IIIrd trimesters and post delivery
      period of normal pregnancy), recurrent spontaneous aborters from pre and post
      immunization. Healthy (male and females) controls were screened for the presence
      of mixed lymphocyte reaction blocking antibodies. The standard mixed lymphocyte
      reaction technique was used to evaluate the inhibitory effect of serum in the
      mixed lymphocyte reaction. Each serum was tested for cytotoxic antibodies.
      Immunoglobulin G and its isotypes were isolated according to the standard
      protocol. RESULTS: In the present study we have observed that there was
      significant inhibition of proliferation response when immunoglobulin G from
      different trimesters of pregnancy were added to one way mixed lymphocyte reaction
      or to phytohemagglutinin activated lymphocyte proliferation assay. Similar
      pattern was seen when immunoglobulin G isolated from adequately immunized women
      with recurrent spontaneous abortion was used. It was further confirmed that
      amongst all the isotypes of immunoglobulin G, only immunoglobulin G-3 was found
      to be positive for the inhibitory effect. CONCLUSIONS: Present study indicates
      that mixed lymphocyte reaction blocking antibodies are immunoglobulin G-3 in
      nature. It is developed during pregnancy and also after immunotherapy in women
      with recurrent spontaneous abortion who subsequently have the successful
      pregnancy.

PMID- 12593677
TI  - Comparative analysis of microsatellite loci in four fruit fly species of the
      genus Ceratitis (Diptera: Tephritidae).
AB  - The possibility to cross-species amplify microsatellites in fruit flies of the
      genus Ceratitis was tested with the polymerase chain reaction (PCR) by analysing
      23 Ceratitis capitata (Wiedemann) microsatellite markers on the genomic DNA of
      three other economically important, congeneric species: C. rosa (Karsch), C.
      fasciventris (Bezzi) and C. cosyra (Walker). Twenty-two primer pairs produced
      amplification products in at least one of the three species tested. The majority
      of the products were similar, if not identical in size to those expected in C.
      capitata. The structures of the repeat motifs and their flanking sequences were
      examined for a total of 79 alleles from the three species. Sequence analysis
      revealed the same repeat type as the homologous C. capitata microsatellites in
      the majority of the loci, suggesting their utility for population analysis across
      the species range. A total of seven loci were differentially present/absent in C.
      capitata, C. rosa, C. fasciventris and C. cosyra, suggesting that it may be
      possible to differentiate these four species using a simple sequence repeat-based
      PCR assay. It is proposed that medfly-based microsatellite markers could be
      utilized in the identification and tracing of the geographical origins of
      colonist pest populations of the four tested species and in the assessment of
      their risk and invasive potentials; thereby assisting regulatory authorities in
      implementing quarantine restrictions and other pest control measures.

PMID- 12593678
TI  - Techniques for dissecting adult aleocharine beetles (Coleoptera: Staphylinidae).
AB  - Methodology for detailed dissections of the phylogenetically most informative
      structures from adult aleocharine staphylinid beetles is provided. These methods
      include specimen preparation, relaxation, clearing, bleaching, dehydration and
      full dissection. A detailed summary of mouthpart and male and female genitalic
      dissections is provided. Recently described character systems, including those of
      the mouthparts and the thoracic regions, have been successfully used in
      phylogenetic studies of aleocharine staphylinids. This paper provides the first
      thorough description of the techniques necessary to reveal these character
      systems.

PMID- 12593679
TI  - Optimized simulation of the control of tsetse flies Glossina pallidipes and G. m.
      morsitans (Diptera: Glossinidae) using odour-baited targets in Zimbabwe.
AB  - In 1984-1985 insecticide-treated targets were deployed in the 600-km2 Rifa
      Triangle, Zambezi Valley, Zimbabwe. Trap catches of Glossina pallidipes Austen
      were modelled using a function combining logistic growth with diffusive movement.
      A simulation routine was linked to a non-linear least-squares optimization
      programme and fits optimized with respect to population carrying capacities,
      rates of growth and movement, and to levels of imposed mortality. In March
      September 1984, the overall additional mortality was 2% per day of adult female
      G. pallidipes, increasing thereafter to 8% per day, due to the deployment of more
      targets, the onset of the hot, dry season and the ground-spraying of the
      adjoining Zambezi escarpment with DDT. For G. m. morsitans Westwood the
      corresponding estimates were 1 and 2% per day. For both species, the deployment
      of four targets km(-2) in a closed population will ensure eradication. For G. m.
      morsitans a halving of target efficacy would reduce the killing rate to the point
      where eradication would be unlikely. Estimated daily displacements were c. 200 m
      for G. m. morsitans and 660 m for G. pallidipes. The lower rate for G. m.
      morsitans means that, while targets kill this species less effectively, re
      invasion of cleared areas is slower. Targets do not markedly affect robust
      populations outside the deployment area. The Zambian tsetse population adjacent
      to the Rifa Triangle declined markedly during the experiment, however, suggesting
      that it is largely maintained by immigration. The methods developed here will be
      applied to data from other campaigns with the aim of improving the efficiency of
      tsetse control programmes.

PMID- 12593680
TI  - Enrichment of a single clone from a high diversity library of phage-displayed
      antibodies by panning with Anopheles gambiae (Diptera: Culicidae) midgut
      homogenate.
AB  - A high diversity library of recombinant human antibodies was selected on complex
      antigen mixtures from midguts of female Anopheles gambiae Giles. The library of
      phage-displayed single chain variable region fragment constructs, derived from
      beta-lymphocyte mRNA of naive human donors, was repeatedly selected and
      reamplified on the insoluble fraction of midgut homogenates. Five rounds of
      panning yielded only one midgut-specific clone, which predominated the resulting
      antibody panel. In A. gambiae, the epitope was found throughout the tissues of
      females but was absent from the midgut of males. The cognate antigen proved to be
      detergent soluble but very sensitive to denaturation and could not be isolated or
      identified by Western blot of native electrophoresis gels or by
      immunoprecipitation. Nevertheless, immunohistology revealed that this sex
      specific epitope is associated with the lumenal side of the midgut. Severe
      bottlenecking may limit the utility of phage display selection from naive
      libraries for generating diverse panels of antibodies against complex mixtures of
      antigens from insect tissues. These results suggest that the selection of
      sufficiently diverse antibody panels, from which mosquitocidal or malaria
      transmission-blocking antibodies can be isolated, may require improved selection
      methods or specifically enriched pre-immunized libraries.

PMID- 12593681
TI  - Biological characteristics of the mirids Macrolophus costalis and Macrolophus
      pygmaeus preying on the tobacco form of Myzus persicae (Hemiptera: Aphididae).
AB  - Biological and population parameters of the predatory bugs Macrolophus costalis
      Fieber and Macrolophus pygmaeus Rambur preying on the tobacco aphid Myzus
      persicae (Sulzer) were examined. Tobacco was used as host plant and all
      experiments were carried out at 23 degrees C and L16:D8. In M. costalis, the
      developmental time for eggs and the total duration of nymphal instars was 13.1
      and 22.2 days and in M. pygmaeus 13.0 and 20.2 days, respectively. Both species
      completed their nymphal development feeding only on plant juices although they
      required significantly more time to attain adulthood than when feeding on prey.
      The longevity of M. costalis females and the preoviposition period were 49.9 and
      5.6 days and those of M. pygmaeus were 50.3 and 6.3 days, respectively. Adult
      males showed a higher longevity than females in both species. The intrinsic rate
      of increase and the mean total number of eggs laid were 0.0644 and 121 in M.
      costalis and 0.0615 and 104 in M. pygmaeus, respectively. Mean total aphid
      consumption by nymphs of M. costalis was 61 aphids, about twice that of M.
      pygmaeus (37 aphids). Total aphid consumption by a male and female pair of M.
      costalis and M. pygmaeus until the death of the female was 244 and 285 aphids,
      respectively. The results of the study are discussed in relation to the impact of
      the two predatory bugs on tobacco aphid populations.

PMID- 12593682
TI  - European monitoring of resistance to insecticides in Myzus persicae and Aphis
      gossypii (Hemiptera: Aphididae) with special reference to imidacloprid.
AB  - The susceptibility to several insecticides of 16 and 8 strains of Myzus persicae
      Sulzer and Aphis gossypii Glover, respectively, received from different European
      countries in 2001 was investigated. Most of the strains were derived from places
      known for their aphid resistance problems to conventional insecticides before
      imidacloprid was introduced. In many regions and agronomic cropping systems
      imidacloprid has been an essential part of aphid control strategies for a decade,
      and therefore the susceptibility of aphid populations to imidacloprid using FAO
      dip tests and diagnostic concentrations in a leaf-dip bioassay was checked.
      Additional insecticides tested were cyfluthrin (chemical class: pyrethroid),
      pirimicarb (carbamate), methamidophos and oxydemeton-methyl (organophosphates).
      Diagnostic concentrations (LC99-values of reference strains) for each insecticide
      were established by dose response analysis using a new leaf-disc dip bioassay
      format in 6-well tissue culture plates. Virtually no resistance to imidacloprid
      in any of the field-derived populations of M. persicae and A. gossypii was
      detected. In contrast, strong resistance was found to pirimicarb and oxydemeton
      methyl, and to a lesser extent also to cyfluthrin. Two strains of A. gossypii
      exhibited reduced susceptibility to imidacloprid when tested directly after
      collection. However, after maintaining them for six weeks in the laboratory, the
      aphids were as susceptible as the reference strain. The diagnostic concentration
      of methamidophos did not reveal any resistance in M. persicae, but did so in four
      strains of A. gossypii.

PMID- 12593683
TI  - Oviposition by introduced Ophelimus eucalypti (Hymenoptera: Eulophidae) and
      morphogenesis of female-induced galls on Eucalyptus saligna(Myrtaceae) in New
      Zealand.
AB  - An Australian gall-inducing eulophid, Ophelimus eucalypti (Gahan) was first
      recorded on the foliage of Eucalyptus botryoides after it invaded New Zealand in
      1987. It has spread throughout the eucalypt plantations in the North Island and
      in the northern parts of the South Island affecting several species of Eucalyptus
      in the section Transversaria (subgenus Symphyomyrtus). Because gall-inducing
      insects usually have extremely narrow host ranges, O. eucalypti that induces
      galls on E. saligna and E. botryoides is currently recognized as a biotype, O.
      eucalypti(Transversaria). Heavily galled leaves abscise from the plant. Repeated
      defoliation led to widespread die-back of susceptible eucalypt species in the
      1990s. Female larvae of O. eucalypti induce circular, protruding galls on the
      leaves of E. botryoides and E. saligna, whereas the males induce pit galls on the
      same species. The biology of O. eucalypti females and the development of their
      galls are described. Adult female O. eucalypti antennate the leaf surface before
      inserting the ovipositor (otherwise concealed within the metasomal apex) into the
      young host leaf. The egg is inserted at approximately 45 degrees and discharged
      between differentiating palisade cells. Callus-type cells surround the egg
      chamber, but cytologically specialized nutritive cells appear once the egg
      hatches and the larva begins to feed. The gall also differentiates a multi
      layered sclerenchymatous tissue around the nutritive tissue. After feeding for
      many months, the larva pupates and the active nutritive tissue degenerates. The
      adult wasp emerges after cutting an exit hole through to the outside of the gall.
      Abscission of heavily galled leaves results in widespread defoliation and loss of
      growth and vigour in susceptible trees in New Zealand.

PMID- 12593684
TI  - Differential parasitism of Plutella xylostella (Lepidoptera: Plutellidae) larvae
      by the parasitoid Cotesia plutellae (Hymenoptera: Braconidae) on two host plant
      species.
AB  - Laboratory experiments were conducted to examine host selection by Cotesia
      plutellae Kurdjumov when larvae of its host, Plutella xylostella (Linnaeus), fed
      on Chinese cabbage, Brassica campestris L. ssp. pekinensis and those fed on
      common cabbage, Brassica oleracea L. var. capitata were provided simultaneously,
      and to investigate the roles of plant and host volatiles in mediating host
      selection. When C. plutellae were provided with equal numbers of host larvae on
      plants of the two species in one arena, the parasitoid parasitized 4- to 15-fold
      more host larvae on Chinese cabbage than on common cabbage. This preference
      changed little with host density. However, an experience of searching coupled
      with an oviposition in a host larva on a leaf of the less-preferred plant, common
      cabbage, significantly increased the preference for parasitizing host larvae on
      this plant and resulted in twice as many host larvae parasitized on this plant
      than on Chinese cabbage. Dual choice tests with a Y-tube olfactometer showed that
      plant volatiles from Chinese cabbage were more attractive to female C. plutellae
      than those from common cabbage when plants of both species were either intact or
      infested. In parallel to the increased parasitism on common cabbage following
      experience, oviposition in a host larva on this less-preferred plant
      significantly increased the response to volatiles emanating from that plant.
      These results indicate that host plants may strongly influence the foraging
      behaviour of C. plutellae, but their differential attractiveness to the
      parasitoid may be altered by experience of the parasitoid.

PMID- 12593685
TI  - Description of the soybean pod gall midge, Asphondylia yushimai sp. n. (Diptera:
      Cecidomyiidae), a major pest of soybean and findings of host alternation.
AB  - The soybean pod gall midge is an important pest of soybean in Japan and is known
      to occur also in Indonesia and China. This gall midge is described from Japan as
      Asphondylia yushimai sp. n. and is clearly distinguished from its congeners by
      the arrangement of the lower frontal horns of the pupa and the sequence of the
      mtDNA COI region. It is concluded that Prunus zippeliana Miquel is a winter host
      of the soybean pod gall midge since haplotypes of the soybean pod gall midge
      coincide with those of the Prunus fruit gall midge that produces fruit galls on
      P. zippeliana. In addition, phenological and distributional information on the
      two gall midges and on their host plants supports the identification of the
      winter host. In Japan, the soybean pod gall midge overwinters as a first instar
      in the fruit galls on P. zippeliana and emerges as an adult from the galls in
      May. In summer and autumn, the soybean pod gall midge has two or more generations
      in the pods of soybean, Glycine max (L.) Merrill or wild fabaceous and
      caesalpiniaceous plants. Thus host alternation by A. yushimai is confirmed. This
      is the second finding of host alternation by a species of Asphondylia, the first
      instance being that of Asphondylia gennadii (Marchal) in Cyprus.

PMID- 12593686
TI  - Geographical versus interspecific differentiation of sand flies (Diptera:
      Psychodidae): a landmark data analysis.

PMID- 12593687
TI  - Functions of antennae and palpi in the mating behaviour of the Colorado potato
      beetle Leptinotarsa decemlineata (Coleoptera: Chrysomelidae).

PMID- 12593693
TI  - Redundant, duplicate, and dual publications: different names with the same bad
      taste.

PMID- 12593694
TI  - A pilot study to determine the feasibility of continuous cefazolin infusion.
AB  - BACKGROUND: Animal studies have shown that continuous infusion of beta-lactam
      antibiotics is more effective than intermittent dosing. We studied several dosing
      regimens of cefazolin in humans to determine safety and whether or not adequate
      serum and tissue antibiotic concentrations could be achieved in patients
      undergoing cardiac bypass. METHODS: A prospective, randomized pilot study was
      conducted at a university-affiliated teaching hospital over a 2-year period in
      patients undergoing first-time coronary artery bypass grafting. One hundred and
      thirty-seven patients were randomized to one of three groups. Group 1 (n = 64)
      received 1 g of cefazolin intravenously before operation and 1 g intravenously at
      the end of cardiopulmonary bypass. Group 2 (n = 35) received 2 g of cefazolin
      intravenously before operation, followed by a continuous intravenous infusion of
      cefazolin at 20 mg/min throughout surgery. Group 3 (n = 38) received 3 g of
      cefazolin intravenously before operation, followed by a continuous intravenous
      infusion of cefazolin at 15 mg/min throughout surgery. Venous blood and
      subcutaneous fat samples were obtained from the sternal wound in a subset of 34
      patients at incision, 0.25 h, 0.5 h, and 1 h; at the end of cardiopulmonary
      bypass; and at wound closure. Venous blood was sampled in the recovery room and
      on postoperative day 1. Cefazolin concentrations in the samples were determined
      by reverse-phase high-performance liquid chromatography using a C18 column.
      RESULTS: Serum cefazolin concentrations were higher for group 3 when compared
      with group 1 at all six intraoperative intervals (p < 0.02) and for group 2 when
      compared with group 1 at four of six intraoperative intervals (p < 0.04). When
      compared with group 1, tissue cefazolin concentrations were higher for group 3 at
      all intraoperative intervals (p < 0.02). No related toxicity or adverse events
      were observed. CONCLUSION: Cefazolin administered as a large preoperative bolus
      with continuous intraoperative infusion resulted in higher serum and tissue
      concentrations when compared with conventional intermittent dosing.
      Pharmacodynamically, continuous infusion of beta-lactam antibiotics may be
      superior to intermittent dosing when used for perioperative prophylaxis against
      wound infection, especially for cases in which the antibiotic is not redosed
      intraoperatively.

PMID- 12593695
TI  - Outcome analysis of intraabdominal infection with resistant gram-positive
      organisms.
AB  - BACKGROUND: Although the microbiology of intraabdominal infection has been well
      described, the role of resistant organisms remains unclear. To evaluate the
      hypothesis that intraabdominal infections from resistant gram-positive cocci
      (rGPC) have worse outcomes compared to those with susceptible organisms, patient
      characteristics and outcomes were compared between these groups. METHODS:
      Analysis of peritoneal infections was performed on prospectively collected data
      of all consecutive surgical infections from December 1996 to June 1999 at a
      university hospital. Intraabdominal infection was defined either by a positive
      peritoneal cavity culture or on clinical grounds (e.g., abscess), which prompted
      antimicrobial or surgical therapy. Resistant Staphylococcus and Enterococcus spp.
      were defined as those strains resistant to oxacillin, gentamicin, or vancomycin.
      RESULTS: Compared to episodes of intraabdominal infection from susceptible
      organisms (n = 365), infections due to rGPC (n = 52) were associated with an
      increased severity of illness (p < 0.0001), longer time from admission to
      treatment (p < 0.0001), longer duration of therapy (p = 0.008), greater
      proportion of nosocomial infection (p < 0.0001), increased length of stay (p <
      0.0001), and an increased mortality rate (9% versus 23%; p = 0.003). However,
      comparison of intraabdominal infection with rGPC to a group controlled for
      severity of illness demonstrated a prolonged time from admission until treatment
      and longer duration of hospitalization but a similar mortality rate between
      groups (17% versus 23%; p = 0.46). CONCLUSION: Intraabdominal infection with rGPC
      is an indicator of poor prognosis and severe illness. Although not an independent
      predictor of mortality, the significantly increased duration of therapy and
      prolonged duration of hospitalization may have considerable economic impact.

PMID- 12593696
TI  - Impact of community-acquired infection on acquisition of nosocomial infection,
      length of stay, and mortality in adult blunt trauma patients.
AB  - The incidence of community-acquired infections (CA) and how it relates to the
      incidence of nosocomial infections (NI) in the adult blunt trauma population is
      unknown. We evaluated this incidence and assessed the impact of age on morbidity
      and mortality. Prospective data were collected on blunt trauma patients admitted
      >48 h over a 2-year period. Each patient was screened for infection by an
      infectious disease specialist. The Centers for Disease Control and Prevention
      (CDC) guidelines were used to diagnose infection. Of the 2,645 patients admitted,
      86% were <65 years of age and 14% were > or =65 years of age. There was not a
      significant difference in Injury Severity Score (ISS) between the two groups. A
      total of 201 (8.8%) of the younger patients were diagnosed with CA; of these,
      52.2% acquired a NI. Additionally, 65 (17.4%) of the older patients were
      diagnosed with a CA; of these, 57% acquired a NI. The combination of CA and NI
      led to the most significant increases in intensive care (ILOS), hospital (HLOS)
      length of stay, and mortality. Patients with the CA had a significantly greater
      risk of obtaining an NI in both age groups. The relative risk (RR) of an older
      patient presenting with a CA was two times greater than in patients <65 years
      old. The greatest relative risk of mortality (RRM) was demonstrated with the
      combination of CA and NI, and age. However, once infected with both CA and NI,
      younger patients had a greater RRM (5.0 vs. 3.9) in the group-specific
      comparison. CA significantly increases the risk of blunt trauma patients
      acquiring an NI. The combination of CA and NI led to the most significant
      increases in HLOS, ILOS, and mortality. Increased age is associated with a
      significantly higher incidence of CA, ILOS, HLOS, and mortality. Once infected
      with both CA and NI, younger patients have a greater risk of mortality.

PMID- 12593697
TI  - Mycotic aneurysm of the descending thoracic aorta caused by Pseudomonas
      aeruginosa in a solid organ transplant recipient: case report and review.
AB  - BACKGROUND: Pseudomonas aeruginosa is a rare cause of aortic mycotic aneurysms.
      Optimal treatment, including reconstructive graft material and appropriate length
      of antibiotic therapy, is being debated. METHODS: We describe a 26-year-old
      kidney-pancreas recipient who developed an aneurysm of the descending thoracic
      aorta caused by P. aeruginosa. RESULTS: After surgical debridement and
      cryopreserved allograft reconstruction, parenteral antibiotics were continued for
      12 months, at which time the patient was converted to oral antibiotic therapy.
      Within 6 months, he redeveloped a thoracic aortic aneurysm, necessitating
      reoperation and lifelong parenteral antibiotic therapy. CONCLUSION: Herein we
      review and discuss the relevant literature concerning surgical and antibiotic
      treatment of mycotic thoracic aneurysms.

PMID- 12593698
TI  - Peritoneal infection with multiple species of Candida: a case report.

PMID- 12593699
TI  - Profile: Ronald V. Maier, M.D. Interview by Vicki Glaser.

PMID- 12593700
TI  - Infection control is a matter of self control.

PMID- 12593701
TI  - Tertiary peritonitis (recurrent diffuse or localized disease) is not an
      independent predictor of mortality in surgical patients with intraabdominal
      infection.
AB  - BACKGROUND: It is well documented that tertiary peritonitis is associated with
      different microbiological flora and worse outcomes than secondary peritonitis. It
      is unknown, however, if these differences can be explained simply by the
      nosocomial nature of tertiary peritonitis and underlying severity of illness.
      METHODS: We reviewed all episodes of intraabdominal infection on the inpatient
      surgical services at a university hospital over a 46-month period. Univariate
      analysis and logistic regression were used to compare 91 episodes of secondary
      peritonitis that progressed to tertiary peritonitis (recurrent diffuse or
      localized intraabdominal infection) to all episodes of secondary peritonitis (n =
      453) to identify predictors for developing tertiary peritonitis. Logistic
      regression was also used to identify predictors of mortality among patients with
      secondary (n = 473) or tertiary peritonitis (n = 129). RESULTS: Of 602 episodes
      of intraabdominal infection identified, there were 473 episodes of secondary
      peritonitis, including 20 patients who died within seven days of diagnosis. A
      total of 129 episodes of tertiary peritonitis were identified, of which 91 were
      preceded by a single episode of secondary peritonitis, and 38 were preceded by an
      episode of secondary peritonitis and at least one prior episode of tertiary
      peritonitis. Tertiary peritonitis was associated with a high APACHE II score
      (14.9 +/- 0.7), pancreatic or small bowel source, drainage only at initial
      intervention, gram-positive and fungal pathogens, and a high mortality rate
      (19%). Increasing APACHE II score (OR 1.07, 95% CI 1.03-1.16, p = 0.0009)
      independently predicted progression from secondary to tertiary peritonitis while
      increasing age (OR 0.98, 95% CI 0.97-0.99, p = 0.01) and appendiceal source (OR
      0.12, 95% CI 0.02-0.68, p = 0.02) predicted non-progression to tertiary
      peritonitis. Independent predictors of mortality in this population included
      increasing age (OR 1.06, 95% CI 1.03-1.1, p < 0.001), increasing APACHE II score
      (OR 1.18, 95% CI 1.11-1.3, p < 0.001), and four comorbidities: cerebrovascular
      disease (OR 4.3, 95% CI 1.4-13.1, p = 0.01), malignant disease (OR 2.9, 95% CI
      1.3-6.5, p = 0.01), hemodialysis dependency (OR 3.8, 95% CI 1.3-11.2, p = 0.02),
      and liver disease (OR 4.2, 95% CI 1.6-15.1, p = 0.03). Tertiary peritonitis was
      not an independent predictor of mortality. CONCLUSIONS: We were unable to
      demonstrate, when compared to secondary peritonitis, that tertiary peritonitis is
      a significant independent predictor of mortality when other variables are taken
      into account. This suggests that the high mortality associated with tertiary
      peritonitis is more a function of the patient population in which it occurs than
      the severity of the pathologic process itself.

PMID- 12593702
TI  - Reduction of IL-10 and nitric oxide synthesis by SR31747A (sigma ligand) in RAW
      murine macrophages.
AB  - BACKGROUND: There are several subtypes of sigma receptor, one of which is found
      throughout the immune system. SR31747A is a unique sigma ligand that possesses
      potent immune modulatory properties. Previous in vivo studies have documented
      that administration of SR31747A in murine models of sepsis resulted in decreased
      proinflammatory (IL-1, IL-6, TNF-alpha) and increased anti-inflammatory (IL-10)
      response (serum, splenocyte). Studies regarding the effect of this sigma ligand
      on purified macrophages are lacking. We therefore sought to investigate the
      effect of SR31747A in LPS-stimulated murine macrophages (RAW 264.7). METHODS: RAW
      cells were incubated at 2.5 x 10(5) cells/well; controls were incubated with
      media alone, experimental groups contained LPS (0.01 microg) and SR31747A (1 nM,
      10 nM, 100 nM, 1 microM, 10 microM). Supernatant and cells were harvested at 24
      and 48 h. Concentrations of nitric oxide (Greiss reaction) and IL-10 were
      determined in the supernatant; cellular IL-10 mRNA was assessed. RESULTS:
      SR31747A induced a dose-dependent reduction in NO and IL-10 protein release in
      LPS-stimulated murine macrophages. The decrease in IL-10 protein synthesis was
      paralleled by a significant dose-dependent reduction in IL-10 mRNA. CONCLUSION:
      SR31747A is a novel immunomodulator that down regulates nitric oxide and IL-10
      protein and mRNA expression. This in vitro reduction of IL-10 protein and mRNA
      expression is in contrast to previous in vivo murine studies. These data suggest
      that peripheral macrophages are not the source of the increased anti-inflammatory
      (IL-10) response induced by SR31747A.

PMID- 12593703
TI  - Hemorrhagic shock resuscitation with a low molecular weight starch reduces
      neutrophil-endothelial interactions and vessel leakage in vivo.
AB  - BACKGROUND: The polymorphonuclear neutrophil (PMN) has been implicated in the
      pathogenesis of endothelial cell (EC) damage and organ injury following
      hemorrhagic shock. Pentastarch (PTS), a low substituted medium molecular weight
      (MW) colloid, improves hemodynamics in hypovolemic shock and cardiac surgery. No
      data exist comparing the immunomodulation of PTS and Ringer's lactate (RL) on the
      activation of PMN in hemorrhagic shock in vivo. METHODS: Using an in vivo murine
      hemorrhagic shock model (blood withdrawal to maintain 50 mmHg x 45 min),
      circulating PMN were observed every 15 minutes using intravital microscopy on
      cremaster muscle. EC-PMN interactions (videorecorded and subsequently analyzed
      blindly), vessel leakage (live epifluorescence after injection of 50 mg/kg
      fluorescent albumin) and PMN expression of L-selectin (immunofluorescent
      monoclonal antibodies and flow cytometry) were evaluated in three resuscitation
      groups: PTS (7.14 mL/kg 10% pentastarch/0.9% NaCl + shed blood, n = 13), RL (RL
      [2 x shed blood volume] + shed blood, n = 13) and SHAM (0 hemorrhage, 0
      resuscitation, n = 9). Significance was evaluated by ANOVA with Bonferroni
      correction. RESULTS: PMN rolling was significantly diminished in PTS and SHAM as
      compared to RL animals at all time points. Similar differences were found in PMN
      adherence to EC at most time points onwards from 15 minutes following
      resuscitation. In vivo vessel permeability was lowest in SHAM and PTS animals
      (mean 0.274 +/- 0.07 and 0.356 +/- 0.15, respectively, p > 0.05) and highest in
      RL animals (0.667 +/- 0.09, p < 0.001 vs PTS or SHAM). PMN L-selectin expression
      tended to be higher in the RL group than either SHAM and PTS groups. There were
      no flow-mechanics differences between groups (vessel diameter, mean red cell
      velocity, shear stress, shear rate). CONCLUSIONS: 10% pentastarch reduces RL
      associated EC-PMN interactions and vessel leakage following hemorrhagic shock.
      These results support the use of low MW starches to resuscitate hemorrhagic
      shock, potentially reducing PMN-mediated tissue injury.

PMID- 12593704
TI  - Neutrophil apoptosis is delayed by trauma patients' plasma via a mechanism
      involving proinflammatory phospholipids and protein kinase C.
AB  - BACKGROUND: Delayed apoptosis of primed neutrophils (PMNs) may facilitate PMN
      mediated tissue injury leading to multiple organ failure (MOF). We previously
      reported delayed apoptosis and priming of PMNs in severely injured patients at
      risk for MOF. Our in vitro and in vivo data have implicated phospholipids in PMN
      cytotoxicity following trauma and shock. The phospholipid signaling pathway
      remains to be elucidated, but may involve protein kinase C (PKC). We hypothesized
      that circulating platelet-activating factor (PAF) and PAF-like proinflammatory
      phospholipids mediate delayed postinjury PMN apoptosis and that PKC is integral
      to the signaling pathway. METHODS: Blood was drawn from severely injured patients
      (n = 6; mean injury severity score = 21 and transfusion = 10 units) at 6 h
      postinjury. The plasma fraction was isolated and incubated (5% CO(2), 37 degrees
      C, 24 h) with PMNs harvested from healthy volunteers. Some PMNs were preincubated
      with a PAF receptor antagonist (WEB 2170, 400 microM) or a PKC inhibitor (Bis I,
      1 microM). Apoptotic index (% PMNs undergoing apoptosis) was assessed
      morphologically. RESULTS: Trauma patients' plasma delayed PMN apoptosis compared
      with plasma from controls. The PMN apoptotic index was not altered by WEB 2170 or
      Bis I alone; however, WEB 2170 or Bis I pretreatment abrogated delayed PMN
      apoptosis in response to trauma patients' plasma. CONCLUSION: Trauma patients'
      plasma delays apoptosis of PMNs. Our data implicate PAF-like phospholipids in
      this effect, and PKC appears to be integral in the signaling process. Further
      elucidation of specific lipids and signaling pathways may reveal clinically
      accessible therapeutic targets to prevent PMN-mediated hyperinflammation.

PMID- 12593705
TI  - Eradication of multi-drug resistant Acinetobacter from an intensive care unit.
AB  - BACKGROUND: Acinetobacter baumannii is a gram-negative coccobacillus that causes
      outbreaks of nosocomial infections in ICUs. Due to resistance to multiple
      antibiotics, management of clusters of A. baumannii is useful as a model in
      eradication of multi-drug resistant infections. We outline the evolution of an A.
      baumannii outbreak, focusing on methods of transmission and multidisciplinary
      measures aimed at eliminating it from the ICU. METHODS: Patients in an urban,
      tertiary care medical center from November 1996 to December 1997 having positive
      cultures for multi-drug resistant A. baumannii are included in this study. A.
      baumannii was isolated on blood agar and MacConkey cultures and identified by
      Vitek panel. Disk diffusion including amikacin, imipenem, polymyxin B, and
      sulbactam were used to determine resistance. RESULTS: An outbreak of 52 patients
      (27 infected, 25 colonized) with 68 positive sites began with the transfer of a
      colonized >50% total body surface area burn patient from an outside hospital.
      Within 3 days, the index patient was in the burn ICU, coronary care unit, and
      medical ICU. Soon, clusters of patients with A. baumannii infections sensitive
      only to polymyxin B were seen in those units and, ultimately, the surgical ICU.
      On typing, 2 strains were found, PFGE B and C. Given the level of antibiotic
      resistance, patients with colonization or infection were cohorted and placed on
      contact isolation. Strict antiseptic measures, such as hand-washing, barrier
      isolation, equipment and room cleaning, sterilization of ventilator equipment,
      and dedication of medical equipment to each patient were instituted. Still,
      positive environmental cultures were found in ventilator water traps, sinks, and
      bedrails. Sporadic cases continued for a total of 13 months, with 10 deaths
      resulting from the infections. CONCLUSION: A. baumannii is a mildly virulent
      organism that becomes resistant to antimicrobials. Because of multiple antibiotic
      resistance, strict contact isolation cohorting and antiseptic technique are the
      primary modes of containment. This outbreak serves as a model of eradication of
      multi-drug resistant organisms from ICUs. These measures will become of greater
      importance as nosocomial organisms develop increasing resistance to
      antimicrobials.

PMID- 12593706
TI  - Plasma complement C5 protects endothelial cells from polymorphonuclear neutrophil
      derived, H2O2-mediated cytotoxicity.
AB  - BACKGROUND: In vitro studies suggest that polymorphonuclear neutrophils (PMN) can
      damage endothelial cells (EC) by releasing hydrogen peroxide. In vivo this can
      lead to anasarca secondary to capillary leakage of fluid, protein, and
      electrolytes. The result is multiple organ dysfunction syndrome, which is
      associated with high mortality. In vivo, circulating PMN-EC interactions take
      place in the presence of plasma, and we have shown previously that plasma affords
      protection to EC from PMN-mediated damage. METHODS: Human umbilical vein
      endothelial cells were primed with cytokines, cultured to a confluent monolayer,
      and coincubated with normal human PMNs. Cytotoxicity was assayed by gamma
      scintigraphy, plasma C5 was determined by sepharose column elution, and H(2)O(2)
      was assayed by R-Phycoerythrin fluorescence. RESULTS: Addition of C5, but not C3,
      to RPMI resulted in EC cytoprotection equivalent to adding whole serum. Removal
      of C5 from serum using F(ab')(2) rabbit IgG anti-human C5 coupled to CNBr
      activated 4 sepharose beads resulted in significant loss of EC cytoprotection
      against H(2)O(2)-mediated damage, whereas adding back C5 restored the
      cytoprotection. C5 also reduced H(2)O(2)-mediated destruction of R-Phycoerythrin.
      CONCLUSIONS: The data suggest that the protection of EC against hydrogen peroxide
      mediated damage is partly mediated through complement component C5.

PMID- 12593707
TI  - Attenuation of pancreatitis-induced pulmonary injury by aerosolized hypertonic
      saline.

PMID- 12593708
TI  - In vino veritas.

PMID- 12593709
TI  - Late immunoneutralization of procalcitonin arrests the progression of lethal
      porcine sepsis.
AB  - BACKGROUND: Procalcitonin (ProCT) is becoming increasingly recognized as a
      mediator as well as a marker of sepsis. Serum ProCT concentrations rise soon
      after induction of sepsis and remain elevated over a prolonged period of time. In
      contrast, many pro-inflammatory cytokines, e.g., tumor necrosis factor alpha (TNF
      alpha) and interleukin-1 beta (IL-1beta), rise and decline early in the course of
      sepsis. Researchers have improved survival in animal models of sepsis by
      prophylactically blocking IL-1beta and TNF-alpha with immunotherapy, but
      therapeutic treatment has been less successful in clinical trials. We
      hypothesized that the sustained elevation of ProCT in the serum would allow for
      effective therapeutic immunoneutralization of this peptide late in the course of
      sepsis. METHODS: Lethal polymicrobial sepsis was induced in 10 castrated, male
      Yorkshire pigs by intraabdominal spillage of cecal contents (1 gm/kg) and
      intraabdominal instillation of 2 x 10(11) cfu of a toxigenic strain of E. coli
      (O18:K1:H7). The treated group (n = 5) received an intravenous infusion of
      purified rabbit antiserum to the aminoterminus of porcine ProCT. The control
      group (n = 5) received nonreactive, purified rabbit IgG. The purified antiserum
      was infused to all animals 3 h after the induction of sepsis, at which time very
      severe physiologic dysfunction was manifest, and many of the animals appeared to
      be preterminal. Physiologic and metabolic parameters were measured until death or
      for 15 h after induction of sepsis, at which time all surviving animals were
      euthanized. RESULTS: Therapeutic immunoneutralization of serum ProCT improved
      most measured physiologic and metabolic parameters in septic pigs. Specifically,
      there was a significant increase in mean arterial pressure, urine output and
      cardiac index in all animals treated with ProCT antibody. Serum creatinine was
      significantly lower in treated animals. Although acidosis was not as severe in
      treated animals, as indicated by higher pH values and lower lactate
      concentrations, these results did not achieve statistical significance.
      Significantly, 11 h after the induction of sepsis there was 100% mortality in the
      control group while only one animal in the treated group expired. CONCLUSION: The
      prolonged elevation of ProCT concentrations in sepsis allows neutralization of
      this peptide to be effective during the course of this disorder. These findings
      suggest that immunoneutralization of ProCT may be a useful treatment in clinical
      situations where sepsis is already fully established.

PMID- 12593710
TI  - A prospective evaluation of the use of emergency department computed tomography
      for suspected acute appendicitis.
AB  - BACKGROUND: Computed tomography (CT) is used increasingly to evaluate suspected
      cases of acute appendicitis (AA) in the emergency department (ED). This
      prospective study was performed to test the hypothesis that the evaluation of AA
      by CT in the ED remains suboptimal and that erroneous interpretation diminishes
      its utility. METHODS: Consecutive patients 18 years of age or older were enrolled
      prospectively if AA was among the first three differential diagnoses listed in
      the record of patients undergoing evaluation of abdominal pain in the ED. Imaging
      of the abdomen and pelvis was obtained at the discretion of the ED staff or
      consultant surgeon. Initial CT interpretation was by a radiology resident or
      fellow along with the surgical staff, but final review by an attending
      radiologist occurred later. Age, gender, presenting symptoms, white blood cell
      (WBC) count, final CT results, and final pathology (for patients undergoing
      operation) were recorded. X +/- SEM, p < 0.05 by chi(2), ANOVA, or MANOVA was
      used for statistical analysis as appropriate. RESULTS: A CT scan was performed in
      104 patients (83% of those meeting entry criteria), 35 of whom were male (mean
      age, 37 +/- 2 years) and 69 of whom were female (mean age, 39 +/- 3 years).
      Thirty-five patients had pathologically proved appendicitis, 28 of whom were
      diagnosed prospectively by CT. There were seven false-negative scans.
      Sensitivity, specificity, and positive predictive value for the initial CT
      reading were 80%, 91%, and 82%, respectively. Gender (p < 0.03), WBC count (p <
      0.0002), and a positive initial CT reading (p < 0.0001) correlated with operative
      management. However, although final CT interpretation did correlate with
      pathologic confirmation of AA (p < 0.0001), initial CT interpretation did not
      correlate with the presence of AA (p = 0.52). CONCLUSION: The ability of CT to
      predict AA is dependent on the interpretative skill of the individual
      interpreting the images. Widespread use of CT in the evaluation of patients for
      AA should be implemented with caution until institution-specific protocols are
      validated.

PMID- 12593711
TI  - Attenuation of pancreatitis-induced pulmonary injury by aerosolized hypertonic
      saline.
AB  - BACKGROUND: The immunomodulatory effects of hypertonic saline (HTS) provide
      potential strategies to attenuate inappropriate inflammatory reactions. This
      study tested the hypothesis that administration of intratracheal aerosolized HTS
      modulates the development of lung injury in pancreatitis. METHODS: Pancreatitis
      was induced in 24 male Sprague-Dawley rats by intraperitoneal injection of 20% L
      arginine (500 mg/100 g body weight). At 24 and 48 h, intratracheal aerosolized
      HTS (7.5% NaCl, 0.5 mL) was administered to 8 rats, while a further 8 received
      0.5 mL of aerosolized normal saline (NS). At 72 hours, pulmonary neutrophil
      infiltration (myeloperoxidase activity) and endothelial permeability
      (bronchoalveolar lavage and wet:dry weight ratios) were assessed. In addition,
      histological assessment of representative lung tissue was performed by a blinded
      assessor. In a separate experiment, polymorphonucleocytes (PMN) were isolated
      from human donors, and exposed to increments of HTS. Neutrophil transmigration
      across an endothelial cell layer, VEGF release, and apoptosis at 1, 6, 12, 18,
      and 24 h were assessed. RESULTS: Histopathological lung injury scores were
      significantly reduced in the HTS group (4.78 +/- 1.43 vs. 8.64 +/- 0.86); p <
      0.001). Pulmonary neutrophil sequestration (1.40 +/- 0.2) and increased
      endothelial permeability (6.77 +/- 1.14) were evident in the animals resuscitated
      with normal saline when compared with HTS (0.70 +/- 0.1 and 3.57 +/- 1.32),
      respectively; p < 0.04). HTS significantly reduced PMN transmigration (by 97.1, p
      = 0.002, and induced PMN apoptosis (p < 0.03). HTS did not impact significantly
      upon neutrophil VEGF release (p > 0.05). CONCLUSIONS: Intratracheal aerosolized
      HTS attenuates the neutrophil-mediated pulmonary insult subsequent to
      pancreatitis. This may represent a novel therapeutic strategy.

PMID- 12593712
TI  - Catheter materials affect the incidence of late blood-borne catheter infection.
AB  - BACKGROUND: Adherence of bacteria and subsequent catheter-related infections
      (CRI) are greatly enhanced by the fibrin sheath that develops on indwelling
      catheters. Since the infection rate of catheters without fibrin sheaths is low
      and the fibrin sheath mediates bacterial adherence, catheter material is not
      thought to affect the incidence of late catheter-related infection. METHODS: A
      total of 276 rats had catheters placed in the right jugular vein with the
      proximal end buried subcutaneously to eliminate exit site infection. Rats were
      divided into two groups: silastic catheters (SC; n = 133) and polyurethane
      catheters (PC; n = 143). Injections of 1 x 10(8) CFU/mL of Staphylococcus
      epidermidis were given via the tail vein on either the day of surgery, day 0 (n =
      53 SC, n = 51 PC), or on postoperative day 10 (n = 50 SC, n = 62 PC). Thirty
      animals from each group (SC, PC) received sterile saline injections on day 10 and
      served as controls. Animals were sacrificed on postinjection day 3. Catheters
      were removed via the chest and placed into trypticase soy broth. Broth was
      incubated at 37 degrees C for 48 h. Microscopy for the fibrin sheath was done on
      20 randomly selected catheters (10/group). Data were compared using Fisher's
      exact test, with p < 0.05 considered significant. RESULTS: Incidence of CRI was
      equal prior to the formation of the fibrin sheath, while CRI was significantly
      higher in silastic catheters in the presence of a fibrin sheath. Without a fibrin
      sheath (day 0), 8/53 silastic catheters and 3/51 polyurethane catheters were
      infected (p = NS). With a fibrin sheath (day 10), 31/50 silastic catheters were
      infected versus 20/62 polyurethane catheters (p < 0.05). Control catheters were
      all culture negative (30/group). With light microscopy, 20/20 catheters had
      fibrin sheaths at day 10 with no visible difference between silastic and
      polyurethane catheters. CONCLUSION: Catheter material does affect the incidence
      of catheter-related infection even when catheters are coated with a fibrin
      sheath. This difference may relate to a difference in the fibrin sheath itself as
      it forms on different catheter materials.

PMID- 12593713
TI  - The female gender protects against pulmonary injury after trauma hemorrhagic
      shock.
AB  - BACKGROUND: Previously, we have documented that lung injury after trauma
      hemorrhagic shock (T/HS) is related to gut injury and that females are more
      resistant to T/HS-induced lung injury than males. However, it is not known if the
      estrus cycle stage at the time of injury influences the female rat's resistance
      to T/HS-induced lung injury. Therefore, the goal of this study was to determine
      if the protective effect of the female gender on lung injury after T/HS is estrus
      cycle stage-specific. To test this hypothesis, female rats were subjected to
      trauma (laparotomy) and hemorrhagic shock (T/HS) during different stages of the
      estrus cycle. Female animals subjected to trauma with sham hemorrhagic shock
      served as the control. METHODS: Female Sprague-Dawley rats during the proestrus,
      estrus, metestrus, or diestrus stages of the menstrual cycle were subjected to a
      midline laparotomy (trauma) and either hemorrhagic shock (MAP = 30 mm Hg x 90
      min) or sham shock. The total volume of blood necessary to induce and maintain
      the shock state was recorded. At the end of the shock period, the animals were
      resuscitated with their shed blood. At 6 h postresuscitation, the animals were
      sacrificed and lung permeability was measured using the Evans blue dye technique
      and by determining the bronchoalveolar (BALF) to plasma protein ratio.
      Additionally, pulmonary leukosequestration was quantitated by measuring pulmonary
      myeloperoxidase levels. RESULTS: T/HS-induced lung injury and increased pulmonary
      leukosequestration were not observed in female rats in the proestrus or estrus
      stages of the menstrual cycle. In contrast, pulmonary permeability was increased
      significantly in the diestrus stage animals after T/HS. That is, the diestrus
      females subjected to T/HS had increased pulmonary permeability to Evans blue dye
      than sham or T/HS proestrus, estrus, and metestrus rats (6.49 +/- 1.33% versus
      1.7 +/- 0.87%, 1.57 +/- 0.54%, 1.78 +/- 0.82%, 3.33 +/- 0.68%, p < 0.01,
      respectively). Similar results were obtained with the BALF protein/plasma protein
      ratio (0.15 +/- 0.017 versus 0.09 +/- 0.009, 0.09 +/- 0.03, 0.08 +/- 0.022, 0.11
      +/- 0.029 p < 0.05, respectively). Although the T/HS metestrus rats had mildly
      increased lung permeability, this increase in T/HS-lung permeability did not
      reach statistical significance. Pulmonary myeloperoxidase levels after T/HS
      displayed a similar trend, with diestrus rats subjected to T/HS having the
      highest level of MPO (p < 0.05 versus sham or T/HS proestrus and estrus but not
      metestrus groups). Linear regression analysis of MPO versus Evans blue dye leak
      revealed a significant correlation between pulmonary neutrophil sequestration and
      lung leak (r = 0.9549; p < 0.0001). CONCLUSION: Protection against T/HS-induced
      lung injury was greatest during the estrus and proestrus stages of the menstrual
      cycle and decreased with progression to diestrus. During the diestrus stage of
      the menstrual cycle when gonadal hormone levels are lowest, the rats are more
      sensitive to T/HS-induced lung injury, indicating that gonadal hormones modulate
      T/HS-induced lung injury.

PMID- 12593714
TI  - Handwashing compliance depends on professional status.
AB  - BACKGROUND: Nosocomial infections can be transmitted from microorganisms on the
      hands of health care workers to patients. Handwashing (HW) has a proven benefit
      in preventing transmission of infection, yet compliance with handwashing,
      especially in intensive care units, ranges between 28% and 74%. METHODS: To
      determine if HW behavior varies as a function of health care professional status
      and patient interaction, we conducted an observational study of a surgical
      intermediate care unit in a large university teaching hospital. HW compliance was
      observed among all health care workers (HCW): physicians (MD; N = 46), nurses
      (RN; N = 295), and nursing support personnel (NSP; N = 93). Over an 8-week
      period, unidentified, trained observers documented all HCW interactions in 1-h
      random blocks. HW opportunities were classified into low and high risk of
      pathogen acquisition and transmission. RESULTS: A total of 493 HW opportunities
      were observed, of which 434 involved MD, RN, and NSP. Two hundred and sixty-one
      low-risk (MD 35, RN 171, NSP 55) and 173 (MD 11, RN 124, NSP 38) high-risk
      interactions were observed. Overall HW rates were low (44%). Significant
      differences existed among HCW, with MDs being the least likely to wash (15%
      versus RN 50%, NSP 37%, p < 0.01). In adjusting for high-risk situations, MDs
      (odds ratio [OR] 5.58, 95% CI 2.49-12.54; NSP, OR 1.73, 95% CI 1.13-2.64; RN, OR
      0.98, 95% CI 0.77-1.23) were significantly less likely to perform HW when
      compared to RNs. Nursing groups were significantly less likely to wash in low
      risk versus high-risk situations (MD 9.2% versus 17.1%; RN 69.4% versus 39.6%;
      NSP 85% versus 23.3%), suggesting individual discrimination of the importance of
      HW. Although nurses were less likely to wash in high-risk situations compared to
      NSP, the overall number of opportunities was greater, suggesting that improvement
      in HW to the level of NSP could have a major impact on infection transmission.
      CONCLUSION: Significant opportunities exist for quality improvement, novel
      educational strategies, and assessment of reasons why MDs and, to a lesser
      extent, RNs fail to follow simple HW practices.

PMID- 12593716
TI  - Monoclonal antibodies with thyroid stimulating activity, at last.

PMID- 12593717
TI  - Thyroid-stimulating monoclonal antibodies.
AB  - Thyrotropin (TSH) receptor monoclonal antibodies (TSHR mAbs) were obtained from
      cDNA-immunized NMRI mice. Three mAb immunoglobulin Gs (IgGs) (TSmAbs 1-3) that
      had distinct V(H )and V(L) region sequences stimulated cyclic adenosine
      monophosphate (cAMP) production in isolated porcine thyroid cells greater than
      10x basal and as little as 20 ng/mL (0.13 nmol/L) of TSmAb 1 IgG caused a 2x
      basal stimulation. TSmAb 1 and 2 Fab fragments were also effective stimulators
      and thyroid-stimulating activities of the IgGs and Fabs were confirmed using TSHR
      transfected Chinese hamster ovary (CHO) cells. The TSmAbs also inhibited (125)I
      labeled TSH binding to TSHR-coated tubes by 50% or more at concentrations of 1
      microg/mL or less and gave 15%-20% inhibition at 20-50 ng/mL. (125)I-labeled
      TSmAbs bound to TSHR-coated tubes with high affinity (approximately 10(10) L/mol)
      and this binding was inhibited by TSHR autoantibodies with both TSH agonist and
      antagonist activities. Inhibition of labeled TSmAb binding by Graves' sera
      correlated well with inhibition of TSH binding (r = 0.96; n = 18; p < 0.001 for
      TSmAb 2). The TSmAbs have considerable potential as (1) new probes for TSHR
      structure-function studies, (2) reagents for new assays for TSHR autoantibodies,
      and (3) alternatives to recombinant TSH in various in vivo applications.

PMID- 12593718
TI  - Characterization of the thyrotropin binding pocket.
AB  - A panel of monoclonal antibodies (mAbs) to the thyrotropin receptor (TSHR) was
      prepared using three different immunization strategies. The mAbs obtained (n =
      138) reacted with linear epitopes covering most of the TSHR extracellular domain
      and with conformational epitopes. mAbs that bound to five different regions of
      the TSHR (amino acids [aa] 32-41, aa 36-42, aa 246-260, aa 277-296, and aa 381
      385) were able to inhibit (125)I-labeled thyrotropin (TSH) binding to solubilized
      TSHR preparations. Fab and immunoglobulin G (IgG) preparations were similarly
      effective inhibitors for mAbs reactive with aa 246-260, aa 277-291 and aa 381-385
      suggesting that these three regions of the TSHR are involved in TSH binding. In
      contrast mAbs reactive with aa 32-41 and aa 36-42 were not effective at
      inhibiting TSH binding when Fab preparations were used, suggesting that these N
      terminal regions of the TSHR were less critical for TSH binding. Our studies
      suggest that three distinct and discontinuous regions of the TSHR (aa 246-260 and
      277-296 on the TSHR A subunit) and aa 381-385 (on the TSHR B subunit) fold
      together to form a complex TSH binding pocket. Alignment of the aa sequences of
      these three regions in TSHRs from different species indicates that they are
      highly conserved.

PMID- 12593719
TI  - Combretastatin A4 phosphate has primary antineoplastic activity against human
      anaplastic thyroid carcinoma cell lines and xenograft tumors.
AB  - Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of
      which is unaltered by current therapeutic modalities. A recent phase 1 clinical
      trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total
      remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the
      African bush willow, Combretum caffrum, which possesses tumor vascular-targeting
      activity. In order to discriminate primary antineoplastic effects from tumor
      antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell
      lines and compared it to paclitaxel, another tubulin-binding agent with
      significant clinical activity. CA4P displayed significant cytotoxicity against
      the ATC cell lines, comparable to that of paclitaxel, and these effects were
      longer lasting in two cell lines compared to the duration of paclitaxel. We
      further investigated the effects of CA4P on xenograft tumors from four ATC cell
      lines injected in athymic nude mice. Significantly lower tumor weights were
      observed in animals treated with CA4P compared to those treated with vehicle
      alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell
      lines also revealed a significantly lower rate of tumor growth in the CA4P
      treated mice compared to those receiving vehicle alone. These results suggest
      that antitumoral effects of CA4P can be consequent to a combination of primary
      antineoplastic effects as well as the potential destruction of tumor vasculature.

PMID- 12593720
TI  - Differential modulation of liver and pituitary triiodothyronine and 9-cis
      retinoid acid receptors by insulin-like growth factor I in rats.
AB  - Triiodothyronine (T(3)) exerts most of its effects through nuclear thyroid
      hormone receptors (TRs) that bind mainly as heterodimers with retinoid-X
      receptors (RXRs) to thyroid hormone response elements in target genes. It is well
      known that T(3) activates the growth hormone (GH)-insulin-like growth factor I
      (IGF-I) axis in rats. In turn, IGF-I inhibits the T(3)-induced GH production in
      cell cultures. The impact of IGF-I on T(3) action has only been partially
      explored. We have presented evidence that IGF-I feeds back to limit specific
      metabolic actions of T(3) in rat liver through a downregulation of nuclear TR
      number and its mRNA expression. We have also found that IGF-I injected to rats
      inhibited pituitary GH production. In this study we aimed at exploring whether
      the IGF-I-induced feedback loop on T(3)-action in the liver also operates in the
      pituitary gland. The mechanism of the liver TR mRNA reduction induced by IGF-I
      was also studied. We evaluated the effect of recombinant human (rh) IGF-I
      administration (240 microg/100 g of body weight subcutaneously every 12 hours for
      48 hours) to adult male Wistar rats on TR and RXR proteins (Western blot) from
      pituitary, liver, brain, and thyroid and TR mRNA (Northern blot) from pituitary
      and liver. The transcriptional rate of liver TR gene (run-on assay) was also
      determined. In pituitary, TR protein and TR mRNA isoforms were reduced by rhIGF
      I. No changes in TR proteins in brain and thyroid were observed. Nuclear run-on
      assay revealed that IGF-I reduced the TR gene transcriptional rate in liver. A
      significant increase in RXR proteins in liver and pituitary without changes in
      thyroid and brain was induced by IGF-I. In conclusion, these results indicate
      that in pituitary, IGF-I downregulates TR expression, similarly as previously
      found in liver. A reduced transcriptional rate of TR gene is implicated in the
      IGF-I effect on the liver. The increase in RXR protein levels may be also
      involved in the expression of T(3) specific actions in liver and pituitary.

PMID- 12593721
TI  - A germline single nucleotide polymorphism at the intracellular domain of the
      human thyrotropin receptor does not have a major effect on the development of
      Graves' disease.
AB  - Graves' disease (GD) is caused by an interplay of genetic factors and
      environmental triggers. The major antigen in GD is the thyrotropin receptor
      (TSHR) on the surface of the thyroid epithelial cell. Population-based case
      control studies have largely shown no association of GD with the D36H (Asp to
      His) and P52T (Pro to Thr) single nucleotide polymorphisms (SNPs) in the N
      terminal region of the extracellular domain of the TSHR gene in Caucasian
      populations. Recently, a D727E (Asp to Glu) SNP in the intracellular C-terminal
      domain of the TSHR was reported to be associated with GD in a Russian population.
      In the present study we assessed whether the codon 727 SNP is associated with GD
      in a Caucasian population. We found no significant differences in codon 727 SNP
      frequencies between GD patients and controls. In addition, our results did not
      show an effect of the SNP on the GD phenotype and on disease severity. Further
      analysis showed no evidence that the TSHR 727 SNP modulated the risk for GD
      conferred by HLA (DR3) and/or CTLA-4 (SNP 49 G allele) genes. A meta-analysis
      combining our data and those of 2 previous studies showed a very weak association
      between the D727E SNP and GD (p = 0.03, relative risk = 1.6). Therefore, we
      concluded that the TSHR gene is not a major gene for GD in our population.

PMID- 12593722
TI  - Evidence that the complement control protein-epidermal growth factor-like domain
      of thyroid peroxidase lies on the fringe of the immunodominant region recognized
      by autoantibodies.
AB  - There is no consensus regarding the location of the immunodominant region (IDR)
      on thyroid peroxidase (TPO) recognized by the majority of autoantibodies. Strong
      evidence indicates that it lies upstream of amino acid 741. However, an epitope
      has been localized to downstream residues 742-848 encompassing a disulfide-rich
      complement control protein (CCP)-like and epidermal growth factor (EGF)-like
      domain. To determine whether these domains comprise part of the IDR, we used a
      recombinant CCP/EGF-like polypeptide to screen a thyroid B-cell-derived
      immunoglobulin gene phage display library. Two unusual TPO autoantibodies were
      isolated. Neither was among the 83 clones previously obtained by panning the same
      library on native or denatured TPO, or TPO with the IDR masked. Fab from these
      clones bound native TPO, one with high affinity (Kd 6 x 10(-10) M), and both
      recognized TPO expressed on the surface of mammalian cells. Phage-expressing
      multiple copies of the antibody (multivalent), but not monovalent Fab from these
      clones, bound to the CCP/EGF polypeptide. Most important, inhibition of TPO
      binding by autoantibodies to the IDR indicated that the epitopes of the two new
      autoantibodies overlap with this region. The value of these two rare clones lies
      in the insight they provide into the location of the TPO IDR. From their binding
      characteristics, we deduce that the CCP/EGF-like domain lies on the fringe of the
      TPO immunodominant region.

PMID- 12593723
TI  - Polymerase chain reaction in the detection of tumor cells: new approaches in
      diagnosis and follow-up of patients with thyroid cancer.
AB  - Thyroid cancers are the most common endocrine malignancies and are being
      diagnosed with increasing frequency. In addition to other measures, diagnosis is
      based on fine-needle aspiration cytology examination. Recently, new assays using
      reverse transcription-polymerase chain reaction (PCR) are being tested to improve
      sensitivity and specificity of primary diagnosis and detection of recurrent
      thyroid cancer. In the preoperative diagnosis of thyroid cancer, several tissue-
      and/or tumor-specific mRNA have been described and in several cases, a higher
      sensitivity and specificity could be achieved using molecular techniques compared
      to conventional methods. In the postoperative follow-up of patients with thyroid
      cancer, conflicting data have been published and the use of PCR techniques
      revealed several problems of the molecular approach, which are based on some
      technical as well as biologic limitations. Despite these problems, which are
      discussed in detail in this review, molecular techniques may nevertheless improve
      the sensitivity and accuracy of fine-needle aspiration of thyroid nodules, fine
      needle aspiration of metastases, and detection of recurrent disease in peripheral
      blood samples.

PMID- 12593724
TI  - Is preoperative investigation of the thyroid justified in patients undergoing
      parathyroidectomy for hyperparathyroidism?
AB  - BACKGROUND: The finding of coexisting nodular thyroid disease during neck
      exploration for hyperparathyroidism (HPT) is reported to range from 20%-60%.
      Thus, the surgeon may encounter a second, unrelated lesion during open
      parathyroidectomy. Furthermore, with the recent introduction of minimally
      invasive surgery for HPT, the entire neck may not be explored, and it is
      important to know the potential risk of missing significant, concurrent thyroid
      disease. The diagnosis and timely treatment of associated thyroid abnormalities
      is desirable because a delay in operating would result in increased morbidity
      associated with a second neck exploration. DESIGN: We examined our 25-year
      experience at a large tertiary academic medical center, to determine the
      incidence and type of concurrent thyroid disease seen in patients with HPT. The
      computerized records of the Department of Pathology, from 1974-1999, were
      reviewed for patients with primary HPT who underwent surgery. RESULTS: A review
      of records from 580 patients who underwent surgery for primary HPT showed 103
      (18%) patients with concomitant thyroid disease at surgery. All 103 underwent
      thyroid resection at the time of parathyroidectomy. Thyroid histology showed: 12
      (12%): well-differentiated papillary carcinomas, 31 (30%): follicular adenomas,
      49 (48%): nodular hyperplasias, 8 (8%): chronic lymphocytic thyroiditis, 1 benign
      cyst, 1 metastasis, and 1 normal. CONCLUSIONS: Synchronous thyroid disease was
      found in 18% of primary HPT patients undergoing surgery, and 12% of thyroid
      lesions were malignant. The overall malignancy rate was 2%. All primary
      malignancies found were papillary carcinomas, of which 7 of 12 (58%) were
      microcarcinomas. The significant association of simultaneous pathology in the two
      glands justifies preoperative thyroid imaging and fine-needle aspiration (FNA)
      biopsy to determine the best surgical approach for patients with HPT.

PMID- 12593725
TI  - Serum activin A levels in different thyroid disorders.
AB  - Activin A belongs to the transforming growth factor-beta superfamily that exerts
      a wide range of biologic activities on cellular proliferation and
      differentiation. Although it was suggested that gonadal tissue is the primary
      site of activin production, several extragonadal sources have subsequently been
      identified, including human thyrocytes. The goal of the present study was to
      evaluate serum activin A levels in a series of patients with different thyroid
      disorders during the active state of the diseases and after recovery. Serum
      activin A levels were evaluated in 60 healthy subjects (controls), 8 with
      multinodular nontoxic goiter (MNG), 30 hyperthyroid (15 with Graves' disease
      (GD), 12 with autonomous hyperfunctioning adenoma (ATA), and 3 with thyrotropin
      (TSH)-secreting pituitary adenoma, 16 hypothyroid (11 with Hashimoto's
      thyroiditis and 5 after total thyroidectomy), and 9 patients with resistance to
      thyroid hormone (RTH) by commercial enzyme-linked immunosorbent assay (ELISA)
      kit. Patients with GD and ATA showed activin A levels higher than those found in
      controls and similar to those observed in MNG (GD, 0.74 +/- 0.3 ng/mL; ATA, 0.86
      +/- 0.4; and MNG; 1.0 +/- 0.2 vs. controls: 0.39 +/- 0.5, p < 0.001), while in
      patients with Hashimoto's thyroiditis, total thyroidectomy or RTH activin A
      levels were similar to those of controls. In conclusion, this study demonstrates
      that thyroid hyperplasia and hyperfunction result in increased levels of activin
      A, although the normal levels observed in thyroidectomized patients clearly
      demonstrate that the thyroid gland is not the predominant source of activin A in
      normal conditions. Because activin A may exert negative action on thyrocyte
      proliferation, it is conceivable that activin A hypersecretion in thyroid
      disorders might represent a counteracting mechanism.

PMID- 12593726
TI  - Relapse of Graves' disease after successful outcome of antithyroid drug therapy:
      results of a prospective randomized study on the use of levothyroxine.
AB  - Antithyroid drugs are effective in restoring euthyroidism in Graves' disease, but
      many patients experience relapse after withdrawal. Prevention of recurrence would
      therefore be a desirable goal. In a prospective study, patients with successful
      outcome of 12 to 15 months antithyroid drug therapy were stratified for risk
      factors and randomly assigned to receive levothyroxine in a variable thyrotropin
      (TSH)-suppressive dose for 2 years or no treatment. The levothyroxine group was
      randomized to continue or discontinue levothyroxine after 1 year. End points
      included relapse of overt hyperthyroidism. Of 346 patients with Graves' disease
      enrolled 225 were euthyroid 4 weeks after antithyroid drug withdrawal and were
      randomly assigned to receive levothyroxine (114 patients) or no treatment
      (controls, 111 patients). Of those not randomized, 39 patients showed early
      relapse within 4 weeks, 61 endogenous TSH suppression, 7 TSH elevation, and 14
      had to be excluded. Dropout rate during the study were 13.3%. Kaplan-Meier
      analyses showed relapse rates to be similar in the levothyroxine group (20% after
      1 year, 32% after 2 years) and the randomized controls (18%, 24%), whereas
      relapses were significantly more frequent in the follow-up group of patients with
      endogenously suppressed TSH (33%, 49%). Levothyroxine therapy did not influence
      TSH-receptor antibody, nor did it reduce goiter size. The best prognostic marker
      available was basal TSH determined 4 weeks after withdrawal of antithyroid drugs
      (posttreatment TSH). The study demonstrates that levothyroxine does not prevent
      relapse of hyperthyroidism after successful restoration of euthyroid function by
      antithyroid drugs and characterizes posttreatment TSH as a main prognostic
      marker.

PMID- 12593727
TI  - A C/T single-nucleotide polymorphism in the region of the CD40 gene is associated
      with Graves' disease.
AB  - Graves' disease (GD) develops as a result of an interaction between
      susceptibility genes and environmental factors. We have previously mapped a
      susceptibility locus for GD on chromosome 20q11 (GD-2), which has recently been
      independently replicated. Among the genes mapped to 20q11 was the CD40 gene, an
      important costimulatory molecule and a good positional candidate gene for GD. We
      investigated whether the CD40 gene was the GD susceptibility gene on 20q11.
      Linkage analysis in a subset of Caucasian families showed a maximum multipoint
      logarithm of odds (LOD) score of 3.3 at the CD40 locus. We then sequenced all 9
      exons of the CD40 gene in 8 probands and 10 controls and identified a new C/T
      single-nucleotide polymorphism (SNP) in the Kozak sequence of the CD40 gene at
      position -1. Case control association analysis of the CD40 C/T(-1) SNP in 154
      Caucasian patients with GD and 118 Caucasian controls showed an association
      between the CC genotype and GD (p = 0.048, relative risk [RR] = 1.6).
      Furthermore, the association was stronger when only the probands from the linked
      families (n = 20) were used (p = 0.009, RR = 4.8). Transmission disequilibrium
      test (TDT) analysis also showed preferential transmission of the C allele of the
      CD40 C/T(-1) SNP to affected individuals (p = 0.02). In conclusion, our results
      suggested that the CD40 gene was a new susceptibility gene for GD within certain
      families because it was both linked and associated with GD.

PMID- 12593728
TI  - Primary tuberculosis of the thyroid gland: report of three cases.
AB  - We report on three cases with rapidly increasing thyroid masses who were referred
      with the provisional diagnosis of thyroid carcinoma. In the two cases, the
      diagnosis of tuberculosis was established after thyroidectomy, but in the third
      case diagnosis was made pre-operatively with acid fast bacilli (AFB) staining and
      culture from fine needle aspiration (FNA) material. Although rare, tuberculosis
      of the thyroid gland should be included in the differential diagnosis of thyroid
      masses. FNA, AFB staining and culture of the aspirate are important diagnostic
      tools in these cases.

PMID- 12593729
TI  - Congenital isolated central hypothyroidism caused by a "hot spot" mutation in the
      thyrotropin-beta gene.
AB  - Two adult siblings presented to our practice with a known history of congenital
      central isolated hypothyroidism. Their growth, development, and general health
      had been normal. Although the disorder was known to result from thyrotropin (TSH)
      deficiency, providers in the past had made multiple adjustments in their
      levothyroxine replacement doses in attempts to normalize serum TSH levels. This
      suggests a need for better education of providers who care for patients with
      central hypothyroidism. We performed DNA sequencing of the TSHbeta gene and
      identified a homozygous single base deletion in codon 105, on exon 3, resulting
      in a frameshift and a premature termination signal at codon 114. This same
      mutation (C105FS114X) has been previously reported in South America and Europe
      and appears to be the most common genetic mutation associated with congenital
      isolated TSH deficiency. The identification of this mutation for the first time
      in the United States suggests that this disorder, now described in patients from
      countries on multiple continents, is more common than previously appreciated and
      may be a mutational "hot spot."

PMID- 12593730
TI  - Association of lichen sclerosus and autoimmune thyroiditis: possible role of
      Borrelia burgdorferi?

PMID- 12593731
TI  - Cutaneous lichen amyloidosis in multiple endocrine neoplasia type 2A.

PMID- 12593732
TI  - Adjuvant effect of lithium on radioiodine treatment of hyperthyroidism.

PMID- 12593736
TI  - Haemagglutinins of pathogenic avian mycoplasmas.
AB  - The pathogenic avian mycoplasmas, Mycoplasma gallisepticum, Mycoplasma synoviae,
      Mycoplasma meleagridis, Mycoplasma iowae and Mycoplasma imitans, synthesize
      haemagglutinins that are immunogenic, variably expressed, surface proteins. The
      haemagglutinins of M. gallisepticum (pMGA), M. synoviae (VlhA) and M. imitans are
      lipoproteins, encoded by related multigene families that appear to have arisen by
      horizontal gene transfer. M. gallisepticum also has genes encoding cytadhesins in
      its genome but these are present as a single copies, while the pMGA gene family
      contains 30 to 70 genes. The switch in expression of distinct pMGA genes (e.g.
      pMGA1.1 to pMGA1.9) generates antigenic variation, which is thought to be
      important in immune evasion but also has significance in the preparation of M.
      gallisepticum antigens for serological diagnosis. In the majority of M. synoviae
      strains, post-translational cleavage of the VlhA protein generates an amino
      terminal part (the lipoprotein MSPB) and a carboxyl-terminal part (MSPA), which
      mediates binding to erythrocytes. The 5'vlhA gene region, which encodes proline
      rich repeats in the amino-terminal part of MSPB, is highly polymorphic among M.
      synoviae strains. Insertions or deletions in the part of vlhA encoding the
      proline-rich repeats cause MSPB length variation in different M. synoviae
      strains. Recombination between the 5'vlhA gene and pseudogenes in the genome
      generates changes in antigenic determinants in the carboxyl two-thirds of the
      MSPB molecule, and in MSPA, resulting in changes in the domains involved in the
      binding of M. synoviae to erythrocytes. Variant haemagglutinins of M.
      gallisepticum (pMGA1.7) and M. synoviae (diverse VlhA forms) share sequences that
      may be responsible for antigenic cross-reactions between M. gallisepticum and M.
      synoviae. Shared epitopes have been demonstrated using specific antibodies
      against MSPB that also recognize proteins of M. gallisepticum and of M. iowae
      (serotype N). Size and antigenic variants have also been reported for M.
      meleagridis and M. iowae proteins, but it is not known if these are their
      haemagglutinins. Advances in the molecular characterization of M. gallisepticum
      (pMGA, pvpA) and M. synoviae (vlhA) genes and their sequencing in numerous
      strains is likely to enable significantly improved epidemiological studies and
      improved tracing of M. gallisepticum and M. synoviae strains in different flocks.

PMID- 12593737
TI  - Detection and estimation of avian infectious bronchitis virus antigen by a novel
      indirect liquid-phase blocking enzyme-linked immunosorbent assay using chicken
      and rabbit affinity purified immunoglobulins.
AB  - An indirect liquid-phase blocking (LPB) enzyme-linked immunosorbent assay (ELISA)
      using chicken and rabbit affinity purified immunoglobulin G (IgG) has been
      developed to detect and estimate avian infectious bronchitis virus (IBV) antigen
      concentration directly in infected allantoic fluid. The method is based on the
      principle of binding of specific IgG to the test IBV antigen and the assay of
      unbound IgG on an antigen-coated ELISA plate. The immunoglobulins are chicken N
      terminal S2 peplomeric protein-specific IgG isolated by immunoaffinity
      chromatography on synthetic peptide coupled to CNBr-activated Sepharose 4B or
      rabbit polyclonal IgG purified from the serum using Protein A Sepharose 4B. The
      assay detected all tested IBV strains and field isolates propagated in chicken
      embryos. Signal to noise ratios were calculated from LPB ELISA absorbance units
      and a diagnostic threshold was established from the signal to noise ratio
      frequency distribution of samples positive or negative for IBV by virus titration
      or reverse transcription polymerase chain reaction. The relative sensitivity of
      the test ranged between 10(5) and 10(6) median egg infectious doses (EID(50)) for
      chicken IgG and between 10(3) and 10(4) EID(50) for rabbit IgG, depending on the
      test strain. The assay is simple and takes less than 3 h to perform. It does not
      require expensive reagents and can be readily adapted to monitor the IBV antigen
      concentration in allantoic fluids during propagation of vaccine strains or in
      samples of freeze-dried, live-attenuated IBV vaccines.

PMID- 12593738
TI  - Restriction fragment length polymorphism analysis of the VP2 gene of Australian
      strains of infectious bursal disease virus.
AB  - Twenty-four Australian strains of infectious bursal disease virus (IBDV) were
      characterized by reverse transcription/polymerase chain reaction-restriction
      fragment length polymorphism and compared with previously published overseas
      strains. A primer pair designed to amplify a 743 base pair fragment of the VP2
      gene was used and restriction fragment length polymorphism profiles were
      determined for each strain using three restriction enzymes, Bst NI, MboI and
      SspI. Australian strains comprised 12 molecular groups that were unique and
      distinct from overseas IBDV strains. A specific SspI site that is used to predict
      a very virulent IBDV phenotype was absent from all Australian strains, contrary
      to a previous finding by Jackwood and Sommer (1999). One Australian strain
      (N1/99) contained an SspI site; however, this was located at a different position
      than that found in very virulent IBDV strains. The results demonstrate that
      restriction fragment length polymorphism can be used to rapidly differentiate
      Australian IBDV strains from overseas strains. However, the existence of a large
      number of molecular groups might preclude its effectiveness for inter-strain
      differentiation.

PMID- 12593739
TI  - Further studies on the use of allopurinol to reduce plasma uric acid
      concentrations in the Red-tailed Hawk (Buteo jamaicensis) hyperuricaemic model.
AB  - The present paper reports the effects of allopurinol in a raptor hyperuricaemic
      model. The study was performed as a follow-up to previous experiments wherein
      allopurinol was used in doses of 100 and 50 mg/kg, and was proved to be toxic at
      these higher dose rates. To investigate whether 25 mg/kg (semel in die) s.i.d.
      allopurinol is a safe and effective dose in Red-tailed Hawks (Buteo jamaicensis)
      to reduce plasma uric acid concentrations, experimental studies were performed
      using the physiologically occurring postprandial hyperuricaemia. Preprandial and
      postprandial plasma concentrations of xanthine, hypoxanthine, allopurinol,
      oxypurinol and uric acid were established by high-performance liquid
      chromatography at various time intervals after receiving allopurinol (25 mg/kg
      SID) or placebo. No significant differences were observed between the
      experimental and the control group. These results indicate that this dose is safe
      to administer; however, this dose failed to cause a significant effect on plasma
      uric acid concentrations. Because of the low therapeutic ratio of allopurinol in
      Red-tailed Hawks, follow-up studies have concentrated on an alternative for the
      treatment of hyperuricaemia, namely urate oxidase.

PMID- 12593740
TI  - Investigations into the uricolytic properties of urate oxidase in a granivorous
      (Columba livia domestica) and in a carnivorous (Buteo jamaicensis) avian species.
AB  - To study the uricolytic properties of urate oxidase in granivorous and
      carnivorous birds, experiments were conducted in pigeons (Columba livia
      domestica) and Red-tailed Hawks (Buteo jamaicensis). Plasma concentrations of
      allantoin and uric acid were determined at various times in experimental groups
      before and after receiving 100, 200, and 600 U/kg urate oxidase once daily and
      were compared with controls. All regimens caused a significant decrease in plasma
      uric acid concentrations within 2 days after the first administration, when
      compared with controls. Furthermore, both doses used in Red-tailed Hawks (200 and
      100 U/kg) caused a significant postprandial suppression of plasma uric acid
      concentrations. Plasma allantoin concentrations were significantly higher when
      compared with controls. The ability of urate oxidase to prevent the physiological
      postprandial hyperuricaemia in Red-tailed Hawks and to reduce plasma uric acid
      concentrations to undetectable levels, shows the great potential of this drug for
      treating avian hyperuricaemia.

PMID- 12593741
TI  - Resistance of broiler outbred lines to infection with Salmonella enteritidis.
AB  - Salmonella infections originating from poultry are one of the major causes of
      food-borne disease. For the control of salmonella in poultry a multifactorial
      approach is more likely to be effective, and the genetic resistance of poultry
      breeds to salmonella infections may be a valuable contribution. Experimental
      Salmonella enteritidis infections were examined in three different broiler
      outbred lines: the FC line, which had been selected for feed conversion
      efficiency; the R line, which had been selected for growth rate; and the C line,
      a commercially available line. The FC line had the highest mortality rate after
      intramuscular inoculation with 5 x 10(6) colony forming units (CFU) of S.
      enteritidis at 2 weeks of age (40% versus 21 and 20% in the other lines).
      However, at slaughter age, the number of birds carrying salmonella in caecal
      contents, and the concentration of salmonella in the caecal contents, was lowest
      in the FC line. The FC and R lines were compared by inoculation with doses
      ranging from 10(2) to 10(7) CFU S. enteritidis. At sublethal doses (10(5) CFU or
      less), the FC line carried significantly less salmonella in caecal contents and
      the rate of systemic infection was lower. The start of shedding was also delayed
      compared with the R line. At doses of 10(6) CFU S. enteritidis or higher, there
      were no differences in salmonella carriage between the lines, and the FC line
      showed higher mortality. In conclusion, resistance to mortality and resistance to
      the carriage of S. enteritidis do not necessarily coincide within lines, as the
      FC line showed high mortality but low carriage, both in survivors of high
      infection doses and in all birds at lower infection doses.

PMID- 12593742
TI  - Development of a lavage procedure to collect crop secretions from live chickens
      for studying crop immunity.
AB  - The crop (ingluvies), an organ for food storage in most avian species, is located
      at the base of the oesophagus. Previous work in our laboratory showed that,
      following infection with Salmonella enteritidis, significant anti-S. enteritidis
      antibody levels could be found in the crops of these birds. Samples in these
      previous studies were obtained by flushing the interiors of crops excised from
      killed birds, which is both labour and animal intensive. A method was sought that
      allowed multiple sampling of the same birds over time. We found that lavage fluid
      could be administered directly into the crop down the oesophagus using a narrow
      diameter plastic tubing attached to a syringe, and the fluid could then be
      aspirated back into the syringe. Antibody-containing crop secretions could be
      collected with minimal discomfort to the test animals. In a study where birds
      were challenged with S. enteritidis, immunoglobulin A anti-S. enteritidis titres
      3 weeks post-challenge were similar in crop samples obtained by live lavage
      versus the flushing of crops removed from killed birds. Such a sampling procedure
      may provide researchers with a simple method to follow mucosal immunity in
      chickens following infection or vaccination regimens.

PMID- 12593743
TI  - Early stages of infectious bursal disease virus infection in chickens detected by
      in situ reverse transcriptase-polymerase chain reaction.
AB  - Two infectious bursal disease virus (IBDV) strains were inoculated both
      intranasally and by eye drop into 5-week-old specific pathogen free chickens. The
      bursa, the liver, the kidney, the spleen, the thymus, the caecal tonsil and the
      thigh muscle were harvested at 4, 8, 16, 28, 40, 56, 72, 96 h post-inoculation
      (p.i.) for IBDV detection by in situ reverse transcriptase-polymerase chain
      reaction and, at the same time, the pathological changes in these tissues were
      investigated. A typical positive signal was detected in the liver, the kidney and
      the spleen of chickens inoculated with the very virulent IBDV H strain at 4 h
      p.i., but not in the thymus, the caecal tonsil or the thigh muscle until 8 h p.i.
      Virus was also found in the liver, the spleen, the kidney, the thymus, the caecal
      tonsils and the muscle of birds inoculated with the cell-adapted Ts strain at 4 h
      p.i. A positive signal was observed in the bursa later than in the other tissues.
      The signals increased markedly at 8 h p.i. A decrease in bursal lymphocytes was
      observed in haematoxylin and eosin stained sections at 28 h p.i. for the H strain
      and at 40 h p.i. for the Ts strain.

PMID- 12593744
TI  - Necrotic enteritis: effect of barley, wheat and corn diets on proliferation of
      Clostridium perfringens type A.
AB  - Necrotic enteritis, caused by Clostridium perfringens type A, is more prevalent
      in broilers fed wheat or barley diets than in those fed a corn diet. We compared
      the effects of wheat, barley and corn diets on in vitro proliferation of C.
      perfringens type A. Bacteria were inoculated into the supernatants delivered from
      either digested or non-digested barley, wheat and corn diets mixed with
      thioglycollate medium (1:3). Colony forming units were counted following
      incubation for 6 h at 40 degrees C. There were no significant differences in
      clostridial proliferation among non-digested diets. Bacterial proliferation in
      the digested wheat and barley diets was significantly higher than in the digested
      corn diet. These findings suggest that the increased incidence of necrotic
      enteritis in broilers fed barley and wheat diets compared with those fed a corn
      diet may be due in part to increased clostridial proliferation associated with
      the wheat and barley diets, or to decreased proliferation associated with the
      corn diet.

PMID- 12593745
TI  - Genotypic heterogeneity of Pasteurella gallinarum as shown by ribotyping and 16S
      rRNA sequencing.
AB  - Forty-five strains mainly isolated from chickens in Zimbabwe and Denmark, two pig
      and three rat isolates all identified as Pasteurella gallinarum by conventional
      phenotypic tests were characterized by ribotyping, and selected strains were
      subsequently analysed by 16S rRNA gene sequencing. High genotypic diversity was
      observed, the number of ribotypes totalling 24. A major group of 47 isolates
      including the type strain of P. gallinarum clustered at 56% similarity and
      included 21 ribotypes. Ribotyping showed that some genotypes of P. gallinarum
      seem to be globally distributed. The three isolates from rodents did not share
      even a single common ribotype fragment with strains from birds and the pig
      isolates. Two avian isolates from Denmark and Zimbabwe and the pig strain showed
      from 97.6 to 99.8% 16S rRNA sequence similarity with the type strain of P.
      gallinarum and with type strains of Pasteurella volantium and Pasteurella avium.
      Two rat strains showed 98.6% 16S rRNA gene sequence similarity with each other,
      but were only related with P. gallinarum at 93% similarity. These isolates showed
      the highest similarity with [Actinobacillus] muris at 96.4 to 95.0% similarity.
      We suggest that conventional identification of P. gallinarum consequently should
      consider the source of isolation to obtain a correct diagnosis, and that
      isolation from animals other than fowl should be confirmed by genotypic analysis
      such as 16S rRNA gene sequence comparison.

PMID- 12593746
TI  - Improved detection of antibodies to Mycoplasma synoviae vaccine MS-H using an
      autologous recombinant MSPB enzyme-linked immunosorbent assay.
AB  - Mycoplasma synoviae is a poultry pathogen causing respiratory disease and
      synovitis. An indirect enzyme-linked immunosorbent assay (ELISA) has previously
      been devised in our laboratory using the major membrane antigen MSPB of M.
      synoviae strain WVU 1853 as antigen. However, sera from chickens inoculated with
      the M. synoviae vaccine strain MS-H showed lower optical densities in the assay
      than chickens infected with wild-type strains. In the present study, we
      investigate whether a low level of antibodies detected in MS-H-vaccinated birds
      is due to the limited ability of the vaccine to elicit antibodies, or to the
      reduced capacity of the antigen to specifically detect antibodies to this strain.
      Preliminary immunostaining experiments using native MSPBs from M. synoviae MS-H
      and WVU 1853 suggested that they were antigenically related but differed in at
      least some epitopes. Using a combination of polymerase chain reaction (PCR) and
      cloning, the gene encoding MSPB (vlhA) was cloned from strain MS-H, and its
      nucleotide sequence was partially determined. Analysis of the partial nucleotide
      sequence of the cloned vlhA gene revealed that it had a high identity (86%) with
      the previously published vlhA sequence from strain WVU 1853, but differed from it
      in several regions. Also, several nucleotide substitutions/deletions were
      detected in the conserved region (nucleotides 1 to 700) of the MS-H vlhA gene. A
      polypeptide, containing amino acids 27 to 299 of the MS-H MSPB, was expressed as
      a fusion protein in Escherichia coli and purified by affinity chromatography. An
      indirect ELISA was developed using the MS-H MSPB as coating antigen and compared
      with that of WVU 1853 MSPB and the commercial rapid serum agglutination test
      using a panel of sera from MS-vaccinated and/or challenged or unvaccinated
      specific pathogen free and commercial field chickens. Analysis of the absorbance
      values from specific pathogen free and field chicken sera showed that MS-H MSPB
      was species specific and more sensitive than the WVU-MSPB ELISA or the rapid
      serum agglutination test in detecting antibodies to the MS-H vaccine strain.
      These results emphasize the importance of using appropriate diagnostic antigens
      for sensitive detection of antibodies following vaccination or challenge with a
      M. synoviae strain.

PMID- 12593747
TI  - The effect of Ornithobacterium rhinotracheale vaccination of broiler breeder
      chickens on the performance of their progeny.
AB  - The effect of Ornithobacterium rhinotracheale vaccination of broiler breeders on
      antibody titres and performance of breeders and broilers was investigated. O.
      rhinotracheale antibody titres and performance data were recorded from 16
      different broiler breeder flocks and from 79 of their broiler progeny flocks.
      Eight breeder flocks were vaccinated with an inactivated O. rhinotracheale
      vaccine while the other eight breeder flocks were left unvaccinated against this
      bacterium. Following vaccination, mean O. rhinotracheale antibody titres in the
      breeders rose to a 6.5 log(2) units higher value than in unvaccinated breeders,
      and remained at a mean titre of 15 log(2) units during the entire production
      period. This resulted in significantly higher maternal antibody titres against O.
      rhinotracheale in the broiler progeny of vaccinated breeder flocks compared with
      the offspring of unvaccinated flocks. Statistical analyses revealed no
      differences in performance between vaccinated and unvaccinated breeders. There
      was a significantly lower mean mortality rate and higher mean production index in
      the broilers derived from vaccinated breeders.

PMID- 12593749
TI  - Conflicts among human values and trust in institutions.
AB  - Institutions contribute to maintaining social order and stability in society. At
      the same time, they restrain the freedom of individuals. Based on the theory of
      value structure and content (Schwartz, 1992), we hypothesized about the relations
      of people's trust in institutions to their value priorities. More precisely, we
      predicted and found that the level of trust in various institutions correlated
      positively with values that stress stability, protection, and preservation of
      traditional practices, and negatively with values that emphasize independent
      thought and action and favour change. In addition, we demonstrated that groups
      defined on the basis of religious affiliation or political orientation exhibited
      contrasting value priorities on the same bipolar dimension. Moreover, differences
      in value priorities accounted for the fact that religious individuals and right
      wing supporters expressed more trust in institutions than non-religious
      individuals and left-wing supporters.

PMID- 12593750
TI  - When expertise backfires: contrast and assimilation effects in persuasion.
AB  - It was proposed that source cues bias message processing in a direction opposite
      to cue valence if message content violates cue-based expectancies (contrast
      hypothesis), but consistent with cue valence if message content is ambiguous
      (bias hypothesis). In line with these hypotheses, students (N = 123) reported
      less favourable thoughts and attitudes after reading weak arguments presented by
      a high (vs. low) expertise source (Expts 1 and 2), and reported more favourable
      thoughts after reading strong arguments presented by a low (vs. high) expertise
      source (Expt 2). Conversely, students' thoughts and attitudes were more (less)
      favourable when a high (low) expertise source presented ambiguous arguments (Expt
      2). Results are discussed in relation to dual- vs. single-process accounts of
      persuasion and models of assimilation and contrast in social judgment.

PMID- 12593751
TI  - The lost e-mail: prosocial reactions induced by uniquely human emotions.
AB  - Leyens et al. (2000) have developed a theory on the role of secondary emotions as
      a uniquely human characteristic. An implication of this theory is that the use of
      secondary emotions, compared to primary emotions, will increase prosocial
      intentions and behaviours. Given the uniquely human character of secondary
      emotions, people who express themselves in terms of these emotions are tacitly
      seen as more human. As a consequence, these individuals share the human nature
      that we usually reserve for our own group or ourselves and will therefore evoke
      prosocial attitudes and behaviours. In two studies, French-speaking participants
      were confronted with an e-mail that started with either a primary or a secondary
      emotion. As expected, secondary emotion messages, compared to primary emotion
      messages, provoked stronger intentions to help the sender (Expt 1) and elicited
      'nicer' responses (Expt 2). Implications for intergroup relations are discussed.

PMID- 12593752
TI  - Justice and the regulation of social relations: when and why do group members
      deny claims to social goods?
AB  - When do group members withhold monetary resources, abandon procedural
      protections, and deny fair and respectful treatment to potential claimants? Two
      experiments investigated the conditions that influence judgments about others'
      entitlement to these three social goods. Past research suggests that exchange
      concerns underlie entitlement judgments such that an instrumentally beneficial
      relationship will promote greater support for claims to social goods. Drawing
      from group-value theory (Lind & Tyler, 1988), an alternative hypothesis is
      proposed which suggests that entitlement judgments are motivated by concerns
      about preserving the core norms and values that comprise the group's identity.
      The findings support the group-value hypothesis that discrimination in
      entitlement judgments is motivated by social identity concerns. Furthermore, this
      tendency to discriminate against those who challenge the group's core norms and
      values is moderated by the nature of the social good. The effect is strongest
      with regard to judgments about economic goods (money) and is attenuated with
      regard to judgments about procedural goods (procedural protection) and especially
      relational goods (fair and respectful treatment). It is suggested that the level
      of discrimination exhibited in the domain of procedural and relational goods is
      kept in check by culturally rooted beliefs that these social goods should be
      distributed according to egalitarian principles.

PMID- 12593753
TI  - Group and person attributions in response to criticism of the in-group.
AB  - This study examined responses to criticism of the in-group as influenced by
      critic's group membership and justifiability of the criticism. Participants
      responded to an article in which the author criticized their school. The critic
      was presented as a student either at the participant's own school (the in-group)
      or at a college higher or lower in status than the in-group school. The content
      of the criticism varied by justifiability. Results demonstrate that attributions
      associated with the person were greater when the critic was a fellow in-group
      member, and group attributions were stronger when he or she was a student from
      the higher status school. Neither attribution type dominated in the low-status
      out-group condition. The content of the criticism did not influence attributions,
      and harmfulness of the criticism-rather than justifiability-seemed to influence
      other responses. Associations between type of attributions (group or person) and
      affective and other perceptual reactions (e.g. anger, perceived accuracy of
      statements) also differed by the critic's group membership. Implications for
      intergroup theory and communication in intergroup conflict are discussed.

PMID- 12593754
TI  - Personality, attachment and sexuality related to dating relationship outcomes:
      contrasting three perspectives on personal attribute interaction.
AB  - Although people can bring personal attributes to their relationships that affect
      how satisfying and enduring those relationships are, it is more often personal
      attribute interaction that directly determines romantic relationship outcomes. In
      this study, three general perspectives on personal attribute interaction
      similarity, complementarity and exchange perspectives-were contrasted empirically
      in their ability to predict dating relationship outcomes. Based on questionnaires
      completed by a sample of 44 heterosexual dating couples, feelings of relationship
      satisfaction were most closely associated with the interaction of socially
      valuable attributes, generally supporting the exchange perspective. Similarity of
      personal attributes was also connected with relationship satisfaction; however,
      this association was in the negative direction. That is, couples with dissimilar
      personality traits, attachment styles and sexual strategies were significantly
      more satisfied with their dating relationships. Complementarity of personal
      attributes had no link to satisfaction, but complementary couples experienced
      significantly higher ratings of relationship commitment, especially couples with
      complementary personalities. Discussion focused on the differences between
      personal attribute connections with romantic satisfaction and commitment and on
      the limitations of the present study.

PMID- 12593755
TI  - Testing the social identity-intergroup differentiation hypothesis: 'We're not
      American eh!'.
AB  - The social identity-intergroup differentiation hypothesis is a hotly debated
      issue among social identity researchers (Brown, 2000; Turner, 1999); it states
      that individuals having a stronger in-group identification will perceive greater
      differences between their in-group and a relevant out-group. This study examines
      the importance of three factors when testing this hypothesis: the strength and
      salience of in-group identification, the relevance of the out-group for social
      comparison, and the relevance of the dimension of social comparison. The
      hypothesis was examined in relation to the national identity of a sample of
      Canadian students. Perceptions of the in-group and out-groups were measured at
      Time 1 (N =171). The same measures were given at Time 2 (N = 77), along with a
      variety of measures of social identity. It was predicted that this hypothesis
      would be supported when the dimension of social comparison was of high relevance
      and only for an important social comparison group (i.e. Americans). Finally, the
      ability of identity to predict differentiation at another point in time was
      examined in order to examine the issue of identity salience and stability.
      Results generally supported the hypotheses and are discussed in relation to prior
      research and the conceptualization of a minority identity.

PMID- 12593756
TI  - Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR
      analysis of a series of xanthates as inhibitors and inactivators of cytochrome
      P450 2B1.
AB  - 1. Various xanthates (R-OCS2) were found to be mechanism-based inactivators of
      cytochrome P450 2B1 (CYP2B1) and CYP2B6 via formation of reactive metabolites. 2.
      In the present study, quantitative structure-activity relationships (QSARs) were
      derived with inhibitory and inactivation potencies of 15 xanthates (R = two to 20
      methylene groups, allyl, cyclohexyl or O-tricyclo[5.2.1.0(2,6)]dec-9-yl (D609))
      against purified, reconstituted rat liver CYP2B1. Factor, regression and
      comparative molecular field analyses (CoMFA) were used. 3. The compounds formed
      two groups whose activities depended on different structural features: the first
      group consisted of compounds with ethyl, propyl, allyl, cyclohexyl and D609
      substituents; the second involved compounds with eight to 20 methylene groups. 4.
      High correlation between the molecular volume and inhibitory potency of the
      xanthates of the second group was found. The inactivation potency in the first
      group correlated with the charge of the first carbon atom of R, identifying this
      atom as a potential target for metabolic attack. A decrease in the inactivation
      potency with an increase in the size of R was observed in the second group. This
      finding could be explained by a decreased rate of metabolism of the long alkyl
      chain compounds and/or by difficulty in binding of the resulting metabolite(s) to
      the enzyme molecule.

PMID- 12593757
TI  - Binding of brominated diphenyl ethers to male rat carrier proteins.
AB  - 1. Two [(14)C]-labelled brominated diphenyl ethers, 2,2',4,4',5
      pentabromodiphenyl ether (BDE-99) and decabromodiphenyl ether (BDE-209), were
      separately administered to the male Sprague-Dawley rat as a single oral dose (2.2
      mg kg(-1) body weight and 3.0 mg kg(-1), respectively). 2. Very low [(14)C] urine
      excretion was observed for both congeners (<1% of the dose), and cumulative
      biliary excretion was approximately 4% for BDE-99 and 9% for BDE-209. 3. More
      than 6% of the pooled urine from the BDE-99-treated rat was protein-bound to an
      18-kDa protein characterized by sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis and Western immunoblot analysis as alpha(2u)-globulin. Eighteen
      per cent of the radioactivity from the pooled urine from the BDE-209 treated rat
      was bound to albumin; no binding to alpha(2u)-globulin was detected. 4. In bile,
      27-39% of the radioactivity from the BDE-99-dosed rat was bound to an
      unidentified 79-kDa protein, whereas essentially all (>87%) of the biliary
      radioactivity from BDE-209 was bound to the 79-kDa protein. Both parent BDE-99
      and-209 and their metabolites were detected by thin layer chromatography in the
      extracted fraction of this bile protein. 5. By differential centrifugation, the
      subcellular localization of the (14)C derived from each congener in selected
      tissues was quantified. The cytosolic [(14)C] from livers of the BDE-209-treated
      rat was bound to a 14-kDa protein, which was characterized as a fatty acid
      binding protein.

PMID- 12593758
TI  - Comparative biotransformation of morphine, codeine and pholcodine in rat
      hepatocytes: identification of a novel metabolite of pholcodine.
AB  - 1. Pholcodine (3-morpholinoethylmorphine), a semi-synthetic alkaloid, is widely
      used as an antitussive agent. 2. Norpholcodine [7,8-didehydro-4,5alpha-epoxy-3-(2
      morpholinoethoxy)morphinan-6alpha-ol] (NP) and pholcodine-N-oxide [1(9a)-dehydro
      (4aR,5S,7aR,9cS,12S)-4a,5,7a,8,9,9a-hexahydro-5-hydroxy-12-methyl-3
      morpholinoethoxy-1H-8,9,c-(iminoethano)phenanthro[4,5-bcd] furan-12-oxide] (PNOX)
      were identified in incubations of pholcodine with freshly isolated rat
      hepatocytes by liquid chromatography/electrospray-mass spectrometry (LC/ESI-MS).
      3. Synthesized NP and PNOX were characterized by mass spectrometry and nuclear
      magnetic resonance (NMR) spectroscopy. 4. N-oxidation was the major metabolic
      pathway for pholcodine, producing a previously unreported metabolite. 5. The
      metabolism of morphine and codeine was also determined using freshly isolated
      hepatocytes. 6. For morphine, 3-glucuronidation was the major metabolic pathway,
      whilst for codeine it was dealkylation (O- and N-). 7. Neither morphine nor its
      metabolites were metabolites of pholcodine. 8. This observation supports the
      hypothesis that the absence of analgesic activity with pholcodine may be due to
      less O-dealkylation in vivo. 9. Together with the slow biotransformation of
      pholcodine (k(met) = 0.021 microM min(-1)) in comparison with morphine (k(met) =
      0.057 microM min(-1)) and codeine (k(met) = 0.112 microM min(-1)), the results
      obtained were consistent with its low addiction potential and suggest that its
      antitussive efficacy is mediated by the parent drug or one of its metabolites
      other than morphine.

PMID- 12593759
TI  - Inhibition of the microsomal metabolism of 1,8-cineole in the common brushtail
      possum (Trichosurus vulpecula) by terpenes and other chemicals.
AB  - 1. Brushtail possums (Trichosurus vulpecula) ingest large amounts of terpenes in
      their diet of Eucalyptus leaf. Previously, we showed that dietary terpenes induce
      the cytochrome P450 enzymes (CYPs) responsible for their metabolism. The present
      study examined the effects of various CYP inhibitors on the metabolism of 1,8
      cineole, the major dietary terpene, by liver microsomes from the possum and rat.
      2. Ketoconazole inhibited the major reactions of terpene-induced microsomes in
      both species: 9-hydroxylation in the possum and 2-hydroxylation in the rat. This
      suggests the involvement of CYP3A enzymes, although in the possum there was a
      lack of the expected inhibition by troleandomycin or activation by alpha
      naphthoflavone, highlighting the differences between species in CYP forms.
      Diethyldithiocarbamate also inhibited 9-hydroxylation in the possum, indicating
      that a CYP2E1-like enzyme contributes to this reaction. 3. Three other dietary
      terpenes were potent competitive inhibitors of 9-hydroxylation in the possum.
      K(i) ( micro M) (mean +/- SE, n = 4) were: alpha-pinene, 4.4 +/- 1.1; limonene,
      7.8 +/- 2.1; p-cymene, 44.3 +/- 11.2; cuminyl alcohol (a p-cymene metabolite),
      6.0 +/- 0.8. It appears likely that p-cymene acts via its metabolite to inhibit
      1,8-cineole metabolism. 4. Inhibitory interactions between dietary terpenes, as
      well as other plant secondary compounds, may impose a significant constraint on
      foliage consumption in the common brushtail possum, therefore explaining the
      obligatory generalist nature of this browsing marsupial and other generalist
      herbivores.

PMID- 12593760
TI  - In vivo metabolism of diallyl disulphide in the rat: identification of two new
      metabolites.
AB  - 1. Diallyl disulphide (DADS), a compound formed from the organosulphur compounds
      present in garlic, is known for its anticarcinogenic effects in animal models. 2.
      The aim was to identify and analyse the metabolites produced in vivo after a
      single oral administration of 200 mg kg(-1) DADS to rats. The organic sulphur
      metabolites present in the stomach, liver, plasma and urine were measured by gas
      chromatography coupled with mass spectrometry over 15 days. 3. Data indicate that
      DADS is absorbed and transformed into allyl mercaptan, allyl methyl sulphide,
      allyl methyl sulphoxide (AMSO) and allyl methyl sulphone (AMSO(2)), which are
      detected throughout the excretion period. Overall, the highest amounts of
      metabolites were measured 48-72h after the DADS administration. AMSO(2) is the
      most abundant and persistent of these compounds. The levels of all the sulphur
      compounds rapidly decline within the first week after administration and
      disappear during the second week. Only AMSO and AMSO(2) are significantly
      excreted in urine. 4. These potential metabolites are thought to be active in the
      target tissues. Our data warrant further studies to check this hypothesis.

PMID- 12593761
TI  - Differences in pharmacokinetics and hepatobiliary transport of a novel anti
      inflammatory agent between normal and adjuvant arthritis rats.
AB  - 1. The pharmacokinetics, particularly the hepatobiliary transport of T-5557 ((3
      methyl-2-oxo-piperadin-3-yl)-acetic acid N'-(3-thieophen-2-yl-8-methoxy
      quinazolin-1-yl)-hydrazide), a novel anti-inflammatory agent, has been examined
      in normal and adjuvant arthritis (AA) rats. 2. Following oral administration of T
      5557, the absolute bioavailability in AA rats was increased by sixfold compared
      with normal rats. The extent of binding T-5557 to plasma proteins obtained from
      AA rats was markedly greater than in normal rats (97.0 versus 88.2%). The biliary
      clearance in AA rats was significantly lower than that in normal rats (1.186
      versus 5.621 ml min(-1) kg(-1)), and lower intrinsic biliary clearance was also
      observed in AA rats (40.33 versus 69.83 ml min(-1) kg(-1)). 3. Concomitant
      administration of T-5557 with quinidine, a potent P-glycoprotein inhibitor, to
      normal rats caused a significant decrease in the biliary clearance of T-5557 by
      37.9%. Moreover, the transport of T-5557 for the apical-to-basal compartment in a
      Caco-2 cells' monolayer was fourfold lower than that for the opposite direction,
      and was increased in the presence of quinidine and verapamil. 4. These results
      suggest that P-glycoprotein is involved in the biliary excretion of T-5557 and
      the decrease in the transport activity as well as the increase in plasma protein
      binding caused the elevated plasma concentration and bioavailability of T-5557 in
      AA rats.

PMID- 12593762
TI  - Decreased hepatobiliary transport of methotrexate in adjuvant arthritis rats.
AB  - 1. We investigated the difference in hepatobiliary transport of methotrexate in
      normal and adjuvant arthritis (AA) rats and substantiated the expression level of
      multidrug resistance-associated protein 2 (MRP2) in the liver. 2. Biliary
      clearance of methotrexate in normal and AA rats was calculated from plasma
      concentrations and biliary excretion following intravenous infusion and hepatic
      uptake clearance was estimated from an integration plot using methotrexate
      concentrations in plasma and liver. 3. Biliary clearance of methotrexate in AA
      rats was 2.30 +/- 0.23 ml min(-1) kg(-1) (mean SD) and significantly lower than
      in normal rats (8.42 +/- 0.81 ml min(-1) kg(-1)). The uptake clearance of
      methotrexate in AA rats was also lower than in normal rats (0.138 versus 0.278 ml
      min(-1) g liver(-1)). 4. MRP2 in the liver was detected by fluorescein
      isothiocyanate-labelled antibody and visualized using a confocal laser microscope
      system. The expression level of MRP2 in AA rats was very low compared with normal
      rats, indicating a down-regulation in AA rats. 5. In conclusion, biliary
      clearance of methotrexate was decreased due to the lower activities in both
      uptake and canalicular secretion, suggesting that several active transporters in
      the liver, including MRP2, are down-regulated in AA rats.

PMID- 12593763
TI  - Studies on the metabolic fate of M17055, a novel diuretic (6). Assessment for
      drug-drug interactions of M17055 in metabolism, distribution and excretion.
AB  - 1. The potential of M17055, a novel diuretic candidate, to affect the activities
      of human CYP enzymes, alter the plasma unbound fraction and compete with
      concomitant drugs in renal secretion as part of an assessment for drug-drug
      interactions in metabolism, distribution and excretion was investigated. 2. The
      effects of M17055 on the activities of human CYP1A2, CYP2E1, CYP2C9, CYP2C19,
      CYP2D6 and CYP3A4 were considered negligible at clinically relevant
      concentrations. 3. The majority of M17055 (99%) was bound to human plasma
      proteins, but it is unlikely to alter the binding of other clinically relevant
      drugs. 4. The renal clearance of M17055 (corrected for the plasma unbound
      fraction in male rats) substantially exceeded the glomerular filtration rate and
      was markedly reduced by treatment with probenecid, suggesting that the renal
      excretion of M17055 is controlled predominantly by an active secretion mechanism.
      5. The results show that M17055 is unlikely to cause or undergo significant
      pharmacokinetic interactions with concomitant drugs in metabolism and
      distribution. However, when it is administered simultaneously with certain
      organic anions, drug-drug interactions during kidney excretion may be possible.

PMID- 12593764
TI  - PCBs alter gene expression of nuclear transcription factors and other heart
      specific genes in cultures of primary cardiomyocytes: possible implications for
      cardiotoxicity.
AB  - 1. Polychlorinated biphenyls (PCBs) are well-known environmental pollutants that
      bioaccumulate mainly in the fatty tissue of animals and humans. Although
      contamination occurs primarily via the food chain, waste combustion leads to
      airborne PCBs. From epidemiological studies, there is substantial evidence that
      cardiovascular disease is linked to air pollution, but little is known about the
      underlying molecular events. 2. We investigated the effects of Aroclor 1254, a
      complex mixture of >80 PCB isomers and congeners, on the expression of nuclear
      transcription factors (GATA-4, Nkx-2.5, MEF-2c, OCT-1) and of downstream target
      genes (atrial and brain natriuretic peptide, alpha- and beta-myosin heavy chain,
      alpha-cardiac and alpha-skeletal actin), which play an important role in cardiac
      biology. 3. We treated cultures of primary cardiomyocytes of adult rats with
      Aroclor 1254 (10.0 micro M) and found significant induction of the transcription
      factor genes GATA-4 and MEF-2c and of genes regulated by these factors, i.e.
      atrial natriuretic peptide, brain-type natriuretic peptide, alpha- and beta
      myosin heavy chain, and skeletal alpha actin. 4. We have shown PCBs to modulate
      expression of genes coding for programmes of cellular differentiation and stress
      (e.g. atrial natriuretic peptide, brain-type natriuretic peptide) and these
      alterations may be important in the increase of cardiovascular disease in
      polluted areas.

PMID- 12593777
TI  - The first cell membranes.
AB  - Organic compounds are synthesized in the interstellar medium and can be delivered
      to planetary surfaces such as the early Earth, where they mix with endogenous
      species. Some of these compounds are amphiphilic, having polar and nonpolar
      groups on the same molecule. Amphiphilic compounds spontaneously self-assemble
      into more complex structures such as bimolecular layers, which in turn form
      closed membranous vesicles. The first forms of cellular life required self
      assembled membranes that were likely to have been produced from amphiphilic
      compounds on the prebiotic Earth. Laboratory simulations show that such vesicles
      readily encapsulate functional macromolecules, including nucleic acids and
      polymerases. The goal of future investigations will be to fabricate artificial
      cells as models of the origin of life.

PMID- 12593778
TI  - Long-term manipulations of intact microbial mat communities in a greenhouse
      collaboratory: simulating earth's present and past field environments.
AB  - Photosynthetic microbial mat communities were obtained from marine hypersaline
      saltern ponds, maintained in a greenhouse facility, and examined for the effects
      of salinity variations. Because these microbial mats are considered to be useful
      analogs of ancient marine communities, they offer insights about evolutionary
      events during the >3 billion year time interval wherein mats co-evolved with
      Earth's lithosphere and atmosphere. Although photosynthetic mats can be highly
      dynamic and exhibit extremely high activity, the mats in the present study have
      been maintained for >1 year with relatively minor changes. The major groups of
      microorganisms, as assayed using microscopic, genetic, and biomarker
      methodologies, are essentially the same as those in the original field samples.
      Field and greenhouse mats were similar with respect to rates of exchange of
      oxygen and dissolved inorganic carbon across the mat-water interface, both during
      the day and at night. Field and greenhouse mats exhibited similar rates of efflux
      of methane and hydrogen. Manipulations of salinity in the water overlying the
      mats produced changes in the community that strongly resemble those observed in
      the field. A collaboratory testbed and an array of automated features are being
      developed to support remote scientific experimentation with the assistance of
      intelligent software agents. This facility will permit teams of investigators the
      opportunity to explore ancient environmental conditions that are rare or absent
      today but that might have influenced the early evolution of these photosynthetic
      ecosystems.

PMID- 12593779
TI  - The reactions of nitrogen heterocycles with acrolein: scope and prebiotic
      significance.
AB  - It has been suggested that life began with a self-replicating RNA molecule.
      However, after much research into the prebiotic synthesis of RNA, the
      difficulties encountered have lead some to hypothesize that RNA was preceded by a
      simpler molecule, one more easily synthesized prebiotically. Many of the proposed
      alternative molecules are based on acrolein, since it reacts readily with
      nucleophiles, such as the nucleobases, via Michael addition and is readily
      synthesized from formaldehyde and acetaldehyde. Reports regarding the reactions
      of nucleobases with concentrated acrolein solutions suggest that this is a
      plausible reaction mechanism, though there are also reports that the "incorrect"
      isomers are obtained. The scope and kinetics of the reaction of acrolein with
      various nitrogen heterocycles are reported here. Reactions of pyrimidines often
      give N(1) adducts as the major products. Reactions of purines often give N(9)
      adducts in good yield. The reactions are rapid under neutral to slightly alkaline
      conditions, and proceed at low temperatures and dilutions. The implications of
      these findings for the origin of life are discussed.

PMID- 12593780
TI  - UV photochemistry of DNA in vitro and in Bacillus subtilis spores at earth
      ambient and low atmospheric pressure: implications for spore survival on other
      planets or moons in the solar system.
AB  - Two major parameters influencing the survival of Bacillus subtilis spores in
      space and on bodies within the Solar System are UV radiation and vacuum, both of
      which induce inactivating damage to DNA. To date, however, spore survival and DNA
      photochemistry have been explored only at the extremes of Earth-normal
      atmospheric pressure (101.3 kPa) and at simulated space vacuum (10(-3)-10(-6)
      Pa). In this study, wild-type spores, mutant spores lacking alpha/beta-type
      small, acid-soluble spore proteins (SASP), naked DNA, and complexes between SASP
      SspC and DNA were exposed simultaneously to UV (254 nm) at intermediate pressure
      (1-2 Pa), and the UV photoproducts cis,syn-thymine-thymine cyclobutane dimer
      (c,sTT), trans,syn-thymine-thymine cyclobutane dimer (t,sTT), and "spore
      photoproduct" (SP) were quantified. At 101.3 kPa, UV-treated wild-type spores
      accumulated only SP, but spores treated with UV radiation at 1-2 Pa exhibited a
      spectrum of DNA damage similar to that of spores treated at 10(-6) Pa, with
      accumulation of SP, c,sTT, and t,sTT. The presence or absence of alpha/beta-type
      SASP in spores was partly responsible for the shift observed between levels of SP
      and c,sTT, but not t,sTT. The changes observed in spore DNA photochemistry at 1-2
      Pa in vivo were not reproduced by irradiation of naked DNA or SspC:DNA complexes
      in vitro, suggesting that factors other than SASP are involved in spore DNA
      photochemistry at low pressure.

PMID- 12593782
TI  - Dissociation of innate and adaptive immunity by UVB irradiation.
AB  - Increasing ultraviolet-B irradiation (UVB) resulting from diminution of
      stratospheric ozone is becoming a serious international problem. UVB irradiation
      exerts not only carcinogenic effects on animals but also causes them to become
      vulnerable to infections by modulating their immune responses. UVB irradiation
      suppresses innate immune functions of cells such as macrophages, neutrophils,
      Langerhans cells, dendritic cells, and the serum component, complement. UVB
      irradiation also causes changes in cytokine profiles, represented by the
      induction of a paradigm switch involving Th1/Th2 phenotypes. According to earlier
      studies, Th1 responses are suppressed, whereas Th2 activities are augmented by
      UVB irradiation. These immune modulations are caused by several pathways via
      cytokines and neuropeptides, and eventually may lead to increasing incidences of
      infection, allergy, and cancer. We have reviewed reports concerning UVB
      irradiation induced immune modulation from the viewpoint of risks for human
      diseases and, in addition, for ecosystems and immunity of lower animals.

PMID- 12593783
TI  - Effects of diesel exhaust particle extracts on Th1 and Th2 immune responses in
      mice.
AB  - The present study was undertaken to investigate the effects of extracts of diesel
      exhaust particles (DEP) on Th1 and Th2 immune responses. In order to separate
      compounds from DEP different in hydrophobicity, a single DEP sample was
      consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane
      (DIC-DEP), methanol (MET-DEP), and 1M ammonia (AMM-DEP). The last unextracted
      residue (UNE-DEP) was also used to test its effect on immune responses. To
      immunize mice, hen egg lysozyme (HEL) was injected i.p. (day 0). Varying doses of
      DEP, each DEP extract, and UNE-DEP were intranasally administered every 2 days
      from days 0 to 18. Anti-HEL IgG2a antibodies in sera and IFN-&#x03B3; secreted
      from spleen cells were measured as an indicator of Th1 immune responses, while
      anti-HEL IgG1 antibodies and IL-4 as that of Th2 responses. The results showed
      that treatment with DEP and DIC-DEP increased both Th1 and Th2 responses to HEL.
      UNE-DEP facilitated Th1 but not Th2 responses, while MET- and AMM-DEP
      administration was followed by enhancement of Th2 but not Th1 responses. Neither
      HEX- nor BEN-DEP modulated Th1 as well as Th2 responses. These results suggest
      that DEP contain various compounds different in hydrophobicity which may affect
      both Th1 and Th2, Th1 but not Th2, and Th2 but not Th1 immune responses.

PMID- 12593784
TI  - A spectrum of antibody (IgG. IgG1, IgM) response in mice infected with
      trichinella spiralis treated with L-mimosine.
AB  - The purpose of this study was to demonstrate the anti-inflammatory effects of L
      mimosine on chronic inflammation, by investigating its effect on the
      immunological response of BALB/c mice infected with the nematode parasite
      Trichinella spiralis. Specific anti-parasite immunoglobulins (IgG, IgG1 and IgM)
      were detected by the ELISA method in the serum of both the treated and the
      untreated animals at different periods of time for 60 days post infection. Two
      groups consisting of 18 mice each were used. The mice were 6 weeks of age. Both
      groups were infected with 220 larvae (L1-T. spiralis) per os: one group was
      administered an intraperitoneal injection of L-mimosine (200 &mgr;g/100 ml/dose)
      for 27 days (the first injection started 7 days before infection) and the second
      group was administered an intraperitoneal injection of saline solution (100
      &mgr;l/dose). Parasite specific IgG, IgG1 and IgM levels were determined in the
      sera of infected, untreated mice. The levels of IgG and IgG1 were increased
      following infection and remained elevated throughout the experimental period,
      while IgM was significantly decreased on the 50th day post-infection. These
      levels were found to be lower in the L-mimosine treated infected mice, compared
      to the untreated mice. The inhibition started from day 10 and continued until day
      60. In healthy animals, the production of immunoglobulins was not measurable. Non
      infected animals treated with L-mimosine also showed no detectable anti-parasite
      specific immunoglobulins.

PMID- 12593785
TI  - Steroid and antihistamines modulate RANTES release in cultured peripheral blood
      mononuclear cells of atopic patients.
AB  - RANTES plays a crucial role in cell recruitment in allergic inflammation. We
      investigated the pharmacological modulation of RANTES release in cultured
      peripheral blood mononuclear cells obtained from allergic patients with active
      asthma. Chemokine production was assessed before and after 15 day treatment with
      histamine-1 receptor antagonists (antihistamines) (Loratadine or Cetirizine) and
      a steroid (Deflazacort), both in unstimulated and PHA-stimulated cell cultures.
      Results were compared with those obtained from placebo-treated patients. During
      the treatment period, patients recorded morning and evening peak expiratory flow
      (PEF) by the mini-Wright procedure. PEF absolute values and diurnal variability
      significantly improved respect to the pre-treatment in steroid-treated patients,
      in comparison to the placebo and antihistamine-treated groups (p&#x003C;0.001 and
      0.01, respectively). PEF diurnal variability in the antihistamine-treated group
      were lower than placebo-treated group without statistical significance (p=0.06).
      No differences could be found in RANTES levels in supernatants of all cultures
      between the two antihistamines. RANTES release significantly decreased in
      supernatants of all cell cultures from steroid (p&#x003C;0.01) and antihistamine
      (p=0.03 and 0.04) groups after treatments, compared to the basal values; whereas
      it increased slightly in controls. Co-variance analysis on RANTES levels,
      adjusting for pre-treatment values, showed a significant reduction of RANTES
      release by PHA-stimulated PBMCs from steroid (p=0.003) and anti-histamine
      (p=0.03) groups, with respect to the placebo group. The same statistical tool
      applied between the steroid and the antihistamine groups showed, after therapy,
      the lowest levels of RANTES to be associated with steroid treatment (p=0.005).
      The study shows that the steroid is the most effective drug in modulating RANTES
      release from PBMCs. However, antihistamines, which are able to reduce cell
      recruitment due to chemokine release, avoiding important side effects, may be
      useful in long term therapy in controlling and preventing allergic inflammation.

PMID- 12593786
TI  - Sublingual allergen-specific immunotherapy in allergic rhinitis and related
      pathologies: Efficacy in a paediatric population.
AB  - The aim of this study was to demonstrate the efficacy and safety of the
      sublingual-swallow allergen-specific immunotherapy (SLIT) in a paediatric
      population suffering from allergic rhinitis and related pathologies. From March
      1994 through March 2000, at our ENT Department 4000 children (1800 male and 2200
      female), aged 3 to14 years, were examined for recurrent nasal obstruction and
      nasal polyps. 2400 (60&#x0025;) of them were allergic and underwent the following
      investigations: Impedance test, Pure tone audiometry, rhinomanometry, Prick test,
      RAST, nasal provocation test and paranasal sinus TC without contrast media. Of
      the allergic group we admitted 288 patients(12&#x0025;) to a 3 yr SLIT, meeting
      the following criteria: children aged 5 years or more, mono-sensitised to one
      allergen and with family cooperation support. After three years of SLIT, we
      observed complete symptom remission and a marked improvement in instrumental
      examinations in 80&#x0025; of these children. The improvement was poor in
      8&#x0025; of patients, while in 12&#x0025; of the subjects no changes in symptoms
      and instrumental results were detected. These results are in agreement with
      previously published studies and confirm that SLIT can be a valid tool for
      treating allergic upper respiratory tract diseases in children.

PMID- 12593787
TI  - Raynaud&#x0027;s phenomenon: Infrared functional imaging applied to diagnosis and
      drug effects.
AB  - A non-invasive, innovative approach to the study of Raynaud&#x0027;s Phenomenon
      is proposed. A group of patients, with respect of a control group, underwent a
      simultaneous assessment of thermal properties of all ten fingers using infrared
      functional imaging (IRFI). The assessment highlighted a quite different behaviour
      between patients with Primary- (PRP) and those with scleroderma -
      Raynaud&#x0027;s Phenomenon (SSc) and, compared with other existing techniques,
      seems to be an objective and effective tool to discriminate between PRP and RP
      secondary to SSc. 18 healthy volunteers (Norm), 20 Primary Raynaud&#x0027;s
      Phenomenon (PRP) and 20 Secondary Scleroderma (SSc) patients were studied
      subsequently to clinical evaluation and nail fold capillaroscopy. High-resolution
      infrared imaging of finger re-warming processes, immediately after a 2 min cold
      stress, allowed to identify objective parameters. Temperature integral Q (the
      temperature evaluation of the area under the time-temperature curve along the re
      warming period) provided particularly effective figures in describing thermal
      properties of the fingers. Grand average Q values were (383.4 &#x2213; 12.5)
      &#x00B0;C*min, (502.9 &#x00B1; 88.1) &#x00B0;C*min and (1022.0 &#x00B1; 110.2)
      &#x00B0;C*min for the PRP, SSc and Normal groups, respectively. Separate
      evaluation of the temperature integral for each finger leads to very similar
      results for the fingers of all the PRP patients; a different thermoregulatory
      response was observed in SSc patients. The sensitivity of the method in order to
      distinguish healthy from ill fingers was 100&#x0025;. The specificity in
      distinguishing SSc from PRP was 95&#x0025;. In addition, IRFI parameters provided
      a better understanding of the impaired control of the finger&#x0027;s temperature
      in PRP and SSc with respect to the Normal group. This pilot study also applied
      IRFI for the measurement of drug effects in patients with Raynaud&#x0027;s
      Phenomenon. Sixteen out of twenty SSc patients were tested in a single 1-hour
      session of N-acetylcysteine infusion. IRFI clearly documented a significant
      increase of face and hands temperature during the drug administration. The grand
      average value of the finger&#x0027;s temperature after the 1 hour NAC
      administration was (29.6 &#x00B1; 3.7) &#x00B0;C, while its value before was
      (27.9 &#x00B1; 3.7) &#x00B0;C (p&#x003C;0.001). N-acetylcysteine seems to act as
      a vasodilator in patients with Raynaud&#x0027;s phenomenon secondary to systemic
      sclerosis (scleroderma).

PMID- 12593788
TI  - Oral desensitisation in cow milk allergy: immunological findings.
AB  - In the literature there are several reports dealing with the possibility of a
      desensitising treatment in food allergy, but there are very few studies about the
      immunological mechanisms of oral desensitisation. We studied the immunological
      modifications in four children who underwent oral desensitisation with cow milk.
      Four children with cow milk allergy underwent oral desensitisation according to a
      standardized protocol. Total IgE, eosinophilic cationic protein in serum, and
      specific IgE and IgG4 to &#x03B1;-lactalbumin, to &#x03B2;-lactoglobulin and to
      casein were determined at the beginning of the treatment and after 6, 12 and 18
      months in the 4 children treated. All the 4 treated patients successfully
      completed the treatment. Specific IgE to casein showed a significant reduction
      (p&#x003C;0.01), while specific IgG4 to &#x03B1;-lactalbumin (p&#x003C;0.02), to
      &#x03B2;-lactoglobulin (p&#x003C;0.01) and to casein (p&#x003C;0.01) showed a
      significant increase. Total IgE, eosinophilic cationic protein, and specific IgE
      to &#x03B1;-lactalbumin and to &#x03B2;-lactoglobulin did not show any
      significant modification. Control patients did not show any immunological
      modification and still had a positive double-blind, placebo-controlled food
      challenge. These results make us think that oral desensitisation in food allergy
      happens with the same mechanisms of traditional desensitising treatments for
      respiratory and insect sting allergies.

PMID- 12593789
TI  - Involvement of herpes simplex type 2 in modulation of gene expression of human
      papillomavirus type 18.
AB  - Human papillomaviruses (HPVs) and herpes simplex virus type 2 (HSV-2) can
      establish latent or persistent infections in the host, and are involved in the
      aetiology of benign and/or malignant lesions of the urogenital tract. To
      investigate the putative interaction between these DNA viruses when a double
      infection occurs, we have studied the effect of HSV-2 infection in HeLa 229 cells
      containing 10-50 copies of HPV type 18 genomic DNA. Twenty hours post HSV-2
      infection, the analysis of mRNA transcripts from E1, E2, E6 early and L1 late
      HPV18 genes was performed in HeLa cells by a semi-quantitative RT-PCR assay. A
      modulation of HPV18 E1 and E6 early genes was observed, resulting in a 9-fold and
      3-fold increased transcription respectively.

PMID- 12593790
TI  - Ritonavir and Saquinavir directly stimulate anterior pituitary prolactin
      secretion, in vitro.
AB  - An association between human immunodeficiency virus type I (HIV-1) protease
      inhibitors (PIs) and galactorrhoea/hyperprolactinemia adverse effect has recently
      been reported in four HIV-1-infected women treated with PIs (indinavir,
      nelfinavir, ritonavir or saquinavir). This could be explained by a direct effect
      of ritonavir and saquinavir on anterior pituitary prolactin (PRL) release, and/or
      an indirect effect of PIs on the secretion of hypothalamic dopamine, which is the
      main PRL inhibitory factor. Anterior pituitaries were explanted from adult male
      Wistar rats, the cells were trypsin dispersed, plated into multiwell cultures and
      incubated for 1 h with either ritonavir or saquinavir (0.01 nM-1&#x03BC;M). PRL
      release into the incubation medium was evaluated by radioimmunoassay.
      Hypothalamic neuronal endings (synaptosomes) were prepared by tissue
      homogenization, incubated with <sup>3</sup>H-dopamine, substituting for the
      endogenous dopamine pool, and perfused with ritonavir or saquinavir, both basally
      and during depolarization (K<sup>+</sup> 15 mM)-induced dopamine release. Beta
      emission from 2 min perfusate fractions, corresponding to <sup>3</sup>H-dopamine
      release, was detected by liquid scintillation scanning. We found that both
      ritonavir and saquinavir are able to significantly stimulate PRL secretion, with
      saquinavir slightly more effective than ritonavir. On the contrary, both protease
      inhibitors do not modify either basal or depolarization-induced dopamine release.
      We can speculate that HIV PIs despite a high affinity for the catalytic site of
      HIV protease, could also bind to and inhibit homologous mammalian proteins in the
      anterior pituitary that are involved in PRL secretion.

PMID- 12593791
TI  - Bronchial hyperresponsiveness in adults with seasonal and perennial rhinitis: is
      there a link for asthma and rhinitis?
AB  - Epidemiological studies have shown that asthma and rhinitis often coexist in the
      same patients and the prevalence of asthma is greater in patients with rhinitis.
      The aim of this study was to evaluate the differences in bronchial reactivity in
      subjects with seasonal and perennial rhinitis. We enrolled 128 subjects with
      seasonal or perennial allergic rhinitis divided into three groups: A with
      perennial rhinitis and allergy to Dermatophagoides Pteronissynus; B with seasonal
      rhinitis and allergy to Graminae and Parietaria, who underwent methacholine
      challenge test (MCHt) during the exposure period (fron March until May); C with
      seasonal rhinitis and allergy to Graminae and Parietaria, who underwent MCHt
      during the non exposure period (from June until February). The PC20 mean values
      of group A (1774.8 &#x00B1; 20.7) and group B (1740.7 &#x00B1; 38.8) were not
      significantly different, but significantly lower than those of group C (3010.0
      &#x00B1; 56.9) (p=0.001). The subjects with group A were positive to the MCHt in
      54.54&#x0025;, against 29.28&#x0025; of group B and 11.62&#x0025; of group C
      (p=0.007). The results show differences in the degree of bronchial
      responsiveness. The dose-response curves documented a lower value of PC20 in the
      group with perennial rhinitis and a statistically significant difference of
      bronchial hyperresponsiveness prevalence between the three groups (p=0.007).

PMID- 12593792
TI  - Conservation of mechanisms controlling entry into mitosis: budding yeast wee1
      delays entry into mitosis and is required for cell size control.
AB  - BACKGROUND: In fission yeast, the Wee1 kinase delays entry into mitosis until a
      critical cell size has been reached; however, a similar role for Wee1-related
      kinases has not been reported in other organisms. SWE1, the budding yeast homolog
      of wee1, is thought to function in a morphogenesis checkpoint that delays entry
      into mitosis in response to defects in bud morphogenesis. RESULTS: In contrast to
      previous studies, we found that budding yeast swe1 Delta cells undergo premature
      entry into mitosis, leading to birth of abnormally small cells. Additional
      experiments suggest that conditions that activate the morphogenesis checkpoint
      may actually be activating a G2/M cell size checkpoint. For example, actin
      depolymerization is thought to activate the morphogenesis checkpoint by
      inhibiting bud morphogenesis. However, actin depolymerization also inhibits bud
      growth, suggesting that it could activate a cell size checkpoint. Consistent with
      this possibility, we found that actin depolymerization fails to induce a G2/M
      delay once daughter buds pass a critical size. Other conditions that activate the
      morphogenesis checkpoint block bud formation, which could also activate a size
      checkpoint if cell size at G2/M is monitored in the daughter bud. Previous work
      reported that Swe1 is degraded during G2, which was proposed to account for
      failure of large-budded cells to arrest in response to actin depolymerization.
      However, we found that Swe1 is present throughout G2 and undergoes
      hyperphosphorylation as cells enter mitosis, as found in other organisms.
      CONCLUSIONS: Our results suggest that the mechanisms known to coordinate entry
      into mitosis in other organisms have been conserved in budding yeast.

PMID- 12593793
TI  - The Synaptonemal complex component C(2)M regulates meiotic crossing over in
      Drosophila.
AB  - BACKGROUND: The synaptonemal complex (SC) is a proteinaceous structure that forms
      between homologously paired meiotic chromosomes. Previous studies have suggested
      that the SC is required for meiotic crossing over in Drosophila. However, only
      one component of this structure, C(3)G, has been identified in Drosophila.
      RESULTS: Mutations in c(2)M cause a reduced frequency of meiotic crossing over
      due, in part, to how recombination events are resolved. Cytological evidence
      suggests that C(2)M is a component of the SC and is required for the assembly of
      C(3)G (a putative transverse filament of the SC) along the chromosomes.
      Additionally, C(2)M localizes along the chromosomes in the absence of C(3)G.
      Despite having a defect in C(3)G localization, c(2)M mutants unexpectedly affect
      crossing over less severely than a c(3)G mutant. There is virtually no crossing
      over in a c(3)G mutant, but c(2)M or c(2)M; c(3)G double mutants produce a
      substantial number of crossovers. The appearance of C(3)G-independent crossovers
      in c(2)M mutants suggests that C(2)M prevents recombination in the absence of
      complete SC formation. CONCLUSIONS: We have identified a new Drosophila SC
      component, C(2)M, that promotes the formation of crossovers. Furthermore, the
      appearance of C(3)G-independent crossovers in c(2)M mutants suggests a novel role
      in preventing recombination in the absence of complete SC.

PMID- 12593794
TI  - The staufen/pumilio pathway is involved in Drosophila long-term memory.
AB  - BACKGROUND: Memory formation after olfactory learning in Drosophila displays
      behavioral and molecular properties similar to those of other species.
      Particularly, long-term memory requires CREB-dependent transcription, suggesting
      the regulation of "downstream" genes. At the cellular level, long-lasting
      synaptic plasticity in many species also appears to depend on CREB-mediated gene
      transcription and subsequent structural and functional modification of relevant
      synapses. To date, little is known about the molecular-genetic mechanisms that
      contribute to this process during memory formation. RESULTS: We used two
      complementary strategies to identify these genes. From DNA microarrays, we
      identified 42 candidate memory genes that appear to be transcriptionally
      regulated in normal flies during memory formation. Via mutagenesis, we have
      independently identified 60 mutants with defective long-term memory and have
      defined molecular lesions for 58 of these. The pumilio translational repressor
      was found from both approaches, along with six additional genes with established
      roles in local control of mRNA translation. In vivo disruptions of four genes-
      staufen, pumilio, oskar, and eIF-5C--yield defective memory. CONCLUSIONS:
      Convergent findings from our behavioral screen for memory mutants and DNA
      microarray analysis of transcriptional responses during memory formation in
      normal animals suggest the involvement of the pumilio/staufen pathway in memory.
      Behavioral experiments confirm a role for this pathway and suggest a molecular
      mechanism for synapse-specific modification.

PMID- 12593795
TI  - Sprouty fine-tunes EGF signaling through interlinked positive and negative
      feedback loops.
AB  - BACKGROUND: Growth factors and their receptor tyrosine kinases play pivotal roles
      in development, normal physiology, and pathology. Signal transduction is
      regulated primarily by receptor endocytosis and degradation in lysosomes
      ("receptor downregulation"). c-Cbl is an adaptor that modulates this process by
      recruiting binding partners, such as ubiquitin-conjugating enzymes. The role of
      another group of adaptors, Sprouty proteins, is less understood; although,
      studies in insects implicated the founder protein in the negative regulation of
      several receptor tyrosine kinases. RESULTS: By utilizing transfection of living
      cells, as well as reconstituted in vitro systems, we identified a dual regulatory
      mechanism that combines human Sprouty2 and c-Cbl. Upon activation of the receptor
      for the epidermal growth factor (EGFR), Sprouty2 undergoes phosphorylation at a
      conserved tyrosine that recruits the Src homology 2 domain of c-Cbl.
      Subsequently, the flanking RING finger of c-Cbl mediates poly-ubiquitination of
      Sprouty2, which is followed by proteasomal degradation. Because phosphorylated
      Sprouty2 sequesters active c-Cbl molecules, it impedes receptor ubiquitination,
      downregulation, and degradation in lysosomes. This competitive interplay occurs
      in endosomes, and it regulates the amplitude and longevity of intracellular
      signals. CONCLUSIONS: Sprouty2 emerges as an inducible antagonist of c-Cbl, and
      together they set a time window for receptor activation. When incorporated in
      signaling networks, the coupling of positive (Sprouty) to negative (Cbl) feedback
      loops can greatly enhance output diversification.

PMID- 12593796
TI  - hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl.
AB  - Sprouty was originally identified in a genetic screen in Drosophila as an
      antagonist of fibroblast (FGF) and epidermal growth factor (EGF) signaling.
      Subsequently, four vertebrate homologs were discovered; among these, the human
      homolog Sprouty 2 (hSpry2) contains the highest degree of sequence homology to
      the Drosophila protein. It has been shown that hSpry2 interacts directly with c
      Cbl, an E3-ubiquitin ligase, which promotes the downregulation of receptor
      tyrosine kinases (RTKs). In this study, we have investigated the functional
      consequences of the association between hSpry2 and c-Cbl. We have found that
      hSpry2 is ubiquitinated by c-Cbl in an EGF-dependent manner. EGF stimulation
      induces the tyrosine phosphorylation of hSpry2, which in turn enhances the
      interaction of hSpry2 with c-Cbl. The c-Cbl-mediated ubiquitination of hSpry2
      targets the protein for degradation by the 26S proteasome. An enhanced
      proteolytic degradation of hSpry2 is also observed in response to FGF
      stimulation. The FGF-induced degradation of hSpry2 limits the duration of the
      inhibitory effect of hSpry2 on extracellular signal-regulated kinase (ERK)
      activation and enables the cells to recover their sensitivity to FGF stimulation.
      Our results indicate that the interaction of hSpry2 with c-Cbl might serve as a
      mechanism for the downregulation of hSpry2 during receptor tyrosine kinase
      signaling.

PMID- 12593797
TI  - The JNK cascade as a biochemical switch in mammalian cells: ultrasensitive and
      all-or-none responses.
AB  - JNK proteins are ubiquitously expressed, evolutionarily conserved MAP kinases
      that are involved in stress responses. Recently, it was shown that the JNK
      cascade in Xenopus oocytes exhibits sustained, all-or-none responses to graded,
      transient stimuli. Here, we have examined the character of the JNK cascade's
      response in mammalian cells. The steady-state responses of JNK to sorbitol and
      anisomycin were found to be highly ultrasensitive in HeLa cells, HEK 293 cells,
      and Jurkat T cells. The JNK responses were also reversible, not sustained, as was
      the case in oocytes. Jurkat cells activated their JNK in response to phorbol
      myristate acetate (PMA), and the response of the entire population of Jurkat
      cells was graded. However, analysis of subpopulations of the PMA-treated Jurkat
      cells revealed that the steady-state responses of both JNK and CD69, a T cell
      surface activation marker, were essentially all-or-none in character. These
      studies show that the JNK cascade commonly exhibits switch-like responses to a
      variety of stimuli.

PMID- 12593798
TI  - Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM
      kinase II interactions are disrupted in PSD-95 mutant mice.
AB  - Chronic pain due to nerve injury is resistant to current analgesics. Animal
      models of neuropathic pain show neuronal plasticity and behavioral reflex
      sensitization in the spinal cord that depend on the NMDA receptor. We reveal
      complexes of NMDA receptors with the multivalent adaptor protein PSD-95 in the
      dorsal horn of spinal cord and show that PSD-95 plays a key role in neuropathic
      reflex sensitization. Using mutant mice expressing a truncated form of the PSD-95
      molecule, we show their failure to develop the NMDA receptor-dependent
      hyperalgesia and allodynia seen in the CCI model of neuropathic pain, but normal
      inflammatory nociceptive behavior following the injection of formalin. In wild
      type mice following CCI, CaM kinase II inhibitors attenuate sensitization of
      behavioral reflexes, elevated constitutive (autophosphorylated) activity of CaM
      kinase II is detected in spinal cord, and increased amounts of phospho-Thr(286)
      CaM kinase II coimmunoprecipitate with NMDA receptor NR2A/B subunits. Each of
      these changes is prevented in PSD-95 mutant mice although CaM kinase II is
      present and can be activated. Disruption of CaM kinase II docking to the NMDA
      receptor and activation may be responsible for the lack of neuropathic behavioral
      reflex sensitization in PSD-95 mutant mice.

PMID- 12593799
TI  - The force-velocity relationship for the actin-based motility of Listeria
      monocytogenes.
AB  - The intracellular movement of the bacterial pathogen Listeria monocytogenes has
      helped identify key molecular constituents of actin-based motility (recent
      reviews ). However, biophysical as well as biochemical data are required to
      understand how these molecules generate the forces that extrude eukaryotic
      membranes. For molecular motors and for muscle, force-velocity curves have
      provided key biophysical data to distinguish between mechanistic theories. Here
      we manipulate and measure the viscoelastic properties of tissue extracts to
      provide the first force-velocity curve for Listeria monocytogenes. We find that
      the force-velocity relationship is highly curved, almost biphasic, suggesting a
      high cooperativity between biochemical catalysis and force generation. Using high
      resolution motion tracking in low-noise extracts, we find long trajectories
      composed exclusively of molecular-sized steps. Robust statistics from these
      trajectories show a correlation between the duration of steps and macroscopic
      Listeria speed, but not between average step size and speed. Collectively, our
      data indicate how the molecular properties of the Listeria polymerization engine
      regulate speed, and that regulation occurs during molecular-scale pauses.

PMID- 12593800
TI  - Notch/RBP-J signaling regulates epidermis/hair fate determination of hair
      follicular stem cells.
AB  - Notch signaling is involved in the cell fate determination of various cell
      lineages. Notch interaction with its ligand induces the cleavage of its
      intracellular domain (IC), and the Notch IC translocates to the nucleus and binds
      to RBP-J to transactivate transcription of target genes. All four Notches in
      mammals bind to RBP-J to exert their transactivation activities. Notch is
      expressed in developing or differentiating epidermis and hairs, inhibits the
      terminal differentiation of the epidermis, and regulates hair differentiation.
      The common stem cells that reside in the upper portion of hair follicles (the
      bulge) contribute to epidermal and hair cell formation. However, it is unknown
      what determines whether hair follicular stem cells will become hairs or
      epidermis. Here we report that conditionally disrupting the mouse RBP-J gene in a
      mosaic pattern to avoid embryonic lethality of RBP-J-deficiency caused hair loss,
      epidermal hyperkeratinization, and epidermal cyst formation. Cyst formation is
      probably due to a combination of the aberrant fate determination of RBP-J
      deficient stem cells to epidermal progenitors and their accelerated
      differentiation into epidermis. These results suggest that Notch/RBP-J signaling
      regulates the cell fate determination of hair follicular stem cells at the bulge
      region.

PMID- 12593801
TI  - Impaired mirror-image imitation in Asperger and high-functioning autistic
      subjects.
AB  - Imitation is crucial for proper development of social and communicative skills.
      Here, we argue that, based on an error analysis of a behavioral imitation task,
      adult Asperger and high-functioning autistic subjects suffer from an intriguing
      deficit of imitation: they lack the natural preference for imitation in a mirror
      image fashion. The imitation task consisted of a simple movement sequence of
      putting a pen with the left or right hand into a green or a blue cup using one of
      two possible grips. The subjects were asked to imitate the experimenter's hand
      movements either using the crossed hand (e.g., the subject's right hand
      corresponding to the experimenter's right hand) for imitation or to imitate as if
      looking in a mirror (e.g., the subject's left hand corresponding to the
      experimenter's right hand). When people normally view other persons face-to-face,
      they prefer to imitate as in a mirror, and observation of mirror-image-like
      movements speeds up performance in nonimitative tasks. However, our autistic
      subjects, defective in social cognition, did not profit from mirror-image
      movements of others. These results provide a new insight into the difficulties
      that autistic subjects face in viewing and understanding actions of others.

PMID- 12593802
TI  - Perceptual organization of local elements into global shapes in the human visual
      cortex.
AB  - The question of how local image features on the retina are integrated into
      perceived global shapes is central to our understanding of human visual
      perception. Psychophysical investigations have suggested that the emergence of a
      coherent visual percept, or a "good-Gestalt", is mediated by the perceptual
      organization of local features based on their similarity. However, the neural
      mechanisms that mediate unified shape perception in the human brain remain
      largely unknown. Using human fMRI, we demonstrate that not only higher
      occipitotemporal but also early retinotopic areas are involved in the perceptual
      organization and detection of global shapes. Specifically, these areas showed
      stronger fMRI responses to global contours consisting of collinear elements than
      to patterns of randomly oriented local elements. More importantly, decreased
      detection performance and fMRI activations were observed when misalignment of the
      contour elements disturbed the perceptual coherence of the contours. However,
      grouping of the misaligned contour elements by disparity resulted in increased
      performance and fMRI activations, suggesting that similar neural mechanisms may
      underlie grouping of local elements to global shapes by different visual features
      (orientation or disparity). Thus, these findings provide novel evidence for the
      role of both early feature integration processes and higher stages of visual
      analysis in coherent visual perception.

PMID- 12593803
TI  - Genome-wide analyses of steroid- and radiation-triggered programmed cell death in
      Drosophila.
AB  - Apoptosis and autophagy are two forms of programmed cell death that play
      important roles in the removal of unneeded and abnormal cells during animal
      development. While these two forms of programmed cell death are morphologically
      distinct, recent studies indicate that apoptotic and autophagic cell death
      utilize some common regulatory mechanisms. To identify genes that are associated
      with apoptotic and autophagic cell death, we monitored changes in gene
      transcription by using microarrays representing nearly the entire Drosophila
      genome. Analyses of steroid-triggered autophagic cell death identified 932 gene
      transcripts that changed 5-fold or greater in RNA level. In contrast, radiation
      activated apoptosis resulted in 34 gene transcripts that exhibited a similar
      magnitude of change. Analyses of these data enabled us to identify genes that are
      common and unique to steroid- and radiation-induced cell death. Mutants that
      prevent autophagic cell death exhibit altered levels of gene transcription,
      including genes encoding caspases, non-caspase proteases, and proteins that are
      similar to yeast autophagy proteins. This study also identifies numerous novel
      genes as candidate cell death regulators and suggests new links between apoptosis
      and autophagic cell death.

PMID- 12593804
TI  - A SAGE approach to discovery of genes involved in autophagic cell death.
AB  - Programmed cell death (PCD), important in normal animal physiology and disease,
      can be divided into at least two morphological subtypes, including type I, or
      apoptosis, and type II, or autophagic cell death. While many molecules involved
      in apoptosis have been discovered and studied intensively during the past decade,
      autophagic cell death is not well characterized molecularly. Here we report the
      first comprehensive identification of molecules associated with autophagic cell
      death during normal metazoan development in vivo. During Drosophila
      metamorphosis, the larval salivary glands undergo autophagic cell death regulated
      by a hormonally induced transcriptional cascade. To identify and analyze the
      genes expressed, we examined wild-type patterns of gene expression in three
      predeath stages of Drosophila salivary glands using serial analysis of gene
      expression (SAGE) [7]. 1244 transcripts, including genes involved in autophagy,
      defense response, cytoskeleton remodeling, noncaspase proteolysis, and apoptosis,
      were expressed differentially prior to salivary gland death. Mutant expression
      analysis indicated that several of these genes were regulated by E93, a gene
      required for salivary gland cell death. Our analyses strongly support both the
      emerging notion that there is overlap with respect to the molecules involved in
      autophagic cell death and apoptosis, and that there are important differences.

PMID- 12593805
TI  - Research fears in funding shake-up.

PMID- 12593807
TI  - Lewis Wolpert.

PMID- 12593808
TI  - The winning system.

PMID- 12593809
TI  - ARFs.

PMID- 12593810
TI  - Sequence similarity in structurally dissimilar proteins.

PMID- 12593811
TI  - RNA and memory: from feeding to localization.
AB  - Ideas about the role of RNA in learning and memory have a checkered past. A new
      study in Drosophila, synthesizing classical forward genetics with DNA
      microarrays, brings us closer to seeing that role clearly.

PMID- 12593812
TI  - Polarised migration: cofilin holds the front.
AB  - Persistent cell locomotion is a key feature of eukaryotic cells responding to
      diverse physiological cues. New work now directly implicates ADF/cofilin proteins
      as essential regulators of polarised cell migration.

PMID- 12593813
TI  - Tube morphogenesis: no pipe dream in Drosophila.
AB  - Tubular organs have characteristic lumen sizes that are generated during
      development. Recent studies of tubular systems in Drosophila have implicated
      intracellular vesicle transport as an important step in lumen expansion.

PMID- 12593814
TI  - Human diversity: our genes tell where we live.
AB  - A detailed genetic analysis of more than a thousand human subjects clusters them
      into five groups corresponding to major geographical regions. This new study
      shows that self-reported ancestry is a good predictor of one's genetic make-up.

PMID- 12593815
TI  - T-cell activation: the power of one.
AB  - Adaptive immunity depends on antigen-specific activation of resting lymphocytes.
      Using high-resolution live-cell imaging, a single ligand has been found to
      trigger a biochemical response in T cells. On the basis of this and other recent
      findings, a 'pseudodimer' with one foreign- and one self-antigen-engaged receptor
      linked via a CD4 molecule has been proposed as the fundamental unit of effective
      T-cell signaling.

PMID- 12593816
TI  - Behavioral choices: how neuronal networks make decisions.
AB  - To survive, animals must constantly make behavioral choices. The analysis of
      simple, almost binary, behavioral choices in invertebrate animals with restricted
      nervous systems is beginning to yield insight into how neuronal networks make
      such decisions.

PMID- 12593817
TI  - Synaptic plasticity: the subcellular location of CaMKII controls plasticity.
AB  - In a neuron's dendritic spine, the location of CaMKII is controlled by a number
      of interacting factors, including its ability to bind calcium/calmodulin, its
      phosphorylation state and the synthesis of new subunits in the dendrites. New
      studies have shown that the exact location of CaMKII is crucial for the form and
      endurance of synaptic plasticity.

PMID- 12593818
TI  - Plant cell cycle: cellularisation of the endoderm needs spatzle.
AB  - Early development of the endosperm of flowering plants involves the formation of
      a syncytium through successive rounds of nuclear division without cell wall
      synthesis. New data reveal that cellularisation of this syncytium requires the
      SPATZLE protein and involves the formation of cell walls similar to those of
      somatic tissues.

PMID- 12593819
TI  - Splicing regulation: the cell cycle connection.
AB  - Many genes are repressed during mitosis, and this is known to involve
      differential phosphorylation of specific factors required for transcription, 3'
      end RNA processing and translation. A recent study suggests that splicing is also
      targeted for mitotic repression, in this case by dephosphorylation of the newly
      identified splicing factor SRp38.

PMID- 12593820
TI  - Neurons take shape.
AB  - To construct the intricate network of connections that supports the functions of
      an adult nervous system, neurons must form highly elaborate processes, extending
      in the appropriate direction across long distances to form synapses with their
      partners. As the nervous system takes shape, the process of neuronal
      morphogenesis is controlled by a broad repertoire of cellular signals. These
      extracellular cues and cellular interactions are translated by receptors at the
      cell surface into physical forces that control the dynamic architecture of the
      neuron as it explores the surrounding terrain. The interpretation of these cues
      involves a large set of intracellular proteins, whose functional logic we are
      just beginning to appreciate. We shall consider the basic mechanics of neuronal
      morphogenesis and some of the emerging pathways that seem to link the outer and
      inner worlds of the neuron.

PMID- 12593821
TI  - Research Governance--what future for nursing research?

PMID- 12593822
TI  - Research: an essential skill of a graduate nurse?
AB  - This paper discusses a research project undertaken by undergraduate nursing
      students, which includes data collection and provides transferable skills as well
      as a secure grounding for future research work. There is an expectation that
      nurse graduates should have research skills, but disagreement about how these
      skills should be acquired. This paper puts forward the case that undergraduate
      nurses should have some experience of "hands-on" research for the same reason
      that they undertake training in clinical skill acquisition, i.e., the skills in
      question are an essential feature of their role as a nurse. It is further argued
      that a research project develops transferable skills, which are expected from
      graduates of any discipline, and are much sought after by employers. In the light
      of present and future changes in nursing roles such transferable skills would
      better equip nurses to meet such changing demands in their professional role.

PMID- 12593823
TI  - Moving to an all graduate profession: preparing preceptors for their role.
AB  - The world of Irish Nurse education has changed significantly over the last number
      of years, moving from certificate to diplomat status, from hospital-based
      training to integration within the higher education sector. The Irish Government
      has now committed pound 223,470,000 for the implementation of a four year pre
      registration nursing degree programme. Consequently, from 2002 onwards all Irish
      pre-registration nurse education will be at graduate level. In recognition of the
      importance of student learning during practice placement the recommended that
      nursing students be supported by a named preceptor. This recommendation has
      significant resource implications in terms of current staff demands, staff
      preparation and ongoing support for the preceptor role. This paper will focus on
      a review of the literature on student support mechanisms during practice
      placements with particular emphasis on the concept of preceptor and
      preceptorship.

PMID- 12593824
TI  - Mental health promotion education in multicultural settings.
AB  - This paper addresses the education of graduate nursing students in mental health
      promotion in multicultural settings. First an overview of the historical
      development of health promotion theory in Canada is presented. Emerging concepts
      in mental health promotion are then considered. Referring to a graduate course on
      youth and mental health promotion, course design, which draws from across
      disciplines and recognizes the complexities in mental health promotion practice
      in multicultural settings, is illustrated. Under a mental health promotion
      perspective healthy development is recognized to arise from the interaction
      between people and systems in society, providing a systems-based understanding of
      the interplay between culture and health. The course's underlying threads,
      consisting of youth development and mental health, culture, and integration of
      learning through an intersectional perspective, and its related substantive
      content and process are discussed. It is concluded that by fostering students'
      critical awareness of intersections (for example, gender, life stage, migrant and
      racialized status), the growth and development of youth from diverse cultural
      backgrounds can be contextualized within existing support, or access barriers to,
      systems in multicultural societies.

PMID- 12593825
TI  - The client as educator: learning about mental illness through the eyes of the
      expert.
AB  - Increasingly, educators are asking clients who have a mental illness to make a
      contribution to nursing students' learning as a way of informing their attitudes
      towards persons experiencing mental illness and thus enhancing care delivery. The
      nature of clients' involvement in the classroom and the quality of learning by
      students through this approach has rarely been questioned. This paper discusses a
      model of client/nurse educator collaboration in a mental health course with
      undergraduate nursing students. It draws on the nursing education experiences of
      the first author, and the personal views of the second author, a user of mental
      health services. Specifically, it addresses positive features of collaboration as
      perceived by students, client, and nurse educator and analyzes some of the
      challenges/issues for the nurse educator. In addition, it outlines helpful
      aspects of the collaborative process for both nurse educator and client, in
      particular, its impact on the client's personal well being. This kind of analysis
      is essential if we are to develop education models of such collaboration that are
      beneficial for all partners in the learning process.

PMID- 12593826
TI  - Teachers' views on curriculum development in health promotion in two Finnish
      polytechnics.
AB  - This study describes teachers' views on how to improve the health promotion
      element in the curricula of two health care polytechnics in Finland. The
      theoretical background of this study draws on curriculum development in nursing
      education and how to promote a human- or resource-centred approach in health
      promotion. The research data were collected by interviewing 10 teachers from both
      the schools involved in nursing or public health nursing education since August
      1997. The data were analysed using content analysis. The findings showed that
      most of the teachers interviewed were involved in local curriculum development.
      This work was impeded by lack of time and real commitment, as well as the
      teachers' desire to protect their own teaching domains. In both polytechnics,
      they regarded the curriculum mainly as a document guiding their own and students'
      work. Teachers in one of the polytechnics emphasised the importance of national
      guidelines in ensuring professional competence, but no one stressed the
      importance of their school as a regional educational institution. Almost all
      agreed that health promotion was adequately included in their curriculum. The
      project "Health for all by year 2000" was taken as the basis for the curriculum
      in both schools, but some teachers expressed a need for an additional study unit.
      The findings revealed teachers' traditional views on health promotion in
      curricula and that there was no evidence of a new approach being adopted.

PMID- 12593827
TI  - An investigation of the lived experiences of registered nurses facilitating
      supernumerary nursing students.
AB  - The aim of this study was to explore and describe the everyday lived experiences
      of registered nurses facilitating supernumerary diploma student nurses in the
      clinical area. The research question; 'How do registered nurses perceive their
      role in relation to supernumerary students?' provided the central focus for the
      study. Using purposive sampling, 10 participants were chosen for the research.
      Semi-structured interviews were used to collect the data. The themes that emerged
      from the data are 'supernumerary status', 'facilitating students', 'rewarding
      experience', 'student interest', 'the diploma programme' and 'issues in nurse
      education'. The findings revealed positive and negative experiences of
      facilitating supernumerary students. Since the diploma programme of pre
      registration nurse education was in its inaugural stages in Ireland at the time
      of this study, a foundation for further research is established. The conclusion
      indicates that facilitating supernumerary student nurses at diploma level can be
      a complex phenomenon for registered nurses.

PMID- 12593828
TI  - Facilitating perception and imagination in generating change through reflective
      practice groups.
AB  - This paper describes the process of facilitating groups of registered nurses to
      generate change in themselves and their practice through guided reflection. The
      concept of perception is explored in respect of individual interpretations of
      personal experiences where perception becomes reality for that individual. Such
      perception is subject to bias and without supported guidance in the reflective
      process inappropriate conclusions are easily generated. Through facilitating
      group deconstruction of the perceived experience the individual is able to
      identify the elements of bias emerging and subsequently reaches valid conclusions
      by reconstructing the experience with reduced elements of subjectivity which are
      more appropriate to personal and practice development. Within the reconstruction
      process, imagination is stimulated by steering individuals within the group
      towards visualising outcomes of planned actions. Use of imagination allows
      internal acting out of events and the identification of consequences of following
      a particular course of action. This process enables generation of appropriate
      actions to take place through development of insight and deeper awareness of
      influences on personal change. Through appropriate developments in personal
      approaches the ensuing changes generated in practice take place through
      considered strategies, which will enhance nursing and care provision.

PMID- 12593829
TI  - Care of older people in nursing homes: an Intensive Programme as an educational
      activity within Erasmus-Socrates.
AB  - The paper describes and discusses an Intensive Programme as a European
      educational activity within Erasmus-Socrates. As nurses and European citizens, it
      is important to know and understand each other's culture and to be able to work
      within a united Europe. Education plays a leading role in the preparation of
      professionals who will have to develop these skills. Based on the aims of Erasmus
      Socrates, an Intensive Programme entitled 'Care of Older People in Nursing Homes'
      was designed, sponsored, and implemented over three continuous academic years
      with the participation of five European countries. The topic was selected due to
      its importance for Europe, as it is a region with an ageing population. A wide
      range of themes was covered using lectures, group discussion, exercises and study
      visits as teaching strategies. Evaluation suggests that the aims of the programme
      were achieved.

PMID- 12593830
TI  - Nurse education in English universities in a period of change: expectations of
      nurse academics for the year 2008.
AB  - In England, the education of nurses in the academic arena has a relatively short
      history arguably representing recent advancement of the nursing discipline. Until
      we undertook this study, however, expectations for the next decade were unknown.
      The current investigation replicates a similar study of Australian nurse
      academics (Sellers & Deans, 1996) which found discrepancies between how nurse
      academics perceived the future development of the profession, compared to how
      they actually expected it to develop. In order to provide information concerning
      the future of nursing education in England and related professional and social
      factors, a random sample of nurse academics was surveyed. Findings indicate that
      although advances have been made, there are a number of concerns regarding the
      development of nursing as a discipline. These include parity of status with other
      academic areas, resource issues, the workload of nurse academics and the
      perception that there is lack of cohesiveness amongst nurses as a professional
      group. Findings in this study closely mirror results in the Australian study
      indicating similarities in how the nursing profession copes with the transition
      from a predominantly hospital based education program to a program grounded in
      academic institutions.

PMID- 12593831
TI  - Is biological science difficult for first-year students or do we simply need more
      information? A response to why is biological science difficult for first-year
      nursing students?

PMID- 12593832
TI  - Is biological science difficult for first year students or do we simply need more
      information? A response to Ian Scott's criticism of 'Why is biological science
      difficult for first-year nursing students? Nurse Education Today 22:3:251-257.

PMID- 12593838
TI  - Hypothesis: a glycoprotein-degradation complex formed by protein-protein
      interaction involves cytoplasmic peptide:N-glycanase.
AB  - A cytoplasmic peptide:N-glycanase has been implicated in the proteasomal
      degradation of newly synthesized misfolded glycoproteins that are exported from
      the endoplasmic reticulum to the cytosol. Recently, the gene encoding this enzyme
      (Png1p) was identified in yeast and shown to bind to the 26S proteasome through
      its interaction with a component of the DNA repair system, Rad23p. Moreover, a
      mouse homologue of Png1p (mPng1p), which has an extended N-terminal domain, was
      found to bind not only to the Rad23 protein, but also to various proteins related
      to the ubiquitin/proteasome pathway. An extended N-terminus of mPng1p, which is
      not found in yeast, contains a potential site of protein-protein interaction
      called the PUB/PUG domain. The PUB/PUG domain is predicted to be helix-rich and
      is found in various proteins that may be involved in the ubiquitin/proteasome
      related pathway. This review will discuss the consequence of the deglycosylation
      reaction by peptide:N-glycanase in cellular processes. In addition, the potential
      importance of the PUB/PUG domain for the formation of a putative "glycoprotein
      degradation complex" will be discussed.

PMID- 12593839
TI  - Lipid-mediated delivery of peptide nucleic acids to pulmonary endothelium.
AB  - Peptide nucleic acid (PNA) is a DNA/RNA mimic in which the phosphodiester (PO)
      linkage is replaced with a peptide bond. It has a number of unique properties
      compared to currently used oligonucleotides including higher affinity towards RNA
      or DNA target, resistance to nucleases or proteases, and minimal non-specific
      interactions with proteins. Clinical applications of PNA, however, are limited by
      its inefficient intracellular delivery. In this study, we have shown that
      delivery of PNA to pulmonary endothelium in intact mice can be greatly improved
      via hybridization with a short PO oligonucleotide that serves as a carrier to
      form complexes with cationic liposomes. We have also shown for the first time
      that unlike a CpG DNA oligo that is highly proinflammatory, a CG-containing PNA
      is inert in triggering TNF-alpha response in cultured macrophages and in mice.
      Thus delivery of PNA to pulmonary endothelium may prove to be a therapeutically
      useful for the treatment of pulmonary vascular diseases.

PMID- 12593840
TI  - Role of Wnt10b and C/EBPalpha in spontaneous adipogenesis of 243 cells.
AB  - This report examines the balance of positive and negative adipogenic factors in a
      line of immortalized 243 embryonic fibroblasts that undergo spontaneous
      preadipocyte differentiation. Control of adipogenesis reflects the interplay of
      factors that promote or inhibit expression of C/EBPalpha and PPARgamma. The 243
      cells express C/EBPalpha early and at elevated levels compared to 3T3-F442A
      preadipocytes or adipocytes. Cell clones were derived from the heterogeneous 243
      population for ability or inability to differentiate into adipocytes. Wnt10b, a
      secreted protein that inhibits adipogenesis, is expressed at high levels in cells
      with low adipogenic potential and is undetectable in preadipocytes that
      spontaneously differentiate. In contrast, C/EBPalpha is expressed at reduced
      levels in cells with low adipogenic potential, and is expressed at high levels in
      preadipocytes that spontaneously differentiate. These data are consistent with a
      model in which decreased Wnt10b, coupled with increased C/EBPalpha, results in
      induction of PPARgamma and spontaneous adipogenesis of 243 cells.

PMID- 12593841
TI  - The ankyrin repeat containing SOCS box protein 5: a novel protein associated with
      arteriogenesis.
AB  - Arteriogenesis, the growth of pre-existing collateral arteries, can be induced in
      rabbit by occlusion of the femoral artery. In order to identify and characterize
      genes differentially expressed during the early phase of arteriogenesis, cDNA of
      collateral arteries 24h after femoral ligation or sham operation was subjected to
      suppression subtractive hybridization. We identified the ankyrin repeat
      containing SOCS box protein 5 (asb5) and cloned the rabbit full-length cDNA. Asb5
      was demonstrated to be a single-copy gene. We localized the asb5 protein in vivo
      in endothelial and smooth muscle cells of collateral arteries as well as in
      satellite cells. Asb5 was significantly upregulated in growing collateral
      arteries on mRNA and protein level. The infusion of doxorubicin in rabbit led to
      a significant decrease of the asb5 mRNA. In summary, our data show that asb5 is a
      novel protein implicated in the initiation of arteriogenesis.

PMID- 12593842
TI  - Smooth muscle uses another promoter to express primarily a form of human Cav1.2 L
      type calcium channel different from the principal heart form.
AB  - Several different first exons and amino termini have been reported for the
      cardiac Ca channel known as alpha(1C) or Ca(V)1.2. The aim of this study was to
      investigate whether the expression of this channel is regulated by different
      promoters in smooth muscle cells and in heart in humans. Ribonuclease protection
      assay (RPA) indicates that the longer first exon 1a is found in certain human
      smooth muscle-containing tissues, notably bladder and fetal aorta, but that it is
      not expressed to any significant degree in lung or intestine. On the other hand,
      all four smooth muscle-containing tissues examined strongly express transcripts
      containing exon 1b, first reported cloned from human fibroblast cells. In
      addition, primary cultures of human colonic myocytes and coronary artery smooth
      muscle cells express predominantly transcripts containing exon 1b. The promoter
      immediately upstream of exon 1b was cloned, and it displays functional promoter
      activity when luciferase-expressing constructs were transfected into three
      different cultured smooth muscle cells: primary human coronary artery smooth
      muscles cells, primary human colonocytes, and the fetal rat aorta-derived A7r5
      cell line. These results indicate that expression in smooth muscle is primarily
      driven by a promoter different from that which drives expression in cardiac
      myocytes.

PMID- 12593843
TI  - Fenofibrate improves lipid metabolism and obesity in ovariectomized LDL receptor
      null mice.
AB  - We investigated whether fenofibrate improves lipid metabolism and obesity in
      female ovariectomized (OVX) or sham-operated (SO) low density lipoprotein
      receptor-null (LDLR-null) mice. All mice fed a high-fat diet exhibited increases
      in serum triglycerides and cholesterol as well as in body weight and white
      adipose tissue (WAT) mass compared to mice fed a low fat control diet. However,
      fenofibrate prevented high-fat diet-induced increases in body weight and WAT mass
      in female OVX LDLR-null mice, but not in SO mice. In addition, administration of
      fenofibrate reduced serum lipids and hepatic apolipoprotein C-III mRNA while
      increasing the mRNA of acyl-CoA oxidase in both groups of mice, however, these
      effects were more pronounced in OVX LDLR-null mice. The results of this study
      provide first evidence that fenofibrate improves both lipid metabolism and
      obesity, in part through PPARalpha activation, in female OVX LDLR-null mice.

PMID- 12593844
TI  - Glutamate-41 of Vibrio harveyi acyl carrier protein is essential for fatty acid
      synthase but not acyl-ACP synthetase activity.
AB  - Bacterial acyl carrier protein (ACP) is a small, acidic, and highly conserved
      protein that supplies acyl groups for biosynthesis of a variety of lipid
      products. Recent modelling studies predict that residues primarily in helix II of
      Escherichia coli ACP (Glu-41, Ala-45) are involved in its interaction with the
      condensing enzyme FabH of fatty acid synthase. Using recombinant Vibrio harveyi
      ACP as a template for site-directed mutagenesis, we have shown that an acidic
      residue at position 41 is essential for V. harveyi fatty acid synthase (but not
      acyl-ACP synthetase) activity. In contrast, various replacements of Ala-45 were
      tolerated by both enzymes. None of the mutations introduced dramatic structural
      changes based on circular dichroism and native gel electrophoresis. These results
      confirm that Glu-41 of ACP is a critical residue for fatty acid synthase, but not
      for all enzymes that utilize ACP as a substrate.

PMID- 12593845
TI  - Yeast inositol mono- and trisphosphate levels are modulated by inositol
      monophosphatase activity and nutrients.
AB  - Yeast lithium-sensitive inositol monophosphatase (IMPase) is encoded by a non
      essential gene pair (IMP1 and IMP2). Inhibition of IMPase with either Li(+) or
      Na(+) or a double null mutation imp1 imp2 causes increased levels of inositol
      monophosphates and reduced level of inositol 1,4,5-trisphosphate. Overexpression
      of the IMP2 gene has the opposite effects and these results suggest that IMPase
      activity is limiting for the inositol cycle. Addition of ammonium to cells
      starved for this nutrient results in a decrease of inositol monophosphates and an
      increase of inositol 1,4,5-triphosphate, pointing to simultaneous regulation of
      both inositol 1,4,5-triphosphate production and IMPase activity.

PMID- 12593846
TI  - Requirement of different signaling pathways mediated by insulin-like growth
      factor-I receptor for proliferation, invasion, and VPF/VEGF expression in a
      pancreatic carcinoma cell line.
AB  - Several oncogenes and growth factors are found to be mutated and overexpressed in
      adenocarcinoma of the pancreas, and may correlate with its highly aggressive
      nature. Insulin-like growth factor (IGF-I) and its receptor (IGF-IR) are highly
      expressed in this tumor type. We examined the IGF-IR-mediated signaling pathways
      in relation to cell proliferation, invasiveness, and expression pattern of
      vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) in the
      pancreatic cancer line ASPC-1. Our findings show that IGF-IR is an important
      growth factor receptor for cell proliferation and invasion, and VPF/VEGF
      expression in ASPC-1. Further experiments indicate that IGF-IR mediates different
      signaling pathways to execute its functions. Activation of Ras by IGF-IR was
      found to be required for the cell invasion. On the other hand Src activation
      through IGF-IR is required for the cell proliferation, invasion, and also
      VPF/VEGF expression. Taken together, our data indicate the importance of IGF-IR
      in growth and invasiveness of the pancreatic cancer cell lines and also point out
      the multiple signaling pathways channeled through this receptor.

PMID- 12593847
TI  - Disruption of a single copy of the p38alpha MAP kinase gene leads to
      cardioprotection against ischemia-reperfusion.
AB  - The p38 mitogen-activated protein kinase (p38) is activated in the heart during
      ischemia-reperfusion. However, it is not clear whether the activation of p38 is
      the protective response or the kinase mediates the cellular damage by ischemia
      reperfusion. We examined the role of p38alpha in ischemia-reperfusion injury by
      studying p38alpha(+/-) mice. The p38alpha protein level in the p38alpha(+/-)
      heart was 50+/-8.7% compared with that in the p38alpha(+/+) heart. Upon
      reperfusion following ischemia for 25min, p38alpha activity was transiently
      increased. The maximum level of p38 activity in p38alpha(+/-) was 60+/-10.5%
      compared with that in p38alpha(+/+). In the p38alpha(+/+) heart, 25min ischemia
      and 2h reperfusion resulted in necrotic injury (37.1+/-2.7% of the area at risk),
      whereas infarct size was drastically reduced to 7.2+/-0.7% in the p38alpha(+/-)
      heart. These suggested that p38alpha plays a pivotal role in the signal
      transduction pathway mediating myocardial cell death caused by ischemia
      reperfusion.

PMID- 12593848
TI  - Role of each immunoglobulin-like loop of nectin for its cell-cell adhesion
      activity.
AB  - Nectins are Ca(2+)-independent immunoglobulin (Ig)-like cell-cell adhesion
      molecules that form cell-cell junctions, cooperatively with or independently of
      cadherins, in a variety of cells. Nectins comprise a family of four members,
      nectin-1, -2, -3, and -4. All nectins have one extracellular region with three Ig
      like loops, one transmembrane segment, and one cytoplasmic tail. It has been
      shown mainly by use of cadherin-deficient L fibroblasts stably expressing each
      nectin that nectins first form homo-cis-dimers and then homo- or hetero-trans
      dimers, causing cell-cell adhesion, and that the formation of the cis-dimers is
      necessary for the formation of the trans-dimers. However, kinetics of the
      formation of these dimers have not been examined biochemically by use of pure
      nectin proteins. We prepared here pure recombinant proteins of extracellular
      fragments of nectin-3 containing various combinations of Ig-like loops, all of
      which were fused to the Fc portion of IgG and formed homo-cis-dimers through the
      Fc portion, and of an extracellular fragment of nectin-1 containing three Ig-like
      loops which was fused to secreted alkaline phosphatase and formed homo-cis
      dimers. We showed here by use of these proteins that the first Ig-like loop of
      nectin-3 was essential and sufficient for the formation of trans-dimers with
      nectin-1, but that the second Ig-like loop of nectin-3 was furthermore necessary
      for its cell-cell adhesion activity.

PMID- 12593849
TI  - Lovastatin stimulates human vascular smooth muscle cell expression of bone
      morphogenetic protein-2, a potent inhibitor of low-density lipoprotein-stimulated
      cell growth.
AB  - Bone morphogenetic proteins (BMPs) stimulate ectopic bone formation in skeletal
      muscle. Here we show that human vascular smooth muscle cells (VSMC) abundantly
      express mRNA encoding for BMP receptor type II, BMP-2, and BMP-7 proteins.
      Treatment with the 3-hydroxy-3-methylglutaryl coenzyme A inhibitor lovastatin (34
      microM) increased BMP-2 gene transcription >14-fold as measured by real-time PCR
      analysis (P<0.05 vs. solvent control). Moreover, VSMC proliferation stimulated
      with native low-density lipoprotein (100 microg of protein/mL) was prevented by
      either human recombinant BMP-2 or BMP-7 at concentrations of 100 ng/mL (P<0.05).
      Both BMPs also inhibited basal cell proliferation (P<0.05). Induction of BMPs and
      subsequent inhibition of VSMC growth and/or induction of vascular bone formation
      could contribute to the mechanisms by which statins increase plaque stability in
      patients with coronary atherosclerosis.

PMID- 12593850
TI  - Two splice variants of CaMKII-anchoring protein are present in the sarcoplasmic
      reticulum of rabbit fast-twitch muscle.
AB  - Anchoring protein alphaKAP targets calmodulin kinase II (CaMKII) to the
      sarcoplasmic reticulum (SR), and in the rabbit is a substrate of CaMKII itself in
      fast-twitch, but not in slow-twitch muscle. This work was aimed at elucidating
      the molecular basis for differential phosphorylation of alphaKAP. Here we show
      that two, immunologically related, size forms (23 and 21 kDa) of alphaKAP are
      present in fast-twitch muscle SR in a 3:1 stoichiometry. Phosphorylation
      experiments identified the shorter form as the CaMKII specific substrate. Both
      forms are shown to be stably integrated into the holoenzyme. Two splice variants
      of alphaKAP were found in rabbit fast-twitch muscle and only one in slow-twitch
      muscle, using RT-PCR. Mobilities on SDS-PAGE are those expected. The shorter
      splice variants lacks the 33-nucleotide sequence inserted by alternative splicing
      present in full-length alphaKAP, akin to differences between variants A and B of
      brain alphaCaMKII. The absence of the 11-amino acid sequence creates a novel
      CaMKII phosphorylation site. Taken together our results show that alternative
      splicing regulates alphaKAP phosphorylation in a fiber-type specific manner.

PMID- 12593851
TI  - Heparin inhibits SMC growth in the presence of human and fetal bovine serum.
AB  - Heparin (HP) has antiproliferative as well as anticoagulant properties, but not
      all HP preparations are equally antiproliferative. A recent report found that HP
      lost its total antiproliferative activity when fetal bovine serum (FBS) was
      replaced with human serum (HS) in culture media. This observation led to the
      investigation of our most potent antiproliferative Upjohn HP preparation effects
      on bovine pulmonary artery smooth muscle cells (PASMC) and systemic SMC growth
      stimulated in the presence of either FBS or HS. Bovine PASMC, human PASMC, and
      bovine aortic SMC were treated with 10 microg/ml Upjohn HP in either 15% FBS or
      15% HS and the cell number was determined by a Coulter counter. We found that
      Upjohn HP significantly inhibited bovine PASMC and systemic SMC proliferation in
      both HS and FBS. The antiproliferative activity of the above HP preparation in HS
      may lead to an effective treatment of pulmonary vascular and systemic remodeling.

PMID- 12593852
TI  - Independency of anti-HIV-1 activity from ribosome-inactivating activity of
      trichosanthin.
AB  - Trichosanthin (TCS) is a type I ribosome-inactivating (RI) protein possessing
      multiple biological and pharmacological activities. Its major action is
      inhibition of human immunodeficiency virus (HIV) replication but the mechanism is
      still elusive. All evidences showed that this action is related to its RI
      activity. Previous studies found that TCS mutants with reduced RI activity
      simultaneously lost some anti-HIV activity. In this study, an exception was
      demonstrated by two TCS mutants retaining almost all RI activity but were devoid
      of anti-HIV-1 activity. Five mutants were constructed by using site-directed
      mutagenesis with either deletion or addition of amino acids to the C-terminal
      sequence. Results showed that the RI activity of mutants with C-terminal deletion
      mutants (TCS(C2), TCS(C4), and TCS(C14)) decreased by 1.2-3.3-fold with parallel
      downshifting of its anti-HIV-1 activity (1.4-4.8-fold). Another two mutants,
      TCS(C19aa) and TCS(KDEL) having 19 amino acid extension and a KDEL signal
      sequence added to the C-terminal sequence, retained all RI activity but
      subsequently lost most of the anti-HIV-1 activity. These findings suggested that
      ribosome inactivation alone might not be adequate to explain the anti-HIV action
      of TCS.

PMID- 12593853
TI  - GL331 inhibits HIF-1alpha expression in a lung cancer model.
AB  - We have studied GL331's anti-cancer mechanisms by studying their effect on the
      tumor-induced angiogenesis. Human lung adenocarcinoma CL1-5 cells were treated
      with GL331 and then maintained in serum-reduced, GL331-free medium for the
      preparation of condition mediums. These condition mediums were tested for their
      capability to induce in vitro angiogenesis, i.e., HUVEC tube formation and
      migration. We found that mediums generated from GL331-treated CL1-5 cells
      presented reduced ability of inducing in vitro angiogenesis. Western blot
      analyses showed that both VEGF and HIF-1alpha were down-regulated in GL331
      treated CL1-5 cells. Northern blot and EMSA analyses showed that GL331 down
      regulated HIF-1alpha expression without decreasing the stability of HIF-1alpha
      mRNA, and that GL331 decreased the binding of CL1-5-derived nuclear components to
      the promoter of HIF-1alpha gene. Therefore, our data showed that GL331 is a
      potent inhibitor of tumor-induced angiogenesis. The underlying mechanisms might
      involve at least the inhibition of HIF-1alpha expression, probably through
      transcriptional repression.

PMID- 12593854
TI  - A HERG current sustains a cardiac-type action potential in neuroblastoma S cells.
AB  - From the adrenergic SH-SY5Y human neuroblastoma clone, we isolated a subclone
      (21S) endowed with a glial-oriented phenotype. At difference from the parental
      clone, 21S cells responded to depolarizing stimuli with overshooting action
      potentials, whose repolarization phase was composed of an initial rapid episode,
      followed by a long-lasting plateau and a slow return to the resting potential
      (V(REST)). The action potential depolarization phase was sustained by a TTX
      sensitive Na(+) current, while the first repolarizing episode was produced by the
      scanty delayed rectifier potassium current (I(KDR)) expressed in 21S cells. The
      bulk of repolarization, including the after-hyperpolarization, was sustained by
      the human eag related (HERG) potassium current (I(HERG)) that also governs
      V(REST) in 21S cells. This double role of I(HERG), together with the poor
      expression of I(KDRs), represents a novel finding in electrophysiology, as well
      as gives a clue to identify a new excitable element of the complex cellular
      population of neuroblastoma.

PMID- 12593855
TI  - Pentoxifylline protects L929 fibroblasts from TNF-alpha toxicity via the
      induction of heme oxygenase-1.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is recognized as a principal mediator of
      a variety of inflammatory conditions. Pentoxifylline (PTX), which can inhibit
      cellular TNF-alpha synthesis, also attenuates the toxic effect of TNF-alpha.
      However, the mechanism underlying PTX-induced cytoprotection is unknown. Heme
      oxygenase 1 (HO-1) is an enzyme which degrades heme into biliverdin, free iron,
      and carbon monoxide (CO). This enzyme has recently been shown to have anti
      inflammatory and cytoprotective effects. In this study, we investigated whether
      protection by PTX against TNF-alpha-mediated toxicity could be related to its
      ability to induce HO-1 expression and HO activity in L929 cells. PTX in the range
      of 0.1-1.0mM significantly induced HO-1 expression and the resulting HO activity.
      Pre-incubation of L929 cells with either PTX or the HO activator hemin resulted
      in the protection of the cells against TNF-alpha-mediated toxicity. Zinc
      protoporphyrin, a specific HO competitive inhibitor, abrogated the protective
      effect of PTX. Hemoglobin, a scavenger of CO, reversed the protective effect of
      PTX. A cytoprotection comparable to PTX was observed when the cells were treated
      with the CO-releasing compound tricarbonyldichlororuthenium(II) dimer. These
      results suggest that HO-1 expression and the ensuing formation of the HO
      metabolite CO may be a novel pathway by which PTX protects L929 cells from TNF
      alpha-mediated toxicity.

PMID- 12593856
TI  - E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models.
AB  - Previously, we have shown that over-expression of either E2F1 or c-Myc promotes
      hepatocarcinogenesis and that E2F1 mice acquire HCC more rapidly than c-Myc
      transgenic mice. We also found that co-expression of E2F1/c-Myc further
      accelerates liver cancer development. Here we describe that the deregulated
      expression of these two transcription factors also affects hepatic ploidy during
      post-natal liver growth and before the onset of tumors. Oncogenic activity of
      E2F1 and/or c-Myc was associated with a persistent increase in hepatocyte
      proliferation. However, E2F1-mediated cell proliferation favored the predominance
      of diploid cells characteristic of pre-neoplastic type of liver growth whereas c
      Myc functioned to accelerate age-related hepatocyte polyploidization. Similarly,
      proliferative advantage conferred by co-expression of E2F1 and c-Myc increased
      the frequency of diploid cells at a young age. Thus, the opposing effects of E2F1
      and c-Myc on hepatocyte ploidy suggest that these two transcription factors have
      different mechanisms by which they control liver proliferation/maturation and
      ultimately, carcinogenesis.

PMID- 12593857
TI  - Differential effect of PKA on the Ca2+ release kinetics of the type I and III
      InsP3 receptors.
AB  - The effects of protein kinase A (PKA) on the inositol 1,4,5-trisphosphate
      (InsP(3)) receptor isoforms type I and type III were studied. The effects of PKA
      on the extent and rate constants for InsP(3)-induced Ca(2+) release (IICR) were
      different for the two isoforms. The effects of PKA on the type I isoform showed a
      biphasic relationship dependent upon the concentration of PKA used. At low
      concentrations of PKA (<50U/ml), both the extent and rate constants for IICR
      increased, while at higher concentrations (>200U/ml) the extent and rate
      constants decreased. The type III isoform showed only an increase in the extent
      of IICR and not in the rate constants. The effects of PKA on the type I InsP(3)
      receptor using single channel electrophysiological studies were also
      investigated. The stimulatory effect of PKA is due to an increase in conductance
      levels and not to a change in the mean open time of the channel.

PMID- 12593858
TI  - Activation of phospholipase D1 by ADP-ribosylated RhoA.
AB  - Clostridium botulinum exoenzyme C3 exclusively ADP-ribosylates RhoA, B, and C to
      inactivate them, resulting in disaggregation of the actin filaments in intact
      cells. The ADP-ribose resides at Asn-41 in the effector binding region, leading
      to the notion that ADP-ribosylation inactivates Rho by blocking coupling of Rho
      to its downstream effectors. In a recombinant system, however, ADP-ribosylated
      Rho bound to effector proteins such as phospholipase D-1 (PLD1), Rho-kinase
      (ROK), and rhotekin. The ADP-ribose rather mediated binding of Rho-GDP to PLD1.
      ADP-ribosylation of Rho-GDP followed by GTP-gamma-S loading resulted in binding
      but not in PLD activation. On the other hand, ADP-ribosylation of Rho previously
      activated by binding to GTP-gamma-S resulted in full PLD activation. This finding
      indicates that ADP-ribosylation seems to prevent GTP-induced change to the active
      conformation of switch I, the prerequisite of Rho-PLD interaction. In contrast to
      recombinant systems, ADP-ribosylation in intact cells results in functional
      inactivation of Rho, indicating other mechanisms of inactivation than blocking
      effector coupling.

PMID- 12593859
TI  - Reduction of antigenicity and allergenicity of genetically modified egg white
      allergen, ovomucoid third domain.
AB  - Ovomucoid (Gal d1) is a major allergen in hen egg white, consisting of three
      tandem domains. In this study, five genetically modified third domain (DIII)
      mutants, which were substituted single or double amino acids within its IgE and
      IgG epitopes were compared with those prepared and their antigenicity and
      allergenicity with native analogue using Western immunoblot and enzyme-linked
      immunosorbent assay. The replacement of phenylalanine at 37 (F37) position with
      methionine caused drastical loss of IgG and IgE binding activities of human sera
      derived from egg allergic patients as well as disruption of the alpha-helix
      structure which comprises a part of the IgG and IgE epitopes. Substituting
      glycine at 32 position in conjunction with F37 showed a synergistic effect of
      decreasing antigenicity. The present study indicated that glycine 32 and
      phenylalanine 37 have an important role on its antigenicity and allergenicity as
      well as structural integrity of ovomucoid DIII.

PMID- 12593860
TI  - Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model
      of hindlimb ischemia.
AB  - Heme oxygenase-1 (HO-1) is an inducible form of heme oxygenase that catabolizes
      heme to carbon monoxide, biliverdin, and ferrous iron. We have investigated
      whether HO-1 can induce angiogenic effects in vivo. Rats were subjected to a
      bolus injection of either wild type adenovirus (ad-wt) or adenovirus encoding HO
      1 (ad-HO-1) through the right femoral artery, which was then removed immediately.
      HO-1 gene transfer resulted in about a sixfold increase in HO-1 protein levels as
      compared to the non-treated animals. The increase in both blood flow and
      capillary density was significantly greater in the ischemic hindlimbs that had
      been injected with ad-HO-1 than in those injected with ad-wt. These angiogenic
      effects of ad-HO-1 infection could be completely abolished by treating the
      animals with the HO inhibitor, zinc protoporphyrin, indicating that they were
      specifically due to the expression of HO-1. Thus, HO-1 gene transfer improves the
      blood flow in ischemic hindlimb, at least in part, via angiogenesis facilitated
      by the induction of this molecule.

PMID- 12593861
TI  - Histone H3 is aberrantly phosphorylated in glutamine-repeat diseases.
AB  - Double-labeling immunohistochemical studies staining with anti-ubiquitin and anti
      phosphoserine antibodies and application of an enzymatic dephosphorylation
      technique reveal neuronal inclusions and affected nuclei to be aberrantly
      phosphorylated in brain tissues with patients with glutamine-repeat diseases.
      Regional distribution of the phosphorylated nuclei in neurons correlates with the
      pathology. To identify the target nuclear protein, transient expression of
      Huntington's disease exon 1 gene containing an expanded glutamine repeat was
      generated in a cell culture and nuclear inclusions were isolated with a
      fluorescence-activated cell sorting system. Immunoblotting studies of the
      aggregated nuclear proteins using anti-phosphoserine antibody demonstrate the
      protein of the aberrant phosphorylation as histone H3. The immunoblots of control
      and diseased brain tissues demonstrate that the phosphorylation of histone H3 is
      commonly increased in the diseased brains. Aberrant phosphorylation of histone H3
      is surmised to be a shared pathological process in glutamine-repeat diseases.

PMID- 12593862
TI  - IRBP-specific Th1 cells from peripheral blood were predominant in the
      experimental autoimmune uveitis.
AB  - Experimental autoimmune uveitis (EAU) is a Th1-cell-mediated autoimmune disease.
      In this study, the correlation between IRBP-specific Th1 cells in PBLs and the
      histological grading in the eyes was evaluated kinetically during EAU induction.
      EAU was induced in B10.A mice with IRBP immunization and the eyes were enucleated
      for histological examination on days 0, 3, 7, 15, and 21 after immunization. To
      determine the Th1-cell-mediated immune response, Th1 cytokines (IL-12p40 and IFN
      gamma) were measured by RT-PCR in inflamed eyes. At mean time, CD4(+) and IFN
      gamma(+) double positive T cells (Th1 cells) from PBLs were analyzed by flow
      cytometry. The level of the IRBP-specific Th1 cells was significantly increased
      and kinetically changed during EAU induction, but the cells reached peak time
      early before the disease was onset. Those IRBP-specific Th1 cells in the PBLs
      were evidence for EAU disease, but its peak time was different from EAU disease
      in the eyes. Our data suggested that it is very important to collect blood from
      patients at a suitable time point and the Th1 cells measured by flow cytometry
      are good marker for disease diagnosis.

PMID- 12593863
TI  - Improvement by repeated administration of 6R-tetrahydrobiopterin of 5,7
      dihydroxytryptamine-induced abnormal behaviors in immature rats.
AB  - To clarify the therapeutic effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin
      (6R-BH(4)) on the abnormal behaviors induced by neonatal 5,7-dihydroxytryptamine
      (5,7-DHT, 100 microg; i.c.v.) treatment in immature rats, 6R-BH(4) (10-40 mg/kg)
      was administered intraperitoneally from 22nd to 28th days or only once on the
      28th day. The locomotion activities decreased dramatically in 5,7-DHT-treated
      rats (p<0.01; as compared to controls) on the 28th day. The reduced locomotion
      was recovered dose-dependently by repeated administration of 6R-BH(4), whereas it
      was not altered after a single injection of 6R-BH(4). In addition, repeated
      administration of 6R-BH(4) significantly facilitated 5-HT turnover ratio (5
      HIAA/5-HT) in the striatum, cerebral cortex, and cerebellum. These findings
      suggest that the behavioral restoration by 6R-BH(4) might be due to the
      enhancement of 5-HT turnover by accumulated but not a single dose of 6R-BH(4).

PMID- 12593864
TI  - The second largest subunit of RNA polymerase II interacts with and enhances
      transactivation of androgen receptor.
AB  - AR may communicate with the general transcription machinery on the core promoter
      to exert its function as a transcriptional modulator. Our previous reports
      demonstrated that AR interacted with TFIIH and positive transcription elongation
      factor b (P-TEFb), and that phosphorylation of the carboxy-terminal domain in the
      largest subunit of RNA polymerase II might play important roles in AR-mediated
      transcription. These results suggest that AR may modulate gene expression by
      enhancing the efficiency of transcriptional elongation. Here we further
      demonstrate that co-expression of the second largest subunit of RNA polymerase II
      (RPB2) enhances AR transactivation. However, co-expression of the other subunits
      of RNA polymerase II or TFIIB did not show preferential enhancement of AR
      mediated transcription. Furthermore, co-transfection of RPB2 with ER showed
      little effect on enhancement of ER transactivation. Together, AR may be able to
      interact with TFIIH, P-TEFb, and RPB2 to enhance transcription from AR target
      genes, such as prostate specific antigen that may play important roles in the
      prostate cancer progression.

PMID- 12593865
TI  - Disclosure of cancer diagnosis and prognosis in Northern Tanzania.
AB  - Whether to tell patients with cancer about their diagnoses and prognoses is a
      matter of great debate. While many argue the importance of giving this
      information to facilitate informed decision-making, others argue that this same
      information can extinguish hope. Although there is some evidence that disclosure
      of this information is now commonplace in many Northern and Western settings,
      there are very few data about this issue from resource-poor nations describing
      physicians' decision-making regarding whether to disclose this information. Using
      a combination of ethnographic and other qualitative methods including participant
      observation, semi-structured interviews, informal interviews, and a review of key
      documents in Northern Tanzania, we map some of the salient issues in this
      setting. Like their colleagues in many other parts of the world, Tanzanian
      physicians often withhold diagnostic and prognostic information from patients. In
      addition, however, to the cultural arguments often used to justify this practice,
      issues of treatment availability and patient poverty also influenced the
      physicians' disclosure practices. Expatriate and Tanzanian physicians practicing
      in Northern Tanzania often had different approaches to informing patients of
      their diagnoses and prognoses. Some Tanzanian physicians advocated the use of a
      "roundabout" approach to disclosure, arguing that it was more reflective of the
      normal mode of discourse in Tanzania than the more direct approach advocated by
      many of their expatriate colleagues. Expatriate physicians and some of their
      Tanzanian colleagues felt that such an indirect approach often left patients
      confused, or indeed, uninformed.

PMID- 12593866
TI  - Social psychological correlates of paying attention to cancer symptoms and
      seeking medical help.
AB  - Social psychological correlates of two main aspects of the process of cancer
      detection, viz. passive detection (i.e., paying attention to cancer symptoms) and
      help-seeking intention, were studied among a-symptomatic Dutch adults. Two
      written questionnaires, with a six-week interval, identified correlates of both
      variables, using a determinant model based on the theory of planned behavior.
      Knowledge, advantages, self-efficacy, being female and being more highly educated
      were associated with passive detection. Knowledge, advantages, moral obligation,
      anticipated regret, social norm, and self-efficacy were correlated with the
      intention to seek help. We suggest that educational programs need to address the
      two variables separately and also need to tailor their content to the various
      social psychological correlates of these two aspects.

PMID- 12593867
TI  - Assessing the quality of life of patients in phase I and II anti-cancer drug
      trials: interviews versus questionnaires.
AB  - This paper discusses two different approaches to assessing quality of life in the
      context of cancer clinical trial participation. Drawing on empirical evidence
      from a study of patients' experiences of phase I and II anti-cancer drug trial
      participation, the paper demonstrates how different methods of collecting data
      about an individual's quality of life (questionnaires and interviews) can lead to
      alternative conclusions about patients' trial experience and the impact of trial
      involvement on their quality of life. Data obtained from the quality of life
      questionnaires interestingly revealed no statistically significant differences in
      any of the scores over time while in-depth interviews uncovered something of the
      psychological, emotional and social impact of taking part in a clinical trial
      from the perspective of the patient. The paper concludes by reflecting on some of
      the methodological issues that arise when assessing the quality of life of
      patients with a life threatening disease in clinical trials.

PMID- 12593868
TI  - Health inequalities in the older population: the role of personal capital, social
      resources and socio-economic circumstances.
AB  - Older people now constitute the majority of those with health problems in
      developed countries so an understanding of health variations in later life is
      increasingly important. In this paper, we use data from three rounds of the
      Health Survey for England, a large nationally representative sample, to analyse
      variations in the health of adults aged 65-84 by indicators of attributes
      acquired in childhood and young adulthood, termed personal capital; and by
      current social resources and current socio-economic circumstances, while
      controlling for smoking behaviour and age. We used six indicators of health
      status in the analysis, four based on self-reports and two based on nurse
      collected data, which we hypothesised would identify different dimensions of
      health. Results showed that socio-economic indicators, particularly receipt of
      income support (a marker of poverty) were most consistently associated with
      raised odds of poor health outcomes. Associations between marital status and
      health were in some cases not in the expected direction. This may reflect bias
      arising from exclusion of the institutional population (although among those
      under 85 the proportion in institutions is very low) but merits further
      investigation, especially as the marital status composition of the older
      population is changing. Analysis of deviance showed that social resources
      (marital status and social support) had the greatest effect on the indicator of
      psychological health (GHQ) and also contributed significantly to variation in
      self-rated health, but among women not to variation in taking three or more
      medicines and among men not to self-reported long-standing illnesses. Smoking, in
      contrast, was much more strongly associated with these indicators than with self
      rated health. These results are consistent with the view that self-rated health
      may provide a holistic indicator of health in the sense of well-being, whereas
      measures such as taking prescribed medications may be more indicative of specific
      morbidities. The results emphasise again the need to consider both socio-economic
      and socio-psychological influences on later life health.

PMID- 12593869
TI  - The effect of social relations with children on the education-health link in men
      and women aged 40 and over.
AB  - Accumulated evidence demonstrates a strong relationship between socioeconomic
      status (SES) and health. Our examination of this relationship focuses on
      education, an established indicator of SES, and tests whether social relations,
      particularly with children, mediate and/or moderate the education-health link for
      middle-aged and older parents. The data are drawn from a regionally
      representative sample of adults (aged 40-93) in the Detroit area, USA. All
      analyses are stratified by gender (N=males: 330; females: 468). A series of
      multiple regression analyses were performed to test whether social relations
      mediate the association between education and health. Although analyses revealed
      no mediation effect, both men and women with less education were found to have
      smaller social networks. Women with more education confided less in their
      children than women with less education did. A series of hierarchical regression
      analyses were performed to test whether social relations variables moderate the
      relationship between education and health. Separate analyses by gender indicated
      that men, but not women, with less education who had larger networks and who
      perceived emotional, financial and sick care support to be available from a child
      had lower scores on a health problems index. Findings indicate that the health of
      lower-educated men in the presence of key social supports parallels the
      advantaged health status of men with higher levels of education. These findings
      suggest that social relationships may be a protective factor for the health of
      men in the lower socioeconomic strata.

PMID- 12593870
TI  - Trends in the association between average income, poverty and income inequality
      and life expectancy in Spain.
AB  - In this paper, we study the relation between life expectancy and both average
      income and measures of income inequality in 1980 and 1990, using the 17 Spanish
      regions as units of analysis. Average income was measured as average total income
      per household. The indicators of income inequality used were three measures of
      relative poverty-the percentage of households with total income less than 25%,
      40% and 50% of the average total household income-the Gini index and the Atkinson
      indices with parameters alpha=1, 1.5 and 2. Pearson and partial correlation
      coefficients were used to evaluate the association between average income and
      measures of income inequality and life expectancy. None of the correlation
      coefficients for the association between life expectancy and average household
      income was significant for men. The association between life expectancy and
      average household income in women, adjusted for any of the measures of income
      inequality, was significant in 1980, although this association decreased or
      disappeared in 1990 after adjusting for measures of poverty. In both men and
      women, the partial correlation coefficients between life expectancy and the
      measures of relative income adjusted for average income were positive in 1980 and
      negative in 1990, although none of them was significant. The results with regard
      to women confirm the hypothesis that life expectancy in the developed countries
      has become more dissociated from average income level and more associated with
      income inequality. The absence of a relation in men in 1990 may be due to the
      large impact of premature mortality from AIDS in regions with the highest average
      total income per household and/or smallest income inequality.

PMID- 12593871
TI  - Psychological distress during unemployment and beyond: social support and
      material deprivation among youth in six northern European countries.
AB  - Psychological distress is a serious problem among unemployed youth, and may lead
      to various social and psychological problems. In this study, we examine patterns
      of distress among previously unemployed youth that have experienced five
      different labor market outcomes over a period of 6 months in Denmark, Finland,
      Iceland, Norway, Scotland and Sweden. We find that moving beyond unemployment is
      associated with less distress, in particular among those who have found permanent
      employment, but also among those who have found temporary employment, have
      returned to school, or are staying at home. Perceptions of material deprivation
      and parental emotional support directly affect distress in all labor market
      outcomes, and mediate the effects of various other factors on such distress. The
      effects of socio-demographic characteristics, living arrangements, unemployment
      history and attitudes, and parental support are found to be specific to gender
      and labor market outcomes, while the effects of material deprivation are uniform
      across all such categories. Further studies are needed to disentangle structural
      and individual effects, the causal complexities involved in processes of social
      support, and to determine the extent to which such models equally predict
      psychological distress among the unemployed and other groups of youth.

PMID- 12593872
TI  - Trends in social inequality in self-reported health in The Netherlands; does
      infant mortality in year of birth as a cohort indicator matter?
AB  - In this article, we study trends in self-reported health (general health and
      chronic conditions) and health inequality in the Netherlands between 1974 and
      1998 using an age-period-cohort framework. We answer two questions: (1) to what
      extent can trends in self-reported health be explained by the current macro
      context (period effect) and by infant mortality in year of birth (cohort effect)?
      And (2) do the effects of period and cohort differ for educational groups? Health
      indicators are self-reported poor health and chronic conditions. The use of 26
      Dutch cross-sectional surveys makes it possible to estimate largely unbiased
      effects of period and cohort simultaneously (controlled for age effects) and thus
      to adequately describe trends in social inequality in health. Our results give
      rise to four conclusions. First, for men poor health has been more or less
      stable, for women there has been an increase. The prevalence of chronic
      conditions has increased for both sexes. Second, adding cohort specific
      experiences to a model including age and period effects is only relevant for
      women's poor health. Decreasing infant mortality in year of birth leads to better
      health and consequently the period effect initially found for women appears to be
      slightly underestimated. Third, we found no trends in social inequalities in self
      reported health due to period effects. Fourth, our analyses do show socially
      unequal trends in health as a result of cohort specific experiences. Contrary to
      our hypothesis, we found that decreased infant mortality in year of birth makes
      for a stronger impact of educational differences on self-reported poor health.
      Concerning chronic conditions no trends for educational groups were found.

PMID- 12593873
TI  - Involving the general public in priority setting: experiences from Australia.
AB  - The discussion over whether community preferences have a legitimate role to play
      in priority setting has been highly polarised. Skeptics warn of the risk of
      establishing a 'dictatorship of the uninformed', while advocates proclaim the
      legitimacy of the participatory process. The one group who appears not to be
      consulted in this debate is the citizens themselves. In this study, a convenience
      sample of 373 citizens attending two medical clinics in central Sydney were
      surveyed about whether the general public has a legitimate role to play in
      informing priority setting in health care. Respondents were presented with three
      different levels of priority setting: across health care programmes, across
      medical procedures, and at a global level. To assist respondents in understanding
      the choices and trade-offs involved, they were given information about current
      levels of funding and the cost-effectiveness of each alternative. Respondents
      were asked whether they felt the preferences of the general public should be used
      to inform priority setting at each level. Of particular interest was the question
      of whether their willingness to use public preferences depended on the level of
      priority setting. Respondents were also asked about who else's preferences should
      be used to inform priority setting at each level. The results suggest that the
      public overwhelmingly want their preferences to inform priority-setting decisions
      in health care. This was seen to be particularly important in informing decisions
      about how to prioritise across broad health care programmes and about the
      criteria to be used to allocate funds across different population groups. In
      contrast, the preferences of medical professionals and health service managers
      were rated most highly in relation to the prioritisation of different treatments
      and medical procedures. In most cases, however, respondents did not advocate the
      use of one particular group's preferences. Even when the preferences of the
      general public were considered most important, it was felt that any decision
      making process needed to be informed by the preferences of a range of groups. The
      preferences of politicians were viewed as least important to processes of
      priority setting in health care.

PMID- 12593874
TI  - The vaginitis monologues: women's experiences of vaginal complaints in a primary
      care setting.
AB  - Vaginal complaints are a common presenting problem in primary care settings. A
      disease model has dominated current research and treatment paradigms, with little
      attention to the illness or experiential dimensions of vaginal complaints. In
      this paper, we report data from a qualitative study of the experiences of women
      diagnosed with vaginitis. In semi-structured interviews with 44 women in New York
      City, United States, we investigated women's interpretations and explanations of
      their illness, their accounts of its impact on their lives, their experiences
      with treatment, and the role of vaginal symptoms in communicating distress and
      anger. We found that women's explanations of vaginal complaints differed
      strikingly from the current medical model described in the literature on
      vaginitis. Vaginal symptoms often occasioned extreme anxiety; their impact on
      social and sexual functioning could be severe. Finally, vaginal symptoms often
      functioned to express distress and gender conflict. These findings have important
      implications for the management of the disorder.

PMID- 12593875
TI  - Interpretations of smoking in film by older teenagers.
AB  - Research testifies that images of tobacco use in popular films are highly
      pervasive and typically glamorised. There are concerns that these images may
      promote motivations to smoke in adolescents, but little is known about how these
      images are interpreted by members of this age group. A qualitative study was
      conducted to explore how older teenagers interpret and decode smoking imagery in
      film. This study builds on earlier work with a younger age group (12 and 13
      years) to explore how various interpretations of smoking imagery shape and
      support common understandings about smoking among older teenagers. Data were
      collected through focus groups. Eighty-eight 16 and 17 year old students were
      interviewed at school. Participants discussed their recollections of and
      responses to recently viewed films. Older teens were receptive to smoking imagery
      when it was used in a credible manner to portray an emotional state, sub-culture
      affiliation, and lifestyle. Experience as a smoker appeared to inflate the
      credibility of realistic smoking images, particularly those presented in gritty
      realism/drama film. Older teens perceived realistic images, as opposed to
      stereotypical images, as a salient reference to their own lives. Stereotypical
      images were also readily recalled and appeared to perform an important role in
      supporting misconceptions about smoking and contributing to popular ideologies
      about tobacco use. Stereotypical images presented in comedy and action genre also
      serve to present paradoxical and contradictory messages about tobacco use. In
      particular, participants recalled tobacco use in film as associated with stress
      and anxiety, drug use, and seduction. Film images of tobacco use in specific
      contexts appear to hold specific and significant meanings for older teens.
      Realistic images offered salient representations of the perceived reality of
      smoking for this group. Pervasive and credible smoking scenes in film may offer
      support and reassurance to older teens who currently smoke or hold ambivalent
      views about smoking. Consistent with younger adolescents, older teens presented a
      predominantly nonchalant response to smoking imagery in film, which is a powerful
      indicator of the pervasiveness and acceptability of smoking in general. In
      contrast with younger adolescent, older teens tend to draw upon their own
      experience with tobacco use when interpreting smoking images in film.

PMID- 12593876
TI  - Public hazards or private tragedies? An exploratory study of the effect of
      coroners' procedures on those bereaved by suicide.
AB  - This study in the UK examined how the suicide inquest can affect bereaved
      relatives and impact upon their grief. In-depth qualitative interviews were
      conducted with a sample of 16 individuals bereaved by suicide in order to explore
      their experiences of the inquest. Thematic analysis was used to identify
      recurrent problems and their effects. Several interviewees had been significantly
      traumatised by the inquest process. They were particularly disturbed by the
      judicial atmosphere, media activity, the invasion of privacy, and giving
      evidence. Exposure to graphic evidence, delayed inquests, confiscated suicide
      notes and the inquest's failure to provide explanation and deal with blame also
      presented problems. Difficulties were compounded by a widespread lack of
      preparation and communication prior to the event. The inquest adversely affected
      resolution of grief in two main ways: by exacerbating common grief reactions
      associated with bereavement by suicide, such as, shame, guilt and anger; and, by
      interfering with necessary grief work, most notably, the task of arriving at a
      meaningful and acceptable account of the death. Other interviewees described more
      positive experiences, one of whom regarded the inquest as helpful to their
      resolution of grief. Whereas these results may not typify all inquest
      experiences, the findings do suggest that a number of reforms are necessary to
      avoid the possibility of the inquest distressing this vulnerable group. Ideally,
      there should be a clear protocol for dealing with bereaved relatives. This is
      currently lacking in the coroners' system.

PMID- 12593877
TI  - Perceptions of health hazards in the narratives of Italian migrant workers at an
      Australian asbestos mine (1943-1966).
AB  - This article reconstructs how workers perceived asbestos hazards, using
      narratives from a group of migrant workers at the crocidolite mine of Wittenoom
      Gorge, Western Australia. The mine employed about 7000 workers over the entire
      period of its operation from 1943 to 1966-relying heavily on migrant workers. The
      exposure to asbestos dust caused a huge number of occupational respiratory
      diseases in workers, leading Wittenoom later to be labelled as a modern
      industrial disaster. Fieldwork involved 137 interviews with Italians who had
      worked at Wittenoom. They constituted 18% of the mine's work-force and were
      employed as miners or millers between 1951 and 1966. We interviewed workers who
      had returned to Italy, relatives of Italian workers now deceased, and workers who
      had settled in Australia. The results confirm the seriousness of the occupational
      exposure to asbestos and the weaknesses of the health surveillance program.
      Although workers were given no health-related information, they felt they were at
      risk and left the job as soon as possible. From the early 1950s onward, some of
      the workers became aware of a long-term connection between work at Wittenoom and
      lung illnesses that required hospitalisation and caused deaths. However, up to
      the early 1960s, workers at the mine were led to believe that the respiratory
      disease spreading among them was tuberculosis.

PMID- 12593878
TI  - The M-C-M' cycle and social capital.
AB  - Social capital has become a popular term over the past two decades amongst
      researchers, policy makers and practitioners from varied disciplines. This
      popularity, however, has resulted in a great deal of confusion over the nature
      and application of social capital in different contexts. This confusion has made
      it difficult to identify and measure social capital within the evaluation of
      specific social and health programmes, one of the aims of which may be to
      stimulate social capital. This paper identifies a theoretical model that seeks to
      capture the dynamic nature of social capital to assist in the development of
      research methods that will facilitate its measurement and exploration within such
      programmes. The model reported in the paper identifies the key components of
      social capital and expresses the relationship between those components in a
      dynamic system based on Marx's description of the process of capital (economic)
      exchanges expressed in the M-C-M' cycle. The M-C-M' cycle is the transformation
      of money (M) into commodities (C), and the change of commodities back again into
      money (M') of altered value. The emphasis within the paper is on the capital
      element of the concept and its transactional nature with the aim of avoiding the
      pitfall of attributing social capital in relation to social behaviours in
      isolation of context and interaction. Importantly, the paper seeks to distinguish
      the central elements of social capital from some of the antecedent factors and
      outcomes often attributed to and confused with social capital adding to the
      problem of providing valid measurement. The model is presented as the basis for
      the measurement of social capital within a transactional process involving the
      investment of social resources in a cyclical process, which may result in net
      gains or losses. This process is described as the R-C-R' cycle following Marx's
      model of economic capital, with the focus being on the transfer of social
      resources (R) rather than money (M). R represents an internal resource held by
      individuals, C the external resource or commodity they obtain from the network
      and the R' the internal resource of altered value. The possibilities of the model
      in assisting in the measurement of social capital specifically in assessing
      formal networks are explored.

PMID- 12593880
TI  - Culture and therapy: complementary strategies for the treatment of type-2
      diabetes in an urban setting in Kerala, India.
AB  - There is an epidemic rise in diabetes in the developing world, with ensuing
      concern about the management and control of the disease. This study investigates
      the use of complementary therapies to manage Type 2 diabetes in an urban
      population in Kerala, a state in Southern India. Using ethnographic methods, it
      shows that the subjects' experiences of the disease and their health management
      decisions are closely linked to their cultural background and the environmental
      resources of the region. Participants in the study relied on biomedicine for
      treating diabetes, but frequently used Ayurvedic medicine and folk herbal
      remedies as supplements. They named 24 local plants and plant products that were
      employed to lower blood glucose levels. Knowledge of tried and tested local or
      regional remedies and their incorporation into individual and community health
      care practices are evidence of medical knowledge as cultural capital. Greater
      attention needs to be paid to the broader systems of the environment and culture
      and their interconnections to understand the use of complementary therapies by
      persons with chronic illnesses such as diabetes.

PMID- 12593879
TI  - A community-based assessment of learning disabilities using environmental and
      contextual risk factors.
AB  - Childhood placement in learning disability (LD) programs in the USA has tripled
      over the last few decades to 6% of all children enrolled in the public schools
      today. The revision of educational laws to improve LD testing and reporting
      guidelines has been credited for these trends. However, some researchers also
      believe that the increase in LD incidence may be due, in part, to chronic low
      level exposure to toxicants such as lead, heavy metals, solvents and others
      chemicals in the physical environment. This study employs the use of geo
      statistical methods to explore the potential linkages between these pollution
      sources and the prevalence rates of LD within an urbanized environment, in the
      USA. The role of contextual factors such as housing quality, poverty, low
      parental educational achievement, and other disadvantages are also examined.
      Using primary data on childhood disabilities for 1997, the LD cases were queried
      and analyzed to identify the spatial clusters within the community. The
      neighborhoods within the LD clusters were then compared to other areas in the
      community on the basis of the environmental and contextual risk factors. The
      results confirmed that areas of high risk for LD were strongly associated with
      historically significant sources of lead toxicity and air pollution facilities.
      Among the socio-economic indicators, the high-risk neighborhoods were
      characterized by multiple/subdivided housing units, poverty, higher percentage of
      residents on public assistance and lower adult educational attainment. Taken
      together, these results suggest the need for a more inclusive multi-disciplinary
      research on LD that extends beyond the classroom context to the neighborhoods and
      communities in which these children reside.

PMID- 12593881
TI  - Diversity in lay perceptions of the sources of human traits: genes, environments,
      and personal behaviors.
AB  - Individual beliefs about the origins of illness and disease contribute to
      personal behavior to gain or maintain health and well-being. Both perceptions of
      the efficacy of recommended actions and the confidence individuals have in their
      ability to carry out prevention and detection practices may be associated with
      beliefs about illness causation. This study explored the perceptions of African
      American and European American men and women ages 18-45 years regarding the
      respective roles of inherited genes, social factors, personal behavior, and
      ecological environment on disease as compared to other human attributes,
      including height, weight, mental abilities, and talents. Results from focus group
      (N=16) data indicated that participants' (N=77) assignment of influence to
      various causative factors varied non-systematically by gender, race, education,
      economic class, and type of characteristic.

PMID- 12593882
TI  - Social capital and sense of insecurity in the neighbourhood: a population-based
      multilevel analysis in Malmo, Sweden.
AB  - The aim of this study was to investigate the influence of social capital on self
      reported sense of insecurity in the neighbourhood. The public health survey in
      Malmo, Sweden in 1994 was a cross-sectional study. A total of 5600 individuals
      aged 20-80 years were asked to answer a postal questionnaire. The participation
      rate was 71%. A multilevel logistic regression model, with individuals at the
      first level and neighbourhoods at the second, was performed. We analysed the
      effect (intra-area correlation, cross-level modification and odds ratios) of
      individual (social participation) and neighbourhood social capital (electoral
      participation in the 1994 municipal election) on sense of insecurity after
      adjustment for compositional factors. Neighbourhood factors accounted for 7.2% of
      the total variance in individual insecurity. This effect was marginally reduced
      when the individual factors were included in the model. In contrast, it was
      reduced by 70% by the introduction of the contextual variable. This study
      suggests that social capital, measured as electoral participation, may partly
      explain the individual's sense of insecurity in the neighbourhood.

PMID- 12593883
TI  - Valuing the benefits and costs of health care programmes: where's the 'extra' in
      extra-welfarism?
AB  - The application of Sen's notion of capabilities to problems of the allocation of
      resources to health in the form of an extra-welfarist framework underlies the
      justification of quality adjusted life years (QALYs) as the method for valuing
      the benefits of health care. In this paper we critically appraise this
      application from both conceptual and empirical perspectives. We show that the
      alleged limitations of the welfarist approach are essentially limitations in its
      application, not in the capacity of the approach to accommodate the concerns of
      extra-welfarists. Moreover, the arguments used to justify the application of the
      extra-welfarist framework are essentially welfarist. We demonstrate that the
      methods used to measure QALYs share their basic theoretical roots with welfarist
      valuation methods, such as willingness to pay (WTP). Although QALYs and WTP share
      many challenges, we argue that WTP provides a method which performs better with
      respect to those challenges. In the context of evaluating alternative allocations
      of health care resources we are left asking what is 'extra' in extra-welfarism?

PMID- 12593884
TI  - Somatic fixation: the harm of healing.
AB  - The term somatic fixation describes a model in which the patient's problems are
      medicalized both by the patient and by the physician. This phenomenon was
      described by a group of researchers from the Netherlands, in 1983. This paper
      discusses somatic fixation and its implications. Somatic fixation should be
      distinguished from "somatization" or "somatoform disorder", which are psychiatric
      diagnoses, although there is probably a large degree of overlap. Predisposing
      factors to somatic fixation include social, cultural and medical circumstances,
      both related to the patient and to the physician. The medical care system may
      predispose to somatic fixation by offering prepaid medical care, and by
      incorporating the "rule out" model in fear of medical law-suits. Preventing
      somatic fixation is a major aim for every physician; being more aware of its
      possible occurrence may help, as well as exploring the patient's history and
      psychosocial background.

PMID- 12593887
TI  - Failures in assisted reproductive technology: an overview.

PMID- 12593888
TI  - Electronic searching of the literature for systematic reviews of screening and
      diagnostic tests for preterm birth.
AB  - BACKGROUND: Published systematic reviews on prediction of preterm birth have
      tended to focus on a limited number of tests and their search strategies have
      often been relatively simple. Evaluation of all available tests in a systemic
      review will require a broad search strategy. AIM: To describe a case study of
      electronic searching for a systematic review of accuracy studies evaluating all
      tests for predicting preterm birth. METHODS: The search strategy, developed to
      capture literatures concerning all the tests en-masse consisted of formulation of
      an appropriate combination of search terms, pilot searches to refine the search
      term combination, selection of relevant databases, and citation retrieval from
      the refined searches for selection of potentially relevant papers. Electronic
      searches were carried out on general bibliographic databases (Biosis, Embase,
      Medline, Pascal and Scisearch), specialised databases (Database of Abstracts of
      Reviews of Effectiveness, Medion, National Research Register, Cochrane Controlled
      Trial Register and Cochrane Database of Systematic Reviews). RESULTS: A total of
      30076 citations were identified. Of these 8855 (29%) citations were duplications
      either within a database or across databases. Of the remaining 21221 citations,
      3333 were considered potentially relevant to the review after assessment by two
      reviewers. These citations covered 19 different tests for predicting preterm
      birth. CONCLUSIONS: This case study suggests that with use of a concerted effort
      to organise and manage the electronic searching it is feasible to undertake broad
      searches for systematic reviews with multiple questions.

PMID- 12593889
TI  - Expectant management of severe preeclampsia and preeclampsia superimposed on
      chronic hypertension between 24 and 34 weeks' gestation.
AB  - BACKGROUND: Timing of delivery is difficult to judge in preeclampsia. OBJECTIVE:
      To compare the differences of maternal and perinatal outcome of patients with
      severe preeclampsia and essential hypertension with superimposed preeclampsia,
      with expectant management at 24-34 weeks' gestation. STUDY DESIGN: A
      retrospective review of a conservative regime using intravenous magnesium
      sulfate, glucocorticoids and antihypertensive drugs, monitored by serial liver
      function tests, full blood count, coagulation profile, and renal function tests.
      Fetal status was assessed by daily non-stress test and ultrasound twice by week.
      RESULTS: A total number of 100 women had severe preeclampsia and 29 superimposed
      preeclampsia. The average pregnancy prolongation was 8.4 and 8.5 days,
      respectively. Oliguria, abruption placentae and HELLP syndrome were frequent
      complications similar in each group. There were no cases of eclampsia or
      disseminated coagulopathy in either group. The total neonatal survival rate was
      93% in both groups. CONCLUSION: Expectant management is equally safe in both
      superimposed preeclampsia and severe preeclampsia of early onset.

PMID- 12593890
TI  - Neonatal outcome of triplet versus twin and singleton pregnancies: a matched case
      control study.
AB  - OBJECTIVE: To determine the neonatal outcome of triplet gestations versus that of
      singletons and twins matched for gestational age. STUDY DESIGN: All live born
      triplet gestations delivered between 1 April 1993 and 31 March 2000 were compared
      to an age matched control group consisting of live born twins and singletons. The
      neonatal outcome of 116 sets of triplets was compared to that of 116 sets of
      twins and 116 singletons. RESULTS: During a 7-year period 116 sets of triplet
      pregnancies were reviewed. Of 116 sets of live born triplets (348 newborns),
      70.67% triplets were born between 33- and 36-week gestation, 28.44% between 28
      and 32 weeks and 0.86% less than 28 weeks. Triplets were smaller in weight than
      singletons but not twins. Apgar score, use of prenatal steroid and sex ratio were
      similar in the three groups. Incidence of respiratory distress syndrome (RDS),
      use of surfactant, infants requiring intubation, pneumothorax, patent ductus
      arteriosus, sepsis, intraventricular hemorrhage, periventricular leucomalacia,
      retinopathy of prematurity, necrotizing enterocolitis, gastroesophageal reflux
      and jaundice requiring phototherapy were not statistically different among the
      three groups. Incidence of major and minor congenital anomalies, percent neonatal
      intensive care unit (NICU) admissions, and mean duration of NICU stay were also
      similar. There was no influence of birth order on neonatal outcome of triplet
      pregnancy and outcome did not significantly change over 7 years of the study
      period. CONCLUSIONS: Triplets have a similar outcome to twins and singletons when
      matched for gestational age. Since outcome is dependent on gestational age, the
      closer the gestational age is to term the better is the outcome.

PMID- 12593891
TI  - Diagnosis of premature rupture of membranes by identification of beta-HCG in
      vaginal washing fluid.
AB  - OBJECTIVE: To evaluate the reliability of vaginal washing fluid beta-HCG for the
      diagnosis of premature rupture of membranes (PROMs) and to determine a cut-off
      value. STUDY DESIGN: A total of 141 pregnant women were recruited. The first
      group consisted of 73 pregnant women between 14 and 41 weeks of gestation with
      the complaint of vaginal fluid leakage. These were further subdivided into two
      subgroups. Group 1-confirmed PROM group (amniotic fluid pooling (+) and nitrazine
      paper test (+); 34 patients). Group 2-suspected but unconfirmed PROM group
      (amniotic fluid pooling (+/-) and/or nitrazine paper test (+/-); 39 patients).
      The control group (Group 3) consisted of 68 pregnant women between 14 and 41
      weeks of gestation without any complaint or complication. All patients underwent
      speculum examination for amniotic fluid pooling, nitrazine paper test, vaginal
      washing fluid beta-HCG sampling and ultrasonographic examination for gestational
      age determination, amniotic fluid index calculation. One-way ANOVA test, Scheffe
      multiple comparison test and receiver operating characteristic (ROC) curve
      analysis were used. RESULTS: Geometric mean values of beta-HCG was found to be 95
      for Group 1, 14 for Group 2, 10 for Group 3 (P<0.0001). The optimal cut-off was a
      beta-HCG value of 65 mIU/ml (sensitivity 68%, specificity 95%, positive
      predictive value 82%, negative predictive value 90%, accuracy 87%). CONCLUSION:
      Vaginal washing fluid beta-HCG determination for the diagnosis of PROM is
      reliable, simple and rapid test.

PMID- 12593892
TI  - Umbilical cord length and parity--the Greek experience.
AB  - OBJECTIVES: To investigate the relationship between parity and cord length, with
      respect to peripartum characteristics. STUDY DESIGN: Parity, cord length,
      placental and birth weight were the studied variables in a sample of 534
      parturients with singleton fetuses. Parturients were divided into four groups:
      primiparous (para-1), secundiparous (para-2), tetriparous (para-3) and
      multiparous (para >3). Oneway ANOVA and post-hoc tests were applied for the
      comparison of mean cord length between the four groups of parity. General Linear
      Model was applied for the detection of covariates. RESULTS: ANOVA yielded
      significant differences between the four groups. Mean cord length was
      significantly higher in women of parity >or=3 than in women with lower parity.
      Although both placental and birth weight were correlated with cord length,
      application of GLM showed that only birth weight could act as a covariate for the
      length differences between parity groups. CONCLUSIONS: Cord length appears to
      increase with advancing parity, the cut-off point being between the second and
      the third labor. We suggest that intrapartum monitoring should be performed in
      all multiparous parturients, because of their propensity for longer cords, and
      thus for related complications.

PMID- 12593893
TI  - Lack of anti-D in women at birth following antepartum immune globulin
      prophylaxis.
AB  - Antepartum prophylaxis using Rh immune globulin suppresses maternal immunization
      to transplacental transfer of Rh-positive fetal cells, and, theoretically, to be
      effective, anti-D should be detectable until birth. We used a sensitive gel
      technique to quantitatively detect the serum concentration of anti-D at birth in
      150 women who had received 300 microg of Rh immune globulin at 28 weeks
      gestation. Our method, which was sensitive enough to detect 20-25 microg, the
      recommended residual amount at birth, was positive in only 21% total, and in only
      13% of women at term. Fifty-seven percent of women with premature births had
      above the recommended level of anti-D.

PMID- 12593894
TI  - Relationship between gonadotrophin secretion, inhibin B and spermatogenesis in
      oligozoospermic men treated with highly purified urinary follicle-stimulating
      hormone (uFSH-HP): a preliminary report.
AB  - PURPOSE: To study the potential relationship between circulating follicle
      stimulating hormone (FSH) gonadotrophin, inhibin B, spermatogenesis and the
      benefit of highly purified urinary FSH (uFSH-HP) treatment in men with
      oligozoospermia. METHODS: Twenty-nine normogonadotropic, normogonadal men with
      oligozoospermia were evaluated. Serum hormonal concentration and spermiogram were
      analyzed before and after 3-month treatment with uFSH-HP. RESULTS: Our results
      support the hypothesis that inhibin B is involved in the physiological regulation
      of FSH secretion and reflects the FSH-stimulated Sertoli cell function. After
      treating with uFSH-HP for 3 months a significant increase in all semen parameters
      was observed in most of the patients. CONCLUSIONS: Although the benefit of
      inhibin B as a prognosis factor in oligozoospermic patients treated with FSH is
      not defined, it can be considered as an important serum marker in reproductive
      and testicular functions. Treatment of oligozoospermic patients with uFSH-HP has
      shown to be an effective and safe therapy.

PMID- 12593895
TI  - Androgen receptor (AR) gene microsatellite polymorphism in postmenopausal women:
      correlation to bone mineral density and susceptibility to osteoporosis.
AB  - OBJECTIVE: To investigate the correlation of the androgen receptor gene
      microsatellite polymorphism (CAG trinucleotide repeat polymorphism on exon 1)
      with bone mineral density and their relationship to osteoporosis in
      postmenopausal women. STUDY DESIGN: A number of 168 of 477 postmenopausal women
      were randomly recruited. The androgen receptor gene microsatellite polymorphism
      was determined using polymerase chain reaction-based microsatellite analysis.
      Bone mineral density of the lumbar spine and proximal femur was measured using
      dual-energy X-ray absorptiometry. RESULTS: The AR genotype was classified from
      "9" to "32" according to the number of CAG trinucleotide repeats they contained
      to represent "signposts". After adjustment for potential confounding factors such
      as age, height, weight, years since menopause, and daily calcium intake, subjects
      with genotype 20+ (n=64) had lower bone mineral density values and a
      significantly greater risk for osteoporosis (OR 4.2, 95% CI 1.0-17.2) when
      compared with subjects with genotype 20- (n=104) at the femoral neck. CONCLUSION:
      The present study suggests that the androgen receptor gene microsatellite
      polymorphism may be a candidate genetic marker for risk of osteoporosis in
      postmenopausal women.

PMID- 12593896
TI  - Serum folate and Vitamin B12 levels in women using modern oral contraceptives
      (OC) containing 20 microg ethinyl estradiol.
AB  - OBJECTIVE: The effects of modern oral contraceptives (OC) on serum concentrations
      of folate and cobalamin are controversial. STUDY DESIGN: Case-control study on
      the cobalamin and folate status of 71 healthy female nulligravidae using "low
      dose" OC for >or=3 months and 170 controls. Factors interfering with vitamin
      metabolism were thoroughly controlled. Serum concentrations were measured by
      commercial assays. The results were evaluated using Mann-Whitney's U-test and
      chi(2) analysis. RESULTS: OC-users showed significantly lower concentrations of
      cobalamin than controls. The rates of women with reduced, normal, and elevated
      levels differed significantly. Nine users but no control had frank cobalamin
      deficiency without clinical symptoms. Folate levels did not differ between the
      groups. Vegetarian diet, smoking or obesity did not have a significant influence.
      CONCLUSIONS: Routine measurement of cobalamin or folate in women using "low dose"
      OC is not warranted. Vitamin supplementation or different contraceptive methods
      should be considered in women with pre-existing cobalamin deficiency or
      restrictive dietary habits.

PMID- 12593897
TI  - Expression of estrogen receptor-alpha, glucocorticoid receptor, beta-catenin and
      glycogen synthase kinase-3beta in the uterus of mice following long-term
      treatment with estrogen and glucocorticoid hormones.
AB  - BACKGROUND: It has been shown that long-term glucocporticoid administration to
      chronically estradiol-treated mice decreases uterine weight, proliferation in all
      uterine tissues, the number of perpendicularly oriented mitoses in uterine
      epithelia and the incidence of atypical endometrial hyperplasia. However,
      mechanisms of chronic glucocorticoid action on estrogen-dependent processes in
      the uterus are unclear. METHODS AND RESULTS: Results of present research showed
      that adding of glucocorticoid dexamethasone (in drinking water, 2mg/l) to
      estradiol-treated mice led to a decrease in the level of glucocorticoid receptor,
      to an increase in levels of estrogen receptor-alpha, beta-catenin and glycogen
      synthase kinase-3beta in uterine tissues of ovariectomized mice at 30, 60 and 90
      days of the treatment. When vehicle was used instead estradiol, dexamethasone did
      not produce detectable changes in all parameters tested at all periods of
      observation. CONCLUSION: Results allow to conclude that estrogen and
      glucocorticoid receptors, beta-catenin and glycogen synthase kinase-3beta are
      involved in estrogen-dependent changes in uterine morphology and hyperplasia
      formation.

PMID- 12593898
TI  - Parallel observation of four methods for screening women under 25 years of age
      for genital infection with Chlamydia trachomatis.
AB  - OBJECTIVES: To compare four methods of screening women for Chlamydia trachomatis
      in an obstetrics and gynaecology department. STUDY DESIGN: A total of 303 healthy
      women under 25 years were recruited from antenatal, induced abortion, and family
      planning clinics. Each underwent parallel testing of endocervical specimens by
      enzyme immunoassay (EIA) and ligase chain reaction (LCR), vulval swabs by LCR,
      and urine by LCR. Outcome measures included sensitivity, specificity,
      acceptability of each method, and the influence of pregnancy. RESULTS: Overall
      prevalence (95% CI) was 9.9% (6.8-14%). All methods had a high rate of detection
      (75-100%), not affected by pregnancy. Urine was most acceptable, followed by
      vulval swabbing. CONCLUSIONS: Opportunistic screening of women under 25 years
      attending obstetric and gynaecology affiliated clinics found high rates of C.
      trachomatis infection. Both urine and vulval swab methods were highly sensitive,
      acceptable, and not affected by pregnancy status. Due to pragmatic issues
      surrounding the urine method, screening by vulval swabs deserves wider
      recognition.

PMID- 12593899
TI  - Interleukin-1beta gene polymorphism in women with vulvar vestibulitis syndrome.
AB  - OBJECTIVE: The pathogenesis of vulvar vestibulitis syndrome remains unknown but
      may be related to a localized chronic inflammation. The relation between this
      syndrome and a polymorphism at position +3953 in the interleukin-1beta gene was
      examined. Allele 2 of this gene has been associated with increased pro
      inflammatory immunity. STUDY DESIGN: Buccal or vestibular swabs from 59 women
      with strictly defined vulvar vestibulitis and from 48 healthy women were tested
      by polymerase chain reaction for the presence of two alleles at the +3953
      interleukin-1beta locus. RESULTS: Allele 2 of the interleukin-1beta gene was
      identified in 27 (46%) women with vulvar vestibulitis as opposed to 12 (25%)
      control women (P=0.03). The interleukin-1beta 1,1 genotype was present in 36
      (75%) controls as opposed to 32 (54%) vulvar vestibulitis syndrome patients
      (P=0.02). All subjects had been previously tested for induced interleukin-1beta
      production in response to bacterial lipopolysaccharide. In both patients and
      controls, possession of allele 2 was associated with a small but non
      statistically significant increase in induced interleukin-1beta production.
      CONCLUSION: Allele 2 in the interleukin-1beta gene is more common in women with
      vulvar vestibulitis syndrome than in other women. Susceptibility to vulvar
      vestibulitis syndrome might be influenced by carriage of this polymorphism.

PMID- 12593900
TI  - Benign gynecological tumors: estimated incidence. Results of the German Cohort
      Study on Women's Health.
AB  - OBJECTIVE: To analyze the lifetime incidence of benign gynecological tumors.
      STUDY DESIGN: The German Cohort Study on Women's Health was launched in 1998 as
      historic cohort study with prospective follow up. The study ascertained self
      reported information on tumors by calendar time. The incidence of benign
      gynecological tumors was calculated from the data of the first cohort period.
      RESULTS: The cohort comprised 396000 women-years of observation and 1676 benign
      tumors were observed. This lead to incidence estimates of 27.0, 18.6, and 23.3
      per 100000 women-years of observation for all benign tumors of the uterus, ovary,
      and breast respectively. CONCLUSION: In absence of other data, it is reasonable
      to use incidence rates generated by a large cohort of German women as a best
      estimate for the population up to 65 years of age.

PMID- 12593901
TI  - A randomized controlled trial of coil removal prior to treatment of pelvic
      inflammatory disease.
AB  - OBJECTIVE: To evaluate the effects of removing coils on the treatment of mild and
      moderate pelvic inflammatory disease (PID). METHODS: Of 126 women who had mild to
      moderate PID during coil usage, 60 were treated following coil removal and 66
      without. Clinical symptoms, findings of gynecologic examination, erythrocyte
      sedimentation rates (mm/h), leukocyte counts (mm(-3)) were recorded before and
      after treatment and recovery rates of symptoms and findings were compared with
      Chi-square and Fisher's absolute Chi-square tests. Student's t-test was used for
      the comparison of mean sedimentation rates and leukocyte counts. RESULTS:
      Recovery rates of pelvic pain, purulent vaginal discharge, dysuria/frequency and
      dyspareunia and clinical improvements in abdominal and cervical tenderness were
      significantly higher (P<0.05) in the coil removed group. CONCLUSIONS: Removing
      the coil before medical therapy, increases the rates of clinical improvement in
      mild to moderate PID.

PMID- 12593902
TI  - Ovarian wedge resection by minilaparatomy in infertile patients with polycystic
      ovarian syndrome: a new technique.
AB  - OBJECTIVE: To determine the effects of ovarian wedge resection by minilaparotomy
      in infertile patients with polycystic ovarian syndrome (PCOS). STUDY DESIGN: One
      hundred and thirty-four anovulatory patients with PCOS, who were previously
      treated with clomiphene citrate and gonadotropins and did not conceive were
      operated via minilaparotomy with microsurgical principles and ovarian wedge
      resection was performed on each subject. Pregnancy rates and adhesion formation
      were investigated retrospectively. RESULTS: A total of 121 pregnancies were
      achieved in 2 years (90%). One hundred and four patients conceived within the
      first 6 months (78%) and the remaining 17 patients conceived within 2 years (13%)
      following the operation. Sixty-eight patients had a second pregnancy later. In
      the post-operative period, 24 patients had cesarean delivery and 20 had
      diagnostic laparoscopy. Out of these 44 patients, only 5 of them were found to
      have minimal adhesions. CONCLUSION: This technique offers high pregnancy rates
      and minimal adhesion formation. Ovarian wedge resection by minilaparotomy might
      be an alternative treatment approach in patients with PCOS who did not conceive
      with standard ovulation induction protocols.

PMID- 12593903
TI  - Proceedings of the fourth Symposium of the Wim Schellekens Foundation
      "Reproduction and Cancer, Cancer and Reproduction".

PMID- 12593904
TI  - Pregnancy in asymmetric blind hemicavity of Robert's uterus--a previously
      unreported phenomenon.
AB  - An 18-year-old primigravida presented following recurrent failed attempts at
      pregnancy termination for intra-uterine fetal death. Clinical examination aroused
      suspicion of non-communicating uterine horn with bicornuate uterus. Examination
      under anaesthesia and laparotomy revealed a partial vaginal septum, complete
      septate uterus with septum deviated to one side and fetus lying in the non
      communicating right blind hemicavity (Robert's uterus). Hysterotomy and
      ipsilateral tubal ligation were performed.

PMID- 12593905
TI  - Conservative management of placenta accreta and unruptured interstitial cornual
      pregnancy using methotrexate.
AB  - We describe two cases which demonstrate methotrexate (mtx) to be an effective
      alternative to surgery in two serious complications of early pregnancy, namely
      placenta accreta diagnosed at attempted evacuation of retained products of
      conception and interstitial cornual pregnancy diagnosed at laparoscopy.

PMID- 12593906
TI  - Spontaneous uterine rupture with amniotic sac protrusion at 28 weeks subsequent
      to previous hysteroscopic metroplasty.
AB  - BACKGROUND: Hysteroscopic metroplasty improves pregnancy outcome in case of
      uterine septum. Uterine rupture during a pregnancy following this procedure may
      occur. CASE: A patient with a history of hysteroscopic resection of a uterine
      septum complicated by fundal perforation, presented at 28 weeks a spontaneous
      uterine rupture with amniotic sac protrusion through the uterine wall disruption.
      CONCLUSION: Uterine rupture during pregnancy following a hysteroscopic
      metroplasty may occur even though it appears to be a very uncommon event.
      Patients who have had this procedure should be aware of this potential risk in
      case of future pregnancies. How to avoid such complication is still unclear.

PMID- 12593907
TI  - Thalassemia intermedia and cavernous transformation of portal vein thrombosis in
      pregnancy.
AB  - We report a rare case of a cavernous transformation of portal vein (CTPV)
      thrombosis accompanied by Thalassemia and thrombophilia during pregnancy that was
      successfully treated by low molecular weight heparin. The clinical presentation,
      diagnosis and the treatment are discussed.

PMID- 12593908
TI  - Submucous infiltration of betamethasone and lidocaine in the treatment of vulvar
      vestibulitis.
AB  - We present a case of persistent vulvar vestibulitis treated for several years
      unsuccessfully that has come to an end using a six week course of submucous
      infiltration of betamethasone and lidocaine in the vestibular area.

PMID- 12593909
TI  - A response to Ben-Noun "what is the Biblical attitude towards personal hygiene
      during vaginal bleeding?".

PMID- 12593911
TI  - Synthesis and pharmacological evaluation of new 1,2-dithiolane based
      antioxidants.
AB  - Molecules containing a dithiolane moiety are widely investigated due to their
      antioxidant properties. The archetypal representative of this class of compounds
      is lipoic acid and indeed the lipoic acid-dihydrolipoic acid couple is part of
      the antioxidant defence system of the cell. In the course of a program aiming to
      find improved antioxidants effective in vivo, we designed, synthesised and
      pharmacologically investigated new lipoic acid analogs. The salient feature of
      these structures is the connection, via a thioamide or a thiocarbamate, of a 1,2
      dithiolane moiety bearing a carbon chain and a N-alkyl-substituted morpholine
      ring. It was expected that the antioxidant and chelating properties of these
      functional groups combined with the basicity of the morpholine ring will impact
      on the antioxidant as well as on the partition and solubility characteristics of
      the compounds. Indeed in vitro and in vivo pharmacological investigation showed
      that these new molecules and especially those containing a thiocarbamate linker
      possess superior antioxidant properties compared with alpha-lipoic acid and to
      the amide or carbamate linker analogs. In particular, some of these compounds
      efficiently cross the blood brain barrier (BBB) thus providing efficient
      protection from lethality in a situation of induced oxidative stress. Moreover
      the absence of the 1,2-dithiolane moiety does not completely abolish antioxidant
      effects thus demonstrating that these compounds are distinct new chemical
      entities and not merely lipoic acid prodrugs. The chemical and pharmacological
      features of these new antioxidants are presented and discussed in the following
      paper.

PMID- 12593912
TI  - A structure-activity relationship study on position-2 of the Galpha(s) C-terminal
      peptide able to inhibit G(s) activation by A2A adenosine receptor.
AB  - For some years synthetic peptides corresponding to the C-terminal sequence of
      Galpha proteins represented an useful tool to study the molecular mechanism of
      the interaction between these proteins and the G protein coupled receptors.
      Recently, we have focused our attention on the study of the A(2A) receptor-G(s)
      protein system. We have synthesised a series of 11-mer peptides from the
      Galpha(s) C-terminus in which residue at position-2 (Leu(393)) has been
      alternatively substituted with amino acids having different physico-chemical
      properties. The aim of our work was to probe the role played by Leu(393) in the
      receptor/Galpha(s) interaction. All synthetic peptides were tested for their
      ability to affect the adenylyl cyclase activity stimulated by agonist activation
      of A(2A) adenosine receptors. Our data point out a relevant role played by the
      side chain of this residue for a correct G protein/receptor coupling, even though
      the presence of other residues at position-2 of Galpha(s) C-terminus is
      tolerated. Furthermore, molecular dynamics calculations on the peptides having
      greater activity show a correlation between the spatial arrangement of the side
      chain of residue at position-2 and biological activity of synthetic peptides.

PMID- 12593913
TI  - Synthesis of aza mono, bi and tricyclic compounds. Evaluation of their anti MDR
      activity.
AB  - Anti MDR activity of a series of acridine, pyridoquinoline, quinoline and
      pyridine analogous amines was evaluated. Interesting activity is displayed by
      tricyclic compounds. Besides ring size, influence of the side chain was studied.

PMID- 12593914
TI  - Design and synthesis of some substituted 1H-pyrazolyl-thiazolo[4,5-d]pyrimidines
      as anti-inflammatory-antimicrobial Agents.
AB  - The synthesis of two novel series of structurally related 1H-pyrazolyl
      derivatives of thiazolo[4,5-d]pyrimidines is described. All the newly synthesised
      compounds were examined for their in vivo anti-inflammatory activity in two
      different bioassays namely; cotton pellet-induced granuloma and carrageenan
      induced paw edema in rats. The in vitro inhibitory activity of the most active
      compounds towards human COX-1 and COX-2 enzymes was also estimated. In addition,
      the ulcerogenic effects and acute toxicity (LD(50)) values of these compounds
      were determined. The same compounds were evaluated for their in vitro
      antimicrobial activity against Escherichia coli, as an example of Gram negative
      bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and
      Candida albicans as a representative of fungi. The results revealed that
      compounds 5a, 9a, 9b, 10b and 12a exhibited anti-inflammatory activity comparable
      to that of indomethacin in both local and systemic in vivo animal models with no
      or minimal ulcerogenic effects (0-10%) and high safety margin (LD(50) > 500 mg
      kg(-1)). In addition, most of them displayed appreciable antibacterial activities
      when compared with ampicillin, especially against S. aureus. Compounds 9a and 12a
      are the most distinctive derivatives identified in the present study because of
      their remarkable in vivo and in vitro anti-inflammatory activity in addition to
      their pronounced antibacterial activities comparable to ampicillin against Gram
      positive and -negative bacteria. Therefore, they are considered as successful
      dual anti-inflammatory-antimicrobial candidates.

PMID- 12593915
TI  - New bis(pyridyl)methane derivatives from 4-hydroxy-2-pyridones: synthesis and
      antitumoral activity.
AB  - Bis(pyridyl)methane derivatives 5-40 were obtained from the reaction of 4-hydroxy
      2-pyridones 3 and 4 with aldehydes. Compounds 5-40 were evaluated for cytotoxic
      activity against a panel of 60 human cancer cell lines by the National Cancer
      Institute and some of them demonstrated inhibitory effects on the growth of a
      wide range of cancer cell lines generally at 10(-5) M level and in some case at
      10(-7) M concentrations.

PMID- 12593916
TI  - Synthesis and anticonvulsant activity of enaminones. Part 7. Synthesis and
      anticonvulsant evaluation of ethyl 4-[(substituted phenyl)amino]-6-methyl-2
      oxocyclohex-3-ene-1-carboxylates and their corresponding 5-methylcyclohex-2-enone
      derivatives.
AB  - Further investigation of the potential anticonvulsant activity of the enaminones
      was attempted to discern the possible role of metabolites as the active/co-active
      entities of the esters of the enaminones. A series of 5-methyl-2-cyclohexene
      enaminones, the hypothesised metabolites corresponding to a sequence of active
      and inactive esters were synthesised and evaluated for anticonvulsant activity.
      With two exceptions, ethyl 4-[(4-cyanophenyl)amino]-6-methyl-2-oxocyclohex-3-ene
      1-carboxylate (1k), and 3-[N-(4-cyanophenyl)amino]-5-methyl-2-cyclohexenone (3g),
      and ethyl 4-(phenylamino)-6-methyl-2-cyclohexenone (1n), and 3-N-(phenylamino)-5
      methyl-2-cyclohexenone (3j), anticonvulsant screening data were parallel, with
      the ester and their putative decarboxylated analogue displaying similar activity.
      The most active analogue evaluated in this series, ethyl 4-[(4
      chlorophenyl)amino]-6-methyl-2-oxocyclohex-3-ene-1-carboxylate (1e), which
      displayed an ED(50) of 16.7 mg kg(-1) and a TD(50) of 110.7 mg kg(-1) (protective
      index, PI = TD(50)/ED(50) = 6.6) in the maximal electroshock seizure (MES) test
      in mice and an ED(50) of 3.0 mg kg(-1) and a TD(50) >250 mg kg(-1) (PI > 83.3) in
      rats in the same evaluation, making this compound the most potent enaminone
      emanating from our laboratories. Pharmacokinetic evaluation of compound 1e in
      rats using LC/MS analysis unequivocally provides evidence that this compound is
      converted into the decarboxylated analogue 3a in the brain and the urine.

PMID- 12593917
TI  - Synthesis and cytotoxicity of podophyllotoxin analogues modified in the A ring.
AB  - Several podophyllotoxin derivatives lacking the methylenedioxy group or with
      different functionalization of the A-ring of the cyclolignan skeleton have been
      prepared and evaluated for their cytotoxic activities on four neoplastic cell
      lines (P-388, A-549, HT-29 and MEL-28). Most of them maintained their
      cytotoxicity at the microM level.

PMID- 12593918
TI  - Synthesis and antifungal activity of new 1-halogenobenzyl-3
      imidazolylmethylindole derivatives.
AB  - A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were
      prepared under mild reaction conditions and tested for their antifungal activity.
      Pharmacomodulation at N(1), C(2) and C(5) of the indole ring and at the level of
      the alkyl chain (R(1)) was carried out starting from the corresponding 3
      acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were
      obtained in satisfactory yields by CO(2) elimination from the intermediate
      carbamates. All of the compounds were evaluated in vitro against two human fungal
      pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003);
      amphotericin B, fluconazole and itraconazole were used as references. Seven out
      of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted
      significant antifungal activity against C. albicans, with MIC in the range of 1-6
      microg mL(-1). As regards inhibitory activity against A. fumigatus, the MIC
      figures of most of our compounds were in excess of 20 microg mL(-1) in contrast
      to the reference drugs, amphotericin B and itraconazole, whose MIC(90) and
      MIC(80) values were 0.14 and 0.50 microg mL(-1), respectively. The most potent
      compound, 45a, exhibited MIC value (8 +/- 1 microg mL(-1)) 16-fold higher than
      that of itraconazole.

PMID- 12593919
TI  - Synthesis and preliminary evaluation of some N-[5-(2-furanyl)-2-methyl-4-oxo-4H
      thieno[2,3-d]pyrimidin-3-yl]-carboxamide and 3-substituted-5-(2-furanyl)-2-methyl
      3H-thieno[2,3-d]pyrimidin-4-ones as antimicrobial agents.
AB  - Two series of N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]
      carboxamide (4a-m) and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3
      d]pyrimidin-4-ones (5a-m) were synthesised using appropriate synthetic route. All
      the test compounds 4a-m and 5a-m were assayed in vitro for antibacterial activity
      against two different strains of Gram-negative (Escherichia coli and S. typhi)
      and Gram-positive (S. aureus, B. subtilis) bacteria and the antimycobacterial
      activity was evaluated against M. tuberculosis and M. avium strains. The minimum
      inhibitory concentration (MIC) was determined for test compounds as well as for
      reference standards. The test compounds have shown significant antibacterial and
      antimycobacterial activity against all the microbial strains used, when tested in
      vitro. In general, along with the thienopyrimidinone ring, substituted amido or
      imino side chain at position 3 is essential for antimicrobial activity. Among the
      compounds tested, compounds 4c, 4e and 4g in N-[5-(2-furanyl)-2-methyl-4-oxo-4H
      thieno[2,3-d]pyrimidin-3-yl]-carboxamide series and compounds 5c, 5e and 5g in 3
      substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones series were
      found to be the most potent. Further the toxicity of most potent compounds 4c, 4e
      and 4g and 5c, 5e and 5g were assessed using hemolytic assay and minimal
      hemolytic concentration (MHCs) were determined. In general, test compounds were
      found to be non-toxic up to a dose level of 200 micromol L(-1) (MHC).

PMID- 12593920
TI  - Design of antineoplastic agents based on the '2-phenylnaphthalene-type'
      structural pattern--synthesis and biological activity studies of 11H-indolo[3.2
      c]quinoline derivatives.
AB  - Designed as a new group of planar molecule containing the proposed 2
      phenylnaphthalene-type structure, a number of 11H-indolo[3.2-c]quinoline
      derivatives were synthesized and evaluated biologically. Several compounds were
      found to possess cytotoxic activity against the growth of human promyelocytic
      leukemia cells (HL-60), against the small cell lung cancer (SCLC), and showed
      good response in the National Cancer Institute preclinical antitumor drug
      discovery 60-cell line panel.

PMID- 12593921
TI  - Choline kinase inhibitory effect and antiproliferative activity of new 1,1',1"
      (benzene-1,3,5-triylmethylene)tris[4-[(disubstituted)amino]pyridinium]
      tribromides.
AB  - Four derivatives of 1,1'-(benzene-1,3-diylmethylene)bis[4-[(disubstituted)amino]
      pyridinium] dibromides (2-5) and six derivatives of 1,1',1"-(benzene-1,3,5
      triylmethylene)-tris[4-[(disubstituted)amino]pyridinium] tribromides (6-11) were
      synthesised and examined for their inhibition of human choline kinase (ChoK) and
      antiproliferative activities. The latter are more potent as ChoK inhibitors than
      the former, but the antiproliferative activities against the HT-29 cell line show
      the opposite tendency. The higher affinity of the trispyridinium compared with
      the bispyridinium ones may be due to direct binding of the third pyridinium group
      to ChoK or may arise from a reduction of the unfavourable entropy of binding via
      an increase of the 'local concentration' of pyridinium groups.

PMID- 12593922
TI  - A sequential high-yielding large-scale solution-method for synthesis of
      philanthotoxin analogues.
AB  - A general, improved procedure for rapid synthesis of philanthotoxin analogues, a
      pharmacologically important class of polyamine conjugates, is described. The
      solution-phase procedure is illustrated by gram-scale synthesis of
      philanthotoxins PhTX-343 and PhTX-12. Selectively protected polyamines are
      coupled to N(alpha)-Fmoc-protected amino acid pentafluorophenyl esters. After
      removal of the N(alpha)-Fmoc group, the amine is coupled with carboxylic acid
      pentafluorophenyl esters. Deprotection followed by a rapid and efficient
      purification by vacuum liquid chromatography on octadecylsilyl silica (RP-18
      phase) gave the philanthotoxin analogues in 74-78% overall yield.

PMID- 12593923
TI  - Acid tolerance and gad mRNA levels of Escherichia coli O157:H7 grown in foods.
AB  - We examined the acid tolerance and gad mRNA levels of Escherichia coli O157:H7
      (three strains) and nonpathogenic E. coli (strains K12, W1485, and B) grown in
      foods. The E. coli cells (approximately 30,000 cells) were inoculated on the
      surface of 10 g of solid food samples (asparagus, broccoli, carrot, celery,
      cucumber, eggplant, ginger, green pepper, onion, potato, radish, tomato and beef)
      and in 10 ml of cow's milk, cultured statically at 10-25 degrees C for 1-14 days,
      and subjected to an acid challenge at 37 degrees C for 1 h in LB medium (pH 3.0).
      When grown at 20 and 25 degrees C in all foods, except for tomato and ginger, the
      strains showed a stationary-phase specific acid tolerance. The acid tolerance of
      the O157 strains changed depending on the types of foods (3-10% survival), but
      was clearly lower than that of the cells grown in EC medium (more than 90%
      survival). Tomato and ginger induced relatively high acid tolerances (10-30%
      survival) in the O157 strains irrespective of the growth phase, probably because
      of their acidity. No remarkable difference was observed in the acid tolerance
      between the O157 and nonpathogenic strains grown in all foods. When grown at 10
      and 15 degrees C in the foods and EC medium, none of the strains showed the
      stationary-phase specific acid tolerance. In beef, broccoli, celery, potato and
      radish, the acid tolerance showed a tendency to decrease with the prolonged
      cultivation time. In other foods, the acid tolerance was almost constant (about
      0.1% survival) irrespective of the growth stage. The mRNA level of glutamate
      decarboxylase genes (gadA and gadB) correlated to the acid tolerance level when
      the E. coli cells were grown at 25 degrees C, but was very low even in the
      stationary phase when the E. coli cells were grown at 15 degrees C or below.

PMID- 12593924
TI  - Microbial quality of shrimp products of export trade produced from aquacultured
      shrimp.
AB  - Bacteriological quality of individually quick frozen (IQF) shrimp products
      produced from aquacultured tiger shrimp (Penaeus monodon) has been analysed in
      terms of aerobic plate count (APC), coliforms, Escherichia coli, coagulase
      positive staphylococci, Salmonella, and Listeria monocytogenes. Eight hundred
      forty-six samples of raw, peeled, and deveined tail-on (RPTO), 928 samples of
      cooked, peeled, and deveined tail-on (CPTO), 295 samples of headless, undeveined
      shell-on (HLSO), and 141 samples of raw, peeled, and deveined tail-off (RPND)
      shrimps were analysed for the above bacteriological parameters. Salmonella was
      isolated in only one sample of raw, peeled tail-on. Serotyping of the strain
      revealed that it was S. typhimurium. While none of the cooked, peeled tail-on
      shrimp samples exceeded the aerobic plate count (APC) of 10(5) colony forming
      units per gram (cfu/g), 2.5% of raw, peeled, tail-on, 6.4% of raw, peeled tail
      off, and 7.5% of headless shell-on shrimp samples exceeded that level. Coliforms
      were detected in all the products, though at a low level. Prevalence of coliforms
      was higher in headless shell-on (26%) shrimps followed by raw, peeled, and
      deveined tail-off (19%), raw, peeled tail-on (10%), and cooked, peeled tail-on
      (3.8%) shrimps. While none of the cooked, peeled tail-on shrimp samples were
      positive for coagulase-positive staphylococci and E. coli, 0.6-1.3% of the raw,
      peeled tail-on were positive for staphylococci and E. coli, respectively.
      Prevalence of staphylococci was highest in raw, peeled tail-off (5%) shrimps and
      the highest prevalence of E. coli (4.8%) was noticed in headless shell-on
      shrimps. L. monocytogenes was not detected in any of the cooked, peeled tail-on
      shrimps. Overall results revealed that the plant under investigation had exerted
      good process control in order to maintain superior bacteriological quality of
      their products.

PMID- 12593925
TI  - Contamination flows of Bacillus cereus and spore-forming aerobic bacteria in a
      cooked, pasteurized and chilled zucchini puree processing line.
AB  - A food processing plant producing pasteurized purees and its zucchini puree
      processing line were examined for contamination with aerobic and facultative
      anaerobic bacterial spores during a day's operation. Multiplication of spores was
      also monitored in the product stored under different conditions. High
      concentrations of Bacillus cereus spores were found in the soil in which the
      zucchinis were grown (4.6+/-0.3 log CFU/g), with a background spore population of
      6.1+/-0.2 log CFU/g. In the processing plant, no B. cereus or psychrotrophic
      bacterial spores were detected on equipment. B. cereus and psychrotrophic
      bacterial spores were detected after enrichment in all samples of raw zucchinis,
      washed zucchinis, of two ingredients (starch and milk proteins) and in processed
      puree at each processing step. Steam cooking of raw zucchinis and pasteurization
      of puree in the final package significantly reduced spore numbers to 0.5+/-0.3
      log CFU/g in the processed food. During storage, numbers of spore-forming
      bacteria increased up to 7.8+/-0.1 log CFU/g in puree after 5 days at 20-25
      degrees C, 7.5+/-0.3 log CFU/g after 21 days at 10 degrees C and 3.8+/-1.1 log
      CFU/g after 21 days at 4 degrees C. B. cereus counts reached 6.4+/-0.5 log CFU/g
      at 20-25 degrees C, 4.6+/-1.9 log CFU/g at 10 degrees C, and remained below the
      detection threshold (1.7 log CFU/g) at 4 degrees C. Our findings indicate that
      raw vegetables and texturing agents such as milk proteins and starch, in spite of
      their low levels of contamination with bacterial spores and the heat treatments
      they undergo, may significantly contribute to the final contamination of cooked
      chilled foods. This contamination resulted in growth of B. cereus and
      psychrotrophic bacterial spores during storage of vegetable puree. Ways to
      eliminate such contamination in the processing line are discussed.

PMID- 12593926
TI  - A hybrid Bayesian-neural network approach for probabilistic modeling of bacterial
      growth/no-growth interface.
AB  - A hybrid probabilistic modeling approach that integrates artificial neural
      networks (ANNs) with statistical Bayesian conditional probability estimation is
      proposed. The suggested approach benefits from the power of ANNs as highly
      flexible nonlinear mapping paradigms, and the Bayes' theorem for computing
      probabilities of bacterial growth with the aid of Parzen's probability
      distribution function estimators derived for growth and no-growth (G/NG) states.
      The proposed modeling approach produces models that can predict the probability
      of growth of targeted microorganism as affected by a set of parameters pertaining
      to extrinsic factors and operating conditions. The models also can be used to
      define the probabilistic boundary (interface) between growth and no-growth, and
      as such can define and predict the values of critical parameters required to keep
      a desired pre-specified bacterial growth risk in check. A modular system
      incorporating the various computational modules was constructed to illustrate the
      application of the hybrid approach to the probabilistic modeling of growth of
      pathogenic Escherichia coli strain as affected by temperature and water activity.
      The proposed approach was compared to other techniques including the traditional
      linear and nonlinear logistic regression. Results indicated that the hybrid
      approach outperforms the other approaches in its accuracy as well as flexibility
      to extract the implicit interrelationships between the various parameters.
      Advantages and limitations of the approach were also discussed and compared to
      those of other techniques.

PMID- 12593927
TI  - Isolation of Salmonella from alfalfa seed and demonstration of impaired growth of
      heat-injured cells in seed homogenates.
AB  - Three major foodborne outbreaks of salmonellosis in 1998 and 1999 were linked to
      the consumption of raw alfalfa sprouts. In this report, an improved method is
      described for isolation of Salmonella from alfalfa seed lots, which had been
      implicated in these outbreaks. From each seed lot, eight samples each containing
      25 g of seed were tested for the presence of Salmonella by the US FDA
      Bacteriological Analytical Manual (BAM) procedure and by a modified method
      applying two successive pre-enrichment steps. Depending on the seed lot, one to
      four out of eight samples tested positive for Salmonella by the standard
      procedure and two to seven out of eight samples tested positive by the modified
      method. Thus, the use of two consecutive pre-enrichment steps led to a higher
      detection rate than a single pre-enrichment step. This result indirectly
      suggested that Salmonella cells on contaminated seeds might be injured and failed
      to fully resuscitate in pre-enrichment broth containing seed components during
      the first 24 h of incubation. Responses of heat-injured Salmonella cells grown in
      buffered peptone water (BPW) and in three alfalfa seed homogenates were
      investigated. For preparation of seed homogenates, 25 g of seeds were homogenized
      in 200 ml of BPW using a laboratory Stomacher and subsequently held at 37 degrees
      C for 24 h prior to centrifugation and filtration. While untreated cells grew at
      about the same rate in BPW and in seed homogenates, heat-injured cells (52
      degrees C, 10 min) required approximately 0.5 to 4.0 h longer to resuscitate in
      seed homogenates than in BPW. This result suggests that the alfalfa seed
      components or fermented metabolites from native bacteria hinder the repair and
      growth of heat-injured cells. This study also shows that an additional pre
      enrichment step increases the frequency of isolation of Salmonella from naturally
      contaminated seeds, possibly by alleviating the toxic effect of seed homogenates
      on repair or growth of injured cells.

PMID- 12593928
TI  - Cytokine responses of human intestinal epithelial-like Caco-2 cells to the
      nonpathogenic bacterium Bacillus subtilis (natto).
AB  - Intestinal epithelial cells produce cytokines in response to pathogenic bacteria.
      However, cellular responses of these cells to nonpathogenic strains, such as
      Bacillus subtilis, are yet to be determined. In this study, we investigate
      whether epithelial-like human colon carcinoma Caco-2 cells produce cytokines in
      response to B. subtilis or B. subtilis (natto). The latter strain is utilized for
      manufacturing the fermented soy food "natto". Live cells of nonpathogenic B.
      subtilis JCM 1465(T), B. subtilis (natto) and E. coli JCM 1649(T), as well as
      pathogenic S. enteritidis JCM 1652 and P. aeruginosa JCM 5516 strains, induced
      secretion of interleukin-6 (IL-6) and/or IL-8, but not IL-7, IL-15 or tumor
      necrosis factor alpha (TNF-alpha). Transepithelial electrical resistance (TER) of
      Caco-2 cell monolayers cultured with E. coli, S. enteritidis or P. aeruginosa
      decreased more rapidly than that of cells cultured with B. subtilis or B.
      subtilis (natto). The amounts of cytokine induced by B. subtilis (natto) cells
      were strain-dependent. Moreover, B. subtilis (natto) cells subjected to
      hydrochloric acid treatment, but not autoclaving, induced a higher secretion of
      IL-6 and IL-8 than intact cells. Tyrosine kinase inhibitors, including AG126 and
      genistein, suppressed cytokine secretion. Our results suggest that the
      nonpathogenic B. subtilis (natto) bacterium induces cytokine responses in
      intestinal epithelial cells via activation of an intracellular signaling pathway,
      such as that of nuclear factor-kappa B (NF-kappaB).

PMID- 12593929
TI  - Adaptive and cross-adaptive responses of persistent and non-persistent Listeria
      monocytogenes strains to disinfectants.
AB  - Persistent and non-persistent Listeria monocytogenes strains were tested for
      initial resistance and adaptive and cross-adaptive responses towards two
      quaternary ammonium compounds, alkyl-benzyl-dimethyl ammonium chloride and n
      alkyldimethyl ethylbenzyl ammonium chloride, one tertiary alkylamine, 1,3
      propanediamine-N-(3-aminopropyl)N-dodecyl, sodium hypochlorite and potassium
      persulphate. The initial resistance of two persistent and two non-persistent L.
      monocytogenes strains was observed to differ. Both types of strains adapted after
      a 2-h sublethal exposure to the quaternary ammonium compounds and the tertiary
      alkylamine, the highest increase in the minimum inhibitory concentration (MIC)
      being 3-fold. Progressively increasing disinfecting concentrations at 10 and 37
      degrees C resulted in adaptation of L. monocytogenes to all disinfectants except
      potassium sulphate. The highest observed increase in MIC was over 15-fold, from
      0.63 to 10 microg/ml of n-alkyldimethyl ethylbenzyl ammonium chloride. All
      strains reached approximately similar MICs. Stability of the increased resistance
      was tested by measuring MICs every seventh day for 28 days. The increased
      resistance to sodium hypochlorite disappeared in 1 week, but the quaternary
      ammonium compounds and the tertiary alkylamine showed increased resistance for 28
      days. These results suggest that cellular changes due to adaptive responses
      continue to have an effect on the resistance some time after the exposure. All
      disinfectants were shown to cause cross-adaptation of L. monocytogenes, the
      highest increase in MIC being almost 8-fold. The only agent that L. monocytogenes
      could not be shown to cross-adapt to was potassium persulphate which did,
      however, cause cross-adaptation to the other disinfectants. The mechanism behind
      these adaptive responses seemed to be non-specific as cross-adaptation was
      observed not only between related but also unrelated disinfectants. These
      findings suggest that sustaining high disinfectant effectiveness may be
      unsuccessful by rotation, even when using agents with different mechanisms of
      action.

PMID- 12593930
TI  - Isolation of Escherichia coli O157:H7 from foods in Greece.
AB  - The presence of Escherichia coli O157:H7 in various foods of animal origin was
      surveyed in northwestern Greece. Six hundred samples of unpasteurized cows',
      ewes' and goats' milk, raw minced meat, uncooked frozen beef hamburgers,
      sandwiches (containing ham or turkey, mixed vegetable salad with mayonnaise and
      lettuce), fresh traditional Greek pork sausages and swine intestines appropriate
      for traditional Greek kokoretsi were assayed for E. coli serogroup O157:H7 using
      the standard cultural method and the immunomagnetic separation technique. The
      pathogen was detected in 1 out of 100 (1.0%) samples of ewes' milk, 1 out of 75
      (1.3%) fresh sausages and 1 out of 50 (2.0%) swine intestines prepared for
      kokoretsi. The isolated strains were nonsorbitol fermenters, MUG-negative, O157
      agglutinating, verotoxin-producing and carried both VT1 and VT2 genes. The three
      isolated strains were tested for antibiotic resistance and were found to be
      susceptible to eight antimicrobial agents (ampicillin, chloramphenicol,
      kanamycin, nalidixic acid, norfloxacin, streptomycin, sulfamethoxazole
      trimethoprim and tetracycline).

PMID- 12593931
TI  - Occurrence and resistance to antibiotics of Campylobacter jejuni and
      Campylobacter coli in animals and meat in northeastern Italy.
AB  - A study was carried out in northeastern Italy during 2000 and 2001 to investigate
      the occurrence of Campylobacter jejuni and Campylobacter coli in animals, cattle,
      pigs, and broilers, and raw meat, beef, pork, and chicken. Campylobacter spp.
      were detected in 53.9% of the cattle, 63.5% of the pigs, and 82.9% of the
      broilers examined. Chicken meat was frequently contaminated (81.3%), while lower
      rates were found in pork meat (10.3%) and beef (1.3%). The resistance to
      antibiotics of the strains was also investigated, and compared to that of human
      clinical isolates. C. coli was generally more resistant than C. jejuni.
      Resistance to quinolones was frequently observed in C. coli isolated in chicken
      meat (78.6%); slightly lower rates were found in C. jejuni isolated in broilers
      (42.2%), chicken meat (52.8%), and humans (38.2%). C. coli was also frequently
      resistant to tetracycline in all sources, while resistance to streptomycin was
      most frequently observed in pig isolates (89.4%).

PMID- 12593932
TI  - Mechanistic studies of the effect of hydroxypropyl-beta-cyclodextrin on in vitro
      transdermal permeation of corticosterone through hairless mouse skin.
AB  - Literature reports reveal that the issue of whether cyclodextrins may act as skin
      permeation enhancers has not been resolved. Accordingly, in vitro skin transport
      studies were conducted to address this question. Corticosterone (3H-CS and/or non
      radiolabeled CS) was chosen as the model permeant for transport experiments with
      hairless mouse skin (HMS) and with a synthetic cellulose membrane of 500
      molecular weight cut off (MWCO), the latter to help establish baseline behavior.
      Hydroxypropyl-beta-cyclodextrin (HPbetaCD) was selected as the representative
      cyclodextrin. The CS/HPbetaCD complexation constant was determined both from
      solubility data (saturation conditions) in phosphate buffered saline (PBS), pH
      7.4 and with data obtained from PBS/silicone polymer partitioning experiments,
      the latter experiments permitting the determination of the complexation constant
      at low CS concentrations. These results were used in the calculations of the free
      CS concentrations in the donor chamber of the transport experiments. The CS
      transport experiments were conducted at CS solubility saturation and under
      supersaturation (resulting from autoclaving at 121 degrees C) conditions as well
      at very low (tracer level) concentrations. The effect of polyvinylpyrrolidone as
      a solution additive was also evaluated. The following were the key outcomes of
      this study. Contrary to literature reports, there was no evidence that HPbetaCD
      is an enhancer for CS transport through HMS. The CS permeability coefficient
      values obtained with HMS in all of the experiments were found to be the same
      within experimental error when calculated on the basis of the free CS
      concentration as the driving force for permeation. The constancy of the
      permeability coefficient in the presence and absence of HPbetaCD is interpreted
      to mean that, in these experiments, HPbetaCD did not alter the barrier properties
      of HMS stratum corneum to any significant extent nor did it enhance CS transport
      in any other manner such as by a carrier mechanism involving the aqueous boundary
      layer or by a carrier mechanism within the stratum corneum.

PMID- 12593933
TI  - Effect of HPMC and Carbopol on the release and floating properties of Gastric
      Floating Drug Delivery System using factorial design.
AB  - The purpose of this study is to investigate the effect of formulation variables
      on drug release and floating properties of the delivery system. Hydroxypropyl
      methylcellulose (HPMC) of different viscosity grades and Carbopol 934P (CP934)
      were used in formulating the Gastric Floating Drug Delivery System (GFDDS)
      employing 2 x 3 full factorial design. Main effects and interaction terms of the
      formulation variables could be evaluated quantitatively by a mathematical model.
      It was found that both HPMC viscosity, the presence of Carbopol and their
      interaction had significant impact on the release and floating properties of the
      delivery system. The decrease in the release rate was observed with an increase
      in the viscosity of the polymeric system. Polymer with lower viscosity (HPMC
      K100LV) was shown to be beneficial than higher viscosity polymer (K4M) in
      improving the floating properties of GFDDS. Incorporation of Carbopol, however,
      was found to compromise the floating capacity of GFDDS and release rate of
      calcium. The observed difference in the drug release and the floating properties
      of GFDDS could be attributed to the difference in the basic properties of three
      polymers (HPMC K4M, K100LV and CP934) due to their water uptake potential and
      functional group substitution.

PMID- 12593934
TI  - Para-acyl-calix-arene based solid lipid nanoparticles (SLNs): a detailed study of
      preparation and stability parameters.
AB  - The preparation and stability parameters of para-acyl-calix[4]arene based solid
      lipid nanoparticles (SLNs) have been investigated. Atomic force microscopy (AFM)
      and photon correlation spectroscopy (PCS) show a mean particle size of 130 nm. In
      terms of preparation parameters, using the solvent displacement method, the
      nature and the volume of the organic solvent, the concentration of the amphiphile
      and the presence of a co-surfactant in the organic phase have been shown to
      affect significantly the size of the produced SLNs. In contrast, the stirring
      speed, the viscosity and the acidity of the aqueous phase and the amphiphile
      hydrophobic chain length have been shown to have no effect. In terms of stability
      parameters, the ionic strength has been shown to affect the short-time SLN
      stability depending on both the anion and the cation studied, with sodium
      sulphate causing precipitation. Ultrasonic, ultraviolet or microwave treatments
      of the SLN suspensions have no effect on the size of the SLNs. The study of the
      effects of short time thermal treatment revealed that the SLNs are not affected
      by one freezing-defreezing cycle and are stable at 100 degrees C in suspension.
      It is difficult to reconstitute the SLN suspensions after freeze-drying. Finally,
      the temporal stability of these suspensions in water has been shown to be
      superior to 1 year. The long-term temporal stability of suspensions stored in
      saline solution has been investigated. It has been demonstrated that the most
      destabilising effects arise from the presence in the storage suspension of
      sulphate ions.1H NMR, X-ray powder diffraction (XPD) and AFM have also been
      carried out on the calix-arene based SLNs and demonstrate the presence of a semi
      organised matrix structure for the SLNs.

PMID- 12593935
TI  - Novel high relaxivity colloidal particles based on the specific phase
      organisation of amphiphilic gadolinium chelates with cholesterol.
AB  - To obtain high T(1)-relaxivity colloidal particles with a simultaneously high
      loading of amphiphilic Gd-chelates, a novel drug dosage form based on the phase
      organisation of amphiphilic gadolinium chelates with cholesterol was developed.
      In order to find a formulation, which exhibit both high T(1)-relaxivity and gives
      small particles a D-optimal mixture design (experimental design) was applied.
      Gadolinium 1,4,7-tris(carboxymethyl)-10-(2-hydroxyhexadecyl)-1,4,7,10
      tetraazacyclododecane (Gd-HHD-DO3A) and cholesterol at approximately equimolar
      ratio proved to form thermodynamic stable disc-like colloidal particles as seen
      by cryo-electron micrographs. T(1)-relaxivity of these particles was typically
      around 20mM(-1)s(-1) and the size below 100 nm (photon correlation spectroscopy
      (PCS)). The particles do most probably not interact with blood components as no
      change in T(1)-relaxivity was observed when the particles were mixed with whole
      blood. The particles were stable at room temperature for at least 6 months.

PMID- 12593936
TI  - Effect of buffer media composition on the solubility and effective permeability
      coefficient of ibuprofen.
AB  - The effect of perfusion medium composition on the two important biopharmaceutical
      parameters drug solubility and permeability was determined for ibuprofen. Eight
      commonly used buffers were examined. Equilibrium solubility, buffer capacity
      profiles and permeability coefficients, using the in situ rat gut perfusion
      model, were determined for each medium at 37 degrees C. The solubility of
      ibuprofen differed sixfold over the range of buffer systems studied. The
      differences in solubility were associated with different pHs of the buffers when
      saturated with drug and also the presence of micelles and divalent ions. The
      solubility of ibuprofen in FeSSIF was significantly higher than predicted from
      the pH due to micellisation, while that in Krebs was significantly lower due to
      ibuprofen-calcium salt formation. Buffer capacities varied over a 40-fold range.
      The pK(a) values of the buffer components were determined from the buffer
      capacity versus pH profiles and were in good agreement with the thermodynamic
      values when corrected for temperature and ionic strength. Smaller, but
      statistically significant differences in P(app) values for ibuprofen were also
      observed between some of the buffers. During perfusion, pHs of the perfusate
      samples gradually changed over time towards a median value of approximately 6.5.
      HBSS gave a P(app) approximately 50% greater than that observed in PBS 7.4.
      Physicochemical factors such as medium pH, buffer capacity and osmolarity should
      be considered when determining the P(app) values of ionisable compounds. Care
      needs to be exercised when comparing P(app) values from different laboratories as
      buffer composition can have a significant effect on both solubility and
      permeability of a drug, whose ionisation is substantially changed over the pH
      range of the buffers. Despite the high amount ionised, ibuprofen appears to be
      well absorbed and it can be classified as a highly permeable drug.

PMID- 12593937
TI  - Characterisation of surface modified salbutamol sulphate-alkylpolyglycoside
      microparticles prepared by spray drying.
AB  - There were three aims of this work: (1). to study the suitability of spray drying
      to prepare surface modified microparticles coated with alkylpolyglycoside
      surfactants (for potential use in metered dose inhalation systems, although their
      use is not reported here); (2). to assess the utility of inverse phase gas
      chromatography (IGC) as a means of assessing the surface properties of modified
      microparticles; and (3). to attempt to relate dynamic surface tension
      measurements with the ability for a molecule to diffuse to a surface during spray
      drying. Microparticles of salbutamol sulphate-alkylpolyglycosides were prepared
      by spray drying from solution and then characterised using scanning electron
      microscopy, particle size analysis (laser diffraction) and inverse gas
      chromatography. Further to this, the critical micelle concentration (CMC) and the
      dynamic surface tension of alkylpolyglycosides were measured. Spray drying a
      solution of salbutamol sulphate with alkylpolyglycosides produced spherical
      amorphous microparticles with a diameter of less than 10 microm. The analysis of
      the surface energies of spray dried salbutamol sulphate showed that the addition
      of alkylpolyglycosides, at concentrations below and above their CMC, decreases
      substantially the basic component of the surface energy. This demonstrates that
      it is possible to sequentially modify the surface energy of the particles.
      Dynamic surface tension measurements of the alkylpolyglycosides above their CMC
      showed that the surfactant that has the least effect on the surface energy of the
      particles, presents the slowest diffusion in water. This may indicate that the
      diffusion of this particular molecule in water may be too slow to allow the
      surfactant to migrate to the surface of the microparticle during the drying
      process. IGC can be useful to analyse the surface energy of the particles after
      spray drying in order to assess the presence of the surfactant on the surface of
      the microparticles.

PMID- 12593938
TI  - In vitro cellular interaction and absorption of dispersed cubic particles.
AB  - A precursor type oily liquid formulation comprising monoolein, Pluronic F-127 and
      ethanol has been prepared as a carrier for lipophilic drugs. When dispersed in
      water, the liquid precursor formulation produces sub-micron (200-500 nm) sized
      lipid particles, named 'nanocubicles'. The interaction between nanocubicles and
      Caco-2 cell was studied, and the absorption of nanocubicles by cells was observed
      by various microscopic techniques. Lipid droplets were observed in cytosol after
      incubation with nanocubicles with time. The degree of pyrene absorption
      encapsulated in nanocubicles was dependent on particle size and incubation time.
      The amount of pyrene absorbed by Caco-2 cells was ca. 20% of total at 37 degrees
      C after an 8-h incubation. When nanocubicles with a bigger average particle size
      (ca. 600 nm) were applied, the uptake rate was reduced to 10% under identical
      experimental conditions. The nanocubicles were easily solubilized by bile salts
      to produce mixed micelles. As bile salt concentration increased, pyrene
      absorption into the jejunum of rat everted sac in vitro increased.

PMID- 12593939
TI  - Differentiated thermal crystallization from amorphous chenodeoxycholic acid
      between the ground specimens derived from the polymorphs.
AB  - Crystallization behavior of amorphous chenodeoxycholic acid (CDCA) was studied
      using X-ray diffraction (XRD), infrared (IR) spectroscopy and differential
      scanning calorimetry (DSC). The two polymorphs of CDCA, form I (mp 166 degrees C)
      and form III (mp 119 degrees C), were ground with a vibrational mill. The ground
      samples of both crystal forms showed halo X-ray diffraction patterns. DSC curves
      of the amorphous samples derived from the form I and form III showed exothermic
      peaks due to the crystallization to the form I at 120 and 147 degrees C,
      respectively. When the ground form III was mixed with the ground form I, the
      crystallization temperature shifted to a lower temperature as the content of the
      ground form I increased. In the case of co-ground sample of form I and form III,
      the crystallization to form I crystals proceeded by two different modes. These
      results indicate that the physicochemical state was different among the ground
      samples of the form I and form III, and that the crystal nuclei played an
      important role on the crystallization process of the amorphous CDCA.

PMID- 12593940
TI  - Formation of the dispersed particles composed of retinol and phosphatidylchiline.
AB  - The purpose of this study was to investigate the dispersal mechanism of retinol
      (Vitamin A, VA) into phospholipid. VA was dispersed with soybean
      phosphatidylcholine (PC) using sonication and the dispersal mechanism was
      evaluated by characterizing the dispersed particles using dynamic light
      scattering, fluorescence spectroscopy and surface monolayer techniques. The
      dispersions in the VA mole fraction range of 0.1-0.7 were stable at room
      temperature for 3 days. A limited amount of VA was incorporated into PC bilayer
      membranes (approximately 3 mol%). The excess VA separated from the PC bilayers
      was stabilized as emulsion particles by the PC surface monolayer. When the PC
      content was less than the solubility in VA (mole fraction of VA: more than 0.8),
      the PC monolayer did not completely cover the hydrophobic VA particle surfaces.
      In the case, the particle size increased drastically and the separation into
      oil/water occurred. The miscibility between VA and PC and the lipid composition
      were critically important for the stability of the dispersed particles
      (coexistence of emulsion particles (surface monolayer of PC+core of VA) with
      vesicular particles (bilayer)) of the lipid mixtures.

PMID- 12593941
TI  - Effect of PVP K-25 on the formation of the naproxen:beta-ciclodextrin complex.
AB  - The aim of this study was to investigate the effects of the presence of the water
      soluble polymer polyvinylpyrrolidone K-25 (MW=24000g/mol) on the complexation of
      the AINE naproxen, in its sodium salt form, with the beta-cyclodextrin. The data
      revealed that the polyvinylpyrrolidone K-25 interacts with the drug as well as
      with the drug:beta-cyclodextrin inclusion complex. The polymer shows more
      affinity for the inclusion complex, K=(6.67+/-0.292) x 10(-5)M(-1) than for the
      free drug, (2.08+/-0.208) x 10(-5)M(-1). The presence of different proportions of
      polymer, in a range 0-1% (w/w) of polyvinylpyrrolidone, does not increase the
      ability of drug-cyclodextrin complexation but important changes in the driving
      force of complex formation were detected, depending on the percentage of
      polyvinylpyrrolidone K-25 present. At low polymer concentrations, the
      complexation process is driven entropically, while at higher PVP proportions it
      is enthalpically favored. In the ternary system, polyvinylpyrrolidone K-25
      partially or totally coats the drug:beta-cyclodextrin inclusion complex
      interacting with the beta-cyclodextrin (through hydrogen bonds), and with the
      naproxen.

PMID- 12593942
TI  - An intravenous formulation decision tree for discovery compound formulation
      development.
AB  - Discovery and pre-clinical animal efficacy assessment formulation development
      efforts are challenged by limited compound availability and stringent timelines.
      The implementation and use of a systematic discovery formulation scheme can
      facilitate this important process. We observed that nearly 85% of Pfizer, Ann
      Arbor discovery compounds (n>300) submitted for discovery and pre-clinical
      injectable formulation development in the year 2000 could be formulated by pH
      adjustment, cosolvent addition, or a combination of the two approaches. Based on
      the vehicle data generated by this laboratory, a discovery formulation decision
      tree, that utilizes the solubilization approaches described above, is proposed.
      The proposed decision tree can be adapted and modified by pharmaceutical
      scientists to conform to best practices put forth by their institutions for
      discovery animal studies requiring injectable dosage forms.

PMID- 12593943
TI  - Circulation and biodistribution profiles of long-circulating PEG-liposomes of
      various sizes in rabbits.
AB  - To determine the largest size of liposomes that can retain stealth behavior
      conferred by poly(ethylene glycol)-DSPE, neutral liposomes were studied in
      rabbits for their circulation and distribution. Five sizes (136.2, 165.5, 209.2,
      275 and 318 nm) of liposomes (DSPC, Cholesterol, PEG-DSPE and alpha-tocopherol,
      90:80:4.5:3.9 molar ratio) were made by extrusion technique and radiolabeled with
      technetium-99m (Tc-99m) to follow their distribution through 24 h. Although all
      liposomes showed prolonged circulation in blood, the amount still in circulation
      at 24 h was dependent on their size. Radioactivity accumulation in spleen
      progressively increased with increase in size of the liposomes. In the size range
      of approximately 160-220 nm, liver uptake was minimum, spleen uptake was moderate
      while the amount of circulating liposomes was maximum. Gamma camera scintigraphy
      corroborated the distribution pattern of liposomes on necropsy. Images within 1h
      showed high blood pool activities for liposomes of all sizes. However, at 24h,
      the blood pool activity was diminished for 275 nm and negligible for 308 nm
      liposomes; the smaller sized liposomes (136.2-209.2 nm) continued to show high
      blood pool activity. The amounts of radioactivity still circulating at 24h were
      46.4, 50.4, 46.8, 36.2 and 14.5% for 136.2, 165.5, 209.2, 275 and 318 nm
      liposomes, respectively. Corresponding circulation T(1/2)s were 21.7, 26.5, 24.9,
      18.7 and 8.9h, respectively. Thus, the optimum size of PEG-liposomes for
      prolonged circulation in rabbits is 160-220 nm. Beyond this range, the stealth
      property of PEG-liposomes is significantly compromised and the distribution is
      characterized by high RES accumulation.

PMID- 12593944
TI  - Evaluation of gliadins nanoparticles as drug delivery systems: a study of three
      different drugs.
AB  - In this paper, biopolymer nanoparticles are studied, which unlike many synthetic
      carriers used for controlled release, are biocompatible and biodegradable
      systems. Gliadins nanoparticles are obtained by a desolvatation method, also
      known as drawning-out precipitation. These particles have been shown to be
      interesting as drug release systems for all-trans-retinoic acid. The aim of this
      paper was to study the influence of the polarity of different drugs on
      nanoparticle characteristics such as size and drug loading efficiency. Three
      drugs of three different polarities were studied: the hydrophobic Vitamin E (VE),
      the slightly polar mixture of linalool and of linalyl acetate (LLA) and the
      cationic amphiphilic benzalkonium chloride (BZC). This comparative work shows
      that the amount of the entrapped VE and LLA is higher than that of the cationic
      BZC, confirming a strong interaction between gliadins and apolar compounds, due
      to the apolarity of the proteins. This interaction results in a low diffusion
      coefficient and a partition coefficient in favour of gliadins, resulting in a low
      permeability coefficient. The drug release kinetics of two substances, LLA and
      BZC, are observed, in showing a burst effect, then a diffusion process, which can
      be modelled assuming that the particles are homogeneous spheres.

PMID- 12593945
TI  - Use of coated microtubular halloysite for the sustained release of diltiazem
      hydrochloride and propranolol hydrochloride.
AB  - Halloysite is a naturally occurring microtubular aluminosilicate mineral. The
      highly water soluble cationic drug, diltiazem HCl, was shown to bind to the
      polyanionic surfaces of the material to achieve a slight sustained release effect
      on dissolution testing due to reversible chemisorption and/or hindered release
      from the drug loaded lumen. A greater sustained release effect was more apparent
      when the less water soluble cationic drug, propranolol HCl, was examined.
      Attempts to further delay drug release by loading diltiazem HCl from a
      polyvinylpyrrolidone solution into the halloysite had little effect. However, a
      range of cationic polymers, including chitosan cross-linked with glutaraldehyde,
      was shown to bind to halloysite and was used to achieve significant delayed drug
      release. Coating with adequate polyethyleneimine was particularly effective at
      delaying drug release, being dependent on the architecture of the interaction
      between the polycation and the mineral. When a range of alkyl-2-cyanoacrylate
      monomers applied from a non-aqueous solvent by an in situ polymerisation
      procedure was examined, diltiazem HCl loaded halloysite dispersed in poly-iso
      butyl cyanoacrylate was found to be the most effective at reducing the burst
      effect noted with aqueous coating systems.

PMID- 12593946
TI  - Effect of Azone upon the in vivo antiviral efficacy of cidofovir or acyclovir
      topical formulations in treatment/prevention of cutaneous HSV-1 infections and
      its correlation with skin target site free drug concentration in hairless mice.
AB  - The purpose of this study is to examine the influence of Azone upon the skin
      target site free drug concentration (C(*)) and its correlation with the in vivo
      antiviral efficacies of cidofovir (HPMPC) and acyclovir (ACV) against HSV-1
      infections. Formulations of HPMPC and ACV with or without Azone were used. The in
      vitro skin flux experiments were performed and the C(*) values were calculated.
      For the in vivo efficacy studies, hairless mice cutaneously infected with HSV-1
      were used and three different treatment protocols were carried out. The protocols
      were chosen based upon when therapy is initiated and terminated in such a way to
      assess the efficacy of the test drug to cure and/or prevent HSV-1 infections. A
      finite dose of the formulation was topically applied twice a day for the
      predetermined time course for each protocol and the lesions were scored on the
      fifth day. For ACV formulation with Azone, the C(*) values and hence the in vivo
      efficacy were much higher than those for that without Azone. In protocol #1,
      however, early treatment did not increase the in vivo efficacy of ACV when
      compared with the standard treatment protocol #3. In protocol #2 where the
      treatment was terminated on the day of virus inoculation, the efficacies for both
      ACV formulations were completely absent. Although the estimated C(*) values for
      HPMPC formulations with and without Azone were comparable, formulation with Azone
      was much more effective than that without Azone in all treatment protocols. HPMPC
      formulations with Azone at similar flux values were much more effective in
      "treating and preventing" HSV-1 infections than those without Azone. For ACV
      formulations, in contrast, addition of Azone has failed to show any effect on the
      preventive in vivo antiviral efficacy and the enhancement of ACV in vivo
      antiviral efficacy was merely the skin permeation enhancement effect of Azone.

PMID- 12593947
TI  - Evaluation of the permeation of peat substances through human skin in vitro.
AB  - Peat and various peat extracts have been successfully applied for a variety of
      clinical indications. Quite apart from the physico-thermal effects, new studies
      point towards the so-called "chemical effects" of peat containing substances.
      These effects include a stimulatory response of the spontaneous contractile
      activity (SCA) of smooth muscle (SM) tissue. The effects are, however, dependent
      on the possible permeability of pharmacologically active substances as naturally
      occurring ingredients of peat. Since peat is a mixture of various products it is
      necessary to examine the various peat types based upon their biological activity
      on SM tissue. In order to unequivocally prove the pharmacological activity of
      cutaneous peat treatment, in vitro permeation measurements of these actives
      across excised human skin can be used.HPLC analysis revealed that aqueous peat
      extracts contain up to 18 fractions of water-soluble compounds of fulvic and
      ulmic acids. These compounds have been found to have a stimulatory response on
      the contractile activity of SM tissue. In vitro diffusion studies showed that the
      permeability of these substances across human full thickness skin (thickness: 200
      um(-1)) is highly selective and the resulting stimulatory activity is dependent
      on the permeated fraction. Especially, the HPLC fractions 7-11 and 14 are able to
      permeate human skin. Fractions 7-11 show a moderate stimulatory effect of SCA on
      SM for more than 90 min whereas fraction 14 shows the strongest stimulatory
      effect which was, however, suppressed after 87 min. These results show that the
      cutaneous therapy with peat treatment results in transcutaneaous permeation of
      biologically active fulvic and ulmic acid derivatives explaining the additional
      "chemical" effect of peat treatment in clinical practice.

PMID- 12593949
TI  - Short-term fluoride and cations release from polyacid-modified composites in a
      distilled water, and an acidic lactate buffer.
AB  - Fluoride and various cations release from three commercial compomers (Dyract,
      Dyract AP and Compoglass-F) and a resin-modified glass ionomer (Fuji-II LC) as a
      control were measured up to 7 days in distilled water and 0.01M lactate buffer
      solution with pH 4.1. The surface morphological change before and after the
      release experiment was observed with a scanning electron microscopy. Fluoride,
      aluminum and strontium ions were released from Dyract, Dyract AP and Fuji-II LC
      much more in the lactate buffer than in the distilled water. With compoglass-F
      containing barium instead of strontium, barium was released in the same way. X
      ray diffraction analysis confirmed that fluoride release from Dyract and Dyract
      AP was derived mainly from SrF(2) contained in Dyract and Dyract AP. However,
      fluoride release from Compoglass-F was derived from glassy phase though it
      contained much fluoride as YbF(3). Cumulative release amount of each species
      versus square root of time plot showed good linearity, indicating that the
      dissolution was controlled by the diffusion mechanism. The surface
      characteristics of disks for each material, which were immersed in the lactate
      buffer, were quite different from the surface before and after immersion in
      deionized water, especially with Dyract. After immersion in the lactate buffer,
      many voids which were left after dissolution of the filler particle, were seen
      obviously on the surface of Dyract.

PMID- 12593948
TI  - Physicochemical characterization and percutaneous delivery of 2,3,5,6
      tetramethylpyrazine.
AB  - The objective of this work is to investigate the percutaneous permeability of
      2,3,5,6-tetramethylpyrazine (TMP), an active ingredient originally isolated from
      Ligusticum wallichii Franch. Certain physicochemical properties of TMP, including
      its partition coefficient and pH-solubility profile, were studied. The influence
      of pH on the percutaneous permeation of TMP was studied in vitro using hairless
      mouse skin. Comparative in vitro permeability of TMP through hairless mouse, rat,
      rabbit, and human cadaver skin was also investigated. The results indicate that
      hairless mouse skin and rat skin were about three to four times more permeable to
      TMP than human cadaver skin. The permeability of TMP through rabbit skin was not
      significantly different from that of human cadaver skin. The observed lag times
      for all skin membranes were about 1-2h. Although pharmacokinetic data are not
      currently available to permit precise calculation of a clinically effective patch
      size, the data from this study indicate that the transdermal delivery of TMP
      should nevertheless be possible.

PMID- 12593950
TI  - Bone response to degradable thermoplastic composite in rabbits.
AB  - The aim of this study was to evaluate biologic behavior of a composite of
      bioactive glass (BAG) (S53P4) and copolymer of poly(epsilon-caprolactone-co-DL
      lactide) in experimental bone defects in rabbits. Twenty New Zealand white
      rabbits were used for the study. Bone defects (4 x 6mm) were prepared in the
      medial surfaces of the femoral condyles and the tibia. Cavities were filled with
      three different composites: composite with 60 wt% of small BAG granules (granule
      size <45 microm) and composites with 40 and 60 wt% of large BAG granules (granule
      size 90-315 microm). Copolymer without BAG was used as a reference material.
      Follow-up period was 8 and 16 weeks. In the femur at 8 weeks all the samples were
      partly surrounded by fibrous capsule. New bone formation was noticed in the areas
      where glass granules were in direct contact with the bone. At 16 weeks fibrous
      capsule was thinner in all samples. Bone ingrowth was found in the superficial
      layers of the composites with large glass granules. However, the percent of
      direct bone contact decreased between 8 and 16 weeks (p < 0.05). In the tibia at
      8 weeks all the samples showed fibrous encapsulation. At 16 weeks fibrous
      capsules were thinner or occasionally disappeared. Bone ingrowth was noticed in
      the samples with large glass granules. Further, new bone formation was found in
      the medullary cavity. No signs of polymer degradation were seen at any time
      point. It can be concluded that the composite of BAG (S53P4) and copolymer of
      poly(epsilon-caprolactone-co-DL-lactide) is biocompatible with the bone tissue
      within the 16 weeks implantation period.

PMID- 12593951
TI  - Transmission electron microscopic investigation of a Pd-Ag-In-Sn dental alloy.
AB  - With the price volatility of palladium, there has been renewed interest in
      palladium-silver alloys for metal-ceramic restorations in dentistry. The
      microstructures of a popular Pd-Ag dental alloy were investigated in the as-cast
      and simulated porcelain-firing heat-treated conditions, using transmission
      electron microscopy. In the as-cast condition, the microstructure was strongly
      influenced by microsegregation, and contained the face-centered cubic Pd solid
      solution matrix, a eutectic structure with lattice parameters that varied for the
      two phases, and a face-centered tetragonal (fct) precipitate. After heat
      treatment, the lattice parameters for the two phases in the eutectic structure
      were uniform, and discontinuous precipitates with [011](matrix) habit planes and
      dislocations appeared in the matrix. An unusual nanostructured constituent was
      found in the fct set of eutectic lamellae in the heat-treated alloys.

PMID- 12593952
TI  - Microcontact printing of novel co-polymers in combination with proteins for cell
      biological applications.
AB  - Microcontact printing (microcP) is a cost effective and simple method to create
      chemically micropatterned surfaces for cell biological applications. We have
      combined the technique with the spontaneous molecular assembly of a polycationic
      PEG-grafted copolymer, poly-L-lysine-g-poly(ethylene glycol) (PLL-g-PEG). PLL-g
      PEG with omega-functionalized PEG chains was print-transferred onto tissue
      culture polystyrene (TCPS) or glass substrates, resulting in patterns with a
      lateral resolution down to 1 microm. Subsequently, dipping in an aqueous solution
      of non-functionalized PLL-g-PEG was used to backfill the non-printed regions of
      the surface, rendering them highly protein and thus cell resistant. In a second
      approach, proteins were stamped and a PLL-g-PEG backfill was applied for
      passivation of the bare surface regions. Printing of peptide(RGD)-functionalized
      PLL-g-PEG or proteins combined with a subsequent PLL-g-PEG backfill can be
      applied to a wide variety of substrate materials with negatively charged surfaces
      such as TCPS, glass and many metal oxides. We have tested the printed surfaces
      with human foreskin fibroblasts for cell adhesion and long-term performance and
      with fish epidermal keratocytes for cell motility and short-time behaviour. Both
      cell types reacted selectively to the surface micropatterns. Fibroblasts adhered
      to the printed (adhesive) regions only, where they remained attached up to at
      least 1 week and were even able to proliferate. Keratocyte spreading and motility
      were also directed by the geometry of the underlying patterns. The results prove
      that microcP in conjunction with the use of PLL-g-PEG and its derivatives
      provides a simple and robust alternative to previously reported micropatterning
      methods for future cell biological and biotechnological applications.

PMID- 12593953
TI  - Effect of molecular weight of poly(epsilon-caprolactone) on interpenetrating
      network structure, apatite-forming ability, and degradability of poly(epsilon
      caprolactone)/silica nano-hybrid materials.
AB  - The effect of molecular weight of poly(epsilon-caprolactone) (PCL) on the
      bioactivity of a PCL/silica nano-hybrid containing calcium salt was investigated.
      Two hybrids were prepared with low and high molecular weight PCLs, respectively,
      through a sol-gel method. Their bioactivities were evaluated using a simulated
      body fluid (SBF), which had almost the same ion concentrations with human blood
      plasma. Fast and uniform nucleation and growth of the apatite crystals were
      observed to occur all through the hybrid surface when low molecular weight PCL
      was used, while slow and random nucleation and growth of the apatite crystals
      were observed to occur when high molecular weight PCL was used, after soaking for
      3 days in the SBF. This phenomenon was explained in terms of the distribution and
      dispersion of silica phase in the hybrid and the ionic activity product of the
      apatite in the SBF, which were dependent on the free volume and degradation rate
      of non-bioactive PCL phase, respectively.

PMID- 12593954
TI  - Bonelike apatite formation on ethylene-vinyl alcohol copolymer modified with
      silane coupling agent and calcium silicate solutions.
AB  - An ethylene-vinyl alcohol copolymer (EVOH) was treated with a silane coupling
      agent and calcium silicate solutions, and then soaked in a simulated body fluid
      (SBF) with ion concentrations approximately equal to those of human blood plasma.
      A smooth and uniform bonelike apatite layer was successfully formed on both the
      EVOH plate and the EVOH-knitted fibers in SBF within 2 days. Part of the
      structure of the resulting apatite-EVOH fiber composite was similar to that of
      natural bone. If this kind of composite can be fabricated into a three
      dimensional structure similar to natural bone, the resultant composite is
      expected to exhibit both mechanical properties analogous to those of natural bone
      and bone-bonding ability. Hence, it has great potential as a bone substitute.

PMID- 12593955
TI  - Casting behavior of titanium alloys in a centrifugal casting machine.
AB  - Since dental casting requires replication of complex shapes with great accuracy,
      this study examined how well some commercial titanium alloys and experimental
      titanium-copper alloys filled a mold cavity. The metals examined were three types
      of commercial dental titanium [commercially pure titanium (hereinafter noted as
      CP-Ti), Ti-6Al-4V (T64) and Ti-6Al-7Nb (T67)], and experimental titanium-copper
      alloys [3%, 5% and 10% Cu (mass %)]. The volume percentage filling the cavity was
      evaluated in castings prepared in a very thin perforated sheet pattern and cast
      in a centrifugal casting machine. The flow behavior of the molten metal was also
      examined using a so-called "tracer element technique." The amounts of CP-Ti and
      all the Ti-Cu alloys filling the cavity were similar; less T64 and T67 filled the
      cavity. However, the Ti-Cu alloys failed to reach the end of the cavities due to
      a lower fluidity compared to the other metals. A mold prepared with specially
      designed perforated sheets was effective at differentiating the flow behavior of
      the metals tested. The present technique also revealed that the more viscous Ti
      Cu alloys with a wide freezing range failed to sequentially flow to the end of
      the cavity.

PMID- 12593956
TI  - Bone tissue reconstruction using titanium fiber mesh combined with rat bone
      marrow stromal cells.
AB  - The study aim was to evaluate the effect of bone marrow stromal cells (BMSCs)
      cultured in titanium fiber mesh and implanted in a rat cranial defect. A total of
      24 titanium meshes were placed in a tube containing 10 ml BMSC suspension (3 x
      10(6)cells/ml) and the tube was rotated on a rotation plate (2 rpm) during 3 h.
      Thereafter, meshes with cells were subcultured for 1 day under standard
      conditions. Cell-loaded implants and non-cell-loaded controls were placed in a 8
      mm cranial defect and retrieved after 3, 15 and 30 days of implantation.
      Histology showed that after 3 days of implantation, the mesh porosity of both
      implant groups was mainly invaded with blood cells. On the other hand, at 15 days
      of implantation, the cell-loaded implants were filled for 15 +/- 10% of their
      volume with bone, while the controls showed 1.5 +/- 3.5% of bone. The 30-day cell
      loaded implants showed 40 +/- 12.5% of bone and the 30-day control implants 17 +/
      14.5%. At both implantation times the differences were statistically
      significant. Therefore, we conclude that inoculation of titanium fiber mesh with
      BMSCs can improve the bone healing capacity of this material.

PMID- 12593957
TI  - Cathepsin B as a soluble marker to monitor the phenotypic stability of engineered
      cartilage.
AB  - The clinical need for improved human autologous chondrocyte transplantation has
      motivated the use of different biomaterials, which are aimed at fixing the cells
      in the defect area and permit their proliferation and differentiation. The
      maintenance of the original phenotype by isolated chondrocytes grown in vitro is
      an important requisite for their use in repairing damaged articular cartilage.
      The methods to verify the expression of cartilage-specific molecules usually
      involve destructive procedures to recover the cells from the scaffolds for tests.
      The aim of our study was to find a soluble marker able to attest the occurrence
      of a differentiation process by chondrocytes grown onto a biomaterial used for
      cell transplantation. We turned our attention to cathepsin B which is known to be
      abnormally synthesized in de-differentiated chondrocytes and scarcely produced in
      the differentiated ones. The production of cathepsin B by human articular
      chondrocytes expanded in vitro and then grown onto a hyaluronan-based polymer
      derivative (Hyaff-11) three-dimensional scaffold was evaluated with a specific
      enzyme-immunoassay at different experimental times together with the expression
      of mRNA by real-time PCR. We showed that cathepsin B, which is abundantly
      produced by chondrocytes grown in a monolayer culture, decreases significantly
      after the cells are seeded onto the scaffold, giving further evidence of a re
      differentiation process. This result suggests cathepsin B a practical soluble
      marker to evaluate the "good" quality of transplantable constructs.

PMID- 12593958
TI  - Engineering cell adhesive surfaces that direct integrin alpha5beta1 binding using
      a recombinant fragment of fibronectin.
AB  - Integrin receptors mediate cell adhesion to extracellular matrices and trigger
      signals that direct cell function. While many integrins bind to the arginine
      glycine-aspartic acid (RGD) motif present in numerous extracellular proteins,
      integrin alpha(5)beta(1) requires both the PHSRN synergy site in the 9th and the
      RGD site in the 10th type III repeat of fibronectin (FN). Binding of
      alpha(5)beta(1) to FN is critical to many cellular processes, including
      osteoblast and myoblast differentiation. This work focused on engineering
      integrin-specific bioadhesive surfaces by immobilizing a recombinant FN fragment
      (FNIII(7-10)) encompassing the alpha(5)beta(1) binding domains of FN. Model
      hybrid surfaces were engineered by immobilizing FNIII(7-10) onto passively
      adsorbed, non-adhesive albumin. Homo- and hetero-bifunctional crosslinkers of
      varying spacer-arm length targeting either the cysteine or lysine groups on
      FNIII(7-10) were investigated in ELISA and cell adhesion assays to optimize
      immobilization densities and activity. FN-mimetic surfaces presenting controlled
      densities of FNIII(7-10) were generated by varying the concentration of FNIII(7
      10) in the coupling solution at a constant crosslinker concentration. Cells
      adhered to these functionalized surfaces via integrin alpha(5)beta(1) and
      blocking with integrin-specific antibodies completely eliminated adhesion. In
      addition, adherent cells spread and assembled focal adhesions containing
      alpha(5)beta(1), vinculin, and talin. This biomolecular engineering strategy
      represents a robust approach to increase biofunctional activity and integrin
      specificity of biomimetic materials.

PMID- 12593959
TI  - Microcapsules with improved mechanical stability for hepatocyte culture.
AB  - Packed-bed or fluidized-bed bioreactor filled with microencapsulated hepatocytes
      has been proposed as one of the promising designs for bioartificial liver assist
      device (BLAD) because of potential advantages of high mass transport rate and
      optimal microenvironment for hepatocyte culture. Recently, we have developed a
      microcapsule system for the encapsulation of hepatocytes. The microcapsules
      consist of an inner core of modified collagen and an outer shell of terpolymer of
      methyl methacrylate, methacrylate and hydroxyethyl methacrylate. Cells
      encapsulated in these microcapsules exhibit enhanced cellular functions.
      Improving the mechanical stability of the microcapsules to withstand the shear
      stress induced by high perfusion rate would be crucial to the success of BLAD
      applications. In this study, we investigated the effects of terpolymer molecular
      weight (M(w)) on the mechanical property of these microcapsules and the
      differentiated functions of encapsulated hepatocytes. Six terpolymers with
      different M(w) were synthesized using radical polymerization in solution by
      adjusting the reaction temperature and the initiator concentration. All the
      terpolymers formed microcapsules with the methylated collagen. While the
      terpolymer M(w) had little effect on the capsule membrane thickness and
      permeability of serum albumin, the mechanical property of the microcapsules was
      significantly improved by the higher M(w) of the terpolymer. Differentiated
      functions of the hepatocytes cultured in the microcapsules, including urea
      synthesis, albumin synthesis and cytochrome P450 metabolic activity, were not
      significantly affected by the terpolymer M(w).

PMID- 12593960
TI  - The production and characteristics of solid lipid nanoparticles (SLNs).
AB  - Modified high shear homogenization and ultrasound techniques were employed to
      produce solid lipid nanoparticles (SLNs). Model drug mifepristone had been
      incorporated in SLNs. The mean particle size measured by laser diffractometry
      (LD) was found to be 106 nm with a narrow particle distribution of polydispersity
      index, 0.278. Differential scanning calorimetry and X-ray diffraction
      measurements suggested that the majority of the SLNs were less ordered
      arrangement of crystals, and this was favorable for increasing the drug loading
      capacity. The drug entrapment efficiency (EE%) of SLNs was more than 87 percent
      and showed relatively long-term physical stability as the leakage was very small
      after being stored for one month. Therefore, seemed this modified method could
      prepare high quality SLNs loading lipophilic drugs. It is a simple, available and
      effective method to produce SLNs.

PMID- 12593961
TI  - Photoinitiator dependent composite depth of cure and Knoop hardness with halogen
      and LED light curing units.
AB  - Light curing units (LCUs) are used for the polymerization of dental composites.
      Recent trends in light curing technology include replacing the halogen LCUs with
      LCUs using light emitting diodes (LEDs) reducing curing times and varying the
      LCUs light output within a curing cycle. This study investigated the time
      dependence of the Knoop hardness and depth of cure of dental composites
      polymerized with a halogen LCU (Trilight) and two LED LCUs (the commercial
      Freelight and custom-made LED LCU prototype). The halogen LCU was used in the
      soft-start (exponential increase of output power) and standard mode. Four dental
      composites (Z100, Spectrum, Definite, Solitaire2) were selected, two of them
      (Definite, Solitaire2) contain co-initiators in addition to the standard
      photoinitiator camphorquinone. The depth of cure obtained with the Trilight in
      the standard mode was statistically significantly greater (p < 0.05) than that
      obtained with the LED LCUs for all materials and curing times. The custom made
      LED LCU prototype (LED63) achieved a statistically significantly greater depth of
      cure than the commercial LED LCU Freelight for all materials and curing times.
      There was no statistical difference in Knoop hardness at the 95% confidence level
      at the surface of the 2 mm thick sample between the LED63 or Trilight (standard
      mode) for the composite Z100 for all times, and for Spectrum for 20s and 40s
      curing time. The composites containing co-initiators showed statistically
      significantly smaller hardness values at the top and bottom of the samples if LED
      LCUs were used instead of halogen LCUs. The experiment revealed that the depth of
      cure test does not and the Knoop hardness test does discriminate between LCUs,
      used for the polymerization of composites containing photoinitiators in addition
      to camphorquinone.

PMID- 12593962
TI  - The effect of increasing copper content in phosphate-based glasses on biofilms of
      Streptococcus sanguis.
AB  - This paper reports the effect of a series of phosphate-based glasses based on the
      Na(2)O-CaO-P(2)O(5) system doped with increasing amounts of copper and the effect
      of this increasing copper content on the viability of an in vitro biofilm of
      Streptococcus sanguis over an 8 day period in a constant depth film fermenter.
      The addition of copper to the glass caused the solubility to change, so the
      glasses were adjusted in order that their solubility in artificial saliva was
      nominally the same (0.3062 +/- 0.07 mg cm(-2) h(-1)). Initial experiments on
      glasses with 1.5% and 10% copper showed that after 6 h there was no statistical
      difference between the copper containing glasses and the non-copper containing
      glass and HA in terms of the viability of the biofilms. However, at 24 h there
      was an approximately 0.8-0.9 log reduction in viability of the biofilms grown on
      the 5% copper glass and an approximately 1.0-1.3 log reduction for the 10% copper
      containing glass. Further experiments on the glass with 10% copper and another
      glass with 15% copper were carried out in a time dependent study. For both
      glasses a clear decrease in viable counts at 24 h was found but for both glasses
      these returned to levels similar to those of controls. The initial decrease in
      viability during the first 24 h is likely to be due to the antibacterial effect
      of the copper and this could be correlated with copper content. The recovery
      after 24 h is probably due to the dead cells forming a barrier, making diffusion
      of the antibacterial ions, increasingly difficult. This study has shown that
      phosphate-based glasses could potentially be used to deliver antibacterial ions
      to help combat oral infections. Copper, which has been shown to have
      antibacterial properties, could be incorporated but some development of the
      glasses used in this investigation may be required. Further work is needed to
      determine the effectiveness of copper containing glasses on oral bacterial
      communities.

PMID- 12593963
TI  - Polymerization and light-induced heat of dental composites cured with LED and
      halogen technology.
AB  - Most commercial light curing units (LCUs) for dental applications use
      conventional halogen bulbs. Commercial LCUs using light emitting diodes (LEDs)
      have recently become established on the market, even though some aspects of their
      performance have not been fully investigated. Temperature rise of dental
      composites during the light-induced polymerization is considered to be a
      potential hazard for the pulp of the tooth. This study, therefore, investigated
      the temperature rise in three different composites (Z100, Durafill, Solitaire2)
      in two shades (A2, A4) polymerized for 40s with two LED LCUs (Freelight, custom
      made LED LCU prototype) and two halogen LCUs (Trilight, Translux). The Trilight
      was used in the standard and soft-start mode. The temperature rise within the
      composites were recorded for 60s with a thermocouple and also observed with a
      high-resolution infrared (HRIR) camera. The factors LCU (p < 0.0001), composite
      (p < 0.0001) and shade (p = 0.0014) had statistically significant influences on
      the temperature rise. All composites cured with the halogen LCUs reached at a
      depth of 2 mm, a statistically significant higher temperature (p < 0.0001) than
      those cured with the LED LCUs. Only one composite showed a statistically
      significant lower temperature rise for the halogen LCUs at the 95% confidence
      level, when the soft-start mode was used instead of the standard mode. In
      general, the composites with the lighter shade (A2) reached higher temperatures
      than the darker shade (A4), if the LED LCUs were used. When the halogen LCUs were
      used, the situation was reversed, the composites with the darker shade (A4)
      reaching higher temperatures than the lighter shade (A2). This study showed that
      a HRIR camera represents a powerful tool for the observation of temperature
      propagation on small samples. This study also showed that LED LCUs represent a
      viable alternative to halogen LCUs for the light polymerization of dental
      composites because of a generally lower temperature increase within the
      composite.

PMID- 12593964
TI  - Acid pretreatment of titanium implants.
AB  - The purpose of this study was to evaluate the effectiveness of several methods of
      cleaning titanium surfaces as pretreatment for surface modifications by analyzing
      the chemical interaction of three acids, such as Na(2)S(2)O(8),H(2)SO(4) and HCl,
      followed by rinsing with acetone or ultrapure water. Chemical evaluation, using X
      ray photoelectron spectroscopy (XPS), and mechanical evaluation, using
      nanoindentation, were employed. XPS revealed that an untreated Ti surface
      consisted of carbon- and nitrogen-containing contaminant and titanium oxide layer
      on metallic titanium substrate. The method involving the combination of 10 N HCl
      and acetone was the most effective of all the methods investigated. Such a
      combination most effectively reduced values of contamination parameters C/Ti and
      N/Ti, as well as the intensity of the titanium oxide component in Ti 2p spectra.
      Chlorine was barely detected from the surface treated with HCl in any
      concentration. Sulfur from the residual S(2)O(8)(2-) or SO(4)(2-), however, was
      detected from the samples treated with either Na(2)S(2)O(8) or H(2)SO(4). The
      S/Ti values depended on concentration of the acidic solution. In addition,
      nanoindentation measurements revealed that Young's modulus of the surface treated
      with 0.1-10 N HCl was not significantly different from that of an untreated
      surface (p > 0.05). Consequently, the HCl/acetone treatment is proposed as an
      excellent decontamination method for the surface preparation process of Ti.

PMID- 12593965
TI  - Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads
      after 5 years of implantation.
AB  - In infected joint arthroplasty, high local levels of antibiotics are achieved
      through temporary implantation of non-biodegradable gentamicin-loaded
      polymethylmethacrylate beads. Despite their antibiotic release, these beads act
      as a biomaterial surface to which bacteria preferentially adhere, grow and
      potentially develop antibiotic resistance. In routine clinical practice, these
      beads are removed after 14 days, but for a variety of reasons, we were confronted
      with a patient in which these beads were left in situ for 5 years. Retrieval of
      gentamicin-loaded beads from this patient constituted an exceptional case to
      study the effects of long-term implantation on potentially colonizing microflora
      and gentamicin release. Gentamicin-release test revealed residual antibiotic
      release after being 5 years in situ and extensive microbiological sampling
      resulted in recovery of a gentamicin-resistant staphylococcal strain from the
      bead surface. This case emphasizes the importance of developing biodegradable
      antibiotic-loaded beads as an antibiotic delivery system.

PMID- 12593966
TI  - Brachyspira hyodysenteriae contains eight linked gene copies related to an
      expressed 39-kDa surface protein.
AB  - A tandemly linked set of four open reading frames (ORFs), identified as vspA-D
      (variable surface protein) had been identified from previous cloning and
      sequencing of clones from a genomic library constructed from Brachyspira
      hyodysenteriae strain B204. The predicted translation products of these closely
      related genes were homologous to (but not identical with) a characterized 39-kDa
      surface-exposed membrane protein from this animal pathogen. Additional screening
      of the genomic library has been performed to retrieve what are believed to be
      additional vsp genes including the one expected to encode this 39-kDa protein.
      Four new vsp genes have been identified and found to be associated in a second
      set of four tandemly linked alleles. This new gene cluster of 7481 nucleotides is
      not adjacent to the original vspA-D gene cluster described but does appear to
      have arisen from a gene (region) duplication event. The new vsp genes (identified
      as vspE-H) are oriented parallel to one another and appear to have a set of
      similar but distinct regulatory elements that may control separate expression of
      their ORFs. The four adjacent ORFs are of similar size (361-390 codons) and share
      from 83% to 90% identity in their amino acid sequence. The organization and
      homologies of these highly conserved multiple gene copies are discussed.

PMID- 12593967
TI  - Characterization of the immune response to Leishmania infantum recombinant
      antigens.
AB  - Leishmaniases have a high prevalence in tropical countries. In order to improve
      existing diagnostic systems based on total Leishmania proteins, and to identify
      antigen candidates for vaccine development, an intensive search for the
      identification of antigens was performed using molecular biology techniques. In
      this study, the immune response to three L. infantum recombinant antigens was
      evaluated. Upon stimulation with KMP11, mononuclear cells from leishmaniasis
      patients produced high levels of IL-10, while a predominant IFN-gamma production
      could be observed in cultures stimulated with H2A and soluble Leishmania antigen.
      All the recombinant antigens induced very little IL-5. KMP11 decreased IFN-gamma
      production by 48% in cultures of peripheral blood mononuclear cells from
      cutaneous leishmaniasis patients who had been stimulated with soluble Leishmania
      antigen. Furthermore, antibodies to KMP11 were detected in the sera from all
      patients with visceral leishmaniasis and in the majority of the sera from
      patients with cutaneous leishmaniasis or individuals with asymptomatic L. chagasi
      infection. Thus, KMP11 is recognized by cells and sera of patients with different
      clinical forms of leishmaniasis, and KMP11, through IL-10 production, proved to
      be a potent antigen in modulating type 1 immune response.

PMID- 12593968
TI  - Affinity of Helicobacter pylori to cholesterol and other steroids.
AB  - Helicobacter pylori has a particular affinity to cholesterol. It is not known,
      however, whether other steroidal substances are bound as well. In order to
      characterize the specificity and nature of the H. pylori-steroid interaction, the
      affinity of H. pylori to cholesterol and several steroidal hormones was
      investigated. Seven strains of H. pylori (five reference strains, two wild
      strains) and one strain each of Staphylococcus epidermidis and Escherichia coli
      were cultured on a cholesterol-free medium. Cholesterol-free bacteria were
      incubated with cyclodextrin-mediated cholesterol and several cyclodextrin
      mediated steroidal hormones (beta-estradiol, testosterone, progesterone,
      hydrocortisone, dexamethasone). The steroid contents of the bacteria were
      determined by gas liquid chromatography. High amounts of cholesterol were
      detected in all H. pylori strains, whilst steroidal hormones were not found.
      Neither S. epidermidis nor E. coli showed an appreciable amount of cholesterol in
      the chromatographic examinations. Bacterial pretreatment with proteinase K
      diminished cholesterol adsorption of H. pylori. These data indicate a specific
      affinity of H. pylori to cholesterol. This unique property might serve as a
      pathogenicity component enabling survival and colonization of H. pylori in the
      gastric environment.

PMID- 12593969
TI  - Enhanced pathogenicity of susceptible strains of the Bacteroides fragilis group
      subjected to low doses of metronidazole.
AB  - Different concentrations of metronidazole are used widely to treat protozoan and
      fungal infections. As an antibacterial drug, metronidazole is mainly used against
      anaerobes, of which the Bacteroides fragilis group is the most important in terms
      of the frequency of recovery and antimicrobial resistance patterns. The objective
      of this study was to investigate (1) in vivo metronidazole-induced modifications
      in the B. fragilis group reflected by altered virulence, and (2) the interference
      of metronidazole in cellular viability of these samples when subjected in vitro
      to human polymorphonuclear leukocytes (PMNs). Strains adapted to low
      metronidazole concentrations were observed to be more virulent, as demonstrated
      experimentally in mice by weight loss, quantitative evidence of tissue damage,
      hemorrhage and anatomopathology of spleen, liver and small intestine samples. A
      significant increase (P < 0.05) in mean bacterial viability rate of about 2.62
      fold was observed for all the drug-adapted strains after contact with human PMNs.
      However, the level of this phenomenon was quite different among the tested
      species. These results draw attention to the risk that prolonged therapy, even
      with low concentrations of metronidazole, may affect the pathogenicity of
      Bacteroides strains, producing changes in host-bacteria relationships.

PMID- 12593970
TI  - Antineutrophil cytoplasmic antibodies directed against bactericidal/permeability
      increasing protein detected in children with cystic fibrosis inhibit neutrophil
      mediated killing of Pseudomonas aeruginosa.
AB  - Antineutrophil cytoplasmic antibodies (ANCA) directed against
      bactericidal/permeability-increasing protein (BPI) were repeatedly found in
      cystic fibrosis (CF) patients. We analyzed the effect of BPI-ANCA in inhibiting
      neutrophil-mediated killing of Pseudomonas aeruginosa. The bactericidal effect
      expressed as percentage of killed bacteria after 1 h incubation with neutrophils
      was 55% when the neutrophils were pretreated with normal human serum, ranged from
      49 to 63% with the sera from control BPI-ANCA-negative groups and sharply
      decreased to the mean 30.5% (range 8-51%) in the presence of BPI-ANCA.
      Furthermore, the effect mediated by BPI-ANCA was dose dependent and reflected the
      titer of BPI-ANCA in tested sera.

PMID- 12593971
TI  - The NKG2D receptor and its ligands-recognition beyond the "missing self"?
AB  - NKG2D is a surface receptor that activates natural killer (NK) cells and delivers
      a co-stimulatory signal to CD8-positive T cells. The ligands of NKG2D are induced
      by cellular stress and are specifically expressed by some tumor cells. This
      sparked the idea of an alternative regulation of NK cells by expression of
      "induced self" ligands on target cells which can overcome the inhibition imparted
      by MHC class I-specific inhibitory receptors.

PMID- 12593972
TI  - Generation of major histocompatibility complex class I antigens.
AB  - Presentation of antigenic peptides by major histocompatibility complex (MHC)
      class I molecules on the surface of antigen-presenting cells is an effective
      extracellular representation of the intracellular antigen content. The
      intracellular proteasome-dependent proteolytic machinery is required for
      generating MHC class I-presented peptides. These peptides appear to be derived
      mainly from newly synthesized defective ribosomal products, ensuring a rapid
      cytotoxic T lymphocyte-mediated immune response against infectious pathogens.
      Here we discuss the generation of MHC class I antigens on the basis of the
      currently understood molecular, biochemical and cellular mechanisms.

PMID- 12593974
TI  - Target cells in vaginal HIV transmission.
AB  - Understanding the mechanisms of HIV transmission to women will be crucial to the
      development of effective strategies to curb this epidemic. Current data suggest
      that HIV has at least two routes to penetrate the vaginal epithelium and reach
      lymphoid tissues, trans-epithelial migration of infected Langerhans cells or
      virus penetration into the lamina propria through loss of epithelial integrity
      resulting in direct infection of lymphocytes, dendritic cells and macrophages.

PMID- 12593973
TI  - Innate immunity is regulated by CD38, an ecto-enzyme with ADP-ribosyl cyclase
      activity.
AB  - Through its production of cyclic adenosine diphosphate ribose, the ecto-enzyme
      CD38 regulates calcium mobilization in neutrophils responding to some, but not
      all, chemoattractants. This signaling defect results in reduced chemotaxis of
      CD38-deficient neutrophils to bacterial peptides and increased susceptibility of
      CD38-deficient mice to bacterial infections.

PMID- 12593975
TI  - Robert Koch.
AB  - This article traces the origins of bacteriological research, with particular
      attention to the role of Robert Koch, and his postulates, on infectious agents.
      By chronologically following Koch's work on anthrax, germ photography and
      tuberculosis, it shows how the visual representation of germs transformed
      laboratory research in medical science.

PMID- 12593977
TI  - Genetic control of Drosophila nerve cord development.
AB  - The Drosophila ventral nerve cord has been a central model system for studying
      the molecular genetic mechanisms that control CNS development. Studies show that
      the generation of neural diversity is a multistep process initiated by the
      patterning and segmentation of the neuroectoderm. These events act together with
      the process of lateral inhibition to generate precursor cells (neuroblasts) with
      specific identities, distinguished by the expression of unique combinations of
      regulatory genes. The expression of these genes in a given neuroblast restricts
      the fate of its progeny, by activating specific combinations of downstream genes.
      These genes in turn specify the identity of any given postmitotic cell, which is
      evident by its cellular morphology and choice of neurotransmitter.

PMID- 12593978
TI  - Induction and patterning of neuronal development, and its connection to cell
      cycle control.
AB  - Nervous tissue is derived from early embryonic ectoderm, which also gives rise to
      epidermal derivatives such as skin. The progression from naive ectoderm to
      differentiated postmitotic neurons involves multiple steps, two of which are
      crucial in shaping the final neurogenesis pattern. First, is the identification
      of the neural plate by the process of neural induction. Second, is the selection
      of a restricted number of sites within the neural plate where neurogenesis, the
      process leading to final differentiation of neural precursors, is initiated.
      Recent findings point to the existence of positive inducers of the neural state,
      whereas, neurogenesis initiation sites appear to be largely defined by
      inhibition. However, both neural induction and the initiation of neurogenesis
      appear to be connected to cell cycle control systems that govern whether stem
      cell maintenance and cell proliferation, or cell specification and
      differentiation, take place.

PMID- 12593979
TI  - Cell cycle and cell fate interactions in neural development.
AB  - Mechanisms coupling cell cycle and cell fate operate at different steps during
      neural development. Intrinsic factors control the cell proliferation of distinct
      brain regions and changes of cell fate competence, whereas components of the cell
      cycle machinery could play a major role in setting the appropriate timing of the
      generation of different cell types.

PMID- 12593980
TI  - Neurons from radial glia: the consequences of asymmetric inheritance.
AB  - Recent work suggests that radial glial cells represent many, if not most, of the
      neuronal progenitors in the developing cortex. Asymmetric cell division of radial
      glia results in the self-renewal of the radial glial cell and the birth of a
      neuron. Among the proteins that direct cell fate in Drosophila melanogaster that
      have known mammalian homologs, Numb is the best candidate to have a similar
      function in radial glia. During asymmetric divisions of radial glial cells, the
      basal cell may inherit the radial glial fibre, while the apical cell sequesters
      the majority of the Numb protein. We suggest two models that make opposite
      predictions as to whether the radial glia or nascent neuron inherit the radial
      glial fiber or the majority of the Numb protein.

PMID- 12593981
TI  - Specification of dorsal spinal cord interneurons.
AB  - To obtain the correct number of each neuronal subtype, there must be mechanisms
      to control progenitor pool size, and factors that control the differentiation of
      these progenitors into specific types of neurons. In the dorsal spinal cord,
      recent advances have begun to define these mechanisms. Eight dorsal interneuron
      populations have now been classified according to their expression of molecular
      markers, their projection patterns, neurotransmitter type, and/or function. The
      ability to identify progenitor cells and neurons in the dorsal spinal cord on the
      basis of the genes they express has provided a framework for identifying
      extrinsic factors that establish proliferation rate and dorsal-ventral polarity
      in the developing neural tube; furthermore, this ability has helped define roles
      for basic helix-loop-helix and homeodomain transcription factors in neuronal cell
      type specification.

PMID- 12593982
TI  - Dorsal-ventral patterning in the mammalian telencephalon.
AB  - The telencephalon is the most diverse region of the brain with respect to both
      morphology and neuronal subtypes. This fact makes the task of unraveling the
      mechanisms underlying the development of this brain region rather daunting.
      Recent attempts to subdivide the embryonic telencephalon into distinct progenitor
      domains along the dorsal-ventral axis have provided an important framework on
      which to begin this process. These progenitor domains are defined by the
      restricted expression of transcriptional regulators and are proposed to give rise
      to specific subtypes of neurons. Work over recent years has provided important
      insights into the establishment and maintenance of these progenitor domains in
      the developing telencephalon.

PMID- 12593983
TI  - Regulation of axial patterning of the retina and its topographic mapping in the
      brain.
AB  - Topographic maps are a fundamental organizational feature of axonal connections
      in the brain. A prominent model for studying axial polarity and topographic map
      development is the vertebrate retina and its projection to the optic tectum (or
      superior colliculus). Linked processes are controlled by molecules that are
      graded along the axes of the retina and its target fields. Recent studies
      indicate that ephrin-As control the temporal-nasal mapping of the retina in the
      optic tectum/superior colliculus by regulating the topographically-specific
      interstitial branching of retinal axons along the anterior-posterior tectal axis.
      This branching is mediated by relative levels of EphA receptor repellent
      signaling. A major recent advance is the demonstration that EphB receptor forward
      signaling and ephrin-B reverse signaling mediate axon attraction to control
      dorsal-ventral retinal mapping along the lateral-medial tectal axis. In addition,
      several classes of regulatory proteins have been implicated in the control of the
      axial patterning of the retina, and its ultimate readout of topographic mapping.

PMID- 12593984
TI  - Development and maintenance of neuronal architecture at the ventral midline of C.
      elegans.
AB  - Work in flies, nematodes and vertebrates has shown that genes involved in axon
      patterning at the ventral midline are functionally conserved across phylogeny.
      Recent studies in Caenorhabditis elegans have implicated several new
      extracellular molecules, such as nidogen and heparan sulfate proteoglycans, in
      axonal tract formation at the midline. Furthermore, a conceptually new mechanism
      that regulates the maintenance of axon positioning at the midline has been
      described in C. elegans.

PMID- 12593985
TI  - Semaphorin junction: making tracks toward neural connectivity.
AB  - Semaphorins constitute one of the largest families of repulsive and attractive
      growth cone guidance proteins. They affect the growth cone's actin cytoskeleton
      through interactions with receptor complexes composed of ligand-binding, signal
      transducing, and modulatory subunits. Our understanding of the intracellular
      signal transduction machinery linking semaphorins to actin dynamics is limited;
      however, recent advances provide a more comprehensive view of the molecular basis
      of neuronal semaphorin signaling.

PMID- 12593986
TI  - Axon targeting in the Drosophila visual system.
AB  - The neuronal wiring of the Drosophila melanogaster visual system is constructed
      through an intricate series of cell-cell interactions. Recent studies have
      identified some of the gene regulatory and cytoskeletal signaling pathways
      responsible for the layer-specific targeting of Drosophila photoreceptor axons.
      Target selection decisions of the R1-R6 subset of photoreceptor axons have been
      found to be influenced by the nuclear factors Brakeless and Runt, and target
      selection decisions of the R7 subset of axons have been found to require the cell
      surface proteins Ptp69d, Lar and N-cadherin. A role for the visual system glia in
      orienting photoreceptor axon outgrowth and target selection has also been
      uncovered.

PMID- 12593987
TI  - Development of the monosynaptic stretch reflex circuit.
AB  - Significant advances have been made during the past few years in our
      understanding of how the spinal monosynaptic reflex develops. Transcription
      factors in the Neurogenin, Runt, ETS, and LIM families control sequential steps
      of the specification of various subtypes of dorsal root ganglia sensory neurons.
      The initiation of muscle spindle differentiation requires neuregulin 1, derived
      from Ia afferent sensory neurons, and signaling through ErbB receptors in
      intrafusal muscle fibers. Several retrograde signals from the periphery are
      important for the establishment of late connectivity in the reflex circuit.
      Finally, neurotrophin 3 released from muscle spindles regulates the strength of
      sensory-motor connections within the spinal cord postnatally.

PMID- 12593988
TI  - Decoding olfaction in Drosophila.
AB  - Recent experiments in Drosophila demonstrate striking stereotypy in the neural
      architecture of the olfactory system. Functional imaging experiments in mammals
      and honeybees suggest a mechanism of odor coding that translates discrete
      patterns of activity in olfactory glomeruli into an odor image. Future
      experiments in Drosophila may permit a direct test of this odor-coding
      hypothesis.

PMID- 12593989
TI  - Assembly and plasticity of the glutamatergic postsynaptic specialization.
AB  - Glutamate mediates most excitatory synaptic transmission in the brain. Synaptic
      strength at glutamatergic synapses shows a remarkable degree of use-dependent
      plasticity and such modifications may represent a physiological correlate to
      learning and memory. Glutamate receptors and downstream enzymes are organized at
      synapses by cytoskeletal proteins containing multiple protein-interacting
      domains. Recent studies demonstrate that these 'scaffolding' proteins within the
      postsynaptic specialization have the capacity to promote synaptic maturation,
      influence synapse size, and modulate glutamate receptor function.

PMID- 12593990
TI  - Hair cell regeneration: winging our way towards a sound future.
AB  - The discovery of hair cell regeneration in the inner ear of birds provides new
      optimism that there may be a treatment for hearing and balance disorders. In this
      review we describe the process of hair cell regeneration in birds; including
      restoration of function, recovery of perception and what is currently known about
      molecular events, such as growth factors and signalling systems. We examine some
      of the key recent findings in both birds and mammals.

PMID- 12593991
TI  - Neurogenesis after ischaemic brain insults.
AB  - Evidence for neuronal self-repair following insults to the adult brain has been
      scarce until very recently. Ischaemic insults have now been shown to trigger
      neurogenesis from neural stem cells or progenitor cells located in the dentate
      subgranular zone, the subventricular zone lining the lateral ventricle, and the
      posterior periventricle adjacent to the hippocampus. New neurons migrate to the
      granule cell layer or to the damaged CA1 region and striatum, where they express
      morphological markers characteristic of those neurons that have died. Some
      evidence indicates that these neurons can re-establish connections and contribute
      to functional recovery.

PMID- 12593992
TI  - New roles for old proteins in adult CNS axonal regeneration.
AB  - The past year has yielded many insights and a few surprises in the field of
      axonal regeneration. The identification of oligodendrocyte-myelin glycoprotein as
      an inhibitor of axonal growth, and the discovery that the three major myelin
      associated inhibitors of CNS regeneration share the same functional receptor, has
      launched a new wave of studies that aim to identify the signaling components of
      these inhibitory pathways. These findings also offer new avenues of research
      directed toward blocking possible therapeutic targets that inhibit regeneration
      and toward encouraging axonal regeneration in the CNS after injury.

PMID- 12593994
TI  - Effects of antenatal corticosteroids on regional brain and non-neural tissue
      water content in the ovine fetus.
AB  - OBJECTIVE: We examined the effects of maternal corticosteroid administration on
      water content in regional tissue in ovine fetuses at 60%, 80%, and 90% of
      gestation. METHODS: After catheters were placed in the fetuses, the ewes were
      given four 6-mg doses of dexamethasone or placebo injections 12 hours apart over
      48 hours. Water content of fetal tissue was determined 18 hours after the last
      injection was given to the ewes. Tissue water was determined by wet-to-dry weight
      ratio in brain (cerebral cortex, caudate nucleus, cerebellum, midbrain, and
      medulla) and non-neural tissues (kidney, liver, muscle, and skin) at each
      gestational age. RESULTS: Water content (P <.05) in brain regions was lower in
      fetuses from dexamethasone-treated than placebo-treated ewes at 60% but not 80%
      or 90% of gestation and in non-neural tissues at each gestational age.
      CONCLUSIONS: Maternal treatment with a corticosteroid regimen similar to that
      used in the clinical setting was associated with small decreases in brain water
      content early but not later in gestation. This corticosteroid treatment regimen
      was also associated with decreased regional non-neural tissue water content at
      60%, 80%, and 90% of gestation.

PMID- 12593995
TI  - Cloning and tissue expression of the tissue prothrombinase Fgl-2 in the Sprague
      Dawley rat.
AB  - OBJECTIVE: To sequence and characterize the expression of the prothrombinase Fgl
      2 in the Sprague-Dawley rat. METHODS: Reverse-transcriptase polymerase chain
      reaction was performed on RNA from spontaneously cycling adult pregnant Sprague
      Dawley rats by using specific Fgl-2 primers. The resulting amplicon was also used
      to screen a rat spleen bacteriophage library and to probe a Northern blot of
      various tissues. The rat Fgl-2 amino acid sequence was compared with the known
      sequences in mouse and human. RESULTS: Fgl-2-specific amplicon bands were
      observed in the rat brain, kidney, liver, ovary, spleen, and gestational day 22
      and postpartum uterus. The rat Fgl-2 cDNA and amino acid sequence were found to
      be homologous with those of human (86% and 74%, respectively) and mouse (91% and
      87%, respectively). Northern blotting demonstrated two different-sized
      transcripts (1.3 and 3.4 kb), and expression was observed in the cervix, heart,
      liver, ovary, and nongestational and gestational day 22 myometrium. CONCLUSION:
      Thrombin is classically generated from the cleavage of the proenzyme prothrombin
      by activated factors V and X. In tissues thrombin appears to be generated by a
      novel prothrombinase Fgl-2 (fibrinogen-like protein) whose activity is stimulated
      by proinflammatory mediators. Fgl-2 provides the mechanistic coupling between
      proinflammatory cytokines and the generation of active thrombin independent of
      the coagulation cascade. Our studies confirmed the expression of Fgl-2 mRNA in
      several rat tissues, including the pregnant uterus, where it could play a key
      role in the initiation of parturition especially in response to local or systemic
      infection.

PMID- 12593996
TI  - Administration of N(omega)-L-arginine methyl ester (L-NAME) impairs endothelium
      dependent relaxation in gravid but not nongravid rats.
AB  - OBJECTIVE: To characterize the impairment of endothelium-dependent relaxation
      induced by administration of the nitric oxide synthase (NOS) inhibitor N(omega)-L
      arginine methyl ester (L-NAME) to gravid rats and to determine whether L-NAME
      affects nongravid rats in a similar manner. METHODS: Acetylcholine (ACh; 0.01-10
      microM) relaxation was studied in aortic segments (contracted with 10 nM
      norepinephrine) from Wistar rats that were hypertensive after receiving L-NAME
      (0.5 mg/mL in drinking water) before gravidity (hypertensive virgin rats [HVR]),
      during gravidity (hypertensive gravid rats [HGR]), or during the last 10 days of
      gravidity to 24 hours postpartum (hypertensive puerperal rats [HPR]). We also
      studied aortic segments from corresponding groups of untreated normotensive rats
      (normotensive gravid rats [NGR], normotensive puerperal rats [NPR], and
      normotensive virgin rats [NVR]). The approximate participations of NO and the
      hyperpolarizing mechanisms in ACh relaxation were calculated from the reduction
      of relaxation observed, respectively, after incubation with the NOS inhibitor
      N(G)-monomethyl-L-arginine (L-NMMA, 0.1 mM) or after contraction with 50 mM of
      potassium chloride. Expression of endothelial NOS protein was studied by Western
      blot in segments of HGR and NGR. RESULTS: Acetylcholine relaxation was reduced in
      HGR compared with NGR, and this reduction correlated with the severity of
      hypertension. In contrast, ACh relaxation in HVR was similar to that in NVR, and
      that of HPR was similar to that in NPR. The NO component of relaxation was
      reduced in HGR but preserved in the other groups. Nevertheless, there were no
      differences in endothelial NOS protein expression between NGR and HGR. The
      hyperpolarizing component in relaxation was enhanced in HVR and HPR but not HGR.
      CONCLUSION: Administration of L-NAME induced an impairment of endothelium
      dependent relaxation, involving both nitric oxide- and hyperpolarizing-dependent
      mechanisms in gravid but not virgin rats; this impairment resolved with delivery.

PMID- 12593997
TI  - Maternal autoantibodies from preeclamptic patients activate angiotensin receptors
      on human trophoblast cells.
AB  - OBJECTIVES: Recent evidence indicates that preeclampsia is associated with the
      presence of autoantibodies capable of activating the angiotensin II receptor,
      AT1. We sought to evaluate the role of AT1 agonistic autoantibodies (AT1-AA) in
      two major features of preeclampsia-increased plasminogen activator inhibitor-1
      (PAI-1) production and shallow trophoblast invasion. METHODS: This study included
      38 pregnant patients, 20 of whom had severe preeclampsia and 18 normotensive
      individuals. Immunoglobulin (Ig)G was purified from these individuals, and the
      presence of AT1-AA was determined based on its ability to stimulate an increase
      in the contraction rate of cultured rat neonatal cardiac myocytes. Immortalized
      human trophoblasts were chosen to study PAI-1 production and secretion after
      treatment with IgG from normotensive and preeclamptic women. An in vitro Matrigel
      invasion assay was used to test the effect of AT1-AA on the invasive properties
      of human trophoblasts. Losartan and cyclosporin A were used to determine whether
      the AT1-AA-induced stimulation of PAI-1 secretion is through the AT1 receptor and
      the calcineurin-nuclear factor of activated t-cells (NFAT)-dependent pathway.
      RESULTS: The results show that IgG from 18 of 20 severely preeclamptic women
      stimulated increased cardiomyocyte contraction rates of 20-40 beats per minute. A
      significant stimulation of PAI-1 secretion from human trophoblasts was observed
      with IgG from the same 18 of 20 patients with severe preeclampsia. Of IgG
      obtained from 18 normotensive pregnant patients, only two showed a relatively low
      level of biologic activity in the cardiomyocyte contraction and PAI-1 secretion
      assays. Activation of AT1 receptors by AT1-AA was blocked by losartan (an AT1
      receptor antagonist) and by a seven amino acid peptide corresponding to a
      sequence present on the second extracellular loop of the AT1 receptor. Activation
      of AT1 receptors by AT1-AA resulted in decreased trophoblast invasiveness as
      determined by the in vitro Matrigel invasion assay. Additional data indicate that
      AT1 receptor activation by AT1-AA is followed by the downstream activation of the
      calcium-dependent calcineurin-NFAT signaling pathway leading to increased PAI-1
      gene expression. CONCLUSION: Our findings suggest that maternal autoantibody with
      the ability to activate AT1 receptors may account for two features of
      preeclampsia, increased PAI-1 production and shallow trophoblast invasion.

PMID- 12593998
TI  - First-trimester blood pressure and gestational diabetes in high-risk Chinese
      women.
AB  - OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with increased
      incidence of hypertensive disorders of pregnancy, which is attributed to maternal
      insulin resistance and hyperinsulinemia. A retrospective case-control study was
      performed to examine the relationship between first-trimester blood pressure (BP)
      and the subsequent development of GDM in high-risk Chinese women. METHODS: The
      systolic and diastolic BP readings at the 9th-12th week of gestation were
      compared between 67 women with GDM and 64 high-risk controls matched for age (+/-
      1 year), height (+/- 1 cm), and booking weight (+/- 1 kg), all with singleton
      pregnancies and delivered within 1 year. The entire cohort was further
      categorized into systolic and diastolic BP quartile groups based on reference
      values established in 215 consecutive pregnant women, and the incidence of GDM
      was correlated with the quartile ranking. RESULTS: The GDM group had
      significantly higher systolic BP (114.0 +/- 12.9 mmHg versus 108.0 +/- 10.6 mmHg,
      P =.004) at the 9th-12th week. There was a positive and significant correlation
      between the incidence of GDM and systolic BP, but not diastolic BP, quartiles,
      and systolic BP above the median value (109 mmHg) was associated with increased
      incidence of GDM. Regression analysis with adjustment for the effects of age over
      35 years and weight greater than 75 kg confirmed that systolic BP above median
      was a significant risk factor for GDM (OR 4.20, 95% CI 1.97, 8.94). CONCLUSION:
      The correlation between first-trimester systolic BP quartiles and incidence of
      GDM could be a feature of insulin resistance and hyperinsulinemia before the
      development of GDM in high-risk Chinese women.

PMID- 12593999
TI  - Correction of insulin resistance and hyperandrogenism in polycystic ovary
      syndrome by combined rosiglitazone and clomiphene citrate therapy.
AB  - OBJECTIVE: To investigate the effects of combined rosiglitazone and clomiphene
      citrate versus clomiphene citrate monotherapy on serum insulin-like growth factor
      1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels in
      polycystic ovary syndrome (PCOS) and to evaluate these therapeutic interventions
      in the link between hyperinsulinemia and hormonal perturbations in PCOS. METHODS:
      We performed a randomized clinical study at the King Abul-Aziz and Cairo
      University Hospitals. We studied 50 women with PCOS. Clinical diagnosis was based
      on hyperandrogenism; hyperinsulinism; oligomenorrhea; or amenorrhea, anovulatory
      cycles, and ultrasonographic findings. They were randomly assigned to two groups
      of 25 women each. One group was treated with rosiglitazone and clomiphene
      citrate; the other was treated only with clomiphene citrate. Serum concentrations
      of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol,
      dehydroepiandrosterone sulfate (DHEAS), free testosterone, IGF-1, and IFGBP-3
      were measured by specific radioimmunoassays before and after treatment. RESULTS:
      Combined rosiglitazone and clomiphene treatment led to a significant reduction in
      area under the insulin curve (AUC insulin), whereas clomiphene monotherapy did
      not lead to this reduction. Both types of treatment induced a significant
      decrease in LH, LH:FSH ratio, free testosterone, and IGF1:IGBP-3 ratio and were
      associated with a significant increase in IGFBP-3 levels. These changes were more
      pronounced in PCOS patients treated with combined rosiglitazone and clomiphene
      than in those treated with clomiphene monotherapy. Regular menstrual cycles
      occurred in 72% of the former group and 48% of the latter. CONCLUSION: Combined
      rosiglitazone and clomiphene was an effective therapeutic regimen for correcting
      insulin resistance in patients with PCOS, possibly by reducing IGF1
      bioavailability to the ovaries, thus modifying the hyperandrogenic
      intrafollicular milieu that occurs in PCOS. In addition, the clinical and
      hormonal responses were better than with clomiphene alone.

PMID- 12594000
TI  - Ethnic variations in uterine leiomyoma biology are not caused by differences in
      myometrial estrogen receptor alpha levels.
AB  - OBJECTIVE: Uterine leiomyomas develop in women of reproductive age and regress
      after menopause, suggesting that they grow in a steroid hormone-dependent
      fashion. Furthermore, it is widely accepted that symptomatic uterine leiomyomas
      occur at a twofold to threefold higher frequency in black women than in white
      women. The present study was designed to investigate a possible physiologic role
      of racial differences in the myometrial estrogen receptor alpha in this
      phenomenon. METHODS: We compared the expression of the estrogen receptor and
      progesterone receptor in myometrium by ligand-binding assay and the estrogen
      receptor alpha by real-time polymerase chain reaction in women from different
      ethnic backgrounds who have uterine leiomyoma. RESULTS: Estrogen receptor and
      progesterone receptor concentrations and estrogen receptor alpha transcription
      levels were not statistically different between ethnic backgrounds. CONCLUSION:
      Neither on a transcriptional nor on a protein level were there statistically
      relevant differences in steroid hormone receptor levels. A causative role for
      these receptors in the ethnic variation of leiomyoma biology seems unlikely.

PMID- 12594001
TI  - Lipopolysaccharide induces interleukin-8 production by human cervical smooth
      muscle cells.
AB  - OBJECTIVE: We examined the effect of lipopolysaccharide (LPS), a component of the
      outer wall of gram-negative bacteria, on expression of the neutrophil
      chemoattractant interleukin-8 (IL-8) and the effects of IL-8 treatment on release
      of matrix metabolizing enzymes in human cervical smooth muscle cells (CSMCs).
      METHODS: Human CSMCs were exposed to Escherichia coli LPS, and the expression of
      IL-8 mRNA was analyzed by Northern blotting. The IL-8 promoter activity was
      examined by dual luciferase assay, and the IL-8 concentration was assessed by
      enzyme-linked immunosorbent assay. We also treated the CSMCs with human IL-8 and
      examined the expression of matrix-degrading enzymes. RESULTS: E coli LPS (100
      ng/mL) increased the expression of IL-8 mRNA 12.8-fold after 3 hours. This up
      regulation was maintained for up to 24 hours. Lipopolysaccharide treatment
      produced a fivefold increase in IL-8 promoter activity in CSMCs transfected with
      an IL-8 promoter-reporter construct. IL-8 concentrations in conditioned medium of
      CSMC cultures treated with E coli LPS increased approximately 18-fold compared
      with the control cultures. Northern blot analysis and zymography revealed that
      exogenous human IL-8 had no significant effect on the expression of matrix
      metalloproteinase (MMP)-1, -3, and tissue inhibitor of metalloproteinase (TIMP)-1
      mRNAs, and on the secretion MMP-2 and -9 in CSMCs. CONCLUSION: We conclude that
      CSMCs respond to LPS with increased expression of IL-8 mRNA and secreted IL-8,
      and that expression of matrix metabolizing enzymes in CSMCs is not directly
      affected by IL-8. IL-8 produced by CSMCs in response to gram-negative infection
      may promote neutrophil invasion, and release of neutrophil matrix-degrading
      enzymes may participate in the matrix remodeling associated with parturition.

PMID- 12594002
TI  - Expression of serum human leukocyte antigen and growth factor levels in a Greek
      family with familial endometriosis.
AB  - OBJECTIVE: An increased incidence of endometriosis in the first-degree relatives
      of patients with endometriosis has been reported, suggesting a familial
      predisposition and possible genetic influence. In this study, we present a family
      with four members who have histologically proven endometriosis (mother and three
      daughters) in two generations and one member with suspected endometriosis in the
      third generation. The aim of this study was to investigate the presence of serum
      soluble class I and class II human leukocyte antigen (sHLA) levels, because they
      have been shown to be reduced in women with endometriosis. We also studied the
      levels of vascular endothelial growth factor (VEGF) and epidermal growth factor
      receptor (EGF-Rc) whose function in angiogenesis implies an active role in
      endometriosis. METHODS: Apart from the family members under study, the control
      groups consisted of 38 women with endometriosis and 30 without any pelvic
      disease. All the soluble factors under investigation were measured by an enzyme
      linked immunosorbent assay technique using a specific immunoassay. RESULTS: All
      the affected family members and the 38 women with endometriosis had very low
      levels of serum-soluble class I and class II HLA levels compared with healthy
      subjects. The circulating levels of VEGF were higher in the endometriosis group
      than the healthy control group, a pattern in accordance with the family members.
      On the contrary, EGF-Rc was negative in controls and women with endometriosis,
      with the exception of certain family members in specific stages of endometriosis.
      CONCLUSION: We studied the association of endometriosis with circulating levels
      of human leukocyte antigens and VEGF in two generations of a single family
      (mother and three daughters). These markers were expressed distinctly in women
      with familial endometriosis.

PMID- 12594003
TI  - Nanosizing: a formulation approach for poorly-water-soluble compounds.
AB  - Poorly-water-soluble compounds are difficult to develop as drug products using
      conventional formulation techniques and are frequently abandoned early in
      discovery. The use of media milling technology to formulate poorly-water-soluble
      drugs as nanocrystalline particles offers the opportunity to address many of the
      deficiencies associated with this class of molecules. NanoCrystal Technology is
      an attrition process wherein large micron size drug crystals are media milled in
      a water-based stabilizer solution. The process generates physically stable
      dispersions consisting of nanometer-sized drug crystals. Nanocrystalline
      particles are a suitable delivery system for all commonly used routes of
      administration, i.e. oral, injectable (IV, SC, and IM) and topical applications.
      In addition, aqueous dispersions of nanoparticles can be post-processed into
      tablets, capsules, fast-melts and lyophilized for sterile product applications.
      The technology has been successfully incorporated into all phases of the drug
      development cycle from identification of new chemical entities to refurbishing
      marketed products for improving their performance and value.

PMID- 12594004
TI  - Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy
      subjects following intravenous, oral and rectal single doses.
AB  - The neurotropic-musculotropic spasmolytic agent denaverine hydrochloride is used
      mainly in the treatment of smooth muscle spasms of the gastrointestinal and
      urogenital tract. Despite its commercial availability as a solution for
      intravenous or intramuscular administration (ampoule) and as a suppository
      formulation, no pharmacokinetic data in man was available to date. Therefore, the
      objectives of this clinical trial were to determine the basic pharmacokinetic
      parameters of denaverine after intravenous administration, to assess the
      feasibility of using the oral route of administration and to characterise the
      bioavailability of the suppository formulation. To achieve this, healthy subjects
      received 50 mg denaverine hydrochloride intravenously, orally and rectally in
      aqueous solutions and rectally as suppository in an open, randomised crossover
      design. Total body clearance, volume of distribution at steady-state and half
      life of denaverine are 5.7 ml/min per kg, 7.1 l/kg and 33.8 h, respectively. The
      absolute bioavailability after oral administration of an aqueous solution is 37%.
      First-pass metabolism leading to the formation of N-monodemethyl denaverine was
      found to be one reason for the incomplete bioavailability after oral
      administration. Rectal administration of an aqueous solution of denaverine
      hydrochloride resulted in a decreased rate (median of C(max) ratios: 26%,
      difference in median t(max) values: 1.9 h) and extent (31%) of bioavailability
      compared to oral administration. Using the suppository formulation led to a
      further reduction in rate (median of C(max) ratios: 30%, difference in median
      t(max) values: 3 h) and extent (42%) of bioavailability compared to the rectal
      solution.

PMID- 12594005
TI  - Microwave-assisted high-speed PCR.
AB  - PCR amplification has emerged as a very important tool in biological research.
      The utility of the PCR is, however, hampered by the fact that it is a slow
      technique. Faster heating cycles are therefore needed, both to enhance the
      activity of the enzyme, and to enable shortening of the reaction times. In this
      paper, polymerase chain reactions with focused microwave irradiation as the
      source of heat were demonstrated for the first time. Thus, it was established
      that continuous microwave heating does not terminate the enzymatic function of
      the polymerase. The results indicate the possibility to shorten the total
      reaction time. In addition, the technique may give the possibility to perform PCR
      reactions in millilitre scale.

PMID- 12594006
TI  - Effects of some antioxidative aporphine derivatives on striatal dopaminergic
      transmission and on MPTP-induced striatal dopamine depletion in B6CBA mice.
AB  - (S)-(+)-boldine, an aporphine alkaloid displaying antioxidative and dopaminergic
      properties, and six of its derivatives (glaucine, 3-bromoboldine, 3-iodoboldine,
      8-aminoboldine, 8-nitrosoboldine and 2,9-O,O'-dipivaloylboldine) were tested for
      these properties in comparison with their parent compound. All the tested
      compounds displayed in vitro antioxidative properties equal to or slightly weaker
      than those of boldine, and equal to or stronger than (+/-)-6-hydroxy-2,5,7,8,
      tetramethylchromane-2-carboxylic acid (Trolox), a water-soluble vitamin E
      analogue, used as a reference compound. All the aporphine compounds tested
      displaced [3H]SCH 23390 and [3H]raclopride from their specific binding sites in
      rat striatum. When tested on dopamine (DA) metabolism in the striatum of B6CBA
      mice, all the compounds, except 8-aminoboldine, increased striatal levels of
      DOPAC and HVA, and the HVA/DA ratio, indicating that they cross the blood-brain
      barrier and that they seem to act as dopamine antagonists in vivo. B6CBA mice
      were sensitive to the neurotoxic action of MPTP on dopaminergic neurons as
      indicated by the strongly decreased striatal levels of DA, DOPAC and HVA
      following administration of MPTP (20 mg/kg, i.p.). Among these aporphine
      derivatives, only 3-bromoboldine was able to reduce the MPTP-induced decrease of
      striatal levels of DA and DOPAC, whereas (R)-apomorphine (5 mg/kg, s.c.) and
      acetylsalicylic acid (100 mg/kg, i.p.), used as reference compounds, were very
      active. These data suggest that potent in vitro antioxidative properties and the
      ability to cross the blood-brain barrier are not sufficient criteria to predict
      the inhibition of neuronal degeneration induced by MPTP.

PMID- 12594007
TI  - In vitro evaluation of patch formulations for topical delivery of gentisic acid
      in rats.
AB  - Gentisic acid (GA) is used in cosmetics as a skin-whitening agent for the
      treatment of skin pigmentary disorders by influencing the synthesis of melanin
      through inhibition of melanosomal tyrosinase activity. In order to achieve
      effective topical delivery of GA to the active site in the skin, a matrix-type
      transdermal delivery system was developed. The in vitro skin permeation as well
      as skin deposition of GA was studied in rats. Among the five pressure-sensitive
      adhesives tested, DuroTak 87-2510 was the most effective to achieve the highest
      permeation rate of GA. Dodecylamine showed the most potent enhancement among the
      enhancers tested, and significantly increased the permeation rate of GA up to
      112.99 (+/-30.12) microg/cm(2) per h at the concentration of 1%, when 6% GA was
      incorporated in DuroTak 87-2510. Moreover, a linear relationship was observed
      between the skin permeation rate of GA and the amount of the skin deposition
      after 12 h of permeation (r(2)=0.95). Thus, the in vitro skin permeation data may
      be useful to determine the amount of GA actually deposited in the skin.

PMID- 12594008
TI  - Effect of ethanolamine salts and enhancers on the percutaneous absorption of
      piroxicam from a pressure sensitive adhesive matrix.
AB  - The effects of salt formation on the percutaneous absorption of piroxicam through
      hairless mouse skin from a pressure sensitive adhesive (PSA) matrix were
      investigated. We also studied the effect of permeation enhancers on the skin
      permeation of piroxicam or piroxicam-ethanolamine (PX-EA) salts from an acrylic
      adhesive matrix. The order of the permeation rates of piroxicam and PX-EA salts
      from the PSA matrix was piroxicam-monoethanolamine salt (PX-MEA)>piroxicam
      diethanolamine salt (PX-DEA)>piroxicam>piroxicam-triethanolamine salt (PX-TEA).
      The enhancer Crovol A40 provided the highest piroxicam and PX-MEA fluxes and
      Plurol oleque the highest PX-DEA and PX-TEA fluxes. The order of piroxicam and PX
      EA salts permeabilities were different for saturated solutions in various
      enhancers and PSA matrix containing the same enhancer, especially when Crovol
      A40, Crovol PK40 or Plurol oleque were used as enhancers. No close relationship
      was found between the fluxes of piroxicam or PX-EA salts from saturated solutions
      and from PSA matrices containing the same enhancer. Maximum piroxicam flux was
      obtained when PX-MEA/PX-TEA (4:6, v/v) was incorporated into a PSA matrix
      containing Crovol PK40.

PMID- 12594009
TI  - Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an
      asymmetric pathway.
AB  - Boron neutron capture therapy (BNCT) is an experimental therapeutic modality
      combining a boron pharmaceutical with neutron irradiation. 4
      Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by
      Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron
      containing pharmaceutical in the first series of Finnish BNCT clinical trials.
      The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L
      tyrosine as the residual impurities. The solubility of L-BPA was enhanced by
      complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F
      preparation is in the physiological range. Careful attention was given to the
      pharmaceutical quality of the BPA-F preparations. Prior to starting clinical
      trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley
      rats. In accordance with earlier studies no adverse effects were observed. After
      completion of the development work L-BPA solution was administered to brain
      tumour patients in conjunction with clinical studies for development and testing
      of BPA-based BNCT. No clinically significant adverse events attributable to the L
      BPA i.v. infusions were observed. We conclude that our synthesis development,
      complementary preclinical and clinical observations justify the safe use of L-BPA
      up to clinical phase III studies with L-BPA produced by the asymmetric pathway,
      originally presented by Malan and Morin in 1996.

PMID- 12594010
TI  - Self-assembled nanoparticles of hydrophobically-modified polysaccharide bearing
      vitamin H as a targeted anti-cancer drug delivery system.
AB  - Vitamin H (biotin) was incorporated into a hydrophobically modified
      polysaccharide, pullulan acetate (PA), in order to improve the cancer-targeting
      activity and internalization of self-assembled nanoparticles. The biotinylated
      pullulan acetate (BPA) nanoparticles were prepared by a diafiltration method and
      the mean diameter was approximately 100 nm. Three samples of biotinylated
      pullulan acetate (BPA), comprising 7 (BPA 1), 20 (BPA 2), and 39 (BPA 3) vitamin
      H groups per 100 anhydroglucose units of PA, were synthesized. The critical
      aggregation concentrations (CAC) of the BPA nanoparticles in distilled water were
      3.1 x 10(-3), 4.3 x 10(-3) and 6.8 x 10(-3) mg/ml for BPA 1, BPA 2, and BPA 3,
      respectively. Adriamycin (ADR) was loaded into the BPA nanoparticles as a model
      drug. The loading efficiencies and ADR content in the BPA nanoparticles decreased
      with increasing vitamin H content due to a lower hydrophobicity. The RITC-labeled
      BPA nanoparticles exhibited very strong adsorption to the HepG2 cells, while the
      RITC-labeled PA nanoparticles did not show any significant interaction. The
      degree of the interaction increased with increasing vitamin H content. Confocal
      laser microscopy also revealed that internalization of the BPA nanoparticles into
      the cancer cells depended on the vitamin H content.

PMID- 12594011
TI  - Arsonoliposomes: effect of arsonolipid acyl chain length and vesicle composition
      on their toxicity towards cancer and normal cells in culture.
AB  - Arsonolipid-containing liposomes were investigated in order to characterize the
      influence of the lipid acyl-chain length and liposome composition on
      cytotoxicity. Three types of cancer cells (HL-60, C6 and GH3), and two types of
      normal cells (HUVEC and RAME) were used. Liposomes containing the lauroyl,
      myristoyl and stearoyl side chain arsonolipids (with different lipid
      compositions) were incubated with a given number of cells and cell viability was
      estimated (MTT assay and trypan blue exclusion). Morphological studies were also
      performed in some cases. In addition, the interaction between some of the
      prepared arsonoliposomes and HUVEC cells was assessed. Results reveal that all
      the studied arsonoliposomes cause a dose dependent inhibition of survival in all
      three malignant cell lines studied (initiated at 10(-6) M). The corresponding
      toxicity against normal cells (HUVEC and RAME) is much lower for all
      arsonoliposomes, except for the lauroyl side chain arsonoliposomes which were
      demonstrated to be relatively toxic towards normal cells, especially RAME. The
      microscopic observations that these vesicles possibly cause apoptosis of most
      cell types studied, as well as the different speed of their cytotoxic activity,
      imply a different mechanism of action for this arsonoliposome type. Taking the
      results of this study in conjunction with our previous results on arsonoliposome
      physical stability and cytotoxicity, it is recommended that palmitoyl-arsonolipid
      arsonoliposomes be used for further investigations in vivo towards the
      development of an anticancer product.

PMID- 12594012
TI  - Biochemical changes in arthritic rats: dehydroascorbic and ascorbic acid levels.
AB  - The objective of this work was to evaluate the use of vitamin C as a biomarker in
      the inflammatory phase of the rat adjuvant arthritis and to correlate it with
      other parameters used for disease evaluation. Paw swelling was used for physical
      evaluation and the levels of ascorbate and dehydroascorbate in the serum of male
      rats, before and after adjuvant arthritis induction, were quantified by a high
      performance liquid chromatography method (HPLC). The optimised HPLC assay enabled
      the quantification of both forms of the vitamin in rat sera, with the same
      extraction method and using different detectors, instead of obtaining
      dehydroascorbate by subtraction of the total ascorbate measurement. This method
      was used to follow the severity of adjuvant arthritis and the results were
      correlated with other already established disease activity parameters. A decrease
      of ascorbic acid and dehydroascorbic acid was observed with the increase of right
      paw circumference during the course of adjuvant arthritis. The disease associated
      changes in the serum concentrations of ascorbic acid, from biosynthesis and from
      recycling, can be evaluated by the direct quantification of dehydroascorbic acid.
      This provides some evidence for the potential of the quantification of these
      biomarkers to study the disease activity, and as a tool for the establishment of
      therapeutic protocols, to evaluate the anti-inflammatory effect of new drugs or
      formulations.

PMID- 12594013
TI  - Validation of an image analysis method for estimating coating thickness on
      pellets.
AB  - A digital image analysis method for the estimation of mean pellet size and
      coating thickness employing optical microscopy was evaluated. The coating
      thickness was expressed as the difference in mean projected area radius of the
      uncoated and the coated pellets. The repeatability, the intermediate precision
      and the robustness of the image analysis method were investigated. The
      repeatability and the intermediate precision of the image analysis method was
      excellent with a low degree of scatter between the measurements. The robustness
      investigation on the image analysis method illustrated the importance of
      controlling and monitoring the illumination technique utilised. Calibration of
      the image analysis equipment was of the highest importance. Using pellets with a
      high degree of sphericity and narrow size distribution, it was sufficient to use
      1000 pellets to estimate the mean pellet size and the coating thickness with an
      accuracy of +/-1.2 microm. An equation is presented for an approximation of the
      number of pellets necessary to achieve a given accuracy in the estimation of mean
      pellet size and coating thickness.

PMID- 12594014
TI  - Enantioselective binding of S- and R-ofloxacin to various synthetic
      polynucleotides.
AB  - The binding properties of S- and R-ofloxacin to poly[d(A-T)(2)], poly[d(G-C)(2)]
      and poly[d(I-C)(2)] were studied by circular dichroism (CD) and various
      fluorescence techniques. The spectral properties of R-ofloxacin did not change
      when it was mixed with poly[d(A-T)(2)] and poly[d(I-C)(2)], indicating that R
      enantiomer does not interact with these polynucleotides. On the other hand, when
      S-ofloxacin was mixed with any polynucleotide, or R-enantiomer with poly[d(G
      C)(2)], characteristic changes in CD and fluorescence were observed. Therefore,
      it is clear that enantiomers of ofloxacin selectively recognize B-form DNA. The
      overall spectral properties of the ofloxacin-polynucleotide complex are similar
      to those of the norfloxacin-polynucleotide complex [Eur. J. Biochem. 267 (2000)
      6018], suggesting that this quinolone also binds in the minor groove of DNA and
      therefore it may be partially inserted between DNA bases or interact with purine
      bases.

PMID- 12594015
TI  - Prokaryotes and the input of polyunsaturated fatty acids to the marine food web.
AB  - The investigation of prokaryotes in aquatic ecology is often limited to their
      role in nutrient cycling and the degradation of organic matter. While this aspect
      of the microbial loop is undoubtedly important, further aspects of bacterial
      roles in marine food webs exist which have not been fully considered in light of
      recent research in related fields. The concept of bacteria providing essential
      nutrients may derive importance from two aspects of their role in the marine
      environment; firstly as a primary food source for omnivorous, sestonivorous and
      filtering benthic animals and secondly as components of the commensal microbial
      communities of marine animals. Many marine organisms lack the de novo ability to
      produce n-3 polyunsaturated fatty acids (PUFA) and hence rely on a dietary supply
      of PUFA. The issue of PUFA origin in the marine food web is particularly salient
      in light of recent research demonstrating the influence of PUFA levels on the
      efficiency of energy transfer between trophic levels. The assumption that
      microalgae provide the bulk of de novo PUFA production for all marine food webs
      must be actively reviewed with respect to particular microbial niches such as sea
      ice, marine animals and abyssal communities.

PMID- 12594016
TI  - Regulation of protein H expression in M1 serotype isolates of Streptococcus
      pyogenes.
AB  - Protein H is an immunoglobulin-binding protein expressed by certain M1 serotypes
      of Streptococcus pyogenes. In a recent study of invasive group A isolates, it was
      found that none of the 16 M1 serotype isolates analyzed expressed protein H on
      their surface despite the presence of the protein H gene (sph) in approximately
      one-third of the isolates. Selection of stable protein H-expressing variants
      could be achieved by infection of prtH(+) non-expressing strains into a mouse
      skin and recovering bacteria from the spleen. This effect was independent of the
      transcription regulator Mga, since a similar effect was noted in an mga(-)
      mutant. Thus, host passage of S. pyogenes can lead to stable high level
      expression of Protein H.

PMID- 12594017
TI  - Three-dimensional reconstruction of a pathogenic yeast Exophiala dermatitidis
      cell by freeze-substitution and serial sectioning electron microscopy.
AB  - The structure of a budding cell of the pathogenic yeast Exophiala dermatitidis
      was observed in three dimensions after freeze-substitution, serial ultrathin
      sectioning and computer reconstruction. The nucleus occupied about 10% of the
      cell volume. The spindle pole body was composed of two disk elements connected by
      an intervening midpiece, and occupied about 0.01% of the cell volume. The cell
      wall consisted of an inner transparent layer, a middle electron-opaque layer, and
      an outer fibrous layer. The mitochondria occupied about 10% of the cell volume.
      There were numerous mitochondria in the mother cell and the bud, but no 'giant
      mitochondrion' was seen. The ratio of mitochondrial volume within the bud to the
      mitochondrial volume of the cell was close to the ratio of bud:cell cytoplasmic
      volume. The results emphasize the importance of good cryofixation for 'perfect'
      preservation of yeast cell structure.

PMID- 12594018
TI  - Inhibition of cell division blocks the synthesis of the second nitrogenase (Nif2)
      in the cyanobacterium Anabaena variabilis.
AB  - Anabaena variabilis ATCC 29413 belongs to the cyanobacteria that use a specific
      cell type, heterocysts, for fixation of atmospheric nitrogen under aerobic
      conditions. Nitrogen fixation under anaerobic conditions is catalyzed by a Mo
      dependent nitrogenase (Nif2) that is expressed in the vegetative cells. We
      demonstrate here using immunolocalization/light microscopy (LM) that the
      synthesis of NifH2 is mainly initiated in dividing vegetative cells along the
      trichomes. Blocking cell division by cephalexin abolished nitrogenase synthesis
      under anaerobic conditions.

PMID- 12594019
TI  - Production of macrosphelide A by the mycoparasite Coniothyrium minitans.
AB  - Coniothyrium minitans, a mycoparasite of sclerotia of Sclerotinia sclerotiorum
      and Sclerotium cepivorum, produced four closely related metabolites inhibitory to
      fungal growth. The major metabolite, identified as macrosphelide A, had IG(50)
      values (the concentration of metabolite to inhibit growth by 50%) of 46.6 and 2.9
      microgram ml(-1) against S. sclerotiorum and S. cepivorum, respectively. This is
      the first report of both antifungal activity due to macrosphelide A as well as
      isolation of macrosphelide A from C. minitans.

PMID- 12594020
TI  - Envelope ultrastructure of uncultured naturally occurring magnetotactic cocci.
AB  - Magnetotactic bacteria are microorganisms that respond to magnetic fields. We
      studied the surface ultrastructure of uncultured magnetotactic cocci collected
      from a marine environment by transmission electron microscopy using freeze
      fracture and freeze-etching. All bacteria revealed a Gram-negative cell wall.
      Many bacteria possessed extensive capsular material and a S-layer formed by
      particles arranged with hexagonal symmetry. No indication of a metal
      precipitation on the surface of these microorganisms was observed. Numerous
      membrane vesicles were observed on the surface of the bacteria. Flagella were
      organized in bundles originated in a depression on the surface of the cells.
      Occasionally, a close association of the flagella with the magnetosomes that
      remained attached to the replica was observed. Capsules and S-layers are common
      structures in magnetotactic cocci from natural sediments and may be involved in
      inhibition of metal precipitation on the cell surface or indirectly influence
      magnetotaxis.

PMID- 12594021
TI  - Genomics-based design of defined growth media for the plant pathogen Xylella
      fastidiosa.
AB  - Based on the genetic analysis of the phytopathogen Xylella fastidiosa genome,
      five media with defined composition were developed and the growth abilities of
      this fastidious prokaryote were evaluated in liquid media and on solid plates.
      All media had a common salt composition and included the same amounts of glucose
      and vitamins but differed in their amino acid content. XDM(1) medium contained
      amino acids threonine, serine, glycine, alanine, aspartic acid and glutamic acid,
      for which complete degradation pathways occur in X. fastidiosa; XDM(2) included
      serine and methionine, amino acids for which biosynthetic enzymes are absent,
      plus asparagine and glutamine, which are abundant in the xylem sap; XDM(3) had
      the same composition as XDM(2) but with asparagine replaced by aspartic acid due
      to the presence of complete degradation pathway for aspartic acid; XDM(4) was a
      minimal medium with glutamine as a sole nitrogen source; XDM(5) had the same
      composition as XDM(4), plus methionine. The liquid and solidified XDM(2) and
      XDM(3) media were the most effective for the growth of X. fastidiosa. This work
      opens the opportunity for the in silico design of bacterial defined media once
      their genome is sequenced.

PMID- 12594022
TI  - Possible quorum sensing in the rumen microbial community: detection of quorum
      sensing signal molecules from rumen bacteria.
AB  - The bioluminescence assay using Vibrio harveyi BB170 was used to examine quorum
      sensing autoinducer 2 (AI-2) activity from cell-free culture fluids of rumen
      bacteria. The assay showed that the culture fluids of four species of rumen
      bacteria, Butyrivibrio fibrisolvens, Eubacterium ruminantium, Ruminococcus
      flavefaciens, and Succinimonas amylolytica, contained AI-2-like molecules.
      Furthermore, homologues for luxS genes were detected in rumen fluids collected
      from three cows and in bacterial cells of P. ruminicola subsp. ruminicola and R.
      flavefaciens. These findings suggest that the quorum-sensing system mediated by
      AI-2 is present in the rumen.

PMID- 12594023
TI  - Effect of root exudates on the exopolysaccharide composition and the
      lipopolysaccharide profile of Azospirillum brasilense Cd under saline stress.
AB  - The effect of wheat root exudates on the exopolysaccharide (EPS) composition and
      the lipopolysaccharide (LPS) profile of Azospirillum brasilense Cd under saline
      stress was studied. EPS of A. brasilense Cd was composed of glucose (47%),
      mannose (3%), xylose (4%), fucose (28%), rhamnose (6%), arabinose (1%) and
      galactose (11%). Under saline stress, A. brasilense produced a totally different
      EPS, composed mainly of galactose. Root exudates induced changes in A. brasilense
      EPS composition only under normal conditions, consisting of higher amounts of
      arabinose and xylose compared with EPS of bacteria grown without root exudates.
      No changes were induced by root exudates when A. brasilense was grown under
      saline stress. Additionally, root exudates induced changes in the LPS profile,
      both under normal and stress conditions.

PMID- 12594024
TI  - A novel cold-tolerant Clostridium strain PXYL1 isolated from a psychrophilic
      cattle manure digester that secretes thermolabile xylanase and cellulase.
AB  - A Clostridium strain PXYL1 was isolated from a cold-adapted cattle manure biogas
      digester at 15 degrees C. It could grow at temperatures as low as 5 degrees C up
      to 50 degrees C with highest specific growth rate at 20 degrees C and is a
      psychrotroph. It produced extracellular hydrolytic enzymes namely xylanase,
      endoglucanase, beta-xylosidase, beta-glucosidase and filter paper cellulase, all
      of which had maximal activity at 20 degrees C. The induction of xylanase was
      highest on birch wood xylan (37 IU(mg protein)(-1)) compared with xylose (1.11
      IU(mg protein)(-1)), cellobiose (1.43 IU(mg protein)(-1)) and glucose (no
      activity). The xylanase was thermolabile with a half-life of 30 min at 40 degrees
      C and 8 min at 50 degrees C but stable for over 2 h at 20 degrees C. The crude
      enzyme released reducing sugars (1.25 g l(-1)) from finger millet flour at 20
      degrees C, while commercial food-grade xylanases showed no hydrolysis at this
      temperature. This is the first report of a Clostridium strain growing at 20
      degrees C and producing an array of xylanolytic and cellulolytic enzymes,
      possessing low temperature optima of 20 degrees C, which may facilitate
      degradation of plant fibre under low-temperature conditions.

PMID- 12594025
TI  - Intraspecies variability of Desulfovibrio desulfuricans strains determined by the
      genetic profiles.
AB  - Fifteen (soil and intestinal) strains of Desulfovibrio desulfuricans species were
      typed by PCR method with the use of primers specific for repetitive extragenic
      palindromic (REP) and enterobacterial repetitive intergenic consensus (ERIC)
      sequences. As a result, characteristic DNA fingerprints for the strains were
      obtained. Moreover, the genetic profiles were found to be useful for typing and
      distinguishing the strains of D. desulfuricans. According to cluster analysis,
      PCR with primers complementary to the sequences REP appeared to be slightly more
      discriminatory than PCR with ERIC primers for the investigated strains. Distinct
      fingerprint patterns of two isolates derived from the same patient pointed to the
      different origin of both strains.

PMID- 12594026
TI  - A TPR-family membrane protein gene is required for light-activated heterotrophic
      growth of the cyanobacterium Synechocystis sp. PCC 6803.
AB  - The unicellular cyanobacterium Synechocystis sp. PCC6803 can grow
      heterotrophically in complete darkness, given that a brief period of illumination
      is supplemented every day (light-activated heterotrophic growth, LAHG), or under
      very weak (<0.5 micromol m(-2) s(-1)) but continuous light. By random insertion
      of the genome with an antibiotic resistance cassette, mutants defective in LAHG
      were generated. In two identical mutants, sll0886, a tetratricopeptide repeat
      (TPR)-family membrane protein gene, was disrupted. Targeted insertion of sll0886
      and three downstream genes showed that the phenotype was not due to a polar
      effect. The sll0886 mutant shows normal photoheterotrophic growth when the light
      intensity is at 2.5 micromol m(-2) s(-1) or above, but no growth at 0.5 micromol
      m(-2) s(-1). Homologs to sll0886 are also present in cyanobacteria that are not
      known of LAHG. sll0886 and homologs may be involved in controlling different
      physiological processes that respond to light of low fluence.

PMID- 12594027
TI  - Purification and characterization of an exo-beta-1,3-glucanase produced by
      Trichoderma asperellum.
AB  - Trichoderma asperellum produces at least two extracellular beta-1,3-glucanases
      upon induction with cell walls from Rhizoctonia solani. A beta-1,3-glucanase was
      purified by gel filtration and ion exchange chromatography. A typical procedure
      provided 35.7-fold purification with 9.5% yield. The molecular mass of the
      purified exo-beta-1,3-glucanases was 83.1 kDa as estimated using a 12% (w/v) SDS
      electrophoresis slab gel. The enzyme was only active toward glucans containing
      beta-1,3-linkages and hydrolyzed laminarin in an exo-like fashion to form
      glucose. The K(m) and V(max) values for exo-beta-1,3-glucanase, using laminarin
      as substrate, were 0.087 mg ml(-1) and 0.246 U min(-1), respectively. The pH
      optimum for the enzyme was pH 5.1 and maximum activity was obtained at 55 degrees
      C. Hg(2+) strongly inhibited the purified enzyme.

PMID- 12594028
TI  - Identification of mixed bacterial DNA contamination in broad-range PCR
      amplification of 16S rDNA V1 and V3 variable regions by pyrosequencing of cloned
      amplicons.
AB  - Using a sensitive and rapid method combining broad-range PCR amplification of
      bacterial 16S rDNA fragments and pyrosequencing for detection, identification and
      typing, we have found contaminating bacterial DNA in our reagents used for PCR.
      Identified bacteria are the water-borne bacterial genera Pseudomonas,
      Stenotrophomonas, Xanthomonas, Ralstonia and Bacillus. Our results are in
      concordance with recent reports of contaminated industrial water systems. In
      light of this conclusion, we believe that there is a need for increased awareness
      of possible contamination in uncertified widely used molecular biology reagents,
      including ultra-pure water. Since sequence-based 16S rDNA techniques are used in
      a variety of settings for bacterial typing and the characterization of microbial
      communities, we feel that future certification of molecular biology reagents, as
      free of nucleic acids, would be advantageous.

PMID- 12594029
TI  - Effect of catalase-specific inhibitor 3-amino-1,2,4-triazole on yeast peroxisomal
      catalase in vivo.
AB  - 3-Amino-1,2,4-triazole (3-AT) is known as an inhibitor of catalase to whose
      active center it specifically and covalently binds. Subcellular fractionation and
      immunoelectronmicroscopic observation of the yeast Candida tropicalis revealed
      that, in 3-AT-treated cells in which the 3-AT was added to the n-alkane medium
      from the beginning of cultivation, catalase transported into peroxisomes was
      inactivated and was present as insoluble aggregated forms in the organelle. The
      aggregation of catalase in peroxisomes occurred only in these 3-AT-treated cells
      and not in cells in which 3-AT was added at the late exponential growth phase.
      Furthermore, 3-AT did not affect the transportation of catalase into peroxisomes.
      The appearance of aggregation only in cells to which 3-AT was added from the
      beginning of cultivation suggests that, in the process of catalase transportation
      into yeast peroxisomes, some conformational change may take place and that
      correct folding may be inhibited by the binding of 3-AT to the active center of
      catalase. Accordingly, 3-AT will be an interesting compound for investigation of
      the transport machinery of the peroxisomal tetrameric catalase.

PMID- 12594030
TI  - Involvement of oxidative stress in the regulation of H(2)S production during
      ultradian metabolic oscillation of Saccharomyces cerevisiae.
AB  - Periodic evolution of H(2)S during aerobic chemostat culture of Saccharomyces
      cerevisiae resulted in ultradian metabolic oscillation via periodic inhibition of
      respiratory activity. To understand the nature of periodic H(2)S evolution, we
      investigated whether oxidative stress is associated with H(2)S production. The
      cellular oxidative states represented by intracellular level of lipid peroxides
      oscillated out of phase with the oscillation of dissolved O(2). Pulse addition of
      antioxidant, oxidative agent or inhibitor of antioxidation enzymes perturbed
      metabolic oscillation producing changes in H(2)S evolution. Analysis of H(2)S
      production profiles during perturbation of oscillation revealed that the amount
      of H(2)S production is closely linked with cellular oxidative states. Based on
      these results and our previous reports, we suggest that oxidative stresses result
      in periodic depletion of glutathione and cysteine, which in turn causes
      stimulation of the sulfate assimilation pathway and H(2)S production.

PMID- 12594032
TI  - A MurG assay which utilises a synthetic analogue of lipid I.
AB  - A standard assay for the MurG enzyme using a lipid I analogue [MurNAc(N(epsilon)
      dansylpentapeptide)-pyrophosphoryl (R,S)-alpha-dihydroheptaprenol] and
      radioactive UDP-N-acetylglucosamine was set up. A high concentration (35%) of
      dimethylsulfoxide was necessary for maximal activity. Separation and quantitation
      were accomplished by reverse-phase high performance liquid chromatography (HPLC)
      in isocratic conditions and on-line radioactivity detection, thereby providing a
      rapid and accurate assay. The kinetic parameters of the MurG reaction were
      determined; the reaction was shown to also catalyse the reverse reaction at a
      measurable rate. A lipid I analogue containing dihydroundecaprenol as the prenyl
      chain turned out to be a poor MurG substrate, presumably owing to aggregation.

PMID- 12594031
TI  - The KlFUS1 gene is required for proper haploid mating and its expression is
      enhanced by the active form of the Galpha (Gpa1) subunit involved in the
      pheromone response pathway of the yeast Kluyveromyces lactis.
AB  - The Kluyveromyces lactis FUS1 gene was cloned, physically characterized and its
      role in the mating response pathway was determined. The gene encodes a putative
      membrane protein, whose structure shows a single membrane-spanning segment, a
      short extracellular amino-terminus and a long carboxy-terminus, located in the
      cytoplasmic side. The predicted primary structure of the protein shows a number
      of serine and threonine residues in the amino-terminus, which in analogy to Fus1p
      of Saccharomyces cerevisiae might be O-glycosylated. A fus1-GFP hybrid protein
      was tentatively located in the plasma membrane of dividing cells and upon
      activation of the pheromone response pathway, the protein seems to be relocated
      at the tip of elongated cells. KlFus1p is required for optimal conjugation of
      sexual partners and its expression is significantly enhanced by overexpression of
      both a constitutively active form of KlGpa1p, the G protein alpha subunit that
      triggers the mating response in this strain, and the KlSte12p transcription
      factor. Inactivation of the KlSte12 protein strongly reduces mating and affects
      KlFUS1 gene expression. The KlFUS1 gene has been deposited in the GenBank under
      accession number AF519444.

PMID- 12594033
TI  - A new method for rapid screening of bacterial species- or subspecies-specific DNA
      probes.
AB  - A simple assay for the rapid screening of bacterial species- or subspecies
      specific DNA probes for the random cloning method is presented, involving the use
      of genomic DNAs as probes and recombinant plasmid DNAs containing genomic DNA
      digested with HindIII as targets. The optimal amount of target DNAs and the
      concentration of digoxigenin-labeled genomic DNA probes were 20 ng and 100 ng ml(
      1) (or 10 ng and 200 ng ml(-1)), respectively. The method was applied to the
      development of Fusobacterium nucleatum subspecies-specific probes. Our results
      showed that four out of 96 probes were F. nucleatum subspecies-specific, which
      was confirmed by Southern blot analysis. Our results indicate that the new method
      can be used for the rapid screening of species- or subspecies-specific probes.

PMID- 12594035
TI  - The ldb1 mutant of Saccharomyces cerevisiae is defective in Pmr1p, the yeast
      secretory pathway/Golgi Ca(2+)/Mn(2+)-ATPase.
AB  - The LDB1 gene of Saccharomyces cerevisiae was identified by complementation of
      the ldb1 mutant phenotype with a genomic library. We found that the ldb1 defect
      is complemented by PMR1 which codes for the yeast secretory pathway/Golgi
      Ca(2+)/Mn(2+)-ATPase. Besides that, the analysis of a null mutation of the PMR1
      gene revealed a phenotype identical to that of ldb1 mutant. Thus, LDB1 must be
      considered a synonym of PMR1.

PMID- 12594034
TI  - Broad and complex antifungal activity among environmental isolates of lactic acid
      bacteria.
AB  - More than 1200 isolates of lactic acid bacteria isolated from different
      environments were screened for antifungal activity in a dual-culture agar plate
      assay. Approximately 10% of the isolates showed inhibitory activity and 4% showed
      strong activity against the indicator mould Aspergillus fumigatus. The antifungal
      spectra for 37 isolates with strong activity and five isolates with low or no
      activity were determined. Several of the strains showed strong inhibitory
      activity against the moulds A. fumigatus, Aspergillus nidulans, Penicillium
      commune and Fusarium sporotrichioides, and also against the yeast Rhodotorula
      mucilaginosa. Penicillium roqueforti and the yeasts Pichia anomala and
      Kluyveromyces marxianus were not inhibited. Several isolates showed reduced
      antifungal activity after storage and handling. The majority of the fungal
      inhibitory isolates were identified by 16S rDNA sequencing as Lactobacillus
      coryniformis. Lactobacillus plantarum and Pediococcus pentosaceus were also
      frequently identified among the active isolates. The degree of fungal inhibition
      was not only related to production of lactic or acetic acid. In addition,
      antifungal cyclic dipeptides were identified after HPLC separation and several
      other active fractions were found suggesting a highly complex nature of the
      antifungal activity.

PMID- 12594036
TI  - Cloning and expression of hyaluronate lyase genes of Streptococcus intermedius
      and Streptococcus constellatus subsp. constellatus(1).
AB  - Hyaluronate lyase (HAase) genes of Streptococcus intermedius and Streptococcus
      constellatus subsp. constellatus were isolated. In S. constellatus subsp.
      constellatus, the deduced amino acid sequence of HAase was most similar to that
      of S. intermedius (68%), whereas the enzyme of S. intermedius was most similar to
      that of S. pneumoniae (72%). Upstream of the HAase gene on the opposite strands,
      an open reading frame of a putative glutathione peroxidase started in S.
      intermedius, and this arrangement was similar to that in S. pneumoniae but unlike
      that in S. constellatus subsp. constellatus. Cell lysates of Escherichia coli
      carrying each streptococcal gene showed HAase activity, demonstrating that each
      cloned gene actually coded for HAase.

PMID- 12594037
TI  - A family history of deoxyribonuclease II: surprises from Trichinella spiralis and
      Burkholderia pseudomallei.
AB  - Deoxyribonuclease IIalpha (DNase IIalpha) is an acidic endonuclease found in
      lysosomes and nuclei, and it is also secreted. Though its Caenorhabditis elegans
      homolog, NUC-1, is required for digesting DNA of apoptotic cell corpses and
      dietary DNA, it is not required for viability. However, DNase IIalpha is required
      in mice for correct development and viability, because undigested cell corpses
      lead to lesions throughout the body. Recently, we showed that, in contrast to
      previous reports, active DNase IIalpha consists of one contiguous polypeptide. To
      better analyze DNase II protein structure and determine residues important for
      activity, extensive database searches were conducted to find distantly related
      family members. We report 29 new partial or complete homologs from 21 species.
      Four homologs with differences at the purported active site histidine residue
      were detected in the parasitic nematodes Trichinella spiralis and Trichinella
      pseudospiralis. When these mutations were reconstructed in human DNase IIalpha,
      the expressed proteins were inactive. DNase II homologs were also identified in
      non-metazoan species. In particular, the slime-mold Dictyostelium, the protozoan
      Trichomonas vaginalis, and the bacterium Burkholderia pseudomallei all contain
      sequences with significant similarity and identity to previously cloned DNase II
      family members. We report an analysis of their sequences and implications for
      DNase II protein structure and evolution.

PMID- 12594038
TI  - Molecular and phylogenetic characterization of Zyx102, a Drosophila orthologue of
      the zyxin family that interacts with Drosophila Enabled.
AB  - Adherens junctions, which are cadherin-mediated junctions between cells, and
      focal adhesions, which are integrin-mediated junctions between cells and the
      extracellular matrix, are protein complexes that link the actin cytoskeleton to
      the plasma membrane and, in turn, to the extracellular environment. Zyxin is a
      LIM domain protein that is found in vertebrate adherens junctions and focal
      adhesions. Zyxin's molecular architecture and binding partner repertoire suggest
      roles in actin assembly and dynamics, cell motility, and nuclear-cytoplasmic
      communication. In order to study the function of zyxin in development, we have
      identified a zyxin orthologue in Drosophila melanogaster that we have termed
      Zyx102. Like its vertebrate counterparts, Zyx102 displays three carboxy-terminal
      LIM domains, a potential nuclear export signal, and three proline-rich motifs,
      one of which matches the consensus for mediating an interaction with Ena/VASP
      (Drosophila Enabled/Vasodilator-stimulated phosphoprotein) proteins. Here we show
      that Zyx102 and Enabled (Ena), the Drosophila member of the Ena/VASP family, can
      interact specifically in vitro and that this interaction does not occur when a
      particular mutant form of Ena, encoded by the lethal ena210 allele, is used.
      Lastly, we show that the zyx102 gene and Drosophila Ena are co-expressed during
      oogenesis and early embryogenesis, indicating that the two proteins may be able
      to interact during the development of the Drosophila egg chamber and early
      embryo.

PMID- 12594040
TI  - Genomic organization of ZP domain containing egg envelope genes in medaka
      (Oryzias latipes).
AB  - To provide insights into the diversity of egg envelope genes in teleosts, we
      determined the genomic organization and the map position of the medaka egg
      envelope genes expressed either in the oocytes or in the liver. There seems to be
      five classes of ZP domain containing egg envelope genes in vertebrates: zpa,
      zpax, zpb, zpc, and zpd. zpa, zpax, and zpb are much closely related than zpc.
      There is an expanded family of teleost-specific zpc genes. The duplication of the
      possible zpb/zpc cluster happened in the teleost lineage may be a cause of liver
      specific ZP gene evolution in teleosts. The inconsistent presence of a repetitive
      amino acid domain among teleost zpb and zpc gene products suggests rapid
      evolution of this domain. In addition, relative abundance of E-boxes in putative
      promoters of medaka oocyte-specific ZP genes suggests their regulation by basic
      helix-loop-helix transcription factors, particularly by FIGalpha.

PMID- 12594039
TI  - The genomic organization of mouse resistin reveals major differences from the
      human resistin: functional implications.
AB  - The resistin gene is a potential candidate for the etiology of insulin resistance
      and type 2 diabetes and has been implicated as the molecular link between type 2
      diabetes and obesity. Unlike the mouse resistin, expression of the human resistin
      appears to be regulated differently. We report comparative analyses of the mouse
      and human genomic fragments encoding the resistin gene. At the amino acid level
      the two proteins exhibit 59% identity. While at the mRNA level the human resistin
      shows 64.4% sequence identity with its mouse counterpart, the mouse resistin
      genomic sequence displays only 46.7% sequence identity with the human resistin
      and is almost three times bigger than the human resistin. The intronic sequences
      per se displayed the least identities (28.7%), however the intron boundaries were
      highly conserved between human and mouse. The mouse resistin carries a very large
      intron in the 3' UTR, which has a number of regulatory sequences possibly
      involved in differential gene expression. Of particular significance is the
      presence of a PPAR/RXR heterodimer binding site within intron X (IntX-PPRE) which
      may possibly confer TZD responsiveness. Oligonucleotides carrying the authentic
      PPAR/RXR binding element (Aco-PPRE) as well as IntX-PPRE specifically bound
      factors (PPAR/RXR heterodimers) present in differentiated 3T3-L1 adipocyte cells
      in an electrophoretic mobility shift assay. IntX-PPRE oligonucleotide modulated
      the expression of the luciferase reporter gene in transient transfection assays
      using 3T3-L1 cells.

PMID- 12594041
TI  - Comparative sequence and expression analyses of four mammalian VPS4 genes.
AB  - The VPS4 gene is a member of the AAA-family; it codes for an ATPase which is
      involved in lysosomal/endosomal membrane trafficking. VPS4 genes are present in
      virtually all eukaryotes. Exhaustive data mining of all available genomic
      databases from completely or partially sequenced organisms revealed the existence
      of up to three paralogues, VPS4a, -b, and -c. Whereas in the genome of lower
      eukaryotes like yeast only one VPS4 representative is present, we found that
      mammals harbour two paralogues, VPS4a and VPS4b. Most interestingly, the Fugu
      fish contains a third VPS4 paralogue (VPS4c). Sequence comparison of the three
      VPS4 paralogues indicates that the Fugu VPS4c displays sequence features
      intermediate between VPS4a and VPS4b. Using complete mammalian VPS4a and VPS4b
      cDNA clones as probes, genomic clones of both VPS4 paralogues in human and mouse
      were identified and sequenced. The chromosomal loci of all four VPS4 genes were
      determined by independent methods. A BLAST search of the human genome database
      with the human VPS4A sequence yielded a double match, most likely due to a faulty
      assembly of sequence contigs in the human draft sequence. Fluorescent in situ
      hybridization and radiation hybrid analyses demonstrated that human and mouse
      VPS4A/a and VPS4B/b are located on syntenic chromosomal regions. Northern blot
      and semi-quantitative reverse transcription analyses showed that mouse VPS4a and
      VPS4b are differentially expressed in different organs, suggesting that the two
      paralogues have developed different functional properties since their divergence.
      To investigate the subcellular distribution of the murine VPS4 paralogues, we
      transiently expressed various fluorescent VPS4 fusion proteins in mouse 3T3
      cells. All tested VPS4 fusion proteins were found in the cytosol. Expression of
      dominant-negative mutant VPS4 fusion proteins led to their concentration in the
      perinuclear region. Co-expression of VPS4a-GFP and VPS4b-dsRed fusion proteins
      revealed a partial co-localization that was most prominent with mutant VPS4a and
      VPS4b proteins. A physical interaction between the mouse paralogues was also
      supported by two-hybrid analyses.

PMID- 12594043
TI  - Analysis of the flanking regions of the human alpha-lactalbumin gene responsible
      for position-effect independent expression.
AB  - Transgenic rats with the 130 kb bacterial artificial chromosome construct bLA,
      including the alpha-lactalbumin gene, had position-independent and copy number
      dependent expression, which confirmed previous experiments using the 210 kb yeast
      artificial construct, yLALBA. To identify elements that confer a position effect,
      we compared the yLALBA and bLA sequences. yLALBA was chimeric. A common 32 kb
      region was identified and the total nucleotide sequence was determined. We
      previously analyzed transgenic rats using polymerase chain reaction to compare
      the integrity and expression of the transgenes. The -6 to +9 kb region is
      considered to be necessary for position-independent expression. Transgenic rats
      lacking the -3.4 to -0.85 kb region had a severe position effect. This 2.5 kb
      region contains two DNaseI hypersensitive sites at -1.0 and -2.8 kb. The 2.5 kb
      region is proposed to be a locus control region of the human alpha-lactalbumin
      gene.

PMID- 12594042
TI  - Alternative splicing of Pax3 produces a transcriptionally inactive protein.
AB  - Pax3, a member of the paired-class homeodomain family of transcription factors,
      plays an important role in embryonic development of neurepithelium and mesenchyme
      derived tissues in the mouse and is an early marker for myogenic differentiation.
      In the present work we identify an alternative splicing event for endogenous Pax3
      in primary mouse myoblasts. The resulting splice variant arises through the
      utilization of a previously unreported splice donor consensus sequence present at
      the junction between exons 7 and 8 in the Pax3 sequence. The use of this splice
      donor site in conjunction with the splice acceptor site present between intron 8
      and exon 9 results in the deletion of exon 8 and removes a majority of the Pax3
      transcriptional activation domain. Consistent with this fact, we demonstrate that
      the alternatively spliced form of Pax3 is transcriptionally inactive and that the
      presence of this isoform can effectively inhibit the activity of the full-length
      protein.

PMID- 12594044
TI  - Genomic organization and alternative transcripts of the human Connexin40 gene.
AB  - The human Cx40 gene (NT_004434.5) was sorted out from the GenBank database and as
      a result of a BLAST homology search, two ESTs (BE784549 from a human lung
      database, and BE732411 from a human placenta database) overlapping with the
      coding exon 2 sequence and upstream regions of the gene were identified. These
      ESTs correspond to two transcripts 1A and 1B, which diverge from each other in
      their 5' regions. The transcript 1A corresponds to the only transcript previously
      identified for the mouse and rat Cx40 genes; whereas the transcript 1B is a new
      transcript. The human Cx40 gene therefore comprises three exons: exon 1A (100
      bp), exon 1B (132 bp) and coding exon 2, with the exons 1A and 1B at 14 and 1.3
      kb of the exon 2, respectively. The expression of these transcripts is cell-type
      specific. Transcript 1A is expressed in endothelial cells. Its expression was
      demonstrated in human umbilical vein endothelial cells (HUVEC). Transcript 1B is
      expressed in placental cytotrophoblasts. Its expression was demonstrated in
      malignant trophoblastic cells, BeWo, JAR and JEG-3, and purified cytotrophoblasts
      from human first trimester placental tissues. Interestingly, both transcripts 1A
      and 1B are expressed in the right atrial appendages (RAA), although the cell-type
      expression of the two transcripts in this particular tissue has not yet been
      determined. Both transcripts were found to be expressed in the various heart
      regions investigated, where transcript 1B was found to always occur rarely in
      comparison with transcript 1A. Transcripts 1A and 1B are both more abundant in
      the atria than in the ventricles. Luciferase reporter gene assays demonstrated
      that two genomic regions containing the exons 1A and 1B induced a cell-type
      specific expression. The 1.2 kb sequence, containing the exon 1A, induced an
      increase of the luciferase activity in HUVEC; whereas the 1.9 kb sequence,
      containing the exon 1B, induces an increase of expression of the luciferase
      activity in BeWo cells. The DNA sequence upstream of the exon 1A contains SP1
      binding sites, but no TATA- or CAAT-box; whereas the region upstream of the exon
      1B is preceded by three CAAT-boxes. Thus, in contrast to the mouse and rat Cx40
      genes, the human Cx40 gene organized in three exons and generates two
      transcripts, which are cell-type specific.

PMID- 12594045
TI  - SF4 and SFRS14, two related putative splicing factors on human chromosome
      19p13.11.
AB  - The splicing of nascent mRNA precursors is an essential step for the expression
      of all intron-containing eukaryotic genes. Removal of intron sequences from
      nascent transcripts is mediated by the spliceosome, a large multicomponent
      complex. We describe here the identification of two genes encoding related,
      putative splicing factors on human chromosome 19p13.11, SF4 (splicing factor 4)
      and SFRS14 (splicing factor arginine/serine-rich 14). Both genes encode proteins
      containing a SURP motif; this domain is found in several splicing proteins
      including Drosophila alternative splicing regulator, suppressor-of-white-apricot
      (SWAP) and the yeast splicing factor, prp21p. In addition, SF4 and SFRS14 contain
      a G-patch domain at their C-termini, a motif present in a large number of
      eukaryotic RNA-binding proteins. SFRS14 also contains an N-terminal region that
      is rich in arginine/serine residues, suggesting SFRS14 is a novel member of the
      SR-related family of pre-mRNA processing factors. We have also identified the
      mouse orthologues of SF4 and SFRS14, based on conserved domain organization and
      high sequence similarity. Interestingly, SFRS14 undergoes alternative 3'-end
      processing events that are conserved between human and mouse, suggesting a
      functional significance.

PMID- 12594046
TI  - An enhancer activates the pig lactase phlorizin hydrolase promoter in intestinal
      cells.
AB  - Lactase phlorizin hydrolase is a small intestinal-specific brush border protein
      commonly used as a specific marker of differentiated enterocytes. A number of
      transcription factors involved in the enterocyte-specific expression of lactase
      phlorizin hydrolase have been identified. An upstream regulatory region, which we
      have named the "LPH enhancer", located at position -894 to -798 in the porcine
      lactase phlorizin hydrolase gene, is necessary for high differentiation-dependent
      LPH expression in intestinal cells. The LPH enhancer was studied by mutation
      analysis, transfection experiments and electrophoretical mobility shift assays.
      The LPH enhancer is active in intestinal cells (Caco-2) and not in non-intestinal
      cells (HeLa). The LPH enhancer is only able to enhance expression when it is
      located in front of an intestinal-specific promoter such as the lactase phlorizin
      hydrolase promoter or the sucrase-isomaltase promoter. In front of an SV40
      derived promoter the LPH enhancer has no stimulatory effect. In addition to the
      lack of promoter-promiscuity, the LPH enhancer is not a classical enhancer in the
      sense that it is not orientation-independent and it cannot function when located
      3' of a reporter gene. The LPH enhancer contains at least three cis-elements (at 
      894 to -880, -880 to -875 and -833 to -814) with functional importance for the
      LPH enhancer activity.

PMID- 12594047
TI  - Genomic structure and promoter analysis of human NeuAc alpha2,3Gal beta1,3GalNAc
      alpha2,6-sialyltransferase (hST6GalNAc IV) gene.
AB  - We have cloned the genomic DNA encoding the human NeuAc alpha2,3Gal beta1,3GalNAc
      alpha2,6-sialyltransferase (hST6GalNAc IV) and analysed its structure. The
      hST6GalNAc IV gene was found to span about 9 kb and to be composed of six exons.
      The 5'-RACE (rapid amplification of cDNA ends) results indicated that mRNA
      isoform of the hST6GalNAc IV was generated by alternative splicing in the 5'
      untranslated region. The expression of this gene was highly restricted in human
      fetal tissues. The potential transcriptional start site was determined by CapSite
      hunting. Sequence analysis of the 5'-flanking region of this gene lacked
      canonical TATA and CAAT boxes, but contained several putative binding sites for
      transcription factors SP1, MZF1, GATA1, LMO2COM, NFAT, HFH8 and USF, etc.
      Functional analysis of the 5'-flanking region by transient expression method
      revealed a high transcriptional activity in both HepG2 cells and Molt4 cells in a
      cell type-dependent manner, but not in SK-N-MC cells. These results suggest cell
      type-specific regulation of the basal hST6GalNAc IV promoter activity.

PMID- 12594048
TI  - Gene structure and minimal promoter of mouse rdh1.
AB  - Mouse rdh1 encodes retinol dehydrogenase type 1 (RDH1), a short-chain
      dehydrogenase, which recognizes as substrates all-trans-retinol, 9-cis-retinol,
      5alpha-androstan-3,17-diol and 5alpha-androstan-3-ol-17-one. RDH1 is the most
      efficient known mouse short-chain dehydrogenase that catalyzes dehydrogenation of
      all-trans-retinol, and contributes to a reconstituted path of all-trans-retinoic
      acid biosynthesis, when coexpressed in reporter cells with any one of three
      retinal dehydrogenases. Rdh1 shows widespread, if not ubiquitous, mRNA expression
      in the mouse beginning no later than embryo day 7. Here we report genomic
      organization, chromosomal localization and analysis of a minimum promoter of
      mouse rdh1. Rdh1 consists of four exons and three introns and spans approximately
      14412 bp. Rdh1 is a single copy gene that maps to chromosome 10D3 with rdh5-9,
      but no known disorder maps precisely to rdh1. Rdh1 has three transcription start
      sites in kidney and one start site in liver. The rdh1 5'-region between -424 and
      +43 induces transcription maximally in COS7, mouse kidney RAG, and mouse liver
      NMu3Li cells. This section has no TATA box, but has a CCAAT box beginning 65 bp
      upstream of the major transcription start site, which is required for
      transcription of transfected reporter constructs. An AP1 binding site at -119
      also activates transfected reporter constructs, and mediates 2-O
      tetradecanoylphorbol-13-acetate (TPA) induced transcription. All-trans-retinoic
      acid antagonizes the TPA affect; however, no RARE or RXRE was found in the
      proximal promoter region, consistent with indirect regulation by all-trans
      retinoic acid.

PMID- 12594049
TI  - Expression of a ripening-related cytochrome P450 cDNA in Cavendish banana (Musa
      acuminata cv. Williams).
AB  - As part of a study to understand the molecular basis of fruit ripening, this
      study reports the isolation and characterization of a banana cytochrome P450
      (P450) cDNA, designated as MAP450-1, which was associated with fruit ripening of
      banana. MAP450-1 encoded a single polypeptide of 507 amino acid residues that
      shared an overall identity of 27-45% with that of several plant P450s, among
      which MAP450-1 was most related phylogenetically to the avocado P450 CYP71A1. The
      polypeptide that possessed residue domains conserved in all P450s was classified
      as CYP71N1. Expression of CYP71N1 varied greatly between banana organs.
      Transcripts were detected only in peel and pulp of the ripening fruit and not in
      unripe fruit tissues at all developmental stages or other organs (root, leaf,
      ovary and flower). During ripening, transcripts were barely detectable in pre
      climacteric and climacteric fruits but, as ripening progressed, they began to
      accumulate and reached a maximum in post-climacteric fruits. CYP71N1 expression
      in pre-climacteric fruit could be upregulated by exogenous application of
      ethylene (1-5 ppm) and treatment of overripe fruit with exogenous sucrose (50-300
      mM) but not glucose downregulated the expression. These results indicate that
      P450s may not play a role in fruit development and its expression is associated
      with ripening, which may be regulated, in part, by ethylene and/or sucrose, at
      the transcript level.

PMID- 12594050
TI  - Lung sensors: complex functions require complex structures.

PMID- 12594051
TI  - Making More MUCS.

PMID- 12594052
TI  - Retinoids, alveolus formation, and alveolar deficiency: clinical implications.

PMID- 12594053
TI  - Dual sensory innervation of pulmonary neuroepithelial bodies.
AB  - The characteristics of the different populations of sensory nerve terminals that
      selectively contact pulmonary neuroepithelial bodies (NEBs) in rat lungs were
      investigated after chemical denervation with capsaicin and compared with control
      lungs. Vagal calbindin D28k and P2X(3) purinoceptor immunoreactive (IR) afferent
      nerve terminals contacting NEBs appeared to have their origin in the nodose
      ganglion. Thick CB/P2X(3)-IR nerve fibers were seen to be myelinated and to lose
      their myelin sheaths just before branching and protruding intraepithelially
      between the NEB cells. This vagal sensory component of the innervation of NEBs
      was not affected by capsaicin nor expressed capsaicin receptors (vanilloid
      receptor subtype 1). A second sensory nerve fiber population that selectively
      innervates pulmonary NEBs in the rat lung consists of thin unmyelinated nonvagal
      substance P/calcitonin gene-related peptide IR nerve fibers, contacting mainly
      the basal pole of pulmonary NEBs, and having their origin in dorsal root ganglia.
      In concordance with vanilloid receptor 1 expression on these nerve terminals, the
      spinal sensory substance P/calcitionin gene-related peptide-IR component of the
      innervation of NEBs was depleted by systemic capsaicin treatment. The complex
      sensory innervation pattern of pulmonary NEBs characterized in the present study
      strongly suggests that, physiologically, pulmonary NEBs represent a group of
      intraepithelial receptors that may be able to accommodate various local and
      central reflex actions, in relation to both chemo- and mechanosensory stimuli.

PMID- 12594054
TI  - Interleukin-9 induces goblet cell hyperplasia during repair of human airway
      epithelia.
AB  - Asthma is characterized by airway inflammation, smooth muscle hyperreactivity,
      and airway remodeling with excessive mucus production. The effect cytokines like
      interleukin (IL)-9 have on airway epithelia has been addressed using murine
      models of asthma, as well as transgenic and knockout mice. Though highly
      informative, differences exist between mouse and human airway epithelia,
      including cellular composition (e.g., Clara cells) and stem cell/plasticity
      capabilities. Therefore, to address cytokine effects on human airway epithelia,
      we have used a primary model system to ask whether IL-9 can alter cell fates of
      human airway epithelia. Here, we show that IL-9 has little effect on fully
      differentiated ciliated human airway epithelia. However, in the setting of airway
      injury repair, IL-9 results in goblet cell hyperplasia. A similar response was
      observed when the epithelium was exposed to IL-9 before it became fully
      differentiated. Moreover, exposure to IL-9 resulted in increased lysozyme and
      mucus production by the epithelia. Thus, a combination of IL-9 and mechanical
      injury can explain, in part, goblet cell hyperplasia that is evident in the lungs
      of individuals with asthma. These data suggest that interventions that limit
      airway epithelial damage, block IL-9, or modulate the repair process should
      result in decreased airway remodeling and prevent the chronic manifestations of
      this disease.

PMID- 12594055
TI  - Retinoic acid inhibits elastase-induced injury in human lung epithelial cell
      lines.
AB  - The protective effects of retinoic acid on elastase-induced lung epithelial cell
      injury were studied using elastase extracted from purulent human sputum, the BEAS
      2B human bronchial epithelial cell line, A549 human type II lung cell line, and
      primary cultures of human tracheal epithelial cells. Elastase decreased viability
      of BEAS-2B cells, A549 cells, and human tracheal epithelial cells in
      concentration- and time-dependent fashions. Elastase also induced apoptosis of
      BEAS-2B cells, A549 cells, and the tracheal epithelial cells detected with cell
      death detection enzyme-linked immunosorbent assay and terminal
      deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)
      methods. Retinoic acid alone did not affect the viability of BEAS-2B cells, A549
      cells, or the tracheal epithelial cells, and did not induce apoptosis of the
      cells. However, retinoic acid prevented the decreases in the viability and
      reduced apoptosis of BEAS-2B cells, A549 cells, and the tracheal epithelial cells
      induced by elastase. Likewise, retinoic acid inhibited caspase 3 activity in BEAS
      2B cells and A549 cells induced by elastase, as well as proteolytic activity of
      elastase. Furthermore, caspase 3 inhibitor inhibited the elastase-induced
      apoptosis of the cells. These findings suggest that retinoic acid may inhibit
      elastase-induced lung epithelial cell injury partly through the inhibition of
      proteolytic activity of elastase and through the inhibition of caspase 3 activity
      by elastase. Retinoic acid may, therefore, have protective effects against the
      elastase-induced lung injury and subsequent development of pulmonary emphysema.

PMID- 12594057
TI  - Intratracheal macrophage-activating lipopeptide-2 reduces metastasis in the rat
      lung.
AB  - Primary surgery of tumors bears the risk of metastasis to organs such as the
      lungs. In order to prevent such metastatic processes, in the present study, local
      intratracheal instillation of macrophage-activating lipopeptide-2 (MALP-2) as a
      bacterial-derived immunomodulator of cellular host defense responses was
      performed, and the effects on tumor cell clearance as well as tumor colonization
      were investigated in the lungs of Fischer 344 (F344) rats. Compared with vehicle
      controls, local administration of MALP-2 parallel to intravenous inoculation of
      MADB106 mammary adenocarcinoma tumor cells resulted in a significant reduction of
      lung colony numbers, whereas MALP-2 application 1 or 3 d afterwards was not
      effective. Quantification of leukocyte subsets in the lung tissue by
      immunohistochemistry revealed a significant increase of the number of monocytes
      in situ, as well as an increased co-localization of Natural Killer (NK) cells
      with tumor cells. Synthetic MALP-2 is easily available, with virtually no
      limitation to the amount of compound, and easily applicable by inhalation.
      Therefore, as local immunostimulative effects of the bacterial antigen MALP-2
      have successfully been demonstrated, its use as an immunotherapeutic agent is
      worth further investigation.

PMID- 12594056
TI  - Reactive oxygen species and extracellular signal-regulated kinase 1/2 mitogen
      activated protein kinase mediate hyperoxia-induced cell death in lung epithelium.
AB  - Therapy with high oxygen concentrations (hyperoxia) is often necessary to treat
      patients with respiratory failure. However, hyperoxia may exacerbate the
      development of acute lung injury, perhaps by increasing lung epithelial cell
      death. Therefore, interrupting lung epithelial cell death is an important
      protective and therapeutic strategy. In the present study, hyperoxia (95% O(2))
      results in murine lung epithelium cell death by DNA-laddering, terminal
      deoxynucleotidyltransferase dUTP nick end labeling, and Annexin V-fluorescein
      isothiocyanate flow cytometry assay. We show that hyperoxia increases superoxide
      production, as assessed by nicotinamide adenine dinucleotide phosphate reduced
      (NADPH) oxidase activity and flow cytometric assay, and increases phospho
      extracellular signal-regulated kinase (ERK)1/2 by Western blot analysis. These
      processes are inhibited by a reactive oxygen species inhibitor, diphenylene
      iodonium (DPI), and by an inhibitor of the mitogen-activated protein (MAP) or ERK
      kinase (MEK)/ERK1/2 pathway, PD98059. ERK1/2 activation in hyperoxia is also
      inhibited by DPI. Hyperoxia-induced cell death is associated with cytochrome c
      release, subsequent caspase 9 and 3 activation, and poly (ADP-ribosyl) polymerase
      cleavage, which can all be suppressed by DPI and PD98059. However, the broad
      caspase inhibitor z-VAD-FMK protects cells from death without affecting
      superoxide generation and ERK1/2 activation. Taken together, our data suggest
      that hyperoxia, by virtue of activating NADPH oxidase, generates reactive oxygen
      species (ROS), which mediates cell death of lung epithelium via ERK1/2 MAPK
      activation, and functions upstream of caspase activation in lung epithelial
      cells.

PMID- 12594058
TI  - Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1
      prevents lung inflammation in a murine model of asthma.
AB  - Airway inflammation is a central feature of asthma and chronic obstructive
      pulmonary disease. Reactive oxygen species (ROS) contribute to inflammation by
      damaging DNA, which, in turn, results in the activation of poly(ADP-ribose)
      polymerase-1 (PARP-1) and depletion of its substrate, nicotinamide adenine
      dinucleotide. Here we show that prevention of PARP-1 activation protects against
      both ROS-induced airway epithelial cell injury in vitro and airway inflammation
      in vivo. H(2)O(2) induced the generation of ROS, PARP-1 activation and
      concomitant nicotinamide adenine dinucleotide depletion, and release of lactate
      dehydrogenase in A549 human airway epithelial cells. These effects were blocked
      by the PARP-1 inhibitor 3-aminobenzamide (3-AB). Furthermore, 3-AB inhibited both
      activation of the proinflammatory transcription factor nuclear factor-kappaB and
      expression of the interleukin-8 gene induced by H(2)O(2) in these cells. In a
      murine model of allergen-induced asthma, 3-AB prevented airway inflammation
      elicited by ovalbumin. Moreover, PARP-1 knockout mice were resistant to such
      ovalbumin-induced inflammation. These protective effects were associated with an
      inhibition of expression of the inducible nitric oxide synthase. These results
      implicate PARP-1 activation in airway inflammation, and suggest this enzyme as a
      potential target for the development of new therapeutic strategies in the
      treatment of asthma as well as other respiratory disorders such as chronic
      obstructive pulmonary disease.

PMID- 12594059
TI  - Bradykinin induces interleukin-6 production in human airway smooth muscle cells:
      modulation by Th2 cytokines and dexamethasone.
AB  - Synthetic function of airway smooth muscle (ASM), defined as secretion of
      cytokines or chemokines, may regulate airway inflammatory responses in chronic
      obstructive lung diseases. Because bradykinin (BK) and interleukin (IL)-6 may
      play important roles in the regulation of airway inflammation, we tested whether
      BK induces IL-6 expression from human ASM cells. BK stimulates IL-6 release in a
      concentration-dependent (0.001-10 micro M) and time-dependent (2-24 h) manner.
      The increases in IL-6 protein and total mRNA were inhibited by the selective B(2)
      receptor antagonist HOE-140 but not by the selective B(1) receptor antagonist
      desArg(9)(Leu(8))-BK. Actinomycin D (a transcription inhibitor), dexamethasone,
      indomethacin, IL-4, and IL-13 (Th(2) type cytokines) inhibited the expression of
      IL-6 by BK. In contrast, BK-induced IL-6 secretion was enhanced by exogenous
      prostaglandin E(2) and salmeterol. Using immunoblot analysis, we showed that BK
      activates ERK1/2 and p38 mitogen-activated protein kinases (MAPK). Blocking
      ERK1/2 with PD98059 or p38 MAPK with SB203580 reduced BK-induced IL-6 expression.
      BK also activates luciferase activity in ASM cells transfected with a reporter
      plasmid containing AP-1 enhancer elements. BK-induced, AP-1-dependent
      transcription was inhibited by indomethacin and dexamethasone. Curcumin, an
      inhibitor of AP-1, also reduced BK-induced IL-6 expression. These data show that
      BK, via the B(2) receptor, induces IL-6 expression in ASM cells by involving
      ERK1/2 and p38 MAPK signaling pathways and the AP-1 transcription factor.
      Moreover, IL-6 secretion by BK is sensitive to corticosteroids and is regulated
      by Th(2)-derived cytokines.

PMID- 12594060
TI  - Proteinase-activated receptor-2 and human lung epithelial cells: disarming by
      neutrophil serine proteinases.
AB  - Proteinase-activated receptor (PAR)-2 is cleaved within its aminoterminal
      extracellular domain by serine proteinases such as trypsin, unmasking a new
      aminoterminus starting with the sequence SLIGKV, which binds intramolecularly and
      activates the receptor. PAR-2 has been reported to be involved in inflammation
      within the lungs. We show that PAR-2 is expressed not only by human alveolar
      (A549), but also by bronchial (16HBE) epithelial cell lines, using RT-PCR and
      flow cytometry with a PAR-2 antibody whose epitope maps over the trypsin cleavage
      site. PAR-2 activation by trypsin and by the activating peptide SLIGKV-NH(2)
      leads to intracellular calcium mobilization in both lung epithelial cells. During
      lung inflammation, airspaces are burdened by neutrophils that release elastase
      and cathepsin G, two serine proteinases. We demonstrate that these proteinases do
      not activate PAR-2, but rather disarm the receptor, preventing activation by
      trypsin but not by SLIGKV-NH(2). Preincubation of a PAR-2-transfected cell line,
      as well as 16HBE and A549 cells, with either proteinase led to the disappearance
      of the cleavage/activation epitope recognized by the PAR-2 antibody. We
      hypothesize that elastase and cathepsin G disarm PAR-2 by proteolysis of the
      extracellular domain downstream from the trypsin cleavage/activation site, while
      leaving unmodified the SLIGKV-NH(2)-binding site. These findings suggest that the
      neutrophil serine proteinases may play a role in PAR-2-mediated lung
      inflammation.

PMID- 12594061
TI  - Surfactant protein A inhibits lipopolysaccharide-induced in vivo production of
      interleukin-10 by mononuclear phagocytes during lung inflammation.
AB  - We previously demonstrated that resident alveolar macrophages from naive mice do
      not synthesize interleukin (IL)-10, whereas mononuclear phagocytes (MP) recruited
      during the lung inflammatory process are transiently competent for IL-10
      production when exposed to lipopolysaccharide (LPS) in vitro. As surfactant
      protein A (SP-A), a member of the collectin family, inhibits LPS-induced in vitro
      IL-10 formation by bone marrow-derived macrophages, we studied its effect on MP
      under in vivo inflammatory conditions. When mice with LPS-induced inflamed lungs
      were given a second intranasal LPS administration, IL-10 concentration recovered
      in the bronchoalveolar lavage fluids varied as a function of the time interval
      between the two LPS doses. Thus, IL-10 concentration increased with the number of
      MP up to Day 3, and then decreased to undetectable values within 24 h, despite a
      continued increase in the number of MP. Analysis of IL-10 mRNA from purified MP
      indicated that gene expression correlated with the IL-10 level in the
      bronchoalveolar lavage fluid. In contrast to IL-10 production, SP-A
      concentrations during LPS-induced inflammation decreased with a nadir at Day 3,
      and then increased significantly within 24 h. Furthermore, intranasal
      administration of exogenous SP-A to mice with LPS-induced inflamed lungs led to a
      repression of the IL-10 production. In summary, this study demonstrates for the
      first time an in vivo inhibitory role of SP-A on the anti-inflammatory activity
      of MP, through inhibition of IL-10 production.

PMID- 12594062
TI  - Tumor necrosis factor-alpha-induced synthesis of interleukin-16 in airway
      epithelial cells: priming for serotonin stimulation.
AB  - Epithelial cells from individuals with asthma or from allergen-sensitized mice
      contain intracellular interleukin (IL)-16 protein, not present in epithelial
      cells from individuals without asthma or unsensitized mice. IL-16 is only present
      in the bronchoalveolar lavage (BAL) fluid following airway challenge with either
      allergen or vasoactive amine. This suggests that the initial response to allergen
      (sensitization) results in synthesis but not secretion of IL-16. In this study,
      we investigated what factors produced during the sensitization phase are
      responsible for epithelial cell priming for IL-16 production. We determined that
      ovalbumin (OVA)-sensitized mice have an increase in systemic tumor necrosis
      factor-alpha levels, and that serum or BAL fluid stimulation of bronchial
      epithelial cells results in production of IL-16 that is subsequently secreted
      only following serotonin stimulation. The mechanism for IL-16 production was
      shown to be caspase-3-dependent, and serotonin-induced secretion of IL-16
      required binding of the serotonin type 2 receptor. The relevance of the priming
      effect associated with sensitization for IL-16 production and storage was
      confirmed in vivo by serotonin airway challenge of OVA-sensitized mice, resulting
      in rapid secretion of IL-16 into BAL fluid. As IL-16 has been shown to regulate
      CD4+ cell recruitment and activation, and is detected early following airway
      challenge of individuals with asthma, this two-step process for IL-16 production
      by epithelial cells may represent a rapid response mechanism in the orchestration
      of allergic airway inflammation.

PMID- 12594063
TI  - Large conductance Ca2+-activated K+ channels sense acute changes in oxygen
      tension in alveolar epithelial cells.
AB  - The rise in alveolar oxygen tension (PO(2)) that occurs as the newborn infant
      takes its first breaths induces removal of liquid from the lung lumen due to ion
      transport across the alveolar epithelium and the activity of alveolar Na(+)
      channel (ENaC). In the present study, we have aimed to identify an ion
      conductance in alveolar epithelial A549 cells that responds to acute changes in
      PO(2). Variation in PO(2) did not affect single-channel ENaC activity. However,
      in these cells we have detected single-channel conductance having properties
      similar to those of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels.
      Reverse transcriptase-polymerase chain reaction and Western blotting demonstrated
      presence of alpha-BKCa channel subunit and iberiotoxin, a blocker of BK(Ca)
      channels, inhibited whole cell K(+) current. Chronic changes in PO(2) did not
      affect expression, recruitment, or function of BK(Ca) channels in A549 cells. In
      contrast, acute changes of PO(2) regulated the BK(Ca) channel activity by
      controlling the channel mean open time. This effect of PO(2) was insensitive to
      inhibitor of flavoproteins, diphenylene iodinium. In addition, decrease in PO(2)
      and iberiotoxin induced membrane depolarization and Ca(2+) oscillations in A549
      cells. We conclude that BK(Ca) channels serve as oxygen sensors in human alveolar
      A549 epithelial cells.

PMID- 12594064
TI  - Surfactant protein B inhibits endotoxin-induced lung inflammation.
AB  - Transgenic mice, in which the level of surfactant protein (SP)-B mature peptide
      varied 5.6-fold between SP-B(+/-) and SP-B-overexpressing lines (SP-B+/+/+), were
      used to test the hypothesis that SP-B protects against endotoxin-induced lung
      inflammation. Intratracheal administration of endotoxin resulted in significantly
      lower concentration of SP-B mature peptide and elevated levels of total protein
      in bronchoalveolar lavage fluid of SP-B(+/-) mice compared with SP-B
      overexpressing mice, indicating that endotoxin treatment leads to impairment of
      SP-B expression coincident with increased lung injury in SP-B(+/-) mice.
      Recruitment of inflammatory cells and elaboration of proinflammatory cytokines in
      bronchoalveolar lavage fluid were reduced in SP-B-overexpressing mice compared
      with SP-B(+/-) mice, suggesting that SP-B inhibited endotoxin-induced lung
      inflammation. Lung compliance and tissue damping were significantly decreased in
      SP-B(+/+) and SP-B(+/-) mice, but were not changed in SP-B(+/+/+) mice,
      consistent with a protective effect of SP-B. The minimum surface tension of large
      aggregate surfactant was significantly lower for surfactant isolated from SP-B
      overexpressing mice, both in the absence and the presence of added plasma
      proteins. These data suggest that SP-B protected against endotoxin-induced lung
      inflammation by enhancing surfactant function, resulting in reduced lung injury,
      decreased influx of inflammatory cells, and lower cytokine levels; in contrast,
      levels of SP-B in SP-B(+/-) mice were further decreased by endotoxin treatment,
      likely exacerbating lung injury in this group.

PMID- 12594065
TI  - Polymorphisms in the IL13, IL13RA1, and IL4RA genes and rate of decline in lung
      function in smokers.
AB  - Targeted expression of interleukin (IL)-13 in the adult murine lung has been
      shown to cause emphysema. We hypothesized that variants in the IL13, IL13RA1, and
      IL4RA genes would be associated with an accelerated rate of decline of lung
      function among smokers. We determined the allele frequencies of five
      polymorphisms in the IL13, IL13RA1, and IL4RA genes in 588 continuing smokers
      chosen from the NHLBI Lung Health Study for having the fastest (n = 282) and
      slowest (n = 306) 5-yr rate of decline of lung function (mean change in FEV(1)
      %predicted/yr = -4.1 and +1.1, respectively). The IL4RA 551RR genotype was
      associated with rapid decline of lung function (odds ratio, 2.24; P = 0.043).
      However, none of the other four polymorphisms was associated with rate of decline
      in lung function. The association of 551RR with rapid decline of lung function
      became more significant in subjects who also had either the IL13 130RR or -1112TT
      genotypes. However, because multiple comparisons were made and only a few
      individuals had the 551RR genotype, these associations may represent type 1
      error. Haplotypes consisting of alleles from the IL13 polymorphisms or from the
      IL4RA polymorphisms were not associated with rate of decline in lung function in
      smokers.

PMID- 12594067
TI  - Teaching career enhancement awards: an opportunity not to miss.

PMID- 12594066
TI  - Shift toward an alternatively activated macrophage response in lungs of NO2
      exposed rats.
AB  - Inflammatory mechanisms are thought to play an important role in the pathogenesis
      of acute and chronic obstructive pulmonary diseases. In a rat inhalation model
      using continuous exposure to 10 ppm nitrogen dioxide for 1, 3, and 20 d, we
      investigated the inflammatory response with particular focus on the activation
      state of alveolar macrophages. Whereas the number of inflammatory cells and total
      protein concentration were increased in the bronchoalveolar lavage (BAL), the
      amount of the proinflammatory cytokine tumor necrosis factor-alpha was markedly
      reduced with increasing exposure time. In contrast, interleukin (IL)-10 and IL-6
      were found at elevated levels and intracellular amounts of suppressor of cytokine
      signaling-3 protein increased in BAL cells. Upon in vitro lipopolysaccharide
      stimulation, BAL cells revealed reduced capability to produce the proinflammatory
      mediators tumor necrosis factor-alpha, IL-1 beta, and nitric oxide, but showed
      markedly increased transcription and protein release for IL-10. In addition,
      elevated levels of IL-6, scavenger receptor B, and suppressor of cytokine
      signaling-3 mRNA were detected in BAL cells from exposed animals. Analyses of
      highly purified alveolar macrophages indicated that changes in the activation
      state of these cells were responsible for the observed effects. In conclusion, a
      priming toward development of the alternatively activated macrophage phenotype
      occurred in the lungs of rats following nitrogen dioxide inhalation.

PMID- 12594068
TI  - Efficient validation of teaching and learning using multiple-choice exams.
AB  - One purpose of this study was to quantify, by means of single-format, multiple
      choice questions at the beginning and end of the course, the extent to which
      first-year medical students learn neuroscience material from an introductory
      course in their curriculum. Compared with their precourse test performance (mean
      = 41.8%), collectively, the students nearly doubled their grade by the end of the
      course (mean = 81.4%). Their scores in subcategories of the material improved in
      inverse proportion to what they knew initially. A second goal was to evaluate a
      two-dimensional, computer-generated matrix as a way to assess test question
      validity and value. The evaluation of individual test questions as assessed from
      the matrix often, but not always, was similar to the classical pedagogical
      analysis that uses difficulty and discrimination indexes. Strengths of the matrix
      are its ability to render data as a gestalt, as well as flexibility and intuitive
      ease of use.

PMID- 12594069
TI  - Osmosis: a macroscopic phenomenon, a microscopic view.
AB  - At present, physical chemistry employs the tools of thermodynamics to treat
      osmosis across a semipermeable membrane. We propose a model in terms of momentum
      transfer, the inherent asymmetry of which leads quantitatively to the van't Hoff
      relationship; qualitatively, the solute molecules can be looked upon as
      micropumps that suck solvent through the pores in the membrane.

PMID- 12594070
TI  - An innovative method to enhance interaction during lecture sessions.
AB  - The B. P. Koirala Institute of Health Sciences, Dharan, is following an
      innovative hybrid curriculum. Conventional lectures are replaced by "structured
      interactive sessions" (SIS). SIS involves increased interchange between teachers,
      students, and lecture contents by proper planning and organized efforts. It can
      promote active learning and heighten attention and motivation. The present study
      was conducted to enhance active interactions during such sessions. The students
      were divided into two groups and asked to come prepared for the lectures.
      Students were encouraged to ask questions and interact informally during
      lectures. A scoreboard was maintained, and student feedback was taken at the end
      of the lecture block. The entire student response was reduced to a student
      acceptability index (SAI). Our results show a statistically significant increase
      in interactions per student per day. A majority of the responses in the
      questionnaire and SAI were favorable. Specific comments and suggestions of
      students were also positive. These results show that simple innovative techniques
      enhance the interactions during a lecture session.

PMID- 12594071
TI  - Inquiry-based laboratory course improves students' ability to design experiments
      and interpret data.
AB  - We redesigned our intermediate-level organismal physiology laboratory course to
      center on student-designed experiments in plant and human physiology. Our primary
      goals were to improve the ability of students to design experiments and analyze
      data. We assessed these abilities at the beginning and end of the semester by
      giving students an evaluation tool consisting of an experimental scenario, data,
      and four questions of increasing complexity. To control for nontreatment
      influences, the improvement scores (final minus initial score for each question)
      of students taking both the laboratory and the companion lecture course were
      compared with those of students taking the lecture course only. The laboratory +
      lecture group improved more than the lecture-only group for the most challenging
      question. This evidence suggests that our inquiry-based curriculum is achieving
      its primary goals. The evaluation tool that we developed may be useful to others
      interested in measuring experimental analysis abilities in their students.

PMID- 12594072
TI  - Laplace's law and the alveolus: a misconception of anatomy and a misapplication
      of physics.
AB  - Both the anatomy and the mechanics of inflation of the alveoli, as presented in
      most textbooks of physiology, have been misunderstood and misrepresented. The
      typical representation of the acinus as a "bunch of grapes" bears no resemblance
      to its real anatomy; the alveoli are not independent little balloons. Because of
      the prevalence of this misconception, Laplace's law, as it applies to spheres,
      has been invoked as a mechanical model for the forces of alveolar inflation and
      as an explanation for the necessity of pulmonary surfactant in the alveolus.
      Alveoli are prismatic or polygonal in shape, i.e., their walls are flat, and
      Laplace law considerations in their inflation apply only to the very small curved
      region in the fluid where these walls intersect. Alveoli do not readily collapse
      into one another because they are suspended in a matrix of connective tissue
      "cables" and share common, often perforated walls, so there can be no pressure
      differential across them. Surfactant has important functions along planar
      surfaces of the alveolar wall and in mitigating the forces that tend to close the
      small airways. Laplace's law as it applies to cylinders is an important feature
      of the mechanics of airway collapse, but the law as it applies to spheres is not
      relevant to the individual alveolus.

PMID- 12594073
TI  - Pulmonary ventilation teaching aid.

PMID- 12594074
TI  - A simple model for understanding cohesive forces of the intrapleural space.

PMID- 12594075
TI  - Toward consistent definitions for preload and afterload--revisited.

PMID- 12594077
TI  - Analysis of malignancy-associated DNA changes in the nuclei of buccal epithelium
      in the pathology of the thyroid and mammary glands.
AB  - The object of the investigation reported in this paper was to study, from the
      point of view of statistical and geometric theory of pattern recognition, the DNA
      optical density distribution peculiarities in the interphase nuclei of buccal
      epithelium present in the pathology of the thyroid and mammary glands. Two new
      indices to characterize this distribution (ratio of modal class volumes and
      relief index) are proposed. It is shown that in malignant neoplasms of the
      thyroid and mammary glands the changes in the nuclei of buccal epithelium are
      characterized by an increase in the optical density of DNA over a range from 0.15
      to 0.30 in conventional units of measure, as compared with its values in benign
      pathological processes. The sensitivity of the proposed criterion for diseases of
      the thyroid gland is equal to 76.2% and the specificity is equal to 85.8%. For
      diseases of the mammary gland (excluding IDLC) we have discovered that the
      sensitivity of the method is equal to 94.29% and its specificity equal to 90.91%.
      In diseases of the mammary gland (including IDLC) we have discovered that the
      sensitivity of the method is equal to 71.42% and its specificity is equal to
      90.91%.

PMID- 12594078
TI  - Datamining protein structure databanks for crystallization patterns of proteins.
AB  - A study of 345 protein structures selected among 1,500 structures determined by
      nuclear magnetic resonance (NMR) methods, revealed useful correlations between
      crystallization properties and several parameters for the studied proteins. NMR
      methods of structure determination do not require the growth of protein crystals,
      and hence allow comparison of properties of proteins that have or have not been
      the subject of crystallographic approaches. One- and two-dimensional statistical
      analyses of the data confirmed a hypothesized relation between the size of the
      molecule and its crystallization potential. Furthermore, two-dimensional Bayesian
      analysis revealed a significant relationship between relative ratio of different
      secondary structures and the likelihood of success for crystallization trials.
      The most immediate result is an apparent correlation of crystallization potential
      with protein size. Further analysis of the data revealed a relationship between
      the unstructured fraction of proteins and the success of its crystallization.
      Utilization of Bayesian analysis on the latter correlation resulted in a
      prediction performance of about 64%, whereas a two-dimensional Bayesian analysis
      succeeded with a performance of about 75%.

PMID- 12594079
TI  - Achieving congruency of phylogenetic trees generated by W-curves of genomic
      sequences.
AB  - Comparative genomic analysis at its most fundamental level involves alignment and
      analysis of linear strings of DNA. Many useful and powerful tools, such as BlastN
      and ClustalW are able to respectively, search for, and align similar strings of
      DNA from a variety of species. However, interesting genomic patterns cannot be
      immediately visualized within the information contact embedded in long genomic
      strings without extensive a priori knowledge. More problematic is the question of
      whether we will be able to crystallize long genomic sequences and analyze their
      true secondary and tertiary structures. It is, of course, these putative motifs
      that are binding to the three-dimensional structures of proteins and inducing
      replication and transcription events. The W-curve is a numerical mapping
      algorithm that allows one to geometrically visualize the information content of
      genomic motifs. Patterns of ALU, LINES, SINEs, and duplication sequences may be
      easily visualized with the W-curve. It is our hope that this pattern recognition
      algorithm will lead to visualization tools to track the evolutionary history of
      motif patterns. The combinatorics of DNA motif crossover-recombination events
      will be more easily followed as we continue to sequence more and more genomes. In
      our laboratory we are currently collaborating with mathematicians and computer
      scientists to develop and test tools, such as the W-curve, for analyzing patterns
      of long genomic sequences. In this paper, we examine the limitations of using the
      W-curve to infer the phylogenetic history of species.

PMID- 12594080
TI  - Using fuzzy logic to confirm the integrity of a pattern recognition algorithm for
      long genomic sequences: the W-curve.
AB  - The W-curve is a numerical mapping algorithm that provides tertiary information
      content of long and short genomic sequences. The most popular genomic pattern
      recognition algorithms depend on string matching of the primary information
      content of short genomic sequences. Herein, we describe a way to define the fuzzy
      properties of the W-curve. This approach improves a distance (dissimilarity)
      between two or more homologous long genomic sequences. Fourier analysis of W
      curves delivers a smoother function for gap-stripped regions. Calculation of
      respective Fourier energies may improve the accuracy of the distance metric used
      to generate a phylogenetic tree of analyzed genomic sequences. This is especially
      the case for long genomic sequences that have been gap-stripped and aligned with
      the aid of previously published heuristic methods. These previous methods
      involved W-curve alignments used in concert with such programs as Clustal that
      use linear dynamic programming to align multiple gap-stripped W-curves.

PMID- 12594081
TI  - Pattern recognition techniques in microarray data analysis: a survey.
AB  - Recent development of technologies (e.g., microarray technology) that are capable
      of producing massive amounts of genetic data has highlighted the need for new
      pattern recognition techniques that can mine and discover biologically meaningful
      knowledge in large data sets. Many researchers have begun an endeavor in this
      direction to devise such data-mining techniques. As such, there is a need for
      survey articles that periodically review and summarize the work that has been
      done in the area. This article presents one such survey. The first portion of the
      paper is meant to provide the basic biology (mostly for non-biologists) that is
      required in such a project. This part is only meant to be a starting point for
      those experts in the technical fields who wish to embark on this new area of
      bioinformatics. The second portion of the paper is a survey of various data
      mining techniques that have been used in mining microarray data for biological
      knowledge and information (such as sequence information). This survey is not
      meant to be treated as complete in any form, since the area is currently one of
      the most active, and the body of research is very large. Furthermore, the
      applications of the techniques mentioned here are not meant to be taken as the
      most significant applications of the techniques, but simply as examples among
      many.

PMID- 12594082
TI  - Automated biological sequence description by genetic multiobjective generalized
      clustering.
AB  - Recent advances in the accessibility of databases containing representations of
      complex objects-exemplified by repositories of time-series data, information
      about biological macromolecules, or knowledge about metabolic pathways-have not
      been matched by availability of tools that facilitate the retrieval of objects of
      particular interest and aid understanding their structure and relations. In
      applications, such as the analysis of DNA sequences, on the other hand,
      requirements to retrieve objects on the basis of qualitative characteristics are
      poorly met by descriptions that emphasize precision and detail rather than
      structural features. This paper presents a method for identification of
      interesting qualitative features in biological sequences. Our approach relies on
      a generalized clustering methodology in which the features being sought
      correspond to the solutions of a multivariable, multiobjective optimization
      problem with features generally corresponding to fuzzy subsets of the object
      being represented. Foremost among the optimization objectives being considered
      are measures of the degree by which features resemble prototypical structures
      deemed to be interesting by database users. Other objectives include feature size
      and, in some cases, performance criteria related to domain-specific constraints.
      Genetic-algorithm methods are employed to solve the multiobjective optimization
      problem. These optimization algorithms discover candidate features as subsets of
      the object being described and that lie in the set of all Pareto-optimal
      solutions-of that problem. These candidate features are then summarized,
      employing again evolutionary-computation methods, and interrelated by employing
      domain-specific relations of interest to the end users. We present results of the
      application of this two-step method to the recognition and summarization of
      interesting features in DNA sequences of Tripanosoma cruzi.

PMID- 12594083
TI  - Mammography and computerized decision systems: a review.
AB  - Computer-aided diagnosis (CAD) systems in mammography have been developed and
      investigated for several years and recently they have left the research stage to
      enter the clinical stage. The purpose of this article is to review the present
      situation of mammography for breast cancer detection and the role played by CAD
      systems. Results from the recent literature show that CAD systems have the
      potential to improve the sensitivities of radiologists in the detection of
      malignant clustered microcalcifications and masses, while keeping specificities
      at acceptable levels. This leads to the conclusion that CAD systems can be
      incorporated into clinical practice as a double reading option to radiologists.
      However, some issues have yet to be tackled for CAD systems to gain better
      acceptance and more widespread use worldwide.

PMID- 12594084
TI  - Functional magnetic resonance of human breast tumors: diffusion and perfusion
      imaging.
AB  - This review is focused on two relatively new developments in magnetic resonance
      imaging (MRI) and their application to breast lesion characterization: diffusion
      and perfusion MRI. Diffusion MRI measures the mobility of the water protons and
      thus provides a window to tissue microstructure. Perfusion MRI measures the rate
      at which blood is delivered to tissue and thus provides information about
      microvasculature. Because both tissue structure and vasculature are likely to
      change in disease states, measurement of diffusion and perfusion may have direct
      physiologic relevance. This review covers topics related to the imaging
      sequences, image analysis, and clinical studies for diffusion and perfusion
      breast MRI. Preliminary studies show that the apparent diffusion coefficient
      (ADC) is a marker of cell density and can distinguish malignant from benign
      lesions. Perfusion MR also shows promise for breast tumor characterization:
      malignant tumors have consistently higher relative tissue blood volumes (rTBV)
      than normal and benign tumors. Additional research is required with large patient
      cohorts to establish these two techniques on a clinical footing.

PMID- 12594085
TI  - Comparison of feature extraction and selection methods in mammogram recognition.
AB  - This paper presents a comparison of feature extraction and selection methods in
      the design of mammogram recognition systems. Mammographic images were classified
      into two categories, normal and cancerous. The following methods of feature
      extraction were investigated: two-dimensional Haar wavelets, histograms, and
      singular value decomposition. The feature patterns were reduced and selected
      using principal component analysis (PCA) and rough sets. The rough sets methods
      were applied to the final selection of the pattern features. Classification of
      mammograms was realized using an error backpropagation neural network.

PMID- 12594086
TI  - Tumor hypoxia and blood vessel detection: an image analysis technique for
      simultaneous tumor hypoxia grading and blood vessel detection in tissue sections.
AB  - We have developed a multistage image analysis technique for the simultaneous
      segmentation of blood vessels and hypoxic regions in dual-stained tumor tissue
      sections. The algorithm, which is integrated in a task-oriented image analysis
      system developed on-site, initially uses the K-nearest neighbor classification
      rule in order to label the image pixels. Classification is based on a training
      set selected from manually drawn regions corresponding to the areas of interest.
      If the output image contains a significant number of misclassified pixels, the
      user has the option to apply a series of specific problem-designed routines
      (texture analysis, fuzzy c-means clustering, and edge detection) in order to
      improve the final segmentation result. Validation experiments indicate that the
      algorithm can robustly detect these biological features, even in tissue sections
      with a very low quality of staining. This approach has also been combined with
      other image analysis based procedures in order to objectively obtain quantitative
      measurements of potential clinical interest.

PMID- 12594087
TI  - Compression and filtration of U.S. medical images with a modified inverse
      difference pyramid.
AB  - In this paper a new approach for compression and filtration of U.S. medical
      images is introduced. The application of the algorithm, based on image processing
      with an inverse difference pyramid (IDP) along with considerable image
      compression, permits filtration of a specific (speckle) noise in ultrasound
      images. The paper describes the principle of image decomposition and its
      modification designed specifically for this medical application. The paper also
      provides images that illustrate some of the results of this work.

PMID- 12594088
TI  - Higher order statistics in computer vision: analysis of images and detection of
      extraneous objects in images.
AB  - The aim of this work is to present methods for classifying images and locating
      extraneous objects within images. Our methods make use of higher order
      statistics, transforms of data into the frequency domain, and characteristics of
      the resulting clusters.

PMID- 12594089
TI  - A review of medical imaging informatics.
AB  - This review of medical imaging informatics is a survey of current developments in
      an exciting field. The focus is on informatics issues rather than traditional
      data processing and information systems, such as picture archiving and
      communications systems (PACS) and image processing and analysis systems. In this
      review, we address imaging informatics issues within the requirements of an
      informatics system defined by the American Medical Informatics Association. With
      these requirements as a framework, we review, in four sections: (1) Methods to
      present imaging and associated data without causing an overload, including image
      study summarization, content-based medical image retrieval, and natural language
      processing of text data. (2) Data modeling techniques to represent clinical data
      with focus on an image data model, including general-purpose time-based
      multimedia data models, health-care-specific data models, knowledge models, and
      problem-centric data models. (3) Methods to integrate medical data information
      from heterogeneous clinical data sources. Advances in centralized databases and
      mediated architectures are reviewed along with a discussion on our efforts at
      data integration based on peer-to-peer networking and shared file systems. (4)
      Visualization schemas to present imaging and clinical data: the large volume of
      medical data presents a daunting challenge for an efficient visualization
      paradigm. In this section we review current multimedia visualization methods
      including temporal modeling, problem-specific data organization, including our
      problem-centric, context and user-specific visualization interface.

PMID- 12594090
TI  - Volume reconstruction for health care: a survey of computational methods.
AB  - In many scientific and technical applications, a three-dimensional (3D) object
      must be reconstructed, either to assist in understanding the object's structure
      or to ease its automatic handling and analysis. Volume reconstruction has been
      used in health care to diagnose, simulate, facilitate surgical planning, develop
      image-guided surgery, facilitate telemedicine, and to assist in many other
      applications. This paper presents a survey of computational methods used to
      achieve volume reconstruction. First, we review 3D imaging techniques. Second,
      since we consider image segmentation the most important and difficult phase of 3D
      reconstruction, we focus on this topic. Subsequently, we concentrate on some of
      the most successful techniques of segmentation used for 3D reconstruction, such
      as active contours. We also review computer graphics and visualization methods
      used with volume reconstruction. Finally, we indicate future lines for research
      in volume reconstruction and 3D imaging for health care.

PMID- 12594091
TI  - Content-based ultrasound image retrieval using a coarse to fine approach.
AB  - One of the current issues for picture archiving and communication systems (PACS)
      is extending retrieval technologies to deal with multimedia information. This is
      particularly important for medical applications that assist in diagnostic
      processes and pathology studies. Accordingly, this paper presents a new approach
      to content-based image retrieval (CBIR) for a clinical ultrasound image database
      (DB). The proposed algorithm consists of two stages so as to maximize the
      retrieval efficiency. In the first stage, a coarse retrieval is performed using
      the statistical characteristics of the wavelet coefficients that narrow the
      search by eliminating up to 70% of the total DB images. In the second stage, a
      fine retrieval is carried out using the Legendre moment of the global histogram
      pdf on the reduced image set preretrieved by the coarse retrieval. When tested on
      an abdominal ultrasound image DB and compared with various other methods, the
      proposed algorithm gave promising results for applying CBIR to clinical
      ultrasound images.

PMID- 12594092
TI  - Designing a patient education framework via use case analysis.
AB  - One of the challenges of developing patient education content in electronic form
      is to determine the information and interaction needs that motivate a patient to
      learn in the first place. We have found that use case analysis of patient
      education helps in clarifying the types of information and interaction required
      to educate a patient effectively. This paper presents a use case model for
      patient education as well as a Java-based framework that facilitates both the
      extension and updating of individually tailored, electronic patient education
      content. The framework defines an abstract interface that represents a particular
      panel of information, and provides a content manager that dynamically discovers
      and refreshes new panels as they are added or modified.

PMID- 12594093
TI  - An XML Gateway to Patient Data for Medical Research Applications.
AB  - As the medical environment becomes increasingly electronic, clinical databases
      are continually growing, accruing masses of patient information. This wealth of
      data is an invaluable source of information to researchers, serving as a testbed
      for the development of new information technologies and as a repository of real
      world data for data mining and population-based studies. However, the true
      utility of this information is not fulfilled, in part because of issues
      pertaining to security and patient confidentiality, but also due to the lack of
      an effective infrastructure to access the data. This paper describes a system,
      DataServer, that permits researchers to query and retrieve data from multiple
      clinical data sources, automatically deidentifying patient data so that it can be
      used for research purposes. DataServer functions as an application framework,
      enabling extensible markup language (XML)-based querying of existing medical
      databases. Key aspects of DataServer include ready inclusion of new information
      resources, minimal processing impact on existing clinical systems via a
      distributed cache, and flexible output representation via XSL (eXtensible Style
      Language) transforms.

PMID- 12594094
TI  - Modeling medical content for automated summarization.
AB  - Medical information is available from a variety of new online resources. Given
      the number and diversity of sources, methods must be found that will enable users
      to quickly assimilate and determine the content of a document. Summarization is
      one such tool that can help users to quickly determine the main points of a
      document. Previous methods to automatically summarize text documents typically do
      not attempt to infer or define the content of a document. Rather these systems
      rely on secondary features or clues that may point to content. This paper
      describes text summarization techniques that enable users to focus on the key
      content of a document. The techniques presented here analyze groups of similar
      documents in order to form a content model. The content model is used to select
      sentences forming the summary. The technique does not require additional
      knowledge sources; thus the method should be applicable to any set of text
      documents.

PMID- 12594095
TI  - Structured reporting in neuroradiology.
AB  - We have developed a system to structure free-text neuroradiology reports using a
      natural language processing program and formatted the output into the digital
      image and communication in medicine (DICOM) standard for structured reporting
      (SR). DICOM SR formats the correspondence of pertinent diagnostic images to the
      radiologist's dictated report of clinical findings. In addition, DICOM SR allows
      the information to be organized into a tree structure. Individual nodes of the
      tree can contain individual items or lists. Structuring the content of free-text
      information allows the creation of hierarchies with defined relationships between
      the concepts contained within the report.

PMID- 12594096
TI  - Integrated visualization of problemcentric urologic patient records.
AB  - The collision of computer-based technologies and the medical environment is
      resulting in an increasingly electronic multimedia patient record, consisting of
      not only the traditional types of data (e.g., clinic notes and laboratory
      reports), but also digital images (e.g., computed tomography and magnetic
      resonance imaging) and other visual representations of patient data (e.g.,
      pulmonary function graphs and urodynamic charts). Given the increasing amount of
      data made available to physicians, it is not only critical that the totality of a
      patient's medical record be accessible to a clinician, but that the diverse data
      be integrated and presented in a manner conducive to patient management: key
      information should be easily discovered. This paper describes a problemcentric
      time-based visualization of urologic conditions, whereby a patient's medical
      history is automatically organized around a medical problem and presented as a
      graphic chronology. Urology-related data in the patient medical record is
      organized in accord with an expert constructed knowledge-base, and plotted on a
      timeline using iconic representations. The user interface permits the physician
      to quickly view multimedia data and to visualize relationships between events in
      the patient's history.

PMID- 12594097
TI  - Image study summarization of MR brain images by automated localization of
      relevant structures.
AB  - The paper discusses a methodology to objectify the patient presenting condition
      by automated selection of relevant images from a serial MR study. Structured data
      entry is used to capture the patient's chief complaint, pertinent history, signs,
      and symptoms. Expert created rules use this data to arrive at a differential and
      to identify the affected brain region/structure. Another expert created knowledge
      base then maps this information to the relevant image type, including image
      sequence specifics and orientation. A DICOM study reader identifies the relevant
      imaging sequences from the MR study. The structure localization method involves a
      search based on principal component analysis. A training set of subimages
      containing the structure of interest is used to generate a basis set of prototype
      images called eigenimages. The structure is located in an image by searching the
      image for a subregion that best matches the basis set. The structure localization
      was used to locate the lateral ventricles and orbits in nine images that were not
      part of the training set. The automated localizations were compared to expert
      localizations and the center of the regions located by the two techniques agreed
      to within +/- 1.7 mm (average for the nine localizations each of two structures).

PMID- 12594098
TI  - Advances in biomedical informatics for the management of cancer.
AB  - Increased access to health care, and advances in education and technology have
      resulted in a larger proportion of the population having longer life expectancy.
      The strong correlation between age and cancer has resulted in a major healthcare
      problem for this century, and until recently cancer has defied any long-lasting
      cure. However, progress, especially in the field of biomedical informatics,
      promises a successful prediction and possibly a permanent cure for cancer within
      the next two decades. Biomedical informatics-with its roots in computer science,
      biomedical engineering, biostatistics, and mathematics-helps to bring the patient
      closer to the physician, facilitates access to specialist information and
      knowledge bases across the world, and makes it possible to identify genetic
      expression profiles for malignant or cancerous cells. This paper reviews the new
      research findings in biomedical informatics, working toward the ultimate goal of
      successfully predicting cancer, solving complex problems in prevention and
      treatment of cancer, and perhaps completely curing the scourge of cancer.

PMID- 12594099
TI  - Decision support system for the analysis of hospital operation indicators.
AB  - The inauguration of national health insurance (NHI) in many countries and their
      worsening financial condition has increased the sensitivity to operational cost
      and efficiency in hospitals. For several years, hospitals have been monitoring
      their operations by analyzing the financial and operational reports that are
      provided. Because of the rapidly changing character of the medical industry,
      statistical data shown on paper are no longer sufficient for decision makers.
      This paper describes a decision support system (DSS) for hospital administrators
      to assist in analyzing their operations efficiently and precisely. In hospitals,
      operational data of outpatients and inpatients are now stored on computers,
      resulting in much easier and faster data acquisition for administrators. The
      proposed system makes suggestions to hospital administrators and is able to self
      learn to improve its future usefulness. With the dual capabilities of integrating
      evaluations and data collecting, the system can assist administrators in
      discovering and resolving problems quickly. The system provides multidimensional
      and multilevel analyses, by using data warehousing techniques, and generates
      appropriate advice to users by employing decision-making methodology. The self
      learning function of the system makes it work like an expert, continually
      modifying its content (knowledge) and generating advice that is promptly updated
      to accord with changes in the medical industry.

PMID- 12594100
TI  - Epicenter location by analysis of interictal spikes: a case study for the use of
      artificial neural networks in biomedical engineering.
AB  - Artificial neural network (ANN) technology is finding increasing application in
      medicine and biomedical engineering. This paper supplies necessary background in
      ANN technology for researchers unfamiliar with this rapidly emerging discipline.
      This introduction to ANN application is cast in the context of epileptic seizure
      epicenter location. This is a very real problem faced by neurosurgeons every day.
      Precise location of the area of excision is currently determined with a network
      of surgically implanted subdural electrodes. This means that the cure entails two
      surgical procedures: one to implant the electrode array that precisely locates
      the epicenter, and another to remove the epicenter. This paper outlines an
      experimental diagnostic software system (DSS) that uses artificial neural network
      (ANN) analysis of magnetoencephalographic (MEG) data to eliminate the first of
      these surgical procedures. The MEG recording is a quick and painless process that
      requires no surgery. This approach has the potential to save time, reduce patient
      discomfort, and eliminate a painful and potentially dangerous surgical step in
      the treatment procedure.

PMID- 12594101
TI  - Mediterranean diet intervention in rheumatoid arthritis.

PMID- 12594102
TI  - Tartrate resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium
      may induce the destruction of articular cartilage.
AB  - OBJECTIVE: To examine the role of tartrate resistant acid phosphatase (TRAP)
      positive mononuclear and multinucleated cells in the destruction of articular
      cartilage in patients with rheumatoid arthritis (RA). METHODS: The presence of
      TRAP positive cells in the synovial tissue of patients with RA was examined by
      enzyme histochemistry and immunohistochemistry. Expression of mRNAs for matrix
      metalloproteinases (MMPs) was assessed by the reverse transcriptase-polymerase
      chain reaction (RT-PCR) and northern blot analysis. Production of MMPs by
      mononuclear and multinucleated TRAP positive cells was examined by
      immunocytochemistry, enzyme linked immunosorbent assay (ELISA) of conditioned
      medium, and immunohistochemistry of human RA synovial tissue. In addition, a
      cartilage degradation assay was performed by incubation of (35)S prelabelled
      cartilage discs with TRAP positive cells. RESULTS: TRAP positive mononuclear
      cells and multinucleated cells were found in proliferating synovial tissue
      adjacent to the bone-cartilage interface in patients with RA. Expression of MMP-2
      (gelatinase A), MMP-9 (gelatinase B), MMP-12 (macrophage metalloelastase), and
      MMP-14 (MT1-MMP) mRNA was detected in TRAP positive mononuclear and
      multinucleated cells by both RT-PCR and northern blot analysis.
      Immunocytochemistry for these MMPs showed that MMP-2 and MMP-9 were produced by
      both TRAP positive mononuclear and multinucleated cells, whereas MMP-12 and MMP
      14 were produced by TRAP positive multinucleated cells. MMP-2 and MMP-9 were
      detected in the conditioned medium of TRAP positive mononuclear cells. TRAP
      positive mononuclear cells also induced the release of (35)S from prelabelled
      cartilage discs. CONCLUSION: This study suggests that TRAP positive mononuclear
      and multinucleated cells located in the synovium at the cartilage-synovial
      interface produce MMP-2 and MMP-9, and may have an important role in articular
      cartilage destruction in patients with RA.

PMID- 12594103
TI  - Retinal findings in systemic sclerosis: a comparison with nailfold
      capillaroscopic patterns.
AB  - OBJECTIVE: To determine the prevalence of retinal disease in systemic sclerosis
      (SSc) and to characterise the findings of retinopathy. Additionally, to analyse
      the association of retinal disease with other clinical/laboratory findings,
      particularly the findings of nailfold capillaries in patients with SSc. METHODS:
      Photographs of the ocular fundi were taken and were evaluated by an
      ophthalmologist who was unaware of the SSc status of the patients. The nailfold
      capillaries were analysed with a dermatoscope. Patients were divided into two
      groups according to the presence (group A) or absence (group B) of retinal
      disease. RESULTS: Retinal findings of the patients with SSc consisted of hard
      exudates, vascular tortuosity, microhaemorrhage, and macular degeneration. The
      prevalence of retinal disease among the patients with SSc was 34% (10/29),
      compared with 8%(3/38) among the controls (p=0.011). The mean systolic blood
      pressure and the age of the patients in group A were significantly higher than
      those in group B. However, there was no significant difference in the nailfold
      capillary damage between groups A and B. CONCLUSION: Retinal abnormalities are
      often seen in patients with SSc and they may reflect the vascular changes
      characteristic of SSc. However, retinal changes may differ in quality from the
      changes of nailfold capillaries.

PMID- 12594104
TI  - An experimental study of a Mediterranean diet intervention for patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: To investigate the efficacy of a Mediterranean diet (MD) versus an
      ordinary Western diet for suppression of disease activity in patients with
      rheumatoid arthritis (RA). METHODS: Patients with well controlled, although
      active RA of at least two years' duration, who were receiving stable
      pharmacological treatment, were invited to participate. All patients were
      randomly allocated to the MD or the control diet (CD). To achieve good compliance
      with prescribed diets all patients were for the first three weeks served the MD
      or the CD, respectively, for lunch and dinner at the outpatient clinic's canteen.
      Clinical examinations were performed at baseline, and again in the 3rd, 6th, and
      12th week. A composite disease activity index (DAS28), a physical function index
      (Health Assessment Questionnaire (HAQ)), a health survey of quality of life
      (Short Form-36 (SF-36)), and the daily consumption of non-steroidal anti
      inflammatory drugs were used as primary efficacy variables. RESULTS: From
      baseline to the end of the study the patients in the MD group (n=26) showed a
      decrease in DAS28 of 0.56 (p<0.001), in HAQ of 0.15 (p=0.020), and in two
      dimensions of the SF-36 Health Survey: an increase in "vitality" of 11.3
      (p=0.018) and a decrease in "compared with one year earlier" of 0.6 (p=0.016).
      For the control patients (n=25) no significant change was seen at the end of the
      study. This difference between the two treatment groups was notable only in the
      second half of the trial. CONCLUSION: The results indicate that patients with RA,
      by adjusting to a Mediterranean diet, did obtain a reduction in inflammatory
      activity, an increase in physical function, and improved vitality.

PMID- 12594105
TI  - Comparison of statistically derived ASAS improvement criteria for ankylosing
      spondylitis with clinically relevant improvement according to an expert panel.
AB  - OBJECTIVE: To investigate whether the recently developed (statistically derived)
      "ASsessment in Ankylosing Spondylitis Working Group" improvement criteria (ASAS
      IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement
      according to the opinion of an expert panel. METHODS: The ASAS-IC consist of four
      domains: physical function, spinal pain, patient global assessment, and
      inflammation. Scores on these four domains of 55 patients with AS, who had
      participated in a non-steroidal anti-inflammatory drug efficacy trial, were
      presented to an international expert panel (consisting of patients with AS and
      members of the ASAS Working Group) in a three round Delphi exercise. The number
      of (non-)responders according to the ASAS-IC was compared with the final
      consensus of the experts. The most important domains in the opinion of the
      experts were identified, and also selected with discriminant analysis. A number
      of provisional criteria sets that best represented the consensus of the experts
      were defined. Using other datasets, these clinically derived criteria sets as
      well as the statistically derived ASAS-IC were then tested for discriminative
      properties and for agreement with the end of trial efficacy by patient and
      doctor. RESULTS: Forty experts completed the three Delphi rounds. The experts
      considered twice as many patients to be responders than the ASAS-IC (42 v 21).
      Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered
      the most important domain by most experts and was also selected as such by
      discriminant analysis. Provisional criteria sets with an agreement of >or=80%
      compared with the consensus of the experts showed high placebo response rates (27
      42%), in contrast with the ASAS-IC with a predefined placebo response rate of
      25%. All criteria sets and the ASAS-IC discriminated well between active and
      placebo treatment (chi(2)=36-45; p<0.001). Compared with the end of trial
      efficacy assessment, the provisional criteria sets showed an agreement of 71-82%,
      sensitivity of 67-83%, and specificity of 81-88%. The ASAS-IC showed an agreement
      of 70%, sensitivity of 62%, and specificity of 89%. CONCLUSION: The ASAS-IC are
      strict in defining response, are highly specific, and consequently show lower
      sensitivity than the clinically derived criteria sets. However, those patients
      who are considered as responders by applying the ASAS-IC are acknowledged as such
      by the expert panel as well as by patients' and doctors' judgments, and are
      therefore likely to be true responders.

PMID- 12594106
TI  - International variation in hip replacement rates.
AB  - OBJECTIVES: To summarise epidemiological data on the frequency of hip
      replacements in the countries of the developed world, especially in countries of
      the Organisation for Economic Cooperation and Development (OECD), and to
      investigate whether missing consensus criteria for the indication for total hip
      replacement (THR) result in different replacement rates. METHODS: Country
      specific hip replacement rates were collected using the available literature,
      different data sources of national authorities, and estimates of leading hip
      replacement manufacturers. RESULTS: According to administrative and literature
      data sources the reported crude primary THR rate varied between 50 and 130
      procedures/100000 inhabitants in OECD countries in the 1990s. The crude overall
      hip implantation rate, summarising THR, partial hip replacement, and hip revision
      procedures, was reported to range from 60 to 200 procedures/100000 inhabitants in
      the late 1990s. Moreover, large national differences were seen in the
      relationship between total and partial hip replacement procedures. CONCLUSION:
      The reported differences in hip replacement rates in OECD countries are
      substantial. They may be due to various causes, including different coding
      systems, country-specific differences in the healthcare system, in total
      expenditure on health per capita, in the population age structure, and in
      different indication criteria for THR.

PMID- 12594107
TI  - HLA class II is associated with distal interphalangeal osteoarthritis.
AB  - OBJECTIVE: To investigate whether there is an association between HLA class II
      and distal interphalangeal osteoarthritis (DIP OA). METHODS: The study group
      consisted of consecutive patients with and without DIP OA aged between 40 and 70
      years. DIP OA was diagnosed by radiology. These patients were referred to an
      "Early Arthritis Clinic" (EAC) with different types of arthritis at an early
      stage. Patients with rheumatoid arthritis, systemic lupus erythematosus,
      spondyloarthropathies, and psoriatic arthritis were excluded for the purpose of
      this study. DNA typing for HLA-DR and x ray examination of the hands were
      performed at enrollment in the EAC. To establish whether the study group was
      representative of the Dutch population, a population based study in Zoetermeer
      (n=3243) for the prevalence of DIP OA and blood donors in the Leiden area
      (n=2400) for the HLA-DR antigen frequencies were used as references. RESULTS:
      Fifty five patients (33%) of the total study group (n=166) had DIP OA. The
      prevalence of DIP OA and frequency of the HLA-DR alleles were similar to those of
      the two reference groups. Within the study group an association between DIP OA
      and HLA-DR2 and DR4 with respectively odds ratios of 2.4 (95% confidence interval
      (CI) 1.1 to 5.0) and 0.3 (95% CI 0.1 to 0.7) was found. No association was found
      between other HLA-DR alleles and DIP OA. CONCLUSION: The study group is a
      representative sample of the Dutch population. The HLA-DR2 allele was more common
      in patients with DIP OA. Furthermore, an inverse relation was observed between
      DIP OA and HLA-DR4. The results confirm findings from other investigations
      implicating HLA-DR2 as a risk factor in the development of DIP OA.

PMID- 12594108
TI  - Disease activity and health status in rheumatoid arthritis: a case-control
      comparison between Norway and Lithuania.
AB  - OBJECTIVE: To compare disease characteristics and health status in patients with
      rheumatoid arthritis (RA) from two countries, Norway and Lithuania. METHODS:
      Patients were recruited from the RA registers in Vilnius (Lithuania) and Oslo
      (Norway). For each patient from Vilnius, a patient matched for age and sex from
      the Oslo register was selected. Sociodemographic characteristics, disease
      process, and health status were compared between the patient groups. RESULTS: 201
      Lithuanian patients and 201 Norwegian patients were included. Mean (SD) age in
      both groups was 55.9 (10.0) years, and 83% were women. Patients from Lithuania
      were less often employed (27% v 42%; p=0.001), had higher disease activity
      expressed by the disease activity score (DAS28; mean (SD) 5.3 (1.0) v 4.4 (1.4);
      p<0.001), had worse physical function by the modified Health Assessment
      Questionnaire (MHAQ; mean (SD) 2.3 (0.8) v 1.6 (0.5); p<0.001), had more often
      comorbidity (73% v 53%; p<0.001) and they reported worse general health measured
      by Short Form-36 Health Survey (SF-36; mean (SD) 23.2 (13.5) v 44.5 (21.3);
      p<0.001). The proportions of patients who had used disease modifying drugs were
      similar, but the pattern of use differed. CONCLUSION: Important differences in
      employment, disease activity, physical function, and self reported health status
      were observed in patients with RA from two northern European countries.
      Socioeconomic inequalities, differences in disease management, and access to
      specialised health care, as well as methodological issues regarding instruments
      and data collection are likely explanations. These data support the view that
      management of RA should be adapted to country-specific needs.

PMID- 12594110
TI  - Arthrosonography of hip and knee joints in the follow up of juvenile rheumatoid
      arthritis.
AB  - OBJECTIVE: To evaluate sensitivity of arthrosonography of hip and knee joints for
      monitoring disease activity in juvenile rheumatoid arthritis (JRA). METHODS:
      Twenty eight patients with JRA with active disease at entry in 15 hips and 38
      knee joints were followed up three times in intervals of 4-6 weeks. Sonographic,
      clinical, and laboratory findings were documented at the same time in clinically
      active and inactive disease. As controls of the sonographic variables 10 children
      without a history of arthritis were examined by ultrasound. RESULTS: In active
      arthritis of the hip joint 19/31 (61%) examinations showed a pathological
      widening of the synovial joint space. There was no significant correlation
      between sonographic and clinical measures of disease activity in coxitis. Marked
      effusion within the suprapatellar pouch was seen in 87% and thickening of the
      synovial membrane in 92% of cases of active gonarthritis in patients with JRA.
      There was a significant difference in the number of patients with joint effusion
      and in the mean joint effusion between patients with clinically active
      gonarthritis at entry and inactive arthritis at follow up (p<0.001). In contrast,
      synovial thickening persisted in about 80% after induction of clinical remission.
      CONCLUSION: The data confirm the high sensitivity of arthrosonography in imaging
      changes in hip and knee joints of patients with JRA. Sonographic effusion of the
      knee provided the highest correlation with measures of clinical disease activity.
      Further prospective studies should evaluate whether persistent thickening of the
      synovial membrane detected by ultrasound in clinically inactive arthritis
      indicates residual inflammatory activity and an increased risk of relapse.

PMID- 12594109
TI  - Myeloid related protein 8 and 14 secretion reflects phagocyte activation and
      correlates with disease activity in juvenile idiopathic arthritis treated with
      autologous stem cell transplantation.
AB  - OBJECTIVES: To determine whether myeloid related proteins (MRP8/MRP14), a complex
      of two S100 proteins related to neutrophil and monocyte activation, might be used
      as a marker for disease activity, and as an early indicator of relapse in
      juvenile idiopathic arthritis. PATIENTS AND METHODS: A group of 12 patients who
      underwent an autologous haematopoietic stem cell transplantation (ASCT) for
      refractory juvenile idiopathic arthritis (JIA) were studied. MRP8/MRP14 serum
      concentrations were determined by a sandwich enzyme linked immunosorbent assay
      (ELISA) as described. Improvement from baseline was described by a definition of
      improvement employing a core set of criteria as detailed previously by Giannini.
      RESULTS: After ASCT, MRP8/MRP14 serum concentrations in JIA showed a positive
      correlation with the Child Health Assessment Questionnaire (CHAQ; r=0.80) and
      erythrocyte sedimentation rate (r=0.45), but not with the total leucocyte count
      (r=0.26). Mean MRP8/MRP14 serum concentrations dropped markedly in the first
      three months after ASCT (p=0.0039) and clinical parameters of disease activity
      such as CHAQ markedly improved (p=0.0039). During a transient relapse there was
      an increase in MRP8/MRP14. CONCLUSIONS: MRP8/MRP14 serum concentration can be
      used as a marker for disease activity in patients who receive an ASCT for
      refractory JIA. This indicates a role of macrophage activation in the
      pathogenesis of JIA. The occurrence of MAS in three patients in this study was
      not preceded by significant changes in MRP8/MRP14 concentration.

PMID- 12594111
TI  - Infliximab or etanercept in the treatment of children with refractory juvenile
      idiopathic arthritis: an open label study.
AB  - OBJECTIVE: To study infliximab and etanercept in the treatment of refractory
      juvenile idiopathic arthritis (JIA). METHODS: In a non-randomised, prospective,
      open label study, 24 patients (mean age 10.2 years, range 3.3-16.3) with
      polyarticular JIA were treated with either infliximab (n=14) or etanercept
      (n=10). The patients had had active polyarthritis for at least one year and
      standard treatment had failed. Anti-tumour necrosis factor (TNF) treatment was
      added to the current drug treatment. Infliximab (3-4 mg/kg) was given
      intravenously at weeks 0, 2, and 6, and thereafter at 4 to 8 week intervals.
      Etanercept (0.4 mg/kg) was given subcutaneously twice a week. Improvement of the
      patients was assessed at 3, 6, and 12 months according to established JIA
      response criteria. RESULTS: In intention to treat analyses, patients in both
      treatment groups improved significantly. ACR Paediatric 50 was achieved at 3, 6,
      and 12 months by 9/10 (90%), 8/9 (89%), and 8/9 (89%) patients with etanercept
      and by 8/12 (67%), 10/12 (83%), and 7/9 (78%) with infliximab, respectively. At
      12 months, ACR Paediatric 75 was achieved by 67% of patients in both treatment
      groups. Five withdrawals due to adverse effects or lack of efficacy occurred in
      the infliximab group and one due to lack of compliance in the etanercept group.
      CONCLUSION: In this open label clinical study of active JIA, both infliximab and
      etanercept provided a significant rapid and sustained reduction in disease
      activity. Adequately powered randomised controlled trials are needed to elucidate
      the long term safety and efficacy of TNF modulators in the treatment of JIA.

PMID- 12594112
TI  - Extracorporeal shock wave therapy for chronic calcific tendinitis of the
      shoulder: single blind study.
AB  - OBJECTIVE: To evaluate the clinical and radiological response of chronic calcific
      tendinitis of the shoulder to extracorporeal shock wave therapy (ESWT) in a
      single blind study. METHODS: 70 patients showing chronic, symptomatic, calcifying
      tendinitis of the shoulder were examined. A single blind randomised study was
      performed with 35 patients undergoing a regular treatment (group 1) and 35 a
      simulated one (group 2). Pain and functional assessment was carried out according
      to Constant and Murley. Variations in the dimension of the calcification were
      evaluated by anteroposterior x ray films. RESULTS: A significant decrease of pain
      and a significant increase in shoulder function was seen in group 1. Examination
      by x ray showed partial resorption of the calcium deposits in 40% of cases and
      complete resorption in 31% of cases in group 1. In the control group no
      significant decrease of pain and no significant increase in shoulder function was
      seen. No modifications were observed by x ray examination. CONCLUSION: Because of
      its good tolerance, safety, and clinical radiological response, ESWT can be
      considered as an alternative treatment for chronic calcific tendinitis of the
      shoulder.

PMID- 12594113
TI  - Does yttrium radiosynovectomy increase the risk of cancer in patients with
      rheumatoid arthritis?
AB  - OBJECTIVE: To study the long term risk of cancer in patients with rheumatoid
      arthritis (RA) who have been treated with yttrium. METHODS: The medical record
      numbers of 1228 patients with RA who were admitted to hospital in 1979-85 were
      identified in the database of Jyvaskyla Central Hospital. Radiosynovectomy of the
      knee joint was performed in a total of 143 patients using yttrium-90 silicate
      during the years 1970-85, while 1075 did not receive yttrium radiosynovectomy; 10
      received yttrium treatment later than 1985 and were excluded from the analysis.
      The Finnish Cancer Registry database was used to examine whether the subjects had
      cancer during the follow up from 1979 until the end of 1999. RESULTS: Nine cases
      of cancer were found among the patients who had received yttrium, whereas the
      expected number based on the incidence among the population in the region was
      14.9. The standardised incidence ratio of cancer was 0.6 (95% confidence interval
      (CI) 0.3 to 1.1) for the patients who received yttrium, and 1.1 (95% CI 0.9 to
      1.3) for the patients who did not receive yttrium. CONCLUSIONS: Yttrium treatment
      did not increase the risk of cancer.

PMID- 12594114
TI  - Can we rely on magnetic resonance imaging when evaluating unstable atlantoaxial
      subluxation?
AB  - OBJECTIVES: To examine whether functional radiography and functional magnetic
      resonance imaging (MRI) are equally efficient in detecting the extent of unstable
      anterior atlantoaxial subluxation (aAAS) in rheumatic patients. METHODS: 23
      patients with unstable aAAS (diagnosed by functional radiography) were examined
      by functional MRI because of a neck symptom. Twenty two patients had rheumatoid
      arthritis and one had juvenile idiopathic arthritis. aAAS was diagnosed if the
      anterior atlantoaxial diameter (AAD) was >3 mm and was considered unstable if the
      AAD differed by >2 mm between flexion and extension radiographs. The AAD was
      measured from radiographs (flexion and extension) and MRI images (flexion and
      neutral). RESULTS: The extent of aAAS during flexion measured by radiography was
      greater than that found by MRI in all 23 patients (mean difference 3 mm (95%
      confidence interval 2 to 4)). In four (17%) patients flexion MRI could not
      demonstrate aAAS detected by radiography. The difference between the AAD
      measurements during flexion by these two methods was substantial (that is, >or=4
      mm) in nine (39%) cases. Severe aAAS (>or=9 mm) was seen in 15 (65%) patients by
      functional radiography and in four (17%) by functional MRI. CONCLUSIONS: The
      magnitude of aAAS was often substantially smaller when measured by functional MRI
      rather than by functional radiography. Thus one cannot rely on the result of
      functional MRI alone; functional radiographs are needed to show the size of
      unstable aAAS. The maximal extent of the subluxation must be taken into account
      when the possible compression of neural structures is evaluated by MRI.

PMID- 12594115
TI  - Gallium-67 SPECT scintigraphy may be useful in diagnosis of temporal arteritis.
AB  - BACKGROUND: Temporal arteritis (TA) is a common syndrome in the elderly,
      consisting of persistent pain in the temporal area of the skull, jaw
      claudication, sudden visual loss, high erythrocyte sedimentation rate, and
      tenderness on palpation in the temporal area. The diagnosis of this condition is
      relatively straightforward when the typical symptoms and a positive temporal
      artery biopsy are present. However, only half of the patients have a positive
      temporal artery biopsy. Other diagnostic procedures, such as colour Doppler
      sonography or superficial carotid artery angiography which have been proved to be
      useful for the diagnosis of TA, do not discriminate between inflammatory and non
      inflammatory temporal artery disease and may be helpful only in experienced
      hands. Gallium-67 ((67)Ga) planar scan was reported to be useful in the diagnosis
      of the disease. Quantitative (67)Ga single photon emission computed tomography
      (SPECT) may raise the accuracy of the diagnosis. OBJECTIVE: To investigate the
      effectiveness and usefulness of (67)Ga SPECT scintigraphy in the diagnosis of TA.
      METHODS: Nine patients (five male, four female) and six controls were included in
      the study. All of them received 8-10 mCi (67)Ga intravenously 48 hours before the
      scan.(67)Ga uptake ratios were calculated on transaxial and coronal slices.
      RESULTS: All patients showed increased uptake in the temporal area of the skull
      compared with controls. CONCLUSION: The data suggest that (67)Ga skull SPECT may
      be useful in the diagnosis of TA, especially if the uptake ratio in the area of
      interest is calculated. Further studies are needed to confirm these data.

PMID- 12594116
TI  - Filaggrin related antibodies among the aged.
AB  - BACKGROUND: The mean age at onset of new cases of rheumatoid arthritis (RA) has
      increased markedly. Because the prevalence of false positive rheumatoid factor
      reactions increases with advancing age, the diagnostic value of this test has
      limitations among the aged. OBJECTIVE: To study the occurrence of two filaggrin
      related antibodies in an aged population. METHODS: The study covered 300 subjects
      aged 78-88 years, one of whom had RA. The sera were tested with enzyme linked
      immunosorbent assays (ELISAs), using filaggrin purified from human skin and
      citrullinated cyclic peptide (CCP) as antigens. RESULTS: One patient with RA was
      positive for both antibodies. When the cut off level for positive reactions was
      set at the 98th centile of healthy blood donors, 24 (8%) of the other subjects
      were positive for antibodies against filaggrin, but only one against CCP.
      CONCLUSION: The test for anti-CCP antibody has better specificity than the test
      for antibodies against filaggrin among the aged.

PMID- 12594117
TI  - Raised serum interleukin 15 levels in Kawasaki disease.
AB  - BACKGROUND: Interleukin (IL)15 is a novel cytokine that induces T cell
      proliferation, B cell maturation, natural killer cell cytotoxicity, and may have
      a pivotal role in the pathogenesis of inflammatory disease, acting upstream from
      tumour necrosis factor alpha (TNFalpha). Kawasaki disease (KD) is an inflammatory
      disease, in which serum levels of inflammatory cytokines such as TNFalpha and IL6
      are increased. OBJECTIVE: To examine the serum levels of IL15 in KD and to
      evaluate the role of IL15 in estimating the severity of inflammation in KD.
      RESULTS AND CONCLUSION: There was a significant increase in the mean (SD) serum
      levels of IL15 measured in the acute stage of KD (11.5 (5.8) pg/ml) compared with
      those in the subacute stage (1.3 (0.9) pg/ml) (p<0.01) and normal controls (0.9
      (1.0) pg/ml) (p<0.01). The increase in IL15 correlated with the increase in
      TNFalpha (r(s)=0.66, p<0.01); however it did not correlate with the levels of
      erythrocyte sedimentation rate and C reactive protein, suggesting that IL15 may
      not be a useful marker in estimating the severity of inflammation in KD.

PMID- 12594118
TI  - Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline.
AB  - OBJECTIVES: To evaluate the effect of minocycline as treatment for cutaneous
      calcinosis in limited cutaneous systemic sclerosis (lcSSc). METHODS: Patients
      with lcSSc who had cutaneous calcinosis causing pain or ulceration, or both, were
      prescribed minocycline 50 or 100 mg daily regularly in an open label manner
      between November 1994 and April 2000. At routine clinical follow up the
      appearance of the calcinosis deposits was assessed clinically and
      radiographically, and the patients' assessment of the degree of discomfort, size,
      and frequency of ulceration was recorded. Demographic data, including disease
      duration, clinical features, and antinuclear antibody (ANA) titres, were also
      recorded. RESULTS: Nine patients have been treated to date. Eight of the nine
      patients were ANA positive, five of whom were positive for anticentromere
      antibodies. Eight patients have shown definite improvement and seven patients
      continue to receive treatment. The frequency of ulceration and inflammation
      associated with the calcinosis deposits decreased with treatment. The size of the
      calcinosis deposits also decreased but was less dramatic than expected.
      Improvement occurred at the earliest after one month of treatment with a mean
      (SD) of 4.8 (3.8) months. The mean (SD) length of treatment was 3.5 (1.9) years.
      An unexpected effect was the darkening of the calcinosis deposits to a blue/black
      colour. CONCLUSIONS: Minocycline may be effective in the control of calcinosis in
      systemic sclerosis. A low dose only is required and appears to be generally well
      tolerated. The mechanism of action may be mainly through inhibition of matrix
      metalloproteinases and anti-inflammatory effects. Calcium binding properties and
      antibacterial actions may also have a role.

PMID- 12594119
TI  - Erdheim-Chester disease in Brazil.

PMID- 12594120
TI  - Erdheim-Chester disease with early onset atherosclerosis and a pseudo-malignant
      phase.

PMID- 12594121
TI  - Antinucleosome antibodies in the diagnosis of systemic lupus erythematosus.

PMID- 12594122
TI  - Bilateral distal fibular and tibial stress fractures associated with heavy
      smoking.
AB  - An unusual case of simultaneous bilateral stress fractures of the distal tibia
      and fibula in a 45 year old white woman is described. The onset of symptoms was
      not associated with a specific episode of trauma, sporting activity, or
      identifiable inflammatory predisposing cause. Her bone density scan, bone
      profile, and biochemistry were all normal. Although stress fractures are well
      recognised, bilateral distal tibial and fibular fractures are particularly rare.
      A high degree of awareness is required for early diagnosis.

PMID- 12594123
TI  - Zoledronate treatment in active Paget's disease.

PMID- 12594124
TI  - Ayurveda in ankylosing spondylitis and low back pain.

PMID- 12594125
TI  - An exceptional radiographic presentation of bilateral insufficiency fractures of
      the proximal tibia in a patient with rheumatoid arthritis.

PMID- 12594126
TI  - Oral contraceptives, rheumatoid arthritis, and androgens.

PMID- 12594127
TI  - Anti-tumour necrosis factor alpha monoclonal antibody therapy for recalcitrant
      cerebral vasculitis in a patient with Behcet's syndrome.

PMID- 12594128
TI  - Tubulointerstitial nephritis and uveitis syndrome: a diagnosis that should be
      considered by rheumatologists.

PMID- 12594129
TI  - Cerebral calcifications in an elderly lupus patient.

PMID- 12594130
TI  - Response of mononuclear cells to lipopolysaccharide and CpG oligonucleotide
      stimulation: possible additive effect in rheumatoid inflammation.

PMID- 12594132
TI  - Reduction of jaw opening in giant cell arteritis.

PMID- 12594133
TI  - Key questions concerning paracetamol and NSAIDs for OA.

PMID- 12594134
TI  - Sedating patients undergoing mechanical ventilation in the intensive care unit-
      winds of change?

PMID- 12594135
TI  - It's NICE to see in the dark.

PMID- 12594136
TI  - Desflurane compared with propofol for postoperative sedation in the intensive
      care unit.
AB  - BACKGROUND: We hypothesized that emergence from sedation in postoperative
      patients in the intensive care unit would be faster and more predictable after
      sedation with desflurane than with propofol. METHODS: Sixty patients after major
      operations were allocated randomly to receive either desflurane or propofol. The
      target level of sedation was defined by a bispectral index(TM) (BIS(TM)) of 60.
      All patients were receiving mechanical ventilation of the lungs for 10.6 (SD 5.5)
      h depending on their clinical state. The study drugs were stopped abruptly in a
      calm atmosphere with the fresh gas flow set to 6 litres min(-1), and the time
      until the BIS increased above 75 was measured (t(BIS75), the main objective
      measure). After extubation of the trachea, when the patients could state their
      birth date, they were asked to memorize five words. RESULTS: Emergence times were
      shorter (P<0.001) after desflurane than after propofol (25th, 50th and 75th
      percentiles): t(BIS75), 3.0, 4.5 and 5.8 vs 5.2, 7.7 and 10.3 min; time to first
      response, 3.7, 5.0 and 5.7 vs 6.9, 8.6 and 10.7 min; time to eyes open, 4.7, 5.7
      and 8.0 vs 7.3, 10.5 and 20.8 min; time to squeeze hand, 5.1, 6.5 and 10.2 vs
      9.2, 11.1 and 21.1 min; time to tracheal extubation, 5.8, 7.7 and 10.0 vs 9.7,
      13.5 and 18.9 min; time to saying their birth date, 7.7, 10.5 and 15.5 vs 13.0,
      19.4 and 31.8 min. Patients who received desflurane recalled significantly more
      of the five words. We did not observe major side-effects and there were no
      haemodynamic or laboratory changes except for a more marked increase in systolic
      blood pressure after stopping desflurane. Using a low fresh gas flow (air/oxygen
      1 litre min(-1)), pure drug costs were lower for desflurane than for propofol (95
      vs 171 Euros day(-1)). CONCLUSIONS: We found shorter and more predictable
      emergence times and quicker mental recovery after short-term postoperative
      sedation with desflurane compared with propofol. Desflurane allows precise timing
      of extubation, shortening the time during which the patient needs very close
      attention.

PMID- 12594137
TI  - Accuracy of feedback-controlled oxygen delivery into a closed anaesthesia circuit
      for measurement of oxygen consumption.
AB  - BACKGROUND: Oxygen consumption (V*O2) is rarely measured during anaesthesia,
      probably because of technical difficulties. Theoretically, oxygen delivery into a
      closed anaesthesia circuit (V*O2-PF; PhysioFlex Draeger Medical Company, Germany)
      should measure V*O2. We aimed to measure V*O2-PF in vitro and in vivo. METHODS:
      Three sets of experiments were performed. V*O2-PF was assessed with five values
      of V*O2 (0-300 ml min(-1)) simulated by a calibrated lung model (V*O2-Model) at
      five values of FIO2 (0.25-0.85). The time taken for V*O2-PF to respond to changes
      in V*O2-Model gave a measure of dynamic performance. In six healthy anaesthetized
      dogs we compared V*O2-PF with V*O2 measured by the Fick method (V*O2-Fick) during
      ventilation with nine values of FIO2 (0.21-1.00). V*O2-PF and V*O2-Fick were also
      compared in three dogs when V*O2 was changed pharmacologically [102 (SD 14), 121
      (17) and 200 (57) ml min(-1)]. In patients during surgery, we measured V*O2-PF
      and V*O2-Fick simultaneously after induction of anaesthesia (n=21) and during
      surgery (n=17) (FIO2 0.3-0.5). RESULTS: Compared with V*O2-Model, V*O2-PF values
      varied from time to time so that averaging over 10 min is recommended.
      Furthermore, at an FIO2 >0.8, V*O2-PF always overestimated V*O2. With FIO2 <0.8,
      averaged V*O2-PF corresponded to V*O2-Model and adapted rapidly to changes.
      Averaged V*O2-PF also corresponded to V*O2-Fick in dogs at FIO2 <0.8. V*O2
      measured by the two methods gave similar results when V*O2 was changed
      pharmacologically. In contrast, V*O2-PF systematically overestimated V*O2-Fick in
      patients by 52 (SD 40) ml min-1 and this bias increased with smaller
      arteriovenous differences in oxygen content. CONCLUSION: V*O2-PF measures V*O2
      adequately within specific conditions.

PMID- 12594138
TI  - Extrapolation to zero-flow pressure in cerebral arteries to estimate intracranial
      pressure.
AB  - BACKGROUND: Cerebral perfusion pressure (CPP) is commonly calculated from the
      difference between arterial blood pressure (AP) and intracranial pressure (ICP).
      ICP can be considered the effective downstream pressure of the cerebral
      circulation. Consequently, cerebral circulatory arrest would occur when AP equals
      ICP. Estimation of AP for zero-flow pressure (ZFP) may thus allow estimation of
      ICP. We estimated ZFP from cerebral pressure-flow velocity relationships so that
      ICP could be measured by transcranial Doppler sonography. METHODS: We studied 20
      mechanically ventilated patients with severe head injury, in whom ICP was
      monitored by epidural pressure transducers. AP was measured with a radial artery
      cannula. Blood flow velocity in the middle cerebral artery (V(MCA)) ipsilateral
      to the site of ICP measurement was measured with a 2 MHz transcranial Doppler
      probe. All data were recorded by a microcomputer from analogue-digital
      converters. ZFP was extrapolated by regression analysis of AP-V(MCA) plots and
      compared with simultaneous measurements of ICP. RESULTS: ZFP estimated from AP
      V(MCA) plots was linearly related to ICP over a wide range of values (r=0.93).
      There was no systematic difference between ZFP and ICP. Limit of agreement (2 SD)
      was 15.2 mm Hg. Short-term variations in ICP were closely followed by changes in
      ZFP. CONCLUSION: Extrapolation of cerebral ZFP from instantaneous AP-V(MCA)
      relationships enables detection of severely elevated ICP and may be a useful and
      less invasive method for CPP monitoring than other methods.

PMID- 12594139
TI  - Remifentanil and nitrous oxide reduce changes in cerebral blood flow velocity in
      the middle cerebral artery caused by pain.
AB  - BACKGROUND: Cerebral blood flow is affected by painful stimuli, and analgesic
      agents may alter the response of cerebral blood flow to pain. We set out to
      quantify the effects of remifentanil and nitrous oxide on blood flow changes
      caused by experimental pain. METHODS: We simulated surgical pain in 10 conscious
      volunteers using increasing mechanical pressure to the tibia. We measured changes
      in cerebral blood flow velocity in the middle cerebral artery (CBFV(MCA)) caused
      by the pain, using transcranial Doppler sonography. We gave increasing doses of
      remifentanil (0.025, 0.05 and 0.1 micro g kg(-1) min(-1)) or nitrous oxide [20%,
      35% and 50% end-tidal concentration (FE'(N(2)O))] and compared these effects on
      blood flow changes. RESULTS: Nitrous oxide increased CBFV(MCA) only when given at
      50% FE'(N(2)O). Remifentanil did not affect CBFV(MCA). Pain increased CBFV(MCA).
      Both agents attenuated this pain-induced change in CBFV(MCA) with the exception
      of nitrous oxide at 20% FE'(N(2)O). CONCLUSIONS: Inhalation of nitrous oxide or
      adminstration of remifentanil attenuated pain-induced changes in CBFV(MCA).

PMID- 12594140
TI  - Intrathecal morphine and clonidine for coronary artery bypass grafting.
AB  - BACKGROUND: After cardiac surgery adequate postoperative analgesia is necessary.
      We assessed analgesia using intrathecal morphine and clonidine. METHODS: In a
      double-blind randomized study, 45 patients having coronary artery bypass graft
      surgery were allocated randomly to receive i.v. patient-controlled analgesia
      (PCA) morphine (bolus, 1 mg; lock-out interval, 7 min) (control group), either
      alone or combined with intrathecal morphine 4 microg kg(-1) or with both
      intrathecal morphine 4 microg kg(-1) and clonidine 1 microg kg(-1). Intrathecal
      injections were performed before the induction of general anaesthesia. Pain was
      measured after surgery using a visual analogue scale (VAS). We recorded i.v. PCA
      morphine consumption during the 24 h after operation. RESULTS: Morphine dosage
      [median (25th-75th percentiles)] was less in the first 24 h in the patients who
      were given intrathecal morphine + clonidine [7 (0-37) mg] than in other patients
      [40.5 (15-61.5) mg in the intrathecal morphine group and 37 (30.5-51) mg in the
      i.v. morphine group]. VAS scores were lower after intrathecal morphine +
      clonidine compared with the control group. Time to extubation was less after
      intrathecal morphine + clonidine compared with the i.v. morphine group [225 (195
      330) vs 330 (300-360) min, P<0.05]. CONCLUSION: Intrathecal morphine and
      clonidine provide effective analgesia after coronary artery bypass graft surgery
      and allow earlier extubation.

PMID- 12594142
TI  - Urinary bladder scanning after day-case arthroscopy under spinal anaesthesia:
      comparison between lidocaine, ropivacaine, and levobupivacaine.
AB  - BACKGROUND: Micturition problems after spinal anaesthesia may delay hospital
      discharge. The use of lidocaine has raised concerns because of the occurrence of
      transient neurological symptoms (TNS). This randomized double-blind study was
      designed to compare the newer local anaesthetics with lidocaine regarding block
      characteristics, micturition problems, and discharge times in day-case spinals
      for arthroscopy. METHODS: Ninety patients received either isobaric lidocaine 60
      mg, ropivacaine 15 mg, or levobupivacaine 10 mg intrathecally. Urinary bladder
      volumes were measured by ultrasound imaging at regular time intervals until a
      post-voiding residual volume (PVRV) less than 100 ml was obtained. Micturition
      problems were classified in five groups ranging from no problems to those
      requiring catheterization. RESULTS: Times to regain a Bromage-1 and -0 motor
      block were similar in the three groups but sensory block regression to L2
      occurred at 145 (30) min in the lidocaine group, 25-30 min (P<0.05) faster than
      the other groups. Lidocaine allowed voiding after 245 (65) min and hospital
      discharge 265 (70) min after spinal injection, 40 min faster than in the two
      other groups. The incidence or degree of micturition problems were not different
      between after discharge, three patients (10%) receiving lidocaine complained of
      symptoms compatible with TNS. CONCLUSIONS: Our study suggested that the three
      local anaesthetics behave similar regarding quality of anaesthesia and motor
      block but voiding and discharge occurred significantly earlier with lidocaine
      although the 40 min difference was not impressive considering a spinal discharge
      time interval of 4-5 h.

PMID- 12594141
TI  - Comparison of ropivacaine 0.5% (in glucose 5%) with bupivacaine 0.5% (in glucose
      8%) for spinal anaesthesia for elective surgery.
AB  - BACKGROUND: Hyperbaric solutions of ropivacaine have been used successfully to
      provide spinal anaesthesia. This study was designed to compare the clinical
      efficacy of hyperbaric ropivacaine with that of the commercially available
      hyperbaric preparation of bupivacaine. METHODS: Forty ASA grade I-II patients
      undergoing lower-abdominal, perineal or lower-limb surgery under spinal
      anaesthesia were recruited and randomized to receive ropivacaine 5 mg ml(-1)
      (with glucose 50 mg ml(-1)), 3 ml or bupivacaine 5 mg ml(-1) (with glucose 80 mg
      ml(-1)), 3 ml. The level and duration of sensory block, intensity and duration of
      motor block, and time to mobilize and micturate were recorded. Patients were
      interviewed at 24 h and at 1 week to identify any residual problems. RESULTS: All
      blocks were adequate for the proposed surgery, but there were significant
      differences between the two groups in mean time to onset of sensory block at T10
      (ropivacaine 5 min; bupivacaine 2 min; P<0.005), median maximum extent
      (ropivacaine T7; bupivacaine T5; P<0.005) and mean duration of sensory block at
      T10 (ropivacaine 56.5 min; bupivacaine 118 min; P=0.001). Patients receiving
      ropivacaine mobilized sooner (ropivacaine mean 253.5 min; bupivacaine 331 min;
      P=0.002) and passed urine sooner (ropivacaine mean 276 min; bupivacaine 340.5
      min; P=0.01) than those receiving bupivacaine. More patients in the bupivacaine
      group required treatment for hypotension (>30% decrease in systolic pressure;
      P=0.001). CONCLUSIONS: Ropivacaine 15 mg in glucose 50 mg ml(-1) provides
      reliable spinal anaesthesia of shorter duration and with less hypotension than
      bupivacaine. The recovery profile for ropivacaine may be of interest given that
      more surgery is being performed in the day-case setting.

PMID- 12594143
TI  - Adjunctive analgesia with intravenous propacetamol does not reduce morphine
      related adverse effects.
AB  - BACKGROUND: Propacetamol is widely used in the management of postoperative pain.
      It decreases morphine requirements but its effect on the incidence of morphine
      related adverse effects remains unknown. METHODS: Patients (550) were randomly
      assigned to receive propacetamol or a placebo over the first 24 h after operation
      in a blinded study. Intravenous morphine titration was performed, after which
      morphine was administered s.c. every 4 h according to their pain score. Pain was
      assessed using a visual analogue scale (VAS). The primary end-point was the
      incidence of morphine-related adverse effects. The main secondary end-points were
      morphine requirements and VAS score. RESULTS: After morphine titration, the VAS
      score and the number of patients with pain relief did not differ between groups.
      Morphine requirements were decreased in the propacetamol group (21 vs 14.5 mg,
      P<0.001) but the incidence of morphine-related adverse effects did not differ
      between groups (42 vs 46%, not significant). In patients with moderate pain
      (n=395), morphine requirements decreased by 37% (P<0.001) and the percentage of
      patients requiring no morphine was greater (21 vs 8%, P=0.002) in the
      propacetamol group. In patients with severe pain (n=155), morphine requirements
      decreased by 18% (P=0.04) in the propacetamol group and the number of patients
      who did not require morphine (3 vs 8%) did not differ significantly. CONCLUSIONS:
      Although propacetamol induced a small morphine-sparing effect, it did not change
      the incidence of morphine-related adverse effects in the postoperative period.
      Moreover, no benefit could be demonstrated in patients with severe postoperative
      pain.

PMID- 12594144
TI  - Comparison of local anaesthetic effects of tramadol with prilocaine for minor
      surgical procedures.
AB  - BACKGROUND: Recent studies have shown that a local anaesthetic action of tramadol
      5% was able to induce a sensory block to pinprick, touch, and cold similar to
      that of lidocaine 1%. The aim of this study was to compare the local anaesthetic
      effects of tramadol hydrochloride with prilocaine. METHODS: Sixty ASA I or II
      patients, undergoing excision of the cutaneous lesions under local anaesthesia,
      were included in the study. Patients were randomly assigned to receive either 1
      ml of tramadol 5% (Group T, n=30) or 1 ml of prilocaine 2% (Group P, n=30)
      intradermally, in a double-blinded fashion. The degree of the burning sensation
      and pain at the injection site was documented. Sensory block was assessed 1 min
      after injection. The patient was asked to report the degree of sensation and to
      grade touch and pinprick sensation. Two minutes after drug administration,
      incision was performed and intensity of pain, felt by the patient was evaluated
      on a four-point scale (0-3). Any local adverse effects were recorded. RESULTS:
      There was no difference in the quality of block between the two groups. Side
      effects were noted in both groups with a significant increase in the incidence of
      local reaction (rash) in Group T (seven patients) when compared with Group P (one
      patient) (P<0.05). Seven patients in Group T vs four patients in Group P
      complained of burning at the injection site (P>0.05). CONCLUSIONS: Intradermal
      tramadol 5% can provide a local anaesthesia similar to the prilocaine but the
      incidence of local adverse effects is higher.

PMID- 12594145
TI  - Comparison of the standard laryngeal mask airway and the ProSeal laryngeal mask
      airway in obese patients.
AB  - BACKGROUND: The ProSeal laryngeal mask airway (PLMA) may have advantages over the
      laryngeal mask airway (LMA) in obese patients. We tested this hypothesis in a
      clinical setting. METHODS: Sixty obese patients (BMI >30) were randomized to
      receive mechanical ventilation (tidal volume 7 ml kg(-1), PEEP 10 cm H(2)O),
      through either the PLMA or the LMA. A gastric tube was used in all patients. Cuff
      pressure was set at 60 cm H(2)O and increased progressively until excessive leak
      occurred. The incidence of sore throat was assessed at recovery and after 1 week.
      RESULTS: The mean leak fraction was 6.1 (SD 2.9)% with the LMA and 6.4 (3.5)%
      with the PLMA (P=0.721). With the PLMA, with no sign of ventilation problems, the
      drainage tube was not patent in three patients. The cuff pressure was >100 cm
      H(2)O in 38% of the LMA group and 7% of the PLMA group (P=0.05). The incidence of
      sore throat was similar in both groups and it was similarly scored in the
      recovery room and 1 week after surgery. CONCLUSIONS: Both the PLMA and the LMA
      can be used for mechanical ventilation of obese patients. The patency of the PLMA
      drainage tube needs to be checked constantly even when an optimal airtight seal
      is present. In obese patients the LMA requires a greater cuff pressure than the
      PLMA, but sore throat is not related to the cuff pressure. Sore throat assessment
      in the recovery room appears as reliable as assessment later.

PMID- 12594146
TI  - Tight control of prehospital ventilation by capnography in major trauma victims.
AB  - BACKGROUND: Tracheal intubation combined with controlled ventilation of the lungs
      is an important part of the prehospital management of major trauma victims, but
      gauging the adequacy of ventilation remains a major problem. METHODS: Ninety
      seven major trauma victims who underwent tracheal intubation in the field and
      controlled ventilation of the lungs during prehospital treatment by a Helicopter
      Emergency Medical Service were assigned randomly to one of two groups: (1)
      monitor group (n=57) and (2) monitor-blind group (n=40), according to whether the
      anaesthetist could or could not see an attached capnograph screen. In the monitor
      blind group ventilation was set by using a tidal-volume of 10 ml kg(-1) estimated
      body weight and an age-appropriate ventilatory frequency. In the monitor group,
      ventilation was adjusted to achieve target end-tidal carbon dioxide values
      determined by the 'physiological state' of the trauma victim. Arterial blood
      gases were measured upon hospital admission while maintaining the ventilation
      initiated in the field and the Pa(CO(2)) value obtained was used as the
      determinant of the adequacy of prehospital ventilation. RESULTS: The incidence of
      'normoventilation' was significantly higher (63.2 vs 20%; P<0.0001) and the
      incidence of 'hypoventilation' upon hospital admission was significantly lower
      (5.3 vs 37.5%; P<0.0001) in the monitor group; patients with severe head and
      chest trauma and haemodynamically unstable patients and those with a high injury
      severity score were significantly more likely to be 'normoventilated' upon
      hospital admission in the monitor group than in the monitor-blind group.
      CONCLUSIONS: The data support the routine use of prehospital capnographic
      monitoring using target end-tidal carbon dioxide values adapted to the
      physiological state of the patient in major trauma victims requiring tracheal
      intubation in the field.

PMID- 12594147
TI  - Occupational stress and burnout in anaesthesia.
AB  - BACKGROUND: Formal studies on stress in anaesthetists have usually measured
      stress through mental or physiological indicators. When using this approach, one
      must be careful not to confuse the effects of stress or outcome variables and the
      sources of stress or antecedent variables. To date, it seems from the literature
      that there is no clear evidence of a common pattern of physiological effects of
      stress for all the sources of stress. Furthermore, work characteristics such as
      job satisfaction, job control and job support may moderate the effects of stress.
      METHODS: We measured the effects of stress together with the sources of stress
      and job characteristics, using self-reported questionnaires rather than
      physiological indicators in order to better diagnose stress in anaesthetists.
      RESULTS: The mean stress level in anaesthetists was 50.6 which is no higher than
      we found in other working populations. The three main sources of stress reported
      were a lack of control over time management, work planning and risks.
      Anaesthetists reported high empowerment, high work commitment, high job challenge
      and high satisfaction. However, 40.4% of the group were suffering from high
      emotional exhaustion (burnout); the highest rate was in young trainees under 30
      years of age. CONCLUSIONS: Remedial actions are discussed at the end of the
      paper.

PMID- 12594148
TI  - Administration of nitric oxide into open lung regions: delivery and monitoring.
AB  - BACKGROUND: Pulsed administration of nitric oxide has proven effective in
      relieving pulmonary hypertension and in improving oxygenation. With this delivery
      method the nitric oxide administration to low ventilated lung regions is avoided
      with subsequent enhancement in oxygenation. This study presents (i) pulsed
      administration technique for nitric oxide during artificial ventilation, (ii)
      evaluation of the delivery in an animal model, and (iii) validation of the
      delivery device in a laboratory setting. METHODS: Nitric oxide was delivered in
      four different pulse volumes synchronously with inspiration. The delivery was
      monitored with a fast responding high sensitivity nitric oxide monitor and nitric
      oxide uptake was calculated. Pulse delivery dose range, accuracy of the delivered
      dose, and stability of successive doses were analysed in a laboratory setting.
      RESULTS: Uptake of the delivered nitric oxide was 87-92%. Measured nitric oxide
      pulse concentration was 1.6-fold the delivery concentration, calculated as the
      ratio of nitric oxide flow to inspiration flow. Dose accuracy and stability were
      both 5% or 3 nmol in the validated range of 3-1000 nmol. CONCLUSION: With pulsed
      administration nitric oxide therapy can be directed to well-ventilated lung
      regions. Avoiding administration to the anatomic dead space eliminates nitric
      oxide exhalation effectively, which makes the method optimal for nitric oxide
      therapy in a rebreathing circuit. The required dose range from paediatric to
      adult is covered by the delivery device with a single nitric oxide gas supply.

PMID- 12594149
TI  - Pre-emptive lidocaine inhibits arterial vasoconstriction but not vasopressin
      release induced by a carbon dioxide pneumoperitoneum in pigs.
AB  - BACKGROUND: We assessed the preventive effects of i.v. or i.p. lidocaine
      administration on increases in vascular resistance produced by carbon dioxide
      pneumoperitoneum and related this to vasopressin release. METHODS: Carbon dioxide
      pneumoperitoneum (14 mm Hg intra-abdominal pressure) was performed in 32
      anaesthetized young pigs and monitored using a pulmonary artery catheter. Animals
      received lidocaine 0.5% (0.5 mg kg(-1)) i.v. (n=9) or 2 ml kg(-1) i.p. (n=9) or
      saline (n=5) 15 min before the pneumoperitoneum and were compared with a control
      group (n=9). RESULTS: I.V. and i.p. lidocaine inhibited increases in mean
      systemic vascular resistance induced by the pneumoperitoneum [2109 (SD 935) and
      2282 (895), respectively, vs 3013 (1067) dyne s(-1) cm(-5) in the control group].
      Cardiac output was increased. Plasma lidocaine concentrations were threefold
      higher after i.p. administration than after i.v. administration. After
      pneumoperitoneum insufflation, plasma lysine-vasopressin concentrations increased
      in all groups (control 74%, saline 65%, i.p. lidocaine 57%, i.v. lidocaine 74%).
      CONCLUSIONS: I.V. and i.p. lidocaine blunted systemic vascular responses to
      carbon dioxide pneumoperitoneum in pigs, but without influencing vasopressin
      release.

PMID- 12594150
TI  - Long QT syndrome and anaesthesia.

PMID- 12594151
TI  - Anaesthesia and tracheobronchial stenting for central airway obstruction in
      adults.
AB  - In the last decade, stents suitable for the management of tracheobronchial
      stenoses and obstruction have evolved from bulky prostheses requiring tracheal
      resection to small devices that are self-expanding and can be inserted using
      fibreoptic techniques. The experience base for this review is more than 100
      patients between 1989 and 2001 who have been anaesthetized for stent insertion.
      Early cases required rigid bronchoscopy for the routine of insertion. Anaesthetic
      techniques have evolved from those that were designed and developed for laser
      surgery in the central airways. The advent of modern devices now extends the
      variety of anaesthetic management techniques that can be used. But the original
      one, based on the requirement for use of a rigid bronchoscope, is best for
      dealing with complications and extracting problem stents. The most frequent
      complication of the processes of stent insertion has been respiratory failure
      because of carbon dioxide retention, consequent on obstruction with secretions in
      the area of the carina. The nature of central airway problems suggests that
      anaesthesia induction, management and teaching should not be founded on the
      conventional model-base of upper airway obstruction.

PMID- 12594152
TI  - Propofol 1% versus propofol 2% in children undergoing minor ENT surgery.
AB  - BACKGROUND: The induction characteristics of propofol 1% and 2% were compared in
      children undergoing ENT surgery, in a prospective, randomized, double-blind
      study. METHODS: One hundred and eight children received propofol 1% (n=55) or 2%
      (n=53) for induction and maintenance of anaesthesia. For induction, propofol 4 mg
      kg(-1) was injected at a constant rate (1200 ml h(-1)), supplemented with
      alfentanil. Intubating conditions without the use of a neuromuscular blocking
      agent were scored. RESULTS: Pain on injection occurred in 9% and 21% of patients
      after propofol 1% and 2%, respectively (P=0.09). Loss of consciousness was more
      rapid with propofol 2% compared with propofol 1% (47 s vs 54 s; P=0.02).
      Spontaneous movements during induction occurred in 22% and 34% (P=0.18), and
      intubating conditions were satisfactory in 87% and 96% (P=0.19) of children
      receiving propofol 1% or 2%, respectively. There were no differences between the
      two groups in respect of haemodynamic changes or adverse events. CONCLUSIONS: For
      the end-points tested, propofol 1% and propofol 2% are similar for induction of
      anaesthesia in children undergoing minor ENT surgery.

PMID- 12594153
TI  - Comparison of four strategies to reduce the pain associated with intravenous
      administration of rocuronium.
AB  - BACKGROUND: I.V. rocuronium produces intense discomfort at the site of injection
      in conscious patients. Four strategies to reduce or prevent this discomfort were
      studied. METHODS: Two hundred and fifty adult patients, ASA I-III, were
      randomized into five groups of 50 patients in a blinded, prospective study. The
      control group received rocuronium 10 mg alone. For the remaining four groups,
      rocuronium 10 mg was mixed with sodium bicarbonate 8.4% 2 ml, fentanyl 100 micro
      g, lidocaine 2% or normal saline. The pH and osmolality of all mixtures were
      measured. Patient data were analysed using ordinal logistic regression.
      Osmolality and pH data were analysed using the Kruskal-Wallis test with Dunn's
      multiple comparison test. RESULTS: When compared with rocuronium alone, only the
      addition of saline failed to significantly reduce the pain reported by patients.
      The addition of fentanyl reduced the complaint of pain by 1.9 times (P<0.049) and
      the addition of lidocaine 2% reduced it by 3.6 times (P<0.0001). Sodium
      bicarbonate 8.4% reduced the reporting of pain by 18.4 times (P<0.0001).
      CONCLUSIONS: Sodium bicarbonate 8.4%, when added to rocuronium, markedly reduces
      the experience of pain during the i.v. administration of a small dose of
      rocuronium.

PMID- 12594154
TI  - Use of a 'hospital-at-home' service for patient optimization before resection of
      phaeochromocytoma.
AB  - The perioperative management of phaeochromocytoma remains a complicated
      anaesthetic challenge, often requiring a prolonged preoperative hospital stay or
      numerous outpatient clinic visits. This is not only inconvenient for the patient,
      it also puts them at additional risk of acquiring hospital infections and is
      expensive to the health service. We present a patient with a phaeochromocytoma
      who was successfully managed preoperatively with phenoxybenzamine in the
      community by a 'hospital-at-home' service. She required no other
      antihypertensives before operation, although glyceryl trinitrate and magnesium
      sulphate were used before induction of anaesthesia. Apart from intervention for a
      chest infection on day 3, she had a relatively smooth hospital course and
      returned home on day 13. We suggest that this may be an appropriate management
      option for selected patients.

PMID- 12594155
TI  - Anaesthesia for awake craniotomy with non-invasive positive pressure ventilation.
AB  - Airway management during awake craniotomy is a crucial part of the anaesthetic
      technique, but it remains the subject of debate. We report two cases of
      anaesthesia for awake craniotomy using non-invasive positive pressure
      ventilation; biphasic positive airway pressure or proportional assist ventilation
      was employed. Both ventilatory techniques provided adequate lung ventilation,
      smooth transition between anaesthesia and arousal, and patient comfort.

PMID- 12594156
TI  - Ventilation by the Open Lung Concept in spite of traumatic lung herniation.
AB  - Traumatic herniation of the lung is uncommon. We report a patient suffering from
      multiple injuries including severe pulmonary contusion and traumatic parasternal
      lung herniation, who developed acute respiratory distress syndrome. In spite of
      the lung herniation, we used mechanical ventilation according to the Open Lung
      Concept. Oxygenation improved rapidly, and early operative stabilization was
      possible.

PMID- 12594157
TI  - A modified nasal trumpet to facilitate fibreoptic intubation.
AB  - BACKGROUND: The modified nasal trumpet (MNT) is a standard nasopharyngeal airway
      with an added distal fenestration and fitted with a 15 mm adaptor to permit
      connection to an anaesthesia circuit. METHODS: Based on its successful use as an
      emergency device in the 'cannot intubate, cannot ventilate' scenario, we
      considered that the MNT would aid fibreoptic intubation by providing a patent
      airway, spontaneous ventilation, and inhalation anaesthesia during the procedure.
      We report use of the MNT for this purpose seven times in six patients with
      difficult airways. RESULTS: In each case, the MNT allowed oxygenation and general
      anaesthesia while maintaining spontaneous ventilation when awake intubation was
      unsuccessful or not possible. CONCLUSION: The MNT has a place in the operating
      room suites as a useful airway management device.

PMID- 12594158
TI  - Coronary artery spasm induced by carotid sinus stimulation during neck surgery.
AB  - We observed four transient episodes of marked ST-segment elevation in a 58-yr-old
      man with no history of coronary artery disease undergoing resection of a
      metastatic neck mass under general anaesthesia. Elevations of the ST segment were
      abrupt, with no change in arterial pressure or heart rate, and resolved
      spontaneously. When the carotid sinus was compressed directly, ST-segment
      elevation was noted 1 min after the onset of stimulation. After surgery, coronary
      angiography showed diffuse, slight narrowing of the distal bed of the
      posterolateral branch of the right coronary artery. Ergonovine caused total
      occlusion of the posterolateral branch of the right coronary artery with chest
      pain and ST-segment elevation, confirming the diagnosis of variant angina. The
      coronary artery spasm seems to have been provoked by vagal activation from
      carotid sinus stimulation during general anaesthesia.

PMID- 12594159
TI  - Pathophysiology and clinical implications of perioperative fluid excess.

PMID- 12594160
TI  - Estimation of critical closing pressure and cerebral perfusion pressure using
      transcranial Doppler.

PMID- 12594161
TI  - Use of the laryngeal tube as a dedicated airway during tracheal intubation.

PMID- 12594162
TI  - Anaesthesia in an adult with Rubinstein-Taybi syndrome.

PMID- 12594163
TI  - Safe dose of levobupivacaine (Chirocaine) in caudal analgesia in children.

PMID- 12594164
TI  - Anaesthesia for Caesarean section in women with heart disease.

PMID- 12594165
TI  - Vaginal examination: a requirement before calling the anaesthetist?

PMID- 12594166
TI  - Recurrent neurological symptoms in a patient after repeat combined spinal and
      epidural anaesthesia.

PMID- 12594167
TI  - Preoperative use of herbal medicines.

PMID- 12594170
TI  - Mechanisms for the reduction of 24,25-dihydroxyvitamin D3 levels and bone mass in
      24-hydroxylase transgenic rats.
AB  - 24-Hydroxylase (CYP24) is an enzyme distributed in the target tissues of
      1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. Two functions for this enzyme
      have been reported: One is production of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]
      and the other is inactivation of 1alpha,25(OH)2D3. To elucidate other physiologic
      roles of CYP24 in vivo, we previously generated rats that constitutively express
      the CYP24 gene. These transgenic (Tg) rats developed unexpected phenotypes, such
      as low plasma levels of 24,25(OH)2D3, lipidemia, and albuminuria. In this study,
      we elucidated the mechanisms for inducing low plasma 24,25(OH)2D3 levels and bone
      loss. Tg rats excreted massive amounts of vitamin D binding protein (DBP), which
      coincided with the loss of albumin. In Tg rats, the renal expression pattern of
      megalin, which serves as an endocytotic receptor responsible for the reuptake of
      urinary proteins such as DBP and albumin, was identical to that of the wild-type
      rats. Excreted albumin appeared to compete for the binding and reabsorption of
      the DBP-25-hydroxyvitamin D3 [25(OH)D3] complex with megalin, resulting in a loss
      of 25(OH)D3 into the urine and subsequent reduction of plasma 24,25(OH)2D3. In
      this prominent rat model of nephritis, supplementation of 25(OH)D3 was effective
      in preventing bone loss in an early stage of renal insufficiency.

PMID- 12594171
TI  - Overexpression of interleukin-12 enables dendritic cells to activate NK cells and
      confer systemic antitumor immunity.
AB  - Dendritic cells (DC) are initiators of T cell-mediated immunity. However, less is
      known about the relationship between DC and natural killer (NK) cells, and direct
      evidence of their interaction in vivo is scarce. Interleukin (IL)-12 is an
      activator of both DC and NK cells. We postulated that secretion of IL-12 by DC
      would enable them to activate NK cells. Bone marrow-derived DC propagated only in
      granulocyte macrophage colony-stimulating factor did not activate NK cells. In
      contrast, DC engineered to express IL-12 markedly stimulated NK cells as
      determined by coculture experiments in vitro, assays of NK cells isolated from
      treated animals, and survival experiments in a systemic tumor model. Activation
      depended on both DC-NK cellular interaction and secretion of IL-12. Adoptive
      transfer of DC expressing IL-12 to mice markedly increased NK cell interferon
      gamma production and lytic activity in vivo. Treated mice were also protected
      against B16 melanoma hepatic metastases. The in vivo effects on NK cells were DC
      specific. Administration of IL-12 protein alone or melanoma cells or fibroblasts
      engineered to secrete IL-12 were only weakly activating. Our findings demonstrate
      that IL-12 expression by DC enables them to activate NK cells and provide
      evidence for a substantial DC-NK relationship in vivo.

PMID- 12594172
TI  - Transport of plasma membrane-derived cholesterol and the function of Niemann-Pick
      C1 Protein.
AB  - To visualize the intracellular transport of plasma membrane-derived cholesterol
      under physiological and pathophysiological conditions, a novel fluorescent
      cholesterol analog, 6-dansyl cholestanol (DChol), has been synthesized. We
      present several lines of evidence that DChol mimics cholesterol. The cholesterol
      probe could be efficiently incorporated into the plasma membrane via cyclodextrin
      donor complexes. The itinerary of DChol from the plasma membrane to the cell was
      studied to determine its dependence on the function of Niemann-Pick C1 (NPC)
      protein. In all cells, DChol moved from the plasma membrane to the endoplasmic
      reticulum. Its further transport to the Golgi complex was observed but with
      marked differences among various cell lines. DChol was finally transported to
      small (approximately 0.5 microm diameter) lipid droplets, a process that required
      functional acyl-CoA:cholesterol acyltransferase. In human NPC fibroblasts, NPC
      like cells, or in cells mimicking the NPC phenotype, DChol was found in enlarged
      (>1 microm diameter) droplets. When the NPC-phenotype was corrected by
      transfection with NPC1, DChol was again found in small-sized droplets. Our data
      show that NPC1 has an essential role in the distribution of plasma membrane
      derived cholesterol by maintaining the small size of cholesterol-containing lipid
      droplets in the cell.

PMID- 12594173
TI  - Glutaredoxin is essential for maintenance of brain mitochondrial complex I:
      studies with MPTP.
AB  - Mitochondrial complex I dysfunction is implicated in the pathogenesis of
      neurodegenerative disorders such as Parkinson's disease. Identification of
      factors involved in maintenance and restoration of complex I function could
      potentially help to develop prophylactic and therapeutic strategies for treatment
      of this class of disorders. Down-regulation of glutaredoxin (thioltransferase, a
      thiol disulfide oxido-reductase) using antisense oligonucleotides results in the
      loss of mitochondrial complex I activity in mouse brain. 1-Methyl-4-phenyl
      1,2,3,6,tetrahydro-pyridine (MPTP), the neurotoxin that causes Parkinson's
      disease-like symptoms in primates and dopaminergic cell loss in mice, acts
      through the inhibition of complex I. Regeneration of complex I activity in the
      striatum occurs concurrently with increase in glutaredoxin activity, 4 h after
      the neurotoxic insult, and is mediated through activation of activating protein
      1. Down-regulation of glutaredoxin using anti-sense oligonucleotides prevents
      recovery of complex I in the striatum after MPTP treatment, providing support for
      the critical role for glutaredoxin in recovery of mitochondrial function in
      brain. Maintenance and restoration of protein thiol homeostasis by glutaredoxin
      may be important factors in preventing complex I dysfunction.

PMID- 12594174
TI  - The N- and C-terminal fragments of ubiquitin are important for the antimicrobial
      activities.
AB  - Secretory granules of chromaffin cells contain catecholamines and several
      antimicrobial peptides derived from chromogranins and proenkephalin-A. These
      peptides are secreted in the extracellular medium following exocytosis. Here, we
      show that ubiquitin is stored in secretory chromaffin granules and released into
      the circulation upon stimulation of chromaffin cells. We also show that the C
      terminal fragment (residues 65-76) of ubiquitin displays, at the micromolar
      range, a lytic antifungal activity. Using confocal laser scan microscopy and
      rhodamine-labeled synthetic peptides, we could demonstrate that the C-terminal
      peptide (residues 65-76) is able to cross the cell wall and the plasma membrane
      of fungi and to accumulate in fungi, whereas the N-terminal peptide (residues 1
      34) is stopped at the fungal wall level. Furthermore, these two peptides act
      synergistically to kill filamentous fungi. Because of the interaction of the C
      terminal sequence of ubiquitin with calmodulin, the synthetic peptide (residues
      65-76) was tested in vitro against calmodulin-dependent calcineurin, an enzyme
      crucial for fungal growth. This peptide was found to inhibit the phosphatase
      activity of calcineurin. Our data show a new property of ubiquitin C-terminal
      derived peptide (65-76) that could be used with N-terminal peptide (1-34) as a
      new potent antifungal agent.

PMID- 12594175
TI  - Spike, a novel BH3-only protein, regulates apoptosis at the endoplasmic
      reticulum.
AB  - We have isolated Spike, a novel and evolutionary conserved BH3-only protein. BH3
      only proteins constitute a family of apoptosis inducers that mediate proapoptotic
      signals. In contrast to most proteins of this family, Spike was not found to be
      associated with mitochondria. Furthermore, unlike the known BH3-only proteins,
      Spike could not interact with all tested Bcl-2 family members, despite its BH3
      domain being necessary for cell killing. Our findings indicate that Spike is
      localized to the endoplasmic reticulum. The endoplasmic reticulum is an organelle
      that has only recently been implicated in regulation of apoptosis. At this
      locale, Spike interacts with Bap31, an adaptor protein for pro-caspase-8 and Bcl
      XL. In doing so, Spike is able to inhibit the formation of a complex between
      Bap31 and the antiapoptotic Bcl-XL protein. Furthermore, Spike transmits the
      signal of specific death receptors. Its down-regulation in certain tumors
      suggests that Spike may also play a role in tumorigenesis. Our findings add new
      insight for how BH3-only and antiapoptotic Bcl-2 proteins regulate cell death.

PMID- 12594176
TI  - TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring
      reverse transcriptase activity and 14-3-3 protein-binding ability.
AB  - The catalytic subunit of telomerase (TERT) is a reverse transcriptase (RT) that
      adds a six-base DNA repeat onto chromosome ends and prevents their shortening
      during successive cell divisions. Telomerase is associated with cell immortality
      and cancer, which may by related to the ability of TERT to prevent apoptosis by
      stabilizing telomeres. However, fundamental information concerning the
      antiapoptotic function of TERT is lacking, including whether RT activity and/or
      nuclear localization are required and where telomerase acts to suppress the cell
      death process. Here, we show that overexpression of wild-type human TERT in HeLa
      cells, and in a cells lacking TERT but containing the telomerase RNA template,
      increases their resistance to apoptosis induced by the DNA damaging agent
      etoposide or the bacterial alkaloid staurosporine. In contrast, TERT mutants with
      disruptions of either the RT domain or a 14-3-3 binding domain fail to protect
      cells against apoptosis, and overexpression of TERT in cells lacking the
      telomerase RNA template is also ineffective in preventing apoptosis. Additional
      findings show that TERT suppresses apoptosis at an early step before release of
      cytochrome c and apoptosis-inducing factor from mitochondria. We conclude that
      both RT activity and 14-3-3 protein binding ability are required for the
      antiapoptotic function of TERT in tumor cells and that TERT can suppress a
      nuclear signal(s) that is an essential component of apoptotic cascades triggered
      by diverse stimuli.

PMID- 12594177
TI  - The antimycotic ciclopirox olamine induces HIF-1alpha stability, VEGF expression,
      and angiogenesis.
AB  - The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of
      oxygen homeostasis. Protein stability and transactivation function of the alpha
      subunit are controlled by iron- and oxygen-dependent hydroxylation of proline and
      asparagine residues. The anti-mycotic ciclopirox olamine (CPX) is a lipophilic
      bidentate iron chelator that stabilizes HIF-1alpha under normoxic conditions at
      lower concentrations than other iron chelators, probably by inhibiting HIF-1alpha
      hydroxylation. As shown by the inhibition of iron-dependent quenching of FITC
      labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher
      affinity for iron than DFX. Initial observations that treatment with 1% CPX, but
      not with placebo, occasionally caused reddening of wound margins in a mouse skin
      wound model prompted us to investigate the capability of CPX to induce
      angiogenesis. CPX-induced HIF-1-mediated reporter gene activity and endogenous
      HIF-1 target gene expression, including elevation of transcription, mRNA, and
      protein levels of the vascular endothelial growth factor (VEGF). In the chick
      chorioallantoic membrane assay, inert polymer disks containing CPX but not the
      solvent alone induced angiogenesis. In summary, these results suggest that CPX
      induces angiogenesis in vivo via HIF-1 and VEGF induction. Therefore, CPX might
      serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for
      therapeutic angiogenesis.

PMID- 12594178
TI  - Does endometriosis really have premalignant potential? A clonal analysis of laser
      microdissected tissue.
AB  - Since 1925, epidemiological and histological evidence for an association between
      endometriosis and ovarian neoplasia has accumulated. Recently, publications
      assaying the clonality of a given cell population have implied endometriosis has
      premalignant properties. However, the human androgen receptor used as a marker in
      these studies is of highly questionable reliability due to the instability of its
      methylation pattern in nonmalignant cells and during the course of malignancy.
      Therefore, we decided to readdress the question of clonality of endometriotic
      foci by using an alternative assay based on a polymorphism of the
      phosphoglycerate kinase-1 gene. We overcame the limitation to using ovarian cysts
      (a problem encountered in other studies) by laser-microdissecting defined tissue
      fractions of interest. From the 13/29 informative patients, a total of 32
      endometriotic samples from various sites was assayed. Only 2/32 samples from
      different patients bore monoclonal tissue. With one of those cases, we present
      the first direct evidence of the two morphological endometric compartments
      comprising a single biphasic developmental unit. Neither monoclonal patient was
      characterized by any outstanding clinical parameters, including neoplasia.
      Individual endometriotic foci from the only patient in this study with neoplasia
      was assayed as being polyclonal. Therefore, former studies stating endometriosis
      as premalignant have to be cautiously reinterpreted.

PMID- 12594179
TI  - Influenza A virus replication is dependent on an antioxidant pathway that
      involves GSH and Bcl-2.
AB  - Growing evidence indicates that viral replication is regulated by the redox state
      of the host cell. We demonstrate that cells of different origins display
      differential permissivity for influenza A virus replication, depending on their
      intracellular redox power as reflected by Bcl-2 expression and glutathione (GSH)
      content. Bcl-2 expressing cells were found to have higher intracellular levels of
      GSH and to produce lower amounts of virus than Bcl-2 negative cells. Two
      different steps in the virus life-cycle were involved in Bcl-2/GSH mediated viral
      inhibition: 1) expression of late viral proteins (in particular hemagglutinin and
      matrix); and 2) nuclear-cytoplasmic translocation of viral ribonucleoproteins
      (vRNPs). Buthionine-sulfoximine-induced inhibition of GSH synthesis in Bcl-2
      expressing cells caused an increase in the expression of late viral proteins but
      did not restore vRNP export to the cytoplasm. Collectively, our findings show
      that both Bcl-2 expression and GSH content contribute to the host cell's ability
      to down-regulate influenza virus replication, although their effects are exerted
      at different stages of the viral life-cycle. In certain cell populations, this
      form of down-regulation might conceivably favor the establishment of persistent
      viral infection.

PMID- 12594180
TI  - Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human
      lymphocytes via its mt1 membrane receptor.
AB  - It is well known that melatonin plays a fundamental role in human neuro
      immunomodulation. Thus, melatonin regulates the production of a large number of
      cytokines, including interleukin-2 (IL-2) in the human system. Both membrane and
      nuclear receptors for melatonin are present in lymphoid cells. However, most of
      these effects have been shown to be mediated by the putative nuclear receptor for
      the neurohormone. In this paper, we show that prostaglandin E2 (PGE2), a potent
      inflammatory mediator, inhibits IL-2 production in human lymphocytes by a cyclic
      AMP (cAMP)-dependent mechanism. In this model, melatonin counteracts the effects
      of PGE2 on IL-2 and cAMP production. We propose that the effect of melatonin is
      mediated by a membrane receptor, since similar results were obtained when cells
      were cultured in the presence of S 20098, a specific melatonin membrane receptor
      agonist. No effect was observed by using CGP 52608, a nuclear receptor agonist.
      Moreover, when cells were stimulated with phorbol myristate acetate (PMA), which
      has been shown to inhibit mt1 melatonin membrane receptor expression, the
      neurohormone failed to counteract the effect of PGE2. Therefore, we postulate,
      for the first time, a physiological role of the mt1 melatonin membrane receptor
      in the human immune system.

PMID- 12594181
TI  - VEGF-induced paracellular permeability in cultured endothelial cells involves
      urokinase and its receptor.
AB  - Vascular endothelial growth factor/vascular permeability factor (VEGF) has been
      implicated in blood/tissue barrier dysfunctions associated with pathological
      angiogenesis, but the mechanisms of VEGF-induced permeability increase are poorly
      understood. Here, the role of VEGF-induced extracellular proteolytic activities
      on the endothelial cell permeability increase is evaluated. Confluent monolayers
      of bovine retinal microvascular endothelial (BRE) cells grown on porous membrane
      were treated with VEGF or urokinase plasminogen activator (uPA), and permeability
      changes were analyzed. uPA-induced permeability was rapid and sustained, but VEGF
      induced permeability showed a biphasic pattern: a rapid and transient phase (1-2
      h) followed by delayed and sustained phase (6-24 h). The delayed, but not the
      early phase of VEGF-induced permeability, was blocked by anti-uPA or anti-uPAR
      (uPA receptor) antibodies and was accompanied by reduced transendothelial
      electrical resistance, indicating the paracellular route of permeability.
      Confocal microscopy and Western blotting showed that VEGF treatment increased
      free cytosolic beta-catenin, which was followed by beta-catenin nuclear
      translocation, upregulation of uPAR, and downregulation of occludin. Membrane
      bound occludin was released immediately after uPA treatment, but with a long
      delay after VEGF treatment, suggesting a requirement for uPAR gene expression. In
      conclusion, VEGF induces a sustained paracellular permeability in capillary
      endothelial cells that is mediated by activation of the uPA/uPAR system.

PMID- 12594182
TI  - Aging enhances lymphocyte cytokine defects after injury.
AB  - Mortality and sepsis after a traumatic injury is greater in the elderly than in
      young individuals. The altered lymphocyte response observed to occur in healthy
      aged individuals is proposed to be a contributing factor to increased mortality.
      The immune response associated with the increased mortality was explored using a
      murine scald injury model. In the absence of injury, aged mice had depressed
      delayed-type hypersensitivity (DTH) and splenocyte proliferative responses
      relative to young mice. There was also an increase with age in the production of
      the TH2 cytokines interleukin (IL)-4 and IL-10 by splenocytes. There was no
      change in the TH1 cytokines IFNgamma or IL-12 with age. However, IL-2 production
      was significantly lower. Following injury, there was a further decrease in the
      DTH response of aged injured mice, compared with aged sham mice. In addition,
      there was a decrease in all of the cytokines examined, regardless of age. In
      contrast, IFNgamma and IL-2 were significantly lower in the aged injured animals
      compared with the young injured animals. These results suggest that the lack of
      an adequate amount of TH1 cytokines shortly after injury in the aged mice may
      parallel the increased incidence of sepsis and death that occurs in aged burn
      patients.

PMID- 12594183
TI  - Temporal activation of c-Jun N-terminal kinase in adult transgenic heart via cre
      loxP-mediated DNA recombination.
AB  - Using a cre-loxP-mediated gene-switch approach, we achieved targeted JNK
      activation in adult hearts. A transgenic model is established carrying a floxed
      gene-switch construct that directs GFP marker gene expression in the absence of
      DNA recombination between two loxP sites. A tamoxifen-inducible Cre recombinase
      was introduced in the transgenic heart by breeding with previously established
      Mer-Cre-Mer transgenic mice. Upon tamoxifen administration in double transgenic
      adult animals, cre-loxP-mediated DNA recombination efficiently switches "off" the
      loxP-flanked GFP expression unit in cardiomyocytes and switches "on" the
      expression of the target gene, MKK7D, a constitutively activated upstream
      activator of c-Jun N-terminal kinases (JNK). Expression of MKK7D in adult hearts
      resulted in significant activation of JNK activities and causes progressive
      cardiomyopathy in transgenic animals. This unique animal model of cardiac
      specific and temporally regulated JNK activation will provide a powerful tool to
      investigate the functional role of the JNK pathway in the development of heart
      failure. Our data also demonstrated that the inducible gene-switch approach
      reported here may also be applicable in other studies to achieve efficient,
      tissue-specific, and temporally regulated genetic manipulation in intact animals.

PMID- 12594184
TI  - Role of cholesterol ester pathway in the control of cell cycle in human aortic
      smooth muscle cells.
AB  - Cholesterol esterification by acyl-CoA:cholesterol acyltransferase (ACAT) and
      proliferation of vascular smooth muscle cells (VSMC) are key events in vascular
      proliferative diseases. Here we performed experiments to ascertain the role of
      cholesterol ester pathway in the control of human aortic VSMC cycle progression.
      Results showed that serum-induced VSMC proliferation was preceded by an increased
      ability of the cells to esterify cholesterol as well as by an increased
      expression of ACAT and multidrug resistance (MDR1) mRNAs and extracellular
      related kinases 1/2 (ERK1/2), whereas caveolin-1 levels were markedly decreased.
      Cell cycle analyses performed in the presence of two inhibitors of cholesterol
      esterification, directly inhibiting ACAT (Sandoz 58-035) or the transport of
      cholesterol substrate from plasma membrane to endoplasmic reticulum
      (progesterone), indicate that each inhibitor suppressed the serum-induced DNA
      synthesis by accumulation of VSMCs in the G1 phase. The effect was associated
      with a rapid inhibition of ERK1/2 mitogenic signaling pathway; a down-regulation
      of cyclin D1, ACAT, and MDR1 mRNA; and an up-regulation of caveolin-1. These data
      provide a plausible link between cholesterol esterification and control of cell
      cycle G1/S transition, supporting the hypothesis that cholesterol esterification
      may accelerate the progression of human vascular proliferative diseases by
      modulating the rate of the VSMC proliferation.

PMID- 12594185
TI  - Stra13, a prostaglandin E2-induced gene, regulates the cellular redox state of
      podocytes.
AB  - Podocyte injury is a central mechanism in the pathogenesis of proteinuria.
      Prostaglandin E2 (PGE2) has been suggested to protect podocytes from cellular
      injury. Here we investigated whether PGE2-induced gene expression accounts for
      the protective role of PGE2 in podocytes. Using a suppressive-subtractive
      hybridization method, we isolated a differentially expressed clone that was
      identified as Stra13, a recently described retinoic acid-inducible gene. PGE2,
      forskolin, and retinoic acid induced a time-dependent up-regulation of Stra13
      mRNA and protein expression in podocytes. To test the function of Stra13 in
      podocytes, Stra13 was overexpressed by using retroviral gene transfer. Compared
      with control cells, cells overexpressing Stra13 showed markedly reduced NADPH
      dependent superoxid anion generation. Furthermore, expression of heme oxygenase 1
      (HO-1) was increased in podocytes overexpressing Stra13. HO-1 plays an important
      protective role in the defense against reactive oxygen species (ROS). After
      stimulation with exogenous ROS, Stra13-overexpressing podocytes were more
      resistant to oxidative stress than were control cells. Our data indicate that
      Stra13 may play an important protective role against oxidative stress in
      podocytes. ROS are involved in the pathogenesis of glomerular inflammation in
      several forms of glomerulonephritis. Therefore, knowledge about protective
      mechanisms may provide insight into new therapeutic strategies for
      glomerulopathies.

PMID- 12594189
TI  - Tackling inequalities in health: the need for building a systematic evidence
      base.

PMID- 12594186
TI  - Chamber-specific differentiation of Nkx2.5-positive cardiac precursor cells from
      murine embryonic stem cells.
AB  - Embryonic stem (ES) cells are a useful system to study cardiac differentiation in
      vitro. It has been difficult, however, to track the fates of chamber-specific
      cardiac lineages, since differentiation is induced within the embryoid body. We
      have established an in vitro culture system to track Nkx2.5(+) cell lineages
      during mouse ES cell differentiation by using green fluorescent protein (GFP) as
      a reporter. Nkx2.5/GFP(+) cardiomyocytes purified from embryoid bodies express
      sarcomeric tropomyosin and myosin heavy chain and heterogeneously express cardiac
      troponin I (cTnI), myosin light chain 2v (MLC2v) and atrial natriuretic peptide
      (ANP). After 4-week culture, GFP(+) cells exhibited electrophysiological
      characteristics specific to sinoatrial (SA) node, atrial, or ventricular type.
      Furthermore, we found that administration of 10(-7) M retinoic acid (RA) to
      embryoid bodies increased the percentage of MLC2v(-)ANP(+) cells; this also
      increased the expression of atrial-specific genes in the Nkx2.5/GFP(+) fraction,
      in a time- and dose-dependent fashion. These results suggest that Nkx2.5(+)
      lineage cells possess the potential to differentiate into various cardiomyocyte
      cell types and that RA can modify the differentiation potential of Nkx2.5(+)
      cardiomyocytes at an early stage.

PMID- 12594192
TI  - Meta-analysis of studies on individual consumption of chlorinated drinking water
      and bladder cancer.
AB  - STUDY OBJECTIVE: To evaluate whether consumption of chlorinated drinking water is
      associated with bladder cancer. DESIGN: A bibliographic search was conducted and
      the authors selected studies evaluating individual consumption of chlorinated
      drinking water and bladder cancer. The authors extracted from each study risk
      estimates for intermediate and long term (>40 years) consumption of chlorinated
      water, stratified by sex when possible, and performed meta-analysis for the two
      exposure levels. A meta-analysis was also performed of the dose-response
      regression slopes. SETTING: Populations in Europe and North America.
      PARTICIPANTS: Those included in six case-control studies (6084 incident bladder
      cancer cases, 10,816 controls) and two cohort studies (124 incident bladder
      cancer cases) fulfilling the inclusion criteria. MAIN RESULTS: Ever consumption
      of chlorinated drinking water was associated with an increased risk of bladder
      cancer in men (combined OR=1.4, 95%CI 1.1 to 1.9) and women (combined OR=1.2,
      95%CI 0.7 to 1.8). The combined OR for mid-term exposure in both genders was 1.1
      (95% CI 1.0 to 1.2) and for long term exposure was 1.4 (95%CI 1.2 to 1.7). The
      combined estimate of the slope for a linear increase in risk was 1.13 (95% CI
      1.08 to 1.20) for 20 years and 1.27 (95% CI 1.15 to 1.43) for 40 years of
      exposure in both sexes. CONCLUSIONS: This meta-analysis of the best available
      epidemiological evidence indicates that long term consumption of chlorinated
      drinking water is associated with bladder cancer, particularly in men. The
      observed relative risk is only moderately high, but the population attributable
      risk could be important as the vast majority of the population of industrialised
      countries is potentially exposed to chlorination byproducts for long time
      periods.

PMID- 12594193
TI  - A comprehensive "Healthy Schools Programme" to promote school health: the Hong
      Kong experience in joining the efforts of health and education sectors.
AB  - Both health and education are linked to economic performance. The success of
      education depends on good health, and vice versa. Modern education should help
      young people to determine values, and accept responsibility for their health and
      social behaviour. The success of health promotion in schools requires the joint
      efforts of both the health and education sectors. A comprehensive programme is
      needed to include teachers' training, curriculum development, community
      participation, changing policies and practices, and research. All these
      components are needed to build up a successful model of a health promoting
      school. The "Healthy Schools Programme" in Hong Kong gives a good example of
      close partnership between the health and education sectors, and moves towards a
      multidisciplinary approach and active learning towards health promotion.

PMID- 12594194
TI  - How did the recent increase in the supply of coronary operations in Finland
      affect socioeconomic and gender equity in their use?
AB  - STUDY OBJECTIVE: To explore how the increased supply of coronary bypass
      operations and angioplasties from 1988 to 1996 influenced socioeconomic and
      gender equity in their use. DESIGN: Register based linkage study; information on
      coronary procedures from the Finnish Hospital Discharge Register in 1988 and 1996
      was individually linked to national population censuses in 1970-1995 to obtain
      patients' socioeconomic data. Data on both hospitalisations and mortality
      attributable to coronary heart disease obtained from similar linkage schemes were
      used to approximate the relative need of procedures in socioeconomic groups.
      SETTING: Finland, 2,094,846 inhabitants in 1988 and 2,401,027 in 1996 aged 40
      years and older, and Discharge Register data from all Finnish hospitals offering
      coronary procedures in 1988 and 1996. MAIN RESULTS: The overall rate of coronary
      revascularisations in Finland increased by about 140% for men and 250% for women
      from 1988 to 1996. Over the same period, socioeconomic and gender disparities in
      operation rates diminished, as did the influence of regional supply of procedures
      on the extent of these differences. However, men, and better off groups in terms
      of occupation, education, and family income, continued to receive more operations
      than women and the worse off with the same level of need. CONCLUSIONS: Although
      revascularisations in Finland increased 2.5-fold overall, some socioeconomic and
      gender inequities persisted in the use of cardiac operations relative to need. To
      improve equity, a further increase of resources may be needed, and practices
      taking socioeconomic and gender equity into account should be developed for the
      referral of coronary heart disease patients to hospital investigations.

PMID- 12594195
TI  - Choosing area based socioeconomic measures to monitor social inequalities in low
      birth weight and childhood lead poisoning: The Public Health Disparities
      Geocoding Project (US).
AB  - STUDY OBJECTIVES: : To determine which area based socioeconomic measures can
      meaningfully be used, at which level of geography, to monitor socioeconomic
      inequalities in childhood health in the US. DESIGN: Cross sectional analysis of
      birth certificate and childhood lead poisoning registry data, geocoded and linked
      to diverse area based socioeconomic measures that were generated at three
      geographical levels: census tract, block group, and ZIP code. SETTING: Two US
      states: Massachusetts (1990 population=6,016,425) and Rhode Island (1990
      population=1,003,464). PARTICIPANTS: All births born to mothers ages 15 to 55
      years old who were residents of either Massachusetts (1989-1991; n=267,311) or
      Rhode Island (1987-1993; n=96 138), and all children ages 1 to 5 years residing
      in Rhode Island who were screened for lead levels between 1994 and 1996 (n=62,514
      children, restricted to first test during the study period). MAIN RESULTS:
      Analyses of both the birth weight and lead data indicated that: (a) block group
      and tract socioeconomic measures performed similarly within and across both
      states, while ZIP code level measures tended to detect smaller effects; (b)
      measures pertaining to economic poverty detected stronger gradients than measures
      of education, occupation, and wealth; (c) results were similar for categories
      generated by quintiles and by a priori categorical cut off points; and (d) the
      area based socioeconomic measures yielded estimates of effect equal to or
      augmenting those detected, respectively, by individual level educational data for
      birth outcomes and by the area based housing measure recommended by the US
      government for monitoring childhood lead poisoning. CONCLUSIONS: Census tract or
      block group area based socioeconomic measures of economic deprivation could be
      meaningfully used in conjunction with US public health surveillance systems to
      enable or enhance monitoring of social inequalities in health in the United
      States.

PMID- 12594196
TI  - Life table methods for quantitative impact assessments in chronic mortality.
AB  - Quantitative health impact assessments of chronic mortality, where the impacts
      are expected to be observed over a number of years, are complicated by the link
      between death rates and surviving populations. A general calculation framework
      for quantitative impact assessment is presented, based on standard life table
      calculation methods, which permits consistent future projections of impacts on
      mortality from changes in death rates. Implemented as a series of linked
      spreadsheets, the framework offers complete flexibility in the sex specific, age
      specific, and year specific patterns of baseline mortality death rates; in the
      predicted impacts upon these; in the weights or values placed on gains in life;
      and in the summary measures of impact. Impacts can be differential by cause of
      death. Some examples are given of predictions of the impacts of reductions in
      chronic mortality in the populations of England and Wales and of Scotland.

PMID- 12594197
TI  - Estimating the lesbian population: a capture-recapture approach.
AB  - STUDY OBJECTIVE: Little is known about the number of women who identify as
      lesbian. Estimates from the US range from 1% to nearly 10%. Accurate estimates
      are critical in order to meet lesbian's healthcare needs and to address health
      problems that may be more prevalent among them. This study used capture-recapture
      methods to estimate the lesbian population of Allegheny County, Pennsylvania.
      DESIGN: Mailing lists from four sources were used to identify lesbians. The
      capture-recapture method and log-linear modelling were used to estimate the
      number of lesbians in the defined geographical area, and the percentage of the
      female population they comprised there was determined through census data.
      SETTING: Allegheny County, Pennsylvania, USA. RESULTS: A total of 2185 unique
      names were identified. The capture-recapture method estimated that the total
      lesbian population of Allegheny County was 7031 (95% CI 5850 to 8576). Therefore,
      based on the 1990 census figures, the county's adult lesbian population was
      estimated to be 1.87% (95% CI 1.56% to 2.28%) of the adult female population.
      CONCLUSIONS: An estimate of the lesbian population is fundamental for addressing
      lesbian's health needs and for developing appropriate research programmes.
      Capture-recapture methods have the potential to provide accurate and reliable
      estimates of this population in any location.

PMID- 12594198
TI  - Effects of the characteristics of neighbourhoods and the characteristics of
      people on cause specific mortality: a register based follow up study of 252,000
      men.
AB  - STUDY OBJECTIVE: To assess the strength of the associations between neighbourhood
      characteristics and mortality, after adjusting for individual characteristics.
      DESIGN AND SETTING: 1990 census records of over 25 year old men in the Helsinki
      Metropolitan area linked to death records in 1991-1995; almost 1.22 million
      person years and 15 000 deaths. Individual characteristics were education,
      occupation based social class, housing tenure, housing density, and living
      arrangements. Proportion of manual workers, proportion of over 60 year olds, and
      social cohesion were measured for 55 small areas, and SAS Glimmix was used to fit
      multilevel models. MAIN RESULTS: Men in areas with high proportion of manual
      workers and low social cohesion have high mortality, particularly among 25-64
      year olds. About 70% of this excess mortality is explained by compositional
      differences of people living in these areas. Accidents and violence, circulatory
      diseases, and alcohol related causes contribute most to these area effects. Area
      characteristics do not consistently modify or mediate the effects of individual
      socioeconomic characteristics on mortality. CONCLUSIONS: As compared with
      individual characteristics neighbourhood characteristics have modest independent
      effects on male mortality. Furthermore, individual socioeconomic characteristics
      are associated with mortality independently of area characteristics. Rather than
      the characteristics of areas, other social contexts, such as peer groups and
      family settings may be more fruitful targets for further research and policy on
      contextual effects on mortality.

PMID- 12594199
TI  - Fruit, vegetables, and antioxidants in childhood and risk of adult cancer: the
      Boyd Orr cohort.
AB  - STUDY OBJECTIVE: To examine associations between food and nutrient intake,
      measured in childhood, and adult cancer in a cohort with over 60 years follow up.
      DESIGN AND SETTING: The study is based on the Boyd Orr cohort. Intake of fruit
      and vegetables, energy, vitamins C and E, carotene, and retinol was assessed from
      seven day household food inventories carried out during a study of family diet
      and health in 16 rural and urban areas of England and Scotland in 1937-39.
      PARTICIPANTS: 4999 men and women, from largely working class backgrounds, who had
      been children in the households participating in the pre-war survey. Analyses are
      based on 3878 traced subjects with full data on diet and social circumstances.
      MAIN RESULTS: Over the follow up period there were 483 incident malignant
      neoplasms. Increased childhood fruit intake was associated with reduced risk of
      incident cancer. In fully adjusted logistic regression models, odds ratios (95%
      confidence intervals) with increasing quartiles of fruit consumption were 1.0
      (reference), 0.66 (0.48 to 0.90), 0.70 (0.51 to 0.97), 0.62 (0.43 to 0.90); p
      value for linear trend=0.02. The association was weaker for cancer mortality.
      There was no clear pattern of association between the other dietary factors and
      total cancer risk. CONCLUSIONS: Childhood fruit consumption may have a long term
      protective effect on cancer risk in adults. Further prospective studies, with
      individual measures of diet are required to further elucidate these relations.

PMID- 12594200
TI  - Early and late growth and blood pressure in adolescence.
AB  - OBJECTIVE: To assess the effect of growth during infancy and childhood on blood
      pressure in adolescence. DESIGN: Birth cohort study. SETTING: Pelotas, southern
      Brazil. PARTICIPANTS: 749 adolescents with complete information on birth weight
      and gestational age, as well as on anthropometric data at all three follow up
      visits (mean age 20 months, 42 months, and 15 years). MAIN OUTCOME MEASUREMENTS:
      Systolic and diastolic blood pressure at adolescence. RESULTS: After controlling
      for possible confounding variables, birth weight was negatively associated with
      systolic blood pressure, one unit increase in standard deviation score of birth
      weight for gestational age was associated with a decrease of 1.23 mm Hg (95%
      confidence intervals -2.03 to -0.43) in systolic blood pressure. Weight for age z
      score at the age of 15 years showed a strong positive association with systolic
      blood pressure, one unit increase in standard deviation score of birth weight for
      gestational age was associated with an increase of 4.4 mm Hg (95% confidence
      intervals 3.50 to 5.3). Diastolic blood pressure was not associated with birth
      weight. For adequate for gestational age infants, the positive association
      between weight in adolescence and blood pressure became stronger when previous
      weights were added to the model. CONCLUSION: This study showed that early--as
      well as--late catch up growth is associated with increased systolic blood
      pressure in adolescence, whereas only late catch up is related with diastolic
      blood pressure. These findings suggest that catch up growth, irrespective of age,
      is associated with increased blood pressure in adolescence.

PMID- 12594202
TI  - Conditional knockdown of proteasomes results in cell-cycle arrest and enhanced
      expression of molecular chaperones Hsp70 and Hsp40 in chicken DT40 cells.
AB  - The 26 S proteasome is an evolutionarily conserved ATP-dependent protease complex
      that degrades poly-ubiquitinated proteins and plays essential roles in a critical
      part of cellular regulation. In vertebrates, the roles of the proteasome have
      been widely studied by use of specific inhibitors, but not genetically. Here, we
      generated a cell line Z(-/-/-)/Z-HA, in which the expression of the catalytic
      subunit of the proteasome, Z (beta2) could be manipulated. This cell line
      expresses exogenous Z protein under the control of a tetracycline-repressible
      promoter in a Z-nullizygous genetic background. Treatment of these cells with
      doxycycline inhibited Z expression and, hence, the function of the proteasome.
      The latter resulted in accumulation of poly-ubiquitinated proteins and
      concomitant induction of molecular chaperones Hsp70 and Hsp40. These results
      suggest a synergistic role for the proteasome with these molecular chaperones to
      eliminate misfolded or damaged proteins in vivo. Furthermore, knockdown of the
      proteasome induced apoptotic cell death following cell-cycle arrest at G(2)/M
      phase. Our Z(-/-/-)/Z-HA cell line would be useful for evaluating proteolytic
      processes catalyzed by the proteasome in many biological events in vertebrate
      cells.

PMID- 12594203
TI  - Synergy of silent and hot spot mutations in importin beta reveals a dynamic
      mechanism for recognition of a nuclear localization signal.
AB  - Molecular recognition of the importin beta-binding (IBB) domain of importin alpha
      by importin beta is critical for the nuclear import of protein cargoes containing
      a classical nuclear localization signal. We have studied the function of four
      conserved tryptophans of importin beta (Trp-342, Trp-430, Trp-472, and Trp-864)
      located at the binding interface with the IBB domain by systematic alanine
      substitution mutagenesis. We found that Trp-864 is a mutational hot spot that
      significantly affects IBB-binding and import activity, whereas residues Trp-342,
      Trp-430, and Trp-472 are mutationally silent when analyzed individually.
      Interestingly, the combination of the hot spot at residue Trp-864 with mutations
      in the other three tryptophans gives rise to a striking synergy that diminishes
      IBB domain binding by up to approximately 1000-fold and, in turn, abolishes
      import activity. We propose that importin beta uses the tryptophans to select and
      stabilize a helical conformation of the IBB domain, which, in turn, conveys
      specific, high affinity binding.

PMID- 12594204
TI  - Polymerization of calsequestrin. Implications for Ca2+ regulation.
AB  - Two distinct dimerization contacts in calsequestrin crystals suggested a
      mechanism for Ca(2+) regulation resulting from the occurrence of coupled Ca(2+)
      binding and protein polymerization. Ca(2+)-induced formation of one contact was
      proposed to lead to dimerization followed by Ca(2+)-induced formation of the
      second contact to bring about polymerization (). To test this mechanism, we
      compared canine cardiac calsequestrin and four truncation mutants with regard to
      their folding properties, structures, and Ca(2+)-induced polymerization. The wild
      type calsequestrin and truncation mutants exhibited similar K(+)-induced folding
      and end-point structures as indicated by intrinsic fluorescence and circular
      dichroism, respectively, whereas the polymerization tendencies of the wild-type
      calsequestrin differed markedly from the polymerization tendencies of the
      truncation mutants. Static laser light scattering and 3,3'-dithiobis
      sulfosuccinimidyl-propionate cross-linking indicated that wild-type protein
      exhibited an initial Ca(2+)-induced dimerization, followed by additional
      oligomerization as the Ca(2+) concentration was raised or as the K(+)
      concentration was lowered. None of the truncation mutants exhibited clear
      stepwise oligomerization that depended on increasing Ca(2+) concentration.
      Comparison of the three-dimensional structure of rabbit skeletal calsequestrin
      with a homology model of canine cardiac calsequestrin from the point of view of
      our coupled Ca(2+) binding and polymerization mechanism leads to a possible
      explanation for the 2-fold reduced Ca(2+) binding capacity of cardiac
      calsequestrin despite very similar overall net negative charge for the two
      proteins.

PMID- 12594205
TI  - Suprachiasmatic nucleus circadian oscillatory protein, a novel binding partner of
      K-Ras in the membrane rafts, negatively regulates MAPK pathway.
AB  - Suprachiasmatic nucleus circadian oscillatory protein (SCOP) is a member of the
      leucine-rich repeat (LRR)-containing protein family. In addition to circadian
      expression in the rat hypothalamic suprachiasmatic nucleus, SCOP is
      constitutively expressed in neurons throughout the rat brain. Here we found that
      a substantial amount of SCOP was localized in the brain membrane rafts, in which
      only K-Ras was abundant among Ras isoforms. SCOP interacted directly through its
      LRR domain with a subset of K-Ras in the guanine nucleotide-free form that was
      present in the raft fraction. This interaction interfered with the binding of
      added guanine nucleotide to K-Ras in vitro. A negative regulatory role of SCOP
      for K-Ras function was examined in PC12 cell lines stably overexpressing SCOP or
      its deletion mutants. Overexpression of full-length SCOP markedly down-regulated
      ERK1/ERK2 activation induced by depolarization or phorbol ester stimulation, and
      this inhibitory effect of overexpressed SCOP was dependent on its LRR domain.
      These results strongly suggest that SCOP negatively regulates K-Ras signaling in
      the membrane rafts, identifying a novel mechanism for regulation of the Ras-MAPK
      pathway.

PMID- 12594207
TI  - Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus
      activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding
      protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved.
AB  - Lipoteichoic acid (LTA) derived from Streptococcus pneumoniae, purified employing
      a chloroform/methanol protocol, and from Staphylococcus aureus, prepared by the
      recently described butanol extraction procedure, was investigated regarding its
      interaction with lipopolysaccharide (LPS)-binding protein (LBP), CD14, Toll-like
      receptors (TLRs)-2 and -4, and MD-2. LTA from both organisms induced cytokine
      synthesis in human mononuclear phagocytes. Activation was LBP- and CD14
      dependent, and formation of complexes of LTA with LBP and soluble CD14 as well as
      catalytic transfer of LTA to CD14 by LBP was verified by PhastGel(TM) native gel
      electrophoresis. Human embryonic kidney (HEK) 293/CD14 cells and Chinese hamster
      ovary (CHO) cells were responsive to LTA only after transfection with TLR-2.
      Additional transfection with MD-2 did not affect stimulation of these cells by
      LTA. Our data suggest that innate immune recognition of LTA via LBP, CD14, and
      TLR-2 represents an important mechanism in the pathogenesis of systemic
      complications in the course of infectious diseases brought about by the
      clinically most important Gram-positive pathogens. However, the involvement of
      TLR-4 and MD-2 in this process was ruled out.

PMID- 12594206
TI  - Association of kinesin light chain with outer dense fibers in a microtubule
      independent fashion.
AB  - Conventional kinesin I motor molecules are heterotetramers consisting of two
      kinesin light chains (KLCs) and two kinesin heavy chains. The interaction between
      the heavy and light chains is mediated by the KLC heptad repeat (HR), a leucine
      zipper-like motif. Kinesins bind to microtubules and are involved in various
      cellular functions, including transport and cell division. We recently isolated a
      novel KLC gene, klc3. klc3 is the only known KLC expressed in post-meiotic male
      germ cells. A monoclonal anti-KLC3 antibody was developed that, in immunoelectron
      microscopy, detects KLC3 protein associated with outer dense fibers (ODFs),
      unique structural components of sperm tails. No significant binding of KLC3 with
      microtubules was observed with this monoclonal antibody. In vitro experiments
      showed that KLC3-ODF binding occurred in the absence of kinesin heavy chains or
      microtubules and required the KLC3 HR. ODF1, a major ODF protein, was identified
      as the KLC3 binding partner. The ODF1 leucine zipper and the KLC3 HR mediated the
      interaction. These results identify and characterize a novel interaction between
      a KLC and a non-microtubule macromolecular structure and suggest that KLC3 could
      play a microtubule-independent role during formation of sperm tails.

PMID- 12594208
TI  - Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse
      hepatitis virus is dependent on host hepatic nuclear factor-4 alpha.
AB  - Fibrinogen-like protein 2/fibroleukin (Fgl2) plays a pivotal role in the
      pathogenesis of both experimental and human fulminant hepatic failure. We have
      reported recently that the nucleocapsid (N) protein from strains of murine
      hepatitis virus (MHV-3, MHV-A59), which cause massive hepatocellular necrosis but
      not from strains (MHV-JHM, MHV-2) which do not produce serious liver disease,
      induces transcription of fgl2. The purpose of the present study was to
      characterize both viral and host factor(s) necessary for viral induced
      transcription of fgl2. Mutation of residues Gly-12, Pro-38, Asn-40, Gln-41, and
      Asn-42 within domain 1 of the N protein of MHV-A59 to their corresponding
      residues found in MHV-2 abrogated fgl2 transcription, whereas mutation of other N
      protein domains, including a protein expressed from an internal reading frame (I
      protein), did not affect fgl2 gene transcription. We then examined the -372 to 
      306 sequence within the 1.3-kb fgl2 promoter region upstream from the
      transcription start site that was previously identified as necessary for N
      protein-induced gene transcription. We demonstrated that the -331/-325 HNF4 cis
      element and its cognate transcription factor, HNF4alpha, are necessary for virus
      induced fgl2 gene transcription. In uninfected macrophages and macrophages
      infected with MHV-2, an unidentified protein occupies the HNF4 cis-element.
      Following stimulation with MHV-A59, it was shown by electrophoretic mobility
      shift assay that HNF4alpha binds the HNF4 cis-element in the fgl2 promoter. We
      further report the unprecedented presence of HNF4alpha in peritoneal macrophages.
      Collectively, the results of this study define both viral and host factors
      necessary for induction of fgl2 prothrombinase gene transcription in MHV
      infection and may provide an explanation for the hepatotrophic nature of MHV
      induced fulminant hepatic failure.

PMID- 12594209
TI  - Extracellular matrix proteins modulate endocytosis of the insulin receptor.
AB  - Internalization of the insulin receptor (IR) is a highly regulated multi-step
      process whose underlying molecular basis is not fully understood. Here we
      undertook to study the role of extracellular matrix (ECM) proteins in the
      modulation of IR internalization. Employing Chinese hamster ovary cells that
      overexpress IR (CHO-T cells), our results indicate that IR internalization
      proceeds unaffected even when Tyr phosphorylation of IR substrates, such as IRS
      1, is impaired (e.g. in CHO-T cells overexpressing IRS-1 whose pleckstrin
      homology domain has been deleted or in CHO-T cells that overexpress the PH/PTB
      domain of IRS-1). In contrast, IR internalization is affected by the context of
      the ECM proteins to which the cells adhere. Hence, IR internalization was
      inhibited 40-60% in CHO-T cells adherent onto galectin-8 (an ECM protein and an
      integrin ligand of the galectin family) when compared with cells adherent onto
      fibronectin, collagen, or laminin. Cells adherent to galectin-8 manifested a
      unique cytoskeletal organization, which involved formation of cortical actin and
      generation of F-actin microspikes that contrasted with the prominent stress
      fibers formed when cells adhered to fibronectin. To better establish a role for
      actin filament organization in IR endocytosis, this process was assayed in CHO-T
      cells (adherent onto fibronectin), whose actin filaments were disrupted upon
      treatment with latrunculin B. Latrunculin B did not affect insulin-induced Tyr
      phosphorylation of IR or its ability to phosphorylate its substrates; still, a 30
      50% reduction in the rate of IR internalization was observed in cells treated
      with latrunculin B. Treatment of cells with nocodazole, which disrupts formation
      of microtubules, did not affect IR internalization. These results indicate that
      proper actin, but not microtubular, organization is a critical requirement for IR
      internalization and suggest that integrin-mediated signaling pathways emitted
      upon cell adhesion to different extracellular matrices and the altered
      cytoskeletal organizations generated thereof affect the itinerary of the insulin
      receptor.

PMID- 12594210
TI  - Interleukin-8-mediated heterologous receptor internalization provides resistance
      to HIV-1 infectivity. Role of signal strength and receptor desensitization.
AB  - Human immunodeficiency virus type 1 (HIV-1) entry into CD4(+) cells requires the
      chemokine receptors CCR5 or CXCR4 as co-fusion receptors. We have previously
      demonstrated that chemokine receptors are capable of cross-regulating the
      functions of each other and, thus, affecting cellular responsiveness at the site
      of infection. To investigate the effects of chemokine receptor cross-regulation
      in HIV-1 infection, monocytes and MAGIC5 and rat basophilic leukemia (RBL-2H3)
      cell lines co-expressing the interleukin-8 (IL-8 or CXCL8) receptor CXCR1 and
      either CCR5 (ACCR5) or CXCR4 (ACXCR4) were generated. IL-8 activation of CXCR1,
      but not the IL-8 receptor CXCR2, cross-phosphorylated CCR5 and CXCR4 and cross
      desensitized their responsiveness to RANTES (regulated on activation normal T
      cell expressed and secreted) (CCL5) and stromal derived factor (SDF-1 or CXCL12),
      respectively. CXCR1 activation internalized CCR5 but not CXCR4 despite cross
      phosphorylation of both. IL-8 pretreatment also inhibited CCR5- but not CXCR4
      mediated virus entry into MAGIC5 cells. A tail-deleted mutant of CXCR1,
      DeltaCXCR1, produced greater signals upon activation (Ca(2+) mobilization and
      phosphoinositide hydrolysis) and cross-internalized CXCR4, inhibiting HIV-1
      entry. The protein kinase C inhibitor staurosporine prevented phosphorylation and
      internalization of the receptors by CXCR1 activation. Taken together, these
      results indicate that chemokine receptor-mediated HIV-1 cell infection is blocked
      by receptor internalization but not desensitization alone. Thus, activation of
      chemokine receptors unrelated to CCR5 and CXCR4 may play a cross-regulatory role
      in the infection and propagation of HIV-1. Since DeltaCXCR1, but not CXCR1, cross
      internalized and cross-inhibited HIV-1 infection to CXCR4, the data indicate the
      importance of the signal strength of a receptor and, as a consequence, protein
      kinase C activation in the suppression of HIV-1 infection by cross-receptor
      mediated internalization.

PMID- 12594211
TI  - Role of SHP-2 tyrosine phosphatase in the DNA damage-induced cell death response.
AB  - SHP-2, a ubiquitously expressed Src hmology 2 (SH2) domain-containing tyrosine
      phosphatase, plays a critical role in the regulation of growth factor and
      cytokine signal transduction. Here we report a novel function of this phosphatase
      in DNA damage-induced cellular responses. Mutant embryonic fibroblast cells
      lacking functional SHP-2 showed significantly decreased apoptosis in response to
      DNA damage. Following cisplatin treatment, induction of p73 and its downstream
      effector p21(Cip1) was essentially blocked in SHP-2 mutant cells. Further
      investigation revealed that activation of the nuclear tyrosine kinase c-Abl, an
      essential mediator in DNA damage induction of p73, was impaired in the mutant
      cells, suggesting a functional requirement of SHP-2 in c-Abl activation.
      Consistent with this observation, the effect of overexpression of c-Abl kinase in
      SHP-2 mutant cells on sensitizing the cells to DNA damage-induced death was
      abolished. Additionally, we found that in embryonic fibroblast cells 30-40% of
      SHP-2 was localized in the nuclei, and that a fraction of nuclear SHP-2 was
      constitutively associated with c-Abl via its SH3 domain. Phosphatase activity of
      nuclear but not cytoplasmic SHP-2 was significantly enhanced in response to DNA
      damage. These results together suggest a novel nuclear function for SHP-2
      phosphatase in the regulation of DNA damage-induced apoptotic responses.

PMID- 12594212
TI  - Microvillar membrane microdomains exist at physiological temperature. Role of
      galectin-4 as lipid raft stabilizer revealed by "superrafts".
AB  - Lipid rafts (glycosphingolipid/cholesterol-enriched membrane microdomains) have
      been isolated as low temperature, detergent-resistant membranes from many cell
      types, but despite their presumed importance as lateral sorting and signaling
      platforms, fundamental questions persist concerning raft function and even
      existence in vivo. The nonionic detergent Brij 98 was used to isolate lipid rafts
      from microvillar membrane vesicles of intestinal brush borders at physiological
      temperature to compare with rafts, obtained by "conventional" extraction using
      Triton X-100 at low temperature. Microvillar rafts prepared by the two protocols
      were morphologically different but had essentially similar profiles of protein-
      and lipid components, showing that raft microdomains do exist at 37 degrees C and
      are not "low temperature artifacts." We also employed a novel method of
      sequential detergent extraction at increasing temperature to define a fraction of
      highly detergent-resistant "superrafts." These were enriched in galectin-4, a
      beta-galactoside-recognizing lectin residing on the extracellular side of the
      membrane. Superrafts also harbored the glycosylphosphatidylinositol-linked
      alkaline phosphatase and the transmembrane aminopeptidase N, whereas the
      peripheral lipid raft protein annexin 2 was essentially absent. In conclusion, in
      the microvillar membrane, galectin-4, functions as a core raft
      stabilizer/organizer for other, more loosely raft-associated proteins. The
      superraft analysis might be applicable to other membrane microdomain systems.

PMID- 12594213
TI  - Mutation of threonine 766 in the epidermal growth factor receptor reveals a
      hotspot for resistance formation against selective tyrosine kinase inhibitors.
AB  - Small molecule inhibitors of protein tyrosine kinases such as STI571 represent a
      major new class of therapeutics for target-selective treatment of human cancer.
      Clinical resistance formation to the BCR-ABL inhibitor STI571 has been observed
      in patients with advanced chronic myeloid leukemia and was frequently caused by a
      C to T single nucleotide change in the Abl kinase domain, which substituted Thr
      315 with isoleucine and rendered BCR-ABL resistant to STI571 inhibition. The
      corresponding mutation in the epidermal growth factor receptor (EGFR) tyrosine
      kinase replaced Thr-766 of the EGFR by methionine and dramatically reduced the
      sensitivity of EGFR to inhibition by selective 4-anilinoquinazoline inhibitors
      such as PD153035. Inhibitor-resistant EGFR exhibited the same signaling capacity
      as wild-type receptor in vivo and provides a useful tool for analyzing EGFR
      mediated signal transduction. Our data identify Thr-766 of the EGFR as a
      structural determinant that bears the potential to become a relevant feature in
      resistance formation during cancer therapy with EGFR-specific 4
      anilinoquinazoline inhibitors.

PMID- 12594214
TI  - The fragile X mental retardation protein FMRP binds elongation factor 1A mRNA and
      negatively regulates its translation in vivo.
AB  - Loss of the RNA-binding protein FMRP (fragile X mental retardation protein) leads
      to fragile X syndrome, the most common form of inherited mental retardation.
      Although some of the messenger RNA targets of this protein, including FMR1, have
      been ascertained, many have yet to be identified. We have found that Xenopus
      elongation factor 1A (EF-1A) mRNA binds tightly to recombinant human FMRP in
      vitro. Binding depended on protein determinants located primarily in the C
      terminal end of hFMRP, but the hnRNP K homology domain influenced binding as
      well. When hFMRP was expressed in cultured cells, it dramatically reduced
      endogenous EF-1A protein expression but had no effect on EF-1A mRNA levels. In
      contrast, the translation of several other mRNAs, including those coding for
      dynamin and constitutive heat shock 70 protein, was not affected by the hFMRP
      expression. Most importantly, EF-1A mRNA and hFMR1 mRNA were coimmunoprecipitated
      with hFMRP. Finally, in fragile X lymphoblastoid cells in which hFMRP is absent,
      human EF-1A protein but not its corresponding mRNA is elevated compared with
      normal lymphoblastoid cells. These data suggest that hFMRP binds to EF-1A mRNA
      and also strongly argue that FMRP negatively regulates EF-1A expression in vivo.

PMID- 12594216
TI  - Effect of glycosylphosphatidylinositol anchor-dependent and -independent prion
      protein association with model raft membranes on conversion to the protease
      resistant isoform.
AB  - Prion protein (PrP) is usually bound to membranes by a
      glycosylphosphatidylinositol (GPI) anchor that associates with detergent
      resistant membranes, or rafts. To examine the effect of membrane association on
      the interaction between the normal protease-sensitive PrP isoform (PrP-sen) and
      the protease-resistant isoform (PrP-res), a model system was employed using PrP
      sen reconstituted into sphingolipid-cholesterol-rich raft-like liposomes (SCRLs).
      Both full-length (GPI(+)) and GPI anchor-deficient (GPI(-)) PrP-sen produced in
      fibroblasts stably associated with SCRLs. The latter, alternative mode of
      membrane association was not detectably altered by glycosylation and was markedly
      reduced by deletion of residues 34-94. The SCRL-associated PrP molecules were not
      removed by treatments with either high salt or carbonate buffer. However, only
      GPI(+) PrP-sen resisted extraction with cold Triton X-100. PrP-sen association
      with SCRLs was pH-independent. PrP-sen was also one of a small subset of
      phosphatidylinositol-specific phospholipase C (PI-PLC)-released proteins from
      fibroblast cells found to bind SCRLs. A cell-free conversion assay was used to
      measure the interaction of SCRL-bound PrP-sen with exogenous PrP-res as contained
      in microsomes. SCRL-bound GPI(+) PrP-sen was not converted to PrP-res until PI
      PLC was added to the reaction or the combined membrane fractions were treated
      with the membrane-fusing agent polyethylene glycol (PEG). In contrast, SCRL-bound
      GPI(-) PrP-sen was converted to PrP-res without PI-PLC or PEG treatment. Thus, of
      the two forms of raft membrane association by PrP-sen, only the GPI anchor
      directed form resists conversion induced by exogenous PrP-res.

PMID- 12594215
TI  - NF-kappa B-dependent induction of cyclin D1 by retinoblastoma protein (pRB)
      family proteins and tumor-derived pRB mutants.
AB  - The retinoblastoma protein (pRB) and its homologues, p107 and p130, prevent cell
      cycle progression from G(0)/G(1) to S phase by forming complexes with E2F
      transcription factors. Upon phosphorylation by G(1) cyclin-cyclin-dependent
      kinase (Cdk) complexes such as cyclin D1-Cdk4/6 and cyclin E-Cdk2, they lose the
      ability to bind E2F, and cells are thereby allowed to progress into S phase.
      Functional loss of one or more of the pRB family members, as a result of genetic
      mutation or deregulated phosphorylation, is considered to be an essential
      prerequisite for cellular transformation. In this study, we found that pRB family
      proteins have the ability to stimulate cyclin D1 transcription by activation of
      the NF-kappaB transcription factor. The cyclin D1-inducing activity of pRB is
      abolished by adenovirus E1A oncoprotein but not by the deletion of the A-box, the
      B-box, or the C-terminal region of the pocket, indicating that multiple pocket
      sequences are independently involved in cyclin D1 activation. Intriguingly, tumor
      derived pRB pocket mutants retain the cyclin D1-inducing activity. Our results
      reveal a novel role of pRB family proteins as potential activators of NF-kappaB
      and inducers of G(1) cyclin. Certain pRB pocket mutants may give rise to a
      cellular situation in which deregulated E2F and cyclin D1 cooperatively promote
      abnormal cell proliferation.

PMID- 12594217
TI  - Differential tyrosine phosphorylation of plasma membrane Ca2+-ATPase and
      regulation of calcium pump activity by carbachol and bradykinin.
AB  - We investigated the effects of thapsigargin (TG), bradykinin (BK), and carbachol
      (CCh) on Ca(2+) entry via endogenous channels in human embryonic kidney BKR21
      cells. After depletion of Ca(2+) stores by either TG, BK, or CCh, the addition of
      Ca(2+) gave a much larger rise in Ca(2+) levels in CCh-treated and TG-treated
      cells than in cells treated with BK. However, in experiments performed with
      Ba(2+), a cation not pumped by Ca(2+)-ATPases, only a modest difference between
      CCh- and BK-stimulated Ba(2+) entry levels was observed, suggesting that the
      large difference in the Ca(2+) response is mediated by a differential regulation
      of Ca(2+) pump activity by CCh and BK. This hypothesis is supported by the
      finding that when Ca(2+) is removed during the stable, CCh-induced Ca(2+) plateau
      phase, the decline of cytosolic Ca(2+) is much faster in the absence of CCh than
      in its presence. In addition, if Ca(2+) is released from a caged Ca(2+) compound
      after a UV pulse, the resulting Ca(2+) peak is much larger in the presence of CCh
      than in its absence. Thus, the large increase in Ca(2+) levels observed with CCh
      results from both the activation of Ca(2+) entry pathways and the inhibition of
      Ca(2+) pump activity. In contrast, BK has the opposite effect on Ca(2+) pump
      activity. If Ca(2+) is released from a caged Ca(2+) compound, the resulting
      Ca(2+) peak is much smaller in the presence of BK than in its absence. An
      investigation of tyrosine phosphorylation levels of the plasma membrane Ca(2+)
      ATPase (PMCA) demonstrated that CCh stimulates an increase in tyrosine
      phosphorylation levels, which has been reported to inhibit Ca(2+) pump activity,
      whereas in contrast, BK stimulates a reduction of PMCA tyrosine phosphorylation
      levels. Thus, BK and CCh have a differential effect both on Ca(2+) pump activity
      and on tyrosine phosphorylation levels of the PMCA.

PMID- 12594218
TI  - Oxygen-linked equilibrium CuB-CO species in cytochrome ba3 oxidase from thermus
      thermophilus. Implications for an oxygen channel ar the CuB site.
AB  - We report the first study of O(2) migration in the putative O(2) channel of
      cytochrome ba(3) and its effect to the properties of the binuclear heme a(3)
      Cu(B) center of cytochrome ba(3) from Thermus thermophilus. The Fourier transform
      infrared spectra of the ba(3)-CO complex demonstrate that in the presence of 60
      80 micro m O(2), the nu(C-O) of Cu(B)1+-C-O at 2053 cm(-1) (complex A) shifts to
      2045 cm(-1) and remains unchanged in H(2)O/D(2)O exchanges and in the pH 6.5-9.0
      range. The frequencies but not the intensities of the C-O stretching modes of
      heme a(3)-CO (complex B), however, remain unchanged. The change in the nu(C-O) of
      complex A results in an increase of k(-2), and thus in a higher affinity of Cu(B)
      for exogenous ligands. The time-resolved step-scan Fourier transform infrared
      difference spectra indicate that the rate of decay of the transient Cu(B)1+-CO
      complex at pH 6.5 is 30.4 s(-1) and 28.3 s(-1) in the presence of O(2).
      Similarly, the rebinding to heme a(3) is slightly affected and occurs with k(2) =
      26.3 s(-1) and 24.6 s(-1) in the presence of O(2). These results provide solid
      evidence that in cytochrome ba(3), the ligand delivery channel is located at the
      Cu(B) site, which is the ligand entry to the heme a(3) pocket. We suggest that
      the properties of the O(2) channel are not limited to facilitating ligand
      diffusion to the active site but are extended in controlling the dynamics and
      reactivity of the reactions of ba(3) with O(2) and NO.

PMID- 12594219
TI  - ISG20, a new interferon-induced RNase specific for single-stranded RNA, defines
      an alternative antiviral pathway against RNA genomic viruses.
AB  - Interferons (IFNs) encode a family of secreted proteins that provide the front
      line defense against viral infections. Their diverse biological actions are
      thought to be mediated by the products of specific but usually overlapping sets
      of cellular genes induced in the target cells. We have recently isolated a new
      human IFN-induced gene that we have termed ISG20, which codes for a 3' to 5'
      exonuclease with specificity for single-stranded RNA and, to a lesser extent, for
      DNA. In this report, we demonstrate that ISG20 is involved in the antiviral
      functions of IFN. In the absence of IFN treatment, ISG20-overexpressing HeLa
      cells showed resistance to infections by vesicular stomatitis virus (VSV),
      influenza virus, and encephalomyocarditis virus (three RNA genomic viruses) but
      not to the DNA genomic adenovirus. ISG20 specifically interfered with VSV mRNA
      synthesis and protein production while leaving the expression of cellular control
      genes unaffected. No antiviral effect was observed in cells overexpressing a
      mutated ISG20 protein defective in exonuclease activity, demonstrating that the
      antiviral effects were due to the exonuclease activity of ISG20. In addition, the
      inactive mutant ISG20 protein, which is able to inhibit ISG20 exonuclease
      activity in vitro, significantly reduced the ability of IFN to block VSV
      development. Taken together, these data suggested that the antiviral activity of
      IFN against VSV is partly mediated by ISG20. We thus show that, besides RNase L,
      ISG20 has an antiviral activity, supporting the idea that it might represent a
      novel antiviral pathway in the mechanism of IFN action.

PMID- 12594220
TI  - N-terminal short sequences of alpha subunits of the G12 family determine
      selective coupling to receptors.
AB  - The Galpha subunits of the G(12) family of heterotrimeric G proteins, defined by
      Galpha(12) and Galpha(13), have many cellular functions in common, such as stress
      fiber formation and neurite retraction. However, a variety of G protein-coupled
      receptors appear to couple selectively to Galpha(12) and Galpha(13). For example,
      thrombin and lysophosphatidic acid (LPA) have been shown to induce stress fiber
      formation via Galpha(12) and Galpha(13), respectively. We recently showed that
      active forms of Galpha(12) and Galpha(13) interact with Ser/Thr phosphatase type
      5 through its tetratricopeptide repeat domain. Here we developed a novel assay to
      measure the activities of Galpha(12) and Galpha(13) by using glutathione S
      transferase-fused tetratricopeptide repeat domain of Ser/Thr phosphatase type 5,
      taking advantage of the property that tetratricopeptide repeat domain strongly
      interacts with active forms of Galpha(12) and Galpha(13). By using this assay, we
      identified that thrombin and LPA selectively activate Galpha(12) and Galpha(13),
      respectively. Galpha(12) and Galpha(13) show a high amino acid sequence homology
      except for their N-terminal short sequences. Then we generated chimeric G
      proteins Galpha(12N/13C) and Galpha(13N/12C), in which the N-terminal short
      sequences are replaced by each other, and showed that thrombin and LPA
      selectively activate Galpha(12N/13C) and Galpha(13N/12C), respectively. Moreover,
      thrombin and LPA stimulate RhoA activity through Galpha(12) and Galpha(13),
      respectively, in a Galpha(12) family N-terminal sequence-dependent manner. Thus,
      N-terminal short sequences of the G(12) family determine the selective couplings
      of thrombin and LPA receptors to the Galpha(12) family.

PMID- 12594221
TI  - Identification of novel ERK2 substrates through use of an engineered kinase and
      ATP analogs.
AB  - The mitogen-activated protein kinases are key regulators of cellular organization
      and function. To understand the mechanisms(s) by which these ubiquitous kinases
      affect specific cellular changes, it is necessary to identify their diverse and
      numerous substrates in different cell contexts and compartments. As a first step
      in achieving this goal, we engineered a mutant ERK2 in which a bulky amino acid
      residue in the ATP binding site (glutamine 103) is changed to glycine, allowing
      this mutant to utilize an analog of ATP (cyclopentyl ATP) that cannot be used by
      wild-type ERK2 or other cellular kinases. The mutation did not inhibit ERK2
      kinase activity or substrate specificity in vitro or in vivo. This method allowed
      us to detect only ERK2-specific phosphorylations within a mixture of proteins.
      Using this ERK2 mutant/analog pair to phosphorylate ERK2-associated proteins in
      COS-1 cells, we identified the ubiquitin ligase EDD (E3 identified by
      differential display) and the nucleoporin Tpr (translocated promoter region) as
      two novel substrates of ERK2, in addition to the known ERK2 substrate Rsk1. To
      further validate the method, we present data that confirm that ERK2
      phosphorylates EDD in vitro and in vivo. These results not only identify two
      novel ERK2 substrates but also provide a framework for the future identification
      of numerous cellular targets of this important signaling cascade.

PMID- 12594222
TI  - A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death.
AB  - TRPM2 is a Ca(2+)-permeable channel that is activated by oxidative stress and
      confers susceptibility to cell death. Here, an isoform of TRPM2 was identified in
      normal human bone marrow that consists of the TRPM2 N terminus and the first two
      predicted transmembrane domains. Because of alternative splicing, a stop codon
      (TAG) is located at the splice junction between exons 16 and 17, resulting in
      deletion of the four C-terminal transmembrane domains, the putative calcium
      permeable pore region, and the entire C terminus. This splice variant was found
      in other hematopoietic cells including human burst forming unit-erythroid-derived
      erythroblasts and TF-1 erythroleukemia cells. Endogenous expression of both the
      short form of TRPM2 (TRPM2-S) and the full length (TRPM2-L) was determined by
      reverse transcriptase-PCR, and localization of endogenous TRPM2 to the plasma
      membrane was demonstrated by confocal microscopy. Heterologous expression of
      TRPM2-S in HEK 293T cells demonstrated similar membrane localization as TRPM2-L,
      and coexpression of TRPM2-S did not alter the subcellular localization of TRPM2
      L. The direct interaction of TRPM2-S with TRPM2-L was demonstrated with
      immunoprecipitation. H(2)O(2) induced calcium influx through TRPM2-L expressed in
      293T cells. Coexpression of TRPM2-S suppressed H(2)O(2)-induced calcium influx
      through TRPM2-L. Furthermore, expression of TRPM2-S inhibited susceptibility to
      cell death and onset of apoptosis induced by H(2)O(2) in cells expressing TRPM2
      L. These data demonstrate that TRPM2-S is an important physiologic isoform of
      TRPM2 and modulates channel activity and induction of cell death by oxidative
      stress through TRPM2-L.

PMID- 12594223
TI  - The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor
      receptor-1 has signaling function comparable with interleukin-6 cytokine
      receptors.
AB  - The reciprocal t(8;13) chromosome translocation results in a fusion gene (FUS) in
      which the N-terminal half of the zinc finger protein ZNF198 is combined with the
      cytoplasmic domain of the fibroblast growth factor receptor-1 (FGFR1). Expression
      of FUS is suggested to provide growth-promoting activity to myeloid cells similar
      to the activity of hematopoietic cytokine receptors. This study determined the
      specificity of FUS to activate signal transduction pathways. Because no tumor
      cell line expressing FUS was available, the mode of FUS action was identified in
      cells transiently and stably transfected with an expression vector for FUS. FUS
      acted as a constitutively active protein-tyrosine kinase and mediated
      phosphorylation of STAT1, 3, and 5 but not STAT4 and 6. The same specificity but
      lower activity was determined for normal FGFR1. STAT activation by FUS, similar
      to that by interleukin-6-type cytokines, promoted STAT-specific induction of
      genes. The functionality of FUS, as well as the relative recruitment of STAT
      isoforms, was determined by the dimerizing function of the zinc finger domain.
      Replacement of the ZNF198 portion by the Bcr portion as present in the t(8;22)
      translocation shifted the signaling toward a more prominent STAT5 activation.
      This study documents that both gene partners forming the fusion oncogene define
      the activity and the signaling specificity of the protein-tyrosine kinase of
      FGFR1.

PMID- 12594224
TI  - Site-specific mutagenesis and domain substitutions in the loading module of the
      nystatin polyketide synthase, and their effects on nystatin biosynthesis in
      Streptomyces noursei.
AB  - The loading module for the nystatin polyketide synthase (PKS) in Streptomyces
      noursei is represented by the NysA protein composed of a ketosynthase (KS(S)),
      acyltransferase, dehydratase, and an acyl carrier protein. The absolute
      requirement of this protein for initiation of nystatin biosynthesis was
      demonstrated by the in-frame deletion of the nysA gene in S. noursei. The role of
      the NysA KS(S) domain, however, remained unclear, since no data on the
      significance of the "active site" serine (Ser-170) residue in the loading modules
      of type I PKSs were available. Site-specific mutagenesis of Ser-170 both in the
      wild-type NysA and in the hybrid loading module containing malonyl-specific
      acyltransferase domain from the extender module had no effect on nystatin
      biosynthesis. A second mutation (S413N) of the NysA KS(S) domain was discovered
      that completely abolished the ability of the hybrids to restore nystatin
      biosynthesis, presumably by affecting the ability of the resulting proteins to
      catalyze the required substrate decarboxylation. In contrast, NysA and its Ser
      170 mutants bearing the same S413N mutation were able to restore nystatin
      production to significant levels, probably by using acetyl-CoA as a starter unit.
      Together, these data suggest that the KS(S) domain of NysA differs from the KS(Q)
      domains found in the loading modules of several PKS type I systems in that the
      active site residue is not significant for its activity.

PMID- 12594225
TI  - Fc Rgamma -independent signaling by the platelet collagen receptor glycoprotein
      VI.
AB  - The platelet collagen receptor glycoprotein VI (GPVI) is structurally homologous
      to multisubunit immune receptors and signals through the immune receptor adaptor
      Fc Rgamma. Multisubunit receptors are composed of specialized subunits thought to
      be dedicated exclusively to ligand binding or signal transduction. However,
      recent studies of the intracellular region of GPVI, a ligand-binding subunit,
      have suggested the existence of protein-protein interactions that could regulate
      receptor signaling. In the present study we have investigated the signaling role
      of the GPVI intracellular domain by stably expressing GPVI mutants in RBL-2H3
      cells, a model system that accurately reproduces the GPVI signaling events
      observed in platelets. Studies of mutant GPVI receptor protein-protein
      interaction and calcium signaling reveal the existence of discrete domains within
      the receptor's intracellular tail that mediate interaction with Fc Rgamma,
      calmodulin, and Src family tyrosine kinases. These receptor interactions are
      modular and mediated by non-overlapping regions of the receptor transmembrane and
      intracellular domains. GPVI signaling requires all three of these domains as
      receptor mutants able to couple to only two interacting proteins exhibited severe
      signaling defects despite normal surface expression. Our results demonstrate that
      the ligand-binding subunit of the GPVI-Fc Rgamma receptor participates directly
      in receptor signaling by interacting with downstream signaling molecules other
      than Fc Rgamma through an adaptor-like mechanism.

PMID- 12594226
TI  - Cell surface expression of the melanocortin-4 receptor is dependent on a C
      terminal di-isoleucine sequence at codons 316/317.
AB  - Loss-of-function mutations in the human melanocortin-4 receptor (MC4R) are
      associated with obesity. Previous work has implicated a C-terminal di-isoleucine
      motif at residues 316/317 in MC4R cell surface targeting. It was therefore of
      interest to examine function and cell surface expression of an MC4R mutation
      found in an obese proband in which one of these isoleucines was substituted by
      threonine (I317T). Single mutant (I316T or I317T) and double mutant (I316T,I317T)
      forms of MC4R were constructed by oligonucleotide-directed mutagenesis and tested
      for function and cell surface expression in transfected cells. Function was
      assessed using assays for agonist, [Nle(4)-d-Phe(7)]alpha-melanocyte-stimulating
      hormone (NDP-alpha-MSH) or forskolin-stimulated cAMP accumulation. Cell surface
      expression was determined by whole-cell binding of [(125)I]NDP-alpha-MSH,
      fluorescence immunocytochemistry and fluorescence-activated cell sorting. Maximal
      cAMP generation of the single mutants was reduced by 40% of wild-type receptor;
      the double mutant further reduced function to 40% of control, effects that were
      mirrored by decreases in cell-surface expression. Quantitative RT-PCR showed
      that, relative to wild-type receptor, transcript levels for the mutated receptors
      were not reduced. The results further implicate the C-terminal di-isoleucines in
      cell surface expression of MC4R and suggest that mutations of residues 316 or 317
      would predict MC4R hypofunction.

PMID- 12594227
TI  - Insulin-secreting beta-cell dysfunction induced by human lipoproteins.
AB  - Diabetes is associated with significant changes in plasma concentrations of
      lipoproteins. We tested the hypothesis that lipoproteins modulate the function
      and survival of insulin-secreting cells. We first detected the presence of
      several receptors that participate in the binding and processing of plasma
      lipoproteins and confirmed the internalization of fluorescent low density
      lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin
      secreting beta-cells. Purified human very low density lipoprotein (VLDL) and LDL
      particles reduced insulin mRNA levels and beta-cell proliferation and induced a
      dose-dependent increase in the rate of apoptosis. In mice lacking the LDL
      receptor, islets showed a dramatic decrease in LDL uptake and were partially
      resistant to apoptosis caused by LDL. VLDL-induced apoptosis of beta-cells
      involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal
      kinase-interacting protein-1. In contrast, the proapoptotic signaling of
      lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of
      c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by
      inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In
      conclusion, human lipoproteins are critical regulators of beta-cell survival and
      may therefore contribute to the beta-cell dysfunction observed during the
      development of type 2 diabetes.

PMID- 12594228
TI  - Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2
      protein expression via different mechanisms contributes to the insulin-induced
      desensitization of its signaling pathways in L6 muscle cells.
AB  - Impaired glucose tolerance precedes type 2 diabetes and is characterized by
      hyperinsulinemia, which develops to balance peripheral insulin resistance. To
      gain insight into the deleterious effects of hyperinsulinemia on skeletal muscle,
      we studied the consequences of prolonged insulin treatment of L6 myoblasts on
      insulin-dependent signaling pathways. A 24-h long insulin treatment desensitized
      the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK
      pathways toward a second stimulation with insulin or insulin-like growth factor-1
      and led to decreased insulin-induced glucose uptake. Desensitization was
      correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein
      levels, which was reversed by the PI3K inhibitor LY294002. Co-treatment of cells
      with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased
      its phosphotyrosine content, enhancing IRS-1/PI3K association. PDK1, mTOR, and
      MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that
      the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its
      commitment to proteasomal degradation. Contrarily, insulin-induced IRS-2 down
      regulation occurred via a PI3K/mTOR pathway. Suppression of IRS-1/2 down
      regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute
      insulin stimulation. Conversely, adenoviral-driven expression of constitutively
      active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels.
      IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by
      insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely
      impaired activation of both kinases. In summary, (i) PI3K mediates insulin
      induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway
      controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major
      adapter molecule linking the insulin receptor to activation of PKB and MAPK,
      (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared
      with 3T3-L1 adipocytes. In conclusion, the reduction in IRS proteins via
      different PI3K-mediated mechanisms contributes to the development of an insulin
      resistant state in L6 myoblasts.

PMID- 12594230
TI  - Development of a real-time reverse transcription polymerase chain reaction assay
      for c-myc expression that allows the identification of a subset of c-myc+ diffuse
      large B-cell lymphoma.
AB  - Absence of a reliable method for determining the level of c-myc expression has
      impeded the analysis of its biological and clinical relevance in tumors. We have
      standardized the conditions for a real-time reverse transcription polymerase
      chain reaction analysis for c-myc expression, including the selection of an
      endogenous reference (18S rRNA), the adequate number of measurements for each
      sample (2 cDNA in triplicate), and suitable controls for determining inter- and
      intrarun variability (standard curve and calibrator). Subsequently, in a series
      of 56 non-Hodgkin's lymphomas, we analyzed the expression of c-myc mRNA, using
      real-time reverse transcription polymerase chain reaction, and of other
      functionally related proteins (bcl-6, p27, cyclin D3, and p53). As expected, all
      eight Burkitt's lymphoma cases analyzed had high levels of c-myc mRNA expression
      compared with that observed in reactive lymphoid tissue. There was a wider range
      of expression in diffuse large B-cell lymphoma, with 30% (15 of 48) of cases
      overexpressing c-myc. This overexpression was largely independent of c-myc
      translocations (4 of 5), as demonstrated by fluorescence in situ hybridization.
      In this large B-cell lymphoma series, a high level of c-myc expression predicted
      lower survival probability, irrespectively of the International Prognostic Index
      risk group classification. A slightly increased frequency of p53 inactivation was
      observed in the cases with c-myc overexpression, which suggests a growth
      advantage in lymphomas with concurrent deregulation of c-myc and p53. In
      addition, a moderate increase in bcl-6 protein expression was observed in the c
      myc-positive cases, suggesting the existence of a complex interrelationship
      between these two genes. These findings suggest that c-myc may play a relevant
      role in the pathogenesis of a subset of large B-cell lymphoma and suggest the
      existence of additional regulatory mechanisms of c-myc expression to c-myc
      rearrangements.

PMID- 12594231
TI  - Matrix metalloproteinase production by COOH-terminal heparin-binding fibronectin
      fragment in rheumatoid synovial cells.
AB  - Fibronectin with IIICS region is present in rheumatoid synovium, and fibronectin
      fragments are increased in rheumatoid joints. We investigated the ability of COOH
      terminal heparin-binding fibronectin fragment (COOH-HBFN-f) containing IIICS to
      induce matrix metalloproteinase (MMP) production and the role of mitogen
      activated protein kinase (MAPK) pathway and CS-1 sequence that can bind
      alpha4beta1 integrin in MMP induction by COOH-HBFN-f in rheumatoid synovial
      fibroblasts (RSF). When RSF in monolayer culture were incubated with COOH-HBFN-f,
      COOH-HBFN-f stimulated the production of MMP-1, MMP-3, and MMP-13 by RSF in
      association with activation of extracellular signal-regulated kinase, p38 MAPK,
      and c-Jun NH(2)-terminal kinase. Immunoprecipitation of cell lysates demonstrated
      the presence of alpha4 integrin in cultured RSF. Similar to COOH-HBFN-f,
      treatment with CS-1 synthetic peptide derived from IIICS resulted in increased
      MMP production and activation of the kinases, although the MMP levels were low.
      Preincubation of RSF with anti-alpha4 integrin antibody resulted in partial
      suppression of the COOH-HBFN-f-stimulated MMP production. Inhibition studies
      using protein kinase inhibitors (PD98059 and SB203580) showed that those MAPK
      pathways contributed to MMP up-regulation by COOH-HBFN-f and CS-1. Thus, the
      present results have clearly shown that COOH-HBFN-f and CS-1 stimulate MMP
      production in association with activation of MAPK pathways in RSF. Integrin
      alpha4beta1 may be partially involved in the MMP induction by COOH-HBFN-f.

PMID- 12594233
TI  - Macrophage response to peripheral nerve injury: the quantitative contribution of
      resident and hematogenous macrophages.
AB  - Whereas local microglial cells of the CNS rapidly respond to injury, little is
      known about the functional role of resident macrophages of the peripheral nervous
      system in nerve pathology. Using bone marrow chimeric rats, we recently
      identified individual resident endoneurial macrophages that rapidly became
      activated after nerve injury. However, the extent of local macrophage activation
      and its quantitative contribution to the total macrophage response is unknown. We
      now have created chimeric mice by transplanting bone marrow from green
      fluorescent protein (GFP)-transgenic mice into irradiated wild-type mice,
      allowing easy differentiation and quantification of hematogenous and resident
      endoneurial macrophages. After sciatic nerve crush injury, both GFP(-) and GFP(+)
      resident macrophages, the latter having undergone physiological turnover from the
      blood before injury, rapidly underwent morphological alterations and increased in
      number. Proliferating GFP(-) and GFP(+) resident macrophages were abundant and
      peaked 3 days after injury. A major lesion-induced influx of hematogenous
      macrophages with a disproportionate increase of GFP(+) macrophages was not
      observed until Day 4. Throughout all time points examined, GFP(-) resident
      macrophages were strikingly frequent, reaching maximum numbers 9.5-fold above
      baseline. There was also a notable proportion of GFP(-) resident endoneurial
      macrophages phagocytosing myelin and expressing major histocompatibility complex
      class II. Our results demonstrate for the first time that the rapid response of
      resident endoneurial macrophages to nerve injury is quantitatively important and
      that local macrophages contribute significantly to the total endoneurial
      macrophage pool during Wallerian degeneration.

PMID- 12594232
TI  - The myofibroblastic conversion of peribiliary fibrogenic cells distinct from
      hepatic stellate cells is stimulated by platelet-derived growth factor during
      liver fibrogenesis.
AB  - The origin of myofibroblasts and the factors promoting their differentiation
      during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the
      proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile
      ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic
      conversion of peribiliary cells distinct from HSC also occurs. We herein examined
      the phenotype of these peribiliary myofibroblasts as compared with
      myofibroblastic HSC and tested whether their differentiation was affected by
      PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in
      rats. After 48 hours, periductular fibrosis in portal tracts colocalized with
      smooth muscle alpha-actin-immunoreactive myofibroblasts, the majority of which
      were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was
      induced in a large number of HSC, which were smooth muscle alpha-actin negative.
      Cultures of peribiliary myofibroblasts were expanded from isolated bile duct
      segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts
      outgrowing from bile duct segments expressed smooth muscle alpha-actin, alpha1
      (I) collagen mRNA, and PDGF receptor-beta subunit. Desmin immunoreactivity
      gradually decreased in cultured peribiliary myofibroblasts, contrasting with
      constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in
      peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC,
      whereas the expression of the complement-activating protease P100 in both cell
      types showed little difference and that of the extracellular matrix component
      fibulin 2 was similar. The expression of smooth muscle alpha-actin protein in
      cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by
      STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct-ligated
      rats, the administration of STI571 caused a significant decrease in peribiliary
      smooth muscle alpha-actin immunoreactivity, and to a lesser extent, a decrease in
      peribiliary fibrosis. These results indicate that peribiliary cells distinct from
      HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at
      lower levels than myofibroblastic HSC and contribute to the initial formation of
      biliary-type liver fibrosis.

PMID- 12594234
TI  - Usefulness of the real-time reverse transcription-polymerase chain reaction assay
      targeted to alpha1,4-N-acetylglucosaminyltransferase for the detection of gastric
      cancer.
AB  - alpha1,4-N-acetylglucosaminyltransferase (alpha4GnT) is a glycosyltransferase
      that forms a unique glycan, GlcNAcalpha1-->4Galbeta-->R, specifically present in
      gastric gland mucous cell-type mucin. Recently, we molecularly cloned human
      alpha4GnT and showed that alpha4GnT is expressed in the mucous cells that secrete
      this particular mucin. In the present study, we first demonstrated that alpha4GnT
      was frequently expressed in gastric cancer cells but not in peripheral blood
      cells using immunohistochemistry. To detect gastric cancer cells circulating in
      the peripheral blood of gastric cancer patients, we quantitatively analyzed the
      expression level of alpha4GnT mRNA in the mononuclear cell fraction of peripheral
      blood using real-time reverse transcription polymerase chain reaction. The
      transcripts of alpha4GnT were detected in the mononuclear cell fraction isolated
      from 62.2% of 37 gastric cancer patients but not from any of 23 healthy
      individuals. Significant correlation was found in the expression levels of
      alpha4GnT mRNA in peripheral blood and alpha4GnT protein in gastric cancer cells.
      Surprisingly, alpha4GnT mRNA was detectable in 80% of five patients with an early
      stage of gastric cancer when the cancer cells were limited to the gastric mucosa,
      and the expression levels of alpha4GnT mRNA were increased in association with
      tumor progression. In three patients with gastric cancer, during postsurgical
      follow-up, the expression levels of alpha4GnT mRNA were decreased after surgical
      removal of gastric cancer. However, significant amounts of the alpha4GnT
      transcripts were again detected in two patients, who eventually developed to the
      recurrence of gastric cancer. Although alpha4GnT was detected in 33.3% of nine
      patients with Helicobacter pylori-infected chronic active gastritis as well as
      all of four patients with peptic ulcer, the mean expression level of alpha4GnT
      mRNA in these benign disorders was lower than that in gastric cancer. These
      results altogether indicate that the quantitative analysis of alpha4GnT mRNA
      expressed in the peripheral blood is useful for the detection and, possibly,
      monitoring of gastric cancer.

PMID- 12594235
TI  - Stem cell factor attenuates liver damage in a murine model of acetaminophen
      induced hepatic injury.
AB  - Acute liver injury is a common cause of intensive care unit visits. In these
      studies, we used a murine model of acetaminophen poisoning to examine the role of
      stem cell factor (SCF) on liver damage. In the initial studies, we identified
      that the liver produces relatively high constitutive levels of SCF. Upon
      administration of acetaminophen, the levels of SCF fell dramatically, correlating
      to damage within the liver. When the liver was allowed to regenerate, the levels
      of SCF again correlated with the liver regeneration. We next treated mice with
      anti-SCF before sublethal doses of acetaminophen and significantly increased
      lethality in anti-SCF-treated animals. When exogenous SCF was given to mice, the
      lethality was significantly reduced compared with the control acetaminophen
      treated animals and the damage within the liver tissue was attenuated. The
      administration of rSCF reduced the level of steady-state mRNA for cytochrome P450
      cyp2E1 enzyme both in vitro and in vivo. These data suggest that SCF functions as
      an important factor that protects livers from acute damage.

PMID- 12594236
TI  - Central role of fibroblast alpha3 nicotinic acetylcholine receptor in mediating
      cutaneous effects of nicotine.
AB  - Smoking is associated with aberrant cutaneous tissue remodeling, such as
      precocious skin aging and impaired wound healing. The mechanism is not fully
      understood. Dermal fibroblasts (DF) are the primary cellular component of the
      dermis and may provide a target for pathobiologic effects of tobacco products.
      The purpose of this study was to characterize a mechanism of nicotine (Nic)
      effects on the growth and tissue remodeling function of DF. We hypothesized that
      the effects of Nic on DF result from its binding to specific nicotinic
      acetylcholine receptors (nAChRs) expressed by these cells and that downstream
      signaling from the receptors alters normal cell functioning, leading to changes
      in skin homeostasis. Using RT-PCR and Western blotting, we found that a 24-hour
      exposure of human DF to 10 micro M Nic causes a 1.9- to 28-fold increase of the
      mRNA and protein levels of the cell cycle regulators p21, cyclin D1, Ki-67, and
      PCNA and a 1.7- to 2-fold increase of the apoptosis regulators Bcl-2 and caspase
      3. Nic exposure also up-regulated expression of the dermal matrix proteins
      collagen type Ialpha1 and elastin as well as matrix metalloproteinase-1.
      Mecamylamine (Mec), the specific antagonist of nAChRs, abolished Nic-induced
      alterations, indicating that they resulted from a pharmacologic stimulation of
      nAChRs expressed by DF. To establish the relevance of these findings to a
      specific nicotinergic pathway, we studied human DF transfected with anti-alpha3
      antisense oligonucleotides and murine DF from alpha3 nAChR knockout mice. In both
      cases, lack of alpha3 was associated with alterations in fibroblast growth and
      function that were opposite to those observed in DF treated with Nic, suggesting
      that the nicotinic effects on DF were mostly mediated by alpha3 nAChR. In
      addition to alpha3, the nAChR subunits detected in human DF were alpha5, alpha7,
      beta2, and beta4. The exposure of DF to Nic altered the relative amounts of each
      of these subunits, leading to reciprocal changes in [(3)H]epibatidine-binding
      kinetics. Thus, some of the pathobiologic effects of tobacco products on
      extracellular matrix turnover in the skin may stem from Nic-induced alterations
      in the physiologic control of the unfolding of the genetically determined program
      of growth and the tissue remodeling function of DF as well as alterations in the
      structure and function of fibroblast nAChRs.

PMID- 12594237
TI  - Proapoptosis and antiapoptosis-related molecules during postnatal pancreas
      development in control and nonobese diabetic mice: relationship with innervation.
AB  - The mouse pancreas, an immature organ at birth, reaches its adult size and
      morphology after weaning (3 weeks of age). Around this time, apoptotic phenomena
      and various types of macrophages are normally present. During development, Fas
      Fas ligand (FasL) interactions are known to play a role in apoptotic events
      involved in tissue remodeling and elimination of damaged cells, and macrophages
      are routinely observed near apoptotic cells. Apoptosis and Fas-FasL interactions
      are also thought to be involved in the pathogenesis of autoimmune diseases,
      particularly type 1 diabetes (T1D). Therefore, we used early postnatal mouse
      pancreata from three control strains (C57BL/6, DBA/2, BALB/c) and from two
      strains with the nonobese diabetic (NOD)-related genetic background (the
      spontaneous T1D NOD model and the lymphocyte-deficient NODscid strain) to study
      apoptotic phenomena together with the molecular and immunohistochemical
      expression of proapoptosis (Fas, FasL) and antiapoptosis (Bcl-2) proteins. First,
      although no major difference in the numbers of total pancreatic apoptotic cells
      was noted among strains, significantly more FasL(+) expression was detected
      immunohistochemically in mice with the NOD genetic background than in control
      pancreata from birth to 1 month of age. Second, FasL(+), Fas(+), and Bcl-2(+)
      structures seemed to be associated with innervation, regardless of the strain and
      age. Third, in control and NOD strains, nerves (identified by immunohistochemical
      labeling of peripherin or neurofilament 200), were often observed in periductular
      and peri-insular areas. Finally, some peripherin-positive nerves expressed the
      interferon-inducible protein-10 chemokine, and various types of macrophages were
      found to be in close proximity. These data highlight an overlooked, innervation
      related aspect of normal mouse postnatal pancreas development with possible
      implications in T1D pathogenesis.

PMID- 12594238
TI  - Novel monoclonal antibody recognition of oxidative DNA damage adduct,
      deoxycytidine-glyoxal.
AB  - Glyoxal, a reactive aldehyde, is a decomposition product of lipid hydroperoxides,
      oxidative deoxyribose breakdown, or autoxidation of sugars, such as glucose. It
      readily forms DNA adducts, generating potential carcinogens such as glyoxalated
      deoxycytidine (gdC). A major drawback in assessing gdC formation in cellular DNA
      has been methodologic sensitivity. We have developed an mAb that specifically
      recognizes gdC. Balb/c mice were immunized with DNA, oxidatively modified by
      UVC/hydrogen peroxide in the presence of endogenous metal ions. Although UVC is
      not normally considered an oxidizing agent, a UVC/hydrogen peroxide combination
      may lead to glyoxalated bases arising from hydroxyl radical damage to
      deoxyribose. This damaging system was used to induce numerous oxidative lesions
      including glyoxal DNA modifications, from which resulted a number of clones.
      Clone F3/9/H2/G5 showed increased reactivity toward glyoxal-modified DNA greater
      than that of the immunizing antigen. ELISA unequivocally showed Ab recognition
      toward gdC, which was confirmed by gas chromatography-mass spectrometry of the
      derivatized adduct after formic acid hydrolysis to the modified base. Binding of
      Ab F3/9 with glyoxalated and untreated oligomers containing deoxycytidine,
      deoxyguanosine, thymidine, and deoxyadenosine assessed by ELISA produced
      significant recognition (p > 0.0001) of glyoxal-modified deoxycytidine greater
      than that of untreated oligomer. Additionally, inhibition ELISA studies using the
      glyoxalated and native deoxycytidine oligomer showed increased recognition for
      gdC with more than a 5-fold difference in IC(50) values. DNA modified with
      increasing levels of iron (II)/EDTA produced a dose-dependent increase in Ab F3/9
      binding. This was reduced in the presence of catalase or aminoguanidine. We have
      validated the potential of gdC as a marker of oxidative DNA damage and showed
      negligible cross-reactivity with 8-oxo-2'-deoxyguanosine or malondialdehyde
      modified DNA as well as its utility in immunocytochemistry. Formation of the gdC
      adduct may involve intermediate structures; however, our results strongly suggest
      Ab F3/9 has major specificity for the predominant product, 5-hydroxyacetyl-dC.

PMID- 12594239
TI  - K-RAS mutations in ovarian and extraovarian lesions of serous tumors of
      borderline malignancy.
AB  - K-RAS mutations are the most frequent molecular genetic alteration in serous
      ovarian tumors of borderline malignancy (SBOT). The pathogenesis of associated
      contralateral tumors and extraovarian implants and Mullerian inclusion cysts is
      obscure. We hypothesized that the comparison of K-RAS mutations in these lesions
      might help to distinguish multifocal from metastatic foci. Eight cases of SBOT
      with known K-RAS mutation (RAS+) and two cases without mutation (RAS-) were
      analyzed for comparison. DNA was extracted from multiple samples of 58 paraffin
      embedded and laser-microdissected ovarian and extraovarian lesions (10 ovarian
      borderline tumors, 8 contralateral tumors, 25 implants, 15 inclusion cysts;
      total: 97 samples). K-RAS exon 1 was amplified by PCR and analyzed by denaturing
      gradient gel electrophoresis and cycle sequencing. In 12 of 14 SBOT and in 2 of 2
      extraovarian implants, the K-RAS mutation could be found in different areas of
      the same lesion, indicating monoclonality. All RAS+ ovarian borderline tumors
      with contralateral tumors (six of six) harbored an identical mutation in both
      ovaries (in one case, a separate surface borderline tumor component contained a
      different mutation in addition). In 4 of 5 RAS+ ovarian tumors with extraovarian
      lesions, RAS mutations were also found in implants (15/21 implants [71%]) and
      more rarely in inclusion cysts (3 of 12 lesions [25%]). These extraovarian
      mutations were always identical to the one in the ovary (18 of 18 [100%]).
      Regarding the contralateral and extraovarian lesions of the two RAS- SBOT, only
      one extraovarian implant contained a RAS mutation. The demonstration of K-RAS
      mutations in Mullerian inclusion cysts and implants of SBOT suggests that K-RAS
      mutations represent a pivotal event during neoplastic transformation of ovarian
      and extraovarian serous epithelium. Considering our observations, the two
      putative pathogenetic mechanisms for the development of implants and
      endosalpingiosis-multifocal tumorigenesis and spread from the ovarian primary
      tumor-seem to coexist.

PMID- 12594240
TI  - Myocardial dysfunction and male mortality in peroxisome proliferator-activated
      receptor alpha knockout mice overexpressing lipoprotein lipase in muscle.
AB  - Free fatty acids (FFA) are liberated from triglyceride-rich lipoproteins by
      lipoprotein lipase (LPL) and are considered to be a principal energy source for
      the heart. The peroxisome proliferator-activated receptor alpha (PPARalpha) is a
      key regulator of FFA catabolism. To investigate its role in cardiac muscle
      metabolism, transgenic mice overexpressing LPL in skeletal and cardiac muscle
      were bred on a PPARalpha knockout background. Fifty-five percent of male animals
      lacking PPARalpha and overexpressing LPL died within 4 months after birth. In
      contrast, females of this genotype stayed alive. Deceased animals exhibited
      cardiopulmonary congestion but had no increase of neutral lipids in the heart.
      Changes in plasma glucose, FFA, lactate, and triglycerides did not clearly
      account for gender-specific differences in mortality; however, they indicated a
      critical role for PPARalpha during fasting. Analysis of cardiac function revealed
      that in isolated perfused hearts, left ventricular developed pressure (a measure
      of contractility) was markedly lower in PPARalpha knockout mice overexpressing
      LPL compared with controls. Glucose uptake of isolated perfused hearts was
      significantly higher in PPARalpha knockout mice with both normal or increased LPL
      expression. However, uptake of FFA was not different among genotypes. In
      contrast, fasted FFA levels were significantly lower in cardiac muscle of
      PPARalpha knockout mice with normal LPL expression (-26%) and PPARalpha knockout
      mice overexpressing LPL (-38%) compared with controls. Our results indicate a
      critical role for PPARalpha in myocardial pump function and suggest that mouse
      models combining different genetic effects such as PPARalpha knockout mice
      overexpressing muscle LPL may be useful to study cardiomyopathies.

PMID- 12594241
TI  - Gene expression profile of serial samples of transformed B-cell lymphomas.
AB  - Follicular lymphoma (FL) is characterized by a continuous rate of relapse and
      transformation to a high-grade lymphoma, usually diffuse large B-cell lymphoma
      (DLBCL), associated with a dismal prognosis and a poor response to conventional
      chemotherapy. The progression of indolent to aggressive FL is accompanied by the
      successive accumulation of recurrent chromosomal defects, but the resultant
      alterations of gene expression are largely unknown. To expand the understanding
      of the pathogenesis of FL transformation, we initially performed oligonucleotide
      microarray analyses using Affymetrix HuFL chips on five cases with matched snap
      frozen lymph nodes before and after transformation. Expression data were analyzed
      using the Affymetrix Microarray Suite 4.0 and Genespring 4.0. Thirty-six genes
      with increased expression and 66 genes with decreased expression associated with
      transformation were identified and functionally classified. The expression of
      differentially expressed genes was confirmed by real-time quantitative RT-PCR
      (QRT-PCR) using a total of seven matched pairs and an additional five FL and five
      unrelated DLBCL. In addition, selected genes were further analyzed by QRT-PCR or
      immunohistochemistry using a large, unrelated series of FL (grades 1 to 3) as
      well as transformed and de novo DLBCL (total of 51 samples). The microarray
      results correlated with the protein expression data obtained from samples at the
      time of initial diagnosis and transformation. Furthermore, the expression of 25
      candidate genes was evaluated by QRT-PCR with a 78% confirmation rate. Some of
      the identified genes, such as nucleobindin, interferon regulatory factor 4, and
      tissue inhibitor of metalloproteinases 1, are already known to be associated with
      high-grade non-Hodgkin's lymphoma. Novel candidate genes with confirmed increased
      and decreased expression in transformed DLBCL include ABL2 and NEK2, and PDCD1
      and VDUP1, respectively. In summary, this study shows that transformation of FL
      to DLBCL is associated with a distinct set of differentially expressed genes of
      potential functional importance.

PMID- 12594242
TI  - Nitric oxide synthase-3 overexpression causes apoptosis and impairs neuronal
      mitochondrial function: relevance to Alzheimer's-type neurodegeneration.
AB  - Dementia in Alzheimer's disease (AD) is correlated with cell loss that is
      mediated by apoptosis, mitochondrial (Mt) dysfunction, and possibly necrosis.
      Previous studies demonstrated increased expression of the nitric oxide synthase 3
      (NOS3) gene in degenerating neurons of AD brains. For investigating the role of
      NOS3 overexpression as a mediator of neuronal loss, human PNET2 central nervous
      system-derived neuronal cells were infected with recombinant adenovirus vectors
      that expressed either human NOS3 or green fluorescent protein cDNA under the
      control of a CMV promoter. NOS3 overexpression resulted in apoptosis accompanied
      by increased levels of p53, p21/Waf1, Bax, and CD95. In addition, NOS3
      overexpression impaired neuronal Mt function as demonstrated by the reduced
      levels of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and
      nicotinamide adenine dinucleotide (reduced form)-tetrazolium reductase activities
      and MitoTracker Red fluorescence. These adverse effects of NOS3 were associated
      with increased cellular levels of reactive oxygen species and impaired membrane
      integrity and were not produced in cells that were transfected with a cDNA
      encoding catalytically inactive NOS3. Importantly, modest elevations in NOS3
      expression, achieved by infection with low multiplicities of adenovirus-NOS3
      infection, did not cause apoptosis but rendered the cells more sensitive to
      oxidative injury by H(2)O(2) or diethyldithiocarbamate. In contrast, treatment
      with NO donors did not enhance neuronal sensitivity to oxidative injury. These
      results suggest that NOS3-induced neuronal death is mediated by Mt dysfunction,
      oxidative injury, and impaired membrane integrity, rather than by NO production,
      and that neuroprotection from these adverse effects of NOS3 may be achieved by
      modulating intracellular levels of oxidative stress.

PMID- 12594244
TI  - Cutting edge: molecular cloning of a killer cell Ig-like receptor in the mouse
      and rat.
AB  - We report the molecular cloning of a KIR3DL1 receptor in the mouse and the rat,
      between 37.4 and 45.4% identical with primate killer cell Ig-like receptors
      (KIRs/CD158). Both mouse and rat molecules contain a pair of immunoreceptor
      tyrosine-based inhibition motifs in their cytoplasmic regions, suggesting an
      inhibitory function. Southern blot analysis indicated a single KIR gene in the
      rat, whereas the mouse genome contains more than one KIR-related element. The rat
      Kir3dl1 locus was mapped to the leukocyte receptor gene complex on chromosome 1,
      whereas mouse Kir3dl1 was localized to the X chromosome. RT-PCR demonstrated that
      KIR3DL1 was selectively expressed by NK cells in both rat and mouse. An epitope
      tagged expression construct of mouse KIR3DL1 transfected into 293T cells induced
      expression of a approximately 55-kDa protein. Our data indicate that KIR
      receptors may contribute to the NK cell receptor repertoire in rodents, alongside
      the Ly-49 family.

PMID- 12594245
TI  - Cutting edge: dysfunctional CD8+ T cells reside in nonlymphoid tissues during
      chronic Trypanosoma cruzi infection.
AB  - Chagas disease is caused by persistent Trypanosoma cruzi infection in muscle
      tissue that ultimately results in chronic inflammation and tissue destruction. It
      is unclear why T. cruzi is cleared from some tissues but persists in others,
      despite an active inflammatory response. In this study, we show that the majority
      of CD8(+) T cells present in muscle tissue express memory and effector cell
      surface markers but have sharply attenuated effector function compared with their
      splenic counterparts. The dysfunction of CD8(+) T cells in the muscle tissue
      suggests a mechanism by which T. cruzi can persist in that location and cause
      inflammatory damage.

PMID- 12594246
TI  - Cutting edge: histamine inhibits IFN-alpha release from plasmacytoid dendritic
      cells.
AB  - Plasmacytoid dendritic cells (DC) are professional APC and a major source of type
      I IFN following viral infection. We previously showed that histamine alters the
      cytokine profiles of maturing monocyte-derived DC resulting in a change from Th1
      to Th2 in their T cell polarizing function. In this study, we show that human
      plasmacytoid DC, activated by either CpG oligodeoxynucleotides or viral
      infection, also respond to histamine through H2 receptors, leading to a marked
      down-regulation of IFN-alpha and TNF-alpha and a moderate switch in their
      capacity to polarize naive T cells. Our findings provide an explanation for low
      levels of type I IFN frequently observed in atopic individuals.

PMID- 12594247
TI  - Cutting edge: mast cell antimicrobial activity is mediated by expression of
      cathelicidin antimicrobial peptide.
AB  - Cathelicidins (caths) are peptides that are expressed at high levels in
      neutrophils and some epithelia and can act as natural antibiotics by directly
      killing a wide range of microorganisms. We hypothesized that caths are expressed
      in mast cells (MCs), because these cells have been previously associated with
      inherent antimicrobial activity. Cultured murine MCs contained abundant amounts
      of cathelin-related antimicrobial peptide (AMP), the murine cath, and this
      expression was inducible by LPS or lipoteichoic acid. Human skin MCs also
      expressed cath as detected by immunohistochemical analysis for the human cath LL
      37. The functional significance of this expression was shown by comparing MCs
      cultured from normal mice to MCs from littermates deficient in the cathelin
      related AMP gene (Cnlp(-)). MCs derived from Cnlp(-/-) animals had a 50%
      reduction in their ability to kill group A STREPTOCOCCUS: These MCs expressed
      equivalent amounts of mRNA for murine beta-defensin-4, a beta-defensin AMP. Thus,
      different antimicrobials can be identified in MCs, and the presence of cath is
      necessary for efficient bacterial killing. These observations suggest that the
      presence of cath is vital to the ability of mammalian MCs to participate in
      antimicrobial defense.

PMID- 12594248
TI  - Cutting edge: scavenging of inflammatory CC chemokines by the promiscuous
      putatively silent chemokine receptor D6.
AB  - In an effort to define the actual function of the promiscuous putatively silent
      chemokine receptor D6, transfectants were generated in different cell types.
      Engagement of D6 by inflammatory CC chemokines elicited no calcium response nor
      chemotaxis, but resulted in efficient agonist internalization and degradation.
      Also in lymphatic endothelium, where this receptor is expressed in vivo, D6 did
      not elicit cellular responses other than ligand internalization and degradation.
      In particular, no evidence was obtained for D6-mediated transcytosis of
      chemokines in the apical-to-basal or basal-to-apical directions. These results
      indicate that D6 acts as an inflammatory chemokine scavenging nonactivatory decoy
      receptors and suggest that in lymphatic vessels D6 may function as a gatekeeper
      for inflammatory CC chemokines, by clearing them and preventing excessive
      diffusion via afferent lymphatics to lymph nodes.

PMID- 12594249
TI  - Combined autoimmune models of arthritis reveal shared and independent qualitative
      (binary) and quantitative trait loci.
AB  - Collagen-induced arthritis (CIA) and proteoglycan-induced arthritis (PGIA) are
      murine models for rheumatoid arthritis both in terms of their pathology and
      genetics. Using the F(2) hybrids of the CIA-susceptible, but PGIA-resistant DBA/1
      mice, and the CIA-resistant, but PGIA-susceptible BALB/c mice, our goals were to
      1) identify both model-specific and shared loci that confer disease
      susceptibility, 2) determine whether any pathophysiological parameters could be
      used as markers that distinguish between nonarthritic and arthritic mice, and 3)
      analyze whether any immune subtraits showed colocalization with arthritis-related
      loci. To identify chromosomal loci, we performed a genome scan on 939 F(2) hybrid
      mice. For pathophysiological analyses, we measured pro- and anti-inflammatory
      cytokines (IL-1, IL-6, TNF-alpha, IFN-gamma, IL-4, IL-10, IL-12), Ag-specific T
      cell proliferation and IL-2 production, serum IgG1 and IgG2 levels of both auto-
      and heteroantibodies, and soluble CD44. In addition to multiple CIA- and PGIA
      related loci identified in previous studies, we have identified nine new CIA- and
      eight new PGIA-linked loci. Comprehensive statistical analysis demonstrated that
      IL-2 production, T cell proliferation, and IFN-gamma levels differed
      significantly between arthritic and nonarthritic animals in both CIA and PGIA
      populations. High levels of TNF-alpha, IFN-gamma, IL-2, and Ab production were
      detected in F(2) hybrids with CIA, whereas T cell proliferation, IL-2 and IFN
      gamma production, and a shift to IgG2a isotype were more characteristic of PGIA.
      Quantitative trait loci analysis demonstrated colocalization of numerous immune
      subtraits with arthritis-related traits. Quantitative trait loci on chromosomes
      5, 10, 17, 18, and X were found to control arthritis in both models.

PMID- 12594250
TI  - The Yaa mutation promoting murine lupus causes defective development of marginal
      zone B cells.
AB  - The accelerated development of systemic lupus erythematosus (SLE) in BXSB male
      mice is associated with the presence of an as yet unidentified mutant gene, Yaa
      (Y-linked autoimmune acceleration). In view of a possible role of marginal zone
      (MZ) B cells in murine SLE, we have explored whether the expression of the Yaa
      mutation affects the differentiation of MZ and follicular B cells, thereby
      implicating the acceleration of the disease. In this study, we show that both
      BXSB and C57BL/6 Yaa mice, including two different substrains of BXSB Yaa males
      that are protected from SLE, displayed an impaired development of MZ B cells
      early in life. Studies in bone marrow chimeras revealed that the loss of MZ B
      cells resulted from a defect intrinsic to B cells expressing the Yaa mutation.
      The lack of selective expansion of MZ B cells in diseased BXSB Yaa males strongly
      argues against a major role of MZ B cells in the generation of pathogenic
      autoantibodies in the BXSB model of SLE. Furthermore, a comparative analysis with
      mice deficient in CD22 or expressing an IgM anti-trinitrophenyl/DNA transgene
      suggests that the hyperreactive phenotype of Yaa B cells, as judged by a markedly
      increased spontaneous IgM secretion, is likely to contribute to the enhanced
      maturation toward follicular B cells and the block in the MZ B cell generation.

PMID- 12594251
TI  - A role for class A scavenger receptor in dendritic cell nibbling from live cells.
AB  - Monocyte-derived dendritic cells (DC) possess the unique capacity to capture Ag
      from live cells through intimate cell contact, a process referred to as nibbling.
      We sought to define the receptor(s) mediating DC nibbling. Uptake of
      fluorescently labeled plasma membrane from live cells by DC was inhibited by
      protease treatment and by a panel of polyanionic ligands, implicating scavenger
      receptors (SR) in this process. Differential expression of SR on DC and
      macrophages correlated with the capacity to acquire membrane from live cells.
      Internalized membrane colocalized with SR ligand and entered the endosomal
      pathway. DC very efficiently acquired and internalized gp100 tumor Ag expressed
      at the surface of viable adenocarcinoma cells via recombinant adenoviral
      infection. Cross-presentation of gp100 by DC to MHC class I-restricted T cells
      was inhibited by polyanionic SR ligand and an Ab to type A SR (SR-A), whereas Ab
      to the class B SR CD36, which mediates uptake of apoptotic cells, induced no
      inhibition. DC capture of fluorescently labeled membrane from live cells was
      partially blocked by SR-A-specific Ab, suggesting that other SR may also be
      contributing to nibbling. DC maturation resulted in a switch in expression from
      type II SR-A (SR-AII) to the SR-AI splice variant. Finally, SR-A was identified
      on interdigitating DC isolated from monkey lymph nodes. These findings define a
      novel role for SR-A, and suggest that Ag uptake from live cells by DC may be
      important in the generation of immunity and in the maintenance of peripheral
      tolerance in vivo.

PMID- 12594252
TI  - Inducible costimulatory molecule-B7-related protein 1 interactions are important
      for the clonal expansion and B cell helper functions of naive, Th1, and Th2 T
      cells.
AB  - Inducing T cell responses requires at least two distinct signals: 1) TCR
      engagement of MHC-peptide and 2) binding of CD28 to B7.1/2. However, the recent
      avalanche of newly described costimulatory molecules may represent additional
      signals which can modify events after the initial two-signal activation.
      Inducible costimulatory molecule (ICOS) is a CD28 family member expressed on T
      cells rapidly following activation that augments both Th1 and Th2 T cell
      responses and has been implicated in sustaining rather than initiating T cell
      responses. Although it is known that blockade of ICOS-B7-related protein 1 (B7RP
      1) in vivo dramatically reduces germinal center formation and Ab production, the
      mechanism(s) remains unclear. An optimal T cell-dependent Ab response requires T
      and B cell activation, expansion, differentiation, survival, and migration, and
      the ICOS-B7RP-1 interaction could be involved in any or all of these processes.
      Understanding this will have important implications for targeting ICOS-B7RP-1
      therapeutically. We have therefore used a double-adoptive transfer system, in
      which all of the above events can be analyzed, to assess the role of ICOS-B7RP-1
      in T cell help for B cell responses. We have shown that ICOS signaling is
      involved in the initial clonal expansion of primary and primed Th1 and Th2 cells
      in response to immunization. Furthermore, while ICOS-B7RP-1 interactions have no
      effect on the migration of T cells into B cell follicles, it is essential for
      their ability to support B cell responses.

PMID- 12594253
TI  - Induction of low dose oral tolerance in monocyte chemoattractant protein-1- and
      CCR2-deficient mice.
AB  - The chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2
      have been shown to play an important role in the migration and trafficking of
      macrophages and Th1 effector cells in experimental autoimmune encephalomyelitis.
      Also, MCP-1 has been reported to regulate oral tolerance induction by inhibition
      of Th1 cell-related cytokines and by the ability of Abs to MCP-1 to inhibit oral
      tolerance. This study demonstrates that neither MCP-1 nor its receptor CCR2 is
      required for the induction of oral tolerance. Mice deletional for either MCP-1 or
      CCR2 had suppressed cell-proliferative and Th1 responses following oral
      administration and immunization with myelin oligodendrocyte glycoprotein (MOG(35
      55)). TGF-beta was up-regulated in fed and immunized deletional mice, while IL-4
      was absent from deletional mice, but up-regulated in controls. Decreased
      experimental autoimmune encephalomyelitis severity was found in MOG(35-55)-fed
      MCP-1 deletional mice, indicating induction of oral tolerance. These results
      demonstrate that MCP-1 is not required for induction of oral tolerance and that
      MCP-1 and CCR2 are essential for up-regulation of IL-4 in tolerized mice.

PMID- 12594254
TI  - Heterogeneity of dendritic cells in the mouse liver: identification and
      characterization of four distinct populations.
AB  - Liver dendritic cells (DC) are believed to play important roles in liver
      immunity, autoimmunity, and in the regulation of hepatic allograft acceptance.
      However, limited information is available on the phenotypes and functions of DC
      in the liver. To address this issue, we isolated DC from murine liver using
      procedures that do not involve collagenase, and characterized the freshly
      isolated DC population that had not been subjected to in vitro expansion. Thence,
      based on the expression of CD4, B220, and CD11b, four subsets or groups of
      hepatic NK1.1(-)CD11c(+) DC were identified with the following phenotypes:
      B220(+)CD4(+), B220(+)CD4(-), B220(-)CD11b(+), and B220(-)CD11b(-). Each subset
      was further characterized both phenotypically and functionally. In addition to
      unique phenotypic expression, each subset displayed different allostimulation
      capability in mixed lymphocyte reaction assays. All four groups developed DC
      morphology following in vitro culture with activation agents and synthesized
      distinct patterns of cytokines in response to different stimuli. Taken together,
      our results suggest that groups I and II are IFN-alpha-producing plasmacytoid DC,
      group III cells are myeloid-related DC, while group IV is a heterogeneous
      population containing both myeloid- and lymphoid-related DC. Our results
      demonstrate the highly heterogeneous nature of hepatic DC, which is in agreement
      with the unique requirements for APC in the complex liver environment.

PMID- 12594255
TI  - Expression of complement 3 and complement 5 in newt limb and lens regeneration.
AB  - Some urodele amphibians possess the capacity to regenerate their body parts,
      including the limbs and the lens of the eye. The molecular pathway(s) involved in
      urodele regeneration are largely unknown. We have previously suggested that
      complement may participate in limb regeneration in axolotls. To further define
      its role in the regenerative process, we have examined the pattern of
      distribution and spatiotemporal expression of two key components, C3 and C5,
      during limb and lens regeneration in the newt Notophthalmus viridescens. First,
      we have cloned newt cDNAs encoding C3 and C5 and have generated Abs specifically
      recognizing these molecules. Using these newt-specific probes, we have found by
      in situ hybridization and immunohistochemical analysis that these molecules are
      expressed during both limb and lens regeneration, but not in the normal limb and
      lens. The C3 and C5 proteins were expressed in a complementary fashion during
      limb regeneration, with C3 being expressed mainly in the blastema and C5
      exclusively in the wound epithelium. Similarly, during the process of lens
      regeneration, C3 was detected in the iris and cornea, while C5 was present in the
      regenerating lens vesicle as well as the cornea. The distinct expression profile
      of complement proteins in regenerative tissues of the urodele lens and limb
      supports a nonimmunologic function of complement in tissue regeneration and
      constitutes the first systematic effort to dissect its involvement in
      regenerative processes of lower vertebrate species.

PMID- 12594256
TI  - Human heat shock protein 60 induces maturation of dendritic cells versus a Th1
      promoting phenotype.
AB  - Heat shock protein (HSP) 60 nonspecifically activates cells of the innate immune
      system. In the present study, we characterized the effects of human HSP60
      maturation, cytokine release, and T cell-activating capacity of bone marrow
      derived dendritic cells (DC). Furthermore, we analyzed HSP60-induced signal
      transduction in DC. HSP60 strongly stimulated DC for maturation and release of
      TNF-alpha, IL-12, and IL-1 beta. However, HSP60 elicited only a weak IL-10
      response in DC suggesting a Th1 bias. HSP60-treated DC induced proliferation of
      allogeneic T cells. Again, a Th1 bias was noted in that cocultures of allogeneic
      T cells and HSP60-treated DC released IFN-gamma but only small amounts of IL-10
      and no detectable IL-4. Signaling via Toll-like receptor 4 was involved in HSP60
      induced cytokine release and maturation because DC of C3H/HeJ mice with a mutant
      Toll-like receptor 4 showed deficient response to HSP60. HSP60 was found to
      rapidly activate the mitogen-activated protein kinases p38, c-Jun N-terminal
      kinase, and extracellular signal-regulated kinase as well as I kappa B in DC.
      Phosphorylation of these signaling molecules was also mediated by LPS, but with
      much slower kinetics. Thus, HSP60 stimulates DC more rapidly than LPS and elicits
      a Th1-promoting phenotype. These results suggest that DC play a pivotal role in
      priming for destructive Th1-type responses at sites of local HSP60 release.

PMID- 12594257
TI  - CD7 is a differentiation marker that identifies multiple CD8 T cell effector
      subsets.
AB  - The adaptive immune response of human CD8 T cells to invading pathogens involves
      the differentiation of naive cells into memory and effector cells. However, the
      lineage relationship between memory and effector cells and the differentiation of
      CD8 T cells into distinct subsets of effector cell subpopulations are subjects of
      considerable debate. CD7 identifies three populations of CD8 T cells: CD7 high
      (CD7(high)), low (CD7(low)), and negative (CD7(neg)) that translate into subsets
      with distinct functional properties. The CD7(high) subset contains naive and
      memory cells and the CD7(low) and CD7(neg) subsets contain effector cells. The
      effector cells can functionally be divided into cytokine-secreting effector CD8 T
      cells and lytic effector CD8 T cells. These data provide a model of human CD8 T
      cell differentiation in which specialized distinct subpopulations can be
      identified by expression of CD7.

PMID- 12594258
TI  - Growth factor independence-1B expression leads to defects in T cell activation,
      IL-7 receptor alpha expression, and T cell lineage commitment.
AB  - T cell differentiation in the thymus is dependent upon signaling through the TCR
      and is characterized by the resulting changes in expression patterns of CD4 and
      CD8 surface coreceptor molecules. Although recent studies have characterized the
      effects of proximal TCR signaling on T cell differentiation, the downstream
      integration of these signals remains largely unknown. The growth factor
      independence-1 (GFI1) and GFI1B transcriptional repressors may regulate cytokine
      signaling pathways to affect lymphocyte growth and survival. In this study, we
      show that Gfi1 expression is induced upon induction of the T cell program. Gfi1B
      expression is low and dynamic during T cell development, but is terminated in
      mature thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed us
      to determine the functional consequences of constitutive expression. GFI1
      potentiates response to TCR stimulation and IL-2, whereas GFI1B-transgenic T
      cells are defective in T cell activation. Moreover, GFI1B-transgenic thymocytes
      display reduced expression of the late-activation marker IL-7R alpha, and a
      decrease in CD4(-)8(+) single-positive T cells that can be mitigated by
      transgenic expression of BCL2 or GFI1. These data show that GFI1 and GFI1B are
      functionally unique, and implicate a role for GFI1 in the integration of
      activation and survival signals.

PMID- 12594259
TI  - Oligodeoxynucleotides without CpG motifs work as adjuvant for the induction of
      Th2 differentiation in a sequence-independent manner.
AB  - The outcomes of immune responses are regulated by various parameters including
      how Ags are handled by APCs. In this study, we describe the intrinsic
      immunomodulatory characteristics of oligodeoxynucleotides (ODNs) that improve the
      Ag presentation by APCs. ODNs (20-mer) containing CpG motifs induced strong Th1
      skewed responses. In contrast, those without CpG motifs enhanced cytokine
      production by effector Th cells without particular skewing toward Th1 responses
      or induced the differentiation of unprimed CD4(+) T cells toward Th2 cells. These
      functional features were prominently envisaged when ODNs were conjugated to the
      Ag, and were underlain by the facilitated binding of ODN-conjugated Ag to Ia(+)
      cells. Despite the functional differences between ODNs with CpG motifs and those
      without CpG motifs, both ODNs bound to Ia(+) cells with similar affinity and
      kinetics. Immunoenhancing activities of the ODNs were not sequence-dependent; the
      characteristics, including the facilitation of Ag capture, enhancement of
      effector Th cell responses, and induction of Th2 cells, were shared by randomly
      synthesized ODNs conjugated to Ag. This is the first study suggesting that ODNs,
      independent of the sequences, enhance immune responses through the promoted
      capture of ODN-conjugated Ag by APCs.

PMID- 12594260
TI  - Polycyclic aromatic hydrocarbons inhibit differentiation of human monocytes into
      macrophages.
AB  - Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are
      ubiquitous environmental carcinogenic contaminants exerting deleterious effects
      toward cells acting in the immune defense such as monocytic cells. To investigate
      the cellular basis involved, we have examined the consequences of PAH exposure on
      macrophagic differentiation of human blood monocytes. Treatment by BP markedly
      inhibited the formation of adherent macrophagic cells deriving from monocytes
      upon the action of either GM-CSF or M-CSF. Moreover, it reduced expression of
      macrophagic phenotypic markers such as CD71 and CD64 in GM-CSF-treated monocytic
      cells, without altering cell viability or inducing an apoptotic process. Exposure
      to BP also strongly altered functional properties characterizing macrophagic
      cells such as endocytosis, phagocytosis, LPS-triggered production of TNF-alpha
      and stimulation of allogeneic lymphocyte proliferation. Moreover, formation of
      adherent macrophagic cells was decreased in response to PAHs distinct from BP
      such as dimethylbenz(a)anthracene and 3-methylcholanthrene, which interact, like
      BP, with the arylhydrocarbon receptor (AhR) known to mediate many PAH effects. In
      contrast, benzo(e)pyrene, a PAH not activating AhR, had no effect. In addition,
      AhR was demonstrated to be present and functional in cultured monocytic cells,
      and the use of its antagonist alpha-naphtoflavone counteracted inhibitory effects
      of BP toward macrophagic differentiation. Overall, these data demonstrate that
      exposure to PAHs inhibits functional in vitro differentiation of blood monocytes
      into macrophages, likely through an AhR-dependent mechanism. Such an effect may
      contribute to the immunotoxicity of these environmental carcinogens owing to the
      crucial role played by macrophages in the immune defense.

PMID- 12594261
TI  - Primary and secondary immunocompetence in mixed allogeneic chimeras.
AB  - Targeted disruption of T cell costimulatory pathways, particularly CD28 and CD40,
      has allowed for the development of minimally myeloablative strategies for the
      induction of mixed allogeneic chimerism and donor-specific tolerance across full
      MHC barriers. In this study we analyze in depth the ability of mixed allogeneic
      chimeras in two strain combinations to mount effective host-restricted and donor
      restricted antiviral CD4 and CD8 responses, as well as the impact of development
      of mixed chimerism on the maintenance of pre-existing memory populations. While
      antiviral CD8 responses in mixed chimeras following acute viral infection with
      lymphocytic choriomeningitis virus Armstrong or vaccinia virus are largely host
      restricted, donor-restricted CD8 responses as well as host- and donor-restricted
      CD4 responses are also readily detected, and virus is promptly cleared. We
      further demonstrate that selection of donor-restricted T cells in mixed chimeras
      is principally mediated by bone marrow-derived cells in the thymus. Conversely,
      we find that mixed chimeras exhibit a deficit in their ability to deal with a
      chronic lymphocytic choriomeningitis virus clone 13 infection. Encouragingly, pre
      existing memory populations are largely unaffected by the development of high
      level mixed chimerism and maintain the ability to control viral rechallenge. Our
      results suggest that while pre-existing T cell memory and primary
      immunocompetence to acute infection are preserved in mixed allogeneic chimeras,
      MHC class I and/or class II tissue matching may be required to fully preserve
      immunocompetence in dealing with chronic viral infections.

PMID- 12594262
TI  - Human invariant V alpha 24-J alpha Q TCR supports the development of CD1d
      dependent NK1.1+ and NK1.1- T cells in transgenic mice.
AB  - A sizable fraction of T cells expressing the NK cell marker NK1.1 (NKT cells)
      bear a very conserved TCR, characterized by homologous invariant (inv.) TCR V
      alpha 24-J alpha Q and V alpha 14-J alpha 18 rearrangements in humans and mice,
      respectively, and are thus defined as inv. NKT cells. Because human inv. NKT
      cells recognize mouse CD1d in vitro, we wondered whether a human inv. V alpha 24
      TCR could be selected in vivo by mouse ligands presented by CD1d, thereby
      supporting the development of inv. NKT cells in mice. Therefore, we generated
      transgenic (Tg) mice expressing the human inv. V alpha 24-J alpha Q TCR chain in
      all T cells. The expression of the human inv. V alpha 24 TCR in TCR C alpha(-/-)
      mice indeed rescues the development of inv. NKT cells, which home preferentially
      to the liver and respond to the CD1d-restricted ligand alpha-galactosylceramide
      (alpha-GalCer). However, unlike inv. NKT cells from non-Tg mice, the majority of
      NKT cells in V alpha 24 Tg mice display a double-negative phenotype, as well as a
      significant increase in TCR V beta 7 and a corresponding decrease in TCR V beta
      8.2 use. Despite the forced expression of the human CD1d-restricted TCR in C
      alpha(-/-) mice, staining with mCD1d-alpha-GalCer tetramers reveals that the
      absolute numbers of peripheral CD1d-dependent T lymphocytes increase at most by 2
      fold. This increase is accounted for mainly by an increased fraction of NK1.1(-)
      T cells that bind CD1d-alpha-GalCer tetramers. These findings indicate that human
      inv. V alpha 24 TCR supports the development of CD1d-dependent lymphocytes in
      mice, and argue for a tight homeostatic control on the total number of inv. NKT
      cells. Thus, human inv. V alpha 24 TCR-expressing mice are a valuable model to
      study different aspects of the inv. NKT cell subset.

PMID- 12594263
TI  - Memory CD8+ T cells provide an early source of IFN-gamma.
AB  - During the non-Ag-specific early phase of infection, IFN-gamma is believed to be
      primarily provided by NK and NKT cells in response to pathogen-derived
      inflammatory mediators. To test whether other cell types were involved in early
      IFN-gamma release, IFN-gamma-producing cells were visualized in spleens and lymph
      nodes of LPS-injected mice. In addition to NK and NKT cells, IFN-gamma was also
      detected in a significant fraction of CD8(+) T cells. CD8(+) T cells represented
      the second major population of IFN-gamma-producing cells in the spleen (
      approximately 30%) and the majority of IFN-gamma(+) cells in the lymph nodes (
      approximately 70%). LPS-induced IFN-gamma production by CD8(+) T cells was MHC
      class I independent and was restricted to CD44(high) (memory phenotype) cells.
      Experiments performed with C3H/HeJ (LPS-nonresponder) mice suggested that CD8(+)
      T cells responded to LPS indirectly through macrophage/dendritic cell-derived IFN
      alpha/beta, IL-12, and IL-18. IFN-gamma was also detected in memory CD8(+) T
      cells from mice injected with type I IFN or with poly(I:C), a synthetic dsRNA
      that mimics early activation by RNA viruses. Taken together, these results
      suggest that in response to bacterial and viral products, memory T cells may
      contribute to innate immunity by providing an early non-Ag-specific source of IFN
      gamma.

PMID- 12594264
TI  - The 19-kDa Mycobacterium tuberculosis protein induces macrophage apoptosis
      through Toll-like receptor-2.
AB  - Macrophages infected with Mycobacterium tuberculosis undergo increased rates of
      apoptosis. Important objectives are to define the microbial factors that cause
      apoptosis, the mechanisms involved and the impact on infection. The 19-kDa M.
      tuberculosis glycolipoprotein (p19) is both cell wall-associated and secreted and
      is a candidate virulence factor. We investigated the potential of recombinant,
      His-tagged p19 lacking the secretion/acylation signal to induce macrophage
      apoptosis. The TUNEL assay and annexin V binding to membrane phosphatidylserine
      were used to measure apoptosis. The results show that p19 does act to induce
      apoptosis in differentiated THP-1 cells and monocyte-derived macrophages and that
      this effect is both dose- and time-dependent. Furthermore, this effect of p19 is
      Toll-like receptor (TLR)-2-mediated because preincubation of either THP-1 cells
      or TLR-2-expressing CHO cells with anti-TLR-2 mAb inhibited apoptosis induced by
      p19. Apoptosis of macrophages in response to p19 was found to be caspase-8
      dependent and caspase-9 independent consistent with a transmembrane pathway
      signaling cell death through TLR-2. The viability of M. tuberculosis in cells
      undergoing apoptosis induced by p19 was significantly reduced suggesting the
      possibility that this may favor containment of infection. Although native p19 is
      a mycobacterial glycolipoprotein, based upon the use of recombinant p19 where the
      acylation signal had been removed, we conclude that it is the polypeptide
      component of p19 that is responsible for signaling through TLR-2 and that the
      lipid moiety is not required.

PMID- 12594265
TI  - BATF transgenic mice reveal a role for activator protein-1 in NKT cell
      development.
AB  - The importance of regulated AP-1 activity during T cell development was assessed
      using transgenic mice overexpressing BATF, a basic leucine zipper transcription
      factor and an AP-1 inhibitor. BATF transgenic animals possess normal thymic
      cellularity and all major T cell subsets, but show impaired thymocyte
      proliferation in vitro and no induction of IL-2, IL-4, IL-5, IL-10, and IL-13
      expression. Since NKT cells are largely responsible for cytokine production in
      the thymus, this population was examined by detection of the V alpha 14-J alpha
      281 TCR, flow cytometry of NK1.1(+) TCR beta(+) cells, and analysis of cytokine
      production by heat-stable Ag(low) thymocytes and peripheral NKT cells stimulated
      in vivo. Results show a severe under-representation of NKT cells in BATF
      transgenic animals, providing the first evidence that the precise control of AP-1
      mediated transcription is critical for the proper emergence of thymus-derived NKT
      cells in the mouse.

PMID- 12594266
TI  - Role of TCR-induced extracellular signal-regulated kinase activation in the
      regulation of early IL-4 expression in naive CD4+ T cells.
AB  - Although extracellular signal-regulated kinase (Erk) activation influences IL-4
      production in various experimental systems, its role during Th differentiation is
      unclear. In this study, we show that Erk plays a critical role in IL-4 expression
      during TCR-induced Th differentiation of naive CD4(+) T cells. Stimulation of
      CD4(+) T cells with a high affinity peptide resulted in sustained Erk activation
      and Th1 differentiation. However, reduction of Erk activity led to a dramatic
      increase in IL-4 production and Th2 generation. Analysis of RNA and nuclear
      proteins of CD4(+) T cells 48 h after stimulation revealed that this was due to
      early IL-4 expression. Interestingly, transient Erk activation resulted in
      altered AP-1 DNA binding activity and the induction of an AP-1 complex that was
      devoid of Fos protein and consisted of Jun-Jun dimers. These data show that in
      the presence of a strong TCR signal, IL-4 expression can be induced in naive
      CD4(+) T cells by altering the strength of Erk activation. In addition, these
      data suggest that TCR-induced Erk activation is involved in the regulation of IL
      4 expression by altering the composition of the AP-1 complex and its subsequent
      DNA binding activity.

PMID- 12594267
TI  - Inhibition of Th2 differentiation and GATA-3 expression by BCL-6.
AB  - The B cell lymphoma (BCL)-6 transcriptional repressor protein is an important
      regulator of Th2 responses. Mice deficient in BCL-6 develop severe Th2-type
      inflammation that can develop even in the absence of IL-4 signaling. We have
      investigated the mechanism for how BCL-6 regulates Th2 cell differentiation and
      have found that IL-6 signaling can promote dramatically increased levels of Th2
      differentiation in BCL-6(-/-) CD4 T cells compared with wild-type CD4 T cells. IL
      6 can induce a low level of Th2 cytokine expression in BCL-6(-/-)STAT6(-/-) cells
      but not in STAT6(-/-) cells. Since the promoters for Th2 cytokines such as IL-4,
      IL-5, IL-10, and IL-13 do not contain consensus BCL-6 DNA binding sites, we
      investigated whether BCL-6 might regulate the GATA-3 transcription factor that
      activates the expression of multiple Th2 cytokines. Consistent with the idea that
      BCL-6 represses GATA-3 expression, we found that GATA-3 levels are up-regulated
      in BCL-6(-/-)STAT6(-/-) CD4 T cells compared with STAT6(-/-) CD4 T cells.
      Retrovirus-mediated expression of BCL-6 in BCL-6(-/-)STAT6(-/-) T cells as well
      as developing wild-type Th2 cells leads to a potent repression of IL-4 and IL-10
      secretion. Retrovirus-mediated expression of BCL-6 in both BCL-6(-/-)STAT6(-/-)
      and wild-type T cells also leads to a significant decrease in GATA-3 protein
      levels. Surprisingly, BCL-6 does not appear to regulate GATA-3 mRNA levels and
      thus BCL-6 appears to regulate GATA-3 expression at a posttranscriptional level.
      Regulation of GATA-3 protein levels is likely a key mechanism for how BCL-6
      regulates Th2 cytokine expression and Th2 differentiation independently of STAT6.
      These data also point to a novel regulatory mechanism for BCL-6 separate from
      transcriptional repression.

PMID- 12594268
TI  - Distinct thresholds for CD8 T cell activation lead to functional heterogeneity:
      CD8 T cell priming can occur independently of cell division.
AB  - To examine the bases for CD8 T cell functional heterogeneity, we analyzed
      responses to partial vs full agonist Ag. An extended period of interaction with
      APCs was required to set the threshold required for cell division in response to
      partial as compared with full agonist Ag. Acquisition of cytolytic function was
      restricted to the divided T cell population. In contrast, the threshold for
      commitment to produce IFN-gamma and express some activation markers appeared
      lower and independent of cell division. Indeed, we characterized a T cell
      population stimulated in response to the partial agonist that was committed to
      produce IFN-gamma, but failed to divide or secrete IL-2. Importantly, this
      activated nondivided population behaved as "primed" rather than "anergized,"
      indicating 1) that priming of CD8 T cells may be induced by suboptimal
      stimulation independent of cell division and 2) that encounter with Ag does not
      always induce a complete differentiation program in naive CD8 T cells, as
      previously reported.

PMID- 12594269
TI  - HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV
      infected individuals in the absence of markers of cellular activation or
      apoptosis.
AB  - Resting CD4(+) T cells containing integrated HIV provirus constitute one of the
      long-lived cellular reservoirs of HIV in vivo. This cellular reservoir of HIV had
      been thought to be quiescent with regard to virus replication based on the
      premise that HIV production in T cells is inexorably linked to cellular
      activation as determined by classical activation markers. The transition of T
      cells within this HIV reservoir from a resting state to an activated HIV
      producing state is believed to be associated with a shorten life span due to
      susceptibility to activation-associated apoptosis. Evidence is mounting, however,
      that HIV production may occur in T cells that have not undergone classic T cell
      activation. HIV encodes several proteins, including envelope and Nef, which
      trigger a variety of signaling pathways associated with cellular activation,
      thereby facilitating HIV replication in nondividing cells. The present study
      demonstrates that production of infectious virus from resting CD4(+) T cells
      isolated from HIV-infected individuals can be induced following exposure of these
      cells to HIV-1 recombinant (oligomeric gp140) envelope protein. Envelope-mediated
      induction of HIV expression occurs in the presence of reverse transcriptase
      inhibitors and is not associated with markers of classic T cell activation,
      proliferation, or apoptosis. The ability of HIV envelope to induce virus
      replication in HIV-infected resting CD4(+) T cells without triggering apoptosis
      provides a mechanism for the virus itself to directly participate in the
      maintenance of HIV production from this cellular reservoir.

PMID- 12594270
TI  - Inhibition of TCR-induced CD8 T cell death by IL-12: regulation of Fas ligand and
      cellular FLIP expression and caspase activation by IL-12.
AB  - In this study we demonstrate the anti-apoptotic effect of IL-12 and its
      underlying mechanism in CD8 T cells. The prolonged stimulation of CD8 T cells
      with anti-CD3 alone caused apoptosis mediated by Fas and the caspase signaling
      pathway. However, costimulation with IL-12 significantly prevented anti-CD3
      induced apoptosis of CD8 T cells. IL-12 decreased the number of Fas ligand
      positive CD8 T cells and inhibited the activation of caspase-8 and caspase-3. In
      addition, IL-12 up-regulated cellular FLIPs but not Bcl-2 family proteins or
      cellular inhibitor of apoptosis proteins. These data suggest that IL-12 provides
      survival signals to CD8 T cells by down-regulating Fas ligand and up-regulating
      cellular FLIPs, followed by inhibiting caspase activation, which implies a role
      for IL-12 in peripheral responses of CD8 T cells in vivo.

PMID- 12594271
TI  - Immediate early effector functions of virus-specific CD8+CCR7+ memory cells in
      humans defined by HLA and CC chemokine ligand 19 tetramers.
AB  - Memory T cells exhibit a high degree of heterogeneity in terms of their phenotype
      and functional characteristics. It has been proposed that the CCR7 chemokine
      receptor divides memory T cell populations into central memory T cells and
      effector memory T cells with distinct functions in secondary immune responses. We
      were interested whether this hypothesis holds true in experiments performed on Ag
      specific CD8(+) T cells. To identify CCR7(+) cells, we engineered a fluorescent
      ligand for CCR7; results with the new CC chemokine ligand 19 chemotetramer were
      verified by staining with a CCR7 mAb. Staining with the CC chemokine ligand 19
      chemotetramer reveals two subsets within CCR7(+) cells: a CCR7(int) population
      containing memory cells and a CCR7(high) population containing naive T cells.
      Phenotypic analysis of MHC class I/peptide tetramer-positive cells revealed that
      HLA-A2-restricted CMV-specific CD8 T cells exhibit the lowest percentage of
      CCR7(+) cells (0.5-5%), while HLA-A2-restricted flu- and HLA-B8-restricted EBV
      specific CD8 T cells showed the highest (45-70%). Intracellular staining of
      unstimulated cells revealed that both CCR7(int)- and CCR7(-)-specific CD8 T cells
      exhibit a detectable level of perforin. Both CCR7(int) and CCR7(-) Ag-specific
      CD8(+) T cells produced IFN-gamma and TNF-alpha following short-term peptide
      stimulation. Therefore, our finding that CCR7(+)CD8(+) T cells are able to exert
      immediate effector functions requires a substantial revision to the central and
      effector memory hypothesis.

PMID- 12594272
TI  - Glucocorticoid-induced apoptosis of thymocytes: requirement of proteasome
      dependent mitochondrial activity.
AB  - Thymocytes undergo negative and positive selection during development in the
      thymus. During this selection process, the majority of thymocytes are eliminated
      by apoptosis through signaling via TCR or die by neglect, possibly mediated
      through glucocorticoids. In this study, we report that thymocytes require
      molecular oxygen to undergo apoptosis induced by dexamethasone (DEX), a synthetic
      glucocorticoid, and treatment with N-acetyl-L-cysteine (NAC), a thiol
      antioxidant, inhibits thymocyte apoptosis in vivo as well as ex vivo. We detected
      elevated intracellular levels of hydrogen peroxide (H(2)O(2)) during DEX-induced
      apoptosis, which is reduced by NAC treatment, indicating that the elevated levels
      of intracellular H(2)O(2) are proapoptotic. We also show that loss of
      mitochondrial membrane potential, cytochrome c release, as well as caspase-3
      activation induced by DEX are attenuated by NAC treatment. We identified the
      production site for H(2)O(2) as the ubiquinone cycle at complex III of
      mitochondria by using various inhibitors of the mitochondrial electron transport
      chain, and we show that the cell death events mediated by mitochondria are also
      significantly reduced when the inhibitors were used. Through inhibition of the
      proteasome, we also show that the production of H(2)O(2) and the cell death
      events mediated by mitochondria are regulated by proteosomal activities in DEX
      induced thymocyte apoptosis. We conclude that in DEX-treated thymocytes, the
      increased production of H(2)O(2) originates from mitochondria and is proapoptotic
      for cell death mediated by mitochondria. We also conclude that all the apoptotic
      events mediated by mitochondria are regulated by proteasomes.

PMID- 12594273
TI  - Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus
      infected and uninfected rhesus macaques.
AB  - We determined average cellular turnover rates by fitting mathematical models to 5
      bromo-2'-deoxyuridine measurements in SIV-infected and uninfected rhesus
      macaques. The daily turnover rates of CD4(+) T cells, CD4(-) T cells, CD20(+) B
      cells, and CD16(+) NK cells in normal uninfected rhesus macaques were 1, 1, 2,
      and 2%, respectively. Daily turnover rates of CD45RA(-) memory T cells were 1%,
      and those of CD45RA(+) naive T cells were 0.5% for CD4(+) T cells and
      approximately 1% for CD4(-)CD45RA(+) T cells. In SIV-infected monkeys with high
      viral loads, the turnover rates of T cells were increased approximately 2-fold,
      and that of memory T cells approximately 3-fold. The turnover of CD4(+)CD45RA(+)
      naive T cells was increased 2-fold, whereas that of CD4(-)CD45RA(+) naive T cells
      was marginally increased. B cells and NK cells also had increased turnover in SIV
      infected macaques, averaging 3 and 2.5% per day, respectively. For all cell types
      studied here the daily turnover rate increased with the decrease of the CD4 count
      that accompanied SIV infection. As a consequence, the turnover rates of CD4(+) T
      cells, CD4(-) T cells, B cells, and NK cells within each monkey are strongly
      correlated. This suggests that the cellular turnover of different lymphocyte
      populations is governed by a similar process which one could summarize as
      "generalized immune activation." Because the viral load and the CD4 T cell count
      are negatively correlated we cannot determine which of the two plays the most
      important role in this generalized immune activation.

PMID- 12594274
TI  - IL-13 is necessary, not simply sufficient, for epicutaneously induced Th2
      responses to soluble protein antigen.
AB  - Th2 responses are clearly involved in the pathogenesis of atopic disease. Thus,
      understanding the factors responsible for Th2 sensitization at sites of allergen
      exposure, such as airway and skin, is crucial for directing therapeutic or
      preventive strategies. Contrary to other models of Th2 sensitization to proteins,
      we have reported that Th2 responses induced by epicutaneous exposure to OVA are
      IL-4 independent. Combined deficiency of both IL-4 and IL-13 signaling did
      prevent Th2 generation, suggesting that IL-13 was mediating these IL-4
      independent responses. It was not clear, however, whether IL-13 was simply
      replacing the need for IL-4 in genetically deficient mice or if IL-13 played a
      unique role. In the present study, we show that Th2 responses induced by
      epicutaneous OVA exposure (including lung inflammatory responses after inhaled Ag
      challenge, OVA-specific IgG1, and draining lymph node IL-5 production) are
      impaired in IL-13-deficient (IL-13(-/-)) mice compared with wild type. In
      contrast, i.p. sensitization of IL-13(-/-) mice resulted in responses equivalent
      to wild type. Generation of contact hypersensitivity to dinitrofluorobenzene,
      which involves Th1 and CD8(+) effector cells, was also intact in IL-13(-/-) mice.
      Taken together, the data indicate that IL-13 is the major inducer of Th2
      generation in the cutaneous microenvironment, being required independently of IL
      4. This fact, in combination with the known abundance of IL-13 in atopic
      dermatitis skin lesions, emphasizes the potentially important role of the skin as
      a site for Th2 sensitization to environmental allergens, particularly in atopic
      individuals.

PMID- 12594275
TI  - Long-term maintenance of gp120-specific immune responses by genetic vaccination
      with the HIV-1 envelope genes linked to the gene encoding Flt-3 ligand.
AB  - DNA vaccines target dendritic cells (DC) to induce Ag-specific immune responses
      in animals. Potent HIV-specific immunity could be achieved by efficient priming
      of the immune system by DNA vaccines. We investigated a novel DNA vaccine
      approach based on the role of growth factors in DC expansion and differentiation.
      To this end, we constructed chimeric genes encoding the HIV envelope
      glycoproteins physically linked to the extracellular domain of Fms-like tyrosine
      kinase receptor-3 ligand (FLex; a DC growth factor; both mouse (m)FLex and human
      (h)FLex). These chimeric gene constructs synthesized biologically active,
      oligomeric FLex:gp120 fusion proteins and induced DC expansion (CD11c(+)CD11b(+))
      when injected i.v. into mice. This DC expansion is comparable to that achieved by
      FLex DNA encoding native FLex protein. When delivered intramuscularly as DNA
      vaccines, hFLex:gp120 induced high frequencies of gp120-specific CD8(+) T cells
      in the presence or absence of FLex DNA-induced DC expansion, but gp120 and
      mFLex:gp120 elicited only low to moderate levels of Ag-specific CD8(+) T cells.
      In contrast, mFLex:gp120 induced high levels of anti-gp120 Abs under identical
      conditions of DNA vaccination. However, the Ab levels in mice immunized with DNA
      vaccines encoding hFLex:gp120 and gp120 proteins were low without DC expansion,
      but reached high levels comparable to that elicited by mFLex:gp120 only after the
      second boost in the presence of DC expansion. Importantly, the gp120-specific
      CD8(+) T cells persisted at high frequency for 114 days (16 wk) after a booster
      injection. These experiments provide insight into the importance of modulating DC
      function in vivo for effective genetic vaccination in animals.

PMID- 12594276
TI  - Regulatory CD8+ T cells control neonatal tolerance to a Th2-mediated
      autoimmunity.
AB  - Exposure of newborn animals to a foreign Ag may result in immunological tolerance
      to that specific Ag, a phenomenon called neonatal tolerance. We have previously
      reported that neonatal administration to Brown-Norway rats of mercury, a heavy
      metal toxicant, induces a dominant tolerance, specific for the chemical otherwise
      responsible for Th2 cell-mediated autoimmune responses in this susceptible strain
      of rats. Neonatal exposure to Ags can prime immunity, rather than inactivate or
      delete responses, and sustain regulatory functions effective against autoreactive
      T cells. Here, we address whether such a tolerant response is due to the
      generation of regulatory cells. The results suggest that the CD8(+) T cell subset
      is involved in neonatal tolerance to mercuric salt-induced Th2 autoimmune
      disease. Thus, we demonstrate that in vivo CD8 depletion breaks tolerance
      following mercury recall in animals under a neonatal tolerance protocol.
      Furthermore, adoptive cotransfer of splenocytes from naive and tolerant rats as
      well as transfer of CD8(+) T cells from tolerant animals prevent naive syngeneic
      rats from developing pathologic Th2 immune responses. These observations indicate
      that CD8(+) T cells are endowed with regulatory functions in neonatal tolerance
      and mediate active suppression. Moreover, neonatal tolerance induced the
      expansion of CD8(+)CD45RC(high) T cells and the emergence of a high percentage of
      IFN-gamma-synthesizing CD8(+) T cells, which probably reflects the implication of
      regulatory Tc1 cells. Thus, in vivo induction of neonatal tolerance suppresses
      Th2 autoimmune responses via generation of a CD8(+) cell-mediated regulatory
      response.

PMID- 12594277
TI  - CD4+CD25- T cells that express latency-associated peptide on the surface suppress
      CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism.
AB  - Murine CD4(+)CD25(+) regulatory cells have been reported to express latency
      associated peptide (LAP) and TGF-beta on the surface after activation, and exert
      regulatory function by the membrane-bound TGF-beta in vitro. We have now found
      that a small population of CD4(+) T cells, both CD25(+) and CD25(-), can be
      stained with a goat anti-LAP polyclonal Ab without being stimulated. Virtually
      all these LAP(+) cells are also positive for thrombospondin, which has the
      ability to convert latent TGF-beta to the active form. In the CD4(+)CD45RB(high)
      induced colitis model of SCID mice, regulatory activity was exhibited not only by
      CD25(+)LAP(+) and CD25(+)LAP(-) cells, but also by CD25(-)LAP(+) cells.
      CD4(+)CD25(-)LAP(+) T cells were part of the CD45RB(low) cell fraction.
      CD4(+)CD25(-)LAP(-)CD45RB(low) cells had minimal, if any, regulatory activity in
      the colitis model. The regulatory function of CD25(-)LAP(+) cells was abrogated
      in vivo by anti-TGF-beta mAb. These results identify a new TGF-beta-dependent
      regulatory CD4(+) T cell phenotype that is CD25(-) and LAP(+).

PMID- 12594278
TI  - Selective induction of high avidity CTL by altering the balance of signals from
      APC.
AB  - High avidity CTL are most effective at clearing viruses and cancer cells.
      Therefore, understanding the mechanisms involved in induction of high avidity CTL
      is critical for effective vaccines. However, no vaccine approach to selectively
      induce high avidity CTL in vivo has been discovered. In a new approach, signals
      from MHC class I (signal 1) and costimulatory molecules (signal 2) were adjusted
      by varying Ag dose and by use of recombinant poxvirus expressing a triad of
      costimulatory molecules (B7-1, ICAM-1, and LFA-3), respectively. Independent of
      CTL avidity, a strong signal 1 resulted in an increased frequency of CD8(+) CTL.
      However, a strong signal 2 was necessary for the induction of high avidity CD8(+)
      CTL that killed target cells more efficiently, and signal 2 played a more crucial
      role in the absence of a strong signal 1. Only CTL induced with strong signal 2
      killed tumor cells endogenously expressing low levels of Ag. Signal 2 contributed
      to the induction of high avidity CD8(+) CTL in both primary and secondary
      responses. Thus, although signal 2 has been known to increase the quantity of CTL
      response, in this study we show that it also improves the quality of CTL
      response. Our data also suggested that dendritic cells play an important role in
      induction of high avidity CD8(+) CTL in vivo. This strategy to selectively induce
      higher avidity CTL may lead to more effective vaccines for viruses and cancer.

PMID- 12594279
TI  - Role of the polymeric Ig receptor in mucosal B cell homeostasis.
AB  - Secretory IgA (SIgA) is the most characteristic component of the mucosal immune
      system and has long been considered the major protective factor that prevents
      pathogens from invading hosts through the mucosae. Recent studies, however, have
      suggested that complete immunity against a range of mucosal bacterial and viral
      pathogens can be achieved in the absence of IgA. Therefore, to further dissect
      the role of SIgA, we generated mice deficient in the polymeric Ig receptor (pIgR(
      /-) mice). As a result of an inability to transport dimeric IgA to the
      secretions, pIgR(-/-) mice are deficient in SIgA and accumulate circulating
      dimeric IgA, with serum levels 100-fold greater than those observed in normal
      mice. Examination of lamina propria mononuclear cells showed that pIgR(-/-) mice
      had approximately 3 times as many IgA-secreting cells as C57BL/6 mice. Further
      analysis showed that these cells displayed the differentiated IgA(+) B220(-)
      phenotype and accounted for a 2-fold increase in the number of lamina propria
      blast cells in the pIgR(-/-) mice. Subsequent experiments showed that OVA
      specific CD4(+) T cell expansion following OVA feeding was not elevated in pIgR(
      /-) mice. Furthermore, no differences in CD8(+) T cell tolerance or induction of
      influenza virus-specific CD8(+) T cells were detected in pIgR(-/-) mice compared
      with controls. Therefore, while SIgA is clearly involved in maintaining some
      parameters of mucosal homeostasis in the intestine, the mechanisms associated
      with its barrier function and the clinical consequences of its deficiency are yet
      to be identified.

PMID- 12594280
TI  - NKT cells provide help for dendritic cell-dependent priming of MHC class I
      restricted CD8+ T cells in vivo.
AB  - Dendritic cells (DC) are potent APCs for naive T cells in vivo. This is evident
      by inducing T cell responses through adoptive DC transfer. Priming specific CTL
      responses in vivo often requires "help". We study alternative sources of help in
      DC-dependent priming of MHC class I-restricted CTL. Priming an anti-viral CTL
      response in naive B6 mice by adoptive transfer of antigenic peptide-pulsed DC
      required CD4(+) T cell help. CTL priming was facilitated by providing MHC class
      II-dependent specific help. Furthermore, transfers of MHC class II-deficient
      pulsed DC into naive, normal hosts, or DC transfers into naive, CD4(+) T cell
      depleted hosts primed CTL inefficiently. Pretreatment of DC with immune
      stimulating oligodeoxynucleotides rendered them more efficient for CD4(+) T cell
      independent priming of CTL. DC copresenting a K(b)-binding antigenic peptide and
      the CD1d-binding glycolipid alpha-galactosyl-ceramide efficiently primed CTL in a
      class II-independent way. To obtain NKT cell-dependent help in CTL priming, the
      same DC had to present both the peptide and the glycolipid. CTL priming by
      adoptive DC transfer was largely NK cell-dependent. The requirement for NK cells
      was only partially overcome by recruiting NKT cell help into DC-dependent CTL
      priming. NKT cells thus are potent helper cells for DC-dependent CTL priming.

PMID- 12594281
TI  - Unique monoclonal antibodies define expression of Fc gamma RI on macrophages and
      mast cell lines and demonstrate heterogeneity among subcutaneous and other
      dendritic cells.
AB  - The mouse Fc gamma RI is one of the most fundamentally important FcRs. It
      participates in different stages of immunity, being a low affinity receptor for T
      independent IgG3 and yet a high affinity receptor for IgG2a, the product of a Th1
      immune response. However, analysis of this receptor has been difficult due
      largely to the failure to generate specific Abs to this FcR. We have made use of
      the polymorphic differences between BALB/c and NOD/Lt mice to generate mAb
      specific for the Fc gamma RI of BALB/c and the majority of in-bred mouse strains.
      Three different mAb were obtained that detected Fc gamma RI encoded by the more
      common Fcgr1(a) and Fcgr1(b) alleles, and although they identified different
      epitopes, none inhibited the binding of IgG to Fc gamma RI. When bound to Fc
      gamma RI, these mAb induced calcium mobilization upon cross-linking. Several
      novel observations were made of the cellular distribution of Fc gamma RI. Resting
      and IFN-gamma-induced macrophages expressed Fc gamma RI as well as mast cell
      lines. Both bone marrow-derived and freshly isolated dendritic cells from spleen
      and lymph nodes expressed Fc gamma RI. A class of DC, uniquely found in s.c.
      lymph nodes, expressed the highest level of Fc gamma RI and also high levels of
      MHC class II, DEC205, CD40, and CD86, with a low level of CD8 alpha,
      corresponding to the phenotype for Langerhans-derived DC, which are highly active
      in Ag processing. Thus, in addition to any role in effector functions, Fc gamma
      RI on APC may act as a link between innate and adaptive immunities by binding and
      mediating the uptake of T-independent immune complexes for presentation, thereby
      assisting in the development of T-dependent immune responses.

PMID- 12594282
TI  - Bone morphogenetic protein-7 inhibits constitutive and interleukin-1 beta-induced
      monocyte chemoattractant protein-1 expression in human mesangial cells: role for
      JNK/AP-1 pathway.
AB  - Bone morphogenetic protein-7 (BMP-7), which belongs to the TGF-beta superfamily,
      has been shown to reduce macrophage infiltration and tissue injury in animal
      models of inflammatory renal disease. To explore the mechanism involved in the
      anti-inflammatory effect, we investigated the effect of BMP-7 on monocyte
      chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells.
      BMP- 7 significantly inhibited constitutive and IL-1 beta-induced MCP-1 protein
      production and MCP-1 mRNA expression by mesangial cells in a time- and
      concentration-dependent manner. BMP-7 also inhibited IL-1 beta-induced monocyte
      chemotactic activity released from the mesangial cells. We examined the role of
      transcription factors NF-kappa B and AP-1 in BMP-7 inhibition of IL-1 beta
      induced MCP-1 expression. IL-1 beta increased NF-kappa B and AP-1 activity and
      both transcription factors mediated IL-1 beta-induced MCP-1 expression in
      mesangial cells. BMP-7 inhibited IL-1 beta-induced AP-1 activity in a
      concentration-dependent manner. In contrast, IL-1 beta-induced NF-kappa B
      activity and I kappa B alpha degradation were not affected by BMP-7. Furthermore,
      IL-1 beta-induced phosphorylation of c-Jun N-terminal kinase was inhibited by BMP
      7. These data suggest that BMP-7 inhibits constitutive and IL-1 beta-induced MCP
      1 expression in human mesangial cells partly by inhibiting c-Jun N-terminal
      kinase activity and subsequent AP-1 activity, and provide new insight into the
      therapeutic potential of BMP-7 in the inflammatory renal diseases.

PMID- 12594283
TI  - C/EBP alpha and Ets protein family members regulate the human myeloid IgA Fc
      receptor (Fc alpha R, CD89) promoter.
AB  - Fc alpha R (CD89), the FcR for IgA, is expressed exclusively in myeloid cells,
      including monocytes/macrophages, neutrophils, and eosinophils, and is thought to
      mediate IgA-triggered cellular functions in immunity. Here we demonstrate that
      the Fc alpha R 5'-flanking region from -102 to -64 relative to the ATG
      translation initiation codon is essential for promoter activity and contains two
      functional binding motifs for C/EBP and Ets family members at -74 and -92,
      respectively. EMSAs and cotransfection experiments show that C/EBP alpha acts as
      a major activator of the Fc alpha R promoter at least in immature myeloid cells.
      In addition, we found two additional functional targets of C/EBP alpha at -139
      and -127. On the other hand, the Fc alpha R Ets binding motif could bind Elf-1
      and mediate the trans-activation by cotransfected Elf-1, but a major component of
      the complex forming on this site appears to be an unidentified Ets-like nuclear
      protein that is preferentially detected in cells of hemopoietic origin.
      Furthermore, separation of the C/EBP and Ets binding sites reduces Fc alpha R
      promoter activity, suggesting some functional interaction between these factors.
      As the in vivo role of Fc alpha R is still incompletely defined, these findings
      reveal the features controlling the Fc alpha R promoter in myeloid lineage and
      provide a foundation for clarifying regulatory mechanisms of Fc alpha R gene
      expression associated with its potential roles.

PMID- 12594284
TI  - The T cell receptor beta locus of the channel catfish, Ictalurus punctatus,
      reveals unique features.
AB  - Previously, a series of clonal alloantigen-dependent T cell lines established
      from the channel catfish revealed distinctly different TCR beta rearrangements.
      Here, a follow-up study of the junctional diversity of these TCR gene
      rearrangements focuses on characterization of the genomic organization of the
      TCRB locus. Surprisingly, a total of 29 JB genes and two substantially different
      CB genes were identified downstream of a single DB gene. This is in contrast to
      the situation in mammals, where two clusters of a DB gene, six or seven JB genes,
      and a CB gene are found in tandem. The catfish CB genes are approximately 36%
      identical at the amino acid level. All 29 catfish JB gene segments appear
      functional. Thirteen were used in the 19 cDNAs analyzed, of these eight were used
      by the 11 catfish clonal alloantigen-dependent T cell lines. As might be
      expected, CDR3 diversity is enhanced by N-nucleotide additions as well as
      nucleotide deletions at the V-D and D-J junctions. Taken together, compared with
      that in mammals, genomic sequencing of the catfish TCR DB-JB-CB region reveals a
      unique locus containing a greater number of JB genes and two distinct CB genes.

PMID- 12594285
TI  - CD8-independent tumor cell recognition is a property of the T cell receptor and
      not the T cell.
AB  - The CD8 coreceptor enhances T cell function by stabilizing the TCR/peptide/MHC
      complex and/or increasing T cell avidity via interactions with the intracellular
      kinases Lck and LAT. We previously reported a CD4(+) T cell (TIL 1383I), which
      recognizes the tumor-associated Ag tyrosinase in the context of HLA-A2. To
      determine whether CD8 independent tumor cell recognition is a property of the
      TCR, we used retroviral transduction to express the TIL 1383I TCR in the CD8(-)
      murine lymphoma, 58 alpha(-)/beta(-). Immunofluorescent staining of TCR
      transduced cells with human TCR V beta subfamily-specific and mouse CD3-specific
      Abs confirmed surface expression of the transferred TCR and coexpression of mouse
      CD3. Transduced effector cells secreted significant amounts of IL-2 following Ag
      presentation by tyrosinase peptide-pulsed T2 cells as well as stimulation with
      HLA-A2(+) melanoma lines compared with T2 cells alone or HLA-A2(-) melanoma
      cells. Further analysis of TCR-transduced clones demonstrated a correlation
      between T cell avidity and cell surface expression of the TCR. Therefore, the TIL
      1383I TCR has sufficient affinity to mediate recognition of the physiologic
      levels of Ag expressed by tumor cells in the absence of CD8 expression.

PMID- 12594286
TI  - Differential kinetics and specificity of EBV-specific CD4+ and CD8+ T cells
      during primary infection.
AB  - The generation and maintenance of virus-specific CD4(+) T cells in humans are not
      well understood. We used short in vitro stimulation assays followed by
      intracellular cytokine staining to characterize the timing, magnitude, and Ag
      specificity of CD4(+) T cells over the course of primary EBV infection. Lytic and
      latent protein-specific CD4(+) T cells were readily detected at presentation with
      acute infectious mononucleosis and declined rapidly thereafter. Responses to BZLF
      1, BMLF-1, and Epstein-Barr nuclear Ag-3A were more commonly detected than
      responses to Epstein-Barr nuclear Ag-1. Concurrent analyses of BZLF-1-specific
      CD4(+) and CD8(+) T cells revealed differences in the expansion, specificity, and
      stability of CD4(+) and CD8(+) T cell-mediated responses over time. Peripheral
      blood EBV load directly correlated with the frequency of EBV-specific CD4(+) T
      cell responses at presentation and over time, suggesting that EBV-specific CD4(+)
      T cell responses are Ag-driven.

PMID- 12594287
TI  - Prime boost vaccination strategies: CD8 T cell numbers, protection, and Th1 bias.
AB  - Vaccination strategies involving priming with DNA and boosting with a poxvirus
      vector have emerged as a preferred combination for the induction of protective
      CD8 T cell immunity. Using IFN-gamma ELISPOT and a series of DNA plasmid,
      peptide, and modified vaccinia Ankara (MVA) vaccine combinations, we demonstrate
      that the DNA/MVA combination was uniquely able to enhance IFN-gamma secretion by
      Ag-specific CD8 T cells. However, CD8 T cell populations induced by DNA/MVA
      vaccination failed to show an enhanced capability to mediate protection in an IFN
      gamma-independent influenza challenge model. The DNA/MVA vaccine strategy was
      also not unique in its ability to induce high numbers of CD8 T cells, with
      optimal strategies simply requiring the use of vaccine modalities that
      individually induce high numbers of CD8 T cells. These experiments argue that
      rivals to DNA/poxvirus vaccination strategies for the induction of optimal
      protective CD8 T cell responses are likely to emerge.

PMID- 12594288
TI  - Reduced CTL response and increased viral burden in substance P receptor-deficient
      mice infected with murine gamma-herpesvirus 68.
AB  - One component of the protective host response against mucosal pathogens includes
      the local production and increased expression of certain neuropeptides and their
      receptors. The present study further demonstrates this fact by investigating the
      contribution that substance P receptor expression makes toward immunity against a
      gamma-herpesvirus infection. Following intragastric inoculation with murine gamma
      herpesvirus 68 (gamma HV-68), expression of substance P and its receptor was
      increased in mucosal and peripheral lymphoid organs in wild-type strains of mice.
      These results suggested that this receptor/ligand pair might be an important
      component of the host response against this viral infection. Such a hypothesis
      was supported by the demonstration that mice, genetically deficient in substance
      P receptor expression, showed an increased viral burden when compared with
      syngeneic C57BL/6 mice. Furthermore, substance P receptor-deficient mice showed a
      reduced CTL response against gamma HV-68, suggesting a mechanism to explain this
      increased viral burden. Such limitations in the Ag-specific CTL response in
      substance P receptor-deficient mice could result from lowered expression of IL-12
      during viral infection. Consistent with this hypothesis, increases in mRNA
      encoding IL-12 and secretion of this cytokine into sera of infected, wild-type
      animals were markedly reduced in substance P receptor-deficient mice. These
      studies demonstrate that genetic elimination of substance P receptors in mice
      results in an increased gamma-herpesvirus burden and an altered host response.

PMID- 12594289
TI  - Activation of TGF-beta by Leishmania chagasi: importance for parasite survival in
      macrophages.
AB  - TGF-beta is a potent regulatory cytokine that suppresses expression of inducible
      NO synthase and IFN-gamma, and suppresses Th1 and Th2 cell development. We
      examined whether functionally active TGF-beta is present in the local environment
      surrounding the invading protozoan Leishmania chagasi. Our prior data showed that
      TGF-beta levels are significantly increased in L. chagasi-infected mice. In the
      current study, we found TGF-beta was also abundant in bone marrows of humans with
      acute visceral leishmaniasis but not in those of uninfected controls.
      Furthermore, L. chagasi infection caused an increase in biologically active TGF
      beta in human macrophage cultures without changing the total TGF-beta. Therefore,
      we investigated the means through which leishmania could augment activated but
      not total TGF-beta. Incubation of latent TGF-beta with Leishmania sp.
      promastigotes caused active TGF-beta to be released from the latent complex. In
      contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate
      TGF-beta. TGF-beta activation by leishmania was prevented by inhibitors of
      cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic
      concentrations of TGF-beta inhibited killing of intracellular L. chagasi in
      macrophages, although the phagocytosis-induced respiratory burst remained intact.
      In contrast, supraphysiologic concentrations of TGF-beta had no effect on
      parasite survival. We hypothesize that the combined effect of abundant TGF-beta
      stores at extracellular sites during infection, and the ability of the parasite
      to activate TGF-beta in its local environment, leads to high levels of active TGF
      beta in the vicinity of the infected macrophage. Locally activated TGF-beta
      could, in turn, enhance parasite survival through its effects on innate and
      adaptive immune responses.

PMID- 12594290
TI  - Severe impairment in early host defense against Listeria monocytogenes in mice
      deficient in acid sphingomyelinase.
AB  - The phagolysosomal compartment is crucial for the defense against infection with
      intracellular pathogens. Within this compartment, the TNF- and IFN-gamma
      responsive acid sphingomyelinase (ASMase) generates the signaling molecule
      ceramide, resulting in the activation of proteases like cathepsin D. To
      investigate the possible role of ASMase as a mediator of the antibacterial
      effects of TNF and IFN-gamma, ASMase(-/-) mice were infected with Listeria
      monocytogenes. ASMase(-/-) mice showed a dramatically increased susceptibility to
      L. monocytogenes (LD(50) approximately 100 CFU) when compared with syngeneic wild
      type mice (LD(50) approximately 10,000 CFU). In L. monocytogenes-challenged
      ASMase(-/-) mice, IFN-gamma serum levels as well as IL-1 beta and IL-6 secretion
      by macrophages were similar to those observed in wild-type C57BL/6 mice. Although
      macrophages and granulocytes from ASMase(-/-) mice showed intact production of
      reactive nitrogen intermediates and oxidative burst, ASMase(-/-) macrophages
      proved completely incapable of restricting the growth of L. monocytogenes in
      vitro. The results of this study suggest that ASMase is crucially required for
      the intracellular control of L. monocytogenes in macrophages and granulocytes by
      nonoxidative mechanisms.

PMID- 12594291
TI  - HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells.
AB  - The integrity of the blood-brain barrier (BBB) is critical for normal brain
      function. Neuropathological abnormalities in AIDS patients have been associated
      with perivascular HIV-infected macrophages, gliosis, and abnormalities in the
      permeability of the BBB. The processes by which HIV causes these pathological
      conditions are not well understood. To characterize the mechanism by which HIV-1
      Tat protein modulates human brain microvascular endothelial cell (HBMEC)
      functions, we studied the effects of HIV-1 Tat in modulating HBMEC apoptosis and
      permeability. Treatment of HBMEC with HIV-1 Tat led to Flk-1/KDR and Flt-4
      receptor activation and the release of NO. The protein levels of endothelial NO
      synthase (NOS) and inducible NOS were increased by HIV-1 Tat stimulation.
      Importantly, HIV-1 Tat caused apoptosis of HBMEC, as evidenced by changes in the
      cleavage of poly(A)DP-ribose polymerase, DNA laddering, and incorporation of
      fluorescein into the nicked chromosomal DNA (TUNEL assay). HIV-1 Tat-mediated
      apoptosis in HBMEC was significantly inhibited in the presence of N-nitro-L
      arginine methyl ester (an inhibitor of NOS) and wortmannin (a phosphoinositol 3
      kinase inhibitor). Furthermore, HIV-1 Tat treatment significantly increased HBMEC
      permeability, and pretreatment with both N-nitro-L-arginine methyl ester and
      wortmannin inhibited the Tat-induced permeability. Taken together, these results
      indicate that dysregulated production of NO by HIV-1 Tat plays a pivotal role in
      brain endothelial injury, resulting in the irreversible loss of BBB integrity,
      which may lead to enhanced infiltration of virus-carrying cells across the BBB.

PMID- 12594292
TI  - Up-regulation of proteinase-activated receptor 1 expression in astrocytes during
      HIV encephalitis.
AB  - Proteinase-activated receptor 1 (PAR-1) is a G protein-coupled receptor that is
      activated by thrombin and is implicated in the pathogenesis of inflammation.
      Although PAR-1 is expressed on immunocompetent cells within the brain such as
      astrocytes, little is known about its role in the pathogenesis of inflammatory
      brain diseases. Herein, we investigated PAR-1 regulation of brain inflammation by
      stimulating human astrocytic cells with thrombin or the selective PAR-1
      activating peptide. Activated cells expressed significantly increased levels of
      IL-1 beta, inducible NO synthase, and PAR-1 mRNA. Moreover, supernatants of these
      same cells were neurotoxic, which was inhibited by an N-methyl-D-aspartate
      receptor antagonist. Striatal implantation of the PAR-1-activating peptide
      significantly induced brain inflammation and neurobehavioral deficits in mice
      compared with mice implanted with the control peptide or saline. Since HIV
      related neurological disease is predicated on brain inflammation and neuronal
      injury, the expression of PAR-1 in HIV encephalitis (HIVE) was investigated.
      Immunohistochemical analysis revealed that PAR-1 and (pro)-thrombin protein
      expression was low in control brains, but intense immunoreactivity was observed
      on astrocytes in HIVE brains. Similarly, PAR-1 and thrombin mRNA levels were
      significantly increased in HIVE brains compared with control and multiple
      sclerosis brains. These data indicated that activation and up-regulation of PAR-1
      probably contribute to brain inflammation and neuronal damage during HIV-1
      infection, thus providing new therapeutic targets for the treatment of HIV
      related neurodegeneration.

PMID- 12594293
TI  - Essential role of phosphoinositide 3-kinase delta in neutrophil directional
      movement.
AB  - Neutrophil chemotaxis is a critical component of the innate immune response.
      Neutrophils can sense an extremely shallow gradient of chemoattractants and
      produce relatively robust chemotactic behavior. This directional migration
      requires cell polarization with actin polymerization occurring predominantly in
      the leading edge. Synthesis of phosphatidylinositol (3,4,5) trisphosphate (PIP3)
      by phosphoinositide 3-kinase (PI3K) contributes to asymmetric F-actin synthesis
      and cell polarization during neutrophil chemotaxis. To determine the contribution
      of the hemopoietic cell-restricted PI3K delta in neutrophil chemotaxis, we have
      developed a potent and selective PI3K delta inhibitor, IC87114. IC87114 inhibited
      polarized morphology of neutrophils, fMLP-stimulated PIP3 production and
      chemotaxis. Tracking analysis of IC87114-treated neutrophils indicated that PI3K
      delta activity was required for the directional component of chemotaxis, but not
      for random movement. Inhibition of PI3K delta, however, did not block F-actin
      synthesis or neutrophil adhesion. These results demonstrate that PI3K delta can
      play a selective role in the amplification of PIP3 levels that lead to neutrophil
      polarization and directional migration.

PMID- 12594294
TI  - IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of
      the receptor activator of NF-kappa B ligand/osteoprotegerin balance.
AB  - IL-17 is a T cell-derived proinflammatory cytokine in experimental arthritis and
      is a stimulator of osteoclastogenesis in vitro. In this study, we report the
      effects of IL-17 overexpression (AdIL-17) in the knee joint of type II collagen
      immunized mice on bone erosion and synovial receptor activator of NF-kappa B
      ligand (RANKL)/receptor activator of NF-kappa B/osteoprotegerin (OPG) expression.
      Local IL-17 promoted osteoclastic bone destruction, which was accompanied with
      marked tartrate-resistant acid phosphatase activity at sites of bone erosion in
      cortical, subchondral, and trabecular bone. Accelerated expression of RANKL and
      its receptor, receptor activator of NF-kappa B, was found in the synovial
      infiltrate and at sites of focal bone erosion, using specific
      immunohistochemistry. Interestingly, AdIL-17 not only enhanced RANKL expression
      but also strongly up-regulated the RANKL/OPG ratio in the synovium. Comparison of
      arthritic mice from the AdIL-17 collagen-induced arthritis group with full-blown
      collagen-arthritic mice having similar clinical scores for joint inflammation
      revealed lower RANKL/OPG ratio and tartrate-resistant acid phosphatase activity
      in the latter group. Interestingly, systemic OPG treatment prevented joint damage
      induced by local AdIL-17 gene transfer in type II collagen-immunized mice. These
      findings suggest T cell IL-17 to be an important inducer of RANKL expression
      leading to loss of the RANKL/OPG balance, stimulating osteoclastogenesis and bone
      erosion in arthritis.

PMID- 12594295
TI  - Activation of peroxisome proliferator-activated receptors in human airway smooth
      muscle cells has a superior anti-inflammatory profile to corticosteroids:
      relevance for chronic obstructive pulmonary disease therapy.
AB  - Airway smooth muscle is actively involved in the inflammatory process in diseases
      such as chronic obstructive pulmonary disease and asthma by 1) contributing to
      airway narrowing through hyperplasia and hypertrophy and 2) the release of GM-CSF
      and G-CSF, which promotes the survival and activation of infiltrating leukocytes.
      Thus, the identification of novel anti-inflammatory pathways in airway smooth
      muscle will have important implications for the treatment of inflammatory airway
      disease. This study identifies such a pathway in the activation of peroxisome
      proliferator-activated receptors (PPARs). PPAR ligands are known therapeutic
      agents in the treatment of diabetes; however, their role in human airway disease
      is unknown. We demonstrate, for the first time, that human airway smooth muscle
      cells express PPAR alpha and -gamma subtypes. Activation of PPAR gamma by natural
      and synthetic ligands inhibits serum-induced cell growth more effectively than
      does the steroid dexamethasone, and induces apoptosis. Moreover, PPAR gamma
      activation, like dexamethasone, inhibits the release of GM-CSF. However, PPAR
      gamma ligands, but not dexamethasone, similarly inhibits G-CSF release. These
      results reveal a novel anti-inflammatory pathway in human airway smooth muscle,
      where PPAR gamma activation has additional anti-inflammatory effects to those of
      steroids. Hence, PPAR ligands might act as potential treatments in human
      respiratory diseases.

PMID- 12594296
TI  - Divergence of mechanisms regulating respiratory burst in blood and sputum
      eosinophils and neutrophils from atopic subjects.
AB  - Eosinophil respiratory burst is an important event in asthma and related
      inflammatory disorders. However, little is known concerning activation of the
      respiratory burst NADPH oxidase in human eosinophils. Conversely, neutrophils are
      known to assemble NADPH oxidase in intracellular and plasma membranes. We
      hypothesized that eosinophils and neutrophils translocate NADPH oxidase to
      distinct intracellular locations, consistent with their respective functions in
      O(2)(-)-mediated cytotoxicity. PMA-induced O(2)(-) release assayed by cytochrome
      c was 3.4-fold higher in atopic human eosinophils than in neutrophils, although
      membrane-permeable dihydrorhodamine-123 showed similar amounts of release.
      Eosinophil O(2)(-) release was dependent on Rac, in that it was 54% inhibited by
      Clostridium difficile toxin B (400-800 ng/ml). In eosinophils stimulated with
      PMA, a pronounced shift of cytosolic Rac to p22(phox)-positive plasma membrane
      was observed by confocal microscopy, whereas neutrophils directed Rac2 mainly to
      intracellular sites coexpressing p22(phox). Similarly, ex vivo sputum eosinophils
      from asthmatic subjects exhibited predominantly plasma membrane-associated
      immunoreactivity for Rac, whereas sputum neutrophils exhibited cytoplasmic Rac2
      staining. Thus, activated sputum eosinophils, rather than neutrophils, may
      contribute significantly to the pathogenesis of asthma by extracellular release
      of tissue-damaging O(2)(-). Our findings suggest that the differential modes of
      NADPH oxidase assembly in these cells may have important implications for oxidant
      mediated tissue injury.

PMID- 12594297
TI  - Synthesis and secretion of monocyte chemotactic protein-1 stimulated by the high
      affinity receptor for IgE.
AB  - In prior studies aggregation of the high affinity receptors for IgE, Fc epsilon
      RI, on a rat mast cell line, RBL-2H3, stimulated transcription of the gene for
      monocyte chemotactic protein-1 (MCP-1) and secretion of the protein.
      Unexpectedly, those delayed events appeared much less constrained by kinetic
      proofreading than had been documented for other receptor-initiated responses. The
      results of the present experiments are consistent with the proposal that the
      biosynthesis and secretion of MCP-1 result from a soluble messenger formed in the
      reaction cascades initiated by the receptor, and that Ca(2+) could serve as that
      messenger. Interestingly, whereas receptor-mediated signals were required for
      transcription of the gene for MCP-1 and secretion of the chemokine, such signals
      were not required for the intervening step of translation of its mRNA.

PMID- 12594298
TI  - Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit human neutrophil
      migration: comparisons between synthetic 15 epimers in chemotaxis and
      transmigration with microvessel endothelial cells and epithelial cells.
AB  - Lipoxins (LX) are bioactive eicosanoids that can be formed during cell to cell
      interactions in human tissues to self limit key responses in host defense and
      promote resolution. Aspirin treatment initiates biosynthesis of carbon 15
      epimeric LXs, and both series of epimers (LX and aspirin-triggered 15-epi-LX)
      display counter-regulatory actions with neutrophils. In this study, we report
      that synthetic lipoxin A(4) (LXA(4)) and 15-epi-LXA(4) (i.e., 15(R)-LXA(4) or
      aspirin-triggered LXA(4)) are essentially equipotent in inhibiting human
      polymorphonuclear leukocytes (PMN) in vitro chemotaxis in response to leukotriene
      B(4), with the maximum inhibition ( approximately 50% reduction) obtained at 1 nM
      LXA(4). At higher concentrations, 15-epi-LXA(4) proved more potent than LXA(4) as
      its corresponding carboxyl methyl ester. Also, exposure of PMN to LXA(4) and 15
      epi-LXA(4) markedly decreased PMN transmigration across both human microvessel
      endothelial and epithelial cells, where 15-epi-LXA(4) was more active than LXA(4)
      at "stopping" migration across epithelial cells. Differences in potency existed
      between LXA(4) and 15-epi-LXA(4) as their carboxyl methyl esters appear to arise
      from cell type-specific conversion of their respective carboxyl methyl esters to
      their corresponding carboxylates as monitored by liquid chromatography tandem
      mass spectrometry. Both synthetic LXA(4) and 15-epi-LXA(4) as free acids activate
      recombinant human LXA(4) receptor (ALXR) to regulate gene expression, whereas the
      corresponding methyl ester of LXA(4) proved to be a partial ALXR antagonist and
      did not effectively regulate gene expression. These results demonstrate the
      potent stereospecific actions shared by LXA(4) and 15-epi-LXA(4) for activating
      human ALXR-regulated gene expression and their ability to inhibit human PMN
      migration during PMN vascular as well as mucosal cell to cell interactions.

PMID- 12594299
TI  - Anti-idiotype x anti-LFA-1 bispecific antibodies inhibit metastasis of B cell
      lymphoma.
AB  - Abs to adhesion molecules can block tumor metastasis. However, they may also
      block the function of normal cells. To circumvent this adverse effect, we
      proposed the use of bispecific Abs that bind simultaneously to an adhesion
      receptor and to a tumor-specific Ag. Such Abs bind more avidly to tumor cells
      that coexpress both target Ags than to normal cells. The Id of the surface Ig of
      malignant B lymphocytes is a tumor-specific Ag. We therefore produced a
      bispecific Ab with specificity to the adhesion molecule LFA-1 and to the Id of
      the murine B cell lymphoma 38C-13. Here we demonstrate that this Ab blocked liver
      metastasis in mice carrying primary s.c. tumors and partially inhibited lymph
      node metastasis. Migration of 38C-13 cells to liver and lymph nodes was inhibited
      by the bispecific Ab, while migration to spleen was not affected. Hence, the
      bispecific Ab-mediated reduction in liver and lymph node metastasis resulted at
      least in part from reduced homing to these organs. In contrast to anti-LFA-1
      monospecific Abs, the anti-Id x anti-LFA-1 bispecific Ab did not affect immune
      responses such as delayed-type hypersensitivity. Hence, bispecific Abs against
      adhesion molecules and against tumor-specific Ags may selectively block tumor
      metastasis in a way that may leave much of the immune system intact.

PMID- 12594300
TI  - High expression of Fas ligand by synovial fluid-derived gamma delta T cells in
      Lyme arthritis.
AB  - Gamma delta T cells accumulate at epithelial barriers and at sites of
      inflammation in various infectious and autoimmune diseases, yet little is
      understood about the function of tissue-infiltrating gamma delta T cells. We
      observe that gamma delta T cells of the V delta 1 subset accumulate in synovial
      fluid of human Lyme arthritis and are intensely cytolytic toward a wide array of
      target cells. Particularly striking is that the cytolytic activity is highly
      prolonged, lasting for at least 3 wk after stimulation of the gamma delta T cells
      with Borrelia burgdorferi. Cytolysis is largely Fas dependent and results from
      very high and prolonged expression of surface Fas ligand, which is
      transcriptionally regulated. This also manifests in a substantial level of self
      induced apoptosis of the gamma delta T cells. In this capacity, certain gamma
      delta T cell subsets may serve as cytolytic sentinels at sites of inflammation,
      and perhaps at epithelial barriers.

PMID- 12594301
TI  - T cell repertoire development in humans with SCID after nonablative allogeneic
      marrow transplantation.
AB  - Transplantation of HLA-identical or haploidentical T cell-depleted allogeneic
      bone marrow (BM) into SCID infants results in thymus-dependent T cell development
      in the recipients. Immunoscope analysis of the TCR V beta repertoire was
      performed on 15 SCID patients given BM transplants. Before and within the first
      100 days after bone marrow transplantation (BMT), patients' PBMC displayed an
      oligoclonal or skewed T cell repertoire, low TCR excision circles (TREC) values,
      and a predominance of CD45RO(+) T cells. In contrast, the presence of high
      numbers of CD45RA(+) cells in the circulation of SCID patients >100 days post-BMT
      correlated with active T cell output by the thymus as revealed by high TREC
      values and a polyclonal T cell repertoire demonstrated by a Gaussian distribution
      of V beta-specific peaks. Ten years after BMT, we observed a decrease of the
      normal polyclonal T cell repertoire and an increase of a more skewed T cell
      repertoire. A decline of TREC levels and a decrease in the number of CD45RA(+)
      cells beyond 10 years after BMT was concomitant with the detection of oligoclonal
      CD3(+)CD8(+)CD45RO(+) cells. The switch from a polyclonal to a more skewed
      repertoire, observed in the CD3(+)CD8(+)CD45RO(+) T cell subset, is a phenomenon
      that occurs normally with decreased thymic output during aging, but not as
      rapidly as in this patient population. We conclude that a normal T cell
      repertoire develops in SCID patients as a result of thymic output and the
      repertoire remains highly diverse for the first 10 years after BMT. The TCR
      diversity positively correlates in these patients with TREC levels.

PMID- 12594302
TI  - Celiac disease association with CD8+ T cell responses: identification of a novel
      gliadin-derived HLA-A2-restricted epitope.
AB  - One of the diagnostic hallmarks of the histological lesions associated with
      celiac disease is the extensive infiltration of the small intestinal epithelium
      by CD8(+) T cells of unknown Ag specificity. In this study, we report recognition
      of the gliadin-derived peptide (A-gliadin 123-132) by CD8(+) T lymphocytes from
      celiac patients. A-gliadin 123-132-specific IFN-gamma production and cytotoxic
      activity were detected in PBMCs derived from patients on gluten-free diet, but
      not from either celiac patients on gluten-containing diet or healthy controls. In
      contrast, A-gliadin 123-132-specific cells were isolated from small intestine
      biopsies of patients on either gluten-free or gluten-containing diets. Short-term
      T cell lines derived from the small intestinal mucosa and specific for the 123
      132 epitope recognized human APC pulsed with either whole recombinant alpha
      gliadin or a partial pepsin-trypsin gliadin digest. Finally, we speculate on a
      possible mechanism leading to processing and presentation of class I-restricted
      gliadin-derived epitopes in celiac disease patients.

PMID- 12594303
TI  - Synergistic anti-tumor responses after administration of agonistic antibodies to
      CD40 and IL-2: coordination of dendritic and CD8+ cell responses.
AB  - In cancer, the coordinate engagement of professional APC and Ag-specific cell
      mediated effector cells may be vital for the induction of effective antitumor
      responses. We speculated that the enhanced differentiation and function of
      dendritic cells through CD40 engagement combined with IL-2 administration to
      stimulate T cell expansion would act coordinately to enhance the adaptive immune
      response against cancer. In mice bearing orthotopic metastatic renal cell
      carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither
      agent administered alone, induced complete regression of metastatic tumor and
      specific immunity to subsequent rechallenge in the majority of treated mice. The
      combination of anti-CD40 and IL-2 resulted in significant increases in dendritic
      cell and CD8(+) T cell number in advanced tumor-bearing mice compared with either
      agent administered singly. The antitumor effects of anti-CD40 and IL-2 were found
      to be dependent on CD8(+) T cells, IFN-gamma, IL-12 p40, and Fas ligand. CD40
      stimulation and IL-2 may therefore be of use to promote antitumor responses in
      advanced metastatic cancer.

PMID- 12594304
TI  - Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized
      with Salmonella enterica serovar typhi strain CVD 908-htrA.
AB  - Type 1 cell-mediated immunity might play an important role in protection from
      typhoid fever. We evaluated whether immunization with Salmonella enterica serovar
      Typhi (S. Typhi) strain CVD 908-htrA (a Delta aroC Delta aroD Delta htrA mutant),
      a leading live oral typhoid vaccine candidate, elicits specific CD4(+) and CD8(+)
      S. Typhi immune responses. Potent CTL responses and IFN-gamma secretion by CD8(+)
      T cells were detected following immunization with CVD 908-htrA in high (4.5 x
      10(8) CFU) and low (5 x 10(7) CFU) dosages. S. Typhi-specific CTL were observed
      in six of eight vaccinees (four high and two low dose) after immunization. Mean
      increases in the frequency of IFN-gamma spot-forming cells (SFC) in the presence
      of S. Typhi-infected targets were 221 +/- 41 SFC/10(6) PBMC and 233 +/- 87
      SFC/10(6) PBMC, in the high and low dose groups, respectively. Strong CD4(+) T
      cell responses were also observed. Increases in the IFN-gamma production to
      soluble S. Typhi flagella (STF) occurred in 82 and 38% of the volunteers who
      received the high and low doses, respectively. Robust correlations were observed
      between volunteers that responded with IFN-gamma SFC to stimulation with S. Typhi
      infected cells and IFN-gamma released in response to stimulation with STF Ags (r
      = 0.822, p < 0.001) and between CTL and IFN-gamma production to STF (r = 0.818, p
      = 0.013). These data demonstrating the concomitant induction of both CD4- and CD8
      mediated CMI are consistent with a significant role for type 1 immunity in
      controlling typhoid infection and support the continuing evaluation of CVD 908
      htrA as a typhoid vaccine candidate.

PMID- 12594306
TI  - T cell-activated macrophages are capable of both recognition and rejection of
      pancreatic islet xenografts.
AB  - Macrophages have been proposed as the major effector cell in T cell-mediated
      xenograft rejection. To determine their role in this response, NOD-SCID mice were
      transplanted with fetal pig pancreas (FPP) before reconstitution with CD4(+) T
      cells from BALB/c mice. Twelve days after CD4(+) T cell reconstitution, purified
      macrophages (depleted of T cells) were isolated from CD4(+) T cell-reconstituted
      FPP recipient mice and adoptively transferred to their nonreconstituted
      counterparts. After adoptive macrophage transfer, FPP recipient mice transferred
      with macrophages from CD4(+) T cell-reconstituted mice demonstrated xenograft
      destruction along with massive macrophage infiltration at day 4 and complete
      graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients
      that received macrophages from nonreconstituted mice showed intact FPP xenografts
      with few infiltrating macrophages at both days 4 and 8 after macrophage transfer.
      The graft-infiltrating macrophages showed increased expression of their
      activation markers. Depletion of endogenous macrophages or any remaining CD4(+) T
      cells did not delay graft rejection in the macrophage-transferred FPP recipients,
      whereas depletion of transferred macrophages with clodronate liposomes prevented
      graft rejection. Our results show that macrophages primed by FPP and activated by
      CD4(+) T cells were attracted from the peripheral circulation and were capable of
      specific targeting and destruction of FPP xenografts. This suggests that in
      xenograft rejection, there are macrophage-specific recognition and targeting
      signals that are independent of those received by T cells.

PMID- 12594305
TI  - Paralytic autoimmune myositis develops in nonobese diabetic mice made Th1
      cytokine-deficient by expression of an IFN-gamma receptor beta-chain transgene.
AB  - Nonobese diabetic (NOD) mice and some human type 1 diabetes (T1D) patients
      manifest low to high levels of other autoimmune pathologies. Skewing their
      cytokine production from a Th1 (primarily IFN-gamma) to a Th2 (primarily IL-4 and
      IL-10) pattern is a widely proposed approach to dampen the pathogenicity of
      autoreactive diabetogenic T cells. However, it is important that altered cytokine
      balances not enhance any other autoimmune proclivities to dangerous levels.
      Murine CD4 T cells are characterized by a reciprocal relationship between the
      production of IFN-gamma and expression of the beta-chain component of its
      receptor (IFN-gamma RB). Thus, NOD mice constitutively expressing a CD2 promoter
      driven IFN-gamma RB transgene in all T cells are Th1-deficient. Unexpectedly,
      NOD.IFN-gamma RB Tg mice were found to develop a lethal early paralytic syndrome
      induced by a CD8 T cell-dependent autoimmune-mediated myositis. Furthermore,
      pancreatic insulitis levels were not diminished in 9-wk-old NOD.IFN-gamma RB Tg
      females, and overt T1D developed in the few that survived to an older age.
      Autoimmune-mediated myositis is only occasionally detected in standard NOD mice.
      Hence, some manipulations diminishing Th1 responses can bring to the forefront
      what are normally secondary autoimmune pathologies in NOD mice, while also
      failing to dependably abrogate pancreatic beta cell destruction. This should
      raise a cautionary note when considering the use of protocols that induce
      alterations in cytokine balances as a means of blocking progression to overt T1D
      in at-risk humans.

PMID- 12594307
TI  - Host response to malaria during pregnancy: placental monocyte recruitment is
      associated with elevated beta chemokine expression.
AB  - Malaria during pregnancy is associated with poor birth outcomes, particularly low
      birth weight. Recently, monocyte infiltration into the placental intervillous
      space has been identified as a key risk factor for low birth weight. However, the
      malaria-induced chemokines involved in recruiting and activating placental
      monocytes have not been identified. In this study, we determined which chemokines
      are elevated during placental malaria infection and the association between
      chemokine expression and placental monocyte infiltration. Placental malaria
      infection was associated with elevations in mRNA expression of three beta
      chemokines, macrophage-inflammatory protein 1 (MIP-1) alpha (CCL3), monocyte
      chemoattractant protein 1 (MCP-1; CCL2), and I-309 (CCL1), and one alpha
      chemokine, IL-8 (CXCL8); all correlated with monocyte density in the placental
      intervillous space. Placental plasma concentrations of MIP-1 alpha and IL-8 were
      increased in women with placental malaria and were associated with placental
      monocyte infiltration. By immunohistochemistry, we localized placental chemokine
      production in malaria-infected placentas: some but not all hemozoin-laden
      maternal macrophages produced MIP-1 beta and MCP-1, and fetal stromal cells
      produced MCP-1. In sum, local placental production of chemokines is increased in
      malaria, and may be an important trigger for monocyte accumulation in the
      placenta.

PMID- 12594308
TI  - Fine-scale mapping at IGAD1 and genome-wide genetic linkage analysis implicate
      HLA-DQ/DR as a major susceptibility locus in selective IgA deficiency and common
      variable immunodeficiency.
AB  - Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are
      the most common primary immunodeficiencies in humans. A high degree of familial
      clustering, marked differences in the population prevalence among ethnic groups,
      association of IgAD and CVID in families, and a predominant inheritance pattern
      in multiple-case pedigrees have suggested a strong, shared genetic
      predisposition. Previous genetic linkage, case-control, and family-based
      association studies mapped an IgAD/CVID susceptibility locus, designated IGAD1,
      to the MHC, but its precise location within the MHC has been controversial. We
      have analyzed a sample of 101 multiple- and 110 single-case families using 36
      markers at the IGAD1 candidate region and mapped homozygous stretches across the
      MHC shared by affected family members. Haplotype analysis, linkage
      disequilibrium, and homozygosity mapping indicated that HLA-DQ/DR is the major
      IGAD1 locus, strongly suggesting the autoimmune pathogenesis of IgAD/CVID. This
      is supported by the highest excess of allelic sharing at 6p in the genome-wide
      linkage analysis of 101 IgAD/CVID families using 383 marker loci, by previously
      reported restrictions of the T cell repertoires in CVID, the presence of
      autoantibodies, impaired T cell activation, and a dysregulation of a number of
      genes in the targeted immune system. IgAD/CVID may thus provide a useful model
      for the study of pathogenesis and novel therapeutic strategies in autoimmune
      diseases.

PMID- 12594309
TI  - Studies investigating pretransplant donor-specific blood transfusion, rapamycin,
      and the CD154-specific antibody IDEC-131 in a nonhuman primate model of skin
      allotransplantation.
AB  - Anti-CD154 variably prolongs allograft survival in nonhuman primates. Rodent
      studies suggest that adding pretransplant donor-specific transfusion (DST) and/or
      rapamycin to anti-CD154 improves survival. The CD154-specific Ab IDEC-131 was
      tested alone and in combination with rapamycin for its ability to inhibit rhesus
      MLRs. The ability of the Ab to block endothelial activation was also assessed.
      IDEC-131 was then tested alone and in combination with DST and/or rapamycin for
      its ability to prevent rejection of full-thickness, MHC-mismatched rhesus skin
      allografts. Animals were monitored for donor-specific hyporesponsiveness by MLR
      and alloantibody determination. IDEC-131 modestly inhibited rhesus MLRs and
      inhibited CD154-dependent endothelial cell activation. Rapamycin combined with
      IDEC-131 additively inhibited MLRs. IDEC-131 modestly prolonged allograft
      survival when compared with no treatment, rapamycin alone, or DST plus rapamycin.
      Adding DST to IDEC-131 did not prolong survival beyond IDEC-131 alone. IDEC-131
      plus rapamycin was effective in prolonging graft survival, although animals had
      episodes of acute rejection before graft demise. Therapy with IDEC-131,
      rapamycin, and DST induced long-term allograft survival without intermittent
      acute rejection. However, no evidence for MLR inhibition was seen, and most
      animals eventually developed alloantibody. All animals ultimately rejected their
      grafts after drug withdrawal. IDEC-131 modestly prolongs rhesus skin allograft
      survival. Rapamycin and rapamycin plus DST improves the efficacy of IDEC-131 in
      prolonging allograft survival. IDEC-131, rapamycin, and DST are a promising
      combination for clinical evaluation in allotransplantation.

PMID- 12594310
TI  - Cardiovascular risk factors and antiretroviral therapy.

PMID- 12594311
TI  - Creutzfeldt-Jakob disease.

PMID- 12594312
TI  - One-year outcomes in survivors of the acute respiratory distress syndrome.
AB  - BACKGROUND: As more patients survive the acute respiratory distress syndrome, an
      understanding of the long-term outcomes of this condition is needed. METHODS: We
      evaluated 109 survivors of the acute respiratory distress syndrome 3, 6, and 12
      months after discharge from the intensive care unit. At each visit, patients were
      interviewed and underwent a physical examination, pulmonary-function testing, a
      six-minute-walk test, and a quality-of-life evaluation. RESULTS: Patients who
      survived the acute respiratory distress syndrome were young (median age, 45
      years) and severely ill (median Acute Physiology, Age, and Chronic Health
      Evaluation score, 23) and had a long stay in the intensive care unit (median, 25
      days). Patients had lost 18 percent of their base-line body weight by the time
      they were discharged from the intensive care unit and stated that muscle weakness
      and fatigue were the reasons for their functional limitation. Lung volume and
      spirometric measurements were normal by 6 months, but carbon monoxide diffusion
      capacity remained low throughout the 12-month follow-up. No patients required
      supplemental oxygen at 12 months, but 6 percent of patients had arterial oxygen
      saturation values below 88 percent during exercise. The median score for the
      physical role domain of the Medical Outcomes Study 36-item Short-Form General
      Health Survey (a health-related quality-of-life measure) increased from 0 at 3
      months to 25 at 12 months (score in the normal population, 84). The distance
      walked in six minutes increased from a median of 281 m at 3 months to 422 m at 12
      months; all values were lower than predicted. The absence of systemic
      corticosteroid treatment, the absence of illness acquired during the intensive
      care unit stay, and rapid resolution of lung injury and multiorgan dysfunction
      were associated with better functional status during the one-year follow-up.
      CONCLUSIONS: Survivors of the acute respiratory distress syndrome have persistent
      functional disability one year after discharge from the intensive care unit. Most
      patients have extrapulmonary conditions, with muscle wasting and weakness being
      most prominent.

PMID- 12594313
TI  - Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma
      and primitive neuroectodermal tumor of bone.
AB  - BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are
      closely related, highly malignant tumors of children, adolescents, and young
      adults. A new drug combination, ifosfamide and etoposide, was highly effective in
      patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had
      a relapse after standard therapy. We designed a study to test whether the
      addition of these drugs to a standard regimen would improve the survival of
      patients with newly diagnosed disease. METHODS: Patients 30 years old or younger
      with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive
      sarcoma of bone were eligible. The patients were randomly assigned to receive 49
      weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide,
      and dactinomycin or experimental therapy with these four drugs alternating with
      courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the
      eligibility requirements. Of 120 patients with metastatic disease, 62 were
      randomly assigned to the standard-therapy group and 58 to the experimental
      therapy group. There was no significant difference in five-year event-free
      survival between the treatment groups (P=0.81). Among the 398 patients with
      nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the
      198 patients in the experimental-therapy group was 69+/-3 percent, as compared
      with 54+/-4 percent among the 200 patients in the standard-therapy group
      (P=0.005). Overall survival was also significantly better among patients in the
      experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard
      therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to
      a standard regimen does not affect the outcome for patients with metastatic
      disease, but it significantly improves the outcome for patients with
      nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or
      primitive sarcoma of bone.

PMID- 12594315
TI  - Detection of pathologic prion protein in the olfactory epithelium in sporadic
      Creutzfeldt-Jakob disease.
AB  - BACKGROUND: Olfactory cortexes and the olfactory tracts are involved in sporadic
      Creutzfeldt-Jakob disease. We examined peripheral regions of the olfactory
      sensory pathway, including the olfactory mucosa, to assess whether pathologic
      infectious prion protein (PrPSc) is deposited in the epithelium lining the nasal
      cavity. METHODS: We studied nine patients with neuropathologically confirmed
      sporadic Creutzfeldt-Jakob disease. We obtained the brain, the cribriform plate
      with the attached olfactory mucosa, and the surrounding respiratory epithelium at
      autopsy. Control samples of nasal mucosa were obtained post mortem or at biopsy
      from age-matched control subjects and from control patients with other
      neurodegenerative diseases. The olfactory and respiratory mucosa and the
      intracranial olfactory system were analyzed by light microscopy,
      immunohistochemistry, and Western blotting for pathological changes and for
      deposition of PrPSc. RESULTS: In all nine patients with sporadic Creutzfeldt
      Jakob disease, PrPSc was found in the olfactory cilia and central olfactory
      pathway but not in the respiratory mucosa. No PrPSc was detected in any of the
      tissue samples from the 11 controls. CONCLUSIONS: Our pathological and
      biochemical studies show that PrPSc is deposited in the neuroepithelium of the
      olfactory mucosa in patients with sporadic Creutzfeldt-Jakob disease, indicating
      that olfactory biopsy may provide diagnostic information in living patients. The
      olfactory pathway may represent a route of infection and a means of spreading
      prions.

PMID- 12594314
TI  - Cardiovascular and cerebrovascular events in patients treated for human
      immunodeficiency virus infection.
AB  - BACKGROUND: Metabolic abnormalities associated with human immunodeficiency virus
      (HIV) infection, including dysglycemia and hyperlipidemia, are increasingly
      prevalent, and there is concern about the possibility of an association with
      accelerated cardiovascular and cerebrovascular disease. METHODS: We conducted a
      retrospective study of the risk of cardiovascular and cerebrovascular disease
      among the 36,766 patients who received care for HIV infection at Veterans Affairs
      facilities between January 1993 and June 2001. RESULTS: For antiretroviral
      therapy, 70.2 percent of the patients received nucleoside analogues, 41.6 percent
      received protease inhibitors, and 25.6 percent received nonnucleoside reverse
      transcriptase inhibitors for a median of 17 months, 16 months, and 9 months,
      respectively. Approximately 1000 patients received combination therapy with a
      protease inhibitor for at least 48 months, and approximately 1000 patients
      received combination therapy with a nonnucleoside reverse-transcriptase inhibitor
      for at least 24 months. Between 1995 and 2001, the rate of admissions for
      cardiovascular or cerebrovascular disease decreased from 1.7 to 0.9 per 100
      patient-years, and the rate of death from any cause decreased from 21.3 to 5.0
      deaths per 100 patient-years. Patient-level regression analyses indicated that
      there was no relation between the use of nucleoside analogues, protease
      inhibitors, or nonnucleoside reverse-transcriptase inhibitors and the hazard of
      cardiovascular or cerebrovascular events, but the use of antiretroviral drugs was
      associated with a decreased hazard of death from any cause. CONCLUSIONS: Use of
      newer therapies for HIV was associated with a large benefit in terms of mortality
      that was not diminished by any increase in the rate of cardiovascular or
      cerebrovascular events or related mortality. Fear of accelerated vascular disease
      need not compromise antiretroviral therapy over the short term. However,
      prolonged survival among HIV infected patients means that longer-term observation
      and analysis are required.

PMID- 12594316
TI  - Images in clinical medicine. Bilateral striatal necrosis associated with
      Mycoplasma pneumoniae infection.

PMID- 12594317
TI  - Readability standards for informed-consent forms as compared with actual
      readability.
AB  - BACKGROUND: Institutional review boards (IRBs) are charged with safeguarding
      potential research subjects with limited literacy but may have an inadvertent
      role in promulgating unreadable consent forms. We hypothesized that text provided
      by IRBs in informed-consent forms falls short of the IRBs' own readability
      standards and that readability is influenced by the level of research activity,
      local literacy rates, and federal oversight. METHODS: To test these hypotheses,
      we conducted a cross-sectional study linking data from several public-use
      sources. A total of 114 Web sites of U.S. medical schools were surveyed for IRB
      readability standards and informed-consent-form templates. Actual readability was
      measured with the Flesch-Kincaid scale, which assigns a score on the basis of the
      minimal grade level required to read and understand English text (range, 0 to
      12). Data on the level of research activity, local literacy rates, and federal
      oversight were obtained from organizational Web sites. RESULTS: The average
      readability score for text provided by IRBs was 10.6 (95 percent confidence
      interval, 10.3 to 10.8) on the Flesch-Kincaid scale. Specific readability
      standards, found on 61 Web sites (54 percent), ranged from a 5th-grade reading
      level to a 10th-grade reading level. The mean Flesch-Kincaid scores for the
      readability of sample text provided by IRBs exceeded the stated standard by 2.8
      grade levels (95 percent confidence interval, 2.4 to 3.2; P<0.001). Readability
      was not associated with either the level of research funding (P=0.89) or local
      rates of literacy (P=0.92). However, the 52 schools that had been made subject to
      oversight by the Office for Human Research Protections (46 percent) had lower
      Flesch-Kincaid scores than the other schools (10.2 vs. 10.9, P=0.005).
      CONCLUSIONS: IRBs commonly provide text for informed-consent forms that falls
      short of their own readability standards. Federal oversight is associated with
      better readability.

PMID- 12594318
TI  - Corticosteroid insufficiency in acutely ill patients.

PMID- 12594319
TI  - Case records of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 6-2003. A nine-year-old girl with progressive weakness and
      areflexia.

PMID- 12594320
TI  - Neuromuscular sequelae of critical illness.

PMID- 12594321
TI  - Therapies for cancer in children--past successes, future challenges.

PMID- 12594322
TI  - The right to health and the nevirapine case in South Africa.

PMID- 12594323
TI  - Public use of automated external defibrillators.

PMID- 12594324
TI  - Medical mystery--the answer.

PMID- 12594325
TI  - Controlling tuberculosis in India.

PMID- 12594326
TI  - Genomic medicine.

PMID- 12594327
TI  - Initial management of glycemia in type 2 diabetes.

PMID- 12594328
TI  - Nondiabetic kidney disease.

PMID- 12594329
TI  - Testing medications in children.

PMID- 12594330
TI  - A case of venlafaxine abuse.

PMID- 12594331
TI  - The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl
      transferase is a major target antigen for cell-mediated immunity to malaria.
AB  - Although there is good evidence that immunity to the blood stages of malaria
      parasites can be mediated by different effector components of the adaptive immune
      system, target antigens for a principal component, effector CD4(+) T cells, have
      never been defined. We generated CD4(+) T cell lines to fractions of native
      antigens from the blood stages of the rodent parasite, Plasmodium yoelii, and
      identified fraction-specific T cells that had a Th1 phenotype (producing IL-2,
      IFN-gamma, and tumor necrosis factor-alpha, but not IL-4, after antigenic
      stimulation). These T cells could inhibit parasite growth in recipient severe
      combined immunodeficient mice. N-terminal sequencing of the fraction showed
      identity with hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT).
      Recombinant HGXPRT from the human malaria parasite, Plasmodium falciparum,
      activated the T cells in vitro, and immunization of normal mice with recombinant
      HGXPRT reduced parasite growth rates in all mice after challenge.

PMID- 12594332
TI  - Bacterial enterotoxins are associated with resistance to colon cancer.
AB  - One half million patients suffer from colorectal cancer in industrialized
      nations, yet this disease exhibits a low incidence in under-developed countries.
      This geographic imbalance suggests an environmental contribution to the
      resistance of endemic populations to intestinal neoplasia. A common
      epidemiological characteristic of these colon cancer-spared regions is the
      prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a
      bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell
      proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable
      enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect
      mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of
      the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic
      nucleotide-gated channel inhibitor, as well as by removal of extracellular
      Ca(2+), or chelation of intracellular Ca(2+). In fact, both the enterotoxin and 8
      br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca(2+) influx
      and inhibition of DNA synthesis in colon cancer cells. Induction of this
      previously unrecognized antiproliferative signaling pathway by bacterial
      enterotoxin could contribute to the resistance of endemic populations to
      intestinal neoplasia, and offers a paradigm for targeted prevention and therapy
      of primary and metastatic colorectal cancer.

PMID- 12594333
TI  - An affibody in complex with a target protein: structure and coupled folding.
AB  - Combinatorial protein engineering provides powerful means for functional
      selection of novel binding proteins. One class of engineered binding proteins,
      denoted affibodies, is based on the three-helix scaffold of the Z domain derived
      from staphylococcal protein A. The Z(SPA-1) affibody has been selected from a
      phage-displayed library as a binder to protein A. Z(SPA-1) also binds with
      micromolar affinity to its own ancestor, the Z domain. We have characterized the
      Z(SPA-1) affibody in its uncomplexed state and determined the solution structure
      of a Z:Z(SPA-1) protein-protein complex. Uncomplexed Z(SPA-1) behaves as an
      aggregation-prone molten globule, but folding occurs on binding, and the original
      (Z) three-helix bundle scaffold is fully formed in the complex. The structural
      basis for selection and strong binding is a large interaction interface with
      tight steric and polar/nonpolar complementarity that directly involves 10 of 13
      mutated amino acid residues on Z(SPA-1). We also note similarities in how the
      surface of the Z domain responds by induced fit to binding of Z(SPA-1) and Ig Fc,
      respectively, suggesting that the Z(SPA-1) affibody is capable of mimicking the
      morphology of the natural binding partner for the Z domain.

PMID- 12594334
TI  - RNA interference of influenza virus production by directly targeting mRNA for
      degradation and indirectly inhibiting all viral RNA transcription.
AB  - Influenza A virus causes widespread infection in the human respiratory tract, but
      existing vaccines and drug therapy are of limited value. Here we show that short
      interfering RNAs (siRNAs) specific for conserved regions of the viral genome can
      potently inhibit influenza virus production in both cell lines and embryonated
      chicken eggs. The inhibition depends on the presence of a functional antisense
      strand in the siRNA duplex, suggesting that viral mRNA is the target of RNA
      interference. However, siRNA specific for nucleocapsid (NP) or a component of the
      RNA transcriptase (PA) abolished the accumulation of not only the corresponding
      mRNA but also virion RNA and its complementary RNA. These siRNAs also broadly
      inhibited the accumulation of other viral, but not cellular, RNAs. The findings
      reveal that newly synthesized NP and PA proteins are required for influenza virus
      transcription and replication and provide a basis for the development of siRNAs
      as prophylaxis and therapy for influenza infection in humans.

PMID- 12594335
TI  - A triple-mutated allele of granzyme B incapable of inducing apoptosis.
AB  - Granzyme B (GzmB) is a serine protease involved in many pathologies, including
      viral infections, autoimmunity, transplant rejection, and antitumor immunity. To
      measure the extent of genetic variation in GzmB, we screened the GzmB gene for
      polymorphisms and defined a frequently represented triple-mutated GzmB allele. In
      this variant, three amino acids of the mature protein Q(48)P(88)Y(245) are
      mutated to R(48)A(88)H(245). In CD8(+) cytotoxic T lymphocytes, GzmB was
      expressed at similar levels in QPY homozygous, QPY/RAH heterozygous, and RAH
      homozygous individuals, demonstrating that RAH GzmB is a stable protein. Active
      RAH GzmB expressed in glioblastoma cell lines displayed proteolytic activity, but
      in contrast to QPY GzmB, it did not accumulate in the nucleus and was unable to
      induce Bid cleavage, cytochrome c release, or apoptosis. Molecular modeling
      showed that the three amino acid substitutions clustered near the C-terminal
      alpha-helix of the protein, indicating that this region of the protein may be
      involved in the intracellular targeting of GzmB. The triple-mutated GzmB allele
      that we describe appears to be incapable of inducing apoptosis in tumor cell
      lines, and its presence could, therefore, influence both the prognosis of cancer
      patients and the success rates of antitumor cellular immunotherapy.

PMID- 12594336
TI  - Gravity-regulated differential auxin transport from columella to lateral root cap
      cells.
AB  - Gravity-induced root curvature has long been considered to be regulated by
      differential distribution of the plant hormone auxin. However, the cells
      establishing these gradients, and the transport mechanisms involved, remain to be
      identified. Here, we describe a GFP-based auxin biosensor to monitor auxin during
      Arabidopsis root gravitropism at cellular resolution. We identify elevated auxin
      levels at the root apex in columella cells, the site of gravity perception, and
      an asymmetric auxin flux from these cells to the lateral root cap (LRC) and
      toward the elongation zone after gravistimulation. We differentiate between an
      efflux-dependent lateral auxin transport from columella to LRC cells, and an
      efflux- and influx-dependent basipetal transport from the LRC to the elongation
      zone. We further demonstrate that endogenous gravitropic auxin gradients develop
      even in the presence of an exogenous source of auxin. Live-cell auxin imaging
      provides unprecedented insights into gravity-regulated auxin flux at cellular
      resolution, and strongly suggests that this flux is a prerequisite for root
      gravitropism.

PMID- 12594337
TI  - Aquaglyceroporin AQP9: solute permeation and metabolic control of expression in
      liver.
AB  - Aquaglyceroporins form the subset of the aquaporin water channel family that is
      permeable to glycerol and certain small, uncharged solutes. AQP9 has unusually
      broad solute permeability and is expressed in hepatocyte plasma membranes.
      Proteoliposomes reconstituted with expressed, purified rat AQP9 protein were
      compared with simple liposomes for solute permeability. At pH 7.5, AQP9
      proteoliposomes exhibited Hg(2+)-inhibitable glycerol and urea permeabilities
      that were increased 63-fold and 90-fold over background. beta-Hydroxybutyrate
      permeability was not increased above background, and osmotic water permeability
      was only minimally elevated. During starvation, the liver takes up glycerol for
      gluconeogenesis. Expression of AQP9 in liver was induced up to 20-fold in rats
      fasted for 24-96 h, and the AQP9 level gradually declined after refeeding. No
      changes in liver AQP9 levels were observed in rats fed ketogenic diets or high
      protein diets, but AQP9 levels were elevated in livers of rats made diabetic by
      streptozotocin injection. When blood glucose levels of the diabetic rats were
      restored to normal by insulin treatments, the AQP9 levels returned to baseline.
      Confocal immunofluorescence revealed AQP9 immunostaining on the sinusoidal
      surfaces of hepatocyte plates throughout the livers of control rats. Denser
      immunostaining was observed in the same distribution in livers of fasted and
      streptozotocin-treated rats. We conclude that AQP9 serves as membrane channel in
      hepatocytes for glycerol and urea at physiological pH, but not for beta
      hydroxybutyrate. In addition, levels of AQP9 expression fluctuate depending on
      the nutritional status of the subject and the circulating insulin levels.

PMID- 12594338
TI  - Regulation of the NK-1 receptor gene expression in human macrophage cells via an
      NF-kappa B site on its promoter.
AB  - We report here that human monocytic/macrophage THP-1 cells express the neurokinin
      1 receptor (NK-1R), and that exposure of these cells to the proinflammatory
      cytokine IL-1 beta increased the expression of the NK-1R gene at the mRNA and
      protein levels. Because IL-1 beta function involves nuclear factor kappa B (NF
      kappa B) activation, these data suggest that this increase in the expression of
      the NK-1R gene is mediated by the NF-kappa B transcription factor. An earlier
      report noted that the promoter region of the human NK-1R gene contains a putative
      binding site for NF-kappa B [Takahashi, K., Tanaka, A., Hara, M. & Nakanishi, S.
      (1992) Eur. J. Biochem. 204, 1025-1033]. Here we demonstrate that this is indeed
      a functional NF-kappa B-binding site, and that NF-kappa B is responsible for
      regulating the expression of the NK-1R gene by binding to the promoter region of
      the NK-1R gene. To further substantiate that the observed NF-kappa B-dependent IL
      1 beta induction of the human NK-1R gene is regulated via a transcriptional event
      through this NF-kappa B site on the NK-1R gene promoter, we transfected THP-1
      cells with a luciferase promoter-reporter construct containing the 5' promoter
      region of the human NK-1R gene. Exposure of these cells to IL-1 beta or
      overexpression of NF-kappa B cDNAs resulted in a significant increase in the
      amount of luciferase activity that was diminished greatly in cells transfected
      with I kappa B alpha, the NF-kappa B inhibitor. These results directly implicate
      NF-kappa B in the regulation of the NK-1R gene and provide a molecular mechanism
      for the increase in expression of the NK-1R gene in responsive cells.

PMID- 12594339
TI  - Photoexcited breathers in conjugated polyenes: an excited-state molecular
      dynamics study.
AB  - pi-conjugated polymers have become an important class of materials for electronic
      devices. Design of these devices requires understanding such processes as
      photochemical reactions, spatial dynamics of photoexcitations, and energy and
      charge transport, which in turn involve complex coupled electron-vibrational
      dynamics. Here we study nonlinear photoexcitation dynamics in the polyene
      oligomers by using a quantum-chemical method suitable for the simulation of
      excited-state molecular dynamics in extended molecular systems with sizes up to
      hundreds of atoms. The method is based on the adiabatic propagation of the ground
      state and transition single-electron density matrices along the trajectory. The
      simulations reveal formation of a self-localized vibronic excitation ("breather"
      or multiquanta bound state) with a typical period of 34 fs and allows us to
      identify specific slow and fast nuclear motions strongly coupled to the
      electronic degrees of freedom. The effect of chain imperfections and chemical
      defects on the dynamics is also investigated. A complementary two-dimensional
      analysis of corresponding transition density matrices provides an efficient way
      to monitor time-dependent real-space localization of the photoexcitation by
      identifying the underlying changes in charge densities and bond orders. Possible
      correlated electronic and vibrational spectroscopic signatures of photoexcited
      breathers are predicted, and generalizations to energy localization in complex
      macromolecules are discussed.

PMID- 12594340
TI  - Relish-mediated immune deficiency in the transgenic mosquito Aedes aegypti.
AB  - The lack of genetic means has been a serious limitation in studying mosquito
      immunity. We generated Relish-mediated immune deficiency (RMID) by transforming
      Aedes aegypti with the Delta Rel transgene driven by the vitellogenin (Vg)
      promoter using the pBac[3xP3-EGFP, afm] vector. A stable transformed line had a
      single copy of the Vg-Delta Rel transgene. The Vg-Delta Rel transgene expression
      was highly activated by blood feeding, and transgenic mosquitoes were extremely
      susceptible to the infection by Gram-negative bacteria. This RMID phenotype was
      characterized by severely reduced postinfection levels of antimicrobial peptides
      genes, defensin and cecropin. Crossing the RMID line with the wild-type strain
      produced the same RMID phenotype, indicating its dominant nature, whereas
      crossing with the Vg-def transgenic line, in which Defensin A was activated by
      blood feeding, restored the immunity to Enterobacter cloacae.

PMID- 12594341
TI  - RNA interference blocks gene expression and RNA synthesis from hepatitis C
      replicons propagated in human liver cells.
AB  - RNA interference represents an exciting new technology that could have
      therapeutic applications for the treatment of viral infections. Hepatitis C virus
      (HCV) is a major cause of chronic liver disease and affects >270 million
      individuals worldwide. The HCV genome is a single-stranded RNA that functions as
      both a messenger RNA and replication template, making it an attractive target for
      the study of RNA interference. Double-stranded small interfering RNA (siRNA)
      molecules designed to target the HCV genome were introduced through
      electroporation into a human hepatoma cell line (Huh-7) that contained an HCV
      subgenomic replicon. Two siRNAs dramatically reduced virus-specific protein
      expression and RNA synthesis to levels that were 90% less than those seen in
      cells treated with negative control siRNAs. These same siRNAs protected naive Huh
      7 cells from challenge with HCV replicon RNA. Treatment of cells with synthetic
      siRNA was effective >72 h, but the duration of RNA interference could be extended
      beyond 3 weeks through stable expression of complementary strands of the
      interfering RNA by using a bicistronic expression vector. These results suggest
      that a gene-therapeutic approach with siRNA could ultimately be used to treat
      HCV.

PMID- 12594342
TI  - [Treatment of intertrochanteric femoral fractures with the use of a modular axial
      fixator device].
AB  - OBJECTIVES: Intertrochanteric femoral fractures are usually encountered in the
      elderly, leading to morbidity and even mortality due to age-related systemic
      complications. In this study, we evaluated the use of a modular axial fixator
      device in the treatment of intertrochanteric femoral fractures. METHODS:
      Intertrochanteric femoral fractures of 25 patients (18 females, 7 males; mean age
      70 years; range 18 to 91 years) were treated by the use of a modular axial
      fixator. The fractures were classified according to the Boyd-Griffin
      classification. Surgery was performed after a mean of 5.76 days following trauma.
      The patients were allowed to walk using crutches on the second postoperative day
      and a single crutch after sufficient callus formation was radiologically
      determined. Final evaluations were made by the Foster's classification. The mean
      follow-up was 12 months (range 6 to 24 months). RESULTS: The mean operation
      duration was 34 minutes. Union was achieved in all patients after a mean of 12.3
      weeks (range 9 to 18 weeks). Three patients (12%) developed varus deformity of 3,
      5, and 9 degrees, respectively. Shortening in a range of 1 cm to 1.5 cm was
      detected in three patients (12%). Postoperatively, 10 patients developed pin
      tract infections, none of which required revision or removal of the fixator.
      Final evaluations yielded excellent and good anatomical results in 72% and 28%,
      and functional results in 80% and 20%, respectively. CONCLUSION: Reducing both
      the operation time and the immobilization period is of vital importance
      particularly in elderly patients with intertrochanteric femoral fractures. Due to
      its short length, the modular axial fixator offers significant advantages
      including higher tolerability, rapid weight bearing allowance, and achievement of
      union without seriously complicating events.

PMID- 12594343
TI  - [Treatment of intraarticular comminuted supracondylar femoral fractures by
      indirect plate osteosynthesis].
AB  - OBJECTIVES: We evaluated the effectiveness of indirect plating, which is accepted
      as a biological fixation, in intraarticular comminuted supracondylar femoral
      fractures. METHODS: Six patients (4 males, 2 females; mean age 35 years; range 14
      to 54 years) had distal femoral fractures of Muller type 33.C2 (n=3) and 33.C3
      (n=3). There were three closed and three open fractures; of open fractures, two
      were type II and one was type III according to the Gustilo-Anderson
      classification. Intraarticular fractures were reconstructed directly through a
      lateral parapatellar incision, while supracondylar fractures were indirectly
      reduced without surgical exposure of the fracture site. The distal anatomically
      reconstructed articular block was fixed to the femoral shaft by a plate inserted
      retrogradely beneath the vastus lateralis muscle, followed by plate fixation to
      the femoral shaft by cortical screws sent percutaneously through stab incisions
      or transmuscularly through limited proximal incisions. The mean follow-up was 25
      months (range 12 to 40 months). RESULTS: The average time until union was 15
      weeks (range 12 to 20 weeks). No refractures, implant failures, or infections
      were encountered. Two patients had restricted knee movements (25% to 50%), three
      had leg length discrepancy (1 to 2.5 cm), and one patient had a valgus deformity
      of 10 degrees. According to the Johner and Wruhs criteria, the results were as
      follows: excellent in one patient, good in one patient, satisfactory in two, and
      poor in two patients. All patients returned to preinjury activity levels.
      CONCLUSION: Biological plate fixation is effective and may be considered an
      alternative to other conventional surgical methods in the treatment of distal
      intraarticular complex supracondylar femoral fractures.

PMID- 12594344
TI  - [Treatment of type II and III open tibial fractures with Ilizarov external
      fixation].
AB  - OBJECTIVES: We evaluated the results of patients who were treated with Ilizarov
      external fixation for type II and III open tibial fractures. METHODS: Forty-five
      patients (4 females, 41 males; mean age 33 years; range 8 to 65 years) with open
      tibial fractures were treated with the Ilizarov external fixator. According to
      the Gustilo-Mendoza classification, the fractures were type II, IIIA, IIIB, and
      IIIC in 12, 20, 9, and 4 patients, respectively. The mean follow-up was 58 months
      and 4 days (range 42 months and 10 days to 66 months and 11 days). The fixators
      were applied for a mean of 17.2 weeks (range 6.8 to 55.7 weeks). RESULTS: Union
      was achieved in all cases. A significant difference was observed between type II
      and III fractures in terms of time to union (p<0.05). Compared to type IIIA
      fractures, the time to union was significantly longer in type IIIB and IIIC
      fractures (p<0.05). The most frequent complication was pin-tract infections
      (27.1%). Refracture occurred in four cases (8.8%). Three patients developed late
      infections at the fracture site. Radiographically, the results were excellent in
      14 patients (31%), good in 22 patients (48.8%), moderate in five patients
      (11.1%), and poor in four patients (8.8%). Functional results were excellent in
      21 patients (46.6%), good in 20 patients (44.4%), and moderate in four patients
      (8.8%). CONCLUSION: Despite technical difficulties and problems associated with
      pin-tract infections, the Ilizarov external fixator may be the preferred
      technique in open tibial fractures because of high union rates, the use of thin K
      wires with minimal traumatic effect, and more successful functional results.

PMID- 12594345
TI  - [Treatment of stiff-knee gait by distal rectus femoris transfer].
AB  - OBJECTIVES: We evaluated the preliminary results of distal rectus femoris
      transfer in patients with stiff-knee gait due to cerebral palsy. METHODS: Eight
      knees of four patients who had stiff-knee gait due to cerebral palsy were treated
      by distal rectus femoris transfer. All the patients were females with a mean age
      of 11 years (range 9.5 to 12 years). Preoperatively and postoperatively, lower
      extremity examinations, the Ely test, and clinical gait analyses were performed.
      Satisfaction levels of the patients and their families were questioned. The mean
      follow-up was 17.5 months (range 3 to 23 months). RESULTS: None of the patients
      manifested flexion contracture of their hips and knees postoperatively. The Ely
      test was negative in all patients. There were no clinical signs of stiff-knee
      gait. All the patients and their families but one expressed their satisfaction
      with clinical and functional results. CONCLUSION: Our clinical results suggest
      that distal rectus femoris transfer is effective in the treatment of stiff-knee
      gait due to cerebral palsy.

PMID- 12594346
TI  - [Long-term results of olecranon fractures treated with tension-band wiring
      technique].
AB  - OBJECTIVES: We evaluated the long-term results of olecranon fractures treated
      with tension-band wiring (Zuggurtung) technique. METHODS: The study included 41
      patients (28 males, 13 females; mean age 48 years; range 20 to 85 years) who
      underwent tension-band wiring osteosynthesis for olecranon fractures. The
      involved side was the right in 25 patients, and the left in 16 patients.
      Associated bone and soft-tissue injuries were detected in 16 patients. There were
      open fractures of Gustilo type 1 in two patients, and type 2 in one patient. The
      fractures were classified according to the Schatzker's system, and the results
      according to the Murphy's system. The mean follow-up was 46.7 months (range 12 to
      141 months). RESULTS: Complete union was obtained in all fractures. According to
      the Murphy's system, the results were very good and good in 31 patients (75.6%),
      fair in five patients (12.2%), and poor in five patients (12.2%). It was obvious
      that fracture type and accompanying trauma had influenced the treatment results.
      Of open fractures, the results were poor in two patients, and fair in one
      patient. Of 10 patients with a fair or poor outcome, eight patients had
      accompanying bone injuries. Complications included migration of the K-wire in two
      patients, and irritation related to K-wires in four patients. CONCLUSION:
      Osteosynthesis with tension-band wiring technique in olecranon fractures offers
      considerable advantages: a stable fixation is obtained at a very low cost,
      development of joint stiffness is avoided by early elbow range of motion, and
      minimal joint stiffness seen in the long term does not present as a functional
      disability.

PMID- 12594347
TI  - [The role of the long head of the biceps in subacromial impingement syndrome and
      arthroscopic assisted tenodesis].
AB  - OBJECTIVES: Tenosynovitis of the long head of the biceps tendon, which commonly
      accompanies subacromial impingement syndrome, is one of the most important
      underlying cause of shoulder pain. We evaluated our experience with arthroscopic
      subacromial decompression and tenodesis of the long head of the biceps using mini
      open approach. METHODS: Among patients who underwent arthroscopic subacromial
      decompression (112 patients) alone or in combination with mini-open rotator cuff
      repair (55 patients), 19 patients (11%; 12 females, 7 males; mean age 47 years,
      range 42 to 62 years) had tenodesis of the long head of the biceps. During
      arthroscopy of the glenohumeral joint, the decision for tenodesis was based on
      the presence of irreversible findings of chronic inflammation such as atrophy,
      excessive fraying, or partial rupture. The patients were divided into two groups
      depending on the surgery, namely, mini-open rotator cuff repair (group 1, 9
      patients) and arthroscopic subacromial decompression alone (group 2, 10
      patients). The mean follow-up was 17.6 months in group 1 (range 12 to 28 months),
      and 19.6 months in group 2 (range 12 to 40 months). RESULTS: Seven patients in
      group 1 (78%) did not complain about pain, while two patients had pain after
      vigorous physical activity. In group 2, nine patients (90%) were pain-free,
      whereas one patient had moderate pain. None of the patients had any cosmetic
      deformity. Two patients in group 1, and one patient in group 2 had mild biceps
      spasms. CONCLUSION: Despite the small sample size and a relatively short follow
      up period, our results for tenodesis may be regarded as satisfactory. Special
      attention should be paid to the arthroscopic evaluation of the biceps tendon and
      tenodesis may be inevitable in the presence of chronic changes.

PMID- 12594348
TI  - [Arthroscopic treatment of rotator cuff calcifying tendinitis].
AB  - OBJECTIVES: We evaluated the effectiveness of arthroscopic treatment in patients
      with rotator cuff calcifying tendinitis unresponsive to conservative treatment.
      METHODS: Arthroscopic treatment was performed in 10 patients (6 females, 4 males;
      mean age 46 years; range 34 to 53 years) in whom pain and functional disability
      persisted for more than a year despite conservative therapy for rotator cuff
      calcifying tendinitis. Arthroscopic bursectomy was also carried out. One patient
      underwent repair for rotator cuff tear. The patients were evaluated before and
      after surgery with the use of Constant scores and direct radiographs. The mean
      follow-up period was 12 months (range 6 to 19 months). RESULTS: The mean Constant
      scores were 66 (range 45 to 70) and 93 (range 89 to 96) before surgery and on
      final examinations, respectively. Postoperative radiographs demonstrated
      incomplete removal of calcifications in four patients; however, complaints of
      pain disappeared in these patients and radiologic controls showed that residual
      deposits underwent spontaneous resorption. CONCLUSION: Arthroscopic removal of
      calcium deposits together with bursectomy seems to be effective and reliable in
      patients with chronic calcifying tendinitis unresponsive to conservative
      treatment.

PMID- 12594349
TI  - [Short-term results of proximal oblique crescentic osteotomy in hallux valgus].
AB  - OBJECTIVES: We evaluated the short-term results of a combination of distal soft
      tissue procedure and a modification of proximal crescentic osteotomy, namely,
      proximal oblique crescentic osteotomy (POCO) in moderate to severe hallux valgus.
      METHODS: Twenty-five male patients (mean age 21 years; range 19 to 26 years) with
      moderate to severe hallux valgus and incongruent joint were treated by the distal
      soft tissue procedure and POCO. Objective evaluations included the hallux valgus
      angle, the intermetatarsal angle, shortening of the first metatarsal bone, and
      angulation at the osteotomy site on weight-bearing anteroposterior and lateral
      radiographs of the foot obtained before surgery and for final examinations.
      Subjective evaluation was made with the use of a patient questionnaire whose
      overall scores ranged from 6 (completely satisfied) to 18 (completely
      dissatisfied). The mean follow-up period was 44 weeks (range 28 to 52 weeks).
      RESULTS: The mean corrections in the hallux valgus angle and the intermetatarsal
      angle were 22.1 degrees and 10.8 degrees, respectively. Shortening of the first
      metatarsal bone (mean 3 mm) occurred in five patients and dorsiflexion deformity
      of the metatarsal head in one patient, which did not lead to transfer
      metatarsalgia. Nine patients expressed complete satisfaction (36%), followed by
      seven and six patients with scores of 7 and 8, respectively. The least
      satisfaction score was 12 in one patient. CONCLUSION: The results suggest that
      metatarsus primus varus, which is the main deformity in moderate to severe hallux
      valgus, can be corrected by POCO. This technique may be preferable in terms of
      ease and a low complication rate.

PMID- 12594350
TI  - [The relationship between the thickness and elasticity of the heel pad and heel
      pain].
AB  - OBJECTIVES: We investigated the factors affecting the thickness and elasticity of
      the heel pad and sought relationship between the heel pad thickness and
      elasticity and heel pain. METHODS: Of 182 patients who presented with a complaint
      of heel pain over a three year period, 50 patients (38 females, 12 males; mean
      age 46 years; range 23 to 73 years) met specific criteria for the study. A
      combined treatment modality was conducted throughout a year which consisted of
      non-steroidal anti-inflammatory drugs, contrast baths, stretching exercises, and
      changes in footwear design. At the end of a year, the results were assessed
      according to the criteria proposed by Wolgin et al. Measurements of heel pad
      thickness were performed according to the technique described by Jorgensen:
      compressibility index of the heel pad was calculated on anteroposterior and
      lateral radiographs of the heel, loaded and unloaded by body weight. RESULTS: The
      results were good in 35 patients (70%), fair in 12 patients (35%), and poor in
      three patients (6%). Four patients (8%) developed recurrences. Increased heel pad
      thickness, decreased elasticity, and delayed healing were observed in males, in
      patients above 40 years of age, in obese patients, in those with a pretreatment
      symptom duration exceeding 12 months, and in those with a greater subcalcaneal
      spur. CONCLUSION: The thickness of heel pad increases in relation to age and
      weight, resulting in decreased elasticity. In addition, subcalcaneal spur may be
      involved in heel pain induction through decreasing heel pad elasticity.

PMID- 12594351
TI  - [Evaluation of functional results in conservatively treated boxer's fractures].
AB  - OBJECTIVES: The aim of this study was to evaluate the effect of dorsal
      angulations up to 30 degrees on the grip strength in conservatively treated
      boxer's fractures. METHODS: The grip strength of 18 patients was evaluated with
      the Jamar dynamometer following conservative treatment for neck fractures of the
      fifth metacarpal. All the patients were males with a mean age of 30.5 years. The
      results were compared with those of intact hands and a control group of 18
      subjects (mean age 31.2 years). The mean follow-up period was 20 months (range 4
      to 48 months). RESULTS: The mean dorsal angulations before and after closed
      reduction were 46 degrees (range 35 degrees -55 degrees ) and 28 degrees (range
      10 degrees -30 degrees ), respectively. Compared to the grip strength of intact
      hands and controls, no statistically significant functional loss was found in
      conservatively treated hands (p>0.05). CONCLUSION: Since no significant
      functional loss occurs in the fifth metacarpal neck fractures having an
      angulation less than 30 degrees, the appropriate treatment seems to be
      conservative whenever this range of reduction is likely to be achieved.

PMID- 12594352
TI  - [A morphologic evaluation of the sacroiliac joint and plate fixation on a pelvic
      model using a S1 pedicular screw, transiliosacral screws, and a compression rod
      for sacroiliac joint injuries].
AB  - OBJECTIVES: Morphological measurements were performed, of the articular surfaces
      and adjacent bone structures of the sacroiliac joint on dry bone specimens to
      determine the projection of the sacroiliac joint on the outer table of the
      posterior ilium. In addition, the effect of plate fixation using transiliosacral
      screws and a pedicular screw on S1 attached via a compression rod was evaluated
      on pelvic models to be applied in sacroiliac joint injuries. METHODS:
      Quantitative caliper measurements of dry bone specimens including 20 os coxae and
      10 sacrum were made on the articular surfaces of the sacrum and the posterior
      ilium, thickness of the posterior iliac bone at different levels, and the
      distance from the outer walls of S1 and S2 foramina to the sacral facies
      articularis. After the construction of a plate matching the projection of the
      lateral sacral mass on the outer table of the posterior ilium, four
      transiliosacral screws were applied lateral to the sacral foramina on pelvic
      models. A pedicular screw sent to S1 was attached to the plate with a threaded
      compression rod. RESULTS: The mean values for the articular surface of (i) the
      posterior ilium were 53.3 mm (base length), 38.5 mm (height), and 56.2 mm (the
      distance from the anterior margin of the articular surface to the spina iliaca
      posterior superior); and (ii) the sacrum, 57.2 mm (base length), and 34.6 mm
      (height). The mean thickness of the posterior ilium was 19.2 mm, and the mean
      distance from the lateral walls of the sacral foramina at S1 and S2 levels to the
      articular surface was 21.7 mm. For the deduced projection, the perpendicular line
      from the middle of the base was found to be the safe zone for screw applications.
      CONCLUSION: Through a plate applied matching the projection area, multiple screws
      may be sent lateral to S1 and S2 foraminal levels without damage to the sacral
      neural and surrounding vital structures. A stable fixation can be achieved by
      combining the plate/screw system with a S1 pedicular screw.

PMID- 12594354
TI  - [Isolated carpometacarpal dislocation of the thumb: a case report].
AB  - The traumatic fracture-dislocation of the first carpometacarpal joint is not
      frequent, isolated dislocation being even more uncommon. A twenty-five-year-old
      male patient was diagnosed as having carpometacarpal dislocation of the thumb by
      means of radiologic and physical examination findings. After immediate reduction,
      the thumb was immobilized in a short thumb spica cast for six weeks, after which
      he was enrolled into a rehabilitation program. No pain or instability were found
      at the end of six months.

PMID- 12594353
TI  - [Treatment of femoral fractures associated with fibrous dysplasia: a case
      report].
AB  - Fibrous dysplasia is a rare condition in which bone tissue is replaced by fibro
      osseous lesions. A sixteen-year-old male patient with fibrous dysplasia underwent
      plate fixation for subtrochanteric fracture of the proximal femur. Eighteen
      months postoperatively, progressive femoral deformity and refracture occurred.
      Upon failure in three-month conservative treatment, the plate was removed and
      intramedullary fixation was performed. Control radiographs at the end of 18
      months after intramedullary fixation showed complete fracture healing. This case
      emphasizes that intramedullary fixation should be the first choice to treat
      femoral fractures and to prevent refractures in patients with fibrous dysplasia.

PMID- 12594355
TI  - [Stress fracture of the fifth metatarsophalangeal sesamoid bone: a case report].
AB  - There is a paucity of published literature on the injuries of the lesser toe
      sesamoids of the foot. A fifty-six-year-old male patient without a major trauma
      history was diagnosed as having a stress fracture of the fifth
      metatarsophalangeal joint medial sesamoid bone. Conservative treatment was
      employed and the patient was followed-up for 25 months without any complaints.
      The sesamoid bone injury of the fifth toe should be included in the differential
      diagnosis of lateral forefoot pain.

PMID- 12594356
TI  - Experimental studies on the role of fructose in the development of diabetic
      complications.
AB  - We examined the role of fructose in the development of diabetic complications.
      Compared with glucose, fructose increased the fluorescence intensity and the
      cross-linking of glycated collagen, and promoted the polymerization of proteins.
      Therefore fructose accelerated the production of advanced glycation end-products
      more than glucose. In addition, fructose enhanced the reactive oxygen or oxygen
      radical generation and the associated degeneration of proteins and lipids. These
      actions of fructose appeared to be due to the formation of dicarbonyl compounds
      such as 3-deoxyglucosone, a highly reactive intermediate product formed in the
      advanced glycation stage. These results suggest that fructose is closely involved
      not only in glycation but also in the polyol pathway and peroxidation reactions
      through free radical formation. Thus, fructose is considered to be a more
      critical reducing sugar associated with the progression of diabetic complications
      than it has been thought until now.

PMID- 12594357
TI  - The C677T mutation in the methylenetetrahydrofolate reductase gene among the
      Indonesian Javanese population.
AB  - The presence of the C677T mutation in the methylenetetrahydrofolate reductase
      (MTHFR) gene has been regarded as a genetic risk factor for coronary artery
      diseases and neural tube defects. Although the prevalence of this mutation has
      been reported from various ethnic populations, few data concerning Indonesian
      populations are available. We have investigated the frequency of the mutation in
      68 Indonesian Javanese (residents of Java Island) and compared it with the data
      from 244 Japanese (residents of Honshu Island). The frequencies of the three
      genotypes in Javanese were C/C 0.84, C/T 0.16 and T/T 0.00, whereas those in
      Japanese were C/C 0.39, C/T 0.48 and T/T 0.13. The rarity of the T/T genotype in
      the Indonesian Javanese population may be due to malnutrition in pregnant women,
      because insufficient intake of folate is considered to be a survival disadvantage
      for fetuses with the T/T genotype. In conclusion, homozygosity for the C677T
      mutation in the MTHFR gene does not constitute a genetic risk factor for coronary
      artery diseases and neural tube defects in the Indonesian Javanese population.

PMID- 12594358
TI  - Establishment of in vivo metastasis model of human adenoid cystic carcinoma:
      detection of metastasis by PCR with human beta-globin gene.
AB  - Cells from the human adenoid cystic carcinoma (ACC) line, KOA-1, originating from
      the minor salivary gland and showing histological features of a dominantly solid
      pattern of ACC, were transplanted into the subcutaneous tissue of nude mice. The
      occurrence of lung metastasis was then examined both histologically and by PCR
      with a human-specific base arrangement of the beta-globin gene. Histologic
      examinations revealed lung metastasis in 5 of 30 mice. On the other hand, PCR
      showed a higher positive rate: 26 of 67 mice (0/10 at 1 month, 5/15 at 2 months,
      and 21/42 at 3 months after the transplantation). When some lungs which showed
      positive results by PCR analysis were transplanted into other mice, KOA-1 tumors
      developed. The results suggested that this experimental model could be a standard
      in vivo model of metastasis of human ACC.

PMID- 12594360
TI  - [Proof of information delivered to patients].

PMID- 12594361
TI  - [Assessment of the quality and psychological impact of information delivered
      using official consent forms in digestive endoscopy].
AB  - AIM: To test the impact of information brochures and informed consent forms in
      patients undergoing digestive endoscopy procedures. METHOD: All patients
      undergoing digestive endoscopy procedures during a two-month period were given
      information about the procedure to be performed by delivery of an information
      form produced by the French Endoscopy and Gastroenterology Societies. The
      patients were then asked to sign an inform consent form. A questionnaire about
      the informed consent form and the consent experience was given to all patients
      after the endoscopic procedure. RESULTS: The questionnaire was completed by 108
      consecutive patients. The informed consent form was completely read by 96.3% and
      understood by 95%. Sixteen percent asked for complementary information, all about
      complications. Twenty percent were distressed by the explanations. Receiving
      written information was surprising for 22.2% of the patients, and distressing for
      18.5% mainly when endoscopy was planned without general anesthesia (P=0.01 versus
      general anesthesia). Obtaining informed consent was qualified as a normal
      procedure for 47.2%, but distressing for 19.4%. It was considered by 41.1% as a
      way for doctors to be discharged from their obligations. CONCLUSION: The informed
      consent forms written by scientific societies are easy to understand. One third
      of the patients were distressed or surprised to be given oral or written
      information. To sign a written consent form before an endoscopy procedure is
      considered to be a means of discharging practitioners from their responsibilities
      for 30% of the patients.

PMID- 12594362
TI  - [Cost of colorectal cancer in France in 1999].
AB  - AIM: Due to high incidence and disease severity, colorectal cancer is a major
      public health concern in western countries. Few studies have been devoted to
      estimating its cost in France. The aim of this study was to analyze the direct
      (medical) and indirect (short-term disability, long-term disability, premature
      death) costs of colorectal cancer in France. METHODS: This cost-of-illness study
      was based on data available for 1999. Two evaluation perspectives were
      considered: French social security system (medical care + daily allowances +
      disability allowances) and the society (medical care + production losses).
      Sources of data used in this analysis were: PMSI (hospital care), EPPM-IMS study
      (ambulatory care) and the GAZEL cohort (short-term disability). RESULTS: Direct
      costs of colorectal cancer in France amounted in 1999 to more than 469.7 million
      euros, of which 98% were induced by hospitalisation (on an outpatient or an
      inpatient basis). Indirect costs represented in 1999 for the French social
      security system an amount of 85.9 million, of which 71% were due to disability
      allowances. Taking into account the society's point of view, indirect costs
      corresponded to production losses of 528.1 million. Total costs of colorectal
      cancer amounted 555.5 million for the social security system and 997 million for
      the society. CONCLUSION: These results confirm the high economic burden of
      colorectal cancer for the French social security system and for the society in
      general.

PMID- 12594363
TI  - [Celiac disease and liver involvement].

PMID- 12594364
TI  - [What can be done for patients with cancer of the digestive tract in 2003?
      Guidelines of the Francophone Federation of Digestive Tract Cancerology--part
      II].

PMID- 12594366
TI  - [Colonic polyps. New lesion entities: endoscopic screening and surveillance].

PMID- 12594367
TI  - [Clinical cases illustrating management after endoscopic resection of colonic
      polyps].

PMID- 12594368
TI  - [Interview: questions to Professor Jean Boyer].

PMID- 12594370
TI  - [New recommendations for diagnosis and virological monitoring of viral
      hepatitis].

PMID- 12594371
TI  - [Screening and hepatitis C management survey in general medicine in the Alpes
      Maritimes and east Var area].
AB  - BACKGROUND: This study was performed to assess screening and management of
      hepatitis C by community-based practitioners in the Alpes Maritimes district in
      the South of France and to compare their practices with the recommendations
      issued by the consensus conferences in 1997 and 1999. This information was to be
      used to adapt continuing medical education to the needs of practitioners in the
      area. METHOD: Two hundred and nineteen general practitioners who were members of
      eighteen continuing medical education associations accepted to complete a
      questionnaire containing eighteen closed questions. It was issued late 1999
      during one of the monthly meetings and completed by all the participating
      physicians. RESULTS: Only 32% of general practitioners knew the conclusions of
      one of the two French and European consensus conferences concerning hepatitis C.
      General practitioner practices were in accordance with recommendations for
      targeted screening in case of transfusion before 1991 (88%), intra-venous drug
      use (94%) and increased ALT (91%); however intra nasal drug use (35%) and
      imprisonment (46%) were underestimated risk factors. Frequency of screening was
      correlated to duration of practice (P<0.01), size of practice (P<0.02) and follow
      up of hepatitis C infected patients, regardless of treatment (P<0.03). Upon
      discovery of a positive HCV status, 80% of general practitioners prescribed
      initial investigations but these included costly and needless procedures such as
      hepatic imaging (56%), RNA quantification (39%) and viral genotype (6%). On the
      other hand, 79% general practitioners recommended a liver biopsy for patients
      with elevated transaminase levels. When transaminase levels were normal, only 13%
      requested qualitative detection of viral RNA. Generally, general practitioners
      were confused concerning the indications for qualitative or quantitative viral
      RNA investigations. Few general practitioners followed treated HCV-infected
      patients and renewed interferon therapy prescriptions. Condom use was advised by
      56% of GPs for couples in which one of the partners had a positive HCV status.
      CONCLUSIONS: This study demonstrates the weak impact of consensus conferences on
      hepatitis C management for general practitioners in the Alpes Maritimes. It
      provides an opportunity to identify the need for specific training which will be
      developed within the Cote d'Azur Hepatitis C Network.

PMID- 12594372
TI  - [Should liver biopsy be systematic during surgery for ulcerative colitis?].
AB  - AIM: The aim of this study was to evaluate the prevalence of primary sclerosing
      cholangitis and other histological liver abnormalities in patients operated on
      for ulcerative colitis and to discuss the advantages of performing a systematic
      liver biopsy during surgery. METHODS: From 1996 to 2001, 21 consecutive patients
      underwent a restorative proctocolectomy or a reoperation after proctocolectomy
      for ulcerative colitis. These patients systematically underwent liver biopsy
      during the procedure. RESULTS: One patient presented with primary sclerosing
      cholangitis (4.7%). This patient was clinically and biologically asymptomatic.
      Four patients had steatosis, 8 had non specific inflammation such as small duct
      cholangitis and 8 had normal liver biopsy. As a result medical treatment was
      adapted and close surveillance of the live was begun. CONCLUSION: Peroperative
      liver biopsy identify primary sclerosing cholangitis or other liver diseases in
      an early diagnosis and help evaluate their stage in order to start appropriate
      treatment.

PMID- 12594373
TI  - [Hepatic and extrahepatic sterol 27-hydroxylase: roles in cholesterol and bile
      acid metabolism and associated diseases].

PMID- 12594374
TI  - [Primary malignant melanoma of the esophagus].
AB  - We report the case of primary malignant melanoma of oesophagus in a 63-year-old
      man who presented with a 8-week history of dysphagia. Esophagoscopy demonstrated
      a polypoid mass expanding in the mid-oesophagus without causing obstruction.
      Based on histological and immunohistochemical studies, the diagnosis of primary
      esophageal malignant melanoma was made. Radical resection was not possible
      because of regional tumour extension at the time of diagnosis. The patient
      underwent percutaneous endoscopic gastrostomy. Death occurred 4 months later
      because of acute respiratory failure.

PMID- 12594375
TI  - [Urogenital expression of a tumor of the terminal ileum].
AB  - Malignant tumors of the small bowel are usually associated with digestive and
      general symptoms. We report the case of a 26-year-old patient who presented with
      right lumbar pain and right testicular pain. Final diagnosis was lymphoma of the
      terminal ileum involving the right pelvic ureter and the right vas deferens. We
      discuss frequency and mechanisms of this very unusual extension of malignant
      small bowel tumors.

PMID- 12594376
TI  - [1,1, 1-trichloroethane-induced chronic active hepatitis].
AB  - 1,1, 1-trichloroethane is derived from carbon tetrachloride and has been widely
      used as an industrial solvent since 1954, because of its supposed lack of
      toxicity. However, several cases of central nervous system toxicity and heart
      disorders due to intoxication by 1,1, 1-trichloroethane have been reported. Cases
      of liver injury are infrequent, with less than 10 cases, unlike 1,1, 2
      trichloroethane that it replaced. We report a case of hepatotoxicity probably due
      to 1,1, 1-trichloroethane exposure, characterized by an original pathologic
      feature of chronic active hepatitis.

PMID- 12594377
TI  - [Acute pancreatitis after clarithromycin and beta-methasone].

PMID- 12594378
TI  - [Acute pancreatitis induced by codeine-acetaminophen association: report of two
      cases].

PMID- 12594379
TI  - [Extraluminal leiomyoma of the sigmoid colon and of the peritoneum].

PMID- 12594381
TI  - [Montelukast induced cytolytic acute hepatitis].

PMID- 12594380
TI  - [Mucosa-associated lyphoid tissue hepatic lymphoma with low-grade malignancy
      associated with primary biliary cirrhosis].

PMID- 12594382
TI  - [Late presentation of Wilson's disease as cirrhosis complicating hepatocellular
      carcinoma].

PMID- 12594384
TI  - [Inflammatory pseudotumor: tumor or pseudotumor?].

PMID- 12594383
TI  - [Ileoanal anastomosis without ileostomy].

PMID- 12594385
TI  - [Histologic changes after stereotactic 11-Gauge directional vacuum assisted
      breast biopsy for mammary calcification: experience in 31 surgical specimens].
AB  - II Gauge directional large core vacuum assisted biopsy has been used recently in
      the etiological diagnosis of microcalcifications. The objective of our work was
      to summarize the histological modifications resulting from vacuum biopsies
      observed on 31 surgical specimens issuing from a series of 109 biopsies performed
      over a 15-month period for malignant and borderline lesions. Histological
      modifications attributable to vacuum biopsies, scar tissue and displacements,
      were searched for in all cases. Scar tissue was seen as granulations,
      inflammation and hemorrhagic tissue associated or not with fat necrosis and/or
      foreign body giant-cell reaction. Displacements were seen as movements of injured
      tissue generally in the vicinity of scar tissue or vascular channels. Scar tissue
      was identified in all cases, presenting as star-shaped tissue measuring 12.8 mm
      on the average. Five displacements of either benign or malignant epithelia or of
      lymphovascular channels were observed (16% of the specimens). Scar tissue seen on
      surgical specimens indicates the location of the mammotome cut and confirms
      correctly directed surgery. It is particularly important to identify scar tissue
      because the lesions are nonpalpable and difficult to localize, or may have been
      totally removed at the initial biopsy. Displacements can be mistaken for
      infiltrating carcinoma or lymphatic invasion and must be carefully localized.
      They seem to be less frequent after vacuum biopsy.

PMID- 12594386
TI  - Recurrent and non-recurrent pigmented villonodular synovitis 1.
AB  - Pigmented villonodular synovitis (PVNS) is a benign intra-articular lesion.
      Patients are at risk for local recurrence. Factors that predict recurrence are
      not established. Two groups of patients were retrieved from our files. One
      consisted of 25 patients who had one or more recurrences within 5 years after
      primary surgery. The second group contained 18 historical controls free of
      recurrence for at least 5 years after primary surgery. Patient medical records
      and surgical notes were reviewed. We compared proliferative activity and DNA
      ploidy using digital image analysis, and other clinicopathologic features between
      the 2 groups of patients. The location of PVNS was significantly different
      between the two groups (p=0.03). In the recurrence group, there were 7 (28%)
      cases with disease in the knee. However, none of the controls had disease in the
      knee. Among recurrent cases, tumors in the knee were, on average, larger than
      tumors in the small joints. The size of all recurrent tumors was not
      significantly different than non-recurrent tumors (median of 1.8 cm versus 1.3
      cm, respectively; p=0.06). There were no significant differences in age, sex,
      completeness of surgical removal, MIB-I index, DNA ploidy, or the percent of
      tumor nuclei in the diploid, S-phase, tetraploid, or hypertetraploid DNA
      histogram categories between the two groups. Our results indicate that recurrent
      PVNS tumors were more likely to be located in the knee, which may be related to
      larger tumor size. Patient age, sex, completeness of surgical removal, DNA
      ploidy, and MIB-I proliferation were not significantly different between
      recurrent and non-recurrent lesions.

PMID- 12594387
TI  - [Inflammatory myofibroblastic tumors].
AB  - Inflammatory myofibroblastic tumors (IMT) are mesenchymal solid tumors that occur
      preferentially in children and young adults. They present as myofibroblastic cell
      proliferations accompanied by plasmocytes and lymphocytes. Recent cytogenetic and
      molecular observations showed non-random abnormalities of chromosomal band 2p23
      resulting in a rearrangement of the ALK gene. This finding of a specific gene
      alteration suggests a neoplastic rather than a reactive inflammatory process for
      IMT tumorigenesis. ALK is a tyrosine kinase oncogene initially found to be
      rearranged in anaplastic large-cell lymphomas (ALCL). Of note, the breakpoints
      within ALK, and also within some of the ALK fusion gene partners, such as TPM3 or
      CLTC, are similar in IMT and ALCL. The consistent involvement of ALK, together
      with the diversity of partner genes, underlines the central role of ALK
      constitutive activation in IMT development, as well as the importance of
      homodimerization mechanisms of the chimeric fusion proteins in this activation.
      Immunohistochemical analyses performed on paraffin embedded tissue sections have
      shown positive ALK expression with cytoplasmic localization in half of the IMT
      cases containing the molecular ALK rearrangement. In conclusion, these novel
      molecular data have defined a group of IMT of neoplastic origin characterized by
      the presence of ALK alterations. The description of ALK gene rearrangements in
      IMT and ALCL is the second example, after the observation of ETV6-NTRK3 in
      congenital fibrosarcoma and in a case of chronic myeloid leukemia, of identical
      gene fusions occurring in two different cell lines: hematopoietic and
      mesenchymal. The search for rearrangement of ALK by fluorescence in situ
      hybridization (FISH) is a useful complementary tool for IMT diagnosis.

PMID- 12594388
TI  - [Langerhans cell histiocytosis of the large bowel].
AB  - Gastrointestinal tract involvement in Langerhans'cell histiocytosis (LCH) is
      unusual. It is most often observed in children, is usually asymptomatic,
      diagnosed at post mortem examination and associated with a disseminated disease.
      We report 2 cases of LCH large bowel involvement occuring in a 50-year- old man
      and in a 71-year-old woman, who presented with digestive symptoms. Histiocytic
      proliferation with reniform nuclei was demonstrated in colonic biopsies it was
      located in the lamina propria, and dissociating the mucosa glands.
      Immunohistochemical study revealed a strong positivity of these cells with anti
      CD1a and anti-PS100 antibodies. Ultrastructural study performed in one case
      showed large cells with reniform and indented nuclei, numerous tubuloreticular
      structures and Birbeck granules. Digestive localization of LCH is exceptional in
      adult, and may be underestimated.

PMID- 12594389
TI  - [Giant cell fibroblastoma recurring as dermatofibrosarcoma. A pediatric case
      report].
AB  - Giant cell fibroblastoma (GCF) is a rare neoplasm occurring mostly in children.
      It has a tendency to recur locally after treatment. We report a new case noticed
      in an five year-old child who developed recurrence a first time three years later
      with the picture of GCF and at a second time with the picture of
      dermatofibrosarcoma protuberans 17 months later.

PMID- 12594390
TI  - [Arrhythmogenic right ventricular cardiomyopathy versus fatty replacement of the
      right ventricle. An autopsy case report].
AB  - We report an autopsy case of a cardiomyopathy characterized by fatty replacement
      of the right ventricular myocardium and compare its clinical and histologic
      characteristics with those of the arrhythmogenic right ventricular
      cardiomyopathy. A 39-year old male died suddenly in a hospital room. He had an
      alcoholic cirrhosis with ascitis, but the clinical examination and the biology
      showed no abnormalities explaining the death. Histologically, in the right
      ventricle, large areas of cardiomyocytes were replaced by fat, but there was no
      fibrosis. In contrast, fibrosis is present in association with fat in
      arrhythmogenic right ventricular cardiomyopathy. Fatty replacement of the right
      ventricle is likely to be a distinct entity. Right ventricular failure has been
      shown to be a possible complication. Sudden death is probably rare and is likely
      to occur when other arrhythmogenic factors are associated.

PMID- 12594391
TI  - [Pulmonary veno-occlusive disease in a patient with HIV infection. A case report
      with autopsy findings].
AB  - We relate the autopsy findings of a case of pulmonary veno-occlusive disease
      which occurred in an HIV-infected intravenous drug abuser. This exceedingly rare
      disease, of unknown cause, is responsible for 10% of primary pulmonary
      hypertension. Histologically, the disease is characterized by a fibrous intimal
      thickening of small and medium sized pulmonary veins associated with congestive
      and dilated capillary network and alveolar haemorrhage. The occurrence of primary
      pulmonary hypertension in HIV positive patients is 25 times more frequent than in
      the general population. This is the third reported case of pulmonary veno
      occlusive disease occurring in a HIV positive patient. It suggests the role of
      HIV in the pathogenesis of these vascular lesions.

PMID- 12594393
TI  - [Unusual urinary bladder polyps].

PMID- 12594392
TI  - [Extra neural perineurioma: an unusal renal tumor].
AB  - Neoplasia composed of perineurial cells include intraneural and extraneural
      perineurioma. The latter is a rare tumor often observed in cutaneous tissue. We
      report a case of extraneural perineurioma developed at the upper pole of the left
      kidney and found during the assessment of a repetitive urinary tract infection in
      a 26 years old man. The tumor was composed of spindle-shaped cells arranged in a
      storiform pattern. The immunohistochemical pattern was EMA+, PS100-.

PMID- 12594394
TI  - [A gastric tumor].

PMID- 12594395
TI  - [Renal pathology: a rare association of immunoglobulin deposits].

PMID- 12594396
TI  - [An esophageal ulcer].

PMID- 12594397
TI  - [A tumor of the kidney which should not be misdiagnosed].

PMID- 12594398
TI  - [A tumor of the ovary in a young woman].

PMID- 12594399
TI  - [Adrenal corticomedullary adenoma. An entity to know].

PMID- 12594400
TI  - [Cystic mature teratoma of the thymus].

PMID- 12594401
TI  - [Pulmonary papillary adenoma: report of two cases].

PMID- 12594403
TI  - Household molds. The truth about these unwanted visitors.

PMID- 12594404
TI  - Married couples are more likely to have the same diseases.

PMID- 12594405
TI  - Mastectomy and lumpectomy are declared equal for survival from many breast
      cancers.

PMID- 12594406
TI  - Getting enough vitamins. Do you need to supplement a healthy diet?

PMID- 12594407
TI  - Nipple discharge. Usually more scary than dangerous.

PMID- 12594408
TI  - Fighting osteoporosis? A strong back is your best defense.

PMID- 12594409
TI  - Am I still immune to smallpox if I was vaccinated as a child?

PMID- 12594410
TI  - What's the difference between extra-virgin olive oil and virgin olive oil?

PMID- 12594411
TI  - Is the calcium in antacids absorbed as well as is the calcium from supplements?

PMID- 12594414
TI  - Maxillary molar distalization or mandibular enhancement: a cephalometric
      comparison of comprehensive orthodontic treatment including the pendulum and the
      Herbst appliances.
AB  - Several methods of Class II treatment that do not rely on significant patient
      compliance have become popular during the last decade, including several versions
      of the Herbst appliance and the pendulum or Pendex molar-distalization
      appliances. Yet, these 2 general approaches theoretically have opposite treatment
      effects, one presumably enhancing mandibular growth, and the other moving the
      maxillary teeth posteriorly. This study examined the treatment effects produced
      by 2 types of the Herbst appliance (acrylic splint and stainless-steel crown)
      followed by fixed appliances, and the pendulum appliance followed by fixed
      appliances. For each of the 3 treatment groups, lateral cephalograms were
      analyzed before the start of treatment (T1) and after the second phase of
      treatment (T2). Patients were matched according to age and sex. The comprehensive
      treatment time for the pendulum group was 31.6 months, and the acrylic and
      crowned Herbst groups were treated for 29.5 months and 28.0 months, respectively.
      Overall from T1 to T2, there were no statistically significant differences in
      mandibular growth among the 3 groups. Skeletal changes accounted for a larger
      portion of molar correction in the Herbst treatment groups than in the pendulum
      group. Patients in the pendulum group had an increase in the mandibular plane
      angle. Conversely, the mandibular plane angle in patients treated with either
      Herbst appliance closed slightly from T1 to T2. At T2, the chin points (pogonion)
      of patients in both Herbst groups, however, were located slightly more anteriorly
      than were the chin points of the pendulum patients. It is likely that the slight
      downward and backward rotation of the mandible occurring during treatment in the
      pendulum patients accounted for much of this difference. The treatment effects
      produced by the 2 types of Herbst appliance were similar at T2, in spite of their
      differences in design. It is important not to generalize the findings of this
      comparison beyond the appliance systems evaluated. The 2 general approaches we
      evaluated involved a substantial dentoalveolar component in the treatment of
      Class II malocclusion. A comparison of a molar-distalizing appliance such as the
      pendulum with other types of functional appliances might yield differing results.

PMID- 12594415
TI  - Incisor trauma and early treatment for Class II Division 1 malocclusion.
AB  - This study investigated incisor trauma in children with overjets greater than or
      equal to 7 mm who were enrolled in a clinical trial of 2-phase early orthodontic
      treatment for Class II malocclusion. In phase 1, children were randomly assigned
      to treatment in the mixed dentition with either modified bionator or combination
      headgear or to a group in which treatment was delayed until the permanent
      dentition. All children received comprehensive treatment during phase 2 if
      necessary. At the start of the trial, 29.1% of the patients had already had some
      incisor trauma. This was not significantly related to dental developmental age.
      During the trial, there was an increase in trauma in all 3 groups, but the
      magnitude of this increase was not significantly greater in the group for which
      treatment was delayed until the permanent dentition. This might suggest that
      orthodontic intervention aimed at reducing trauma should begin very soon after
      the eruption of the maxillary incisors. However, the injuries tended to be minor,
      and the expected cost of treatment related to incisor trauma was small compared
      with the expected additional cost of a 2-phase orthodontic intervention.

PMID- 12594417
TI  - Expectations of treatment and satisfaction with dentofacial appearance in
      orthodontic patients.
AB  - The aim of this study was to investigate correlations between satisfaction with
      dental and facial appearance and expectations of orthodontic treatment. The
      effects of sex and age on these variables were also explored. A sample of 154
      patients who applied for orthodontic treatment at the Academic Centre of
      Dentistry Amsterdam, The Netherlands, completed 2 questionnaires, containing 16
      items on satisfaction with facial appearance and 23 items on expectations of
      orthodontic treatment. First, the structure of the questionnaires was analyzed.
      Next, correlations between patients' expectations, satisfaction with facial
      appearance, age, and sex were examined. A multiple regression analysis was used
      to estimate the effect of the initial facial satisfaction on expectations of
      orthodontic treatment. Principal components analysis of the questionnaire about
      expectations showed 4 factors with an Eigenvalue greater than 1, accounting for
      72% of the total variance. These were defined as "general well-being," "self
      image/appearance," "future dental health," and "oral function." We found that
      "satisfaction with facial appearance" could be divided into 2 factors, each with
      an Eigenvalue greater than 1, accounting for 64% of the total variance. These
      were interpreted as "general facial appearance" and "dental appearance."
      Significant correlations were found between satisfaction with dental appearance
      and patients' expectations. These correlations were invariant over gender, but
      not over age. It was concluded that satisfaction with dental appearance is a
      significant predictor of orthodontic patients' expectations of treatment.

PMID- 12594418
TI  - Bialveolar protrusion in a Zimbabwean sample.
AB  - This study was undertaken to assess dentoalveolar relationships in a well
      balanced sample of adult black Zimbabweans. Lateral cephalograms of 25 men and 25
      women 18 to 38 years of age with Class I occlusions were obtained from the
      University of Zimbabwe. Twelve angular and 6 linear measurements were analyzed,
      and men and women were compared with the Student t test. No statistically
      significant difference was noted between the 2 sexes. The Zimbabwean sample had a
      low Frankfort-mandibular plane angle (19.6 degrees +/- 5.5 degrees ) with a
      receding chin as shown by the negative Pog-NB measurement (-0.7 +/- 1.5 mm). Both
      the maxilla (SNA = 88.5 degrees +/- 4.7 degrees ) and the mandible (SNB = 83.3
      degrees +/- 4.4 degrees ) were prognathic, and the ANB difference was large (5.3
      degrees +/- 2.7 degrees ). The maxillary incisors were more upright compared with
      those of white people as measured by the angle of the maxillary incisor to NA
      line (20.6 degrees +/- 7.7 degrees ), while the mandibular incisors were severely
      proclined (IMPA = 105.8 degrees +/- 6.0 degrees, L1-Apog = 6.9 degrees +/- 2.7
      degrees, L1-NB = 37.6 degrees +/- 4.9 degrees ), and this proclination was
      considered to be compensatory to the prognathic maxilla.

PMID- 12594419
TI  - Prevalence of third molar impaction in orthodontic patients treated nonextraction
      and with extraction of 4 premolars.
AB  - The purposes of this study were to confirm that premolar extraction treatment is
      associated with mesial movement of the molars concomitant with an increase in the
      eruption space for the third molars and to test the hypothesis that such
      treatment reduces the frequency of third molar impaction. Lateral cephalograms,
      panoramic or periapical radiographs, and study models made before (T1) and after
      (T2) treatment and a minimum of 10 years postretention (T3) of 157 patients were
      selected from the postretention sample at the Department of Orthodontics of the
      University of Washington, Seattle. Treatment for 105 patients included the
      extraction of 4 premolars; the other 53 were treated nonextraction. These
      patients represented all the extraction and nonextraction patients in the sample
      who had at least 1 third molar at T1 or T2 and who showed evidence of full
      eruption or closure of the root apex at T2 or T3. Student t tests showed higher
      scores for third molar impaction (P <.01), less mesial movement of the molars
      from T1 to T2 (P <.01), and smaller retromolar space at T2 (P <.001) in both
      arches of the nonex patients than in the ex patients. Similarly, molar movement
      was more mesial from T1 to T2 in the maxilla (P <.01) and in the mandible (P
      <.05), and the retromolar space was larger in both arches (P <.001) of the
      patients with eruption than in those with impaction of the third molars. Our
      results suggest that premolar extraction therapy reduces the frequency of third
      molar impaction because of increased eruption space concomitant with mesial
      movement of the molars during space closure.

PMID- 12594420
TI  - Speech performance in lingual orthodontic patients measured by sonagraphy and
      auditive analysis.
AB  - Esthetically appealing, externally invisible, lingually applied orthodontic
      brackets are in increasing demand. Because the brackets are placed lingually,
      however, they appear to cause some problems with respect to speech. This study is
      the first to present a prospective evaluation of the articulation of 23 patients
      with lingual brackets by means of an innovative combination of test methods. An
      acoustic, objective evaluation of articulation measured by digital sonagraphy was
      related to a semiobjective auditive evaluation by 10 speech professionals, to a
      semiobjective auditive evaluation by close contacts of the patients, and to a
      subjective auditive evaluation by the patients themselves, the latter 2 using
      standardized questionnaires. The tests were performed before (T1), within 24
      hours after (T2), and 3 months (+/- 1 week) after (T3) the start of therapy. In
      comparison with the initial findings, a significant deterioration in articulation
      was recorded with all test methods at T2 and T3. Using a new combination of
      methods, our investigations show the need for detailed briefing of patients about
      the extent and duration of changes in speech resulting from lingual brackets.

PMID- 12594421
TI  - Lateral functional shift of the mandible: Part I. Effects on condylar cartilage
      thickness and proliferation.
AB  - Lateral functional shift of the mandible is characterized by transverse rotation
      of the entire mandible about a vertical axis toward 1 side of the head. The
      effect of this shift is that the condyle on the side opposite the direction of
      the shift is displaced anteriorly, or protruded, while the condyle on the side
      toward the shift is more stable positionally and is likely to be slightly
      retruded. According to the view that growth of the mandibular condylar cartilage
      (MCC) adapts to its local functional-biomechanical environment, differential
      changes in metabolic activity of the MCC would be expected on the nonprotruded
      and the protruded sides. To evaluate this hypothesis, 21 rats (28 days old) were
      fitted with intraoral positioners designed to shift the mandibular postural
      position asymmetrically. Cartilage thickness and BrdU labeling index in the MCC
      3, 7, and 14 days after placement of the positioners were compared with those in
      age-matched controls that received no positioners. Cartilage thickness in the MCC
      on the protruded side was significantly greater than that in the controls at each
      time interval, with the difference increasing slightly with time. The labeling
      index for the protruded MCC was significantly greater than the controls at both 7
      and 14 days after positioner placement. Trends on the nonprotruded side were
      generally opposite, culminating in reduced thickness and proliferation after 14
      days. Thickness and labeling index were greater on the protruded side at every
      time interval except 3 days (labeling index). These trends in cartilage thickness
      and proliferation are consistent with previous studies of MCC changes after
      bilateral functional protrusion or retrusion. These data suggest that changes in
      MCC thickness and proliferative activity might accompany a lateral functional
      shift of the mandible in growing persons.

PMID- 12594422
TI  - Lateral functional shift of the mandible: Part II. Effects on gene expression in
      condylar cartilage.
AB  - There is considerable evidence that proliferation and growth in the mandibular
      condylar cartilage (MCC) might be altered after a change in the postural position
      of the mandible. However, almost nothing is known about the molecular basis of
      this response. Using semiquantitative reverse-transcription polymerase chain
      reaction, we examined the expression of insulin-like growth factor-1 (Igf-1),
      fibroblast growth factor-2 (Fgf-2), and their receptors (Igf-1r, Fgfr1, Fgfr2,
      and Fgfr3) in the MCC of 28 day-old rats at 3, 7, and 14 days after placing
      intraoral appliances designed to produce a lateral functional shift of the
      mandible. This shift resulted in a transverse rotation of the mandible so that
      the condyle on the side away from the shift was distracted anteriorly (ie,
      protruded) from the glenoid fossa, while the contralateral condyle remained in
      place or moved slightly posteriorly (ie, nonprotruded). Gene expression for 5 of
      the 6 genes studied was significantly different (P <.05) between the protruded
      and the nonprotruded sides. In nearly every instance at the 3- and 7-day
      intervals, mRNA expression on the protruded side compared with age-matched
      controls was altered in the opposite direction from the nonprotruded side.
      Especially on the protruded side, the most pronounced differences from the
      control were evident at 3 and 7 days. In general, the changes in gene expression
      preceded the alterations in proliferative activity documented previously. These
      data suggest that alterations in the mRNA expression of Igf-1, Fgf-2, and their
      receptors might underlie in part changes in MCC proliferative activity after
      alteration in mandibular posture.

PMID- 12594423
TI  - Comparison of radiographic and photographic measurement of mandibular asymmetry.
AB  - This study compared measurement of mandibular asymmetry by digitization of
      mandibular outlines from standardized facial photographs and posteroanterior
      cephalometric radiographs. Four ratios were used in calculating asymmetry: area
      (relative size of right and left mandibular segments), perimeter or length of
      outlines, compactness (shape), and moment. The records of 28 patients with
      varying degrees of asymmetry were used. A significant relationship was found for
      3 of the ratios (area, compactness, and moment) between measurements from
      photographs and radiographs. A further comparison showed that measurements from
      the radiographs correlated more closely with those from photographs when the
      mastoid processes were used as a baseline, rather than latero-orbitale.
      Repeatability of mandibular outline digitization proved satisfactory. Although
      digitization from standardized photographs is the preferred approach, the results
      indicated that posteroanterior cephalometric radiographs can be used similarly.
      Unlike other cephalometric analyses for mandibular asymmetry, this method avoids
      problems of landmark identification, thus presenting a clinically useful method
      of quantifying asymmetry, eg, in auditing the surgical-orthodontic correction of
      asymmetry or monitoring change over time.

PMID- 12594424
TI  - Panoramic radiographs: a tool for investigating skeletal pattern.
AB  - The objective of this study was to investigate the possibility of enhancing the
      clinical versatility of the panoramic radiograph, which is an indispensable tool
      for dental diagnosis. The material of this study consisted of lateral
      cephalograms and panoramic radiographs obtained from 30 patients. A correlation
      test was performed between the parametric measurements, and the predictability
      level of the cephalometric measurements from panoramic radiograms was determined
      by using regression equations. The equations showed that the Go-Gn/S-N, ANS
      PNS/Go-Me (palatal plane/mandibular plane), and Co-Go/Go-Me parameters could be
      predicted from panoramic radiographs within statistically significant levels, and
      their predictability levels were 20.6%, 15.6%, and 11.2%, respectively.
      Statistically significant correlations and predictability levels were also
      determined for the cephalometric and corresponding panoramic parameters in which
      Frankfort horizontal plane was used. It can be concluded that even though
      panoramic radiographs provide information on the vertical dimensions of
      craniofacial structures, clinicians should be vigilant when predicting skeletal
      cephalometric parameters from panoramic radiographs, because of their lower
      predictability percentages.

PMID- 12594425
TI  - Pathologic findings in orthodontic radiographic images.
AB  - Orthodontists routinely use radiography to diagnose malocclusions, plan
      treatment, and assess progress or the achievement of treatment goals. These films
      often contain evidence of oral or dentofacial pathology that require dental or
      medical consultation and treatment. This study is a cross-sectional survey of 396
      orthodontic patients under treatment at a single time whose x-ray films were
      examined for pathologic findings by oral radiologists or treating clinicians. The
      results showed that more than 6% of these patients had significant findings, some
      with medical ramifications.

PMID- 12594426
TI  - An innovative orthodontic-prosthetic approach for a patient with dental and
      skeletal asymmetry.
AB  - A 26-year-old woman with dentofacial asymmetry shown by hemimandibular elongation
      and dental asymmetry was treated with a conservative orthodontic-prosthetic
      approach. The mechanics and sequence of treatment are described.

PMID- 12594427
TI  - Litigation, legislation, and ethics: Inferences, presumptions, and certainties.

PMID- 12594428
TI  - Life lessons.

PMID- 12594430
TI  - Follow the ethical path.

PMID- 12594432
TI  - Don't get fooled by AMI mimics. Understanding S-T elevation.

PMID- 12594433
TI  - 200-City Survey. JEMS' Annual Report on EMS Operational and Clinical Trends in
      the Country's 200 Most Populous Cities for 2002.

PMID- 12594434
TI  - Is the scene safe? New realities require extra vigilance.

PMID- 12594435
TI  - EMS generation next. Precepting programs develop future EMS generations despite
      widely varying curricula and teaching modalities.

PMID- 12594436
TI  - SNL and street life. Tips from a 25-year EMS mentor.

PMID- 12594437
TI  - An abstract, abnormal anomaly. The mystery of seizures and how to treat them in
      the field.

PMID- 12594439
TI  - Ready, aim, fire! New IO device simplifies vascular access in severe cases.

PMID- 12594440
TI  - The new IT thing. Does EMS understand information technology?

PMID- 12594441
TI  - Bennies. A financial strategy for valuable people.

PMID- 12594442
TI  - Excuses, excuses.

PMID- 12594443
TI  - Motivated by money.

PMID- 12594448
TI  - The problem of decompensated heart failure: nomenclature, classification, and
      risk stratification.
AB  - Despite its high prevalence and significant rates of associated morbidity and
      mortality, the syndrome of decompensated heart failure remains poorly defined and
      vastly understudied. Few high-quality epidemiologic studies, randomized
      controlled trials, or published guidelines are available to guide the management
      of this complex disease. In addition, there is no consensus definition of the
      clinical problem that it presents, no agreed upon nomenclature to describe its
      clinical features, and no recognized classification scheme for its patient
      population; all of which has contributed to the lack of therapeutic development
      in this critical arena of cardiovascular disease. This review outlines the scope
      of the problem and proposes a system of nomenclature and classification
      sufficiently simple for general acceptance among clinicians while still
      encompassing the heterogeneity of the patient population. It also defines the
      current understanding of strategies for risk stratification in the setting of
      decompensated heart failure.

PMID- 12594447
TI  - Current medical treatment for the exacerbation of chronic heart failure resulting
      in hospitalization.

PMID- 12594449
TI  - Dyspnea as an end point in clinical trials of therapies for acute decompensated
      heart failure.

PMID- 12594450
TI  - B-type natriuretic peptide: from bench to bedside.

PMID- 12594451
TI  - Design considerations and proposed template for clinical trials in hospitalized
      patients with decompensated chronic heart failure.

PMID- 12594452
TI  - Rationale and study design for a multicenter, randomized, double-blind, placebo
      controlled study of the effects of tolvaptan on the acute and chronic outcomes of
      patients hospitalized with worsening congestive heart failure.

PMID- 12594453
TI  - Rationale and design of the pilot randomized study of nesiritide versus
      dobutamine in heart failure (PRESERVD-HF).

PMID- 12594454
TI  - Tezosentan in patients with acute heart failure and acute coronary syndromes:
      design of the fourth Randomized Intravenous Tezosentan Study (RITZ-4).

PMID- 12594455
TI  - Rationale and design of the Initiation Management Predischarge: Process for
      Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) study.

PMID- 12594456
TI  - Concomitant use of a positive inotropic agent to create a bridge to the
      successful initiation of beta-blocker therapy in patients with heart failure: a
      proposal for a trial.

PMID- 12594457
TI  - Surrogate end points in heart failure trials.

PMID- 12594458
TI  - Direct measurement of the transfer rate of chloroplast DNA into the nucleus.
AB  - Gene transfer from the chloroplast to the nucleus has occurred over evolutionary
      time. Functional gene establishment in the nucleus is rare, but DNA transfer
      without functionality is presumably more frequent. Here, we measured directly the
      transfer rate of chloroplast DNA (cpDNA) into the nucleus of tobacco plants
      (Nicotiana tabacum). To visualize this process, a nucleus-specific neomycin
      phosphotransferase gene (neoSTLS2) was integrated into the chloroplast genome,
      and the transfer of cpDNA to the nucleus was detected by screening for kanamycin
      resistant seedlings in progeny. A screen for kanamycin-resistant seedlings was
      conducted with about 250,000 progeny produced by fertilization of wild-type
      females with pollen from plants containing cp-neoSTLS2. Sixteen plants of
      independent origin were identified and their progenies showed stable inheritance
      of neoSTLS2, characteristic of nuclear genes. Thus, we provide a quantitative
      estimate of one transposition event in about 16,000 pollen grains for the
      frequency of transfer of cpDNA to the nucleus. In addition to its evident role in
      organellar evolution, transposition of cpDNA to the nucleus in tobacco occurs at
      a rate that must have significant consequences for existing nuclear genes.

PMID- 12594459
TI  - Formation of recent martian gullies through melting of extensive water-rich snow
      deposits.
AB  - The observation of gullies on Mars indicates the presence of liquid water near
      the surface in recent times, which is difficult to reconcile with the current
      cold climate. Gullies have been proposed to form through surface runoff from
      subsurface aquifers or through melting of near-surface ice under warmer
      conditions. But these gullies are observed to occur preferentially in cold mid
      latitudes, where the presence of liquid water is less likely, and on isolated
      surfaces where groundwater seepage would not be expected, making both potential
      explanations unsatisfactory. Here I show that gullies can form by the melting of
      water-rich snow that has been transported from the poles to mid-latitudes during
      periods of high obliquity within the past 10(5) to 10(6) years (refs 5, 6).
      Melting within this snow can generate sufficient water to erode gullies in about
      5,000 years. My proposed model for gully formation is consistent with the age and
      location of the gullies, and it explains the occurrence of liquid water in the
      cold mid-latitudes as well as on isolated surfaces. Remnants of the snowpacks are
      still present on mid-latitude, pole-facing slopes, and the recent or current
      occurrence of liquid water within them provides a potential abode for life.

PMID- 12594461
TI  - How to publish in Nature.

PMID- 12594460
TI  - Regulated degradation of a class V myosin receptor directs movement of the yeast
      vacuole.
AB  - Normal cellular function requires that organelles be positioned in specific
      locations. The direction in which molecular motors move organelles is based in
      part on the polarity of microtubules and actin filaments. However, this alone
      does not determine the intracellular destination of organelles. For example, the
      yeast class V myosin, Myo2p, moves several organelles to distinct locations
      during the cell cycle. Thus the movement of each type of Myo2p cargo must be
      regulated uniquely. Here we report a regulatory mechanism that specifically
      provides directionality to vacuole movement. The vacuole-specific Myo2p receptor,
      Vac17p, has a key function in this process. Vac17p binds simultaneously to Myo2p
      and to Vac8p, a vacuolar membrane protein. The transport complex, Myo2p-Vac17p
      Vac8p, moves the vacuole to the bud, and is then disrupted through the
      degradation of Vac17p. The vacuole is ultimately deposited near the centre of the
      bud. Removal of a PEST sequence (a potential signal for rapid protein
      degradation) within Vac17p causes its stabilization and the subsequent 'backward'
      movement of vacuoles, which mis-targets them to the neck between the mother cell
      and the bud. Thus the regulated disruption of this transport complex places the
      vacuole in its proper location. This may be a general mechanism whereby
      organelles are deposited at their terminal destination.

PMID- 12594462
TI  - In support of xeno-optimism.

PMID- 12594463
TI  - Statement on the consideration of biodefence and biosecurity.

PMID- 12594464
TI  - Nobel laureate slams misconduct smear.

PMID- 12594465
TI  - Error reports threaten to unravel databases of mitochondrial DNA.

PMID- 12594466
TI  - Researchers fear the future as Congress settles 2003 budget.

PMID- 12594467
TI  - Journals tighten up on biosecurity.

PMID- 12594468
TI  - Paper retracted as co-author admits forgery.

PMID- 12594469
TI  - Ministers back gene-crop advisers.

PMID- 12594470
TI  - Dolly's death leaves researchers woolly on clone ageing issue.

PMID- 12594471
TI  - Poor farmers warned against Internet transgenic crop deals.

PMID- 12594472
TI  - Cosmologists look forward to clearer picture.

PMID- 12594473
TI  - Windfall spurs rare Israeli-Palestinian research effort.

PMID- 12594475
TI  - Complex systems: All together now.

PMID- 12594476
TI  - Materials science: To the heart of glass.

PMID- 12594477
TI  - Scientific freedom: some face a lonely dilemma.

PMID- 12594478
TI  - Gene flow might turn wimps into superweeds.

PMID- 12594479
TI  - Scientific freedom: new strategies are needed.

PMID- 12594480
TI  - Venezuelan government is backing science.

PMID- 12594481
TI  - Free access to publicly funded databases is vital.

PMID- 12594482
TI  - GreenSea's interest in fertilizing sea with iron.

PMID- 12594483
TI  - Eastern Europe nurtures talent for the West.

PMID- 12594484
TI  - Biodefence on the research agenda.

PMID- 12594490
TI  - Science in culture: Leonardo lifts off.

PMID- 12594492
TI  - Molecular biology: A fix for RNA.

PMID- 12594493
TI  - Quantum computing: The qubit duet.

PMID- 12594494
TI  - Neurobiology: Interneurons take charge.

PMID- 12594495
TI  - Animal behaviour: How self-organization evolves.

PMID- 12594496
TI  - Electronics: Polymers light the way.

PMID- 12594498
TI  - Applied physics: Son et lumiere.

PMID- 12594497
TI  - Molecular chaperones: Plugging the transport gap.

PMID- 12594501
TI  - Climate modelling: Severe summertime flooding in Europe.

PMID- 12594502
TI  - Ecology: Parthenogenesis in an outsider crayfish.

PMID- 12594504
TI  - An exceptionally preserved Lower Cretaceous ecosystem.
AB  - Fieldwork in the Early Cretaceous Jehol Group, northeastern China has revealed a
      plethora of extraordinarily well-preserved fossils that are shaping some of the
      most contentious debates in palaeontology and evolutionary biology. These
      discoveries include feathered theropod dinosaurs and early birds, which provide
      additional, indisputable support for the dinosaurian ancestry of birds, and much
      new evidence on the evolution of feathers and flight. Specimens of putative basal
      angiosperms and primitive mammals are clarifying details of the early radiations
      of these major clades. Detailed soft-tissue preservation of the organisms from
      the Jehol Biota is providing palaeobiological insights that would not normally be
      accessible from the fossil record.

PMID- 12594505
TI  - The importance of water to oceanic mantle melting regimes.
AB  - The formation of basaltic crust at mid-ocean ridges and ocean islands provides a
      window into the compositional and thermal state of the Earth's upper mantle. But
      the interpretation of geochemical and crustal-thickness data in terms of magma
      source parameters depends on our understanding of the melting, melt-extraction
      and differentiation processes that intervene between the magma source and the
      crust. Much of the quantitative theory developed to model these processes has
      neglected the role of water in the mantle and in magma, despite the observed
      presence of water in ocean-floor basalts. Here we extend two quantitative models
      of ridge melting, mixing and fractionation to show that the addition of water can
      cause an increase in total melt production and crustal thickness while causing a
      decrease in mean extent of melting. This may help to resolve several enigmatic
      observations in the major- and trace-element chemistry of both normal and hotspot
      affected ridge basalts.

PMID- 12594506
TI  - Investigation of the obscuring circumnuclear torus in the active galaxy Mrk231.
AB  - Active galaxies are characterized by prominent emission from their nuclei. In the
      'unified' view of active galaxies, the accretion of material onto a massive
      compact object--now generally believed to be a black hole--provides the
      fundamental power source. Obscuring material along the line of sight can account
      for the observed differences in the nuclear emission, which determine the
      classification of AGN (for example, as Seyfert 1 or Seyfert 2 galaxies). Although
      the physical processes of accretion have been confirmed observationally, the
      structure and extent of the obscuring material have not been determined. Here we
      report observations of powerful hydroxyl (OH) line emissions that trace this
      obscuring material within the circumnuclear environment of the galaxy Markarian
      231. The hydroxyl (mega)-maser emission shows the characteristics of a rotating,
      dusty, molecular torus (or thick disk) located between 30 and 100 pc from the
      central engine. We now have a clear view of the physical conditions, the
      kinematics and the spatial structure of this material on intermediate size
      scales, confirming the main tenets of unification models.

PMID- 12594507
TI  - Quantum oscillations in two coupled charge qubits.
AB  - A practical quantum computer, if built, would consist of a set of coupled two
      level quantum systems (qubits). Among the variety of qubits implemented, solid
      state qubits are of particular interest because of their potential suitability
      for integrated devices. A variety of qubits based on Josephson junctions have
      been implemented; these exploit the coherence of Cooper-pair tunnelling in the
      superconducting state. Despite apparent progress in the implementation of
      individual solid-state qubits, there have been no experimental reports of
      multiple qubit gates--a basic requirement for building a real quantum computer.
      Here we demonstrate a Josephson circuit consisting of two coupled charge qubits.
      Using a pulse technique, we coherently mix quantum states and observe quantum
      oscillations, the spectrum of which reflects interaction between the qubits. Our
      results demonstrate the feasibility of coupling multiple solid-state qubits, and
      indicate the existence of entangled two-qubit states.

PMID- 12594508
TI  - Probing molecular dynamics with attosecond resolution using correlated wave
      packet pairs.
AB  - Spectroscopic measurements with increasingly higher time resolution are generally
      thought to require increasingly shorter laser pulses, as illustrated by the
      recent monitoring of the decay of core-excited krypton using attosecond photon
      pulses. However, an alternative approach to probing ultrafast dynamic processes
      might be provided by entanglement, which has improved the precision of quantum
      optical measurements. Here we use this approach to observe the motion of a D2+
      vibrational wave packet formed during the multiphoton ionization of D2 over
      several femtoseconds with a precision of about 200 attoseconds and 0.05
      angstroms, by exploiting the correlation between the electronic and nuclear wave
      packets formed during the ionization event. An intense infrared laser field
      drives the electron wave packet, and electron recollision probes the nuclear
      motion. Our results show that laser pulse duration need not limit the time
      resolution of a spectroscopic measurement, provided the process studied involves
      the formation of correlated wave packets, one of which can be controlled; spatial
      resolution is likewise not limited to the focal spot size or laser wavelength.

PMID- 12594509
TI  - Multi-colour organic light-emitting displays by solution processing.
AB  - Organic light-emitting diodes (OLEDs) show promise for applications as high
      quality self-emissive displays for portable devices such as cellular phones and
      personal organizers. Although monochrome operation is sufficient for some
      applications, the extension to multi-colour devices--such as RGB (red, green,
      blue) matrix displays--could greatly enhance their technological impact. Multi
      colour OLEDs have been successfully fabricated by vacuum deposition of small
      electroluminescent molecules, but solution processing of larger molecules
      (electroluminescent polymers) would result in a cheaper and simpler manufacturing
      process. However, it has proved difficult to combine the solution processing
      approach with the high-resolution patterning techniques required to produce a
      pixelated display. Recent attempts have focused on the modification of standard
      printing techniques, such as screen printing and ink jetting, but those still
      have technical drawbacks. Here we report a class of electroluminescent polymers
      that can be patterned in a way similar to standard photoresist materials--soluble
      polymers with oxetane sidegroups that can be crosslinked photochemically to
      produce insoluble polymer networks in desired areas. The resolution of the
      process is sufficient to fabricate pixelated matrix displays. Consecutive
      deposition of polymers that are luminescent in each of the three RGB colours
      yielded a device with efficiencies comparable to state-of-the-art OLEDs and even
      slightly reduced onset voltages.

PMID- 12594510
TI  - Precise dating of Dansgaard-Oeschger climate oscillations in western Europe from
      stalagmite data.
AB  - The signature of Dansgaard-Oeschger events--millennial-scale abrupt climate
      oscillations during the last glacial period--is well established in ice cores and
      marine records. But the effects of such events in continental settings are not as
      clear, and their absolute chronology is uncertain beyond the limit of (14)C
      dating and annual layer counting for marine records and ice cores, respectively.
      Here we present carbon and oxygen isotope records from a stalagmite collected in
      southwest France which have been precisely dated using 234U/230Th ratios. We find
      rapid climate oscillations coincident with the established Dansgaard-Oeschger
      events between 83,000 and 32,000 years ago in both isotope records. The oxygen
      isotope signature is similar to a record from Soreq cave, Israel, and deep-sea
      records, indicating the large spatial scale of the climate oscillations. The
      signal in the carbon isotopes gives evidence of drastic and rapid vegetation
      changes in western Europe, an important site in human cultural evolution. We also
      find evidence for a long phase of extremely cold climate in southwest France
      between 61.2 +/- 0.6 and 67.4 +/- 0.9 kyr ago.

PMID- 12594511
TI  - New ages for human occupation and climatic change at Lake Mungo, Australia.
AB  - Australia's oldest human remains, found at Lake Mungo, include the world's oldest
      ritual ochre burial (Mungo III) and the first recorded cremation (Mungo I). Until
      now, the importance of these finds has been constrained by limited chronologies
      and palaeoenvironmental information. Mungo III, the source of the world's oldest
      human mitochondrial DNA, has been variously estimated at 30 thousand years (kyr)
      old, 42-45 kyr old and 62 +/- 6 kyr old, while radiocarbon estimates placed the
      Mungo I cremation near 20-26 kyr ago. Here we report a new series of 25 optical
      ages showing that both burials occurred at 40 +/- 2 kyr ago and that humans were
      present at Lake Mungo by 50-46 kyr ago, synchronously with, or soon after,
      initial occupation of northern and western Australia. Stratigraphic evidence
      indicates fluctuations between lake-full and drier conditions from 50 to 40 kyr
      ago, simultaneously with increased dust deposition, human arrival and continent
      wide extinction of the megafauna. This was followed by sustained aridity between
      40 and 30 kyr ago. This new chronology corrects previous estimates for human
      burials at this important site and provides a new picture of Homo sapiens
      adapting to deteriorating climate in the world's driest inhabited continent.

PMID- 12594512
TI  - Architecture and material properties of diatom shells provide effective
      mechanical protection.
AB  - Diatoms are the major contributors to phytoplankton blooms in lakes and in the
      sea and hence are central in aquatic ecosystems and the global carbon cycle. All
      free-living diatoms differ from other phytoplankton groups in having silicified
      cell walls in the form of two 'shells' (the frustule) of manifold shape and
      intricate architecture whose function and role, if any, in contributing to the
      evolutionary success of diatoms is under debate. We explored the defence
      potential of the frustules as armour against predators by measuring their
      strength. Real and virtual loading tests (using calibrated glass microneedles and
      finite element analysis) were performed on centric and pennate diatom cells. Here
      we show that the frustules are remarkably strong by virtue of their architecture
      and the material properties of the diatom silica. We conclude that diatom
      frustules have evolved as mechanical protection for the cells because exceptional
      force is required to break them. The evolutionary arms race between diatoms and
      their specialized predators will have had considerable influence in structuring
      pelagic food webs and biogeochemical cycles.

PMID- 12594513
TI  - Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo.
AB  - Neural-network oscillations at distinct frequencies have been implicated in the
      encoding, consolidation and retrieval of information in the hippocampus. Some
      GABA (gamma-aminobutyric acid)-containing interneurons fire phase-locked to theta
      oscillations (4-8 Hz) or to sharp-wave-associated ripple oscillations (120-200
      Hz), which represent different behavioural states. Interneurons also entrain
      pyramidal cells in vitro. The large diversity of interneurons poses the question
      of whether they have specific roles in shaping distinct network activities in
      vivo. Here we report that three distinct interneuron types--basket, axo-axonic
      and oriens-lacunosum-moleculare cells--visualized and defined by synaptic
      connectivity as well as by neurochemical markers, contribute differentially to
      theta and ripple oscillations in anaesthetized rats. The firing patterns of
      individual cells of the same class are remarkably stereotyped and provide unique
      signatures for each class. We conclude that the diversity of interneurons,
      innervating distinct domains of pyramidal cells, emerged to coordinate the
      activity of pyramidal cells in a temporally distinct and brain-state-dependent
      manner.

PMID- 12594514
TI  - Yeast genome duplication was followed by asynchronous differentiation of
      duplicated genes.
AB  - Gene redundancy has been observed in yeast, plant and human genomes, and is
      thought to be a consequence of whole-genome duplications. Baker's yeast,
      Saccharomyces cerevisiae, contains several hundred duplicated genes.
      Duplication(s) could have occurred before or after a given speciation. To
      understand the evolution of the yeast genome, we analysed orthologues of some of
      these genes in several related yeast species. On the basis of the inferred
      phylogeny of each set of genes, we were able to deduce whether the gene
      duplicated and/or specialized before or after the divergence of two yeast
      lineages. Here we show that the gene duplications might have occurred as a single
      event, and that it probably took place before the Saccharomyces and Kluyveromyces
      lineages diverged from each other. Further evolution of each duplicated gene pair
      such as specialization or differentiation of the two copies, or deletion of a
      single copy--has taken place independently throughout the evolution of these
      species.

PMID- 12594515
TI  - CD4+ T cells are required for secondary expansion and memory in CD8+ T
      lymphocytes.
AB  - A long-standing paradox in cellular immunology concerns the conditional
      requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T
      lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses
      can be primed in the absence of CD4+ T cells, others, such as those mediated
      through 'cross-priming' by host antigen-presenting cells, are dependent on T(H)
      cells. A clearer understanding of the contribution of T(H) cells to CTL
      development has been hampered by the fact that most T(H)-independent responses
      have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)
      dependent responses generally require secondary in vitro re-stimulation for their
      detection. Here, we have monitored the primary and secondary responses of T(H)
      dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are
      dispensable for primary expansion of CD8+ T cells and their differentiation into
      cytotoxic effectors. However, secondary CTL expansion (that is, a secondary
      response upon re-encounter with antigen) is wholly dependent on the presence of
      T(H) cells during, but not after, priming. Our results demonstrate that T-cell
      help is 'programmed' into CD8+ T cells during priming, conferring on these cells
      a hallmark of immune response memory: the capacity for functional expansion on re
      encounter with antigen.

PMID- 12594516
TI  - STAT3 signalling is required for leptin regulation of energy balance but not
      reproduction.
AB  - Secretion of leptin from adipocytes communicates body energy status to the brain
      by activating the leptin receptor long form (LRb). LRb regulates energy
      homeostasis and neuroendocrine function; the absence of LRb in db/db mice results
      in obesity, impaired growth, infertility and diabetes. Tyr 1138 of LRb mediates
      activation of the transcription factor STAT3 during leptin action. To investigate
      the contribution of STAT3 signalling to leptin action in vivo, we replaced the
      gene encoding the leptin receptor (lepr) in mice with an allele coding for a
      replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that
      specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice,
      lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db
      mice are infertile, short and diabetic, s/s mice are fertile, long and less
      hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is
      elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin
      system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus
      mediates the effects of leptin on melanocortin production and body energy
      homeostasis, whereas distinct LRb signals regulate NPY and the control of
      fertility, growth and glucose homeostasis.

PMID- 12594517
TI  - Human and bacterial oxidative demethylases repair alkylation damage in both RNA
      and DNA.
AB  - Repair of DNA damage is essential for maintaining genome integrity, and repair
      deficiencies in mammals are associated with cancer, neurological disease and
      developmental defects. Alkylation damage in DNA is repaired by at least three
      different mechanisms, including damage reversal by oxidative demethylation of 1
      methyladenine and 3-methylcytosine by Escherichia coli AlkB. By contrast, little
      is known about consequences and cellular handling of alkylation damage to RNA.
      Here we show that two human AlkB homologues, hABH2 and hABH3, also are oxidative
      DNA demethylases and that AlkB and hABH3, but not hABH2, also repair RNA. Whereas
      AlkB and hABH3 prefer single-stranded nucleic acids, hABH2 acts more efficiently
      on double-stranded DNA. In addition, AlkB and hABH3 expressed in E. coli
      reactivate methylated RNA bacteriophage MS2 in vivo, illustrating the biological
      relevance of this repair activity and establishing RNA repair as a potentially
      important defence mechanism in living cells. The different catalytic properties
      and the different subnuclear localization patterns shown by the human homologues
      indicate that hABH2 and hABH3 have distinct roles in the cellular response to
      alkylation damage.

PMID- 12594518
TI  - The complete folding pathway of a protein from nanoseconds to microseconds.
AB  - Combining experimental and simulation data to describe all of the structures and
      the pathways involved in folding a protein is problematical. Transition states
      can be mapped experimentally by phi values, but the denatured state is very
      difficult to analyse under conditions that favour folding. Also computer
      simulation at atomic resolution is currently limited to about a microsecond or
      less. Ultrafast-folding proteins fold and unfold on timescales accessible by both
      approaches, so here we study the folding pathway of the three-helix bundle
      protein Engrailed homeodomain. Experimentally, the protein collapses in a
      microsecond to give an intermediate with much native alpha-helical secondary
      structure, which is the major component of the denatured state under conditions
      that favour folding. A mutant protein shows this state to be compact and contain
      dynamic, native-like helices with unstructured side chains. In the transition
      state between this and the native state, the structure of the helices is nearly
      fully formed and their docking is in progress, approximating to a classical
      diffusion-collision model. Molecular dynamics simulations give rate constants and
      structural details highly consistent with experiment, thereby completing the
      description of folding at atomic resolution.

PMID- 12594520
TI  - Capturing competencies.

PMID- 12594521
TI  - Forensics offers career opportunities for the Sherlock Holmes of the future--and
      the work is far from elementary.

PMID- 12594522
TI  - NTP Toxicology and Carcinogenesis Studies of Nickel Subsulfide (CAS No. 12035-72
      2) in F344 Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Nickel subsulfide is used in the manufacture of lithium batteries and is a major
      component in the refining of certain nickel ores. Nickel subsulfide was nominated
      as part of a class study of nickel compounds, for which there was little
      information on the toxic and carcinogenic effects of inhalation exposure. Male
      and female F334/N rats and B6C3F1 mice were exposed to nickel subsulfide (at
      least 97% pure; the mean value for the mass median aerodynamic diameter at each
      exposure concentration ranged from 2.0 to 2.2 mm by inhalation 6 hours per day, 5
      days per week, for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium, and mouse peripheral blood samples were
      analyzed for frequency of micronucleated normochromatic erythrocytes. 16-DAY
      STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to
      atmospheres containing 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel subsulfide/m(3)
      (equivalent to 0, 0.44, 0.88, 1.83, 3.65, and 7.33 mg nickel/m(3)) 6 hours per
      day, 5 days per week for a total of 12 exposure days during a 16-day period.
      Additionalmgroups of three male and three female rats were exposed to 0, 0.6,
      2.5, or 10 mg/m(3) for tissue burden studies. One male exposed to 10 mg nickel
      subsulfide/m(3) in the core study died on day 14; all other rats survived until
      the end of the study. Final mean body weights and mean body weight gains of males
      exposed to 5 or 10 mg nickel subsulfide/m(3) and females exposed to 2.5, 5, or 10
      mg/m(3) were significantly lower than those of the controls. Clinical findings of
      toxicity on day 5 of the study included labored respiration in 10 mg/m(3) males
      and 5 and 10 mg/m(3) females and dehydration in 5 and 10 mg/m(3) females.
      Absolute and relative lung weights of 2.5, 5, and 10 mg/m(3) males and all
      exposed groups of females were significantlymgreater than those of the controls,
      as was the absolute lung weight of 1.2 mg/m(3) males. Inflammation of the lung
      and atrophy of the nasal olfactory epithelium occurred in all exposed mgroups.
      The concentrations of nickel in the lungs of exposedmgroups of rats increased
      with exposure concentration (males, 7 to 67 mg nickel/g lung; females, 9 to 77
      mg/g lung). 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice
      were exposed to atmospheres containing 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel
      subsulfide/m(3) for 6 hours per day, 5 days per week for a total of 12 exposure
      days during a 16-day period. Additional groups of three male and three female
      mice were exposed to 0, 0.6, 2.5, or 10 mg/m(3) for tissue burden studies. All
      male and female mice exposed to 10 mg nickel subsulfide/m(3) in the core study
      died before the end of the study; the death of one female was accidental. One
      control male, one control female, and one 1.2 mg/m(3) male also died before the
      end of the study. Final mean body weights and mean body weight gains of 5 mg/m(3)
      males were significantly lower than those of the controls. Clinical findings at
      day 5 included labored respiration in 10 mg/m(3) males and females. The absolute
      lung weight of 5 mg/m(3) males, the absolute and relative lung weights of 10
      mg/m(3) males and 5 mg/m(3) females, and the relative lung weight of 10 mg/m(3)
      females were significantly greater than those of the controls. Inflammation of
      the lung occurred in 2.5, 5, and 10 mg/m(3) male and female mice, fibrosis of the
      lung occurred in 5 mg/m(3) males and females, and lymphoid hyperplasia of the
      bronchial lymph nodes and atrophy of the nasal olfactory epithelium occurred in
      1.2, 2.5, 5, and 10 mg/m(3) males and females. Nickel concentrations in the lung
      of exposed male and female mice were greater than those of the controls (males,
      10 to 20 mg nickel/g lung; females, 8 to 20 mg/g lung) 13-WEEK STUDY IN RATS:
      Groups of 10 male and 10 female F344/N rats were exposed to atmospheres
      containing 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulfide/m(3) (equivalent
      to 0, 0.11, 0.22, 0.44, 0.88, and 1.83 mg nickel/m(3)) 6 hours per day, 5 days
      per week for 13 weeks. Additional groups of 18 male and 18 female female rats
      were exposed to 0, 0.15, 0.6, or 2.5 mg/m(3) for tissue burden studies. All core
      study rats survived until the end of the study. Final mean body weights and mean
      body weight gains of 2.5 mg/m(3) males were significantly lower than those of the
      controls; final mean body weights of all other exposure groups were similar to
      those of the controls. Chemical-related clinical findings included labored
      respiration in 2.5 mg/m(3) males and females during weeks 2 through 7. In
      general, neutrophil and erythrocyte counts, hematocrit values, and hemoglobin
      concentrations were minimally increased in exposed rats. Absolute and relative
      lung weights of all exposed groups were significantly greater than those of the
      controls. Increases in the number of alveolar macrophages, interstitial
      infiltrates, or incidences of chronic inflammation of the lung occurred in all
      groups exposed to nickel subsulfide concentrations of 0.3 mg/m(3) or greater; the
      severity of these lesions generally increased with increasing exposure
      concentration. Increases in the number of alveolar macrophages were observed in
      0.15 mg/m(3) males and females. Lymphoid hyperplasia of the bronchial and
      mediastinal lymph nodes was observed in rats exposed to 0.3 mg/m(3) or greater.
      Most 0.6, 1.2, and 2.5 mg/m(3) males and females had atrophy of the nasal
      olfactory epithelium, and the severity generally increased with increasing
      exposure concentration. Nickel concentrations in the lung increased with exposure
      concentration and were greater than those in the controls in rats exposed for 13
      weeks (males, 5 to 18 mg nickel/g lung; females, 5 to 17 mg/g lung). 13-WEEK
      STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to
      atmospheres containing 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulfide/m(3)
      for 6 hours per day, 5 days per week for 13 weeks. Additional groups of six male
      and six female mice were exposed to 0, 0.15, 0.6, or 2.5 mg/m(3) for tissue
      burden studies. Final mean body weights of all exposure groups were similar to
      those of the controls. No chemical-related clinical findings were observed.
      Lymphocyte counts in 1.2 and 2.5 mg/m(3) males were minimally greater than that
      of the controls. Hemoglobin concentrations and erythrocyte counts in 0.3, 0.6,
      1.2, and 2.5 mg/m(3) females were minimally greater than those of the controls.
      Absolute and relative lung weights of 1.2 and 2.5 mg/m(3) males and females were
      significantly greater than those of the controls. An increase in alveolar
      macrophages was present in mice from the 0.3 mg/m(3) and higher exposure groups.
      Chronic inflammation and fibrosis were observed in the lung of 1.2 and 2.5
      mg/m(3) males and females. Interstitial infiltrates of lymphocytes were observed
      in mice exposed to 0.6, 1.2, or 2.5 mg/m(3). Lymphoid hyperplasia of the
      bronchial lymph nodes was observed in groups exposed to 1.2 or 2.5 mg/m(3).
      Atrophy of the nasal olfactory epithelium occurred in 0.6, 1.2, and 2.5 mg/m(3)
      males and females, and incidences and severity generally increased with
      increasing exposure concentration. At 13 weeks, nickel concentrations in the
      lungs of exposed mice were greater than those of the controls (males, 3 to 17 g
      nickel/g lung; females, 6 to 23 mg/g lung), and these concentrations increased
      with increasing exposure concentration. 2-YEAR STUDY IN RATS: Survival, Body
      Weights, Clinical Findings, and Hematology: Groups of 63 male and 63 female
      F344/N rats were exposed to 0, 0.15, or 1 mg nickel subsulfide/m(3) (equivalent
      to 0, 0.11, or 0.73 mg nickel/m(3)) by inhalation for 6 hours per day, 5 days per
      week for 104 weeks. Survival of exposed males and female rats was similar to that
      of the controls. Mean body weights of males and females exposed to 0.15 mg/m(3)
      were similar to those of the controls. Mean body weights of rats exposed to 1
      mg/m(3) were lower than those of the controls throughout the second year of the
      study. Chemical-related clinical findings included rapid and shallow breathing
      following exposure periods. Hematocrit values and hemoglobin concentrations in 1
      mg/m(3) males and females and the erythrocyte count in 1 mg/m(3) males were
      mildly greater than those in the controls. Pathology Findings: In general, the
      absolute and relative lung weights of exposed males and females were
      significantly greater than those of the controls at 7 and 15 months. There were
      exposure-related increases in the incidences of alveolar/bronchiolar adenoma in
      males, alveolar/bronchiolar carcinoma in males and females, and
      alveolar/bronchiolar adenoma or carcinoma (combined) in males and females at 2
      years. Nonneoplastic lung lesions generally observed in exposed males and females
      included fibrosis; chronic active inflammation; focal alveolar epithelial
      hyperplasia, macrophage hyperplasia, and proteinosis; bronchial lymphoid
      hyperplasia; and interstitial inflammation. At 2 years, there were significant
      exposure-related increases in the incidences of benign pheochromocytoma,
      malignant pheochromocytoma, and benign or malignant pheochromocytoma (combined)
      in males and of benign pheochromocytoma in females. The incidence of adrenal
      medulla hyperplasia in 1 mg/m(3) females was significantly greater than that of
      the controls At 2 years, the incidences of chronic active inflammation of the
      nose in 1 mg/m(3) females and of olfactory epithelial atrophy in 1 mg/m(3) males
      and females were significantly greater than those of the controls. The incidences
      of lymphoid hyperplasia of the bronchial lymph node in exposed males at 7 and 15
      months and in exposed males and females at 2 years were significantly greater
      than those of the controls. Incidences of macrophage hyperplasia in the bronchial
      lymph node of exposed males at 15 months and exposed males and females at 2 years
      were greater than those of the controls. Tissue Burden Analyses: Nickel
      concentrations in the lungs of exposed rats were greater than those of the
      controls at 7 months (males, 6 to 9 mg nickel/g lung; females, 6 to 9 mg/g lung)
      and 15 months (males, 4 to 3 mg nickel/g lung; females, 4 to 7 mg/g lung). 2-YEAR
      STUDY IN MICE: Survival, Body Weights, Clinical Findings, and Hematology: Groups
      of 80 male and 80 female B6C3F1 mice were exposed to 0, 0.6, or 1.2 mg nickel
      subsulfide/m(3) (equivalent to 0, 0.44, or 0.88 mg nickel/m(3)) by inhalation for
      6 hours per day, 5 days per week for 105 weeks. Survival of exposed male and
      female mice was similar to that of the controls. Mean body weights of 0.6 and 1.2
      mg/m(3) males and females were less than those of the controls throughout the
      second year of the study. Chemical-related clinical findings in male and female
      mice included labored respiration following exposure periods. The hematocrit
      value and the segmented neutrophil, monocyte, lymphocyte, and total leukocyte
      counts in 1.2 mg/m(3) females were greater than those in the controls. Pathology
      Findings: Absolute and relative lung weights of exposed males and females were
      generally significantly greater than those of the controls at 7 and 15 months.
      The incidence of alveolar/bronchiolar carcinoma in 0.6 mg/m(3) females and the
      incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in 0.6 mg/m(3)
      males and 0.6 and 1.2 mg/m(3) females were significantly less than those of the
      controls. In general, the incidences of chronic active inflammation;
      bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia and
      proteinosis; interstitial infiltration; and fibrosis in exposed groups of males
      and females were greater than those of the controls at 7 and 15 months and at 2
      years. The incidences of atrophy of the nasal olfactory epithelium and
      inflammation of the nose in exposed mice were also generally greater than those
      of the controls. At 2 years, the incidences of degeneration of olfactory
      epithelium in exposed females were significantly less than that of the controls.
      The incidences of lymphoid hyperplasia of the bronchial lymph node in 1.2 mg/m(3)
      males at 15 months, in 0.6 and 1.2 mg/m(3) females at 15 months, and in 0.6 and
      1.2 mg/m(3) males and females at 2 years were significantly greater than those of
      the controls. The incidences of macrophage hyperplasia in 1.2 mg/m(3) males at 7
      and 15 months, in 0.6 and 1.2 mg/m(3) females at 15 months, and in 0.6 and 1.2
      mg/m(3) males and females at 2 years were significantly greater than those of the
      controls. Tissue Burden Analyses: Nickel concentrations in the lungs of exposed
      mice were greater than those of the controls at 7 months (males, 10 to 11 mg
      nickel/g lung; females, 10 to 14 mg/g lung) and 15 months (males, 12 to 20 mg
      nickel/g lung; females, 15 to 26 mg/g lung). GENETIC TOXICOLOGY: Nickel
      subsulfide was considered to be equivocal in the Salmonella gene mutation assay
      overall. Sporadic weakly positive and equivocal responses were obtained in strain
      TA100 with and without S9 metabolic activation enzymes; all other
      strain/activation combinations gave negative results. No increase in the
      frequency of micronucleated erythrocytes was observed in peripheral blood samples
      from male or female mice exposed to nickel subsulfide by inhalation for 13 weeks.
      CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was
      clear evidence of carcinogenic activity of nickel subsulfide in male F344/N rats
      based on increased incidences of alveolar/bronchiolar adenoma, carcinoma, and
      adenoma or carcinoma (combined) and on increased incidences of benign, malignant,
      and benign or malignant (combined) pheochromocytoma of the adrenal medulla. There
      was clear evidence of carcinogenic activity of nickel subsulfide in female F344/N
      rats based on increased incidences of alveolar/bronchiolar carcinoma and
      alveolar/bronchiolar adenoma or carcinoma (combined) and an increased incidence
      of benign pheochromocytoma of the adrenal medulla. There was no evidence of
      carcinogenic activity of nickel subsulfide in male or female B6C3F1 mice exposed
      to 0.6 or 1.2 mg/m(3). Exposure of male and female rats to nickel subsulfide by
      inhalation for 2 years resulted in inflammation, hyperplasia, and fibrosis in the
      lung; inflammation and atrophy of the olfactory epithelium in the nose; and
      hyperplasia in the adrenal medulla (females). Exposure of male and female mice to
      nickel subsulfide by inhalation for 2 years resulted in inflammation,
      bronchialization, hyperplasia, and fibrosis in the lung and inflammation and
      atrophy of the olfactory epithelium in the nose. Synonyms: Heazlewoodite, nickel
      subsulphide, nickel sulfide (3:2), a-nickel sulfide (3:2) crystalline, nickel
      sulphide, nickel tritadisulphide, trinickel disulfide

PMID- 12594523
TI  - NTP Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol
      (FR-1138(R)) (CAS No. 3296-90-0) in F344 Rats and B6C3F1 Mice (Feed Studies).
AB  - 2,2-Bis(bromomethyl)-1,3-propanediol is used as a fire retardant in unsaturated
      polyester resins, in molded products, and in rigid polyurethane foam. 2,2
      Bis(bromomethyl)-1,3-propanediol was chosen for study because it is a widely used
      flame retardant and little toxicity and carcinogenicity data were available.
      Groups of male and female F344/N rats and B6C3F1 mice were exposed to technical
      grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for 13 weeks or 2
      years. Genetic toxicology studies were conducted in Salmonella typhimurium,
      cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral
      blood. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets
      containing 0, 1,250, 2,500, 5,000, 10,000, or 20,000 ppm 2,2-bis(bromomethyl)-
      1,3-propanediol for 13 weeks. These levels corresponded to approximately 100,
      200, 400, 800, or 1,700 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight
      (males) and 100, 200, 400, 800, or 1,600 mg/kg (females). No rats died during the
      studies. The final mean body weights and weight gains of 5,000, 10,000, and
      20,000 ppm males and females were significantly lower than those of the controls.
      Feed consumption by exposed animals was lower than that by controls at week 1,
      but was generally similar to or slightly higher than that by controls at week 13.
      No chemical-related clinical findings were observed. Chemical-related differences
      in clinical pathology parameters included increased urine volumes accompanied by
      decreased urine specific gravity and minimally increased protein excretion in
      10,000 and 20,000 ppm males. In females, urine parameters were less affected than
      males. Water deprivation tests demonstrated that male and female rats were able
      to adequately concentrate their urine in response to decreased water intake.
      Serum protein and albumin concentrations in female rats exposed to 2,500 ppm and
      higher were slightly lower than those of the controls. Renal papillary
      degeneration was present in 5,000 and 10,000 ppm males, and in 20,000 ppm males
      and females. Hyperplasia of the urinary bladder was present in 20,000 ppm males.
      13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets
      containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)-1,3
      propanediol for 13 weeks. These levels corresponded to approximately 100, 200,
      500, 1,300, or 3,000 mg 2,2-bis(bromomethyl)-1,3-propanediol/kg body weight
      (males) and 140, 300, 600, 1,200, or 2,900 mg/kg (females). One control female,
      two males and one female receiving 625 ppm, one female receiving 1,250 ppm, one
      female receiving 2,500 ppm, one female receiving 5,000 ppm, and three males
      receiving 10,000 ppm died during the study. The final mean body weights and body
      weight gains of males and females receiving 1,250, 2,500, 5,000, or 10,000 ppm
      and of females receiving 625 ppm were significantly lower than those of the
      controls. Feed consumption by exposed mice was generally higher than that by
      controls throughout the study. Clinical findings included abnormal posture and
      hypoactivity in 10,000 ppm male and female mice. Blood urea nitrogen
      concentrations of 5,000 ppm females and 10,000 ppm males and females were greater
      than those of controls. Also, urine specific gravity was lower in 10,000 ppm
      females. Differences in organ weights generally followed those in body weights.
      Papillary necrosis, renal tubule regeneration, and fibrosis were observed in the
      kidneys of 2,500 and 5,000 ppm males and 10,000 ppm males and females. Urinary
      bladder hyperplasia was observed in 5,000 and 10,000 ppm males and females. 2
      YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000,
      or 10,000 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 weeks.
      Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3
      propanediol in feed for 104 to 105 weeks. A stop-exposure group of 70 male rats
      received 20,000 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 3 months,
      after which animals received undosed feed for the remainder of the 2-year styear
      study. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200,
      or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. Stop
      exposure males received an average daily dose of 800 mg/kg. Ten animals from the
      0 ppm male group and the 20,000 ppm stop-exposure group were evaluated at 3
      months; nine or 10 control animals and five to nine animals from each of the
      continuous-exposure groups were evaluated at 15 months. Survival, Body Weights,
      Feed Consumption, and Clinical Findings: Survival of 5,000 and 10,000 ppm
      continuous-exposure study males and females and 20,000 ppm stop-exposure males
      was significantly lower than that of the controls. Mean body weights of exposed
      male and female rats receiving 10,000 ppm and stop-exposure males receiving
      20,000 ppm were lower than those of the controls throughout most of the study. In
      the continuous-exposure study, feed consumption by exposed rats was generally
      similar to that by controls throughout the study. In 20,000 ppm stop-exposure
      males, the feed consumption was lower than that by controls. Clinical findings
      included skin and/or subcutaneous masses on the face, tail, and the ventral and
      dorsal surfaces of exposed rats. Pathology Findings: In the 2-year continuous and
      stop-exposure studies in male rats, exposure to 2,2-bis(bromomethyl)-1,3
      propanediol was associated with neoplastic effects in the skin, mammary gland,
      Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines,
      mesothelium, urinary bladder, lung, thyroid gland, hematopoietic system, and
      seminal vesicle. Nonneoplastic effects in the kidney, lung, thyroid gland,
      seminal vesicle, pancreas, urinary bladder, and forestomach were also observed.
      In females, 2-year exposure to 2,2-bis(bromomethyl)-1,3-propanediol was
      associated with neoplastic effects in the oral cavity, esophagus, mammary gland,
      and thyroid gland. Nonneoplastic effects in the kidney were also observed. These
      findings are outlined in the two summary tables. 2-YEAR STUDY IN MICE: Groups of
      60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2
      bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. Average daily
      doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males)
      and 40, 80, or 170 mg/kg (females). Eight to 10 animals from each group were
      evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical
      Findings: Survival of 1,250 ppm males and females was significantly lower than
      that of the controls. Mean body weights of exposed male and female mice were
      similar to controls throughout the study. Final mean body weights were also
      generally similar to those of controls. Feed consumption by exposed male and
      female mice was similar to that by controls. Clinical findings included tissue
      masses involving the eye in exposed mice. Pathology Findings: Exposure of male
      mice to 2,2-bis(bromomethyl)-1,3-propanediol for 2 years was associated with
      neoplastic effects in the harderian gland, lung, and kidney. Exposure of female
      mice to 2,2-bis(bromomethyl)-1,3-propanediol was associated with increased
      incidences of neoplasms of the harderian gland, lung, and skin. Nonneoplastic
      effects in the lung were also observed in exposed females. These findings are
      outlined in the two summary tables. GENETIC TOXICOLOGY: 2,2-Bis(bromomethyl)-1,3
      propanediol was mutagenic in Salmonella typhimurium strain TA100 when tested in
      the presence of induced 30&percnt; hamster liver S9; all other strain/activation
      combinations gave negative results. In cultured Chinese hamster ovary cells, 2,2
      bis(bromomethyl)-1,3-propanediol induced chromosomal aberrations only in the
      presence of S9; no induction of sister chromatid exchanges was observed in
      cultured Chinese hamster ovary cells after treatment with 2,2-bis(bromomethyl)
      1,3-propanediol, with or without S9. In vivo, 2,2-bis(bromomethyl)-1,3
      propanediol induced significant increases in the frequencies of micronucleated
      erythrocytes in male and female mice. Significant increases in micronuclei were
      observed in peripheral blood samples from male and female mice exposed to 2,2
      bis(bromomethyl)-1,3-propanediol for 13 weeks via dosed feed. Results of a bone
      marrow micronucleus test in male mice, where 2,2-bis(bromomethyl)-1,3-propanediol
      was administered by gavage, were considered to be equivocal due to inconsistent
      results obtained in two trials. An additional bone marrow micronucleus test was
      performed with male and female mice and 2,2-bis(bromomethyl)-1,3-propanediol was
      administered as a single intraperitoneal injection; results of this test were
      positive in females and negative in males. CONCLUSIONS: Under the conditions of
      these 2-year feed studies, there was clear evidence of carcinogenic activity of
      2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on
      increased incidences of neoplasms of the skin, subcutaneous tissue, mammary
      gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large
      intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal
      vesicle, and the increased incidence of mononuclear cell leukemia. There was
      clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol
      in female F344/N rats based on increased incidences of neoplasms of the oral
      cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of
      carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice
      based on increased incidences of neoplasms of the harderian gland, lung, and
      kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)
      1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms
      of the harderian gland, lung, and subcutaneous tissue. Slight increases in the
      incidences of neoplasms of the pancreas and kidney in male rats; forestomach in
      male mice; and forestomach, mammary gland, and circulatory system in female mice
      may have also been related to treatment. Exposure of male and female rats to 2,2
      bis(bromomethyl)-1,3-propanediol was associated with alveolar/bronchiolar
      hyperplasia in the lung (males only); focal atrophy, papillary degeneration,
      transitional epithelial hyperplasia (pelvis), and papillary epithelial
      hyperplasia in the kidney; follicular cell hyperplasia in the thyroid gland
      (males only); hyperplasia in the seminal vesicle and pancreas (males only);
      mucosal hyperplasia in the forestomach (males only); and urinary bladder
      hyperplasia (males only). Exposure of mice to 2,2-bis(bromomethyl)-1,3
      propanediol was associated with hyperplasia of the alveolar epithelium in
      females. Synonyms: 2,2-Bis(2-bromomethyl)-1,3-propanediol; 1,3-dibromo-2,2
      dihydroxymethylpropane; 1,3-dibromo-2,2-dimethylolpropane; 2,2-dibromomethyl-1,3
      propanediol; dibromopentaerythritol; dibromoneopentyl glycol; pentaerythritol
      dibromide; pentaerythritol dibromohydrin

PMID- 12594524
TI  - NTP Toxicology and Carcinogenesis Studies of Nickel Oxide (CAS No. 1313-99-1) in
      F344 Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Nickel oxide (NiO) "sinters" are used in stainless steel and alloy steel
      production. Nickel oxide was nominated by the National Cancer Institute to the
      NTP for testing because exposure to this form of nickel is prevalent in the
      nickel industry. Increased incidences of lung and nasal sinus cancers have
      occurred among workers in certain nickel refining facilities, and nickel oxide
      was studied as part of a class study of nickel compounds. Male and female F344/N
      rats and B6C3F1 mice were exposed to nickel oxide (high temperature, green nickel
      oxide; mass median diameter 2.2 +/- 2.6 &mgr;m; at least 99% pure) by inhalation
      for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in
      peripheral blood of B6C3F1 mice exposed to nickel oxide for 13 weeks. 16-DAY
      STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0,
      1.2, 2.5, 5, 10, or 30 mg nickel oxide/m(3)(equivalent to 0, 0.9, 2.0, 3.9, 7.9,
      or 23.6 mg nickel/m(3)) by inhalation for 6 hours per day, 5 days per week for a
      total of 12 exposure days during a 16-day period. Additional groups of five male
      and five female rats were exposed to 0, 1.2, 5, or 10 mg/m(3) for tissue burden
      studies. All core study rats survived until the end of the study, final mean body
      weights of exposed male and female rats were similar to those of the controls,
      and there were no clinical findings related to nickel oxide exposure. Absolute
      and relative lung weights of male and female rats exposed to 10 or 30 mg/m(3)
      were significantly greater than those of the controls. Pigment particles in
      alveolar macrophages or within the alveolar spaces were observed in the lungs of
      exposed groups of males and females. Chronic-active inflammation and accumulation
      of macrophages in alveolar spaces of the lungs and hyperplasia in the respiratory
      tract lymph nodes were most severe in 10 and 30 mg/m(3) males and females.
      Hyperplasia of bronchial lymph nodes occurred in 30 mg/m(3) rats. Atrophy of the
      olfactory epithelium was observed in one male and one female exposed to 30
      mg/m(3). The concentrations of nickel oxide in the lungs of exposed groups of
      rats were greater than those in the lungs of control groups (males, 42 to 267 mg
      nickel/g lung; females, 54 to 340 mg/g lung). 16-DAY STUDY IN MICE: Groups of
      five male and five female B6C3F1 mice were exposed to 0, 1.2, 2.5, 5, 10, or 30
      mg nickel oxide/m(3) by inhalation for 6 hours per day, 5 days per week for a
      total of 12 exposure days during a 16-day period. Additional groups of five male
      and five female mice were exposed to 0, 1.2, 2.5, or 5 mg/m(3) for tissue burden
      studies. No exposure-related deaths occurred among core study mice, and final
      mean body weights of exposed male and female mice were similar to those of the
      controls. There were no chemical-related clinical findings. Pigment particles
      were present in the lungs of mice exposed to 2.5 mg/m(3) or greater. Accumulation
      of macrophages in alveolar spaces was observed in the lungs of 10 and 30
      mg/m(3)males and females. The concentrations of nickel oxide in the lungs of
      exposed groups of mice were significantly greater than those in the lungs of
      control animals (males, 32 to 84 mg nickel/g lung; females, 31 to 71 mg/g lung).
      13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed
      to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m(3) (equivalent to 0, 0.4, 0.9,
      2.0, 3.9, or 7.9 mg nickel/m(3)) by inhalation for 6 hours per day, 5 days per
      week for 13 weeks. Additional groups of 18 male and 18 female rats were exposed
      to 0, 0.6, 2.5, or 10 mg/m(3) for tissue burden studies. No exposure-related
      deaths occurred among core study rats, final mean body weights of exposed male
      and female rats were similar to those of the controls, and no clinical findings
      in any group were related to nickel oxide exposure. Lymphocyte, neutrophil,
      monocyte, and erythrocyte counts; hematocrit values; and hemoglobin and mean cell
      hemoglobin concentrations in exposed rats were minimally to mildly greater than
      those of the controls; these differences were most pronounced ironounced in
      females. Mean cell volumes in exposed rats were generally less than those in the
      controls. Absolute and relative lung weights of exposed groups of males and
      females were generally significantly greater than those of controls. Chemical
      related nonneoplastic lesions were observed in the lungs of male and female rats
      exposed to concentrations of 2.5 mg/m(3) or higher, and the severity of these
      lesions generally increased with exposure concentration. Accumulation of alveolar
      macrophages, many of which contained black, granular pigment, was generally
      observed in all exposed groups of males and females, and increased incidences of
      inflammation occurred in males and females exposed to 2.5 mg/m(3) or higher. In
      addition, lymphoid hyperplasia and pigment occurred in the bronchial and
      mediastinal lymph nodes of 2.5, 5, and 10 mg/m(3) males and females. The
      concentration of nickel oxide in the lungs of 0.6, 2.5, and 10 mg/m(3)males was
      greater than in the lungs of controls at 4, 9, and 13 weeks, and nickel continued
      to accumulate in the lung at the end of the 13-week exposures (4 weeks, 33 to 263
      mg nickel/g lung; 9 weeks, 53 to 400 mg/g lung; 13 weeks, 80 to 524 mg/g lung).
      13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed
      to 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel oxide/m(3) by inhalation for 6 hours per
      day, 5 days per week for 13 weeks. Additional groups of six male and six female
      mice were exposed to 0, 0.6, 2.5, or 10 mg/m(3) for tissue burden studies. No
      exposure-related deaths occurred among core study animals, final mean body
      weights of exposed male and female mice were similar to those of the controls,
      and no clinical findings in any group were related to nickel oxide exposure.
      Hematocrit values and erythrocyte counts in 5 and 10 mg/m(3) females were
      minimally greater than those of the controls, as was the hemoglobin concentration
      in 5 mg/m(3) females. Absolute and relative lung weights of 10 mg/m(3) males and
      females were significantly greater than those of controls, and absolute and
      relative liver weights of 10 mg/m(3) males were significantly less than those of
      controls. Accumulation of alveolar macrophages, many of which contained pigment
      particles, occurred in all groups of mice exposed to nickel oxide. Inflammation
      (chronic active perivascular infiltrates or granulomatous) occurred in 2.5, 5,
      and 10 mg/m(3) males and females. In addition, lymphoid hyperplasia and pigment
      occurred in the bronchial lymph nodes of males and females exposed to 2.5 mg/m(3)
      or higher. The concentration of nickel in the lung was greater than that of
      controls in 0.6, 2.5, and 10 mg/m(3) males at 13 weeks (42 to 736 mg nickel/g
      lung). 2-YEAR STUDY IN RATS: Survival, Body Weights, Clinical Findings, and
      Hematology Groups of 65 male and 65 female F344/N rats were exposed to 0, 0.62,
      1.25, or 2.5 mg nickel oxide/m(3) (equivalent to 0, 0.5, 1.0, or 2.0 mg
      nickel/m(3)) by inhalation for 6 hours per day, 5 days per week for 104 weeks.
      Survival of exposed male and female rats was similar to that of the controls.
      Mean body weights of 1.25 mg/m(3) females and 2.5 mg/m(3) males and females were
      slightly lower than those of the controls during the second year of the study. No
      chemical-related clinical findings were observed in male or female rats during
      the 2-year study. No chemical-related differences in hematology parameters were
      observed in male or female rats at the 15-month interim evaluation. Pathology
      Findings: Absolute and relative lung weights of 1.25 and 2.5 mg/m(3) males and
      females were significantly greater than those of the controls at 7 and 15 months.
      At 2 years, there were exposure-related increased incidences of
      alveolar/bronchiolar adenomas alveolar/bronchiolar adenoma or carcinoma
      (combined) in males and females. Incidences of atypical alveolar epithelial
      hyperplasia in the lungs generally increased with increasing exposure
      concentration in male and female rats. Chronic inflammation of the lung was
      observed in most exposed rats at 7 and 15 months and at 2 years; the incidences
      in exposed males and females at 2 years were significantly greater than those in
      the controls, and the severity of the inflammation increased in exposed groups.
      The incidences of pigmentation in the alveolus of exposed groups of males and
      females were significantly greater than those of the controls at 7 and 15 months
      and at 2 years. Pigmentation in the bronchial lymph nodes similar to that in the
      lungs was observed in all exposure groups with the exception of 0.62 mg/m(3)males
      and females at 7 months. Lymphoid hyperplasia was observed in the bronchial lymph
      nodes of 1.25 and 2.5 mg/m(3) males and females at 7 and 15 months, and the
      incidence at 2 years generally increased with exposure concentration. At 2 years,
      there was an exposure-related increase in the incidence of benign
      pheochromocytoma in males and females. The incidences of benign pheochromocytoma
      and adrenal medulla hyperplasia in 2.5 mg/m(3) females and the incidence of
      benign or malignant pheochromocytoma (combined) in 2.5 mg/m(3) males were
      significantly greater than those in the controls. Tissue Burden Analyses: Nickel
      concentrations in the lungs of exposed rats were greater than those in the
      controls at 7 and 15 months (7 months, 173 to 713 mg nickel/g lung; 15 months,
      262 to 1,116 mg/g lung), and nickel concentrations increased with increasing
      exposure concentration and with time. 2-YEAR STUDY IN MICE: Survival, Body
      Weights, Clinical Findings, and Hematology Groups of 74 to 79 B6C3F1 mice were
      exposed to 0, 1.25, 2.5, or 5 mg nickel oxide/m(3) by inhalation for 6 hours per
      day, 5 days per week for 104 weeks. Survival of exposed male and female mice was
      similar to that of the controls. Mean body weights of 5 mg/m(3) females were
      slightly lower than those of the controls during the second year of the study. No
      chemical-related clinical findings were observed in male or female mice during
      the 2-year study. No chemical-related differences in hematology parameters were
      observed in male or female mice at the 15-month interim evaluation. Pathology
      Findings: At 2 years, the incidence of alveolar/bronchiolar adenoma in 2.5
      mg/m(3) females was significantly greater than that of the controls, as was the
      incidence of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/m(3)
      females. Generally, incidences of chronic inflammation increased with exposure
      concentration in males and females at 7 and 15 months. Bronchialization of
      minimal severity in exposed animals and proteinosis were first observed at 15
      months. At 2 years, the incidences of chronic inflammation, alveolar epithelial
      hyperplasia, and proteinosis in exposed groups of males and females were
      significantly greater than those of the controls. The severity of chronic
      inflammation increased with exposure concentration in females, and proteinosis
      was most severe in 5 mg/m(3) males and females. Pigment occurred in the lungs of
      nearly all exposed mice at 7 and 15 months and at 2 years, and the severity
      increased with exposure concentration. Lymphoid hyperplasia occurred in two
      animals after 7 months; at 15 months, lymphoid hyperplasia occurred in males
      exposed to 2.5 and 5 mg/m(3) and in all exposed groups of females. At 2 years,
      lymphoid hyperplasia occurred in some control animals, but this lesion was still
      observed more often in exposed males and females and the incidence increased with
      exposure concentration. Pigmentation was observed in the bronchial lymph nodes of
      exposed males and females at 7 and 15 months and in nearly all exposed animals at
      2 years. Tissue Burden Analyses: Nickel concentrations in the lungs of exposed
      mice were significantly greater than those in the controls at 7 and 15 months (7
      months, 162 to 1,034 mg nickel/g lung; 15 months, 331 to 2,258 mg/g lung), and
      nickel concentrations increased with increasing exposure concentration and with
      time. GENETIC TOXICOLOGY: No increase in the frequency of micronucleated
      normochromatic erythrocytes was observed in peripheral blood samples from male or
      female mice exposed to nickel oxide. CONCLUSIONS: Under the conditions of these 2
      year inhalation studies, there was some evidence of carcinogenic activity of
      nickel oxide in male F344/N rats based on increased incidences of
      alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of
      benign or malignant pheochromocytoma (combined) of the adrenal medulla. There was
      some evidence of carcinogenic activity of nickel oxide in female F344/N rats
      based on increased incidences of alveolar/bronchiolar adenoma or carcinoma
      (combined) and increased incidences of benign pheochromocytoma of the adrenal
      medulla. There was no evidence of carcinogenic activity of nickel oxide in male
      B6C3F1 mice exposed to 1.25, 2.5, or 5 mg/m(3). There was equivocal evidence of
      carcinogenic activity of nickel oxide in female B6C3F1 mice based on marginally
      increased incidences of alveolar/bronchiolar adenoma in 2.5 mg/m(3) females and
      of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/m(3) females.
      Exposure of rats to nickel oxide by inhalation for 2 years resulted in
      inflammation and pigmentation in the lung, lymphoid hyperplasia and pigmentation
      in the bronchial lymph nodes, and hyperplasia of the adrenal medulla (females).
      Exposure of mice to nickel oxide by inhalation for 2 years resulted in
      bronchialization, proteinosis, inflammation, and pigmentation in the lung and
      lymphoid hyperplasia and pigmentation in the bronchial lymph nodes. Synonyms:
      Bunsenite; C.I. 77777; green nickel oxide; mononickel oxide; nickel monoxide;
      nickel oxide sinter 75; nickel protoxide; nickel (II) oxide; nickel (T+) oxide;
      nickelous oxide

PMID- 12594525
TI  - NTP Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 116-14
      3) in F344 Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Tetrafluoroethylene is used in the production of polytetrafluoroethylene
      (Teflon(R)) and other polymers. Tetrafluoroethylene was nominated by the National
      Cancer Institute for toxicity and carcinogenicity studies based on the potential
      for human exposure to the chemical due to the large production volume and on the
      lack of adequate data for tetrafluoroethylene in the literature. Male and female
      F344/N rats and B6C3F1 mice were exposed to tetrafluoroethylene (98% to 99% pure)
      by whole body inhalation exposure for 16 days, 13 weeks, or 2 years. Genetic
      toxicity studies were conducted in mouse peripheral blood erythrocytes. 16-DAY
      STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0,
      312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6
      hours per day, 5 days per week for a total of 12 exposures during a 16-day
      period. All rats survived to the end of the study. The final mean body weights
      and body weight gains of males and females exposed to 5,000 ppm were
      significantly less than those of the controls. The mean body weight gain of
      females exposed to 2,500 ppm was also significantly less than that of the
      controls. There were no exposure-related clinical findings in male or female
      rats. There were no significant differences in hematology parameters that were
      considered to be related to tetrafluoroethylene exposure. Absolute and relative
      kidney weights of all exposed groups of males were significantly greater than
      those of the controls, as were those of females in the 2,500 and 5,000 ppm
      groups. The absolute kidney weight of females exposed to 1,250 ppm was also
      significantly greater than that of the controls. The relative liver weights of
      all exposed groups of males and the absolute liver weights of males in the 625
      and 2,500 ppm groups were significantly greater than those of the controls.
      Increased incidences of renal tubule degeneration occurred in males and females
      exposed to 625 ppm or greater; this lesion was located predominantly at the
      corticomedullary junction. The severity of degeneration increased with increasing
      exposure concentration and was slightly greater in males than females. 16-DAY
      STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0,
      312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6
      hours per day, 5 days per week for a total of 12 exposures during a 16-day
      period. All mice survived to the end of the study. Final mean body weights and
      body weight gains of all exposed groups of mice were similar to those of the
      controls. There were no exposure-related clinical findings in male or female
      mice. There were no significant differences in hematology parameters that were
      considered to be related to tetrafluoroethylene exposure. The absolute and
      relative liver weights of females exposed to 5,000 ppm were significantly greater
      than those of the controls, as was the absolute kidney weight of females in that
      group and the absolute liver weight of females in the 2,500 ppm group. Renal
      tubule karyomegaly was observed in male and female mice in the 1,250, 2,500, and
      5,000 ppm groups, and the severity of this lesion increased with increasing
      exposure concentration. Karyomegaly was located predominantly in the inner renal
      cortex. 13-WEEK STUDY IN RATS: Groups of 10 male and 9 or 10 female F344/N rats
      were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by
      inhalation for 6 hours per day, 5 days per week, for 13 weeks. All rats survived
      to the end of the study. The final mean body weight and body weight gain of males
      exposed to 5,000 ppm were significantly less than those of the controls, as was
      the mean body weight gain of females in this exposure group. There were no
      clinical findings attributed to exposure to tetrafluoroethylene. Exposure of rats
      to tetrafluoroethylene resulted in a concentration-dependent normocytic,
      normochromic, nonresponsive anemia consistent with a secondary hypoproliferative
      anemia. An exposure concentration-dependent proteinuria also occurred, consistent
      with renal tubule th renal tubule degeneration observed histopathologically. The
      absolute and relative liver weights of all exposed groups of males and of females
      in the 5,000 ppm group were significantly greater than those of the controls. The
      absolute and relative right kidney weights of males and females exposed to 1,250
      ppm or greater and of females in the 625 ppm group were also significantly
      greater than those of the controls. There were no differences in sperm morphology
      or vaginal cytology parameters between control and exposed groups of rats.
      Incidences of renal tubule degeneration in males exposed to 625 ppm or greater
      and in females exposed to 2,500 or 5,000 ppm were significantly greater than
      those in the controls. Renal lesions were similar to those observed in the 16-day
      study and were located predominantly at the corticomedullary junction. 13-WEEK
      STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0,
      312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6
      hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the
      study. Final mean body weights and body weight gains of all exposed groups of
      male and female mice were generally similar to those of the controls. There were
      no clinical findings that were considered to be related to tetrafluoroethylene
      exposure. Exposure of mice to tetrafluoroethylene resulted in a concentration
      dependent normocytic, normochromic, nonresponsive anemia, consistent with a
      secondary hypoproliferative anemia, and in polyuria. Differences in sperm
      morphology parameters and estrous cycle lengths were not considered to be
      exposure related. Incidences of karyomegaly of the renal tubule epithelial cells
      in male and female mice exposed to 1,250 ppm or greater were significantly
      greater than those in the controls. Karyomegaly was similar to that observed in
      the 16-day study and was observed primarily in the inner renal cortex. 2-YEAR
      STUDY IN RATS: Groups of 60 male rats were exposed to 156, 312, or 625 ppm and
      groups of 60 female rats were exposed to 312, 625, or 1,250 ppm
      tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 104
      weeks, with an observation period of 11 days following the final exposure. Ten
      male and ten female rats from each exposure group were evaluated at 15 months for
      organ weights and clinical pathology. Survival, Body Weights, and Clinical
      Findings: Survival rates of males in the 625 ppm group and of all exposed groups
      of females were significantly less than those of the controls. Mean body weights
      of males exposed to 625 ppm were lower than those of the controls from week 81
      until the end of the study, and the mean body weight of 1,250 ppm females was
      slightly lower than that of the controls at the end of the study. The only
      clinical finding associated with exposure to tetrafluoroethylene was opacity of
      the eyes in exposed groups of female rats; this change was observed
      microscopically as cataracts. Hematology, Clinical Chemistry, and Urinalysis: At
      the 15-month interim evaluation, there were no differences in hematology,
      clinical chemistry, or urinalysis parameters that were considered to be related
      to tetrafluoroethylene exposure. Pathology Findings: The absolute and relative
      kidney weights of males exposed to 625 ppm and females exposed to 1,250 ppm and
      the absolute kidney weight of females exposed to 625 ppm were significantly
      greater than those of the controls at the 15-month interim evaluation. At 15
      months, renal tubule hyperplasia was observed in one male exposed to 312 ppm and
      one male and one female exposed to 625 ppm; oncocytic hyperplasia was observed in
      one female exposed to 1,250 ppm. At the end of the study, incidences of renal
      tubule adenoma were greater in males and females exposed to 312 ppm or greater
      than those in the controls. This exposure-related increase was confirmed by
      examination of step sections (extended evaluations). At the end of the study, the
      incidences of renal tubule hyperplasia in males exposed to 625 ppm and females
      exposed to 1,250 ppm were significantly greater than those in the controls. The
      incidences of renal tubule adenoma and renal tubule adenoma or carcinoma
      (combined) in the extended evaluations and in the standard and extended
      evaluations (combined) in the 1,250 ppm female group and the 625 ppm male group
      were significantly greater than those in the controls, and the incidences
      occurred with significant positive trends. Oncocytic hyperplasia was observed at
      the end of the study in one male exposed to 312 ppm and in three females exposed
      to 1,250 ppm. At 15 months and at the end of the study, the incidences of renal
      tubule degeneration in all exposed groups of males and in females in the 625 and
      1,250 ppm groups were greater than those in the controls. Renal tubule
      degeneration was similar to that observed in the 13-week study and was located
      predominantly at the corticomedullary junction. The severity of nephropathy
      generally increased with increasing exposure concentration in male rats at 15
      months and 2 years. The absolute and relative liver weights of females in the
      1,250 ppm group and the absolute liver weight of females exposed to 625 ppm were
      significantly greater than those of the controls at the 15-month interim
      evaluation. At 2 years, the incidences of hepatocellular carcinoma and
      hepatocellular adenoma or carcinoma (combined) in males exposed to 312 ppm, the
      incidences of hepatocellular adenoma and adenoma or carcinoma (combined) in
      females in all exposed groups, and the incidences of hepatocellular carcinoma in
      females exposed to 312 or 625 ppm were significantly greater than those in the
      controls. Also at 2 years, the incidence of hemangiosarcoma in females exposed to
      625 ppm was significantly greater than that in the controls. In all exposed
      groups of males, the incidences of clear cell foci at 15 months were greater than
      those in the controls; at 2 years, the incidences of eosinophilic foci in all
      exposed groups of males and the incidences of basophilic and mixed cell foci in
      males in the 312 and 625 ppm groups were greater than those in the controls. The
      incidences of mixed cell foci at 15 months in females exposed to 625 or 1,250 ppm
      and at 2 years in females exposed to 1,250 ppm were also significantly greater
      than those in the controls. At the end of the 2-year study, increased incidences
      of cystic degeneration occurred in the liver of all exposed groups of males, and
      increased incidences of hepatic angiectasis were observed in exposed groups of
      females. Incidences of mononuclear cell leukemia in males exposed to 156 ppm and
      in all exposed groups of females were significantly greater than those in the
      controls. Incidences of cataracts in females exposed to 1,250 ppm were greater
      than those in the controls at the end of the 2-year study. At the end of the
      study, there were slight increases in the incidences of testicular interstitial
      cell adenoma in rats exposed to 312 or 625 ppm. 2-YEAR STUDY IN MICE: Groups of
      58 male and 58 female B6C3F1 mice were exposed to 0, 312, 625, or 1,250 ppm
      tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 95 to
      96 weeks. Ten male and ten female mice from each exposure group were evaluated at
      15 months for organ weights. Survival, Body Weights, and Clinical Findings: The
      survival rates of all exposed groups of males and females were significantly less
      than those of the controls. Because of the reduced survival due to exposure
      related liver neoplasms, the study was terminated during week 96. Mean body
      weights of exposed groups of males and females were generally similar to those of
      the controls, except at the end of the study, when they were somewhat less than
      those of the controls. There were no clinical findings related to
      tetrafluoroethylene exposure. Pathology Findings: At the 15-month interim
      evaluation, there were no differences in absolute or relative kidney, liver, or
      lung weights between exposed and control groups of mice. At the end of the study,
      the incidences of multifocal coagulative necrosis of the liver were increased in
      males in the 625 and 1,250 ppm groups. Also at the end of the study, females in
      all exposed groups had greater incidences of hematopoietic cell proliferation in
      the liver than the controls. Angiectasis occurred in all exposed groups of males
      and females at 15 months and at the end of the study. At the 15-month interim
      evaluation, hemangiosarcomas were observed in three males exposed to 1,250 ppm
      and in one female exposed to 312 ppm. The incidences of hemangiosarcoma in all
      exposed groups of males and females at the end of the study were significantly
      greater than those in the controls and exceeded the historical chamber control
      ranges. Also at the end of the study, the incidences of hemangioma in males and
      females exposed to 312 ppm and in males exposed to 625 ppm were also
      significantly greater than those in the controls and exceeded the range in
      historical chamber controls. At 15 months, hepatocellular adenomas and carcinomas
      occurred in control males and all exposed groups of males and females. Females
      exposed to 625 or 1,250 ppm had significantly greater incidences of eosinophilic
      foci than the controls at the 15-month interim evaluation. At the end of the
      study, the incidences of eosinophilic foci in males exposed to 625 or 1,250 ppm
      and in females exposed to 312 or 625 ppm were significantly greater than those in
      the controls. In male and female mice, increased incidences of a variety of
      hepatocellular neoplasms, including adenomas, multiple adenomas, carcinomas, and
      multiple carcinomas, were considered related to tetrafluoroethylene exposure. At
      the end of the study, the incidences of histiocytic sarcoma (all organs) in all
      exposed groups of males and females were significantly greater than those in the
      controls and exceeded the historical control ranges for all organs. The greatest
      incidences of histiocytic sarcomas were observed in the liver and lung, but these
      neoplasms were also observed in the spleen, lymph nodes, bone marrow, and kidney.
      Significantly increased incidences of renal tubule dilatation (males) and
      karyomegaly (males and females), located predominantly in the inner cortex, were
      observed in mice exposed to 625 or 1,250 ppm at 15 months. At the end of the
      study, the increased incidences of dilatation and karyomegaly in all exposed
      groups of males and of karyomegaly in 1,250 ppm females were generally
      significant. Incidences of hematopoietic cell proliferation in the spleen of all
      exposed groups of males and females were significantly greater than those in the
      controls at the end of the study. Additionally, the severity of this lesion
      increased with increasing exposure concentration. GENETIC TOXICOLOGY: No
      increases in the frequency of micronucleated erythrocytes were observed in
      peripheral blood samples obtained from male and female mice at the end of the 13
      week inhalation study of tetrafluoroethylene. CONCLUSIONS: Under the conditions
      of these 2-year inhalation studies, there was clear evidence of carcinogenic
      activity of tetrafluoroethylene in male F344/N rats based on increased incidences
      of renal tubule neoplasms (mainly adenomas) and hepatocellular neoplasms. There
      was clear evidence of carcinogenic activity of tetrafluoroethylene in female
      F344/N rats based on increased incidences of renal tubule neoplasms, liver
      hemangiosarcomas, hepatocellular neoplasms, and mononuclear cell leukemia. There
      was clear evidence of carcinogenic activity of tetrafluoroethylene in male and
      female B6C3F1 mice based on increased incidences of liver hemangiomas and
      hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas. Slight
      increases in the incidences of mononuclear cell leukemia and testicular
      interstitial cell adenomas in male rats may have been related to exposure to
      tetrafluoroethylene. Exposure of rats to tetrafluoroethylene resulted in
      increased incidences of renal tubule hyperplasia and degeneration in males and
      females, increased severity of kidney nephropathy in males, and increased
      incidences of liver angiectasis and cataracts in females. Exposure of mice to
      tetrafluoroethylene resulted in increased incidences of hematopoietic cell
      proliferation of the liver in females, liver angiectasis in males and females,
      renal tubule dilatation in males, renal tubule karyomegaly in males and females,
      and splenic hematopoietic cell proliferation in males and females. Synonyms:
      Perfluoroethylene; tetrafluoroethene; 1,1,2,2-tetrafluoroethylene; TFE

PMID- 12594526
TI  - NTP Toxicology and Carcinogenesis Studies of Triethanolamine (CAS No. 102-71-6)
      in F344 Rats and B6C3F1 Mice (Dermal Studies).
AB  - Triethanolamine is widely used as an ingredient in emulsifiers, thickeners,
      wetting agents, detergents, and alkalinizing agents in cosmetic products; as a
      chemical intermediate for anionic and nonionic surfactants and surface active
      agents in household cleaning agents, textiles, herbicides, pharmaceutical
      ointments, and other products; as a vulcanization accelerator in the manufacture
      of rubber; and in many other industrial applications. The National Cancer
      Institute nominated triethanolamine for study because of its widespread use in
      cosmetics and other consumer products, its high potential for worker exposure due
      to its many industrial uses, and its potential for conversion to the carcinogen N
      -nitrosodiethanolamine. Dermal application was chosen as the route of exposure to
      mimic the principal means of human exposure to triethanolamine and because
      considerable systemic exposure is achieved with this route. Male and female
      F344/N rats and B6C3F1 mice received triethanol amine (purity 98% or greater) by
      dermal application for 13 weeks or 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells,
      Drosophila melano gaster, and mouse peripheral blood erythrocytes. 13-WEEK STUDY
      IN RATS: Groups of 10 male and 10 female rats were topically administered 0, 125,
      250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or
      2,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All rats
      survived to the end of the study. Final mean body weights and weight gains of
      males and females administered 2,000 mg/kg and the mean body weight gain of
      females administered 1,000 mg/kg were significantly less than those of the
      vehicle controls. Clinical observations included irritation, scaliness, and
      crustiness of the skin at the site of application for males and females. Males
      also had discoloration, and two males administered 2,000 mg/kg had ulceration at
      the site of application. Changes in clinical pathology parameters were minor and
      consistent with inflammation at the site of application. Kidney weights were
      generally greater in males and females administered 500, 1,000, or 2,000 mg/kg
      than in the vehicle controls. Microscopic lesions attributed to triethanolamine
      administration included acanthosis and inflammation at the site of application,
      nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in
      males and females. These lesions generally occurred with dose-related increases
      in incidence and severity in males and females. 13-WEEK STUDY IN MICE: Groups of
      10 male and 10 female mice were topically administered 0, 250, 500, 1,000, or
      2,000 mg triethanolamine per kilogram body weight in acetone or 4,000 mg/kg neat
      triethanolamine, 5 days per week, for 13 weeks. All mice survived to the end of
      the study. The final mean body weight and weight gain of males in the 250 mg/kg
      group were less than those of the vehicle controls. Clinical findings were
      observed only in mice in the 4,000 mg/kg groups and included scaliness,
      irritation, and discoloration at the site of triethanolamine application for
      males and females and skin erosion at this site in one male. The absolute kidney
      and liver weights of males and females administered 4,000 mg/kg were greater than
      those of the vehicle controls; relative kidney weights of males administered
      1,000 mg/kg or greater and females in all dosed groups were also greater than
      those of the vehicle controls. Microscopic examination of the skin of dosed mice
      indicated acanthosis and inflammation at the site of application. Acanthosis
      occurred in all dosed groups and in one vehicle control female; the severity
      increased with increasing dose in males and females. Inflammation was observed in
      males and females in the 4,000 mg/kg groups and in one female in the 2,000 mg/kg
      group. 2-YEAR STUDY IN RATS: Based on the presence of acanthosis and inflammation
      at the site of application at the higher doses in the 13-week study,
      triethanolamine doses selected for the 2-year study in rats were 32, 63, and 125
      mg/kg for malesr males and 63, 125, and 250 mg/kg for females. Groups of 60 male
      and 60 female rats were topically administered triethanolamine in acetone 5 days
      per week for 103 weeks. Ten male and ten female rats from each group were
      evaluated at 15 months for organ weights and histopathology. Survival, Body
      Weights, Clinical Findings, and Organ Weights: The survival rate of females in
      the 250 mg/kg group was slightly less than that of the vehicle controls. The mean
      body weight of females administered 250 mg/kg ranged from 9&percnt; to 12&percnt;
      less than that of the vehicle controls between weeks 73 and 93. Male and female
      rats receiving triethanolamine had irritated skin at the site of application; in
      dosed females, the site of application also had a crusty appearance. The number
      of animals in which these findings were observed increased with increasing dose.
      At the 15-month interim evaluation, the absolute left and right kidney weights
      and relative right kidney weight of females administered 250 mg/kg were
      significantly greater than those of the vehicle controls. Pathology Findings: The
      incidence of acanthosis at the site of application in males administered 125
      mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed
      females were greater than in the vehicle controls at the 15-month interim
      evaluation and at the end of the 2-year study. Males in the 125 mg/kg group also
      had greater incidences of inflammation and ulceration than the vehicle controls,
      and females receiving 125 or 250 mg/kg had greater incidences of epidermal
      erosion than the vehicle controls at 2 years. There were no skin neoplasms at or
      away from the site of application that were considered related to treatment with
      triethanolamine. At the end of the study, renal tubule adenomas were observed in
      seven dosed males and in one vehicle control female and one female in the 63
      mg/kg group. One male in the 125 mg/kg group and one female in the 250 mg/kg
      group had renal tubule hyperplasia. Extended (step-section) evaluation of the
      kidneys of all male rats revealed additional renal tubule adenomas in one vehicle
      control male, one male in the 32 mg/kg group, two males in the 63 mg/kg group,
      and three males in the 125 mg/kg group (including one male from the 15-month
      interim evaluation). An oncocytoma was also identified in one male in the 32
      mg/kg group. Hyperplasia was identified in eight additional vehicle control males
      and in 19 additional dosed males. The total incidences (combined standard and
      extended evaluations) of renal tubule adenoma in dosed male rats were slightly
      greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg,
      2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total incidence of hyperplasia in
      dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The
      severity of hyperplasia in males in the 32 and 125 mg/kg groups was greater than
      that in the vehicle controls. 2-YEAR STUDY IN MICE: Based on dose-related
      inflammation at the site of application in the 13-week study, triethanolamine
      doses selected for the 2-year study in mice were 200, 630, and 2,000 mg/kg for
      males and 100, 300, and 1,000 mg/kg for females. Groups of 60 male and 60 female
      mice were topically administered triethanolamine in acetone 5 days per week for
      103 weeks. Ten male and ten female mice from each group were evaluated at 15
      months for organ weights and histopathology. Survival, Body Weights, Clinical
      Findings, and Organ Weights: Survival rates of all dosed groups of males and
      females were similar to those of the vehicle controls. The mean body weight of
      males administered 2,000 mg/kg ranged from 8&percnt; to 10&percnt; less than that
      of the vehicle controls from week 69 through the end of the study. Clinical
      findings included irritation and discoloration of the skin at the site of
      application for most males in the 2,000 mg/kg group and a few females in the
      1,000 mg/kg group; males administered 200 or 630 mg/kg also had skin irritation.
      At the 15-month interim evaluation, the right kidney weights of male mice that
      received 630 or 2,000 mg/kg and the left kidney weights of males that received
      2,000 mg/kg were significantly greater than those of the vehicle controls.
      Pathology Findings: Acanthosis and inflammation of the skin were observed at the
      site of application in male and female mice at the 15-month interim evaluation
      and at the end of the 2-year study. In males in the 2,000 mg/kg group, the
      incidences of both lesions were significantly greater than those in the vehicle
      controls at both time points; however, the severities of acanthosis and
      inflammation did not increase with dose. At the end of the study, the incidence
      of inflammation in females in the 1,000 mg/kg group was significantly greater
      than that in the vehicle controls. One vehicle control male and two males in each
      of the 630 and 2,000 mg/kg groups had ulcers at the site of application. At the
      15-month interim evaluation, hepatocellular carcinomas were observed in dosed and
      vehicle control males and hepatocellular adenomas in dosed and vehicle control
      males and females; however, the incidences were not dose related. Nonneoplastic
      lesions observed at 15 months included foci of cellular alteration in a few dosed
      males and females; eosinophilic foci were also observed in two vehicle control
      females. At the end of the 2-year study, females in the 1,000 mg/kg group had
      significantly greater incidences of hepatocellular adenoma and multiple adenomas
      and a greater combined incidence of hepatocellular adenoma and carcinoma than the
      vehicle controls (adenoma: vehicle control, 22/50; 100 mg/kg, 22/50; 300 mg/kg,
      24/50; 1,000 mg/kg, 40/50; multiple adenomas: 11/50, 9/50, 13/50, 29/50; combined
      adenoma and carcinoma: 23/50, 26/50, 28/50, 41/50). Females in the 300 mg/kg
      group had significantly greater incidences of hepatocellular carcinoma (1/50,
      4/50, 7/50, 5/50) and eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the
      vehicle controls. Incidences of hepatocellular adenoma and multiple adenomas in
      males in the 2,000 mg/kg group were significantly greater than those in the
      vehicle controls (adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 630 mg/kg,
      29/50; 2,000 mg/kg, 37/50; multiple adenomas: 17/50, 18/50, 17/50, 29/50). Three
      males in the 2,000 mg/kg group had hepatoblastomas, and males in this group also
      had significantly greater incidences of hepatocellular neoplasms (combined)
      (adenoma, carcinoma, and hepatoblastoma: 31/50, 34/50, 33/50, 42/50) and
      eosinophilic foci (10/50, 17/50, 11/50, 23/50) than the vehicle controls. Male
      mice had a pattern of nonneoplastic liver lesions along with silver-staining
      helical organisms within the liver which suggested an infection with Helicobacter
      hepaticus. With polymerase chain reaction-based assays and culture, the presence
      of an organism compatible with H. hepaticus was confirmed. An increased incidence
      of hepatocellular neoplasms in male mice has been shown to be associated with H.
      hepaticus infection when hepatitis is also present. Therefore, interpretation of
      the increased incidence of hepatocellular neoplasms in mice was confounded.
      GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or
      in vivo short-term tests performed by the NTP. It did not induce mutations in
      Salmonella typhimurium, and no induction of sister chromatid exchanges or
      chromosomal aberrations in cultured Chinese hamster ovary cells exposed to
      triethanolamine was noted. These in vitro tests were conducted with and without
      S9 metabolic activation. Triethanolamine did not induce sex-linked recessive
      lethal mutations in germ cells of adult male Drosophila melanogaster exposed by
      feeding or injection. No increase in the frequency of micronucleated erythrocytes
      was observed in peripheral blood samples of male and female mice that received
      dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the
      conditions of these dermal studies, there was equivocal evidence of carcinogenic
      activity of triethanolamine in male F344/N rats based on a marginal increase in
      the incidence of renal tubule cell adenoma. There was no evidence of carcinogenic
      activity in female F344/N rats receiving 63, 125, or 250 mg triethanolamine per
      kilogram body weight. The study in male and female B6C3F1 mice was considered
      inadequate, because the presence of a Helicobacter hepaticus infection
      complicated inter pretation of the relationship between triethanolamine
      administration and liver neoplasms in these animals. Dosed rats and mice had
      varying degrees of acanthosis and inflammation, dosed rats had ulceration, and
      dosed female rats had epidermal erosion at the site of skin application.
      Synonyms: Nitrilo-2,2',2"-triethanol; 2,2',2"-nitrilotriethanol; 2,2',2"
      nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine;
      tri(hydroxyethyl)amine; 2,2',2"-trihydroxytriethylamine; trihydroxytriethylamine;
      tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; triethylolamine; trolamine
      Trade Names: Daltogen; Sterolamide; Thiofaco T-35

PMID- 12594527
TI  - NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3)
      in F344 Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses
      of aliphatic nitrites. It is also an ingredient of various incenses or room
      odorizers and is used as a euphoric. The chemical has also been used as a jet
      propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the
      Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity
      studies because of its possible contribution to the high incidence of Kaposi's
      sarcoma among male homosexual acquired immune deficiency syndrome patients and
      because of the lack of available data on the potential carcinogenicity of
      isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to
      isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks,
      or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,
      cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse
      peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female
      F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420,
      840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours
      per day, 5 days per week for a total of 12 exposures during a 16-day period. All
      males and females exposed to 600 or 800 ppm and one 400 ppm female died on the
      first day of the study. Final mean body weights and mean body weight gains of 400
      ppm males and females were significantly lower than those of the controls.
      Clinical findings observed in 400 ppm males and females included ocular
      discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung
      weights of all exposed groups of males and of 200 and 400 ppm females were less
      than those of the controls. Chemical-related hyperplasia of the bronchial
      epithelium was observed in 200 and 400 ppm males and females and hyperplasia of
      the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less.
      Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and
      females and bone marrow hematopoietic hyperplasia was observed in rats exposed to
      400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1
      mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840,
      1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per
      day, 5 days per week for a total of 12 exposures during a 16-day period. Three
      males and four females exposed to 800 ppm died before the end of the study. Final
      mean body weights and mean body weight gains of 600 and 800 ppm males and females
      were significantly lower than those of the controls. Mice exposed to 400 ppm or
      greater were lethargic and exhibited hunched posture and rough coats. Absolute
      and relative lung weights of 600 and 800 ppm males and the relative lung weight
      of 600 ppm females were significantly greater than those of the controls.
      Chemical-related hyperplasia of the bronchiolar epithelium was observed in all
      exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus
      was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN
      RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75,
      150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl
      nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats
      survived to the end of the study. Final mean body weights and mean body weight
      gains of 300 ppm males and females were significantly lower than those of the
      controls, as was the mean body weight gain of 150 ppm females. Clinical findings
      observed during the study included ruffled fur in 300 ppm males and females,
      hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A
      very mild chemical-related methemoglobinemia and anemia occurred in male and
      female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia
      occurred in the bone marrow of all exposed groups of males and females and was
      considered to be a secondary response to the anemia and methed methemoglobinemia.
      There was minimal hemosiderin pigment accumulation in the spleens of males and
      females exposed to 75 ppm or greater, mild to moderate epithelial cell
      hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and
      minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the
      bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN
      MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75,
      150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl
      nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There
      were no chemical-related deaths. Final mean body weights and mean body weight
      gains of 150 and 300 ppm females were significantly less than those of the
      controls. Final mean body weights and mean body weight gains of exposed groups of
      males were similar to those of the controls. There were no chemical-related
      clinical findings. A very mild chemical-related methemoglobinemia occurred in
      male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred
      in the 300 ppm groups. In the lung, increased incidences of mild to moderate
      hyperplasia of the bronchiolar epithelium occurred in males and females exposed
      to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater
      and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the
      nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the
      spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or
      greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the
      spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or
      greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia,
      and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial
      lesions observed in 300 ppm males and females, isobutyl nitrite exposure
      concentrations selected for the 2-year inhalation study in rats were 37.5, 75,
      and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or
      150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by
      inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10
      female rats from each group were evaluated at 15 months for clinical pathology
      and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and
      Clinical Chemistry: Survival rates of exposed groups of rats were greater than
      those of the controls, and the survival rates of 75 and 150 ppm males were
      significantly greater than that of the control. Mean body weights of 150 ppm
      males and females were 3&percnt; to 11&percnt; lower than those of the controls
      throughout the course of the study. There were no clinical findings considered to
      be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia
      occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings:
      Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or
      carcinoma (combined) occurred with significant positive trends in exposed males
      and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm
      males and females were significantly greater than those in the controls. The
      incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm
      male rats than that in the controls. The incidences of alveolar epithelial
      hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups
      of females. The incidences of mononuclear cell leukemia in exposed groups of
      males and females were significantly less than those in the controls. 2-YEAR
      STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the
      mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females,
      isobutyl nitrite exposure concentrations selected for the 2-year inhalation study
      in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were
      exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3))
      isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103
      weeks. As many as 10 male and 10 female mice from each group were evaluated at 15
      months for clinical pathology and histopathology. Survival, Body Weights,
      Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of
      exposed groups of males were similar to those of the controls. Survival rates of
      exposed groups of females were greater than those of the controls, and the
      survival rate in 37.5 ppm females was significantly greater than that of the
      controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm
      females were similar to those of the controls throughout the study. Mean body
      weights of 150 ppm females were lower than those of the controls from week 20
      until the end of the study. There were no biologically significant clinical
      findings noted in the 2-year study in mice. A very mild methemoglobinemia and
      anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology
      Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar
      adenoma or carcinoma (combined) occurred with significant positive trends in
      exposed males and females, and the incidences of these neoplasms were
      significantly greater than those in the controls in 75 ppm males and in 150 ppm
      males and females. Incidences of alveolar epithelial hyperplasia were
      significantly increased in 75 and 150 ppm male and female mice. Thyroid gland
      follicular cell adenoma occurred with a significant positive trend in male mice;
      the incidences of thyroid gland follicular cell hyperplasia were increased in all
      exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm
      were significantly greater than those in the controls. Incidences of serous
      exudate and olfactory epithelium atrophy in the nose of 150 ppm females were
      significantly greater than those in the controls. Incidences of minimal to mild
      hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly
      greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was
      found to be mutagenic in vitro and in vivo. It induced base-pair substitution
      mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid
      exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells.
      Positive responses in the S. typhimurium tests required S9 activation, but
      isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary
      cells with and without S9. In vivo, no induction of sex-linked recessive lethal
      mutations was noted in the germ cells of male Drosophila melanogaster exposed to
      isobutyl nitrite via feeding or injection. However, significant increases in
      micronucleated normochromatic erythrocytes were observed in the peripheral blood
      of male and female mice treated with isobutyl nitrite for 90 days by inhalation.
      CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was
      clear evidence of carcinogenic activity of isobutyl nitrite in male and female
      F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and
      alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of
      carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on
      the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar
      adenoma or carcinoma (combined) in males and females. The increased incidence of
      thyroid gland follicular cell adenoma in male mice may have been related to
      isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by
      inhalation for 2 years resulted in increased incidences of alveolar epithelial
      hyperplasia (male and female rats and mice), thyroid gland follicular cell
      hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate
      and atrophy of the olfactory epithelium of the nose (female mice). Exposure of
      rats to isobutyl nitrite by inhalation for 2 years resulted in decreased
      incidences of mononuclear cell leukemia in males and females.

PMID- 12594528
TI  - NTP Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 75-05-8) in
      F344/N Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Acetonitrile is used primarily as a solvent in extractive distillation and
      crystallization of pharmaceutical and agricultural products and as a catalyst in
      chemical reactions. It was nominated for testing by the National Cancer Institute
      due to its presence in drinking water supplies and the environment, due to lack
      of information on the carcinogenicity of alkyl cyanides, and because of
      widespread worker exposure. Male and female F344/N rats and B6C3F1 mice were
      exposed to acetonitrile (at least 99% pure) by inhalation for 13 weeks or 2
      years. Genetic toxicology studies were conducted in Salmonella typhimurium,
      cultured Chinese hamster ovary cells, and peripheral blood of B6C3F1 mice exposed
      to acetonitrile for 13 weeks. 13-WEEK STUDY IN RATS: Groups of 10 male and 10
      female F344/N rats were exposed to 0, 100, 200, 400, 800, or 1,600 ppm
      (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by
      inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three
      female rats that received 1,600 ppm and one male that received 800 ppm died
      during the study. At exposure concentrations up to and including 800 ppm, the
      final mean body weights and body weight gains were generally similar to those of
      the controls. At 1,600 ppm, body weight gain was lower and the final mean body
      weights of both males and females were significantly lower than those of the
      controls. Hypoactivity and ruffled fur were observed during the first week of the
      study in males receiving 800 ppm and males and females receiving 1,600 ppm.
      Additional clinical findings in 1,600 ppm males that died during week 1 were
      ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings
      included nonresponsive, normocytic, normochromic anemia in 1,600 ppm males and
      females and in 800 ppm females, and decreased triiodothyronine (T3)
      concentrations in 1,600 ppm females. Absolute and relative thymus weights were
      significantly lower than those of the controls in the 800 and 1,600 ppm males and
      females. Females exposed to 1,600 ppm had significantly greater absolute and
      relative heart, kidney, and liver weights than those of the controls. There were
      no clear exposure-related histopathologic effects, although pulmonary congestion
      and edema and hemorrhage in the lung and brain were seen in some rats that died
      early. These lesions are consistent with cyanide-induced anoxia. 13-WEEK STUDY IN
      MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 100, 200,
      400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3))
      acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. All
      mice exposed to 1,600 ppm died during the first 3 weeks of the study. In
      addition, one 400 ppm female and one male and four females from the 800 ppm
      groups also died before the end of the study. Body weight gains were similar to
      those of controls for all surviving groups of mice except the 800 ppm males, for
      which the final mean body weight was slightly lower than that of the controls.
      Clinical findings observed during the first week in 800 and 1,600 ppm mice were
      hypoactivity and a hunched, rigid posture. In males that received 200 ppm and
      above, absolute liver weights were greater than that of the controls and relative
      liver weights were greater in all exposed groups. In 800 ppm females, the
      absolute liver weight was greater than that of the controls and relative liver
      weights of females that received 400 ppm and above were greater than that of the
      controls. Lesions clearly associated with acetonitrile exposure were observed in
      the stomach, predominantly the forestomach, of males that received 400 ppm and
      above and of females that received 200 ppm and above. Histologically, these focal
      or multifocal pale to dark raised lesions consisted of areas of focal epithelial
      hyperplasia and ulceration, sometimes associated with hemosiderin deposition. An
      increased incidence of cytoplasmic vacuolation occurred in the liver of males and
      females exposed to 400 or 800 ppm. A lack of fatty degenerative change was
      observed inrved in the X-zone of the adrenal cortex of 800 and 1,600 ppm female
      mice. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of
      acetonitrile were based on reduced survival of 800 ppm males and 1,600 ppm males
      and females in the 13-week study. Groups of up to 56 male and 56 female rats were
      exposed to 0, 100, 200, or 400 ppm (equivalent to 0, 168, 335, or 670 mg/m(3))
      acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years.
      Eight male and eight female rats from each exposure group were evaluated at 15
      months for histopathology and hematology parameters. Survival, Body Weights,
      Clinical Findings, and Hematology: Two-year survival, mean body weights, organ
      weights, behavior, general health, and appearance of exposed male and female rats
      were similar to those of the controls. The hematologic effects observed were
      minor and of no biological significance. Pathology Findings: The incidences of
      hepatocellular adenoma (3/48), hepatocellular carcinoma (3/48), and
      hepatocellular adenoma or carcinoma (combined; 5/48) were greater in male rats
      exposed to 400 ppm than in the controls (one carcinoma). The incidences of
      hepatocellular adenoma and hepatocellular carcinoma were within the range of
      historical controls. However, the incidence of hepatocellular adenoma or
      carcinoma (combined) slightly exceeded the range of historical controls
      (2&percnt;-8&percnt;). In addition, the incidences of basophilic, eosinophilic,
      and mixed cell foci in 400 ppm males were marginally greater than in controls,
      suggesting hepatotoxicity of acetonitrile. There were no exposure-related liver
      lesions in female rats. 2-YEAR STUDY IN MICE: The exposure concentrations
      selected for the 2-year study were based on reduced survival and gross and
      histopathologic lesions in 400, 800, and 1,600 ppm groups of male and female mice
      in the 13-week study. Groups of 60 male and 60 female mice were exposed to 0, 50,
      100, or 200 ppm (equivalent to 0, 84, 168, or 335 mg/m(3)) acetonitrile by
      inhalation for 6 hours per day, 5 days per week for 2 years. Ten male and 10
      female mice from each exposure group were evaluated at 15 months for
      histopathology. Survival, Body Weights, and Clinical Findings: Two-year survival
      of exposed male and female mice was similar to that of the controls, except that
      the survival of male mice in the 200 ppm group was significantly greater than
      that of the controls. Mean body weights and organ weights of exposed groups of
      male and female mice were similar to those of the controls, and no clinical
      observations in any group were clearly related to acetonitrile exposure.
      Pathology Findings: There were no increases in the incidences of neoplasms that
      were considered related to acetonitrile exposure in mice. The incidence of
      squamous hyperplasia of the epithelium of the forestomach was significantly
      increased at 15 months in 200 ppm females. At 2 years, the increased incidence of
      this lesion was dose related in all exposed groups of males and females. GENETIC
      TOXICOLOGY: Acetonitrile was not mutagenic in Salmonella typhimurium strain TA97,
      TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation. In
      cultured Chinese hamster ovary cells, acetonitrile produced a weakly positive
      response in the sister chromatid exchange test without, but not with, S9. A small
      increase in chromosomal aberrations was observed in cultured Chinese hamster
      ovary cells treated with acetonitrile in the presence, but not in the absence, of
      S9. A significant increase in micronucleated normochromatic erythrocytes was
      observed in peripheral blood samples from male mice treated with acetonitrile for
      13 weeks; the frequency of micronucleated erythrocytes in female mice was not
      affected by exposure to acetonitrile. CONCLUSIONS: Under the conditions of these
      2-year inhalation studies, there was equivocal evidence of carcinogenic activity
      of acetonitrile in male F344/N rats based on marginally increased incidences of
      hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic
      activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm.
      There was no evidence of carcinogenic activity of acetonitrile in male or female
      B6C3F1 mice exposed to 50, 100, or 200 ppm. Exposure to acetonitrile by
      inhalation resulted in increased incidences of hepatic basophilic foci in male
      rats and of squamous hyperplasia of the forestomach in male and female mice.
      Synonyms: Cyanomethane, ethanenitrile, ethyl nitrile, methanecarbonitrile, methyl
      cyanide, nitrile of acetic acid

PMID- 12594529
TI  - NTP Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)
      Tetrahydrocannabinol (CAS No. 1972-08-3) in F344 Rats and B6C3F1 Mice (Gavage
      Studies).
AB  - 1-Trans-delta(9)-tetrahydrocannabinol (THC) was nominated by the National Cancer
      Institute to the NTP for study because it is the major psychoactive component of
      marijuana and a widely used Schedule I substance. Male and female F344/N rats and
      B6C3F1 mice received THC (97% pure) in corn oil by gavage for 13 weeks, 13 weeks
      with a 9-week recovery period, or 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and
      mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10
      female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil
      by gavage, 5 days per week for 13 weeks. Six male and six female rats receiving
      500 mg/kg died before the end of the study. The final mean body weights and
      weight gains of all dosed groups of males and females, except 5 mg/kg females,
      were significantly lower than those of the controls. Feed consumption by dosed
      groups was similar to that by controls. Clinical findings observed during the
      study included lethargy, sensitivity to touch, convulsions, tremors, and
      aggressiveness. There were no clinical pathology differences considered to be
      directly related to the administration of THC. The absolute and relative uterus
      weights of 50, 150, and 500 mg/kg females were significantly lower than those of
      the controls. Treatment-related multifocal atrophy was observed in the testes of
      150 and 500 mg/kg males; uterine and ovarian hypoplasia observed in 150 and 500
      mg/kg females was also considered to be related to THC administration. Based on
      final mean body weights and mortality observed in the 13-week study, doses
      selected for the 2-year rat study were 12.5, 25, and 50 mg/kg. 13-WEEK STUDY IN
      MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 50, 150, or 500 mg
      THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. There
      were no treatment-related deaths. The final mean body weight and weight gain of
      500 mg/kg males were significantly lower than those of the controls. Clinical
      findings included lethargy and aggressiveness, and both male and female mice in
      all dosed groups were easily startled. There were no absolute or relative organ
      weight differences, clinical pathology differences, or microscopic changes
      observed that were considered to be related to the administration of THC. Due to
      the minimal THC-related effects observed in the 13-week study, doses selected for
      the 2-year mouse study were 125, 250, and 500 mg/kg. 13-WEEK WITH 9-WEEK RECOVERY
      STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150,
      or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks,
      and then were allowed to recover during a 9-week treatment-free period. Five male
      and eight female 500 mg/kg rats, five male and two female 150 mg/kg rats, and
      three male and two female 50 mg/kg rats died before the end of the study. During
      the 13-week dosing period, mean body weight gains of all dosed groups of rats
      were lower than those of the controls but returned to normal during the recovery
      period. Final mean body weights of all dosed groups were similar to those of the
      controls. Clinical findings observed during the recovery period included
      sensitivity to touch, convulsions, and aggressiveness. The absolute right testis
      weight of 500 mg/kg males was significantly lower than that of the controls.
      Treatment-related multifocal atrophy of the testis was observed in 150 and 500
      mg/kg males. There were no treatment-related lesions observed in females
      administered THC. 13-WEEK WITH 9-WEEK RECOVERY STUDY IN MICE: Groups of 10 male
      and 10 female mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in
      corn oil by gavage, 5 days per week for 13 weeks, and then were allowed to
      recover during a 9-week treatment-free period. The final mean body weights of all
      dosed groups were similar to those of the controls. Clinical findings observed
      during the study included lethargy and aggressiveness, and both male and female
      mice in all dosed groups were easily startled. The absolutebsolute and relative
      uterus weights of 150 and 500 mg/kg female mice were significantly lower than
      those of the controls, as was the absolute uterus weight of 50 mg/kg females. 2
      YEAR STUDY IN RATS: Groups of 62 vehicle control male rats, 60 low-dose male
      rats, 70 mid- and high-dose male rats, and 60 female rats were administered 0,
      12.5, 25, or 50 mg THC/kg body weight in corn oil by gavage for 104 to 105 weeks.
      Nine or ten animals from each group were evaluated at 15 months. Survival, Body
      Weights, and Clinical Findings: Survival of all dosed groups was generally
      significantly greater than that of the controls. Mean body weights of dosed
      groups of males and females were lower than those of the controls throughout the
      study. Convulsions and seizures were observed in all dosed groups of male and
      female rats, usually following dosing or handling. Hematology and Clinical
      Chemistry: At the 15-month interim evaluation, total leukocyte and lymphocyte
      counts in all dosed groups of females were greater than those of the controls,
      and platelet counts in these groups were lower than that of the controls. Levels
      of follicle stimulating and luteinizing hormones in all dosed groups of males
      were significantly greater than those of the controls, as was the serum
      corticosterone level of 25 mg/kg females. Pathology Findings: No increased
      incidences of neoplasms were considered related to administration of THC. The
      incidences of mammary gland fibroadenoma and uterine stromal polyps were
      decreased in dosed groups of females, as were the incidences of pituitary gland
      adenomas, interstitial cell adenomas of the testis, and pancreatic adenomas in
      dosed males. 2-YEAR STUDY IN MICE: Groups of 62 vehicle control male mice, 60 low
      dose male mice, 61 mid-dose male mice, and 60 high-dose male mice and 60 female
      mice were administered 0, 125, 250, or 500 mg THC/kg body weight in corn oil by
      gavage for 104 to 105 weeks (males) or 105 to 106 weeks (females). Survival, Body
      Weights, and Clinical Findings: Survival of 500 mg/kg males was significantly
      less than that of the controls; survival of all other groups of males and of all
      dosed groups of females was similar to that of the controls. Mean body weights of
      all dosed groups were markedly lower than those of the controls throughout the
      study. Clinical findings in dosed groups included hyperactivity, convulsions, and
      seizures which occurred following dosing or handling. Hematology: At the 15-month
      interim evaluation, total leukocyte and lymphocyte counts in all dosed groups of
      males were significantly lower than those of the controls. Pathology Findings:
      Increased incidences of thyroid gland follicular cell adenoma occurred in 125
      mg/kg males and females, but the increase was not dose-related. Increased
      incidences of thyroid gland follicular cell hyperplasia occurred in all dosed
      groups of males and females. Increased incidences of forestomach hyperplasia and
      ulcers occurred in all groups of males administered THC. Incidences of
      hepatocellular adenoma and of hepatocellular adenoma or carcinoma (combined)
      occurred with a significant negative trend in male and female mice, as did
      incidences of eosinophilic foci and fatty change in the liver. GENETIC
      TOXICOLOGY: THC was not mutagenic in Salmonella typhimurium strains TA97, TA98,
      TA100, or TA1535 with or without rat and hamster liver S9 fractions. In cultured
      Chinese hamster ovary cells, THC induced sister chromatid exchanges at the
      highest dose tested in the presence of S9; at this dose level, cell cycle delay
      indicative of toxicity was observed. THC did not induce chromosomal aberrations
      in cultured Chinese hamster ovary cells with or without S9 metabolic activation
      enzymes. In vivo, no increase in the frequency of micronucleated erythrocytes was
      observed in the peripheral blood of male or female mice administered THC by
      gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage
      studies, there was no evidence of carcinogenic activity of 1-trans-delta(9)
      tetrahydrocannabinol in male or female F344/N rats administered 12.5, 25, or 50
      mg/kg. There was equivocal evidence of carcinogenic activity of THC in male and
      female B6C3F1 mice based on the increased incidences of thyroid gland follicular
      cell adenomas in 125 mg/kg groups. Increased incidences of thyroid gland
      follicular cell hyperplasia occurred in male and female mice, and increased
      incidences of hyperplasia and ulcers of the forestomach were observed in male
      mice. The incidences of mammary gland fibroadenomas and uterine stromal polyps
      were decreased in dosed groups of female rats, as were the incidences of
      pancreatic adenomas, pituitary gland adenomas, and interstitial cell adenomas of
      the testis in dosed male rats and liver neoplasms in dosed mice. These decreases
      were likely related to lower body weights in dosed animals. Synonyms: 3-Pentyl
      6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6h-dibenzo(b,d)pyran-1-ol; delta1
      tetrahydrocannabinol; (-)-delta1-3,4-trans- tetrahydrocannabinol; delta(9)
      tetrahydrocannabinon; THC; delta1-THC; delta(9)-THC

PMID- 12594530
TI  - NTP Toxicology and Carcinogenesis Studies of Scopolamine Hydrobromide Trihydrate
      (CAS No. 6533-68-2) in F344 Rats and B6C3F1 Mice (Gavage Studies).
AB  - Scopolamine hydrobromide trihydrate is used in ophthalmic preparations and as a
      preanesthetic sedative. Its major use is in transdermal patches for the treatment
      of motion sickness. Scopolamine hydrobromide trihydrate was selected for study
      because of considerable human exposure resulting from its use in prescription and
      over-the-counter preparations. Scopolamine was a suspect carcinogen because it
      contains an aliphatic epoxide moiety which may act as a biological alkylating
      agent. Male and female F344/N rats and B6C3F1 mice received scopolamine
      hydrobromide trihydrate (89% pure) in distilled water by gavage for 16 days, 14
      weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella
      typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood
      erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were
      administered 0, 75, 150, 300, 600, or 1,200 mg scopolamine hydrobromide
      trihydrate/kg body weight in distilled water by gavage for 16 days. All rats
      survived to the end of the study. The final mean body weights and body weight
      gains of males receiving 600 and 1,200 mg/kg and the mean body weight gain of
      males receiving 300 mg/kg were significantly lower than those of the control
      group. Clinical findings included bilateral pupillary dilation in all dosed
      animals and red eyelids in males and females receiving 1,200 mg/kg. There were no
      significant treatment-related gross or microscopic lesions. 16-DAY STUDY IN MICE:
      Groups of five male and five female mice were administered 0, 150, 250, 450, 900,
      or 1,800 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water
      by gavage for 16 days. One male and two females receiving 1,800 mg/kg and one
      female receiving 150 mg/kg died during the study. The final mean body weights and
      body weight gains of dosed mice were similar to those of the control groups.
      Clinical findings related to scopolamine hydrobromide trihydrate administration
      included bilateral pupillary dilation and squinting in all dosed males and
      females. The relative liver weights of males receiving 1,800 mg/kg and of females
      in all dosed groups were significantly greater than those of the control groups.
      There were no significant treatment-related gross or microscopic lesions. 14-WEEK
      STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 15, 45,
      135, 400, or 1,200 mg scopolamine hydrobromide trihydrate/kg body weight in
      distilled water by gavage for 14 weeks. One female receiving 45 mg/kg, one male
      and one female receiving 135 mg/kg, six males and one female receiving 400 mg/kg,
      and eight males and seven females receiving 1,200 mg/kg died during the study.
      The final mean body weights and mean body weight gains of all dosed males and
      females were significantly lower than those of the control groups. Clinical
      findings included bilateral pupillary dilation in all dosed males and females and
      reddening of the eyes in 15 mg/kg males and 135, 400, and 1,200 mg/kg males and
      females. Hematocrit, hemoglobin concentration, and/or erythrocyte count in male
      and female rats receiving 45 mg/kg or greater were slightly higher than those of
      the control groups. In general, these changes were most prominent in rats in the
      400 and 1,200 mg/kg groups. Higher hematocrit, hemoglobin concentration, and
      erythrocyte count were likely due to hemoconcentration from dehydration (relative
      erythrocytosis). A minimal to mild mature neutrophilia, evidenced by higher
      segmented neutrophil numbers than in the control group, occurred in all dosed
      male rats. Sperm morphology and vaginal cytology parameters in dosed rats were
      similar to those in the control groups. Nine male and five female dosed rats died
      from esophageal obstructions consisting of feed and bedding material in the
      posterior pharynx. Tracheal obstruction occurred concurrently with esophageal
      obstruction as a result of food build-up in the oropharyngeal region. This
      condition is considered to be secondary to the inhibitory effects of scopolamine
      hydrobromide trihydrate on salivary gland secretions and on esopon esophageal
      smooth muscle involved in swallowing. There were no other significant treatment
      related gross or microscopic findings. 14-WEEK STUDY IN MICE: Groups of 10 male
      and 10 female mice were administered 0, 15, 45, 135, 400, or 1,200 mg scopolamine
      hydrobromide trihydrate/kg body weight in distilled water by gavage for 14 weeks.
      One male receiving 135 mg/kg and two males and one female receiving 1,200 mg/kg
      died during the study. The final mean body weights and mean body weight gains of
      all dosed male groups and females receiving 45 mg/kg and above were significantly
      lower than those of the control groups. Clinical observations included bilateral
      pupillary dilation, hyperactivity, and hypoactivity. A minimal to mild mature
      neutrophilia, similar to that which occurred in the 14-week rat study, occurred
      in male mice receiving 45 mg/kg or greater. As in the rat study, there was no
      microscopic evidence of inflammation that could account for the neutrophilia. The
      estrous cycle length of 1,200 mg/kg females was significantly greater than that
      in the control group. There were no significant treatment-related gross or
      microscopic lesions. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats
      were administered 0, 1, 5, or 25 mg scopolamine hydrobromide trihydrate/kg body
      weight in distilled water by gavage for 104 weeks. Ten males and ten females from
      each dose group, excluding the 1 mg/kg female group, were evaluated at 15 months.
      Survival, Body Weights, Clinical Findings, and Ophthalmic Examination Findings:
      The survival rates of female rats receiving 1 and 25 mg/kg were significantly
      lower than that of the control group. Mean body weights of 1 and 5 mg/kg males
      and females were similar to those of the controls throughout the study. However,
      mean body weights of 25 mg/kg males and females were generally lower than those
      of the control groups after about week 25. Clinical findings included bilateral
      pupillary dilation in all dosed males and females. Ophthalmic examination
      revealed no significant findings. Hematology: Compared to controls, hematocrit
      was slightly higher in the 25 mg/kg male rats, similar to the effects observed in
      the 14-week study; this is consistent with dehydration resulting in
      hemoconcentration. Reticulocyte numbers in the 25 mg/kg female rats were slightly
      lower than those in the controls. This result is consistent with the lower body
      weights, and thus a decreased nutritional status, exhibited by these animals.
      Plasma Scopolamine Determinations: The serum scopolamine concentrations were 6 ng
      scopolamine/mL serum for the 5 mg/kg female sample and 12 and 28 ng/mL for the 25
      mg/kg male and female samples, respectively. The amounts of scopolamine in the
      other serum samples were below the minimum detection limit (4 ng/mL) of the
      analysis method. Neurobehavioral Findings: Horizontal motor activity of 25 mg/kg
      females was significantly greater than that of the control group on days 90, 180,
      and 360. Startle response of 5 and 25 mg/kg females was significantly lower than
      that of the control group on day 90. On day 180, passive avoidance of 25 mg/kg
      males was significantly lower than that of the control group. Pathology Findings:
      The incidences of adenoma of the pituitary gland pars distalis decreased with
      increasing dose in both male and female rats; however, this trend was only
      significant in males (males: vehicle control, 19/49; 1 mg/kg, 17/49; 5 mg/kg,
      13/50; 25 mg/kg, 10/50; females: 20/50, 13/60, 14/50, 10/50). The incidences of
      adenoma of the pituitary gland pars distalis in 25 mg/kg males and all groups of
      dosed females were below the NTP historical control range. The incidences of
      hyperplasia were not significantly different from those in the control groups.
      The incidences of mononuclear cell leukemia in 25 mg/kg males and females were
      significantly lower than those of the control groups (males: 33/50, 21/50, 26/50,
      24/50; females: 20/50, 6/60, 13/50, 4/50). The incidence of mononuclear cell
      leukemia in females receiving 25 mg/kg was well below the NTP historical range. 2
      YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered 0, 1,
      5, or 25 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water
      by gavage for 104 to 105 weeks. Ten control animals and ten animals from each
      dose level were evaluated at 15 months. Survival, Body Weights, Clinical
      Findings, and Ophthalmic Examination Findings Survival of dosed males and females
      was similar to that of the controls. The mean body weights of males and females
      receiving 1 mg/kg were similar to those of the control groups throughout the
      majority of the study. The mean body weights of 5 mg/kg males and females were
      slightly lower than those of the controls. The mean body weights of males and
      females receiving 25 mg/kg were lower than those of the control groups after week
      13. Clinical findings included bilateral pupillary dilation in all dosed male and
      female groups. Ophthalmic examination revealed no significant findings.
      Hematology: Hematocrit, hemoglobin concentration, and erythrocyte count in 25
      mg/kg female mice were slightly lower than those in the control group. These
      results are consistent with development of a minimal normocytic, normochromic
      nonresponsive anemia. The anemia may be related to the lower body weights
      exhibited by these animals and are presumed to be due to a decreased nutritional
      status. Pathology Findings: The combined incidences of hepatocellular neoplasms
      (adenoma or carcinoma) occurred with a significant negative trend in males and
      females (males: vehicle control, 30/50; 1 mg/kg, 33/50; 5 mg/kg, 14/50; 25 mg/kg,
      15/50; females: 22/51, 21/50, 16/50, 9/51). The combined incidences of
      hepatocellular neoplasms in 5 and 25 mg/kg males were within the NTP historical
      control range. The incidences of clear cell foci and eosinophilic foci in dosed
      male groups, and eosinophilic foci in 25 mg/kg females, were significantly lower
      than those of the control groups. The incidences of many spontaneously occurring
      nonneoplastic lesions were significantly lower in dosed mice than in the control
      groups and usually decreased with increasing dose. These included kidney
      nephropathy, alveolar epithelial hyperplasia, hyperplasia of the pancreatic
      islets, bone marrow myelofibrosis, hyperplasia of the pituitary gland pars
      distalis, cystic hyperplasia of the uterus, and hematopoietic cell proliferation
      of the spleen. The decreased incidences of these spontaneous lesions were most
      likely a result of lower body weights in dosed animals. GENETIC TOXICOLOGY:
      Scopolamine hydrobromide trihydrate did not induce mutations in any of five
      strains of Salmonella typhi murium, with or without S9 metabolic activation
      enzymes, nor did it induce sister chromatid exchanges in cultured Chinese hamster
      ovary cells, with or without S9. A weakly positive response was obtained,
      however, in a chromosomal aberrations test conducted in cultured Chinese hamster
      ovary cells with very high doses of scopolamine hydrobromide trihydrate in the
      presence of S9; without S9, no increase in aberrations was noted. Despite the
      evidence for chromosomal damage observed in vitro, no increase in the frequencies
      of micronucleated normochromatic erythrocytes was observed in peripheral blood
      samples of male or female mice exposed to scopolamine hydrobromide trihydrate for
      14 weeks by gavage. CONCLUSIONS: Under the conditions of these 2-year gavage
      studies, there was no evidence of carcinogenic activity of scopolamine
      hydrobromide trihydrate in male or female F344/N rats or B6C3F1 mice administered
      1, 5, or 25 mg/kg. Synonyms: Scopolamine hydrobromide, 6,7-epoxytropan-3-yl,
      euscopol, hydroscine hydrobromide, hyoscine bromide, (-)-hyoscine hydrobromide,
      hysco, isoscopil, scopolammonium bromide, (s)-tropate hydrobromide trihydrate,
      l&alpha;-tropyl-a-scopine

PMID- 12594532
TI  - Null mutations in the N-acetylglutamate synthase gene associated with acute
      neonatal disease and hyperammonemia.
AB  - N-acetylglutamate synthase (NAGS) is a mitochondrial enzyme that catalyzes the
      formation of N-acetylglutamate, an essential allosteric activator of carbamyl
      phosphate synthetase I, the first enzyme of the urea cycle. Liver NAGS deficiency
      has previously been found in a small number of patients with hyperammonemia. The
      mouse and human NAGS genes have recently been cloned and expressed in our
      laboratory. We searched for mutations in the NAGS gene of two families with
      presumed NAGS deficiency. The exons and exon/intron boundaries of the NAGS gene
      were sequenced from genomic DNA obtained from the parents of an infant from the
      Faroe Islands who died in the neonatal period and from two Hispanic sisters who
      presented with acute neonatal hyperammonemia. Both parents of the first patient
      were found to be heterozygous for a null mutation in exon 4 (TGG-->TAG,
      Trp324Ter). Both sisters from the second family were homozygous for a single base
      deletion in exon 4 (1025delG) causing a frameshift and premature termination of
      translation. The finding of deleterious mutations in the NAGS gene confirms the
      genetic origin of NAGS deficiency. This disorder can now be diagnosed by DNA
      testing allowing for carrier detection and prenatal diagnosis.

PMID- 12594533
TI  - High level of male-biased Scandinavian admixture in Greenlandic Inuit shown by Y
      chromosomal analysis.
AB  - We have used binary markers and microsatellites on the Y chromosome to analyse
      diversity in a sample of Greenlandic Inuit males. This sample contains Y
      chromosomes typical of those found in European populations. Because the Y
      chromosome has a unique and robust phylogeny of a time depth that precedes the
      split between European and Native American populations, it is possible to assign
      chromosomes in an admixed population to either continental source. On this basis,
      58+/-6% of these Y chromosomes have been assigned to a European origin. The high
      proportion of European Y chromosomes contrasts with a complete absence of
      European mitochondrial DNA and indicates strongly male-biased European admixture
      into Inuit. Comparison of the European component of Inuit Y chromosomes with
      European population data suggests that they have their origins in Scandinavia.
      There are two potential source populations: Norse settlers from Iceland, who may
      have been assimilated 500 years ago, and the Danish-Norwegian colonists of the
      eighteenth century. Insufficient differentiation between modern Icelandic and
      Danish Y chromosomes means that a choice between these cannot be made on the
      basis of diversity analysis. However, the extreme sex bias in the admixture makes
      the later event more likely as the source.

PMID- 12594535
TI  - Linkage analysis of prostate cancer susceptibility: confirmation of linkage at
      8p22-23.
AB  - Frequent loss of heterogeneity in prostate cancer cells and linkage studies of
      families affected by hereditary prostate cancer (HPC) have implied that the short
      arm of chromosome 8, specifically 8p22-23, may harbor a prostate-cancer
      susceptibility gene. In a recent study, seven potentially important mutations in
      the macrophage scavenger receptor 1 gene (MSR1), located at 8p22, were observed
      in families affected with HPC, and an indication of co-segregation between these
      mutations and prostate cancer was reported. In an attempt to confirm linkage at
      8p22-23, we performed linkage analyses in 57 families affected with HPC
      (ascertained throughout Sweden) by using 13 markers on the short arm of
      chromosome 8. In the complete set of families, evidence for prostate cancer
      linkage was observed at 8p22-23, with a peak hold of 1.08 (P=0.03), observed at
      D8S1731, approximately 1 cM centromeric to the MSR1 gene. At marker D8S1135, the
      closest marker to MSR1, a hlod of 1.07 (P=0.03) was observed. Evidence of linkage
      was seen in families with early-onset HPC and in families with a small number of
      affected individuals. The peak multipoint non-parametric linkage score was 2.01
      (P=0.03) at D8S552 in the 14 pedigrees with mean age at onset <65 years, and 2.25
      (P=0.01) at D8S1731 in the 36 pedigrees with fewer than five affected family
      members. Thus, we have confirmed evidence for prostate cancer linkage at 8p22-23.
      Follow-up studies to evaluate the possible association between prostate cancer
      and genes in this region, especially the MSR1 gene, are warranted.

PMID- 12594536
TI  - Non-pungent capsaicinoids from sweet pepper synthesis and evaluation of the
      chemopreventive and anticancer potential.
AB  - BACKGROUND: Capsiate, the non-pungent ester isoster of capsaicin, and its
      dihydroderivative are the major capsaicinoids of sweet peppers. The remarkable
      difference between the sensory properties of capsaicin vs capsiate is solely due
      to the way the vanillyl and the acyl moieties of this basic structural motif are
      linked, via an amide bond in capsaicin-type compounds and via an ester bond in
      capsiate-type compounds. AIM OF THE STUDY: Since capsaicin induces apoptosis in
      tumoral cells by a vanilloid receptor type 1(VR1)-independent pathway, we
      examined the effects of capsiates derived from sweet peppers in the ROS
      generation and induction of apoptosis in tumoral cells and if these are mediated
      independently from VR1. METHODS: We have developed an expeditious synthesis of
      capsiates based on the esterification of vanillol with the Mitsunobu protocol.
      Capsiate-induction of apoptosis, generation of reactive oxygen species and
      disruption of the mitochondria transmembrane potential in tumoral cell lines were
      measured by flow cytometry. Chemopreventive activity was studied in a two-stage
      mouse skin carcinogenesis assay. RESULTS: Capsiates induce apoptosis that was
      preceded by an increase in the production of reactive oxygen species and by a
      subsequent loss of mitochondria transmembrane potential (DeltaPsi(m)). These
      properties were retained in simplified synthetic analogues of natural capsiates,
      one of which (nor-dihydrocapsiate) showed powerful chemopreventive activity.
      CONCLUSIONS: These results suggest that capsiates and related synthetic analogues
      target a variety of pathways involved in cancer development and inflammation, and
      have considerable potential for dietary health benefits as well as for
      pharmaceutical development.

PMID- 12594537
TI  - Effects of quercetin and rutin on vascular preparations: a comparison between
      mechanical and electrophysiological phenomena.
AB  - BACKGROUND: Several studies have indicated that quercetin promotes relaxation of
      vascular smooth muscle both in vivo and in vitro. However, Saponara et al.
      [(2002) Br J Pharmacol 135: 1819-1827] have demonstrated that quercetin is an
      activator of vascular L-type Ca(2+) channels. AIM OF THE STUDY: We investigated
      the mechanical and electrophysiological properties of quercetin and its rutoside,
      rutin, in an attempt to clarify how Ca(2+) channel activation might be related to
      the myorelaxing activity. METHODS: Aorta ring preparations and single tail artery
      myocytes were employed for functional and patch-clamp experiments, respectively.
      RESULTS: Rutin was found to relax intact rat aorta rings, which had been
      precontracted with phenylephrine (pIC(50) = 5.65 +/- 0.31) but in contrast had no
      effect on depolarised (60 mM K(+)) preparations or on those from which the
      endothelium had been removed. Furthermore, rutin did not affect L-type Ca(2+)
      current recorded in rat tail artery myocytes. The quercetin-induced relaxation of
      intact rings precontracted with phenylephrine exhibited two components
      characterised by 6.23 +/- 0.38 and 4.66 +/- 0.09 pIC(50), respectively. Removal
      of the endothelium abolished the first component, leaving the second unaltered.
      Moreover, quercetin was found to relax 60 mM K(+) depolarised rings with a
      pIC(50) of 4.59 +/- 0.03. The application of quercetin in isolated smooth muscle
      cells brought about a marked increase of L-type Ca(2+) current (pEC(50) = 5.09 +/
      0.05). Unlike quercetin, Bay K 8644 contracted aorta rings preincubated with 10,
      20 or 30 mM K(+). The myotonic effect of Bay K 8644 was observed both in the
      absence or presence of 30 microM quercetin. The application of Bay K 8644 (10-100
      nM) caused a further significant increase in L-type Ca(2+) current in rat tail
      artery myocytes stimulated with 30 microM quercetin. CONCLUSIONS: Quercetin is a
      naturally occurring L-type Ca(2+) channel agonist. This effect, however, is
      overwhelmed by quercetin-induced vasorelaxation taking place via pathways which
      are more relevant than L-type Ca(2+) influx in the hierarchy of functional
      competencies.

PMID- 12594538
TI  - Evaluation of the bioavailability and metabolism in the rat of punicalagin, an
      antioxidant polyphenol from pomegranate juice.
AB  - BACKGROUND & AIMS: Punicalagin is an antioxidant ellagitannin of pomegranate
      juice. This compound is responsible for the high antioxidant activity of this
      juice. Nothing is known about the bioavailability and metabolism of punicalagin
      or other food ellagitannins. The present work aims to evaluate the
      bioavailability and metabolism of punicalagin in the rat as an animal model.
      DESIGN: Two groups of rats were studied. One fed with standard rat diet (n = 5)
      and another with the same diet plus 6 % punicalagin (n = 5). Samples of urine and
      faeces were taken during 37 days and plasma every week. The different metabolites
      were analysed by HPLC-MS-MS. RESULTS: The daily intake of punicalagin ranged from
      0.6 to 1.2 g. Values around 3-6 % the ingested punicalagin were excreted as
      identified metabolites in faeces and urine. In faeces, punicalagin is transformed
      to hydrolysis products and partly metabolites by the rat microflora to 6H
      dibenzo[b,d]pyran-6-one derivatives. In plasma, punicalagin was detected at
      concentrations around 30 microg/mL, and glucuronides of methyl ether derivatives
      of ellagic acid were also detected. 6H-Dibenzo[b,d]pyran-6-one derivatives were
      also detected especially during the last few weeks of the experiment. In urine,
      the main metabolites observed were the 6H-dibenzo[b,d]pyran-6-one derivatives, as
      aglycones or glucuronides. CONCLUSION: As only 3-6 % of the ingested punicalagin
      was detected as such or as metabolites in urine and faeces, the majority of this
      ellagitannin has to be converted to undetectable metabolites (i. e. CO(2)) or
      accumulated in non-analysed tissues, however with only traces of punicalagin
      metabolites being detected in liver or kidney. This is the first report on the
      absorption of an ellagitannin and its presence in plasma. In addition, the
      transformation of ellagic acid derivatives to 6H-dibenzo[b,d]pyran-6-one
      derivatives in the rat is also confirmed.

PMID- 12594539
TI  - Deglycosylation by small intestinal epithelial cell beta-glucosidases is a
      critical step in the absorption and metabolism of dietary flavonoid glycosides in
      humans.
AB  - BACKGROUND: Pharmacokinetic studies have shown that the small intestine is the
      major site of absorption for many flavonoid glucosides. Flavonoids are generally
      present as glycosylated forms in plants and foods, but there is increasing
      evidence that the forms reaching the systemic circulation are glucuronidated,
      sulphated and methylated derivatives. Hence, first-pass metabolism (small
      intestine-liver) appears to involve a critical deglycosylation step for which the
      mechanisms are not known. AIMS: To explore the hypothesis that deglycosylation is
      a prerequisite to absorption and metabolism of dietary flavonoid glycosides, to
      identify the enzymes responsible, and relate their specificities with absorption
      kinetics. METHODS: Flavonoid glycoside hydrolysing enzymes were isolated from
      samples of human small intestine and liver using chromatographic techniques. The
      proteins were characterised with respect to the cellular fraction with which they
      were associated, molecular weight, specificity for various substrates, and cross
      reactions with antibodies. Cellular models were used to mimic the small
      intestine. RESULTS: Protein extracts from human jejunal mucosa were highly
      efficient in hydrolysing flavonoid glycosides, consistent with an enterocyte
      mediated deglycosylation process. Considerable inter-individual variation was
      observed [e. g. range, mean and standard deviation for rate of hydrolysis of
      quercetin-3-glucoside (n = 10) were 6.7-456, 96, and 134 nmol min(-1) (mg
      protein)(-1), respectively]. Two beta-glucosidases with activity towards
      flavonoid glycosides were isolated from human small intestine mucosa: lactase
      phlorizin hydrolase (LPH; localised to the apical membrane of small intestinal
      epithelial cells) and cytosolic beta-glucosidase (CBG), indicating a role of
      human LPH and CBG from small intestine in flavonoid absorption and metabolism.
      Hydrolysis of flavonoid glycosides was only detected in cultured cells exhibiting
      beta-glucosidase activity. CONCLUSIONS: The absorption of dietary flavonoid
      glycosides in humans involves a critical deglycosylation step that is mediated by
      epithelial beta-glucosidases (LPH and CBG). The significant variation in beta
      glucosidase activity between individuals may be a factor determining variation in
      flavonoid bioavailability.

PMID- 12594540
TI  - Antiproliferative effect of antioxidant polyphenols from grape in murine Hepa
      1c1c7.
AB  - BACKGROUND: Grapes and wine contain high concentrations of polyphenolic
      compounds. Although their cancer protective effect has been well documented,
      their activity as anticarcinogens should be cautiously considered since the
      molecular bases of action and their applicability to human cancer prevention are
      still unclear. AIM OF THE STUDY: We studied the antioxidant/antiradical activity
      and the antiproliferative effect in vitro of different polyphenolic mixtures,
      extracted from grapes and fractionated through RP-HPLC. METHODS: The polyphenolic
      fractions were chemically characterized and their antioxidant/antiradical
      activity was determined by the DPPH assay. Mouse hepatoma Hepa-1c1c7 cells were
      used to study the cell growth inhibition capacity of these fractions by MTT
      assay. Their capacity of altering cell cycle and possible induction of apoptosis
      was examined using FACS analysis. RESULTS: The original polyphenolic fraction OW,
      which contained gallic acid (GA), (+)-catechin (Cat), (-)-epicatechin (Ec),
      glycosylated flavonols (F) and procyanidin oligomers was fractionated into
      fraction I, composed of monomers and small oligomers, and fraction II that
      included flavonols and procyanidin oligomers of higher molecular weight. The
      three polyphenolic fractions tested showed quite similar antiradical activity,
      although fraction I was the most potent antiradical agent (lowest ED(50) value: 9
      microg). Fraction II was the least potent cell growth inhibitor (highest IC(50)
      value: 100 microg/ml) but showed the strongest effect on the cell cycle of Hepa
      1c1c7, inducing apoptosis in those cells. The original fraction OW was
      demonstrated to have the most potent cell growth inhibition effect (lowest IC(50)
      value: 43 microg/ml). However, it only appeared to alter cell cycle of Hepa-1c1c7
      at concentrations higher than its IC(50) and did not induce apoptosis in those
      cells. A similar effect on cell cycle and apoptosis was encountered for fraction
      I. CONCLUSIONS: The polyphenolic fractions tested in this study were potent
      antiradical agents and exerted an antiproliferative effect in mouse hepatoma Hepa
      1c1c7 cells; the fraction with the highest degree of polimerization and
      galloylation (fraction II) had the most influence on the cell cycle and induction
      of apoptosis on Hepa-1c1c7.

PMID- 12594541
TI  - Researching on new species of "Mate": Ilex brevicuspis: phytochemical and
      pharmacology study.
AB  - BACKGROUND: Ilex paraguariensis St. Hilaire (Aquifoliaceae) ("Mate" or "Yerba
      mate") is one of the most commercialized plants of South America which grows
      naturally in NE Argentina, Uruguay, SE Brazil and E Paraguay, where it is also
      cultivated. It is used to prepare a tea-like beverage (infusions or decoctions)
      appreciated for its peculiar flavor, stimulation and nutritional properties. Ilex
      brevicuspis Reisseck grows in the same habitat and is widely used as a substitute
      or adulterant of Ilex paraguariensis. In a previous work, methylxanthines
      (caffeine, theobromine and theophylline) were not detected in it by HPLC. AIM OF
      THE STUDY: This study was undertaken in order to isolate, identify and quantify
      the polyphenolic compounds (caffeoyl derivatives and flavonoids) and to
      investigate some of the pharmacological activities of I. brevicuspis, related
      with the traditional use of the "Mate" (choleretic, intestinal propulsion and
      antioxidant activities). Acute toxicity was also investigated. METHODS:
      Decoctions, like extracts, were prepared in order to compare the results with
      preparations commonly used by the local people. For the phytochemical analysis,
      the extracts were analyzed by HPLC with a diode array detector. Choleretic and
      intestinal propulsion activities were assayed in rats. Sodium dehydrocholate
      (DHC) was used as a choleretic reference standard. Antioxidant activity was
      tested in liposomes that were oxidized by the free radical generator 2,2'-azobis
      [amidinopropane] chloride (AAPH). RESULTS: For the first time in I. brevicuspis
      the following compounds were isolated and quantified: A) caffeoyl derivative
      compounds (chlorogenic acid; caffeic acid; 3,4-dicaffeoylquinic acid; 3,5
      dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid. B) flavonoids (rutin,
      quercetin and kaempferol). Biological activity assays demonstrated that I.
      brevicuspis extracts produced a significant increase of bile flow (BF) in rats in
      the first 30 min period and in the percentage of BF increase accumulated at 120
      min. It also produced an increase in the intestinal propulsion activity.
      Moreover, this species showed a high antioxidant activity. The acute toxicity
      test showed that Ilex brevicuspis did not produce any sign of toxicity at the
      analyzed doses. CONCLUSIONS: An Argentinean Ilex specie ( I. brevicuspis) has
      choleretic, intestinal propulsion, antioxidant activities and these results may
      lead to the potential development of a new "Yerba Mate" and/or
      phytopharmaceutical products, without central nervous system (CNS) stimulant
      activity.

PMID- 12594542
TI  - Enzymic production of a feruloylated oligosaccharide with antioxidant activity
      from wheat flour arabinoxylan.
AB  - BACKGROUND: Main cereals such as rice, wheat, barley, and corn belong to the
      family Gramineae and have similar cell-wall composition. Since cereal cell walls
      are a good source of dietary fibre, meeting one-half of the daily requirement of
      30 g of dietary fibre can be achieved by the regular consumption of cereals. Many
      studies have dealt with the isolation of feruloylated oligosaccharides from
      Gramineae by treatment with polysaccharide hydrolysing enzymes. AIM OF THIS
      STUDY: Therefore, the purpose of this study was to investigate the production of
      feruloylated oligosaccharides from insoluble wheat flour arabinoxylan (WFAX) by
      treatment with a Thermoascus aurantiacus family 10 endoxylanase (XYLI) and the
      evaluation of their antioxidant activity. METHODS: The main feruloylated
      oligosaccharide was purified by anion-exchange and size-exclusion chromatography
      (SEC). Alkaline saponification and acid hydrolysis were used for product
      identification. Evaluation of antioxidant activity was performed by the 2,2
      diphenyl-1-picrylhydrazyl (DPPH) reduction assay and the inhibition of copper
      mediated oxidation of low density lipoprotein (LDL). RESULTS: The optimal
      conditions for WFAX hydrolysis using the XYLI have been determined to be 100 U g(
      1) of WFAX for 30 min at 50 degrees C. Saponification of the oligosaccharide
      released FA and oligosaccharide. The released oligosaccharide consisted of
      arabinose and xylose in a molar ratio of 1:3 and these results support the
      identity of the feruloylated oligosaccharide as feruloyl arabinoxylotrisaccharide
      (FAX(3)). FAX(3) showed profound antioxidant activity in 2,2-diphenyl-1
      picrylhydrazyl (DPPH) reduction assay exhibiting an antiradical efficiency of
      0.035 (x 10(-3)) and inhibited the copper-mediated oxidation of human low density
      lipoprotein (LDL) in a dose-dependent manner with almost complete inhibition at
      32 microM. CONCLUSION: A feruloylated oligosaccharide (FAX3) was isolated from
      WFAX after enzymatic treatment with XYLI. We verified antioxidant activity of
      FAX(3) which may be important in preventing or reducing the progression of
      atherosclerosis by inhibiting the peroxidation of lipoproteins.

PMID- 12594543
TI  - Antioxidant activity of extracts from the leaves of Smallanthus sonchifolius.
AB  - BACKGROUND & AIMS: Yacon ( Smallanthus sonchifolius, Asteraceae) is a native
      Andean plant, cultivated for its tubers throughout South America. The leaves are
      used in folk medicine as a medicinal tea for hypoglycemia. This paper describes
      the antioxidant activity of various extracts from S. sonchifolius leaves for
      their content of phenolic components. METHODS: The dried leaves were extracted in
      several ways. Two fractions were selected for their high content of phenolic
      compounds and analyzed by RP-HPLC. The antioxidant activity of these fractions
      was tested in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and xanthine/XOD superoxide
      radical scavenging assays, as inhibition of lipoperoxidation of subcellular
      membranes and as protective activity against oxidative injury of rat hepatocytes
      in primary cultures. RESULTS AND CONCLUSIONS: The presence of protocatechuic (2.5
      and 0.12 mg/g), chlorogenic (9.9 and 1.7 mg/g), caffeic (14.7 and 0.09 mg/g) and
      ferulic (traces) acids were determined in the two fractions. Both fractions
      showed potent antioxidant activity in DPPH (IC(50) = 16.1 +/- 3.4 and 24.3 +/-
      2.7 mg/ml) and xanthine/XOD superoxide radical scavenging (42.0 +/- 20.3 and 34.3
      +/- 11.4 SOD equivalents (U/mg)) tests, they inhibited the lipoperoxidation of
      rat liver subcellular membranes and they protected rat hepatocytes against
      oxidative injury. Our results may predetermine the use of S. sonchifolius leaves
      in human diet as a potential remedy in the prevention of chronic diseases caused
      by radicals, e. g., arteriosclerosis.

PMID- 12594544
TI  - Dealing with variability in food production chains: a tool to enhance the
      sensitivity of epidemiological studies on phytochemicals.
AB  - BACKGROUND: Many epidemiological studies have tried to associate the intake of
      certain food products with a reduced risk for certain diseases. Results of these
      studies are often ambiguous, conflicting, or show very large deviations of
      trends. Nevertheless, a clear and often reproduced inverse association is
      observed between total vegetable and fruit consumption and cancer risk. Examples
      of components that have been indicated to have a potential protective effect in
      food and vegetables include antioxidants, allium compounds and glucosinolates.
      AIM: The food production chain can give a considerable variation in the level of
      bioactive components in the products that are consumed. In this paper the effects
      of this variability in levels of phytochemicals in food products on the
      sensitivity of epidemiological studies are assessed. METHODS: Information on the
      effect of variation in different steps of the food production chain of Brassica
      vegetables on their glucosinolate content is used to estimate the distributions
      in the levels in the final product that is consumed. Monte Carlo simulations of
      an epidemiological cohort study with 30,000 people have been used to assess the
      likelihood of finding significant associations between food product intake and
      reduced cancer risk. RESULTS: By using the Monte Carlo simulation approach, it
      was shown that if information on the way of preparation of the products by the
      consumer was quantified, the statistical power of the study could at least be
      doubled. The statistical power could be increased by at least a factor of five if
      all variation of the food production chain could be accounted for. CONCLUSIONS:
      Variability in the level of protective components arising from the complete food
      production chain can be a major disturbing factor in the identification of
      associations between food intake and reduced risk for cancer. Monte Carlo
      simulation of the effect of the food production chain on epidemiological cohort
      studies has identified possible improvements in the set up of such studies. The
      actual effectiveness of food compounds already identified as cancer-protective by
      current imprecise methods is likely to be much greater than estimated at present.

PMID- 12594545
TI  - MR colonography with fecal tagging: comparison between 2D turbo FLASH and 3D
      FLASH sequences.
AB  - The objective of this study was to compare inversion recovery turbo 2D fast low
      angle shot (FLASH) and 3D FLASH sequences for fecal-tagged MR colonography
      studies. Fifteen consecutive patients with indications for colonoscopy underwent
      MR colonography with fecal tagging. An inversion recovery turbo-FLASH sequence
      was applied and compared in terms of artifacts presence, efficiency for masking
      residual stool, and colonic wall conspicuity with a fat-saturated 3D FLASH
      sequence. Both sequences were acquired following administration of paramagnetic
      contrast agent. Contrast-to-noise ratio and relative contrast between colonic
      wall and lumen were calculated and compared for both sequences. Turbo 2D FLASH
      provided fewer artifacts, higher efficiency for masking the residual stool, and
      colonic wall conspicuity equivalent to 3D FLASH. An inversion time of 10 ms
      provided homogeneously low signal intensity of the colonic lumen. Contrast to
      noise between colonic wall and lumen was significantly higher in the 3D FLASH
      images, whereas differences in relative contrast were not statistically
      significant. An optimized inversion-recovery 2D turbo-FLASH sequence provides
      better fecal tagging results and should be added to the 3D FLASH sequence when
      designing dark-lumen MR colonography examination protocols.

PMID- 12594546
TI  - Dry preparation for virtual CT colonography with fecal tagging using water
      soluble contrast medium: initial results.
AB  - The purpose of this study was to evaluate the feasibility of a dry bowel
      preparation, i.e. without laxative fluids, for virtual CT colonography (VCTC),
      and its impact on patient acceptance compared with conventional colonoscopy (CC).
      A randomly chosen patient population scheduled for CC ( n=11) was first submitted
      to VCTC after a dry preparation, consisting of low-residue meals combined with a
      small amount of a iodinated water-soluble contrast medium during each meal 3 days
      before VCTC. In different colon segments and between different persons, the
      degree of tagging in VCTC was evaluated and graded. Patient acceptance and future
      preference were assessed for both preparations as well as for both
      investigations. The mixing of the contrast with the intestinal content results in
      contrast impregnated stool, the tagged feces. The degree of fecal tagging was
      good in the majority of the patients and the colonic segments, especially in the
      descending colon and sigmoid. Furthermore, patient acceptance and preference were
      clearly in favour of VCTC compared with CC merely because of the non-invasiveness
      of the dry preparation. Dry bowel preparation and VCTC is a promising approach
      towards a patient-friendly colon cancer-screening setup.

PMID- 12594547
TI  - Experimental colonic phantom for the evaluation of the optimal scanning technique
      for CT colonography using a multidetector spiral CT equipment.
AB  - Our objective was to optimize a scanning protocol for CT colonography using a
      multidetector scanner with an adaptive-array matrix in a phantom study. A colonic
      phantom with 27 simulated lesions was examined using a multidetector CT scanner
      (Somatom Plus 4 Volume Zoom, Siemens, Erlangen, Germany). Three scanning
      protocols were tested: (a) collimation 1.0 mm, slice thickness 1.0 mm; (b)
      collimation 2.5 mm, slice thickness 3.0 mm; and (c) collimation 2.5 mm, slice
      thickness 5.0 mm. Image analysis was performed by two radiologists blinded to the
      construction of the phantom and to imaging parameters. Sensitivity for lesion
      detection and image quality was assessed. Computed tomographic colonography
      detected 27 of 27 lesions with protocol 1 (sensitivity 100%); 26 of 27 lesions
      with protocol 2 (sensitivity 96.3%); and 23 of 27 lesions with protocol 3
      (sensitivity 85.2%). Image quality was graded as optimal for protocol 1, good for
      protocol 2, and poor for protocol 3. When multidetector CT equipment with an
      adaptive-array matrix is used, protocols with 1.0- or 3.0-mm slice thickness have
      a sensitivity for the detection of lesions higher than that obtained with a 5.0
      mm slice thickness. Image quality decreases progressively when the slice
      thickness is increased; therefore, in a clinical setting, we recommend the use of
      a high-resolution protocol (1.0-mm effective slice thickness) with the highest
      pitch value in order to reduce scanning time. Dose exposure for such a protocol
      if combined with 80 mAs is within the range limits recommended by the ICRP for
      abdominal CT scanning.

PMID- 12594548
TI  - Non-invasive detection of liver fibrosis: Is superparamagnetic iron oxide
      particle-enhanced MR imaging a contributive technique?
AB  - The purpose of our study was to evaluate the ability of superparamagnetic iron
      oxide (SPIO)-enhanced MR imaging to detect liver fibrosis in patients with
      chronic liver disease and to compare the findings with histopathological data.
      Sixty-seven patients with chronic hepatitis ( n=58) or focal nodular hyperplasia
      (FNH; n=9) were studied using a 1.5-T MR system. The protocol included proton
      density-weighted, T2-weighted spin-echo (SE) and fast SE (FSE) sequences before
      and after SPIO administration and T2*-weighted gradient-recalled-echo (GRE)
      sequences after SPIO. Pre- and post-contrast T2-weighted and T2*-weighted
      sequences were retrospectively evaluated by three independent observers for
      evidence of non-tumor hypersignal intensities. Three liver patterns were
      considered: thick reticulations; thin reticulations; and/or multiple areas of
      hypersignal intensities. Unenhanced or enhanced patterns were compared with
      histopathological specimens, which had been obtained by percutaneous biopsy of
      the right lobe within a maximum of 12 months of MR examination. Liver fibrosis
      was histologically graded using a five-level scale (F0-F4), according to the
      METAVIR classification. Histopathology demonstrated significant fibrosis (F2-F4)
      in 57 patients, non-significant fibrosis in 1 patient (F1), and normal liver
      surrounding FNH in 9 patients (F0). After SPIO administration, at least one
      pattern of non-tumor hypersignal intensities was seen in 43 (76%) of the 57
      patients with F>/=2 with good agreement (kappa=0.68) compared with 2 (20%) of the
      10 F0/1 patients ( p<0.01). Attenuated non-homogeneous liver-signal intensities
      with persistent thick reticulations, thin reticulations, or multiple areas of
      hypersignals were observed in, respectively, 30, 52, and 56% of patients with
      F>/=2 with moderate agreement (kappa=0.51). Before SPIO, MR images were positive
      in 21 of 57 (37%) F>/=2 and zero F0/1 patients. Post-contrast proton-density
      weighted and T2*-weighted GRE were the most sensitive sequences for detecting non
      tumor hypersignal intensities. In patients with chronic liver diseases, SPIO
      enhanced MR imaging exhibits non-tumor hypersignal intensities indicative of
      liver fibrosis by decreasing the signal from the non-fibrotic areas where Kupffer
      cells are present.

PMID- 12594549
TI  - Detection of liver metastases by pulse inversion harmonic imaging during Levovist
      late phase: comparison with conventional ultrasound and helical CT in 160
      patients.
AB  - The aim of this study was to evaluate capabilities of pulse inversion harmonic
      imaging (PIHI) with Levovist in detection of liver metastases compared with
      conventional ultrasound (US) and helical CT (HCT). One hundred sixty consecutive
      patients with known malignancies were evaluated by conventional US, PIHI 2 min
      (40 patients) or 4 min (120 patients) after Levovist injection and HCT.
      Conspicuity and number of the identified metastatic lesions were evaluated and
      assessed by statistical analysis (significance p<0.05). Mean diameter of the
      smallest identified metastases was computed for conventional US, PIHI and HCT. In
      cases where PIHI revealed more lesions suspicious for metastases than HCT,
      intraopertive US with surgical biopsy or 3-6-month US follow-up were performed to
      confirm diagnosis. Images were stored on magneto-optical disk and evaluated off
      line by a dedicated software. Metastases conspicuity was significantly improved
      on PIHI if compared with conventional US ( p<0.05). In 49 patients all the
      employed imaging techniques did not reveal any lesion, whereas in the remaining
      111 patients, 28 patients revealed more than five metastatic lesions and 83
      patients presented from one to five metastatic lesions. In comparison with
      conventional US, PIHI revealed more metastases in 39/83 (47%), the same number in
      44/83 (53%) and a lower number in 0/83 (0%) patients. In comparison with HCT,
      PIHI revealed more metastases in 10/83 (12%), the same number in 61/83 (74%) and
      a lower number in 12/83 (14%) patients. Average number +/- SD (standard
      deviation) of confirmed metastases for patients was 2.21+/-1.6 for conventional
      US, 3.1+/-2.44 for PIHI and 3.05+/-2.41 for HCT. The difference between PIHI and
      conventional US was statistically significant ( p<0.0001), whereas the difference
      between PIHI and HCT was not significant ( p=0.9). The smallest identified
      metastases presented 3-mm mean diameter on PIHI, 5-mm on HCT and 7-mm on
      conventional US. PIHI with Levovist is a reliable technique in metastases
      detection.

PMID- 12594550
TI  - Assessment of calcium scoring performance in cardiac computed tomography.
AB  - Electron beam tomography (EBT) has been used for cardiac diagnosis and the
      quantitative assessment of coronary calcium since the late 1980s. The
      introduction of mechanical multi-slice spiral CT (MSCT) scanners with shorter
      rotation times opened new possibilities of cardiac imaging with conventional CT
      scanners. The purpose of this work was to qualitatively and quantitatively
      evaluate the performance for EBT and MSCT for the task of coronary artery calcium
      imaging as a function of acquisition protocol, heart rate, spiral reconstruction
      algorithm (where applicable) and calcium scoring method. A cardiac CT semi
      anthropomorphic phantom was designed and manufactured for the investigation of
      all relevant image quality parameters in cardiac CT. This phantom includes
      various test objects, some of which can be moved within the anthropomorphic
      phantom in a manner that mimics realistic heart motion. These tools were used to
      qualitatively and quantitatively demonstrate the accuracy of coronary calcium
      imaging using typical protocols for an electron beam (Evolution C-150XP, Imatron,
      South San Francisco, Calif.) and a 0.5-s four-slice spiral CT scanner (Sensation
      4, Siemens, Erlangen, Germany). A special focus was put on the method of
      quantifying coronary calcium, and three scoring systems were evaluated (Agatston,
      volume, and mass scoring). Good reproducibility in coronary calcium scoring is
      always the result of a combination of high temporal and spatial resolution;
      consequently, thin-slice protocols in combination with retrospective gating on
      MSCT scanners yielded the best results. The Agatston score was found to be the
      least reproducible scoring method. The hydroxyapatite mass, being better
      reproducible and comparable on different scanners and being a physical
      quantitative measure, appears to be the method of choice for future clinical
      studies. The hydroxyapatite mass is highly correlated to the Agatston score. The
      introduced phantoms can be used to quantitatively assess the performance
      characteristics of, for example, different scanners, reconstruction algorithms,
      and quantification methods in cardiac CT. This is especially important for
      quantitative tasks, such as the determination of the amount of calcium in the
      coronary arteries, to achieve high and constant quality in this field.

PMID- 12594551
TI  - MR imaging at rest early after myocardial infarction: detection of preserved
      function in regions with evidence for ischemic injury and non-transmural
      myocardial infarction.
AB  - Patients with subacute myocardial infarction were studied to detect regions of
      ischemic injury but with preserved myocardial function combining different MRI
      techniques. On a 1.5-T imaging system 27 patients were examined 7-14 days after
      acute myocardial infarction. The imaging protocol included T2-weighted fast spin
      echo imaging, a cine fast low-angle shot (FLASH) 2D technique to determine
      regional function at rest, and a first pass as well as late contrast enhancement
      perfusion study injecting 0.1 mmol/kg Gd-DTPA. Preserved function was compared
      with the transmural extent of first-pass perfusion phenomena, increased T2 signal
      intensity (SI), and late contrast enhancement. Semi-quantitative first-pass
      perfusion parameters were correlated with quantitative myocardial wall thickening
      (MWT) and degree of coronary artery stenosis. Indicating ischemic injury
      increased T2 SI and late enhancement was present in 29 and 26% of segments.
      Preserved function was found predominantly in segments with non-transmural late
      enhancement (112 of 338 segments with late enhancement) and transmural increase
      of T2 SI (129 of 386 segments with increased T2 SI). A high-grade perfusion
      deficit was detected in 4% of all segments and regularly associated with markedly
      decreased systolic function. Correlation of first-pass perfusion parameters was
      observed with MWT (r=0.50-0.90, p<0.001) but not with the degree of coronary
      artery stenosis. Our data suggest that preserved function was detected in non
      transmural myocardial infarction demonstrated by non-transmural late enhancement
      and increase of T2 SI.

PMID- 12594552
TI  - Use of high flip angle in T1-prepared FAST sequences for myocardial perfusion
      quantification.
AB  - This study reports on the first use of high flip angle and radio-frequency (RF)
      spoiling in T1-prepared fast acquisition in steady state (FAST) sequence for
      myocardial perfusion in patients. T1 dynamic range was measured in vitro with a
      FAST, an RF FAST and a snapshot fast low-angle shot (FLASH) sequences with a 90
      degrees flip angle. Myocardial perfusion was then measured twice in 6 patients
      during the same MR session. The RF FAST and FLASH, but not the FAST sequence,
      demonstrated an extended T1 dynamic range; however, the FLASH images were
      degraded by artifacts not present on the RF FAST images. The myocardial perfusion
      indices K1 (first-order transfer constant from the blood to the myocardium for
      the Gd-DTPA) and Vd (distribution volume of Gd-DTPA in myocardium) did not differ
      significantly between the two injections. K1 was 0.48+/-0.12 ml/min g(-1) and Vd
      was 12.5+/-2.9%. With an extended T1 dynamic range and the sensitivity required
      for myocardial perfusion quantification, the RF FAST sequence with a 90 degrees
      flip angle outperformed the snapshot FLASH sequence in terms of image quality and
      the FAST sequence in terms of contrast dynamic range.

PMID- 12594553
TI  - Pneumonia: high-resolution CT findings in 114 patients.
AB  - The objective of the present study was to assess the high-resolution CT
      appearances of different types of pneumonia. The high-resolution CT scans
      obtained in 114 patients (58 immunocompetent, 59 immunocompromised) with
      bacterial, Mycoplasma pneumoniae, viral, fungal, and Pneumocystis carinii
      pneumonias were analyzed retrospectively by two independent observers for
      presence, pattern, and distribution of abnormalities. Areas of air-space
      consolidation were not detected in patients with viral pneumonia and were less
      frequently seen in patients with Pneumocystis carinii pneumonia (2 of 22
      patients, 9%) than in bacterial (30 of 35, 85%), Mycoplasma pneumoniae (22 of 28,
      79%), and fungal pneumonias (15 of 20, 75%; p<0.01). There was no significant
      difference in the prevalence or distribution of consolidation between bacterial,
      Mycoplasma pneumoniae, and fungal pneumonias. Extensive symmetric bilateral areas
      of ground-glass attenuation were present in 21 of 22 (95%) patients with
      Pneumocystis carinii pneumonia and were not seen in other pneumonias except in
      association with areas of consolidation and nodules. Centrilobular nodules were
      present less commonly in bacterial pneumonia (6 of 35 patients, 17%) than in
      Mycoplasma pneumoniae (24 of 28, 96%), viral (7 of 9, 78%), or fungal (12 of 20,
      92%) pneumonia ( p<0.01). Except for Pneumocystis carinii pneumonia and
      Mycoplasma pneumoniae pneumonia, which often have a characteristic appearance,
      high-resolution CT is of limited value in the differential diagnosis of the
      various types of infective pneumonia.

PMID- 12594554
TI  - Computed tomography characteristics of advanced primary pulmonary
      lymphoepithelioma-like carcinoma.
AB  - Our objectives were to document CT features of advanced primary pulmonary
      lymphoepithelioma-like carcinoma (LELC) and to determine features that may assist
      differentiation from other non-small cell lung cancers (NSCLC). Imaging and
      clinical data of all patients with biopsy-proven pulmonary LELC ( n=12) were
      retrieved from a database of all NSCLC patients over a 2-year period. Twenty-five
      controls were recruited from other inoperable non-LELC NSCLC patients from the
      database. Pre-treatment CT scans of the thorax of both study and control patients
      were reviewed for lobe involved; tumour site, borders and size; and pleural,
      vascular or pulmonary involvement. Presence of lymphangitis carcinomatosis was
      noted. Lymph node metastasis was characterised as ipsilateral or contralateral
      enlarged (>1 cm) mediastinal or hilar nodes, or as peribronchovascular nodal
      spread. Differences between the two groups were tested using Mann-Whitney rank
      sum test. The LELC tumours were significantly larger (45.67 vs 17.71 cm(2)) than
      controls and were closely associated with the mediastinum. There were more LELC
      tumours with well-defined borders ( p<0.001) and fewer with spiculated borders (
      p<0001) than non-LELC tumours. There was increased peribronchovascular nodal
      spread ( p=0.01) and vascular encasement ( p=0.02) in LELC compared with non-LELC
      tumours. Advanced primary pulmonary LELC has distinct radiological features, and
      can appear as well-defined tumour closely associated with the mediastinum, with
      peribronchovascular spread and vascular encasement.

PMID- 12594555
TI  - Complication rate and diagnostic yield of 515 consecutive ultrasound-guided
      biopsies of renal allografts and native kidneys using a 14-gauge Biopty gun.
AB  - Our objective was to evaluate the safety and diagnostic efficacy of the
      ultrasound-guided renal biopsy procedure using an automated biopsy device (Biopty
      gun) with a 14-gauge needle. Five hundred fifteen consecutive ultrasound-guided
      renal biopsies performed in two large university hospitals were retrospectively
      reviewed. Three hundred forty-five biopsies were performed on renal allografts
      and 170 on native kidneys. The tissue specimen was adequate for histological
      evaluation in 95.3% of the cases (94.8% in the transplanted kidney group, 96.5%
      in the native kidney group). The overall complication rate was 12.2% and was
      significantly higher in the native kidney group (19.4%) than in the renal
      allograft group (8.7%). Major complications occurred in 2.7% of the cases (2.9%
      of the renal allografts and 2.4% of the native kidney biopsies), including one
      procedure-related death and the loss of the renal allograft in two other
      patients. Minor complications were noted in 9.5% of the biopsies and there were
      significantly more in the group of the native kidneys (17.1%) than in the group
      of the transplanted kidneys (5.8%). Renal biopsy with an automated device using a
      14-gauge needle has a high tissue recovery rate, but it is associated with a
      small risk of serious complications.

PMID- 12594556
TI  - Imaging spectrum of adrenal pseudocysts on CT.
AB  - The aim of this study was to analyze the imaging spectrum of adrenal pseudocysts
      on CT. The CT images of seven patients with pathologic diagnosis of adrenal
      pseudocysts in our hospital were reviewed for the size, cystic part, solid part,
      septum, calcification, acute hematoma, and layering appearance. The presence or
      absence of contrast enhancement of solid parts in each lesion was also assessed
      if possible. Of the seven adrenal pseudocysts, there were three pure cystic,
      three mixed cystic and solid, and one solid lesions on CT. Two of the three
      cystic pseudocysts were septated with calcifications. Layering appearance was
      present in two mixed lesions. There were central calcifications and acute
      hematomas in one solid mass. In our study, there was no contrast enhancement of
      the solid parts of adrenal pseudocysts. The CT appearances of adrenal pseudocysts
      may range from cystic, mixed, to solid masses. The presence of solid parts of
      adrenal pseudocysts on CT mimics those of adrenal neoplasms; however, no contrast
      enhancement of the solid part in the lesion may help in the diagnosis of adrenal
      pseudocysts and their differentiation from adrenal neoplasms.

PMID- 12594557
TI  - Comparison of voiding cystourethrography and double-balloon urethrography in the
      diagnosis of complex female urethral diverticula.
AB  - The preoperative work-up of female urethral diverticula should provide the
      surgeon with maximum data regarding the anatomy and structure of the
      diverticulum. Preoperatively, the number of diverticula, as well as the location,
      size, configuration, and communication to the urethra need to be clearly
      depicted. The objective of this study was to compare the information gained by
      voiding cystourethrography (VCUG) and positive-pressure double-balloon
      urethrography (DBU), and to verify which imaging modality can better delineate
      the features of the diverticula. Twelve women with a presumptive clinical
      diagnosis of a urethral diverticulum underwent VCUG followed by DBU, and the
      radiological data from each modality were compared. In 4 of 12 patients (33.3%)
      VCUG completely failed in demonstrating the diverticulum, whereas DBU showed a
      large complex diverticulum in 2 patients and a distinct mid-urethral diverticulum
      in 2 patients. In the remaining 8 women (66.7%) VCUG delineated only the lower
      part of the diverticulum, whereas DBU depicted a large diverticulum extending
      beneath the bladder neck in 3 patients and multiple diverticula in 5 patients.
      The sensitivity of DBU and VCUG, in our series, was therefore 100 and 66.7%,
      respectively. The DBU supplied excellent documentation regarding the location,
      size, configuration, and communication of the diverticula to the urethra in every
      case, which markedly facilitated surgical excision of the diverticula in 9 of 12
      patients. Three patients refused surgery and elected conservative treatment. In
      our experience, VCUG had a low sensitivity as a screening test for the diagnosis
      of female urethral diverticula, and failed to demonstrate properly the major
      structural characteristics of the diverticula, whereas DBU was highly sensitive
      as a diagnostic tool and supplied excellent anatomical delineation of the
      diverticula.

PMID- 12594558
TI  - Digital radiography of scoliosis with a scanning method: radiation dose
      optimization.
AB  - The aim of this study was optimization of the radiation dose-image quality
      relationship for a digital scanning method of scoliosis radiography. The
      examination is performed as a digital multi-image translation scan that is
      reconstructed to a single image in a workstation. Entrance dose was recorded with
      thermoluminescent dosimeters placed dorsally on an Alderson phantom. At the same
      time, kerma area product (KAP) values were recorded. A Monte Carlo calculation of
      effective dose was also made. Image quality was evaluated with a contrast-detail
      phantom and Visual Grading. The radiation dose was reduced by lowering the image
      intensifier entrance dose request, adjusting pulse frequency and scan speed, and
      by raising tube voltage. The calculated effective dose was reduced from 0.15 to
      0.05 mSv with reduction of KAP from 1.07 to 0.25 Gy cm(2) and entrance dose from
      0.90 to 0.21 mGy. The image quality was reduced with the Image Quality Figure
      going from 52 to 62 and a corresponding reduction in image quality as assessed
      with Visual Grading. The optimization resulted in a dose reduction to 31% of the
      original effective dose with an acceptable reduction in image quality considering
      the intended use of the images for angle measurements.

PMID- 12594559
TI  - Ultrasound of the spinal cord in children: its role.
AB  - This article covers the indications for spinal ultrasound including its
      advantages and disadvantages in comparison with spinal MR. We describe the
      features of a normal spinal ultrasound and those features which may be found in
      infants with spinal dysraphism.

PMID- 12594560
TI  - Transcranial Doppler ultrasonography in neurologically asymptomatic children and
      young adults with sickle cell disease.
AB  - The purpose of the study was to evaluate transcranial Doppler ultrasonography for
      identifying cerebrovascular disease in neurologically asymptomatic children and
      young adults with sickle cell disease. A total of 47 consecutive patients with
      sickle cell disease (28 females, 19 males; age range 8 months to 29 years, mean
      age 9 years 6 months) were evaluated by transcranial color and duplex Doppler
      ultrasonography via transtemporal and occipital (2-MHz probe) as well as by
      transocular (5-MHz probe) approach. Eleven vessels (middle, posterior, anterior
      cerebral artery, vertebral artery, ophthalmic artery on each side and basilar
      artery) were analyzed in each patient. Following nine transcranial Doppler
      findings predictive for cerebrovascular disease, patients with one or more of
      those abnormal sonographic findings underwent MR imaging and MR angiography. In 8
      patients with abnormal transcranial Doppler the MR angiography was normal. Thirty
      one patients demonstrated normal results. In 15 of 16 patients with one or more
      abnormal Doppler findings (34% of all studied patients) MR imaging and MR
      angiography were performed. The MR angiography disclosed cerebrovascular stenosis
      in 7 patients (15% of all patients, 44% of those with pathological transcranial
      Doppler findings). In one of those patients MR imaging revealed silent peripheral
      ischemic infarction as well. Our findings indicate the usefulness of transcranial
      Doppler ultrasonography to reveal occult cerebrovascular lesions in
      neurologically asymptomatic patients with sickle cell disease. It should
      regularly be performed in all sickle cell patients in order to detect patients at
      risk for later stroke. Patients with homozygous disease and a high frequency of
      preceding sickle cell crises should be followed most closely.

PMID- 12594561
TI  - Contrast-enhanced three-dimensional MR angiography of neck vessels: does
      dephasing effect alter diagnostic accuracy?
AB  - The aim of this study was to evaluate diagnostic accuracy of contrast-enhanced
      MRA (CEMRA) compared with digital subtraction angiography (DSA) in studying neck
      vessels of 48 patients. In three groups of patients, we used three MRA protocols
      differing for voxel size to assess if intravoxel dephasing effects could modify
      accuracy of CEMRA. Accuracy and correlation with DSA results were calculated in
      all patients and separately in the three groups. A qualitative analysis of the
      likeness between morphology of the stenosis in CEMRA and DSA images was also
      assessed. In all patients accuracy and agreement with DSA were 96% and k=0.85 in
      subclavian arteries, 96% and k=0.84 in vertebral artery, 97% and k=0.88 in common
      carotid arteries, and 94% and k=0.86 in internal carotid arteries. In the three
      groups accuracy and agreement with DSA did not show any significant difference.
      Qualitative analysis of CEMRA and DSA images revealed a better agreement in
      depicting the morphology of stenosis using a smaller voxel size. The CEMRA
      represents a powerful tool for the non-invasive evaluation of neck vessels.
      Overestimation trend of CEMRA is confirmed and the reduction of voxel size,
      decreasing the dephasing intravoxel effect, allows to have a better overlapping
      of stenosis morphology on CEMRA compared with DSA, but it does not yield
      diagnostic gain in the stenosis grading.

PMID- 12594562
TI  - Proton magnetic resonance spectroscopy ((1)H MRS) of human brain tumours:
      assessment of differences between tumour types and its applicability in brain
      tumour categorization.
AB  - Our objective was to evaluate the usefulness of proton magnetic resonance
      spectroscopy ((1)H MRS) in categorizing brain tumours. In vivo single-voxel (1)H
      MRS at an echo time of 136 ms was performed in 108 patients with brain neoplasms
      that included 29 meningiomas (MEN), 15 low-grade astrocytomas (LGA), 12
      anaplastic astrocytomas (AA), 25 glioblastomas (GBM) and 27 metastases (MET).
      Time-domain fitted areas of nine resonances were evaluated in all spectra. Twenty
      five additional tumours were prospectively included as independent test set.
      Differences in at least two resonances were found in all pairwise comparisons of
      tumour groups except in GBM vs MET. Large lipid resonance at 1.30 ppm was found
      to be characteristic of GBM and MET, and alanine was characteristic of MEN.
      Significant differences were found between LGA and AA in choline-containing
      compounds and total creatine resonances. When implemented in a stepwise
      algorithm, these findings correctly classified 84% (21 of 25) tumours in the
      independent test set. Some additional utility was found in glycine/myo-inositol
      at 3.55 ppm for bilateral differentiation between GBM and MET (9 of 11, 82%
      correct classification in the test set). (1)H MRS provides useful information to
      categorize the most common brain tumours that can be implemented in clinical
      practice with satisfactory results.

PMID- 12594563
TI  - Cerebrospinal fluid changes after intravenous injection of gadolinium chelate:
      assessment by FLAIR MR imaging.
AB  - Fluid-attenuated inversion recovery (FLAIR) sequence is currently used in
      clinical practice. Some reports emphasize the possibility that, in pathologic
      conditions, intravenous injection of gadolinium chelates may lead to an increased
      signal inside the cerebrospinal fluid (CSF). The aim of this study was to
      evaluate the presence of CSF signal changes in pathologic conditions causing
      blood-brain barrier disruption or neovascularization when imaging is performed
      after intravenous injection of gadolinium. We obtained FLAIR sequences after
      gadolinium injection from 33 patients affected by different intracranial
      pathologies and 10 control subjects. Patients were affected by ischemic stroke in
      the subacute phase, from 2 to 7 days from onset of symptoms (12 patients),
      meningiomas (8 patients), high-grade gliomas (5 patients), previous surgical
      procedures for intra-axial neoplasms (5 patients), and multiple sclerosis with
      active plaques (3 patients). Magnetic resonance imaging was performed in patients
      and controls using a 1.5-T magnet, using T2- and T1-weighted FLAIR sequences. The
      FLAIR sequence was acquired before and 1-3 h after injection of a standard dose
      of gadolinium. In those patients affected by ischemic lesions, FLAIR sequences
      were repeated the next days and 3-4 days later. The CSF signal was visually
      evaluated by two readers and scored from 0 to 3 depending by the degree of
      enhancement. The location of CSF signal changes (close to the lesion,
      hemispheric, or diffuse) was also considered. The CSF signal was markedly
      increased after 3 h from intravenous injection of gadolinium in all the patients
      with stroke, in those with previous surgery, and in those with high-grade gliomas
      whose neoplasm's surface was in contact with the subarachnoid spaces (SAS) or
      ventricles; a strong enhancement was also evident inside the necrotic component
      of the tumor. The CSF changes were more evident close to the pathology and/or in
      the hemisphere involved by the pathology. Moderate CSF enhancement was observed
      in the SAS close to meningiomas. No signal changes were evident in all the
      others. In those patients with stroke imaged in the following days, CSF signal
      showed to be diffuse to both hemispheres the next day and returned to normal
      values within 2 days. In patients affected by pathologies with blood-brain
      barrier breakdown or neovascularization close the SAS or the ventricles, CSF
      changes, related to gadolinium leakage, are likely when FLAIR sequences are
      acquired 2-24 h after i.v. injection of the contrast. This pattern should be
      known in order to differentiate it from that of subarachnoid hemorrhage.

PMID- 12594564
TI  - Malformations of the midline commissures: MRI findings in different forms of
      callosal dysgenesis.
AB  - Malformations of the corpus callosum (CC) may occur in many different syndromes.
      Various forms have been observed. We report seven cases of malformation of the
      CC. Special attention is directed towards the development of the fornix and
      hippocampus as a hippocampal commissure is a prerequisite of normal hippocampal
      development. The clinical disability of the patients presented here differed
      significantly, which may in part be due to the different extent of this cerebral
      malformation. The relevance of the concomitant aplasia of the limbic system has
      not been addressed in detail previously in the literature.

PMID- 12594565
TI  - Fatigue stress injuries of the pelvic bones and proximal femur: evaluation with
      MR imaging.
AB  - The purpose of this study was to determine the prevalence and the distribution as
      well as male/female differences in patients with hip or pelvic pain based on MRI
      results. Three hundred forty consecutive conscripts (45 women, 295 men; age range
      18-29 years; mean age 20.7 years) suffering from stress-related hip, buttock or
      groin pain took part in the study. All 340 patients underwent MR imaging.
      Radiographic data were available for 215 patients. Two radiologists interpreted
      the images by consensus. In MRI 174 stress injuries were diagnosed in 137
      patients (32 women, 105 men). The incidence of bone stress injuries in women was
      significantly higher than that in men ( p<0.0001). One hundred five of the
      injuries (60%) were related to the proximal femur, 70 (67%) to the neck, 34 (32%)
      to the proximal shaft, and one (1%) to the head. Sixty-nine of the 174 stress
      injuries (40%) concerned the pelvic bones: sacrum 28 (41%); inferior pubic ramus
      34 (49%); superior pubic ramus 3 (4%); iliac bone 3 (4%); and acetabulum 1 (1%).
      In 31 of the 174 cases (18%) symptoms were contralateral to MR findings. Thirty
      three of the 137 patients (24%) had multiple bone stress injuries, 29 had two
      bone stress injuries and 4 patients had three. The sensitivity of radiography was
      37%, specificity 79%, accuracy 60%, positive predictive value 59% and negative
      predictive value 61%. The kappa value for agreement between radiography and MRI
      was poor (0.17, p=0.0008). Patients suffering from stress-related hip pain MRI
      revealed bone stress injuries in 40%; of these, 60% were located in the proximal
      femur and 40% in the pelvic bones. For accurate diagnosis of bone stress
      injuries, and to ensure appropriate treatment, the entire pelvis and both
      proximal femurs should be studied simultaneously by means of MRI.

PMID- 12594566
TI  - Clinical impact of MRI in acute wrist fractures.
AB  - The purpose of this study was to evaluate the clinical impact of MRI in the early
      diagnosis of wrist trauma. High-resolution MR imaging was performed on a 1.5-T
      unit (Symphony Quantum, Siemens, Erlangen, Germany) using coronal and axial T1-
      and T2-weighted fat-saturated turbo-spin-echo sequence via a dedicated wrist coil
      within a mean of 6.6 days after initial radiographs in 54 patients (56 wrists)
      with clinical suspicion of wrist fractures and normal plain or indistinct
      radiographs. Initial radiographs were evaluated independently by two senior
      radiologists and the hand surgeon without knowledge of the MRI findings. The
      initial treatment protocol was based on evaluation of plain films and clinical
      findings by the hand surgeon. Treatment protocol was changed after MRI
      examination if necessary. In 31 of 56 wrists MRI findings resulted in a change of
      diagnosis. There were false-positive diagnoses on plain radiographs in nearly one
      half ( n=25) of the patients. False-negative diagnoses on plain radiographs
      resulted in 6 cases. Magnetic resonance imaging detected additional injuries of
      soft tissue in more than one third ( n=20). In 22 of 56 wrists the period of
      immobilization could be shortened or ended, in 12 of 56 it was prolonged, and in
      3 of 56 a surgical intervention was necessary. In 19 wrists MRI had no
      therapeutic consequences. Our data demonstrate the high clinical impact of MRI in
      the detection of acute wrist fractures. We recommend MRI of the wrist immediately
      on the day of trauma if there is clinical suspicion and normal plain radiographs.
      Accurate diagnosis by MRI examination within the first days following trauma may
      reduce economic costs due to shortened immobilization time in cases with a
      suspected fracture but plain radiographs.

PMID- 12594567
TI  - MR imaging of meniscal bucket-handle tears: a review of signs and their relation
      to arthroscopic classification.
AB  - Our objective was to review the MR imaging signs of meniscal bucket-handle tears
      and assess the relevance of these signs to the arthroscopic classification of
      displaced meniscal tears. Forty-five menisci in 42 patients who had a diagnosis
      of bucket-handle tear either on MR imaging or on subsequent arthroscopy (in which
      Dandy's classification of meniscal tears was used) were retrospectively analyzed
      for MR imaging findings of double posterior cruciate ligament (PCL), fragment
      within the intercondylar notch, absent bow tie, flipped meniscus, double-anterior
      horn, and disproportional posterior horn signs. Arthroscopy, which was considered
      as the gold standard, revealed 41 bucket-handle tears (either diagnosed or not
      diagnosed by MR imaging) in 38 patients (33 males, 5 females). There was a
      statistically significant male preponderance for the occurrence of meniscal
      bucket-handle tears. Overall, sensitivity and positive predictive value of MR
      imaging for the detection of meniscal bucket-handle tears were calculated as 90%.
      Common MR imaging signs of meniscal bucket-handle tears in arthroscopically
      proven cases of such tears were the fragment in the notch and absent bow tie
      signs (98% frequency for each). Double-PCL, flipped meniscus, double-anterior
      horn, and disproportional posterior horn signs, however, were less common (32,
      29, 29, and 27%, respectively). An arthroscopically proven bucket-handle tear was
      found in all patients who displayed at least three of the six MR imaging signs of
      meniscal bucket-handle tears. The presence of three or more MR imaging signs of
      meniscal bucket-handle tears is highly suggestive of this condition.

PMID- 12594568
TI  - Contrast-enhanced MR imaging with fat suppression in adult-onset septic
      spondylodiscitis.
AB  - Spinal infections typically involve vertebrae as well as discs, and for this
      reason they are called septic spondylodiscitis. Magnetic resonance imaging is the
      most sensitive imaging method for the evaluation of this group of spinal
      diseases. The use of contrast-enhanced T1-weighted sequences with fat
      suppression, if correctly applied, may increase information provided by MRI.
      Firstly, this technique allows the primary vertebral focus, which often precedes
      disc involvement, to be identified at a very early stage. When the disease
      spreads, T1-weighted fat-suppressed gadolinium dimeglumine (Gd-DTPA) enhanced
      images provide macroscopic details of the primary vertebral focus, disc
      involvement patterns, and pathways of infection diffusion. All this information,
      when correlated with laboratory tests, may be useful in identifying the
      infectious agents (tuberculous vs piogenic forms), thus enabling a suitable
      therapy to be started. This technique is also useful in the assessment of the
      real extension of the disease, providing a clear depiction of paravertebral space
      involvement and of psoas muscle abscesses. Dangerous complications, such as
      meningitis, myelitis, and epidural abscesses, may be more promptly diagnosed and
      fully evaluated with fat-suppressed post-contrast T1-weighted images. Finally,
      this imaging technique may help to differentiate infectious processes from
      degenerative disorders, extradural neoplastic processes, and rheumatic diseases.

PMID- 12594569
TI  - Pseudolesions in mammography.

PMID- 12594570
TI  - Generation of tumor cell lysate-loaded dendritic cells preprogrammed for IL-12
      production and augmented T cell response.
AB  - Dendritic cells (DC) loaded with tumor associated antigens (TAA) are often used
      for the vaccination of cancer patients; however methodologies for the vaccine
      preparation have not yet been standardized. The purpose of this work was to
      optimize the ex-vivo production of functional TAA-loaded DC that would produce
      interleukin-2 (IL-12) and enhance the T cell response. We generated ex-vivo DC
      from human monocytes with granulocyte macrophage-colony stimulating factor (GM
      CSF) and IL-4, and whole necrotic tumor cells (cell lysates) of cancer cell lines
      were used as model TAA. DC were loaded with lysates without or with additional
      tumor necrosis factor-alpha (TNF-alpha), or cytokine combination treatments and
      tested for functional ability in vitro. Tumor cell lysates alone did not fully
      mature DC either phenotypically or functionally. After antigen uptake additional
      maturation signals were necessary. TNF-alpha matured DC phenotypically, but
      additional interferon-gamma (IFN-gamma) treatment was necessary to achieve
      functional maturation, the production of significant amounts of IL-12. Since IL
      12 production by DC increased during the first 24 h of maturation and declined by
      48 h, proper timing of the ex-vivo DC treatment was crucial for the generation of
      functionally mature antigen-loaded DC. Our results suggest that after allowing 4
      h of tumor lysate uptake by immature DC, further treatment with TNF-alpha and IFN
      gamma for 24 h provides the optimal conditions to obtain functional TAA-loaded
      DC. These TAA-loaded cytokine pretreated DC then prime naive T cells, and enhance
      both T helper 1 (Th1), Th2 and cytotoxic T lymphocyte (CTL) responses, that are
      necessary to achieve an effective, specific anti-tumor response.

PMID- 12594571
TI  - Heat shock protein 70 expression induces antitumor immunity during intracellular
      hyperthermia using magnetite nanoparticles.
AB  - In this study we demonstrated that heat shock protein (HSP) 70 expression by
      hyperthermia induced antitumor immunity in the T-9 rat glioma. Our hyperthermic
      system using magnetic nanoparticles induced necrotic cell death that correlated
      with HSP70 expression. We purified the HSP70-peptide complexes from the tumor
      after hyperthermia to investigate whether HSP70 was involved in the antitumor
      immunity, and we found that in the F344 rats immunized with T-9-derived HSP70 the
      tumor growth of T-9 was significantly suppressed. Tumor rejection assay after
      hyperthermic treatment of implanted T-9 cells with incorporated magnetite
      cationic liposomes (MCL) was performed to investigate whether antitumor immunity
      was induced by release of HSP70 from the necrotic cells in the F344 rat. Tumor
      growth was strongly suppressed in the rats subjected to hyperthermia of implanted
      T-9 cells, and 50% of rats were protected from challenge with T-9 cells.
      Immunogenicity was enhanced when the HSP70-overexpressing T-9 cells were killed
      via necrosis in rats by hyperthermia, after which all rats were completely
      protected from challenge with T-9 cells. Our hyperthermic system produces
      vaccination with HSP70-peptide via necrotic tumor cell death in vivo, resulting
      in antitumor immunity. This phenomenon, which may be termed in situ vaccination,
      has important implications for the development of novel antitumor therapies.

PMID- 12594572
TI  - The abl/bcr gene product as a novel leukemia-specific antigen: peptides spanning
      the fusion region of abl/bcr can be recognized by both CD4+ and CD8+ T
      lymphocytes.
AB  - Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation
      leading to the Philadelphia chromosome. Two fusion genes are created by this
      translocation: bcr/abl and abl/bcr. The fusion regions of both translocation
      products are unique and strictly limited to leukemia cells, giving rise to
      potential tumor-specific antigens. Although several studies on the immunogenicity
      of peptides spanning the bcr/abl fusion region have been reported, little is
      known about the corresponding reciprocal translocation product abl/bcr. Here we
      report that synthetic peptides representing the fusion region of the abl/bcr
      forms a1bb3 and a1bb4 can be specifically recognized by HLA-A2-restricted
      cytotoxic T lymphocytes from healthy donors. Furthermore, HLA-matched a1bb3
      expressing CML cells can be recognized by a1bb3-specific HLA-A2-restricted T
      cells, indicating natural processing and presentation of abl/bcr protein by
      leukemia cells. Moreover, a 19-mer peptide encompassing this class I-binding
      sequence also elicited a1bb3-specific class II-restricted T-cell responses. Thus,
      both class I- and class II-restricted T-cell responses can be stimulated in
      healthy donors by abl/bcr peptides in vitro. Because abl/bcr is expressed in the
      majority of CML patients, it may represent a highly leukemia-specific antigen
      with potential use in immunotherapy.

PMID- 12594573
TI  - A novel adenovirus expressing human 4-1BB ligand enhances antitumor immunity.
AB  - 4-1BB ligand (4-1BBL), a member of the tumor necrosis factor (TNF) superfamily,
      interacts with 4-1BB (CDw137) expressed on activated T cells and delivers a
      costimulatory signal for T cell activation and growth. Various studies have
      demonstrated a role for murine 4-1BB in immune function, but relatively few
      investigations of human 4-1BB have been conducted. Here we report on the
      construction of a recombinant E1/E3-deleted adenovirus encoding human 4-1BBL (Ad4
      1BBL) and its stimulation of antitumor immunity. Ad4-1BBL was able to efficiently
      infect several human adenocarcinoma cell lines and induce 4-1BBL expression on
      the cell surface within 24 h, this enhancing the antitumor activity not only of
      lymphokine-activated killer cells with a T cell phenotype (T-LAK) but also naive
      peripheral blood mononuclear cells (PBMC). This antitumor activity with T-LAK
      cells was further enhanced by addition of bispecific antibody (BsAb; anti
      MUC1xanti-CD3). Cocultivation of Ad4-1BBL-infected tumor cells with either T-LAK
      cells or PBMC resulted in significant elevation of interferon-gamma (IFN-gamma),
      interleukin-2 (IL-2), and granulocyte-macrophage colony-stimulating factor (GM
      CSF) production. Furthermore, remarkable tumor growth inhibition was observed in
      cholangiocarcinoma-grafted severe combined immunodeficient (SCID) mice to which
      Ad4-1BBL and T-LAK cells were administered when tumor size exceeded 5 mm in
      diameter. These results provide strong evidence in support of the efficacy of
      adenovirally delivered 4-1BBL for genetic immunotherapy of cancer.

PMID- 12594574
TI  - Squamous cell carcinoma cells differentially stimulate NK cell effector
      functions: the role of IL-18.
AB  - Tumor cells stimulate natural killer (NK) cell effector functions, but the
      regulation of cytokine secretion and cytolysis is incompletely understood. We
      tested whether oral and pharyngeal squamous cell carcinoma cell lines
      differentially stimulated NK cell interferon-gamma (IFN-gamma) secretion and
      cytolysis using a clone of the NK-92-transformed human NK cell line, NK92.35. SCC
      4 and SCC-25 cells, but not FaDu or Cal 27 cells, stimulated robust NK92.35 IFN
      gamma secretion. All four carcinoma cell lines were lysed by NK92.35 cells. These
      findings indicate that carcinoma cells differentially stimulate NK cell IFN-gamma
      secretion and cytolysis. In Transwell experiments, a combination of SCC-4 or SCC
      25 cell soluble factors and contact with FaDu cells synergistically stimulated
      NK92.35 cell IFN-gamma secretion. Stimulatory SCC-4 cells constitutively secreted
      IL-18, a cytokine that potently augments IFN-gamma secretion by T cells and NK
      cells. In contrast, poorly stimulatory FaDu cells produced little or no IL-18,
      but synergized with recombinant IL-18 to stimulate NK92.35 IFN-gamma secretion.
      mAb to IL-18 or IL-18 receptor diminished SCC-4-stimulated IFN-gamma secretion by
      NK92.35 cells and by nontransformed NK cells. Thus, IL-18 was necessary for
      optimal carcinoma stimulation of NK cell IFN-gamma secretion. In vivo, oral and
      upper aerodigestive tract epithelia and carcinomas produced IL-18, but one
      squamous cell carcinoma had heterogeneous IL-18 expression. Thus IL-18 production
      can account for squamous cell carcinoma differential stimulation of NK cell
      effector functions in vitro and may be important for stimulation of NK cells in
      vivo.

PMID- 12594575
TI  - Expression of HER2/neu is uncommon in human neuroblastic tumors and is unrelated
      to tumor progression.
AB  - Neuroblastic tumors (NT) are the most frequently occurring extracranial solid
      tumors during childhood. The overall 5-year survival is approximately 20% for
      patients with metastatic disease. Novel treatments are therefore intensively
      sought and tumor-targeted immuno- and chemotherapy appear promising. The HER2/neu
      oncogene, which is highly homologous to the EGF receptor, was initially isolated
      from rat neuroblastoma cells. HER2/neu over-expression is frequently detected in
      breast tumors and constitutes an important unfavorable prognostic factor.
      HER2/neu is a suitable target for antibody-based immunotherapy, as demonstrated
      by the clinical efficacy of the Herceptin monoclonal antibody (mAb), which reacts
      with its extracellular domain. Expression of HER2/neu has also been reported to
      be a negative prognostic factor in a small survey of NT tumors. Here, we have
      investigated HER2/neu expression in 14 human and 2 murine neuroblastoma (NB) cell
      lines by flow cytometric analysis and in 93 NT by means of a certified
      immunohistochemical system. HER2/neu over-expression was found in 2 human cell
      lines and 11 tumors (14% for both types of samples). No significant association
      was found between HER2/neu expression and stage, age, sex, ploidy, histological
      type or subtype. Moreover, log rank test indicated that overall and event-free
      survival was not significantly different in HER2/neu positive and negative
      patients. These data suggest that HER2/neu should not be considered as a relevant
      prognostic factor in NT, and that HER2/neu-based immunotherapy may be feasible
      only in a minority of NT patients.

PMID- 12594576
TI  - A basal membrane-like structure surrounding tumour nodules may prevent
      intraepithelial leucocyte infiltration in colorectal cancer.
AB  - Epithelial tumours consist of an epithelial compartment and a stromal
      compartment, which are sometimes separated by a basal membrane-like structure. We
      sought to determine whether these factors have prognostic value in 84 curatively
      resected stage II and III colorectal cancer by immunohistochemically staining
      tumours for leucocytes (CD45) and extracellular matrix, and to assess the
      presence of a basal membrane-like structure. Leucocyte infiltration was also
      assessed in hematoxylin-eosin (HE) stained sections. Most leucocytes were located
      in the tumour stroma. A relatively high intraepithelial leucocyte infiltration
      was significantly correlated with a lower level of tumour recurrence (P=0.03) and
      a longer disease-free survival (P=0.05), whereas leucocytes located in the tumour
      stroma (P=0.92) or at the advancing margin (p=0.06) were not. Intraepithelial
      leucocyte infiltration was also significantly correlated with leucocyte
      infiltration in the tumour stroma (P=0.02) and at the advancing tumour margin
      (P=0.005), and as assessed in HE-stained tumour sections (P=0.05), but each of
      these parameters on its own did not have a prognostic value in predicting disease
      free survival. Moreover, the presence of a basal membrane-like structure
      surrounding the tumour epithelium was inversely correlated with the number of
      intraepithelial leucocytes (P=0.05), suggesting that this membrane-like structure
      functions as a barrier to intraepithelial leucocyte infiltration. We conclude
      that leucocytes must be in the direct vicinity of tumour cells to affect tumour
      growth. The presence of an extracellular matrix barrier seems to prevent this
      interaction.

PMID- 12594577
TI  - Amifostine protects lymphocytes during radiotherapy and stimulates expansion of
      the CD95/Fas and CD31 expressing T-cells, in breast cancer patients.
AB  - A large body of experimental research supports the anti-neoplastic activity of
      cellular and humoral immunity. Disease and therapy-related immune suppression may
      be important on the treatment outcome or on the subsequent course of the
      malignant disease. The aim of the study was to investigate the efficacy of
      amifostine in preventing the immunological toxicity of post-operative
      radiotherapy (RT) in breast cancer patients. Using flow-cytometry, we examined
      comparatively the peripheral blood lymphocytic subpopulations in breast cancer
      patients undergoing conventional post-operative RT versus a hypofractionated
      accelerated RT scheme combined with amifostine (HypoARC) administration. Despite
      the higher radiation dose intensity delivered in the HypoARC group, a significant
      protection of CD4, CD8, CD19 and CD56 subtypes by amifostine was noted. We
      further focused on two interesting CD4/CD8 subpopulations involved in cellular
      apoptosis and trans-endothelial migration, namely the CD95/Fas and CD31 positive
      lymphocytes. Amifostine protected and induced expansion of these subtypes, which
      could contribute to the maintenance of a high burden of tumor infiltrating
      lymphocytes during therapy. It is suggested that amifostine effectively protects
      lymphocytes against RT, which may enhance the efficacy of the latter. The
      clinical impact of the CD95(+) and CD31(+) T-cell immunological modulation
      induced by amifostine requires further investigation.

PMID- 12594579
TI  - The adrenergic coin: perfusion and metabolism.

PMID- 12594580
TI  - Nutritional papers in ICU patients: what lies between the lines?
AB  - The abundance of literature related to nutritional support reflects its recently
      recognised role in preventing metabolic complications and gut dysfunction during
      critical illness. However, some published studies lack relevance to critically
      ill patients, as a result of the selection of subjects and outcome variables, or
      flaws in the study design, as well as in the type, composition, timing, route of
      administration and amount of nutritional support given. This review will
      highlight these confounding factors by describing two imaginary (but typical)
      clinical trials and by analysing some studies published. The point at issue is
      that basic quality requirements, such as the formulation of a prospective
      hypothesis and the delineation of the effects of the reference treatment, are
      often lacking in many studies published. Data analysis was often found to be
      biased by the absence of statistical power calculation and intention-to-treat
      analysis. Globally, studies designed to assess the effects of nutritional support
      on the outcome of critically ill patients, rarely fulfil basic quality
      requirements and should therefore be interpreted cautiously. We suggest simple
      strategies or study design that will allow important questions to be answered by
      future clinical trials.

PMID- 12594582
TI  - Outcome of postoperative pneumonia in the Eole study.
AB  - OBJECTIVES: Prognosis factors of ventilator-associated pneumonia (VAP) have been
      largely investigated, while the data concerning postoperative pneumonia (POP) are
      scarce. The aim of this multicenter, prospective study was to evaluate the
      predictive factors of mortality due to POP and the impact of initial antibiotic
      therapy on outcome. METHODS: Two hundred centers were included. Diagnosis of POP
      was assessed on clinical and laboratory criteria, chest X-ray changes and
      microbiological criteria, when possible. Outcomes of the patients were noted. An
      independent committee made a retrospective assessment of appropriateness of
      antimicrobial therapy. RESULTS: The overall mortality among the 556 cases of POP
      was 23% (126 patients). Five parameters were independently associated with
      mortality: American Society of Anesthesiology (ASA) grade 3 or more ( p<0.001),
      age 64 years or more ( p<0.01), time to onset of pneumonia more than 3 days (
      p<0.01), mottling ( p<0.05) and hypotension ( p<0.05). Among the 322
      microbiologically confirmed cases of pneumonia, 92 received inappropriate
      antibiotic (AB) therapy (29%). No difference in mortality was observed between
      the patients receiving inappropriate and appropriate AB therapy (22.8 vs 16.9%).
      In this subgroup, three parameters remained independently associated with
      mortality: ASA grade 3 or higher ( p<0.001), time to onset of pneumonia more than
      3 days ( p<0.05) and hypotension ( p<0.05). Inappropriate initial AB did not
      modify the model ( p=0.22). CONCLUSIONS: Five independent predictive factors for
      mortality of POP were identified. Despite a trend toward decreased mortality with
      appropriate initial antimicrobial therapy, no difference was observed between the
      groups. Polymicrobial pneumonia or non-fermenting Gram-negative bacilli appeared
      to be a risk factor for inappropriate AB.

PMID- 12594581
TI  - Peripartum cardiomyopathy: a condition intensivists should be aware of.
AB  - We use an illustrative case of severe peripartum cardiomyopathy with congestive
      heart failure to introduce this topic and proceed to cover its pathophysiology,
      incidence, management and outcome.

PMID- 12594583
TI  - Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective
      cohort study.
AB  - OBJECTIVE: The aim of this study was to investigate whether serial serum neuron
      specific enolase (NSE) can be used to predict neurological prognosis in patients
      remaining comatose after cardiopulmonary resuscitation (CPR). DESIGN.
      Observational cohort study. Clinicians were blinded to NSE results. SETTING:
      Eighteen-bed general ICU. PATIENTS: Comatose patients admitted to the ICU after
      CPR. INTERVENTIONS: Serum NSE was measured at admission and daily for 5 days.
      MEASUREMENTS AND RESULTS: Patients received full intensive treatment until
      recovery or until absence of cortical response to somatosensory evoked potentials
      more than 48 h after CPR proved irreversible coma. Of the 110 patients included
      (mean GCS at ICU admission 3, range 3--9), 34 regained consciousness, five of
      whom died in hospital. Seventy-six patients did not regain consciousness, 72 of
      whom died in hospital. Serum NSE at 24 h and at 48 h after CPR was significantly
      higher in patients who did not regain consciousness than in patients who regained
      consciousness (at 24 h: median NSE 29.9 microg/l, range 1.8-250 vs 9.9 microg/l,
      range 4.5-21.5, P<0.001; at 48 h: median 37.8 microg/l, range 4.4-411 vs 9.5
      microg/l, range 6.2-22.4, P= 0.001). No patient with a serum NSE level >25.0
      microg/l at any time regained consciousness. Addition of NSE to GCS and
      somatosensory evoked potentials increased predictability of poor neurological
      outcome from 64% to 76%. CONCLUSIONS: High serum NSE levels in comatose patients
      at 24 h and 48 h after CPR predict a poor neurological outcome. Addition of NSE
      to GCS and somatosensory evoked potentials increases predictability of
      neurological outcome.

PMID- 12594584
TI  - A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the
      medical intensive care unit.
AB  - OBJECTIVE: To evaluate dexmedetomidine for sedation of patients in the medical
      ICU. DESIGN AND SETTING: Prospective observational study in an intensive care
      unit of a university hospital. PATIENTS. Twelve ventilated patients with median
      APACHE II score 23 (range 10-26). INTERVENTIONS: Patients received a loading
      dexmedetomidine infusion of 1 microg x kg(-1) over 10 min followed by a
      maintenance infusion rate of 0.2-0.7 microg x kg(-1) x h(-1) for up to 7 days.
      After experience with the first four patients this maintenance rate of infusion
      was increased to a maximum of 2.5 microg kg(-1) x h(-1). If required, propofol
      and morphine provided rescue sedation and analgesia, respectively. RESULTS: The
      first four patients with dexmedetomidine infusion at 0.7 microg x kg(-1) x h(
      1)all required rescue sedation with a propofol infusion. A protocol amendment
      allowed the next eight patients to receive higher dexmedetomidine infusions (mean
      1.0+/- microg x kg(-1) x h(-1)). Five of the next eight patients did not required
      propofol, and two patients only required minimal propofol infusions (20-40 mg x
      h(-1)). A further patient, with hepatic encephalopathy, required a propofol at 50
      100 mg x h(-1). Only modest falls in arterial pressure, heart rate and cardiac
      output were seen, and no rebound sequelae occurred on discontinuation of
      dexmedetomidine. Adverse cardiovascular events were nearly all confined to the
      initial loading dose period of dexmedetomidine. CONCLUSIONS: Sedation with
      dexmedetomidine is efficacious in critically ill medical patients requiring
      mechanical ventilation in the intensive care unit. A reduction in loading
      infusion is advised, but higher maintenance infusions may be required to that
      seen previously in the postoperative ICU patient.

PMID- 12594585
TI  - Estimation of regional lung volume changes by electrical impedance pressures
      tomography during a pressure-volume maneuver.
AB  - OBJECTIVE: To assess the degree of linearity between lung volume and impedance
      change by electrical impedance tomography (EIT) in pigs with acute lung injury
      and to investigate regional impedance changes during a pressure-volume maneuver.
      DESIGN AND SETTING: Experimental animal study in a university research
      laboratory. PATIENTS AND PARTICIPANTS: Nine pigs with lung injury induced by lung
      lavage. INTERVENTIONS: The lungs were insufflated to four different lung volumes.
      Next the lungs were inflated in steps up to 40 cm H(2)O and then in steps
      deflated. MEASUREMENTS AND RESULTS: EIT measurements were performed. Impedance
      was highly linear with lung volume ( r(2)=0.97). From the pressure-volume
      maneuver regional pressure-impedance (P-I) curves were obtained in the upper half
      (ventral) and lower half (dorsal) of the thoracic cross-section. Excellent fit
      was found of the regional P-I curves with a predefined sigmoid equation (
      r(2)=0.998). The P-I curves after lavage were markedly different than before
      lavage. The P-I curves recorded after lavage displayed a strong heterogeneity on
      the inflation limb: Lower corner pressure (traditionally lower inflection point)
      was significantly higher in the dorsal (28.3+/-4.1 cm H(2)O) than in the ventral
      region (17.5+/-4.3 cm H(2)O). The deflation limb displayed a more homogeneous
      pattern. Upper corner pressure and true inflection point, where the curve slope
      is maximal, in the dorsal region were only slightly higher than in the ventral
      region (1-2 cm H(2)O). CONCLUSIONS: EIT and automated curve fitting provide
      information on regional lung inflation and deflation which may be of clinical use
      for optimizing ventilator settings.

PMID- 12594586
TI  - Critically ill patients readmitted to intensive care units--lessons to learn?
AB  - OBJECTIVE: To evaluate risk factors in critically ill patients who were
      readmitted to an intensive care unit (ICU) during their hospital stay. DESIGN:
      Prospective multicenter cohort study. PATIENTS AND SETTING: A total of 15180
      patients discharged from 30 medical, surgical and mixed ICUs in Austria over a 2
      year period. MEASUREMENTS AND RESULTS: The data analyzed included data on
      patients' clinical characteristics, Simplified Acute Physiology Score II (SAPS
      II), Logistic Organ Dysfunction system (LOD), Simplified Therapeutic Intervention
      Scoring System (TISS-28), length of ICU stay, ICU mortality and hospital
      mortality. Of the 15180 patients who survived the first ICU stay, 780 patients
      (5.1%) were readmitted. These patients had more than a fourfold risk of dying
      during their hospital stay (21.7 vs 5.2%, p<0.001). For mechanically ventilated
      patients, the time between extubation and discharge during the first ICU stay was
      significantly shorter for readmitted than for non-readmitted patients (median 1
      vs 2 days, p<0.001). On the day of their first ICU discharge, readmitted patients
      were in greater need of organ support, with more patients still requiring
      ventilatory, cardiovascular and renal support than non-readmitted patients.
      CONCLUSIONS: The results of this study provide evidence that there exists a group
      of patients at higher risk of readmission to the ICU. At the time of their first
      ICU discharge, these patients presented with residual organ dysfunctions, which
      were associated with an increased risk of being readmitted. Optimizing organ
      functions in these patients before discharge from the ICU could result in reduced
      readmission rates.

PMID- 12594587
TI  - Cyclooxygenase-2 and inducible nitric oxide synthase in omental arteries
      harvested from patients with severe liver diseases: immuno-localization and
      influence on vascular tone.
AB  - OBJECTIVE: To investigate the expression of inducible cyclooxygenase (COX-2) and
      inducible nitric oxide synthase (iNOS) and the role of vasodilatory prostanoids
      and endogenous nitric oxide (NO) in small omental arteries harvested from
      patients with severe liver diseases. DESIGN: Ex vivo study of resistance
      arteries. SETTING. Intensive care unit. PATIENTS: Twenty patients undergoing
      liver transplantation for fulminant hepatic failure (FHF, n=6), cirrhogenous
      viral hepatitis (CH, n=6) and limited hepatocarcinoma (controls, n=8).
      INTERVENTIONS: Western blot and immunohistochemical labeling for assessment of
      COX-2 and iNOS expression and localization and ex vivo vascular reactivity
      studies. MEASUREMENTS AND RESULTS: Significant upregulation of COX-2 and iNOS
      expressions were detected in arteries from FHF and CH patients with a greater
      increase in the former than in the latter. Ex vivo contractile responses to
      norepinephrine and the thromboxane A(2) analog, U46619, were not significantly
      different between patients with severe liver dysfunction and controls. Exposure
      to either the NO-synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME),
      the cyclooxygenase inhibitor, indomethacin, or their combination did not
      significantly modify contractions of agonists in controls and CH patients. In
      FHF, the specific COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)
      methanesulfonamide (1 micro m/l), but not L-NAME, significantly enhanced the
      maximal effect ( p<0.01) and the sensitivity ( p<0.01) to norepinephrine.
      CONCLUSIONS: COX-2 and iNOS are upregulated in omental arteries from patients
      with cirrhogenous hepatitis and fulminant hepatic failure. Whereas neither NO nor
      vasodilatory prostaglandins seem to play a major role in counteracting arterial
      contractility of arteries from control patients, COX-2 derivatives are involved
      in lowering the arterial contractility of vessels harvested from FHF patients.

PMID- 12594588
TI  - Mortality and the nature of metabolic acidosis in children with shock.
AB  - HYPOTHESIS: Mortality in children with shock is more closely related to the
      nature, rather than the magnitude (base deficit/excess), of a metabolic acidosis.
      OBJECTIVE: To examine the relationship between base excess (BE),
      hyperlactataemia, hyperchloraemia, 'unmeasured' strong anions, and mortality.
      DESIGN: Prospective observational study set in a multi-disciplinary Paediatric
      Intensive Care Unit (PICU). PATIENTS: Forty-six children, median age 6 months
      (1.5-14.4), median weight 5 kg (3.2-8.8), admitted to PICU with shock.
      INTERVENTIONS: Predicted mortality was calculated from the paediatric index of
      mortality (PIM) score. The pH, base excess, serum lactate, corrected chloride,
      and 'unmeasured' strong anions (Strong Ion Gap) were measured or calculated at
      admission and 24 h. MEASUREMENTS AND RESULTS: Observed mortality ( n=16) was 35%,
      with a standardised mortality ratio (SMR) of 1.03 (95% CI 0.71-1.35). There was
      no significant difference in admission pH or BE between survivors and
      nonsurvivors. There was no association between elevation of 'unmeasured' anions
      and mortality, although there was a trend towards hyperchloraemia in survivors (
      P=0.08). Admission lactate was higher in nonsurvivors (median 11.6 vs 3.3 mmol/l;
      P=0.0003). Area under the mortality receiver operating characteristic curve for
      lactate was 0.83 (955 CI 0.70-0.95), compared to 0.71 (95% CI 0.53-0.88) for the
      PIM score. Admission lactate level >5 mmol/l had maximum diagnostic efficiency
      for mortality, with a likelihood ratio of 2.0. CONCLUSION: There is no
      association between the magnitude of metabolic acidosis, quantified by the base
      excess, and mortality in children with shock. Hyperlactataemia, but not elevation
      of 'unmeasured' anions, is predictive of a poor outcome.

PMID- 12594589
TI  - Effects of epinephrine and norepinephrine on hemodynamics, oxidative metabolism,
      and organ energetics in endotoxemic rats.
AB  - OBJECTIVE: To determine whether epinephrine increases lactate concentration in
      sepsis through hypoxia or through a particular thermogenic or metabolic pathway.
      DESIGN: Prospective, controlled experimental study in rats. SETTING: Experimental
      laboratory in a university teaching hospital. INTERVENTIONS: Three groups of
      anesthetized, mechanically ventilated male Wistar rats received an intravenous
      infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after
      90 min by epinephrine ( n=14), norepinephrine ( n=14), or hydroxyethyl starch (
      n=14). Three groups of six rats served as time-matched control groups and
      received saline, epinephrine, or norepinephrine from 90 to 180 degrees min. Mean
      arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial
      blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and
      180 min after endotoxin challenge. At the end of experiments biopsy samples were
      taken from the liver, heart, muscle, kidney, and small intestine for tissue
      adenine nucleotide and lactate/pyruvate measurements. MEASUREMENTS AND RESULTS:
      Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric,
      and renal blood flow. Plasmatic and tissue lactate increased with a high
      lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The
      ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs.
      Epinephrine and norepinephrine increased mean arterial pressure to baseline
      values. Epinephrine increased aortic blood flow while renal blood low decreased
      with both drugs. Plasmatic lactate increased with a stable L/P ratio with
      epinephrine and did not change with norepinephrine compared to endotoxin values.
      Nevertheless epinephrine and norepinephrine when compared to endotoxin values did
      not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or
      liver. In kidney both drugs decreased ATP concentration. CONCLUSIONS: Our data
      demonstrate in a rat model of endotoxemia that epinephrine-induced
      hyperlactatemia is not related to cellular hypoxia.

PMID- 12594590
TI  - Terlipressin dose response in healthy and endotoxemic sheep: impact on
      cardiopulmonary performance and global oxygen transport.
AB  - OBJECTIVE: To determine whether a goal-directed terlipressin infusion increases
      mean arterial pressure without causing a pulmonary vasopressive effect and
      whether this response impacts on key parameters of oxygen transport in healthy
      and endotoxemic sheep. DESIGN AND SETTING: Prospective controlled trial in a
      university research laboratory. ANIMALS AND INTERVENTIONS: Six conscious adult
      ewes instrumented for chronic study received terlipressin as titrated infusion
      started with 10 microg x kg(-1) x h(-1) and increased by 5 microg x kg(-1) x h(
      1) every 15 min, either until mean arterial pressure was increased by 15 mmHg
      from baseline, or a maximum of 40 microg x kg(-1) x h(-1) was given. Following 24
      h of recovery sepsis was induced and maintained in the same ewes by a continuous
      infusion of endotoxin ( Salmonella typhosa, 10 ng x kg(-1) min(-1)). After 16 h
      of endotoxemia the sheep were again treated with terlipressin. MEASUREMENTS AND
      RESULTS: Systemic oxygen delivery and consumption were calculated before and
      after the titration period; hemodynamic parameters were measured every 15 min.
      The increase in mean arterial pressure was greater during endotoxemia than in
      healthy controls. In both states terlipressin administration decreased cardiac
      index and diminished oxygen delivery and consumption. While mean pulmonary
      arterial pressure remained constant, terlipressin increased the pulmonary
      vascular resistance index in endotoxemic sheep. CONCLUSIONS: During ovine
      endotoxemia titrated terlipressin reversed hypotension but impaired the pulmonary
      circulation. The observed decrease in oxygen delivery may carry the risk of
      tissue hypoxia especially in sepsis, where oxygen demand is typically increased.

PMID- 12594591
TI  - Inhibitory effects of hyperglycemia on neural activity of the vagus in rats.
AB  - OBJECTIVES: Although it has been demonstrated that hyperglycemia inhibits
      gastrointestinal (GI) motility, its inhibitory mechanism remains unclear. DESIGN:
      Electrophysiological study. SETTINGS: As GI motility is under the influence of
      the vagus, we studied the effects of hyperglycemia on neural activity of the
      dorsal motor nucleus of vagi (DMV) in anesthetized rats. MEASUREMENTS AND
      RESULTS: A tungsten electrode was placed in the left side of the DMV area and
      extracellular electrical signals from the electrode were recorded. Single unit
      nerve activity was identified by the discriminator. D-glucose infusion elevated
      the peripheral blood glucose concentration from 3.4-5.9 mm to 12.0-21.8 mm and
      the neural firing of the DMV was significantly reduced by D-glucose infusion.
      After the 30 min D-glucose infusion, saline was re-infused for 90 min. Blood
      glucose level returned to 6.5-7.8 m m and the neural firing partially recovered
      90 min after the saline re-infusion. There was a significant negative correlation
      observed between the counts of neural spikes and blood glucose concentrations (
      r=0.84, p<0.01). CONCLUSION: It is suggested that hyperglycemia impairs GI
      motility by inhibiting vagal efferent activity. A recent study in intensive care
      unit (ICU) patients demonstrated that uncontrolled hyperglycemia is associated
      with poor outcomes. We propose that glycemia control is crucial in ICU patients
      to maintain the GI motility and vagus nerve activity.

PMID- 12594593
TI  - Massive hemoptysis requiring intensive care.
AB  - OBJECTIVES: Massive hemoptysis can cause airway or hemodynamic compromise
      requiring intensive care. We reviewed the management and outcome of this group of
      patients in our institution. DESIGN: Retrospective analysis. SETTING: Medical
      intensive care unit (MICU) in a tertiary care hospital. PATIENTS: Patients (29
      patients with 31 episodes) who were admitted to the MICU for massive hemoptysis
      (greater than 300 ml/24 h or requiring intubation) between August 1997 and April
      2001. MANAGEMENT: Patients were intensively monitored and electively intubated if
      there was danger of airway compromise. Fiberoptic bronchoscopy was performed to
      assess the site of bleeding and patients had bronchial artery embolisation if
      deemed suitable. Patients in whom bleeding could not be controlled were referred
      for emergency surgery. RESULTS: In 26/31 (84%) episodes, patients required
      intubation. Bronchoscopy was more helpful in localising the bleeding (site of
      bleeding identified in 90%) than chest X-ray alone (identified site of bleeding
      in 64%). Bleeding was stopped with medical therapy in 8/31 (26%) patient;
      16/31(51%) patients were successfully treated with embolisation. Only four (13%)
      patients went for emergency surgery, of whom one died. Overall in-hospital
      mortality was 4/31 patients (13%). Over a 2 year follow-up, 6/27 (22%) survivors
      had recurrent hemoptysis and another 4 (15%) died of unrelated causes.
      CONCLUSIONS: Intensive care and monitoring with endotracheal intubation, when
      necessary, are useful in massive hemoptysis. Bronchoscopy should be performed to
      help localise the bleeding site. Embolisation is a suitable first-line treatment
      for massive hemoptysis, reserving emergency surgery for cases where the above
      measures are insufficient to control bleeding.

PMID- 12594592
TI  - Mechanisms of inducible nitric oxide synthase (iNOS) inhibition-related
      improvement of gut mucosal acidosis during hyperdynamic porcine endotoxemia.
AB  - OBJECTIVE: To determine the mechanisms of improved gut mucosal acidosis
      associated with selective inducible nitric oxide synthase (iNOS) inhibition.
      DESIGN: Prospective, controlled experimental study. SETTING: Animal research
      laboratory. ANIMALS: Fourteen domestic pigs. INTERVENTIONS: Anesthetized and
      mechanically ventilated pigs received continuous i.v. endotoxin for 24 h. A
      selective iNOS-inhibitor (1400 W, n=8) or vehicle (control, n=6) was started at
      12 h of endotoxin and infused until the end of the experiment. MEASUREMENTS AND
      RESULTS: Before as well as at 12 and 24 h of endotoxin, portal venous flow
      (ultrasound probe), intestinal oxygen (O(2)) extraction, portal venous-arterial
      carbon dioxide (CO(2)) content difference and ileal mucosal-arterial PCO(2) gap
      (fiberoptic sensor) were assessed together with video recordings of the villous
      microcirculation (number of perfused/unperfused villi) using orthogonal
      polarization spectral imaging via an ileostomy. The gut wall microvascular blood
      flow (units) and hemoglobin O(2) saturation ( micro Hb-O(2)) were assessed with a
      combined laser Doppler flow and remission spectrophotometry probe. 1400 W blunted
      the otherwise progressive rise in the PCO(2) gap without affecting portal venous
      flow, regional O(2) and CO(2) exchange or the number of unperfused villi. While
      endotoxin markedly aggravated the heterogeneity of the microvascular blood flow
      and oxygenation, 1400 W had no further effect. CONCLUSIONS: Given the
      uninfluenced parameters of the ileal mucosal microcirculation in our model of
      long-term porcine endotoxemia, selective iNOS inhibition probably improved the
      PCO(2) gap due to a redistribution of the microvascular perfusion within the gut
      wall and/or an amelioration of the cellular respiration.

PMID- 12594594
TI  - Characteristics of discrepancies between clinical and autopsy diagnoses in the
      intensive care unit: a 5-year review.
AB  - OBJECTIVES: To characterise discrepancies between clinical and autopsy diagnoses
      in patients who die in the intensive care unit. DESIGN: Retrospective chart
      review. SETTING: Ten-bed closed mixed adult intensive care unit in a tertiary
      referral teaching hospital. PARTICIPANTS: All the clinical notes and autopsy
      reports of 346 patients who died in the intensive care unit in 1996-2000.
      INTERVENTIONS: Discrepancies between clinical and autopsy diagnoses were reviewed
      by two intensivists, a specialist in infectious diseases, a pathologist and an
      anaesthesiologist. New findings which would have changed current therapy in the
      intensive care unit were categorised as a Class I discrepancy, and those related
      to death but which would not have altered therapy as a Class II discrepancy.
      RESULTS: Of 2370 patients admitted, 388 (16.4%) died. An autopsy was performed in
      346 (89%) of the deceased patients. A Class I discrepancy was found in 8 patients
      (2.3%) and a Class II discrepancy in 11 patients (3.2%). Five of the eight (62%)
      Class I discrepancies were infections which occurred in patients already treated
      for another infections. CONCLUSION: Despite the availability of advanced
      diagnostic facilities, especially infectious complications seem to remain
      undiagnosed. Autopsy is a valuable tool with which to monitor diagnostic accuracy
      in these patients.

PMID- 12594595
TI  - The use of the activated clotting time for monitoring heparin therapy in
      critically ill patients.
AB  - OBJECTIVE: To determine the correlation between activated clotting time (ACT) and
      activated partial thromboplastin time (aPTT) in patients receiving intravenous
      unfractionated heparin therapy, and the accuracy of the ACT in predicting the
      level of anticoagulation. DESIGN: Paired aPTT and ACT measurements were obtained
      from a convenience sample of critically ill patients requiring intravenous
      unfractionated heparin. The aPTT was determined in the hospital laboratory and
      ACT measurements were performed with a portable device. SETTING: The intensive
      care unit of Ghent University Hospital, a tertiary care facility with 54 beds.
      PATIENTS AND PARTICIPANTS: Twenty-eight patients were studied prospectively; a
      total of 105 paired samples were obtained. The indication for heparin therapy was
      cerebral ischemia in 8, various cardiac conditions in 10, pulmonary embolism in
      3, continuous hemofiltration in 3, and peripheral arterial thrombosis in 4.
      RESULTS: There was a significant correlation between aPTT and ACT. Analysis of
      variance showed a significant difference in ACT between different levels of
      anticoagulation, aPTT shorter than 60 s (group 1), aPTT 60-90 s (group 2), and
      aPTT longer than 90 s (group 3): 142+/-16.7 s in group 1 vs. 155+/-29.6 and 192+/
      39.1 in groups 2 and 3. CONCLUSIONS: The correlation between the aPTT and the ACT
      in this ICU setting is poor; ACT cannot differentiate between low and therapeutic
      levels of anticoagulation. The use of the ACT for monitoring low to moderate
      doses of heparin in ICU patients cannot be recommended.

PMID- 12594596
TI  - Plastic bronchitis mimicking foreign body aspiration that needs a specific
      diagnostic procedure.
AB  - OBJECTIVE: To report two children admitted to our emergency department with
      respiratory failure, one for status asthmaticus with pneumomediastinum and
      requiring mechanical ventilation and the other for high suspicion of foreign body
      aspiration. INTERVENTIONS: Bronchoscopy revealed obstructive plugs and permitted
      their extraction and their identification as bronchial casts after the immersion
      in normal saline. Allergy was suspected in the first one, and Hemophilus
      influenzae infection was present in the second. The outcome was favorable.
      CONCLUSIONS: Plastic bronchitis is an infrequent cause of acute life-threatening
      respiratory failure that can mimic foreign body aspiration or status asthmaticus.
      Bronchoscopic extraction must be performed urgently in the case of severe
      obstruction. This entity is probably underestimated as the casts with their
      specific ramifications are difficult to recognize. We recommend the immersion in
      normal saline of all plugs discovered in children with predisposing diseases
      mainly represented by infections, allergy, acute chest syndrome, and congenital
      cardiopathies.

PMID- 12594597
TI  - A new prognostic scoring system for meningococcal septic shock in children:
      comparison with three other scoring systems.

PMID- 12594599
TI  - Gut mucosal lactate concentrations estimated by luminal equilibrium dialysis.

PMID- 12594601
TI  - Drotrecogin alfa (activated) for the treatment of meningococcal purpura
      fulminans.

PMID- 12594602
TI  - Survival after drinking lethal dose of acetone.

PMID- 12594604
TI  - Comprehensive Critical Care: a national strategic framework in all but name.

PMID- 12594605
TI  - [What's new in upper gastrointestinal tract surgery?].

PMID- 12594606
TI  - [Fixation of humeral head fractures with antegrade intramedullary nailing].
AB  - The new method of antegrade intramedullary fixation of humeral head fractures is
      based on a straight proximal humeral nail with special head fixation screws and
      conventional interlocking screws at the proximal end of the shaft fragment
      leaving an axillary nerve shelter space in between. The nail acts as a central
      load carrier. The head fixation screws run through threaded holes in the proximal
      end of the nail thus being held in a stiff angle and without gliding. The entry
      points of these screws correspond to the anatomical main portions of the lesser
      and greater tubercle. They allow a three-dimensional screw grip to the
      subchondral bony layer of the head fragment. The purpose of this intramedullary
      construct is to keep the fracture stable at a grade which allows instant
      postoperative active exercise and which corresponds to the needs of mechanical
      tranquility in a predominantly endosteal healing area. In a prospective clinical
      study 45 patients could be followed up after 3, 6 and 12 months. We found an
      ongoing improvement of the postoperative results up to an average Constant Score
      of 85.7 pts after one year. The complication rate was 16 %. The main complication
      was the screw protrusion into the joint.

PMID- 12594607
TI  - [Experiences with the OrTra-prosthesis in primary prosthetic replacement of
      fractures of the humeral head--indication, technique and results].
AB  - Displaced three - and four - part fractures of the humeral head are at high risk
      for a poor functional outcome after internal fixation. Primary prosthetic
      replacement can restore the pretraumatic anatomy and early mobilisation is
      possible. Functional outcome after hemiarthroplasty of the shoulder joint after
      trauma however is poor, regardless the type of implant used. However, a stable,
      painless joint is obtained at a "one time surgery". In our institute from April
      1996 until January 2001 fifty-eight primary OrTra-prostheses were implanted. In
      43 patients we could perform the follow up. The patients revealed a mean range of
      active movement from about flex./ext. 54 degrees/0/40 with abd./add. 67
      degrees/0/20 degrees. Most important for the patients was the achieved painfree
      shoulder in 86% (ASES index) of all cases.

PMID- 12594608
TI  - [Total shoulder arthroplasty vs. hemiarthroplasty].
AB  - Shoulder arthroplasty remains problematic despite the dramatic development of the
      new implant systems, due to the anatomical characteristics of the shoulder joint.
      The development of the modern third and fourth generation of shoulder prostheses
      enables the surgeon by its the three dimensional modularity to adjust the
      inclination and dorsomedial offset and to reconstruct the anatomic center of
      rotation. The fixation of the glenoid component is one of the most complicated
      aspects in the total shoulder arthroplasty. The main criteria regarding hemi- or
      total arthroplasty are based on morphological changes in the glenoid, the
      condition of the rotator cuff muscles, disorder etiology, age and activity level
      of the patient. The cup arthroplasty has proven itself as an alternative to
      standard humeral shaft arthroplasty. The main advantages of this new system are
      the elimination of the obligatory humeral head resection and the possibility of
      converting to the classical humeral shaft prosthesis method. First experiences
      with the cup system have been evaluated in the department of accident and
      reconstructive surgery of the UKBF in Berlin as part of a clinical trial. Between
      March 1998 and June 1999 15 shoulder prostheses in 14 patients were implanted in
      this hospital. The implants were inserted 8 times in a rheumatic shoulder, 4
      times in posttraumatic arthrosis and in 3 humeral head necroses. 13 patients with
      14 prostheses were available for follow up. An improvement from 23 to 55 average
      score points (Constant-Score) was attained by implantation of the cup system
      within a mean postoperative observation period of 6.1 months.

PMID- 12594609
TI  - [The cannulated blade plate 90 degrees for displaced proximal humeral fractures
      in elderly patients].
AB  - Aim of the study was to analyse the results following osteosynthesis of proximal
      humerus fractures with cannulated blade plate 90 degrees (Synthes, Mathys
      Medizinaltechnik AG, Bettlach, Schweiz) in elderly patients. Between 6/1998 and
      12/1999 we treated 20 patients (12 female, 8 male) > 65 years (65-92 y, 75 y)
      with the cannulated blade plate (fracture type according to AO: 8 x 11-A3, 5 x 11
      B1, 3 x 11-B2, 1 x 11-B3 und 3 x 11-C2). Regarding to mechanical and functional
      advantages we modified the 90 degrees angulation of the implant by bending
      intraoperatively up to 110-120 degrees. Early post-op physiotherapy was
      permitted. The radiological results of all patients were evaluated and in 13
      patients a clinical follow-up (median 8 months) was obtained. According to the
      Constant-score 62 points on average were achieved, which corresponds to a
      satisfactory result (contralateral shoulder 92 points). Complications due to the
      implant were loosening of the blade plate in 3 cases (A3, B2, C2) and 1
      perforation of the blade plate (C2). The consecutive reoperation consisted in a
      compound osteosynthesis with the blade plate (A3, B2) in 2 cases, a prosthetic
      replacement and a removal of the implant (C2) in 1 case respectively. Neither
      infection, major nerve and vessel trauma nor avascular necrosis occurred. The
      cannulated blade plate 90 degrees represents a justified alternative in the
      treatment of displaced fractures of the proximal humerus in elderly patients.
      Commendable indications are fracture types A and B according to AO with stable
      fixation of the blade plate in the humeral head, which allow early physiotherapy
      and avoid an alteration of the rotator cuff. C-type fractures tend to
      complications (2/3).

PMID- 12594610
TI  - [Locking plate osteosynthesis for fractures of the proximal humerus].
AB  - BACKGROUND: Beside non-operative treatment the therapeutic options for proximal
      fractures of the humerus range from closed reduction and transcutaneous K-wiring
      to total joint replacement. While the first is regarded as minimally invasive the
      latter is a rather complex intervention. Plating has been disregarded as
      combining the disadvantages of an extended approach with too often insufficient
      primary postoperative stability. The new concept of completely angle stabile
      plate fixation aims on improving this balance by achieving greater stability even
      in osteoporotic fractures. STUDY DESIGN: This retrospective analysis compares 51
      patients treated with a partially (39) or complete (12) angle stabile humeral
      plate (Konigseeplatte in two modifications) with 32 patients treated according to
      surgeons preference with conventional plates or K-wires. Both groups were treated
      at the same department during the same period and did not differ in their age nor
      sex distribution. RESULTS: Until discharge there were 2 secondary dislocations
      discovered in group 1 and 7 in group 2. The follow-up rate was 47.1 % (24/51) in
      group 1 and 46.8 % (15/32) in group 2. The time interval from surgery amounted to
      1.2 (0.66-1.75) and 1.0 (0.72-1.32) years respectively. Among the patients
      available for follow-up in group 1 8 had sustained a two-, 8 a three- and 3 a
      four-part fracture according to Neer's classification. In group two there were
      accordingly 2 two-, 8 three- and 1 four part fractures. Clinical assessment using
      Neer's score revealed an average of 71,8 (63.9-79.8) points in group 1 and 67.6
      (47.3-78.7) in group 2. When the results of Neer's scores were expressed in
      percentage of the unaffected arm a mean of 73.6 (65.6-81.8) in group 1 and 69.3
      (51.8-86.9) was obtained. The only statistically significant difference was
      observed within the sub-group of three-part fractures: treated by angle stabile
      plates (group 1) these patients (n = 8) achieved a mean Neer-Score of 81 (77-86)
      compared to 68 (52-84) (n = 8). In group 1 70.8 % of patients followed-up
      presented an "excellent" or "good" result according to Neer's criteria, in group
      2 60 % did so. CONCLUSION: We conclude from our first experience with angle
      stabile plates for fractures of the proximal humerus that particularly in three
      part fractures this method might improve functional outcome and is worth further
      consideration and testing.

PMID- 12594611
TI  - [New possibilities in fracture visualization by means of CT: reconstructions, 3D
      plannings--difficult joint fractures--modern management--improved visualization
      and operative planning in joint fractures].
AB  - After having been introduced in the seventies computed tomography (CT) has become
      an important instrument for the diagnosis of difficult joint fractures. With the
      evolution of the Spiral-CT with multiplanar reformations and three-dimensional
      (3D-) reconstructions the quality of visualization has been improved
      considerably. In comparison with conventional radiography the actual CT scanners
      give a clear image of the fracture configuration and the degree of fragment
      displacement in joint fractures. Additional information about sub-/luxations of
      the joint, impaction and comminution is also clearly visualized by the CT. This
      means a rise in quality of fracture classification and enables a detailed view of
      the fracture pattern. These findings provide the basis for gratifying treatment
      regimens and surgical management of the injured joint. By the use of innovative
      reconstruction methods the CT allows exact visualization of internal
      fixations/osteosynthesis and secondary angular/rotation or length deformities
      postoperatively. Furthermore, reconstructed 3D-views enable preoperative computer
      simulated plannings of internal fixations and of reduction control
      intraoperatively. In fact, the actual Spiral-CT scanners are nearly equivalent in
      costs and total radiation dose compared to the performance of special projections
      of conventional radiographs. Thus, we recommend to enlarge the performance of
      additional CT diagnostic in difficult joint fractures and special pre- or
      postoperative cases.

PMID- 12594612
TI  - [Open reduction and internal fixation of unstable sacral fractures].
AB  - Sacral fractures are frequently misdiagnosed or overlooked, as the majority of
      the patients are suffering from polytrauma situations. Obvious clinical signs
      both of the fracture and the associated neurological complications are missing. A
      poor longterm outcome with pain and urogenital disorders is frequent. Based on
      clinical and biomechanical studies a new concept for internal fixation of
      transsacral pelvic instabilities combined with decompression of the central canal
      is applied. To approach the sacrum, a posterior longitudinal incision is carried
      out and can be modified according to the fracture pattern. Decompression and
      anatomic reduction is performed and the fracture stabilized with minimized small
      fragment implants which are solely fixed in the sacrum. 32 patients were treated
      according to this protocol between 1989 and 1996. Bony healing occurred in all
      but one case. A complete anatomical sacral reconstruction was achieved in 80 % of
      the cases, another 16 % had close to anatomic (< 5 mm) reconstruction. In eight
      cases a primary neurologic deficit was present, with five complete or partial
      recoveries directly postoperative. Complications occurred in seven patients with
      two secondary displacements.

PMID- 12594614
TI  - [Fixation of periprosthetic femur fractures with the less invasive stabilization
      system (LISS)--a new minimally invasive treatment with locked fixed-angle
      screws].
AB  - The Less Invasive Stabilization System (LISS) is a minimally invasive technique
      indicated for fixation of periprosthetic fractures. This new system allows
      percutaneous placement of cortical-shaft screws and fixation of the fracture with
      fixed-angle locked screws with minimal surgical exposure of the mostly
      osteoporotic bone and without disturbance of the existing total joint
      replacement. Immediate range-of-motion exercises are begun postoperatively. A
      retrospective clinical review of 5 patients (2 total hip arthroplasties, 3 total
      knee arthroplasties) was performed to describe indications, surgical technique,
      intra- and postoperative complications and patient follow-up. Indications are
      periprosthetic distal femur fractures, per- and supracondylar fractures.
      Contraindications are none, except existing medical comorbidities. Extraarticular
      fractures were treated via stab incisions over the lateral femoral condyle.
      Fractures with intraarticular displacement were fixed via an anterolateral
      parapatellar approach to the knee joint. After anatomic reduction of femoral
      condyles, articular fragments are fixed with Kirschner wires, followed by closed
      reduction aligning the articular fragments controlling length, axis and rotation.
      The LISS is introduced proximally under the M. vastus lateralis along the femur.
      It is fixed with self-drilling cortical shaft screws, locked fixed-angle screws
      both proximally and distally. Range-of-motion exercises are begun on the second
      day postoperatively. Time to full weight bearing averaged 6-8 weeks depending on
      clinical and radiological findings. Benefits of the LISS technique include the
      minimally invasive approach with increased primary stability using monocortical
      fixings thus eliminating the need for spongiosaplasty and blood transfusion.
      Disadvantages of the percutaneous placement of the LISS include malplacement on
      the femur, proximal screw pull-out and postoperative rotational and axial
      malalignment.

PMID- 12594613
TI  - [Cemented versus uncemented hip replacement--rational decision making using the
      BiCONTACT total hip system].
AB  - The BiCONTACT femoral stem has been developed as a modular system which is
      suitable for both cemented and uncemented implantation. A highly standardized
      procedure using an identical set of instruments for both modes of fixation
      ensures bone preservation. Primary stability is achieved by special design
      parameters. The cementless implants are coated proximally, thus facilitating
      osteointegration and proximal load transfer. Cemented stems provide an identical
      design but a smooth surface and are anchored by a homogenous cement mantle. The
      BiCONTACT stem is in use in the BG Trauma Center Tuebingen since 14 years and a
      consecutive series of 250 cases (series A) with uncemented implantation and of
      250 cases (series B) with cemented implantation has been analyzed in two
      different prospective follow-up studies. Long-term survival after 11 years was
      97.1 % (95 % confidence limits: 93.8 %-98.7 %) for series A, the follow-up rate
      was 99.2 %. For series B, the follow up-rate was also 99.2 %, survival estimate
      after 11 years was 97.5 % (95 % CI: 94.2 %-99.0 %).

PMID- 12594615
TI  - [Unicondylar knee arthroplasty--indications and outcome].
AB  - Continuous development of new materials, improved operative technique and exact
      patient selection lead to increasing survival rates of unicondylar sleigh
      arthroplasties during the last decade as it's demonstrated in this review on the
      literature. During the 80s the average survival rate after 5 years was 85 %,
      after 9 years 60 %. In the 90s significantly better results were noted with 5 and
      10 years survival in more than 95 % of the cases. Thus, like current studies
      prove, unicondylar sleigh arthroplasties have reached the standard of complete
      surface replacement. Additionally minimal loss of bone stock, sparing of the
      crucial ligaments and of the femoropatellar joint as well as short operation time
      and low morbidity are advantages of these arthroplasties.

PMID- 12594616
TI  - [The hinged knee prosthesis: outdated design or valuable implant for difficult
      cases?].
AB  - There are excellent results after unconstraint or semiconstraint bi- or
      tricompartimental total knee arthroplasty in case of uncomplicated degenerative
      joint disease of the knee. In the Swedish knee study, cumulative survival of
      unconstraint or semiconstraint knee prostheses was about 90 % at 10 years. In
      studies of single institutions, survival rates of more than 90 % at 15 years are
      reported. However, there is a need of more constraint designs because of the
      increasing number of complex total knee arthroplasties with disrupted collateral
      ligaments, deformities with flexion extension gap imbalance, comminuted distal
      femur fracture, distal femoral non-union in elderly patients and revision with
      massive bone loss. Initial hinged total knee designs were associated with a high
      failure rate. More recent designs have improved the femorotibial articulation and
      reduced the polyethylene wear. The bone resection necessary in actual hinged
      designs is similar to the resection in modern condylar prostheses. Due to these
      improvements, long-term survival of the best hinged designs are similar to the
      best condylar designs. In our study of a consecutive series of 422 hinged Blauth
      prostheses, the cumulative survival of the prostheses was 94.4 % at 20 years.
      Therefore, the hinged knee prosthesis is a valuable implant in case of complex
      total knee arthroplasty.

PMID- 12594617
TI  - [Soft tissue balancing in total condylar knee arthroplasty].
AB  - Soft tissue balancing and correct bone cuts are an entity in correcting
      malalignment in total knee arthroplasty, and cannot be considered isolated.
      Distinct bony deformations/deviations need enlarged soft tissue management. The
      extent of resection of the bone stock has to be planned exactly before the
      operation. Exact soft tissue balancing is necessary to stabilize the corrected
      knee. Soft tissue balancing has to be done primarily on the side of the
      contracture by lengthening of the shortened and contracted structures. After
      balancing the ligaments should have the same tension in extension and flexion
      together with the same height of the extension and flexion gap. Because of the
      classic resection of the tibial head, the femoral resection must follow the
      Insall-Line, that means 3 degrees to 5 degrees outer rotation in relation to the
      condyles. Only in this way a symmetric flexion gap can be achieved in combination
      with ligamentous stability in extension and flexion.

PMID- 12594618
TI  - [Complications after total knee arthroplasty].
AB  - Complications after total knee arthroplasty were evaluated prospectively after a
      total of 321 procedures. 53 (16.5 %) patients showed postoperative courses
      deviating from the routine. Of these 5.0 % developed clinically relevant deep
      vein thromboses, the rate of deep infections was 1.6 %, 3.7 % of the patients
      suffered from persisting or recurrent joint effusions, arthrofibrosis was
      observed in 4.4 % of the patients and 1.9 % were affected by wound complications.
      In most patients deep infections were treated by removal of the implants and
      reimplantation after clearing of the infection. The primary treatment of
      arthrofibrosis consisted of manipulation under general or regional anaesthesia.
      Patients with recurrent joint effusions received punctions, which had to be
      repeated in some cases. In one patient an intraarticular drainage had to be
      inserted. The conservative or surgical therapy of wound complications depended on
      the patient's situation. In patients with thrombosis distal to the trifurcation
      of the popliteal vein anticoagulation with heparin was continued. In contrast, in
      patients with femoral or popliteal venous thrombosis the anticoagulation was
      changed to cumarine derivates.

PMID- 12594619
TI  - [Biomechanical properties (compressive strength and compressive pressure at
      break) of hyaline cartilage under axial load].
AB  - INTENTION OF THE STUDY: Explanations concerning the physical properties of
      hyaline cartilage are different. It was the intention of this study to determine
      the material parameters of hyaline cartilage under axial load (elasticity,
      plasticity, elasticity and module pressure stress to break). METHODS: Specimens
      from the medial femoral condyle (chondro-cortical ships) from adult female
      domestic pigs (n=28) were used for the experiments. The specimens were completely
      embedded in plaster to minimize shearing. Axial load was carried out by an
      universal mechanical testing machine (Zwick Z2.5/TS1S, Ulm, Germany) to determine
      elastic and plastic deformation and pressure stress to break. RESULTS: Axial load
      up to 5 MPa produces an almost elastic deformation, an increasing axial load
      results in a plastic deformation. In the range of 3 to 5 MPa the principle of
      Hooke is valid. The elasticity module amounted to 39.2 +/- 11.9 N/mm(2),
      determined under 3.8 MPa axial load. An axial load of 25.8 +/- 5.2 MPa (sigma max
      ) causes a break of cartilage. A strong correlation between break resistance and
      thickness of the chondral slice (r=0.71; p < 0.05) was observed. CONCLUSIONS: The
      low module of chondral elasticity characterizes this tissue as "soft". Moderate
      axial load causes an ideal elastic, higher axial load a plastic deformation. The
      medium pressure to break to amounted 25.8 MPa. The medium pressure to break of
      25.8 MPa is comparable with the forces produced by an unrestrained limited
      downfall from a height of 4.3 m. It must be concluded that isolated chondral
      fractures are rare consequences of a trauma as long as accompanying ligamentous
      or osseous damages are not found.

PMID- 12594620
TI  - [New perspectives of pharmacotherapy in gastroenterology].

PMID- 12594621
TI  - [Drug-induced pancreatitis].

PMID- 12594622
TI  - [Combination therapy for chronic viral hepatitis C].

PMID- 12594623
TI  - [Pharmacological treatment of ascites and hepatorenal syndrome].

PMID- 12594624
TI  - [Therapy of chronic inflammatory bowel diseases with azathioprine, 6
      mercaptopurine and 6-thioguanine. Clinico-pharmacologic aspects].

PMID- 12594625
TI  - [Role of nuclear receptors in hepatic and intestinal drug transport].

PMID- 12594626
TI  - [Endoscopic treatment of gastroesophageal reflux].

PMID- 12594627
TI  - [Drug treatment of gastroesophageal reflux disease].

PMID- 12594628
TI  - [Which interactions are there for equal doses of acetylsalicylic acid and ACE
      inhibitors?].

PMID- 12594629
TI  - [When is a diagnosis of borreliosis advisable?].

PMID- 12594630
TI  - [Hormone replacement therapy in menopause].

PMID- 12594634
TI  - Adenovirus type 21-associated acute flaccid paralysis during an outbreak of hand
      foot-and-mouth disease in Sarawak, Malaysia.
AB  - We report the virological and clinical features of 8 children who presented with
      adenovirus-associated acute flaccid paralysis (AFP) during an epidemic of
      enterovirus type 71 (EV71)-associated hand-foot-and-mouth disease (HFMD) in
      Sarawak, Malaysia, in 1997. Neutralization tests and phylogenetic analysis
      revealed adenovirus type 21 (Ad21), although DNA restriction digests suggested
      that this virus was different from the prototype Ad21. Four children had upper
      limb monoparesis, 2 had lower-limb monoparesis (one of whom had changes in the
      anterior spinal cord noted on magnetic resonance imaging), and 2 had flaccid
      paraparesis. At follow-up, 4 children were noted to have made full recoveries and
      3 had residual flaccid weakness and wasting. Neurophysiological investigation
      revealed a mixture of axonal and demyelinating features in motor and sensory
      nerves, with denervation. These findings suggest that Ad21 might cause AFP by
      anterior horn cell damage or neuropathy of the brachial or lumbosacral plexus.
      The occurrence of these unusual adenovirus infections during an outbreak of EV71
      associated HFMD suggests that an interaction between the 2 viruses may have
      occurred.

PMID- 12594633
TI  - A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine
      for weekly prophylaxis against Plasmodium falciparum.
AB  - Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for
      malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate
      dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled
      chemoprophylaxis trial was conducted with adult residents of northern Ghana to
      determine the minimum effective weekly dose of tafenoquine for the prevention of
      infection by Plasmodium falciparum. The primary end point was a positive malaria
      blood smear result during the 13 weeks of study drug coverage. Relative to the
      placebo, all 4 tafenoquine dosages demonstrated significant protection against P.
      falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence
      interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week,
      87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine
      dosage of 250 mg/week also demonstrated significant protection against P.
      falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was
      little difference between study groups in the adverse events reported, and there
      was no evidence of a relationship between tafenoquine dosage and reports of
      physical complaints or the occurrence of abnormal laboratory parameters.
      Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and
      effective against P. falciparum infection in this study population.

PMID- 12594635
TI  - Two doses of a lipid formulation of amphotericin B for the treatment of
      Mediterranean visceral leishmaniasis.
AB  - To evaluate the efficacy of a short course of a lipid formulation of amphotericin
      B (L-AmB) for the treatment of Mediterranean visceral leishmaniasis (VL), an open
      prospective study was conducted. Forty-one children with parasitologically
      confirmed leishmaniasis received L-AmB, 10 mg/kg daily for 2 days. The comparison
      groups were 30 children who, in a previous study, were treated with L-AmB, 4
      mg/kg daily for 5 days, and 52 children who were treated with meglumine
      antimoniate. At 6 months after completion of treatment, overall treatment success
      was noted for 40 of 41 children treated with 2 doses of L-AmB, 27 of 30 children
      treated with 5 doses of L-AmB, and 47 of 52 children treated with meglumine
      antimoniate. Abatement of fever, reduction in spleen size, and correction of
      laboratory parameters occurred more quickly among the children who received 2
      doses of L-AmB than among the comparison groups, and the total estimated cost of
      the 2-dose regimen was also lower than that of the other regimens. Two doses of L
      AmB, 10 mg/kg each, is cost-effective therapy for Mediterranean VL in children.

PMID- 12594636
TI  - Acute encephalopathy associated with influenza A virus infection.
AB  - Twenty-one patients aged 4-78 years with influenza A virus-associated acute
      encephalopathy were studied. Influenza A virus could be detected only in a
      cerebrospinal fluid (CSF) specimen obtained from 1 of 18 patients, despite the
      use of a highly sensitive polymerase chain reaction assay. Six patients
      experienced influenzal encephalopathy during the course of respiratory illness.
      Five of these patients had hypoprothrombinemia and 4 had increased serum
      creatinine levels, indicating hepatic and/or renal dysfunction. Fourteen patients
      experienced postinfluenzal encephalopathy <or=3 weeks after resolution of acute
      respiratory symptoms. In 6 patients, focal areas of high signal intensity were
      visible on T2-weighted magnetic resonance images of the brain. Adenovirus DNA was
      detected in CSF specimens obtained from 4 (36%) of 11 patients with
      postinfluenzal encephalopathy. Thus, influenzal encephalopathy is frequently
      associated with metabolic disorders, whereas postinfluenzal encephalopathy
      appears to have different possible etiologies.

PMID- 12594637
TI  - Klebsiella infection in patients with thalassemia.
AB  - Klebsiella infection has previously been reported in a few patients with
      transfusion-dependent thalassemia. The incidence and clinical spectrum of this
      infection in our cohort of patients were reviewed retrospectively. Among 160
      patients observed for 12 years, there were 15 episodes of Klebsiella infection
      that occurred in 12 patients (7.5%), resulting in an incidence of 0.78 infections
      per 100 patient-years. The clinical spectrum included sinusitis (4 cases),
      intracranial infection (5 cases), septicemia (4 cases), and abscesses of the
      liver, lung, kidney, and parotid gland (1 case each). Three patients had
      recurrent infections involving different sites, 2 (16%) died of fulminant
      septicemia, and 3 (25%) had significant permanent neurological deficits. The
      antibiotic susceptibility pattern for the isolates was similar to the pattern for
      isolates recovered in the community. With regard to predisposing factors, iron
      overload and liver function derangement were found to be significant on
      univariate analysis (P=.046 and P=.049, respectively) but insignificant on
      multivariate analysis. Klebsiella infection was a serious and frequently
      encountered complication in our patients with transfusion-dependent thalassemia,
      resulting in high mortality and morbidity rates.

PMID- 12594638
TI  - Recurrent Clostridium difficile colitis: case series involving 18 patients
      treated with donor stool administered via a nasogastric tube.
AB  - Clostridium difficile-associated diarrhea and colitis have emerged as major
      complications associated with use of systemic antimicrobials. In this study, the
      medical records for 18 subjects who received donor stool by nasogastric tube for
      recurrent C. difficile infection during a 9-year period at a single institution
      were retrospectively reviewed. During the period between the initial diagnosis of
      C. difficile colitis and the stool treatments, the 18 subjects received a total
      of 64 courses of antimicrobials (range, 2-7 courses; median, 3 courses). During
      the 90 days after receipt of treatment with stool, 2 patients died of unrelated
      illnesses. One of the 16 survivors experienced a single recurrence of C.
      difficile colitis during 90-day follow-up. No adverse effects associated with
      stool treatment were observed. Patients with recurrent C. difficile colitis may
      benefit from the introduction of stool from healthy donors via a nasogastric
      tube.

PMID- 12594639
TI  - Chlamydia antibody response in healthy volunteers immunized with nonchlamydial
      antigens: a randomized, double-blind, placebo-controlled study.
AB  - Serological analysis is often used for the diagnosis of chlamydial infections.
      However, an increase in Chlamydia antibodies has been reported in patients with
      parvovirus and Mycoplasma infections. Whether this antibody response is the
      result of dual infection or nonchlamydial antigen stimulation is unknown. In a
      randomized study, 48 healthy volunteers either were immunized against yellow
      fever, polio, diphtheria, and tetanus (the group receiving intervention with
      nonchlamydial antigen) or received saline injections (the placebo group). The
      change in antibody levels was compared between the 2 groups. The Chlamydia
      recombinant lipopolysaccharide enzyme-linked immunosorbent assay (Medac) showed
      an increase in the antibody titer in the intervention group, compared with that
      in the control group (for immunoglobulin M, P=.004; for immunoglobulin A, P=.038;
      and for immunoglobulin G, P=.056), but no differences between study groups was
      found when the C. pneumoniae enzyme immunoassay (EIA; ThermoLabsystems), the C.
      pneumoniae EIA (Medac), and the microimmunofluorescence test (MRL) were used. An
      increase in antibodies to Chlamydia organisms can be measured after exposure to
      nonchlamydial antigens, depending on the test used.

PMID- 12594640
TI  - Adverse clinical and economic outcomes attributable to methicillin resistance
      among patients with Staphylococcus aureus surgical site infection.
AB  - Data for 479 patients were analyzed to assess the impact of methicillin
      resistance on the outcomes of patients with Staphylococcus aureus surgical site
      infections (SSIs). Patients infected with methicillin-resistant S. aureus (MRSA)
      had a greater 90-day mortality rate than did patients infected with methicillin
      susceptible S. aureus (MSSA; adjusted odds ratio, 3.4; 95% confidence interval,
      1.5-7.2). Patients infected with MRSA had a greater duration of hospitalization
      after infection (median additional days, 5; P<.001), although this was not
      significant on multivariate analysis (P=.11). Median hospital charges were 29,455
      dollars for control subjects, 52,791 dollars for patients with MSSA SSI, and
      92,363 dollars for patients with MRSA SSI (P<.001 for all group comparisons).
      Patients with MRSA SSI had a 1.19-fold increase in hospital charges (P=.03) and
      had mean attributable excess charges of 13,901 dollars per SSI compared with
      patients who had MSSA SSIs. Methicillin resistance is independently associated
      with increased mortality and hospital charges among patients with S. aureus SSI.

PMID- 12594641
TI  - Risk factors associated with tuberculin skin test positivity among university
      students and the use of such factors in the development of a targeted screening
      program.
AB  - The present study evaluated the accuracy of a risk assessment questionnaire (RAQ)
      for identifying candidates for tuberculin testing. A 33-question RAQ was
      administered to students before they underwent tuberculin screening at Virginia
      Commonwealth University (Richmond). Test operating characteristics for the
      complete and abbreviated RAQs compared to tuberculin skin test (TST) results were
      determined. Of 5382 students screened, 125 (2.3%) had a positive TST result; 113
      (90.4%) of these 125 students had >or=1 affirmative response on the RAQ (i.e., a
      "positive RAQ"). The prevalence of TST positivity among students not born in the
      United States was 33.2-fold higher than that among students born in the United
      States. A 2-question RAQ had a sensitivity of 81.6%, a specificity of 91.0%, and
      positive and negative predictive values of 17.7% and 99.5%, respectively. Risk
      assessment can be an accurate means of identifying candidates for tuberculin
      screening.

PMID- 12594642
TI  - Sexually transmitted diseases other than human immunodeficiency virus infection
      in older adults.
AB  - Sexually active older adults may engage in activities that put them at risk for
      sexually transmitted diseases (STDs). A brief review of the main STDs among older
      adults, including the epidemiology, clinical presentations, and diagnosis of and
      treatment recommendations for such STDs, is presented.

PMID- 12594643
TI  - Combination antibiotic therapy for infective endocarditis.
AB  - Despite the availability of new and potent antibiotics, modern echocardiography,
      and advanced surgical techniques, infective endocarditis (IE) is still associated
      with high morbidity and mortality rates. Use of synergistic antibiotic
      combinations is an appealing way to optimize therapy for IE. This review focuses
      on evidence-based recommendations for combination antimicrobial therapy for IE
      due to the most common etiologic pathogens. Few proven synergistic approaches for
      the treatment of IE have been globally demonstrated via in vitro models,
      experimental IE models, and human clinical trials, except for IE due to
      enterococci. Novel approaches, such as short-course aminoglycoside therapy and
      double-beta-lactam combination therapy, appear to be promising for treatment of
      enterococcal IE. Short-course combination therapy involving agents with activity
      against the cell wall (CWAs) and aminoglycosides is highly effective for IE
      caused by viridans group streptococci. Although synergistic combination therapy
      with CWAs-aminoglycosides remains widely used by clinicians for Staphylococcus
      aureus IE, few definitive human data exist that demonstrate the clinical benefit
      of such an approach.

PMID- 12594644
TI  - Can postexposure vaccination against smallpox succeed?
AB  - What can be achieved by the vaccination of individuals exposed to smallpox virus
      after release of the virus by bioterrorists? There exist several past sources of
      information on postexposure vaccination failures from which it may be inferred
      that prompt vaccination of contacts (i.e., individuals exposed to smallpox) often
      prevented smallpox altogether, that revaccination of previously vaccinated
      individuals at any time during the first week of the incubation period was
      largely protective, and that revaccination done even as late as the second week
      of the incubation period attenuated disease and prevented most deaths. Primary
      vaccination done within 4 days of exposure was also usually protective at least
      from serious illness. Modern contingency planning against the release of smallpox
      virus during a bioterrorist attack should therefore include the capacity for
      prompt tracing and (re)vaccination of all contacts. Because a growing majority of
      the population has never before been vaccinated against smallpox and, so, may be
      unreachable within 4 days, anticipatory vaccination of sections of the
      populations of potential target countries should be considered if the
      bioterrorist threat intensifies.

PMID- 12594645
TI  - Voriconazole: a new triazole antifungal agent.
AB  - Voriconazole is a second-generation azole antifungal agent that shows excellent
      in vitro activity against a wide variety of yeasts and molds. It can be given by
      either the intravenous or the oral route; the oral formulation has excellent
      bioavailability. The side effect profile of voriconazole is unique in that non
      sight-threatening, transient visual disturbances occur in approximately 30% of
      patients given the drug. Rash (which can manifest as photosensitivity) and
      hepatitis also occur. The potential for drug-drug interactions is high and
      requires that careful attention be given to dosage regimens and monitoring of
      serum levels and effects of interacting drugs. Voriconazole has been approved for
      the treatment of invasive aspergillosis and refractory infections with
      Pseudallescheria/Scedosporium and Fusarium species, and it will likely become the
      drug of choice for treatment of serious infections with those filamentous fungi.

PMID- 12594646
TI  - Key issues for a potential human immunodeficiency virus vaccine.
AB  - A safe, effective, and affordable vaccine remains the best long-term hope for
      bringing the global human immunodeficiency virus/acquired immunodeficiency
      syndrome (HIV/AIDS) epidemic under control. Recent scientific developments have
      suggested that the first generation of HIV vaccines available for public health
      care use will likely be of low to moderate efficacy, compared with currently
      licensed vaccines for other diseases. Nevertheless, such "partially effective"
      HIV vaccines could provide considerable individual and public health benefits. A
      consultation was held in January 2002 to advise the Centers for Disease Control
      and Prevention (Atlanta, Georgia) about critical issues that need to be addressed
      in anticipation of the eventual licensure and availability of an HIV vaccine in
      the United States. The present article summarizes the major issues discussed at
      the consultation with regard to the potential use of a partially effective
      vaccine in HIV prevention programs in the United States and the activities that
      are needed to prepare for vaccine availability.

PMID- 12594647
TI  - Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in
      human immunodeficiency virus-infected patients: a randomized trial by the CIOP
      Study Group.
AB  - This subgroup analysis assessing secondary prophylaxis for Pneumocystis carinii
      pneumonia (PCP) describes a multicenter, open-labeled, randomized, controlled
      trial evaluating the discontinuation of PCP prophylaxis. The main inclusion
      criterion was a history of PCP and an increase in the CD4 cell count to >200
      cells/microL associated with receipt of highly active antiretroviral therapy for
      >or=3 months. The primary end point was the development of definitive or
      presumptive PCP. A total of 146 patients were enrolled (77 in the treatment
      discontinuation arm). After >2 years, 1 definitive and 1 presumptive case of PCP
      were observed, both of which occurred in patients who discontinued therapy. In
      most patients, secondary prophylaxis for PCP can be safely discontinued after
      potent antiretroviral therapy is initiated, but the threshold of >200 CD4
      cells/microL may not be considered absolutely safe. Patients who present with
      symptoms after discontinuation of secondary prophylaxis should be evaluated for
      PCP despite high CD4 count and complete virus suppression.

PMID- 12594648
TI  - Review of human immunodeficiency virus type 1-related opportunistic infections in
      sub-Saharan Africa.
AB  - Understanding the natural history of human immunodeficiency virus type 1 (HIV-1)
      and opportunistic infections in sub-Saharan Africa is necessary to optimize
      strategies for the prophylaxis and treatment of opportunistic infections and to
      understand the likely impact of antiretroviral therapy. We undertook a systematic
      review of the literature on HIV-1 infection in sub-Saharan Africa to assess data
      from recent cohorts and selected cross-sectional studies to delineate rates of
      opportunistic infections, associated CD4 cell counts, and associated mortality.
      We searched the MEDLINE database and the Cochrane Database of Systematic Reviews
      and Cochrane Clinical Trials Register for English-language literature published
      from 1990 through April 2002. Tuberculosis, bacterial infections, and malaria
      were identified as the leading causes of HIV-related morbidity across sub-Saharan
      Africa. Of the few studies that reported CD4 cell counts, the range of cell
      counts at the time of diagnosis of opportunistic infections was wide. Policies
      regarding the type and timing of opportunistic infection prophylaxis may be
      region specific and urgently require further study.

PMID- 12594649
TI  - Bacterial vaginosis is a strong predictor of Neisseria gonorrhoeae and Chlamydia
      trachomatis infection.
AB  - To evaluate whether bacterial vaginosis predicts the acquisition of sexually
      transmitted diseases (STDs), we studied 255 nonpregnant female subjects aged 15
      30 who reported recent sexual contact with a male partner in whom either
      gonococcal or chlamydial urethritis or nongonococcal urethritis was diagnosed.
      Compared to subjects with normal vaginal flora, subjects with bacterial vaginosis
      were more likely to test positive for Neisseria gonorrhoeae (odds ratio [OR],
      4.1; 95% confidence interval [CI], 1.7-9.7) and Chlamydia trachomatis (OR, 3.4;
      95% CI, 1.5-7.8). Subjects colonized vaginally by hydrogen peroxide-producing
      lactobacilli were less likely to receive a diagnosis of chlamydial infection or
      gonorrhea than subjects without such lactobacilli. Bacterial vaginosis was a
      strong predictor of gonorrhea and chlamydial infection among subjects who
      reported recent exposure to a male partner with urethritis. These data support
      the importance of vaginal flora in the defense against STD acquisition.

PMID- 12594650
TI  - Diverse etiologies for chronic fatigue syndrome.

PMID- 12594652
TI  - Removing hospitalization as a barrier to immunization.

PMID- 12594654
TI  - Diagnosis of rabies by use of brain tissue dried on filter paper.

PMID- 12594655
TI  - Persistent MRSA bacteremia in a patient with low linezolid levels.

PMID- 12594656
TI  - First case of Mycobacterium ulcerans disease (Buruli ulcer) following a human
      bite.
AB  - Mycobacterium ulcerans disease (MUD) is rapidly reemerging in many countries,
      especially in West African countries. Antecedent trauma has often been related to
      the lesions that characterize this frequently crippling disease. We report here
      the first case of MUD that followed a human bite at the site where the lesion
      later occurred.

PMID- 12594657
TI  - Tsukamurella tyrosinosolvens intravascular catheter infection identified using
      16S ribosomal DNA sequencing.
AB  - Cultures of blood from a hemodialysis line repeatedly yielded a gram-positive
      rod. The organism was identified as Tsukamurella tyrosinosolvens by 16S ribosomal
      DNA sequencing, and the patient was treated successfully by removal of the line.

PMID- 12594658
TI  - Diabetes mellitus, insulin, and melioidosis in Thailand.
AB  - A review of case records for 1817 Thai patients with melioidosis revealed that
      <10% of the 382 patients with diabetes mellitus were insulin dependent. This
      provides evidence against the hypothesis that insulin deficiency contributes to
      the known susceptibility to melioidosis in patients with diabetes mellitus.

PMID- 12594659
TI  - Moving from open to laparoscopic appendicectomy.

PMID- 12594660
TI  - Insulin resistance in sepsis.

PMID- 12594661
TI  - Non-suture methods of vascular anastomosis.
AB  - BACKGROUND: The main aim of performing a vascular anastomosis is to achieve
      maximal patency rates. An important factor to achieve that goal is to minimize
      damage to the vessel walls. Sutures inevitably induce vascular wall damage, which
      influences the healing of the anastomosis. Over time, several alternatives to
      sutures have become available. METHODS: A Medline literature search was performed
      to locate English, German and French language articles pertinent to non-suture
      methods of vascular anastomosis. Manual cross-referencing was also performed and
      many historical articles were included. RESULTS AND CONCLUSION: The non-suture
      techniques can be categorized into five groups based on the materials used:
      rings, clips, adhesives, stents and laser welding. With all these techniques a
      faster and less traumatic anastomosis can be made compared with sutures. However,
      each device is associated with technique-related complications. As a consequence,
      suturing continues to be the standard approach. The disadvantages of the non
      suture techniques include: rigidity and a non-compliant anastomosis with rings;
      toxicity, leakage and aneurysm formation with adhesives; early occlusion with
      stents; cost, reduced strength in larger-sized vessels and demand for surgical
      skills with laser welding. Further refinement is needed before widespread
      adoption of these techniques can occur. Clips, however, may be particularly
      promising but long-term evaluation is required.

PMID- 12594662
TI  - Interstitial ablative techniques for hepatic tumours.
AB  - BACKGROUND: Most patients with liver tumours are not suitable for surgery but
      interstitial ablative techniques may control disease progression and improve
      survival rates. METHODS: A review was undertaken using Medline of all reported
      studies of cryoablation, radiofrequency ablation, microwave ablation,
      interstitial laser photocoagulation, high-intensity focused ultrasound and
      ethanol ablation of primary liver tumours and hepatic metastases. RESULTS:
      Although there are no randomized clinical trials, cryoablation, thermal ablation
      and ethanol ablation have all been shown to be associated with improved
      palliation in patients with primary and secondary liver cancer. The techniques
      can be undertaken safely with minimal morbidity and mortality. CONCLUSION:
      Although surgical resection remains the first line of treatment for selected
      patients with primary and secondary liver malignancies, interstitial ablative
      techniques are promising therapies for patients not suitable for hepatic
      resection or as an adjunct to liver surgery.

PMID- 12594663
TI  - Bone marrow micrometastasis in breast cancer.
AB  - BACKGROUND: Several studies have demonstrated that bone marrow micrometastasis in
      patients with breast cancer is an independent prognostic factor for systemic
      recurrence and poorer survival. METHODS: This review describes the detection and
      clinical significance of micrometastatic cells in bone marrow, and examines the
      correlation between such micrometastasis and established clinicopathological
      prognostic factors. The relevant English language literature on bone marrow
      micrometastasis in breast cancer was searched via Medline (1975-2002), cross
      referencing with key articles on the subject. RESULTS AND CONCLUSION: The balance
      of evidence favours the hypothesis that bone marrow micrometastasis impacts on
      disease-free and overall survival. Further prospective studies are required to
      examine this in greater detail, with particular reference to early node-negative
      breast cancer and the value of adjuvant systemic therapy in patients with bone
      marrow micrometastasis.

PMID- 12594665
TI  - Lesion progression with time and the effect of vascular occlusion following
      radiofrequency ablation of the liver.
AB  - BACKGROUND: The effectiveness of radiofrequency ablation (RFA) under selective
      vascular occlusion and its effects on architecture and viability of normal liver
      parenchyma was studied in a porcine model. METHODS: RFA was applied in the liver
      under general anaesthesia in 18 pigs. Six animals were killed immediately after
      the procedure and 12 at 24 h. RFA was performed sequentially under four
      conditions: (1) without vascular occlusion, (2) during occlusion of the hepatic
      artery, (3) during occlusion of the portal vein and (4) during occlusion of the
      hepatic artery and portal vein. Liver biopsies from the treated area were stained
      for conventional histological examination, reduced nicotinamide adenine
      dinucleotide diaphorase and 5'-nucleotidase activity. RESULTS: Vascular occlusion
      significantly increased the size of the coagulation centre after RFA. Combined
      portal venous and arterial occlusion had no additional effect on lesion size
      compared with venous or arterial occlusion alone. After 24 h, deterioration of
      viability was observed in the parenchyma up to 3 cm from the coagulated area.
      CONCLUSION: The efficacy of RFA in liver increases with occlusion of the portal
      vein or hepatic artery. The extent of secondary heat-induced necrosis in liver
      parenchyma should be considered for determination of the final size of the
      ablated area.

PMID- 12594664
TI  - Prevention of pleural effusion following hepatectomy using argon beam
      coagulation.
AB  - BACKGROUND: Postoperative pleural effusion occurs frequently after hepatectomy.
      The value of the argon beam coagulator (ABC) for the prevention of pleural
      effusion after hepatectomy in patients with hepatocellular carcinoma was studied.
      METHODS: Sixty patients were divided randomly into two groups: an ABC group (n =
      28), in which the cut surface of the hepatic ligaments and bare area of the
      retroperitoneum were cauterized using an ABC, and a control group (n = 32) in
      which the ABC was not applied. Patient characteristics, preoperative and
      postoperative liver function, and postoperative pleural effusion were compared
      between the two groups. RESULTS: There were no significant differences between
      the two groups with respect to histological findings, clinical stage, type of
      resection, operative data, and preoperative and postoperative laboratory data.
      One of 28 patients in the ABC group and nine of 32 patients in the control group
      had pleural effusion. The incidence was significantly lower in the ABC group than
      in the control group (P = 0.01). Pleurocentesis was needed in two of the ten
      patients and thoracic drainage in four patients. CONCLUSION: Application of an
      ABC to the cut surface of the hepatic ligaments and bare area of retroperitoneum
      after liver mobilization may prevent postoperative pleural effusion.

PMID- 12594666
TI  - Serum antigen(s) drive the proinflammatory T cell response in acute pancreatitis.
AB  - BACKGROUND: Immune cells and cytokines are central to the systemic inflammatory
      response syndrome and multiple organ failure associated with acute pancreatitis.
      The specific role of T cells in this response is unclear, and this study focused
      on evaluating T cell activation and its regulation in patients with acute
      pancreatitis. METHODS: Peripheral blood samples of 14 patients with acute
      pancreatitis were obtained within 24 h of the onset of pain, within 48 h and at 1
      week. T cell expression of surface markers CD69, CD62L and CD25 was measured. The
      production of interleukin (IL) 10 and IL-2 in vitro in response to the
      superantigen Staphylococcus enterotoxin B (SEB) was assessed. Serum samples from
      these patients were co-cultured with peripheral blood mononuclear cells from
      volunteers in the presence or absence of cytotoxic T lymphocyte-associated
      antigen (CTLA) 4 immunoglobulin, a specific inhibitor of antigen-dependent T cell
      activation. RESULTS: Expression of CD69 was significantly increased in CD3(+) and
      CD4(+) populations at 48 h and 1 week, and on CD8(+) cells at 1 week. There was a
      significant increase in the production of SEB-induced IL-2 compared with findings
      in controls, but no significant IL-10 response. Serum from patients with
      pancreatitis activated normal T cells. This response was abolished completely by
      CTLA-4. CONCLUSION: Acute pancreatitis results in the systemic activation of T
      cells. These cells are primed for a proinflammatory response to antigen
      stimulation and can be inhibited by antigen-specific T cell blockade. These data
      indicate that the immunoinflammatory response in acute pancreatitis is fueled by
      one or more serum antigens and offer prospects for further understanding of the
      aetiogenesis of pancreatitis.

PMID- 12594667
TI  - Size of the pancreatic head as a prognostic factor for the outcome of Beger's
      procedure for painful chronic pancreatitis.
AB  - BACKGROUND: Duodenum-preserving resection of the head of the pancreas (DPRHP)
      according to Beger has been developed as an alternative to pylorus-preserving
      resection of the pancreatic head for painful chronic pancreatitis. METHODS:
      Between 1988 and 2000, 36 consecutive DPRHPs were performed. The group was
      divided into patients with (group 1; n = 23) and without (group 2; n = 13)
      significant enlargement of the pancreatic head. Pain was the indication for
      surgery in all patients. RESULTS: Complications occurred in 12 patients,
      necessitating reoperation in 11. Initial overall results were favourable;
      significant improvement or complete relief of pain was reported in 27 of 35
      patients. Long-term results were obtained in 27 of 30 patients; the overall
      success rate was 16 of 27, 13 of 16 patients with distinct enlargement of the
      pancreatic head and 3 of the 11 with minimal or no enlargement (P = 0.018).
      CONCLUSION: DPRHP can be performed with good early results. This effect is
      sustained in patients with distinct localized disease of the pancreatic head. In
      those without, the long-term results are disappointing.

PMID- 12594668
TI  - Factors predictive of 5-year survival after transarterial chemoembolization for
      inoperable hepatocellular carcinoma.
AB  - BACKGROUND: Transarterial chemoembolization (TACE) is widely used for
      unresectable hepatocellular carcinoma (HCC), but the long-term survival benefit
      remains unclear. METHODS: Pretreatment variables were analysed for factors
      predictive of actual 5-year survival from a prospective database of patients with
      inoperable HCC treated by TACE between 1989 and 1996. RESULTS: Complete 5-year
      follow-up (median 91 months) was obtained for 320 patients who underwent a median
      of 4 (range 1-41) TACEs. Median tumour size was 9 (range 1-28) cm. There were 25
      5-year survivors (8 per cent), including eight with tumours larger than 10 cm in
      diameter and three with portal vein branch involvement. On univariate analysis,
      female gender (P = 0.037), absence of ascites (P = 0.028), platelet count below
      150 x10(9) per litre (P = 0.011), albumin concentration greater than 35 g/l (P =
      0.04), alpha-fetoprotein level below 1000 ng/ml (P = 0.007), unilobar tumour (P =
      0.027), fewer than three tumours (P = 0.015), absence of venous invasion (P =
      0.011), and tumour diameter less than 8 cm (P = 0.021) were significant
      predictors of 5-year survival. Albumin concentration greater than 35 g/l (P =
      0.011), unilobar tumour (P = 0.012) and alpha-fetoprotein level below 1000 ng/ml
      (P = 0.014) were independent prognostic factors on multivariate analysis.
      CONCLUSION: Five-year survival is possible with TACE for inoperable HCC, even in
      some patients with advanced tumours. Unilobar tumours, alpha-fetoprotein level
      below 1000 ng/ml and albumin concentration greater than 35 g/l were factors
      predictive of 5-year survival.

PMID- 12594669
TI  - Prognostic factors influencing surgical management and outcome of
      gastrointestinal stromal tumours.
AB  - BACKGROUND: The purpose of this study was to review surgical experience with
      gastrointestinal stromal tumours (GISTs) at a single tertiary university
      hospital, and to identify morphological and genetic prognostic markers of tumour
      progression. METHODS: Forty-eight GISTs from 39 patients were reviewed
      retrospectively. The prognostic significance of DNA copy number changes, measured
      by comparative genomic hybridization (CGH), and morphological markers in low-risk
      and high-risk tumours were investigated. RESULTS: Significantly more patients
      died from disease after incomplete tumour resection than after complete primary
      resection (P = 0.020). Tumour size of 5 cm or greater, mitotic count of 2 or
      more, and proliferative activity greater than 10 per cent were significantly
      associated with a shorter recurrence-free survival (P = 0.020, P = 0.001 and P =
      0.002 respectively). Patients with low-risk tumours had a significantly better
      outcome than those with high-risk GISTs, both in terms of overall and recurrence
      free survival (P < or = 0.001). CGH performed on 16 tumours revealed fewer DNA
      sequence copy number changes in low-risk than in high-risk GISTs. Non-progressive
      GISTs contained significantly fewer genetic alterations than recurrent or
      metastatic tumours (P < 0.001). Only tumours with more than five changes showed
      disease progression. CONCLUSION: Complete surgical resection is the most
      important means of cure for GISTs. DNA copy number changes are related to the
      behaviour of these tumours and may serve as additional prognostic markers.

PMID- 12594670
TI  - Evaluation of POSSUM and P-POSSUM scoring systems in patients undergoing
      colorectal surgery.
AB  - BACKGROUND: The Physiological and Operative Severity Score for the enUmeration of
      Mortality and morbidity (POSSUM) and Portsmouth POSSUM (P-POSSUM) equations were
      derived from a heterogeneous general surgical population and have been used
      successfully as audit tools to provide risk-adjusted operative mortality rates.
      Their applicability to high-risk emergency colorectal operations has not been
      established. METHODS: POSSUM variables were recorded for 1017 patients undergoing
      major elective (n = 804) or emergency (n = 213) colorectal surgery in ten
      hospitals. Subgroup analysis was performed to investigate the predictive
      capability of POSSUM and P-POSSUM in emergency and elective surgery and in
      patients in different age groups. RESULTS: The overall operative mortality rate
      was 7.5 per cent (POSSUM-estimated mortality rate 8.2 per cent; P-POSSUM
      estimated mortality rate 7.1 per cent). In-hospital deaths increased
      exponentially with age. Both scoring systems overpredicted mortality in young
      patients and underpredicted mortality in the elderly (P < 0.001). Death was
      underpredicted by both systems for emergency cases, significantly so at a
      simulated emergency caseload of 47.9 per cent (P < 0.05). CONCLUSION: There is a
      lack of calibration of POSSUM and P-POSSUM systems at the extremes of age and
      high emergency workload. This has important implication in clinical practice, as
      consultants with a high emergency workload may seem to underperform when these
      scoring systems are applied. Recalibration or remodelling strategies may
      facilitate the application of POSSUM-based systems in colorectal surgery.

PMID- 12594671
TI  - Assessment of the accuracy of transrectal ultrasonography in anorectal neoplasia.
AB  - BACKGROUND: Accurate preoperative staging of anorectal neoplasia is required to
      identify patients for whom local excision or adjuvant therapy may be appropriate.
      The objectives of this study were to review the accuracy of endoluminal
      transrectal ultrasonography (TRUS) in the staging of rectal cancers and to
      determine the learning curve before optimal staging accuracy can be achieved.
      METHODS: The results of all TRUS examinations for the assessment of anorectal
      neoplasia performed by two colorectal surgeons at two teaching hospitals of the
      University of Sydney from 1991 to 2001 were collected prospectively. RESULTS: Of
      the 433 patients examined by TRUS, 356 were included, of whom 263 (73.9 per cent)
      had nodal status assessed histologically. Of the 77 patients excluded, 50 had
      undergone radiotherapy before operation. TRUS achieved excellent accuracy when
      compared with histopathology reports using kappa statistics for standard Union
      Internacional Contra la Cancrum (UICC) staging (kappa = 0.89), tumour wall
      penetration (kappa = 0.70), lymph node detection (kappa = 0.66) and a proposed
      new staging system (kappa = 0.94). In addition, the increase in TRUS accuracy
      with operator experience demonstrates the need to perform 50 or more procedures
      before optimal accuracy is achieved. CONCLUSION: TRUS provides an appropriate
      investigation with which to select patients with T1 tumours for local excision,
      and patients with T3 or T4 tumours for preoperative radiotherapy. The relative
      inaccuracy of staging T2 tumours by TRUS has led to a proposed alternative
      ultrasonographic staging system.

PMID- 12594672
TI  - Smoking affects the outcome of transanal mucosal advancement flap repair of trans
      sphincteric fistulas.
AB  - BACKGROUND: The aim of the study was to identify variables affecting the outcome
      of transanal advancement flap repair (TAFR) for perianal fistulas of
      cryptoglandular origin. METHODS: Between 1995 and 2000, a consecutive series of
      105 patients (65 women, 40 men), with a median age of 44 (range 19-72) years was
      included in the study. The patients were recruited from the colorectal
      departments of two university medical centres. Patients with a rectovaginal
      fistula and those with a fistula due to Crohn's disease were excluded. The
      following variables were assessed: age, sex, number of previous attempts at
      repair, preoperative seton drainage, fistula type, presence of horseshoe
      extensions, location of the internal opening, postoperative drainage, body mass
      index and the number of cigarettes smoked per day. The results were analysed by
      means of multiple logistic regression. RESULTS: The median follow-up was 14
      months. No differences were observed between the two centres. TAFR was successful
      in 72 patients (69 per cent). None of the variables affected the outcome of the
      procedure, except for smoking habit of the patient. In patients who smoked the
      observed healing rate was 60 per cent, whereas a rate of 79 per cent was found in
      patients who did not smoke. This difference was statistically significant (P =
      0.037). Moreover, a significant correlation was observed between the number of
      cigarettes smoked per day and the healing rate (P = 0.003). CONCLUSION: Cigarette
      smoking affects the outcome of TAFR in patients with a cryptoglandular perianal
      fistula.

PMID- 12594673
TI  - Preoperative assessment of prognostic factors in rectal cancer using high
      resolution magnetic resonance imaging.
AB  - BACKGROUND: The aim was to determine the accuracy of preoperative magnetic
      resonance imaging (MRI) in the evaluation of pathological prognostic factors that
      influence local recurrence and survival in rectal cancer. METHODS: Ninety-eight
      patients undergoing total mesorectal excision for biopsy-proven rectal cancer
      were assessed prospectively using high-resolution MRI for tumour (T) and nodal
      (N) staging using the tumour node metastasis classification, depth of extramural
      tumour spread, the presence or absence of extramural venous invasion, a
      threatened circumferential resection margin and serosal involvement at or above
      the peritoneal reflection. Preoperative magnetic resonance assessment of these
      prognostic factors was compared with histopathological findings in carefully
      matched whole-mount sections of the resection specimen. RESULTS: There was 94 per
      cent weighted agreement (weighted kappa = 0.67) between MRI and pathology
      assessment of T stage. Agreement between MRI and histological assessment of nodal
      status was 85 per cent (kappa = 0.68). Although involvement of small veins by
      tumour was not discernible using MRI, large (calibre greater than 3 mm)
      extramural venous invasion was identified correctly in 15 of 18 patients (kappa =
      0.64). MRI predicted circumferential resection margin involvement with 92 per
      cent agreement (kappa = 0.81). Seven of nine patients with peritoneal perforation
      by tumour (stage T4) were identified correctly using MRI. CONCLUSION: High
      resolution MRI of the rectum allows preoperative identification of important
      surgical and pathological prognostic risk factors. This may allow both better
      selection and assessment of patients undergoing preoperative therapy.

PMID- 12594674
TI  - Meta-analysis suggests antibiotic prophylaxis is not warranted in low-risk
      patients undergoing laparoscopic cholecystectomy.

PMID- 12594675
TI  - Outcome of patients with severe chronic groin pain following repair of groin
      hernia (Br J Surg 2002; 89: 1310-1315).

PMID- 12594677
TI  - Long term results of surgery for early gastric cancer (Br J Surg 2002; 89: 1035
      1042).

PMID- 12594678
TI  - Chronic pain after laparoscopic and open mesh repair of groin hernia (Br J Surg
      2002; 89: 1476-1479).

PMID- 12594679
TI  - Identifying patients for blood conservation strategies (Br J Surg 2002; 89: 1176
      1182).

PMID- 12594680
TI  - Randomized study of the effectiveness of closing laparoscopic trocar wounds with
      octylcyanoacrylate, adhesive papertape or poliglecaprone (Br J Surg 2002; 89:
      1370-1375).

PMID- 12594681
TI  - Meta-analysis of relaparotomy for secondary peritonitis (Br J Surg 2002; 89: 1516
      1524).

PMID- 12594682
TI  - Meta-analysis of techniques for closure of midline abdominal incisions (Br J Surg
      2002; 89: 1350-1356).

PMID- 12594683
TI  - Pathogenesis and clinical management of hereditary non-polyposis colorectal
      cancer (Br J Surg 2002; 89: 1357-1369).

PMID- 12594686
TI  - Four French catheters for diagnostic coronary angiography.
AB  - A randomized study was conducted to assess the feasibility of 4 Fr catheters for
      diagnostic coronary angiograms. A total of 1,114 consecutive patients were
      randomized to 4 or 5 Fr catheters. Ease of use of catheters was subjectively
      assessed by the primary operator and the picture quality was assessed by two
      independent observers with a good interobserver variability (r = 0.94; P <
      0.001). Predischarge local complications were recorded by the attending
      physician. No statistically significant difference was observed in the picture
      quality for the left coronary artery, right coronary artery, aorta, left
      ventricle, venous grafts, or renal arteries between the two groups. Fluoroscopy
      time (7.1 +/- 5.6 for 4 Fr vs. 6.7 +/- 5.7 min for 5 Fr) and contrast quantity
      (140 +/- 58 vs. 144 +/- 57 ml) were comparable between the two groups. There was
      a statistically significant difference in favor of the 5 Fr group as regards
      maneuverability of catheters (93% vs. 79%; P < 0.001), and 5 Fr pigtail catheters
      crossed the aortic valve easier than the 4 Fr pigtail catheters (91% vs. 81%; P <
      0.001). Crossover to the other catheter size or a larger sheath was more frequent
      with 4 Fr catheters (33/522 vs. 3/592; P < 0.001). Median time to hemostasis was
      9 min for 4 Fr and 14 min for 5 Fr (P < 0.001). Of the 4 Fr patients, 84% could
      be mobilized at 1 hr and 86% of 5 Fr patients at 2 hr. Significant hematomas were
      observed in 2% with 4 Fr or 5 Fr and small hematomas in 10% and 16%, respectively
      (P = NS). Time to discharge was comparable in both groups (4.0 +/- 3.2 with 4 Fr
      vs. 4.3 +/- 3.7 hr with 5 Fr). The 4 Fr catheters are a good alternative for
      diagnostic coronary angiograms. The increased difficulty in maneuverability and a
      need for catheter changes in 70% are compensated for in part by easier
      hemostasis. With increasing use and finesse of these catheters, the difficulty in
      maneuverability are likely to be overcome.

PMID- 12594687
TI  - Evaluation of a spasmolytic cocktail to prevent radial artery spasm during
      coronary procedures.
AB  - Radial artery spasm is a frequent complication of the transradial approach for
      coronary angiography and angioplasty. Recently, we have been able to quantify
      spasm using the automatic pullback device. The objective of this study was to
      assess the efficacy of an intra-arterial vasodilating cocktail in reducing the
      incidence and severity of radial artery spasm. A hundred patients undergoing
      coronary procedures via the radial artery were divided into two groups of 50
      each. Patients in group A received intra-arterial cocktail (5 mg of verapamil
      plus 200 micro g nitroglycerine in 10 ml of normal saline), while patients in
      group B did not receive any vasodilating drug. The pullback device was used for
      sheath removal at the end of the procedure. Seven (14%) patients in group A
      experienced pain (i.e., pain score of III-V) during automatic sheath removal, as
      compared to 17 (34%) in group B (P = 0.019). The mean pain score was
      significantly lower in group A than in group B (1.7 +/- 0.94 vs. 2.08 +/- 1.07; P
      = 0.03). The maximal pullback force (MPF) was also significantly lower for group
      A (0.53 +/- 0.52 kg; range, 0.10-3.03 kg) as compared to group B (0.76 +/- 0.45
      kg; range, 0.24-1.99 kg; P = 0.013). Only 4 (8%) patients in group A had an MPF
      value greater than 1.0 kg, suggesting the presence of significant radial artery
      spasm, as opposed to 11 (22%) in group B (P = 0.029). Administration of an intra
      arterial vasodilating cocktail prior to sheath insertion reduces the occurrence
      and severity of radial artery spasm.

PMID- 12594689
TI  - Closure device euphoria?

PMID- 12594688
TI  - Effect of a closure device on complication rates in high-local-risk patients:
      results of a randomized multicenter trial.
AB  - Clinical trials have shown that coronary stenting is associated with a high level
      of complications at the access site. Arterial sealing devices have proven their
      efficacy in obtaining immediate hemostasis after sheath removal, in allowing
      early ambulation, and in improving patient comfort. However, there is no report
      showing a reduction of local complications related to their use. The purpose of
      this multicenter study was to compare randomly the efficacy of Angio-Seal versus
      compression methods of hemostasis in reducing the rate of access site
      complications after coronary angioplasty in 612 selected patients with higher
      risk of local events satisfying at least one of the following high-risk criteria:
      age > 70, previous puncture at the same site, history of hypertension, treatment
      with ticlopidine at least 2 days before the procedure, use of abciximab, 8 Fr
      access, prolonged heparin treatment after the angioplasty, and use of lytics if
      fibrinogen > 1 g/l. Group A (n = 306) had immediate sheath removal, Angio-Seal
      implantation, and cessation of bed rest 4 hr after the intervention. Group B (n =
      306) had sheath removal according to local practice and cessation of bed rest 6
      18 hr after the hemostasis procedure, also according to local practice. Clinical
      follow-up was done at 1 hr, 4 hr, 24 hr, discharge, and 7 days and a systematic
      color flow duplex sonography was performed to confirm diagnosis of access site
      complication. In group A, device deployment and immediate hemostasis were
      obtained in, respectively, 96.8% and 87% of patients. Time to hemostasis was
      shorter in group A: 5 vs. 52 min (P < 0.001). Cessation of bed rest was
      dramatically reduced in group A (438 +/- 450 min) vs. group B (952 +/- 308 min; P
      < 0.001). The cumulative rate of complications, using a composite primary
      endpoint, at 7 days was significantly different between the two groups: 5.9% of
      group A patients and 18% of group B patients (P < 0.001). This difference was
      mainly due to the dramatic reduction of prolonged bleeding in group A patients.
      Angio-Seal device use in high-local-risk patients allows immediate sheath removal
      and hemostasis with a reduction of local event rate despite a higher level of
      anticoagulation, compared to regular compression techniques, directly related to
      a dramatic decrease of prolonged bleeding.

PMID- 12594690
TI  - Influence of stent treatment strategies in the long-term outcome of patients with
      long diffuse coronary lesions.
AB  - Diffuse coronary lesions (length > 20 mm) are still considered high risk for
      percutaneous intervention even in the current stent era. We compared the 2-year
      outcome of patients with long diffuse stenosis treated by three different stent
      strategies. In addition, we also analyzed the possible factors influencing a
      favorable late outcome. Our series is constituted by 232 patients with 247 long
      lesions treated between May 1994 and April 1999; 82 patients received one single
      long stent (group 1), 71 patients were treated by overlapped multiple stents
      (group 2), and 79 with multiple nonoverlapped stents (group 3). The mean age was
      59 +/- 11 years. There were not significant differences between groups in terms
      of age, risk factors, clinical presentation, type of lesion, or adjunctive
      medical therapy. Patients from group 1 had shorter lesions (29 +/- 10 mm) than
      patients from groups 2 (41 +/- 15 mm) and 3 (36 +/- 14; P < 0.05). Major cardiac
      events (death, acute myocardial infarction, or repeat revascularization) at 24 +/
      12 months follow-up took place in 39 patients (17%). The probabilities of being
      free of major events at follow-up were 71%, 78%, and 80% for group 1, 2, and 3
      respectively (P = NS). Only three variables were identified as significant
      predictors of these late events: smaller vessel size, smaller minimal lumen
      diameter after stenting, and the type of lesion being restenotic as compared with
      native stenosis. Patients with diffuse lesions treated by single long stents did
      not have a better late outcome than those who received multiple stents. The best
      late outcome was observed in those patients who had bigger vessel size, larger
      poststent lumen dimensions and native lesions, regardless of the stent deployment
      strategy used.

PMID- 12594691
TI  - Procedural outcomes of repeated transradial coronary procedure.
AB  - We evaluated the changes in radial arterial diameter and the procedural outcomes
      of repeated transradial procedures through the same radial artery in 117 cases.
      No significant differences were found in the mean diameter of the radial artery
      between preprocedure and 1 day after procedure on initial and repeated
      procedures. However, the mean radial arterial diameter was significantly
      decreased from 2.63 +/- 0.35 to 2.51 +/- 0.29 mm during follow-up after the
      initial procedure (P = 0.01). There was no significant difference in the vascular
      access times of the initial and repeated procedures (2.9 +/- 3.1 vs. 3.3 +/- 3.6
      min; P = 0.08), and procedural success of repeated procedure was similar to those
      of the initial procedure. However, the incidence of radial arterial occlusion was
      higher for repeated procedures (2.6% vs. 0%; P = 0.01). We conclude that the
      repeated use of the radial artery is feasible in most patients with a high
      procedural success rate and low vascular complications.

PMID- 12594692
TI  - Right or left side?

PMID- 12594693
TI  - Increased secretion of insulin during oral glucose tolerance test can be a
      predictor of stent restenosis in nondiabetic patients.
AB  - Insulin is known to stimulate proliferation and migration of vascular smooth
      muscle cells. As the predominant mechanism of restenosis after stent implantation
      is neointimal tissue proliferation, one can expect a relationship between
      hyperinsulinemia and restenosis in these patients. The aim of this study was to
      determine whether hyperinsulinemia during oral glucose tolerance test is a
      predictor of the development of restenosis after stent implantation in
      nondiabetic patients. We prospectively studied 52 nondiabetic patients with
      effort angina who underwent elective stent implantation for single-vessel
      coronary artery disease. In order to increase the statistical power of the study,
      numerous exclusion criteria were applied. All patients were subjected to a 75 g
      oral glucose tolerance test a day before the stent implantation and underwent
      follow-up angiography 6 months later. Plasma insulin levels in fasting (6.77 +/-
      1.57 vs. 5.36 +/- 1.35 micro U/ml; P = 0.005), at 30 min (102.48 +/- 10.6 vs.
      47.74 +/- 12.75 micro U/ml; P = 0.001), 1 hr after (120.23 +/- 14.1 vs. 63.08 +/-
      12.62 micro /ml; P = 0.001), 2 hr after (63.58 +/- 8.64 vs. 34.88 +/- 6.82 micro
      /ml; P = 0.001), and 3 hr after (25.71 +/- 5.65 vs. 23.02 +/- 4.61 micro /ml; P =
      0.04) loading were significantly higher in patients with stent restenosis than in
      patients without stent restenosis. Insulin area and insulin area/glucose area
      were also significantly higher in patients with stent restenosis than in patients
      without (219.5 +/- 23.8 vs. 118.9 +/- 21.8, P = 0.001, and 0.62 +/- 0.09 vs. 0.33
      +/- 0.06, P = 0.001, respectively). By multiple logistic regression analysis,
      insulin area during oral glucose tolerance test was found to be an independent
      predictor of stent restenosis (OR = 1.12; 95% CI = 1.01-1.25; P = 0.031). In
      conclusion, nondiabetic patients with hyperinsulinemia during oral glucose
      tolerance test have a high risk for restenosis after stent implantation, and
      performing this simple test before intervention may be useful for the prediction
      of stent restenosis.

PMID- 12594694
TI  - Percutaneous suture-mediated closure of femoral access sites deployed through the
      procedure sheath: initial clinical experience with a novel vascular closure
      device.
AB  - The objective of this study was to assess the initial safety and feasibility of a
      novel suture-mediated device for closure of femoral access sites immediately
      after diagnostic or interventional cardiac catheterization. In a prospective
      study, 150 patients (mean age, 61.5 years; 109 male) underwent femoral access
      closure with a novel suture closure device (Superstitch, Sutura) immediately
      after diagnostic (n = 106) or interventional (n = 44) catheterization procedures,
      independently of the coagulation status. All patients were monitored for 24 hr
      after the procedure. The closure device was successfully deployed in 92% of
      patients. Immediate hemostasis was achieved in 77% of patients with no
      differences between patients undergoing diagnostic catheterization or coronary
      interventions (79% vs. 73%; P = 0.659). After 2 min of additional light manual
      compression, hemostasis was achieved in 92% of patients. There was one major
      complication requiring vascular surgery (0.7%). The novel suture closure device
      is a safe and effective device that allows for immediate closure of femoral
      puncture sites after both diagnostic and interventional procedures with a low
      rate of major complications.

PMID- 12594695
TI  - Intracoronary beta-brachytherapy in chronic total occlusions: a subgroup analysis
      from the RENO registry.
AB  - Conventional interventional therapy has been less rewarding in chronic total
      occlusion (CTO). Brachytherapy by its antiproliferative and positive remodeling
      effect may be more efficacious. Forty-six centers registered 1,098 consecutive
      patients undergoing brachytherapy with the BetaCath system. Of these, 78 patients
      had 82 lesions (CTO) at presentation-the study population. With 67% in-stent CTO,
      8% graft CTO, 4% recurrent CTO, long lesions (27.6 +/- 20.9 mm), and 31%
      diabetes, the cohort had high risk for recurrence. The in-hospital event rate was
      1.3%. Six-month follow-up revealed 1.3% death, 5.1% myocardial infarction, 21.8%
      target vessel revascularization, 77.8% improved angina, 34.5% binary restenosis,
      12.7% reocclusion, and 10.3% late thrombosis. The results were comparable to all
      other patients in the registry, although late thrombosis rate was higher in the
      CTO group (10.3% vs. 5.0%; P = 0.047). In the in-stent CTO subgroup (n = 52;
      66.7%), there was no in-hospital event, no follow-up death or myocardial
      infarction, restenosis in 35.1%, and reocclusion in 10.8% of patients. In
      comparison, death or myocardial infarction was significantly higher in de novo
      CTO subgroup (P = 0.005). Compared to all other in-stent restenosis patients in
      the registry, the patients with in-stent CTO had similar clinical and
      angiographic event rate. Thus, beta-brachytherapy was safe, feasible, and
      effective in this broad population of high-risk patients with CTO presenting in
      day-to-day practice. It was particularly effective in in-stent CTO, where
      conventional interventional strategies are disappointing.

PMID- 12594696
TI  - Brachytherapy in total coronary occlusions: Quidquid agis, prudenter agas, et
      respice finem.

PMID- 12594697
TI  - Debulking does not benefit patients undergoing intracoronary beta-radiation
      therapy for in-stent restenosis: insights from the START trial.
AB  - Intracoronary brachytherapy has become the current treatment of choice for
      patients with in-stent restenosis (ISR). The aim of the present study was to
      determine whether plaque extraction using debulking techniques prior to
      brachytherapy would improve the outcomes of patients with ISR. Patients enrolled
      into the START (n = 476) and START-40 (n = 205) trials were divided into four
      subgroups according to their treatment assignments: debulking-radiation,
      debulking-placebo, balloon angioplasty (BA) radiation, and BA placebo. Patients
      were further divided according to their ISR lesion length: all lesions, > 15 mm,
      and > 19 mm. Restenosis rates were higher in placebo, nonradiated lesions
      undergoing debulking (52.7%) vs. BA alone (38.5%; P = 0.04). Postprocedural
      minimal lumen diameter (MLD) was similar among the subgroups. Outcomes were
      similar between debulking and BA within each therapeutic arm. MLD after debulking
      radiation was greater in patients with ISR > 15 mm (post-MLD was 1.9 vs. 1.7 mm;
      P = 0.06) but not in the placebo. Debulking radiation patients had greater MLD at
      follow-up, but restenosis (23.5% after debulking vs. 32.7% BA alone) and late
      loss (0.3 mm in both subgroups) were not statistically different. There was a
      trend toward higher mortality among debulked patients (3.7%) compared to BA alone
      (0.8%). In patients with ISR > 19 mm, four patients died following debulking
      radiation as compared to no death after BA (P = 0.05). Our results do not support
      the strategy of plaque extraction prior to intracoronary beta-radiation for ISR.

PMID- 12594698
TI  - Oral acetylcysteine does not protect renal function from moderate to high doses
      of intravenous radiographic contrast.
AB  - The use of radiographic contrast during cardiac catheterization can cause acute
      renal failure with an increase in morbidity and mortality. Prophylactic
      acetylcysteine plus intravenous hydration have been shown to prevent contrast
      induced nephropathy (CIN) in patients with chronic renal failure undergoing
      computed tomography scan, who receive low doses of intravenous contrast. Whether
      the use of prophylactic acetylcysteine can decrease the incidence of CIN when
      larger doses of contrast are used remains to be determined. We sought to evaluate
      whether the prophylactic administration of acetylcysteine plus intravenous
      hydration is superior to intravenous hydration alone in prevention of CIN in
      patients with chronic renal failure undergoing cardiac catheterization and
      receiving moderate to high doses of intravenous contrast (> 1 cc/kg). Seventy
      three consecutive patients with renal insufficiency who received intravenous
      hydration and 600 mg of acetylcysteine twice a day 24 hr before and the day of
      the cardiac catheterization were compared with 106 consecutive patients who
      received hydration alone. Baseline and 48-hr serum creatinine concentrations were
      compared between the two groups before and after cardiac catheterization.
      Multivariate and univariate analysis were performed to assess the effects of
      acetylcysteine and other clinical variables in the change of serum creatinine
      after the procedure. Both groups had comparable clinical characteristics and
      received similar volumes of intravenous hydration. The volume of contrast used
      was similar for the two groups (2.2 +/- 1.7 vs. 2.3 +/- 1.5 cc/kg; P = 0.67). A
      mean change in serum creatinine of 0.17 +/- 0.54 mg/dl for the acetylcysteine
      group vs. 0.19 +/- 0.40 mg/dl for the control group (P = 0.77) was observed at 48
      hr. The incidence CIN was 13% in the acetylcysteine vs. 12% in the control group
      (P = 0.84). Acetylcysteine, whether analyzed with multivariate or univariate
      analysis, failed to demonstrate a significant effect in the change of serum
      creatinine after cardiac catheterization. In patients with chronic renal
      insufficiency, acetylcysteine in a dose of 600 mg twice a day before and after
      cardiac catheterization, along with intravenous fluids, is as effective as fluids
      alone in the prevention of CIN when moderate to high doses of contrast are used.

PMID- 12594699
TI  - Protection from contrast-induced nephropathy: is the answer in?

PMID- 12594700
TI  - New balloon-thermography catheter for in vivo temperature measurements in human
      coronary atherosclerotic plaques: a novel approach for thermography?
AB  - Although ex vivo studies showed marked thermal heterogeneity in atheromatic
      plaques, in in vivo human studies trivial temperature variations are recorded due
      to the cooling effect of blood flow. We investigated a new balloon-thermogaphy
      catheter for temperature measurements during coronary flow interruption. A
      thermistor probe is positioned at the distal segment of the catheter. At the
      opposite site of the thermistor, a balloon is placed. By inflation of the
      balloon, coronary flow is interrupted. Ten patients with effort angina were
      studied. Coronary flow velocity was continuously recorded. Temperature was
      recorded at the proximal vessel wall and at the lesion before, during, and after
      complete interruption of blood flow by inflation of the balloon. DeltaTp was
      assigned as the difference between the background temperature and the maximal
      temperature during and after balloon inflation. DeltaTl was assigned as the
      difference between the atherosclerotic plaque and the proximal vessel wall. The
      procedure was not complicated. DeltaTp during and after balloon inflation was
      0.01 +/- 0.01 degrees C and -0.003 +/- -0.01 degrees C (P < 0.001), respectively.
      DeltaTl was 0.07 +/- 0.04 degrees C at baseline, 0.17 +/- 0.06 degrees C (59.3%
      +/- 11.8% increase) during, and 0.07 +/- 0.05 degrees C after flow interruption
      (P < 0.001). DeltaTl was greater than DeltaTp during and after impairment of flow
      (P < 0.001). In vivo atherosclerotic plaque temperature recording seems to be
      feasible with this new balloon-thermography catheter. This device may introduce a
      new approach for the detection of thermal heterogeneity in plaques by addressing
      the issue of cooling effect of blood flow.

PMID- 12594701
TI  - In-hospital outcomes of contemporary percutaneous coronary interventions in the
      very elderly.
AB  - Coronary heart disease is the leading cause of death among the elderly (> 65
      years) and the very elderly (> 85 years). Little information is available
      regarding the outcome of very elderly patients referred for PCI in the current
      era of improved techniques, devices, and pharmacotherapy. The objective of the
      current study was to evaluate the clinical characteristics and outcomes of very
      elderly patients > or = 85 years of age in a large, contemporary, multi
      institutional PCI database. Five hospitals in the New York City metropolitan area
      contributed these prospectively defined data elements on consecutive patients
      undergoing PCI from 1 January 1998 to 1 October 1999. Of 10,847 patients, 5,341
      (49%) were younger than 65 years, 3,342 (31%) were 65-74 years, 1,885 (17%) were
      75-84 years, and 279 (2.6%) were at least 85 years of age. Following PCI, the
      very elderly developed stroke (P < 0.001) and renal failure requiring dialysis (P
      = 0.002) more commonly than younger patients following PCI. The very elderly had
      a significantly increased in-hospital mortality rate at 2.5% (P < 0.001).
      However, on multivariate analysis, age > or = 85 years was not an independent
      predictor of in-hospital mortality (OR = 1.22; 95% CI = 0.37-4.07). The very
      elderly should not be refused PCI on the basis of advanced age alone.

PMID- 12594702
TI  - Gadolinium-based percutaneous coronary intervention in a patient with renal
      insufficiency.
AB  - We report the first case of using gadolinium as a contrast agent to perform
      percutaneous coronary intervention in a patient with an acute coronary syndrome
      and a history of renal insufficiency. The procedure was well tolerated without
      any complications or nephrotoxicity. The images obtained with gadolinium were of
      good quality.

PMID- 12594703
TI  - War against the iodinated renal assault.

PMID- 12594704
TI  - Use of filterwire EX for distal embolic protection during complex percutaneous
      coronary interventions: four case studies.
AB  - We describe four successful cases demonstrating the use of a novel filter
      guidewire (FilterWire EX) during complex percutaneous coronary interventions in
      saphenous vein grafts (n = 3) and native coronary artery (n = 1) for prevention
      of distal embolization and consequently myonecrosis.

PMID- 12594705
TI  - Successful treatment of distal coronary guidewire-induced perforation with
      balloon catheter delivery of intracoronary thrombin.
AB  - Distal coronary artery perforation with a coronary guidewire is a relatively rare
      but potentially fatal complication during PTCA. Historically, these types of
      perforations have been easy to control with reversal of heparin anticoagulation
      combined with prolonged distal balloon inflation. In the modern era, with
      widespread use of potent glycoprotein IIb/IIIa inhibitors, this type of distal
      wire perforation has become more difficult to manage and potentially lethal. In
      this article, we report two cases of guidewire-related distal coronary artery
      perforation, successfully treated using a new technique using localized, distal
      intracoronary thrombin injection. During prolonged low-pressure balloon
      inflation, a small dose of thrombin was injected just proximal to the wire
      perforation site via the lumen of a coronary balloon catheter. This approach
      appears to be a relatively rapid and effective way to control this troublesome
      complication.

PMID- 12594706
TI  - Intrapericardial administration of basic fibroblast growth factor: myocardial and
      tissue distribution and comparison with intracoronary and intravenous
      administration.
AB  - Growth factor-induced angiogenesis is being investigated in ischemic heart
      disease. Intracoronary and intravenous delivery are the most practical, but are
      limited by low myocardial uptake and significant systemic recirculation. The
      pericardial space may act as a drug delivery reservoir with increased myocardial
      uptake and reduced systemic toxicities. This study was designed to investigate
      the myocardial and tissue deposition and retention of basic fibroblast growth
      factor (FGF-2) after intrapericardial administration in normal and chronically
      ischemic animals. Twelve Yorkshire pigs were used for the study [six normal and
      six animals with chronic myocardial ischemia (ameroid constrictor on LCx)] with
      bolus intrapericardial administration of (125)I-FGF-2 (25 micro Ci) with 30 micro
      g of cold FGF-2 and 3 mg of heparin. Tissue and myocardial distribution was
      determined at 1 and 24 hr by measuring (125)I-bFGF-specific activity. In
      addition, regional myocardial deposition was determined using (125)I-bFGF
      activity and organ level autoradiography. The heart (pericardium and myocardium)
      accounted for the majority of (125)I-bFGF activity in ischemic animals (30.9% at
      1 hr and 23.9% at 24 hr). Left anterior descending artery territory activity/gm
      of tissue for nonischemic and ischemic animals was 0.01% and 0.01% at 1 hr and
      0.0009% and 0.12% at 24 hr, respectively. LCx territory activity for nonischemic
      and ischemic animals was 0.006% and 0.008% at 1 hr and 0.03% and 0.05% at 24 hr,
      respectively. Endocardial activity was low at all time points. Liver uptake was
      0.47% (nonischemic) and 0.34% (ischemic) at 1 hr and 0.23% (nonischemic) and
      0.54% (ischemic) at 24 hr. Intrapericardial delivery of FGF-2 provides markedly
      higher myocardial deposition and retention and lower systemic recirculation than
      intracoronary or intravenous delivery at the expense of poor subendocardial
      penetration. This limitation, however, did not affect its efficacy.

PMID- 12594707
TI  - I dream of gene(y).

PMID- 12594708
TI  - Fluoroscopic image quality in the film and filmless eras: a standardized
      comparison performed in coronary interventional facilities.
AB  - One hundred and one coronary interventional systems (45 primarily film-based
      predigital systems, labeled group 1; and 56 filmless digital systems, labeled
      group 2) were examined over a 5-year period using a standardized imaging phantom.
      Fluoroscopic image intensifier input dose, high-contrast spatial resolution, low
      contrast sensitivity, and static and dynamic low-contrast resolution were
      assessed under several conditions simulating patient body habitus. The
      distribution of spatial resolutions in group 2 facilities favored higher line
      pair resolution over group 1 (P = 0.01). Contrast sensitivity (smallest-diameter
      hole visualized) was consistently and significantly enhanced with the use of
      digital imaging under both medium (P = 0.001) and large (P = 0.002) patient
      habitus simulations. Low-contrast video resolution (number of wires seen) under
      static (P = 0.007) and dynamic (P = 0.002) conditions was also improved in the
      digital facilities. However, image intensifer input dose was similar in both
      groups (group 1 median dose, 23 mR/min; group 2 median dose, 26 mR/min; P = NS).
      Fluoroscopic spatial resolution in digital filmless laboratories was
      significantly improved when compared to predigital, film-based laboratories. Low
      contrast sensitivity and low- contrast video resolution under both static and
      dynamic conditions were also significantly improved in the digital laboratories.
      Notably, the input dose of radiation required to produce these improved
      fluoroscopic images was similar between groups.

PMID- 12594709
TI  - Approach to manuscript preparation and submission: how to get your paper
      accepted.

PMID- 12594710
TI  - SCAI statement on drug-eluting stents: practice and health care delivery
      implications.

PMID- 12594711
TI  - Prevalence of renal artery stenosis requiring revascularization in patients
      initially referred for coronary angiography.
AB  - To evaluate the prevalence of clinically significant renal artery stenosis (RAS)
      in patients referred for coronary angiography, we analyzed data on 2,439
      consecutive patients. Patients underwent selective renal angiography in
      conjunction with coronary angiography if refractory hypertension (blood pressure
      > 140/90 on two drugs) or flash pulmonary edema was present. A total of 1,089
      renal arteries of 534 patients were evaluated. Twelve percent (137/1,089) of the
      renal arteries in 19% (101/534) of patients had > 70% diameter stenosis in at
      least one vessel. Bilateral renal artery stenosis was present in 26% (26/101) of
      patients. One hundred and thirty-two of the 137 vessels underwent stent
      revascularization due to clinical renovascular hypertension. Acute clinical
      success (< 20% diameter stenosis without death or urgent surgery) was 98%
      (99/101). Due to high prevalence and effective available treatment, we recommend
      routine screening for RAS in all patients with refractory hypertension referred
      for coronary angiography.

PMID- 12594712
TI  - Drive-by renal angiography: searching for an algorithm on an unlighted path.

PMID- 12594713
TI  - Percutaneous closure of a ruptured sinus of Valsalva aneurysm using the Amplatzer
      Duct Occluder.
AB  - Sinus of Valsalva aneurysms are rare congenital anomalies. When they rupture,
      they can lead to the development of biventricular failure as a result of systemic
      pulmonary shunting. Surgical repair has been the traditional treatment for these
      aneurysms. We present a case of a 54 year old man in whom a ruptured sinus of
      Valsalva aneurysm was successfully closed using a catheter-based approach with
      the Amplatzer Duct Occluder.

PMID- 12594714
TI  - Nonsurgical closure of rupture of aneurysm of sinus of Valsalva.

PMID- 12594715
TI  - Treatment of recurrent stroke and pulmonary thromboembolism with percutaneous
      closure of a patent foramen ovale and placement of inferior vena cava filter.
AB  - The association between recurrent episodes of pulmonary embolism, stroke, and
      congenital anomalies of the clotting system features a condition of increased
      risk of recurrences despite anticoagulant therapy. We report the successful
      management of this association with percutaneous closure of the foramen ovale and
      placement of an inferior caval vein filter.

PMID- 12594716
TI  - Instructions for use: instructions for whom?

PMID- 12594717
TI  - BOLD-fMRI response vs. transcranial magnetic stimulation (TMS) pulse-train
      length: testing for linearity.
AB  - PURPOSE: To measure motor and auditory cortex blood oxygenation level-dependent
      (BOLD) functional magnetic resonance imaging (fMRI) response to impulse-like
      transcranial magnetic stimulation (TMS) pulses as a function of train length.
      MATERIALS AND METHODS: Interleaved with fMRI at 1.5 T, TMS pulses 0.3-msec long
      were applied at 1 Hz to the motor cortex area for thumb. Six subjects were
      studied in a TR = 1 second session administering trains of 1, 2, 4, 8, and 16
      pulses, and a TR = 3 seconds session administering trains of 1, 2, 4, 8, 16, and
      24 pulses. A simple hemodynamic model with finite recovery and saturation was
      used to quantitatively characterize the BOLD-fMRI response as a function of train
      length. RESULTS: In both the activations directly induced in motor cortex by TMS
      and the indirect activations in auditory cortex caused by the sound of the TMS
      coil firing, the BOLD-fMRI responses to multiple pulses were well described by a
      summation of single-pulse impulse functions. CONCLUSION: Up to 24 discrete
      pulses, BOLD-fMRI response to 1 Hz TMS in both motor cortex and auditory cortex
      were consistent with a linear increase in amplitude and length with train length,
      possibly suggesting that stimuli of 1 to 2 seconds may be too long to represent
      impulses.

PMID- 12594718
TI  - 1H magnetic resonance spectroscopy in human hydrocephalus.
AB  - PURPOSE: To evaluate cerebral metabolism in clinical hydrocephalus with (1)H
      magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: In 24 children and
      adults with progressive, arrested, or normal pressure hydrocephalus, long-echo
      time (1)H MR spectra were acquired from periventricular white matter and
      intraventricular cerebrospinal fluid (CSF). Metabolite ratios, and the presence
      of lactate, were compared with 38 age-matched controls. RESULTS: Metabolite
      ratios of patients were within the 95% confidence interval (CI) of controls. A
      small lactate resonance was detected in 20% of control and hydrocephalic
      subjects. Lactate was consistently visible in CSF spectra, though lactate
      concentrations were normal. The CSF lactate T(2) was long in comparison with the
      known intracellular metabolite T(2) relaxation times. In three neonates with
      hydrocephalus and spina bifida, 3-hydroxybutyrate was detected in CSF in vivo.
      CONCLUSION: Within the limits of the present methods, (1)H MRS could not detect
      cerebral metabolic abnormalities in human hydrocephalus and provided no
      additional diagnostic information. The long T(2) of lactate in CSF explains its
      high visibility. Hence, the detection of lactate in spectra acquired from voxels
      that contain CSF does not necessarily imply cerebral ischemia.

PMID- 12594719
TI  - Accuracy and reproducibility of manual and semiautomated quantification of MS
      lesions by MRI.
AB  - PURPOSE: To evaluate the accuracy, reproducibility, and speed of two
      semiautomated methods for quantifying total white matter lesion burden in
      multiple sclerosis (MS) patients with respect to manual tracing and to other
      methods presented in recent literature. MATERIALS AND METHODS: Two methods
      involving the use of MRI for semiautomated quantification of total lesion burden
      in MS patients were examined. The first method, geometrically constrained region
      growth (GEORG), requires user specification of lesion location. The second
      technique, directed multispectral segmentation (DMSS), requires only the location
      of a single exemplar lesion. Test data sets included both clinical MS data and MS
      brain phantoms. RESULTS: The mean processing times were 60 minutes for manual
      tracing, 10 minutes for region growth, and 3 minutes for directed segmentation.
      Intra- and interoperator coefficients of variation (CVs) were 5.1% and 16.5% for
      manual tracing, 1.4% and 2.3% for region growth, and 1.5% and 5.2% for directed
      segmentation. The average deviations from manual tracing were 9% for region
      growth and 5.7% for directed segmentation. CONCLUSION: Both semiautomated methods
      were shown to have a significant advantage over manual tracing in terms of speed
      and precision. The accuracy of both methods was acceptable, given the high
      variability of the manual results.

PMID- 12594720
TI  - On the synchronization of transcranial magnetic stimulation and functional echo
      planar imaging.
AB  - PURPOSE: To minimize artifacts in echo-planar imaging (EPI) of human brain
      function introduced by simultaneous transcranial magnetic stimulation (TMS).
      MATERIALS AND METHODS: Distortions due to TMS pulses (0.25 msec, 2.0 T) were
      studied at 2.0 T before and during EPI. RESULTS: Best results were obtained if
      both the EPI section orientation and the frequency-encoding gradient were
      parallel to the plane of the TMS coil. Under these conditions, a TMS pulse caused
      image distortions when preceding the EPI sequence by less than 100 msec.
      Recordings with a magnetic field gradient pick-up coil revealed transient
      magnetic fields after TMS, which are generated by eddy currents in the TMS coil.
      TMS during image acquisition completely spoiled all transverse magnetizations and
      induced disturbances ranging from image corruption to mild image blurring,
      depending on the affected low and high spatial frequencies. Simultaneous TMS and
      radio-frequency (RF) excitation gave rise to T1-dependent signal changes that
      lasted for several seconds and yielded pronounced false-positive activations
      during functional brain mapping. CONCLUSION: To ensure reliable and robust
      combinations, TMS should be applied at least 100 msec before EPI while completely
      avoiding any pulses during imaging.

PMID- 12594721
TI  - MRI-guided access to the retropharynx.
AB  - PURPOSE: To describe MR-guided access to the retropharynx for precise fine-needle
      aspiration cytology (FNAC), and other indications for needle placement. MATERIALS
      AND METHODS: A retrospective review was made of 15 procedures that had been
      performed on 14 patients. These patients had a retropharyngeal mass on MRI and
      had undergone MR-guided minimally invasive access to the retropharynx for either
      diagnostic or therapeutic intervention in the period of October 1989 to January
      2000. RESULTS: All 14 patients underwent MR-guided access to the retropharynx for
      FNAC without immediate or delayed complications. MRI confirmed that the biopsy
      needle was within the retropharyngeal mass in all patients. MR-guided FNAC
      revealed five true-positive, five true-negative, four indeterminate, and no false
      positive cases. Ten of the 14 patients (71%) had diagnostic aspirations. In one
      patient with retropharyngeal extension of carcinoma, an MR-guided approach was
      used for the experimental interstitial laser therapy (ILT). CONCLUSION: The
      results suggest that an MR-guided retromandibular approach to biopsy of
      retropharyngeal mass is minimally invasive and safe.

PMID- 12594722
TI  - Normal human left and right ventricular dimensions for MRI as assessed by turbo
      gradient echo and steady-state free precession imaging sequences.
AB  - PURPOSE: To establish normal ranges of left ventricular (LV) and right
      ventricular (RV) dimensions as determined by the current pulse sequences in
      cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: Sixty normal
      subjects (30 male and 30 female; age range, 20-65) were examined; both turbo
      gradient echo (TGE) and steady-state free precession (SSFP) pulse sequences were
      used to obtain contiguous short-axis cine data sets from the ventricular apex to
      the base of the heart. The LV and RV volumes and LV mass were calculated by
      modified Simpson's rule. RESULTS: Normal ranges were established and indexed to
      both body surface area (BSA) and height. There were statistically significant
      differences in the measurements between the genders and between TGE and SSFP
      pulse sequences. For TGE the LV end-diastolic volume (EDV)/BSA (mL/m(2)) in males
      was 74.4 +/- 14.6 and in females was 70.9 +/- 11.7, while in SSFP in males it was
      82.3 +/- 14.7 and in females it was 77.7 +/- 10.8. For the TGE the LV mass/BSA
      (g/m(2)) in males was 77.8 +/- 9.1 and in females it was 61.5 +/- 7.5, while in
      SSFP in males it was 64.7 +/- 9.3 and in females it was 52.0 +/- 7.4. For TGE the
      RV EDV/BSA (mL/m(2)) in males was 78.4 +/- 14.0 and in females it was 67.5 +/-
      12.7, while in SSFP in males it was 86.2 +/- 14.1 and in females it was 75.2 +/-
      13.8. CONCLUSION: We have provided normal ranges that are gender specific as well
      as data that can be used for age-specific normal ranges for both SSFP and TGE
      pulse sequences.

PMID- 12594723
TI  - Time-resolved contrast-enhanced pulmonary MR angiography using sensitivity
      encoding (SENSE).
AB  - PURPOSE: To evaluate the relationship between gadolinium concentration and signal
      to-noise ratio (SNR) on sensitivity encoding (SENSE) images, and determine the
      appropriate bolus injection protocol for visualizing pulmonary circulation.
      MATERIALS AND METHODS: Eighteen different gadolinium concentration phantoms (0,
      0.01, 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.5, 2.0, 5.0, 10.0, 20.0, 30.0,
      50.0, and 100.0 mmol/L) were analyzed to determine the relationship between
      gadolinium concentration and SNR on SENSE images in a phantom study. In an in
      vivo study, 3 mL (protocol A) or 6 mL (protocol B) of Gd-DTPA BMA at 3 mL/second,
      and 5 mL of Gd-DTPA BMA at 5 mL/second (protocol C) were administered to eight
      normal volunteers for contrast-enhanced (CE) pulmonary MR angiography (MRA) with
      SENSE. The peak SNRs of pulmonary parenchyma and the difference in SNR between
      pulmonary artery (PA) and pulmonary vein (PV) at peak SNR in the PA were
      statistically evaluated. RESULTS: For each flip angle at each gadolinium
      concentration, the SNRs and contrast-to-noise ratios (CNRs) of the SENSE images
      were significantly lower than those acquired with a nonparallel imaging technique
      (P < 0.05). The peak SNR of the pulmonary parenchyma, and differences in SNR
      between the PA and PV at the peak SNR of the PA obtained with a 5-mL/second bolus
      injection protocol were found to be significantly higher than those obtained with
      other protocols (P < 0.05). CONCLUSION: 3D-CE-MRA using SENSE demonstrated
      linearity between gadolinium concentration and SNR, and resulted in MRA with high
      spatial and temporal resolution with the aid of a sharp bolus injection protocol.

PMID- 12594724
TI  - Breast cancer detection in gadolinium-enhanced MR images by static region
      descriptors and neural networks.
AB  - PURPOSE: To automate the diagnosis of malignancy by classifying breast tissues as
      negative or positive for malignancy in gadolinium-enhanced dynamic magnetic
      resonance (MR) images, using static region descriptors and a neural network
      classifier. MATERIALS AND METHODS: We propose a novel approach whereby the
      classifier evaluates a number of parameters that identify important tumor
      characteristics, as obtained by digital image processing techniques. These
      parameters include static signal intensity (SI) after contrast enhancement, mass
      margin descriptors, evaluation of mass shape by calculation of eccentricity, mass
      size, and mass granularity by texture analysis. Datasets for 14 patients were
      obtained by use of the 1.5T PMRTOW Clinical Imager. RESULTS: Statistical
      performance evaluation of the neural networks indicated 90%-100% sensitivity, 91%
      100% specificity, and 91%-100% accuracy. CONCLUSION: Although this work is
      preliminary, it may reduce overall health-care time and costs, and enable higher
      accuracy in automated breast cancer detection systems.

PMID- 12594725
TI  - Comparison of MR and PET imaging for the evaluation of liver metastases.
AB  - PURPOSE: To compare the accuracy of fluoro-18-deoxyglucose positron emission
      tomography (FDG-PET) and dynamic-enhanced magnetic resonance imaging (MRI) scans
      in the diagnosis of liver metastatic lesions from colon and other sources.
      MATERIALS AND METHODS: Thirty consecutive patients with known or suspected
      metastatic lesions were scanned by both MRI and PET. Histopathology and/or
      clinical outcome, including cross-sectional imaging follow up, were used as a
      gold standard. RESULTS: Of 30 patients, 16 were positive by pathology and/or
      clinical outcome and 14 were negative for liver metastases. The sensitivity,
      specificity, and positive and negative predictive values on MRI were 85.7%, 100%,
      100%, and 89%, respectively, compared to 71%, 93.7%, 90.9%, and 79% on FDG-PET.
      The difference between the two methods was not significant (X(2) = 0.2, P >
      0.05). CONCLUSION: Our study showed no significant difference in detection of
      liver metastases using MRI or FDG-PET. However, MRI has advantages in spatial
      resolution and lesion characterization.

PMID- 12594726
TI  - Lipid content in the musculature of the lower leg assessed by fat selective MRI:
      intra- and interindividual differences and correlation with anthropometric and
      metabolic data.
AB  - PURPOSE: To assess the muscular lipid content (LC) in different muscle groups of
      the lower leg by a magnetic resonance imaging technique working with chemical
      shift selective excitation, and comparison with anthropometric and metabolic
      data. MATERIALS AND METHODS: Examinations were performed in 67 volunteers (54
      male/13 female, age 29 +/- seven years) on a 1.5 T whole body imager, applying a
      highly selective spectral-spatial technique for fat selective MRI. LC was
      measured in six calf muscles and correlated with body mass index (BMI), percent
      body fat (PFAT), and insulin sensitivity (IS) of the subjects. RESULTS: Mean
      muscular LC of all subjects was between 2.0% (Tibialis posterior [TP]) and 3.8%
      (Peroneus muscles) with female subjects showing a significantly higher LC in all
      muscle groups (P < 0.05 each). LCs correlated moderately with BMI (R between 0.39
      [TP] and 0.53 [GM]) and with PFAT (R between 0.38 [TP] and 0.62 [GM]). Insulin
      resistant subjects showed slightly but not significantly increased LC compared to
      insulin-sensitive subjects in BMI-matched subgroups. CONCLUSION: The fat
      selective MRI technique allows a reliable non-invasive measure of muscular lipids
      - even in muscle groups with inherent low LC - within a relatively short
      measurement time of about three minutes. The presented data reveal interesting
      interrelationships between LC and anthropometric and metabolic data, and
      therefore provide new insight into muscular fat metabolism.

PMID- 12594727
TI  - T2 quantitation of articular cartilage at 1.5 T.
AB  - PURPOSE: To evaluate sources of error when using a multiecho sequence for
      quantitative T2 mapping of articular cartilage at 1.5 T. MATERIALS AND METHODS:
      Phantom measurements were used to assess the contribution of stimulated echoes to
      inaccuracy of T2 measurements in cartilage using a multiecho sequence. Five
      volunteer studies compared in vivo single-echo spin echo results to multiecho,
      single-slice and multiecho, multislice acquisitions for assessment of both the
      stimulated echo and magnetization transfer contrast (MTC) contributions to T2
      measurement inaccuracy. RESULTS: Phantom experiments demonstrated that
      substantial inaccuracy (10%-13% longer T2 values) is introduced from stimulated
      echoes with a multiecho sequence with slice-selective refocusing pulses. The in
      vivo volunteer studies also demonstrated increases in measured T2 by up to 48%
      with a multiecho sequence. Use of the multiecho sequence in the multislice mode
      resulted in T2 values closer to the single-echo standards for the volunteer
      studies. However, this apparent increased accuracy should be regarded as
      circumstantial, as it only occurs because the error due to MTC has the opposite
      sign compared to the error due to the stimulated echo contribution. CONCLUSION:
      Use of a multiecho, multislice sequence for cartilage T2 measurements should be
      undertaken with the caution that substantial inaccuracy is introduced from
      stimulated echoes and MTC.

PMID- 12594728
TI  - Imaging the physical and morphological properties of a multi-zone young articular
      cartilage at microscopic resolution.
AB  - PURPOSE: To characterize a number of physical and morphologic properties of young
      articular cartilage. These properties include the anisotropy of T(2) relaxation,
      optical retardation, orientation of the collagen fibrils, total thickness of the
      tissue, number of histologic sub-zones in the tissue, width of individual sub
      zones, and correlation between the depths of the local T(2) maxima and the local
      retardation minima. MATERIALS AND METHODS: Microscopic magnetic resonance imaging
      (mciro MRI) and polarized light microscopy (PLM) were used to examine three side
      by-side specimens from a humeral head of a three-month-old beagle that exhibited
      a unique topographic heterogeneity from three-zones centrally to multi-zone
      peripherally. RESULTS: The centrally located specimen showed that the collagen
      fibrils across the tissue depth have a pattern of the classic three histologic
      sub-zones (tangential, transitional, and radial). A much more complicated multi
      zone structure was found in the specimen located peripherally, with a second
      transitional zone and a second tangential zone located at the deep part of the
      tissue. We also showed that the orientation of the collagen fibrils that form the
      cocoon-shaped territorial matrix surrounding the clusters of chondrocytes can be
      imaged by our PLM technique. CONCLUSION: The results from the young animal in
      this report, together with our observations from older animals, demonstrate that
      MRI and PLM can be used to study the epiphyseal expansion of cartilage in young
      animals during its growth and subsequent loss in older animals. An illustrative
      model for the structure of collagen fibrils in a humeral head is suggested as an
      extension to the classic three-zone model for young articular cartilage.

PMID- 12594729
TI  - Investigating the stimulus-dependent temporal dynamics of the BOLD signal using
      spectral methods.
AB  - PURPOSE: To compare several spectral parameters using different durations of
      visual hemifield stimulation in order to explore the different temporal behavior
      of the blood oxygenation-level dependent (BOLD) signal in various brain regions.
      MATERIALS AND METHODS: Spectral methods were applied to three different groups of
      subjects with visual stimulation lasting 6, 12, and 30 seconds. Furthermore,
      diffusion weighting was applied in an interleaved way. The core of the data
      processing was the computation of the spectral density matrix using the
      multidimensional weighted covariance estimate. Spectral parameters of coherence
      and phase shift were computed. RESULTS: The correlation between signal changes
      and phase shifts was dependent on the duration of the visual stimulation. The
      shorter the duration of visual stimulation, the stronger the correlation between
      percentage signal change and phase shift. CONCLUSION: The experiments with short
      and long stimuli differed mainly in the distribution of the activated voxels in
      the plane of percentage signal change and phase shift. It was revealed that the
      height of the signal change depends on the phase shift, whereas the diffusion
      weighting has no influence.

PMID- 12594732
TI  - HSP27 is markedly induced in Schwann cell columns and associated regenerating
      axons.
AB  - It is well known that regenerating axons enter Schwann cell (SC) columns, within
      which they grow to reinnervate the appropriate targets. The current study
      detected a marked induction of a 27-kDa heat shock protein (HSP27) in the SC
      columns of crush-injured rat sciatic nerves. Immunohistochemical studies showed
      the first appearance of strong HSP27-immunoreactive linear structures in the
      proximal stump near an injury site 7 h after an operation. The HSP27
      immunoreactive linear structures crossed the injury site to the distal stump 2
      days after the operation. They then extended in a more proximal and more distal
      direction and were found to have propagated through the entire length of the
      nerve 1 week after the operation. This pattern of expression was maintained until
      3 weeks after the operation. Double-immunofluorescent labeling and confocal laser
      microscopy confirmed that the linear structures consisted of SC columns and
      associated multiple axons. The HSP27-immunoreactive SC columns expressed glial
      fibrillary acidic protein, but not S-100 protein. Electron microscopy and
      immunoelectron microscopy demonstrated that reactive Schwann cells (SCs) and the
      associated axons with an outgrowing profile exhibited a strong immunoreactivity
      to HSP27, with the former containing a greater number of bundles of intermediate
      filaments. It is suggested that HSP27 may play an essential role in axonal
      outgrowth, especially by contributing to cytoskeletal dynamics in SCs.

PMID- 12594733
TI  - AMPA/kainate receptors in mouse spinal cord cell-specific display of receptor
      subunits by oligodendrocytes and astrocytes and at the nodes of Ranvier.
AB  - Spinal cord white matter is susceptible to AMPA/kainate (KA)-type glutamate
      receptor-mediated excitotoxicity. To understand this vulnerability, it is
      important to characterize the distribution of AMPA/KA receptor subunits in this
      tissue. Using immunohistochemistry and laser confocal microscopy, we studied the
      expression sites of AMPA/KA receptor subunits in mouse spinal cord. The white
      matter showed consistent immunoreactivity for AMPA receptor subunit GluR2/3 and
      KA receptor subunits GluR6/7 and KA2. In contrast, antibodies against GluR1,
      GluR2, GluR4 (AMPA), and GluR5 (KA) subunits showed only weak and occasional
      labeling of white matter. However, gray matter neurons did express GluR1 and
      GluR2, as well as GluR2/3. The white matter astrocytes were GluR2/3 and GluR6/7
      immunopositive, while the gray matter astrocytes displayed primarily GluR6/7.
      Both exclusively and abundantly, KA2 labeled oligodendrocytes and myelin,
      identified by CNPase expression. Interestingly, myelin basic protein, another
      myelin marker, showed less correlation with KA2 expression, placing KA2 at
      specific CNPase-containing subdomains. Focal points of dense KA2 labeling showed
      colocalization with limited, but distinct, axonal regions. These regions were
      identified as nodes of Ranvier by coexpressing the nodal marker, ankyrin G.
      Overall, axonal tracts showed little, if any, AMPA/KA receptor expression. The
      proximity of oligodendrocytic KA2 to the axonal node and the paucity of axonal
      AMPA/kainate receptor expression suggest that excitotoxic axonal damage may be
      secondary and, possibly, mediated by oligodendrocytes. Our data demonstrate
      differential expression of glutamate AMPA and KA receptor subunits in mouse
      spinal cord white matter and point to astrocytes and oligodendrocytes as
      potential targets for pharmacological intervention in white matter glutamate
      excitotoxicity.

PMID- 12594734
TI  - High-molecular-weight tropomyosins localize to the contractile rings of dividing
      CNS cells but are absent from malignant pediatric and adult CNS tumors.
AB  - Tropomyosin has been implicated in the control of actin filament dynamics during
      cell migration, morphogenesis, and cytokinesis. In order to gain insight into the
      role of tropomyosins in cell division, we examined their expression in developing
      and neoplastic brain tissue. We found that the high-molecular-weight tropomyosins
      are downregulated at birth, which correlates with glial cell differentiation and
      withdrawal of most cells from the cell cycle. Expression of these isoforms was
      restricted to proliferative areas in the embryonic brain and was absent from the
      adult, where the majority of cells are quiescent. However, they were induced
      under conditions where glial cells became proliferative in response to injury.
      During cytokinesis, these tropomyosin isoforms were associated with the
      contractile ring. We also investigated tropomyosin expression in neoplastic CNS
      tissues. Low-grade astrocytic tumors expressed high-molecular-weight
      tropomyosins, while highly malignant CNS tumors of diverse origin did not (P </=
      0.001). Furthermore, high-molecular-weight tropomyosins were absent from the
      contractile ring in highly malignant astrocytoma cells. Our findings suggest a
      role for high-molecular-weight tropomyosins in astrocyte cytokinesis, although
      highly malignant CNS tumors are still able to undergo cell division in their
      absence. Additionally, the correlation between high-molecular-weight tropomyosin
      expression and tumor grade suggests that tropomyosins are potentially useful as
      indicators of CNS tumor grade.

PMID- 12594735
TI  - Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia.
AB  - We assessed the effects of soluble molecules (supernatants) produced by pro-
      (Th1) and anti- (Th2) inflammatory T-cell lines on the capacity of adult human
      CNS-derived microglia to express or produce selected cell surface and soluble
      molecules that regulate immune reactivity or impact on tissue protection/repair
      within the CNS. Treatment of microglia with supernatants from allo-antigen and
      myelin basic protein-specific Th1 cell lines augmented expression of cell surface
      molecules MHC class II, CD80, CD86, CD40, and CD54, enhanced the functional
      antigen-presenting cell capacity of microglia in a mixed lymphocyte reaction, and
      increased cytokine/chemokine secretion (TNFalpha, IL-6, and CXCL10/IP-10). These
      Th1-induced effects were not reproduced by interferon-gamma (IFNgamma) alone and
      were only incompletely blocked by anti-IFNgamma antibody. Th2 cell supernatant
      treatments did not alter costimulatory/adhesion molecule expression or induce
      cytokine/chemokine production by microglia. Th2 treatment, furthermore, failed to
      reduce the induction observed in response to Th1 supernatants. Neither Th1 nor
      Th2 supernatants induced production of the neurotrophin molecules, nerve growth
      factor, or brain-derived neurotrophic factor. Our results suggest that soluble
      molecules released by Th1 and not Th2 cells that infiltrate the CNS can stimulate
      resident microglia to acquire enhanced effector and accessory cell functions; the
      Th1-induced effects were not downregulated by Th2 supernatant-mediated bystander
      suppression.

PMID- 12594736
TI  - Protective effect of glial cells against lipopolysaccharide-mediated blood-brain
      barrier injury.
AB  - Numerous infections of the central nervous system are characterized by altered
      blood-brain barrier (BBB) functions leading to brain damage. To study the
      mechanisms that cause BBB disruption in these pathologies, we used an in vitro
      BBB model consisting of a coculture of brain capillary endothelial cells and
      glial cells. When these endothelial cells were submitted alone to
      lipopolysaccharide (LPS), added in the luminal compartment, a huge increase in
      the paracellular permeability of the monolayer was observed. As glial cells
      surrounding the brain capillaries are of prime importance in specifying at least
      some cellular properties, we investigated whether glial cells would be able to
      modulate this endothelial cell response to LPS. When endothelial cells were
      incubated with LPS added luminally, in the presence of glial cells, LPS
      surprisingly had no effect on the endothelial cell monolayer permeability,
      suggesting a protective effect of glial cells on the LPS-mediated injury. As in
      our experiments, the endotoxin does not interact with the glial cell population.
      This protective effect suggests a close communication between cerebral
      endothelial cells and brain parenchymal cells. In our coculture model, the glial
      cell population is a mixture of astrocytes, oligodendrocytes, and microglial
      cells. Further experiments performed with purified astrocytes showed that
      microglial cells or oligodendrocytes, or both, are essential for the complete
      protection of the endothelial cell monolayer integrity. All these results are
      direct evidence for a modulatory effect of glial cells on brain capillary
      endothelial cell response in the pathogenesis of endotoxemia.

PMID- 12594737
TI  - Lentiviral vectors for gene delivery to normal and demyelinated white matter.
AB  - Lentiviral vectors are increasingly used for gene delivery to neurons and in
      experimental models of neurodegeneration. Their use in gene delivery to white
      matter and their potential value in preventing or repairing CNS demyelination has
      received less attention. Here we show using a VSV-G-pseudotyped HIV-derived
      vector expressing the marker gene LacZ that lentiviral vectors transduce the
      major macroglial cell types present in normal white matter (astrocytes,
      oligodendrocytes, and oligodendrocyte progenitors). Injection of lentiviral
      vectors causes an inflammatory response at the injection site characterized by
      OX42(+) and ED1(+) macrophages, but only a few CD8(+) and no CD4(+) lymphocytes,
      and mild demyelination. Injection of lentiviral vectors into areas of toxin
      induced demyelination resulted in significant numbers of cells expressing the
      marker gene and was a more effective means of gene delivery than was a LacZ
      expressing murine retroviral vector.

PMID- 12594738
TI  - Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and
      activity in C6 glioma cells.
AB  - The synthetic glucocorticoid dexamethasone is routinely used to stabilize
      patients with malignant gliomas. One putative target for glucocorticoid action is
      inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as
      well as the host immune cells. In this study, we characterize the stimulatory
      effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor-alpha
      (TNFalpha), as well as the inhibitory effect of glucocorticoids, on iNOS gene
      expression and activity in C6 glioma cells cultured in vitro. LPS significantly
      increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased
      with time up to 72 h. Although TNFalpha alone induced neither iNOS mRNA
      expression nor nitrite formation, it significantly potentiated the effect of LPS
      on both. iNOS activity induced by LPS with or without TNFalpha was dose
      dependently inhibited by dexamethasone, reaching a maximum of approximately 83%
      inhibition. This was completely reversed by the addition of RU38486, an
      antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA
      expression; however, the maximum inhibition obtained was only 10%. These results
      suggest that as for induction of iNOS activity in C6 cells in vitro, the
      stimulatory effect of LPS is mainly due to an action at the transcriptional
      level. TNFalpha does not have intrinsic inducing activity, but has potentiating
      effects at the transcriptional and possibly at the posttranscriptional levels in
      the presence of LPS. The inhibitory effect of dexamethasone is GR-mediated and is
      mainly due to action at the posttranscriptional level.

PMID- 12594739
TI  - Diffusion parameters of the extracellular space in human gliomas.
AB  - Tumor cell migration through the extracellular space (ECS) might be affected by
      its pore size and extracellular matrix molecule content. ECS volume fraction
      alpha (alpha = ECS volume/total tissue volume), tortuosity lambda (lambda(2) =
      free/apparent diffusion coefficient) and nonspecific uptake k' were studied by
      the real-time tetramethylammonium method in acute slices of human tissue. The
      diffusion parameters in temporal cortical tissue resected during surgical
      treatment of temporal lobe epilepsy (control) were compared with those in brain
      tumors. Subsequently, tumor slices were histopathologically classified according
      to the grading system of the World Health Organization (WHO), and proliferative
      activity was assessed. The average values of alpha, lambda, and k' in control
      cortex were 0.24, 1.55, and 3.66 x 10(-3)s(-1), respectively. Values of alpha,
      lambda, and k' in oligodendrogliomas did not significantly differ from controls.
      In pilocytic astrogliomas (WHO grade I) as well as in ependymomas (WHO grade II),
      alpha was significantly higher, while lambda and k' were unchanged. Higher values
      of alpha as well as lambda were found in low-grade diffuse astrocytomas (WHO
      grade II). In cellular regions of high-grade astrocytomas (WHO grade III and IV),
      alpha and lambda were further increased, and k' was significantly larger than in
      controls. Classic medulloblastomas (WHO grade IV) had an increased alpha, but not
      lambda or k', while in the desmoplastic type alpha and k' remained unchanged, but
      lambda was greatly increased. Tumor malignancy grade strongly corresponds to an
      increase in ECS volume, which is accompanied by a change in ECS structure
      manifested by an increase in diffusion barriers for small molecules.

PMID- 12594740
TI  - Functional characterization of mannose receptor expressed by immunocompetent
      mouse microglia.
AB  - The mannose receptor is a pattern-recognition receptor involved in innate and
      adaptive immunity. The receptor is mainly expressed by macrophages and, within
      the brain, by astrocytes and microglia. This study reports for the first time the
      effects of two classical proinflammatory (interferon-gamma, IFNgamma) and anti
      inflammatory (interleukin-4, IL-4) cytokines on the levels of expression and
      activity of the mannose receptor expressed by mouse microglia, the brain resident
      macrophages. As observed for macrophages, IFNgamma treatment led to a decrease
      and IL-4 to an increase of mannose receptor expression. Consequently, the rates
      of pinocytosis were strongly upregulated by IL-4 and inhibited by IFNgamma. This
      latter, however, resumed with time and reached again the constitutive rate of
      pinocytosis. This recovery resulted from an increased pinocytic activity of the
      few mannose receptor molecules still expressed by IFNgamma-treated microglia.
      This may suggest a brain-specific regulation of the effects of IFNgamma since
      such a phenomenon has not been observed in macrophages. Together, these
      observations demonstrate that cytokine-stimulated immunocompetent microglia
      express a functional mannose receptor.

PMID- 12594742
TI  - Dynamic shim updating (DSU) for multislice signal acquisition.
AB  - Dynamic shim updating (DSU) is a technique for achieving optimal magnetic field
      homogeneity over extended volumes by dynamically updating an optimal shim setting
      for each individual slice in a multislice acquisition protocol. Here the
      practical implementation of DSU using all first- and second-order shims is
      described. In particular, the hardware modifications and software requirements
      are demonstrated. Furthermore, the temporal effects of dynamically switching shim
      currents are investigated and a Z(2)-to-Z(0) compensation unit is described and
      implemented to counteract the temporal Z(0) variations following a change in the
      Z(2) shim current. The optimal shim settings for all slices are determined with a
      quantitative and user-independent, multislice phase-mapping sequence. The
      performance of DSU is evaluated from multislice phase maps and spectroscopic
      images acquired on rat brain in vivo. DSU improved the magnetic field homogeneity
      over all spatial slices, with a more pronounced effect on the slices positioned
      away from the magnet isocenter, thereby making the magnetic field homogeneity
      highly uniform over an extended volume.

PMID- 12594741
TI  - MR molecular imaging of the Her-2/neu receptor in breast cancer cells using
      targeted iron oxide nanoparticles.
AB  - MR molecular imaging is an exciting new frontier in the biomedical applications
      of MR. One of the clinically relevant targets is the tyrosine kinase Her-2/neu
      receptor, which has a significant role in staging and treating breast cancer. In
      this study Her-2/neu receptors were imaged in a panel of breast cancer cells
      expressing different numbers of the receptors on the cell membrane. Commercially
      available streptavidin-conjugated superparamagnetic nanoparticles were used as
      targeted MR contrast agent. The nanoparticles were directed to receptors
      prelabeled with a biotinylated monoclonal antibody and generated strong T(2) MR
      contrast in Her-2/neu-expressing cells. The contrast observed in MR images was
      proportional to the expression level of Her-2/neu receptors determined
      independently with FACS analysis. In these experiments, iron oxide nanoparticles
      were attached to the cell surface and were not internalized into the cells, which
      is a major advantage for in vivo applications of the method.

PMID- 12594744
TI  - Mapping fiber orientation in human muscle by proton MR spectroscopic imaging.
AB  - Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) was used to determine
      muscle fiber orientations in human calf muscles. The method is based on the fact
      that some resonances show orientation-dependent dipolar splitting, caused by
      incomplete motional averaging. This leads to proton spectra that depend strongly
      on the angle between muscle fibers and the magnetic field B(0). The orientation
      dependent dipolar splittings were mapped using a fit with a basis set of
      predefined coupling patterns reflecting the fiber orientation. The fitted
      coupling patterns were displayed as images and assigned to different muscles
      based on segmented MR images. They showed gross differences in fiber orientation
      between some muscles, including m. soleus and m. tibialis anterior, for all
      subjects. In addition, smaller but significant differences between subjects were
      detected, which could be due to localization differences or real interindividual
      differences. Since dipolar splitting affects metabolite intensities, it is
      important to take this effect into account when calculating metabolite
      concentrations from MR spectra in muscle tissue. Spatial maps of the MR signals
      of trimethyl-ammonium groups and creatine/ phosphocreatine revealed significant
      differences in intensity between muscles.

PMID- 12594743
TI  - Myocardial triglycerides and systolic function in humans: in vivo evaluation by
      localized proton spectroscopy and cardiac imaging.
AB  - Recent experimental data suggest that adiposity directly damages the heart by
      promoting ectopic deposition of triglyceride, a process known as myocardial
      steatosis. The goal of this study was to develop and validate proton magnetic
      resonance spectroscopy ((1)H MRS) as an in vivo tool to measure myocardial lipid
      content. Complementary studies in rat tissue ex vivo and in 15 healthy humans in
      vivo provided evidence that (1)H MRS constitutes a reproducible technique for the
      measurement of myocardial triglyceride. In myocardial tissue from Zucker rats,
      the (1)H MRS measurement of triglyceride matched that obtained by biochemical
      measurement (P < 0.001). In human subjects triglyceride was evident in the hearts
      of even the very lean individuals and was elevated in overweight and obese
      subjects. Increased myocardial triglyceride content was accompanied by elevated
      LV mass and suppressed septal wall thickening as measured by cardiac imaging.

PMID- 12594745
TI  - Functional magnetic resonance imaging of the human brain based on signal
      enhancement by extravascular protons (SEEP fMRI).
AB  - Functional magnetic resonance imaging (fMRI) studies of the human brain were
      carried out at 3 Tesla to investigate an fMRI contrast mechanism that does not
      arise from the blood oxygen-level dependent (BOLD) effect. This contrast
      mechanism, signal enhancement by extravascular protons (SEEP), involves only
      proton-density changes and was recently demonstrated to contribute to fMRI signal
      changes in the spinal cord. In the present study it is hypothesized that SEEP
      fMRI can be used to identify areas of neuronal activity in the brain with as much
      sensitivity and precision as can be achieved with BOLD fMRI. A detailed analysis
      of the areas of activity, signal intensity time courses, and the contrast-to
      noise ratio (CNR), is also presented and compared with the BOLD fMRI results.
      Experiments were carried out with subjects performing a simple finger-touching
      task, or observing an alternating checkerboard pattern. Data were acquired using
      a conventional BOLD fMRI method (gradient-echo (GE) EPI, TE = 30 ms), a
      conventional method with reduced BOLD sensitivity (GE-EPI, TE = 12 ms), and SEEP
      fMRI (spin-echo (SE) EPI, TE = 22 ms). The results of this study demonstrate that
      SEEP fMRI may provide better spatial localization of areas of neuronal activity,
      and a higher CNR than conventional BOLD fMRI, and has the added benefit of lower
      sensitivity to field inhomogeneities.

PMID- 12594746
TI  - Mechanism of magnetization transfer during on-resonance water saturation. A new
      approach to detect mobile proteins, peptides, and lipids.
AB  - The mechanism of magnetization transfer (MT) between water and components of the
      proton spectrum was studied ex vivo in a perfused cell system and in vivo in the
      rat brain (n = 5). Water was selectively labeled and spectral buildup
      consequential to transfer of longitudinal magnetization was followed as a
      function of time. At short mixing time (T(m)), nitrogen-bound solvent
      exchangeable protons were observed, predominantly assigned to amide groups of
      proteins and peptides. At longer T(m), intramolecular nuclear Overhauser
      enhancement (NOE) was observed in the aliphatic proton region, leading to a
      mobile-macromolecule-weighted spectrum that resembles typical protein spectra
      described in the literature. This effect on the proton spectrum is distinct from
      that of classical off-resonance MT, which has been shown to be due to the
      immobile solid-like proton pool. When studying a solution of major brain
      metabolites under physiological concentrations and conditions (pH), no transfer
      effects were observed, in line with expectations based on reduced NOE effects in
      rapidly tumbling molecules and the fast proton exchange rates of amino, amine,
      SH, and OH groups. The spectral intensities of the amide protons may serve as
      indicators for pH and cellular levels of mobile proteins and peptides, while the
      aliphatic components are representative of several types of mobile
      macromolecules, including proteins, peptides, and lipids.

PMID- 12594747
TI  - Effects of equilibrium exchange on diffusion-weighted NMR signals: the
      diffusigraphic "shutter-speed".
AB  - A general picture is presented of the implications for diffusion-weighted NMR
      signals of the parsimonious two-site-exchange (2SX) paradigm. In particular, it
      is shown that the diffusigraphic "shutter-speed," tau(-1) identical with
      |q(2)(D(A) - D(B))|, is a useful concept. The "wave-number" q has its standard
      definition (given in the text), and D(A) and D(B) are the apparent diffusion
      coefficients (ADCs) of molecules in the two "sites," A and B, if there is no
      exchange between them. At low gradient strengths (center of q-space), tau(-1) is
      less than rate constants for intercompartmental water molecule exchange in most
      tissue cases. Thus, the exchange reaction appears fast. However, q is increased
      during the course of most experiments and, as it is, the shutter-speed becomes
      "faster" and the exchange reaction, the kinetics of which do not change, appears
      to slow down. This causes a multiexponential behavior in the diffusion-weighting
      dimension, b, which also has its standard definition. This picture is found to be
      in substantial agreement with a number of different experimental observations. It
      is applied here to literature (1)H(2)O data from a yeast cell suspension and from
      the human and the rat brain. Since the equilibrium transcytolemmal water exchange
      reaction appears to be in the fast-exchange-limit at small b, the initial slope
      represents the weighted-average of the ADCs of intra- and extracellular water. Of
      course, in tissue the former is in the significant majority. Furthermore, a
      consideration of reasonable values for the other 2SX parameters suggests that,
      for resting brain tissue, the intracellular water ADC may be larger than the
      extracellular water ADC. There are some independent inferences of this, which
      would have ramifications for many applications of diffusion-weighted MRI.

PMID- 12594748
TI  - Macrophage labeling by SPIO as an early marker of allograft chronic rejection in
      a rat model of kidney transplantation.
AB  - Anatomical and functional information (renography, perfusion) was obtained by MRI
      in a life-supporting transplantation model, in which Lewis rats received kidneys
      from Fisher 344 donors. Renography and perfusion analyses were carried out with
      Gd-DOTA and small particles of iron oxide (SPIO), respectively. Starting 12 weeks
      posttransplantation, images from grafts of untreated recipients exhibited
      distinctive signal attenuation in the cortex. Animals treated with cyclosporin
      (Sandimmune Neoral; Novartis Pharma, Basel, Switzerland) to prevent acute
      rejection showed a signal attenuation in the cortex at 33 weeks
      posttransplantation, while kidneys from rats treated additionally with everolimus
      (Certican; Novartis), a rapamycin derivative, had no changes in anatomical
      appearance. A significant negative correlation was found between the MRI cortical
      signal intensity and the histologically determined iron content in macrophages
      located in the cortex. Renography revealed a significantly reduced functionality
      of the kidneys of untreated controls 33 weeks after transplantation, while no
      significant changes in perfusion were observed in any group of rats. These
      results suggest the feasibility, by labeling macrophages with SPIO, of detecting
      signs of graft rejection significantly earlier than when changes in function
      occur. Monitoring early changes associated with chronic rejection can have an
      impact in preclinical studies by shortening the duration of the experimental
      period and by facilitating the investigation of novel immunomodulatory therapies
      for transplantation.

PMID- 12594749
TI  - Comparison of the return-to-the-origin probability and the apparent diffusion
      coefficient of water as indicators of necrosis in RIF-1 tumors.
AB  - Two model-independent measures of diffusion, the apparent diffusion coefficient
      (ADC) and return-to-the-origin probability enhancement (R) were compared for
      their ability to detect tissue necrosis in RIF-1 murine tumors. Both reflect the
      degree of restriction experienced by the endogenous water molecules; however, the
      ADC is calculated from the initial linear slope of the diffusion attenuation
      curve, while R is calculated from data that includes the non-monoexponential part
      of the curve. In spectroscopic studies (n = 9), neither the ADC nor R showed a
      strong correlation with tumor volume. In imaging studies (n = 14), ADC, R, and
      T(2) were calculated on a pixel-by-pixel basis. There, the mean ADC and mean R
      for the entire imaging slice showed reasonable correlation with necrotic tumor
      fraction (r(2) = 0.679 and -0.665, respectively). The mean T(2) value yielded a
      poor correlation (r(2) = 0.436). Regions-of-interest were chosen from areas
      identified as either necrotic or viable and the resulting sets of ADC and R
      values were subjected to discriminant analysis to determine the identification
      error rate. The error was greater for R than for the ADC (P < 0.001). Therefore,
      in this application, the use of the non-monoexponential part of the diffusion
      attenuation curve does not provide additional identification power.

PMID- 12594752
TI  - SMASH navigators.
AB  - The additional data acquired when using multiple receiver coils is commonly used
      to improve SNR or reduce acquisition times. It may also be used to remove image
      artifacts by selectively replacing corrupt data. In the present study, a
      correction scheme is presented based on simultaneous acquisition of spatial
      harmonics (SMASH) that enables detection and correction of motion artifacts
      caused by 2D translations. Newly measured data is compared with predictions from
      previously measured data by making negative and positive spatial harmonics.
      Differences are attributed to motion occurring in the interval between the
      acquisition of separate phase encode lines and correction parameters are
      determined. Two types of rigid body motion are considered: 1) object and coil
      array move, and 2) object only moves, since each causes different phase errors in
      k-space. Simulation, phantom, and volunteer experiments demonstrate the validity
      of the technique.

PMID- 12594750
TI  - Indirect 17(O)-magnetic resonance imaging of cerebral blood flow in the rat.
AB  - Proton T(1rho)-dispersion MRI is demonstrated for indirect, in vivo detection of
      (17)O in the brain. This technique, which may be readily implemented on any
      clinical MRI scanner, is applied towards high-resolution, quantitative mapping of
      cerebral blood flow (CBF) in the rat by monitoring the clearance of (17)O
      enriched water. Strategies are derived and employed for 1) quantitation of
      absolute H(2) (17)O tracer concentration from a ratio of high- and low-frequency
      spin-locked T(1rho) images, and 2) mapping CBF without having to transform the
      T(1rho) signal to H(2) (17)O tracer concentration. Absolute regional blood flow
      was mapped in a single 3-mm brain slice at an in-plane resolution of 0.4 x 0.8 mm
      within a 5-min tracer washout time; these data are consistent with the less
      localized CBF measurements reported in the literature. T(1rho)-weighted imaging
      yields excellent signal-to-noise ratios, spatiotemporal resolution, and
      anatomical contrast for mapping CBF.

PMID- 12594751
TI  - Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) in early knee
      osteoarthritis.
AB  - Delayed contrast-enhanced MRI of cartilage (dGEMRIC) is a noninvasive technique
      to study cartilage glycosaminoglycan (GAG) content in vivo. This study evaluates
      dGEMRIC in patients with preradiographic degenerative cartilage changes.
      Seventeen knees in 15 patients (age 35-70) with arthroscopically verified
      cartilage changes (softening and fibrillations) in the medial or lateral femoral
      compartment, knee pain, and normal weight-bearing radiography were included. MRI
      (1.5 T) was performed precontrast and at 1.5 and 3 hr after an intravenous
      injection of Gd-DTPA(2-) at 0.3 mmol/kg body weight. T(1) measurements were made
      in regions of interest in medial and lateral femoral cartilage using sets of five
      turbo inversion recovery images. Precontrast, R(1) (R(1) = 1/T(1), 1/s) was
      slightly lower in diseased compared to reference compartment, indicating
      increased hydration (P = 0.01). Postcontrast, R(1) was higher in diseased than in
      reference compartment at 1.5 hr, 3.45 +/- 0.90 and 2.64 +/- 0.58 (mean +/- SD),
      respectively (P < 0.01), as well as at 3 hr, 2.94 +/- 0.60 and 2.50 +/- 0.37,
      respectively (P = 0.01). The washout of the contrast medium was faster in
      diseased cartilage as shown by a higher R(1) at 1.5 than at 3 hr in the diseased
      but not in the reference compartment. In conclusion, dGEMRIC can identify GAG
      loss in early stage cartilage disease with a higher sensitivity at 1.5 than 3 hr.

PMID- 12594753
TI  - Quantitative imaging of magnetization transfer using an inversion recovery
      sequence.
AB  - A new imaging method has been developed for quantitatively measuring
      magnetization transfer (MT). It uses a simple inversion recovery sequence,
      although one with very short (milliseconds) inversion times, and thus can be
      implemented on clinical imaging systems with little modification to existing
      pulse sequences. The sequence requires an inversion pulse with a length much
      longer than T(2m) (typically 10 micros) and much shorter than T(2f) (typically
      tens of ms) and 1/k(mf) (typically tens of ms), where T(2m) and T(2f) are the
      transverse relaxation times of the immobile macromolecular and free water
      protons, respectively, and k(mf) is the rate of MT between these populations. The
      resultant NMR signal is sensitive to MT when this inversion pulse affects the
      mobile and immobile proton pools to different degrees and by appropriate analysis
      of the signals obtained for different inversion times, quantitative information
      can be derived on the macromolecular content and exchange rates within the
      sample. The method has been used in conjunction with echo planar imaging to
      produce maps of the spatial distribution of the macromolecular content and MT
      rate in cross-linked bovine serum albumin. Comparisons between this method and
      other quantitative MT techniques are discussed.

PMID- 12594754
TI  - Fast method for correcting image misregistration due to organ motion in time
      series MRI data.
AB  - Time-series MRI data often suffers from image misalignment due to patient
      movement and respiratory and other physiologic motion during the acquisition
      process. It is necessary that this misalignment be corrected prior to any
      automated quantitative analysis. In this article a fast and automated technique
      for removing in-plane misalignment from time-series MRI data is presented. The
      method is computationally efficient, robust, and fine-tuned for the clinical
      setting. The method was implemented and tested on data from 21 human subjects,
      including myocardial perfusion imaging, renal perfusion imaging, and blood-oxygen
      level-dependent cardiac T(2*) imaging. In these applications 10-fold or better
      reduction in image misalignment is reported. The improvement after registration
      on representative time-intensity curves is shown. Although the method currently
      corrects translation motion using image center of mass, the mathematical
      framework of our approach may be extended to correct rotation and other higher
      order displacements.

PMID- 12594755
TI  - Rapid combined T1 and T2 mapping using gradient recalled acquisition in the
      steady state.
AB  - A novel, fully 3D, high-resolution T(1) and T(2) relaxation time mapping method
      is presented. The method is based on steady-state imaging with T(1) and T(2)
      information derived from either spoiling or fully refocusing the transverse
      magnetization following each excitation pulse. T(1) is extracted from a pair of
      spoiled gradient recalled echo (SPGR) images acquired at optimized flip angles.
      This T(1) information is combined with two refocused steady-state free precession
      (SSFP) images to determine T(2). T(1) and T(2) accuracy was evaluated against
      inversion recovery (IR) and spin-echo (SE) results, respectively. Error within
      the T(1) and T(2) maps, determined from both phantom and in vivo measurements, is
      approximately 7% for T(1) between 300 and 2000 ms and 7% for T(2) between 30 and
      150 ms. The efficiency of the method, defined as the signal-to-noise ratio (SNR)
      of the final map per voxel volume per square root scan time, was evaluated
      against alternative mapping methods. With an efficiency of three times that of
      multipoint IR and three times that of multiecho SE, our combined approach
      represents the most efficient of those examined. Acquisition time for a whole
      brain T(1) map (25 x 25 x 10 cm) is less than 8 min with 1 mm(3) isotropic
      voxels. An additional 7 min is required for an identically sized T(2) map and
      postprocessing time is less than 1 min on a 1 GHz PIII PC. The method therefore
      permits real-time clinical acquisition and display of whole brain T(1) and T(2)
      maps for the first time.

PMID- 12594756
TI  - Multiecho sequences with variable refocusing flip angles: optimization of signal
      behavior using smooth transitions between pseudo steady states (TRAPS).
AB  - A variation of the rapid acquisition with relaxation enhancement (RARE) sequence
      (also called turbo spin-echo (TSE) or fast spin-echo (FSE)) is presented. This
      technique uses variable flip angles along the echo train such that magnetization
      is initially prepared into the static pseudo steady state (PSS) for a low
      refocusing flip angle (alpha < 180 degrees ). It is shown that after such a
      preparation, magnetization will always stay very close to the static PSS even
      after significant variation of the subsequent refocusing flip angles. This allows
      the design of TSE sequences in which high refocusing flip angles yielding 100% of
      the attainable signal are applied only for the important echoes encoding for the
      center of k-space. It is demonstrated that a reduction of the RF power (RFP) by a
      factor of 2.5-6 can be achieved without any loss in signal intensity. The
      contribution of stimulated-echo pathways leads to a reduction of the effective TE
      by a factor f(t), which for typical implementations is on the order of 0.5-0.8.
      This allows the use of longer echo readout times, and thus longer echo trains,
      for acquiring images with a given T(2) contrast.

PMID- 12594757
TI  - A correlative measure for processing multiangle diffusion-weighted images.
AB  - A simple metric for the shared diffusion anisotropy between two voxels is
      proposed. The metric has large values when the diffusion is highly anisotropic in
      both voxels and oriented in the same direction. This metric can be used in
      several ways, three of which are illustrated in this article. First, the metric
      can be used to rapidly calculate a fractional anisotropy measure using an
      arbitrary number of measured diffusion values. Second, a simple way to exploit
      the metric for filtering DWI data with neighboring voxels with similar diffusion
      characteristics is shown. Third, the metric can be used to create color images
      that reflect tract orientation.

PMID- 12594758
TI  - A simple measure of flow disorder and wall shear stress in phase contrast MRI.
AB  - A method for estimating the standard deviation of velocity within a voxel is
      proposed. This estimate is based on data collected using a phase-contrast MRI
      technique. Simulations are presented to characterize the estimate and in vivo
      data are shown. Several different uses of the estimate are proposed, including
      obtaining a measure of wall shear stress, aiding in data combination from
      different phase-contrast MRI datasets, and mitigation of flow void artifacts.

PMID- 12594759
TI  - In vivo multiple-mouse imaging at 1.5 T.
AB  - A multiple-mouse solenoidal MR coil was developed for in vivo imaging of up to 13
      mice simultaneously to screen for tumors on a 1.5 T clinical scanner. For the
      coil to be effective as a screening tool, it should permit acquisition of MRIs in
      which orthotopic tumors with diameters >2 mm are detectable in a reasonable
      period of time (<1 hr magnet time) and their sizes accurately measured. Using a
      spin echo sequence, we demonstrated that this coil provides sufficient
      sensitivity for moderately high resolution images (156-176 microm in plane
      resolution, 1.5 mm slice thickness). This spatial resolution permitted detection
      of primary brain tumors in transgenic/knockout mice and orthotopic xenografts.
      Brain tumor size as measured by MRI was correlated with size measured by
      histopathology (P < 0.001). Metastatic tumors in the mouse lung were also
      successfully imaged in a screening setting. The multiple mouse coil is simple in
      construction and may be implemented without any significant modification to the
      hardware or software on a clinical scanner.

PMID- 12594760
TI  - In vivo detection of a pH-sensitive nitroxide in the rat stomach by low-field ESR
      based techniques.
AB  - A study was made of the in vivo detectability of a pH-sensitive, imidazolidine
      spin probe, and the efficacy of low-frequency electron spin resonance (ESR)-based
      techniques for pH measurement in vitro and in vivo in rats. The techniques used
      were longitudinally-detected ESR (LODESR) and field-cycled dynamic nuclear
      polarization (FC-DNP) for in vitro and in vivo measurements, and radiofrequency
      (RF)- and X-band ESR for comparisons in vitro. The spin probe was hexamethyl
      imidazolidine (HMI) with a pK of 4.6. All techniques detected HMI. Detection by
      FC-DNP implies coupling between the free radical and solvent water spins.
      Separations between the three spectral lines of the nitroxide radical, relative
      to measurement frequency, were consistent with theory. The overall spectrum width
      from unprotonated HMI (pH > pK) was greater than that from protonated agent (pH <
      pK). This was observed in vitro and in vivo. Longer-term studies showed that HMI
      is detectable and has the same spectral width (i.e., is at the same pH) up to 2
      hr after gavage into the stomach, although the magnitude of the signal decreases
      rapidly during the first hour. These findings demonstrate the suitability of
      LODESR and FC-DNP for monitoring HMI and measuring pH in vivo. These techniques
      would be useful for monitoring disease and drug pharmacology in the living
      system.

PMID- 12594761
TI  - Effects of hematocrit and oxygen saturation level on blood spin-lattice
      relaxation.
AB  - In the present study blood T(1) was determined as a function of hematocrit and
      oxygen saturation. T(1) showed a significant linear dependency on both of these
      parameters. In addition, oxygen dissolved in blood plasma in hyperoxygenated
      blood resulted in relaxation enhancement, comparable in size to that due to the
      change in oxygenation state of hemoglobin. As blood T(1) is a key factor for
      quantification of flow with arterial spin labeling methods, the influence of T(1)
      variation in the physiological range of hematocrit and oxygen saturation to flow
      determination is discussed.

PMID- 12594762
TI  - Proton transverse relaxation rate (R2) images of liver tissue; mapping local
      tissue iron concentrations with MRI [corrected].
AB  - Proton transverse relaxation rate (R(2)) imaging measurements were made on post
      mortem iron-loaded human liver tissue samples (both intact and dissected into
      approximately 1-cm cubes) from a single subject. Iron concentrations for the
      dissected samples as measured by atomic absorption spectrometry varied from 10.8
      to 23.3 mg Fe.g(-1) dry tissue. A significant linear correlation between the mean
      R(2) and iron concentration of each sample was found (r = 0.95). In addition,
      regions of liver tissue with micronodular cirrhosis exhibited lower R(2) values,
      corresponding to the displacement of iron by fibrotic septa. The cirrhotic tissue
      was clearly identified as a separate peak in the R(2) distribution of the tissue.
      The relaxivity of the iron did not appear to depend on the microarchitecture of
      the tissue.

PMID- 12594763
TI  - Quantitative measurements of proton spin-lattice (T1) and spin-spin (T2)
      relaxation times in the mouse brain at 7.0 T.
AB  - The goal of this work is to provide regional T(1) and T(2) values at a field
      strength of 7 T for the normal mouse brain at 6 weeks and 1 year old. A novel
      segmented snapshot FLASH sequence was used to measure T(1) in the hippocampus,
      corpus callosum, and the retrosplenial granular (RSG) cortex; T(2) measurements
      were made in the same regions using a single spin echo sequence repeated at six
      separate echo times. Both T(1) and T(2) measurements were validated with phantom
      measurements.

PMID- 12594764
TI  - Dynamic exercise imaging with an MR-compatible stationary cycle within the
      general electric open magnet.
AB  - Many cases of muscular ischemia do not manifest without increased metabolic
      demand. Hence, diagnosis of intermittent claudication often requires inducing
      physiologic challenge, such as by exercise. Cine phase-contrast MRI can
      concurrently acquire cross-sectional vascular anatomy and through-plane blood
      velocities, enabling blood flow rate quantification. An MR-compatible stationary
      cycle was designed, constructed, and tested for flow quantification in large
      arteries during lower-limb exercise in a General Electric Signa SP 0.5 T open
      magnet. The cycle demonstrated smooth cycling during image acquisition, has
      freewheeling capability, is adjustable for subject size and strength, and can
      quantify workload. A healthy 59-year-old male was imaged at the supraceliac and
      infrarenal levels of the abdominal aorta at rest and during exercise. An exercise
      workload of 47.9 W was achieved. His heart rate increased from 52 to 78 bpm,
      supraceliac flow increased from 1.7 to 3.7 L/min, and infrarenal flow increased
      from 0.4 to 3.2 L/min from rest to exercise.

PMID- 12594765
TI  - Albumin-binding MR blood pool agents as MRI contrast agents in an intracranial
      mouse glioma model.
AB  - Intravenous MRI contrast agents are commonly used to improve the detection of
      intracranial tumors and other central nervous system (CNS) lesions for diagnosis
      and treatment planning. Two small-molecule, albumin-binding blood pool contrast
      agents (MP-2269 and MS-325) of potential clinical significance were evaluated at
      1.5 Tesla in a mouse glioma model and compared with an extracellular contrast
      agent (OptiMARK). Tumor image contrast was significantly enhanced and long-lived
      following administration of 30 micromole/kg of the blood pool agents:
      specifically, contrast enhancement peaked slowly at 25-30 min following
      administration, remained constant for >3 hr, and returned to baseline within 20
      hr. Comparable but "transient" enhancement was achieved using 100 micromole/kg
      OptiMARK: specifically, contrast enhancement peaked rapidly at 2-5 min following
      administration and then declined over 40 min. The blood pool contrast agents
      demonstrated an approximately threefold increased dose-effectiveness and a
      lengthened window of tumor contrast enhancement in comparison to commonly
      available extracellular contrast agents. This demonstrates the potential of
      alternative contrast-enhanced (CE) MRI examination protocols for tumor detection.

PMID- 12594767
TI  - Reduced k-space encoding for dual-contrast TrueFISP imaging.
AB  - Dual-contrast TrueFISP imaging relies on the use of two RF pulses with different
      RF flip-angles for enhancing image contrast and performing automatic tissue
      classification based on multispectrum clustering. The original technique,
      however, involves an extended imaging time, which limits its clinical
      application. The purpose of this study is to compare the applicability of two
      reduced k-space sampling techniques, reduced imaging using generalized series
      reconstruction (RIGR) and key-hole imaging, for minimizing the imaging time
      required. The performance of both approaches was evaluated theoretically and
      practically using 3D cine datasets acquired from eight asymptomatic subjects.

PMID- 12594766
TI  - Computing oxygen-enhanced ventilation maps using correlation analysis.
AB  - Correlation maps of oxygen-enhanced ventilation were obtained in nine healthy
      volunteers using complete and selected image series. The complete series included
      all images acquired with the subjects alternately inhaling room air and 100%
      oxygen. The selected series were the subsets of the complete series and included
      only co-registered images that showed matched diaphragmatic position at maximal
      expiration. Cross-correlation was computed between the time response function of
      each pixel and the input function representing the alternation between periods of
      room air and 100% oxygen inhalation. The confidence level for the correlation
      analysis was set to 0.01. Pulmonary parenchymal anatomy was consistently
      reproduced throughout the lung, even in anterior slices where published data have
      reported correlation problems. The overall average correlation coefficient was
      0.66 +/- 0.07 for the complete series and 0.75 +/- 0.08 for the selected series.
      It was concluded that correlation analysis could be used to reconstruct
      qualitative oxygen-enhanced ventilation maps.

PMID- 12594768
TI  - Efficient measurement and calculation of MR diffusion anisotropy images using the
      Platonic variance method.
AB  - The Platonic variance method produces MR diffusion anisotropy (DA) images with a
      minimum amount of computational effort. It can be programmed in a self-contained
      MR sequence, thus eliminating the need for postprocessing on a separate
      workstation. The method uses gradient acquisition schemes, based on Platonic
      solids: the "icosahedric" scheme (N = 6), the "dodecahedric" scheme (N = 10), and
      combinations thereof. For these schemes the average of the diffusion tensor
      eigenvalues equals the average of the measured apparent diffusion coefficients
      (ADCs), and the variance of the eigenvalues equals 5/2 times the variance of the
      diffusion coefficients. This results in compact expressions for anisotropy
      measures, directly in terms of the acquired images, i.e., without calculating the
      eigenvalues or even the tensor elements. The resulting anisotropy images were
      shown to be identical to the ones traditionally derived. It is expected that this
      method will considerably promote the routine use of DA imaging.

PMID- 12594769
TI  - Detecting stiff masses using strain-encoded (SENC) imaging.
AB  - A method is proposed for detecting stiff masses using strain-encoded (SENC)
      magnetic resonance imaging (MRI). An object of interest is compressed to produce
      local strain distribution that depends on local elasticity, where intensities
      correlate with the local through-imaging-plane strain component. Because the
      strain is lower inside a stiff mass than in the surrounding soft tissue, an
      intensity contrast in the resulting images would enable direct detection of the
      mass without postprocessing. The technique was validated by a phantom experiment
      in which a gel phantom with a stiff region was used. The advantages of the
      proposed method include short imaging time and uncomplicated postprocessing.
      However, in its current form the technique does not measure elasticity.

PMID- 12594770
TI  - Asphalt--a continuing challenge.
AB  - Assessing the health risks of complex mixtures of polynuclear aromatic
      hydrocarbons such as diesel fumes and asphalt or bitumen continues to be a major
      challenge for occupational and environmental health scientists. The special
      Asphalt issue of the American Journal of Industrial Medicine (Cancer Mortality
      Among European Asphalt Workers (Am.J.Ind.Med. Volume 43, Number 1, 2003)
      presented the results of a major multi-country epidemiological study of a group
      of workers exposed to one common commercial PAH mixture, asphalt or bitumen.

PMID- 12594771
TI  - External cause-specific summaries of occupational fatal injuries. Part I: an
      analysis of rates.
AB  - BACKGROUND: Industries and occupations vary with respect to the incidence of
      fatal injuries and their causes. METHODS: Fatalities from the National Traumatic
      Occupational Fatality database (years 1983-1994) serve as the basis for examining
      external cause of death code specific rates. Industries and occupations are
      compared with respect to rate and frequency of fatal injuries. In addition,
      external causes of injury (E-codes) are examined across all industries and
      occupations as well as within industries and occupations to evaluate which events
      would be identified by frequency ordered comparisons versus injury rate ordered
      comparisons. RESULTS: Machinery, electric current, homicide, falls, and
      transportation-related events are identified by high frequency and rate of
      occurrence. CONCLUSIONS: The external cause categories of homicide, machinery
      related, motor-vehicle-related, electric current, and falls, account for over one
      half of all occupational fatal injuries. Targeted interventions in homicide may
      be especially warranted in sales and service occupations and in the retail trade
      and services industries. In addition, younger workers might be targeted for
      special interventions designed to identify hazardous practices, procedures, and
      solutions to reduce fatalities associated with electrocution or falls from
      buildings.

PMID- 12594772
TI  - External cause-specific summaries of occupational fatal injuries. Part II: an
      analysis of years of potential life lost.
AB  - BACKGROUND: Fatal injury surveillance data provide an opportunity to assess the
      impact of occupational injuries and may indicate which industries or occupations
      are appreciably more hazardous than others, and thus should be given priority in
      public health intervention. METHODS: Fatalities from the National Traumatic
      Occupational Fatality surveillance system served as the basis for examining
      external cause (E-code) specific impact summaries. Years of potential life lost
      (YPLL) were calculated for fatal injuries in the years 1983-1994. Industries and
      occupations were compared with respect to frequency of fatal injuries. In
      addition, injuries in categories of external causes are examined across all
      industries and occupations. RESULTS: Machinery, electric current, homicide,
      falls, and transportation-related are the external cause groups highlighted by
      high frequency/rate of occurrence. Electric current event groups are also
      characterized by high average YPLL. Poisoning, conflagration, and lightning were
      also identified in several occupations as having high associated average YPLL.
      CONCLUSIONS: The external-cause-specific analysis of average YPLL identified
      industries and occupations where, on average, younger workers were dying in fatal
      injuries. Noteworthy in this assessment were homicides and falls. The YPLL
      measure coupled with more commonly employed indices (e.g., rates) may provide a
      fuller description of the impact of occupational fatal injuries.

PMID- 12594773
TI  - Factors associated with women's risk of rape in the military environment.
AB  - BACKGROUND: Health hazards specific to women workers have not been adequately
      documented. This study assessed military environmental factors associated with
      rape occurring during military service, while controlling for pre-military trauma
      experiences. METHODS: A national cross-sectional survey of 558 women veterans
      serving in Vietnam or in subsequent eras was obtained through structured
      telephone interviews. RESULTS: Rape was reported by 30% (n = 151) of
      participants, with consistent rates found across eras [corrected]. Military
      environmental factors were associated with increased likelihood of rape,
      including: sexual harassment allowed by officers (P < 0.0001), unwanted sexual
      advances on-duty (P < 0.0001) and in sleeping quarters (P < 0.0001). CONCLUSION:
      Violence towards military women has identifiable risk factors. Work and living
      environments where unwanted sexual behaviors occurred were associated with
      increased odds of rape. Officer leadership played an important role in the
      military environment and safety of women. Assailant alcohol and/or drug abuse at
      time of rape was notable. Interventions and policies based on modifiable
      environmental risk factors are needed to increase protection for women in the
      workplace.

PMID- 12594774
TI  - Renal cell cancer risk and occupational exposure to trichloroethylene: results of
      a consecutive case-control study in Arnsberg, Germany.
AB  - BACKGROUND: German studies of high exposure prevalence have been debated on the
      renal carcinogenicity of trichloroethylene (TRI). METHODS: A consecutive hospital
      based case-control study with 134 renal cell cancer (RCC) cases and 401 controls
      was conducted to reevaluate the risk of TRI in this region which were estimated
      in a previous study. Exposure was self-assessed to compare these studies.
      Additionally, the job history was analyzed, using expert-based exposure
      information. RESULTS: The logistic regression results, adjusted for age, gender,
      and smoking, confirmed a TRI-related RCC risk in this region. Using the database
      CAREX for a comparison of industries with and without TRI exposure, a significant
      excess risk was estimated for the longest held job in TRI-exposing industries
      (odds ratio (OR) 1.80, 95% confidence interval (CI) 1.01-3.20). Any exposure in
      "metal degreasing" was a RCC risk factor (OR 5.57, 95% CI 2.33-13.32). Self
      reported narcotic symptoms, indicative of peak exposures, were associated with an
      excess risk (OR 3.71, 95% CI 1.80-7.54). CONCLUSIONS: The study supports the
      human nephrocarcinogenicity of trichloroethylene.

PMID- 12594775
TI  - Role of underlying pulmonary obstruction in short-term airway response to metal
      working fluid exposure: a reanalysis.
AB  - BACKGROUND: Among epidemiologic studies that found evidence for associations
      between exposures to metal working fluids (MWF) and pulmonary function
      impairments, one found effects restricted to workers with fixed obstruction at
      baseline. We reanalyzed a previously published study on MWF exposure and cross
      shift pulmonary function to further evaluate this finding. METHODS: Pulmonary
      function was measured cross-shift on Monday and Friday in 131 male automotive
      workers. Quantitative personal MWF exposure data were available. Those with an
      FEV(1)/FVC ratio of <or=0.72 were considered obstructed. RESULTS: There was a
      trend towards increasing incidence of cross-shift decrement in FEV(1) as MWF
      exposure increased in the full cohort as well as when the results were restricted
      to the 19 (14.5%) who were obstructed. Those with obstruction were slightly more
      likely to show decrements in FEV(1) on Fridays. Removing the obstructed subgroup
      did not appear to substantially weaken the exposure-response relation.
      CONCLUSIONS: No important differences were found in cross-shift effects of MWF
      between obstructed and non-obstructed workers.

PMID- 12594776
TI  - Firefighting and risk of testicular cancer: results from a German population
      based case-control study.
AB  - BACKGROUND: There is some evidence of an elevated risk for testicular cancer
      among firefighters. METHODS: We performed a population-based case-control study
      including 269 testicular cancer cases and 797 controls matching on age and region
      with a special focus on occupational exposures. Job tasks were coded according to
      the International Standard Classification of Occupations (ISCO 68). We used
      conditional logistic regression to calculate odds ratios (OR). RESULTS: Three
      controls (0.4%) and four cases (1.5%) ever worked as firefighters. Firefighters
      showed an increased odds of testicular cancer in the matched evaluation (OR =
      4.3, 95% confidence interval (95% CI) 0.7-30.5). The adjustment for a history of
      cryptorchidism or family history of testicular cancer did not alter our results.
      CONCLUSION: Although the association between firefighting and testicular cancer
      risk is based on only small numbers of exposed subjects in our study, the finding
      is consistent with a recent cohort study from New Zealand. Occupational hazards
      experienced by firefighters may increase the risk of testicular cancer.

PMID- 12594777
TI  - Cancer mortality in a cohort of male German iron foundry workers.
AB  - BACKGROUND: Observations of an increased incidence of cancers of the upper aero
      digestive tract (pharynx, esophagus, larynx, lung) among workers of local German
      foundries gave rise to concern about a potentially elevated occupational risk of
      those cancer sites. The purpose of the study was to examine whether occupational
      exposure in iron foundries increases the risk of cancer. METHODS: A historical
      cohort study of 17,708 male German production workers in 37 iron foundries who
      were first employed in 1950-1985 with a minimum employment period of 1 year was
      initiated. Employment and occupational histories were collected. Mortality was
      compared with that of the German general population during 1950-1993 using a new
      method for computing the SMR when not all causes of death are available (called
      SMR*). RESULTS: Mortality from all causes was elevated to SMR = 115.4 (95%
      confidence interval (CI) = 111.9-119.1), as was for total cancer (SMR* = 123.8,
      CI = 102.1-152.6), especially cancers of the lung (SMR* = 163.9, CI = 123.9
      223.0) and liver (SMR* = 322.5, CI = 149.5-844.8), and diseases of the
      respiratory system (SMR* = 147.6, CI = 100.4-221.5). Non-significant elevations
      of mortality were also found for cancers of the mouth and pharynx (SMR* = 153.5,
      CI = 82.3-359.8) and larynx (SMR* = 173.1, CI = 85.5-550.5). Mortality from
      various causes of death was higher among workers with shorter exposure periods
      than among long-term employees. The elevated mortality persisted for years and
      decades after termination of employment. CONCLUSIONS: The results provide further
      evidence for an increased risk of lung cancer and possibly other cancers of the
      upper aero-digestive tract among foundry workers. Special attention should be
      paid to the strongly increased mortality from liver cancer and the mortality
      pattern among employees having terminated work.

PMID- 12594778
TI  - Pancreatic cancer mortality and organochlorine pesticide exposure in California,
      1989-1996.
AB  - BACKGROUND: Occupational studies have suggested a possible link between
      organochlorine pesticides and the occurrence of pancreatic cancers. California
      maintains a death file and a pesticide reporting system that allows examination
      of this relationship for residents of high use areas. METHODS: We employed a
      mortality odds ratio design to compare deaths from pancreatic cancer (1989-1996)
      with a random sample of non-cancer deaths. Using pesticide data for three
      agricultural counties, we classified 102 ZIP codes in quartiles of pesticide
      usage for 1972-1989. Using logistic regression we estimated the effect of
      pesticide applications by ZIP code controlling for possible confounders. RESULTS:
      Among long-term residents, pancreatic cancer mortality was elevated for those
      living in ZIP codes with the highest use of four pesticides: 1,3-dichloropropene
      (1,3-d), captafol, pentachloronitrobenzene (PCNB), and dieldrin. No dose-response
      relationship was observed. CONCLUSIONS: Our study suggests increased pancreatic
      cancer mortality among long-term residents in areas of high application rates of
      1,3-d (an EPA-classified probable human carcinogen), captafol,
      pentacholoronitrobenzene (PCNB), and dieldrin.

PMID- 12594779
TI  - Work injuries among Finnish farmers: a national register linkage study 1996-1997.
AB  - BACKGROUND: Farming is one of the most injury-prone occupations in Finland as it
      is in other countries. Our goals were to describe work injuries of Finnish
      farmers and to compare occupational injury rates between various subgroups.
      METHODS: A national cohort of 69,629 full-time farmers and their 11,657
      compensated injuries were identified from an insurance company database. Cohort
      data were merged with a population census and farm register. Relative incidence
      rates were calculated using Poisson regression. RESULTS: Men had higher injury
      rates than women, except with regard to injuries caused by animals. Dairy and hog
      farming were the riskiest activities, and injury rates increased with the number
      of dairy cows. CONCLUSIONS: One-half of insured farmers in Finland are full-time
      farmers, which may have lead to underestimation of risk in Finnish injury
      statistics. Dairy farming is of particular concern because it is both common and
      has a high injury rate.

PMID- 12594780
TI  - Using respirators and goggles to control exposure to air pollutants in an anatomy
      laboratory.
AB  - BACKGROUND: Engineering or administrative methods are often insufficient or
      impractical to control exposure to chemicals in anatomy laboratories. This study
      explored the feasibility of wearing one or a combination of respirators and
      goggles used as personal protective equipment (PPE) to control exposure in one
      such laboratory. METHODS: A group of 28 subjects were briefly trained in wearing
      PPE, fit-tested, and asked to complete a questionnaire regarding their subjective
      reaction after wearing the assigned PPE ensemble while working in the laboratory.
      The subjects' exposure to formaldehyde was also measured and generally exceeded
      the recommended limits. RESULTS: When a full-face respirator or the combination
      of a half-mask respirator and goggles was worn, a majority of subjects reported
      no odor problem and no irritation to eyes or upper respiratory system. Subjects
      accepted the PPE to certain degrees, but those using respirators encountered
      difficulties communicating with others. CONCLUSIONS: The combination of a half
      mask respirator and goggles was the most feasible ensemble to control exposure to
      air pollutants in an anatomy laboratory.

PMID- 12594781
TI  - RE: An alternate characterization of hazard in occupational epidemiology: years
      of life lost per years worked. Am J Ind Med 42:1-10, 2002.

PMID- 12594783
TI  - Rational determination of charge distributions for free energy calculations.
AB  - Point charges derived from RHF/6-31G* electrostatic potentials are attractive
      because they tend to exaggerate the polarity of solvated molecules, thereby
      compensating in an average fashion missing induction effects. In the context of
      free energy calculations, wherein the molecule is transferred from a polar
      environment to a nonpolar one, we propose a more rational approach based on a
      self-consistent reaction field computation at a higher level of theory,
      supplemented by an estimation of the corresponding distortion energy to account
      for the change of polarity of the surroundings. Application of this method to the
      test cases acetamide, acetic acid, methyl acetate and phenol, using
      multinanosecond molecular dynamics/"umbrella sampling" simulations, yields
      consistent hydration free energies in reasonably good agreement with experiment.

PMID- 12594784
TI  - Comparison of electron density properties in frozen and relaxed electronic
      distributions.
AB  - Two kinds of electron densities for several small molecules (H(2), FH,
      CH(3)CH(3), CH(3)NH(2), CH(3)OH, and CH(3)F) have been generated for a wide range
      of bond distances. The first one, as the sum of the electron density of the
      isolated fragments, and the second one by optimizing the electron density at each
      given geometrical disposition. A number of properties of this two electronic
      distributions have been compared (position of the bond critical points, electron
      density, Laplacian, curvatures, and local energies). The differences, associated
      to the bond formation, are found to be very important for most of the cases.

PMID- 12594785
TI  - Chemical information from the source function.
AB  - The source function, which enables one to equate the value of the electron
      density at any point within a molecule to a sum of atomic contributions, has been
      applied to a number of cases. The source function is a model-independent,
      quantitative measure of the relative importance of an atom's or group's
      contribution to the density at any point in a system, and it represents a
      potentially interesting tool to provide chemical information. It is shown that
      the source contribution from H to the electron density rho(b) at the bond
      critical point in HX diatomics decreases with increasing X's electronegativity,
      and that this decrease is a result of significant changes in the Laplacian
      distribution within the H-basin. It is also demonstrated that the source function
      from Li to rho(b) in LiX diatomics is a more sensitive index of atomic
      transferability than it is the lithium atomic energy or population. The observed
      changes are such as to ensure a constant percentage source contribution from Li
      to rho(b) throughout the LiX series, rather than a constant source as one would
      expect in the limit of perfect atomic transferability. Application of the source
      function to planar lithium clusters has revealed that the source function clearly
      discriminates between a nonnuclear electron density maximum and a maximum
      associated to a nucleus, on the basis of the relative weight of the source
      contributions from the basin associated to the maximum and from the remaining
      basins in the cluster. The source function has also allowed for a classification
      of hydrogen bonds in terms of characteristic source contributions to the density
      at the H-bond critical point from the H involved in the H-bond, the H-donor D,
      and the H-acceptor A. The source contribution from the H appears as the most
      distinctive marker of the H-bond strength, being highly negative for isolated H
      bonds, slightly negative for polarized assisted H-bonds, close to zero for
      resonance-assisted H-bonds, and largely positive for charge-assisted H-bonds. The
      contributions from atoms other than H, D, and A strongly increase with decreasing
      H-bond strength, consistently with the parallel increased electrostatic character
      of the interaction. The correspondence between the classification provided by the
      Electron Localization Function topologic approach and by the source function has
      been highlighted. It is concluded that the source function represents a practical
      tool to disclose the local and nonlocal character of the electron density
      distributions and to quantify such a locality and nonlocality in terms of a
      physically sound and appealing chemical partitioning.

PMID- 12594786
TI  - An improved algorithm to locate critical points in a 3D scalar field as
      implemented in the program MORPHY.
AB  - A new algorithm for location of the critical points in general scalar fields is
      described. The new method has been developed as part of an on-going process to
      exploit the topologic analysis of general 3D scalar fields. Part of this process
      involves the use of topologic information to seed the critical point search
      algorithm. The continuing move away from topologic studies of just the electron
      density requires more general algorithms and the ability to easily "plug in" new
      functions, for example, the Laplacian of the electron density ( triangle down
      (2)rho), the Electron Localisation Function (ELF), the Localised Orbital Locator
      (LOL), the Lennard-Jones function (LJF), as well as any new functions that may be
      proposed in the future. Another important aspect of the current algorithm is the
      retention of all possible intermediate information, for example, the paths
      describing the connectivity of critical points, as well as an ability to restart
      searches, something that becomes increasingly important when analysing larger
      systems. This new algorithm represents a core part of a new local version of the
      MORPHY code. We distinguish nine universal types of gradient paths.

PMID- 12594787
TI  - Ab initio determination of the electric multipole moments and static
      (hyper)polarizability of HCCX, X = F, Cl, Br, and I.
AB  - We report electric multipole moments and (hyper)polarizabilities for the
      haloethynes HCCX, X = F, Cl, Br, and I. The molecular properties have been
      obtained from finite-field self-consistent field, Moller-Plesset perturbation
      theory and coupled cluster calculations with large, carefully optimized basis
      sets of gaussian-type functions. The mean dipole (hyper)polarizability and the
      mean quadrupole polarizability near the Hartree-Fock limit are alpha/e(2)a(0)
      (2)E(h) (-1) = 23.74 (HCCF), 37.26 (HCCCl), 43.97 (HCCBr), 56.44 (HCCI),
      beta/e(3)a(0) (3)E(h) (-2) = -73.9 (HCCF), -67.0 (HCCCl), -39.5 (HCCBr), 42.7
      (HCCI), gamma/e(4)a(0) (4)E(h) (-3) = 4,914 (HCCF), 6,554 (HCCCl), 9,328 (HCCBr),
      14,949 (HCCI), and C/e(2)a(0) (4)E(h) (-1) = 160.3 (HCCF), 317.1 (HCCCl), 471.2
      (HCCBr), 671.2 (HCCI). Electron correlation has a small effect on the dipole
      polarizability but affects strongly the hyperpolarizability. Agreement with the
      available experimental data is more or less fair for HCCF, HCCCl, and HCCBr but
      less satisfactory for HCCI.

PMID- 12594788
TI  - Application of the quantum theory of atoms in molecules to selected physico
      chemical and biophysical problems: focus on correlation with experiment.
AB  - This article reviews how the quantum theory of atoms in molecules (QTAIM) can be
      used to predict experimental physico-chemical properties of molecules of biologic
      interest: the amino acids, the polycyclic aromatic hydrocarbons (PAH), and the
      opiates, for example, morphine and PEO. The predicted experimental properties are
      as diverse as the partial molar volumes, the free energies of hydration, the
      second code-letter in the genetic code, the resonance energies, and the proton
      spin-spin coupling constants. Recent examples of the utilization of QTAIM to
      construct excellent statistical models (with squared correlation coefficients
      (r(2)) > 0.9) correlating properties of the electron density and of the pair
      density to experiment are reviewed. Some new results on the solvent effects on
      electron delocalization are also presented.

PMID- 12594789
TI  - Hirshfeld partitioning of the electron density: atomic dipoles and their relation
      with functional group properties.
AB  - Atomic dipole moments, derived within the Hirshfeld partitioning of the molecular
      electron density, have been studied for compounds of the type H-X and Cl-X, for a
      series of functional groups X frequently encountered in organic molecules. In the
      case of the H-X compounds, the component of the atomic dipole moment on H along
      the axis connecting H with the central atom in X is found to be linearly
      correlated with the electronegativity of X, the hardness of X playing no
      significant role. In the case of the Cl-X compounds, the situation is less clear.
      However, evidence seems to point to the conclusion that for these compounds, also
      the group hardness plays an important role.

PMID- 12594790
TI  - Wave functions derived from experiment. V. Investigation of electron densities,
      electrostatic potentials, and electron localization functions for
      noncentrosymmetric crystals.
AB  - The constrained Hartree-Fock method using experimental X-ray diffraction data is
      extended and applied to the case of noncentrosymmetric molecular crystals. A new
      way to estimate the errors in derived properties as a derivative with respect to
      added Gaussian noise is also described. Three molecular crystals are examined:
      ammonia [NH(3)], urea [CO(NH(2))(2)], and alloxan [(CO)(4)(NH)(2)]. The energetic
      and electrical properties of these molecules in the crystalline state are
      presented. In all cases, an enhancement of the dipole moment is observed upon
      application of the experimental constraint. It is found that the phases of the
      structure factors are robustly determined by the constrained Hartree-Fock model,
      even in the presence of simulated noise. Plots of the electron density,
      electrostatic potential, and the electron localization function for the molecules
      in the crystal are displayed. In general, relative to the Hartree-Fock model,
      there is a depletion of charge around hydrogen atoms and lone pair regions, and a
      build-up of charge within the molecular framework near nuclei, directed along the
      bonds. The electron localization function plots reveal an increase in the pair
      density between vicinal hydrogen atoms.

PMID- 12594791
TI  - Ab initio quality one-electron properties of large molecules: development and
      testing of molecular tailoring approach.
AB  - The development of a linear-scaling method, viz. "molecular tailoring approach"
      with an emphasis on accurate computation of one-electron properties of large
      molecules is reported. This method is based on fragmenting the reference
      macromolecule into a number of small, overlapping molecules of similar size. The
      density matrix (DM) of the parent molecule is synthesized from the individual
      fragment DMs, computed separately at the Hartree-Fock (HF) level, and is used for
      property evaluation. In effect, this method reduces the O(N(3)) scaling order
      within HF theory to an n.O(N'(3)) one, where n is the number of fragments and N',
      the average number of basis functions in the fragment molecules. An algorithm and
      a program in FORTRAN 90 have been developed for an automated fragmentation of
      large molecular systems. One-electron properties such as the molecular
      electrostatic potential, molecular electron density along with their topography,
      as well as the dipole moment are computed using this approach for medium and
      large test chemical systems of varying nature (tocopherol, a model polypeptide
      and a silicious zeolite). The results are compared qualitatively and
      quantitatively with the corresponding actual ones for some cases. This method is
      also extended to obtain MP2 level DMs and electronic properties of large systems
      and found to be equally successful.

PMID- 12594792
TI  - Electron probability distribution in AIM and ELF basins.
AB  - The probabilities of finding a certain number of electrons enclosed in a given
      volume is calculated and discussed for a series of molecules. Two different
      methodologies to do the partition of the molecular space in separate volumes are
      investigated: the Atoms in the Molecules, AIM, topologic analysis of the density,
      and the topologic analysis of the Electron Localization Function (ELF). The
      formulas to calculate the probability distribution are reviewed and the way to
      implement them shortly explained. For a series of molecules, we present how the
      probability distribution complement the chemical information about the
      localization of the electrons in certain regions of the space. The calculations
      show that the probability of finding Z electrons in the AIM atomic basin
      associated to an atom of atomic number Z is, in general, low, even when the
      average number of electrons is close to Z. The probability distribution on the
      ELF basins associated to bonds yields new insight about the nature of the
      respective bond.

PMID- 12594793
TI  - Electrostatic potentials and covalent radii.
AB  - We begin with a brief overview of the electrostatic potential V(r) as a
      fundamental determinant of the properties of systems of electrons and nuclei. The
      minimum of V(r) along the internuclear axis between two bonded atoms is a natural
      and physically meaningful boundary point, at which the electrostatic forces of
      the two nuclei upon an element of charge exactly cancel. We propose that the
      distances from nuclei to V(r) bond minima provide the basis for a well-defined
      set of covalent radii. Density functional calculations at the B3PW91/6-311+G**
      level were carried out for 59 molecules to locate the V(r) minima in 95 bonds and
      use these as the basis for determining single- and multiple-bond covalent radii
      for eight first- and second-row atoms plus hydrogen. It was found to be
      unrealistic to assign a single covalent radius to each atom; different values are
      needed for bonds to first- and second-row atoms, as well as to hydrogen. Using
      these results, we are able to predict the bond lengths of 33 single and multiple
      bonds with average errors of less than 0.04 A relative to experimental data.

PMID- 12594794
TI  - Transferable atom equivalent multicentered multipole expansion method.
AB  - The transferability of atomic and functional group properties is an implicit
      concept in chemistry. The work presented here describes the use of Transferable
      Atom Equivalents (TAE) to represent molecular electrostatic potential fields
      through the use of integrated atomic multipole moments that are associated with
      each TAE atom type used in the reconstruction. TAE molecular surface
      distributions of electrostatic potentials are compared with analytical ab initio
      and empirical (Gasteiger) partial charge reference models for several
      conformations of test peptides. Surface electrostatic potential distributions
      computed using TAE multipole representations were found to converge at the
      octopole level, with incremental improvement observed when hexadecapoles were
      included. Molecular electrostatic potential fields that were produced using the
      TAE method were observed to be responsive to conformational changes and to
      compare well with ab initio reference distributions. Generation of TAE atom types
      and their associated multipoles does not involve fitting to sample electrostatic
      potential fields, but rather utilizes integrated AIM atomic electron density
      distributions within representative chemical environments. The RECON program was
      used for TAE reconstruction. RECON is capable of processing 5,000 drug-sized
      molecules or 25 proteins per minute per 1.7 GHz P4 Linux processor.

PMID- 12594796
TI  - Contrast-enhanced power Doppler sonography and helical computed tomography for
      assessment of vascularity of small hepatocellular carcinomas before and after
      percutaneous ablation.
AB  - PURPOSE: We compared the usefulness of Levovist-enhanced power Doppler imaging
      (PDI) and helical CT in the depiction of tumor vascularity before and after
      percutaneous ablation of small hepatocellular carcinomas (HCCs). METHODS: Thirty
      one cirrhotic patients with solitary unresectable HCCs smaller than 5 cm (mean
      size, 2.7 +/- 0.8 cm; range, 1.5-5.0 cm) recruited over a 15-month period were
      treated with percutaneous ethanol injection (n = 9) or radiofrequency ablation (n
      = 22). PDI, contrast-enhanced PDI (using Levovist), and multiphase contrast
      enhanced helical CT were performed before and after percutaneous ablation, and
      vascularity findings were compared. RESULTS: Levovist significantly increased
      baseline intratumoral Doppler signals on PDI compared to non-contrast PDI. The
      most frequent tumor vascularity pattern was heterogeneous (45%). Vascularity was
      identified in all tumors by both contrast-enhanced PDI and helical CT before
      ablation. After percutaneous ablation, intratumoral vascularity was detected in
      11 tumors by contrast-enhanced PDI and in 15 tumors by CT. The sensitivity,
      specificity, and diagnostic accuracy of contrast-enhanced PDI in demonstrating
      intratumoral vascularity, with CT being the gold standard, were 66%, 93%, and
      81%, respectively. There was significant agreement between the 2 modalities in
      the depiction of tumor vascularity after ablation (kappa = 0.6, p = 0.001).
      However, there were 5 false negatives and 1 false positive with contrast-enhanced
      PDI. Complete tumor necrosis was achieved in 21 patients (68%). CONCLUSIONS:
      There was a good concordance between contrast-enhanced PDI and helical CT in the
      depiction of HCC vascularity before and after percutaneous ablation. However,
      although contrast-enhanced PDI may be useful for real-time guidance of treatment,
      its low sensitivity makes it inadequate to accurately assess the completeness of
      ablation.

PMID- 12594797
TI  - Spontaneous nontraumatic intrasplenic pseudoaneurysm: causes, sonographic
      diagnosis, and prognosis.
AB  - PURPOSE: The aim of this study was to describe the incidence, causes, sonographic
      features, therapy, and prognosis of nontraumatic intrasplenic pseudoaneurysms
      (NTISPs), a rare complication of splenic infarction or infiltration by malignant
      systemic disorders or infectious diseases. METHODS: We retrospectively reviewed
      the medical and sonographic records of all patients seen at our clinic from July
      1985 through December 2000 to identify patients with a sonographic diagnosis of
      spontaneous nontraumatic splenic rupture. We then examined the features of the
      resulting cases to identify patients in whom NTISPs were revealed by color
      Doppler sonography. RESULTS: In total, 41 patients were identified. Among those
      patients, 5 (12%) had NTISPs. Three of those 5 patients had an underlying
      malignant disorder (1 case of non-Hodgkin's lymphoma and 2 cases of chronic
      myelogenous leukemia), and the other 2 had an inflammatory disease (1 case of
      endocarditis and 1 case of pancreatitis). Three of the patients also had splenic
      infarctions. Three patients underwent splenectomy; in 2 of them, secondary
      delayed splenic rupture occurred before or during splenectomy. In 2 other
      patients, spontaneous thrombosis of the aneurysms occurred (after 16 hours in 1
      and 15 days in the other). CONCLUSIONS: NTISPs may occur in about 12% of patients
      with sonographically detected nontraumatic spontaneous splenic rupture. NTISPs
      appear to be associated with an increased risk of secondary delayed splenic
      rupture, although spontaneous thrombosis may occur. Short-term follow-up
      sonographic examinations, particularly with color Doppler imaging, are
      recommended for early recognition of progression of NTISPs, which can guide
      treatment decisions.

PMID- 12594798
TI  - Duplex Doppler sonography of transplant renal artery stenosis.
AB  - PURPOSE: The aim of this study was to evaluate the accuracy of duplex Doppler
      sonography in diagnosing transplant renal artery stenosis (TRAS) and to determine
      which parameter is the most reliable for making that diagnosis. METHODS: Over a 3
      year period, we sonographically evaluated patients who were referred for
      investigation of possible TRAS. We investigated the following parameters: peak
      systolic velocity (PSV) in the external iliac and renal arteries, acceleration
      time and acceleration in the intrarenal arteries, acceleration time in the renal
      artery, resistance index, and the ratio of the PSVs in the renal and external
      iliac arteries. We also used MR angiography and digital subtraction arteriography
      to verify the degree of stenosis. After the evaluations, the patients were
      classified into 2 groups, 1 with and the other without significant stenosis (>
      50% narrowing of the lumen) on digital subtraction arteriography. We also
      included a control group of patients who had undergone renal transplantation at
      least 6 months before, had had a good course after transplantation, had a
      diastolic blood pressure of 90 mm Hg or less, and were taking a maximum of 1
      antihypertensive drug. RESULTS: Our study population consisted of 22 patients
      suspected to have TRAS (10 without and 12 with confirmed significant stenosis)
      and 19 control patients. We found statistically significant differences between
      the mean values of these 3 groups except for the PSV in the iliac artery and the
      resistance index in the intrarenal arteries. The most accurate parameters to use
      in diagnosing TRAS were an acceleration time of 0.1 second or higher in the renal
      and intrarenal arteries, a PSV of greater than 200 cm/second in the renal artery,
      and a ratio of PSVs in the renal and external iliac arteries of greater than 1.8.
      CONCLUSIONS: Duplex Doppler sonography is an excellent method for screening
      patients suspected to have TRAS and can help select which of those patients
      should undergo digital subtraction arteriography.

PMID- 12594799
TI  - Transcranial Doppler findings in middle cerebral arterial occlusive disease in
      relation to degree of stenosis and presence of concomitant stenoses.
AB  - PURPOSE: We evaluated the accuracy of transcranial Doppler (TCD) criteria in
      detecting middle cerebral artery (MCA) stenoses other than solitary severe
      stenoses. METHODS: Three TCD criteria were evaluated in patients with acute MCA
      territory infarction who also underwent angiography: abnormalities in mean
      velocity (MV), focal areas of spectral waveform abnormalities, and compensatory
      increase in MV in collateral vessels. RESULTS: Among 102 patients studied,
      angiography revealed MCA lesions in 48: 16 had uncomplicated lesions (single
      stenosis of moderate to severe degree), 19 had mildly complicated lesions (single
      MCA stenosis of other than moderate to severe degree, or moderate to severe MCA
      stenosis with a concomitant lesion outside the MCA), and 13 had severely
      complicated lesions (MCA stenosis of other than moderate to severe degree with a
      concomitant lesion outside the MCA). The sensitivity of abnormalities in MV in
      uncomplicated MCA lesions was 81%, whereas it was 53% in mildly complicated MCA
      lesions and 38% in severely complicated MCA lesions. However, a compensatory
      increase in MV in collaterals was more frequently found in complicated MCA
      lesions, and focal areas of spectral waveform abnormalities were observed fairly
      consistently in all groups. CONCLUSIONS: TCD findings of focal areas of spectral
      waveform abnormalities and compensatory collateral flow were common in
      complicated MCA lesions and may improve the specificity of TCD in the diagnosis
      of MCA stenosis.

PMID- 12594800
TI  - The small spleen: sonographic patterns of functional hyposplenia or asplenia.
AB  - PURPOSE: Functional hyposplenia or asplenia (FAS) can be associated with
      potential fatal infections. The diagnosis of FAS is traditionally made on liver
      spleen scintigraphy and finding Howell-Jolly bodies within erythrocytes. In this
      retrospective study, our goal was to identify any characteristic sonographic
      findings of the spleen in patients with FAS in an attempt to determine whether
      the diagnosis of FAS can be made sonographically. METHODS: In a review of all
      medical and sonographic records from the period of January 1, 1985, through
      December 31, 2001, we identified 24 patients (11 men, 13 women) in whom FAS had
      been diagnosed by liver-spleen scintigraphy (n = 13) or the finding of Howell
      Jolly bodies (n = 11). The following sonographic parameters were determined: size
      of spleen (small, normal, or large), echotexture of the spleen (homogeneous
      versus inhomogeneous), echogenicity (isoechoic versus hyperechoic), presence of
      focal splenic lesions, and patterns of splenic vascularization as determined by
      color Doppler sonography (absent flow, hilar flow, or parenchymal flow). RESULTS:
      The spleen was small in 20 patients (83%) and normal in the other 4 (17%).
      Echotexture was homogeneous in 13 patients (54%) and inhomogeneous in 11 (46%).
      The spleen was isoechoic in 18 cases (75%) and hyperechoic in 6 (25%). Six
      patients (25%) had focal lesions. Color Doppler sonography showed absent flow in
      4 patients (17%), hilar flow in 17 (71%), and hilar and parenchymal
      vascularization in 3 (12%). CONCLUSIONS: Sonographic findings in the spleen of
      patients with FAS are characterized predominantly by a small spleen with absence
      of parenchymal vascularization on color Doppler sonography in most cases. Future
      prospective studies will be necessary to confirm these findings and to determine
      whether FAS can be diagnosed reliably with sonography.

PMID- 12594801
TI  - Sliding appendiceal inguinal hernia: preoperative sonographic diagnosis.
AB  - We report the case of a 3-month-old boy with a right-sided sliding appendiceal
      inguinal hernia that was diagnosed preoperatively with sonography. Surgery was
      performed, and intraoperative and histopathologic evaluations also revealed
      changes in the appendix that could have led to complications if left untreated.
      The infant's recovery was uneventful, and he was discharged on the second day
      after surgery. This condition is usually diagnosed intraoperatively, and to the
      best of our knowledge, this is only the second report in the English-language
      medical literature in which such a case was correctly diagnosed preoperatively
      with sonography. In our case, the early sonographic diagnosis led to early
      intervention and the avoidance of potential complications.

PMID- 12594802
TI  - Pasteurella multocida tenosynovitis of the hand: sonographic findings.
AB  - Pasteurella multocida is a common cause of infection in humans subsequent to
      bites or scratches by dogs and, particularly, cats. This infection usually
      results in superficial skin and soft tissue infections. Sonography can be used
      for diagnosing inflammatory conditions affecting tendons, including acute and
      chronic tenosynovitis. P. multocida tenosynovitis is rare, and the diagnosis can
      be missed if adequate tests are not performed. We report 2 cases of P. multocida
      tenosynovitis of the hand and wrist in which sonography played a valuable role in
      assessing the affected tissues and guiding fine-needle aspiration of fluid
      accumulations in the involved tendon sheaths. The diagnosis was confirmed
      microbiologically in each case.

PMID- 12594803
TI  - Sonographic diagnosis of Bouveret's syndrome.
AB  - A case of Bouveret's syndrome with obstruction of the duodenojejunal flexure
      diagnosed preoperatively by sonography is presented. A 48-year-old man with a
      history of cholelithiasis presented with colicky pain of 2 days' duration. Real
      time sonography revealed a fluid-distended stomach and duodenum and a 3.4-cm
      bright curvilinear echo with dense shadowing in the duodenojejunal flexure,
      suggesting a gallstone. In addition, there was pneumobilia and evidence of
      chronic cholecystitis. The findings were confirmed with CT, which showed a
      partially calcified gallstone at the duodenojejunal flexure, pneumobilia, and a
      fistulous communication between the gallbladder and duodenum. At surgery, a large
      gallstone was found impacted at the duodenojejunal flexure. The stone and
      gallbladder were successfully removed and the fistula repaired. The sonographic
      diagnosis of Bouveret's syndrome enabled early surgical intervention.

PMID- 12594804
TI  - Twin gestation in one horn of a bicornuate uterus.
AB  - We report a rare case of twin pregnancy in the same horn of a bicornuate uterus.
      This patient's uterine malformation was detected for the first time when she
      experienced abdominal pain at 6 weeks of amenorrhea. Transabdominal and
      transvaginal sonographic examinations were performed. Both embryos showed cardiac
      motion on transvaginal sonography. The patient was re-examined monthly. Her
      pregnancy ended in spontaneous abortion at 22 weeks. Two live male fetuses were
      delivered, but they both died immediately after their birth. Sonography,
      particularly transvaginal sonography, is valuable for early detection of uterine
      abnormalities that may affect the outcome of pregnancy.

PMID- 12594805
TI  - Well-functioning double-orifice mitral valve in a young adult.
AB  - We report the case of a rare congenital anomaly, a double-orifice mitral valve,
      in a 23-year-old woman who was asymptomatic and had no history of heart disease.
      Transthoracic and multiplane transesophageal echocardiography revealed 2
      functionally normal orifices of equal size, the least frequent anatomic
      presentation of this anomaly. We prescribed antibiotic prophylaxis because of the
      concomitant presence of a mildly stenotic bicuspid aortic valve and recommended
      annual follow-up examinations to monitor both lesions for possible progression.

PMID- 12594806
TI  - A pivotal role for ERK in the oncogenic behaviour of malignant melanoma?
AB  - During the process of oncogenic transformation, melanoma cells escape from normal
      growth-control mechanisms and acquire the ability to invade surrounding tissues
      and organs. The Ras/Raf/MEK/ERK pathway is a major pathway involved in the
      control of growth signals, cell survival and invasion. Melanomas are known to
      harbour activating mutations of both Ras and BRAF, suggesting that the downstream
      effector ERK may be playing a major role in the oncogenic behaviour of these
      tumours. The past few years have seen a growth in the understanding of the role
      of ERK and the MAP kinase pathway in melanoma. The aim of the current review is
      to assess the role of ERK in melanoma behaviour and to determine whether
      modulation of these kinases could offer new therapeutic opportunities.

PMID- 12594807
TI  - Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex
      effect on migration of breast carcinoma cells.
AB  - Membrane type-1 matrix metalloproteinase (MT1-MMP) and alphavbeta3 integrin have
      been directly implicated in tumor cell dissemination and metastasis. We have
      demonstrated that in the case of breast carcinoma MCF7 cells co-expressing MT1
      MMP and alphavbeta3 integrin, the proteinase processes the pro-alphav integrin
      subunit, thus facilitating alphavbeta3 integrin maturation and cell migration on
      vitronectin. Our findings show that cell surface MT1-MMP is a short-lived protein
      with a life span in the range of several hours. In contrast, turnover of
      alphavbeta3 integrin is much slower. The half-life of alphavbeta3 heterodimer is
      about 24 hr. This large difference in life span allowed us to distinguish between
      the effects of MT1-MMP on cell migration brought by matrix proteolysis from those
      imposed through alphavbeta3 integrin maturation. We then modulated the enzyme's
      activity by a potent hydroxamate MMP inhibitor, Prinomastat (AG3340), to analyze
      the divergent effects of MT1-MMP on cell migration. Although Prinomastat
      immediately blocked MT1-MMP-mediated matrix degradation, the pool of MT1-MMP
      modified alphavbeta3 integrin molecules was still capable of mediating cell
      matrix interactions. To our considerable surprise, inhibition of MT1-MMP
      dependent vitronectin proteolysis by Prinomastat allowed a several-fold increase
      in migration of MCF7 cells co-expressing MT1-MMP and alphavbeta3 integrin. In
      contrast, long-term Prinomastat inhibition of MT1-MMP-dependent pro-alphav
      cleavage and thus alphavbeta3 integrin maturation strongly inhibited cell
      motility. Our studies suggest that MT1-MMP could actually promote cell migration
      via modification of the cell surface receptors, including alphavbeta3 integrin,
      rather than facilitate cell migration through direct cleavage of the matrix
      proteins.

PMID- 12594809
TI  - Different tumors in bone each give rise to a distinct pattern of skeletal
      destruction, bone cancer-related pain behaviors and neurochemical changes in the
      central nervous system.
AB  - Pain is the most common presenting symptom in patients with bone cancer and bone
      cancer pain can be both debilitating and difficult to control fully. To begin to
      understand the mechanisms involved in the generation and maintenance of bone
      cancer pain, we implanted 3 well-described murine tumor cell lines, 2472 sarcoma,
      B16 melanoma and C26 colon adenocarcinoma into the femur of immunocompromised C3H
      SCID mice. Although each of the tumor cell lines proliferated and completely
      filled the intramedullary space of the femur within 3 weeks, the location and
      extent of bone destruction, the type and severity of the pain behaviors and the
      neurochemical reorganization of the spinal cord was unique to each tumor cell
      line injected. These data suggest that bone cancer pain is not caused by a single
      factor such as increased pressure induced by intramedullary tumor growth, but
      rather that multiple factors are involved in generating and maintaining bone
      cancer pain.

PMID- 12594808
TI  - Radiation stimulates HGF receptor/c-Met expression that leads to amplifying
      cellular response to HGF stimulation via upregulated receptor tyrosine
      phosphorylation and MAP kinase activity in pancreatic cancer cells.
AB  - Hepatocyte growth factor (HGF) is a stromal-derived cytokine that plays a crucial
      role in invasion and metastasis of tumor cells through the interaction with HGF
      receptor, c-Met, which is frequently overexpressed in pancreatic cancer. The
      present study was designed to investigate the change in HGF receptor and HGF
      mediated signaling after irradiation in pancreatic cancer cells. Six cell lines
      from human pancreatic cancer were included in the study. Gamma-radiation was used
      for irradiation treatment. The changes in expression levels of c-Met were
      evaluated by immunoblot and confirmed morphologically by indirect
      immunofluorescence staining. Whether the resultant alteration in c-Met would
      cascade as biologically usable signals upon HGF ligation was traced by receptor
      tyrosine phosphorylation analysis and mitogen activated protein kinase (MAP
      kinase or MAPK) activity assay. The various biological responses to HGF
      (including cell proliferation, cell scattering, migration and invasion) were
      evaluated as well. We also used a 4-kringle antagonist of HGF, NK4, to block the
      HGF/c-Met signaling pathway. Both immunoblot and immunofluorescent analysis
      showed moderate increased expression of c-Met in 3 of 6 pancreatic cancer cell
      lines after irradiation. The actions seemed to be dose-responsible, which began
      at 3 hr and reached its peak value at 24 hr following irradiation. The radiation
      increased expression of c-Met could transform into magnifying receptor tyrosine
      phosphorylation reaction and MAP kinase activity once the ligand was added,
      fairly corresponding with alteration in the receptor. Sequentially, the cellular
      responses to HGF, including scattering and invasion but not proliferation, were
      enhanced. Also, in the presence of HGF, the elevated receptor could help to
      recover the radiation-compromised cell migration. A recombinant HGF antagonist,
      NK4 could effectively block these aberrant effects activated by irradiation both
      in molecular and cellular levels, thus suggesting the deep involvement of the c
      Met/HGF pathway in the enhanced malignant potential after irradiation. These
      results suggest that radiation may promote HGF-induced malignant biological
      behaviors of certain pancreatic cancer cells through the up-regulated HGF/c-Met
      signal pathway. Selectively targeted blockade of the HGF/c-Met pathway could help
      to abolish the enforced malignant behavior of tumor cells by irradiation and
      therefore may improve the efficacy of radiotherapy for pancreatic cancer.

PMID- 12594810
TI  - In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to
      human neuroblastoma.
AB  - Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. In
      advanced disease stages, prognosis is poor and treatments have limited efficacy,
      thus novel strategies are warranted. The synthetic retinoid Fenretinide (HPR)
      induces apoptosis in NB and melanoma cell lines. We reported an in vitro
      potentiation of HPR effects on melanoma cells when the drug is incorporated into
      GD2-targeted immunoliposomes (anti-GD2-SIL-HPR). We investigated the antitumor
      activity of anti-GD2-SIL-HPR against NB cells, both in vitro and in vivo. Anti
      GD2-SIL showed specific, competitive binding to and uptake by, various NB cell
      lines. In in vitro cytotoxicity studies, NB cells, incubated with 30 microM HPR
      entrapped in anti-GD2-immunoliposomes, showed a significant reduction in cellular
      growth compared to free HPR, HPR entrapped in Ab-free liposomes or anti-GD2 empty
      liposomes. In an in vivo NB metastatic model, we demonstrated that anti-GD2-SIL
      HPR completely inhibited the development of macroscopic and microscopic
      metastases in comparison to controls. Similar, but significantly less potent,
      antitumor effect was observed also in mice treated with anti-GD2 immunoliposomes
      without HPR (anti-GD2-SIL-blank) or anti-GD2 MAb alone (p = 0.0297 and p =
      0.0294, respectively, vs. anti-GD2-SIL-HPR). Moreover, our results clearly
      demonstrated that although anti-GD2 MAb had a strong antitumor effect in this in
      vivo NB model, 100% curability was obtained only after treatment with anti-GD2
      SIL-HPR (p < 0.0001). Anti-GD2 liposomal HPR should receive clinical evaluation
      as adjuvant therapy of neuroblastoma.

PMID- 12594811
TI  - Decrease of DNA methyltransferase 1 expression relative to cell proliferation in
      transitional cell carcinoma.
AB  - In many common cancers such as transitional cell carcinoma (TCC), specific genes
      are hypermethylated, whereas overall DNA methylation is diminished. Genome-wide
      DNA hypomethylation mostly affects repetitive sequences such as LINE-1
      retrotransposons. Methylation of these sequences depends on adequate expression
      of DNA methyltransferase I (DNMT1) during DNA replication. Therefore, DNMT1
      expression relative to proliferation was investigated in TCC cell lines and
      tissue as well as in renal carcinoma (RCC) cell lines, which also display
      hypomethylation, as indicated by decreased LINE-1 methylation. Cultured normal
      uroepithelial cells or normal bladder tissue served as controls. In all tumor
      cell lines, DNMT1 mRNA as well as protein was decreased relative to the DNA
      replication factor PCNA, and DNA hypomethylation was present. However, the
      extents of hypomethylation and DNMT1 downregulation did not correlate. Reporter
      gene assays showed that the differences in DNMT1 expression between normal and
      tumor cells were not established at the level of DNMT1 promoter regulation.
      Diminished DNMT1:PCNA mRNA ratios were also found in 28/45 TCC tissues but did
      not correlate with the extent of DNA hypomethylation. In addition, expression of
      the presumed de novo methyltransferases DNMT3A and DNMT3B mRNAs was investigated.
      DNMT3B overexpression was observed in about half of all high-stage TCC (DNMT3B
      vs. tumor stage, chi(2): p = 0.03), whereas overexpression of DNMT3A was rarer
      and less pronounced. Expression of DNMT3A and DNMT3B in most RCC lines was higher
      than in TCC lines. Our data indicate that DNMT1 expression does not increase
      adequately with cell proliferation in bladder cancer. This relative
      downregulation probably contributes to hypomethylation of repetitive DNA but does
      not determine its extent alone.

PMID- 12594812
TI  - Susceptibility of multidrug resistance tumor cells to apoptosis induction by
      histone deacetylase inhibitors.
AB  - The main goal of our study has been to analyze the efficiency of new anticancer
      drugs, specifically histone deacetylase inhibitors, in tumor cells bearing a
      multidrug resistance phenotype. We report that the histone deacetylase
      inhibitors, Trichostatin A and Suberoylanilide Hydroxamic Acid (SAHA),
      dramatically reduce cell viability and promote apoptosis in different drug
      resistant cells, affecting in a much lesser extent to their parental drug
      sensitive counterparts. The differential effects induced by Trichostatin A and
      SAHA between drug-sensitive and drug-resistant cells are reflected on the main
      characteristics of the resistant phenotype. Thus, reverse transcription-PCR and
      Western immunoblots confirm that both histone deacetylase inhibitors promote
      endogenous down-regulation of P-glycoprotein, which is overexpressed in the drug
      resistant cells. Transfection of drug-sensitive cells with the P-glycoprotein
      cDNA ruled out the a priori possible association between apoptosis and down
      regulation of P-glycoprotein induced by the histone deacetylase inhibitors. The
      results suggest a therapeutic potential of histone deacetylase inhibitors in the
      treatment of cancers with acquired resistance.

PMID- 12594813
TI  - Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells
      stably transfected with ER alpha.
AB  - Resveratrol (Res) is a phytoestrogen found in grapes and present in red wine. Res
      has been shown to function as an estrogen receptor (ER) agonist, but it remains
      unclear whether it may also exert antagonist activity. Our aim was to study the
      effects of Res at both the molecular (TGFalpha gene activation) and the cellular
      (cell growth) levels in breast cancer cells stably transfected with wild-type
      (wt) ER(D351) and mutant (mut) ER (D351Y). TGFalpha mRNA induction was used as a
      specific marker of estradiol (E(2)) responsiveness. Res caused a concentration
      dependent (10(-8)-10(-4) M) stimulation of TGFalpha mRNA, indicating that it acts
      as an estrogen agonist in these cell lines. The pure antiestrogen ICI 182,780
      (ICI) blocked Res-induced activation of TGFalpha, consistent with action through
      an ER-mediated pathway. Further studies that combined treatments with E(2) and
      Res showed that Res does not act as an antagonist in the presence of various (10(
      11)-10(-8) M) concentrations of E(2). To determine whether Res can be classified
      as a type I or type II estrogen (Jordan et al., Cancer Res 2001;61:6619-23,), we
      examined Res with the D351G ER in the TGFalpha assay and found that Res belongs
      to the type I estrogens. Both Res and E(2) had concentration-dependent growth
      inhibitory effects in cells expressing wtER and D351Y ER. Although the pure
      antiestrogen ICI blocked the growth inhibitory effects of E(2), it did not block
      the inhibitory effects of Res, suggesting that the antiproliferative effects of
      Res also involve ER-independent pathways. Interestingly, Res differentially
      affected the levels of ER protein in these 2 cell lines: Res down-regulated wtER
      levels while significantly up-regulating the amount of mutD351Y ER. Co-treatment
      with ICI resulted in strongly reduced ER levels in both cell lines. Gene array
      studies revealed Res-induced up-regulation of more than 80 genes, among them a
      profound activation of p21(CIP1)/WAF1, a gene associated with growth arrest. The
      p21(CIP1)/WAF1 protein levels measured by Western blotting confirmed Res-induced
      significant up-regulation of this protein in both cell lines. In summary, Res
      acts as an ER agonist at low doses but also activates ER-independent pathways,
      some of which inhibit cell growth.

PMID- 12594814
TI  - Expression of peroxisome proliferator-activated receptors (PPARs) in human
      urinary bladder carcinoma and growth inhibition by its agonists.
AB  - Recent studies have demonstrated that peroxisome proliferator activator
      receptors(PPAR)-gamma is expressed in various cancer tissues and its ligand
      induces growth arrest of these cancer cells through apoptosis. In our study, we
      investigated the expression of PPAR-alpha, beta and gamma in human bladder tumor
      (BT) and normal bladder (NB) tissues as well as the effects of PPAR-gamma
      ligands. Specimens were obtained from 170 patients with BT and 20 with NB. The
      expressions were investigated using RT-PCR and immunohistochemical methods. We
      also investigated the inhibitory effect of PPAR-gamma ligands on BT-derived cell
      line. Immunoreactive PPAR-alpha and -beta were significantly apparent in both BT
      and NB tissues. Although no marked expression of PPAR-gamma was observed in NB
      tissue, significant expression was found in BT tissue. The extent and intensity
      of immunoreactive PPAR-gamma polypeptides in BT cells were statistically much
      greater than those of NB cells. Correlation between PPAR-gamma expression and
      tissue type or progression of bladder cancer was observed; PPAR-gamma expression
      was higher in G3 of bladder cancer than in G1 and was higher in advanced than in
      early cancer. PPAR-gamma agonists, troglitazone and 15-deoxy-Delta(12, 14)
      prostaglandin J(2) inhibited the growth of the BT cells. PPAR-gamma is expressed
      in bladder tumor, and results suggest that PPAR-gamma ligands may mediate potent
      antiproliferative effects against BT cells. Thus, PPAR-gamma has the ability to
      become a new target in treatment of bladder tumor.

PMID- 12594816
TI  - Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and
      voided urine of urinary bladder cancer patients.
AB  - High frequency loss of 3p21.3 region where RASSF1A located was demonstrated in
      several tumors. We aimed to investigate the methylation status of RASSF1A and the
      frequency of LOH in 3p21.3 region in bladder cancer. Three bladder cancer cell
      lines, 40 cases of bladder TCC and 14 cases of paired voided urine samples were
      subjected to methylation analysis. By methylation specific PCR, complete
      methylation of promoter region of RASSF1A gene were detected in cell lines T24
      and UMUC3. Demethylation treatment re-expressed RASSF1A in these 2 cell lines.
      Methylation of RASSF1A was also detected in 47.5% (19/40) of the TCC cases but
      not in 6 carcinoma in situ (CIS) or 6 normal urothelium samples. For LOH study,
      loss of 3p21.3 region was detected in 57.9% (11/19) of our cases. Interestingly,
      methylation of RASSF1A was found in 72.7% (8/11) of the cases with LOH but only
      in 12.5% (1/8) of the cases without LOH. Methylation of RASSF1A was detected in
      50% (7/14) of voided urine samples, but not in normal control. It showed a higher
      sensitivity than conventional urine cytology in detecting cancer cells,
      especially for low grade cases. In conclusion, our results demonstrated a high
      frequency of RASSF1A methylation with frequent LOH in 3p21.3 region in bladder
      cancer. It suggested that it may be a potential tumor suppressor gene in this
      chromosomal region and can be silenced by promoter hypermethylation. Detection of
      aberrant gene methylation in routine voided urine was feasible and may provide a
      non-invasive and sensitive approach for cancer detection.

PMID- 12594815
TI  - Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF
      C autocrine loops.
AB  - Malignant mesothelioma (MM) is a locally aggressive tumor that originates from
      the mesothelial cells of the pleural and sometimes peritoneal surface.
      Conventional treatments for MM, consisting of chemotherapy or surgery give little
      survival benefit to patients, who generally die within 1 year of diagnosis.
      Hence, there is an urgent need for the development of alternative therapies.
      Vascular endothelial growth factor (VEGF) is an autocrine growth factor for MM.
      The closely related molecule, VEGF-C, is also implicated in malignant
      mesothelioma growth. VEGF-C and its cognate receptor VEGFR-3 are co-expressed in
      mesothelioma cell lines. A functional VEGF-C autocrine growth loop was
      demonstrated in mesothelioma cells by targeting VEGF-C expression and binding to
      VEGFR-3. The ability of novel agents that reduce the levels of VEGF and VEGF-C to
      inhibit mesothelioma cell growth in vitro was assessed. Antisense oligonucleotide
      (ODN) complementary to VEGF that inhibited VEGF and VEGF-C expression
      simultaneously specifically inhibited mesothelioma cell growth. Similarly,
      antibodies to VEGF receptor (VEGFR-2) and VEGF-C receptor (VEGFR-3) were
      synergistic in inhibiting mesothelioma cell growth. In addition, a diphtheria
      toxin-VEGF fusion protein (DT-VEGF), which is toxic to cells that express VEGF
      receptors was very effective in inhibiting mesothelioma cell growth in vitro.
      These results indicate that targeting VEGF and VEGF-C simultaneously may be an
      effective therapeutic approach for malignant mesothelioma.

PMID- 12594817
TI  - Interleukin-10 genotypes associate with the risk of gastric carcinoma in
      Taiwanese Chinese.
AB  - The association of cytokine genotypes with gastric carcinoma (GC) may be
      influenced by environmental factors and varies among different populations. Few
      studies have addressed the impact of different cytokine genotypes on the
      development and progression of GC. We analyzed 11 functional polymorphisms in
      tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-4 and IL-10 genes
      in 220 Taiwanese Chinese with GC and in 230 healthy controls. The risk of
      genotypes was adjusted with confounding environmental risks. Our results revealed
      that the frequency of Helicobacter pylori infection [odds ratio (OR) 1.7, 95%
      confidence interval (CI) 1.19-2.56], cigarette smoking (OR 2.02, 95% CI 1.38
      2.95) and high IL-10 producer genotype (OR 2.67, 95% CI 1.29-5.50) was
      significantly increased in the entire GC patients. Among different subtypes of
      GC, a higher risk of developing diffuse type (OR 1.64, 95% CI 1.01-2.67) or
      cardia cancer (OR 2.44, 95% CI 1.13-2.67) was observed for the CT/CC genotype of
      IL-4 at the position -590, whereas the high IL-10 producer genotype was
      significantly linked with the risk of cardia cancer (OR 3.21, 95% CI 1.06-9.73)
      or advanced stage (OR 2.29, 95% CI 1.12-4.64). No association was noted between
      GC and controls in the distribution of IL-1 and TNF-alpha genotypes. Logistic
      regression analyses revealed that H. pylori infection (OR 1.7, 95% CI 1.14-2.52),
      cigarette smoking (OR 1.87, 95% CI 1.27--2.96) and IL-10 genotype (OR 2.54, 95%
      CI 1.24-5.61) are independent risks for GC. Independent effects of IL-10
      genotype, H. pylori infection and cigarette smoking indicate that carcinogenesis
      of GC is influenced by a variety of host and environmental factors.

PMID- 12594818
TI  - Hodgkin lymphoma and Epstein-Barr virus (EBV): no evidence to support hit-and-run
      mechanism in cases classified as non-EBV-associated.
AB  - The Epstein-Barr virus (EBV) is associated with a proportion of Hodgkin lymphoma
      (HL) cases, and this association is believed to be causal. The aetiology of cases
      lacking EBV in the tumour cells (EBV HRS-ve), which make up the majority of cases
      in western countries, is obscure. It has been suggested that EBV may also cause
      these tumours by using a hit-and-run mechanism. Support for this idea comes from
      the finding that most young adult patients, who are likely to have a good immune
      response to EBV, have EBV HRS-ve HL. We investigated this possibility using a
      combined serologic and molecular approach. Analysis of EBV seroprevalence rates
      in an epidemiologic study of young adult HL revealed that cases with EBV HRS-ve
      HL were more likely to be EBV-seronegative than controls. Furthermore, additional
      studies clearly showed that some HL patients have never been infected by EBV.
      Quantitative PCR was used to look for the presence of deleted EBV genomes in a
      series of adult cases with both EBV HRS+ve and HRS-ve HL. Subgenomic fragments
      were detected in equimolar proportions. This study, therefore, found no evidence
      to support the idea that a hit-and-run mechanism involving EBV plays a role in
      the pathogenesis of HL.

PMID- 12594819
TI  - Expression of the free beta-subunit of human chorionic gonadotropin in renal cell
      carcinoma: prognostic study on tissue and serum.
AB  - Expression of the free beta-subunit of human chorionic gonadotropin (hCGbeta) in
      malignant tumors is frequently associated with aggressive disease. We have shown
      previously that the pretreatment serum concentration of hCGbeta is an independent
      prognostic variable in patients with renal cell carcinoma (RCC). We now compare
      the serum levels with the expression of hCGbeta antigen and mRNA in tumor tissue
      and studied whether these are associated with the clinical outcome. Serum samples
      were collected before surgery from patients with RCC (n = 256) and from 84
      apparently healthy controls. HCGbeta in serum was measured by a time-resolved
      immunofluorometric assay. Tissue expression was detected by immunohistochemical
      staining of a tissue microarray (TMA) comprising 229 samples, and in selected
      cases by reverse transcription polymerase chain reaction (RT-PCR) of hCGbeta mRNA
      (n = 20) from tumor tissue. The prognostic value of hCGbeta in serum and tissue
      and the association with usual clinicopathological variables was analyzed by the
      Kaplan-Meier method, the log-rank test, Cox multiple hazard regression, Mann
      Whitney U-test or Kruskal-Wallis test. The serum concentrations of hCGbeta were
      increased in 27% of the RCC patients and patients with increased hCGbeta levels
      had significantly shorter survival time than those with levels below the median
      (cut-off 1.2 pmol l(-1), p = 0.0044). HCGbeta antigen was detected in 15% (35 of
      229) of the tumors by immunohistochemistry, and hCGbeta mRNA in 8 of 20 samples
      (40%) by RT-PCR. Tissue positivity for hCGbeta antigen was not associated
      significantly with mRNA expression, serum concentrations of hCGbeta or survival.
      In multivariate analysis tumor stage, grade, size and serum hCGbeta were
      independent prognostic variables. The serum concentration of hCGbeta is an
      independent prognostic variable in RCC. Tissue expression of hCGbeta detected by
      immunohistochemistry occurs in 15% of RCCs but it is not significantly associated
      with prognosis. Expression at the mRNA level seems to be associated with other
      predictors of adverse outcome.

PMID- 12594820
TI  - Circulating levels of sex steroid hormones and risk of ovarian cancer.
AB  - Experimental and epidemiological evidence supports a role for sex steroid
      hormones in the pathogenesis of ovarian cancer. We investigated the association
      between ovarian cancer risk and pre-diagnostic blood concentrations of
      testosterone, androstenedione, DHEAS, estrone and SHBG. A case-control study
      nested within 3 cohorts, in New York (USA), Umea (Sweden) and Milan (Italy),
      included 132 subjects with primary invasive epithelial ovarian cancer. For each
      case subject, 2 controls were selected who matched a case on cohort, menopausal
      status, age and date of recruitment and, if premenopausal, day of the menstrual
      cycle at blood donation. Only women who did not use exogenous hormones at blood
      donation were included in the study. Conditional logistic regression was used to
      relate cancer risk to sex steroid hormone concentrations with adjustment for
      potential confounders. No clear association was observed between ovarian cancer
      risk and any of the 5 hormones under study. In the premenopausal group, the risk
      appeared to increase with increasing blood concentrations of androstenedione
      (upper vs. lower tertile OR = 2.35; 95% CI = 0.81-6.82.), but the small number of
      subjects in the sub-group precluded reaching unambiguous conclusions about such
      association. Our study does not support previous observations relating elevations
      in blood levels of the major sex steroid hormones to an increased risk of ovarian
      cancer, but offers some evidence that elevated circulating androstenedione before
      menopause may be associated with increased ovarian cancer risk.

PMID- 12594821
TI  - Sociodemographic determinants of incidence of primary fallopian tube carcinoma,
      Finland 1953-97.
AB  - Primary fallopian tube carcinoma is very rare. In Western countries, it accounts
      for about 1% of all female genital malignant tumors. Its etiology remains poorly
      known, but high parity is considered to be protective. We studied determinants of
      incidence of primary fallopian tube carcinoma in Finland. Incidence rates for
      primary fallopian tube carcinoma, according to the population based Finnish
      Cancer Registry, from 1953- 97 were assessed by age, year of diagnosis, and type
      of residential area. Standardized incidence ratios (SIRs) for the years 1971- 95
      were calculated by occupation and social class variables taken from the 1970
      Population Census. There were 485 cases of primary fallopian tube carcinoma
      registered during 45 years. The age-adjusted incidence rate increased from
      1.2/1000000 in 1953-57 to 5.4/1000000 in 1993-97. This 4.5-fold increase in
      incidence rate corresponds to a 7-fold increase in the number of new cases. The
      increase is attributable to the age group beyond 55 years, the peak incidence
      occurring between 60-64 years. Although the relative increase in incidence rate
      has been larger in rural areas than in cities, the rate in the latter remains 2
      fold. Women in the 2 highest social classes had a 1.8-fold incidence (95% CI =
      1.2-2.6) as compared to the lowest social class. Women in agriculture and those
      not working outside the home had only half the cancer incidence of those in
      academic or clerical occupations. The incidence of primary fallopian tube
      carcinoma increases in Finland. Evidently, the incidence has increased
      simultaneously with the affluence of urban life. Part of the variation in
      incidence correlates with variation in parity.

PMID- 12594822
TI  - Helicobacter pylori and carcinogenesis of gastric B-cell lymphomas.
AB  - Primary non-Hodgkin's lymphomas of the stomach are associated with Helicobacter
      pylori infection. We analyzed gastric lymphoma onset data with respect to prior
      H. pylori infections based on the multistage theory of carcinogenesis. This
      theory provides a link between epidemiological data and biological processes. The
      study involved 133 patients, aged 29-75 years, diagnosed with marginal zone B
      cell lymphoma (MZBL) and diffuse large cell B-cell lymphoma (DLBL). A 2
      parametric Weibull model was applied to MZBL and DLBL onset data. Median age of
      diagnosis of MZBL (DLBL) was 59 years (55 years) in males and 65.5 years (64
      years) in females. Infection with H. pylori was found in 81.3% (59.5%) of the
      patients diagnosed with MZBL (DLBL). Lymphoma latency data were fitted to Weibull
      distributions with a shape parameter of 5.7 for MZBL cases and 4.2 for DLBL. The
      shape parameter that indicates the number of steps in carcinogenesis was
      approximately independent of the status of infection with H. pylori in DLBL in
      contrast to MZBL. It was shown that gastric lymphoma onset data can be described
      by Weibull distribution functions. The findings support the hypothesis that MZBL
      and DLBL have different lines of development. There is indication of stronger
      antigen dependency in the carcinogenesis of MZBL in comparison to DLBL.

PMID- 12594823
TI  - CYP1A1 T3801 C polymorphism and lung cancer: a pooled analysis of 2451 cases and
      3358 controls.
AB  - CYP1A1 is involved in the metabolism of benzopyrene, a suspected lung carcinogen;
      it is therefore conceivable that genetically determined variations in its
      activity modify individual susceptibility to lung cancer. The role of the CYP1A1
      MspI polymorphism in lung cancer has been widely studied but has not been fully
      clarified. We have included 2,451 cases and 3,358 controls in a pooled analysis
      of 22 case-control studies on CYP1A1 and lung cancer risk. We found a clear
      association between the CYP1A1 homozygous MspI restriction fragment length
      polymorphism (RFLP) and lung cancer risk in Caucasians (age- and gender-adjusted
      odds ratio = 2.36; 95% confidence interval 1.16-4.81); other associations were
      weaker or not statistically significant. The association with the homozygous
      variant was equally strong for squamous cell carcinomas and adenocarcinomas among
      Caucasians. We analyzed the risk by duration of smoking: for Caucasian subjects
      with the MspI RFLP combined variants (homozygotes plus heterozygotes), the
      increase in the risk of lung cancer was steeper than among the individuals with
      the homozygous reference allele. Our analysis suggests that Caucasians with
      homozygous variant CYP1A1 polymorphism have a higher risk of lung cancer. The
      data were more consistent among Caucasians, with a strong association between the
      homozygous variant in both squamous cell carcinomas and adenocarcinomas, and a
      stronger association in men than in women. The analyses were more inconsistent
      and failed to reach statistical significance in Asians. This observation might be
      due to design specificities or unknown effect modifiers in the Asian studies.

PMID- 12594824
TI  - Expression of SH2D1A in five classical Hodgkin's disease-derived cell lines.
AB  - The Src homology 2 domain protein 1A (SH2D1A) is a small, 128-amino acid protein
      consisting of a single SH2 domain; it is probably involved in signal regulation.
      It is expressed in activated T and natural killer (NK) cells, but not in B
      lymphocytes. It was discovered in studies on the rare hereditary condition X
      linked lymphoproliferative disease (XLP). Individuals with this condition either
      lack or carry an altered protein. The serious symptoms (fatal mononucleosis)
      present almost exclusively at the first encounter with Epstein-Barr virus (EBV).
      The absence of SH2D1A in B cells, which are the targets of EBV, has to be
      reconciled with this clinical situation. In an earlier search for B lymphocytes
      expressing SH2D1A, we detected it in EBV-carrying type I Burkitt's lymphoma (BL)
      lines. We now show SH2D1A in 5 EBV-negative classical Hodgkin's disease (HD)
      derived cell lines. Two lines belong to the T lineage and 3 to the B lineage. One
      B-HD line, which originated from nodular lymphocyte-predominant Hodgkin's
      lymphoma and differed in phenotype, was SH2D1A-negative. This finding is in
      accordance with the previously reported abundant SH2D1A mRNA in Hodgkin and Reed
      Sternberg (HRS) cells. We thus found SH2D1A expression in lines of malignant
      origin assigned to the B lineage. Its presence in HRS cells may lead us closer to
      an understanding of the pathophysiology of the serious syndrome connected with
      EBV infection in XLP patients, because HRS-like cells have been detected in the
      lymphoid tissue of patients with infectious mononucleosis. It is likely therefore
      that in addition to the demonstrated functional defect of T and NK cells imposed
      by the SH2D1A mutation, the behavior of certain EBV-infected B lymphocytes is
      also modified.

PMID- 12594826
TI  - NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B
      cell antigen receptor.
AB  - Cross-linking of the B cell antigen receptor (BCR) with an anti-IgM antibody has
      been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells.
      However, the apoptotic mechanism triggered via BCR remains unknown. Here we
      reports a mechanism of BCR ligation-induced apoptosis involving protein
      phosphatase calcineurin and its specific substrate, transcriptional factor NF-AT.
      In response to BCR cross-linking, endogenous calcineurin was rapidly activated,
      and this facilitated nuclear translocation of NF-ATc2, a subtype of NF-AT
      members. Interestingly, nuclear-imported NF-ATc2 functioned pro-apoptotically in
      BL cells. The effect of NF-ATc2 was efficiently blocked with FK506, which
      prevented its nuclear translocation through inactivation of calcineurin. In
      addition, TR3 induction during BCR cross-linking was reduced by FK506 and the
      VIVIT peptide, which is a highly selective inhibitor for NF-AT. This strongly
      suggests that activation of NF-ATc2 by calcineurin is essential for TR3
      recruitment, and that TR3 can be considered as a candidate for death effector in
      BCR-mediated apoptosis. Therefore, NF-ATc2 plays a crucial role in BCR-mediated
      apoptosis in type IBL, providing greater insight into unique BL characteristics
      through BCR signaling.

PMID- 12594827
TI  - Beta-catenin expression in thymocytes accelerates thymic involution.
AB  - Age-related thymic involution in mammals is accompanied by decreased generation
      of naive T cells without significant reduction in the number of peripheral T
      cells. This leads to inefficient immune responses and inadequate combating of
      infections and other challenges to the immune system in older mammals. The
      molecular mechanisms that underlie this phenomenon are not known. In this report
      we show that expression of beta-catenin in thymocytes enhances thymic involution.
      The effect of beta-catenin expression is seen in all the thymic sub-populations,
      suggesting that an age-related developmental process is accelerated. We also show
      that, as in normal mice, thymic involution does not lead to a drastic reduction
      in splenic T cells in beta-catenin-transgenic mice. This study identifies beta
      catenin expression in thymocytes as a molecular target of age-related thymic
      involution.

PMID- 12594828
TI  - C-kit+ FcR+ myelocytes are increased in cancer and prevent the proliferation of
      fully cytolytic T cells in the presence of immune serum.
AB  - Immunogenic cancers induce both IgG antibodies and CD8(+) cytotoxic T lymphocytes
      (CTL). Rejection of almost all immunogenic tumors depends ultimately on CTL. When
      tumors grow progressively, IgG continues to be produced but CTL may no longer be
      demonstrable. Using syngeneic mixed lymphocyte tumor cell cultures, we found that
      proliferation of fully activated proliferating CTL is prevented by a small
      subpopulation of immature myeloid c-kit(+) FcR(+) cells, for convenience referred
      to as "barrier cells". Both, FcR on barrier cells and IgG linked to TGF-beta (IgG
      TGF-beta) present in immune serum, are obligatory for barrier cells to prevent
      proliferation of CTL, suggesting that IgG-TGF-beta binds FcR to activate
      suppression. Growing tumors increase barrier cells in the spleen. Interfering
      with the cells or molecules essential for barrier cells to prevent proliferation
      of CTL may enhance tumor and other CD8(+) CTL-mediated immunity.

PMID- 12594829
TI  - CD1a and CD1b surface expression is independent from de novo synthesized
      glycosphingolipids.
AB  - CD1 molecules resemble classical MHC molecules in structure, bind self and
      bacterial glycolipids and present them to T cells. Whether the CD1 antigen
      binding groove becomes filled during maturation and traffic to the cell surface
      is an important and still unsolved biological question. As most cell types
      synthesize complex glycosphingolipids (GSL), which also stimulate CD1-restricted
      T cells, it could be possible that these ligands associate with nascent CD1
      molecules. Here, we show that treatment of cells with drugs blocking at different
      levels the de novo and salvage pathways of GSL synthesis does not prevent surface
      expression of CD1a and CD1b. Furthermore, transfection of CD1A and CD1B genes in
      a mutant cell line unable to synthesize glucosylceramides and galactosylceramides
      showed normal surface expression of both CD1 molecules. Lack of GSL did not
      induce intracellular CD1 accumulation as indicated by confocal microscopy. The
      same results were obtained by transfecting the Lec series of mutants, which are
      deficient in sugar addition to glycolipids and glycoproteins. These findings
      demonstrate that endogenous de novo synthesized GSL are not mandatory for CD1a
      and CD1b negotiating surface expression.

PMID- 12594830
TI  - Generation of an effective anti-tumor immunity after immunization with xenogeneic
      antigens.
AB  - Central and peripheral tolerance mechanisms are expected to hamper the generation
      of effective immunity against tumors. To break self tolerance against malignant
      gliomas, we assessed the therapeutic potential of self/foreign antigen cross
      reactivity in an immunocompetent rat glioma model. Immunotherapy of tumors using
      xenogeneic human glioma membrane proteins (HGP) as a vaccine inhibited tumor
      growth, whereas no significant effect was obtained with rat glioma membrane
      proteins (RGP). In contrast to RGP, HGP elicited a specific IgG immune response
      that cross-reacted with RGP. This immune response was found to be mainly a Th1
      type response. On tumor sections stained with hematoxylin and eosin, glioma cells
      are sparse and apoptotic in HGP-immunized rats, whereas control tumors showed
      condensed and viable cells. Tumor-specific CTL were induced in HGP-immunized
      rats. Immunohistochemical analysis revealed that a significant number of CD8(+)
      and CD4(+) cells infiltrated into tumors from HGP-vaccinated rats, whereas RGP
      vaccination led to only few tumor-infiltrating T cells. Taken together, the data
      establish the in vivo applicability of the cross-stimulation between self and
      foreign antigens as an alternative way to break tolerance against the poorly
      immunogenic gliomas.

PMID- 12594831
TI  - Association of T cell antigen CD7 with type II phosphatidylinositol-4 kinase, a
      key component in pathways of inositol phosphate turnover.
AB  - CD7 is a 40-kDa glycoprotein that is expressed on prothymocytes and persists
      during T cell differentiation. CD7 has been demonstrated to generate, like other
      costimulatory molecules, intracellular signals that modulate T cell function.
      However, although it binds to phosphatidylinositol 3-kinase (PI 3-kinase), the
      signaling events mediated by CD7 are not completely understood. In this context,
      phosphatidylinositol 4-kinase (PI 4-kinase) is a key enzyme involved in a variety
      of events, from the modeling of the actin cytoskeleton to the activation of
      protein kinase C. In this study, we show for the first time that PI 4-kinase of
      55 kDa can associate with CD7. The enzyme activity was insensitive to wortmannin,
      but was inhibited by adenosine, a characteristic for type II PI 4-kinase.
      Together, our findings demonstrate that type II PI 4-kinases are integral
      components of the CD7 signaling pathway and may play a role of CD7 in co
      stimulation and thymic differentiation.

PMID- 12594832
TI  - Membrane-bound form of fractalkine induces IFN-gamma production by NK cells.
AB  - Natural killer (NK) cells participate in both innate and adaptive immunity, in
      part by their prompt secretion of cytokines including IFN-gamma, a pro
      inflammatory cytokine with an important role in Th1 polarization. To assess the
      involvement of fractalkine in inflammatory processes, we examined the effect of
      fractalkine on IFN-gamma production by NK cells. Although soluble chemokines,
      including MCP-1 and RANTES as well as fractalkine, had a negligible effect on IFN
      gamma production, immobilized fractalkine markedly induced IFN-gamma production
      by NK cells in a dose-dependent manner. Pretreatment of NK cells with the
      phosphatidylinositol 3-kinase (PI 3-K) inhibitor, wortmannin, completely
      inhibited the production of IFN-gamma induced by fractalkine, and pretreatment
      with the protein tyrosine kinase inhibitor, herbimycin A, partially suppressed
      the response, suggesting that augmentation of IFN-gamma production in response to
      fractalkine treatment of NK cells involves signaling through PI 3-K and protein
      tyrosine kinases. Furthermore, co-culture of NK cells with fractalkine
      transfected 293E cells markedly enhanced IFN-gamma production by NK cells
      compared with co-culture with control 293E cells. These findings may indicate a
      paracrine feedback loop system in which endothelial cells may be activated to
      produce more fractalkine, and also suggest a role for fractalkine expressed on
      endothelial cells in Th1 polarization through the stimulation of IFN-gamma
      production by NK cells.

PMID- 12594833
TI  - Severe Mycobacterium bovis BCG infections in a large series of novel IL-12
      receptor beta1 deficient patients and evidence for the existence of partial IL-12
      receptor beta1 deficiency.
AB  - Cell mediated immunity plays a critical role in human host defence against
      intracellular bacteria. In patients with unusual, severe infections caused by
      poorly pathogenic species of mycobacteria and salmonellae, genetic deficiencies
      have been identified in key genes in the type-1 cytokine pathway, especially in
      IFNGR1 and IL12RB1. Here, we analyzed 11 patients originating from Turkey and
      suffering from unusual Mycobacterium bovis Bacille Calmette-Guerin infections
      following vaccination, and found that most patients (n=8) are deficient in IL
      12Rbeta1 expression and function. No defects were found in patients' IFN-gammaR
      or IL-18R. In addition, a first patient suffering from partial IL-12Rbeta1
      deficiency is described. This patient presented with an intermediate cellular and
      immunological phenotype: a consistent, low response to IL-12 was found, which
      could be further augmented by IL-18. Despite a lack of cell surface IL-12Rbeta1
      expression, normal levels of intracellular IL-12Rbeta1 protein were detectable,
      which was not seen in the other, completely IL-12Rbeta1 deficient patients
      examined. Moreover, this patient had a relatively mild clinical phenotype and was
      the only individual with a single homozygous amino acid substitution in IL
      12Rbeta1 (C198R). Collectively, our findings indicate that idiopathic, unusually
      severe infections due to M. bovis BCG can be caused by complete as well as
      partial IL-12Rbeta1 deficiency.

PMID- 12594834
TI  - Concerted action of perforin and granzymes is critical for the elimination of
      Trypanosoma cruzi from mouse tissues, but prevention of early host death is in
      addition dependent on the FasL/Fas pathway.
AB  - CTL and NK cells are critical for resistance to acute Trypanosoma cruzi
      infection, but are also implicated in the pathology induced by this intracellular
      protozoan parasite. Here we explore to what extent the two main cytolytic
      pathways of CTL and NK cells, i.e. the granule exocytosis and the Fas ligand
      (FasL)/Fas pathways, are responsible for the elimination of parasites from mouse
      tissues and control of organ pathology. For this purpose we have employed mouse
      strains with targeted gene defects in one or more components - including
      perforin, granzyme A and granzyme B, and Fas - of either of the two cytolytic
      pathways, and we used the highly pathogenic T. cruzi strain Tulahuen. We show
      that parasites are effectively cleared from infected tissues independently of the
      FasL/Fas pathway by the concerted action of perforin and the two granzymes.
      However, prevention of pathology and early host death is critically dependent in
      addition on an operational FasL/Fas interaction. Thus, in contrast to C57BL/6
      (B6) wild-type mice, mouse strains with deficiencies in either the FasL/Fas or
      the perforin/granzyme pathway similarly suffer from early death, independently of
      their differential capacity to control parasite growth; this finding indicates
      that the two cytolytic pathways control distinct but vital processes during
      infection with T. cruzi.

PMID- 12594835
TI  - Clonally expanded CD4+CD28null T cells in rheumatoid arthritis use distinct
      combinations of T cell receptor BV and BJ elements.
AB  - Clonally expanded, autoreactive CD4(+)CD28(null) cells can be found in the
      peripheral blood of patients with rheumatoid arthritis and have been shown to be
      associated with severeextra-articular disease manifestations. We investigated the
      size of the CD4(+)CD28(null) compartment and the TCR beta chain repertoire of
      expanded CD4(+) clonotypes in 94 rheumatoid arthritis patients by complementarity
      determining region 3 (CDR3) length analysis (spectratyping) in the BV6 and BV14
      TCR families, with primers specific for three arbitrarily chosen beta chain
      joining elements (BJ1S2, BJ2S3 and BJ2S7). The spectratyping results showed a
      strong correlation of the size of the CD4(+)CD28(null) compartment with the
      detected number of BV14 clonotypes, whereas no association with BV6
      oligoclonality was found. Only clones using the BV14-BJ1S2 and BV14-BJ2S3
      combinations contributed to this correlation, however, whereas BV14-BJ2S7 clones
      did not. This preferential correlation implies a role for the TCR beta chain in
      stimulating clonal outgrowth and argues against the previously suggested
      superantigenic stimulation of in-vivo-expanded clones. Instead, since no evidence
      for shared antigen specificity could be detected, clonal expansion of T cells in
      rheumatoid arthritis might be influenced by the BJ elements because of changes in
      the flexibility of the protein backbone of the beta-chain.

PMID- 12594837
TI  - Natural killer cell-mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D
      interactions.
AB  - Natural killer cells have been reported to be able to kill various transformed
      and virus-infected target cells. It was recently observed that NK cells also
      could kill syngeneic dorsal root ganglia (DRG) neurons by a perforin-dependent
      mechanism. We demonstrate here that this phenomenon does not reflect a general
      ability of NK cells to kill neurons in culture. While DRG neurons of the
      peripheral nervous system were readily killed, ventral spinal cord neurons and
      hippocampal neurons of the central nervous system (CNS) were resistant to lysis.
      The resistance to NK cell-mediated lysis of the latter neurons was not related to
      protection by MHC class I molecules, since similar beta(2)-microglobulin(-/-)
      neurons were equally resistant to lysis. While exploring other possible molecular
      mechanisms for the selective triggering of lysis of DRG neurons, we observed that
      the retinoic acid early inducible gene-1 (RAE-1), the product of which is a
      ligand for the NK cell-activating receptor NKG2D, was expressed at high levels in
      the DRG neurons. In contrast, RAE-1 was expressed only at very low levels in the
      resistant CNS-derived neurons. Blocking NK cells withanti-NKG2D antibodies
      inhibited NK cell-mediated killing of the DRG neurons. Thus, we demonstrate that
      NK cell-mediated lysis of DRG neurons correlates with the expression of RAE-1 and
      that this lysis is dependent on activation of NK cells via NKG2D. This
      observation demonstrates that NK cells can kill non-pathogen-infected or non
      transformed syngeneic cells through activation of the NKG2D receptor.

PMID- 12594836
TI  - Dok protein family members are involved in signaling mediated by the type 1
      Fcepsilon receptor.
AB  - Aggregation of type 1 Fcepsilon receptors (FcepsilonRI) on mast cells activates a
      biochemical cascade that culminates in secretion of inflammatory mediators, as
      well as in changes of cell morphology and adhesion properties. Some of the
      intracellular components involved in the early coupling events are still
      unidentified. Here we show that two adaptor proteins, downstream of tyrosine
      kinases (Dok)-1 and Dok-2, are involved in the FcepsilonRI coupling cascade in
      the rat mucosal-type mast cells of the RBL-2H3 line. Dok-1 is found to be
      constitutively associated with the FcepsilonRI, even in untreated cells, and this
      interaction is not affected by this receptor's aggregation. Both Dok forms
      undergo a fast and relatively long-term tyrosyl-phosphorylation. This
      modification of Dok-1 increases its association with RasGAP, suggesting that it
      is modulating Ras activity. Indeed, we further found that FcepsilonRI-mediated
      Ras/Raf1/Erk signaling as well as the de novo synthesis of TNF-alpha are markedly
      reduced in cells overexpressing Dok-1. Moreover, FcepsilonRI clustering causes
      both Dok-1 and Dok-2 to become docking sites for other signaling molecules
      including Nck, CrkL and Cas. The latter proteins have been implicated
      particularly in regulation of the actin-cytoskeletal reorganization. Hence Dok
      1/Dok-2 may also be involved in the FcepsilonRI-stimulated processes of
      cytoskeleton rearrangement required for cell adhesion, membrane ruffling and
      exocytosis.

PMID- 12594838
TI  - The ability of murine dendritic cell subsets to direct T helper cell
      differentiation is dependent on microbial signals.
AB  - Dendritic cells (DC) initiate T cell responses and direct the class of T cell
      immunity through the production of Th-polarizing cytokines. In the mouse,
      immunization with CD8alpha(+) DC has led to Th1 priming whereas immunization with
      CD8alpha(-) DC has been associated with Th2 induction. Here, we use a direct T
      cell priming assay in vitro to re-examine the Th-directing potential of total DC
      or purified CD4(+) DC, CD8alpha(+) DC or CD4(-) CD8alpha(-) (double-negative; DN)
      DC subsets from mouse spleen. We show that the default Th effector phenotype
      induced by priming with DC depends on the protocol used for T cell purification,
      the T cell:antigen-presenting cell ratio and the antigen dose but is only
      marginally affected by DC subtype. All DC subsets can direct increased Th1
      development in response to microbial stimuli known to elicit IL-12 production.
      Similarly, all subsets can suppress Th1 development and allow Th2 cellsto expand
      upon exposure to IL-10-inducing microbial agents. The flexibility of DC in
      directing Th development in function of microbial signals argues against the
      notion of pre-determined "DC1" and "DC2" subsets and suggests that multiple DC
      subtypes can direct an appropriate Th response to different classes of infectious
      agents.

PMID- 12594839
TI  - Experimental African trypanosomiasis: IFN-gamma mediates early mortality.
AB  - In this study, we demonstrate that Kupffer cells in the livers of highly
      susceptible BALB/c mice infected with Trypanosoma congolense were loaded with
      trypanosomal antigen and appeared highly activated. This was associated with an
      enlarged capillary bed in the livers and decreased blood pressure of these mice
      towards the terminal stage. Blocking of murine IL-10 receptor (IL-10R)in vivo
      shortened the survival time of highly susceptible T. congolense-infected BALB/c
      mice. Anti-IL-10R treatment decreased the survival of relatively resistant T.
      congolense-infected C57BL/6 mice dramatically. Blocking of the IL-10R also
      significantly shortened the survival time of mice infected with T. brucei. The
      acute death of trypanosome-infected mice treated with anti-IL-10R antibodies in
      vivo was associated with focal liver necrosis, with significantly increased
      plasma levels of IL-6, IL-10, IL-12p40 and IFN-gamma and enhanced synthesis of IL
      6, IL-12p40 and IFN-gamma by spleen cell cultures. Anti-IL-10R-induced death of
      T. congolense-infected C57BL/6 mice could be prevented by administration of a
      neutralizing antibody specific forIFN-gamma. We conclude that phagocytosis of a
      critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory
      response syndrome and, depending on the degree of Kupffer cell activation, is
      followed by death that is mediated by IFN-gamma. The role of trypanosome-pulsed
      macrophages, T cells and genetic influences is discussed in a synopsis.

PMID- 12594840
TI  - Preferential apoptosis of CD56dim natural killer cell subset in patients with
      cancer.
AB  - Natural killer (NK) cells (CD56(+)/CD3(-)) in the circulation of cancer patients
      were reported to have low NK activity and undergo spontaneous apoptosis. A
      possible relationship between apoptosis and impaired NK activity was studied by
      Annexin V-binding and NK-cell assays performed with peripheral blood mononuclear
      cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal
      controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3,
      CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was
      tested against K562 targets in 4-h (51)Cr-release assays. The ratio of
      CD56(dim)/CD56(bright) NK cells was significantly different in patients vs.
      controls (10 vs. 16; p<0.01). A significantly greater percentage of CD56(dim) NK
      cells bound Anx in HNC patients (27+/-17%, median +/- SD) or BC (46+/-18%) than
      in NC (15+/-18%, p<0.04 and p<0.0002, respectively). CD56(dim) NK cells were
      preferentially targeted for apoptosis. NK activity was significantly lower in
      patients with HNC and BC than in NC (p<0.009). An inverse correlation between NK
      activity and the percent of Anx(+)CD56(dim) NK cells was observed in cancer
      patients (p =0.002) but not in NC. In patients, circulating CD56(dim) NK cells
      were targeted for apoptosis, leading to low levels of NK activity.

PMID- 12594841
TI  - Soluble HLA-A,-B,-C and -G molecules induce apoptosis in T and NK CD8+ cells and
      inhibit cytotoxic T cell activity through CD8 ligation.
AB  - There is convincing evidence that soluble HLA-A,-B,-C (sHLA-A,-B,-C) and soluble
      HLA-G (sHLA-G) antigens can induce apoptosis in CD8(+) activated T cells although
      there is scanty and conflicting information about the mechanism(s) by which sHLA
      A,-B,-C antigens and sHLA-G antigens induce apoptosis. In this study we have
      compared the apoptosis-inducing ability of sHLA-A,-B,-C antigens with that of
      sHLA-G1 antigens in CD8(+) T lymphocytes and CD8(+) NK cells. Furthermore we have
      compared the inhibitory effect of sHLA-A,-B,-C antigens and of sHLA-G1 antigens
      on the activity of EBV-specific CD8(+) cytotoxic T lymphocytes (CTL). sHLA
      molecules were purified from serum and from the supernatant of HLA class I
      negative cells transfected with one gene encoding either classical or non
      classical HLA class I antigens. Both classical and non-classical sHLA class I
      molecules trigger apoptosis in CD8(+) T lymphocytes and in CD8(+) NK cells, which
      lack the T cell receptor, and their apoptotic potency is comparable. The binding
      of sHLA-A,-B,-C and sHLA-G1 molecules to CD8 leads to Fas ligand (FasL) up
      regulation, soluble FasL (sFasL) secretion and CD8(+) cell apoptosis by Fas/sFasL
      interaction. Moreover, classical and non-classical sHLA class I molecules inhibit
      the cytotoxic activity of EBV-specific CD8(+) CTL. As the amount ofsHLA-G
      molecules detectable in normal serum is significantly lower than that of sHLA-A,
      B,-C molecules, the immunomodulatory effects of sHLA class I molecules purified
      from serum are likely to be mainly attributable to classical HLA class I
      antigens. As far as the potential in vivo relevance of these findings is
      concerned, we suggest that classical sHLA class I molecules may play a major
      immunoregulatory role in clinical situations characterized by activation of the
      immune system and elevated sHLA-A,-B,-C serum levels. In contrast, non-classical
      HLA class I molecules may exert immunomodulatory effects in particular conditions
      characterized by elevated sHLA-G levels such as pregnancy and some neoplastic
      diseases.

PMID- 12594842
TI  - Anti-CD28 has a potent adjuvant effect on the antibody response to soluble
      antigens mediated through CTLA-4 by-pass.
AB  - With the surge in potential new vaccines produced as recombinant proteins or
      synthetic peptides has come a pressing need to identify safe, potent
      immunological adjuvants to enhance immunogenicity of these antigens. CD28 is an
      important costimulatory molecule for T cells, and it has been shown that cell
      surface expression of its ligands, CD80 and CD86, can enhance cellular immune
      responses against tumor cells, however, these tumor cells do not normally express
      the ligands. Many new vaccines will be based upon soluble recombinant antigens,
      and in vaccination with these antigens CD80 and CD86 would normally be expressed
      on activated antigen-presenting cells and additional stimulation through CD28
      would not be predicted to enhance responses further. However, we show here that,
      surprisingly, CD28 antibody can very strongly enhance immune responses against
      soluble proteins, but only when directly attached to the antigen. The mode of
      action of CD28 antibodies appears to be linked to their ability to signal through
      CD28, but not to bind the negative feedback regulatory antigen, CTLA-4. CD28
      stimulants may represent novel, highly effective and safe immunological adjuvants
      for use with a wide range of prophylactic and therapeutic vaccines.

PMID- 12594844
TI  - The kidney as a second site of human C-reactive protein formation in vivo.
AB  - C-reactive protein (CRP) is the main acute phase reactant in humans. Its
      production is presumably restricted to the liver but extrahepatic expression by
      inflamed tissue has not been studied in detail. By real-time PCR and
      immunohistochemistry we here show that renal cortical tubular epithelial cells
      (TEC) express CRP mRNA and protein within 6 h after stimulation with conditioned
      medium (CM) or IL-6, but not IL-1alpha or TNF-alpha. Western blot analysis with
      monoclonal anti-CRP antibody that recognizes native CRP revealed protein
      secretion into supernatants of CM-stimulated TEC cultures. While hepatoma-derived
      Hep3B cells could be induced similarly, peripheral blood mononuclear cells could
      not. CRP mRNA transcripts were observed in nephrectomized renal allografts with
      severe acute rejection but not with chronic allograft nephropathy (CAN). Of 19
      needle biopsies of acutely rejecting kidney transplants, 15 demonstrated CRP mRNA
      production with the relative expression levels increasing with the severity of
      rejection. On the other hand, none of 7 graft biopsies with acute tubular
      necrosis (ATN) or CAN showed CRP mRNA expression. By using monoclonal anti-CRP
      antibody, cortical tubules as well as glomerular cells were shown to locally
      express CRP in rejecting, but not in ATN kidneys. We conclude that inflamed
      kidneys represent a so far unknown site of CRP formation in vivo. These data shed
      new light on the acute phase reaction not merely representing a systemic
      inflammatory pathway but probably being part of the local immune response.

PMID- 12594843
TI  - Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell
      populations in the colonic mucosa of patients with Crohn's disease.
AB  - Dentritic cells (DC) as antigen-presenting cells are most likely responsible for
      regulation of abnormal T cell activation in Crohn's disease (CD), a chronic
      inflammatory bowel disease. We have analyzed the expression of activation and
      maturation markers on DC in the colon mucosa from patients with CD compared with
      normal colon, using immunohistochemical techniques. We found two distinct
      populations of DC present in CD patients: a DC-specific ICAM-3 grabbing non
      integrin (DC-SIGN)(+) population that was present scattered throughout the
      mucosa, and a CD83(+) population that was present in aggregated lymphoid nodules
      and as single cells in the lamina propria. In normal colon the number of DC
      SIGN(+) DC was lower and CD83(+) DC were detected only in very few solitary
      lymphoid nodules. Co-expression of activation markers and cytokine synthesis was
      analyzed with three-color confocal laser scanning microscopy analysis. CD80
      expression was enhanced on the majority of DC-SIGN(+) DC in CD patients, whereas
      only a proportion of the CD83(+) DC co-expressed CD80 in CD as well as in normal
      tissue. Surprisingly, IL-12 and IL-18 were only detected in DC-SIGN(+) DC and not
      in CD83(+) DC. A similar pattern of cytokine production was observed in normal
      colon albeit to a much lesser extent. The characteristics of these in-situ
      differentiated DC markedly differ from the in-vitro-generated DC that
      simultaneously express DC-SIGN, CD83 and cytokines.

PMID- 12594845
TI  - Naive CD8+ T cell recruitment and proliferation are dependent on stage of
      dendritic cell maturation.
AB  - Dendritic cells (DC) play a crucial role in controlling the initiation and
      orientation of antigen (Ag)-specific immune responses. It is widely accepted that
      optimal T cell priming requires mature DC. Although the molecular events
      associated with DC activation have been extensively studied, little is known
      about the consequences of DC maturation on recruitment and expansion of naive T
      cells. In the present study, we used a model tumor Ag to show that the kinetics
      of human DC maturation drastically affect the induction of Ag-specific effector
      CD8(+) T cells. In absence of exogenous cytokines and CD4 help, only DC at early
      stages of maturation were able to generate high frequencies of CTL. This
      expansion resulted from both enhanced recruitment and intense proliferation ofT
      cell precursors and could lead to an increase of up to 1,000-fold in the final
      number of effector T cells compared to non-matured DC. In our model, larger
      recruitment of naive CD8(+) cells did not modify the overall avidity of the Ag
      specific T cell population.

PMID- 12594846
TI  - Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal
      model for autoimmune disease studies.
AB  - Linkage studies indicate close associations of certain HLA alleles with
      autoimmune diseases. To better understand how specific HLA alleles are related to
      disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing
      a 550-kb yeast artificial chromosome (YAC) construct containing the complete
      DRalpha, DRbeta1, DRbeta3, DQalpha, and DQbeta regions. The transgenic mouse
      (4D1/C2D) in an I-Abeta(o) background appears healthy with no signs of autoimmune
      diseases. Lymphoid tissues as well as CD4(+) T cells develop normally.
      Characterization of the transgene expression demonstrates that approximately 90%
      of B cells express high levels of DR3 and 50-70% of B cells express DQ2. CD11c(+)
      dendritic cells express high levels of DR and DQ. Approximately 12-18% of resting
      T cells are positive for DR expression, and further up-regulation to 40-50%
      expression is seen upon activation with anti-CD3/anti-CD28 mAb. These results
      suggest that the transgenic construct confers a high fidelity to the normal human
      temporal and spatial expression profile. Analysis of T cell receptor repertoire
      in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection.
      Furthermore, transgenic mice respond to a DR3-restricted antigen, demonstrating
      antigen processing and presentation by antigen-presenting cells (APC). Purified T
      cells from ovalbumin (OVA)-immunized 4D1 mice respond to human APC co-cultured
      with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T
      cells. Immunoglobulin isotype switching is also observed, indicating functional T
      B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid
      development and functionality that are mediated by HLA transgenes and can be used
      to investigate HLA-associated immunological questions.

PMID- 12594847
TI  - NKT cells are dispensable in the induction of oral tolerance but are
      indispensable in the abrogation of oral tolerance by prostaglandin E.
AB  - NK1.1(+) alpha beta T cells (NKT cells) regulate the Th1/Th2 balance in response
      to dietary Ag, which may be involved in regulation of oral tolerance. OVA
      specific IgE and IgG(1) Ab levels were significantly lower following an i.p.
      injection of OVA (in CFA) in C57BL/6 mice orally given a single, high dose (25
      mg) of OVA than in those orally given PBS. The oral tolerance was normally
      induced in Jalpha281(-/-) mice which lack Valpha14(+) NKT cells, suggesting that
      NKT cells are dispensable for induction of oral tolerance. Treatment with PGE(1)
      or PGE(2 )abrogated the oral tolerance in Jalpha281(+/+) mice; this abrogation
      was accompanied by an OVA-specific Th2-dominant response. The abrogation of oral
      tolerance by PGE(1 )was not evident in Jalpha281(-/-) mice. Treatment with PGE(1)
      induced an early increase in IL-4 production by liver NKT cells in normal mice
      and neutralization of the early IL-4 by administration of anti-IL-4 mAb abolished
      PGE(1)-induced abrogation of oral tolerance. These results suggest that liver NKT
      cells producing IL-4 are responsible for the down-regulation of oral tolerance
      that is caused by the PGE molecules.

PMID- 12594848
TI  - Selective intracellular retention of virally induced NKG2D ligands by the human
      cytomegalovirus UL16 glycoprotein.
AB  - Human cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to
      evade the antiviral immune defense of the host. Recently, using soluble
      recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some
      ligands of the activating immunoreceptor NKG2D and, therefore, may also function
      as a viral immunomodulator. However, the role of UL16 during the course of HCMV
      infection remained unclear. Here, we demonstrate that HCMV infection of
      fibroblasts induces expression of all known NKG2D ligands (NKG2DL). However,
      solely MICA and ULBP3 reach the cellular surface to engage NKG2D, whereas MICB,
      ULBP1 and ULBP2 are selectively retained in the endoplasmic reticulum by UL16.
      UL16-mediated reduction of NKG2DL cell surface density diminished NK
      cytotoxicity. Thus, UL16 functions by capturing activating ligands for cytotoxic
      lymphocytes that are synthesized in response to HCMV infection.

PMID- 12594849
TI  - Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP
      kinase pathways.
AB  - H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR
      signals have been analyzed in mouse CD4(+) Th2 cells, expressing H4/ICOS at
      higher levels than Th1 clones. Anti-H4/ICOS antibodies strongly enhanced CD3
      mediated tyrosine phosphorylation of ZAP-70, zeta, or Vav, as well as
      extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38
      MAP kinase activation in these cells. The association of phosphoinositide 3
      kinase (PI-3K) to H4/ICOS was enhanced by H4/ICOS cross-linking, and PI-3K
      inhibitors inhibited ERK and JNK activation and IL-4/IL-10 secretion, but not p38
      MAP kinase or ZAP-70 activation. H4/ICOS-mediated activation of JNK, but not ERK
      or p38, is partially dependent on the expression of CD4 by the cells, whereas
      H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin
      D, an inhibitor of actin polymerization, inhibited ZAP-70, MAP kinase activation,
      or IL-4/IL-10 secretion. Neither cyclosporin A nor inhibitors of PKC produced
      detectable inhibition of ZAP-70 phosphorylation or MAP kinase activation in these
      Th2 cells. Cyclosporin A strongly inhibited IL-4, but not IL-10 secretion. ERK or
      JNKinhibitors partially inhibited IL-4 and IL-10 secretion, while PKC or p38
      inhibitors had no significant effects on IL-4 or IL-10 secretion. Taken together,
      our data show clear similarities of costimulation mechanisms between H4/ICOS and
      CD28 during the early steps of TCR activation.

PMID- 12594850
TI  - Isolation and functional characterization of regulatory CD25brightCD4+ T cells
      from the target organ of patients with rheumatoid arthritis.
AB  - In the homeostasis of the immune system regulatory cells play a major role.
      Removal of one group of regulatory cells, the CD25(+)CD4(+) T cells, leads to
      autoimmune manifestations in experimental animal models, and reintroduction of
      this population prevents disease. This study addresses the role of such
      regulatory T cells in humans with an autoimmune disease, where we demonstrate the
      presence of CD25(bright)CD4(+) T cells in the target organ of patients with
      active rheumatoid arthritis. The patients displayed an enrichment of
      CD25(bright)CD4(+) T cells in synovial fluid as compared to peripheral blood.
      These cells are functional regulatory cells, as they were able to suppress in
      vitro proliferation of autologous T cells, both from synovial and peripheral
      blood origin. Although the frequency of CD25(bright)CD4(+) T cells varied between
      patients, it was found to be constant over time in any one joint during each
      relapse. Numbers were also comparable in two inflamed knee joints of one and the
      same patient, emphasizing the symmetry of the disease. In summary, it is striking
      that in addition to all activated, potentially pathological T cells the synovial
      fluid from RA patients also contains CD25-expressing CD4(+) T cells with a
      regulatory capacity.

PMID- 12594851
TI  - Prevention of mucosally induced uveitis with a HSP60-derived peptide linked to
      cholera toxin B subunit.
AB  - Oral administration of the uveitogenic peptide (aa 336-351) derived from human
      HSP60 induced clinical and histological manifestations of uveitis in 65.8%
      (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in
      parallel experiments with the peptide linked to recombinant cholera toxin B
      subunit (rCTB), also given by mouth (chi(2)=34.2, p<0.0001). The protective
      efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of
      mesenteric lymph node cells from tolerized rats prevented the development of
      uveitis. A significantly higher proportion of regulatory CD4(+)CD45RC(low)RT6(+)
      subset of Th2 memory cells were found in the mesenteric lymph nodes (p<0.005) and
      spleens (p</=0.05) of tolerized rats without uveitis, as compared with immunized
      rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or
      the uveal tract showed significant increases in IL-10 and TGF-beta mRNA but
      decreases in IFN-gamma and IL-12 mRNA in tolerized, as compared with immunized
      animals. Thus, the mechanism of tolerance, preventing the development of uveitis
      may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and
      Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral
      administration of the peptide-rCTB conjugate.

PMID- 12594852
TI  - Intramuscular transfer of naked calcitonin gene-related peptide gene prevents
      autoimmune diabetes induced by multiple low-dose streptozotocin in C57BL mice.
AB  - The imbalance of Th1/Th2 subsets is an important pathogenic mechanism for insulin
      dependent diabetes mellitus (IDDM). Calcitonin gene-related peptide (CGRP) has
      been found to play important roles in the regulation of T lymphocytes. We
      hypothesize that exogenous CGRP administration during insulitis may modulate the
      balance of Th lymphocytes, thereby providing a therapeutic intervention for IDDM.
      We established CGRP gene transfer by naked plasmid injection into the skeletal
      muscles with electroporation enhancement. The effect of CGRP gene transfer on
      pathogenesis of IDDM was observedin autoimmune diabetic C57BL mice induced by
      multiple low-dose streptozotocin (MLDS) administration. The treatment
      significantly decreased morbidity of diabetes, ameliorated hyperglycemia and
      insulin deficiency, and inhibited lymphocyte infiltration into the islets,
      indicating the protection of beta cells against autoimmune destruction. CGRP gene
      transfer significantly inhibited T cell proliferation and secretion of the Th1
      cytokine IFN-gamma, increased the level of the Th2 cytokine IL-10, but had no
      effect on IL-4 and TGF-beta1 secretion. CGRP gene transfer also decreased IL-12
      and IFN-gamma levels in peritoneal effusion. Our results demonstrate that CGRP
      gene transfer selectively suppresses the pro-inflammatory Th1 subsets and promote
      anti-inflammatory Th2 subsets, resulting in amelioration of beta cell destruction
      and reduction of IDDM occurrence in mice with MLDS-induced diabetes.

PMID- 12594853
TI  - Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN-gamma
      production induced by IL-12 alone or together with IL-18.
AB  - IL-12 activates TYK2 and Janus kinase (JAK)-2 to induce the phosphorylation of
      various signal transducers and activators of transcription (STAT) proteins.
      However, little is known regarding how these JAK exhibit the distinct biological
      effects of IL-12. Using two JAK inhibitors, tyrphostin A1 (A1) for TYK2 and
      tyrphostin B42 (B42) for JAK2, we investigated the involvement of JAK2 and TYK2
      in IL-12-induced T cell proliferation and IFN-gamma production. B42, but not A1,
      inhibited T cell proliferation along with down-regulation of IL-12-induced c-Myc
      expression and STAT5 phosphorylation. In contrast, A1 but not B42 inhibited
      STAT4/STAT3 phosphorylation and IFN-gamma production. IL-18, but not IL-12,
      induced activator protein-1 (AP-1) responsible for high levels of IFN-gamma
      promoter activation. However, this IL-18 effect depended on the interaction of AP
      1 with STAT4. A1 prevented AP-1 binding by inhibiting STAT4 involvement and down
      regulated synergistic IFN-gamma promoter activation. These results indicate that
      JAK2 activation is required for IL-12-mediated T cell growth, whereas the TYK2
      STAT4 signaling pathway is critical for IFN-gamma expression that is mediated by
      IL-12 alone and enhanced synergistically by combination with IL-18.

PMID- 12594854
TI  - Double-edged effect of Vgamma9/Vdelta2 T lymphocytes on viral expression in an in
      vitro model of HIV-1/mycobacteria co-infection.
AB  - A reciprocal influence exists between mycobacteria and HIV: HIV-infected
      individuals are more susceptible to mycobacterial infections and, on the other
      hand, mycobacterial infection results inacceleration of HIV disease progression.
      Vgamma9/Vdelta2 T lymphocytes are known to participate in the defense against
      intracellular pathogens, including Mycobacterium tuberculosis. Indeed, they kill
      mycobacteria-infected macrophages and, upon recognition of mycobacterial Ag,
      release TNF-alpha and IFN-gamma, which are also up-regulators of HIV expression.
      To assess whether mycobacteria-activated gamma delta T lymphocytes contribute to
      the enhancement of HIV replication, we established an in vitro model mimicking
      HIV and mycobacteria co-infection with the latently HIV-infected promonocytic U1
      cell line and Vgamma9/Vdelta2 peripheral lymphocytes stimulated with
      mycobacterial Ag. gamma delta T cell activation determined two distinct, but
      connected effects, namely U1cell death and HIV expression. Both effects were
      mainly mediated by release of TNF-alpha and IFN-gamma from activated gamma delta
      lymphocytes, although Fas-FasL interaction also contributed to U1 apoptosis. The
      final outcome on U1 survival, and thus, on HIV expression, highly depended on
      mycobacterial Ag concentration coupled to the differential secretory potency of
      gamma delta cells. In particular, the induction of viral expression prevailed at
      low Ag concentration and with lower cytokine production by mycobacteria-activated
      gamma delta cells. Notably, during the course of HIV infection, Vgamma9/Vdelta2
      lymphocytes are reported to be functionally impaired and may thus indirectly
      influence the progression of HIV disease. In addition, a predominant inhibition
      of viral replication was encountered when mycobacteria-activated gamma delta T
      cells were co-cultured with primary HIV-infected macrophages. Thus, we suggest
      that specific recognition of mycobacterial Ag by gamma delta T lymphocytes in co
      infected individuals may modulate viral replication through the complex array of
      soluble factors released.

PMID- 12594857
TI  - Reproducibility of oligonucleotide arrays using small samples.
AB  - BACKGROUND: Low RNA yields from small tissue samples can limit the use of
      oligonucleotide microarrays (Affymetrix GeneChips). Methods using less cRNA for
      hybridization or amplifying the cRNA have been reported to reduce the number of
      transcripts detected, but the effect on realistic experiments designed to detect
      biological differences has not been analyzed. We systematically explore the
      effects of using different starting amounts of RNA on the ability to detect
      differential gene expression. RESULTS: The standard Affymetrix protocol can be
      used starting with only 2 micrograms of total RNA, with results equivalent to the
      recommended 10 micrograms. Biological variability is much greater than the
      technical variability introduced by this change. A simple amplification protocol
      described here can be used for samples as small as 0.1 micrograms of total RNA.
      This amplification protocol allows detection of a substantial fraction of the
      significant differences found using the standard protocol, despite an increase in
      variability and the 5' truncation of the transcripts, which prevents detection of
      a subset of genes. CONCLUSIONS: Biological differences in a typical experiment
      are much greater than differences resulting from technical manipulations in
      labeling and hybridization. The standard protocol works well with 2 micrograms of
      RNA, and with minor modifications could allow the use of samples as small as 1
      micrograms. For smaller amounts of starting material, down to 0.1 micrograms RNA,
      differential gene expression can still be detected using the single cycle
      amplification protocol. Comparisons of groups of four arrays detect many more
      significant differences than comparisons of three arrays.

PMID- 12594855
TI  - A major role for tapasin as a stabilizer of the TAP peptide transporter and
      consequences for MHC class I expression.
AB  - Tapasin is a member of the MHC class I loading complex where it bridges the TAP
      peptide transporter to class I molecules. The main role of tapasin is assumed to
      be the facilitation of peptide loading and optimization of the peptide cargo.
      Here, we describe another important function for tapasin. In tapasin-deficient
      (Tpn(-/-)) mice the absence of tapasin was found to have a dramatic effect on the
      stability of the TAP1/TAP2 heterodimeric peptide transporter. Steady-state
      expression of TAP protein was reduced more than 100-fold from about 3 x 10(4) TAP
      molecules per wild-type splenocyte to about 1 x 10(2) TAP per Tpn(-/-)
      splenocyte. Thus, a major function of murine tapasin appears to be the
      stabilization of TAP. The low amount of TAP moleculesin Tpn(-/-) lymphocytes is
      likely to contribute to the severe impairment of MHC class I expression.
      Surprisingly, activation of Tpn(-/-) lymphocytes yielded strongly enhanced class
      I expression comparable to wild-type levels, although TAP expression remained low
      and in the magnitude of several hundred molecules per cell. The high level of
      class I on activated Tpn(-/-) cells depended on peptides generated by the
      proteasome as indicated by blockade with the proteasome-specific inhibitor
      lactacystin. Lymphocyte activation induced an increase in ubiquitinated proteins
      that are cleaved into peptides by the proteasome. These findings suggest that in
      the presence of a large peptide pool in the cytosol, a small number of TAP
      transporters is sufficient to translocate enough peptides for high class I
      expression. However, these class I molecules were less stable than those of wild
      type cells, indicating that tapasin is not only required for stabilization of TAP
      but also for optimization of the spectrum of bound peptides.

PMID- 12594859
TI  - Principles and problems in surgical infections. Introduction.

PMID- 12594858
TI  - Genomic organization of ATOX1, a human copper chaperone.
AB  - BACKGROUND: Copper is an essential trace element that plays a critical role in
      the survival of all living organisms. Menkes disease and occipital horn syndrome
      (OHS) are allelic disorders of copper transport caused by defects in a X-linked
      gene (ATP7A) that encodes a P-type ATPase that transports copper across cellular
      membranes, including the trans-Golgi network. Genetic studies in yeast recently
      revealed a new family of cytoplasmic proteins called copper chaperones which bind
      copper ions and deliver them to specific cellular pathways. Biochemical studies
      of the human homolog of one copper chaperone, ATOX1, indicate direct interaction
      with the Menkes/OHS protein. Although no disease-associated mutations have been
      reported in ATOX1, mice with disruption of the ATOX1 locus demonstrate perinatal
      mortality similar to that observed in the brindled mice (Mobr), a mouse model of
      Menkes disease. The cDNA sequence for ATOX1 is known, and the genomic
      organization has not been reported. RESULTS: We determined the genomic structure
      of ATOX1. The gene contains 4 exons spanning a genomic distance of approximately
      16 kb. The translation start codon is located in the 3' end of exon 1 and the
      termination codon in exon 3. We developed a PCR-based assay to amplify the coding
      regions and splice junctions from genomic DNA. We screened for ATOX1 mutations in
      two patients with classical Menkes disease phenotypes and one individual with
      occipital horn syndrome who had no alterations detected in ATP7A, as well as an
      adult female with chronic anemia, low serum copper and evidence of mild dopamine
      beta-hydroxylase deficiency and no alterations in the ATOX1 coding or splice
      junction sequences were found. CONCLUSIONS: In this study, we characterized the
      genomic structure of the human copper chaperone ATOX1 to facilitate screening of
      this gene from genomic DNA in patients whose clinical or biochemical phenotypes
      suggest impaired copper transport.

PMID- 12594860
TI  - Basic aspects of and general problems in surgical infections.
AB  - Antibiotics are important in the prophylaxis and treatment of surgical infections
      as well as in the management of nosocomial infections acquired postoperatively in
      surgical patients. Surgeons encounter a range of infectious conditions, including
      established single-pathogen infections of soft tissues, polymicrobial intra
      abdominal infections, and resistant gram-negative nosocomial infections such as
      ventilator-associated and aspiration pneumonia. Preoperative antibiotic
      administration has been shown to reduce the risk of surgical site infections and
      is now an accepted part of the standard care for most surgical patients. In
      patients with established single-pathogen or polymicrobial infections requiring
      surgery, studies have shown appropriate empiric antibiotic therapy to be an
      important adjunct to surgical intervention and general supportive measures in
      improving patient outcome. Antibiotics are also essential for those who develop
      postoperative nosocomial infections. Empiric coverage of the most likely
      causative organisms, especially in synergistic polymicrobial mixed infections, is
      one of the keys to successful prophylaxis and treatment of surgical infections.

PMID- 12594861
TI  - The importance of beta-lactamase resistance in surgical infections.
AB  - Substantial costs are associated with the treatment of nosocomial infections, 2
      million cases of which occur annually in the United States. Hospital-acquired,
      gram-negative infection has become an increasing problem, particularly in the
      intensive care unit where up to 40% of the most frequently isolated strains of
      Enterobacteriaceae are resistant to standard beta-lactam antibiotics. Among
      several mechanisms of acquisition of resistance, beta-lactamase production
      accounts for a high percentage of treatment failures and relapses. By the end of
      the 1980s, some 10-30% of all nosocomial infections were caused by type-1 beta
      lactamase-producing gram-negative isolates, and Enterobacter species had emerged
      as a major resistant pathogen. The beta-lactam/beta-lactamase inhibitor
      combinations, such as ampicillin/sulbactam, represent an innovative approach to
      the problem of beta-lactamase-mediated resistance. Clinical use of these agents
      has been associated with low rates of resistance and new data suggest they may
      have a specific role in controlling the emergence and spread of nosocomial
      infections.

PMID- 12594862
TI  - The role of beta-lactam/beta-lactamase inhibitor combinations in surgical
      infections.
AB  - Many surgical infections are characterized by synergistic polymicrobial mixed
      infection, for which broad-spectrum antimicrobial therapy is usually administered
      on an empiric basis. Until relatively recently, standard empiric therapeutic
      regimens have involved the use of two or more antibiotics, such as
      aminoglycosides and anti-anaerobic agents, to achieve adequate aerobic and
      anaerobic coverage. There are often substantial drawbacks, however, such as drug
      induced toxicity and high costs of treatment. Evidence from a number of clinical
      studies suggests that single-agent therapy with beta-lactam/beta-lactamase
      inhibitor combinations is a suitable and cost-effective alternative to multidrug
      regimens, as well as to monotherapy with cephalosporins or carbapenems in the
      treatment of intra-abdominal, gynecologic, and diabetic foot infections, and
      brain abscesses. These agents are also suitable for use in perioperative
      prophylaxis and may offer benefits over other agents in terms of reduced
      incidence of surgical wound infections and lower costs.

PMID- 12594863
TI  - Ask not for whom the bell tolls (ceftazidime), it tolls for thee.

PMID- 12594864
TI  - Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise.
AB  - BACKGROUND: Inhibition of nitric oxide synthase (NOS) has held promise as a novel
      and important therapeutic target for sepsis for over a decade. However, the
      question as to whether an inhibitor of NOS will prove to be efficacious in human
      septic shock remains unanswered. METHODS: Review of the pertinent English
      language medical literature. RESULTS: Observations of the induction of NOS (iNOS,
      NOS2) by proinflammatory cytokines led to the hypothesis that nitric oxide (NO)
      relaxes vascular smooth muscle, thereby producing vasodilation and hypotension in
      sepsis. Other effects of NO in vascular tone may be manifested by refractoriness
      to vasopressors or myocardial dysfunction. However, such negative effects of NO
      are balanced by the role of NO in maintaining microvascular perfusion and host
      defenses against invading pathogens. Initial animal studies of septic shock
      modulated by the administration of competitive inhibitors of NOS demonstrated
      that NOS inhibition might be beneficial therapy for clinical septic shock.
      However, subsequent animal studies have produced variable results, and a phase
      III clinical trial of a nonselective NOS inhibitor has failed to show benefit for
      therapy of septic shock. CONCLUSION: A better understanding of the effects of NOS
      and its inhibitors is needed as is an understanding of the underlying
      pathophysiology of sepsis. Moreover, a nontoxic, short-acting, titratable,
      specific inhibitor of NOS2 has yet to be identified and tested. Until then,
      efforts should be designed to describe more completely the role of NO in the
      pathophysiology of sepsis.

PMID- 12594865
TI  - Hazardous crossing: immunosuppression and nosocomial infections in solid organ
      transplant recipients.
AB  - BACKGROUND: During the past decade, ever-increasing numbers of patients have
      undergone renal, pancreatic, small bowel, hepatic, cardiac, or lung
      transplantation as therapy for various types of renal disease requiring dialytic
      therapy. Indications for solid organ transplantation include type I and, rarely,
      type II diabetes mellitus; hyperalimentation-dependent short gut syndrome; and
      formerly fatal liver, cardiac, or pulmonary failure. Significant improvements in
      patient and allograft survival have been observed in all categories.
      Unfortunately, despite such improved results, the risks of infection related to
      immunosuppression continue to be substantial. METHODS: Review of pertinent
      studies from the English literature. RESULTS: Suppression of host defenses by
      exogenous immunosuppressive agents renders patients susceptible to invasion by
      either resident or environmental bacterial, fungal, viral, and protozoal microbes
      or parasites. In such patients, invasion of organisms that produce mild infection
      in nonimmunosuppressed individuals can produce severe, lethal disease. Moreover,
      even low-virulence microbes may invade, proliferate, and cause disease in the
      immunosuppressed host; such organisms are referred to as "opportunistic"
      pathogens when they cause disease under these conditions. CONCLUSION: Advances in
      the field of transplantation have been substantial, particularly in the
      regulation of therapeutic immunosuppression, in prophylactic measures to prevent
      infection, and in more effective diagnosis and treatment modalities.

PMID- 12594866
TI  - Controversies in the management of necrotizing enterocolitis.
AB  - BACKGROUND: Necrotizing enterocolitis (NEC) is the most frequent and lethal
      disease that affects the gastrointestinal tract of the premature infant.
      Controversy persists as to the most appropriate management once the diagnosis is
      confirmed. METHODS: Review of the pertinent medical literature. RESULTS: The
      incidence of NEC is increasing, but the survival rate is not. Initial management
      of NEC consists of bowel rest, orogastric decompression, intravenous hydration,
      and broad-spectrum antibiotics; surgical intervention is typically reserved for
      infants with advanced disease or evidence of intestinal perforation. There is no
      consensus in the literature regarding the optimal treatment strategy for patients
      who require surgical intervention. There exists a lack of randomized trials
      comparing definitive intestinal resection with or without primary anastomosis,
      intestinal diversion with limited resection, or peritoneal drainage without
      resection. CONCLUSION: An individualized approach must be taken to achieve
      optimum survival for patients with NEC. Isolated perforation, in our opinion, is
      best managed with resection and enterostomy, whereas pan-intestinal involvement
      is best managed with proximal diversion alone.

PMID- 12594867
TI  - Herpesviruses: emerging nosocomial pathogens?
AB  - BACKGROUND: Herpesviruses are ubiquitous pathogens that are known to cause
      infection in humans and animals. It is likely that more than 90% of adults have
      been infected by one or more herpesviruses. As hospitalized patients become
      increasingly immunosuppressed by virtue of illness or therapies, it is
      increasingly likely that human herpesvirus infection will become manifest in the
      hospital. Whether these manifestations represent manifestations of reactivated
      latent disease or true nosocomial infections is an open question. METHODS: Review
      of the pertinent English-language literature. RESULTS: There are eight known
      herpesviruses that cause disease in humans. Herpesviruses are double-stranded DNA
      viruses. The prototypical structure consists of an inner DNA core that is encased
      within a nucleocapsid that is icosahedral in configuration and consists of
      capsomere subunits. Herpesvirus infection generally occurs when virus is
      transmitted in oral secretions from an infected to a naive host. Clinical
      reactivation syndromes can occur in transplant patients, cancer chemotherapy
      patients, and patients with acquired immunodeficiency syndrome. Life-threatening
      infections are most closely associated with human herpesvirus-5
      (cytomegalovirus), whereas the relationships between human herpesvirus-7 and
      clinical disease are largely undefined. CONCLUSION: Clinical expressions of
      herpesvirus in surgical patients are not nosocomial infections, but are in the
      vast majority of cases the reactivation of latent infection. Reactivation disease
      can be lethal to the immunosuppressed host.

PMID- 12594869
TI  - Necrotizing soft tissue infections: are we making any progress?
AB  - BACKGROUND: Necrotizing soft tissue infections are a group of diseases with
      significant associated mortality. A wide spectrum of bacteria can be involved,
      and diagnosis can be difficult. METHODS: Review of pertinent literature of the
      diagnosis and therapy of necrotizing soft-tissue infection. RESULTS: Mortality
      and other adverse outcomes are directly related to advanced age, the presence of
      organ system failure, lactic acidemia, the percentage of body surface area
      involved with infection, and delays in operative management. Patients usually die
      early from the consequences of septic shock, whereas late mortality is related to
      multiple organ failure. CONCLUSION: Early recognition and treatment can lower
      mortality from necrotizing soft tissue infection. Prompt operative debridement,
      broad-spectrum antimicrobials, and physiologic support are important components
      of treatment.

PMID- 12594868
TI  - Ethanol abuse and the trauma patient.
AB  - BACKGROUND: Alcohol intoxication has long been associated with an increased risk
      of injury from a number of mechanisms and with trauma recidivism. It is less
      certain whether alcohol abuse is associated with worse outcomes for a given
      degree of injury. METHODS: Review of the pertinent English-language literature.
      RESULTS: The vasodilator effects of alcohol may hamper fluid resuscitation,
      especially in head-injured patients. Acute and chronic alcohol intoxication both
      have substantial effects on the cellular and molecular responses necessary to
      fight infection. High alcohol concentrations exert an immunosuppressive effect on
      production of proinflammatory cytokines such as tumor necrosis factor and
      interleukin-1. However, the clinical effects of the immunosuppression are
      variable and difficult to discern in heterogeneous trauma patient populations
      with variable degrees of intoxication. CONCLUSION: Alcohol has a profound impact
      on the epidemiology of injury, but the physiology and biochemical effects in an
      individual patient may be difficult to predict. Identification of intoxicated
      persons is essential, despite economic disincentives to do so, because even brief
      targeted intervention programs can decrease substantially the patient's risk of
      subsequent injury.

PMID- 12594870
TI  - Relevance and utility of peritoneal cultures in patients with peritonitis.
AB  - BACKGROUND: The pathogenic organisms responsible for the manifestations of
      secondary peritonitis have been well characterized through almost 30 years of
      experimental and clinical studies. Enteric gram-negative organisms and anaerobes
      predominate, with Escherichia coli and Bacteroides fragilis, respectively, being
      the most frequent isolates. This flora is remarkably consistent across patients
      and institutions. As a result of this consistency and the availability of well
      established effective empiric antimicrobial regimens, many surgeons believe that
      cultures of peritoneal exudates in patients with peritonitis offer no useful
      information and no clinical benefit. METHODS: Review of pertinent antibiotic and
      management trials in the management of intraabdominal infection. RESULTS: There
      is increasing evidence that identification of organisms resistant to the chosen
      empiric antibiotic regimen portends a higher likelihood of failure. What is not
      clear is whether postoperative changes in the regimen in accordance with
      sensitivity patterns of the isolates offers any clinical advantage. In most
      circumstances, the data provided allow for simplification of the antibiotic
      regimen. CONCLUSION: The potential for reducing antibiotic exposure and the value
      of information derived from surveillance of microbial sensitivity patterns
      support the routine performance of peritoneal cultures.

PMID- 12594871
TI  - Peritoneal host defenses: modulation by carbon dioxide insufflation.
AB  - BACKGROUND: The host response to inflammatory stimuli in the peritoneal cavity
      consists of coordinated interactions of physical factors, cells, and soluble
      mediator molecules. Following infection, this is characterized by rapid
      eradication of large numbers of bacteria via the diaphragmatic lymphatics,
      clearance of bacteria through phagocytosis and intracellular killing, and,
      finally, sequestration of residual bacteria by inflammatory fibrinous exudate.
      Increasingly, surgical infections and major operations with the potential for
      postoperative infection are being managed laparoscopically, with CO(2)
      insufflation. The effects of CO(2) on intraperitoneal host defenses are still
      being defined. METHODS: Review of the pertinent literature and results from our
      laboratory. RESULTS: Exposure of peritoneal macrophages in vitro to CO(2) causes
      intracellular acidification, which in turn suppresses production of tumor
      necrosis factor (TNF) in response to exposure to lipopolysaccharide (LPS). In
      comparison, neither room air nor helium had any effect on cytosolic pH or the
      peritoneal macrophage response to LPS. Insufflation of CO(2) into the
      preperitoneal space in vivo caused similar peritoneal lining acidosis and reduced
      TNF production compared with insufflation of helium. CONCLUSION: CO(2)
      pneumoperitoneum created during laparoscopy appears to exert immunosuppressive
      effects through its ability to acidify the intracellular compartment of
      inflammatory cells. This may contribute to the improved recovery in patients
      undergoing laparoscopic surgery.

PMID- 12594872
TI  - New alternatives in management of the infected vascular prosthesis.
AB  - BACKGROUND: Infection of vascular prosthetics implanted for arterial occlusive
      disease occurs in approximately 1-5% of patients, including early and late
      clinical presentation. The incidence of infection depends on the anatomical site,
      with the highest rate occurring in vascular access grafts placed for hemodialysis
      and in inguinal and lower extremity incisions in patients undergoing bypass
      procedures for femoropopliteal tibial occlusion. Treatment of prosthetic graft
      infection has traditionally included antimicrobials, excision of the infected
      prosthesis, and extraanatomical bypass. With the recognition that prosthetic
      infection secondary to Staphylococcus epidermidis can be managed with less
      extensive procedures, clinical data have been reported on in situ replacement
      with antibiotic-bonded prostheses. Patients who have S. aureus isolated,
      including methicillin-resistant S. aureus, or gram-negative pathogens, still
      require conventional graft excision and extraanatomical bypass. METHODS:
      Selective review of the English-language literature. RESULTS: Recent clinical
      series show that management by graft excision of infected infrarenal aortic
      prosthetics and axillofemoral bypass results in 2- and 5-year survival rates of
      67% and 47%, and limb salvage rates in survivors of 93% and 82% at 2 and 5 years.
      In situ replacement with a rifampicin-bonded prosthesis has been accomplished
      successfully in smaller numbers of patients and shows promising early results.
      Other methods under study include cryopreserved arterial and femoral vein
      allografts and autogenous femoral vein grafts, but data are limited when used as
      replacement for infected prosthetics. CONCLUSION: Advances in the management of
      infected vascular prostheses over the last decade have led to improved mortality
      and decreased amputation rates with conventional excision and extraanatomical
      bypass. Newer methods including in situ graft replacement with antibiotic
      impregnated prosthetics appear suitable for low-virulence S. epidermidis
      infection. Early results are promising for cryopreserved allografts and
      autogenous femoral vein in situ grafts; however, more clinical experience and
      longer follow-up will be needed to confirm their durability in a contaminated
      field.

PMID- 12594873
TI  - Consensus statement on submission and publication of manuscripts.

PMID- 12594875
TI  - The pneumonia conundrum.

PMID- 12594877
TI  - The use of computed tomography for the diagnosis of acute appendicitis in
      children does not influence the overall rate of negative appendectomy or
      perforation.
AB  - BACKGROUND: Computed tomography (CT) has been used more frequently to diagnose
      acute appendicitis in children. The purpose of this study was to determine
      whether the use of CT has any influence on negative appendectomy or perforation
      rates. METHODS: Review of a prospective database of children having appendectomy
      for suspected acute appendicitis. Negative appendectomy and perforation rates
      were determined by correlation with final pathology reports. RESULTS: Eighty-five
      consecutive patients underwent appendectomy for the suspicion of acute
      appendicitis. The overall negative appendectomy rate was 17.6%, being 19.4% in
      females and 16.6% in males (p = 0.75). The overall accuracy, sensitivity and
      positive predictive value of CT were 75%, 91%, and 81%, respectively. Patients
      that had CT did not have a significantly lower rate of negative appendectomy
      (17.9% vs. 19.3%, p > 0.99) or perforation (26% vs. 17%; p = 0.53). CONCLUSIONS:
      The use of CT for the diagnosis of appendicitis in children does not change the
      negative appendectomy rate. Results of studies performed in adults may not be
      extrapolated to the evaluation of children with suspected acute appendicitis.

PMID- 12594876
TI  - Prophylactic chlorhexidine oral rinse decreases ventilator-associated pneumonia
      in surgical ICU patients.
AB  - BACKGROUND: Pneumonia is one of the most common nosocomial infections in
      hospitalized patients. The risk of nosocomial pneumonia increases with age,
      severity of acute illness and preexisting co-morbid conditions. Ventilator
      associated pneumonia (VAP) significantly increases morbidity, length of stay,
      resource utilization and mortality. The purpose of this study was to determine
      whether adherence to a ventilator weaning protocol (WP) and the use of
      chlorhexidine gluconate (CH) oral rinse for oral hygiene would decrease the
      incidence of VAP in surgical ICU patients. METHODS: A prospective study was
      conducted over a period of 10 months (October 1998-July 1999) in surgical ICU
      patients requiring mechanical ventilation (n = 95). During the first 5 months, a
      WP was applied to all patients requiring mechanical ventilation. During the
      following 5 months, a CH 0.12% oral rinse administered twice daily was added to
      the protocol, initiated on ICU admission in all intubated patients. The data
      collection included age, gender, race, risk factors, co-morbid conditions,
      severity of the acute illness (APACHE II) at admission, duration of ventilation,
      ICU and total-hospital length of stay, and incidence of VAP and in-hospital
      mortality rates. Both WP and WP+CH groups were compared using the National
      Nosocomial Infection Surveillance (NNIS) and hospital databases as historic
      controls. RESULTS: The institution of the WP alone led only to a slight decrease
      in the incidence of VAP but a significant reduction in the median duration of
      mechanical ventilation by 40% (4.5 days, p < 0.008). The addition of CH to the WP
      led to a significant reduction and delay in the occurrence of VAP (37% overall,
      75% for late VAP, p < 0.05). The median duration of mechanical ventilation in
      this group was similar to that of the WP group. There was no significant
      difference in the overall hospital or ICU length of stay between the groups.
      CONCLUSIONS: Improved oral hygiene via topical CH application in conjunction with
      the use of a WP is effective in reducing the incidence of VAP and the duration of
      mechanical ventilation in surgical ICU patients.

PMID- 12594879
TI  - Wound erysipelas following appendectomy caused by group B beta-hemolytic
      Streptococcus (Streptococcus agalactiae).
AB  - BACKGROUND: Case description of a patient who developed erysipelas of the
      surgical wound following appendectomy for acute appendicitis, and literature
      review of invasive group B streptococcal infections. METHODS: A 65-year-old man
      with perforated appendicitis underwent urgent appendectomy and drainage.
      Antibiotic prophylaxis with tobramycin (100 mg) and metronidazole (500 mg) was
      administered. At surgery, a phlegmon was identified with free perforation of the
      appendix and purulent peritoneal fluid. Appendectomy, irrigation with 0.9% NaCl
      solution, and drainage with a Silastic closed-suction drain was performed. A
      literature search in all languages was performed using MEDLINE, using the search
      terms surgical site infection, wound infection, group B streptococcus,
      Streptococcus agalactiae, necrotizing fasciitis, and postoperative infection.
      RESULTS: Erysipelas of the surgical wound developed on the fourth postoperative
      day. Intravenous penicillin and amoxicillin/clavulanic acid were administered
      empirically. Culture of the wound drainage identified Streptococcus agalactiae
      and a few colonies of Escherichia coli. The broad-spectrum antibiotic was
      discontinued, and a 10-day course of penicillin was completed. CONCLUSIONS:
      Erysipelas of the surgical wound is unusual, and infection with group B
      streptococci is rare compared with infection by group A streptococci.
      Streptococcus agalactiae is recognized to be increasingly virulent, with an
      increasing predilection for bacteremic infections in healthy hosts. Although
      Streptococcus agalactiae remains highly susceptible to antimicrobial agents
      effective against gram-positive cocci, the changing epidemiology and potentially
      invasive nature of these infections should have clinicians alert to the
      possibility of infection caused by group B streptococci.

PMID- 12594878
TI  - Clinical trial results with linezolid, an oxazolidinone, in the treatment of soft
      tissue and postoperative gram-positive infections.
AB  - BACKGROUND: Infectious complications encountered after major surgery include
      operative site infections and nosocomial pneumonia. Recent infection surveillance
      programs have identified the increasing pathogenic role of gram-positive bacteria
      in these infections and the high prevalence of methicillin-resistant
      Staphylococcus aureus (MRSA) in the United States and abroad. Surgical site
      infections and nosocomial pneumonia, often serious infections, are associated
      with adverse clinical outcomes including bacteremia and its resultant
      complications, as well as the socioeconomic consequences of excess
      hospitalization and discharge to nursing care. METHODS: The essential triad for
      management of postoperative soft tissue infection consists of thorough appraisal
      of the infection site for reintervention, culture of drainage or infected tissue,
      and prompt initiation of empiric antimicrobial therapy designed to cover the most
      probable causative pathogens. Broad-spectrum antimicrobial regimens are often
      necessary for empiric therapy of skin and soft tissue infections or nosocomial
      pneumonia; however, regimens should be tailored to the most effective and
      clinically appropriate agent based on results of susceptibility testing. RESULTS:
      Results of the clinical trial experience with the first United States Food and
      Drug Administration (FDA)-approved antimicrobial in the new class of
      oxazolidinones, linezolid, are reviewed. CONCLUSION: In randomized, controlled
      trials, linezolid 600 mg twice daily (intravenously or orally) provided effective
      antimicrobial therapy for gram-positive soft tissue infections, including MRSA,
      and nosocomial pneumonia in which S. aureus was a causative pathogen.

PMID- 12594880
TI  - Wound infections after femoral popliteal bypass.

PMID- 12594881
TI  - Wound infection after infrainguinal bypass operations: multivariate analysis of
      putative risk factors.
AB  - Reported wound infection rates for infrainguinal bypass operations range from 17%
      to 44%, but there is limited appreciation of which characteristics of patients or
      operations are reliable markers of increased wound infection risk. The purpose of
      the present study was to analyze all wound infections observed after
      infrainguinal bypass operations during 20 years of practice in a large teaching
      institution. Independent risk factors for wound infection development were
      identified. During the 20-year period ending 31 December, 1997, 978 male patients
      underwent infrainguinal bypass operations at the Minneapolis Department of
      Veterans Affairs Medical Center. Wound infections complicated the recovery of 129
      of these patients during a 30-day postoperative surveillance interval.
      Multivariate logistic regression analysis was used to test the association
      between wound infection occurrence and putative risk factors that were either
      features of patients or characteristics of the operations. The following
      variables were examined: obesity, prosthetic graft placement, diabetes mellitus,
      steroid use, anticoagulation use, length of preoperative hospital stay,
      development of incisional hematoma, duration of operation, and the preoperative
      presence of a non-healing wound in the extremity being revascularized. The
      overall wound infection rate was 13.2% (129/978). In a final logistic regression
      model, obesity was a significant and independent predictor of wound infection
      (Relative Risk 2.6, 95% confidence interval, 1.35-4.90), as was development of a
      post-operative incisional hematoma (Relative Risk 6.44, 95% confidence interval,
      2.95-14.08). No other explanatory variable was significantly associated with
      wound infection development.

PMID- 12594882
TI  - Transcellular transport is not required for transmucosal bacterial passage across
      the intestinal membrane ex vivo.
AB  - The mechanisms underlying the process of bacterial translocation are poorly
      defined. Possible routes for transmucosal passage of bacteria include
      transcellular and paracellular channels. Bacterial engulfment is a prerequisite
      for transcellular transport. To determine whether transcellular transport is
      required for transmucosal bacterial passage, we examined the effect of various
      inhibitors of endocytosis, such as colchicine, cytochalasin B, and sodium
      fluoride on transmucosal passage of bacteria across an ileal mucosal membrane
      mounted in the Ussing chamber. Colchicine and sodium fluoride increased the rate
      of decline of the potential difference across the membranes. However, neither
      colchicine, cytochalasin B, nor sodium fluoride affected the incidence of
      transmucosal bacterial passage. Sodium fluoride, which depletes intracellular
      ATP, significantly decreased the number of bacteria that passed per membrane. Our
      data suggest that transcellular transport may not be required for spontaneous
      transmucosal passage of bacteria, and furthermore bacterial passage may be, at
      least in part, an energy-dependent process.

PMID- 12594883
TI  - The diagnostic value of fungal surveillance cultures in critically ill patients.
AB  - BACKGROUND: Heavy fungal colonization is a known risk factor for fungal
      infection, yet the value of fungal surveillance cultures is uncertain. METHODS:
      To evaluate the utility of fungal surveillance cultures in predicting fungal
      infections, we evaluated surveillance fungal cultures over a three month period
      in a prospective, cohort study conducted at a university medical center with a
      large tertiary referral population. We enrolled 172 patients in the Oncology
      Center and the medical and surgical intensive care units at Johns Hopkins
      Hospital. RESULTS: Surveillance cultures from five sites were obtained twice
      weekly and evaluated for prediction of subsequent fungal infection. Infections
      were prospectively defined and evaluated by a panel of clinicians. Test
      characteristics were assessed. Of 159 eligible patients, 14 (9%) developed
      invasive fungal infections. Having two or more surveillance sites positive in a
      single day had an odds ratio of 8.2 (1.1-358.0) (p = 0.03), a negative predictive
      value of 0.98, sensitivity of 0.92, and a likelihood ratio of 1.6 for a fungal
      infection. In a multiple logistic regression model and Kaplan-Meier analysis,
      fungal burden was strongly and independently associated with infection (p <
      0.05). CONCLUSIONS: Surveillance cultures are helpful in determining fungal
      colonization but do not have a high positive predictive value for fungal
      infection in a broad population of intensive care unit patients. However, fungal
      infection is more likely in heavily colonized patients, and surveillance cultures
      show that fungal infection is extremely unlikely in patients without fungal
      colonization.

PMID- 12594884
TI  - Comparing the attitudes of surgeons with those of infectious disease specialists
      regarding antibiotic treatment and prophylaxis of abdominal surgical infections.

PMID- 12594885
TI  - Solving the puzzle of multiple organ dysfunction syndrome.

PMID- 12594887
TI  - Advances in the understanding of multiple organ failure.
AB  - Multiple organ failure (MOF) is currently the most common cause of late death
      after injury and surgery. The pathogenesis of MOF remains incompletely understood
      but in all likelihood results from a combination of dysregulated balance between
      inflammatory response and immune function, maldistribution of microcirculatory
      blood flow, and ischemia/reperfusion injury. Advances in the understanding of the
      pathogenesis of MOF have been hampered by a lack of precise animal models,
      accurate definitions of disease, consistent means to qualitatively and
      quantitatively diagnose disease, and a definable at-risk group of patients for
      study. Several recent advances in critical care and proposed new therapies hold
      promise for improving the outcome of patients with multiple injuries who are at
      risk for MOF. However, as recent clinical trials have shown, studies
      demonstrating an improvement in outcome from use of these therapeutic agents are
      difficult to design. The purpose of this article is to discuss the evolution,
      clinical course, and pathogenesis of MOF, to attempt to better define and
      quantitate MOF, and to describe recent studies aimed at identifying an at-risk
      study population for improved treatment and prevention strategies for MOF.

PMID- 12594886
TI  - Multiple organ dysfunction syndrome: past, present and future.
AB  - In the past, our approach to multiple organ failure in the injured or critically
      ill surgical patient was driven by attempts to simplify a complex process. Early
      studies focused on uncontrolled invasive infection (sepsis) as the driving force
      of multiple organ dysfunction syndrome (MODS). However, some patients with
      adequately controlled infection and those without sepsis nevertheless develop
      MODS and signs of systemic inflammation. This discrepancy led to investigations
      of systemic activation of inflammation by a wider variety of biological
      modulators than just infection. Despite the apparent involvement of biological
      modulators such as endotoxin, tumor necrosis factor, and interleukin-1 receptor
      in MODS, agents that neutralize these modulators have failed to thwart the
      progression of sepsis, septic shock, and organ failure. A new paradigm suggests
      that, in the critically ill patient at risk for organ failure, an integrated
      process propagates an excessive systemic inflammatory response and/or an
      inadequate compensatory anti-inflammatory response. Future studies should examine
      the balance between these two processes at the level of the individual patient
      with organ failure. Careful stratification of individual patient responses to
      inflammatory stressors may be an essential step for creating better strategies
      for therapeutic interventions that can restore balance between the pro
      inflammatory and anti-inflammatory processes in the critically ill patient and
      possibly prevent organ failure.

PMID- 12594888
TI  - Epidemiology of multiple organ dysfunction syndrome in critical surgical illness.
AB  - Multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and
      mortality in surgical intensive care units (SICUs). Multiple organ dysfunction
      syndrome remains the most important factor associated with mortality in the SICU.
      Illness severity scores such as the Acute Physiology and Chronic Health
      Evaluation-III (APACHE III) and the magnitude of the systemic inflammatory
      response syndrome (SIRS) at the time of SICU admission are useful in stratifying
      patients at risk for MODS and subsequent mortality. Assessment of key organ
      systems shows that mortality correlates with the overall severity of organ
      dysfunction and the number of involved organ systems, as well as to individual
      organs that fail. Despite the prognostic utility of SIRS/MODS, definitions of
      dysfunction of individual organs have shortcomings. The problem with quantitating
      MODS lies in the inability to adequately define organ dysfunction, especially of
      the gastrointestinal tract, liver, and central nervous system. Biological
      indicators of organ dysfunction may prove to be better markers for MODS in the
      future.

PMID- 12594889
TI  - Emerging bacterial pathogens: a consensus of the scientific data and the risk for
      development of multiple organ dysfunction syndrome.
AB  - Antibiotic resistance in the hospital setting is continuing to increase,
      particularly in intensive care units (ICUs) and other areas of the hospital such
      as oncology units, where the use of empiric broad-spectrum antibiotics is common.
      The problem of antibiotic resistance is also compounded in the immunocompromised
      patient. Multi-drug resistance is common among both Gram-positive and -negative
      bacteria, and becoming more prevalent among fungi (yeast). Two major antibiotic
      resistant pathogens include extended-spectrum beta-lactamase producing Klebsiella
      pneumoniae (ESBL-KP) and vancomycin-resistant enterococci (VRE). When infections
      occur with ESBL-KP, a carbapenem antibiotic is usually the drug of choice. When
      infection occurs with VRE, specific therapy is bacteriostatic, and the clinician
      may have to rely on empirically selected antibiotics or combinations of
      antibiotics to achieve a positive outcome. Two newly-approved agents, linezolid
      and quinupristin/dalfopristin can be used to treat infections caused by resistant
      gram-positive cocci, but the latter is approved for use against VR-E. faecium.
      Risk factors for the development of ESBL-KP include the use of extended-spectrum
      cephalosporins such as ceftazidime. Risk factors for the development of VRE
      include inappropriate use of vancomycin, extended-spectrum cephalosporins, and
      antianaerobic drug therapy such as clindamycin. Several institutions have
      documented a reduction in one or both of these resistant pathogens following a
      decrease in the use of extended-spectrum cephalosporins combined with the
      increased use of extended-spectrum penicillins/beta-lactamase inhibitor
      combinations, such as piperacillin/tazobactam, for the empiric therapy of
      infections. For VRE, a reduction in the inappropriate use of vancomycin is also
      an important interventional strategy along with improved infection control
      practice.

PMID- 12594890
TI  - Pathogenesis of multiple organ dysfunction syndrome--endotoxin, inflammatory
      cells, and their mediators: cytokines and reactive oxygen species.
AB  - Multiple organ dysfunction syndrome (MODS) is caused by an overwhelming,
      uncontrolled systemic inflammatory response that is activated by a number of
      hostile stimuli including sepsis, hypovolemic shock, and severe trauma resulting
      in massive tissue injury. The indiscriminate activation of the inflammatory
      response due to these insults causes loss of the host's ability to localize the
      inflammation to the focus of the problem, leading to systemic inflammation and
      severe host tissue damage and subsequent MODS. While the major players, namely
      neutrophils, macrophages, endotoxin, cytokines, and oxidants have been known for
      some time, the disease processes responsible for the pathogenesis of MODS have
      only recently been elucidated. Our newly found knowledge has resulted in the
      development of novel therapeutic strategies to prevent or treat MODS, such as
      scavenging toxic oxygen species and inhibiting endotoxin, or cytokine production,
      or cytokine activity. Unfortunately, these strategies have not resulted in
      improved mortality rates among patients with MODS. The complex nature of the host
      response to severe insults combined with the fact that the host has multiple,
      redundant parallel systems to deal with various insults has made it difficult for
      clinical interventions to adequately ameliorate the disease process among
      patients at risk for MODS. The purpose of this article is to attempt to "dissect
      out" several individual components of the inflammatory response that play
      important roles in the development of MODS and to review some potentially
      beneficial approaches to combat these harmful processes.

PMID- 12594891
TI  - Molecular biology of multiple organ dysfunction syndrome: injury, adaptation, and
      apoptosis.
AB  - Injury will equal or surpass communicable disease in the year 2020 as the number
      one cause of lost disability-adjusted life-years worldwide. The major cause of
      "late death" after trauma is organ dysfunction, commonly as a complication of
      shock or sepsis. The pathophysiology of injury-induced organ dysfunction is
      poorly characterized but has been linked to systemic inflammation as a result of
      infection (either obvious or occult) or massive tissue injury (systemic
      inflammatory response syndrome, SIRS). Subsequent complications of organ
      dysfunction, including death, may also stem from immunosuppression characteristic
      of what has been called the counter-regulatory anti-inflammatory response
      syndrome (CARS). At the cellular level, injurious stimuli trigger adaptive stress
      responses that include changes in gene expression. Multiple organ dysfunction
      syndrome (MODS) is the summation of these stress responses to severe systemic
      injury, integrated at the cellular, organ, and host levels. We hypothesize that a
      complete understanding at the molecular level of the stress responses induced by
      injury will aid in the development of therapeutic strategies for treating MODS in
      the critically ill surgical patient. This paper reviews recent data from our
      Cellular Injury and Adaptation Laboratory relevant to our understanding of MODS
      pathophysiology, particularly as it relates to stress-induced cell death by
      apoptosis. Our data suggest that inhibition of stress-induced apoptosis may
      improve survival after severe injury.

PMID- 12594892
TI  - Pathogenesis of multiple organ dysfunction syndrome: gut origin, protection, and
      decontamination.
AB  - Clinical and experimental studies performed over the past several decades have
      implicated bacterial and endotoxin translocation (BET) from the gut to distant
      organs in the pathogenesis of multiple organ dysfunction syndrome (MODS).
      Experimental studies in animals directed at maintaining the integrity of the
      intestinal mucosa have shown efficacy in preventing BET and the induction of
      distant inflammatory processes, suggesting that the egress of bacteria and their
      surface endotoxins might be pivotal in inducing MODS. However, clinical studies
      have failed to convincingly recapitulate these beneficial effects. Selective
      digestive decontamination, although it effectively decreases rates of respiratory
      infection, has failed to reduce MODS in critically ill patients and, except in
      certain patient subsets, has had no demonstrable effect on mortality.
      Nevertheless, the gut is an immunologically active organ that, irrespective of
      BET occurrence, appears to contribute significantly to the development of distant
      organ dysfunction following ischemia/reperfusion injury. Resuscitation strategies
      aimed at minimizing the inflammatory effects of gut-derived mediators, such as
      toxic oxygen species, appear promising in preventing the development of distant
      organ injury in the critically ill patient.

PMID- 12594893
TI  - Prevention and treatment of multiple organ dysfunction syndrome: lessons learned
      and future prospects.
AB  - Gram-negative bacteria commonly cause serious infections in hospitalized
      patients, and those that lead to bacteremic episodes and sepsis syndrome are
      associated with the highest mortality rate. Sepsis syndrome frequently progresses
      to multisystem organ dysfunction and failure, with as many as 400,000 cases
      occurring annually. Unfortunately, the associated mortality rate remains about
      40%. Lipopolysaccharide (LPS, endotoxin), an integral component of the gram
      negative bacterial outer membrane, plays a critical role in the pathophysiology
      of this lethal disease process. It is capable of interacting with host
      macrophages, a process that leads to the secretion of an increasingly well
      characterized array of macrophage cytokines. Several different classes of
      compounds that bind directly to LPS and thereby neutralize its effects are being
      examined. These consist of anti-LPS monoclonal antibodies (mAbs), naturally
      occurring proteins and their derivatives (e.g., bactericidal/permeability
      increasing protein [BPI], Limulus anti-LPS factor [LALF]), and certain
      antibiotics (polymyxin B, taurolidine). The molecular biology of BPI, LALF, and
      LPS binding protein (LBP, which augments the host response to LPS) is of
      considerable interest, as each demonstrates considerable genetic sequence
      homology. Although two anti-LPS monoclonal antibodies (HA-1A, E5) did not
      demonstrate efficacy during sepsis syndrome, information obtained from these
      clinical trials provided investigators with the ability to better understand this
      disease process. However, a detailed understanding of the biology of endotoxin
      antagonism is beginning to emerge, and the application of this knowledge in the
      clinical setting provides hope that it may be possible to reduce the mortality of
      sepsis syndrome caused by these microorganisms to a statistic well below the
      current 40%.

PMID- 12594894
TI  - Can one use biologic modifiers to prevent multiple organ dysfunction syndrome
      after abdominal infections?
AB  - Postoperative or trauma-induced intra-abdominal infections can result in sepsis
      and multiple organ dysfunction syndrome (MODS). Enteric bacteria and endotoxin
      released from the gut into the peritoneal cavity in response to injury can
      directly stimulate the inflammatory cascade responsible for the development of
      systemic inflammation and subsequent MODS. Therapeutic strategies, such as
      biologic modifiers that are aimed at blocking or enhancing specific mediators of
      the inflammatory response, have been developed and tested in animal models with
      varying efficacy in preventing mortality. Specific therapies that have shown
      beneficial effects in animal models have not proved successful in prospective,
      randomized human studies, and it is as yet unclear whether cytokine-based
      therapies will ultimately have a role in preventing MODS. Testing novel therapies
      in appropriate animal models that closely simulate human intra-abdominal
      infection is crucial in developing drugs that will be beneficial in preventing
      sepsis-induced mortality in critically ill patients.

PMID- 12594895
TI  - CDC guideline for the prevention of surgical site infection.

PMID- 12594896
TI  - Editorial: enterococcus in perspective.

PMID- 12594897
TI  - Coverage of enterococci in community acquired secondary peritonitis: results of a
      randomized trial.
AB  - INTRODUCTION: The increasing number of enterococcal infections in hospitals and
      reports about the development of resistance of these bacteria make it necessary
      to review their importance as co-pathogens in secondary peritonitis. MATERIALS
      AND METHODS: A prospective randomized controlled trial on primary therapy of
      secondary peritonitis was carried out in six centers comparing cephalosporin
      based antibiotic therapy to acylaminopenicillin-based therapy. RESULTS:
      Enterococci were only cultured in 6 of 110 cases from the abdomen and were found
      in only 5 cases of postoperative complications. No differences were found between
      penicillin-based vs. cephalosporin-based therapy. CONCLUSION: The study supports
      the view that these bacteria continue to play a minor role in secondary
      peritonitis. The point has to be emphasized, however, that the patients under
      study were in relatively good condition (APACHE II median 9 for cephalosporins
      and 10 for penicillins) and that postoperative cases of peritonitis were
      excluded.

PMID- 12594898
TI  - Salvage therapy of open, infected surgical wounds: a retrospective review using
      Techni-Care.
AB  - OBJECTIVE: To determine outcome of infected surgical wounds treated with 3% para
      chloro-meta-xylenol + 3% phospholipid PTC [PCMX-PL] (Techni-Care). DESIGN:
      Retrospective review of patient records. SETTING: University hospital. PATIENTS:
      Thirty consecutively treated patients (sixteen male, fourteen female) who had
      developed open infected wounds (twenty-one abdominal [seventy percent], nine
      extremity [thirty percent]). Mean patient age was 50.1 years. All wounds were
      treated with commonly practiced wound care techniques (e.g., debridement,
      frequent dressing changes using saline or topical antibiotics, and, in most
      cases, parenteral antibiotics) for an extended period of time prior to
      intervention (mean = 35 days). INTERVENTIONS: PCMX-PL, a topical microbicide, was
      used as adjunctive therapy. Eight outcome parameters were analyzed: (1) patient
      morbidity and mortality; (2) wound healing; (3) number of debridements; (4) wound
      culture results; (5) leukocytosis (peripheral white blood cell count > 10,000
      cells/microl); (6) number of febrile days (temperature > 101 degrees F); (7)
      length of hospital stay; and (8) number of days of intensive care. RESULTS: No
      treatment failures or adverse reactions to PCMX-PL were seen. Twenty (sixty-seven
      percent) wounds were healed or had been successfully closed while ten (thirty
      three percent) were granulating well at sixty-day follow-up. The number of
      debridements, positive wound cultures, white-blood-cells, and febrile days
      decreased after PCMX-PL treatment began. CONCLUSIONS: Despite severe underlying
      diseases, all patients were discharged from the hospital with closed or healing
      wounds. We recommend treatment with PCMX-PL as an adjunctive therapy for infected
      wounds particularly when standard care measures have failed.

PMID- 12594899
TI  - Surgeons and infectious disease specialists: different attitudes towards
      antibiotic treatment and prophylaxis in common abdominal surgical infections.
AB  - BACKGROUND: The role of medical infectious disease (ID) specialists in the
      treatment of surgical infections is increasing but no information is available
      regarding the therapeutic perception held by these non-surgeons treating surgical
      infections. The purpose of this study was to assess the attitude of the ID
      specialists towards antibiotic treatment and prophylaxis of common abdominal
      surgical infections and to compare it with that of surgeons "interested" in this
      field. METHODS: A questionnaire, polling opinions regarding the management of
      common surgical infections, was sent to 396 medical ID specialists (New York
      State) and 515 surgeon members of the Surgical Infection Society (SIS). The
      questions covered areas involving choice of antibiotics, and timing and duration
      of treatment in given clinical scenarios, including elective and emergent
      colorectal surgery, perforated peptic ulcer, and appendicitis. RESULTS: Response
      rates for the medical and surgical groups were 10.1% and 15.6%, respectively.
      Regarding prophylactic use of antimicrobials, the pattern of administration was
      similar for the two groups. Regarding therapeutic use, on average medical ID
      specialists used antibiotics twice as long as the surgical group. The main reason
      identified was the failure of medical ID specialists to understand the conceptual
      difference between contamination and infection. CONCLUSIONS: Medical ID
      specialists may overtreat common surgical infections with antibiotics. Surgical
      infections should be treated by surgeons.

PMID- 12594900
TI  - A new surgical site infection (SSI) prevention guideline.

PMID- 12594901
TI  - Effect of preoperative neomycin-erythromycin intestinal preparation on the
      incidence of infectious complications following colon surgery. 1973.

PMID- 12594902
TI  - Mega scrotum in pyoderma fistulans sinifica (fox den disease).

PMID- 12594903
TI  - Minimizing resistance and maximizing outcomes in surgical patients through
      appropriate antibiotic use.

PMID- 12594904
TI  - Cytotoxicity of liquid disinfectants.
AB  - This study was prompted by toxic responses to disinfecting agents reported in
      patients after surgical procedures and in sensitized health care personnel. We
      evaluated the cytotoxicity of seven substances used in the formulation of common
      liquid chemical disinfectants and sterilants. We found that a standard method
      based on direct microscopic examination of cell cultures was insensitive and may
      result in an underestimation of the risk that disinfectants pose to health care
      personnel or patients who are exposed to these substances. Using independent
      quantitative tests measuring the integrity of the cellular membrane, metabolic
      activity, or cell growth, we found that there is a several-hundredfold difference
      in the relative toxicity of various disinfecting substances. The concentration
      toxic in 50% of the cell population (TC(50)) that was found for each disinfectant
      was similar in a variety of cell lines from human, monkey, or mouse origin.
      Statistical analysis of TC(50)s suggests that liquid disinfecting agents could be
      classified in three main groups according to their relative toxicity, with: (1)
      mild (TC(50) > 1 mM, including phenol, hydrogen peroxide, and formaldehyde); (2)
      moderate (1mM > TC(50) > 0.1 mM, sodium hypochlorite); and (3) severe (TC(50) <
      0.1 mM, glutaraldehyde, cupric ascorbate, and peracetic acid) toxicity. These
      data suggest a vast difference in the potential risk of various disinfectants and
      sterilants. The data presented in this study should help to define the relative
      toxic risk of different disinfecting substances to patients and health care
      personnel and assist in the selection of safer microbicidal formulations.

PMID- 12594905
TI  - Pyogenic liver abscess.
AB  - BACKGROUND: A current assessment of liver abscesses should allow for better
      understanding of the pathogenesis of the disease and improve the effectiveness of
      diagnosis and treatment. Amebic liver abscess occurs more commonly than pyogenic
      liver abscess on a worldwide basis. However, in the United States, pyogenic liver
      abscess predominates. The purpose of our study was to evaluate the etiology,
      management, morbidity, and mortality of all patients admitted to our medical
      center with diagnoses of pyogenic liver abscess between 1983 and 1996. METHODS: A
      retrospective chart review was performed on all patients admitted to our medical
      center, Louisiana State University Medical Center, Shreveport, with diagnoses of
      pyogenic liver abscess. RESULTS: Twenty patients were admitted with diagnoses of
      pyogenic liver abscess. The subjects were 65% (13/20) male and 65% (13/20)
      African-American and had an average age of 52 years. The most common presenting
      symptoms were fever and pain. The most common physical finding was right upper
      quadrant tenderness. The most common etiologies of pyogenic liver abscesses were
      cryptogenic, trauma, and biliary, while portal vein was the source for only 10%
      of the cases. The right lobe of the liver was involved in 95% of the cases, and
      70% of these liver abscesses were solitary. Computed tomography (CT)-and
      ultrasound-guided percutaneous drainage were performed in 85% (17/20) of patients
      with liver abscesses. One patient was treated by open drainage, three patients
      were treated with antibiotics alone, and three patients did not respond to
      aspiration and catheter placement, which subsequently required open drainage. The
      culture results were as follows: 50% were gram-negative organisms, 25% were gram
      positive organisms, 10% were anaerobic organisms, and 15% of the abscess were
      sterile. Sixty percent of the positive abscess cultures were polymicrobial.
      CONCLUSIONS: CT scan- and ultrasound-guided percutaneous drainage of pyogenic
      liver abscesses were safe and effective methods of treatment. The right lobe of
      the liver was involved in 95% of cases. Although no one species predominated,
      gram-negative bacteria were the most common organism cultured, and 60% of the
      abscesses were polymicrobial. There was no in-house mortality in this review.

PMID- 12594906
TI  - Modern surgical antibiotic prophylaxis and therapy--less is more.
AB  - Recent findings and recommendations on the use of antibiotics in surgery, both
      prophylactically and as therapy, suggest that adverse events associated with
      antibiotics remain a major cause of morbidity and mortality. Wound infection
      rates generally parallel the presence of one or more of three key risk factors;
      the overall medical condition of the patient, a prolonged operative time, and a
      contaminated or dirty operative field. The first choice of prophylactic drug
      should generally be a first- or second-generation cephalosporin, unless the
      patient is highly allergic to penicillin. Effective prophylaxis can almost always
      be achieved with a single dose of antibiotic, but the dose must be administered
      soon before the incision. New guidelines for the prevention of bacterial
      endocarditis have reduced both the types of cases that require prophylaxis, and
      the doses of antibiotic necessary to achieve prophylaxis. Some cases that
      required endocarditis prophylaxis previously no longer require prophylaxis.
      Rational antibiotic therapy demands rapid diagnosis and treatment. It is also
      crucial to distinguish among infection, contamination, and inflammation as soon
      as possible; contamination requires only a single dose of antibiotic, whereas
      sterile inflammation requires none at all. The choice of antibiotic for
      postoperative infection, including intra-abdominal infection, should consider the
      severity of illness and the risk of resistant bacteria. Failure to stratify for
      risk may prolong treatment unnecessarily, confound the interpretation of future
      studies, and increase the prevalence of bacterial resistance.

PMID- 12594907
TI  - Diagnosis and treatment of intra-abdominal abscesses.
AB  - Despite recent advances in the diagnosis and management of intra-abdominal
      abscesses, these infections still cause substantial morbidity and mortality. Low
      pH, large bacterial inocula, poor perfusion, the presence of hemoglobin, and
      large amounts of fibrin (which impedes antibiotic penetration) make the abscess a
      cloistered environment that is penetrated poorly by many antimicrobial therapies.
      Therefore, management of these infections requires prompt recognition, early
      localization, and effective drainage, as well as appropriate antimicrobial use.
      Although various imaging techniques, such as ultrasonography, gallium scans, and
      indium-labeled white-blood-cell scans, can be used for the diagnosis and
      localization of intra-abdominal abscesses, computer-assisted tomography is the
      most useful study. Once the diagnosis is made and the abscess is localized,
      treatment should begin promptly. Percutaneous or open surgical drainage should be
      used. Broad-spectrum antibiotics should be given until culture and sensitivity
      data are obtained. Once these data are obtained, a therapy with appropriate
      coverage that is likely to work in the abscess environment should be chosen.
      Percutaneous drainage is inappropriate for abscesses in the posterior subphrenic
      space or in the porta hepatis, for those among loops of small bowel, for
      suspected echinococcal cysts, and for abscesses containing necrotic or neoplastic
      tissues. Finally, surgeons need to be cognizant of risk factors, such as advanced
      age, obesity, complex abscesses, and high Acute Physiology and Chronic Health
      Evaluation (APACHE) II or APACHE III scores, which correlate with poor outcomes
      for these patients.

PMID- 12594908
TI  - Overview of resistant gram-positive pathogens in the surgical patient.
AB  - Staphylococci and enterococci are the most common pathogens in surgical-site and
      bloodstream infections. The emergence of drug resistance among these gram
      positive bacteria thus poses a substantial threat to patients with surgical
      infections. Resistance to methicillin/oxacillin is frequently observed in
      Staphylococcus aureus isolates and is often accompanied by multidrug resistance.
      Vancomycin is usually the treatment of choice for infections caused by
      methicillin-resistant S. aureus (MRSA), so the recent appearance of S. aureus
      isolated with intermediate sensitivity to vancomycin is cause for concern.
      Vancomycin resistance has already appeared in most species of enterococci.
      Infections caused by vancomycin-resistant enterococci (VRE) are associated with
      increased mortality compared to infections caused by vancomycin-sensitive
      isolates. Measures for preventing vancomycin resistance include reducing the use
      of vancomycin and other agents that appear to be associated with VRE, including
      third-generation cephalosporins and anti-anaerobic drugs. Third-generation
      cephalosporins have also been implicated in the increased prevalence of MRSA
      infections. Prudent use of existing antibiotics is an essential strategy for
      combating the rising tide of drug-resistant gram-positive pathogens.

PMID- 12594909
TI  - The consequences of suppression of anaerobic bacteria.
AB  - Anaerobic bacteria such as Bacteroides fragilis, Peptostreptococcus species, and
      Fusobacterium species, when accompanied by aerobic bacteria or in the presence of
      dead tissue, can cause severe infections. This article discusses the most common
      type of anaerobic infection, i.e., infection after colonic contamination of the
      abdominal cavity and soft tissues. Colonic anaerobes rarely cause infections as
      solitary pathogens. Mixed infections of aerobes and anaerobes are treated by
      source control, surgical drainage and debridement, and combination antibiotic
      therapy. Antimicrobial treatment should cover both anaerobes and aerobes;
      treatment of mixed infections with anti-anaerobic agents alone is likely to
      result in abscess formation. Recent trends toward cost cutting and the advent of
      antibiotics with good coverage of both aerobes and relevant pathogenic anaerobes
      have led to increased single-agent therapy with cefoxitin, cefotetan,
      ampicillin/sulbactam, imipenem/cilastatin, ticarcillin/clavulanate,
      trovafloxacin/alatrofloxacin, and piperacillin/tazobactam. In the past 15 years,
      research has begun to focus on the gut barrier, particularly on the beneficial
      effects of anaerobic microflora. Directing antibiotic therapy against the
      anaerobe when it is involved in clinical infection is important; however, the
      negative consequences of anti-anaerobic antibiotic therapy on the beneficial
      effects of normal distal gut colonization must also be considered.

PMID- 12594910
TI  - The role of beta-lactam antimicrobials as single agents in treatment of intra
      abdominal infection.
AB  - Broad-spectrum beta-lactam antibiotics have several advantages in the treatment
      of intra-abdominal infections. These agents are effective against gram-negative
      rods and anaerobes, reach therapeutic levels rapidly after parenteral
      administration, and, in the absence of penicillin allergy, generally exhibit low
      toxicity. The second-generation cephalosporins (e.g., cefoxitin, cefotetan) are
      used widely in surgical prophylaxis, trauma, and treatment of mild-to-moderate
      community-acquired infections, but limitations in their spectra and microbial
      resistance restrict their utility in more serious infections. Extended-spectrum
      penicillin/beta-lactamase-inhibitor combinations are effective in the treatment
      of intra-abdominal infections and include enterococci in their spectrum. Gram
      negative aerobe resistance has developed to ampicillin/sulbactam.
      Piperacillin/tazobactam, a ureidopenicillin with increased gram-negative coverage
      and enhanced antipseudomonal activity, has proved to be effective in clinical
      trial therapy for intra-abdominal infections. The very broad spectrum carbapenems
      -imipenem/cilastatin and meropenem--are effective for serious infections or
      resistant organisms and are often used in the intensive care unit or for
      nosocomial intra-abdominal infection. These classes of beta-lactams comprise a
      range of antimicrobials that can be targeted effectively as single agents to both
      prevention and treatment of intra-abdominal infection.

PMID- 12594911
TI  - The role of quinolones in abdominal surgery.
AB  - The quinolone antibiotics have been a major advance for the treatment of various
      types of infections. These agents have generally good safety profiles, broad
      spectrum activity, and favorable pharmacokinetics. In addition, several of these
      antibiotics are available in both intravenous and oral formulations, which allows
      for sequential therapy resulting in potential cost savings. However, patients can
      develop serious central nervous system side effects (seizures) and phototoxicity.
      In addition, the bioavailability of agents in this class can be reduced by
      coadministration with cations, such as magnesium, aluminum, calcium, and iron,
      which may make bioavailability unpredictable in patients. Although older
      quinolones such as ciprofloxacin were effective as prophylactic agents for
      biliary procedures and colorectal surgery and for the treatment of intra
      abdominal infections, the use of these older quinolones was limited by the
      development of resistant organisms. In addition, because these agents had poor
      activity against anaerobes such as Bacteroides fragilis, the agents had to be
      combined with an antianaerobic agent, such as metronidazole, when anaerobic
      coverage was required. Recently, a new quinolone, trovafloxacin, has become
      available. Trovafloxacin has demonstrated increased activity against anaerobes in
      animal and human studies. However, the clinical profile of trovafloxacin for
      abdominal infections has not been fully demonstrated, and there is some concern
      that its activity against aerobic gram-negative bacilli, especially Pseudomonas
      aeruginosa, may not equal that of ciprofloxacin. Moreover, the safety profile of
      trovafloxacin is disadvantageous owing to reports of severe hepatic toxicity.

PMID- 12594912
TI  - Decreased antimicrobial resistance following changes in antibiotic use.
AB  - The widespread use of perioperative antibiotic prophylaxis makes surgical
      procedures an important component of overall antibiotic use. Attempts to reduce
      costs and limit the emergence of resistance among pathogenic bacteria by altering
      antibiotic use must therefore encompass surgical prophylaxis. Several recent
      reports have linked the use of third-generation cephalosporins with beta-lactam
      resistance in gram-negative bacteria and with vancomycin resistance in
      Enterococcus. Fortunately, susceptibility can often be restored by replacing
      third-generation cephalosporins with drugs that are less likely to foster
      resistance; a penicillin/beta-lactamase inhibitor combination is often a suitable
      substitute. An antibiotic resistance management program can effect the type of
      changes in antimicrobial use necessary to forestall or reverse an outbreak of
      resistant pathogens. Such a plan was implemented at Methodist Hospital,
      Indianapolis, Indiana, in 1995. Piperacillin/tazobactam (in combination with an
      aminoglycoside) was added to the formulary, primarily as empiric therapy,
      replacing the use of third-generation cephalosporins such as ceftazidime.
      Following this change, the prevalences of vancomycin-resistant Enterococcus,
      methicillin-resistant Staphylococcus aureus, and other resistant gram-negative
      bacilli were all reduced. As this effective formulary change shows, appropriate
      changes in antibiotic drug, dosage, and administration route can limit the
      emergence of resistance and ultimately lower costs.

PMID- 12594913
TI  - Roundtable discussion of antibiotic therapy in surgical infections.

PMID- 12594914
TI  - Chloroplasts and mitochondria: functional genomics and evolution. Proceedings of
      a meeting. 26-28 June 2002.

PMID- 12594915
TI  - Genomes at the interface between bacteria and organelles.
AB  - The topic of the transition of the genome of a free-living bacterial organism to
      that of an organelle is addressed by considering three cases. Two of these are
      relatively clear-cut as involving respectively organisms (cyanobacteria) and
      organelles (plastids). Cyanobacteria are usually free-living but some are
      involved in symbioses with a range of eukaryotes in which the cyanobacterial
      partner contributes photosynthesis, nitrogen fixation, or both of these. In
      several of these symbioses the cyanobacterium is vertically transmitted, and in a
      few instances, sufficient unsuccessful attempts have been made to culture the
      cyanobiont independently for the association to be considered obligate for the
      cyanobacterium. Plastids clearly had a cyanobacterial ancestor but cannot grow
      independently of the host eukaryote. Plastid genomes have at most 15% of the
      number of genes encoded by the cyanobacterium with the smallest number of genes;
      more genes than are retained in the plastid genome have been transferred to the
      eukaryote nuclear genome, while the rest of the cyanobacterial genes have been
      lost. Even the most cyanobacteria-like plastids, for example the "cyanelles" of
      glaucocystophyte algae, are functionally and genetically very similar to other
      plastids and give little help in indicating intermediates in the evolution of
      plastids. The third case considered is the vertically transmitted intracellular
      bacterial symbionts of insects where the symbiosis is usually obligate for both
      partners. The number of genes encoded by the genomes of these obligate symbionts
      is intermediate between that of organelles and that of free-living bacteria, and
      the genomes of the insect symbionts also show rapid rates of sequence evolution
      and AT (adenine, thymine) bias. Genetically and functionally, these insect
      symbionts show considerable similarity to organelles.

PMID- 12594916
TI  - The function of genomes in bioenergetic organelles.
AB  - Mitochondria and chloroplasts are energy-transducing organelles of the cytoplasm
      of eukaryotic cells. They originated as bacterial symbionts whose host cells
      acquired respiration from the precursor of the mitochondrion, and oxygenic
      photosynthesis from the precursor of the chloroplast. The host cells also
      acquired genetic information from their symbionts, eventually incorporating much
      of it into their own genomes. Genes of the eukaryotic cell nucleus now encode
      most mitochondrial and chloroplast proteins. Genes are copied and moved between
      cellular compartments with relative ease, and there is no obvious obstacle to
      successful import of any protein precursor from the cytosol. So why are any genes
      at all retained in cytoplasmic organelles? One proposal is that these small but
      functional genomes provide a location for genes that is close to, and in the same
      compartment as, their gene products. This co-location facilitates rapid and
      direct regulatory coupling. Redox control of synthesis de novo is put forward as
      the common property of those proteins that must be encoded and synthesized within
      mitochondria and chloroplasts. This testable hypothesis is termed CORR, for co
      location for redox regulation. Principles, predictions and consequences of CORR
      are examined in the context of competing hypotheses and current evidence.

PMID- 12594917
TI  - How big is the iceberg of which organellar genes in nuclear genomes are but the
      tip?
AB  - As more and more complete bacterial and archaeal genome sequences become
      available, the role of lateral gene transfer (LGT) in shaping them becomes more
      and more clear. Over the long term, it may be the dominant force, affecting most
      genes in most prokaryotes. We review the history of LGT, suggesting reasons why
      its prevalence and impact were so long dismissed. We discuss various methods
      purporting to measure the extent of LGT, and evidence for and against the notion
      that there is a core of never-exchanged genes shared by all genomes, from which
      we can deduce the "true" organismal tree. We also consider evidence for, and
      implications of, LGT between prokaryotes and phagocytic eukaryotes.

PMID- 12594918
TI  - On the origins of cells: a hypothesis for the evolutionary transitions from
      abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to
      nucleated cells.
AB  - All life is organized as cells. Physical compartmentation from the environment
      and self-organization of self-contained redox reactions are the most conserved
      attributes of living things, hence inorganic matter with such attributes would be
      life's most likely forebear. We propose that life evolved in structured iron
      monosulphide precipitates in a seepage site hydrothermal mound at a redox, pH and
      temperature gradient between sulphide-rich hydrothermal fluid and iron(II)
      containing waters of the Hadean ocean floor. The naturally arising, three
      dimensional compartmentation observed within fossilized seepage-site metal
      sulphide precipitates indicates that these inorganic compartments were the
      precursors of cell walls and membranes found in free-living prokaryotes. The
      known capability of FeS and NiS to catalyse the synthesis of the acetyl
      methylsulphide from carbon monoxide and methylsulphide, constituents of
      hydrothermal fluid, indicates that pre-biotic syntheses occurred at the inner
      surfaces of these metal-sulphide-walled compartments, which furthermore
      restrained reacted products from diffusion into the ocean, providing sufficient
      concentrations of reactants to forge the transition from geochemistry to
      biochemistry. The chemistry of what is known as the RNA-world could have taken
      place within these naturally forming, catalyticwalled compartments to give rise
      to replicating systems. Sufficient concentrations of precursors to support
      replication would have been synthesized in situ geochemically and
      biogeochemically, with FeS (and NiS) centres playing the central catalytic role.
      The universal ancestor we infer was not a free-living cell, but rather was
      confined to the naturally chemiosmotic, FeS compartments within which the
      synthesis of its constituents occurred. The first free-living cells are suggested
      to have been eubacterial and archaebacterial chemoautotrophs that emerged more
      than 3.8 Gyr ago from their inorganic confines. We propose that the emergence of
      these prokaryotic lineages from inorganic confines occurred independently,
      facilitated by the independent origins of membrane-lipid biosynthesis: isoprenoid
      ether membranes in the archaebacterial and fatty acid ester membranes in the
      eubacterial lineage. The eukaryotes, all of which are ancestrally heterotrophs
      and possess eubacterial lipids, are suggested to have arisen ca. 2 Gyr ago
      through symbiosis involving an autotrophic archaebacterial host and a
      heterotrophic eubacterial symbiont, the common ancestor of mitochondria and
      hydrogenosomes. The attributes shared by all prokaryotes are viewed as
      inheritances from their confined universal ancestor. The attributes that
      distinguish eubacteria and archaebacteria, yet are uniform within the groups, are
      viewed as relics of their phase of differentiation after divergence from the non
      free-living universal ancestor and before the origin of the free-living
      chemoautotrophic lifestyle. The attributes shared by eukaryotes with eubacteria
      and archaebacteria, respectively, are viewed as inheritances via symbiosis. The
      attributes unique to eukaryotes are viewed as inventions specific to their
      lineage. The origin of the eukaryotic endomembrane system and nuclear membrane
      are suggested to be the fortuitous result of the expression of genes for
      eubacterial membrane lipid synthesis by an archaebacterial genetic apparatus in a
      compartment that was not fully prepared to accommodate such compounds, resulting
      in vesicles of eubacterial lipids that accumulated in the cytosol around their
      site of synthesis. Under these premises, the most ancient divide in the living
      world is that between eubacteria and archaebacteria, yet the steepest
      evolutionary grade is that between prokaryotes and eukaryotes.

PMID- 12594919
TI  - Eukaryotic genome evolution: rearrangement and coevolution of compartmentalized
      genetic information.
AB  - The plant cell operates with an integrated, compartmentalized genome consisting
      of nucleus/cytosol, plastids and mitochondria that, in its entirety, is regulated
      in time, quantitatively, in multicellular organisms and also in space. This
      genome, as do genomes of eukaryotes in general, originated in endosymbiotic
      events, with at least three cells, and was shaped phylogenetically by a massive
      and highly complex restructuring and intermixing of the genetic potentials of the
      symbiotic partners and by lateral gene transfer. This was accompanied by
      fundamental changes in expression signals in the entire system at almost all
      regulatory levels. The gross genome rearrangements contrast with a highly
      specific compartmental interplay, which becomes apparent in interspecific nuclear
      plastid cybrids or hybrids. Organelle exchanges, even between closely related
      species, can greatly disturb the intracellular genetic balance ("hybrid
      bleaching"), which is indicative of compartmental coevolution and is of relevance
      for speciation processes. The photosynthetic machinery of plastids, which is
      embedded in that genetic machinery, is an appealing model to probe into genomic
      and organismic evolution and to develop functional molecular genomics. We have
      studied the reciprocal Atropa belladonna-Nicotiana tabacum cybrids, which differ
      markedly in their phenotypes, and found that transcriptional and post
      transcriptional processes can contribute to genome/plastome incompatibility.
      Allopolyploidy can influence this phenomenon by providing an increased, cryptic
      RNA editing potential and the capacity to maintain the integrity of organelles of
      different taxonomic origins.

PMID- 12594920
TI  - Evolution of the chloroplast genome.
AB  - We discuss the suggestion that differences in the nucleotide composition between
      plastid and nuclear genomes may provide a selective advantage in the
      transposition of genes from plastid to nucleus. We show that in the adenine,
      thymine (AT)-rich genome of Borrelia burgdorferi several genes have an AT-content
      lower than the average for the genome as a whole. However, genes whose plant
      homologues have moved from plastid to nucleus are no less AT-rich than genes
      whose plant homologues have remained in the plastid, indicating that both classes
      of gene are able to support a high AT-content. We describe the anomalous
      organization of dinoflagellate plastid genes. These are located on small circles
      of 2-3 kbp, in contrast to the usual plastid genome organization of a single
      large circle of 100-200 kbp. Most circles contain a single gene. Some circles
      contain two genes and some contain none. Dinoflagellate plastids have retained
      far fewer genes than other plastids. We discuss a similarity between the
      dinoflagellate minicircles and the bacterial integron system.

PMID- 12594923
TI  - Redox and light regulation of gene expression in photosynthetic prokaryotes.
AB  - All photosynthetic organisms control expression of photosynthesis genes in
      response to alterations in light intensity as well as to changes in cellular
      redox potential. Light regulation in plants involves a well-defined set of red-
      and blue-light absorbing photoreceptors called phytochrome and cryptochrome. Less
      understood are the factors that control synthesis of the plant photosystem in
      response to changes in cellular redox. Among a diverse set of photosynthetic
      bacteria the best understood regulatory systems are those synthesized by the
      photosynthetic bacterium Rhodobacter capsulatus. This species uses the global two
      component signal transduction cascade, RegB and RegA, to anaerobically de-repress
      anaerobic gene expression. Under reducing conditions, the phosphate on RegB is
      transferred to RegA, which then activates genes involved in photosynthesis,
      nitrogen fixation, carbon fixation, respiration and electron transport. In the
      presence of oxygen, there is a second regulator known as CrtJ, which is
      responsible for repressing photosynthesis gene expression. CrtJ responds to redox
      by forming an intramolecular disulphide bond under oxidizing, but not reducing,
      growth conditions. The presence of the disulphide bond stimulates DNA binding
      activity of the repressor. There is also a flavoprotein that functions as a blue
      light absorbing anti-repressor of CrtJ in the related bacterial species
      Rhodobacter sphaeroides called AppA. AppA exhibits a novel long-lived photocycle
      that is initiated by blue-light absorption by the flavin. Once excited, AppA
      binds to CrtJ thereby inhibiting the repressor activity of CrtJ. Various
      mechanistic aspects of this photocycle will be discussed.

PMID- 12594921
TI  - Genomic reduction and evolution of novel genetic membranes and protein-targeting
      machinery in eukaryote-eukaryote chimaeras (meta-algae).
AB  - Chloroplasts originated just once, from cyanobacteria enslaved by a biciliate
      protozoan to form the plant kingdom (green plants, red and glaucophyte algae),
      but subsequently, were laterally transferred to other lineages to form eukaryote
      eukaryote chimaeras or meta-algae. This process of secondary symbiogenesis
      (permanent merger of two phylogenetically distinct eukaryote cells) has left
      remarkable traces of its evolutionary role in the more complex topology of the
      membranes surrounding all non-plant (meta-algal) chloroplasts. It took place
      twice, soon after green and red algae diverged over 550 Myr ago to form two
      independent major branches of the eukaryotic tree (chromalveolates and cabozoa),
      comprising both meta-algae and numerous secondarily non-photosynthetic lineages.
      In both cases, enslavement probably began by evolving a novel targeting of
      endomembrane vesicles to the perialgal vacuole to implant host porter proteins
      for extracting photosynthate. Chromalveolates arose by such enslavement of a
      unicellular red alga and evolution of chlorophyll c to form the kingdom Chromista
      and protozoan infrakingdom Alveolata, which diverged from the ancestral
      chromalveolate chimaera. Cabozoa arose when the common ancestor of euglenoids and
      cercozoan chlorarachnean algae enslaved a tetraphyte green alga with chlorophyll
      a and b. I suggest that in cabozoa the endomembrane vesicles originally budded
      from the Golgi, whereas in chromalveolates they budded from the endoplasmic
      reticulum (ER) independently of Golgi-targeted vesicles, presenting a potentially
      novel target for drugs against alveolate Sporozoa such as malaria parasites and
      Toxoplasma. These hypothetical ER-derived vesicles mediated fusion of the
      perialgal vacuole and rough ER (RER) in the ancestral chromist, placing the
      former red alga within the RER lumen. Subsequently, this chimaera diverged to
      form cryptomonads, which retained the red algal nucleus as a nucleomorph (NM)
      with approximately 464 protein-coding genes (30 encoding plastid proteins) and a
      red or blue phycobiliprotein antenna pigment, and the chromobiotes (heterokonts
      and haptophytes), which lost phycobilins and evolved the brown carotenoid
      fucoxanthin that colours brown seaweeds, diatoms and haptophytes. Chromobiotes
      transferred the 30 genes to the nucleus and lost the NM genome and nuclear-pore
      complexes, but retained its membrane as the periplastid reticulum (PPR),
      putatively the phospholipid factory of the periplastid space (former algal
      cytoplasm), as did the ancestral alveolate independently. The chlorarachnean NM
      has three minute chromosomes bearing approximately 300 genes riddled with pygmy
      introns. I propose that the periplastid membrane (PPM, the former algal plasma
      membrane) of chromalveolates, and possibly chlorarachneans, grows by fusion of
      vesicles emanating from the NM envelope or PPR. Dinoflagellates and euglenoids
      independently lost the PPM and PPR (after diverging from Sporozoa and
      chlorarachneans, respectively) and evolved triple chloroplast envelopes
      comprising the original plant double envelope and an extra outermost membrane,
      the EM, derived from the perialgal vacuole. In all metaalgae most chloroplast
      proteins are coded by nuclear genes and enter the chloroplast by using bipartite
      targeting sequences--an upstream signal sequence for entering the ER and a
      downstream chloroplast transit sequence. I present a new theory for the four-fold
      diversification of the chloroplast OM protein translocon following its insertion
      into the PPM to facilitate protein translocation across it (of both periplastid
      and plastid proteins). I discuss evidence from genome sequencing and other
      sources on the contrasting modes of protein targeting, cellular integration, and
      evolution of these two major lineages of eukaryote "cells within cells". They
      also provide powerful evidence for natural selection's effectiveness in
      eliminating most functionless DNA and therefore of a universally useful non-genic
      function for nuclear non-coding DNA, i.e. most DNA in the biosphere, and dramatic
      examples of genomic reduction. I briefly argue that chloroplast replacement in
      dinoflagellates, which happened at least twice, may have been evolutionarily
      easier than secondary symbiogenesis because parts of the chromalveolate protein
      targeting machinery could have helped enslave the foreign plastids.

PMID- 12594922
TI  - Coordination of plastid and nuclear gene expression.
AB  - The coordinated expression of genes distributed between the nuclear and plastid
      genomes is essential for the assembly of functional chloroplasts. Although the
      nucleus has a pre-eminent role in controlling chloroplast biogenesis, there is
      considerable evidence that the expression of nuclear genes encoding
      photosynthesis-related proteins is regulated by signals from plastids.
      Perturbation of several plastid-located processes, by inhibitors or in mutants,
      leads to decreased transcription of a set of nuclear photosynthesis-related
      genes. Characterization of arabidopsis gun (genomes uncoupled) mutants, which
      express nuclear genes in the presence of norflurazon or lincomycin, has provided
      evidence for two separate signalling pathways, one involving tetrapyrrole
      biosynthesis intermediates and the other requiring plastid protein synthesis. In
      addition, perturbation of photosynthetic electron transfer produces at least two
      different redox signals, as part of the acclimation to altered light conditions.
      The recognition of multiple plastid signals requires a reconsideration of the
      mechanisms of regulation of transcription of nuclear genes encoding
      photosynthesis-related proteins.

PMID- 12594924
TI  - Parasite plastids: maintenance and functions.
AB  - Malaria and related parasites retain a vestigial, but biosynthetically active,
      plastid organelle acquired far back in evolution from a red algal cell. The
      organelle appears to be essential for parasite transmission from cell to cell and
      carries the smallest known plastid genome. Why has this genome been retained? The
      genes it carries seem to be dedicated to the expression of just two
      "housekeeping" genes. We speculate that one of these, called ycf24 in plants and
      sufB in bacteria, is tied to an essential "dark" reaction of the organelle--fatty
      acid biosynthesis. "Ball-park" clues to the function of bacterial suf genes have
      emerged only recently and point to the areas of iron homeostasis, [Fe-S] cluster
      formation and oxidative stress. We present experimental evidence for a physical
      interaction between SufB and its putative partner SufC (ycf16). In both malaria
      and plants, SufC is encoded in the nucleus and specifies an ATPase that is
      imported into the plastid.

PMID- 12594926
TI  - Gene expression in plant mitochondria: transcriptional and post-transcriptional
      control.
AB  - The informational content of the mitochondrial genome in plants is, although
      small, essential for each cell. Gene expression in these organelles involves a
      number of distinct transcriptional and post-transcriptional steps. The complex
      post-transcriptional processes of plant mitochondria such as 5' and 3' RNA
      processing, intron splicing, RNA editing and controlled RNA stability extensively
      modify individual steady-state RNA levels and influence the mRNA quantities
      available for translation. In this overview of the processes in mitochondrial
      gene expression, we focus on confirmed and potential sites of regulatory
      interference and discuss the evolutionary origins of the transcriptional and post
      transcriptional processes.

PMID- 12594925
TI  - On the origin of mitochondria: a genomics perspective.
AB  - The availability of complete genome sequence data from both bacteria and
      eukaryotes provides information about the contribution of bacterial genes to the
      origin and evolution of mitochondria. Phylogenetic analyses based on genes
      located in the mitochondrial genome indicate that these genes originated from
      within the alpha-proteobacteria. A number of ancestral bacterial genes have also
      been transferred from the mitochondrial to the nuclear genome, as evidenced by
      the presence of orthologous genes in the mitochondrial genome in some species and
      in the nuclear genome of other species. However, a multitude of mitochondrial
      proteins encoded in the nucleus display no homology to bacterial proteins,
      indicating that these originated within the eukaryotic cell subsequent to the
      acquisition of the endosymbiont. An analysis of the expression patterns of yeast
      nuclear genes coding for mitochondrial proteins has shown that genes predicted to
      be of eukaryotic origin are mainly translated on polysomes that are free in the
      cytosol whereas those of putative bacterial origin are translated on polysomes
      attached to the mitochondrion. The strong relationship with alpha-proteobacterial
      genes observed for some mitochondrial genes, combined with the lack of such a
      relationship for others, indicates that the modern mitochondrial proteome is the
      product of both reductive and expansive processes.

PMID- 12594928
TI  - Biochemical and evolutionary aspects of anaerobically functioning mitochondria.
AB  - Mitochondria are usually considered to be the powerhouses of the cell and to be
      responsible for the aerobic production of ATP. However, many eukaryotic organisms
      are known to possess anaerobically functioning mitochondria, which differ
      significantly from classical aerobically functioning mitochondria. Recently,
      functional and phylogenetic studies on some enzymes involved clearly indicated an
      unexpected evolutionary relationship between these anaerobically functioning
      mitochondria and the classical aerobic type. Mitochondria evolved by an
      endosymbiotic event between an anaerobically functioning archaebacterial host and
      an aerobic alpha-proteobacterium. However, true anaerobically functioning
      mitochondria, such as found in parasitic helminths and some lower marine
      organisms, most likely did not originate directly from the pluripotent ancestral
      mitochondrion, but arose later in evolution from the aerobic type of mitochondria
      after these were already adapted to an aerobic way of life by losing their
      anaerobic capacities. This review will focus on some biochemical and evolutionary
      aspects of these fermentative mitochondria, with special attention to fumarate
      reductase, the synthesis of the rhodoquinone involved, and the enzymes involved
      in acetate production (acetate : succinate CoA-transferase and succinyl CoA
      synthetase).

PMID- 12594927
TI  - Mitochondria and hydrogenosomes are two forms of the same fundamental organelle.
AB  - Published data suggest that hydrogenosomes, organelles found in diverse anaerobic
      eukaryotes that make energy and hydrogen, were once mitochondria. As
      hydrogenosomes generally lack a genome, the conversion is probably one way. The
      sources of the key hydrogenosomal enzymes, pyruvate : ferredoxin oxidoreductase
      (PFO) and hydrogenase, are not resolved by current phylogenetic analyses, but it
      is likely that both were present at an early stage of eukaryotic evolution. Once
      thought to be restricted to a few unusual anaerobic eukaryotes, the proteins are
      intimately integrated into the fabric of diverse eukaryotic cells, where they are
      targeted to different cell compartments, and not just hydrogenosomes. There is no
      evidence supporting the view that PFO and hydrogenase originated from the
      mitochondrial endosymbiont, as posited by the hydrogen hypothesis for
      eukaryogenesis. Other organelles derived from mitochondria have now been
      described in anaerobic and parasitic microbial eukaryotes, including species that
      were once thought to have diverged before the mitochondrial symbiosis. It thus
      seems possible that all eukaryotes may eventually be shown to contain an
      organelle of mitochondrial ancestry, to which different types of biochemistry can
      be targeted. It remains to be seen if, despite their obvious differences, this
      family of organelles shares a common function of importance for the eukaryotic
      cell, other than energy production, that might provide the underlying selection
      pressure for organelle retention.

PMID- 12594929
TI  - General discussion.

PMID- 12594930
TI  - Evolution of photosynthetic prokaryotes: a maximum-likelihood mapping approach.
AB  - Reconstructing the early evolution of photosynthesis has been guided in part by
      the geological record, but the complexity and great antiquity of these early
      events require molecular genetic techniques as the primary tools of inference.
      Recent genome sequencing efforts have made whole genome data available from
      representatives of each of the five phyla of bacteria with photosynthetic
      members, allowing extensive phylogenetic comparisons of these organisms. Here, we
      have undertaken whole genome comparisons using maximum likelihood to compare 527
      unique sets of orthologous genes from all five photosynthetic phyla.
      Substantiating recent whole genome analyses of other prokaryotes, our results
      indicate that horizontal gene transfer (HGT) has played a significant part in the
      evolution of these organisms, resulting in genomes with mosaic evolutionary
      histories. A small plurality phylogenetic signal was observed, which may be a
      core of remnant genes not subject to HGT, or may result from a propensity for
      gene exchange between two or more of the photosynthetic organisms compared.

PMID- 12594931
TI  - Type I photosynthetic reaction centres: structure and function.
AB  - We review recent advances in the study of the photosystem I reaction centre,
      following the determination of a spectacular 2.5 A resolution crystal structure
      for this complex of Synechococcus elongatus. Photosystem I is proving different
      to type II reaction centres in structure and organization, and the mechanism of
      transmembrane electron transfer, and is providing insights into the control of
      function in reaction centres that operate at very low redox potentials. The
      photosystem I complex of oxygenic organisms has a counterpart in non-oxygenic
      bacteria, the strictly anaerobic phototrophic green sulphur bacteria and
      heliobacteria. The most distinctive feature of these type I reaction centres is
      that they contain two copies of a large core polypeptide (i.e. a homodimer),
      rather than a heterodimeric arrangement of two related, but different,
      polypeptides as in the photosystem I complex. To compare the structural
      organization of the two forms of type I reaction centre, we have modelled the
      structure of the central region of the reaction centre from green sulphur
      bacteria, using sequence alignments and the structural coordinates of the S.
      elongatus Photosystem I complex. The outcome of these modelling studies is
      described, concentrating on regions of the type I reaction centre where important
      structure-function relationships have been demonstrated or inferred.

PMID- 12594932
TI  - Photosystem II: evolutionary perspectives.
AB  - Based on the current model of its structure and function, photosystem II (PSII)
      seems to have evolved from an ancestor that was homodimeric in terms of its
      protein core and contained a special pair of chlorophylls as the photo-oxidizable
      cofactor. It is proposed that the key event in the evolution of PSII was a
      mutation that resulted in the separation of the two pigments that made up the
      special chlorophyll pair, making them into two chlorophylls that were neither
      special nor paired. These ordinary chlorophylls, along with the two adjacent
      monomeric chlorophylls, were very oxidizing: a property proposed to be intrinsic
      to monomeric chlorophylls in the environment provided by reaction centre (RC)
      proteins. It seems likely that other (mainly electrostatic) changes in the
      environments of the pigments probably tuned their redox potentials further but
      these changes would have been minor compared with the redox jump imposed by
      splitting of the special pair. This sudden increase in redox potential allowed
      the development of oxygen evolution. The highly oxidizing homodimeric RC would
      probably have been not only inefficient in terms of photochemistry and charge
      storage but also wasteful in terms of protein or pigments undergoing damage due
      to the oxidative chemistry. These problems would have constituted selective
      pressures in favour of the lop-sided, heterodimeric system that exists as PSII
      today, in which the highly oxidized species are limited to only one side of the
      heterodimer: the sacrificial, rapidly turned-over D1 protein. It is also
      suggested that one reason for maintaining an oxidizable tyrosine, TyrD, on the D2
      side of the RC, is that the proton associated with its tyrosyl radical, has an
      electrostatic role in confining P(+) to the expendable D1 side.

PMID- 12594933
TI  - C-type cytochromes: diverse structures and biogenesis systems pose evolutionary
      problems.
AB  - C-type cytochromes are a structurally diverse group of haemoproteins, which are
      related by the occurrence of haem covalently attached to a polypeptide via two
      thioether bonds formed by the vinyl groups of haem and cysteine side chains in a
      CXXCH peptide motif. Remarkably, three different post-translational systems for
      forming these cytochromes have been identified. The evolution of both the
      proteins themselves and the biogenesis systems poses many questions to which
      answers are currently being sought. In this article we review the progress that
      has been made in understanding the need for covalent attachment of haem to
      proteins in cytochromes c and the complex systems involved in their formation.

PMID- 12594935
TI  - Therapeutic dilemmas in the management of uterine papillary serous carcinoma.
AB  - Uterine papillary serous carcinoma (UPSC) affects 1% to 10% of patients with
      endometrial malignancies. UPSC is more aggressive than conventional endometrial
      cancer because UPSC presents with advanced disease, similar to epithelial ovarian
      cancer. There are several biomarkers for UPSC, which indicate that the
      pathogenesis of this condition is different than epithelial ovarian and
      conventional endometrial cancer. There are no risk factors for UPSC. Extended
      surgical staging is the optimal surgical approach for patients without known
      distant metastases. Patients with stage IA disease do not benefit from further
      adjuvant therapy. Adjuvant pelvic radiotherapy reduces pelvic relapse in
      intermediate- and high-risk patients (stage IC, II, and III disease) and extends
      survival rates of patients when administered with chemotherapy. In this setting,
      chemotherapy (with or without adjuvant radiotherapy) is a platinum-based regimen,
      combined with doxorubicin and cyclophosphamide. A newer regimen is paclitaxel,
      with or without platinum. An alternative approach for treating patients with UPSC
      has been to use whole abdominal radiotherapy. The results of Gynecologic Oncology
      Group protocol 122, which involves patients with UPSC who are being treated with
      chemotherapy and whole abdominal radiotherapy, are expected to reveal a minimal
      difference between these arms in overall survival rates. In patients experiencing
      distant or extensive abdominal relapse, management has been palliative, using
      platinum-based regimens or single-agent therapy to assess response. Treatment for
      patients with further relapse must be individualized because there are no studies
      addressing these scenarios. Palliative radiotherapy should be offered to patients
      needing symptom control for metastatic or progressive local disease. Many of
      these patients face a significant risk of treatment failure and death because of
      distant relapse. Therefore, the use of randomized trials to evaluate new
      therapies is critical.

PMID- 12594934
TI  - The redox protein construction kit: pre-last universal common ancestor evolution
      of energy-conserving enzymes.
AB  - Genome analyses and the resolution of three-dimensional structures have provided
      evidence in recent years for hitherto unexpected family relationships between
      redox proteins of very diverse enzymes involved in bioenergetic electron
      transport. Many of these enzymes appear in fact to be constructed from only a
      limited set of building blocks. Phylogenetic analysis of selected units from this
      "redox enzyme construction kit" indicates an origin for several prominent
      bioenergetic enzymes that is very early, lying before the divergence of Bacteria
      and Archaea. Possible scenarios for the early evolution of selected complexes are
      proposed based on the obtained tree topologies.

PMID- 12594936
TI  - Prophylactic surgery and other strategies for reducing the risk of familial
      ovarian cancer.
AB  - The goal of a cancer prevention program is to improve the mortality rates of
      patients. No risk-reduction strategy is proven to reduce mortality rates of women
      at increased risk for ovarian cancer. Methods of ovarian cancer surveillance are
      unproven in high-risk women. According to some studies, the use of oral
      contraceptives in high-risk women reduces ovarian cancer risk. Prophylactic
      salpingo-oophorectomy is the most effective method of cancer risk reduction in
      women at high risk for ovarian cancer. However, women who undergo prophylactic
      salpingo-oophorectomy remain at risk for primary peritoneal cancer. A minority of
      women with BRCA1 and BRCA2 mutations are diagnosed with occult cancer at the time
      of surgical prophylaxis. Surgical prophylaxis should include complete removal of
      the fallopian tubes and ovaries, procurement of peritoneal cytology, and thorough
      evaluation of the tubes and ovaries by an expert pathologist. Beginning at age 30
      years, women with BRCA1 and BRCA2 germline mutations should have an annual or
      semiannual screening, consisting of serum CA-125 measurement and transvaginal
      ultrasound, until the completion of childbearing. After the completion of
      childbearing and by age 40 years, women should undergo prophylactic salpingo
      oophorectomy.

PMID- 12594937
TI  - Human papillomavirus therapy for the prevention and treatment of cervical cancer.
AB  - Cervical carcinoma is associated with human papillomavirus infection.
      Proliferation of cancer cells depends on the continual expression of the E6 and
      E7 viral oncogenes. This article includes treatment strategies that can interfere
      with expression or function of the proteins and immunotherapeutic approaches that
      can eliminate cells that express E6 and E7 proteins.

PMID- 12594938
TI  - Endometrial cancer: treatment of nodal metastases.
AB  - Surgical staging has changed the method by which patients with endometrial cancer
      are managed. Before the routine use of lymph node dissection, patients were
      presumed to have nodal disease based on imaging studies, palpation, and biopsy.
      The move to a surgically based staging system in 1988 created a new subgroup of
      patients who had documented nodal disease. The risk of nodal involvement is
      related primarily to tumor grade and depth of myometrial invasion. Although
      patients with nodal disease are uncommon, treatment of these patients poses
      multiple challenges. It is our belief that unless nodes are surgically assessed,
      the clinician will not know whether the nodes are involved. A thorough
      lymphadenectomy with removal of nodal tissue from multiple pelvic sites and from
      bilateral para-aortic regions is recommended for most patients with endometrial
      cancer. Identification of positive nodes allows appropriate postoperative
      therapies to be used, and data support that nodal dissection may be therapeutic
      and prognostic. Patients with positive nodes should receive radiation therapy
      directed to the nodal distribution, with patients having involved para-aortic
      nodes receiving an extended field. Whole abdominal radiation has been used,
      especially in patients with adnexal disease or positive cytology. The role of
      whole abdominal radiation remains in question. The most promising treatment
      option is combination therapy with sequential radiation and chemotherapy. Active
      chemotherapy agents in endometrial cancer are doxorubicin, cisplatin, and
      paclitaxel.

PMID- 12594939
TI  - The role of aromatase inhibitors in early breast cancer.
AB  - The role of hormonal therapy for the treatment of patients with early stage
      breast cancer has been evaluated in many studies. The results of these studies
      establish tamoxifen as the gold standard of hormonal therapy for the adjuvant
      treatment of hormone receptor-positive invasive breast cancer in pre- and
      postmenopausal women. Studies show tamoxifen reduces the risk of invasive breast
      cancer in women at increased risk for the disease, including women with ductal
      carcinoma in situ. Tamoxifen has adverse effects such as hot flashes, increased
      risk of uterine cancer in postmenopausal women, and rare occurrence of
      thromboembolic disease. Despite the multiple therapeutic roles of tamoxifen,
      alternatives are needed. Aromatase inhibitors (AI) are drugs with antiestrogenic
      activity. AIs function by inhibiting the peripheral conversion of adrenally
      synthesized androstenedione to estradiol through inhibition of the aromatase
      enzyme. AIs do not suppress estradiol synthesis by the ovary adequately.
      Therefore, AIs are effective in reducing circulating estradiol levels in
      postmenopausal women, but not premenopausal women. Selective nonsteroidal AIs,
      including anastrozole (Arimidex; AstraZeneca, Wilmington, DE) and letrozole
      (Femara; Novartis, East Hanover, NJ), and the steroidal AI exemestane (Aromasin;
      Pharmacia, Peapack, NJ) have been associated with increased specificity and
      improved therapeutic index compared to nonselective AIs such as
      aminoglutethamide. Nonsteroidal and steroidal AIs have demonstrated to be
      superior to megestrol acetate in second-line therapy of postmenopausal women with
      metastatic breast cancer, and selective nonsteroidal AIs have shown to be
      superior to tamoxifen in first-line therapy of postmenopausal women with
      metastatic breast cancer. The ATAC (Arimidex, tamoxifen, alone, or in
      combination) trial is the only published randomized trial comparing the efficacy
      of an AI to tamoxifen for the adjuvant treatment of women with early breast
      cancer. This large study showed that at a median follow-up time of 33 months,
      anastrozole alone results in significant improvement in disease-free survival
      rates, reduction in contralateral breast cancers, and increased tolerability,
      compared to tamoxifen in postmenopausal women. Although the long-term effects of
      AIs are not known, the early positive results of the ATAC trial led to the
      approval of anastrozole by the US Food and Drug Administration for use as
      adjuvant hormonal therapy for postmenopausal women with hormone receptor-positive
      invasive breast cancer. Thus, there is an alternative to tamoxifen for
      postmenopausal women with relative/absolute contraindications to tamoxifen use or
      patients who choose not to take tamoxifen because of its side-effect profile. New
      AIs may challenge the position of tamoxifen as the gold standard for the
      treatment of early stage breast cancer in postmenopausal women.

PMID- 12594940
TI  - Adjuvant systemic therapy of early stage breast cancer.
AB  - Adjuvant chemotherapy reduces the risk of recurrence and mortality in patients
      with early stage breast cancer. Anthracycline-based regimens are the most widely
      used standard in the United States. The inclusion of the taxanes into adjuvant
      chemotherapy programs offers an improvement in disease-free survival rates and
      probably overall survival rates compared to an anthracycline-based regimen alone.
      Although adjuvant chemotherapy is effective in all age groups, the magnitude of
      benefit is greatest in younger premenopausal patients. Treatment decisions need
      to be individualized. Dose-dense chemotherapy approaches are promising and can be
      considered an option for patients with early stage breast cancer. Adjuvant
      tamoxifen therapy should be administered for 5 years in patients with hormone
      receptor-positive breast cancer. Adjuvant tamoxifen should be administered after
      the completion of adjuvant chemotherapy. Data from the ATAC (Arimidex, tamoxifen,
      alone, or in combination) trial provide a compelling argument for choosing
      anastrozole as adjuvant endocrine therapy in postmenopausal women with hormone
      receptor-positive early stage breast cancer. Long-term follow-up of patients is
      necessary to determine the effects of chronic aromatase inhibitor treatment on
      bone density, cognitive function, and other endpoints.

PMID- 12594941
TI  - Bone metastases in breast cancer.
AB  - Patients with advanced breast cancer who develop bone metastases suffer from long
      term skeletal morbidity. Complications of bone metastases include pain,
      pathologic fractures, and spinal cord compression, which have a significant
      impact on the quality of life of patients. Treatment options for patients with
      bone metastases include surgery, radiation, and analgesics to reduce bone pain
      and to prevent or repair fractures. Intravenous bisphosphonates can delay the
      onset of bone metastasis and reduce the percentage of patients who experience
      skeletal complications of bone metastasis, thus reducing skeletal morbidity. For
      the past 6 years, pamidronate disodium (90 mg administered by 2-hour intravenous
      infusion) has been the treatment of choice for the prevention of skeletal
      complications of bone metastases in patients with breast cancer. However, a more
      potent bisphosphonate, zoledronic acid (4 mg administered by 15-minute
      intravenous infusion), was approved for use and has improved efficacy in patients
      with bone metastases. Because of the increased efficacy and more convenient
      infusion time, zoledronic acid may become the new standard of care for the
      treatment and prevention of skeletal complications secondary to bone metastases
      in patients with breast cancer. Phase III clinical trials have shown that
      patients with an existing skeletal complication are more likely to develop
      subsequent complications compared with patients who have not experienced a
      complication. Therefore, zoledronic acid therapy should be initiated when the
      patient is diagnosed with bone metastasis.

PMID- 12594942
TI  - Male breast cancer.
AB  - Treatments for men with breast cancer are based largely on accepted regimens for
      women with the disease. Surgical treatment of the primary tumor should be a
      mastectomy. Lymph node assessment can be done by conventional axillary node
      dissection or, similar to selected women with small primary tumors, by sentinel
      node dissection. Decisions regarding adjuvant systemic treatment should be made
      on the same basis as for women. Axillary node status, tumor size, hormone
      receptor status, and the health of the patient are important considerations in
      determining what adjuvant treatment is offered. The role of radiation after
      mastectomy in men is not well defined, but radiation should be used in patients
      at high risk for local recurrence. For patients with metastatic disease,
      treatment is based on the hormone receptor status of the tumor and is similar to
      the treatment for women. Because most men with breast cancer have hormone
      receptor-positive disease, hormonal therapy is a mainstay of treatment and
      tamoxifen remains the front-line drug of choice, although the latest generation
      of aromatase inhibitors have supplanted tamoxifen as a first-line therapy for
      women. As a second-line hormonal therapy for men, orchiectomy or a luteinizing
      hormone-releasing hormone agonist with or without an antiandrogen are reasonable
      alternatives. There are no reports regarding the use of the antiestrogen
      fulvestrant in men, but its mechanism of action and efficacy in women suggest
      that it will be a useful agent in hormone receptor-positive male breast cancer.
      For men with hormone-resistant disease, palliative chemotherapy with the same
      agents used for treatment of women with breast cancer is appropriate.

PMID- 12594943
TI  - Management of breast cancer diagnosed during pregnancy.
AB  - Breast cancer during pregnancy is generally defined as cancer occurring during
      pregnancy or within 1 year of delivery, although treatment options are the most
      complicated when the disease is diagnosed during gestation. The challenges of
      treatment during gestation are discussed in this article. In general, a pregnant
      woman with breast cancer should be treated similarly to the nonpregnant patient,
      with specific recommendations tailored to gestational age at diagnosis, stage of
      the tumor, and the personal preferences of the patient. Despite the increasing
      literature focusing on treatment decisions, there are little prospective data
      regarding treatment or long-term outcome information to provide toxicity data
      that can be used to advise patients and guide decisions. Most of the
      retrospective and anecdotal data are based on the possibility of fetal loss or
      demise with specific treatment or treatment administered at specific times during
      pregnancy. Therefore, it is impossible to accurately quantify risks to the fetus
      or the mother, and decisions should be made after careful discussion between the
      patient, her family, and the medical team. The physician must have a clear
      understanding of the pharmacology and teratogenic potential of individual agents,
      thus limiting risks.

PMID- 12594944
TI  - At the innate frontiers between mother and fetus: linking abortion with
      complement activation.
AB  - The intricate mechanisms regulating fetomaternal interactions are still largely
      uncharacterized. Recent papers have revealed a major role for the innate immune
      system during abortion. Different experimental conditions-deletion of a
      complement regulator, injection of anti-phospholipid antibodies into mothers, or
      allo-recognition of fetuses in the presence of an IDO inhibitor-all lead to
      complement activation, inflammation, and fetal loss. These observations also
      raise new questions on the relationship between the adaptive and innate systems
      during pregnancy.

PMID- 12594945
TI  - Hierarchical interactions control CD4 gene expression during thymocyte
      development.
AB  - CD4 gene regulation provides an ideal model for understanding the molecular
      events that drive T cell development. In this paper we use a transgenic approach
      to identify a CD4 LCR containing a stage-specific thymocyte enhancer (TE) and a
      region that protects against position effect variegation. Surprisingly, the TE
      acts indirectly through the previously defined proximal enhancer and is strongly
      induced upon commitment to the T cell lineage. We also describe a complex series
      of hierarchical control element interactions that orchestrate CD4 expression
      throughout thymopoiesis. These data provide a framework for understanding how CD4
      gene expression is regulated in response to lineage commitment decisions.

PMID- 12594946
TI  - Regulation of anti-phosphatidylserine antibodies.
AB  - The degree of heavy chain (H) editing, the types of Vkappa editors, and the
      pattern of Jkappa usage are correlated with a range of the affinity of anti-DNA.
      This range was determined by the number and location of arginine (R) residues in
      the VH. We, here, changed a key arginine residue in the VH of anti-DNA transgene
      to glycine, which sharply reduces the affinity for dsDNA. However, complete
      reversion of this anti-DNA to germline enhances the affinity for
      phosphatidylserine (PS). The B cells of this low-affinity anti-DNA and anti-PS
      transgenic mouse are tightly regulated by receptor editing. Thus, anti-PS B cells
      are another example of a constitutive self-antigen regulated in the bone marrow.

PMID- 12594947
TI  - The repertoires of circulating human CD8(+) central and effector memory T cell
      subsets are largely distinct.
AB  - Memory T cells are divided into central and effector subsets with distinct
      functions and homing capabilities. We analyzed the composition and dynamics of
      the CD8(+) T cell repertoire of these subsets within the peripheral blood of four
      healthy individuals. Both subsets had largely distinct and autonomous TCRbeta
      repertoires. Their composition remained stable over a 9 month period, during
      which no cell passage between these subsets was detected despite important size
      variation of several clones. In one donor, four out of six TCRbeta clonotypes
      specific for the influenza A virus were detected in the central subset only,
      while the two others were shared. Altogether, these observations suggest that
      most effector memory T cells may not have derived from the central memory subset.

PMID- 12594948
TI  - The crystal structure of a TL/CD8alphaalpha complex at 2.1 A resolution:
      implications for modulation of T cell activation and memory.
AB  - TL is a nonclassical MHC class I molecule that modulates T cell activation
      through relatively high-affinity interaction with CD8alphaalpha. To investigate
      how the TL/CD8alphaalpha interaction influences TCR signaling, we characterized
      the structure of the TL/CD8alphaalpha complex using X-ray crystallography. Unlike
      antigen-presenting molecules, the TL antigen-binding groove is occluded by
      specific conformational changes. This feature eliminates antigen presentation,
      severely hampers direct TCR recognition, and prevents TL from participating in
      the TCR activation complex. At the same time, the TL/CD8alphaalpha interaction is
      strengthened through subtle structure changes in the TL alpha3 domain. Thus, TL
      functions to sequester and redirect CD8alphaalpha away from the TCR, modifying
      lck-dependent signaling.

PMID- 12594949
TI  - Deficiency of the mouse complement regulatory protein mCd59b results in
      spontaneous hemolytic anemia with platelet activation and progressive male
      infertility.
AB  - Basal complement activity presents a potential danger for "self" cells that are
      tightly protected by complement regulators including CD59. Mice express two Cd59
      genes (mCd59a and mCd59b); mCd59b has approximately a 6-fold higher specific
      activity than mCd59a. Consistently, mCd59b knockout mice present a strong
      phenotype characterized by hemolytic anemia with increased reticulocytes,
      anisopoikilocytosis, echinocytosis, schistocytosis, free hemoglobin in plasma,
      hemoglobinuria with hemosiderinuria, and platelet activation. Remarkably, mCd59b(
      /-) males express a progressive loss of fertility associated with immobile
      dysmorphic and fewer sperm cells after 5 months of age. This work indicates that
      mCd59b is a key complement regulator in mice and that CD59 is critical in
      protecting self cells; it also provides a novel model to study complement
      regulation in human diseases.

PMID- 12594950
TI  - Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of
      immunoglobulin heavy chain gene rearrangements.
AB  - Production of immunoglobulin heavy chain (IgH) protein feeds back to terminate
      further V(H) gene recombination, a phenomenon also referred to as allelic
      exclusion. Here we provide evidence to support the proposition that allelic
      exclusion is the consequence of terminating signals that activate V(H) genes for
      recombination. For the largest V(H)J558 family of genes, this occurs by
      attenuating IL-7/IL-7R signals in pre-B cells. Loss of these signals reverts the
      V(H) locus to a chromatin state that is associated with hypoacetylated histones
      and is less accessible to nucleases. Furthermore, hyperacetylation and
      accessibility of unrearranged V(H) genes can be restored in allelically excluded
      splenic B cells by activating this pathway. Thus, transient signals mediate V(H)
      gene activation and inactivation during development.

PMID- 12594951
TI  - Sequential waves of functionally related proteins are expressed when B cells
      prepare for antibody secretion.
AB  - Upon encounter with antigen, B lymphocytes differentiate into Ig-secreting plasma
      cells. This step involves a massive development of secretory organelles, most
      notably the endoplasmic reticulum. To analyze the relationship between organelle
      reshaping and Ig secretion, we performed a dynamic proteomics study of B lymphoma
      cells undergoing in vitro terminal differentiation. By clustering proteins
      according to temporal expression patterns, it appeared that B cells anticipate
      their secretory role in a multistep process. Metabolic capacity and secretory
      machinery expand first to accommodate the mass production of IgM that follows.

PMID- 12594952
TI  - Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T
      cell activation.
AB  - The relative roles of CD8, TCR:pepMHC affinity, and TCR:pepMHC dissociation rate
      in T cell activation have remained controversial. To determine the relationships
      among these factors, we used T cells transfected with normal and in vitro
      engineered alphabeta TCRs, in the presence or absence of CD8. The TCRs exhibited
      a wide range of affinities (K(D) values of 80 microM to 5 nM). T cells with the
      highest affinity TCRs were efficiently stimulated by peptide, with or without
      CD8. In contrast, CD8 was required for T cells that expressed TCRs with
      affinities typical of syngeneic reactions (K(D) values above approximately 3
      microM). The results suggest that virtually all normal syngeneic interactions
      require CD8, which enhances peptide sensitivity by one million-fold or more.

PMID- 12594953
TI  - Accelerated migration of respiratory dendritic cells to the regional lymph nodes
      is limited to the early phase of pulmonary infection.
AB  - Respiratory dendritic cells (RDC) are believed to play a central role in the
      induction of adaptive immune responses to pulmonary infection. Herein we examine
      the basal migration of RDC from the lungs to secondary lymphoid tissues and their
      enhanced maturation/migration after pulmonary infection/inflammation. We
      demonstrate that the accelerated migration of RDC to the draining peribronchial
      lymph nodes occurs only during the first 24 hr after pulmonary virus infection.
      RDC are refractory to further migration thereafter in spite of ongoing virus
      replication and pulmonary inflammation. We further demonstrate that induction of
      this RDC refractory state suppresses additional RDC mobilization to subsequent
      pulmonary virus infection and results in concomitant suppression of an antiviral
      pulmonary CD8(+) T cell response.

PMID- 12594954
TI  - Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI
      as an inhibitory BLyS receptor.
AB  - BLys , a key cytokine that sustains B cell maturation and tolerance, binds three
      receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major
      functional role for BR3 and a redundant one for BCMA in B cell function. TACI's
      role is controversial based on defects in TI antibody responses accompanied by B
      cell hyperplasia in knockout mice. We have presently characterized a precise role
      for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis,
      proteinurea, and elevated levels of circulating autoantibodies. Treatment of B
      cells with TACI agonistic antibodies inhibits proliferation in vitro and
      activation of a chimeric receptor containing the TACI intracellular domain
      induces apoptosis. These results demonstrate the critical requirement for TACI in
      regulating B cell homeostasis.

PMID- 12594955
TI  - Rev activity determines sensitivity of HIV-1-infected primary T cells to CTL
      killing.
AB  - The HIV Nef protein is thought to promote HIV immune evasion by downmodulating
      MHC-I and protecting infected cells from CTL killing. In addition, we
      demonstrated that Rev, an HIV regulatory protein needed for expression of the HIV
      late genes, can influence CTL killing. When Rev activity level was reduced by
      virtue of amino acid alterations in the Rev protein sequence, infected cells were
      more resistant to anti-Gag and anti-Env CTL killing. A screen of primary viral
      isolates revealed that viruses derived from asymptomatic, infected people had
      lower Rev activity, lower Gag levels, and greater resistance to anti-Gag CTL
      killing. Thus, rev alleles with low activity may have a selective advantage in
      infected people with effective immune responses.

PMID- 12594956
TI  - Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP
      J signaling pathway.
AB  - We found that Msx2-interacting nuclear target protein (MINT) competed with the
      intracellular region of Notch for binding to a DNA binding protein RBP-J and
      suppressed the transactivation activity of Notch signaling. Although MINT null
      mutant mice were embryonic lethal, MINT-deficient splenic B cells differentiated
      about three times more efficiently into marginal zone B cells with a concomitant
      reduction of follicular B cells. MINT is expressed in a cell-specific manner:
      high in follicular B cells and low in marginal zone B cells. Since Notch
      signaling directs differentiation of marginal zone B lymphocytes and suppresses
      that of follicular B lymphocytes in mouse spleen, the results indicate that high
      levels of MINT negatively regulate Notch signaling and block differentiation of
      precursor B cells into marginal zone B cells. MINT may serve as a functional
      homolog of Drosophila Hairless.

PMID- 12594957
TI  - Plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in
      drug-resistant lines.
AB  - The rapid emergence of multidrug-resistant Plasmodium falciparum is a worldwide
      concern. Despite the magnitude of the problem, the mechanisms involved in this
      phenomenon are not well understood. One current proposal suggests that toxic heme
      molecules are degraded by glutathione (GSH), and that anti-malarial drugs, such
      as chloroquine (CQ), inhibit this degradation, thus implicating GSH in drug
      resistance. Furthermore, in some strains of Plasmodium berghei and P. falciparum,
      chloroquine resistance is accompanied by an increase in glutathione levels and
      increased activity in GSH-related enzymes. We are investigating the relationship
      between the gamma-glutamylcysteine synthetase (ggcs) gene, the rate-limiting
      enzyme in de novo synthesis of GSH, and drug resistance in P. berghei at the
      molecular level. In this report, we have demonstrated an increase in pbggcs mRNA
      levels associated with CQ and mefloquine (MFQ) resistance. In addition, the
      pbggcs gene locus structure was shown to be similar and localized to chromosome 8
      in four parasite lines of P. berghei with different drug resistance profiles.
      This work suggests a link between increased GSH levels and drug resistance in
      Plasmodium.

PMID- 12594958
TI  - Entamoeba histolytica: acute granulomatous intestinal lesions in normal and
      neutrophil-depleted mice.
AB  - To study the role of neutrophils in the innate resistance to Entamoeba
      histolytica intestinal infection in mice, animals were treated with anti
      neutrophil monoclonal antibodies prior to intracecal parasite inoculation and the
      resulting lesions were compared with normal mice that had been equally infected.
      In contrast to our previous finding that neutrophils are critical in eliminating
      E. histolytica infection in the liver, we show here that neutrophils are not
      absolutely required to eliminate E. histolytica infection from the intestine.
      Although the neutrophils are not critical for resolution of the E. histolytica
      infection, neutrophils do appear to provide some measure of protection as the
      intestinal amoeba burden was higher at early timepoints after infection in the
      neutropenic animals. In addition, we found that while both the normal and the
      neutrophil-depleted mice developed ulcerative lesions in the colon, the
      neutropenic mice had an increased frequency of granulomas that formed around the
      amoeba. Thus, our findings appear to be the first evidence showing that
      granulomatous inflammation can occur after intestinal infection in mice using
      axenically cultured amoeba.

PMID- 12594959
TI  - Trypanosoma cruzi: host selenium deficiency leads to higher mortality but similar
      parasitemia in mice.
AB  - Selenium is an essential trace element and its deficiency was implicated in heart
      diseases. We recently showed low Se levels in chronic chagasic patients with
      cardiomyopathy. Herein, mice were depleted in Se by feeding the mothers with chow
      containing only 0.005 mg Se/kg and maintaining this diet for offspring, that were
      further infected with Trypanosoma cruzi. Survival rate was significantly lower in
      Se deficient than in control mice. Parasitemia was similar in all groups.
      Necrotic heart lesions were found after infection (high CK-MB levels). No
      outbreaks of parasite growth were detected in chronic survivors submitted or not
      to a second Se depletion. The present results confirm our hypothesis that a
      nutritional deficiency in Se is associated to a higher mortality during T. cruzi
      infection. The potential beneficial effect of Se supplementation is a
      perspective. Hypothesis to explain the higher susceptibility of Se-depleted mice
      to T. cruzi infection are discussed.

PMID- 12594960
TI  - Distinct characteristics of two intestinal protein compartments discriminated by
      using fenbendazole and a benzimidazole resistant isolate of Haemonchus contortus.
AB  - The intestine of Haemonchus contortus is hypersensitive to the effects of the
      anthelmintic fenbendazole (FBZ). The effects are postulated to stem from
      disruption of microtubules and interference with apical secretory vesicle
      transport, followed by release of digestive enzymes into the intestinal cell
      cytoplasm. Here, FBZ caused marker proteins for both apical (pepsinogen-like
      protease, PEP-1) and basal (cystatin-like protein) protein compartments to became
      homogeneously distributed in the cytoplasm of H. contortus intestinal cells. The
      observations with PEP-1 support the hypothesis that release of hydrolytic enzymes
      into the intestinal cell cytoplasm contributes to the mechanism of benzimidazole
      efficacy. A benzimidazole resistant isolate of H. contortus expressed type 1 and
      2 intestinal beta-tubulin transcripts that would encode predominantly tyr200 and
      phe200 variants, respectively. This isolate was resistant to the known intestinal
      cell alterations induced by FBZ treatment in the susceptible isolate, including
      inhibition of apical vesicle transport. These results implicate type 1 beta
      tubulin in mediating apical vesicle transport in intestinal cells and suggest
      that the tyr200 variant is a determinant of FBZ resistance in intestinal cells.
      In contrast, the basal protein compartment demonstrated sensitivity to FBZ
      treatment in these otherwise "resistant" worms. Hence, distinct FBZ-sensitive
      components appear to be involved in distributing intestinal proteins into the
      described apical and basal compartments of normal worms.

PMID- 12594961
TI  - Babesia gibsoni: molecular cloning and characterization of Rab6 and Rab11
      homologues.
AB  - Members of the Rab subfamily of GTPases have been implicated as important
      components in vesicle trafficking in the eukaryotes, individual Rab proteins have
      a remarkable degree of specific subcellular localization. As a first step towards
      developing a set of compartment specific probes for studying protein trafficking
      in Babesia-infected erythrocyte, here we describe the cloning and
      characterization of Rab6 and Rab11 gene homologues in Babesia gibsoni (BgRab6 and
      BgRab11). The deduced amino acid sequence of both BgRab6 and BgRab11 contained
      the highly conserved GTP-binding consensus sequence and C-terminal cysteines.
      Northern blotting analysis of total RNA hybridized a 1.3 kb band on both BgRab6
      and BgRab11 probed blots consistent with the expected size. Using a GTP-binding
      assay we demonstrated that Escherichia coli expressed recombinant BgRab6 and
      BgRab11 were able to bind GTP. BgRab6 and BgRab11 represent the first two
      molecular markers of B. gibsoni.

PMID- 12594962
TI  - Entamoeba histolytica: purification and characterization of ornithine
      decarboxylase.
AB  - Ornithine decarboxylase, a rate-limiting enzyme in polyamine biosynthesis in
      eukaryotes, was stabilized and purified from trophozoites of the parasite
      protozoan E. histolytica. Analytical electrophoresis revealed the presence in the
      purified preparations of a major polypeptide of 45 kDa and barely detectable
      amounts of two other proteins of 70 and 120 kDa. Both the 45 and 70 kDa
      polypeptides were recognized by a mouse anti-ODC monoclonal antibody. The major
      polypeptide exhibited amino terminal sequence homology in the range of 40-73%
      with ODCs from other organisms. The immunoreactive polypeptide of 70 kDa was not
      identified. The molecular masses of 216 and 45 kDa determined for the native
      enzyme by gel filtration and for the major polypeptide by SDS-PAGE, respectively,
      suggest that the amoeba ODC is a homopentamer. Dialysis against hydroxylamine
      rendered the enzyme activity fully dependent on pyridoxal 5'-phosphate (PLP). As
      expected for an oligomeric enzyme, ODC activity exhibited sigmoidal kinetics when
      it was measured as a function of increasing concentrations of L-ornithine and PLP
      yielding S(0.5) values of 0.45 and 0.18 mM, respectively. Purified ODC was
      inhibited by 1,3-diaminopropane and 2,4-diamino-2-butanone but was largely
      insensitive to inhibition by alpha-difluoromethylornithine (DFMO), indicating
      that the enzyme may not be a suitable target for this anti-parasitic drug. Other
      features of the amoeba ODC were common with the enzyme from prokaryotes and
      eucaryotes.

PMID- 12594963
TI  - Trypanosoma brucei: in vitro slender-to-stumpy differentiation of culture
      adapted, monomorphic bloodstream forms.
AB  - Pleomorphic Trypanosoma brucei strains are characterized by their ability to
      differentiate from replicating long slender forms into non-dividing short stumpy
      forms in the mammalian host. The differentiation process can be efficiently
      induced in vitro by treatment with the membrane-permeable cAMP derivative 8-(4
      chlorophenylthio)-cAMP (pCPTcAMP). In contrast, monomorphic T. brucei strains do
      not differentiate to stumpy forms in the host. Here, we show that exposure of
      monomorphic, culture-adapted T. brucei bloodstream forms to pCPTcAMP allowed
      their subsequent differentiation into short stumpy forms. The stumpy nature of
      pCPTcAMP-treated parasites was confirmed by (1) morphological change, (2)
      inhibition of growth and DNA synthesis, (3) cell cycle arrest in the G(1)/G(0)
      phase, (4) expression of NADH diaphorase activity and dihydrolipoamide
      dehydrogenase, (5) disappearance of the small subunit of ribonucleotide
      reductase, (6) up-regulation of the major lysosomal membrane protein, and (7)
      efficient transformation into replicating procyclic insect forms after induction
      with citrate/cis-aconitate. Our results indicate that the inability of
      monomorphic T. brucei bloodstream forms to differentiate into short stumpy forms
      in the host may be due to a failure in the signalling pathway rather than in the
      differentiation process itself. Treatment of monomorphic bloodstream trypanosomes
      with pCPTcAMP could be a useful method for identifying the genes involved in the
      slender-to-stumpy differentiation process.

PMID- 12594964
TI  - Clonorchis sinensis: glutathione S-transferase as a serodiagnostic antigen for
      detecting IgG and IgE antibodies.
AB  - Human Clonorchis sinensis infection is endemic in East Asian countries.
      Glutathione S-transferases (GSTs) are anti-oxidant enzymes found in all living
      creatures as well as in trematodes. In this study, we examined the recombinant
      26kDa GST protein of C. sinensis (Cs26GST) for its serodiagnostic antigenicity
      toward IgG and IgE antibodies by ELISA and immuno-enhanced chemiluminescence,
      respectively. In IgG ELISA, recombinant Cs26GST showed 33.3% sensitivity and 100%
      specificity for trematode-infected human sera. In the case of the IgE antibody,
      recombinant Cs26GST showed 50.0% sensitivity and 93.2% specificity for
      clonorchiasis infection. We propose that the recombinant Cs26GST is a potent
      serodiagnostic antigen for detecting C. sinensis-specific IgG and IgE antibodies,
      and that it be best used as an antigenic cocktail in combination with other
      antigens.

PMID- 12594965
TI  - In vitro culture of the avian echinostome Himasthla elongata: from redia to
      marita.
AB  - Axenic primary cultures of Himasthla elongata rediae harvested from
      hepatopancreas of naturally infected marine prosobranch snail Littorina littorea
      were maintained in Leibovitz's L-15 medium (osmolarity of approximately 780 mOsm,
      pH 7.8, temperature 14 degrees C under normal atmospheric conditions). Cultured
      rediae were active, motile and demonstrated high synthetic activity in metabolic
      labelling experiment. Long-term cultivation experiment showed 50% survival level
      of the rediae for up to 70 days and significant differences between mortality in
      redia groups derived from different host individuals. Half of the rediae in the
      most robust group survived for up to 163 days, when the experiment was
      terminated. Development and emergence of in vivo preformed cercariae and daughter
      rediae was observed. Cercariae in the culture also encysted, transformed into
      metacercariae and some of them in one to two weeks after the transformation
      spontaneously excysted into juvenile maritae. The employed culture system is
      characterized by a very low level of proteolytic activity. This system is
      suggested as a method permitting to obtain rediae secretory-excretory products
      free of host-derived contaminants.

PMID- 12594966
TI  - Characterization of cDNA encoding a L37a ribosomal protein from Taenia crassiceps
      and its potential use in phylogenetic reconstructions.
AB  - In this study, we characterized for the first time the complete sequence of a
      L37a cDNA from a cestode specie: Taenia crassiceps. A phylogenetic analysis of
      L37a ribosomal proteins from distant animal species is presented and the
      potential use of such proteins in molecule-based phylogeny is discussed.

PMID- 12594968
TI  - Heilpraktiker.

PMID- 12594969
TI  - A survey on psychiatric patients' use of non-medical alternative practitioners:
      incidence, methods, estimation, and satisfaction.
AB  - OBJECTIVES: We investigated to what extent psychiatric inpatients consult
      Heilpraktiker, i.e. non-academically trained providers of complementary and
      alternative medicine (CAM), which diagnostic and therapeutic methods
      Heilpraktiker employ, how patients assess Heilpraictikers' professional
      competence, CAM in general and issues of satisfaction for those who have had
      experience with Heilpraktiker. DESIGN: Four hundred and seventy three patients
      admitted to a psychiatric university department during a 9-month period filled
      out a questionnaire developed for this investigation. RESULTS: About one third of
      the patients had consulted a Heilpraktiker, a quarter of these for their current
      psychiatric illness. Women were in the majority. Patients with the highest
      secondary school education consulted Heilpraktiker less often. There was
      considerable 'customer loyalty' towards Heilpraktiker. Largely the same
      diagnostic and treatment methods were employed for mental illness as for somatic
      complaints. Except for iridology, exotic or dangerous methods played a secondary
      role. Patients generally revealed a very positive attitude toward Heilpraktiker
      and CAM, although methods were rated differently. CAM enjoyed greater
      appreciation among women and patients who had consulted Heilpraktiker. Patients
      with personal experience were, on the whole, very satisfied with the professional
      competence, with the atmosphere in the practice and staff concern for the
      patient's well-being. Degree of satisfaction correlated closely with frequency of
      consultation. More patients with neurotic disorders considered the cost
      unreasonable than others, despite comparatively frequent visits. CONCLUSIONS:
      Psychiatric patients seek out Heilpraktiker to a considerable degree. Especially
      those who have relevant experience rank Heilpraktiker highly, in particular due
      to their 'psychotherapeutic' attitude, but professional competence is also
      valued. Methods of CAM received mixed reviews from patients but are generally
      seen in a positive light. It is recommended that doctors collecting case history
      data on their patients also ask about experience with alternative practitioners
      and treatments.

PMID- 12594970
TI  - Attitudes to the contribution of placebo in acupuncture--a survey.
AB  - Interest in placebo is increasing, and recent research suggests that the
      therapeutic consequence of placebo is generated through mental processes in which
      attitudes are important. The aim of this study is therefore to explore attitudes
      and beliefs concerning placebo effect in acupuncture therapy, among doctors,
      patients and acupuncturists. From February 1994 until June 1995, four anonymous
      questionnaires were distributed among 1135 randomly selected doctors, 294 medical
      students, 432 acupuncturists and a random sample of 653 in the general population
      in Norway. Fifty-seven percent indicated the treatment effect seen in acupuncture
      as mainly a genuine acupuncture effect, 30% indicated that half of the effect in
      acupuncture comes from placebo, while 13% indicated that the treatment effect in
      acupuncture is mainly based on placebo. Doctors and students express a more
      skeptical view than the others, and having tried acupuncture for one's own
      disease is significantly associated with a less skeptical view within all study
      groups. Attitudes to the use of acupuncture for cancer patients are associated
      with attitudes to placebo for doctors and medical students, but not for the
      general population or acupuncturists.

PMID- 12594971
TI  - The placebo response and effect of time in a trial of acupuncture to treat nausea
      and vomiting in early pregnancy.
AB  - OBJECTIVES: The sham control is widely used in acupuncture research, and its
      adequacy may be assessed by exploring the 'credibility' of the intervention. We
      aimed to examine the credibility of the study intervention, to quantify the size
      of the placebo response and effect of time in reducing nausea in early pregnancy.
      DESIGN: Five hundred and ninety-three women with nausea or vomiting in early
      pregnancy volunteered to participate in a randomised controlled trial, conducted
      at the Women's and Children's Hospital, South Australia. OUTCOME MEASURES: Women
      completed the Rhodes Index of Nausea and Vomiting and the Credibility Rating
      Scale. RESULTS: The credibility of the acupuncture and sham acupuncture
      interventions were not different. The relative change in nausea at the end of the
      first week of the study was estimated to be 28% attributed to a time effect and
      7% to the placebo response. At the end of the third week, there was a further
      small increase in time effect (32%) and the placebo response (17%). CONCLUSION:
      Sham acupuncture is a credible control and allows assessment of the size of the
      placebo response.

PMID- 12594972
TI  - Relief of chronic neck and shoulder pain by manual acupuncture to tender points-
      a sham-controlled randomized trial.
AB  - OBJECTIVES: To compare the effects of real acupuncture to tender points for neck
      and shoulder pain and stiffness (Japanese: katakori) with those of sham
      acupuncture. DESIGN: Randomized-controlled trial. METHODS: Thirty-four volunteers
      from an acupuncture school with complaints of chronic pain and stiffness, who had
      no arm symptoms and gave informed consent, were randomly allocated to acupuncture
      or sham groups. Acupuncture or sham acupuncture was applied to the tender points
      once a week for 3 weeks. In the acupuncture group the acupuncture needle was
      inserted to the muscle, then the sparrow pecking technique was applied five
      times. Sham acupuncture was done without insertion of the needle. Dull pain and
      stiffness were evaluated by visual analog scale (VAS) before, and every 2 days
      after the first needling for 1 month. Pressure pain threshold on the tender
      points was measured before and after each treatment. RESULTS: There was no
      statistical difference of VAS scores between acupuncture and sham groups 9 days
      after the last treatment. However, the acupuncture group showed significant
      reduction of VAS scores immediately after and/or 1 day after the real acupuncture
      treatments (P<0.01). The effect tended to be prolonged after repeated treatment.
      Pressure pain thresholds tended to increase after real acupuncture treatment but
      not after sham acupuncture. CONCLUSIONS: Acupuncture applied to tender points
      appears to have short-term effects on neck and shoulder pain and stiffness, but
      this study was unable to demonstrate any long-term superiority over sham
      acupuncture.

PMID- 12594973
TI  - The effects of lavender (Lavendula angustifolium) baths on psychological well
      being: two exploratory randomised control trials.
AB  - OBJECTIVE: Two important aspects of psychological well-being are positive mood
      state and a positive outlook with respect to the future. This study investigates
      the use of lavender baths to improve these aspects of psychological well-being.
      DESIGN: A single blind, randomised control trial. SETTING: The participants' home
      and interview rooms at the University of Wolverhampton. PARTICIPANTS: Eighty
      women not receiving treatment for psychological disorders who were staff or
      students at the University of Wolverhampton. Forty participated in Study 1 and 40
      in Study 2. INTERVENTION: Participants were randomly allocated to use either
      grapeseed oil or 80% grapeseed oil and 20% lavender oil in their bath for 14
      days. MAIN OUTCOME MEASURES: In Study 1, the UWIST mood adjective checklist. In
      Study 2, the MacLeod and Byrne Future Events procedure. RESULTS: In Study 1
      psychologically positive mood changes were found after the bathing regimen for
      energetic arousal, tense arousal, hedonic tone and anger-frustration. Only anger
      frustration showed a selective effect for lavender oil. In the second study
      negative responses about the future were selectively reduced after lavender oil
      baths. CONCLUSIONS: These results are encouraging and suggest further
      investigation using potential patients may result in the development of a useful
      procedure for improving psychological well-being.

PMID- 12594974
TI  - Phytic acid (IP6), novel broad spectrum anti-neoplastic agent: a systematic
      review.
AB  - INTRODUCTION: Phytic acid or IP6 has been extensively studied in animals and is
      being promoted as an anti-cancer agent in health food stores. It is naturally
      found in legumes, wheat bran, and soy foods. It is believed to be the active
      ingredient that gives these substances their cancer fighting abilities. Proposed
      mechanisms of action include gene alteration, enhanced immunity, and anti-oxidant
      properties. METHODS: A Medline search from 1966 to May 2002 using the keywords
      phytic acid and cancer, and limiting the search to the subheadings of therapeutic
      uses, prevention, and adverse effects revealed 28 studies. These studies were
      included in the review. RESULTS: A great majority of the studies were done in
      animals and showed that phytic acid had anti-neoplastic properties in breast,
      colon, liver, leukemia, prostate, sarcomas, and skin cancer. There were no human
      studies. Side effects included chelation of multivalent cations, and an increase
      in bladder and renal papillomas. This increase in papilloma formation only
      occurred with the sodium salt of phytic acid. It did not occur with either the
      potassium or magnesium salts. CONCLUSIONS: There is a large body of animal
      evidence to show that phytic acid may have a role in both the prevention and
      treatment of many forms of cancer. There is clearly enough evidence to justify
      the initiation of Phase I and Phase II clinical trials in humans.

PMID- 12594975
TI  - Complementary and alternative groups contemplate the need for effectiveness,
      safety and cost-effectiveness research.
AB  - OBJECTIVE: To examine the views of complementary and alternative medicine (CAM)
      groups on the need to demonstrate the effectiveness, safety and cost
      effectiveness of their therapies and practices. DESIGN: Qualitative interviews
      were conducted with 22 representatives of three CAM groups (chiropractic,
      homeopathy and Reiki). Qualitative content analysis was used to identify
      similarities and differences among and across groups. SETTING: Ontario, Canada.
      RESULTS: There were striking differences in the views of the three sets of
      respondents. The chiropractors agreed that it was essential for their group to
      provide scientific evidence that their interventions work, are safe and cost
      effective. The leaders of the homeopathic group were divided on these points and
      the Reiki respondents showed virtually no interest in undertaking such research.
      CONCLUSIONS: CAM groups that are more formally organized are most likely to
      recognize the importance of scientific research on their practices and therapies.

PMID- 12594979
TI  - The margin for error when releasing the high bar for dismounts.
AB  - In Men's Artistic Gymnastics the current trend in elite high bar dismounts is to
      perform two somersaults in an extended body shape with a number of twists. Two
      techniques have been identified in the backward giant circles leading up to
      release for these dismounts (J. Biomech. 32 (1999) 811). At the Sydney 2000
      Olympic Games 95% of gymnasts used the "scooped" backward giant circle technique
      rather than the "traditional" technique. It was speculated that the advantage
      gained from the scooped technique was an increased margin for error when
      releasing the high bar. A four segment planar simulation model of the gymnast and
      high bar was used to determine the margin for error when releasing the bar in
      performances at the Sydney 2000 Olympic Games. The eight high bar finalists and
      the three gymnasts who used the traditional backward giant circle technique were
      chosen for analysis. Model parameters were optimised to obtain a close match
      between simulated and actual performances in terms of rotation angle (1.2 degrees
      ), bar displacements (0.014 m) and release velocities (2%). Each matching
      simulation was used to determine the time window around the actual point of
      release for which the model had appropriate release parameters to complete the
      dismount successfully. The scooped backward giant circle technique resulted in a
      greater margin for error (release window 88-157 ms) when releasing the bar
      compared to the traditional technique (release window 73-84 ms).

PMID- 12594980
TI  - Generating dynamic simulations of movement using computed muscle control.
AB  - Computation of muscle excitation patterns that produce coordinated movements of
      muscle-actuated dynamic models is an important and challenging problem. Using
      dynamic optimization to compute excitation patterns comes at a large
      computational cost, which has limited the use of muscle-actuated simulations.
      This paper introduces a new algorithm, which we call computed muscle control,
      that uses static optimization along with feedforward and feedback controls to
      drive the kinematic trajectory of a musculoskeletal model toward a set of desired
      kinematics. We illustrate the algorithm by computing a set of muscle excitations
      that drive a 30-muscle, 3-degree-of-freedom model of pedaling to track measured
      pedaling kinematics and forces. Only 10 min of computer time were required to
      compute muscle excitations that reproduced the measured pedaling dynamics, which
      is over two orders of magnitude faster than conventional dynamic optimization
      techniques. Simulated kinematics were within 1 degrees of experimental values,
      simulated pedal forces were within one standard deviation of measured pedal
      forces for nearly all of the crank cycle, and computed muscle excitations were
      similar in timing to measured electromyographic patterns. The speed and accuracy
      of this new algorithm improves the feasibility of using detailed musculoskeletal
      models to simulate and analyze movement.

PMID- 12594981
TI  - A three-dimensional numerical simulation of mandible fracture reduction with
      screwed miniplates.
AB  - A three-dimensional finite element model of a fractured human mandible treated
      with plating technique was developed to simulate and to study the biomechanical
      loads and the stress field distribution. Biomechanical properties of bone have
      been thoroughly investigated experimentally. In this work, using the finite
      element method, complete clinical conditions (after surgical reduction, post
      operatory period, complete healing period) were simulated. The mandible fracture
      was located in the symphysis region and one or two titanium miniplates, fixed
      with monocortical screws, were evaluated. The behaviour of a reduced human
      mandible with screwed miniplates, as well as its complete healing, is
      investigated and described.

PMID- 12594982
TI  - Optical determination of anisotropic material properties of bovine articular
      cartilage in compression.
AB  - The precise nature of the material symmetry of articular cartilage in compression
      remains to be elucidated. The primary objective of this study was to determine
      the equilibrium compressive Young's moduli and Poisson's ratios of bovine
      cartilage along multiple directions (parallel and perpendicular to the split line
      direction, and normal to the articular surface) by loading small cubic specimens
      (0.9 x 0.9 x 0.8 mm, n =15) in unconfined compression, with the expectation that
      the material symmetry of cartilage could be determined more accurately with the
      help of a more complete set of material properties. The second objective was to
      investigate how the tension-compression nonlinearity of cartilage might alter the
      interpretation of material symmetry. Optimized digital image correlation was used
      to accurately determine the resultant strain fields within the specimens under
      loading. Experimental results demonstrated that neither the Young's moduli nor
      the Poisson's ratios exhibit the same values when measured along the three
      loading directions. The main findings of this study are that the framework of
      linear orthotropic elasticity (as well as higher symmetries of linear elasticity)
      is not suitable to describe the equilibrium response of articular cartilage nor
      characterize its material symmetry; a framework which accounts for the distinctly
      different responses of cartilage in tension and compression is more suitable for
      describing the equilibrium response of cartilage; within this framework,
      cartilage exhibits no lower than orthotropic symmetry.

PMID- 12594983
TI  - Model and influence of mitral valve opening during the left ventricular filling.
AB  - The flow inside a model left ventricle during filling (diastole) is simulated by
      the numerical solution of the equations of motion under the axisymmetric
      approximation. The left ventricle is taken with a truncated ellipsoid geometry,
      and a simple conceptual model is introduced to simulate the presence of the
      moving mitral valve. A relevant role during the left ventricle diastolic flow, as
      already discussed by other authors, is played by the travelling vortex wake that
      is formed from the transmitral jet during the early filling acceleration phase.
      The presence of a moving valve is found to produce a non-simultaneous spatial
      development of the entering bulk flow and a slightly more complex vortex wake
      structure; the results are discussed in comparison with fixed valve ones. They
      are analysed also in terms of M-mode representation suggesting a physical
      interpretation of the pattern detected in the clinical measurements that extends
      the one given previously on the basis of fixed valve models.

PMID- 12594984
TI  - Ligament fibre recruitment and forces for the anterior drawer test at the human
      ankle joint.
AB  - Although the anterior drawer test at the ankle joint is commonly used in routine
      clinical practice, very little is known about the sharing of load between the
      individual passive structures and the joint response at different flexion
      angles.A mathematical model of the ankle joint was devised to calculate ligament
      fibre recruitment and load/displacement curves at different flexion angles.
      Ligaments were modelled as three-dimensional arrays of fibres, and their
      orientations at different flexion angles were taken from a previously validated
      four-bar-linkage model in the sagittal plane. A non-linear stress/strain
      relationship was assumed for ligament fibres and relevant mechanical parameters
      were taken from two reports in the literature. Talus and calcaneus were assumed
      to move as a single rigid body. Antero/distal motion of the talus relative to the
      tibia was analysed. The ankle joint was found to be stiffer at the two extremes
      of the flexion range, and the highest laxity was found around the neutral
      position, confirming previous experimental works. With a first dataset, a 20N
      anterior force produced 4.3, 5.5, and 4.4mm displacement respectively at 20
      degrees plantarflexion, at neutral, and at 20 degrees dorsiflexion. At 10 degrees
      plantarflexion, for a 6mm displacement, 65% of the external force was supported
      by the anterior talofibular, 11% by the deep anterior tibiotalar and 5.5% by the
      tibionavicular ligament. Corresponding results from a second dataset were 1.4,
      2.4 and 1.8mm at 40N force, and 80%, 0% and 2% for a 3mm displacement. A
      component of the contact force supported the remainder.

PMID- 12594985
TI  - Timing of administration of transforming growth factor-beta and epidermal growth
      factor influences the effect on material properties of the in situ frozen-thawed
      anterior cruciate ligament.
AB  - One of the future goals in ligament reconstruction is to prevent graft
      deterioration after transplantation. The aim of this study is to clarify whether
      an administration of TGF-beta1 and EGF significantly affect biomechanical
      properties of the in situ frozen-thawed anterior cruciate ligament (ACL), an ACL
      autograft model, and to elucidate whether the timing of this administration may
      influence its effect. Rabbits were randomly divided into 4 groups after the
      freeze-thaw treatment with liquid nitrogen was applied to the right knee. In 2
      groups, 4-ng TGF-beta1 and 100-ng EGF mixed with 0.2-ml fibrin sealant were
      applied around the ACL at 3 and 6 weeks after the treatment, respectively. In the
      remaining two groups, only 0.2-ml fibrin sealant was applied around the ACL at 3
      and 6 weeks, respectively. In each group, all animals were sacrificed at 12 weeks
      after the freeze-thaw treatment. These growth factors applied at 3 weeks
      significantly inhibited not only the increase of water content and the cross
      sectional area of the ACL but also reduction of the tensile strength and the
      tangent modulus of the ACL (p<0.0001), which were induced by the freeze-thaw
      treatment. However, the application at 6 weeks did not significantly affect the
      changes of these parameters after the treatment. This study demonstrated that the
      timing of administration of TGF-beta and EGF after the freeze-thaw treatment
      significantly influences its effect on the biomechanical properties of the frozen
      thawed ACL.

PMID- 12594986
TI  - Modeling of time-dependent force response of fingertip to dynamic loading.
AB  - An extended exposure to repeated loading on fingertip has been associated to many
      vascular, sensorineural, and musculoskeletal disorders in the fingers, such as
      carpal tunnel syndrome, hand-arm vibration syndrome, and flexor tenosynovitis. A
      better understanding of the pathomechanics of these sensorineural and vascular
      diseases in fingers requires a formulation of a biomechanical model of the
      fingertips and analyses to predict the mechanical responses of the soft tissues
      to dynamic loading. In the present study, a model based on finite element
      techniques has been developed to simulate the mechanical responses of the
      fingertips to dynamic loading. The proposed model is two-dimensional and
      incorporates the essential anatomical structures of a finger: skin, subcutaneous
      tissue, bone, and nail. The skin tissue is assumed to be hyperelastic and
      viscoelastic. The subcutaneous tissue was considered to be a nonlinear, biphasic
      material composed of a hyperelastic solid and an invicid fluid, while its
      hydraulic permeability was considered to be deformation dependent. Two series of
      numerical tests were performed using the proposed finger tip model to: (a)
      simulate the responses of the fingertip to repeated loading, where the contact
      plate was assumed to be fixed, and the bone within the fingertip was subjected to
      a prescribed sinusoidal displacement in vertical direction; (b) simulate the
      force response of the fingertip in a single keystroke, where the keyboard was
      composed of a hard plastic keycap, a rigid support block, and a nonlinear spring.
      The time-dependent behavior of the fingertip under dynamic loading was derived.
      The model predictions of the time-histories of force response of the fingertip
      and the phenomenon of fingertip separation from the contacting plate during
      cyclic loading agree well with the reported experimental observations.

PMID- 12594987
TI  - Keep on your toes: gait initiation from toe-standing.
AB  - Gait initiation from toe-standing is common in patients with upper motor neurone
      (UMN) pathology as well as in able-bodied subjects during certain dance and
      athletic situations. It is unclear whether balance problems in patients who toe
      walk are due to the underlying pathology, or due to initiating gait from toe
      standing. The aim of this study was to compare the biomechanics of gait
      initiation from toe-standing to that from heel-toe standing in healthy able
      bodied subjects. Data were collected for three seconds prior to, and three
      seconds after, a visual signal to initiate gait. Ground reaction force and centre
      of pressure (COP) data were collected with an AMTI force platform, and
      electromyographic and kinematic data were collected from each limb with a Vicon
      motion analysis system. When initiating gait from toe-standing, there was a
      smaller backward displacement of the COP compared to heel-toe standing. In
      addition, greater forward momentum was generated, and there was an increase in
      gastrocnemius, rectus femoris and biceps femoris muscle activity. There were no
      differences in COP displacement or momentum generated in the mediolateral
      direction for the two conditions. Thus, initiating gait from toe-standing allows
      one to generate greater amounts of forward momentum but not at the expense of
      generating excessive stance-side momentum. This may be an advantageous method of
      initiating movement for dancers and athletes in certain situations. This work
      also suggests that balance problems in patients with UMN pathology are likely due
      to the underlying pathology and are not due to initiating gait from toe-standing.

PMID- 12594988
TI  - Muscles in microgravity: from fibres to human motion.
AB  - In simulated or actual microgravity, human and animal postural muscles undergo
      substantial atrophy: after about 270 days, the muscle mass attains a constant
      value of about 70% of the initial one. Most animal studies reported preferential
      atrophy of slow twitch fibres whose mechanical properties change towards the fast
      type. However, in humans, at the end of a 42-days bed rest study, a similar
      atrophy of slow and fast fibres was observed. After microgravity, the maximal
      force of several muscle groups showed a substantial decrease (6-25% of pre-flight
      values). The maximal power during very short "explosive" efforts of 0.25-0.30s
      showed an even greater fall, being reduced to 65% after 1 month and to 45% (of
      pre-flight values) after 6 months. The maximal power developed during 6-7s "all
      out" bouts on an isokinetic cycloergometer was reduced to a lesser extent,
      attaining about 75% of pre-flight values, regardless of the flight duration. In
      these same subjects, the muscle mass of the lower limbs declined by only 9-13%.
      Thus, a substantial fraction of the observed decreases of maximal power is
      probably due to a deterioration of the motor co-ordination brought about by the
      absence of gravity. To prevent this substantial decay of maximal absolute power,
      we propose that explosive exercise be added to the daily in-flight training
      schedule. We also describe a system aimed at reducing cardiovascular
      deconditioning wherein gravity is simulated by the centrifugal acceleration
      generated by the motion of two counter rotating bicycles ridden by the astronauts
      on the inner wall of a cylindrical space module. Finally, cycling on circular or
      elliptical tracks may be useful to reduce cardiovascular deconditioning in
      permanently manned lunar bases. Indeed, on the curved parts of the path, a
      cyclist generates an outward acceleration vector (ac). To counterbalance ac, the
      cyclist must lean inwards, so that the vectorial sum of ac plus the lunar gravity
      tends to the acceleration of gravity prevailing on Earth.

PMID- 12594989
TI  - Biomechanical simulations of forward fall arrests: effects of upper extremity
      arrest strategy, gender and aging-related declines in muscle strength.
AB  - Computer simulation was used to predict the extent to which age-related muscle
      atrophy may adversely affect the safe arrest of a forward fall onto the arms. The
      biomechanical factors affecting the separate risks for wrist fracture or head
      impact were examined using a two-dimensional, 5-link, forward dynamic model. The
      hypothesis was tested in older females that age-related loss in muscular strength
      renders the use of the arms ineffective in arresting a forward fall without
      either a torso impact exceeding 0.5m/s or distal forearm loads sufficient to
      fracture the wrist. The results demonstrate that typical age-related decline in
      arm muscle strength substantially reduces the ability to arrest a forward fall
      without the elbows buckling and, therefore, a risk of torso and/or head impact.
      The model predicted that older women with below-average bone strength risk a
      Colles fracture when arresting typical falls, particularly with an extended arm.

PMID- 12594990
TI  - Comparison of blood particle deposition models for non-parallel flow domains.
AB  - Adhesions of monocytes and platelets to a vascular surface, particularly in
      regions of flow stagnation, recirculation, and reattachment, are a significant
      initial event in a broad spectrum of particle-wall interactions that
      significantly influence the formation of stenotic lesions and mural thrombi. A
      number of approximations are available for the simulation of both monocyte and
      platelet interactions with the vascular surface. For the simulation of blood
      particle adhesion, this study hypothesizes that: (a) the discrete element
      approach, which accounts for finite particle size and inertia, is advantageous in
      the context of non-parallel flow domains including stagnation, recirculation, and
      reattachment; and (b) the likelihood for particle deposition may be effectively
      approximated as being non-linearly proportional to local particle concentration,
      residence time, and wall proximity. Models such as wall shear stress
      correlations, the multicomponent mixture approach, and Lagrangian particle
      tracking with and without hydrodynamic particle-wall interactions were evaluated.
      Quantitative performance of the selected models was established by comparisons to
      available experimental data sets for non-parallel axisymmetric suspension flows
      of monocytes and platelets. Factors including the convective-diffusive transport
      of particles, finite particle size and inertia, as well as near-wall hydrodynamic
      interactions were found to significantly influence blood particle deposition. Of
      the models studied, the near-wall residence time approach was found to be a
      particularly effective indicator for the deposition of monocytes (r2=0.74) and
      platelets (r2=0.57), given that nano-scale physical and biochemical effects must
      be greatly approximated in computational simulations involving relatively large
      scale geometries and complex flow fields.

PMID- 12594991
TI  - A femoral neck fracture model in rabbits.
AB  - A technique was developed to create a reproducible femoral neck fracture in vitro
      using 5-month-old JW/CSK series male rabbits. Force attenuation of a newly
      developed damping material was also evaluated using this model. Ten pairs of the
      femora with smaller deviations in length and weight were harvested and cleaned of
      soft tissue. Either a right or left of each pair of the specimens was randomly
      selected and put into either the control or the experimental group, both of which
      contained equal numbers of the right and left femora. The specimens were attached
      to an L-shaped plate and embedded in a resin from the proximal diaphysis to the
      distal end so as to maintain a consistent position of the femora. They were
      mounted and fixed on a pedestal slanted in the coronal plane at 20 degrees. The
      impact load testing was conducted using an impact mallet dropped from a height of
      3 cm. The impact load was applied onto the femoral head. To the specimens in the
      experimental group, attenuated impact forces were loaded through the damping
      material, but those in the control group were subjected to forces directly
      transmitted without the material. All the impact testing was performed in a
      temperature and humidity controlled chamber. All of the femoral specimens exposed
      to the direct impact forces (controlled group) sustained fracture at the neck.
      The fracture line passed from the base of the femoral head laterally and to the
      calcar area just proximal to the minor trochanter medially. The location of each
      fracture line was almost identical among the specimens. None of the specimens
      that were exposed to the impact force through the damping material (experimental
      group) sustained fracture macroscopically and roentgenographically.

PMID- 12594992
TI  - Dynamic measurement of internal solid displacement in articular cartilage using
      ultrasound backscatter.
AB  - Mechanics of articular cartilage can be represented using poroelastic theories
      where fluid and solid displacements are viscously coupled to create a time
      dependent spatially heterogeneous behavior. In recent models of this tissue,
      finite element methods have been used to predict tissue deformation as a function
      of time for adult articular cartilage bearing a characteristic depth-dependent
      structure and composition. However, current experimental methods are limited in
      providing verification of these predictions. The current study presents an
      apparatus for imaging the radial displacement profile of cartilage in unconfined
      compression using an ultrasound technique called elastography. We acquired
      ultrasound A-scans across the lateral diameter of full-thickness cartilage disks
      containing a thin layer of underlying bone, during axial compression.
      Elastography was then applied to correlate temporally sequential A-scans to
      estimate the solid radial displacement profile in articular cartilage while it
      undergoes compression and stress-relaxation. Both time-dependent and depth
      dependent solid radial displacement profiles were obtained with a precision
      better than 0.2 micro The results generally agree with predictions of poroelastic
      models, demonstrating lateral expansion with an effective Poisson's ratio just
      after completion of the compression phase of the mechanical tests reaching values
      from 0.18 to 0.4 (depending on compression speed), followed by contraction to
      lower values. A more restricted movement was observed at both the articular
      surface and near to the subchondral bone than at regions midway between these two
      locations.

PMID- 12594993
TI  - Fiberoptic measurement of tendon forces is influenced by skin movement artifact.
AB  - Fiberoptic cables have previously been used for tendon force measurements in
      vivo. To measure forces in the Achilles tendon, a cable is passed mediolaterally
      through the skin and tendon, transverse to the loading axis. As the tendon is
      loaded, its fibers compress the cable and modulate the intensity of transmitted
      light, which can be related to tendon force by an in situ calibration. The
      relative movement between skin and tendon at the cable entry and exit sites may
      cause error by bending the cable and thus altering transducer output. Cadaver
      simulations of walking were conducted to compare fiberoptic measurements of
      Achilles tendon forces to known loads applied to the tendon by actuators attached
      in series. Force measurement errors, which were high when the skin was intact
      (RMS errors 24-81% peak forces), decreased considerably after skin removal (RMS
      errors 10-33% peak forces). The fiberoptic transducer is a useful tool for
      measurement of tendon forces in situ under natural loading conditions when skin
      can be removed, but caution should be exercised during in vivo use of this
      technique or under circumstances where skin is in contact with the fiberoptic
      cable at the insertion and exit sites.

PMID- 12594995
TI  - Analysis of L-cone/M-cone visual pigment gene arrays in females by long-range
      PCR.
AB  - The L-cone/M-cone visual pigment gene arrays were analyzed in a group of 63
      Japanese females consisting of 7 applicants for examination of their carrier
      status, 14 color-deficient females, 6 obligate carriers with no genotypic data
      available for affected father or sons, and 36 color-normals. The first and the
      downstream genes, the entire region from the promoter to exon 6, were each
      amplified very efficiently by the long-range PCR to give products of 15.8 and
      14.4 kb, respectively. The products were gel-purified and used as the template in
      the second PCR for exon 5. The region from intron 4 of the last genes, to the
      nearest neighbor gene, TEX28, was also efficiently amplified by the long-range
      PCR and the gel-purified products (27.5 kb) were used as the template in the
      second PCR for exon 5. The status of the 7 applicants was thought to be 3 non
      carriers, 2 protan carriers and 2 deutan carriers. All of the 14 color-deficient
      females had unusual arrays in which an M gene was present as the first gene, an L
      gene(s) was present downstream, or a single L gene constituted both of the two
      arrays. One protanopic subject, A348, had an L gene as one of the first genes.
      The 6 obligate carriers also had unusual arrays with the exception of the mother
      of the A187, a male subject with pigment color defect. In the 36 color-normal
      individuals, 4 had downstream L genes. The long-range PCR method is useful for
      analysis of the L/M visual pigment genes.

PMID- 12594994
TI  - Kinematic modeling of single muscle fiber during diaphragm shortening.
AB  - Understanding the kinematics of the diaphragm muscle at the single fiber level is
      important in understanding the mechanics of its membrane. Nevertheless, the
      geometric parameters of single muscle fiber contraction remain poorly understood.
      We modeled the kinematics of a single muscle fiber of the diaphragm to determine
      the relationships among fiber shape, perimeter of the fiber cross-section, and
      apparent surface area of the fiber during muscle shortening. We used the models
      to identify which constraints on the geometric parameters are most consistent
      with physiological data on diaphragmatic muscle shortening. Our kinematic models
      use isovolumic fibers with elliptical cross-sections, and these models have the
      following properties: (1) constant cross-sectional shape, (2) inextensible cross
      sectional perimeter, (3) constant cross-sectional transverse dimension, or (4)
      constant apparent surface area. These models were investigated during muscle
      shortening of the diaphragm from functional residual capacity to total lung
      capacity. The model that matches physiologic data best has zero transverse strain
      and has a relationship between fiber shape and muscle shortening consistent with
      published data on single muscle fiber mechanics.

PMID- 12594996
TI  - Alterations of kynurenic acid content in the retina in response to retinal
      ganglion cell damage.
AB  - The present study is the first to examine the modulation of retinal kynurenic
      acid (KYNA) content in response to N-methyl-D-aspartate (NMDA)-induced cell death
      in adult rat retinal ganglion cells (RGC). Adult Brown Norway rats were
      intravitreally injected with NMDA or PBS. Surviving RGC were retrogradely labeled
      with fluorogold and counted in wholemounts of retinas 2, 7 and 14 days after
      injection. Retinal KYNA content was measured by HPLC at the same time points. RGC
      numbers decreased significantly 2, 7 and 14 days after NMDA injection if compared
      to control retinas. KYNA concentration increased significantly two days after
      NMDA-injection. However, 7 and 14 days after injection retinal KYNA content was
      found markedly decreased in NMDA-treated eyes as compared to controls. It is
      conceivable that KYNA deficiency is causally related to the pathology of
      excitotoxic retinal diseases.

PMID- 12594997
TI  - Temporal integration for stereoscopic vision.
AB  - With normal binocular vision, maximal stereoacuity requires an extended viewing
      duration, but the relationship between the critical viewing duration for
      stereopsis and other variables affecting stereoacuity is unknown. The purposes of
      the study were to investigate the properties of normal temporal integration for
      stereoscopic vision with respect to the effects of contrast and spatial frequency
      of the stimuli and to determine whether the temporal summation of disparity is
      affected in deficient stereopsis caused by abnormal binocular vision during
      infancy. Psychophysical methods were used to measure stereothresholds in human
      and monkey subjects with either normal binocular vision or abnormal binocular
      vision. The results showed that the critical viewing duration for stereoscopic
      depth discrimination was independent of variations in basic stimulus parameters
      and/or the subject's stereoacuity. A critical duration of approximately 100 ms
      was found for both local (narrowband Gabor and broadband line targets) and global
      (dynamic random dots) stimuli. Although stereothresholds increased with
      decreasing stimulus contrast, the properties of temporal integration did not.
      Stereothresholds were substantially elevated for monkeys and humans with abnormal
      binocular vision, but the critical durations for these subjects were not
      significantly different from those of subjects with normal binocular vision.
      Overall, the results demonstrate that the general properties of temporal
      integration for stereopsis are similar to other detection and discrimination
      tasks that do not require binocular processing. In addition, increased
      integration time does not account for the elevated stereothresholds of subjects
      with abnormal binocular vision.

PMID- 12594998
TI  - Local and global contributions to shape discrimination.
AB  - Humans are remarkably sensitive in detecting small deviations from circularity.
      In tasks involving discrimination between closed contours, either circular in
      shape or defined by sinusoidal modulations of the circle radius, human
      performance has been shown to be limited by global processing. We assessed the
      amount of global pooling for different pattern shapes (different radial
      modulation frequencies, RF) when circular deformation was restricted to a
      fraction of the contour. The results show that the improvement in performance
      depends on the modulation frequency (the pattern shape) when increasing the
      number of cycles of an RF pattern. Global processing only extends up to
      modulation frequencies between 5 and 10. For higher frequencies, performance can
      be predicted by probability summation. Position uncertainty cannot explain these
      effects. In a circumstance where global pooling exceeds probability summation
      (RF=5), we split the pattern up into five identical segments conserving the total
      amount of information presented. Thresholds are significantly affected by
      different global arrangements of these segments: (a) Occluding small parts of the
      pattern shows a significant effect on the position of occluders with performance
      lowest when gaps are placed at the points of maximum curvature. (b) Shifting
      segments away from the pattern centre (exploded condition) or displaying them out
      of concentric context (spiral condition) shuts down global processing. (c)
      Jittering segments radially disrupts both global and local processing. We
      conclude that RF patterns in the global processing range are analysed by
      detecting the points of maximum curvature and that, in this range, the visual
      system can only reliably process up to about 5 local curvature extrema.

PMID- 12594999
TI  - The dynamics of bi-stable alternation in ambiguous motion displays: a fresh look
      at plaids.
AB  - Prolonged observations of moving plaids lead to bi-stable alternations between
      coherency and transparency. However, most studies of plaids used brief
      presentations and a 2AFC between the two interpretations, thus overlooking the
      dynamical aspect of plaid perception. In other domains, most notably binocular
      rivalry, it was shown that the dynamics of the bi-stable alternations reveal
      important insights about the underlying mechanisms. Here we develop methods to
      study the dynamics of plaid perception. Observers continually indicated their
      percept (coherency or transparency) during presentations that lasted 1-5 min. Two
      measures of the relative strength of the coherency percept were derived from
      those data: C/[C+T], the relative time spent seeing coherency, and RTtransp, the
      response time to report transparency. Those measures are independent of each
      other yet tightly correlated, and both show systematic relations to manipulations
      of plaid parameters. Furthermore, the two measures are sensitive to manipulations
      in wide parametric regimes, including ranges where brief-presentation methods
      suffer from "ceiling" and "floor" effects. We conclude that studying the dynamics
      of bi-stability in plaids can provide new and unsuspected findings about motion
      integration and segmentation.

PMID- 12595000
TI  - Attentional selection of overlapped shapes: a study using brief shape
      aftereffects.
AB  - Prior studies using brief stimulus sequences revealed "opponent shape
      aftereffects", indicative of direct opponent coding of global shape attributes
      such as aspect ratio, skew, taper, curvature, and convexity (perhaps in IT).
      Further, aftereffects from overlapped opponent pairs of adaptor shapes (e.g.,
      concave and convex shapes) were substantially modulated by attention [Vision Res.
      41 (2001) 3883]. Hypothetically, (1) attention might weight the attended and
      ignored contours at early stages of processing, or (2) it might sway opposing
      neural activity (e.g., of convex- vs. concave-tuned units) at the stage of
      opponent shape coding. Attentional modulation was equivalent for opponent pairs
      (producing opposite aftereffects) and non-opponent pairs (producing orthogonal
      aftereffects) of overlapped adaptor shapes, whether convexity or aspect-ratio
      aftereffects were measured. Further, the degree of attentional modulation
      obtained for these aftereffects (approximately 60%) was comparable to that
      obtained for V4 cells [J. Neurosci. 19 (1999) 1736]. Taken together, differential
      contour weighting appears to be the primary mechanism of attentional modulation
      of brief shape aftereffects.

PMID- 12595001
TI  - Further evidence for global orientation processing in circular Glass patterns.

PMID- 12595003
TI  - Comparison of the time courses of concomitant and nonconcomitant vertical phoria
      adaptation.
AB  - Vertical phoria adaptation was measured before, during, and after 1 h of training
      with either a prism or magnifying lens. With the prism (concomitant adaptation) a
      single vertical disparity was presented at primary position. With the magnifier
      (nonconcomitant adaptation) two vertical disparities of opposite sign were
      presented along the vertical meridian. Following adaptation, binocular vision was
      prevented with an eye patch, and vertical phorias were measured periodically
      along the primary vertical meridian over the course of 8 h. Despite individual
      variation, adaptation followed approximately exponential time courses. The
      average time constants for the decay of concomitant and nonconcomitant adaptation
      were 31 and 83 min, respectively. There was no consistent relationship between
      the rates of acquisition and decay nor was there a strong relationship between
      the gains of the adaptive responses and the rates of decay although there was a
      general trend for the gains of the nonconcomitant responses to be higher and the
      rate of decay slower than the concomitant responses. The results support the
      notion that concomitant and nonconcomitant phoria adaptation involve different
      mechanisms but not the contention that adaptation to prisms is easier or more
      robust than adaptation to lenses.

PMID- 12595004
TI  - A neural network model of spiral-planar motion tuning in MSTd.
AB  - Neurophysiological studies in MSTd report the existence of motion pattern
      selective cells whose visual motion properties span a continuum of values,
      suggesting a role in estimates of self-motion from optic flow. Biologically
      motivated models of heading estimation support this view, having identified
      similar visual motion properties within their "neural" structures. While such
      models have addressed the computational sufficiency of their respective feed
      forward designs they have not explicitly examined the underlying computational
      structures, particularly as they relate to the interaction between planar and
      spiral motion responses within MSTd. Here we use an expanded stimulus training
      set that includes planar motions to extend the range of neurophysiological
      properties identified within an existing network structure [Network: Comput.
      Neural Syst. 9 (1998) 467]. In doing so, we quantify the emergent planar motion
      properties within the network hidden layer and examine how they interact,
      functionally and computationally, with cardinal/spiral motion pattern responses.
      Throughout the hidden layer we demonstrate that the input activation associated
      with a unit's preferred planar motion is consistent with an overlapping gradient
      hypothesis [J. Neurophysiol. 65(6) (1991) 1346]. Together with the change to a
      peripheral excitation profile in the presence of a unit's preferred spiral motion
      these results suggest a more complex computational architecture in which the
      cell's 'classical' receptive field properties are dependent on the type of
      stimulus used to map them. Based on the computational model we propose an
      experimental paradigm to investigate the existence of equivalent computational
      structures in MSTd.

PMID- 12595005
TI  - The detection of direction-defined and speed-defined spatial contours: one
      mechanism or two?
AB  - It is now accepted that the visual system integrates local orientation
      information across space to define spatial contours [Vision Research 33 (1993)
      173]. More recently, it has been shown that similar integration occurs for the
      direction of local motion signals, in different parts of the visual field, if
      they are aligned along the axis of a spatial contour [Vision Research 42 (2002)
      653]. Here we ask whether similar spatial-linking rules hold for contours
      comprised of local elements that share only a common speed (but not direction),
      in the presence of background elements which collectively have the same mean
      speed as the contour but considerable random variation in the speeds of the
      individual elements. Furthermore we investigate the detection of spatial contours
      that are defined by a common speed that is different (both locally and globally)
      from that of the background elements. The results show that there is a
      significant, albeit relatively weak, speed-association field with preferential
      linking between spatially proximal elements that have similar speeds. Although a
      salient speed difference between the contour and the background elements enhances
      detection performance for motion-defined contours, it does so primarily via a
      different route to that of direction linking. We suggest that for motion-defined
      contours the Gestalt notions of "common fate" and "good continuity", that
      describe the parsing of local velocity information into objects, boundaries and
      contours, are mediated via separate underlying perceptual mechanisms.

PMID- 12595006
TI  - Inhibition of nitrobenzene-induced DNA and hemoglobin adductions by dietary
      constituents.
AB  - Nitrobenzene (NB), a widely used industrial chemical, is a likely human
      carcinogen. Many dietary constituents can suppress the DNA-adduction, acting as
      the inhibitors of cancer. In this study, we investigated the inhibitory effects
      of vitamin C (VC), vitamin E (VE), tea polyphenols (TP), garlic squeeze,
      curcumin, and grapestone extract on NB-DNA and NB-hemoglobin (Hb) adductions in
      mice using an ultrasensitive method of accelerator mass spectrometry (AMS) with
      14C-labelled nitrobenzene. All of these dietary constituents showed their
      inhibitory effects on DNA or Hb adduction. VC, VE, TP and grapestone extract
      could efficaciously inhibit the adductions by 33-50%, and all of these six agents
      could inhibit Hb adduction by 30-64%. We also investigated resveratrol, curcumin,
      VC and VE as inhibitors of NB-DNA adduction in vitro using liquid scintillation
      counting technique. These agents in the presence of NADPH and S9 components also
      pronouncedly blocked DNA adduction in a dose-dependent profile. Our study
      suggests that these seven constituents may interrupt the process of NB-induced
      chemical carcinogenesis.

PMID- 12595007
TI  - Transfer of orally administrated iodine-131 into chicken eggs.
AB  - Radioactive iodine-131 as both as free iodide (Na131I) and covalently bound to
      aniline (aniline-131I) was added to the drinking water of two Leghorn laying hens
      as a single dose and also as a cumulative dose over 1 week. The radioactivity of
      the principal parts of the eggs, i.e. shell, white, and yolk, was measured, and
      the radioactivity levels per gram material, and percent of the total
      radioactivity were calculated. The radioactivity measurements were continued for
      1 month following the administration of 131I. In the case of the single dose
      administration, the results obtained showed that about 15% of the total
      radioactivity administered as Na131I was transported into the egg structure;
      compared to only about 1% for aniline-131I. After cumulative administration,
      about 15% of the total administered radioactivity was transported into the egg
      structure with both forms of 131I. This was probably because of metabolic
      cleavage of iodine bonds in the labeled aniline molecules during the longer
      period of exposure. These results also showed considerable accumulation of 131I
      in the egg yolks. In the case of the single dose administration, 131I can be
      detected in eggs up to about 20 days after administration, and up to about 30
      days, in the case of the cumulative administration over 1 week.

PMID- 12595010
TI  - Lithium target performance evaluation for low-energy accelerator-based in vivo
      measurements using gamma spectroscopy.
AB  - The operating conditions at McMaster KN Van de Graaf accelerator have been
      optimized to produce neutrons via the (7)Li(p, n)(7)Be reaction for in vivo
      neutron activation analysis. In a number of earlier studies (development of an
      accelerator based system for in vivo neutron activation analysis measurements of
      manganese in humans, Ph.D. Thesis, McMaster University, Hamilton, ON, Canada;
      Appl. Radiat. Isot. 53 (2000) 657; in vivo measurement of some trace elements in
      human Bone, Ph.D. Thesis. McMaster University, Hamilton, ON, Canada), a
      significant discrepancy between the experimental and the calculated neutron doses
      has been pointed out. The hypotheses formulated in the above references to
      explain the deviation of the experimental results from analytical calculations,
      have been tested experimentally. The performance of the lithium target for
      neutron production has been evaluated by measuring the (7)Be activity produced as
      a result of (p, n) interaction with (7)Li. In contradiction to the formulated
      hypotheses, lithium target performance was found to be mainly affected by
      inefficient target cooling and the presence of oxides layer on target surface. An
      appropriate choice of these parameters resulted in neutron yields same as
      predicated by analytical calculations.

PMID- 12595011
TI  - Study of air pollutants in Hong Kong using energy dispersive X-ray fluorescence.
AB  - Airborne particulate samples were collected from various reference sites in Hong
      Kong and the energy dispersive X-ray fluorescence (EDXRF) intensities for 19
      chemical elements were recorded. Principal component analysis (PCA) was employed
      so that the variances of these 19 original variables were captured by a few new
      indices called principal components or PCs. Data points for similar sources were
      automatically grouped together in a plot of the first three PCs (PC plot). Data
      for the monitoring site Mong Kok were located within the area defined by
      vehicular emissions. As such, the main air pollutant at this site was concluded
      to originate from vehicular emissions. A fraction of data for the Causeway Bay
      monitoring site also fell into this same identified area, so the main air
      pollutant could also be vehicular emissions. Some of the data located either on
      or outside the border can be explained in terms of meteorology.

PMID- 12595012
TI  - Determination of multi-element profiles of street dust using energy dispersive X
      ray fluorescence (EDXRF).
AB  - Street dust samples have been collected in different areas in Hong Kong
      associated with various levels of traffic and pedestrian flow, and the
      concentrations of 23 chemical elements have been determined using energy
      dispersive X-ray fluorescence (EDXRF). The 23 studied elements were Na, Al, Si,
      Cl, Ti, Ba, V, Cr, Mn, Fe, Co, K, Ca, Ni, Cu, Zn, As, Pb, Rb, Sr, Y, Zr and Sn. A
      profile for average street dust for Hong Kong has been determined by taking
      average values for different areas. The values for the Hong Kong street dust are
      commensurate with the values derived in previous investigations or for other
      countries, except that Hong Kong street dust has much higher Cl, Ca and As
      concentrations. A factor analysis gives four sources for the street dust in Hong
      Kong: namely, mixture of metallic dust and crustal material, vehicles, road
      pavement materials, and mixture of marine aerosols and crustal material.

PMID- 12595015
TI  - Direct labelling of octreotide with 99mTc: effect of different concentration of
      reducing agents and amount of sodium pertechnetate on radiolabelling efficiency.
AB  - Octreotide, a synthetic analog of natural hormone somatostatin, was labelled with
      99mTc. Labelling was accomplished by reduction of the cysteine bridge, which
      provided sulfhydryl groups for chelating with 99mTc. Sodium ascorbate and sodium
      dithionite in different concentrations were used as reducing agents. Different
      amounts of sodium pertechnetate were used for labelling of peptide. When the mass
      ratio of peptide and sodium ascorbate was 1:100 and the final concentration of
      dithionite in the labelling vial was 0.2-0.4 microg/microl with 0.18-1.48 GBq
      sodium pertechnetate more than 80% radiolabelling efficiency was confirmed by RP
      HPLC, ITLC-SG and C18 Cartridge analysis. The stability of the 99mTc-peptide bond
      was evaluated by human serum challenge and that showed the stability was 90%
      after 4h.

PMID- 12595032
TI  - Mucoadhesive microspheres containing gentamicin sulfate for nasal administration:
      preparation and in vitro characterization.
AB  - In this study, suitable microsphere formulations were designed in order to
      provide the absorption of a high polar drug through nasal mucosa. For this
      purpose, gentamicin sulfate (GS) was chosen as a model drug and used at different
      drug/polymer ratios in the microsphere formulations. The microspheres were
      prepared by spray drying technique. Hydroxypropyl methylcellulose was used as a
      mucoadhesive polymer in the formulations to increase the residence time of the
      microspheres on the mucosa. Sodium cholate was added into the formulations for
      increasing the absorption of GS through nasal mucosa. The in vitro
      characteristics of the microspheres were determined. The microspheres were
      evaluated with respect to the particle size, production yield, encapsulation
      efficiency, shape and surface properties, drug-polymer interaction, mucoadhesive
      property, in vitro drug release and suitability for nasal drug delivery.

PMID- 12595031
TI  - Neuropharmacological study of hetero[2,1]benzothiazepine derivatives analogues of
      tianeptine.
AB  - Neuropharmacological studies were conducted in mice with a number of
      hetero[2,1]benzothiazepine derivatives, analogues of tianeptine. Seven of the 12
      compounds under study potentiated the actions of 5-hydroxytryptophan (5-HTP, 50
      mg/kg i.p.) and/or antagonised the hypothermia induced by high doses of
      apomorphine. Moreover, some of them inhibited the head twitches induced by 5-HTP
      (250 mg/kg i.p.) and the stereotyped behaviour and/or climbing behaviour of low
      doses of apomorphine. These compounds also produced a slight inhibition of
      exploratory behaviour in the holeboard test. On the other hand, no significant
      muscle relaxant, anticonvulsant and anxiolytic activities were observed at any
      dose employed. Together, these data suggest that some of the compounds under
      study exert antidepressant and neuroleptic effects in mice with no muscle
      relaxant, anxiolytic and anticonvulsant activities.

PMID- 12595033
TI  - Synthesis and in vitro calcium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7
      trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives.
AB  - In this study, a series of 4-aryl-7,7-dimethyl and 1,7,7-trimethyl
      1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones (1-25) were synthesized by
      condensing urea or N-methylurea with 5,5-dimethyl-1,3-cyclohexanedione and
      appropriate aromatic aldehydes according to the Biginelli reaction. The
      structures of the compounds were confirmed by spectral data and elementary
      analysis. The calcium antagonist activity of the compounds was tested in vitro on
      isolated rat ileum and lamb carotid artery. Compounds 16 and 19 were the most
      active derivatives on isolated rat ileum compared with the standard nicardipine.
      On isolated aortic strips of lamb the calcium antagonist activity of compound 16
      (maximum relaxant effect: 38.83+/-5.84%) was found as high as that of nicardipine
      (maximum relaxant effect: 35.50+/-4.16%) used as a reference drug.

PMID- 12595034
TI  - Synthesis and pharmacological properties of N,N-dialkyl(dialkenyl)amides of 7
      methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4
      tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid.
AB  - Synthesis of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4
      tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5-9) and their 1-[2-hydroxy
      3-(4-phenyl-1-piperazinyl)propyl] derivatives (10-14) is described. Compounds 10
      14 were tested for analgesic and sedative activities as well as for mu-opioid
      receptors binding affinities. All the amides, being the object of investigation,
      displayed an interesting analgesic action, which in case of the compounds 10-12
      and 14 was superior to that of acetylsalicylic acid in two different tests.
      Furthermore all the amides (10-14) significantly suppressed the spontaneous
      locomotor activity, prolonged barbiturate sleep in mice and showed a weak
      affinity to mu-opioid receptors.

PMID- 12595035
TI  - Antiinflammatory and antinociceptive activities of some benzotriazolylalkanoic
      acids.
AB  - Sets of benzotriazol-1/2-ylalkanoic acids (1, 2, 3) and benzotriazol-1
      yloxyalkanoic acids (4, 5) were prepared and tested for antiinflammatory
      activity; when significant activity was observed also the antinociceptive
      activity was explored. While the acids of structure 1, 4 and 5 were devoid of
      antiinflammatory action, most 2-(benzotriazol-1/2-yl)propionic acids (2, 3)
      exhibited significant activity as antiinflammatory and antinociceptive agents,
      with compound 2c and 3a being the most active in the two assays, respectively.
      The dextrorotatory enantiomer of 2c ((+)-2c) was also prepared and found to be
      practically as active as the racemic mixture, though some differences in the
      steepness of the dose-response curves were observed.

PMID- 12595036
TI  - PEGylation of the antimicrobial peptide nisin A: problems and perspectives.
AB  - Nisin is a natural antimicrobial peptide produced by Lactococcus lactis and
      widely employed as food preservative. Its low solubility in neutral aqueous
      solutions, its instability at physiological pH and its rapid breakdown by
      proteolytic enzymes has limited its use for processed foods (processed cheese,
      milk and derivatives, canned vegetables). The conjugation to poly(ethylene
      glycol) (PEG) could improve its solubility and protect it towards enzymes present
      in non optimally processed food. We report the synthesis of a PEG-nisin
      conjugate, and the microbiology assays against some bacterial cell lines.

PMID- 12595037
TI  - Quinoxaline chemistry. Part 15. 4-[2-Quinoxalylmethylenimino]-benzoylglutamates
      and -benzoates, 4-[2-quinoxalylmethyl-N-methylamino]-benzoylglutamates as
      analogues of classical antifolate agents. Synthesis, elucidation of structures
      and in vitro evaluation of antifolate and anticancer activities.
AB  - We report on an extension of our previous discovery of in vitro anticancer
      activity of trifluoromethylquinoxalines as analogues of classical and non
      classical antifolic methotrexate and trimetrexate. In this case a small number of
      Schiff bases were obtained from the reaction of 2-bromethyl-3-R
      6(7)trifluoromethylquinoxaline and ethyl p-aminobenzoylglutamate, ethyl p
      aminobenzoate, p-toluidine instead of the expected 4-[2-quinoxalyl]methyl-N
      methylanilino derivatives, which in turn formed with N-methylanilino derivatives.
      The reaction mechanism has been put forward. Structure elucidation of both Schiff
      bases and N-methylanilino analogues was achieved by a combination of 1H and 13C
      NMR spectra and hetcor experiments. Compounds 3a, 3b, 3c, 8, 11, 12, 13, Ie were
      tested in antifolic enzyme assay [Lactobacillus casei (LcTS), Leishmania major
      (LmTs), human Thymidylate synthase (hTs), human TS, human dihydrofolate reductase
      (hDHFR)] while compounds 3a, 3b, 3c were tested for anticancer activity. These
      results seem to indicate that the Schiff bases are somewhat active either as
      anticancer or as folate inhibitors, while compound Ie was selectively active
      against hDHFR with an inhibition constant (Ki) of 200 nM with a specificity of
      about 1000-folds with respect to hTS.

PMID- 12595038
TI  - Synthesis and in vitro antifungal and cytotoxicity evaluation of substituted 4,5
      dihydronaphtho[1,2-d][1,2,3]thia(or selena)diazoles.
AB  - Unsubstituted 4,5-dihydronaphtho[1,2-d][1,2,3]thia (or selena)diazoles (2a, 2b),
      prepared from the semicarbazone (1a), were nitrated using fuming nitric acid at 0
      degrees C to yield various mono-nitrated dihydronaphthalenes (3a-3e). Related
      sulfamoyl derivatives (4a, 4b) were prepared using chlorosulfonic acid, followed
      by the addition of ammonia solution. Synthesis of 6,9-dimethoxy-4,5
      dihydronaphtho[1,2-d][1,2,3]thiadiazole derivative (2c) was performed using 5,8
      dimethoxy-alpha-tetralone semicarbazone (1b) and thionylchloride at low
      temperature. At 10 ppm concentration, all compounds showed low toxicity (higher
      than 80% survival) on brine shrimps, while at 100 ppm concentration compounds 2d,
      3d, and 4b exhibited toxicity (less than 60% survival). Compounds 3a, 3e, and
      especially 4a showed significant antifungal activity against Cryptococcus
      neoformans. Compound 4a, while being the most active antifungal agent in this
      series, possessed low toxicity.

PMID- 12595039
TI  - The mass spectrometric behaviour of fluorinated ephedrines under different
      protonating conditions.
AB  - The behaviour of di- and tri-fluorinated-ephedrines and -norephedrines has been
      studied by fast atom bombardment, atmospheric pressure chemical ionisation (APCI)
      and electrospray ionisation (ESI) experiments and compared with that of the
      unfluorinated analogues. Under all the employed ionisation conditions [MH](+) and
      [MH-H(2)O](+) species are mainly produced. Both high- and low-energy collisional
      experiments were performed on the protonated molecules to put in evidence any
      possible significant differences due to different ionisation methods. Multiple
      MS/MS experiments, performed by ion trap, allowed establishment of the
      decomposition pathways at lower activation energy. The data thus obtained
      indicate that the presence of fluorinated substituents leads to a higher
      stability of the molecular species, with strengthening of the C(1)-C(2) bond of
      the molecule and with a lower proclivity to thermally-induced dehydration.

PMID- 12595040
TI  - Synthesis and hypoglycemic activity of some substituted flavonyl
      thiazolidinedione derivatives--fifth communication: flavonyl benzyl substituted
      2,4-thiazolidinediones.
AB  - A new series of 3-benzyl(p-substituted benzyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)
      benzylidene]-2,4-thiazolidinediones (8a-e) were synthesized. These products were
      prepared by Knoevenagel reaction from 3'-flavone carboxaldehyde and 3-substituted
      2,4-thiazolidinediones. In vitro insulinotropic activity was determined for
      compounds 6a-e, 7a-e, 8b and 8c.

PMID- 12595041
TI  - Conformationally restrained ceramide analogues: effects of lipophilic
      modifications on the antiproliferative activity.
AB  - Conformationally restrained analogues of ceramide containing thiouracil or uracil
      moieties in their polar head, substituted with an ethyl group in their 6
      positions, proved to inhibit cell proliferation and induce apoptosis. A series of
      new thiouracil and uracil analogues of ceramide possessing several 6-alkyl- or 6
      arylalkyl-substituents, were synthesized and tested as inhibitors of cell
      proliferation. The lipophilic substituents introduced in the 6-position were pure
      alkyls (n-propyl, n-butyl, i-butyl, neo-pentyl), or aryl-alkyls (2-phenylethyl).
      Although a significant antiproliferative activity was maintained in most
      compounds synthesized, none of them showed any improvement with respect to their
      6-ethyl-substituted counterparts.

PMID- 12595042
TI  - 2002 Radvin lecture in basic science. Artificial organs: basic science meets
      critical care.

PMID- 12595043
TI  - Impact of a cancer screening program on breast cancer stage at diagnosis in a
      medically underserved urban community.
AB  - BACKGROUND: Our previous report showed that the disparity in breast carcinoma
      survival between black and white women because of advanced stage of disease at
      presentation in poor black women is related to their low socioeconomic status and
      lack of health insurance. This observation led to establishment of a community
      oriented free cancer screening service. STUDY DESIGN: To evaluate the impact of
      screening on breast cancer stage at diagnosis, analysis of data from the Harlem
      Hospital Tumor Registry between 1995 and 2000 was performed and compared with our
      1964-1986 report. RESULTS: Twenty-three percent of cancers (324 of 1,405)
      diagnosed between 1995 and 2000 were breast carcinoma. Data confirm that lack of
      insurance remains a major problem among poor black women. We observed a marked
      fall, from 49% in our earlier report to 21% in this study, in late-stage (III and
      IV) disease at presentation. This fall is associated with significant (p < 0.001)
      improvement in early detection of breast cancer, with 41% of cancers in stages 0
      and I in this data compared with 6% in the previous study. Of note, 53% of women
      with breast carcinoma had breast-conserving surgery and 45% had modified radical
      mastectomy in this study; 71% had radical or modified radical mastectomy in the
      earlier report. CONCLUSIONS: This study confirms the importance of a free cancer
      screening program in the improvement of early-stage breast cancer detection,
      treatment, and survival in a poor urban community.

PMID- 12595044
TI  - Clinical benefits in endoscopic thyroidectomy by the axillary approach.
AB  - BACKGROUND: Surgical treatments for thyroid diseases require skin incisions that
      can result in prominent scars, complaints resulting from adhesions, hypesthesia,
      and paresthesia in the neck. We have developed an endoscopic thyroidectomy using
      an axillary approach. In this article, we compare our original technique with
      conventional open surgery from the aspects of surgical invasiveness and patients'
      complaints after surgery. STUDY DESIGN: Each procedure was performed in 20
      patients with follicular tumors. The two groups were similar for age, gender, and
      the mean diameter of the thyroid tumor. No statistically significant difference
      in the final pathological diagnosis was found between the two groups. Surgical
      invasiveness and patients' complaints after surgery were compared using results
      of the operation and a questionnaire. RESULTS: The operating time for open
      surgery was significantly shorter than that for endoscopic surgery (p < 0.01). In
      the endoscopic surgery group, the patient questionnaires revealed that 4 patients
      had severe anterior chest pain on the first postoperative day. The postoperative
      pain decreased after, and we could not find any difference between the two groups
      with regard to postoperative pain. Three months after surgery, one patient who
      had received an endoscopic procedure complained of slight hypesthesia, and none
      of the patients complained of discomfort while swallowing. Among the patients who
      underwent open surgery, 13 patients (65%; p < 0.01) complained of hypesthesia or
      paresthesia and 6 patients (30%; p < 0.05) complained of discomfort while
      swallowing. All of the patients treated using the endoscopic procedure were
      satisfied with the cosmetic results, but 15 patients who underwent open surgery
      complained of unsatisfactory cosmetic results (p < 0.01). CONCLUSIONS: The
      incidence of postoperative complaints after endoscopic surgery is considerably
      lower than that after open surgery.

PMID- 12595045
TI  - Patterns of recurrence in patients with melanoma and histologically negative but
      RT-PCR-positive sentinel lymph nodes.
AB  - BACKGROUND: We studied the patterns of recurrence of patients with only reverse
      transcriptase-polymerase chain reaction (RT-PCR) evidence of regional nodal
      spread to see whether or not proposed treatment interventions are likely to be
      effective. STUDY DESIGN: One hundred seventy-five patients who underwent
      selective lymphadenectomy for clinical stage I and II melanomas were included in
      this analysis. We preserved a portion of each sentinel lymph node (SLN) in liquid
      nitrogen in the operating room and performed RT-PCR on the specimens to detect
      the melanoma/melanocyte-specific marker tyrosinase. We then compared the pattern
      of recurrence (regional dermal metastases, regional nodal recurrence, or distant
      metastatic spread) of the patients with histologically positive SLNs to that of
      patients who had histologically negative SLNs. RESULTS: The mean followup time of
      the 175 patients was 33.83 months (SD = 15.94, median = 34.17, maximum = 62.95,
      minimum = 6.21). Thirty-four patients had at least one histologically positive
      SLN, and 17 of these patients had a recurrence (50%). Of the 141 patients that
      had histologically negative SLNs, 73 had SLNs that were also negative for
      tyrosinase by RT-PCR, and none of these patients had a recurrence. Of the 68
      patients that had histologically negative but RT-PCR-positive SLNs, 14 had a
      recurrence (20.6%). CONCLUSIONS: Because the pattern of recurrence of patients
      with only RT-PCR evidence of melanoma in SLNs was identical to that in patients
      who had histologically evident melanoma in the SLN and underwent subsequent
      completion lymphadenectomy, we conclude that completion lymphadenectomy might be
      ineffective in decreasing the recurrence rate of patients with only RT-PCR
      evidence of melanoma in SLNs.

PMID- 12595048
TI  - Surgical therapy for anorectal melanoma.
AB  - BACKGROUND: Anorectal melanoma is a rare but highly lethal malignancy.
      Historically, radical resection was considered the "gold standard" for treatment
      of potentially curable anorectal melanoma. The dismal prognosis of this disease
      has prompted us to recommend wide local excision as the initial therapeutic
      approach. The purpose of this study was to review our results in patients who
      underwent wide local excision or radical surgery (abdominoperineal resection
      [APR]) for localized anorectal melanoma. STUDY DESIGN: We reviewed the charts of
      all patients referred for resection of anorectal melanoma between 1988 and 2002.
      Endpoints included overall survival, disease-free survival, and local, regional,
      or systemic recurrence. RESULTS: Fifteen patients underwent curative-intent
      surgery; four underwent APR and 11 underwent wide local excision. Eight patients
      (53%) are alive; 7 (47%) are disease-free (followup 6 months to 13 years). Of 12
      patients who have been followed for more than 2 years, 4 are alive (33%) and 3
      are disease-free (25%). Seven patients have been followed for more than 5 years
      and two are alive and disease-free (29%). All of the longterm survivors underwent
      local excision as the initial operation. There were no differences in local
      recurrence, systemic recurrence, disease-free survival, or overall survival
      between the APR group and the local excision group. Local recurrence occurred in
      50% of the APR group and 18% of the local excision group; regional recurrence
      occurred in 25% versus 27%. Distant metastases were common (75% versus 36%).
      CONCLUSION: In patients who have undergone resection with curative intent for
      anorectal melanoma, most recurrences occur systemically regardless of the initial
      surgical procedure. Local resection does not increase the risk of local or
      regional recurrence. APR offers no survival advantage over local excision. We
      advocate wide local excision as primary therapy for anorectal melanoma when
      technically feasible.

PMID- 12595049
TI  - Current practice patterns in the treatment of perforated appendicitis in
      children.
AB  - BACKGROUND: The treatment of perforated appendicitis in children often involves a
      combination of surgical and medical therapy. The aim of this study was to
      document the degree of consensus in the current management of perforated
      appendicitis in children. STUDY DESIGN: A survey was sent to all practicing
      pediatric surgeons in North America in April 2000 who were members of the
      American Pediatric Surgical Association for 1999-2000. Survey questions pertained
      to preoperative, perioperative, and postoperative practice patterns, particularly
      those issues related to use of antibiotic therapy. RESULTS: Among eligible
      surgeons, 80.2% completed the survey. Although more than 80% of respondents
      practiced in an academic setting, only 17% of surgeons used a formal clinical
      practice guideline to direct care. Responses varied substantially in the duration
      of postoperative antibiotic therapy, the use of intravenous or oral agents or
      both, and the duration of hospitalization. A considerable number of patients are
      receiving a portion of their intravenous antibiotic therapy as outpatients.
      CONCLUSIONS: There is little apparent consensus in the many aspects of
      perioperative and postoperative care of perforated appendicitis in children
      across North America. Only a fraction of surgeons currently uses a formal
      clinical practice guideline for treatment of perforated appendicitis, although
      increased pressures to develop more cost-effective therapeutic strategies can
      encourage development of additional guidelines. Definitive evidence to inform
      development of such guidelines and enhance consensus is lacking. Further studies
      are needed across institutions to better inform clinical decisions in light of a
      changing practice environment and treatment alternatives.

PMID- 12595050
TI  - A636P is associated with early-onset colon cancer in Ashkenazi Jews.
AB  - BACKGROUND: Hereditary predisposition to colorectal cancer most often manifests
      itself as familial adenomatous polyposis from mutations of APC, or hereditary
      nonpolyposis colorectal cancer, resulting from mutations of MSH2, MLH1, MSH6, or
      other genes. Previously, we described a rare founder mutation MSH2*1906C > G in
      Ashkenazi Jews that was found in 8 of 1,345 individuals (0.6%) of Ashkenazi
      descent with colorectal cancer. This study seeks to characterize the proportion
      of individuals of Ashkenazi heritage with very early-onset colon cancer
      (diagnosed at age 40 or younger) that could be attributed to MSH2*1906C>G. STUDY
      DESIGN: We analyzed the carrier frequency of MSH2*1906C>G in paraffin samples
      from 31 Jewish patients age 40 or less, diagnosed with colorectal cancer at
      Memorial Sloan-Kettering and lymphocyte-derived DNA from 10 patients. We did not
      select for family history. Genotyping for MSH2*1906C>G was performed by
      polymerase chain reaction and restriction enzyme digestion methods. RESULTS: We
      detected the MSH2*1906G>C mutation in 3 of the 41 samples (7.14%) of patients who
      had colorectal cancer diagnosed at age 40 or younger. This incidence is
      significantly greater than the 8 in 1,345 (0.6%) we observed for cases of
      colorectal cancer in Ashkenazi Jews not selected for age (p = 0.004). CONCLUSION:
      Although very rare in the population, MSH2*1906G>C is found at an increased
      frequency in young Jewish patients with colorectal cancer. These results suggest
      that testing for the MSH2*1906G>C mutation should be included in the evaluation
      of Ashkenazi Jewish individuals diagnosed with early-onset colon cancer.

PMID- 12595051
TI  - Inflammatory pseudotumor of the liver: demographics, diagnosis, and the case for
      nonoperative management.
AB  - BACKGROUND: Inflammatory pseudotumor of the liver (IPL) is an unusual tumor-like
      condition that is becoming recognized as an important differential diagnosis in
      the patient presenting with liver masses. This report describes six cases of IPL.
      STUDY DESIGN: Clinical, diagnostic, pathologic, and followup data were collected
      prospectively on six patients presenting to a specialist hepatobiliary unit.
      RESULTS: Six patients with IPL presented over a 2-year period. Median age was 35
      years (range 2 to 79 years) and five patients were men. Three patients were
      Polynesian (Tongan and Samoan) and one was New Zealand Maori. Five patients
      presented with nonspecific symptoms (fever, arthralgia, myalgia) and IPL was an
      incidental finding in one patient. At presentation, four patients had elevated
      white cell counts, and five patients had abnormal liver function tests with
      elevations in alkaline phosphotase and gamma-glutamyl transferase the most
      commonly seen. Carcinogenic embryonic antigen and alpha fetoprotein were normal
      in all patients, although one was a known hepatitis B carrier. In all cases of
      IPL, diagnosis was made on core biopsy of the liver lesions and all patients were
      managed nonoperatively with complete resolution of the tumors. Two patients had
      marked reduction in systemic symptoms (fever and pain) from a short course of
      oral steroids. CONCLUSIONS: IPL appears to be a relatively common problem in
      Maori and Polynesians. Recognition and differentiation of this condition from
      malignant liver lesions are important to avoid unnecessary surgery.

PMID- 12595052
TI  - Laparoscopic versus open left lateral hepatic lobectomy: a case-control study.
AB  - BACKGROUND: After technical advances in hepatic surgery and laparoscopic surgery,
      some teams evaluated the possibilities of laparoscopic liver resections. The aim
      of our study was to assess the results of laparoscopic left lateral lobectomy
      (bisegmentectomy 2-3) and to perform a case-control comparison with the same
      operation performed by open surgery. STUDY DESIGN: From 1996 to 2002, 60
      laparoscopic resections were performed in selected patients, including 18 left
      lateral lobectomies. The resected lesions were benign tumors, hepatocellular
      carcinomas with compensated cirrhosis, and metastases. Surgical procedures were
      performed with a harmonic scalpel, an ultrasonic dissector, linear staplers, and
      portal pedicule clamping when necessary. Results were compared with those of
      patients who underwent open left lateral lobectomies selected from our liver
      resection database in a case-control analysis. Both groups were similar for age,
      type and size of the tumor, and presence of underlying liver disease. RESULTS:
      Compared with laparotomy, laparoscopic left lateral lobectomies were associated
      with a longer surgical time (202 versus 145 minutes, p < 0.01), a longer portal
      triad clamping (39 versus 23 minutes, p < 0.05), and a decreased blood loss (236
      versus 429 mL, p < 0.05). There were no deaths in either group, and the morbidity
      rates were 11% in the laparoscopic group and 15% in the open group. There were no
      specific complications of hepatic resection after laparoscopy (no hemorrhage,
      subphrenic collection, or biliary leak), but some were observed in the open
      group. CONCLUSIONS: This study demonstrates the safety of laparoscopic left
      lateral lobectomy. Despite longer operation and clamping time, without any
      clinical consequences, the laparoscopic approach was associated with decreased
      blood loss and absence of specific complications of the hepatic resection.

PMID- 12595053
TI  - Significance of hepatic resection combined with inferior vena cava resection and
      its reconstruction with expanded polytetrafluoroethylene for treatment of liver
      tumors.
AB  - BACKGROUND: Resection of the IVC is required when a liver tumor invading the IVC
      is completely removed. The purpose of this study was to evaluate the clinical
      significance of hepatectomy combined with IVC resection and reconstruction with
      an ePTFE graft for treatment of invasive liver tumors and to discuss the validity
      of this surgery. STUDY DESIGN: Eleven selected patients with liver tumors
      underwent various types of hepatectomy with retrohepatic IVC resection, followed
      by IVC reconstruction. The postoperative courses, clinicopathologic features of
      the tumors, operative procedures, and outcomes of the patients were studied.
      RESULTS: Ten of 11 patients did not require an active ventriculovenous bypass
      using a biopump. Invasion to the IVC was histologically proved in 9 of the 11
      patients. After reconstruction, all artificial vessel grafts maintained patency
      throughout the observation period. Four patients are still alive with cancer-free
      status ranging from approximately 11 years to 5 months. One-year, 3-year, and 5
      year survival rates were 63.6%, 38.2%, and 25.5%, respectively, with a 50%
      survival of 29 months. CONCLUSIONS: IVC resection and its reconstruction with
      ePTFE for treatment of liver tumors was safely performed on 11 selected patients
      with a 50% survival of 29 months. Patency of the graft was maintained for the
      longterm without infectious complications. This surgical procedure is indicated
      in some select patients in whom IVC invasion is extensive.

PMID- 12595054
TI  - The American surgical spirit.

PMID- 12595055
TI  - What's new in vascular surgery.

PMID- 12595056
TI  - What's new in general surgery: burns and metabolism.

PMID- 12595057
TI  - Dieulafoy's disease.

PMID- 12595058
TI  - Intraabdominal pseudocysts as a complication of ventriculoperitoneal shunts.

PMID- 12595059
TI  - Some psychologic problems seen in surgery.

PMID- 12595060
TI  - The importance of opioid tolerance: a therapeutic paradox.

PMID- 12595061
TI  - Resection of tumors of the ischiorectal fossa.

PMID- 12595062
TI  - The 2-mm trocar: a safe and effective way of closing trocar sites using existing
      equipment.

PMID- 12595063
TI  - Asking too much of administrative data?

PMID- 12595066
TI  - Biophysical and biochemical characteristics of cutin, a plant barrier biopolymer.
AB  - Cutin is a support biopolyester involved in waterproofing the leaves and fruits
      of higher plants, regulating the flow of nutrients among various plant cells and
      organs, and minimizing the deleterious impact of pathogens. Despite the
      complexity and intractable nature of this biopolymer, significant progress in
      chemical composition, molecular architecture and, more recently, biosynthesis
      have been made in the past 10 years. This review is focused in the description of
      these advances and their physiological impacts to improve our knowledge on plant
      cutin, an unusual topic in most plant physiology and biochemistry books and
      reviews.

PMID- 12595067
TI  - NMR investigation of the catalytic mechanism of arylamine N-acetyltransferase
      from Salmonella typhimurium.
AB  - Arylamine N-acetyltransferases (NAT) are a family of enzymes found in both
      eucaryotes and procaryotes, which catalyse the N-acetylation of a range of
      arylamine and hydrazine drugs and carcinogenic arylamines, using acetyl Coenzyme
      A as a cofactor. Here we describe a nuclear magnetic resonance (NMR)
      investigation of the interaction of substrates with Salmonella typhimurium NAT.
      For solution NMR investigations, pure recombinant NAT from S. typhimurium was
      used at up to 0.1 mM. We demonstrate that a hydrazine substrate, isoniazid (INH),
      binds to the protein in the absence of the cofactor, acetyl CoA, and thereby
      suggest that even though the catalysis may follow a ping-pong pathway, ligand
      enzyme interactions can occur in the absence of acetyl CoA.

PMID- 12595068
TI  - Pyridoxal isonicotinoyl hydrazone inhibits iron-induced ascorbate oxidation and
      ascorbyl radical formation.
AB  - Previous work from our laboratory demonstrated that pyridoxal isonicotinoyl
      hydrazone (PIH) has in vitro antioxidant activity against iron plus ascorbate
      induced 2-deoxyribose degradation due to its ability to chelate iron; the
      resulting Fe(III)-PIH(2) complex is supposedly unable to catalyze oxyradical
      formation. A putative step in the antioxidant action of PIH is the inhibition of
      Fe(III)-mediated ascorbate oxidation, which yields the Fenton reagent Fe(II)
      [Biochim. Biophys. Acta 1523 (2000) 154]. In this work, we demonstrate that PIH
      inhibits Fe(III)-EDTA-mediated ascorbate oxidation (measured at 265 nm) and the
      formation of ascorbyl radical (in electron paramagnetic resonance (EPR) studies).
      The efficiency of PIH against ascorbate oxidation, ascorbyl radical formation and
      2-deoxyribose degradation was dose dependent and directly proportional to the
      period of preincubation of PIH with Fe(III)-EDTA. The efficiency of PIH in
      inhibiting ascorbate oxidation and ascorbyl radical formation was also inversely
      proportional to the Fe(III)-EDTA concentration in the media. When EDTA was
      replaced by the weaker iron ligand nitrilotriacetic acid (NTA), PIH was much more
      effective in preventing ascorbate oxidation, ascorbyl radical formation and 2
      deoxyribose degradation. Moreover, the replacement of EDTA with citrate, a
      physiological chelator with a low affinity for iron, also resulted in PIH having
      a higher efficiency in inhibiting iron-mediated ascorbate oxidation and 2
      deoxyribose degradation. These results demonstrate that PIH removes iron from
      EDTA (or from either NTA or citrate), forming an iron-PIH complex that cannot
      induce ascorbate oxidation effectively, thus inhibiting iron-mediated oxyradical
      formation. These results are of pharmacological relevance because PIH has been
      considered for experimental chelating therapy in iron-overload diseases.

PMID- 12595069
TI  - The effect of nerve growth factor on the early responses during the process of
      wound healing.
AB  - In this study, we investigated the role of nerve growth factor (NGF)-incorporated
      collagen on wound healing in rats. Full-thickness excision wounds were made on
      the back of female rats weighing about 150-160 g. Topical application of NGF
      incorporated collagen, at a concentration of 1 microg/1.2 mg collagen/cm(2), once
      a day, for 10 days resulted in complete healing of wounds on the 15th day. The
      concentrations of collagen, hexosamine and uronic acid in the granulation tissue
      were determined. The NGF-incorporated collagen-treated rats required shorter
      duration for the healing with an increased rate of wound contraction.
      Histological and electron microscopical evaluations were also performed, which
      reveal the activation of fibroblasts and endoplasmic reticulum and therefore
      increased level of collagen synthesis due to NGF application. These results
      clearly indicate that the topical application of NGF-incorporated collagen
      enhanced the rate of healing of excision wounds.

PMID- 12595070
TI  - Interaction of the parathyroid hormone receptor with the 14-3-3 protein.
AB  - The receptor for parathyroid hormone (PTH) and PTH-related protein (PTHrP)
      regulates calcium homeostasis, bone remodeling and skeletal development. 14-3-3
      proteins bind to signaling proteins and act as molecular scaffolds and regulators
      of subcellular localization. We show that the parathyroid hormone receptor (PTHR)
      interacts with 14-3-3 and the proteins colocalize within the cell. 14-3-3
      interacts with the C-terminal tail of the receptor containing a consensus 14-3-3
      binding motif, but additional binding sites are also used. Protein kinase-A
      treatment of the receptor and especially the C-terminal tail reduces 14-3-3
      binding. The expressed C-terminal tail is primarily localized in the nucleus,
      supporting the function of a putative nuclear localization signal that could be
      involved in the previously described nuclear localization of PTHR. The observed
      interaction between PTHR and the 14-3-3 protein implies that 14-3-3 could
      contribute to regulation of PTHR signaling.

PMID- 12595071
TI  - Identification of repressor element 1 in cytochrome P450 genes and their negative
      regulation by RE1 silencing transcription factor/neuron-restrictive silencer
      factor.
AB  - RE1 silencing transcription factor/neuron-restrictive silencing factor
      (REST/NRSF) mediates transcriptional repression in many neuron-specific genes by
      interaction with the repressor element 1/neuron-restrictive silencing element
      (RE1/NRSE). This element has been identified at least in 20 neuron specific
      genes. REST/NRSF is highly expressed in non-neuronal tissues, where it is thought
      to repress gene transcription. We performed a BLAST search to look for the
      presence of RE1/NRSE elements in the rat cytochrome P450 genes. We identified the
      presence of RE1/NRSE element in the cytochrome P450 genes CYP1A1, 2A2, 2E1 and
      3A2. Electrophoretic mobility shift assay and supershift assays were carried out
      to prove functionality of these sites and detect the interaction of REST/NRSF
      with this sequence. Cotransfection studies in PC12 cells with a plasmid
      containing the RE1 element of the CYP genes, cloned upstream of the minimal type
      II sodium channel promoter, in the presence of REST/NRSF, showed a marked
      expression inhibition of the CAT reporter gene. These data suggest that the RE1
      elements that exist in these four CYP genes might be a target for the REST/NRSF
      transcription factor and such an interaction might play a role in the negative
      regulation of these genes.

PMID- 12595072
TI  - Theanine, gamma-glutamylethylamide, is metabolized by renal phosphate-independent
      glutaminase.
AB  - The distribution of theanine-degrading activity in Wistar rats was examined and
      this activity was detected only in the kidney. Judging from polyacrylamide gel
      electrophoresis, theanine-degrading enzyme from rat kidney was purified almost to
      homogeneity. Theanine-degrading activity was co-purified with glutaminase
      activity, and the relative activity for theanine was about 85% of that for L
      glutamine throughout purification. Substrate specificity of purified enzyme
      preparation coincided well with the data of phosphate-independent glutaminase [EC
      3.5.1.2], which had been previously reported. It was very curious that gamma
      glutamyl methyl and ethyl esters were more effectively hydrolyzed than theanine
      and L-glutamine, in view of relative activity and K(m) value. It was suggested
      that gamma-glutamyl moiety in theanine molecule was transferred to form gamma
      glutamylglycylglycine with relative ease in the presence of glycylglycine. On the
      other hand, purified phosphate-dependent glutaminase did not show theanine
      degrading activity at all. Thus, it was concluded that theanine was hydrolyzed by
      phosphate-independent glutaminase in kidney and suggested that, as for the
      metabolic fate of theanine, its glutamyl moiety might be transferred by means of
      gamma-glutamyl transpeptidase reaction to other peptides in vivo.

PMID- 12595073
TI  - Neutron and X-ray scattering by ox corneal stroma differentially loaded with
      bound anions.
AB  - Ox corneas at near physiological hydration were subjected to two variables: the
      amount of chloride ions bound to them and exposure of various mixtures of
      H(2)O/D(2)O as solvent. The preparations were then exposed to a neutron beam and
      the contrast match points, at which the collagen fibrils of the corneal stroma
      most nearly matched the scattering density of the various H(2)O/D(2)O mixtures,
      were measured. In both cases of high and low bound chloride, the contrast match
      points of the collagen fibril were equal, indicating that there were no
      significant changes in the water of electrostriction at the fibril surface when
      chloride ions bind to the stroma. The data suggest that the ligands which bind
      anions to corneal stroma are not located at the collagen fibril surface. When the
      chloride binding ligands were extracted from the corneal stroma there were
      significant changes in the structure of the fibrils. We suggest that the chloride
      binding ligands may be located within the collagen fibril.

PMID- 12595074
TI  - Anti-angiogenic and anti-tumor invasive activities of tissue inhibitor of
      metalloproteinase-3 from shark, Scyliorhinus torazame.
AB  - In order to investigate the anti-angiogenic activity of shark TIMP-3 (sTIMP-3) in
      endothelial cells, angiogenic assays including in vitro invasion assay, migration
      assay, zymogram assay and tube formation assay were performed. We observed that
      the overexpression of sTIMP-3 decreased the invasive capacity by about 70%, the
      migratory activity by about 50% and the production of gelatinase A in bovine
      aortic endothelial cells (BAECs). In addition, the overexpression of sTIMP-3
      interfered with the formation of capillary-like network in endothelial cells. We
      also examined whether sTIMP-3 shows the anti-invasive activity in cancer cells.
      We found that the overexpression of sTIMP-3 diminished the invasive ability of
      the human fibrosarcoma HT1080 cells by about 40%. Also, the production of
      specific gelatinases was suppressed in the cancer cells. Therefore, we propose
      that sTIMP-3 acts as the inhibitor of angiogenesis in endothelial cells and the
      suppressor of tumor invasion in human fibrosarcoma HT1080 cells.

PMID- 12595075
TI  - Differences between glycogen biogenesis in fast- and slow-twitch rabbit muscle.
AB  - Skeletal muscle glycogen is an essential energy substrate for muscular activity.
      The biochemical properties of the enzymes involved in de novo synthesis of
      glycogen were analysed in two types of rabbit skeletal muscle fiber (fast- and
      slow-twitch). Glycogen concentration was higher in fast-twitch muscle than in
      slow-twitch muscle, but the latter contained many more small intermediate
      acceptor molecules that could act as glycogen synthase substrates. The enzymes
      involved in de novo synthesis of glycogen in fast-twitch muscle were strongly
      stimulated by Glc-6-P, but those in slow-twitch muscle were not.

PMID- 12595076
TI  - Direct evidence for recycling of myeloperoxidase-catalyzed phenoxyl radicals of a
      vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxy chromane, by
      ascorbate/dihydrolipoate in living HL-60 cells.
AB  - Myeloperoxidase (MPO)-catalyzed one-electron oxidation of endogenous phenolic
      constituents (e.g., antioxidants, hydroxylated metabolites) and exogenous
      compounds (e.g., drugs, environmental chemicals) generates free radical
      intermediates: phenoxyl radicals. Reduction of these intermediates by endogenous
      reductants, i.e. recycling, may enhance their antioxidant potential and/or
      prevent their potential cytotoxic and genotoxic effects. The goal of this work
      was to determine whether generation and recycling of MPO-catalyzed phenoxyl
      radicals of a vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxychromane (PMC),
      by physiologically relevant intracellular reductants such as ascorbate/lipoate
      could be demonstrated in intact MPO-rich human leukemia HL-60 cells. A model
      system was developed to show that MPO/H(2)O(2)-catalyzed PMC phenoxyl radicals
      (PMC*) could be recycled by ascorbate or ascorbate/dihydrolipoic acid (DHLA) to
      regenerate the parent compound. Absorbance measurements demonstrated that
      ascorbate prevents net oxidation of PMC by recycling the phenoxyl radical back to
      the parent compound. The presence of DHLA in the reaction mixture containing
      ascorbate extended the recycling reaction through regeneration of ascorbate. DHLA
      alone was unable to prevent PMC oxidation. These conclusions were confirmed by
      direct detection of PMC* and ascorbate radicals formed during the time course of
      the reactions by EPR spectroscopy. Based on results in the model system, PMC* and
      ascorbate radicals were identified by EPR spectroscopy in ascorbate-loaded HL-60
      cells after addition of H(2)O(2) and the inhibitor of catalase, 3-aminotriazole
      (3-AT). The time course of PMC* and ascorbate radicals was found to follow the
      same reaction sequence as during their recycling in the model system. Recycling
      of PMC by ascorbate was also confirmed by HPLC assays in HL-60 cells. Pre-loading
      of HL-60 cells with lipoic acid regenerated ascorbate and thus increased the
      efficiency of ascorbate in recycling PMC*. Lipoic acid had no effect on PMC
      oxidation in the absence of ascorbate. Thus PMC phenoxyl radical does not
      directly oxidize thiols but can be recycled by dihydrolipoate in the presence of
      ascorbate. The role of phenoxyl radical recycling in maintaining antioxidant
      defense and protecting against cytotoxic and genotoxic phenolics is discussed.

PMID- 12595077
TI  - In vitro interaction of macrocyclic photosensitizers with intact mitochondria: a
      spectroscopic study.
AB  - Six water-soluble macrocyclic photosensitizers, the members of two groups of
      expanded porphyrins (metallotexaphyrins and free-base sapphyrins) containing
      hydrophilic substituents and meso-tetra(4-sulfonatophenyl)-porphyrin, were tested
      by UV-Vis absorption and resonance Raman spectroscopy in the in vitro binding
      experiments with intact mitochondria isolated from swine liver. Studied
      macrocycles showed markedly different affinity to mitochondria. The highest
      uptake was observed for sapphyrin-sugar conjugate and metallotexaphyrins.
      Sapphyrin-polyamine conjugates exhibit something less affinity to mitochondria,
      while the porphyrin of anionic character showed very low mitochondrial uptake.
      Obtained spectroscopic results confirm that the binding process altered the self
      aggregation degree of expanded porphyrins.

PMID- 12595078
TI  - Pulse radiolysis, electron paramagnetic resonance spectroscopy and theoretical
      calculations of caffeic acid oligomer radicals.
AB  - Seven representative compounds isolated from Salvia officinalis, among them
      caffeic acid, the dimer rosmarinic acid and oligomers of caffeic acid, were
      investigated with regard to their antioxidant potential both expressed by the
      radical scavenging activity and the stability and structure of the intermediate
      radicals. Pulse-radiolytic investigation revealed very high rate constants with
      both hydroxyl and azide radicals. Evidence from kinetic modelling calculations
      suggested unusual complex behavior due to the presence of both O(4)- and O(3)
      semiquinones and - in two cases - formation and decay of a hydroxyl radical
      adduct at the vinyl side chain. EPR spectroscopy studies, which included
      dihydrocaffeic acid as a model for the saturated side chains of the oligomers,
      confirmed that the radical structures after oxidation in slightly alkaline
      solutions are representing dissociated O(4)-semiquinones. While according to
      calculations based on hybrid density-functional theory the other radical
      structures are valid intermediates, they cannot be observed except by pulse
      radiolysis due to their fast decay.

PMID- 12595079
TI  - Inhibition of lipopolysaccharide-induced pro-inflammatory cytokine expression via
      suppression of nuclear factor-kappaB activation by Mallotus japonicus
      phloroglucinol derivatives.
AB  - An aqueous acetone extract obtained from the pericarps of Mallotus japonicus
      (MJE) was observed to inhibit pro-inflammatory cytokine (tumor necrosis factor
      alpha (TNF-alpha) and interleukin-6 (IL-6) production in a lipopolysaccharide
      (LPS)-activated murine macrophage-like cell line, RAW 264.7, or human blood
      monocytes. Several phloroglucinol derivatives were isolated from the pericarps as
      active compounds. Among these compounds, isomallotochromanol and
      isomallotochromene were the most potent in inhibiting cytokine production. MJE
      and the phloroglucinol derivatives significantly reduced these cytokine mRNA
      expressions. Gel shift analysis revealed that stimulation of macrophages with LPS
      caused an increase in the DNA binding activity of nuclear factor-kappaB (NF
      kappaB), which was inhibited by isomallotochromanol and isomallotochromene.
      Western blot analysis showed that LPS reduced the IkappaB-alpha level in
      macrophages, while 10 microM isomallotochromanol and 10 microM isomallotochromene
      attenuated the LPS-induced decrease in IkappaB-alpha protein. We conclude that
      these phloroglucinol derivatives inhibit pro-inflammatory cytokine production and
      mRNA expression via suppression of NF-kappaB activation in activated macrophages.

PMID- 12595080
TI  - Stabilisation of tyrosinase by reversed micelles for bioelectrocatalysis in dry
      organic media.
AB  - The enzymatic and bioelectrocatalytic activity of tyrosinase from mushrooms was
      studied in a system of reversed micelles formed by Aerosol OT (AOT) in hexane.
      The optimal catechol oxidising activity of tyrosinase incorporated in reversed
      micelles was found at a hydration degree of w(0)=25. The catalytic activity was
      comparable with tyrosinase activity in aqueous media. When immobilized at an Au
      electrode, either directly or in reversed micelles, tyrosinase exhibited a
      similar efficiency of the bioelectrocatalytic reduction of O(2) mediated by
      catechol; however, a rapid decrease in the activity correlated with the
      destruction of reversed micelles and/or the removal of tyrosinase from the
      electrode surface. The system containing tyrosinase in reversed micelles with
      caoutchouk, spread on the surface of the Au electrode and successively covered
      with a Nafion membrane layer, was found to result in stable tyrosinase-modified
      electrodes, which were resistant to inactivation in dry acetonitrile. The
      proposed technique offers possibilities for further development of highly active
      and stable surfactant/enzyme-modified electrodes for measurements carried out in
      organic solvents.

PMID- 12595081
TI  - Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability
      to glutathione peroxidase.
AB  - Glycation (nonenzymatic glycosylation of proteins) is known to be increased as a
      result of hyperglycaemia in diabetes. Moreover, cell glutathione concentration
      has been found to be lower in diabetics and such depletion may impair the cell
      defence against toxic radical species. Ribose being a potent reducing sugar
      expected to be increased in cells of diabetics where the pentose phosphate
      pathway is enhanced, its putative condensation with glutathione was investigated.
      Reduced glutathione (GSH) was incubated with ribose and the structure of the
      resultant product was assessed by mass spectrometry, as well as the measurement
      of its remaining thiol group. A covalent reaction clearly occurred between the
      reducing sugar and GSH, to give an adduct named N-ribosyl-1-glutathione. This
      adduct appears to be the Amadori product resulting from the condensation of the
      primary amine group of GSH with the aldehyde group of ribose. Interestingly, the
      adduct could not be used as a proper substrate by glutathione peroxidase although
      it keeps its thiol group. We conclude that the coupling of GSH with a
      monosaccharide such as ribose might contribute to the decreased cell GSH and
      glutathione peroxidase activity observed in diabetics.

PMID- 12595082
TI  - The effect of temperature on FMN absorption spectra in rigid poly(vinyl alcohol)
      matrices.
AB  - Electronic absorption spectra of flavomononucleotide (FMN) in poly(vinyl alcohol)
      films (PVA) were measured over the concentrations ranging from 6.9 x 10(-4) to
      6.8 x 10(-1) M and temperatures from 263 to 338 K. The FMN absorption spectra
      measurements performed at room temperature have shown two ranges of different
      changes as a function of dye concentration. For concentrations c<10(-1) M (range
      I) the spectra exhibited regular changes showing an isosbestic point, which
      evidences the equilibrium between monomers and dimers. However, for range II
      (c>1.05 x 10(-1) M) the FMN absorption spectra occurred to be almost independent
      of concentration and they nearly overlapped with the dimer spectrum (within the
      error limit). Temperature measurements have shown that the FMN absorption spectra
      in PVA are stable over a wide temperature range. The mean distances between FMN
      molecules in PVA films are calculated. For maximal concentrations (from the range
      II), they are below 13.1 A, whereas the mean dimensions of FMN monomers and
      dimers are 15.8 and 21.1 A, respectively, which indicates that the orientation of
      dimers and monomers in the PVA film cannot be random at high concentrations.
      Molecules are partly ordered, adopting approximately parallel orientation, which
      is in agreement with the calculations of dimer structure by molecular modelling
      method (MMM).

PMID- 12595083
TI  - Protection against oxidative protein damage induced by metal-catalyzed reaction
      or alkylperoxyl radicals: comparative effects of melatonin and other
      antioxidants.
AB  - Melatonin is a well-known hydroxyl radical (*OH) scavenger that protects DNA and
      lipids from free radical attack. In this paper, we studied the ability of
      melatonin to prevent oxidative damage to bovine serum albumin (BSA) induced by
      two different paradigms: the metal-catalyzed oxidation (MCO) induced by
      Cu(2+)/H(2)O(2) and the alkoxyl and alkylperoxyl radicals formed by the azo
      initiator 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH, 40 mM). The
      protective effects of melatonin were compared with 6-hydroxy-2,5,7,8
      tetramethylchroman-2-carboxylic acid (trolox), glutathione (GSH), ascorbate,
      3,4',5-trihydroxy-trans-stilbene (resveratrol, 0.1 microM-4 mM) and mannitol (50
      microM-100 mM). Melatonin efficiently prevented protein modification induced by
      both models, as assayed by polyacrylamide gel electrophoresis and carbonyl
      content. Both trolox and ascorbate had an obvious pro-oxidant effect in the
      Cu(2+)/H(2)O(2) model, whereas both prevented BSA damage induced by AAPH. In the
      MCO model, the efficacy of GSH in terms of protein protection was higher than
      melatonin at relatively high concentrations (250 microM-4 mM); however, at lower
      concentrations (50-250 microM), the efficacy of melatonin was superior to GSH. D
      Mannitol (50 microM-100 mM) and resveratrol did not protect BSA from the site
      specific damage induced by Cu(2+)/H(2)O(2). On the other hand, the relative
      protective efficiency in the AAPH model was melatonin approximately
      trolox>GSH>ascorbate.

PMID- 12595084
TI  - Interaction of rifampicin and isoniazid with large unilamellar liposomes:
      spectroscopic location studies.
AB  - The location of isoniazid and rifampicin, two tuberculostatics commonly used for
      the treatment of Mycobacterium tuberculosis and Mycobacterium avium complex
      infectious diseases, in bilayers of dimyristoyl-L-alpha-phosphatidylcholine
      (DMPC) and dimyristoyl-L-a-phosphatidylglycerol (DMPG) have been studied by 1H
      NMR and fluorimetric methods. Steady-state fluorescence intensity and
      fluorescence energy transfer studies between rifampicin and a set of
      functionalized probes [n-(9-anthroyloxy)stearic acids, n=2, 12] reveal that, in
      both systems, isoniazid is located at the membrane surface whereas rifampicin is
      deeply buried inside the lipid bilayers. Steady-state fluorescence anisotropy
      studies performed with the probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and
      trimethylammonium-diphenylhexa-triene (TMA-DPH), not only corroborate the above
      results, but also show that no changes in membrane fluidity were detected in
      either liposome. The 1H NMR results, in DMPC liposomes, confirm the location of
      rifampicin near the methylene group of the acyl chains of the lipid bilayers.

PMID- 12595085
TI  - Delivery to macrophages and toxic action of etoposide carried in mouse red blood
      cells.
AB  - Erythrocytes could be used as physiological carriers of active compounds. Several
      substances can be loaded into erythrocytes by hypotonic dialysis methods.
      Furthermore, carrier erythrocyte membrane can be chemically modified in order to
      promote increased arrival of the loaded compound to macrophages. In this work, we
      have prepared erythrocytes loaded with etoposide. We found conditions to obtain
      high etoposide encapsulation yields with minor alteration of some cell parameters
      of these carrier erythrocytes. Etoposide loaded into erythrocytes is mainly
      localised in the cytoplasmic compartment. Membrane modification of etoposide
      loaded erythrocytes with band 3 crosslinkers produces an increased incorporation
      of the drug into macrophages mainly by phagocytosis process. The toxic effect of
      etoposide conveyed in these carrier erythrocytes determined as DNA fragmentation
      in macrophages was higher than that shown by free etoposide added at the same
      concentration in the culture medium to macrophages. These results seem to
      indicate the usefulness of this model to deliver this anti-tumour compound to
      macrophages, which might be useful in therapy.

PMID- 12595086
TI  - Human beta-secretase activity in yeast detected by a novel cellular growth
      selection system.
AB  - Sequential processing of the transmembrane amyloid precursor protein (APP) by the
      beta-secretase BACE and by the gamma-secretase causes secretion of Abeta
      peptides. Extracellular aggregation of these peptides in the brain is a major
      hallmark of Alzheimer's disease. For therapeutic purposes and the development of
      specific inhibitors, it is important to characterize these secretases. We have
      established a cellular growth selection system for functional expression of human
      BACE in the yeast Saccharomyces cerevisiae. A fragment of APP bearing the beta
      site, the transmembrane domain and the cytosolic tail was fused to the C-terminus
      of the yeast enzyme invertase, which is normally secreted to allow cell growth in
      the presence of sucrose as the sole carbon source. The resulting invertase-APP
      fusion protein was expressed as a type-I transmembrane protein in intracellular
      compartments of yeast cells lacking endogenous invertase. In these cells, co
      expression of human BACE restored cell growth on selective plates upon cleavage
      of the invertase-APP fusion protein. The cellular growth selection system
      presented here can be generally applied to screen for secretases that
      specifically cleave membrane-bound substrates. Furthermore, this system provides
      the basis for a high-throughput screen for identifying secretase inhibitors that
      are active in eukaryotic cells.

PMID- 12595087
TI  - Ultrasonically induced cell damage and active oxygen generation by 4
      formyloximeetylidene-3-hydroxyl-2-vinyl-deuterio-porphynyl(IX)-6-7-diaspartic
      acid: on the mechanism of sonodynamic activation.
AB  - Ultrasonically induced cell damage and active oxygen generation with 4
      formyloximeetylidene-3-hydroxyl-2-vinyl-deuterio-porphynyl(IX)-6-7-diaspartic
      acid (ATX-S10) were compared in the same in vitro insonation setup. Sarcoma 180
      cells suspended in air-saturated PBS were exposed to ultrasound at 2 MHz for up
      to 60 s in the presence and absence of ATX-S10. The viability was determined by
      Trypan blue exclusion test. Ultrasonically induced active oxygen generation in
      the presence and absence of ATX-S10 in air-saturated aqueous solutions of 50 mM
      2,2,6,6-tetramethyl-4-piperidone was detected by electron spin resonance (ESR).
      Significant enhancement of the rates of both ultrasonically induced cell damage
      and nitroxide generation was demonstrated with 40-160 microM ATX-S10. Both rates
      correlated very well. The enhancement of both rates with ATX-S10 was suppressed
      by 10 mM histidine. These results suggest that ultrasonically generated active
      oxygen plays a primary role in the ultrasonically induced cell damage in the
      presence of ATX-S10.

PMID- 12595088
TI  - Effects of 50-Hz magnetic fields on the signalling pathways of fMLP-induced shape
      changes in invertebrate immunocytes: the activation of an alternative "stress
      pathway".
AB  - N-formyl-Meth-Leu-Phe (fMLP)-induced immunocyte shape changes in the mussel
      Mytilus galloprovincialis through both the phosphatidylinositol and the cAMP
      pathways are studied. Fifteen- and thirty-minute exposures of mussels to 50-Hz
      magnetic fields (MFs) at intensities of 300 and 400 microT do not provoke
      permanent cell damage, since immunocytes maintain the capacity to respond to
      fMLP. This avoidance of external insult seems to be achieved through the
      activation of a "stress pathway" which is not functionally detectable in
      nonexposed animals and which involves mitogen activated protein (MAP) kinase
      members. This phenomenon is clearly evident at 400 microT. Contemporaneously, a
      different expression of Jun transcriptional regulatory proteins is also found.

PMID- 12595089
TI  - Inhibition of formyl-methionyl-leucyl-phenylalanine-stimulated phospholipase D
      activation in rat neutrophils by the synthetic isoquinoline DMDI.
AB  - The expression of phospholipase D (PLD) isoenzymes in neutrophils was
      investigated using reverse transcription-polymerase chain reaction analysis.
      Amplification products of predicted size were obtained from rat neutrophils with
      nucleotide sequences corresponding to PLD1a and PLD2. 1-(3',4'-Dimethoxybenzyl)
      6,7-dichloroisoquinoline (DMDI) inhibited the formyl-methionyl-leucyl
      phenylalanine (fMLP)-stimulated PLD activation in rat neutrophils. The underlying
      cellular signaling mechanism of DMDI inhibition was investigated. The fMLP
      induced protein tyrosine phosphorylation and the membrane translocation of ADP
      ribosylation factor (ARF) and Rho A in neutrophils was attenuated by DMDI in a
      concentration-dependent manner. However, neither the membrane association of
      protein kinase C-alpha and -beta isoenzymes in fMLP-stimulated cells nor the
      GTPgammaS- and phorbol 12-myristate 13-acetate-stimulated membrane translocation
      of ARF and Rho A in a cell-free system was affected significantly by DMDI. These
      results indicate that the expression of PLD1a and PLD2 mRNA in neutrophils.
      Attenuation of protein tyrosine phosphorylation and the membrane association of
      ARF and Rho A probably play a concerted role in the inhibition of PLD by DMDI in
      rat neutrophils in response to fMLP.

PMID- 12595090
TI  - Kinetics and activation parameter analyses of hydrolysis and interconversion of
      2',5'- and 3',5'-linked dinucleoside monophosphate at extremely high
      temperatures.
AB  - Kinetic analysis of hydrolytic stability of 2',5'- and 3',5'-linked dinucleoside
      monophosphate (N(2)'pN and N(3)'pN) was successfully performed in aqueous
      solution at 175-240 degrees C using a new real-time monitoring method for rapid
      hydrothermal reactions. The half-lives of NpN were in the range 2-8 s at 240
      degrees C and apparent activation energy decreases in the order
      U(2)'pU>A(2)'pA>G(2)'pG>U(3)pU approximately C(3)'pC>A(3)pA. The stability of
      phosphodiester bond was dependent on the types of base moiety and phosphodiester
      linkages, but no systematic correlation was found between the structure and
      stability. The interconversion of 2',5'-adenylyladenosine monophosphate (A(2)'pA)
      and 3',5'-adenylyladenosine monophosphate (A(3)'pA) was enhanced in the presence
      of D- or L-histidine. The rate constants of degradation of NpN were dissected
      into the rate constants of hydrolysis and interconversion between N(2)'pN and
      N(3)'pN using a computer program SIMFIT. Kinetic analysis supports the mechanism
      that imidazolium ion and imidazole catalyze interconversion and hydrolysis even
      under hydrothermal environments. The activation parameters for the hydrolysis and
      interconversion of NpN were systematically determined for the first time from the
      temperature dependence of the rate constants, where both DeltaH(app)( not equal )
      and DeltaS(app)( not equal ) for 2',5'-linked NpN are larger than those for 3',5'
      linked NpN. These parameters support the pseudorotation mechanism through
      pentacoordinate intermediate from 2',5'- and 3',5'-linked NpN, where the average
      value of DeltaH( not equal ) (pseudorotation) was estimated to be 30+/-18 kJ mol(
      1) at 175-240 degrees C.

PMID- 12595091
TI  - Hydrogen-peroxide-induced heme degradation in red blood cells: the protective
      roles of catalase and glutathione peroxidase.
AB  - Catalase and glutathione peroxidase (GSHPX) react with red cell hydrogen
      peroxide. A number of recent studies indicate that catalase is the primary enzyme
      responsible for protecting the red cell from hydrogen peroxide. We have used flow
      cytometry in intact cells as a sensitive measure of the hydrogen-peroxide-induced
      formation of fluorescent heme degradation products. Using this method, we have
      been able to delineate a unique role for GSHPX in protecting the red cell from
      hydrogen peroxide. For extracellular hydrogen peroxide, catalase completely
      protected the cells, while the ability of GSHPX to protect the cells was limited
      by the availability of glutathione. The effect of endogenously generated hydrogen
      peroxide in conjunction with hemoglobin autoxidation was investigated by in vitro
      incubation studies. These studies indicate that fluorescent products are not
      formed during incubation unless the glutathione is reduced to at least 40% of its
      initial value as a result of incubation or by reacting the glutathione with
      iodoacetamide. Reactive catalase only slows down the depletion of glutathione,
      but does not directly prevent the formation of these fluorescent products. The
      unique role of GSHPX is attributed to its ability to react with hydrogen peroxide
      generated in close proximity to the red cell membrane in conjunction with the
      autoxidation of membrane-bound hemoglobin.

PMID- 12595092
TI  - Lead-revealed lipid organization in human hair.
AB  - Human hair lipids form a complex mixture of composition close to that of sebum.
      Part of these lipids appears in an organized state that has been studied by
      diffraction techniques in the literature. Nevertheless, information on the
      structure of these lipids remains very scarce due to their low contribution to
      global hair diffraction pattern. Here we show that appropriate lead treatment
      considerably enhances organized lipid features observed by microbeam synchrotron
      radiation diffraction experiments. We attribute these features to the formation
      of lead soaps of free fatty acids. Specific orientation of hair "lipid crystals"
      in planes parallel to the hair axis is clearly demonstrated. Inclusion of these
      lipids in the bulk of the hair shaft is shown by diffraction experiments
      following removal of the cuticular outermost layer of hair. Moreover,
      microfluorescence and diffraction experiments are consistent with part of the
      lipids being present as calcium soaps in native hair. We therefore consider lead
      fixation as a powerful tool to evaluate the lipid organization in human hair for
      medical, environmental and archaeological purposes, including lead poisoning.

PMID- 12595093
TI  - Avidin is a heparin-binding protein. Affinity, specificity and structural
      analysis.
AB  - The specificity, affinity and stoichiometry of the interaction between avidin and
      glycosaminoglycans (GAGs) have been investigated using heparin-coated microtiter
      plate assays, a filter binding assay and surface plasmon resonance (SPR) analysis
      using a BIAcore 2000 biosensor. Avidin binds heparin and heparan sulfate, and
      chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate or hyaluronan were
      unable to compete for binding. Highest-affinity binding was observed with
      heparin, and weaker binding was seen when using heparan sulfate or low molecular
      weight heparin preparations. This indicated that only specific polysaccharide
      structures tightly interact with avidin. Approximately two avidin molecules bind
      to each heparin molecule with an overall affinity of 160 nM. The interaction is
      pH dependent, increasing five-fold upon decreasing the pH from 7.5 to 5.5, while
      binding was negligible at pH 9. We demonstrate the potential of fluorescent
      avidin derivatives as a tool for the detection of heparin and heparan sulfates on
      surfaces by application to both heparin immobilized on polystyrene plates and
      heparan sulfate on cell surfaces.

PMID- 12595094
TI  - Isolation and characterization of a new advanced glycation endproduct of
      dehydroascorbic acid and lysine.
AB  - Proteins are subject of posttranslational modification by sugars and their
      degradation products in vivo. The process is often referred as glycation. L
      Dehydroascorbic acid (DHA), an oxidation product of L-ascorbic acid (vitamin C),
      is known as a potent glycation agent. A new product of modification of lysine
      epsilon -amino group by DHA was discovered as a result of the interaction between
      Boc-Lys and dehydroascorbic acid. The chromatographic and spectral analyses
      revealed that the structure of the product was 1-(5-ammonio-5-carboxypentyl)-3
      oxido-4-(hydroxymethyl)pyridinium. The same compound was isolated from DHA
      modified calf lens protein after hydrolysis and chromatographic separation. The
      study confirmed that L-erythrulose is an important intermediate of modification
      of proteins by DHA. The structure of the reported product and in vitro
      experiments suggested that L-erythrulose could further transform to L-threose, L
      erythrose and glycolaldehyde under conditions similar to physiological. The
      present study revealed that the modification of epsilon -amino groups of lysine
      residues by DHA is a complex process and could involve a number of reactive
      carbonyl species.

PMID- 12595095
TI  - Targets of oxidative stress in yeast sod mutants.
AB  - Eukaryotic cells have developed mechanisms to rapidly respond towards the
      environment by changing the expression of a series of genes. There is increasing
      evidence that reactive oxygen species (ROS), besides causing damage, may also
      fulfill an important role as second messengers involved in signal transduction.
      Recently, we have demonstrated that deletion of SOD1 is beneficial for the
      acquisition of tolerance towards heat and ethanol stresses. The present report
      demonstrates that a sod1 mutant was the only one capable of acquiring tolerance
      against a subsequent stress produced by menadione, although this mutant strain
      had exhibited high sensitivity to oxidative stress. By measuring the level of
      intracellular oxidation, lipid peroxidation as well as glutathione metabolism, we
      have shown that in the SOD1-deleted strain, an unbalance occurs in the cell redox
      status. These results indicated that the capacity of acquiring tolerance to
      oxidative stress is related to a signal given by one or all of the above factors.

PMID- 12595096
TI  - Efficient synthesis of glyceroyl beta-lactoside and its derivatives through a
      condensation reaction by cellulase.
AB  - Condensation reaction between lactose and glycerol was effectively catalyzed by
      utilizing a commercially available cellulase preparation from Trichoderma reesei.
      The enzyme induced the formation of 1-O-beta-lactosyl-(R,S)-glycerol (1) and 2-O
      beta-lactosyl glycerol (2) in a molar ratio of 7:3 and in a 20% yield based on
      lactose added. The enzyme also induced the condensation of lactose with 1,3
      propanediol to produce O-beta-lactosyl propanediol (3) in a yield of 15%. When
      various alkanols (N: 2-8) and allyl alcohol were used in the condensation
      reaction, the corresponding alkyl and allyl beta-lactoside were obtained in the
      yields of 0.9-3.8% of the desired compounds.

PMID- 12595097
TI  - Decreased activity and impaired induction of nitric oxide synthase by
      lipopolysaccharides in streptozotocin-induced diabetic rats.
AB  - The effect of diabetes was determined on nitric oxide synthase (NOS) activity in
      rat heart and liver. The diabetes was induced by streptozotocin (STZ) and NOS
      activity was determined after 1 or 12 weeks post-STZ injection. In both tissues,
      the majority of NOS activity was associated with endothelial constitutive calcium
      sensitive NOS (ecNOS) isoform and found in the particulate (100,000xg pellet)
      fraction in young rats. The diabetes as well as age reduced this activity
      significantly in heart, whereas only the age caused a decrease in ecNOS activity
      in liver tissue. Lipopolysaccharides (LPS) induced calcium-insensitive iNOS
      activity in both young and old rats. The induction was significantly higher (up
      to 10-fold) in liver as compared to heart. Although the maximum induction of iNOS
      in young rats was almost similar in diabetic tissues as compared to control
      animals, there was a lag period for induction of iNOS in diabetic tissues. In old
      diabetic rats, the induction by LPS was almost completely abolished. These
      results suggest that diabetes causes either no change or a decrease in ecNOS
      activity and impairment in the induction of iNOS by LPS in rat heart and liver.

PMID- 12595098
TI  - Spin-spin interaction in ethanolamine deaminase.
AB  - The adenosylcobalamin coenzyme-dependent ethanolamine deaminase from Salmonella
      typhimurium catalyzes the deamination of aminoethanol to acetaldehyde and
      ammonia. The radical intermediate observed during steady state turnover of
      substrate aminoethanol has been characterized by continuous wave electron
      paramagnetic resonance (EPR) spectroscopy [J. Am. Chem. Soc. 121 (1999) 10522].
      This study presents simulations of EPR spectra of this radical intermediate.
      Quantitative fits to the EPR spectra are achieved with a model of isotropic
      exchange and magnetic dipolar interaction between the substrate-derived radical
      and the Co(II) in the corrin ring. The simulated parameters are compared with
      those of substrate analog 2-aminopropanol-derived radical in the same enzyme. The
      comparison confirms that the aminoethanol-derived product radical interacts more
      weakly with the Co(II) than the 2-aminopropanol-derived radical and suggests that
      the reduction of isotropic exchange between the aminoethanol-derived product
      radical and the Co(II) is probably due to orientational-dependent wave function
      overlap. Successful fits to the radical line shapes of different isotope
      substitutions unequivocally establish that the observed radical intermediate is
      an pi-electron-based product radical. The derived principal hyperfine values for
      the 13C(alpha) and 1H(alpha) nucleus are consistent with previous electron
      nuclear double resonance (ENDOR) studies on similar radicals, thus providing
      reliable experimental hyperfine coupling constants for comparison with quantum
      mechanical-based calculations to gain further insight into the molecular
      structure of the observed radical.

PMID- 12595099
TI  - (-)Epigallocatechin-3-gallate inhibits gelatinase activity of some bacterial
      isolates from ocular infection, and limits their invasion through gelatine.
AB  - The objective of this paper is to assess the gelatinase production by some ocular
      pathogenic bacterial strains, and evaluate the ability of (-)epigallocatechin-3
      gallate (EGCg) to inhibit this gelatinase activity and thus limit bacterial
      invasion. The effect of EGCg on bacterial gelatinase activity was tested by
      classic zymography methods, while its effect on bacterial invasion was evaluated
      through the ability of growing bacteria to liquefy and thus penetrate a semisolid
      gelatine substrate. It was found that EGCg inhibits bacterial gelatinases with an
      IC(50) of about 0.2 mM, and limits invasion of gelatinase-positive bacteria at
      concentrations above 2 mM. These results show for the first time that EGCg, as
      well as having direct antibacterial activity, can also inhibit bacterial
      gelatinases, thus limiting their invasion on gelatine. Possible use of EGCg is
      thus suggested as an adjuvant in antibacterial chemotherapy.

PMID- 12595100
TI  - Diffusion weighted imaging: have we found the 'Holy Grail' of diagnostic imaging
      or is it still a game of numbers?

PMID- 12595101
TI  - Basic principles of diffusion-weighted imaging.
AB  - In diffusion-weighted MRI (DWI), image contrast is determined by the random
      microscopic motion of water protons. During the last years, DWI has become an
      important modality in the diagnostic work-up of acute ischemia in the CNS. There
      are also a few promising reports about the application of DWI to other regions in
      the human body, such as the vertebral column or the abdomen. This manuscript
      provides an introduction into the basics of DWI and Diffusion Tensor imaging. The
      potential of various MR sequences in concert with diffusion preparation are
      discussed with respect to acquisition speed, spatial resolution, and sensitivity
      to bulk physiologic motion. More advanced diffusion measurement techniques, such
      as high angular resolution diffusion imaging, are also addressed.

PMID- 12595102
TI  - Diffusion weighted magnetic resonance imaging in stroke.
AB  - Diffusion weighted magnetic resonance imaging has evolved from an esoteric
      laboratory experiment to a critical aspect of routine clinical care of the
      patient presenting with symptoms suspicious of acute ischemic stroke. The purpose
      of this article is to review the basis of diffusion weighted imaging (DWI), to
      consider its application in acute stroke and to recognize potential pitfalls and
      stroke mimics that might be encountered. Included in the discussion are comments
      on the elimination of 'T2 shine through' phenomena as well as construction of
      pixel-by-pixel maps of the apparent diffusion coefficient (ADC). Furthermore,
      discussion of techniques such as parallel imaging (using SENSE) and PROPELLER
      sequences will be introduced as methods potentially allowing DWI to be utilized
      in areas usually associated with prohibitive susceptibility artifact (e.g. the
      base of the brain). Finally, the concept of interventional therapeutic approaches
      to salvaging ischemic tissue is introduced, both in terms of the ischemic
      penumbra (defined by a diffusion/perfusion mismatch) and also in terms of the
      potential reversibility of the diffusion-weighted hyperintensity, associated with
      the lesion core.

PMID- 12595103
TI  - Diffusion-weighted MR imaging findings in a patient with herpes simplex
      encephalitis.
AB  - INTRODUCTION: Herpes simplex meningoencephalitis is one of the most common viral
      central nervous system infection in adults. Early diagnosis is essential for
      treatment. CASE REPORT: We present a case of a 68-year-old female patient with
      herpes simplex infection. On admission, she was in severe clinical condition.
      Diffusion-weighted (DW) magnetic resonance imaging detected brain involvement
      better than conventional sequences. After acyclovir therapy, the patient fully
      recovered. CONCLUSION: DW magnetic resonance imaging is expected to provide a
      more sensitive imaging in herpes simplex patients than conventional sequences.

PMID- 12595104
TI  - Characterization of normal brain and brain tumor pathology by chisquares
      parameter maps of diffusion-weighted image data.
AB  - OBJECTIVE: To characterize normal and pathologic brain tissue by quantifying the
      deviation of diffusion-related signal from a simple monoexponential decay, when
      measured over a wider than usual range of b-factors. METHODS AND MATERIALS: Line
      scan diffusion imaging (LSDI), with diffusion weighting at multiple b-factors
      between 100 and 5000 s/mm(2), was performed on 1.5 T clinical scanners. Diffusion
      data of single slice sections were acquired in five healthy subjects and 19 brain
      tumor patients. In-patients, conventional T2-weighted and contrast-enhanced T1
      weighted images were obtained for reference purposes. The chisquare (chi(2))
      error parameter associated with the monoexponential fits of the measured tissue
      water signals was then used to quantify the departure from a simple
      monoexponential signal decay on a pixel-by-pixel basis. RESULTS: Diffusion
      weighted images over a wider b-factor range than typically used were successfully
      obtained in all healthy subjects and patients. Normal and pathologic tissues
      demonstrated signal decays, which clearly deviate from a simple monoexponential
      behavior. The chi(2) of cortical and deep grey matter was considerably lower than
      in white matter. In peritumoral edema, however, chi(2) was 68% higher than in
      normal white matter. In highly malignant brain tumors, such as glioblastoma
      multiforme (GBM) or anaplastic astrocytoma, chi(2) values were on average almost
      400% higher than in normal white matter, while for one low grade astrocytoma and
      two cases of metastasis, chi(2) was not profoundly different from the chi(2)
      value of white matter. Maps of the chi(2) values provide good visualization of
      spatial details. However, the tumor tissue contrast generated appeared in many
      cases to be different from the enhancement produced by paramagnetic contrast
      agents. For example, in cases where the contrast agent only highlighted the rim
      of the tumor, chi(2) enhancement was present within the solid part of the tumor.
      CONCLUSION: The deviation from a purely monoexponential diffusion signal decay
      becomes evident as diffusion encoding is extended well beyond the normal range.
      The chi(2) error parameter as a measure of this deviation seems to provide
      sufficient lesion contrast to permit differentiation of malignant brain tumors
      from normal brain tissue.

PMID- 12595105
TI  - Apparent diffusion coefficient: a quantitative parameter for in vivo tumor
      characterization.
AB  - PURPOSE: The purpose of the this study was to evaluate the potential of diffusion
      weighted imaging (DWI) to distinguish different tissue compartments in early,
      intermediate and advanced tumor stages. MATERIALS AND METHODS: Twenty-two male
      mice were induced with squamous cell tumor (SCCVII) and scanned with a clinical
      1.5 T scanner. T1-SE, T2-FSE, diffusion weighted Line-Scan-MRI and contrast
      enhanced T1-SE were obtained from mice with early (tumor volume 10-100 mm(3)),
      intermediate (200-600 mm(3)), advanced tumors (600-1000 mm(3)) and tumor necrosis
      (>1500 mm(3)). The apparent diffusion coefficient (ADC) of different tumor
      compartments was calculated offline with a pixel-by-pixel method. The animals
      were sacrificed immediately after scanning and histopathologic correlation was
      performed. RESULTS: In early stages of tumor development, tumors appeared
      homogeneous on diffusion weighted images with an ADC of 0.64+/-0.06 x 10(-3)
      mm(2)/s. With tumor progression the ADC in the rim areas of tumor increased
      significantly (intermediate stage: 0.70+/-0.11 x 10(-3) mm(2)/s; advanced stage:
      0.88+/-0.11 x 10(-3) mm(2)/s; tumor necrosis 1.03+/-0.06 x 10(-3) mm(2)/s),
      whereas the ADC in viable tumor remained constant. Histologically the areas with
      an increased ADC correlated well with areas of necrosis (reduced cell density).
      CONCLUSION: The ADC is a non-invasive technique to monitor changes in the
      biological structure of tumor tissue during tumor progression. Thus, DWI is a
      potential diagnostic tool for in-vivo tissue characterization.

PMID- 12595106
TI  - Diffusion-weighted magnetic resonance imaging for monitoring diffusion changes in
      rectal carcinoma during combined, preoperative chemoradiation: preliminary
      results of a prospective study.
AB  - PURPOSE: To evaluate the clinical value of diffusion-weighted magnetic resonance
      imaging (DW-MRI) to monitor response of primary carcinoma of the rectum to
      preoperative chemoradiation by measuring tumor apparent diffusion coefficient
      (ADC). MATERIALS AND METHODS: Diffusion data of nine patients undergoing
      preoperative combined chemoradiation for clinical staged T3, N(0-2), M(0)
      carcinoma of the rectum were analyzed. Diffusion-weighted echo-planar MR images
      were obtained prior to and at specified intervals during chemoradiation and ADCs
      calculated from acquired tumor images. RESULTS: Comparison of mean ADC and
      cumulative radiation dose showed a significant decrease of mean ADC at the 2nd (P
      = 0.028), 3rd (P = 0.012), and 4th (P = 0.008) weeks of treatment. Cytotoxic
      edema and fibrosis were considered as reasons for ADC decrease. CONCLUSION: This
      study demonstrated tumor ADC changes via detection of therapy-induced alterations
      in tumor water mobility. Our results indicate that diffusion-weighted imaging may
      be a valuable clinical tool to diagnose the early stage of radiation-induced
      fibrosis.

PMID- 12595107
TI  - In vivo MR tractography using diffusion imaging.
AB  - Diffusion in structured tissue, such as white matter or muscle, is anisotropic.
      MR diffusion tensor imaging (DTI) measures anisotropy per pixel and provides the
      directional information relevant for MR tractography or fiber tracking in vivo.
      MR tractography is non-invasive, relatively fast, and can be repeated multiple
      times without destructing important tissue. Moreover, the combination with other
      MR images is relatively simple. In this paper, the basic principles of
      tractography are presented. Different tracking methods with varying degrees of
      complexity are introduced and their potential strengths and weaknesses are
      discussed. Clinical applications and different strategies for evaluating the
      fidelity of tracking results are reviewed.

PMID- 12595108
TI  - Diffusion-weighted magnetic resonance imaging of cerebral white matter
      development.
AB  - Diffusion-weighted magnetic resonance imaging (DWI) has become a sensitive tool
      to monitor white matter development. Different applications of diffusion-weighted
      techniques provide information about premyelinating, myelinating, and
      postmyelinating states of white matter maturation. Mirroring maturational
      processes on the cellular level, DWI has to be regarded as a morphological method
      as well as a functional instrument, giving insight into molecular processes
      during the formation of axons and myelin sheets and into the steric arrangement
      of white matter tracts the formation of which is strongly influenced by their
      function.

PMID- 12595109
TI  - Diffusion tensor imaging in normal aging and neuropsychiatric disorders.
AB  - The application of diffusion imaging to the quantitative study of the effects of
      normal aging and neuropsychiatric diseases on brain tissue microstructure has
      witnessed its greatest development just over the last few years. Measures derived
      from diffusion imaging have already been shown to have great utility in
      identifying age- and disease-related degradation of regional microstructure,
      particularly of white matter. Investigations comparing diagnoses hold promise for
      contribution to differential diagnosis. Correlations with cognitive and motor
      performance provide evidence for functional ramifications of these diffusion
      measures.

PMID- 12595110
TI  - Diffusion weighted MR imaging of acute Wernicke's encephalopathy.
AB  - We report a case of Wernicke's encephalopathy in which diffusion-weighted MR
      images demonstrated symmetrical hyperintense lesions in the paraventricular area
      of the third ventricles and medial thalami. Apparent diffusion coefficient
      mapping showed isointensity in the aforementioned areas. Diffusion-weighted MR
      images may provide evidence of vasogenic edema associated with thiamine
      deficiency, proven in the histopathology of experimental animals. In addition,
      diffusion-weighted MRI has many advantages over T2 or FLARE-weighted brain MRI in
      detecting structural and functional abnormalities in Wernicke's encephalopathy.

PMID- 12595111
TI  - Towards physical dynamic tolerance: an approach to resolve the conflict between
      free will and physical determinism.
AB  - This paper attempts to resolve the conflict between free will and determinism.
      The problem is approached by demonstrating that: (a) some well-established
      experimental observations indicate that irreversibility persists at the molecular
      level, (b) microscopic reversibility is not fully compatible with macroscopic
      irreversibility, (c) an overall consistency can be maintained if microscopic
      reversibility is regarded only as an excellent approximation, whereas microscopic
      irreversibility together with chaos can account for macroscopic reversibility,
      and (d) endogenous noise serves a vital function of nerve excitation. Thus, the
      mean of position and momentum specified by a non-deterministic law of motion
      gives the law its superficially deterministic behavior and predictability,
      whereas its dispersion grants dynamic tolerance and irreversibility. Therefore,
      causality is preserved while a limited degree of freedom allows for the exercise
      of free will. However, it is argued that free will can never be proven or
      disproven by a conventional behavioral experiment.

PMID- 12595112
TI  - Quantum mechanics in first, second and third person descriptions.
AB  - Although quantum mechanics in third person descriptions is certainly legitimate
      insofar as one is sure about what each energy quantum is all about, quantum
      mechanics in first person descriptions comes to the surface once one raises the
      issue of how each quantum transforms itself as measuring and interacting with the
      others of the similar nature. Each energy quantum is taken as the robust
      confinement of interactions, whose first person descriptions address the quantum
      involved in the process of measuring other quanta internally. In addition, the
      issue of how the robust confinement of interactions could come into being and
      develop is a matter of quantum mechanics in second person descriptions.
      Biological activities including cell motility and muscle contraction address the
      issue of quantum coherence accessible in quantum mechanics in second person
      descriptions.

PMID- 12595113
TI  - Replication and transcription processes in the molecular biology of gene
      expressions: control paradigms of the DNA quantum holographic information channel
      in nanobiotechnology.
AB  - All physical phenomena are information-theoretic in origin. Conversely, the
      hereditary genetic information contained in the cell nuclei should be considered
      from the quantum physical point of view. The present paper applies quantum
      holography to the DNA and the messenger RNA of the molecular biology of gene
      expressions in order to understand the semi-conservative replication and
      transcription processes of the DNA double helix in terms of the quantization
      action on the stereometric architecture of quantum information biology.

PMID- 12595114
TI  - Reconstruction of noisy patterns by bistable gradient neural-like network.
AB  - An attractor bistable gradient neural-like network (BGN) described in Chinarov
      and Menzinger (BioSystems 55 (2000) 137) is applied to restoration of unknown
      patterns, which have been highly corrupted by multiplicative and additive
      Gaussian white noise. This becomes possible due to competitive advantage of BGN
      that derives from it: nice generalization capabilities, existence of the unique
      attractor with the lowest energy that is worked out when several patterns are
      stored by the network, and fast guaranteed convergence to this attractor.

PMID- 12595115
TI  - Declarative simulation of dynamicals systems: the 812 programming language and
      its application to the simulation of genetic networks.
AB  - A major part of biological processes can be modeled as dynamical systems (DS),
      that is, as a time-varying state. In this article, we advocate a declarative
      approach for prototyping the simulation of DS. We introduce the concepts of
      collection, stream and fabric. A fabric is a multi-dimensional object that
      represents the successive values of a structured set of variables. A declarative
      programming language, called 8 1/2 has been developed to support the concept of
      fabrics. Several examples of working 8 1/2 programs are given to illustrate the
      relevance of the fabric data structure for simulation applications and to show
      how recursive fabric definitions can be easily used to model various biological
      phenomena in a natural way (a resolution of PDE, a simulation in artificial life,
      the Turing diffusion-reaction process and various examples of genetic networks).
      In the conclusion, we recapitulate several lessons we have learned from the 8 1/2
      project.

PMID- 12595116
TI  - Cellulat: an agent-based intracellular signalling model.
AB  - The theory of behaviour-based systems (or autonomous agents) constitutes a useful
      approach for the modelling of intracellular signalling networks. In this sense, a
      cell can be seen as an adaptive autonomous agent or as a society of such agents,
      where each can exhibit a particular behaviour depending on its cognitive
      capabilities. We present an intracellular signalling model obtained by
      integrating several computational techniques into an agent-based paradigm.
      Cellulat, the model, takes into account two essential aspects of the
      intracellular signalling networks: (1) cognitive capacities, which are modelled
      as the agent abilities to interact with the surrounding medium and (2) a spatial
      organisation, this last obtained using a shared data structure through which the
      agents communicate between them. We propose a methodology for the modelling of
      intracellular signalling pathway using Cellulat and we discuss the goal of a
      virtual laboratory based on our model and presently under development.

PMID- 12595117
TI  - The effect of molecular inhibition on evolutionary learning: studies in the
      hypernetwork architecture.
AB  - The hypernetwork architecture is a biologically inspired learning model based on
      abstract molecules and molecular interactions that exhibits functional and
      organizational correlation with biological systems. Hypernetwork organisms were
      trained, by molecular evolution, to solve N-input parity tasks. We found that
      learning improves when molecules exhibit inhibitory sites, allowing molecular
      inhibition and opening the possibility of forming negative feedback regulatory
      pathways. Optimal learning is achieved when at least 20% of the molecules in each
      cell have inhibitory sites. Intra-cellular as well as inter-cellular molecular
      inhibitions play an important role in the information processing of hypernetwork
      organisms, by maintaining a balance of the molecular cascade reactions. Similar
      mechanisms inside neurons are considered important for memory.

PMID- 12595118
TI  - Exploring the dynamic background of the developmental processes and cell
      reactions with the use of an ultraweak photon emission.
AB  - Any reactions of the living systems are to a great extent context-dependent.
      Meanwhile, the biological essence of a "context" remains to be obscure. We
      suggest that it may be based upon an ensemble of molecular-supramolecular
      oscillators, which have different characteristic times. For testing this
      hypothesis, we applied the Fourier statistics to the time series of the records
      of an ultraweak photon emission (UWPE) registered from fish eggs and embryos and
      from cell cultures. We detected the regular changes of the UWPE Fourier spectra
      (FS) during embryonic development and physiological reactions of cell cultures.
      In many cases, such changes were going on in a holistic manner, i.e. involving
      broad spectral areas rather than single frequency maxims. FS of the earlier
      developmental stages showed greater instability and the presence of a short-range
      order only. On the contrary, at the advanced developmental stages a long-range
      order has emerged within the spectra. Another distinction of the highly organized
      biological samples (developing embryos, confluent fibroblasts cultures) from non
      biological controls and "poorly organized" samples (non-fertilized eggs, non
      confluent, poorly spread cell cultures) was the UWPE correlation dynamics which
      was more cooperative in highly organized samples. A non-invasive technique of
      UWPE registration may be useful for exploring a fluctuated oscillatory background
      of the developmental and physiological states of biological samples.

PMID- 12595119
TI  - Cells coupled by voltage-dependent gap junctions: the asymptotic dynamical limit.
AB  - We study the steady state and dynamical properties of a pair of cells coupled by
      a voltage-dependent gap junction. The cells have linear membrane properties, and
      the gap junction is modelled using a simple Markov chain with a voltage-dependent
      transition matrix. We first show that the voltage-independent case is globally
      convergent using energy dissipation as a Lyapunov function for the cells, and
      standard results on the convergence of homogeneous Markov chains for the
      junction. For the voltage-dependent case, we use the difference in cell and gap
      junction time scales to reduce the coupled equations for cells and the gap
      junction to a single equation for the gap junction, but with a transition matrix
      that depends upon the current gap junction state. We identify cooperativity as
      key property behind the global convergence of Markov chains and investigate
      convergence of the voltage-dependent system by establishing some conditions under
      which cooperativity is preserved.

PMID- 12595120
TI  - A hybrid machine model of rice blast fungus, Magnaporthe grisea.
AB  - The fungus, Magnaporthe grisea (Rice blast fungus) is a major agricultural
      problem affecting rice and related food crops. The way that the fungus invades
      the host plant and propagates itself is a very important scientific problem and
      recent advances in research into the genetic basis of these processes can be used
      to build a simple partial model using hybrid computational modelling techniques.
      The possible potential benefits of doing this include the use of computer
      simulation and automated analysis through techniques such as model checking to
      understand the complex behaviour of such systems. The example is a metaphor for
      the process of trying to integrate and understand much of the vast amounts of
      genomic and other data that is being produced in current molecular biology
      research.

PMID- 12595121
TI  - Physiologically realistic modelling of a mechanism for neural representation of
      intervals of time.
AB  - A model for a recurrent network of bistable spiking neurons is examined. Each
      neuron is described by a leaky-integrate-and-fire formulation with biophysically
      realistic currents and noise. Specially, neuronal bistability is equipped by
      after-depolarisation current. Results obtained by computer simulation show that
      spiking of each neuron starting at an initial time continues for an extended
      period and then suddenly ceases at around a certain time. We hypothesise that
      activation of neurons that starts at t = 0 and voluntarily ceases at t = T is a
      neural underpinning of internal representation of an interval of time T. The
      above results theoretically support this hypothesis by demonstrating one possible
      mechanism to generate such time course of neuronal activation.

PMID- 12595122
TI  - Bio-inspired computing tissues: towards machines that evolve, grow, and learn.
AB  - Biological inspiration in the design of computing machines could allow the
      creation of new machines with promising characteristics such as fault-tolerance,
      self-replication or cloning, reproduction, evolution, adaptation and learning,
      and growth. The aim of this paper is to introduce bio-inspired computing tissues
      that might constitute a key concept for the implementation of 'living' machines.
      We first present a general overview of bio-inspired systems and the POE model
      that classifies bio-inspired machines along three axes. The Embryonics project-
      inspired by some of the basic processes of molecular biology--is described by
      means of the BioWatch application, a fault-tolerant and self-repairable watch.
      The main characteristics of the Embryonics project are the multicellular
      organization, the cellular differentiation, and the self-repair capabilities. The
      BioWall is intended as a reconfigurable computing tissue, capable of interacting
      with its environment by means of a large number of touch-sensitive elements
      coupled with a color display. For illustrative purposes, a large-scale
      implementation of the BioWatch on the BioWall's computational tissue is
      presented. We conclude the paper with a description of bio-inspired computing
      tissues and POEtic machines.

PMID- 12595123
TI  - Clinical and lay preferences for the explicit prioritisation of elective waiting
      lists: survey evidence from Wales.
AB  - Waiting lists are a persistent feature of public health care systems. The United
      Kingdom National Health Service (NHS) is considering priority scoring systems as
      a means of ensuring that patients are treated according to clinical need rather
      than maximum waiting time targets. Our objective was to elicit the preferences of
      those involved in the finance, delivery and receipt of elective health care
      regarding the clinical and social factors that should and should not determine
      waiting time. We conducted a postal survey of 750 general practitioners, 500
      consultants, 29 health authority commissioners and 1000 members of the general
      public across Wales. We found both professional and lay support for a more
      explicit system of rationing access to elective health care by waiting list. The
      majority of each of the survey groups believe that level of pain, rate of
      deterioration of disease, level of distress and level of disability should play
      the most influential role in determining waiting times. They agree that age,
      ability to pay, cost of treatment, evidence of cost-effectiveness, existence of
      dependants, and self-inflicted ill health should have little or no influence on
      patient priority. In conclusion, were the NHS to widen its use of waiting list
      priority scoring systems, our study suggests that there may be some degree of
      consensus as to the criteria to be used.

PMID- 12595124
TI  - The effect of funding policy on day of week admissions and discharges in
      hospitals: the cases of Austria and Canada.
AB  - This paper compares two different funding policies for inpatients, the case-based
      approach in Austria versus the global budgeting approach in Canada. It examines
      the impact of these funding policies on length of stay of inpatients as one key
      measure of health outcome. In our study, six major clinical categories for
      inpatients are selected in which the day of the week for admission is matched to
      the particular day of the week of discharge for each individual case. The
      strategic statistical analysis proves that funding policies have a significant
      impact on the expected length of stay of inpatients. For all six clinical
      categories, Austrian inpatients stayed longer in hospitals compared to Canadian
      inpatients. Moreover, inpatients were not admitted and discharged equally
      throughout the week. We also statistically prove for certain clinical categories
      that more inpatients are discharged on certain days such as Mondays or Fridays
      depending on the funding policy. Our study is unique in the literature and our
      conclusions indicate that, with the right incentives in place, the length of stay
      can be decreased and discharge anomalies can be eliminated, which ultimately
      leads to a decrease in healthcare expenditures and an increase in healthcare
      effectiveness.

PMID- 12595125
TI  - The influence of change of legislation concerning sickness absence on physicians'
      performance as certifiers. A population-based study.
AB  - In Sweden, a change of the legislation for sickness absence became effective on
      1st October, 1995. The purpose of the change was to reduce costs for sickness
      absence by exclusion of non-medical criteria for sick-listing, more part-time
      sick-listing and faster rehabilitation. This study was conducted in order to
      describe and analyse certification practice of various physician categories,
      before and after the change in legislation. Thirty-one thousand seven hundred and
      thirty certificates for sickness absence, collected by the local offices of the
      National Social Insurance Board in eight Swedish counties, fulfilled the
      inclusion criteria. The number of certificates decreased temporarily. The number
      of certified net days, i.e. crude days multiplied by degree, tended to increase
      and there was no shift from full to partial sick-listing during the period. There
      were small changes regarding case mix, i.e. patient characteristics, and sick
      listing physician category. The results were almost unchanged when these small
      changes were taken into account. General practitioners issued significantly
      shorter periods of sick-leave than the other categories both years. The goals of
      the legislative change were thus not met. The result of the study indicates that
      other factors than the legislation may be more important for physicians'
      practice.

PMID- 12595126
TI  - A perspective on the analysis of credible commitment and myopia in health sector
      decision making.
AB  - This paper examines the role of credible commitment in facilitating long-term
      decision making in health care. Commitments are defined as an undertaking by one
      party to perform a certain task in the future.Policy objectives and political
      imperatives within public sector organisations can often mean that decision
      making takes place on shifting institutional terrain. This creates incentives on
      decision making that favours those choices that yield short-term gains. Such
      myopia is not necessarily consistent with organisational objectives and the
      implementation of policies that promote such objectives. These incentive problems
      can be formally modelled in terms of prisoners' dilemma and co-ordination games.
      Measures that promote public sector organisations to credibly commit to various
      values or policy positions can assist in reconciling individual and
      organisational objectives by allowing decision makers, in good faith, to build
      long-term outcomes into their decision making. In effect they allow co-operation
      and co-ordination. Given these potential gains, credible commitment can occur
      spontaneously but when not, may need to be facilitated by a third party (notably
      the State). Such forms of commitment are usually apparent in various policy
      measures such as health service constitutions, long-term contracting, legislation
      and incentive payments. Measures that secure credible commitment allow the
      discount rate to be reduced on long-term decisions of not only public sector
      organisations but also those stakeholders who rely on stable public sector
      institutions. However, the importance of the notion of commitment needs to be
      recognised against the background of other institutional factors that may
      influence decision making.

PMID- 12595127
TI  - Israelis evaluate their health care system before and after the introduction of
      the national health insurance law.
AB  - This article reports on the evaluation of the Israeli health care system made by
      samples of Israeli Jewish urban citizens aged 45-74 at two points in time: 1993
      and 2000. In 1993, 44% of the population thought that only minor changes were
      needed; 47% stated that fundamental changes were needed, and 9% thought that the
      system should be completely rebuilt. In 2000 the respective percentages were 37,
      49 and 14%. In the 2 years of the survey, 40% thought the health sector should
      receive top national priority in government spending. The findings are analyzed
      with respect to the changes that occurred between 1993 and 2000-in particular,
      the introduction of the National Health Insurance Law (NHIL) in 1995 and
      subsequent related legislation. It is argued that while the NHIL has been an
      important social achievement, its micro-management details and subsequent
      legislation failed to keep up with the public expectations. Similar changes in
      public opinion of health systems occurred over the last decade in several other
      western nations, which reformed their systems. Policy makers should find ways to
      assure that reforms, which might be necessary for a more efficient allocation of
      resources from society's point of view, will also respond to the individuals'
      expectations.

PMID- 12595128
TI  - Should I stay or should I go? Waiting lists and cross-border care in the
      Netherlands.
AB  - The recent ruling of the European Court of Justice in the case Smits-Peerbooms
      explicitly mentions undue delay as a legitimisation for cross-border care within
      the EU. In the Netherlands, waiting times are well above the norm set by several
      health care parties as well as maximally acceptable waiting times elicited in
      patients. This might indicate that Dutch patients are often entitled to care in
      other Member States, in the sense that insurers cannot withhold reimbursement of
      cross-border care in the present situation. However, experiments clearly
      demonstrate that few Dutch patients are willing to travel abroad. Patients seem
      to prefer longer waiting in the Netherlands over shorter waiting by going abroad,
      even those living in border regions. In addition, mobility of patients within the
      Netherlands is very modest. Given this inertia in patient mobility, in the short
      run, cross-border care will probably remain an insignificant phenomenon in terms
      of quantities of patients travelling abroad and therefore the impact of the Smits
      Peerbooms rulings is limited.

PMID- 12595129
TI  - Planning for health sector reform in post-conflict situations: Kosovo 1999-2000.
AB  - The restoration and development of health care systems in post-conflict
      situations and complex emergencies are attracting attention. Kosovo is unique in
      being a post-conflict situation, in a former socialist country, with an unclear
      political future, under temporary UN administration. The World Health
      Organization (WHO) led a process of developing a health policy framework for the
      emergency period that included elements of health sector reform, a somewhat
      controversial initiative. Reform elements of the policy were consistent with
      normative health policies in much of eastern and central Europe. There was
      tension between the need to have a policy in place rapidly and the desire to be
      participatory. Policy to deal with emergency situations that is not available at
      the time required is of limited value. Although there was some tension between
      relief and development agendas, the policy process did direct significant
      resources and effort in directions that contributed to longer-term reform and
      development. A policy framework does not ensure compliance with policy unless
      issues of authority, mandate, and leadership are clear. A rapidly developed
      health policy framework at the onset of an emergency is desirable. Policy
      developers should be experienced, seen as being neutral and be relatively
      independent of any specific donor or interest group. WHO is well situated to play
      this role if it meets certain conditions.

PMID- 12595130
TI  - Workplace violence in Alberta and British Columbia hospitals.
AB  - Workplace violence is a significant and widespread public health concern among
      health care workers, including nurses. With growing awareness of how practice
      environments influence patient outcomes and the retention of health
      professionals, it is timely to consider the impact of workplace violence in
      hospitals. Registered nurses in Alberta and British Columbia, Canada were
      surveyed on their experiences of violence in the workplace over the last five
      shifts. Our results suggest that nurses are experiencing many incidences of
      violence in a given work week, particularly in the emergency, psychiatric, and
      medical-surgical settings. Most violent acts are perpetrated by patients, but
      there is also a significant portion of violence and abuse committed by hospital
      co-workers, particularly emotional abuse and sexual harassment. Our results also
      indicate that the majority of workplace violence is not reported. We suggest that
      using the Broken Windows theory might be a useful tool to conceptualize why
      workplace violence occurs, and that this framework be used to begin to develop
      new violence prevention policies and strategies.

PMID- 12595131
TI  - Health sector regulation in Thailand: recent progress and the future agenda.
AB  - This paper reviews the current system of regulation and assesses its
      effectiveness in the health-care system of Thailand. In order to achieve this,
      extensive documentary reviews were performed and supplemented by in-depth
      interviews. We found the existing regulatory framework to be fairly comprehensive
      with rules and roles firmly established. Regulations cover almost all relevant
      private and public organisations including individuals. However, the incomplete
      performance of regulatory functions was detected resulting in problems of
      overburdened staff and delays in performance of functions. Our recommendations
      propose the promotion of professional ethics and continuing education, an effort
      to narrow the gap between expectation and reality through public education, and
      the empowering of consumer organisations. The increasing popularity of medical
      lawsuits and professional insurance, which in part reflects the imperfect
      administration of the system, highlights the need for careful consideration of
      how best to handle the increase in complaints. The mapping of the regulatory
      system in this paper, together with the discussion of how to cope with the
      expansion of medicine as a business and with greater consumerism, will be of
      interest to other middle income countries that seek to reform and strengthen
      their regulatory system.

PMID- 12595132
TI  - Genetically modified organisms: novel technologies and applications.

PMID- 12595133
TI  - Complex restriction enzymes: NTP-driven molecular motors.
AB  - Survival is assuredly the prime directive for all living organisms either as
      individuals or as a species. One of the main challenges encountered by bacterial
      populations is the danger of bacteriophage attacks, since infection of a single
      bacterium may rapidly propagate, decimating the entire population. In order to
      protect themselves against this acute threat, bacteria have developed an array of
      defence mechanisms, which range from preventing the infection itself via
      interference with bacteriophage adsorption to the cell surface and prevention of
      phage DNA injection, to degradation of the injected phage DNA. This last defence
      mechanism is catalysed by the bacterial restriction-modification (R-M) systems,
      and in particular, by nucleoside 5'-triphosphate (NTP)-dependent restriction
      enzymes, e.g. type I and type III R-M systems or the modification-dependent
      endonucleases. Type I and type III restriction systems have dual properties. They
      may either act as methylases and protect the host's own DNA against restriction
      by methylating specific residues, or they catalyse ATP-dependent endonuclease
      activity so that invading foreign DNA lacking the host-specific methylation is
      degraded. These defence mechanism systems are further complemented by the
      presence of methylation-dependent, GTP-dependent endonucleases, that restricts
      specifically methylated DNA. Although all three types of endonucleases are
      structurally very different, they share a common functional mechanism. They
      recognise and bind to specific DNA sequences but do not cleave DNA within those
      target sites. They belong to the general class of DNA motor proteins, which use
      the free energy associated with nucleoside 5'-triphosphate hydrolysis to
      translocate DNA so that the subsequent DNA cleavage event occurs at a distance
      from the endonuclease recognition site. Moreover, DNA cleavage appears to be a
      random process triggered upon stalling of the DNA translocation process and
      requiring dimerisation of the bound endonucleases for a concerted break of both
      DNA strands. In this review, we present a detailed description and analysis of
      the functional mechanism of the three known NTP-dependent restriction systems:
      type I and type III restriction-modification enzymes, as well as the methylation
      dependent McrBC endonuclease.

PMID- 12595134
TI  - Genetically modified bacteria in agriculture.
AB  - Certain bacteria isolated from soils possess properties that allow them to exert
      beneficial effects on plants either by enhancing crop nutrition or by reducing
      damages caused by pathogens or pests. Some of them, such as rhizobia,
      azospirilla, and agrobacteria, have been traditionally released in fields as seed
      inoculants and they often lead to increases in the yield of different crops while
      the application of others, such as pseudomonads, often fails to give the expected
      results. Bacteria genetically modified to be easily traceable and/or to be
      improved in their expression of beneficial traits have been constructed and
      released with plants in a number of experimental field plots. With these
      releases, it has been possible to monitor the modified inoculant bacteria after
      their introduction in field ecosystems and to assess their impact on the resident
      microflora. Local environmental factors appeared as playing a crucial role in the
      survival and persistence of bacteria once released in fields and in the
      expression of the beneficial traits whether improved or not. The spread of
      inoculant bacteria from their point of dissemination was limited. Transient
      shifts in favour of the released bacteria and in disfavour of some members of the
      bacterial and fungal populations present in the plant rhizosphere might occur
      with certain released bacteria. The changes observed were, however, less
      important than those observed under usual agricultural practices. Gene transfer
      from resident population to introduced bacteria was detected in one case. The
      transconjugants were found only transiently in the phytosphere of plants but not
      in soils. No differences between the survival, spread, persistence in field and
      ecological impacts of genetically modified bacteria and of the corresponding
      unmodified parent strain could be detected.

PMID- 12595135
TI  - Genetically modified lactic acid bacteria: applications to food or health and
      risk assessment.
AB  - Lactic acid bacteria have a long history of use in fermented food products.
      Progress in gene technology allows their modification by introducing new genes or
      by modifying their metabolic functions. These modifications may lead to
      improvements in food technology (bacteria better fitted to technological
      processes, leading to improved organoleptic properties em leader ), or to new
      applications including bacteria producing therapeutic molecules that could be
      delivered by mouth. Examples in these two fields will be discussed, at the same
      time evaluating their potential benefit to society and the possible risks
      associated with their use. Risk assessment and expected benefits will determine
      the future use of modified bacteria in the domains of food technology and health.

PMID- 12595136
TI  - Engineering of non-conventional yeasts for efficient synthesis of macromolecules:
      the methylotrophic genera.
AB  - Methylotrophic yeasts, named after their ability to grow on methanol as the sole
      carbon source, have raised large interest as recombinant protein factories. In
      this review, we explain the basic mechanisms underlying this interest and
      describe the minimal requirements to transform the two genera recognized as
      methylotrophic, Pichia and Candida, into a powerful protein production tool. We
      present a comparison between this group of yeasts and the conventional yeasts
      used as expression system in view of productivity, level of secretion and quality
      of post-translational modifications. Selected examples of recombinant protein
      produced by methylotrophic yeast are also included.

PMID- 12595137
TI  - Between myth and reality: genetically modified maize, an example of a sizeable
      scientific controversy.
AB  - Maize is a major crop plant with essential agronomical interests and a model
      plant for genetic studies. With the development of plant genetic engineering
      technology, many transgenic strains of this monocotyledonous plant have been
      produced over the past decade. In particular, field-cultivated insect-resistant
      Bt-maize hybrids are at the centre of an intense debate between scientists and
      organizations recalcitrant to genetically modified organisms (GMOs). This debate,
      which addresses both safety and ethical aspects, has raised questions about the
      impact of genetically modified (GM) crops on the biodiversity of traditional
      landraces and on the environment. Here, we review some of the key points of maize
      genetic history as well as the methods used to stably transform this cereal. We
      describe the genetically engineered Bt-maizes available for field cultivation and
      we investigate the controversial reports on their impacts on non-target insects
      such as the monarch butterfly and on the flow of transgenes into Mexican maize
      landraces.

PMID- 12595138
TI  - Plant biotechnology in agriculture.
AB  - Knowledge on plant genomes has progressed during the past few years. Two plant
      genomes, those of Arabidopsis thaliana and rice, have been sequenced. Our present
      knowledge of synteny also indicates that, despite plasticity contributing to the
      diversity of the plant genomes, the organization of genes is conserved within
      large sections of chromosomes. In parallel, novel plant transformation systems
      have been proposed, notably with regard to plastid transformation and the removal
      of selectable marker genes in transgenic plants. Furthermore, a number of recent
      works considerably widen the potential of plant biotechnology.

PMID- 12595139
TI  - Transgenic, transplastomic and other genetically modified plants: a Canadian
      perspective.
AB  - Since the mid 1990s, genetically modified (GM) crops have been grown commercially
      in Canada on a scale that has increased steadily over the years. An intense
      debate ensued, as elsewhere, and many fears were expressed regarding not only the
      technology itself but some of the main GM crops being grown. It would seem
      appropriate at this time to examine how these novel crops compare to crops bred
      by more traditional means and what impacts these GM crops have had based on
      experience and not merely on conjecture. To begin, we will put things in a
      historical perspective and recall how domestication and conventional plant
      breeding have shaped the crops of today. Then, we will describe briefly the
      distinctive features of GM plants (obtained so far mainly by nuclear
      transgenesis) and how these novel crops are regulated in Canada. We will then
      give two examples of widely grown GM crops in Canada (insect-resistant corn and
      herbicide-tolerant canola) and examine the main questions that were raised as
      well as the actual impacts these crops have had on the farm. These examples will
      help us outline some of the limitations of the current generation of GM plants
      and, finally, we will try to get a glimpse of the future by examining some recent
      technical developments in the field of recombinant DNA technologies applied to
      plant breeding.

PMID- 12595140
TI  - Techniques for the removal of marker genes from transgenic plants.
AB  - The presence of marker genes encoding antibiotic or herbicide resistances in
      genetically modified plants poses a number of problems. Various techniques are
      under development for the removal of unwanted marker genes, while leaving
      required transgenes in place. The aim of this brief review is to describe the
      principal methods used for marker gene removal, concentrating on the most recent
      and promising innovations in this technology.

PMID- 12595141
TI  - Improvement of drought tolerance in maize: towards the functional validation of
      the Zm-Asr1 gene and increase of water use efficiency by over-expressing C4-PEPC.
AB  - Water availability is one of the major limiting factors for plant growth. Maize
      is particularly sensitive to water stress at reproductive stages with a strong
      impairment of photosynthesis and grain filling. Here, we describe the use of
      genetic transformation first to assess the role of a candidate gene Asr1-a
      putative transcription factor-as an explanation for genetically linked drought
      tolerance Quantitative Trait Loci (QTLs), and second to modify CO(2) fixation
      rates in leaves through changes of C(4) phosphoenolpyruvate carboxylase (C(4)
      PEPC) activity. Transgenic Asr1 over-expressing lines show an increase in foliar
      senescence under drought conditions. The highest C(4)-PEPC overexpressing line
      exhibited an increase (+30%) in intrinsic water use efficiency (WUE) accompanied
      by a dry weight increase (+20%) under moderate drought conditions. Opposite
      effects were observed for transgenic plants under-expressing the corresponding
      proteins. The data presented here indicate the feasibility to increase the level
      of endogenous biochemical activities related to water economy and/or drought
      tolerance, and opens a way to develop maize varieties more tolerant to dry
      growing conditions.

PMID- 12595142
TI  - Animal transgenesis: recent data and perspectives.
AB  - Gene transfer to generate transgenic animals is used more and more to study gene
      regulation and function. It is also an essential tool to prepare pharmaceuticals
      or pig organs for transplantation to humans. It is also expected to be a potent
      way to generate farm animals having traits that cannot emerge by conventional
      selection. During the last few years, the different techniques to generate
      transgenic animals and obtain a well-controlled expression of the transgenes have
      been quite significantly improved. This paper is a brief summary of the most
      recent relevant data in this field.

PMID- 12595143
TI  - Construction of a swine artificial chromosome: a novel vector for transgenesis in
      the pig.
AB  - A de novo SAC was constructed by making use of YAC technology and a humanized
      yeast strain. The construct (about 310 kb) contained pig centromeric DNA and the
      Neo gene. The construct was introduced into a pig cell line by yeast-mammalian
      cell fusion and G418 resistant clones were obtained. One clone was characterized
      by FISH and shown to contain an episomally located microchromosome containing
      YAC, Neo and pig centromere sequences. FISH analysis over time showed that the
      SAC was mitotically stable for at least 34 generations in the absence of
      selection. The size of the SAC was determined by confocal microscopy of the SAC
      and shown to be approximately 7 Mb, which is about 25-fold greater than the size
      of the original YAC. From its behavior in pulsed field gel electrophoresis, FISH
      analysis of stretched DNA fibers, and its appearance under scanning confocal
      microscopy, it was concluded that the SAC is a circularized and multimerized
      derivative of the original YAC. Possible applications as vectors for animal
      transgenesis are discussed.

PMID- 12595144
TI  - Pathways to motor neuron degeneration in transgenic mouse models.
AB  - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder
      characterized by the selective loss of motor neurons. A pathological hallmark of
      both sporadic and familial ALS is the presence of abnormal accumulations of
      neurofilament and peripherin proteins in motor neurons. In the past decade,
      transgenic mouse approaches have been used to address the role of such
      cytoskeletal abnormalities in motor neuron disease and also to unravel the
      pathogenesis caused by mutations in the gene coding for superoxide dismutase 1
      (SOD1) that account for ~20% of familial ALS cases. In mouse models, disparate
      effects could result from different types of intermediate filament (IF)
      aggregates. Perikaryal IF accumulations induced by the overexpression of any of
      the three wild-type neurofilament proteins were quite well tolerated by motor
      neurons. Indeed, perikaryal swellings provoked by NF-H overexpression can even
      confer protection against toxicity of mutant SOD1. Other types of IF aggregates
      seem neurotoxic, such as those found in transgenic mice overexpressing either
      peripherin or an assembly-disrupting NF-L mutant. Moreover, understanding the
      toxicity of SOD1 mutations has been surprisingly difficult. The analysis of
      transgenic mice expressing mutant SOD1 has yielded complex results, suggesting
      that multiple pathways may contribute to disease that include the involvement of
      non-neuronal cells.

PMID- 12595145
TI  - Vectors derived from simian immunodeficiency virus (SIV).
AB  - In contrast to other retroviruses, lentiviruses have the unique property of
      infecting non-proliferating cells. Thus vectors derived from lentiviruses are
      promising tools for in vivo gene delivery applications. Vectors derived from
      human primate and non-primate lentiviruses have recently been described and,
      unlike retroviral vectors derived from murine leukemia viruses, lead to stable
      integration of the transgene into quiescent cells in various organs. Despite all
      the safety safeguards that have been progressively introduced in lentiviral
      vectors, the clinical acceptance of vectors derived from pathogenic lentiviruses
      is subject to debate. It is therefore essential to design vectors derived from a
      wide range of lentivirus types and to comparatively examine their properties in
      terms of transduction efficiency and bio-safety. Here, we review the properties
      of lentiviral vectors derived from simian immunodeficiency virus (SIV).

PMID- 12595146
TI  - Quality control of biotechnology-derived vaccines: technical and regulatory
      considerations.
AB  - Vaccines for human use have been produced for decades using classical
      manufacturing methods including culture of viruses and bacteria followed by
      various concentration-, inactivation-, detoxification-, conjugation production
      processes. Availability of techniques for molecular biology and for the complete
      chemical synthesis of genes provides prospects of genetic engineering of
      microorganisms so as to generate novel biotechnological/biological-derived
      vaccines. The potential large-scale availability of biotechnology-derived
      vaccines makes feasible their evaluation in the prevention and/or treatment of
      various infectious, chronic, degenerative and cancer human diseases. There are
      potential safety concerns that arise from the novel manufacturing processes and
      from the complex structural and biological characteristics of the products. These
      products have distinguishing characteristics to which consideration should be
      given in a well-defined quality control testing programme. The evaluation of
      their quality, safety, efficacy and stability necessitate complex analytical
      methods and appropriate physicochemical, biochemical and immunochemical methods
      for the analysis of the molecular entity. A flexible approach to the control of
      these novel products is being developed by regulatory authorities so that
      recommendations can be modified in the light of experience of research and
      development in vaccinology, production and use of biotechnology products and with
      the further development of new technologies.

PMID- 12595147
TI  - Age-related changes and gender differences in time estimation.
AB  - A study was carried out in which age and gender differences were studied in the
      performance of an empty interval production task. The duration of these intervals
      was 10 s, 1 and 5 min. The sample was made up of 140 subjects, half male and half
      female, in seven different age groups from 8 to 70 years old. The age range
      permitted us to identify when differences begin to be significant. The results
      show an age-related increase in the underproduction of the intervals. The
      differences between age groups attained significance from 51 to 60 years onward.
      With regard to gender, the main result was a greater underproduction of longer
      intervals (1 and 5 min) for women. These findings were interpreted in terms of
      different models of time estimation.

PMID- 12595148
TI  - The effect of prolonged viewing on the recognition of global and local levels of
      hierarchically constructed patterns.
AB  - Two experiments were carried out to examine delays in the recognition of test
      patterns after prolonged (25 s) viewing of an adaptation pattern which was
      composed of either the same or different local components and global structures.
      In the case of geometric patterns that contained a few relatively large elements,
      there were significant delays of about 70 ms in the global decision task when the
      test and adaptation stimuli (TS and AS) were of the same pattern, or when they
      had the same structure but different components. In contrast, in the case of
      geometric patterns that were composed of many relatively small elements, such a
      figural relation between the AS and the TS did not affect the recognition speed
      of the TSs either in the global or in the local decision task. These results
      suggest that prolonged viewing reduces the efficiency of global processing and
      that such a disruptive effect occurs depending upon the number and the relative
      size of the elements that make up the whole pattern.

PMID- 12595149
TI  - Congruency-induced blindness: a cost-benefit analysis.
AB  - Targets are identified more accurately when they are presented during an
      incongruent response (e.g., a left-pointing arrowhead presented during a right
      key press) than during a congruent response (e.g., a left-pointing arrowhead
      presented during a left key press). This effect, referred to here as congruency
      induced blindness, has been hypothesised to result from the occupation of feature
      codes. According to the code occupation hypothesis (Behav. Brain Sci.; J.
      Experim. Psychol.: Human Percept. Perform.; Vis. Cogn., in press), only costs of
      congruency between features of a planned or executed action and a to-be-perceived
      target should be observed; neither costs nor benefits of incongruency are
      predicted by this account. In the present study, we investigated costs and
      benefits in identifying left and right targets directly by manipulating neutral
      response type and the symbols used to cue the neutral response, which produced
      four neutral conditions. Three important results emerged: (1). a significant main
      effect of RSI (suggesting that increasing temporal overlap between a planned
      action and target presentation interferes with perceptual reports of the target),
      (2). a significant main effect of congruency (showing that impairment is code
      specific), and (3). clear-cut costs with little evidence for benefits. Other
      complex patterns of results provided additional information relevant for extant
      theories of perception-action interactions.

PMID- 12595150
TI  - Display-control arrangement correspondence and logical recoding in the Hedge and
      Marsh reversal of the Simon effect.
AB  - When left and right keypresses are made to stimuli in left and right locations,
      and stimulus location is irrelevant to the task, responses are typically faster
      when stimulus location corresponds with response location than when it does not
      (the Simon effect). This effect reverses when the relevant stimulus-response
      mapping is incompatible, with responses being slower when stimulus and response
      locations correspond (the Hedge and Marsh reversal). Simon et al. (Acta Psychol.
      47 (1981) 63) reported an exception to the Hedge and Marsh reversal for a
      situation in which the relevant stimulus dimension was the color of a centered
      visual stimulus and the irrelevant location information was left or right tone
      location. In contrast, similar experiments have found a reversal of the Simon
      effect for tone location when relevant visual locations were mapped incompatibly
      to responses. We conducted four experiments to investigate this discrepancy. Both
      results were replicated. With an incompatible mapping, irrelevant tone location
      showed a small reverse Simon effect when the relevant visual dimension was
      physical location but not when the color of a centered stimulus or the direction
      in which an arrow pointed conveyed the visual location information. The reversal
      occurred in a more standard Hedge and Marsh task in which the irrelevant
      dimension was location of the colored stimulus, but only when the response keys
      were visibly labeled. Several of the results suggest that display-control
      arrangement correspondence is the primary cause of the Hedge and Marsh reversal,
      with logical recoding playing only a secondary role.

PMID- 12595151
TI  - Hemispheric differences in stop task performance.
AB  - This study examined hemispheric specialization for stop task performance. It was
      found that inhibitory performance was better for stop signals presented in the
      right visual field. This result provided support for the hypothesis that, during
      stop task performance, subjects call upon the left-lateralized neural system that
      is involved in active attention. It was suggested that a stop task requires such
      a mode of attention because subjects maintain a tonic readiness for inhibitory
      action while being engaged in the stop task's go routine. Subjects are
      continuously alert for possible stop signals while discriminating between go
      stimuli. The stop task may be considered a typical activation task.

PMID- 12595152
TI  - Effects of acute bouts of exercise on cognition.
AB  - A review was conducted of studies that assessed the effects of acute bouts of
      physical activity on adults' cognitive performance. Three groups of studies were
      constituted on the basis of the type of exercise protocol employed. Each group
      was then evaluated in terms of information-processing theory. It was concluded
      that submaximal aerobic exercise performed for periods up to 60 min facilitate
      specific aspects of information processing; however, extended exercise that leads
      to dehydration compromises both information processing and memory functions. The
      selective effects of exercise on cognitive performance are explained in terms of
      Sanders' [Acta Psychol. 53 (1983) 61] cognitive-energetic model.

PMID- 12595153
TI  - Fas- or FasL-deficient mice display an increased sensitivity to nitrobenzene
      induced testicular germ cell apoptosis.
AB  - We have previously reported that the Fas/Apo-1/CD95-mediated apoptosis-inducing
      signaling system participates in the initiation of toxicant-induced testicular
      germ cell apoptosis. The contribution of Fas-mediated signaling is especially
      evident in the initiation of germ cell apoptosis after mono-(2
      ethylhexyl)phthalate (MEHP)-induced Sertoli cell injury. In previous work, we
      demonstrated that the incidence of germ cell apoptosis after MEHP exposure is
      significantly reduced in B6.SMNC3H-Fas(gld,gld) (gld) mice that express a
      dysfunctional form of the FasL protein (the associated ligand that activates
      Fas). This has led to the hypothesis that activation of the Fas-mediated
      signaling pathway is a common mechanism for the initiation of germ cell apoptosis
      after toxicant-induced Sertoli cell injury. To test this hypothesis, we evaluated
      the sensitivity of testicular germ cells of wild-type, gld- and Fas-deficient
      CBA/KlJms-Tnfrsf6lpr-cg((lpr-cg)) (lpr(cg)) mice to undergo apoptosis after
      exposure to the Sertoli cell toxicant nitrobenzene (NB). Adult, 8-week-old gld
      mice treated with a single oral dose of NB (800 mg/kg) were observed to have a
      higher apoptotic index (AI; 66.1+/-1.3) 24 h after exposure as compared with the
      wild-type C57BL/6 (C57) mice (50.4+/-1.8). Similarly, 8-week-old lpr(cg) mice
      treated with NB displayed a higher AI 24 h after exposure (45.1+/-4.6) as
      compared with the wild-type CBA/KlJms (CBA) mice (32.1+/-3.8). Interestingly,
      exposure of both peri-pubertal 4-week-old C57 and gld mice showed a similar
      increase in the incidence of germ cell apoptosis after NB (600 mg/kg) exposure.
      Taken together, these findings indicate that Fas-mediated signaling is not
      required for NB-induced germ cell apoptosis and imply that a dysfunctional Fas
      signaling system sensitizes adult mice to NB-induced germ cell elimination.

PMID- 12595154
TI  - Xenobiotic inducible regions of the human arylamine N-acetyltransferase 1 and 2
      genes.
AB  - Arylamine N-acetyltransferase (NAT) enzymes catalyze the addition of an acetyl
      group from acetyl-CoA to a terminal nitrogen on a suitable substrate such as
      environmentally relevant compounds and pharmaceuticals. In human, there are two
      highly polymorphic active allozymes, NAT1 and -2, and one inactive pseudogene,
      NATP. The expression of these enzymes is tissue-specific such that NAT1 is
      ubiquitously expressed and NAT2 is confined mainly to liver and colorectal
      tissues. We hypothesized that these genes would be tissue-specifically
      transcriptionally regulated, and so we isolated putative proximal control regions
      for both the NAT genes, which were inserted into luciferase vectors and
      transiently transfected into human liver and bladder cells. The transfected cells
      were dosed with 4-aminosalicylic acid, sulfamethazine or solvent and the
      resulting luciferase activity was measured. We found that both NAT1 and -2
      regions were inducible in liver cells by both xenobiotics but only one of the
      NAT1 regions was inducible again by both xenobiotics in bladder cells. These
      results suggest that the NAT genes may be tissue-specifically transcriptionally
      regulated.

PMID- 12595155
TI  - Binding of nitrobenzene to hepatic DNA and hemoglobin at low doses in mice.
AB  - Nitrobenzene (NB) is a widely used industrial chemical, and is considered a
      hazardous air pollutant. Evidence has recently showed that nitrobenzene is an
      animal carcinogen. We investigated the binding of 14C-NB to hepatic DNA and Hb in
      mice at low doses using an ultrasensitive method of accelerator mass spectrometry
      (AMS). In a dose-response profile, NB-DNA and NB-Hb adduct levels increased with
      increasing administered doses from 0.1 microg/kg b.w. to 10 mg/kg b.w. with a
      good linearity in a log/log presentation. At 2 h after NB administration, NB-DNA
      adduct levels were about twofold greater than that of NB-Hb at all doses. In the
      time course study NB-DNA adduct levels reduced rapidly through an exponential
      decay profile, whereas NB-Hb adducts showed a different decay mode, declining
      rather slowly to low levels. Our findings on the genotoxicity of NB do furnish a
      significant evidence in support of the probable carcinogenic property of NB
      previously reported.

PMID- 12595156
TI  - Correlation of micronuclei-induction with the cell survival in HeLa cells treated
      with a base analogue, azidothymidine (AZT) before exposure to different doses of
      gamma-radiation.
AB  - The effect of 0.1 microM azidothymidine (AZT) a pyrimidine analogue has been
      studied on the growth kinetics, cell survival and micronuclei formation in HeLa
      cells exposed to 0, 0.25, 0.5, 1, 2 and 3 Gy of 60Co gamma-radiation. The AZT
      pretreatment resulted in a significant decline in the cell growth kinetics, cell
      survival and cell proliferation indices when compared with the PBS+irradiation
      group at 20, 30 and 40 h post-irradiation. Conversely, the frequency of
      micronucleated binucleate cells (MNBNC) elevated in a dose dependent manner in
      both PBS+irradiation and AZT+irradiation group. This elevation in MNBNC-induction
      was significantly higher in the latter when compared with the former group at all
      post-irradiation scoring time periods studied. The dose-response relationship for
      micronuclei induction for both the PBS+irrradiation and AZT+irradiation groups
      was linear. The biological response was studied by correlating the cell survival
      with MNBNC-induction. The cell survival and MNBNC-induction showed a close but
      inverse relationship and this relationship gave a best fit on the linear
      quadratic model.

PMID- 12595157
TI  - Inhibition of nitrosodiethylamine-induced hepatocarcinogenesis by dietary
      turmeric in rats.
AB  - Turmeric, widely used in food and medicine has been shown to prevent
      benzo(a)pyrene [B(a)P] or dimethylbenz(a)anthracene (DMBA)-induced forestomach,
      skin and mammary tumors in mice and/or rats. In this study we examine the
      modulatory effects of turmeric on nitrosodiethylamine (NDEA)-induced
      hepatocarcinogenesis in rats. Female Wistar rats were administered NDEA (200 ppm)
      through drinking water (5 days per week) for 4 weeks. Control and/or NDEA-treated
      rats received 0, 0.2, 1.0 or 5.0% turmeric diet (w/w) either before (2 weeks),
      during (4 weeks) and after NDEA exposure (10 weeks) or starting from 24 h after
      NDEA exposure for 10 weeks. NDEA-treated rats receiving 1 or 5% turmeric before,
      during and after carcinogen exposure showed significant decrease in number of
      gamma glutamyl transpeptidase (GGT) positive foci measuring >500 or >1000 microm
      and decrease in the incidence of NDEA-induced focal dysplasia (FD) and
      hepatocellularcarcinomas. Decrease in the number of GGT positive foci measuring
      >1000 microm was also observed in NDEA-treated rats receiving 0.2% turmeric,
      although no decrease in tumor incidence was noted. On the other hand, similar
      levels of turmeric treatment (0.2, 1 and 5%) after exposure to NDEA did not show
      any protective effects. The underlying mechanism(s) of chemoprevention of NDEA
      induced hepatocarcinogenesis need to be explored.

PMID- 12595158
TI  - Mechanisms of the inhibitory effects of selenium and mercury on the activity of
      delta-aminolevulinate dehydratase from mouse liver, kidney and brain.
AB  - Mercury is known to interact with selenite and when the two are co-administered,
      one reduces the toxicity of the other. The main goal of this study was to
      investigate the simultaneous in vitro effects of sodium selenite (Se(4+)) and
      mercuric chloride (Hg(2+)) on the activity of hepatic, renal and cerebral delta
      aminolevulinate dehydratase (delta-ALA-D) of adult male mice (Swiss albino).
      Hg(2+) inhibited delta-ALA-D from tissue supernatants and the IC(50) values for
      hepatic, renal and cerebral enzyme inhibition were 38+/-4.2, 67.5+/-4.3 and
      46.2+/-3.7 microM, respectively. Se(4+) displayed a higher inhibitory action
      toward delta-ALA-D activity than Hg(2+). Simultaneous addition of Se(4+) and
      Hg(2+) to the delta-ALA-D assay increased the inhibition of the enzyme. Se(4+)
      and Hg(2+) oxidized total -SH groups from hepatic, renal and cerebral
      supernatants, although the effect of Se(4+) decreased in the presence of
      increasing concentrations of Hg(2+). The oxidation of -SH groups from a dithiol
      (DTT), a monothiol glutathione (GSH) and a protein (albumin) increased in the
      presence of Hg(2+). Only DTT was oxidized by Se(4+) and the oxidation decreased
      in the presence of Hg(2+), suggesting the formation of a chemical complex. This
      complex did not inhibit delta-ALA-D. These results suggest a similar inhibitory
      mechanism of Se(4+) and Hg(2+) on delta-ALA-D in which oxidation of sulfhydryl
      groups located at the active site of the enzyme is an essential step.
      Furthermore, decreasing oxidative effects of selenite on sulfhydryl groups from
      DTT in the presence of mercury are believed to occur as the result of the
      formation of an inactive ternary complex of the thiol-Hg-Se type, which does not
      inhibit delta-ALA-D.

PMID- 12595159
TI  - Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in
      human and rat hepatoma cell lines.
AB  - Rosiglitazone (RSG), an agonist of peroxisome proliferator-activated receptor
      gamma (PPARgamma), induces minor toxicity in humans relative to another PPARgamma
      agonist, troglitazone (TRO). In contrast, recent reports suggest that RSG causes
      growth arrest and apoptosis of normal and cancerous cells. Therefore, in this
      study, we investigated the relative toxicities of TRO and RSG on three different
      hepatoma cell lines, and observed that TRO, but not RSG, was cytotoxic.
      Additionally, we studied the mechanism by which TRO induced damage to HepG2
      hepatoma cells. Our results indicated that TRO increased the levels of p53, p27,
      and p21, while it reduced the levels of cyclin D1 and phospho-Rb in a time
      dependent manner. Increased p27 and p21 levels coincided with reduced activities
      of cell cycle dependent kinases (cdk) such as cdk2- and cyclin A-protein kinases
      24 h after TRO treatment. These results demonstrate that TRO, but not RSG, causes
      G1 arrest of hepatoma cells, most likely through changing the levels of cell
      cycle regulators. Furthermore, because RSG did not affect the levels of cell
      cycle regulators, TRO-mediated growth inhibition appears independent of PPARgamma
      activation.

PMID- 12595167
TI  - Accumulation and transformation of DSP toxins in mussels Mytilus
      galloprovincialis during a toxic episode caused by Dinophysis acuminata.
AB  - The time course of several outbreaks of the diarrhetic shellfish poisoning (DSP)
      producer Dinophysis acuminata and the consequent kinetic of accumulation and loss
      of toxins in mussels Mytilus galloprovincialis feeding on them was studied.
      Samples of mussels and seawater were frequently (2-3 times a week) collected from
      a raft in the Ri;a de Vigo. DSP toxins content of mussels and water was analyzed
      by HPLC-FD and phytoplankton was quantified in an inverted light microscope. Only
      okadaic acid (OA) and some of its conjugated forms (OA CF), estimated by
      enzymatic hydrolysis, were found in the plankton samples obtained, comprised
      mainly of D. acuminata cells. The main accumulated form in mussels was OA
      reaching a maximum of 10.1 microg OA g(-1) in the digestive gland (d.g.) in 16
      days, falling below the quarantine level (ca. 2 microg OA g(-1) d.g.) by 45 days.
      The low polarity conjugated forms (LPCF), estimated by hexane extraction,
      accounted for 6.2% of the total toxin burden of the mussels. To quantify the
      rates of the processes involved in the accumulation, transformation and loss of
      the toxins, two dynamic models, a one-compartment and a two-compartment,
      including OA and its conjugated forms as variables were designed and implemented.
      The one-compartment model provided a good fit to the OA and LPCF actual data
      (r(2)=0.92 and r(2)=0.94, respectively). The two-compartment model did not fit
      the data markedly better than its one-compartment counterpart (r(2)=0.93 and
      r(2)=0.95, for OA and LPCF, respectively). High hydrolysis rates were estimated
      for most of the OA CF, which means that these forms came largely from the
      ingested plankton. The low estimated acylation rates support the previous point
      and suggest that the formation of LPCF by direct acylation of the OA is of little
      importance in M. galloprovincialis. Only in cases where the intoxication period
      is very long, can the formed acyl-derivatives be important, because they seem to
      accumulate for a long time in the mussels, as suggested by the low hydrolysis and
      depuration rates estimated from model fitting.

PMID- 12595168
TI  - Effects of dissolved metals and other hydrominerals on in vivo intestinal zinc
      uptake in freshwater rainbow trout.
AB  - For aquatic organisms, zinc is both an essential nutrient and an environmental
      contaminant. The intestine is potentially the most important route of zinc
      absorption, yet little is known regarding this uptake pathway for zinc in fish. A
      recently developed in vivo perfusion system was used to investigate the effect of
      luminal composition upon intestinal zinc uptake in freshwater rainbow trout
      (Oncorhynchus mykiss). Perfusate cadmium and copper had specific, yet distinct,
      antagonistic effects upon lumen to tissue zinc movement. Copper significantly
      reduced the proportion of zinc taken up from the perfusate, and concomitantly
      limited the passage of zinc into the circulation and beyond. Conversely, cadmium
      decreased subepithelial zinc accumulation, with rates falling to 29 nmol g(-1) h(
      1) from the control (zinc alone) values of 53 nmol g(-1) h(-1). Calcium had a
      similar action to copper, also reducing post-intestinal zinc accumulation from
      0.06 to 0.02 nmol g(-1) h(-1), an effect attributed to interactions between
      calcium and the zinc uptake pathway. In addition to these effects, luminal
      composition also had a marked influence upon epithelial response to zinc.
      Calcium, copper and magnesium all greatly reduced zinc-induced mucus secretion.
      Cadmium, a toxic metal, significantly increased mucus secretion. It is proposed
      that these modifications were related to the essentiality of each element, and
      their potential mechanisms of uptake. Despite changes at the epithelium, the post
      epithelial accumulation of zinc was dependent mainly upon the nature of the
      competing cation. Intestinal saline ion substitution experiments suggested a
      potential link of potassium ion efflux to zinc uptake. The effect of pH buffering
      of luminal solutions was also investigated.

PMID- 12595169
TI  - Estrogenic effect of dietary 4-tert-octylphenol in rainbow trout (Oncorhynchus
      mykiss).
AB  - The estrogenic effect of dietary 4-tert-octylphenol (octylphenol) in rainbow
      trout Oncorhynchus mykiss was investigated. Octylphenol was administered orally
      to sexually immature rainbow trout every second day for 11 days in doses between
      0.4 and 50 mgkg(-1)2 d(-1). Plasma vitellogenin was measured at day 0, 6 and 11
      and at the end of the experiments, the amounts of octylphenol retained in liver
      and muscle were determined. Increases in average plasma vitellogenin levels were
      seen at exposure to 40 mg octylphenol kg(-1) every second day; the most sensitive
      fish responded to 30 mgkg(-1). Doses below 20 mg octylphenol kg(-1)2 d(-1) had no
      effect. The ED(50) value for induction of vitellogenin synthesis was 35 mg
      octylphenol kg(-1)2 d(-1). Only 1 to 2 per thousand of the total amount of
      octylphenol administered orally over the 11 days experimental period was retained
      in muscle and liver at the end of the experiment. A clear dose-related increase
      was observed for concentrations of octylphenol in both liver and muscle of fish
      exposed to doses between 0.4 and 50 mgkg(-1)2 d(-1). A significant correlation
      was found between the concentrations of octylphenol in the liver and vitellogenin
      level in plasma.

PMID- 12595170
TI  - In vivo metabolism and organ distribution of a branched 14C-nonylphenol isomer in
      pond snails, Lymnaea stagnalis L.
AB  - The branched isomers of p-nonylphenol (NP) are perceived to be more resistant to
      biodegradation in aquatic environments as well as to have more estrogen-like
      toxicity than the straight chain isomers. By use of GC-MS, some of them have been
      identified and found to exist in higher concentrations in the isomeric compound
      mixture than the straight chain isomers. The investigations of the distribution
      and metabolism of these branched isomers in aquatic organisms are therefore
      considered to be important in understanding the mechanisms of toxicity of NP. A
      single tertiary isomer of NP, 4(3'-,6'-dimethyl-3'-heptyl)-phenol, was
      synthesized in the laboratory and used in in vivo studies of its organ
      distribution and metabolism in Lymnaea stagnalis L., following a constant
      exposure of the organisms to 14C-NP isomer in water over a period of 8 days at an
      average exposure concentration of 105 ppb (range: 93-116 ppb). The results
      obtained clearly showed the distribution and bioconcentration of the isomer
      residues in various internal organs of Lymnaea after uptake in water and food.
      Analysis of the extracts of the organ tissues and faeces by HPLC and GC-MS after
      digestion with Pankreatin/beta-glucuronidase and nitric acid, respectively,
      showed that the isomer was metabolized by conjugation to glucuronic acid and
      hydroxylation to a catechol. The findings from these studies and their
      implications in the biotransformation and estrogenicity of NP in Lymnaea
      stagnalis L. are further discussed in detail in this paper.

PMID- 12595171
TI  - Waterborne ethynylestradiol induces vitellogenin and alters metallothionein
      expression in lake trout (Salvelinus namaycush).
AB  - Estrogenic contaminants isolated from waters receiving sewage treatment plant
      effluents are known to induce the egg yolk precursor vitellogenin (VTG) in male
      fish. Levels of the metal binding protein metallothionein (MT) have also been
      shown to be affected by estrogens in fish. It has been postulated that MT
      declines in estrogen exposed fish to facilitate transfer of the essential metal
      Zn to cellular components required for VTG synthesis. To examine the changes in
      MT and VTG concentrations in fish exposed to an estrogen contaminant, lake trout
      (Salvelinus namaycush) were exposed to waterborne ethynylestradiol at 0, 4, 40 or
      400 ng/l(-1) for 21 days. Blood and tissues were collected after 21 days of
      exposure to measure circulating levels of VTG as well as MT concentrations in
      liver and kidney. VTG increased in male and female fish from all three exposure
      groups compared to control fish. MT in liver significantly decreased in males and
      females compared to the controls, in the two highest exposures. MT in kidney was
      significantly higher in both sexes of fish exposed to the two highest
      concentrations of ethynylestradiol. These data are supportive of a relationship
      between estrogen exposure and the regulation of MT. Further studies to examine
      the specific links between estrogen exposure, VTG induction and regulation of
      essential metals like Zn are required.

PMID- 12595172
TI  - Toxicokinetics and biotransformation of p-nitrophenol in red abalone (Haliotis
      rufescens).
AB  - Red abalone (Haliotis rufescens) were exposed to 3.6 microM (0.5 ppm) 14C
      labelled p-nitrophenol (PNP) for 24 h, then were allowed to depurate in clean
      seawater for another 24 h. Absorption, conditional uptake clearance and
      elimination rate constants were 0.12+/-0.04 h(-1), 3.2+/-1.1 ml g(-1) h(-1) and
      0.05+/-0.02 h(-1), respectively. The sigmoidal shape of the PNP uptake curve
      suggests a biphasic process. A whole-organism total concentration factor (TCF) of
      2.37+/-0.07 was determined from equilibrium tissue and water concentrations, with
      the highest concentration of PNP plus metabolites found in gill tissue (11.8+/
      0.2 nmol g(-1), wet weight). Digestive gland, foot muscle and remaining body
      tissues accumulated 8.8+/-0.9, 7.7+/-0.6 and 7.5+/-0.6 nmol g(-1) radiolabelled
      residues, respectively. Abalone depurated 91.6% of absorbed PNP within 24 h, of
      which 87.5+/-3.1% was unmetabolized parent compound, 13.1+/-3.1% was p
      nitrophenylsulfate, 0.32+/-0.09% was p-nitroanisole, and 0.14+/-0.07% was p
      acetamidophenol.

PMID- 12595173
TI  - An in vivo microdialysis method for the qualitative analysis of hepatic phase I
      metabolites of phenol in rainbow trout (Oncorhynchus mykiss).
AB  - Development of reliable and accurate methodologies for determination of
      xenobiotic hepatic biotransformation rate and capacity parameters is important to
      the derivation of precise physiologically-based toxicokinetic (PB-TK) models.
      Biotransformation data incorporated into PB-TK models has, for the most part,
      depended on in vitro techniques designed to mimic the in vivo environment;
      however, data from direct in vitro/in vivo comparisons is limited. In this
      investigation we describe for the first time a method using in vivo microdialysis
      (MD) to qualitatively assess hepatic xenobiotic biotransformation of phenol in an
      unanesthetized fish. MD probes were surgically implanted into the livers of adult
      rainbow trout which were subsequently confined to respirometer-metabolism
      chambers. Phenol (1-300 mM) was delivered directly to the liver via the MD probe
      at a perfusion rate of 1 microl min(-1) which consistently resulted in a relative
      delivery of 77-85% of the phenol in the perfusate to the tissue over a 3 day
      experimental time frame. Location of the probe within the liver was also shown to
      have no effect on the delivery of phenol or on the type or quantity of phase I
      metabolites formed. Production of hydroquinone (HQ) and catechol (CAT), the
      primary phase I metabolites of phenol, was monitored through direct sampling of
      the hepatic extracellular fluid space via the MD probe. HQ and CAT production
      increased with increasing time of perfusion and with increasing concentration of
      phenol delivered to the liver. In the future, data obtained through in vivo MD
      will be useful in resolving uncertainties in biotransformation rate and capacity
      parameters, which are central to fish PB-TK modeling of chemical disposition.

PMID- 12595174
TI  - Evaluation of the toxicological effects of perfluorooctane sulfonic acid in the
      common carp (Cyprinus carpio).
AB  - In the present study we evaluated the toxicological effects of a scarcely
      documented environmental pollutant, perfluorooctane sulfonic acid (PFOS), on
      selected biochemical endpoints in the common carp, Cyprinus carpio. Juvenile
      organisms were exposed to PFOS through a single intraperitoneal injection (liver
      concentrations ranging from 16 to 864 ng/g after 5 days of exposure) and after 1
      and 5 days effects were assessed in liver and serum of the exposed organisms. The
      investigation of the hepatotoxicity of PFOS included the determination of the
      peroxisome proliferating potential (peroxisomal palmitoyl CoA oxidase and
      catalase activity) and the compounds influence on the average DNA basepair length
      (ABPL) by agarose gel electrophoresis. Total antioxidant activity (TAA),
      cholesterol and triglyceride levels were monitored in the serum. After 1 day of
      exposure the ABPL was significantly increased in the 270 and 864 ng/g treatment
      groups. After 5 days of exposure significant increases relative to the control
      were observed for the 16, 270 and 864 ng/g treatment groups. Enzyme leakage from
      the liver was investigated by measurement of alanine aminotransferase (ALT) and
      aspartate aminotransferase (AST) activities in the serum. At 561, 670 and 864
      ng/g PFOS a significant increase in serum ALT activity became apparent after 5
      days of exposure with values ranging from 159 to 407% relative to the control.
      For serum AST activity a significant increase for the 864 ng/g treatment group
      was observed with a value of 112% relative to the control. Determination of the
      polymorphonuclear leukocyte migration into liver tissue as assessed through
      myeloperoxidase (MPO) activity in liver, was used as an indicator for
      inflammation. It appeared that inflammation was not involved in the observed
      membranous enzyme leakage for the 561, 670 and 864 ng/g PFOS treatment groups.
      The results of this study suggest that PFOS induces inflammation-independent
      enzyme leakage through liver cell membranes that might be related to cell
      necrosis. Furthermore, results show that PFOS does not significantly affects
      serum antioxidant levels nor does it clearly induce peroxisome proliferation in
      carp. This study also points out that PFOS might interfere with homeostasis of
      the DNA metabolism. The results of these biochemical analyses were used to
      perform an initial hazard assessment study indicating that PFOS levels observed
      in tissues of wildlife populations could induce a clear rise in serum
      transaminase levels indicative for disruption of hepatocyte membrane integrity.

PMID- 12595175
TI  - A multivariate, spatiotemporal analysis of electromagnetic time-frequency data of
      recognition memory.
AB  - Electromagnetic indices of "fast" (above 12 Hz) oscillating brain activity are
      much more likely to be considerably attenuated by time-averaging across multiple
      trials than "slow" (below 12 Hz) oscillating brain activity. To the extent that
      both types of oscillations represent the activity of temporally and
      topographically separable neural populations, time averaging can cause a loss of
      brain activity information that is important both conceptually and for multimodal
      integration with hemodynamic techniques. To address this issue for recognition
      memory, simultaneous electroencephalography (EEG) and whole-head
      magnetoencephalography (MEG) recordings of explicit word recognition from 11
      healthy subjects were analyzed in two different ways. First, the time course of
      neural oscillations ranging from theta (4.5 Hz) to gamma (42 Hz) frequencies were
      identified using single-trial continuous wavelet transforms. Second, traditional
      analyses of amplitude variations of time-averaged EEG and MEG signals, event
      related potentials (ERPs), and fields (ERFs) were performed and submitted to
      distributed source analyses. To identify data patterns that covaried with the
      difference between correctly recognized studied (old) words and correctly
      rejected nonstudied (new) words, a multivariate statistical tool, partial least
      squares (PLS), was applied to both types of analyses. The results show that ERPs
      and ERFs are mainly displaying those neural indices of recognition memory that
      oscillate in the theta (4.5-7.5 Hz), alpha (8-11.5), and to some extent in the
      beta1 (12-19.5 Hz) frequency range. The sources of the ERPs/ERFs were in good
      agreement with the topography of theta/alpha/beta 1 oscillations in being
      confined to the anterior temporal lobe at 400 ms and being distributed across
      temporal, parietal, and occipital areas between 500 and 700 ms. Gamma
      oscillations covaried either positively or negatively with theta/alpha/beta1
      oscillations. A positive covariance, for instance, was detected over left
      anterior temporal sensors as early as 200-350 ms and is compatible with studies
      in rodents showing that gamma and theta oscillations emerge together out of the
      interaction of the hippocampus and the entorhinal and perirhinal cortices. Fast
      beta oscillations (20-29.5 Hz), on the other hand, did not strongly covary with
      slow oscillations and were likely to arise from neural populations not adequately
      represented in ERPs/ERFs. In summary, by providing a more comprehensive
      description of electromagnetic signals, time-frequency data are of potential
      benefit for integrating electrophysiological and hemodynamic indices of brain
      activity and also for integrating human and animal electrophysiology.

PMID- 12595176
TI  - Deformation-based surface morphometry applied to gray matter deformation.
AB  - We present a unified statistical approach to deformation-based morphometry
      applied to the cortical surface. The cerebral cortex has the topology of a 2D
      highly convoluted sheet. As the brain develops over time, the cortical surface
      area, thickness, curvature, and total gray matter volume change. It is highly
      likely that such age-related surface changes are not uniform. By measuring how
      such surface metrics change over time, the regions of the most rapid structural
      changes can be localized. We avoided using surface flattening, which distorts the
      inherent geometry of the cortex in our analysis and it is only used in
      visualization. To increase the signal to noise ratio, diffusion smoothing, which
      generalizes Gaussian kernel smoothing to an arbitrary curved cortical surface,
      has been developed and applied to surface data. Afterward, statistical inference
      on the cortical surface will be performed via random fields theory. As an
      illustration, we demonstrate how this new surface-based morphometry can be
      applied in localizing the cortical regions of the gray matter tissue growth and
      loss in the brain images longitudinally collected in the group of children and
      adolescents.

PMID- 12595177
TI  - The relationship between changes in intrinsic optical signals and cell swelling
      in rat spinal cord slices.
AB  - Changes in intrinsic optical signals could be related to cell swelling; however,
      the evidence is not compelling. We measured light transmittance, ECS volume
      fraction (alpha), and extracellular K+ in rat spinal cord slices during
      electrical stimulation and the application of elevated potassium, NMDA, or
      anisoosmotic solutions. Dorsal root stimulation (10 Hz/1 min) induced an
      elevation in extracellular K+ to 6-8 mM, a light transmittance increase of 6-8%,
      and a relative ECS volume decrease of less than 5%; all of these changes had
      different time courses. The application of 6 or 10 mM K+ or NMDA (10(-5) M) had
      no measurable effect on alpha, but light transmittance increased by 20-25%. The
      application of 50 or 80 mM K+ evoked a 72% decrease in alpha while the light
      transmittance increase remained as large as that in 6 or 10 mM K+. While the
      change in alpha persisted throughout the 45-min application, light transmittance,
      after peaking in 6-8 min, quickly returned to control levels and decreased below
      them. Astrocytic hypertrophy was observed in 6, 10, and 50 mM K+. The same
      results followed the application of 10(-4) M NMDA or hypotonic solution (160
      mmol/kg). The elevation of extracellular K+ after NMDA application, corresponding
      to increased neuronal activity, had a similar time course as the light
      transmittance changes. Furosemide, Cl(-)-free, or Ca(2+)-free solution blocked or
      slowed down the decreases in alpha, while the light transmittance increases were
      unaffected. In hypertonic solution (400 mmol/kg), alpha increased by 30-40%,
      while light transmittance decreased by 15-20%. Thus, light transmittance changes
      do not correlate with changes in ECS volume but are associated with neuronal
      activity and morphological changes in astrocytes.

PMID- 12595178
TI  - Differential cortical activation during voluntary and reflexive saccades in man.
AB  - A saccade involves both a step in eye position and an obligatory shift in spatial
      attention. The traditional division of saccades into two types, the "reflexive"
      saccade made in response to an exogenous stimulus change in the visual periphery
      and the "voluntary" saccade based on an endogenous judgement to move gaze, is
      supported by lines of evidence which include the longer onset latency of the
      latter and the differential effects of lesions in humans and primates on each. It
      has been supposed that differences between the two types of saccade derive from
      differences in how the spatial attention shifts involved in each are processed.
      However, while functional imaging studies have affirmed the close link between
      saccades and attentional shifts by showing they activate overlapping cortical
      networks, attempts to contrast exogenous with endogenous ("covert") attentional
      shifts directly have not revealed separate patterns of cortical activation. We
      took the "overt" approach, contrasting whole reflexive and voluntary saccades
      using event-related fMRI. This demonstrated that, relative to reflexive saccades,
      voluntary saccades produced greater activation within the frontal eye fields and
      the saccade-related area of the intraparietal sulci. The reverse contrast showed
      reflexive saccades to be associated with relative activation of the angular gyrus
      of the inferior parietal lobule, strongest in the right hemisphere. The frequent
      involvement of the right inferior parietal lobule in lesions causing hemispatial
      neglect has long implicated this parietal region in an important, though as yet
      uncertain, role in the awareness and exploration of space. This is the first
      study to demonstrate preferential activation of an area in its posterior part,
      the right angular gyrus, during production of exogenously triggered rather than
      endogenously generated saccades, a finding which we propose is consistent with an
      important role for the angular gyrus in exogenous saccadic orienting.

PMID- 12595179
TI  - Maintenance versus manipulation in verbal working memory revisited: an fMRI
      study.
AB  - Working memory (WM) is the ability to keep a limited amount of information "on
      line" for immediate use during short intervals. Verbal WM has been hypothesized
      to consist of neuroanatomically segregated components, i.e., maintenance
      (storage, rehearsal, and matching) and manipulation (reordering or updating),
      corresponding to ventrolateral and dorsolateral prefrontal cortex. Previous
      imaging studies of maintenance vs manipulation processes in WM have produced
      inconsistent results, which may have been due to methodological issues such as
      low statistical power and the use of insertion (subtraction) designs. In the
      present functional magnetic resonance imaging study we used parametric versions
      of both a prototypical maintenance task (Sternberg) and a prototypical
      manipulation task (n-letter back task) in 21 healthy subjects. Increased signal
      correlated with load common for both tasks was found in bilateral dorsolateral
      and anterior prefrontal, left ventrolateral prefrontal, and bilateral parietal
      regions. Workload x task interactions were found in bilateral dorsolateral
      prefrontal cortex for manipulation vs maintenance, but also for responding vs
      encoding (storage) in the maintenance task. Therefore, our data support a
      functional rather than a neuroanatomical distinction between maintenance and
      manipulation, given our finding that these tasks differentially activate
      virtually identical systems.

PMID- 12595180
TI  - Dynamic changes in the cerebral metabolic rate of O2 and oxygen extraction ratio
      in event-related functional MRI.
AB  - Dynamic changes in the cerebral metabolic rate of oxygen (CMRO(2)) and oxygen
      extraction ratio (OER) in an event-related functional MRI (ER-fMRI) were measured
      in this study. Six subjects participated in this study at a magnetic field of 1.9
      T. Cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) changes
      were acquired during the brief visual stimulation, and the corresponding changes
      in CMRO(2) and OER were then determined. The results showed that the maximum
      relative changes in CMRO(2) and OER were about 10.36 +/- 0.85 and -6.54 +/-
      0.55%, respectively, while the maximum changes in CBF and BOLD were approximately
      17.35 +/- 1.37 and 1.03 +/- 0.06%, respectively. The CBF, CMRO(2), and OER
      changes reach their maximum approximately 1 s earlier than the BOLD signal change
      (4.15 +/- 0.21, 4.16 +/- 0.21, and 4.17 +/- 0.21 s vs 5.12 +/- 0.24 s after
      stimulation, P < 0.05).

PMID- 12595181
TI  - A region of mesial prefrontal cortex tracks monetarily rewarding outcomes:
      characterization with rapid event-related fMRI.
AB  - The function of the mesial prefrontal cortex (MPFC: including Brodman areas
      10/12/32) remains an enigma. Current theories suggest a role in representing
      internal information, including emotional introspection, autonomic control, and a
      "default state" of semantic processing. Recent evidence also suggests that parts
      of this region may also play a role in processing reward outcomes. In this study,
      we investigated the possibility that a region of the MPFC would be preferentially
      recruited by monetary reward outcomes using a parametric monetary incentive delay
      (MID) task. Twelve healthy volunteers participated in functional magnetic
      resonance scans while playing the MID task. Group analyses indicated that while
      the ventral striatum was recruited by anticipation of monetary reward, a region
      of the MPFC instead responded to rewarding monetary outcomes. Specifically,
      volume-of-interest analyses indicated that when volunteers received $5.00 after
      anticipating a $5.00 win, MPFC activity increased, whereas when volunteers did
      not receive $5.00 after anticipating a $5.00 win, MPFC activity decreased,
      relative to outcomes with no incentive value. These findings suggest that in the
      context of processing monetary rewards, a region of the MPFC preferentially
      tracks rewarding outcomes.

PMID- 12595182
TI  - Left and right occipital cortices differ in their response to spatial cueing.
AB  - We investigated cue and target-related laterality effects with event-related
      fMRI. Both left and right occipital areas responded maximally when both cue and
      target were presented in the contralateral visual hemifield (VF), and minimally
      when cue and target were presented in the ipsilateral VF. However, whereas signal
      increases in right ventromedial and lateral occipital cortex were intermediate in
      those trials in which the cue appeared in the VF contralateral to the target
      (invalid cue trials), signal strength in left occipital cortex was almost
      identical for valid and invalid cues, i.e., high for RVF cues, and low for LVF
      cues, independent of the VF of the target. These data support theories which
      postulate a greater ability of the right hemisphere for bilateral processing.
      However, these laterality effects were observed earlier in the visual pathway
      than previously thought, leading to the question whether the hemispheric
      differences observed in occipital cortex are generated in the activated areas or
      are the effect of reentrant processes from more anterior areas, potentially in
      parietal cortex.

PMID- 12595183
TI  - Neurodevelopmental vulnerability of the corpus callosum to childhood onset
      localization-related epilepsy.
AB  - Recent research has suggested that childhood onset of localization-related
      (focal) temporal lobe epilepsy is associated with a generalized adverse effect on
      cognition and brain structure, especially cerebral white matter volume. This
      study examined the neurodevelopmental impact of childhood onset epilepsy on
      corpus callosum volume and the cognitive consequences of reduced cerebral
      connectivity. Healthy controls (n = 15) and patients with temporal lobe epilepsy
      (n = 32) were matched on gender and handedness, and childhood and adult onset
      epilepsy groups were matched on duration of epilepsy (mean = 19 years) but varied
      in neurodevelopmental age at onset of recurrent seizures. Results showed that
      childhood onset of temporal lobe epilepsy was associated with significant
      volumetric reduction of the corpus callosum compared to both late onset and
      healthy controls, with the latter two groups not differing from one another. The
      volumetric loss was most evident in posterior followed by anterior corpus
      callosum. Volumetric reduction of the corpus callosum in temporal lobe epilepsy
      was of clinical significance with smaller volumes associated with poorer
      performance on measures of nonverbal problem solving, immediate memory, speeded
      complex psychomotor ability and fine motor dexterity. These findings indicate
      that childhood onset of temporal lobe epilepsy is associated with an adverse
      neurodevelopmental impact on brain connectivity which is of clinical consequence
      and theoretical interest.

PMID- 12595184
TI  - Optimization of experimental design in fMRI: a general framework using a genetic
      algorithm.
AB  - This article describes a method for selecting design parameters and a particular
      sequence of events in fMRI so as to maximize statistical power and psychological
      validity. Our approach uses a genetic algorithm (GA), a class of flexible search
      algorithms that optimize designs with respect to single or multiple measures of
      fitness. Two strengths of the GA framework are that (1) it operates with any sort
      of model, allowing for very specific parameterization of experimental conditions,
      including nonstandard trial types and experimentally observed scanner
      autocorrelation, and (2) it is flexible with respect to fitness criteria,
      allowing optimization over known or novel fitness measures. We describe how
      genetic algorithms may be applied to experimental design for fMRI, and we use the
      framework to explore the space of possible fMRI design parameters, with the goal
      of providing information about optimal design choices for several types of
      designs. In our simulations, we considered three fitness measures: contrast
      estimation efficiency, hemodynamic response estimation efficiency, and design
      counterbalancing. Although there are inherent trade-offs between these three
      fitness measures, GA optimization can produce designs that outperform random
      designs on all three criteria simultaneously.

PMID- 12595185
TI  - Separating distractor rejection and target detection in posterior parietal cortex
      -an event-related fMRI study of visual marking.
AB  - Successful survival in a competitive world requires the employment of efficient
      procedures for selecting new in preference to old information. Recent behavioral
      studies have shown that efficient selection is dependent not only on properties
      of new stimuli but also on an intentional bias that we can introduce against old
      stimuli. Event-related analysis of functional magnetic resonance imaging data
      from a task involving visual search across time as well as space indicates that
      the superior parietal lobule is specifically involved in processes leading to the
      efficient segmentation of old from new items, whereas the temporoparietal
      junction area and the ascending limb of the right intraparietal sulcus are
      involved in the detection of salient new items and in response preparation. The
      study provides evidence for the functional segregration of brain regions within
      the posterior parietal lobe.

PMID- 12595186
TI  - Modulating the experience of agency: a positron emission tomography study.
AB  - This study investigated agency, the feeling of being causally involved in an
      action. This is the feeling that leads us to attribute an action to ourselves
      rather than to another person. We were interested in the effects of
      experimentally modulating this experience on brain areas known to be involved in
      action recognition and self-recognition. We used a device that allowed us to
      modify the subject's degree of control of the movements of a virtual hand
      presented on a screen. Four main conditions were used: (1) a condition where the
      subject had a full control of the movements of the virtual hand, (2) a condition
      where the movements of the virtual hand appeared rotated by 25 degrees with
      respect to the movements made by the subject, (3) a condition where the movements
      of the virtual hand appeared rotated by 50 degrees, and (4) a condition where the
      movements of the virtual hand were produced by another person and did not
      correspond to the subject's movements. The activity of two main brain areas
      appeared to be modulated by the degree of discrepancy between the movement
      executed and the movement seen on the screen. In the inferior part of the
      parietal lobe, specifically on the right side, the less the subject felt in
      control of the movements of the virtual hand, the higher the level of activation.
      A reverse covariation was observed in the insula. These results demonstrate that
      the level of activity of specific brain areas maps onto the experience of causing
      or controlling an action. The implication of these results for understanding
      pathological conditions is discussed.

PMID- 12595187
TI  - Differential effects of low-frequency rTMS at the occipital pole on visual
      induced alpha desynchronization and visual-evoked potentials.
AB  - Visual-induced alpha desynchronization (VID) and visual-evoked potentials (VEPs)
      characterize occipital activation in response to visual stimulation but their
      exact relationship is unclear. Here, we tested the hypothesis that VID and VEPs
      reflect different aspects of cortical activation. For this purpose, we determined
      whether VID and VEPs are differentially modulated by low-frequency repetitive
      transcranial magnetic stimulation (rTMS) over the occipital pole. Scalp EEG
      responses to visual stimuli (flashed either to the left or to the right visual
      field) were recorded for 8 min in six healthy subjects (1) before, (2)
      immediately following, and (3) 20 min after left occipital rTMS (1 Hz, 10 min).
      The parameters aimed to reduce cortical excitability beyond the end of the TMS
      train. In addition, simple reaction times to visual stimulation were recorded
      (left or right hand in separate blocks). In all subjects, VID was significantly
      and prominently reduced by rTMS (P = 0.0001). In contrast, rTMS failed to
      modulate early VEP components (P1/N1). A moderate effect was found on a late VEP
      component close to manual response onset (P = 0.014) but this effect was in the
      opposite direction to the VID change. All changes were restricted to the targeted
      left occipital cortex. The effects were present only after right visual field
      stimulation when a right hand response was required, were associated with a
      behavioral effect, and had washed out 20 min after rTMS. We conclude that VID and
      early VEPs represent different aspects of cortical activation. The findings that
      rTMS did not change early VEPs and selectively affected VID and late VEPs in
      conditions where the visual input must be transferred intrahemispherically for
      visuomotor integration (right visual field/right hand) are suggestive of rTMS
      interference with higher-order visual functions beyond visual input. This is
      consistent with the idea that alpha desynchronization serves an integrative role
      through a corticocortical "gating function."

PMID- 12595188
TI  - From diffusion tractography to quantitative white matter tract measures: a
      reproducibility study.
AB  - The aim of this study is to propose methods for assessing the reproducibility of
      diffusion tractography algorithms in future clinical studies and to show their
      application to the tractography algorithm developed in our unit, fast marching
      tractography (FMT). FMT estimates anatomical connectivity between brain regions
      using the information provided by diffusion tensor imaging. Three major white
      matter pathways were investigated in 11 normal subjects--anterior callosal
      fibers, optic radiations, and pyramidal tracts. FMT was used to generate maps of
      connectivity metric, and regions of voxels with highest connectivity metric to an
      anatomically defined starting point were identified for each tract under
      investigation. The reproducibilities of tract-"normalized" volume (NV) and
      fractional anisotropy (FA) measurements were assessed over such regions. The
      values of tract volumes are consistent with the postmortem data. Coefficients of
      variation (CVs) for FA and NV ranged from 1.7 to 7.1% and from 2.2 to 18.6%,
      respectively. CVs were lowest in the anterior callosal fibers (range: 1.7- 7.8%),
      followed by the optic radiations (range: 1.2-18.6%) and pyramidal tracts (range:
      2.6-15.5%), suggesting that fiber organization plays a role in determining the
      level of FMT reproducibility. In conclusion, these findings underline the
      importance of assessing the reliability of diffusion tractography before
      investigating white matter pathology.

PMID- 12595189
TI  - Brain tissue volume changes in relapsing-remitting multiple sclerosis:
      correlation with lesion load.
AB  - The aim of this study was to simultaneously measure in vivo volumes of gray
      matter (GM), normal white matter (WM), abnormal white matter (aWM), and cerebro
      spinal fluid (CSF), and to assess their relationship in 50 patients with
      relapsing-remitting multiple sclerosis (RR-MS) (age range, 21-59; mean EDSS, 2.5;
      mean disease duration, 9.9 years), using an unsupervised multiparametric
      segmentation procedure applied to brain MR studies. Tissue volumes were
      normalized to total intracranial volume providing corresponding fractional
      volumes (fGM, faWM, fWM, and fCSF), subsequently corrected for aWM-related
      segmentation inaccuracies and adjusted to mean patients' age according to age
      related changes measured in 54 normal volunteers (NV) (age range 16-70). In MS
      patients aWM was 23.8 +/- 29.8 ml (range 0.4-138.8). A significant decrease in
      fGM was present in MS patients as compared to NV (49.5 +/- 3.2% vs 53.3 +/- 2.1%;
      P < 0.0001), with a corresponding increase in fCSF (13.0 +/- 3.8% vs 9.1 +/-
      2.4%; P < 0.0001). No difference could be detected between the two groups for fWM
      (37.5 +/- 2.6% vs 37.6 +/- 2.2%). faWM correlated inversely with fGM (R = -0.434,
      P < 0.001 at regression analysis), and directly with fCSF (R = 0.473, P < 0.001),
      but not with fWM. There was a significant correlation between disease duration
      and EDSS, while no relationship was found between EDSS or disease duration and
      fractional volumes. Brain atrophy in RR-MS is mainly related to GM loss, which
      correlates with faWM. Both measures do not appear to significantly affect EDSS,
      which correlates to disease duration.

PMID- 12595190
TI  - Frontostriatal system in planning complexity: a parametric functional magnetic
      resonance version of Tower of London task.
AB  - In the present study, we sought to investigate which brain structures are
      recruited in planning tasks of increasing complexity. For this purpose, a
      parametric self-paced pseudo-randomized event-related functional MRI version of
      the Tower of London task was designed. We tested 22 healthy subjects, enabling
      assessment of imaging results at a second (random effects) level of analysis.
      Compared with baseline, planning activity was correlated with increased blood
      oxygenation level-dependent (BOLD) signal in the dorsolateral prefrontal cortex,
      striatum, premotor cortex, supplementary motor area, and visuospatial system
      (precuneus and inferior parietal cortex). Task load was associated with increased
      activity in these same regions. In addition, increasing task complexity was
      correlated with activity in the left anterior prefrontal cortex, a region
      supposed to be specifically involved in third-order higher cognitive functioning.

PMID- 12595191
TI  - Magnetic resonance imaging of changes elicited by status epilepticus in the rat
      brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and
      direct correlation with tissue and cell damage.
AB  - The rat brain was investigated with structural and functional magnetic resonance
      imaging (MRI) 12 h after the arrest of pilocarpine-induced status epilepticus
      lasting 4 h. Histopathological data, obtained immediately after MRI analysis,
      were correlated with the images through careful evaluation of tissue shrinkage.
      Diffusion-weighted and T2-weighted imaging showed changes throughout the cerebral
      cortex, hippocampus, amygdala, and medial thalamus. However, only T2-weighted
      imaging, based on rapid acquisition relaxation-enhanced sequences, revealed in
      the cortex inhomogeneous hyperintensity that was highest in a band corresponding
      to layer V. Regional cerebral blood volume (rCBV) maps were generated using T2*
      weighted gradient-echo images and an ultrasmall superparamagnetic iron oxide
      contrast agent. In the cortex, rCBV peaked in superficial and deep bands
      exhibiting a distribution complementary to the highest T2-weighted intensity.
      Selective rCBV increase was also documented in the hippocampus and subcortical
      structures. In tissue sections, alterations indicative of marked edema were found
      with Nissl staining in areas corresponding to the highest T2-weighted intensity.
      Degenerating neurons, revealed by FluoroJadeB histochemistry, were instead
      concentrated in tissue exhibiting hyperperfusion in rCBV maps, such as
      hippocampal subfields and dentate gyrus, cortical layers II/III and VI, and
      medial thalamus. The data indicate that:(i) T2-weighted imaging provides a
      sensitive tool to investigate edematous brain alterations that follow sustained
      seizures; (ii) rCBV maps reveal regional hyperperfusion; (iii) rCBV peaks in
      tissue exhibiting marked neurodegeneration, which may not be selectively revealed
      by structural MRI. The findings provide an interpretation of the brain response
      to sustained seizures revealed in vivo by different strategies of MRI analysis.

PMID- 12595192
TI  - Single-shot T(2)* mapping with 3D compensation of local susceptibility gradients
      in multiple regions.
AB  - Macroscopic magnetic field inhomogeneities severely limit sensitivity of blood
      oxygenation level-dependent (BOLD) functional MRI (fMRI) in frontal and central
      brain regions close to brain stem. A single-shot multiecho echo-planar imaging
      method (TurboPEPSI) was developed that combines quantitative T(2)* mapping with
      gradient compensation of local susceptibility inhomogeneities in multiple volumes
      of interest (VOIs). Gradient compensation was optimized in individual subjects
      based on magnetic field mapping and applied at selected echo times, interleaved
      with acquisition of uncompensated echoes. Intrinsic T(2)* values from
      uncompensated echoes were obtained in real-time simultaneously with effective
      T(2)* values from gradient compensated echoes. It is demonstrated that up to
      three VOIs can be compensated in a single excitation, in addition to collecting
      uncompensated data, using 8-echo acquisition on a clinical 1.5 Tesla scanner. A
      theory was developed to optimize the sequence of uncompensated and compensated
      echoes to achieve maximum BOLD sensitivity. Gradient compensation increased
      effective T(2)* values in left and right amygdala on average by 18.8 +/- 7.5 ms,
      while maintaining sensitivity in uncompensated brain areas. In orbitofrontal
      cortex effective T(2)* values increased by 22.2 +/- 5.3 ms. A CO(2) challenge
      paradigm was used to demonstrate that this gradient compensation method
      significantly enhances BOLD signal changes in amygdala as compared to
      conventional echo-planar imaging (EPI) and uncompensated TurboPEPSI.

PMID- 12595193
TI  - "Change the mind and you change the brain": effects of cognitive-behavioral
      therapy on the neural correlates of spider phobia.
AB  - Questions pertaining to the neurobiological effects of psychotherapy are now
      considered among the most topical in psychiatry. With respect to this issue,
      positron emission tomography (PET) findings indicate that cognitive and
      behavioral modifications, occurring in a psychotherapeutic context, can lead to
      regional brain metabolic changes in patients with major depression or obsessive
      compulsive disorder. The goal of the present functional magnetic resonance
      imaging (fMRI) study, which constitutes the first neuroimaging investigation of
      the effects of cognitive-behavioral therapy (CBT) using an emotional activation
      paradigm, was to probe the effects of CBT on the neural correlates of spider
      phobia. In order to do so, fMRI was used in subjects suffering from spider phobia
      (n = 12) to measure, before and after effective CBT, regional brain activity
      during the viewing of film excerpts depicting spiders. Normal control subjects
      were also scanned (once) while they were exposed to the same film excerpts.
      Results showed that, in phobic subjects before CBT, the transient state of fear
      triggered, during the viewing of the phobogenic stimuli, was correlated with
      significant activation of the right dorsolateral prefrontal cortex (Brodmann area
      BA 10), the parahippocampal gyrus, and the visual associative cortical areas,
      bilaterally. For normal control subjects (n = 13), only the left middle occipital
      gyrus and the right inferior temporal gyrus were significantly activated. In
      phobic subjects before CBT, the activation of the dorsolateral prefrontal cortex
      (BA 10) may reflect the use of metacognitive strategies aimed at self-regulating
      the fear triggered by the spider film excerpts, whereas the parahippocampal
      activation might be related to an automatic reactivation of the contextual fear
      memory that led to the development of avoidance behavior and the maintenance of
      spider phobia. After successful completion of CBT, no significant activation was
      found in the dorsolateral prefrontal cortex (BA 10) or the parahippocampal gyrus.
      These findings suggest that a psychotherapeutic approach, such as CBT, has the
      potential to modify the dysfunctional neural circuitry associated with anxiety
      disorders. They further indicate that the changes made at the mind level, within
      a psychotherapeutic context, are able to functionally "rewire" the brain.

PMID- 12595194
TI  - Brain activation using triggered event-related fMRI.
AB  - EEG-triggered fMRI provides a method for localizing the sources of brain
      electrical activity, such as epileptic discharges. Extending single-image
      acquisitions, following an event on the EEG, into triggered image series
      acquisitions may allow BOLD time courses to be obtained, such as those observed
      in event-related (ER) fMRI experiments. However, in contrast to the standard ER
      fMRI, triggered image series are greatly affected by magnetization non-steady
      state effects. The purpose of this paper is to show that the BOLD responses can
      be recovered using subtraction between two triggered image series having
      different functional contrasts. In order to evaluate this technique, a comparison
      with standard ER-fMRI using motor cortex activation task was made in 5
      volunteers. We conclude that this can be a useful technique for studying brain
      activation associated with irregularly appearing stimuli.

PMID- 12595195
TI  - Echogenicity of the substantia nigra in relatives of patients with sporadic
      Parkinson's disease.
AB  - Increased echogenicity of the substantia nigra (SN) on ultrasound is a typical
      sonographic finding in Parkinson's disease (PD). Sonographic signal intensity of
      the SN is related to tissue iron content with higher iron level being associated
      with increased echogenicity. Recent findings indicate that hyperechogenicity of
      the SN represents an important susceptibility factor for nigrostriatal
      degeneration. In this study we determined the prevalence of a characteristic
      ultrasound sign of Parkinson's disease in first-degree relatives of PD patients.
      Fourteen patients with sporadic PD and 58 of their relatives underwent
      neurological, neuropsychological, and ultrasound examination. In addition, four
      pairs of relatives (one member of each pair exhibiting increased echogenicity of
      the SN and the other with regular SN echogenicity) underwent (18)F-Dopa PET
      examination. On transcranial sonography, 26 of the 58 relatives exhibited SN
      hyperechogenicity. Twenty-four relatives showed minor signs of motor slowing.
      Relatives with SN hyperechogenicity more often showed signs of hypokinesia (16 v
      8 relatives; U test, P = 0.01) and impaired executive functions (Tower of London
      task, problems solved with the minimum number of moves; U test, P = 0.012) than
      relatives without this echo pattern. In addition, (18)F-Dopa uptake (influx
      constants) at the putamen was reduced in subjects with SN hyperechogenicity
      compared to their relatives without this ultrasound sign (Wilcoxon, P = 0.03). In
      conclusion, approximately 45% of relatives of PD patients exhibited an increased
      echogenicity of the SN. This sign is associated with clinical findings and
      objective measurements, indicating some degree of impaired nigrostriatal
      function.

PMID- 12595196
TI  - Quantitative fMRI assessment of the differences in lateralization of language
      related brain activation in patients with temporal lobe epilepsy.
AB  - Defining language lateralization is important to minimize morbidity in patients
      treated surgically for temporal lobe epilepsy (TLE). Functional magnetic
      resonance imaging (fMRI) offers a promising, noninvasive, alternative strategy to
      the Wada test. Here we have used fMRI to study healthy controls and patients with
      TLE in order to (i) define language-related activation patterns and their
      reproducibility; (ii) compare lateralization determined by fMRI with those from
      of the Wada test; and (iii) contrast different methods of assessing fMRI
      lateralization. Twelve healthy right-handed controls and 19 right-handed
      preoperative patients with TLE (12 left- and seven right-TLE) were studied at 3T
      using fMRI and a verbal fluency paradigm. A Wada test also was performed on each
      of the patients. Greater activation was found in several areas in the right
      hemisphere for the left-TLE group relative to controls or right-TLE patients.
      Relative hemispheric activations calculated based on either the extent or the
      mean signal change gave consistent results showing a more bihemispheric language
      representation in the left-TLE patients. There was good agreement between the
      Wada and fMRI results, although the latter were more sensitive to involvement of
      the nondominant right hemisphere. The reproducibility of the fMRI values was
      lowest for the more bihemispherically represented left-TLE patients. Overall, our
      results further demonstrate that noninvasive fMRI measures of language-related
      lateralization may provide a practical and reliable alternative to invasive
      testing for presurgical language lateralization in patients with TLE. The high
      proportion (33%) of left-TLE patients showing bilateral or right hemispheric
      language-related lateralization suggests that there is considerable plasticity of
      language representation in the brains of patients with intractable TLE.

PMID- 12595197
TI  - Emotional context modulates subsequent memory effect.
AB  - Emotions have been shown to modulate memory processes. However, the neuronal
      substrate underlying these modulatory effects is largely unknown. Using event
      related functional magnetic resonance imaging (fMRI), we investigated whether the
      context of emotional encoding modulates brain activation predictive for
      subsequent recall of emotionally neutral material. While inferior frontal
      activation predicted recall in general, our data show that in a positive encoding
      context, recall was predicted by activation of right anterior parahippocampal and
      extrastriate visual brain areas, whereas in a negative encoding context, recall
      was predicted by activation of the amygdala. Thus, we could demonstrate that
      successful episodic encoding is differentially modulated by emotional context.
      These results contribute to the understanding of the interaction of emotion and
      cognition and moreover are of general relevance for studies of episodic memory.

PMID- 12595198
TI  - Differential brain activation patterns during perception of voice and tone onset
      time series: a MEG study.
AB  - Evoked magnetic fields were recorded from 18 adult volunteers using
      magnetoencephalography (MEG) during perception of speech stimuli (the endpoints
      of a voice onset time (VOT) series ranging from /ga/ to /ka/), analogous
      nonspeech stimuli (the endpoints of a two-tone series varying in relative tone
      onset time (TOT), and a set of harmonically complex tones varying in pitch.
      During the early time window (approximately 60 to approximately 130 ms post
      stimulus onset), activation of the primary auditory cortex was bilaterally equal
      in strength for all three tasks. During the middle (approximately 130 to 800 ms)
      and late (800 to 1400 ms) time windows of the VOT task, activation of the
      posterior portion of the superior temporal gyrus (STGp) was greater in the left
      hemisphere than in the right hemisphere, in both group and individual data. These
      asymmetries were not evident in response to the nonspeech stimuli. Hemispheric
      asymmetries in a measure of neurophysiological activity in STGp, which includes
      the supratemporal plane and cortex inside the superior temporal sulcus, may
      reflect a specialization of association auditory cortex in the left hemisphere
      for processing speech sounds. Differences in late activation patterns potentially
      reflect the operation of a postperceptual process (e.g., rehearsal in working
      memory) that is restricted to speech stimuli.

PMID- 12595199
TI  - Functional MR imaging in assessment of language dominance in epileptic patients.
AB  - The value of functional MR Imaging (fMRI) in assessing language lateralization in
      epileptic patients candidate for surgical treatment is increasingly recognized.
      However few data are available for left-handed patients. Moreover determining
      factors for atypical dominance in patients investigated with contemporary imaging
      have not been reported. We studied 20 patients (14 males, 6 females; 9 right
      handed, 11 left handed) aged from 9 to 48 years, investigated for intractable
      partial epilepsy. Epileptic focus location was temporal in 14 cases,
      extratemporal in 6, and lateralized in the left hemisphere in 11/20. Hemispheric
      dominance for language was evaluated by both Wada test and fMRI using a silent
      word generation paradigm in all patients. Furthermore, a postictal speech test
      was performed in 15 patients. An fMRI language lateralization index was
      calculated from the number of activated pixels (Student's t test, P < 0.0001) in
      the right and left hemispheres. The Wada test showed a right hemispheric
      dominance in 8 patients (6 were left handed and 2 right handed) and a left
      hemispheric dominance in 12 patients (5 were left handed and 7 right handed).
      These results were concordant with clinical postictal examination in 11/15
      patients (73%). Clinical status did not allow a conclusion about hemispheric
      dominance for the remaining 4 patients. FMRI was concordant with the Wada test in
      19/20 cases. For one left-handed patient, fMRI showed bilateral activation,
      whereas the Wada test demonstrated a right hemispheric dominance. Right language
      lateralization was significantly correlated with left lateralized epilepsy (P <
      0.05) but was not correlated with age at epilepsy onset, early brain injury
      (before 6 years), and lobar localization of epileptogenic focus. However the lack
      of a significant relationship between these factors and atypical language
      lateralization may be related to the small sample size.

PMID- 12595200
TI  - Reproducibility of the word frequency effect: comparison of signal change and
      voxel counting.
AB  - We determined the reproducibility of both the direction and the effect size of
      the word frequency effect (WFE) as it relates to associative semantic judgments.
      Sixteen volunteers were scanned twice. At the group level of analysis, signal
      change and voxel counting could both reproducibly detect the existence of a WFE.
      However, signal change data showed less intersession variation, particularly in
      the left inferior frontal gyrus. The effect size of WFE was well reproduced only
      with signal change measurements. In consideration of the signal change data,
      statistical threshold did not have a major effect on the detection or
      determination of the effect size. In general, while the direction of the WFE was
      reasonably reproducible at the individual level, the effect size was far less
      well reproduced. These findings suggest that with existing techniques, fMRI may
      be used to track changes in brain activation stemming from improvement in
      language proficiency at the group level but not at the individual level.

PMID- 12595201
TI  - Practice-related effects demonstrate complementary roles of anterior cingulate
      and prefrontal cortices in attentional control.
AB  - The purpose of this study was to test the hypothesis that the dorsolateral
      prefrontal cortex (DLFPC), not the anterior cingulate cortex (ACC), plays the
      predominant role in implementing top-down attentional control. To do so, we used
      fMRI to examine practice-related changes in neural activity during a variant of
      the Stroop task. The results indicated that the DLPFC's activity decreased
      gradually as the need for control was reduced (as indexed by behavioral
      measures), while the ACC's activity dropped off rapidly. Such a pattern is
      consistent with the DLPFC taking a leading role in implementing top-down
      attentional control and the ACC being involved in other aspects of attentional
      control, such as response-related processes. In addition, with practice, there
      was a reduction in activity within cortical systems handling the processing of
      task-irrelevant information capable of interfering with task performance. This
      finding suggests that with practice the brain is capable of identifying and
      strategically inhibiting such processing.

PMID- 12595202
TI  - Estimation of FMRI response delays.
AB  - We present an efficient algorithm using the Hilbert Transform for estimating the
      delay of the BOLD response to neuronal stimulation. With minimal additional
      computations, the algorithm estimates parameters generated in the widely used
      cross-correlation method and simplifies the interpolation required to estimate
      the response delay from the cross-correlation function. We examined errors in the
      Hilbert-based delay estimate associated with the use of DFT on short-duration
      discrete signals and proposed a method for minimizing these errors. Furthermore,
      we compared the delay estimates obtained with the Hilbert method to those
      obtained using the onset of the BOLD response. The Hilbert method resulted in
      less variance in the delay estimate despite the potential for higher variability
      in the latter part of the BOLD response. This improved delay estimate was
      attributed to the reduced sensitivity of the Hilbert method to noise
      contamination compared to the onset method.

PMID- 12595203
TI  - Comparison of MR imaging against physical sectioning to estimate the volume of
      human cerebral compartments.
AB  - The purpose of this study was to compare magnetic resonance imaging (MRI) against
      physical sectioning techniques to estimate the volume of human cerebral
      hemisphere compartments (cortex, subcortex, and their union, called "total"). The
      volume of these compartments was estimated postmortem for six human subjects from
      MRI virtual sections and from physical sections using the Cavalieri design with
      point counting. Cursory paired t tests revealed no significant differences
      between the two methods for any of the three compartments considered, although P
      = 0.06 for the subcortex. A sharper analysis incorporating recent error
      prediction formulae revealed a significant discrepancy between the two methods in
      the estimation of subcortex and total volume for three of the specimens. Yet,
      none of these analyses is adequate to detect possible biases. The incorporation
      of an explanatory variable, namely hemisphere weight, and the adoption of a
      specific gravity rho = 1.04 g/cm(3) for the material, enabled us to carry out an
      allometric analysis for the total compartment which revealed a significant bias
      of the MRI data. The new error prediction formulae are illustrated by way of
      example, and their accuracy is checked by a resampling experiment on a data set
      of 274 MRI sections.

PMID- 12595204
TI  - Differential modulation of subcortical target and cortex during deep brain
      stimulation.
AB  - The combination of electrical deep brain stimulation (DBS) with functional
      imaging offers a unique model for tracing brain circuitry and for testing the
      modulatory potential of electrical stimulation on a neuronal network in vivo. We
      therefore applied parametric positron emission tomography (PET) analyses that
      allow characterization of rCBF responses as linear and nonlinear functions of the
      experimentally modulated stimulus (variable stimulator setting). In patients with
      electrodes in the thalamic ventrointermediate nucleus (VIM) for the treatment of
      essential tremor (ET) here we show that variations in voltage and frequency of
      thalamic stimulation have differential effects in a thalamo-cortical circuitry.
      Increasing stimulation amplitude was associated with a linear raise in rCBF at
      the thalamic stimulation site, but with a nonlinear rCBF response in the primary
      sensorimotor cortex (M1/S1). The reverse pattern in rCBF changes was observed
      with increasing stimulation frequency. These results indicate close connectivity
      between the stimulated nucleus (VIM) and primary sensorimotor cortex. Likewise,
      stimulation parameter-specific modulation occurs at this simple interface between
      an electrical and a cerebral system and suggests that the scope of DBS extends
      beyond an ablation-like on-off effect: DBS could rather allow a gradual tuning of
      activity within a neuronal circuit.

PMID- 12595205
TI  - Early diagnosis of Alzheimer's disease: contribution of structural neuroimaging.
AB  - To accurately predict the development of Alzheimer's disease (AD) at its
      predementia stage would be a major breakthrough from both therapeutic and
      research standpoints. In this review, our focus is on markers obtained with
      structural imaging--especially magnetic resonance imaging (MRI)--and on studies
      of subjects at risk of developing AD. Among the latter, amnestic mild cognitive
      impairment (MCI) is currently the most commonly accepted reference, and therefore
      is specially targeted in this review. MCI refers to patients with significant but
      isolated memory impairment relative to subjects of identical age. Consistent with
      established histopathological data, structural imaging studies comparing patients
      with early probable AD to healthy aged subjects have shown that the most specific
      and sensitive features of AD at this stage are hippocampal and entorhinal cortex
      atrophy, especially when combined with a reduced volume of the temporal
      neocortex. MCI patients have significant hippocampal atrophy when compared to
      aged normal controls. When comparing patients with probable AD to MCI subjects,
      hippocampal region atrophy significantly extends to the neighboring temporal
      association neocortex. However, only longitudinal studies of MCI subjects are
      suited to assess (in a retrospective way) the predictive value of initial atrophy
      measurements for progression to AD. Few such studies have been published so far
      and for the most they were based on small samples. Furthermore, the comparison
      among studies is clouded by differences in both populations studied and MRI
      methodology used. Nevertheless, comparing the initial MRI data of at-risk
      subjects who convert to AD at follow-up to those of nonconverters suggests that a
      reduced association temporal neocortex volume combined with hippocampal or
      anterior cingulate cortex atrophy may be the best predictor of progression to AD.
      These data, although still preliminary, are consistent with postmortem studies
      describing the hierarchical progression of tau lesions in normal aging and early
      stages of AD, such that damage to the medial temporal lobe and association cortex
      would account for the memory and nonmemory cognitive impairments, respectively,
      the combination of which is required to operationally define probable AD. Future
      research in this field should capitalize on thorough methodology for brain
      structure delineation, and combine atrophy measurements to cognitive and/or
      functional imaging data.

PMID- 12595206
TI  - Objects and their actions: evidence for a neurally distributed semantic system.
AB  - An influential model of conceptual knowledge claims that objects are represented
      in a distributed network of cortical areas that store information about different
      types of attributes, such as form, colour, and motion (A. Martin et al., 2000,
      in: The Cognitive Neurosciences, 2nd ed., MIT Press, Cambridge). Two specific
      claims of this account are that (a) the motions and actions associated with
      objects (along with other attributes) are automatically activated whenever the
      object concept is evoked and (b) topographically distinct neural regions are
      responsible for motion/action attributes pertaining to objects in the categories
      of tools and animals. We used fMRI to examine the neural activation associated
      with conceptual processing of nouns referring to animals and tools and for verbs
      referring to tool-associated actions (e.g., drilling, painting) and biological
      actions (e.g., walking, jumping). We found that object names and their associated
      actions activated the same set of neural regions (left fusiform gyrus, superior
      and middle temporal cortex) consistent with the claim that word tool and animal
      concepts implicitly activate the actions associated with them. However, there was
      no evidence of category specificity for either objects or actions, with
      essentially the same activations for the form and motion attributes of both
      living and nonliving categories.

PMID- 12595207
TI  - Demyelination and cortical reorganization: functional MRI data from a case of
      subacute combined degeneration.
AB  - Although it is accepted that functional changes of the cortex can occur in
      patients with white matter diseases of the brain and might have an adaptive role
      in limiting the clinical consequences of subcortical injury, the pathological
      substrates able to elicit such cortical changes are still unknown. This
      multiparametric magnetic resonance study of a patient with an early diagnosis of
      subacute combined degeneration suggests that demyelination alone does not
      necessarily induce adaptive functional changes of the cerebral cortex.

PMID- 12595234
TI  - Regional expression of p75NTR contributes to neurotrophin regulation of
      cerebellar patterning.
AB  - Neurotrophins were initially identified as critical regulators of neuronal
      survival. However, these factors have many additional functions. In the
      developing cerebellum the roles of the neurotrophins BDNF and NT3 include a
      surprising effect on patterning, as revealed by changes in foliation in
      neurotrophin-deficient mice. Here we examine the potential role of p75NTR in
      cerebellar development and patterning. We show that p75NTR is expressed at
      highest levels in the region of the cerebellum where foliation is altered in BDNF
      and NT3 mutants. Although the cerebellar phenotype of p75NTR mutant animals is
      indistinguishable from wild type, mutation of p75NTR in BDNF heterozygotes
      results in defects in foliation and in Purkinje cell morphologic development.
      Taken together, these data suggest that p75NTR activity is critical for
      cerebellar development under pathologic circumstances where neurotrophin levels
      are reduced.

PMID- 12595235
TI  - Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in
      astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair.
AB  - Our laboratory has identified mouse and human monoclonal antibodies that promote
      myelin repair in multiple models of demyelinating disease. We have proposed that
      these antibodies promote remyelination by directly activating central nervous
      system glia. Intracellular calcium concentration was monitored using a Fura2
      ratiometric assay. Repair-promoting antibodies induced distinct Ca2+ signals in
      both astrocytes and oligodendrocytes. Astrocyte Ca2+ signaling is mediated by a
      phospholipase C-dependent pathway while oligodendrocyte Ca2+ signaling is
      mediated via AMPA-sensitive glutamate receptors. An antibody's ability to induce
      Ca2+ signals is statistically correlated with promotion of myelin repair. These
      findings support the hypothesis that remyelination-promoting antibodies are
      acting directly at the surface of glial cells to induce calcium-dependent
      physiologic reparative function.

PMID- 12595236
TI  - Xrx1 controls proliferation and multipotency of retinal progenitors.
AB  - We investigated the function of Xrx1 during Xenopus retinogenesis. Xrx1
      overexpression lengthens mitotic activity and ectopically activates the
      expression of markers of undifferentiated progenitors in the developing retina.
      We assayed Xrx1 ability to support proliferation with a cell-autonomous mechanism
      by in vivo lipofection of single retinal progenitors. Xrx1 overexpression
      increases clonal proliferation while Xrx1 functional inactivation exerts the
      opposite effect. We also compared the effects of Xrx1 with those of the cyclin
      dependent kinase cdk2, a strong mitotic promoter. Despite the similar increase in
      clonal proliferation displayed by both factors, Xrx1 and cdk2 act differently on
      retinal cell fate determination. cdk2/cyclinA2 lipofected retinas show a decrease
      in early-born cell types as ganglion cells and cones and an increase in late-born
      types such as bipolar neurons. On the contrary, Xrx1 lipofected retinas show no
      changes in the proportions of the different cell types, thus suggesting a role in
      supporting multipotency of retinal progenitors.

PMID- 12595238
TI  - Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor
      induced regeneration of adult rat retinal ganglion cell axons.
AB  - In vitro, cyclic AMP (cAMP) elevation alters neuronal responsiveness to
      diffusible growth factors and myelin-associated inhibitory molecules. Here we
      used an established in vivo model of adult central nervous system injury to
      investigate the effects of elevated cAMP on neuronal survival and axonal
      regeneration. We studied the effects of intraocular injections of neurotrophic
      factors and/or a cAMP analogue (CPT-cAMP) on the regeneration of axotomized rat
      retinal ganglion cell (RGC) axons into peripheral nerve autografts. Elevation of
      cAMP alone did not significantly increase RGC survival or the number of
      regenerating RGCs. Ciliary neurotrophic factor increased RGC viability and axonal
      regrowth, the latter effect substantially enhanced by coapplication with CPT
      cAMP. Under these conditions over 60% of surviving RGCs regenerated their axons.
      Neurotrophin-4/5 injections also increased RGC viability, but there was reduced
      long-distance axonal regrowth into grafts, an effect partially ameliorated by
      cAMP elevation. Thus, cAMP can act cooperatively with appropriate neurotrophic
      factors to promote axonal regeneration in the injured adult mammalian central
      nervous system.

PMID- 12595237
TI  - Isoform-specific binding of the tyrosine phosphatase PTPsigma to a ligand in
      developing muscle.
AB  - PTPsigma is a receptor tyrosine phosphatase that is expressed widely in the
      developing nervous system and that controls the growth and retinotopic mapping of
      retinal axons. PTPsigma is also expressed in motor neurons where its function is
      unclear. Given that invertebrate relatives of PTPsigma can control motor axon
      guidance, target contact, and synaptogenesis, we have asked if extracellular
      ligands exist for cPTPsigma, the avian PTPsigma orthologue, in the neuromuscular
      system. Of the two major isoforms cPTPsigma1 and cPTPsigma2, only the shorter
      cPTPsigma1 isoform is expressed in developing spinal motor neurons and their
      axons. We show that ectodomains of cPTPsigma1, but not of cPTPsigma2, bind
      specifically to developing skeletal myotubes. The putative myotube ligand is not
      related to the previously described binding of cPTPsigma to heparan sulfates
      within the proteoglycans agrin and collagen XVIII, since heparinase treatment of
      myotubes does not alter cPTPsigma1 binding and since most mutations that abolish
      binding of cPTPsigma1 to heparin do not affect myotube binding. The expression of
      cPTPsigma1 in motor axons and its direct binding to target myotubes suggest an
      isoform-specific role for axonally expressed cPTPsigma1 during establishment or
      maintenance of neuromuscular contacts.

PMID- 12595239
TI  - Genomic organization and embryonic expression of Igsf8, an immunoglobulin
      superfamily member implicated in development of the nervous system and organ
      epithelia.
AB  - Igsf8 is an immunoglobulin protein that binds to the tetraspanin molecules, CD81
      and CD9. We describe the genomic organization of mouse and human Igsf8, and
      reveal a dynamic expression pattern during embryonic and fetal development. Igsf8
      is first expressed at E9.5 in a ventral domain of the neural tube, with dorsal
      expression apparent at E10.5. We show that the ventral, but not the dorsal,
      domain of neural tube expression is dependent on Shh signaling. From E11.5, Igsf8
      is expressed at the lateral edge of the ventricular zone, in early postmitotic
      neuroblasts, and in dorsal root and cranial ganglia. Igsf8 is also expressed in
      the branchial arches, dorsal pancreatic primordium, neural retina, olfactory
      epithelium, gut, kidney, and lung.

PMID- 12595241
TI  - A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABA(A)
      receptors by cAMP-dependent protein kinase via selective interaction with
      receptor beta subunits.
AB  - GABA(A) receptors, the key mediators of fast synaptic inhibition in the brain,
      are predominantly constructed from alpha(1-6), beta(1-3), gamma(1-3), and delta
      subunit classes. Phosphorylation by cAMP-dependent protein kinase (PKA)
      differentially regulates receptor function dependent upon beta subunit identity,
      but how this kinase is selectively targeted to GABA(A) receptor subtypes remains
      unresolved. Here we establish that the A-kinase anchoring protein 150 (AKAP150),
      directly binds to the receptor beta1 and beta3, but not to alpha1, alpha2,
      alpha3, alpha6, beta2, gamma2, or delta subunits. Furthermore, AKAP79/150 is
      critical for PKA-mediated phosphorylation of the receptor beta3 subunit.
      Together, our observations suggest a mechanism for the selective targeting of PKA
      to GABA(A) receptor subtypes containing the beta1 or beta3 subunits dependent
      upon AKAP150. Therefore, the selective interaction of beta subunits with AKAP150
      may facilitate GABA(A) receptor subtype-specific functional modulation by PKA
      activity which may have profound local effects on neuronal excitation.

PMID- 12595240
TI  - Transforming growth factor beta2 is released from PC12 cells via the regulated
      pathway of secretion.
AB  - Transforming growth factor beta2 (TGF-beta2), a prototypic member of a large
      superfamily of multifunctional cytokines, is expressed by neurons and glial
      cells. Its subcellular compartmentalization and release from neurons, however,
      are largely unknown. Here we show that TGF-beta2 colocalizes with the trans-Golgi
      network marker TGN38 and a marker molecule for secretory granules, chromogranin B
      (CgB), in PC12 cells. Similarly, primary hippocampal neurons show colocalization
      of TGN38 and TGF-beta2. A substantial amount of endogenous as well as transfected
      TGF-beta2 in PC12 cells comigrates with CgB on an equilibrium gradient,
      suggesting costorage in secretory granules. TGF-beta biological activity peaks in
      identical fractions. Depolarization of PC12 cells with high potassium triggers
      colocalization of CgB and TGF-beta2 at the cell surface, suggesting their
      regulated corelease from secretory granules. High potassium also liberates
      biologically active TGF-beta from PC12 cells and primary neurons. Our results
      indicate that a substantial portion of TGF-beta2 is secreted by the regulated
      secretory pathway in PC12 cells and hippocampal neurons.

PMID- 12595242
TI  - Tissue inhibitor of metalloproteinase 1 inhibits excitotoxic cell death in
      neurons.
AB  - The upregulation of TIMP-1 following an excitotoxic injury has recently been
      hypothesized to be part of a general neuronal response that mediates long-lasting
      changes involved in tissue reorganization and possibly neuroprotection. In this
      study we have shown for the first time that within hours of applying TIMP-1 in
      recombinant form or by adenovirus-mediated gene transfer, neurons are highly
      protected against excitotoxic injury. Neither TIMP-3 nor a nonsecretable form of
      TIMP-1 protected neurons. TIMP-1 conferred highly significant protection to
      hippocampal cells exposed to a wide range of glutamic acid concentrations in both
      dissociated and organotypic hippocampal cultures. TIMP-1 did not prevent
      apoptotic cell death or death mediated by chemical ischemia. The observed
      neuroprotection may be explained by a decrease in calcium influx into neurons
      following stimulation with glutamate. These findings have a fundamental
      implication for our understanding of the physiological role of secreted TIMP-1 in
      the central nervous system.

PMID- 12595243
TI  - Activity blockade increases the number of functional synapses in the hippocampus
      of newborn rats.
AB  - During development neuronal circuitries are refined by activity. Here we studied
      the role of spontaneous electrical activity in the regulation of synapse
      formation in the intact newborn (Postnatal Day 3; P3) rat hippocampus in vitro.
      The blockade of the spontaneous network activity with TTX led to an increase in
      the number of functional excitatory synapses in the CA3 area of the developing
      hippocampus. In parallel, there was a substantial increase in the expression
      levels of the presynaptic markers synaptophysin, synaptotagmin, and synapsin I
      and of GluR1 AMPA receptor subunits. These changes were associated with an
      increase in the frequency and amplitude of AMPA receptor-mediated miniature
      excitatory postsynaptic currents (mEPSCs). Our correlated immunocytochemical,
      electronmicroscopical, and electrophysiological experiments indicate that in the
      developing hippocampus spontaneous network activity controls the number of
      functional synapses.

PMID- 12595244
TI  - Activation of Ras is necessary and sufficient for upregulation of vanilloid
      receptor type 1 in sensory neurons by neurotrophic factors.
AB  - We have analyzed signaling pathways involved in neurotrophic factor (NTF)-induced
      upregulation of nociceptive properties, specifically vanilloid receptor type 1
      (VR1), by adult rat dorsal root ganglion neurons. Upregulation of VR1 by nerve
      growth factor and glial cell line-derived neurotrophic factor is partially
      blocked by a MEK inhibitor. Dominant negative Ras, but not Rap, blocks NTF
      induced ERK activation and VR1 upregulation. Activated Ras mimics NTF-mediated
      induction of VR1 in dorsal root ganglion neurons. An inhibitor of
      phosphatidylinositol 3-kinase, LY294002, also inhibited NTF-induced VR1
      upregulation. However, this may at least in part be due to a block of NTF-induced
      ERK activation. Constitutive simultaneous stimulation of both ERK and
      phosphatidylinositol 3-kinase is not sufficient for VR1 upregulation. Together,
      the data suggest that VR1 expression by dorsal root ganglion neurons is regulated
      by common Ras-dependent pathways.

PMID- 12595245
TI  - A model for statistical significance of local similarities in structure.
AB  - Structural biology can provide three-dimensional structures for proteins of
      unknown function. When sequence or structure comparisons fail to suggest a
      function, insights can come from discovery of functionally important local
      structural patterns. Existing methods to detect such patterns lack rigorous
      statistics needed for widespread application. Here, we derive a formula to
      calculate statistical significance of the root-mean-square deviation between
      atoms in such patterns. When combined with a database search method, our
      statistics permit true functional or structural patterns in different folds to be
      discerned from noise. The approach is highly complementary to fold comparison for
      providing functional clues for new structures, and is key for the detection of
      recurrences of any new pattern.

PMID- 12595246
TI  - A calcium-driven conformational switch of the N-terminal and core domains of
      annexin A1.
AB  - In 1993, Huber and co-workers published the structure of an N-terminally
      truncated version of human annexin A1 lacking the first 32 amino acid residues
      (PDB code: 1AIN). In 2001, we reported the structure of full-length porcine
      annexin A1 including the N-terminal domain in the absence of calcium ions (PDB
      code: 1HM6). The latter structure did not reflect a typical annexin core fold,
      but rather a surprising interaction of the N-terminal domain and the core domain.
      Comparing these two structures revealed that in the full-length structure the
      first 12 residues of the N-terminal domain insert into the core of the protein,
      thereby replacing and unwinding one of the alpha-helices (helix D in repeat 3)
      that is involved in calcium binding. We hypothesized that this structure in the
      absence of calcium ions represents the inactive form of the protein. Furthermore,
      we proposed that upon calcium binding, the N-terminal domain would be expelled
      from the core domain and that the core D-helix would reform in the proper
      conformation for calcium coordination. Herein, we report the X-ray structure of
      full-length porcine annexin A1 in the presence of calcium. This new structure
      shows a typical annexin core structure as we hypothesized, with the D-helix back
      in place for calcium coordination while parts of the now exposed N-terminal
      domain are disordered. We could locate eight calcium ions in this structure, two
      of which are octa-coordinated and two of which were not observed in the structure
      of the N-terminally truncated annexin A1. Possible implications of this calcium
      induced conformational switch for the membrane aggregation properties of annexin
      A1 will be discussed.

PMID- 12595247
TI  - Comparative promoter analysis and its application in analysis of PTH-regulated
      gene expression.
AB  - Taking advantage of the "working draft" of the human genome and the MIT shotgun
      assembly of the mouse genome, we performed a comparative promoter analysis of
      human RefSeq mRNA (sequences from GenBank's RefSeq database). By combining this
      analysis with a transcription factor (TF) binding site analysis using a TRANSFAC
      position weight matrix (PWM) search, 86% of non-specific TF sites were removed.
      Using a set of genes that are regulated by parathyroid hormone (PTH), a
      statistical analysis was performed on the conserved TF binding sites among a set
      of eight human and mouse genes. From among the eight genes tested, we obtained a
      set of 31 TFs, suggesting possible roles for associated genes in PTH-mediated
      pathways. All three known PTH-responsive TFs (AP1, RUNX2, CREB) were correctly
      predicted by this analysis as well as two other potential TFs (VDR and CEBP
      Delta). Additionally, a model was made to describe the TF site characteristic
      module of PTH-regulated genes. This model was then used to search all human
      RefSeq gene promoters with established human-mouse ortholog relationships to
      identify other PTH-regulated genes. This comparative approach combined with
      statistical analysis proved to be sufficiently specific to decipher critical TFs
      involved in PTH-regulated pathways.

PMID- 12595248
TI  - Characterisation of a non-canonical genetic code in the oxymonad Streblomastix
      strix.
AB  - The genetic code is one of the most highly conserved characters in living
      organisms. Only a small number of genomes have evolved slight variations on the
      code, and these non-canonical codes are instrumental in understanding the
      selective pressures maintaining the code. Here, we describe a new case of a non
      canonical genetic code from the oxymonad flagellate Streblomastix strix. We have
      sequenced four protein-coding genes from S.strix and found that the canonical
      stop codons TAA and TAG encode the amino acid glutamine. These codons are
      retained in S.strix mRNAs, and the legitimate termination codons of all genes
      examined were found to be TGA, supporting the prediction that this should be the
      only true stop codon in this genome. Only four other lineages of eukaryotes are
      known to have evolved non-canonical nuclear genetic codes, and our phylogenetic
      analyses of alpha-tubulin, beta-tubulin, elongation factor-1 alpha (EF-1 alpha),
      heat-shock protein 90 (HSP90), and small subunit rRNA all confirm that the
      variant code in S.strix evolved independently of any other known variant. The
      independent origin of each of these codes is particularly interesting because the
      code found in S.strix, where TAA and TAG encode glutamine, has evolved in three
      of the four other nuclear lineages with variant codes, but this code has never
      evolved in a prokaryote or a prokaryote-derived organelle. The distribution of
      non-canonical codes is probably the result of a combination of differences in
      translation termination, tRNAs, and tRNA synthetases, such that the eukaryotic
      machinery preferentially allows changes involving TAA and TAG.

PMID- 12595249
TI  - Active-site copper and zinc ions modulate the quaternary structure of prokaryotic
      Cu,Zn superoxide dismutase.
AB  - The influence of the constitutive metal ions on the equilibrium properties of
      dimeric Photobacterium leiognathi Cu,Zn superoxide dismutase has been studied for
      the wild-type and for two mutant protein forms bearing a negative charge in the
      amino acid clusters at the dimer association interface. Depletion of copper and
      zinc dissociates the two mutant proteins into monomers, which reassemble toward
      the dimeric state upon addition of stoichiometric amounts of zinc. Pressure
      dependent dissociation is observed for the copper-depleted wild-type and mutated
      enzymes, as monitored by the fluorescence shift of a unique tryptophan residue
      located at the subunit association interface. The spectral shift occurs slowly,
      reaching a plateau after 15-20 minutes, and is fully reversible. The recovery of
      the original fluorescence properties, after decompression, is fast (less than
      four minutes), suggesting that the isolated subunit has a relatively stable
      structure, and excluding the presence of stable intermediates during the dimer
      monomer transition. The dimer dissociation process is still incomplete at 6.5
      kbar for the copper-depleted wild-type and mutated enzymes, at variance with what
      is generally observed for oligomeric proteins that dissociate below 3 kbar.
      Measurement of the degree of dissociation, at two different protein
      concentrations, allows us to calculate the standard volume variation upon
      association, Delta V, and the dissociation constant K(d0), at atmospheric
      pressure, (25 ml/mol and 3 x 10(-7)M, respectively). The holoprotein is fully
      dimeric even at 6.5 kbar, which allows us to evaluate a lower Delta G degrees
      limit of 11.5 kcal/mol, corresponding to a dissociation constant K(d0)<10(-9)M.

PMID- 12595250
TI  - RpoD promoters in Campylobacter jejuni exhibit a strong periodic signal instead
      of a -35 box.
AB  - We have used a hidden Markov model (HMM) to identify the consensus sequence of
      the RpoD promoters in the genome of Campylobacter jejuni. The identified promoter
      consensus sequence is unusual compared to other bacteria, in that the region
      upstream of the TATA-box does not contain a conserved -35 region, but shows a
      very strong periodic variation in the AT-content and semi-conserved T-stretches,
      with a period of 10-11 nucleotides. The TATA-box is in some, but not all cases,
      preceded by a TGx, similar to an extended -10 promoter. We predicted a total of
      764 presumed RpoD promoters in the C.jejuni genome, of which 654 were located
      upstream of annotated genes. A similar promoter was identified in Helicobacter
      pylori, a close phylogenetic relative of Campylobacter, but not in Escherichia
      coli, Vibrio cholerae, or six other Proteobacterial genomes, or in Staphylococcus
      aureus. We used upstream regions of high confidence genes as training data
      (n=529, for the C.jejuni genome). We found it necessary to limit the training set
      to genes that are preceded by an intergenic region of >100bp or by a gene
      oriented in the opposite direction to be able to identify a conserved sequence
      motif, and ended up with a training set of 175 genes. This leads to the
      conclusion that the remaining genes (354) are more rarely preceded by a (RpoD)
      promoter, and consequently that operon structure may be more widespread in
      C.jejuni than has been assumed by others. Structural predictions of the regions
      upstream of the TATA-box indicates a region of highly curved DNA, and we assume
      that this facilitates the wrapping of the DNA around the RNA polymerase
      holoenzyme, and offsets the absence of a conserved -35 binding motif.

PMID- 12595251
TI  - Coupling of drug protonation to the specific binding of aminoglycosides to the A
      site of 16 S rRNA: elucidation of the number of drug amino groups involved and
      their identities.
AB  - 2-Deoxystreptamine (2-DOS) aminoglycoside antibiotics bind specifically to the
      central region of the 16S rRNA A site and interfere with protein synthesis.
      Recently, we have shown that the binding of 2-DOS aminoglycosides to an A site
      model RNA oligonucleotide is linked to the protonation of drug amino groups.
      Here, we extend these studies to define the number of amino groups involved as
      well as their identities. Specifically, we use pH-dependent 15N NMR spectroscopy
      to determine the pK(a) values of the amino groups in neomycin B, paromomycin I,
      and lividomycin A sulfate, with the resulting pK(a) values ranging from 6.92 to
      9.51. For each drug, the 3-amino group was associated with the lowest pK(a), with
      this value being 6.92 in neomycin B, 7.07 in paromomycin I, and 7.24 in
      lividomycin A. In addition, we use buffer-dependent isothermal titration
      calorimetry (ITC) to determine the number of protons linked to the complexation
      of the three drugs with the A site model RNA oligomer at pH 5.5, 8.8, or 9.0. At
      pH 5.5, the binding of the three drugs to the host RNA is independent of drug
      protonation effects. By contrast, at pH 9.0, the RNA binding of paromomycin I and
      neomycin B is coupled to the uptake of 3.25 and 3.80 protons, respectively, with
      the RNA binding of lividomycin A at pH 8.8 being coupled to the uptake of 3.25
      protons. A comparison of these values with the protonation states of the drugs
      predicted by our NMR-derived pK(a) values allows us to identify the specific drug
      amino groups whose protonation is linked to complexation with the host RNA. These
      determinations reveal that the binding of lividomycin A to the host RNA is
      coupled to the protonation of all five of its amino groups, with the RNA binding
      of paromomycin I and neomycin B being linked to the protonation of four and at
      least five amino groups, respectively. For paromomycin I, the protonation
      reactions involve the 1-, 3-, 2'-, and 2"'-amino groups, while, for neomycin B,
      the binding-linked protonation reactions involve at least the 1-, 3-, 2', 6'-,
      and 2"'-amino groups. Our results clearly identify drug protonation reactions as
      important thermodynamic participants in the specific binding of 2-DOS
      aminoglycosides to the A site of 16S rRNA.

PMID- 12595252
TI  - The effect of tautomeric constant on the specificity of nucleotide incorporation
      during DNA replication: support for the rare tautomer hypothesis of substitution
      mutagenesis.
AB  - The nucleoside analogue dP (6-(2-deoxy-beta-D-ribofuranosyl)-3,4-dihydro-6H,8H
      pyrimido[4,5-c][1,2]oxazin-2-one) displays ambivalent hydrogen bonding
      characteristics whereby the imino tautomer of P can base-pair with adenine and
      its amino tautomer can base-pair with guanine. Fixed imino and amino tautomers of
      6-methyl-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-2-one (N-methyl P) have
      been synthesised and their structures obtained by X-ray crystallography. The
      tautomeric constant of N-methyl P has been calculated from pK(a) values of the
      fixed tautomers and the kinetic parameters for the incorporation of its 5'
      triphosphate (dPTP) by exonuclease-free Klenow fragment of DNA polymerase I have
      been determined. A strong correlation between the tautomeric constant and the
      incorporation specificity of dPTP is found. These results lend support to the
      proposal that the minor tautomeric forms of the natural bases may play an
      important role in substitution mutagenesis during DNA replication. Furthermore,
      they imply that DNA polymerases impose specific steric requirements on the base
      pair during nucleotide incorporation.

PMID- 12595253
TI  - DNA polymerase X of African swine fever virus: insertion fidelity on gapped DNA
      substrates and AP lyase activity support a role in base excision repair of viral
      DNA.
AB  - DNA polymerase X (pol X) from African swine fever virus (ASFV) is the smallest
      naturally ocurring DNA-directed DNA polymerase (174 amino acid residues)
      described so far. Previous biochemical analysis has shown that ASFV pol X is a
      highly distributive, monomeric enzyme, lacking a proofreading 3'-5' exonuclease.
      Also, ASFV pol X binds intermediates of the single-nucleotide base excision
      repair (BER) process, and is able to efficiently repair single-nucleotide gapped
      DNA. In this work, we perform an extensive kinetic analysis of single correct and
      incorrect nucleotide insertions by ASFV pol X using different DNA substrates: (i)
      a primer/template DNA; (ii) a 1nt gapped DNA; (iii) a 5'-phosphorylated 1nt
      gapped DNA. The results obtained indicate that ASFV pol X exhibits a general
      preference for insertion of purine deoxynucleotides, especially dGTP opposite
      template C. Moreover, ASFV pol X shows higher catalytic efficiencies when filling
      in gapped substrates, which are increased when a phosphate group is present at
      the 5'-margin of the gap. Interestingly, ASFV pol X misinserts nucleotides with
      frequencies from 10(-4) to 10(-5), and the insertion fidelity varies depending on
      the substrate, being more faithful on a phosphorylated 1nt gapped substrate. We
      have analyzed the capacity of ASFV pol X to act on intermediates of BER repair.
      Although no lyase activity could be detected on preincised 5'-deoxyribose
      phosphate termini, ASFV pol X has lyase activity on unincised abasic sites.
      Altogether, the results support a role for ASFV pol X in reparative BER of
      damaged viral DNA during ASFV infection.

PMID- 12595254
TI  - Visualizing RNA extrusion and DNA wrapping in transcription elongation complexes
      of bacterial and eukaryotic RNA polymerases.
AB  - Transcription ternary complexes of Escherichia coli RNA polymerase and yeast RNA
      polymerase III have been analyzed by atomic force microscopy. Using the method of
      nucleotide omission and different DNA templates, E.coli RNAP has been stalled at
      position +24, +70 and +379 and RNAP III at position +377 from the starting site.
      Conformational analysis of E.coli RNAP elongation complexes reveals an average
      DNA compaction of 22nm and a DNA deformation compatible with approximately 180
      degrees DNA wrapping against the enzyme. The extent of protein-DNA interaction
      attributed to wrapping, however, is less than that of corresponding open promoter
      complexes. DNA wrapping was also observed for RNAP III elongation complexes,
      which showed a DNA compaction of 30nm. When the RNA polymerases were stalled far
      from the promoter (+379 and +377), the growing RNA transcript was often visible
      and it was prevalently seen exiting from the enzyme on the opposite side relative
      to the smallest angle subtended by the upstream and downstream DNA arms.
      Surprisingly, we found that many complexes had a second RNAP, not involved in
      transcription, bound to the growing RNA of a ternary complex. DNA wrapping in the
      elongation complex suggests a possible mechanism by which the polymerase may
      overcome the physical barrier to transcription imposed by the nucleosomes.

PMID- 12595255
TI  - The ScPex13p SH3 domain exposes two distinct binding sites for Pex5p and Pex14p.
AB  - Pex13p is an essential component of the peroxisomal protein import machinery and
      interacts via its C-terminal SH3 domain with the type II SH3-ligand Pex14p and
      the non-PXXP protein Pex5p. We report the solution structure of the SH3 domain of
      Pex13p from Saccharomyces cerevisiae and the identification of a novel-binding
      pocket, which binds a non-PXXP-peptide representing the binding site of Pex5p.
      Chemical shift assays revealed the binding sites for Pex5p and Pex14p ligand
      peptides to be distinct and spatially separated. Competition assays demonstrated
      that the two ligand peptides can bind simultaneously to the SH3 domain.

PMID- 12595256
TI  - A comprehensive view on proteasomal sequences: implications for the evolution of
      the proteasome.
AB  - Proteasomes are large multimeric self-compartmentizing proteases, which play a
      crucial role in the clearance of misfolded proteins, breakdown of regulatory
      proteins, processing of proteins by specific partial proteolysis, cell cycle
      control as well as preparation of peptides for immune presentation. Two main
      types can be distinguished by their different tertiary structure: the 20S
      proteasome and the proteasome-like heat shock protein encoded by heat shock locus
      V, hslV. Usually, each biological kingdom is characterized by its specific type
      of proteasome. The 20S proteasomes occur in eukarya and archaea whereas hslV
      protease is prevalent in bacteria. To verify this rule we applied a genome-wide
      sequence search to identify proteasomal sequences in data of finished and yet
      unfinished genome projects. We found several exceptions to this paradigm: (1)
      Protista: in addition to the 20S proteasome, Leishmania, Trypanosoma and
      Plasmodium contained hslV, which may have been acquired from an alpha
      proteobacterial progenitor of mitochondria. (2) Bacteria: for Magnetospirillum
      magnetotacticum and Enterococcus faecium we found that each contained two
      distinct hslVs due to gene duplication or horizontal transfer. Including
      unassembled data into the analyses we confirmed that a number of bacterial
      genomes do not contain any proteasomal sequence due to gene loss. (3) High G+C
      Gram-positives: we confirmed that high G+C Gram-positives possess 20S proteasomes
      rather than hslV proteases. The core of the 20S proteasome consists of two
      distinct main types of homologous monomers, alpha and beta, which differentiated
      into seven subtypes by further gene duplications. By looking at the genome of the
      intracellular pathogen Encephalitozoon cuniculi we were able to show that
      differentiation of beta-type subunits into different subtypes occurred earlier
      than that of alpha-subunits. Additionally, our search strategy had an important
      methodological consequence: a comprehensive sequence search for a particular
      protein should also include the raw sequence data when possible because proteins
      might be missed in the completed assembled genome. The structure-based multiple
      proteasomal alignment of 433 sequences from 143 organisms can be downloaded from
      the URL dagger and will be updated regularly.

PMID- 12595257
TI  - Differential action of natural selection on the N and C-terminal domains of 2'-5'
      oligoadenylate synthetases and the potential nuclease function of the C-terminal
      domain.
AB  - 2'-5' Oligoadenylate synthetases (OAS) are a family of enzymes, which are best
      known for their important role in interferon-dependent antiviral mechanisms, but
      are also involved in the regulation of apoptosis, cell growth and differentiation
      in vertebrates. These enzymes bind double-stranded RNA and catalyze the synthesis
      of 2'-5' oligoadenylates from ATP. Several 2'-5' oligoadenylate synthetase-like
      proteins, which lack the ability to synthesize 2'-5' A, have been recently
      identified in humans and mice; the functions of these inactivated OAS derivatives
      remain unknown. Examination of phylogenetic trees shows that OAS inactivation in
      mammals occurred on several independent occasions. Comparative sequence analysis
      of OAS, poly(A)-polymerases, TRF4/sigma-family polymerases, archaeal CCA-adding
      enzymes and uridilyltransferases from trypanosomes resulted in the identification
      of a C-terminal domain, which is conserved in all these enzymes and is distinct
      from the nucleotidyltransferase domain. Secondary structure prediction shows that
      this domain has a four-helix core, which is most closely related to the ATP-cone
      domain, a regulatory nucleotide-binding domain present in ribonucleotide
      reductases and several other enzymes and transcription regulators. These
      observations, taken together with the experimental evidence of nuclease activity
      in the TRF4/sigma-family of polymerases, suggest that the C-terminal domain of
      OAS and their homologs might have nuclease activity. The putative nuclease domain
      is preferentially conserved in OAS derivatives that lack an active
      nucleotidyltransferase domain and, as indicated by the analysis of the ratio of
      synonymous to non-synonymous substitutions, appears to be subject to purifying
      selection in these proteins. In contrast, phylogenetic analysis provided evidence
      of episodic positive selection in the mouse OAS-like proteins with inactivated
      nucleotidyltransferase domains, which suggests that some of these proteins might
      have distinct antiviral functions.

PMID- 12595258
TI  - Crystal structure of Schizosaccharomyces pombe riboflavin kinase reveals a novel
      ATP and riboflavin-binding fold.
AB  - The essential redox cofactors riboflavin monophosphate (FMN) and flavin adenine
      dinucleotide (FAD) are synthesised from their precursor, riboflavin, in
      sequential reactions by the metal-dependent riboflavin kinase and FAD synthetase.
      Here, we describe the 1.6A crystal structure of the Schizosaccharomyces pombe
      riboflavin kinase. The enzyme represents a novel family of phosphoryl
      transferring enzymes. It is a monomer comprising a central beta-barrel clasped on
      one side by two C-terminal helices that display an L-like shape. The opposite
      side of the beta-barrel serves as a platform for substrate binding as
      demonstrated by complexes with ADP and FMN. Formation of the ATP-binding site
      requires significant rearrangements in a short alpha-helix as compared to the
      substrate free form. The diphosphate moiety of ADP is covered by the glycine-rich
      flap I formed from parts of this alpha-helix. In contrast, no significant changes
      are observed upon binding of riboflavin. The ribityl side-chain might be covered
      by a rather flexible flap II. The unusual metal-binding site involves, in
      addition to the ADP phosphates, only the strictly conserved Thr45. This may
      explain the preference for zinc observed in vitro.

PMID- 12595259
TI  - Engineered fibronectin type III domain with a RGDWXE sequence binds with enhanced
      affinity and specificity to human alphavbeta3 integrin.
AB  - Fibronectin is an extracellular matrix protein with broad binding specificity to
      cell surface receptors, integrins. The tenth fibronectin type III domain (FNfn10)
      is a small, autonomous domain of fibronectin containing the RGE sequence that is
      directly involved in integrin binding. However, in isolation FNfn10 only weakly
      bind to integrins. We reasoned that high-affinity and high-specificity variants
      of FNfn10 to a particular integrin could be engineered by optimizing residues
      surrounding the integrin-binding RGD sequence in the flexible FG loop. Affinity
      maturation of FNfn10 to alphavbeta3 integrin, an integrin up-regulated in
      angiogenic endothelial cells and in some metastatic tumor cells, yielded
      alphavbeta3-binding FNfn10 mutants with a novel RGDWXE consensus sequence. We
      characterized one of the RGDWXE-modified clones, FNfn10-3JCLI4, as purified
      protein. FNfn10-3JCLI4 binds with high affinity and specificity to purified
      alphavbeta3 integrin. Alanine scanning mutagenesis suggested that both the
      tryptophan and glutamic acid residues following the RGD sequence are required for
      maximal affinity and specificity for alphavbeta3. FNfn10-3JCLI4 specifically
      stained alphavbeta3-positive cells as detected with flow cytometry and it
      inhibited alphavbeta3-dependent cell adhesion. As with the anti-alphavbeta3
      antibody LM609, FNfn10-3JCLI4 can interfere with in vitro capillary formation.
      Taken together, these data show that FNfn10-3JCL14 is a specific, high-affinity
      alphavbeta3-binding protein that can inhibit alphavbeta3-dependent cellular
      processes similar to an anti-alphavbeta3 monoclonal antibody. These properties,
      combined with the small, monomeric, cysteine-free and highly stable structure of
      FNfn10-3JCLI4, may make this protein useful in future applications involving
      detection and targeting of alphavbeta3-positive cells.

PMID- 12595260
TI  - On the interaction between gp41 and membranes: the immunodominant loop stabilizes
      gp41 helical hairpin conformation.
AB  - gp41 is the protein responsible for the process of membrane fusion that allows
      primate lentiviruses (HIV and SIV) to enter into their host cells. gp41
      ectodomain contains an N-terminal and a C-terminal heptad repeat region (NHR and
      CHR) connected by an immunodominant loop. In the absence of membranes, the NHR
      and CHR segments fold into a protease-resistant core with a trimeric helical
      hairpin structure. However, when the immunodominant loop is not present (either
      in a complex formed by HIV-1 gp41-derived NHR and CHR peptides or by mild
      treatment with protease of recombinant constructs of HIV-1 gp41 ectodomain, which
      also lack the N-terminal fusion peptide and the C-terminal Trp-rich region)
      membrane binding induces a conformational change in the gp41 core structure.
      Here, we further investigated whether covalently linking the NHR and CHR segments
      by the immunodominant loop affects this conformational change. Specifically, we
      analyzed a construct corresponding to a fragment of SIVmac239 gp41ectodomain
      (residues 27-149, named e-gp41) by means of surface plasmon resonance, Trp and
      rhodamine fluorescence, ATR-FTIR spectroscopy, and differential scanning
      calorimetry. Our results suggest that the presence of the loop stabilizes the
      trimeric helical hairpin both when e-gp41 is in aqueous solution and when it is
      bound to the membrane surface. Bearing in mind possible differences between HIV-1
      and SIV gp41, and considering that the gp41 ectodomain constructs analyzed to
      date lack the N-terminal fusion peptide and the C-terminal Trp-rich region, we
      discuss our observations in relation to the mechanism of virus-induced membrane
      fusion.

PMID- 12595261
TI  - Crystal structures of Aspergillus oryzae aspartic proteinase and its complex with
      an inhibitor pepstatin at 1.9A resolution.
AB  - The X-ray structures of Aspergillus oryzae aspartic proteinase (AOAP) and its
      complex with inhibitor pepstatin have been determined at 1.9A resolution. AOAP
      was crystallized in an orthorhombic system with the space group P2(1)2(1)2(1) and
      cell dimensions of a=49.4A, b=79.4A, and c=93.6A. By the soaking of pepstatin,
      crystals are transformed into a monoclinic system with the space group C2 and
      cell dimensions of a=106.8A, b=38.6A, c=78.7A, and beta=120.3 degrees. The
      structures of AOAP and AOAP/pepstatin complex were refined to an R-factor of
      0.177 (R(free)=0.213) and of 0.185 (0.221), respectively. AOAP has a crescent
      shaped structure with two lobes (N-lobe and C-lobe) and the deep active site
      cleft is constructed between them. At the center of the active site cleft, two
      Asp residues (Asp33 and Asp214) form the active dyad with a hydrogen bonding
      solvent molecule between them. Pepstatin binds to the active site cleft via
      hydrogen bonds and hydrophobic interactions with the enzyme. The structures of
      AOAP and AOAP/pepstatin complex including interactions between the enzyme and
      pepstatin are very similar to those of other structure-solved aspartic
      proteinases and their complexes with pepstatin. Generally, aspartic proteinases
      cleave a peptide bond between hydrophobic amino acid residues, but AOAP can also
      recognize the Lys/Arg residue as well as hydrophobic amino acid residues, leading
      to the activation of trypsinogen and chymotrypsinogen. The X-ray structure of
      AOAP/pepstatin complex and preliminary modeling show two possible sites of
      recognition for the positively charged groups of Lys/Arg residues around the
      active site of AOAP.

PMID- 12595262
TI  - P but not R-axis interface is involved in cooperative binding of NAD on
      tetrameric phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Bacillus
      stearothermophilus.
AB  - Homotetrameric phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
      from Bacillus stearothermophilus can be described as a dimer of dimers with three
      non-equivalent P, R, and Q interfaces. In our previous study, negative
      cooperativity in NAD binding to wild-type GAPDH was interpreted according to the
      induced-fit model in terms of two independent dimers with two interacting binding
      sites in each dimer. Two dimeric mutant GAPDHs, i.e. Y46G/S48G and D186G/E276G,
      were shown to exhibit positive cooperativity in NAD binding. Based on the
      molecular modeling of the substitutions and the fact that the most extensive
      inter-subunit interactions are formed across the P-axis interface of the
      tetramer, it was postulated that both dimeric mutant GAPDHs were of O-P type.
      Therefore, the P-axis interface was assumed to play a major role in causing
      cooperativity in NAD binding.Here, two other mutant GAPDHs, Y46G/R52G and D282G,
      have been studied. Using small angle X-ray scattering, the dimeric form of the
      D282G mutant GAPDH is shown to be of O-R type whereas both dimeric mutant GAPDHs
      Y46G/R52G and Y46G/S48G are of O-P type. Similarly to dimeric Y46G/S48G mutant
      GAPDH, the dimeric Y46G/R52G mutant GAPDH exhibits positive cooperativity in NAD
      binding. On the other hand, no significant cooperativity in NAD binding to the
      dimeric form of the D282G mutant GAPDH is observed, whereas its tetrameric
      counterpart exhibits negative cooperativity, similarly to the wild-type enzyme.
      Altogether, the results support the view that the P-axis interface is essential
      in causing cooperativity in NAD binding by transmitting the structural
      information induced upon cofactor binding from one subunit to the other one
      within O-P/Q-R dimers in contrast to the R-axis interface, which does not
      transmit structural information within O-R/Q-P dimers. The absence of activity of
      O-P and O-R dimer GAPDHs is the consequence of a pertubation of the conformation
      of the active site, at least of the nicotinamide subsite, as evidenced by the
      absence of an ion pair between catalytic residues C149 and H176 and the greater
      accessibility of C149 to a thiol kinetic probe.

PMID- 12595263
TI  - The structure and thermal motion of the B800-850 LH2 complex from Rps.acidophila
      at 2.0A resolution and 100K: new structural features and functionally relevant
      motions.
AB  - The structure at 100K of integral membrane light-harvesting complex II (LH2) from
      Rhodopseudomonas acidophila strain 10050 has been refined to 2.0A resolution. The
      electron density has been significantly improved, compared to the 2.5A resolution
      map, by high resolution data, cryo-cooling and translation, libration, screw
      (TLS) refinement. The electron density reveals a second carotenoid molecule, the
      last five C-terminal residues of the alpha-chain and a carboxy modified alpha
      Met1 which forms the ligand of the B800 bacteriochlorophyll. TLS refinement has
      enabled the characterisation of displacements between molecules in the complex.
      B850 bacteriochlorophyll molecules are arranged in a ring of 18 pigments composed
      of nine approximate dimers. These pigments are strongly coupled and at their
      equilibrium positions the excited state dipole interaction energies, within and
      between dimers, are approximately 370cm(-1) and 280cm(-1), respectively. This
      difference in coupling energy is similar in magnitude to changes in interaction
      energies arising from the pigment displacements described by TLS tensors. The
      displacements appear to be non-random in nature and appear to be designed to
      optimise the modulation of pigment energy interactions. This is the first time
      that LH2 pigment displacements have been quantified experimentally. The
      calculated energy changes indicate that there may be significant contributions to
      inter-pigment energy interactions from molecular displacements and these may be
      of importance to photosynthetic energy transfer.

PMID- 12595264
TI  - Distinctive solution conformation of phosphatase inhibitor CPI-17 substituted
      with aspartate at the phosphorylation-site threonine residue.
AB  - We present solution NMR structures for wild-type and mutated forms of CPI-17, a
      phosphoinhibitor for protein phosphatase 1. Phosphorylation of Thr38 of CPI-17
      produces a >1000-fold increase in inhibitory potency for myosin phosphatase. We
      compared the 1H-15N heteronuclear single quantum coherence spectroscopy (HSQC)
      chemical shifts of wild-type CPI-17, partially phosphorylated CPI-17 and CPI-17
      with Thr38 replaced with Asp to introduce a negative charge. There was a switch
      in the protein conformation due to either Asp substitution or phosphorylation, so
      we determined the solution NMR structure of the CPI-17 T38D mutant as a model for
      the active (phospho-) conformation. The structures reveal a molecular switch in
      conformation that involves the rotation of two of the four helices in the four
      helix bundle. Despite this conformational switch, there was little increase in
      the inhibitory potency with T38D. We propose that for this inhibitor, a negative
      charge at residue 38 is sufficient to trigger an active conformation, but a
      phosphoryl group is required for full inhibitory potency against protein
      phosphatase-1.

PMID- 12595265
TI  - NMR structure of the human doppel protein.
AB  - The NMR structure of the recombinant human doppel protein, hDpl(24-152), contains
      a flexibly disordered "tail" comprising residues 24-51, and a globular domain
      extending from residues 52 to 149 for which a detailed structure was obtained.
      The globular domain contains four alpha-helices comprising residues 72-80
      (alpha1), 101-115 (alpha2(a)), 117-121 (alpha2(b)), and 127-141 (alpha3), and a
      short two-stranded anti-parallel beta-sheet comprising residues 58-60 (beta1) and
      88-90 (beta2). The fold of the hDpl globular domain thus coincides nearly
      identically with the structure of the murine Dpl protein. There are close
      similarities with the human prion protein (hPrP) but, similar to the situation
      with the corresponding murine proteins, hDpl shows marked local differences when
      compared to hPrP: the beta-sheet is flipped by 180 degrees with respect to the
      molecular scaffold formed by the four helices, and the beta1-strand is shifted by
      two residues toward the C terminus. A large solvent-accessible hydrophobic cleft
      is formed on the protein surface between beta2 and alpha3, which has no
      counterpart in hPrP. The helix alpha2 of hPrP is replaced by two shorter helices,
      alpha2(a) and alpha2(b). The helix alpha3 is shortened by more than two turns
      when compared with alpha3 of hPrP, which is enforced by the positioning of the
      second disulfide bond in hDpl. The C-terminal peptide segment 144-149 folds back
      onto the loop connecting beta2 and alpha2. All but four of the 20 conserved
      residues in the globular domains of hPrP and hDpl appear to have a structural
      role in maintaining a PrP-type fold. The conservation of R76, E96, N110 and R134
      in hDpl, corresponding to R148, E168, N183 and R208 in hPrP suggests that these
      amino acid residues might have essential roles in the so far unknown functions of
      PrP and Dpl in healthy organisms.

PMID- 12595267
TI  - Improving the thermodynamic stability of the leucine zipper of max increases the
      stability of its b-HLH-LZ:E-box complex.
AB  - Max is a member of the b-HLH-LZ (basic region-helix1-loop-helix2-leucine zipper)
      family of eukaryotic transcription factors. It is the obligate partner of the
      related b-HLH-LZ proteins, c-Myc and Mad1, with which it forms heterodimers on
      target DNA. While c-Myc and Mad1 require Max for DNA-binding, Max itself can form
      a homodimer that recognizes E-box DNA sequences (CACGTG) in gene promoters that
      are targeted by c-Myc. Evidence suggests that this mode of binding by Max may
      repress c-Myc transcriptional activity, and this may have applications in the
      control of the aberrant activity of c-Myc during certain oncogenic
      transformations. To enhance this repressive potential of Max, we sought to
      stabilize Max homodimers. We have designed a double mutant (N78V/H81L) located in
      the coiled-coil interface of the leucine zipper domain and we demonstrate that
      these mutations do indeed increase the stability of the protein. The mutations
      also improve the stability of the complex with cognate DNA. Thermal denaturations
      monitored by circular dichroism reveal two transitions that are due to
      intermediate folding states for both the wild-type and mutant proteins; this is
      supported by detailed thermodynamic analyses. A formalism to characterize the
      temperature-dependence of the unfolding, including the effect of intermediates,
      is presented.

PMID- 12595266
TI  - Structure and function of an archaeal homolog of survival protein E (SurEalpha):
      an acid phosphatase with purine nucleotide specificity.
AB  - The survival protein E (SurE) family was discovered by its correlation to
      stationary phase survival of Escherichia coli and various repair proteins
      involved in sustaining this and other stress-response phenotypes. In order to
      better understand this ancient and well-conserved protein family, we have
      determined the 2.0A resolution crystal structure of SurEalpha from the
      hyperthermophilic crenarchaeon Pyrobaculum aerophilum (Pae). This first structure
      of an archaeal SurE reveals significant similarities to and differences from the
      only other known SurE structure, that from the eubacterium Thermatoga maritima
      (Tma). Both SurE monomers adopt similar folds; however, unlike the Tma SurE
      dimer, crystalline Pae SurEalpha is predominantly non-domain swapped. Comparative
      structural analyses of Tma and Pae SurE suggest conformationally variant regions,
      such as a hinge loop that may be involved in domain swapping. The putative SurE
      active site is highly conserved, and implies a model for SurE bound to a
      potential substrate, guanosine-5'-monophosphate (GMP). Pae SurEalpha has optimal
      acid phosphatase activity at temperatures above 90 degrees C, and is less
      specific than Tma SurE in terms of metal ion requirements. Substrate specificity
      also differs between Pae and Tma SurE, with a more specific recognition of purine
      nucleotides by the archaeal enzyme. Analyses of the sequences, phylogenetic
      distribution, and genomic organization of the SurE family reveal examples of
      genomes encoding multiple surE genes, and suggest that SurE homologs constitute a
      broad family of enzymes with phosphatase-like activities.

PMID- 12595269
TI  - Computational simulation of the statistical properties of unfolded proteins.
AB  - A simple Monte Carlo method was used to generate ensembles of simulated
      polypeptide conformations that are restricted only by steric repulsion. The
      models used for these simulations were based on the sequences of four real
      proteins, ranging in size from 26 to 268 amino acid residues, and included all
      non-hydrogen atoms. Two sets of calculations were performed, one that included
      only intra-residue steric repulsion terms and those between adjacent residues,
      and one that included repulsion terms between all possible atom pairs, so as to
      explicitly account for the excluded volume effect. Excluded volume was found to
      increase the average radius of gyration of the chains by 20-40%, with the
      expansion factor increasing with chain length. Contrary to recent suggestions,
      however, the excluded volume effect did not greatly restrict the distribution of
      dihedral angles or favor native-like topologies. The average dimensions of the
      ensembles calculated with excluded volume were consistent with those measured
      experimentally for unfolded proteins of similar sizes under denaturing
      conditions, without introducing any adjustable scaling factor. The simulations
      also reproduced experimentally determined effective concentrations for the
      formation of disulfide bonds in reduced and unfolded proteins. The statistically
      generated ensembles included significant numbers of conformations that were
      nearly as compact as the corresponding native proteins, as well as many that were
      as accessible to solvent as a fully extended chain. On the other hand,
      conformations with as much buried surface area as the native proteins were very
      rare, as were highly extended conformations. These results suggest that the
      overall properties of unfolded proteins can be usefully described by a random
      coil model and that an unfolded polypeptide can undergo significant collapse
      while losing only a relatively small fraction of its conformational entropy.

PMID- 12595268
TI  - Quantitative analysis of aspartate receptor signaling complex reveals that the
      homogeneous two-state model is inadequate: development of a heterogeneous two
      state model.
AB  - The two-state model of receptor activation, in which a receptor population exists
      in equilibrium between a single on-state and a single off-state, has long been
      considered a viable model for the signaling behavior of bacterial chemoreceptors.
      Here, we show that this simple, homogeneous two-state model is adequate for a
      pure receptor population with just one adaptation state, but fails to account
      quantitatively for the observed linear relationship between the apparent
      attractant affinity (K(1/2)) and kinase activity (V(obs)(apo)) as the adaptation
      state is varied. Further analysis reveals that the available data are instead
      consistent with a heterogeneous two-state model in which covalent modification of
      receptor adaptation sites changes the microscopic properties of the on-state or
      off-state. In such a system, each receptor molecule retains a single on-state and
      off-state, but covalent adaptation generates a heterogeneous population of
      receptors exhibiting a range of different on-states or off-states with different
      microscopic parameters and conformations. It follows that covalent adaptation
      transforms the receptor from a simple, two-state toggle switch into a variable
      switch. In order to identify the microscopic parameters most sensitive to
      covalent adaptation, six modified, two-state models were examined in which
      covalent adaptation alters a different microscopic parameter. The analysis
      suggests that covalent adaptation primarily alters the ligand-binding affinity of
      the receptor off-state (K(D1)). By contrast, models in which covalent adaptation
      alters the ligand-binding affinity of the receptor on-state, the maximal kinase
      stimulation of the on-state or off-state, cooperative interactions between
      receptors, or the assembly of the receptor-kinase signaling complex are
      inconsistent with the available evidence. Overall, the findings support a
      heterogeneous two-state model in which modification of the receptor adaptation
      sites generates a population of receptors with heterogeneous off-states differing
      in their attractant affinities. In the process of testing the effects of covalent
      adaptation on the assembly of the receptor-kinase signaling complex, a new method
      for estimating the stoichiometric ratio of receptor and CheA in the ternary
      signaling complex was devised. This method suggests that the ratio of receptor
      dimers to CheA dimers in the assembled complex is 6:1 or less.

PMID- 12595270
TI  - Sub-atomic resolution crystal structure of cholesterol oxidase: what atomic
      resolution crystallography reveals about enzyme mechanism and the role of the FAD
      cofactor in redox activity.
AB  - The crystal structure of cholesterol oxidase, a 56kDa flavoenzyme was
      anisotropically refined to 0.95A resolution. The final crystallographic R-factor
      and R(free) value is 11.0% and 13.2%, respectively. The quality of the electron
      density maps has enabled modeling of alternate conformations for 83 residues in
      the enzyme, many of which are located in the active site. The additional observed
      structural features were not apparent in the previous high-resolution structure
      (1.5A resolution) and have enabled the identification of a narrow tunnel leading
      directly to the isoalloxazine portion of the FAD prosthetic group. The
      hydrophobic nature of this narrow tunnel suggests it is the pathway for molecular
      oxygen to access the isoalloxazine group for the oxidative half reaction.
      Resolving the alternate conformations in the active site residues provides a
      model for the dynamics of substrate binding and a potential oxidation triggered
      gating mechanism involving access to the hydrophobic tunnel. This structure
      reveals that the NE2 atom of the active site histidine residue, H447, critical to
      the redox activity of this flavin oxidase, acts as a hydrogen bond donor rather
      than as hydrogen acceptor. The atomic resolution structure of cholesterol oxidase
      has revealed the presence of hydrogen atoms, dynamic aspects of the protein and
      how side-chain conformations are correlated with novel structural features such
      as the oxygen tunnel. This new structural information has provided us with the
      opportunity to re-analyze the roles played by specific residues in the mechanism
      of the enzyme.

PMID- 12595271
TI  - Efficient conformational sampling of local side-chain flexibility.
AB  - Side-chain flexibility of ligand-binding sites needs to be considered in the
      rational design of novel inhibitors. We have developed a method to generate
      conformational ensembles that efficiently sample local side-chain flexibility
      from a single crystal structure. The rotamer-based approach is tested here for
      the S1' pocket of human collagenase-1 (MMP-1), which is known to undergo
      conformational changes in multiple side-chains upon binding of certain
      inhibitors. First, a raw ensemble consisting of a large number of conformers of
      the S1' pocket was generated using an exhaustive search of rotamer combinations
      on a template crystal structure. A combination of principal component analysis
      and fuzzy clustering was then employed to successfully identify a core ensemble
      consisting of a low number of representatives from the raw ensemble. The core
      ensemble contained geometrically diverse conformers of stable nature, as
      indicated in several cases by a relative energy lower than that of the minimised
      template crystal structure. Through comparisons with X-ray crystallography and
      NMR structural data we show that the core ensemble occupied a conformational
      space similar to that observed under experimental conditions. The synthetic
      inhibitor RS-104966 is known to induce a conformational change in the side-chains
      of the S1' pocket of MMP-1 and could not be docked in the template crystal
      structure. However, the experimental binding mode was reproduced successfully
      using members of the core ensemble as the docking target, establishing the
      usefulness of the method in drug design.

PMID- 12595276
TI  - Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a
      rat model of glomerulonephritis.
AB  - Activation and proliferation of glomerular mesangial cells play an important role
      in the development of mesangioproliferative glomerulonephritis. We investigated
      the role of hepatocyte growth factor (HGF) in regulating activated mesangial cell
      proliferation. In glomeruli of normal rats, mesangial cells barely expressed the
      c-Met/HGF receptor. However, when mesangioproliferative glomerulonephritis was
      induced in rats by the administration of an anti-Thy 1.1 antibody, glomerular HGF
      expression transiently decreased along with mesangiolysis, and activation of
      mesangial cells was associated with upregulation of the c-Met receptor. Activated
      mesangial cells in culture also expressed the c-Met/HGF receptor. Although
      addition of HGF to cultured mesangial cells did not increase DNA synthesis, HGF
      did diminish PDGF-induced DNA synthesis. PDGF induced activation of ERK, which
      continued for at least 48 h. When PDGF and HGF were simultaneously added, HGF
      inhibited the prolonged activation of ERK, which suggests that early inactivation
      of PDGF-induced ERK may be involved in the inhibitory effect of HGF on mesangial
      cell proliferation. Furthermore, administration of HGF to rats with anti-Thy 1.1
      nephritis resulted in a selective suppression of activated mesangial cell
      proliferation, and this suppressive effect was associated with attenuation of
      phosphorylated glomerular ERK. These results indicate that HGF counteracts PDGF
      induced mesangial cell proliferation and functions as a negative regulator of
      activated mesangial cell proliferation.

PMID- 12595275
TI  - Redox regulation of HIF-1alpha levels and HO-1 expression in renal medullary
      interstitial cells.
AB  - The present study hypothesized that superoxide (O2(-)*) importantly contributes
      to the regulation of hypoxia-inducible factor (HIF)-1alpha expression at
      posttranscriptional levels in renal medullary interstitial cells (RMICs) of rats.
      By Western blot analysis, it was found that incubation of RMICs with O2(-)*
      generators xanthine/xanthine oxidase and menadione significantly inhibited the
      hypoxia- or CoCl(2)-induced increase in HIF-1alpha levels and completely blocked
      the increase in HIF-1alpha levels induced by ubiquitin-proteasome inhibition with
      CBZ-LLL in the nuclear extracts from these cells. Under normoxic conditions, a
      cell-permeable O2(-)* dismutase (SOD) mimetic, 4-hydroxyl-tetramethylpiperidin
      oxyl (TEMPOL) and PEG-SOD, significantly increased HIF-1alpha levels in RMICs.
      Two mechanistically different inhibitors of NAD(P)H oxidase, diphenyleneiodonium
      and apocynin, were also found to increase HIF-1alpha levels in these renal cells.
      Moreover, introduction of an anti-sense oligodeoxynucleotide specific to NAD(P)H
      oxidase subunit, p22(phox), into RMICs markedly increased HIF-1alpha levels. In
      contrast, the OH* scavenger tetramethylthiourea had no effect on the accumulation
      of HIF-1alpha in these renal cells. By Northern blot analysis, scavenging or
      dismutation of O2(-)* by TEMPOL and PEG-SOD was found to increase the mRNA levels
      of an HIF-1alpha-targeted gene, heme oxygenase-1. These results indicate that
      increased intracellular O2(-)* levels induce HIF-1alpha degradation independently
      of H(2)O(2) and OH* radicals in RMICs. NAD(P)H oxidase activity may importantly
      contribute to this posttranscriptional regulation of HIF-1alpha in these cells
      under physiological conditions.

PMID- 12595277
TI  - Season and testosterone affect contractile properties of fast calling muscles in
      the gray tree frog Hyla chrysoscelis.
AB  - In anurans, circulating levels of androgens influence certain secondary sexual
      characteristics that are expressed only during the breeding season. We studied
      the contractile properties of external oblique muscles (used to power sound
      production) in a species of North American gray tree frog, Hyla chrysoscelis,
      during the breeding season and also in testosterone-treated captive males and
      females after the breeding season. Compared with the muscles of breeding-season
      males, the trunk muscles of postbreeding-season males have 50% less mass, 60%
      longer twitches, and 40% slower shortening velocities. Testosterone levels
      similar to those found in breeding-season male hylid frogs restore the
      contractile speed and mass of male trunk muscles and also convert the small slow
      trunk muscles of females into larger fast-contracting muscles. We conclude that
      androgens likely play a key role in altering the contractile properties of these
      muscles in males during the annual cycle, allowing them to operate in the
      breeding season at the frequencies required to produce the characteristic rapidly
      pulsed calls of this species. Females as well as nonbreeding-season males do not
      produce advertising calls, and therefore the slower muscles found in these
      animals may allow more economic operation of these muscles. The effects of
      testosterone on female trunk muscles indicate the potential of this hormone in
      contributing to the sexual dimorphism in size and contractile properties of these
      muscles, but this dimorphism is likely due to the interaction of more than one
      hormone.

PMID- 12595278
TI  - CO2 transduction in avian intrapulmonary chemoreceptors is critically dependent
      on transmembrane Na+/H+ exchange.
AB  - Avian intrapulmonary chemoreceptors (IPC) are vagal respiratory afferents that
      are inhibited by high lung Pco(2) and excited by low lung Pco(2). Previous work
      suggests that increased CO(2) inhibits IPC by acidifying intracellular pH (pH(i))
      and that pH(i) is determined by a kinetic balance between the rate of
      intracellular carbonic anhydrase-catalyzed CO(2) hydration/dehydration and
      transmembrane extrusion of acids and/or bases by various exchangers. Here, the
      role of amiloride-sensitive Na(+)/H(+) exchange (NHE) in the IPC CO(2) response
      was tested by recording single-unit action potentials from IPC in anesthetized
      ducks, Anas platyrhynchos. For each of the IPC tested, blockade of the NHE using
      dimethyl amiloride (DMA) elicited a marked (>50%) dose-dependent decrease in mean
      IPC discharge (P < 0.05), suggesting that NHE is important for pH(i) regulation
      and CO(2) transduction in IPC. In addition, activation of the NHE using 12-O
      tetradecanoylphorbol 13-acetate stimulated six of the seven IPC tested, although
      the overall effect was not statistically significantly (P = 0.07). Taken
      together, these findings suggest that CO(2) transduction in IPC is dependent on
      transmembrane NHE although it is likely to be much slower than carbonic anhydrase
      catalyzed hydration-dehydration of CO(2).

PMID- 12595279
TI  - Peptides that regulate food intake: effect of peptide histidine isoleucine on
      consummatory behavior in rats.
AB  - Peptide histidine isoleucine (PHI) and VIP are derived from the same precursor.
      While central VIP decreases food intake, potential effects of PHI on feeding have
      not been studied. In the current study, we found that PHI administered
      intracerebroventricularly (ICV) or into the hypothalamic paraventricular nucleus
      (PVN) or central nucleus of the amygdala (CeA) decreased food consumption in
      overnight-deprived rats. The magnitude of an anorexigenic response to PHI
      differed depending on the injection route: ICV-infused peptide evoked the most
      potent effect. We determined that that only PVN- and CeA-injected PHI did not
      have aversive consequences. In addition, we infused anorexigenic doses of PHI via
      the same routes and assessed Fos immunoreactivity of PVN oxytocin (OT) and
      vasopressin (VP) neurons using double immunohistochemistry. OT and VP are thought
      to promote feeding termination. PHI increased the percentage of Fos-positive OT
      neurons regardless of the injection route. PVN- and ICV-infused PHI induced
      activation of VP cells. We conclude that central PHI has an inhibitory influence
      on food intake in rats. The PVN, with OT and VP neurons, and CeA may be involved
      in the mediation of anorexigenic effects of PHI.

PMID- 12595280
TI  - Role of angiotensin in body fluid homeostasis of mice: fluid intake, plasma
      hormones, and brain Fos.
AB  - CD1 mice injected peripherally with either ANG I or ANG II failed to drink
      substantial amounts of water or NaCl, yet showed strong Fos immunoreactivity (ir)
      in subfornical organ (SFO). Mice injected with furosemide showed modest
      stimulation of NaCl intake either 3 or 24 h later, were hypovolemic, and showed
      elevated plasma renin activity (PRA). The pattern of Fos-ir in the brain after
      furosemide was similar to that seen after peripheral injection of ANG II. Mice
      became hypovolemic after subcutaneous injection of polyethylene glycol (PEG),
      showed large increases in PRA, aldosterone, and water intake, but did not show
      sodium appetite. PEG-treated mice had strong activation of SFO as well as other
      brain regions previously shown to be related to ANG-associated drinking in rats.
      ANG II appears to have a modified role in the behavioral response to fluid loss
      in mice compared with rats.

PMID- 12595281
TI  - Hypovolemia and MSNA discharge patterns: assessing and interpreting sympathetic
      responses.
AB  - We previously demonstrated that diuretic-induced hypovolemia resulted in an
      enhanced baroreflex-mediated increase in integrated muscle sympathetic nerve
      activity (MSNA) and vasomotor tone during lower body negative pressure (LBNP) (Am
      J Physiol Heart Circ Physiol 282: H645-H655, 2002). The purpose of this study was
      to perform a retrospective analysis of these data and examine the ability of
      relative MSNA burst amplitude distributions to highlight differences in baseline
      sympathetic nerve discharge patterns. An additional purpose was to determine
      whether differential responses in MSNA burst frequency and burst amplitude affect
      conclusions regarding sympathetic reflex control. MSNA, stroke volume (SV,
      Doppler), and estimated central venous pressure (CVP, dependent arm technique)
      were measured during LBNP within the placebo (Normo) and diuretic (Hypo; 100
      mg/day spironolactone for 3 days) conditions (n = 8). Compared with Normo, MSNA
      burst frequency at rest was elevated, and there was a rightward shift in the
      median of the relative burst amplitude distribution (P < 0.05) in Hypo. During
      LBNP, the larger rise in total MSNA during Hypo versus Normo was due to greater
      increases in relative burst amplitude with no difference in the burst frequency
      response. The MSNA burst frequency response to LBNP was shifted to a higher
      position on the same MSNA-CVP curve during Hypo compared with Normo. In contrast,
      the Hypo burst amplitude response was shifted to a new curve with a slope that
      was similar to the Normo relationship. These data support the use of probability
      distribution analysis to examine intraindividual differences in baseline and
      reflex-mediated increases in MSNA burst amplitude. Furthermore, the differential
      effect of hypovolemia on the responses of burst frequency and amplitude during
      graded LBNP suggests that burst frequency data alone may not adequately represent
      reflex control of sympathetic outflow.

PMID- 12595282
TI  - Mechanism of thrombin-induced vasodilation in human coronary arterioles.
AB  - Thrombin (Thromb), activated as part of the clotting cascade, dilates conduit
      arteries through an endothelial pertussis toxin (PTX)-sensitive G-protein
      receptor and releases nitric oxide (NO). Thromb also acts on downstream
      microvessels. Therefore, we examined whether Thromb dilates human coronary
      arterioles (HCA). HCA from right atrial appendages were constricted by 30-50%
      with endothelin-1. Dilation to Thromb (10(-4)-1 U/ml) was assessed before and
      after inhibitors with videomicroscopy. There was no tachyphylaxis to Thromb
      dilation (maximum dilation = 87.0%, ED(50) = 1.49 x 10(-2)). Dilation to Thromb
      was abolished with either hirudin or denudation but was not affected by PTX.
      Neither N(omega)-nitro-l-arginine methyl ester (n = 7), indomethacin (n = 9),
      (1)H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (n = 6), tetraethylammonium
      chloride (n = 5), nor iberiotoxin (n = 4) reduced dilation to Thromb. However,
      KCl (maximum dilation = 89 +/- 5 vs. 20 +/- 10%; P < 0.05; n = 7),
      tetrabutylammonium chloride (maximum dilation = 79 +/- 7 vs. 21 +/- 4%; P < 0.05;
      n = 5), and charybdotoxin (maximum dilation = 89 +/- 4 vs. 10 +/- 2%; P < 0.05; n
      = 4) attenuated dilation to Thromb. In contrast to animal models, Thromb-induced
      dilation in human arterioles is independent of G(i)-protein activation and NO
      release. However, Thromb dilation is endothelium dependent, is maintained on
      consecutive applications, and involves activation of K(+) channels. We speculate
      that an endothelium-derived hyperpolarizing factor contributes to Thromb-induced
      dilation in HCA.

PMID- 12595283
TI  - Acetoacetate augments beta-adrenergic inotropism of stunned myocardium by an
      antioxidant mechanism.
AB  - Blunted beta-adrenergic inotropism in stunned myocardium is restored by
      pharmacological (N-acetylcysteine) and metabolic (pyruvate) antioxidants. The
      ketone body acetoacetate is a natural myocardial fuel and antioxidant that
      improves contractile function of prooxidant-injured myocardium. The impact of
      acetoacetate on postischemic cardiac function and beta-adrenergic signaling has
      never been reported. To test the hypothesis that acetoacetate restores
      contractile performance and beta-adrenergic inotropism of stunned myocardium,
      postischemic Krebs-Henseleit-perfused guinea pig hearts were treated with 5 mM
      acetoacetate and/or 2 nM isoproterenol at 15-45 and 30-45 min of reperfusion,
      respectively, while cardiac power was monitored. The myocardium was snap frozen,
      and its energy state was assessed from phosphocreatine phosphorylation potential.
      Antioxidant defenses were assessed from GSH/GSSG and NADPH/NADP(+) redox
      potentials. Stunning lowered cardiac power and GSH redox potential by 90 and 70%,
      respectively. Given separately, acetoacetate and isoproterenol each increased
      power and GSH redox potential three- to fivefold. Phosphocreatine potential was
      70% higher in acetoacetate- vs. isoproterenol-treated hearts (P < 0.01). In
      combination, acetoacetate and isoproterenol synergistically increased power and
      GSH redox potential 16- and 7-fold, respectively, doubled NADPH redox potential,
      and increased cAMP content 30%. The combination increased cardiac power four- to
      sixfold vs. the individual treatments without a coincident increase in
      phosphorylation potential. Potentiation of isoproterenol's inotropic actions
      endured even after acetoacetate was discontinued and GSH potential waned,
      indicating that temporary enhancement of redox potential persistently restored
      beta-adrenergic mechanisms. Thus acetoacetate increased contractile performance
      and potentiated beta-adrenergic inotropism in stunned myocardium without
      increasing energy reserves, suggesting its antioxidant character is central to
      its beneficial actions.

PMID- 12595284
TI  - Increased myofibrillar protein phosphatase-1 activity impairs rat aortic smooth
      muscle activation after hypoxia.
AB  - We hypothesized that increased myofibrillar type 1 protein phosphatase (PP1)
      catalytic activity contributes to impaired aortic smooth muscle contraction after
      hypoxia. Our results show that inhibition of PP1 activity with microcystin-LR (50
      nmol/l) or okadaic acid (100 nmol/l) increased phenylephrine- and KCl-induced
      contraction to a greater extent in aortic rings from rats exposed to hypoxia (10%
      O(2)) for 48 h than in rings from normoxic animals. PP1 inhibition also restored
      the level of phosphorylation of the 20-kDa myosin light chain (LC(20)) during
      maximal phenylephrine-induced contraction to that observed in the normoxic
      control group. Myofibrillar PP1 activity was greater in aortas from rats exposed
      to hypoxia than in normoxic rats (P < 0.05). Levels of the protein myosin
      phosphatase-targeting subunit 1 (MYPT1) that mediates myofibrillar localization
      of PP1 activity were increased in aortas from hypoxic rats (193 +/- 28% of the
      normoxic control value, P < 0.05) and in human aortic smooth muscle cells after
      hypoxic (1% O(2)) incubation (182 +/- 18% of the normoxic control value, P <
      0.05). Aortic levels of myosin light chain kinase were similar in normoxic and
      hypoxic groups. In conclusion, after hypoxia, increased MYPT1 protein and
      myofibrillar PP1 activity impair aortic vasoreactivity through enhanced
      dephosphorylation of LC(20).

PMID- 12595285
TI  - ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and
      Na+/H+ exchanger-mediated effect.
AB  - This study investigated, in rabbit papillary muscles (n = 61) and human auricular
      strips (n = 7), effects of endothelin-1 (ET-1; 0.1-10 nM) on diastolic myocardial
      properties. ET-1 (1 nM) was also given in the presence of selective ET(A) or
      ET(B) antagonism, nonselective ET(A)/ET(B) antagonism, and Na(+)/H(+) exchanger
      inhibition. Effects of 6.3 mM Ca(2+) were also studied. ET-1 dose dependently
      increased inotropism. In contrast to baseline, in the presence of ET-1, resting
      tension (RT) decreased, after an isometric twitch, 3.4 +/- 1.4, 6.9 +/- 1.5, and
      12.5 +/- 3.1% with 0.1, 1, and 10 nM, respectively, reflecting an increase in
      myocardial distensibility. ET-1 effects were abolished with selective ET(A) as
      well as with nonselective ET(A)/ET(B) antagonism, whereas they were still present
      with ET(B) antagonism. Na(+)/H(+) exchanger inhibition abolished ET-1 effects on
      distensibility, whereas it only partially inhibited positive inotropic effect.
      Ca(2+) increased inotropism to a similar extent to ET-1 (1 nM) but did not affect
      distensibility. ET-1 therefore increased diastolic distensibility of acutely
      loaded human and nonhuman myocardium. This effect is mediated by ET(A) receptors,
      requires Na(+)/H(+) exchanger activation, and cannot be elicited by Ca(2+).

PMID- 12595286
TI  - Differential response of cardiac fibroblasts from young adult and senescent rats
      to ANG II.
AB  - The intracardiac ANG II-forming pathway is activated in the senescent myocardium,
      raising the possibility of enhanced ANG II effects on cardiac fibroblasts. This
      study established an in vitro model of cultured cardiac fibroblasts from aged
      rats to examine if the response of these cells to ANG II is modified in the aged
      heart. Levels of mRNA encoding renin, angiotensinogen, and the AT(1) receptor
      subtype in cardiac fibroblasts from young adult and senescent rats were
      quantified by RT-PCR, net collagen production by a hydroxyproline-based assay,
      and transforming growth factor (TGF)-beta levels using a commercial kit. In
      cardiac fibroblasts from young adult rats, ANG II significantly enhanced AT(1)
      mRNA levels, net collagen production, and TGF-beta production. In fibroblasts
      from the aged myocardium, ANG II downregulated AT(1) mRNA expression, had a less
      pronounced effect on net collagen production, and had no effect on TGF-beta
      production. Such age-related modification of the response of cardiac fibroblasts
      to ANG II may counteract the effects of augmented intracardiac ANG II production
      in the senescent heart, limiting fibrogenesis.

PMID- 12595287
TI  - Vascular and metabolic response to cycle exercise in sedentary humans: effect of
      age.
AB  - We measured leg blood flow (LBF), drew arterial-venous (A-V) blood samples, and
      calculated muscle O(2) consumption (VO(2)) during incremental cycle ergometry
      exercise [15, 30, and 99 W and maximal effort (maximal work rate, WR(max))] in
      nine sedentary young (20 +/- 1 yr) and nine sedentary old (70 +/- 2 yr) males.
      LBF was preserved in the old subjects at 15 and 30 W. However, at 99 W and at
      WR(max), leg vascular conductance was attenuated because of a reduced LBF (young:
      4.1 +/- 0.2 l/min and old: 3.1 +/- 0.3 l/min) and an elevated mean arterial blood
      pressure (young: 112 +/- 3 mmHg and old: 132 +/- 3 mmHg) in the old subjects. Leg
      A-V O(2) difference changed little with increasing WR in the old group but was
      elevated compared with the young subjects. Muscle maximal VO(2) and cycle WR(max)
      were significantly lower in the old subjects (young: 0.8 +/- 0.05 l/min and 193
      +/- 7 W; old: 0.5 +/- 0.03 l/min and 117 +/- 10 W). The submaximally unchanged
      and maximally reduced cardiac output associated with aging coupled with its
      potential maldistribution are candidates for the limited LBF during moderate to
      heavy exercise in older sedentary subjects.

PMID- 12595288
TI  - Influence of coronary artery diameter on eNOS protein content.
AB  - The purpose of this study was to test the hypothesis that the content of
      endothelial nitric oxide synthase (eNOS) protein (eNOS protein/g total artery
      protein) increases with decreasing artery diameter in the coronary arterial tree.
      Content of eNOS protein was determined in porcine coronary arteries with
      immunoblot analysis. Arteries were isolated in six size categories from each
      heart: large arteries [301- to 2,500-microm internal diameter (ID)], small
      arteries (201- to 300-microm ID), resistance arteries (151- to 200-microm ID),
      large arterioles (101- to 150-microm ID), intermediate arterioles (51- to 100
      microm ID), and small arterioles(<50-microm ID). To obtain sufficient protein for
      analysis from small- and intermediate-sized arterioles, five to seven arterioles
      1-2 mm in length were pooled into one sample for each animal. Results establish
      that the number of smooth muscle cells per endothelial cell decreases from a
      number of 10 to 15 in large coronary arteries to 1 in the smallest arterioles.
      Immunohistochemistry revealed that eNOS is located only in endothelial cells in
      all sizes of coronary artery and in coronary capillaries. Contrary to our
      hypothesis, eNOS protein content did not increase with decreasing size of
      coronary artery. Indeed, the smallest coronary arterioles had less eNOS protein
      per gram of total protein than the large coronary arteries. These results
      indicate that eNOS protein content is greater in the endothelial cells of conduit
      arteries, resistance arteries, and large arterioles than in small coronary
      arterioles.

PMID- 12595290
TI  - Amelioration of ischemia-reperfusion injury with cyclic peptide blockade of ICAM
      1.
AB  - Neutrophils are pivotal in the pathogenesis of ischemia-reperfusion (I/R) injury
      leading to muscle damage. Firm adhesion of neutrophils to the endothelium is
      initiated by an interaction between intercellular adhesion molecular-1 (ICAM-1)
      on the endothelium and beta(2)-integrins on neutrophils. Inhibition of ICAM-1
      dependent binding using monoclonal antibodies has been shown to be efficacious in
      ameliorating I/R injury by preventing the influx of neutrophils into the ischemic
      tissue. We recently described a cyclic peptide that is a potent and selective
      inhibitor of ICAM-1 (IP25) in vitro. In this study, we tested the hypothesis that
      IP25-mediated blockade of ICAM-1 would inhibit neutrophil influx during
      reperfusion of ischemic tissue and consequently attenuate muscle injury in a
      tourniquet hindlimb murine model of I/R injury. Varying amounts of peptide drug
      were injected at the beginning of the reperfusion period. The neutrophil influx
      and size of infarction at the end of 2 h of reperfusion were compared with those
      in untreated control mice and contralateral nonischemic limbs. Mice receiving
      IP25 immediately before reperfusion showed a 56% reduction in neutrophil
      infiltration in the ischemic muscle, accompanied by a 40% reduction in the
      infarct size. No effect on I/R injury was seen if IP25 administration was delayed
      for 60 min after reperfusion. We conclude that IP25 effectively inhibits ICAM-1
      mediated adhesion of neutrophils to the endothelium in mice leading to a
      protective effect and suggests that synthetic peptide antagonists have a
      potential role as therapeutic tools.

PMID- 12595291
TI  - Role of short-term cardiovascular regulation in heart period variability: a
      modeling study.
AB  - A mathematical model of short-term cardiovascular regulation is used to
      investigate how heart period variability reflects the action of the autonomic
      regulatory mechanisms (vagal and sympathetic). The model includes the pulsating
      heart, the systemic (splanchnic and extrasplanchnic) and pulmonary circulation,
      the mechanical effect of respiration on venous return, two groups of receptors
      (arterial baroreceptors and lung stretch receptors), the sympathetic and vagal
      efferent branches, and a very low-frequency (LF) vasomotor noise. All model
      parameters were given on the basis of physiological data from the literature. We
      used data from humans whenever possible, whereas parameters for the regulation
      loops are derived from dog experiments. The model, with basal parameter values,
      produces a heart period power spectrum with two distinct peaks [a high frequency
      (HF) peak at the respiratory rate and a LF peak at approximately 0.1 Hz].
      Sensitivity analysis on the mechanism gains suggests that the HF peak is mainly
      affected by the vagal mechanism, whereas the LF peak is increased by a high
      sympathetic gain and reduced by a high vagal gain. Moreover, the LF peak depends
      significantly on the reactivity of resistance vessels and is affected by noise,
      amplified by the sympathetic control loop at its resonance frequency. The model
      may represent a new tool to study alterations in the heart period spectrum on the
      basis of quantitative physiological hypotheses.

PMID- 12595292
TI  - Glycated collagen cross-linking alters cardiac mechanics in volume-overload
      hypertrophy.
AB  - Alteration of hemodynamic loading induces remodeling that includes changes in
      myocardial properties and extracellular matrix structure. We investigated the
      hypothesis that cardiac hypertrophy due to volume overload produces changes in
      myocardial diastolic mechanics and stiffness that are in part due to alterations
      in advanced glycation end-product (AGE) collagen cross-linking. Rats developed
      volume overload induced by arteriovenous fistula (AVF). To assess the dependence
      of AGE cross-linking on mechanics, we prevented AGE formation by administering
      the drug aminoguanidine (AG) to one group of AVF rats (AG+AVF). Volume overload
      did not modify collagen concentration. Right ventricular AGE cross-links were
      modestly elevated in AVF hearts but were significantly reduced by AG. AVF rats
      exhibited significantly increased septal AGE cross-links that were inhibited in
      the AG+AVF group. AVF-induced increases in left ventricular longitudinal
      stiffness and septal circumferential stiffness were prevented in AG+AVF hearts.
      Volume overload appears to regionally modify AGE collagen cross-linking and
      stiffness, and AG treatment prevented these increases, demonstrating that AGE
      cross-linking plays a role in mediating diastolic compliance in volume-overload
      hypertrophy.

PMID- 12595293
TI  - Exercise training regulates SOD-1 and oxidative stress in porcine aortic
      endothelium.
AB  - Vascular oxidative stress contributes to endothelial dysfunction. Aerobic
      exercise training improves vascular function. The purpose of this study was to
      test the hypothesis that exercise training would improve the balance of
      antioxidant to prooxidant enzymes and reduce markers of oxidative stress in
      aortic endothelial cells (AEC). Female Yucatan miniature pigs either remained
      sedentary (SED) or were exercise trained (EX) for 16-19 wk. EX pigs had increased
      AEC SOD-1 protein levels and Cu/Zn SOD activity of the whole aorta compared with
      SED pigs. Protein levels of other antioxidant enzymes (SOD-2, catalase) were not
      affected by exercise training. Protein levels of p67(phox), a subunit of the
      prooxidant enzyme NAD(P)H oxidase, were reduced in EX vs. SED AEC. These EX
      adaptations were associated with lower AEC malondialdehyde levels and decreased
      phosphorylation of ERK-1/2. Endothelial nitric oxide synthase protein, protein
      nitrotyrosine content, and heme oxygenase-1 protein were not different in EX vs.
      SED pigs. We conclude that chronic aerobic exercise training influenced both
      antioxidant and prooxidant enzymes and decreased indexes of oxidative stress in
      AEC. These adaptations may contribute to improved endothelial function with
      exercise training.

PMID- 12595294
TI  - Alpha 1-adrenergic receptor responses in alpha 1AB-AR knockout mouse hearts
      suggest the presence of alpha 1D-AR.
AB  - Two functional alpha(1)-adrenergic receptor (AR) subtypes (alpha(1A) and
      alpha(1B)) have been identified in the mouse heart. However, it is unclear
      whether the third known subtype, alpha(1D)-AR, is also present. To investigate
      this, we determined whether there were alpha(1)-AR responses in hearts from a
      novel mouse model lacking alpha(1A)- and alpha(1B)-ARs (double knockout) (ABKO).
      In Langendorff-perfused hearts, alpha(1)-ARs were stimulated with phenylephrine.
      For ABKO hearts, phenylephrine reduced left ventricular pressure and coronary
      flow (to 87 +/- 2% and 86 +/- 4% of initial, respectively, n = 11, P < 0.01).
      These effects were blocked by prazosin and 8-[2-[4-(2-methoxyphenyl)-1
      piperazinyl]-8-azaspirol[4,5]decane-7,9-dione] dihydrochloride, suggesting that
      alpha(1D)-AR-mediated responses were present. In contrast, right ventricular
      trabeculae from ABKO hearts did not respond to phenylephrine, suggesting that in
      ABKO perfused hearts, the effects of phenylephrine were not mediated by direct
      actions on cardiomyocytes. A novel finding was that alpha(1)-AR stimulation
      caused positive inotropy in the wild-type mouse heart, in contrast to negative
      inotropy observed in mouse cardiac muscle strips. We conclude that mouse hearts
      lacking alpha(1A)- and alpha(1B)-ARs retain functional alpha(1)-AR responses
      involving decreases of coronary flow and ventricular pressure that reflect
      alpha(1D)-AR-mediated vasoconstriction. Furthermore, alpha(1)-AR inotropic
      responses depend critically on the experimental conditions.

PMID- 12595295
TI  - Pregnancy alters hemodynamic responses to hemorrhage in conscious rabbits.
AB  - Pregnant animals are less able to maintain mean arterial pressure (MAP) during
      hemorrhage compared with nonpregnant animals, but the hemodynamic basis of this
      difference is unknown. The hypothesis that pregnancy attenuates responses of
      cardiac output, as well as total peripheral resistance (TPR) and femoral
      conductance, to hemorrhage was tested in conscious rabbits in both the pregnant
      and nonpregnant state (n = 10). During continuous slow blood loss (2% of the
      initial blood volume per minute), MAP was maintained initially in both groups.
      However, MAP then abruptly decreased to <45 mmHg in all animals after a smaller
      percentage of the initial blood volume was removed in pregnant compared with
      nonpregnant rabbits (43.6 +/- 1.7%, nonpregnant; 29.6 +/- 2.2%, pregnant; P <
      0.005). The more rapid transition to hypotension exhibited by pregnant rabbits
      was associated with greater initial falls in cardiac output (-56 +/- 10 ml/min,
      nonpregnant; -216 +/- 33 ml/min, pregnant; P < 0.005) and stroke volume (0.8 +/-
      0.1 ml/beat, nonpregnant; -1.3 +/- 0.1 ml/beat, pregnant; P < 0.05). In addition,
      the increase in TPR as a function of the decrease in cardiac output was markedly
      attenuated (P < 0.0001) during pregnancy. Whereas femoral conductance decreased
      in nonpregnant rabbits, it did not change significantly in pregnant animals. In
      conclusion, the lesser ability of conscious pregnant rabbits to maintain MAP
      during hemorrhage is due largely to a greater decrease in cardiac output but also
      to inadequate reflex increases in TPR, possibly in part in the femoral vascular
      bed.

PMID- 12595296
TI  - Inferior vena caval hemodynamics quantified in vivo at rest and during cycling
      exercise using magnetic resonance imaging.
AB  - Compared with the abdominal aorta, the hemodynamic environment in the inferior
      vena cava (IVC) is not well described. With the use of cine phase-contrast
      magnetic resonance imaging (MRI) and a custom MRI-compatible cycle in an open
      magnet, we quantified mean blood flow rate, wall shear stress, and cross
      sectional lumen area in 11 young normal subjects at the supraceliac and
      infrarenal levels of the aorta and IVC at rest and during dynamic cycling
      exercise. Similar to the aorta, the IVC experienced significant increases in
      blood flow and wall shear stress as a result of exercise, with greater increases
      in the infrarenal level compared with the supraceliac level. At the infrarenal
      level during resting conditions, the IVC experienced higher mean flow rate than
      the aorta (1.2 +/- 0.5 vs. 0.9 +/- 0.4 l/min, P < 0.01) and higher mean wall
      shear stress than the aorta (2.0 +/- 0.6 vs. 1.3 +/- 0.6 dyn/cm(2), P < 0.005).
      During exercise, wall shear stress remained higher in the IVC compared with the
      aorta, although not significantly. It was also observed that, whereas the aorta
      tapers inferiorly, the IVC tapers superiorly from the infrarenal to the
      supraceliac location. The hemodynamic and anatomic data of the IVC acquired in
      this study add to our understanding of the venous circulation and may be useful
      in a clinical setting.

PMID- 12595297
TI  - Cerebral artery responses to pressure and flow in uremic hypertensive and
      spontaneously hypertensive rats.
AB  - Impaired cerebral blood flow autoregulation is seen in uremic hypertension,
      whereas in nonuremic hypertension autoregulation is shifted toward higher
      perfusion pressure. The cerebral artery constricts in response to a rise in
      either lumen pressure or flow; we examined these responses in isolated middle
      cerebral artery segments from uremic Wistar-Kyoto rats (WKYU), normotensive
      control rats (WKYC), and spontaneously hypertensive rats (SHR). Pressure-induced
      (myogenic) constriction developed at 100 mmHg; lumen flow was then increased in
      steps from 0 to 98 microl/min. Some vessels were studied after endothelium
      ablation. Myogenic constriction was significantly lower in WKYU (28 +/- 2.9%)
      compared with both WKYC (39 +/- 2.5%, P = 0.035) and SHR (40 +/- 3.1%, P =
      0.018). Flow caused constriction of arteries from all groups in an endothelium
      independent manner. The response to flow was similar in WKYU and WKYC, whereas
      SHR displayed increased constriction compared with WKYU (P < 0.001) and WKYC (P <
      0.001). We conclude that cerebral myogenic constriction is decreased in WKYU,
      whereas flow-induced constriction is enhanced in SHR.

PMID- 12595299
TI  - Early effects of metabolic inhibition on intracellular Ca2+ in toad pacemaker
      cells: involvement of Ca2+ stores.
AB  - The early effects of metabolic inhibition on intracellular Ca(2+) concentration
      ([Ca(2+)](i)), Ca(2+) current, and sarcoplasmic reticulum (SR) Ca(2+) content
      were studied in single pacemaker cells from the sinus venosus of the cane toad.
      The amplitude of the spontaneous elevations of systolic [Ca(2+)](i) (Ca(2+)
      transients) was reduced after 5-min exposure to 2 mM NaCN from 338 +/- 30 to 189
      +/- 37 nM (P < 0.005, n = 9), and the spontaneous firing rate was reduced from 27
      +/- 2 to 12 +/- 4 beats/min (P < 0.002, n = 9). It has been proposed that CN(-)
      acts by inhibition of cytochrome P-450, resulting in a reduction of cAMP and
      Ca(2+) current. To test this proposal, we used clotrimazole, a cytochrome P-450
      inhibitor, which also decreased the Ca(2+) transients and firing rate. CN(-)
      caused an insignificant fall of Ca(2+) current (23 +/- 11%) but a substantial
      reduction of SR Ca(2+) content (by 65 +/- 5%), whereas clotrimazole produced a
      larger reduction of Ca(2+) current and did not affect the SR Ca(2+) content. Thus
      the main effect of CN(-) does not seem to be through inhibition of cytochrome P
      450. In conclusion, CN(-) appears to reduce Ca(2+) release from the SR mainly by
      reducing SR Ca(2+) content. A likely cause of the decreased SR content is reduced
      Ca(2+) uptake by the SR pump.

PMID- 12595301
TI  - Sodium restriction prevents cardiac hypertrophy and oxidative stress in
      angiotensin II hypertension.
AB  - The influence of a low-sodium (LS) diet was assessed on the cardiac and renal
      alterations and pro-oxidant effect associated with a 10-day infusion of
      angiotensin II (200 or 400 ng. kg(-1). min(-1), osmotic pumps). Tail-cuff
      pressure (TCP), albuminuria, and renal blood flow were determined at the end of
      the experiments. Heart weight index (HWI) and production of superoxide anion
      (O(2)(-).) by the left ventricle and H(2)O(2) by the aorta was measured with the
      use of bioluminescence. Although the final TCP was similar in LS and normal
      sodium (NS) rats infused with high and low doses of angiotensin II, respectively,
      the increase in HWI was prevented by the LS diet. Sodium restriction reduced the
      rise in albuminuria without a change in the renal effect of angiotensin II. The
      increased production of O(2)(-). and H(2)O(2) observed in NS rats was abrogated
      in LS rats. The beneficial influence of dietary sodium restriction on target
      organ damage induced by angiotensin II is independent of arterial pressure
      reduction and possibly related to attenuation of the prooxidant effect of the
      peptide.

PMID- 12595302
TI  - Role of c-Src in regulation of endothelial nitric oxide synthase expression
      during exercise training.
AB  - We have shown that c-Src plays a role in shear stress stimulation of endothelial
      nitric oxide synthase (eNOS) expression in cultured cells. To examine the role of
      c-Src in vivo, we exercised C57Blk/6 and c-Src heterozygous (c-Src(+/-)) mice on
      a treadmill for 3 wk. Western analysis demonstrated that c-Src(+/-) mice express
      less than one-half the normal amount of c-Src. Exercise increased heart rate and
      blood pressure to identical levels in both strains as determined using
      radiotelemetry. Exercise training increased eNOS protein >2-fold in the aorta and
      1.7-fold in the heart in C57Blk/6 mice but had no effect on eNOS protein levels
      in c-Src(+/-) mice. In contrast to exercise, treatment of mice with mevastatin,
      which stimulates expression of eNOS posttranscriptionally, increased eNOS protein
      in both strains. Training also increased aortic extracellular superoxide
      dismutase protein expression, which is regulated by nitric oxide, in C57Blk/6
      mice but not in c-Src(+/-)mice. These data indicate that c-Src has an important
      role in modulating vascular adaptations to exercise training, in particular
      increasing eNOS and extracellular superoxide dismutase protein expression.

PMID- 12595304
TI  - Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic
      syndrome.
AB  - Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder
      characterized by persistent eosinophilia and organ involvement. Different
      treatments have been investigated in HES with modest success. It has been
      suggested that imatinib is active in HES. We treated 9 patients with HES with 100
      mg imatinib daily. Doses for patients without response after 4 weeks were
      increased to 400 mg daily. Prior therapy had failed for 7 patients. Five patients
      responded: 4 achieved sustained complete remission lasting a median of 12+ weeks
      (range, 9+ to 36+ weeks), and 1 had a transient response. One patient died in
      complete remission. Responses occurred within 4 weeks of therapy; only 1
      responder required an increase in dose to 400 mg daily. Three of 4 nonresponders
      failed to respond to an increase in dose. Toxicity was minimal. We conclude that
      imatinib therapy is effective for HES.

PMID- 12595305
TI  - Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous
      antithrombin polymerization in vivo associated with severe childhood thrombosis.
AB  - There is increasing evidence that serpin conformational alteration caused by
      single point mutations can be responsible for protein deficiency associated with
      human diseases. A typical example is the alpha1-antitrypsin deficiency caused by
      the Z variant carrying a Glu342Lys substitution. Only a few cases of
      "conformational disease" involving other serpins have been described so far. We
      investigated a severe antithrombin deficiency in a 13-month-old child with fever
      and cerebral venous thrombosis. The infant was found to be homozygous for a new
      antithrombin gene mutation (7396T>C, predicting a Phe229Leu antithrombin
      variant), and heterozygous for the factor V Leiden mutation. Mild atypical
      antithrombin deficiency was found in both parents, who were first cousins,
      asymptomatic, and heterozygous for the same antithrombin gene mutation. The
      Phe229Leu variant, which does not readily fit into the current classification of
      antithrombin deficiency, was shown to be a thermolabile antithrombin that
      spontaneously polymerized in the proband's circulation. This points to a key role
      for the conserved Phe at position 229, which is near the reactive site loop in a
      region critical for serpin function and stability. Molecular modeling suggested
      how the mutation might destabilize this region of the protein and thereby favor
      reactive site loop insertion and polymerization. This study provides the first
      direct evidence of antithrombin polymerization in vivo causing antithrombin
      deficiency and severe thrombotic disease.

PMID- 12595307
TI  - The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for
      Bcr/Abl-induced leukemia.
AB  - The chronic myelogenous leukemia (CML)-like myeloproliferative disorder observed
      in the BCR/ABL murine bone marrow transduction and transplantation model shares
      several features with the human disease, including a high response rate to the
      tyrosine kinase inhibitor imatinib mesylate (STI571). To study the impact of
      chronic imatinib mesylate treatment on the CML-like illness, mice were maintained
      on therapeutic doses of this drug and serially monitored. Unexpectedly, despite
      excellent systemic control of the CML-like illness, many of the mice developed
      progressive neurologic deficits after 2 to 4 months of imatinib mesylate therapy
      because of central nervous system (CNS) leukemia. Analysis of imatinib mesylate
      cerebral spinal fluid concentrations revealed levels 155- fold lower than in
      plasma. Thus, in the mouse, the limited ability of imatinib mesylate to cross the
      blood-brain barrier allowed the CNS to become a sanctuary for Bcr/Abl-induced
      leukemia. This model will be a useful tool for the future study of novel anti-CML
      drugs and in better defining the mechanisms for limited imatinib mesylate
      penetration into the CNS.

PMID- 12595306
TI  - CD8+ T cells from patients with acute multiple sclerosis display selective
      increase of adhesiveness in brain venules: a critical role for P-selectin
      glycoprotein ligand-1.
AB  - Multiple sclerosis (MS) is considered an autoimmune inflammatory disease of the
      central nervous system. Under physiologic conditions, we compared the
      adhesiveness of CD4+ and CD8+ lymphocytes from nontreated patients with acute,
      relapsing-remitting multiple sclerosis (RRMS) and from healthy donors. We show
      that in patients with RRMS CD8+, but not with RRMS CD4+, T cells display
      increased rolling and arrest in inflamed murine brain venules. Moreover, CD8+,
      but not CD4+, lymphocytes from MS patients show increased rolling on P-selectin
      in vitro. Anti-P-selectin glycoprotein ligand-1 (PSGL-1) antibodies dramatically
      block the recruitment of CD8+ cells in brain vessels of patients with MS,
      suggesting that PSGL-1 represents a novel pharmaceutical target that may be
      exploited to block the selective entrance of CD8+ cells during early
      inflammation. Vascular cell adhesion molecule-1 (VCAM-1), but not PSGL-1, is
      critical for the adhesion of CD4+ cells in MS patients, highlighting a
      fundamental dichotomy in the mechanisms governing the recruitment of lymphocyte
      subsets in RRMS. Importantly, 7-color fluorescence-activated cell sorter (FACS)
      analysis, together with functional data, indicates that a large fraction of CD8+
      cells from MS patients display the characteristics of memory-effector phenotype.
      In conclusion, our results show that CD8+, but not CD4+, T cells from patients
      with RRMS in the acute phase of the disease display increased ability to be
      recruited in inflamed brain venules.

PMID- 12595308
TI  - Identification of thrombin activatable fibrinolysis inhibitor (TAFI) in human
      platelets.
AB  - Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like
      proenzyme that after activation down-regulates fibrinolysis. Platelets are known
      to contain antifibrinolytic factors that are secreted during platelet activation.
      Therefore, the presence of TAFI in platelets was analyzed. TAFI was identified in
      platelets in a concentration of about 50 ng/1 x 109 platelets and was secreted on
      platelet activation. Thrombin-mediated activation of platelet-derived TAFI
      resembled that of plasma-derived TAFI with respect to stimulation by
      thrombomodulin and spontaneous loss of activity at 37 degrees C. The different
      glycosylation of platelet-derived TAFI compared with plasma-derived TAFI suggests
      that platelet-derived TAFI is synthesized in the megakaryocyte. This suggestion
      was substantiated by the detection of mRNA in the megakaryocytic cell lines DAMI
      and CHRF, representing the intermediate and late stages of megakaryocyte
      development. These results establish the presence of TAFI in platelets and
      suggest a role for platelet-derived TAFI in the protection of the clot against
      fibrinolysis.

PMID- 12595309
TI  - HGF receptor up-regulation contributes to the angiogenic phenotype of human
      endothelial cells and promotes angiogenesis in vitro.
AB  - Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic growth factor
      and a powerful stimulator of angiogenesis, which acts on cells by binding to the
      c-met receptor. The exact role of the endogenous HGF/c-met system in one or more
      steps of the angiogenic process is not completely understood. To contribute to
      this question we used immunocytochemical analysis, Western blotting, and reverse
      transcription-polymerase chain reaction to study the expression of c-met in
      endothelial cells cultured in different growth conditions. We found that c-met is
      not colocalized with vascular endothelial (VE)-cadherin in cell-cell junctions. c
      met and VE-cadherin were shown to be inversely regulated by cell density, at both
      the protein and the mRNA levels. We established that c-met is up-regulated during
      the in vitro recapitulation of several steps of angiogenesis. The c-met
      expression was increased shortly after switching to angiogenic growth conditions
      and remained high during the very first steps of angiogenesis, including cell
      migration, and cell proliferation. The endothelial cells in which the expression
      of c-met was up-regulated were more responsive to HGF and exhibited a higher rate
      of morphogenesis. Moreover, the antibody directed against the extracellular
      domain of the c-met inhibited angiogenesis in vitro. Our results suggest that c
      met is a marker of angiogenic phenotype for endothelial cells and represents an
      attractive target for the development of new antiangiogenic therapies.

PMID- 12595310
TI  - Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded
      UCB cells: results of a phase 1 trial using the AastromReplicell System.
AB  - Allogeneic stem cell transplantation with umbilical cord blood (UCB) cells is
      limited by the cell dose a single unit provides recipients. Ex vivo expansion is
      one strategy to increase the number of cells available for transplantation.
      Aastrom Biosciences developed an automated continuous perfusion culture device
      for expansion of hematopoietic stem cells (HSCs). Cells are expanded in media
      supplemented with fetal bovine serum, horse serum, PIXY321, flt-3 ligand, and
      erythropoietin. We performed a phase 1 trial augmenting conventional UCB
      transplants with ex vivo-expanded cells. The 28 patients were enrolled on the
      trial between October 8, 1997 and September 30, 1998. UCB cells were expanded in
      the device, then administered as a boost to the conventional graft on
      posttransplantation day 12. While expansion of total cells and colony-forming
      units (CFUs) occurred in all cases, the magnitude of expansion varied
      considerably. The median fold increase was 2.4 (range, 1.0-8.5) in nucleated
      cells, 82 (range, 4.6-266.4) in CFU granulocyte-macrophages, and 0.5 (range, 0.09
      2.45) in CD34+ lineage negative (lin-) cells. CD3+ cells did not expand under
      these conditions. Clinical-scale ex vivo expansion of UCB is feasible, and the
      administration of ex vivo-expanded cells is well tolerated. Augmentation of UCB
      transplants with ex vivo-expanded cells did not alter the time to myeloid,
      erythroid, or platelet engraftment in 21 evaluable patients. Recipients of ex
      vivo-expanded cells continue to have durable engraftment with a median follow-up
      of 47 months (range, 41-51 months). A randomized phase 2 study will determine
      whether augmenting UCB transplants with ex vivo-expanded UCB cells is beneficial.

PMID- 12595311
TI  - Exosite-dependent regulation of factor VIIIa by activated protein C.
AB  - Activated protein C (APC) is a natural anticoagulant serine protease in plasma
      that down-regulates the coagulation cascade by degrading cofactors Va and VIIIa
      by limited proteolysis. Recent results have indicated that basic residues of 2
      surface loops known as the 39-loop (Lys37-Lys39) and the Ca2+-binding 70-80-loop
      (Arg74 and Arg75) are critical for the anticoagulant function of APC. Kinetics of
      factor Va degradation by APC mutants in purified systems have demonstrated that
      basic residues of these loops are involved in determination of the cleavage
      specificity of the Arg506 scissile bond on the A2 domain of factor Va. In this
      study, we characterized the properties of the same exosite mutants of APC with
      respect to their ability to interact with factor VIIIa. Time course of the factor
      VIIIa degradation by APC mutants suggested that the same basic residues of APC
      are also critical for recognition and degradation of factor VIIIa. Sodium dodecyl
      sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the factor VIIIa
      cleavage reactions revealed that these residues are involved in determination of
      the specificity of both A1 and A2 subunits in factor VIIIa, thus facilitating the
      cleavages of both Arg336 and Arg562 scissile bonds in the cofactor.

PMID- 12595312
TI  - A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin
      avidity by endothelial chemokines results in impaired leukocyte arrest on
      vascular endothelium under shear flow.
AB  - Leukocyte arrest on vascular endothelium under disruptive shear flow is a
      multistep process that requires in situ integrin activation on the leukocyte
      surface by endothelium-displayed chemoattractants, primarily chemokines. A
      genetic deficiency of leukocyte adhesion to endothelium associated with defective
      beta2 integrin expression or function (LAD-1) has been described. We now report a
      novel severe genetic disorder in this multistep process associated with
      functional defects in multiple leukocyte integrins, reflected in recurrent
      infections, profound leukocytosis, and a bleeding tendency. This syndrome is
      associated with an impaired ability of neutrophil and lymphocyte beta1 and beta2
      integrins to generate high avidity to their endothelial ligands and arrest cells
      on vascular endothelium in response to endothelial chemoattractant signals.
      Patient leukocytes roll normally on endothelial selectins, express intact
      integrins and G protein-coupled chemokine receptors (GPCR), spread on integrin
      ligands, and migrate normally along a chemotactic gradient. Activation of beta2
      integrins in response to GPCR signals and intrinsic soluble ligand binding
      properties of the very late activation antigen-4 (VLA-4) integrin are also
      retained in patient leukocytes. Nevertheless, all integrins fail to generate firm
      adhesion to immobilized ligands in response to in situ GPCR-mediated activation
      by chemokines or chemoattractants, a result of a primary defect in integrin
      rearrangement at ligand-bearing contacts. This syndrome is the first example of a
      human integrin-activation deficiency associated with defective GPCR stimulation
      of integrin avidity at subsecond contacts, a key step in leukocyte arrest on
      vascular endothelium under shear flow.

PMID- 12595313
TI  - ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with
      unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene
      expression profile.
AB  - The presence or absence of somatic mutations in the expressed immunoglobulin
      heavy chain variable regions (IgVH) of chronic lymphocytic leukemia (CLL) cells
      provides prognostic information. Patients whose leukemic cells express unmutated
      IgVH regions (Ig-unmutated CLL) often have progressive disease, whereas patients
      whose leukemic cells express mutated IgVH regions (Ig-mutated CLL) more often
      have an indolent disease. Given the difficulty in performing IgVH sequencing in a
      routine diagnostic laboratory, this prognostic distinction is currently
      unavailable to most patients. Pilot gene expression profiling studies in patients
      with CLL identified genes that were differentially expressed between the Ig
      unmutated and Ig-mutated CLL subtypes. Here, we have profiled an expanded cohort
      of 107 patients and show that ZAP-70 is the gene that best distinguishes the CLL
      subtypes. Ig-unmutated CLL expressed ZAP-70 5.54-fold more highly than Ig-mutated
      CLL (P < 10(-21)). ZAP-70 expression correctly predicted IgVH mutation status in
      93% of patients. ZAP-70 expression and IgVH mutation status were comparable in
      their ability to predict time to treatment requirement following diagnosis. In 7
      patients, ZAP-70 expression and IgVH mutation status were discordant: 4 Ig
      mutated CLLs had high ZAP-70 expression and 3 Ig-unmutated CLLs had low ZAP-70
      expression. Among these ZAP-70 "outliers," those with Ig-mutated CLL had clinical
      features that are uncharacteristic of this CLL subtype: 2 required early
      treatment and 2 used a mutated VH3-21 gene, an IgVH gene that has been associated
      with progressive disease. We developed reverse transcriptase-polymerase chain
      reaction and immunohistochemical assays for ZAP-70 expression that can be applied
      clinically and would yield important prognostic information for patients with
      CLL.

PMID- 12595314
TI  - Erythropoiesis from acetyl LDL incorporating endothelial cells at the preliver
      stage.
AB  - Erythropoiesis is characterized by 2 waves of production during mouse
      embryogenesis: a primitive one originating from the yolk sac (YS) and a
      definitive one produced from both the YS and the embryo proper. How the latter
      wave is generated remains unclear. To investigate our hypothesis that endothelial
      cells (ECs) could generate erythroid cells, we designed a method to label ECs at
      10 days after coitus. This labeling method associates 2 techniques: an
      intracardiac inoculation that allows molecules to be delivered into the
      bloodstream followed by a whole-embryo culture period. DiI-conjugated acetylated
      low-density lipoproteins (Ac-LDL-DiI) were used to specifically tag ECs from the
      inside. One hour after inoculation, DiI staining was found along the entire
      endothelial tree. Fluorescence-activated cell sorter (FACS) analysis revealed
      that DiI+ cells were CD31+, CD34+, and CD45-, an antigen makeup characteristic of
      the endothelial lineage. Twelve hours after inoculation, 43% of DiI+ circulating
      cells belonged to the erythroid lineage. These cells expressed Ter119 and
      displayed an adult globin chain arrangement; thus they belonged to the definitive
      lineage as confirmed in erythroid colony formation. The remaining cells likely
      represent committed white blood cells or multipotent progenitors, as revealed by
      a mixed-colony formation. Beyond the 29-somite stage, the proportion of DiI+
      erythroid cells gradually decreased. These results demonstrate the generation of
      hematopoietic cells from an endothelial intermediate, using in vivo tracing. We
      provide evidence for a release of these cells into the circulation and
      hypothesize that these cells are able to colonize the fetal liver and generate
      definitive erythrocytes in vivo.

PMID- 12595315
TI  - The role of G-protein signaling in hematopoietic stem/progenitor cell
      mobilization.
AB  - The directed migration of mature leukocytes to inflammatory sites and the
      lymphocyte trafficking in vivo are dependent on G protein-coupled receptors and
      delivered through pertussis toxin (Ptx)-sensitive Gi-protein signaling. In the
      present study, we explored the in vivo role of G-protein signaling on the
      redistribution or mobilization of hematopoietic stem/progenitor cells (HPCs). A
      single injection of Ptx in mice elicits a long-lasting leukocytosis and a
      progressive increase in circulating colony-forming unit-culture (CFU-C) and
      colony-forming unit spleen (CFU-S). We found that the prolonged effect is
      sustained by a continuous slow release of Ptx bound to red blood cells or other
      cells and is potentially enhanced by an indirect influence on cell proliferation.
      Plasma levels of certain cytokines (interleukin 6 [IL-6], granulocyte colony
      stimulating factor [G-CSF]) increase days after Ptx treatment, but these are
      unlikely initiators of mobilization. In addition to normal mice, mice genetically
      deficient in monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9
      (MMP-9), G-CSF receptor, beta2 integrins, or selectins responded to Ptx
      treatment, suggesting independence of Ptx-response from the expression of these
      molecules. Combined treatments of Ptx with anti-very late activation antigen
      (anti-VLA-4), uncovered potentially important insight in the interplay of
      chemokines/integrins, and the synergy of Ptx with G-CSF appeared to be dependent
      on MMP-9. As Ptx-mobilized kit+ cells display virtually no response to stromal
      derived factor 1 (SDF-1) in vitro, our data suggest that disruption of CXCR4/SDF
      1 signaling may be the underlying mechanism of Ptx-induced mobilization and
      indirectly reinforce the notion that active signaling through this pathway is
      required for continuous retention of cells within the bone marrow. Collectively,
      our data unveil a novel example of mobilization through pharmacologic modulation
      of signaling.

PMID- 12595316
TI  - KRN5500: a novel therapeutic agent with in vitro activity against human B-cell
      chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic
      pathway of apoptosis.
AB  - Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative,
      emphasizing the need for identification of new therapies for this disease.
      KRN5500 is a novel agent that has a unique sensitivity pattern in the National
      Cancer Institute cell line screening panel, suggesting a unique mechanism of
      action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear
      cells from CLL patients (n = 11) to varying concentrations of this agent.
      Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4
      days at KRN5500 concentrations of 2.50 microM, 0.276 microM, and 0.139 microM,
      respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis
      involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase
      3 effector caspase; however, expression of the antiapoptotic mitochondrial
      membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has
      significant in vitro activity against human CLL cells, thus providing support for
      introduction of this agent into clinical trials for patients with CLL.

PMID- 12595317
TI  - HLA-matched related hematopoietic cell transplantation for chronic-phase CML
      using a targeted busulfan and cyclophosphamide preparative regimen.
AB  - Allogeneic blood or marrow transplantation (BMT) is a curative therapy for
      chronic myeloid leukemia (CML). We have previously reported that the
      pharmacologic targeting of busulfan combined with cyclophosphamide (TBU/CY) can
      minimize regimen-related toxicity while preserving antileukemic effects. We
      report here on 131 consecutive chronic-phase CML patients treated with allogeneic
      related BMT using a TBU/CY preparative regimen, where the busulfan dose was
      targeted to achieve a steady-state plasma concentration of at least 900 ng/mL.
      The median age of the patients was 43 years (range, 14-66 years). Estimates of
      the probabilities of nonrelapse mortality, relapse, survival, and disease-free
      survival 3 years after transplantation were 14%, 8%, 86%, and 78%, respectively.
      Age had no statistically significant effect on survival. Although approximately
      60% of the patients developed clinically extensive chronic graft-versus-host
      disease, the median Karnofsky score at last contact date among survivors was 95%.
      Of surviving patients, 11% were molecularly positive for the bcr-abl mRNA at last
      contact, with a median level of bcr-abl transcripts of 4.6 copies/microg RNA.
      These data suggest that TBU/CY is a very effective preparative regimen for CML in
      chronic phase, associated with an expected survival at 3 years of approximately
      85%, with most patients being in molecular remission.

PMID- 12595318
TI  - Mortality patterns in British and US radiologists: what can we really conclude?

PMID- 12595319
TI  - High grade and non-high grade ductal carcinoma in situ on dynamic MR mammography:
      characteristic findings for signal increase and morphological pattern of
      enhancement.
AB  - The objective of this review is to describe characteristic MR mammographic
      findings for signal increase and morphological patterns of enhancement in pure
      ductal carcinoma in situ (DCIS) and to differentiate between high grade and non
      high grade lesions. The dynamic MR examination (1.5 T unit, contrast enhanced
      T(1) weighted two dimensional fast field echo, 96 ms repetition time, 5.0 ms echo
      time, 80 degrees flip angle) of 39 consecutive patients with pure DCIS was
      evaluated retrospectively. Categories were defined for signal increase
      (C1=normal, C2=slow, continuous, C3=strong initial and slow further increase,
      C4=strong initial increase followed by a plateau phenomenon, and C5=strong
      initial increase followed by a washout phenomenon) and morphological patterns
      (M0=no pattern observed, M1=linear or linear-branched, M2=segmental dotted or
      granular, M3=segmental homogeneous, and M4=focal spot-like). Time-intensity
      curves showing a C4 and C5 signal increase were considered suspicious for
      malignancy. All cases were correlated with histology. 62% of all tumours had a
      plateau or washout (C4, C5), 77% showed a strong initial signal increase (C3-C5).
      On evaluation of time-intensity curves alone MR mammography (MRM) findings were
      suspicious for malignancy in 62% of all DCIS cases. A segmental enhancement was
      found in 82% of all enhancing tumors and the M2 pattern in 73%. In a combined
      analysis of signal increase and morphology, 70% of non-high grade and 92% of high
      grade DCISs were correctly described as suspicious. The difference between non
      high grade and high grade DCIS was not significant (p=0.148), while significant
      differences were found between G1 and G3 DCISs and between G1 and G2 DCISs
      (p<0.05). All G2 and G3 DCISs showed noticeable signal enhancement. The mean
      histological tumour size of non-high grade DCISs was smaller than that for high
      grade DCIS (p<0.05). The hallmark of DCIS on dynamic MRM was unilateral segmental
      enhancement, most commonly with a granular dotted morphology (M2). Hormone
      effects need to be considered as the main differential diagnosis. Signal
      enhancement kinetics similar to invasive carcinoma were seen in the majority of
      cases. A combined analysis of morphological pattern and signal enhancement
      considerably improved rate of detection. G2 and G3 DCISs were correctly diagnosed
      with a significantly higher rate of detection (92%) than G1 DCIS (53%) (p<0.05).
      Different average size of G1, G2 and G3 DCIS on pathology cannot be excluded as a
      reason for differences found. Normal MRM seems to exclude high grade DCIS.

PMID- 12595320
TI  - Image features of true positive and false negative cancers in screening
      mammograms.
AB  - The location, tissue background and imaging characteristics of true positive and
      false negative screens of breast cancers have been studied. This data can aid
      decisions in optimizing the display of mammographic information with the
      objective of minimizing false negative screens. Screening mammograms for four
      groups of women were digitized; those with screen detected cancers, those with
      false negative interval cancers, and matched normals for both groups. The optical
      density (OD) distribution in the main breast region of each mammogram was
      determined. The OD in three regions of interest around the cancers was also
      measured. Cancer locations were mapped and warped onto a typical image to show
      their spatial distribution. Where a cancer was detectable by calcifications alone
      it had a relatively low probability of being a false negative interval cancer.
      The mean OD differences between the cancer and the cancer background region
      (excluding calcifications) were approximately a factor of two lower in dense
      breasts compared with other breast types. Poorly defined masses that became
      interval cancers had mean OD differences that were approximately a factor of 0.1
      OD lower than those that were detectable by screening. 22% of false negative
      cancers were located near the chest wall edge of the mammograms compared with 10%
      of the true positives. The results indicate the importance of effectively
      displaying information in the lighter areas of the mammogram, corresponding to
      glandular tissues, with sufficient contrast for suspicious mammographic details
      to be detected. Where the mean OD differences between the cancer and its
      background region are low, as measured for some poorly defined masses, there is
      an increased risk of a false negative interval cancer. Particular attention
      should be given to the chest wall area of the film, especially in the lower
      retroglandular region, during routine screening.

PMID- 12595321
TI  - CT findings in patients with familial Mediterranean fever during an acute
      abdominal attack.
AB  - The aim of this study is to present the abdominal CT findings of patients with
      familial Mediterranean fever (FMF) examined during an acute abdominal attack. CT
      scans of 17 patients (10 women and 7 men; age range 11-45 years) were
      retrospectively reviewed. Attention was directed to mesenteric or peritoneal
      abnormalities and to the presence of appendiceal pathology. Patients were divided
      into two groups; group A (n=14) consisted of patients with an acute abdominal
      attack caused by FMF, and group B (n=3) consisted of patients whose attack proved
      to be owing to a separate pathology requiring surgery. Characteristic CT findings
      of acute abdomen in FMF included mesenteric pathology (n=12), mainly of engorged
      vessels with thickened mesenteric folds, mesenteric lymphadenopathy (n=6) and
      ascites (n=6). Signs of focal peritonitis were found in four patients.
      Radiologists should be familiar with such CT findings of peritoneal irritation in
      patients with FMF during an acute attack, and may suggest this clinical diagnosis
      in the proper clinical setting in a patient who has not been previously
      diagnosed. Alternatively, the radiologist should be aware of the possibility of a
      concurrent acute appendicitis or other acute abdominal pathology in patients with
      known FMF and should search for it.

PMID- 12595322
TI  - Balloon dilatation of anastomotic strictures secondary to surgical repair of
      oesophageal atresia.
AB  - The purpose of this study was to evaluate the efficiency and safety of
      oesophageal balloon dilatation in strictures secondary to surgical treatment of
      oesophageal atresia in 25 children. Patients comprised 15 males and 10 females,
      aged 1-36 months. Median age was 4 months (interquartile range (IQR)=19). The
      strictures were more than 50% of oesophageal lumen and the delay from surgical
      treatment to balloon dilatation varied from 1 month to 36 months. Associated
      gastroesophageal reflux was noted in 15 patients. All procedures were performed
      under sedation using fluoroscopic guidance. Balloons of increasing diameter, 4-20
      mm were used. Water soluble contrast swallow was performed after each dilatation
      session. A total of 115 balloon dilatation sessions were performed with a range
      of 1-14 procedures per patient (median 4 dilatations, IQR=4.5). Dilatation
      relieved the stricture in all patients over a follow-up period varying from 4
      months to 33 months. The best results were noted in children under 6 months, who
      needed two or few dilatation sessions, with relative risk (RR) of 0.52 and 95%
      confidence interval of 0.29-0.92. The presence of associated gastroesophageal
      reflux indicated a high risk (RR of 12, p<0.001) for undergoing more than two
      balloon dilatation sessions. The only serious complications observed were two
      cases of oesophageal perforation, which were treated conservatively.
      Fluoroscopically guided balloon dilatation is a safe and effective treatment in
      the management of strictures secondary to surgical repair of oesophageal atresia,
      especially when started early (within 6 months of surgery) and not associated
      with gastroesophageal reflux.

PMID- 12595323
TI  - Skin dose and dose-area product values in patients undergoing intracoronary
      brachytherapy.
AB  - Entrance skin doses, dose-area product (DAP) values, fluoroscopy times and
      digital cine acquisition data were measured for 86 patients undergoing
      intracoronary brachytherapy procedures with beta sources, to estimate risk of
      skin injuries. Interventions were carried out in three dedicated X-ray
      interventional cardiology rooms equipped with X-ray systems operating in pulsed
      modes, with high filtration and edge filter options. Skin dose distribution was
      analysed in detail in 56 patients using slow films and thermoluminescent
      dosimetry. Digital recording of Digital Imaging and Communications in Medicine
      cine images also allowed analysis of the technical parameters used throughout the
      procedures. A protocol for clinical follow-up of these patients at the cardiology
      service is also presented, which prescribes special attention when a threshold
      dose is reached. Median values for DAP, fluoroscopy time and number of frames
      were 81.2 Gy cm(2), 17.5 min and 1569 frames, respectively, and maximum values
      were 323.3 Gy cm(2), 46.2 min and 3213 frames, respectively. In two cases,
      maximum skin doses in a procedure reached 3.5 Gy and 4.6 Gy. Comparing median
      values in this study, intracoronary brachytherapy involved approximately two-fold
      the DAP used in percutaneous transluminal coronary angioplasty procedures
      performed during the same period in the same catheterization laboratories, as a
      consequence of the need to monitor the radioactive source location used for the
      treatment of stenoses and the intravascular ultrasound. Special care must be paid
      in those cases of high dose in relation to potential patient skin injuries and
      late effects.

PMID- 12595324
TI  - Simultaneous mapping of blood volume and endothelial permeability surface area
      product in gliomas using iterative analysis of first-pass dynamic contrast
      enhanced MRI data.
AB  - We describe a novel method for the calculation of endothelial permeability
      surface area product from dynamic contrast enhanced MRI. The technique uses
      iterative estimation to automatically decompose tissue residue function into
      intravascular and extravascular components, which are subsequently used to
      generate tumour blood volume, which is equal to relative cerebral blood volume
      calculated from T(1) weighted images and corrected for contamination by contrast
      agent leakage (rCBV(T1)(corrected), and endothelial permeability (k(fp)) maps.
      The technique was assessed in patients with cerebral glioma (n=5) by examining
      the reproducibility of endothelial permeability and rCBV(T1)(corrected) between
      two separate examinations conducted with a 2-day interval. The technique produces
      maps of endothelial permeability that appear to be free of any contribution from
      intravascular contrast agent. Maps of rCBV(T1)(corrected) show close correlation
      with maps of blood volume calculated from independently acquired dynamic
      susceptibility weighted MRI examinations, with no evidence of residual
      permeability effects. The results were highly reproducible with strong intra
      class correlation between the two examinations for mean values and for 97.5
      percentiles of endothelial permeability and rCBV(T1)(corrected). The excellent
      reproducibility of this technique and the ability to calculate endothelial
      permeability and rCBV(T1)(corrected) values from rapidly acquired data sets offer
      considerable advantages over conventional approaches and support the use of this
      methodology for therapeutic monitoring or trials of novel therapeutic agents.

PMID- 12595325
TI  - A method for the systematic selection of technique factors in paediatric CT.
AB  - A method for the systematic selection of paediatric CT technique factors is
      described. The approach is based on the assumption that the level of image noise
      acceptable for a given adult CT image is also acceptable for the equivalent
      paediatric examination. A simple exponential attenuation model is proposed.
      Effective linear attenuation coefficients were initially established from a
      series of phantom measurements simulating head, chest and abdomen examinations at
      120 kVp, then extended for a range of tube potentials and beam qualities using a
      beam spectral model. Application of the method is demonstrated using phantoms
      representing head, chest and abdomen sections for neonate and ages 1 year, 5
      years, 10 years, 15 years and adult.

PMID- 12595326
TI  - Accident and emergency and general practitioner plain radiograph reporting by
      radiographers and radiologists: a quasi-randomized controlled trial.
AB  - Two specially trained radiographers at York District Hospital have been reporting
      appendicular plain radiograph X-ray examinations for Accident and Emergency (A&E)
      patients since February 1995. This study explores the potential for further
      expanding their reporting role. This was achieved by assessing the two
      radiographers' and a group of consultant radiologists' ability to report on a
      retrospectively selected random stratified sample of 400 A&E and General
      Practitioner (GP) plain radiograph X-ray examinations for all body areas. Using
      receiver operating characteristic (ROC) curve analyses there was no statistically
      significant difference at the 5% level between the area under the ROC curves for
      the radiographers and consultant radiologists when reporting A&E or GP plain
      radiographs. It may be feasible to expand the reporting role of suitably trained
      radiographers to include plain radiograph X-ray examinations for all A&E patients
      and for GP patients, with no detriment to the quality of reports.

PMID- 12595327
TI  - Primitive neuroectodermal tumour in a 60-year-old man: a case report and
      literature review.
AB  - Primitive neuroectodermal tumour (PNET) is very rare, especially in adults. We
      report a 60-year-old man presented with a PNET. The symptoms at the time of
      diagnosis were intense headache, Broca's aphasia and right hemiparesis. Only an
      open biopsy was performed. Irradiation of the primary tumour was the main
      treatment (total tumour dose 59.8 Gy) because of serious haematological side
      effects due to chemotherapy. The patient tolerated radiation therapy extremely
      well and his neurological symptoms were improved. 1 month after completion of
      radiotherapy, MRI showed no regression of the tumour. Clinical deterioration was
      observed 10 months after the initial diagnosis and the patient died 2 months
      later. In cases of PNET, initial therapy is surgical bulk reduction whenever
      possible. Irradiation of the cerebrospinal axis is justified as a routine
      treatment but, owing to the radioresistance of the tumour, the addition of
      multiregimen chemotherapy appears to improve survival, according to the
      literature.

PMID- 12595328
TI  - Adenomyoma mimicking an aggressive uterine neoplasm on MRI.
AB  - This case report concerns a nulliparous female with prolonged vaginal bleeding,
      where MRI demonstrated a mass with an aggressive, tumour like appearance
      involving the posterior aspect of the uterus. Histological examination confirmed
      that this was an adenomyoma. The unusual imaging appearance of this lesion and
      its differential diagnosis are discussed. Adenomyoma should be considered in the
      differential diagnosis of aggressive-appearing uterine masses.

PMID- 12595330
TI  - Right upper quadrant pain.

PMID- 12595329
TI  - Percutaneous vertebroplasty: indications, contraindications, and technique.
AB  - Percutaneous vertebroplasty is an emerging interventional technique in which
      surgical polymethylmethacrylate is injected via a large bore needle into a
      vertebral body under imaging guidance. This technique provides increased strength
      and pain relief in vertebrae weakened by a variety of bone diseases. The current
      indication for vertebroplasty is intractable non-radicular pain caused by
      compression fractures due to osteoporosis, myeloma, metastases and aggressive
      vertebral haemangioma. Contraindications include bleeding disorder, unstable
      fracture and lack of definable vertebral collapse. Our technique of percutaneous
      vertebroplasty is illustrated in this pictorial review.

PMID- 12595332
TI  - The normal main pulmonary artery diameter.

PMID- 12595333
TI  - Circulation Research: reflections on the founding editor, Carl J. Wiggers.

PMID- 12595334
TI  - The FAKs about blood vessel assembly.

PMID- 12595335
TI  - Cardioprotection with high-density lipoproteins: fact or fiction?

PMID- 12595336
TI  - Mechanism of pacemaking in I(K1)-downregulated myocytes.
AB  - Biological pacemakers were recently created by genetic suppression of inward
      rectifier potassium current, I(K1), in guinea pig ventricular cells. We simulated
      these cells by adjusting I(K1) conductance in the Luo-Rudy model of the guinea
      pig ventricular myocyte. After 81% I(K1) suppression, the simulated cell reached
      steady state with pacemaker period of 594 ms. Pacemaking current is carried by
      the Na+-Ca2+ exchanger, I(NaCa), which depends on the intracellular calcium
      concentration [Ca2+]i. This [Ca2+]i dependence suggests responsiveness (increase
      in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally.
      Simulations of betaAS demonstrate such responsiveness, which depends on I(NaCa)
      expression. However, a simultaneous betaAS-mediated increase in the slow delayed
      rectifier, I(Ks), limits betaAS sensitivity.

PMID- 12595337
TI  - Oxygen sensing by primary cardiac fibroblasts: a key role of p21(Waf1/Cip1/Sdi1).
AB  - In mammalian organs under normoxic conditions, O2 concentration ranges from 12%
      to <0.5%, with O2 approximately 14% in arterial blood and <10% in the myocardium.
      During mild hypoxia, myocardial O2 drops to approximately 1% to 3% or lower. In
      response to chronic moderate hypoxia, cells adjust their normoxia set point such
      that reoxygenation-dependent relative elevation of PO2 results in perceived
      hyperoxia. We hypothesized that O2, even in marginal relative excess of the PO2
      to which cardiac cells are adjusted, results in activation of specific signal
      transduction pathways that alter the phenotype and function of these cells. To
      test this hypothesis, cardiac fibroblasts (CFs) isolated from adult murine
      ventricle were cultured in 10% or 21% O2 (hyperoxia relative to the PO2 to which
      cells are adjusted in vivo) and were compared with those cultured in 3% O2 (mild
      hypoxia). Compared with cells cultured in 3% O2, cells that were cultured in 10%
      or 21% O2 demonstrated remarkable reversible G2/M arrest and a phenotype
      indicative of differentiation to myofibroblasts. These effects were independent
      of NADPH oxidase function. CFs exposed to high O2 exhibited higher levels of
      reactive oxygen species production. The molecular signature response to perceived
      hyperoxia included (1) induction of p21, cyclin D1, cyclin D2, cyclin G1, Fos
      related antigen-2, and transforming growth factor-beta1, (2) lowered telomerase
      activity, and (3) activation of transforming growth factor-beta1 and p38 mitogen
      activated protein kinase. CFs deficient in p21 were resistant to such O2
      sensitivity. This study raises the vital broad-based issue of controlling ambient
      O2 during the culture of primary cells isolated from organs.

PMID- 12595338
TI  - Differential actions of PAR2 and PAR1 in stimulating human endothelial cell
      exocytosis and permeability: the role of Rho-GTPases.
AB  - Endothelial cell proteinase activated receptors (PARs) belong to a family of
      heterotrimeric G protein-coupled receptors that are implicated in leukocyte
      accumulation and potentiation of reperfusion injury. We characterized the effect
      and the signal transduction pathways recruited after stimulation of endothelial
      PAR2. We used von Willebrand Factor (vWF) release and monolayer permeability to
      peroxidase to report Weibel-Palade body (WPB) exocytosis and pore formation,
      respectively. Human umbilical vein endothelial cells (HUVECs) were stimulated
      with the selective PAR2 agonist peptide SLIGRL-NH2 or PAR1 agonist peptide TFLLR
      NH2. PAR2 stimulation resulted in WPB exocytosis like PAR1 stimulation but,
      unlike PAR1, failed to increase monolayer permeability. BAPTA-AM inhibited PAR2
      induced exocytosis, indicating a PAR2 calcium-dependent signal in ECs. Moreover,
      PAR2-like PAR1-stimulated exocytosis requires actin cytoskeleton remodeling,
      because vWF release is inhibited if the cells were pretreated with
      Jasplakinolide. Rho-GTPase activity is required for PAR-stimulated exocytosis,
      because inactivation of this family of actin-regulatory proteins with Clostridium
      difficile toxin B blocked exocytosis. Expression of dominant-negative mutant
      Cdc42(17N) inhibited exocytosis whereas neither dominant-negative Rac(17N)
      expression nor C3 exotoxin treatment affected vWF release. PAR2 stimulated RhoA
      GTP weakly compared with the PAR1 agonist. We conclude that both PAR2 and PAR1
      elicit WP body exocytosis in a calcium and Cdc42 GTPase-dependent manner. In
      contrast, the differential effect of PAR1 versus PAR2 activation to increase
      monolayer permeability correlates with weak RhoA activation by the PAR2 agonist.

PMID- 12595339
TI  - Shear stress causes nuclear localization of endothelial glucocorticoid receptor
      and expression from the GRE promoter.
AB  - We tested the hypothesis that steady laminar shear stress activates the
      glucocorticoid receptor (GR) and its transcriptional signaling pathway in an
      effort to investigate the potential involvement of GR in shear stress-induced
      antiatherosclerosis actions in the vasculature. In both bovine aortic endothelial
      cells (BAECs) and NIH3T3 cells expressing GFP-GR chimeric protein, wall shear
      stress of 10 or 25 dynes/cm2 caused a marked nuclear localization of GFP-GR
      within 1 hour to an extent comparable to induction with 25 micromol/L
      dexamethasone. The shear mediated nuclear localization of GFP-GR was
      significantly reduced by 25 micromol/L of the MEK1 inhibitor (PD098059) or the PI
      3-kinase inhibitor (LY294002). Also, Western blots demonstrated translocation of
      endogenous GR into nucleus of sheared BAECs. Promoter construct studies using
      glucocorticoid response element (GRE)-driven expression of secreted alkaline
      phosphatase (SEAP) indicated that BAECs exposed to shear stress of 10 and 25
      dynes/cm2 for 8 hours produced >9-fold more SEAP (n=6; P<0.005) than control
      cells, a level comparable to that observed with dexamethasone. Shear stress
      enhanced SEAP expression at 6 hours was reduced 50% (n=5; P<0.005) by MEK1/2 or
      PI 3-kinase inhibitors, but not by the NO inhibitor, L-NAME. Finally, in human
      internal mammary artery, endothelial GR is found to be highly nuclear localized.
      We report a new shear responsive transcriptional element, GRE. The finding that
      hemodynamic forces can be as potent as high dose glucocorticoid steroid in
      activating GR and GRE-regulated expression correlates with the atheroprotective
      responses of endothelial cells to unidirectional arterial shear stress.

PMID- 12595341
TI  - Liposomal delivery of heat shock protein 72 into renal tubular cells blocks
      nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and
      subsequent ischemia-induced apoptosis.
AB  - Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting
      a variety of cells from toxins, thermal stress, and ischemic injury. The
      cytoprotective role and mechanism of action of HSP72 in renal cell ischemic
      injury remain unclear. To study this, HSP72 was introduced (liposomal transfer)
      or induced (thermal stress, 43 degrees Cx1 hour) in renal tubular cells (LLC-PK1)
      with Western blot confirmation. Cells were subjected to simulated ischemia 24
      hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72
      on nuclear factor-kappaB (NF-kappaB) activation (electrophoretic mobility shift
      assay and immunohistochemistry), IkappaBalpha production (Western blot),
      postischemic tumor necrosis factor-alpha (TNF-alpha) production (RT-PCR), and
      apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF
      alpha in apoptosis was determined (anti-TNF-alpha neutralizing antibody). Results
      demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72
      prevented NF-kappaB activation and translocation, TNF-alpha gene transcription,
      and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF
      alpha neutralization also inhibited ischemia-induced renal tubular cell
      apoptosis. These results indicate that liposomal delivery of HSP72 inhibits
      ischemia-induced renal tubular cell apoptosis by preventing NF-kappaB activation
      and subsequent TNF-alpha production. Further elucidation of the mechanisms of HSP
      induced cytoprotection may result in therapeutic strategies that limit or prevent
      ischemia-induced renal damage.

PMID- 12595340
TI  - Depletion of intracellular Ca2+ stores sensitizes the flow-induced Ca2+ influx in
      rat endothelial cells.
AB  - Hemodynamic shear stress elicits a rise in endothelial [Ca2+]i, which may serve
      as a key second messenger to regulate many flow-associated physiological and
      biochemical processes. In the present study, we used Mn2+ quenching of
      fluorescent dye Fluo3 as an assay to investigate the Ca2+ influx of rat aortic
      endothelial cells in response to flow. We found that the Ca2+ signaling in
      response to flow could be greatly influenced by the status of intracellular Ca2+
      stores. Depletion of intracellular Ca2+ stores by thapsigargin (4 micromol/L) or
      cyclopiazonic acid (10 micromol/L) drastically sensitized the Ca2+ influx in
      response to flow. Ca2+-mobilizing agonist bradykinin (100 nmol/L) or ATP (100
      micromol/L) had similar sensitizing effect. The effect of bradykinin or ATP was
      blocked by Xestospongin C and U73122, suggesting that the sensitization was
      related to the IP3-mediated store depletion. On the other hand, the Mn2+
      quenching in response to flow was greatly reduced by ochratoxin A (100 nmol/L),
      an agent that could increase the filling state of intracellular Ca2+ stores. In
      addition, we found that depletion-sensitized Ca2+ influx in response to flow was
      mediated by a PKG-inhibitable cation channel and that the influx was affected by
      membrane potential and K+ channel activity. In conclusion, the present study
      argues for a critical role of intracellular Ca2+ status in determining the Ca2+
      signaling in response to flow and it provides a general mechanistic explanation
      for the stimulatory role of blood-borne agonists on flow-induced Ca2+ influx.

PMID- 12595342
TI  - Focal adhesion kinase is required for blood vessel morphogenesis.
AB  - The nonreceptor tyrosine kinase focal adhesion kinase (FAK) is a point of
      convergence for signals from extracellular matrix, soluble factors, and
      mechanical stimuli. Targeted disruption of the fak gene in mice leads to death at
      embryonic day 8.5 (E8.5). FAK-/- embryos have severely impaired blood vessel
      development. Gene expression and in vitro differentiation studies revealed that
      endothelial cell differentiation was comparable in FAK-/- and wild-type E8.5
      embryos. We examined the role of FAK in blood vessel morphogenesis using an in
      vitro tubulogenesis assay and three different culture systems: FAK+/+ and FAK-/-
      embryoid bodies, FAK+/+ and FAK-/- endothelial cells, and human umbilical vein
      endothelial cells expressing antisense FAK, a dominant-negative fragment of FAK,
      or wild-type FAK. In all of these systems, endothelial cells deficient in FAK
      expression or function displayed a severely reduced ability to form tubules in
      Matrigel. These studies demonstrate clearly that the vascular defects in FAK-/-
      mice result from the inability of FAK-deficient endothelial cells to organize
      themselves into vascular networks, rather than from defects in tissue-specific
      differentiation.

PMID- 12595343
TI  - Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial
      growth factor and cGMP after stroke in the rat.
AB  - We investigated the effects of NO on angiogenesis and the synthesis of vascular
      endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in
      the rat. Compared with control rats, systemic administration of an NO donor,
      DETANONOate, to rats 24 hours after stroke significantly enlarged vascular
      perimeters and increased the number of proliferated cerebral endothelial cells
      and the numbers of newly generated vessels in the ischemic boundary regions, as
      evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with
      DETANONOate significantly increased VEGF levels in the ischemic boundary regions
      as measured by ELISA. A capillary-like tube formation assay was used to
      investigate whether DETANONOate increases angiogenesis in ischemic brain via
      activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube
      formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H
      [1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a
      neutralized antibody against VEGF receptor 2 significantly attenuated DETANONOate
      induced capillary-like tube formation. Moreover, systemic administration of a
      phosphodiesterase type 5 inhibitor (Sildenafil) to rats 24 hours after stroke
      significantly increased angiogenesis in the ischemic boundary regions. Sildenafil
      and an analog of cyclic guanosine monophosphate (cGMP) also induced capillary
      like tube formation. These findings suggest that exogenous NO enhances
      angiogenesis in ischemic brain, which is mediated by the NO/cGMP pathway.
      Furthermore, our data suggest that NO, in part via VEGF, may enhance angiogenesis
      in ischemic brain.

PMID- 12595344
TI  - Conditional expression of a dominant-negative c-Myb in vascular smooth muscle
      cells inhibits arterial remodeling after injury.
AB  - Inhibiting activity of the c-Myb transcription factor attenuates G1 to S phase
      cell cycle transitions in vascular smooth muscle cells (SMCs) in vitro. To
      determine the effects of arterial SMC-specific expression of a dominant-negative
      c-Myb molecule (Myb-Engrailed) on vascular remodeling in vivo, we performed
      carotid artery wire-denudation in 2 independent lines of binary transgenic mice
      with SM22alpha promoter-defined Doxycycline-suppressible expression of Myb
      Engrailed. Adult mice with arterial SMC-specific expression of Myb-Engrailed were
      overtly normal in appearance and did not display any changes in cardiovascular
      structure or physiology. However, bromodeoxyuridine-defined arterial SMC
      proliferation, neointima formation, medial hyperplasia, and arterial remodeling
      were markedly decreased in mice expressing arterial SMC-restricted Myb-Engrailed
      after arterial injury. These data suggest that c-Myb activity in arterial SMCs is
      not essential for arterial structure or function during development, but is
      involved in the proliferation of arterial SMCs as occurs in vascular pathology,
      and that the expression of a dominant-negative c-Myb can dramatically reduce
      adverse arterial remodeling in an in vivo model of restenosis. As such, this
      model represents a novel tissue-specific strategy for the potential gene therapy
      of diseases characterized by arterial SMC proliferation.

PMID- 12595345
TI  - Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary
      microvascular function.
AB  - Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation
      and has been implicated in many cardiovascular diseases associated with elevated
      oxidative stress. However, its direct vasomotor action and its linkage to
      oxidative stress-induced vascular dysfunction in the coronary microcirculation
      remain elusive. In this study, we directly assessed the vasomotor action of Ang
      II in isolated porcine coronary arterioles and also examined whether Ang II can
      modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide
      production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and
      dilations at higher concentrations (>10 nmol/L). Ang II type 1 (AT(1)) receptor
      antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT(2))
      receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a
      significant arteriolar NO production and dilation. NO synthase inhibitor N(G)
      monomethyl-L-arginine (L-NMMA) abolished stimulated NO production and attenuated
      vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II
      (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II-mediated
      inhibition was not observed in the presence of L-NMMA or after endothelial
      removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH
      oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited
      losartan- and TEMPOL-sensitive superoxide production in arterioles. These results
      demonstrate that Ang II evokes AT1 receptor-mediated vasoconstriction and AT2
      receptor-mediated vasodilation of coronary arterioles. Ang II at a subvasomotor
      level impairs endothelium-dependent NO-mediated dilation attributable to elevated
      superoxide production via AT1 receptor activation of NADPH oxidase. These data
      may partly explain the impaired coronary flow regulation in heart diseases
      associated with an upregulated renin-angiotensin system.

PMID- 12595346
TI  - High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion
      injury by reducing cardiac tumor necrosis factor-alpha content and enhancing
      prostaglandin release.
AB  - The incidence and severity of primary cardiac events are inversely related to the
      plasma concentration of high-density lipoproteins (HDLs). We investigated whether
      HDLs may exert a direct cardioprotection in buffer-perfused isolated rat hearts,
      which underwent a 20-minute low-flow ischemia followed by a 30-minute
      reperfusion. The administration of HDLs at physiological concentrations (0.5 and
      1.0 mg/mL) during the 10 minutes immediately before ischemia rapidly and
      remarkably improved postischemic functional recovery and decreased creatine
      kinase release in the coronary effluent. Reconstituted HDLs containing
      apolipoprotein A-I (apoA-I) and phosphatidylcholine, but not lipid-free apoA-I or
      phosphatidylcholine liposomes, were also effective in protecting the heart from
      ischemia-reperfusion injury. HDLs at reperfusion were less effective than when
      given before ischemia. HDLs caused a dose-dependent reduction of ischemia-induced
      cardiac tumor necrosis factor-alpha (TNF-alpha) expression and content, which
      correlated with the improved functional recovery. A parallel increase of TNF
      alpha release in the coronary effluent was observed, due to a direct binding of
      cardiac TNF-alpha to HDLs. Taken together, these findings argue for a cause
      effect relationship between the HDL-mediated removal of TNF-alpha from the
      ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a
      recombinant TNF-alpha-blocking protein, caused a dose-dependent improvement of
      postischemic functional recovery. HDLs also enhanced ischemia-induced
      prostaglandin release, which may contribute to the cardioprotective effect. A low
      plasma HDL level may expose the heart to excessive ischemia-reperfusion damage,
      and HDL-targeted therapies may be helpful to induce immediate or delayed
      myocardial protection from ischemia-reperfusion injury.

PMID- 12595347
TI  - Sarcoplasmic reticulum Ca2+ release is not a dominating factor in sinoatrial node
      pacemaker activity.
AB  - Recent work on isolated sinoatrial node cells from rabbit has suggested that
      sarcoplasmic reticulum Ca2+ release plays a dominant role in the pacemaker
      potential, and ryanodine at a high concentration (30 micromol/L blocks
      sarcoplasmic reticulum Ca2+ release) abolishes pacemaking and at a lower
      concentration abolishes the chronotropic effect of beta-adrenergic stimulation.
      The aim of the present study was to test this hypothesis in the intact sinoatrial
      node of the rabbit. Spontaneous activity and the pattern of activation were
      recorded using a grid of 120 pairs of extracellular electrodes. Ryanodine 30
      micromol/L did not abolish spontaneous activity or shift the position of the
      leading pacemaker site, although it slowed the spontaneous rate by 18.9+/-2.5%
      (n=6). After ryanodine treatment, beta-adrenergic stimulation still resulted in a
      substantial chronotropic effect (0.3 micromol/L isoproterenol increased
      spontaneous rate by 52.6+/-10.5%, n=5). In isolated sinoatrial node cells from
      rabbit, 30 micromol/L ryanodine slowed spontaneous rate by 21.5+/-2.6% (n=13). It
      is concluded that sarcoplasmic reticulum Ca2+ release does not play a dominating
      role in pacemaking in the sinoatrial node. The full text of this article is
      available at http://www.circresaha.org.

PMID- 12595348
TI  - Cyclic variation of intracellular calcium: a critical factor for cardiac
      pacemaker cell dominance.
AB  - While a diversity of cell types and distribution within the sinoatrial node and
      cell-cell interactions add complexity to a complete elucidation of the heart's
      pacemaker function, it has become clear that cyclic variation of submembrane
      [Ca2+] and activation of the Na+-Ca2+ exchanger during diastolic depolarization
      (DD) act in concert with ion channels to confer on sinoatrial node cells (SANCs)
      their status of dominance with respect to pacemaker function. Studies using
      confocal microscopy indicate that subsarcolemmal Ca2+ release via ryanodine
      receptors occurs not only in response to the action potential (AP) upstroke, but
      also during the DD, and this is augmented by beta-adrenergic receptor (beta-AR)
      stimulation. Spontaneous APs simulated by mathematical SANC models beat at a
      faster rate when this subsarcolemmal Ca2+ waveform measured under beta-AR
      stimulation is introduced into the modeling scheme. Thus, in future investigation
      of pacemaker functioning in health, disease, and disease therapies the "bar ought
      to be raised" to embrace the impact of cyclic variation in submembrane [Ca2+] on
      pacemaker function. The full text of this article is available at
      http://www.circresaha.org.

PMID- 12595349
TI  - Ottawa ankle rules for the injured ankle.

PMID- 12595350
TI  - Should psychiatrists protect the public?

PMID- 12595351
TI  - Patients choosing their hospital.

PMID- 12595352
TI  - Fewer new drugs from the pharmaceutical industry.

PMID- 12595353
TI  - Zinc deficiency.

PMID- 12595355
TI  - GMC may be open to accusations of racial bias.

PMID- 12595356
TI  - NICE to start assessing diagnostic and treatment procedures.

PMID- 12595357
TI  - WHO accused of watering down tobacco treaty.

PMID- 12595358
TI  - Anti-Glaxo campaign heats up in United States.

PMID- 12595359
TI  - Italian police investigate GSK Italy for bribery.

PMID- 12595360
TI  - EU parliament calls for tougher rules on breast implants.

PMID- 12595361
TI  - Dutch health service is asked to draw up smallpox contingency plans.

PMID- 12595362
TI  - AIDS vaccine trial begins in Uganda.

PMID- 12595363
TI  - WHO faces funding controversy over new food fund.

PMID- 12595365
TI  - Junior doctor is cleared of manslaughter after feeding tube error.

PMID- 12595366
TI  - US court rules that insane prisoners can be executed.

PMID- 12595369
TI  - Whistle blowing consultant suspended again.

PMID- 12595377
TI  - Pneumonia causes panic in Guangdong province.

PMID- 12595378
TI  - Accuracy of Ottawa ankle rules to exclude fractures of the ankle and mid-foot:
      systematic review.
AB  - OBJECTIVE: To summarise the evidence on accuracy of the Ottawa ankle rules, a
      decision aid for excluding fractures of the ankle and mid-foot. DESIGN:
      Systematic review. DATA SOURCES: Electronic databases, reference lists of
      included studies, and experts. REVIEW METHODS: Data were extracted on the study
      population, the type of Ottawa ankle rules used, and methods. Sensitivities, but
      not specificities, were pooled using the bootstrap after inspection of the
      receiver operating characteristics plot. Negative likelihood ratios were pooled
      for several subgroups, correcting for four main methodological threats to
      validity. RESULTS: 32 studies met the inclusion criteria and 27 studies reporting
      on 15 581 patients were used for meta-analysis. The pooled negative likelihood
      ratios for the ankle and mid-foot were 0.08 (95% confidence interval 0.03 to
      0.18) and 0.08 (0.03 to 0.20), respectively. The pooled negative likelihood ratio
      for both regions in children was 0.07 (0.03 to 0.18). Applying these ratios to a
      15% prevalence of fracture gave a less than 1.4% probability of actual fracture
      in these subgroups. CONCLUSIONS: Evidence supports the Ottawa ankle rules as an
      accurate instrument for excluding fractures of the ankle and mid-foot. The
      instrument has a sensitivity of almost 100% and a modest specificity, and its use
      should reduce the number of unnecessary radiographs by 30-40%.

PMID- 12595379
TI  - Maternal consumption of coffee during pregnancy and stillbirth and infant death
      in first year of life: prospective study.
AB  - OBJECTIVE: To study the association between coffee consumption during pregnancy
      and the risk of stillbirth and infant death in the first year of life. DESIGN:
      Prospective follow up study. SETTING: Aarhus University Hospital, Denmark, 1989
      96. PARTICIPANTS: 18 478 singleton pregnancies in women with valid information
      about coffee consumption during pregnancy. MAIN OUTCOME MEASURES: Stillbirth
      (delivery of a dead fetus at > or =28 weeks' gestation) and infant death (death
      of a liveborn infant during the first year of life). RESULTS: Pregnant women who
      drank eight or more cups of coffee per day during pregnancy had an increased risk
      of stillbirth compared with women who did not drink coffee (odds ratio=3.0, 95%
      confidence interval 1.5 to 5.9). After adjustment for smoking habits and alcohol
      intake during pregnancy, the relative risk of stillbirth decreased slightly.
      Adjustment for parity, maternal age, marital status, years of education,
      occupational status, and body mass index did not substantially change the
      estimates of association. There was no significant association between coffee
      consumption and death in the first year of life after adjustment for smoking
      habits during pregnancy. CONCLUSION: Drinking coffee during pregnancy is
      associated with an increased risk of stillbirth but not with infant death.

PMID- 12595380
TI  - Longitudinal study of childhood wheezy bronchitis and asthma: outcome at age 42.

PMID- 12595381
TI  - Spontaneous loss of early pregnancy and risk of ischaemic heart disease in later
      life: retrospective cohort study.

PMID- 12595382
TI  - Incidence of erectile dysfunction and characteristics of patients before and
      after the introduction of sildenafil in the United Kingdom: cross sectional study
      with comparison patients.

PMID- 12595383
TI  - Relation between hormone replacement therapy and ischaemic heart disease in
      women: prospective observational study.
AB  - OBJECTIVE: To investigate the risk of ischaemic heart disease and myocardial
      infarction among women using hormone replacement therapy, especially the
      potential modifying effect of cardiovascular risk factors. DESIGN: Prospective
      observational study. SETTING: Denmark. PARTICIPANTS: 19 898 nurses aged 45 and
      over completing a questionnaire on lifestyle and use of hormone replacement
      therapy in 1993. MAIN OUTCOME MEASURES: All cases of death and incident cases of
      ischaemic heart disease and myocardial infarction until the end of 1998. RESULTS:
      Current users of hormone replacement therapy smoked more, consumed more alcohol,
      had lower self rated health, but were slimmer and had a lower prevalence of
      diabetes than never users. In current users compared with never users, hormone
      replacement therapy had no protective effect on ischaemic heart disease (hazard
      ratio 1.2, 0.9 to 1.7) or myocardial infarction (1.0, 0.6 to 1.7), whereas
      current users with diabetes had an increased risk of death (3.2, 1.4 to 7.5),
      ischaemic heart disease (4.2, 1.4 to 12.5), and myocardial infarction (9.2, 2.0
      to 41.4) compared with never users with diabetes. CONCLUSION: Hormone replacement
      therapy showed no protective effect on ischaemic heart disease, but there was a
      significantly increased risk of death from all causes and ischaemic heart disease
      among women with diabetes.

PMID- 12595384
TI  - Pilot study of the roles of personality, references, and personal statements in
      relation to performance over the five years of a medical degree.
AB  - OBJECTIVES: To compare the power of three traditional selection procedures (A
      levels, personal statements, and references) and one non-traditional selection
      procedure (personality) to predict performance over the five years of a medical
      degree. DESIGN: Cohort study over five years. SETTING: Nottingham medical school.
      PARTICIPANTS: Entrants in 1995. MAIN OUTCOME MEASURES: A level grades, amounts of
      information contained in teacher's reference and the student's personal
      statement, and personality scores examined in relation to 18 different
      assessments. RESULTS: Information in the teacher's reference did not consistently
      predict performance. Information in the personal statement was predictive of
      clinical aspects of training, whereas A level grades primarily predicted
      preclinical performance. The personality domain of conscientiousness was
      consistently the best predictor across the course. A structural model indicated
      that conscientiousness was positively related to A level grades and preclinical
      performance but was negatively related to clinical grades. CONCLUSION: A
      teacher's reference is of no practical use in predicting clinical performance of
      medical students, in contrast to the amount of information contained in the
      personal statement. Therefore, simple quantification of the personal statement
      should aid selection. Personality factors, in particular conscientiousness, need
      to be considered and integrated into selection procedures.

PMID- 12595385
TI  - Investigation and management of chronic dysphagia.

PMID- 12595386
TI  - Teaching large groups.

PMID- 12595387
TI  - Epistaxis: an overlooked cause of massive haematemesis in cirrhosis.

PMID- 12595388
TI  - Strategies for preventing heroin overdose.

PMID- 12595389
TI  - New BMJ policy on economic evaluations. Response of NHS Economic Evaluation
      Database Research Team.

PMID- 12595390
TI  - Self help smoking cessation in pregnancy. Programmes for smoking cessation can
      work.

PMID- 12595391
TI  - WHO advocates investment in global infrastructure for outbreaks such as smallpox.

PMID- 12595392
TI  - Polyspecific snake antivenom may help in antivenom crisis.

PMID- 12595393
TI  - Randomised controlled trial for twin delivery.

PMID- 12595394
TI  - Thrombolysis with recombinant streptokinase in Cuba.

PMID- 12595395
TI  - Checklists for myocardial infarction should be precise.

PMID- 12595396
TI  - Copying letters to patients. Psychiatrists omit information from letters when
      they know patients will be sent copies.

PMID- 12595398
TI  - How can we reduce the stigma of mental illness?

PMID- 12595399
TI  - Disclosing personal health information: Daniella's dilemma.

PMID- 12595401
TI  - Detecting adverse events using information technology.
AB  - CONTEXT: Although patient safety is a major problem, most health care
      organizations rely on spontaneous reporting, which detects only a small minority
      of adverse events. As a result, problems with safety have remained hidden. Chart
      review can detect adverse events in research settings, but it is too expensive
      for routine use. Information technology techniques can detect some adverse events
      in a timely and cost-effective way, in some cases early enough to prevent patient
      harm. OBJECTIVE: To review methodologies of detecting adverse events using
      information technology, reports of studies that used these techniques to detect
      adverse events, and study results for specific types of adverse events. DESIGN:
      Structured review. METHODOLOGY: English-language studies that reported using
      information technology to detect adverse events were identified using standard
      techniques. Only studies that contained original data were included. MAIN OUTCOME
      MEASURES: Adverse events, with specific focus on nosocomial infections, adverse
      drug events, and injurious falls. RESULTS: Tools such as event monitoring and
      natural language processing can inexpensively detect certain types of adverse
      events in clinical databases. These approaches already work well for some types
      of adverse events, including adverse drug events and nosocomial infections, and
      are in routine use in a few hospitals. In addition, it appears likely that these
      techniques will be adaptable in ways that allow detection of a broad array of
      adverse events, especially as more medical information becomes computerized.
      CONCLUSION: Computerized detection of adverse events will soon be practical on a
      widespread basis.

PMID- 12595402
TI  - The effects of promoting patient access to medical records: a review.
AB  - The Health Insurance Privacy and Portability Act (HIPPA) stipulates that patients
      must be permitted to review and amend their medical records. As information
      technology makes medical records more accessible to patients, it may become more
      commonplace for patients to review their records routinely. This article analyzes
      the potential benefits and drawbacks of facilitating patient access to the
      medical record by reviewing previously published research. Previous research
      includes analysis of clinical notes, surveys of patients and practitioners, and
      studies of patient-accessible medical records. Overall, studies suggest the
      potential for modest benefits (for instance, in enhancing doctor-patient
      communication). Risks (for instance, increasing patient worry or confusion)
      appear to be minimal in medical patients. The studies, however, were of limited
      quality and low statistical power to detect the variety of outcomes that may
      result from implementation of a patient-accessible medical record. The data from
      these studies lay the foundation for future research.

PMID- 12595403
TI  - Handheld computing in medicine.
AB  - Handheld computers have become a valuable and popular tool in various fields of
      medicine. A systematic review of articles was undertaken to summarize the current
      literature regarding the use of handheld devices in medicine. A variety of
      articles were identified, and relevant information for various medical fields was
      summarized. The literature search covered general information about handheld
      devices, the use of these devices to access medical literature, electronic
      pharmacopoeias, patient tracking, medical education, research, business
      management, e-prescribing, patient confidentiality, and costs as well as
      specialty-specific uses for personal digital assistants (PDAs). The authors
      concluded that only a small number of articles provide evidence-based information
      about the use of PDAs in medicine. The majority of articles provide descriptive
      information, which is nevertheless of value. This article aims to increase the
      awareness among physicians about the potential roles for handheld computers in
      medicine and to encourage the further evaluation of their use.

PMID- 12595404
TI  - Webcasting videoconferences over IP: a synchronous communication experiment.
AB  - A multipoint videoconference was webcast live to an audience who could
      communicate with conference panelists and each other via chat. The
      videoconference, webcast, and chat were done entirely over the Internet. Seven
      panelists at four conference sites that had Internet2 connectivity and were
      located in different time zones within the continental United States discussed
      the topic of "Evaluating Health Professions Education and Information Resources
      on the Web." This discussion was broadcast to individuals and groups at various
      U.S. locations who had expressed an interest in the topic and had sufficient
      connectivity for receiving the video stream. Webcast recipients could log on a
      chat server and type questions and comments to the panelists and other viewers.
      The experiment's rationale, procedures, and outcomes are described, and issues
      associated with the use of the technologies are identified.

PMID- 12595405
TI  - Automating complex guidelines for chronic disease: lessons learned.
AB  - There is scant published experience with implementing complex, multistep
      computerized practice guidelines for the long-term management of chronic
      diseases. We have implemented a system for creating, maintaining, and navigating
      computer-based clinical algorithms integrated with our electronic medical record.
      This article describes our progress and reports on lessons learned that might
      guide future work in this field. We discuss issues and obstacles related to
      choosing and adapting a guideline for electronic implementation, representing and
      executing the guideline as a computerized algorithm, and integrating it into the
      clinical workflow of outpatient care. Although obstacles were encountered at each
      of these steps, the most difficult were related to workflow integration.

PMID- 12595406
TI  - Telehealth technologies and applications for terrorism response: a report of the
      2002 coastal North Carolina domestic preparedness training exercise.
AB  - Effective response to natural or man-made disasters (i.e., terrorism) is
      predicated on the ability to communicate among the many organizations involved.
      Disaster response exercises enable disaster planners and responders to test
      procedures and technologies and incorporate the lessons learned from past
      disasters or exercises. On May 31 and June 1, 2002, one such exercise event took
      place at the Camp Lejeune Marine Corps Base in Jacksonville, North Carolina.
      During the exercise, East Carolina University tested: (1) in-place Telehealth
      networks and (2) rapidly deployable communications, networking, and data
      collection technologies such as satellite communications, local wireless
      networking, on-scene video, and clinical and environmental data acquisition and
      telemetry. Exercise participants included local, county, state, and military
      emergency medical services (EMS), emergency management, specialized response
      units, and local fire and police units. The technologies and operations concepts
      tested at the exercise and recommendations for using telehealth to improve
      disaster response are described.

PMID- 12595407
TI  - The effect of computer-generated reminders on charting deficiencies in the ICU.
AB  - OBJECTIVE: To examine the effect of computer-generated reminders on nurse
      charting deficiencies in two intensive care units. DESIGN: Nurses caring for a
      group of 60 study patients received patient-specific paper reminder reports when
      charting deficiencies were found at mid-day. Nurses caring for a group of 60
      control patients received no reminders. A group of 60 retrospective patients was
      also formed. MEASUREMENTS: The average numbers of charting deficiencies at the
      end of the shift in each of the three groups were compared using two planned
      orthogonal contrasts. RESULTS: The average in the study group patients was 1.02
      deficiencies per day per patient, whereas the control group the average was 1.40
      deficiencies per day per patient (p = 0.001). The average number of end-of-shift
      deficiencies in the pooled prospective (study/control) population was 1.21
      deficiencies per day per patient, compared with the average in the retrospective
      group of 1.56 deficiencies per day per patient (p < 0.001). CONCLUSION: The
      decrease was likely due both to the appropriate response of the nurses to the
      reminders and to a learned attentiveness to the tasks on the part of the nurses
      who cared for study patients. Greater gains were hindered by incomplete
      "coupling" of the reminders to the end-of-shift deficiencies and by inaccuracies
      in the reminders.

PMID- 12595408
TI  - A cross-site qualitative study of physician order entry.
AB  - OBJECTIVE: To describe the perceptions of diverse professionals involved in
      computerized physician order entry (POE) at sites where POE has been successfully
      implemented and to identify differences between teaching and nonteaching
      hospitals. DESIGN: A multidisciplinary team used observation, focus groups, and
      interviews with clinical, administrative, and information technology staff to
      gather data at three sites. Field notes and transcripts were coded using an
      inductive approach to identify patterns and themes in the data. MEASUREMENTS:
      Patterns and themes concerning perceptions of POE were identified. RESULTS: Four
      high-level themes were identified: (1) organizational issues such as
      collaboration, pride, culture, power, politics, and control; (2) clinical and
      professional issues involving adaptation to local practices, preferences, and
      policies; (3) technical/implementation issues, including usability, time,
      training and support; and (4) issues related to the organization of information
      and knowledge, such as system rigidity and integration. Relevant differences
      between teaching and nonteaching hospitals include extent of collaboration, staff
      longevity, and organizational missions. CONCLUSION: An organizational culture
      characterized by collaboration and trust and an ongoing process that includes
      active clinician engagement in adaptation of the technology were important
      elements in successful implementation of physician order entry at the
      institutions that we studied.

PMID- 12595409
TI  - Incentives and barriers that influence clinical computerization in Hong Kong: a
      population-based physician survey.
AB  - OBJECTIVE: Given the slow adoption of medical informatics in Hong Kong and Asia,
      we sought to understand the contributory barriers and potential incentives
      associated with information technology implementation. DESIGN AND MEASUREMENTS: A
      representative sample of 949 doctors (response rate = 77.0%) was asked through a
      postal survey to rank a list of nine barriers associated with clinical
      computerization according to self-perceived importance. They ranked seven
      incentives or catalysts that may influence computerization. We generated mean
      rank scores and used multidimensional preference analysis to explore key
      explanatory dimensions of these variables. A hierarchical cluster analysis was
      performed to identify homogenous subgroups of respondents. We further determined
      the relationships between the sets of barriers and incentives/catalysts
      collectively using canonical correlation. RESULTS: Time costs, lack of technical
      support and large capital investments were the biggest barriers to
      computerization, whereas improved office efficiency and better-quality care were
      ranked highest as potential incentives to computerize. Cost vs. noncost,
      physician-related vs. patient-related, and monetary vs. nonmonetary factors were
      the key dimensions explaining the barrier variables. Similarly, within-practice
      vs external and "push" vs "pull" factors accounted for the incentive variables.
      Four clusters were identified for barriers and three for incentives/catalysts.
      Canonical correlation revealed that respondents who were concerned with the costs
      of computerization also perceived financial incentives and government regulation
      to be important incentives/catalysts toward computerization. Those who found the
      potential interference with communication important also believed that the
      promise of improved care from computerization to be a significant incentive.
      CONCLUSION: This study provided evidence regarding common barriers associated
      with clinical computerization. Our findings also identified possible incentive
      strategies that may be employed to accelerate uptake of computer systems.

PMID- 12595410
TI  - XML Schema Representation of DICOM Structured Reporting.
AB  - OBJECTIVE: The Digital Imaging and Communications in Medicine (DICOM) Structured
      Reporting (SR) standard improves the expressiveness, precision, and comparability
      of documentation about diagnostic images and waveforms. It supports the
      interchange of clinical reports in which critical features shown by images and
      waveforms can be denoted unambiguously by the observer, indexed, and retrieved
      selectively by subsequent reviewers. It is essential to provide access to
      clinical reports across the health care enterprise by using technologies that
      facilitate information exchange and processing by computers as well as provide
      support for robust and semantically rich standards, such as DICOM. This is
      supported by the current trend in the healthcare industry towards the use of
      Extensible Markup Language (XML) technologies for storage and exchange of medical
      information. The objective of the work reported here is to develop XML Schema for
      representing DICOM SR as XML documents. DESIGN: We briefly describe the document
      type definition (DTD) for XML and its limitations, followed by XML Schema (the
      intended replacement for DTD) and its features. A framework for generating XML
      Schema for representing DICOM SR in XML is presented next. MEASUREMENTS: None
      applicable. RESULTS: A schema instance based on an SR example in the DICOM
      specification was created and validated against the schema. The schema is being
      used extensively in producing reports on Philips Medical Systems ultrasound
      equipment. CONCLUSION: With the framework described it is feasible to generate
      XML Schema using the existing DICOM SR specification. It can also be applied to
      generate XML Schemas for other DICOM information objects.

PMID- 12595411
TI  - Harriet Helen Werley, PhD, RN, FAAN, FACMI.

PMID- 12595412
TI  - Policy and the future of adverse event detection using information technology.

PMID- 12595413
TI  - Regions of PspA/EF3296 best able to elicit protection against Streptococcus
      pneumoniae in a murine infection model.
AB  - Pneumococcal surface protein A (PspA) can elicit protection against Streptococcus
      pneumoniae in mouse infection models. PspA is classified by serology and amino
      acid sequence into two major families that are divided by sequence into five
      clades. The most variable portion of the molecule is the alpha-helical domain,
      which comprises the N-terminal half of PspA. Prior studies of a family 1 PspA
      protein observed that protective antibodies are reactive with epitopes in the
      alpha-helical domain and that most cross-protective epitopes mapped to the 108
      most C-terminal amino acids of the alpha-helical region. In these studies, we
      have used six overlapping recombinant fragments of family 2, clade 3 PspA/EF3296
      to map the protection-eliciting regions of its alpha-helical domain. The three
      fragments, which included the 104 most C-terminal amino acids of the alpha
      helical domain (314 to 418), could each elicit protection against EF3296. A
      fragment comprising amino acids 75 to 305 failed to elicit significant
      protection. A fragment containing amino acids 1 to 115 elicited protection
      against EF3296 in BALB/c mice but not in CBA/N mice. All three fragments
      containing amino acids 314 to 418 were able to elicit cross-protection against
      pneumococci expressing PspA proteins of clades 2, 3, 4, and 5. Cross-protection
      elicited by these three fragments was easier to demonstrate in CBA/N mice than in
      BALB/c mice. The 1-to-115 fragment, however, elicited some cross-protection
      against clades 2 and 4 in BALB/c mice but not in CBA/N mice. These studies
      provide support for the importance of the C-terminal 104 and N-terminal 115 amino
      acids of the alpha-helical region of PspA in the elicitation of cross-protection.

PMID- 12595414
TI  - Identification and characterization of a Streptococcus pyogenes operon involved
      in binding of hemoproteins and acquisition of iron.
AB  - The hemolytic Streptococcus pyogenes can use a variety of heme compounds as an
      iron source. In this study, we investigate hemoprotein utilization by S.
      pyogenes. We demonstrate that surface proteins contribute to the binding of
      hemoproteins to S. pyogenes. We identify an ABC transporter from the iron complex
      family named sia for streptococcal iron acquisition, which consists of a
      lipoprotein (siaA), membrane permease (siaB), and ATPase (siaC). The sia
      transporter is part of a highly conserved, iron regulated, 10-gene operon. SiaA,
      which was localized to the cell membrane, could specifically bind hemoglobin. The
      operon's first gene encodes a novel bacterial protein that bound hemoglobin,
      myoglobin, heme-albumin, and hemoglobin-haptoglobin (but not apo-haptoglobin) and
      therefore was named Shr, for streptococcal hemoprotein receptor. PhoZ fusion and
      Western blot analysis showed that Shr has a leader peptide and is found in both
      membrane-bound and soluble forms. An M1 SF370 strain with a polar mutation in shr
      was more resistant to streptonigrin and hydrogen peroxide, suggesting decreased
      iron uptake. The addition of hemoglobin to the culture medium increased cell
      resistance to hydrogen peroxide in SF370 but not in the mutant, implying the sia
      operon may be involved in hemoglobin-dependent resistance to oxidative stress.
      The shr mutant demonstrated reduced hemoglobin binding, though cell growth in
      iron-depleted medium supplemented with hemoglobin, whole blood, or ferric citrate
      was not affected, suggesting additional systems are involved in hemoglobin
      utilization. SiaA and Shr are the first hemoprotein receptors identified in S.
      pyogenes; their possible role in iron capture is discussed.

PMID- 12595415
TI  - Antibodies raised against Bcvir15, an extrachromosomal double-stranded RNA
      encoded protein from Babesia canis, inhibit the in vitro growth of the parasite.
AB  - As part of a search for homologous members of the Plasmodium falciparum Pf60
      multigene family in the intraerythrocytic protozoan parasite Babesia canis, we
      report here the characterization of a cDNA of 1,115 bp, which was designated
      Bcvir for its potential viral origin. The Bcvir cDNA contained two overlapping
      open reading frames (ORFs) (ORF1 from nucleotide [nt] 61 to 486 and ORF2 from nt
      417 to 919), where Bcvir15, the deduced ORF1 peptide (M(1) to I(141)), is the
      main expressed product. The Bcvir cDNA was derived from an extrachromosomal dsRNA
      element of 1.2 kbp that was always found associated with a double-stranded RNA
      (dsRNA) of 2.8 kbp by hybridization, and no copy of this cDNA sequence was found
      in B. canis genomic DNA. Biochemical characterization of Bcvir15, by using
      polyclonal rabbit sera directed against recombinant proteins, indicated that it
      is a soluble protein which remained associated with the cytoplasm of the B. canis
      merozoite. Interestingly, purified immunoglobulins from the anti-glutathione S
      transferase-Bcvir15 (at a concentration of 160 micro g/ml) induced 50% inhibition
      of the in vitro growth of B. canis, and the inhibitory effect was associated with
      morphological damage of the parasite. Our data suggest that the extrachromosomal
      dsRNA-encoded Bcvir15 protein might interfere with the intracellular growth of
      the parasite rather than with the process of invasion of the host cell by the
      merozoite. Epitope mapping of Bcvir15 identified three epitopes that might be
      essential for the function of the protein.

PMID- 12595416
TI  - The Afa/Dr adhesins of diffusely adhering Escherichia coli stimulate interleukin
      8 secretion, activate mitogen-activated protein kinases, and promote
      polymorphonuclear transepithelial migration in T84 polarized epithelial cells.
AB  - Afa/Dr diffusely adhering Escherichia coli (Afa/Dr DAEC) strains cause
      symptomatic urinary tract and intestinal infections. The proinflammatory effects
      of Afa/Dr DAEC strains in vitro have been not investigated to date. In the
      present study, we used confluent polarized monolayers of intestinal cell line T84
      to evaluate the consequences of epithelial infection by Afa/Dr DAEC strains in
      terms of proinflammatory response. Polymorphonuclear leukocyte (PMNL) migration
      across the epithelial barrier was induced after incubation of the T84 monolayers
      with the wild-type Afa/Dr DAEC strain C1845 harboring the fimbrial F1845 adhesin
      and strain IH11128 harboring the Dr hemagglutinin, and the E. coli laboratory
      strain HB101 was transformed with the pSSS1 plasmid, producing Afa/Dr F1845
      adhesin. PMNL migrations were correlated with a basolateral secretion of
      interleukin-8 by T84 cells and were abolished after incubation of epithelial
      cells with an anti-decay accelerating factor (DAF) antibody that recognized the
      short consensus repeat 3 domain of DAF (monoclonal antibody 1H4). Moreover,
      Afa/Dr DAEC strains induced tyrosine phosphorylation of several T84 proteins and
      activated the mitogen-activated protein kinases (ERK1/2 mitogen-activated
      protein, P38, and Jun-C kinases). These data demonstrated for the first time
      that, in vitro, Afa/Dr DAEC strains exert a proinflammatory signal in intestinal
      epithelial cells.

PMID- 12595417
TI  - Production of the type IV secretion system differs among Brucella species as
      revealed with VirB5- and VirB8-specific antisera.
AB  - Expression of the virB operon, encoding the type IV secretion system required for
      Brucella suis virulence, occurred in the acidic phagocytic vacuoles of
      macrophages and could be induced in minimal medium at acidic pH values. To
      analyze the production of VirB proteins, polyclonal antisera against B. suis
      VirB5 and VirB8 were generated. Western blot analysis revealed that VirB5 and
      VirB8 were detected after 3 h in acidic minimal medium and that the amounts
      increased after prolonged incubation. Unlike what occurs in the related organism
      Agrobacterium tumefaciens, the periplasmic sugar binding protein ChvE did not
      contribute to VirB protein production, and B. suis from which chvE was deleted
      was fully virulent in a mouse model. Comparative analyses of various Brucella
      species revealed that in all of them VirB protein production increased under
      acidic conditions. However, in rich medium at neutral pH, Brucella canis and B.
      suis, as well as the Brucella abortus- and Brucella melitensis-derived vaccine
      strains S19, RB51, and Rev.1, produced no VirB proteins or only small amounts of
      VirB proteins, whereas the parental B. abortus and B. melitensis strains
      constitutively produced VirB5 and VirB8. Thus, the vaccine strains were still
      able to induce virB expression under acidic conditions, but the VirB protein
      production was markedly different from that in the wild-type strains at pH 7.
      Taken together, the data indicate that VirB protein production and probably
      expression of the virB operon are not uniformly regulated in different Brucella
      species. Since VirB proteins were shown to modulate Brucella phagocytosis and
      intracellular trafficking, the differential regulation of the production of these
      proteins reported here may provide a clue to explain their role(s) during the
      infection process.

PMID- 12595419
TI  - Identification of genetic loci required for capsular expression in Vibrio
      vulnificus.
AB  - Transposon mutagenesis of an encapsulated, virulent strain of Vibrio vulnificus
      1003(O) led to the identification of four genetic regions that are essential to
      capsular polysaccharide (CPS) expression and virulence. Of the four regions,
      three are believed to be part of a capsule gene locus comprised of biosynthesis,
      polymerization, and transport genes clustered on a single chromosomal fragment.
      Genes indicating a Wzy-dependent system of polymerization and transmembrane
      export are present, suggesting that the CPS of V. vulnificus is lipid linked. The
      fourth region, while it contains a gene essential for CPS expression, is
      characteristic of an integron-gene cassette region, similar to the super integron
      of V. cholerae. It is not believed to be part of a CPS gene locus and is located
      in a region of the chromosome separate from the putative CPS loci. It is
      comprised of open reading frames (ORFs) carrying genes of unknown function
      surrounded by direct repeats. This region also contains IS492, an insertion
      sequence located numerous times throughout a region of the genome, demonstrating
      a restriction fragment length polymorphism among an encapsulated and
      nonencapsulated morphotype of V. vulnificus. Collectively, 22 ORFs were
      recognized: 13 capsule synthesis genes, 4 insertion sequences, 1 truncated
      biosynthesis gene, and 4 genes of unknown function. This study has led to the
      identification of previously unrecognized genetic loci that may help to increase
      the understanding of capsular genetics and antigenic diversity among V.
      vulnificus strains.

PMID- 12595418
TI  - Enteral immunization with attenuated recombinant Listeria monocytogenes as a live
      vaccine vector: organ-dependent dynamics of CD4 T lymphocytes reactive to a
      Leishmania major tracer epitope.
AB  - Listeria monocytogenes is considered as a potential live bacterial vector,
      particularly for the induction of CD8 T cells. The CD4 T-cell immune response
      triggered after enteral immunization of mice has not yet been thoroughly
      characterized. The dynamics of gamma interferon (IFN-gamma)- and interleukin-4
      (IL-4)-secreting CD4 T cells were analyzed after priming through intragastric
      delivery of an attenuated delta actA recombinant L. monocytogenes strain
      expressing the Leishmania major LACK protein; a peptide of this protein, LACK(158
      173) peptide (pLACK), is a well-characterized CD4 T-cell target in BALB/c mice.
      Five compartments were monitored: Peyer's patches, mesenteric lymph nodes (MLN),
      spleen, liver, and blood. A single intragastric inoculation of delta actA-LACK-LM
      in BALB/c mice led to colonization of the MLN and spleen at a significant level
      for at least 3 days. Efficient priming of IFN-gamma-secreting pLACK-reactive CD4
      T cells was observed in all tested compartments. Interestingly, IL-4-secreting
      pLACK-reactive CD4 T cells were detectable at day 6 or 7 only in blood and liver.
      The absence of translocation of viable bacteria through the intestinal epithelium
      after further delta actA-LACK-LM inoculations was concomitant with the absence of
      an increase in the level of IFN-gamma secreted by the MLN, blood, and splenic
      pLACK-reactive Th1 T cells, although the levels remained significantly above the
      basal level. No change in this population size was detected in the spleen.
      However, an increase in the number of intragastric inoculations had a clinical
      beneficial effect in L. major-infected BALB/c mice. L. monocytogenes thus
      presents the potential of an efficient vector for induction of CD4 T cells when
      administered by the enteral route.

PMID- 12595420
TI  - Position-based scanning for comparative genomics and identification of genetic
      islands in Haemophilus influenzae type b.
AB  - Bacteria exhibit extensive genetic heterogeneity within species. In many cases,
      these differences account for virulence properties unique to specific strains.
      Several such loci have been discovered in the genome of the type b serotype of
      Haemophilus influenzae, a human pathogen able to cause meningitis, pneumonia, and
      septicemia. Here we report application of a PCR-based scanning procedure to
      compare the genome of a virulent type b (Hib) strain with that of the laboratory
      passaged Rd KW20 strain for which a complete genome sequence is available. We
      have identified seven DNA segments or H. influenzae genetic islands (HiGIs)
      present in the type b genome and absent from the Rd genome. These segments vary
      in size and content and show signs of horizontal gene transfer in that their
      percent G+C content differs from that of the rest of the H. influenzae genome,
      they contain genes similar to those found on phages or other mobile elements, or
      they are flanked by DNA repeats. Several of these loci represent potential
      pathogenicity islands, because they contain genes likely to mediate interactions
      with the host. These newly identified genetic islands provide areas of
      investigation into both the evolution and pathogenesis of H. influenzae. In
      addition, the genome scanning approach developed to identify these islands
      provides a rapid means to compare the genomes of phenotypically diverse bacterial
      strains once the genome sequence of one representative strain has been
      determined.

PMID- 12595421
TI  - Enteric salmonella infection inhibits Paneth cell antimicrobial peptide
      expression.
AB  - Paneth cells, highly secretory epithelial cells found at the bases of small
      intestinal crypts, release a variety of microbicidal molecules, including alpha
      defensins and lysozyme. The secretion of antimicrobials by Paneth cells is
      thought to be important in mucosal host defense against invasion by enteric
      pathogens. We explored whether enteric pathogens can interfere with this arm of
      defense. We found that oral inoculation of mice with wild-type Salmonella
      enterica serovar Typhimurium decreases the expression of alpha-defensins (called
      cryptdins in mice) and lysozyme. Oral inoculation with Salmonella serovar
      Typhimurium strains that are heat killed, lack the PhoP regulon, and lack the
      SPI1 type III secretion system or with Listeria monocytogenes does not have this
      effect. Salmonella may gain a specific survival advantage in the intestinal lumen
      by decreasing the expression of microbicidal peptides in Paneth cells through
      direct interactions between Salmonella and the small intestinal epithelium.

PMID- 12595422
TI  - Allelic variation in TLR4 is linked to susceptibility to Salmonella enterica
      serovar Typhimurium infection in chickens.
AB  - Toll-like receptor 4 (TLR4) is part of a group of evolutionarily conserved
      pattern recognition receptors involved in the activation of the immune system in
      response to various pathogens and in the innate defense against infection. We
      describe here the cloning and characterization of the avian orthologue of
      mammalian TLR4. Chicken TLR4 encodes a 843-amino-acid protein that contains a
      leucine-rich repeat extracellular domain, a short transmembrane domain typical of
      type I transmembrane proteins, and a Toll-interleukin-1R signaling domain
      characteristic of all TLR proteins. The chicken TLR4 protein shows 46% identity
      (64% similarity) to human TLR4 and 41% similarity to other TLR family members.
      Northern blot analysis reveals that TLR4 is expressed at approximately the same
      level in all tissues tested, including brain, thymus, kidney, intestine, muscle,
      liver, lung, bursa of Fabricius, heart, and spleen. The probe detected only one
      transcript of ca. 4.4 kb in length for all tissues except muscle where the size
      of TLR4 mRNA was ca. 9.6 kb. We have mapped TLR4 to microchromosome E41W17 in a
      region harboring the gene for tenascin C and known to be well conserved between
      the chicken and mammalian genomes. This region of the chicken genome was shown
      previously to harbor a Salmonella susceptibility locus. By using linkage
      analysis, TLR4 was shown to be linked to resistance to infection with Salmonella
      enterica serovar Typhimurium in chickens (likelihood ratio test of 10.2, P =
      0.00138), suggesting a role of TLR4 in the host response of chickens to
      Salmonella infection.

PMID- 12595423
TI  - Microarray analysis of mRNA levels from RAW264.7 macrophages infected with
      Brucella abortus.
AB  - Identification of host responses at the gene transcription level provides a
      molecular profile of the events that occur following infection. Brucella abortus
      is a facultative intracellular pathogen of macrophages that induces chronic
      infection in humans and domestic animals. Using microarray technology, the
      response of macrophages 4 h following B. abortus infection was analyzed to
      identify early intracellular infection events that occur in macrophages. Of the
      >6,000 genes, we identified over 140 genes that were reproducibly differentially
      transcribed. First, an increase in the transcription of a number of
      proinflammatory cytokines and chemokines, such as tumor necrosis factor alpha,
      interleukin-1beta (IL-1beta), IL-1alpha, and members of the SCY family of
      proteins, that may constitute a general host recruitment of antibacterial
      defenses was evident. Alternatively, Brucella may subvert newly arriving
      macrophages for additional intracellular infection. Second, transcription of
      receptors and cytokines associated with antigen presentation, e.g., major
      histocompatibility complex class II and IL-12p40, were not evident at this 4-h
      period of infection. Third, Brucella inhibited transcription of various host
      genes involved in apoptosis, cell cycling, and intracellular vesicular
      trafficking. Identification of macrophage genes whose transcription was inhibited
      suggests that Brucella utilizes specific mechanisms to target certain cell
      pathways. In conclusion, these data suggest that B. abortus can alter macrophage
      pathways to recruit additional macrophages for future infection while
      simultaneously inhibiting apoptosis and innate immune mechanisms within the
      macrophage, permitting intracellular survival of the bacterium. These results
      provide insights into the pathogenic strategies used by Brucella for long-term
      survival within a hostile environment.

PMID- 12595424
TI  - Deletion of two-component regulatory systems increases the virulence of
      Mycobacterium tuberculosis.
AB  - Two-component regulatory signal transduction systems are widely distributed among
      bacteria and enable the organisms to make coordinated changes in gene expression
      in response to a variety of environmental stimuli. The genome sequence of
      Mycobacterium tuberculosis contains 11 complete two-component systems, four
      isolated homologous regulators, and three isolated homologous sensors. We have
      constructed defined mutations in six of these genes and measured virulence in a
      SCID mouse model. Mice infected with four of the mutants (deletions of devR,
      tcrXY, trcS, and kdpDE) died more rapidly than those infected with wild-type
      bacteria. The other two mutants (narL and Rv3220c) showed no change compared to
      the wild-type H37Rv strain. The most hypervirulent mutant (devRdelta) also grew
      more rapidly in the acute stage of infection in immunocompetent mice and in gamma
      interferon-activated macrophages. These results define a novel class of genes in
      this pathogen whose presence slows down its multiplication in vivo or increases
      its susceptibility to host killing mechanisms. Thus, M. tuberculosis actively
      maintains a balance between its own survival and that of the host.

PMID- 12595425
TI  - The shufflon of Salmonella enterica serovar Typhi regulates type IVB pilus
      mediated bacterial self-association.
AB  - Previously, it was shown that type IVB pili encoded by the Salmonella enterica
      serovar Typhi pil operon are used to facilitate bacterial entry into human
      intestinal epithelial cells in vitro and that such entry is inhibited by purified
      prepilin (pre-PilS) protein (X.-L. Zhang, I. S. M. Tsui, C. M. C. Yip, A. W. Y.
      Fung, D. K.-H. Wong, X. Dai, Y. Yang, J. Hackett, and C. Morris, Infect. Immun.
      68:3067-3073, 2000). The pil operon concludes with a simple shufflon, and a
      recombinase gene product (Rci) inverts DNA in the C-terminal region of the pilV
      gene to allow synthesis of two distinct PilV proteins, PilV1 and PilV2, which are
      presumptive minor pilus proteins. We show here that the type IVB pili mediate
      bacterial self-association, but only when the PilV1 and PilV2 proteins are not
      expressed. This may be achieved in wild-type serovar Typhi by rapid DNA inversion
      activity of the shufflon. We show that the inversion activity inhibits the
      expression of genes inserted between the 19-bp inverted repeats used for Rci
      mediated recombination and that the activity of Rci increases when DNA is
      supercoiled. The data suggest that serovar Typhi self-associates under conditions
      (such as low oxygen tension in the gut) that favor DNA supercoiling. These
      results explain (i) the function of the serovar Typhi shufflon and (ii) why there
      are only two possible shufflon states, in contrast to the many possible states of
      other shufflon systems. The data further indicate that a very early step in
      serovar Typhi pathogenesis may be type IVB pilus-mediated self-association of
      bacteria in the anaerobic human small intestine prior to invasion of the human
      gut epithelium. The suggested type IVB pilus-dependent step in typhoid fever
      pathogenesis may partially explain the enhanced invasiveness of serovar Typhi for
      humans.

PMID- 12595426
TI  - Inhalational poisoning by botulinum toxin and inhalation vaccination with its
      heavy-chain component.
AB  - Botulinum toxin is the etiologic agent responsible for the disease botulism,
      which is characterized by peripheral neuromuscular blockade. Botulism is
      ordinarily encountered as a form of oral poisoning. The toxin is absorbed from
      the lumen of the gut to reach the general circulation and is then distributed to
      peripheral cholinergic nerve endings. However, there is a widespread presumption
      that botulinum toxin can also act as an inhalation poison, which would require
      that it be absorbed from the airway. Experiments have been done to show that both
      pure toxin and progenitor toxin (a complex with auxiliary proteins) are
      inhalation poisons. Interestingly, the data indicate that auxiliary proteins are
      not necessary to protect the toxin or to facilitate its absorption. When studied
      on rat primary alveolar epithelial cells or on immortalized human pulmonary
      adenocarcinoma (Calu-3) cells, botulinum toxin displayed both specific binding
      and transcytosis. The rate of transport was greater in the apical-to-basolateral
      direction than in the basolateral-to-apical direction. Transcytosis was energy
      dependent, and it was blocked by serotype-specific antibody. The results
      demonstrated that the holotoxin was not essential for the process of binding and
      transcytosis. Both in vivo and in vitro experiments showed that the heavy-chain
      component of the toxin was transported across epithelial monolayers, which
      indicates that the structural determinants governing binding and transcytosis are
      found in this fragment. The heavy chain was not toxic, and therefore it was
      tested for utility as an inhalation vaccine against the parent molecule. This
      fragment was shown to evoke complete protection against toxin doses of at least
      10(4) times the 50% lethal dose.

PMID- 12595427
TI  - Expression and immunogenicity of Mycoplasma hyopneumoniae heat shock protein
      antigen P42 by DNA vaccination.
AB  - Mycoplasma hyopneumoniae is the etiological agent of swine enzootic pneumonia, a
      chronic nonfatal disease affecting pigs of all ages. The goal of this study was
      to design DNA vaccines by constructing plasmid pcDNA3/P42, carrying the heat
      shock protein gene P42 of M. hyopneumoniae, and to evaluate the immune responses
      elicited in BALB/c mice. The expression of P42 was first examined in transfected
      NIH 3T3 cells by reverse transcription-PCR to ensure that the construct was
      functional. The humoral and cell-mediated immune responses induced by the plasmid
      were further evaluated in BALB/c mice through intramuscular injection. Both
      immunoglobulin G1 (IgG1) and IgG2a levels were 64 times those of the control
      groups during the first 8 weeks. The levels of interleukin-2 (IL-2), IL-4, and
      gamma interferon mRNAs in the immunized animals were elevated, and the
      proliferation of spleen cells was also enhanced in the immunized animals. The
      results indicate that pcDNA3/P42 DNA immunization induces both Th1 and Th2 immune
      responses. In addition, antiserum from the immunized animals was found to inhibit
      the growth of M. hyopneumoniae. The present study reveals that DNA vaccination
      could be a new strategy against infection by M. hyopneumoniae and may have
      potential for developing vaccines for other infectious diseases as well.

PMID- 12595428
TI  - Rho GTPase is activated by cytotoxic necrotizing factor 1 in peripheral blood T
      lymphocytes: potential cytotoxicity for intestinal epithelial cells.
AB  - Some strains of Escherichia coli related to acute cystitis or colitis produce a
      toxin named cytotoxic necrotizing factor 1 (CNF-1). CNF-1 mediates its effects on
      epithelial cells or phagocytes via the permanent activation of small GTP-binding
      proteins, caused by the toxin-induced deamidation of Glu(63) of p21 Rho. The
      behavior of peripheral blood T lymphocytes during the acute phase of bacterial
      colitis has been poorly investigated. Our study was conducted to test whether (i)
      peripheral blood T lymphocytes can be activated by CNF-1 and (ii) CNF-1-activated
      T lymphocytes are cytotoxic against intestinal epithelial cells. Activation of T
      lymphocytes by CNF-1 was assessed by electrophoresis, flow cytometry, confocal
      microscopy, and electron microscopy studies. Assays for migration and adherence
      of CNF-1-treated T lymphocytes were performed in Transwell chambers with T84
      intestinal epithelial cells grown on polycarbonate semipermeable filters. CNF-1
      induced a decrease in the electrophoretic mobility of the GTP-binding protein Rho
      in treated T lymphocytes. CNF-1 provoked an increase in the content of actin
      stress fibers and pseudopodia in T lymphocytes. Several adherence molecules were
      clustered into cytoplasmic projections in CNF-1-treated T lymphocytes and
      adherence of such lymphocytes on the basolateral pole of T84 was increased,
      resulting in cytotoxicity toward epithelial cells. Such enhanced adherence in
      response to CNF-1 was dependent on p42-44(MAP) kinase activation of T
      lymphocytes. Taken together, these results suggest that CNF-1, by acting on T
      lymphocytes, may increase in an important fashion the virulence of certain
      strains of E. coli against the intestinal epithelia.

PMID- 12595429
TI  - Purification, gene cloning, gene expression, and mutants of Dps from the obligate
      anaerobe Porphyromonas gingivalis.
AB  - The periodontopathogen Porphyromonas gingivalis is an obligate anaerobe that is
      devoid of catalase but exhibits a relatively high degree of resistance to
      peroxide stress. In the present study, we demonstrate that P. gingivalis contains
      a Dps homologue that plays an important role in the protection of cells from
      peroxide stress. The Dps protein isolated from P. gingivalis displayed a ferritin
      like spherical polymer consisting of 19-kDa subunits. Molecular cloning and
      sequencing of the gene encoding this protein revealed that it had a high
      similarity in nucleotide and amino acid sequences to Dps proteins from other
      species. The expression of Dps was significantly increased by exposure of P.
      gingivalis to atmospheric oxygen in an OxyR-dependent manner, indicating that it
      is regulated by the reactive oxygen species-regulating gene oxyR. The Dps
      deficient mutants, including the dps single mutant and the ftn dps double mutant,
      showed no viability loss upon exposure to atmospheric oxygen for 6 h. In contrast
      to the wild type, however, these mutants exhibited the high susceptibility to
      hydrogen peroxide, thereby disrupting the viability. On the other hand, no
      significant difference in sensitivity to mitomycin C and metronidazole was
      observed between the wild type and the mutants. Furthermore, the dps single
      mutant, compared with the wild type, showed a lower viability in infected human
      umbilical vein endothelial cells.

PMID- 12595430
TI  - Immunogenicity and protective immunity induced by synthetic peptides associated
      with putative immunodominant regions of Streptococcus mutans glucan-binding
      protein B.
AB  - Glucan-binding protein B (GbpB) from Streptococcus mutans has been shown to
      induce protective immunity to dental caries in experimental models. Having
      recently sequenced the gbpB gene, our objective in this study was to identify
      immunogenic regions within the GbpB sequence for use in subunit vaccines.
      Potential regions of immunogenicity were sought by use of a matrix-based
      algorithm (EpiMatrix) to estimate the binding characteristics of peptides derived
      from the GbpB sequence by using a database of known major histocompatibility
      complex class II binding alleles. Screening the entire sequence revealed several
      peptides with estimated high binding probabilities. Two N-terminal 20-mer
      peptides (SYI and QGQ) subtending two of these regions were synthesized. A
      preliminary experiment, in which these peptides were synthesized in the multiple
      antigenic peptide format and were used to subcutaneously immunize Sprague-Dawley
      rats twice at a 21-day interval, revealed that the SYI peptide induced a higher
      percentage of responses to the inciting peptide as well as to intact GbpB, as
      measured by enzyme-linked immunosorbent assay. The effect of immunization with
      the SYI peptide construct on the cariogenicity of S. mutans was then investigated
      by immunizing weanling Sprague-Dawley rats twice at a 9-day interval with SYI or
      with phosphate-buffered saline. All rats were then orally infected with S. mutans
      strain SJ. After a 78-day infection period, the SYI-immunized groups had
      significant reductions in dental caries on both smooth and occlusal surfaces
      compared with the sham-immunized group. Thus, these experiments indicated that at
      least one linear sequence, derived from the N-terminal third of GbpB, was
      sufficiently immunogenic to induce a protective immune response in this
      experimental rat model for dental caries.

PMID- 12595431
TI  - Evidence that development of severe cardiomyopathy in human Chagas' disease is
      due to a Th1-specific immune response.
AB  - The role of interleukin 10 (IL-10) and gamma interferon (IFN-gamma) on the
      development of pathology in human Chagas' disease was investigated. Two
      categories of patients, low and high producers of IFN-gamma, were identified
      based on the levels of secretion of this cytokine in the supernatant of
      peripheral blood mononuclear cell (PBMC) cultures. Eighty-three percent of the
      patients presenting with cardiac disease (CARD) of different degrees and 59% of
      the patients with the indeterminate form of disease (IND) were identified as high
      IFN-gamma producers. PBMC from IND patients classified as low IFN-gamma producers
      secreted significantly higher amounts of IL-10 than did those from other groups.
      Flow cytometry analysis demonstrated that in PBMC from the IND group, the
      majority of the IL-10-producing cells were monocytes (CD14(High+) cells), whereas
      in the CARD group, the major sources of IFN-gamma were T lymphocytes (CD3(+)
      CD4(+) cells). These results suggest an association between the production of IFN
      gamma by CD3(+) CD4(+) cells and morbidity in Chagas' disease, whereas the
      production of IL-10 by macrophages/monocytes leads to regulation of the immune
      response in IND patients. We hypothesize that an exacerbated production of IFN
      gamma against Trypanosoma cruzi antigens favors the development of a strong Th1
      response in CARD patients, which leads to progression of heart disease.

PMID- 12595432
TI  - Trypanosoma cruzi infection modulates in vivo expression of major
      histocompatibility complex class II molecules on antigen-presenting cells and T
      cell stimulatory activity of dendritic cells in a strain-dependent manner.
AB  - A striking feature of Chagas' disease is the diversity of clinical presentations.
      Such variability may be due to the heterogeneity among Trypanosoma cruzi isolates
      or to the host immune response. Employing two strains which differ in their
      virulence, we investigated the effect of in vivo infection on professional
      antigen-presenting cells (APC). Acute infection with the virulent RA strain
      downregulated the expression of major histocompatibility complex (MHC) class II
      on splenic dendritic cells (DC) and inhibited its induction on peritoneal
      macrophages and splenic B cells. It also impaired the ability of DC to prime
      allogeneic T cells and to form homotypic clusters, suggesting a low maturation
      state of these cells. In contrast, the low-virulence K98 strain maintained the
      expression of MHC class II on DC or stimulated it on peritoneal macrophages and B
      cells and preserved DC's T-cell priming capacity and homotypic clustering. DC
      from RA-infected mice elicited a lower activation of T. cruzi-specific T-cell
      proliferation than those from K98-infected mice. APC from RA-infected mice that
      reached the chronic phase of infection restored MHC class II levels to those
      found in K98-infected mice and upregulated costimulatory molecules expression,
      suggesting that the immunosuppression caused by this strain is only transient.
      Taken together, the results indicate that in vivo infection with T. cruzi
      modulates APC functionality and that this is accomplished in a strain-dependent
      manner.

PMID- 12595433
TI  - Polymorphic membrane protein H has evolved in parallel with the three disease
      causing groups of Chlamydia trachomatis.
AB  - Chlamydia trachomatis is a human pathogen causing trachoma, urogenital disease,
      and lymphogranuloma venereum (LGV). A family of nine polymorphic membrane protein
      genes (pmpA to pmpI), resembling autotransporter proteins, has recently been
      discovered in C. trachomatis. pmp genes are large and predicted to be outer
      membrane proteins. We hypothesized that they would contain useful nucleotide
      sequence variability for epidemiologic studies. Since sequence information is
      available only for serovars D and L2, we sought to determine the amount of
      diversity within an individual pmp gene among serovars. We used restriction
      fragment length polymorphism (RFLP) analysis as a primary screen to assess the
      amount of sequence divergence among the pmp genes for serovars A to L3 of C.
      trachomatis. RFLP analysis showed little variation for some of the genes, such as
      pmpA, but substantial variation in others, such as pmpI. pmpH and pmpE yielded
      RFLP patterns that clustered the 15 serovars into ocular, urogenital, and LGV
      groups, and both proteins have been localized to the outer membrane. Therefore,
      we chose to sequence pmpE, pmpH, and pmpI from each of the 15 serovars.
      Evolutionary analysis showed three distinct divergence patterns. PmpI was least
      variable, resulting in an ambiguous evolutionary pattern. PmpE showed a high
      degree of diversity in the ocular strains compared to the other strains. Finally,
      the evolution of PmpH shows three groups that reflect disease groups, suggesting
      this protein may play a role in pathogenesis.

PMID- 12595434
TI  - Functional CD40 expression induced following bacterial infection of mouse and
      human osteoblasts.
AB  - Bacterially induced bone infections often result in significant local
      inflammatory responses which are coupled with loss of bone. However, the
      mechanisms necessary for the protective host response, or those responsible for
      pathogen-induced bone loss, are not clear. Recent evidence demonstrates that
      bacterially infected osteoblasts secrete chemokines and cytokines, suggesting
      that these cells may have an unappreciated role in supporting localized
      inflammation. In this study, mouse and human osteoblasts were investigated for
      their ability to express functional CD40 upon exposure to two important pathogens
      of bone, Staphylococcus aureus and Salmonella enterica serovar Dublin. Bacterial
      infection of cultured mouse or human osteoblasts resulted in increased CD40 mRNA
      and CD40 protein expression induced by either pathogen. Importantly, CD40
      expression by osteoblasts was functional, as assessed by ligation of this
      molecule with recombinant, soluble CD154. CD40 activity was assessed by induction
      of interleukin-6 and granulocyte-macrophage colony-stimulating factor in
      osteoblasts following ligation. Cocultures of activated CD4(+) T lymphocytes and
      osteoblasts could interact via CD40 and CD154, since an antibody against CD40
      could block macrophage inflammatory protein-1alpha secretion. Taken together,
      these studies conclusively demonstrate that infected osteoblasts can upregulate
      expression of functional CD40 molecules which mediate cytokine secretion. This
      surprising result further supports the notion that bone-forming osteoblasts can
      directly interact with CD154-expressing cells (i.e., T lymphocytes) and can
      contribute to the host response during bone infection.

PMID- 12595435
TI  - Expression of truncated Internalin A is involved in impaired internalization of
      some Listeria monocytogenes isolates carried asymptomatically by humans.
AB  - Fourteen human carriage Listeria monocytogenes isolates were compared to sporadic
      and epidemic-associated human strains in order to ascertain the pathogenic
      behavior of these unrecognized asymptomatic strains. Experimental infection of 14
      day-old chick embryos revealed that the majority of the carriage strains were
      attenuated for virulence. Of the 10 attenuated carriage strains, 5 were affected
      in their invasion capacities in vitro. Western blot analysis with antibody
      directed against InlA, the surface protein implicated in the internalization in
      host cells, allowed correlation between the ability of the carriage strains to
      enter Caco-2 cells and InlA expression. Indeed, these five carriage strains
      produced truncated forms of InlA. Four of the five truncated forms of InlA had an
      apparent molecular mass of 47 kDa. In order to assess the existence of a genetic
      lineage, partial sequences of inlA gene of these four strains were compared and
      revealed that they had a high degree of sequence conservation at the gene
      (99.86%) and amino acid (100%) levels. Comparison of their nucleotide sequences
      with that of the corresponding segment of inlA from EGD-e and Scott A strains,
      taken as epidemic references, showed more divergence. Taken together, these
      observations suggest the presence of specific traits that characterize L.
      monocytogenes strains isolated during asymptomatic carriage. Some of these traits
      could provide some explanations about the determinants that make them unable to
      cause systemic human infection.

PMID- 12595436
TI  - Nitric oxide partially controls Coxiella burnetii phase II infection in mouse
      primary macrophages.
AB  - In most primary or continuous cell cultures infected with the Q-fever agent
      Coxiella burnetii, bacteria are typically sheltered in phagolysosome-like, large
      replicative vacuoles (LRVs). We recently reported that only a small proportion of
      mouse peritoneal macrophages (PMPhi) infected with a nonvirulent, phase II strain
      of C. burnetii developed LRVs and that their relative bacterial load increased
      only slowly. In the majority of infected PMPhi, the bacteria were confined to the
      small vesicles. We show here that nitric oxide (NO) induced by the bacteria
      partially accounts for the restricted development of LRVs in primary macrophages.
      Thus, (i) PMPhi and bone marrow-derived macrophages (BMMPhi) challenged with
      phase II C. burnetii produced significant amounts of NO; (ii) the NO synthase
      inhibitors aminoguanidine and N-methyl-L-arginine reduced the production of NO
      and increased the frequency of LRVs (although the relative bacterial loads of
      individual LRVs did not change, the estimated loads per well increased
      appreciably); (iii) gamma interferon (IFN-gamma) or the NO donor sodium
      nitroprusside, added to BMMPhi prior to or after infection, reduced the
      development and the relative bacterial loads of LRVs and lowered the yield of
      viable bacteria recovered from the cultures; and (iv) these effects of IFN-gamma
      may not be entirely dependent on the production of NO since IFN-gamma also
      controlled the infection in macrophages from inducible NO synthase knockout mice.
      It remains to be determined whether NO reduced the development of LRVs by acting
      directly on the bacteria; by acting on the traffic, fusion, or fission of cell
      vesicles; or by a combination of these mechanisms.

PMID- 12595437
TI  - Activation of natural killer T cells by alpha-galactosylceramide impairs DNA
      vaccine-induced protective immunity against Trypanosoma cruzi.
AB  - Innate immunity as a first defense is indispensable for host survival against
      infectious agents. We examined the roles of natural killer (NK) T cells in
      defense against Trypanosoma cruzi infection. The T. cruzi parasitemia and
      survival of CD1d-deficient mice exhibited no differences compared to wild-type
      littermates. NK T-cell activation induced by administering alpha
      galactosylceramide (alpha-GalCer) to T. cruzi-infected mice significantly changed
      the parasitemia only in the late phase of infection and slightly improved
      survival when mice were infected intraperitoneally. The combined usage of alpha
      GalCer and benznidazole, a commercially available drug for Chagas' disease, did
      not enhance the therapeutic efficacy of benznidazole. These results suggest that
      NK T cells do not play a pivotal role in resistance to T. cruzi infection. In
      addition, we found that the coadministration of alpha-GalCer with DNA vaccine
      impaired the induction of epitope-specific CD8(+) T cells and undermined the DNA
      vaccine-induced protective immunity against T. cruzi. Our results, in contrast to
      previous reports demonstrating the protective roles of NK T cells against other
      infectious agents, suggest that these cells might even exhibit adverse effects on
      vaccine-mediated protective immunity.

PMID- 12595438
TI  - Congenital exposure to Plasmodium falciparum antigens: prevalence and antigenic
      specificity of in utero-produced antimalarial immunoglobulin M antibodies.
AB  - Congenital Plasmodium falciparum malaria in newborns is uncommon in sub-Saharan
      Africa. A significant number of infants, however, become infected or exposed to
      malarial antigens either in utero or at delivery and have the potential to
      produce antimalarial antibodies and memory cells before their first natural
      infection. In Yaounde, Cameroon, parasite-specific immunoglobulin M (IgM) was
      detected in 14% of cord blood samples. The IgM antibodies reacted with a wide
      range of asexual-stage antigens, with each newborn having its own unique pattern
      of IgM reactivity. PCR-based detection and genotyping of cord blood parasites
      found that the prevalence, total number of parasite genotypes, and complexity of
      infection were higher in newborns who had produced antimalarial IgM than those
      who had not. Maternal placental malaria and anemia were associated with the
      production of P. falciparum-specific IgM by the fetus. The effect of early immune
      priming on acquisition of immunity by infants is unknown and merits further
      investigation, since a significant proportion of Cameroonian newborns developed a
      humoral response to malaria before birth.

PMID- 12595439
TI  - Macrophage migration inhibitory factor plays a critical role in mediating
      protection against the helminth parasite Taenia crassiceps.
AB  - To determine the role of endogenous migration inhibitory factor (MIF) in
      regulation of immune response during murine cysticercosis caused by the helminth
      parasite Taenia crassiceps, we analyzed the course of T. crassiceps infection in
      MIF(-/-) BALB/c mice. MIF(-/-) mice were highly susceptible to T. crassiceps and
      developed significantly higher parasite loads compared to similarly infected
      MIF(+/+) mice. Throughout the course of infection, Taenia crassiceps soluble
      antigen-stimulated spleen cells from both MIF(+/+) and MIF(-/-) mice produced
      significant and comparable levels of interleukin-4 (IL-4), but those from MIF(-/
      ) mice produced significantly more IL-13, as well as gamma interferon (IFN
      gamma), suggesting that the susceptibility of MIF(-/-) mice to T. crassiceps was
      not due to the lack of IFN-gamma production. Interestingly, low levels of both
      total and specific immunoglobulin G2a were observed in MIF(-/-) cysticercotic
      mice despite the high IFN-gamma levels; in addition, peritoneal macrophages
      obtained from T. crassiceps-infected MIF(-/-) mice at different time points
      failed to respond efficiently to stimulation in vitro with lipopolysaccharide
      plus IFN-gamma and produced significantly lower levels of IL-12, tumor necrosis
      factor alpha, and NO compared to those from MIF(+/+) mice. These findings
      demonstrate that MIF plays a critical role in mediating protection against T.
      crassiceps in vivo. Moreover, these findings also suggest that impaired
      macrophage function rather than the lack of Th1 development may be responsible
      for mediating susceptibility to T. crassiceps.

PMID- 12595440
TI  - Structural characterization of the N terminus of IpaC from Shigella flexneri.
AB  - The primary effector for Shigella invasion of epithelial cells is IpaC, which is
      secreted via a type III secretion system. We recently reported that the IpaC N
      terminus is required for type III secretion and possibly other functions. In this
      study, mutagenesis was used to identify an N-terminal secretion signal and to
      determine the functional importance of the rest of the IpaC N terminus. The 15 N
      terminal amino acids target IpaC for secretion by Shigella flexneri, and placing
      additional amino acids at the N terminus does not interfere with IpaC secretion.
      Furthermore, amino acid sequences with no relationship to the native IpaC
      secretion signal can also direct its secretion. Deletions introduced beyond amino
      acid 20 have no effect on secretion and do not adversely affect IpaC function in
      vivo until they extend beyond residue 50, at which point invasion function is
      completely eliminated. Deletions introduced at amino acid 100 and extending
      toward the N terminus reduce IpaC's invasion function but do not eliminate it
      until they extend to the N-terminal side of residue 80, indicating that a region
      from amino acid 50 to 80 is critical for IpaC invasion function. To explore this
      further, the ability of an IpaC N-terminal peptide to associate in vitro with its
      translocon partner IpaB and its chaperone IpgC was studied. The N-terminal
      peptide binds tightly to IpaB, but the IpaC central hydrophobic region also
      appears to participate in this binding. The N-terminal peptide also associates
      with the chaperone IpgC and IpaB is competitive for this interaction. Based on
      additional biophysical data, we propose that a region between amino acids 50 and
      80 is required for chaperone binding, and that the IpaB binding domain is located
      downstream from, and possibly overlapping, this region. From these data, we
      propose that the secretion signal, chaperone binding region, and IpaB binding
      domain are located at the IpaC N terminus and are essential for presentation of
      IpaC to host cells during bacterial entry; however, IpaC effector activity may be
      located elsewhere.

PMID- 12595441
TI  - Phenotypic switching in Mycoplasma gallisepticum hemadsorption is governed by a
      high-frequency, reversible point mutation.
AB  - Mycoplasma gallisepticum is a flask-shaped organism that commonly induces chronic
      respiratory disease in chickens and infectious sinusitis in turkeys. Phenotypic
      switching in M. gallisepticum hemadsorption (HA) was found to correlate with
      phase variation of the GapA cytadhesin concurrently with that of the CrmA
      protein, which exhibits cytadhesin-related features and is encoded by a gene
      located downstream of the gapA gene as part of the same transcription unit. In
      clones derived from strain R(low), detailed genetic analyses further revealed
      that on-off switching in GapA expression is governed by a reversible base
      substitution occurring at the beginning of the gapA structural gene. In HA(-)
      variants, this event generates a stop codon that results in the premature
      termination of GapA translation and consequently affects the expression of CrmA.
      Sequences flanking the mutation spot do not feature any repeated motifs that
      could account for error-prone mutation via DNA slippage and the exact mechanism
      underlying this high-frequency mutational event remains to be elucidated. An HA(
      ) mutant deficient in producing CrmA, mHAD3, was obtained by disrupting the crmA
      gene by using transposition mutagenesis. Despite a fully functional gapA gene,
      the amount of GapA detected in this mutant was considerably lower than in HA(+)
      clonal variants, suggesting that, in absence of CrmA, GapA might be subjected to
      a higher turnover.

PMID- 12595442
TI  - A surface amebic cysteine proteinase inactivates interleukin-18.
AB  - Amebiasis is a major cause of morbidity and mortality worldwide. Invasion by
      Entamoeba histolytica trophozoites causes secretion of proinflammatory cytokines
      from host epithelial cells, leading to a local acute inflammatory response,
      followed by lysis of colonic cells. Extracellular cysteine proteinases from
      amebic trophozoites are key virulence factors and have a number of important
      interactions with host defenses, including cleavage of immunoglobulin G (IgG),
      IgA, and complement components C3 and C5. Amebic lysates have also been shown to
      activate the precursor to interleukin 1-beta (proIL-1beta), mimicking the action
      of caspase-1. IL-18 is also a central cytokine, which induces gamma interferon
      (IFN-gamma) and activates macrophages, one of the main host defenses against
      invading trophozoites. Because proIL-18 is also activated by caspase-1, we
      evaluated whether amebic proteinases had a similar effect. Instead, we found that
      recombinant proIL-18 was cleaved into smaller fragments by the complex of surface
      associated and released amebic proteinases. To evaluate the function of an
      individual proteinase from the complex pool, we expressed an active surface
      proteinase, EhCP5, which is functional only in E. histolytica. Recombinant EhCP5
      expressed in Pichia pastoris had kinetic properties similar to those of the
      native enzyme with respect to substrate specificity and sensitivity to proteinase
      inhibitors. In contrast to the activation of proIL-1beta by amebic lysates, the
      purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive
      fragments. These studies suggest that the acute host response and amebic invasion
      result from a complex interplay of parasite virulence factors and host defenses.
      E. histolytica may block the host inflammatory response by a novel mechanism,
      inactivation of IL-18.

PMID- 12595443
TI  - Analysis of the role of Bphs/Hrh1 in the genetic control of responsiveness to
      pertussis toxin.
AB  - In vivo intoxication with Bordetella pertussis toxin (PTX) elicits a variety of
      physiological responses including a marked leukocytosis, disruption of glucose
      regulation, adjuvant activity, alterations in vascular function, hypersensitivity
      to vasoactive agents, and death. We recently identified Bphs, the locus
      controlling PTX-induced hypersensitivity to the vasoactive amine histamine, as
      the histamine H(1) receptor (Hrh1). In this study Bphs congenic mice and mice
      with a disrupted Hrh1 gene were used to examine the role of Bphs/Hrh1 in the
      genetic control of susceptibility to a number of phenotypes elicited following in
      vivo intoxication. We report that the contribution of Bphs/Hrh1 to the overall
      genetic control of responsiveness to PTX is restricted to susceptibility to
      histamine hypersensitivity and enhancement of antigen-specific delayed-type
      hypersensitivity responses. Furthermore, the genetic contribution of Bphs/Hrh1 to
      vasoactive amine sensitization is specific for histamine, since hypersensitivity
      to serotonin was unaffected by Bphs/Hrh1. Bphs/Hrh1 also did not significantly
      influence susceptibility to the lethal effects, the leukocytosis response,
      disruption of glucose regulation, and histamine-independent increases in vascular
      permeability associated with in vivo intoxication. Nevertheless, significant
      interstrain differences in susceptibility to the lethal effects of PTX and
      leukocytosis response were observed. These results indicate that the phenotypic
      variation in responsiveness to PTX reflects the genetic control of distinct
      intermediate phenotypes rather than allelic variation in genes controlling
      overall susceptibility to intoxication.

PMID- 12595444
TI  - Human immune response to outer membrane protein CD of Moraxella catarrhalis in
      adults with chronic obstructive pulmonary disease.
AB  - Moraxella catarrhalis is a common cause of lower respiratory tract infection in
      adults with chronic obstructive pulmonary disease (COPD). The antibody response
      to outer membrane protein (OMP) CD, a highly conserved surface protein of M.
      catarrhalis under consideration as a vaccine antigen, was studied in adults with
      COPD following 40 episodes of infection or colonization. Following infection or
      colonization, 9 of 40 patients developed new serum immunoglobulin G (IgG) to OMP
      CD, as measured by enzyme-linked immunosorbent assay. Adsorption assays revealed
      that a proportion of the serum IgG was directed toward surface-exposed epitopes
      on OMP CD in six of the nine patients who developed new IgG to OMP CD. Immunoblot
      assays with fusion peptide constructs indicated that the new antibodies that
      developed after infection or colonization recognized conformational epitopes,
      particularly in the carboxy region of the protein. Three of 28 patients developed
      new mucosal IgA to OMP CD in sputum supernatants. This study establishes that OMP
      CD is a target of a systemic and mucosal immune response following infection and
      colonization in some patients with COPD.

PMID- 12595445
TI  - HilE interacts with HilD and negatively regulates hilA transcription and
      expression of the Salmonella enterica serovar Typhimurium invasive phenotype.
AB  - The ability of Salmonella enterica serovar Typhimurium to traverse the intestinal
      mucosa of a host is an important step in its ability to initiate gastrointestinal
      disease. The majority of the genes required for this invasive characteristic are
      encoded on Salmonella pathogenicity island 1 (SPI1), and their expression is
      controlled by the transcriptional activator HilA, a member of the OmpR/ToxR
      family of proteins. A variety of genes (hilC, hilD, fis, sirA/barA, csrAB, phoB,
      fadD, envZ/ompR, fliZ, hilE, ams, lon, pag, and hha) have been identified that
      exert positive or negative effects on hilA expression, although the mechanisms by
      which these gene products function remain relatively unclear. Recent work
      indicates that the small DNA-binding protein, Hha, has a significant role in
      repressing hilA transcription and the invasive phenotype, particularly in
      response to osmolarity signals. We have characterized the Salmonella-specific
      gene, hilE, and found that it plays an important regulatory role in hilA
      transcription and invasion gene expression. Mutation of hilE causes derepression
      of hilA transcription, and overexpression of hilE superrepresses hilA expression
      and the invasive phenotype. Bacterial two-hybrid experiments indicate that the
      HilE protein interacts with HilD, suggesting a possible mechanism for HilE
      negative regulation of hilA gene expression and the Salmonella invasive
      phenotype. Finally, we have found that the hilE gene resides on a region of the
      serovar Typhimurium chromosome that has many characteristics of a pathogenicity
      island.

PMID- 12595446
TI  - Intrapulmonary expression of macrophage inflammatory protein 1alpha (CCL3)
      induces neutrophil and NK cell accumulation and stimulates innate immunity in
      murine bacterial pneumonia.
AB  - Macrophage inflammatory protein 1alpha (MIP-1alpha) (CCL3) is an important
      mediator of leukocyte recruitment and activation in a variety of inflammatory
      states, including infection. A recombinant human type 5 adenovirus containing the
      murine MIP-1alpha cDNA (AdMIP-1alpha) was constructed to determine the effect of
      transient intrapulmonary expression of MIP-1alpha on leukocyte recruitment,
      activation, and bacterial clearance in a murine model of Klebsiella pneumoniae
      pneumonia. The intratracheal administration of AdMIP-1alpha resulted in both time
      and dose-dependent expression of MIP-1alpha mRNA and protein within the lung.
      Importantly, the intrapulmonary overexpression of MIP-1alpha resulted in a
      maximal 35- and 100-fold reduction in lung and blood bacterial burden,
      respectively, in animals cochallenged with K. pneumoniae, which was associated
      with a significant increase in neutrophil and activated NK cell accumulation.
      Furthermore, the transgenic expression of MIP-1alpha during bacterial pneumonia
      resulted in enhanced expression of gamma interferon mRNA, compared to that
      observed in Klebsiella-challenged animals pretreated with control vector. These
      findings indicate an important role for MIP-1alpha in the recruitment and
      activation of selected leukocyte populations in vivo and identify this cytokine
      as a potential immunoadjuvant to be employed in the setting of localized
      bacterial infection.

PMID- 12595447
TI  - Reduced glutathione is required for pertussis toxin secretion by Bordetella
      pertussis.
AB  - The abilities of cysteine-containing compounds to support growth of Bordetella
      pertussis and influence pertussis toxin transcription, assembly, and secretion
      were examined. Cysteine is an essential amino acid for B. pertussis and must be
      present for protein synthesis and bacterial growth. However, cysteine can be
      metabolized to sulfate, and high concentrations of sulfate can selectively
      inhibit transcription of the virulence factors, including pertussis toxin, via
      the BvgAS two-component regulatory system in a process called modulation. In
      addition, pertussis toxin possesses several disulfide bonds, and the cysteine
      containing compound glutathione can influence oxidation-reduction reactions and
      perhaps disulfide bond formation. Bacterial growth was not observed in the
      absence of a source of cysteine. Oxidized glutathione, as a sole source of
      cysteine, also did not support bacterial growth. Cysteine, cystine, and reduced
      glutathione did support bacterial growth, and none of these compounds caused
      modulation at the concentrations tested. Similar amounts of periplasmic pertussis
      toxin were detected regardless of the source of cysteine; however, in the absence
      of reduced glutathione, pertussis toxin was not efficiently secreted. Addition of
      the reducing agent dithiothreitol was unable to compensate for the lack of
      reduced glutathione and did not promote secretion of pertussis toxin. These
      results suggest that reduced glutathione does not affect the accumulation of
      assembled active pertussis toxin in the periplasm but plays a role in efficient
      pertussis toxin secretion by the bacterium.

PMID- 12595448
TI  - Complement activation influences Staphylococcus aureus adherence to endothelial
      cells.
AB  - The ability of Staphylococcus aureus to adhere to endothelial cells (EC) is a
      critical step in the development of metastatic infection. The role of complement
      in S. aureus binding to EC remains uninvestigated. Log-phase S. aureus,
      expressing minimal capsule, was incubated with serum under various conditions,
      washed, and then incubated at 37 degrees C for 30 min with cultured human
      umbilical vein EC (ATCC CRL-1730). Adherence was scored visually after staining
      with acridine orange. Incubation in 10% heat-inactivated human serum increased
      adherence to endothelial cells by 488% compared to organisms incubated in buffer.
      Incubating S. aureus in complement-active normal human serum (NHS) decreased
      binding to EC by 58% compared to organisms incubated in heat-inactivated serum.
      The importance of active complement was confirmed by experiments using serum with
      added EDTA or cobra venom factor, a protein that depletes C3. The expression of
      capsule by S. aureus strongly interfered with adherence. It has been shown that
      an important protein for S. aureus adhesion to EC is fibronectin. S. aureus
      adherence to purified fibronectin increased by 511% after incubation in heat
      inactivated serum, compared to that of organisms incubated in buffer. This
      decreased by 56% in complement-active serum, suggesting that inhibition of S.
      aureus adherence to EC is due, in part, to complement-mediated diminished binding
      to fibronectin. Interestingly, when EC were exposed to S. aureus-activated serum
      and then washed, binding by S. aureus was 234% higher than that of EC exposed to
      NHS. Thus, complement-activated EC have increased S. aureus binding, while
      complement on the bacterial surface markedly reduces adherence.

PMID- 12595449
TI  - Experimental Pseudomonas aeruginosa keratitis in interleukin-10 gene knockout
      mice.
AB  - Pseudomonas aeruginosa keratitis is one of the most destructive diseases of the
      cornea. The host response to this infection is critical to the outcome. The
      cytokine interleukin-10 (IL-10) is thought to play an important role in
      modulating excessive inflammation and antimicrobial defenses. We have found that
      in IL-10(-/-) mice there is a significant decrease in bacterial load in corneas
      at 7 days postchallenge with P. aeruginosa. This decrease was accompanied by a
      reduction in neutrophil numbers in the cornea and changes in cytokine levels
      compared to those of wild-type mice. A characteristic increase in
      neovascularization in the cornea was found in the IL-10(-/-) mice. This increased
      angiogenesis correlated with an increased expression of KC, whereas the kinetics
      of macrophage inflammatory peptide 2 expression correlated with neutrophil
      numbers. This finding suggests that KC may play a role in corneal angiogenesis.
      The source of IL-10 in mouse corneas was identified as a subpopulation of
      infiltrating cells and keratocytes. This study demonstrates that IL-10 plays an
      important role in regulating the balance of inflammatory mediators during P.
      aeruginosa infection of the cornea.

PMID- 12595450
TI  - Localized eosinophil degranulation mediates disease in tropical pulmonary
      eosinophilia.
AB  - To explore the mechanisms underlying the eosinophil-mediated inflammation of
      tropical pulmonary eosinophilia (TPE), bronchoalveolar lavage (BAL) fluid, serum,
      and supernatants from pulmonary and blood leukocytes (WBC) from patients with
      acute TPE (n = 6) were compared with those obtained from healthy uninfected
      individuals (n = 4) and from patients with asthma (n = 4) or elephantiasis (n =
      5). Although there were no significant differences in the levels of interleukin-4
      (IL-4), IL-5, IL-13, eotaxin, granulocyte-macrophage colony-stimulating factor,
      RANTES, or eosinophil cationic protein, there was a marked increase in eosinophil
      derived neurotoxin (EDN) both systemically and in the lungs of individuals with
      TPE compared to each of the control groups (P < 0.02). Moreover, there was a
      compartmentalization of this response, with EDN levels being higher in the BAL
      fluid than in the serum (P < 0.02). Supernatants from WBC from either whole blood
      or BAL cells were examined for chemokines, cytokines, eosinophil degranulation
      products, and arachidonic acid metabolites. Of the many mediators examined
      particularly those associated with eosinophil trafficking-only EDN (in BAL fluid
      and WBC) and MIP-1alpha (in WBC) levels were higher for TPE patients than for the
      non-TPE control groups (P < 0.02). These data suggest it is the eosinophilic
      granular protein EDN, an RNase capable of damaging the lung epithelium, that
      plays the most important role in the pathogenesis of TPE.

PMID- 12595451
TI  - Functional genomics approach to the identification of virulence genes involved in
      Edwardsiella tarda pathogenesis.
AB  - Edwardsiella tarda is an important cause of hemorrhagic septicemia in fish and
      also of gastro- and extraintestinal infections in humans. Here, we report the
      identification of 14 virulence genes of pathogenic E. tarda that are essential
      for disseminated infection, via a genome-wide analysis. We screened 490 alkaline
      phosphatase fusion mutants from a library of 450,000 TnphoA transconjugants
      derived from strain PPD130/91, using fish as an infection model. Compared to the
      wild type, 15 mutants showed significant decreases in virulence. Six mutants had
      insertions in the known virulence-related genes, namely, fimA, gadB, katB, pstS,
      pstC, and ssrB. Some mutants corresponded to known genes (astA, isor, and ompS2)
      that had not been previously shown to be involved in pathogenesis, and three had
      insertions in two novel genes. In vivo infection kinetics experiments confirmed
      the inability of these attenuated mutants to proliferate and cause fatal
      infection in fish. Screening for the presence of the above-described virulence
      genes in six virulent and seven avirulent strains of E. tarda indicated that
      seven of the genes were specific to pathogenic E. tarda. The genes identified
      here may be used to develop vaccines and diagnostic kits as well as for further
      studying the pathogenesis of E. tarda and other pathogenic bacteria.

PMID- 12595452
TI  - Genetic characterization and immunogenicity of coli surface antigen 4 from
      enterotoxigenic Escherichia coli when it is expressed in a Shigella live-vector
      strain.
AB  - The genes that encode the enterotoxigenic Escherichia coli (ETEC) CS4 fimbriae,
      csaA, -B, -C, -E, and -D', were isolated from strain E11881A. The csa operon
      encodes a 17-kDa major fimbrial subunit (CsaB), a 40-kDa tip-associated protein
      (CsaE), a 27-kDa chaperone-like protein (CsaA), a 97-kDa usher-like protein
      (CsaC), and a deleted regulatory protein (CsaD'). The predicted amino acid
      sequences of the CS4 proteins are highly homologous to structural and assembly
      proteins of other ETEC fimbriae, including CS1 and CS2, and to CFA/I in
      particular. The csaA, -B, -C, -E operon was cloned on a stabilized plasmid
      downstream from an osomotically regulated ompC promoter. pGA2-CS4 directs
      production of CS4 fimbriae in both E. coli DH5alpha and Shigella flexneri 2a
      vaccine strain CVD 1204, as detected by Western blot analysis and bacterial
      agglutination with anti-CS4 immune sera. Electron-microscopic examination of
      Shigella expressing CS4 confirmed the presence of fimbriae on the bacterial
      surface. Guinea pigs immunized with CVD 1204(pGA2-CS4) showed serum and mucosal
      antibody responses to both the Shigella vector and the ETEC fimbria CS4. Among
      the seven most prevalent fimbrial antigens of human ETEC, CS4 is the last to be
      cloned and sequenced. These findings pave the way for CS4 to be included in
      multivalent ETEC vaccines, including an attenuated Shigella live-vector-based
      ETEC vaccine.

PMID- 12595453
TI  - Two novel superantigens found in both group A and group C Streptococcus.
AB  - Two novel streptococcal superantigen genes (speL(Se) and speM(Se)) were
      identified from the Streptococcus equi genome database at the Sanger Center.
      Genotyping of 8 S. equi isolates and 40 Streptococcus pyogenes isolates resulted
      in the detection of the orthologous genes speL and speM in a restricted number of
      S. pyogenes isolates (15 and 5%, respectively). Surprisingly, the novel
      superantigen genes could not be found in any of the analyzed S. equi isolates.
      The results suggest that both genes are located on a mobile element that enables
      gene transfer between individual isolates and between streptococci from different
      Lancefield groups. S. equi pyrogenic exotoxin L (SPE-L(Se))/streptococcal
      pyrogenic exotoxin L (SPE-L) and SPE-M(Se)/SPE-M are most closely related to
      SMEZ, SPE-C, SPE-G, and SPE-J, but build a separate branch within this group.
      Recombinant SPE-L (rSPE-L) and rSPE-M were highly mitogenic for human peripheral
      blood lymphocytes, with half-maximum responses at 1 and 10 pg/ml, respectively.
      The results from competitive binding experiments suggest that both proteins bind
      major histocompatibility complex class II at the beta-chain, but not at the alpha
      chain. The most common targets for both toxins were human Vbeta1.1 expressing T
      cells. Seroconversion against SPE-L and SPE-M was observed in healthy blood
      donors, suggesting that the toxins are expressed in vivo. Interestingly, the speL
      gene is highly associated with S. pyogenes M89, a serotype that is linked to
      acute rheumatic fever in New Zealand.

PMID- 12595454
TI  - Primed peritoneal B lymphocytes are sufficient to transfer protection against
      Brugia pahangi infection in mice.
AB  - Lymphatic filariasis is a tropical disease caused by the nematode parasites
      Wuchereria bancrofti and Brugia malayi. Whereas the protective potential of T
      lymphocytes in filarial infection is well documented, investigation of the role
      of B lymphocytes in antifilarial immunity has been neglected. In this
      communication, we examine the role of B lymphocytes in antifilarial immunity,
      using Brugia pahangi infections in the murine peritoneal cavity as a model. We
      find that B lymphocytes are required for clearance of primary and challenge
      infections with B. pahangi third-stage larvae (L3). We assessed the protective
      potential of peritoneal B lymphocytes by adoptive transfer experiments. Primed
      but not naive peritoneal B cells from wild-type mice that had been immunized with
      B. pahangi L3 protected athymic recipients from challenge infection. We evaluated
      possible mechanisms by which B cells mediate protection. Comparisons of cytokine
      mRNA expression between B-lymphocyte-deficient and immunocompetent mice following
      B. pahangi infection suggest that B cells are required for the early production
      of Th2-type cytokines by peritoneal cells. In addition, B-cell-deficient mice
      demonstrate a defect in inflammatory cell recruitment to the peritoneal cavity
      following B. pahangi infection. The data demonstrate a critical role of B
      lymphocytes in antifilarial immunity in naive mice and in the memory response in
      primed mice.

PMID- 12595455
TI  - Isolation of acid-inducible genes of Mycobacterium tuberculosis with the use of
      recombinase-based in vivo expression technology.
AB  - A better understanding of mycobacterial gene regulation under certain stress
      conditions (e.g., low pH) may provide insight into mechanisms of adaptation
      during infection. To identify mycobacterial promoters induced at low pH, we
      adapted the recombinase-based in vivo expression technology (RIVET) promoter trap
      system for use with mycobacteria. Our results show that the TnpR recombinase of
      transposon gammadelta is active in Mycobacterium smegmatis and Mycobacterium
      tuberculosis. We developed a method to perform sequential double selection with
      mycobacteria by using RIVET, with a kanamycin preselection and a sucrose
      postselection. A library of M. tuberculosis DNA inserted upstream of tnpR was
      created, and using the double selection, we identified two promoters which are
      upregulated at low pH. The promoter regions drive the expression of a gene
      encoding a putative lipase, lipF (Rv3487c), as well as a PE-PGRS gene, Rv0834c,
      in a pH-dependent manner in both M. smegmatis and M. tuberculosis. The acid
      inducibility of lipF and Rv0834c was independent of the stress response sigma
      factor, SigF, as acid induction of the two genes in an M. tuberculosis sigF
      mutant strain was similar to that in the wild-type strain. No induction of lipF
      or Rv0834c was observed during infection of J774 murine macrophages, an
      observation which is in agreement with previous reports on the failure of
      phagosomes containing M. tuberculosis to acidify.

PMID- 12595456
TI  - CD40-CD40 ligand costimulation is not required for initiation and maintenance of
      a Th1-type response to Leishmania major infection.
AB  - Although previous studies demonstrated a requirement for CD40-CD40 ligand (CD40L)
      interaction in the development of resistance to Leishmania infection, we recently
      showed that mice lacking the gene for CD40L (CD40L(-/-) mice) can control
      Leishmania major infection when they are infected with reduced numbers of
      parasites. In this study, we examine the cytokine pattern in healing versus
      nonhealing CD40L(-/-) mice and investigated whether CD40 activation is required
      for resistance to reinfection. We observed that CD4(+) cells in healed CD40L(-/-)
      mice produce high levels of gamma interferon compared to cells from nonhealing,
      high-dose-inoculated mice. In addition, we observed a higher frequency of
      interleukin-12 (IL-12)- producing cells and a reduced number of IL-4-producing
      cells in mice infected with reduced numbers of parasites. Importantly, we found
      that healed CD40L(-/-) mice are highly resistant to reinfection with a large
      parasite inoculum. In addition, by comparing the cytokine patterns at an early
      and late stage of infection in nonhealing CD40L(-/-) mice, we demonstrated that
      nonhealing CD40L(-/-) mice produce a weak Th1-type response during the early
      stage of infection, but this response wanes as a Th2-type response emerges during
      late stages of infection. Anti-IL-4 antibody treatment, starting either at the
      beginning of infection or at week 4 postinfection enabled CD40L(-/-) mice to
      control a high-dose infection. Together, these results show that CD40-CD40L
      interaction, although important for IL-12 production in high-dose infections, is
      not required for either the development or maintenance of resistance in mice
      infected with reduced numbers of parasites.

PMID- 12595457
TI  - Enterohemorrhagic Escherichia coli O157:H7 disrupts Stat1-mediated gamma
      interferon signal transduction in epithelial cells.
AB  - Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a clinically important
      bacterial enteropathogen that manipulates a variety of host cell signal
      transduction cascades to establish infection. However, the effect of EHEC O157:H7
      on Jak/Stat signaling is unknown. To define the effect of EHEC infection on
      epithelial gamma interferon (IFN-gamma)-Stat1 signaling, human T84 and HEp-2
      epithelial cells were infected with EHEC O157:H7 and then stimulated with
      recombinant human IFN-gamma. Cells were also infected with different EHEC
      strains, heat-killed EHEC, enteropathogenic E. coli (EPEC) O127:H6, and the
      commensal strain E. coli HB101. Nuclear and whole-cell protein extracts were
      prepared and were assayed by an electrophoretic mobility shift assay (EMSA) and
      by Western blotting, respectively. Cells were also processed for
      immunofluorescence to detect the subcellular localization of Stat1. The EMSA
      revealed inducible, but not constitutive, Stat1 activation upon IFN-gamma
      treatment of both cell lines. The EMSA also showed that 6 h of EHEC O157:H7
      infection, but not 30 min of EHEC O157:H7 infection, prevented subsequent Stat1
      DNA binding induced by IFN-gamma, whereas infection with EPEC did not.
      Immunoblotting showed that infection with EHEC, but not infection with EPEC,
      eliminated IFN-gamma-induced Stat1 tyrosine phosphorylation in both dose- and
      time-dependent fashions and disrupted inducible protein expression of the Stat1
      dependent gene interferon regulatory factor 1. Immunofluorescence revealed that
      EHEC infection did not prevent nuclear accumulation of Stat1 after IFN-gamma
      treatment. Also, Stat1 tyrosine phosphorylation was suppressed by different EHEC
      isolates, including intimin-, type III secretion- and plasmid-deficient strains,
      but not by HB101 and heat-killed EHEC. These findings indicate the novel
      disruption of host cell signaling caused by EHEC infection but not by EPEC
      infection.

PMID- 12595458
TI  - Attenuated virulence of a Burkholderia cepacia type III secretion mutant in a
      murine model of infection.
AB  - Type III secretion systems are utilized by a number of gram-negative bacterial
      pathogens to deliver virulence-associated proteins into host cells. Using a PCR
      based approach, we identified homologs of type III secretion genes in the gram
      negative bacterium Burkholderia cepacia, an important pulmonary pathogen in
      immunocompromised patients and patients with cystic fibrosis. One of the genes,
      designated bscN, encodes a member of a family of ATP-binding proteins believed to
      generate energy driving virulence protein secretion. Genetic dissection of the
      regions flanking the bscN gene revealed a locus consisting of at least 10 open
      reading frames, predicted to encode products with significant homology to known
      type III secretion proteins in other bacteria. A defined null mutation was
      generated in the bscN gene, and the null strain and wild-type parent strain were
      examined by use of a murine model of B. cepacia infection. Quantitative
      bacteriological analysis of the lungs and spleens of infected C57BL/6 mice
      revealed that the bscN null strain was attenuated in virulence compared to the
      parent strain, with significantly lower bacterial recovery from the lungs and
      spleens at 3 days postinfection. Moreover, histopathological changes, including
      an inflammatory cell infiltrate, were more pronounced in the lungs of mice
      infected with the wild-type parent strain than in those of mice infected with the
      isogenic bscN mutant. These results implicate type III secretion as an important
      determinant in the pathogenesis of B. cepacia.

PMID- 12595459
TI  - Geographical structure of diversity and differences between symptomatic and
      asymptomatic infections for Plasmodium falciparum vaccine candidate AMA1.
AB  - Plasmodium falciparum apical membrane antigen 1 (AMA1) is a prime malaria vaccine
      candidate. Antigenic diversity within parasite populations is one of the main
      factors potentially limiting the efficacy of any asexual-stage vaccine, including
      one based on AMA1. The DNA coding for the most variable region of this antigen,
      domain I, was sequenced in 168 samples from the Wosera region of Papua New
      Guinea, including samples from symptomatic and asymptomatic infections.
      Neutrality tests applied to these sequences provided strong evidence of selective
      pressure operating on the sequence of ama1 domain I, consistent with AMA1 being a
      target of protective immunity. Similarly, a peculiar pattern of geographical
      diversity and the particular substitutions found were suggestive of strong
      constraints acting on the evolution of AMA1 at the population level, probably as
      a result of immune pressure. In addition, a strong imbalance between symptomatic
      and asymptomatic infections was detected in the frequency of particular residues
      at certain polymorphic positions, pointing to AMA1 as being one of the
      determinants of the morbidity associated with a particular strain. The
      information yielded by this study has implications for the design and assessment
      of AMA1-based vaccines and provides additional data supporting the importance of
      AMA1 as a malaria vaccine candidate.

PMID- 12595460
TI  - Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve
      damage in leprosy.
AB  - Nerve damage is a clinical hallmark of leprosy and a major source of patient
      morbidity. We investigated the possibility that human Schwann cells are
      susceptible to cell death through the activation of Toll-like receptor 2 (TLR2),
      a pattern recognition receptor of the innate immune system. TLR2 was detected on
      the surface of human Schwann cell line ST88-14 and on cultured primary human
      Schwann cells. Activation of the human Schwann cell line and primary human
      Schwann cell cultures with a TLR2 agonist, a synthetic lipopeptide comprising the
      N-terminal portion of the putative Mycobacterium leprae 19-kDa lipoprotein,
      triggered an increase in the number of apoptotic cells. The lipopeptide-induced
      apoptosis of Schwann cells could be blocked by an anti-TLR2 monoclonal antibody.
      Schwann cells in skin lesions from leprosy patients were found to express TLR2.
      It was possible to identify in the lesions Schwann cells that had undergone
      apoptosis in vivo. The ability of M. leprae ligands to induce the apoptosis of
      Schwann cells through TLR2 provides a mechanism by which activation of the innate
      immune response contributes to nerve injury in leprosy.

PMID- 12595461
TI  - Intravenous mouse infection model for studying the pathology of Enterococcus
      faecalis infections.
AB  - An intravenous mouse infection model was used to compare the virulence of
      Enterococcus faecalis strains, to study bacterial localization and organ
      histopathology, and to examine the effects of Nramp1 and gamma interferon (IFN
      gamma) on the course of infection. Infection of BALB/c mice with 5 x 10(8) CFU of
      E. faecalis JH2-2, MGH-2, 418, DS16C2, or OG1X revealed the following virulence
      ranking (from highest to lowest): MGH-2, 418, DS16C2, JH2-2, and OG1X.
      Discernible differences in the number of MGH-2 and JH2-2 bacteria were observed
      at 7 days (168 h) in the blood (P = 0.037), at 72 h in the liver (P = 0.002), and
      at 8 h in the spleen (P = 0.036). At these time points, the number of MGH-2
      bacteria was higher in the blood and liver while the number of JH2-2 bacteria was
      higher in the spleen. At 72 h, livers from MGH-2-infected mice had higher numbers
      of coalescing aggregates of leukocytes and a greater degree of caseous necrosis
      than those from JH2-2-infected mice. These results indicate a correlation between
      the virulence of the E. faecalis strain, the number of bacteria in the liver, and
      the degree of histopathology of the liver at 72 h postinfection. IFN-gamma was
      important in E. faecalis infection, since IFN-gamma gene knockout mice had
      reduced mortality and massive coagulative necrosis was observed in wild-type
      mice. The contribution of Nramp1 was unclear, since Nramp1(-/-) mice and the
      respective control mice were innately resistant to E. faecalis. The mortality of
      mice in this model is probably due to induction of cytokine release and massive
      coagulative necrosis.

PMID- 12595462
TI  - Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the
      IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of
      nitric oxide.
AB  - Nitric oxide (NO(.)) produced by inducible nitric oxide synthase (iNOS) is an
      important host defense molecule against Mycobacterium tuberculosis in mononuclear
      phagocytes. The objective of this study was to determine the role of the
      IkappaBalpha kinase-nuclear factor kappaB (IKK-NF-kappaB) signaling pathway in
      the induction of iNOS and NO(.) by a mycobacterial cell wall lipoglycan known as
      mannose-capped lipoarabinomannan (ManLAM) in mouse macrophages costimulated with
      gamma interferon (IFN-gamma). NF-kappaB was activated by ManLAM as shown by
      electrophoretic mobility shift assay, by immunofluorescence of translocated NF
      kappaB in intact cells, and by a reporter gene driven by four NF-kappaB-binding
      elements. Transduction of an IkappaBalpha mutant (Ser32/36Ala) significantly
      inhibited NO(.) expression induced by IFN-gamma plus ManLAM. An activated SCF
      complex, a heterotetramer (Skp1, Cul-1, beta-TrCP [F-box protein], and ROC1)
      involved with ubiquitination, is also required for iNOS-NO(.) induction. Two NF
      kappaB-binding sites (kappaBI and kappaBII) present on the 5'-flanking region of
      the iNOS promoter bound ManLAM-induced NF-kappaB similarly. By use of reporter
      constructs in which one or both sites are mutated, both NF-kappaB-binding
      positions were essential in iNOS induction by IFN-gamma plus ManLAM. IFN-gamma
      induced activation of the IRF-1 transcriptional complex is a necessary component
      in host defense against tuberculosis. Although the 5'-flanking region of the IRF
      1 promoter contains an NF-kappaB-binding site and ManLAM-induced NF-kappaB also
      binds to this site, ManLAM was unable to induce IRF-1 expression. The influence
      of mitogen-activated protein kinases on IFN-gamma plus ManLAM induction of iNOS
      NO(.) is not due to any effects on ManLAM induction of NF-kappaB.

PMID- 12595463
TI  - Protection against fatal Pseudomonas aeruginosa pneumonia in mice after nasal
      immunization with a live, attenuated aroA deletion mutant.
AB  - Studies of immunity to Pseudomonas aeruginosa have indicated that a variety of
      potential immunogens can elicit protection in animal models, utilizing both
      antibody- and cell-mediated immune effectors for protection. To attempt to
      optimize delivery of multiple protective antigens and elicit a broad range of
      immune effectors, we produced an aroA deletion mutant of the P. aeruginosa
      serogroup O2/O5 strain PAO1, designated PAO1deltaaroA. Previously, we reported
      that this strain elicits high levels of opsonic antibody directed against many
      serogroup O2/O5 strains after nasal immunization of mice and rabbits. Here, we
      assessed the protective efficacy of immunization with PAO1deltaaroA against acute
      fatal pneumonia in mice. After active immunization, high levels of protection
      were achieved against an ExoU-expressing cytotoxic variant of the parental strain
      PAO1 at doses up to 1,000-fold greater than the 50% lethal dose. Significant
      protection against PAO1 and two of four other serogroup O2/O5 strains was also
      found, but there was no protection against serogroup-heterologous strains. The
      serogroup O2/O5 strains not protected against were killed in opsonophagocytic
      assays as efficiently as the strains with which protection was seen, indicating a
      lack of correlation of protection and opsonic killing within the serogroup. In
      passive immunization experiments using challenge with wild-type PAO1 or other
      noncytotoxic members of the O2/O5 serogroup, there was no protection despite the
      presence of high levels of opsonic antibody in the mouse sera. However, passive
      immunization did prevent mortality from pneumonia due to the cytotoxic PAO1
      variant at low-challenge doses. These data suggest that a combination of humoral
      and cellular immunity is required for protection against P. aeruginosa lung
      infections, that such immunity can be elicited by using aroA deletion mutants,
      and that a multivalent P. aeruginosa vaccine composed of aroA deletion mutants of
      multiple serogroups holds significant promise.

PMID- 12595464
TI  - Amino acid sequence requirements in the hinge of human immunoglobulin A1 (IgA1)
      for cleavage by streptococcal IgA1 proteases.
AB  - The amino acid sequence requirements in the hinge of human immunoglobulin A1
      (IgA1) for cleavage by IgA1 proteases of different species of Streptococcus were
      investigated. Recombinant IgA1 antibodies were generated with point mutations at
      proline 227 and threonine 228, the residues lying on either side of the peptide
      bond at which all streptococcal IgA1 proteases cleave wild-type human IgA1. The
      amino acid substitutions produced no major effect upon the structure of the
      mutant IgA1 antibodies or their functional ability to bind to Fcalpha receptors.
      However, the substitutions had a substantial effect upon sensitivity to cleavage
      with some streptococcal IgA1 proteases, with, in some cases, a single point
      mutation rendering the antibody resistant to a particular IgA1 protease. This
      effect was least marked with the IgA1 protease from Streptococcus pneumoniae,
      which showed no absolute requirement for either proline or threonine at residues
      227 to 228. By contrast, the IgA1 proteases of Streptococcus oralis,
      Streptococcus sanguis, and Streptococcus mitis had an absolute requirement for
      proline at 227 but not for threonine at 228, which could be replaced by valine.
      There was evidence in S. mitis that proteases from different strains may have
      different amino acid requirements for cleavage. Remarkably, some streptococcal
      proteases appeared able to cleave the hinge at a distant alternative site if
      substitution prevented efficient cleavage of the original site. Hence, this study
      has identified key residues required for the recognition of the IgA1 hinge as a
      substrate by streptococcal IgA1 proteases, and it marks a preliminary step
      towards development of specific enzyme inhibitors.

PMID- 12595466
TI  - Role of the Brucella suis lipopolysaccharide O antigen in phagosomal genesis and
      in inhibition of phagosome-lysosome fusion in murine macrophages.
AB  - Brucella species are gram-negative, facultative intracellular bacteria that
      infect humans and animals. These organisms can survive and replicate within a
      membrane-bound compartment inside professional and nonprofessional phagocytic
      cells. Inhibition of phagosome-lysosome fusion has been proposed as a mechanism
      for intracellular survival in both cell types. However, the molecular mechanisms
      and the microbial factors involved are poorly understood. Smooth
      lipopolysaccharide (LPS) of Brucella has been reported to be an important
      virulence factor, although its precise role in pathogenesis is not yet clear. In
      this study, we show that the LPS O side chain is involved in inhibition of the
      early fusion between Brucella suis-containing phagosomes and lysosomes in murine
      macrophages. In contrast, the phagosomes containing rough mutants, which fail to
      express the O antigen, rapidly fuse with lysosomes. In addition, we show that
      rough mutants do not enter host cells by using lipid rafts, contrary to smooth
      strains. Thus, we propose that the LPS O chain might be a major factor that
      governs the early behavior of bacteria inside macrophages.

PMID- 12595465
TI  - CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by
      lipopolysaccharide and type 1 piliated Escherichia coli.
AB  - The gram-negative bacterium Escherichia coli is the leading cause of urinary
      tract infection. The interaction between type 1 piliated E. coli and bladder
      epithelial cells leads to the rapid production of inflammatory mediators, such as
      interleukin-6 (IL-6) and IL-8. Conflicting reports have been published in the
      literature regarding the mechanism by which uroepithelial cells are activated by
      type 1 piliated E. coli. In particular, the role of lipopolysaccharide (LPS) in
      these responses has been an area of significant debate. Much of the data arguing
      against LPS-mediated activation of bladder epithelial cells have come from
      studies using a renal epithelial cell line as an in vitro model of the urinary
      epithelium. In this report, we analyzed three bladder epithelial cell lines and
      demonstrated that they all respond to LPS. Furthermore, the LPS responsivity of
      the cell lines directly correlated with their ability to generate IL-6 after E.
      coli stimulation. The LPS receptor complex utilized by the bladder epithelial
      cell lines included CD14 and Toll-like receptors, and signaling involved the
      activation of NF-kappaB and p38 mitogen-activated protein kinase. Also, reverse
      transcription-PCR analysis demonstrated that bladder epithelial cells express
      CD14 mRNA. Thus, the molecular machinery utilized by bladder epithelial cells for
      the recognition of E. coli is very similar to that described for traditional
      innate immune cells, such as macrophages. In contrast, the A498 renal epithelial
      cell line did not express CD14, was hyporesponsive to LPS stimulation, and
      demonstrated poor IL-6 responses to E. coli.

PMID- 12595467
TI  - Venezuelan equine encephalitis virus-vectored vaccines protect mice against
      anthrax spore challenge.
AB  - Anthrax, a disease usually associated with herbivores, is caused by the bacterium
      Bacillus anthracis. The current vaccine licensed for human use requires a six
      dose primary series and yearly boosters and causes reactogenicity in up to 30% of
      vaccine recipients. A minimally reactogenic vaccine requiring fewer inoculations
      is warranted. Venezuelan equine encephalitis (VEE) virus has been configured for
      use as a vaccine vector for a wide variety of immunogens. The VEE vaccine vector
      is composed of a self-replicating RNA (replicon) containing all of the VEE virus
      nonstructural genes and a multiple-cloning site in place of the VEE structural
      genes. Four different anthrax vaccines were constructed by cloning the protective
      antigen (PA) gene from B. anthracis into the VEE vaccine vector. The anthrax
      vaccines were produced by assembling the vectors into propagation-deficient VEE
      replicon particles in vitro. A/J mice inoculated subcutaneously with three doses
      of the mature 83-kDa PA vaccine were completely protected from challenge with the
      Sterne strain of B. anthracis. Similar results were obtained with vaccines
      composed of the PA gene fused to either the B. anthracis secretory sequence or to
      a tissue plasminogen activator secretory sequence in three additional mouse
      strains. Mice were unprotected from challenge after inoculation with the carboxy
      terminal 63-kDa PA vaccine. These results suggest that these VEE-vectored
      vaccines may be suitable as candidate vaccines against anthrax.

PMID- 12595468
TI  - Shiga toxin 1 triggers a ribotoxic stress response leading to p38 and JNK
      activation and induction of apoptosis in intestinal epithelial cells.
AB  - Shiga toxins made by Shiga toxin-producing Escherichia coli (STEC) are associated
      with hemolytic uremic syndrome. Shiga toxins (Stxs) may access the host systemic
      circulation by absorption across the intestinal epithelium. The effects of Stxs
      on this cell layer are not completely understood, although animal models of STEC
      infection suggest that, in the gut, Stxs may participate in both immune
      activation and apoptosis. Stxs have one enzymatically active A subunit associated
      with five identical B subunits. The A subunit inactivates ribosomes by cleaving a
      specific adenine from the 28S rRNA. We have previously shown that Stxs can induce
      multiple C-X-C chemokines in intestinal epithelial cells in vitro, including
      interleukin-8 (IL-8), and that Stx-induced IL-8 expression is linked to induction
      of c-Jun mRNA and p38 mitogen-activated protein (MAP) kinase pathway activity. We
      now report Stx1 induction of both primary response genes c-jun and c-fos and
      activation of the stress-activated protein kinases, JNK/SAPK and p38, in the
      intestinal epithelial cell line HCT-8. By 1 h of exposure to Stx1, mRNAs for c
      jun and c-fos are induced, and both JNK and p38 are activated; activation of both
      kinases persisted up to 24 h. Stx1 enzymatic activity was required for kinase
      activation; a catalytically defective mutant toxin did not activate either. Stx1
      treatment of HCT-8 cells resulted in cell death that was associated with caspase
      3 cleavage and internucleosomal DNA fragmentation; this cytotoxicity also
      required Stx1 enzymatic activity. Blocking Stx1-induced p38 and JNK activation
      with the inhibitor SB202190 prevented cell death and diminished Stx1-associated
      caspase 3 cleavage. In summary, these data link the Stx1-induced ribotoxic stress
      response with both chemokine expression and apoptosis in the intestinal
      epithelial cell line HCT-8 and suggest that blocking host cell MAP kinases may
      prevent these Stx-associated events.

PMID- 12595469
TI  - Lymphoid follicle-dense mucosa at the terminal rectum is the principal site of
      colonization of enterohemorrhagic Escherichia coli O157:H7 in the bovine host.
AB  - Escherichia coli O157:H7 causes bloody diarrhea and potentially fatal systemic
      sequelae in humans. Cattle are most frequently identified as the primary source
      of infection, and E. coli O157:H7 generally colonizes the gastrointestinal tracts
      of cattle without causing disease. In this study, persistence and tropism were
      assessed for four different E. coli O157:H7 strains. Experimentally infected
      calves shed the organism for at least 14 days prior to necropsy. For the majority
      of these animals, as well as for a naturally colonized animal obtained from a
      commercial beef farm, the highest numbers of E. coli O157:H7 were found in the
      feces, with negative or significantly lower levels detected in lumen contents
      taken from the gastrointestinal tract. Detailed examination demonstrated that in
      these individuals the majority of tissue-associated bacteria were adherent to
      mucosal epithelium within a defined region extending up to 5 cm proximally from
      the recto-anal junction. The tissue targeted by E. coli O157:H7 was characterized
      by a high density of lymphoid follicles. Microcolonies of the bacterium were
      readily detected on the epithelium of this region by immunofluorescence
      microscopy. As a consequence of this specific distribution, E. coli O157:H7 was
      present predominantly on the surface of the fecal stool. In contrast, other E.
      coli serotypes were present at consistent levels throughout the large intestine
      and were equally distributed in the stool. This is a novel tropism that may
      enhance dissemination both between animals and from animals to humans. The
      accessibility of this site may facilitate simple intervention strategies.

PMID- 12595470
TI  - Role of Toll-like receptor signaling in the apoptotic response of macrophages to
      Yersinia infection.
AB  - Macrophages encode several Toll-like receptors (TLRs) that recognize bacterial
      components, such as lipoproteins (TLR2) or lipopolysaccharides (TLR4), and
      activate multiple signaling pathways. Activation of transcription factor NF
      kappaB by TLR2 or TLR4 signaling promotes proinflammatory and cell survival
      responses. Alternatively, TLR2 or TLR4 signaling can promote apoptosis if the
      activation of NF-kappaB is blocked. The gram-negative bacterial pathogen Yersinia
      pseudotuberculosis secretes into macrophages a protease (YopJ) that inhibits the
      activation of NF-kappaB and promotes apoptosis. We show that primary macrophages
      expressing constitutively active inhibitor kappaB kinase beta (IKKbeta) are
      completely resistant to YopJ-dependent apoptosis, indicating that YopJ inhibits
      signaling upstream of IKKbeta. Apoptosis is reduced two- to threefold in TLR4(-/
      ) macrophages infected with Y. pseudotuberculosis, while the apoptotic response
      of TLR2(-/-) macrophages to Y. pseudotuberculosis infection is equivalent to that
      of wild-type macrophages. Therefore, TLR4 is the primary source of apoptotic
      signaling in Yersinia-infected macrophages. Our results also show that a small
      percentage of macrophages can die as a result of an apoptotic process that is
      YopJ dependent but does not require TLR2 or TLR4 signaling.

PMID- 12595471
TI  - Effects of respiratory Mycoplasma pneumoniae infection on allergen-induced
      bronchial hyperresponsiveness and lung inflammation in mice.
AB  - Airway mycoplasma infection may be associated with asthma pathophysiology.
      However, the direct effects of mycoplasma infection on asthma remain unknown.
      Using a murine allergic-asthma model, we evaluated the effects of different
      timing of airway Mycoplasma pneumoniae infection on bronchial hyperresponsiveness
      (BHR), lung inflammation, and the protein levels of Th1 (gamma interferon [IFN
      gamma]) and Th2 (interleukin 4 [IL-4]) cytokines in bronchoalveolar lavage fluid.
      When mycoplasma infection occurred 3 days before allergen (ovalbumin)
      sensitization and challenge, the infection reduced the BHR and inflammatory-cell
      influx into the lung. This was accompanied by a significant induction of Th1
      responses (increased IFN-gamma and decreased IL-4 production). Conversely, when
      mycoplasma infection occurred 2 days after allergen sensitization and challenge,
      the infection initially caused a temporary reduction of BHR and then increased
      BHR, lung inflammation, and IL-4 levels. Our data suggest that mycoplasma
      infection could modulate both physiological and immunological responses in the
      murine asthma model. Our animal models may also provide a new means to understand
      the role of infection in asthma pathogenesis and give evidence for the asthma
      hygiene hypothesis.

PMID- 12595473
TI  - Role of PLB1 in pulmonary inflammation and cryptococcal eicosanoid production.
AB  - Cryptococcal phospholipase (PLB1) is a secreted enzyme with lysophospholipase
      hydrolase and lysophospholipase transacylase activities. To investigate the role
      of PLB1 in the evasion of host immune responses, we characterized pulmonary
      immune responses to the parental (H99), the plb1 mutant, and the plb1(rec)
      reconstituted mutant strains of Cryptococcus neoformans in mice. PLB1 was
      required for virulence during infection acquired via the respiratory tract. Mice
      infected with either H99 or the plb1(rec) strain generated a nonprotective
      inflammatory response with subsequent eosinophilia, while mice infected with the
      plb1 mutant generated a protective immune response that controlled the infection.
      Because PLB1 is believed to facilitate virulence through host cell lysis, we
      examined the interaction of these strains with macrophages. The plb1(rec) mutant
      exhibited decreased survival during coculture with macrophages. One factor which
      may be involved in the survival of yeast in the presence of macrophages is fungal
      eicosanoid production. Host eicosanoids have been shown to down-modulate
      macrophage functions. plb1 exhibited a defect in eicosanoid production derived
      from exogenous arachidonoyl-phosphatidylcholine, suggesting that PLB1 is required
      for the release of arachidonic acid from phospholipids. These data suggest that
      cryptococcal PLB1 may act as a virulence factor by enhancing the ability to
      survive macrophage antifungal defenses, possibly by facilitating fungal
      eicosanoid production.

PMID- 12595472
TI  - Mutant Escherichia coli heat-labile toxin B subunit that separates toxoid
      mediated signaling and immunomodulatory action from trafficking and delivery
      functions.
AB  - The homopentameric B-subunit components of Escherichia coli heat-labile
      enterotoxin (EtxB) and cholera toxin (CtxB) possess the capacity to enter
      mammalian cells and to activate cell-signaling events in leukocytes that modulate
      immune cell function. Both properties have been attributed to the ability of the
      B subunits to bind to GM1-ganglioside receptors, a ubiquitous glycosphingolipid
      found in the plasma membrane. Here we describe the properties of EtxB(H57S), a
      mutant B subunit with a His-->Ser substitution at position 57. The mutant was
      found to be severely defective in inducing leukocyte signaling, as shown by
      failure to (i) trigger caspase 3-mediated CD8(+)-T-cell apoptosis, (ii) activate
      nuclear translocation of NF-kappaB in Jurkat T cells, (iii) induce a potent anti
      B-subunit response in mice, or (iv) serve as a mucosal adjuvant. However, its GM1
      binding, cellular uptake, and delivery functions remained intact. This was
      further validated by the finding that EtxB(H57S) was as effective as EtxB in
      delivering a conjugated model class I epitope into the major histocompatibility
      complex class I pathway of a dendritic cell line. These observations imply that
      GM1 binding alone is not sufficient to trigger the signaling events responsible
      for the potent immunomodulatory properties of EtxB. Moreover, they demonstrate
      that its signaling properties play no role in EtxB uptake and trafficking. Thus,
      EtxB(H57S) represents a novel tool for evaluating the complex cellular
      interactions and signaling events occurring after receptor interaction, as well
      as offering an alternative means of delivering attached peptides in the absence
      of the potent immunomodulatory signals induced by wild-type B subunits.

PMID- 12595474
TI  - The zinc-dependent major histocompatibility complex class II binding site of
      streptococcal pyrogenic exotoxin C is critical for maximal superantigen function
      and toxic activity.
AB  - The cocrystal structure of streptococcal pyrogenic exotoxin C (SPE C) with HLA
      DR2a (DRA*0101,DRB5*0101) revealed a zinc-dependent interaction site through
      residues 167, 201, and 203 on SPE C and residue 81 on the beta-chain of HLA-DR2a
      (DRA*0101,DRB5*0101). Mutation of these SPE C residues resulted in dramatically
      reduced biological activities. Thus, the zinc-dependent major histocompatibility
      complex II binding site is critical for maximal biological function of SPE C.

PMID- 12595475
TI  - Effects of ectopically expressed neuronal Wiskott-Aldrich syndrome protein
      domains on Rickettsia rickettsii actin-based motility.
AB  - Neuronal Wiskott-Aldrich syndrome protein (N-WASP) and the actin-related protein
      2/3 (Arp2/3) complex have emerged as critical host proteins that regulate
      pathogen actin-based motility. Actin tail formation and motility in Listeria
      monocytogenes require the Arp2/3 complex but bypasses N-WASP signaling. Motility
      of Shigella flexneri and vaccinia virus requires both N-WASP and the Arp2/3
      complex. Functional roles for these cytoskeletal regulatory proteins in actin
      based motility of Rickettsia rickettsii have not been established. In this study,
      functional domains of N-WASP tagged with green fluorescent protein that have
      characterized effects on Shigella and vaccinia virus actin-based motility were
      ectopically expressed in HeLa cells infected with R. rickettsii to assess their
      effects on rickettsial motility. S. flexneri-infected cells were used as a
      control. Expressed N-WASP domains did not localize to R. rickettsii or their
      actin tails. Expression of N-WASP missing the VCA domain (for "verprolin
      homology, cofilin homology, and acidic domains"), which acts as a dominant
      negative form of N-WASP, completely inhibited actin-based motility of S. flexneri
      while only moderately inhibiting motility of R. rickettsii. Similarly, expression
      of the VCA domain, which acts as a dominant-negative with respect to Arp2/3
      complex function, severely inhibited actin-based motility of S. flexneri (no
      motility observed in the majority of expressing cells) but only moderately
      inhibited R. rickettsii motility. These results, taken together with the
      differential effects on motility observed upon expression of other N-WASP
      domains, suggest that actin-based motility of R. rickettsii is independent of N
      WASP and the Arp2/3 complex.

PMID- 12595476
TI  - Studies of the mechanism of action of the aerolysin-like hemolysin of Aeromonas
      sobria in stimulating T84 cells to produce cyclic AMP.
AB  - We previously reported that the aerolysin-like hemolysin of Aeromonas sobria
      stimulates T84 cells to produce cyclic AMP, which then emerges in the culture
      medium. In order to clarify the mechanism of action of the hemolysin, we examined
      the involvement of adenosine nucleotide. The results show that the hemolysin
      stimulates T84 cells to release ATP, which is then converted to adenosine by
      ectonucleotidase. The adenosine generated might stimulate the P1 adenosine
      receptors of T84 cells to produce cyclic AMP.

PMID- 12595477
TI  - Cell adhesion and Ca2+ signaling activity in stably transfected Trypanosoma cruzi
      epimastigotes expressing the metacyclic stage-specific surface molecule gp82.
AB  - Metacyclic trypomastigotes of Trypanosoma cruzi express a developmentally
      regulated 82-kDa surface glycoprotein (gp82) that has been implicated in host
      cell invasion. gp82-mediated interaction of metacyclic forms with target cells
      induces in both cells activation of the signal transduction pathways, leading to
      intracellular Ca(2+) mobilization, which is required for parasite
      internalization. Noninfective epimastigotes do not express detectable levels of
      gp82 and are unable to induce a Ca(2+) response. We stably transfected
      epimastigotes with a T. cruzi expression vector carrying the metacyclic stage
      gp82 cDNA. These transfectants produced a functional gp82, which bound to and
      triggered a Ca(2+) response in HeLa cells, in the same manner as the metacyclic
      trypomastigote gp82. Such properties were not found in epimastigotes transfected
      with the plasmid vector alone. Epimastigotes expressing gp82 on the surface
      adhered to HeLa cells but were not internalized. Treatment of gp82-expressing
      epimastigotes with forskolin, an activator of adenylyl cyclase that increases the
      metacyclic trypomastigote entry into target cells, did not promote parasite
      internalization. P175, an intracellular tyrosine phosphorylated protein, which
      appears to play a role in gp82-dependent signaling cascade in metacyclic forms,
      was undetectable in epimastigotes, either transfected or not with pTEX-gp82.
      Overall, our results indicate that gp82 is required but not sufficient for target
      cell invasion.

PMID- 12595478
TI  - Role of interleukin-6 in the control of acute and chronic Giardia lamblia
      infections in mice.
AB  - In this study, we investigated the role of interleukin-6 (IL-6) in Giardia
      lamblia infections in mice. Elevated IL-6 expression was found in wild-type mice
      15 days postinfection. Furthermore, IL-6-deficient mice controlled infections
      only slowly although normal immunoglobulin A production was observed. Thus, IL-6
      is necessary for early control of acute G. lamblia infections.

PMID- 12595479
TI  - Interleukin-6-deficient mice are highly susceptible to Giardia lamblia infection
      but exhibit normal intestinal immunoglobulin A responses against the parasite.
AB  - In the present study, interleukin-6 (IL-6)-deficient mice were infected with
      Giardia lamblia clone GS/M-83-H7. Murine IL-6 deficiency did not affect the
      synthesis of parasite-specific intestinal immunoglobulin A. However, in contrast
      to wild-type mice, IL-6-deficient animals were not able to control the acute
      phase of parasite infection. Reverse transcription-PCR-based quantitation of
      cytokine mRNA levels in peripheral lymph node cells exhibited a short-term up
      regulation of IL-4 expression in IL-6-deficient mice that seemed to be associated
      with failure in controlling the parasite population. This observation suggests a
      further elucidation of IL-4-dependent, Th2-type regulatory processes regarding
      their potential to influence the course of G. lamblia infection in the
      experimental murine host.

PMID- 12595480
TI  - Nonhuman primate model for Listeria monocytogenes-induced stillbirths.
AB  - Listeria monocytogenes, isolated from outbreaks in either human or nonhuman
      primate populations, was administered orally at doses ranging from 10(6) to
      10(10) CFU. Four of 10 treated animals delivered stillborn infants. L.
      monocytogenes was isolated from fetal tissue, and the pathology was consistent
      with L. monocytogenes infection as the cause of pregnancy loss. For all
      pregnancies resulting in stillbirths, L. monocytogenes was isolated from maternal
      feces, indicating that L. monocytogenes had survived and had probably colonized
      the gastrointestinal tract. Antibodies and antigen-specific lymphocyte
      proliferation against Listeria increased in animals that had stillbirths.

PMID- 12595481
TI  - N-terminal E-cadherin peptides act as decoy receptors for Listeria monocytogenes.
AB  - The observation that E-cadherin is the principal epithelial receptor for the
      bacterial pathogen Listeria monocytogenes led us to investigate whether N
      terminal fragments of E-cadherin containing the L. monocytogenes binding domain
      could inhibit entry of the bacteria into cultured epithelial cells. Here we
      demonstrate that a conditioned medium from a gastric cancer cell line (Kato III)
      that carries a truncating CDH-1 mutation 3' of the L. monocytogenes binding
      domain can inhibit the uptake of the bacteria into Caco-2 cells. The inhibitory
      activity of the Kato III conditioned medium could be mimicked by incubation of
      the bacteria with a recombinant 26-kDa N-terminal E-cadherin peptide prior to
      infection. Furthermore, these data suggest that cleavage of the 80-kDa
      extracellular domain of E-cadherin from the cell surface may provide an innate
      form of pathogen defense by acting as a decoy receptor for L. monocytogenes.

PMID- 12595482
TI  - Expression of variant surface antigens by Plasmodium falciparum parasites in the
      peripheral blood of clinically immune pregnant women indicates ongoing placental
      infection.
AB  - Placenta-sequestered Plasmodium falciparum parasites that cause pregnancy
      associated malaria (PAM) in otherwise clinically immune women express distinct
      variant surface antigens (VSA(PAM)) not expressed by parasites in nonpregnant
      individuals. We report here that parasites from the peripheral blood of
      clinically immune pregnant women also express VSA(PAM), making them a convenient
      source of VSA(PAM) expressors for PAM vaccine research.

PMID- 12595483
TI  - Interleukin-12 regulates chemokine gene expression during the early immune
      response to Leishmania major.
AB  - Following infection with Leishmania major, the chemokines XCL1, CXCL10, and CCL2
      were preferentially expressed in draining lymph nodes of resistant mice.
      Neutralization of interleukin 12 (IL-12) or gamma interferon in resistant mice
      resulted in decreased chemokine expression, while administration of IL-12 to
      susceptible mice resulted in an increase in the level of chemokine gene
      expression.

PMID- 12595484
TI  - DsbA of Pseudomonas aeruginosa is essential for multiple virulence factors.
AB  - DsbA is a periplasmic thiol:disulfide oxidoreductase which contributes to the
      process of protein folding by catalyzing the formation of disulfide bonds. In
      this study, we demonstrate that the dsbA gene is required for the expression of
      the type III secretion system under low-calcium inducing conditions,
      intracellular survival of P. aeruginosa upon infection of HeLa cells, and
      twitching motility. The diverse phenotypes of the dsbA mutant are likely due to
      its defect in the folding of proteins that are involved in various biological
      processes, such as signal sensing, protein secretion, and defense against host
      clearing. In light of its effect on various virulence factors, DsbA could be an
      important target for the control of P. aeruginosa infections.

PMID- 12595485
TI  - Effect of vaccination with refined components of the organism on infection of
      mice with Mycobacterium leprae.
AB  - Only native products of Mycobacterium leprae, whether cell wall, cytosol, or
      membrane derived, can confer protective immunity against challenge in the mouse
      footpad. Previously, recombinant proteins were shown to be ineffective. The cell
      wall skeleton-the mycolyl-arabinogalactan-peptidoglycan complex-devoid of
      proteins is not protective.

PMID- 12595486
TI  - Purification of fully activated Clostridium botulinum serotype B toxin for
      treatment of patients with dystonia.
AB  - Clostridium botulinum serotype B toxins 12S and 16S were separated by using a
      beta-lactose gel column at pH 6.0; toxin 12S passed through the column, whereas
      toxin 16S bound to the column and eluted with lactose. The fully activated
      neurotoxin was obtained by applying the trypsin-treated 16S toxin on the same
      column at pH 8.0; the neurotoxin passed through the column, whereas remaining
      nontoxic components bound to the column. The toxicity of this purified fully
      activated neurotoxin was retained for a long period by addition of albumin in the
      preparation.

PMID- 12595487
TI  - Bacterial [Cu,Zn]-cofactored superoxide dismutase protects opsonized,
      encapsulated Neisseria meningitidis from phagocytosis by human
      monocytes/macrophages.
AB  - Superoxide dismutase cofactored by copper and zinc ([Cu,Zn]-SOD) contributes to
      the protection of opsonized serogroup B Neisseria meningitidis against
      phagocytosis by human monocytes/macrophages, with sodC mutant organisms being
      endocytosed in significantly higher numbers than are wild-type organisms. The
      influence of [Cu,Zn]-SOD was found to be exerted at the stage of phagocytosis,
      rather than at earlier (modulating surface association) or later (intracellular
      killing) stages.

PMID- 12595488
TI  - Clostridium difficile vaccine and serum immunoglobulin G antibody response to
      toxin A.
AB  - There is a strong association between serum antibody responses to toxin A and
      protection against Clostridium difficile diarrhea. A parenteral C. difficile
      toxoid vaccine induced very-high-level responses to anti-toxin A immunoglobulin G
      (IgG) in the sera of healthy volunteers. After vaccination, the concentrations of
      anti-toxin A IgG in the sera of all 30 recipients exceeded the concentrations
      that were associated with protection in previous clinical studies. Furthermore,
      the median concentration of serum anti-toxin A IgG in the test group was 50-fold
      higher than the previous threshold. These findings support the feasibility of
      using a vaccine to protect high-risk individuals against C. difficile-associated
      diarrhea and colitis.

PMID- 12595489
TI  - RhBG and RhCG, the putative ammonia transporters, are expressed in the same cells
      in the distal nephron.
AB  - Two nonerythroid homologs of the blood group Rh proteins, RhCG and RhBG, which
      share homologies with specific ammonia transporters in primitive organisms and
      plants, could represent members of a new family of proteins involved in ammonia
      transport in the mammalian kidney. Consistent with this hypothesis, the
      expression of RhCG was recently reported at the apical pole of all connecting
      tubule (CNT) cells as well as in intercalated cells of collecting duct (CD). To
      assess the localization along the nephron of RhBG, polyclonal antibodies against
      the Rh type B glycoprotein were generated. In immunoblot experiments, a specific
      polypeptide of Mr approximately 50 kD was detected in rat kidney cortex and in
      outer and inner medulla membrane fractions. Immunocytochemical studies revealed
      RhBG expression in distal nephron segments within the cortical labyrinth,
      medullary rays, and outer and inner medulla. RhBG expression was restricted to
      the basolateral membrane of epithelial cells. The same localization was observed
      in rat and mouse kidney. RT-PCR analysis on microdissected rat nephron segments
      confirmed that RhBG mRNAs were chiefly expressed in CNT and cortical and outer
      medullary CD. Double immunostaining with RhCG demonstrated that RhBG and RhCG
      were coexpressed in the same cells, but with a basolateral and apical
      localization, respectively. In conclusion, RhBG and RhCG are present in a major
      site of ammonia secretion in the kidney, i.e., the CNT and CD, in agreement with
      their putative role in ammonium transport.

PMID- 12595490
TI  - Corticosteroids induce expression of aquaporin-1 and increase transcellular water
      transport in rat peritoneum.
AB  - The water channel aquaporin-1 (AQP1) is the molecular counterpart of the
      ultrasmall pore responsible for transcellular water permeability during
      peritoneal dialysis (PD). This water permeability accounts for up to 50% of
      ultrafiltration (UF) during a hypertonic dwell, and its loss can be a major
      clinical problem for PD patients. By analogy with the lung, the hypothesis was
      tested that corticosteroids may increase AQP1 expression in the peritoneal
      membrane (PM) and improve water permeability and UF in rats. First, the
      expression and distribution of the glucocorticoid receptor (GR) in the PM and
      capillary endothelium was documented. Time-course and dose-response analyses
      showed that a daily IM injection of dexamethasone (1 or 4 mg/kg) for 5 d induced
      an approximately twofold increase in the expression of AQP1 at the mRNA and
      protein levels. The GR antagonist RU-486 completely inhibited the dexamethasone
      effect. The functional counterpart of the increased AQP1 expression was a
      significant increase in sodium sieving and net UF across the PM, contrasting with
      a lack of effect on the osmotic gradient and permeability for small solutes. The
      latter observation reflected the lack of effect of corticosteroids on nitric
      oxide synthase (NOS) activity and endothelial NOS isoform expression in the PM.
      In conclusion, corticosteroids induce AQP1 expression in the capillary
      endothelium of the PM, which is reflected by increased transcellular water
      permeability and UF. These data emphasize the critical role of AQP1 during PD and
      suggest that pharmacologic regulation of AQP1 may provide a target for
      manipulating water permeability across the PM.

PMID- 12595491
TI  - Urinary concentrating defect in hypothyroid rats: role of sodium, potassium, 2
      chloride co-transporter, and aquaporins.
AB  - Hypothyroidism is associated with impaired urinary concentrating ability in
      humans and animals. The purpose of this study was to examine protein expression
      of renal sodium chloride and urea transporters and aquaporins in hypothyroid rats
      (HT) with diminished urinary concentration as compared with euthyroid controls
      (CTL) and hypothyroid rats replaced with L-thyroxine (HT+T). Hypothyroidism was
      induced by aminotriazole administration. Body weight, water intake, urine output,
      solute and urea excretion, serum and urine osmolality, serum creatinine, 24-h
      creatinine clearance, and fractional excretion of sodium were comparable among
      the three groups. However, with 36 h of water deprivation, HT rats demonstrated
      significantly greater urine flow rates and decreased urine and medullary
      osmolality as compared with CTL and HT+T rats at comparable plasma vasopressin
      concentrations. Western blot analyses revealed decreased renal protein abundance
      of transporters, including Na-K-2Cl, Na-K-ATPase, and NHE3, in HT rats as
      compared with CTL and HT+T rats. Protein abundance of renal AQP1 and urea
      transporters UTA(1) and UTA(2) did not differ significantly among study groups.
      There was however a significant decrease in protein abundance of AQP2, AQP3, and
      AQP4 in HT rats as compared with CTL and HT+T rats. These findings demonstrate a
      decrease in the medullary osmotic gradient secondary to impaired countercurrent
      multiplication and downregulation of aquaporins 2, 3, and 4 as contributors to
      the urinary concentrating defect in the hypothyroid rat.

PMID- 12595492
TI  - The calcimimetic AMG 073 as a potential treatment for secondary
      hyperparathyroidism of end-stage renal disease.
AB  - Current treatment of secondary hyperparathyroidism in chronic kidney failure with
      calcium and active vitamin D is potentially limited by hypercalcemia and
      hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment
      of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone
      (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid
      calcium-sensing receptor (CaR) to extracellular calcium. The current study
      evaluates the efficacy and safety of AMG 073 when added to conventional treatment
      of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one
      hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite
      standard therapy with calcium, phosphate binders, and active vitamin D sterols,
      were treated in this 18-wk, dose-titration study with single daily oral doses of
      AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum
      phosphorus, and calcium x phosphorus levels were compared between AMG 073 and
      placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with
      an increase of 3% in placebo patients (P = 0.001). A significantly greater
      proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared
      with placebo patients (20%; P = 0.029). Also, a significantly greater proportion
      of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo
      patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG
      073 patients compared with an increase of 11.3% in placebo patients (P = 0.013).
      Adverse event rates were low and mostly mild to moderate in severity; however,
      the incidence of vomiting was higher in AMG 073 patients. In this study, the
      calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and
      effective means to attain significant reductions in PTH and calcium x phosphorus
      levels in ESRD patients. AMG 073 represents a novel and promising therapy to
      improve the management of secondary hyperparathyroidism.

PMID- 12595493
TI  - Differential contribution of three mitogen-activated protein kinases to PDGF-BB
      induced mesangial cell proliferation and gene expression.
AB  - This study examined the role of mitogen-activated protein (MAP) kinase in PDGF-BB
      induced proliferation and gene expression of human mesangial cells (MC). PDGF-BB
      stimulation of MC increased mRNA for transforming growth factor-beta1 (TGF
      beta1), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator
      inhibitor-1 (PAI-1) and increased the cell numbers. To inhibit activation of
      extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK),
      and p38, MC were infected with recombinant adenovirus containing dominant
      negative mutants of ERK, JNK, and p38 (Ad-DN-ERK, Ad-DN-JNK, Ad-DN-p38,
      respectively), respectively. Infection of MC with Ad-DN-ERK or Ad-DN-JNK
      inhibited PDGF-BB-induced increase in [(3)H]thymidine incorporation and cell
      numbers, whereas Ad-DN-p38 did not. Ad-DN-ERK inhibited MCP-1 and PAI-1 mRNA
      expression in MC, but not TGF-beta1. Ad-DN-JNK and Ad-DN-p38 inhibited TGF-beta1
      and MCP-1 mRNA expression, but not PAI-1. The inhibition of activator protein-1
      (AP-1) in MC, by adenovirus containing dominant-negative mutant of c-Jun (Ad-DN-c
      Jun), inhibited PDGF-BB-induced cell proliferation and TGF-beta1, MCP-1, and PAI
      1 expressions. Furthermore, Ad-DN-JNK or Ad-DN-p38, but not Ad-DN-ERK, attenuated
      PDGF-BB-induced AP-1 activation in MC, indicating the involvement of JNK and p38
      in AP-1 activation. Our results indicated that ERK and JNK, but not p38,
      participated in PDGF-BB-induced MC proliferation. PDGF-BB-induced expression of
      TGF-beta1 was mediated by JNK and p38, MCP-1 expression was through ERK, JNK, and
      p38, whereas PAI-1 expression was due to only ERK. AP-1 activation, which was
      partially due to JNK and p38 activations, was involved in MC proliferation and
      these three gene expressions. Thus, three MAP kinases seem to contribute to
      progression of glomerular disease via different molecular mechanisms.

PMID- 12595494
TI  - PPAR agonists protect mesangial cells from interleukin 1beta-induced
      intracellular lipid accumulation by activating the ABCA1 cholesterol efflux
      pathway.
AB  - Previous studies have demonstrated that inflammatory cytokines such as
      interleukin-1beta (IL-1beta) promote lipid accumulation in human mesangial cells
      (HMC) by dysregulating the expression of lipoprotein receptors. Intracellular
      lipid accumulation is governed by both influx and efflux; therefore, the effect
      of IL-1beta on the efflux of lipid from HMC was investigated. IL-1beta was shown
      to inhibit (3)H-cholesterol efflux from HMC and increase total intracellular
      cholesterol concentration, probably as a result of reduced expression of the
      adenosine triphosphate (ATP) binding cassette A1 (ABCA1), a transporter protein
      involved in apolipoprotein-A1 (apo-A1)-mediated lipid efflux. To ascertain the
      molecular mechanisms involved, expression of peroxisome proliferator-activated
      receptors (PPAR) and liver X receptoralpha (LXRalpha) were examined. IL-1beta (5
      ng/ml) reduced PPARalpha, PPARgamma, and LXRalpha mRNA expression. Activation of
      PPARgamma with the agonist prostaglandin J2 (10 micro M) and of PPARalpha with
      either bezafibrate (100 micro M) or Wy14643 (100 micro M) both increased LXRalpha
      and ABCA1 gene expression also and enhanced apoA1-mediated cholesterol efflux
      from lipid-loaded cells, even in the presence of IL-1beta. A natural ligand of
      LXRalpha, 25-hydroxycholesterol (25-OHC), had similar effects; when used together
      with PPAR agonists, an additive effect was observed, indicating co-operation
      between PPAR and LXRalpha in regulating ABCA1 gene expression. This was supported
      by the observation that overexpression of either PPARalpha or PPARgamma by
      transfection enhanced LXRalpha and ABCA1 gene induction by PPAR agonists. Taken
      together with previous data, it appears that, in addition to increasing lipid
      uptake, inflammatory cytokines promote intracellular lipid accumulation by
      inhibiting cholesterol efflux through the PPAR-LXRalpha-ABCA1 pathway. These
      results suggest potential mechanisms whereby inflammation may exacerbate lipid
      mediated cellular injury in the glomerulus and in other tissues and indicate that
      PPAR agonists may have a protective effect.

PMID- 12595495
TI  - CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating
      active alpha5beta1 integrin in human mesangial cells.
AB  - Excessive deposition of fibronectin in the glomerular mesangium in diabetic
      nephropathy (DN) is partly due to the induction of transforming growth factor
      beta (TGF-beta) by high glucose. TGF-beta induces its downstream mediator
      connective tissue growth factor (CTGF), which stimulates fibronectin matrix
      synthesis, a process that requires the presence of alpha5beta1 integrin. Although
      TGF-beta has been shown to upregulate alpha5beta1 integrin expression in human
      mesangial cells (HMC), little is known about the effect of CTGF on levels of this
      receptor. This study tested whether CTGF modulates alpha5beta1 expression by HMC
      in culture and whether changes induced by TGF-beta are mediated through the
      induction of CTGF. FACS analysis showed that both TGF-beta and CTGF significantly
      increased cell-surface alpha5beta1 levels compared with basal conditions. RT-PCR
      indicated that the changes were at the level of transcription. Treatment of cells
      with TGF-beta and antisense CTGF oligonucleotides significantly reduced the TGF
      beta-induced increases in alpha5beta1 levels. CTGF and TGF-beta also
      significantly increased levels of ligand-occupied cell-surface beta1 integrins
      and cell adhesion to fibronectin, the main alpha5beta1 substrate. Antisense CTGF
      significantly reduced the number of adherent cells from TGF-beta-stimulated
      cultures. Finally, alpha5beta1 blocking antibodies inhibited HMC fibronectin
      matrix deposition, confirming the importance of this receptor for this process.
      Taken together, these data provide evidence that CTGF controls alpha5beta1
      expression by HMC in vitro. Alterations in alpha5beta1 levels induced by TGF-beta
      are mediated at least in part through the induction of CTGF, and specific
      targeting of either alpha5beta1 or CTGF could be useful in controlling excessive
      fibronectin matrix production in DN.

PMID- 12595496
TI  - Digital three-dimensional reconstruction and ultrastructure of the mouse proximal
      tubule.
AB  - Mice are prime targets of experimental gene modification and have become object
      of an increasing number of biologic studies in renal physiology, development, and
      molecular biology. Phenotypic changes in response to gene modification require
      detailed information on normal structure. However, detailed analyses of normal
      mouse kidney structure and organization are lacking. This study describes the 3D
      organization and ultrastructural, segmental variation of the mouse kidney
      proximal tubule. A total of 160 proximal tubules in three C57/BL/6J mouse kidneys
      were analyzed on 800 serial sections from each kidney from the surface to the
      inner stripe of the outer zone of medulla. All tubules were reconstructed in 3D
      and visualized by interactive computer graphics. A quantitative ultrastructural
      analysis of the mouse proximal tubule at every 300 to 400 micro m was performed.
      The 3D representation revealed a distinct organization of the mouse proximal
      tubule, each occupying a separate domain within the cortex. Superficial proximal
      tubules have long straight parts converging into clusters within the medullary
      rays. Tubules originating deeper within the cortex become longer and increasingly
      tortuous. In the medullary rays, these are arranged in layers outside the
      clusters of more superficial tubules. In contrast to rat and human kidney, no
      major segmental variation in the ultrastructure of the proximal tubule was
      identified, and no parameters enabled definition of distinct segments in this
      strain of mice. In conclusion, significant new information on the 3D organization
      of the murine proximal tubule has been obtained. Quantitative, ultrastructural
      analyses of mouse proximal tubules reveal substantial differences compared with
      other species.

PMID- 12595497
TI  - Production of the novel mesangial autocrine growth factors GDNF and IL-10 is
      regulated by the immunomodulator AS101.
AB  - Mesangial cell (MC) proliferation is essential for the pathogenesis and
      progression of various glomerular diseases. This study shows that glial cell line
      derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth
      factors that play a pivotal role in rat MC proliferation in vitro. Downstream
      targets of GDNF signaling and their role in MC hyperplasia are identified. The
      phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB
      were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates
      GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1)
      expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin
      E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event
      for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor
      that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic
      tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate
      (AS101), extensively decreased MC clonogenicity despite GDNF upregulation.
      Identification of the mesangial GDNF and IL-10 pathways as critical mediators of
      mesangial cell proliferation may provide another target for therapeutic
      intervention in certain glomerular diseases. In vivo animal studies using AS101,
      currently undergoing phase II clinical trials on cancer patients, are warranted
      to determine its potential in the management of glomerular diseases associated
      with mesangial cell proliferation.

PMID- 12595498
TI  - TGF-beta1-mediated inhibition of HK-2 cell migration.
AB  - Restoration of proximal tubular cell (PTC) integrity and function after ischemic
      injury involves cell proliferation and migration. Hypoxia is a known stimulus for
      PTC TGF-beta1 synthesis. This study examines the effect of TGF-beta1 on PTC
      migration. A model of PTC injury was used consisting of mechanically wounding a
      monolayer of HK2 cells followed by repopulation of the denuded area by time lapse
      photomicroscopy. Repopulation was the result of cell migration but not
      proliferation. Addition of TGF-beta1 led to a marked inhibition of cell migration
      increased expression of paxillin and vincullin and their incorporation into dense
      focal adhesion plaques. This was associated with increased association of focal
      adhesion components with the f-actin cytoskeleton. There was also increased beta3
      integrin expression and increased synthesis of the matrix component fibronectin.
      The effect on migration and focal adhesion reorganisation was abrogated by
      inhibitors of the RhoA downstream target ROCK, suggesting that signaling events
      resulting from altered beta3 integrin expression initiate the TGF-beta1 response.
      These results suggest that, by inhibition of cell migration, increased expression
      of TGF-beta1 after ischemia delays recovery of proximal tubule structure and
      function. We speculate that this may contribute to permanent alteration in renal
      tubular function after severe ischemic injury.

PMID- 12595499
TI  - Development of renal disease in people at high cardiovascular risk: results of
      the HOPE randomized study.
AB  - In people with diabetes, renal disease tends to progress from microalbuminuria to
      clinical proteinuria to renal insufficiency. Little evidence has been published
      for the nondiabetic population. This study retrospectively analyzed changes of
      proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation)
      study, which compared ramipril's effects to placebo in 9297 participants,
      including 3577 with diabetes and 1956 with microalbuminuria. This report is
      restricted to 7674 participants with albuminuria data at baseline and at follow
      up. Inclusion criteria were known vascular disease or diabetes plus one other
      cardiovascular risk factor, exclusion criteria included heart failure or known
      impaired left ventricular function, dipstick-positive proteinuria (>1+), and
      serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted
      subsequent clinical proteinuria for the study participants overall (adjusted odds
      ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants
      without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with
      diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria
      (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859
      participants; 1542 developed new microalbuminuria, and 317 participants developed
      clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87;
      95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at
      high risk for cardiovascular disease are also at risk for a progressive rise in
      albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic
      and in diabetic people. Ramipril prevents or delays the progression of
      albuminuria.

PMID- 12595500
TI  - Glomerular ultrafiltration in normal and preeclamptic pregnancy.
AB  - GFR and renal plasma flow (RPF) decrease in preeclampsia, a serious hypertensive
      complication of pregnancy. Serial data derived in late pregnancy (LP) and >5 mo
      postpartum (PP) in 13 healthy controls and 10 preeclamptic women (13 and 5,
      respectively) returning PP for theoretical analysis of neutral dextran sieving
      curves (theta(D)), are presented and are used to calculate the key determinants
      of glomerular ultrafiltration. Normal LP hyperfiltration was associated with
      increases in RPF and the ultrafiltration coefficient (K(f)), as well as in the
      nondiscriminatory shunt pathway (omega(0)) and the SD of pore size (S).
      Preeclamptic LP showed the largest omega(0) and S values, indicating a loss of
      size-selectivity, accompanying reduced K(f) and RPF, both of which are implicated
      in the relative hypofiltration. Despite a 100-fold increase in urinary albumin
      excretion (UAE), LP preeclamptic theta(D) values were reduced for the equivalent
      neutral dextran (36A), providing indirect evidence for a loss of glomerular
      barrier charge-selectivity. All the determinants of GFR and all modeled
      parameters were comparable across both groups PP, strong evidence that
      preeclamptic glomerular dysfunction resolves.

PMID- 12595501
TI  - Hyperhomocysteinemia induces renal hemodynamic dysfunction: is nitric oxide
      involved?
AB  - Hyperhomocysteinemia is associated with endothelial dysfunction, although the
      underlying mechanism is unknown. Previous studies have shown that nitric oxide
      (NO) plays an important role in the regulation of systemic and renal
      hemodynamics. This study investigated whether hyperhomocysteinemia induces renal
      oxidative stress and promotes renal dysfunction involving disturbances of the NO
      pathway in Wistar rats. During 8 wk, control (C) and hyperhomocysteinemic (HYC)
      groups had free access to tap water and homocysteine-thiolactone (HTL, 50 mg/kg
      per d), respectively. At 8 wk, plasma homocysteine concentration, renal
      superoxide anion (O(2)), nitrotyrosine, and nitrite+nitrate levels, and renal
      function were measured. To assess NO involvement, the responses to L-Arginine (L
      Arg, 300 mg/kg) and N(G)-nitro-L-arginine-methyl-ester (L-NAME, 20 microg/kg per
      min for 60 min) were analyzed. The HYC group showed higher homocysteine
      concentration (7.6 +/- 1.7 versus 4.9 +/- 1.0 micromol/L; P < 0.001), (O(2)
      production (157.92 +/- 74.46 versus 91.17 +/- 29.03 cpm. 10(3)/mg protein), and
      nitrite+nitrate levels (33.4 +/- 5.1 versus 11.7 +/- 4.3 micro mol/mg protein; P
      < 0.001) than the control group. Western blot analyses showed a nitrotyrosine
      mass 46% higher in the HYC group than in the controls. Furthermore, the HYC group
      showed lower GFR, renal plasma flow (RPF), and higher renal vascular resistance
      (RVR) than the controls. After L-Arg administration, the responses of GFR, RPF,
      and RVR were attenuated by 36%, 40%, and 50%, respectively; after L-NAME, the
      responses of RPF and RVR were exaggerated by 79% and 112%, respectively. This
      suggests a reduced NO bioavailability to produce vasodilation and an enhanced
      sensitivity to NO inhibition. In conclusion, hyperhomocysteinemia induces
      oxidative stress, NO inactivation, and renal dysfunction involving disturbances
      on the NO-pathway.

PMID- 12595502
TI  - Activation of the G(i) heterotrimeric G protein by ANCA IgG F(ab')2 fragments is
      necessary but not sufficient to stimulate the recruitment of those downstream
      mediators used by intact ANCA IgG.
AB  - Anti-neutrophil cytoplasm autoantibodies (ANCA) are implicated in the
      pathogenesis of systemic vasculitis. Intact ANCA IgG activate superoxide
      generation in cytokine-primed neutrophils after binding their antigens and co
      engaging Fcgamma receptors (FcgammaR). The contribution of antigen binding via
      ANCA F(ab')(2) fragments to signaling has been unclear. This study shows that
      both ANCA IgG and F(ab')(2) fragments of ANCA IgG induce significant GTPase
      activity, which could be blocked with pertussis toxin and anti-G(i) protein
      antibodies. Pertussis toxin inhibited ANCA IgG-induced superoxide generation but
      was without effect on superoxide production after conventional FcgammaR ligation.
      ANCA F(ab')(2) fragments did not induce superoxide generation. ANCA IgG activated
      PI 3-kinase-generating PIP(3), activated protein kinase B (PKB), and p21(ras);
      activation of each mediator was inhibited with pertussis toxin, but PI3K and PKB
      were not activated by ANCA IgG F(ab')(2) fragments. Intact ANCA IgG induced
      tyrosine phosphorylation, whereas F(ab')(2) fragments did not, and ANCA IgG
      mediated superoxide generation was inhibited with genistein. Both genistein and
      pertussis toxin together completely abrogated the ANCA-induced oxidative burst.
      Genistein also inhibited ANCA IgG-induced PIP(3) generation and p21(ras)
      activation. These data implicate a novel ANCA IgG stimulated signaling pathway
      that involves both F(ab')(2)-mediated antigen binding and Fc-mediated FcgammaR
      ligation in cooperative interactions between G(i) proteins and tyrosine kinases
      that facilitates activation of downstream mediators.

PMID- 12595503
TI  - Administration of a soluble recombinant complement C3 inhibitor protects against
      renal disease in MRL/lpr mice.
AB  - Complement receptor 1-related gene/protein y (Crry) in rodents is a potent
      membrane complement regulator that inhibits complement C3 activation by both
      classical and alternative pathways. To clarify the role of complement in lupus
      nephritis, MRL/lpr mice were given Crry as a recombinant protein (Crry-Ig) from
      12 to 24 wk of age. Control groups were given saline or normal mouse IgG. Sera
      and urine were collected biweekly. Only 1 of 20 (5%) Crry-Ig-treated mice
      developed renal failure (BUN > 50 mg/dl) compared with 18 of 38 (47.4%) mice in
      control groups (P = 0.001). BUN levels at 24 wk were reduced from 68.8 +/- 9.7
      mg/dl in control groups to 38.5 +/- 3.9 mg/dl in the Crry-Ig-treated group (P <
      0.01). Urinary albumin excretion at 24 wk was also significantly reduced from 5.3
      +/- 1.4 mg/mg creatinine in the control groups to 0.5 +/- 0.2 mg/mg creatinine in
      the Crry-Ig-treated group (P < 0.05). Of the histologic data at 24 wk, there was
      a significant reduction in scores for glomerulosclerosis and C3d, IgG, IgG3, and
      IgA staining intensity in glomeruli in complement-inhibited animals. Crry-Ig
      treated animals were also protected from vasculitic lesions. Although there was
      no effect on relevant autoimmune manifestations such as anti-double stranded DNA
      titers or cryoglobulin IgG3 levels, circulating immune complex levels were
      markedly higher in complement-inhibited animals. Thus, inhibition of complement
      activation with Crry-Ig significantly reduces renal disease in MRL/lpr lupus
      mice. The data support the strategy of using recombinant complement C3 inhibitors
      to treat human lupus nephritis.

PMID- 12595504
TI  - OFD1, the gene mutated in oral-facial-digital syndrome type 1, is expressed in
      the metanephros and in human embryonic renal mesenchymal cells.
AB  - Oral-facial-digital syndrome type 1 (OFD1) causes polycystic kidney disease (PKD)
      and malformations of the mouth, face and digits. Recently, a gene on Xp22, OFD1,
      was reported to be mutated in a limited set of OFD1 patients. This study
      describes mutation analysis in six further OFD1 families. Additionally, gene
      expression was sought in human development. In two OFD1 kindreds affected by PKD,
      a frameshift mutation and a splice-site mutation were detected. In four
      apparently sporadic cases, three frameshift and a missense mutation were found.
      Using RT-PCR of RNA from first-trimester normal human embryos, both alternative
      splice forms of mRNA (OFD1a and OFD1b) were found to be widely expressed in
      organogenesis. Northern blot detected OFD1 mRNA in metanephros, brain, tongue,
      and limb, all organs affected in the syndrome. A polyclonal antibody directed to
      a C-terminal OFD1a epitope detected a 120-kD protein in the metanephros and in
      human renal mesenchymal cell lines. In normal human embryos, OFD1a
      immunolocalized to the metanephric mesenchyme, oral mucosa, nasal and cranial
      cartilage, and brain. Moreover, using normal human renal mesenchymal cell lines,
      the immunoreactive protein colocalized with gamma-tubulin, suggesting that OFD1
      is associated with the centrosome. First, it is concluded that OFD1 mutations
      would generally be predicted to result in unstable transcripts or nonfunctional
      proteins. Second, OFD1 is expressed in human organogenesis; on the basis of the
      metanephric expression pattern, the results suggest that OFD1 plays a role in
      differentiation of metanephric precursor cells.

PMID- 12595505
TI  - Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked
      hereditary nephritis): results from a canine model.
AB  - Alport syndrome refers to a hereditary disorder characterized by progressive
      renal disease and a multilaminar appearance to the glomerular basement membrane
      (GBM). In a small group of patients with Alport syndrome, cyclosporine A was
      reported to decrease proteinuria and maintain stable renal function over 7 to 10
      yr of follow-up. The present study examined the effect of cyclosporine A on GBM
      structure and the progression to renal failure in a canine model of X-linked
      Alport syndrome. Affected male dogs and normal male dogs treated with
      cyclosporine A underwent serial renal biopsies. Body weight, serum concentrations
      of creatinine and albumin, and GFR were sequentially determined. Controls
      consisted of untreated dogs that developed end-stage renal failure by 8 mo of
      age. Renal biopsies were assessed for glomerulosclerosis and the percent of
      multilaminar GBM as measured by image analysis. Significant differences were
      found between treated and untreated affected dogs for weight, serum creatinine,
      and GFR. There was a significant delay in the progression of multilaminar change
      to the GBM, although treated affected dogs at termination had attained
      approximately 100% split GBM as did untreated affected dogs. A significant
      difference in the number of sclerotic glomeruli was also noted; treated dogs
      rarely developed obsolete glomeruli during the period studied. Interstitial
      fibrosis was not significantly affected by cyclosporine A treatment. These
      findings indicate that cyclosporine A is beneficial in slowing, but not stopping,
      the clinical and pathologic progression of Alport syndrome. At least part of this
      beneficial effect comes from a delayed deterioration of GBM structure, which in
      turn may be related to glomerular hemodynamics altered by cyclosporine A.

PMID- 12595506
TI  - The lack of cyclin kinase inhibitor p27(Kip1) ameliorates progression of diabetic
      nephropathy.
AB  - Cyclin kinase inhibitor p27(Kip(1)) (p27) has been shown to be upregulated in
      glomeruli of diabetic animals and mesangial cells cultured under high glucose.
      This study was an investigation of the role of p27 in the progression of diabetic
      nephropathy. Mice deficient in p27 (p27 -/-) and wild-type mice (p27 +/+) were
      studied 12 wk after diabetes induction by streptozotocin. Blood glucose and BP
      were comparable between diabetic p27 +/+ and p27 -/- mice. The kidney weight to
      body weight ratio and glomerular volume increased in diabetic p27 +/+ mice. In
      contrast, these parameters did not change in diabetic p27 -/- mice. Similarly,
      albuminuria developed in diabetic p27 +/+ mice but not in diabetic p27 -/- mice.
      The mesangial expansion was significantly milder in diabetic p27 -/- mice than
      that in diabetic p27 +/+ mice. These changes were associated with a similar
      increase in glomerular TGF-beta expression in diabetic p27 +/+ and p27 -/- mice.
      However, glomerular protein expression of fibronectin, a target of TGF-beta,
      increased only in diabetic p27 +/+ mice. In mesangial cells cultured from p27 +/+
      mice, exposure to high glucose caused significant increases in total protein
      content and [(3)H]-leucine incorporation. On the other hand, high glucose caused
      a significant reduction in these parameters in cells from p27 -/- mice.
      Phosphorylation of 4E-BP1, the translation inhibitor, increased after exposure to
      high glucose in p27 +/+ cells. In p27 -/- cells, the level of phosphorylated 4E
      BP1 was higher than that in control p27 +/+ cells and decreased under high
      glucose conditions. In conclusion, renal hypertrophy, glomerular hypertrophy, and
      albuminuria did not develop, and mesangial expansion was milder in diabetic p27 
      /- mice despite glomerular TGF-beta upregulation. These results suggest that
      controlling p27 function may ameliorate diabetic nephropathy.

PMID- 12595507
TI  - Delayed treatment with lithospermate B attenuates experimental diabetic renal
      injury.
AB  - Extracellular matrix (ECM) accumulation in the glomerular mesangium is a
      characteristic feature of diabetic nephropathy. While transforming growth factor
      beta1 (TGF-beta1) is the final mediator of ECM accumulation, reactive oxygen
      species (ROS) and protein kinase C (PKC) are the upstream signaling molecules
      that mediate hyperglycemia-induced ECM expansion. Magnesium lithospermate B (LAB)
      is an active component isolated from Salvia miltiorrhizae with known
      renoprotective properties due to its antioxidative effects. Thus, the present
      study examined the effects of LAB on renal injury in streptozotocin-induced
      diabetic rats (STZR) and on the activation of mesangial cells cultured under high
      glucose conditions. Ten micrtograms of LAB/kg per day was started 8 wk after
      streptozotocin injection and continued for a period of 8 wk. It significantly
      suppressed renal malondialdehyde (MDA), microalbuminuria, glomerular hypertrophy,
      mesangial expansion, and the upregulation of renal TGF-beta1, fibronectin, and
      collagen in STZR without significantly affecting plasma glucose. Both 30 mM of
      glucose and 100 uM of H(2)O(2) significantly increased TGF-beta1 and fibronectin
      protein secretion by mesangial cells. LAB at 10 micro g/ml inhibited high glucose
      and H(2)O(2)-induced TGF-beta1 and fibronectin secretion. LAB also inhibited
      glucose-induced intracellular ROS generation and PKC activation in mesangial
      cells, but it did not directly inhibit PKC activity at dosages that inhibited ROS
      generation. The in vitro data of this study show that LAB inhibits ROS generation
      leading to PKC activation and TGF-beta1 and fibronectin upregulation in mesangial
      cells cultured under high glucose conditions. Moreover, delayed treatment with
      LAB was found to significantly suppress the progression of renal injury in STZR.
      LAB may become a new therapeutic agent for the treatment of diabetic nephropathy.

PMID- 12595508
TI  - Pharmacokinetics of mycophenolate mofetil in patients with autoimmune diseases
      compared renal transplant recipients.
AB  - Mycophenolate mofetil (MMF), being effectively used as immunosuppressant in
      transplant medicine, has recently attracted interest as therapeutic agent for
      autoimmune diseases (AID). For these patients, no pharmacokinetic (PK) data are
      available. This study is an investigation of single-dose concentration-time
      profiles of 1 g off MMF in 16 patients with AID, including 10 patients with ANCA
      associated vasculitis and 6 patients with systemic lupus erythematosus, and
      compares them with profiles of 16 renal transplant recipients (RTX). Mycophenolic
      acid (MPA) blood levels were measured by both HPLC and EMIT, and MPA-glucuronide
      was determined by HPLC. In AID, mean MPA concentrations at 12 h were
      significantly higher compared with RTX (4.1 +/- 3.27 versus 1.8 +/- 1.15 mg/L; P
      = 0.018), whereas peak concentrations were lower (P = 0.017). However, mean MPA
      AUC at 12 h as well as at 24 h were comparable between both groups. In contrast
      to RTX, there was an association in AID between MPA trough levels at 12 h and at
      24 h with AUC(0-12) (P < 0.05 and P < 0.01). MPA trough concentrations at 24 h
      provided an estimation of AUC(0-24 h) in both patient groups (P < 0.001 and P <
      0.01; AID and RTX, respectively). Compared with RTX, MPA-PK seems to be less
      affected in AID by renal function. Inter-individual variability of PK parameters
      was high in both groups. These data indicate that there are differences of MPA-PK
      between RTX and AID. The use of therapeutic drug monitoring in patients with AID
      appears to be clinically practicable and may be valuable to optimize individual
      immunosuppressive therapy.

PMID- 12595509
TI  - Restriction of dietary glycotoxins reduces excessive advanced glycation end
      products in renal failure patients.
AB  - Advanced glycation endproduct (AGE) levels are elevated in renal failure patients
      and may contribute to the excessive cardiovascular disease in this population.
      Diet-derived AGE are major contributors to the total body AGE pool. It was
      postulated that a reduction in dietary AGE intake might impact on the high
      circulating AGE levels in renal failure patients. Twenty-six nondiabetic renal
      failure patients on maintenance peritoneal dialysis were randomized to either a
      high or a low AGE diet for 4 wk. Three-day dietary records, fasting blood, 24-h
      urine, and dialysis fluid collections were obtained at baseline and end of study.
      AGE levels were determined by ELISA for N(epsilon)-carboxymethyl-lysine (CML) and
      methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low
      dietary AGE intake decreased serum CML (34%; P < 0.002), serum MG (35%; P <
      0.008), CML-LDL (28%; P < 0.011), CML-apoB (25%; P < 0.028), dialysate CML (39%;
      P < 0.03), and dialysate MG output (40%; P < 0.04). High dietary AGE intake
      increased serum CML (29%; P < 0.028), serum MG (26%; P < 0.09), CML-LDL (50%; P <
      0.011), CML-apoB (67%; P < 0.028), and dialysate CML output (27%; P < 0.01).
      Serum AGE correlated with BUN (r = 0.6, P < 0.002 for CML; r = 0.4, P < 0.05 for
      MG), serum creatinine (r = 0.76, P < 0.05 for CML; r = 0.55, P < 0.004 for MG),
      total protein (r = 0.4, P < 0.05 for CML; r = 0.4, P < 0.05 for MG), albumin (r =
      0.4, P < 0.02 for CML; r = 0.4, P < 0.05 for MG), and phosphorus (r = 0.5, P <
      0.006 for CML; r = 0.5, P < 0.01 for MG). It is concluded that dietary
      glycotoxins contribute significantly to the elevated AGE levels in renal failure
      patients. Moreover, dietary restriction of AGE is an effective and feasible
      method to reduce excess toxic AGE and possibly cardiovascular associated
      mortality.

PMID- 12595510
TI  - LCAT-dependent conversion of prebeta1-HDL into alpha-migrating HDL is severely
      delayed in hemodialysis patients.
AB  - Prebeta1-HDL is a minor HDL subfraction that acts as an efficient initial
      acceptor of cell-derived free cholesterol. During 37 degrees C incubation, plasma
      prebeta1-HDL decreases over time due to its conversion to alpha-migrating HDL by
      lecithin:cholesterol acyltransferase (LCAT). This conversion may be delayed in
      hemodialysis patients who have decreased LCAT activity. To clarify whether LCAT
      dependent conversion of prebeta1-HDL to alpha-migrating HDL is delayed in
      hemodialysis patients, prebeta1-HDL concentrations were determined in 45
      hemodialysis patients and 45 gender-matched control subjects before and after 37
      degrees C incubation with and without the LCAT inhibitor. It was found that the
      baseline prebeta1-HDL concentration in hemodialysis patients was more than twice
      that in the controls (44.9 +/- 21.4 versus 19.8 +/- 6.7 mg/L apoAI; P < 0.001).
      After 2-h incubation, the LCAT-dependent decrease in prebeta1-HDL in hemodialysis
      patients was about one-third of that in the controls (30 +/- 27 versus 97 +/- 17%
      of baseline; P < 0.01). The LCAT-dependent rate of decrease in prebeta1-HDL
      levels (DR(prebeta1)) was the same for samples from hemodialysis patients
      exhibiting normal (> or =1.03 mmol/L) and low HDL-cholesterol levels (32 +/- 32
      versus 28 +/- 23% of baseline; NS). DR(prebeta1) was positively correlated with
      LCAT activity (r = 0.617; P < 0.001). In conclusion, the LCAT-dependent
      conversion of prebeta1-HDL to alpha-migrating HDL is severely delayed in
      hemodialysis patients. The impaired catabolism of prebeta1-HDL may accelerate
      atherosclerosis in hemodialysis patients.

PMID- 12595511
TI  - Primary vesicoureteric reflux as a predictor of renal damage in children
      hospitalized with urinary tract infection: a systematic review and meta-analysis.
AB  - Renal parenchymal disease after urinary tract infection (UTI) has been associated
      with the development of hypertension and renal functional impairment. A
      systematic literature review and meta-analysis was performed to determine how
      effectively the finding of primary vesicoureteric reflux (VUR) on micturating
      cystography (MCU) in children hospitalized with UTI predicted renal parenchymal
      disease on (99m)Technetium-dimercaptosuccinic acid ((99m)Tc-DMSA) scintigraphy.
      Medline, Embase, and PubMed were use to find reports with original data for
      children hospitalized with bacteriologically-proven UTI who had undergone both
      MCU and (99m)Tc-DMSA scintigraphy, and which also reported both positive and
      negative results of these tests. A meta-analysis of likelihood ratios positive
      and negative for MCU was then performed, including tests for heterogeneity.
      Twelve valid studies were found, seven with data for 537 children, with a
      positive (99m)Tc-DMSA scan prevalence of 59% overall, and seven studies with data
      for 1062 kidneys, with a positive (99m)Tc-DMSA scan prevalence of 36%. The
      likelihood ratio positive for MCU was 1.96 (95% CI, 1.51 to 2.54) for children,
      and 2.34 (1.53 to 3.57) for kidneys. The likelihood ratio negative was 0.71 (0.58
      to 0.85) for children and 0.72 (0.61 to 0.86) for kidneys. There was evidence of
      heterogeneity. The meta-analysis showed that a positive MCU increases the risk of
      renal damage in hospitalized UTI patients by about 20%, whereas a negative MCU
      increases the chance of no renal involvement by just 8%. VUR is hence a weak
      predictor of renal damage in pediatric patients hospitalized with UTI. Physicians
      should be aware of the limitations of using MCU-detected primary VUR as an
      effective screening test for renal damage in this population. Furthermore, the
      pathogenesis of renal damage in such patients is probably complex because it is
      often detected without demonstrable VUR.

PMID- 12595512
TI  - Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney
      transplants from ischemia/reperfusion injury.
AB  - Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers
      against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad
      HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused
      with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and
      transplanted orthotopically into LEW recipients, followed by contralateral native
      nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of
      histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were
      analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with
      PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d,
      respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all
      groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01)
      in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio
      at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1
      group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and
      glomerulosclerosis was more severe in Ad-beta-gal group at all time points.
      Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased
      before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated
      group for 3 d after transplantation. Concomitantly, HO enzymatic activity was
      increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group,
      compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was
      discernible early posttransplant in the Ad-HO-1 group alone. These findings are
      consistent with protective effects of HO-1 overexpression using a gene transfer
      approach against severe renal I/R injury, with reduced mortality and attenuation
      of tissue injury.

PMID- 12595513
TI  - Renal transplantation: can we reduce calcineurin inhibitor/stop steroids?
      Evidence based on protocol biopsy findings.
AB  - How to combine antirejection drugs and which is the optimal dose of steroids and
      calcineurin inhibitors beyond the first year after kidney transplantation to
      maintain adequate immunosuppression without major side effects are far from
      clear. Kidney transplant patients on steroid, cyclosporine (CsA), and
      azathioprine were randomized to per-protocol biopsy (n = 30) or no-biopsy (n =
      29) 1 to 2 yr posttransplant. Steroid or CsA were discontinued or reduced on the
      basis of biopsy to establish effects on drug-related complications, acute
      rejection, and graft function over 3 yr of follow-up. Serum creatinine, GFR
      (plasma clearance of iohexol), RPF (renal clearance of p-aminohippurate), CsA
      pharmacokinetics, and adverse events were monitored yearly. At the end, patients
      underwent a second biopsy. Per-protocol biopsy histology revealed no lesions (n =
      5, steroid withdrawal), CsA nephropathy (n = 13, CsA discontinuation/reduction),
      or chronic rejection (n = 12, standard therapy). Reducing the drug regimen led to
      overall fewer side effects related to immunosuppression as compared with standard
      therapy or no-biopsy. Steroids were safely stopped with no acute rejection or
      graft loss. Complete CsA discontinuation was associated with acute rejection in
      the first four patients. Lowering CsA to low target CsA trough (30 to 70 ng/ml)
      never led to acute rejection or major renal function deterioration. Biopsy
      patients on conventional regimen had no acute rejection, one graft loss, no
      significant change in GFR, and significant RPF decline. No-biopsy controls: no
      acute rejection, one graft loss, significant decline of GFR and RPF. By serial
      biopsy analysis, severe lesions did not develop in patients with steroid
      discontinuation in contrast to patients on standard therapy over follow-up. CsA
      reduction did not adversely affect histology. Per-protocol biopsy more than 1 yr
      after kidney transplantation is a safe procedure to guide change of drug regimen
      and to lower the risk of major side effects.

PMID- 12595514
TI  - CD4 cell lymphopenia and atherosclerosis in renal transplant recipients.
AB  - Several animal studies suggest that T cell-mediated immunodeficiency may play a
      role in the progression of atherosclerosis. This study examined the association
      between lymphocyte subsets and atherosclerotic events in renal transplant
      recipients. A total of 302 consecutive renal transplant recipients were enrolled
      in this prospective study. Peripheral blood lymphocyte subsets were quantified
      and analyzed with respect to other known cardiovascular risk factors. The
      patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and
      CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3),
      respectively. CD4 levels were positively related to transplant duration (r =
      0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five
      atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower
      in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P <
      0.0001). Cox regression analysis showed that patients in the three upper
      quartiles of CD4 cell count had a decreased risk of CVE compared with those in
      the lowest quartile. There was a linear increase in risk of CVE with decreasing
      CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile
      (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile.
      In conclusion, CD4 lymphocytopenia is an independent risk factor for the
      development of cardiovascular complications in renal transplant recipients,
      suggesting that impaired immune response promotes accelerated atherogenesis in
      this population.

PMID- 12595515
TI  - Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI)
      as surrogate end point for long-term graft survival in multicenter studies.
AB  - This study is an investigation of whether a protocol biopsy may be used as
      surrogate to late graft survival in multicenter renal transplantation trials.
      During two mycophenolate mofetil trials, 621 representative protocol biopsies
      were obtained at baseline, 1 yr, and 3 yr. The samples were coded and evaluated
      blindly by two pathologists, and Chronic Allograft Damage Index (CADI) score was
      constructed. At 1 yr, only 20% of patients had elevated (>l.5 mg/100 ml) serum
      creatinine, whereas 60% of the biopsies demonstrated an elevated (>2.0) CADI
      score. The mean CADI score at baseline, 1.3 +/- 1.1, increased to 3.3 +/- 1.8 at
      1 yr and to 4.1 +/- 2.2 at 3 yr. The patients at 1 yr were divided into three
      groups, those with CADI <2, between 2 and 3.9, and >4.0, the first two groups
      having normal (1.4 +/- 0.3 and 1.5 +/- 0.6 mg/dl) and the third group pathologic
      (1.9 +/- 0.8 mg/dl) serum creatinine. At 3 yr, there were no lost grafts in the
      low CADI group, six lost grafts (4.6%) in the in the elevated CADI group, and 17
      lost grafts (16.7%) in the high CADI group (P < 0.001). One-year histologic CADI
      score predicts graft survival even when the graft function is still normal. This
      observation makes it possible to use CADI as a surrogate end point in prevention
      trials and to identify the patients at risk for intervention trials.

PMID- 12595516
TI  - Cytomegalovirus disease after prophylaxis with oral ganciclovir in renal
      transplantation: the importance of HLA-DR matching.
AB  - This study assessed the incidence of cytomegalovirus (CMV) disease and associated
      outcomes after oral ganciclovir prophylaxis in renal transplantation. A
      retrospective analysis was performed of all adult renal transplant recipients at
      a single transplant center transplanted between August 16, 1996, and December 31,
      2000. CMV disease prophylaxis included ganciclovir 1000 mg orally thrice daily
      prescribed for 90 d in D-/R+ cases and 180 d in D+/R- and D+/R+ cases. Forty
      (9.1%) of 470 patients studied were diagnosed with CMV disease, which varied
      significantly by CMV serostatus and number of HLA-DR matches. The highest
      incidence of disease, 26.2%, was in D+/R- patients with zero HLA-DR matches. Five
      year graft survival was 56.8% with CMV disease compared with 79.1% without (P <
      0.001). Five-year graft survival with CMV disease was 75.9% with one or two HLA
      DR matches versus 16.2% with zero HLA-DR matches (P < 0.001). CMV remains an
      important factor in long-term graft survival after oral ganciclovir prophylaxis.
      However, we have observed that the adverse impact of CMV disease on graft
      survival is apparent only in patients with zero HLA-DR matches. These results
      call for the development of new CMV disease prophylaxis and treatment strategies
      in patients with zero HLA-DR matches. In addition, organ allocation policies
      discouraging combining CMV-seropositive donors and zero HLA-DR matches may be
      worth consideration.

PMID- 12595518
TI  - Prevention and treatment of acute renal failure in sepsis.

PMID- 12595517
TI  - Inducible gene silencing in podocytes: a new tool for studying glomerular
      function.
AB  - Glomerular filtration is one of the primary functions of the kidney. Podocytes, a
      highly specialized cell type found in glomeruli, are believed to play a critical
      role in that function. Null mutations of genes expressed in podocytes like WT1,
      nephrin, and NEPH1 result in an embryo and perinatal lethal phenotype and
      therefore do not allow the functional analysis of these genes in the adult
      kidney. Here is describes the generation of a model that will allow such studies.
      We have engineered transgenic mice in which the disruption of targeted genes can
      be induced in a temporally controlled fashion in podocytes. For this, a transgene
      encoding the mutated estrogen receptor-Cre recombinase fusion protein was
      introduced into the mouse genome. Animals were crossed with Z/AP reporter mice to
      test for efficient and inducible recombination. We found that, after injection of
      inducer drug tamoxifen, Cre fusion protein translocates to the nuclei of
      podocytes, where it becomes active and mediates recombination of DNA carrying
      loxP target sequences. These animals provide for the first time a tool for
      silencing genes selectively in podocytes of adult animals.

PMID- 12595519
TI  - Podocyte differentiation and glomerulogenesis.

PMID- 12595520
TI  - Complement inhibitors and glomerulonephritis: are we there yet?

PMID- 12595521
TI  - P27Kip1: the "rosebud" of diabetic nephropathy?

PMID- 12595522
TI  - A native peptide ligation strategy for deciphering nucleosomal histone
      modifications.
AB  - Post-translational modifications of histones influence both chromatin structure
      and the binding and function of chromatin-associated proteins. A major limitation
      to understanding these effects has been the inability to construct nucleosomes in
      vitro that harbor homogeneous and site-specific histone modifications. Here, we
      describe a native peptide ligation strategy for generating nucleosomal arrays
      that can harbor a wide range of desired histone modifications. As a first test of
      this method, we engineered model nucleosomal arrays in which each histone H3
      contains a phosphorylated serine at position 10 and performed kinetic analyses of
      Gcn5-dependent histone acetyltransferase activities. Recombinant Gcn5 shows
      increased histone acetyltransferase activity on nucleosomal arrays harboring
      phosphorylated H3 serine 10 and is consistent with peptide studies. However, in
      contrast to analyses using peptide substrates, we find that the histone
      acetyltransferase activity of the Gcn5-containing SAGA complex is not stimulated
      by H3 phosphorylation in the context of nucleosomal arrays. This difference
      between peptide and array substrates suggests that the ability to generate
      specifically modified nucleosomal arrays should provide a powerful tool for
      understanding the effects of post-translational histone modifications.

PMID- 12595523
TI  - Yeast dihydroxybutanone phosphate synthase, an enzyme of the riboflavin
      biosynthetic pathway, has a second unrelated function in expression of
      mitochondrial respiration.
AB  - aE280/U1 is a pet mutant of Saccharomyces cerevisiae partially deficient in
      cytochromes a, a3, and cytochrome b. The ability of this mutant to respire is
      restored by RIB3, a gene previously shown to code for 3,4-dihydroxy-2-butanone-4
      phosphate synthase (DHBP synthase), an enzyme of the riboflavin biosynthetic
      pathway. The sequences of RIB3 from wild type and aE280/U1 indicated a single
      base change resulting in an A137T substitution. The alanine 137 is a conserved
      residue located in a cavity on the surface of the protein distant from the active
      site and from the subunit interaction domain involved in homodimer formation. The
      respiratory defect elicited by this mutation cannot be explained by a flavin
      insufficiency based on the following evidence: 1) growth of the aE280/U1 on
      respiratory substrates is not rescued by exogenous riboflavin; 2) the levels of
      flavin nucleotides are not significantly different in the mutant and wild type.
      We proposed that in addition to its known function in riboflavin synthesis, RIB3
      also functions in expression of mitochondrial respiration. Restoration by
      riboflavin of growth of a rib3 deletion mutant on glucose but not
      glycerol/ethanol also supported this conclusion. An antibody against the N
      terminal half of DHBP synthase was used to study its subcellular distribution.
      Most of the protein was localized in the cytosolic fraction, but a small fraction
      was detected in the mitochondrial intermembrane space.

PMID- 12595524
TI  - Lysophosphatidic acid stimulates brush border Na+/H+ exchanger 3 (NHE3) activity
      by increasing its exocytosis by an NHE3 kinase A regulatory protein-dependent
      mechanism.
AB  - Na(+)/H(+) exchanger 3 (NHE3) kinase A regulatory protein (E3KARP) has been
      implicated in cAMP- and Ca(2+)-dependent inhibition of NHE3. In the current
      study, a new role of E3KARP is demonstrated in the stimulation of NHE3 activity.
      Lysophosphatidic acid (LPA) is a mediator of the restitution phase of
      inflammation but has not been studied for effects on sodium absorption. LPA has
      no effect on NHE3 activity in opossum kidney (OK) proximal tubule cells, which
      lack expression of endogenous E3KARP. However, in OK cells exogenously expressing
      E3KARP, LPA stimulated NHE3 activity. Consistent with the stimulatory effect on
      NHE3 activity, LPA treatment increased the surface NHE3 amount, which occurred by
      accelerating exocytic trafficking (endocytic recycling) to the apical plasma
      membrane. These LPA effects only occurred in OK cells transfected with E3KARP.
      The LPA-induced increases of NHE3 activity, surface NHE3 amounts, and exocytosis
      were completely inhibited by pretreatment with the PI 3-kinase inhibitor,
      LY294002. LPA stimulation of the phosphorylation of Akt was used as an assay for
      PI 3-kinase activity. LY294002 completely prevented the LPA-induced increase in
      Akt phosphorylation, which is consistent with the inhibitory effect of LY294002
      on the LPA stimulation of NHE3 activity. The LPA-induced phosphorylation of Akt
      was the same in OK cells with and without E3KARP. These results show that LPA
      stimulates NHE3 in the apical surface of OK cells by a mechanism that is
      dependent on both E3KARP and PI 3-kinase. This is the first demonstration that
      rapid stimulation of NHE3 activity is dependent on an apical membrane PDZ domain
      protein.

PMID- 12595525
TI  - Acetylation of cAMP-responsive element-binding protein (CREB) by CREB-binding
      protein enhances CREB-dependent transcription.
AB  - The coactivator function of cAMP-responsive element-binding protein (CREB)
      binding protein (CBP) is partly caused by its histone acetyltransferase activity.
      However, it has become increasingly clear that CBP acetylates both histones and
      non-histone proteins, many of which are transcription factors. Here we
      investigate the role of CBP acetylase activity in CREB-mediated gene expression.
      We show that CREB is acetylated within the cell and that in vitro, CREB is
      acetylated by CBP, but not by another acetylase, p300/CBP-associated factor. The
      acetylation sites within CREB were mapped to three lysines within the CREB
      activation domain. Although inhibition of histone deacetylase activity results in
      an increase of CREB- or CBP-mediated gene expression, mutation of all three
      putative acetylation sites in the CREB activation domain markedly enhances the
      ability of CREB to activate a cAMP-responsive element-dependent reporter gene.
      Furthermore, these CREB lysine mutations do not increase interaction with the CRE
      or CBP. These data suggest that the transactivation potential of CREB may be
      modulated through acetylation by CBP. We propose that in addition to its
      functions as a bridging molecule and histone acetyltransferase, the ability of
      CBP to acetylate CREB may play a key role in modulating CREB-mediated gene
      expression.

PMID- 12595526
TI  - Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co
      activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its
      transactivation potential.
AB  - Daxx has been reported to function as a transcriptional modulator in the nucleus.
      In the present study, we have explored the role of Daxx in regulating the
      transcriptional activity of the glucocorticoid receptor (GR). Overexpression of
      Daxx suppressed GR-mediated activation of the mouse mammary tumor virus promoter
      in COS-1, HeLa, and 293T cells. In vitro and in vivo studies revealed that Daxx
      could directly bind to GR. The mapping analysis further demonstrated that the C
      terminal region of Daxx-(501-740) mediates the interaction and transcriptional
      repression of GR. The repressive effect of Daxx and Daxx-(501-740) on GR could be
      alleviated by co-expression of promyelocytic leukemia protein (PML). Furthermore,
      immunofluorescence analysis showed that overexpression of wild-type PML results
      in the translocation of Daxx and Daxx-(501-740) to the PML oncogenic domains
      (PODs). By contrast, a PML sumoylation-defective mutant failed to recruit Daxx to
      PODs and to reverse the Daxx repression effect on GR. Accordingly, As(2)O(3)
      treatment rendered the sequestration of endogenous Daxx to the PODs, leading to
      an enhancement of GR transactivation in COS-1 cells. Taken together, these
      findings suggest that recruitment of Daxx into the subnuclear POD structures
      sequesters it from the GR/co-activators complex, thereby alleviating its
      repressive effects. Our present studies provide the important link between
      Daxx/PML interaction and GR transcriptional activation.

PMID- 12595527
TI  - VE-cadherin-induced Cdc42 signaling regulates formation of membrane protrusions
      in endothelial cells.
AB  - The cytoplasmic domain of cadherins and the associated catenins link the
      cytoskeleton with signal transduction pathways. To study the signaling function
      of non-junctional VE-cadherin, which can form during the loss VE-cadherin
      homotypic adhesion, wild type VE-cadherin or VE-cadherin cytoplasmic domain
      (DeltaEXD) was expressed in sub-confluent endothelial cells. We observed that
      Cdc42 was activated in transfected cells and that these cells also developed
      Cdc42-dependent >70-microm-long plasma membrane protrusions. The formation of
      these structures required actin polymerization, and they developed specifically
      in endothelial cells as compared with epithelial cells. Expression of the VE
      cadherin cytoplasmic domain lacking the beta-catenin binding site also induced
      Cdc42 activation; thus, its activation cannot be ascribed to beta-catenin
      binding. However, these cells were not able to form the protrusions. These
      results suggest that the cytoplasmic domain of non-junctional VE-cadherin can
      serve as a scaffold involved in Cdc42 activation at the endothelial plasma
      membrane. beta-Catenin and the associated alpha-catenin may serve as support
      sites for actin polymerization, leading to formation of long plasma membrane
      protrusions. Thus, non-junctional VE-cadherin actively participates in inside-out
      signaling at the plasma membrane, leading to the development of endothelial
      membrane protrusions.

PMID- 12595528
TI  - Metaphosphate in the active site of fructose-1,6-bisphosphatase.
AB  - The hydrolysis of a phosphate ester can proceed through an intermediate of
      metaphosphate (dissociative mechanism) or through a trigonal bipryamidal
      transition state (associative mechanism). Model systems in solution support the
      dissociative pathway, whereas most enzymologists favor an associative mechanism
      for enzyme-catalyzed reactions. Crystals of fructose-1,6-bisphosphatase grow from
      an equilibrium mixture of substrates and products at near atomic resolution (1.3
      A). At neutral pH, products of the reaction (orthophosphate and fructose 6
      phosphate) bind to the active site in a manner consistent with an associative
      reaction pathway; however, in the presence of inhibitory concentrations of K+
      (200 mm), or at pH 9.6, metaphosphate and water (or OH-) are in equilibrium with
      orthophosphate. Furthermore, one of the magnesium cations in the pH 9.6 complex
      resides in an alternative position, and suggests the possibility of metal cation
      migration as the 1-phosphoryl group of the substrate undergoes hydrolysis. To the
      best of our knowledge, the crystal structures reported here represent the first
      direct observation of metaphosphate in a condensed phase and may provide the
      structural basis for fundamental changes in the catalytic mechanism of fructose
      1,6-bisphosphatase in response to pH and different metal cation activators.

PMID- 12595529
TI  - Interaction of Tl+ with product complexes of fructose-1,6-bisphosphatase.
AB  - Fructose-1,6-bisphosphatase requires divalent cations (Mg2+, Mn2+, or Zn2+) for
      catalysis, but a diverse set of monovalent cations (K+, Tl+, Rb+, or NH(4)(+))
      will further enhance enzyme activity. Here, the interaction of Tl+ with fructose
      1,6-bisphosphatase is explored under conditions that support catalysis. On the
      basis of initial velocity kinetics, Tl+ enhances catalysis by 20% with a K(a) of
      1.3 mm and a Hill coefficient near unity. Crystal structures of enzyme complexes
      with Mg2+, Tl+, and reaction products, in which the concentration of Tl+ is 1 mm
      or less, reveal Mg2+ at metal sites 1, 2, and 3 of the active site, but little or
      no bound Tl+. Intermediate concentrations of Tl+ (5-20 mm) displace Mg2+ from
      site 3 and the 1-OH group of fructose 6-phosphate from in-line geometry with
      respect to bound orthophosphate. Loop 52-72 appears in a new conformational
      state, differing from its engaged conformation by disorder in residues 61-69. Tl+
      does not bind to metal sites 1 or 2 in the presence of Mg2+, but does bind to
      four other sites with partial occupancy. Two of four Tl+ sites probably represent
      alternative binding sites for the site 3 catalytic Mg2+, whereas the other sites
      could play roles in monovalent cation activation.

PMID- 12595530
TI  - Lipopolysaccharide stimulates p38-dependent induction of antiviral genes in
      neutrophils independently of paracrine factors.
AB  - Lipopolysaccharide (LPS) induces neutrophils to synthesize and secrete pro
      inflammatory cytokines and chemokines, which are regulated at both the
      transcriptional and translational level. We reported previously that neutrophils
      stimulated with LPS induce expression of genes typically expressed in response to
      stimulation with antiviral type I interferons (IFN), such as myxovirus resistance
      1 (MX1). However, we present evidence that this response of neutrophils to
      lipopolysaccharide occurs in the absence of interferon-dependent signaling.
      Lipopolysaccharide-stimulated neutrophils do not phosphorylate the interferon
      associated transcription factors signal transducer and activator of transcription
      1 and -3, and medium from lipopolysaccharide-stimulated cells was unable to
      induce MX1 gene expression, suggesting a soluble factor is not involved.
      Furthermore, LPS did not alter expression of IFNA and IFNB genes. In contrast to
      neutrophils, LPS-stimulated human monocyte-derived macrophages induced the
      expression of MX1, but IFNB was induced, and medium from LPS-stimulated monocyte
      derived macrophages supported MX1 induction. An inhibitor of p38 kinase blocked
      induction of MX1 by lipopolysaccharide, but not IFNalpha, in neutrophils, and
      induction of MX1 was dependent on protein synthesis. LPS, but not IFNalpha,
      substantially activated p38. In contrast, the induction of MX1 by LPS in monocyte
      derived macrophages was insensitive to p38 inhibition, although p38 is
      phosphorylated in LPS-stimulated but not IFNalpha-stimulated monocyte-derived
      macrophages. The expression of MX1 in neutrophils and monocyte-derived
      macrophages is mediated by TLR4 but not TLR2. The data presented here indicate
      that lipopolysaccharide activates novel interferon-independent signaling pathways
      in neutrophils and that induction of antiviral genes is a consequence of exposure
      of neutrophils to bacterial products.

PMID- 12595531
TI  - A novel ERK-dependent signaling process that regulates interleukin-2 expression
      in a late phase of T cell activation.
AB  - Engagement of the T cell antigen receptor (TCR) rapidly induces multiple signal
      transduction pathways, including ERK activation. Here, we report a critical role
      for ERK at a late stage of T cell activation. Inhibition of the ERK pathway 2-6 h
      after the start of TCR stimulation significantly impaired interleukin-2 (IL-2)
      production, whereas the same treatment during the first 2 h had no effect. ERK
      inhibition significantly impaired nuclear translocation of c-Rel with a minimum
      reduction of NF-AT activity. Requirement for sustained ERK activation was also
      confirmed using primary T cells. To induce sustained activation of ERK, T cells
      required continuous engagement of TCR. Stimulation of T cells with soluble anti
      TCR antibody resulted in activation of ERK lasting for 60 min, but failed to
      induce IL-2 production. In contrast, plate-bound anti-TCR antibody activated ERK
      over 4 h and induced IL-2. Furthermore, T cells treated with soluble anti-TCR
      antibody produced IL-2 when phorbol 12-myristate 13-acetate, which activates ERK,
      was present in the culture medium 2-6 h after the start of stimulation. Together,
      the data demonstrate the presence of a novel activation process following TCR
      stimulation that requires ERK-dependent regulation of c-Rel, a member of the NF
      kappaB family.

PMID- 12595532
TI  - The hepatitis C virus NS2 protein is an inhibitor of CIDE-B-induced apoptosis.
AB  - Chronic hepatitis C virus (HCV) infection frequently leads to liver cancer. To
      determine the viral factor(s) potentially involved in viral persistence, we
      focused our work on NS2, a viral protein of unknown function. To assign a role
      for NS2, we searched for cellular proteins that interact with NS2. Performing a
      two-hybrid screen on a human liver cDNA library, we found that NS2 interacted
      with the liver-specific pro-apoptotic CIDE-B protein. Binding specificity of NS2
      for CIDE-B was confirmed by cell-free assays associated with colocalization
      studies and coprecipitation experiments on human endogenous CIDE-B. CIDE-B, a
      member of the novel CIDE family of apoptosis-inducing factors, has been reported
      to show strong cell death-inducing activity in its C-terminal domain. We show
      that this CIDE-B killing domain is involved in the NS2 interaction. NS2 binding
      was sufficient to inhibit CIDE-B-induced apoptosis because an NS2 deletion mutant
      unable to interact with CIDE-B in vitro lost its capacity to interfere with CIDE
      B cell death activity. Although it has been reported that CIDE-B-induced
      apoptosis is characterized by mitochondrial localization, the precise apoptotic
      mechanism remained unknown. Here, we show that CIDE-B induced cell death in a
      caspase-dependent manner through cytochrome c release from mitochondria.
      Furthermore, we found that NS2 counteracted the cytochrome c release induced by
      CIDE-B. In vivo, the CIDE-B protein level was extremely low in adenovirus
      infected transgenic mice expressing the HCV polyprotein compared with that in
      wild-type mice. We suggest that NS2 interferes with the CIDE-B-induced death
      pathway and participates in HCV strategies to subvert host cell defense.

PMID- 12595533
TI  - The anticonvulsant valproate increases the turnover rate of gamma-aminobutyric
      acid transporters.
AB  - Valproate is an important anticonvulsant currently in clinical use for the
      treatment of seizures. We used electrophysiological and tracer uptake methods to
      examine the effect of valproate on a gamma-aminobutyric acid (GABA) transporter
      (mouse GAT3) expressed in Xenopus laevis oocytes. In the absence of GABA,
      valproate (up to 50 mm) had no noticeable effect on the steady-state electrogenic
      properties of mGAT3. In the presence of GABA, however, valproate enhanced the
      GABA-evoked steady-state inward current in a dose-dependent manner with a half
      maximal concentration of 4.6 +/- 0.5 mm. Maximal enhancement of the GABA-evoked
      current was 275 +/- 10%. Qualitatively similar observations were obtained for
      human GAT1 and mouse GAT4. The valproate enhancement did not alter the Na(+) or
      Cl(-) dependence of the steady-state GABA-evoked currents. Uptake experiments
      under voltage clamp suggested that the valproate enhancement of the GABA-evoked
      current was matched by an enhancement in GABA uptake. Thus, despite the increase
      in GABA-evoked current, ion/GABA co-transport remained tightly coupled. Uptake
      experiments indicated that valproate is not transported by mouse GAT3 in the
      absence or presence of GABA. Valproate also enhanced the rate of the partial
      steps involved in transporter presteady-state charge movements. We propose that
      valproate increases the turnover rate of GABA transporters by an allosteric
      mechanism. The data suggest that at its therapeutic concentration, valproate may
      enhance the activity of neuronal and glial GABA transporters by up to 10%.

PMID- 12595534
TI  - F1F0-ATP synthase. Binding of delta subunit to a 22-residue peptide mimicking the
      N-terminal region of alpha subunit.
AB  - The stator in F(1)F(0)-ATP synthase resists strain generated by rotor torque. In
      Escherichia coli the b(2)delta subunit complex comprises the stator, bound to
      subunit a in F(0) and to alpha(3)beta(3) hexagon of F(1). Proteolysis and cross
      linking had suggested that N-terminal residues of alpha subunit are involved in
      binding delta. Here we demonstrate that a synthetic peptide consisting of the
      first 22 residues of alpha ("alpha N1-22") binds specifically to isolated wild
      type delta subunit with high affinity (K(d) = 130 nm), accounting for a major
      portion of the binding energy when delta-depleted F(1) and isolated delta bind
      together (K(d) = 1.4 nm). Stoichiometry of binding of alpha N1-22 to delta at
      saturation was 1/1, showing that in intact F(1)F(0)-ATP synthase only one of the
      three alpha subunits is involved in delta binding. When alpha N1-22 was incubated
      with delta subunits containing mutations in helices 1 or 5 on the F(1)-binding
      face of delta, peptide binding was impaired as was binding of delta-depleted
      F(1). Residues alpha 6-18 are predicted to be helical, and a potential helix
      capping box occurs at residues alpha 3-8. Circular dichroism measurements showed
      that alpha N1-22 had significant helical content. Hypothetically a helical region
      of residues alpha N1-22 packs with helices 1 and 5 on the F(1)-binding face of
      delta, forming the alpha/delta interface.

PMID- 12595535
TI  - Conformation-dependent post-translational glycosylation of tyrosinase.
      Requirement of a specific interaction involving the CuB metal binding site.
AB  - Tyrosinase, the rate-limiting enzyme in mammalian melanogenesis, is a copper
      containing transmembrane glycoprotein. Tyrosinase undergoes a complex post
      translational processing before reaching the melanosomal membrane. This
      processing involves N-glycosylation in several sites, including one located in
      the CuB copper binding site, movement from the endoplasmic reticulum (ER) to the
      Golgi, copper binding, and sorting to the melanosome. Aberrant processing is
      causally related to the depigmented phenotype of human melanomas. Moreover, some
      forms of albinism and several other pigmentary syndromes are considered ER
      retention diseases or trafficking defects. A critical step in tyrosinase
      maturation is the acquisition of an ER export-competent conformation recognized
      positively by the ER quality control system. However, the minimal structural
      requirements allowing exit from the ER to the Golgi have not yet been identified
      for tyrosinase or other melanosomal proteins. We addressed this question by
      analyzing the enzymatic activity and glycosylation pattern of mouse tyrosinase
      point mutants and chimeric constructs, where selected portions of tyrosinase were
      replaced by the homologous fragments of the highly similar tyrosinase-related
      protein 1. We show that a completely inactive tyrosinase point mutant lacking a
      critical histidine residue involved in copper binding is nevertheless able to
      exit from the ER and undergo further processing. Moreover, we demonstrate that
      tyrosinase displays at least two sites whose glycosylation is post-translational
      and most likely conformation-dependent and that a highly specific interaction
      involving the CuB site is essential not only for correct glycosylation but also
      for exit from the ER and enzymatic activity.

PMID- 12595536
TI  - Oxidation and nitrosation of thiols at low micromolar exposure to nitric oxide.
      Evidence for a free radical mechanism.
AB  - Although the nitric oxide (.NO)-mediated nitrosation of thiol-containing
      molecules is increasingly recognized as an important post-translational
      modification in cell signaling and pathology, little is known about the factors
      that govern this process in vivo. In the present study, we examined the chemical
      pathways of nitrosothiol (RSNO) production at low micromolar concentrations of
      .NO. Our results indicate that, in addition to nitrosation by the .NO derivative
      dinitrogen trioxide (N2O3), RSNOs may be formed via intermediate one-electron
      oxidation of thiols, possibly mediated by nitrogen dioxide (.NO2), and the
      subsequent reaction of thiyl radicals with .NO. In vitro, the formation of S
      nitrosoglutathione (GSNO) from .NO and excess glutathione (GSH) was accompanied
      by the formation of glutathione disulfide, which could not be ascribed to the
      secondary reaction of GSH with GSNO. Superoxide dismutase significantly increased
      GSNO yields and the thiyl radical trap, 5,5-dimethyl-1-pyrroline N-oxide (DMPO),
      inhibited by 45 and 98% the formation of GSNO and GSSG, respectively. Maximum
      nitrosation yields were obtained at an oxygen concentration of 3%, whereas higher
      oxygen tensions decreased GSNO and increased GSSG formation. When murine
      fibroblasts were exposed to exogenous .NO, RSNO formation was sensitive to DMPO
      and oxygen tension in a manner similar to that observed with GSH alone. Our data
      indicate that RSNO formation is favored at oxygen concentrations that typically
      occur in tissues. Nitrosothiol formation in vivo depends not only on the
      availability of .NO and O2 but also on the degree of oxidative stress by
      affecting the steady-state concentration of thiyl radicals.

PMID- 12595537
TI  - Detection of integrin alpha IIbbeta 3 clustering in living cells.
AB  - In platelets, bidirectional signaling across integrin alpha(IIb)beta(3) regulates
      fibrinogen binding, cytoskeletal reorganization, cell aggregation, and spreading.
      Because these responses may be influenced by the clustering of alpha(IIb)beta(3)
      heterodimers into larger oligomers, we established two independent methods to
      detect integrin clustering and evaluate factors that regulate this process. In
      the first, weakly complementing beta-galactosidase mutants were fused to the C
      terminus of individual alpha(IIb) subunits, and the chimeras were stably
      expressed with beta(3) in Chinese hamster ovary cells. Clustering of
      alpha(IIb)beta(3) should bring the mutants into proximity and reconstitute beta
      galactosidase activity. In the second method, alpha(IIb) was fused to either a
      green fluorescent protein (GFP) or Renilla luciferase and transiently expressed
      with beta(3). Here, integrin clustering should stimulate bioluminescence
      resonance energy transfer between a cell-permeable luciferase substrate and GFP.
      These methods successfully detected integrin clustering induced by anti
      alpha(IIb)beta(3) antibodies. Significantly, they also detected clustering upon
      soluble fibrinogen binding to alpha(IIb)beta(3). In contrast, no clustering was
      observed following direct activation of alpha(IIb)beta(3) by MnCl(2) or an anti
      alpha(IIb)beta(3)-activating antibody Fab in the absence of fibrinogen.
      Intracellular events also influenced alpha(IIb)beta(3) clustering. For example, a
      cell-permeable, bivalent FK506-binding protein (FKBP) ligand stimulated
      clustering when added to cells expressing an alpha(IIb)(FKBP)(2) chimera
      complexed with beta(3). Furthermore, alpha(IIb)beta(3) clustering occurred in the
      presence of latrunculin A or cytochalasin D, inhibitors of actin polymerization.
      These effects were enhanced by fibrinogen, suggesting that actin-regulated
      clustering modulates alpha(IIb)beta(3) interaction with ligands. These studies in
      living cells establish that alpha(IIb)beta(3) clustering is modulated by
      fibrinogen and actin dynamics. More broadly, they should facilitate
      investigations of the mechanisms and consequences of integrin clustering.

PMID- 12595538
TI  - Magnesium ion-dependent activation of the RecA protein involves the C terminus.
AB  - Optimal conditions for RecA protein-mediated DNA strand exchange include 6-8 mm
      Mg(2+) in excess of that required to form complexes with ATP. We provide evidence
      that the free magnesium ion is required to mediate a conformational change in the
      RecA protein C terminus that activates RecA-mediated DNA strand exchange. In
      particular, a "closed" (low Mg(2+)) conformation of a RecA nucleoprotein filament
      restricts DNA pairing by incoming duplex DNA, although single-stranded overhangs
      at the ends of a duplex allow limited DNA pairing to occur. The addition of
      excess Mg(2+) results in an "open" conformation, which can promote efficient DNA
      pairing and strand exchange regardless of DNA end structure. The removal of 17
      amino acid residues at the Escherichia coli RecA C terminus eliminates a
      measurable requirement for excess Mg(2+) and permits efficient DNA pairing and
      exchange similar to that seen with the wild-type protein at high Mg(2+) levels.
      Thus, the RecA C terminus imposes the need for the high magnesium ion
      concentrations requisite in RecA reactions in vitro. We propose that the C
      terminus acts as a regulatory switch, modulating the access of double-stranded
      DNA to the presynaptic filament and thereby inhibiting homologous DNA pairing and
      strand exchange at low magnesium ion concentrations.

PMID- 12595539
TI  - JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible
      nitric-oxide synthase and decrease in contractility of adult ventricular
      myocytes.
AB  - Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)
      dependent pathway. However, mechanisms underlying IL-6-induced NO production
      remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways
      activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways
      have not been identified in adult cardiac myocytes. In this study, we identified
      activation of these two pathways during IL-6 stimulation and examined their roles
      in IL-6-induced NO production and decrease in contractility of adult ventricular
      myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr(705)) and ERK1/2 (at
      Tyr(204)) within 5 min that peaked at 15-30 min and returned to basal levels at 2
      h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase
      inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase
      inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but
      not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein,
      increased NO production, and decreased cardiac contractility after 2 h of
      incubation. These effects were blocked by genistein and AG490 but not PD98059. We
      conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways,
      but only JAK2/STAT3 signaling mediated the NO-associated decrease in
      contractility.

PMID- 12595540
TI  - Evidence for a mechanism of recombination during reverse transcription dependent
      on the structure of the acceptor RNA.
AB  - Genetic recombination is a major force driving retroviral evolution. In
      retroviruses, recombination proceeds mostly through copy choice during reverse
      transcription. Using a reconstituted in vitro system, we have studied the
      mechanism of strand transfer on a major recombination hot spot we previously
      identified within the genome of HIV-1. We show that on this model sequence the
      frequency of copy choice is strongly influenced by the folding of the RNA
      template, namely by the presence of a stable hairpin. This structure must be
      specifically present on the acceptor template. We previously proposed that strand
      transfer follows a two-step process: docking of the nascent DNA onto the acceptor
      RNA and strand invasion. The frequency of recombination under copy choice
      conditions was not dependent on the concentration of the acceptor RNA, in
      contrast with strand transfer occurring at strong arrests of reverse
      transcription. During copy choice strand transfer, the docking step is not rate
      limiting. We propose that the hairpin present on the acceptor RNA could mediate
      strand transfer following a mechanism reminiscent of branch migration during DNA
      recombination.

PMID- 12595541
TI  - Evidence for the differential effects of nucleocapsid protein on strand transfer
      in various regions of the HIV genome.
AB  - An in vitro strand transfer assay that mimicked recombinational events occurring
      during reverse transcription in HIV-1 was used to assess the role of nucleocapsid
      protein (NC) in strand transfer. Strand transfer in highly structured nucleic
      acid species from the U3 3' long terminal repeats, gag-pol frameshift region, and
      Rev response element were strongly enhanced by NC. In contrast, weakly structured
      templates from the env and pol-vif regions transferred well without NC and showed
      lower enhancement. The lack of strong polymerase pause sites in the latter
      regions demonstrated that non-pause driven mechanisms could also promote
      transfer. Assays conducted using NC zinc finger mutants supported a differential
      role for the two fingers in strand transfer with finger 1 (N-terminal) being more
      important on highly structured RNAs. Overall this report suggests a role for
      structural intricacies of RNA templates in determining the extent of influence of
      NC on recombination and illustrates that strand transfer may occur by several
      different mechanisms depending on the structural nature of the RNA.

PMID- 12595542
TI  - A single site-specific trans-opened 7,8,9,10-tetrahydrobenzo[a]pyrene 7,8-diol
      9,10-epoxide N2-deoxyguanosine adduct induces mutations at multiple sites in DNA.
AB  - Site-specific mutagenicity of trans-opened adducts at the exocyclic N(2)-amino
      group of guanine by the (+)-(7R,8S,9S,10R)- and (-)-(7S,8R,9R,10S)-enantiomers of
      a benzo[a]pyrene 7,8-diol 9,10-epoxide (7-hydroxyl and epoxide oxygen are trans,
      BPDE-2) has been determined in Chinese hamster V79 cells and their repair
      deficient counterpart, V-H1 cells. Four vectors containing single 10S-BPDE-dG or
      10R-BPDE-dG adducts positioned at G(0) or G(-1) in the analyzed 5'-ACTG(0)G(-1)GA
      sequence of the non-transcribed strand were separately transfected into the
      cells. Mutations at each of the seven nucleotides were analyzed by a novel primer
      extension assay using a mixture of one dNTP complementary to the mutated
      nucleotide and three other ddNTPs and were optimized to quantify levels of a
      mutation as low as 1%. Only G --> T mutations were detected at the adducted
      sites; the 10S adduct derived from the highly carcinogenic (+)-diol epoxide was
      40-50 and 75-140% more mutagenic than the 10R adduct in V79 and V-H1 cells,
      respectively. Importantly, the 10S adducts, but not the 10R adducts, induced
      separate non-targeted mutations at sites 5' to the G(-1) and G(0) lesions (G(0) -
      > T and C --> T, respectively) in both cell lines. Neither the T 5' to G(0) nor
      sites 3' to the lesions showed mutations. Non-targeted mutations may enhance
      overall mutagenicity of the 10S-BPDE-dG lesion and contribute to the much higher
      carcinogenicity and mutagenicity of (+)-BPDE-2 compared with its (-)-enantiomer.
      Our study reports a definitive demonstration of mutations distal to a site
      specific polycyclic aromatic hydrocarbon adduct.

PMID- 12595543
TI  - Crystal structure of Pterocarpus angolensis lectin in complex with glucose,
      sucrose, and turanose.
AB  - The crystal structure of the Man/Glc-specific seed lectin from Pterocarpus
      angolensis was determined in complex with methyl-alpha-d-glucose, sucrose, and
      turanose. The carbohydrate binding site contains a classic Man/Glc type
      specificity loop. Its metal binding loop on the other hand is of the long type,
      different from what is observed in other Man/Glc-specific legume lectins. Glucose
      binding in the primary binding site is reminiscent of the glucose complexes of
      concanavalin A and lentil lectin. Sucrose is found to be bound in a conformation
      similar as seen in the binding site of lentil lectin. A direct hydrogen bond
      between Ser-137(OG) to Fru(O2) in Pterocarpus angolensis lectin replaces a water
      mediated interaction in the equivalent complex of lentil lectin. In the turanose
      complex, the binding site of the first molecule in the asymmetric unit contains
      the alphaGlc1-3betaFruf form of furanose while the second molecule contains the
      alphaGlc1-3betaFrup form in its binding site.

PMID- 12595545
TI  - De novo cytosine methylation in the differentiating macronucleus of the
      stichotrichous ciliate Stylonychia lemnae.
AB  - Dramatic DNA reorganization and elimination processes occur during macronuclear
      differentiation in ciliates. In this study we analyzed whether cytosine
      methylation of specific sequences plays a functional role during DNA
      rearrangement. Three classes of sequences, macronuclear-destined sequences (MDSs,
      pCE7), members from a large family of transposon-like elements and micronuclear
      specific sequences (pLJ01), differing in their structure and future destiny
      during nuclear differentiation, were studied in the micronucleus, the developing
      macronucleus and, when present, in the mature macronucleus. While the MDSs become
      processed to a 1.1 and 1.3 kb gene-sized macronuclear DNA molecule, the family of
      transposon-like elements represented by MaA81 becomes removed late in the course
      of polytene chromosome formation. The micronuclear-specific sequence pLJ01 is
      eliminated together with bulk micronuclear DNA during degradation of polytene
      chromosomes. No methylated cytosine could be detected in the vegetative
      macronucleus and no difference in methylation pattern was observed either between
      micronucleus and developing macronucleus in MDSs or in a micronuclear-specific
      sequence. However, a significant percentage of the cytosines contained in the
      transposon-like element becomes methylated de novo in the course of macronuclear
      differentiation. This is the first demonstration that cytosine methylation in
      specific sequences occurs during macronuclear differentiation and may provide a
      first step towards understanding epigenetic factors involved in DNA processing.

PMID- 12595544
TI  - Downstream elements of mammalian pre-mRNA polyadenylation signals: primary,
      secondary and higher-order structures.
AB  - Primary, secondary and higher-order structures of downstream elements of
      mammalian pre-mRNA polyadenylation signals [poly(A) signals] are re viewed. We
      have carried out a detailed analysis on our database of 244 human pre-mRNA
      poly(A) signals in order to characterize elements in their downstream regions. We
      suggest that the downstream region of the mammalian pre-mRNA poly(A) signal
      consists of various simple elements located at different distances from each
      other. Thus, the downstream region is not described by any precise consensus.
      Searching our database, we found that approximately 80% of pre-mRNAs with the
      AAUAAA or AUUAAA core upstream elements contain simple downstream elements,
      consisting of U-rich and/or 2GU/U tracts, the former occurring approximately 2
      fold more often than the latter. Approximately one-third of the pre-mRNAs
      analyzed here contain sequences that may form G-quadruplexes. A substantial
      number of these sequences are located immediately downstream of the poly(A)
      signal. A possible role of G-rich sequences in the polyadenylation process is
      discussed. A model of the secondary structure of the SV40 late pre-mRNA poly(A)
      signal downstream region is presented.

PMID- 12595546
TI  - The crystal structure of an alternating RNA heptamer r(GUAUACA) forming a six
      base-paired duplex with 3'-end adenine overhangs.
AB  - The crystal structure of an alternating RNA heptamer r(GUAUACA) has been
      determined to 2.0 A resolution and refined to an R(work) of 17.1% and R(free) of
      18.5% using 2797 reflections. The heptamer crystallized in the space group C222
      with a unit cell of a = 25.74, b = 106.58, c = 30.26 A and two independent
      strands in the asymmetric unit. Each heptamer forms a duplex with its symmetry
      related strand and each duplex contains six Watson-Crick base pairs and 3'-end
      adenosine overhangs. Therefore, two kinds of duplex (duplex 1 and duplex 2) are
      formed. Duplexes 1 stack on each other forming a pseudo-continuous column, which
      is typical of the RNA packing mode, while duplex 2 is typical of A-DNA packing
      with its termini in abutting interactions. Overhang adenine residues stack within
      the duplexes with C3'-endo sugar pucker and C2'-endo sugar pucker in duplexes 1
      and 2, respectively. A Na+ ion in the crystal lattice is water bridged to two N1
      atoms of symmetry-related A7 bases.

PMID- 12595547
TI  - Imprinting regulation of the murine Meg1/Grb10 and human GRB10 genes; roles of
      brain-specific promoters and mouse-specific CTCF-binding sites.
AB  - The imprinted mouse gene Meg1/Grb10 is expres sed from maternal alleles in almost
      all tissues and organs, except in the brain, where it is expressed biallelically,
      and the paternal allele is expressed preferentially in adulthood. In contrast,
      the human GRB10 gene shows equal biallelic expression in almost all tissues and
      organs, while it is almost always expressed paternally in the fetal brain. To
      elucidate the molecular mechanisms of the complex imprinting patterns among the
      different tissues and organs of humans and mice, we analyzed in detail both the
      genomic structures and tissue-specific expression profiles of these species.
      Experiments using 5'-RACE and RT-PCR demonstrated the existence in both humans
      and mice of novel brain- specific promoters, in which only the paternal allele
      was active. The promoters were located in the primary differentially methylated
      regions. Interest ingly, CTCF-binding sites were found only in the mouse promoter
      region where CTCF showed DNA methylation-sensitive binding activity. Thus, the
      insulator function of CTCF might cause reciprocal maternal expression of the
      Meg1/Grb10 gene from another upstream promoter in the mouse, whereas the human
      upstream promoter is active in both parental alleles due to the lack of the
      corresponding insulator sequence in this region.

PMID- 12595548
TI  - Efficient cloning and engineering of entire mitochondrial genomes in Escherichia
      coli and transfer into transcriptionally active mitochondria.
AB  - We have devised an efficient method for replicating and stably maintaining entire
      mitochondrial genomes in Escherichia coli and have shown that we can engineer
      these mitochondrial DNA (mtDNA) genome clones using standard molecular biological
      techniques. In general, we accomplish this by inserting an E.coli replication
      origin and selectable marker into isolated, circular mtDNA at random locations
      using an in vitro transposition reaction and then transforming the modified
      genomes into E.coli. We tested this approach by cloning the 16.3 kb mouse
      mitochondrial genome and found that the resulting clones could be engineered and
      faithfully maintained when we used E.coli hosts that replicated them at
      moderately low copy numbers. When these recombinant mtDNAs were replicated at
      high copy numbers, however, mtDNA sequences were partially or fully deleted from
      the original clone. We successfully electroporated recombinant mouse
      mitochondrial genomes into isolated mouse mitochondria devoid of their own DNA
      and detected robust in organello RNA synthesis by RT-PCR. This approach for
      modifying mtDNA and subsequent in organello analysis of the recombinant genomes
      offers an attractive experimental system for studying many aspects of vertebrate
      mitochondrial gene expression and is a first step towards true in vivo
      engineering of mammalian mitochondrial genomes.

PMID- 12595549
TI  - Highly efficient catalytic RNA cleavage by the cooperative action of two Cu(II)
      complexes embodied within an antisense oligonucleotide.
AB  - Based on our recent studies of RNA cleavage by oligonucleotide-terpyridine.Cu(II)
      complex 5'- and/or 3'-conjugates, we designed 2'-O-methyloligonucleotides with
      two terpyridine-attached nucleosides at contiguous internal sites. To connect the
      2'-terpyridine-modified uridine residue at the 5'-side to the 5'-O-terpyridyl
      nucleoside residue at the 3'-side, a dimethoxytrityl derivative of 5
      hydroxypropyl-5'-O-terpyridyl-2'-deoxyuridine-3'-phosphoramidite was newly
      synthesized. Using this unit, we constructed two terpyridine conjugates, with
      either an unusual phophodiester bond or the bond extended by a propanediol(s)
      containing linker. Cleavage reactions of the target RNA oligomer, under the
      conditions of conjugate excess in the presence of Cu(II), indicated that the
      conjugates precisely cleaved the RNA at the predetermined site and that one
      propanediol-containing linker was the most appropriate for inducing high cleavage
      activity. Furthermore, a comparison of the activity of the propanediol agent with
      those of the control conjugates with one complex confirmed that the two complexes
      are required for efficient RNA cleavage. The reaction of the novel cleaver
      revealed a bell-shaped pH-rate profile with a maximum at pH approximately 7.5,
      which is a result of the cooperative action of the complexes. In addition, we
      demonstrated that the agent catalytically cleaves an excess of the RNA, with the
      kinetic parameter kcat/K(m) = 0.118 nM(-1) x h(-1).

PMID- 12595550
TI  - Identification of the ATP-binding site in the terminase subunit pUL56 of human
      cytomegalovirus.
AB  - Human cytomegalovirus (HCMV) terminase is composed of subunits pUL56 (130 kDa)
      and pUL89 ( approximately 75 kDa), encoded by the UL56 and UL89 genes. In a
      recent investigation, we demonstrated that the main ATPase activity is associated
      with the large terminase subunit pUL56. The protein has two putative ATP-binding
      sites, which were suggested to be composed of the sequence (amino acids 463-470)
      for ATP-binding site 1 and YNETFGKQ (amino acids 709-716) for the second site. We
      now demonstrate using a 1.5 kb fragment encoding the C-terminal half of pUL56
      that ATP-binding site 1 is not critical for the function, whereas ATP-binding
      site 2 is required for the enzymatic activity. Mutation G714A in this protein
      reduced the ATPase activity to approximately 65% and the double mutation
      G714A/K715N showed a reduction up to 75%. However, the substitution of E711A
      revoked the effect of the substitutions. The functional character of the ATP
      binding site was demonstrated by transfer of YNETFGKQLSIACLR (709-723) to
      glutathione-S-transferase (GST). Interestingly, vanadate, an ATPase inhibitor,
      has the ability to block the ATPase activity of pUL56 as well as of Apyrase,
      while the antitumor ATP-mimetic agent geldanamycin, did not affect the ATP
      binding of pUL56. Furthermore, in contrast to an inactive control compound, the
      specific HCMV terminase inhibitor BDCRB showed a partial inhibition of the pUL56
      specific ATPase activity. Our results clearly demonstrated that (i) the enzymatic
      activity of the terminase subunit pUL56 could be inhibited by vanadate, (ii) only
      the ATP-binding site 2 is critical for the pUL56 function and (iii) glycine G714
      is an invariant amino acid.

PMID- 12595551
TI  - Base pair opening within B-DNA: free energy pathways for GC and AT pairs from
      umbrella sampling simulations.
AB  - The conformational pathways and the free energy variations for base opening into
      the major and minor grooves of a B-DNA duplex are studied using umbrella sampling
      molecular dynamics simulations. We compare both GC and AT base pair opening
      within a double-stranded d(GAGAGAGAGAGAG)* d(CTCTCTCTCTCTC) oligomer, and we are
      also able to study the impact of opening on the conformational and dynamic
      properties of DNA and on the surrounding solvent. The results indicate a two
      stage opening process with an initial coupling of the movements of the bases
      within the perturbed base pair. Major and minor groove pathways are energetically
      comparable in the case of the pyrimidine bases, but the major groove pathway is
      favored for the larger purine bases. Base opening is coupled to changes in
      specific backbone dihedrals and certain helical distortions, including untwisting
      and bending, although all these effects are dependent on the particular base
      involved. Partial opening also leads to well defined water bridging sites, which
      may play a role in stabilizing the perturbed base pairs.

PMID- 12595552
TI  - The structure of full-length LysR-type transcriptional regulators. Modeling of
      the full-length OxyR transcription factor dimer.
AB  - The LysR-type transcriptional regulators (LTTRs) comprise the largest family of
      prokaryotic transcription factors. These proteins are composed of an N-terminal
      DNA binding domain (DBD) and a C-terminal cofactor binding domain. To date, no
      structure of the DBD has been solved. According to the SUPERFAMILY and MODBASE
      databases, a reliable homology model of LTTR DBDs may be built using the
      structure of the Escherichia coli ModE transcription factor, containing a winged
      helix- turn-helix (HTH) motif, as a template. The remote, but statistically
      significant, sequence similarity between ModE and LTTR DBDs and an alignment
      generated using SUPERFAMILY and MODBASE methods was independently confirmed by
      alignment of sequence profiles representing ModE and LTTR family DBDs. Using the
      crystal structure of the E.coli OxyR C-terminal domain and the DBD alignments we
      constructed a structural model of the full-length dimer of this LTTR family
      member and used it to investigate the mode of protein-DNA interaction. We also
      applied the model to interpret, in a structural context, the results of numerous
      biochemical studies of mutated LTTRs. A comparison of the LTTR DBD model with the
      structures of other HTH proteins also provides insights into the interaction of
      LTTRs with the C-terminal domain of the RNA polymerase alpha subunit.

PMID- 12595553
TI  - Mapping the triphosphatase active site of baculovirus mRNA capping enzyme LEF4
      and evidence for a two-metal mechanism.
AB  - The 464-amino acid baculovirus LEF4 protein is a bifunctional mRNA capping enzyme
      with triphosphatase and guanylyltransferase activities. The N-terminal half of
      LEF4 constitutes an autonomous triphosphatase catalytic domain. The LEF4
      triphosphatase belongs to a family of metal-dependent phosphohydrolases, which
      includes the RNA triphosphatases of fungi, protozoa, Chlorella virus and
      poxviruses. The family is defined by two glutamate-containing motifs (A and C),
      which form a metal-binding site. Most of the family members resemble the fungal
      and Chlorella virus enzymes, which have a complex active site located within the
      hydrophilic interior of a topologically closed eight stranded beta barrel (the so
      called 'triphosphate tunnel'). Here we probed whether baculovirus LEF4 is a
      member of the tunnel subfamily, via mutational mapping of amino acids required
      for triphosphatase activity. We identified four new essential side chains in LEF4
      via alanine scanning and illuminated structure-activity relationships by
      conservative substitutions. Our results, together with previous mutational data,
      highlight five acidic and four basic amino acids that are likely to comprise the
      LEF4 triphosphatase active site (Glu9, Glu11, Arg51, Arg53, Glu97, Lys126,
      Arg179, Glu181 and Glu183). These nine essential residues are conserved in LEF4
      orthologs from all strains of baculoviruses. We discerned no pattern of
      clustering of the catalytic residues of the baculovirus triphosphatase that would
      suggest structural similarity to the tunnel proteins (exclusive of motifs A and
      C). However, there is similarity to the active site of vaccinia RNA
      triphosphatase. We infer that the baculovirus and poxvirus triphosphatases are a
      distinct lineage within the metal-dependent RNA triphosphatase family.
      Synergistic activation of the LEF4 triphosphatase by manganese and magnesium
      suggests a two-metal mechanism of gamma phosphate hydrolysis.

PMID- 12595554
TI  - The crystal structure of the complex between a disaccharide anthracycline and the
      DNA hexamer d(CGATCG) reveals two different binding sites involving two DNA
      duplexes.
AB  - The crystal structure of the complex formed between the anthracycline antibiotic
      3'-deamino-3'- hydroxy-4'-(O-L-daunosaminyl)-4-demethoxydoxo rubicin (MEN 10755),
      an active disaccharide analogue of doxorubicin, and the DNA hexamer d(CGATCG) has
      been solved to a resolution of 2.1 A. MEN 10755 exhibits a broad spectrum of
      antitumor activities, comparable with that of the parent compound, but there are
      differences in the mechanism of action as it is active in doxorubicin-resistant
      tumors and is more effective in stimulating topoisomerase DNA cleavage. The
      structure is similar to previously crystallised anthracycline- DNA complexes.
      However, two different binding sites arise from drug intercalation so that the
      two halves of the self-complementary duplex are no longer equivalent. In one site
      both sugar rings lie in the minor groove. In the other site the second sugar
      protrudes out from the DNA helix and is linked, through hydrogen bonds, to
      guanine of a symmetry-related DNA molecule. This is the first structure of an
      anthracycline-DNA complex where an interaction of the drug with a second DNA
      helix is observed. We discuss the present findings with respect to the relevance
      of the amino group for DNA binding and to the potential role played by the second
      sugar in the interactions with topoisomerases or other cellular targets.

PMID- 12595555
TI  - The highly related DEAD box RNA helicases p68 and p72 exist as heterodimers in
      cells.
AB  - The RNA helicases p68 and p72 are highly related members of the DEAD box family
      of proteins, sharing 90% identity across the conserved core, and have been shown
      to be involved in both transcription and mRNA processing. We previously showed
      that these proteins co-localise in the nucleus of interphase cells. In this study
      we show that p68 and p72 can interact with each other and self-associate in the
      yeast two-hybrid system. Co-immunoprecipitation experiments confirmed that p68
      and p72 can interact in the cell and indicated that these proteins preferentially
      exist as hetero-dimers. In addition, we show that p68 can interact with NFAR-2, a
      protein that is also thought to function in mRNA processing. Moreover, gel
      filtration analysis suggests that p68 and p72 can exist in a variety of complexes
      in the cell (ranging from approximately 150 to approximately 400 kDa in size),
      with a subset of p68 molecules being in very large complexes (>2 MDa). The
      potential to exist in different complexes that may contain p68 and/or p72,
      together with a range of other factors, would provide the potential for these
      proteins to interact with different RNA substrates and would be consistent with
      recent reports implying a wide range of functions for p68/p72.

PMID- 12595556
TI  - The ribonuclease H activity of the reverse transcriptases of human
      immunodeficiency viruses type 1 and type 2 is modulated by residue 294 of the
      small subunit.
AB  - Reverse transcriptases (RTs) exhibit DNA polymerase and ribonuclease H (RNase H)
      activities. The RTs of human immunodeficiency viruses type 1 and type 2 (HIV-1
      and HIV-2) are composed of two subunits, both sharing the same N-terminus (which
      encompasses the DNA polymerase domain). The smaller subunit lacks the C-terminal
      segment of the larger one, which contains the RNase H domain. The DNA polymerase
      domain of RTs resembles a right hand linked to the RNase H domain by a connection
      subdomain. Despite the high homology between HIV-1 and HIV-2 RTs, the RNase H
      activity of the latter is substantially lower than that of HIV-1 RT. The thumb
      subdomain of the small subunit controls the level of RNase H activity. We show
      here that Gln294, located in this thumb, is responsible for this difference in
      activity. A HIV-2 RT mutant, where Gln294 in the small subunit was replaced by a
      proline (present in HIV-1 RT), has an activity almost 10-fold higher than that of
      the wild-type RT. A comparative in vitro study of the kinetic parameters of the
      RNase H activity suggests that residue 294 affects the K(m) rather than the kcat
      value, influencing the affinity for the RNA.DNA substrate.

PMID- 12595557
TI  - Putative intermediary stages for the molecular evolution from a ribozyme to a
      catalytic RNP.
AB  - A hypothetical evolutionary pathway from a ribozyme to a catalytic RNA-protein
      complex (RNP) is proposed and examined. In this hypothesis for an early phase of
      molecular evolution, one RNA-RNA interaction in the starting ribozyme is replaced
      with an RNA-protein interaction via two intermediary stages. At each stage, the
      original RNA-RNA interaction and a newly introduced RNA-protein interaction are
      designed to coexist. The catalytic RNPs corresponding to the intermediary stages
      were constructed by employing the Tetrahymena ribozyme together with molecular
      modeling. Analyses of the RNPs indicate that the protein can fully replace the
      original role of the RNA-RNA interaction in the starting ribozyme and that the
      association of a protein with a ribozyme might be beneficial for improving the
      ribozymatic activity.

PMID- 12595558
TI  - Comparing the fine specificity of DNA binding by NF-kappaB p50 and p52 using
      principal coordinates analysis.
AB  - Principal coordinates analysis has been proposed as an efficient way of
      predicting the binding affinity of a transcription factor to different DNA
      motifs, as it can model complex interactions that are difficult to represent with
      standard position-weight matrices. Here we evaluate its ability to distinguish
      the DNA binding properties of two closely related proteins, the homodimeric forms
      of NF-kappaB p50 and p52. When tested experimentally against 50 different
      variants of the generalised NF-kappaB motif GGRRNNYYCC, the binding specificities
      of p50 and p52 were similar but not identical (correlation rho = 0.86). These
      experimental data can be modelled accurately with six principal coordinates that
      are similar for p50 and p52, plus one principal coordinate that is significantly
      stronger for p52 than for p50, relating to the inner positions of the binding
      site. These findings are compatible with crystallographic data showing that p52
      has greater ability than p50 to form water molecule-mediated hydrogen bonds with
      inner nucleotide positions of the binding site.

PMID- 12595559
TI  - Identification of the SRC pyrimidine-binding protein (SPy) as hnRNP K:
      implications in the regulation of SRC1A transcription.
AB  - The human SRC gene encodes pp60(c-src), a non-receptor tyrosine kinase involved
      in numerous signaling pathways. Activation or overexpression of c-Src has also
      been linked to a number of important human cancers. Transcription of the SRC gene
      is complex and regulated by two closely linked but highly dissimilar promoters,
      each associated with its own distinct non-coding exon. In many tissues SRC
      expression is regulated by the housekeeping-like SRC1A promoter. In addition to
      other regulatory elements, three substantial polypurine:polypyrimidine (TC)
      tracts within this promoter are required for full transcriptional activity.
      Previously, we described an unusual factor called SRC pyrimidine-binding protein
      (SPy) that could bind to two of these TC tracts in their double-stranded form,
      but was also capable of interacting with higher affinity to all three pyrimidine
      tracts in their single-stranded form. Mutations in the TC tracts, which abolished
      the ability of SPy to interact with its double-stranded DNA target, significantly
      reduced SRC1A promoter activity, especially in concert with mutations in critical
      Sp1 binding sites. Here we expand upon our characterization of this interesting
      factor and describe the purification of SPy from human SW620 colon cancer cells
      using a DNA affinity-based approach. Subsequent in-gel tryptic digestion of
      purified SPy followed by MALDI-TOF mass spectrometric analysis identified SPy as
      heterogeneous nuclear ribonucleoprotein K (hnRNP K), a known nucleic-acid binding
      protein implicated in various aspects of gene expression including transcription.
      These data provide new insights into the double- and single-stranded DNA-binding
      specificity, as well as functional properties of hnRNP K, and suggest that hnRNP
      K is a critical component of SRC1A transcriptional processes.

PMID- 12595560
TI  - Sequence-specific minor groove binding by bis-benzimidazoles: water molecules in
      ligand recognition.
AB  - The binding of two symmetric bis-benzimidazole compounds, 2,2-bis-[4'-(3"
      dimethylamino-1"-propyloxy)phenyl]-5,5-bi-1H-benzimidazole and its
      piperidinpropylphenyl analog, to the minor groove of DNA, have been studied by
      DNA footprinting, surface plasmon resonance (SPR) methods and molecular dynamics
      simulations in explicit solvent. The footprinting and SPR methods find that the
      former compound has enhanced affinity and selectivity for AT sequences in DNA.
      The molecular modeling studies have suggested that, due to the presence of the
      oxygen atom in each side chain of the former compound, a water molecule is
      immobilized and effectively bridges between side chain and DNA base edges via
      hydrogen bonding interactions. This additional contribution to ligand-DNA
      interactions would be expected to result in enhanced DNA affinity, as is
      observed.

PMID- 12595561
TI  - Protein concerted motions in the DNA-human topoisomerase I complex.
AB  - The collective motions of the core and C-terminal domains of human topoisomerase
      I (topo I) have been analysed by molecular dynamics simulation of the protein in
      covalent complex with a 22 bp DNA duplex. The analysis evidenced a great number
      of correlated movements of core subdomain I and II residues, and a central role
      for helix 5 in the protein-DNA communication, in particular with the scissile
      strand downstream of the cleavage site. The flow of information between these
      core subdomains and DNA suggests that subdomains I and II play an essential role
      in the DNA relaxation process. In core subdomain III the majority of DNA
      contacting residues do not communicate with protein regions far from DNA,
      suggesting that they have a structural role. However, selected core subdomain III
      residues, involved in the orientation of the active site region, show correlated
      movements with residues distant from DNA, indicating that the information
      concerning the catalytic event is also transmitted. The flexibility of two loops
      formed by residues 519-520 and 580-584 seems indispensable to the dynamic
      participation of core subdomain III to the DNA cleavage and religation steps. The
      motion of specific residues has also been found to explain the effect of single
      point mutations that make topo I resistant to the anticancer drug camptothecin.

PMID- 12595562
TI  - The role of minor groove functional groups in DNA hydration.
AB  - Here we describe the crystal structure of modified [d(CGCGAATTCGCG)]2 refined to
      2.04 A. The modification, which affects only the two thymines at the central ApT
      step, involves isosteric removal of the 2-keto oxygen atoms and substitution of
      the N1 nitrogen with carbon. The crystal structure reveals the ability of this
      modified thymine to effectively base pair with adenine in [d(CGCGAAtTCGCG)]2. The
      structure also suggests that the minor groove 'spine of hydration' is
      destabilized but essentially intact.

PMID- 12595563
TI  - Adjacent DNA sequences modulate Sox9 transcriptional activation at paired Sox
      sites in three chondrocyte-specific enhancer elements.
AB  - Expression of the type XI collagen gene Col11a2 is directed to cartilage by at
      least three chondrocyte-specific enhancer elements, two in the 5' region and one
      in the first intron of the gene. The three enhancers each contain two heptameric
      sites with homology to the Sox protein-binding consensus sequence. The two sites
      are separated by 3 or 4 bp and arranged in opposite orientation to each other.
      Targeted mutational analyses of these three enhancers showed that in the intronic
      enhancer, as in the other two enhancers, both Sox sites in a pair are essential
      for enhancer activity. The transcription factor Sox9 binds as a dimer at the
      paired sites, and the introduction of insertion mutations between the sites
      demonstrated that physical interactions between the adjacently bound proteins are
      essential for enhancer activity. Additional mutational analyses demonstrated that
      although Sox9 binding at the paired Sox sites is necessary for enhancer activity,
      it alone is not sufficient. Adjacent DNA sequences in each enhancer are also
      required, and mutation of those sequences can eliminate enhancer activity without
      preventing Sox9 binding. The data suggest a new model in which adjacently bound
      proteins affect the DNA bend angle produced by Sox9, which in turn determines
      whether an active transcriptional enhancer complex is assembled.

PMID- 12595564
TI  - Analysis of helicase activity and substrate specificity of Drosophila RECQ5.
AB  - RecQ5 is one of five RecQ helicase homologs identified in humans. Three of the
      human RecQ homologs (BLM, WRN and RTS) have been linked to autosomal recessive
      human genetic disorders (Bloom syndrome, Werner syndrome and Rothmund-Thomson
      syndrome, respectively) that display increased genomic instability and cause
      elevated levels of cancers in addition to other symptoms. To understand the role
      of RecQ helicases in maintaining genomic stability, the WRN, BLM and Escherichia
      coli RecQ helicases have been characterized in terms of their DNA substrate
      specificity. However, little is known about other members of the RecQ family.
      Here we show that Drosophila RECQ5 helicase is a structure-specific DNA helicase
      like the other RecQ helicases biochemically characterized so far, although the
      substrate specificity is not identical to that of WRN and BLM helicases.
      Drosophila RECQ5 helicase is capable of unwinding 3' Flap, three-way junction,
      fork and three-strand junction substrates at lower protein concentrations
      compared to 5' Flap, 12 nt bubble and synthetic Holliday junction structures,
      which can be unwound efficiently by WRN and BLM.

PMID- 12595565
TI  - RNA sequences that work as transcriptional activating regions.
AB  - We describe a set of RNA molecules that work as transcriptional activators when
      tethered to DNA. These RNA activating regions were found amongst a randomized set
      of molecules bearing variants of a 10 nt loop attached to an RNA stem. The
      various RNA activating regions all bear an identical five- residue sequence with
      an interspersed sixth residue. The result shows that although all natural
      activating regions characterized thus far are peptidic, this function can be
      served by other kinds of moieties as well.

PMID- 12595566
TI  - Transcriptional activation by AP-2alpha is modulated by the oncogene DEK.
AB  - Cell differentiation and development are highly regulated processes at the
      transcriptional level. One of the main transcription factors that regulate these
      processes is AP-2alpha, a cell-type specific protein required for vertebrate
      development and embryogenesis. AP-2alpha also regulates apoptosis and cell-cycle
      specific events by interacting with the oncogene c-Myc. In searching for novel AP
      2alpha- interacting factors, using an affinity chromatography approach, we have
      observed that oncoprotein DEK interacts with AP-2alpha in vitro. The existence of
      an interaction between AP-2alpha and DEK in cellular cultures was demonstrated by
      expression of a tagged AP-2alpha form followed by immunodetection. By transient
      co-expression experiments using a reporter for APOE promoter activity we have
      found that DEK stimulates the transactivation activity of AP-2alpha over APOE
      promoter. Finally, electrophoretic mobility shift assays suggested that DEK
      enhances the DNA-binding activity of AP-2alpha. Our data suggest a novel cellular
      function of DEK as a transcriptional co-activator.

PMID- 12595567
TI  - Ageing and telomeres: a study into organ- and gender-specific telomere
      shortening.
AB  - Telomeres, the non-coding sequences at the ends of chromosomes, in the absence of
      telomerase, progressively shorten with each cell division. Shortening of
      telomeres can induce cell cycle arrest and apoptosis. The aim of this study was
      to investigate age- and gender-related changes in telomere length in the rat and
      to detect possible tissue- specific rates of telomere shortening. Changes with
      age in telomere lengths were assessed by Southern blotting in the kidney,
      pancreas, liver, lung and brain of male and female rats. We determined the
      percentage of telomeres in various molecular size regions rather than measuring
      the average telomere length. The latter was unable to detect telomere shortening
      in the tissues. The percentage of short telomeres increased with age in the
      kidney, liver, pancreas and lung of both males and females, but not in the brain.
      Males had shorter telomeres than females in all organs analysed except the brain,
      where the lengths were similar. These findings indicate that telomeres shorten in
      the rat kidney, liver, pancreas and the lung in an age-dependent manner. These
      data also provide a novel mechanism for the gender-related differences in
      lifespan and suggest a tissue-specific regulation of telomere length during
      development and ageing in the rat.

PMID- 12595568
TI  - SNPs by AFLP (SBA): a rapid SNP isolation strategy for non-model organisms.
AB  - Despite the great potential of single nucleotide polymorphism (SNP) markers in
      evolutionary studies, in particular for inferring population genetic parameters,
      SNP analysis has almost exclusively been limited to humans and 'genomic model'
      organisms, due to the lack of available sequence data in non-model organisms.
      Here, we describe a rapid and cost effective method to isolate candidate SNPs in
      non-model organisms. This SNP isolation strategy consists basically in the direct
      sequencing of amplified fragment length polymorphism bands. In a first
      application of this method, 10 unique DNA fragments that contained 24 SNPs were
      discovered in 11.11 kb of sequenced genomic DNA of a non-model species, the brown
      trout (Salmo trutta).

PMID- 12595569
TI  - Fluorescent labelling of cRNA for microarray applications.
AB  - Microarrays of oligonucleotide expression libraries can be hybridised with either
      cDNA, generated from mRNA during reverse transcription, or cRNA, generated in an
      Eberwine mRNA amplification procedure. While methods for fluorescent labelling of
      cDNA have been thoroughly investigated, methods for cRNA labelling have not. To
      this purpose, we developed an aminoallyl-UTP (aa-UTP) driven cRNA labelling
      protocol and compared it in expression profiling studies using spotted 7.5 K
      65mer murine oligonucleotide arrays with labelling via direct incorporation of Cy
      UTPs. The presence of dimethylsulfoxide during coupling of aa-modified cRNA with
      N-hydroxysuccinimide-modified, fluorescent Cy dyes greatly enhanced the labelling
      efficiency, as analysed by spectrophotometry and fluorescent hybridisation
      signals. Indirect labelling using aa-UTP resulted in 2- to 3-fold higher degrees
      of labelling and fluorescent signals than labelling by direct incorporation of Cy
      UTP. By variation of the aa-UTP:UTP ratio, a clear optimal degree of labelling
      was found (1 dye per 20-25 nt). Incorporation of more label increased Cy3 signal
      but lowered Cy5 fluorescence. This effect is probably due to quenching, which is
      more prominent for Cy5 than for Cy3. In conclusion, the currently developed
      method is an efficient, robust and inexpensive technique for fluorescent
      labelling of cRNA and allows sensitive detection of gene expression profiles on
      oligonucleotide microarrays.

PMID- 12595570
TI  - Cre-mediated germline mosaicism: a new transgenic mouse for the selective removal
      of residual markers from tri-lox conditional alleles.
AB  - The binary Cre-lox conditional knockout system requires an essential part of the
      target gene to be flanked by loxP sites, enabling excision in vivo upon Cre
      expression. LoxP sites are introduced by homologous recombination, together with
      a selectable marker. However, this marker can disturb gene expression and should
      be removed. The marker is therefore often prepared with a third, flanking loxP
      site (tri-lox construct), facilitating its selective removal by partial Cre-lox
      recombination. We have shown that this excision can be achieved in vivo in the
      germline using EIIaCre transgenic mice, and have described the advantages of in
      vivo over in vitro removal. We show here that MeuCre40, a new transgenic mouse,
      more reliably and reproducibly generates an optimal partial mosaic Cre-lox
      recombination pattern in the early embryo. This mosaicism was transmitted to the
      germline and to many other tissues. Alleles with partial deletions, in particular
      floxed alleles from which the selectable marker was removed, were readily
      recovered in the next generation, after segregation from the transgene.
      Segregation via paternal or maternal transmission led to successful recovery of
      the alleles of interest. We also obtained total deletion of the floxed regions in
      the same experiment, making this transgene a polyvalent Cre-lox tool. We
      rigorously tested the ability of MeuCre40 to solve tri-lox problems, by using it
      for the in vivo removal of neo(R)- and hprt-expression cassettes from three
      different tri-lox mutants.

PMID- 12595571
TI  - New restriction enzymes discovered from Escherichia coli clinical strains using a
      plasmid transformation method.
AB  - The presence of restriction enzymes in bacterial cells has been predicted by
      either classical phage restriction-modification (R-M) tests, direct in vitro
      enzyme assays or more recently from bacterial genome sequence analysis. We have
      applied phage R-M test principles to the transformation of plasmid DNA and
      established a plasmid R-M test. To validate this test, six plasmids that contain
      BamHI fragments of phage lambda DNA were constructed and transformed into
      Escherichia coli strains containing known R-M systems including: type I (EcoBI,
      EcoAI, Eco124I), type II (HindIII) and type III (EcoP1I). Plasmid DNA with a
      single recognition site showed a reduction of relative efficiency of
      transformation (EOT = 10(-1)-10(-2)). When multiple recognition sites were
      present, greater reductions in EOT values were observed. Once established in the
      cell, the plasmids were subjected to modification (EOT = 1.0). We applied this
      test to screen E.coli clinical strains and detected the presence of restriction
      enzymes in 93% (14/15) of cells. Using additional subclones and the computer
      program, RM Search, we identified four new restriction enzymes, Eco377I, Eco585I,
      Eco646I and Eco777I, along with their recognition sequences, GGA(8N)ATGC,
      GCC(6N)TGCG, CCA(7N)CTTC, and GGA(6N)TATC, respectively. Eco1158I, an
      isoschizomer of EcoBI, was also found in this study.

PMID- 12595572
TI  - De novo production of diverse intracellular antibody libraries.
AB  - Many therapeutic targets are intracellular proteins and molecules designed to
      interact with them must effectively bind to their target inside the cell.
      Intracellular antibodies (intrabodies) recognise and bind to proteins in cells
      and various methods have been developed to produce such molecules. Intracellular
      antibody capture (IAC) is based on a genetic screening approach and is a facile
      methodology with which effective intracellular antibodies can be obtained. During
      the development of the IAC technology, consensus immunoglobulin variable
      frameworks were identified which can form the basis of intrabody libraries for
      direct screening. In this paper, we describe the de novo synthesis of intrabody
      libraries based on the IAC consensus sequence. The procedure comprises in vitro
      production of a single antibody gene fragment from oligonucleotides and
      diversification of CDRs of the immunoglobulin variable domain by mutagenic PCR.
      Completely de novo intrabody libraries can be rapidly generated in vitro by these
      approaches. As an example, a single immunoglobulin VH domain intrabody library
      was screened directly in yeast with an oncogenic BCR-ABL antigen bait and
      distinct antigen binders were isolated illustrating the functional utility of the
      library. This second generation IAC approach (IAC2) has many practical
      advantages, in particular the ability to isolate intrabodies by direct genetic
      selection, which obviates the need for in vitro production of antigen for pre
      selection of antibody fragments.

PMID- 12595573
TI  - Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic
      adenosine 3',5'-monophosphate by relaxin.
AB  - The G protein-coupled receptors LGR7 and LGR8 have recently been identified as
      the primary receptors for the polypeptide hormone relaxin and relaxin-like
      factors. RT-PCR confirmed the existence of mRNA for both LGR7 and LRG8 in THP-1
      cells. Whole cell treatment of THP-1 cells with relaxin produced a biphasic time
      course in cAMP accumulation, where the first peak appeared as early as 1-2 min
      with a second peak at 10-20 min. Selective inhibitors for phosphoinositide 3
      kinase (PI3K), such as wortmannin and LY294002, showed a dose-dependent
      inhibition of relaxin-mediated increases in cAMP, specific for the second peak of
      the relaxin time course. Adenylyl cyclase activation by relaxin in purified
      plasma membranes from THP-1 cells was not inhibited by LY294002, consistent with
      a mechanism involving direct stimulation by a Galphas-coupled relaxin receptor.
      However, reconstitution of membranes with cytosol from THP-1 cells enhanced
      adenylyl cyclase activity and restored LY294002 sensitivity. In addition, relaxin
      increased PI3K activity in THP-1 cells. Neither the effects of relaxin nor the
      inhibition of relaxin by LY294002 was mediated by the activity of
      phosphodiesterases. Taken together, we show that PI3K is required for the
      biphasic stimulation of cAMP by relaxin in THP-1 cells and present a novel signal
      transduction pathway for the activation of adenylyl cyclase by a G protein
      coupled receptor.

PMID- 12595574
TI  - Regulation of myostatin in vivo by growth and differentiation factor-associated
      serum protein-1: a novel protein with protease inhibitor and follistatin domains.
AB  - Myostatin, a member of the TGFbeta superfamily, is a potent and specific negative
      regulator of skeletal muscle mass. In serum, myostatin circulates as part of a
      latent complex containing myostatin propeptide and/or follistatin-related gene
      (FLRG). Here, we report the identification of an additional protein associated
      with endogenous myostatin in normal mouse and human serum, discovered by affinity
      purification and mass spectrometry. This protein, which we have named growth and
      differentiation factor-associated serum protein-1 (GASP-1), contains multiple
      domains associated with protease-inhibitory proteins, including a whey acidic
      protein domain, a Kazal domain, two Kunitz domains, and a netrin domain. GASP-1
      also contains a domain homologous to the 10-cysteine repeat found in follistatin,
      a protein that binds and inhibits activin, another member of the TGFbeta
      superfamily. We have cloned mouse GASP-1 and shown that it inhibits the
      biological activity of mature myostatin, but not activin, in a luciferase
      reporter gene assay. Surprisingly, recombinant GASP-1 binds directly not only to
      mature myostatin, but also to the myostatin propeptide. Thus, GASP-1 represents a
      novel class of inhibitory TGFbeta binding proteins.

PMID- 12595575
TI  - Gab2 tyrosine phosphorylation by a pleckstrin homology domain-independent
      mechanism: role in epidermal growth factor-induced mitogenesis.
AB  - In primary rat hepatocyte cultures, activation of phosphatidylinositol 3-kinase
      is both necessary and sufficient to account for epidermal growth factor (EGF)
      induced DNA synthesis. In these cells, three major p85-containing complexes were
      formed after EGF treatment: ErbB3-p85, Shc-p85, and a multimeric Gab2-Grb2-SHP2
      p85, which accounted for more than 80% of total EGF-induced PI3K activity (Kong,
      M., C. Mounier, J. Wu, and B. I. Posner, J Biol Chem, 2000, 275:36035-36042).
      More recently, we found that EGF-dependent tyrosine phosphorylation of endogenous
      Gab2 is essential for EGF-induced DNA synthesis in rat hepatocytes. Here we show
      that, after EGF treatment, ErbB3-p85 and Shc-p85 complexes were localized to
      plasma membrane and endosomes, whereas the multimeric Gab2-Grb2-SHP2-p85 complex
      was formed rapidly (peak at 30 sec) and exclusively in cytosol. Western blotting
      of subcellular fractions from intact liver and immunofluorescence analyses in
      cultured hepatocytes demonstrated that EGF did not promote the association of
      cytosolic Gab2 with cell membranes. These observations prompted us to evaluate
      the role of the PH domain of Gab2 in regulating its function. Overexpression of
      the PH domain of Gab2 did not affect EGF-induced Gab2 phosphorylation, PI3K
      activation, and DNA synthesis. Overexpressed Gab2 lacking the PH domain
      (DeltaPHGab2) was comparable to wild-type Gab2 in respect to EGF-induced tyrosine
      phosphorylation, recruitment of p85, and DNA synthesis. In summary, after EGF
      stimulation, ErbB3, Shc, and Gab2 are differentially compartmentalized in rat
      liver, where they associate with and activate PI3K. Our data demonstrate that
      Gab2 mediates EGF-induced PI3K activation and DNA synthesis in a PH domain
      independent manner.

PMID- 12595576
TI  - Microtransplantation of membranes from cultured cells to Xenopus oocytes: a
      method to study neurotransmitter receptors embedded in native lipids.
AB  - The Xenopus oocyte is used as a convenient cell expression system to study the
      structure and function of heterogenic transmitter receptors and ion channels.
      Recently, we introduced a method to microtransplant already assembled
      neurotransmitter receptors from the human brain to the plasma membrane of Xenopus
      oocytes. The same approach was used here to transplant neurotransmitter receptors
      expressed from cultured cells to the oocytes. Membrane vesicles prepared from a
      human embryonic kidney cell line (HEK293) stably expressing the rat glutamate
      receptor 1 were injected into oocytes, and, within a few hours, the oocyte plasma
      membrane acquired alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type
      glutamate receptors, which had the same properties as those expressed in the
      original HEK cells. Analogously, oocytes injected with membranes prepared from
      rat pituitary GH(4)C1 cells, stably expressing homomeric human neuronal alpha 7
      nicotinic acetylcholine receptors (alpha 7-AcChoRs), incorporated in their plasma
      membrane AcChoRs that behaved as those expressed in GH(4)C1 cells. Similar
      results were obtained with HEK cells stably expressing heteromeric human neuronal
      alpha 4 beta 2-AcChoRs. All this makes the Xenopus oocyte a powerful tool for
      detailed investigations of receptors and other proteins expressed in the membrane
      of cultured cells.

PMID- 12595577
TI  - A splice variant of the G protein beta 3-subunit implicated in disease states
      does not modulate ion channels.
AB  - A single-nucleotide polymorphism (C825T) in the GNB3 gene produces an alternative
      splice variant of the heterotrimeric G protein beta3 subunit (Gbeta3).
      Translation of the alternatively spliced mRNA results in a protein product,
      Gbeta3-s, in which 41 amino acids are deleted from Gbeta3. Interestingly,
      previous studies indicate that the C825T allele occurs with a high frequency in
      patients with certain vascular disorders. However, little information is
      available regarding the functional role Gbeta3-s might play in ion channel
      modulation. To examine this aspect, Gbeta3 or Gbeta3-s, along with either Ggamma2
      or Ggamma5, were expressed in rat sympathetic neurons by nuclear microinjection
      of vector encoding the desired protein. In contrast to Gbeta3, expression of
      Gbeta3-s did not modulate N-type Ca(2+) or G protein-gated inwardly rectifying
      K(+) channels. In addition, Gbeta3-s did not appear to complex with a pertussis
      toxin-insensitive mutant of Galpha(i2) or couple to natively expressed alpha(2)
      adrenergic receptors. Finally, fluorescence resonance energy transfer (FRET)
      measurements indicated that enhanced yellow fluorescent protein (EYFP)-labeled
      Gbeta3-s does not form a Gbetagamma heterodimer when coexpressed with enhanced
      cyan fluorescent protein (ECFP)-labeled Ggamma2. Therefore, when expressed in
      sympathetic neurons, Gbeta3-s appears to lack biological activity--hence
      pathological conditions in patients carrying the homozygous C825T allele may
      result from a functional knockout of Gbeta3.

PMID- 12595578
TI  - Increasing the efficiency of fuzzy logic-based gene expression data analysis.
AB  - DNA microarray technology can accommodate a multifaceted analysis of the
      expression of genes in an organism. The wealth of spatiotemporal data generated
      by this technology allows researchers to potentially reverse engineer a
      particular genetic network. "Fuzzy logic" has been proposed as a method to
      analyze the relationships between genes and help decipher a genetic network. This
      method can identify interacting genes that fit a known "fuzzy" model of gene
      interaction by testing all combinations of gene expression profiles. This paper
      introduces improvements made over previous fuzzy gene regulatory models in terms
      of computation time and robustness to noise. Improvement in computation time is
      achieved by using a cluster analysis as a preprocessing method to reduce the
      total number of gene combinations analyzed. This approach speeds up the algorithm
      by a factor of 50% with minimal effect on the results. The model's sensitivity to
      noise is reduced by implementing appropriate methods of "fuzzy rule aggregation"
      and "conjunction" that produce reliable results in the face of minor changes in
      model input.

PMID- 12595579
TI  - Abnormal contractile activity and calcium cycling in cardiac myocytes isolated
      from DMPK knockout mice.
AB  - Dysfunction of the gene encoding DMPK (myotonic dystrophy protein kinase) has
      been implicated in the human neuromuscular disease myotonic dystrophy (DM1). The
      cardiac features of the disease include progressive conduction defects and
      ventricular arrhythmias. These defects have been observed in hearts of mice
      deficient for DMPK function. We have investigated the role of DMPK in the
      function of ventricular cardiomyocytes using dmpk knockout (KO) mice. A deficit
      in DMPK caused enhanced basal contractility of single cardiomyocytes and an
      associated increase in intracellular Ca(2+), measured using fura-2. Biochemical
      measurements indicated hyperphosphorylation of phospholamban (PLB) in KO mice.
      This suggests increased Ca(2+) uptake into the sarcoplasmic reticulum (SR) as the
      underlying cause of enhanced contractility. This conclusion was supported by the
      larger amplitude of caffeine-induced Ca(2+) release from the SR in KO
      cardiomyocytes. Concurrent with hyperphosphorylated PLB, the response to
      isoprenaline was reduced. These observations suggest dmpk has a modulatory role
      in the control of intracellular Ca(2+) concentration in mouse ventricular
      cardiomyocytes, loss of which may contribute to cardiac dysfunction in DM1.

PMID- 12595580
TI  - Age-related impairment of the transcriptional responses to oxidative stress in
      the mouse heart.
AB  - To investigate the transcriptional response to oxidative stress in the heart and
      how it changes with age, we examined the cardiac gene expression profiles of
      young (5-mo-old), middle-aged (15-mo-old), and old (25-mo-old) C57BL/6 mice
      treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were
      killed at 0, 1, 3, 5, and 7 h after paraquat treatment, and the gene expression
      profile was obtained with high-density oligonucleotide microarrays. Of 9,977
      genes represented on the microarray, 249 transcripts in the young mice, 298
      transcripts in the middle-aged mice, and 256 transcripts in the old mice
      displayed a significant change in mRNA levels (ANOVA, P < 0.01). Among these, a
      total of 55 transcripts were determined to be paraquat responsive for all age
      groups. Genes commonly induced in all age groups include those associated with
      stress, inflammatory, immune, and growth factor responses. Interestingly, only
      young mice displayed a significant increase in expression of all three isoforms
      of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate
      early response genes (IEGs) found to be induced by paraquat was considerably
      higher in the younger animals. These results demonstrate that, at the
      transcriptional level, there is an age-related impairment of specific inducible
      pathways in the response to oxidative stress in the mouse heart.

PMID- 12595581
TI  - The antioxidant milieu at asthmatic respiratory tract surfaces.

PMID- 12595582
TI  - Learning, memory, and transcription factors.
AB  - Cognitive disorders in children have traditionally been described in terms of
      clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or
      neuropathology. Relatively little is known about how these disorders affect the
      chemical reactions involved in learning and memory. Experiments in fruit flies,
      snails, and mice have revealed some highly conserved pathways that are involved
      in learning, memory, and synaptic plasticity, which is the primary substrate for
      memory storage. These can be divided into short-term memory storage through local
      changes in synapses, and long-term storage mediated by activation of
      transcription to translate new proteins that modify synaptic function. This
      review summarizes evidence that disruptions in these pathways are involved in
      human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry
      syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down
      syndrome, X-linked alpha-thalassemia/mental retardation, cretinism, Huntington
      disease, and lead poisoning.

PMID- 12595583
TI  - Antioxidants and oxidative stress in BAL fluid of atopic asthmatic children.
AB  - Earlier studies in adults have indicated that increased oxidative stress may
      occur in the blood and airways of asthmatic subjects. Therefore the aim of this
      study was to compare the concentrations of antioxidants and protein carbonyls in
      bronchoalveolar lavage fluid of clinically stable atopic asthmatic children (AA,
      n = 78) with our recently published reference intervals for nonasthmatic children
      (C, n = 124). Additionally, lipid peroxidation products (malondialdehyde) in
      bronchoalveolar lavage fluid and several antioxidants in plasma were determined.
      Bronchoalveolar lavage concentrations (median and interquartile range) of
      ascorbate [AA: 0.433 (0.294-0.678) versus C: 0.418 (0.253-0.646) micromol/L],
      urate [AA: 0.585 (0.412-0.996) versus C: 0.511 (0.372-0.687) micromol/L], alpha
      tocopherol [AA: 0.025 (0.014-0.031) versus C: 0.017 (0.017-0.260) micromol/L],
      and oxidized proteins as reflected by protein carbonyls [AA: 1.222 (0.970-1.635)
      versus C: 1.243 (0.813-1.685) nmol/mg protein] were similar in both groups (p >
      0.05 in all cases). The concentration of protein carbonyls correlated
      significantly with the number of eosinophils, mast cells, and macrophages in AA
      children only. Concentrations of oxidized proteins and lipid peroxidation
      products (malondialdehyde) correlated significantly in AA children (r = 0.614, n
      = 11, p = 0.044). Serum concentrations of ascorbate, urate, retinol, alpha
      tocopherol, beta-carotene, and lycopene were similar in both groups whereas alpha
      carotene was significantly reduced in asthmatics. Overall, increased
      bronchoalveolar lavage eosinophils indicate ongoing airway inflammation, which
      may increase oxidatively modified proteins as reflected by increased protein
      carbonyl concentrations.

PMID- 12595584
TI  - von Willebrand factor and its propeptide in children with diabetes. Relation
      between endothelial dysfunction and microalbuminuria.
AB  - It has been shown that patients with insulin-dependent diabetes mellitus have
      elevated von Willebrand factor (vWF) plasma concentrations. Plasma fibrinogen,
      vWF, and its propeptide concentrations have been evaluated in 102 children with
      insulin-dependent diabetes mellitus to determine whether an increase of vWF and
      its propeptide levels precedes and may predict the development of persistent
      microalbuminuria. The patients have been divided into two groups according to the
      presence or absence of microalbuminuria at the end of follow-up. They have been
      followed up for at least 8 y. Control group consisted of 80 age- and sex-matched
      healthy volunteers. At the beginning of the study there was no significant
      difference in fibrinogen, vWF, and its propeptide levels between patients and
      control subjects. During the follow-up, a significant increase of plasma vWF and
      its propeptide has been observed in the group of patients who later developed
      microalbuminuria but not in those who remained normoalbuminuric. This increase
      started 3 y and become statistically significant (p < 0.01) 2 y before the onset
      of microalbuminuria, persisting until the end of the study. During the entire
      follow-up plasma values of fibrinogen persisted in the normal range. In
      conclusion, an increase in plasma concentration of vWF and its propeptide
      precedes microalbuminuria and, therefore, can be useful to identify children with
      insulin-dependent diabetes mellitus at risk to develop incipient nephropathy
      later in life.

PMID- 12595585
TI  - Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare
      patient subgroup.
AB  - Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase,
      presents with a wide spectrum of manifestations. Although Gaucher disease has
      been divided into three clinical types, patients with atypical presentations
      continue to be recognized. A careful phenotypic and genotypic assessment of
      patients with unusual symptoms may help define factors that modify phenotype in
      this disorder. One such example is a rare subgroup of patients with type 3
      Gaucher disease who develop progressive myoclonic epilepsy. We evaluated 16
      patients with myoclonic epilepsy, nine of whom were diagnosed by age 4 y with
      severe visceral involvement and myoclonus, and seven with a more chronic course,
      who were studied between ages 22 and 40. All of the patients had abnormal
      horizontal saccadic eye movements. Fourteen different genotypes were encountered,
      yet there were several shared alleles, including V394L (seen on two alleles),
      G377S (seen on three alleles), and L444P, N188S, and recombinant alleles (each
      found on four alleles). V394L, G377S, and N188S are mutations that have
      previously been associated with non-neuronopathic Gaucher disease. The spectrum
      of genotypes differed significantly from other patients with type 3 Gaucher
      disease, where genotypes L444P/L444P and R463C/null allele predominated. Northern
      blot studies revealed a normal glucocerebrosidase transcript, whereas Western
      studies showed that the patients studied lacked the processed 56 kD isoform of
      the enzyme, consistent with neuronopathic Gaucher disease. Brain autopsy samples
      from two patients demonstrated elevated levels of glucosylsphingosine, a toxic
      glycolipid, which could contribute to the development of myoclonus. Thus,
      although there were certain shared mutant alleles found in these patients, both
      the lack of a shared genotype and the variability in clinical presentations
      suggest that other modifiers must contribute to this rare phenotype.

PMID- 12595586
TI  - Verbal dyspraxia and galactosemia.
AB  - Classical galactosemia is an autosomal recessive disorder resulting from
      deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal
      dyspraxia is an unusual outcome in galactosemia. Here we validated a simplified
      breath test of total body galactose oxidation against genotype and evaluated five
      potential biochemical risk indicators for verbal dyspraxia in galactosemia:
      cumulative percentage dose (CUMPCD) of (13)CO(2) in breath, mean erythrocyte
      galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary
      galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with
      galactosemia took a (13)C-galactose bolus, and the (CUMPCD) of (13)CO(2) in
      expired air was determined. Patients with <5% CUMPCD had mutant alleles that
      severely impaired human GALT enzyme catalysis. Patients with > or =5% CUMPCD had
      milder mutant human GALT alleles. Twenty-four patients consented to formal speech
      evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly
      lower CUMPCD values (2.84 +/- 5.76% versus 11.51 +/- 7.67%; p < 0.008) and
      significantly higher mean erythrocyte galactose-1-phosphate (3.38 +/- 0.922 mg/dL
      versus 1.92 +/- 1.28 mg/dL; p = 0.019) and mean urinary galactitol concentrations
      (192.4 +/- 75.8 mmol/mol creatinine versus 122.0 +/- 56.4; p = 0.048) than
      patients with normal speech. CUMPCD values <5%, mean erythrocyte galactose-1
      phosphate levels >2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol
      creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and
      5, respectively. We conclude that total body oxidation of galactose to CO(2) in
      expired air reflects genotype and that this breath test is a sensitive predictor
      of verbal dyspraxia in patients with galactosemia.

PMID- 12595587
TI  - Relation of streptococcal pyrogenic exotoxin C as a causative superantigen for
      Kawasaki disease.
AB  - We previously reported that the frequency of TCRBV2 and TCRBV6S5-bearing T-cells
      was high in patients in the acute phase of Kawasaki disease (KD) and that
      streptococcal pyrogenic exotoxin C (SPE-C) was a potent stimulator of these TCRBV
      bearing T-cells. To further elucidate the pathogenesis of KD, we examined the T
      cell receptor (TCR) repertoire, human leukocyte antigen (HLA)-DRB1 genotype, and
      antibody responses to recombinant(r) SPE-C in patients with KD. We also performed
      in vitro stimulation with rSPE-A and rSPE-C of peripheral blood mononuclear cells
      from healthy donors and characterized the reacting T-cells. The percentage of T
      cells bearing TCRBV2 and TCRBV6S5 was high in patients in the acute stage of KD.
      rSPE-C stimulation of PBMC from healthy donors induced expansion of TCRBV2 and
      TCRBV6S5-bearing T-cells. Furthermore, serum levels of anti-SPEC antibodies,
      which did not display antimitogenic activity, were higher in patients with acute
      KD than in age-matched controls. The frequencies of the DRB1*04051, 0406, and
      0901 were high, whereas that of the DRB1*1101 was low among patients with KD as
      compared with the healthy adults.

PMID- 12595588
TI  - Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin
      resistance in Lepr(db/+) mice.
AB  - Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM)
      pregnancy and is associated with increased risk of adult obesity and type II
      diabetes mellitus, however mechanisms linking GDM and later disease remain poorly
      understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse
      develops spontaneous GDM and the fetuses display characteristics similar to
      infants of GDM mothers. We examined the effects of GDM on maternal insulin
      resistance, fetal growth, and postnatal development of hepatic insulin
      resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p < 0.05) in
      pups from ad libitum-fed db/+ mothers compared with wild-type (WT) controls. Pair
      feeding db/+ mothers to the intake of WT mothers normalized fetal weight despite
      less than normal maternal insulin sensitivity. More stringent caloric restriction
      reduced insulin and glucose levels below WT controls and resulted in fetal
      intrauterine growth restriction. The level of hepatic insulin receptor protein
      was decreased by 28% to 31% in both intrauterine growth restriction and fetuses
      from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wk
      old adult offspring from GDM mothers, body weight was similar to WT offspring,
      however, the females from GDM mothers were fatter and hyperinsulinemic compared
      with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key
      intermediate in insulin signaling, was severely decreased in the livers of adult
      GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately
      increased in the adult offspring from GDM mothers. These results suggest that
      spontaneous GDM in the pregnant Lepr(db/+) mouse is triggered by overfeeding, and
      this effect results in obesity and insulin resistance in the livers of the adult
      offspring. The specific decrease in Akt phosphorylation in livers of adult
      offspring suggests that this may be a mechanism for reduced insulin-dependent
      physiologic events, such as suppression of hepatic glucose production, a defect
      associated with susceptibility to type II diabetes mellitus.

PMID- 12595589
TI  - Modulation of human intestinal epithelial cell IL-8 secretion by human milk
      factors.
AB  - Necrotizing enterocolitis (NEC) seems to result from the inflammatory response of
      an immature intestine. Human milk is protective against NEC via an unknown
      mechanism. We hypothesized that specific factors found in human milk would
      decrease stimulated IL-8 secretion in intestinal epithelial cells. HT29-cl19A and
      Caco2 cells were compared with the fetal human primary intestinal epithelial cell
      line H4 and temperature-sensitive conditionally immortalized fetal human
      intestinal (tsFHI) cells. Cells were pretreated with transforming growth factor
      beta (TGF-beta), erythropoietin (Epo), IL-10, or epidermal growth factor (EGF) at
      physiologic concentrations before stimulation with tumor necrosis factor-alpha
      (TNF-alpha) or IL-1beta, and then IL-8 was measured by ELISA. The fetal cells
      produced significantly more IL-8 when stimulated by TNF-alpha or IL-1beta. There
      were also differences in the pattern of alteration of IL-8 secretion by human
      milk factors. In HT29-cl19A cells, IL-10 inhibited TNF-alpha-stimulated IL-8
      secretion by 52%, and EGF increased secretion by 144%. In H4 cells, TGF-beta1 and
      Epo inhibited TNF-alpha-stimulated IL-8 secretion to control levels, and EGF
      increased secretion by 29%. IL-1beta-stimulated IL-8 secretion was inhibited 25%
      by TGF-beta1 in Caco2 cells and in H4 cells was inhibited by TGF-beta1, Epo, and
      TGF-beta2. TsFHI cells confirmed H4 cell results. Fetal human enterocytes have an
      exaggerated IL-8 secretion in response to TNF-alpha and IL-1beta. TGF-beta and
      Epo decrease this stimulated IL-8 secretion, which may partially explain the
      protective effect of human milk in NEC.

PMID- 12595590
TI  - Maternal milk reduces severity of necrotizing enterocolitis and increases
      intestinal IL-10 in a neonatal rat model.
AB  - Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature
      infants. Maternal milk has been suggested to be partially protective against NEC;
      however, the mechanisms of this protection are not defined. The aim of this study
      was to examine the effect(s) of artificial feeding of rat milk (RM)-versus cow
      milk-based rat milk substitute (RMS) on the development of NEC in a neonatal rat
      model and elucidate the role of inflammatory cytokines in NEC pathogenesis.
      Newborn rats were artificially fed with either collected RM or RMS. Experimental
      NEC was induced by exposure to asphyxia and cold stress and evaluated by
      histologic scoring of damage in ileum. Intestinal cytokine mRNA expression was
      determined by real-time PCR. Cytokine histologic localization was performed by
      confocal microscopy. Similar to human NEC, artificial feeding of RM reduces the
      incidence and severity of NEC injury in neonatal rats. Freezing and thawing of
      collected RM did not eliminate the protective effect of maternal milk. Ileal IL
      10 expression was significantly increased in the RM group compared with RMS.
      Increased IL-10 peptide production was detected in the RM group with signal
      localized predominantly in the cytoplasm of villus epithelial cells. These
      results suggest that the protective effect of maternal milk is associated with
      increased production of anti-inflammatory IL-10 in the site of injury. Better
      understanding of the mechanisms underlying these protective effects could be
      beneficial either in the prevention of NEC or in the development of future
      therapeutic strategies to cure NEC.

PMID- 12595591
TI  - Zinc as a potential enteroprotector in oral rehydration solutions: its role in
      nitric oxide metabolism.
AB  - Zinc has been recognized as an antioxidant with potential for chronic and acute
      effects. Oxidative damage produced by free radicals, including nitric oxide (NO),
      is responsible for certain types of intestinal malabsorption syndromes and
      diarrhea. Under physiologic or mildly stimulatory conditions for NO synthesis,
      the small intestine characteristically is in a proabsorptive state; however, an
      excessive production of NO triggers formation of cyclic nucleotides, which cause
      secretion and malabsorption. In this study, we hypothesized that low-molecular
      weight, soluble zinc chelates could modulate the effects of induced NO excess on
      the small intestine. In vitro experiments demonstrated that zinc-citrate or zinc
      histidine at > or =0.66 mM, as well as a known NO scavenger, 2-[carboxyphenyl]
      4,4,4,4-tetramethylimidazoline-1-oxyl-3-oxide, at 2 microM, were effective at
      removing chemically generated NO. In vivo jejunal perfusions, conducted in
      healthy rats under anesthesia, showed that c-PTIO reduced the proabsorptive
      effects produced by 1 mM L-arginine, the precursor of NO. In a standard oral
      rehydration solution, 1 mM zinc-citrate partially reversed the antiabsorptive
      effects on potassium caused by an excess of NO generated from 20 mM L-arginine
      but did not alter sodium or water absorption. The data are consistent with the
      view that soluble zinc compounds incorporated into an oral rehydration solution
      may deserve further attention as a means to scavenge NO with fluids used for the
      treatment of chronic or acute diarrhea, especially in malnourished children who
      are often zinc deficient.

PMID- 12595592
TI  - Endostatin and vascular endothelial cell growth factor (VEGF) in piglet lungs:
      effect of inhaled nitric oxide and hyperoxia.
AB  - Pulmonary hyperoxic injury manifests as widespread alveolar-epithelial and
      microvascular endothelial cell necrosis, resolution of which requires
      angiogenesis. We investigated the hypothesis that inhaled nitric oxide (iNO) and
      hyperoxia each decreases lung vascular endothelial growth factor (VEGF)
      expression but increases endostatin and that concurrent administration of both
      gases will show a greater effect. Piglets were randomized to breathe for 5 d room
      air (RA); RA + NO (RA + 50 ppm NO), O(2) (hyperoxia, F(I)O(2) >0.96), O(2) + NO,
      or O(2) + NO + REC (O(2) + NO plus recovery in 50% O(2) for 72 h. After the
      piglets were killed, we measured lung capillary leak, VEGF mRNA, VEGF, and
      endostatin protein in homogenates, plasma, and lavage. VEGF mRNA decreased
      significantly with O(2) and O(2) + NO compared with breathing RA (p < or = 0.05).
      VEGF protein declined in the experimental groups with a significant reduction in
      the recovery group compared with the RA group (p < or = 0.05). Similar but more
      dramatic, endostatin declined in all groups relative to the RA group (p < 0.001).
      Lavage fluid VEGF protein and lung capillary leak rose significantly with O(2)
      and O(2) + NO compared with RA, but endostatin was unchanged. At 72 h of recovery
      from hyperoxia, VEGF mRNA and lavage fluid VEGF but not lung VEGF protein had
      normalized. Hyperoxia and iNO suppresses lung endostatin expression, but iNO
      unlike hyperoxia alone does not alter lung VEGF production. Hyperoxia
      paradoxically raises lavageable VEGF levels. This latter effect and that on VEGF
      mRNA level but not protein is abrogated by recovery in reduced F(I)O(2) for 72 h.

PMID- 12595593
TI  - Molecular species compositions of lung and pancreas phospholipids in the
      cftr(tm1HGU/tm1HGU) cystic fibrosis mouse.
AB  - Fatty acid analysis of phospholipid compositions of lung and pancreas cells from
      a cystic fibrosis transmembrane regulator (CFTR) negative mouse (cftr(-/
      ))suggested that a decreased concentration of docosahexaenoate (22:6(n-3)) and
      increased arachidonate (20:4(n-6)) may be related to the disease process in
      cystic fibrosis (CF). Consequently, we have determined compositions of the major
      phospholipids of lung, pancreas, liver, and plasma from a different mouse model
      of CF, the cftr(tm1HGU/tm1HGU) mouse, compared with ZTM:MF-1 control mice.
      Electrospray ionization mass spectrometry permitted the quantification of all of
      the individual molecular species of phosphatidylcholine (PtdCho),
      phosphatidylethanolamine (PtdEtn), phosphatidylglycerol (PtdGly),
      phosphatidylserine (PtdSer), and phosphatidylinositol (PtdIns). There was no
      deficiency of 22:6(n-3) in any phospholipid class from lung, pancreas, or liver
      from mice with the cftr(tm1HGU/tm1HGU). Instead, the concentration of 20:4(n-6)
      was significantly decreased in plasma PtdCho species and in pancreas and lung
      species of PtdEtn, PtdSer, and PtdIns. These results demonstrate the variability
      of membrane phospholipid compositions in different mouse models of CF and suggest
      that in cftr(tm1HGU/tm1HGU) mice, the apparent deficiency was of 20:4n-6- rather
      than of 22:6n-3-containing phospholipid species. They highlight a need for
      detailed phospholipid molecular species analysis of cells expressing mutant CFTR
      from children with CF before the therapeutic effects of administering high doses
      of 22:6(n-3)-containing oils to children with CF can be fully evaluated.

PMID- 12595594
TI  - 3-Chlorotyrosine as a marker of protein damage by myeloperoxidase in tracheal
      aspirates from preterm infants: association with adverse respiratory outcome.
AB  - Oxidative injury is implicated in the development of chronic lung disease in
      preterm infants with respiratory distress. However, direct evidence of a causal
      role is limited and the source of reactive oxidants has not been identified. We
      have previously shown that protein carbonyl levels in tracheal aspirates
      correlate positively with myeloperoxidase, suggesting that neutrophil oxidants
      could be the source of this protein injury. We have extended these observations
      by measuring 3-chlorotyrosine, a specific biomarker of the neutrophil oxidant,
      hypochlorous acid, in tracheal aspirate proteins (144 samples) from 69 infants
      with birth weight <1500 g. 3-Chlorotyrosine levels were higher in these infants
      than in larger infants without respiratory distress (median 83 compared with 13
      micromol/mol tyrosine). They correlated strongly with myeloperoxidase activity
      (correlation coefficient 0.75, p < 0.0001) and to a lesser extent with protein
      carbonyls. 3-Chlorotyrosine levels (at 1 wk after birth) correlated negatively
      with birth weight or gestational age. They were significantly higher in infants
      who developed chronic lung disease (oxygen requirement at 36 wk postmenstrual
      age) than in those who did not (median 88 and 49 micromol/mol tyrosine,
      respectively) and correlated with days of supplemental oxygen. 3-Chlorotyrosine
      was also significantly higher in infants who had lung infection or were
      Ureaplasma urealyticum positive. Our results are the first evidence that
      chlorinated proteins are produced in the lungs of premature infants and that they
      are higher in infection. The higher 3-chlorotyrosine levels in infants who
      develop chronic lung disease suggest that neutrophil oxidants contribute to the
      pathology of this disease.

PMID- 12595595
TI  - In vivo measurements of changes in respiratory mechanics with age in mice
      deficient in surfactant protein D.
AB  - Mice deficient in surfactant protein D [SP-D (-/-)] develop progressive emphysema
      with age, associated with loss of parenchymal tissue, subpleural fibrosis, and
      accumulation of abnormal elastin fibers. We measured the changes in lung
      function, partitioned into components for the airways and lung parenchyma,
      occurring with age in SP-D (-/-) mice at three ages (n = 8 per group) (5, 8, and
      13 wk). Impedance spectra between 0.25 and 19.625 Hz were calculated and a model,
      consisting of an airway compartment [airway resistance (Raw) and inertance (Iaw)]
      and a constant-phase tissue compartment [coefficients of tissue damping (G) and
      elastance (H)], was fitted to the data. Hysteresivity was calculated as G/H.
      Adult values of Raw, G, and H are reached by 8 wk of age in wild-type controls.
      Raw and H were lower at all ages in SP-D (-/-) compared with the wild-type
      controls (p = 0.006 and 0.029, respectively), and a similar trend was seen in G
      (p = 0.060). The patterns of change in respiratory mechanics were similar in both
      SP-D (+/+) and (-/-) groups. There were no changes in hysteresivity with age and
      no differences between wild-type and SP-D (-/-) mice. These data demonstrate that
      the changes in lung structure in SP-D (-/-) mice are reflected in the mechanical
      properties of both airway and lung parenchyma measured in vivo.

PMID- 12595596
TI  - Effects of high PCO2 on ventilated preterm lamb lungs.
AB  - High PCO(2) levels attenuate reperfusion injury and ventilation-induced injury in
      isolated and perfused lungs. We asked whether premature lambs could tolerate 6 h
      of ventilation with a PCO(2) >80 mm Hg and whether the high PCO(2) modulated the
      ventilator-induced injury. Preterm surfactant-treated lambs were ventilated for
      30 min with a high tidal volume (V(T)) to induce lung injury. The lambs then were
      ventilated for 5.5 h with a V(T) of 6-9 mL/kg to achieve a PCO(2) of 40-50 mm Hg
      in the control group. CO(2) was added to the ventilator circuit of a high PCO(2)
      group to maintain an average PCO(2) of 95 +/- 5 mm Hg. The high PCO(2) lambs had
      heart rates, blood pressures, plasma cortisol values, and oxygenation equivalent
      to the control lambs. The lungs of the high PCO(2) group had significantly higher
      gas volumes and had less lung injury by histopathology. Indicators of
      inflammation (white blood cells, hydrogen peroxide production, and IL-1beta and
      IL-8 cytokine mRNA expression in cells from the alveolar wash) qualitatively
      indicated less injury in the high PCO(2) group, although the differences were not
      significant. Preterm lambs tolerated a very high PCO(2) without physiologic
      compromise for 6 h. The high PCO(2) may attenuate ventilator-induced lung injury
      in the preterm.

PMID- 12595597
TI  - Asphyxia aggravates systemic hypotension but not pulmonary hypertension in
      piglets with meconium aspiration.
AB  - Meconium aspiration and birth asphyxia are both separately connected to
      significant pulmonary and systemic hemodynamic changes in newborns, but, although
      these insults frequently coexist, their combined effects on the neonatal
      circulation are still controversial. To determine the pulmonary and systemic
      circulatory changes induced by pulmonary meconium contamination with concurrent
      asphyxia, 41 anesthetized and ventilated newborn piglets (10-12 d) were studied
      for 6 h. Eleven piglets were instilled with a bolus of human meconium
      intratracheally, and 10 piglets had meconium instillation with immediate
      induction of an asphyxic insult. Eight piglets had only asphyxia and 12
      ventilated piglets served as controls. Meconium instillation (with and without
      asphyxia) resulted in a sustained decrease in the oxygenation, which remained,
      however, on the control level in the asphyxic group. Although meconium
      insufflation (with and without asphyxia) increased pulmonary artery pressure and
      vascular resistance progressively during the study period, the meconium-induced
      hypertensive effect was actually diminished by additional asphyxia. Asphyxia
      alone did not have any effect on these pulmonary hemodynamic parameters. On the
      other hand, whereas systemic arterial pressure and vascular resistance remained
      on the control level after meconium instillation alone, asphyxia (with and
      without pulmonary meconium insult) resulted in a sustained fall in systemic
      pressure already by 4 h. Our data thus indicate that although the coexisting
      asphyxia seems to moderate the meconium aspiration-induced pulmonary hypertensive
      response, this additional asphyxic insult does not affect the associated
      hypoxemia, but rather significantly exacerbates systemic hypotension.

PMID- 12595598
TI  - Inhibition of in vivo constriction of fetal ductus arteriosus by endothelin
      receptor blockade in rats.
AB  - The fetal ductus can be constricted by drugs, including cyclooxygenase inhibitors
      (indomethacin), nitric oxide synthesis antagonists [N-nitro-L-arginine monomethyl
      ester (L-NAME)], and glucocorticoid hormones (dexamethasone). Constriction of the
      fetal ductus by endothelin (ET) 1 was reported in an in vitro study. We studied
      the preventive effect of a dual ET receptor antagonist (bosentan) and a selective
      ET-A blocker (CI-1020) on pharmacologic fetal ductal constriction in rats. Near
      term pregnant Wistar rats at d 21 and preterm rats at d 19 were used. The fetal
      ductus was constricted by four medications: orogastric administration of
      indomethacin (10 mg/kg) on fetal d 21, orogastric indomethacin 1 mg/kg combined
      with muscular injection of L-NAME (10 mg/kg) on fetal d 21, and muscular
      injection of L-NAME or dexamethasone (1 mg/kg) on fetal d 19. Bosentan (0.1, 1,
      10, or 100 mg/kg) was injected intraperitoneally either simultaneously with
      indomethacin, L-NAME, or dexamethasone, or 4 h after administration of 10 mg/kg
      indomethacin. CI-1020 (0.01, 0.1, 1, or 10 mg/kg) was injected intraperitoneally
      simultaneously with indomethacin. After maternal atlas dislocation, cesarean
      section, fetal whole-body freezing, and cutting on the freezing microtome,
      measurements were made of the inner diameters of the ductus, main pulmonary
      artery, and ascending aorta. Bosentan blocked fetal ductal constriction by
      indomethacin, indomethacin plus L-NAME in the near-term rats, and constriction by
      L-NAME and dexamethasone in the preterm rats dose dependently. Fetal ductal
      constriction was nearly completely blocked by simultaneously administered 100
      mg/kg of bosentan or 10 mg/kg of CI-1020. Dual ET receptor antagonist (bosentan)
      and selective ET-A blocker (CI-1020) prevent constriction of the fetal ductus
      arteriosus induced by ductus-constricting agents in rats, indicating that ET and
      ET-A receptors are essential in fetal ductal constriction.

PMID- 12595599
TI  - A new air displacement plethysmograph for the measurement of body composition in
      infants.
AB  - ABSTRACT This article introduces and evaluates the PEA POD Infant Body
      Composition System, an air displacement plethysmograph designed for the
      assessment of body composition in infants between birth and 6 mo of age. The
      performance of the PEA POD was evaluated by repeated testing of National
      Institute of Standards and Technology-traceable weights and volumes. Mass was
      measured in a single session. Volume was measured in four sessions during a 2-d
      period (five times/session for both). The mean values for repeated mass
      measurements were almost identical to the masses of traceable weights. The SD and
      CV for repeated volume measurements were 1.1-4.5 mL and 0.02-0.09%, respectively.
      Both the mean SD and CV were within very narrow ranges (1.4-3.1 mL for SD and
      0.03-0.08% for CV) across all volume levels. Furthermore, mean CV values using
      results from the four sessions indicated excellent within- and between-day
      reliability. Regression analyses (by session or with all sessions combined) of
      the measured volume against actual volume gave very low standard error of the
      estimate (SEE) (0.853-1.957 mL) and very high R(2) (1.000), with the intercept
      and slope not significantly different from 0 and 1, respectively. The mean
      percentage error in volume measurements was < or =0.05% at all volume levels. The
      study findings and the operational and physical characteristics of the system
      indicate that the PEA POD has the potential to provide clinicians and researchers
      with a diagnostic and research tool that is accurate, easily used by operators,
      and comfortable for subjects.

PMID- 12595600
TI  - Age-related differences in the direct cardiac effects of cisapride: narrower
      safety range in the hearts of young rabbits.
AB  - Although cisapride is widely used to treat gastrointestinal motility disorders,
      it has been associated with QT prolongation, torsades de pointes, and cardiac
      arrest. Only in children, however, has atrioventricular (AV) block after
      cisapride been reported. This study used Langendorff perfusion to determine the
      direct effects of cisapride (0.03, 0.1, 0.3, and 1 microM) on the conduction
      properties of neonatal (<7 d) and adult (>3 mo) rabbit hearts. At a clinically
      relevant dose (0.03 microM), cisapride slowed the recovery of the His-Purkinje
      system. At 0.1 microM, the refractoriness of the His-Purkinje system and
      conduction through this system were prolonged. Corrected QT intervals and the
      ventricular refractory period were also lengthened. These parameters were
      significantly more prolonged in neonates than in adults. The level of AV block at
      rapid atrial pacing shifted from the AV node to the His-Purkinje system, with an
      ED(50) of 0.06 and 0.52 microM in the neonate and the adult, respectively. In the
      neonate, cisapride even resulted in infranodal AV block rhythm (ED50 = 0.12
      microM), but this was not the case in the adult. Polymorphic ventricular
      tachycardia after cisapride was induced in one in seven neonates (14%;, 0.1
      microM) and in one in seven adults (14%; 0.03 microM). It is concluded that
      cisapride may affect the refractoriness of cardiac tissue and that the His
      Purkinje system seems to be the most sensitive. In neonatal hearts, this
      modification may, in fact, progress to infranodal AV block. Such susceptibility
      to cisapride strongly indicates that the therapeutic safety range used for the
      young heart should be narrowed.

PMID- 12595601
TI  - Perinatal cocaine exposure stimulates the expression and activation of CREB in
      the neonatal rat heart.
AB  - cAMP response binding protein (CREB) is a transcriptional factor known to
      regulate gene expression. Phosphorylation of CREB at serine 133 is necessary for
      CREB activation, and quantification of phospho-CREB (p-CREB) expression is an
      index of CREB activation. Because CREB expression and activation in specific
      brain regions are modified after chronic cocaine administration, we sought to
      determine whether chronic perinatal cocaine exposure affects the expression of
      CREB and p-CREB in the postnatal rat heart. Pregnant rats were treated daily with
      saline (control) or cocaine at 20 mg/kg (C20) or 60 mg/kg (C60) by intragastric
      administration throughout gestation. The expression of total CREB and p-CREB was
      quantified in nuclear extracts isolated from 1- and 7-d-old neonatal rat hearts.
      Cardiac nuclear p-CREB was increased in the C20 and C60 groups on d 1 and 7 of
      age compared with their respective age-matched control groups. The increase in p
      CREB expression corresponded to an increase in cAMP response element binding
      activity. We also assayed nuclear protein kinase A activity, which was up
      regulated in d 1 animals with prenatal cocaine exposure, but was comparable in
      all groups at d 7. Our results suggest that perinatal cocaine exposure stimulates
      CREB activation in the neonatal heart, and it may be mediated by different
      mechanisms at d 1 and d 7. The changes in myocardial CREB activation induced by
      perinatal cocaine exposure are likely to result in modified gene expression in
      the neonatal heart that may account for the cardiac dysfunction reported in human
      neonates born to cocaine-abusing mothers.

PMID- 12595602
TI  - 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular
      biology of the anemia of chronic disease: a hypothesis.
AB  - The anemia of chronic disease is a common disorder that afflicts patients with a
      wide variety of inflammatory conditions including arthritis, malignancies,
      infections, and inflammatory bowel disease. It results in significant morbidity
      and may be severe enough to require blood transfusions. The pathogenesis of
      anemia of chronic disease is not fully understood, but poor maintenance of red
      blood cell mass has been observed at three levels: 1) iron is not efficiently
      recycled from reticuloendothelial macrophages to erythroid precursors, 2)
      erythroid precursors respond poorly to erythropoietin, and 3) red blood cell
      survival is decreased. Whether each of these changes is related to the same
      effector of the inflammatory process is unknown. We have had the opportunity to
      investigate severe anemia of chronic disease in an unusual group of patients with
      glycogen storage disease type 1a. We found that anemia was directly related to
      the presence of large hepatic adenomas that inappropriately produced a new
      peptide hormone, hepcidin. Hepcidin has recently been identified as part of the
      innate immune response and is a key regulator of cellular iron egress. Based on
      our findings in this patient group, we propose a central role for hepcidin in
      anemia of chronic disease, linking the inflammatory process with iron recycling
      and erythropoiesis. We present a hypothesis based on our findings.

PMID- 12595603
TI  - Society for Pediatric Research Presidential Address 2002: first principles.

PMID- 12595604
TI  - American Pediatric Society Presidential Address 2002: the third third.

PMID- 12595606
TI  - Who was John Howland and why was an award named after him 50 years ago?

PMID- 12595607
TI  - American Pediatric Society John Howland Award 2002: presentation.

PMID- 12595608
TI  - American Pediatric Society John Howland Award 2002: acceptance.

PMID- 12595609
TI  - The effects of Cenozoic global change on squirrel phylogeny.
AB  - By modifying habitats and creating bridges and barriers between landmasses,
      climate change and tectonic events are believed to have important consequences
      for diversification of terrestrial organisms. Such consequences should be most
      evident in phylogenetic histories of groups that are ancient, widespread, and
      diverse. The squirrel family (Sciuridae) is one of very few mammalian families
      endemic to Eurasia, Africa, and North and South America and is ideal for
      examining these issues. Through phylogenetic and molecular-clock analyses, we
      infer that arrival and diversification of squirrels in Africa, on Sunda Shelf
      islands, across Beringea, and across the Panamanian isthmus coincide in timing
      and location with multiple well-documented sea-level, tectonic, and
      paleontological events. These precise correspondences point to an important role
      for global change in the diversification of a major group of mammals.

PMID- 12595610
TI  - Small-diameter silicon nanowire surfaces.
AB  - Small-diameter (1 to 7 nanometers) silicon nanowires (SiNWs) were prepared, and
      their surfaces were removed of oxide and terminated with hydrogen by a
      hydrofluoric acid dip. Scanning tunneling microscopy (STM) of these SiNWs,
      performed both in air and in ultrahigh vacuum, revealed atomically resolved
      images that can be interpreted as hydrogen-terminated Si (111)-(1 x 1) and Si
      (001)-(1 x 1) surfaces corresponding to SiH3 on Si (111) and SiH2 on Si (001),
      respectively. These hydrogen-terminated SiNW surfaces seem to be more oxidation
      resistant than regular silicon wafer surfaces, because atomically resolved STM
      images of SiNWs were obtained in air after several days' exposure to the ambient
      environment. Scanning tunneling spectroscopy measurements were performed on the
      oxide-removed SiNWs and were used to evaluate the electronic energy gaps. The
      energy gaps were found to increase with decreasing SiNW diameter from 1.1
      electron volts for 7 nanometers to 3.5 electron volts for 1.3 nanometers, in
      agreement with previous theoretical predictions.

PMID- 12595611
TI  - Telephone helplines in rheumatology.

PMID- 12595612
TI  - Central nervous system involvement in the antiphospholipid (Hughes) syndrome.
AB  - The antiphospholipid (Hughes) syndrome (APS) is characterized by arterial and/or
      venous thrombosis and pregnancy morbidity in the presence of anticardiolipin
      antibodies and/or lupus anticoagulant. APS can occur either as a primary disorder
      or secondary to a connective tissue disease, most frequently systemic lupus
      erythematosus. Central nervous system (CNS) involvement is one of the most
      prominent clinical manifestations of APS, and includes arterial and venous
      thrombotic events, psychiatric features and a variety of other non-thrombotic
      neurological syndromes. In this review we focus on the common and some of the
      less common CNS manifestations that have been reported in association with
      antiphospholipid antibodies.

PMID- 12595613
TI  - Pathological lymphocyte activation by defective clearance of self-ligands in
      systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is one of the autoimmune diseases extensively
      studied by immunologists and physicians. The main focus regarding SLE
      pathophysiology has been placed on abnormal cell surface receptor function on
      lymphocytes. However, recent studies have revealed that defective clearance of
      apoptotic cells causes self-antigen accumulation, which could trigger the
      activation of autoreactive lymphocytes. Thus, here we review current findings
      about the association of the defective clearance of autoantigens and SLE,
      focusing on mutations in the DNase I locus and their relationship to SLE.

PMID- 12595614
TI  - Prevalence of antineutrophil cytoplasmic autoantibodies in patients with
      tuberculosis.
AB  - OBJECTIVE: To determine the prevalence of antineutrophil cytoplasmic
      autoantibodies (ANCA) in sera of patients with tuberculosis compared with healthy
      control subjects and a group of patients with atopic asthma. METHODS: The
      presence of ANCA was examined in patients with tuberculosis, and in asthmatic
      patients and healthy subjects as control groups, by means of indirect
      immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to detect
      anti-proteinase 3 (PR3-ANCA) and antimyeloperoxidase (MPO-ANCA) antibodies.
      RESULTS: ANCA were present in 20 (44.4%) of 45 tuberculosis patients by IIF (16 c
      ANCA, four p-ANCA) and in 18 (40%) patients by ELISA (15 PR3-ANCA, three MPO
      ANCA). High odds ratios for ANCA positivity were observed for tuberculosis
      patients when compared with both control groups. ANCA results were not related to
      the category of tuberculosis, stage of disease, presence of concomitant diseases
      or pharmacotherapy. CONCLUSIONS: As many clinical similarities between
      tuberculosis and Wegener's granulomatosis exist, we propose that a positive ANCA
      test in patients living in countries with a high prevalence of tuberculosis must
      be carefully interpreted as indicative of systemic vasculitis, especially when no
      signs of extrapulmonary involvement occur.

PMID- 12595615
TI  - Prevalence, patterns of disease and outcome in patients with systemic lupus
      erythematosus who develop severe haematological problems.
AB  - OBJECTIVE: To evaluate the prevalence of major haemolytic disease-severe
      autoimmune haemolytic anaemia and severe thrombocytopenia-and to assess when
      these features develop. We also sought to analyse the clinical and serological
      outcomes of patients with haemolytic anaemia and thrombocytopenia with systemic
      lupus erythematosus (SLE) as compared with patients without these cytopenias.
      METHODS: We reviewed retrospectively all the available case notes from our lupus
      cohort of 305 patients followed up between 1978 and 2000 (mean follow-up 7 yr).
      We identified 30 patients with SLE (9.8%), of whom 20 (6.6%) had severe
      haemolytic anaemia and 10 (3.3%) had severe thrombocytopenia. Each patient was
      matched for age, sex and ethnicity with two control patients. RESULTS: We
      recorded a total of 42 episodes of severe haematological events: four patients
      had a second haemolytic episode and eight patients had a second thrombocytopenic
      episode. Five patients had both thrombocytopenia and haemolytic anaemia. One per
      cent of patients had severe haemolytic anaemia prior to the diagnosis of SLE and
      2.5% of patients presented with these haematological disorders. Haemolytic
      anaemia and thrombocytopenia were associated with renal involvement
      (0.01>P>0.001) and anticardiolipin antibodies (ACL) (0.01>P>0.001), but not anti
      dsDNA antibodies. Calculation of the BILAG index at the time of severe
      haematological crisis demonstrated that renal, central nervous system involvement
      and general symptoms are more frequently present. Forty-one per cent of patients
      were already on either prednisolone (<10 mg) or an immunosuppressive agent at the
      onset of the event. CONCLUSION: Our data demonstrate that both haemolytic anaemia
      and thrombocytopenia are associated with ACL but not anti-dsDNA antibodies. When
      faced with a patient with a severe haematological manifestation of lupus, active
      disease in other organs is likely to be present.

PMID- 12595616
TI  - Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion
      protein, and case study of anti-tumour necrosis factor receptor superfamily 1A
      fusion protein, in tumour necrosis factor receptor associated periodic syndrome
      (TRAPS): clinical and laboratory findings in a series of seven patients.
AB  - OBJECTIVE: To assess the effects prospectively of tumour necrosis factor (TNF)
      receptor superfamily (TNFRSF) fusion proteins TNFRSF1B (etanercept) and TNFRSF1A
      (p55TNFr-Ig) in patients with TNF receptor associated periodic syndrome (TRAPS).
      METHODS: Seven patients with a clinical and genetic diagnosis of TRAPS received
      subcutaneous etanercept for 24 weeks. One of these patients had previously
      received an intravenous infusion of p55TNFr-Ig. Therapeutic response was assessed
      by comparing corticosteroid requirement, acute-phase response and an established
      scoring system over 20 weeks, both on and off etanercept. RESULTS: Etanercept was
      well tolerated. The five corticosteroid-responsive patients required
      significantly less corticosteroids and demonstrated reductions in acute-phase
      reactants on etanercept. The two patients not requiring corticosteroids had small
      reductions in disease activity scores. The effect of p55TNFr-Ig in a single
      patient with TRAPS remains unclear. CONCLUSIONS: Etanercept does not abolish
      inflammatory attacks but improves disease activity allowing corticosteroid
      reduction. Etanercept may be clinically useful in replacing or reducing steroid
      requirements in the treatment of TRAPS. A formal trial of etanercept to establish
      its role in clinical management is indicated.

PMID- 12595617
TI  - Plasma plasmin-alpha2-plasmin inhibitor complex levels are increased in systemic
      sclerosis patients with pulmonary hypertension.
AB  - OBJECTIVE: To determine the frequency and clinical significance of plasma plasmin
      alpha(2)-plasmin inhibitor complex (PIC) in patients with systemic sclerosis
      (SSc). METHODS: Plasma samples from 74 patients with SSc and 32 healthy
      volunteers were examined by a specific enzyme-linked immunosorbent assay.
      RESULTS: Elevated plasma PIC levels were present in 35 of the 74 patients (47.3%)
      with SSc. The patients with elevated plasma PIC levels had pulmonary hypertension
      (PH) at a significantly higher incidence than those with normal PIC levels (31.4
      vs 7.7%, P<0.01). When PH was classified into isolated PH (IPH) and secondary PH
      (SPH), the presence of IPH was significantly greater in patients with elevated
      PIC levels than in those with normal levels (25.7 vs 5.1%, P<0.02). CONCLUSIONS:
      These results suggest that plasma PIC levels may be a marker of PH, especially
      IPH, in patients with SSc.

PMID- 12595618
TI  - A simplified disease activity index for rheumatoid arthritis for use in clinical
      practice.
AB  - OBJECTIVE: The objective of this study was to verify the usefulness of a simple
      disease activity index (SDAI) for rheumatoid arthritis (RA). METHODS: The SDAI is
      the numerical sum of five outcome parameters: tender and swollen joint count
      (based on a 28-joint assessment), patient and physician global assessment of
      disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive
      protein (mg/dl, normal <1 mg/dl). Analysis initially focused on MN301, one of the
      three phase III clinical trials of leflunomide, in order to assess possible
      correlations between the SDAI and the Health Assessment Questionnaire (HAQ) and
      Disease Activity Score 28 (DAS 28). Results were then compared with the other two
      trials, MN302 and US301. A total of 1839 patients were evaluated. At baseline, 6
      and 12 months, the SDAI, DAS 28, American College of Rheumatology (ACR) response
      criteria and mean HAQ scores were determined for each patient and compared by
      linear regression for significant correlation. The SDAI was compared
      qualitatively to the ACR 20% at 3, 6 and 12 months. The index was further
      validated by comparing the SDAI with survey results obtained from
      rheumatologists' evaluations of disease activity in test cases. The survey
      results included defining categorical changes in the SDAI indicating major, minor
      or no improvement in disease activity in response to treatment. Changes in total
      Sharp score at 6 and 12 months of treatment were determined for each of these
      categories of the SDAI and for comparable categories of the DAS 28. RESULTS: The
      mean SDAI calculated for patients at baseline in study MN301 was 50.06 (range
      25.10-96.10) and was, respectively, 50.55 (range 22.10-98.10) and 43.20 (range
      12.90-78.20) in studies MN302 and US301. In all three trials, the SDAI was
      correlated with a high level of statistical significance to the DAS 28 and HAQ
      scores at baseline, endpoint and change at endpoint. Patients achieving the ACR
      20, 50, 70 or 90% response showed proportionate changes in the SDAI. Analysis of
      surveyed physician responses showed a significant association between the
      perception of disease activity and the SDAI, as well as changes in the SDAI.
      Qualitative analysis of radiographic progression at 6 and 12 months for patients
      showing either major, minor or no improvement of the SDAI showed correspondingly
      larger increases of the total Sharp score at 12 months. CONCLUSION: The SDAI is a
      valid and sensitive assessment of disease activity and treatment response that is
      comparable with the DAS 28 and ACR response criteria; it is easy to calculate and
      therefore a viable tool for day-to-day clinical assessment of RA treatment.
      Overall results indicate that the SDAI has content, criterion and construct
      validity.

PMID- 12595619
TI  - Factors affecting knee cartilage volume in healthy men.
AB  - OBJECTIVES: To understand the factors that influence joint cartilage in health
      and disease as they are important for the prevention and management of
      osteoarthritis. METHODS: We conducted a cross-sectional study to determine
      factors influencing knee cartilage volume in 45 males aged (mean+/-S.D.) 52.5+/
      13.2 yr. RESULTS: Total and medial tibial volumes were inversely associated with
      age, body mass index (BMI) and amount of physical activity and positively
      associated with total bone content. BMI explained the largest amount of the
      variation in tibial cartilage volume (18.7%). There were similar findings at the
      lateral tibial cartilage, but for age and total bone content this did not reach
      statistical significance. There was a positive association with serum
      testosterone at all tibial cartilage sites, but this only reached statistical
      significance for medial tibial cartilage, where serum testosterone explained up
      to 8% of the variation in cartilage volume. CONCLUSIONS: Modifiable risk factors
      of osteoarthritis also appear to be significant determinants of tibial cartilage
      volume. Serum testosterone may provide one possible explanation for gender
      differences in tibial cartilage volume and prevalence of tibiofemoral
      osteoarthritis. The proposed link between osteoarthritis and knee cartilage
      volume and the effect of testosterone will need to be confirmed in longitudinal
      studies.

PMID- 12595620
TI  - Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals.
AB  - OBJECTIVE: To examine prospectively the accuracy of an initial diagnosis for
      fibromyalgia (FM). METHODS: All patients newly referred for rheumatology
      consultation in a 6-month period were evaluated prospectively for either a
      preceding, current or subsequent diagnosis of FM. Clinical characteristics,
      previous and subsequent management and health care utilization were assessed. The
      final diagnosis at 6 months was verified and accuracy regarding the diagnosis of
      FM was assessed. RESULTS: Seventy six (12%) of all new patients were either
      referred with a question of FM or finally diagnosed with FM. At the final
      evaluation the accuracy of the diagnosis regarding FM by either the referring
      physician or by the rheumatologist at the time of the initial visit was correct
      in 34% of patients. The FM group in comparison with those with some other
      rheumatological diagnosis had more tender points (12.5 vs 4) and were more
      fatigued. In contrast, prolonged early morning stiffness and limitation of lumbar
      spinal mobility in more than one plane was more common in the non-FM group.
      CONCLUSION: There is a disturbing inaccuracy, mostly observed to be
      overdiagnosis, in the diagnosis of FM by referring physicians. This finding may
      help explain the current high reported rates of FM and caution physicians to
      consider other diagnostic possibilities when addressing diffuse musculoskeletal
      pain.

PMID- 12595621
TI  - Predictors of radiological progression and changes in hand bone density in early
      rheumatoid arthritis.
AB  - OBJECTIVE: To identify predictors for radiological and functional outcome and
      bone loss in the hands in early rheumatoid arthritis (RA) during the first 2 yr
      of disease and to study the relationship between these variables. METHODS: An
      inception cohort of consecutively recruited patients was examined at baseline and
      after 12 and 24 months using X-rays of hands and feet, clinical [28-joint count,
      Health Assessment Questionnaire (HAQ), global visual analogue scale (VAS), grip
      strength] and laboratory (erythrocyte sedimentation rate, C-reactive protein,
      markers of bone formation and resorption) measurements and dual-energy X-ray
      absorptiometry measurements of the hands. RESULTS: Joint destruction increased
      significantly during the study, with the Larsen score at baseline as the
      strongest predictor. Radiological progression and bone loss over 24 months were
      significantly retarded in patients responding to therapy. The effects of the
      shared epitope and initial high inflammatory activity on radiological progression
      were overridden by the therapeutic response. Radiological progression correlated
      significantly with bone loss. Global VAS, Larsen score and HAQ at inclusion
      significantly predicted change in HAQ over time. CONCLUSIONS: Radiological
      progression and bone loss were retarded by early therapeutic response. Bone loss
      was related to radiological progression.

PMID- 12595622
TI  - Association of damage with autoantibody profile, age, race, sex and disease
      duration in systemic lupus erythematosus.
AB  - OBJECTIVE: To determine if there is any association between autoantibody profile
      and damage in a cohort of patients with systemic lupus erythematosus (SLE).
      METHODS: A prospective cohort of SLE patients attending two SLE clinics in
      Birmingham was analysed. All patients fulfilled ARA criteria for SLE. Detailed
      clinical and serological information was recorded at each visit. Damage according
      to the Systemic Lupus International Collaborating Clinics/American College of
      Rheumatology Damage Index (SLICC/ACR DI) was recorded 6-monthly and the last
      score in the year 2000 or prior to death was used in the analysis. Univariate
      analysis was performed with the chi(2) test, Fisher's exact test or univariate
      analysis of variance. Multivariate analysis was done with binary logistic
      regression. RESULTS: A total of 348 patients (326 females) were studied,
      comprising 208 Caucasians, 65 Afro-Caribbeans, 59 Asians, four Orientals and 12
      others. There were 32 (9.2%) deaths and 156 (44.8%) patients had damage recorded
      during follow-up. The presence of damage showed no significant association with
      race, sex or anti-cardiolipin, anti-Ro, anti-La, anti-Sm, anti-RNP and anti-dsDNA
      antibodies. Only age, disease duration and other antibodies to extractable
      nuclear antigens (ENA) were found to be associated with the presence of damage.
      When individual organ damage was analysed, the only significant associations were
      of anti-Ro with ocular damage and of other anti-ENA antibodies (anti-Scl-70
      and/or anti-Jo-1) with premature gonadal failure. Other autoantibodies were not
      predictive of damage in individual organs. CONCLUSIONS: Although autoantibodies
      are useful in diagnosis and predicting disease activity in SLE, they do not
      appear to be useful in predicting damage in SLE.

PMID- 12595623
TI  - Effects of rheumatoid arthritis on sexual activity and relationships.
AB  - OBJECTIVES: The primary aim of this research was to assess patients' perceptions
      of the effects of rheumatoid arthritis (RA) on their sexual relationship and
      sexual activity, the causes of any difficulties and who they would turn to for
      help. METHODS: A self-report questionnaire was distributed to 74 patients
      attending a regional rheumatology clinic and returned by prepaid post. Fifty-nine
      questionnaires were returned (response rate 80%) and 57 of them were usable.
      RESULTS: Thirty-five per cent of the cohort thought that their disease strained
      their relationship with their partner, and reasons for this included curtailment
      of daily and social activities, changes in the balance of the relationship,
      emotional changes and changed financial circumstances. Over half (56%) of the
      patients found that their arthritis placed limitations on sexual intercourse and
      the principal reasons cited were fatigue and pain. Sexual ability was important
      to 58% of the sample and ageing had a negative impact on its importance
      (P<0.005). Poor communication was a major problem, patients being reluctant to
      approach health professionals and vice versa. The topic of sexual relationships
      was broached with patients attending one nurse practitioner's clinic, but only
      one other patient had ever been offered any discussion. Thirty-nine per cent of
      the cohort would consider talking to someone if they had a problem and the nurse
      and the doctor were the professionals most often chosen. CONCLUSION: RA impacts
      on the sexual lives of a large minority of patients and this is a problem that
      patients and health professionals are reluctant to discuss face to face. However,
      patients do appear to be willing to complete questionnaires and this may be an
      acceptable format for assessment. Further training and support is needed by
      nurses and other health professionals in this sadly neglected area.

PMID- 12595624
TI  - Suicides in persons suffering from rheumatoid arthritis.
AB  - OBJECTIVE: To assess the demographic and psychosocial profiles of patients with
      rheumatoid arthritis (RA) who committed suicide. Two control groups were used:
      osteoarthritis (OA) and suicide victims with neither RA nor OA. METHOD: A study
      based on a prospective, 13-yr follow-up database with linkage to national
      hospital discharge registers of all suicides (1296 males, 289 females) committed
      during the years 1988-2000 in the province of Oulu situated in northern Finland.
      RESULTS: Females were significantly over-represented among RA patients who
      committed suicide (52.6% RA women vs 17.3% women with neither RA nor OA).
      Comorbid depressive disorders preceded suicides in 90% of the female RA patients.
      Before their suicide, 50% of the female RA patients (vs 11% of the male RA
      patients) had experienced at least one suicide attempt. The method of suicide was
      violent in 90% of the RA females. RA males were less often depressive, but
      committed suicide after experiencing shorter periods of RA and fewer admissions
      than females. CONCLUSION: Attempted suicides and especially depression in female
      RA patients should be taken more seriously into account than previously in
      clinical work so that the most appropriate psychiatric treatment can be provided
      for such patients.

PMID- 12595625
TI  - Rheumatoid arthritis and macrovascular disease.
AB  - OBJECTIVE: To measure the extent of subclinical atherosclerosis in patients with
      rheumatoid arthritis (RA) compared with controls, and to evaluate any potential
      vascular risk factors. METHODS: Forty RA patients were compared with an age- and
      sex-matched control group. Non-invasive vascular tests, i.e. carotid duplex
      scanning [measuring common carotid artery intima-media thickness (IMT)], ankle
      brachial blood pressure index (ABPI) and QT dispersion on ECG (QTD), were
      performed. Traditional risk factors such as high blood pressure, blood sugar,
      lipids and steroid usage were assessed. RESULTS: The average IMT (S.E.) in RA
      patients was 0.73 (0.03) mm, compared with 0.62 (0.03) mm in the control group
      (P=0.01, Mann-Whitney). Ten out of 40 RA patients (25%) had an ABPI < 1.0
      compared with 1/40 (2.5%) in the control group (P=0.007, Fisher's). QTD was
      higher in RA patients; mean (S.E.) 55 (2.70) ms compared with 40 (2.50) ms in the
      control group (P < 0.001, t-test). There were no significant differences in the
      prevalence of high blood pressure, diabetes or lipid profiles. However, patients
      on steroids had a higher mean QTD (S.E.): 63.5 (4) compared with 48 (2.7) ms in
      those patients who had not received long-term steroids (P=0.003, t-test).
      CONCLUSION: RA patients have an increased risk of subclinical vascular disease as
      was shown by a higher prevalence of carotid disease, peripheral arterial disease
      and increased QTD. Among traditional risk factors we found a history of steroid
      usage to be one of the potential risk factors.

PMID- 12595626
TI  - Urinary levels of creatine and other metabolites in the assessment of
      polymyositis and dermatomyositis.
AB  - BACKGROUND: A simple and reliable method is needed to assess disease activity and
      monitor the efficacy of therapy in polymyositis (PM) and dermatomyositis (DM).
      This study used in vitro proton ((1)H) magnetic resonance spectroscopy (MRS) to
      explore whether excretion of urinary metabolites can be used as a reliable marker
      of disease in PM and DM patients. METHODS: Urine samples were obtained from PM/DM
      patients (n=34), healthy controls (50) and subjects with known muscle-wasting
      conditions including adult-onset muscular dystrophy (8), stroke patients (10),
      rheumatoid arthritis (RA) patients on steroids (13) and not on steroids (16) and
      patients with alcoholic myopathy (12). Levels of urinary metabolites were then
      correlated with creatine kinase (CK) activities and quadriceps muscle strength.
      RESULTS: Creatine was detected in the urine in 26 of 35 patients with PM/DM, four
      of 60 cases with other medical disorders (including one with adult-onset
      dystrophy, one with a stroke and two with RA who were not on steroids) and 10 of
      50 healthy controls. The urinary creatine/creatinine ratio exceeded 0.4 in 20
      patients with PM/DM but no patients with other medical disorders and no healthy
      controls. These differences were highly significant (P<0.001) by Kruskal-Wallis
      test (comparing all groups) and by Mann-Whitney U-tests (comparing individual
      groups with PM/DM cases). Citrate, glycine, choline-containing compounds and
      taurine levels were significantly increased in PM/DM when compared with controls.
      There were positive correlations between CK activities and choline-containing
      compounds (r=0.78, P=0.0006) and also between CK activities and betaine (r=0.57,
      P=0.026). CONCLUSIONS: This study shows significant differences in the urinary
      levels of creatine, choline-containing metabolites, betaine and citrate in PM/DM
      subjects compared with controls, although further work is required to elucidate
      the underlying metabolic processes.

PMID- 12595627
TI  - Development of rheumatoid arthritis is not associated with two polymorphisms in
      the Crohn's disease gene CARD15.
AB  - INTRODUCTION: It has been proposed that genetic susceptibility loci for
      rheumatoid arthritis (RA) may be shared with other autoimmune/inflammatory
      diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome
      16q12 has been associated with Crohn's disease (CD) in several independent
      populations. CARD15 is an excellent functional and positional candidate gene for
      RA. METHODS: Genomic DNA was obtained from 392 RA cases and 471 ethnically
      matched healthy controls. All samples were genotyped for two polymorphisms in
      CARD15, 1007fs and R702W, using 5' nuclease reporter assays. Allele frequencies
      were compared between cases and controls using the chi(2) test. Estimated
      haplotype frequencies across the two mutations were determined using the EH
      program. RESULTS: The allele frequency of the 1007fs variant in RA cases was 1.8%
      compared with 1.6% in normal controls (not significant). The frequency of the
      R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of
      the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying
      both mutations was rare, with estimated frequency <0.01%. This study provided
      high power to detect an association of similar magnitude to that in Crohn's
      disease. These data therefore exclude the possibility that the contribution of
      these mutations to RA is comparable to that seen in CD. CONCLUSION: Within
      defined statistical parameters, we excluded a role for the CARD15 1007fs and
      R702W variants in RA susceptibility. These data do not preclude a role for other
      polymorphisms in the CARD15 gene in RA susceptibility. Results from other
      autoimmune and inflammatory diseases will reveal whether the CARD15 gene is in
      fact a common autoimmune susceptibility locus.

PMID- 12595628
TI  - The -308 polymorphism in the tumour necrosis factor (TNF) gene promoter region
      and ex vivo lipopolysaccharide-induced TNF expression and cytotoxic activity in
      Chilean patients with rheumatoid arthritis.
AB  - OBJECTIVE: To investigate the association of the -308 polymorphism in the
      promoter region of the tumour necrosis factor (TNF) gene with susceptibility to
      the development of RA. We also explored the expression and cytotoxicity of TNF in
      relation to the -308 polymorphism. METHODS: We recruited 92 RA patients and 42
      healthy control subjects. Genotyping for the TNF promoter was performed by
      polymerase chain reaction-restriction fragment length polymorphism analysis. To
      study the overexpression of TNF we used a whole-blood culture system. TNF
      cytotoxicity was assessed in the L929 cell line. RESULTS: The TNF2 allele was
      found in 23% of RA patients and 10% of controls. Although both groups showed high
      variability in serum TNF concentration, in the lipopolysaccharide-induced TNF
      level and in the cytotoxicity of the cytokine in the L929 cell line, these
      differences were not associated with the -308 TNF polymorphism. CONCLUSION: No
      associations were found between the -308 TNF promoter polymorphism, serum and ex
      vivo TNF levels and the cytotoxic activity of TNF in RA patients.

PMID- 12595629
TI  - Hydroxypyridinium collagen crosslinks in serum, urine, synovial fluid and
      synovial tissue in patients with rheumatoid arthritis compared with
      osteoarthritis.
AB  - OBJECTIVE: To investigate the relationship between inflammation markers and
      content of pyridinium crosslinks in hydrolysates of synovial tissue and to
      specify the significance of urinary excreted pyridinoline, released primarily
      from collagen I and II of bone and cartilage, and deoxypyridinoline released
      especially from collagen I of bone and dentin, dependent on disease activity in
      rheumatoid arthritis (RA). METHODS: Synovial tissue and fluid from knee
      endoprosthesis surgery, as well as simultaneously obtained serum and urine, were
      collected from 12 patients with inactive RA or RA with low disease activity [iRA:
      C-reactive protein (CRP) <28 mg/l], 10 with active RA (aRA: CRP > or =28 mg/l)
      and 21 with OA. After preparation of the synovial tissue, including hydrolysis,
      completely released synovial pyridinoline and deoxypyridinoline crosslinks as
      well as those from synovial fluid, serum and urine were investigated using a
      gradient ion-paired reversed-phase HPLC method. Crosslink levels in synovial
      tissue are expressed as mol/mol collagen, assuming 300 residues of hydroxyproline
      per collagen molecule, also measured by HPLC. RESULTS: In the synovial tissue of
      aRA patients we found significantly elevated total pyridinoline concentrations
      and pyridinoline/deoxypyridinoline (Pyr/Dpyr) quotients compared with the iRA and
      OA controls, indicating an elevated crosslinking density of mature synovial
      tissue collagen with increased activity of RA. Pyridinoline levels and the
      Pyr/Dpyr ratio were correlated with those of urine and with acute-phase reactants
      in RA patients. Compared with serum crosslink levels, which were unrelated to
      disease activity, the urinary concentration of pyridinoline was increased by a
      factor of 2 and showed a simultaneous increase with increasing synovitis.
      CONCLUSION: Both crosslinking density and degradation of mature collagen from
      synovial tissue depend on the disease activity in RA. Urinary excretion of
      associated crosslinks, expressed as the Pyr/Dpyr ratio, correlates with those in
      synovial tissue and may be confirmed as a marker of synovial tissue collagen
      degradation. We suggest that increased crosslinking of mature collagen in the
      synovial tissue of RA is related to an inflammation-dependent regulation of
      collagen synthesis in activated synovial fibroblasts, in which lysyl oxidase
      represents the final enzymatic step for crosslinking.

PMID- 12595630
TI  - Fenofibrate enhances urate reduction in men treated with allopurinol for
      hyperuricaemia and gout.
AB  - OBJECTIVE: To assess the short-term urate-lowering effect of fenofibrate in men
      on long-term allopurinol therapy for hyperuricaemia and gout. METHODS: Ten male
      patients (38-74 yr) with a history of chronic tophaceous or recurrent acute gout
      with hyperuricaemia and on established allopurinol at 300-900 mg/day for > or =3
      months were studied in an open-crossover study of fenofibrate therapy.
      Allopurinol at the established dose was continued throughout the study. Clinical
      and biochemical assessments (serum urate and creatinine, 24-h urinary excretion
      of urate and creatinine, liver function tests, creatine kinase and fasting serum
      lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily
      therapy with micronized fenofibrate (Lipantil Micro) at 200 mg and (iii) 3 weeks
      after fenofibrate was withdrawn. RESULTS: Fenofibrate was associated with a 19%
      reduction in serum urate after 3 weeks of treatment (mean+/-S.E. 0.37+/-0.04 vs
      0.30+/-0.02 mM/l; P=0.004). The effect was reversed after a 3-week fenofibrate
      withdrawal period (0.30+/-0.02 vs 0.38+/-0.03 mM/l). There was a rise in uric
      acid clearance with fenofibrate treatment of 36% (7.2+/-0.9 vs 11.4+/-1.6 ml/min,
      normal range 6-11; P=0.006) without a significant change in creatinine clearance.
      Both total cholesterol and serum triglycerides were also reduced. No patient
      developed acute gout whilst taking fenofibrate. CONCLUSIONS: Fenofibrate has a
      rapid and reversible urate-lowering effect in patients with hyperuricaemia and
      gout on established allopurinol prophylaxis. Fenofibrate may be a potential new
      treatment for hyperuricaemia and the prevention of gout, particularly in patients
      with coexisting hyperlipidaemia or those resistant to conventional therapy for
      hyperuricaemia.

PMID- 12595631
TI  - The cost-effectiveness of infliximab (Remicade) in the treatment of rheumatoid
      arthritis in Sweden and the United Kingdom based on the ATTRACT study.
AB  - OBJECTIVE: The cost per quality-adjusted life-year (QALY) of infliximab
      (Remicade) treatment in rheumatoid arthritis (RA) was estimated on the basis of a
      clinical trial comparing infliximab plus methotrexate with methotrexate alone in
      428 patients with advanced disease [Anti-Tumour Necrosis Factor Trial in
      Rheumatoid Arthritis with Concomitant Therapy (ATTRACT)]. METHODS: The effect of
      infliximab on disease progression and related costs and utilities was estimated
      using two disease progression models based on epidemiological cohorts followed
      for up to 15 yr in Sweden and the UK. The clinical trial data were used directly
      in the model and extrapolated to 10 yr using a cohort from the epidemiological
      studies matched for gender, age, time since onset of RA and disease severity.
      RESULTS: One to two years of treatment with infliximab treatment reduced direct
      and indirect resource consumption in both countries, thereby partly offsetting
      the treatment cost. In the base case, including both direct and indirect costs,
      the cost per QALY gained was SEK 32 000 (euro 3440) in Sweden and GBP 21 600
      (euro 34 800) for 1 yr of treatment. The respective QALY gains were 0.248 and
      0.298. With 2 yr of treatment, the costs per QALY gained were SEK 150 000 (euro
      16 100) and GBP 29 900 (euro;48 200). CONCLUSIONS: Although 1-2 yr of treatment
      with infliximab will lead to savings in both direct and indirect costs, these
      will not offset the drug cost. However, the cost-effectiveness ratios remain
      within the usual range for treatments to be recommended for use.

PMID- 12595632
TI  - The G1 domain of aggrecan released from porcine articular cartilage forms stable
      complexes with hyaluronan/link protein.
AB  - OBJECTIVE: To raise peptide antibodies recognizing the C-terminal amino acid
      sequence in the G1 domain of porcine aggrecan, generated by the action of either
      aggrecanase or neutral metalloproteinase(s), in rabbits and to use them to
      investigate the release of aggrecan from porcine articular cartilage. METHOD: An
      explant culture system was used to investigate the release of the G1 domain of
      aggrecan from porcine articular cartilage treated with retinoic acid or
      interleukin 1beta and to study how the activity of these agents is modified by
      the proteinase inhibitor, batimastat (BB94). RESULTS: Retinoic acid and
      interleukin 1beta induced both enzyme activities and the release of the G1 domain
      into the culture medium. Proteinase activity was significantly reduced when the
      tissue was incubated in the presence of BB94. The functional properties of the
      enzyme-generated G1 domain were studied using large-pore, agarose/polyacrylamide
      gel electrophoresis, and it was shown to interact with hyaluronan and link
      protein. CONCLUSIONS: The results show that there must be a mechanism for
      removing a functional G1 domain from aggrecan during tissue turnover using this
      culture system.

PMID- 12595633
TI  - Symmetry and clustering of symptomatic hand osteoarthritis in elderly men and
      women: the Framingham Study.
AB  - OBJECTIVE: While symmetry and clustering of radiographic hand osteoarthritis (OA)
      have been described in middle-aged women, these have not been studied in elderly
      individuals and similar investigations are lacking for symptomatic hand OA. The
      goal of this study was to study patterns of joint involvement in symptomatic hand
      OA among elderly Caucasian men and women. METHODS: Using data from the Framingham
      Osteoarthritis Study, we defined a joint as having symptomatic OA if it had
      symptoms and radiographic OA (Kellgren and Lawrence grade > or =2). We assessed
      clustering of symptomatic OA using a chi(2)-test and evaluated the
      interrelationship of occurrence of symptomatic OA among different joints with
      generalized estimating equations. RESULTS: Of 976 subjects (age 71-99 yr, 36%
      men) examined, symptomatic OA more often affected multiple hand joints in an
      individual than would be expected by chance (P<0.001). The presence of
      symptomatic OA at a particular joint was strongly associated with symptomatic OA
      in the same joint of the opposite hand, followed by other joints in the same row
      of the same hand, and then other joints in the same ray of the same hand. The
      symmetrical pattern of symptomatic OA was more apparent in women than in men.
      CONCLUSION: Our study demonstrates that symptomatic OA often affects multiple
      hand joints, and is more likely to cluster by row than by ray. The disease also
      occurs in a remarkably symmetrical pattern, especially in women.

PMID- 12595634
TI  - Lack of evidence for a direct involvement of muscle infection by parvovirus B19
      in the pathogenesis of inflammatory myopathies: a follow-up study.
AB  - OBJECTIVE: To clarify the association between parvovirus B19 and myositis.
      METHODS: Biopsy samples of muscle from eight patients with inflammatory
      myopathies were studied for the presence of B19 DNA by polymerase chain reaction.
      Expression of VP1 and VP2 capsid proteins was evaluated by immunohistochemistry.
      Interleukin 6 (IL-6) production was measured in the supernatant of myoblasts
      following incubation with parvovirus B19. RESULTS: In seven samples, detection of
      B19 DNA was negative. The expression of VP1 and VP2 capsid proteins was not
      observed by immunohistochemistry. In one patient, detection was transiently
      positive but became negative despite a flare-up of muscle disease. In vitro,
      parvovirus B19 was not able to induce IL-6 production by myoblasts. CONCLUSION:
      Our results do not support the direct implication of parvovirus B19 in the
      pathogenesis of myositis.

PMID- 12595635
TI  - Novel autoantibodies to pituitary gland specific factor 1a in patients with
      rheumatoid arthritis.
AB  - OBJECTIVE: We recently identified a new protein, pituitary gland specific factor
      1a (PGSF1a), that is specifically transcribed in the pituitary gland. In our
      investigation of anti-PGSF1a antibody for pituitary diseases, we examined it in
      patients with RA and other autoimmune diseases. We unexpectedly discovered the
      frequent existence of anti-PGSF1a antibody in patients with RA. We therefore
      examined the prevalence of this antibody to understand its clinical significance
      in RA. METHODS: Anti-PGSF1a antibody was detected by radioligand assay using
      recombinant (35)S-labelled PGSF1a protein. Antibody activity is expressed as an
      index that was obtained by comparison with normal pooled serum. RESULTS: RA
      patients had a significantly higher mean anti-PGSF1a antibody index (n=46, 1.28+/
      0.38, P < 0.001) than healthy controls (n=36, 1.04+/-0.13). Indices greater than
      the cut-off value (mean+2 S.D. of healthy controls) were found in 43.5% (20/46)
      and 10.0% (2/20) of patients with RA and osteoarthritis, respectively. There was
      no correlation between the activities of anti-PGSF1a antibodies and titres of
      rheumatoid factor (RF) or serum C-reactive protein concentrations, but RA
      patients with more erosive disease had a higher mean anti-PGSF1a antibody index.
      Four of eight sera samples obtained from RF-negative RA patients were positive
      for anti-PGSF1a antibodies. CONCLUSION: Anti-PGSF1a antibody is a useful new
      marker for the diagnosis of RA, especially for RF-negative RA, and may relate to
      clinical manifestations of RA.

PMID- 12595636
TI  - Evaluation of the association of autoantibodies with mortality in the very
      elderly: a cohort study.
AB  - OBJECTIVE: To evaluate whether autoantibodies in the absence of rheumatic
      diseases increase the risk of mortality among very elderly subjects who are
      otherwise in good functional condition. METHODS: Autoantibodies were measured in
      1987 in 156 elderly nursing home residents (median age 84 yr) who were followed
      subsequently over 14.6 yr. RESULTS: Eleven subjects had anticardiolipin
      antibodies, 30 had rheumatoid factor and 19 had antibodies to single-stranded DNA
      (ssDNA). Other autoantibodies were more rare. During follow-up, 144 subjects
      died. Adjusting for age as a time-dependent covariate, the hazard ratio for death
      was 0.71 [95% confidence interval (CI) 0.38-1.32] for anticardiolipin antibodies,
      0.93 (95% CI 0.60-1.41) for rheumatoid factor, 1.08 (95% CI 0.65-1.79) for
      antibodies to ssDNA, and 0.99 (95% CI, 0.70-1.41) for any autoantibody. Hazard
      ratios were similar when adjusted also for sex and clinical conditions.
      CONCLUSION: Our results exclude the possibility that the autoantibodies evaluated
      increase substantially the risk of death among very elderly subjects in good
      functional condition.

PMID- 12595637
TI  - Cytostatic therapy for AA amyloidosis complicating psoriatic spondyloarthropathy.
AB  - Psoriatic spondyloarthropathy (PSA) can occasionally be complicated by AA
      amyloid, and renal amyloidosis should be suspected in patients with PSA who have
      unexplained proteinuria. The diagnosis of amyloidosis can be made either
      histologically or by radiolabelled serum amyloid P component (SAP) scintigraphy.
      Prognosis is determined by the extent of organ involvement and associated
      impairment of function, and by the degree of response of the underlying disease
      to anti-inflammatory therapy. A review of the literature identified less than a
      dozen cases of AA amyloidosis complicating PSA, and the outcome in most cases was
      poor. We report here the favourable clinical course of a middle-aged Caucasian
      male patient with severe PSA who developed renal AA amyloidosis, in whom
      treatment with oral chlorambucil led to stabilization of the amyloid deposits and
      resolution of the associated nephrotic syndrome. We review the diagnosis and
      treatment of AA amyloidosis, including the management of patients with underlying
      inflammatory spondyloarthropathies, and propose the possible role of a
      therapeutic trial of anti-tumour necrosis factor alpha in patients with amyloid
      complicating inflammatory rheumatic diseases.

PMID- 12595638
TI  - Computer-assisted learning in undergraduate and postgraduate rheumatology
      education.
AB  - Computers and the Internet form a large part of our professional and personal
      lives. There are advantages and disadvantages to computer-assisted learning which
      will be discussed. An Internet and Medline search was performed to assess the
      educational content of rheumatology websites and also their effect on learning in
      the undergraduate and postgraduate setting.

PMID- 12595639
TI  - Interstitial lung disease associated with juvenile dermatomyositis: clinical
      features and efficacy of cyclosporin A.
AB  - OBJECTIVES: Interstitial lung disease (ILD) is a rare complication of juvenile
      dermatomyositis (JDM). The aim of this study was to clarify the clinical features
      of JDM-associated ILD and to evaluate the efficacy of cyclosporin A (CSA).
      METHODS: We reviewed clinical records of 10 cases of JDM that were admitted to
      Hokkaido University Hospital between April 1990 and March 2001. RESULTS: Five
      cases were complicated with ILD, three with interstitial pneumonia and two with
      bronchiolitis obliterans organizing pneumonia. ILD was associated with active JDM
      and progressed despite corticosteroid therapy. Testing for anti-Jo-1 antibody was
      negative in all cases. Respiratory symptoms were initially noticed in only one
      case. In the other cases, ILD was first detected by routine examination of chest
      X-ray. All the cases received CSA (3-5 mg/kg/day) in combination with
      prednisolone. One patient died of respiratory failure, but the others responded
      well to treatment with CSA. CONCLUSION: ILD should be evaluated carefully in all
      cases of JDM regardless of respiratory symptoms. CSA is a choice for steroid
      resistant cases of JDM-associated ILD.

PMID- 12595640
TI  - Reduced perforin expression in systemic juvenile idiopathic arthritis is restored
      by autologous stem-cell transplantation.
AB  - OBJECTIVES: Familial haemophagocytic lymphohistiocytosis (FHL) is a disorder
      characterized by deficient cytotoxic T-cell function and activated macrophages,
      owing to a defect in the perforin gene and absent perforin expression. Because
      symptoms of patients with systemic juvenile idiopathic arthritis (sJIA) are
      sometimes clinically very similar to those with FHL, we studied whether perforin
      expression in sJIA patients would be reduced also. METHODS: We determined the
      perforin expression levels on two subsets of CD8(+) cells (CD8(+)CD28(-)CD45RA(-)
      and CD8(+)CD28(-)CD45RA(+)) and natural killer (NK) cells from patients with sJIA
      under conventional treatment as well as before and after autologous stem-cell
      transplantation (ASCT). RESULTS: CD45RA(-) cytotoxic effector cells of sJIA
      patients (n=13) express significantly lower levels of perforin than polyarticular
      juvenile idiopathic arthritis (pJIA, n=9) patients [sJIA mean fluorescence
      intensity (MFI) 34.6; pJIA MFI 98.0] or control donors (MFI 124.6, n=5). A
      similar pattern was seen in the CD45RA(+) subset. Also NK cells from sJIA
      patients expressed significantly less intracellular perforin (sJIA MFI 398.4;
      controls MFI 972.4). In four patients with sJIA who were treated with ASCT, a
      clear increase in perforin expression was found at 12 months after ASCT in both
      cytotoxic effector cell subsets (CD45RA(-) subset before ASCT MFI 13.2; 12 months
      after ASCT MFI 172.3). CONCLUSION: We conclude that perforin expression can be
      severely reduced in sJIA. This finding may implicate defective cytotoxicity and
      haemophagocytosis and could thus explain why sJIA may be complicated by
      macrophage activation syndrome. ASCT leads to a reconstitution of the (T cell)
      immune system with a normal expression of perforin.

PMID- 12595641
TI  - Anterior knee pain: a long-term follow-up.
AB  - OBJECTIVE: To assess the long-term outcome of anterior knee pain diagnosed in
      childhood. METHOD: Forty-eight patients diagnosed with anterior knee pain in
      childhood were contacted by postal questionnaire 4-18 yr after initial
      presentation. RESULTS: The 22 respondents comprised 16 women and six men, with
      mean age at follow-up of 22 yr. Twenty of 22 (91%) still had knee pains, eight
      daily, two weekly and 10 occasionally. In 10 (45%) the pain affected their daily
      life and in eight (36%) it restricted their physical activities. Twelve (54%)
      used painkillers. Ten (45%) had developed other diagnoses: four had psoriasis and
      six arthritis, of whom one had ankylosing spondylitis. Fifteen (68%) had symptoms
      in other joints at follow-up. CONCLUSION: These results suggest that anterior
      knee pain that occurs in childhood may not be so benign a condition as thought.

PMID- 12595642
TI  - Can hepatitis C virus infection and interferon-alpha undo the HLA
      DRB1*0402/DQB1*0302 protection against rheumatoid arthritis?

PMID- 12595643
TI  - Post-partal sacral fatigue fracture.

PMID- 12595645
TI  - Symmetry in inflammatory polyarthritis.

PMID- 12595644
TI  - Carcinoma of the prostate presenting as polymyalgia rheumatica.

PMID- 12595646
TI  - Helicobacter pylori infection in rheumatoid arthritis: effect of drugs on
      prevalence and correlation with gastroduodenal lesions.

PMID- 12595648
TI  - Kaposi's sarcoma in psoriatic arthritis.

PMID- 12595649
TI  - Churg-Strauss syndrome: the use of cyclophosphamide in mononeuritis.

PMID- 12595650
TI  - Successful therapy with low-dose colchicine in intermittent hydrarthrosis.

PMID- 12595651
TI  - Improvement of acquired partial lipodystrophy with rosiglitazone despite ongoing
      complement activation.

PMID- 12595652
TI  - Pathological fractures due to intraosseous fat necrosis associated with
      pancreatitis.

PMID- 12595654
TI  - Trimethoprim-sulphamethoxazole for the treatment of Wegener's granulomatosis.

PMID- 12595655
TI  - Methotrexate prescribing records: a primary and secondary care audit.

PMID- 12595657
TI  - Two cultures.

PMID- 12595658
TI  - Statement on scientific publication and security.

PMID- 12595659
TI  - 2003 budget. Science agencies get most of what they want, finally.

PMID- 12595660
TI  - Space research. Amid troubles, station science gains a center.

PMID- 12595661
TI  - Neuroscience. Snooty exchanges are key to mouse society.

PMID- 12595662
TI  - Paleontology. Primitive jawed fishes had teeth of their own design.

PMID- 12595663
TI  - Microbial forensics. Report spells out how to fight biocrimes.

PMID- 12595664
TI  - Evolution. How global change shaped the squirrel family.

PMID- 12595665
TI  - Scientific workforce. MIT broadens minority-only programs.

PMID- 12595666
TI  - Next linear collider. Collision course with reality.

PMID- 12595667
TI  - Next linear collider. Why physicists long for the straight and narrow.

PMID- 12595668
TI  - Next linear collider. One collider, many countries: how to share the wealth?

PMID- 12595669
TI  - Bioterrorism. Security rules leave labs wanting more guidance.

PMID- 12595670
TI  - West Nile virus. Researchers scramble to track virus's impact on wildlife.

PMID- 12595671
TI  - American Association for the Advancement of Science meeting. Gravity waves elude
      first scrutiny.

PMID- 12595672
TI  - American Association for the Advancement of Science meeting. Subterranean coal
      fires spark disaster.

PMID- 12595673
TI  - The ever-elusive liberal education.

PMID- 12595674
TI  - A part of the human genome sequence.

PMID- 12595675
TI  - Comment on "Failure of bone marrow cells to transdifferentiate into neural cells
      in vivo".

PMID- 12595677
TI  - Scientists and the Venezuelan crisis.

PMID- 12595678
TI  - Agriculture. Science for African food security.

PMID- 12595679
TI  - Genomics. Molecular prodigality.

PMID- 12595680
TI  - Signal transduction. Capturing polo kinase.

PMID- 12595681
TI  - Materials science. A bright bio-inspired future.

PMID- 12595682
TI  - Paleoanthropology. Encore Olduvai.

PMID- 12595683
TI  - Experience-dependent plasticity for auditory processing in a raptor.

PMID- 12595684
TI  - Encoding pheromonal signals in the accessory olfactory bulb of behaving mice.
AB  - Many mammalian species rely on pheromones-semiochemicals produced by other
      members of the same species-to communicate social status and reproductive
      readiness. To assess how the central nervous system integrates the complex
      repertoire of pheromones, we recorded from single neurons in the accessory
      olfactory bulb, a nucleus that processes pheromonal signals, of male mice engaged
      in natural behaviors. Neuronal firing was robustly modulated by physical contact
      with male and female conspecifics, with individual neurons activated selectively
      by specific combinations of the sex and strain of conspecifics. We infer that
      mammals encode social and reproductive information by integrating vomeronasal
      sensory activity specific to sex and genetic makeup.

PMID- 12595685
TI  - Direct fabrication of large micropatterned single crystals.
AB  - Micropatterning of single crystals for technological applications is a complex,
      multistep process. Nature provides alternative fabrication strategies, when
      crystals with exquisite micro-ornamentation directly develop within preorganized
      frameworks. We report a bio-inspired approach to growing large micropatterned
      single crystals. Micropatterned templates organically modified to induce the
      formation of metastable amorphous calcium carbonate were imprinted with calcite
      nucleation sites. The template-directed deposition and crystallization of the
      amorphous phase resulted in the fabrication of millimeter-sized single calcite
      crystals with sub-10-micron patterns and controlled crystallographic orientation.
      We suggest that in addition to regulating the shape, micropatterned frameworks
      act as sites for stress and impurity release during the amorphous-to-crystalline
      transition. The proposed mechanisms may have direct biological relevance and
      broad implications in materials synthesis.

PMID- 12595686
TI  - Giant supramolecular liquid crystal lattice.
AB  - Self-organized supramolecular organic nanostructures have potential applications
      that include molecular electronics, photonics, and precursors for nanoporous
      catalysts. Accordingly, understanding how self-assembly is controlled by
      molecular architecture will enable the design of increasingly complex structures.
      We report a liquid crystal (LC) phase with a tetragonal three-dimensional unit
      cell containing 30 globular supramolecular dendrimers, each of which is self
      assembled from 12 dendron (tree-like) molecules, for the compounds described
      here. The present structure is one of the most complex LC phases yet discovered.
      A model explaining how spatial arrangement of self-assembled dendritic aggregates
      depends on molecular architecture and temperature is proposed.

PMID- 12595687
TI  - A discrete self-assembled metal array in artificial DNA.
AB  - DNA has a structural basis to array functionalized building blocks. Here we
      report the synthesis of a series of artificial oligonucleotides, d(5'-GH(n)C-3')
      (n = 1 to 5), with hydroxypyridone nucleobases (H) as flat bidentate ligands.
      Right-handed double helices of the oligonucleotides, nCu2+.d(5'-GH(n)C-3')2 (n =
      1 to 5), were quantitatively formed through copper ion (Cu2+)-mediated
      alternative base pairing (H-Cu2+-H), where the Cu2+ ions incorporated into each
      complex were aligned along the helix axes inside the duplexes with the Cu2+-Cu2+
      distance of 3.7 +/- 0.1 angstroms. The Cu2+ ions were coupled ferromagnetically
      with one another through unpaired d electrons to form magnetic chains.

PMID- 12595688
TI  - Molecular fossil record of elevated methane levels in late Pleistocene coastal
      waters.
AB  - Accumulating evidence suggests that methane has been released episodically from
      hydrates trapped in sea floor sediments during many intervals of rapid climate
      warming. Here we show that sediments from the Santa Barbara Basin deposited
      during warm intervals in the last glacial period contain molecular fossils that
      are diagnostic of aerobic and anaerobic methanotrophs. Sediment intervals with
      high abundances of these compounds indicate episodes of vigorous methanotrophic
      activity in methane-laden water masses. Signals for anaerobic methanotrophy in
      44,100-year-old sediment are evidence for particularly intense methane emissions
      and suggest that the basin's methane cycle can profoundly affect oxygen budgets
      in the water column.

PMID- 12595689
TI  - Late Pliocene Homo and hominid land use from Western Olduvai Gorge, Tanzania.
AB  - Excavation in the previously little-explored western portion of Olduvai Gorge
      indicates that hominid land use of the eastern paleobasin extended at least
      episodically to the west. Finds included a dentally complete Homo maxilla (OH 65)
      with lower face, Oldowan stone artifacts, and butchery-marked bones dated to be
      between 1.84 and 1.79 million years old. The hominid shows strong affinities to
      the KNM ER 1470 cranium from Kenya (Homo rudolfensis), a morphotype previously
      unrecognized at Olduvai. ER 1470 and OH 65 can be accommodated in the H. habilis
      holotype, casting doubt on H. rudolfensis as a biologically valid taxon.

PMID- 12595690
TI  - Positional cloning of the human quantitative trait locus underlying taste
      sensitivity to phenylthiocarbamide.
AB  - The ability to taste the substance phenylthiocarbamide (PTC) has been widely used
      for genetic and anthropological studies, but genetic studies have produced
      conflicting results and demonstrated complex inheritance for this trait. We have
      identified a small region on chromosome 7q that shows strong linkage
      disequilibrium between single-nucleotide polymorphism (SNP) markers and PTC taste
      sensitivity in unrelated subjects. This region contains a single gene that
      encodes a member of the TAS2R bitter taste receptor family. We identified three
      coding SNPs giving rise to five haplotypes in this gene worldwide. These
      haplotypes completely explain the bimodal distribution of PTC taste sensitivity,
      thus accounting for the inheritance of the classically defined taste
      insensitivity and for 55 to 85% of the variance in PTC sensitivity. Distinct
      phenotypes were associated with specific haplotypes, which demonstrates that this
      gene has a direct influence on PTC taste sensitivity and that sequence variants
      at different sites interact with each other within the encoded gene product.

PMID- 12595691
TI  - Impact of genetic manipulation on the fitness of Anopheles stephensi mosquitoes.
AB  - Genetic modification of mosquitoes offers exciting possibilities for controlling
      malaria, but success will depend on how transformation affects the fitness of
      modified insects. The expression of an exogenous gene, the mutations caused by
      its insertion, and inbreeding while transformed lines are established can all
      lead to reductions in fitness. Factors influencing fitness were investigated in
      cage experiments with four lines of transgenic Anopheles stephensi, a vector
      species of human malaria. The results indicate direct costs of the introduced
      transgene in at least three out of the four lines, as well as an apparent cost of
      the inbreeding involved in making transgenic homozygotes.

PMID- 12595692
TI  - Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic
      substrates.
AB  - We have developed a proteomic approach for identifying phosphopeptide binding
      domains that modulate kinase-dependent signaling pathways. An immobilized library
      of partially degenerate phosphopeptides biased toward a particular protein kinase
      phosphorylation motif is used to isolate phospho-binding domains that bind to
      proteins phosphorylated by that kinase. Applying this approach to cyclin
      dependent kinases (Cdks), we identified the polo-box domain (PBD) of the mitotic
      kinase polo-like kinase 1 (Plk1) as a specific phosphoserine (pSer) or
      phosphothreonine (pThr) binding domain and determined its optimal binding motif.
      This motif is present in known Plk1 substrates such as Cdc25, and an optimal
      phosphopeptide containing the motif disrupted PBD-substrate binding and
      localization of the PBD to centrosomes. This finding reveals how Plk1 can
      localize to specific sites within cells in response to Cdk phosphorylation at
      those sites and provides a structural mechanism for targeting the Plk1 kinase
      domain to its substrates.

PMID- 12595693
TI  - Separate evolutionary origins of teeth from evidence in fossil jawed vertebrates.
AB  - Placoderms are extinct jawed fishes of the class Placodermi and are basal among
      jawed vertebrates. It is generally thought that teeth are absent in placoderms
      and that the phylogenetic origin of teeth occurred after the evolution of jaws.
      However, we now report the presence of tooth rows in more derived placoderms, the
      arthrodires. New teeth are composed of gnathostome-type dentine and develop at
      specific locations. Hence, it appears that these placoderm teeth develop and are
      regulated as in other jawed vertebrates. Because tooth development occurs only in
      derived forms of placoderms, we suggest that teeth evolved at least twice,
      through a mechanism of convergent evolution.

PMID- 12595694
TI  - Synaptic plasticity in spinal lamina I projection neurons that mediate
      hyperalgesia.
AB  - Inflammation, trauma, or nerve injury may cause enduring hyperalgesia, an
      enhanced sensitivity to painful stimuli. Neurons in lamina I of the spinal dorsal
      horn that express the neurokinin 1 receptor for substance P mediate this abnormal
      pain sensitivity by an unknown cellular mechanism. We report that in these, but
      not in other nociceptive lamina I cells, neurokinin 1 receptor-activated signal
      transduction pathways and activation of low-threshold (T-type) voltage-gated
      calcium channels synergistically facilitate activity- and calcium-dependent long
      term potentiation at synapses from nociceptive nerve fibers. Thereby, memory
      traces of painful events are retained.

PMID- 12595695
TI  - COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain
      stressor.
AB  - Responses to pain and other stressors are regulated by interactions between
      multiple brain areas and neurochemical systems. We examined the influence of a
      common functional genetic polymorphism affecting the metabolism of catecholamines
      on the modulation of responses to sustained pain in humans. Individuals
      homozygous for the met158 allele of the catechol-O-methyltransferase (COMT)
      polymorphism (val158met) showed diminished regional mu-opioid system responses to
      pain compared with heterozygotes. These effects were accompanied by higher
      sensory and affective ratings of pain and a more negative internal affective
      state. Opposite effects were observed in val158 homozygotes. The COMT val158met
      polymorphism thus influences the human experience of pain and may underlie
      interindividual differences in the adaptation and responses to pain and other
      stressful stimuli.

PMID- 12595696
TI  - Structural analysis of Tityus serrulatus Ts1 neurotoxin at atomic resolution:
      insights into interactions with Na+ channels.
AB  - The structure of the Ts1 toxin from the Brazilian scorpion Tityus serrulatus was
      investigated at atomic resolution using X-ray crystallography. Several positively
      charged niches exist on the Ts1 molecular surface, two of which were found to
      coordinate phosphate ions present in the crystallization solution. One phosphate
      ion is bound to the conserved basic Lys1 residue at the Ts1 N-terminus and to
      residue Asn49. The second ion was found to be caged by residues Lys12, Trp54 and
      Arg56. Lys12 and Tyr/Trp54 residues are strictly conserved in all classical
      scorpion beta-neurotoxins. The cavity formed by these residues may represent a
      special scaffold required for interaction between beta-neurotoxins and sodium
      channels. The charge distribution on the Ts1 surface and the results of earlier
      chemical modification studies and side-directed mutagenesis experiments strongly
      indicate that the phosphate-ion positions mark plausible binding sites to the
      Na(+) channel. The existence of two distinct binding sites on the Ts1 molecular
      surface provides an explanation for the competition between Ts1, depressant
      (LqhIT2) and excitatory (AaHIT) neurotoxins.

PMID- 12595697
TI  - Structural comparison of Escherichia coli L-asparaginase in two monoclinic space
      groups.
AB  - The functional L-asparaginase from Escherichia coli is a homotetramer with a
      molecular weight of about 142 kDa. The X-ray structure of the enzyme,
      crystallized in a new form (space group C2) and refined to 1.95 A resolution, is
      compared with that of the previously determined crystal form (space group P2(1)).
      The asymmetric unit of the new crystal form contains an L-asparaginase dimer
      instead of the tetramer found in the previous crystal form. It is found that
      crystal contacts practically do not affect the conformation of the protein. It is
      shown that subunit C of the tetrameric form is in a conformation which is
      systematically different from that of all other subunits in both crystal forms.
      Major conformational differences are confined to the lid loop (residues 14-27).
      In addition, the stability of this globular protein is analyzed in terms of the
      interactions between hydrophobic parts of the subunits.

PMID- 12595698
TI  - Crystal structures of r(GGUCACAGCCC)2.
AB  - Crystals of small RNAs, which regularly diffract to very high resolution, can
      often be readily obtained. Unfortunately, for some RNAs the conformations adopted
      in the crystalline form are different from those found in solution. For example,
      short RNAs that form hairpins in solution virtually never crystallize thus;
      rather, they form duplexes. Nevertheless, these unintended structures have
      contributed greatly to the understanding of RNA structure. In a similar
      occurrence, the homodimer r(GGUCACAGCCC)(2) has been crystallized from an 11
      mer/12-mer heteroduplex, r(GGCUGAAGUCCG)/r(GGUCACAGCCC). This surprising
      phenomenon was observed under a variety of crystallization conditions. The
      structure of the homoduplex was determined from crystals that differed in the
      precipitant used and the type of metal present. In all cases, the resulting
      homoduplexes contain ten base pairings, of which the central six are non
      canonical pairings. In two of the variants, ordered metal-binding sites were
      observed: two equivalent octacoordinate Tl(+) sites in one and two equivalent
      nanocoordinate Ba(2+) sites in another.

PMID- 12595699
TI  - Crystal structure of rGd(CGCGCG): a Z-DNA hexamer duplex with a 5'-(rG) overhang.
AB  - The crystal structure of the heptamer rGd(CGCGCG) has been determined at 1.54 A
      resolution with R(work) and R(free) of 0.191 and 0.235, respectively. The crystal
      belongs to space group P2(1)2(1)2(1), with unit-cell parameters a = 17.96, b =
      31.47, c = 44.73 A and two independent strands in the asymmetric unit. The
      chimera forms a Z-DNA hexamer duplex d(CGCGCG)(2), with the 5'-overhang rG
      invisible in the density. The replacement of rG in the 5' terminus of d(GCGCGCG)
      changes the reverse Hoogsteen G.G base pairing of the 5'-overhang dG (Pan et al.,
      1997). However, the replacement does not change the helix from Z-form to A-form
      or the water-structure motifs in the Z-DNA double-helical structure.

PMID- 12595700
TI  - Development of a force field for conditional optimization of protein structures.
AB  - Conditional optimization allows the incorporation of extensive geometrical
      information in protein structure refinement, without the requirement of an
      explicit chemical assignment of the individual atoms. Here, a mean-force
      potential for the conditional optimization of protein structures is presented
      that expresses knowledge of common protein conformations in terms of interatomic
      distances, torsion angles and numbers of neighbouring atoms. information is
      included for protein fragments up to several residues long in alpha-helical, beta
      strand and loop conformations, comprising the main chain and side chains up to
      the gamma position in three distinct rotamers. Using this parameter set,
      conditional optimization of three small protein structures against 2.0 A observed
      diffraction data shows a large radius of convergence, validating the presented
      force field and illustrating the feasibility of the approach. The generally
      applicable force field allows the development of novel phase-improvement
      procedures using the conditional optimization technique.

PMID- 12595701
TI  - Direct experimental observation of the hydrogen-bonding network of a glycosidase
      along its reaction coordinate revealed by atomic resolution analyses of
      endoglucanase Cel5A.
AB  - Non-covalent interactions between protein and ligand at the active centre of
      glycosidases play an enormous role in catalysis. Dissection of these hydrogen
      bonding networks is not merely important for an understanding of enzymatic
      catalysis, but is also increasingly relevant for the design of transition-state
      mimics, whose tautomeric state, hydrogen-bonding interactions and protonation
      contribute to tight binding. Here, atomic resolution ( approximately 1 A)
      analysis of a series of complexes of the 34 kDa catalytic core domain of the
      Bacillus agaradhaerens endoglucanase Cel5A is presented. Cel5A is a 'retaining'
      endoglucanase which performs catalysis via the formation and subsequent breakdown
      of a covalent glycosyl-enzyme intermediate via oxocarbenium-ion-like transition
      states. Previous medium-resolution analyses of a series of enzymatic snapshots
      has revealed conformational changes in the substrate along the reaction
      coordinate (Davies et al., 1998). Here, atomic resolution analyses of the series
      of complexes along the pathway are presented, including the 'Michaelis' complex
      of the unhydrolysed substrate, the covalent glycosyl-enzyme intermediate and the
      complex with the reaction product, cellotriose. These structures reveal intimate
      details of the protein-ligand interactions, including most of the carbohydrate
      associated H atoms and the tautomeric state of crucial active-centre groups in
      the pH 5 orthorhombic crystal form and serve to illustrate the potential for
      atomic resolution analyses to inform strategies for enzyme inhibition.

PMID- 12595702
TI  - Structure of native phosphoglucose isomerase from rabbit: conformational changes
      associated with catalytic function.
AB  - Phosphoglucose isomerase (PGI) is a housekeeping enzyme of metabolism that
      catalyses the interconversion of glucose 6-phosphate and fructose 6-phosphate,
      with roles in the glycolytic and gluconeogenic pathways. PGI is also a
      multifunctional protein that manifests the properties of a cytokine in a wide
      array of cellular processes, including the production of immunoglobulin by B
      cells and tumour-cell differentiation. The crystal structure of PGI in the native
      form from rabbit muscle has been solved at a resolution of 2.5 A by a combination
      of multiple isomorphous replacement and multi-crystal averaging techniques.
      Comparison with published structures of rabbit PGI in complex with three
      inhibitors and with the substrate fructose 6-phosphate reveals a number of
      conformational changes that may be associated with catalytic function. These
      occur in the small domain around the sugar phosphate-binding site, in a small
      helix carrying His388 and in a helix near the C-terminal end. One of these may be
      the structural rearrangement that has been postulated to be the rate-limiting
      step for catalysis.

PMID- 12595703
TI  - Combinatorial crystallization of an RNA-protein complex.
AB  - One of the most difficult steps in X-ray crystallography of a ribonucleoprotein
      (RNP) complex is obtaining crystals that diffract to high resolution. This paper
      describes a procedure for identifying the optimal lengths of the nucleic acid
      components that provide high-quality crystals of the RNP. Both strands of an RNA
      duplex were varied in a systematic manner to generate a large number of unique
      RNPs that were screened for crystallization behavior. As observed in the
      crystallization of other nucleic acids and their complexes, the exact length of
      the RNA chains was found to be critical in obtaining diffraction-quality
      crystals, even though the relative molecular weights of the protein and RNA
      components were approximately 50 and approximately 10 kDa, respectively. In
      particular, the helix-loop-helix structure in the mRNA for the Saccharomyces
      cerevisiae ribosomal protein L30, which functions as an autoregulatory element
      for L30 expression, was synthesized as two separate RNA chains of variable length
      (12-14 and 15-17 nucletides). Duplex formation of these RNAs formed the
      asymmetric, internal loop-binding site for L30. 16 such RNA duplexes, varying by
      +/-1 residue at the 5' or 3' end of either chain, were used to prepare 16 unique
      complexes with a maltose-binding protein-L30 fusion protein. The complexes were
      screened against 48 standard crystallization conditions in 2304 experiments,
      yielding 30 conditions with single crystals in the initial screen. The most
      promising of these is being used for structure determination.

PMID- 12595704
TI  - The structure of T6 human insulin at 1.0 A resolution.
AB  - The structure of T(6) human insulin has been determined at 120 K at a resolution
      of 1.0 A and refined to a residual of 0.183. As a result of cryofreezing, the
      first four residues of the B chain in one of the two crystallographically
      independent AB monomers in the hexameric [Zn(1/3)(AB)(2)Zn(1/3)](3) complex
      undergo a conformational shift that displaces the C(alpha) atom of PheB1 by 7.86
      A relative to the room-temperature structure. A least-squares superposition of
      all backbone atoms of the room-temperature and low-temperature structures yielded
      a mean displacement of 0.422 A. Omitting the first four residues of the B chain
      reduced the mean displacement to 0.272 A. At 120 K, nine residues were found to
      exhibit two discrete side-chain conformations, but only two of these residues are
      in common with the seven residues found to have disordered side chains in the
      room-temperature structure. As a result of freezing, the disorder observed at
      room temperature in both ArgB22 side chains is eliminated. The close contact
      between pairs of O( epsilon 2) atoms in GluB13 observed at room temperature is
      maintained at cryotemperature and suggests that a carboxylate-carboxylic acid
      centered hydrogen bond exists [-C(=O)-O.H.O-C(=O)-] such that the H atom is
      equally shared between the two partially charged O atoms.

PMID- 12595705
TI  - Automated tracing of electron-density maps of proteins.
AB  - The tracing of experimental electron maps in the field of protein crystallography
      is not a rate-limiting step for structure elucidation, but does represent the
      process that requires the most expertise and user time. This paper presents a
      method for automatically tracing the electron-density maps of proteins which can
      reliably generate a C(alpha) trace for protein maps with data in the resolution
      range 1.5-4 A. The number of C(alpha) atoms placed and the precision of atom
      placement depends on the quality of the map, but even with poor maps (FOM
      approximately 0.5) the algorithm can provide a significant saving in time over
      conventional methods of interpretation. The interpretation of six experimental
      maps is presented at different resolutions and levels of phase error; these show
      that data with an FOM of 0.7 or better can be entirely traced with no user
      intervention.

PMID- 12595706
TI  - Phasing at high resolution using Ta6Br12 cluster.
AB  - The Ta(6)Br(12)(2+) cluster compound is known to be a powerful reagent for
      derivatization of crystals of large macromolecules at low resolution. The cluster
      is a regular octahedron of six Ta atoms with 12 bridging Br atoms at the edges of
      the octahedron. The cluster is compact, of approximately spherical shape, with a
      radius of about 6 A. Both tantalum and bromine display a significant anomalous
      diffraction signal at their absorption edges at 1.25 and 0.92 A, respectively. At
      resolutions lower than 5 A the tantalum cluster behaves as a super-atom and
      provides very large isomorphous and anomalous signals, which significantly
      diminish at about 4 A. However, beyond 3 A the individual Ta atoms can be
      resolved and the phasing power of the cluster increases again. The
      Ta(6)Br(12)(2+) cluster has been used for phasing four different proteins at high
      resolution. Ta(6)Br(12)(2+) appeared to be a mild derivatization reagent and,
      despite partial incorporation, led to a successful solution of crystal structures
      by the single-wavelength anomalous diffraction (SAD) approach.

PMID- 12595707
TI  - Crystallization and preliminary X-ray diffraction studies of two different
      crystal forms of the lipase 2 isoform from the yeast Candida rugosa.
AB  - The yeast Candida rugosa produces several closely related lipases which show a
      high degree of sequence identity (between 77 and 88% for pairs of proteins).
      Despite this high sequence identity, they exhibit markedly different substrate
      specificities, indicating that subtle structural differences may produce
      significant functional changes. Isoform 2 (lip2) has been crystallized using the
      hanging-drop vapour-diffusion method at 291 K. Diffraction-quality crystals have
      been obtained from two different experimental conditions (designated A and B,
      respectively). Type A crystals belong to space group P1 and have unit-cell
      parameters a = 62.15, b = 91.14, c = 108.46 A, alpha = 90.78, beta = 106.31,
      gamma = 86.91 degrees; type B crystals are monoclinic with a nearly hexagonal
      topology, with unit-cell parameters a = 116.11, b = 225.55, c = 116.06 A, beta =
      119.89 degrees, and belong to space group P2(1). Diffraction data were collected
      to a resolution of 1.97 A at a synchrotron facility from type A crystals and to
      2.65 A on an in-house rotating-anode generator from type B crystals. Whereas the
      triclinic crystal reveals monomeric lip2, the monoclinic crystal contains dimeric
      lip2.

PMID- 12595708
TI  - Purification and crystallization of the N-terminal domain from the human
      doublecortin-like kinase.
AB  - The unique doublecortin-like tandem of two homologous domains is found in certain
      microtubule-associated proteins such as doublecortin (DCX) and doublecortin-like
      kinase (DCLK). It is responsible for interactions with tubulin/microtubules and
      regulates microtubule dynamics. Here, the expression and purification of the
      tandem from human DCLK (residues 49-280) and of the isolated domains (residues 49
      154 and 176-280) and the successful crystallization of the N-terminal domain (N
      DCLK) are reported. High-quality wild-type crystals were obtained and a complete
      native data set was collected to 1.5 A resolution. The crystals belong to space
      group C2, with unit-cell parameters a = 85.98, b = 29.62, c = 40.33 A, beta =
      101.3 degrees. Crystals of SeMet-substituted N-DCLK (Leu120Met) were also
      obtained, but they exhibit the symmetry of space group P2(1), with unit-cell
      parameters a = 38.81, b = 29.43, c = 40.1 A, beta = 115.7 degrees.

PMID- 12595709
TI  - Crystallization and preliminary crystallographic analysis of extracellular
      fragment X3 of YWK-II/APPH: a human sperm membrane protein related to the
      Alzheimer betaA4-amyloid precursor protein.
AB  - Crystals of extracellular fragment X3 of a human sperm membrane protein YWK
      II/APPH have been grown at 291 K using 8% PEG 4000 as precipitant by the vapour
      diffusion method. The diffraction pattern of the crystal extends to 2.9 A
      resolution at 100 K using Cu Kalpha radiation in-house. The crystals belong to
      space group P2(1), with unit-cell parameters a = 46.0, b = 43.7, c = 90.2 A,
      alpha = gamma = 90.0, beta = 106.6 degrees. Furthermore, a selenomethionine
      (SeMet) derivative of the protein was overexpressed in the same expression system
      and was purified in a reducing environment. The derivative crystals were obtained
      under similar conditions. Subsequently, a single-wavelength data set was
      collected to 2.38 A resolution from the derivative crystal at ESRF. The crystals
      belong to space group P2(1), with unit-cell parameters a = 46.2, b = 44.0, c =
      88.3 A, alpha = gamma = 90.0, beta = 103.6 degrees. The presence of one molecule
      per asymmetric unit gives a crystal Volume per protein mass (V(M)) of 2.8 A(3)
      Da(-1) and a solvent content of 56.4% by Volume.

PMID- 12595710
TI  - Crystallization and initial X-ray diffraction of BtuB, the integral membrane
      cobalamin transporter of Escherichia coli.
AB  - BtuB, the cobalamin transporter from Escherichia coli, has been overexpressed,
      purified and crystallized. The purified protein was solubilized in n-octyl
      tetraoxyethylene (C(8)E(4)) and was crystallized using sitting-drop vapor
      diffusion with PEG 3350 and magnesium acetate as precipitants (pH 6.5). Two
      crystal forms have been obtained. Crystal type I belongs to space group P3(1)21,
      with unit-cell parameters a = b = 81.6, c = 210.0 A, alpha = beta = 90, gamma =
      120 degrees. Crystal type II belongs to space group P3(1)21, with unit-cell
      parameters a = b = 81.6, c = 226.0 A, alpha = beta = 90, gamma = 120 degrees.
      Each crystal form contains a monomer in the asymmetric unit. Diffraction for
      crystal type I extends to 2.0 A and diffraction for crystal type II extends to
      2.7 A. Both crystal forms are suitable for structure determination.

PMID- 12595712
TI  - Purification, crystallization and preliminary X-ray diffraction studies of
      recombinant class A non-specific acid phosphatase of Salmonella typhimurium.
AB  - The phoN gene of Salmonella enterica sv. Typhimurium strain MD6001 was cloned in
      the multicopy plasmid pBluescript SK(-). The nucleotide sequence of the cloned
      gene differs from the corresponding S. typhimurium LT2 sequence at 23 residues,
      leading to 15 amino-acid differences, but was very close to the S. typhi phoN
      sequence (only three nucleotide and two amino-acid differences). The recombinant
      PhoN protein was purified to homogeneity. Two forms of crystals were harvested
      from a single crystallization condition. Diffraction intensity data were
      collected using a laboratory X-ray source to resolution limits of 2.5 and 2.8 A
      for crystals belonging to space group C2 and C222(1), respectively. Based on non
      crystallographic symmetry, four monomers of PhoN are expected to be present in
      the asymmetric unit of the C2 unit cell. Two monomers of a biologically active
      dimer in the asymmetric unit of the C222(1) unit cell are expected from the
      Matthews coefficient.

PMID- 12595711
TI  - Crystallization and preliminary X-ray crystallographic analysis of SP1, a novel
      chaperone-like protein.
AB  - SP1 (108 amino acids) is a boiling-stable stress-responsive protein. It has no
      significant sequence homology to other stress-related proteins or to small heat
      shock proteins (sHsps). SP1 activity is ATP-independent, similar to other small
      heat-shock proteins. Based on these features, it is expected that the structure
      function relationship of SP1 will be unique. In this work, the crystallization
      and preliminary crystallographic data of native SP1 and its selenomethionine
      derivative are described. Recombinant SP1 and its selenomethionine derivative
      were expressed in Escherichia coli and used for crystallization experiments. SP1
      crystals were grown from 0.1 M HEPES pH 7.5, 20% PEG 3K, 0.2 M NaCl. One to four
      single crystals appeared in each droplet within a few Days and grew to dimensions
      of about 0.5 x 0.5 x 0.8 mm after about two weeks. Diffraction studies of these
      crystals at low temperature indicated that they belong to space group I422, with
      unit-cell parameters a = 89, b = 89, c = 187 A. Efforts to crystallize the
      selenomethionine derivative of SP1 are in progress.

PMID- 12595713
TI  - Crystallization and preliminary crystallographic studies of juvenile hormone
      binding protein from Galleria mellonella haemolymph.
AB  - Juvenile hormone-binding protein (JHBP) isolated from Galleria mellonella
      haemolymph has been crystallized using the hanging-drop method in two polymorphic
      forms. The best diffracting crystals (2.7 A) are trigonal, space group P3(1)21
      (or P3(2)21), with unit-cell parameters a = 110.4, c = 93.9 A. X-ray diffraction
      data have been collected for the native crystals using synchrotron radiation and
      cryogenic conditions (100 K).

PMID- 12595714
TI  - Crystallization and preliminary crystallographic studies of mung bean cytokinin
      specific binding protein.
AB  - Cytokinins, or plant growth hormones, bind with very high affinity to cytokinin
      specific binding proteins (CSBPs). Recombinant mung bean CSBP has been
      overexpressed in Escherichia coli and crystallized in complex with zeatin, a
      natural plant growth hormone. The crystals belong to the hexagonal system, space
      group P6(2) or P6(4), with unit-cell parameters a = 113.62, c = 86.85 A, contain
      two to five copies of the protein in the asymmetric unit and diffract X-rays to
      1.25 A resolution.

PMID- 12595715
TI  - Preliminary crystallographic studies of glycogen synthase from Agrobacterium
      tumefaciens.
AB  - Crystals of the glycogen synthase (GS) from Agrobacterium tumefaciens have been
      grown that diffract to 2.6 A resolution. The enzyme, which is homologous to the
      starch synthases of plants, catalyzes the last reaction step in the biosynthesis
      of glycogen. It is a alpha-retaining glucosyltransferase that uses ADP-glucose to
      incorporate additional glucose monomers onto the growing glycogen polymer. Its
      homology with mammalian GSs is marginal, but several regions shown to be
      important in catalysis are strictly conserved. Knowledge of the crystal structure
      of GS will be a major advance in the understanding of glycogen/starch metabolism
      and its regulation. A rational approach in enzyme engineering can subsequently be
      envisaged. The multiwavelength anomalous diffraction approach will be used to
      solve the phase problem.

PMID- 12595716
TI  - Crystallization and preliminary X-ray analysis of an alkaline serine protease
      from Nesterenkonia sp.
AB  - A novel calcium-independent serine protease from an alkaliphilic bacterium,
      Nesterenkonia sp. AL20, has been purified and crystallized at 296 K using sodium
      formate as the main precipitant. This enzyme is optimally active at pH 10,
      exhibits high stability towards autolytic digestion and its stability is not
      affected by the presence of EDTA or detergents. The triangular prism-shaped
      crystals diffracted X-rays to beyond 1.5 A at a synchrotron beamline, with space
      group R3 and unit-cell parameters a = b = 92.26, c = 137.88 A. A complete data
      set has been collected to 1.39 A resolution. The asymmetric unit is estimated and
      confirmed by self-rotation function calculation to contain two molecules, giving
      a crystal Volume per protein mass (V(M)) of 2.68 A(3) Da(-1) and a solvent
      content of 54%.

PMID- 12595717
TI  - Expression, purification, crystallization and preliminary crystallographic
      analysis of Trypanosoma brucei phosphofructokinase.
AB  - Phosphofructokinase from Trypanosoma brucei (TbPFK) was purified from a
      recombinant expression system in Escherichia coli by metal-affinity
      chromatography via its N-terminal His tag. The yield was 15-20 mg of pure enzyme
      per litre of culture. M(r) was shown to be 55 585 by mass spectrometry. Crystals
      suitable for X-ray diffraction analysis were obtained by the hanging-drop method
      of vapour diffusion with sodium formate as the precipitating agent. Monoclinic
      crystals of the apoenzyme grew within one week, as did orthorhombic crystals of
      PFK in the presence of enzymic reaction products or an active-site inhibitor.
      Initial attempts to solve the structure by molecular replacement with bacterial
      PFK structures as search models proved unrewarding, but a multiple-copy search
      with a polyalanine model was successful. In addition, heavy-atom soaking with
      platinum and mercury has yielded derivatives suitable for X-ray diffraction. A
      combination of the phase information from the molecular-replacement solution and
      the heavy-atom derivatives should allow structure solution of TbPFK. The
      availability of this first eukaryotic PFK structure will be of particular
      significance for structure-based drug design and will also provide important
      additional structural evidence for the allosteric control of PFK activity.

PMID- 12595718
TI  - Crystallization and preliminary X-ray analysis of a xyloglucan
      endotransglycosylase from Populus tremula x tremuloides.
AB  - Xyloglucan endotransglycosylases (XETs) cleave and religate xyloglucan polymers
      in plant cell walls. Recombinant XET from poplar has been purified from a Pichia
      pastoris expression system and crystallized. Two different crystal forms were
      obtained by vapour diffusion from potassium sodium tartrate and from an imidazole
      buffer using sodium acetate as a precipitant. Data were collected from these
      crystal forms to 3.5 and 2.1 A resolution, respectively. The first crystal form
      was found to belong to space group P3(1)21 or P3(2)21 (unit-cell parameters a =
      98.6, b = 98.6, c = 98.5 A) and the second crystal form to space group P6(3)
      (unit-cell parameters a = 188.7, b = 188.7, c = 46.1 A).

PMID- 12595719
TI  - Crystallization of the membrane-containing bacteriophage PRD1 in quartz
      capillaries by vapour diffusion.
AB  - Crystals of bacteriophage PRD1, a virus containing an internal lipid bilayer,
      have been grown in thin-walled quartz capillary tubes by vapour diffusion as a
      means of eliminating mechanical handling of the crystals during data collection.
      It has been found that the addition of polyethylene glycol 20 000 (PEG 20K) to
      the mother liquor that bathes the crystals allows far higher resolution
      diffraction intensities to be observed. Growing and treating the crystals in this
      way has produced a small number of crystals which are particularly amenable to X
      ray diffraction analysis.

PMID- 12595720
TI  - Crystallization and preliminary X-ray analysis of swine vesicular disease virus
      (SVDV).
AB  - Three different crystal forms of the swine vesicular disease virus (SVDV),
      isolate SPA/2/'93, were obtained by the hanging-drop vapour-diffusion technique
      using ammonium sulfate and sodium/potassium phosphate as precipitants. Monoclinic
      crystals, space group C2, with unit-cell parameters a = 473.7, b = 385.3, c =
      472.8 A, beta = 100.4 degrees, contain one virus pArticle in the crystal
      asymmetric unit and diffract to 3.0 A resolution. A second type of crystals had a
      cubic morphology and diffracted beyond 2.6 A resolution. These crystals belong to
      a primitive orthorhombic space group, with unit-cell parameters a = 319.6, b =
      353.8, c = 377.7 A, and contain half a virus pArticle in the asymmetric unit. A
      third type of crystals, with a prismatic shape and belonging to space group I222,
      was also obtained under similar crystallization conditions. These latter
      crystals, with unit-cell parameters a = 318.3, b = 349.9, c = 371.7 A, diffract
      to at least 3.0 A resolution and contain 15 protomers per asymmetric unit; this
      requires that three perpendicular crystal twofold axes coincide with three of the
      viral pArticles' dyad axes.

PMID- 12595721
TI  - Purification, crystallization and preliminary X-ray analysis of Caenorhabditis
      elegans ubiquitin-conjugation enzyme M7.1.
AB  - M7.1 is a class IV ubiquitin-conjugation enzyme (UBC) that belongs to the
      ubiquitination cascade in Caenorhabditis elegans. The clone for this UBC has been
      overexpressed in Escherichia coli and the 16.7 kDa protein was purified from the
      soluble fraction. M7.1 was crystallized by sitting-drop vapor diffusion in 10%
      ethanol, 1.5 M NaCl at 277.5 K. Crystals diffracted to 1.75 A and belong to the
      orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 44.3, b =
      54.3, c = 60.2 A. The asymmetric unit contains a single monomer. A molecular
      replacement model has been determined and refinement is in progress.

PMID- 12595722
TI  - Purification, N-terminal sequencing, partial characterization, crystallization
      and preliminary crystallographic analysis of two glycosylated serine proteinases
      from Agkistrodon acutus venom.
AB  - AaV-SP-I and AaV-SP-II, two glycosylated serine proteinases from Agkistrodon
      acutus venom with fibrinogenolysis and esterolysis activities, have been purified
      to homogeneity by three-step ion-exchange chromatography. Estimated by SDS-PAGE,
      the molecular weights of AaV-SP-I and AaV-SP-II are about 32 and 31 kDa under
      reducing conditions and 26 and 25 kDa under non-reducing conditions,
      respectively. The first 24 N-terminal amino-acid residues are the same in both
      sequences and display a high homology with those of several snake-venom serine
      proteinases. However, the proteins possess obviously distinct carbohydrate
      contents. Using the conventional hanging-drop vapour-diffusion method, single
      crystals of both enzymes were grown that were suitable for X-ray diffraction
      analysis. The crystals of AaV-SP-I and AaV-SP-II belong to space groups
      P2(1)2(1)2(1) and C2, respectively. In each case there is only one molecule in
      the asymmetric unit.

PMID- 12595723
TI  - Expression, purification and preliminary X-ray characterization of CTP synthetase
      from Thermus thermophilus HB8.
AB  - A recombinant form of the CTP synthetase from Thermus thermophilus HB8 (tCTPs)
      was grown as colourless crystals by the hanging-drop vapour-diffusion technique
      using ammonium sulfate or sodium citrate as a precipitating agent. The crystals
      belong to space group I222, with unit-cell parameters a = 88.2, b = 118.9, c =
      142.7 A, alpha = beta = gamma = 90 degrees, and are most likely to contain a
      monomer in the asymmetric unit with a V(M) value of 3.07 A(3) Da(-1). The
      crystals obtained from ammonium sulfate and sodium citrate solutions diffract X
      rays to a resolution of 2.25 A using synchrotron X-ray sources and to a
      resolution of 2.35 A using Cu Kalpha X-rays from a rotating-anode generator.

PMID- 12595724
TI  - Coexpression, purification, crystallization and preliminary X-ray
      characterization of glycine decarboxylase (P-protein) of the glycine-cleavage
      system from Thermus thermophilus HB8.
AB  - Thermus thermophilus (Tth) HB8 glycine decarboxylase (P-protein) is an
      alpha(2)beta(2) tetrameric enzyme with a total molecular mass of 200 kDa. The
      alpha- and beta-subunits of the Tth P-protein have been coexpressed in
      Escherichia coli and purified as a stable complex. Dynamic light-scattering
      measurements indicated the recombinant protein to be monodisperse and its size to
      be consistent with an alpha(2)beta(2) tetrameric composition. Crystals of the
      protein have been grown in polyethylene glycol 3350 using the vapour-diffusion
      method at 291 K. Synchrotron radiation from BL45XU at SPring-8 was used to
      measure a complete native data set to 2.4 A resolution. The crystals belong to
      the trigonal space group P3(1)21 or P3(2)21, with unit-cell parameters a = b =
      89.5, c = 371.0 A. Estimation of the crystal packing (V(M) = 2.15 A(3) Da(-1))
      and self-rotation function analysis suggest the presence of one alpha(2)beta(2)
      tetramer per asymmetric unit, with the molecules related by non-crystallographic
      twofold symmetry.

PMID- 12595725
TI  - Expression, purification and preliminary crystallographic analysis of human
      sorbitol dehydrogenase.
AB  - Human sorbitol dehydrogenase (SDH) was expressed in Escherichia coli BL21 cells
      and purified using ammonium sulfate precipitation and anion-exchange and dye
      affinity chromatography. Purified SDH was crystallized from polyethylene glycol
      solutions using the hanging-drop vapour-diffusion method. X-ray data were
      collected to 2.75 A resolution. The crystals belong to the monoclinic C2 space
      group, with unit-cell parameters a = 145.9, b = 52.3, c = 169.0 A, beta = 101.8
      degrees. This is the first crystallization report of human sorbitol
      dehydrogenase.

PMID- 12595726
TI  - Crystallization and preliminary X-ray crystallographic studies of
      phosphopantetheine adenylyltransferase from Helicobacter pylori.
AB  - Phosphopantetheine adenylyltransferase (PPAT; EC 2.7.7.3) is an essential enzyme
      in the coenzyme A (CoA) biosynthetic pathway and catalyzes the reversible
      transfer of an adenylyl group from ATP to 4'-phosphopantetheine to form 3'
      dephospho-CoA. PPAT from Helicobacter pylori has been overexpressed in
      Escherichia coli and crystallized at 296 K using sodium chloride as a precipitant
      by the hanging-drop vapour-diffusion method. X-ray diffraction data have been
      collected to 2.00 A resolution at 100 K using synchrotron radiation. The crystals
      belong to the trigonal space group P3(1)21 or P3(2)21, with unit-cell parameters
      a = b = 80.50, c = 143.05 A, alpha = beta = 90, gamma = 120 degrees. Six monomers
      of PPAT are likely to be present in the asymmetric unit, giving a V(M) of 2.39
      A(3) Da(-1) and a solvent content of 49%.

PMID- 12595727
TI  - Crystallization and preliminary X-ray analysis of the Mj0684 gene product, a
      putative aspartate aminotransferase, from Methanococcus jannaschii.
AB  - A putative aspartate aminotransferase from the hyperthermophilic archaeon
      Methanococcus jannaschii encoded by the Mj0684 gene has been overexpressed in
      Escherichia coli and crystallized at 296 K using the sitting-drop vapour
      diffusion method. The crystals belong to space group P4(1)2(1)2 (or P4(3)2(1)2),
      with unit-cell parameters a = b = 111.87, c = 60.86 A. They diffract to 2.2 A
      resolution using Cu Kalpha X-rays. The asymmetric unit contains a single subunit
      of the recombinant Mj0684 gene product, giving a corresponding V(M) of 2.25 A(3)
      Da(-1) and a solvent content of 45.3% by Volume. An X-ray diffraction data set
      has been collected to 2.2 A at 295 K.

PMID- 12595728
TI  - Crystallization and preliminary X-ray crystallographic studies of salt-tolerant
      glutaminase from Micrococcus luteus K-3.
AB  - Glutaminase from the marine bacterium Micrococcus luteus K-3 (Micrococcus
      glutaminase) is a salt-tolerant protein which shows equivalent activities both in
      the absence and the presence of 3 M sodium chloride and is distinct from
      halophilic proteins, which are inactivated in the absence of salt. To investigate
      the mechanisms of the salt-tolerant adaptation of Micrococcus glutaminase, the
      glutaminase and its major fragment containing about 80% of the protein were
      crystallized using the hanging-drop vapour-diffusion method. The glutaminase
      crystals belong to space group P622, with unit-cell parameters a = b = 111.4, c =
      210.9 A, alpha = beta = 90, gamma = 120 degrees, and diffract to 2.6 A
      resolution. The fragment crystals belong to space group F222, with unit-cell
      parameters a = 115.7, b = 116.4, c = 144.9 A, alpha = beta = gamma = 90 degrees,
      and diffract to 2.4 A resolution. Data from selenomethionine (SeMet) substituted
      glutaminase crystals and from SeMet-substituted fragment crystals were collected
      to 2.6 and 2.4 A resolution, respectively. Structural analyses of the glutaminase
      and its fragment are currently being attempted using the multiwavelength
      anomalous diffraction (MAD) phasing method.

PMID- 12595729
TI  - Crystallization and preliminary X-ray crystallographic studies of chorismate
      synthase from Helicobacter pylori.
AB  - Chorismate synthase (EC 4.6.1.4) catalyzes the transformation of 5
      enolpyruvylshikimate 3-phosphate to chorismate in the last step of the shikimate
      pathway. Chorismate synthase from Helicobacter pylori fused with an eight-residue
      C-terminal tag was overexpressed in soluble form in Escherichia coli. It was
      crystallized at 296 K using polyethylene glycol 400 as a precipitant. A set of X
      ray diffraction data was collected to 2.5 A resolution using synchrotron
      radiation. The crystals belong to the tetragonal space group I4, with unit-cell
      parameters a = b = 145.79, c = 130.98 A. The asymmetric unit contains a tetramer,
      giving a crystal Volume per protein mass (V(M)) of 2.13 A(3) Da(-1) and a solvent
      content of 42.3%.

PMID- 12595730
TI  - Crystallization and preliminary analysis of native and N-terminal truncated
      isoforms of toluene-4-monooxygenase catalytic effector protein.
AB  - Single crystals have been obtained of the toluene 4-monooxygenase catalytic
      effector protein, the SeMet-enriched protein and a truncated isoform missing ten
      amino acids from the N-terminus. Complete X-ray diffraction data sets have been
      collected and analyzed to 2.0, 3.0 and 1.96 A resolution for the native, SeMet
      and truncated isoform crystals, respectively. The native and SeMet proteins
      crystallized in space group P6(1)22 (unit-cell parameters a = b = 86.41 +/- 0.15,
      c = 143.90 +/- 0.27 A), whereas the truncated isoform crystallized in space group
      P2(1)3 (a = b = c = 86.70 +/- 0.47 A). Matthews coefficient calculations suggest
      either two or three molecules per asymmetric unit in the P6(1)22 space group and
      two molecules per asymmetric unit in the P2(1)3 space group. Experimental phases
      from MAD analysis of the SeMet isoform and molecular replacement of the truncated
      isoform confirm the presence of two molecules per asymmetric unit in each case.
      These crystallographic results are the first available for the evolutionarily
      related but functionally diversified catalytic effector proteins from the
      multicomponent diiron monooxygenase family.

PMID- 12595731
TI  - Crystallization of a member of the recFOR DNA repair pathway, RecO, with and
      without bound oligonucleotide.
AB  - RecFOR proteins are important for DNA repair by homologous recombination in
      bacteria. The RecO protein from Thermus thermophilus was cloned and purified, and
      its binding to oligonucleotides was characterized. The protein was crystallized
      alone and in complex with a 14-mer oligonucleotide. Both crystal forms grow under
      different crystallization conditions in the same space group, P3(1)21 or P3(2)21,
      with almost identical unit-cell parameters. Complete data sets were collected to
      2.8 and 2.5 A for RecO alone and for the RecO-oligonucleotide complex,
      respectively. Visual comparison of the diffraction patterns between the two
      crystal forms and calculation of an R(merge) of 33.9% on F indicate that one of
      the crystal forms is indeed a complex of RecO with bound oligonucleotide.

PMID- 12595732
TI  - Crystallization and preliminary X-ray characterization of cytochrome c" from the
      obligate methylotroph Methylophilus methylotrophus.
AB  - Cytochrome c" from the obligate methylotroph Methylophilus methylotrophus is a 15
      kDa monohaem protein which has a c-type haem covalently linked to the protein
      chain. Two histidine residues are the axial ligands of the Fe atom in the
      oxidized form. This cytochrome is one of the few known haem proteins which
      undergoes a change of spin state of the Fe atom upon reduction, with the
      detachment of an axial histidine ligand. Initial crystallization conditions
      involved the utilization of cadmium chloride as an additive and resulted in
      highly mosaic crystals with poor diffraction properties. Optimization of the
      crystallization conditions was achieved by slowing the nucleation process
      utilizing agarose gels and viscous additives such as PEG, ethylene glycol and
      glycerol. Addition of glycerol to the crystallization buffer produced crystals
      suitable for X-ray diffraction, with a reduced solvent content and mosaicity,
      which diffracted to a maximum resolution of 1.19 A using synchrotron radiation.
      The crystals obtained under these conditions were employed for structure solution
      using the multiwavelength anomalous dispersion method at the Fe K edge.

PMID- 12595733
TI  - Crystallization and preliminary X-ray analysis of candoxin, a novel reversible
      neurotoxin from the Malayan krait Bungarus candidus.
AB  - Candoxin, a novel three-finger toxin from Bungarus candidus, is a reversible
      antagonist of muscle (alphabetagammadelta) but a poorly reversible antagonist of
      neuronal alpha7 nicotinic acetylcholine receptors. It has a molecular weight of
      7344 Da, with 66 amino-acid residues including ten half-cystines. The fifth
      disulfide bridge is located at the tip of loop I (Cys6-Cys11) instead of in loop
      II as found in other alpha-neurotoxins. Interestingly, candoxin lacks the segment
      cyclized by the fifth disulfide bridge at the tip of the middle loop of long
      chain neurotoxins, which was reported to be critical for binding to alpha7
      receptors. As a first step to determining its three-dimensional structure,
      candoxin was crystallized by the hanging-drop vapour-diffusion technique in
      conditions around 1.5 M sodium chloride, 10%(v/v) ethanol. The crystals formed
      belonged to the hexagonal system, space group P6(2)22, with unit-cell parameters
      a = 54.88, b = 54.88, c = 75.54 A, alpha = beta = 90, gamma = 120 degrees, and
      diffract to a resolution of 1.80 A. The crystallographic asymmetric unit contains
      one molecule of candoxin, with an estimated solvent content of 44.6%. Attempts to
      solve these structures by molecular-replacement methods have not been successful
      and a heavy-atom derivative search has been initiated.

PMID- 12595734
TI  - Crystallization and preliminary X-ray crystallographic analysis of the trimer
      core from measles virus fusion protein.
AB  - Two heptad-repeat regions (HR1 and HR2) are highly conserved in paramyxovirus
      fusion proteins and form a stable helical trimer of heterodimers [(HR1-HR2)(3)]
      after the fusion between viral and cellular membranes. In this study, two HR
      regions of the fusion protein of measles virus, a member of the paramyxoviruses,
      were selected and overexpressed as a single chain (named 2-Helix) connected by an
      amino-acid linker using a GST-fusion expression system in Escherichia coli.
      Crystals of 2-Helix protein (GST removed) could be obtained from many conditions
      using the sitting- or hanging-drop vapour-diffusion method. A complete data set
      was collected in-house to 1.9 A resolution from a single crystal. The crystal
      belongs to space group P6, with unit-cell parameters a = b = 51.637, c = 67.058
      A. To facilitate the crystal structure solution, SeMet-substituted 2-Helix
      crystals, grown under similar conditions to the native, were also obtained and
      diffracted X-rays to 1.8 A using synchrotron radiation.

PMID- 12595736
TI  - Crystallization and preliminary X-ray study of human dipeptidyl peptidase IV
      (DPPIV).
AB  - Human DPPIV has been expressed in the baculovirus system and purified and
      crystallized using the hanging-drop method. A crystal was obtained from 180 mM
      Gly-NaOH buffer pH 9.5 containing 18% PEG 4000 and 180 mM sodium acetate. The
      crystal belongs to the orthorhombic space group P2(1)2(1)2(1), with unit-cell
      parameters a = 118.04, b = 125.92, c = 136.84 A, and diffracts beyond 2.6 A
      resolution. There are two molecules per asymmetric unit, indicating a solvent
      content of 57.6%.

PMID- 12595735
TI  - Crystallization and preliminary X-ray diffraction studies of a mosquito
      larvicidal toxin from Bacillus thuringiensis subsp. israelensis.
AB  - The Cry4B delta-endotoxin from Bacillus thuringiensis subsp. israelensis is
      specifically toxic to mosquito larvae. For a better understanding of the
      mechanism of toxicity, chymotrypsin-activated Cry4B toxin (68 kDa) has been
      purified and crystallized in sodium bromide at neutral pH. The well formed
      crystals belong to the rhombohedral space group R32, with unit-cell parameters a
      = b = 185.82, c = 187.93 A, and diffracted X-rays to 1.75 A resolution. The
      asymmetric unit contains one toxin molecule and 74% solvent content, as shown by
      molecular replacement from a composite model of the homologous Cry3A and Cry1Aa.
      The purified protein and crystals both possessed mosquitocidal activity.

PMID- 12595737
TI  - The production, purification and crystallization of a pocilloporin pigment from a
      reef-forming coral.
AB  - Reef-building corals contain fluorescent pigments termed pocilloporins that
      function by regulating the light environment of coral and acting as a
      photoprotectant in excessive sunlight. These pocilloporins are related to the
      monomeric green fluorescent protein and the tetrameric DsRed fluorescent
      proteins, which have widespread use as biotechnological tools. An intensely blue
      coloured pocilloporin, termed Rtms5, was expressed in Escherichia coli, purified
      and crystallized. Rtms5 was shown to be tetrameric, with deep blue crystals that
      diffract to 2.2 A resolution and belong to space group I4(1)22. The colour of
      this pocilloporin was observed to be sensitive to pH and a yellow (pH 3.5) and a
      red form (pH 4.5) of Rtms5 were also crystallized. These crystals belong to space
      group P4(2)22 and diffract to 2.4 A resolution or better.

PMID- 12595738
TI  - Using rational screening and electron microscopy to optimize the crystallization
      of succinate:ubiquinone oxidoreductase from Escherichia coli.
AB  - The membrane-bound respiratory complex II, succinate:ubiquinone oxidoreductase
      (SQR) from Escherichia coli, has been anaerobically expressed, then purified and
      crystallized. The initial crystals obtained were small and diffracted poorly. In
      order to facilitate structure determination, rational screening and sample
      quality analysis using electron microscopy was implemented. The crystals of SQR
      from E. coli belong to the trigonal space group R32, with unit-cell parameters a
      = b = 138.7, c = 521.9 A, and diffract to 2.6 A resolution. The optimization
      strategy used for obtaining well diffracting SQR crystals is applicable to a wide
      range of membrane proteins.

PMID- 12595739
TI  - The dual role of CHAPS in the crystallization of stromelysin-3 catalytic domain.
AB  - CHAPS [3-[(3-cholamidopropyl) dimethylammonio]-1-propane sulfonate] is a non
      denaturing detergent widely used for protein solubilization and stabilization.
      CHAPS was used to avoid protein aggregation during concentration of the
      recombinant stromelysin-3 (ST3) catalytic domain and was required to stabilize
      the protein, allowing its crystallization. The crystal structure of the complex
      between the ST3 catalytic domain and a phosphinic inhibitor shows two CHAPS
      molecules binding to ST3 in two different orientations. One CHAPS molecule is
      masking a hydrophobic surface of the protein, thus avoiding protein aggregation.
      This detergent molecule is also involved in packing interactions. The other
      detergent molecule is located in a pocket formed by the N- and C-terminal parts
      of the ST3 and stabilizes a loop that normally binds a Ca atom.

PMID- 12595740
TI  - Structure of a tetragonal crystal form of Escherichia coli 2-C-methyl-D
      erythritol 4-phosphate cytidylyltransferase.
AB  - 2-C-Methyl-D-erythritol 4-phosphate cytidylyltransferase is an essential enzyme
      in the mevalonate-independent pathway of isoprenoid biosynthesis. The structure
      of a tetragonal crystal form has been solved by molecular replacement and refined
      to 2.4 A resolution. Structure and sequence comparisons suggest that the enzyme
      is a suitable target for a structure-based approach to the development of novel
      broad-spectrum antibiotics. However, the absence of ligands in the enzyme active
      site together with the moderate resolution of the structure indicates that this
      tetragonal crystal form is inferior to that of a previously reported highly
      ordered monoclinic form [Richard et al. (2001), Nature Struct. Biol. 8, 641-647].

PMID- 12595741
TI  - The organization of divalent cations in the active site of cadmium Escherichia
      coli fructose-1,6-bisphosphate aldolase.
AB  - Previously determined crystal structures of the zinc enzyme Escherichia coli
      class II fructose-1,6-bisphosphate aldolase display good agreement for the
      protein structure but a differing metal-ion organization in the active site. The
      structure of the enzyme with Cd(2+) in place of Zn(2+) has now been determined to
      2.0 A resolution to facilitate cation identification. The protein structure was
      essentially identical to other structures and five Cd(2+) positions were
      identified. Two of the cations are at the active site; one corresponds to the
      catalytic ion and the other provides a structural contribution. These Cd(2+)
      sites are equivalent to two Zn(2+) ions observed when the enzyme is complexed
      with a transition-state mimic and confirm our assignment of the roles played by
      these ions.

PMID- 12595742
TI  - Sheldrick's 1.2 A rule and beyond.
AB  - An average profile of squared normalized structure factors as a function of
      resolution, /E/2>(d*), calculated from a large ensemble of high-resolution
      protein models, is presented. An interpretation is given that provides a
      structural explanation for Sheldrick's 1.2 A rule for the applicability of direct
      methods. The implications for the potential effectiveness of extended direct
      methods, incorporating stereochemical knowledge, are discussed.

PMID- 12595743
TI  - Identification and immunohistochemical characterization of a mucin-like
      glycoprotein expressed in early stage breast carcinoma.
AB  - In this report we describe a cDNA sequence, BS106, identified from Incyte
      Genomics LifeSeq Expressed Sequence Tag database. A multi-tissue mRNA expression
      array, northern blots, and RT-PCR assays demonstrate the expression of BS106 in
      mammary, salivary and prostate glands, but not in other tissue types. BS106 mRNA
      was detected in 90% of the breast tissues examined. The cDNA encodes a 90-amino
      acid protein characterized as a small, mucin-like protein based on amino acid
      composition, extensive O-linked glycosylation, and expression profile. BS106
      protein was recombinantly expressed in human embryonic kidney 293 cells and the
      secreted product was purified from the culture media. Monoclonal antibodies were
      prepared and used for immunohistochemical analysis of early stage breast cancer.
      BS106 protein was detected in the vast majority of carcinomas (70-100%) and
      overexpressed in approximately 30% of the 22 specimens analyzed. BS106 protein
      was not detected in other solid tumor types including bladder carcinoma, colon
      carcinoma, endometrial carcinoma, gastric carcinoma, squamous cell lung
      carcinoma, adenocarcinoma of the lung, ovarian carcinoma, pancreatic and
      prostatic carcinoma.

PMID- 12595744
TI  - N-(4-hydroxyphenyl)-retinamide selectively increases All-TRANS retinoic acid
      inhibitory effects in HER2/NEU-overexpressing breast cancer cells.
AB  - We previously reported that overexpression of the HER2/NEU oncogene induces all
      TRANS retinoic acid (ATRA) resistance in breast cancer cells. N-(4-hydroxyphenyl)
      retinamide (4HPR), a synthetic analogue of ATRA, has been shown to repress the
      expression of HER2/neu and its family member, epidermal growth factor receptor
      (EGFR). We investigated whether 4HPR, by suppressing HER2/neu or EGFR expression,
      could sensitize breast cancer cells to ATRA. At 1.3 micro M concentration (a
      clinically pharmacologically achievable dose), 4HPR increased ATRA sensitivity
      synergistically in HER2/NEU-overexpressing BT-474, MDA-MB-453, and MCF-7/Her2
      breast cancer cells. However, 4HPR did not sensitize EGFR-overexpressing MDA-MB
      468, Hs578T, and MCF-7/EGFR breast cancer cells to ATRA. The increased inhibitory
      effects in HER2/NEU-overexpressing cells were not correlated with increases in
      expression levels of p21(WAF1/CIP1) or retinoblastoma protein. Combining 4HPR
      with ATRA may lead to a novel, selective therapeutic or chemopreventive strategy
      against HER2/NEU-overexpressing breast tumors.

PMID- 12595745
TI  - Prostate-specific antigen in nipple aspiration fluid: menstrual cycle variability
      and correlation with serum prostate-specific antigen.
AB  - OBJECTIVES: To determine the variability of prostate-specific antigen (PSA) in
      the breast ductal fluid (nipple aspiration fluid, NAF) during the menstrual
      cycles of healthy premenopausal women. METHODS: Fifteen female volunteers
      underwent weekly nipple aspiration of ductal fluid from both breasts for the
      duration of two menstrual cycles. A highly sensitive and specific Third
      Generation PSA Assay (IMMULITE); Diagnostic Products Corporation, DPC) was used
      to detect NAF and serum PSA. Associations between NAF PSA and paired serum
      hormone levels of the pituitary-ovarian axis were tested using the Spearman rank
      correlation and the Wilcoxon signed rank test. Analysis of variance on log
      transformed NAF PSA was used to determine the intra- and intervolunteer
      variability. RESULTS: NAF PSA ranged from <0.003 to 133,330 ng PSA/g total
      protein (median 2,030 ng/g). No repeatable pattern of change was observed for
      individual volunteers and no significant association between NAF PSA and any
      pituitary-ovarian axis serum hormone was detected. There was no correlation
      between serum and NAF PSA. CONCLUSIONS: Weekly NAF sampling in healthy
      premenopausal women to provide adequate volumes for PSA analysis was successfully
      achieved. Considerable variation was observed for NAF PSA, which may limit the
      future potential for this tumor marker in NAF. This variability was not
      associated with hormones of the pituitary-ovarian axis and did not show repeated
      cyclical variability during the menstrual cycle. Serum PSA does not appear to be
      an acceptable indicator of NAF PSA levels.

PMID- 12595746
TI  - Possible involvement of the nuclear RZR/ROR-alpha receptor in the antitumor
      action of melatonin on murine Colon 38 cancer.
AB  - Experimental evidence has shown that melatonin (MLT) may act through both
      membrane and nuclear receptors. Moreover, it was proposed that the nuclear MLT
      receptor is identical with nuclear orphan receptors called RZR/ROR. Our earlier
      results suggest that the antitumor action of MLT depends mainly on nuclear
      signaling. In the present study, we investigated whether CGP 55644 (an antagonist
      of the nuclear RZR/RORalpha receptor) changes the oncostatic effects of MLT on
      murine Colon 38 cancer. The experiment was performed on adult male B6D2F1 mice.
      MLT or CGP were given either alone or combined during 10 days, and cell
      proliferation, apoptosis and the proliferation/apoptosis (P/A) ratio were
      determined. Cell proliferation was assessed by incorporation of bromodeoxyuridine
      into tumor cell nuclei (labeling index - LI). The number of apoptotic cells using
      the TUNEL method was considered as an index of apoptosis. It was found that MLT
      inhibited cell proliferation. Addition of CGP to MLT diminished the
      antiproliferative effect of MLT. Moreover, MLT increased the apoptotic index, but
      CGP decreased apoptosis. In addition, CGP given together with MLT blocked its
      proapoptotic effect. Given alone, MLT strongly lowered the P/A ratio, and
      addition of CGP to MLT abolished the effect of MLT on the P/A ratio. Based on our
      data, we conclude that nuclear RZR/RORalpha receptors participate in the
      oncostatic action of MLT.

PMID- 12595747
TI  - Epitopes on CA 125 from cervical mucus and ascites fluid and characterization of
      six new antibodies. Third report from the ISOBM TD-1 workshop.
AB  - CA 125 is found in body fluids in a variety of molecular weight forms. The
      largest species are found in normal abdominal fluid and cervical mucus. The
      present study therefore incorporated CA 125 derived from these sources as well as
      ascites fluid to investigate if the source of CA 125 influenced epitope
      characterization. Ascites-derived CA 125 varied in size from about 190 to about
      2,700 kD. Cervical mucus-derived CA 125 treated with ultrasound changed its
      apparent size from more than 20,000 to 700 kD. Epitope mapping of antibodies was
      not grossly influenced by the size or source of CA 125 used as target. However,
      low-molecular-weight CA 125, i.e. ascites fractions CA 17/E, CA 17/F and CA 10/7,
      did show differences in certain assay combinations and cross-inhibition patterns
      which probably can be explained by steric effects due to the smaller size
      compared with the most abundant forms of CA 125 present in serum and other body
      fluids. The specificity of six new monoclonal antibodies to CA 125 was tested by
      cross-inhibition and immunometric assay combinations and compared to reference
      antibodies. One antibody, X306, belonged to the OC125-like antibodies. Four
      antibodies, X52, X75, X325 and VK8, were M11-like. The sixth antibody, 7C12,
      reacted with an epitope which was difficult to define. This antibody was
      inhibited by M11-like antibodies and OV197. However, used as an inhibitor, 7C12
      inhibited only itself. We grouped it as an OV197-like antibody, but clearly
      different from OV197. The topography of epitopes was studied by analyzing all
      antibody pairs in immunoradiometric assays. These results confirmed the grouping
      of antibodies described above and are in accordance with previous findings that
      the highest signal is obtained using an OC125-like antibody or OV197 on the solid
      phase and an M11-like antibody as tracer. The composition of the sample in terms
      of high- and low-molecular-weight species of CA 125 was measured, with different
      responses depending on the antibody pair used. This might be one reason for
      discrepancies between assay results for CA 125 using different assays.

PMID- 12595748
TI  - Regeneration of primary sensory neurons.
AB  - Primary sensory neurons have an inherent capacity for regeneration of their cut,
      crushed, or chemically lesioned axons. This capacity is displayed to a much
      greater extent after lesions of the peripheral axons than after lesions of their
      centrally directed axons. Additionally, the surrounding tissue determines to a
      significant extent the degree of recovery: whereas the peripheral nerve tissue
      provides neurotrophic support and a favorable environment for axonal growth, the
      central terminals of primary sensory neurons face a non-permissive and inhibitory
      glial tissue. Mechanical lesions of the peripheral axons of dorsal root ganglion
      (DRG) sensory neurons can be repaired by the intrinsic regenerative capacity of
      the neuron itself, when outgrowing axons from the proximal stump are able to
      transverse the tissue scar and reach the distal stump of the nerve. Bridging the
      gap with an autologous nerve graft or a short artificial graft filled with nerve
      growth factor (NGF) can improve recovery. Neurotoxic lesions of the axon
      terminals are effectively recovered by intermittent local or systemic NGF
      injections. A recovery from a diabetic sensory neuropathy probably requires the
      continuous delivery of NGF or additional neurotrophic factors. A recovery from a
      dorsal rhizotomy or from a dorsal column lesion can possibly be achieved by the
      concomitant transgene-mediated overexpression of neurotrophins, the
      transformation of the DRG neuron cells to a competence for regrowth, and the
      counteraction of the growth-inhibitory nature of the central nervous system
      tissue.

PMID- 12595749
TI  - Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F
      13640 in the formalin model of tonic nociceptive pain.
AB  - Previously, we have reported that in rat models of chronic pain, in particular,
      the very-high-efficacy 5-HT(1A) agonist F 13640 induces unprecedented pain relief
      by novel neuroadaptative mechanisms that involve inverse tolerance and
      cooperation with nociceptive stimulation in producing analgesia. The present
      studies detailed the actions of F 13640 and other compounds in the formalin model
      of tonic nociceptive pain. Intraperitoneal injection of F 13640 (0.01-2.5 mg/kg;
      t -15 min) caused a dose-dependent and complete inhibition of the paw elevation
      and paw licking that occurred both early (0-5 min) and late (22.5-27.5 min) after
      the intraplantar injection of diluted formaldehyde (2.5%) in the rat. The extent
      to which F 13640 and other 5-HT(1A) receptor ligands inhibited these pain
      behaviors correlated (p < 0.05) with the extent to which they activated 5-HT(1A)
      receptors. Under similar conditions, some inhibitory effects were also observed
      with various agents that are known to produce analgesia by different peripheral
      and/or central mechanisms (e.g., opioids, NA/5-HT reuptake inhibitors, COX-2
      inhibitors and other nonsteroidal anti-inflammatory drugs, gabapentin, and ABT
      594). However, with the possible exception of morphine, the effects of all of
      these agents at nontoxic doses were lower than those of F 13640, in particular in
      inhibition of early paw elevation. The 5-HT(1A) antagonist WAY 100635, but not
      naloxone, antagonized the actions of F 13640. These results help to establish
      large-magnitude 5-HT(1A) receptor activation as a new molecular mechanism of
      profound, central analgesia and suggest that F 13640 may be particularly
      effective against pain arising from severe tonic nociceptive stimulation.

PMID- 12595750
TI  - Effect of interleukin 6 on the hepatic metabolism of itraconazole and its
      metabolite hydroxyitraconazole using primary human hepatocytes.
AB  - A potential cytokine-drug interaction between interleukin 6 (IL-6) and
      itraconazole (ITZ) was studied using human hepatocytes in primary culture.
      Cultures from 5 adult males (mean age 42 +/- 15 years) who had not received any
      medicines known to interact with CYP3A4 were studied. Cultures were exposed to
      ITZ 500 ng/ml, and the effects of 120 microg/ml cimetidine, 50 ng/ml human IL-6,
      or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h.
      Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC
      and normalized to total cellular protein. Mean intracellular concentrations
      between groups were compared using one-way Anova (f test; p < 0.10) and
      corresponding Bonferroni versus control test for multiple comparisons (p < 0.02).
      Mean intracellular ITZ concentrations between the groups were similar at all time
      points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6
      did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent
      metabolism.

PMID- 12595751
TI  - A new isoquinolinone derivative with noble vasorelaxation activity.
AB  - The pharmacological effects of BDPBI (7-bromo-1,4-dihydro-2-phenyl-4,4-bis(4
      pyridinylmethyl)2H-isoquinolin-3-one dihydrochloride) were tested on isolated
      endothelium-containing or denuded aorta of the guinea pig. BDPBI with the formula
      C(27)H(24)BrCl(2)N(3)O was synthesized starting with 3-isochromanone. In the
      endothelium-containing preparations of the aortic rings, phenylephrine (PHE; 10
      micromol/l) elicited contracture and acetylcholine (ACh; 10 micromol/l) or BDPBI
      (0.01-10 micromol/l) elicited relaxation effects on the PHE-precontracted
      preparations. The BDPBI-elicited effect on the PHE-precontracted aortic rings was
      not altered in the presence of adrenergic blockers (propranolol or yohimbine; 1
      micromol/l) or pretreated preparations with aspirin, indomethacin (10 micromol/l)
      or L-NAME (1 mmol/l). However, the relaxation effects of BDPBI were blocked if
      the preparations were pretreated with diphenhydramine (10 micromol/l) or
      chloropheniramine maleate (10 micromol/l). In contrast to lower concentrations of
      atropine (1 micromol/l), higher concentrations of atropine (30 micromol/l) did
      block the effects of BDPBI on the PHE-precontracted aortic rings. HTMT dimaleate
      (0.01-10 micromol/l), a histamine H(1) receptor agonist, also elicited relaxation
      effects on the PHE-precontracted preparation, and the effects were blocked if the
      preparations were pretreated with diphenhydramine or chloropheniramine maleate.
      On isolated denuded aorta of the guinea pig, BDPBI did not elicit relaxation
      effects on the PHE-precontracted aortic rings. These results demonstrated that
      the vasorelaxation effect of BDPBI on PHE-precontracted aortic rings is partly
      dependent on the activation of a histaminergic receptor from the vascular
      endothelium. We suggested that BDPBI would be an effective vasorelaxant for
      cardiovascular systems.

PMID- 12595752
TI  - Protein kinase C and phosphoinositol-3-kinase mediate differentiation or
      proliferation of slice-derived rat microglia.
AB  - Granulocyte-macrophage colony-stimulating factor plays an important role in the
      activation of microglia in the central nervous system. We have recently shown
      (see text) that granulocyte-macrophage colony-stimulating factor activates the
      proliferation and subsequent migration of microglia from organotypic cortex brain
      slices. The aim of this study was to investigate whether this activation is
      modulated by different putative intracellular pathway inhibitors. Our data show
      that the protein kinase C inhibitor staurosporine enhanced the proliferation as
      well as the differentiation of slice-derived microglia, while the phosphoinositol
      3-kinase inhibitor LY294002 markedly suppressed the proliferative activity. In
      conclusion, proliferation, migration, as well as differentiation of rat microglia
      are highly regulated by intracellular signaling cascades.

PMID- 12595753
TI  - Oxidative-stress-related changes in the livers of bile-duct-ligated rats.
AB  - The role of reactive oxygen species in liver fibrogenesis is not yet clarified.
      The aim of this study was to investigate oxidative-stress-related changes in
      cirrhotic rats. Cirrhosis was induced by bile duct ligation in Sprague-Dawley
      rats. Plasma malondialdehyde (MDA), hepatic 8-hydroxy-2'-deoxyguanosine (8-OHdG),
      hepatic mitochondrial respiratory functions and gene transcripts were measured at
      2 and 4 weeks after surgery in bile-duct-ligated (BDL) and sham-operated-operated
      rats. The results showed progressive increases in the levels of plasma MDA,
      hepatic 8-OHdG and procollagen I and III mRNA expression, and progressive
      impairment of hepatic mitochondrial respiratory function in BDL rats at 2 and 4
      weeks after ligation compared with sham-operated rats. Moreover, at 4 weeks after
      ligation, BDL rats exhibited reduced plasma glutathione and vitamin E levels,
      impaired hepatic mitochondrial electron transport enzyme activities and oxidative
      phosphorylation function. In addition, hepatic mRNA expression of transforming
      growth factor-beta1 was increased. Hepatomegaly, abnormal plasma alanine
      transaminase and aspartate transaminase levels, and portal hypertension were
      noted in BDL rats. Our results suggest that bile duct ligation in the rat induces
      mitochondrial dysfunction and biochemical and molecular changes related to
      oxidative stress in the liver.

PMID- 12595754
TI  - Mechanisms of adrenergic control of sino-atrial node discharge.
AB  - Among the mechanisms proposed for the increase in discharge of sino-atrial node
      (SAN) by norepinephrine (NE) are an increase in the hyperpolarization-activated
      current I(f) and in the slow inward current I(Ca,L). If I(f) is the primary
      mechanism, cesium (a blocker of I(f)) should eliminate the positive chronotropic
      effect of NE. If I(Ca,L), is involved, [Ca(2+)](o) should condition NE effects.
      We studied the electrophysiological changes induced by NE in isolated guinea pig
      SAN superfused in vitro with Tyrode solution (both SAN dominant and subsidiary
      pacemaker mechanisms are present) as well as with high [K(+)](o), higher Cs(+) or
      Ba(2+) (only the dominant pacemaker mechanism is present). In Tyrode solution, NE
      (0.5-1microM) increased the SAN rate and adding Cs(+) (approximately 12 mM)
      caused a decaying voltage tail during diastole in subsidiary pacemakers. NE
      enhanced the Cs(+)-induced tail, and increased the rate but less than in Tyrode
      solution. In higher [Cs(+)](o) (15- 18 mM), Ba(2+) (1 mM) or Ba(2+) plus Cs(+)
      (10 mM) dominant action potentials (not followed by a tail) were present and NE
      accelerated them as in Tyrode solution. In high [K(+)](o), NE increased the rate
      in the absence and presence of Cs(+), Ba(2+) or Ba(2+) plus Cs(+). In these
      solutions, NE increased the overshoot and maximum diastolic potential of dominant
      action potentials (APs) and increased the rate by steepening diastolic
      depolarization and shifting the threshold for upstroke to more negative values.
      High [Ca(2+)](o) alone increased the rate and NE enhanced this action, whereas
      low [Ca(2+)](o) reduced or abolished the increase in rate by NE. In SAN quiescent
      in high [K(+)](o) plus indapamide, NE induced spontaneous discharge by decreasing
      the resting potential and initiating progressively larger voltage oscillations.
      Thus, NE increases the SAN rate by acting primarily on dominant APs in a manner
      consistent with an increase of I(Ca,L) and I(K) and under conditions where I(f)
      is either blocked or not activated. NE INITIATES spontaneous discharge by
      inducing voltage oscillations unrelated to I(f).

PMID- 12595755
TI  - Ascorbyl palmitate as a carrier of ascorbate into neural tissues.
AB  - We have investigated the hypothesis that a lipid-soluble derivative of ascorbic
      acid, ascorbyl-6-palmitate (AP), could serve as a carrier of ascorbate into
      neural tissues. Ascorbate could then exert its physiological effects in the
      biomembranes that are the target sites of the cellular signaling pathways which
      are normally hardly accessible to this water-soluble compound. The potential role
      of AP would require that it penetrates into tissues. The major objective of the
      study was to determine whether ascorbate could be recovered from cerebral cortex
      and carotid body tissues, both sensitive to the hypoxic stimulus, after AP given
      by gavage. Biological samples were analyzed by HPLC for the determination of
      ascorbate. We found that ascorbate was recovered from the tissues studied. Its
      content was higher in both tissues, by nearly an order of magnitude, after
      ingestion of AP than after ingestion of ascorbic acid, and the ascorbate level
      was higher in the carotid body than in the cortex. Hypoxia decreased the
      ascorbate content which implies physiological activity of ascorbate carried
      alongside the AP molecule. The lipophilic AP was able to cross biological
      barriers and satisfied the tissue demand for ascorbate better than the
      hydrophilic form. AP should be considered as the preferred form of transport of
      ascorbate into neural tissues. The results of this study suggest wider
      pharmacological applications of ascorbyl palmitate.

PMID- 12595756
TI  - Roles of ionotropic glutamate receptors in early developing neurons derived from
      the P19 mouse cell line.
AB  - We cultured a P19 mouse teratocarcinoma cell line and induced its neuronal
      differentiation to study the function of ionotropic glutamate receptors (GluRs)
      in early neuronal development. Immunocytochemical studies showed 85% neuronal
      population at 5 days in vitro (DIV) with microtubule-associated protein 2
      positive staining. Thirty percent and 50% of the cells expressed the alpha-amino
      3-hydroxy-5-methyl-4-isopropinonate (AMPA) receptor subunit, GluR2/3, and the
      kainate (kainic acid; KA) receptor subunit, GluR5/6/7, respectively. In Western
      blot analysis, the temporal expression of GluR2/3 began to appear at 3 DIV,
      whereas GluR5/6/7 was already expressed in the undifferentiated cells. P19
      derived neurons began to respond to glutamate, AMPA and KA, but not to the
      metabotropic GluR agonist trans-1-aminocyclopentane-1,3-decarboxylic acid, by 5
      DIV in terms of increases in intracellular calcium and phospholipase C-mediated
      poly-phosphoinositide turnover. Furthermore, KA reduced cell death of P19-derived
      neurons in both atmospheric and hypobaric conditions in a phospholipase C
      dependent manner. The common AMPA/KA receptor antagonist, 6-cyano-7
      nitroquinoxaline-2,3-dione, but not the AMPA receptor antagonist, 1,2,3,4
      tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium,
      profoundly increased hypobaric insult-induced neurotoxicity. In a flow cytometry
      study, the nerve growth factor-mediated antiapoptotic effect was facilitated by
      AMPA, with an induction of TrkA, but not p75(NTR) expression. Therefore, AMPA and
      KA receptors might mediate neurotrophic functions to facilitate neurotrophic
      factor signaling to protect neurons against hypoxic insult in early neuronal
      development.

PMID- 12595757
TI  - Bradykinin B2 receptor-mediated proliferation via activation of the
      Ras/Raf/MEK/MAPK pathway in rat vascular smooth muscle cells.
AB  - It has been suggested that bradykinin (BK) plays an important role in regulating
      neointimal formation after vascular injury. However, implication of BK in the
      growth of rat vascular smooth muscle cells (VSMCs) is controversial. Therefore,
      we examined the mitogenic effect of BK on VSMCs associated with activation of
      mitogen-activated protein kinase (MAPK). Both [(3)H]thymidine incorporation and
      p42/p44 MAPK phosphorylation were activated by BK in time- and concentration
      dependent manners. Pretreatment of these cells with neither pertussis toxin nor
      cholera toxin attenuated the BK-induced responses. Pretreatment of VSMCs with Hoe
      140 (a selective B(2) receptor antagonist), U73122 (an inhibitor of phospholipase
      C), and BAPTA/AM (an intracellular Ca(2+) chelator) inhibited both
      [(3)H]thymidine incorporation and p42/p44 MAPK phosphorylation in response to BK.
      BK-induced [(3)H]thymidine incorporation and p42/p44 MAPK phosphorylation were
      inhibited by pretreatment of VSMCs with tyrosine kinase inhibitors (genistein and
      herbimycin A), protein kinase C (PKC) inhibitors (staurosporine, Go-6976, and Ro
      318220), an MAPK kinase inhibitor (PD98059), and a p38 MAPK inhibitor (SB203580).
      Overexpression of the dominant negative mutants, H-Ras-15A and Raf-N4, suppressed
      p42/p44 MAPK activation induced by BK and PDGF-BB, indicating that Ras and Raf
      may be required for activation of these kinases. From these results, we concluded
      that the mitogenic effect of BK is mediated through activation of the
      Ras/Raf/MEK/MAPK pathway similar to that of PDGF-BB. BK-mediated MAPK activation
      was modulated by Ca(2+), PKC, and tyrosine kinase all of which are associated
      with cell proliferation in rat cultured VSMCs.

PMID- 12595758
TI  - Green tea constituent (-)-epigallocatechin-3-gallate inhibits Hep G2 cell
      proliferation and induces apoptosis through p53-dependent and Fas-mediated
      pathways.
AB  - (-)-Epigallocatechin-3-gallate (EGCG) is a polyphenolic compound found in green
      tea. It has been reported to possess a wide range of pharmacological properties,
      and is one of the most promising chemopreventive agents for cancer. To provide a
      better understanding of the preventive effect of EGCG on liver cancer, we
      examined EGCG for its effect on proliferation and cell cycle progression in a
      human liver cancer cell line, Hep G2. The results showed that EGCG inhibited the
      proliferation of Hep G2 by inducing apoptosis and blocking cell cycle progression
      in the G1 phase. ELISA showed that EGCG significantly increased the expression of
      p53 and p21/WAF1 protein, and this contributed to cell cycle arrest. An
      enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand
      (mFasL) and soluble Fas ligand (sFasL), as well as Bax protein, was responsible
      for the apoptotic effect induced by EGCG. Taken together, our study suggests that
      the induction of p53 and the activity of the Fas/FasL apoptotic system play major
      roles in the antiproliferative activity of EGCG in Hep G2 cells.

PMID- 12595759
TI  - Characterization and functionality of cell surface molecules on human mesenchymal
      stem cells.
AB  - We have characterized adhesion molecules on the surface of multipotential human
      mesenchymal stem cells (hMSCs) and identified molecules whose ligands are present
      on mature hematopoietic cells. Flow cytometric analysis of hMSCs identified the
      expression of integrins: alpha1, alpha2, alpha3, alpha5, alpha6, alphav, beta1,
      beta3, and beta4, in addition to ICAM-1, ICAM-2, VCAM-1, CD72, and LFA-3.
      Exposure of hMSCs to IL-1alpha, TNFalpha or IFNgamma up-modulated ICAM-1 surface
      expression, whereas only IFNgamma increased both HLA-class I and -class II
      molecules on the cell surface. Whole cell-binding assays between the hMSCs and
      hematopoietic cell lines showed that T lymphocytic lines bound hMSCs with higher
      affinity than lines of either B lymphocytes or those of myeloid lineage.
      Experiments using autologous T lymphocytes isolated from peripheral blood
      mononuclear cells showed that hMSCs exhibited increased affinity for activated T
      lymphocytes compared to resting T cells by quantitative whole cell binding and
      rosetting assays. Flow cytometric analysis of rosetted cells demonstrated that
      both CD4+ and CD8+ cells bound to hMSCs. To determine the functional significance
      of these findings, we tested the ability of hMSCs to present antigen to T
      lymphocytes. hMSCs pulsed with tetanus toxoid stimulated proliferation and
      cytokine production (IL-4, IL-10, and IFNgamma) in a tetanus-toxoid-specific T
      cell line. Maximal cytokine production correlated with maximal antigen-dependent
      proliferation. These data demonstrate physiological outcome as a consequence of
      interactions between hMSCs and human hematopoietic lineage cells, suggesting a
      role for hMSCs in vivo to influence both hematopoietic and immune function(s).

PMID- 12595760
TI  - An LKB1-interacting protein negatively regulates TNFalpha-induced NF-kappaB
      activation.
AB  - The Peutz-Jeghers syndrome (PJS) is a hereditary disorder that predisposes an
      individual to benign and malignant tumors in multiple organ systems. Recently,
      the locus responsible for PJS was mapped genetically to the LKB1 gene, with a
      subsequent investigation proving that it is responsible for most cases of PJS.
      LKB1 encodes a nuclear serine/threonine protein kinase, and potential tumor
      suppressing activity has been attributed to LKB1 kinase. However, how LKB1 exerts
      its tumor-suppressing function remains to be determined. In this report, we
      describe the identification of a putative human LKB1-interacting protein, FLIP1,
      using the yeast two-hybrid system. Two regions of the LKB1 sequence have been
      determined to be crucial for the interaction with FLIP1. FLIP1 encodes a protein
      of 429 amino acids with a predicted molecular weight of 47 kd. In contrast to
      LKB1, which is mainly nuclear, FLIP1 is a cytoplasmic protein, and its expression
      is ubiquitous in all human tissues examined to date. Interestingly, deletion of
      the 195 N- terminal amino acids allows FLIP1 to enter the nucleus, suggesting the
      presence of a regulatory mechanism through its N-terminus for nuclear entry. In
      addition, we found that ectopic expression of FLIP1 selectively blocks cytokine
      induced NF-kappaB activation. The involvement of FLIP1 in the regulation of NF
      kappaB activity may shed new light on the role of LKB1 in tumor suppression.

PMID- 12595761
TI  - Reconstitution of TGF-beta sensitivity in the VACO-411 human colon carcinoma line
      by somatic cell fusion with MCF-7.
AB  - We characterized the mechanism of transforming growth factor beta (TGF-beta)
      resistance in the VACO-411 human colon carcinoma line. VACO-411 is unique for
      several reasons, including having a novel mutator phenotype and wild-type p53.
      Like many colon tumors, VACO-411 is not growth inhibited by TGF-beta. However,
      VACO-411 represents a subset of colon tumors that are resistant to TGF-beta
      mediated growth inhibition, despite the expression of functional TGF-beta
      receptors. VACO-411 expresses cell surface TGF-beta receptor types I and II, and
      the coding regions of these receptors are wild type. To further characterize the
      nature of the VACO-411 defect, we fused VACO-411 with the human breast carcinoma
      line MCF-7. MCF-7 is also resistant to TGF-beta-mediated growth inhibition.
      However, unlike VACO-411, MCF-7 lacks cell surface expression of TGF-beta
      receptor type II, but does contain an intact postreceptor signaling pathway, as
      shown by regeneration of TGF-beta sensitivity following wild-type TGF-beta
      receptor type II transfection. In contrast to parental VACO-411 and MCF-7, the
      morphologically distinct cell hybrids were growth inhibited by TGF-beta.
      Therefore, the TGF-beta defect in VACO-411 is a postreceptor, loss-of-function
      mutation which can be genetically complemented. The data suggest that the VACO
      411 defect in TGF-beta signaling will be able to be further complemented by
      microcell-mediated chromosome transfer.

PMID- 12595762
TI  - Apolipoprotein E gene polymorphism, hypercholesterolemia and glomerular
      filtration rate in type 2 diabetic subjects: a 9-year follow-up study.
AB  - OBJECTIVE: To study the association between apolipoprotein E (apoE) genotype and
      the rate of decline in glomerular filtration rate (GFR) in type 2 diabetic
      patients in a 9-year prospective study. METHODS: GFR was determined in 84 type 2
      diabetic patients by plasma clearance of (51)Cr-EDTA at baseline and after 9
      years of follow-up. ApoE genotypes were determined by polymerase chain reaction
      and restriction enzyme HHAI digestion and designated as epsilon4 allele group
      (apoE4/2, 4/3 and 4/4 genotypes; n = 20) and non-epsilon4 allele group (apoE3/3
      and E3/2 genotypes; n = 64). We focused our analysis on those patients who were
      more likely to progress to diabetic renal disease, i.e. whose GFR fell more than
      expected in the normal course of ageing [1 ml x min(-1) x (1.73 m(2))(-1) per
      year]. RESULTS: In the whole population, the decline in the GFR did not differ
      statistically significantly between the apoE genotype groups [p = 0.65 with
      analysis of variance for repeated variables (RANOVA) for interaction between apoE
      genotype group and time point]. However, among patients whose GFR changed more
      than 9 ml x min(-1) x (1.73 m(2))(-1), GFR showed a statistically significantly
      greater decline in the epsilon4 allele group (n = 11) than in the non-epsilon4
      allele group (n = 43) [from 116 +/- 36 to 80 +/- 29 ml x min(-1) x (1.73 m(2))(
      1) vs. from 119 +/- 20 to 96 +/- 18 ml x min(-1) x (1.73 m(2))(-1); p = 0.005
      with RANOVA]. CONCLUSION: ApoE allele epsilon4 may speed up the rate of decline
      of the GFR in patients with progressive diabetic renal disease.

PMID- 12595763
TI  - Antibody reactivity to HIV-1 Vpu in HIV-1/AIDS patients on highly active
      antiretroviral therapy.
AB  - Human immunodeficiency virus type 1 (HIV-1) Vpu protein promotes both
      extracellular release of viral particles and degradation of CD4 in the
      endoplasmic reticulum. The correlation of anti-Vpu antibody (Ab) reactivity to
      Vpu and AIDS disease progression was studied in 162 HIV-1/AIDS patients after
      they had received highly active antiretroviral therapy (HAART) for 1 year. Anti
      Vpu Ab reactivity was analyzed by Western blot using a recombinant Vpu protein.
      Results showed that at baseline (prior to initiation of HAART), 31.5% of patients
      (51/162) had anti-Vpu Ab. The proportion of anti-Vpu Ab in patients with CD4
      counts > or =500, 200-500 and <200/mm(3) were 40.6, 34.7 and 14.3%, respectively
      (chi(2) test, p < 0.05). In addition, decreasing levels of anti-Vpu Ab reactivity
      were significantly correlated with increasing levels of HIV-1 viral load. After
      receiving HAART for 1 year, 7 of 111 anti-Vpu Ab-negative patients (6.3%)
      seroconverted (- --> + group) and 8 of 51 anti-Vpu Ab-positive (15.7%) patients
      became negative (+ --> - group). Among 104 anti-Vpu Ab-negative patients, 40 were
      selected for analysis of the VPU gene. All of them had an intact VPU gene.
      Patients were further divided into four groups according to their anti-Vpu Ab
      serostatus and anti-HIV-1 Ab was measured. The results showed that only the anti
      Vpu Ab seroconverted group (- --> +) had increased serum levels of anti-HIV-1 Abs
      after 1 year of HAART, while the other three groups (+ --> +, - --> - and + --> 
      ) had decreased serum levels of anti-HIV-1 Abs after 1 year of HAART (p < 0.05).
      In conclusion, the presence of anti-Vpu Ab is associated with improved prognosis
      following HIV-1 infection, and seroconversion of anti-Vpu Ab in patients on HAART
      indicates significant recovery of immunity.

PMID- 12595764
TI  - Expression and purification of E2/NS1 protein of hepatitis C virus and detection
      of anti-E2/NS1 antibodies in chronic liver disease patients.
AB  - Glycoproteins on the surface of viral particles present the main target of
      neutralizing antibodies. The structural proteins of most Flaviviruses are known
      to elicit neutralizing antibodies and, thus, to help in both the natural
      resolution of the infection and the protection from challenge with homologous
      hepatitis C virus (HCV). Because such antigens are associated with the viral
      clearance in both humans and chimpanzees, we aimed to express the E2/NS1 protein
      of HCV and to study the role of anti-E2/NS1 antibodies in the natural resolution
      of HCV infection. The prevalence of anti-E2/NS1 antibodies to recombinant E2/NS1
      protein was seen by Western blot in chronic liver disease patients (15 chronic
      hepatitis and 12 cirrhotic patients), who were positive for anti-HCV and negative
      for HBV infection. The study also included 2 negative controls (positive for HBV
      infection and negative for anti-HCV antibodies) and 2 healthy controls (negative
      for both HBV and HCV infection). Anti-E2/NS1 was present in 20% of the chronic
      hepatitis and 16% of the cirrhosis patients. None of the controls were positive
      for anti-E2/NS1 antibodies. Serum samples positive for anti-E2/NS1 antibodies
      were also positive for HCV RNA by RT/PCR. Accordingly, the presence of anti
      E2/NS1 may have very little or no role in the natural resolution of HCV
      infection.

PMID- 12595766
TI  - Comprehensive deep venous thrombosis prevention strategy after total-knee
      arthroplasty.
AB  - OBJECTIVE: Venous thromboembolism after total-knee arthroplasty represents a
      common early postoperative complication resulting in significant morbidity.
      Despite this, the optimal prophylactic regimen is controversial. The prevalence
      of venous thromboembolism has been cited as high as 35% in patients receiving
      pharmacologic prevention alone. We investigated the efficacy of a comprehensive
      prevention protocol encompassing the use of epidural anesthesia, aspirin, venous
      foot compression pumps, and early mobilization in a series of consecutive total
      knee arthroplasties. DESIGN: A series of 100 consecutive total-knee arthroplasty
      patients were enrolled into the prospective trial. All patients were allowed full
      weight bearing on the first postoperative day and ambulation as tolerated. Venous
      foot compression pumps and aspirin were used immediately after surgery in the
      totality of subjects. Seventy-five percent of the patients were transferred to an
      acute rehabilitation service during the first postoperative week. The presence of
      deep-vein thrombosis was subsequently determined with the routine use of venous
      duplex scans. RESULTS: Three patients (3%) demonstrated evidence of distal deep
      vein thrombosis. No patient had symptomatic pulmonary embolism. CONCLUSION: The
      combination of epidural anesthesia, aspirin, immediate postoperative venous foot
      compression pumps, and early ambulation together seem to be a more effective
      approach to prevent the occurrence of thromboembolic events after knee
      replacements than pharmacologic prevention alone.

PMID- 12595767
TI  - Family member knowledge and expectations for functional recovery after stroke.
AB  - OBJECTIVE: To assess the stroke knowledge and expectations for recovery among the
      family members of stroke patients in an acute rehabilitation hospital. DESIGN:
      Survey study of 50 family members of stroke patients undergoing inpatient
      rehabilitation at a single urban rehabilitation hospital. RESULTS: Sixty percent
      of participants were able to identify whether their family member had sustained a
      cerebral hemorrhage or infarct; 48% were able to identify at least one treatment
      provided to their family member for his or her stroke. The average length of stay
      predicted by participants closely matched the average patient length of stay.
      Participants tended to overestimate the functional abilities of their family
      member with a stroke, both on initial assessment and discharge. This
      overestimation was more substantial for discharge functional ability than for
      initial assessment. Participants were able to predict discharge location with
      substantial accuracy (82% agreement, kappa = 0.41). CONCLUSIONS: The knowledge of
      stroke etiology and functional outcome of family members of individuals
      undergoing rehabilitation after stroke shows significant limitations.
      Participants' ability to predict functional outcome on discharge was worse than
      their knowledge of current functional status. Participant predictions of length
      of stay and discharge disposition were areas of relative strength. Further
      efforts are needed to enhance the knowledge level of family members of patients
      undergoing rehabilitation after stroke.

PMID- 12595768
TI  - Influence of poststroke urinary incontinence on disability: the nursing home
      setting.
AB  - OBJECTIVE: To characterize the association of poststroke urinary incontinence
      with disability progression in nursing home residents. DESIGN: In this
      prospective cohort study, the Minimum Data Set from the State of New York between
      1994 and 1997 was utilized. From a pool of over 240,000 potential subjects, 500
      met inclusion/exclusion criteria. Previously continent, first-time stroke
      survivors were classified as being continent or incontinent immediately after
      their stroke and were followed for changes in activities of daily living status
      (disability) at quarterly intervals for a 1 yr. In addition, a post hoc analysis
      was performed examining changes in activities of daily living status from the
      prestroke condition and exploring the relationship between poststroke impairments
      in continence and limitations in mobility. RESULTS: An almost 2-fold difference
      in level of disability was noted poststroke among those who were incontinent
      those who were continent (P < 0.001). This difference in disability level
      remained unchanged for 1 yr. Through the post hoc analysis, it was determined
      that, although the onset of stroke produced significant elevations in disability
      for both continent and incontinent stroke survivors (P < 0.001), the presence of
      an impairment in urinary continence was associated with a significantly greater
      increase (94% 13%) in disability (P < 0.001). In addition, incontinence occurred
      more frequently among those who had a loss in mobility function. CONCLUSION:
      Incontinence is a clinical factor after stroke that is associated with greater
      disability among nursing home residents. These findings have clinical
      implications for physiatrists and nursing home clinicians and provide a context
      in which future disability research can be conducted.

PMID- 12595769
TI  - Nutritional assessment of patients with neuromuscular diseases.
AB  - OBJECTIVE: To study the nutritional status of patients with Duchenne muscular
      dystrophy and amyotrophic lateral sclerosis. DESIGN: A total of 34 Duchenne
      muscular dystrophy and seven amyotrophic lateral sclerosis patients were studied.
      Body mass index, patient's body weight for zero muscle mass as a percentage of
      the theoretical weight for zero muscle mass, and creatinine-height index were
      calculated. RESULTS: Substantial differences were found between body mass index
      and percentage of expected weight for zero muscle mass. No amyotrophic lateral
      sclerosis patients were classified as overweight by body mass index, whereas five
      were overweight by the percentage of expected weight for zero muscle mass method.
      Five Duchenne muscular dystrophy patients were classified as overweight by body
      mass index, and 30 were overweight by the percentage of expected weight for zero
      muscle mass. According to the creatinine-height index, no patient with
      amyotrophic lateral sclerosis or Duchenne muscular dystrophy showed normal body
      muscle mass. No correlation was found between creatinine-height index, percentage
      of expected weight for zero muscle mass, and body mass index. CONCLUSIONS: The
      body mass index should be used with caution for the evaluation of the nutritional
      status of patients with amyotrophic lateral sclerosis and Duchenne muscular
      dystrophy. Indices that incorporate the assessment of the compartmental
      distribution of muscle and fat are more sensitive.

PMID- 12595770
TI  - Effects of a 1.5-day multidisciplinary outpatient treatment program for
      fibromyalgia: a pilot study.
AB  - OBJECTIVE: The purpose of this pilot study was to determine the effect of a 1.5
      day multidisciplinary fibromyalgia treatment program on impact of illness,
      depression, and life fulfillment. DESIGN: A sample of 100 consecutive enrollees
      in a 1.5-day multidisciplinary group outpatient fibromyalgia treatment program
      between February 14, 2000, and May 9, 2000, in a tertiary medical center was used
      for this study. The Fibromyalgia Impact Questionnaire, the Life Fulfillment and
      Satisfaction Scales, and the Center for Epidemiologic Studies Depression Scale
      were administered to subjects immediately preceding the treatment program and by
      mail 1 mo after completing the program. RESULTS: The 78 subjects who returned
      their surveys 1 mo after treatment demonstrated significant improvement in the
      area of the impact of illness as measured by the Fibromyalgia Impact
      Questionnaire total score (51.3-44.7, P < 0.002). There was no significant
      improvement in depressive symptoms (P < 0.056) or the level of life fulfillment
      (P < 0.53). Subjects with depression improved on the Fibromyalgia Impact
      Questionnaire to the same degree as those without depression. The 22
      nonresponders did not differ significantly from the responders in the variables
      of sex, age, pretreatment Fibromyalgia Impact Questionnaire score, marital
      status, educational level, family income, duration of symptoms, or history of
      depression. CONCLUSIONS: These results suggest that a 1.5-day multidisciplinary
      fibromyalgia treatment program does have a significant positive effect on the
      impact of illness among patients with fibromyalgia with or without concomitant
      depression and may be a cost-effective model for the treatment of these patients.

PMID- 12595771
TI  - Suprascapular nerve entrapment in newsreel cameramen.
AB  - OBJECTIVES: To determine presence of suprascapular nerve entrapment in a group of
      newsreel cameramen. DESIGN: Thirty-six men working as newsreel cameramen
      participated in the study. In addition to musculoskeletal and neurologic
      examinations, bilateral suprascapular nerve conduction studies and needle
      electromyography were performed. A group of 19 healthy, male volunteers were
      included in the study as normal controls for suprascapular nerve conduction
      studies. RESULTS: In newsreel cameramen, mean suprascapular nerve latency was
      3.20 +/- 0.56 msec and 2.84 +/- 0.36 msec for right and left shoulders,
      respectively (P = 0.001). The mean latency difference between right and left
      suprascapular nerves was -0.05 +/- 0.19 msec in the control group and 0.36 +/-
      0.58 msec in the cameramen group (P < 0.001). Six subjects' right suprascapular
      nerve motor latencies were 2 SD above the normal mean values. There was no
      relationship between suprascapular nerve latencies and the age, professional
      life, and number of hours worked daily by the subjects. CONCLUSIONS: Carrying a
      heavy, mobile camera on the shoulder might cause suprascapular nerve entrapment
      in newsreel cameramen. This could be considered an occupational disorder of the
      suprascapular nerve, like meat-packer's neuropathy.

PMID- 12595772
TI  - Investigating neck pain in wheelchair users.
AB  - OBJECTIVE: Despite the fact that wheelchair users are exposed to risk factors for
      neck and upper back pain (NP), little is known about the impact and possible
      diagnoses associated with NP. The purpose of this study was to examine the
      significance of NP in wheelchair users and to determine if a portion of the NP
      may be myofascial in origin. DESIGN: Cross-sectional cohort study using
      questionnaires and physical exams to evaluate NP in a convenience sample of
      wheelchair users from the National Veteran's Wheelchair Games. Main outcome
      measures included reported NP, visual analog scale of neck complaints, Neck
      Disability Index, and physical examination findings of trigger points. RESULTS:
      Sixty-six percent of subjects reported NP since becoming a wheelchair user and,
      60% reported pain during the past month. Neither age nor length of time in a
      wheelchair was significantly different between those subjects who did and those
      subjects who did not report pain. Of those respondents who reported NP, 60%
      visited the doctor about the pain and 40% limited their daily activities due to
      the pain. Trigger-point palpation reproduced pain in 54% of those respondents who
      experienced pain in the past month (n = 34). CONCLUSION: This study provides a
      first step in defining the prevalence and significance of NP among wheelchair
      users. Clinicians who work with this population need to ask subjects about
      symptoms and consider a myofascial origin for that pain when considering
      treatment.

PMID- 12595773
TI  - Effectiveness of physical therapy for patients with neck pain: an individualized
      approach using a clinical decision-making algorithm.
AB  - OBJECTIVE: The purpose of this study was to determine the effectiveness of an
      individualized physical therapy intervention in treating neck pain based on a
      clinical reasoning algorithm. Treatment effectiveness was examined by assessing
      changes in impairment, physical performance, and disability in response to
      intervention. DESIGN: One treatment group of 30 patients with neck pain completed
      physical therapy treatment. The control group of convenience was formed by a
      cohort group of 27 subjects who also had neck pain but did not receive treatment
      for various reasons. There were no significant differences between groups in
      demographic data and the initial test scores of the outcome measures. A quasi
      experimental, nonequivalent, pretest-posttest control group design was used. A
      physical therapist rendered an eclectic intervention to the treatment group based
      on a clinical decision-making algorithm. Treatment outcome measures included the
      following five dependent variables: cervical range of motion, numeric pain
      rating, timed weighted overhead endurance, the supine capital flexion endurance
      test, and the Patient Specific Functional Scale. Both the treatment and control
      groups completed the initial and follow-up examinations, with an average duration
      of 4 wk between tests. RESULTS: Five mixed analyses of variance with follow-up
      tests showed a significant difference for all outcome measures in the treatment
      group compared with the control group. After an average 4 wk of physical therapy
      intervention, patients in the treatment group demonstrated statistically
      significant increases of cervical range of motion, decrease of pain, increases of
      physical performance measures, and decreases in the level of disability. The
      control group showed no differences in all five outcome variables between the
      initial and follow-up test scores. CONCLUSIONS: This study delineated algorithm
      based clinical reasoning strategies for evaluating and treating patients with
      cervical pain. The algorithm can help clinicians classify patients with cervical
      pain into clinical patterns and provides pattern-specific guidelines for physical
      therapy interventions. An organized and specific physical therapy program was
      effective in improving the status of patients with neck pain.

PMID- 12595774
TI  - Successful pregnancy in a patient with spinal muscular atrophy and severe
      kyphoscoliosis.
AB  - Pregnancy imposes a load on the respiratory system that is usually easily assumed
      because of alterations in the thoracoabdominal architecture. It is presumed that
      the respiratory mechanical disadvantage of severe kyphoscoliosis and the muscle
      weakness of spinal muscular atrophy impede these adaptations sufficiently to
      preclude a successful gestation. We report the case of a successful pregnancy in
      a woman with spinal muscular atrophy, severe uncorrected scoliosis, and the
      lowest spirometric values reported in the literature without the use of
      ventilatory support. This patient demonstrates that women with severe
      kyphoscoliosis and a profound ventilatory limitation can carry a successful
      pregnancy well into the third trimester without requiring full ventilatory
      support.

PMID- 12595775
TI  - Successful pregnancies for ventilator users.
AB  - This case series describes full-term pregnancies despite no autonomous ability to
      breathe due to poliomyelitis or ventilatory insufficiency due to severe
      kyphoscoliosis. Three women with postpoliomyelitis who were continuously
      dependent on noninvasive intermittent positive pressure ventilation and one woman
      who developed ventilatory insufficiency due to severe kyphoscoliosis became
      pregnant and delivered healthy, full-term babies. They had vital capacities of
      240, 250, 280 (5% of normal), and 880 ml (14% of normal), respectively, when
      becoming pregnant. The up to continuous use of noninvasive intermittent positive
      pressure ventilation can permit the natural completion of pregnancies of women
      with little or no ability to breathe unaided.

PMID- 12595776
TI  - Depression in preschool children.

PMID- 12595777
TI  - Adolescent nicotine use.

PMID- 12595778
TI  - Children with gender nonconformity.

PMID- 12595779
TI  - Ten-year research update review: child sexual abuse.
AB  - OBJECTIVE To provide clinicians with current information on prevalence, risk
      factors, outcomes, treatment, and prevention of child sexual abuse (CSA). To
      examine the best-documented examples of psychopathology attributable to CSA.
      METHOD Computer literature searches of and for key words. All English-language
      articles published after 1989 containing empirical data pertaining to CSA were
      reviewed. RESULTS CSA constitutes approximately 10% of officially substantiated
      child maltreatment cases, numbering approximately 88,000 in 2000. Adjusted
      prevalence rates are 16.8% and 7.9% for adult women and men, respectively. Risk
      factors include gender, age, disabilities, and parental dysfunction. A range of
      symptoms and disorders has been associated with CSA, but depression in adults and
      sexualized behaviors in children are the best-documented outcomes. To date,
      cognitive-behavioral therapy (CBT) of the child and a nonoffending parent is the
      most effective treatment. Prevention efforts have focused on child education to
      increase awareness and home visitation to decrease risk factors. CONCLUSIONS CSA
      is a significant risk factor for psychopathology, especially depression and
      substance abuse. Preliminary research indicates that CBT is effective for some
      symptoms, but longitudinal follow-up and large-scale "effectiveness" studies are
      needed. Prevention programs have promise, but evaluations to date are limited.

PMID- 12595780
TI  - A feasibility study of the children's medication algorithm project (CMAP)
      algorithm for the treatment of ADHD.
AB  - OBJECTIVE: To determine whether an algorithm for the treatment of attention
      deficit/hyperactivity disorder (ADHD) can be implemented in a community mental
      health center. METHOD: Fifty child and adolescent patients at Texas community
      mental health centers who met criteria for ADHD were treated according to an
      algorithm-based disease management program for ADHD. Psychiatrists were trained
      in the use of the algorithm, and each subject underwent a baseline assessment
      consisting of a structured interview and standardized rating scales. Subjects
      were monitored for 4 months. At the end of treatment, the psychiatrists completed
      the Clinical Global Impression Scale (CGI) and the baseline rating scales were
      repeated. The primary variables of interest were psychiatrist and family
      adherence to the algorithm. To examine impact on treatment outcome, the CGI of
      the algorithm subjects was compared with CGIs based on chart reviews of 118
      historical controls. RESULTS: Psychiatrists implemented the major aspects of the
      algorithm, but the detailed tactics of the algorithm (use of fixed titration of
      stimulants) were less well adhered to. CONCLUSIONS: An algorithm for the
      treatment of ADHD can be implemented in a community mental health center.

PMID- 12595781
TI  - Poison centers' experience with methylphenidate abuse in pre-teens and
      adolescents.
AB  - OBJECTIVE: To evaluate trends and toxicity of methylphenidate abuse in pre-teens
      and adolescents reported to poison centers. METHOD: The 1993-1999 American
      Association of Poison Control Centers Toxic Exposure Surveillance System was
      queried for methylphenidate abuse cases in children aged 10 through 19 years that
      were followed to known outcome. Main outcome measures included number of cases
      annually, toxicity, management site, and coded medical outcome. RESULTS: Of 759
      cases, 42.7% involved 10-through 14-year-olds. For the 530 (70.0%) cases
      involving methylphenidate only, the frequency increased sevenfold from 1993 to
      1999. Of 570 patients (75.1%) managed in a health care facility, 398 were
      discharged from the emergency department and 172 were admitted. Symptoms occurred
      more commonly in exposures involving coingestants (84.3%) than in methylphenidate
      only exposures (71.1%). The most common symptoms in adolescents with
      methylphenidate only were tachycardia (31.7%), agitation/irritability (25.7%),
      and hypertension (11.5%). Outcomes were no effect in 189 cases (24.9%) and mild,
      moderate, and severe in 318 (41.9%), 245 (32.3%), and 7 (0.9%) patients,
      respectively. CONCLUSIONS: Poison center data demonstrate increasing frequency of
      methylphenidate abuse. While the majority of adolescents experienced clinical
      effects and were managed in a health care facility, outcomes were good,
      especially in cases involving methylphenidate only.

PMID- 12595782
TI  - Boys with ADHD in social interaction with a nonfamiliar adult: an observational
      study.
AB  - OBJECTIVE: To clarify the nature of social interaction deficits in boys with
      attention-deficit hyperactivity disorder (ADHD). METHOD: Twenty Dutch hyperactive
      boys and 19 peer controls were observed using an ethological method during social
      interaction with a nonfamiliar adult (a student). Social behavior was
      operationalized in terms of the duration and frequency of visual and verbal
      behavior elements and scored during a conversation and a play segment. RESULTS:
      During the conversation segment, the boy with ADHD and the student were less
      socially involved in each other. During the play segment, boys with ADHD talked
      to themselves more and seemed to direct their attention to the student more than
      control boys did. The students praised the boys with ADHD more frequently and
      asked them more questions about their play activities than the control boys.
      CONCLUSIONS: Boys with ADHD demonstrate poor social attention during conversation
      and elicit structure-providing behavior in nonfamiliar adults. It is postulated
      that poor self-regulatory mechanisms may mediate their social problems.

PMID- 12595783
TI  - Proton magnetic resonance spectroscopy investigation of the right frontal lobe in
      children with attention-deficit/hyperactivity disorder.
AB  - OBJECTIVE: To investigate neurometabolite concentrations in right prefrontal
      white matter in children with attention-deficit/hyperactivity disorder (ADHD) and
      relations of neurometabolites with attention skill and frontal anatomy. METHOD:
      Single voxel proton magnetic resonance spectroscopy ( H-MRS), quantitative
      morphometric analysis of left and right dorsolateral frontal volumes, and
      assessment of attentional problems with the Conners Continuous Performance Test
      were undertaken in 23 children (17 male) with ADHD (with no comorbid learning
      disabilities) and 24 matched controls (16 male). RESULTS: No overall group
      differences were found for any neurometabolite. However, a group by sex
      interaction was noted for -acetylaspartate, such that girls with ADHD had
      especially low concentrations. Morphological analyses revealed smaller right (but
      not left) dorsolateral volumes in children with ADHD, and in the ADHD group this
      volume correlated with neurometabolite concentrations. In the ADHD group
      Continuous Performance Test performance was related to both dorsolateral volume
      and the creatine-phosphocreatine peak from H-MRS. CONCLUSIONS: These results add
      to a growing body of evidence suggesting sex-specific neurobiological differences
      in ADHD and draw attention to relationships between neurochemistry, neuroanatomy,
      and performance in children with ADHD. Study limitations include small sample
      size and clinical heterogeneity among the children with ADHD.

PMID- 12595784
TI  - A school-based mental health program for traumatized Latino immigrant children.
AB  - OBJECTIVE: To pilot-test a school mental health program for Latino immigrant
      students who have been exposed to community violence. METHOD: In this quasi
      experimental study conducted from January through June 2000, 198 students in
      third through eighth grade with trauma-related depression and/or posttraumatic
      stress disorder symptoms were compared after receiving an intervention or being
      on a waitlist. The intervention consisted of a manual-based, eight-session, group
      cognitive-behavioral therapy (CBT) delivered in Spanish by bilingual, bicultural
      school social workers. Parents and teachers were eligible to receive
      psychoeducation and support services. RESULTS: Students in the intervention group
      ( = 152) had significantly greater improvement in posttraumatic stress disorder
      and depressive symptoms compared with those on the waitlist ( = 47) at 3-month
      follow-up, adjusting for relevant covariates. CONCLUSIONS: A collaborative
      research team of school clinicians, educators, and researchers developed this
      trauma-focused CBT program for Latino immigrant students and their families. This
      pilot test demonstrated that this program for traumatized youths, designed for
      delivery on school campuses by school clinicians, can be implemented and
      evaluated in the school setting and is associated with a modest decline in trauma
      related mental health problems.

PMID- 12595785
TI  - Predictors of treatment response in anxious-depressed adolescents with school
      refusal.
AB  - OBJECTIVE: To identify predictors of treatment response to 8 weeks of cognitive
      behavioral therapy (CBT) among anxious-depressed adolescents with school refusal,
      half of whom received imipramine plus CBT and half of whom received placebo plus
      CBT. METHOD: A hierarchical multiple regression analysis was used to evaluate the
      following variables as potential predictors of treatment response as measured by
      school attendance at the end of treatment: baseline severity (school attendance
      at baseline), drug group (imipramine versus placebo), presence of separation
      anxiety disorder (SAD), and presence of avoidant disorder (AD). RESULTS: Baseline
      attendance, CBT plus imipramine, SAD, and AD were significant predictors of
      treatment response and accounted for 51% of the variance in outcome.
      Specifically, a higher rate of attendance at baseline and receiving imipramine
      predicted a better response to treatment whereas the presence of SAD and AD
      predicted a poorer response to treatment. The relationship between
      sociodemographic variables and treatment outcome was also evaluated. Age and
      socioeconomic status were unrelated to school attendance after treatment. Males
      had significantly higher rates of attendance after treatment than females.
      CONCLUSIONS: Adolescents with school refusal are a heterogeneous population and
      require individualized treatment planning. Variables such as diagnosis and
      severity at the start of treatment should be taken into consideration when
      planning treatment.

PMID- 12595786
TI  - Cognitive-behavioral treatment of generalized anxiety disorder among adolescents:
      a case series.
AB  - Seven adolescents received a cognitive-behavioral treatment targeting generalized
      anxiety disorder. The treatment consisted of awareness training, worry
      interventions, and relapse prevention. The worry interventions targeted
      specifically intolerance of uncertainty, beliefs about worry, problem solving,
      and cognitive avoidance. According to the Anxiety Disorders Interview Schedule
      for diagnosis of generalized anxiety disorder, self-report questionnaire scores,
      and time spent worrying every day, three adolescents showed clinically
      significant change at post-test which was maintained at 6- and 12-month follow-up
      assessments. Minimal to moderate improvement was observed for other participants.
      Factors that may explain these differences are discussed.

PMID- 12595787
TI  - A two-year follow-up of psychodynamic psychotherapy for internalizing disorders
      in children.
AB  - OBJECTIVE: To evaluate short- and long-term effects of time-limited psychodynamic
      psychotherapy (PP) for children with internalizing disorders. METHOD: Fifty-eight
      outpatient children (6.3-10.9 years old), seen in a process of routine care and
      meeting criteria for depressive or anxiety disorder, were assigned to either
      active treatment or community services. Subjects were measured at baseline, after
      6 months, and at a 2-year follow-up, by Children's Global Assessment Scale (C
      GAS) and Child Behavior Checklist (CBCL). RESULTS: Major improvements in the
      experimental group were found in C-GAS and CBCL. These differences are noted at
      different times, with the C-GAS findings seen at 6 months and the CBCL findings
      at 2-year follow-up. Significant differences were found also for externalizing
      syndrome scales. CONCLUSIONS: PP is effective in treating internalizing disorders
      in routine outpatient care. The benefits of treatment are manifest both
      immediately and with delayed onset (sleeper effect). The finding that PP patients
      sought mental health services at a significantly lower rate than comparison
      conditions represents an important economic impact of PP.

PMID- 12595788
TI  - The clinical picture of depression in preschool children.
AB  - OBJECTIVE: To investigate the clinical characteristics of depression in preschool
      children. METHOD: One hundred seventy-four subjects between the ages of 3.0 and
      5.6 years were ascertained from community and clinical sites for a comprehensive
      assessment that included an age-appropriate psychiatric interview for parents.
      Modifications were made to the assessment of major depressive disorder (MDD)
      criteria so that age-appropriate manifestations of symptom states could be
      captured. Typical and "masked" symptoms of depression were investigated in three
      groups: depressed (who met all MDD criteria except duration criterion), those
      with nonaffective psychiatric disorders (who met criteria for attention
      deficit/hyperactivity disorder and/or oppositional defiant disorder), and those
      who did not meet criteria for any psychiatric disorder. RESULTS: Depressed
      preschool children displayed "typical" symptoms and vegetative signs of
      depression more frequently than other nonaffective or "masked" symptoms.
      Anhedonia appeared to be a specific symptom and sadness/irritability appeared to
      be a sensitive symptom of preschool MDD. CONCLUSIONS: Clinicians should be alert
      to age-appropriate manifestations of typical MDD symptoms and vegetative signs
      when assessing preschool children for depression. "Masked" symptoms of depression
      occur in preschool children but do not predominate the clinical picture. Future
      studies specifically designed to investigate the specificity and sensitivity of
      the symptoms of preschool depression are now warranted.

PMID- 12595789
TI  - Comparing DISC-IV and clinician diagnoses among youths receiving public mental
      health services.
AB  - OBJECTIVES: To compare the prevalence and agreement of diagnoses based on
      Diagnostic Interview Schedule for Children Version IV (DISC-IV) and clinician
      assignment for youths receiving public mental health services between 1996 and
      1997 and to examine potential predictors of diagnostic agreement. METHOD:
      Participants included 240 youths aged 6-18 years. Past-year prevalence rates and
      kappa statistics were calculated for four diagnostic categories: anxiety, mood,
      attention-deficit/hyperactivity disorder (ADHD), and disruptive behavior
      disorders (DBD). Potential predictors of diagnostic agreement were examined with
      logistic regression analysis. RESULTS: The prevalence of ADHD, DBD, and anxiety
      disorders was significantly higher based on the DISC-IV, while the prevalence of
      mood disorders was significantly higher based on clinician assignment. Diagnostic
      agreement was poor overall. The kappa values ranged from -0.04 for anxiety
      disorders to 0.22 for ADHD. Significant predictors of agreement varied by
      diagnosis and included symptom severity, comorbidity, youth age and gender, and
      school-based problem identification. CONCLUSIONS: Consistent with previous
      findings of poor diagnostic agreement between structured interviews and
      clinicians, these results call for a better understanding of factors affecting
      diagnostic assignment across different methods. This is especially important if
      researchers continue to use structured interviews to determine prevalence,
      establish diagnosis-based treatment guidelines, and disseminate evidence-based
      treatments to community mental health settings.

PMID- 12595790
TI  - Genetic influences on childhood competencies: a twin study.
AB  - OBJECTIVE: To estimate genetic, environmental, and rater contrast influences on
      parental reports of Activities, Social, School, and Total Competence scales of
      the Child Behavior Checklist (CBCL). METHOD: Parents of 492 twin pairs aged 8-12
      years completed CBCLs. Genetic, shared and unique environmental, and rater bias
      effects were estimated for the Activities, Social, School, and Total Competence
      scales. Data on boys and girls were analyzed separately. RESULTS: Moderate
      genetic influences were found only for the School scale (60%-76%), while shared
      environment accounted for most of the variance in Activities, Social, and Total
      Competence scales. Gender differences are reported. Similar to a prior twin study
      of CBCL problem syndromes, there was no evidence of rater bias. CONCLUSIONS:
      Estimates of genetic influence on these child competence domains were high for
      School Competence, while social competence and activity competence evidenced
      higher levels of shared environmental influences. Organization and wording of
      CBCL items may avoid rater biases in reporting. These findings have implications
      for interventions to improve school, social, and activities competence.

PMID- 12595791
TI  - Callous/unemotional traits and social-cognitive processes in adjudicated youths.
AB  - OBJECTIVE: There seem to be two dimensions associated with psychopathic traits in
      youths: a callous/unemotional factor (C/U) and an impulsivity/conduct problems
      factor (I/CP). This study sought to clarify the nature of these two factors and
      examine their relation with social-cognitive problems in incarcerated
      adolescents. METHOD: One hundred sixty-nine male and female adjudicated youths
      were recruited for participation. Self-report measures and archival data were
      used to assess psychopathic traits, emotional distress, behavioral dysregulation,
      social-cognitive processes, and delinquency severity. RESULTS: Analyses
      demonstrated that the I/CP factor is associated with increased levels of
      dysregulated behavior, while the C/U dimension is related to deficits in empathy.
      The two factors exhibited differential relations with measures of emotional
      distress and fearfulness. C/U traits were associated with an increased focus on
      the positive aspects of aggression and a decreased focus on the negative aspects
      of hostile acts. Findings remained after controlling for demographic
      characteristics, abuse history, intellectual abilities, and delinquency severity.
      CONCLUSIONS: Results provide support for the two-dimensional nature of
      psychopathy in youths and suggest that C/U traits are associated with lower
      emotional distress and a specific social information-processing pattern. The
      potential implications for working with adjudicated youths exhibiting C/U traits
      are noted.

PMID- 12595792
TI  - Genetics of childhood disorders: XLVIII. Learning and memory, Part 1: Fragile X
      syndrome update.

PMID- 12595793
TI  - High field magnetic resonance imaging evaluation of superparamagnetic iron oxide
      nanoparticles in a permanent rat myocardial infarction.
AB  - RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate
      superparamagnetic iron oxide (SPIO) nanoparticles to discriminate infarcted from
      normal tissue after myocardial infarction using high field MR imaging (7 tesla).
      MATERIALS AND METHODS: Permanent myocardial infarction was induced in rats. SPIO
      nanoparticles (1 mg Fe/kg) were assessed with T1-weighted gradient echo sequence
      to visualize the myocardial infarction 48 hours after ligature (n = 6).
      Furthermore, MR Imaging was performed using a T2-weighted RARE sequence and
      nanoparticles were injected (5 or 10 mg Fe/kg) on 36 rats 5, 24 or 48 hours after
      infarction. RESULTS: No changes in contrast between normal and infarcted
      myocardium was observed after nanoparticle injection on T1-weighted images.
      However, nanoparticles induced a significant contrast increase between normal and
      infarcted myocardium on T2-weighted images whatever the delay between infarction
      and imaging (2.99 +/- 1.66 preinjection vs. 7.82 +/- 1.96 after SPIO injection at
      a dose of 5 mg Fe/kg 5 hours postinfarction, P = 0.0001). CONCLUSIONS:
      Nanoparticle injection made it possible to discriminate normal from infarcted
      myocardium on T2-weighted images. However, the high magnetic field prevented the
      visualization of the T1 effect of SPIO nanoparticles.

PMID- 12595795
TI  - Resistive index: an experimental study of acute complete unilateral ureteral
      obstruction.
AB  - RATIONALE AND OBJECTIVES: To study the effects of acute complete unilateral
      ureteral obstruction (UUO) and release on porcine renal resistive index (RI).
      METHODS: Under general anesthesia, UUO was induced in six pigs. RI was measured
      bilaterally at predetermined intervals for 4 hours of UUO and 1 hour of release.
      Additionally, measures of renal blood flow (RBF), glomerular filtration rate
      (GFR), arterial blood pressure, renal vascular resistance (RVR), and ipsilateral
      renal intrapelvic pressure (IPP) were obtained. RESULTS: UUO and resultant
      progressive IPP increase caused prompt and significant ipsilateral RI elevation,
      and contralateral RI decrease. Concomitantly, ipsilateral RVR increased
      significantly while RBF and GFR declined, both significantly. Release of
      obstruction saw an almost immediate normalization of ipsilateral RI, RVR and RBF
      while ipsilateral GFR assumed 80% of baseline value 15 minutes postobstruction.
      Throughout the experiment, ipsilateral RI correlated significantly with changes
      in IPP, GFR, RBF, and RVR with correlation coefficients of 0.844, -0.851, -0.898,
      and 0.836 respectively ( < 0.001). CONCLUSIONS: UUO causes a divergent RI
      response that is instantly reversed upon release. IPP seems to be the principal
      effector of these changes in the early phases of UUO.

PMID- 12595796
TI  - Magnetic resonance-guided transcortical biopsy of bone marrow lesions using a
      magnetic resonance imaging-compatible piezoelectric power drill: preliminary
      experience.
AB  - RATIONALE AND OBJECTIVES: To test utility and specific properties of a
      commercially available MRI compatible power drill for MR guided transcortical
      bone biopsy. METHODS: In 17 patients MR-guided bone biopsy was performed in an
      open low-field scanner (0.2 T), using a piezoelectrically powered drilling
      machine. Target lesions were osteoblastic in four and nonsclerosed intramedullary
      in 13 cases. Titanium drills sized 3 to 4 mm and an outer cannula were coaxially
      used for power assisted cortical trephination. For intramedullary lesion
      sampling, spring loaded biopsy guns and sharpened cannulas were additionally
      applied in seven and fluid aspiration in two patients, respectively. RESULTS: The
      piezoelectric device proved to be fully MR compatible. Trephination and
      subsequent biopsy was successful in all patients without major complications. The
      drilling procedure could entirely be performed inside the magnet in case of a
      lateral approach (n = 11). The net drilling time averaged 7.8 minutes for
      trephination of nonimpaired diaphyseal bone, but was up to 50 minutes in case of
      thickened femoral bone. Procedures were complicated by frequent drill loosening,
      drill obstruction by cortical bone (n = 4) and impaired periosteal grip (n = 5)
      with damage to the outer cannula (n = 3). CONCLUSIONS: The piezoelectric power
      drill can be applied safely in a low-field MRI environment and is a valuable tool
      to facilitate transcortical bone biopsy.

PMID- 12595794
TI  - A vascular stent as an active component for locally enhanced magnetic resonance
      imaging: initial in vivo imaging results after catheter-guided placement in
      rabbits.
AB  - RATIONALE AND OBJECTIVE: A vascular stent constructed as a high frequency
      resonator improves the local signal-to-noise ratio at magnetic resonance (MR)
      imaging. After catheter placement and intravascular expansion, the stent can be
      used as an inductively coupled coil for MRI. The imaging properties of this
      balloon-expandable active MRI stent (AMRIS) were evaluated after x-ray
      fluoroscopy guided placement in the abdominal aorta of five rabbits using MR
      angiography (MRA) and flow measurements. METHODS: The AMRIS was implanted in the
      abdominal aorta of five rabbits using a balloon catheter inserted through the
      common carotid artery. The rabbits were examined by MRA (3D fast low-angle shot)
      at 1.5 tesla before and after intravenous injection of an iron-oxide-based blood
      pool contrast medium (dose 50 micro mol Fe/kg) and flow measurements (ECG
      triggered phase contrast cine gradient-echo sequence). Signal-to-noise ratios
      (SNR) were calculated and flow volume curves were generated. The in-stent
      increase in temperature was measured in vitro using a fiberoptic thermometry
      system. RESULTS: The SNR was 5.0 +/- 0.6 outside the stent and 23.2 +/- 14.1
      within the stent ( < 0.0 5) in plain MRA, 19.5 +/- 5.0 outside and 30.7 +/- 8.2
      within the stent ( < 0.05) in contrast enhanced MRA, and 5.8 +/- 1.6 and 13.9 +/-
      5.9, respectively ( < 0.05) in the magnitude images of the flow measurements.
      Flow volume curves within and distal to the stent were comparable. CONCLUSIONS:
      The expandable active MRI stent produces local signal enhancement in MRA and MR
      flow measurements after catheter placement and thus may improve assessment of the
      stented vessel segment by MR imaging.

PMID- 12595797
TI  - Accuracy of computer-aided measurements in endovascular stent-graft planning: an
      experimental study with two phantoms.
AB  - RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the accuracy of
      the new measurement software, created for aortic stent-graft planning. The
      software finds semiautomatically the centerline of the vessel from computer
      tomographic angiography data and calculates semiautomatically diameters and
      lengths. MATERIALS AND METHODS: Two phantoms were constructed, scanned by CT and
      measured with the measurement software. Results were compared with the known
      dimensions of the phantoms and mean fractional errors were calculated. Linear
      regression analysis was also made between measured and known diameters. RESULTS:
      The mean fractional error (+/- SD) for all diameter measurements combined was
      0.017 +/- 0.011. In the linear regression analysis, was 1.000. For length
      measurements, the mean fractional error (+/- SD) was 0.009 +/- 0.0006.
      CONCLUSIONS: The software enables accurate measurements perpendicular or parallel
      to the semiautomatically created centerline path.

PMID- 12595798
TI  - Peripheral quantitative computed tomography for the detection of diabetic
      osteopathy: a study in the Goto-Kakizaki rat.
AB  - RATIONALE AND OBJECTIVE: To assess the utility of dual energy x-ray
      absorptiometry (DEXA) and peripheral quantitative computed tomography (pQCT) in
      detecting trabecular and cortical bone changes in diabetes as a model of
      osteopenia. MATERIALS AND METHODS: The tibia from 10 type-2 diabetic Goto
      Kakizaki (GK) rats and 10 control Wistar rats were analyzed by DEXA, pQCT, and
      ash weight determination. RESULTS: DEXA of GK rats showed a significant reduction
      in mineral content (32%) and density (24%) of the metaphysis, but not of the
      diaphysis. PQCT disclosed that the reduction of density predominantly pertained
      to the trabecular bone (reduced by 62%). Periosteal and endosteal circumferences
      of the diaphyses were increased and cortical thickness was unchanged leading to
      increased moment of inertia. CONCLUSIONS: This study suggests that in osteopathic
      conditions, cortical and trabecular bone should be separately examined within
      specific subregions to obtain relevant information. Loss of metaphyseal
      trabecular bone seems to be a predominant feature in diabetic rats. Moreover,
      there is increased moment of inertia in the diaphysis implying increased
      strength. These diagnostic features of diabetic osteopathy can only be assessed
      by pQCT. It may prove that similar changes occur in human type-2 diabetes, which
      could explain the susceptibility to periarticular fracture and Charcot
      arthropathy.

PMID- 12595800
TI  - Sensitivity to detect small coronary artery calcium lesions with varying slice
      thickness using electron beam tomography.
AB  - RATIONALE AND OBJECTIVE: To estimate the sensitivity to find small coronary
      artery calcium lesions with use of different slice widths with electron beam
      tomography. MATERIALS AND METHODS: Two studies were performed. Study 1 utilized
      double scanning of a stationary cork phantom with three different slice thickness
      (1.5, 3, and 6 mm). Fifty different calcific lesions (all <20 mm2 in area) fitted
      in 10 cork coronary arteries were utilized. The calcium foci area, peak value and
      score were measured and compared. In group 2, 30 patients underwent coronary
      artery calcium (CAC) screen studies. Each patient was scanned with both 3-mm and
      6-mm scan widths in a same study time. Lesions with < 20 mm2 of area of CAC were
      measured on both 3-mm and 6-mm images. The mean and peak Hounsfield unit measure,
      and Agatston score were compared between both images. RESULTS: In the cork study,
      the sensitivity to detect small calcium foci were 96% (48/50), 82% (41/50), and
      34% (17/50) in images with 1.5-, 3-, and 6-mm slice thickness, respectively.
      There is a smaller value in mass, and calcium volume in 6-mm images than 1.5-mm
      and 3-mm images ( P< 0.001). There was no significant difference between the true
      value and measured value from 1.5-mm and 3-mm images. In the human study, 18
      (30%) of 60 CAC lesions with an area < 20 mm2 defined on 3 mm images were not
      visible on 6-mm images. Sensitivity of small lesions (P< 5 mm2) was 48% using 6
      mm slices. There was a smaller value in CAC area, mean and peak Hounsfield units
      and score measured from 6-mm images, as compared with 3 mm slices ( P< 0.05).
      CONCLUSION: Thinner slice imaging has a higher sensitivity to detect small
      calcium focus. There was no significant change in score between 3 mm and 1.5 mm
      on the cork phantom study. However, the use of 6-mm slices should be discouraged,
      as this protocol both underestimates calcific mass and misses a significant
      number of calcific lesions in both a phantom and human study.

PMID- 12595799
TI  - Contrast media augmented apoptosis of cultured renal mesangial, tubular,
      epithelial, endothelial, and hepatic cells.
AB  - RATIONALE AND OBJECTIVE: Nephrotoxicity of contrast media, resulting in apoptosis
      and acute necrosis of tubular cells, is well documented. No studies concerning
      mesangial cells apoptosis have been published yet. AIM: Apoptosis of cultured
      mesangial, tubular, and hepatic cell lines was investigated following exposure to
      different contrast media. METHODS: Apoptosis was assessed by TUNEL assay and
      verified by Mayer Hematoxylin staining. RESULTS: Iopromide, Ioxaglate, and
      Ioxatalamate induced apoptosis in all cell cultures at final concentrations
      ranged from 0.1% to 10.0%. However, only 1% to 10% Iomeprol elicited a
      significant apoptosis. Moreover, at 10% concentration, Iomeprol induced
      significantly less apoptosis than Iopromide, Ioxaglate, or Ioxatalamate.
      CONCLUSIONS: First, Iomeprol, which has a different physico-chemical properties,
      proved to be less proapoptotic compared with other contrast compounds. Second,
      all types of cells similarly respond by apoptosis to contrast media induced
      injury. However, apoptosis of mesangial cells might generate additional
      deleterious effects in vivo.

PMID- 12595801
TI  - Vestibular schwannomas and auditory function: options in large T3 and T4 tumors?
AB  - OBJECTIVE: While hearing preservation has become an accepted treatment goal,
      there are still major doubts whether and to what extent this aim is feasible in
      large tumors that cover the auditory nerve and involve the brainstem. METHODS:
      One thousand eight hundred (1,800) vestibular schwannomas (VS) were operated on
      at Nordstadt Neurosurgical Department from 1978 to 1999 by the senior surgeon
      (MS). There were 1,800 tumors in 1,750 patients, 1,605 patients had unilateral
      tumors, 145 patients had neurofibromatosis type 2 with bilateral tumors, 195 of
      which were treated surgically in our unit. Preservation of the cochlear nerve was
      attempted when ever possible. The audiometric data are analyzed by Hannover
      Classification System graded in steps of 20 dB by audiometry and in steps of 10%
      to 30% by speech discrimination. Those data were set into relation with the
      Hannover tumor extension grading T1 to T4. RESULTS: Overall preservation rate was
      40% with considerable differences, though, depending on the preoperative hearing
      quality and the tumor extension. Best results were obtained for intrameatal
      tumors (T1) with 56% and small intra-extrameatal tumors (T2) with 57%
      preservation rate. While preservation rate was at 44% in medium-sized tumors
      (T3), it was at 20% for T4 tumors with brainstem compression or even dislocation.
      However, satisfactory chances were encountered in cases with normal or good
      preoperative hearing, on average 54%, specifically 71% in T1, 69% in T2, 58% in
      T3 and 29% in T4. Regarding the quality of the preserved hearing, up to one third
      of cases in T1 and T2 may retain their preoperative hearing level, while this
      ranges around 20% for T3 and 10% to 14% in T4 tumors. DISCUSSION: For long,
      hearing preservation in medium sized or large tumors has not received any
      attention because of the presumed lack of realistic chances and the expected bad
      quality. Obviously, hearing preservation may be achieved in relevant numbers and
      at satisfactory quality levels. This aspects appears important to be addressed
      further in view of the fact that over 70% of tumors are presented for surgery at
      T3 or T4 extensions. CONCLUSION: The summit of hearing preservation has not been
      reached as improvements are still achieved even in most difficult conditions.

PMID- 12595802
TI  - [Preservation of hearing function in the radiosurgical treatment of unilateral
      vestibular schwannomas. Preliminary results].
AB  - INTRODUCTION: Preservation of functional hearing can be now attempted during the
      surgical treatment of a vestibular schwannomas. The probability of functional
      hearing preservation for each of the neurosurgical approaches is currently under
      evaluation. We report here a preliminary evaluation of our radiosurgical
      experience. MATERIAL AND METHOD: In Marseilles, we performed 800 gamma-knife
      procedures for cochleovestibular schwannomas by between July 1992 and December
      2000. These patients were evaluated systematically according to a prospective
      methodology. We report here the study of the population of 211 patients with
      unilateral schwannoma and a functional preoperative hearing (Gardner and
      Robertson 1 or 2) treated as first intention, with a follow-up longer than two
      years. RESULTS: Hearing was improved with the radiosurgery in 3% of cases with a
      average gain of 10 decibels. Average loss in decibel on the four main frequencies
      (500, 1,000, 2,000, 4,000 Hz) was 17 dB. The probability of functional hearing
      preservation with radio surgery was high: 73%. However, this probability depended
      on numerous factors related to the patient and to the "operative technique". The
      main parameters of predictability were limited preoperative tonal loss, Gardner
      and Robertson stage 1 (versus 2), multiisocentric planning, peripheral dose lower
      than 13 Gy. So a Gardner and Robertson stage 1 intracanalicular tumor treated in
      accordance with "the state of the art" with a gamma-knife and a marginal dose
      inferior to 13 Gy has a probability of functional conservation at 2 years greater
      than 95%. CONCLUSION: Our results are preliminary and they require the
      confirmation of a more extensive and more prolonged follow-up. However, the large
      size of this population and the systematic methodology should help us in
      determining more precisely the place of radiosurgery and especially to better
      inform the patients of their chances of hearing preservation according to their
      individual risk profile.

PMID- 12595805
TI  - Angiographic cerebral vasospasm and delayed ischemic deficit on anterior part of
      the circle of Willis. Usefulness of transcranial Doppler.
AB  - BACKGROUND AND PURPOSE: After subarachnoid hemorrhage (SAH), cerebral vasospasm
      (VS) may be revealed by cerebral angiography, during follow-up clinical
      examination with the occurrence of delayed ischemic deficit (DID). Moreover,
      transcranial Doppler (TCD) could be useful in determining the level of the
      velocimetric threshold. The aims of the study were, on a prospectively collected
      series of 460 patients, to assess angiographic VS incidence, to determine
      possible risk factors, and to evaluate diagnostic sensitivity and specificity of
      TCD. PATIENTS AND METHOD: A total of 460 patients consecutively operated on for
      an aneurysm located on the anterior portion of the circle of Willis (mean age
      47.2 +/- 14 years, sex ratio F/M=1.18) were included in the study. Preventive
      treatment against VS was administered in all patients. On the 10(th) day, we
      performed the following routine examinations: cerebral angiography, CT scan and
      TCD. RESULTS: Angiographic VS occurred in 38.5% of the patients, and the single
      risk factor was delayed admission (p=0.02, Mann-Whitney test). DID occurred in
      15.6% and was complicated by cerebral infarct in 4.7%. The risk factors were
      admission date (p=0.001, Mann-Whitney test) and severity of arterial narrowing
      (significant tendency). Diagnostic sensitivity of TCD decreased from 83.6% for
      MCA aneurysms, to 66.6% for ICA aneurysms and 40.6% for AcoA aneurysms. Diagnosis
      specificity remained between 88.6% and 97.6% for the 3 locations. CONCLUSION: The
      unique risk factor for angiographic VS and DID was the admission date. TCD
      demonstrated high specificity but its sensitivity was too low for the aneurysms
      located far from the middle cerebral artery bifurcation.

PMID- 12595803
TI  - [Acoustic neuromas and serviceable hearing: choosing the surgical approach].
AB  - The principal objectives of acoustic neuroma surgery in the order of priority are
      absence of mortality and neurological morbidity, total removal of the lesion,
      preservation of facial function, and preservation of hearing. The aim of this
      work was to evaluate the selection criteria and the therapeutic strategy for
      hearing preservation in acoustic neuroma management. This retrospective study
      included 436 consecutive patients referred to our department for an acoustic
      neuroma. The population comprised 365 patients (84%) treated surgically, 66
      patients (15%) managed conservatively, and 5 irradiated patients (1%). The mean
      age was 54 years (range: 13-87). The mean follow-up period was 24 months (range:
      1-120). The surgical approaches were translabyrinthine in 294 (81%), retrosigmoid
      in 37 (10%), and through the middle fossa in 34 cases (9%). Approaches preserving
      the labyrinth were employed in patients aged less than 60 years with lesions
      measuring <or=2 cm and a serviceable hearing (pure tone average <50 dB and speech
      discrimination score >or=50%). A serviceable hearing was preserved in 53% of the
      cases with a serviceable hearing in 44% of the cases. Postoperative normal or
      subnormal facial function was obtained in 72 to 98% of cases depending on tumor
      size. Two cases (0.5%) of recurrence were reported. In conclusion, our surgical
      strategy based on age, tumor size and pre-operative hearing function permitted
      hearing preservation in 50% of selected cases, a high rate of facial function
      preservation and a low risk of recurrence.

PMID- 12595806
TI  - [Glioblastomas: clinical study and search for prognostic factors].
AB  - Glioblastoma multiform is one of the most devastating primary tumors in
      neurooncology. We analyzed prognosis factors in patients with grade IV
      glioblastoma treated between 1993 and 1997. The 22 long-term survival patients
      (survival over 26 months) were extracted from our 30 years archives and the 2
      populations are compared. The incidence was 2.6/100,000h/year, 62% male and 38%
      female, mean age 59 years, mean survival 12 months, median survival time 9
      months. Multivariate analysis showed that younger age, surgical treatment and
      radiotherapy were all dependent prognosis factors for better survival.
      Statistically, survival was best for total surgical removal of tumors, followed
      by tumor gross resection then biopsy. Clinical status and inextirpable tumor
      location were also prognosis factors. The free interval time between total
      surgery and tumor reappearance was strongly correlated with survival (r=0.94).
      This suggests that some grade IV gliomas follow a quicker course, others
      exhibiting slow growth. Each of the prognosis factors was confirmed in the long
      survival patients. Prevalence of all glioblastomes was 4.3%. Their mean age was
      42 and mean survival 62 months. A larger proportion of these patients had total
      surgery and radiotherapy. The time lapse before tumor reappearance was longer.
      Deep tumor locations were less frequent. The proportion of secondary versus
      primary glioblastomas was the greatest difference between the long-term and
      regular survivors. Secondary glioblastomas were found in only 4% of the standard
      population and in 23 to 41% in the long-term survivors (p<0.01). Primary
      glioblastomas typically show EGFR over expression and mutation (variant III). The
      pathway to secondary glioblastoma involves early P53 mutation. Despite the fact
      that the anatomopathologist regards similar tissues under the microscope, these
      subtypes of glioblastomas are distinct disease entities which evolve through
      different genetic pathways and exhibit different outcomes.

PMID- 12595807
TI  - [Endoscopic third ventriculostomy for management of obstructive hydrocephalus
      secondary to supratentorial intraventricular hematoma. Case report].
AB  - We report two cases of intraventricular hematoma with obstructive hydrocephalus.
      We perform endoscopic treatment of the hydrocephalus: aspiration of the hematoma
      associated with a third ventriculostomy. Both patients respectively aged 59 and
      74 years had an obstructive hydrocephalus due to intraventricular hemorrage. The
      patient neurological status worsen at day 6 for patient No. 1 and at day 4 for
      patient No. 2. Endoscopic ventriculoscopy was performed respectively at day 6 and
      at day 5. Operatively, immediate vision was poor but was progressively improved
      by repetitive irrigation with Ringer-lactate (RL). Obstruction of the right Monro
      foramen by clot was observed. Introduction of the neuroendoscope into the third
      ventricle was possible after suction of the hematoma. Perforation of the floor of
      the third ventricle was performed after identification of the mammillary bodies
      and the infundibulum. Neurological status recovered within 10 days after surgery
      and the patients were referred to a medical unit. The patients were independent
      at home. The one-year MRI follow-up study showed a functional acqueduc in case 1
      and a non-functional acqueduc in case 2 indicating in this case that the
      ventriculocisternotomy was useful. Intraventricular hematoma is not a
      contraindication for endoscopic third ventriculostomy. If possible, waiting for 6
      or 5 days to allow the structuring of the blood clot and using large irrigation
      RL may facilitate the endoscopic procedure. This indication for endoscopic third
      ventriculostomy constitutes an alternative to external ventricular drainage which
      is significatively associated with complication (infection and obstruction). We
      cannot affirm that the removal of the clots and ventriculocisternostomy versus
      temporary external drainage avoids secondary hydrocephalus.

PMID- 12595808
TI  - [Nocardia farcinica brain abscess: clinical and specific radiological findings
      and management. Report of two cases in immunononcompromised patients].
AB  - Nocardia spp. cerebral abscesses are rare and usually occur in immunocompromised
      patients. We report two recent cases of cerebral abscesses due to Nocardia
      farcinica in immunocompetent patients and review the literature about diagnosis
      and therapeutic issues. Outcome was good for the two patients following an early
      identification of the bacteria. Stereotactic biopsy was performed in one case and
      craniotomy with excision of the abscess in the other case. In both cases,
      complete identification of the bacteria could be achieved, followed by prolonged
      antibiotic therapy. Exposure to the germ (mainly telluric) is often difficult to
      suspect from the past medical history of the patient. Diagnosis is also
      unexpected. Despite the typically and characteristic aspect on CT and MRI,
      specific identification and anti-microbial sensitivity profiles are necessary to
      optimize treatment. In some rare cases, unusual species like Nocardia farcinica,
      can be resistant to numerous antibiotics requiring adjustments of medical
      management. Early identification of the bacteria is necessary to achieve good
      outcome in immunocompetents patients.

PMID- 12595809
TI  - [Sphenoid sinus lymphoma. Case report and review of the literature].
AB  - A 64-year-old man presented to his general practitioner with an history of
      headaches and recent diplopia. Neuroradiological investigation showed a sphenoid
      sinus mass involving the sella and the clivus. Diagnosis of non-Hodgkin lymphoma
      was made via a transsphenoidal approach. The patient subsequently underwent a 6
      month course of chemotherapy (M COPPA protocol) followed by 50 Gy locoregional
      radiotherapy. At three years follow-up the patient was in complete clinical and
      radiological remission. This case underscores the importance of thorough
      radiological work-up for accurate identification of tumor masses involving the
      pituitary fossa and provides an opportunity to review the literature on the
      management of this rare entity.

PMID- 12595810
TI  - Secondary tetraplegia due to giant-cell tumors of the cervical spine.
AB  - BACKGROUND AND PURPOSE: Giant-cell tumor of the bone is a neoplasm which rarely
      affects the spine, and occurs even more infrequently above the sacrum. The
      symptomatology depends on the tumor site, and may be attributable to a
      compression mechanism. Spinal cord injury is seldom a complication and
      tetraplegia is even more infrequent. In this paper, we present an unusual case
      involving a giant cell tumor. We also review its possible diagnoses and
      treatments. CLINICAL CASE: We present the case of giant-cell tumors in the
      cervical spine affecting C6 and C7, in a young woman who suffered tetraplegia due
      to spinal cord compression. After surgery and radiotherapy, the tumor reappeared,
      requiring a second operation. CONCLUSION: Early clinical diagnosis of giant-cell
      tumors of the spine is difficult because their development tends to go unnoticed.
      Imaging techniques, especially MRI, help identify them; but their diagnosis still
      requires histopathologic tests. Resection of the neoplasm is recommended, when
      possible. Curettage may allow recurrence and radiotherapy may lead to sarcomatous
      degeneration of the tumor.

PMID- 12595811
TI  - [Intramedullary spinal cord metastasis: is there a place for surgery? Case report
      and review of literature].
AB  - BACKGROUND AND PURPOSE: The usual onset of intramedullary spinal cord metastases
      at an advanced stage of cancer disease explains that surgical removal of such
      lesions is rarely performed. We tried to define the place for surgery in the
      management of such lesions. METHODS: We report the observation of a 52-year-old
      male patient presenting with a metastasis of the conus medullaris revealing a
      lung cancer. Surgical excision of the lesion led to pain relief and improvement
      of bladder dysfunction. We present a review of pertinent literature. RESULTS:
      Surgery allows histological diagnosis in case of isolated, revealing tumor. In
      other selected cases, radical removal of intramedullary metastases could improve
      the quality and comfort of life although it does not seem to affect the duration
      of survival.

PMID- 12595813
TI  - Reproductive life events and sexual functioning in women: case reports.
AB  - Are reproductive life events in women associated with an increased risk of sexual
      dysfunction? Female sexual dysfunction effects up to 40% of women in the United
      States between 18 and 59 years of age. Sexual dysfunction may be accompanied by
      fluctuations in gonadal hormone secretion, making women more vulnerable to sexual
      symptoms, especially during times of reproductive life events. Reproductive life
      events, such as the use of birth control pills, various phases of the menstrual
      cycles, postpartum and lactation states, and perimenopause, are highly correlated
      with changes in sex steroids. As an understanding of the role of sex steroids on
      sexual functioning is elucidated, clinicians will be able to offer more specific
      and effective treatment options for women during various phases of reproductive
      life. Several case studies are presented to illustrate the unique clinical
      considerations that a clinician must consider when treating the biologic
      component of female sexual dysfunction.

PMID- 12595814
TI  - Selective phosphodiesterase type-5 inhibitor treatment of serotonergic reuptake
      inhibitor antidepressant-associated sexual dysfunction: a review of diagnosis,
      treatment, and relevance.
AB  - Sexual dysfunction related to antidepressants, particularly serotonin reuptake
      inhibitors is a major cause of premature treatment discontinuation. This places
      patients at increased risk for recurrence, relapse, chronicity, and mortality
      (eg, suicide). The clinical assessment requires a comprehensive evaluation of
      sexual function, including libido, arousal, orgasm, and resolution prior to
      affective disorder, disturbances associated with the emergence of depression, and
      changes or dysfunctions associated with antidepressant treatment. Other factors
      to be included for evaluating sexual dysfunction include inquiry for concurrent
      medical conditions, somatic treatments, lifestyle risk factors, and response to
      antidepressants. Current treatment approaches to antidepressant-associated sexual
      dysfunction have relied on open-label reports, literature reviews, and clinical
      wisdom. Without double-blind, placebo-controlled studies to support them, too
      much non-evidence-based treatment may be offered to patients. Advances into
      nonadrenergic-noncholinergic novel signal transduction, specifically
      phosphodiesterase type-5 inhibitors, offer new opportunities for developing
      evidence-based treatments for this side effect and improving depression disease
      management outcomes.

PMID- 12595815
TI  - Neurochemical aspects of the sexual response cycle.
AB  - What drives the human sexual response cycle? The human sexual response cycle is a
      highly complex phenomenon that encompasses many transmitters and transmitter
      systems centrally and peripherally. The endocrine system is also intricately
      involved in the brain and in the periphery organs. Integration of these systems
      is a function of the nervous system that ultimately produces a vast array of
      cognitive, emotional, physiological, and behavioral responses. Therefore, it is
      not surprising that a disturbance in even a single system will lead to
      dysfunction in one or more phases of the sexual response cycle. This article
      highlights the complex roles the aminergic system plays along with key hormones
      that are equally involved. The article also points out how rudimentary and
      fragmented our knowledge is in this field and how few controlled studies are
      available. The potential for development of specific agents that target selective
      sexual dysfunctions is exemplified in sildenafil, the first such agent ever to be
      brought to market.

PMID- 12595816
TI  - The clinical evaluation of common sexual concerns.
AB  - Whose job is it to discover and manage patients' sexual concerns? If you believe
      that you have a role to play, just what is that role and how will you perform it?
      Sexual disorders are common, yet infrequently diagnosed. A willingness to inquire
      about sexual function is the most critical diagnostic step for clinicians. Once a
      problem is discovered, a systematic diagnostic process can uncover etiologic
      organic and psychogenic factors using customary diagnostic tools, including
      taking a psychosexual and medical history, comprehensive and focused physical
      examinations, psychological assessment instruments, laboratory tests, and special
      procedures.

PMID- 12595817
TI  - Pharmacologic management of sexual dysfunction: benefits and limitations.
AB  - What is the current knowledge concerning the pharmacologic treatment of human
      sexual dysfunction? A number of interventions, including oral phophodiesterase
      inhibitors and intracorporeal agents with vasodilatory effects, are available to
      treat male erectile disorder. Serotonergic drugs have been shown to be effective
      in the treatment of rapid ejaculation. Various lines of research suggest that
      high dosages of androgenic agents may eventually have a role in the treatment of
      decreased libido in females. There may be a role for phophodiesterase inhibitors
      in the treatment of a subgroup of women with arousal disorders. Normal sexual
      function involves successful integration of biological, psychological, and
      interpersonal influences. Clinical psychiatry with its biopsychosocial model
      should incorporate the treatment of human sexual dysfunction within its purview.

PMID- 12595818
TI  - Moving on.

PMID- 12595819
TI  - Nursing and the Agency for Healthcare Research and Quality (AHRQ): an agenda.

PMID- 12595821
TI  - Issues in Internet research.

PMID- 12595820
TI  - A NINR initiative to address health disparities.

PMID- 12595822
TI  - Magnet hospital staff nurses describe clinical autonomy.
AB  - BACKGROUND: Considerable and longstanding confusion abounds as to what is meant
      by the concept "autonomy." The 2 dimensions of autonomy-rooted in the clinical
      act and the autonomy of the discipline or profession-are used interchangeably and
      measured with the same tools. PURPOSE: The purpose of this research was to
      ascertain staff nurses' concept of autonomy, to empirically quantify nurse
      autonomy, and to determine the relationship between degree of autonomy and staff
      nurses' rankings of quality care on their units and their own job satisfaction.
      METHOD: Two hundred seventy-nine volunteer staff nurses from 14 magnet hospitals
      were interviewed individually with the open-ended question and request, "Can you
      practice autonomously? Give an example of a typical situation that illustrates
      that you practice autonomously," and with two 10-point rating scales on job
      satisfaction and quality of care given on their units. Responses were subjected
      to constant comparative and thematic analyses. On the basis of 3 themes
      frequency, organizational sanction, and scope-a 5-category ranked autonomy scale
      was developed. These magnet hospital staff nurses restrict the concept of
      autonomy to the clinical act. There is a strong relationship between degree of
      autonomy as measured by the ranked scale and rankings of job satisfaction and
      quality of care. An unexpected finding was that 26% of these nurses working in
      magnet hospital reported situations of unsupported or no autonomy. DISCUSSION:
      This research is particularly meaningful for nurse managers and researchers.
      Nurse managers must empower nurses, provide support, provide opportunities for
      nurses to increase competence, and reward and sanction staff nurse autonomy.
      After further refinement, the ranked-category scale will be useful in studying
      the effect of educational efforts and organizational support on the development
      of clinical autonomy.

PMID- 12595823
TI  - An enriched research experience for minority undergraduates--a step toward
      increasing the number of minority nurse researchers.
AB  - This article describes a partnership between a research-intensive university and
      a historical minority-serving institution to create a year-long Research
      Enrichment and Apprenticeship Program for 9 undergraduate minority nursing
      students. The apprenticeship program provides undergraduate students an
      opportunity to directly experience nursing research and has the long-term goal of
      increasing the number of racial and ethnic minority researchers in nursing.

PMID- 12595825
TI  - Barriers to increasing native Hawaiian, Samoan, and Filipino nursing students:
      perceptions of students and their families.
AB  - This article presents the results of an innovative approach to increase the
      numbers of native Hawaiian, Samoan, and Filipino students who enroll in and
      complete the bachelor of nursing in science degree. The approach used 2 methods
      to obtain input. The first was a series of focus groups comprising current and
      potential students in the nursing program. The second method was a survey of
      community elders, parents, and high school students in schools with large
      enrollments of native Hawaiians, Samoans, and Filipinos. The results made clear
      that Asian Pacific Islanders are composed of distinct groups that have many
      diverse concerns that need to be addressed in the recruitment and retention
      phases. One surprise was the low interest in incorporating traditional healing
      into the curriculum. It was clear that high school students should be given
      information on nursing early and effectively because this is a key component of
      their interest in a nursing career.

PMID- 12595826
TI  - The proving grounds: combat nursing in Vietnam.
AB  - PURPOSE: The profession of nursing has been greatly influenced by war, and the
      heroic nature of the work of nursing is often emphasized during war. The purpose
      of this research was to examine the stories of nurses' experiences during combat
      in Vietnam and identify themes that would corroborate, refute, or expand prior
      historical research. ORGANIZING CONSTRUCT AND METHODS: A content analysis to
      determine recurrent themes was performed on 18 oral histories of military nurses
      who served in Vietnam that were previously collected and published. Analysis of
      these collections of oral histories was conducted, and thick quotes contextualize
      and substantiate the thematic claims. FINDINGS AND CONCLUSIONS: This research
      confirms the analysis of prior historical research on nursing in Vietnam by
      finding similar experiences recorded in oral histories and further claims that an
      authentic professional identity is often forged during the hardships and heroic
      opportunities of war.

PMID- 12595827
TI  - The power of storytelling.

PMID- 12595828
TI  - Angiographic changes in vein grafts: stable surrogate or seductive siren?

PMID- 12595829
TI  - Are menstruating women protected from heart disease because of, or in spite of,
      estrogen? Relevance to the iron hypothesis.

PMID- 12595830
TI  - Don't miss this opportunity: Diagnosing diabetes.

PMID- 12595831
TI  - A bridge for the 21st century in heart transplantation?

PMID- 12595832
TI  - Beta-blockers and reverse remodeling: what are the implications?

PMID- 12595833
TI  - Diabetes and percutaneous coronary intervention: the sweet smell of success?

PMID- 12595834
TI  - The finer points of race and hypertension.

PMID- 12595835
TI  - Specialty care for heart failure: does it improve outcomes?

PMID- 12595836
TI  - Percutaneous coronary interventions without on-site cardiac surgery: a stretch
      for much-needed evidence.

PMID- 12595837
TI  - Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus
      mutants tenecteplase and lanoteplase during treatment of acute myocardial
      infarction.
AB  - BACKGROUND: Quantification of fibrinolytic activity (FAct) in clinical practice
      has been abandoned because of the complexity of existing assays. The relationship
      between thrombolytic drug concentration and FAct is complex. FAct profiles of
      currently used thrombolytic drugs were not characterized. METHODS: By use of a
      system that quantifies FAct by shortening of clot lysis onset time (LOT), we
      measured LOT in vitro with incremented concentrations of alteplase (t-PA) and
      tenecteplase (TNK-tPA) and ex vivo in patients with acute myocardial infarction
      who were receiving front-loaded t-PA (n = 31), 30 to 40 mg TNK-tPA (n = 19), and
      120 kU/kg lanoteplase ([n-PA] n = 23). RESULTS: In vitro, FAct depended on drug
      concentration by means of a double exponential model revealing 2 distinct
      activity zones (weak/strong). Ex vivo, no FAct was detected before agent
      administration (LOT > 1200 seconds). Ten minutes after a bolus was given, FAct
      was sharply increased in all patients, but it increased more with TNK-tPA than
      with t-PA or n-PA (mean LOT of 109, 125, and 130 seconds, respectively, P <.05).
      At 90 minutes, accelerated infusion of t-PA resulted in FAct that remained
      stronger than that observed for TNK-tPA (P <.0001) or n-PA (P =.011). At 180
      minutes, significant FAct (LOT <600 seconds) was only observed in patients who
      received n-PA. CONCLUSION: This study provides the first direct comparison of
      FAct between t-PA, TNK-tPA, and n-PA by use of the LOT test, the results of which
      are reliably related to drug concentration. The ideal FAct profile would combine
      an immediate strong FAct of relatively short duration, as seen with TNK-tPA, that
      may contribute to its better efficacy/safety profile in the Assessment of Safety
      and Efficacy of a New Thrombolytic Agent-2 (ASSENT-2) trial. Prolonged FAct after
      n-PA may contribute to increased hemorrhagic complications, as seen in the
      Intravenous n-PA for Treatment of Infarcting Myocardium Early-2 (InTIME-2) trial.
      Thus, characterizing FAct profiles might provide insights in developing more
      efficient thrombolytic regimens.

PMID- 12595838
TI  - Double-blind, placebo-controlled, randomized trial of prophylactic metoprolol for
      reduction of hospital length of stay after heart surgery: the beta-Blocker Length
      Of Stay (BLOS) study.
AB  - BACKGROUND: Atrial fibrillation (AF) is a common complication of heart surgery.
      Previous studies have shown that there is an association between postoperative AF
      and prolongation of hospital length of stay. No previous trials have been
      primarily directed at demonstrating that the use of drugs that prevent AF would
      shorten length of stay and reduce the costs of postoperative care. METHODS: A
      randomized, double-blind, placebo-controlled trial of metoprolol was performed in
      patients immediately after nonemergent heart surgery. Metoprolol was given orally
      at a dose of 100 mg per day after the patient's arrival in the intensive care
      unit until hospital discharge or 14 days, whichever was sooner. This dose was
      increased to 150 mg per day after the enrollment of 411 patients. The primary
      outcome measure of the study was hospital length of stay from admission to
      intensive care unit until hospital discharge. There were 1000 patients enrolled,
      evenly distributed to the metoprolol and placebo groups. RESULTS: There was a 20%
      reduction in the risk of AF developing with metoprolol, from 39% of patients to
      31% of patients (P =.01). There was no effect of treatment on hospital length of
      stay, which was 152 +/- 61 hours for placebo and 155 +/- 90 hours for metoprolol
      (P = 0.79). The cost of postoperative care in the 2 treatment groups was similar.
      CONCLUSION: Prophylactic metoprolol reduces the risk of AF after heart surgery.
      It does not reduce hospital length of stay. Although it is cost effective for the
      reduction of AF, it did not reduce the overall cost of care.

PMID- 12595839
TI  - Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs.
AB  - BACKGROUND: Outpatient direct current (DC) cardioversion is performed routinely,
      yet scant data support this approach. We studied the efficacy, safety, and costs
      of outpatient cardioversion. METHODS: A retrospective analysis of outpatient
      cardioversions was performed in a 5-year period at an academic medical center in
      532 consecutive outpatients with an atrial tachyarrhythmia. The protocol included
      anticoagulation (international normalized ratio >or=2.0) for >or=4 consecutive
      weekly draws and then DC cardioversion with the patient under intravenous
      anesthesia. Arrhythmia symptoms, antiarrhythmic therapy use, and costs were
      evaluated. RESULTS: Ninety percent of patients were discharged in sinus rhythm
      after cardioversion with a median number of shocks of 1 (range, 1-6) for atrial
      flutter (n = 113), atrial tachycardia (n = 13), and atrial fibrillation (n =
      406). Sixty-seven percent of patients were treated with an antiarrhythmic drug.
      The complication rate was 2.6%, with 11 unplanned admissions. Thromboemboli
      occurred only in patients whose anticoagulation deviated from protocol and
      included chronic hemianopsia starting 4 days after cardioversion, transient right
      sided weakness, and cerebral vascular accident 3 days after cardioversion,
      despite negative results on a transesophageal echocardiogram. Two patients had
      postcardioversion pulmonary edema. Bradycardia developed in 4 patients; transient
      pacemaker noncapture after the shock occurred in 4 patients. Transient postshock
      rhythms also included AV nodal Wenckebach and junctional rhythm. One patient had
      aspiration pneumonia. The mean cost of cardioversion was 464 dollars. Fees for
      anesthesia ranged from 525 dollars to 650 dollars. The anesthetic costs ranged
      from 2.84 dollars to 21.47 dollars. The cardiology fee averaged 501 dollars.
      CONCLUSION: Outpatient cardioversion is a low risk, effective, and economical
      procedure.

PMID- 12595841
TI  - Increased C-reactive protein level after coronary stent implantation in patients
      with stable coronary artery disease.
AB  - BACKGROUND: Elevation of C-reactive protein (CRP), among other markers of
      inflammation, is associated with an increased risk for cardiac events in patients
      with known coronary diseases and in apparently healthy individuals. Moreover, in
      patients with acute coronary syndromes, elevated serum levels of CRP are strongly
      predictive of the risk for death from cardiac causes. The purpose of this study
      was to investigate whether mechanical rupture of an atherosclerotic coronary
      plaque during elective stent implantation in patients with stable coronary artery
      disease (CAD) at low risk will cause a significant increase in serum levels of
      CRP. METHODS AND RESULTS: We measured serum CRP levels in 40 patients. Group 1
      consisted of 12 consecutive patients with stable coronary disease who were at low
      risk, before and after elective coronary stent implantation. We compared the
      results in these patients to those of patients in 2 control groups: group 2
      consisted of 12 consecutive patients with non-ST-segment elevation acute coronary
      syndrome (NSTSE ACS) who were undergoing coronary stent implantation, and group 3
      included 16 consecutive patients with stable or unstable CAD who were undergoing
      diagnostic coronary angiography only without PCI. Peripheral blood samples for
      CRP level testing were withdrawn before percutaneous coronary intervention or
      angiography at the completion of the procedure, and 6, 20, and 48 hours
      thereafter. All patients with stable CAD (group 1) had a significant and uniform
      increase in serum CRP levels after elective stent implantation. The low mean
      baseline serum CRP levels increased 4.9 +/- 4.1-fold 20 hours after coronary
      intervention (2.1 +/- 1.2 before, 7.9 +/- 3.4 after, P <.002). The baseline CRP
      level was much higher in the patients with unstable coronary syndromes (group 2).
      In this group, only a 2.1-fold increase in mean CRP level was observed after
      stent implantation (7.4 +/- 5.5 before, 14.1 +/- 9.6 after, P <.004). Also, the
      response in this group was less uniform when compared with that in the stable CAD
      group. By contrast, in patients undergoing diagnostic coronary angiography, the
      mean baseline CRP level was higher than in the patients in the group with stable
      CAD; however, the mean CRP after the procedure was not significantly elevated in
      this group (4.5 +/- 3.6 before, 5.5 +/- 3.7 20 hours after, P = not significant).
      CONCLUSIONS: Mechanical disruption of an atherosclerotic coronary plaque during
      elective coronary stent implantation in patients with stable CAD who are at low
      risk causes a systemic inflammatory response expressed by marked elevation in CRP
      concentration.

PMID- 12595840
TI  - Onset and extent of platelet inhibition by clopidogrel loading in patients
      undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus
      Occurrence (PRONTO) trial.
AB  - BACKGROUND: Despite the common practice of clopidogrel loading for coronary
      stenting, the time dependence and degree of platelet inhibition after this
      therapy are not well defined. We sought to establish an optimal clopidogrel
      dosing regimen for sustained platelet inhibition in stented patients. METHODS AND
      RESULTS: Platelets were assessed by conventional aggregation with 5 micromol/L
      adenosine diphosphate (ADP), 1 microg/mL collagen (COLL), and 750 micromol/L
      arachidonic acid; whole blood aggregation by 1 microg/mL collagen (WBA); shear
      induced closure time (CT); contractile force (CF); and expression of 9 surface
      receptors by flow cytometry in 100 patients undergoing elective stent placement
      without glycoprotein (GP) IIb/IIIa receptor antagonists. Blood was obtained at
      baseline and serially over 5 days poststenting after different clopidogrel
      loading regimens: 300 mg 24 hours before (Group A), 12 hours before (Group B), 3
      to 6 hours before (Group C), and 75 mg at the time of intervention (Group D).
      Before stenting, ADP, COLL, CT, and WBA were reduced by clopidogrel loading (P
      <.05). CF was not affected by clopidogrel. Before stenting, GP IIb/IIIa
      expression increased in groups A through C (P <.05), whereas PECAM-1 and CD107a
      were reduced (P <.05). At 2 hours and 2 days poststenting, platelets, in general,
      exhibited an increase in activity that was most inhibited by clopidogrel loading.
      Clopidogrel inhibited GP Ib, platelet/endothelial cell adhesion molecule-1, CD
      107a, CD 151, and GP IIb/IIIa expression at day 5 poststenting. CONCLUSION: A 300
      mg clopidogrel load given 3 to 24 hours before stenting inhibits platelets at the
      time of the procedure and reduces poststent activity more than a 75 mg dose given
      at the time of the procedure. The inhibition of adhesive molecule expression may
      also contribute an antithrombotic effect. Poststent activation of platelets may
      warrant higher periprocedural dosing.

PMID- 12595842
TI  - Predictors and implications of residual plaque burden after coronary stenting: an
      intravascular ultrasound study.
AB  - BACKGROUND: Residual plaque burden after coronary stenting may be visualized by
      use of intravascular ultrasound. Determinants and implications of residual
      atherosclerotic plaque burden after coronary stenting are not well established.
      In particular, the implications of residual plaque burden, after adjusting for
      confounding factors, are still unknown. METHODS: Sixty-two consecutive patients
      (age 56 +/- 9 years) undergoing coronary stenting under intravascular ultrasound
      imaging guidance were prospectively studied. A total of 616 slices were analyzed
      (every 2 mm of stent length) from motorized pull-back recordings. Residual plaque
      burden was calculated as residual plaque/vessel area x 100. RESULTS: In 565
      slices (89%), both residual plaque area and stent area could be measured. Mean
      residual plaque burden was 46.5% +/- 6%. By use of multiple regression analysis,
      lesion plaque area and reference segment plaque burden were identified as
      independent predictors of residual plaque burden after stenting. In addition, a
      significant correlation was found between residual plaque burden and most
      relevant angiographic parameters at follow-up (including minimal lumen diameter,
      percent diameter stenosis, and loss index), which persisted after adjustment.
      Furthermore, stents with a residual plaque burden >or=46% had higher a restenosis
      rate (relative risk [RR] 4.4, 95% CI 1.09-18.2, P =.03). On logistic regression
      analysis, residual plaque burden (RR 4.8, 95% CI 4.1-5.6, P =.01) and diabetes
      (RR 4.3, 95% CI 3.6-5.1, P =.03) emerged as the only independent predictors of
      restenosis. CONCLUSIONS: The amount of residual plaque burden after coronary
      stenting plays an independent role on the late angiographic outcome of these
      patients.

PMID- 12595843
TI  - Angiographic changes in saphenous vein grafts are predictors of clinical
      outcomes.
AB  - BACKGROUND: Previous studies have suggested that angiographic evidence of disease
      progression in coronary arteries increases the risk of subsequent coronary
      clinical events. This study ascertained whether patients enrolled in the Post
      Coronary Artery Bypass Graft Clinical Trial (POST CABG) who had substantial
      progression of atherosclerosis in >or=1 saphenous vein grafts (on the basis of
      assessment of baseline and follow-up angiograms obtained 4-5 years after study
      entry), but who had not reported clinical symptoms before follow-up angiography,
      were at a higher risk of subsequent events than patients who did not have
      substantial progression of atherosclerosis (decrease >or=0.6 mm in lumen diameter
      at site of greatest change from baseline). METHODS: All 1351 patients enrolled in
      the trial underwent baseline angiography; only the 961 patients who had follow-up
      angiography and no coronary events before the follow-up study were included in
      this analysis. The clinical center staff contacted patients to ascertain the
      events that had occurred after follow-up angiography (approximately 3.4 years
      later). RESULTS: Sixty-nine patients had died; 870 patients or relatives were
      interviewed, and 22 patients could not be contacted. Univariable estimates of
      relative risk associated with substantial progression ranged from 2.2 (P <.001)
      for cardiovascular death or nonfatal myocardial infarction to 3.3 (P <.001) for
      revascularization. Multivariable and univariable estimates of risk were similar.
      CONCLUSIONS: The findings provide evidence that patients who had substantial
      progression of atherosclerosis in vein grafts are at an increased risk for
      subsequent coronary events and suggest that angiographic changes in vein grafts
      are appropriate surrogate measures for clinical outcomes.

PMID- 12595844
TI  - Diabetes mellitus is associated with a shift in the temporal risk profile of
      inhospital death after percutaneous coronary intervention: an analysis of 25,223
      patients over 20 years.
AB  - BACKGROUND: Numerous studies have demonstrated that patients with diabetes have
      higher rates of restenosis, late myocardial infarction, and late death after
      percutaneous coronary interventions (PCI). However, it remains unclear whether
      patients with diabetes mellitus also have an increased hazard for early death
      after either elective or urgent PCI. METHODS: Patients undergoing PCI at the Mid
      American Heart Institute between 1980 and 1999 were identified. The main end
      point was inhospital death. Patients were stratified both by diabetes status and
      whether they underwent elective or urgent PCI. RESULTS: There were 17,341
      nondiabetic patients and 4308 patients with diabetes who underwent elective PCI.
      There were 2946 nondiabetic patients and 628 patients with diabetes who underwent
      urgent PCI. Multivariate analysis demonstrated that diabetes was associated with
      increased inhospital mortality rate after any PCI (odds ratio 1.4, 95% CI 1.1
      1.8, P =.003). The unadjusted inhospital mortality rates for the nondiabetic
      patients and patients with diabetes were 0.8% and 1.4%, respectively (P <.001),
      after elective PCI. The mortality rate was 6.9% for the nondiabetic patients and
      12.7% for the patients with diabetes (P <.001) after urgent PCI. The inhospital
      mortality rates among diabetic patients appear to be decreasing over time among
      the elective cohort (elective PCI diabetes-time interaction, P =.007) but not in
      the urgent cohort (urgent PCI-diabetes-time interaction, P =.68). CONCLUSIONS:
      There has been an improvement in the inhospital survival rate among patients with
      diabetes in the elective PCI cohort. This improved hospital survival has yet to
      be realized among patients with diabetes undergoing urgent PCI.

PMID- 12595845
TI  - Low-risk percutaneous coronary interventions without on-site cardiac surgery: two
      years' observational experience and follow-up.
AB  - BACKGROUND: We studied the safety and efficacy of performing low-risk elective
      and acute infarct percutaneous coronary interventions at a community hospital
      without cardiac surgical capability. METHODS: Immanuel St Joseph's Hospital is
      located 85 miles from St Mary's Hospital, which is the nearest center with on
      site cardiac surgery. All components of the Mayo Clinic percutaneous coronary
      intervention program were replicated at Immanuel St Joseph's Hospital, including
      a telemedicine system to enable real-time consultation with interventional and
      cardiac surgical colleagues during procedures. RESULTS: From March 1999 to June
      2001, 196 patients underwent elective percutaneous coronary intervention at
      Immanuel St Joseph's Hospital. Procedural success was achieved in 195 (99.5%)
      patients, with 1 (0.5%) inhospital death. At mean follow-up of 8.2 months, 2
      (1.0%) additional patients died of noncardiac causes and 15 (7.7%) patients
      required target vessel revascularization. From March 2000 to June 2001, 89
      patients underwent primary percutaneous coronary intervention for acute
      myocardial infarction. Procedural success was achieved in 83 (93.3%) patients,
      with 3 (3.4%) inhospital deaths. At 30-day follow up, no additional patients
      died, had recurrent myocardial infarction, or required target vessel
      revascularization. No patients required transfer to another facility for emergent
      cardiac surgery for a procedure-related complication. CONCLUSIONS: Low-risk
      elective and acute infarct percutaneous coronary interventions can be performed
      with safety and efficacy at a community hospital without cardiac surgical
      capability by following rigorous standards.

PMID- 12595846
TI  - Prevalence, predictors, and consequences of unrecognized diabetes mellitus in
      3266 patients scheduled for coronary angiography.
AB  - BACKGROUND: Previous population-based studies have reported a proportion of
      undiagnosed diabetes in the range between 25% and 50%. However, data on
      undiagnosed diabetes in a high-risk population, such as patients scheduled for
      coronary angiography, are lacking. Therefore, we sought to determine prevalence,
      predictors, and consequences of unrecognized diabetes in patients scheduled for
      coronary angiography. METHODS: This analysis involved 3266 patients scheduled for
      coronary angiography who have been enrolled in the Ludwigshafen Risk and
      Cardiovascular Health study. RESULTS: Five hundred fifty-six patients (17.0%) had
      known diabetes. Another 486 patients with previously unrecognized diabetes
      (17.9%) were diagnosed in the remaining 2710 presumed nondiabetic subjects.
      Therefore, 486 (46.6%) of a total of 1042 patients with diabetes were previously
      undiagnosed, raising the diabetic proportion of enrolled patients to 31.9%. In
      half of the newly diagnosed patients with diabetes, the disease was detectable
      only by use of glucose challenge. Independent predictors of unrecognized type 2
      diabetes were C-reactive protein >5 mg/L, arterial hypertension, body mass index
      >30 kg/m(2), age >or=65 years, and a positive family history of diabetes.
      Compared with nondiabetic subjects, patients with unrecognized type 2 diabetes
      showed a significantly increased risk for coronary artery disease (odds ration
      [OR] 1.7, 95% CI 1.3-2.3) and multivessel disease (OR 1.4, 95% CI 1.1-1.8), and a
      borderline association with myocardial infarction (OR 1.2, 95% CI 1.0-1.5). Oral
      glucose challenge was not superior to fasting glucose in predicting this
      increased cardiovascular risk. CONCLUSION: In half of the patients scheduled for
      coronary angiography, diabetes was previously unrecognized. In a high-risk
      population of patients scheduled for coronary angiography, screening for diabetes
      should be performed routinely to initiate timely preventive efforts.

PMID- 12595847
TI  - Marked improvement in left ventricular ejection fraction during long-term beta
      blockade in patients with chronic heart failure: clinical correlates and
      prognostic significance.
AB  - BACKGROUND: Some patients with heart failure (HF) may have a marked improvement
      in left ventricular ejection fraction (LVEF) after long-term beta-blockade. We
      compared the clinical characteristics and the prognosis of these patients with
      those of other patients. METHODS: One hundred seventy-one patients with chronic
      HF were assessed before and after 9 to 12 months of maintenance therapy with
      metoprolol or carvedilol. RESULTS: Thirty-eight patients (22%) showed an increase
      in their LVEF >or=15 units (from 20% +/- 8% to 43% +/- 10%). Compared with the
      other patients (LVEF change from 21% +/- 7% to 26% +/- 9%, P <.0001 for
      differences between groups), these patients also had a greater decline in the
      left ventricular end-diastolic volume (from 175 +/- 74 mL/m(2) to 113 +/- 36
      mL/m(2)) and in the right atrial, mean pulmonary artery, and pulmonary wedge
      pressures, with a greater increase in the cardiac index, stroke volume index,
      stroke work index, and maximal functional capacity. Their long-term prognosis was
      excellent, with a 2-year cumulative survival rate of 95%, versus 81% for the
      other patients, and a hospitalization-free survival rate of 73%, versus 50% for
      the other patients (all P <.05). By means of multivariate analysis, only the
      nonischemic cause of HF and the mean arterial pressure at baseline were
      independently associated with an increase of >or=0.15 in LVEF. CONCLUSIONS:
      Patients who show a marked improvement in their LVEF after long-term beta
      blockade have an excellent prognosis and have a high prevalence of nonischemic HF
      and a higher blood pressure at baseline.

PMID- 12595848
TI  - Is specialty care associated with improved survival of patients with congestive
      heart failure?
AB  - BACKGROUND: Implementation of the complex treatment strategies that have been
      shown to improve survival of patients with congestive heart failure (CHF) may
      require certain expertise. We wanted to examine the association between pattern
      of outpatient care and survival of patients with CHF. METHODS: In a retrospective
      cohort study conducted with national Veterans Health Administration (VHA)
      databases, we examined the association between the pattern of outpatient care and
      survival in 11,661 patients discharged from VA hospitals between October 1, 1991,
      and September 30, 1992, with the primary diagnosis of CHF (cohort 1). Patients
      were divided into 4 groups, on the basis of their pattern of outpatient care over
      a 12-month period after discharge: 1) general medicine clinic visits only (GM
      only); 2) cardiology clinic visits only (CARD-only); 3) general medicine and
      cardiology (MIXED) clinic visits; and 4) neither general medicine nor cardiology
      clinic visits (no-GM/CARD). We used the Cox proportional hazards model to
      evaluate 1-year survival, controlling for clinical and demographic factors.
      Consistency of our results was examined by performing identical analysis on a
      cohort of patients discharged from VHA hospitals between October 1, 1994, and
      September 30, 1995 (cohort 2, n = 10,141). RESULTS: The overall 1-year mortality
      rate was 23% in the primary cohort. The unadjusted mortality rate was highest for
      patients in the no-GM/CARD follow up (29%) and lowest for patients in the MIXED
      group (19%). By use of the MIXED group as reference and adjusting for important
      clinical and demographic factors, the risk of death (risk ratio [95% CI]) was
      1.12 (0.94-1.34) in the CARD-only group, 1.26 (1.15-1.38) in the GM-only group,
      and 1.48 (1.28-1.72) in the no-GM/CARD group. Cohort-2 results were consistent
      with cohort 1 for most covariates, and significant survival differences were
      again found between GM-only and the MIXED group (1.25 [1.14-1.37]). CONCLUSIONS:
      We found an improved survival associated with cardiologist care and a mixture of
      general practitioner and cardiologist care compared with general practitioner
      care. The pattern of outpatient care may therefore be important for the survival
      of patients with CHF.

PMID- 12595849
TI  - Response of the right ventricle to acute pulmonary vasodilation predicts the
      outcome in patients with advanced heart failure and pulmonary hypertension.
AB  - OBJECTIVES: This study was designed to assess whether testing of potential
      reversibility of pulmonary hypertension (PHT) may be a useful means of defining
      the short-term prognosis of patients with advanced heart failure and elevated
      pulmonary artery pressure. In such patients, the reversibility of PHT after acute
      vasodilator administration is associated with a low early mortality rate after
      heart transplantation. However, its short-term prognostic value has not yet been
      determined. METHODS AND RESULTS: Between 1994 and 1998, 76 patients with advanced
      heart failure and PHT underwent right heart cathetherization. The hemodynamic
      measurements, including thermodilution-derived right ventricular ejection
      fraction, were repeated after an intravenous bolus of nitroglycerin (NTG). During
      a median follow-up period of 8.2 months (25% and 75% centiles, 3.3 and 18.9
      months), 47 patients had a cardiac event (death or urgent heart transplantation).
      With Cox survival analysis, a multivariate model that included the New York Heart
      Association class and the hemodynamic variables obtained after NTG administration
      allowed a better assessement of the short-term prognosis of the patients than a
      model including the baseline variables. The evaluation of right ventricular
      function during the acute NTG-induced pulmonary vasodilation was of critical
      importance in obtaining such a refinement in the prognostic stratification.
      CONCLUSIONS: The prognostic evaluation of patients with advanced heart failure
      and PHT should include the assessment of the changes of right ventricular
      ejection fraction after acute afterload reduction.

PMID- 12595850
TI  - New phenotype of familial dilated cardiomyopathy and conduction disorders.
AB  - BACKGROUND: Familial dilated cardiomyopathy (FDCM) is attributed to defects in
      cytoskeletal proteins, and different patterns of inheritance and phenotypic
      expressions according to assorted-protein modifications have been identified to
      date. We describe a clinical family study with 24 individuals in 3 generations
      affected by dilated cardiomyopathy (DCM) and cardiac conduction abnormalities.
      METHODS AND RESULTS: After a follow-up period of 25 +/- 14 months, DCM developed
      in 7 male adults, 6 with associated arterioventricular block (AVB); and 10 female
      and 7 male adults had several degrees of isolated AVB. This particular clinical
      expression, with a strong predominance of dilation of the heart developing in the
      male population and the vertical distribution of patients affected with AVB, is
      consistent with autosomal dominant inheritance involving both cardiac
      abnormalities. CONCLUSIONS: The presence of isolated AVB or that associated with
      DCM in a large number of individuals in the same family, in which members of the
      male sex seems to be predominantly affected by cardiac dilatation, differs from
      other FDCMs that have been described previously. This FDCM has an autosomal
      dominant pattern of inheritance with variable phenotypic expressivity, in which
      AVB may constitute in itself the only manifestation of this entity. To date, we
      have been unable to identify the mechanism of inheritance, and we advance some
      theoretical considerations about possible mechanisms.

PMID- 12595851
TI  - Comparison of dobutamine versus milrinone therapy in hospitalized patients
      awaiting cardiac transplantation: a prospective, randomized trial.
AB  - BACKGROUND: The use of dobutamine or milrinone for inotropic support in patients
      with heart failure awaiting cardiac transplantation is largely arbitrary and
      based on institutional preference. The costs and effectiveness of these drugs
      have yet to be compared in a prospective, randomized study. METHODS: We compared
      clinical outcomes and costs associated with the use of dobutamine or milrinone in
      36 hospitalized patients awaiting cardiac transplantation. Patients were randomly
      assigned to receive either dobutamine or milrinone at the time of initial
      hospitalization and were followed until death, transplantation, or placement of
      mechanical cardiac support (intra-aortic balloon pump or left ventricular assist
      device). RESULTS: Seventeen patients were randomly assigned to receive dobutamine
      (mean dose 4.1 +/- 1.4 microg/kg/min) and 19 patients received milrinone (mean
      dose 0.39 +/- 1.0 microg/kg/min). Therapy lasted 50 +/- 46 days for those in the
      dobutamine group and 63 +/- 45 days in the milrinone group. We did not detect
      differences between the 2 groups in right heart hemodynamics, death, need for
      additional vasodilator/inotropic therapy, or need for mechanical cardiac support
      before transplantation. Ventricular arrhythmias requiring increased
      antiarrhythmic therapy occurred frequently in both groups. Total acquisition cost
      of milrinone was significantly higher than that of dobutamine (16,270 dollars +/-
      1334 vs 380 dollars +/- 533 P <.00001). CONCLUSIONS: Both dobutamine and
      milrinone can be used successfully as pharmacologic therapy for a bridge to heart
      transplantation. Despite similar clinical outcomes, treatment with milrinone
      incurs greater cost.

PMID- 12595852
TI  - Intravenous prostaglandin E1 reduces monocyte chemoattractant protein-1 levels in
      peripheral arterial obstructive disease.
AB  - OBJECTIVES: Blood monocytes are the precursors of the lipid-laden foam cells that
      are the hallmark of early atherosclerotic lesions, and monocyte chemoattractant
      protein-1 (MCP-1) plays important roles in their recruitment to the vessel wall.
      In this study, we measured serum levels of MCP-1 in patients with peripheral
      arterial obstructive disease (PAOD) and investigated whether intravenous
      prostaglandin E1 (PGE1) treatment, which produces clinical benefits in PAOD,
      might decrease such levels. METHODS: Eight patients with PAOD at Fontaine stage
      II to IV were treated with a daily intravenous infusion of 10 microg of PGE1 for
      7 consecutive days. Blood samples before and after 7-day PGE1 treatment were used
      for assays of MCP-1, interleukin-6 (IL-6), high-sensitivity C-reactive protein
      (hs-CRP), von Willebrand factor (vWF), and endothelin-1 (ET-1). RESULTS: Serum
      MCP-1 levels in patients with PAOD were significantly higher than those in
      healthy control subjects (263.8 +/- 52.8 vs 136.5 +/- 15.0 pg/mL, P =.002). PGE1
      administration for 7 days resulted in a significant decrease in the MCP-1 level,
      from 263.8 +/- 52.8 to 196.1 +/- 25.5 pg/mL (P =.02), whereas levels of IL-6, hs
      CRP, and ET-1 and the activity of vWF were not affected. CONCLUSIONS: Serum MCP-1
      levels were elevated in patients with PAOD, indicating the involvement of
      activation of monocytes in the pathogenesis of this disorder. Parenteral
      administration of PGE1 appeared to decrease circulating MCP-1 levels, which might
      lead to the suppression of the development of atherosclerotic lesions in patients
      with PAOD.

PMID- 12595853
TI  - Clinical and economic outcomes of multivessel coronary stenting compared with
      bypass surgery: a single-center US experience.
AB  - BACKGROUND: Randomized trials comparing multivessel stenting with coronary artery
      bypass surgery (CABG) have demonstrated similar rates of death and myocardial
      infarction but higher rates of repeat revascularization after stenting. The
      impact of these alternative strategies on overall medical care costs is
      uncertain, particularly within the US health care system. METHODS: We performed a
      retrospective, matched cohort study to compare the clinical and economic outcomes
      of multivessel stenting and bypass surgery. The stent group consisted of 100
      consecutive patients who underwent stenting of >or=2 major native coronary
      arteries at our institution. The CABG group consisted of 200 patients who
      underwent nonemergent isolated bypass surgery during the same time frame, matched
      (2:1) for age, sex, ejection fraction, diabetes mellitus, and extent of coronary
      disease. Detailed clinical follow-up and resource utilization data were collected
      for a minimum of 2 years. Total costs were calculated by use of year 2000 unit
      prices. RESULTS: Over a median follow up period of 2.8 years, there were no
      significant differences in all-cause mortality rates (3.0% vs 3.0%), Q-wave
      myocardial infarction (5.1% vs 4.0%), or the composite of death or myocardial
      infarction (7.1% vs 7.0%) between the stent and CABG groups (P = not significant
      for all comparisons). However, at 2-year follow up, patients with stents were
      more likely to require >or=1 repeat revascularization procedure (32.0% vs 4.5%, P
      <.001). The initial cost of multivessel stenting was 43% less than the cost of
      CABG (11,810 dollars vs 20,574 dollars, P <.001) and remained 27% less (17,634
      dollars vs 24,288 dollars, P =.005) at 2 years. CONCLUSIONS: Multivessel stenting
      and CABG result in comparable risks of death and myocardial infarction. Despite a
      higher rate of repeat revascularization, multivessel stenting was significantly
      less costly than CABG through the first 2 years of follow-up.

PMID- 12595854
TI  - Antiplatelet effects of angiotensin-converting enzyme inhibitors compared with
      aspirin and clopidogrel: a pilot study with whole-blood aggregometry.
AB  - BACKGROUND: Although specific antiplatelet drugs are well-established and
      effective in atherosclerosis prevention, recent clinical trials have also shown
      that use of angiotensin-converting enzyme (ACE) inhibitors results in a decrease
      in cardiovascular events. Therefore, in this study, we sought to assess the
      coagulative activity of patients with cardiovascular disease grouped for
      treatment with either ACE inhibitors, aspirin, clopidogrel/aspirin, or none of
      these medications. METHODS: Blood samples from 303 patients with cardiovascular
      disease were analyzed with whole-blood aggregometry. Platelet aggregation was
      determined by the increase in impedance across paired electrodes in response to
      the aggregatory agents adenosine diphosphate (ADP) or collagen. RESULTS: As the
      central finding, platelet aggregation was attenuated by ACE inhibitors and by
      aspirin or clopidogrel/aspirin, which was indicated by a lower impedance increase
      compared with no medication. With ACE inhibition, platelet aggregation decreased
      by 33% (P =.042) after ADP induction. No significant antithrombotic effect was
      seen with aspirin alone (17%, P = 1.0), whereas a decrease in ADP-induced
      platelet aggregation was extensive with clopidogrel/aspirin (85%, P =.001). After
      collagen induction, platelet aggregation was reduced by 16% (P =.028) in the
      presence of ACE inhibitor therapy, whereas inhibition with aspirin and
      clopidogrel/aspirin was 23% (P =.004) and 35% (P =.026), respectively, compared
      with participants who were not treated. CONCLUSIONS: These ex vivo data on whole
      blood aggregometry provide direct evidence that ACE inhibitors decrease platelet
      aggregation, whereas aspirin and clopidogrel are confirmed as established
      antithrombotics. Pleiotropic effects of ACE inhibition on platelet function may
      contribute to the clinical benefit observed with this drug class on major
      cardiovascular end points.

PMID- 12595855
TI  - Development and validation of a simple model to predict severe coronary artery
      disease after myocardial infarction: potential impact on cardiac catheterization
      use in the United States and Canada.
AB  - BACKGROUND: Improved patient selection may optimize the efficiency of cardiac
      catheterization in both high- and low-rate regions. The purpose of this study was
      to develop and validate a clinical model for predicting high-risk coronary artery
      disease (CAD) after myocardial infarction (MI) and to examine the model's
      potential impact on the use rate of both US and Canadian catheterization
      practices. METHODS AND RESULTS: By the use of baseline clinical variables from
      1122 patients in the angiographic substudy of the Global Use of Strategies to
      Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-1) trial, we developed
      a model that was predictive of severe CAD (left main or triple-vessel disease).
      The final model, which included prior MI, age, sex, hyperlipidemia, and decreased
      left ventricular ejection fraction (C-index = 0.70), was externally validated in
      781 patients in the GUSTO IIb trial. Although the probability of severe CAD
      predicted 5-year survival, the frequency of catheterization in both Canada and
      the United States bore no relationship to severe CAD risk in the GUSTO-1 trial.
      By use of the model, we estimated that as much as 15% of US catheterizations from
      both GUSTO-1 and GUSTO IIb might have been avoided, without significantly
      compromising the number of patients with severe CAD who were identified
      (sensitivity = 0.94). By applying the model to Canadian practices, an additional
      30 cases of severe CAD might have been identified per every 1000 catheterizations
      performed, without increasing the catheterization rate. CONCLUSIONS: The
      likelihood of severe CAD after ST-elevation MI may be predicted from simple
      baseline clinical variables. The use of a severe CAD predictive model to guide
      patient selection might enhance the cost-effectiveness of both aggressive and
      conservative catheterization practices.

PMID- 12595856
TI  - Comparison of the predischarge exercise thallium-201 perfusion defect after
      myocardial infarction with myocardium at risk measured during acute infarction
      with technetium-99m sestamibi imaging.
AB  - BACKGROUND: Exercise thallium-201 imaging provides a noninvasive estimate of the
      amount of myocardium presumed to be at risk of infarcting should a complete
      occlusion of the coronary stenosis occur. The relationship between the size of
      the exercise thallium perfusion defect and the extent of myocardium supplied by a
      diseased coronary artery has not been established. This study evaluates that
      presumed correlation. METHODS: Patients were injected intravenously with
      technetium-99m sestamibi during acute myocardial infarction before thrombolysis
      or conventional therapy to quantify the myocardium at risk. Twenty-six patients
      who underwent risk-area assessment subsequently underwent clinically driven,
      predischarge, submaximal exercise imaging with thallium-201. The exercise testing
      was performed on day 7 +/- 2 days. A conventional polar map display was used to
      quantify the perfusion defect. RESULTS: The myocardium at risk determined by
      technetium-99m sestamibi at the time of infarction was 30% +/- 20% of the left
      ventricle. The mean exercise thallium-201 defect was 34% +/- 22% of the left
      ventricle. The exercise defect tended to be slightly larger than the myocardium
      at risk (4% +/- 10% of the left ventricle, P =.05). There was a close correlation
      between the 2 measurements (r = 0.89, SE = 9.4, P <.0001). CONCLUSIONS: This
      study shows a close correlation between the myocardium "at risk" assessed acutely
      by technetium-99m sestamibi and the "presumed at-risk area" determined by
      thallium-201 imaging on predischarge exercise testing. This finding supports the
      concept that the size of the exercise thallium defect caused by coronary stenosis
      indicates the likely size of a myocardial infarction resulting from occlusion of
      that stenosis.

PMID- 12595857
TI  - Postexercise hypotension differs between white and black women.
AB  - BACKGROUND: Because data are lacking, we examined the acute effect of exercise on
      ambulatory blood pressure (BP) in premenopausal white women (n = 18) and black
      women (n = 15) with normal (n = 21) and high (n = 12) BP. METHODS: Women
      performed 40 minutes of control and moderate-intensity exercise. BP and hormones
      were measured before, during, and after the control and exercise periods. By
      means of RMANCOVA (repeated measures analysis of covarience), we tested whether
      BP and hormones differed with time and between ethnic, BP, and experimental
      groups. Multiple regression analysis was used to examine hormonal mediators of
      the postexercise BP response. RESULTS: Among white women with hypertension,
      average daytime systolic (S) and diastolic (D) BP decreased 11.0 +/- 3.3 mm Hg (
      2.9, -19.1; P =.017) and 8.2 +/- 2.8 mm Hg (-1.2, -13.9; P =.000), from 142.6 +/-
      5.8 mm Hg and 96.1 +/- 2.8 mm Hg, respectively, after exercise. Among black women
      with high BP, mean daytime SBP rose 12.5 +/- 5.2 mm Hg (-2.0, 27.1; P =.000)
      after exercise, from 121.8 +/- 6.1 mm Hg, whereas DBP was similar before and
      after exercise (81.4 +/- 4.3 mm Hg and 82.8 +/- 4.7 mm Hg, respectively). In
      white women without hypertension, daytime SBP and DBP were similar before and
      after exercise. In black women without hypertension, mean daytime SBP increased
      6.3 +/- 2.6 mm Hg (0.4, 12.1; P =.000) after exercise from 103.6 +/- 1.4 mm Hg,
      and DBP did not change. In black women, hypertension (P = 0.000) and exercise
      mediated insulin decreases (P =.005) explained 85.6% of the postexercise SBP
      response (P =.000). In white women, hypertension (P =.003) and baseline plasma
      renin (P =.049) accounted for 53.3% of the postexercise SBP response (P =.001).
      Exercise acutely reduced daytime BP in white women, but not in black women with
      high BP. CONCLUSION: Endurance exercise may adversely affect the BP of black
      women.

PMID- 12595858
TI  - Outcome of significant functional tricuspid regurgitation after percutaneous
      mitral valvuloplasty.
AB  - BACKGROUND: The outcome of significant functional tricuspid regurgitation (TR)
      associated with mitral stenosis (MS) after percutaneous mitral valvuloplasty
      (PMV) remains to be clarified. METHODS: From 265 patients who underwent PMV at
      our institution from 1995 to 2000 and who were regularly observed, we selected 71
      patients (55 women, mean age 43 +/- 11 years) who showed significant moderate to
      severe functional TR before PMV. We analyzed data from the echocardiograms
      performed before, 24 hours after, and long after the intervention (29 +/- 12
      months) and analyzed clinical outcomes. Resolution of TR was defined as trace or
      mild TR on the follow-up color Doppler study. RESULTS: Patients with moderate to
      severe TR showed more severe MS and pulmonary hypertension and more atrial
      fibrillation than patients with less than moderate TR. TR was resolved on the
      follow-up echocardiography in 23 of the 71 patients with significant TR before
      PMV (32%). The TR jet area before PMV (P <.05) and the late decrement of peak
      transmitral pressure gradient (P <.01) were independent determinants of
      resolution. TR was resolved in only 6.7% of patients (1/15) with an unsuccessful
      long-term PMV result, but was resolved in 39% of patients (22/56) with a
      successful long-term result (P <.05). During the clinical follow-up period (mean
      length 38 +/- 20 months), 4 patients underwent open heart surgery 24 to 39 months
      after PMV, and there was no overall mortality. CONCLUSIONS: Significant
      functional TR was associated with more severe MS, and it could be diminished when
      the transmitral pressure gradient was sufficiently relieved with PMV.

PMID- 12595859
TI  - Randomized comparison of mounted versus unmounted stents: the multicenter COMUS
      trial.
AB  - BACKGROUND: Although the use of premounted stents on a delivery balloon has
      almost completely eliminated the initially used hand-crimping procedure, no data
      are available that prove the superiority of one or the other approach on a
      randomized basis. Therefore, this study was designed to examine whether the use
      of premounted stents is comparable with the hand-crimping procedure. METHODS: A
      total of 123 patients (64 treated with unmounted stents, 59 treated with
      premounted stents) were examined in a multicenter, randomized, prospective study.
      There were no significant differences in patient characteristics between groups.
      RESULTS: Primary end points (acute, postinterventional [within 72 hours], and
      late complications related to the stenting procedure) were reached in 1 patient
      treated with an unmounted stent versus 2 patients with mounted stents (P = not
      significant). In patients with angiographic follow up (n = 84, mean follow-up
      period 6 +/- 1 months), the total rate of restenosis was 27% (unmounted 12,
      mounted 11, P = not significant). Secondary end points were procedural success of
      stenting and maximal balloon inflation pressure needed for optimal stenting
      results by use of angiography. There were no differences in secondary end points
      for both techniques. The mean balloon pressure was 12.56 +/- 2.1 atmospheres
      (unmounted) and 12.12 +/- 1.92 atmospheres (mounted, P = not significant).
      CONCLUSION: Stenting with premounted devices was demonstrated to have a similar
      clinical and angiographic outcome as the hand-crimping approach for maximal
      inflation pressure, procedural success, major cardiac events, and rate of
      restenosis after 6 months of follow up. Thus, the more convenient use of a
      premounted stent provides procedural safety and efficacy comparable with a hand
      crimped system.

PMID- 12595860
TI  - Low restenosis rate of the NIR coronary stent: results of the Danish multicenter
      stent study (DANSTENT)--a randomized trial comparing a first-generation stent
      with a second-generation stent.
AB  - BACKGROUND: Larger studies evaluating the angiographic results of second
      generation stents are scarce. The objectives of this study were to assess current
      standards of angiographic and clinical outcomes after implantation of the second
      generation stainless steel stent, NIR (Medinol Ltd, Tel Aviv, Israel), and to
      compare the outcomes with those of the first-generation Palmaz-Schatz (PS) stent
      (Johnson & Johnson, Warren, NJ). METHODS: Patients having coronary artery lesions
      that could be covered by a stent of 15 mm in length were randomly assigned to
      receive the NIR or the PS. Procedural success, 6-month angiographic findings, and
      1-year clinical outcomes were determined. RESULTS: In 424 patients included in
      the study, the overall procedural success rate was high (NIR 98%, PS 99%, P
      =.90). Follow-up angiography was conducted in 91% of the patients. The overall
      rate of angiographic restenosis was low in both groups (NIR 9.9%, PS 12.6%, P
      =.35). We found a low restenosis rate in vessels with a minimal lumen diameter
      >3.1 mm after the procedure, particularly in the NIR group (<6%). The rate of
      target lesion revascularization after 1 year did not differ (NIR 12%, PS 10%, P
      =.47). CONCLUSIONS: The angiographic and clinical outcomes after implantation of
      the second-generation stainless steel stent were not significantly better than
      those of the first-generation stent. The low restenosis rates, particularly in
      patients with the largest minimal lumen diameters after stent implantation,
      warrants circumspection when planning the evaluation of newer stent technologies
      that aim to further reduce coronary restenosis.

PMID- 12595861
TI  - Quantification of abciximab-induced platelet inhibition is assay dependent: a
      comparative study in patients undergoing percutaneous coronary intervention.
AB  - BACKGROUND: The best method for measuring the degree of platelet inhibition with
      glycoprotein (GP) IIb-IIIa antagonists during percutaneous coronary intervention
      (PCI) and the optimal degree of periprocedural inhibition is uncertain. Low
      molecular weight heparins have been reported to cause less platelet activation
      than unfractionated heparin. Therefore, compared with unfractionated heparin
      (UHF), a low molecular weight heparin could enhance measured platelet inhibition.
      In this study, we compared 3 methods of measuring platelet inhibition and
      investigated the effects of half doses of abciximab in combination with either
      UFH or the low molecular weight heparin dalteparin in patients undergoing PCI
      with planned abciximab administration. METHODS: Abciximab-induced platelet
      inhibition was measured serially by means of 3 assays: 1) GP IIb-IIIa receptor
      occupancy, 2) binding of the activated GP IIb-IIIa-specific monoclonal antibody
      PAC1, and 3) agglutination of platelets with fibrinogen-coated beads (RPFA).
      Forty patients were randomly allocated to receive either UFH (70 U/kg) or
      dalteparin (60 IU/kg), followed by a half dose of abciximab (0.125 mg/kg)
      administered twice at 10-minute intervals. Assays were obtained 10 minutes after
      each half dose of abciximab and 8 to 10 and 24 hours after abciximab
      administration. RESULTS: No differences between UFH and dalteparin were observed.
      At each time-point measured, the mean percent platelet inhibition as determined
      by means of the receptor occupancy assay and PAC1 binding assay was less than the
      degree of inhibition determined by means of the RPFA. CONCLUSIONS: The results of
      targeted levels of platelet inhibition cannot be extrapolated between different
      clinical trials of GP IIb-IIIa antagonists unless the same assay is used.
      Dalteparin, compared with UFH, does not enhance platelet inhibition or receptor
      occupancy by abciximab, as demonstrated by means of 3 separate assays.

PMID- 12595862
TI  - Effects of oral soy protein on markers of inflammation in postmenopausal women
      with mild hypercholesterolemia.
AB  - BACKGROUND: Nitric oxide (NO) may protect arteries against atherosclerosis, as
      suggested by experimental studies. Estrogen therapy enhances the bioactivity of
      NO in the vasculature of healthy postmenopausal women, but is not acceptable for
      long-term use by many women. Observational studies have demonstrated beneficial
      cardiovascular effects of soy protein in premenopausal and postmenopausal women.
      We examined whether the consumption of isolated soy protein may improve markers
      of vascular inflammation in postmenopausal women with hypercholesterolemia.
      METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled, crossover
      study, 24 postmenopausal women with hypercholesterolemia received 25 g of soy
      protein or a placebo daily for 6 weeks, with treatment periods separated by 1
      month. Markers of vascular inflammation were measured by enzyme-linked
      immunosorbent assay methods, including: soluble interleukin-2 receptor (sIL-2r),
      E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular
      cell adhesion molecule-1 (VCAM-1). There was no effect of soy protein in
      comparison with placebo on the inflammatory markers: the sIL-2r level was 942.2
      +/- 335.3 pg/mL with soy protein and 868.5 +/- 226.9 pg/mL with placebo (P
      =.311); E-selectin was 39.6 +/- 16.5 ng/mL with soy protein and 42.1 +/- 17.6
      ng/mL with placebo (P =.323); P-selectin was 157.9 +/- 67.9 ng/mL with soy
      protein and 157.5 +/- 47.6 ng/mL with placebo, (P =.977); ICAM-1 was 266.0 +/-
      81.3 ng/mL with soy protein and 252.5 +/- 82.7 ng/mL with placebo (P =.435); VCAM
      1 was 402.7 +/- 102.1 ng/mL with soy protein and 416.4 +/- 114.8 ng/mL with
      placebo (P =.53). CONCLUSIONS: Consumption of 25 g of isolated soy protein daily
      for 6 weeks does not substantially affect markers of vascular inflammation in
      postmenopausal women with hypercholesterolemia.

PMID- 12595863
TI  - Effect of atorvastatin and pravastatin on serum C-reactive protein.
AB  - BACKGROUND: Extra-lipid effects of statins, such as anti-inflammatory actions,
      may contribute to their clinical benefit. These effects, with important
      implications for the concept of a statin "class effect," may be drug specific or
      may be related to the extent of lipid lowering. METHODS: We randomized 130
      patients to treatment with either atorvastatin (80 mg daily, n = 63) or
      pravastatin (40 mg daily, n = 67), and measured serum lipids, C-reactive protein,
      and fibrinogen at baseline and after 3 months of therapy. RESULTS: Mean C
      reactive protein (CRP) levels were significantly reduced in both groups, with a
      36% reduction in the atorvastatin group (0.39 +/- 0.36 to 0.25 +/- 0.27, P =.001)
      and a 22% reduction observed in the pravastatin group (0.40 +/- 0.33 to 0.31 +/-
      0.32, P =.003). A reduced or unchanged CRP level was seen in 67.2% of pravastatin
      treated patients (45/67) and 73% of atorvastatin- treated patients (46/63) (P
      =.47). There was no difference between drugs in either the absolute or relative
      reductions in CRP levels. However, whereas the reduction of CRP with pravastatin
      was unrelated to the degree of low-density lipoprotein reduction (r = -.05, P
      =.69), atorvastatin-induced CRP reductions correlated directly to the change in
      low-density lipoprotein-C (r =.33, P =.009). CONCLUSIONS: High-dose atorvastatin
      and pravastatin both reduce CRP levels. However, whereas pravastatin's effect on
      CRP is independent of lipid-lowering efficacy, these data suggest that lipid
      dependent mechanisms are, at least in part, active in atorvastatin-treated
      patients.

PMID- 12595864
TI  - Cytomegalovirus seropositivity, infectious burden, and coronary artery disease.

PMID- 12595866
TI  - Prostaglandin E1 temporarily decreases adhesion molecules.

PMID- 12595868
TI  - Complex regional pain syndrome--diagnostic, mechanisms, CNS involvement and
      therapy.
AB  - Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and
      causalgia) are neuropathic pain conditions of one extremity developing
      inadequately after a trauma. The initiating trauma affects primarily the
      extremity, but can also be a central lesion (e.g., spinal cord injury, stroke).
      CRPS is clinically characterized by sensory, autonomic and motor disturbances.
      Pathophysiologically there is evidence for functional changes within the central
      nervous system and for involvement of peripheral inflammatory processes. The
      sympathetic nervous system plays a key role in maintaining pain and autonomic
      dysfunction in the affected extremity. After a primary central lesion, secondary
      peripheral changes in the paretic extremity are suggested to be important in
      initiating a CRPS. Though there is no diagnostic gold standard, careful clinical
      evaluation and additional test procedures should lead to an adequate diagnosis.
      An early diagnosis and an interdisciplinary approach are important for optimal
      and successful treatment.

PMID- 12595869
TI  - Searching the literature for information on traumatic spinal cord injury: the
      usefulness of abstracts.
AB  - STUDY DESIGN: Systematic review of abstracts of published papers presumed to
      contain information on chronic pain in persons with spinal cord injury (SCI).
      OBJECTIVES: To determine to what degree papers on SCI are abstracted in such a
      way that they can be retrieved, and evaluated as to the paper's applicability to
      a reader's questions. SETTING: US--academic department of rehabilitation
      medicine. METHODS: 868 abstracts published in Medline were independently examined
      by two out of 13 screeners, who answered four questions on the subjects and
      nature of the paper with 'Yes', 'No' or 'insufficient information'. Frequency of
      ratings 'insufficient information', and screener agreement were evaluated as
      affected by screener and abstract/paper characteristics. RESULTS: Screeners could
      not determine whether the paper dealt with persons with traumatic SCI for 37% of
      abstracts; whether chronic pain was a topic could not be determined in 18%.
      Physicians were less willing than other disciplines to assign 'insufficient
      information'. Screener agreement was better than chance, but not at the level
      suggested for quality measurement. Screener discipline and task experience did
      not make a difference, nor did abstract length, structure, or decade of
      publication of the paper. CONCLUSION: Authors need to improve the quality of
      abstracts to make retrieval and screening of relevant papers more effective and
      efficient. SPONSORSHIP: National Institute on Disability and Rehabilitation
      Research.

PMID- 12595870
TI  - Clinical features associated with recurrence of tumours of the spinal cord and
      cauda equina.
AB  - STUDY DESIGN: Retrospective review of consecutive cases of recurrent spinal cord
      and cauda equina tumours. OBJECTIVES: We sought to identify factors and
      conditions resulting in re-operation to treat recurrences of spinal cord and
      cauda equina tumours. SETTING: Keio University Hospital, Tokyo, Japan. METHODS:
      Re-operation was performed in 39 patients with spinal cord and cauda equina
      tumours. Times of operation, interval between operations, affected spinal level,
      tumour site on cross section, configurations among dumb-bell tumours, and
      pathologic diagnoses were analysed. Recurrence rates were defined in terms of the
      number of cases with re-operation due to tumour recurrence relative to the total
      number of surgical cases for the same period at our institution. RESULTS:
      Recurrence rates were relatively high for intradural, extramedullary tumours and
      for tumours located anteriorly rather than laterally. Of patients with
      intradural, extramedullary plus extradural tumours who underwent initial surgery
      at our hospital, 75% (9/12) recurred; all tumours had dumb-bell-type
      configurations. The overall rate of re-operation due to tumour recurrence in 249
      cases was 7.2% at our institution. By tumour types, 40% of malignant schwannomas
      recurred (2/5), as did 35.7% of neurofibromas (5/14), and 33.3% of ependymomas
      (6/18). CONCLUSION: Risk factors for tumour recurrence were anterior location, an
      intradural, extramedullary plus extradural site, extensive dumb-bell tumours, and
      pathologic diagnoses of neurofibroma, ependymoma, or malignant schwannoma.

PMID- 12595871
TI  - The role of upper limb surgery in tetraplegia.
AB  - STUDY DESIGN: A retrospective follow-up study. OBJECTIVES: To assess the value of
      surgery on the tetraplegic hand to improve its function. SETTING: Spinal unit.
      Hospital La Fe. Valencia (Spain). METHOD: We reviewed the functional results
      obtained in 15 patients (10 males and 5 females) operated on at our hospital
      between 1988 and 1997. We performed 66 surgical procedures on 20 upper limbs.
      After a year or more the patients were evaluated by two independent examiners not
      related with the surgeons, using the questionnaire of Lamb and Chan modified by
      Mohammed, taking into account the change in the performance of activities of
      daily living (ADL), the patient's satisfaction, and the fulfillment of their
      expectations. RESULTS: A good or excellent result was obtained in 71.4% of our
      patients, 85.7% were satisfied with the operation and 57.2% said that the surgery
      did not meet their expectations. The bad results occurred in patients with
      previous joint rigidity, ocular sensibility, pain, and lack of motivation.
      CONCLUSION: Hand surgery improved the function of tetraplegics and should be
      performed more frequently. The hands should be cared for from the very beginning
      to keep them supple. The information given to the patients should be realistic.

PMID- 12595872
TI  - Energy consumption of locomotion with orthosis versus Parastep-assisted gait: a
      single case study.
AB  - STUDY DESIGN: Single case study. OBJECTIVES: To evaluate the energy expenditure
      during ambulation with the Advanced Reciprocating Gait Orthosis (ARGO), with and
      without functional electrical stimulation (FES), and with the Parastep system in
      a single subject, in order to avoid the effect of inter-subject variability.
      SETTING: The Centre of Sport Medicine and Bioengineering Centre 'Don C Gnocchi'
      Foundation ONLUS IRCCS, Milano, Italy. METHODS: A single patient (lesion level T5
      T6) was trained specifically for each walking system and was evaluated after each
      training period. The effects of FES on muscle conditioning, spasticity and bone
      density were also evaluated. The HR/VO2 relationship and the energy cost of
      locomotion were measured during wheelchair (WHCH) use, during locomotion with
      ARGO (with and without FES) and Parastep system at different speeds. RESULTS: The
      following was observed at the end of the whole training: (a) circumferences of
      both lower limbs and quadriceps forces were increased, whereas fatigue index was
      slightly decreased, spasticity and bone density were unchanged; (b) compared to
      WHCH locomotion, the slope of HR/VO2 curves with ARGO was higher (slope
      difference=51.1 b 1O2(-1)), with ARGO+FES was similar (slope difference=-5.3 b
      1O2(-1)) and with Parastep was smaller (slope difference=-55.6 b 1O2(-1)); (c) HR
      increased linearly with all locomotion systems, but did not rise above 125 bpm
      with Parastep; (d) the cost of locomotion was higher with Parastep than with ARGO
      (with and without FES), tested at each velocity; (e) Parastep appears to be
      easier to use for the subject. CONCLUSIONS: (a) FES can improve ambulation with
      orthosis, but the cost of locomotion remains very high; (b) the Parastep assisted
      gait elicits a higher energy expenditure than other orthoses, probably due to the
      lower speed of locomotion and to the high isometric effort of the stimulated
      muscles. SPONSORSHIP: This work has been partially supported by the Italian
      Minister of Public Health (Ricerca Finalizzata IRCCS no ICS030.7/RF97.25).

PMID- 12595873
TI  - Gallstones in spinal cord injury (SCI): a late medical complication?
AB  - STUDY DESIGN: Prospective controlled study. OBJECTIVES: To assess the prevalence
      of cholelithiasis among chronic spinal spinal cord injured (SCI) male patients of
      the ACHS (Asociacion Chilena de Seguridad). To evaluate statistically the
      prevalence of cholelithiasis among SCI patients compared to a control group and
      to the general male Chilean population. To assess the correlation between
      cholelithiasis in chronic SCI patients and usual risk factors such as age,
      obesity and diabetes mellitus. To assess the association of cholelithiasis in
      chronic SCI patients and the duration of the spinal cord injury. SETTING:
      Rehabilitation Service at the Hospital del Trabajador, in Santiago, Chile.
      METHODS: One hundred SCI patients followed up at the Hospital del Trabajador on a
      regular basis were included in the study; one group consisted of 76 subjects
      rated ASIA A or B and the other group consisted of 24 subjects rated ASIA C and
      D. They were all male, older than 20 years old (average age: 41,9 and 42,6
      respectively), and suffered from a spinal cord injury greater than one year of
      evolution. The control group (CG) consisted of 100 male volunteers, without both
      SCI and history of biliary disease, aged 40.3 years old in average. All three
      groups underwent ultrasonographic imaging evaluation of the gallbladder and the
      biliary tract between 1998 and 2000. RESULTS: The prevalence of cholelithiasis
      among the groups was the following: 25% in the SCI patients ASIA A and B (19/76),
      25% in the SCI patients ASIA C and D (6/24) and 9% (1/100) in the CG. The
      statistical analysis showed a value of P=0.0037, thus establishing a significant
      association between cholelithiasis and SCI, both complete and incomplete. The
      difference was not statistically significant when correlating the presence of
      cholelithiasis with the neurological level of the injury--above and below T10
      (24,1 and 25%, respectively)--with the duration of the SCI, with age, obesity and
      diabetes mellitus. CONCLUSIONS: SCI represents a major risk factor for the
      development of cholelithiasis, and it should be considered a late, secondary
      complication of a spinal cord injury. SPONSORSHIP: The present work is sponsored
      by the Fundacion Cientifica y Tecnologica of the ACHS, grant No 2899.

PMID- 12595874
TI  - The amelioration of the suffering associated with spinal cord injury with
      subperception transcranial electrical stimulation.
AB  - STUDY DESIGN: Double blind, partial crossover. OBJECTIVES: To evaluate the
      analgesic activity of a novel cranial electrostimulus in people with spinal cord
      injury (SCI). SETTING: Hereward College, a residential centre that provides
      educational facilities for students with disabilities. METHODS: Subjects with SCI
      experiencing chronic pain were randomly assigned into two groups, one of which
      received sham and the other transcranial electrostimulation treatment (TCET) on
      two occasions daily for four successive days. After a 'wash-out' period of 8
      weeks all subjects returned and received the identical stimulus that the treated
      cohort received on the first arm of the study. RESULTS: Pain measurements applied
      before and after each session indicated that the pain decreased in the treated
      group to 51% of that reported at the commencement of treatment; reported pain
      intensity did not decrease significantly in the sham treated subjects. The same
      (sham) subject group reported experiencing 59% of the pain at the end of the
      second arm of the study (TCET) as on the first arm (sham). No significant
      differences were determined between the mood of all subjects estimated before and
      after each sham or TCET treatment session. The reported analgesic, and combined
      antidepressant and anxiolytic drug use in subjects receiving TCET on the second
      arm of the study, was 46% and 53% respectively of the average pre-study drug use.
      No similar decrease in the use of the drugs was noted in the same subjects after
      sham treatment on the first arm of the study. Salivary cortisol determinations
      made prior to and after each sham and treatment session implicated this corticoid
      in the pain-relieving mode of action of the treatment, but could not be
      associated with any changes in mood. Subjects receiving TCET had significantly
      higher urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) output after the TCET
      treatment period than sham stimulation, implicating increased central
      noradrenaline (NA) metabolism in the observed effects. CONCLUSION: The subjects
      reported less pain during, and immediately after receiving this transcranial
      treatment, although they were using less medication than when receiving sham
      treatment.

PMID- 12595875
TI  - Experience of tension-free vaginal tape for the treatment of stress incontinence
      in females with neuropathic bladders.
AB  - STUDY DESIGN: Retrospective. OBJECTIVE: To evaluate the safety and efficacy of
      the tension-free vaginal tape (TVT) for the treatment of stress incontinence in
      females with neuropathic bladders. SETTING: London Spinal Injuries Unit, Stanmore
      & Institute of Urology, London, UK. METHODS: Twelve women (mean age 53.3 years;
      range 41-80 years) with neuropathic bladder dysfunction and stress urinary
      incontinence were treated with tension-free vaginal tape (TVT) between November
      1997 and December 2000. The group consisted of women with: (i) traumatic spinal
      cord injuries (n=3); (ii) post lumbar spinal surgery (n=6); (iii) spinal stenosis
      (n=3). Four of the 12 patients had previously failed surgery for stress
      incontinence. All patients underwent pre- and post-TVT evaluation with video
      urodynamic studies. RESULTS: Mean follow-up was 27.1 months (range 17-54 months).
      Three patients were voiding spontaneously (stress voiding) before surgery and
      continued to do so post-operatively. The remaining 9 were performing clean
      intermittent self-catheterisation before the insertion of TVT and continued to do
      so after the surgery. At follow up 10 patients (83.3%) were dry. The procedure
      failed in one patient and the other complained of mild leakage, but she reported
      a decrease in the number of pads used. One patient developed detrusor
      hyperreflexia on post-operative video-urodynamics but there was no evidence of
      stress incontinence. One patient had a bladder perforation on insertion of TVT,
      managed successfully with extended use of a urethral catheter post-operatively.
      Three patients developed post-operative urinary tract infection successfully
      treated with oral antibiotics. CONCLUSIONS: Tension-free vaginal tape insertion
      is minimally invasive, safe and effective for the treatment of stress
      incontinence in females with bladder neuropathy with intrinsic sphincter
      deficiency. Previous surgery for incontinence did not affect post-operative
      complications or outcome.

PMID- 12595876
TI  - Gender related differences in pain in spinal cord injured individuals.
AB  - STUDY DESIGN: Out of a population of 456 patients with spinal cord injuries
      (SCI), 130 having pain were selected after matching, based on gender, age,
      American Spinal Injury Association (ASIA) impairment grade and level of lesion.
      OBJECTIVE: To investigate whether gender differences with regard to pain
      perception and prevalence exist in a population of patients following spinal cord
      injury. SETTING: Spinalis SCI Unit (out-patient clinic), Stockholm, Sweden.
      METHOD: 130 patients suffering from pain were assessed over a 12-month period in
      a yearly health control. RESULTS: SCI women had a higher prevalence of
      nociceptive pain than men and their use of analgesics was greater. However, no
      differences between the sexes could be seen regarding pain and localization,
      onset, distribution, factors affecting pain, number of painful body regions, pain
      descriptors, ratings of pain intensities or in pain and life satisfaction.
      CONCLUSION: This study showed that SCI men and women describe their pain very
      similarly. However, SCI women had a higher prevalence of nociceptive pain than
      men and their use of opiates and non-steroid anti-inflammatory drugs (NSAIDs) was
      greater.

PMID- 12595877
TI  - Outcome of a 12-week programme for management of the spinal cord injured with
      participation of patient's relations at Hilltop Orthopaedic Hospital, Enugu,
      Nigeria.
AB  - STUDY DESIGN: Description of 12-week programme of treatment. OBJECTIVES: In
      Enugu, Nigeria, not all spinal injured (SCI) can be treated in teaching and
      orthopaedic hospitals. The 12-week programme was developed with the aim of
      getting such patients back into society as useful and independent as possible,
      using the patients relations to complement the deficiency in personnel. SETTING:
      Enugu, Nigeria. METHODS: Staged weekly programmes of assessment and treatment
      were mapped out to end at the twelfth week. Spinal injured patients of less than
      2 weeks duration were entered into these programmes as they presented. Outcome
      was assessed at the end of the twelfth week. The study lasted for 6 years
      (January 1996 to December 2000). RESULTS: Seventy-four patients were admitted
      into the study. Nine patients had incomplete cord injury of Frankel C while 65
      had clinically complete injury of Frankel A on admission. Eight of the nine
      incomplete injuries improved to Frankel D and walked home within the 12-week
      programme. In the clinically complete group, eight died. Out of the 57 remaining,
      six recovered to Frankel D and walked home, while the remaining 51 who did not
      recover, 49 were conversant with wheelchair use within the 12-week programme.
      CONCLUSION: It is concluded that adoption of this programme would allow the
      spinal cord injured to get expert treatment within a reasonable time in less
      ideal hospital settings where man-power and skilled members of the spinal cord
      injury treatment team are lacking.

PMID- 12595878
TI  - Third annual meeting of the California Spinal Cord Injury/Neural Regeneration
      Consortium March 20-21, 2002, the Reeve-Irvine Research Center of the University
      of California, Irvine, USA.

PMID- 12595879
TI  - Use of expert judgment in exposure assessment: part 2. Calibration of expert
      judgments about personal exposures to benzene.
AB  - The recent movement of regulatory agencies toward probabilistic analyses of human
      health and environmental risks has focused greater attention on the quality of
      the estimates of variability and uncertainty that underlie them. Of particular
      concern is how uncertainty--a measure of what is not known--is characterized, as
      uncertainty can play an influential role in analyses of the need for regulatory
      controls or in estimates of the economic value of additional research. This paper
      reports the second phase of a study, conducted as an element of the National
      Human Exposure Assessment Survey (NHEXAS), to obtain and calibrate exposure
      assessment experts judgments about uncertainty in residential ambient,
      residential indoor, and personal air benzene concentrations experienced by the
      nonsmoking, nonoccupationally exposed population in U.S. EPA's Region V.
      Subjective judgments (i.e., the median, interquartile range, and 90% confidence
      interval) about the means and 90th percentiles of each of the benzene
      distributions were elicited from the seven experts participating in the study.
      The calibration or quality of the experts' judgments was assessed by comparing
      them to the actual measurements from the NHEXAS Region V study using graphical
      techniques, a quadratic scoring rule, and surprise and interquartile indices. The
      results from both quantitative scoring methods suggested that, considered
      collectively, the experts' judgments were relatively well calibrated although on
      balance, underconfident. The calibration of individual expert judgments appeared
      variable, highlighting potential pitfalls in reliance on individual experts. In a
      surprising finding, the experts' judgments about the 90th percentiles of the
      benzene distributions were better calibrated than their predictions about the
      means; the experts tended to be overconfident in their ability to predict the
      means. This paper is also one of the first calibration studies to demonstrate the
      importance of taking into account intraexpert correlation on the statistical
      significance of the findings. When the judgments were assumed to be independent,
      analysis of the surprise and interquartile indices found evidence of poor
      calibration (P<0.05). However, when the intraexpert correlation in the study was
      taken into account, these findings were no longer statistically significant. The
      analysis further found that the experts' judgments scored better than estimates
      of Region V benzene concentrations simply drawn from earlier studies of ambient,
      indoor and personal benzene levels in other U.S. cities. These results suggest
      the value of careful elicitation of expert judgments in characterizing exposures
      in probabilistic form. Additional calibration studies need to be undertaken to
      corroborate and extend these findings.

PMID- 12595880
TI  - Description of trihalomethane levels in three UK water suppliers.
AB  - Samples of drinking water are routinely analysed for four trihalomethanes (THMs),
      which are indicators of by-products of disinfection with chlorine, by UK water
      suppliers to demonstrate compliance with regulations. The THM data for 1992-1993
      to 1997-1998 for three water suppliers in the north and midlands of England were
      made available for a UK epidemiological study of the association between
      disinfection by-products and adverse birth outcomes. This paper describes the THM
      levels in these three supply regions and discusses possible sources of variation.
      THM levels varied between different suppliers' water, and average THM levels were
      within the regulatory limits. Chloroform was the predominant THM in all water
      types apart from the ground water of one supplier. The supplier that distributed
      more ground and lowland surface water had higher dibromochloromethane (DBCM) and
      bromoform levels and lower chloroform levels than the other two suppliers. In the
      water of two suppliers, seasonal fluctuations in bromodichloromethane (BDCM) and
      DBCM levels were found with levels peaking in the summer and autumn. In the other
      water supplier, chloroform levels followed a similar seasonal trend whereas BDCM
      and DBCM levels did not. For all three water suppliers, chloroform levels
      declined throughout 1995 when there was a drought period. There was a moderate
      positive correlation between the THMs most similar in their structure (chloroform
      and BDCM, BDCM and DBCM, and DBCM and bromoform) and a slight negative
      correlation between chloroform and bromoform levels.

PMID- 12595881
TI  - Influences on human internal exposure to environmental platinum.
AB  - Different influences on internal exposure to platinum are investigated and for
      the first time weighted in environmentally exposed subjects as far as individual
      internal platinum concentrations are concerned. Detailed medical and
      environmental histories as well as oral cavity status were assessed in 84
      dermatological patients, and internal platinum exposure was determined by
      analyzing platinum in urine using adsorptive voltammetry (AV). Platinum
      concentrations ranged from <0.9 (detection limit) to 65.5 ng Pt/l urine.
      Influence of different types and age of alloy restorations and therefore
      relevance of the exposure pathway due to solubilization of platinum in saliva
      could be demonstrated. No platinum-related health effects (contact stomatitis,
      asthma or kidney conditions) were observed. Analysis of covariance showed the
      number of noble dental alloy restorations (P<0.0001) and to a lesser extent age
      (P=0.0017) to independently influence internal platinum exposure. Even though
      spread of environmental platinum has increased, internal platinum exposure is low
      in subjects without assessable medical or dental devices (usually <4.5 ng/l
      urine) and not related to adverse health effects. For the first time, detailed
      individual information on possible exposure pathways to platinum were considered
      in an analysis of relevant influential factors: Car traffic exposure and
      dermatological condition showed no association with internal platinum exposure.
      Uptake from platinum containing noble metal dental alloy restorations (NMDAR) is
      of greatest relevance, surmounting the influence of each year of lifetime on
      platinum body load by more than 10-fold.

PMID- 12595882
TI  - Measurement of volatile organic compounds inside automobiles.
AB  - The objective of the current study was to evaluate the types and concentrations
      of volatile organic compounds (VOCs) in the passenger cabin of selected sedan
      automobiles under static (parked, unventilated) and specified conditions of
      operation (i.e., driving the vehicle using air conditioning alone, vent mode
      alone, or driver's window half open). Data were collected on five different
      passenger sedan vehicles from three major automobile manufacturers. Airborne
      concentrations were assessed using 90-min time-weighted average (TWA) samples
      under U.S. Environmental Protection Agency (USEPA) Method IP-1B to assess
      individual VOC compounds and total VOCs (TVOCs) calibrated to toluene. Static
      vehicle testing demonstrated TVOC levels of approximately 400-800 microg/m(3) at
      warm interior vehicle temperatures (approximately 80 degrees F), whereas TVOCs at
      least fivefold higher were observed under extreme heat conditions (e.g., up to
      145 degrees F). The profile of most prevalent individual VOC compounds varied
      considerably according to vehicle brand, age, and interior temperature tested,
      with predominant compounds including styrene, toluene, and 8- to 12-carbon VOCs.
      TVOC levels under varied operating conditions (and ventilation) were generally
      four- to eightfold lower (at approximately 50-160 microg/m(3)) than the static
      vehicle measurements under warm conditions, with the lowest measured levels
      generally observed in the trials with the driver's window half open. These data
      indicate that while relatively high concentrations of certain VOCs can be
      measured inside static vehicles under extreme heat conditions, normal modes of
      operation rapidly reduce the inside-vehicle VOC concentrations even when the air
      conditioning is set on recirculation mode.

PMID- 12595883
TI  - Nondietary ingestion of pesticides by children in an agricultural community on
      the US/Mexico border: preliminary results.
AB  - An environmental measurement and correlation study of nondietary ingestion of
      pesticides was carried out in a colonia in south Texas. The purpose of the study
      was to evaluate young children's exposure to environmental levels of
      organophosphate (OP) pesticides in the household. Samples were collected to
      measure levels of OP pesticides in housedust and on children's hands. These, in
      turn, were compared to levels of OP pesticide metabolites in urine. A total of 52
      children, 25 boys and 27 girls, participated in the spring and summer of 2000.
      The children were 7-53 months of age at the time of recruitment. Univariate and
      multivariate regression analyses were carried out using SAS statistical software.
      Seventy-six percent of housedust samples and 50% of hand rinse samples contained
      OP pesticides. All urine samples had at least one metabolite and over 95% had at
      least two metabolites above the limit of detection (LOD). Total OP loadings in
      the housedust ranged from nondetectable (nd) to 78.03 nmol/100 cm(2) (mean=0.15
      nmol/100 cm(2); median=0.07 nmol/100 cm(2)); total OP loadings on the children's
      hands ranged from nd to 13.40 nmol/100 cm(2) (mean=1.21 nmol/100 cm(2);
      median=1.41 nmol/100 cm(2)), and creatinine corrected urinary levels (nmol/mol
      creatinine) of total OP metabolites ranged from 3.2 to 257 nmol/mol creatinine
      (mean=42.6; median 27.4 nmol/mol creatinine). Urinary metabolites were inversely
      associated with the age of the child (in months) with the parameter estimate
      (pe)=-2.11, P=0.0070, and 95% confidence interval -3.60 to -0.61. The
      multivariate analysis observed a weak association between concentrations of OP
      pesticides in housedust, loadings in housedust, and concentration on hands, hand
      surface area, and urinary levels of OP metabolites. However, hand loadings of OP
      pesticides were more strongly associated (r(2)=0.28; P=0.0156) with urinary
      levels of OP metabolites (pe=6.39; 95% CI 0.98-11.80). This study's preliminary
      findings suggest that surface loadings of pesticides, on hands, are more highly
      correlated with urinary bioassays and, therefore, may be more useful for
      estimation of exposure in epidemiologic studies than levels of pesticides in
      housedust.

PMID- 12595884
TI  - Risks to children from exposure to lead in air during remedial or removal
      activities at Superfund sites: a case study of the RSR lead smelter Superfund
      site.
AB  - Superfund sites that are contaminated with lead and undergoing remedial action
      generate lead-enriched dust that can be released into the air. Activities that
      can emit lead-enriched dust include demolition of lead smelter buildings, stacks,
      and baghouses; on-site traffic of heavy construction vehicles; and excavation of
      soil. Typically, air monitoring stations are placed around the perimeter of a
      site of an ongoing remediation to monitor air lead concentrations that might
      result from site emissions. The National Ambient Air Quality (NAAQ) standard,
      established in 1978 to be a quarterly average of 1.5 microg/m(3), is often used
      as a trigger level for corrective action to reduce emissions. This study explored
      modeling approaches for assessing potential risks to children from air lead
      emissions from the RSR Superfund site in West Dallas, TX, during demolition and
      removal of a smelter facility. The EPA Integrated Exposure Uptake Biokinetic
      (IEUBK) model and the International Commission of Radiologic Protection (ICRP)
      lead model were used to simulate blood lead concentrations in children, based on
      monitored air lead concentrations. Although air lead concentrations at monitoring
      stations located in the downwind community intermittently exceeded the NAAQ
      standard, both models indicated that exposures to children in the community areas
      did not pose a significant long-term or acute risk. Long-term risk was defined as
      greater than 5% probability of a child having a long-term blood lead
      concentration that exceeded 10 microg/dl, which is the CDC and the EPA blood lead
      concern level. Short-term or acute risk was defined as greater than 5%
      probability of a child having a blood lead concentration on any given day that
      exceeded 20 microg/dl, which is the CDC trigger level for medical evaluation
      (this is not intended to imply that 20 microg/dl is a threshold for health
      effects in children exposed acutely to airborne lead). The estimated potential
      long-term and short-term exposures at the downwind West Dallas community did not
      result in more than 5% of children exceeding the target blood lead levels. The
      models were also used to estimate air lead levels for short-term and long-term
      exposures that would not exceed specified levels of risk (risk-based
      concentrations, RBCs). RBCs were derived for various daily exposure durations (3
      or 8 h/day) and frequencies (1-7 days/week). RBCs based on the ICRP model ranged
      from 0.3 (7 days/week, 8 h/day) to 4.4 microg/m(3) (1 day/week, 3 h/day) for long
      term exposures and were lower than those based on the IEUBK model. For short-term
      exposures, the RBCs ranged from 3.5 to 29.0 microg/m(3). Recontamination of
      remediated residential yards from deposition of air lead emitted during remedial
      activities at the RSR Superfund site was also examined. The predicted increase in
      soil concentration due to lead deposition at the monitoring station, which
      represented the community at large, was 3.0 mg/kg. This potential increase in
      soil lead concentration was insignificant, less than 1% increase, when compared
      to the clean-up level of 500 mg/kg developed for residential yards at the site.

PMID- 12595885
TI  - Fluoride concentrations in three types of commercially packed tea drinks in
      Taiwan.
AB  - Tea is a popular drink around the world. It is also one of the major sources of
      fluoride intake. The objectives of this study were to assess fluoride
      concentrations in popular non-, semi-, and full-fermented tea drinks sold on the
      Taiwan market. Concentration differences among three types of commercially
      available tea drinks (tea leaf, tea bag, and packaged tea beverage) were
      explored. Several influential factors in intake concentrations were evaluated.
      The acute threshold intake (ATI) and allowable daily intake (ADI) of those tea
      drinks were also estimated. For each commercial type, samples from the most
      popular tea in one particular fermentation degree (non, semi, and full) were
      randomly purchased and analyzed for fluoride concentrations. Fluoride levels in
      different rounds of tea, in different containers, and with different ratios of
      water and tea leaf were also assessed. In total, 132 tea samples were analyzed.
      The mean fluoride concentrations in leaf tea without the first round, leaf tea
      with the first round, bagged tea, and packaged tea were 7.04, 7.79, 5.37, and
      25.7 mg/l, respectively. Most of the intake concentrations in those samples
      exceeded 4 mg/l F, the lower bound of fluoride levels reported in the literatures
      to be associated with a lower IQ in children and a higher risk of bone fracture.
      Fluoride concentrations in packaged tea were the highest among the three types of
      commercially available tea. For studied leaf and bagged tea, almost a constant
      amount of fluoride was infused from the same amount of tea leaf regardless of the
      water volume. Besides this, making tea with glass or pottery tea makers would not
      affect fluoride intake concentrations. Acute intoxication is unlikely to occur.
      However, tea lovers in high fluoride content areas shall consider limit their
      consumption of tea drinks to avoid potential chronic effects.

PMID- 12595886
TI  - EXPOLIS simulation model: PM2.5 application and comparison with measurements in
      Helsinki.
AB  - PM(2.5) exposure distributions of adult Helsinki citizens were simulated using a
      probabilistic simulation framework. Simulation results were compared to
      corresponding personal exposure distributions measured in the EXPOLIS study in
      Helsinki. The simpler models 1 and 2 (with two and three microenvironments,
      respectively) predict the general outline of the exposure distributions
      reasonably well. Compared to the observed exposure distribution, the mean is
      underestimated by less than 3 microg m(-3) (20%) and the standard deviation by 23
      35%. In the improved simulation models (3 and 4), the environmental tobacco smoke
      (ETS)-exposed subjects are excluded, the time-activity models of working and
      nonworking subpopulations are modeled separately, and the correlations of input
      concentration and time fraction variables have been accounted for. The output of
      these models was very close to the observed distributions; the differences in the
      means were less than 0.1 microg m(-3) and the differences in standard deviation
      less than 1%. We conclude that when the required input data are available or can
      be reliably estimated, the target population PM(2.5) exposure distributions can
      be predicted accurately enough for most practical purposes using this kind of a
      microenvironment model.

PMID- 12595887
TI  - Gene therapy progress and prospects: therapeutic angiogenesis for limb and
      myocardial ischemia.
AB  - After extensive investigation in preclinical studies and recent clinical trials,
      gene therapy has been established as a potential method to induce therapeutic
      angiogenesis in ischemic myocardial and limb disease. Advancements in viral and
      nonviral vector technology including cell-based gene transfer will continue to
      improve transgene transmission and expression efficiency. An alternative strategy
      to the use of transgenes encoding angiogenic growth factors is therapy based on
      transcription factors such as hypoxia-inducible factor-1alpha (HIF-1alpha) that
      regulate the expression of multiple angiogenic genes. Further understanding of
      the underlying biology of neovascularization is needed to determine the ability
      of growth factors to induce functionally significant angiogenesis in patients
      with atherosclerotic disease and associated comorbid conditions including
      endothelial dysfunction, which may inhibit blood vessel growth. The safety and
      tolerability of therapeutic angiogenesis by gene transfer has been demonstrated
      in phase I clinical trials. However, limited evidence of efficacy resulted from
      early phase II studies of angiogenic gene therapy for ischemic myocardial and
      limb disease. The utility of therapeutic angiogenesis by gene transfer as a
      treatment option for ischemic cardiovascular disease will be determined by
      adequately powered, randomized, placebo-controlled phase II and III clinical
      trials.

PMID- 12595888
TI  - ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating,
      and anti-tumour properties.
AB  - Herpes simplex virus type-1 (HSV1) in which the neurovirulence factor ICP34.5 is
      inactivated has been shown to direct tumour-specific cell lysis in several tumour
      models. Such viruses have also been shown to be safe in Phase I clinical trials
      by intra-tumoral injection in glioma and melanoma patients. Previous work has
      used serially passaged laboratory isolates of HSV1 which we hypothesized may be
      attenuated in their lytic capability in human tumour cells as compared to more
      recent clinical isolates. To produce ICP34.5 deleted HSV with enhanced oncolytic
      potential, we tested two clinical isolates. Both showed improved cell killing in
      all human tumour cell lines tested compared to a laboratory strain (strain 17+).
      ICP34.5 was then deleted from one of the clinical isolate strains (strain JS1).
      Enhanced tumour cell killing with ICP34.5 deleted HSV has also been reported by
      the deletion of ICP47 by the up-regulation of US11 which occurs following this
      mutation. Thus to further improve oncolytic properties, ICP47 was removed from
      JS1/ICP34.5-. As ICP47 also functions to block antigen processing in HSV infected
      cells, this mutation was also anticipated to improve the immune stimulating
      properties of the virus. Finally, to provide viruses with maximum oncolytic and
      immune stimulating properties, the gene for human or mouse GM-CSF was inserted
      into the JS1/34.5-/47- vector backbone. GM-CSF is a potent immune stimulator
      promoting the differentiation of progenitor cells into dendritic cells and has
      shown promise in clinical trials when delivered by a number of means. Combination
      of GM-CSF with oncolytic therapy may be particularly effective as the necrotic
      cell death accompanying virus replication should serve to effectively release
      tumour antigens to then induce a GM-CSF-enhanced immune response. This would, in
      effect, provide an in situ, patient-specific, anti-tumour vaccine. The viruses
      constructed were tested in vitro in human tumour cell lines and in vivo in mice
      demonstrating significant anti-tumour effects. These were greatly improved
      compared to viruses not containing each of the modifications described. In vivo,
      both injected and non-injected tumours showed significant shrinkage or clearance
      and mice were protected against re-challenge with tumour cells. The data
      presented indicate that JS1/ICP34.5-/ICP47-/GM-CSF acts as a powerful oncolytic
      agent which may be appropriate for the treatment of a number of solid tumour
      types in man.

PMID- 12595889
TI  - A novel strategy for in vivo expansion of transplanted hepatocytes using
      preparative hepatic irradiation and FasL-induced hepatocellular apoptosis.
AB  - A strategy for inducing preferential proliferation of the engrafted hepatocytes
      over host liver cells should markedly increase the benefit of hepatocyte
      transplantation for the treatment of liver diseases and ex vivo gene therapy. We
      hypothesized that preparative hepatic irradiation (HIR) to inhibit host
      hepatocellular regeneration in combination with the mitotic stimulus of host
      hepatocellular apoptosis should permit repopulation of the liver by transplanted
      cells. To test this hypothesis, congeneic normal rat hepatocytes were
      transplanted into UDP-glucuronosyltransferase (UGT1A1)-deficient jaundiced Gunn
      rats (a model of Crigler-Najjar syndrome type I), following HIR and adenovirus
      mediated FasL gene transfer. Progressive repopulation of the liver by engrafted
      UGT1A1-proficient hepatocytes over 5 months was demonstrated by the appearance of
      UGT1A1 protein and enzyme activity in the liver, biliary bilirubin glucuronides
      secretion, and long-term normalization of serum bilirubin levels. This is the
      first demonstration of massive hepatic repopulation by transplanted cells by HIR
      and FasL-induced controlled apoptosis of host liver cells.

PMID- 12595890
TI  - Intercellular trafficking and enhanced in vivo antitumour activity of a non
      virally delivered P27-VP22 fusion protein.
AB  - VP22, a structural protein from herpes simplex virus type I, exhibits the unique
      property of intercellular trafficking. This protein is exported from primary
      expressing cells and subsequently imported into neighbouring cells. This property
      is conserved when VP22 is genetically fused to a protein, making it a promising
      tool to enhance the delivery of a gene product. We chose to study the
      intercellular transport and biological effect of a fusion protein between the
      putative tumour suppressor gene p27(Kip1) and VP22. We show that in vitro,
      P27VP22 is able to spread as efficiently as VP22. Functionality of the P27VP22
      protein was demonstrated by its ability to inhibit cyclin/CDK2 complexes
      activity. In proliferation and clonogenicity assays, transfection with the
      P27VP22 plasmid resulted in a stronger cell growth inhibition when compared to
      transfection with the p27(Kip1) vector. In vivo, sub cutaneous tumours
      established in nude mice were injected with naked DNA encoding P27 or P27VP22.
      Our results show that P27VP22 can spread in vivo and that injections of the
      P27VP22 plasmid resulted in a significantly greater antitumour activity than
      injections of the P27 plasmid. This study confirms the usefulness of VP22
      mediated delivery and suggests that P27VP22 may have applications in cancer gene
      therapy.

PMID- 12595891
TI  - Development of an Ad7 cosmid system and generation of an Ad7deltaE1deltaE3HIV(MN)
      env/rev recombinant virus.
AB  - A strategy to circumvent immune responses to adenovirus (Ad) resulting from
      natural infection or repeated vector administrations involves sequential use of
      vectors from different Ad serotypes. To further develop an Ad-HIV recombinant
      AIDS vaccine approach, a replication-defective recombinant Ad from a non-subgroup
      C virus was required. Using a cosmid system, we generated an
      Ad7deltaE1deltaE3HIV(MN) env/rev recombinant virus and compared expression of the
      inserted HIV genes with a similarly constructed replication-competent
      Ad7deltaE3HIV(MN)env/rev recombinant. Ad7deltaE1deltaE3HIV(MN)env/rev expressed
      both HIV env and rev gene products. The envelope protein was correctly processed
      and functional, mediating syncytia formation of Ad7deltaE1deltaE3HIV(MN) env/rev
      infected cells and CD4(+) T lymphocytes. Ad7deltaE1deltaE3HIV(MN)env/rev could be
      amplified on 293-ORF6 cells, containing the E4 ORF6 gene, shown earlier to
      support production of an Ad7 vector lacking the E1a gene. The utility of this
      cell line is now extended to the production of replication-defective Ad7
      recombinants lacking E1a, E1b, and protein IX genes. Sequential immunizations
      with Ad-HIV recombinants based in different Ad serotypes have been shown to
      effectively elicit both humoral and cellular HIV-specific immune responses. The
      recombinant Ad7deltaE1deltaE3HIV(MN)env/rev will be useful in such AIDS vaccine
      strategies. Further, these studies have created new cosmid vectors that can be
      applied to generation of single- or double-deleted Ad7 recombinants with foreign
      genes inserted into the E1 and/or E3 regions.

PMID- 12595892
TI  - Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene
      expression from an adenoviral vector in the adult rat brain depending on the
      transduced area.
AB  - Targeting therapeutic transgene expression to defined tissues is a major task in
      the development of safe and efficient gene therapy protocols. Recombinant
      adenovirus is an attractive vector because it can be prepared in huge quantity
      and new generation vectors possess very large cloning capacities combined with
      reduced immunogenicity. In the brain, adenovirus transduces mainly glial cells,
      making it difficult to use this vector system in applications that need
      expression of therapeutic proteins in neurons. Here, we show that by using a
      small fragment of the human synapsin 1 gene promoter, we were able to restrict
      transgene expression from an adenoviral vector exclusively to neurons.
      Furthermore, we obtained stable long-term transgene expression from this vector
      in striatum and thalamus at appropriate vector dose. Other promoters like the CMV
      and U1snRNA promoters also mediated transgene expression over several months, but
      mainly in glial cells. Although the NSE promoter was relatively neuron specific,
      it still expressed in glial cells also, and was clearly outperformed by the
      synapsin promoter with respect to transcriptional neuronal targeting. As an
      important feature of adenoviral-mediated gene transfer to the brain, we
      demonstrate that dopaminergic neurons of the substantia nigra do not allow for
      long-term expression from adenoviral vectors. Strikingly, these neurons appeared
      to specifically attenuate transgene expression by deleting the adenoviral genome.

PMID- 12595893
TI  - Generation of expression constructs that secrete bioactive alphaMSH and their use
      in the treatment of experimental autoimmune encephalomyelitis.
AB  - alpha Melanocyte-stimulating hormone (alphaMSH) is a 13 amino acid peptide with
      potent anti-inflammatory effects. We created two DNA expression constructs
      (miniPOMC and pACTH1-17) that encode bioactive versions of the alphaMSH peptide,
      and tested these constructs for therapeutic effects in experimental autoimmune
      encephalomyelitis (EAE). Each construct contained the sequences for alphaMSH, as
      well as the sequences that are involved in the secretion and processing of the
      POMC gene with the assumption that these sequences would promote processing and
      release of the encoded alphaMSH peptide. The differences between the two
      constructs lie at the C-terminal end where amino acids necessary for amidation of
      alphaMSH were included in only the pACTH1-17 construct. These two constructs were
      tested in vitro in bioassays, and in vivo in a mouse model of EAE. The results
      show that although bioactive peptides are secreted from cells transfected with
      either construct, there appears to be a significant therapeutic effect only with
      the pACTH1-17 construct which contains the extra C-terminal amino acids. The data
      suggest that it is possible to engineer DNA expression vectors encoding small
      secreted peptides such as alphaMSH, and that similar type constructs may be
      useful as therapeutics for the treatment of inflammatory diseases.

PMID- 12595894
TI  - Inhibition of NFkappaB activation using cis-element 'decoy' of NFkappaB binding
      site reduces neointimal formation in porcine balloon-injured coronary artery
      model.
AB  - Application of DNA technology to regulate the transcription of disease-related
      genes has important therapeutic potential. The transcription factor NFkappaB
      plays a pivotal role in the transactivation of inflammatory and adhesion molecule
      genes, leading to vascular lesion formation. Double-stranded DNA with high
      affinity for NFkappaB may be introduced as 'decoy' cis elements to bind NFkappaB
      and block the activation of genes mediating inflammation, resulting in effective
      drugs for treating intimal hyperplasia. In this study, we tested the feasibility
      of NFkappaB decoy therapy to treat neointimal formation in a porcine coronary
      artery balloon injury model as a pre-clinical study. An angioplasty catheter was
      introduced into the left anterior descending coronary artery of the pig to cause
      vascular injury. First, we tested the feasibility of transfection of FITC-labeled
      NFkappaB decoy ODN using a hydrogel balloon catheter. Fluorescence due to
      NFkappaB decoy ODN could be detected throughout the medial layer. Therefore, we
      transfected NFkappaB decoy ODN into the balloon-injured LAD using a hydrogel
      catheter. Histological evaluation demonstrated that the neointimal area in the
      balloon-injured artery was significantly reduced by NFkappaB decoy ODN as
      compared to scrambled decoy ODN at 1 week after single transfection, accompanied
      by a significant reduction in PCNA-positive stained cells (P < 0.01).
      Interestingly, the reduction of ICAM-positive staining was observed, accompanied
      by the inhibition of migration of macrophages. Of importance, intravascular
      ultrasound (IVUS) confirmed that neointimal area in the balloon-injured artery
      was significantly reduced by NFkappaB decoy ODN at 4 weeks after transfection (P
      < 0.01). Interestingly, the inhibition of neointimal area was only limited to the
      lesion transfected with NFkappaB decoy ODN, while other lesions without NFkappaB
      decoy ODN demonstrated a marked increase in neointimal formation. Here, we report
      the successful in vivo transfer of NFkappaB decoy ODN using a hydrogel catheter
      to inhibit vascular lesion formation in balloon-injured porcine coronary artery.

PMID- 12595895
TI  - Looking back and looking forward.

PMID- 12595896
TI  - Susceptibility to mycobacterial infections: the importance of host genetics.
AB  - There is substantial evidence that host genetic factors are important in
      determining susceptibility to mycobacteria. Several different techniques have
      been used to identify the genes involved. Studies of an inbred strain of mice
      with increased susceptibility to mycobacteria, salmonella and leishmania
      infections led to the identification of the natural resistance-associated
      macrophage protein gene (Nramp1). Case-control studies have confirmed the
      importance of the human equivalent of this gene, NRAMP1, and have also suggested
      that the major histocompatibility complex and vitamin-D receptor genes may be
      involved in determining human susceptibility to mycobacteria. Studies of
      individuals with the rare condition of increased susceptibility to disseminated
      bacille Calmette-Guerin and other atypical mycobacterial infections have
      identified several abnormalities in the genes encoding the interferon gamma
      receptor (IFNgammaR) ligand binding chain, IFNgammaR signal transduction chain,
      IFNgamma signal transduction and activation of transcription-1, interleukin 12
      receptor beta1 subunit and interleukin 12 p40 subunit. A genome-wide linkage
      study has been performed to identify genes exerting a major effect on
      tuberculosis susceptibility in the general population. Linkages were found to
      markers on chromosomes 15 and X. Studies to identify the genes responsible are in
      progress.

PMID- 12595897
TI  - Autoimmune regulator: from loss of function to autoimmunity.
AB  - The autoimmune regulator (AIRE) is a gene where mutations cause the recessively
      inherited disorder called autoimmune polyendocrinopathy-candidiasis-ectodermal
      dystrophy (APECED) or autoimmune polyendocrinopathy syndrome type 1 (APS1).
      Variable combinations of autoimmune endocrine diseases such as Addison's disease,
      hypoparathyroidism, and type 1 diabetes characterize APECED. The AIRE protein has
      several domains indicative of a transcriptional regulator. AIRE contains two PHD
      (plant homeodomain) type zinc fingers, four nuclear receptor binding LXXLL
      motifs, a putative DNA-binding domain named SAND and, in addition, a highly
      conserved N-terminal domain similar to the homogenously staining region domain of
      the Sp100 protein. At the subcellular level, AIRE is expressed in nuclear dots
      resembling promyelocytic leukemia nuclear bodies, which are associated with
      several transcriptionally active proteins. AIRE is primarily expressed in thymic
      medullary epithelial cells and monocyte-dendritic cells in the thymus but also in
      a rare subset of cells in the lymph nodes, spleen and fetal liver. The disease,
      caused by mutations in AIRE, its function as a protein involved in transcription,
      and its restricted expression in cells important in negative selection, all
      together suggest that AIRE is a central protein in the maintenance of immune
      tolerance. In this review of the recent literature we discuss the results of
      these studies with particular attention on the AIRE expression pattern and its
      function as a transcriptional regulator, as well as the effects of patient
      mutations on the molecular characteristics of the protein.

PMID- 12595898
TI  - Evaluation of human leukocyte N-formylpeptide receptor (FPR1) SNPs in aggressive
      periodontitis patients.
AB  - Polymorphonuclear neutrophils (PMNs) are attracted to sites of infection by N
      formylpeptide (fMLP) chemoattractants. The high-affinity fMLP receptor (FPR1) of
      phagocytic cells interacts with bacterial fMLP and mediates chemotaxis,
      degranulation, and superoxide production. These cellular functions are disrupted
      in PMN from aggressive periodontitis (AP) patients. Two FPR1 gene single
      nucleotide polymorphisms (SNPs), c.329T>C and c.378C>G, have been associated with
      a localized form of AP in African-American patients. To evaluate the generality
      of these SNPs in AP patients, we sequenced a 363 bp interval of the FPR1 gene in
      an ethnically diverse group of patients (n=111) and controls (n=115). Neither
      c.329T>C nor c.378C>G were detected in the 452 alleles sequenced. Six SNPs were
      identified including two located in the FPR1 second extracellular loop that were
      significantly associated with the AP phenotype in African-American patients
      (p.R190W, P=0.0033; and p.N192K, P=0.0018). These two SNPs show three predominant
      haplotypes, each associated with a different disease risk in African-Americans.
      These data do not support the hypothesis that the FPR1 SNPs c.329T>C and c.378C>G
      play an etiologic role in aggressive periodontitis, but do suggest that SNPs in
      the second extracellular loop may be etiologically important.

PMID- 12595899
TI  - Genetic polymorphisms in mouse genes regulating age-sensitive and age-stable T
      cell subsets.
AB  - To see whether genetic polymorphisms regulate inter-individual differences in T
      cell subset levels, we have conducted a genome scan in two populations of mice,
      bred as the progeny of a cross between CB6F1 females and C3D2F1 males. The data
      document quantitative trait loci (QTL) with statistically significant effects on
      CD4, CD8, and CD8 memory T cells, and on subsets of CD4 and CD8 T cells that
      express P-glycoprotein. Some of the loci detected were robust, in the sense that
      they produced effects of similar size both in mated female mice, and in a
      population that included male and female virgin animals. Some of the effects were
      stable, in that they were apparent at both 8 and 18 months of age, but others
      were age-specific, showing effects either at 8 or at 18 months but not at both
      ages. Genes that had an effect on the same T cell subset were in almost all cases
      additive rather than epistatic, and their combined effects could produce large
      overall effects, leading in the most dramatic case to a two-fold difference in
      CD8 memory cells. The analysis also documented two QTL, on chromosomes 4 and 13,
      that regulate an age-sensitive composite index of T cell subset pattern which has
      been shown previously to be a predictor of life expectancy in these mice. The
      analysis thus reveals both subset-specific genes and others which modulate the
      overall pattern of age-sensitive changes in T cell subset distributions.

PMID- 12595900
TI  - DOK4 and DOK5: new Dok-related genes expressed in human T cells.
AB  - Dok proteins are adapter proteins involved in signal transduction. Several
      intracellular proteins expressed in lymphocytes meet the criteria of membrane
      associated adapter proteins such as members of the Dok family. To understand the
      role and the formation of multiprotein networks involving Dok proteins in T
      lymphocytes, we search for potential additional members of this family. Here, we
      describe the two new human dok-related genes DOK4 and DOK5 and present data
      showing the expression of DOK4 and DOK5 genes in T cells. These genes are the
      orthologues of mouse Dok4 and Dok5 genes. Based on analysis of phylogenetic trees
      and exon/intron structure of Dok family members, DOK4 and DOK5 define a subfamily
      within dok genes distinct from DOK1, DOK2 and DOK3. So, Dok-4 and Dok-5 molecules
      constitute a new group of adapter proteins in T cells, requiring further
      functional analysis.

PMID- 12595902
TI  - Cloning and characterization of human complement component C7 promoter.
AB  - To study the transcriptional regulation of the human complement component C7, a 1
      kb promoter fragment was cloned and the transcription start site was determined.
      C7 is expressed by the hepatoma-derived cell line Hep-3B, but not by Hep-G2.
      Transfection of these cell lines with different C7 promoter-luciferase constructs
      demonstrated that 1 kb of the 5'-flanking region contains the necessary elements
      for driving C7 transcription in a tissue-specific manner and showed that the
      sequence between -29/+102 retained the majority of C7 promoter activity in Hep
      3B. Electrophoretic mobility shift assays suggested that the binding of the
      C/EBPalpha transcription factor to a C/EBP sequence located at +42 is essential
      for C7 expression. To investigate whether the absence of C/EBPalpha expression in
      Hep-G2 cells is responsible for the lack of C7 transcription, Hep-G2 cells were
      transfected with a C/EBPalpha expression vector. C/EBPalpha transactivated the C7
      luciferase reported gene and restored the C7 expression in Hep-G2 cells.

PMID- 12595901
TI  - Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex
      distinct from HLA-DQB1, -DQA1 and -DRB1.
AB  - Susceptibility to, and protection against development of type 1 diabetes (T1D)
      are primarily associated with the highly polymorphic exon 2 sequences of the HLA
      class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested
      that additional genes in the HLA complex influence T1D risk, albeit to a lesser
      degree than the class II genes. We have previously shown that allele 3 of
      microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I
      region, is associated with a reduction in risk conferred by the DQ2-DR3
      haplotype. Here we replicate this finding in two populations from Sweden and
      France. We also show that markers in the HLA class II, III and centromeric class
      I regions contribute to the DQ2-DR3 associated risk of T1D, independently of
      linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated
      gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a
      region of strong LD. By haplotype mapping, we have located the most likely
      location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region
      between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.

PMID- 12595903
TI  - Loss of a single allele of SHIP exacerbates the immunopathology of Pten
      heterozygous mice.
AB  - Phosphatidylinositol 3-kinase (PI3K) has emerged as a critical component of
      multiple immune system intracellular signalling pathways. The levels and relative
      ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P(2))
      and phosphatidylinositol (3,4,5) trisphosphate (PIP(3)), are regulated by
      inositol phosphatases such as Pten and SHIP. Interestingly, mice heterozygous for
      Pten, a 3'-inositol phosphatase, develop a progressive lymphoproliferative
      syndrome with autoimmune features. Given the importance of PIP(3) species in
      regulating immune responses, we hypothesized that heterozygosity for the 5'
      inositol phosphatase SHIP might exacerbate the autoimmune phenotype of Pten(+/-)
      mice. In keeping with this, mice heterozygous for both Pten and SHIP developed
      lymphoproliferation, hypergammaglobulinaemia, autoantibody titres and renal
      pathology that were more severe than that of Pten(+/-) mice. These results
      suggest that the relative levels of phosphatidylinositol phosphatases are likely
      critical to immune system homeostasis and they also highlight the potential for
      gene dosage effects in regulating susceptibility and/or severity of autoimmunity.

PMID- 12595904
TI  - Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families
      displaying mixed leprosy subtypes.
AB  - Each year an estimated 600000 new leprosy cases are diagnosed worldwide. The
      spectrum of the disease varies widely from limited tuberculoid forms to extensive
      lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy
      is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To
      address a postulated oligogenic control of leprosy pathogenesis, we investigated
      in the present study linkage of leprosy susceptibility, leprosy clinical
      subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying
      known or suspected leprosy susceptibility loci. The only significant result
      obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human
      chromosome 6p21 (P(corrected)=0.00126). In addition, we established that within
      the same family different HLA/TNF haplotypes segregate into patients with
      different leprosy subtypes directly demonstrating the importance of this genome
      region for the control of clinical leprosy presentation.

PMID- 12595905
TI  - Interleukin 10 polymorphisms in ankylosing spondylitis.
AB  - Genetic polymorphisms of the IL10 promoter region have been implicated in many
      autoimmune diseases, including seronegative spondyloarthropathies. We studied
      three SNPs (IL10-1087, -824, and -597) and two microsatellites (IL10R and IL10G)
      lying within the promoter region of IL10 for association with susceptibility to
      and clinical manifestations of ankylosing spondylitis (AS), a common form of
      spondyloarthritis. Four hundred and sixty-eight individuals from 182 Finnish
      families affected with AS were studied. No association between individual IL10
      promoter region polymorphisms or marker haplotype was observed with
      susceptibility to AS, but weak association was noted between the IL10-597 and 
      824 SNPs and age of disease onset (P=0.01 for each SNP). The IL10.G4 allele was
      associated with BASFI (corrected for disease duration) (P=0.03). We conclude that
      IL10 promoter polymorphisms have no significant effect on susceptibility to AS,
      but may play a minor role in determining age of disease onset and disease
      severity.

PMID- 12595906
TI  - CARD15 gene mutations are not associated with ankylosing spondylitis.
AB  - An insertion mutation at nucleotide 3020 (3020insC) and a missense mutation
      G2722C in the CARD15 gene on chromosome 16p have been reported to be associated
      with Crohn's disease (CD). The protein encoded by the CARD15 gene is expressed in
      peripheral monocytes and regulates apoptosis and NF-kappaB activation, factors
      which play an important role in inflammation. Since CD and ankylosing spondylitis
      (AS) are interrelated disorders, we have investigated whether these mutations in
      the CARD15 gene are also associated with AS. We studied 113 unrelated AS patients
      and 152 unrelated healthy controls. No significant differences were found between
      patients and controls in the prevalence of the insertion 3020insC mutation and
      the G2722C missense mutation, OR = 1.36, 95% CI: 0.27-6.84, P = 0.70 and OR =
      0.58; 95% CI: 0.18-1.94; P = 0.38, respectively. We conclude that the insertion
      3020insC mutation and the G2722C missense mutation in the CARD15 gene are not
      involved in the susceptibility to AS.

PMID- 12595907
TI  - 77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis:
      evidence for a genetic link.
AB  - Autoimmune hepatitis is a chronic immune-mediated disease characterized by a loss
      of tolerance against liver resident antigens. The genetic background of
      autoimmune hepatitis is considered to be polygenic. Here we analyzed the genetic
      association of the tyrosine phosphatase CD45 and autoimmune hepatitis. CD45 plays
      an important role in normal antigen receptor mediated signaling in T and B cells.
      A point mutation at nucleotide position 77 of the CD45 gene results in abnormal
      CD45 splicing. In this study a significantly higher frequency of the 77 C/G
      genotype was observed in 190 autoimmune hepatitis patients when compared to 210
      healthy blood donors. Our data identify CD45 as a gene associated with AIH, and
      further substantiates the hypothesis that CD45 represents a modifier gene of
      human autoimmunity.

PMID- 12595908
TI  - Variation in immune response genes and chronic Q fever. Concepts: preliminary
      test with post-Q fever fatigue syndrome.
AB  - Acute primary Q fever is followed by various chronic sequelae. These include
      subacute Q fever endocarditis, granulomatous reactions in various organs or a
      prolonged debilitating post-infection fatigue syndrome (QFS). The causative
      organism, Coxiella burnetii, persists after an initial infection. The differing
      chronic outcomes may reflect variations within cytokine and accessory immune
      control genes which affect regulation of the level of persistence. As a
      preliminary test of the concept we have genotyped QFS patients and controls for
      gene variants spanning 15 genes and also examined HLA-B and DR frequencies. QFS
      patients exhibited a significantly increased frequency of HLA-DR-11 compared with
      controls and also significant differences in allelic variant frequencies within
      the NRAMP, and IFNgamma genes. These results indicate a possible genetic role in
      the expression of overt chronic Q fever. Further studies will be undertaken to
      increase sample sizes, to survey other forms of chronic Q fever and to examine Q
      fever patients who have recovered without sequelae.

PMID- 12595910
TI  - Dehydroepiandrosterone (DHEA) and the aging brain: flipping a coin in the
      "fountain of youth".
AB  - The physiological role of dehydroepiandrosterone (DHEA) and its sulphated ester
      DHEA(S) has been studied for nearly 2 decades and still eludes final
      clarification. The major interest in DHEA derives from its unique pattern of
      activity. Its levels exhibit a dramatic age-related decline that supports
      significant involvement of DHEA(S) in the aging process. Particularly relevant to
      the aging process is the functional decline that involves memory and cognitive
      abilities. DHEA is derived mainly from synthesis in the adrenal glands and
      gonads. It can also be detected in the brain where it is derived from a synthesis
      that is independent from peripheral steroid sources. For this reason DHEA and
      other steroid molecules have been named "neurosteroids." Pharmacological studies
      on animals provided evidence that neurosteroids could be involved in learning and
      memory processes because they can display memory-enhancing properties in aged
      rodents. However, human studies have reported contradictory results that so far
      do not directly support the use of DHEA in aging-related conditions. As such, it
      is important to remember that plasma levels of DHEA(S) may not reflect levels in
      the central nervous system (CNS), due to intrinsic ability of the brain to
      produce neurosteroids. Thus, the importance of neurosteroids in the memory
      process and in age-related cognitive impairment should not be dismissed.
      Furthermore, the fact that the compound is sold in most countries as a health
      food supplement is hampering the rigorous scientific evaluation of its potential.
      We will describe the effect of neurosteroids, in particular DHEA, on
      neurochemical mechanism involved in memory and learning. We will focus on a novel
      effect on a signal transduction mechanism involving a classical "cognitive
      kinase" such as protein kinase C. The final objective is to provide additional
      tools to understand the physiological role and therapeutic potentials of
      neurosteroids in normal and/or pathological aging, such as Alzheimer's disease.

PMID- 12595909
TI  - SL651498, a GABAA receptor agonist with subtype-selective efficacy, as a
      potential treatment for generalized anxiety disorder and muscle spasms.
AB  - SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H
      pyrido[3,4-b]indol-1-one) was identified as a drug development candidate from a
      research program designed to discover subtype-selective GABA(A) receptor agonists
      for the treatment of generalized anxiety disorder and muscle spasms. The drug
      displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i)
      = 6.8 nM) and alpha(2) (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5
      containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A)
      receptors confirm these findings and indicate intermediate affinity for the
      alpha(3)beta(2)gamma(2) subtype. SL651498 behaves as a full agonist at
      recombinant rat GABA(A) receptors containing alpha(2) and alpha(3) subunits, and
      as a partial agonist at recombinant GABA(A) receptors expressing alpha(1) and
      alpha(5) subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant
      effects qualitatively similar to those of benzodiazepines (BZs) [minimal
      effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However,
      unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation
      at doses much higher than those having anxiolytic-like activity (MED: 30 to 100
      mg/kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce
      tolerance to its anticonvulsant activity or physical dependence. It was much less
      active than BZs in potentiating the depressant effects of ethanol or impairing
      cognitive processes in rodents. The differential profile of SL651498 as compared
      to BZs may be related to its selective efficacy at the alpha(2)- and alpha(3)
      containing GABA(A) receptors. This suggests that selectively targeting GABA(A)
      receptor subtypes can lead to drugs with increased clinical specificity. SL651498
      represents a promising alternative to agents currently used for the treatment of
      anxiety disorders and muscle spasms without the major side effects seen with
      classical BZs.

PMID- 12595911
TI  - JL 13, an atypical antipsychotic: a preclinical review.
AB  - The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic
      drug has revealed a close similarity to clozapine, however with some major
      advantages. JL 13 was characterized as a weak D(2) antagonist, both in vitro and
      in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has
      no affinity for the 5-HT(2C) receptor. In vivo microdialysis experiments in rat
      showed that JL 13, like clozapine, preferentially increased extracellular
      dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or
      striatum. Behavioral studies showed that JL 13, like clozapine, has the profile
      of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced
      stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced
      climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but
      antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the
      paw test, it was more effective in prolonging hindlimb retraction time than
      prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13
      reversed the apomorphine- and amphetamine-induced disruption of prepulse
      inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a
      high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or
      any significant motor side effects. In rats and squirrel monkeys JL 13 induced a
      high degree of generalization (70%) to clozapine. Regarding behavioral
      toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in
      haloperidol-sensitized monkeys. After acute administration, again like clozapine,
      JL 13 induced only a transient increase in circulating prolactin. Last but not
      the least, regarding a possible hematological toxicity, unlike clozapine, JL 13
      did not present sensitivity to peroxidase-induced oxidation. Moreover, its
      electrooxidation potential was close to that of loxapine and far from that of
      clozapine. Taking all these preclinical data into account, it appears that JL 13
      is a promising atypical antipsychotic drug.

PMID- 12595912
TI  - The pharmacology of CP-154,526, a non-peptide antagonist of the CRH1 receptor: a
      review.
AB  - Since CRH has been shown to mediate stress-induced physiological and behavioral
      changes, it has been hypothesized that CRH receptor antagonists may have
      therapeutic potential in disorders that involve excessive CRH activity. CP
      154,526 and its close analog antalarmin are potent, brain-penetrable, selective
      nonpeptide CRH1 receptor antagonists that were discovered in an effort to develop
      compounds with efficacy in CNS disorders precipitated by stress. Since its
      discovery many investigators have used CP-154,526 as a tool to study the
      pharmacology of CRH and its receptors and to evaluate its therapeutic potential
      in a variety of CNS and peripheral disorders. Systemically-administered CP
      154,526 has been demonstrated to antagonize CRH- and stress-induced
      neuroendocrine, neurochemical, electrophysiological, and behavioral effects.
      These findings support the hypothesis that CRH1 receptor antagonists may have
      therapeutic utility in a number of neuropsychiatric disorders. CP-154,526, as
      well as other CRH1 receptor antagonists that have since been discovered, have
      also shown activity in several preclinical models of anxiety, depression, and
      substance abuse, while having little effect on locomotor activity and motor
      function. Although these effects are on occasion inconsistent among different
      laboratories, clinical evaluation of CRH1 antagonists appears justified on the
      basis of these and clinical data implicating the involvement of CRH in several
      CNS disorders. The effects of CRH1 antagonists on cognition, neurodegeneration,
      inflammation, and the gastrointestinal system have not been as extensively
      characterized and additional studies will be necessary to evaluate their
      therapeutic potential in these areas.

PMID- 12595914
TI  - Enrasentan, an antagonist of endothelin receptors.
AB  - Endothelins are powerful vasoconstrictor agents produced by endothelial cells and
      identified by Yanagisawa et al. in 1988. Two types of receptors for endothelins
      have been identified: ET(A) receptors are located on smooth muscle cells of the
      vascular wall and are responsible for endothelin-induced vasoconstriction while
      ET(B) receptors are located on endothelial cells and induce these cells to
      release NO and prostacyclin. Moreover, these peptides not only cause a potent and
      prolonged vasoconstriction but are also known to enhance cell proliferation and
      to stimulate extracellular matrix accumulation. High levels of plasma or tissue
      endothelins have been found in patients with heart failure, diabetes, stroke,
      primary pulmonary hypertension, liver cirrhosis and other diseases. Given these
      effects of endothelins, blocking their receptors might be a new way to reduce
      blood pressure and to treat other illnesses. Accordingly, many endothelin
      antagonists have been developed and evaluated in animals and humans. Enrasentan
      is a mixed ET(A) and ET(B) receptor antagonist with a higher affinity for ET(A)
      receptors, although it cannot be considered a selective antagonist. In an animal
      model of hypertension and cardiac hypertrophy the drug has reduced blood
      pressure, prevented cardiac hypertrophy and preserved myocardial function. In
      rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure
      and prevented cardiac and renal damage. In rats with stroke the drug reduced the
      ischemic area in the brain. Enrasentan has been added to conventional treatment
      in patients with heart failure (NYHA Class 2-3) and no addictive effect of the
      drug has been observed. This is in contrast with results obtained in animal
      models and still has not been explained. In conclusion, many possible clinical
      applications can be suggested for this drug, but further studies are necessary to
      better evaluate its therapeutic efficacy.

PMID- 12595913
TI  - Moclobemide: therapeutic use and clinical studies.
AB  - Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been
      extensively evaluated in the treatment of a wide spectrum of depressive disorders
      and less extensively studied in anxiety disorders. Nearly all meta-analyses and
      most comparative studies indicated that in the acute management of depression
      this drug is more efficacious than placebo and as efficacious as tricyclic (or
      some heterocyclic) antidepressants or selective serotonin reuptake inhibitors
      (SSRIs). There is a growing evidence that moclobemide is not inferior to other
      antidepressants in the treatment of subtypes of depression, such as dysthymia,
      endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded
      depression as with other antidepressants limited evidence suggests that
      moclobemide has consistent long-term efficacy. However, more controlled studies
      addressing this issue are needed. For patients with bipolar depression the risk
      of developing mania seems to be not higher with moclobemide than with other
      antidepressants. The effective therapeutic dose range for moclobemide in most
      acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one
      controlled trial and one long-term open-label study found moclobemide to be
      efficacious in social phobia, three controlled trials subsequently revealed
      either no effect or less robust effects with the tendency of higher doses (600 -
      900 mg/d) to be more efficacious. Two comparative trials demonstrated moclobemide
      to be as efficacious as fluoxetine or clomipramine in patients suffering from
      panic disorder. Placebo-controlled trials in this indication are, however, still
      lacking. A relationship between the plasma concentration of moclobemide and its
      therapeutic efficacy is not apparent but a positive correlation with adverse
      events has been found. Dizziness, nausea and insomnia occurred more frequently on
      moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic
      actions, moclobemide has been better tolerated than tri- or heterocyclic
      antidepressants. Gastrointestinal side effects and, especially, sexual
      dysfunction were much less frequent with moclobemide than with SSRIs. Unlike
      irreversible MAO-inhibitors, moclobemide has a negligible propensity to induce
      hypertensive crisis after ingestion of tyramine-rich food ("cheese-reaction").
      Therefore, dietary restrictions are not as strict. However, with moclobemide
      doses above 900 mg/d the risk of interaction with ingested tyramine might become
      clinically relevant. After multiple dosing the oral bioavailability of
      moclobemide reaches almost 100%. At therapeutic doses, moclobemide lacks
      significant negative effects on psychomotor performance, cognitive function or
      cardiovascular system. Due to the relative freedom from these side effects,
      moclobemide is particularly attractive in the treatment of elderly patients.
      Moclobemide is a substrate of CYP2C19. Although it acts as an inhibitor of
      CYP1A2, CYP2C19, and CYP2D6, relatively few clinically important drug
      interactions involving moclobemide have been reported. It is relatively safe even
      in overdose. The drug has a short plasma elimination half-life that allows
      switching to an alternative agent within 24 h. Since it is well tolerated,
      therapeutic doses can often be reached rapidly upon onset of treatment. Steady
      state plasma levels are reached approximately at one week following dose
      adjustment. Patients with renal dysfunction require no dose reduction in contrast
      to patients with severe hepatic impairment. Cases of refractory depression might
      improve with a combination of moclobemide with other antidepressants, such as
      clomipramine or a SSRI. Since this combination has rarely been associated with a
      potentially lethal serotonin syndrome, it requires lower entry doses, a slower
      dose titration and a more careful monitoring of patients. Combination therapy
      with moclobemide and other serotonergic agents, or opioids, should be undertaken
      with caution, although no serious adverse events have been published with
      therapeutic doses of moclobemide to date. On the basis of animal data the
      combined use of moclobemide with pethidine or dextropropoxyphene should be
      avoided. There is no evidence that moclobemide would increase body weight or
      produce seizures. Some preclinical data suggest that moclobemide may have
      anticonvulsant property.

PMID- 12595915
TI  - Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen
      exchanger isoform 1 (NHE-1).
AB  - The sodium-hydrogen exchanger isoform-1 (NHE-1) plays an important role in the
      myocardial response to ischemia-reperfusion; inhibition of this exchanger
      protects against ischemic injury, including reduction in infarct size. Herein we
      describe a novel, potent, and highly selective NHE-1 inhibitor, zoniporide (CP
      597,396; [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl] guanidine).
      Zoniporide inhibits human NHE-1 with an IC(50) of 14 nM, has >150-fold
      selectivity vs. other NHE isoforms, and potently inhibits ex vivo NHE-1-dependent
      swelling of human platelets. This compound is well tolerated in preclinical
      animal models, exhibits moderate plasma protein binding, has a t(1/2) of 1.5 h in
      monkeys, and has one major active metabolite. In both in vitro and in vivo rabbit
      models of myocardial ischemia-reperfusion injury, zoniporide markedly reduced
      infarct size without adversely affecting hemodynamics or cardiac function. In the
      isolated heart (Langendorff), zoniporide elicited a concentration-dependent
      reduction in infarct size (EC(50) = 0.25 nM). At 50 nM it reduced infarct size by
      83%. This compound was 2.5-20-fold more potent than either eniporide or
      cariporide (EC(50)s of 0.69 and 5.11 nM, respectively), and reduced infarct size
      to a greater extent than eniporide. In open chest, anesthetized rabbits,
      zoniporide also elicited a dose-dependent reduction in infarct size (ED(50) =
      0.45 mg/kg/h) and inhibited NHE-1-mediated platelet swelling (93% inhibition at 4
      mg/kg/h). Furthermore, zoniporide attenuated postischemic cardiac contractile
      dysfunction in conscious primates, and reduced both the incidence and duration of
      ischemia-reperfusion-induced ventricular fibrillation in rats. Zoniporide
      represents a novel class of potent and selective human NHE-1 inhibitors with
      potential utility for providing cardioprotection in a clinical setting.

PMID- 12595916
TI  - Pharmacology of the ACAT inhibitor avasimibe (CI-1011).
AB  - Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical
      development (phase III trials). It was safe when administered to rats, dogs, and
      humans. In vitro studies in human macrophages demonstrated that avasimibe reduces
      foam cell formation not only by enhancing free cholesterol efflux, but also by
      inhibiting the uptake of modified LDL. The concentration-dependent reduction in
      cellular cholesteryl ester content in these cells was not accompanied by an
      increase in intracellular free cholesterol, which is in agreement with a good
      safety profile for avasimibe. In the liver, avasimibe caused a significant
      reduction in the secretion of apo B and apo B-containing lipoproteins into
      plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid
      synthesis in cultured rat hepatocytes, and its administration to rats did not
      produce an increase in lithogenicity index of the bile. The hypolipidemic
      efficacy of the compound was demonstrated in cholesterol-fed as well as in non
      cholesterol-fed animals. In these models, plasma cholesterol levels were reduced,
      mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are
      scarce, but in a study performed in 130 men and women with combined
      hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day,
      significantly reduced plasma total triglyceride and VLDL-cholesterol. Although
      total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must
      be stressed that animal data suggest that avasimibe may have direct
      antiatherosclerotic activity in addition to its cholesterol-lowering effect.
      Avasimibe treatment can also contribute to increase plaque stability, as it
      reduces the accumulation of lipids in the arterial wall, inhibits macrophage
      infiltration into the media and reduces matrix metalloproteinase expression and
      activity. Moreover, avasimibe and statins have been shown to have synergistic
      effects, and the combination therapy may not only inhibit atherosclerotic lesion
      progression but also induce lesion regression, independently of changes in plasma
      cholesterol.

PMID- 12595917
TI  - Dual ACE and NEP inhibitors: a review of the pharmacological properties of MDL
      100240.
AB  - The Angiotensin I converting enzyme (ACE, EC 3.4.14.1, kininase II) and neutral
      endopeptidases (NEP, NEP 24.11) are mechanistically related metallopeptidases.
      They play a key role in the regulation of blood pressure, body fluid homeostasis
      and cell growth. Therefore, they are implicated in the pathogenesis of arterial
      hypertension, congestive heart failure, left ventricular remodeling after
      myocardial infarction and other cardiovascular diseases. Furthermore, since these
      two metallopeptidases possess some subsite and substrate similarities, as
      indicated by their interaction with certain mercaptoalkanoyl inhibitors, they are
      regarded as an important common target for pharmacological inhibition with a
      single drug. MDL 100240 is a pro-drug that, upon conversion to MDL 100173, acts
      as a potent dual inhibitor of ACE and NEP with a balanced activity on both
      enzymes. Only very limited pharmacokinetic studies with MDL 100240 have been
      published. These studies used a high pressure liquid chromatography method with
      UV absorbance detection to quantify the drug. According to the studies in dogs
      the terminal t(1/2) of MDL 100173 was 35.7 h. The area under the curve for total
      MDL 100173 was nearly 10-fold greater than the sum of the areas under the curve
      for MDL 100240 and for unconjugated MDL 100173. These results support the
      hypothesis that MDL 100240 is hydrolyzed in plasma to the active thiol, MDL
      100173, which is rapidly conjugated with endogenous plasma thiols thus providing
      a pathway for elimination. Studies in vivo in experimental models of hypertension
      and congestive heart failure confirmed the vasodilatory and natriuretic effects
      of MDL, which appear to be independent of the degree of activation of the renin
      angiotensin-aldosterone system. In addition, MDL 100240 showed an impressive
      effectiveness both in preventing and in regressing hypertension-induced vascular
      remodeling and cardiac hypertrophy. Accordingly, MDL 100240 is being developed
      for the treatment of cardiovascular diseases, including hypertension and
      congestive heart failure. If the promises of this novel therapeutic strategy are
      fulfilled, clinical trials are expected to demonstrate advantages of MDL 100240
      over pure ACE inhibitors.

PMID- 12595918
TI  - The P2Y(1) receptor as a target for new antithrombotic drugs: a review of the
      P2Y(1) antagonist MRS-2179.
AB  - MRS-2179 is a selective P2Y(1) receptor antagonist, a strong inhibitor of ADP
      induced platelet aggregation in vitro and ex vivo. By i.v. administration to mice
      MRS-2179 increases resistance to thromboembolism induced by a mixture of collagen
      and epinephrine or by a tissue factor. Likewise, it significantly increases the
      time to thrombus formation in a ferric chloride-induced model of localized
      arterial thrombosis. MRS-2179 also confers resistance to localized venous
      thrombosis, which is dependent on thrombin generation and in which platelets play
      a relatively minor role as compared to stasis or activation of coagulation. These
      data provide considerable encouragement for the development of new P2Y(1)
      receptor antagonists. Nevertheless, the properties of MRS-2179 indicate that new
      compounds should be optimized in order to increase the half-life of the molecule
      in vivo and its selectivity and potency at the P2Y(1) receptor. Further
      directions include the synthesis of molecules with modifications of the
      nucleotide structure which replace the fragile moiety by a stable bond and should
      lead to a non-hydrolysable structure. In conclusion, P2Y(1) antagonists have been
      shown to be efficient antithrombotic agents. MRS-2179 is the first P2Y(1)
      antagonist with antithrombotic action. Its effectiveness demonstrates that the
      P2Y(1) receptor is a potentially promising target for drugs designed to treat
      thrombotic syndromes.

PMID- 12595919
TI  - NTP Initiation/Promotion Study of o-Benzyl-p-Chlorophenol (CAS No. 120-32-1) in
      Swiss (CD-1(R)) Mice (Mouse Skin Study).
AB  - o-Benzyl-p-chlorophenol (BCP), an aryl halide, is a broad spectrum germicide used
      in disinfectant solutions and soap formulations in United States hospitals and
      households. Human exposure to BCP occurs by absorption through the skin and
      mucous membranes and by ingestion. BCP was studied because of the widespread
      human exposure and because BCP is an irritant and certain phenolic compounds are
      weak promoters of skin neoplasia. Groups of Swiss (CD-1(R)) mice were used to
      study BCP in a 1-year mouse skin initiation/promotion protocol. Genetic
      toxicology studies were conducted in Salmonella typhimurium and cultured Chinese
      hamster ovary cells. 1-YEAR INITIATION/PROMOTION STUDY: Groups of 50 male and 50
      female Swiss (CD-1(R)) mice were topically exposed to BCP to study its effect as
      an initiator, promoter, and complete carcinogen. A number of control groups were
      included in these studies as a reference for the responses of the mouse skin to o
      -benzyl- p -chlorophenol (see following table). See report abstract or full
      report for Dose Regimen for Reference Controls in the 1-Year Initiation/Promotion
      Study of o -Benzyl- p - Chlorophenol. BCP in acetone was tested as an initiator
      with the promoter 12- O -tetradecanoylphorbol-13-acetate (TPA). The potential of
      BCP as an initiator was studied by applying a single 100 mL dose of BCP in
      acetone at a concentration of 10 mg/mL to the dorsal interscapular region of the
      backs of mice during week 1 of the study. Following the initial BCP application,
      mice were administered promoting doses of 5 mg TPA three times per week in 100 mL
      acetone for the first 6 months of the study and once weekly for the final 6
      months of the study. BCP in acetone was tested as a promoter with the initiator
      7,12-dimethylbenz(a)anthracene (DMBA). Mice were administered a single initiating
      dose of 50 mL DMBA in 100 mL acetone. Beginning on the second week of the study,
      mice received 100 mL applications of 0.1, 1.0, or 3.0 mg BCP in acetone three
      times weekly for up to 51 weeks. Comparative control groups used during the study
      of BCP as a promoter included: vehicle control (acetone/acetone); promoter
      control (TPA/TPA); and initiator control (DMBA/acetone). The potential for BCP to
      act as a complete carcinogen was studied by applying a single initiating dose of
      10 mg BCP in 100 mL of acetone, followed by tri-weekly 100 mL applications of
      0.1, 1.0, or 3.0 mg BCP to 50 male and 50 female Swiss (CD-1(R)) mice for 52
      weeks. The responses of these groups were compared to vehicle control
      (acetone/acetone) and complete carcinogen control (acetone/DMBA) groups. The
      following table shows the various groups with BCP as a promoter, an initiator,
      and as a complete carcinogen. See full report or abstract for Dose Regimen in the
      1-Year Initiation/Promotion Study of o - Benzyl- p -Chlorophenol. Results in the
      Study of BCP as a Complete Carcinogen: BCP acted as an irritant when tested as a
      complete carcinogen using a single initiating dose of 10 mg BCP followed by
      repetitive applications of 0.1, 1.0, or 3.0 mg BCP for up to 52 weeks, and many
      of the mice developed cutaneous lesions of scaling/crusts and ulceration. During
      the course of the study, a single papilloma was first observed after 12 weeks in
      one 0.1 mg BCP male mouse. One 3.0 mg BCP female was observed with a papilloma at
      week 10, and three 0.1 mg BCP females were observed with papillomas between weeks
      22 and 27. No mice administered BCP/BCP had papillomas at the end of the study,
      and no malignant cutaneous epithelial tumors were observed at the application
      sites on any BCP/BCP mice. Thus, in the present study, BCP was not a complete
      carcinogen. Results in the Study of BCP as an Initiator: One vehicle control
      (acetone/acetone) male mouse had developed crusts at the site of application at
      necropsy, but no male or female vehicle controls had developed papillomas. Mice
      administered BCP/TPA developed application site lesions including scaling/crusts,
      ulceration, and irritation; the incidences of these lesions were similar to those
      in the initiator/promoter control (DMBA/TPA) /TPA) groups. After 22 weeks
      papillomas were observed in 12/50 male mice administered BCP/TPA. After 12 weeks
      papillomas were observed in 7/50 female mice administered BCP/TPA. However, the
      incidences of papillomas in mice administered BCP/TPA were lower than those in
      mice administered TPA/TPA (males, 16/50; females, 16/50) and were much lower than
      those in DMBA/TPA mice (males, 40/50; females, 48/50). Although the incidences of
      papillomas in mice administered BCP as an initiator were significantly greater
      than those in the vehicle controls, the incidences were not significantly
      different from those in TPA/TPA mice. Thus, in the present study, BCP did not
      demonstrate initiating potential. Results in the Study of BCP as a Promoter:
      During the course of the study, incidences of scaling and/or crusts, ulceration,
      and irritation were observed at the site of application in DMBA/BCP male and
      female mice, and the incidences were dose-related. Incidences of scaling and/or
      crusts, ulceration, and irritation in 3.0 mg BCP mice were similar to the
      incidences of these lesions in initiator/promoter control (DMBA/TPA) group, but
      much higher than the incidences of these lesions in the initiator control
      (DMBA/acetone) group. A dose-related increased incidence of papillomas was
      observed in males (DMBA/acetone, 8/50; DMBA/0.1 mg BCP, 3/50;DMBA/1.0 mg BCP,
      5/50; and DMBA/3.0 mg BCP, 14/50) and females (2/50, 6/50, 6/50, and 18/50). The
      incidence of papillomas in DMBA/3.0 mg BCP females was significantly greater
      (P<0.001) than that in DMBA/acetone females; the incidence of papillomas in
      DMBA/3.0 mg BCP males was marginally increased (P=0.077). No acetone/acetone mice
      developed papillomas. Although a higher percentage of DMBA/3.0 mg BCP mice
      developed papillomas over the course of the study than did DMBA/acetone controls,
      the time it took for half of the number of responding animals to develop
      papillomas was similar between DMBA/acetone groups and DMBA/3.0 mg BCP groups
      (DMBA/acetone males, week 38; DMBA/acetone females, week 34; DMBA/3.0 mg BCP
      males, week 36; DMBA/3.0 mg BCP females, week 37). However, the time to
      appearance of the first papilloma was shorter in DMBA/3.0 mg BCP mice (males,
      week 18; females, week 10) than in DMBA/acetone mice (males, week 26; females,
      week 27). BCP was considered to have promotion potential because the incidences
      of papillomas in mice treated with DMBA/3.0 mg BCP were greater than those in
      DMBA/acetone (initiator control) mice and because topical exposure to BCP alone
      caused no significant increased incidence of papillomas. However, the incidences
      of papillomas in DMBA/3.0 mg BCP mice (males, 14/50; females, 18/50) were much
      less than the incidences in DMBA/TPA (promoter control) mice (males, 40/50;
      females, 48/50); thus, BCP was classified as a weak promoter. GENETIC TOXICOLOGY:
      o -Benzyl- p -chlorophenol did not induce gene mutations in Salmonella
      typhimurium strains TA98, TA100, TA1535, or TA1537, and it did not induce sister
      chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary
      cells. All tests were performed with and without S9 activation. CONCLUSIONS:
      Under the conditions of this 1-year mouse skin initiation/promotion study in
      Swiss (CD-1&reg;) mice, o -benzyl- p -chlorophenol was a cutaneous irritant and a
      weak skin tumor promoter relative to strong promoters such as TPA. BCP had no
      activity as an initiator or as a complete carcinogen.

PMID- 12595920
TI  - NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss
      Webster and B6C3F1 Mice (Feed Studies).
AB  - Oxazepam is one of a number of benzodiazepines used therapeutically as a sedative
      hypnotic and antianxiety agent. Toxicology and carcinogenesis studies were
      performed by administering oxazepam (greater than 99% pure) in feed to male and
      female Swiss-Webster and B6C3F1 mice for 14 weeks, 57 weeks (Swiss-Webster), or 2
      years (B6C3F1). Neurobehavioral assessments were performed during the studies.
      Genetic toxicology studies were conducted in Salmonella typhimurium and cultured
      Chinese hamster ovary cells, and peripheral blood samples were analyzed for
      frequency of micronucleated normochromatic erythrocytes. Supplemental studies
      were performed to compare the metabolism and toxicokinetics of oxazepam in the
      two mouse strains, to evaluate the effect on liver cell replication rates, to
      perform clinical pathology assessments, and to examine the mutation spectrum and
      frequency of activated H-ras oncogenes in liver neoplasms from the 2-year study
      with B6C3F1 mice. 14-WEEK STUDY IN SWISS-WEBSTER MICE: Groups of 10 male and 10
      female Swiss-Webster mice received oxazepam in feed at concentrations of 0, 625,
      1,250, 5,000, 10,000 ppm for 14 weeks. One 625 ppm male and one 10,000 female
      were killed moribund before the end of the study, and the condition of the female
      mouse was attributed to oxazepam exposure. Mean body weight gains of exposed
      groups were similar to those of the controls. Exposed mice displayed chemical
      related sedation and lethargy during the first study week, but appeared normal
      thereafter. In the neurobehavioral studies, reductions in grip strength were
      evident in both male and female mice at week 2 and persisted in males through
      week 11. An antianxiety effect was detected in exposed mice in measures of motor
      activity, startle response, and reactions to thermal stimulus. At necropsy,
      absolute and relative liver weights were increased in an exposure-related manner
      and were approximately two-fold greater in 10,000 ppm mice than in controls.
      Centrilobular hepatocellular hypertrophy was present only in exposed mice, and
      the severity increased with dose. 14-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male
      and 10 female B6C3F1 mice received oxazepam in feed at concentrations of 0,
      Groups of 10 male and 10 female Swiss-Webster mice 625, 1,250, 2,500, 5,000, or
      10,000 ppm for 14 weeks. received oxazepam in feed at concentrations of 0, There
      were no deaths that were clearly related to 625,1,250, 2,500, 5,000, or 10,000
      ppm for 14 weeks. oxazepam exposure. Mean body weight gains of One 625 ppm male
      and one 10,000 ppm female were exposed groups were similar to those of the
      controls. Exposed mice displayed chemical-related sedation and lethargy during
      only the first study week. In neurobehavioral studies, reductions in grip
      strength were evident in males at week 2 but were no longer observed at week 12.
      An antianxiety effect was noted in exposed mice in measures of motor activity,
      startle response, and reactions to a thermal stimulus (females). At necropsy,
      absolute and relative liver weights were increased in an exposure-related manner
      and were approximately two-fold greater in 10,000 ppm mice than in controls.
      Centrilobular hepatocellular hypertrophy was present only in exposed mice, and
      the severity increased with dose. CHRONIC STUDIES: Groups of 60 male and 60
      female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations
      of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice
      received 125 ppm in feed to allow for study of a group with projected serum
      concentrations of oxazepam similar to those achieved in humans taking a
      therapeutic dose. Ten male and 10 female B6C3F1 mice per group were evaluated at
      15 months. Average daily oxazepam consumption varied throughout the studies, and
      the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm
      groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the
      5,000 ppm groups. Serum oxazepam concentrations determined at 57 weeks in Swiss
      Webster mice and at the 15-month interim evaluation of B6C3F1 mice 1 mice were
      approximately 1 ug/mL in the 125 ppm groups, 4 to 7 &mu;g/mL in the 2,500 ppm
      groups, and 7 to 10 &mu;g/mL in the 5,000 ppm groups. Neurobehavioral assessments
      during the chronic studies of each strain of mice were confounded by the poor
      survival and deteriorating condition of mice with hepatic neoplasia. However,
      within the limitations of the studies, there were no notable changes in the types
      of behaviors observed compared to those observed in the 14-week studies, nor was
      there an enhancement in the degree to which they were exhibited. 57-Week Study in
      Swiss-Webster Mice: Survival, Body Weights, Feed and Compound Consumption, and
      Clinical Findings: At 57 weeks, survival of exposed mice was significantly lower
      than that of controls (males: O ppm, 45/60; 2,500 ppm, 19/60; 5,000 ppm, 10/60;
      females: 47/60, 28/59, 17/59), causing the study to be terminated. Mean body
      weights of exposed males were similar to controls until week 17; afterwards, mean
      body weights of exposed male groups were lower than those of controls. Final mean
      body weights of exposed males were 9% lower than that of the controls. The mean
      body weight of 2,500 ppm females was greater than that of the controls throughout
      the study. Females receiving 5,000 ppm had a mean body weight greater than that
      of the controls early in the study; after week 29, the mean body weight of this
      group was similar to that of the controls. Feed consumption by exposed males and
      females was slightly lower than that by the controls, and females in all groups,
      including controls, consumed slightly more feed than males throughout the study.
      Dietary levels of 2,500 and 5,000 ppm oxazepam resulted in average daily compound
      consumption levels of 270 and 570 mg/kg for males and 320 and 670 mg/kg for
      females. Hypoactivity and sedation were observed in exposed mice during the first
      week of the study. There were no other clinical findings associated with oxazepam
      exposure. Pathology Findings: Systemic amyloidosis was the principal cause of
      death in mice dying before the study was terminated. The lower survival of mice
      receiving oxazepam was attributed to an increase in the extent and severity of
      amyloid deposits in many organs, including the heart and kidney. Atrial
      thrombosis and pulmonary lesions consistent with chronic heart failure occurred
      at higher incidences and with greater severity in exposed mice. The incidence of
      hepatocellular adenomas (males: 1/60, 35/60, 50/60; females: 0/60, 22/59, 47/59)
      and carcinomas (males: 0/60, 5/60,19/60; females: 1/60, 1/59, 11/59) were
      increased in exposed mice. The incidences of eosinophilic foci were also
      increased in exposed mice (males: 0/60, 22/60, 22/60; females: 0/60, 20/59,
      14/59), and there was evidence of increased centrilobular hepatocyte hypertrophy
      (males: 12/60, 46/60, 47/60; females: 3/60, 51/59, 53/59). 2-Year Study in B6C3F1
      Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical
      Findings: Survival of mice receiving 2,500 and 5,000 ppm was significantly lower
      than that of controls (males: O ppm, 45/50; 125 ppm, 44/50; 2,500 ppm, 15/50;
      5,000 ppm, 0/50; females: 39/50, 41/50, 2/50, 0/50). Mean body weight gains of
      exposed male and female mice were similar to controls until about week 15 when
      weight gains for mice exposed to 2,500 or 5,000 ppm slowed in relation to
      controls, resulting in weight gains approximately 30&percnt; to 40&percnt; lower
      than those of the controls throughout the remainder of the study. Mean body
      weight gain of male mice exposed to 125 ppm was similar to that of the controls,
      while that of female mice receiving 125 ppm was 10&percnt; to 15&percnt; lower
      than that of the controls after about week 45. Feed consumption by exposed males
      and females was similar to that by controls. Dietary levels of 125, 2,500, and
      5,000 ppm resulted in average daily oxazepam consumption levels of 12, 310, and
      690 mg/kg body weight for males and 15, 350, and 780 mg/kg for females. In the
      5,000 ppm groups, lethargy and sedation were observed in a few mice during the
      first week of study. Pathology Findings: The early deaths of many of the B6C3F1
      mice exposed to oxazepam were attributed to a marked increase in the incidences
      of hepatoblastoma (males: 0/49, 2/50, 21/50, 13/50; females: 0/50, 1/50, 8/50,
      8/50), hepatocellular adenoma (males: 17/49,18/50, 34/50, 32/50; females: 25/50,
      35/50, 35/50, 36/50), and hepatocellular carcinoma (males: 9/49, 5/50, 45/50,
      50/50; females: 9/50, 5/50, 49/50, 44/50). Moderate hypertrophy of centrilobular
      hepatocytes occurred in mice receiving 2,500 and 5,000 ppm (males: 0/49, 2/50,
      26/50, 43/50; females: 0/50, 2/50,11/50, 29/50). An increase in the incidence of
      follicular cell hyperplasia of the thyroid gland occurred in all exposed groups
      of mice (males: 4/49, 22/50, 49/50, 47/50; females: 16/50, 34/50, 49/50, 44/50),
      and thyroid gland follicular cell adenoma was increased in exposed females (0/50,
      4/50, 5/50, 6/50). Testicular atrophy occurred in the 2,500 and 5,000 ppm groups
      (1/50, 0/50, 25/50, 38/50), and the incidence of epididymal Iymphocyte
      infiltration was increased in all exposed groups (2/50,14/50, 33/50, 21/50). The
      frequency of hepatocellular neoplasms with an activated H-ras oncogene in the
      B6C3F1 mice and the mutation spectrum of the H-ras gene were determined. The
      mutation spectrum of the H-ras genes in the relatively few neoplasms from exposed
      mice that did have an activated H-ras did not differ from the spectrum of
      mutations observed in neoplasms from controls, but the proportion of neoplasms
      with an activated H-ras gene decreased with increasing oxazepam dose. While 11 of
      19 (58&percnt;) neoplasms from control mice had an activated H-ras gene, only 1
      of 40 neoplasms from mice receiving 2,500 or 5,000 ppm oxazepam exhibited a
      similar molecular lesion. Thirteen of 37 (35&percnt;) neoplasms from mice in the
      125 ppm group had an activated H-ras oncogene, suggesting that, although the
      incidence of all liver neoplasms was not statistically increased compared to
      controls, there was an increase in a similar subset of neoplasms (lacking an
      activated H-ras) that occurred with increased incidence at higher doses.
      SUPPLEMENTAL STUDIES: Because exposure to oxazepam caused increased incidences of
      liver neoplasms, supplemental short-term studies were performed. Oxazepam given
      in feed to male B6C3F1 mice at 25, 125, 2,500, or 5,000 ppm for up to 13 weeks
      was found to cause a dose-related increase in nuclear labeling index in studies
      measuring the incorporation of bromodeoxyuridine into replicating liver cells.
      This increase was statistically significant at all but the 25 ppm exposure level
      and was limited to mice evaluated at 15 days. Cell replication rates in most
      groups evaluated at 30 days and after were similar to control rates. There was
      minimal evidence suggestive of hepatocyte necrosis either by light microscopy or
      in clinical chemistry measures. There was, however, evidence of cholestasis,
      likely due to physical obstruction of bile canaliculi by swollen hepatocytes. The
      metabolic fate and toxicokinetics of oxazepam were evaluated in each strain of
      mice and were compared to published data from human studies. Both mice and humans
      form glucuronides of oxazepam and form 3- and 4-hydroxy and methoxy derivatives
      of the phenyl group. Oxidative metabolism of the phenyl group appears to be more
      prevalent in mice than is reported for humans. Elimination half-lives of parent
      compound do not differ between Swiss-Webster and B6C3F1 mice and are similar to
      values reported for humans. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any
      of several strains of Salmonella typhimurium, nor did it induce sister chromatid
      exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells.
      These in vitro tests were performed with and without S9 metabolic activation.
      Results from an in vivo mouse peripheral blood micronucleus test performed on the
      B6C3F1 mice used in the 14-week study were also negative. CONCLUSIONS: Under the
      conditions of these feed studies, there was clear evidence of carcinogenic
      activity of oxazepam in male and female Swiss-Webster mice based on increased
      incidences of hepatocellular adenoma and carcinoma. There was clear evidence of
      carcinogenic activity of oxazepam in male and female B6C3F1 mice based on
      increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma.
      Increased incidences of hyperplasia of thyroid gland follicular cells in male and
      female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were
      also related to oxazepam exposure. Administration of oxazepam to Swiss-Webster
      mice resulted in centrilobular hepatocellular hypertrophy and increased
      incidences and severity of systemic amyloidosis. Administration of oxazepam to
      B6C3F1 mice also resulted in centrilobular hepatocellular hypertrophy. Synonyms:
      7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2 H - 1,4-benzodiazepin-2-one Trade
      Names: Tazepam, Wy-3498, Serax

PMID- 12595921
TI  - NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23
      7) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an
      intermediate in the manufacture of pesticides, dyes, and industrial solvents.
      Groups of male and female F344/N rats and B6C3F1 mice were exposed to p
      nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for
      toxicity and carcinogenicity studies. Genetic toxicology studies were conducted
      in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary
      cells, and in studies of erythrocyte micronucleus formation in mice in the 13
      week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were
      given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed
      for 14 days. All rats survived until the end of the study. Male and female rats
      given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000,
      20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the
      final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%,
      and 65% that of the controls. There were no clinical findings that were
      characteristic of organ-specific toxicity. Absolute and relative spleen weights
      were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm.
      There were decreases in erythrocyte count and hemoglobin and hematocrit values
      and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin
      concentration that were most pronounced in the 20,000 and 40,000 ppm groups.
      Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000
      ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was
      present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p
      nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm
      males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm
      males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of
      the thymus in males and atrophy of the ovary, bone marrow, and thymus in females.
      14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0,
      2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14
      days. Three males and two females given 40,000 ppm died during the study. All
      other animals survived until the end of the study. Male mice given 20,000 and
      40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of
      20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were
      significantly lower than those of the controls. There were no clinical findings
      related to organ-specific toxicity although lethargy and ataxia were observed in
      40,000 ppm mice. Relative liver weights were significantly increased in 20,000
      and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative
      thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000
      ppm females were reduced. No significant differences in hematology parameters
      occurred in exposed mice. Testicular degeneration was observed in three 20,000
      ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in
      40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats
      were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed
      for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660
      mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived
      until the end of the study. Mean body weight gains and final mean body weights
      were significantly less than those of the controls in 2,500, 5,000, and 10,000
      ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings
      related to organ-specific toxicity. Differences in spleen weights and hematology
      parameters characteristic of regenerative anemia were observed in males and
      females, primarily in groups given 10,000 ppm. The absolute and relative spleen
      weights were significantly increased in 10,000 ppm males and females and the
      relative spleen weights were significantly increased in 5,000 ppm males hts were
      significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz
      bodies, and reticulocyte counts were increased and erythrocyte counts,
      hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females.
      Congestion, pigmentation, and accumulation of macrophages in the spleen and
      pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males.
      Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A
      yellowish brown pigment (hemosiderin) in the spleen and kidney was associated
      with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present
      in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was
      present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p
      nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of
      the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE:
      Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or
      20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily
      doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460,
      970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the
      study, except one 1,250 ppm female that was killed accidentally. Final mean body
      weights and mean body weight gains of all exposed males and of 5,000, 10,000, and
      20,000 ppm females were significantly lower than those of the controls. No
      clinical findings or differences in organ weights or histopathology related to
      organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS:
      Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p
      nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each
      exposure group were evaluated at 15 months. Survival, Body Weights, Feed
      Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500
      ppm males were similar to that of the controls. Two-year survival of 5,000 ppm
      males was marginally greater than that of the controls and was attributed in part
      to a decrease in the severity of nephropathy and a decrease in the incidence of
      mononuclear cell leukemia. Survival of exposed females was similar to that of the
      controls. Mean body weights of 5,000 ppm males were 2&percnt; to 8&percnt; lower
      than those of the controls through week 80. Final mean body weights of exposed
      males were similar to that of the controls. Mean body weights of 5,000 ppm
      females were 2&percnt; to 9&percnt; lower than those of the controls during the
      first year of the study and were 10&percnt; to 16&percnt; lower during the second
      year of the study. Final mean body weights of exposed females were 97&percnt;
      (1,250 ppm), 92&percnt; (2;500 ppm), and 84&percnt; (5,000 ppm) that of the
      controls. Feed consumption by exposed males and females was similar to that by
      the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid
      delivered approximately 50, 100, or 210 mg/kg body weight per day to males and
      60, 125, or 250 mg/kg per day to females. There were no clinical findings
      attributable to organ-specific toxicity. Pathology Findings: There were increases
      in the incidences of clitoral gland adenoma and of clitoral gland adenoma or
      carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The
      incidences of clitoral gland adenoma or carcinoma (combined) in the exposed
      groups (29&percnt; to 31&percnt;) exceeded the historical control mean incidence
      (11&percnt;) and range (2&percnt; to 21&percnt;) in female F344/N rats in recent
      2-year NTP feed studies. The increased incidences of clitoral gland neoplasms
      were considered to be some evidence of carcinogenic activity in female rats
      exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral
      gland in exposed females were marginally lower than that of the controls (10/50,
      6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of
      nephropathy in male rats. Male rat kidneys were examined using both single and
      step-section analyses, and the incidences of renal tubule neoplasms were not
      statistically greater than those of the controls. Mild hyaline droplet
      accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in
      the 13-week study, but this effect was not severe enough to lead to a chemical
      related neoplastic response in the 2-year study as has been observed with other
      chemicals. At the 15-month interim evaluation, hematologic parameters
      characteristic of a mild regenerative anemia and significant differences in
      spleen weights were noted in 5,000 ppm females. These differences included
      decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen
      weights, and hemosiderin accumulation in splenic macrophages. At 2 years,
      significant decreases in the incidences of mononuclear cell leukemia were
      observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50,
      26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this
      decrease is unknown, decreases in the incidence of mononuclear cell leukemia have
      also been observed in 2year studies with other amine/nitro compounds. 2-YEAR
      STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500,
      or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females
      from each exposure group were evaluated at 15 months. Survival, Body Weights,
      Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice
      were similar to those of the controls. Mean body weights of 5,000 ppm males were
      6&percnt; to 12&percnt; lower than those of the controls after week 17, and mean
      body weights of 5,000 ppm females were 12&percnt; to 24&percnt; lower than those
      of the controls after week 16. The final mean body weight of 5,000 ppm females
      was 19&percnt; less than that of the controls; final mean body weights of males
      were similar to that of the controls. Feed consumption by exposed mice was
      similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p
      nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males
      and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of
      organ-specific toxicity. No chemical-related effects on hematology parameters
      were noted at the 15-month interim evaluation. Pathology Findings: There were no
      increases or decreases in neoplasms in male or female mice that were considered
      to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid
      was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No
      mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without
      S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal
      aberrations in cultured Chinese hamster ovary cells in the absence of S9; with
      S9, results of both tests were negative. In vivo, no increase in micronuclei was
      observed in peripheral blood erythrocytes of male or female mice administered p
      nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions
      of these 2-year feed studies, there was no evidence of carcinogenic activity of p
      nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm.
      There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female
      F344/N rats based on increases in the incidences of clitoral gland adenoma and of
      clitoral gland adenoma or carcinoma (combined). There was no evidence of
      carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice
      exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in
      the incidences of mononuclear cell leukemia in exposed male and female rats. p
      Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4
      Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p
      carboxynitrobenzene

PMID- 12595922
TI  - NTP Comparative Initiation/Promotion Skin Paint Studies of B6C3F1 Mice, Swiss (CD
      1(R)) Mice, and SENCAR Mice.
AB  - In 1983, an ad hoc panel on chemical carcinogenesis testing and evaluation
      recommended additional methods that should be used by the National Toxicology
      Program (NTP) for the detection and evaluation of chemical carcinogens. One
      recommendation was that there should be an increased emphasis on short-term tests
      to detect agents that do not exert genetic effects such as some promoting agents.
      Initiation/promotion models have been used routinely to identify chemicals with
      promoting potential and to study tumorigenesis. In one model, a topical
      subcarcinogenic dose of a chemical is first applied to the back of the skin
      (initiation) followed by repeated topical applications of one or more chemicals
      (promotion) and the skin is monitored for tumor development. Mouse skin has been
      shown to be more responsive (i.e., develops tumors using this protocol) than
      other commonly used laboratory rodent models. However, not all mouse strains are
      equally sensitive. The skin tumor response of the B6C3F1 mouse using the
      initiation/promotion protocol was not known. Since the B6C3F1 mouse is commonly
      used in NTP carcinogenesis studies and much is known of its biology and response
      to chemical carcinogens, known initiators and promoters were used to compare the
      tumor response sensitivity of B6C3F1 mouse skin to that of two often-used
      responsive strains, Swiss (CD-1(R)) and SENCAR mice. The combination of 7,12-
      dimethylbenz(a)anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-
      acetate (TPA) promotion was selected because this pair is routinely used to study
      tumorigenesis. However, DMBA requires metabolic activation to achieve initiation
      and it was possible that the B6C3F1 mouse metabolism might not make this
      conversion (DiGiovanni and Juchau, 1980). Therefore, a second study was conducted
      using N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a direct acting carcinogen, as
      the initiator. MNNG is not used as frequently for mouse skin studies as is DMBA.
      In addition to the promoter TPA, benzoyl peroxide (BPO), a non-phorbol ester and
      known promoter after DMBA initiation, was also used (Slaga et al., 1981). Each
      initiating chemical was used in combination with each promoting chemical as
      described on the study design table below. Additional groups of male and female
      mice of each strain were treated with repeated applications of acetone (vehicle
      control), repeated applications of promoter (TPA or BPO) without prior initiation
      treatment (promoter reference controls), or a single application of the initiator
      (DMBA or MNNG) followed by repeated applications of acetone (initiator controls).
      All three strains of mice demonstrated sensitivity by developing skin tumors
      after topical application of the chemicals under study (DMBA, MNNG, TPA, and
      BPO). The most sensitive of the three strains appeared to be SENCAR mice, in the
      sense that lower doses of the test chemical were generally required to produce
      effects equivalent to those in the other two strains. Skin tumors also tended to
      develop earlier and with greater multiplicity in SENCAR mice than in the other
      two strains. By these criteria, the overall sensitivity of Swiss (CD-1(R)) mice
      was intermediate, and B6C3F1 mice showed the least overall sensitivity to dermal
      carcinogenicity. In response to recommendations regarding specific short-term
      tests and also on the skin tumor response sensitivity of various initiators and
      promoters, SENCAR mice would be the most acceptable strain to use for such
      studies. Though the B6C3F1 mice were less responsive in the skin
      initiation/promotion protocol, promotion data from this strain may, at times, be
      of more use in explaining mechanisms of tumor development (e.g. when there is a
      strain specific response observed in 2-year carcinogenicity studies or effects on
      melanocytes are suspected). See the full report or study abstract for table of
      Study Design for the 1-Year Comparative Initiation/Promotion Skin Paint Studies.
      The 1-year complete carcinogen studies used repeated applications of low
      concentrations of the carcinogens DMBA and MNNG. The skin tumor response in aln
      all three strains under these conditions was more similar than in the initiation
      and promotion studies. There was a high incidence of skin tumors in all three
      strains with both carcinogens. More B6C3F1, and SENCAR mice developed skin tumors
      and averaged more tumors per mouse than did Swiss (CD-1&reg;) mice. Skin tumors
      developed earlier in SENCAR mice than in B6C3F1 and Swiss (CD-1&reg;) mice.
      Although B6C3F1 mice exhibited the lowest overall sensitivity to the
      initiation/promotion protocol when compared to Swiss (CD-1&reg;) and SENCAR mice,
      the response of B6C3F1 mice was similar to Swiss (CD-1&reg;) and SENCAR mice for
      complete carcinogen studies.

PMID- 12595923
TI  - NTP Toxicology and Carcinogenesis Studies of Ozone (CAS No. 10028-15-6) and
      Ozone/NNK (CAS No. 10028-15-6/ 64091-91-4) in F344/N Rats and B6C3F1 Mice
      (Inhalation Studies).
AB  - There is widespread concern over the health effects of oxidant air pollutants.
      The state of California and the Health Effects Institute (HEI) (a nonprofit
      research institute funded jointly by the U.S. Environmental Protection Agency
      [USEPA] and combustion engine manufacturers) nominated ozone for evaluation in
      long-term animal studies. The NTP study designs were a result of a series of
      meetings at the NIEHS with scientists from NIEHS, USEPA, and HEI, as well as
      experts from academic institutions working in the area of air pollutants. Male
      and female F344/N rats and B6C3F1 mice were exposed to ozone by inhalation for 4
      weeks, 2 years, or for 124 weeks (rats) or 130 weeks (mice). The oxygen used to
      generate the ozone was greater than 99.9% pure. Additional groups of male F344/N
      rats were administered injections of 4-(N-methyl-Nnitrosamino)-1-(3-pyridyl)-1
      butanone (NNK) (~99% pure) 3 times per week for 20 weeks and exposed to ozone by
      inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella
      typhimurium. 4-WEEK OZONE STUDY IN RATS: Groups of five male and five female
      F344/N rats were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation 6 hours per
      day, 5 days per week, for a total of 20 days. All rats survived to the end of the
      study. The final mean body weights and mean body weight gains of 0.5 ppm males
      and females and of 1.0 ppm females were similar to those of the controls. The
      final mean body weight of 1.0 ppm males was 7% lower than that of the controls.
      Clinical findings included hypoactivity in 1.0 ppm males and females and ruffled
      fur in exposed groups of males. Male and female rats exposed to 0.5 or 1.0 ppm
      developed multifocal lesions of the lung, which consisted of infiltration of
      granulocytes and macrophages with extension of the bronchial epithelium into the
      alveolar ducts. Female rats exposed to ozone developed minimal squamous
      metaplasia of the laryngeal epithelium at the base of the epiglottis. Absolute
      and relative lung weights of all exposed groups of males and females were greater
      than those of the controls, and absolute and relative thymus weights of all
      exposed groups were generally lower than those of the controls. 4-WEEK OZONE
      STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0,
      0.5, or 1.0 ppm ozone by inhalation 6 hours per day, 5 days per week, for a total
      of 20 days. All mice survived to the end of the study. The final mean body
      weights and body weight gains of all exposed groups of mice were less than those
      of the controls. Hypoactivity was observed in 1.0 ppm mice. Male and female mice
      exposed to 0.5 or 1.0 ppm ozone developed patchy, multifocal lesions of the lung,
      which consisted of infiltration of granulocytes and macrophages with extension of
      the bronchial epithelium into the alveolar ducts. The relative lung weight of 1.0
      ppm males was significantly greater than that of the controls. There were no
      other statistically significant differences in absolute or relative organ weights
      in males or females. 2-YEAR OZONE STUDY IN RATS: The 2-year study was designed to
      include the present USEPA standard (0.12 ppm), the maximum concentration believed
      compatible with long-term survival (1.0 ppm), and an intermediate concentration
      (0.5 ppm). Groups of 50 male and 50 female F344/N rats were exposed to 0, 0.12,
      0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 105
      weeks. Survival, Body Weights, and Clinical Findings: Survival of exposed groups
      of rats was similar to that of the controls at the end of the study. The mean
      body weights of 0.12 and 0.5 ppm males and females were similar to those of the
      controls throughout the study. The mean body weights of 1.0 ppm males and females
      were slightly lower than those of the controls throughout the study. Hypoactivity
      was observed in male and female rats exposed to ozone. Pathology Findings:
      Increased incidences of ozone-induced metaplasia occurred in the nose and lung of
      rats exposed to 0.5 or 1.0 ppm ozone. The lesions in the nose were characterized
      by an increase in the number of goblin the number of goblet cells in the
      respiratory epithelium with mild squamous metaplasia of the cuboidal epithelium
      on the lateral wall. The increase in the number of goblet cells was found
      primarily in level I and II epithelium occurring along the lateral wall and on
      the maxilloturbinates and nasoturbinates. The metaplasia in the lung was a patchy
      multifocal lesion consisting of extension of the bronchial epithelium into the
      alveoli of the centriacinar region. This may represent more an extension of the
      bronchial epithelium into the pulmonary parenchyma than an actual transition of
      one epithelial cell type into another. There were increased incidences of
      squamous metaplasia at the base of the epiglottis characterized by one or more
      layers of flattened epithelial cells where low cuboidal cells are normally found.
      There were no increases in the incidences of alveolar/bronchiolar adenoma or
      carcinoma in either males or females exposed to ozone. LIFETIME OZONE STUDY IN
      RATS: For this study, rats were exposed to 0.5 and 1.0 ppm ozone for an
      additional 6 months to determine the effect of extended exposure on neoplasm
      incidence. Groups of 50 male and 50 female F344/N rats were exposed to 0, 0.5, or
      1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 125 weeks.
      Survival, Body Weights, and Clinical Findings: Survival rates of exposed rats
      were similar to those of the controls. The mean body weights of 0.5 ppm males and
      females were similar to those of the controls throughout the study. The mean body
      weights of 1.0 ppm males and females were slightly lower than those of the
      controls for the first two years of the study. Hypoactivity was observed in
      exposed groups of males and females. Pathology Findings: Increased incidences of
      metaplasia occurred in the nose, larynx, and lung of rats exposed to 0.5 or 1.0
      ppm ozone. The lung lesions were multifocal, centriacinar and were characterized
      by the presence of cuboidal epithelium (ciliated and nonciliated) along the
      alveolar ducts where type I epithelium is normally present. Inflammation
      (histiocytic infiltration) and interstitial fibrosis were observed in the lung of
      exposed males and females, and hyperplasia was observed in the nose of exposed
      male and female groups. There were no ozone-related increased incidences of
      neoplasms. 2-YEAR OZONE/NNK STUDY IN MALE RATS: An intermediate concentration of
      0.5 ppm ozone was combined with exposure to two levels of a known carcinogen (0.1
      and 1.0 mg NNK/kg body weight) in order to determine if ozone promotes the
      carcinogenic process or acts as a cocarcinogen. Groups of 48 male F344/N rats
      were exposed to 0 or 0.5 ppm ozone by inhalation, 6 hours per day, 5 days per
      week for 105 weeks. During the first 20 weeks of the study, these rats were
      subcutaneously injected with 0, 0.1, or 1.0 mg NNK per kg body weight in
      trioctanoin three times weekly. Survival and Body Weights: Two-year survival
      rates of male rats were similar in all groups. Final mean body weights of all
      males exposed to NNK alone or NNK and ozone were similar to that of the controls,
      with the exception of rats exposed to 1.0 mg NNK/kg body weight and 0.5 ppm
      ozone. Hypoactivity was observed in males exposed to NNK and ozone, in those
      exposed to NNK without ozone, and in those exposed to ozone only. Pathology
      Findings: Alveolar epithelial metaplasia and interstitial fibrosis occurred in
      all groups of rats exposed to ozone or to NNK and ozone, but not in those exposed
      to NNK without ozone. Increased incidences of hyperplasia occurred in groups of
      rats exposed to NNK or to ozone and NNK. Incidences of hyperplasia were similar
      among groups of rats exposed to NNK only. An increased incidence of
      alveolar/bronchiolar adenoma or carcinoma (combined) occurred in rats
      administered 1.0 mg/kg NNK, with or without ozone. The administration of ozone
      did not affect the occurrence of pulmonary neoplasms or nonneoplastic lesions in
      rats administered NNK. 2-YEAR OZONE STUDY IN MICE: The 2-year study was designed
      to include the present USEPA standard (0.12 ppm), the maximum concentration
      believed compatible with long-term survival (1.0 ppm), and an intermediate
      concentration (0.5 ppm). Groups of 50 male and 50 female B6C3F1 mice were exposed
      to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per
      week, for 105 weeks. Survival, Body Weights, and Clinical Findings: Survival
      rates of exposed mice were generally similar to those of the controls; the 2-year
      survival rate of 1.0 ppm females was greater than that of the controls. The mean
      body weights of 0.12 and 0.5 ppm males were similar to that of the controls
      throughout the study; the mean body weights of 1.0 ppm males and of all exposed
      groups of females were generally lower than those of the controls throughout the
      study. Hypoactivity was observed in male and female mice exposed to ozone.
      Pathology Findings: Increased incidences of metaplasia occurred in the nose and
      lung of mice exposed to 0.5 or 1.0 ppm ozone. The metaplasia in the nose
      consisted of increased thickening and extension of the squamous epithelium in the
      anterior portion of the nasal passage. The metaplasia in the lung consisted of
      extension of the bronchial epithelium into the alveoli of the centriacinar
      region. There were increased incidences of hyperplasia in the nose characterized
      by thickening of the noncuboidal (transitional) epithelium. There were increased
      incidences of hyperplasia in the epiglottis of female mice, a change that was
      characterized by a minimal increase in the thickness of the epithelium.
      Incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were
      marginally increased in 0.5 and 1.0 ppm males (0 ppm, 14/50; 0.12 ppm, 13/50; 0.5
      ppm, 18/50; 1.0 ppm, 19/50) and were increased in 1.0 ppm females (6/50, 7/50,
      9/49, 16/50). LIFETIME OZONE STUDY IN MICE: For this study, mice were exposed to
      0.5 and 1.0 ppm ozone for 30 months to determine the effect of extended exposure
      on neoplasm incidence. Groups of 50 male and 50 female B6C3F1 mice were exposed
      to 0, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week,
      for 130 weeks. Survival and Body Weights: Survival rates of exposed mice were
      similar to those of the controls. The mean body weights of 0.5 ppm males and
      females were similar to those of the controls throughout the study. The mean body
      weights of 1.0 ppm males and females were generally lower than those of the
      controls throughout the study. Hypoactivity was observed in male and female mice
      exposed to ozone. Pathology Findings: The incidences of alveolar/bronchiolar
      adenoma and carcinoma (combined) were marginally increased in exposed males (0
      ppm, 16/49; 0.5 ppm, 22/49; 1.0 ppm, 21/50) and in exposed females (6/50, 8/49,
      12/50). Increased incidences of metaplasia occurred in the nose, larynx, and lung
      of exposed groups of males and females, and the incidences of hyperplasia were
      increased in the larynx and nose of exposed mice. The morphology of the lesions
      was similar to that seen in the 2-year study. There were no ozone-related
      increases in alveolar epithelial hyperplasia. GENETIC TOXICOLOGY: Ozone was
      mutagenic in Salmonella typhimurium strain TA102, with and without S9 metabolic
      activation. CONCLUSIONS: Under the conditions of these 2-year and lifetime
      inhalation studies, there was no evidence of carcinogenic activity of ozone in
      male or female F344/N rats exposed to 0.12, 0.5, or 1.0 ppm. There was equivocal
      evidence of carcinogenic activity of ozone in male B6C3F1 mice based on increased
      incidences of alveolar/bronchiolar adenoma or carcinoma. There was some evidence
      of carcinogenic activity of ozone in female B6C3F1 mice based on increased
      incidences of alveolar/bronchiolar adenoma or carcinoma. There was no evidence
      that exposure to 0.5 ppm ozone enhanced the incidence of NNK-induced pulmonary
      neoplasms in male rats. Exposure of male and female rats to ozone for 2 years or
      125 weeks was associated with goblet cell hyperplasia and squamous metaplasia in
      the nose, squamous metaplasia in the larynx, and metaplasia (extension of
      bronchial epithelium into the centriacinar alveolar ducts) and interstitial
      fibrosis in the lung. Exposure of male and female mice to ozone for 2 years or
      130 weeks was associated with hyperplasia and squamous metaplasia in the nose and
      inflammation (histiocytic infiltration) and metaplasia (extension of bronchial
      epithelium into the centriacinar alveolar ducts) of the lung.

PMID- 12595924
TI  - NTP Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS
      No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - Methylphenidate hydrochloride is a drug used in the treatment of narcolepsy and
      attention deficit hyperactivity disorders. This drug was nominated for study by
      the Food and Drug Administration and the National Cancer Institute because of its
      widespread use in human medicine and because of lack of data on its potential
      carcinogenicity. Oral administration is the most common route of human exposure.
      Toxicology and carcinogenicity studies were conducted by administering
      methylphenidate hydrochloride (USP grade) ad libitum in feed to groups of male
      and female F344/N rats and B6C3F1, mice for 14 days, 13 weeks, or 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium and in
      cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male
      and five female F344/N rats were fed diets containing 0, 16, 62, 250, 1,000, or
      4,000 ppm methylphenidate hydrochloride for 14 days. All rats survived to the end
      of the study. The final mean body weights of 4,000 ppm male and female rats were
      9% lower than those of the controls. Absolute and relative liver weights of 4,000
      ppm males and females were significantly greater than those of the controls.
      Clinical findings during the first week of the study included hyperactivity in
      4,000 ppm males and females, but these animals appeared to be normal during the
      second week of treatment. No treatment-related gross lesions were observed;
      however, centrilobular hypertrophy was observed in 4,000 ppm males and females.
      14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1, mice were fed
      diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate
      hydrochloride for 14 days. Three 4,000 ppm males died during the second week of
      the study; all other mice survived to the end of the study. The final mean body
      weight of 4,000 ppm females was 11% lower than that of the controls, and the mean
      body weight gains of 1,000 and 4,000 ppm males and females were also
      significantly lower than those of the controls. Absolute and relative liver
      weights of all exposed groups of males and of 4,000 ppm females were
      significantly greater than those of the controls. Hyperactivity was observed
      during the second week of the study in some 4,000 ppm males. Degeneration and
      necrosis of the renal tubule epithelium were observed in two 4,000 ppm males.
      Hepatocellular hypertrophy was observed in males and females exposed to 1,000 or
      4,000 ppm and in males exposed to 250 ppm. 13-WEEK STUDY IN RATS: Groups of 10
      male and 10 female F344/N rats were fed diets containing 0, 125, 250, 500, 1,000,
      or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical
      related effects on survival. Mean body weight gains of 500, 1,000, and 2,000 ppm
      males and females and of 250 ppm females were significantly lower than those of
      the controls. Final mean body weights of exposed males and females were similar
      to those of the controls. During the first week of the study, feed consumption by
      2,000 ppm rats was less than that by controls, but during the remainder of the
      study feed consumption by exposed and control groups was similar. Rats exposed to
      125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 8, 15, 30, 70,
      or 130 mg methylphenidate hydrochloride per kilogram body weight per day (males)
      or 9, 18, 30, 70, or 150 mg/kg per day (females). Clinical findings in 1,000 and
      2,000 ppm females included slight hypersensitivity to touch, hyperactivity, and
      increased vocalization during handling periods. Absolute and relative liver
      weights of 2,000 ppm males and females were significantly greater than those of
      the controls, as were the relative liver weights of 1,000 ppm males and females.
      No chemical-related differences in bone length, bone density, or nose-to-rump
      lengths were noted in males or females, nor were there treatment related
      histopathologic lesions. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female
      B6C3F1, mice were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm
      methylphenidate hydrochloride for 13 weeks. There were no chemical-related
      effects on ed effects on survival. Final mean body weights of males exposed to
      250, 500, 1,000, or 2,000 ppm and of 2,000 ppm females were significantly lower
      than those of the controls. The final mean body weights of other exposed male and
      female groups were similar to those of the controls. During the first week of the
      study, feed consumption by 2,000 ppm mice was less than that by controls; feed
      consumption by exposed groups was similar to that by the controls throughout the
      remainder of the study. Mice exposed to 125, 250, 500, 1,000, or 2,000 ppm
      received approximate doses of 15, 30, 70, 115, or 230 mg/kg per day (males) or
      15, 30, 70, 125, or 260 mg/kg per day (females). No chemical-related clinical
      findings were observed. Absolute and relative liver weights of 1,000 and 2,000
      ppm males and females were significantly greater than those of the controls, as
      were the relative liver weights of 125, 250, and 500 ppm males. Centrilobular
      hypertrophy and hepatocellular degeneration or necrosis were observed in males
      exposed to 500, 1,000, or 2,000 ppm methylphenidate hydrochloride. 2-YEAR STUDY
      IN RATS: Based on the increased liver weights and lower body weight gains in
      2,000 ppm rats in the 13-week study, the high dose selected for the 2-year rat
      study was 1,000 ppm. Groups of 70 male and 70 female F344/N rats were fed diets
      containing 0, 100, 500, or 1,000 ppm methylphenidate hydrochloride for up to 2
      years. As many as 10 male and 10 female rats per exposure group were evaluated at
      9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and
      Clinical Findings: Survival of exposed rats was similar to that of the controls
      at the end of the study. Mean body weights of 500 and 1,000 ppm males were
      3&percnt; to 10&percnt; lower than those of the controls from week 30 to the end
      of the study; during the same time period, mean body weights of 500 and 1,000 ppm
      females were 4&percnt; to 24&percnt; less than those of the controls. Final mean
      body weights of rats exposed to 100, 500, or 1,000 ppm were 102&percnt;,
      95&percnt;, or 90&percnt; (males) and 96&percnt;, 89&percnt;, or 78&percnt;
      (females) those of the controls. Rats exposed to 100, 500, or 1,000 ppm
      methylphenidate hydrochloride in feed received approximate doses of 5, 25, or 50
      mg/kg per day (males and females). The only chemical-related clinical finding was
      an increased incidence of fighting among group-housed males exposed to 1,000 ppm.
      Hematology and Clinical Chemistry: No biologically significant differences in
      hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology
      Findings: In female rats exposed to 500 or 1,000 ppm, the incidence of mammary
      gland fibroadenomas was decreased (0 ppm, 15/49; 100 ppm, 13/50; 500 ppm, 6/ 48;
      1,000 ppm, 5/50), and the decrease was considered to be related to chemical
      administration. No significant chemical-related increases in neoplasm incidences
      were observed in male or female rats. 2-YEAR STUDY IN MICE: Based on the liver
      toxicity and lower body weight gains observed in 1,000 and 2,000 ppm mice in the
      13-week study, the high dose selected for the 2-year study was 500 ppm. Groups of
      70 male and 70 female B6C3F1 mice were fed diets containing 0, 50, 250, or 500
      ppm methylphenidate hydrochloride for 2 years. As many as 10 male and 10 female
      mice per exposure group were evaluated at 9 or 15 months. Survival, Body Weights,
      Feed and Compound Consumption, and Clinical Findings: Survival of exposed mice
      was similar to that of the controls at the end of the study. Mean body weights of
      mice exposed to 250 or 500 ppm were 3&percnt; to 11&percnt; lower than those of
      the controls throughout much of the study; during the same time period, mean body
      weights of 250 ppm females were 3&percnt; to 7&percnt; lower than those of the
      controls. Final mean body weights of mice exposed to 50, 250, or 500 ppm were
      97&percnt;, 89&percnt;, or 93&percnt; (males) and 98&percnt;, 93&percnt;, or
      97&percnt; (females) that of the controls. Mice exposed to 50, 250, or 500 ppm
      methylphenidate hydrochloride in feed were estimated to have received 6, 30, or
      60 mg/kg body weight per day (males) or 8, 40, or 80 mg/kg per day (females).
      There were no chemical related clinical findings. Hematology and Clinical
      Chemistry: No biologically significant differences in hematology or clinical
      chemistry parameters occurred at 9 or 15 months. Pathology Findings: The
      principal lesions associated with the administration of methylphenidate
      hydrochloride occurred in the liver. A few hepatocellular neoplasms were observed
      in control and exposed male mice at the 9-and 15-month interim evaluations, but
      the incidences in exposed groups were not significantly increased. At the end of
      the 2-year study, incidences of eosinophilic foci were increased in 500 ppm males
      and females. Increased incidences of hepatoblastoma occurred in 500 ppm males (0
      ppm, 0/50; 50 ppm, 1/50; 250 ppm, 1/50; 500 ppm, 5/50). Increased incidences of
      hepatocellular adenoma also occurred in 500 ppm males (18/50, 18/50, 16/50,
      29/50) and females (6/49, 10/48, 10/49, 28/50). The incidences of hepatocellular
      carcinoma were similar among control and exposed mice. GENETIC TOXICOLOGY:
      Methylphenidate hydrochloride was not mutagenic in Salmonella typhimurium strains
      TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic
      activation (S9). Methylphenidate hydrochloride was also tested for induction of
      sister chromatid exchanges and chromosomal aberrations in cultured Chinese
      hamster ovary cells. In the chromosomal aberrations tests, positive results were
      not consistently dependent upon the presence or absence of S9 activation. Sister
      chromatid exchanges were not increased in the presence of S9, but one laboratory
      did obtain a positive response without S9 by testing higher doses than were used
      in tests With S9. CONCLUSIONS: Under the conditions of these 2-year feed studies,
      there was no evidence of carcinogenic activity of methylphenidate hydrochloride
      in male or female F344/ N rats receiving 100, 500, or 1,000 ppm. There was some
      evidence of carcinogenic activity of methylphenidate hydrochloride in male and
      female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. Treatment
      of female rats with methylphenidate hydrochloride was associated with a decrease
      in the incidence of mammary gland fibroadenomas. Administration of
      methylphenidate hydrochloride to male and female mice resulted in increased
      incidences of eosinophilic foci. Synonyms: a-phenyl-2-piperidineacetic acid
      methyl ester hydrochloride; methylphenidylacetate hydrochloride; a-phenyl-a-(2
      piperidyl)acetic acid methyl ester hydrochloride; methyl a-phenyl-a-(2
      piperidyl)acetate hydrochloride

PMID- 12595925
TI  - NTP Toxicology and Carcinogenesis Studies of Benzethonium Chloride (CAS No. 121
      54-0) in F344/N Rats and B6C3F1 Mice (Dermal Studies).
AB  - Benzethonium chloride is used primarily in cosmetics for its antimicrobial and
      cationic surfactant properties. Benzethonium chloride was nominated by the
      National Cancer Institute to the NTP for study from a class study of chemicals
      used as biocides. The chemical was selected based on a suspicion of
      carcinogenicity and its known widespread human exposure. Male and female F344/N
      rats and B6C3F1 mice were topically administered benzethonium chloride (greater
      than 98% pure) for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 16
      DAY STUDY IN RATS: Groups of five male and five female F344/N rats were topically
      administered 0, 6.3, 12.5, 25, 50, or 100 mg benzethonium chloride/kg body
      weight. Rats were administered a total of 12 doses in a fixed volume of 250
      &mgr;L ethanol. All rats survived to the end of the study. The final mean body
      weights and body weight gains of rats administered 50 or 100 mg benzethonium
      chloride/kg body weight were significantly less than those of the controls.
      Clinical findings at necropsy included thickening or hardening of the skin at the
      site of application in all rats administered 50 or 100 mg/kg and in 25 mg/kg
      males. Lesions at the site of application appeared crusty or red-grey in color.
      Epithelial hyperplasia with or without inflammation occurred at the site of
      application in all groups of males and females administered benzethonium
      chloride. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice
      were topically administered 0, 6.3, 12.5, 25, 50, or 100 mg benzethonium
      chloride/kg body weight. Mice were administered a total of 12 doses in a fixed
      volume of 100 &mgr;L ethanol. One 100 mg/kg male mouse died on day 4 of the
      study. Final mean body weights of all groups of males and females were similar to
      those of the controls. Clinical findings included mild irritation at the site of
      application in 50 and 100 mg/kg males and females and in 25 mg/kg males.
      Epithelial hyperplasia with or without inflammation occurred at the site of
      application in all groups of males and females administered benzethonium
      chloride. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were
      topically administered 0, 1.56, 3.13, 6.25, 12.5, or 25 mg benzethonium
      chloride/kg body weight, 5 days per week for 13 weeks. Doses were administered in
      ethanol at a volume not exceeding 300 &mgr;L. All rats survived to the end of the
      study. The final mean body weight and body weight gain of 25 mg/kg males were
      significantly lower than those of the controls. The final mean body weights of
      all other groups of males and of all groups of females were similar to those of
      the controls. Clinical findings included irritation at the site of application in
      groups administered 3.13 mg/kg or greater. There were no differences in absolute
      or relative organ weights considered to be related to chemical administration.
      Epithelial hyperplasia was observed at the site of application in all groups of
      males and females administered benzethonium chloride. Additionally, inflammation
      and ulceration were observed at the site of application in males and females
      administered 3.13 mg/kg or greater. Based on the lesions observed in the 13-week
      study, benzethonium chloride dose levels selected for the 2-year dermal study in
      male and female rats were 0.15, 0.5, and 1.5 mg/kg. 13-WEEK STUDY IN MICE: Groups
      of 10 male and 10 female B6C3F1 mice were topically administered 0, 1.56, 3.13,
      6.25, 12.5, or 25 mg benzethonium chloride/kg body weight, 5 days per week for 13
      weeks. Doses were administered in ethanol at a volume not exceeding 100 &mgr;L.
      All mice survived to the end of the study. The final mean body weights of all
      dosed groups of males and females were similar to those of the controls; the mean
      body weight gain of 25 mg/kg males was significantly less than that of the
      controls. Males administered 6.25, 12.5, or 25 mg/kg developed irritation,
      thickening of the skin, scales, and/or discoloration at the site of application,
      as did femaleale mice administered 12.5 or 25 mg/kg. Increased incidences of
      epithelial hyperplasia and inflammation were observed at the site of application
      in all groups of males and females administered benzethonium chloride. Based on
      the lesions observed in the 13-week study, benzethonium chloride dose levels
      selected for the 2-year dermal study in mice were 0.15, 0.5, and 1.5 mg/kg. 2
      YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were topically
      administered 0, 0.15, 0.5, or 1.5 mg benzethonium chloride/kg body weight 5 days
      per week for 103 weeks. Doses were administered in ethanol, and dose volumes were
      adjusted weekly according to the average body weights of the groups. As many as
      nine rats per group were evaluated after 15 months of chemical administration.
      Survival, Body Weights, and Clinical Findings: Survival of dosed rats was similar
      to that of the controls throughout the study. Mean body weights of all dosed
      groups of males and females were similar to those of the controls throughout the
      study. Reddening of the skin was observed at the site of application in all dosed
      groups of males and females. There were no other clinical findings considered to
      be related to chemical administration. Pathology Findings: There were no
      increased incidences of neoplasms in dosed male or female rats that were
      attributed directly to the administration of benzethonium chloride. Increased
      incidences of epithelial hyperplasia, sebaceous gland hyperplasia, and ulcers
      were observed at the site of application in dosed females. The incidence of
      epithelial hyperplasia was increased in 0.5 and 1.5 mg/kg males. 2-YEAR STUDY IN
      MICE: Groups of 60 male and 60 female B6C3F1 mice were topically administered 0,
      0.15, 0.5, or 1.5 mg benzethonium chloride/kg body weight 5 days per week for 103
      weeks. Doses were administered in ethanol, and dose volumes were adjusted weekly
      according to the average body weights of the groups. As many as 10 mice per group
      were evaluated after 15 months of chemical administration. Survival, Body
      Weights, and Clinical Findings: Survival of dosed mice was similar to that of the
      controls throughout the study. Mean body weights of all dosed groups of males and
      females were similar to those of the controls throughout the study. Reddening of
      the skin was observed at the site of application in all dosed groups of males and
      in 0.15 mg/kg females. There were no other clinical findings attributed to
      chemical administration. Pathology Findings: There were no increased incidences
      of neoplasms in dosed males or females that were related to administration of
      benzethonium chloride. Increased incidences of epithelial hyperplasia were
      observed at the site of application in dosed males and females. GENETIC
      TOXICOLOGY: Benzethonium chloride was not mutagenic in Salmonella typhimurium
      strains TA98, TA100, TA1535, or TA1537 and did not induce sister chromatid
      exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. All
      tests were conducted with and without S9 metabolic activation enzymes.
      CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no
      evidence of carcinogenic activity of benzethonium chloride in male or female
      F344/N rats receiving 0.15, 0.5, or 1.5 mg/kg. There was no evidence of
      carcinogenic activity in male or female B6C3F1 mice receiving 0.15, 0.5, or 1.5
      mg/kg. Exposure of rats and mice to benzethonium chloride by dermal application
      in ethanol for 2 years resulted in epithelial hyperplasia in male and female rats
      and mice and sebaceous gland hyperplasia and ulcers in female rats at the site of
      application. Synonyms: Benzyldimethyl- p -(1,1,3,3-tetramethylbutyl)
      phenoxyethoxy-ethylammonium chloride; diisobutylphenoxyethoxyethyldimethyl benzyl
      ammonium chloride; p -tert-octylphenoxyethoxyethyldimethylbenzyl ammonium
      chloride Trade names: Anti-germ 77, Antiseptol, BZT, Diapp, Disilyn, Hyamine,
      Hyamine 1622, Phemeride, Phemithyn, Polymine D, Quatrachlor, Solamine

PMID- 12595926
TI  - NTP Toxicology and Carcinogenesis Studies of Hexachlorocyclopentadiene (CAS No.
      77-47-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Hexachlorocyclopentadiene is an intermediate used in the manufacture of flame
      retardants, resins, and chlorinated cyclodiene pesticides. Toxicology and
      carcinogenesis studies were conducted by exposing male and female F344/N rats and
      B6C3F1 mice to atmospheres containing hexachlorocyclopentadiene (approximately
      98% pure) for 6 hours per day, 5 days per week, for 13 weeks or 2 years. A stop
      exposure evaluation was conducted in male B6C3F1 mice to determine the influence
      of exposure level and exposure duration on the development of nonneoplastic
      lesions of the respiratory tract and on their regression or progression after
      exposure was stopped. Genetic toxicology studies were conducted in Salmonella
      typhimunum, cultured Chinese hamster ovary cells, Drosophila melanogaster, and
      mouse peripheral blood samples were analyzed for frequency of micronucleated
      normochromatic erythrocytes. 13-WEEK STUDY IN RATS: Groups of 10 male and 10
      female rats were exposed to atmospheres containing 0, 0.04, 0.15, 0.4, 1, or 2
      ppm (equivalent to 0, 0.45, 1.67, 4.46, 11.14, and 22.28 mg/m(3))
      hexachlorocyclopentadiene. Additional rats were exposed to 0, 0.04, 0.4, or 2 ppm
      hexachlorocyclopentadiene and evaluated for differences in clinical pathology
      parameters. All rats in the 1 and 2 ppm groups died during the first 4 weeks of
      the study. The final mean body weight and mean body weight gain of males exposed
      to 0.4 ppm were significantly lower than those of the controls. Listlessness was
      observed in 2 ppm rats from week 1, in 1 ppm rats from week 2, and in 0.4 ppm
      rats during week 3. Rats exposed to 1 or 2 ppm also experienced respiratory
      distress. No chemical-related differences in hematology, clinical chemistry, or
      urinalysis parameters were observed in male or female rats. Absolute and relative
      lung weights of 0.4 ppm males were significantly greater than those of the
      controls. Inflammation (necrotizing, chronic, or suppurative) of the nose,
      larynx, trachea, and lung was observed in 0.4, 1, and 2 ppm males and females.
      Squamous metaplasia of the epithelial lining of the nose of 0.4 ppm males and 1
      and 2 ppm males and females was also observed. 13-WEEK STUDY IN MICE: Groups of
      10 male and 10 female mice were exposed to atmospheres containing 0, 0.04, 0.15,
      0.4, 1, or 2 ppm (equivalent to 0, 0.45, 1.67, 4.46, 11.14, and 22.28 mg/m(3))
      hexachlorocyclopentadiene. Additional mice were exposed to 0, 0.04, 0.4, or 2 ppm
      and evaluated for differences in clinical pathology parameters. All 2 ppm mice
      died during the first week of exposure. All 1 ppm mice died during the first 5
      weeks of exposure. Five males and two females in the 0.4 ppm group died during
      the first 2 weeks of exposure. Deaths in the other groups were not related to
      hexachlorocyclopentadiene exposure. Final mean body weights of males exposed to
      0.15 and 0.4 ppm and the body weight gain of 0.4 ppm males were significantly
      lower than those of the controls. Treatment-related clinical findings included
      listlessness in 0.4 and 1 ppm males and females. No chemical-related differences
      in hematology, clinical chemistry, or urinalysis parameters were observed in male
      or female mice. Necrosis or inflammation of the nose, larynx, trachea, or lung
      occurred in mice exposed to 0.4,1, and 2 ppm hexachlorocyclopentadiene. Squamous
      metaplasia of the larynx or trachea was observed in 0.15, 0.4, and 1 ppm males
      and in 0.4 and 1 ppm females. 2-YEAR STUDY IN RATS: Survival, Body Weights,
      Clinical Findings, and Urinalysis Groups of 60 male and 60 female rats were
      exposed to atmospheres containing 0, 0.01, 0.05, or 0.2 ppm (equivalent to 0,
      0.11, 0.56, and 2.28 mg/m(3)) hexachlorocyclopentadiene. Survival rates and mean
      body weights of exposed rats were similar to those of the controls. No chemical
      related clinical findings were observed in male or female rats during the 2-year
      study. No differences in urinalysis parameters at the 15-month interim evaluation
      could be attributed to exposure to hexachlorocyclopentadiene. Pathology Findings:
      No increases in neoplasm incidences could be attributed to
      hexachlorocyclorocyclopentadiene. Toxicity was limited to the respiratory tract
      and included an increase in the incidence of pigmentation of the respiratory
      epithelium of the nose, trachea, and the bronchi and bronchioles of the lung in
      both males and females. Exposure to hexachlorocyclopentadiene also caused an
      increase in the incidence of squamous metaplasia of the laryngeal epithelium of
      exposed females; the incidences in 0.01 and 0.2 ppm females were significantly
      greater than that of the controls. The severity of squamous metaplasia was
      minimal in all exposed and control females. 2-YEAR STUDY IN MICE: Survival, Body
      Weights, Clinical Findings, and Urinalysis Groups of 60 male and 60 female mice
      were exposed to atmospheres containing 0, 0.01, 0.05, or 0.2 ppm (equivalent to
      0, 0.11, 0.56, and 2.28 mg/m(3)) hexachlorocyclopentadiene. The 2-year survival
      rate of female mice in the 0.2 ppm group was marginally lower than that of the
      controls due to a higher incidence of ovarian inflammation in 0.2 ppm females.
      Mean body weights of 0.2 ppm males (weeks 62 to 103) and females (throughout the
      study) were lower than those of the controls. No clinical findings in male or
      female mice were attributed to chemical exposure during the 2-year study. There
      were no chemical-related differences in urinalysis parameters at the 15-month
      interim evaluation. Pathology Findings: The site of toxicity of
      hexachlorocyclopentadiene exposure in mice in the 2-year study was the
      respiratory tract. Chemical-related pigmentation of the respiratory epithelium of
      the nose, trachea, and lung and suppurative inflammation of the nose were
      observed. No increased neoplasm incidences in males or females could be
      attributed to hexachlorocyclopentadiene exposure. STOP-EXPOSURE EVALUATION:
      Survival, Body Weights, and Clinical Findings Groups of male mice were exposed to
      atmospheres containing 0.2 ppm hexachlorocyclopentadiene for 33 or 66 weeks or
      0.5 ppm for 26 or 42 weeks followed by exposure to air until the end of the
      study. Fifty male mice from each stop-exposure group were evaluated at 2 years.
      Two-year survival rates of stop exposure groups were similar to that of the
      controls. Final mean body weights of stop-exposure groups were similar to that of
      the controls. No chemical related clinical findings were observed. Pathology
      Findings: Nonneoplastic respiratory tract lesions similar to those observed in
      the core study were observed in males in the stop-exposure groups. Chemical
      related pigmentation and inflammation of the respiratory epithelium were
      persistent as indicated by their presence in many male mice after recovery
      periods of 62 to 78 weeks, and the incidence and severity of the lesions were
      related to exposure concentration and duration. GENETIC TOXICOLOGY:
      Hexachlorocyclopentadiene was not mutagenic in Salmonella typhimurium strains
      TA98, TA100, TA1535, and TA1537 when tested with and without S9.
      Hexachlorocyclopentadiene did induce sister chromatid exchanges and chromosomal
      aberrations in cultured Chinese hamster ovary cells, with and without S9. No
      induction of sex-linked recessive lethal mutations was observed in male
      Drosophila melanogaster treated with hexachlorocyclopentadiene by feeding or
      injection, and no increase in the frequency of micronucleated erythrocytes was
      seen in male or female B6C3F1 mice exposed to hexachlorocyclopentadiene by
      inhalation for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year
      studies, there was no evidence of carcinogenic activity of
      hexachlorocyclopentadiene in male or female F344/N rats or B6C3F1 mice exposed to
      0.01, 0.05, or 0.2 ppm. Exposure of rats to hexachlorocyclopentadiene produced
      pigmentation of the respiratory epithelium of the nose, trachea (males), and
      bronchi and bronchioles of the lung. Squamous metaplasia of the laryngeal
      epithelium occurred in female rats exposed to hexachlorocyclopentadiene.
      Suppurative inflammation of the nose as well as pigmentation of the respiratory
      mucosal epithelium occurred in mice exposed to hexachlorocyclopentadiene.
      Synonyms: Perchlorocyclopentadiene, hexachloro-1,3-cyclopentadiene, HEX, HCPD,
      HCCP, HCCPD Trade Name: C-56-Graphlox

PMID- 12595927
TI  - NTP Toxicology and Carcinogenesis Studies of t -Butyl Alcohol (CAS No. 75-65-0)
      in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
AB  - t -Butyl alcohol is widely used in the manufacture of perfumes and a variety of
      cosmetics. It is also used as a raw material in the production of isobutylene,
      which may be used to produce methyl tertiary butyl ether, a common gasoline
      additive, or to produce butyl elastomers used in the production of automobile
      tires. Male and female F344/N rats and B6C3F1 mice were given t -butyl alcohol
      (greater than 99% pure) in drinking water for 13 weeks or 2 years. The genetic
      toxicity of t -butyl alcohol was assessed by testing the ability of the chemical
      to induce mutations in various strains of Salmonella typhimurium and in L5178Y
      mouse lymphoma cells, sister chromatid exchanges and chromosomal aberrations in
      cultured Chinese hamster ovary cells, and by measuring the frequency of
      micronucleated erythrocytes in mouse peripheral blood. 13-WEEK STUDY IN RATS:
      Groups of 10 male and 10 female F344/N rats were given 0, 2.5, 5, 10, 20, or 40
      mg/mL t -butyl alcohol in drinking water for 13 weeks. All males and six females
      given 40 mg/mL died during the study. Final mean body weights of 10 and 20 mg/mL
      males and of 40 mg/mL females were 12%, 17%, or 21% less than those of the
      corresponding controls, respectively. Serum sorbitol dehydrogenase activities in
      10 and 20 mg/mL males were greater than that in the controls after 13 weeks.
      Serum alanine aminotransferase activity in 40 mg/mL females was greater than that
      in the controls after 2 weeks and greater in all exposed females after 13 weeks.
      Urine volumes of 10, 20, and 40 mg/mL males and females decreased, and urine
      specific gravity values increased. Transitional epithelial hyperplasia and
      inflammation of the urinary bladder were observed in 20 and 40 mg/mL males and 40
      mg/mL females. Absolute and relative liver weights of all exposed groups of
      females and relative liver weights of 5, 10, and 20 mg/mL males were
      significantly greater than those of the controls. Absolute and relative kidney
      weights of all exposed groups of males and females were significantly greater
      than those of the controls. Incidences of mineralization of the kidney were
      significantly increased in 10, 20, and 40 mg/mL males. The severity of
      nephropathy in 2.5, 5, 10, and 20 mg/mL males was significantly greater than that
      of the controls as was the accumulation of hyaline droplets in the kidney of 5,
      10, and 20 mg/mL males. The incidences of nephropathy in 10, 20, and 40 mg/mL
      females were significantly greater than that of the controls. 13-WEEK STUDY IN
      MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 2.5, 5, 10, 20,
      or 40 mg/mL t -butyl alcohol in drinking water for 13 weeks. The deaths of two
      males and one female in the 40 mg/mL group were attributed to exposure to t 
      butyl alcohol. The final mean body weights of 20 and 40 mg/mL males and 40 mg/mL
      females were significantly lower than those of the controls. There were no
      biologically significant differences in hematology parameters of exposed and
      control groups of mice. Transitional epithelial hyperplasia and inflammation were
      observed in the urinary bladder of 20 and 40 mg/mL males and 40 mg/mL females. 2
      YEAR STUDY IN RATS: Groups of 60 F344/N rats were given 0, 1.25, 2.5, or 5 mg/mL
      t -butyl alcohol (males) or 0, 2.5, 5, or 10 mg/mL t -butyl alcohol (females) in
      drinking water for 2 years. These correspond to average daily doses of
      approximately 90, 200, or 420 mg t -butyl alcohol/kg body weight for males and
      approximately 180, 330, or 650 mg t -butyl alcohol/kg body weight for females.
      Ten rats per group were evaluated after 15 months of chemical administration.
      Survival, Body Weights, and Water Consumption: Survival rates of 5 mg/mL males
      and 10 mg/mL females were significantly lower than those of the controls. The
      final mean body weights of exposed groups of males were 15% to 24% lower than
      that of the controls, and the final mean body weight of 10 mg/mL females was 21%
      lower than that of the controls. Water consumption by males increased with dose;
      water consumption by females decreased with dose. Hematology and Urinalysis: At
      the 15-month inte. Hematology and Urinalysis: At the 15-month interim evaluation,
      there were no significant differences in hematology parameters in males and
      females, and there were no significant differences in urinalysis parameters in
      males. Females given 5 or 10 mg/mL had increased urine specific gravities and
      decreased urine volumes. Pathology Findings: At the 15-month interim evaluation,
      relative kidney weights of 2.5 and 5 mg/mL males and absolute and relative kidney
      weights of 2.5, 5, and 10 mg/mL females were significantly greater than those of
      the controls. At 2 years, the incidence of mineralization in the kidney increased
      with dose and that of 5 mg/mL males was significantly greater than that of the
      controls. In the standard evaluation at the end of the study, the incidences of
      focal renal tubule hyperplasia and of adenoma were increased in exposed males and
      a carcinoma was observed in one 5 mg/mL male. Renal tubule hyperplasia occurred
      in one 10 mg/mL female. An extended evaluation of the kidney identified
      additional male rats with hyperplasia (control, 11/50; 1.25 mg/mL, 13/50; 2.5
      mg/mL, 11/50; 5 mg/mL, 19/50) and renal tubule adenoma (7/50, 8/50, 15/50,
      10/50); renal tubule carcinomas were identified in two 1.25 mg/mL males and in
      one 2.5 mg/mL male. Renal tubule adenoma was identified in one 5 mg/mL male from
      the 15-month extended evaluation. In the standard and extended evaluations
      combined, there were dose-related increased incidences of hyperplasia and
      adenoma. The severity of nephropathy and the incidence and severity of
      transitional cell hyperplasia of the kidney were increased in exposed male and
      female rats. Linear foci of mineralization were present in the renal papilla of
      exposed males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice
      were given 0, 5, 10, or 20 mg/mL t -butyl alcohol in drinking water for 2 years.
      Exposure levels of 5, 10, or 20 mg/mL delivered average daily doses of
      approximately 540, 1,040, or 2,070 mg t -butyl alcohol/kg body weight to males
      and approximately 510, 1,020, or 2,110 mg/kg to females. Survival, Body Weights,
      and Water Consumption: Survival of 20 mg/mL males was significantly lower than
      that of the controls. The final mean body weights of exposed groups of males were
      similar to those of the controls. The mean body weights of females given 20 mg/mL
      were 10&percnt; to 15&percnt; lower than those of the controls from week 13 to
      the end of the study. Water consumption by exposed groups of males and females
      was similar to that by the controls. Pathology Findings: Incidences of thyroid
      gland follicular cell hyperplasia were significantly increased in all exposed
      groups of males and in 10 and 20 mg/mL females. The incidence of follicular cell
      adenoma or carcinoma (combined) was marginally increased in 10 mg/mL males (0
      mg/mL, 1/60; 5 mg/mL, 0/59; 10 mg/mL, 4/59; 20 mg/mL, 2/57). The incidence of
      follicular cell adenoma was significantly increased in 20 mg/mL females (2/58,
      3/60, 2/59, 9/59). The incidences of chronic inflammation and transitional
      epithelial hyperplasia of the urinary bladder were increased in 20 mg/mL males
      and to a lesser extent in 20 mg/mL females. GENETIC TOXICOLOGY: t -Butyl alcohol
      was tested for induction of genetic damage in vitro and in vivo, and all results
      were negative. In vitro, t -butyl alcohol was negative in Salmonella typhimurium
      and mouse lymphoma cell mutation tests, and it did not induce sister chromatid
      exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells.
      These in vitro studies were conducted with and without metabolic activation (S9).
      In vivo, no increase in micronucleated erythrocytes was observed in peripheral
      blood samples from mice administered t -butyl alcohol in drinking water for 13
      weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies,
      there was some evidence of carcinogenic activity of t -butyl alcohol in male
      F344/N rats based on increased incidences of renal tubule adenoma or carcinoma
      (combined). There was no evidence of carcinogenic activity in female F344/N rats
      receiving 2.5, 5, or 10 mg/mL t -butyl alcohol. There was equivocal evidence of
      carcinogenic activity of t -butyl alcohol in male B6C3F1 mice based on the
      marginally increased incidences of follicular cell adenoma or carcinoma
      (combined) of the thyroid gland. There was some evidence of carcinogenic activity
      of t -butyl alcohol in female B6C3F1 mice based on increased incidences of
      follicular cell adenoma of the thyroid gland. Exposure to t -butyl alcohol was
      associated with mineralization and renal tubule hyperplasia in male rats,
      transitional epithelial hyperplasia and increased severity of nephropathy of the
      kidney in male and female rats, follicular cell hyperplasia of the thyroid gland
      in male and female mice, and chronic inflammation and hyperplasia of the urinary
      bladder in male mice and to a lesser extent in female mice. Synonyms: 2-Methyl-2
      propanol, 2-methylpropan-2-ol, TBA, t -butanol, tertiary butyl alcohol, t -butyl
      hydroxide, trimethyl carbinol, trimethyl methanol

PMID- 12595928
TI  - NTP Toxicology and Carcinogenesis Studies of 4,4'-Thiobis(6- t -butyl- m -cresol)
      (CAS No. 96-69-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - 4,4'-Thiobis(6- t -butyl- m -cresol) (TBBC) is used in the rubber and plastics
      industries as an antioxidant. TBBC is also used as a stabilizer in polyethylene
      and polyolefin packaging materials for foodstuffs. Toxicology and carcinogenesis
      studies were conducted by administering TBBC (99% pure) in feed to groups of male
      and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium and cultured
      Chinese hamster ovary cells. 15-DAY STUDY IN RATS: Groups of 10 male and 10
      female F344/N rats were fed diets containing 0, 1,000, 2,500, 5,000, 10,000 or
      25,000 ppm TBBC for 15 days. Rats given to 1,000, 2,500, 5,000, or 10,000 ppm
      received approximate doses of 95, 235, 335, or 365 mg TBBC per kilogram body
      weight per day (males) or 85, 220, 325, or 270 mg/kg per day (females).
      Approximate doses for rats receiving 25,000 ppm could not be calculated due to
      early deaths. All 25,000 ppm rats and three male and four female 10,000 ppm rats
      died. Surviving rats in the 10,000 ppm groups had a significant weight loss and
      the final mean body weights of 5,000 and 10,000 ppm male and female rats were
      significantly lower than those of the controls. Male and female rats exposed to
      5,000, 10,000, or 25,000 ppm TBBC consumed markedly less feed than the controls.
      Diarrhea occurred in 5,000, 10,000, and 25,000 ppm males and females. The
      principal lesions attributed to the administration of TBBC were renal papillary
      and tubule necroses which occurred in 10,000 ppm rats. Focal necrosis or erosions
      of the glandular stomach also occurred in some 10,000 ppm rats. Changes observed
      in the thymus and spleen were attributed to debilitation or stress; bone marrow
      depletion was attributed to nutrient deficiency accompanying weight loss. 15-DAY
      STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets
      containing 0, 1,000, 2,500, 5,000, 10,000, or 25,000 ppm TBBC for 15 days. Mice
      given 1,000, 2,500, or 5,000 ppm received approximate doses of 285, 585, or 475
      mg TBBC per kilogram body weight per day (males) or 360, 950, or 1,030 mg/kg per
      day (females). Approximate doses for mice given 10,000 or 25,000 ppm could not be
      calculated due to early deaths. All 10,000 and 25,000 ppm mice died, as did eight
      males and eight females given 5,000 ppm. A significant weight loss occurred in
      surviving 5,000 ppm males and females and the final mean body weights of 2,500
      ppm females and 5,000 ppm males and females were significantly lower than those
      of the controls. Feed consumption by mice given 5,000, 10,000, or 25,000 ppm was
      markedly reduced. Diarrhea occurred in all 25,000 ppm mice and in most male and
      female mice given 5,000 or 10,000 ppm. Renal tubule necrosis occurred in eight
      males and three females in the 5,000 ppm groups. Lymphocytic depletion of
      Iymphoid tissues in many 5,000 ppm males and females was attributed to
      debilitation and stress or to nutrient deficiency accompanying weight loss. 13
      WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets
      containing 0, 250, 500, 1,000, 2,500, or 5,000 ppm TBBC for 13 weeks. These
      exposure levels delivered approximate doses of 15, 30, 60, 165, or 315 mg TBBC
      per kilogram body weight per day (males) or 15, 35, 70, 170, or 325 mg/kg per day
      (females). All rats survived to the end of the study. The final mean body weight
      of 5,000 ppm males was 40% lower than that of the controls; the final mean body
      weight of 5,000 ppm females was 27% lower than that of the controls. Feed
      consumption by male and female rats exposed to 5,000 ppm TBBC was markedly lower
      than that by the controls throughout the study. The absolute and relative liver
      weights of 5,000 ppm females were significantly greater than those of the
      controls. Serum alkaline phosphatase (ALP) levels were significantly higher in
      2,500 and 5,000 ppm males and slightly higher in 5,000 ppm females. Serum alanine
      aminotransferase levels were significantly higher in 2,500 and 5,000 ppm males
      and females. Hematocrit and hemoglobin concentrations and mean erythroions and
      mean erythrocyte volume (MCV) values were significantly lower in 1,000, 2,500,
      and 5,000 ppm males than in controls; MCV values were also significantly lower in
      5,000 ppm females. A dose-related significant increase in forelimb and hindlimb
      grip strength was observed in exposed male and female rats. Histopathologic
      findings in the liver of 2,500 and 5,000 ppm males and females included
      hypertrophy of Kupffer cells, bile duct hyperplasia, and individual cell necrosis
      of hepatocytes; centrilobular hepatocyte hypertrophy also occurred in males and
      females exposed to 5,000 ppm TBBC. Macrophages were increased in size and number
      in the mesenteric Iymph nodes of males and females exposed to 5,000 ppm, and to a
      lesser extent in 2,500 ppm male and female rats. Pigmentation and degeneration of
      the renal cortical tubule epithelial cells was also present in males and females
      in the 2,500 and 5,000 ppm groups; cortical tubule necrosis occurred in 5,000 ppm
      males and females. 13-WEEK STUDY IN MICE: Groups of up to 10 male and 10 female
      B6C3F1 mice were fed diets containing 0, 100, 250, 500, 1,000, or 2,500 ppm TBBC
      for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 65,
      145, or 345 mg TBBC per kilogram body weight per day (males) or 10, 35, 60, 165,
      or 340 mg/kg per day (females). All mice survived to the end of the study. The
      final mean body weights of 2,500 ppm males and of 500,1,000, or 2,500 ppm females
      were significantly lower than those of the controls. Feed consumption by 2,500
      ppm males averaged 24&percnt; lower than that by controls through week 3 and was
      similar to that by controls for the remainder of the study. Feed consumption by
      females receiving 2,500 ppm averaged 27&percnt; less than that by the controls
      during most of the study. The absolute and relative liver weights of males and
      females exposed to 2,500 ppm TBBC were slightly but significantly greater than
      those of the controls. Males exposed to 500, 1,000, or 2,500 ppm and females
      exposed to 2,500 ppm had significantly increased absolute and relative spleen
      weights. No clinical findings in mice were considered chemical related.
      Hematocrit concentrations and erythrocyte counts of males receiving 1,000 or
      2,500 ppm were significantly less than those of the controls; hemoglobin
      concentration in males receiving 2,500 ppm was significantly less and mean
      erythrocyte volume was significantly less in males receiving 2,500 ppm. Females
      in the 1,000 and 2,500 ppm groups had significantly decreased hematocrit
      concentrations and erythrocyte counts; 2,500 ppm females also had significantly
      decreased hemoglobin concentrations and mean erythrocyte volumes. Kupffer cell
      hypertrophy, bile duct hyperplasia, and an increase in size and number of
      macrophages in mesenteric Iymph nodes were present in 2,500 ppm male and female
      mice. 2-YEAR STUDY IN RATS: Doses selected for the 2-year study of TBBC were
      based on the lower body weights and liver and kidney toxicity observed at 5,000
      ppm in the 13-week study. Groups of 115 male and 75 female F344/N rats were fed
      diets containing 0, 500, 1,000, or 2,500 ppm TBBC for 2 years. Based on average
      daily feed consumption, these exposure levels resulted in a daily ingestion of
      TBBC of approximately 20, 40, or 100 mg/kg body weight for males and 20, 45, or
      120 mg/kg body weight for females. Hematology, clinical chemistry, and urinalysis
      evaluations were performed on 15 male and 15 female rats from each group at 3, 9,
      and 15 months. Also at 15 months, an additional 10 male and 10 female rats from
      each group were evaluated for histopathology, hematology, and clinical chemistry.
      Forty male rats per group were evaluated for neurotoxic effects. Survival, Body
      Weights, Feed Consumption, and Clinical Findings: Two-year survival rates and
      mean body weights of exposed male and female rats were generally similar to those
      of the controls. The mean body weights of 2,500 ppm male rats were slightly lower
      than those of the controls throughout the study. At week 65, the mean body weight
      of 2,500 ppm females was 14&percnt; lower than that of the controls, but the
      final mean body weight of this group was 6&percnt; lower than that of the control
      group. Feed consumption, behavior, and general health and appearance of exposed
      male and female rats were similar to those of the controls. Hematology and
      Clinical Chemistry: Results of the hematology evaluation were not uniformly
      consistent at 3, 9, and 15 months in one set of rats, nor were they consistent
      between the two sets of rats evaluated at 15 months. Slight but significant
      decreases in hematocrit levels, hemoglobin concentrations, and erythrocyte counts
      were observed in the 1,000 and 2,500 ppm groups in one set of males at 15 months.
      Similar significant decreases in hematocrit level and hemoglobin concentration
      occurred in 2,500 ppm females at 9 months. Mean erythrocyte hemoglobin and mean
      erythrocyte hemoglobin concentration of 2,500 ppm females were also significantly
      lower than those of controls at 9 months and in both sets of female rats
      evaluated at 15 months. Platelet counts of 2,500 ppm male and female rats were
      slightly but significantly higher than those of controls at 3 and 9 months.
      Platelet counts were also slightly but significantly increased in 2,500 ppm males
      of one set evaluated at 15 months, and in 2,500 ppm females of the second set
      evaluated at 15 months. Serum activities of alkaline phosphatase, alanine
      aminotransferase, and sorbitol dehydrogenase in 2,500 ppm males were
      significantly greater than those in the controls at 3, 9, and 15 months. Alkaline
      phosphatase activities in both sets of 1,000 ppm males evaluated at 15 months
      were also significantly greater than those of controls. Serum activities of
      alanine aminotransferase and sorbitol dehydrogenase in 2,500 ppm females were
      also significantly greater than those in controls at 3, 9, and 15 months.
      Neurotoxicity Findings: There were no significant inhibitory effects of TBBC on
      motor nerve excitability or conduction, neuromuscular transmission, or muscle
      contractility. There were no microscopic lesions in the sciatic nerve, quadriceps
      muscle, or teased nerve preparations of sciatic nerve that could be attributed to
      TBBC administration. Pathology Findings: At the 15-month interim evaluation, the
      absolute and relative liver weights of 2,500 ppm female rats were significantly
      greater than those of controls; at 15 months and at the end of the study, the
      incidences of Kupffer cell hypertrophy, hepatocyte cytoplasmic vacuolization, and
      mixed cell foci were also significantly increased. At the end of the study, the
      incidence of hepatocellular fatty change was significantly increased in 2,500 ppm
      females. The incidence of Kupffer cell hypertrophy was significantly increased in
      2,500 ppm males at 15 months and at 2 years; the incidence of cytoplasmic
      vacuolization was significantly increased in all exposed males at 15 months but
      only moderately increased in 1,000 and 2,500 ppm males at 2 years; the incidence
      of basophilic foci was significantly increased in 2,500 ppm males at 15 months
      and the incidence of mixed cell foci was significantly increased in 1,000 and
      2,500 ppm male rats at 2 years. The incidences of hepatocellular adenoma or
      carcinoma (combined) in exposed male rats were not significantly greater than
      that in the controls (0 ppm, 1/50; 500 ppm, 3/50; 1,000 ppm, 3/50; 2,500 ppm,
      5/49), were within the historical control range, and were not considered chemical
      related. The severity of nephropathy was significantly increased in 2,500 ppm
      female rats. There was a significant negative trend in the incidence of mammary
      gland fibroadenoma, adenoma, or carcinoma (combined) in female rats (32/50,
      24/50, 11/50, 16/50), and the incidences of fibroadenoma in 1,000 and 2,500 ppm
      females were significantly less than that of the controls. 2-YEAR STUDY IN MICE:
      Because of the reduction in body weights, the increase in liver and spleen
      weights, and the accompanying histopathologic changes in the liver of 2,500 ppm
      male and female mice in the 13-week study, the doses selected for the 2-year
      study were 250, 500, and 1,000 ppm. Groups of 80 male and 80 female mice were fed
      diets containing 0, 250, 500, or 1,000 ppm TBBC for 2 years. Based on average
      daily feed consumption, these exposure levels resulted in the daily ingestion of
      approximately 30, 60, or 145 mg TBBC/kg body weight for males and 45, 110, or 255
      mg TBBC/kg body weight for females. Nine or 10 animals from each exposure group
      were evaluated at 3, 9, and 15 months. Survival, Body Weights, Feed Consumption,
      and Clinical Findings: Two-year survival rates of exposed male and female mice
      were similar to those of the controls. The final mean body weights of male and
      female mice exposed to 1,000 ppm were 8&percnt; and 18&percnt; lower than those
      of the controls, respectively. The final mean body weights of females exposed to
      250 or 500 ppm were 8&percnt; to 9&percnt; lower than that of the controls. Feed
      consumption by exposed males was similar to that by controls, and there were no
      clinical findings attributed to TBBC administration. Hematology and Clinical
      Chemistry: Hematocrit level, hemoglobin concentration, and erythrocyte count in
      1,000 ppm male mice were significantly lower than those in controls at the 15
      month interim evaluation. Serum alkaline phosphatase activities in 1,000 ppm
      males were slightly but significantly greater than those in controls at 3 and 9
      months, as was the serum alkaline phosphatase activity in 1,000 ppm females at 9
      months. Serum levels of total bilirubin in all exposed groups of males were
      significantly greater than those in controls at 9 and 15 months. Pathology
      Findings: In the liver of male mice, negative trends in the incidences of fatty
      change, clear cell foci, and adenoma or carcinoma combined occurred at the end of
      the 2-year study. There were no compound-related increased incidences of
      neoplasms or nonneoplastic lesions in mice receiving TBBC for 2 years. A negative
      trend in the incidence of fatty change in the liver of male mice also occurred at
      15 months. GENETIC TOXICOLOGY: 4,4'-Thiobis(6- t -butyl- m -cresol) was not
      mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with
      or without exogenous metabolic activation (S9). Sister chromatid exchanges were
      induced in cultured Chinese hamster ovary cells treated with TBBC, with and
      without S9, but no increases in chromosomal aberrations were noted in cultured
      Chinese hamster ovary cells after treatment with TBBC. CONCLUSIONS: Under the
      conditions of these 2-year feed studies, there was no evidence of carcinogenic
      activity of 4,4'-thiobis(6- t -butyl- m -cresol) in male or female F344/N rats
      administered 500, 1,000, or 2,500 ppm or in male or female B6C3F1, mice
      administered 250, 500, or 1,000 ppm. Nonneoplastic lesions associated with
      exposure to TBBC included: Kupffer cell hypertrophy, cytoplasmic vacuolization,
      and mixed cell foci in the liver of male and female rats, fatty change in the
      liver of female, rats, and an increase in the severity of nephropathy in the
      kidney of female rats. In addition, decreased incidences of fibroadenoma,
      adenoma, or carcinoma (combined) were observed in the mammary gland of female
      rats. Decreases also occurred in the incidences of fatty change, clear cell foci,
      and adenoma or carcinoma (combined) in the liver of male mice. Synonyms: 4,4'
      Thiobis(6- t -butyl-3-cresol); bis(3- t -butyl-4-hydroxy-6-methylphenyl)sulfide

PMID- 12595929
TI  - The effect of different drying methods for single step adhesive systems on
      microleakage of tooth colored restorations.
AB  - The purpose of this in vitro study was to evaluate microleakage of tooth colored
      restoratives and accompanying single step adhesive systems using two drying
      methods (syringe air versus "sponge" applicator blotting). Eighty teeth were
      randomly assigned to four material groups. Class V cavity preparations, located
      half in enamel and half in cementum at the cementoenamel junction (CEJ), with a
      1.0 mm enamel bevel were completed. The adhesive/composite groups included: (1)
      Single-Bond/Z-100 Composite, (2) Prime & Bond 2.1/Dyract AP Compomer, (3)
      OptiBond Solo Plus/Prodigy Composite, and (4) Scotchbond MultiPurpose/Z-100
      Composite. Each material group (n=20), consisted of preparation Subgroups dried
      with syringe air (A), (n=10) and sponge applicators (B), (n=10). The preparations
      were conditioned, rinsed, and gently dried followed by placement of the
      primer/adhesive and restorative materials. All teeth were thermocycled, stained
      with methylene blue dye, invested in clear acrylic resin, and sectioned
      longitudinally through the center of the restoration. Readings were taken at the
      occlusal and gingival surface positions of each restoration section. A ratio (%)
      of wall length to amount of leakage along each wall was established. One-way
      Analysis of Variance (ANOVA) testing revealed: (1) no significant (p<0.05)
      differences existed between materials at the occlusal surface position in
      Subgroups A and B (syringe vs. applicator drying), (2) significantly (P<0.05)
      greater leakage of OptiBond Solo Plus compared to Single-Bond, Prime & Bond 2.1,
      and Scotchbond MultiPurpose at the gingival surface position in Subgroups A and
      B, (3) significantly (p<0.05) greater leakage of OptiBond Solo Plus compared to
      Single-Bond and Scotchbond MultiPurpose, combining the occlusal/gingival surface
      position scores, (4) no significant difference existed between Single-Bond
      Subgroups A/B, OptiBond Solo Plus Subgroups A/B, Scotchbond MultiPurpose
      Subgroups A/B, (5) significantly (p<0.05) greater leakage of Prime & Bond 2.1
      Subgroup B compared to Subgroup A, (6) no significant (p<0.05) difference existed
      between material groups, except OptiBond Solo Plus (occlusal vs. gingival surface
      position), (7) no significant (p<0.05) difference between Single-Bond, OptiBond
      Solo Plus, and Scotchbond MultiPurpose comparing both Subgroups, same materials,
      and surface positions, and (8) no significant (p<0.05) difference existed between
      Prime & Bond 2.1, comparing both Subgroups, occlusal surface position. In the
      present study, significantly greater leakage was revealed with OptiBond Solo Plus
      compared to the other material groups, especially at the gingival surface
      positions. Significantly greater leakage was also recorded with OptiBond Solo
      Plus and Prime & Bond 2.1 sponge applicator drying as compared to the same
      materials, syringe air drying.

PMID- 12595930
TI  - A review of drug-induced oral reactions.
AB  - Every drug can produce untoward consequences, even when used according to
      standard or recommended methods of administration. Adverse drug reactions can
      involve every organ and system of the body and are frequently mistaken for signs
      of underlying disease. Similarly, the mouth and associated structures can be
      affected by many drugs or chemicals. Good oral health, including salivary
      function, is very important in maintaining whole body health. Regarding different
      parts of the oral system, these reactions can be categorized to oral mucosa and
      tongue, periodontal tissues, dental structures, salivary glands, cleft lip and
      palate, muscular and neurological disorders, taste disturbances, drug-induced
      oral infection, and facial edema. In this article, the drugs that may cause
      adverse effects in the mouth and related structures are reviewed. The knowledge
      about drug-induced oral adverse effects helps health professionals to better
      diagnose oral disease, administer drugs, improve patient compliance during drug
      therapy, and may influence a more rational use of drugs.

PMID- 12595931
TI  - The effect of a 10% carbamide peroxide home bleaching system on the gingival
      health.
AB  - Esthetics plays an important role in dentistry today. Because of an increased
      emphasis on beauty and health, cosmetic dentistry has been the thrust to the
      forefront of many practices. Many health products are used for bleaching teeth,
      but all side effects are not known. Tooth sensitivity and gingival irritation are
      the most common side effects, but they are typically mild and transient in
      nature. The aim of this investigation was to evaluate objectively the effect of
      10% carbamide peroxide gel (Opalescence Utradent Inc, USA) on gingival health by
      measuring changes in Bleeding Index, Plaque Index, and Gingival Index. Eighteen
      subjects, 11 female and 7 male, age range 15-30 years (mean 24 years), were
      selected for the study as a convenient sample. Their teeth had either fluorosis,
      dental stains, smoking, or tetracycline staining. The Opalescence system was used
      as office monitored, at-home bleaching for three weeks. There was a statistically
      significant reduction in bleeding on probing (1% - 37%, p < or = 0.003), Plaque
      Index (4% - 50%, p < or = 0.000), and Gingival Index (2.5% - 34%, p < or =
      0.002). Only two subjects reported tooth hypersensitivity, and none of the
      subjects complained about gingival irritation. There was a positive change in
      tooth color as far as staining was concerned. Further research including
      randomized controlled, double blind clinical trials is needed to confirm these
      findings and to examine other factors related to bleaching of teeth.

PMID- 12595932
TI  - Evidence-based decision making in action: Part 2--evaluating and applying the
      clinical evidence.
AB  - This is the second of a two-part series addressing the use of evidence-based
      decision making (EBDM) in the use of home bleaching. In Part 1, a case scenario
      demonstrated the skills involved in (1) structuring a clinical question and (2)
      conducting an online search using PubMed.1 Part 2 demonstrates the third and
      fourth steps in the EBDM process, i.e., (3) critical appraisal to assess the
      validity of a study and (4) applying that information to clinical decision
      making. This 4-step approach to EBDM recognizes that clinicians can never be
      completely current with all conditions, medications, materials, and products.
      Thus, EBDM provides a mechanism for addressing these gaps in knowledge in order
      to provide the best care possible.

PMID- 12595933
TI  - A large glandular odontogenic cyst of the mandible: report of case.
AB  - Glandular odontogenic cyst (GOC) is generally considered uncommon, but several
      investigators claim there is a more frequent occurrence than previously thought.
      However these case reports lacked confirming data to validate their claim. On the
      other hand, it is possible that cases of central mucepidermoid carcinoma or later
      periodontal cyst might be viewed as glandular odontogenic cyst. This is a report
      of a case of a 70-year old male who presented with a firm swelling in the right
      side of his edentulous mandible. Radiographic examination revealed a multilocular
      radiolucent lesion in the mandible extending from the right first premolar to the
      left second premolar and reaching the inferior mandible. Clinical findings, the
      health history, and microscopic examination of excised tissue confirmed the
      diagnosis of GOC. The lesion was excised and post-operative healing was
      uneventful.

PMID- 12595934
TI  - The Health Insurance Portability and Accountability Act: practice of dentistry in
      the United States: privacy and confidentiality.
AB  - This paper introduces the reader to the Health Insurance Portability and
      Accountability Act (HIPAA) of 1996 legislation in the context of its relationship
      to the Electronic Oral Health Record (EOHR). Privacy and confidentiality issues
      for administrative data are addressed in terms of the broader relationship of
      such data to the EOHR leaving the HIPAA-defined administrative transactions and
      security issues for the entire practice for a subsequent presentation.
      Educational requirements are presented that aid the dentist and the practice
      staff in understanding the broad and long-term implications of the HIPAA
      legislation.

PMID- 12595935
TI  - Persistent painful ulcer of the posterior lingual mandibular mucosa.
AB  - An ulcer involving the left posterior mandibular lingual mucosa was the chief
      complaint of this 55-year old white man. (Figure 1) The ulcer was first noted
      about one month previously and no local eliciting factors could be identified.
      The ulcer had become progressively more painful in spite of antibiotic treatment
      (cephalexin, 500 mg, q.i.d, 8 days) and concomitant use of benzydamine
      hydrochloride rinse. The patient was healthy with no medical problems other than
      occasional nasal "stuffiness," which was treated, as required, with budesonide
      nasal spray.

PMID- 12595936
TI  - Managing regulated waste in dental environments.

PMID- 12595937
TI  - [Clinical Trials with children: need brings about method]

PMID- 12595938
TI  - [Internal invoicing of end products manufactured by a hospital Pharmacy
      Department]
AB  - OBJECTIVE: To calculate actual costs of end products manufactured by a Pharmacy
      Department. MATERIAL AND METHODS: Quality standards, overall production in
      relative value units (RVUs), and complexity degree of a pharmacy department are
      assessed. Actual cost of RVUs and manufactured end products is calculated.
      RESULTS: The Pharmacy Department is classified as quality level II. The total
      number of produced RVUs is 2,334,355.86, with a complexity degree of 2.20 and a
      cost per RVU of 0.87 euros. Pharmacy Department cost imputation per RVU has
      relevant discrepancies when compared to traditional shared cost systems regarding
      drug consumption. CONCLUSIONS: The inclusion of a product catalogue within
      Pharmacy Departments allows overall and department-specific activities to be
      acknowledged, as well as mean complexity, strengths and issues in need of
      improvement, in order to include them within pharmacy department planning.
      Furthermore, it allows for more realistic product charging to requesting
      departments.

PMID- 12595939
TI  - [Risk Factors associated with post-chemotherapy vomiting in patients with breast
      cancer (II): analysis of the duration of emesis]
AB  - OBJECTIVE: To identify the risk factors associated with the duration of emesis
      after high-dose chemotherapy in high risk breast cancer patients and to assess
      the predictive performance of a mathematical model. METHODS: Cox regression model
      was developed to predict the duration of emesis, and different prognostic factors
      were evaluated: anthropometric characteristics, cyclophosphamide and carboplatin
      clearance, administration of ondansetron or tropisetron, and emesis intensity
      classified as a function of emetic protection degree. RESULTS: The emetic
      episodes started and finished, 3 and 8 days, from the beginning of chemotherapy,
      respectively. The probability of finishing the emesis episodes is 2 times higher
      in patients receiving ondansetron treatment with than in those receiving
      tropisetron and, 8 times higher in patient with major or complete emetic
      protection than in those with minor emetic protection or treatment failure.
      CONCLUSION: The antiemetic protection with ondansetron after high dose of
      chemotherapy in high risk breast cancer patients is more effective option than
      tropisetron because the duration of emesis is lower.

PMID- 12595940
TI  - [Assessing an algorithm for the therapeutic swapping of calcium antagonists]
AB  - INTRODUCTION AND OBJECTIVE: Therapeutic swapping is one of the activities a
      Pharmacist ascribed to a Unitary Dose area should undertake. The goal of this
      work is to assess the impact the definition of a clearly laid-out criteria
      algorithm for therapeutic swapping regarding calcium antagonists. MATERIAL AND
      METHODS: The study periods spanned from January to December 2000 before algorithm
      delivery and from January to April 2001, once the algorithm was in operation.
      Both the number of prescriptions received at the Pharmacy Department Unitary Dose
      Area and the number of pharmaceutical acts regarding drugs not included within
      the Pharmacotherapeutic Guidelines (MNIGFT) and belonging in the Calcium
      Antagonists Group were collected: direct replacements, active principle swapping,
      dosage / pharmaceutical formula swapping, and accepted drugs. Study variables
      were: a) compliance with pharmacotherapeutic guidelines during prescription, such
      as adjusted number of prescribed MNIGFTs per 1,000 prescriptions, and b)
      pharmaceutical action adequacy, such as percentage of non-proper therapeutic
      swaps (performed on the same active principle / dosage, but with better
      alternatives as defined later in the algorithm). RESULTS: After algorithm
      implementation a 47.1% decrease in active principles swapping, and a 7.7%
      decrease in MNIGFT-accepted calcium antagonists, was seen. Similarly, the number
      of dosage / pharmaceutical formula swaps was increased by 28.6%, and that of non
      proper swaps was decreased by 48.0% when compared to the previous period.
      CONCLUSION: Establishing an algorithm for therapeutic swapping improves
      compliance with the Pharmacotherapeutic Guidelines during calcium antagonist
      prescription and the quality of therapeutic swapping as performed by pharmacists
      regarding this group of drugs.

PMID- 12595941
TI  - [Errors in the oral administration of medicines in two health centres]
AB  - OBJECTIVE: To know how medicines should be administered, to detect if there are
      any interaction whith food and the most frequent errors. METHOD: A descriptive
      study has been carried out in two health centres where we have evaluated if the
      oral medicines have been correctly dispensed. So as to do this, the summary of
      medicines' characteristics and/or medicine prospects were used. RESULTS: The
      daily administered medication for 40 patients was evaluated during one day in two
      different hospitals. We administered 274 medicines in hospital A and 238
      medicines in hospital B wich correspond to 344 and 330 oral dosis. In hospital A
      138 (23,4%) mistakes were made and another 65 potential errors were detected. It
      is unsure if these potential errors were made or not as we do not know if the
      medication was taken correctly by the patient. In hospital B 95 (25,0%) errors
      were committed. No other possible errors were observed. The most frequent errors
      that have been commited are: not to dilute the medication with water, to
      administer the medicine with milk and/or antiacid medicine, to take medicine with
      meals instead of taking them in abstinence. Not warning the pacient to swallow
      medicines without chewing them. Other errors were concerning the relationship
      between medication and meals. DISCUSSION: Many of the mistakes that are made when
      taking medicines are due to the lack of knowledge of the correct usage or lack of
      information.

PMID- 12595942
TI  - [Interferon beta as a therapy for multiple sclerosis]
AB  - Introduction of interferon beta in multiple sclerosis treatment represented a
      great advance: they are efficacious drugs, capable of reducing rate and severity
      of relapses, besides improving disease parameters, measured by MR imaging
      techniques. However, some controversy has been raised on optimal doses, ways and
      frequency of administration. In this article, the authors review studies about
      the efficacy of the existing products, as well as evidences for and against a
      dose-effect relationship. Although differences in clinical trials make
      comparisons difficult, available data indicate that efficacy of the three
      products is quite similar. There is no basis to believe that an increase in dose
      or frequency over those used in phase III trials may lead to a parallel efficacy
      improvement.

PMID- 12595944
TI  - ?

PMID- 12595943
TI  - [Critical elements for the extension of working hours in an in-hospital Pharmacy
      Department]
AB  - INTRODUCTION: Individualised drug dispensation facilitates compliance with
      validated prescriptions, the application of criteria for rational use, the
      prevention and solution of drug-related problems. However, its complexity entails
      a risk for errors in procedure design and implementation, which renders quality
      assessment and continual improvement mandatory. OBJECTIVE: To analyse critical
      elements justifying the extension of working hours in an in-hospital Pharmacy
      Department, and other improvements within the pharmaco-therapeutic process
      through activity and hospital care quality indicators. METHODS: This is an
      observational, analytic study wherein seven activity and quality indicators were
      established. Regarding the latter, a qualitative and quantitative cause analysis
      was performed. The study period was from April to June 2001. RESULTS: Monthly
      average of hospital admissions was 641+/-50; of these, 40% take place during the
      evening-night hours, and 559+/-197 scheduled surgical procedures were performed.
      A total of 1,499+/-158 monthly prescriptions were processed, representing
      36,790+/-733 doses. Eighteen percent of daily prescriptions were received at 14
      15 h, and 21% were offset 24 h with respect to prescription date. During the
      evening-night period the on-call supervisor visited the Pharmacy 4 times a day to
      dispense 10 drugs corresponding to 4 patients; 47.7% of cases took place at 15-21
      h, patient admissions and pharmacy dispensation errors being the main reason for
      visits. CONCLUSIONS: Extending the hours of operation in a Pharmacy Department
      would improve pharmaco-therapeutic patient care, but this should be associated
      with an integral improvement of doctor and both ward and pharmacy nursing staff
      work procedures.

PMID- 12595945
TI  - ?

PMID- 12595947
TI  - ?

PMID- 12595946
TI  - ?

PMID- 12595948
TI  - An evaluation of the effect of NAS-181, a new selective 5-HT(1B) receptor
      antagonist, on extracellular 5-HT levels in rat frontal cortex.
AB  - In the mammalian brain 5-HT(1B) receptors are present as autoreceptors regulating
      the release of serotonin (5-HT) by inhibitory feedback. The antagonistic
      properties of NAS-181 ((R)-(+)-2-[[[3-(Morpholinomethyl)-2H-chromen-8
      yl]oxy]methyl] morpholine methane sulfonate), a new selective antagonist for the
      rodent 5-HT(1B) receptor, were determined by using an agonist-induced decrease of
      extracellular 5-HT. The 5-HT(1B) receptor agonist CP93129 (0.030.3 microM)
      applied by reversed microdialysis, dose-dependently reduced 5-HT levels in rat
      frontal cortex. The suppressant effect of CP93129 (0.1 microM) was smaller in the
      presence of fluvoxamine (3-10 microM), a 5-HT reuptake inhibitor. The effects of
      NAS-181 on CP93129 were compared with GR127935, a mixed 5-HT (1B/1D) receptor
      antagonist, and SB224289, a 5-HT(1B) receptor antagonist. Both in the presence
      and absence of fluvoxamine, the suppressant effect of CP93129 on extracellular 5
      HT was attenuated by NAS-181 (1 microM) and GR127935 (10 microM), but not by
      SB224289 (1 microM). In the absence of fluvoxamine, GR127935, SB224289 and NAS
      181 all reduced 5-HT levels, suggesting partial agonistic properties of these
      compounds. In conclusion, the results show that NAS-181 is a potent 5-HT(1B)
      receptor antagonist.

PMID- 12595949
TI  - Beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives as potent agonists
      at somatostatin sst(4) receptors.
AB  - Four linear beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptides (1-4) were
      investigated as somatostatin sst(4) receptor agonists on recombinant human and
      mouse somatostatin receptors. Human somatostatin receptor subtypes 1-5 (sst(1
      5)), and mouse somatostatin receptor subtypes 1,3,4 and 5, were characterised
      using the agonist radioligands [(125)I]LTT-SRIF-28, [(125)I][Tyr(10)]CST(14) and
      [(125)I]CGP 23996 in stably transfected Chinese hamster lung fibroblast (CCL39)
      cells. The peptides bound selectively to sst(4) receptors with nanomolar affinity
      (pK(d)=5.4-7.8). The peptides were investigated on second messenger systems both
      as agonists, and as antagonists to SRIF-14-mediated effects in CCL39 cells
      expressing mouse sst(4 )receptors, via measurement of inhibition of forskolin
      stimulated adenylate cyclase activity, and stimulation of luciferase expression.
      The peptides showed full agonism or pronounced partial agonism (40 to 100%
      relative intrinsic activity) in both inhibition of forskolin-stimulated adenylate
      cyclase activity (pEC(50)=5.5-6.8), and luciferase expression (pEC(50)=5.5-6.5).
      The agonist potential was confirmed since antagonism was very difficult to
      establish. The data show that beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide
      derivatives have agonist potential at recombinant somatostatin sst(4) receptors.
      Therefore, they may be used to elucidate physiological and biochemical effects
      mediated by sst(4), and may also have potential as therapeutic agents.

PMID- 12595950
TI  - Dual and selective antagonism of neurokinin NK(1) and NK(2) receptor-mediated
      responses in human colon mucosa.
AB  - The neurokinin (NK) receptors, NK(1) and NK(2), which are activated by substance
      P (SP) and NKA, have been identified as potential therapeutic targets in
      irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here we have
      investigated the effects of a novel dual NK(1) and NK(2) receptor antagonist,
      namely DNK333 upon responses elicited by [Sar(9), Met(O(2))(11)]-SP (SMSP) and
      [betaAla(8)]-NKA(4-10) in isolated human colon mucosa mounted in Ussing chambers.
      A selective NK(1) receptor antagonist, SR140333 and NK(2) receptor antagonist,
      SR48968 have been tested for comparison. Additions of SMSP (100 nM) or
      [betaAla(8)]-NKA(4-10) (100 nM) increased basal short-circuit current and
      responses to both peptides were inhibited by DNK333, while SR140333 only
      inhibited SMSP and SR48968 blocked only [betaAla(8)]-NKA(4-10) responses.
      SR140333 did not attenuate [betaAla(8)]-NKA(4-10) effects and SR48968 had no
      effect upon SMSP responses. Carbachol (1 micro M) responses were not altered by
      any of the three NK antagonists. We conclude that activation of either NK(1) or
      NK(2) receptors can stimulate epithelial ion transport in human colon mucosa and
      that the novel dual antagonist, DNK333 may be of potential therapeutic interest
      in the treatment of IBD and IBS.

PMID- 12595951
TI  - New milrinone analogues: in vitro study of structure-activity relationships for
      positive inotropic effect, antagonism towards endogenous adenosine, and
      inhibition of cardiac type III phosphodiesterase.
AB  - Two mechanisms are responsible for the positive inotropic effect of the
      cardiotonic drug milrinone, i.e., inhibition of type III cAMP phosphodiesterase
      (PDE III), and displacement of endogenous adenosine from A(1) inhibitory
      receptor. Since PDE III inhibition may increase the likelihood of cardiac
      arrhythmias by increasing cAMP content, our attention focused on the synthesis of
      new compounds with more pronounced characteristics as adenosine antagonists. In
      this work, four new milrinone analogues were studied, in comparison with the
      parent drug, for their effects on the contractility of guinea pig isolated atrial
      preparations, their ability to antagonize endogenous adenosine at the level of
      A(1) receptor, and to inhibit the activity of PDE III partially purified from
      guinea pig heart. The new compounds present various chemical substitutions with
      respect to the parent drug: in compounds SF397 (methyl 5-cyano-2-methyl-6-oxo-1,6
      dihydropyridine-3-carboxylate) and SF399 (benzyl 5-cyano-2-methyl-6-oxo-1,6
      dihydropyridine-3-carboxylate), the 4-pyridil moiety of milrinone was replaced
      with a methoxycarbonyl and a benzyloxycarbonyl group, respectively; the same
      structural modifications were also associated with the replacement of the cyano
      group in 5-position with an acetyl group in compounds SF416 (methyl 5-acetyl-2
      methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF419 (benzyl 5-acetyl-2
      methyl-6-oxo-1,6-dihydropyridine-3-carboxylate). All the new compounds had a
      marked positive inotropic effect, most of them also being more active and more
      potent than milrinone. When their affinity for A(1) receptor was assessed as the
      displacement of [(3)H] 8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX) from
      cardiac membranes, SF397 and SF399 showed affinity (K(i) of about 600 nM) similar
      to that of milrinone (K(i) 550 nM). By contrast, SF416 and SF419 had very low
      (K(i) of about 10000 nM) or scarce (K(i) of about 2000 nM) anti-adenosine
      component, respectively. All the new compounds inhibited PDE III activity, their
      K(i) values proceeding in the following order: milrinone (3.80 microM) <SF397
      (7.00 microM) <SF399 (8.80 microM) <SF416 (35.00 microM) SF419< (155.00 microM).
      To better characterize the mechanisms responsible for the positive inotropic
      response of the new compounds, we also investigated the effects of new analogues
      on some systems (ATP-dependent Ca(2+) uptake, Ca(2+)ATPase, Na(+)/K(+)ATPase,
      Na(+)/Ca(2+) exchange carrier) or a receptor (beta-adrenoceptor) mainly involved
      in the control of cardiac contractility. None of the tested compounds inhibited
      enzyme or transport systems; however, SF397, SF399 and SF416, although to
      different extents, had a direct beta-adrenergic action. Indications about
      structure-activity relationships are tentatively discussed, in order to obtain
      useful information for the design of new analogues with better pharmacological
      profiles.

PMID- 12595952
TI  - Local acamprosate modulates dopamine release in the rat nucleus accumbens through
      NMDA receptors: an in vivo microdialysis study.
AB  - The effects of acamprosate on the in vivo dopamine extracellular levels in the
      nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in
      these effects were investigated. Microdialysis in freely moving rats was used to
      assess dopamine levels before and during simultaneous perfusion of acamprosate
      and/or different agonists or antagonists of NMDA receptors. Perfusion with
      acamprosate at concentrations of 0.5 and 5 mM provoked a concentration-dependent
      increase in extracellular dopamine in nucleus accumbens. The lowest concentration
      of acamprosate assayed (0.05 mM) had no effect on dopamine levels. Infusion of
      NMDA (25 and 500 microM) and the glutamate uptake blocker, L-trans-pyrrolidine
      2,4-dicarboxilic acid (PDC) (0.5 mM) into the NAc caused a significant increase
      in DA, whereas acamprosate (0.05 mM) co-infusion with these compounds blocked or
      attenuated the NMDA and PDC-induced increases in DA levels. Co-infusion of the
      selective antagonist of NMDA receptors, DL-2-amino-5-phosphonopentanoic acid
      (AP5) (400 microM) with acamprosate (0.5 mM), did not reduce the increase of DA
      levels induced by acamprosate. These results demonstrate that acamprosate is able
      to modulate DA extracellular levels in NAc via NMDA receptors and suggest that
      acamprosate acts as an antagonist of NMDA receptors.

PMID- 12595953
TI  - Autoradiographic quantification of neurochemical markers of serotonin, dopamine
      and opioid systems in rat brain mesolimbic regions following chronic St John's
      wort treatment.
AB  - Effects of chronic treatment with St John's wort (SJW, Hypericum perforatum) on
      neurochemical markers of serotonin, dopamine and opioid systems in mesolimbic
      regions of the fawn-hooded rat were investigated by quantitative autoradiography.
      After 10 days' treatment, SJW significantly increased [(3)H]citalopram binding to
      5-HT transporters in multiple mesolimbic regions. In contrast, SJW resulted in a
      region-specific alteration of [(3)H]mazindol binding to dopamine transporters,
      such as increased binding of [(3)H]mazindol in the olfactory tubercle and
      decreased binding in the ventral tegmental area. In addition, SJW also resulted
      in differential modulation of the binding properties of 5-HT(1A)-, 5-HT(2A)- and
      mu-opioid receptors in a region-specific manner. The ability of SJW to affect 5
      HT, dopamine and opioid systems in mesolimbic regions in the CNS, either by a
      direct or by indirect (adaptation) mechanism, may help to explain the efficacy of
      SJW in the treatment of depression clinically and in some of the behavioural
      effects observed in experimental rodents.

PMID- 12595954
TI  - Reduction of extracellular dopamine and metabolite concentrations in rat striatum
      by low doses of acute cyamemazine.
AB  - The low incidence of extrapyramidal effects with atypical neuroleptics has been
      ascribed to their 5-HT(2A)- and 5-HT(2C)-serotonin receptor antagonistic
      properties. On the other hand, the acute increase in striatal dopamine release by
      submaximal dopamine D(2) autoreceptor blockade can be respectively reduced and
      increased by 5-HT(2A)- and 5-HT(2C)-antagonists. Cyamemazine is a neuroleptic
      D(2)- and 5-HT(2A)-receptor antagonist, with small antagonistic activity at 5
      HT(2C) receptors and low incidence of extrapyramidal side effects. Therefore,
      submaximal cyamemazine was tested in rats for its acute action on the
      extracellular concentrations of dopamine and dopamine metabolites (DOPAC:
      3,4,dihydroxyphenylacetic acid and HVA: 4-hydroxy-3-methoxy-phenyl-acetic acid)
      in the corpus striatum. The serotonin metabolite 5-HIAA (5-hydroxy-indole-acetic
      acid) was measured in parallel. Rats prepared for microdialysis (striatum) were
      intraperitoneally given cyamemazine 1 mg/kg, 5 mg/kg or vehicle ( n=4 in each
      group). Dopamine, DOPAC, HVA and 5-HIAA concentrations in perfusates under basal
      conditions and after stimulation by high K(+) were measured by HPLC coupled to
      electrochemical detection. Cyamemazine 1 mg/kg significantly reduced
      extracellular concentrations of basal dopamine (-77%), DOPAC (-54%), HVA (-54%)
      and 5-HIAA (-65%). No such effects were seen with the dose of cyamemazine 5 mg/kg
      or for K(+)-evoked dopamine release. In conclusion, submaximal cyamemazine can
      acutely reduce basal dopamine release and metabolism in the rat striatum. Such
      unusual action can be explained by the original pharmacological profile of
      cyamemazine (potent D(2)- and 5-HT(2A)-antagonist, with small antagonistic
      activity at 5-HT(2C) receptors). Further experiments are required to explain the
      low incidence of extrapyramidal side actions with cyamemazine.

PMID- 12595955
TI  - Gastric hypersecretion associated to iodoacetamide-induced mild gastritis in
      mice.
AB  - Disturbances of gastric motor, secretory and/or sensory functions are frequently
      associated with gastritis. The aim of this study was to characterize motor and
      secretory alterations associated to chemically-induced gastritis in mice. Mild
      gastritis was induced with 0.1% iodoacetamide administered intragastrically and
      added to the drinking water for a 6 days period. A significant loss of body
      weight and a reduction in food and water intake was observed in iodoacetamide
      treated animals compared with those receiving vehicle. At the end of the
      treatment period, no macroscopic alterations were observed in the gastric mucosa
      of iodoacetamide-treated mice. However, histological sections revealed a mixed
      inflammatory infiltrate, with a predominance of mast cells in the submucosa;
      suggesting a mild gastritis. Gastric emptying rate of a nutrient solid meal was
      not modified in mice with gastritis compared with normal controls. In animals
      with gastritis, basal gastric acid secretion was increased compared with normal
      controls. Basal gastric acid secretion was not modified by either indomethacin or
      compound 48/80. Secretory response to secretagogues (pentagastrin and histamine)
      was enhanced during gastritis. Hypersecretory responses to both gastrin and
      histamine in iodoacetamide-treated mice were blocked by the mast cell stabilizer
      sodium cromoglycate, and enhanced by indomethacin, without affecting the
      secretory response in normal mice. These results suggest that mild gastritis
      alters gastric acid secretory responses through a mechanism related, at least
      partially, to mast cells activation. Moreover, prostaglandins also modulate
      secretory responses during mild inflammation. This animal model of gastritis
      might be useful to characterize pathophysiological changes and potential
      therapeutic targets in secretory-related gastric pathologies.

PMID- 12595956
TI  - Caffeine enhances myocardial uptake of idarubicin but reverses its negative
      inotropic effect.
AB  - Idarubicin (IDA) is a member of an important class of anticancer agents, the
      anthracycline antibiotics. Although the clinical efficacy of anthracyclines is
      limited by a high incidence of severe cardiac toxicity, our understanding of IDA
      transport into the heart is still limited. In a previous study, we demonstrated
      that IDA is transported into the heart by a saturable mechanism. Based on in
      vitro data suggesting an enhancement by methylxanthines of IDA influx in leukemia
      cells, this study was designed to test the hypothesis that a commonly used
      methylxanthine, caffeine, might influence the myocardial uptake of IDA. In the
      Langendorff rat heart, after infusion of 0.5 mg IDA during 10 min, the presence
      of caffeine (1 microM) in perfusate enhanced the residual amount of IDA in the
      heart by 30% due to a 2.7-fold increase in the maximal uptake rate V(max).
      Theophylline (3 micro M), in contrast, did not influence the uptake process but
      caused a slight decrease of fractional myocardial sequestration rate (19%
      reduction). Caffeine reversed the cardiodepressive action of IDA (49% decrease in
      left ventricular developed pressure at the end of infusion) to a positive
      inotropic effect (18% increase of basal level). Theophylline significantly
      attenuated the negative inotropic effect of IDA (only 21% decrease) and led to
      positive inotropism in the washout phase (21% increase at the end of experiment).
      We speculate that co-administration of caffeine may enhance the chronic
      cardiotoxicity of IDA by increasing its accumulation in the heart.

PMID- 12595957
TI  - Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour
      necrosis factor-alpha treated anaesthetized rats.
AB  - Administration of tumour necrosis factor-alpha (TNF-alpha) produces progressive
      reduction in cardiac output (CO) by affecting preload, afterload and cardiac
      contractility. We have examined the effect of an endothelin receptor antagonist,
      tezosentan (1, 3 or 10 mg/kg), on CO, heart rate (HR), blood pressure (BP), mean
      circulatory filling pressure (P(mcf)), resistance to venous return (RVR),
      arterial resistance (AR), dP/dt, stroke volume (SV), plasma levels of NO(2)(
      )/NO(3)(-), and inducible nitric oxide synthase (iNOS) activity in lungs, ex
      vivo, following treatment with TNF-alpha (30 microg/kg) in anaesthetized rats.
      Treatment with TNF-alpha alone resulted in significant reduction in CO (40+/-4%),
      dP/dt (24+/-2%), P(mcf) (24+/-2%), BP (21+/-3%) and SV (38+/-5%) ( n=6; mean +/-
      SEM), and significant increases in RVR (38+/-9%) and AR (45+/-6%). There were no
      significant changes in HR or in plasma levels of NO(2)(-)/NO(3)(-) in animals
      treated with TNF-alpha but there was a modest but significant increase in iNOS
      activity. Tezosentan alone did not have any effect on haemodynamics, plasma
      levels of NO(2)(-)/NO(3)(-) or iNOS activity. Tezosentan at the highest dose
      abolished the effects of TNF-alpha on dP/dt, AR, and RVR. In animals treated with
      a combination of TNF-alpha and highest dose of tezosentan CO, P(mcf), BP, and SV
      were reduced by 28+/-5%, 16+/-3%, 21+/-4%, and 27+/-5%, respectively. Tezosentan
      was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on
      P(mcf). It is likely that the negative impact of TNF-alpha on CO in tezosentan
      treated animals could be entirely attributed to reduction in preload.

PMID- 12595958
TI  - Differential effects of K(ATP) channel blockers on [(3)H]-noradrenaline overflow
      after short- and long-term exposure to (+)-oxaprotiline or desipramine.
AB  - To test whether prolonged uptake blockade can lead to changes in the function of
      ATP-dependent potassium (K(ATP)) channels we investigated in rat neocortex slices
      the effects of K(ATP) channel blockers on electrically evoked [(3)H]
      noradrenaline ([(3)H]-NA) overflow after short- (45 min) and long-term (210 min)
      exposure to the NA uptake blockers (+)-oxaprotiline or desipramine (1 microM
      each). The K(ATP) channel blocker glibenclamide (1 micro M) increased the evoked
      [(3)H]-NA overflow by 42% after short-term uptake inhibition. This effect was
      confirmed by tolbutamide and glipizide, two other K(ATP) channel antagonists. The
      evoked [(3)H]-NA overflow was enhanced by 73% following short-term uptake
      blockade (15 min) and by 110% following long-term blockade (180 min). After long
      term blockade (210 min), however, glibenclamide failed to further enhance the
      overflow of [(3)H]-NA. The alpha(2)-autoreceptor-mediated feedback control was
      not involved in the glibenclamide-induced increase in [(3)H]-NA overflow after
      short-term uptake blockade or in the increase in [(3)H]-NA overflow due to long
      term uptake blockade per se. The Na(+)/K(+)-ATPase inhibitor ouabain diminished
      the glibenclamide-induced enhancement of [(3)H]-NA overflow after short-term
      uptake blockade, suggesting that an operative Na(+)/K(+)-ATPase is the
      prerequisite of activation of K(ATP) channels. These results suggest that short
      term uptake blockade activates the Na(+)/K(+)-ATPase, thereby reducing
      intracellular ATP which allows transient opening of K(ATP) channels. Activation
      of the Na(+)/K(+)-ATPase may increase the Na(+) gradient, probably over the
      membrane of noradrenergic nerve terminals. The resulting hyperpolarisation leads
      to inhibition of the evoked overflow which can be reversed, i.e. enhanced, by
      K(ATP) channel blockers. In contrast, longer lasting uptake blockade seems to
      reduce the activity of the Na(+)/K(+)-ATPase and hence the consumption of ATP. As
      a consequence, reduced Na(+) and K(+) gradients may facilitate transmitter
      release. Closure of K(ATP) channels by accumulating ATP may further promote
      membrane depolarisation and transmitter release. The unexpected effect of longer
      exposure to uptake blockers could be somehow related to the clinical time latency
      of the antidepressant efficacy of monoamine uptake blockers.

PMID- 12595959
TI  - Inhibitory effects of atropine and hexamethonium on the angiotensin II-induced
      contractions of rat anococcygeus smooth muscles.
AB  - We have evaluated the interaction between angiotensin II (Ang II) and the
      cholinergic transmission in anococcygeus smooth muscles isolated from rats
      treated (sympathectomised group) or not (vehicle group) with reserpine and alpha
      methyl-p-tyrosine. For this, we contracted the tissues with Ang II in the
      presence and absence of atropine and hexamethonium. Ang II induced concentration
      dependent contractions, which did not undergo temporal changes in tissues
      isolated from both groups of rats. In the vehicle group, Ang II induced more
      potent contractions than in the sympathectomised group. In the sympathectomised
      rat group, atropine inhibited the contractions induced by Ang II in a
      concentration-dependent fashion with no decrease in E(max). Additionally,
      hexamethonium inhibited the contraction induced by Ang II in a concentration
      dependent fashion with a decrease in E(max). Association of atropine and
      hexamethonium produced Ang II-induced curves with rightward shifts from the
      control curve with a decrease in E(max). Incubation with N(G)-nitro-L-arginine
      methyl ester (L-NAME) reversed the effects of atropine and hexamethonium
      association. Conversely, in the vehicle group of rats, atropine and hexamethonium
      did not produce any significant effect. However, in the presence of yohimbine,
      atropine shifted the Ang II-induced curves to the right of the control curve with
      no E(max) decrease. Results suggest that there is a positive interaction between
      Ang II and cholinergic transmission in the rat anococcygeus smooth muscle
      mediated by angiotensin receptors located on pre-ganglionic cells.

PMID- 12595960
TI  - UFP-101, a high affinity antagonist for the nociceptin/orphanin FQ receptor:
      radioligand and GTPgamma(35)S binding studies.
AB  - Studies of the pharmacology of nociceptin/orphanin FQ (N/OFQ) and its receptor
      (NOP) have been hampered by the lack of a range of high potency antagonists. In
      this study we have examined the effects of a novel N/OFQ analogue
      [Nphe(1),Arg(14),Lys(15)]N/OFQ NH(2) hereafter referred to as UFP-101.
      [(3)H]N/OFQ competition binding and GTPgamma(35)S binding assays were performed
      using CHO cells expressing the human NOP receptor (CHO(hNOP)). UFP-101 (pK(i) of
      10.14+/-0.09) and a range of NOP selective agonists displaced [(3)H]N/OFQ binding
      with the following rank order of affinity: [Arg(14),Lys(15)]N/OFQ>[(
      pF)Phe(4)]N/OFQ(1-13)NH(2)>N/OFQ(1-13)NH(2)>UFP-101>N/OFQ>Ro64
      6198>[Nphe(1)]N/OFQ(1-13)NH(2). N/OFQ, N/OFQ(1-13)NH(2), [( pF)Phe(4)]N/OFQ(1
      13)NH(2), [Arg(14),Lys(15)]N/OFQ and Ro64-6198 also produced a concentration
      dependent (pEC(50) values of 8.75+/-0.11, 9.28+/-0.15, 9.69+/-0.04, 9.12+/-0.11
      and 8.09+/-0.07 respectively) and saturable stimulation of GTPgamma(35)S binding
      and all were full agonists. UFP-101 did not stimulate GTPgamma(35)S binding per
      se, but produced a concentration dependent and parallel rightward shift in the
      concentration response curves to all agonists. UFP-101 yielded pA(2) values in
      the range 8.4-9.0. For comparison a pA(2) for [Nphe(1)]N/OFQ(1-13)NH(2) (the
      template for UFP-101) against N/OFQ of 7.33+/-0.08 was obtained. Slope factors
      for the Schild regression lines were approximately 1 indicating competitivity.
      When UFP-101 is compared with its template molecule [Nphe(1)]N/OFQ(1-13)NH(2),
      Arg(14),Lys(15) substitution produced approximately 1 log greater potency. We
      suggest that due to its high potency UFP-101 should prove a further useful tool
      in the evaluation of the N/OFQ-NOP receptor system.

PMID- 12595961
TI  - Somatostatin inhibits potassium-evoked glutamate release by activation of the
      sst(2) somatostatin receptor in the mouse retina.
AB  - In the mammalian retina, somatostatin (SRIF-14) acts through distinct receptor
      subtypes (sst(1-5)). Among them, sst(2) has been localized to numerous retinal
      cells, including photoreceptors and rod bipolar cells (RBCs). The specific role
      of sst(2) in the retina is largely undetermined. In this study, we characterized
      retinas of mice with targeted deletion of sst(2) (sst(2) KO) and we investigated
      functions of sst(2) in respect to its possible modulation of glutamate (GLU)
      release, as measured by HPLC. In contrast with wild-type (WT) mice, sst(2) mRNA
      and sst(2A) immunoreactivity were no longer detectable in the retina of sst(2) KO
      mice. In retinal explants of WT mice, SRIF and its analogue octreotide that
      displays high selectivity for sst(2), similarly reduced the evoked release of GLU
      without affecting its basal level. In sst(2) KO retinas, SRIF or octreotide did
      not affect GLU release indicating that they act at sst(2). Unexpectedly, the
      compound CYN-154806, although introduced as the first potent sst(2) antagonist,
      reduced the evoked release of GLU with equipotency to SRIF and octreotide. Its
      inhibitory effect was no longer observed in sst(2) KO retinas, indicating that
      this substance acts at sst(2) receptors as an agonist. In conclusion, SRIF
      controls evoked release of GLU through sst(2) receptors and this control may
      represent part of a mechanism by which SRIF regulates GLU concentration in the
      retina.

PMID- 12595962
TI  - Evidence for the primary role for 4-aminopyridine-sensitive K(v) channels in
      beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig
      gastrointestinal smooth muscles.
AB  - Gastrointestinal smooth muscles exhibit relaxation in response to the stimulation
      of beta-adrenoceptors with catecholamines. Subtypes of beta-adrenoceptors which
      mediate catecholamine-elicited relaxations in gastrointestinal smooth muscles are
      predominantly atypical beta-adrenoceptors including beta(3)-adrenoceptors.
      Gastrointestinal smooth muscle relaxations mediated via beta(3)-adrenoceptors can
      occur independently of intracellular cyclic adenosine monophosphate (AMP)
      elevation. One of the mechanisms responsible for cyclic AMP-independent smooth
      muscle relaxation following activation of G(s) protein-coupled receptors could be
      activation of voltage-gated K(+) channels. In the present study, possible
      contribution of two types of K(+) (large-conductance, Ca(2+)-sensitive and
      voltage-gated K(+), BK(Ca); voltage-gated, K(v)) channels to beta(3)-adrenoceptor
      mediated, cyclic AMP-independent relaxations was compared in gastric fundus and
      duodenum smooth muscles isolated from the guinea-pig. In these gastrointestinal
      smooth muscles, three catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)
      adrenaline) and two beta(3)-adrenoceptor agonists ((R(*), R(*))-(+/-)-4-[2-[(2-(3
      chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium (BRL37344)
      and (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy] -1,3-dihydro-2H
      benzimidazol-2-one] hydrochloride ((+/-)-CGP12177A)) elicited a concentration
      dependent relaxation in the presence of beta(1)- and beta(2)-adrenoceptor
      antagonists. The relaxations were unaffected by an adenylyl cyclase inhibitor, SQ
      22536 (100 microM), which indicates their characteristic of cyclic AMP
      independency. On the other hand, the SQ-22536-resistant, beta(3)-adrenoceptor
      mediated relaxant components were potently attenuated when the tone was raised
      using high-KCl (80 mM) or in the presence of a K(v) channel blocker, 4
      aminopyridine (4-AP, 1-3 mM). Iberiotoxin (100 nM), a selective blocker of BK(Ca)
      channels which significantly contribute to cyclic AMP-independent vascular smooth
      muscle relaxations induced through activation of G(s) protein-coupled receptors,
      did not apparently show any inhibitory effects on SQ-22536-resistant, beta(3)
      adrenoceptor-mediated relaxations in these gastrointestinal smooth muscles. The
      present results indicate that 4-AP-sensitive K(v) channels play a primary role in
      beta(3)-adrenoceptor-mediated, cyclic AMP-independent relaxations of guinea-pig
      gastrointestinal smooth muscles. In these smooth muscles, BK(Ca) channels seem to
      apparently contribute insignificantly to cyclic AMP-independent relaxations
      following stimulation of beta(3)-type of adrenoceptors.

PMID- 12595963
TI  - Effects of clopidogrel and ticlopidine on experimental diabetic ischemic
      retinopathy in rats.
AB  - Ticlopidine, a thienopyridine that prevents the progression of diabetic
      retinopathy in humans, was recently shown to increase nitric oxide (NO)
      production in human neutrophils. The thienopyridine clopidogrel has been found to
      be clinically useful in the secondary prevention of thrombotic events. The aim of
      the present study was to evaluate the effect of clopidogrel on ischemic
      retinopathy in streptozotocin-diabetic rats and its influence on prostanoids and
      NO production. We compared nondiabetic rats and rats after 3 months of diabetes
      that were given three doses (1, 10 or 20 mg/kg per day p.o.) of ticlopidine or
      clopidogrel from the first day of diabetes. The variables recorded after 3 months
      of diabetes were platelet aggregation, thromboxane B(2) (TxB(2)) production, 6
      keto-prostaglandin F(1)(alpha) (stable metabolite of prostacyclin), aortic NO,
      plasma nitrites/nitrates, and the percentage of the retinal surface occupied by
      horseradish peroxidase (HRP)-permeable vessels. In diabetic rats, platelet
      aggregation and thromboxane concentration were increased, and prostacyclin, NO
      and area occupied by HRP-permeable vessels were decreased. Ticlopidine and
      clopidogrel reduced the maximum extent of platelet aggregation in a dose
      dependent manner: maximal inhibition with respect to untreated diabetic rats was
      48.6% with ticlopidine and 66.6% with clopidogrel. Ticlopidine reduced
      thromboxane B(2) only at a dose of 20 mg/kg per day p.o. (47.4% inhibition) and
      clopidogrel at doses of 10 mg/kg per day (51% inhibition) or 20 mg/kg per day
      (51.7% inhibition). Aortic prostacyclin production did not change after treatment
      with either thienopyridine. Treatment with ticlopidine reduced the inhibition of
      NO production in untreated rats (89.6% inhibition) to 0.9%, and clopidogrel
      reduced inhibition to 30%. Treatment with ticlopidine or clopidogrel reduced the
      retinal nonperfused area from 86.8% inhibition in untreated rats to 45.6% and
      25.3%, respectively. In conclusion, the early administration of thienopyridines
      in streptozotocin-diabetic rats partly prevented the appearance of diabetic
      retinal ischemia.

PMID- 12595964
TI  - Protease-activated receptor-2-mediated contraction in the rat urinary bladder:
      the role of urinary bladder mucosa.
AB  - The role of protease-activated receptor-2 (PAR-2) in the regulation of the rat
      urinary bladder contractility was investigated. Both trypsin and PAR-2 activating
      peptide (SLIGRL-NH(2)) produced a concentration-dependent contractile response in
      the urinary bladder preparations. These contractions were abolished by removal of
      the urinary bladder mucosa and were significantly reduced by indomethacin (10
      microM). These results suggest that activation of PAR-2 stimulates release of
      prostaglandins from mucosal layer and thereby contracts rat urinary bladder
      smooth muscles.

PMID- 12595965
TI  - Preliminary pharmacological characterisation of an interleukin-13-enhanced
      calcium-activated chloride conductance in the human airway epithelium.
AB  - Interleukin (IL)-13 (10 ng/ml for 48 h) treatment of human bronchial epithelial
      cells induced a hypersecretory ion transport phenotype. Ussing chamber
      experiments demonstrated that this phenotypic change was characterised by an
      almost complete inhibition of the amiloride-sensitive short circuit current (ISC)
      and the appearance of an enhanced calcium-activated chloride conductance (CaCC).
      The peak increases in ISC (anion secretion) in response to UTP and ionomycin were
      increased by >8 fold and >13 fold respectively following IL-13 treatment. Changes
      in intra-cellular Ca(2+) levels following agonist exposure were not different
      between control and IL-13 treatments. The sensitivity of this IL-13-enhanced CaCC
      to several chloride channel-blocking molecules was determined following
      permeabilisation of the basolateral membrane and the establishment of a
      basolateral to apical chloride gradient. Under these conditions changes in ISC
      were regulated exclusively by the apical membrane and the current stimulated by
      ionomycin was sensitive to the chloride channel blockers diisothocyanatostilbene
      2,2'-disulfonic acid (DIDS), dinitrostilben-2,2'-disulfonic acid (DNDS) and 5
      nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) but was insensitive to
      tamoxifen. An understanding of the pharmacological profile of this conductance
      will ultimately aid in the determination of its molecular identity and function
      in the human airway epithelium.

PMID- 12595967
TI  - Regulatory T cells in the induction and maintenance of peripheral transplantation
      tolerance.
AB  - It is now possible to induce donor-specific transplantation tolerance in adult
      rodents using non-depleting monoclonal antibodies against T cell co-receptor and
      co-stimulation molecules or by immunisation with tolerogenic antigen-presenting
      cells. It is a common finding of all these models of peripheral tolerance, as
      well as of various mouse models of autoimmune disease, that regulatory CD4(+) T
      cells are the principal mediators. There are currently no specific markers for
      regulatory T cells, but in some autoimmune models their activity has been
      associated with the expression of activation markers such as CD25 and CTLA4, or
      anti-inflammatory cytokines such as IL-10 and TGF-beta. CD4(+)CD25(+) T cells
      from both naive and tolerised donors are able to transfer tolerance to grafts in
      lymphopenic recipients, and this may be directly applicable to bone-marrow
      transplantation. The challenge is now to understand the biological principles
      that allow such immune re-programming so that they can be safely applied to
      clinical organ grafting.

PMID- 12595968
TI  - Long-term calcineurin inhibition and magnesium balance after renal
      transplantation.
AB  - Regulation of magnesium balance is achieved by a steady-state mechanism in which
      intake and output are maintained at an equal level. Dietary magnesium intake,
      total and ionized plasma magnesium levels, and urinary magnesium were assessed in
      46 renal transplant recipients treated with cyclosporine, nine transplant
      recipients who had never been on cyclosporine, and 31 healthy volunteers. Dietary
      magnesium intake [13.5 (11.0-15.1) mmol/day vs 13.0 (11.1-16.0) mmol/day and 13.7
      (11.4-16.7) mmol/day, respectively; median and interquartile range] and urinary
      magnesium excretion [4.31 (3.57-5.89) vs 4.39 (3.56-6.02) and 5.01 (3.73-6.01)
      mmol/day, respectively] were similar in renal transplant recipients treated with
      cyclosporine, transplant recipients who had never been on cyclosporine, and
      control subjects. Total [0.74 (0.70-0.78) vs 0.80 (0.74-0.84) and 0.81 (0.79
      0.87) mmol/l), respectively] and ionized [0.49 (0.46-0.52) vs 0.53 (0.50-0.58)
      and 0.54 (0.52-0.59) mmol/l, respectively] plasma magnesium were significantly
      lower in renal transplant recipients on cyclosporine than in transplant
      recipients without cyclosporine, and healthy controls. These observations
      indicate a modified magnesium steady state in renal transplant recipients treated
      with cyclosporine.

PMID- 12595969
TI  - The influence of early steroid withdrawal on body composition and bone mineral
      density in renal transplantation patients.
AB  - Corticosteroid treatment may have an important effect on body composition and
      bone mineral density (BMD) in renal transplantation (RTx) patients. We
      investigated the effect of early steroid withdrawal on body composition and BMD
      of RTx patients in a prospective design. Post-transplant immunosuppression
      consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Three months
      after RTx, 27 patients participating in a multi-center trial were randomized
      either to continue steroids (at a dose of 10 mg/day, n=17; steroid+) or be
      withdrawn from steroids within 2 weeks (n=10; steroid-). Body composition and BMD
      (lumbar spine (L2-L4) and femoral neck) were measured by dual-energy X-ray
      absorptiometry (DEXA) just before and 3 months after randomization. With regard
      to body composition, fat mass tended to increase in the steroid+ group (1.1+/-2.3
      kg; P=0.084), but did not change in the steroid- group. Increase in body fat
      percentage tended to be higher (P=0.08) in the steroid+ group (0.6+/-2.7%) than
      in the steroid- group (-0.7+/-2.1%). The change in lean body mass was not
      significantly different between the two groups. BMD of the lumbar spine and
      femoral neck decreased significantly in the steroid+ group (-1.4+/-3.2% and 
      2.3+/-2.9%, respectively, P<0.05) while no changes were observed in the steroid-
      group. The change in BMD of the lumbar spine was significantly different between
      the steroid+ and the steroid- group, whereas the change in BMD of the femoral
      neck was not significantly different. Thus, the increase in fat mass tended to be
      higher in the group continuing on steroids, though not significant, due to large
      inter-individual variation. In general, the effect of early steroid withdrawal on
      body composition after RTx appears to be modest. In addition, early steroid
      withdrawal seems to have beneficial effects on BMD in RTx patients, especially in
      the lumbar region.

PMID- 12595970
TI  - Evaluation of warm ischemia-reperfusion injury using heat shock protein in the
      rat liver.
AB  - We focused on heat shock protein 70 (HSP70) as a marker of viability in hepatic
      warm ischemia-reperfusion. Segmental hepatic warm ischemia was produced in rats
      for 15, 30, 60, 90, 120, or 180 min. Liver sections were evaluated at 30, 60, and
      120 min of reperfusion. Expression of HSP70 and messenger RNA (mRNA), apoptosis,
      and apoptosis-associated genes such as Bcl-2 and Bax were studied. Expression of
      HSP70 and mRNA was augmented as warm ischemia was prolonged, but was markedly
      suppressed in livers with more than 120 min of ischemia. The highest accumulation
      of HSP70 was observed in the nucleus. In livers subjected to longer duration of
      warm ischemia, necrosis and apoptosis were evident and Bcl-2 mRNA expression and
      Bcl-2/Bax protein ratio were markedly diminished. Apoptosis may be related to the
      process of cellular injury induced by warm ischemia-reperfusion. Expression of
      HSP70 and the Bcl-2 family can be effective markers of viability in hepatic warm
      ischemia-reperfusion.

PMID- 12595971
TI  - Successful liver transplantation from agonal non-heart-beating donors in pigs.
AB  - An effective way to overcome shortage of donors in liver transplantation (LTx) is
      to consider such from non-heart-beating donors (NHBDs). We investigated how a
      liver graft should be treated before and/or after procurement for successful LTx
      from an NHBD. Porcine LTx was performed with FR167653 (FR), a dual inhibitor of
      tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and/or
      prostaglandin E(1) (PG). Animals were allocated to an FR group (n=4, donors and
      recipients were treated with FR), a PG group (n=4, donors and recipients were
      treated with PG), or an FRPG group (n=4, donors and recipients were treated with
      both FR and PG). No recipients in the FR group and only two of four recipients in
      the PG group survived, whereas all recipients in the FRPG group survived.
      Suppression of TNF-alpha and IL-1beta and maintenance of microcirculation are the
      key to successful transplantation from NHBDs.

PMID- 12595972
TI  - The effects of immunosuppressants on FAS-mediated activation-induced cell death
      in human T lymphocytes.
AB  - The effects of cyclosporin A (CsA) and methylprednisolone (MP) on Fas-mediated
      activation-induced cell death (FMAICD) of T lymphocytes were examined. T
      lymphocytes were activated with the immobilized anti-CD 3 and CD 28 monoclonal
      antibodies (MoAbs) (activation phase) and incubated further with the agonistic
      MoAb against Fas (death phase). Cell proliferation and DNA fragmentation were
      measured by XTT and diphenylamine assay. CsA in the activation phase inhibited
      DNA fragmentation mediated by anti-Fas MoAb but not MP. The combination of CsA
      and MP at the lower concentrations had little effect on FMAICD, although they had
      similar degrees of suppression on T lymphocyte proliferation as the maximum
      obtained by CsA or MP alone. In the death phase, MP induced apoptosis without
      7C11 and CsA had no effects. These results indicate that the combination of CsA
      and MP at low concentrations could maintain FMAICD with the suppression on T
      lymphocyte proliferation.

PMID- 12595973
TI  - Liver transplantation for hepatocellular cancer: should the current indication
      criteria be changed?
AB  - Liver transplantation (LTx) is the best treatment for hepatocellular carcinoma
      (HCC), but should be offered only to selected patients. The usual procedure is to
      transplant only for small and unilobular tumors. The aim of this paper is to
      verify whether the actual indication criteria are still justified. The details of
      121 patients with HCC who were submitted to LTx from 1985 to 2000 were analyzed.
      Age, gender, liver disease, Child class, alpha-fetoprotein (AFP) level, presence
      of tumor capsule, vascular invasion, size and number of nodules, histological
      grade, and pTNM were considered. The 5- and 10-year actuarial survival rates were
      61.7% and 53.1%. Freedom from recurrence was 85.9% and 85.9%, respectively. At
      univariate analysis, size, presence of capsule, AFP levels, vascular invasion,
      grade, pTNM, transarterial chemoembolization (TACE), Child class, and age were
      all significantly related to survival and/or cancer recurrence. Presence of
      capsule, AFP levels, and viral cirrhosis were independent variables in Cox's
      analysis for survival, whereas histological grade, AFP levels, and vascular
      invasion were significant independent variables for recurrence. In conclusion, a
      strict selection should be made to optimize graft allocation while size and
      multifocality should probably no longer be considered a contraindication for LTx.
      Histological grade, AFP levels, and vascular invasion, as indicator of tumor
      behavior, more likely reflect the risk of recurrence.

PMID- 12595974
TI  - The cost effectiveness of lung transplantation compared with that of heart and
      liver transplantation in the Netherlands.
AB  - This study was performed to assess the main reasons for the unfavorable cost
      effectiveness of lung transplantation compared with that of heart and liver
      transplantation. Costs, effects, and cost-effectiveness ratios of Dutch lung,
      heart, and liver transplantation programs were compared. The data are based on
      three Dutch technology assessments of transplantation, with minor adjustments for
      time and methods. In result, mainly follow-up costs of lung transplantation are
      higher than costs of heart and liver transplantation-- 50,300 US dollars, 121,500
      US dollars, and 95,300 US dollars, respectively--in the first 3 years after
      transplantation. The survival gain realized by lung transplantation is small (4.4
      years) compared with heart (8.8 years) and liver (14.7 years) transplantation.
      Costs per life-year gained were 77,000 US dollars, 38,000 US dollars, and 26,000
      US dollars for lung, heart, and liver transplantation, respectively. The
      unfavorable cost effectiveness of lung transplantation is largely related to a
      relatively small survival gain and high follow-up costs.

PMID- 12595975
TI  - Incidence of minor and major amputations after pancreas/kidney transplantation.
AB  - Among other complications, diabetes mellitus leads to peripheral vascular disease
      with the risk of limb amputation. This retrospective study analyzed the incidence
      of amputations after simultaneous pancreas-kidney transplantation (SPK). Between
      June 1994 and February 2001, 200 SPKs, nine pancreas-after-kidney- (PAK) and one
      pancreas transplantation alone (PTA) were performed. The overall 5-year patient,
      pancreas-, and kidney-graft survival rates were 92.4%, 80.2% and 85.6%,
      respectively. Mean age at transplantation was 38.7 years, mean duration of
      diabetes was 26.9 years, mean duration of dialysis was 26.7 months. Nineteen
      (9.5%) patients after SPK (seven female/12 male) underwent 33 amputations, on
      average 18.7 months after transplantation. Longer duration of dialysis and a
      previous history of amputation were significant risk factors for an amputation
      after SPK ( P=0.014, P<0.001). Thus, early referral for SPK before dialysis
      initiation may be beneficial in preventing amputation.

PMID- 12595976
TI  - Comparison of effectiveness of two urinary drainage systems in intensive care
      unit: a prospective, randomized clinical trial.
AB  - OBJECTIVE: In a previous non-randomized study, we demonstrated that no difference
      occurred in the rate of acquisition of bacteriuria between a complex closed
      drainage system (CCDS) and a two-chamber drainage system (TCDS) in patients in an
      intensive care unit (ICU). To confirm this result, we performed a randomized,
      prospective, and powerful study assessing the effectiveness of the CCDS and the
      TCDS in ICU patients. DESIGN: Randomized, prospective, and controlled study.
      SETTING: Medico-surgical intensive care unit (16 beds) in a teaching hospital.
      PATIENTS AND INTERVENTIONS: Three hundred and eleven patients requiring an
      indwelling urinary catheter for longer than 48 h were assigned individuals to the
      TCDS group or CCDS group to compare the rate of acquisition of bacteriuria.
      MEASUREMENTS AND RESULTS: Patients did not receive prophylactic antibiotics
      during placement management or catheter withdrawal. Urine samples were obtained
      weekly for the duration of catheterization and within 24 h after catheter
      removal, and each time symptoms of urinary infection were suspected. There was no
      statistical difference in the rate of bacteriuria between the two groups.
      Bacteriuria occurred in 8% and 8.5% of patients for TCDS and CCDS, respectively.
      Rates of urinary tract infection were 12.1 and 12.8 episodes per 1,000 days of
      catheter. CONCLUSION: This randomized study, that compares the effectiveness of a
      TCDS and a CCDS in ICU patients, confirms the results of our previous study. No
      differences were noted between the two systems (a =0.05). The higher cost of CCDS
      is not justified for ICU patients.

PMID- 12595977
TI  - Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony
      stimulating factor in patients with severe sepsis.
AB  - OBJECTIVE: To evaluate the effect of recombinant human granulocyte-macrophage
      colony-stimulating factor (rhGM-CSF) on immunoparalysis as defined by a sustained
      decrease of HLA-DR expression on monocytes in patients with severe sepsis.
      DESIGN: Prospective, non-randomised observational study. SETTING: Two
      anaesthesiological intensive care units of a university hospital. INTERVENTION:
      Administration of a daily dose of 5 micro g/kg rhGM-CSF over a period of 3 days.
      PATIENTS: Nine consecutive patients with severe sepsis and a documented HLA-DR
      expression on peripheral monocytes of less than 150 mean fluorescence intensity
      (MFI) over a period of at least 48 h prior to intervention. MEASUREMENTS AND
      RESULTS: Mean MFI was 69.4+/-13.2 24 h before and 56.7+/-8.2 on the day of the
      administration of 5 micro g/kg rhGM-CSF. Within 24 h a significant increase of
      HLA-DR expression to a mean of 327.7+/-78.8 MFI was observed in all patients.
      This increase was maintained on days 2-10. It was accompanied by a significant
      rise in white blood count. The ex vivo TNF-alpha production in whole blood after
      lipopolysaccharide (LPS)-stimulation increased significantly from a mean of 82+/
      29.2 pg/ml to 793+/-546.8 pg/ml. Apart from febrile reactions in two patients, no
      side effects were recorded. No increases of pro-inflammatory markers (IL-6, C
      reactive protein, LPS-binding protein, procalcitonin) were observed. SOFA values
      before and after rhGM-CSF did not differ significantly. The mortality rate was
      33%. CONCLUSION: This preliminary study demonstrates that rhGM-CSF upregulates
      HLA-DR expression on monocytes in septic patients with multi-organ dysfunction.
      Moreover, with the concomitant increase of the ex vivo whole blood TNF-alpha
      response, this upregulation of a monocytic activation marker is paralleled by a
      functional recovery.

PMID- 12595978
TI  - Hemodynamic profiles of patients with dengue hemorrhagic fever during toxic
      stage: an echocardiographic study.
AB  - OBJECTIVE: To study left ventricular performance and hemodynamic abnormalities
      during different stages of dengue hemorrhagic fever (DHF). DESIGN AND SETTING:
      Observational study in a tertiary medical school hospital. PATIENTS: Twenty-four
      patients with serologically confirmed diagnosis of dengue virus infection and DHF
      according to the WHO criteria. METHODS: Echocardiography was performed during
      toxic, convalescent stages and at least 2 weeks after discharge (recovery). Left
      ventricular ejection fraction, rate-corrected velocity of circumferential fiber
      shortening adjusted for end-systolic meridional wall stress (VCFC/ESS) Z score,
      end-diastolic volume Z score, cardiac index, heart rate, mean arterial pressure,
      and total systemic vascular resistance (SVR) were compared between different
      stages of DHF. RESULTS: Ejection fraction and VCFC/ESS were significantly lower
      during the toxic stage than after recovery. End-diastolic volume was low during
      toxic stage and returned to normal during convalescence and recovery. Cardiac
      index was low during the toxic stage due to decreased preload (low end-diastolic
      volume) and depressed left ventricular ejection fraction. Cardiac index remained
      subnormal during convalescence due to sinus bradycardia. Wide variation in heart
      rate during toxic stage resulted in a small, nonsignificant increase compared to
      recovery. With treatment, heightened SVR resulted in relatively normal mean
      arterial pressure throughout the course of the illness. CONCLUSIONS: The
      mechanism of decreased cardiac output during toxic stage of DHF is complex.
      Decreased preload is accompanied by decreased left ventricular performance, and
      possibly a subnormal heart rate response in some patients.

PMID- 12595979
TI  - Infectious diseases as a trigger in thrombotic microangiopathies in intensive
      care unit (ICU) patients?
AB  - OBJECTIVE: Thrombotic microangiopathy (TMA) has been associated with a large
      number of underlying diseases. We conducted a descriptive, retrospective study
      including all TMA adult patients admitted to our ICU, with a particular interest
      in infectious episodes as a trigger of TMA. PATIENTS: All adult patients (30)
      with a diagnosis of TMA admitted to the medical ICU at Saint-Louis Hospital
      (Paris, France) between 1992 and 1998 were retrospectively included. METHODS: All
      patients with clinical and microbiological evidence of bacterial infection were
      treated with intravenous antibiotics. The specific treatment of TMA consisted in
      solvent/detergent-treated plasma administration by plasma exchange or high volume
      plasma infusion (30 ml/kg per day) in fractionated doses. RESULTS: Among the 30
      adult patients studied, TMA in 16 (53%) was associated with microbiologically
      documented infection. An acute infection was found in 8/9 patients with an HIV
      related TMA, in 2/6 patients with a systemic lupus erythematosus (SLE)-related
      TMA and in 3/6 patients with TMA associated with other disorders. In three
      patients, an acute infectious disease was the only cause associated with the TMA.
      Four other patients had clinical manifestations suggesting an infection process
      but without bacteriological documentation. Escherichia coli was isolated in 7/16
      cases and verotoxin was found in the stools of two other patients. All patients
      were treated with plasma administration and those with evidence of infection were
      systematically and intensively treated with antibiotics. Eventually 8 patients
      died (27%), 20 (67%) reached complete remission and 2 partial remission.
      CONCLUSION: Bacterial infections are commonly observed amongst TMA patients
      hospitalized in ICUs and may act as a trigger of this disease. Screening for
      infection is a requirement in patients with TMA, either idiopathic or associated
      with other conditions.

PMID- 12595980
TI  - Measurement of functional residual capacity by nitrogen washout during partial
      ventilatory support.
AB  - OBJECTIVE: Evaluation of an open circuit multiple breath nitrogen washout (MBNW)
      technique for measurement of functional residual capacity (FRC) during partial
      ventilatory support using corrections for gas viscosity, sampling delay time, and
      re-inspired nitrogen. DESIGN: Measurements in a lung model with known reference
      volume simulating spontaneous breathing and duplicate measurements in patients
      breathing spontaneously with partial ventilatory support. SETTING. Experimental
      laboratory and intensive care units of a university hospital. PATIENTS: Eighteen
      patients with acute respiratory failure. INTERVENTIONS: Change of FiO(2) from
      baseline to 1.0. MEASUREMENTS AND MAIN RESULTS: FRC was measured by MBNW during
      spontaneous breathing with continuous positive airway pressure, pressure support
      ventilation, proportional assist ventilation, automatic tube compensation, and
      airway pressure release ventilation. In the lung model, repeated measurements at
      three volumes were done with all partial ventilatory support modalities, and
      baseline FiO(2 )was varied with one mode and FRC. The mean of differences between
      MBNW (FRC(MBNW)) and reference was 28 ml (1.6%), and the 2.SD-interval was 84 ml
      (4.9%) for all modes. Measurements up to a baseline FiO(2) of 0.8 showed
      differences of 5 ml (-0.3%) and the 2.SD-interval of 38 ml (2.2%) between
      reference and FRC(MBNW). In 18 patients, 66 duplicate measurements revealed a
      mean difference of 30 ml (0.9%) with a coefficient of repeatability of 358 ml
      (13%) independent of ventilatory mode and chronological order. CONCLUSION: This
      study suggests that, using corrections for gas viscosity, sampling delay time,
      and re-inspired nitrogen, FRC can be determined with good repeatability in
      patients and good accuracy in a lung model during partial ventilatory support.

PMID- 12595981
TI  - Ventilator-associated pneumonia and atelectasis: evaluation through
      bronchoalveolar lavage fluid analysis.
AB  - OBJECTIVE: Surfactant offers protection against alveolar collapse and contributes
      to the local defense mechanism, but it is unclear if surfactant alterations have
      a role in the development of atelectasis or ventilator-associated pneumonia
      (VAP). The present study was undertaken to monitor surfactant, as well as
      biochemical BAL fluid alterations, during the course of VAP and atelectasis in
      mechanically ventilated patients without primary cardiopulmonary disease, to
      elucidate the pathogenesis and to differentiate these two entities. DESIGN.
      Prospective controlled study. SETTING: 14-bed general ICU of a 750-bed University
      Hospital. PATIENTS: Sixty-one ventilated patients, without primary
      cardiopulmonary disease-normal initial chest X-ray, satisfactory oxygenation
      (PaO(2)/FiO(2)>300 mmHg), and expected time of ventilation exceeding 2 weeks-were
      initially enrolled. Twelve of them developed VAP and eight lobar or segmental
      atelectasis during the 2-week study period. INTERVENTIONS: An initial BAL was
      performed in all patients within 48 h from admission. Patients who developed VAP
      or atelectasis were subjected to a second and third BAL during and after the
      resolution of VAP or atelectasis, respectively. MEASUREMENTS AND RESULTS: VAP and
      atelectasis resulted in a significant increase of total protein and markers of
      inflammation, such as PAF and neutrophils, which partially remitted after their
      resolution. Large surfactant aggregates, which contribute to surface tension
      decrease, were significantly reduced during both entities and remained low even
      after their resolution. CONCLUSIONS: BAL alterations during VAP and atelectasis
      suggest increased alveolar-capillary permeability, severe surfactant
      abnormalities, and signs of local inflammatory reaction. These alterations are
      associated with the observed deteriorated gas exchange and lung mechanics and
      could predispose to further lung injury in ventilated patients.

PMID- 12595982
TI  - The effect of infusions of adrenaline, noradrenaline and dopamine on cerebral
      autoregulation under propofol anaesthesia in an ovine model.
AB  - OBJECTIVE: To compare the effects of infusions of adrenaline, noradrenaline and
      dopamine on cerebral autoregulation under steady-state propofol anaesthesia with
      the awake state. DESIGN: Prospective, randomised, interventional animal study.
      SETTING: University laboratory. SUBJECTS: Six studies in two cohorts of adult
      ewes: awake and steady-state propofol anaesthesia (15 mg/min). INTERVENTIONS: In
      random order, each animal received ramped infusions of adrenaline, noradrenaline
      (0-40 microg/min) and dopamine (0-40 microg/kg per min). MEASUREMENTS AND
      RESULTS: Cerebral blood flow (CBF) was measured continuously from changes in
      Doppler velocities in the sagittal sinus and normalised to a PaCO(2) 35 mmHg.
      Propofol decreased CBF by 55% relative to pre-anaesthesia values (p=0.0001). All
      three catecholamines significantly and equivalently increased mean arterial
      pressure (MAP) from baseline in a dose-dependent manner in both awake and
      propofol cohorts. Adrenaline significantly increased CBF from baseline in both
      awake sheep (p<0.01) and during propofol anaesthesia (p<0.001); noradrenaline and
      dopamine did not statistically increase CBF. When comparing the effects of
      individual catecholamines with each other within each cohort, no statistically
      significant difference between the catecholamines was demonstrated. (p>0.05).
      Using linear regression analysis, normalised CBF was correlated against
      associated changes in MAP. No significant differences were demonstrated between
      the slopes of regression lines for adrenaline, noradrenaline and dopamine in
      either cohort (ANCOVA). There was a statistically significant difference between
      the intercepts of the awake and propofol cohorts (p<0.0001), but no difference
      between the slopes (p=0.69). CONCLUSIONS: Over a specific dose range,
      catecholamine-induced hypertension caused increased CBF during steady-state
      propofol anaesthesia. This effect was offset by an associated reduction in CBF
      caused by propofol. The concomitant administration of propofol and catecholamines
      was not associated with altered autoregulatory function compared to the awake
      state.

PMID- 12595983
TI  - The functional outcome and quality of life of children after admission to an
      intensive care unit.
AB  - OBJECTIVE: To evaluate the long-term outcome of children following admission to a
      paediatric intensive care unit. DESIGN: Prospective, long-term follow-up study.
      SETTING: Sixteen-bed multi-disciplinary paediatric intensive care unit in a free
      standing, university, tertiary, teaching hospital. PATIENTS: All children
      consecutively admitted to the paediatric intensive care unit from 1(st) January,
      1995, to 31(st) December, 1995. INTERVENTIONS: Outcome was evaluated, by
      telephone interview, at a median of 3.5 years (range 2.3-6 years) after admission
      to the intensive care unit using a modification of the Glasgow Outcome Score
      (GOS) to assess functional outcome and the Health State Utility Index (Mark 1) to
      assess quality of life. MEASUREMENTS AND MAIN RESULTS: Of the children admitted
      to the intensive care unit, 83.8% were alive at the time of follow-up. While
      10.3% of the survivors had an unfavourable outcome and were likely to live
      dependent on care, 89.7% had a favourable outcome and were likely to lead an
      independent existence. Although 16.4% had an unfavourable quality of life, 83.6%
      of the children survived with a favourable quality of life. At the time of follow
      up, 16.2% of the children were dead: 49% died in the intensive care unit, 5% died
      in hospital and 46% died after discharge from hospital. CONCLUSIONS: The majority
      of children admitted to a paediatric intensive care unit survive with an
      excellent functional outcome and quality of life. Long-term outcome assessment
      provides a basis for observing trends in outcome over time within the same
      institution.

PMID- 12595984
TI  - Introgression of a quantitative trait locus for yield from Glycine soja into
      commercial soybean cultivars.
AB  - The value of exotic germplasm in broadening the genetic base of most crops has
      been demonstrated many times. However, the difficulties involved in working with
      exotic germplasm have limited their utility in plant breeding. Unwanted linkages
      often thwart the successful incorporation of beneficial exotic genes into
      commercial lines. Thus, the use of exotics in traditional breeding makes the
      process of crop improvement a tedious, time-consuming and expensive endeavor. The
      availability of molecular markers makes it possible to isolate specific genomic
      regions and transfer them into commercial varieties with minimal linkage drag. We
      found a yield-enhancing quantitative trait locus (QTL) from Glycine soja (Siebold
      and Zucc.) by evaluating a population of 265 BC(2) individuals from a cross
      between HS-1 and PI 407305. The yield QTL was located on linkage group B2(U26) of
      the soybean [Glycine max (L.) Merrill] genetic linkage map. In a 2-year, multi
      location study, individuals carrying the PI 407305 haplotype at the QTL locus
      demonstrated a 9.4% yield advantage over individuals that did not contain the
      exotic haplotype. When tested in a more uniform "HS-1-like" background in two
      locations, we observed an 8% yield advantage for lines that carry the PI 407305
      haplotype. We further assessed the QTL effect in various elite soybean genetic
      backgrounds. The yield effect was consistently observed in only two of six
      genetic backgrounds. Individuals carrying the PI 407305 haplotype at the QTL
      locus had a 9% yield advantage in yield trials across locations. Despite the
      limited adaptability of this yield-QTL across genetic backgrounds, this study
      demonstrates the potential of exotic germplasm for yield enhancement in soybean.

PMID- 12595985
TI  - Identification and mapping of the QTL for aluminum tolerance introgressed from
      the new source, Oryza Rufipogon Griff., into indica rice (Oryza sativa L.).
AB  - This study was conducted to identify and map the quantitative trait locus (QTL)
      controlling Al tolerance in rice using molecular markers. A population of 171
      F(6) recombinant inbred lines (RILs) derived from the cross of Oryza sativa
      (IR64), the Al susceptible parent, and Oryza rufipogon, the Al tolerant parent,
      was evaluated for Al tolerance using a nutrient solution with and without 40 ppm
      of active Al(+3). A genetic map, consisting of 151 molecular markers covering
      1,755 cM with an average distance of 11.6 cM between loci, was constructed. Nine
      QTLs were dentified including one for root length under non-stress conditions
      (CRL), three for root length under Al stress (SRL) and five for relative root
      length (RRL). O. rufipogon contributed favorable alleles for each of the five
      QTLs for RRL, which is a primary parameter for Al tolerance, and individually
      they explained 9.0-24.9% of the phenotypic variation. Epistatic analysis revealed
      that CRL was conditioned by an epistatic effect, whereas SRL and RRL were
      controlled by additive effects. Comparative genetic analysis showed that QTLs for
      RRL, which mapped on chromosomes 1 and 9, appear to be consistent among different
      rice populations. Interestingly, a major QTL for RRL, which explained 24.9% of
      the phenotypic variation, was found on chromosome 3 of rice, which is conserved
      across cereal species. These results indicate the possibilities to use marker
      assisted selection and pyramiding QTLs for enhancing Al tolerance in rice.
      Positional cloning of such QTLs introgressed from O. rufipogon will provide a
      better understanding of the Al tolerance mechanism in rice and the evolutionary
      genetics of plant adaptation to acid-soil conditions across cereal species.

PMID- 12595986
TI  - Identification of genetic markers linked to banana streak disease expression in
      inter-specific Musa hybrids.
AB  - Recently-introduced inter-specific Musa hybrids, bred for improved yield and
      resistance to diseases, have been found to be widely infected with banana streak
      virus (BSV), the causal agent of banana streak disease (BSD). One hypothesis
      suggests: (1) that BSD occurrence in these inter-specific hybrids results from
      activation of BSV-Ol endogenous pararetrovirus sequences (EPRV) integrated into
      the Musa genome rather than from external sources of infection, and (2) that the
      process of genetic hybridisation may be one factor involved in triggering
      episomal expression of the BSV integrants. In order to test this hypothesis we
      carried out a genetic analysis of BSD incidence in a F1 triploid ( Musa AAB)
      population produced by inter-specific hybridisation between virus and disease
      free diploid Musa balbisiana (BB) and tetraploid Musa acuminata (AAAA) parents.
      Half of the F1 progeny of this cross expressed BSV particles. Using PCR
      amplification to determine the presence or absence of BSV-Ol EPRVs, it was
      determined that this endogenous sequence was specific to the M. babisiana genome
      and occurred in a homozygous state. Using bulk segregant analysis, ten AFLP
      markers co-segregating with the absence and/or presence of BSV infection were
      identified in the M. balbisiana genome, but were absent from the M. acuminata
      genome. Seven of these markers segregated with the presence of a BSV particle and
      three with the absence of BSV particles. Analysis of the segregation of these
      markers using a test-cross configuration allowed the construction of a genetic
      map of the linkage group containing the locus associated with BSV infection in
      the F1 hybrid population. These data indicate that a genetic mechanism is
      involved in BSV appearance, and suggest that a monogenic allelic system confers
      the role of carrier to the M. balbisiana parent.

PMID- 12595987
TI  - Molecular mapping of the Rf1 gene restoring pollen fertility in PET1-based F1
      hybrids in sunflower (Helianthus annuus L.).
AB  - Up to now a single cytoplasmic male sterility (CMS) source, PET1, is used
      worldwide for hybrid breeding in sunflower. Introgression of the restorer gene
      Rf1, responsible for fertility restoration, into new breeding material requires
      tightly linked markers to perform an efficient marker-assisted selection. A
      survey of 520 decamer primers by bulked segregant analyses identified five RAPD
      markers linked to the restorer gene Rf1. In a F(2) population of 183 individuals
      one of the RAPD markers, OPK13_454, mapped 0.8 cM from Rf1, followed by OPY10_740
      with 2 cM. Bulked segregant analyses using 48 AFLP primer combinations identified
      17 polymorphisms, which could be mapped in the same linkage group as Rf1.
      E33M61_136, and E41M48_113 were mapped 0.3 cM and 1.6 cM from the gene,
      respectively. Conversion of E41M48_113 into a sequence-specific marker resulted
      in a monomorphic pattern. However, two of the RAPD markers, OPK13_454 and
      OPY10_740, were successfully converted into SCAR markers, HRG01 and HRG02, which
      are now available for marker-assisted selection. To investigate the utility of
      these SCAR markers in other cross-combinations they were tested in a set of 20
      lines. Comparison of the patterns of 11 restorer and nine maintainer lines of
      PET1 demonstrated that the markers OPK13_454/HRG01 and HRG02 were absent in all
      maintainer lines but present in all restorer lines, apart from the high oleic
      line RHA348 and the dwarf line Gio55. In addition, restorer lines developed from
      the interspecific hybrids Helianthus annuus x Helianthus mollis and H. annuus x
      Helianthus rigidus gave the same characteristic amplification products.

PMID- 12595988
TI  - A high-density linkage map in Brassica juncea (Indian mustard) using AFLP and
      RFLP markers.
AB  - A high-density genetic linkage map of Brassica juncea (2n = 36) was constructed
      with 996 AFLP (amplified fragment length polymorphism) and 33 RFLP (restriction
      fragment length polymorphism) markers using a F1-derived doubled-haploid (DH)
      population of 123 individuals. This mapping population was developed by crossing
      a well-adapted, extensively grown Indian variety Varuna and a canola quality line
      Heera. The two lines are highly divergent and contain a number of contrasting
      qualitative and quantitative traits of high agronomic value. AFLPs were generated
      by the use of restriction enzymes EcoRI or PstI in combination with either MseI
      or TaqI. Using 91 primer pairs, a total of 1,576 parental polymorphic bands were
      detected of which 996 were used for mapping. In addition, 33 RFLP markers,
      developed from genomic clones of B. napus, were added to the map. The segregation
      of each marker and linkage analysis was performed using the program JoinMap
      version 2.0. The 1,029 mapped-markers were aligned in 18 linkage groups, which is
      the haploid chromosome number of the species, at LOD values ranging from 5 to 8.
      The total map length was 1,629 cM with an average marker interval of 3.5 cM. AFLP
      markers generated by EcoRI were more clustered, whereas PstI markers showed more
      extensive distribution. A set of 26 primer pairs (9 EcoRI/ MseI, 6 EcoRI/ TaqI, 6
      PstI/ MseI and 5 PstI/ TaqI) generating 385 markers were identified for AFLP
      based whole-genome selection as these markers covered 96% of the genome mapped
      with the 91 primer pairs. The map developed in the present study could be used
      for dissection and the transfer of agronomically important traits and favourable
      QTLs from ill-adapted exotic germplasm to cultivated Indian varieties.

PMID- 12595989
TI  - Mapping the Fas locus controlling stearic acid content in soybean.
AB  - Increasing the stearic acid content to improve soybean [ Glycine max (L) Merr]
      oil quality is a desirable breeding objective for food-processing applications.
      Although a saturated fatty acid, stearic acid has been shown to reduce total
      levels of blood cholesterol and offers the potential for the production of solid
      fat products (such as margarine) without hydrogenation. This would result in the
      reduction of the level of trans fat in food products and alleviate some current
      health concerns. A segregating F(2) population was developed from the cross
      between Dare, a normal stearic acid content cultivar, and FAM94-41, a high
      stearic acid content line. This population was used to assess linkage between the
      Fas locus and simple sequence repeat (SSR) markers. Three SSR markers, Satt070,
      Satt474 and Satt556, were identified to be associated with stearic acid (P <
      0.0001, r(2) > 0.61). A linkage map consisting of the three SSR markers and the
      Fas locus was then constructed in map order, Fas, Satt070, Satt474 and Satt556,
      with a LOD score of 3.0. Identification of these markers may be useful in
      molecular marker-assisted breeding programs targeting modifications in soybean
      fatty acids.

PMID- 12595990
TI  - Isolation and expression analysis of salt stress-associated ESTs from contrasting
      rice cultivars using a PCR-based subtraction method.
AB  - Salt stress adversely affects the growth of rice plants. To understand the
      molecular basis of salt-stress response, four subtracted cDNA libraries were
      constructed employing specific NaCl-stressed tissues from salt-tolerant (CSR 27
      and Pokkali) and salt-sensitive (Pusa basmati 1) rice cultivars. An efficient PCR
      based cDNA subtraction method was employed for the isolation of the salt-stress
      responsive cDNA clones. In all, 1,266 cDNA clones were isolated in the course of
      this study, out of which 85 clones were end-sequenced. Database search of the
      sequenced clones showed that 22 clones were homologous to genes that have earlier
      been implicated in stress response, 34 clones were novel with respect to their
      function and six clones showed no homology to sequences in any of the public
      database. Northern analysis showed that the transcript expression pattern of
      selected clones was variable amongst the cultivars tested with respect to stress
      regulation.

PMID- 12595991
TI  - The characterisation and mapping of a family of LMW-gliadin genes: effects on
      dough properties and bread volume.
AB  - Analysis of a cDNA library from wheat cv Wyuna endosperm, indicated a significant
      size and sequence variation among seed-endosperm protein genes. In this study, a
      family of low-molecular-weight seed protein genes are analysed that are related
      to the gliadins and the low-molecular-weight glutenin subunits. Sequence analysis
      and comparison of these proteins showed that they are closely related to a 17-kDa
      protein from barley, epsilon hordein, which plays a role in beer foam stability
      in the brewing industry. Mapping of these genes in wheat shows that they are
      located on group 7 and 4 chromosomes, as opposed to a group 1 and 6 location for
      the glutenins and gliadins. It is possible that this family of proteins forms a
      new class of seed-endosperm proteins important in defining the quality
      characteristics of wheat flour. Therefore, a representative gene from this family
      was expressed in Escherichia coli and the purified protein was supplemented into
      a base wheat flour. Rheological analysis showed that the protein effected dough
      strength and resistance break down during mixing of the dough, and provided a 20%
      increase in loaf height after baking.

PMID- 12595992
TI  - Resistance gene-analog polymorphism markers co-segregating with the YR5 gene for
      resistance to wheat stripe rust.
AB  - The Yr5 gene confers resistance to all races of the stripe rust pathogen (
      Puccinia striiformis f. sp. tritici) of wheat in the United States. To develop
      molecular markers for Yr5, a BC(7):F(3) population was developed by backcrossing
      the Yr5 donor ' Triticum spelta album' (TSA) with the recurrent parent 'Avocet
      Susceptible' (AVS). Seedlings of the Yr5 near-isogenic lines (AVS/6* Yr5), AVS,
      TSA, and the BC(7):F(3) lines were tested with North American races of P.
      striiformis f. sp. tritici under controlled greenhouse conditions. The single
      gene was confirmed by a 1:2:1 segregation ratio for homozygous-resistant,
      heterozygous and homozygous-susceptible BC(7):F(3) lines. Genomic DNA was
      extracted from the parents (the Yr5 near-isogenic line and AVS) and 202
      BC(7):F(3) lines. The resistance gene-analog polymorphism (RGAP) technique was
      used to identify molecular markers. The parents and the homozygous-resistant and
      homozygous-susceptible BC(7):F(3) bulks were used to identify putative RGAP
      markers for Yr5. Association of the markers with Yr5 was determined using
      segregation analysis with DNA from the individual BC(7):F(3) lines. Of 16 RGAP
      markers confirmed by segregation analysis with 109 BC(7):F(3) lines, and nine of
      the markers confirmed with an additional 93 BC(7):F(3) lines, three markers co
      segregated with the resistance allele and three markers co-segregated with the
      susceptibility allele at the Yr5 locus. The other four markers were tightly
      linked to the locus. Analysis of a set of Chinese Spring nulli-tetrasomic lines
      with three markers that co-segregated with, or were linked to, the susceptibility
      allele confirmed that the Yr5 locus is on chromosome 2B. Of five RGAP markers
      that were cloned and sequenced, markers Xwgp-17 and Xwgp-18 that co-segregated
      with the Yr5 locus were co-dominant and had 98% homology with each other in both
      DNA and translated amino-acid sequences. The two markers had 97% homology with a
      resistance gene-like sequence from Aegilops ventricosa and had significant
      homology with many known plant resistance genes, resistance gene analogs and
      expressed sequence tags (ESTs) from wheat and other plant species. The markers
      Xwgp-17 and Xwgp-18 also had significant homology with the NB-ARC domain that is
      in several genes for plant resistance to diseases, nematode cell death and human
      apoptotic signaling. These markers should be useful to clone Yr5 and combine Yr5
      with other genes for durable and superior resistance for the control of stripe
      rust.

PMID- 12595993
TI  - Introgression of 1Dx5+1Dy10 into tritordeum.
AB  - The uses of hexaploid tritordeum as a crop for human consumption require
      improvement of its bread-making quality. For this purpose chromosome 1D of bread
      wheat with the Glu-D1 allele encoding for high-molecular-weight glutenin subunits
      Dx5+Dy10 was introgressed into tritordeum. Different primary tritordeums were
      crossed with wheats carrying subunits Dx5+Dy10. The hybrids were backcrossed to
      tritordeum and seeds for the next backcross (or selfing) were selected for the
      presence of chromosome 1D using SDS-PAGE. Forty two chromosome plants carrying
      subunits Dx5+Dy10 were obtained after two backcrosses and selfing. Chromosome
      characterization of these plants using fluorescence in situ hybridisation (FISH)
      proved that either chromosome substitution 1H(ch)/1D or 1A/1D had been obtained.
      A homozygous plant with a translocation of the entire 1DL arm to 1H(ch)S was also
      obtained. The complete chromosome substitution lines have better agronomic
      characteristics than the lines with translocations.

PMID- 12595994
TI  - Molecular dissection of the genetic relationships of source, sink and transport
      tissue with yield traits in rice.
AB  - Source, sink, and translocation capacity of assimilates play important roles
      during the formation of grain yield. The present study was conducted to
      characterize the genetic bases of traits representing source, sink and transport
      tissue, and their relationships with yield traits in rice, by analyzing QTLs for
      these traits and various ratios among them. The genetic materials were a
      recombinant inbred population derived from a cross between two indica cultivars
      Zhenshan 97 and Minghui 63, the parents of the most-widely grown hybrid rice in
      China. Using a linkage map that covers a total of 1,796 cM based on 221 molecular
      marker loci, a total of 81 QTLs were identified for the 15 traits studied (three
      leaf areas as the source, total spikelets per panicle as the sink, the number of
      large vascular bundles in the stem as transport tissue, three source to sink
      ratios, three transport tissue to source ratios, one transport tissue to sink
      ratio and three yield traits). The amount of variation explained by individual
      QTLs ranged from 1.12% to 24.14%. Five QTLs were identified to show interaction
      effects with the environment, which explained from 3.19% to 9.15% of the
      variation. The results showed that close linkage or pleiotropy is the genetic
      basis for the correlations of grain yield traits with source, sink, transport
      tissue and the various ratios among them. Of the 25 QTLs identified for source
      sink-transport tissue trait, and 43 for various ratios, 8 and 22 QTLs,
      respectively, were mapped to the similar genomic blocks harboring QTLs for yield
      traits, especially for grain weight. Co-location of QTLs for yield traits with
      those for ratios among source, sink and transport tissue may provide a genetic
      explanation for the physiological expression of yield traits, and also suggest
      that improvement in ratios among source, sink and transport tissue may result in
      improvement in yield potential.

PMID- 12595995
TI  - QTL analysis for grain protein content using SSR markers and validation studies
      using NILs in bread wheat.
AB  - QTL interval mapping for grain protein content (GPC) in bread wheat was conducted
      for the first time, using a framework map based on a mapping population, which
      was available in the form of 100 recombinant inbred lines (RILs). The data on GPC
      for QTL mapping was recorded by growing the RILs in five different environments
      representing three wheat growing locations from Northern India; one of these
      locations was repeated for 3 years. Distribution of GPC values followed normal
      distributions in all the environments, which could be explained by significant g
      x e interactions observed through analyses of variances, which also gave
      significant effects due to genotypes and environments. Thirteen (13) QTLs were
      identified in individual environments following three methods (single-marker
      analysis or SMA, simple interval mapping or SIM and composite interval mapping or
      CIM) and using LOD scores that ranged from 2.5 to 6.5. Threshold LOD scores
      (ranging from 3.05 to 3.57), worked out and used in each case, however, detected
      only seven of the above 13 QTLs. Only four (QGpc.ccsu-2B.1; QGpc.ccsu-2D.1;
      QGpc.ccsu-3D.1 and QGpc.ccsu-7A.1) of these QTLs were identified either in more
      than one location or following one more method other than CIM; another QTL
      (QGpc.ccsu-3D.2), which was identified using means for all the environments, was
      also considered to be important. These five QTLs have been recommended for marker
      assisted selection (MAS). The QTLs identified as above were also validated using
      ten NILs derived from three crosses. Five of the ten NILs possessed 38
      introgressed segments from 16 chromosomes and carried 42 of the 173 markers that
      were mapped. All the seven QTLs were associated with one or more of the markers
      carried by the above introgressed segments, thus validating the corresponding
      markers. More markers associated with many more QTLs to be identified should
      become available in the future by effective MAS for GPC improvement.

PMID- 12595996
TI  - Isolate-specific QTLs of resistance to leaf stripe (Pyrenophora graminea) in the
      'Steptoe' x 'Morex' spring barley cross.
AB  - Leaf stripe caused by the fungus Pyrenophora graminea represents a serious threat
      to grain yield in organically grown barley and in conventional Nordic and
      Mediterranean districts, for which resistant cultivars are necessary. A medium
      density, molecular marker map derived from a 'Steptoe' (partially resistant) x
      'Morex' (susceptible) spring barley cross and its derived doubled-haploid mapping
      population inoculated with the fungus made it possible to identify QTLs of
      resistance to leaf stripe. In order to investigate isolate-specificity of partial
      resistance, the 'Steptoe' x 'Morex' segregating population was inoculated with
      two highly virulent P. graminea isolates, Dg2 and Dg5. The present study
      demonstrates that partial resistance to leaf stripe of cv 'Steptoe' is governed
      in part by shared loci and in part by isolate-specific ones. One QTL is common to
      the resistance for the two isolates, on the long arm of chromosome 2 (2H), two
      QTLs are linked on chromosome 3 (3H), and the remaining two are isolate-specific,
      respectively for isolate Dg2 on chromosome 2 (2H) and for isolate Dg5 on
      chromosome 7 (5H). The QTL in common is that with the major effect on the
      resistance for each isolate, explaining 18.3% and 30.9% R(2) respectively for Dg2
      and Dg5. The isolate-specific QTLs mapped in the 'Steptoe' x 'Morex' barley
      reference map support the assumption of Parlevliet and Zadoks (1977) that partial
      resistance may be due to minor gene-for-minor-gene interactions. Map comparisons
      of the QTLs with the known qualitative resistance genes to leaf stripe, Rdg1 (2H)
      and Rdg2 (7H), as well as with other QTLs of partial resistance in barley, show
      that the QTL for resistance to both isolates mapped on the long arm of chromosome
      2 (2H) does not coincide with the qualitative Rdg1 gene but is linked to it at
      about 30 cM. One isolate-specific QTL of resistance to P. graminea, mapped on the
      short arm of chromosome 2 (2H), is coincident with a QTL for resistance to
      Pyrenophora teres previously mapped in the 'Steptoe' x 'Morex' cross.

PMID- 12595997
TI  - Single nucleotide polymorphisms in cytochrome P450 genes from barley.
AB  - Plant cytochrome P450s are known to be essential in a number of economically
      important pathways of plant metabolism but there are also many P450s of unknown
      function accumulating in expressed sequence tag (EST) and genomic databases. To
      detect trait associations that could assist in the assignment of gene function
      and provide markers for breeders selecting for commercially important traits,
      detection of polymorphisms in identified P450 genes is desirable. Polymorphisms
      in EST sequences provide so-called perfect markers for the associated genes. The
      International Triticeae EST Cooperative data base of 24,344 ESTs was searched for
      sequences exhibiting homology to P450 genes representing the nine known clans of
      plant P450s. Seventy five P450 ESTs were identified of which 24 had best matches
      in Genbank to P450 genes of known function and 51 to P450s of unknown function.
      Sequence information from PCR products amplified from the genomic template DNA of
      11 barley varieties was obtained using primers designed from six barley P450 ESTs
      and one durum wheat P450 EST. Single nucleotide polymorphisms (SNPs) between
      barley varieties were identified using five of the seven PCR products. A maximum
      of five SNPs and three haplotypes among the 11 barley lines were detected in
      products from any one primer pair. SNPs in three PCR products led to changes
      between barley varieties in at least one restriction site enabling genotyping and
      mapping without the expense of a specialist SNP detection system. The overall
      frequency of SNPs across the 11 barley varieties was 1 every 131 bases.

PMID- 12595998
TI  - Identification of a 47-kb DNA fragment containing Xa4, a locus for bacterial
      blight resistance in rice.
AB  - Bacterial blight caused by Xanthomonas oryzae pv oryzae is a devastating disease
      in rice worldwide. The resistance gene Xa4 has been widely used in breeding
      programs and played an important role in protecting rice from this disease. Using
      642 highly susceptible individuals and a random sample of 255 individuals from an
      F(2) population developed from a cross between IRBB4 and IR24, the Xa4 gene was
      genetically mapped to a region less than 1 cM. A contig map was constructed for
      the Xa4 region consisting of six non-redundant bacterial artificial chromosome
      (BAC) clones and spanning approximately 500 kb in length. Analysis of
      recombination events in the Xa4 region located the gene locus to one BAC, 3H8.
      Assay of the recombinants using the subclones of 3H8 in combination with sequence
      analysis further narrowed the Xa4 locus down to a 47-kb fragment.

PMID- 12595999
TI  - Reproduction and cytogenetic characterization of interspecific hybrids derived
      from Cucumis hystrix Chakr. x Cucumis sativus L.
AB  - Interspecific hybrids between Cucumis hystrix Chakr. (2n = 2 x = 24) and Cucumis
      sativus L. (2n = 2 x = 14) were produced by means of F(1) (2n = 19) embryo rescue
      and subsequent chromosome doubling. The hybridity was confirmed by genomic in
      situ hybridization (GISH) and chromosome analysis. The amphidiploid (2n = 38) was
      self-pollinated and backcrossed to cucumber resulting in lines with improved
      crossability to C. sativus. Examination of shape, stainability, and germination
      rate of pollen grains and yield as a function of mature fruit set per ten
      pollinated flowers indicated a tendency for increased fertility in BC(1)S(1)
      progeny when compared to F(1) and amphidiploid offspring. Cytogenetic
      characterization of F(1) and amphidiploid progeny was performed. Generally normal
      meioses produced viable pollen grains, and fertilization resulted in partial
      fertility restoration in amphidiploid progeny. Chromosome anomalies such as
      "frying-pan trivalent", chromosome lagging and spindle mis-orientation were also
      observed. In most of the PMCs of the F(1) diploid hybrid progeny, 19 univalents
      were observed at diakinesis and MI. In the amphidiploid, more than 90% of the
      configurations at MI consisted of the predicted 19 bivalents and less than 5%
      contained multivalents [trivalents (2.3%) + quadrivalents (0.3%)], suggesting the
      presence of preferential pairing, and a distinctive parental genome as well. The
      chiasmata observed between homoeologous chromosomes further demonstrated the
      introgression of the C. hystrix genome into that of C. sativus.

PMID- 12596000
TI  - Isolation and molecular characterization of atrazine tolerant barley mutants.
AB  - Two atrazine-tolerant barley mutants were isolated from atrazine-selection
      experiments performed on barley chloroplast-mutator plants. Genetic analysis
      demonstrated that atrazine tolerance was maternally inherited. Molecular
      characterization of the mutants was performed by PCR amplification of an internal
      fragment of the chloroplast gene psbA. The BstXI restriction patterns of the
      amplified fragments showed two bands in both tolerant barley mutants and only one
      in the atrazine-sensitive control. The 277-bp amplified fragments from the
      parental line and both atrazine-tolerant mutants were cloned and sequenced.
      Sequence analysis showed a single nucleotide substitution in both barley atrazine
      tolerant mutants, i.e. A to G at the +790 position of the psbA gene-coding
      sequence. This point mutation corresponds to an amino-acid change of serine- to 
      glycine and creates a BstXI restriction site. Our results confirmed the
      conservative variability involved in atrazine tolerance which was previously
      reported for several other species. To our knowledge this is the first report on
      the obtention of atrazine-tolerant barley. This finding provides support to the
      hypothesis that, in addition to a wide variety of chlorophyll deficiencies, the
      barley chloroplast mutator genotype induces variability in other traits, which
      could include agronomically valuable mutants.

PMID- 12596001
TI  - New findings in apple S-genotype analysis resolve previous confusion and request
      the re-numbering of some S-alleles.
AB  - Apple trees display gametophytic self-incompatibility which is controlled by a
      series of polymorphic S-alleles. To resolve the discrepancies in S-allele
      assignment that appeared in the literature, we have re-examined the identity of S
      alleles known from domestic apple cultivars. Upon an alignment of S-allele
      nucleotide sequences, we designed allele-specific primer pairs to selectively
      amplify a single S-allele per reaction. Alternatively, highly similar S-alleles
      that were co-amplified with the same primer pair were discriminated through their
      distinct restriction digestion pattern. This is an extension of our previously
      developed allele-specific PCR amplification approach to reveal the S-genotypes in
      apple cultivars. Amplification parameters were optimised for the unique detection
      of the 15 apple S-alleles of which the nucleotide sequences are known. Both the
      old cultivars with a known S-genotype and a number of more common cultivars were
      assayed with this method. In most cases, our data coincided with those obtained
      through phenotypic and S-RNase analysis. However, three S-alleles were shown to
      relate to RNases that were previously proposed as being encoded by distinct S
      alleles. For another S-allele the corresponding gene product has not been
      discriminated. Consequently, we propose the re-numbering of these four S-alleles.
      Furthermore, two alleles that were previously identified as S(27a) and S(27b) now
      received a distinct number, despite their identical S-specificity. To ease
      widespread future analysis of S-genotypes, we identified common cultivars that
      may function as a witness for bearing a particular S-allele. We discuss the
      assignment of new S-alleles which should help to avoid further confusion.

PMID- 12596002
TI  - Analysis of genetic diversity and population structure within Florida coconut
      (Cocos nucifera L.) germplasm using microsatellite DNA, with special emphasis on
      the Fiji Dwarf cultivar.
AB  - Using 15 simple sequence repeat (SSR) microsatellite DNA loci, we analyzed
      genetic variation within Cocos nucifera germplasm collections at two locations in
      south Florida, representing eight cultivars. The loci were also used in a
      parentage analysis of progeny of the 'Fiji Dwarf' variety at both locations. A
      total of 67 alleles were detected, with eight the highest number at any one
      locus. These loci identified 83 of the 110 individual palms. Gene diversity of
      the 15 loci ranged from 0.778 to 0.223, with a mean of 0.574. 'Fiji Dwarf',
      'Malayan Dwarf', 'Green Nino' and 'Red Spicata' cultivars resolve as distinct
      clusters in a neighbor joining tree using modified Rogers distance, while the
      tall varieties form two aggregates. The highest gene diversity was found in the
      tall cultivars (H = 0.583 cumulatively), and the lowest in the 'Malayan Dwarf' (H
      = 0.202). After the tall coconuts, the 'Fiji Dwarf' was most genetically diverse
      (H = 0.436), and had the largest number of unique alleles. Genetic identity is
      highest among the 'Malayan Dwarf' phenotypes, and between the tall varieties. The
      'Red Malayan Dwarf' is genetically distinct from the 'Green' and 'Yellow Malayan
      Dwarf' phenotypes, which cannot be distinguished with the SSR loci used. Off-type
      'Malayan Dwarf' phenotypes (putative hybrids with talls) can be identified
      genotypically. Parentage analyses of 30 'Fiji Dwarf' progeny propagated from five
      adults surrounded by other cultivars estimate that only 20% of the progeny were
      out-crossed to the other varieties, while 40-46% were possible selfs. This
      suggests that a seed-production orchard of the variety maintained at reasonable
      distance from other varieties, will likely yield only 'Fiji Dwarf' genotypes. Our
      data are discussed in the context of hypotheses of coconut dissemination around
      the world.

PMID- 12596003
TI  - Development of isothiocyanate-enriched broccoli, and its enhanced ability to
      induce phase 2 detoxification enzymes in mammalian cells.
AB  - Broccoli florets contain low levels of 3-methylsuphinylpropyl and 4
      methylsulphinylbutyl glucosinolates. Following tissue disruption, these
      glucosinolates are hydrolysed to the corresponding isothiocyanates (ITCs), which
      have been associated with anticarcinogenic activity through a number of
      physiological mechanisms including the induction of phase II detoxification
      enzymes and apoptosis. In this paper, we describe the development of ITC-enriched
      broccoli through the introgression of three small segments of the genome of
      Brassica villosa, a wild relative of broccoli, each containing a quantitative
      trait locus (QTL), into a broccoli genetic background, via marker-assisted
      selection and analysis of glucosinolates in the florets of backcross populations.
      Epistatic and heterotic effects of these QTLs are described. The ITC-enriched
      broccoli had 80-times the ability to induce quinone reductase (a standard assay
      of phase II induction potential) when compared to standard commercial broccoli,
      due both to an increase in the precursor glucosinolates and a greater conversion
      of these into ITCs.

PMID- 12596004
TI  - Age-age and trait-trait correlations for Eucalyptus grandis Hill ex Maiden and
      their implications for optimal selection age and design of clonal trials.
AB  - Previous results from seven locations of Eucalyptus grandis clonal trials in
      Colombia supported the a priori contention of sub-dividing them into three
      different environmental zones for testing and deployment. Within these zones, the
      determination of age-age genetic correlations for both height and mean annual
      increment (MAI) showed that strong age-age correlations are present for a
      rotation age of 6 years starting at 3 years age and, thereafter, suggesting this
      age as appropriate for selection. This biological selection age coincides with an
      "economical" age for selection based on discounted selection efficiency in
      perpetuity, considering a range of interest rates between 10% and 20%. High
      genetic correlations between wood density at 3 years and 6 years as well as the
      lack of genetic correlation between this trait and growth traits, also favors
      selection at age 3 and facilitates breeding strategies that consider the
      utilization of both traits for improvement. A simulation of optimal clonal test
      designs indicated that by using six locations and six blocks per location in a
      single-tree plot design, between 80% and 90% of the maximum selection efficiency
      could be obtained. This type of design allows testing of a large number of
      genotypes across a reasonable number of locations in a cost-effective manner.

PMID- 12596005
TI  - Sequence and properties of HMW subunit 1Bx20 from pasta wheat (Triticum durum)
      which is associated with poor end use properties.
AB  - The gene encoding high-molecular-weight (HMW) subunit 1Bx20 was isolated from
      durum wheat cv. Lira. It encodes a mature protein of 774 amino acid residues with
      an M(r) of 83,913. Comparison with the sequence of subunit 1Bx7 showed over 96%
      identity, the main difference being the substitution of two cysteine residues in
      the N-terminal domain of subunit 1Bx7 with tyrosine residues in 1Bx20. Comparison
      of the structures and stabilities of the two subunits purified from wheat using
      Fourier-transform infra-red and circular dichroism spectroscopy showed no
      significant differences. However, incorporation of subunit 1Bx7 into a base flour
      gave increased dough strength and stability measured by Mixograph analysis, while
      incorporation of subunit 1Bx20 resulted in small positive or negative effects on
      the parameters measured. It is concluded that the different effects of the two
      subunits could relate to the differences in their cysteine contents, thereby
      affecting the cross-linking and hence properties of the glutenin polymers.

PMID- 12596006
TI  - Development and characterization of microsatellite markers for Cryptomeria
      japonica D.Don.
AB  - Thirty four microsatellite markers for Cryptomeria japonica D. Don were developed
      by searching three types of library: a database of C. japonica cDNA sequences, a
      standard non-enriched genomic DNA library and a microsatellite-enriched library
      using magnetic particles. The enrichment of microsatellite sequences using
      magnetic particles is very efficient compared to the other two methods both in
      terms of the numbers of markers generated, and in the polymorphism they detect.
      The microsatellites developed from the genomic DNA library generally have longer
      repeat sequences and are more polymorphic than those from cDNA. All the developed
      microsatellite markers in this study showed polymorphism among 28 plus trees
      selected from locations scattered throughout Japan. The mean number of alleles
      per locus (MNA) detected in the 28 plus trees ranged from 2 to 21 with an average
      of 7.5. The Polymorphism Information Content (PIC) ranged from 0.160 to 0.936
      with an average of 0.666. Co-dominant segregation of alleles in a three
      generation pedigree of C. japonica was demonstrated at 34 microsatellite loci,
      and the segregation was not distorted from Mendelian expectation for all loci. In
      12 out of 34 loci, a null allele was detected. Key relationships between
      polymorphic parameters, such as MNA and PIC, and the characteristics of
      microsatellite sequences, such as the longest repeat number, total repeat number
      and total number of nucleotides, were investigated using rank correlation
      coefficients, Kendall's tau. A positive correlation was found between repeat
      lengths and polymorphisms. The markers provide sufficient resolution for
      investigating gene flow within forests and seed orchards, and for genome mapping.

PMID- 12596007
TI  - Genetic analysis of loci associated with partial resistance to Sclerotinia
      sclerotiorum in rapeseed (Brassica napus L.).
AB  - Sclerotinia stem rot is the most devastating disease of rapeseed (Brassica napus
      L.) in China. Quantitative trait loci (QTLs) involved in resistance to
      Sclerotinia sclerotiorum were detected in a rapeseed population of 128-F(2:3)
      families derived from a cross between the male sterility restorer line H5200 and
      a partial resistant line Ning RS-1. A total of 107 molecular markers including 72
      RFLPs, 30 AFLPs, 3 SSRs and 2 RAPDs were employed to construct a genetic linkage
      map with 23 linkage groups covering 1,625.7 cM with an average space of 15.2 cM.
      Resistance was assessed empirically at two developmental stages: with a detached
      leaf inoculation at the seedling stage and in vivo stem inoculation at the mature
      plant stage. The observed resistance was scored for each plant as leaf resistance
      at the seedling stage (LRS) and stem resistance at the mature plant stage (SRM).
      A total of 13 loci were identified by one-way ANOVA and six QTLs were detected
      with MapMaker-QTL. We found that three of the six QTLs were associated with leaf
      resistance at the seedling stage and collectively accounted for 40.7% of the
      total phenotypic variation, each accounting for 23.2%, 16.6% and 13.6%
      respectively. Three QTLs were found corresponding to the disease resistance at
      the mature plant stage, explaining 49.0% of the phenotypic variation. Epistasis
      was observed for the resistance and the additive by additive interactions were
      the predominant type of epistasis. It was concluded that both single-locus QTLs
      and epistatic interactions played important roles in Sclerotinia resistance in
      rapeseed.

PMID- 12596008
TI  - Identification of DNA markers of tobacco linked to bacterial wilt resistance.
AB  - Bacterial wilt caused by Ralstonia solanacearum is one of the most destructive
      soil-borne diseases in the world. Breeding resistant commercial varieties of
      tobacco is difficult because most donor candidates' resistance is controlled by
      polygenes. In this paper, we demonstrate the identification of useful DNA markers
      for bacterial wilt-resistant tobacco breeding. One hundred and seventeen markers
      were identified by the amplified fragment length polymorphism (AFLP) method
      between W6, a burley variety with resistance originating from a Japanese domestic
      variety, Hatano, and Michinoku 1, a commercial burley wilt-susceptible variety,
      using 3,072 primer combinations. These markers were analyzed in 125 doubled
      haploid lines, derived from F(1) hybrids between W6 and Michinoku 1, and a
      linkage map consisting of ten linkage groups was drawn. The resistance phenotype
      of each of these lines was investigated on the basis of the average of disease
      severity obtained from field trials over two growing cycles. Quantitative trait
      loci (QTL) analysis was performed on the marker phenotypes and the resistance
      phenotype of each line. One QTL for the bacterial wilt resistance of W6 and DNA
      markers associated with this QTL were identified on a linkage group consisting of
      15 markers, 32 cM in length. This QTL explained more than 30% of the variance in
      resistance among these lines.

PMID- 12596009
TI  - Exploitation of heterosis for carotenoid content in African marigold (Tagetes
      erecta L.) and its correlation with esterase polymorphism.
AB  - African marigold (Tagetes erecta L.), a major source of carotenoids, is also
      grown as a cut flower and a garden flower in addition to being grown for its
      medicinal values. We studied gene action, combining ability and heterosis, aiming
      at genetic improvement of T. erecta for enhanced carotenoid content in petals,
      and report for the first time that heterosis can be exploited for total
      carotenoids and its commercially important fractions. Total content of
      carotenoids and lutein appears to be governed by dominance (or non-additive) gene
      action, while content of xanthophyll esters is governed by both additive and
      dominance (or non-additive) gene actions. Specific combining ability variance was
      predominant for all the three traits. General and specific combining abilities
      and heterosis were highly significant. Heterobeltiosis was also positive. General
      combining ability (GCA) variances were not significantly correlated to
      performance per se. There was also no correlation between performance per se of
      normal petalled pollen parents and the performance of crosses made between male
      sterile (female) and male-fertile (pollen) parents. These findings suggest that
      carotenoid content should not be the only criterion considered in the selection
      of parental lines. Studies on esterase in seeds and peroxidase in seedlings
      revealed a relatively high level of polymorphism in esterase with a total of 14
      isoforms, whereas peroxidase showed low polymorphism. Similarity indices between
      different parental combinations, calculated based on seed esterase polymorphism,
      showed a significant negative correlation (r = -0.479, P = 0.05) with heterosis
      for carotenoid content. This indicates that the selection of parents with wider
      variation in their esterase profiles may possibly be exploited for genetic
      enhancement of carotenoids in T. erecta.

PMID- 12596011
TI  - [Poststroke depression: risk factors and effects on the course of the stroke].
AB  - The incidence of poststroke depression (PSD) varies between 20% and 25% as a
      major variant and an additional 10% and 20% as a minor variant. Its prevalence
      peaks 3-6 months after stroke onset. In nearly a quarter of all PSD patients,
      depressive symptoms persist over at least 2 years.Several longitudinal studies
      have identified different factors which may increase the risk of PSD. Most
      probably, the severity of the neurological deficit, female gender, history of
      previous psychiatric disorders, and bad social living conditions increase the
      risk of PSD. It is uncertain whether lesion location or size modulate PSD risk.
      Increasing age is not associated with a higher PSD incidence. In contrast, it is
      obvious that PSD is associated with less favorable outcome and higher mortality.
      The degree of disability and quality of life are significantly reduced in PSD
      patients. In conclusion, PSD is presently a not predictable complication of
      ischemic stroke which is significantly associated with less favorable
      outcome.Early diagnosis and adequate therapy are still necessary in stroke
      rehabilitation.

PMID- 12596012
TI  - [Fibrate and statine myopathy].
AB  - Fibrates and statines are useful in preventing arteriosclerosis and
      thromboembolic events. However, they should be administered with caution. The
      risk of fibrate/statine myopathy, the most common side effect of fibrate/statine
      therapy, increases with dosage, combination of a fibrate with a
      statine,hypothyroidism, renal insufficiency, and intake of cytochrome P450
      inhibitors. In case of clinical signs of a fibrate/statine myopathy such as
      proximal myalgias, stiffness,weakness, and dark urine, appropriate investigations
      should be initiated. If they establish the diagnosis of fibrate/statine myopathy,
      lipid lowering drugs should be immediately withdrawn. If rhabdomyolysis is
      present, prompt and adequate therapy is required. Though muscle abnormalities are
      rare side effects, fibrate/statine therapy should be regularly monitored with
      regard to clinical and laboratory alterations. The new "superstatines"
      rosuvastatine and pitavastatine reduce serum cholesterol more effectively than
      the established statines, but it is not known if they also have fewer muscular
      side effects than established statines.

PMID- 12596013
TI  - [Experimental microvascular and clotting changes--significance for acute stroke
      therapy].
AB  - Ischemia and reperfusion cause significant alterations in the structure and
      functional integrity of the cerebral microvasculature. Clinical sequelae include
      cerebral oedema, haemorrhagic transformation with the extravasation of cellular
      blood elements, and possible parenchymal haemorrhage. Vascular changes originate
      from structural changes of the vascular wall and from interactions with blood
      components such as leukocytes. This leads to the activation of various
      pathophysiological cascades including the clotting system, its inhibitors,matrix
      metalloproteases, and serine proteases. This article focuses on the degradation
      of the microvascular basal lamina, which is formed by extracellular matrix
      proteins such as type IV collagen, fibronectin, and laminin. Extracellular matrix
      proteins are degraded by matrix metalloproteases and serine proteases. Tissue
      plasminogen activator (t-PA), a serine protease commonly administered for
      thrombolysis, activates matrix metalloproteinases in turn, amplifying local
      proteolytic activity. Clinical implications and possible therapeutic strategies
      are discussed.

PMID- 12596014
TI  - [Language acquisition and statistical learning].
AB  - Statistical learning is a basic mechanism of information processing in the human
      brain. The purpose lies in the extraction of probabilistic regularities from the
      multitude of sensory inputs. Principles of statistical learning contribute
      significantly to language acquisition and presumably also to language recovery
      following stroke. The empirical database presented in this manuscript
      demonstrates that the process of word segmentation, acquisition of a lexicon, and
      acquisition of simple grammatical rules can be entirely explained through
      statistical learning. Statistical learning is mediated by changes in synaptic
      weights in neuronal networks. The concept therefore stands at the transition to
      molecular biology and pharmacology of the neuronal synapse. It still remains to
      be shown if all aspects of language acquisition can be explained through
      statistical learning and which regions of the brain are involved in or capable of
      statistical learning. Principles of effective language training are obvious
      already. Most important is the massive, repeated interactive exposure. Conscious
      processing of the stimulus material may not be essential. The crucial principle
      is a high cooccurrence of language and corresponding sensory processes. This
      requires a more intense training frequency than traditional aphasia treatment
      programs provide.

PMID- 12596015
TI  - [Quality of life in patients with remitting-relapsing multiple sclerosis in
      Germany].
AB  - The concept of health-related quality of life (QoL) includes physical,
      psychological,and social aspects. This pertains to consequences of chronic
      diseases and their therapies beyond biological or pharmacological relations. A
      considerable amount of literature concerning QoL has been published with regard
      to neurological and non-neurological entities. This study summarizes data from a
      study in 717 persons with remitting-relapsing multiple sclerosis (MS). Of
      them,576 could be reevaluated longitudinally after 1 year of treatment with
      interferon-beta 1a (44 microg subcutaneous Rebif once weekly). Compared to
      populations of healthy controls or other patients, considerable reductions in the
      eight subscales and both physical and emotional sum scales of the German version
      of the short form of the Rand Health Questionnaire (SF-36) questionnaire were
      assessed. These reductions were even more pronounced in persons with gait
      impairments. Most SF-36 scales only modestly correlated to physical disability.
      This indicates that QoL as reported by patients does not depend solely on the
      physical symptoms of MS. Most findings remained stable for the study population
      as a whole during 1 year of therapy, while statistically significant improvements
      were found in clinical responders as defined in this study (relapse-free,
      physically stable, stable or improved in physician's judgement). Side effects of
      therapy were not reflected in lower QoL scale values. Implications of findings
      for future concepts in MS therapy are discussed.

PMID- 12596016
TI  - [Facioscapulohumeral muscular dystrophy. The spectrum of clinical manifestations
      and molecular genetic changes].
AB  - Although the gene for facioscapulohumeral muscular dystrophy (FSHD) has not been
      identified so far, 4q35 deletion represents a diagnostic marker of the disease.
      In the present study, 46 consecutive symptomatic patients with 4q35 FSHD
      deletions or typical FSHD clinical features were evaluated. The patients were
      divided into three groups: 33 patients (72%) with typical FSHD phenotype and 4q35
      FSHD deletion, eight (17%) with atypical (non-Landouzy-Dejerine) FSHD phenotype
      but with 4q35 FSHD deletion, and five patients (11%) with the typical FSHD
      phenotype but without FSHD 4q35 deletion. Apparently, the 4q35 deletion is
      associated not only with Landouzy-Dejerine FSHD but also with a variety of
      "atypical" FSHD forms. On the other hand, the Landouzy-Dejerine FSHD phenotype is
      possibly a polyetiological syndrome caused in some patients by other genetic
      effects than 4q35 deletion.

PMID- 12596017
TI  - [Neuromuscular complications after allogeneic bone marrow transplantation].
AB  - Neuromuscular syndromes following allogeneic bone marrow transplantation (BMT),
      although occasionally described,were not the focus of studies concerning
      neurologic complications following bone marrow transplantation. In this study,we
      summarize different polyneuropathy syndromes following BMT and report on patients
      with myasthenia gravis and inflammatory neuromuscular disorders such as myositis
      or fasciitis. Concerning the etiology of neuropathies, a neurotoxicity of
      immunosuppressants,a preexisting disorder due to the underlying disease as well
      as an association with graft-versus-host disease (GVHD) is discussed.GVHD
      associated polyneuropathies as well as muscular complications have been found to
      occur during the early BMT phase, while myasthenia gravis is a late neurologic
      complication of GVHD.

PMID- 12596019
TI  - [The megadolichobasilar artery--a clinical chameleon].
AB  - The megadolichobasilar artery is a rare vascular disease, which usually becomes
      apparent either due to cerebral ischemia or due to compression of the brainstem
      or the cranial nerves, thereby leading to a large variety of neurological
      symptoms. We report on a patient who suffered a sudden right-sided deafness
      accompanied by vertigo and vomiting. Initially, an idiopathic sensorineural
      hearing loss was diagnosed and later on, after no improvement took place in spite
      of conservative therapy, a rupture of the round window membrane was suspected.
      Two weeks after the first symptoms had occurred the patient developed a
      hemiparesis on the left side.Radiology disclosed a dilated and partially
      thrombosed basilar artery as well as a paramedian pontine infarction. We
      therefore assumed that the patient's symptoms had been caused by thrombotic
      occlusion of the labyrinthine artery and several rami ad pontem. The article
      reviews the great variety of clinical symptoms caused by megadolichobasilar
      artery and discusses important therapeutic options.

PMID- 12596018
TI  - [Rhabdomyolysis following cerivastatin monotherapy--implications for therapy with
      HMG-CoA reductase inhibitors].
AB  - Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor
      (statine) to treat hypercholesterolemia until its withdrawal from the market
      following 52 reports of death due to drug-related rhabdomyolysis and acute renal
      failure. In most cases, cerivastatine was applied in combination with drugs which
      influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450
      isoenzymes. We report a well-documented case of acute rhabdomyolysis following
      cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle
      biopsy.Finally,we give an overview of the current knowledge concerning therapy
      with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine
      from the market.

PMID- 12596020
TI  - [Isolated cranial nerve palsy secondary to carotid dissection].
AB  - Cranial nerve palsy has a variety of causes such as cerebral ischemia, nerve
      ischemia in diabetes, infectious and noninfectious meningitis, subarachnoid
      hemorrhage, malignant tumors of the skull base, neck, or upper mediastinum,
      aortic aneurysm, surgery of the thyroid,and many more. We report two cases of
      spontaneous carotid dissections leading to cranial nerve palsies, which is an
      uncommon cause of isolated cranial nerve palsies.ICA dissection must therefore be
      included in the differential diagnosis of lower cranial nerve palsy and should be
      assessed by duplex ultrasound and MRI as is demonstrated in our cases.

PMID- 12596021
TI  - [Craniocerebral trauma].
AB  - In cases of craniocerebral trauma there may be primary and secondary cerebral
      lesions. The principal goal of treatment is to minimize secondary cerebral trauma
      by optimized therapy. In the primary treatment phase monitoring of vital signs
      (blood pressure and respiration) is of crucial importance. CT diagnosis is
      followed by treatment of any increase in intracranial pressure by relief of
      hematomas, CSF drainage and appropriate intensive care measures.

PMID- 12596022
TI  - [The concept of psychosis and psychotic qualities].
AB  - The term "psychosis," first used by Canstatt and then by von Feuchtersleben,
      originally meant "psychic neurosis," one of several forms of one disease group.
      The term was taken up by Flemming and introduced among other typical indications
      such as psychic disturbance, psychic disease, mind disease, and madness around
      1875 in the German-speaking world."Psychosis" was understood from the beginning
      as a cerebral pathology which found its expression in psychic symptomatology. The
      broadest interpretation of the concept of psychosis prior to the turn of the
      nineteenth to the twentieth centuries has today been reduced to the modern
      differentiations of psychopathologies and neuroses. Since then, no consensus has
      been reached on the extent of the concept of psychosis.We have remained at the
      "persistent unclarity" described by H. Kindt. Contemporary diagnostic systems
      have done without the concept of psychosis. The indication "psychotic" which has
      taken its place and is based primarily on characteristically schizophrenic
      phenomena is also unclear. Independently of the unsolved problem of
      differentiation, there remains the question of psychotic qualities which are
      understandable on biologic and psychopathologic levels at the same time and which
      combine biologic, interpretative, and descriptive elements, uniting them in the
      field of biologic and clinical psychiatry.

PMID- 12596023
TI  - [Hermeneutic psychopathology of psychoses: scientific basis, concepts, and
      clinical aspects].
AB  - Besides biological psychiatry and its neurobiological field, the psychotic
      patient's subjectivity and his changed relations to himself and others can be
      isolated as a field of hermeneutic-psychopathological research. After addressing
      methodological problems and various approaches of hermeneutic psychopathology
      (transcendental-phenomenological analysis, existence analysis), the logical
      analytic approach in hermeneutic psychopathology as elaborated by Muller-Suur is
      discussed as a way of investigating psychotic experiences and their inherent
      structures of meaning.Finally, the clinical relevance of hermeneutic
      psychopathology is examined.

PMID- 12596024
TI  - [The significance of structural dynamics for a theory of neurosis and personality
      disorders].
AB  - Following the psychopathological approach of Janzarik (structural dynamics), this
      paper develops a two-dimensional theory for the understanding of neuroses and
      personality disorders. The dynamic dimension serves to describe the
      symptomatology between the two poles of anxiety and depression. The structural
      dimension differs according to the maturity of the personal identity between
      mature neurotic personality organization on the one hand and severe personality
      disorder on the other.

PMID- 12596025
TI  - [Meaning of "becoming" in the Japanese psychopathologic view as compared with the
      German-speaking view].
AB  - Until now, Japanese cultural concepts such as "ki" and "aida" were used to
      introduce new perspectives to psychopathology. Universal concepts can also serve
      this purpose when the culturally different connotations are worked out. In this
      study,we discuss the concept "becoming," which is not only universal but also
      undoubtedly one of the key words in psychiatry. As is well known,Zutt made a
      contribution to psychopathology with a clear differentiation between "becoming"
      and "doing." It is interesting that some Japanese linguists also mentioned the
      same difference, namely that between the Japanese logic of "becoming" and the
      Western logic of "doing." Accordingly, tai-jin-kyofu as anxiety about "becoming"
      is contrasted with sociophobia as anxiety about "doing." However, "becoming" in
      the sense of Zutt is different from the Japanese in three aspects,namely the
      physical, social and temporal ones. These differences refer to the various
      meanings of "nature." Finally,we mention the possibility of applying the Japanese
      term "becoming" to psychopathology.

PMID- 12596026
TI  - [Development of delusion in view of Luhmann's systems theory].
AB  - The systems theory of Niklas Luhmann declares itself as a universal theory and
      therefore claims applicability to any social and psychic phenomenon.In spite of
      its high complexity, to many it seems too vague and nonspecific. The possible
      usefulness of this theory should be demonstrated on the example of the
      development of delusion, still a mysterious and unexplained phenomenon. Within
      the framework of Luhmann's systems theory, delusion can be considered a
      communication disorder and therefore a phenomenon within the social system. Both
      the autopoietic systems society and psyche are based on and processed by meaning
      but cannot communicate directly, and they are mutually nontransparent and
      unpredictable. Due to this fact, the interface between the two systems is a
      potential source of disturbances. Luhmann defines the distinction of information,
      message, and understanding as the crucial element to connect the social system
      with the psychic one. If the psychic system fails to recognize the message of an
      information correctly or is unable to negotiate between understanding and
      misunderstanding messages, it detaches itself from the social system to which it
      is normally closely connected. This detachment releases the possibility of
      unhindered autistic fulfillment of desires and uncontrolled fear. Due to the
      meaning-based autopoiesis of the psychic system,these released thoughts and
      emotions still appear in meaningfully condensed form as delusions.

PMID- 12596027
TI  - [Patient satisfaction with psychiatric services. Findings of a key date survey].
AB  - The aim of this study was to gain more empirical ideas for the concept of patient
      satisfaction and its usefulness as an instrument for quality assurance by
      analyzing the relationship between inpatient experiences and inpatient
      satisfaction with psychiatric services. Data were obtained from 91 inpatients of
      the Psychiatric Hospital of the Ludwig-Maximilians-University in Munich (85% of
      all patients who had been in hospital at least 3 weeks and who could be asked) by
      questionnaires on a fixed day. Patients had been asked about their overall
      satisfaction as well as their experiences with special aspects of the
      services.Overall satisfaction was high, but there was a remarkable amount of
      adverse experience with components concerning patient information and time with a
      psychiatrist offered to the patients. The results give evidence that
      communication and empathy of the medical staff are key indicators of patient
      satisfaction and dissatisfaction. Furthermore, results suggest that global
      satisfaction scores should not be used as an instrument of quality assurance.

PMID- 12596028
TI  - [Subjective quality of life. Critical look at a modern construct].
AB  - The scientific usefulness of the popular construct "subjective quality of
      life"(QoL) is critically investigated in a psychiatric context. Six problem areas
      were chosen: QoL is rooted in different scientific traditions (area I) and
      characterized by definitional uncertainty (area II). It is conceptually and
      empirically confounded with several other psychosocial constructs and lacks clear
      causal specificity (area III). The operationalization of QoL comprises a great
      number of heterogeneous instruments (area IV), and there are additional problems
      created by methodological and statistical issues (area V).Finally, there is no
      integrative, theoretical model that can be tested empirically in a systematic way
      (area VI). These problems support the conclusion that subjective QoL is a
      preparadigmatic or scientifically immature concept which should be applied with
      caution and under strict methodological standards when used to answer clinically
      relevant questions.

PMID- 12596029
TI  - [The spectrum of bipolar disorders].
AB  - On the basis of epidemiology, neurobiology and clinical observation, the
      classification of bipolar disorders has shown considerable development and
      expansion in recent years. In particular, the recognition of mixed states, the
      introduction of bipolar II disorders, increasing awareness of the diagnosis of
      hypomania, as well as the interest in cyclothymic disorders and temperament have
      led to a shift in diagnostic attitudes in the USA, as well as in European
      countries. In this article, the possible clinical and scientific benefits of such
      tendencies are discussed, as are the risks of broadening bipolar disorders beyond
      DSM-IV. Also demonstrated is how several "modern" concepts of bipolarity have
      deep roots in the history of German psychiatry; a mixity scale based on
      Kraepelin's classification of affective mixed states is presented.

PMID- 12596030
TI  - [Comorbidity of tinnitus and psychiatric disorders].
AB  - If anxiety-related disorders or depressive episodes occur along with tinnitus
      disease, psychiatric treatment can become necessary. Also, tinnitus coincides
      with psychoses. It has been shown that patients suffering from psychic
      disturbances can also develop tinnitus phenomena, which must be treated
      differently from the basic disease. So these patients can suffer additionally
      (and also independently!) from tinnitus,which requires separate, differentiated
      ear, nose, and throat treatment.

PMID- 12596031
TI  - [Psychotherapy of positive symptoms in the treatment of patients with
      schizophrenia psychosis].
AB  - While the treatment of positive symptoms of patients with schizophrenic psychosis
      appeared until recently to be solely pharmacotherapeutic, new research findings
      show the efficacy of cognitive-behavioural psychotherapy (CBT) on positive
      symptoms in chronic psychotic patients. In addition, the effectiveness even in
      acute and recent-onset psychosis could be shown in some studies. The effects of
      CBT and standard care in psychosis compared to standard care alone and to other
      psychosocial interventions plus standard care are reviewed. The results of
      several studies and one meta-analysis show that CBT in schizophrenia patients has
      a direct effect on psychotic symptoms such as hallucinations as well as on
      relapse prevention. In routine settings,however,CBT has until now only rarely
      been delivered to these patients. In so-called large pragmatic trials, which
      might be subsumed as phase IIIb studies, the effects are tested. The therapeutic
      approach with the components of CBT for psychosis are described: building a
      therapeutic relationship, cognitive-behavioural coping strategies, developing an
      understanding of the experience of psychosis,working on hallucinations and
      delusions, addressing negative self-evaluations, anxiety, and depression,managing
      risk of relapse and social disability. Further clinical implications are
      described (capability of learning the therapeutic strategies, deliverability in
      broader clinical settings, acceptability by patients, combination with atypical
      neuroleptic drugs,and treatment of choice in risk populations).

PMID- 12596032
TI  - [The "Psychopathologic laboratory" at Burgholzli. Development and termination of
      the working relationship of C.G. Jung and Eugen Bleuler].
AB  - C.G. Jung was on the staff of the University Psychiatric Clinic in Zurich
      ("Burgholzli"), headed by Eugen Bleuler, from 1900 to 1909; he became a senior
      physician in 1905. In correspondence with Sigmund Freud, Jung claimed that he had
      informed Bleuler about the subject of psychoanalysis and had recruited him for
      the movement. In fact, it can be shown that Bleuler was familiar with Freud's
      publications even before Jung came to Burgholzli and that he had written a very
      positive review of the hysteria study. Jung received his doctorate (1902) and
      postdoctoral qualification as university lecturer based on Bleuler's reports to
      the Department of Medicine and continued to give lectures on certain recurring
      topics, such as the theory of hysteria, until the summer semester of 1914, well
      after his resignation. Minutes of department meetings that have not previously
      been evaluated appear to indicate that the department's rejection of the founding
      of a "psychopathologic research laboratory," expected by Jung,was a major factor
      leading to his resignation on March 7, 1909. The importance of other events for
      Bleuler's relationship with Jung--the unsuccessful attempt at an analytical
      treatment of Otto Gross or Jung's relationship with Sabina Spielrein--cannot be
      demonstrated based on current sources.

PMID- 12596033
TI  - Kir channels in the CNS: emerging new roles and implications for neurological
      diseases.
AB  - Inwardly rectifying potassium (Kir) channels have long been regarded as
      transmembrane proteins that regulate the membrane potential of neurons and that
      are responsible for [K(+)] siphoning in glial cells. The subunit diversity within
      the Kir channel family is growing rapidly and this is reflected in the multitude
      of roles that Kir channels play in the central nervous system (CNS). Kir channels
      are known to control cell differentiation, modify CNS hormone secretion, modulate
      neurotransmitter release in the nigrostriatal system, may act as hypoxia-sensors
      and regulate cerebral artery dilatation. The increasing availability of genetic
      mouse models that express inactive Kir channel subunits has opened new insights
      into their role in developing and adult mammalian tissues and during the course
      of CNS disorders. New aspects with respect to the role of Kir channels during CNS
      cell differentiation and neurogenesis are also emerging. Dysfunction of Kir
      channels in animal models can lead to severe phenotypes ranging from early
      postnatal death to an increased susceptibility to develop epileptic seizures. In
      this review, we summarize the in vivo data that demonstrate the role of Kir
      channels in regulating morphogenetic events, such as the proliferation,
      differentiation and survival of neurons and glial cells. We describe the way in
      which the gating of Kir channel subunits plays an important role in polygenic CNS
      diseases, such as white matter disease, epilepsy and Parkinson's disease.

PMID- 12596034
TI  - Age-related decline in the tyrosine hydroxylase-immunoreactive innervation of the
      amygdala and dentate gyrus in mice.
AB  - Numbers of catecholaminergic neurons are known to decline with aging. Whether
      projections of these neurons to the forebrain are similarly affected is not
      known. High densities of tyrosine hydroxylase-immunoreactive (TH-ir) fibers are
      found in the hippocampal formation (CA1-3, dentate gyrus) and in the amygdala of
      normal adult mice. We report here that densities of TH-ir fibers in the amygdala
      and hippocampus in aged mice (21-26 months) decrease dramatically and in a
      subregion-specific fashion. There is a reduction of 35% in the dentate gyrus,
      while hippocampal regions CA1 through CA3 are almost entirely spared. In the
      amygdala the lateral, basolateral, basomedial, and central nucleus were affected,
      with fiber reduction ranging from 19% to 34%. These results indicate that the age
      related decline of TH-ir catecholaminergic cell bodies in the substantia nigra
      and the ventral tegmental area induces substantial losses of TH-ir fibers in the
      amygdala and dentate gyrus, but not in other areas of the hippocampal formation.
      This suggests that region-specific factors may be implicated in the regulation of
      maintenance vs. degeneration of TH-ir fibers during aging.

PMID- 12596035
TI  - Morphology of neurons cultured from subdivisions of the mouse cochlear nucleus.
AB  - This study was designed to characterize the dendritic organization of cochlear
      nucleus (CN) cells grown in primary cell culture and to assess differences among
      cultures grown from different regions of CN. Cultures were prepared from
      postnatal mice and processed using microtubule-associated protein 2 (MAP2) or
      gamma-aminobutyric acid (GABA) immunohistochemistry. CN neurons were successfully
      cultured from preparations grown from either the anteroventral subdivision of the
      nucleus (AVCN), the posterior region [posteroventral (PVCN) and dorsal (DCN)
      subnuclei], or the whole CN, although the cultured neurons did not exhibit
      complex dendritic patterns characteristic of CN neurons in vivo. Neurons cultured
      from the entire nucleus exhibited an increased rate of survival compared to those
      cultured from either the anterior or posterior regions, although similar types of
      cells were observed in all preparations. The majority of cultured CN neurons were
      GABA-positive and had soma areas that were similar to the areas of immature
      GABAergic neurons measured in CN sections. Small cells (soma areas <or=60
      microm(2)) with one to three symmetrically organized dendrites and large non
      GABAergic cells (>or=120 microm(2)) were also present in significant numbers.
      Overall, CN cultures consisted of a heterogeneous population of neurons that had
      less elaborate dendritic organizations than cells of corresponding size that have
      been described in adult animals in vivo.

PMID- 12596036
TI  - The expression pattern and assembly profile of synaptic membrane proteins in
      ribbon synapses of the developing mouse retina.
AB  - In the present study, we generated a systematic overview of the expression
      pattern and assembly profile of synaptic membrane proteins in ribbon synapses of
      the developing mouse retina. Using indirect immunofluorescence microscopy, we
      analyzed the spatial and temporal distribution of 11 important membrane and
      membrane-associated synaptic proteins (syntaxin 1/3, SNAP-25, synaptobrevin 2,
      synaptogyrin, synaptotagmin I, SV2A, SV2B, Rab3A, clathrin light chains, CSP and
      neuroligin I) during synaptogenesis. The temporospatial distribution of these
      synaptic proteins was "normalized" by the simultaneous visualization of the
      synaptic vesicle protein synaptophysin, which served as an internal reference
      protein. We found that expression of various synaptic membrane proteins started
      at different time points and changed progressively during development. At early
      stages of development synaptic vesicle membrane proteins at extrasynaptic
      locations did not always colocalize with synaptophysin, indicating that these
      proteins probably do not reside in the same transport vesicles. Despite a non
      synchronized onset of protein expression, clustering and colocalization of all
      synaptic membrane proteins at ribbon synapses roughly occurred in the same time
      window (between day 4 after birth, P4, and P5). Thus, the basic synaptic membrane
      machinery is already present in ribbon synapses before the well-known complete
      morphological maturation of ribbon synapses between P7 and P12. We conclude that
      ribbon synapse formation is a multistep process in which the concerted
      recruitment of synaptic membrane proteins is a relatively early event and clearly
      not the final step.

PMID- 12596037
TI  - Immunohistochemical characterisation of pelvic autonomic ganglia in male mice.
AB  - Pelvic ganglia are mixed sympathetic-parasympathetic ganglia and provide the
      majority of the autonomic innervation to the urogenital organs. Here we describe
      the structural and histochemical features of the major pelvic ganglion in the
      male mouse and compare two different mouse strains. The basic structural features
      of the ganglion are similar to those in the male rat. Almost all pelvic ganglion
      cells are monopolar and most are cholinergic. All contain either neuropeptide Y
      (NPY) or vasoactive intestinal peptide (VIP), or both peptides together. The
      peptide coexistence varies between strains, with C57BL/6 mice having similar
      proportions of neurons with NPY alone, VIP alone or both peptides. In contrast,
      virtually all pelvic neurons in the Quackenbush-Swiss (QS) strain express NPY,
      i.e. the level of VIP/NPY coexistence is much higher. Cholinergic axons provide
      the major nerve supply to epithelia of reproductive organs, bladder smooth muscle
      and, as described previously, penile erectile tissue. They also provide a minor
      component of the smooth muscle innervation of the prostate gland, seminal
      vesicles and vas deferens. Virtually all non-cholinergic pelvic ganglion cells
      are noradrenergic and contain NPY. Their major target is smooth muscle of
      reproductive organs. This study shows that the male mouse pelvic ganglion bears
      many similarities to that in the rat, but that VIP/NPY colocalisation is much
      more common in the mouse. We also show that there are differences in peptide
      expression in parasympathetic pelvic neurons between strains of mice. These
      studies provide the framework for future investigations on neural regulation of
      urogenital function, particularly in transgenic and knockout models.

PMID- 12596038
TI  - TGFbeta1 limits the expansion of the osteoprogenitor fraction in cultures of
      human bone marrow stromal cells.
AB  - Currently, there is considerable interest in the possibility of using cultured
      human bone marrow stromal cells (BMSCs) for skeletal tissue engineering. However,
      the factors that regulate their ex vivo expansion and promote their osteogenic
      maturation remain poorly defined. Using BMSCs obtained from a large cohort of
      adult donors, the effects of transforming growth factor (TGF)beta1 on these
      processes have been determined. BMSCs were found to express TGFbeta receptors
      (TbetaRs) I, II, III (betaglycan) and CD105/endoglin. The expression of TbetaRs I
      and II, but not TbetaR III or endoglin, was linked to the cells' state of
      maturation. Treatment with TGFbeta increased the colony-forming efficiency (CFE)
      of marrow cell suspensions but reduced the median diameter of the colonies that
      formed and the number of cells harvested at the end of primary culture. Treatment
      with TGFbeta also resulted in a significant downregulation in the expression of
      the developmental markers alkaline phosphatase (AP) and STRO-1. The reduction in
      AP was due to a decrease in the absolute number of cells expressing this enzyme
      and in the level (sites/cell) at which it was expressed. Overall, the changes in
      the expression of STRO-1 and AP are consistent with TGFbeta acting to decrease
      the size of the osteoprogenitor fraction, and hence the potential clinical
      utility of the cultured cell population.

PMID- 12596039
TI  - Development and regression of non-capillary vessels in the bovine corpus luteum.
AB  - The corpus luteum life cycle is accompanied by capillary growth, maturation and
      degeneration. Arterial blood vessels are thought to undergo hyperplasia and
      hypertrophy during the stage of regression, as is the case with non-capillary
      vessels. In this study, we used morphological studies to show that the
      development of non-capillary vessels occurs at other corpus luteum stages. Non
      capillary vessels were present at the developmental stage of the corpus luteum,
      and increased markedly in number in the subsequent stages. After double-staining
      for ASM-1 actin and Ki-67 nuclear antigen, the proliferation of smooth muscle
      cells (SMCs) was only detected during stages of development and secretion. When
      the capillaries had disappeared at the regression stage, the arterial blood
      vessel walls thickened noticeably. This was attributed to the development of
      fibroelastosis as shown by staining for collagenous and elastic fibres. In
      conclusion, the bovine corpus luteum represents a physiological model for
      studying arteriolization at all stages of development and secretion. At the
      regression stage, arterioregression sets in.

PMID- 12596040
TI  - Suppression of beta-casein gene expression by inhibition of protein synthesis in
      mouse mammary epithelial cells is associated with stimulation of NF-kappaB
      activity and blockage of prolactin-Stat5 signaling.
AB  - The protein synthesis inhibitor cycloheximide (Chx) suppresses prolactin-induced
      beta-casein gene expression in the mammary epithelial cell line COMMA-D. As the
      mechanism underlying this effect is unclear, the effects of protein synthesis
      inhibitors on interactions of transcription factors with the beta-casein promoter
      were examined. Suppression of prolactin-induced beta-casein gene expression
      occurred in both COMMA-D cells and primary mammary cell cultures with as little
      as 2 h protein synthesis inhibition. This was associated with changes in
      transcription factors interacting at a response element in the proximal region of
      the rat beta-casein promoter. Inhibition of protein synthesis was associated with
      NF-kappaB binding at a site immediately 3' to the Stat5-binding site at position
      97-89 of the beta-casein promoter, suppression of Stat5 DNA-binding activity, and
      inhibition of Stat5 tyrosine phosphorylation. Treatment with the NF-kappaB
      inhibitor parthenolide failed to restore prolactin responsiveness. These results
      show that protein synthesis inhibition is associated with both blockage of
      prolactin-Stat5 signaling and NF-kappaB binding to the beta-casein promoter, but
      that the latter is not necessary for the suppression of beta-casein expression.

PMID- 12596041
TI  - An in vitro long-term culture model for normal human mammary gland: expression
      and regulation of steroid receptors.
AB  - Steroids and their nuclear receptors play crucial roles in the development and
      maintenance of normal functions of the human mammary gland (HMG). They have also
      been implicated in breast carcinogenesis. However, the study of steroid action in
      normal HMG has been hampered by experimental difficulties. By using a newly
      established in vitro long-term culture method, we successfully cultured normal
      HMG tissue for more than 2 months without detriment to its morphology or steroid
      receptor expression. Expression of the cellular structural and extracellular
      matrix proteins was similar to that prior to culture, and HMG tissue retained its
      properties of steroid receptor expression and regulation. Addition of 17-beta
      estrogen to mammary tissues markedly increased the expression of progesterone
      receptor (PR) but only slightly affected that of the estrogen receptor (ER).
      Medroxyprogesterone acetate down-regulated the expression of PR within 24-48 h
      and also increased the expression of androgen receptor. When HMG tissue was
      cultured in medium containing normal or dextran-coated charcoal-stripped fetal
      calf serum or normal human serum, the expression and regulation of steroid
      hormone receptors were similar, although different in extent. When serum was
      omitted, the morphology of HMG was normal after 1 week, but the expression and
      regulation of ER and PR were altered. Thus, as HMGs retain the capacity to
      express steroid receptors in culture, this long-term culture system is probably a
      good model for studying the regulation of the mammary gland by steroids.

PMID- 12596043
TI  - Myostatin precursor is present in several tissues in teleost fish: a comparative
      immunolocalization study.
AB  - In this study, the distribution of myostatin was investigated during larval and
      postlarval developmental stages of Sparus aurata(sea bream), Solea solea(sole)
      and Brachydanio rerio(zebrafish) by immunohistochemistry using antisera raised
      against a synthetic peptide located within the precursor region of sea bream
      myostatin. All the three species examined showed the strongest immunoreactivity
      in red skeletal muscle in juveniles and adults. During larval development of sea
      bream, strong staining was detected in skin and brain. Immunoreactivity was also
      found in muscle, pharynx, gills, pancreas and liver. From metamorphosis,
      immunoreactivity was identifiable in the oesophagus, in the apical portion of the
      stomach epithelium, in the intestinal epithelium and in renal tubules. In larval
      zebrafish at hatching, the most intense myostatin immunoreactivity was evident in
      the skin epithelium. Immunoreactivity was also found in the retina and brain. In
      the adult, an intense immunostaining occurred in the gastrointestinal tract as
      well as in the ovary. In sole larvae, immunoreactivity was found in liver and
      intestine. Our results support the hypothesis suggested earlier that myostatins
      in fish have retained a different partition (compared with mammals) of the
      expression patterns and functions which characterized the ancestral gene before
      the duplication event that gave rise to growth differentiation factor-11 (GDF-11)
      and GDF-8 (myostatin).

PMID- 12596042
TI  - Gene expression profile of mouse bone marrow stromal cells determined by cDNA
      microarray analysis.
AB  - Bone marrow stromal cells (BMSC) have gained increased attention because of their
      multipotency and adult stem cell character. They have been shown to differentiate
      into other cell types of the mesenchymal lineage and also into non-mesenchymal
      cells. The exact identity of the original cells, which are isolated from bone
      marrow by their selective adherence to plastic, remains unknown to date. We have
      established and characterized mouse BMSC cultures and analyzed three independent
      samples by cDNA microarrays. The expression profile was compared with two
      previous expression studies of human BMSC and revealed a high degree of
      concordance between different techniques and species. To gain clues about the
      positional context and biology of the isolated cells within the bone marrow
      stroma, we searched our data for genes that encode proteins of the extracellular
      matrix, cell adhesion proteins, cytoskeletal proteins and cytokines/cytokine
      receptors. This analysis revealed a close association of BMSC with vascular cells
      and indicated that BMSC resemble pericytes.

PMID- 12596044
TI  - Vitamin A prevents the irreversible proliferation of vaginal epithelium induced
      by neonatal injection of keratinocyte growth factor in mice.
AB  - Exposure of female mice to estrogen during the perinatal period results in
      estrogen-independent persistent proliferation and cornification of the vaginal
      epithelium when the animals become adults. However, the occurrence of such
      irreversible vaginal changes is blocked by concurrent vitamin A treatment.
      Neonatal exposure to keratinocyte growth factor (KGF), which is a paracrine
      mediator of epithelial-mesenchymal interactions, also induces the persistent
      proliferation and cornification of the vaginal epithelium in adult mice. This
      study was designed to examine whether concurrent administration of vitamin A
      inhibits the development of the irreversible vaginal changes in mice exposed
      neonatally to KGF. The vaginal epithelium in ovariectomized 35-day-old mice given
      5 microg of KGF for 3 days after birth possessed a significantly larger number of
      layers and increased thickness as compared to that in control mice. Concurrent
      injections of 100 IU of vitamin A acetate inhibited the occurrence of the
      irreversible proliferation of the vaginal epithelium. These changes were equal to
      the results observed when 20 micro g of estrogen with or without vitamin A
      acetate was administered for 5 days after birth. Unlike the case of estrogen
      treatment, the effect of neonatal treatment with KGF seemed to appear after a
      latent period, since the vaginal epithelium did not show proliferation soon after
      the treatment. We discuss the inhibitory effect of VA on the irreversible vaginal
      changes induced by neonatal KGF treatment with reference to endocrine disruption
      by neonatal estrogen exposure.

PMID- 12596045
TI  - Localization of serotonin and its possible role in early embryos of Tritonia
      diomedea(Mollusca: Nudibranchia).
AB  - A classical neurotransmitter serotonin (5-HT) was detected immunochemically using
      laser scanning microscopy at the early stages of Tritonia diomedea development.
      At the one- to eight-cell stages, immunolabeling suggested the presence of 5-HT
      in the cytoplasm close to the animal pole. At the morula and blastula stages, a
      group of micromeres at the animal pole showed immunoreactivity. At the gastrula
      stage no immunoreactive cells were detected, but they arose again at the early
      veliger stage. Antagonists of 5-HT(2) receptors, ritanserin and cyproheptadine,
      as well as lipophilic derivatives of dopamine blocked cleavage divisions or
      distorted their normal pattern. These effects were prevented by 5-HT and its
      highly lipophilic derivates, serotoninamides of polyenoic fatty acids, but not by
      the hydrophilic (quaternary) analog of 5-HT, 5-HTQ. The results confirm our
      earlier suggestion that endogenous 5-HT in pre-nervous embryos acts as a
      regulator of cleavage divisions in nudibranch molluscs.

PMID- 12596046
TI  - Growth hormone-releasing hormone neurons in the anestrus cat do not express
      progesterone receptors.
AB  - Ovarian steroids have been implicated in the regulation of growth hormone (GH)
      secretion in several species and increased progesterone secretion has been
      associated with elevated circulating GH levels in the cat. These high GH
      concentrations may be due, at least in part, to a direct action of progesterone
      on growth hormone-releasing hormone (GHRH) neurons. Using standard
      immunocytochemical methods coupled to high-temperature antigen retrieval, the
      objective of this study was to determine whether progesterone receptors were
      colocalized in GHRH neurons of the anestrus cat. GHRH perikarya were restricted
      to the infundibular nucleus and the ventral ventromedial nucleus and although
      frequently surrounded by numerous progesterone receptor-immunoreactive cells,
      none was colocalized. This study, therefore, provides evidence that, in the adult
      anestrus female cat, GHRH neurons do not express nuclear progesterone receptors.

PMID- 12596047
TI  - Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its
      involvement in dilated cardiomyopathy.
AB  - Alpha T-catenin is a novel member of the alpha-catenin family, which shows most
      abundant expression in cardiomyocytes and in peritubular myoid cells of the
      testis, pointing to a specific function for alpha T-catenin in particular muscle
      tissues. Like other alpha-catenins, alpha T-catenin provides an indispensable
      link between the cadherin-based cell-cell adhesion complex and the cytoskeleton,
      to mediate cell-cell adhesion. By isolating genomic clones, combined with
      database sequence analysis, we have been able to determine the structure of the
      CTNNA3 and Ctnna3 genes, encoding human and mouse alpha T-catenin, respectively.
      The positions of the exon-exon boundaries are completely conserved in CTNNA3,
      Ctnna3, and the alpha N-catenin encoding CTNNA2 gene. They overlap largely with
      the boundaries of the CTNNA1 and CTNNAL1 genes encoding alpha E-catenin and alpha
      catulin, respectively. This emphasizes that these alpha-catenin genes evolved
      from the same ancestor gene. Nevertheless, the introns of CTNNA3 and Ctnna3 are
      remarkably large (often more than 100 kb) compared with introns of other CTNNA
      genes. The CTNNA3 gene was mapped to chromosome band 10q21 by both fluorescence
      in situ hybridization and polymerase-chain-reaction-based hybrid mapping. This
      region encodes a gene for autosomal dominant familial dilated cardiomyopathy
      (DCM), a common cause of morbidity and mortality. As alpha T-catenin is highly
      expressed in healthy heart tissue, we have considered CTNNA3 as a candidate
      disease gene in a family showing DCM linkage to the 10q21-q23 locus. Mutation
      screening of all 18 exons of the CTNNA3 gene in this family has, however, not
      detected any DCM-linked CTNNA3 mutations.

PMID- 12596048
TI  - Influence of interleukin-12 receptor beta1 polymorphisms on tuberculosis.
AB  - Host genetic factors may be important determinants of susceptibility to
      tuberculosis, and several candidate gene polymorphisms have been shown to date. A
      series of recent reports concerning rare human deficiencies in the type-1
      cytokine pathway suggest that more subtle variants of relevant genes may also
      contribute to susceptibility to tuberculosis at the general population level. To
      investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene
      predispose individuals to tuberculosis, we studied these genes by single-strand
      conformational polymorphism analysis and direct sequencing. Although no common
      polymorphisms could be identified in the IL-12R beta 2 gene ( IL-12RB2), we
      confirmed four single nucleotide polymorphisms (SNPs; 641A-->G, 684C-->T, 1094T-
      >C, and 1132G-->C) causing three missense variants (Q214R, M365T, G378R) and one
      synonymous substitution in the extracellular domain of the IL-12R beta 1 gene (
      IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D'=0.98), and
      two common haplotypes of IL12RB1(allele 1: Q214-M365-G378; allele 2: R214-T365
      R378) were revealed. Polymerase chain reaction/restriction fragment length
      polymorphism and sequence analyses were used to type IL12RB1polymorphisms in 98
      patients with tuberculosis and 197 healthy controls in Japanese populations. In
      our case-control association study of tuberculosis, the R214-T365-R378 allele
      (allele 2) was over-represented in patients with tuberculosis, and homozygosity
      for R214-T365-R378 (the 2/2 genotype) was significantly associated with
      tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P=0.013). In healthy subjects,
      homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling,
      according to differences in cellular responses to IL-12 between two haplotypes.
      These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1,
      contribute to tuberculosis susceptibility in the Japanese population. This
      genetic variation may predispose individuals to tuberculosis infection by
      diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial
      dysfunction of interferon-gamma-mediated immunity.

PMID- 12596049
TI  - Founder effect of the C9 R95X mutation in Orientals.
AB  - A nonsense mutation at codon 95 (R95X) in the C9 gene is responsible for most
      Japanese C9 deficiency (C9D) cases, with a carrier frequency of 6.7%. Upon
      analysis of microsatellite markers and newly identified dinucleotide repeat
      number polymorphisms in the 3' flanking region of the C9 gene, a founder effect
      was demonstrated for the R95X mutation of the C9 gene in Japanese. Screening for
      the R95X mutation in Korean and Chinese individuals showed that the R95X carrier
      frequencies in Koreans and Chinese were 2.0% and 1.0%, respectively. Although
      homozygotes for the R95X mutation were not found in Korea or China, the shared
      haplotype of the dinucleotide repeat number polymorphisms appeared to be
      associated with the R95X mutation in the heterozygotes in Korea and China. The
      founder effect found in East Asians (Japanese, Koreans and Chinese) but not in
      Caucasians, as well as the haplotype sharing in only a small chromosomal
      interval, suggested that the R95X mutation of C9 gene was ancient and had
      occurred after the divergence of East Asians and Caucasians, and before migration
      of the Yayoi people to Japan. Since the mortality of meningococcal infections in
      complement-deficient patients is lower than that in normal individuals, a founder
      effect and a selective advantage in isolation might be the main reasons for the
      high frequency of the R95X mutation in Japan.

PMID- 12596050
TI  - Testing hypotheses of language replacement in the Caucasus: evidence from the Y
      chromosome.
AB  - A previous analysis of mtDNA variation in the Caucasus found that Indo-European
      speaking Armenians and Turkic-speaking Azerbaijanians were more closely related
      genetically to other Caucasus populations (who speak Caucasian languages) than to
      other Indo-European or Turkic groups, respectively. Armenian and Azerbaijanian
      therefore represent language replacements, possibly via elite dominance involving
      primarily male migrants, in which case genetic relationships of Armenians and
      Azerbaijanians based on the Y-chromosome should more closely reflect their
      linguistic relationships. We therefore analyzed 11 bi-allelic Y-chromosome
      markers in 389 males from eight populations, representing all major linguistic
      groups in the Caucasus. As with the mtDNA study, based on the Y-chromosome
      Armenians and Azerbaijanians are more closely-related genetically to their
      geographic neighbors in the Caucasus than to their linguistic neighbors
      elsewhere. However, whereas the mtDNA results show that Caucasian groups are more
      closely related genetically to European than to Near Eastern groups, by contrast
      the Y-chromosome shows a closer genetic relationship with the Near East than with
      Europe.

PMID- 12596051
TI  - FMR1 haplotype analyses among Indians: a weak founder effect and other findings.
AB  - This study on allelic/haplotypic fragile X associations evaluated using STR
      (DXS548, FRAXAC1, FRAXAC2) and SNP (ATL1) markers flanking the (CGG)(n) locus of
      FMR1is the first report from the large ethnically complex Indian population.
      Results have been compared with allele/haplotype distributions reported for other
      major ethnic groups, including White Caucasians, Africans, and Pacific Asians.
      Though overall allele frequency distributions at the individual loci are more
      similar to Western Caucasians compared with others, significant differences are
      observed in haplotypic associations with the mutated X. The striking findings
      are: (1) high diversity and heterozygosity of haplotypes among fragile X
      chromosomes ( n=40) and controls ( n=262), including four haplotypes found
      exclusively in this study sample; (2) weak association of DXS548-FRAXAC1-FRAXAC2
      haplotypes, 2-1-3, 6-3-3+ and 7-4-6+ with the disorder, and absence of White
      Caucasian fragile X haplotypes 6-4-4 and 6-4-5; (3) weak founder effect for the
      fragile X expansion mutation in the Indians; (4) lack of a continuum of haplotype
      based FMR1 alleles between intermediate (CGG)(n) size ranges and expanded
      alleles; (5) exclusion of ATL1 as a candidate genetic indicator of FMR1
      instability. The high STR-based haplotype diversity observed among fragile X
      lineages, irrespective of ethnic alliances, strongly suggests the
      inappropriateness of using STR haplotypes to infer predisposition to instability
      among ethnically separated fragile X pedigrees and may reiterate the need for
      identifying newer SNPs from this region to not only determine true founder
      effects for the fragile X mutation, but also decipher possible mechanisms leading
      to CGG instability.

PMID- 12596052
TI  - Relevance of sequence and structure elements for deletion events in the
      dystrophin gene major hot-spot.
AB  - Large intragenic deletions within the DMD locus account for about 60% of Duchenne
      and Becker muscular dystrophy patients. Two deletion hot-spots have been
      described in the dystrophin gene, but the mechanisms that determine chromosome
      breaks in these regions are unknown, and the huge dimensions of the gene have
      hampered the description of a consistent number of breakpoint sequences. A long
      distance polymerase chain reaction strategy was used to amplify 20 deletion
      junctions involving the major hot-spot and to describe breakpoint position at the
      sequence level. These junctions were analyzed together with previously reported
      breakpoint locations so as to increase the sample number and possibly provide a
      comprehensive study. Minisatellite core sequences, chi elements, translin-binding
      sites, Pur elements, and matrix attachment regions were sought over the whole
      gene. Sequence-dependent DNA curvature and duplex stability were also calculated
      throughout the gene, and their cumulative frequency distribution was evaluated.
      No association with either sequence or structure elements involved in known
      illegitimate recombination mechanisms was identified. This study highlights the
      importance of a whole gene approach to rule out the presumptive role of specific
      features that, when locally analyzed, might suggest involvement in gene
      rearrangements.

PMID- 12596053
TI  - Patterns of associations of clinical features in neurofibromatosis 1 (NF1).
AB  - Neurofibromatosis 1 (NF1) is a common, fully penetrant autosomal dominant
      disease. The clinical course is generally progressive but highly variable, and
      the pathogenesis is poorly understood. We studied statistical associations among
      13 of the most common or important clinical features in data from four separate
      sets of NF1 patients: a "developmental sample" of 1,413 probands from the NNFF
      International Database, an independent "validation sample" of 1,384 probands from
      the same database, 511 affected relatives of these probands, and 441 patients
      from a population-based registry in northwest England. We developed logistic
      regressive models for each of the 13 features using the developmental sample and
      attempted to validate these models in the other three samples. Age and gender
      were included as covariates in all models. Models were successfully developed and
      validated for ten of the 13 features analysed. The results are consistent with
      grouping nine of the clinical features into three sets: (1) cafe-au-lait spots,
      intertriginous freckling and Lisch nodules; (2) cutaneous, subcutaneous and
      plexiform neurofibromas; (3) macrocephaly, optic glioma and other neoplasms. In
      addition, three-way interactions among cafe-au-lait spots, intertriginous
      freckling and subcutaneous neurofibromas indicate that the first two groups are
      not independent. Our studies show that some individuals with NF1 are more likely
      than others to develop certain clinical features of the disease. Some NF1
      features appear to share pathogenic mechanisms that are not common to all
      features.

PMID- 12596054
TI  - A study of cryptic terminal chromosome rearrangements in recurrent miscarriage
      couples detects unsuspected acrocentric pericentromeric abnormalities.
AB  - Fifty chromosomally normal couples with three or more miscarriages were examined
      using fluorescent in situ hybridisation (FISH) and a library of subtelomere
      specific probes together with alphoid repeats mapping to the acrocentric
      centromeres. Six abnormalities were found. Firstly, a cryptic reciprocal
      subtelomere translocation between the long arm of a chromosome 3 and the short
      arm of a chromosome 10. The other five cryptic abnormalities involved the
      acrocentric chromosome pericentromeric regions and in one case also Yp. Two
      patients had a rearranged chromosome 13, where the centromeric region was found
      to be derived from the short arm, centromere and proximal long arm of chromosome
      15. Another two patients had a derived chromosome 22, where the centromere was
      replaced by two other centromeres, one derived from chromosome 14 and the other
      from either chromosome 13 or 21, while one patient had the subtelomere region of
      Yp translocated onto the short arm of a chromosome 21. These abnormalities may be
      the underlying cause of the recurrent miscarriages, because they may result in
      abnormal pairing configurations at meiosis leading to non-disjunction of whole
      chromosomes at metaphase I. The frequency of rearrangements seen in the recurrent
      miscarriage patient population was significantly different from that in the
      control group ( P=0.0096, Fisher's exact test) due to the acrocentric
      pericentromeric abnormalities.

PMID- 12596055
TI  - A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13
      q14 in a large Italian family.
AB  - Non-syndromic hearing loss is the most common sensory disorder in humans; 15%-20%
      of cases are transmitted as a dominant trait (NSDA) with 40 loci having been
      mapped and 16 genes having been identified. Here, we report the mapping of a
      novel NSDA locus, DFNA48, to chromosome 12q13-q14 in a large multigenerational
      Italian family. A maximum lod score of 3.31 was obtained with marker D12S83,
      whereas markers D12S347 and D12S1703 defined a region of approximately 18 cM.
      Positional candidate genes are being screened for deafness-causing mutations.

PMID- 12596057
TI  - Rudolf Virchow (1821-1902).
AB  - Rudolf Virchow died 100 years ago. The author summarizes the multifaceted
      personality of this man who so profoundly influenced the shaping of contemporary
      surgical and experimental pathology and played an important role in designing the
      social structure of modern Germany. Goethe's influence in the development of 19th
      century morphology is also suggested.

PMID- 12596058
TI  - The new Vienna classification of epithelial neoplasia of the gastrointestinal
      tract: advantages and disadvantages.
AB  - A number of seminars have shown considerable differences between Japanese and
      Western pathologists in the diagnostic differentiation of reactive changes,
      dysplasia and well-differentiated adenocarcinoma in gastroenterological biopsy
      material. Lesions that most Western pathologists identify as "dysplasia" are
      often considered adenocarcinomas in Japan. A comparison of the biopsy-based
      diagnoses with those established in resected mucosa, however, reveals appreciable
      diagnostic inexperience on the part of Western pathologists, with significant
      discrepancies between their diagnoses based on biopsies and those based on
      resected material. Against this background, a new classification of epithelial
      neoplasia of the gastrointestinal tract was drafted on the occasion of the World
      Congress of Gastroenterology in Vienna in 1998. By collapsing the diagnoses "high
      grade adenoma/dysplasia, noninvasive carcinoma (carcinoma in situ), and suspected
      invasive carcinoma" into a single category ("noninvasive high-grade neoplasia",
      category 4), this scheme should largely eliminate the diagnostic discrepancies
      between Western and Japanese pathologists. As with every classification, the
      Vienna classification has its advantages and disadvantages; these are discussed
      here. The most important advantage of the Vienna classification is that the
      various categories are associated with different recommendations for further
      diagnostic and therapeutic measures. This applies in particular to category 4,
      with the recommendation for only local treatment initially (endoscopic mucosal
      resection or surgical excision). Since the introduction of the Vienna
      classification, the new World Health Organization classification of neoplasia of
      the gastrointestinal tract has recently been published, in which the term
      dysplasia has been replaced by "intraepithelial neoplasia". This means that the
      Vienna classification needs to be modified accordingly.

PMID- 12596059
TI  - Cytogical features of calcifying epithelial odontogenic tumor (Pindborg tumor)
      with abundant cementum-like material.
AB  - Calcifying epithelial odontogenic tumor (CEOT) is a rare tumor, most frequently
      occurring in the mandible and composed of large sheets of epithelial cells,
      sometimes showing nuclear pleomorphism. This paper was aimed at reporting of the
      cytological features of an unusual case of CEOT, affecting a 14-year-old female,
      with abundant deposition of intercellular calcified material. The cytological
      preparations were characterized by large clusters of scarcely cohesive, large
      polyhedral cells and abundant calcified material. The latter consisted of
      intensely basophilic substance either in large clusters or discrete concretions
      and, at high-power view, occasional tumor cells also contained calcified
      material. Histologically, the uncalcified stroma displayed focal Congo Red
      positivity with the typical birefringence under polarized light. The neoplastic
      cells were consistently immunoreactive for epithelial membrane antigen, vimentin
      and, to a lesser extent, for wide spectrum cytokeratins (AE1 AE3) and
      cytokeratins 8-18 and 19. The cytological features of CEOT are rather
      characteristic, and the detection of intra- and extracellular calcifications may
      help to differentiate this neoplasm from others that most commonly arise in this
      area.

PMID- 12596060
TI  - Mucinous colon carcinomas with microsatellite instability have a lower
      microvessel density and lower vascular endothelial growth factor expression.
AB  - We determined the association between cyclooxygenase-2 (COX-2), vascular
      endothelial growth factor (VEGF) expression, microvessel density (MVD) and
      microsatellite instability (MSI) or the histological type in colon
      adenocarcinomas. Sixty-six cases were studied, 28 MSI+ and 38 MSI-. MSI phenotype
      was determined using polymerase chain reaction. MVD was assessed after CD31
      staining in ten x400 fields (0.96 mm(2)) in the most vascularized areas. VEGF and
      COX-2 expression were studied by means of immunohistochemistry. MVD positively
      correlated with the levels of VEGF expression (P=10(-4)) and also with the levels
      of COX-2 expression (P=0.007). MVD and VEGF expression were lower in MSI+
      carcinomas (P=0.002 and P=0.03 respectively). When mucinous tumors were excluded
      from the statistical analysis, the association between low MVD, low VEGF and MSI
      status disappeared (P=0.5, P=1, respectively). MSI+ mucinous carcinomas had a
      lower MVD and VEGF expression than other MSI+ carcinomas (P=0.008 and P=0.004,
      respectively) and MSI- mucinous carcinomas (P=0.01 and P=0.001, respectively).
      COX-2 expression was lower in medullary carcinomas (P=0.001). In conclusion,
      mucinous MSI+ colon carcinomas represent a special group of colon adenocarcinomas
      relating to angiogenesis, with a lower MVD and VEGF expression than both MSI-
      mucinous carcinomas and MSI+ non-mucinous carcinomas. A low COX-2 expression
      could be related to the medullary phenotype. However, this has to be confirmed in
      a larger series. Finally, the low MVD of MSI+ mucinous colon adenocarcinomas
      could participate in their overall better prognosis.

PMID- 12596061
TI  - Expression of integrin-linked kinase is closely correlated with invasion and
      metastasis of gastric carcinoma.
AB  - Integrin-linked kinase (ILK), a serine/threonine protein kinase, implicates in
      cellular control of cell-matrix interactions and cell proliferation that is
      associated with a highly invasive phenotype of certain tumors. To study whether
      ILK is involved in the development and progression of gastric carcinoma, we
      examined the expression of ILK in gastric carcinoma cell lines, primary gastric
      carcinomas and corresponding non-neoplastic mucosa using reverse-transcription
      polymerase chain reaction (RT-PCR) and immunohistochemistry and analyzed the
      relationship with clinicopathological parameters. The expression of ILK mRNA was
      detected in 4 of 5 gastric carcinoma cell lines and 22 of 35 (63%) microdissected
      tumor samples of primary gastric carcinoma using RT-PCR. The incidence of cases
      with ILK mRNA expression was significantly higher in scirrhous and intermediate
      type (82%) than in medullary type (44%) (P=0.0204). Significant association was
      detected between ILK mRNA expression and presence of nodal metastasis (P=0.0388).
      Immunohistochemically, strong expression of ILK protein (over 50% of tumor cells
      were positive) was detected in 69% (84/122) of primary gastric carcinomas,
      whereas no ILK expression was found in non-neoplastic gastric epithelia. Strong
      expression of ILK protein was significantly associated with scirrhous and
      intermediate type (P=0.0217), deep invasion of tumor cells in gastric wall
      (P=0.0006), and presence of nodal metastasis (P=0.0176). These results strongly
      suggest that ILK may participate not only in stomach carcinogenesis especially of
      scirrhous and intermediate types but also in invasion and metastasis of gastric
      carcinoma. ILK might be a novel molecular marker for aggressive gastric cancer.

PMID- 12596062
TI  - Small intestinal biopsies in celiac disease: duodenal or jejunal?
AB  - BACKGROUND: For diagnosis and follow-up of celiac disease, pediatric societies
      advise that intestinal mucosal specimens should be obtained using suction capsule
      from the jejunum. This procedure is strenuous for patients, time-consuming,
      expensive and requires radiographic guidance. Mucosal biopsies from the distal
      duodenum can be obtained more easily under endoscopic vision using forceps. The
      aim of the present study was to compare biopsies taken from the duodenal mucosa
      by forceps and from the jejunal mucosa using suction capsule with respect to
      histological outcome. METHODS: For this study, 171 paired biopsies were taken
      from 109 patients (1-75 years) from the distal duodenal mucosa using jumbo
      forceps and from the jejunal mucosa using Crosby suction capsule. Histological
      interpretation was performed according to a modified Marsh classification,
      including partial-, subtotal and total villous atrophy as Marsh IIIA, B, and C.
      RESULTS: Fourteen suction capsule biopsies were of insufficient quality to be
      interpreted (8%). All duodenal forceps biopsies produced adequate material for
      histological scoring. No differences in histological scoring were seen in 145 of
      157 compared biopsies (92%). Of 12 biopsies in which a discrepancy was present, 4
      showed more severe lesions in the duodenum and 8 more severe lesions in the
      jejunum. The differences were of clinical significance, i.e., including the
      presence and absence of villous atrophy in 9 of 157 paired biopsies (6%).
      CONCLUSION: In the present study, we demonstrated that mucosal specimens taken
      from the distal duodenal and jejunal mucosa are strongly correlated. Clinically
      significant discrepancies were present in only 6% of paired biopsies. Therefore
      we suggest that, in diagnosis and follow-up of celiac disease, mucosal specimens
      may be taken from the duodenum using forceps to obtain adequate material for
      histological interpretation.

PMID- 12596063
TI  - Expression of cyclo-oxygenase-2 is correlated with high intratumoral microvessel
      density and low apoptotic index in human esophageal squamous cell carcinomas.
AB  - Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to
      prostanoids. COX-2 expression has been found in many malignancies. This study
      analyzed the correlation between COX-2 expression and angiogenesis or apoptosis
      in human esophageal carcinomas. The study examined the expression of COX-2 in six
      esophageal carcinoma cell lines and in 100 esophageal squamous cell carcinomas,
      comparing intratumoral microvessel density (IMVD) and apoptotic index (AI) by
      immunohistochemistry and TUNEL methods. COX-2 was variably expressed in all the
      cell lines examined. COX-2 immunoreactivity was observed mainly in the cytoplasm
      of carcinoma cells. Significantly higher mean IMVD and lower AI were noted in the
      51 strong COX-2 expressing cases than in the 49 weak cases. IMVD and AI were
      negatively correlated. COX-2 expression was higher in the tumors with lymphatic
      invasion than in the others. These data indicate that COX-2 expression is
      associated with increased intratumoral microvessels and suppression of tumor cell
      apoptosis. Thus COX-2 might play an important role in the angiogenesis and
      regulation of apoptosis in esophageal squamous cell carcinomas.

PMID- 12596064
TI  - Follicular lymphoma of the gallbladder and extrahepatic bile ducts.
AB  - We report a case of a 63-year-old female, who presented with symptoms and signs
      of an acute biliary tract obstruction with jaundice and pain. Ultrasound together
      with intraoperative examination suggested a Klatskin tumour. Following radical
      resection, a tumour located predominantly in the wall of gallbladder, but
      infiltrating extensively also the walls of cystic, common hepatic and choledochus
      duct, was found. On the basis of cell morphology and the results of
      immunohistochemical analysis, the tumour was classified as an extranodal
      follicular lymphoma, grade II of the gallbladder, involving also hilar
      extrahepatic bile ducts. To the best of our knowledge, this is the first report
      of an extranodal follicular lymphoma in this location. A postoperative follow-up
      of more than 3 years has been completely uneventful without any symptoms or signs
      of disease recurrence.

PMID- 12596065
TI  - Immunophenotypical changes of neoplastic cells and tumor-associated macrophages
      in a rat dendritic cell sarcoma-derived transplantable tumor line (KB-D8).
AB  - Basically, dendritic cell-derived sarcomas are characterized by expression of
      major histocompatibility complex class-II molecules, but the biological
      properties of the tumor cells remain to be elucidated. Recently, we established a
      novel transplantable cell line (KB-D8) from a dendritic cell sarcoma found in an
      F344 rat. In the present study, we investigated immunophenotypical changes of KB
      D8 tumor cells and tumor-associated macrophages (TAMs) appearing in relation to
      tumor development in syngeneic F344 rats. A number of neoplastic cells in 0.5-cm
      diameter KB-D8 tumors showed immunoreactions to OX6 (specific for rat antigen
      presenting cells), ED1 (for rat exudate macrophages), and ED2 (for rat resident
      macrophages), and 72% and 11% of the OX6+ cells were double-immunostained with
      ED1 and ED2, respectively. Interestingly, the immunoreactions to these antibodies
      were gradually reduced with increasing size of KB-D8 tumors of 1-, 2-, and 3-cm
      diameter. These findings indicated that immunophenotypes of dendritic cell
      derived sarcomas may be changeable depending on microenvironmental conditions in
      vivo. Many TAMs seen outside KB-D8 tumors reacted to OX6, ED1, and ED2; the
      numbers of TAMs immunopositive for these antibodies also decreased as the tumor
      grew. Similarly, the earlier temporary increase and subsequent gradual decrease
      in ED2+ and OX6+ cell numbers were observed in the spleen and liver of KB-D8
      bearing rats. The reverse-transcription polymerase chain reaction showed mRNA
      expressions of granulocyte/macrophage-colony stimulating factor, monocyte
      chemoattractant protein-1, and osteopontin in KB-D8 tumor tissues. Although the
      functional roles (biphasic roles: suppressing or promoting) of these factors
      should be investigated further in relation to tumor development, the factors
      might be partially responsible for the TAM reactions. KB-D8 would be a useful
      experimental model to investigate the biological characteristics of dendritic
      cell sarcomas and tumor immunology in the host.

PMID- 12596066
TI  - A murine model of granulomatous colitis with mesenteric lymphadenitis induced by
      mycobacterial cord factor.
AB  - Granulomatous colitis is a major entity of human intestinal diseases. We
      previously reported that intravenous injection of mycobacterial cord factor (CF),
      a potent macrophage activator, induced pulmonary granulomas in mice with enhanced
      production of Th1 cytokines and chemokines. In this study we made a murine model
      of granulomatous colitis by intramural injection of CF. A single dose of 300
      microg CF was injected into the wall of the rat and mouse colon in the form of
      liposomes. After 1 week granulomas developed at the injection site, extending
      from the subserosa to the lamina propria, and persisted for longer than 6 weeks.
      They were composed mainly of ED1-positive macrophages, which often underwent
      apoptosis, and CD4(+) and CD8(+) lymphocytes, which preferentially infiltrated
      around the macrophage accumulation. Myofibroblast proliferation was not
      prominent, and no appreciable fibrosis resulted after the decline of granulomas.
      Although the intestinal epithelium was involved in inflammation, tissue injuries
      such as mucosal erosion or ulceration were not induced. When granulomas were
      formed near the Peyer's patches, they invaded deeply into the lymphoid tissue,
      producing many small islands. The mesenteric lymph nodes also had many
      granulomatous islands in the cortex and medulla, but the liver and spleen
      displayed no granulomatous changes, suggesting that liposomal CF spreads via the
      lymphatic vessels from the injection site. The CF-induced colonic granulomas
      associated with mesenteric lymphadenitis will be useful for investigating human
      granulomatous colitis.

PMID- 12596067
TI  - Detection of gene expression of vascular endothelial growth factor and flk-1 in
      the renal glomeruli of the normal rat kidney using the laser microdissection
      system.
AB  - The recent development of the laser microdissection (LMD) technique enables one
      to target particular tissues or cells for gene or protein analyses. The purpose
      of this study was to detect local mRNA expression of vascular endothelial growth
      factor (VEGF) and its receptor, flk-1, in the glomeruli of normal rat kidneys
      using the LMD system. Frozen sections of the kidney of 8-week-old male Wistar
      rats were made. The glomeruli were dissected from the frozen sections with the
      LMD system, and total RNA was extracted from 200 glomeruli in each kidney.
      Reverse-transcription polymerase chain reaction (RT-PCR) revealed the local mRNA
      expression of three isoforms of VEGF, flk-1 and GAPDH in the glomeruli. Moreover,
      the real-time PCR was performed to evaluate the experimental condition for
      quantification of VEGF and flk-1 mRNA expression using this system, and the
      results showed that at least 10 glomeruli might be needed for quantifying local
      VEGF mRNA expression. However, cDNA from 200 glomeruli was not enough for
      quantitative evaluation of flk-1 mRNA with this system. These results demonstrate
      the reproducibility of the analysis of mRNA expression in the renal glomeruli
      using the LMD system and also suggest that the application of the LMD technique
      will provide information to further our understanding of the mechanisms involved
      in kidney diseases.

PMID- 12596068
TI  - Collagenofibrotic glomerulopathy with a widespread expression of type-V collagen.
AB  - Collagenofibrotic glomerulopathy is considered as a form of glomerulopathy in
      which organized collagen type III progressively deposits. We report a case of
      this disease with widespread expression of collagen type V. A 65-year-old woman
      was admitted to our hospital for further evaluation of nephrotic-range
      proteinuria. The patient had had anemia and hypertension for 9 years, and
      proteinuria for 3 years. A renal biopsy specimen showed a remarkable mesangial
      expansion with Congo red-negative and periodic acid-Schiff-positive deposits. At
      the ultrastructural level, two forms of bundling fibers were found in the
      mesangium and subendothelial side of the glomerular basement membranes (GBM). The
      GBM itself appeared normal. Immunohistochemical investigation showed that the
      glomerular lesions were strongly reactive with both anti-collagen type-III and -V
      antibodies. Immunoelectron microscopy demonstrated collagen type V in both forms
      of bundling fibers. Despite therapy, her renal function declined. The clinical
      course and renal pathology of this case were in accordance with collagenofibrotic
      glomerulopathy except for the widespread expression of collagen type V. Collagen
      type V is a fibrillar collagen capable of forming banding fibrils. This report
      poses the question whether collagen type V accumulates only in this particular
      case or whether it is a normal component in collagenofibrotic glomerulopathy.

PMID- 12596069
TI  - Phimosis as a cause of the prune belly syndrome: comparison to a more common
      pattern of proximal penile urethra obstruction.
AB  - The pathogenesis of the prune belly syndrome (PBS) remains controversial, but two
      theories predominate. The first theory supports an obstructive phenomenon early
      in gestation leading to irreversible damage to the genitourinary tract and
      abdominal wall. The second theory suggests mesodermal injury between the 6th and
      10th weeks of gestation as the primary abnormality. This paper reports of two
      fetuses with the PBS phenotype that were examined postmortem at our institution.
      Thorough examination of the lower urinary tract allowed demonstration of anatomic
      obstruction of the urethra in both cases. One case illustrated a relatively
      common pattern of proximal penile urethral obstruction, a flap-like obstruction
      between the prostatic and penile urethra. The other case provided what we believe
      to be the first description of PBS caused by severe phimosis.

PMID- 12596070
TI  - Pulmonary metastases from a low-grade endometrial stromal sarcoma confirmed by
      chromosome aberration and fluorescence in-situ hybridization approaches: a case
      of recurrence 13 years after hysterectomy.
AB  - Pulmonary metastasis from low-grade endometrial stromal sarcomas (ESSs)
      occasionally are found after long, disease-free periods, mostly as incidental
      histological or radiological discoveries. We describe a case of low-grade ESS
      presenting as nodular pulmonary metastases finally diagnosed by estrogen-receptor
      staining, cytogenetic and fluorescence in situ hybridization (FISH) analyses, and
      perusal of the histology of hysterectomy material. An abnormal nodule in the lung
      field was discovered by means of chest X-ray of a 47-year-old woman. She had been
      disease free for 13 years after hysterectomy for an alleged leiomyoma. A computed
      tomographic scan revealed nodules, with fluctuation in size over the 2-year
      period, in both lungs. Finally the lesion in the left lung was resected, and
      pulmonary endometriosis was suspected because of the lack of stromal cell nuclear
      atypia and positive immunohistochemical reactions for estrogen and progesterone
      receptors. However, a characteristic karyotype was identified cytogenetically:
      46, XX, t(7;17)(p15;q11), the translocation of which, specific to ESS, was
      confirmed by FISH analysis. A final diagnosis of pulmonary metastases from an ESS
      could be made by reviewing the histology of the previous uterine tumor. In this
      case, metastatic lesions from an ESS showed a decrease as well as an increase in
      size, despite the malignant potential. Immunostaining for estrogen and
      progesterone receptors and cytogenetic and FISH analyses, together with clinical
      information on the past gynecological history, are valuable diagnostic keys.

PMID- 12596071
TI  - Mantle cell lymphoma with Homer-Wright rosettes.

PMID- 12596072
TI  - [Quo vadis cardiologia? Or: An nescis, mi fili, quantilla prudentia mundus
      regatur? (Pope Julius III)].
AB  - In order to recognize and to solve problems, a look in the future is essential
      despite many uncertainties. Besides sound bed side-teaching, the main aim in the
      education of the students should be to acquire self-responsiveness and an
      attitude of permanent learning. It is more than doubtful whether the high
      expectations of health politicians will be met to limit the cost of in-patient
      treatment by introducing diagnosis-related groups in combination with evidence
      based medicine, as this method has several severe limitations in order to fulfill
      this duty. The new financial system based on diagnosis-related groups will be in
      favor of private investors compared to the government-dependent university
      hospitals. The changing population pyramid implies not only higher costs but in
      addition severe medical problems. Within the changing society, alterations in the
      patient's behavior are to be expected. Several factors will contribute to make
      the doctor's profession less attractive. In the developing countries a rapid
      increase in the non-communicative diseases, i.e., in coronary heart disease, has
      to be expected. Apart from the prolongation of life - especially during its
      terminal phase - it is mainly the allocation of resources between industrialized
      and developing countries which will determine the ethical discussion. Germany has
      lost its leading position of the 19th and beginning of the 20th century in
      medical sciences. This was based on the liberal university system introduced by
      Wilhelm von Humboldt. Several pioneering innovations of German cardiologists
      during the 20th century have not strengthened German industry - in contrast to
      the situation in the 19th century. The general conditions in Germany, which are
      not research oriented, have prompted the majority of the pharmaceutical firms to
      transfer their research activities into foreign countries. In addition Germany's
      cardiological research has lost basic sciences partners for clinically orientated
      basic research, as many institutes which formerly worked in the cardiovascular
      field, are now devoted to other specialties. Restrictive legal regulations--such
      as the law regulating working hours, anti-corruption laws and the new legal
      university framework--are not conducive to internationally competitive research.
      Creative and innovative research requires liberal general conditions and cannot
      be planed.

PMID- 12596073
TI  - [History of atrial fibrillation].
AB  - The authors review the history of atrial fibrillation, the most frequent
      clinically observed cardiac arrhythmia. A French "clinicopathologist", Jean
      Baptist de Senac (1693-1770), was the first who assumed a correlation between
      "rebellious palpitation" and a stenosis of the mitral valve. From an analysis of
      simultaneously recorded arterial and venous pressure curves, the Scottish Sir
      James Mackenzie (1853-1925) demonstrated that a presystolic a wave cannot be seen
      on the jugular phlebogram during "pulsus irregularis perpetuus". The first human
      ECG depicting atrial fibrillation was published by Willem Einthoven (1860-1927)
      in 1906. The proof of a direct connection between absolute arrhythmia and
      auricular fibrillation was established by two Viennese physicians, Rothberger and
      Winterberg. The major discoveries relating to the pathomechanism and the clinical
      features of atrial fibrillation in the 20(th) century stemmed from the scientific
      activities of Karel Frederik Wenckebach, Sir Thomas Lewis, Gordon Moe, and
      Maurits Allessie.

PMID- 12596074
TI  - Genetics of arrhythmogenic right ventricular cardiomyopathy--status quo and
      future perspectives.
AB  - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial
      disorder of unknown origin. In recent years, the disease has been recognized as a
      major cause of ventricular tachyarrhythmias and sudden cardiac death in young
      patients with apparently normal hearts. Although characteristic structural,
      imaging and electrocardiographic features are included in a proposed catalogue of
      diagnostic criteria, the correct diagnosis of ARVC often remains difficult. Much
      effort has been undertaken to enlarge the knowledge on pathophysiological
      mechanisms of the disease. The role of molecular genetics for the pathogenesis of
      ARVC is discussed in the following review. On the basis of linkage analyses in
      large families affected by ARVC, there is growing evidence for genetic
      alterations in ARVC, which, in the majority of chromosomal loci (seven) reported
      so far, follow a Mendelian autosomal-dominant pattern of inheritance with
      variable penetrance and polymorphic phenotype. Besides this, two autosomal
      recessive forms of ARVC are known. These can be differentiated from the autosomal
      dominant forms not only in terms of the mode of inheritance but also as to their
      specific phenotype: patients with Naxos disease exhibit characteristic hair and
      skin abnormalities and experience a more severe course of disease. Patients with
      another autosomal-recessive form display the typical but milder signs of ARVC
      together with opacifications of the crystalline lens. So far, two mutations in
      cardiac genes responsible for the development of ARVC have been reported. A
      homozygous two base pair deletion in the gene encoding for the cytoskeletal
      protein plakoglobin seems to account for the evolution of Naxos disease. The
      second mutation affecting the cardiac ryanodine receptor gene was found in
      patients with ARVC-2. Routine genetic testing of patients or relatives with a
      suspected diagnosis of ARVC is not available at present but may become the future
      gold standard with potential implications for a better understanding of the
      pathogenesis and management of the disease.

PMID- 12596075
TI  - [Non-invasive assessment of coronary flow reserve--valuable functional
      information in cardiac workflow].
AB  - Coronary flow reserve (CFR) can be determined echocardiographically in the LAD in
      about 90% and in the RCA in more than 70% of patients, respectively, by the use
      of modern high-resolution ultrasound equipment. For this purpose either high
      frequency fundamental imaging or echo-contrast enhanced harmonic Doppler
      technology is used. The main advantage of the method lies in its noninvasiveness
      and the lack of radiation exposure. In combination with coronary morphologic
      findings obtained from heart catheterization, CFR is helpful in the planning of
      further invasive procedures for coronary artery disease and in the estimation of
      the prognosis of such procedures. The functional status after PTCA of LAD/RCA or
      mammary bypass surgery can be evaluated during follow-up monitoring. Alteration
      in the coronary microcirculation can also be discovered in a non-invasive manner;
      improvement of microcirculatory disorders by adequate therapy can be assessed by
      serial measurements of CFR

PMID- 12596076
TI  - Usefulness of a non-invasive scoring system in predicting the outcome of
      electrophysiologic studies in non-invasively unexplained syncope.
AB  - BACKGROUND: An electrophysiologic study is a useful method to clarify the cause
      of non-invasively unexplained syncope in 18-60% of patients. However, it is
      invasive with possible procedure-related complications. Therefore, it would be
      helpful to identify patients in whom an electrophysiologic study is useful for
      diagnosis of syncope. METHODS: Patients with unexplained syncope were
      prospectively enrolled in a registry, if an electrophysiologic study was
      performed. The study group comprised of 643 consecutive patients. RESULTS: The
      electrophysiologic study revealed conduction abnormalities and tachyarrhythmias
      accounting for syncope in 35% of patients. Using a logistic regression model,
      history of injury during syncope (p<0.001), ejection fraction < or =40% (p=0.03),
      and PR interval >0.2 s (p=0.001) were independent predictors of an abnormal
      electrophysiologic study. These three clinical and easily measurable variables
      were entered into a scoring system. The maximal score consisted of 3 points. A
      score of >1 predicts a positive electrophysiologic study result in more than 70%
      of patients with non-invasively unexplained syncope. CONCLUSION:
      Electrophysiologic abnormalities were detected in 35% of patients with
      unexplained syncope. A history of injury, ejection fraction < or =40% and a PR
      interval >200 ms were independent predictors for a positive electrophysiologic
      study.

PMID- 12596077
TI  - Idiopathic monomorphic ventricular tachycardia originating from the left aortic
      sinus cusp in children: endocardial mapping and radiofrequency catheter ablation.
AB  - BACKGROUND: Idiopathic repetitive monomorphic ventricular tachycardia with an
      inferior axis and left bundle branch block pattern typically originates from the
      superior right ventricular outflow tract. When indicated, radiofrequency catheter
      ablation is usually safe and effective. However, a left ventricular origin has
      been described recently in adult patients in whom ablation attempts in the right
      ventricular outflow tract were unsuccessful. Experience in pediatric patients is
      limited. PATIENTS AND METHODS: Since 1998, 13 young patients suffering from
      symptomatic ventricular tachycardia episodes with an inferior axis and left
      bundle branch block pattern underwent an electrophysiological study and
      radiofrequency catheter ablation. In 2 patients, age 13 and 15 years, no
      endocardial local electrograms preceding the surface ECG QRS complex could be
      recorded within the right ventricular outflow tract during ventricular ectopy.
      Detailed mapping within the left ventricular outflow tract and in the aortic root
      revealed local electrograms 25 and 53 ms earlier than the QRS complex and a 11/12
      and 12/12 lead match during pacing inferior and anterior to the ostium of the
      left main coronary artery in the left aortic sinus cusp. Earliest activation was
      recorded 10 and 12 mm away from the coronary artery ostium identified
      angiographically. In each of the patients, one single radiofrequency current
      application (60 degrees C, 30 W, duration 30 and 60 s, respectively) resulted in
      complete cessation of ventricular ectopy. Subsequent selective injection into the
      left coronary artery did not reveal any abnormalities. During follow-up (2 and 34
      months) off any antiarrhythmic drugs, both of the patients are in continuous
      normal sinus rhythm. CONCLUSION: In young patients with symptomatic idiopathic
      ventricular tachycardia originating from the left aortic sinus cusp,
      radiofrequency catheter ablation was safe and effective.

PMID- 12596079
TI  - Randomized comparison of direct and provisional stenting in de novo coronary
      artery lesions: the RADICAL study.
AB  - BACKGROUND: Although preliminary reports have demonstrated excellent primary
      success and improved economics with direct stenting, a clinically relevant
      reduction of restenosis rate has not been documented yet. AIMS: Aims of the study
      were the comparison of restenosis rate (primary endpoint), procedural success,
      fluoroscopy time, amount of contrast dye and clinical outcome (secondary
      endpoints). METHODS AND RESULTS: Between January and December 1999, 250 patients
      were randomly assigned either to direct stent implantation without predilatation
      (DS; 125 patients) or provisional stenting (PB; 125 patients) and followed for
      7.9+/-2.7 (6-9) months. Angiographic follow-up was available in 92.0% of
      patients. Procedural success rate was 92.8% in DS and 100% in PB (n.s.), while
      radiation exposure was lower (4.7+/-4.3 versus 5.1+/-1.8 min; p<0.0001) with DS.
      Conversely, the amount of contrast dye (131+/-62 versus 139+/-36 ml; n.s.) was
      not different between DS and PB. Direct stenting leads to a 25.0% reduction in
      binary restenosis rate (15.7% in DS versus 20.9% in PB), indicating an
      advantageous trend, missing however the level of statistical significance.
      Similarly, there was a trend to fewer major cardiac events with DS (DS 16.8%, PB
      21.6%). CONCLUSIONS: We conclude that direct stenting is at least as safe and
      efficacious as balloon dilatation followed by provisional stent implantation, but
      failed to reduce restenosis rate or improve outcome within 6 months. Larger
      prospective randomized trials are required to assess the potential of direct
      stenting to reduce restenosis rate and improve clinical outcome in subgroups of
      patients.

PMID- 12596078
TI  - Prognostic value of non-sustained ventricular tachycardias after acute myocardial
      infarction in the thrombolytic era: importance of combination with frequent
      ventricular premature beats.
AB  - PURPOSE: of this study was to re-evaluate the association between ventricular
      arrhythmias and long-term mortality after acute myocardial infarction (AMI) in
      the thrombolytic era. METHODS: MITRA (maximal individual therapy in patients with
      AMI) is a multicenter registry of 54 hospitals in Germany investigating patients
      with AMI. RESULTS: 2420 patients received Holter ECG. Positive Holter ECG was
      defined: > or =10 ventricular premature beats (VPB)/h, or > or =4 couplets/d, or
      > or =1 non-sustained ventricular tachycardia (nsusVT)/d, or their combination.
      Mortality rates (median 17 months) were 6.5% without ventricular arrhythmias,
      with > or =10 VPB/h 15.2% and with the combination of > or =10 VPB/h plus either
      > or =4 couplets/d or > or =1 nsusVT/d 23.4%. In multivariate analysis, none of
      the ventricular arrhythmias alone correlated with mortality. There was a
      significant association between mortality and the combination of > or =10 VPB/h
      plus > or =4 couplets/d (OR 2.3) or > or =10 VPB/h plus > or =1 nsusVT/d (OR
      2.8). CONCLUSION: Non-sustained VTs are only associated with poor prognosis if
      combined with frequent VPBs.

PMID- 12596080
TI  - [A case of coronary vasospasm treated with stent placement].
AB  - We report about a 49 year old woman with repeated chest pain at rest. During
      hyperventilation significant ST-segment elevation in leads V1-V5 appeared.
      Bicycle stress test did not provoke any ECG changes. Coronary angiography showed
      a significant stenosis of the left anterior descending coronary artery.
      Successful balloon angioplasty followed by stent implantation was performed.
      After an uneventful course of twelve months, hyperventilation could provoke
      neither chest pain nor ECG changes again without any antispastic medical
      treatment. Impact of fixed atherosclerotic lesions for the occurrence of coronary
      vasospasm, usefulness of hyperventilation as a non-invasive provocation test and
      therapy are discussed.

PMID- 12596081
TI  - Partial malposition of PFO closure device: indication for elective surgical
      removal? Discussion of indications, procedural and anatomical aspects.
AB  - Partial malposition of a PFO closure device occurred, probably due to a right
      atrial ligamentous structure. Despite absence of residual shunt and uneventful
      postprocedural course, elective surgical removal was performed. Indications,
      procedural and anatomical aspects are discussed.

PMID- 12596082
TI  - [Catheter ablation of ectopic atrial tachycardia by electrical pulmonary vein
      disconnection].
AB  - We report a 25-year-old female patient with a long history of symptomatic
      paroxysmal supraventricular tachycardia. Electroanatomic activation mapping
      demonstrated a focal tachycardia originating in the right upper pulmonary vein, 3
      cm distal to the ostium. Due to the recent experiences in the management of focal
      atrial fibrillation with catheter ablation, direct ablation applied inside the
      pulmonary vein was avoided. Instead, an electrical disconnection of the pulmonary
      musculature from the left atrium guided by a circumferential 10-electrode mapping
      catheter was performed. The patient has since been asymptomatic during follow-up.

PMID- 12596083
TI  - Smoking cessation strategies for real-life situations?

PMID- 12596084
TI  - Functional genomics and gene microarrays--the use in research and clinical
      medicine.
AB  - In the year 2000, the Human Genome Project Consortium presented the first
      complete draft of the human genome together with Celera Genetics. Since then, the
      so-called "post-genome era" has started. Microarrays are capable of profiling
      gene expression patterns of tens of thousands of genes in a single experiment and
      thus allow a systematic analysis of DNA and RNA variation. They seem likely to
      become a standard tool of both molecular biology research and clinical
      diagnostics. These prospects have attracted great interest and investment from
      both the public and private sectors. This review introduces the principle of
      microarray technology and gives an overview of its current and future potential
      in clinical medicine.

PMID- 12596085
TI  - Five-day plan for smoking cessation using group behaviour therapy.
AB  - The "Five-Day Plan to Stop Smoking" (FDP) is an educational group technique for
      smoking cessation. We studied a cohort of 123 smokers (55 men, 68 women, mean age
      42 years) who participated in 11 successive FDP sessions held in Switzerland
      between 1995 and 1998 and who were followed up for at least 12 months by
      telephone or direct interview. Overall, 102 of the 123 subjects (83%) had stopped
      smoking by the end of the FDP, and self-declared smoking cessation rate was 25%
      after one year. The following factors potentially associated with outcome were
      studied: age, sex, smoking habit duration, cigarettes per day, Fagerstrom Test
      for Nicotine Dependence (FTND), group size, and medical presence among the group
      leaders. Smoking habit duration was the only variable which showed a
      statistically significant association with success: the rate of smoking cessation
      was higher among patients who had smoked for less than 20 years (34.7% vs. 18.9%,
      p = 0.049). Stress was the most common cause of relapse. The FDP appears to be an
      effective smoking cessation therapy. Propositions are made in order to improve
      the success rate of future sessions.

PMID- 12596086
TI  - Endovascular stent-grafting for diseases of the descending thoracic aorta.
AB  - PRINCIPLES: Endoluminal stent-grafts are emerging as a less invasive alternative
      to conventional open surgery in the management of descending thoracic aortic
      dissections and aneurysms. We describe our experience with endovascular stent
      grafting in the treatment of thoracic aorta pathology. METHODS: 17 Patients were
      treated with 23 endovascular stents. The underlying pathology was an
      atherosclerotic aneurysm verum (n = 5), a type B dissection with contained
      rupture (n = 3), an intramural haematoma with contained rupture (n = 1) and a
      false aneurysm of unknown origin (n = 1). One patient had Marfan's syndrome and
      six patients had a traumatic rupture of the descending aorta. RESULTS: Overall 23
      stent-grafts were implanted. In one patient, conversion to an open graft
      replacement of the descending aorta was necessary. One patient died. In four
      patients (23.5%) a left carotid-subclavia bypass or transposition was performed
      to achieve a sufficient neck for the proximal stent-graft landing zone. The
      postoperative control-CT scans revealed a total of six endoleaks (EL) (four type
      I, one type II and one type IV). Two patients needed a graft extension in a
      second operation (4 days and 18 month after the first operation), two EL (one
      type I and one type II) disappeared after 9 and 18 months, respectively and two
      EL are still under observation. One patient developed a paresis after conversion
      to open graft replacement. CONCLUSIONS: A variety of diseases of the descending
      aorta can be treated by endoluminal stent-grafting, which seems to be a valid
      alternative to open repair in well selected cases. Mortality and morbidity in our
      small series were low. Continuous follow-up is mandatory.

PMID- 12596087
TI  - Integrity in science.

PMID- 12596089
TI  - Advances in thoracic surgery : emphysema and simultaneous bronchial carcinoma.

PMID- 12596090
TI  - Current management of acute bronchiolitis in Switzerland.
AB  - INTRODUCTION: Acute bronchiolitis is the most common lower respiratory tract
      infection in the first year of life. Current expert opinion and scientific data
      suggest that pharmaceutical agents have little impact on the natural course of
      the disease. METHODS: Postal questionnaires were sent to all Swiss paediatricians
      to assess their current practice for treating acute bronchiolitis in children.
      RESULTS: Of a total of 937 questionnaires, 541 (58%) were returned. Of the
      respondents, 422 (78%) treat children with acute bronchiolitis. Up to 99% of
      paediatricians used bronchodilators in the outpatient and inpatient management,
      either routinely (up to 62%) or occasionally (37%). Steroids were used by 41% of
      the respondents in outpatient management and by 57% in inpatient management. The
      paediatric respiratory physicians tended to use bronchodilators and
      corticosteroids less frequently than the general paediatricians. CONCLUSIONS: A
      wide variation in the treatment of bronchiolitis was noted. Despite lack of
      evidence of benefit most Swiss paediatricians use pharmaceutical agents in the
      management of acute bronchiolitis. In particular, bronchodilators and
      corticosteroids were used in inpatient management in Switzerland much more
      frequently than recently reported for Australian paediatricians. National
      guidelines could be helpful in reducing the variations in the management of acute
      bronchiolitis in our country.

PMID- 12596091
TI  - Emotional and behavioral problems in migrant children.
AB  - OBJECTIVES: To assess emotional (depression, anxiety and self-esteem) and
      behavioural problems in migrant children and to compare them with non-migrant
      children. METHODS: 526 students (60% boys, 40% girls) aged 11.23 +/- 1.05, at
      five schools in Adana, Turkey in areas with a high migrant population were
      included in this study. 182 children (35%) were migrants and 344 children (65%)
      were non-migrants. The Depression Inventory for Children (CDI), the State-Trait
      Anxiety Inventory for Children (STAI-C) and the Coopersmith Self-Esteem Inventory
      (CSEI) were administered to the pupils at their school and Rutter's Teachers
      Rating Scale (RTRS) was administered to their teachers. Sociodemographic
      variables were recorded on the basis of school records and the children's report.
      RESULTS: In the migrant group, fathers were less educated and had more employment
      problems, homes were rented and the children were unsuccessful at school. Migrant
      children had significantly lower self-esteem with higher depression and anxiety.
      Behavioural symptoms on RTRS were not significant with regard to migration. No
      significant correlation was found between psychometric tests and father's
      education, duration of residence after migration or room density. CONCLUSIONS: We
      found significant emotional but no behavioural problems in Turkish migrant
      children compared to Turkish non-migrant children. Further prospective studies
      are needed to clarify the long-term course of the various types of distress and
      the individual prognosis of migrant adjustment.

PMID- 12596092
TI  - Necrolytic migratory erythema (glucagenoma)-like skin lesions induced by EGF
      receptor inhibition.

PMID- 12596093
TI  - The role of intestinal transplantation in the management of babies with extensive
      gut resections.
AB  - BACKGROUND/PURPOSE: Modern neonatal care, surgical treatment, and total
      parenteral nutrition (TPN) have improved survival rate for babies with extensive
      gut resections. The authors examined the role of intestinal transplantation in
      the treatment of these patients. METHODS: The authors reviewed all pediatric
      intestinal transplants performed for short bowel syndrome at our center (70
      transplants performed between Aug 1994 and Feb 2002). Factors affecting patient
      survival were analyzed. RESULTS: Older patient age at the time of transplant was
      a significant factor favorably affecting patient survival (P =.031). Trends
      toward better survival rates were observed in those transplants performed more
      recently (P =.063), in those patients with greater body weight (P =.084), in
      those not hospitalized at the time of transplant (P =.14), and in those without
      concomitant liver failure (P =.12). Three-year survival rate for patients greater
      than age 2 years and without liver failure was 90%. However, 32% of our
      recipients underwent transplant at age less than one year, and most in this group
      (75%) had concomitant liver failure. CONCLUSIONS: For babies with irreversible
      intestinal failure, intestinal transplantation is a life-saving option. Results,
      which have recently improved, are best when transplantation compliments more
      conservative surgical treatments and TPN. However, there is a subset of patients
      who have liver disease early requiring urgent transplant.

PMID- 12596094
TI  - Dietary lipids alter the effect of steroids on the transport of glucose after
      intestinal resection: Part I. Phenotypic changes and expression of transporters.
AB  - BACKGROUND/PURPOSE: Glucocorticosteroids alter the function of the intestine.
      This study was undertaken to assess the effect on D-glucose uptake of budesonide
      (Bud), prednisone (Pred), or dexamethasone (Dex) in animals with a 50% intestinal
      resection and fed chow or a diet enriched with saturated (SFA) or polyunsaturated
      fatty acids (PUFA). METHODS: In vitro ring uptake technique, Western blots, and
      Northern blots were performed. RESULTS: Bud increased the jejunal D-glucose
      uptake, and this effect was prevented by feeding PUFA. SGLT1 and Na+/K+ ATPase
      protein and mRNA abundance did not correlate with the change in the rate of
      uptake of glucose. CONCLUSIONS: (1) Bud increased the jejunal glucose uptake, (2)
      the activity of the sugar transporter does not correlate with the abundance of
      protein or their respective mRNAs, (3) th Bud effect on glucose uptake is
      prevented by feeding PUFA. Thus, the desired intestinal adaptive response after
      intestinal resection may be enhanced further by the administration of the locally
      acting steroid budesonide and by feeding a saturated compared with a
      polyunsaturated fatty acid diet.

PMID- 12596095
TI  - The occurrence of unusual smooth muscle bundles expressing alpha-smooth muscle
      actin in human intestinal atresia.
AB  - BACKGROUND/PURPOSE: Intestinal dysmotility is an important problem in the
      postoperative management of patients with intestinal atresia (IA). Changes in the
      intramural components have so far been histochemically and immunohistochemically
      examined in both the proximal and distal segments of IA, but no detailed analysis
      of the muscular elements has been performed. The aim of this study was to
      carefully examine any alterations in the muscular elements in the intestines from
      patients with IA. METHODS: Resected intestines were obtained from 6 patients with
      ileal atresia, 4 patients with jejunal atresia, and 3 controls without
      gastrointestinal diseases obtained by autopsy (congenital diaphragmatic hernia).
      All specimens were immunochemically stained with a monoclonal antibody to alpha
      smooth muscle actin (alpha-SMA) as a smooth muscle marker. RESULTS: In the normal
      small intestine, almost all the enteric smooth musculature were positive for
      alpha-SMA antiserum, except for the bulk of the circular musculature. In the
      proximal segments of all cases with IA, a reduced staining intensity for alpha
      SMA was observed mainly in the severely hypertrophic muscle layers. In addition,
      some bundles of smooth muscle also were located in the submucosal connective
      tissue near the border of the innermost layer of the circular musculature, in
      which large amounts of smooth muscle fibers extended occasionally from the
      innermost layer of the circular musculature to the muscularis mucosae in the
      proximal segments of 4 cases. In the distal segments of IA, the distribution of
      alpha-SMA-positive smooth muscle fibers was similar to that in the control
      intestines, excluding mild to moderate hypertrophy of the muscular layers.
      CONCLUSIONS: Both severe hypertrophy and a reduced immunoreactivity for alpha-SMA
      were observed in the circular muscle layer of the proximal segments. In addition,
      the occurrence of alpha-SMA-positive abnormal smooth muscle fibers was recognized
      in the submucosal layers of the proximal segments, thus, suggesting a delay in
      the intestinal muscular formation or a regressive reaction secondary to
      dilatation. These muscular alterations in the proximal segments might be
      considered to contribute to the postoperative intestinal dysmotility in IA cases.

PMID- 12596097
TI  - Three-dimensional imaging clarifies the process of tracheoesophageal separation
      in the rat.
AB  - BACKGROUND/PURPOSE: The process of tracheoesophageal separation during early
      development of the foregut has been disputed and has led to difficulties
      explaining how congenital abnormalities of the trachea and esophagus might occur.
      This study clarifies the embryogenesis of tracheoesophageal separation by using
      sequential 3-dimensional imaging at crucial stages of foregut development.
      METHODS: Timed pregnant Sprague Dawley rats were killed at days 11, 11.5, 12,
      12.5, and 13. The embryos were harvested, histologically sectioned, and stained
      with H&E. Digitized photographs were taken of sequential serial transverse
      sections and their tracings layered in a 3-dimensional rendering program before
      being "skinned" to produce a 3-dimensional object. RESULTS: The first respiratory
      structures to develop are the bronchi on day 11.5. They are evident first as
      bulges on the ventrolateral wall of the foregut approximately two thirds of the
      way between the lowest pharyngeal pouch and the level of the hepatic diverticulum
      and pancreatic buds. Lateral grooves dorsal to the respiratory bud on the lateral
      walls extend cranially. On day 12 the lateral bulges have developed into the 2
      main bronchi, although the trachea is yet to separate from the foregut. On days
      12.5 to 13 the trachea progressively elongates, and by day 13 tracheoesophageal
      separation is complete. CONCLUSIONS: After the main bronchi have developed, the
      trachea forms when the ventral component of the foregut is "cut" away from the
      dorsal component. There is an area of apoptosis at the point of tracheoesophageal
      separation, and, as the embryo grows, this causes the separation point to stay at
      a constant distance from the pharynx. Meanwhile, the trachea and esophagus distal
      to it increase dramatically in length. The area immediately caudal to the initial
      point of tracheoesophageal separation ultimately forms the stomach.

PMID- 12596096
TI  - Surgical necrotizing enterocolitis: are intestinal lesions more severe in infants
      with low birth weight?
AB  - PURPOSE: This study examines whether the intestinal lesions of necrotizing
      enterocolitis (NEC) in infants undergoing surgery are more severe in patients
      with extremely low birth weight (BW). METHODS: Between 1980 and 2000, 128 infants
      underwent laparotomy for NEC: 90 in the acute phase, and 38 for secondary
      stenosis. Resections were limited to areas of transparietal bowel necrosis and to
      secondary stenoses. The authors studied the extent of initial bowel lesions at
      initial laparotomy, and, in the survivors, the extent of bowel resections and the
      existence of digestive sequelae, with a median follow-up of 24 (range, 1 to 247)
      months. Children with BW < or =1,000 g (group 1, 22 patients) and greater than
      1,000 g (group 2, 103 patients) were compared by using chi(2) and t test.
      RESULTS: Patients' survival rate was 87%: 68% and 91% in the groups 1 and 2,
      respectively (P =.01). No significant difference between the 2 groups was seen:
      (1) for the rate of patients with panintestinal lesions at initial surgery (12%);
      (2) in the survivors, the ratio of remaining to total length of jejuno-ileum
      (mean 88%), the number of colonic segments resected (mean 1.2), the rate of
      survivors without distal ileum (34%), ileo-caecal valve (39%), or right colon
      (29%); and (3) for the existence of digestive symptoms, even minor, at last
      follow-up (25%). CONCLUSIONS: Although the prognosis of surgical NEC was worse in
      infants with extremely low birth weight, the intestinal lesions were not found
      more severe in these patients.

PMID- 12596098
TI  - Sternal cleft: a surgical opportunity.
AB  - PURPOSE: The aim of this study was to evaluate the results from the surgical
      techniques utilized to repair congenital sternal cleft. METHODS: From January,
      1987 to January, 2001, 5,182 patients were seen for chest wall malformations.
      Eight (0.15%) had sternal cleft. The age at presentation ranged from 15 days to 5
      years. Six were girls (75%). The associated malformations were congenital cardiac
      malformations (2 patients), maxillofacial hemangioma (1 patient). All of them
      underwent a surgical repair, which could be classified into 3 methods: group 1
      had primary closure of the defect (3 patients); group 2 underwent partial
      resection of the first, second, and third costal cartilages, disruption of the
      sternoclavicular junction, and closure of the sternal bars with stainless steel
      wire (3 patients); and group 3 had mobilization and approximation of the
      sternocleidomastoid muscles with closure achieved with costal homograft and
      prosthetic mesh (2 patients). The interval for postoperative follow-up was 1 to 8
      years. RESULTS: Group 1 patients developed well, although 2 of them had a slight
      degree of pectus excavatum in the long term not requiring surgical correction.
      Group 2 Patients developed without problems in all cases. One of the patients
      from group 3 had unsatisfactory aesthetic and functional results. He underwent
      reoperation with the second technique, achieving an improved result. CONCLUSIONS:
      Primary closure of the sternal cleft is the easiest technique. It should be
      performed in young infants. In the long term it can lead to a mild degree of
      pectus excavatum. The costal cartilage resection with mobilization of the
      clavicle achieved excellent results and allowed ready approximation of both
      sternal halves avoiding the use of costal grafts and prosthetic material.

PMID- 12596099
TI  - Transanal one-stage endorectal pull-through for Hirschsprung's disease in infants
      and children.
AB  - PURPOSE: This report presents the technique and results of transanal one-stage
      endorectal pull-through procedure in children with rectosigmoid lesions from
      Hirschsprung's disease. METHODS: Eight children aged one month to 6 years with
      frozen section biopsy-proven Hirschsprung's disease underwent transanal one-stage
      endorectal pull-through procedures during a 12-month period. A rectosigmoid
      transitional zone was suggested by contrast enema in 7 patients; rectal manometry
      was done to confirm the diagnosis in one patient. Preoperative colonic irrigation
      to evacuate feces out of the dilated colon was done in the hospital. Bowel
      preparation was the same as conventional colorectal surgery. Full-thickness
      rectal biopsy at 1 to 2 cm above the dentate line was submitted for pathologic
      diagnosis. A rectal mucosectomy dissection was started 0.5 cm proximal to the
      dentate lines and was extended into the intraperitoneal rectum. The muscular
      sleeve was divided circumferentialy at 3 to 4 cm proximal to the dentate line,
      exposing the intraperitoneal rectum and allowing full-thickness mobilization of
      the rectosigmoid colon out of the anus. Aganglionic colon segment was resected,
      and the normal colon was pull down to anastomose with the distal end of anorectal
      mucosa. RESULTS: Operating time, including taking frozen sections, ranged from
      110 to 180 minutes. The length of bowel resections ranged from 9 to 25 cm. The
      length of hospital stay depended on the amount of fecal impaction in the colon.
      Older children with substantial fecal impaction required 2 weeks of preoperative
      saline enema. One infant needed 3 days for bowel preparation, the same as for
      conventional colorectal surgery. The hospital stay ranged from 6 to 7 days in
      children younger than 2 years and 10 to 28 days in older children. There were no
      intraoperative or postoperative complications related to the pull-through
      procedure. One case of colitis occurred in the 6-year-old child, which required
      rectal tube decompression one week after the operation. Seven patients passed
      stool within 24 hours after surgery. All patients had normal bowel movements
      within 3 weeks. There was no rectal cuff stricture or enterocolitis during one
      year of follow-up. CONCLUSIONS: Transanal one-stage endorectal pull-through
      operations for rectosigmoid lesions from Hirschsprung's disease can be performed
      successfully in all ages of children with good results, avoiding transabdominal
      exploration. The early postoperative enterocolitis in the older children might
      occur and should be treated urgently. The partial coloanal anastomosis
      obstruction found in older children could be treated by placing a rectal tube
      into the anus to decompress the dilated pull-through colon. The limitation of
      this approach is that retroperitoneal fixation of the descending colon could not
      be dissected by the transanal route.

PMID- 12596100
TI  - Submucosal pressure-air insufflation facilitates endorectal mucosectomy in
      transanal endorectal pull-through procedure in patients with Hirschsprung's
      disease.
AB  - BACKGROUND: Most children with Hirschsprung's disease (HD) can be treated with a
      transanal endorectal pull-through (TEP) procedure. The authors have developed a
      simple technique of submucosal pressure-air insufflation (SI) to facilitate the
      submucosal dissection, which is one of the crucial parts of the operation.
      METHODS: Six patients with HD were treated by using TEP in one year. After
      adequate positioning and exposure, anal mucosa was incised 1 cm above the dentate
      line, and 4-quadrant SI with a simple system of scalp-vein needle connected to a
      20-mL syringe was used in all of the patients. Submucosal proctectomy,
      aganglionic and dilated segment colectomy, and coloanal anastomosis were
      completed transanally, but, in 2 of the patients, laparoscopic assistance to
      release the colon was required. RESULTS: There were no intraoperative and
      postoperative complications related to SI. Submucosal dissections were completed
      smoothly in all of the patients with negligible amount of bleeding. The only
      complication during the submucosal dissection was mucosal perforation at the site
      of previous rectal biopsy in 2 patients. Average operating time was 2.7 hours
      (range, 90-180 min), and mean length of resected bowel was 22.5 cm (range, 12 to
      42 cm). Follow-up is 8 to 14 months. Frequent bowel movements (>8 times per day)
      and perianal dermatitis were observed in 2 patients but returned to acceptable
      limits in 3 months. One patient had to undergo reoperation for adhesive
      intestinal obstruction. CONCLUSIONS: SI is simple, and offers a safe and faster
      dissection with minimum amount of bleeding during the endorectal mucosectomy in
      TEP procedure.

PMID- 12596101
TI  - Anorectal manometric evaluation of children and adolescents postsurgery for
      Hirschsprung's disease.
AB  - BACKGROUND: Little is known about anorectal function in patients after surgery
      for Hirschsprung's disease. Therefore, the authors evaluated anorectal sphincter
      function after corrective surgery. METHODS: Thirty-five patients were studied
      after corrective surgery for Hirschsprung's disease. Sixteen of them had
      anorectal manometry performed also before surgery. The clinical outcome, the
      highest anal resting pressure, the presence of the rectosphincteric reflex (RSR),
      and of high amplitude propulsive waves were evaluated. RESULTS: A total of 89%
      were doing poorly. Three had a fair and only one had a good outcome at the time
      of manometry 4.4 years after corrective surgery. RSR was absent in 33 and
      abnormal in 2 patients. The preoperative anal resting pressure was 45 +/- 14 mm
      Hg and postoperatively 45 +/- 13 mm Hg (P >.3). The anal resting pressure was 44
      +/- 16 mm Hg in the 19 patients evaluated only postoperatively. Propulsive waves
      > or =50 mm Hg were present in 60% of patients. CONCLUSIONS: Four years
      postsurgery, patients had a persistent absence of RSR regardless of the type of
      surgery. There was no significant difference in anal resting pressure between
      patients with and without sphincterotomy or between different surgical
      procedures. The presence of propulsive waves was not a prognostic indicator for
      achieving bowel control.

PMID- 12596102
TI  - Anal shift: preliminary results.
AB  - BACKGROUND/PURPOSE: Perineal ectopic anus in female infants is not a very
      uncommon congenital anomaly. The close proximity of the ectopic anus with the
      vulva and the stenosed opening seen in large majority of cases necessitate some
      form of surgical correction. A variety of surgical procedures like cutback,
      posterior anal transposition, PSARP, or ASAPR, with or without diverting
      colostomy have been described in the literature. However, in dealing with a case
      of ectopic anus, the authors thought a much simpler surgical correction would
      suffice giving an aesthetically and functionally acceptable perineum. This new
      and simple surgical procedure developed by Ashok Shah, Anal Shift is described in
      this report. METHODS: Twelve female infants with anterior ectopic anus, between 3
      and 18 months of age who had undergone surgical correction by this new method
      (Anal Shift) is reported. Five of these children had severe and 2 had mild anal
      stenosis. The new technique described in detail includes shifting and creation of
      a new anus in the anatomically normal site and construction of the perineal body.
      Colostomy was not done in any of them. RESULTS: The cases had been followed up
      for 12 to 24 months. Anal function was normal with satisfactory vulvo-anal
      distance without any stenosis. One patient had superficial anterior wound
      dehiscence; she underwent reoperation with good results. CONCLUSIONS: Anal Shift
      is a simple surgical procedure. It does not necessitate lateral dissection,
      therefore, the rectal support and the neurovascular supply to the rectum remains
      undisturbed, eliminating any chance of retraction. The anterior half of the
      neoanus does not have a suture line, thereby minimizing the chances of stricture
      formation. Anal Shift appears to be a safe, simple and satisfactory surgical
      procedure to correct anterior ectopic anus in girls without a colostomy.

PMID- 12596103
TI  - Cellular mechanisms of interleukin-12-mediated neuroblastoma regression.
AB  - BACKGROUND/PURPOSE: Interleukin-12 (IL-12) is a proinflammatory cytokine with
      potent antitumor effects. Previous studies from the authors laboratory showed
      regression of established neuroblastoma in mice vaccinated with IL-12 transduced
      dendritic cells (DC). Although regression was associated with intense T cell
      infiltration, the precise role of T cells is unknown. The purpose of this work is
      to study the cellular mechanisms in IL-12-mediated tumor regression. METHODS:
      Three groups of mice (n = 12) received subcutaneous inoculation with 1 x 10(6)
      murine neuroblastoma cells (TBJ). Anti-CD4 (T helper), anti-CD8 (T cytotoxic), or
      antiasialo-GM1 (natural killer) antibodies were injected intravenously at 3-day
      intervals to deplete various immune effector cell populations. Mice in each
      depletion group and the control (nondepleted) group were injected intratumorally
      on day 7 with 1 x 10(6) DC IL-12-transduced DC. Tumors were harvested for
      morphometry and immunohistochemistry at 21 days. RESULTS: CD4 depletion had no
      effect on tumor growth in either control or IL-12-vaccinated animals. In
      contrast, CD8-depleted animals treated with IL-12-transduced DC underwent initial
      regression followed by progressive tumor growth (P <.01). These tumors were
      smaller in size at the same time-point. However, NK cell depletion (antiasialo
      GM1) completely abrogated the antitumor effects of IL-12-transduced DC, leading
      to progressive tumor growth from the outset. There was no difference between the
      control and treated animals in this group. CONCLUSIONS: Contrary to our
      hypothesis that IL-12 DC primarily function to stimulate a T cell-mediated
      response, these data suggest that NK cells are essential for the initial
      antitumor response of animals treated with IL-12-transduced DC. CD8+ T cells
      appear to be necessary effector cells for complete rejection of tumor and
      possibly memory. NK cells are responsible for the early immune response.
      Furthermore, CD4+ (T helper) cells did not play any role in IL-12-induced
      regression. These results imply that for DC to generate an effective antitumor
      response against neuroblastoma both acquired and innate effector cells are
      required.

PMID- 12596104
TI  - Expression of PPAR-gamma is correlated with the clinical course of neuroblastoma.
AB  - BACKGROUND/PURPOSE: Neuroblastoma is a common pediatric tumor of the sympathetic
      nervous system. Unlike the ones found in older children, the tumors found in
      patients younger than one year of age often show spontaneous differentiation and
      regression. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a
      member of the nuclear hormone receptor superfamily is expressed in several human
      cancers. Recently, PPAR-gamma has been reported to be expressed in neuroblastoma,
      and the agonist of this receptor caused differentiation of neuroblastoma cells.
      METHODS: In this report we studied the expression of PPAR-gamma mRNA, using
      LightCycler in neuroblastoma samples diagnosed in 17 patients under the age of
      one year. RESULTS: Twelve samples showed PPAR-gamma mRNA expression. There was no
      significant difference in the PPAR-gamma mRNA expression based on age, histology,
      staging, and DNA ploidy. The PPAR-gamma mRNA expression level was significantly
      correlated with the change in urinary vanillyl mandelic acid (VMA). The
      neuroblastoma samples resected from patients who showed a decrease in their
      urinary VMA before the operation showed significantly higher PPAR-gamma
      expression than those from patients who showed an increase in their urinary VMA
      before the operation. CONCLUSIONS: PPAR-gamma may have played a role in the
      reduction of VMA and possibly in the regression of early-onset neuroblastoma.

PMID- 12596105
TI  - Serum insulinlike growth factor-I in biliary atresia.
AB  - BACKGROUND/PURPOSE: Low level of Insulinlike growth factor-I (IGF-I) has been
      reported in children with chronic liver disease like biliary atresia (BA)
      awaiting liver transplantation. However, there has been no report on IGF-I in BA
      managed without liver transplantation. METHODS: The authors measured IGF-I and
      growth hormone (GH) in 21 postoperative BA, and 17 choledochal cysts (CC) as a
      control with normal liver function. To avoid an influence of aging, IGF-I was
      analyzed after converting them into a newly defined index "IGF%." IGF% is
      proportional to the lower limit of the value of IGF-I in gender- and age-matched
      normal control previously reported in literature. RESULTS: IGF% in BA was
      significantly lower than that in CC. IGF% tended to be lower in Kasai's type III
      (atresia at the porta hepatis) and higher in the jaundice-free group. IGF% in
      patients with esophageal varices was significantly lower. The correlation between
      choline esterase and IGF% was positive and that for TTT and IGF% was negative.
      CONCLUSIONS: Low level of IGF-I is a characteristic finding in BA, especially in
      patients without need of liver transplantation. And it may reflect the severity
      of pathologic changes (ie, hepatic fibrosis and reduced volume of normally
      functioning liver) in BA liver.

PMID- 12596106
TI  - Isolation and identification of biofilm microorganisms from silicone gastrostomy
      devices.
AB  - BACKGROUND/PURPOSE: Silicone gastrostomy devices (tubes and "buttons") are used
      extensively for long-term feeding and administration of special diets and
      medications. However, their potential for harboring microorganisms and possibly
      compromising the host largely is unknown. This study was conducted to isolate and
      identify the microbial species in viable biofilms attached to these devices in a
      pediatric cohort. METHODS: A total of 78 domains on 18 silicone gastrostomy
      devices (12 "buttons" and 6 tubes converted to skin level devices), previously
      used for feeding (3 to 47 months) in children ranging in age from 6 months to 17
      years were analyzed for microbial content. Biofilms were removed from the
      silicone tube surfaces and inoculated into enriched nutrient media using standard
      procedures. Intact biofilms also were observed using scanning electron microscopy
      (SEM) and confocal scanning laser microscopy. RESULTS: All devices analyzed in
      this investigation were found to exhibit biofilm growth. Of the 24 identified
      bacterial species, the predominant genera included Bacillus, Enterococcus, and
      Staphylococcus. Control studies of the tubes under SEM showed a multitude of
      crevices serving as niches for microbial colonization. Observation of the
      attached biofilm by SEM showed various biomasses with numerous morphologies.
      CONCLUSIONS: Biofilm composition and attachment to silicone enteral access
      devices has not received appropriate attention previously. This study shows that
      devices are colonized with various bacteria and fungi posing a potential threat
      to patients, particularly those who are immunocompromised. These microorganisms
      also may play a significant role in the formation of granulation tissue and
      contribute to device failure.

PMID- 12596107
TI  - Testosterone therapy in microphallic hypospadias: topical or parenteral?
AB  - BACKGROUND/PURPOSE: Local or systemic application of testosterone is reported to
      stimulate penile growth. Intramuscular testosterone has been found to be
      effective in 50% of patients; however, variable results have been reported with
      topical testosterone. The current study is an attempt to compare the efficacy of
      intramuscular versus topical testosterone application. METHODS: A total of 26
      consecutive patients with hypospadias and small penis (<2SD for given age) were
      studied prospectively. These patients were recruited alternately into group A or
      group B. Each group consisted of 13 patients. In group A, penile growth was
      accomplished by topical application of testosterone (Testoviron, oily solution
      containing testosterone propionate, 25 mg, and testosterone enanthate, 110 mg,
      equivalent to about 100 mg of testosterone, Schering, Germany) with a dose of 2
      mg/kg/wk, for 3 weeks. While in group B, testosterone (same preparation as above)
      was administered by intramuscular injection weekly for 3 consecutive weeks.
      Penile length, diameter, and secondary effects were recorded before, during, and
      3 weeks after the therapy by a single observer. RESULTS: Significant penile
      growth (P <.01) was noticed in both the groups of patients when compared with
      pretherapy with maximum response observed during the third week of therapy
      (reaching from an average pretherapy length of 2.0 cm and 1.8 cm to 3.18 cm and
      3.11 cm posttherapy in group A and B patients, respectively). Seven patients in
      each group had growth of at least 50% compared with the initial size. The basal
      serum testosterone was within the normal range in both the groups. During therapy
      the serum testosterone was elevated above the basal level in all patients, but
      within the normal range except in 2 patients of group A. In these 2 children the
      serum testosterone level crossed the normal range. Linear growth did not alter
      significantly for the chronological age. Two patients of group A went on to have
      pubic hair, one of them had elevated testosterone level above the normal range.
      There was a surge in serum testosterone in all children, although significant
      penile enlargement was observed in 60% children in group A and 75% in group B.
      CONCLUSIONS: Although the desired therapeutic effect of testosterone was achieved
      in both the groups, this study failed to show any significant difference between
      the 2 routes of administration. However, in group A, (topical) serum testosterone
      crossed the normal range in 15% of patients and was associated with significant
      reversible side effects.

PMID- 12596108
TI  - Ultrasonographic diagnosis for potential contralateral inguinal hernia in
      children.
AB  - PURPOSE: The authors describe the diagnostic approach and the reliability of the
      diagnosis using their ultrasonographic classification for potential contralateral
      inguinal hernia in children. METHODS: In children presenting with unilateral
      inguinal hernia, the contralateral processus vaginalis in the inguinal canal was
      examined preoperatively by ultrasonography with a 10-MHz transducer. The
      findings, with increment and decrement of the intraabdominal pressure, were
      categorized into 6 types as follows: type I, the intraabdominal organ is observed
      in the inguinal canal; type II, the patent processus vaginalis (PPV) is seen
      cystlike at the internal ring of the inguinal canal; type III, the PPV is widened
      with abdominal pressure increment (the length of the PPV is longer than 20 mm);
      type IV, the PPV contains moving fluid without PPV widening; type V, the PPV is
      widened with abdominal pressure increment (the length is shorter than 20 mm);
      type VI, others. Types I through IV were regarded as potential candidates for
      inguinal hernia. The diagnostic performance of the clinical examination, with or
      without the assistance of ultrasonography was analyzed retrospectively. RESULTS:
      The development rates of contralateral inguinal hernia following unilateral
      herniorrhaphy, before and after application of ultrasonographic diagnosis, were
      10.2% (28 of 274 cases) and 1.5% (4 of 271 cases), respectively. The difference
      was statistically significant according to Fisher's Exact probability test.
      CONCLUSIONS: Contralateral herniorrhaphy should be performed on inguinal hernia
      candidates when ultrasonography shows types I through IV.

PMID- 12596109
TI  - Magill forceps extraction of upper esophageal coins.
AB  - BACKGROUND/PURPOSE: This study demonstrates a minimally invasive technique for
      upper esophageal coin extraction. METHODS: A retrospective review was conducted
      of 36 children who had upper esophageal coins extracted using a Magill forceps.
      RESULTS: All coins were removed without complication in approximately 45 seconds
      (33 on the first attempt, 3 on the second attempt). CONCLUSIONS: This technique
      minimizes instrumentation of the esophagus and is highly successful at removing
      coins lodged at or immediately below the level of the cricipharyngeus muscle.

PMID- 12596110
TI  - Evaluation of bone mineral density with dual x-ray absorptiometry for
      osteoporosis in children with bladder augmentation.
AB  - BACKGROUND/PURPOSE: Osteoporosis can appear as a result of metabolic acidosis in
      patients with bladder augmentation and total bladder replacement. These patients
      must be monitored for early diagnosis and osteoporosis to avoid related
      complications such as fracture. The current method for diagnosis of osteoporosis
      mainly involves bone densitometry. Dual x-ray absorptiometry (DXA) provides bone
      mineral content and bone mineral density (BMD). The purpose of this report is to
      determine the value of BMD measurement with DXA in the diagnosis and follow-up of
      osteoporosis and evaluation of response to treatment in the patients with bladder
      augmentation and total bladder replacement. METHODS: Six patients with bladder
      extrophy and neurogenic bladder underwent colocystoplasty, ureterocystoplasty,
      and total bladder replacement. The Sigmoid colon segment was used for
      colocystoplasty. DXA (Hologic 2000 DXA) was used for measuring bone mineral
      content and density. Results for lumbar spinal BMD were expressed as the average
      of L1 through L4 values. Each patient's BMD was compared with the mean BMD in the
      young normal population (T score) and in the age- and sex-matched group (Z
      score). But because our patients were children, BMD was evaluated according to Z
      score. Arterial blood gas analysis was obtained periodically with BMD
      measurement. Arterial blood pH and HCO(3) levels of the patients were compared
      with normal values, which ranged from 7.35 to 7.45 for pH and from 22 to 27
      mmol/L for HCO3. RESULTS: Arterial blood pH of 5 of 6 patients (83.3%) and HCO3
      levels of all patients were low. Ten BMD measurements were obtained for 6
      children. One patient underwent BMD measurement 3 times, 2 patients underwent
      twice, and the others once. Z scores of 4 of 6 patients (66.6%) were decreased.
      Blood pH, HCO3 level, and BMD of 2 patients increased after oral bicarbonate
      intake. Two patients had normal BMD. One of these patients had
      ureterocystoplasty. The other had undergone colocystoplasty but was incontinent.
      CONCLUSIONS: Intestinal segments have been used for bladder augmentation and
      total bladder replacement. Exposure of highly absorptive intestinal mucosa to
      urine has been associated with electrolyte abnormalities and metabolic acidosis.
      Hyperchloremic acidosis leads to bone demineralization. DXA provides bone mineral
      content and BMD for diagnosis of osteoporosis. DXA is preferred because the low
      radiation dose (average, 2 to 4 mrem), accuracy, low price, and short examination
      time. Not only can BMD confirm the diagnosis of osteoporosis, but it also can be
      used to monitor the course of the disease and the effectiveness of treatment.

PMID- 12596111
TI  - Omental infarction: risk factors in children.
AB  - PURPOSE: A series of 4 cases of omental infarction are analyzed. It is shown that
      obesity, as well as idiosyncratic anatomy, are factors in the development of this
      rare clinicopathologic entity. METHODS: The authors reviewed the preoperative and
      operative records of all patients. RESULTS: All of the cases of omental
      infarction were seen in obese children. Other than persistent right-sided
      abdominal pain, there were no other signs or symptoms. None of the patients had
      an elevated white blood cell count, and none had fever. CONCLUSIONS: Computed
      tomography scanning is noted to be helpful in making the diagnosis. Laparoscopy
      is noted to be the procedure of choice, because standard incisions may preclude
      one from a proper exploration.

PMID- 12596112
TI  - Appendicitis in children: a ten-year update of therapeutic recommendations.
AB  - BACKGROUND/PURPOSE: In 1990, the authors reported excellent outcomes using a
      standard protocol to treat pediatric appendicitis. This protocol has been
      simplified further and a large retrospective review was conducted to assess
      current outcomes. METHODS: All patients treated for presumed appendicitis between
      April 1997 and December 1999 were reviewed. All patients received preoperative
      gentamicin and clindamycin. Patients with complicated appendicitis received
      postoperative ampicillin, gentamicin, and clindamycin or metronidazole. All
      wounds were closed primarily without drains. Patients with complicated
      appendicitis were discharged when their ileus resolved, they remained afebrile
      for 24 hours, and had a normal leukocyte count. RESULTS: A total of 648 patients
      were reviewed. A total of 9.4% of appendices were pathologically normal, 55.6%
      were simple acute, 15.7% were gangrenous, and 19.3% were perforated. Hospital
      stay was 2.21 +/- 2.04 days for normal, 1.39 +/-.89 for simple acute, 2.97 +/-
      1.25 for gangrenous, and 6.31 +/- 3.51 days for perforated appendices. There were
      no wound infections in patients with normal or simple acute appendices. Two minor
      intraabdominal infections (0.56%) occurred in patients with simple appendicitis.
      Patients with complicated appendicitis (gangrenous or perforated) had wound
      infection and intraabdominal infection rates of 2.6% and 4.4%, respectively.
      CONCLUSIONS: The authors' current protocol results in reasonable hospital stays
      and good outcomes. It serves as an evidence-based standard of care for the
      treatment of pediatric appendicitis.

PMID- 12596113
TI  - Intrapancreatic gastric duplication cyst presenting as lower gastrointestinal
      bleeding.
AB  - This report describes a rare foregut malformation of a noncontiguous gastric
      duplication cyst embedded within the body and tail of the pancreas. An 8-month
      old boy presented with massive malena of 3 days' duration. The laparotomy showed
      an intrapancreatic cyst with bleeding and ulcer perforation into a loop of
      adherent jejunum. Histologically, the cyst contained gastric mucosa. This is
      believed to be the first reported instance of an intrapancreatic gastric
      duplication causing massive lower gastrointestinal bleeding in an infant.

PMID- 12596114
TI  - Malignant stromal tumor of the colon in an infant: diagnostic difficulties and
      differential diagnosis.
AB  - Gastrointestinal stromal tumor is a rare pathology in childhood. It may occur
      anywhere along the alimentary tract and represents with a wide spectrum of signs
      and symptoms according to location. An infant with malignant colonic stromal
      tumor that has presented with a huge abdominal mass and lower gastrointestinal
      bleeding is reported to discuss the difficulties in diagnosis and differential
      diagnosis of this unusual tumor.

PMID- 12596115
TI  - Newborn with an open posterior hip dislocation and sciatic nerve injury after
      intrauterine radiofrequency ablation of a sacrococcygeal teratoma.
AB  - Advanced prenatal ultrasonography techniques have allowed for better
      understanding of the natural history, treatment, and prognosis of sacrococcygeal
      teratomas. Several intrauterine surgical techniques to debulk the tumor when
      fetal and maternal life are in jeopardy have been described. Orthopaedic
      impairment, such as lower extremity weakness and swelling, also has been
      described in association with sacrococcygeal teratomas. The authors report on a
      newborn in whom a large soft tissue defect overlying the posterior hip region
      with direct exposure of the disarticulated hip joint existed at the time of
      birth, which resulted from intrauterine radiofrequency ablation of a
      sacrococcygeal teratoma. This unexpected complication has resulted in a loss of
      sciatic nerve function, malformation of the acetabulum and femoral head, and loss
      of the left ischium, coccyx, inferior sacrum, gluteal, adductor and piriformis
      muscles, and posterior hip capsule. At 16 months of age, the patient has a
      flaccid left lower extremity with a hypoplastic hip joint.

PMID- 12596116
TI  - Octreotide-induced hypoxemia and pulmonary hypertension in premature neonates.
AB  - The authors report 2 cases of premature neonates who had enterocutaneous fistula
      complicating necrotizing enterocolitis. Pulmonary hypertension developed after
      administration of a somatostatin analogue, octreotide, to enhance resolution of
      the fistula. The authors discuss the mechanism of the occurrence of this
      complication and recommend caution of its use in high-risk premature neonates.

PMID- 12596117
TI  - Total pneumonectomy as a salvage procedure for pulmonary arteriovenous
      malformation in a newborn: report of one case.
AB  - Pulmonary arteriovenous malformations are infrequent lesions diagnosed rarely in
      the neonatal period. A case of arteriovenous malformation involving an entire
      lung in a newborn is described. Because of an untractable cyanosis with heart
      failure, an emergency left total pneumonectomy had to be done at 18 hours of
      life. Cyanosis disappear immediately, and the newborn recovered normal cardiac
      function.

PMID- 12596118
TI  - Obstructive jaundice caused by primary choledochal hydatid cyst mimicking
      radiologically choledochal cyst.
AB  - A 12-year-old girl with obstructive jaundice that was initially misinterpreted
      radiologically as having choledochal cyst is presented. A primary hydatid cyst in
      the wall of the common bile duct causing obstruction was found at operation. The
      authors emphasize that hydatid cyst should be included in the list of
      differential diagnoses of obstructive jaundice and cystic lesions located around
      the biliopancreatic junction in children.

PMID- 12596119
TI  - Teratoid Wilms' tumor: report of a unilateral case.
AB  - Teratoid Wilms' tumor is a rare histologic variant of the classical Wilms' tumor,
      containing predominantly heterologous tissues (adipose, glial, muscle, cartilage,
      or bone). This report presents the case of a teratoid Wilms' tumor in a 4-year
      old girl. The mass, which originated from the right kidney, was very large and
      encased the inferior vena cava and renal vessels. The child did not respond to
      chemo- or radiotherapy and underwent operation. Despite the enormous dimensions
      of the tumor and the involvement of the inferior vena cava, a radical excision
      was obtained, and now the child is well 32 months after surgery. The behavior of
      this kind of tumor usually is not aggressive, and the outcome is good. Surgery
      should be the treatment of choice, because the efficacy of chemotherapy and
      radiotherapy is probably reduced by the high amount of differentiated and mature
      tissue which characterizes this neoplasm.

PMID- 12596120
TI  - MURCS association and rectovestibular fistula: case report of a patient treated
      with one-stage posterior sagittal anorectoplasty and sigmoid loop vaginoplasty.
AB  - MURCS association is rare, first described by Duncan in 1979, including nonrandom
      association of Mullerian duct aplasia or hypoplasia (MU), renal agenesis or
      ectopy (R), and cervicothoracic somite dysplasia. A 5-year-old girl was admitted
      to the clinic with a complaint of anteriorly located anus. Physical and
      radiologic examination of the patient found MURCS association with anorectal
      malformation (ARM) of rectovestibular-type fistula. She had multiple vertebral
      anomalies, left renal agenesis, vaginal and uterine agenesia, with a normal
      female 46,XX karyotype. Posterior sagittal anorectoplasty (PSARP) and sigmoid
      loop vaginal reconstruction was performed as a one-stage operation for the
      treatment of vaginal agenesis and ARM. There were no complications in the
      postoperative period. This combined one-stage operation can be used easily in the
      treatment of some components of the MURCS association such as vaginal agenesis
      and ARM as an associated anomaly.

PMID- 12596121
TI  - Duplication of pouch colon associated with duplication of the lower genitourinary
      tract.
AB  - The authors report on a baby with imperforate anus associated with duplication of
      descending colon, double pouch colon type IV, duplication of the urinary bladder,
      and a bifid penis. The interesting presentation of this problem and its
      management is discussed with a brief review of the probable embryologic basis for
      such an anomaly. Such a duplication of pouch colon has not been described
      previously.

PMID- 12596122
TI  - Bronchopulmonary foregut malformation: a large bronchogenic cyst communicating
      with an esophageal duplication cyst.
AB  - A 1-year-old boy with a bronchopulmonary foregut malformation presented with a
      large mediastinal bronchogenic cyst associated with pulmonary sequestration, a
      cervical esophageal duplication cyst, a bronchial communication between these
      cysts, and 2 small bronchogenic cysts around the communication. These lesions
      were resected followed by an uneventful recovery.

PMID- 12596123
TI  - Atypical parasitic ischiopagus conjoined twins.
AB  - Occurrence of asymmetrical or parasitic conjoined twins (CT) is rare, and
      currently they are classified analogically to the common unions of symmetrical
      CT. The authors report on an infant with a parasitic third limb attached to the
      left lateral aspect of the autosite trunk, in whom male gonadal tissue was found
      histologically. Parasite parts included complete left lower limb, hemipelvis,
      lumbosacral vertebral column, spinal cord, and one kidney with ureter and adrenal
      gland. Autosite anomalies comprised a small left diaphragmatic defect,
      omphalocele, exstrophy of cloaca, and lumbar meningomyelocele. The authors
      considered this case to be a rare atypical parasitic ischiopagus CT. The
      differential diagnosis of the type of twining and other entities with caudal
      duplications is analyzed briefly.

PMID- 12596124
TI  - Aplasia cutis cerebri with partial acrania--total reconstruction in a severe case
      and review of the literature.
AB  - BACKGROUND: Aplasia cutis cerebri with partial acrania is a rare anomaly that can
      involve the epidermis, dermis, and subcutaneous tissues of the scalp with
      significant bone defect. METHODS: The authors present the first successful report
      of providing one-stage complete cover in a case of aplasia cutis cerebri with
      major skull defect by using local rotational flaps. Also presented is a review of
      literature. RESULTS: The newborn had a receding forehead and a large scalp defect
      from frontal to occipital bone measuring 10 x 8 cm2 involving full thickness of
      cranium centrally, thereby exposing the dura. Local rotation flaps were raised
      from the scalp to cover the 10- x 8-cm2 defect. The edges of the defect were
      showing granulation tissue with ingrowth of epithelium. Partial-thickness skin
      grafts were used to cover the raw area left at the nape of the neck after raising
      the rotation flaps. The child was discharged on the 19th postoperative day.
      CONCLUSIONS: Aplasia cutis cerebri with partial acrania, as in our case, has a
      high mortality rate secondary to infection or to hemorrhage from ulceration of
      the sagittal sinus. The successful outcome of our one-stage local rotational
      scalp flap technique provided complete cover to this major scalp defect. This
      technique will definitely improve the management of this complex disorder keeping
      the morbidity to the minimum.

PMID- 12596125
TI  - Neonatal periappendicular abscess--updated treatment.
AB  - The authors present a case of periappendicular abscess in a 5-day-old full-term
      neonate. Prompt diagnosis enabled us to deliver conservative treatment followed
      by interval laparoscopic appendectomy, instead of a risky urgent laparotomy. This
      is the first description of an advanced imaging-guided drainage procedure,
      followed by minimal invasive surgery, for the treatment of periappendicular
      abscess at such a young age.

PMID- 12596126
TI  - Chronic inspiratory stridor secondary to a retained penetrating radiolucent
      esophageal foreign body.
AB  - Although foreign body ingestions are common in infants and young children,
      penetration of the esophagus is a relatively rare event. Timely diagnosis is
      impeded by the absence of classical symptoms and by the ingestion of radiolucent
      foreign bodies. The authors present a 17-month-old girl with a 6-month history of
      inspiratory stridor. An extensive workup found a penetrating radiolucent foreign
      body at the thoracic inlet.

PMID- 12596127
TI  - Two-channel method for retrieval of gastric trichobezoar: report of a case.
AB  - Large gastric trichobezoars usually are difficult to remove gastroscopically
      without gradual fragmentation. Surgical retrieval of trichobezoars may be
      recommended, which requires laparotomy and gastrotomy. The authors report a case
      in which an 11-year-old girl with a trichobezoar underwent successful removal
      using gastroscopy with laparoscopically assisted fragmentation.

PMID- 12596129
TI  - Cross-cultural comparison of perianesthesia nursing: challenges encountered in
      the PACU.
AB  - Nurses often consider caring for the pediatric patient in the PACU stressful.
      This stress may be compounded when providing this care in a foreign country. This
      article compares and contrasts the challenges experienced by one nurse when
      working in both Russia and China as a PACU nurse for the volunteer group,
      Operation Smile. Topics discussed in this article include the physical setup of
      the PACU; safety issues within the PACU; and the importance of communication,
      pain management, and parents within the PACU. The author elaborates on how to
      provide safe, competent, and culturally sensitive care to children within the
      PACU setting.

PMID- 12596130
TI  - Factors affecting nurses' decisions to join and maintain membership in
      professional associations.
AB  - Large organized associations are the most effective tools for the nursing
      profession for influencing policies that protect the members and continues to
      provide the highest quality nursing care to the public. Although nursing
      comprises the largest number of health care workers in the country, fewer and
      fewer nurses are joining the professional associations that represent them. This
      study explores factors affecting the membership decisions of nurses practicing in
      the perianesthesia setting. Surveys were mailed to a random sample of current and
      former members of ASPAN. All participants identified variables that affected
      their decision to join their professional association. Nonmembers were asked to
      identify reasons for not renewing membership. The variables most strongly
      influencing members and nonmembers to join ASPAN were self-improvement,
      education, new ideas, programs, professionalism, validation of ideas, improvement
      of my profession, improvement of my work, and maintenance of professional
      standards. The only variable that was rated statistically significantly higher by
      current members was "improvement of my work." All other 28 variables rated in the
      study were scored similarly by both groups, indicating that members and
      nonmembers continue to possess the same professional values. Former members
      indicated that major deterrents to membership were cost and lack of time. In an
      economic and cultural environment that requires balancing multiple demands,
      professional associations need to consider the limited time available to nurses
      and examine ways to provide professional development opportunities that are more
      easily accessible.

PMID- 12596131
TI  - Latex allergies in the health care worker.
AB  - A dramatic increase in the incidence of latex allergies in health care workers
      followed the surge in latex glove use accompanying the rise of human
      immunodeficiency virus (HIV) in the early 1980s. This increase in latex glove use
      was driven by the release of Universal Precautions issued by the Centers for
      Disease Control (CDC) in response to the rise of HIV and other blood-borne
      pathogens. Efforts to stem allergic responses in the workplace have relied on the
      substitution of other materials for latex. Unfortunately, there is so much latex
      in everyday life that avoiding this allergen is exceedingly difficult once one is
      sensitized. Additionally, there are numerous cross reactants that are present in
      the environment. The situation is further confounded by the introduction of
      genetically manipulated foods and agricultural products that contain defense
      proteins genetically inserted to protect plants from pests and pathogens. Many of
      these defense proteins are antigens that will cross react with latex. Sensitivity
      reactions, once developed, may progress to the point at which the health care
      worker is excluded from working. This report provides an overview of rubber
      products and cross reactants, allergic reactions, and latex sensitivity for the
      health care worker.

PMID- 12596133
TI  - Conflict, communication, and collaboration: Improving interactions between nurses
      and physicians.

PMID- 12596132
TI  - The postanesthesia care of an adult renal transplant recipient.
AB  - Renal transplantation is the most common type of solid organ transplant performed
      in this country. For the PACU nurse, the immediate postoperative care of a renal
      transplant recipient can present a very unique and interesting challenge. Like
      all patients arriving to the PACU, the initial assessment of an immediate
      postoperative renal transplant recipient should first address the routine
      postsurgical concerns of airway, respiration, and hemodynamics. Most renal
      transplant programs have set protocols for the care required during the immediate
      posttransplant stay in the PACU. The postanesthesia nurse caring for these
      patients must become knowledgeable of these protocols. The following is a review
      of the immediate postanesthesia care for both the "fresh" renal transplant and
      the care of the long-term renal transplant recipient who has had surgery.

PMID- 12596134
TI  - How satisfied is your patient? The service side of care delivery: part 2.

PMID- 12596135
TI  - Accountability for pain relief: Use of comfort-function goals.

PMID- 12596136
TI  - The word at our fingertips: internet resources for nursing research.

PMID- 12596137
TI  - Disparity of health care.

PMID- 12596140
TI  - What is the nature of the first-formed intermediates in the electrophilic
      halogenation of alkenes, alkynes, and allenes?
AB  - The pi complexes first formed as essential intermediates from alkenes, alkynes,
      and allenes with bromine have been investigated in different solvents by UV
      spectroscopy in combination with stopped-flow techniques allowing the
      determination of the equilibrium constants, K(f). Using alkenes with sterically
      protected double bonds, such as di-tert-butylstilbene and tetraneopentylethylene,
      the reaction stops at the stage of the 1:1 and 1:2 pi complex of the alkene with
      bromine as persistent species in 1,2-dichlorethane as solvent. Calculations by
      state-of-art ab initio and DFT methods reproduces the experimentally determined
      thermodynamic values quite well, and reveal the preferred structures and nature
      of both complexes for ethene, ethyne, and allene. Consideration of the entropy
      term reveals that complexes are stabilized in solution owing to reduction of the
      entropy loss by restricted translations and rotation. According to calculations
      these species are Mulliken-outer-type complexes with no or little charge transfer
      from bromine to the double or triple bond, respectively. The 1:2 complex has a
      close structural relationship to the bromonium- or bromirenium ion, which is the
      subsequent intermediate on the reaction coordinate. Steric influences show a
      strong effect on the K(f) value, which can be explained by the polarizibility of
      the parent system. Addition-elimination often occurs. In bromination of
      adamantylidenadamantane and its derivatives the reaction stops at the stage of
      the bromonium ion. The effect of various polar groups situated in equatorial
      homoallyl positions on the stability of corresponding pi complex and bromonium
      ion has been studied in this series.

PMID- 12596141
TI  - Catalytic hydrogenation by triruthenium clusters: a mechanistic study with
      parahydrogen-induced polarization.
AB  - The reactivity of the cluster family [Ru(3)(CO)(12-x)(L)(x)] (in which L=PMe(3),
      PMe(2)Ph, PPh(3) and PCy(3), x=1-3) towards hydrogen is described. When x=2,
      three isomers of [Ru(3)(H)(mu-H)(CO)(9)(L)(2)] are formed, which differ in the
      arrangement of their equatorial phosphines. Kinetic studies reveal the presence
      of intra- and inter-isomer exchange processes with activation parameters and
      solvent effects indicating the involvement of ruthenium-ruthenium bond
      heterolysis and CO loss, respectively. When x=3, reaction with H(2) proceeds to
      form identical products to those found with x=2, while when x=1 a single isomer
      of [Ru(3)(H)(mu-H)(CO)(10)(L)] is formed. Species [Ru(3)(H)(mu-H)(CO)(9)(L)(2)]
      have been shown to play a kinetically significant role in the hydrogenation of an
      alkyne substrate through initial CO loss, with rates of H(2) transfer being
      explicitly determined for each isomer. A less significant secondary reaction
      involving loss of L yields a detectable product that contains both a pendant
      vinyl unit and a bridging hydride ligand. Competing pathways that involve
      fragmentation to form [Ru(H)(2)(CO)(2)(L)(alkyne)] are also observed and shown to
      be favoured by nonpolar solvents. Kinetic data reveal that catalysis based on
      [Ru(3)(CO)(10)(PPh(3))(2)] is the most efficient although [Ru(3)(H)(mu
      H)(CO)(9)(PMe(3))(2)] corresponds to the most active of the detected
      intermediates.

PMID- 12596142
TI  - A novel extended covalent tripod for assembling nine-coordinate lanthanide(III)
      podates: a delicate balance between flexibility and rigidity.
AB  - The introduction of long semirigid spacers between the capping carbon atom of the
      tripod and the unsymmetrical tridentate binding units provides the novel,
      extended covalent podand tris-[2-[2-(6-diethylcarbamoylpyridin-2-yl)-1-ethyl-1H
      benzoimidazol-5-yl-methoxy]ethyl]methane (L(15)). Reaction of L(15) with
      lanthanide(III) in acetonitrile produces stable podates [Ln(L(15))](3+) (Ln=La
      Lu) in which three tridentate binding units are facially organized. These wrap
      around the nine-coordinate pseudo-tricapped trigonal-prismatic metal ions. The
      crystal structure of [La(L(15))](ClO(4))(3) (18, LaC(67)H(82)N(12)O(18)Cl(3),
      trigonal, R3c, Z=6) reveals the formation of a C(3)-symmetrical triple-helical
      podate. Two slightly different arrangements of the flexible ethylenoxy parts of
      the spacer are observed in the solid state in agreement with the formation of two
      conformational isomers (M:m) in a 4:1 ratio. A qualitative analysis of the
      aromatic diamagnetic anisotropies affecting the NMR signals of [Ln(L(15))](3+)
      (Ln=La, Y, Lu) in solution, combined with the quantitative determination of
      electron-induced relaxation in the paramagnetic complex [Nd(L(15))](3+),
      demonstrate that the solid state structure is maintained in solution. This leads
      to a mixture of two triple-helical conformers of similar stabilities and that do
      not interconvert on the NMR timescale between 243 and 343 K. Particular attention
      has been given to the structural programming of extended covalent tripods for
      facially organizing unsymmetrical tridentate binding units around Ln(III).
      Photophysical measurements show that L(15) efficiently protects the metallic
      coordination spheres and sensitizes Eu(III) and Tb(III) upon UV irradiation.

PMID- 12596143
TI  - Experimental and theoretical charge density study of the neurotransmitter
      taurine.
AB  - The experimental electron density distribution in taurine, 2-aminoethane sulfonic
      acid, 1, has been determined from high-resolution X-ray diffraction data
      collected at a temperature of 100 K. Taurine crystallizes as a zwitterion in the
      monoclinic space group P2(1)/c. Topological analysis of the experimental electron
      density and a comparison with high-level theoretical gas-phase calculations show
      that the crystal environment has a significant influence on the electronic
      configuration of the sulfonate moiety in 1, which in the crystal is more
      delocalized than in the gas phase. This crystal effect is mainly due to hydrogen
      bonding.

PMID- 12596144
TI  - Synthesis of alpha-(2-->5)Neu5Gc oligomers.
AB  - A facile synthesis of the sialic acid oligomers alpha-(2-->5)Neu5Gc (1) is
      presented. Monosaccharides 2-4 with suitable functionality were used as the
      building blocks. After selective removal of the paired carboxyl and amine
      protecting groups, the fully protected oligomers were assembled through
      consecutive coupling of the building blocks by well established peptide coupling
      techniques. By this approach, fully protected oligomers as large as an
      octasaccharide were synthesized. Deprotection of these fully protected oligomers
      was conducted in two steps (LiCl in refluxing pyridine and 0.1 n NaOH) to afford
      the desired products in high yield. Enzymatic degradation of the octamer with
      neuraminidase, monitored by capillary electrophoresis (CE), was also
      accomplished. The stepwise exo-cleavage adducts were all well separated and
      identified in the CE spectrum. The strategy described here for solution-phase
      synthesis also provides the basis for future solid-phase synthesis of poly-alpha
      (2-->5)Neu5Gc.

PMID- 12596145
TI  - Solid-phase synthesis of the cyclic lipononadepsipeptide [N-Mst(Ser1), d-Ser4, L
      Thr6, L-Asp8, L-Thr9]syringotoxin.
AB  - An optimized solid-phase strategy for the preparation of the cyclic
      lipononadepsipeptide [N-Mst(L-Ser1), D-Ser4, L-Thr6, L-Asp8, L-Thr9]syringotoxin
      is reported. The strategy is based on the use of a mild orthogonal protection
      scheme and the incorporation of the nonproteinogenic amino acid (Z)-Dhb into the
      peptide chain as the dipeptide Fmoc-Thr(tBu)-(Z)-Dhb-OH. The didehydrodipeptide
      was synthesized by a water-soluble carbodiimide-induced beta-elimination of a
      protected dipeptide containing a residue of Thr with its free hydroxy side chain
      unprotected.

PMID- 12596146
TI  - A new cryptophane receptor featuring three endo-carboxylic acid groups:
      synthesis, host behavior and structural study.
AB  - Examples of a new type of cryptophane molecule incorporating aromatic groups in
      the bridges (1-4) and, for the first time, being also supplied with three endo
      positional ionizable carboxylic acid functions (1) have been synthesized and
      characterized. The cryptophane triester 2 yielded a solvate (channel inclusion
      compound) with trichloromethane and water, the X-ray crystal structure of which
      is reported. The complexation of 1 with low-molecular-weight alcohols in solution
      was studied, and the liquid-liquid extraction of different metal ions including
      alkali (Na(+), Cs(+)), alkaline earth (Mg(2+), Ca(2+), Sr(2+), Ba(2+)), and the
      lanthanide metal ions Eu(3+) and Yb(3+) in an extraction system containing metal
      nitrate buffer/H(2)O/1/CHCl(3) was examined. Molecular modeling calculations of
      the cryptophanes 1 and 2, and of the Eu(3+) complex of 1 were carried out
      contributing to the discussion.

PMID- 12596147
TI  - An insight into the local aromaticities of polycyclic aromatic hydrocarbons and
      fullerenes.
AB  - In this work we quantify the local aromaticity of six-membered rings in a series
      of planar and bowl-shaped polycyclic aromatic hydrocarbons (PAHs) and fullerenes.
      The evaluation of local aromaticity has been carried out through the use of
      structurally (HOMA) and magnetically (NICS) based measures, as well as by the use
      of a new electronically based indicator of aromaticity, the para delocalization
      index (PDI), which is defined as the average of all the Bader delocalization
      indices between para-related carbon atoms in six-membered rings. The series of
      PAHs selected includes C(10)H(8), C(12)H(8), C(14)H(8), C(20)H(10), C(26)H(12),
      and C(30)H(12), with benzene and C(60) taken as references. The change in the
      local aromaticity of the six-membered rings on going from benzene to C(60) is
      analyzed. Finally, we also compare the aromaticity of C(60) with that of C(70),
      open [5,6]- and closed [6,6]-C(60)NH systems, and C(60)F(18).

PMID- 12596148
TI  - Instantaneous SmI2/H2O/amine-mediated reductions in THF.
AB  - The SmI(2)-mediated reductions of ketones, imines, and alpha,beta-unsaturated
      esters have been shown to be instantaneous in the presence of H(2)O and an amine
      in THF. The SmI(2)-mediated reductions are not only shown to be fast and
      quantitative by the addition of H(2)O and an amine, but the workup procedures are
      also simplified. Competing experiments with SmI(2)/H(2)O/amine confirmed that
      alpha,beta-unsaturated esters could be selectively reduced in the presence of
      ketones or imines. Comparison of analogue ligands showed that nitrogen and
      phosphorus ligands are superior to oxygen and sulfur ligands in these reductions.
      The trialkylphosphine 1,2-bis(dimethylphosphino)ethane (DMPE) provided a primary
      kinetic isotope effect, yielding a k(H)/k(D) of 4.5.

PMID- 12596149
TI  - The total synthesis of (-)-callystatin A.
AB  - Callystatin A is a prominent member of a class of natural products which display
      promising growth inhibition of cancer cells in their biological profile. The
      challenging structure and the interesting biological activity of (-)-callystatin
      A fueled our interest in the synthesis of this marine natural product. We
      achieved the total synthesis using a highly convergent approach joining four
      subunits together with a Wittig olefination, a selective Heck reaction and an
      aldol reaction as the pivotal steps. The aldol reaction as one of the final
      transformations during the synthesis opens fast access to a variety of structural
      analogues and circumvents tedious protecting group manipulations. Here we report
      an improved synthesis utilizing a modified vinyl iodide which shortens the
      synthesis by two steps. Additionally, first biological results will be reported.

PMID- 12596150
TI  - Highly sensitive amplified electronic detection of DNA by biocatalyzed
      precipitation of an insoluble product onto electrodes.
AB  - The amplified detection of a target DNA, based on the alkaline phosphatase
      oxidative hydrolysis of the soluble 5-bromo-4-chloro-3-indoyl phosphate to the
      insoluble indigo product as an amplification path, is addressed by two different
      sensing configurations. The accumulation of the insoluble product on Au
      electrodes or Au/quartz crystals alters the interfacial electron-transfer
      resistance at the Au electrode or the mass associated with the piezoelectric
      crystal, thus enabling the quantitative transduction of the DNA sensing by
      Faradaic impedance spectroscopy or microgravimetric quartz crystal microbalance
      measurements, respectively. One sensing configuration involves the association of
      a complex consisting of the target DNA and a biotinylated oligonucleotide to the
      functionalized transducers. The binding of the avidin/alkaline phosphatase
      conjugate to the sensing interface followed by the biocatalyzed precipitation
      provides the amplification path for the analysis of the target DNA. This analysis
      scheme was used to sense the target DNA with a sensitivity limit that corresponds
      to 5 x 10(-14) M. The second amplified detection scheme involves the use of a
      nucleic-acid-functionalized alkaline phosphatase as a biocatalytic conjugate for
      the precipitation of the insoluble product. Following this scheme, the
      functionalized transducers are interacted with the analyzed sample that was
      pretreated with the oligonucleotide-modified alkaline phosphatase, followed by
      the biocatalyzed precipitation as the amplification route for the analysis of the
      target DNA. By the use of this configuration, a detection limit corresponding to
      5 x 10(-13) M was achieved. Real clinical samples of the Tay-Sachs genetic
      disorder were easily analyzed by the developed detection routes.

PMID- 12596151
TI  - Structural regulation of a peptide-conjugated graft copolymer: a simple model for
      amyloid formation.
AB  - The self-assembly of peptides and proteins into beta-sheet-rich high-order
      structures has attracted much attention as a result of the characteristic
      nanostructure of these assemblies and because of their association with
      neurodegenerative diseases. Here we report the structural and conformational
      properties of a peptide-conjugated graft copolymer, poly(gamma-methyl-L
      glutamate) grafted polyallylamine (1) in a water-2,2,2-trifluoroethanol solution
      as a simple model for amyloid formation. Atomic force microscopy revealed that
      the globular peptide 1 self-assembles into nonbranching fibrils that are about 4
      nm in height under certain conditions. These fibrils are rich in beta-sheets and,
      similar to authentic amyloid fibrils, bind the amyloidophilic dye Congo red. The
      secondary and quaternary structures of the peptide 1 can be controlled by
      manipulating the pH, solution composition, and salt concentration; this indicates
      that the three-dimensional packing arrangement of peptide chains is the key
      factor for such fibril formation. Furthermore, the addition of carboxylic acid
      terminated poly(ethylene glycol), which interacts with both of amino groups of 1
      and hydrophobic PMLG chains, was found to obviously inhibit the alpha-to-beta
      structural transition for non-assembled peptide 1 and to partially cause a beta
      to-alpha structural transition against the 1-assembly in the beta-sheet form.
      These findings demonstrate that the amyloid fibril formation is not restricted to
      specific protein sequences but rather is a generic property of peptides. The
      ability to control the assembled structure of the peptide should provide useful
      information not only for understanding the amyloid fibril formation, but also for
      developing novel peptide-based material with well-defined nanostructures.

PMID- 12596152
TI  - Complexation behavior of a highly preorganized 7,7-diphenylnorbornane-derived
      macrocycle: towards the design of molecular clocks.
AB  - The syntheses of two new cyclophane hosts, 4 and 6, are described. The main
      difference between them is the higher degree of preorganization of 4 as a
      consequence of the inclusion of the 7,7-diphenylnorbornane (DPN) subunit. The
      inner cavity of 4 adopts a belt-shaped structure, while 6 has a twisted geometry.
      In the solid state, the molecules of macrocycle 6 are stacked along an axis to
      form nanotubular structures. Compounds 4 and 6 form two of the strongest
      complexes between arene cyclophanes and Ag(+) reported up to date. The silver
      cation is located inside the cavity of the macrocycles. The stability of 4.Ag(+)
      is considerably higher than that of 6.Ag(+). The additional stabilization of
      4.Ag(+) is attributed to higher preorganization of macrocycle 4. DNMR experiments
      as well as theoretical calculations carried out with 4.Ag(+) show evidence of
      Ag(+)-hopping between two different binding sites inside the macrocycle. This
      phenomenon could be the basis for the design of molecular clocks.

PMID- 12596153
TI  - A theoretical study on the complete catalytic cycle of the hetero-Pauson-Khand
      type [2+2+1] cycloaddition reaction of ketimines, carbon monoxide and ethylene
      catalyzed by iron carbonyl complexes.
AB  - The [2+2+1] cycloaddition reaction of 1,4-diazabutadienes, carbon monoxide and
      ethylene catalyzed by iron carbonyl complexes produces pyrrolidin-2-one
      derivatives. Only one of the two imine moieties is activated during the
      catalysis. The mechanism of this cycloaddition reaction is studied by density
      functional theory at the B3LYP/6-311++G(d,p) level of theory. In accordance with
      experimental results, a [(diazabutadiene)Fe(CO)(3)] complex of square-pyramidal
      geometry is used as the starting compound S of the catalytic cycle. Based on
      experimental experience, the reaction with ethylene is considered to take place
      before any interaction with carbon monoxide. According to the computational
      results, the reaction does not proceed by ligand dissociation followed by
      addition of ethylene and subsequent intramolecular activation steps but by the
      approach of an ethylene molecule from the base of the square-pyramidal complex.
      This reaction yields an intermediate I(4) in which ethylene is coordinated to the
      iron centre and a new C-C bond between ethylene and one of the imine groups is
      formed. The insertion of a terminal carbon monoxide ligand into the metal-carbon
      bond between ethylene and iron produces the key intermediate I(7). The reaction
      proceeds by metal-assisted formation of a lactam P. The catalytic cycle is closed
      by a ligand-exchange reaction in which the diazabutadiene ligand substitutes P
      with reformation of S. This reaction pathway is found to be energetically favored
      over a reductive elimination. It leads to the experimentally observed
      heterocyclic product P and a reactive [Fe(CO)(3)] fragment.

PMID- 12596154
TI  - A theoretical case study of type I and type II beta-turns.
AB  - NMR chemical shielding anisotropy tensors have been computed by employing a
      medium size basis set and the GIAO-DFT(B3LYP) formalism of electronic structure
      theory for all of the atoms of type I and type II beta-turn models. The models
      contain all possible combinations of the amino acid residues Gly, Ala, Val, and
      Ser, with all possible side-chain orientations where applicable in a dipeptide.
      The several hundred structures investigated contain either constrained or
      optimized phi, psi, and chi dihedral angles. A statistical analysis of the
      resulting large database was performed and multidimensional (2D and 3D) chemical
      shift/chemical-shift plots were generated. The (1)H(alpha-13)C(alpha),
      (13)C(alpha-1)H(alpha-13)C(beta), and (13)C(alpha-1)H(alpha-13)C' 2D and 3D plots
      have the notable feature that the conformers clearly cluster in distinct regions.
      This allows straightforward identification of the backbone and side-chain
      conformations of the residues forming beta-turns. Chemical shift calculations on
      larger For-(L-Ala)(n)-NH(2) (n=4, 6, 8) models, containing a single type I or
      type II beta-turn, prove that the simple models employed are adequate. A limited
      number of chemical shift calculations performed at the highly correlated CCSD(T)
      level prove the adequacy of the computational method chosen. For all nuclei,
      statistically averaged theoretical and experimental shifts taken from the
      BioMagnetic Resonance Bank (BMRB) exhibit good correlation. These results confirm
      and extend our previous findings that chemical shift information from selected
      multiple-pulse NMR experiments could be employed directly to extract folding
      information for polypeptides and proteins.

PMID- 12596155
TI  - Vilsmeier formylation of 5,10,15-triphenylcorrole: expected and unusual products.
AB  - 5,10,15-Triphenylcorrole (1) reacts with the Vilsmeier reagent (POCl(3)/DMF) to
      give the corresponding 3-formyl derivative 3 as the major product. The
      regioselectivity of the reaction was proven by X-ray crystallography and only
      traces of the 2-formyl isomer were observed. A more polar product is also
      observed and this compound becomes the major product when an excess of DMF is
      used for the preparation of the Vilsmeier reagent, while the formation of the 3
      formyl isomer is almost completely suppressed. X-ray crystallography allowed us
      to identify this compound as the fully substituted N-ethane bridged derivative 4,
      formed from the attack of the Vilsmeier reagent at the inner core of the
      macrocycle. This compound is unique among porphyrinoid macrocycles, and further
      confirms the peculiarity of corrole chemistry.

PMID- 12596156
TI  - Supramolecular control of two-dimensional phase behavior.
AB  - We have used directed two-component self-assembly to "pattern" organic monolayers
      on the nanometer scale at the liquid/solid interface. The ability of the scanning
      tunneling microscope to investigate structural details in these adlayers was used
      to gain insight into the two-component two-dimensional phase behavior. The
      components are symmetrically alkylated bisurea derivatives (R1-urea-spacer-urea
      R2; R1, R2=alkyl, spacer=alkyl or bisthiophene). The bisthiophene unit acts as a
      marker and its bisurea derivative (T2) is a component in all the mixtures
      investigated. By varying the position of the hydrogen-bond forming urea groups
      along the molecule and the length of the alkyl chains of the other components,
      the effect of 1) hydrogen bonding, 2) molecule length, 3) odd-even effects, and
      4) shape complementarity on the two-dimensional phase behavior was investigated.
      Insight into the effect of these parameters leads to the control of the two
      dimensional patterning: from randomly intermixed systems to phase separation.

PMID- 12596157
TI  - Atomic properties of selected biomolecules: quantum topological atom types of
      hydrogen, oxygen, nitrogen and sulfur occurring in natural amino acids and their
      derivatives.
AB  - Molecular electron densities are generated at B3LYP/6-311+G(2d,p)//HF/6-31G(d)
      level for 57 molecules, including one conformation of each naturally occurring
      amino acid and smaller derived molecules. The electron densities are partitioned
      into atomic fragments according to the approach of quantum chemical topology
      (QCT). A set of 547 unique topological atoms is obtained, containing 421
      hydrogens, 63 oxygens, 57 nitrogens and 6 sulfurs. Each atom is described by
      seven properties: volume, kinetic energy, monopole, dipole, quadrupole, octupole
      and hexadecapole moment. Cluster analysis groups atoms into atom types based on
      their similarity expressed in the discrete 7D space of atomic properties. Using a
      separation criterion we distinguish seven hydrogen, six oxygen, two nitrogen and
      six sulfur atom types.

PMID- 12596158
TI  - Ni0-catalyzed cyclotrimerization of 1,3-butadiene: a comprehensive density
      functional investigation on the origin of the selectivity.
AB  - A comprehensive theoretical investigation of the mechanism for the Ni(0)
      catalyzed cyclotrimerization of 1,3-butadiene by the [Ni(0)(eta(2)-butadiene)(3)]
      active catalyst complex is presented by employing a gradient-corrected DFT
      method. All critical elementary processes of the catalytic cycle have been
      scrutinized, namely, oxidative coupling of two butadienes, butadiene insertion
      into the allyl-Ni(II) bond, allylic isomerization in both octadienediyl-Ni(II)
      and dodecatrienediyl-Ni(II) species, and reductive elimination under ring
      closure. For each of these elementary steps several conceivable routes and also
      the different stereochemical pathways have been probed. The favorable route for
      oxidative coupling start from the prevalent [Ni(0)(eta(2)-butadiene)(3)] form of
      the active catalyst through coupling between the terminal non-coordinated carbon
      atoms of two reactive eta(2)-butadiene moieties; this is assisted by an ancillary
      butadiene in eta(2)-mode. The initial eta(3),eta(1)(C(1))-octadienediyl-Ni(II)
      product is the active precursor for subsequent butadiene insertion, which
      preferably takes place into the eta(3)-allyl-Ni(II) bond. The insertion is driven
      by a strong thermodynamic force. Therefore, the dodecatrienediyl-Ni(II) products,
      with the most favorable bis(eta(3)-allyl),Delta-trans isomers in particular,
      represent a thermodynamic sink. Commencing from a preestablished equilibrium
      between the various bis(eta(3)-allyl),Delta-trans forms of the
      [Ni(II)(dodecatrienediyl)] complex, the major cyclotrimer products, namely all-t
      CDT, c,c,t-CDT and c,t,t-CDT, are formed along competing paths by reductive
      elimination under ring closure, which is shown to be rate-controlling. The all-c
      CDT-generating path is completely precluded by both thermodynamic and kinetic
      factors, giving rise to negligibly populated bis(eta(3)-allyl),Delta-cis
      precursor isomers. The regulation of the selectivity of the CDT formation as well
      as the competition between the two reaction channels for generation of C(12)- and
      C(8)-cycloolefins is elucidated.

PMID- 12596159
TI  - Acetylenic quinoxalinoporphyrazines as photosensitisers for photodynamic therapy.
AB  - A range of lipo- and hydrophilic derivatives of the new class of octaalkynyl
      tetra-[6,7]-quinoxalinoporphyrazines (TQuiPors), analogues of the
      naphthalocyanines, were prepared in two steps starting from functionalised hexa
      1,5-diyne-3,4-diones. Divalent zinc and magnesium ions were introduced into the
      macrocyclic core. Whereas the triisopropylsilyl-, 3,5-di-tert-butylphenyl- and 4
      triisopropylsilyloxyphenyl-terminated acetylenic TQuiPors are lipophilic and
      hence soluble in standard organic solvents, a polyethylene glycol-substituted
      derivative was found to dissolve in DMSO as well as in ethanol/water mixtures.
      The new chromophores are characterised by intense UV/Vis/NIR absorptions, most
      notably by bands at 770 nm with extinction coefficients exceeding 500 000 M(-1)
      cm(-1). With a view to possible photodynamic therapy applications, the potency of
      the chromophores to sensitise the formation of singlet oxygen was examined, both
      qualitatively using a 1,3-diphenylisobenzofuran assay, and quantitatively by the
      determination of the singlet oxygen quantum yields. It was found that all
      TQuiPors produce singlet oxygen when irradiated in the presence of air. In
      particular, the octaalkynyl Zn-TQuiPor generates singlet oxygen with a quantum
      yield of 56 %, thereby rivalling, and, in conjunction with its absorption
      profile, even exceeding the standards set by established PDT agents. The
      photostabilities of the TQuiPors were assessed and generally found to be
      satisfactory, but dependent on the solvent and the wavelength of the incident
      light.

PMID- 12596165
TI  - The electrophilic substitution of arenes: is the pi complex a key intermediate
      and what is its nature?

PMID- 12596166
TI  - The direct catalytic asymmetric cross-aldol reaction of aldehydes.

PMID- 12596167
TI  - NMR spectroscopy techniques for screening and identifying ligand binding to
      protein receptors.
AB  - Binding events of ligands to receptors are the key for an understanding of
      biological processes. Gaining insight into protein-protein and protein-ligand
      interactions in solution has recently become possible on an atomic level by new
      NMR spectroscopic techniques. These experiments identify binding events either by
      looking at the resonance signals of the ligand or the protein. Ideally, both
      techniques together deliver a complete picture of ligand binding to a receptor.
      The approaches discussed in this review allow screening of compound libraries as
      well as a detailed identification of the groups involved in the binding events.
      Also, characterization of the binding strength and kinetics is possible,
      competitive binding as well as allosteric effects can be identified, and it has
      even been possible to identify ligand binding to intact viruses and membrane
      bound proteins.

PMID- 12596168
TI  - Improved methanol-to-olefin catalyst with nanocages functionalized through ship
      in-a-bottle synthesis from PH3.

PMID- 12596169
TI  - Structural color and the lotus effect.

PMID- 12596170
TI  - Ionic quaterrylenebis(dicarboximide): a novel mesogen and long-wavelength
      polarizing material.

PMID- 12596171
TI  - Sc3N@C68: folded pentalene coordination in an endohedral fullerene that does not
      obey the isolated pentagon rule.

PMID- 12596172
TI  - A three-dimensional array for multiparallel synthesis.

PMID- 12596173
TI  - Hyperstranded DNA architectures observed by cold-spray ionization mass
      spectrometry.

PMID- 12596174
TI  - Hydrogen from methane and supercritical water.

PMID- 12596175
TI  - [Ge8[N(SiMe3)2]6]: a ligand-stabilized Ge cluster compound with formally zero
      valent Ge atoms.

PMID- 12596176
TI  - Preparation and asymmetric hydrogenation of beta-aryl-substituted beta
      acylaminoacrylates.

PMID- 12596177
TI  - Synthesis of the first fully active lipoteichoic acid.

PMID- 12596178
TI  - A spiro-fused triarylaminium radical cation with a triplet ground state.

PMID- 12596179
TI  - [1.1]Diborataferrocenophane: a highly efficient Li+ scavenger.

PMID- 12596180
TI  - Intercalation of alkali metal cations into layered organotitanium oxides.

PMID- 12596181
TI  - Unselective phenolic coupling of methyl 2-hydroxy-4-methoxy-6-methylbenzoate--a
      valuable tool for the total synthesis of natural product families.

PMID- 12596182
TI  - A nanotubular 3D coordination polymer based on a 3d-4f heterometallic assembly.

PMID- 12596183
TI  - Trinuclear ruthenium polyhydride complexes with a triply bridging ligand: [[(eta5
      C5Me5)Ru]3(mu3-M)(mu-H)3(mu3-H)] (M=Li, MgiPr, and ZnEt) and [[(eta5
      C5Me5)Ru]3(mu3-M)(mu-H)3] (M=AlEt and GaMe).

PMID- 12596184
TI  - Asymmetric epoxidation of homoallylic alcohols and application in a concise total
      synthesis of (-)-alpha-bisabolol and (-)-8-epi-alpha-bisabolol.

PMID- 12596185
TI  - Phospholane-oxazoline ligands for Ir-catalyzed asymmetric hydrogenation.

PMID- 12596186
TI  - A highly practical and enantioselective reagent for the allylation of aldehydes.

PMID- 12596187
TI  - A general oxidative cyclization of 1,5-dienes using catalytic osmium tetroxide.

PMID- 12596192
TI  - New catalyzed three-component cycloadditions for the synthesis of eight-membered
      carbocycles.

PMID- 12596193
TI  - A Kaiser Wilhelm Institute for Cologne! Emil Fischer, Konrad Adenauer, and the
      Meirowsky endowment.

PMID- 12596194
TI  - Vancomycin assembly: nature's way.
AB  - Antibiotics are precious resources in the fight to combat bacterial infections
      caused by pathogenic organisms. Vancomycin is one of the antibiotics of last
      resort in the treatment of life-threatening infections by gram-positive bacteria.
      The rules by which nature assembles the glycopeptide (vancomycin) and
      lipoglycopeptide (teicoplanin) antibiotics are becoming elucidated and verified:
      first amino acids are synthesized, then joined together and cross-linked. This
      knowledge opens up approaches for reprogramming strategies at the level of
      altered monomers, swapped assembly lines, and different post-assembly tailoring
      enzymes.

PMID- 12596195
TI  - A microfluidic system for controlling reaction networks in time.

PMID- 12596196
TI  - Vesicles and polymerized vesicles from thiophene-containing rod-coil block
      copolymers.

PMID- 12596197
TI  - Design and synthesis of gamma-dipeptide derivatives with submicromolar affinities
      for human somatostatin receptors.

PMID- 12596198
TI  - Liquid-crystal templating of conducting polymers.

PMID- 12596199
TI  - Single crystals of the disubstituted anthracene 9,10-(Ph2P=S)2C14H8 selectively
      and reversibly detect toluene by solid-state fluorescence emission.

PMID- 12596200
TI  - Stereoselective solid-phase synthesis of chiral piperidine derivatives by using
      an immobilized galactose auxiliary.

PMID- 12596201
TI  - A new principle in combinatorial asymmetric transition-metal catalysis: mixtures
      of chiral monodentate P ligands.

PMID- 12596202
TI  - Reactions of triazacyclohexanes with CuCl2: surprising formation of a dimer
      between two [CuCl2]- ions with an unsupported cuprophilic attraction.

PMID- 12596204
TI  - Creation of a superhydrophobic surface from an amphiphilic polymer.

PMID- 12596203
TI  - Small circular oligodeoxynucleotides achieved from self-assembling entities.

PMID- 12596205
TI  - Catalytic functionalization of hydrocarbons by sigma-bond-metathesis chemistry:
      dehydrosilylation of methane with a scandium catalyst.

PMID- 12596206
TI  - The palladium-catalyzed addition of organoboronic acids to alkynes.

PMID- 12596207
TI  - Why trimerization? Computational elucidation of the origin of selective
      trimerization of ethene catalyzed by [TaCl3(CH3)2] and an agostic-assisted
      hydride transfer mechanism.

PMID- 12596208
TI  - A one-pot four-component (ABC2) synthesis of macrocycles.

PMID- 12596209
TI  - The first thorium arene complex: a divalent synthon.

PMID- 12596210
TI  - Spiroannulation by alkylation and reductive cyclization of nitriles.

PMID- 12596212
TI  - Real-time chemical-shift scaling in high-resolution NMR spectroscopy.

PMID- 12596211
TI  - Single-pot conversion of methane into acetic acid in the absence of CO and with
      vanadium catalysts such as amavadine.

PMID- 12596213
TI  - From alkenylsilanes to ketones with air as the oxidant.

PMID- 12596214
TI  - Organic-catalyst-mediated cyclopropanation reaction.

PMID- 12596216
TI  - Antitubercular isoniazid and drug resistance of Mycobacterium tuberculosis--a
      review.
AB  - Isoniazid is one of the most potent drugs available for tuberculosis treatment.
      As a pro-drug it requires activation, which is performed by catalase/peroxidase.
      The active principle, whose identity has not yet been determined unambiguously,
      then acts on at least one target molecule, the enoyl-acyl carrier protein,
      required for the synthesis of the vital mycolic acids present in the cell wall of
      the bacterium. Some other targets have been proposed in order to explain the
      unusual potency of isoniazid; however, the supporting data are still
      controversial. We thoroughly discuss the action of isoniazid, resistance
      mechanisms, and the possible active product, which includes an isonicotinic acid
      NADH adduct as well as a meta-isomer of NADH. Both structures have been probed
      positively in a 3D modeling analysis.

PMID- 12596217
TI  - C16 and C17 substituted derivatives of pregnenolone and progesterone as
      inhibitors of 17alpha-hydroxylase-C17, 20-lyase: synthesis and biological
      evaluation.
AB  - 17 alpha-hydroxylase-C17, 20-lyase (P450 17, CYP 17) is a key enzyme in androgen
      biosynthesis and a target for the treatment of prostate cancer. In order to find
      novel inhibitors for this enzyme, several compounds bearing different moieties
      able to complex with the heme iron located in the active site of the enzyme were
      synthesized. The moieties were introduced into the 16-position of pregnenolone
      and progesterone. Their inhibitory activities toward human and rat CYP 17 were
      determined and compared to the activities of the corresponding 17-substituted
      compounds. It became apparent that the 16-substituted compounds were less active
      than the parent compounds: they were either moderate or poor inhibitors of the
      target enzyme. Tested for inhibition of human 5 alpha-reductase 1 and 2--a target
      for the treatment of benign prostatic hyperplasia (BPH)--the title compounds
      showed some inhibitory activity.

PMID- 12596218
TI  - Novel high energy intermediate analogues with triazasterol-related structures as
      inhibitors of ergosterol biosynthesis. Part I: synthesis and antifungal activity
      of N-alkyl-N'-(phenethyl- and cyclohexenylethyl)guanidines and N2-substituted 2
      imidazolinamines.
AB  - A series of N-alkyl-N'-(phenethyl- and cyclohexenylethyl) guanidines and N(2)-
      and N(2), 4-substituted imidazolin-2-amine hydrochlorides with triazasterol
      related structures was designed and synthesized as stable analogues to mimic high
      energy intermediates of ergosterol biosynthesis. The in vitro antifungal
      susceptibility tests with a standard panel of pathogenic fungi revealed moderate
      to strong antimycotic effects of the sixteen prepared compounds, in some cases
      comparable with the activity observed for itraconazole.

PMID- 12596220
TI  - Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4
      oxoquinazoline derivatives.
AB  - Synthesis of some new derivatives of 2-aryl-4-oxo-1-(4-quinazolyl)quinazolines is
      described. Methyl N-(4-quinazolyl)anthranilate was allowed to react with phenyl
      iso(thio)cyanate to give 3-phenyl-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydro-2, 4
      dioxo- and 4-oxo-2-thioxoquinazolines (3a and 3b respectively) Alternatively,
      anthranilic acid amide derivatives were subjected to cyclization with aromatic
      aldehydes to give 2-aryl-4-oxo-1-(4-quinazolyl)-1, 2, 3, 4-tetrahydroquinazolines
      5. On the other hand, 2-chloro-4-(4-substituted 1-piperazinyl)quinazoline
      derivatives were subjected to the same type of reactions at the 2-position to
      afford the corresponding quinazoline derivatives 8 and 10 respectively.
      Furthermore, the acid amide 4b cyclized with acid chlorides to give the
      corresponding 2-aryl-1-(2-chloro-4-quinazolyl)-4-oxo-1, 4-dihydroquinazolines 11
      from which the triazoloquinazoline derivatives 13 and 15 were synthesized through
      the intermediate hydrazine derivatives 12. Most of the newly synthesized
      compounds were tested for their antiinflammatory activities. However, some of the
      novel compounds were found to exhibit good antiinflammatory potencies.

PMID- 12596219
TI  - Structure-activity relationship studies of 1-substituted 3-dodecanoylindole-2
      carboxylic acids as inhibitors of cytosolic phospholipase A2-mediated arachidonic
      acid release in intact platelets.
AB  - A series of 3-dodecanoylindole-2-carboxylic acid derivatives with varied
      carboxylic acid substituents at the indole 1-position were synthesized and
      evaluated for their ability to inhibit arachidonic acid release in human
      platelets mediated by the cytosolic phospholipase A(2). Structure-activity
      relationship studies revealed that increasing the polarity of these substituents
      by the introduction of additional polar groups in the proximity of the carboxylic
      acid moiety reduced activity. Conformational restriction of the indole-1
      carboxylic acid substituents in distinct positions as well as extending the
      length of these residues led to compounds which did not substantially differ in
      their potencies.

PMID- 12596221
TI  - Novel 3-arylamino- and 3-cycloalkylamino-5, 6-diphenyl-pyridazines active as ACAT
      inhibitors.
AB  - A new series of pyridazine derivatives, structurally related to the previously
      reported ACAT inhibitors 3-(cyclo)alkylamino-5, 6-diphenyl-pyridazines, were
      synthesized and tested for their inhibitory properties. Substitution of the 3
      alkylamino chain with a phenylamino group maintains activity. In contrast, the
      presence of either substituents on the phenylamino group or aliphatic rings
      having more or less than six carbon atoms lowers it.

PMID- 12596222
TI  - Sex steroids, ANGELS and osteoporosis.
AB  - Osteoporosis is characterized by reduced bone density and strength. Bone mass
      peaks between age 30 and 40 and then declines. This can be accelerated by factors
      including menopause and insufficient dietary calcium. Hormone replacement therapy
      (HRT) is currently the standard treatment for osteoporosis. However, growing
      concern over potential side effects of HRT has driven a search for alternative
      therapies. A recent report 1 reveals a potential alternative to HRT: a gender
      neutral synthetic steroid that increases bone mass and strength without affecting
      reproductive organs. This compound acts via a novel extranuclear sex steroid
      receptor signaling mechanism that has important implications for nuclear receptor
      biology and human health.

PMID- 12596223
TI  - A Hes1-based oscillator in cultured cells and its potential implications for the
      segmentation clock.
AB  - During somitogenesis an oscillatory mechanism termed the "segmentation" clock
      generates periodic waves of gene expression, which translate into the periodic
      spatial pattern manifest as somites. The dynamic expression of the clock genes
      shares the same periodicity as somitogenesis. Notch signaling is believed to play
      a role in the segmentation clock mechanism. The paper by Hirata et al.(1)
      identifies a biological clock in cultured cells that is dependent upon the Notch
      target gene Hes1, and which shows a periodicity similar to that of the
      segmentation clock. This finding opens the possibility that the same oscillator
      mechanism might also operate in other tissues or cell types.

PMID- 12596224
TI  - Nonculturable bacteria: programmed survival forms or cells at death's door?
AB  - Upon starvation and growth arrest, Escherichia coli cells gradually lose their
      ability to reproduce. These apparently sterile/nonculturable cells initially
      remain intact and metabolically active and the underlying molecular mechanism
      behind this sterility is something of an enigma in bacteriology. Three different
      models have been proposed to explain this phenomenon. The first theory suggests
      that starving cells become nonculturable due to cellular deterioration, are
      moribund, and show some of the same signs of senescence as aging organisms. The
      two other theories suggest that genetically programmed pathways, rather than
      stochastic deterioration, trigger nonculturability. One "program" theory suggests
      that nonculturability is the culmination of an adaptive pathway generating
      dormant survival forms, similar to spore formation in differentiating bacteria.
      The other "program" theory states that starved cells lose viability due to
      activation of genetic modules mediating programmed cell death. The different
      models will be reviewed and evaluated in light of recent data on the physiology
      and molecular biology of growth-arrested E. coli cells.

PMID- 12596225
TI  - Kidney development and the fetal programming of adult disease.
AB  - Recent evidence, from both epidemiological and animal experimental studies,
      suggest that the very first environment, the intrauterine, is extremely important
      in determining the future health of the individual. Genetic and 'lifestyle'
      factors impinge on, and can exacerbate, a 'programming' effect of an adverse
      fetal environment. In this review, we present compelling evidence to suggest that
      one of the major organs affected by an unfavourable prenatal environment is the
      kidney. Many of the factors that can affect fetal renal development (i.e.
      exposure to excess glucocorticoids, insufficient vitamin A, protein/calorie
      malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen
      system), also produce hypertension in the adult animal. When nephron number is
      compromised during kidney development, maladaptive functional changes occur and
      can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is
      during the very earliest stages of kidney development that the vulnerability to
      these effects occurs.

PMID- 12596226
TI  - Sex-determination gene and pathway evolution in nematodes.
AB  - The pathway that controls sexual fate in the nematode Caenorhabditis elegans has
      been well characterized at the molecular level. By identifying differences
      between the sex-determination mechanisms in C. elegans and other nematode
      species, it should be possible to understand how complex sex-determining pathways
      evolve. Towards this goal, orthologues of many of the C. elegans sex regulators
      have been isolated from other members of the genus Caenorhabditis. Rapid sequence
      evolution is observed in every case, but several of the orthologues appear to
      have conserved sex-determining roles. Thus extensive sequence divergence does not
      necessarily coincide with changes in pathway structure, although the same forces
      may contribute to both. This review summarizes recent findings and, with
      reference to results from other animals, offers explanations for why sex
      determining genes and pathways appear to be evolving rapidly. Experimental
      strategies that hold promise for illuminating pathway differences between
      nematodes are also discussed.

PMID- 12596227
TI  - Phylogenomics of type II DNA topoisomerases.
AB  - Type II DNA topoisomerases (Topo II) are essential enzymes implicated in key
      nuclear processes. The recent discovery of a novel kind of Topo II (DNA
      topoisomerase VI) in Archaea led to a division of these enzymes into two non
      homologous families, (Topo IIA and Topo IIB) and to the identification of the
      eukaryotic protein that initiates meiotic recombination, Spo11. In the present
      report, we have updated the distribution of all Topo II in the three domains of
      life by a phylogenomic approach. Both families exhibit an atypical distribution
      by comparison with other informational proteins, with predominance of Topo IIA in
      Bacteria, Eukarya and viruses, and Topo IIB in Archaea. However, plants and some
      Archaea contain Topo II from both families. We confront this atypical
      distribution with current hypotheses on the evolution of the three domains of
      life and origin of DNA genomes.

PMID- 12596228
TI  - Molecular architecture of intermediate filaments.
AB  - Together with microtubules and actin microfilaments, approximately 11 nm wide
      intermediate filaments (IFs) constitute the integrated, dynamic filament network
      present in the cytoplasm of metazoan cells. This network is critically involved
      in division, motility and other cellular processes. While the structures of
      microtubules and microfilaments are known in atomic detail, IF architecture is
      presently much less understood. The elementary 'building block' of IFs is a
      highly elongated, rod-like dimer based on an alpha-helical coiled-coil structure.
      Assembly of cytoplasmic IF proteins, such as vimentin, begins with a lateral
      association of dimers into tetramers and gradually into the so-called unit-length
      filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately
      yielding mature IFs after a compaction step. For nuclear lamins, however,
      assembly starts with a head-to-tail association of dimers. Recently, X-ray
      crystallographic data were obtained for several fragments of the vimentin dimer.
      Based on the dimer structure, molecular models of the tetramer and the entire
      filament are now a possibility.

PMID- 12596229
TI  - Does cholesterol use the mitochondrial contact site as a conduit to the
      steroidogenic pathway?
AB  - The first and rate-limiting step of steroidogenesis is the transfer of
      cholesterol from the outer mitochondrial membrane to the inner membrane where it
      is converted to pregnenolone by cytochrome P450 side-chain cleavage (P450scc).
      This reaction is modulated in the gonads and adrenals by the steroidogenic acute
      regulatory protein (StAR), however, the mechanism used by StAR is not understood.
      The outer and inner mitochondrial membranes are joined at contact sites that are
      thought to be held in place by protein complexes that bridge the two membranes.
      While it is generally accepted that proteins are imported into the mitochondrion
      via contact sites, it is not clear whether cholesterol takes the same conduit to
      the inner membrane. Strategies to combat diseases caused by interrupted
      cholesterol transfer will rely on a full understanding of the steroidogenic
      mechanism. The challenge for the future is to determine whether StAR relies on
      the molecular architecture that spans the mitochondrial intermembrane space to
      deliver its cargo.

PMID- 12596230
TI  - On the mechanism of Wolbachia-induced cytoplasmic incompatibility: confronting
      the models with the facts.
AB  - The endocellular bacterium Wolbachia manipulates the reproduction of its
      arthropod hosts for its own benefit by various means, the most widespread being
      cytoplasmic incompatibility (CI). To date, the molecular mechanism involved in CI
      has not been elucidated. We examine here three different CI models described in
      previous literature, namely, the "lock-and-key", "titration-restitution" and
      "slow-motion" models. We confront them with the full range of CI patterns
      discovered so far, including the most complex ones such as multiple infections,
      asymmetrical and partial compatibility relationships and the existence of
      Wolbachia variants that can rescue the host from CI but not induce it. We
      conclude that the lock-and-key model is the most parsimonious of the models and
      fits the observations best. The two other models cannot be categorically
      invalidated, but they encounter some difficulties that make additional hypotheses
      necessary.

PMID- 12596231
TI  - Statistical bioinformatic methods in microbial genome analysis.
AB  - It is probable that, increasingly, genome investigations are going to be based on
      statistical formalization. This review summarizes the state of art and
      potentiality of using statistics in microbial genome analysis. First, I focus on
      recent advances in functional genomics, such as finding genes and operons,
      identifying gene conversion events, detecting DNA replication origins and
      analysing regulatory sites. Then I describe how to use phylogenetic methods in
      genome analysis and methods for genome-wide scanning for positively selected
      amino acids. I conclude with speculations on the future course of genome
      statistical modeling.

PMID- 12596232
TI  - AraC protein: a love-hate relationship.
AB  - In the bacterium Escherichia coli, the AraC protein positively and negatively
      regulates expression of the proteins required for the uptake and catabolism of
      the sugar L-arabinose. This essay describes how work from my laboratory on this
      system spanning more than thirty years has aided our understanding of positive
      regulation, revealed DNA looping (a mechanism that explains many action-at-a
      distance phenomena) and, more recently, has uncovered the mechanism by which
      arabinose shifts AraC from a state where it prefers to bind to two well-separated
      DNA half-sites and form a DNA loop to a state where it binds to two adjacent half
      sites and activates transcription. This work required learning how to assay,
      purify, and work with a protein possessing highly uncooperative biochemical
      properties. Present work is focussed on understanding arabinose-responsive
      mechanism in atomic detail and is also directed towards understanding protein
      structure and function well enough to be able to engineer the allosteric
      mechanism seen in AraC onto other proteins.

PMID- 12596233
TI  - Alzheimer vaccine: amyloid-beta on trial.
AB  - A new therapeutic approach is being developed for the treatment of Alzheimer's
      disease (AD). This approach involves the deliberate induction of an autoimmune
      response to amyloid-beta (Abeta) peptide, the constituent of neuritic plaques
      that is thought to cause the neurodegeneration and dementia in AD. If this
      approach is to be effective, antibodies must be produced that can selectively
      target the toxic forms of Abeta, while leaving the functionally-relevant forms of
      Abeta and its precursor protein untouched. Furthermore, an approach needs to be
      found that avoids provoking an acute neuroinflammatory response. The situation is
      made even more challenging by uncertainty regarding which isoforms of Abeta
      contribute to the pathogenesis of AD.

PMID- 12596234
TI  - Cytogenetics in reproductive medicine: the contribution of comparative genomic
      hybridization (CGH).
AB  - Cytogenetic research has had a major impact on the field of reproductive
      medicine, providing an insight into the frequency of chromosomal abnormalities
      that occur during gametogenesis, embryonic development and pregnancy. In humans,
      aneuploidy has been found to be relatively common during fetal life,
      necessitating prenatal screening of high-risk pregnancies. Aneuploidy rates are
      higher still during the preimplantation stage of development. An increasing
      number of IVF laboratories have attempted to improve pregnancy rates by using
      preimplantation genetic diagnosis (PGD) to ensure that the embryos transferred to
      the mother are chromosomally normal. This paper reviews some of the techniques
      that are key to the detection of aneuploidy in reproductive samples including
      comparative genomic hybridization (CGH). CGH has provided an unparalleled insight
      into the nature of chromosome imbalance in human embryos and polar bodies. The
      clinical application of CGH for the purposes of PGD and the future extensions of
      the methodology, including DNA microarrays, are discussed.

PMID- 12596236
TI  - Entomopathogenic effect of Aspergillus giganteus and Penicillium corylophilum on
      two triatomine vectors of Chagas disease.
AB  - Two strains, Penicillium corylophilum and Aspergillus giganteus, of the most
      frequent species found in a survey of triatomines, were used for bioassays in the
      second and fourth nymphs stage of Triatoma infestans and Panstrongylus megistus.
      Two procedures, bite and pulverization, were used and compared. A. giganteus was
      most effective, causing mortality in at least 50% of the nymphs of the two
      species tested with exception of the nymphs of the fourth stage of P. megistus.
      Variation in entomopathogenic capacity of the fungal species were observed in the
      experiments. The two procedures used proved effective.

PMID- 12596237
TI  - Screening for soluble methane monooxygenase in methanotrophic bacteria using
      combined molecular and biochemical methods for hydroxylase detection.
AB  - Three well known methanotrophic bacteria (Methylosinus trichosporium OB3b,
      Methylocystis sp. WI 14, and Methylocystis sp. GB 25) and three newly isolated
      methanotrophic bacteria (Methylocystis sp. WI 11, Methylocystis sp. X, and FI-9)
      were screened for sMMO considering the existence of hydroxylase (component A)
      genes as well as its gene expression. For these purposes monoclonal antibodies
      that specifically recognize each subunit of the hydroxylase of Methylocystis sp.
      WI 14 (alpha-subunit [9E5/F2], beta-subunit [4E2/G11], gamma-subunit [10G3/D7])
      were produced. PCR amplification using well known primers showed that the
      hydroxylase encoding genes appear to be only present in M. trichosporium OB3b,
      Methylocystis sp. WI 11 and WI 14, and in the isolate FI-9. Western and ELISA
      analysis using the monoclonal antibodies revealed that all subunits of
      hydroxylase were present. However, in FI-9, only the alpha-subunit of the
      hydroxylase might be expressed. Surprisingly, in Methylocystis sp. GB 25, where
      no sMMO activity and no amplification with sMMO specific primers was obtained,
      the antibody 4E2/G11 recognized a protein band with exactly the same molecular
      mass as the beta-subunit of the hydroxylase. Methylocystis sp. X showed no
      positive reaction in any of the tests. In combination with the detection methods
      currently used, the described antibodies provide a powerful tool for detecting
      even partially expressed hydroxylase genes.

PMID- 12596238
TI  - Genotypic and phenotypic characteristics of antibiotic-producing soil
      Streptomyces investigated by RAPD-PCR.
AB  - Random amplified polymorphic DNA (RAPD) analysis has been used to determine the
      relatedness of 73 antibiotic-producing soil Streptomyces isolates that were
      recovered from different soil habitats in Jordan based on their RAPD-PCR
      fingerprints. Genetic polymorphisms between these isolates showed three common
      bands of 2777, 800 and 250 bp shared by approximately (95%) of them. Some
      specific bands were also observed. Further analysis of RAPD patterns with the
      UPGMA resulted in clustering the tested isolates into two main super clusters.
      Super cluster I was more homogenous than super cluster II and contained all the
      reference strains. However, super cluster II consists of unrelated isolates
      within five small groups. As RAPD fingerprints of the tested isolates linked to
      their phenotypes, differentiation between isolates with different cultural
      properties was observed.

PMID- 12596239
TI  - A novel membrane glycoprotein of Escherichia coli.
AB  - A novel glycoprotein (Gp45) has been isolated and purified from Escherichia coli.
      To our knowledge, Gp45 is the third glycoprotein isolated from E. coli membrane
      and it is the second in the non-pathogenic strain of the organism. For the
      isolation of Gp45, cell extract or membrane fraction was treated with sodium
      deoxycholate for 4 h and precipitated with trichloroacetic acid (TCA). The
      supernatant fraction of TCA containing the Gp45 was further purified on DEAE
      Sephadex A-25. SDS-PAGE showed a single band at 45 kDa position that stained with
      periodic-Schiff reagent. It contained 60% carbohydrate and 40% protein content.
      The monosaccharide composition also substantiated the characteristics of the
      glycoprotein. The E. coli grown in presence of (14)C-glucosamine further
      confirmed the localization and biosynthesis of this glycoprotein on the membrane
      during the growth phase. Bacitracin, a general inhibitor of the glycosylation,
      inhibited its biosynthesis.

PMID- 12596240
TI  - Identification of a major protein upon phosphate starvation of Pseudomonas
      aeruginosa PAO1.
AB  - To understand the physiology of non-differentiating bacteria exposed to nutrient
      deprivation and stress, various approaches have been employed in combination with
      detailed analysis of protein synthesis pattern. In this study, separation of
      proteins from clarified cell extracts of Pseudomonas aeruginosa PAO1 grown under
      phosphorus limiting conditions was achieved by high resolution two-dimensional
      gel electrophoresis (2-DE). Limitation of phosphate in the growth medium revealed
      significant differences in the 2-DE pattern of proteins between phosphate starved
      cells and an unstarved control. A major protein identified as PstS, a phosphate
      binding protein of the pts operon was exclusively found on 2-DE gels of phosphate
      starved bacteria. The identity of protein was established based on the results of
      Edman degradation, amino acid analysis and mass spectrometry. PstS was also found
      in other pseudomonads, and therefore, it can be used as a landmark protein in
      proteomic studies. Additionally, we propose utilizing pstS of pseudomonads for
      testing bioavailable phosphate from soils and water streams.

PMID- 12596241
TI  - Survival and accumulation of microorganisms in soils irrigated with secondary
      treated wastewater.
AB  - Secondary-treated wastewater was used to irrigate forage crops during two years
      (1994 and 1995). The bacteriological quality of the soil irrigated with both
      secondary treated wastewater (without chlorination) and with potable water was
      evaluated. The following three treatments were investigated in this study: i)
      irrigation with potable water in amount equivalent to 100% of the class A Pan
      evaporation reading (as taken from the nearest Meteorological Weather Station);
      ii) irrigation with treated wastewater in amount equivalent to 100% of the A Pan
      reading and iii) irrigation with treated wastewater in amount equivalent to 125%
      of the A Pan reading. At the end of the last growing season, soil samples were
      collected at two soil depths and subjected to microbiological analysis. The
      bacteriological analysis showed that the total aerobic bacterial counts of
      surface soil were similar in all irrigated plots, suggesting that the use of this
      wastewater did not stimulate or inhibit these microflora. Surface soil was found
      to have higher bacterial counts than deeper soil suggesting bacterial removal
      from irrigation water by the first few centimeters of soil due to natural
      infiltration of soil. The total coliforms ranged from 2.1 x 10(3) CFU/g to 4.2 x
      10(3) CFU/g while fecal coliforms were less, ranging from 1.2 x 10(2) CFU/g to
      4.2 x 10(2) CFU/g. No detectable helminth eggs were recorded in the treated
      wastewater used for irrigation. The results strongly suggest the necessity to
      treat wastewater effluents to an extent to which no or very few residual
      bacterial contaminants will be detected.

PMID- 12596242
TI  - Induction of phenol utilization in Pseudomonas CF600 grown under varying nitrogen
      levels.
AB  - This study demonstrates the effect of various nitrogen levels in the medium along
      with different carbon sources in the media on the utilization of phenol by
      Pseudomonas CF600. Experiments were carried out using cultures derived from
      minimal media containing the carbon sources phenol and citrate, followed by
      varying nitrogen levels in the medium. Respirometric analysis under different
      conditions was carried out with cells using phenol and catechol as substrates.
      When nitrogen was limiting in the medium, phenol induced higher oxygen uptake
      rates, whereas catechol was independent of the nitrogen levels. These
      observations were also supported by the residual phenol levels in the medium with
      different levels of nitrogen as NH(4) ion. Results show that nitrogen-limiting
      conditions favor the phenol utilization by Pseudomonas CF600.

PMID- 12596243
TI  - The activities of the two thioredoxins from Streptomyces aureofaciens are not
      interchangeable.
AB  - The physico-chemical features of the NADPH-thioredoxin reductase (TRR) and two
      thioredoxins from Streptomyces aureofaciens (A14) are reported. The activity of
      pure S. aureofaciens thioredoxin reductase decreased drastically in the presence
      of NADPH or NADH while NADP(+), NAD(+), as well as S. aureofaciens thioredoxin-1
      (TR1) activated the enzyme activity significantly. TR1 fully protected the enzyme
      from inactivation and also promoted its complete reactivation. S. aureofaciens
      thioredoxin-2 (TR2) did not protect thioredoxin reductase from NADPH
      inactivation. The results indicate that although the two thioredoxins from S.
      aureofaciens have similar biochemical properties, their essential oxidoreductase
      activities are not interchangeable.

PMID- 12596244
TI  - The influence of co-cultivation on expression of the antifungal protein in
      Aspergillus giganteus.
AB  - The afp gene of Aspergillus giganteus encodes a small, highly basic polypeptide
      with antifungal activity, named Antifungal Protein (AFP). The protein is secreted
      by the mould and inhibits the growth of various filamentous fungi. In this paper
      we report that co-cultivation of A. giganteus with various microorganisms alters
      afp expression. It was found that co-cultivation modulates afp expression on the
      level of transcription, using a reporter system based on the beta-glucuronidase
      gene. The presence of Fusarium oxysporum triggered afp transcription whereas dual
      cultures of A. giganteus and A. niger resulted in suppression of afp
      transcription. Growth tests performed with several carbon and nitrogen sources,
      revealed that the influence of co-cultivation is strongly dependent on the medium
      composition.

PMID- 12596245
TI  - Comparison of aspartate transcarbamoylase regulation in Pseudomonas alcaligenes
      and Pseudomonas mendocina.
AB  - The regulation of aspartate transcarbamoylase activity in cell extracts of
      Pseudomonas alcaligenes ATCC 14909 and Pseudomonas mendocina ATCC 25411 was
      compared. Under saturating substrate concentrations, pyrophosphate, CTP, UDP and
      ADP were highly inhibitory of the P. alcaligenes transcarbamoylase activity while
      pyrophosphate, UDP, ADP, ATP and GTP were the most effective inhibitors of the P.
      mendocina transcarbamoylase. By examining transcarbamoylase inhibition by
      ribonucleotide triphosphates, it was possible to differentiate these species
      assigned to different DNA homology groups and such an analysis might prove useful
      in the reclassification of Pseudomonas species.

PMID- 12596246
TI  - Quantitative image analysis of cellular protein translocation induced by magnetic
      microspheres: application to the EGF receptor.
AB  - BACKGROUND: The molecular analysis of intracellular signal transduction requires
      technologies that address quantitatively the activation of signaling proteins and
      formation of molecular complexes without disrupting cellular integrity. METHODS:
      Cells expressing the epidermal growth factor receptor (EGFR) in its endogenous
      form or fused to green fluorescent protein were incubated with 1-microm
      microspheres covalently functionalized with EGF. The disposition of the plasma
      membrane about the microspheres was analyzed by high-resolution confocal
      microscopy in combination with computational resolution enhancement and optimized
      fixation procedures. Receptor activation and translocation of signaling proteins
      to the microspheres was quantitated by image processing protocols for recovering
      the microsphere-associated fluorescence and the fluorescence in the local
      environment. RESULTS: EGF-functionalized microspheres were internalized in an
      activation-dependent manner similar to that of the soluble growth factor. The
      correlation of receptor activation and recruitment of a signaling protein was
      analyzed quantitatively by isolating immunofluorescence signals from the
      microspheres and from their immediate environment. CONCLUSIONS: The microsphere
      based approach provides a quantitative analysis of cellular signal transduction
      with subcellular resolution under conditions maintaining cellular integrity. The
      analysis of signaling-induced (co)localization of proteins around a microsphere
      complements other technologies directly probing for molecular interactions such
      as fluorescence resonance energy transfer.

PMID- 12596247
TI  - Automated analysis of morphometric parameters for accurate definition of
      erythrocyte cell shape.
AB  - BACKGROUND: Modification of erythrocyte morphology is clinically important in
      hematology and medicine. Its detection is routinely performed by subjective
      microscopic evaluation, which is difficult and strongly dependent on the
      operator's expertise. We developed an original automated methodology to analyze
      erythrocyte cell shape modification to support and improve the operator's
      capability and expedite measurements. METHODS: We used morphometric parameters
      derived from optical microscope images elaborated with an image processing
      software (NIH Scion Image) to construct a new application for statistical
      multivariate discriminant analysis. RESULTS: For each cell type the elaboration
      of the morphometric parameters allowed us to develop a chromogenic index, a
      dimension index, a biconcavity index, and a density profile. The measurements of
      these indexes were used to construct a statistical methodology that could
      discriminate among erythrocyte morphologies according to Bessis. When applied
      casewise, the model effectively differentiated between discocytes, target cells,
      ovalocytes, macrocytes, and microcytes, with an agreement of 70% between actual
      and predicted classifications. CONCLUSIONS: The results clearly demonstrated that
      a set of opportunely selected morphometric parameters derived from optical
      microscope images and statistically analyzed can effectively discriminate with a
      high degree of certainty among different shape modifications that red blood cells
      can undergo in various in vitro and in vivo conditions. This method represents
      the first attempt to automate the definition of erythrocyte morphology and may
      have important applications in cases in which the detection of erythrocyte cell
      shape changes is crucial.

PMID- 12596248
TI  - Toluidine blue test for sperm DNA integrity and elaboration of image cytometry
      algorithm.
AB  - BACKGROUND: Sperm DNA integrity is of paramount importance in the prognosis of
      fertility. We applied image cytometry to a toluidine blue (TB) test we recently
      proposed. METHODS: Sperm samples from 33 men were assayed for standard sperm
      parameters and classified as normal or abnormal. Sperm smears were subjected to
      the TB test, DNA denaturation testing with acridine orange (AO), and terminal
      deoxyuridine triphosphate biotin nick end labeling (TUNEL). In CCD image
      analysis, TB-stained sperm cell heads were microscopically assigned to one of
      four color groups (dark, blue, light violet, and light blue). The optical
      densities of 6,600 cells in green and red CCD images were used to elaborate an
      algorithm for discrimination of these groups. RESULTS: The proportions of sperm
      in TB color groups, as estimated with the developed image cytometry algorithm,
      correlated with microscopic features. The number of TB dark cells correlated with
      the number of AO-red and TUNEL(+) cells. The proportion of TB dark cells in
      normal samples did not exceed 35%. Light-blue sperm cell heads prevailed in
      normal samples, whereas dark and blue sperm cell heads dominated in abnormal
      samples. CONCLUSIONS: The TB test was suitable for the assessment of sperm cell
      DNA integrity. The elaborated image cytometry algorithm can be used for this
      purpose and for finer determination of sperm nucleus status.

PMID- 12596249
TI  - Troglitazone-induced intracellular oxidative stress in rat hepatoma cells: a flow
      cytometric assessment.
AB  - BACKGROUND: Troglitazone (TRO), a thiazolidinedione (TZD) peroxisome proliferator
      activated receptor gamma agonist, was recently withdrawn from the market because
      of rare but serious hepatotoxicity. Previous studies investigating the
      cytotoxicity of TRO in cultured rat hepatocytes have conjectured about the role
      of oxidative stress in TRO-induced hepatotoxicity. Therefore, we investigated
      whether TRO induces oxidative stress and, if so, the portion of the TRO molecule
      responsible for the induction of oxidative stress. METHODS: Novikoff rat hepatoma
      (N1S1) cells were incubated with TRO, troglitazone quinone (TQ),
      thiazolidinedione-phenoxyacetic acid (TD-PAA) or rosiglitazone (RSG). Membrane
      peroxidation, intracellular glutathione (GSH) content, and cellular viability
      were monitored simultaneously by multiparameter flow cytometry. RESULTS: TRO and
      TQ increased membrane peroxidation, decreased intracellular GSH, and decreased
      cell viability in a concentration-dependent manner. In contrast, TD-PAA and RSG
      neither increased membrane peroxidation nor induced loss of cell viability. In
      addition, TRO caused a concentration-dependent increase in intracellular
      superoxide generation accompanied by a collapse in mitochondrial membrane
      potential. CONCLUSION: Multiparameter flow cytometric evaluation of N1S1 cells
      indicated that the chromane ring of TRO, rather than the TZD moiety, may be
      responsible for oxidative stress and suggested that a direct effect on
      mitochondrial physiology may play a role in TRO-mediated hepatotoxicity.

PMID- 12596250
TI  - Comparison of proliferation and rapid cytokine induction assays for flow
      cytometric T-cell epitope mapping.
AB  - BACKGROUND: T-cell epitope mapping by flow cytometry based on rapid ex vivo
      peptide-specific cytokine induction in T cells is very efficient and time saving
      compared with traditional assays. We investigated whether the same epitopes could
      be identified by proliferation studies. METHODS: An assay based on rapid
      interferon-gamma induction in T cells (6 h of ex vivo stimulation) was run in
      parallel with a proliferation assay based on the incremental loss of carboxy
      fluorescein diacetate succinimidyl ester staining in proliferating cells. The
      proliferation assay was chosen because it can be evaluated by high-resolution
      modern multiparameter flow cytometry. In both cases, T cells were stimulated with
      the same cytomegalovirus-derived peptides. The peptides identified by the rapid
      induction of interferon-gamma were compared with those inducing T-cell
      proliferation. RESULTS: Most epitopes were identified by proliferation and rapid
      cytokine induction methods; however, each method also identified epitopes that
      the other one did not. In general, rapid cytokine induction was associated with
      considerably less background noise, making epitope identification easier, and,
      owing to the short stimulation time necessary, several identification steps could
      be carried out on material stored in the incubator. CONCLUSIONS: Even though most
      epitopes were identified by both approaches, the rapid cytokine induction method
      had major logistic advantages. However, it may be best to use both assays,
      particularly in situations in which the identification of epitopes may depend on
      prior clonal T-cell expansion.

PMID- 12596253
TI  - Insulin-like growth factor-II/mannose-6-phosphate receptor: widespread
      distribution in neurons of the central nervous system including those expressing
      cholinergic phenotype.
AB  - The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is
      single transmembrane glycoprotein that plays a critical role in the trafficking
      of lysosomal enzymes and the internalization of circulating IGF-II. At present,
      there is little information regarding the cellular distribution of the IGF-II/M6P
      receptor within the adult rat brain. With the use of immunoblotting and
      immunocytochemical methods, we found that the IGF-II/M6P receptor is widely but
      selectively expressed in all major brain areas, including the olfactory bulb,
      striatum, cortex, hippocampus, thalamus, hypothalamus, cerebellum, brainstem, and
      spinal cord. Intense IGF-II/M6P receptor immunoreactivity was apparent on
      neuronal cell bodies within the striatum, deeper layers (layers IV and V) of the
      cortex, pyramidal and granule cell layers of the hippocampal formation, selected
      thalamic nuclei, Purkinje cells of the cerebellum, pontine nucleus and
      motoneurons of the brainstem as well as in the spinal cord. Moderate neuronal
      labeling was evident in the olfactory bulb, basal forebrain areas, hypothalamus,
      superior colliculus, midbrain areas, granule cells of the cerebellum and in the
      intermediate regions of the spinal gray matter. We also observed dense neuropil
      labeling in many regions, suggesting that this receptor is localized in dendrites
      and/or axon terminals. Double-labeling studies further indicated that a subset of
      IGF-II/M6P receptor colocalizes with cholinergic cell bodies and fibers in the
      septum, striatum, diagonal band complex, nucleus basalis, cortex, hippocampus,
      and motoneurons of the brainstem and spinal cord. The observed widespread
      distribution and colocalization of IGF-II/M6P receptor in the adult rat brain
      provide an anatomic basis to suggest a multifunctional role for the receptor in a
      wide-spectrum of central nervous system neurons, including those expressing a
      cholinergic phenotype.

PMID- 12596251
TI  - Fluorescence lifetime-based discrimination and quantification of cellular DNA and
      RNA with phase-sensitive flow cytometry.
AB  - BACKGROUND: Simultaneous measurement of cellular DNA and RNA content provides
      information for determination of the functional status of cells and, clinically,
      for the diagnosis and grading assessment of various tumors. Most current flow
      cytometric methods are based on resolving the fluorescence emission spectra of
      dyes that bind preferentially to either type of nucleic acid. However, several
      monochromatic nucleic acid-binding fluorochromes display resolvable differences
      in fluorescence lifetime when bound to DNA or RNA. The differences in the
      lifetime of one fluorescent probe provide an alternate means to distinguish the
      binding of one probe to these cellular macromolecules and to simultaneously
      measure their cellular contents. METHODS: Three nucleic acid intercalating dyes,
      propidium iodide, ethidium bromide, and ethidium homodimer 1, were selected to
      study differences in fluorescence lifetimes when bound to cellular DNA and RNA.
      Fixed HL-60 cells were treated with specific nucleases to initially determine the
      lifetime values of each dye when bound to the cellular DNA, RNA, or both. The
      lifetime values were then used as the signatures to resolve the cellular DNA and
      RNA contents in untreated cells. RESULTS: All three dyes showed fluorescence
      lifetime differences when bound to RNase-treated, DNase-treated, or untreated
      cells. With these lifetime values, the fluorescence emissions from DNA, RNA, or
      DNA/RNA were resolved from untreated cells with the use of phase-sensitive
      detection. The lifetime differences resulting from the binding to either type of
      nucleic acid depended on the dye, the staining concentration, and the analysis
      condition. CONCLUSIONS: The lifetimes of the nucleic acid-binding fluorochromes
      were altered when binding to different macromolecules under different conditions.
      Phase-sensitive flow cytometry provided a unique means for simultaneous
      discrimination and quantification of subcellular macromolecules with one
      fluorescent probe. The data demonstrated the capabilities for resolving relative
      cellular DNA and RNA contents based on fluorescence lifetime.

PMID- 12596254
TI  - Laminar and cellular targets of individual thalamic reticular nucleus axons in
      the lateral geniculate nucleus in the prosimian primate Galago.
AB  - The visual sector of the thalamic reticular nucleus is the source of the primary
      inhibitory projection to the visual thalamic relay nucleus, the dorsal lateral
      geniculate nucleus. The purpose of this study was to investigate laminar and
      cellular targets of individual thalamic reticular nucleus axons in the highly
      laminated lateral geniculate nucleus of the prosimian primate Galago to better
      understand the nature and function of this projection. Thalamic reticular axons
      labeled anterogradely by means of biotinylated dextran amine were examined by
      using light microscopic serial reconstruction and electron microscopic analysis
      in combination with postembedding immunohistochemical labeling for the
      neurotransmitter gamma-aminobutyric acid (GABA). The synaptic targets of labeled
      reticular terminal profiles were primarily GABA-negative dendrites (79-84%) of
      thalamocortical cells, whereas up to 16% were GABA-positive dendritic shafts or
      F2 terminals of interneurons. Reconstructed thalamic reticular nucleus axons were
      narrowly aligned along a single axis perpendicular to the geniculate laminar
      plane, exhibiting a high degree of visuotopic precision. Individual reticular
      axons targeted multiple or all geniculate laminae, with little laminar
      selectivity in the distribution of swellings with regard to the eye of origin or
      to the parvocellular, koniocellular, or magnocellular type neurons contained in
      the separate layers of the Galago lateral geniculate nucleus. These results
      suggest that cells in the visual thalamic reticular nucleus influence the lateral
      geniculate nucleus retinotopically, with little regard to visual functional
      streams.

PMID- 12596255
TI  - Dynamics of microglia in the developing rat brain.
AB  - Entrance of mesodermal precursors into the developing CNS is the most well
      accepted origin of microglia. However, the contribution of proliferation and
      death of recruited microglial precursors to the final microglial cell population
      remains to be elucidated. To investigate microglial proliferation and apoptosis
      during development, we combined proliferating cell nuclear antigen (PCNA)
      immunohistochemistry, in situ detection of nuclear DNA fragmentation (TUNEL), and
      caspase-3 immunohistochemistry with tomato lectin histochemistry, a selective
      microglial marker. The study was carried out in Wistar rats from embryonic day
      (E) 16 to postnatal day (P) 18 in cerebral cortex, subcortical white matter, and
      hippocampus. Proliferating microglial cells were found at all ages in the three
      brain regions and represented a significant fraction of the total microglial cell
      population. The percentage of microglia expressing PCNA progressively increased
      from the embryonic period (25-51% at E16) to a maximum at P9, when the great
      majority of microglia expressed PCNA (92-99%) in all the brain regions analyzed.
      In spite of the remarkable proliferation and expansion of the microglial
      population with time, the density of microglia remained quite constant in most
      brain regions because of the considerable growth of the brain during late
      prenatal and early postnatal periods. In contrast, apoptosis of microglia was
      detected only at certain times and was restricted to some ameboid cells in white
      matter and primitive ramified cells in gray matter, representing a small fraction
      of the microglial population. Therefore, our results point to proliferation of
      microglial precursors in the developing brain as a physiological mechanism
      contributing to the acquisition of the adult microglial cell population. In
      contrast, microglial apoptosis occurs only locally at certain developmental
      stages and thus seems less crucial for the establishment of the final density of
      microglia.

PMID- 12596256
TI  - Distribution of dendrites of descending neurons and its implications for the
      basic organization of the cockroach brain.
AB  - To determine precisely the brain areas from which descending neurons (DNs)
      originate, we examined the distribution of somata and dendrites of DNs in the
      cockroach brain by retrogradely filling their axons from the cervical connective.
      At least 235 pairs of somata of DNs were stained, and most of these were grouped
      into 22 clusters. Their dendrites were distributed in most brain areas, including
      lateral and medial protocerebra, which are major termination areas of output
      neurons of the mushroom body, but not in the optic and antennal lobes, the
      mushroom body, the central complex, or the posteroventral part of the lateral
      horn. The last area is the termination area of major types of olfactory
      projection neurons from the antennal lobe, i.e., uni- and macroglomerular
      projection neurons, so these neurons have no direct connections with DNs. The
      distribution of axon terminals of ascending neurons overlaps with that of DN
      dendrites. We propose, based on these findings, that there are numerous parallel
      processing streams from cephalic sensory areas to thoracic locomotory centers,
      many of which are via premotor brain areas from which DNs originate. In addition,
      outputs from the mushroom body, central complex, and posteroventral part of the
      lateral horn converge on some of the premotor areas, presumably to modulate the
      activity of some sensorimotor pathways. We propose, based on our results and
      documented findings, that many parallel processing streams function in various
      forms of reflexive and relatively stereotyped behaviors, whereas indirect
      pathways govern some forms of experience-dependent modification of behavior.

PMID- 12596257
TI  - Olfactory ensheathing cells: time lapse imaging of cellular interactions, axonal
      support, rapid morphologic shifts, and mitosis.
AB  - Olfactory ensheathing cells (OECs) have considerable potential for facilitating
      axonal growth across regions of spinal cord and brain injury but in this context
      have been studied primarily in static images of fixed tissue from the olfactory
      system or after transplantation. In the present work, we studied the behavior of
      live OECs, and their interactions with neurons, Schwann cells, and astrocytes by
      using cells that express the reporter gene coding for green fluorescent protein
      (GFP); the work is based on combinations of fluorescence, phase contrast, digital
      time lapse imaging, and P75 immunocytochemical identification. Cultures,
      explants, and regions of olfactory system slices rich in OECs enhanced axonal
      growth of cerebellar granule cells or hippocampal neurons; axons grew parallel to
      the long axis of fusiform OECs. Neuron cell bodies and axons preferred OECs over
      artificial substrates. Axons and neuron cell bodies can take active or passive
      roles in extension and migration on underlying motile OECs and move from one OEC
      to another. Axon extension was facilitated to a similar degree by OECs and
      Schwann cells, whereas astrocytes were more likely to integrate with existing
      OECs than with Schwann cells. OECs showed a dramatic ability to rapidly change
      shape, size, and direction of migration and to undergo mitosis. Mitosis was
      characterized by a quick retraction of all processes, thereby forming a sphere
      that divided into spherical daughter cells within minutes. Progeny OECs might
      take on the parental or a non-parental morphotype, with both daughter cells
      showing robust expression of GFP. Together these OEC data demonstrated a
      substantial plasticity and capability for relatively rapid changes in structure
      and support the view that OECs have multiple attributes favorable for enhancing
      axonal extension and neuronal migration after central nervous system injury.

PMID- 12596258
TI  - Synaptic remodeling in the dorsal motor nucleus of the vagus nerve following
      vagal-hypoglossal nerve anastomosis in the cat.
AB  - Horseradish peroxidase (HRP) retrograde tracing techniques and morphometric
      analyses were performed to investigate synaptic remodeling associated with
      neuronal and glial changes in the dorsal motor nucleus of the vagus (DMV) of cats
      after vagal-hypoglossal nerve anastomosis (VHA). At 25 days postoperation (dpo),
      in the early target-reinnervation stage, there were 50% fewer presynaptic boutons
      containing round vesicles (R) or round and large dense-cored synaptic vesicles
      (R+D) contacting HRP-labeled DMV motoneurons. The loss of R boutons was
      maintained throughout the remaining postoperative intervals up to 500 dpo,
      whereas R+D boutons were further reduced at 123 dpo but were restored at 315 dpo,
      so that, by 500 dpo, 71.4% of them had gained access to the DMV motoneurons.
      Boutons containing pleomorphic synaptic vesicles (P) were completely disconnected
      from the DMV motoneurons at 25 dpo and did not reappear even in the long-term
      reinnervation stage. Loss and recovery of presynaptic boutons occurred in
      parallel with changes in astroglial ensheathment of the DMV motoneurons. It is
      suggested that synaptic remodeling associated with astroglial ensheathment in the
      DMV may be influenced by some retrogradely transported factors/signals derived
      from the newly acquired target organ, viz. tongue skeletal musculature. Our
      results further suggest that the observed changes in boutonal configurations may
      be attributable to modified functions of the DMV motoneurons induced by VHA.

PMID- 12596259
TI  - Consistency matrices: quantified structure alignments for sets of related
      proteins.
AB  - Comparing two remotely similar structures is a difficult problem: more often than
      not, resulting structure alignments will show ambiguities and a unique answer
      usually does not even exist. In addition, alignments in general have a limited
      information content because every aligned residue is considered equally
      important. To solve these issues to a certain extent, one can take the
      perspective of a whole group of similar structures and then evaluate common
      structural features. Here, we describe a consistency approach that, although not
      actually performing a multiple structure alignment, does produce the information
      that one would conceivably want from such an experiment: the key structural
      features of the group, e.g., a fold, which in this case are projected onto either
      a pair of proteins or a single protein. Both representations are useful for a
      number of applications, ranging from the detection of (partially) wrong structure
      alignments to protein structure classification and fold recognition. To
      demonstrate some of these applications, the procedure was applied to 195 SCOP
      folds containing a total of 1802 domains sharing very low sequence similarity.

PMID- 12596260
TI  - Dynamic fluorescence studies of beta-glycosidase mutants from Sulfolobus
      solfataricus: effects of single mutations on protein thermostability.
AB  - Multiple sequence alignment on 73 proteins belonging to glycosyl hydrolase family
      1 reveals the occurrence of a segment (83-124) in the enzyme sequences from
      hyperthermophilic archaea bacteria, which is absent in all the mesophilic members
      of the family. The alignment of the known three-dimensional structures of
      hyperthermophilic glycosidases with the known ones from mesophilic organisms
      shows a similar spatial organizations of beta-glycosidases except for this
      sequence segment whose structure is located on the external surface of each of
      four identical subunits, where it overlaps two alpha-helices. Site-directed
      mutagenesis substituting N97 or S101 with a cysteine residue in the sequence of
      beta-glycosidase from hyperthermophilic archaeon Sulfolobus solfataricus caused
      some changes in the structural and dynamic properties as observed by circular
      dichroism in far- and near-UV light, as well as by frequency domain fluorometry,
      with a simultaneous loss of thermostability. The results led us to hypothesize an
      important role of the sequence segment present only in hyperthermophilic beta
      glycosidases, in the thermal adaptation of archaea beta-glycosidases. The
      thermostabilization mechanism could occur as a consequence of numerous favorable
      ionic interactions of the 83-124 sequence with the other part of protein matrix
      that becomes more rigid and less accessible to the insult of thermal-activated
      solvent molecules.

PMID- 12596261
TI  - Ab initio construction of polypeptide fragments: Accuracy of loop decoy
      discrimination by an all-atom statistical potential and the AMBER force field
      with the Generalized Born solvation model.
AB  - The accuracy of model selection from decoy ensembles of protein loop
      conformations was explored by comparing the performance of the Samudrala-Moult
      all-atom statistical potential (RAPDF) and the AMBER molecular mechanics force
      field, including the Generalized Born/surface area solvation model. Large
      ensembles of consistent loop conformations, represented at atomic detail with
      idealized geometry, were generated for a large test set of protein loops of 2 to
      12 residues long by a novel ab initio method called RAPPER that relies on fine
      grained residue-specific phi/psi propensity tables for conformational sampling.
      Ranking the conformers on the basis of RAPDF scores resulted in selected
      conformers that had an average global, non-superimposed RMSD for all heavy
      mainchain atoms ranging from 1.2 A for 4-mers to 2.9 A for 8-mers to 6.2 A for 12
      mers. After filtering on the basis of anchor geometry and RAPDF scores, ranking
      by energy minimization of the AMBER/GBSA potential energy function selected
      conformers that had global RMSD values of 0.5 A for 4-mers, 2.3 A for 8-mers, and
      5.0 A for 12-mers. Minimized fragments had, on average, consistently lower RMSD
      values (by 0.1 A) than their initial conformations. The importance of the
      Generalized Born solvation energy term is reflected by the observation that the
      average RMSD accuracy for all loop lengths was worse when this term is omitted.
      There are, however, still many cases where the AMBER gas-phase minimization
      selected conformers of lower RMSD than the AMBER/GBSA minimization. The
      AMBER/GBSA energy function had better correlation with RMSD to native than the
      RAPDF. When the ensembles were supplemented with conformations extracted from
      experimental structures, a dramatic improvement in selection accuracy was
      observed at longer lengths (average RMSD of 1.3 A for 8-mers) when scoring with
      the AMBER/GBSA force field. This work provides the basis for a promising hybrid
      approach of ab initio and knowledge-based methods for loop modeling.

PMID- 12596262
TI  - Ab initio construction of polypeptide fragments: efficient generation of
      accurate, representative ensembles.
AB  - We describe a novel method to generate ensembles of conformations of the main
      chain atoms [N, C(alpha), C, O, Cbeta] for a sequence of amino acids within the
      context of a fixed protein framework. Each conformation satisfies fundamental
      stereo-chemical restraints such as idealized geometry, favorable phi/psi angles,
      and excluded volume. The ensembles include conformations both near and far from
      the native structure. Algorithms for effective conformational sampling and
      constant time overlap detection permit the generation of thousands of distinct
      conformations in minutes. Unlike previous approaches, our method samples dihedral
      angles from fine-grained phi/psi state sets, which we demonstrate is superior to
      exhaustive enumeration from coarse phi/psi sets. Applied to a large set of loop
      structures, our method samples consistently near-native conformations, averaging
      0.4, 1.1, and 2.2 A main-chain root-mean-square deviations for four, eight, and
      twelve residue long loops, respectively. The ensembles make ideal decoy sets to
      assess the discriminatory power of a selection method. Using these decoy sets, we
      conclude that quality of anchor geometry cannot reliably identify near-native
      conformations, though the selection results are comparable to previous loop
      prediction methods. In a subsequent study (de Bakker et al.: Proteins 2003;51:21
      40), we demonstrate that the AMBER forcefield with the Generalized Born solvation
      model identifies near-native conformations significantly better than previous
      methods.

PMID- 12596263
TI  - Structure of the YibK methyltransferase from Haemophilus influenzae (HI0766): a
      cofactor bound at a site formed by a knot.
AB  - The crystal structures of YibK from Haemophilus influenzae (HI0766) have been
      determined with and without bound cofactor product S-adenosylhomocysteine
      (AdoHcy) at 1.7 and 2.0 A resolution, respectively. The molecule adopts an
      alpha/beta fold, with a topology that differs from that of the classical
      methyltransferases. Most notably, HI0766 contains a striking knot that forms the
      binding crevice for the cofactor. The knot formation is correlated with an
      alternative arrangement of the secondary structure units compared with the
      classical methyltransferases. Two loop regions undergo conformational changes
      upon AdoHcy binding. In contrast to the extended conformation of the cofactor
      seen in the classical methyltransferase structures, AdoHcy binds to HI0766 in a
      bent conformation. HI0766 and its close sequence relatives are all shorter
      versions of the more remotely related rRNA/tRNA methyltransferases of the spoU
      sequence family. We propose that the spoU sequence family contains the same core
      domain for cofactor binding as HI0766 but has an additional domain for substrate
      binding. The substrate-binding domain is absent in HI0766 sequence family and may
      be provided by another Haemophilus influenzae partner protein, which is yet to be
      identified.

PMID- 12596264
TI  - Local protein unfolding and pathogenesis of polyglutamine-expansion diseases.
AB  - Polyglutamine expansion diseases are caused by the abnormal lengthening of a
      glutamine repeat in the respective protein and are believed to progress via a
      common mechanism. Here a hypothesis based on protein unfolding is formulated to
      enhance understanding of the pathogenesis of these diseases. Nine disease
      proteins of this family were investigated with an unfolding prediction protocol
      based on calculating the net charge and the overall hydrophobicity from the
      primary sequence. These protein sequences were analysed with and without their
      respective nonpathogenic glutamine repeats. When full-length protein sequences
      were studied, the calculations suggest that unexpanded polyglutamine repeats have
      a minimal effect on the global folding state of the parent proteins. When
      confined to a local context approximating the size of a single-protein domain,
      the calculations suggest that all nine sequences including a normal-length
      polyglutamine repeat correspond to the unfolded state. The unfolding predictions
      were applied to two model systems and were found to be consistent with published
      experimental data. Despite its simplicity, this analysis can be extended to
      simulate repeat length-dependent protein unfolding, an event speculated to
      precede aggregation and disease progression. This work highlights the correlation
      between glutamine repeats and protein unfolding and provides insight into the as
      yet unknown polyglutamine expansion pathogenic mechanism.

PMID- 12596265
TI  - Prediction of folding rates and transition-state placement from native-state
      geometry.
AB  - A variety of experimental and theoretical studies have established that the
      folding process of monomeric proteins is strongly influenced by the topology of
      the native state. In particular, folding times have been shown to correlate well
      with the contact order, a measure of contact locality. Our investigation focuses
      on identifying additional topologic properties that correlate with experimentally
      measurable quantities, such as folding rates and transition-state placement, for
      both two- and three-state folders. The validation against data from 40
      experiments shows that a particular topological property that measures the
      interdependence of contacts, termed cliquishness or clustering coefficient, can
      account with statistically significant accuracy both for the transition state
      placement and especially for folding rates. The observed correlations can be
      further improved by optimally combining the distinct topological information
      captured by cliquishness and contact order.

PMID- 12596266
TI  - BATMAS30: amino acid substitution matrix for alignment of bacterial transporters.
AB  - Aligned amino acid sequences of three functionally independent samples of
      transmembrane (TM) transport proteins have been analyzed. The concept of TM
      kernel is proposed as the most probable transmembrane region of a sequence. The
      average amino acid composition of TM-kernels differs from the published amino
      acid composition of transmembrane segments. TM-kernels contain more alanines,
      glycines, and less polar, charged, and aromatic residues in contrast to non-TM
      proteins. There are also differences between TM-kernels of bacterial and
      eukaryotic proteins. We have constructed amino acid substitution matrices for
      bacterial TM-kernels, named the BATMAS (BActerial Transmembrane MAtrix of
      Substitutions) series. In TM-kernels, polar and charged residues, as well as
      proline and tyrosine, are highly conserved, whereas there are more substitutions
      within the group of hydrophobic residues, in contrast to non-TM-proteins that
      have fewer, relatively more conserved, hydrophobic residues. These results
      demonstrate that alignment of transmembrane proteins should be based on at least
      two amino acid substitution matrices, one for loops (e.g., the BLOSUM series) and
      one for TM-segments (the BATMAS series), and the choice of the TM-matrix should
      be different for eukaryotic and bacterial proteins.

PMID- 12596267
TI  - Efficient identification of side-chain patterns using a multidimensional index
      tree.
AB  - Convergent evolution often produces similar functional sites in nonhomologous
      proteins. The identification of these sites can make it possible to infer
      function from structure, to pinpoint the location of a functional site, to
      identify enzymes with similar enzymatic mechanisms, or to discover putative
      functional sites. In this article, a novel method is presented that (a) queries a
      database of protein structures for the occurrence of a given side chain pattern
      and (b) identifies interesting side-chain patterns in a given structure. For
      efficiency and to make a robust statistical evaluation of the significance of a
      similarity possible, patterns of three residues (or triads) are considered. Each
      triad is encoded as a high-dimensional vector and stored in an SR
      (Sphere/Rectangle) tree, an efficient multidimensional index tree. Identifying
      similar triads can then be reformulated as identifying neighboring vectors. The
      method deals with many features that otherwise complicate the identification of
      meaningful patterns: shifted backbone positions, conservative substitutions,
      various atom label ambiguities and mirror imaged geometries. The combined
      treatment of these features leads to the identification of previously
      unidentified patterns. In particular, the identification of mirror imaged side
      chain patterns is unique to the here-described method. Interesting triads in a
      given structure can be identified by extracting all triads and comparing them
      with a database of triads involved in ligand binding. The approach was tested by
      an all-against-all comparison of unique representatives of all SCOP
      superfamilies. New findings include mirror imaged metal binding and active sites,
      and a putative active site in bacterial luciferase.

PMID- 12596268
TI  - Molecular dynamics simulations of peptides and proteins with a continuum
      electrostatic model based on screened Coulomb potentials.
AB  - A continuum electrostatics approach for molecular dynamics (MD) simulations of
      macromolecules is presented and analyzed for its performance on a peptide and a
      globular protein. The approach incorporates the screened Coulomb potential (SCP)
      continuum model of electrostatics, which was reported earlier. The model was
      validated in a broad set of tests some of which were based on Monte Carlo
      simulations that included single amino acids, peptides, and proteins. The
      implementation for large-scale MD simulations presented in this article is based
      on a pairwise potential that makes the electrostatic model suitable for fast
      analytical calculation of forces. To assess the suitability of the approach, a
      preliminary validation is conducted, which consists of (i) a 3-ns MD simulation
      of the immunoglobulin-binding domain of streptococcal protein G, a 56-residue
      globular protein and (ii) a 3-ns simulation of Dynorphin, a biological peptide of
      17 amino acids. In both cases, the results are compared with those obtained from
      MD simulations using explicit water (EW) molecules in an all-atom representation.
      The initial structure of Dynorphin was assumed to be an alpha-helix between
      residues 1 and 9 as suggested from NMR measurements in micelles. The results
      obtained in the MD simulations show that the helical structure collapses early in
      the simulation, a behavior observed in the EW simulation and consistent with
      spectroscopic data that suggest that the peptide may adopt mainly an extended
      conformation in water. The dynamics of protein G calculated with the SCP implicit
      solvent model (SCP-ISM) reveals a stable structure that conserves all the
      elements of secondary structure throughout the entire simulation time. The
      average structures calculated from the trajectories with the implicit and
      explicit solvent models had a cRMSD of 1.1 A, whereas each average structure had
      a cRMSD of about 0.8A with respect to the X-ray structure. The main
      conformational differences of the average structures with respect to the crystal
      structure occur in the loop involving residues 8-14. Despite the overall
      similarity of the simulated dynamics with EW and SCP models, fluctuations of side
      chains are larger when the implicit solvent is used, especially in solvent
      exposed side-chains. The MD simulation of Dynorphin was extended to 40 ns to
      study its behavior in an aqueous environment. This long simulation showed that
      the peptide has a tendency to form an alpha-helical structure in water, but the
      stabilization free energy is too weak, resulting in frequent interconversions
      between random and helical conformations during the simulation time. The results
      reported here suggest that the SCP implicit solvent model is adequate to describe
      electrostatic effects in MD simulation of both peptides and proteins using the
      same set of parameters. It is suggested that the present approach could form the
      basis for the development of a reliable and general continuum approach for use in
      molecular biology, and directions are outlined for attaining this long-term goal.

PMID- 12596269
TI  - Hidden order in the GroEL-GroES-(ADP)7 chaperonin: forms, folding, and ADP
      binding sites.
AB  - A molecular crystallography approach reveals the existence of a hidden order in
      GroEL-GroES-(ADP)(7). The new crystallographic symmetry concepts required are
      first illustrated for a hypothetical planar molecule. Their application to the
      chaperonin complex leads to molecular forms with vertices having integral
      coordinates (the indices) with respect to a symmetry-adapted basis and to folding
      points approximated by ideal C(alpha) positions with rational indices connected
      by integral scale-rotations, just as for the vertices of the molecular forms. The
      Mg(+2)-ions at nucleotide binding sites are symmetry-related in a similar way to
      C(alpha)'s folding points.

PMID- 12596270
TI  - Characterization of the electrophile binding site and substrate binding mode of
      the 26-kDa glutathione S-transferase from Schistosoma japonicum.
AB  - The 26-kDa glutathione S-transferase from Schistosoma japonicum (Sj26GST), a
      helminth worm that causes schistosomiasis, catalyzes the conjugation of
      glutathione with toxic secondary products of membrane lipid peroxidation. Crystal
      structures of Sj26GST in complex with glutathione sulfonate (Sj26GSTSLF), S-hexyl
      glutathione (Sj26GSTHEX), and S-2-iodobenzyl glutathione (Sj26GSTIBZ) allow
      characterization of the electrophile binding site (H site) of Sj26GST. The S
      hexyl and S-2-iodobenzyl moieties of these product analogs bind in a pocket
      defined by side-chains from the beta1-alpha1 loop (Tyr7, Trp8, Ile10, Gly12,
      Leu13), helix alpha4 (Arg103, Tyr104, Ser107, Tyr111), and the C-terminal coil
      (Gln204, Gly205, Trp206, Gln207). Changes in the Ser107 and Gln204 dihedral
      angles make the H site more hydrophobic in the Sj26GSTHEX complex relative to the
      ligand-free structure. These structures, together with docking studies, indicate
      a possible binding mode of Sj26GST to its physiologic substrates 4-hydroxynon-2
      enal (4HNE), trans-non-2-enal (NE), and ethacrynic acid (EA). In this binding
      mode, hydrogen bonds of Tyr111 and Gln207 to the carbonyl oxygen atoms of 4HNE,
      NE, and EA could orient the substrates and enhance their electrophilicity to
      promote conjugation with glutathione.

PMID- 12596271
TI  - Time scale of protein aggregation dictated by liquid-liquid demixing.
AB  - The growing impact of protein aggregation pathologies, together with the current
      high need for extensive information on protein structures are focusing much
      interest on the physics underlying the nucleation and growth of protein
      aggregates and crystals. Sickle Cell Hemoglobin (HbS), a point-mutant form of
      normal human Hemoglobin (HbA), is the first recognized and best-studied case of
      pathologically aggregating protein. Here we reanalyze kinetic data on nucleation
      of deoxy-HbS aggregates by referring them to the (concentration-dependent)
      temperature T(s) characterizing the occurrence of the phase transition of liquid
      liquid demixing (LLD) of the solution. In this way, and by appropriate scaling of
      kinetic data at different concentrations, so as to normalize their spans, the
      apparently disparate sets of data are seen to fall on a master curve. Expressing
      the master curve vs. the parameter epsilon = (T - T(s)) / T(s), familiar from
      phase transition theory, allows eliciting the role of anomalously large
      concentration fluctuations associated with the LLD phase transition and also
      allows decoupling quantitatively the role of such fluctuations from that of
      microscopic, inter-protein interactions leading to nucleation. Referring to
      epsilon shows how in a narrow temperature span, that is at T - T(s), nucleation
      kinetics can undergo orders-of-magnitude changes, unexpected in terms of ordinary
      chemical kinetics. The same is true for similarly small changes of other
      parameters (pH, salts, precipitants), capable of altering T(s) and consequently
      epsilon. This offers the rationale for understanding how apparently minor changes
      of parameters can dramatically affect protein aggregation and related diseases.

PMID- 12596272
TI  - Prevention of damage caused by sural nerve withdrawal for nerve grafting.
AB  - Sural nerve withdrawal in peripheral nerve surgery is commonly performed for
      grafting nerve lesions with gap. Notwithstanding its popular use, this procedure
      is not entirely without fault as painful neuromas can occur after the withdrawal.
      We have treated 24 cases of painful neuromas of sural nerve after withdrawal; 11
      of which were treated surgically. A safe procedure to cure and to prevent such
      neuromas is described - the electrical coagulation of the stump of the nerve by
      slowly increasing the intensity of the current. This procedure has been devised
      based on the fact that electrically burnt patients do not produce painful
      neuromas. An experimental histological study performed on rats demonstrated that
      slow electrical burning of the stump of a severed nerve prevents the formation of
      intraneural fibrosis which, on the contrary, forms abundantly when the cut nerve
      is not coagulated.

PMID- 12596273
TI  - Hand surgery and the internet: results of a worldwide survey.
AB  - The opportunities offered by the Internet are employed increasingly in medicine.
      To obtain data on the extent to which the Internet is used by hand surgeons,
      survey forms were sent to 1043 participants of the Congress of the IFSSH in
      Vancouver in 1998. Ninety-four per cent of the respondents use the Internet. Most
      of the participants use the World Wide Web for literature searches, information
      on events and to read scientific articles. E-mail is used for general and
      scientific communication with colleagues and also for transmission of patient
      related data. Perceived apprehensions include secure transmission of sensitive
      data, slow data transmission, and the lack of structure and of an authority to
      control the contents of the Internet. Virtual congresses and a newsgroup on hand
      surgery seem to be worthwhile future goals. Some problems pointed out in this
      survey have already been solved, at least partially, and possible solutions for
      the rest are discussed.

PMID- 12596274
TI  - Factors influencing prognosis after direct repair of the flexor pollicis longus
      tendon: multivariate regression model analysis.
AB  - Few studies have focused on the relevance of early motion exercise on repair of
      the flexor pollicis longus tendon. We evaluated 29 patients with flexor pollicis
      longus tendon lacerations treated by direct end-to-end suture, and statistically
      assessed the clinical factors that influenced the results by using a multivariate
      logistic regression model. Association with age, vascular damage and timing of
      repair did not affect the results. Patients with flexor pollicis longus tendon
      lacerations in zone II or with the tendon stumps retracted proximally had a
      significantly high risk of unsatisfactory results. Postoperative passive flexion
      and active extension exercise using rubber bands significantly decreased the risk
      of unsatisfactory results in these conditions. Results of this study indicate
      that early postoperative motion is useful after every FPL tendon repair,
      particularly in patients with zone II laceration or retraction of the proximal
      tendon stump.

PMID- 12596275
TI  - A dynamic anatomical study of ulnar nerve motion after anterior transposition for
      cubital tunnel syndrome.
AB  - Cubital tunnel syndrome is the second most commonly encountered compression
      neuropathy of the upper limb. Multiple techniques for surgical management have
      been proposed but no universally accepted algorithm for management exists. Six
      cadaveric upper limbs underwent ulnar nerve decompression and anterior
      transposition into subcutaneous and then submuscular positions. After marking
      nerves with tungsten, radiological examination of nerve motion was performed and
      nerve angulations were measured in the region of the flexor carpi ulnaris (FCU)
      origin. Comparison of ulnar nerves in each position revealed statistically
      significant greater angulation after subcutaneous transposition than after
      submuscular transposition with the elbow held in full flexion. This point of
      angulation may act as a secondary point of compression or as a focus for neuritis
      and scar formation. This finding can contribute to the understanding of why
      differing outcomes may be observed after different forms of anterior
      transposition.

PMID- 12596276
TI  - Maintaining wrist function in severe rheumatoid arthritis: a case study of
      revision Swanson wrist arthroplasty staged via a wrist fusion in rheumatoid
      arthritis.
AB  - We present a case of revision Swanson wrist arthroplasty staged via a wrist
      fusion in a patient with rheumatoid arthritis. Due to extensive bone loss in the
      rheumatoid patient, it may not be possible initially to revise a wrist
      arthroplasty; however after fusion with a bone graft to regain bone stock we have
      demonstrated that this is possible. It may even be possible to convert such a
      fusion to a total wrist arthroplasty.

PMID- 12596277
TI  - The radiological appearance of recurrent phalangeal sarcoidosis.
AB  - Sarcoidosis of the phalanx is rare and is usually associated with severe systemic
      disease. We present a patient with recurrent phalangeal sarcoidosis and new
      evidence of a changing radiological pattern. The clinical presentation and
      outcome is discussed. High dose steroid treatment and careful long-term follow-up
      is recommended.

PMID- 12596278
TI  - Static scapholunate dissociation diagnosed by scapholunate gap view in wrists
      with or without distal radius fractures.
AB  - This prospective study investigated static scapholunate dissociation (SLD) in
      wrists associated with distal radius fractures. SLD was detected as a widening of
      the scapholunate (SL) joint interval by SL gap view. Ninety-six distal radius
      fractures and 154 normal wrists were investigated by SL gap view, which is better
      for detecting SLD than the standard posteroanterior (PA) view. Incidences of non
      symptomatic SLD detected by SL gap view in normal wrists increased by age. In the
      young age bracket, incidences of SLD in distal radius fractures were
      significantly higher than in normal wrists. Our results indicated that in
      patients younger than 30 years old, SLD in distal radius fractures was a fracture
      caused abnormality. In those over 30, ascribing SLD to the fracture was
      difficult. Close examinations, like arthroscopy and dynamic cineradiography, need
      to be made in patients with SLD associated with distal radius fractures,
      especially in those younger than 30.

PMID- 12596279
TI  - Kienbock's disease in systemic lupus erythematosus.
AB  - We report two cases of Kienbock's disease associated with systemic lupus
      erythematosus SLE. The characteristics of these cases associated with SLE
      differed from those previously reported for Kienbock's disease. Corticosteroid
      may be a cause of Kienbock's disease in SLE.

PMID- 12596280
TI  - Interposition arthroplasty for osteoarthritis of trapezio metacarpal joint:
      results of a modified incision and technique of interposing with early
      mobilisation.
AB  - Sixty flexor carpi radialis (FCR) tendon interposition arthroplasties were done
      using a modified incision from Froimson's approach for osteoarthritis (OA) of
      thumb carpo metacarpal joint (CMCJ) The tendon was made to resemble an anchovy
      fillet to preserve pillar length (average 7.5 mm). There was no incidence of
      injury to the superficial branch of the radial nerve. Graded mobilisation was
      commenced at two weeks. Our average follow-up for five and a half years shows
      good results, viz. pain relief (100%), power grip (21 kg), pinch grip (4.2 kg),
      tripod grip (5.5 kg), key grip (6.5 kg), ability to touch base and tip of little
      finger (91.6%) and (96.6%), respectively. Activities of daily living (ADL)
      without pain in turning a key (96.7%), opening jar top (100%), bottle top
      (93.4%), wringing cloth (86.7%), and using scissors (88.4%). None of them
      suffered reflex sympathetic dystrophy (RSD) and mobility was almost equal to the
      non-operated hand. Our experience with this modified incision and technique of
      interposing with early mobilisation has shown good functional outcome with no
      significant operative or postoperative complications.

PMID- 12596281
TI  - Application of splinting in hand rehabilitation: a reflection of local practice.
AB  - Occupational therapists in Hong Kong have been very active in the management of
      patients with traumatic hand injuries due to industrial accidents. Splints have
      been prescribed as an adjunct to the exercise programme in rehabilitation. Other
      than the conventional thermoplastic splinting materials, metal hinges, coils and
      plastic strapping were used in splinting. The ultimate goal is to maximise the
      hand functions such that these workers could resume their work roles.

PMID- 12596282
TI  - Classification of hand splinting.
AB  - The terminology in describing splint or orthosis has been reviewed but there is
      no one single system adopted universally. Joint efforts by doctors, therapists
      and orthotists had been set up to review the classification of splint. Four ways
      of classifying hand splints have been introduced: namely, eponym, acronym,
      descriptive classification system and the classification system proposed by the
      American Society of Hand Therapists. These systems include the use of rote memory
      or logical deduction in grouping of splints. This paper describes the advantages
      and disadvantages of each classification system. Neither one of the systems
      stands out to be the best. A combination of the advantages of different systems,
      such as precision and logical deduction, may be an option for developing a new
      system. Moreover, communication, documentation and other environmental factors
      should also be considered.

PMID- 12596283
TI  - Evidence-based practice in splinting the injured hand.
AB  - Evidence-based medicine has been practised in the early 1990s in the Western
      countries and its model has aroused interests in the Asian countries including
      Hong Kong in the late 1990s. The need for evidence-based practice was called upon
      by Sackett and his colleagues 14-16 mainly because of the exponential growth of
      new evidence of treatment effectiveness. There is a great demand for clinicians
      to search for the best evidence and to incorporate into the daily practice so as
      to ensure the best quality and standard of treatment. This paper is to review the
      development and process of evidence-based practice in the area of hand splinting
      for our local clinicians. Some major problems were identified in the delivery of
      clinical evidence-based practice, and suggestions have been made to overcome
      these problems with a view in supporting its model in the local clinical field.

PMID- 12596284
TI  - Physiological and biomechanical principles in splinting the traumatised hands.
AB  - The aim of this article is to review the biological sequence of wound repair and
      the rationale of using splintage to modify the healing process. Appropriate use
      of splintage and controlled stress can prevent adhesion and periarticular
      fibrosis. Splinting prescribed at appropriate timing and methods will enhance
      wound healing and tissue remodelling. In reverse, it will cause permanent damage
      to the tissues.

PMID- 12596285
TI  - Management of simple finger injuries: the splinting regime.
AB  - Mallet finger injury, ligamentous sprain and dislocation of proximal
      interphalangeal (PIP) joint of fingers are very common types of simple hand
      injuries. Immediate correction of alignment and protection of the injured area
      will facilitate early joint movement while maximising functional recovery. This
      article is to introduce the fabrication of three simple finger splints to tackle
      these injuries for quick and effective conservative treatment. They are the
      mallet finger splint, buddy splint and dorsal finger block splint. The
      indications and functions of the three types of splints are discussed. The
      fabrication process will be illustrated; including materials needed, pattern
      drafting and steps of molding. Wearing regime and precautions will be highlighted
      to ensure effective patient compliance to splinting programme for the finger
      injuries.

PMID- 12596286
TI  - Splinting programme for patients with burnt hand.
AB  - Splintage is commonly used in conjunction with pressure therapy to tackle the
      contracted scars, make it supple and thus minimise dysfunction. A static or
      dynamic splint can provide valuable therapy that goes beyond any treatment
      session. The patient's active participation in the splint programme can
      facilitate early recovery. A good splinting design and wearing regime often
      depends on the therapist's understanding and integration of visco-elastic
      properties in soft tissues, maturation process of hypertrophic scars and
      mechanical principles in splinting. Different types of splints serve different
      functions at different stages of rehabilitation. A suitable and efficient
      application of splints can minimise most of the corrective surgical intervention
      and alleviate psychological trauma. This article attempts to highlight the
      clinical rationale and special considerations when applying different splintage
      on burns patients with upper limbs involvement.

PMID- 12596287
TI  - Splinting programmes for tendon injuries.
AB  - It is beyond doubt that splinting programmes have often been an integral and
      important part of the rehabilitation process in tendon injuries. Over the past
      three decades, hand splints for tendon injuries of various designs and different
      mobilisation programmes have been developed in the hope of pursuing better
      clinical and functional outcome for patients. In this paper, the development of
      different splinting programmes in flexor and extensor tendon injuries and the
      current practice in some acute hospitals in Hong Kong were discussed.

PMID- 12596288
TI  - Splinting for peripheral nerve injury in upper limb.
AB  - The prognosis and speed of peripheral nerve recovery depend very much on the
      level of injury, severity of injury, the surgical intervention and the subsequent
      rehabilitative process. Many high level injuries may take years or months for the
      affected peripheral nerve to recover. Prolonged muscle imbalance causes joint
      contractures and over-stretching of denervated muscles. Without proper care, hand
      function recovery may be limited even the nerve regenerated afterwards. During
      the nerve regeneration period, splinting is one of the most useful modality to
      minimise deformities, prevent joint contractures and substitute loss motor
      control. Proper splinting encourages early use of the injured hand in daily
      activities. There are different types of splinting design for median nerve palsy,
      ulnar nerve palsy and radial nerve palsy. Dynamic splinting techniques are
      frequently employed to allow early prehension activities. Other therapeutic
      techniques, including pressure garment and sensory re-education are useful to
      enhance better functional return after nerve repair.

PMID- 12596289
TI  - Management of stiff hand: an occupational therapy perspective.
AB  - Joint stiffness, resulting from a variety of complications after hand injuries,
      remains a common problem. Prolonged swelling, scar formation and shortening of
      soft tissue after prolonged period of immobilisation are the major causes leading
      to the loss of joint range of motion. Treatment used to improve the joint
      stiffness should be integrative and problem-focused. Pressure therapy, active and
      passive mobilisation through remedial activities and corrective splinting should
      be started as soon as problems arise. Applying low-load stress through prolonged
      periods of time onto the shortened tissue at its maximum tolerable range is the
      main principle in restoration of passive joint range of motion. The greater the
      joint limitation becomes, the longer the time the splint should be applied.
      Therapists should understand the process of tissue healing and different
      functions of splints before a correct and effective splint can be prescribed
      properly.

PMID- 12596290
TI  - Percutaneous cannulated screw fixation of acute scaphoid fractures.
AB  - Percutaneous cannulated screw fixation (PCSF) of acute scaphoid fractures has
      been shown to consistently produce good results. It is less invasive and avoids
      damage to the radiocarpal ligaments. The scar is good. The procedure could be
      performed under Bier's block anaesthesia. No cast is required after the operation
      and the range of wrist motion is regained early. Most recently reported series
      achieved more than 95% primary radiological fracture union. The functional
      results were good. The surgical technique of PCSF is described in detail and
      special tricks for difficult problems are highlighted.

PMID- 12596291
TI  - A cadaveric model for biomechanical study of fixation methods for AO type C2
      fractures of distal radius: design and testing with dorsal plating fixation.

PMID- 12596292
TI  - Primary lymphocutaneous nocardiosis caused by Nocardia otitidiscaviarum.
AB  - A case of primary lymphocutaneous nocardiosis caused by Nocardia otitidiscaviarum
      in a 69-year-old previously healthy woman is described. The organism was
      identified in cultures of pus specimens. The patient was treated with a six-month
      course of oral trimethoprim-sulfamethoxazole chemotherapy following incision and
      drainage, and the infection completely resolved.

PMID- 12596293
TI  - Multiple tendons of the abductor pollicis longus muscle.
AB  - In the case presented below, we observed abductor pollicis longus (APL) dividing
      into five sections shortly after exiting the first compartment. Many variations
      of APL may be seen and it is essential to know these variations in the practice
      of hand surgery.

PMID- 12596294
TI  - Isolated radial nerve palsy in a newborn: report of two cases.
AB  - Two newborns with history of difficult birth were diagnosed within 24 hours after
      birth with isolated radial nerve palsy. Both newborns recovered completely.
      Awareness and multidisciplinary approach is essential.

PMID- 12596295
TI  - Bowenoid basal cell carcinoma of the thumb: a case report and review of the
      literature.
AB  - Basal cell carcinoma (BCC) is the most common skin malignancy arising from cells
      of the basal layer of the epithelium or from the external root sheath of the hair
      follicle. BCC of the digit is a rare entity. The article presents one such case
      of bowenoid BCC of the thumb which required amputation at the MP joint.

PMID- 12596296
TI  - A recurrent case of carpal tunnel syndrome in haemodialysis.
AB  - Herein is described a haemodialysis patient with bilateral carpal tunnel syndrome
      suffering from recurrence unilaterally after undergoing numerous surgeries of
      varying methods. On the left side, she received carpal tunnel release via open
      method in our clinic, and has not suffered from recurrence in eight years. On the
      right side, she received endoscopic carpal tunnel release twice in seven years,
      and subsequently underwent open carpal tunnel release in our clinic for
      recurrence. For carpal tunnel syndrome in haemodialysis patients, we recommend
      open surgery rather than endoscopic surgery.

PMID- 12596298
TI  - [Progress and actuality of human assistant reproduction and derivative
      technology]

PMID- 12596297
TI  - Digital nerve grafting using the terminal branch of posterior interosseous nerve:
      a report of three cases.
AB  - We report three cases of digital nerve grafting using the terminal branch of
      posterior interosseous nerve.

PMID- 12596299
TI  - [Detection of multiple loci in single cell by primer extension preamplification
      and nest PCR]
AB  - OBJECTIVE: To investigate the feasibility of multiple loci detection in single
      cell by primer extension preamplification (PEP) followed by nest PCR. METHODS:
      Using PEP, the whole genomic DNA in single lymphocyte or single blastomere was
      amplified. In addition, CD17, nt-28 and linked ATTTT repeat for beta-thalassemia,
      F508 and linked GATT repeat for cystic fibrosis, DMD exon 17 and 48 for Duchenne
      muscular dystrophy, short tandem repeats of D18S51, D21S11 and D21S1411, and sex
      determination gene SRY of the Y chromosome were all detected using nest-PCR from
      a small aliquot of the PEP reaction. RESULTS: The rate of successful single
      lymphocyte amplification was 89.5%(false positive 0.48%false negative 2.5%). The
      rate of successful single blastomere amplification was 85.56%(false positive 3%).
      CONCLUSION: The PEP technique followed by nest PCR analysis of single cell is
      very useful for simultaneous detection of multiple gene loci. It may be
      applicable for preimplantation genetic diagnosis.

PMID- 12596300
TI  - [Preimplantation genetic diagnosis: two successful cases]
AB  - OBJECTIVE: To establish a technology of preimplantation genetic diagnosis.
      METHODS: Intracytoplasm sperm injection and blastomere biopsy were performed on
      two women at the advanced age with the fallopian tube obstruction. Normal embryos
      were selected for embryo transfer after fluorescence in-situ hybridziation in
      biopsied blastomere. RESULTS: The levels of serum HCG were increased 20 days
      after embryo transfer and ultrasonography in 16 gestation weeks showed the fetal
      growth and structure are normal. CONCLUSION: Two successful clinical pregnancies
      achieved after preimplantation genetic diagnosis.

PMID- 12596301
TI  - [Follicle-stimulating hormone receptor levels in relation to ovarian cycling
      response from gonadotropin hormone stimulation]
AB  - OBJECTIVE: To investigate the relationship between the ovarian response, induced
      by gonadotropin hormone, and levels of follicle-stimulating hormone receptor
      (FSHR). METHODS: The level of ovarian response was divided into three groups
      based on the number of follicles obtained during oocyte retrieval: poor
      responders (<4 follicles), normal responders (4 approximate, equals 13) and high
      responders(>13 follicles). FSHR mRNA was measured using reverse transcription
      polymerase chain reaction (RT-PCR). RESULTS: The expression of FSHR mRNA in the
      poor responders was 0.54+/-0.07. This was much lower than that of the normal
      responders who were at 0.90+/-0.17,and the high responders who were at 1.20+/
      0.45(P<0.05). CONCLUSION: Ovarian response induced by gonadotropin hormone
      stimulation is correlated with the level of FSHR mRNA in the granulosa cells.

PMID- 12596302
TI  - [Impact of leptin levels on outcome of in vitro fertilization-embryo transfer]
AB  - OBJECTIVE: To investigate the impact of ovarian stimulation on leptin levels and
      their effect on in vitro fertilization-embryo transfer (IVF-ET). METHODS: In 39
      women who underwent IVF-ET, serum and follicular fluid leptin and E(2) levels
      were measured by enzyme-linked immunosorbent assay and radioimmunoassay. Blood
      samples were collected just prior to FSH and HCG injection and follicles
      puncture. Follicular fluid was collected at the time of oocyte retrieval.
      RESULTS: The serum leptin levels before HCG administration (26.1+/-2.3)&mgr;g/L
      were significantly higher than before FSH administration (9.3+/-1.0)&mgr;g/L and
      oocyte retrieval (15.8+/-2.3)&mgr;g/L(P<0.001). On the day of oocyte retrieval,
      there was no significant difference between the serum leptin(15.8+/
      2.3)&mgr;g/L.and the follicular fluid leptin (18.5+/-2.2)&mgr;g/L. Serum and
      follicular leptin levels in successful pregnancies were significantly
      lower(P<0.05) than in women with failed conception. CONCLUSION: It could indicate
      that high leptin levels may interfere with the developing of dominant follicles.

PMID- 12596303
TI  - [The effect of the expression of matrix metalloproteinase-9 and tissue inhibitor
      of metalloproteinase-1 protein on the window phase of endometrial implantation in
      unexplained infertillie women]
AB  - OBJECTIVE: To explore the role of matrix metalloproteinase-9 (MMP-9) and tissue
      inhibitor of metalloproteinase-1 ( TIMP-1) protein on embryo implantation in
      unexplained infertile women. METHODS: Forty three women were divided into two
      groups: 29 unexplained infertile (study group) and 14 women with normal fertile
      function (control group).Immunohistochemical analysis was applied to measure the
      cell expression of MMP-9 and TIMP-1 in the endometrial implantation window phase
      of the two groups. RESULTS: The cells positive for these solu-ble proteinases
      were found in the epithelial and stromal cells in all endometrial samples. Semi
      quantitative analysis showed that,MMP-9 and TIMP-1 were weaker in the endometrial
      glandular cells of infertile women then in those of the control group(MMP
      9:230.79+/-43.92 compared with 307.78+/-44.25; TIMP-1:233.05+/-48.51 compared
      with 297.86+/-35.56,P<0.05). There was no statistical correlation between MMP-9
      and TIMP-1 with blood estradiol(E(2)) and progesterone (P) in the two groups
      (P>0.05). But in control group, there was a negative correlation tendency in MMP
      9/P and TIMP-1/P (MMP-9/P: r=-0.330,TIMP-1/P: r=-0.401). CONCLUSION: In
      unexplained inferrile women, the low expression of MMP-9 and TIMP-1 protein in
      the implantation window phase may be one of the important factors that affect the
      embryo impantation.

PMID- 12596304
TI  - [Endometrial insulin-like growth factor II and type I receptor in unexplained
      infertility and its steroid regulation]
AB  - OBJECTIVE: To investigate the endometrial expression of insulin-like growth
      factor II(IGF-II) and type I receptor(IGF-1R) in unexplained infertility.
      METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to
      detect and quantify endometrial IGF-II and IGF-I R mRNA experession in the mid
      luteal phase. Serum concentrations of estradiol(E(2)) and progesterone (P) were
      measured by radioimmunoassays. Thirty-four women with unexplained infertility
      were included in the study group. Twenty-one women with normal fertility were
      selected as the control group. RESULTS: Endometrial IGF-II and IGF-I R mRNA
      experession during the midluteal phase were significantly lower in the study
      group than in the control group (0.662 +/- 0.371 compared with 0.961+/- 0.389, P<
      0.05; 0.582 +/- 0.257 compared with 0.829 +/-0.341, P< 0.05 respectively). The
      average serum P level in the study group was significantly lower than in the
      control group (23.782 +/-15.459 compared with 43.142 +/- 16.549nmol/L, P< 0.005).
      IGF-II mRNA expression correlated positively with IGF-I R mRNA expression in the
      two groups. Serum P level correlated positively with IGF-II and IGF-I R mRNA
      expression in the two groups. CONCLUSION: IGF-II and IGF-I R may play an
      important role in the implantation process. Their decreased expression relating
      to decreased P level may be important in unexplained infertility.

PMID- 12596305
TI  - [Gonadotropin-releasing hormone agonist stimulation test in anovulatory women]
AB  - OBJECTIVE: To evaluate the predictive value of ovarian response to the
      gonadotropin-releasing hormone agonist (GnRH-alpha) stimulation test (GAST) in
      anovulatory women during ovulation induction treatment. METHODS: Thirty-five
      patients entered and completed the study. Following administration of GnRH-alpha
      during the early follicular phase, the relationship between estradiol (E(2))
      response, ovarian response and subsequent pregnancy was investigated. RESULTS:
      Three patterns of E(2) response were noted. Pattern A patients were hyper
      responders in induction treatment;their peak E(2) levels were the highest
      (14426.6 pmol/L) and they produced the most mature follicales (27.3 +/- 9.7 ).
      Thus pattern A patients had the highest risk of ovarian hyperstimulation syndrome
      (OHSS). (81.8 % ), cancellation cycle rate(72.7 % )and low pregnancy rate(18.2 %
      ). Pattern B patients had a favorable ovarian response with the highest pregnancy
      rate(62.5 % ). Pattern C was associated with a poor ovarian response. CONCLUSION:
      During ovulation induction treatment, GAST can be used to predict ovarian
      response of anovulatory women. This technique may enable us to design an ovarian
      induction protocol that would both reduce OHSS and increase pregnancy rate.

PMID- 12596306
TI  - [Correlation between polyspermy and the outcome of in vitro fertilization-embryo
      transfer]
AB  - OBJECTIVE: To explore the influence of polyspermy on IVF outcomes in in vitro
      fertilization and embryo transfer(IVF-ET). METHODS: The data from 496 IVF-ET
      cycles and 5349 oocytes were analyzed retrospectively. A comparison of a number
      of fertility parameters with and without polyspermy was done. The fertility
      parameters were the number of oocytes retrieved, percentage of mature oocytes,
      fertilization rate, cleavage rate, occytes for ET, pregnancy rate. RESULTS: The
      percentage of mature occytes, fertilization rate, cleavage rate was 67.0 %,76.7
      %and 95.6 %, respectively( P< 0.01). The pregnancy rate was higher in polyspermic
      fertilization cycles (25.7 %) than in cycles without polyspermy(23.6 %),but with
      no statistical significance ( P>0.05). CONCLUSION: Polyspermic fertilization is
      correlated with improved oocyte receptibility to sperm and could be considered as
      an encouraging sign for the success of IVF.

PMID- 12596307
TI  - [Molecular cloning of human IL-7cDNA and construction of eukaryotic vector
      expressing hIL-7]
AB  - OBJECTIVE: To construct a vector expressing eukaryotic human interluken-7(hIL-7).
      METHODS: hIL-7 DNA was identified and cloned (cDNA) from human spleen tissue
      using reverse transcription polymerase chain reaction (RT-PCR). We incorporated
      the cDNA into the pMD18-T plasmid. The pMD18-T plasmid was then inserted into a
      dual expression vector (prokaryotic and eukaryotic) pBK-CMV and called pBK-CMV
      hIL-7. We used pBK-CMV-hIL-7 vector to infect E.coli DH5alpha. The expression of
      the recombinant hIL-7 protein (rhIL-7) by E.coli DH5alpha was analyzed using SDS
      PAGE and western blot testing. RESULTS: The genetically engineered E.coli
      DH5alpha did express rhIL-7 confirmed by western blot. CONCLUSION: The successful
      construction of genetically engineered eukaryotic gene for hIL-7 was done, This
      will enable further research into therapeutic uses for hIL-7.

PMID- 12596308
TI  - [Rapid screening of katG gene mutation in isoniazid-resistant Mycobacterium
      tuberculosis]
AB  - OBJECTIVE: To evaluate the relationship between katG gene mutation and isoniazid
      (INH) resistance and to develop a rapid screening method of point mutation in the
      katG gene associated with MTB resistance. METHODS: Twenty-four clinical isolates
      of MTB with 8 INH resigtance isolates and 16 INH-sensitive isolates were analyzed
      by PCR-RFLP, with the H(37)Rv reference strain as the control. RESULTS: G-->C
      point mutations were detected in 7 of 8 isoniazid-resistant strains and no gene
      mutation was shown in 16 isoniazid-sensitive isolates. The sensitivity and
      specificity were 87.5 % and 100 % respectively. No katG gene sequence deletion
      was observed in any specimen. CONCLUSION: Our results suggest katG gene mutation
      is one of the most important mechanisms of INH-resistant TB. PCR-RFLP may be
      useful in detection of katG gene mutation.

PMID- 12596309
TI  - [A study of human enteric nervous system development in the middle stage of
      embryogenesis]
AB  - OBJECTIVE: To investigate the development of the enteric nervous system(ENS) in
      the middle stage(the 4th approximate, equals 6th months) of human embryogenesis.
      METHODS: A histologic evaluation of the clonic enteric nervous system was done
      using NADPHd histochemistry, PAP immunohistochemistry, with anti-PGP 9.5 and anti
      S-100 protein. RESULTS: During this stage of embryology three things were noted.
      (1)The nerves in the myenteric layer increased markedly. This was shown by the
      PGP 9.5 immunoreactive nerves spreading out and the S-100 protein immunoreactive
      nerves forming a "bamboo basket"pattern. (2)The whole myenteric colon showed
      nitrigeric nerves paralleling the growth of the myofibers in the circular muscle
      layer. Nitrigeric perikara were rarely found in the extrinsic submucosal
      layer.(3) In the whole-mounted preparations reactive nerves formed the complex
      nerve net in the myenteric layer. CONCLUSION: The middle stage of embryogensis is
      very important to the development of the colon ENS.

PMID- 12596310
TI  - [Changes of element contents and their interrelationship in tibia of osteoporotic
      rats]
AB  - OBJECTIVE: To observe the changes of bone element contents in osteoporosis and
      their interrelationship. METHODS: Twelve female SD rats,10-month-old, were
      bilaterally ovariectomized (OVX group) and another ten rats were received sham
      operation under anesthesia (SHAM group).The element contents in tibia, including
      Ca, P, Mg, Zn, Mn, Fe, Cu, Mo and Cr, were determined by atomic absorption
      spectrophotometer 7 month later. The data of contents of all elements were
      analyzed by simple regression. RESULTS: Compared with the SHAM group rats, the
      contents of Ca, P and Mg were decreased by 6.6 %(P<0.05), 6.3 %(P<0.05) and 14.9
      %(P<0.01) respectively. The contents of Zn and Fe were reduced by 15.2 %(P<0.01)
      and 35.1 %(P<0.01) separately, Mo and Cr were decreased by 12.2 %(P>0.05) and
      14.0 %(P>0.05), while the contents of Mn, Cu and Co were shown no change. There
      was a significant correlation among the contents of Mg, Mn, Zn, Ca and P.
      CONCLUSION: The contents of Ca, P, Mg, Zn and Fe were matkedly reduced in bone of
      osteoporotic rats induced by ovariectomy.

PMID- 12596311
TI  - [Effect of HOE642 on ischemic myocardium reperfusion injury]
AB  - OBJECTIVE: To investigate whether the specific sodium-hydrogen antiporter HOE642
      could modifies myocardial ischemia and reperfusion injury. METHODS: The isolated
      working rat heart model was used. The rats were divided into four subgroups:
      Ischemic reperfusion (Control group),HOE642 given before Ischemia (HOE-Pr),
      HOE642 given during Ischemia (HOE-Is), HOE642 given during reperfusion (HOE-Re).
      LVDP, LVEDP, arrythmia, coronary flow and myocardial enzymes were measured.
      RESULTS: HOE642 given 15 minutes before ischemia increased coronary flow and
      significantly improved cardiac function, reduced the severity of ischemia,
      reperfusion arrhythmia and myocardial CK-MB, LDH release, but had no effect on
      heart rate. HOE642 given during ischemia only reduced LVEDP, the ischemia
      severity, reperfusion arrhythmia and myocardial enzyme release. It had no effect
      on heart rate or LVDP. There were no effects when the drug was given during
      reperfusion. CONCLUSION: HOE642 demonstrates significant cardioprotective
      effects. These protective effects are most significant when the drug is given
      before ischemia is induced.

PMID- 12596312
TI  - [intercellular adhesion molecule-1 and CD11a/CD18 expression in coronary heart
      disease]
AB  - OBJECTIVE: To investigate the expression of soluble intercellular adhesion
      molecule-1(sICAM-1) and CD11a/CD18 in coronary heart disease(CHD). METHODS: The
      sICAM-1 and CD11a/CD18 levels were measured by ELISA and flow cytlemetry in 76
      CHD patients and 65 healthy subjects. RESULTS: The level of sICAM-1 and
      CD11a/CD18 were significantly higher in CHD patients than healthy subjects [SICAM
      1(g/L):263.5 +/-66.2 compared with 205.9 +/-57.2, P<0.01; CD11a/CD18 (%):33.7 +/
      6.4 compared with 19.3 +/-8.1, P<0.001]. They were also significantly higher in
      acute myocardial infarct and unstable angina than that of stable angina patients.
      There was correlation between sICAM-1 and CD11a/CD18(r=0.436, P<0.01).
      CONCLUSION: Elevated levels of sICAM-1 and CD11a/CD18 associated with unstable
      angina and myocardial infarction may indicate their significant role in the
      pathogenesis of acute coronary events.

PMID- 12596313
TI  - [Radiofrequency catheter ablation autonomic nerve injury]
AB  - OBJECTIVE: To investigate the correlation between RFCA catheter cumulative energy
      and autonomic nerve injury. METHODS: Forty-one patients with paroxysmal
      supraventricular tachycardia were enrolled, Patients were excluded if they had
      Diabetes, Hypertension, Congestive Heart Failure or other organic heart disease.
      HRV and biochemical markers were measured before and after the RFCA. RESULTS:
      Compared with pre-ablation values,there was significantly decrease in post
      ablation low frequency (LF) and high frequency (HF). This was noted in both the
      septal group (AVNRT and septal pathway) and free wall group (free wall accessory
      pathway).Post-procedure,the sensitivity of cardiac troponin I(cTnI) for
      myocardial injury detection was 58.3%, AST was 41.7%. This was significantly
      higher than other markers(CK:4.2%, CK-MB:10.4%, LDH:20.8%). The post-ablation
      sensitivity of cTnI was 54.2%, 6.3% and 52.1%at 1 hour, 12 hours, and 24 hours
      respectively. A significant correlation between cumulative energy and delta
      HF(r=0.688,P=0.01) or delta LF (r=0.462, P<0.05).was noted in free wall
      group.(delta HF=pre-ablation HF-post-ablation HF/pre-ablation HF x 100%). There
      was no significant correlation between biochemical markers and either delta HF or
      delta LF. CONCLUSION: RFCA induced injury on cardiac autonomic nerves related to
      both cumulative energy and ablation site,but not size of myocardial injury as
      determined by cTnI measurement. cTnI is an excellent biochemical marker of
      myocardial injury.

PMID- 12596314
TI  - [A comparative study of marginal microleakage using three different cements in
      ceramic crowns]
AB  - OBJECTIVE: To evaluate the marginal microleakage of IPS-Empress 2 all-ceramic
      crowns using three different cements. METHODS: Twenty-four IPS-Empress 2 all
      ceramic crowns were built and luted onto standardly prepared human upper third
      molars using three different cements. All samples were thermocycled then
      submerged in 2% fuchsin for 24 hours. The marginal microleakage at tooth-cement
      and ceramic crown-cement interfaces was observed using light stereomicroscopy.
      RESULTS: The Panavia F adhesive luting system demonstrated the least
      microleakage(0.90+/-0.75, 0.46+/-0.37). Dyract compomer cement showed an
      intermediate level of microleakage (4.71+/-1.68, 5.28+/-1.48). Harvard zinc
      phosphate cement was associated with severe microleakage in all specimens( 6.99+/
      0.04, 6.99+/-0.04). THe differences in microleakage among the three cements was
      highly significant(P<0.01). CONCLUSION: Panavia F adhesive luting system was the
      most effective dental cement to prevent microleakage. It can be used for IPS
      Empress 2 posterior all-ceramic crowns.

PMID- 12596315
TI  - [Dental malocclusion among juveniles in Hangzhou municipality]
AB  - OBJECTIVE: To investigate the prevalence rate, malocclusion type and treatment
      rate as well as awareness of malocclusion among children and adolescents living
      in the Hangzhou municipality. METHODS: 1818 children and adolescents ages 7
      approximate, equals 16 living in Hangzhou municipality were evaluated. RESULTS:
      The overall malocclusion rate was 35.75%. In Angle's classification: Angle I 593
      cases (32.62%), Angle II 48 cases(2.64%),Angle III 9 cases (0.49%). Among the
      malocclusion type of crowding was mixed dentition 70.66%,permanent dentition
      85.89%. In the overjet malocclusion mixed dentition was noted in 60.57% and
      permanent dentition in 51.05%.The type of overbite was mixed dentition
      67.82%,permanent dentition 31.23%. In the crossbite of anterior teeth mixed
      dention was noted in 12.30% and permanent dention in 9.91%. Overall treatment
      rate for malocclusion was 10.15%.CONCLUSION: Among Hangzhou municipality
      juveniles there is both inadequate prevention and treatment of dental
      malocclusion.

PMID- 12596316
TI  - [Transurethral resection of prostate perioperative hypotension]
AB  - OBJECTIVE: To identify the factors to transurethral resection of prostate (TURP)
      perioperative hypotension. METHODS: The study group included 130 patients
      undergoing TURP. The control group included 50 patients who had suprapubic
      prostatectomy. Absorption of irrigation fluid was measured by determining the
      serum gentamycin level. Blood loss of PURP patients was calculated as the product
      of the irrigation fluid volume and hemoglobin concentration (determined with a
      photometer) divided by the preopreative blood hemoglobin concentration. Body
      temperature was recorded using a rectal probe. Serum electrolytes were determined
      pre-and postop. RESULTS: The blood loss in study group (380.2+/-98.3)ml was
      significantly less than in the control group (460.1+/-52.5)ml, P<0.05. However,
      the incidence of hypotension was significantly higher than the control group 28%,
      8%), P<0.01. Factors associated with TURP hypotension included volume of
      irrigation fluid absorption, blood loss, reduction in core temperature, decrease
      of serum sodium, operating time, prostate weight and volume and history of
      cardiovascular disease. After Logistic regression analysis, the most significant
      factors were excessive absorption of irrigation fluid and rapid central cooling.
      CONCLUSION: In our study TURP hypotension most closely correlated with volume of
      irrigation fluid absorbed and reduction in core temperature.

PMID- 12596317
TI  - [Free alpha hCG--a serum marker for pregnancy-induced hypertension]
AB  - OBJECTIVE: To evaluate the free alpha subunit of human chorionic gonadotropin
      (FalphahCG) as a marker for pregnancy-induced hypertension (PIH). METHODS: The
      study group consisted of 74 pregnant women with hypertension. PIH admitted at 21
      43 weeks of gestation. The control group was 37 non-PIH women. Serum FalphahCG
      was measured by radioimmunoassay with monoclonal technology. Using Youden's index
      of the receiver operator characteristic curve(ROC), a threshold value was
      determined. RESULTS: FalphahCG levels in PIH women were significantly higher than
      in the control group women [(556+/-428)IU/L compared with (232+/
      131)IU/L,P<0.001].Using 260 IU/L of FalphahCG as the threshold value yields a
      sensitivity of 81.1% and specificity of 75.7% with a Youden's index of 0.57 for
      predicting PIH. CONCLUSION: Serum FalphahCG may serve as a useful marker to
      predict PIH.

PMID- 12596318
TI  - [Continous intrapartum fetal heart monitoring]
AB  - OBJECTIVE: To observe the prognostic value of intrapartum continuous fetal heart
      monitoring(FHM). METHODS: A review of 150 patients who had intrapartum FHM was
      performed. The relation between fetal heart rate and amniotic fluid condition,
      newborn Apgar scores, and delivery method was determined. RESULTS: Among the 150
      cases,normal fetal heart rates were recorded in 108 cases. The abnormalities in
      the other 42 cases with abnormal FHM were as follows: cloudy amniotic fluid 27
      cases(64.3%)compared with 17/108 (15.7%) in the normal FHM group (P<0.005); 10
      cases (23.8%) had Apgar scores <8 compared with only 2 (1.85%) in the normal FHM
      group (P<0.005). In the abnormal FHM group,there were 15 cases (35.7%) of
      spontaneous labor,10 cases (23.8%) of forceps delivery and 17 cases (40.5%) of C
      section compared with 81, 3, and 24 (75%,2.8%, and 22.2%) respectively in the
      normal FHM group (P<0.005). Spontaneous delivery was more common in the normal
      FHM (75%)compared with abnormal FHM group(35.7%). C-section rate was higher in
      the abnormal FHM group (40.5%) (P<0.005). CONCLUSION: Intrapartum fetal heart
      monitoring detects early fetal distress and thus may lead to earlier intervention
      such as C-section during the perinatal period.

PMID- 12596319
TI  - [A comparative study of computer assistant sperm analysis with rontine sperm
      analysis]
AB  - OBJECTIVE: To compare computer assisted sperm analysis (CASA) with routine sperm
      analysis (RSA) in evaluation of male fertility. METHODS: The results of CASA were
      compared with the RSA of 27 males normal fertility and 317 males with
      infertility. RESULTS: Using the CASA, deformity rate was lower than RSA, it was
      25.10+/-8.57 and 31.48+/-12.81 in the fertile and infertile groups respectively,
      whereas, RSA was 35.56+/-9.58 and 54.56+/-13.47. Fertile group motility had a
      significant difference, it was 61.35+/-7.62 and 83.96+/-6.67. Sperm vitality of
      grades A was 9.10+/-5.50 and 30.33+/-8.85. The vitality of grades B was 31.16+/-
      12.35 and 49.93+/-8.56, the vitality of grades C awas 21.06 +/-14.19,and 3.70+/
      2.12, the vitality of grades D was 38.66+/-7.62 and 16.04+/-6.67. When two
      techniques were adopted, the mobility had no difference in infertile group
      (42.53+/-14.95 and 43.09+/-13.96), the sperm vitality was decreased in grades B
      (CASA 22.67+/-14.96,RSA 33.32+/-13.47), increased in grades C(CASA 17.08+/
      13.47,RSA 7.68+/-5.82), they had significant differences (P<0.01). The grade B
      sperms in the non-forward moving group, CASA was 2.77+/-6.01, RSA 0. In addition,
      VSL, VCL, VAP, ALH, sperm trace and static diagram were adopted. CONCLUSION:
      Using the CASA,the distinguished ability to sperm shape and vigor was lower than
      RSA, but the quantize marker (such as straight line velocity, curved velocity,
      average path velocity and ALH) and moving, static images could reflect on sperms
      quality more objectively.

PMID- 12596320
TI  - [Determination of VMA/Cr and HVA/Cr in random urine collection for the diagnosis
      of neuroblastoma]
AB  - OBJECTIVE: To evaluate the VMA/Cr and HVA/Cr of random urine in the diagnosis of
      neuroblastoma. METHODS: VMA/Cr and HVA/Cr were examined in 50 normal children and
      11 cases of neuroblastoma (NB) aged 1 approximate, equals 5 years. The
      concentration of 4-hydroxy-3-methoxy-mandelic acid (VMA) and homovanillic acid
      (HVA) in random urine collection were analyzed by high-performance liquid
      chromatography and creatinine (Cr) analyzed by auto-biochemical analyzer.
      RESULTS: The normal range of VMA/Cr and HVA/Cr were <14.9 mmol/mol and <23.8
      mmol/mol, respectively. The positive rate of VMA/Cr and HVA/Cr in NB patients was
      90.9%. CONCLUSION: Determination of VMA/Cr and HVA/Cr in random urine collection
      can be used for NB diagnosis.

PMID- 12596321
TI  - [Blue light source in phototherapy]
AB  - OBJECTIVE: To explore the efficacy of blue light-emitting diodes(LEDs) as a novel
      light source for phototherapy. METHODS: Equimolar bilirubin standard albumin
      solutions were irradiated with two light sources; LEDs and single side
      conventional blue light( sCBL). Light intensity was measured with a light meter.
      The emission intensity of LEDs was the same as sCBL. To estimate the effects of
      the two light sources, the change in bilirubin isomer before and during
      phtotherapy was determined using high-performance liquid chromatography. RESULTS:
      The effects of different light sources on equimolar bilirubin standard albumin
      solutions, the lumirubin (LR) and 4Z, 15E-Bilirubin IX alpha(ZE) formation of
      LEDs was the same as sCBL(P>0.05). CONCLUSION: LEDs is equally effective as
      single sCBL for phototherapy in vitro.

PMID- 12596322
TI  - [Clincal analysis of congenital adrenal hypeplasia]

PMID- 12596323
TI  - Hospitals are going the extra mile to contribute to the community.

PMID- 12596324
TI  - OCR issues long-awaited HIPAA privacy guidance.

PMID- 12596325
TI  - Step by step. Creating a plan for capital outlays saves money in the future.

PMID- 12596326
TI  - In training. Mixing television with textbooks improves job satisfaction.

PMID- 12596327
TI  - Guidelines linked to improving patient outcomes.

PMID- 12596328
TI  - The ESRD regulatory landscape: a primer and resource. Part 1.

PMID- 12596329
TI  - Enhancing dialysis services,  revenue,  quality, and efficiency through
      computerization. The impact of medication error reduction.

PMID- 12596330
TI  - Resourceful caregiving.

PMID- 12596331
TI  - Family and social support as metaphors for building geriatric nursing capacity.

PMID- 12596332
TI  - Elder abuse and neglect assessment.

PMID- 12596333
TI  - Evidence-based protocol. Family bereavement support before and after the death of
      a nursing home resident.
AB  - Front-line caregivers in nursing homes frequently provide bereavement support to
      family members before and after the death of a nursing home resident. Use of the
      evidence-based guideline "Family Bereavement Support Before and After the Death
      of a Nursing Home Resident" (Davidson, 2002) can reduce uncertainty and increase
      the confidence of staff providing before and after death care to families, and
      can ensure all families receive consistent bereavement support.

PMID- 12596334
TI  - Korean adult child caregivers of older adults with dementia. Predictors of burden
      and satisfaction.

PMID- 12596335
TI  - Friends and social support in dementia caregiving. Assessment and intervention.
AB  - The purpose of this article is to explore the topic of friends as a spontaneously
      occurring response in open-ended interviews with dementia caregivers and to
      propose guidelines for assessment and intervention based on current knowledge.
      The sample includes 176 open-ended baseline interviews with dementia caregivers
      drawn from the National Caregivers Training Study, a 4-year multi-site,
      randomized, community-based, psycho-educational intervention study. References to
      friends were present in 60 of the 176 baseline transcripts. More than 50% of the
      references were positive, 63% referred to the present, 80% of the content scores
      were greater than 1, and 66% were categorized as emotional support or social
      integration for caregivers. Meaningful categories exist and can be helpful in
      structuring the assessment of support from friends. Data support prior research
      suggesting that friends are providers and facilitators of emotional support and
      social integration. Although further research is needed on the concept of social
      support in general and social network providers in particular (e.g., friends),
      current knowledge allows for preliminary recommendations for assessment and
      intervention of friends and social support.

PMID- 12596336
TI  - Training family caregivers of patients with dementia. A structured workshop
      approach.
AB  - The Minnesota Family Workshop consisted of seven weekly 2-hour sessions that
      provided education, family support, and skills training to primary family
      caregivers of patients with dementia, and other accompanying family members. The
      interdisciplinary faculty used a general stress and coping model to design the
      caregiver education program. To increase family involvement, the Minnesota Family
      Workshop required at least one other family member accompany the primary
      caregiver to the sessions. In addition, a concurrent adapted activity group was
      offered for the patients with dementia. This 14-hour curriculum with specific
      weekly objectives and activities detailed in this article was successful in
      reducing burden among caregivers of patients with dementia.

PMID- 12596337
TI  - Resident and family perspectives. The first year in a long-term care facility.
AB  - The purpose of this longitudinal study was to explore perspectives, needs, and
      expectations of residents (N = 6) and family members (N = 3) of the resident's
      first year in a long-term care facility. The narrative method and a semi
      structured interview guide were used to obtain participants' views at 2 and 6
      weeks, and 3, 6, 9, and 12 months after admission. During data analysis, six
      themes emerged, which suggest implications for gerontological nursing education
      and practice. The authors conclude that by listening to residents and family
      members, nurses can use this information to improve life for residents and
      dignify them as individuals.

PMID- 12596338
TI  - What is the role of the employee assistance program in case management?

PMID- 12596339
TI  - Finding disability related information on the Web.

PMID- 12596340
TI  - Women's health issues and the occupational health nurse's role.

PMID- 12596341
TI  - Identifying women at risk for coronary artery disease.
AB  - Women differ from men in presentation, pathology, and prevention of CAD. After
      women at risk are identified, primary and secondary prevention measures should be
      implemented for individual workers and their families. To be effective in
      managing CAD, risk reduction measures should be employed. However, nurses also
      need to be able to identify the often atypical symptoms that women present with
      in CAD to provide appropriate and swift care (Anderson, 2001). The occupational
      health nurse is in a unique position to assist in improving the health of many
      within the worksite. The nurse can perform the risk assessment and plan with
      employees to reduce the identified risks and, thus, improve the quality of their
      lives. Getting employees engaged in self care by helping to set realistic goals
      and acting as a support in their endeavors toward this end could be the incentive
      needed to begin on the path to a healthier lifestyle.

PMID- 12596342
TI  - Polycystic ovarian syndrome. A challenge for occupational health nursing.
AB  - Polycystic ovarian syndrome is a complex problem affecting as many as 10% of a
      company's female work force. The condition commonly presents with symptoms of
      oligomenorrhea or amenorrhea, central obesity, and hirsutism. Stein (1935) first
      postulated the condition as cystic ovaries resulting from continuous LH
      stimulation. A current hypothesis is that PCOS may be two conditions--one
      resulting from LH and a second the result of a hyperinsulinemia. Weight loss and
      exercise, often difficult to maintain, can often return a woman to normal
      ovulatory cycles. First line pharmocotherapy includes OCs with desogestral as the
      progestin component. Antiandrogens such as spironolactone can be added to
      increase the antiandrogen effect. The occupational health nurse may be the only
      health care provider with whom the employee comes into contact who is able to see
      the impact of the syndrome over time, thus allowing the opportunity to counsel
      employees about long term risk reducing behaviors.

PMID- 12596343
TI  - Metabolic syndrome.
AB  - This article discusses metabolic syndrome, which has recently been defined by the
      National Institutes of Health (2001) and affects approximately 47 million
      Americans. Suggestions have been included for risk factor identification,
      prevention measures, and intervention guidelines for the components of metabolic
      syndrome. Many Americans with metabolic syndrome will be in the workplace. Thus,
      the role of the occupational health nurse in the prevention of metabolic syndrome
      is vital. Prevention measures for metabolic syndrome focus on the education and
      encouragement of employees to attain or maintain healthy lifestyles. For
      employees with identified risk factors, collaboration between the occupational
      health nurse and the employee provide an avenue for healthy employee outcomes.

PMID- 12596344
TI  - Bloodborne pathogens. What you need to know--Part I.
AB  - Since the emergence of the AIDS epidemic in the early 1980s, progressive
      regulatory strategies have been aimed at decreasing the risk of bloodborne
      pathogen exposures in health care workers. It is important to understand the
      evolution of these bloodborne pathogen strategies that have been vital to
      maintaining the health and safety of workers in potentially high risk
      environments. Occupational health clinicians need to communicate to employees how
      each of these strategies has helped decrease the day to day risks health care
      workers potentially face. Standard precautions remain one of the best ways health
      care workers can protect themselves against exposures. It has been more than 15
      years since standard precautions were first introduced. Some health care workers
      have become lax in using these very simple techniques. Occupational health
      clinicians need to remind employees of the importance of taking care of
      themselves by using proper protective equipment. Recent federal and state needle
      safe legislation has heightened employee and employer awareness about the
      importance of new, safer medical devices. These devices [table: see text] must be
      used properly to truly decrease the potential risks to health care workers.
      Occupational health care clinicians can be pivotal in the forefront of needle
      safety initiatives in their institution. Occupational health nurses in health
      care settings should be active members of needle safe and bloodborne pathogen
      committees and participate in product evaluation. Clinicians should advocate for
      employees to be properly trained to use new devices and reinforce the importance
      of using safety devices properly to employees. The risks of transmission for HIV,
      HBV, and HCV are indisputable in environments where workers are potentially
      exposed to blood or body fluids. Knowledge about how exposure occurs, the risks
      of transmission in health care workers, and preventive strategies available can
      assist the employee to work safely without unnecessary fear or anxiety. Part II
      of this article (February 2003) is a more indepth discussion about each of the
      three bloodborne pathogens of greatest concern to health care workers. The
      general prevalence, risk groups, prophylaxis, and treatment of HBV, HCV, and HIV
      are elaborated. Common blood tests for each of these pathogens are also
      explained.

PMID- 12596345
TI  - Role overload.

PMID- 12596346
TI  - [Anatomical variation of the helix root (Radicis Helicis)].
AB  - The root of the helix is not a smooth structure and morphologically constant but
      shows a series of irregularities, which are described in this article. 288
      patients were aleatory studied and found some prominences, localized on the root
      of the helix. There are two tubercules--upper and lower--and one cleft or groove
      facing the lower branch of the antehelix. We report these variants as well as the
      prevalences dues to the age and sex.

PMID- 12596347
TI  - [Enophthalmos presenting as a silent sinus pathology].
AB  - Without any signs of trauma or surgery medical history, the spontaneous
      enophthalmos could be secondary to maxillary sinus hypoplasia on the same side.
      The pathology which often lacks symptoms causes resorption and remodeling of the
      orbital floor. We present one case of maxillary sinus hypoplasia with
      enophthalmos and big ethmoidal bullae associated to septal deformity. Review of
      the bibliography in relation to the causes, medical history and treatment.

PMID- 12596348
TI  - [Acute obstructive nasal syndrome as expression of infectious mononucleosis. A
      case report].
AB  - The infectious mononucleosis (IM) is a disease which mainly affects people
      between 15 and 24 years old. We present a case of a men, of 42 years, who has an
      infectious mononucleosis localized in the nasopharynx area, as its first and
      unique feature. This patient was admitted at hospital for an urgent treatment. We
      refer the clinical symptoms, diagnose, main complications and treatment of the
      condition.

PMID- 12596349
TI  - Tumour morphology and radiotherapy immediate response in laryngeal tumours.
AB  - Laryngeal cancer is relatively frequent in South Europe countries and its
      incidence suffered variations in last decades. Treatment options are usually
      based on histology, T category and stage. Tumors unchain in neighbour tissues the
      presence of cells that normally are associated to inflammatory response. A
      possible association between tumour inflammatory response and radiotherapy
      efficacy is focused in occasional papers. Several histological parameters
      (histologic type, nuclear grade, desmoplasia, necrosis, and cells normally
      involved in inflammatory response) were analysed in biopsy material obtained from
      67 patients with laryngeal cancer treated with primary radiotherapy in our
      department. Statistical analyses were made in order to assess a possible
      association between tumour morphology and radiotherapy response.

PMID- 12596350
TI  - [Hemangiomas and superficial vascular malformations of the face and neck].
AB  - Hemangiomas and superficial vascular anomalies of the head and neck form what
      usually calls the angiomas. Many terms exist in the literature for that reason
      the classification of the ISSVA, admitted by most of the doctors, helps us in
      naming the different anomalies. The processing of this pathology needs a
      multidisciplinary collaboration with doctors of different specialties. The
      evolution of the radiological, surgical techniques of laser, and who knows, of
      the research, allows to hope us to cure some of the particularly dangerous
      anomalies like the arteriovenous malformations. We presented here the different
      technics used in 2001 in the management of hemangioma and superficial vascular
      anomalies insisting on a multidisciplinary approach.

PMID- 12596351
TI  - [Morphometric and stereologic nuclear values obtained from the study of a
      population suffering from nasopharyngeal carcinoma].
AB  - Computer nuclear morphometry and stereology are attractive methods because its
      objectivity and cheapness allowing histologic diagnosis when identifying minimal
      variations respectively the normality and also detect negligible disparities
      between anormal cells which could escape to the assessment of the pathologist. We
      present the data gained from several morphogenic and stereologic parameters
      resulting of measurements of tumoral cells procured from 40 patients with
      nasopharyngeal carcinomata. Middle values have been: nuclear area 27.70 microns
      2; nuclear perimeter 20.80 microns; nuclear factor of form 0.81 microns; nuclear
      outline index 4.01; nuclear orientation angle 87.29 degrees; nuclear
      ellipsiticity 704.14; nuclear regularity 61.83; middle lineal length 4.30, middle
      linear distance 107.94; and nuclear volume 118.80 microns 3. Our series is the
      largest studied till now of all found in the literature. Comparison our data with
      those of previous publications.

PMID- 12596352
TI  - [Advanced squamous carcinoma of external ear canal].
AB  - Squamous carcinoma of the external ear canal (CEEC) is an uncommon neoplasm which
      prognostic changes following the tumour spread. Because of its location in ECC as
      well as the anatomical fissures between osseous and cartilaginous parties it's
      possible the spread to areas of surgical accessibility complicated restricting
      the complete tumoral removal. We report one of those cases, when first visited
      had already meningeal infiltration and was accordingly treated with radiotherapy.
      Analysis of the case and review of the literature.

PMID- 12596353
TI  - [Sudden hearing loss. Clinical case].
AB  - In spite of the advance in the diagnose and treatment of sudden hearing loss and
      specially in the autoimmune sensorineural hearing loss, it is on the field of
      investigation to fix a specific mark for the latter allness. We refer the
      diagnostic and therapeutic use of sudden hearing loss and the autoimmune
      sensorial hearing loss.

PMID- 12596354
TI  - [Syndrome owing to aberrant nervous regeneration. Frey and Bogorad syndrome].
AB  - Two cases of anomalous nervous regeneration seen lastly in our Department suggest
      us this brief reconsideration specially on the physiopathology of these group of
      malaties triggered during the development of salivary reflex.

PMID- 12596355
TI  - Patenting DNA.
AB  - The protection of inventions based on human DNA sequences has been achieved
      mainly through application of the patent system. Over the past decade, there has
      been continuing debate about whether this use of intellectual property rights is
      acceptable. Companies and universities have been active during this period in
      filing thousands of patent applications. Although many have argued that to claim
      a DNA sequence in a patent is to claim a discovery, patent law allows discoveries
      that are useful to be claimed as part of an invention. As the technology to
      isolate DNA sequences has advanced, the criterion for inventiveness, necessary
      for any invention to be eligible for filing, has become more difficult to justify
      in the case of claims to DNA sequences. Moreover, the discovery that a gene is
      associated with a particular disease is, it is argued, to discover a fact about
      the world and undeserving of the status of an invention. Careful examination of
      the grounds for allowing the patenting of DNA sequences as research tools
      suggests such rewards will rarely be justified. The patenting of DNA sequences as
      chemical intermediates necessary for the manufacture of therapeutic proteins is,
      however, reasonable given that the information within the sequence is applied to
      produce a tangible substance which has application as a medicine. Despite the
      legal, technical and political complexities of applying the flexibilities with
      the current law, it is argued that much could be achieved in the area of
      patenting DNA by raising the thresholds for patentability.

PMID- 12596356
TI  - Personalized medicine.
AB  - Personalized medicine simply means the prescription of specific therapeutics best
      suited for an individual based on pharmacogenetic and pharmacogenomic
      information. The basis of personalized medicine are reviewed. Several
      technologies are used including single nucleotide polymorphism genotyping.
      haplotyping, gene expression studies by biochip/microarrays and proteomics.
      Molecular diagnostics will play an important role in the development of
      personalized medicine, in which therapy and diagnosis will be integrated. There
      are several examples of the personalized medical approach, which include genotype
      based selection of patients for effective cancer therapy, to spare those who
      would not respond or would suffer undesirable side effects. Personalized therapy
      is financially feasible, as it will reduce the costs of drug development by
      shortening the drug development cycle. The introduction of pharmacogenomics into
      clinical trials is reducing the chances of failed clinical trials and increasing
      the prospects of safer and more effective therapies for specific groups of
      patients. Several advantages, as well as challenges to the development of
      personalized medicine are examined. Personalized medicine is anticipated to be an
      acceptable part of medical practice by the year 2010.

PMID- 12596357
TI  - The increasing importance of genetic variation in drug discovery and development.
AB  - Genetic variations are playing an increasing role in drug discovery, particularly
      in disease-specific drug target identification and in drug candidate profiling to
      predict drug response in genetically heterogeneous patient populations. Recently,
      genetic studies have successfully contributed to the identification of new
      susceptibility genes, disease mechanisms and potentially novel disease-specific
      drug targets for common diseases such as Type II diabetes, Crohn's disease,
      asthma and osteoporosis. Numerous variants of cytochrome P450 enzymes and the
      pregnane X receptor, recently associated with protein expression and altered
      catalytic activities, may prove to be of use in the future in drug candidate
      profiling.

PMID- 12596358
TI  - Recent advances in the pharmacogenetics of cancer chemotherapy.
AB  - Patient response to chemotherapy varies widely between individuals.
      Pharmacogenetics is the study of inherited DNA polymorphisms that influence drug
      disposition and effects, the goal of which is the individualization of drug
      treatment. As unpredictable efficacy and high levels of systemic toxicity are
      common in cancer chemotherapy, pharmacogenetics is particularly appealing for
      oncology. Recent studies have shown that polymorphisms in genes involved in drug
      metabolism, nucleotide synthesis and DNA repair contribute to inter-patient
      variability in the efficacy and toxicity of many chemotherapy agents. This review
      will discuss recent developments in the most clinically relevant examples of
      cancer pharmacogenetics, and how genetic differences among individuals are
      shaping the future of cancer chemotherapy.

PMID- 12596359
TI  - From genomics to cancer vaccines: patient-tailored or universal vaccines?
AB  - There is little doubt about the existence of tumor-associated antigens and T-cell
      mediated immune responses against cancer antigens. Antitumor immunity has been
      identified in many patients with very different types of cancer. Nevertheless,
      there is still no consensus regarding the correct targets to be used for cancer
      immunotherapy, including cancer vaccines and adoptive T-cell transfer of tumor
      antigen-specific T-cells. Certainly, functional genomics and proteomics will have
      implications on the field of tumor antigen discovery due to the possibility of
      molecular characterization of whole transcriptomes and proteomes of cancer cells,
      thereby also identifying potential new targets for cancer immunotherapy. Based on
      fundamental immunological knowledge, it is hypothesized that the most promising
      approach would be patient-tailored. Alternatively, if genes are identified in the
      majority of all cancers, a more universal approach to cancer vaccines can be
      envisioned. Success with these opposing strategies will greatly rely on whether
      it is possible to induce robust immunity against the antigens identified, whether
      technical and regulatory issues of patient-tailored approaches can be adequately
      addressed, and certainly also which approach will be economically more
      advantageous.

PMID- 12596360
TI  - Enabling parallel protein analysis through mass spectrometry.
AB  - The targets of the majority of drugs on the market and in development are
      proteins, and the efficient analysis of these molecules is critical to defining
      targets for better therapeutic intervention. Mass spectrometry is currently the
      key technology for parallel protein analysis (also referred to as proteomics). In
      this review we will describe recent advances in mass spectrometry
      instrumentation, methods and applications that are likely to impact drug
      discovery.

PMID- 12596361
TI  - Protein microarrays: a powerful tool to study cancer.
AB  - Protein microarrays offer a robust way of examining the cellular proteome. The
      use of protein arrays to study cancer will enable better understanding of the
      molecular events associated with tumor development and progression. The use of
      antigen and antibody arrays could revolutionize the area of biomarker discovery,
      deciphering biochemical and signaling pathways and pharmaceutical research. This
      review will focus on current developments in the area of protein microarrays and
      their application in the study of cancer.

PMID- 12596362
TI  - Protein interaction mapping for target validation: the need for an integrated
      combinatory process involving complementary approaches.
AB  - Identification, selection, validation and prioritization of targets for
      therapeutic intervention requires understanding of the biological role of
      individual proteins in cellular pathways. Unraveling the ways in which proteins
      interact with each other appears to be crucial in achieving that goal. A number
      of recently described high-throughput approaches for analyzing cellular protein
      protein interactions and previously proposed prediction procedures are compared
      in this review. The relative advantages of each method are discussed in relation
      to reproducibility, comprehensiveness and biological significance. It is
      concluded that only a combination of complementary biochemical technologies
      supported by reliable algorithms, will provide exhaustive maps of protein
      interactions for a cellular interactome.

PMID- 12596363
TI  - Technology evaluation: ALVAC-CEA/B7.1, Aventis Pasteur/Therion.
AB  - Therion Biologics, in collaboration with Aventis Pasteur, is developing ALVAC
      CEA/B7.1, a recombinant, pox virus-based vaccine that targets carcinoembryonic
      antigen (CEA) found on the surface of lung and colorectal tumor cells, for the
      potential treatment of lung and colorectal cancer. The vaccine is in phase II
      clinical trials for these indications.

PMID- 12596364
TI  - Technology evaluation: MLN-591, Cornell University/BZL
      Biologics/ImmunoGen/Millennium.
AB  - MLN-591 is a monoclonal antibody specific for prostate-specific membrane antigen
      that is being developed by Cornell University, BZL Biologics, ImmunoGen Inc and
      Millennium Pharmaceuticals Inc for the potential treatment of prostate cancer.
      MLN-591 was in phase II trials by May 2002.

PMID- 12596365
TI  - [Archives of the Tropical Medicine Society: F. Mesnil].

PMID- 12596366
TI  - [Visceral lesions in mammals and birds exposed to agents of human cercarial
      dermatitis].
AB  - Over the past few years, the cercarial dermatitis has become a new problem of
      public health, obviously linked to the prolonged stay of migrant birds on our
      territory. This is a skin affection characterized by pruriginous and papulous
      eruptions caused by penetration of avian bilharzian larvae under the skin. These
      larvae are emitted by molluscs, mostly limneids. In aquatic birds, especially in
      migrating Anatidae, these larvae reach the visceral vessels, become adults in a
      few weeks, lay eggs, then degenerate. Corresponding miracidia contaminate new
      limneids. Since 1993, the total number of annual cases of cercarial dermatitis
      has increased from only ten to thousands in France and the affection rages in
      pools where limneids, migrating water birds and swimmers gather together. Fever,
      respiratory and/or digestive allergic symptoms appear in some cases. This
      clinical pattern has encouraged to undertake research on the future of these
      bilharzian larvae in mammals organism. A preliminary investigation on a rodent
      model showed that, once the skin barrier had been crossed, the schistosomulae
      migrated into the lungs of the host; there they survived a week and induced
      lesions. The goal of this study is to carry on the research, over a longer
      period, after exposure to cercariae, simultaneously in mammals and birds, with
      two species of bilharziae present in France. The selected models are the gerbil
      Meriones unguiculatus for mammals, and the ducks Anas platyrhynchos and Cairina
      moschata, for birds. 5 M. unguiculatus and 2 A. platyrhynchos were exposed to
      cercariae emitted by Radix auricularia; 2 gerbils and 5 A. platyryhnchos to
      larvae of R. peregra, 3 C. moschata to larvae emitted by two species of molluscs:
      70-230 from R. auricularia and 330-585 from R. peregra. 5 gerbils died between 2
      and 5 weeks after exposure, 2 gerbils sacrificed early, served as control animals
      for skin manifestations. Eight ducks were sacrificed between 2 and 4 weeks after;
      the 2 last ones, exposed several times, were sacrificed respectively 7 and 13
      weeks after the first exposure. Visceral and skin samples were submitted to
      histological study. The control gerbils developed skin dermatitis. In ducks, R.
      auricularia was the vector of Trichobilharzia franki, whose selective dwelling
      site was the mesentery; R. peregra was the vector of an indeterminate species
      found in the lungs and nose. This species is called Bilharzia sp. in this study.
      The ducks, exposed to two kinds of larvae, displayed worms in these two main
      locations. In gerbils, T. franki induced lesions in the mesenteric veins and the
      peritoneum. Bilharzia sp. gave rise to lesions in lung arteries, pleura and liver
      veins. Vascular changes encompassed endothelitis and lymphocytic vasculitis,
      while serosa displayed mesothelial hyperplasia. The types of lesions observed in
      gerbils were noticed in ducks, and, according to the species of bilharzia, in the
      homologous viscera. Additional foreign body granulomas centred on worm's debris
      or their eggs, and vascular thromboses were present, too. In addition, ducks
      displayed lesions involving several other viscera including the intestine, the
      kidneys and the peripheral nerves. These changes were multiple and diffuse in C.
      moschata exposed to two species of bilharziae. They were observed mainly in
      mesenteric and intestinal vessels, pulmonary arteries and hepatic veins. In
      gerbils, the lesions persisted 2 to 5 weeks after exposure, but worms were not
      identified in the neighbouring tissues near the damaged vessels. In ducks,
      lesions were important between 2 and 7 weeks after exposure; they co-existed with
      live or dead worms, sometimes paired, with or without eggs. The hepatic lesions
      regressed 13 weeks, after exposure. In mammals and birds, young worms could
      migrate into the same visceral vessels, and stimulating formation of persistent
      lesions. In individuals exposed to the same cercariae, development of similar
      lesions would be probable.

PMID- 12596367
TI  - [Comparative study of four malaria diagnostic techniques used in Ivory Coast].
AB  - The biological diagnosis of malaria plays an important part in the patients'
      treatment for malaria. Thus, many techniques have been developed to reach this
      purpose. We have compared four of them concerning 196 patients from October, 1996
      to January, 1997 in Abidjan. Thick blood film has been chosen as the technique
      for reference. It has come out that the plasmodic index was 18.3%. The Plasmodium
      falciparum has been the only encountered species. The different sensitivities of
      the QBC test and of the Parasight F test reached 100% against 83.3% in the case
      of the thin blood film. The QBC test and the thin blood film had each a
      specificity of 100% against 88.1% for the Parasight F test. Unlike the QBC test,
      the thick blood film and the thin blood film have remained the most difficult to
      be realised. Therefore, the analysis of parameters of credibility (sensitivity,
      specificity), predictable values and the time involved will allow in a given
      situation to use the appropriate biological diagnosis technique.

PMID- 12596368
TI  - [Giant bladder calculus in two male farmers in Madagascar].
AB  - We report two cases of giant calculus in two male farmers in 1999. They were
      operated on in the urologic ward by lithocystotomy. Infrared spectrophotometric
      analysis, carried out in Bordeaux, gave us the main components of the stones.
      These stones weighed respectively 350 g and 450 g. Research of common aetiology
      such as vesical neck stricture, prostatic hypertrophy, urethral stricture and
      urinary bladder diverticula was unsuccessful in case of the first patient; in the
      opposite, the second one had vesical diverticula discovered operatively. But two
      phenomena came out from this aetiologic investigation: particular regimen of
      these farmers (much starchy food) and geographical situation of their health
      centre (far from their home). We must make general practitioners sensitive to
      this early signs of the disease in order to provide their patients a precocious
      and better care.

PMID- 12596369
TI  - [Radiography and ultrasonography in the management of bladder tumors: 71 cases at
      the National Hospital Center of Yalgado Ouedraogo (Burkina Faso)].
AB  - The bladder's cancer is frequent in West Africa. Urinary schistosomiasis
      endemicity helps to explain this high incidence. It is a pathology of late
      diagnosis, little or badly explored by imaging. Through a retrospective survey of
      71 patients' files aged in average of 51.7 years, all having a bladder's tumour
      which is clinically shown by an haematuria, the major symptom, often by a pelvic
      volume, and who have all gone through an abdominal echography and/or intravenous
      urography (IVU) and/or retrograde urethrocystography (UCR), we have tried to
      point out the role of imaging in the caring of this pathology in our working
      context. Imaging, with a 98.5% sensibility for sonography and 100% for IVU, took
      part in all the cases to the diagnosis, to the search of urinary signs of reflux,
      associated signs authorizing a diagnostic orientation, but was excluded from the
      evolutive follow-up due to the poverty of our populations. So, despite some
      limits specific to the survey, particularly the absence of historadiological
      comparison for all the files, echography and IVU with cystography have always led
      to malignancy diagnosis. Therefore they should be requested for any patient
      consulting for haematuria.

PMID- 12596370
TI  - [Sudden deafness in sickle cell anemia: a case report].
AB  - The non-expected deafness is quite obvious or easily diagnosed cause. The sickle
      cell disease is one of the aetiologies of this one. We present one case observed
      on a 30 years old patient. There is a close connection between the vascular
      factor of the non-expect deafness and the erythrocytic falciformation of sickle
      cell anaemia causing the obliteration of the terminal auditory internal artery
      and generating the ischaemia of the cochlea anoxia. The high sensitivity of the
      cochlea to anoxia and its great fragility require an early therapy in order to
      recover auditory capacity. Patients suffering from sickle cell disease should be
      encouraged to have a regular assessment of audition.

PMID- 12596371
TI  - [Infibulation complications: three vaginal plastic surgeries at Kossodo (Burkina
      Faso)].
AB  - From 01 November 2000 to 31 October 2001, three cases of infibulation were
      referred to the gynecological and obstetrical sanitary branch of Kossodo, which
      corresponds to 1.6% frequency. It concerns young patients (average age = 19
      years), Mossi, who had an excision done between age 6 and 14. The main reason for
      reference was the impossibility to have sexual intercourse. There were no post
      chirurgical consequences. The possible consequences are psychological trauma,
      dyspaneuria, dystocy of flabby tissues during future deliveries.

PMID- 12596372
TI  - [Gastrointestinal manifestations of AIDS in adults in Mali].
AB  - Our main objective consists in evaluating the frequency of digestive signs and
      digestive opportunistic infections in AIDS patients with diarrhea. The
      prospective study occurred from January 1997 to July 1998 in Bamako hospitals.
      The patients underwent a clinical examination, blood and stools tests, and
      sometimes upper digestive endoscopy. Among 434 cases of AIDS, 426 patients (98%)
      had at least one digestive sign. The main digestive signs were diarrhea (80.1%),
      abdominal pains (62.2%), vomiting (47.2%) and dysphagea (36.6%). Isospora belli
      and Cryptosporidium parvum have been pointed up in respectively 9% and 16.3% of
      examined specimen. Echerichia coli was found in 8.6% of stool cultures and in
      2.9% in the case of Salmonella Arizonae. Twenty cases of Kaposi's sarcoma were
      diagnosed and mycosis was found in 71.9% of patients. In conclusion, digestive
      change is a constant phenomenon in AIDS patients. Patients survival could be
      improved by early management, improvement of diagnosis and provisioning of
      medicines.

PMID- 12596373
TI  - [Immunodepression and pulmonary infections].
AB  - The acquired immunosuppressed states are increasingly numerous. Pneumopathies are
      a frequent, serious complication and etiologic diagnosis is often difficult. The
      nature of the micro-organism in question is a function of the immunizing type of
      deficiency. In neutropenias, the infections are primarily bacterial, their
      potential gravity being correlated with the depth of the deficiency into
      polynuclear, or fungic, especially in prolonged neutropenias. The aspleened
      states are responsible for a deficit of the macrophage system and contribute to
      the infections with encapsulated germs (pneumococci, klebsiellas...). The organic
      grafts imply an attack of cell-mediated immunity, in the particular case of the
      auxiliary T lymphocytes (CD4)), with a special predisposition for viral and
      fungic infections. During VIH infection, the immunizing deficit of CD4
      lymphocytes worsens with time. At the early stage, the infections are especially
      bacterial. At the more advanced stages, the pulmonary pneumocystosis and
      tuberculosis dominate. At the late stage, finally, deep immunosuppression allows
      emerging of the atypical mycobacteries. In the deficiencies of humoral immunity
      (congenital hypogammaglobulinemias, lymphoid hemopathies B), the germs to be
      mentioned are the pneumococcus, Haemophilus influenzae, the salmonellas and the
      legionellas. Immunosuppressed pneumopathies are characterized by radio-clinical
      pictures of very variable gravity, ranging from focused acute pneumopathy to
      bilateral diffuse pneumopathy with acute respiratory distress syndrome, with
      phases of atypical tables with respiratory symptomatology larval or absent. The
      highlighting of the micro-organisms in question requires urgent complementary
      investigations: hemocultures, bronchiolo-alveolar washing. In certain cases, it
      will be possible to resort to the transtracheal puncture or transthoracic
      puncture guided by tomodensitometry, and if necessary to pulmonary biopsy under
      videothoracoscopy. Emergency of the anti-infectious treatment imposes, in
      general, a presumptive treatment directed according to the immunizing deficiency
      in question and etiologic suspicion. It will be associated, if necessary, with
      urgent measurements of respiratory intensive care.

PMID- 12596374
TI  - [Therapeutic efficacy of chloroquine in the uncomplicated malaria due to
      Plasmodium falciparum in hospital patients in central Ivory Coast (1997-2000)].
AB  - A study in vivo of Plasmodium falciparum sensitivity to chloroquine was carried
      out from April 1997 to February 2000 at Yamoussoukro, Kossou and Bouake in the
      central region of Cote d'Ivoire. This study was included in the national
      Plasmodium falciparum-sensitivity program. One hundred and sixteen subjects
      consulting for suspected malaria were included according to the WHO's standard of
      14 days. Chloroquine was administered on a dosage of 25 mg/kg, spread over three
      days. Among 108 subjects who finished the treatment, 26.9% (29/108) had
      therapeutic failure to chloroquine (23 precocious therapeutic failure and 6 late
      therapeutic failure). Chloroquine was more efficacious in Yamoussoukro (87.5% of
      clinical appropriate response) and Bouake (82.5%) than in Kossou (61.7%).
      Parasitic reduction on subjects with therapeutic failure was higher than 85%. The
      risk of therapeutic failure is not linked to age of patient. Before a revaluation
      of this situation, chloroquine should always be recommended as a first-line
      treatment for uncomplicated malaria for the local populations.

PMID- 12596375
TI  - [Preliminary study on isoniazid-epiroprim combination in a tuberculosis murine
      model].
AB  - The purpose of this study regarding isoniazid-epiroprim's association applied to
      antituberculosis chemotherapy, carried through murine model, initiated into
      Institut Pasteur of Cote d'Ivoire and worked out at Institut Pasteur of Paris was
      to evaluate the epiroprim's effect alone and associated with isoniazid on
      Mycobacterium tuberculosis. Sixteen mouses (lineage C57Bl/6) were inoculated by
      venous way with 10(5) viable bacillus (strain H37Rv) suspended in 500 microliters
      sterile physiological aqueous solution and were shared out into 4 sets. Fifteen
      days later the sets have been submitted or not to a daily treatment by gavage
      during three weeks (epiroprim, isoniazid, isoniazid plus epiroprim). The mouses
      were euthanasied, spleen and lung were removed from each animal. The titres of
      determined bacillus into those organs prove that isoniazid and epiroprim
      associated seem more efficacious than the isoniazid monotherapy for mouses
      pulmonary tuberculosis. Bacillus obtained are sensitive to isoniazid.

PMID- 12596376
TI  - [Current aspects of Pott's disease in Tunisia. 29 cases].
AB  - It is a retrospective study, reviewing all cases of vertebral tuberculosis
      recorded between 1989 and 1999 in La Rabta Hospital (Tunis). 29 patients have
      been included whose average age was 49 years. The main symptoms which appeared
      within a average period of six months were vertebral pain, associated with fever
      in half of the cases. The diagnosis of infectious spondylitis was made according
      to the results of Computer tomography in 26 cases. The diagnosis of infection was
      confirmed by characteristic histological pattern and/or culture biopsy. 27
      patients were cured without complications except for 2 of them who developed a
      spinal cord compression. This complication was quickly stemmed by steroid
      therapy.

PMID- 12596377
TI  - [Botulism in Casablanca. (11 cases)].
AB  - Botulism is a rare but severe disease. Whereas until 1980, only one case of
      botulism had been reported in our department, in 1999, a real botulism epidemic
      took place in Morocco. To our knowledge, it's the first outbreak of that kind in
      Morocco. We report here an epidemiologic and descriptive study of 11 patients
      suffering from botulism, admitted at the Infectious Diseases department and in
      the Medical Intensive Care Unit of Ibn Rochd University Hospital, from August,
      the 10th to October, the 1st, 1999. Clinical diagnosis of botulism was made, at
      the admission, on ocular signs (diplopia, ptosis), swallowing troubles and/or
      muscle weakness. There was no fever, no trouble of conscience and normal
      reflexes, at the early stage of the disease. The average age of patients was of
      23.9 years +/- 12.07. Three patients were first admitted in the Medical Intensive
      Care Unit. The period before symptom appearance varied between 7 and 96 hours.
      Dysphagia sore throat, dry mouth and dysphonia were always found in all patients,
      with normal conscience. The fever was noted in 3 cases, polypnea in 3 cases
      leading to respiratory assistance in 2 cases. Neurologic findings were dominated
      by ptosis and hypotonia. The search of botulism toxin B in blood was positive in
      6 cases. The electromyography showed clear signs of botulism. The evolution was
      favourable in 10 cases. Respiratory complications were found in 2 cases and
      infectious complications in 4 cases. One patient died. The period of
      hospitalization varied between 10 to 24 days with an average stay of 15.8 days.
      Eating "mortadella" has been noticed in 7 patients) and investigations permitted
      to identify the factory of "mortadella" as well as the toxin's type B responsible
      for these poisoning. It appears clearly that it is important to reinforce hygiene
      controls. Physicians and specialists in public health must be aware of the
      severity of this illness, knowing that the recovery is shortened when the
      treatment is administered on an early stage of the disease.

PMID- 12596378
TI  - [Geographic origin of endomyocardial fibrosis treated at the central hospital of
      Maputo (Mozambique) between 1987 and 1999].
AB  - Endomyocardial Fibrosis (EMF) is a restrictive myocardiopathy of unknown
      aetiology, which is specific to tropical areas. In order to document the
      geographical distribution of this disease in Southern Mozambique, we reviewed the
      medical records of patients treated at Maputo Central Hospital between 1987 and
      1999. Analysis was restricted to cases originating from the 3 provinces of
      Southern Mozambique. Cumulative incidences were computed for the period of 1987
      1999, by age group, sex and residential district at disease onset. The
      geographical distribution of the disease in the 34 districts (administrative
      subdivisions) of the study area was mapped. Between 1987 and 1999, 118 cases of
      EMF originating from Maputo, Gaza and Inhambane provinces were diagnosed at
      Maputo Central Hospital. Seventy seven patients (65%) were living in Inhambane
      Province at the time of disease onset. Cumulative incidence for this province was
      6.9/100,000 over the study period of 1987-1999. Comparatively, cumulative
      incidences were respectively 1.7/100,000 for Maputo and 1.0/100,000 for Gaza
      Province (chi 2 = 64.3, p < 10(-5)). All the patients were native from 22 out of
      the 34 districts of these 3 provinces. Affected districts were all located in the
      coastal area and higher cumulative incidence was computed for Inharrime district
      (18.3/100,000). This study confirmed that endomyocardial fibrosis is endemic in
      some areas of South Mozambique, but did not allow to measure the true magnitude
      of the disease which is probably grossly underestimated. The geographical
      distribution of EMF in South Mozambique reinforce the environmental hypothesis of
      aetiologic disease.

PMID- 12596379
TI  - [Risk factors associated with prematurity at the University Hospital of Lome,
      Togo].
AB  - OBJECTIVE: To determine the premature birth rate and the risk factors of preterm
      delivery linked to local conditions of life. METHOD: It is a prospective study
      including all births before 37 amenorrhoea weeks. All social, medical and
      behavioural factors linked to preterm deliveries have been analysed for and
      compared with those of the medical literature. RESULTS: Out of 1672 alive births,
      we identified 186 (11.1%) cases of prematurity and 30.1% of lethality. The main
      risk factors of preterm delivery were history of adverse pregnancy outcome
      (17.2%), history of induced abortion (11.3%), maternal age under 20 (26.3%),
      under 20 year old primipara (38.7%), inadequate antenatal care (66.6%), low level
      of education (38.7%) and mother suffering of overwork (29%). Other associated
      factors such as premature membrane rupture, malaria, urinary infections, gravidic
      toxaemia, genital infections and above all "unmarried-under 20 year old-primipara
      with low level of education and low socio-economical status", were significantly
      linked to preterm delivery. CONCLUSION: The risk factors thus identified
      correspond with the well-known factors. But many factors significantly linked to
      preterm delivery were local features whose importance could be reduced through
      better means of perinatal care and prevention.

PMID- 12596380
TI  - [Atractylis gummifera L. poisoning: a case report].
AB  - Intoxication by Atractylis gummifera L. frequently happens in Morocco. It's often
      accidental and mortal if no precocious and effective treatment. In order to take
      stock of this intoxication of which diagnosis is clinical and treatment
      symptomatic, we suggest to analyze one clinical case of the intoxication by
      Atractylis gummifera L. on a 12 year old child who accidentally ingested this
      plant.

PMID- 12596381
TI  - [Multifocal forms of Buruli ulcer: clinical aspects and management difficulties
      in 11 cases].
AB  - OBJECTIVE: A certain number of authors have in literature pointed out multifocal
      forms of Buruli ulcer but no study was ever dedicated to them. The purpose of
      this study is to be more specific about the clinical aspects and to show how
      difficult it is for those multifocal forms of Buruli ulcer to be operated on.
      METHOD: The 11 patients who were accepted for the study were subjected to an
      interrogation, a thorough clinical examination, research of BAAR in ulcers and
      operative pieces with a direct examination after Ziehl-Neelsen colouring. Each of
      these patients underwent a surgical treatment under general anaesthesia or spinal
      anaesthesia depending on the seat of the lesions under cover of pre and post
      operative therapy by antibiotics. RESULTS: Initial lesions preferentially were
      located at limbs level; new foci appeared within an average period of 3 months,
      ranging from 1 to 15 months in some cases. All body parts could be the seats of
      secondary foci. Depending on the patients, the number of foci varied from 3 to 7.
      Furthermore, amputation has been necessary for the complete healing of four
      patients. The average operation was 2.4 by patient ranged from 2 to 5. We
      observed the healing of all the patients within an average hospitalisation time
      of 6.3 months running sometimes from 4 to 13 months. In addition to amputations,
      4 patients presented after-effects as articular stiffness, retractions of the
      hand's dorsal face and knee's retraction. CONCLUSION: Those multifocal forms can,
      with good reason, be considered as malignant form of Buruli ulcer.

PMID- 12596382
TI  - [Prevalence and perception of schistosomiasis in a periurban school of Bamako in
      Mali].
AB  - The prevalence of urinary and intestinal schistosomiasis, the knowledge, attitude
      and practice (KAP) regarding the disease among both the children and their
      parents were investigated in Djikoroni para, a Suburban area of Bamako. The
      prevalence of Schistosoma haematobium and S. mansoni were respectively 69.8% and
      8.7%. Compared with the girls, the boys were significantly more infected by S.
      haematobium (p = 5.10(-3)), but no difference between the sexes was observed for
      S. mansoni (p = 0.36). Interviews indicated that 88% of children and 91% of
      adults considered micro-haematuria as a pathology, but did not know anything
      about intestinal schistosomiasis. The low sensitivity of micro-haematuria (56.8%)
      and of the criterion "abdominal pains" (66.7%) indicated that they couldn't be
      relevant diagnosis signs. The symptoms and mode of transmission were generally
      well understood for S. haematobium but not for S. mansoni. The later parasite,
      its intermediate host and their interactions were unknown. The main man water
      contacts are bathing and playing in the Woyowayanko and in the Niger river.
      Inadequate perception of schistosomiasis contributes to maintain schistosomiasis
      at a high level of prevalence in Djikoroni.

PMID- 12596383
TI  - [Water contacts in dracunculiasis-infected patients in Mali: transmission risk
      activities].
AB  - The aim of this study lies in the identification of human activities responsible
      for the transmission of the Guinea worm in an endemic village in Diema Region in
      Mali. Human water contacts observations started after a census followed by the
      implementation of a bi-monthly notification system, carried out from May to
      November 1993. Water contacts were noticed and observed from the mid-July to the
      end of November of the same year. The first case of dracunculiasis observed was
      randomly drawn out of a list of the families with obvious cases. The patent case
      activities involving either surface water, traditional wells or bore-hole water
      were recorded for 10 consecutive days. During this observation period, contacts
      made by other patients with the same water sources were also recorded. After 14
      days, the case list was updated and a new case selected out of families
      previously selected. This cycle was repeated until the end of the study period. A
      "contact at risk for transmission" was defined by a close correspondence between
      the location of the worm's emergence and the surface of the skin exposed to
      water, within two weeks following emergence. Contacts were described according to
      water sources, activities in relation to water, date, gender and age.
      Observations were made on 103 patients who had 2506 activities in relation with a
      water body: 1132 of these activities implied a skin contact with the water. Only
      133 (9%) of these water contacts were at risk for transmission, 75% took place
      during the months of August and September, 80% were related to surface waters and
      20% to traditional wells. Woman household activities and boys games were the
      major activities at risk, in contrast to economic activities (watering cattle).
      The low proportion of "at risk activities" evaluated in this study suggests that
      a small number of water contacts is sufficient to maintain the transmission. The
      case implications of the current eradication strategy might not be sufficient
      alone to break the transmission and should therefore be associated with a
      reinforcement of the use of filters for drinking water together with an health
      education.

PMID- 12596384
TI  - [An experimental tool essential for the evaluation of insecticides: the testing
      huts].
AB  - The following study analyses the potentialities of the experimental huts built in
      M'be Valley (Cote d'Ivoire) where the evaluations of the insecticide products
      have been carried out for many years in line with the WHOPES protocol on the
      methodology of stage 2 assays. Starting a testing station first requires a good
      knowledge of the sensitivity of Anopheles gambiae to the main insecticide
      families. Then thanks to the experimental huts the efficacy of the various means
      of treatment can be compared with the one in untreated huts; this study focuses
      on house spraying using 100 mg a.i./m2 and bednets impregnated with lambda
      cyhalothrin at a dose of 15 mg a.i./m2. The fipronil used in house spraying
      doesn't show any repellent effect, however it does have an irritating effect that
      increases the natural exophily of An. gambiae females entering the testing huts.
      The blood-feeding rate recorded in the treated huts was reduced to 24% and to 38%
      mortality rate consisting mainly of a 24 hours delayed mortality. The bednets
      treated with lambda-cyhalothrin have greatly reduced the contact between man and
      vector since the entry rate of An. gambiae females was cut down by 68% compared
      to the control. The exophily of this anopheles was twofold greater with the
      impregnated bednets and the blood-feeding rate reduced to 47%. Finally the global
      mortality rate, two thirds of immediate mortality, one third of delayed
      mortality, reached 35%. The experimental huts in the M'be Valley therefore
      provide essential information regarding the selection of the most efficacious
      insecticides against An. gambiae. This experimental method must be extended to
      other sites in order to finalize ever more selective and appropriate means of
      control against nuisance and disease-vector mosquitoes.

PMID- 12596385
TI  - [Tick-borne diseases and ecosystem modifications in Lorraine].

PMID- 12596386
TI  - Gastrointestinal stromal tumours: an analysis based on personal experience.
AB  - We present our experience in the treatment of 18 patients affected by
      gastrointestinal stromal tumours (GIST) from January 1988 to march 2002. The
      ratio M.F was of 2:1 and the median age of 68.6 years. In 13 patients the tumours
      were located in the stomach while in 5 patients in the jejunum ileum area. In 7
      patients the neoplasms were malignant. All the patients were operated and in 11
      patients a partial gastric resection was carried out. 2 patients had a total
      gastrectomy and 5 had a small bowel resection. The diagnostic and therapeutic
      options and the uncertain prognosis of these neoplasms are discussed.

PMID- 12596387
TI  - Valproic acid in migraine prophylaxis of young patients. Three new reports.
AB  - Several clinical studies report the efficacy of valproic acid in migraine
      prophylaxis of adult patients and its well tolerability. In childhood and
      adolescent patients its use is usually restricted to epilepsy and very few cases
      have been reported in literature on the use of valproic acid for "juvenile
      migraine". We describe three pediatric patients fulfilling the International
      Headache Society (IHS) criteria for migraine with and without aura treated with
      low dose of sodium valproate (10 mg/Kg/die) for six months. They had previously
      undergone other migraine preventive treatment unsuccessfully. We obtained a good
      response in all cases: in only one subject, prophylactic treatment was stopped
      because of weight gain, as adverse effect. In conclusion, in accord with other
      authors, we suggest that valproic acid may be helpful in the prophylaxis migraine
      in pediatric age.

PMID- 12596388
TI  - Progressive familial intrahepatic cholestasis.
AB  - Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of
      autosomal recessive childhood cholestasis of hepatocellular origin. PFIC 1, also
      known as Byler disease, was first described in Amish kindred. It is characterized
      by cholestasis often arising in the neonatal period and it leads to death due to
      liver failure. PFIC 1, like Benign Recurrent Intrahepatic Cholestasis (BRIC)
      which is the benign form of the same disease, recognizes mutations in the ATP8B1
      gene. PFIC 2 disease is clinically similar to PFIC 1 but it has a different gene
      mutation causing a defect in the Bile Salt Export Pump (BSEP), exclusively
      expressed in the liver and involved in the canalicular secretion of bile acids.
      PFIC 3 usually appears later in life and it has a higher risk of portal
      hypertension, gastrointestinal bleeding and liver failure. This particular form
      of disease (the only one with high serum values of g-glutamil transpeptidase), is
      associated to a genetic defect in the class III multidrug resistance protein
      (MDR). External biliary diversion and ursodeoxycholic acid therapy, should be
      considered as the initial therapy in these patients, even if liver
      transplantation still seems to be the only solution for most patients.

PMID- 12596389
TI  - Three years of experience with the clos nail for tibial shaft fractures.
AB  - The Clos tibial nail is a new interlocking dynamic compression nail. From
      September 1998 to September 2001 fifty-six patients who had tibial shaft
      fractures were treated. Depending on positioning of the blocking screw, the
      system can be mounted in four different configurations: static configuration (19
      cases), dynamic configuration (30 cases), static-compression configuration (1
      case), and dynamic-compression configuration (6 cases). There were 40 male and 16
      female (average age of 42 years); 36 simple fractures and 20 multifragmentary
      fractures. The fibula was safe in two cases, fractured at the same level of the
      tibial fracture in 34 cases and fractured at another level in 20 cases. The mean
      time to full weight bearing was 11 weeks (10-14). There were no cases of delayed
      union or dynamization or infections. All the fractures healed in a mean time of
      16 weeks (10-20 weeks). There were 3 malunions, one in varus and two in valgus,
      and one patient healed with 3 cm of shortening. All patients returned to their
      previous activity levels.

PMID- 12596390
TI  - Percutaneous endoscopic gastrostomy after Billroth II gastrectomy.
AB  - Percutaneous endoscopic gastrostomy (PEG) is a valid alternative to surgical
      gastrostomy to provide nutritional support in patients unable to ingest food.
      Previous Billroth II gastroresection is no longer a controindication. We describe
      our experience with 5 cases of PEG placement in patients who had previously
      undergone Billroth II gastroresection.

PMID- 12596392
TI  - Three grammar problems found by reviewers.

PMID- 12596391
TI  - The target-journal approach: teaching manuscript submission skills.
AB  - All of my students learned to appreciate the written contributions of others and
      to recognize their own responsibilities as consumers and writers of nursing
      literature. By preselecting one familiar target journal, students were able to
      learn the manuscript submission process, identify with their nurse-author
      colleagues, and perceive themselves as contributing members of the profession. I
      found this project to be fun for the teacher and students! Helping new writers
      see their names in print is an honor, an inspiration, and a total joy!

PMID- 12596393
TI  - Varicose veins.

PMID- 12596394
TI  - Breastfeeding adopted babies.

PMID- 12596395
TI  - For moms who cannot get out of bed.

PMID- 12596396
TI  - For moms who cannot get out of bed.

PMID- 12596397
TI  - Marion's message. Vaginal delivery on demand?

PMID- 12596398
TI  - How do you prevent c-sections?

PMID- 12596399
TI  - A butcher's dozen.

PMID- 12596400
TI  - A VBAC primer. Technical issues for midwives.

PMID- 12596401
TI  - Suturing a cesarean wound.

PMID- 12596402
TI  - Re: The cesarean birth article.

PMID- 12596403
TI  - Choosing caesarean section.

PMID- 12596404
TI  - 7 steps toward cesarean prevention.

PMID- 12596405
TI  - Midwifery care for the VBAC woman.

PMID- 12596406
TI  - Cesarean birth: what about the baby?

PMID- 12596407
TI  - VBAC: trust, respect and humility.

PMID- 12596408
TI  - Cruci/section: my baby was cut out with a knife.

PMID- 12596409
TI  - Optimal fetal positioning: making a great turn around.

PMID- 12596410
TI  - Homeopathic medicine for the postpartum period.

PMID- 12596411
TI  - Midwives and cytotec: a true story.

PMID- 12596412
TI  - The power of no! Birth at the CASA Clinic, Mexico.

PMID- 12596413
TI  - Spain: the story of a male midwife.

PMID- 12596414
TI  - Midwifery in the Yukon.

PMID- 12596415
TI  - Fetal demise: helping a mother cope with her pain.

PMID- 12596416
TI  - Vitamin K and hepatitis B vaccine.

PMID- 12596417
TI  - Ungloved hands.

PMID- 12596418
TI  - Misoprostol (Cytotec).

PMID- 12596419
TI  - HypnoBirthing.

PMID- 12596420
TI  - [SV40: a possible co-carcinogen of asbestos in the pathogenesis of
      mesothelioma?].
AB  - BACKGROUND: The etiopathogenic role of asbestos in causing malignant mesothelioma
      of the pleura is clearly supported by an impressive amount of data. Despite the
      frequent association with previous exposure to asbestos, only a relatively small
      fraction of those exposed develop malignant mesothelioma. The long latency period
      between initial exposure and onset of the tumor suggests that human mesothelioma,
      like many other tumors, has a multi-stage evolution with the occurrence of many
      mutating events involving various tumorigenic agents, probably in part initiating
      and in part promoting development. Recently this has raised great interest in the
      scientific world, in an attempt to identify possible factors which together with
      asbestos may have a role in developing this rare malignant tumor. Ionizing
      radiations and genetic susceptibility have occasionally been identified as the
      culprits. A virus called SV40 has been gaining increasing scientific credibility
      since the mid 1990's as a potential co-carcinogen of asbestos. OBJECTIVES: The
      aim of this article was to examine the supposed interaction between asbestos and
      SV40 in the pathogenesis of mesothelioma and the way this simian virus has become
      a human virus. METHODS: All biomolecular and epidemiological data available from
      medical literature along with the results of the experiments performed during the
      last 7 years in our department laboratories were reviewed and compared. RESULTS:
      The first two pieces of experimental evidence of the presence of SV40-like DNA
      sequences in mesothelioma samples were obtained in 1994 in the United States, and
      one year later in our laboratories. After these two studies many research groups
      started carrying out similar experiments, obtaining comparable results in most
      cases. Moreover, beyond the mere detection of viral DNA sequences large amount of
      biomolecular data has recently been added in favour of its role in the
      pathogenesis of mesothelioma. Epidemiological studies published to date were
      unable to provide similar unanimous results. Data regarding the source of human
      infection are still debatable, even if the inadvertent administration of
      contaminated poliovaccines to millions of people in Europe and the United States
      between 1955 and 1963 remains one of the most reasonable hypotheses. CONCLUSIONS:
      On the basis of all the biomolecular data reviewed and partially on the basis of
      epidemiological studies, SV40 seems to be the best candidate as a cofactor with
      asbestos in the development of human mesothelioma.

PMID- 12596422
TI  - Mortality of a cohort of road construction and maintenance workers with work
      disability compensation.
AB  - BACKGROUND: Surveillance systems of occupational mortality are useful tools to
      identify cases of diseases suspected as occupational and to monitor their
      occurrence over time, in space and in population subgroups. Many surveillance
      systems make use of administrative data in which information about occupations
      and/or economic sectors of the subjects enrolled is reported, such as death
      certificates, hospital discharge data, census data, tax and pension records, and
      workers' compensation archives. OBJECTIVES: In the present study we analyzed the
      mortality of a cohort of road construction and maintenance workers enrolled
      through the Italian national archive of work disability compensations, also in
      order to evaluate the possible use of this administrative source to monitor
      occupational mortality. METHODS: 8,000 subjects (7,879 males) receiving a
      disability compensation while working in the "road construction and maintenance"
      sector were identified from INAIL (National Institute for Insurance of Accidents
      at Work) archives. Vital status of these subjects was ascertained using the
      information available in INAIL archives and in the national tax register. For
      those found to be deceased from INAIL or tax archives, or without any information
      on vital status, a mail follow-up was started. We considered as observation
      period the years from 1980 to 1993. A record linkage with the ISTAT (Italian
      Institute of Statistics) national mortality registry was performed and the cause
      of death was retrieved for 964 out of 1,259 subjects. The analysis was restricted
      to males, leaving altogether 863 observed deaths with ascertained cause (84.7% of
      1,019 total male deaths). SMR for overall mortality and PMR for specific cause
      mortality were computed, using the general Italian male population as reference.
      RESULTS: Overall mortality was significantly reduced (SMR = 79.0; 95% CI = 74.2
      84.0). Proportional mortality analysis revealed significant excess risks for all
      malignant tumours (332 deaths, PMR = 1.08) and for digestive diseases (87 deaths,
      PMR = 1.34), while mortality for cardiovascular diseases was significantly
      decreased (288 deaths, PMR = 0.90). Among specific causes of death, significant
      excess mortality was found for cancer of testicles (2 deaths, PMR = 5.98), liver
      and biliary ducts (32 deaths, PMR = 1.40), and for silicosis (10 deaths, PMR =
      3.07) and cirrhosis (64 deaths, PMR = 1.40). CONCLUSIONS: The excess mortality
      observed for all cancers, digestive diseases and silicosis, and the decreased
      risk for cardiovascular diseases are in agreement with the results of other
      studies conducted on workers in road construction and maintenance. As expected,
      the low overall mortality and the reduced risk from cardiovascular diseases
      indicate that these workers present a strong "healthy worker effect".

PMID- 12596421
TI  - [Tuscany mesothelioma registry (1988-2000): evaluation of asbestos exposure].
AB  - BACKGROUND: The Tuscany Mesothelioma Register (ARTMM) records pleural malignant
      mesothelioma cases of Tuscany residents, diagnosed by histological, cytological,
      or clinical (radiography or computerized tomography) examinations. The ARTMM
      began in 1988 and estimates mesothelioma incidence in Tuscany and collects
      information on past asbestos exposure of mesothelioma cases. OBJECTIVES: The aim
      of this paper was to describe the incidence of pleural mesothelioma cases in
      Tuscany and to analyse their possible past asbestos exposures. METHODS: We
      considered pleural mesothelioma cases recorded in ARTMM in the period 1988-2000
      and interviews collected for these cases. In order to identify past asbestos
      exposure in the occupational and non-occupational history of patients, interviews
      were carried out using a standardised questionnaire. RESULTS: In the period 1988
      2000, 494 pleural malignant mesothelioma cases were recorded in the ARTMM; 82%
      were males. In the periods 1988-1993, 1994-1997, 1998-2000 the incidence rates,
      standardised on the Italian population (per 100,000), were respectively 1.15,
      1.57, 2.58 among males; 0.29; 0.27; 0.29 among females. Information on
      occupational history was collected for 418 mesothelioma patients (85% of recorded
      cases): 173 mesothelioma cases were directly interviewed; for 245 cases relatives
      or work colleagues were interviewed. Occupational asbestos exposure was ranked as
      certain, probable or possible in 72% of the interviewed cases (80% of males; 20%
      of females). Environmental and non-occupational asbestos exposure was identified
      in 1% of males, and 3% of females. In 24% of the interviewed cases (15% of males;
      74% of females) no known asbestos exposure was identified. Occupational asbestos
      exposure occurred in maritime activities (shipyards, dock work, merchant and
      regular Navy), the building industry, railway carriage construction and
      maintenance, rail transport, textile industries (mainly rag sorting), electricity
      production, asbestos cement manufacture, chemical, iron and steel industries and
      in glass manufacturing. In Tuscany two areas are distinguished for their well
      documented and massive use of asbestos: the coastal areas (Livorno and Massa
      Carrara) for maritime activities, and the areas of Pistoia and Arezzo for railway
      carriage construction and repair. Mesothelioma incidence rates in these areas are
      the highest in the whole region. CONCLUSIONS: Further investigation is needed in
      order to identify unknown asbestos uses and consequent exposure, in particular
      for females. Uncertainty as regards occurrence of asbestos exposure persists in
      the textile industries where the mesothelioma epidemics have not yet declined.
      Research hypotheses are addressed on the re-use of jute bags previously
      containing asbestos, therefore collection of further information on periods and
      methods of this recycling activity is essential.

PMID- 12596423
TI  - [Indoor radon pollution in houses in the Apulian Region of Italy and evaluation
      of the probability of lung cancer in the population].
AB  - BACKGROUND: Radon-222 is a gaseous radioactive chemical which can be transformed
      into other radioactive chemicals, defined as "products of decay" or "radon's
      daughter". The modality of radon penetration into the buildings depends on the
      convection motion created in the ground, which suck it back, so causing the
      penetration. The principal effect on human health is the increase risk of lung
      cancer, in proportion to the concentration and the time people spend indoors with
      exposure to radon. OBJECTIVES: The study proposed to estimate the expected cases
      of radon-induced lung cancer in the population of Apulia due to contamination by
      indoor radon. METHODS: The study used the data obtained in a national survey made
      by ANPA (National Environmental Protection Agency) and ISS (High Health
      Institute), with the collaboration of the Regional Reference Centres for the
      Control of Environmental Radioactivity (CRR). In the Apulia Region 310 families
      (5000 nationwide) were involved, which were selected so as to constitute a
      representative sample both of the region and the country. Appropriate instruments
      for the measurement of mean concentrations of indoor radon (passive nuclear trace
      monitors were installed in the homes of the sample families in two different
      periods of year). We evaluated the variations of indoor radon concentration in
      the houses during spring-summer and autumn-winter periods, observing a
      predictable increase in the latter period. We assessed concentrations in relation
      to: 1. architectural features and location, 2. construction year, 3. building
      material, 4. presence of windows. RESULTS: We found higher contamination in the
      oldest non-cement buildings and on the lower floors. In Lecce and Castri di Lecce
      we found a mean radon concentration higher than the national and the regional
      mean, which is equivalent to annual exposure of 0.54 and 0.46 WLM respectively.
      For these levels we estimated that the expected cases of radon-induced lung
      cancer will be 1.5 in Lecce and 1.3 in Castri per 10,000 inhabitants. CONCLUSION:
      The results of our investigations confirm that indoor radon pollution is a
      significant problem as it is one of the main causes of lung cancer. Hence,
      precautionary measures to reduce as much as possible exposure to indoor radon are
      highly recommended.

PMID- 12596424
TI  - Strenuous exercise and action of antioxidant enzymes.
AB  - BACKGROUND: During the course of evolution, the antioxidant system has developed
      in order to prevent cell damage and to maintain equilibrium between production of
      free radicals and their neutralization. Because of increased oxygen consumption
      and energy utilization during physical work, oxidative stress may be expected. A
      review of current literature revealed no consistent data regarding activity of
      antioxidant enzymes during strenuous exercise. OBJECTIVES: The aim of this paper
      was to identify the activity of antioxidant enzymes in erythrocytes during
      strenuous short-term exercise. METHODS: The activity of superoxide dismutase
      (SOD), glutathione peroxidase (GPX), and glutathione reductase (GR) were
      investigated. Also, glucose-6-phosphate dehydrogenase (G-6-PDH) activity was
      studied in order to assess the level of recovery of reduced glutathione (GSH) by
      maintaining NADPH. Peripheral blood was drawn before (1) and immediately after
      (2) the test completed. Modified Astrand's protocol on a bicycle ergometer was
      used to achieve strenuous exercise in volunteers. RESULTS: The results obtained
      were: SOD1--897.95 +/- 99.85 U/g Hb and SOD2--828.38 +/- 75.12 U/g Hb; GPX1-
      30.19 +/- 4.03 U/g Hb and GPX2--26.00 +/- 4.85 U/g Hb; GR1--58.29 +/- 8.23 U/L
      and GR2--62.67 +/- 7.29 U/L; G-6-PDH1--14.97 +/- 3.79 IU/g Hb and G-6-PDH2--16.5
      +/- 2.74 IU/g Hb. The difference was statistically highly significant: p < 0.001
      for SOD, GPX, and GR activities, and p = 0.018 for G-6-PDH activity. CONCLUSION:
      The results reflect the presence of oxidative stress in erythrocytes after
      strenuous exercise. Further investigations should clarify the role of other
      antioxidant-relevant compounds during exercise such vitamins, trace elements, and
      metals and enable estimation of the level of damage caused by generation of free
      radicals (e.g., malonyl dialdehyde, 8-hydroxydeoxyguanosine etc.). All this
      information together will undoubtedly give us clear insight into free radical
      generation during strenuous workloads.

PMID- 12596425
TI  - [The European Directive 2002/44/CE on the protection of workers from risks
      resulting from mechanical vibration].
AB  - This paper provides comments on the European Directive 2002/44/CE of 25 June 2002
      on the minimum health and safety requirements regarding the exposure of workers
      to the risks arising from physical agents (vibration) (sixteenth individual
      Directive according to Article 16(1) of Directive 89/291/EEC). The European
      Directive on mechanical vibration was published in the Official Journal of the
      European Communities L 177/13 on 6 July 2002. The Directive includes the
      definitions of hand-arm vibration and whole-body vibration, establishes the daily
      exposure limit values and action values for mechanical vibration, and gives
      provisions related to (i) determination and assessment of risks, (ii) measures
      aimed at avoiding or reducing exposure, (iii) information, training, consultation
      and participation of workers, (iv) health surveillance of the exposed workers,
      and (v) derogations and transitional periods for the implementation of the
      obligations of employers when the daily exposure limit values are exceeded. The
      author discusses the strong link which exists between the assessment of risk due
      to vibration exposure at the workplace and the health surveillance of the exposed
      workers. The occupational health physician, as a specialist with expertise in
      human factors and in the early detection of vibration-related adverse health
      effects, will have an important role in the assessment of risks arising from
      mechanical vibration in order to implement an effective health surveillance of
      the exposed workers. The Member States must bring into force the requirements of
      the Directive no later than 6 July 2005.

PMID- 12596427
TI  - A comparative study of the phonology of pre-school children with specific
      language impairment (SLI), language delay (LD) and normal acquisition.
AB  - The phonology of two groups of SLI (n = 5) and LD (n = 5) children was analysed
      at age 3 and compared with two control groups: an age control (n = 5) and a
      language level control (measured using the MLU-W) (n = 5). Children with SLI and
      LD showed a delay in the acquisition of segments, syllabic structures and word
      structures, and in the simplification processes, compared with their age control
      group. However, SLI children also displayed significant differences vis-a-vis
      their language level controls, mainly in early acquisitions: vowels, nasals and
      stops at the segmental level, and in CV structures at the syllabic level. There
      is also a simplification process that seems to be more prevalent in these
      children than in their language level controls, namely, the deletion of
      unstressed syllables, mainly initial ones. The results enable SLI to be
      distinguished from LD and suggest that the development of SLI phonology is
      deviant. This deviation is interpreted as being a plateau in early acquisitions
      when later acquisitions have already appeared. The results are considered in the
      light of Leonard's surface hypothesis and an exclusively linguistic cause for
      this disorder is ruled out.

PMID- 12596428
TI  - Vowel and diphthong development in Cantonese-speaking children.
AB  - Spontaneous speech samples were collected from 40 Cantonese-speaking children
      aged between 10 and 27 months. Over 7,000 vowels and diphthongs were transcribed
      and analysed to determine the accuracy of production of Cantonese vowels and
      diphthongs. A model of feature complexity was derived from the distinctive
      features of vowels to predict the route of development of vowels and diphthongs.
      Two factors were found to affect development: a linguistic factor (frequency of
      occurrence in the ambient language) and an articulatory factor (feature
      complexity). Early dependence on the feature complexity of segments at 15-18
      months is superseded by ambient language influences by 24 months of age.

PMID- 12596430
TI  - Prosecutors seek to expand the use of federal statutes.

PMID- 12596429
TI  - Imitation of nonwords by hearing impaired children with cochlear implants:
      suprasegmental analyses.
AB  - In this study, we examined two prosodic characteristics of speech production in 8
      10-year-old experienced cochlear implant (CI) users who completed a nonword
      repetition task. We looked at how often they correctly reproduced syllable number
      and primary stress location in their responses. Although only 5% of all nonword
      imitations were produced correctly without errors, 64% of the imitations
      contained the correct syllable number and 61% had the correct placement of
      primary stress. Moreover, these target prosodic properties were correctly
      preserved significantly more often for targets with fewer syllables and targets
      with primary stress on the initial syllable. Syllable and stress scores were
      significantly correlated with measures of speech perception, intelligibility,
      perceived accuracy, and working memory. These findings suggest that paediatric CI
      users encode the overall prosodic envelope of nonword patterns, despite the loss
      of more detailed segmental properties. This phonological knowledge is also
      reflected in other language and memory skills.

PMID- 12596431
TI  - ERISA preemption conflict in the Third Circuit.

PMID- 12596432
TI  - Sources of health insurance and characteristics of the uninsured: analysis of the
      March 2002 Current Population Survey.

PMID- 12596433
TI  - Plague.

PMID- 12596434
TI  - Leaders in medicine: Gordon Deckert, MD.

PMID- 12596435
TI  - Peripheral arterial disease--Part I: Diagnosis, epidemiology and risk factors.
AB  - While knowledge about peripheral arterial disease (PAD) appears well
      disseminated, the condition still goes largely undiagnosed and untreated. We
      reviewed the current literature and found that PAD is a common condition that is
      equally prevalent in men and women. Most cases are asymptomatic and more so in
      women. Having PAD increases morbidity and mortality, as well as concomitant
      cardiovascular disease. Given the lack of symptoms in most patients, we recommend
      diagnosing PAD using non-invasive instruments such as the Ankle-Brachial Index
      (ABI). This paper deals with the diagnosis, epidemiology and risk factors for
      PAD.

PMID- 12596436
TI  - Nursing Home Reform and House Bill 2019: past, present, and future.
AB  - On May 25, 2000, in the wake of the scandal at the Oklahoma State Department of
      Health related to corruption on the inspection of nursing homes and assisted
      living facilities, the Oklahoma State Legislature passed House Bill 2019 (HB
      2019). Known as the Oklahoma 2001 Healthcare Initiative, HB 2019 has as one of
      its main purposes the improvement of the public health care system (i.e.
      Medicaid) in the state through the provision of increased health services and
      benefits, especially to residents (Medicaid and non-Medicaid) in nursing homes.
      This article will review and discuss the past, present, and future implications
      of HB 2019 both on the care delivered to nursing home residents and on the
      providers of that care.

PMID- 12596437
TI  - Medicaid program information.

PMID- 12596438
TI  - The case for Tort Reform.

PMID- 12596439
TI  - Births: final data for 2001.
AB  - OBJECTIVES: This report presents 2001 data on U.S. births according to a wide
      variety of characteristics. Data are presented for maternal demographic
      characteristics including age, live-birth order, race, Hispanic origin, marital
      status, and educational attainment; maternal characteristics (medical risk
      factors, weight gain, tobacco, and alcohol use); medical care utilization by
      pregnant women (prenatal care, obstetric procedures, complications of labor
      and/or delivery, attendant at birth, and method of delivery); and infant
      characteristics (period of gestation, birthweight, Apgar score, abnormal
      conditions, congenital anomalies, and multiple births). Also presented are birth
      and fertility rates by age, live-birth order, race, Hispanic origin, and marital
      status. Selected data by mother's State of residence are shown, as well as data
      on month and day of birth, sex ratio, and age of father. Trends in fertility
      patterns and maternal and infant characteristics are described and interpreted.
      METHODS: Descriptive tabulations of data reported on the birth certificates of
      the 4.026 million births that occurred in 2001 are presented. Denominators for
      population-based rates are derived from the 1990 U.S. census. As a result, rates
      are generally larger than would be the case if 2000-based estimates were used.
      The magnitude of the overestimate will vary by population subgroup; overestimates
      are likely greatest for those of Hispanic origin. RESULTS: The number of births,
      the birth rate, fertility rate, and total fertility rates all declined 1 percent
      in 2001. The teenage birth rate reached another historic low. Birth rates for
      women in their twenties declined slightly, whereas rates for women aged 30 to 44
      years continued to rise. Births to unmarried women changed very little. Smoking
      by pregnant women was down again. Women were more likely to begin care in the
      first trimester of pregnancy (83.4 percent). The cesarean delivery rate rose for
      the fifth consecutive year to 24.4 percent; the primary cesarean rate was up 5
      percent and the rate of vaginal births after a previous cesarean fell 20 percent.
      Preterm and low birthweight levels both rose for 2001. The twin birth rate
      continued to climb, and following 2 years of decline, the rate of triplet/+
      births also increased.

PMID- 12596440
TI  - [The essential functions of public health and their evaluation].

PMID- 12596441
TI  - [Cell lineage and programmed death: implications in developmental biology and
      biomedicine].

PMID- 12596442
TI  - Should the use of DDT be revived for malaria vector control?
AB  - Indoor residual spraying with DDT was the principle method by which malaria
      transmission was eradicated or greatly reduced in many countries between the late
      1940s and 1970s. Since then, decreasing use of DDT has been associated with a
      resurgence of malaria in India, Sri Lanka, former Soviet Central Asia, Zanzibar,
      Venezuela and several other Latin American countries. In India and Zanzibar, DDT
      resistance in vectors, as well as a decline in spray coverage, are probable
      causes of reduced effectiveness of DDT in recent decades. In southern Europe,
      eradication of malaria transmission was achieved by DDT spraying in the 1940s and
      50s and eradication has been sustained by adequate treatment of imported human
      malaria cases. In the highlands of Madagascar and South Africa, recent reversion
      to DDT spraying has been successful in stemming resurgences of malaria. Continued
      use of DDT for vector control, but not for agriculture, is approved by the
      Stockholm Convention on Persistent Organic Pollutants. DDE residues in breast
      milk have been associated with DDT anti-malaria spraying in South Africa, but it
      is not known whether this is harmful. A claimed association of DDE residues with
      breast cancer have not been substantiated. There is a recent report of
      association of DDE residues with probability of premature birth; the possible
      relevance of this to anti-malarial use of DDT should be investigated. In
      Colombia, testing of the DDT stockpile for suspensibility, DDT resistance in
      Anopheles darlingi and investigation of the present affordability of widespread
      spraying with DDT, compared with alternative chemicals, are recommended.

PMID- 12596443
TI  - [The Langerhans' cell].
AB  - Langerhans cells are antigen-presenting cells that play a key role in the
      initiation and regulation of immune response. They are localized in stratified
      epithelia, such as epidermis, and migrate to the lymphoid organs in order to
      present antigens introduced in the skin so that the T cell response can be
      initiated. Light and electron microscopy images of the cells demonstrate their
      morphology within the epidermis and as they migrate to the culture medium.
      Factors inducing migration are reviewed, as well as the therapeutic potential of
      these factors in regulating the immune response.

PMID- 12596444
TI  - [Comparison between OptiMAL and the thick smear tests for malaria diagnosis in an
      endemic area during a non-epidemic period].
AB  - The capacity of Optimal to diagnose malaria was compared with the thick smear
      test in two representative samples, one with acute febrile syndrome (AFS) n =
      107, and another diagnosed by thick smear test (AFS + M) n = 82. The samples were
      chosen from patients at the malaria diagnostic clinic in Turbo, Antioquia,
      Colombia, between June and August 2000. The study was designed to be descriptive,
      prospective, and cross-sectional. The two tests were applied simultaneously in
      the AFS group (parallel, double blind design), and in sequential form in the AFS
      + M group. The thick smear test was the standard test. Optimal tests were carried
      out according to the manufacturer's instructions. In the parallel design, Optimal
      showed, for Plasmodium falciparum, a sensitivity of 40% [95% CI: 18-67], a
      specificity of 98% (95% CI: 92-100) and positive and negative predictive values
      of 75% (95% CI: 36-96) and 91% (95% CI: 83-96%), respectively. For Plasmodium
      vivax, it showed a sensitivity of 97% (95% CI: 82-100), a specificity of 89% (95%
      CI: 80-95) and positive and negative predictive values of 79% (95% CI: 62-90) and
      98% (95% CI: 91-100). With the sequential design, Optimal showed a sensitivity of
      67% (95% CI: 52-79) and 97% (95% CI: 83-100) for P. falciparum and P. vivax,
      respectively. For P. falciparum, the sensitivity was directly proportional to the
      parasitemia, while the sensitivity for P. vivax was independent from the
      parasitemia. The diagnostic values and operative characteristics of the thick
      smear test surpassed the Optimal test in its sensitivity for P. falciparum; the
      specificities were similar. Both tests were nearly identical in their diagnostic
      capacity for P. vivax. These results recommend that the thick smear test be
      retained as a routine or reference test for malaria diagnosis, with Optimal used
      as an ancillary test.

PMID- 12596445
TI  - [Patterns of antihypertensive agents use in 11,947 Colombian patients].
AB  - In Colombian populations older than 15 years, 12.6% suffer from hypertensive
      disease. Pharmacological therapies for hypertension and associated diseases were
      compared for 11,947 adult hypertensive patients of both sexes. All had been in
      treatment for more than 3 months (November/01-January/02), and were distributed
      among six Colombian cities. The data were retrieved from medication consumption
      registers that were maintained by the institutions that distribute medications to
      patients selected for the study. The average age of patients was 55.8 +/- 13.8,
      and 67.7% were women. Men were older (p < 0.05) and consumed other drugs more
      than women (67.7% vs. 62.4%, p < 0.05); 53.2% of patients received only one drug
      and 46.8% received between 2 to 5 drugs for hypertension disease. Medications
      most commonly prescribed were hydrchlorothiazide (31.8%), captopril (27.9%),
      verapamil (27.6%), enalapril (25%), metoprolol (15.1%) and propranolol (14.9%).
      The most common combinations were hydrochlorothiazide + ACE inhibitors (n =
      2,001), hydrochlorothiazide + calcium channel antagonists (n = 1,367), verapamil
      + ACE inhibitors (n = 1,153) and hydrochlorothiazide + beta blocker (n = 1,021).
      Other prescribed medications included ASA as antiplatelet (38.2% of patients),
      nonsteroidal anti-inflammatory drugs (NSAID, 16.2%), lipid-lowering drugs
      (11.8%), hypoglycemic agents (10.9%) and antiulcerous drugs (9.6%). Some agents
      are probably underemployed (ACE inhibitors, ASA) and others overused
      (antiulcerous). Potentially dangerous pharmacological interactions were
      discovered in 410 cases (3.43%). Significant differences occurred in physicians'
      formulations among the six cities, but rational prescription patterns prevailed.
      Newly designed educational strategies are recommended to prevent administration
      of potential harmful combinations. Further exploration of clinical results in
      these formulations is indicated.

PMID- 12596446
TI  - [Malnutrition and its association with intestinal parasitism among children from
      a village in the Colombian Amazonian region].
AB  - Intestinal parasites and malnutrition cause high morbidity among children in
      developing countries. A study to establish the associations between intestinal
      parasitism and undernourishment was undertaken in a village in the Colombian
      Amazon region. Two hundred thirty seven children each provided four stool samples
      for parasitic analysis. Anthropometric indices were calculated based on height
      and weight (HAZ), weight and age (WAZ) and height and weight (WHZ) using the
      international growth standards recommended by the World Health Organization. Of
      the 237 children, 86.1% were carrying parasites, 54% had 2 or more parasites, 30%
      were stunted, 10% were underweight, and 2.5% were wasting. HAZ and WAZ indices
      were inversely related to age and number of parasites. Socioeconomic status was
      positively correlated with the number of parasites and inversely related to the
      HAZ index (p < 0.05). In conclusion, frequencies of undernourishment and
      intestinal parasites among the sample population were higher than the national
      average for Colombia. As previous studies have indicated, age, intestinal
      parasitism and socio-economic level are variables significantly related to
      nutritional state.

PMID- 12596447
TI  - [Karyotypic comparison of five species of Lutzomyia (diptera: psychodidae) of the
      series townsendi and the verrucarum group in Colombia].
AB  - Cytogenetic characteristics were established for five native species of
      phlebotomine sand flies (Lutzomyia, series townsendi, verrucarum group):
      Lutzomyia longiflocosa, Lutzomyia townsendi, Lutzomyia spinicrassa, Lutzomyia
      torvida and Lutzomyia youngi. Karyotypes and chromosomal morphometry were
      compared. Using the squash technique, brain tissues from late 4th instar larvae
      provided the necessary mitotic chromosomes. Chromosomal measurements were made on
      the following chromosomal characteristics: short arm, long arm, arm ratio, total
      length, relative length, centromeric index and relative length average of
      chromosomes. Chromosomes were classified according to their morphometry and
      position of the centromere. The taxonomic distance was calculated, and the
      relationships among the species displayed in a phenogram. All five species
      possessed four pairs of chromosomes as diploid number (2N = 8). None of the
      karyotypes indicated presence of heteromorphic chromosomes. Statistical analysis
      of the morphometric data showed highly significant differences among the
      chromosomes pairs of the five species. However, the total length of the genome
      was very similar, with the exception of L. youngi. In conclusion, these closely
      related species were distinguishable at cytological level.

PMID- 12596448
TI  - [Phenotypic diagnosis of primary immunodeficiencies in Antioquia, Colombia, 1994
      2002].
AB  - Recurrent infections are a frequent cause of medical visits. They can be due to a
      heterogeneous group of dysfunctions that increase the susceptibility to
      pathogenic and opportunistic microorganisms, such as immunological deficiencies.
      To define an opportune rational treatment and to guide the molecular diagnosis of
      primary immunodeficiency diseases, we establish a program for the phenotypic
      diagnosis of these illnesses in Antioquia, Colombia, including clinical and
      laboratory evaluations of patients who present recurrent infections with abnormal
      evolution. Between August 1, 1994 and July 31, 2002, phenotypic diagnosis of
      primary immunodeficiency was made in 98 patients. Similar to data reported in the
      literature, antibody deficiencies were the most frequent (40.8%), followed by
      combined deficiencies (21.4%). This phenotypic characterization has allowed for
      appropriate treatments for each patient and, in some cases, functional and
      molecular studies that can lead to a definite molecular diagnosis.

PMID- 12596449
TI  - [Axillary granular parakeratosis].
AB  - Axillary granular parakeratosis is an alteration of keratin characterized by a
      thick parakeratotic horny layer with abundant intracellular keratohyalin
      granules. It was first described in 1991 and since then 32 cases have been
      reported from USA, Europe and Australia. Lesions may affect intertriginous areas
      other than the axilla. The disease has apparently not been previously described
      in Latin America. Three overweight Colombian women were diagnosed with axillary
      granular parakeratosis. They presented encrusted, hyperkeratotic, hyperpigmented
      and pruriginous papules and plaques which affected both axillae in two women and
      only one in the other. Lesions had persisted for two and four months in two
      patients and for one year in the third. Clinical diagnoses were benign familiar
      pemphigus and tinea nigra. Skin biopsies showed a thick parakeratotic basophilic
      horny layer. Electron microscopy demonstrated a high content of keratohyalin
      granules. No Langerhans cells were demonstrated in the lesions using IHC for S
      100 protein. No fungi were seen with the PAS stain. Infundibula showed thick
      horny plugs with changes similar to those seen in the epidermis. Dermal tissue
      showed few perivascular lymphocytes. These findings suggest that the disease has
      an irritative pathogenesis. Clinical histories indicated that the three women
      were overweight and used several types of antiperspirants. These factors plus
      local irritation and humidity apparently triggered the keratinization response.

PMID- 12596450
TI  - [Experimental inoculation of Terminalia catappa seedlings with an environmental
      isolate of Cryptococcus neoformans var. gattii serotype C ].
AB  - In 1997, our laboratory reported for the first time the isolation of Cryptococcus
      neoformans var. gattii serotype C associated with almond tree (Terminalia
      catappa) detritus. This finding led to a more detailed follow up of the
      association between the plant and the yeast. Preliminary data have shown that
      survival of the yeast in almond trees seedlings goes beyond 100 days. The aim of
      the present study was to establish if under the conditions previously studied, C.
      neoformans var. gattii would remain viable for longer periods. A total of 83
      almond tree seedings, 20-40 cm high, were inoculated with C. neoformans var.
      gattii serotype C (INS-755). Assays were carried out inoculating the stem or the
      soil where the seedlings were planted. Observations were undertaken for a period
      of up to 12 months. As processing techniques we employed the endophytic fungi
      procedure (stems), maceration (roots, leaves) and standard suspension method
      (soils). Additionally, microscopic visualization of the yeast in plant tissues
      was done with trypan blue plus lactophenol. C. neoformans var. gattii was
      recovered from the inoculated plants for a period of up to 12 months post
      inoculation; additionally, the fungus had the capacity to migrate from the stem
      to the soil and viceversa, without causing macroscopic or microscopic alterations
      in the plant tissues. This finding suggests that there appears to be an
      association between the host plant and C. neoformans var. gattii in the
      environment.

PMID- 12596451
TI  - [Comparison of three neuro-tracing techniques for identification of the sciatic
      spinal nerve origin in mice].
AB  - To identify sensory and motor neurons associated with the sciatic nerve in adult
      mice, three methods for applying fluorescent tracers (Fluorogold and Dil) were
      investigated: direct application, intraneural injection and impregnation of a
      sectioned nerve in a silicone chamber. Most accurate localization of the neurons
      on the dorsal root ganglia and spinal cord was accomplished by introducing the
      proximal stump of a transected sciatic nerve into a silicone chamber, filled with
      tracers and then decalcifying the tissue. Fluorogold was an effective tracing
      agent, in contrast to Dil, which was not. In addition to associations with
      cephalic ganglia L4, L5 and L6, as seen in rats, contributory neurons to the
      sciatic nerve were located in other ganglia in the mouse. These findings show
      that the silicone chamber-tissue decalcification technique is a viable tool for
      obtaining comparative neuroanatomical information in the mouse model.

PMID- 12596452
TI  - [Research on health and violence: a step forward in prevention].

PMID- 12596453
TI  - [World report on violence and health].
AB  - In 1996, the World Health Assembly declared violence a major public health issue.
      To follow up on this resolution, on October 3 this year, WHO released the first
      World Report on Violence and Health. The report analyses different types of
      violence including child abuse and neglect, youth violence, intimate partner
      violence, sexual violence, elder abuse, self-directed violence, and collective
      violence. For all these types of violence, the report explores the magnitude of
      the health and social effects, the risk and protective factors, and the types of
      prevention efforts that have been initiated. The launch of the report will be
      followed by a 1-year Global Campaign on Violence Prevention, focusing on
      implementation of the recommendations. This article summarises some of the main
      points of the world report.

PMID- 12596454
TI  - [Mental health in situations of armed conflict].
AB  - Mental health is a serious problem in Latin America where many communities have
      been directly affected by armed conflict, communities in which large population
      groups have been displaced or have sought refuge. Research studies and
      epidemiological statistics are summarized to emphasize the psychosocial
      consequences of traumatic events associated with armed conflict. In addition to
      specific psychological disorders, other more generalized are considered such as
      fear, affliction, diseases, social disorder, violence and psychoactive substance
      consumption. Finally, the main points of a mental health plan for emergency
      situations are described which include the following: (1) preliminary diagnosis,
      (2) increase, decentralize and strengthen mental health public services, (3)
      psychosocial attention to the prevailing disorders--with emphasis on childhood
      problems, (4) initiate training and use of non-specialized personnel, and (5)
      identification of special needs requiring attention by psychologists and
      psychiatrists. Other aspects emphasized were community education, training,
      social communication, community organization, social participation,
      interinstitutional coordination, flexibility, sustainability, and specific
      actions in accordance with local needs.

PMID- 12596455
TI  - [Social and economic impact of violence in the Americas].
AB  - Violence is a social and a public health problem that has grown in the Americas
      in recent decades that has negative effects on social, health, and the economy of
      countries, communities, families, and individuals. More than 115,000 people are
      murdered every year, the majority of them are men; other 55,000 commit suicide.
      In 20 to 60% of households some form of domestic violence against girls, boys,
      women, and the elderly occurs; juvenile gangs, involved in violent and criminal
      activities, increases at alarming rate. Other forms of violence are wars and
      internal or international conflicts, political violence, abductions, lynching,
      multinational violence by organized crime units involved in narcotic trafficking,
      sexual trade or smuggling of weapons. The public health approach is based on a
      methodology of work, as follows: 1. Characterization of the problem in its basic
      variables of person, place, time, circumstances, and related situations; 2.
      Identification of causes, associations, or risk factors; 3. Proposal of
      interventions and their evaluation; 4. Extension of the evaluated interventions.
      Violence is an intentional act of multicausal origin. Various factors are
      interconnected showing the relations among them. Those which have been primarily
      studied or that have shown greater evidence are discussed. A historical look is
      proposed, that integrates the repression and control, the prevention and the
      recovery of the social fabric. Violence demands an expenditure of money that
      represents a significant proportion of the GDP that was estimated in $168 billion
      dollars for Latin America. Violence can be prevented. Primary prevention projects
      are driven to avoid the occurrence of a violent act, but if it has already
      occurred it is necessary to avoid its repetition, through secondary prevention
      projects. Tertiary prevention is applied in order to avoid major damages; it aims
      at improving the quality of life of those already traumatized. The programs
      should be comprehensive and sustained in the medium and long terms. Finally,
      comments have been made on PAHO and WHO policies, in particular the recently
      launched World Report on Violence and Health, a working tool for violence
      prevention.

PMID- 12596456
TI  - [Decrease in violence and delinquency in Bogota, Colombia, 1994-2002].
AB  - The present article shows reliable data on Bogota's homicide decreasing rates and
      presents the strategies applied during the past 8 years which partly explain such
      decrease.

PMID- 12596457
TI  - [Violence metastasis or questioned health].
AB  - The relationship between violence and health was examined from a psychoanalytical
      perspective, showing why the conditions of violence, being structural, become the
      main obstacle to healthy living conditions in the present scientific era. The
      importance and reliance on individual and community positive attitudes when
      implementing health strategies are shown, emphasizing that these attitudes are an
      essential requirement for the recovery of health conditions. This conclusion does
      not ignore the likelihood that the principles of health strategies are often
      themselves questionable within the structural framework of violence.

PMID- 12596458
TI  - [Experiences and psycosocial impact on soldier boys and girls from the civil war
      in El Salvador].
AB  - Exploratory research with 293 excombatants who participated as child soldiers in
      the El Salvador civil war as FMLN (Marti Front for National Liberation) members
      or as Armed Forces soldiers was conducted to examine their current living
      conditions and the impact of past military experience. Although nearly ten years
      have passed since the peace accords were signed, the excombatant exhibited signs
      of emotional disturbance. Current underprivileged living conditions and social
      marginalization were decisive factors which inhibited reentry into civilian life
      and constituted an important psychosocial impact by placing at risk their
      integration at the family, community and society levels.

PMID- 12596459
TI  - The relationship between violent video games, acculturation, and aggression among
      Latino adolescents.
AB  - Multiple factors are involved in the occurrence of aggressive behavior. The
      purpose of this study was to evaluate the hypotheses that Latino middle school
      children exposed to higher levels of video game playing will exhibit a higher
      level of aggression and fighting compared to children exposed to lower levels and
      that the more acculturated middle school Latino children will play more video
      games and will prefer more violent video games compared to less acculturated
      middle school Latino children. This study involved 5,831 students attending eight
      public schools in Texas. A linear relationship was observed between the time
      spent playing video games and aggression scores. Higher aggression scores were
      significantly associated with heavier video playing for boys and girls (p <
      0.0001). The more students played video games, the more they fought at school (p
      < 0.0001). As Latino middle school students were more acculturated, their
      preference for violent video game playing increased, as well as the amount of
      time they played video games. Students who reported speaking more Spanish at home
      and with their friends were less likely to spend large amounts of time playing
      video games and less likely to prefer violent video games (p < 0.05).

PMID- 12596460
TI  - [Suicidal ideation among university adolescents: prevalence and associated
      factors].
AB  - A cross sectional study quantified the prevalence of suicidal ideation among
      university students less than 18 years old and determined variables associated
      with suicidal ideation. One hundred and ninety-seven students from the National
      University of Colombia in Bogota were selected by a random stratified sampling.
      The instrument applied for the measurement of risk factors was the psychiatric
      interview-approach. The statistical analysis included description of variables,
      estimation of prevalence by population and social stratum, bivariate analysis and
      logistic regression to evaluate associated factors. A prevalence of 4.4% of
      suicidal ideation was found at the time of the interview and 13% during the past
      year. Suicide ideation and suicide attempts were more frequent in women. The
      prevalence of depressive disorders was higher than that reported for the general
      population in the same age group. Childhood abuse was related with psychiatric
      disorders and with suicidal ideation. Recommendations for the clinical evaluation
      of suicidal-patients are provided.

PMID- 12596461
TI  - [Suicide in Bogota: an increasing phenomenon in young populations].
AB  - An observational analytic study was carried out to analyze bimodal patterns
      related with age in suicidal victims in Bogota during 1990, 1995 and 2000 using
      information from autopsy reports. The analysis was based on statistical models of
      finite mixture distributions, and parameters were estimated with maximum
      likelihood methods. Two hundred and twenty two suicides were analyzed in 1990,
      272 in 1995, and 330 in 2000. The presence of a bimodal distribution in each one
      of the analyzed years was demonstrated. As time passes, the means became
      progressively smaller. Age showed a bimodal distribution during the analyzed
      period. Means tendencies suggest that suicide is becoming more frequent among
      young people. Additional research and specific mental health strategies are
      recommended for these risk groups.

PMID- 12596462
TI  - [Epidemiologic profile of the population displaced by the internal armed conflict
      of the country in a neighborhood of Cartagena, Colombia, 2000].
AB  - Colombia faces internal displacement as a consequence of internal armed conflict.
      From 1985 to the present, it is estimated that 1,500,000 people have been
      displaced. A transversal descriptive study aimed at characterizing the health
      situation of this highly vulnerable and continually growing population was
      carried out in Cartagena between September and December, 2000. The sample size
      was calculated to meet a 2% precision, 40% of maximum expected prevalence, design
      effect of 2 and 15% of information loss, total sample size 1.600 home's
      interviews. Single-stage sampling with replacement was done by clusters. To
      socioeconomic, sanitary conditions, morbidity and mental health variables was
      done univariate analysis, determining frequencies, central trend and dispersion,
      as well as a bivariate analysis to determine X2 or Fisher exact test, p values
      and stratified analysis. The study found severe deterioration in socioeconomic
      conditions, high exposure to violence (80% was exposed to violence before
      displacement and murder cause 60% of deads in teenagers and adults after
      displacement but even children under 4 years-old was affected by this
      phenomenon), family disintegration, bad sanitary conditions, high prevalence of
      tracing diseases in all ages (80% of under 5 years-old had respiratory symptoms,
      30% diarrhoea and 32% purulent lesions in skin), school desertion (20% children
      between 5 and 11 years and 16% teenagers), late schooling, poor performance at
      school, high proportion of working children (4% children between 5 and 11 years
      and 20% teenagers), low affiliation to social security systems (only 20% under 5
      years-old children and 50% adults), low coverage and access to health services,
      among many other factors whose interaction affects this population's physical and
      mental health. We found that is difficult to make an early detection of
      internally displaced populations and thus provide adequate health care when such
      displacements are recent or involve individual persons. Results show that is
      essential to implement a surveillance system based on community leaders to
      increase efficiency, access and opportunity in health care for displaced
      populations.

PMID- 12596464
TI  - Accurate quantum-chemical prediction of enthalpies of formation of small
      molecules in the gas phase.
AB  - The coupled-cluster approach, including single and double excitations and
      perturbative corrections for triple excitations, is capable of predicting
      molecular electronic energies and enthalpies of formation of small molecules in
      the gas phase with very high accuracy (specifically, with error bars less than 5
      kJmol-1), provided that the electronic wavefunction is dominated by the Hartree
      Fock configuration. This capability is illustrated by calculations on molecules
      containing O-H and O-F bonds, namely OH, FO, H2O, HOF, and F2O. To achieve this
      very high accuracy, it is imperative to account for electron-correlation effects
      in a quantitative manner, either by using explicitly correlated two-particle
      basis functions (R12 functions) or by extrapolating to the limit of a complete
      basis. Besides taking into account harmonic zero-point vibrational energies, it
      is also necessary to account for anharmonic corrections to the zero-point
      vibrational energies, to include the core orbitals into the coupled-cluster
      calculations, and to account for spin-orbit corrections and scalar relativistic
      effects. These additional corrections constitute small but significant
      contributions in the range of 1-4 kJmol-1 to the enthalpies of formation of the
      aforementioned molecules. The highly accurate coupled-cluster results, obtained
      by employing R12 functions and by including various corrections, are compared
      with standard Kohn-Sham density-functional calculations as well as with the
      Gaussian-2 and complete-basis-set model chemistries.

PMID- 12596463
TI  - Raman spectroscopy--a prospective tool in the life sciences.
AB  - Although the physics of Raman spectroscopy and its application to purely chemical
      problems is long established, it offers a noninvasive, nondestructive, and water
      insensitive probe to problems in the life sciences. Starting from the principles
      of Raman spectroscopy, its advantages, and methods for signal enhancement, the
      bulk of the review highlights recent applications. Structural investigations of a
      hormone receptor, testing the biocompatibility of dental implants, probing soil
      components and plant tissue alkaloids, and localization of single bacteria are
      just four problems in which Raman spectroscopy offers a solution or complements
      existing methods.

PMID- 12596465
TI  - Molecular logic circuits.
AB  - Miniaturization has been an essential ingredient in the outstanding progress of
      information technology over the past fifty years. The next, perhaps ultimate,
      limit of miniaturization is that of molecules, which are the smallest entities
      with definite size, shape, and properties. Recently, great effort has been
      devoted to design and investigate molecular-level systems that are capable of
      transferring, processing, and storing information in binary form. Some of these
      nanoscale devices can, in fact, perform logic operations of remarkable
      complexity. This research--although far from being transferred into technology-
      is attracting interest, as the nanometer realm seems to be out of reach for the
      "top-down" techniques currently available to microelectronics industry. Moreover,
      such studies introduce new concepts in the "old" field of chemistry and stimulate
      the ingenuity of researchers engaged in the "bottom-up" approach to
      nanotechnology.

PMID- 12596466
TI  - On the dissociation of aromatic radical anions in solution.
AB  - A new theoretical formulation is given for the reaction rate and path for the
      important reaction class of aromatic radical anion dissociation in solution [Ar
      X]-.-->Ar. + X-, and is illustrated for the case of the cyanochlorobenzene
      radical anion [CN-phi-CI]-. in dimethylformamide. Among the theory's novel
      features is the inclusion of the conical intersection aspect of this ground
      electronic state problem, which is key in allowing the reaction to occur and
      which has a significant impact on the reaction barrier height. Reasonable
      agreement with the experimental rate is found.

PMID- 12596467
TI  - Correlation of molecular assembly and interactions in crystals and Langmuir
      Blodgett films of N-(2,4-dinitrophenyl)-n-octadecylamine.
AB  - Correlation of molecular organization in crystals and in ultrathin films is of
      fundamental interest in the design of molecular materials based on thin films. We
      have chosen as a test case, N-(2,4-dinitrophenyl)-n-octadecylamine (DNPOA), a
      potential candidate for the fabrication of Langmuir-Blodgett (LB) films for
      quadratic nonlinear optical applications. Like several other 4-nitroaniline
      derivatives, DNPOA does not form stable monolayers at the air-water interface.
      This has precluded investigations of their organization in LB films. We have
      stabilized composite Langmuir films of DNPOA with the phospholipid molecule DSPC
      and fabricated their LB films. Successful growth of single crystals of DNPOA
      allowed structure determination and detailed analysis of molecular associations
      in the solid state. Electronic absorption spectra of DNPOA in solution, in the
      solid state and in the LB film are investigated. Modeling of the various spectral
      signatures by semiempirical computations on molecular clusters extracted from the
      crystal lattice provides insight into the correlation between the molecular
      organization in crystals and in LB films.

PMID- 12596468
TI  - Gas-phase chemistry of ethynylamine, -phosphine and -arsine. Structure and
      stability of their Cu+ and Ni+ complexes.
AB  - The Cu+ and Ni+ binding energies of ethynylamine, ethynylphosphine and
      ethynylarsine have been calculated at the B3LYP/6-311 + G(2df,2p)//B3LYP/6
      311G(d,p) level of theory. Significant differences between nitrogen-containing
      and phosphorus- or arsenic-containing compounds have been found regarding
      structural effects upon metal cation association. While for ethynylamine the
      global minimum of the potential energy surface corresponds to the complex in
      which the metal cation binds to the beta-carbon, for ethynylphosphine the most
      favourable process corresponds to phosphorus attachment. For ethynylarsine, the
      conventional pi-complex is the most stable one. This behavior resembles that
      found for the corresponding vinyl analogues, with the only exception being the
      arsenic derivative. The calculated Cu+ and Ni+ binding energies for attachment to
      the heteroatom follow a different trend, P > As > N, to that predicted for the
      corresponding proton affinities, P > N > As. Cu+ and Ni+ binding energies are
      almost identical when the metal cation binds to the heteroatom. However, Ni+
      binding energies are slightly larger than Cu+ binding energies when the metal
      cation interacts with the C identical to C bond.

PMID- 12596470
TI  - Organisation and reactivity of nanoparticles at molecular interfaces. Part II.
      Dye sensitisation of TiO2 nanoparticles assembled at the water|1,2-dichloroethane
      interface.

PMID- 12596469
TI  - Monte Carlo simulation of the assembly of bis-biotinylated DNA and streptavidin.
AB  - We present Monte Carlo simulations of the self-assembly of bivalent bis
      biotinylated DNA molecules with the tetravalent biotin-binding protein
      streptavidin (STV). By fitting the STV binding probabilities for the four
      possible valencies, the modelling correctly reproduces the dependencies of
      various network parameters experimentally observed in an earlier study. The
      combined results from the experimental and theoretical studies suggest that the
      binding probability for divalent STV formation is about 50 times larger than for
      the formation of trivalent and about 200 times larger than for tetravalent STV.
      In accordance with the experimental results, the modelling also indicates that
      the mixture of an equimolar ratio of DNA and STV leads to a maximum in size of
      the oligomeric DNA-STV clusters formed. Furthermore, we found a percolation
      transition in which the DNA cluster size increases rapidly with increasing DNA
      concentration resulting in the formation of a single supercluster at elevated
      concentrations. This behaviour coincides with the occurrence of an immobile band
      previously observed in electrophoretic experiments, indicating the formation of
      extremely large DNA-STV aggregate networks.

PMID- 12596471
TI  - Transient optical studies of interfacial energetic disorder at nanostructured dye
      sensitised inorganic/organic semiconductor heterojunctions.

PMID- 12596472
TI  - Reactivity of the convex and concave surfaces of single-walled carbon nanotubes
      (SWCNTs) towards addition reactions: dependence on the carbon-atom
      pyramidalization.

PMID- 12596473
TI  - Rydberg-valence interactions in monoolefins: dispersing electronic properties in
      1,1'-bicyclohexylidene.

PMID- 12596474
TI  - A photochromic liquid crystal system.

PMID- 12596475
TI  - [Air pollution is still the cause of many deaths fifty years after the London's
      killer smog].

PMID- 12596476
TI  - [Endocrine ophthalmopathy. A clinical problem with treatment difficulties].

PMID- 12596477
TI  - [Psychiatric consultation-liaison in Sweden surveyed: A patchwork of
      reimbursement schemes, organizational structures and levels of ambition].
AB  - In order to make a survey of consultation-liaison (c-l) psychiatric activity a
      questionnaire was distributed to all psychiatric departments in Sweden. Questions
      were asked concerning organization, reimbursement and indicators of the quality
      level of services. 42 of 72 possible responders returned the questionnaire (58%).
      The department-affiliated services work with few exceptions at a basic level of
      consultation, and existing liaison activities seldom have any organizational
      connection to the psychiatric departments. There is no commonly accepted
      organizational model and the use of professional categories other than
      psychiatrists is rare. Five psychiatric departments have special c-l units and
      research is pursued almost exclusively at these. A majority of respondents
      express a need for expansion. So far, the services have been working at a level
      of gentlemen's agreement between clinics, but a number of compensatory schemes
      are under way.

PMID- 12596478
TI  - [New therapeutic methods for spasticity and dystonia in children with cerebral
      palsy require multidisciplinary team work. Comprehensive approach yields good
      results].
AB  - New effective methods to reduce spasticity and dystonia are now included in the
      treatment of children with cerebral palsy (CP): selective dorsal rhizotomy (SDR),
      continuous intrathecal infusion of baclofen by an implanted pump or intramuscular
      injections of botulinumtoxin A. SDR is the only method that can reduce the
      spasticity permanently. Strong evidence exists for a positive impact of SDR on
      the function of the children. A multidisciplinary approach is required as it is
      essential to choose the best treatment for each child in each developmental
      period. In Lund physicians and physiotherapeuts from different disciplines such
      as paediatric orthopaedic surgery, neurosurgery and neurology form a central
      spasticity team which co-operates with the local child habilitation services. We
      have found that a common structured and standardized follow-up programme with
      early intervention against muscle hypertonia and imbalance can prevent hip
      luxation and contractures in children with CP.

PMID- 12596479
TI  - [Recommended management of carpal tunnel syndrome. First wrist splinting, surgery
      in sensory deficit/atrophy].

PMID- 12596480
TI  - [Breaking down barriers--about the art of escorting drugs into the brain].

PMID- 12596481
TI  - [Ivar Wickman's academic misfortune. About an appointment to the post and an
      academic defect].

PMID- 12596482
TI  - [2002--a year of harvest for entrepreneurs within alternative medicine].

PMID- 12596483
TI  - [Proposal to a national family practice system is not compatible with the legal
      right to access to health service].

PMID- 12596484
TI  - [The same situation for the homeless before and after the introduction of
      compulsory care--the municipalities do not follow the legislation].

PMID- 12596485
TI  - [Osteoporosis: DXL heel measurement sensibly used is enough for clinical use].

PMID- 12596486
TI  - [The difficult art of evidence interpretation--benefit of sensitivity and
      specificity].

PMID- 12596487
TI  - [Thoughts about tolerance. Foreskin--a symbol with two faces].

PMID- 12596488
TI  - [An epidemiologic blunder about vitamin C].

PMID- 12596489
TI  - Slow but sure.

PMID- 12596490
TI  - Pregnant cause.

PMID- 12596491
TI  - Intermediate care. It takes two.
AB  - An intermediate care scheme launched by a primary care trust in April 2000 is now
      receiving 90 referrals a month, mainly from GPs and community staff. Patients
      receive an assessment within two hours of referral and care within four hours.
      Patients can refer themselves and ambulance crews can also refer patients to the
      scheme, preventing hospital admissions. The scheme operates from 8 am to 8 pm,
      seven days a week and it is hoped to extend it to 24 hours.

PMID- 12596492
TI  - Finance salaries. Account the cost.
AB  - Post-qualification salaries have increased by 4-7 per cent, a slowdown on last
      year's figures when increases were often more than 10 per cent. The highest
      increases this year tended to be in medium-sized trusts where newly qualified
      accountants' salaries rose 8.2 per cent. Directors of finance in large trusts
      earn about 20 per cent more than in medium trusts and about 40 per cent more than
      in small ones. Newly qualified accountants in large trusts earn 5 per cent more
      than in medium-sized trusts and 13 per cent more than in small ones. The survey
      is based on an analysis of salaries from Hays' jobs database, and salaries of
      registered candidates.

PMID- 12596493
TI  - Therapeutic advocacy. Helping children help their parents make decisions.

PMID- 12596494
TI  - Dry hands untreated by moisturizers. Investigation into patient's occupation
      provides information useful for diagnosis.

PMID- 12596496
TI  - Peripheral vascular disease. Diagnosing and treating the 3 most common peripheral
      vasculopathies.
AB  - A common sign of generalized atherosclerosis, peripheral vascular disease (PVD)
      occurs as a result of arterial narrowing or obstruction that restricts blood flow
      to distal tissues. Prevalence of PVD ranges from 3% in patients age > 55, to 11%
      in patients age > 65, to 20% in those age 75 and older. Cerebrovascular/carotid
      disease, abdominal aortic aneurysms, and peripheral arterial occlusive disease
      are the most common peripheral vasculopathies seen by primary care physicians.
      All require aggressive medical management to prevent potentially serious
      complications and may require referral to vascular surgeons for evaluation.
      Prevention remains the best therapy.

PMID- 12596495
TI  - Tinnitus. Diagnosis and treatment of this elusive symptom.
AB  - More than 37 million Americans experience tinnitus, and adults age 40 to 70 are
      most often affected. Tinnitus is a symptom, not a disease, and as such has many
      different causes. Tinnitus is classified as vibratory and nonvibratory and is
      further subdivided into objective and subjective categories. The evaluation of
      tinnitus always begins with a thorough history and physical examination, with
      further testing performed when indicated. Many medical and nonmedical treatments
      exist, with varying degrees of success and safety. Once the physician determines
      that the patient does not have a life-threatening or obviously treatable
      underlying condition, the patient should be counseled, reassured that the
      tinnitus is not a life-threatening disease, and offered appropriate treatment.
      The degree to which the tinnitus bothers the patient will help determine the
      extent of treatment necessary.

PMID- 12596497
TI  - Mental health problems in assisted living residents. The physician's role in
      treatment and staff education.

PMID- 12596498
TI  - Assisted living facilities. What they are and how to find one.

PMID- 12596499
TI  - Folate status in Germany 1997-2000.
AB  - Data about folate intake and blood values of the German population, published
      between 1997 and 2000, have been reviewed. Median folate intake is about 250
      micrograms/day in the adult population, which indicates a high likelihood of
      inadequate intake when compared to the Estimated Average Requirement (EAR) of 320
      micrograms/day. Only a few studies have evaluated serum and erythrocyte folate or
      plasma homocysteine as a marker of folate status. The most representative data
      show that 25% of German women of childbearing age have an inadequate recent
      folate intake. Only 13.3% of the women have red blood cell folate values above
      the critical value of 400 micrograms/day established by Daly et al (1995). Folic
      acid fortification of food is shown to be responsible for about 25% of folate
      intake in the German child and adolescent population in one study. If we
      extrapolate these data to the general population, folic acid fortification could
      be the explanation for the differences observed between folate intake and blood
      values. The discrepancy might also be explained by slight inaccuracies in food
      composition tables. Folate intake from fortified food or from supplements is not
      taken into account in most of the studies, which is a variable that can lead to
      confusion. Nutrition surveys should adapt official composition tables for local
      food patterns, and include fortified commercial foods, in order to make folate
      intake data more accurate. However, representative serum and erythrocyte folate
      values are lacking for most age groups. Before taking public health measures
      concerning folate fortification of food, the real folate status of the German
      population should be established.

PMID- 12596500
TI  - Vitamins A and E in serum in relation to weight and lung function in patients
      with advanced pulmonary disease.
AB  - The objective of the study was to examine whether serum concentrations of retinol
      (vitamin A) and alpha-, beta-, and gamma-tocopherols (vitamin E) are affected by
      underweight and weight gain. The analysis was carried out in underweight (n = 42,
      of whom 24 had chronic obstructive pulmonary disease) and normal-weight (n = 29,
      of whom 16 had chronic obstructive pulmonary disease) candidates for lung
      transplantation before and after dietary intervention for weight gain. In all the
      patients, serum concentrations of retinol at baseline and changes in retinol were
      positively associated with body mass index (unstandardized regression
      coefficient, b = 0.03; p = 0.05) and an increase in weight (b = 0.09, p = 0.02)
      after dietary intervention, respectively. At baseline, serum retinol
      concentrations were positively correlated with forced vital capacity (b = 0.24, p
      < 0.05) and forced expiratory volume in one second (b = 0.17, p < 0.05). In
      patients with chronic obstructive pulmonary disease (COPD), tocopherols were
      higher in the underweight patients than in the normal-weight ones, while it was
      an opposite tendency in patients with other lung diseases. Only in patients with
      lung diseases other than COPD was there found a positive association between
      tocopherols and lung gas diffusion. In patients with other diagnoses compared
      with patients with COPD, a positive change in serum tocopherol status after
      weight gain was suggested.

PMID- 12596501
TI  - Ascorbic acid content of blood plasma, erythrocytes, leukocytes and liver in
      camels (Camelus dromedarius) without or with parasite infections.
AB  - Healthy camels (Camelus dromedaris) and those naturally infected with
      trypanosomiasis, sarcoptic mange, and helminthiasis were compared as to ascorbic
      acid (vitamin C) contents of red blood cells, white blood cells, whole blood,
      plasma, and liver. The camels were kept under natural grazing conditions in
      Sudan. Reduced levels of vitamin C were found in camels with parasite infections,
      especially in animals with trypanosomiasis. It is suggested that the low vitamin
      C status in infected camels is caused by increased utilization and/or decreased
      synthesis of vitamin C.

PMID- 12596502
TI  - Cholate feeding counteracts calcium-induced depression of apparent fat
      digestibility in rats.
AB  - This study tested the hypothesis that cholate feeding would counteract the
      earlier described calcium-induced inhibition of fat digestion. Rats were fed
      semipurified diets; either low (0.25%, w/w) or high (1.0%) in calcium, the latter
      diets being without or with 0.5% added sodium cholate. Apparent fat digestibility
      was 95.6% of intake in the rats fed the low-calcium diet. Calcium feeding
      significantly lowered apparent fat digestibility to 82.6%, but in the presence of
      cholate it was 91.2%. It is concluded that the inhibitory effect of calcium on
      fat digestion is mediated by diminishing the availability of bile acids.

PMID- 12596503
TI  - Seasonal variation of food consumption and selected nutrient intake in Linxian, a
      high risk area for esophageal cancer in China.
AB  - Linxian, China, is a region with high incidence of esophageal cancer and a
      history of poor nutritional status. Nutrition Intervention Trials were conducted
      in this area from 1985 through 1991 and found a reduction in total cancer
      mortality in the group receiving supplementation of beta-carotene/selenium/alpha
      tocopherol. The positive results of those trials have, in part, been ascribed to
      the poor nutritional status of this population. To investigate more recent food
      patterns, nutrient intakes, and seasonal variations in the diet, dietary surveys
      were conducted among the residents of Linxian in 1996. Food consumption data were
      collected among 104 households in spring and 106 households in autumn using a
      method of food inventory changes. Intake of nutrients was estimated and compared
      to the Chinese Recommended Dietary Allowance (RDA). In both seasons, the five
      most common food groups consumed were cereals, fresh vegetables, yams, seasoning,
      and eggs. Low nutrient intakes were found for selenium (79% RDA and 66% RDA),
      zinc (72% RDA and 62% RDA), vitamin B2 (64% RDA and 52% RDA), and calcium (53%
      RDA and 39% RDA) in both spring and autumn. A large seasonal variation was seen
      in the consumption of leafy vegetables, root vegetables and eggs, all of which
      might have contributed to the lower intake of vitamin A (25% RDA), vitamin C (75%
      RDA), protein (76% RDA), and vitamin E (78% RDA) in autumn. These indicate that
      the nutrient intake in Linxian is inadequate for a number of vitamins and
      minerals including those shown to be associated with esophageal cancer.

PMID- 12596504
TI  - Erythrocyte glutathione reductase activity and riboflavin nutritional status in
      early-weaned piglets.
AB  - The reliability of erythrocyte glutathione reductase activity (EGRAC) as an
      indicator of riboflavin (vitamin B2) status was determined in 36 piglets weaned
      at two weeks of age. Total B2 metabolites determined by high-performance liquid
      chromatography (HPLC) in plasma, red blood cells, and liver were used as
      reference values. There was no correlation between EGRAC values and total B2
      metabolites either in circulation (r < 0.15, p > 0.08) or in liver (r < 0.01, p >
      0.95). EGRAC does not appear to be a reliable biochemical indicator of vitamin B2
      status in the pig.

PMID- 12596505
TI  - Effect of traditional food supplementation during pregnancy on maternal weight
      gain and birthweight.
AB  - The effects of supplementary traditional food on pregnant women were investigated
      in a clinical trial in Islamshahr, a suburban area 35 km southwest of Tehran. The
      study comprised 53 healthy mothers who were neither addicts nor on medication and
      were free from genetic disorders. The pregnant mothers' health was evaluated by
      their weight gain, that of lactating mothers by breast milk adequacy, and that of
      newborns by their weight at birth. The experimental group received traditional
      food (rice-milk porridge, lentils, pottage, cheese, yogurt, eggs, and milk with
      bread), supplying an extra 400 kcal energy and 15 g protein from the fourth month
      of pregnancy until childbirth. All subjects were weighed monthly. To ascertain
      breast milk sufficiency, the duration of exclusive breastfeeding and the growth
      trend of infants were surveyed. The study showed the weight gain in the
      experimental and control groups to be 11.0 +/- 2.9 and 8.5 +/- 3 kg respectively;
      the difference was 29.4% and statistically significant (p < 0.02). The
      confounding variables (energy and protein intake, age, height, BMI, age at first
      pregnancy, parity, last pregnancy spacing, number of children, number of
      miscarriages, duration of residence in the area, family size, education, housing,
      occupation of the mother or her husband) did not reveal any significant
      differences. Maternal weight gain was higher in the experimental compared to the
      control group. Birth weights in experimental and control groups were 3.33 +/- 0.4
      and 3.08 +/- 0.3 kg, respectively. This difference, which amounts to 8.1%, was
      statistically significant (p < 0.05). While the two groups of newborns had equal
      breastfeeding duration, heights and weights of newborns were significantly higher
      in the experimental group. This was also confirmed when compared to the NCHS
      figures.

PMID- 12596506
TI  - [Prospects of the search for novel anxiolytics].
AB  - Based on an analysis of the present-day knowledge of the pathogenesis of stress,
      neurosis, and neurosis-like states, the paper highlights the spectrum of
      pharmacological activity and the mechanisms of action of the commonly used
      anxiolytics. The main trends in the search for new anxiolytics in Russia and
      abroad are considered and the most promising directions are indicated. A special
      attention is devoted to drugs of the new generation, representing agents with
      different tropicity toward benzodiazepine and GABA receptor subunits, endogenous
      and exogenous membrane regulators of these receptors, glutamatergic and
      serotoninergic anxiolytics, hormones, nucleic acid metabolites, substances
      influencing energy metabolism, neuropeptides with anxiolytic action, etc. A new
      classification of anxiolytics based on the mechanisms of their action is
      proposed. A special focus is placed on the achievements of Russian
      pharmacologists in the design and development of the new generation of
      anxiolytics.

PMID- 12596507
TI  - [Locomotor activity and expression of c-Fos protein in the brain of C57BL and
      Balb/c mice: effects of D-amphetamine and sydnocarb].
AB  - Effects of the psychostimulants D-amphetamine and sydnocarb on the locomotor
      activity and c-Fos protein expression in the brain of C57BL and BALB/c mice was
      studied. The drugs significantly increase the locomotor activity and the level of
      c-Fos protein in the brain structures of both lines. The effect of D-amphetamine
      with respect to the locomotor activity was more pronounced in C57BL mice, which
      correlates with a higher level of the c-Fos expression in the secondary motor
      cortex. At the same time syndocarb more significantly than D-amphetamine induces
      expression of the c-Fos protein in the nucleus accumbens core of C57BL mice.
      Injection of an 0.85% NaCl solution led to a moderate increase in the locomotor
      activity in the mice of both lines, while the c-Fos expression in the secondary
      motor cortex and septum was more pronounced in C57BL than in BALB/c mice.

PMID- 12596508
TI  - [Monoaminergic and aminoacidergic mechanisms of the posterior hypothalamus in
      realization of the antiaversive effects of anxiosedative and anxioselective
      agents in various anxiety models].
AB  - Experiments using the "illuminated site" and "threatening situation" avoidance
      tests on rats after preliminary intraperitoneal injection of monoamines, mediator
      amino acids, and their agonists and antagonists, followed by microinjection of
      the same combinations into the posterior hypothalamus revealed functional
      ambiguity in the neurochemical profile of this limbic brain formation in
      realization of the anxiety states of various genesis. Pharmacological analysis
      was performed after preliminary injection of various anxiosedative and
      anxioselective agents into the posterior hypothalamus. It was found that the
      antiaversive action of chloridiazepoxide, fenibut, and indoter is manifested only
      under conditions of dominating fear motivation and is mediated by a GABAergic
      mechanism in the posterior hypothalamus. The anxiolytic effect of campiron is
      manifested only under negative-stressor zoosocial impact conditions and is
      mediated by the serotoninergic profile of synaptic switching in this limbic brain
      formation.

PMID- 12596509
TI  - [Metabolism of neuroactive amino acids in the rat cerebral cortex during morphine
      intoxication].
AB  - The effect of acute and chronic morphine intoxication on the content of
      aspartate, glutamate, glutamine, glycine, and GABA in rat brain was studied.
      Under the acute intoxication conditions, the most pronounced changes were
      observed for a morphine dose of 10 mg/kg (b.w.) and manifested by prevailing
      excitation processes in this part of CNS. On the contrary, the chronic
      introduction of morphine led to an increase in the content of inhibitory amino
      acids.

PMID- 12596510
TI  - [The effect of novel class III anti-arrhythmia agents cardiocyclide and nibentan
      during activation of cardiac beta-adrenoreceptors].
AB  - The effect of cardiocyclide and nibentan--class III antiarrhythmics--on the heart
      rate frequencies (HRF) and the EEG intervals (PQ, QRS, QT, and QTc) was
      experimentally studied on narcotized rats under conditions of the isoproterenol
      induced activation of beta-adrenergic structures. It was established that
      cardiocyclide retains properties of the class III drug, as manifested by
      decreased HRF and increased QT duration in the absence of changes in the
      conductivity. In contrast, the activity of nibentan was decreased on the
      background of activation of the sympathetic system.

PMID- 12596511
TI  - [Combined administration of mexidol and anti-arrhythmia agents].
AB  - The influence of mexidol on the acute toxicity and electrophysiological effects
      of nibentan, propranolol, and verapamil was experimentally studied. It was found
      that mexidol potentiates the ability of propranolol and verapamil to inhibit
      automatism of the sinus node and suppresses the ability of all the three drugs to
      increase the refractory period of myocardium. It is suggested that these effects
      are related to the action of mexidol upon ion channels.

PMID- 12596512
TI  - [Pharmacokinetic and pharmacodynamic effects of isradipine in patients with
      arterial hypertension].
AB  - It was established that a regular administration of isradipine is accompanied by
      an increase in the mean values of Cmax (by 21.7%) and AUC (by 21.8%), which leads
      to extension of the pharmacodynamics effects without cumulation (the values of
      Clt, T1/2, and Tmax remain unchanged). The maximum hemodynamic effect of
      isradipine upon a single administration in a single dose of 5 mg coincides with
      the time or reaching the maximum drug concentration in the blood (Tmax). There is
      a reliable correlation between the hypotensive effect, the peripheral vascular
      resistance, and the concentration of isradipine.

PMID- 12596513
TI  - [Binding of dicyclohexylamide derivatives of N-substituted aminocarboxylic acids
      with muscarinic cholinoreceptors and beta-adrenoreceptors].
AB  - The binding of N-substituted aminocarboxylic acid dicyclohexylamide (NACA-DCHA)
      derivatives to M-1 muscarinic cholinoreceptors (MRs) in rat brain cortex and and
      beta-1 adrenoreceptors (ARs) in rat heart was studied. The maximum MR affinity
      was observed for AL-275 (IC50, 2.8 microM) and AL-315 (IC 50, 3.2 microM)
      preparations. The other compounds (except AL-310 with IC50 > 100 microM)
      interacted with MR at a lower affinity. The binding to beta-1 AR in rat heart was
      observed for a single preparation AL-298 (IC50, 38 microM). The antimuscarinic
      activity of some NACA-DCHA derivatives, especially AL-275 and AL-315) may play a
      significant role in realization of the antiarrhythmic activity.

PMID- 12596514
TI  - [Correction with zaditen of impaired activity of pancreatic digestive enzymes in
      sensitization and anaphylactic shock].
AB  - The effect of the antihistaminic drug zaditen on the activity of pancreatic
      digestive enzymes was studied in white rats under sensitization and anaphylactic
      shock conditions. The sensitization and anaphylaxis are accompanied by
      significant changes in the spectrum and activity of pancreatic enzymes (alpha
      amylase, protease complex, lipase), leading to disorders in the digestion and
      assimilation of proteins, fats, and carbohydrates. Zaditen reduced negative
      changes in the enzyme secretion system of pancreas under conditions of this
      pathology.

PMID- 12596515
TI  - [Effect of interferon-alpha on the platelet aggregation and cyclic nucleotide
      system in chronic viral hepatitis].
AB  - Platelet aggregation (PA) and the content of cyclic nucleotides (CN) was studied
      in a group of 44 patients with chronic viral hepatitis (CVH) and liver cirrhosis
      (LC) in comparison to 10 healthy volunteers. The analyses were performed before
      and 6 h after interferon-alpha (IFN-alpha) administration. The CN content was
      increased in CVH cases and was maximum in LC patients, while the platelet
      aggregation was reduced in CVH patients and was minimum in the LC group. The CN
      level increased and the functional activity of platelets decreased, depending on
      the degree of disorder. After the first introduction of IFN-alpha, the CN content
      in thrombocytes decreased in LC and low-PA CVH patients, but increased in high-PA
      CVH cases. IFN-alpha produced a normalizing effect on the platelet functioning in
      the patients with CVH and LC.

PMID- 12596517
TI  - [The effect of unithiol on the changes in immunotoxicity of 2
      chloroethenylchloroarsine].
AB  - The results of experiments on Wistar rats under conditions of acute intoxication
      with 2-chloroethenyldichloroarsine (beta-chlorovinyldichloroarsine) (0.75 LD50)
      showed that unithiol increases antiinfectious nonspecific resistance (NSR) of the
      organism. This is manifested by improved NSR characteristics: increased activity
      of the natural killer cells, predominant formation of antibodies to thymus
      dependent antigen, and development of delayed-type hypersensitivity. However, no
      complete recovery of the NSR parameters impaired by 2-chloroethenyldichloroarsine
      is observed.

PMID- 12596516
TI  - [Effect of droperidol and tramadol combination on the hemostasis in rabbits].
AB  - The effect of a combined administration of analgesic droperidol and neuroleptic
      tramadol (tramal) on the plasma coagulation and platelet aggregation was studied
      on awake rabbits. Both tramadol and droperidol, as well as their combination,
      enhance the coagulation of plasma proteins and suppress the thrombocyte
      deaggregation process.

PMID- 12596518
TI  - [Pharmacological analysis of the pathogenesis of acute poisoning with the
      synthetic pyrethroid cypermethrin using the hydrobiont Daphnia magna Straus].
AB  - The results of pharmacological analysis are presented which provide information
      on the pathogenesis of acute cypermethrin poisoning that involves disturbances in
      various systems of the organism. These include changes in the system of
      excitatory amino acids (EAAs) and violation of the free radical generation
      processes, Na + channel functioning, cholinergic transmission, etc. The screening
      of drugs belonging to various pharmacological groups influencing the toxicity of
      pyrethroids (EAA receptor antagonists, antioxidants, Na + channel blockers, M
      cholinoreceptor blockers) revealed promising agents for the treatment of
      cypermethrin poisoning.

PMID- 12596519
TI  - [Protective effect of adenosine receptor agonists in a model of spinal cord
      injury in rats].
AB  - Possibilities of the neuroprotector therapy using adenosine and
      cyclopentyladenosine (CPA), an adenosine receptor agonist, were studied on a
      model of spinal cord injury by compression in rats (most closely reproducing the
      analogous clinical pathological process in humans). The model was induced by
      slow, graded compression of the spinal cord at the thoracic level. Adenosine and
      CPA were introduced 60 min before injury by subcutaneous injections in a dose of
      300 and 2.5 micrograms/kg, respectively. The protective effect was judged by
      comparing the neurological, electromyographic, and histopathological changes in
      animals with the model injury and in the control group (adenosine and CPA
      background). The A1-agonist CPA injections produced a pronounced, statistically
      significant neuroprotector effect on the given spinal cord injury model in rats.
      The neuroprotective effect of adenosine was significant but not as strong. It is
      concluded that it is expedient to use A-agonists in clinics.

PMID- 12596520
TI  - [Comparative study of the effect of dimephosphon monophosphonate and xydiphone
      biphosphonate on the histomorphometric indices of rat vertebra in a model of
      glucocorticosteroid osteoporosis].
AB  - The efficacy of monophosphonate dimephosphon and diphosphonate xydiphon was
      compared by experiments in rats with an osteoporosis model induced by the chronic
      administration of prednisolone. The glucocorticosteroid decreased the total
      density of trabecules (in both bone and cartilage tissues) in histological
      micropreparations of lumbar vertebrae and reduced the total bone cell count and
      the calcium content in the bone tissue. Dimephosphon, administered on the
      prednisolone background over the same period of time, normalized the total
      relative density of trabecules (by increasing the cartilage content), the total
      bone cell count, and the calcium content. Under the same conditions, xydiphone
      normalized the total relative density of trabecules (by increasing the bone
      content), but did not influence the prednisolone-decreased content of cartilage,
      total cell count, and calcium content in the vertebrae. Thus, the test results
      reveal a significant advantage of dimephosphon over xydiphone.

PMID- 12596521
TI  - [The original novel nootropic and neuroprotective agent noopept].
AB  - The paper describes pharmacological properties of the new nootropic drug noopept
      created using an original approach based on the imitation of a nonpeptide
      nootrope structure by means of the short-peptide design. In particular, the
      structure of pyracetam was designed using dipeptide nootropes. Experimental
      investigations of noopept (N-phenylacetyl-L-polyglycine ethyl ester) showed that
      the new drug exceeds pyracetam both with respect to the effective dose level
      (1000 times lower for noopept than for pyracetam) and in the spectrum of
      mnemotropic activity. In contrast to pyracetam facilitating only the early stages
      of the memory process, noopept positively influences the memory consolidation and
      retrieval steps as well. The new drug produces an additional selective anxiolytic
      action. The pronounced neuroprotective effect of noopept was demonstrated both in
      vivo (in cases of various forms of brain ischemia) and in vitro (on various
      neuronal models). The drug action is based on the antioxidant effect, the
      antiinflammatory action, and the ability to inhibit the neurotoxicity of excess
      calcium and glutamate, and to improve the blood rheology. It was established for
      the first time that the activity of noopept is retained both upon parenteral
      introduction and upon peroral administration, which is a principal advantage of
      this proline-containing dipeptide over other, more complex peptides. This
      property provided a basis for the development of a medicinal form of noopept for
      peroral usage. At present, noopept tablets (noopept 5 and 10 mg) are under
      clinical assessment as a means of treating cognitive deficiency of
      cerebrovascular and post-traumatic origin.

PMID- 12596522
TI  - [Immunotropic properties of pineal melatonin].
AB  - An analysis of the presently available data shows that the principal pineal
      hormone melatonin is capable of influencing, both directly and indirectly, the
      state of the immune system. The immunotropic activity of this hormone can account
      for the stress-protective, antitumor, and antiviral effects of melatonin.

PMID- 12596523
TI  - [Effect of haloperidol on development of amnesia in aggressive and submissive
      mice].
AB  - The effect of haloperidol on the passive avoidance habit retrieval upon amnesia
      was studied in C57BL/6J mice with aggressive and submissive behavioral
      stereotypes formed under agonist confrontation conditions. In the control
      (untreated) group, the efficacy of the amnesic action of detention in the
      dangerous compartment on the learning day was reduced for the aggressive
      stereotype as compared to the submissive one. In the aggressive mice, the
      administration of haloperidol (0.5 mg/kg) one hour before learning deteriorated
      the conditional reaction retrieval between 2nd and 13th days of test. In the
      submissive mice, the administration of haloperidol produced a prolonged
      antiamnesic effect. Thus, the effect of haloperidol on the violated memory trace
      reproduction depends on the individual behavioral state.

PMID- 12596524
TI  - [The role of non-NMDA glutamate receptors in the EEG effects of chronic
      administration of noopept GVS-111 in awake rats].
AB  - Participation of the non-NMDA glutamate receptor subtype in the formation of the
      EEG frequency spectrum was studied in wakeful rats upon a long-term (10 x 0.2
      mg/kg, s.c.) administration of the nootropic dipeptide GVS-111 (noopept or N
      phenylacetyl-L-prolyglycine ethylate). The EEGs were measured with electrodes
      implanted into somatosensor cortex regions, hippocampus, and a cannula in the
      lateral ventricle. The acute reactions (characteristic of nootropes) in the alpha
      and beta ranges of EEG exhibited inversion after the 6th injection of noopept and
      almost completely vanished after the 9th injection. Preliminary introduction of
      the non-NMDA antagonist GDEE (glutamic acid diethyl ester) in a dose of 1 mumole
      into the lateral ventricle restored the EEG pattern observed upon the 6th dose of
      GVS-111. The role of glutamate receptors in the course of a prolonged
      administration of nootropes, as well as the possible mechanisms accounting for a
      difference in the action of GVS-111 and piracetam are discussed.

PMID- 12596525
TI  - [Effect of 17beta-estradiol on haloperidol effects in Wistar rats].
AB  - It is established that the haloperidol catalepsy is much less pronounced in
      Wistar females than in males. Estradiol (10 mg/kg, i.p.) decreased intensity of
      the haloperidol catalepsy, reduced the haloperidol-induced increase in the
      dopamine turnover, and decreased the level of dopamine metabolites in nucleus
      accumbens of both female and male test animals. However, these effects are also
      more pronounced in females.

PMID- 12596526
TI  - [Effect of morphine and naloxone on the biorhythm of pain sensitivity of mice
      after unilateral inactivation of cerebral hemispheres].
AB  - The effects of morphine (5 mg/kg, i.p.) and naloxone (1 mg/kg, i.p.) on the
      formation of pain sensitivity biorhythms was studied in the tail-flick test on
      adult male SHR mice upon unilateral inactivation of cerebral hemispheres by
      Leao's method of spreading potassium depression. It was established that morphine
      changed the rhythmogenic properties of both left and right hemispheres, inverted
      the phase of circadian rhythm, and produced the most pronounced analgesic action
      in the stage of maximum pain sensitivity (minimum pain threshold). Naloxone
      affected the pain rhythm predominantly in the operated and right-hemisphere
      active animals, which confirmed the increased role of opioids in the process of
      rhythm regulation in mice.

PMID- 12596527
TI  - [Structural-metabolic characteristics of erythrocyte membrane in patients with
      paranoid schizophrenia undergoing psychopharmacotherapy].
AB  - Structural features of the hydrophobic compartment and external parts of the
      erythrocyte membrane, Na+ and K+ ATPase activity, intensity of the free-radical
      oxidation of lipids, and the surface relief of erythrocytes were studied in
      paranoic schizophrenia patients before and after a course of pharmacotherapy. It
      was established that the administration of neuroleptics in therapeutic doses does
      not cause damage of the erythrocyte membrane.

PMID- 12596528
TI  - [Electrophysiological effects of ethacizine in experimental myocardial infarction
      and stimulation of sympathetic heart innervation].
AB  - The electrophysiological effect of ethacizine, an antiarrhythmic agent of class
      IC, was studied in dogs with experimental myocardial infarction under the beta
      adrenergic stimulation conditions. It was found that ethacizine (i) slows down
      the atrioventricular conduction and the AV-node conduction; (ii) increases the
      time of the sinus node function recovery; and (iii) increases the effective
      atrioventricular refractory periods. Under the conditions of isoproterenol
      induced stimulation of the beta-adrenergic structures, some of the ethacizine
      effects (e.g., increased refractoriness) completely disappeared and the other
      (slowed down conduction) decreased. As the stimulation frequency was increased,
      the effect of ethacizine upon the conduction exhibited a decrease. Upon the
      isoproterenol injection, dependence of the QRS complex on the forced rhythm
      frequency disappeared.

PMID- 12596529
TI  - [Cerebrovascular and renal actions of bilobil and its effect on the metal ligand
      homeostasis (clinico-experimental study].
AB  - The tests on rats with common carotid artery occlusion showed that bilobil
      increases the cerebral blood flow and decreases brain edema, thus decreasing the
      loss of experimental animals. The drug also increases the blood circulation and
      improves the excretory function of kidneys. Under clinical conditions, bilobil
      increases the cerebral blood flow, normalizes the metal ligand homeostasis, and
      improves the antioxidant status in children with early forms of cerebrovascular
      disease (neurocirculate distonia) and attention deficit hyperactivity syndrome.

PMID- 12596530
TI  - [Effect of combined administration of acetylsalicylic acid and antioxidants on
      cellular and plasma hemostasis].
AB  - It was found that upsovit (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg),
      composition 1 (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg; hypoxen, 50
      mg), and composition 2 (acetylsalicylic acid, 330 mg; ascorbic acid, 200 mg;
      hypoxen, 100 mg) inhibit thrombocyte aggregation in vitro. Hypoxen per se induces
      the aggregation of thrombocytes, but inhibited the ADP aggregation. Intravenous
      injections of upsovit in rabbits did not influence the ADP aggregation, but
      inhibited the collagen aggregation, while composition 2 inhibited the aggregation
      processes of both types. Besides, the intravenous injections of upsovit decreased
      the thromboplastin time and the activated partial thromboplastin time (APTT) and
      reduced the protein C activity, while influencing neither the heparin cofactor
      activity of antithrombin III nor the level of fibrinogen and its degradation
      products. In contrast, composition II did not change the thromboplastin time,
      APTT, and the protein C activity, but increased the heparin cofactor activity.

PMID- 12596531
TI  - [Hemostimulating properties of cropanol during cytostatics-induced
      myelosuppression].
AB  - The granulocyte lineage reaction and its mechanism were studied in the bone
      marrow of patients with breast cancer in stage III-IV treated according to a
      specific CAF scheme including cropanol, an antitumor drug of the animal origin.
      It was found that the bone marrow cytopoiesis suppressed by the cytostatics is
      stimulated by cropanol on the level of committed precursors, morphologically
      differentiated bone marrow elements, and peripheral blood.

PMID- 12596532
TI  - [Effect of dopamineamides of polyunsaturated fatty acids on blood coagulation
      system and cerebral circulation].
AB  - A series of original dopaminamides of polyunsaturated fatty acids were
      synthesized and characterized with respect to antiaggregant and cerebrovascular
      stimulant properties. It was established that dopaminamides of linolic,
      dimethyllinolic, docosapentaenoic, docosahexaenoic (DHEA) and stearidonic (C18:4
      and C18:3) acids decrease ADP and arachidonic acid (AA) induced human thrombocyte
      aggregation in vitro. The most pronounced antiaggregant effect was observed for
      DHEA dopaminamide: in a dose of 10 mg/kg, this agent produced a significant
      decrease in the AA induced thrombocyte aggregation. DHEA per se in the same dose
      increases the activated partial thromboplastin time (APTT), while not affecting
      the prothrombin time. The synthesized dopaminamides of arachidonic,
      eicosapentaenoic, and docosahexaenoic acids stimulate local circulation in the
      cerebral cortex. The most pronounced cerebrovascular effect was also produced by
      DHEA dopaminamide.

PMID- 12596533
TI  - [Effect of propofol and ketamine on lipid metabolism and lipid peroxidation in
      rats].
AB  - Ketamine (50 mg/kg, i.p.) increases the intensity of lipolysis in Wistar male
      rats, as manifested by increasing content of nonetherified fatty acids and
      cholesterol in the blood serum. This drug also enhances the lipid peroxidation
      (LPO) process, as manifested by the content of LPO products in the blood serum
      and in the liver and heart tissues. Propofol in the same dose also influences the
      lipid metabolism and LPO intensity, but to a lower extent.

PMID- 12596534
TI  - [Effect of ladasten on proliferative activity and apoptosis in peripheral blood T
      lymphocytes ].
AB  - The effects of ladasten (0.1-10 microM) on the proliferative activity, apoptosis,
      and expression of the apoptosis protein regulators (bcl-2 and p53) was studied in
      72-h cultures of T-lymphocytes of human peripheral blood activated by anti
      CD3MCA. In the concentration interval from 0.01 to 1 microM, ladasten produced a
      comitogenic effect. The drug changed neither the activity of caspase 3 and the
      proportion of cells in the late apoptosis stage (Hoechst 33342 stain test), nor
      the bcl-2 expression, but increased the p53 expression in the activated cells.
      Irrespective of the concentration, ladasten protected activated lymphocytes in
      the cell culture from apoptosis induced by the topoisomerase I inhibitor
      camptothecin or by hydrogen peroxide (provided that the drug was added to the
      culture simultaneously with the apoptosis inductor). At the same time,
      lymphocytes cultivated in the presence of ladasten acquired resistance with
      respect to apoptosis induced by hydrogen peroxide, but not by camptothecin. It is
      suggested that the immunomodulant activity of ladasten are related to the
      comitogenic effect and the increase in resistance of the activated T-lymphocytes
      with respect to non-receptor-induced apoptosis.

PMID- 12596535
TI  - [Effect of mexidol on the homeostasis and lipid peroxidation in paracetamol
      poisoning].
AB  - It is established that mexidol (3-hydroxy-6-methyl-2-ethylpyridine succinate)
      influences the state of homeostasis in guinea pigs intoxicated with paracetamol.
      Paracetamol administered in toxic doses disturbs the functions of liver and
      kidneys, violates the lipid, carbohydrate, and mineral metabolism, activates the
      lipid peroxidation (LPO) process, and decreases the level of antioxidant
      protection. Treatment of the test animals with mexidol (25 mg/kg) decreases the
      cytolysis of hepatocytes, the development of cholestasis, the degree of
      hepatocellular insufficiency, the growth of endogenous intoxication, the drop of
      calcium content, the growth of iron content in the blood serum, and the content
      of final LPO products. The mexidol treatment activated the enzymatic chain of the
      antioxidant system.

PMID- 12596536
TI  - [Hepatoprotective properties of liquid extract of Rhodiola rosea].
AB  - The effect of a liquid extract from Rhodiola rosea on the functional state of rat
      liver with experimental toxic hepatitis was studied. The extract produces a
      hepatoprotective effect, as manifested by normalized activity of aspartate
      aminotransferase and alkaline phosphatase, normalized content of medium-molecular
      weight peptides, urea, and bilirubin, and reduced activity of alanine
      aminotransferase and glutathione-S-transferase in the blood plasma of rats with
      the toxic hepatitis model.

PMID- 12596537
TI  - [Immune and autoimmune effects of ethanol].
AB  - It is established that ethyl alcohol exhibits both immune and autoimmune effects.
      The blood of healthy people always contains a small amount of ethanol- and
      dopamine-sensitized lymphocytes and autoantibodies specific to these compounds.
      The ability of lymphocytes to interact with ethanol or dopamine bound to
      erythrocytes shows evidence that the corresponding receptors are available on the
      erythrocyte membrane. The action of ethanol upon these receptors leads to the
      development of immune response in vivo and ex vivo. The administration of ethanol
      is accompanied by an increase in the number of ethanol-sensitive lymphocytes
      which can be detected, thus indicating the presence of excess ethanol. The blood
      of patients with alcohol addiction contains of ethanol- and dopamine-sensitized
      lymphocytes and anti-ethanol antibodies. This is indicative of the permanent
      pathologic synthesis of autoantibodies specific to ethanol and dopamine. These
      data confirm the concept of the immune mechanism of chemical homeostasis,
      according to which the immune system participates in regulation of these
      biologically active agents and in maintenance of the chemical homeostasis in the
      organism. These conclusions extend our notions about the immune and autoimmune
      aspects of pathogenesis of the chronic alcohol intoxication and constitute a
      basis for further development of the laboratory diagnostic methods.

PMID- 12596538
TI  - [Effect of piracetam on photosensitivity of the retina and timing of the visual
      motor reaction with head injury].
AB  - The chronic administration of piracetam over a period of four weeks in patients
      with heavy cerebrocraneal traumas led to a significant decrease in the retina
      sensitivity threshold and in the sensomotor response delay time. It is suggested
      that the increase in the sensitivity is related to the nootrope effect upon the
      GABAergic processes in the retina.

PMID- 12596540
TI  - Spin forbidden chemical reactions of transition metal compounds. New ideas and
      new computational challenges.
AB  - Many reactions of transition metal compounds involve a change in spin. These
      reactions may proceed faster, slower--or at the same rate as--otherwise
      equivalent processes in which spin is conserved. For example, ligand substitution
      in [CpMo(Cl)2(PR3)2] is faster than expected, whereas addition of dinitrogen to
      [Cp*Mo(Cl)(PMe3)2] is slow. Spin-forbidden oxidative addition of ethylene to
      [Cp*Ir(PMe3)] occurs competitively with ligand association. To explain these
      observations, we discuss the shape of the different potential energy surfaces
      (PESs) involved, and the energy of the minimum energy crossing points (MECPs)
      between them. This computational approach is of great help in understanding the
      mechanisms of spin-forbidden reactions, provided that accurate calculations can
      be used to predict the relevant PESs. Density functional theory, especially using
      gradient-corrected and hybrid functionals, performs reasonably well for the
      difficult problem of predicting the energy splitting between different spin
      states of transition metal complexes, although careful calibration is needed.

PMID- 12596539
TI  - [Experimental study of the effect of glucosamine hydrochloride on metabolic and
      repair processes in connective tissue structures].
AB  - The effects of glucosamine hydrochloride on the metabolic and repair processes
      were studied on a model of post-traumatic osteoarthrosis in the articular
      cartilage and on a model of post-traumatic keratitis in the cornea. The
      administration of glucosamine hydrochloride stimulated repair and favored
      inhibition of dystrophic post-traumatic processes in the connective-tissue
      structures. It is suggested that a probable mechanism of the drug action consists
      in stimulation of the synthesis of glucosaminoglycanes and collagen.

PMID- 12596541
TI  - Recent developments in computational actinide chemistry.
AB  - This review describes recent computational investigations into the electronic and
      geometric structures of molecular actinide compounds. Following brief
      introductions to (i) the effects of relativity in chemistry and (ii) ab initio
      and density functional quantum chemical methods, four areas of contemporary
      research are discussed. These are pi backbonding in uranium complexes, the
      geometric structures of bis benzene actinide compounds, the valence electronic
      structure of the uranyl ion, and the inverse trans influence in pseudo-octahedral
      [AnOX5]n-. Comparisons are made with experimental studies, and similarities and
      differences between d- and f-block chemistry are highlighted.

PMID- 12596542
TI  - Solid oxide fuel cells.
AB  - Despite being first demonstrated over 160 years ago, and offering significant
      environmental benefits and high electrical efficiency, it is only in the last two
      decades that fuel cells have offered a realistic prospect of being commercially
      viable. The solid oxide fuel cell (SOFC) offers great promise and is presently
      the subject of intense research activity. Unlike other fuel cells the SOFC is a
      solid-state device which operates at elevated temperatures. This review discusses
      the particular issues facing the development of a high temperature solid-state
      fuel cell and the inorganic materials currently used and under investigation for
      such cells, together with the problems associated with operating SOFCs on
      practical hydrocarbon fuels.

PMID- 12596543
TI  - The electronic structure of Cu+, Ag+, and Au+ zeolites.
AB  - A variety of procedures have been used to prepare d10-zeolite materials. The
      electronic structure of these materials can be regarded to a first approximation
      as a superposition of the framework, of the charge compensating ions, of solvent
      molecules and of guest species. Zeolite oxygen to d10-ion charge transfer
      transitions dominate the electronic spectra if the ions coordinate to the zeolite
      oxygens. Specific coordination sites can influence the energy and the intensity
      of these transitions remarkably. Intra guest transitions dominate in quantum dot
      materials, as discussed in detail for luminescent Ag2S zeolite A. The zeolite is
      not needed for the photocatalytic water oxidation on Ag+/AgCl photo anodes with
      visible light. It can, however, be used to increase the active surface area
      substantially.

PMID- 12596544
TI  - Explorations of conical intersections and their ramifications for chemistry
      through the Jahn-Teller effect.
AB  - Much recent progress has been made theoretically and computationally towards
      understanding the importance of conical intersections for chemical reactions.
      Nonetheless, experimental characterization of conical intersections has proven
      extremely difficult with one striking exception: the Jahn-Teller conical
      intersection. This article overviews the fundamental similarity of a variety of
      conical intersections and demonstrates how the spectroscopy of Jahn-Teller active
      molecules can be used to characterize them. Specific results are reviewed for
      four representative Jahn-Teller active molecules, C5H5, C6H6+, Ag3 and CH3O.

PMID- 12596545
TI  - Organometallic sesquialkoxides of aluminium, gallium and indium.
AB  - Organometallic sesquihalides of aluminium are important intermediates in
      technical processes. However, those compounds and their homologues with gallium
      or indium centers have not been structurally characterized so far. On the other
      hand organometallic sesquialkoxides have been isolated. The major synthetic
      routes and the structures of the corresponding products will be discussed.
      Furthermore, cage-contructiveness reactions having sesquialkoxides as educts will
      be shown. Discussion will focus primarily on the syntheses, the spectroscopic
      findings and a structural comparison. Especially the structural motifs deserve
      attention because of the structural connection to the well-known earth metal
      alkoxides.

PMID- 12596546
TI  - [Layer I neurons and their significance in the neocortex embryogenesis].
AB  - The literature data and the results of authors own investigations are presented
      on microarchitectonics and development of molecular layer (layer I) of mammalian
      neocortex. It originates from the marginal zone of primordial plexiform layer,
      common with primitive neopallial primordium of reptiles and amphibia, which
      maintains its initial organization during phylo- and ontogenesis of vertebrates.
      During initial stages of corticogenesis all migrating neurons establish contacts
      with Cajal-Retzius cells which coordinate location and exact spatial
      stratification of neuroblasts in growing cortical plate. The detailed analysis of
      fundamental mechanisms controlling embryogenesis of neocortex is presented
      including a) histogenesis of pyramidal and non-pyramidal neurons; b) unifying
      theory of cytoarchitectonic differentiation of neocortex proposed by M. Marin
      Padilla; c) factors of cytoarchitectonic differentiation of cortical areas and
      specialization of brain hemispheres in mammalian ontogenesis and evolution. The
      thesis, according to which morphofunctional maturation of both pyramidal and non
      pyramidal neurons begins as a result of their contacts with a system of
      thalamocortical afferent fibers, is substantiated. They grow from the subcortical
      white matter, initiate layer-by-layer ascending cortical maturation and,
      ultimately, divide it into descrete functional territories.

PMID- 12596547
TI  - [Characteristics of neurons from the anterior region of the rat amygdaloid body
      by electron microscopy].
AB  - Dark and light neurons with morphological signs of secretory activity are
      described within one of the major sexually dimorphic zones of brain amygdaloid
      nucleus (anterior cortical nucleus). Dark neurons are of medium size, they have
      large nuclei and well developed perikarya. The latter contain numerous free
      ribosomes and mitochondria, dilated rough endoplasmic reticulum cisterns,
      hypertrophied Golgi complex with forming secretory granules. Elementary
      neurosecretory granules (ENG) 75-300 nm in size were found in light
      neurosecretory cells, which seem to be similar to dark cells but are at different
      phase of functional activity. Synapses of all types known, containing small light
      vesicles, vesicles with dense core and ENG, were found in active neuropil.

PMID- 12596548
TI  - [Nitric oxide synthase in neurons of the vagal nucleus dorsalis and ganglion
      nodosum and its changes following acetylcholine inhalation in the norm and in
      experimental bronchial asthma].
AB  - The expression NADPH-diaphorase and inducible NO-synthase (NOS) was studied in
      vagal nucleus dorsalis and ganglion nodosum neurons following acethylcholine
      inhalation in healthy rats and rats with ovalbumin-induced experimental bronchial
      asthma (BA). It was found that NOS activity regulation is mediated by
      cholinoreceptors; functioning of this mechanism is disturbed in hypoxic state. It
      is shown that both in conditions of physiological norm and in experimental BA,
      changes in NOS activity are determined by its constitutive, neuronal isoform.

PMID- 12596549
TI  - [Interaction of sensory neurons and satellite cells during stimulation of the
      nerve regeneration].
AB  - Using the model of pharmacological stimulation of rat sciatic nerve regeneration,
      the effect of pyrimidine derivative ximedon on survival of different populations
      of LIV-LV dorsal root ganglion neurons, their expression of antiapoptotic Bcl-2
      protein and number of neurons surrounded by vimentin-positive satellite cell, was
      studied. 90 days after nerve cutting, ximedon was found to reduce posttraumatic
      death of neurons having both medium-sized and large perikarya by 35.5% and 42.8%,
      respectively, to support Bcl-2 expression in all neuronal populations and to
      modify vimentin expression in satellite cells. After nerve cutting, the number of
      small and medium-sized neurons with vimentin-expressing satellite cells was
      significantly increased while the population of large neurons was diminished.
      Nerve regeneration stimulation by ximedon induced the increase in the number of
      large neurons, surrounded by vimentin-expressing satellite cells, up to the
      levels found in intact animals.

PMID- 12596550
TI  - [Formation sources and topographic characteristics of the pelvic plexus in furry
      animals of Canidae and Mustelidae families].
AB  - Using preparation methods, the topography and the formation sources of pelvic
      plexus (PP) were studied in animals of Canidae (silver-black fox, blue fox) and
      Mustelidae (sable, American mink) families. Maximal differences in PP topography
      and PP-forming nerves were found between species (Canidae-Mustelidae), whereas
      the intraspecies differences were less pronounced. Intraspecies sex-associated
      differences in PP topography are associated with only quantitative parameters,
      while those in PP formation sources and in peculiarities of PP-forming nerves'
      branching pattern are qualitative in nature. There is a distinct correlation
      between PP structural type (diffuse, compact, mixed) and peculiarities of its
      ganglionic apparatus: in diffuse type the juxta- and intraogan position of
      ganglia is prevalent, while in compact type the extraorgan position is more
      common.

PMID- 12596551
TI  - [Age differences in the post-reperfusion recovery of structure of the human
      myocardium].
AB  - The ultrastructure of myocardium was studied in children and adults with
      congenital heart defects 1 hour after intraoperational cardiac arrest followed by
      reperfusion. It was established that the intensity of adaptation reactions which
      provide the structural homeostasis, is progressively reduced with age resulting
      in gradual depletion of compensatory reserves. The presence of preoperational
      compensatory-adaptive reserve in children defines the possibility and adequacy of
      post-ischemic myocardial regeneration and restoration of its contractile
      function. The depletion of compensatory reserves in adults is one of the main
      reasons for development of post-reperfusion myocardial injury and of its plastic
      insufficiency.

PMID- 12596552
TI  - [Morphological characteristics of cardiomyocyte death in the experimental
      myocardial infarction in rats with various emotional reaction].
AB  - The peculiarities of morphological signs of cardiomyocyte death in the lesion
      focus in experimental myocardial infarction were studied. Infarction was induced
      by ligation of descending branch of the left heart coronary artery in outbred
      rats with 180-200 g body mass, which were previously subdivided into highly
      emotional (HE) and low emotional (LE) groups according to "open field" test.
      Microscopic study has shown that in the infarction focus of animals of both HE
      and LE groups cardiomyocyte death types were found that differed primarily by the
      state of myofibrils. Relaxation and contracture types of cardiomyocyte death were
      typical to HE animals, while lytic cardiomyocyte necrosis prevailed in LE group.

PMID- 12596553
TI  - [Cytoarchitechtonics of the lymphoid tissue associated with the cecum wall in man
      in adolescence].
AB  - Cytoarchitectonics of lymphoid nodules (including apex, central zone and basis)
      and mucosal lamina propria cellular composition were studied in histological
      sections of cecum wall (dome area) in adolescents aged 12-16 years. It is shown
      that within lymphoid nodules the lowest cell concentration per unit section area
      is found in the apical area. The latter is also a region containing significant
      number of plasma cells. Apparent rarefication of cells in the central part of
      lymphoid nodules, high content of eosinophils, plasma cells and macrophages,
      increased cell destruction in lamina propria of cecal mucosa collectively
      indicate the changes in barrier function in intestinal wall of adolescents.
      Timing of these changes coincides with hormonal reorganization of the whole
      organism.

PMID- 12596554
TI  - [Morphological and functional changes in lymphoid organs after mud treatment].
AB  - Course application of curative mud results in changes structure and cellular
      composition of all the lymphoid organs studied: thymus, mesenterial and popliteal
      lymph nodes. These changes are mainly unidirectional and are characterized by
      increased reactions of humoral immunity.

PMID- 12596555
TI  - [Effect of enterosorption on the liver morphology anf function in mechanical
      jaundice].
AB  - Using histological, morphometric and biochemical methods, the comparative
      analysis of the effect of carbon-mineral enterosorbent SUMS-1 and of new
      generation aluminium oxide-based enterosorbent SIAL on the course of pathologic
      process--experimentally induced mechanical jaundice--was performed. The
      possibility of their use for the correction of morpho-functional disturbances of
      liver tissues is demonstrated. The conduction of clinical trials for the clinical
      application of these substances is recommended.

PMID- 12596556
TI  - [Functional morphology of the ovary appendages].
AB  - The dimensions and structure of parovarium (PO) were studied in women of
      different age groups. It is established that PO size increases up to fertile age
      and is reduced after the menopause. Epitheliocytes of PO tubules in women of
      fertile age are characterized by high synthetic and secretory activity. The shape
      of epitheliocytes changes from cuboidal in neonates to columnar in fertile age
      and to squamous--after the menopause.

PMID- 12596557
TI  - [Morphological and functional characteristics of the urogenital diaphragm in
      women].
AB  - Macroscopical study of muscle layer of urogenital diaphragm in women has revealed
      two muscles situated between its superior and inferior fasciae--m. transversus
      perinei profundus (MTPP) and sphincter urethrae (SU),--which are separated by
      connective tissue. In females, SU is not ring-shaped, but is an arched structure
      situated in front of urethral lumen intertwining into urethral outer circular
      muscular layer. MTPP consists of three groups of bundles: anterior, medium and
      posterior. Anterior bundles of MTPP are periurethral and directly interlace with
      urethral muscular wall. Medium and posterior bundles of this muscle do not reach
      the urethral wall and act on the muscular wall of vagina. The study of
      histotopographic sections of urethral muscular wall made from the level of neck
      of the urinary bladder to the urogenital diaphragm, showed that the urethral
      outer circular muscular layer contains both bundles of smooth muscle cells and
      striated muscle fibers which ascend from urogenital diaphragm attaining an
      oblique-circular course. Major part of urethral striated muscle fibers, as well
      as SU and MTPP fibers belong to "red", slow-twitch, tonic fiber type.

PMID- 12596558
TI  - [Dynamics of echomorphometric human crural skin characteristics during dosed
      stretching].
AB  - The dynamics of echo-morphometric parameters of crural skin was studied in
      patients with congenital shortening of lower extremity in the process of its
      operative elongation. It is demonstrated that dosed stretch results in increased
      skin thickness. After the completion of distraction, the skin thickness exceed
      preoperation levels by 48.7% (in patients aged 5-8 years), 20.9% (in patients
      aged 10-14 years) and 26.7% (in adults). Skin acoustic density after distraction
      termination reached the preoperation level in children and adolescents, while it
      was increased in adults.

PMID- 12596559
TI  - [In vivo assessment of various parameters of the brain ventricles with magnetic
      resonance tomography].

PMID- 12596560
TI  - [Histochemical identification of myocytes on total preparations from lymphatic
      vessels].

PMID- 12596561
TI  - ["Dark" and "light" cells].

PMID- 12596562
TI  - [Paratuberculosis: the pathogen and routes of infection].
AB  - Paratuberculosis, caused by Mycobacterium avium subspecies paratuberculosis (M.
      paratuberculosis), is a chronic and incurable enteritis of ruminants with
      economic importance worldwide. The infectious agent is an acid-fast rod defined
      solely based on its mycobactin-dependent growth in vitro and the presence of
      insertion element IS900. The bacterium, which is difficult to culture primarily
      due to its extremely slow growth, occurs not only in cattle but also in other
      ruminant. In addition, it has been isolated from non-ruminant species. Despite
      its wide spectrum of potential hosts the contact between adult cattle and calves
      is the predominant route of infection within a herd as well as among herds. To
      interrupt this route of infection hygienic measures, primarily for the housing
      and feeding of calves, as well as diagnostic measures prior to trading of cattle
      are urgently required.

PMID- 12596563
TI  - [Pathogenesis and immune reactions of paratuberculosis].
AB  - Mycobacterium avium subspecies paratuberculosis (M. ptb) is known as the cause of
      paratuberculosis for over a century but the knowledge on biology of the organism
      and pathogenesis of the disease is still limited. There are several reasons for
      the present lack of progress, these are (i) the extremely slow growth of the
      bacterium, a feature which has also protected the organism against researchers,
      (ii) confusion over its taxonomy and identification, (iii) limited possibilities
      for the application of molecular biology techniques, and (iv) the extremely long
      incubation period in natural infection for which no suitable laboratory model
      exists. Despite these discouraging facts, recent research efforts have led to
      important findings, which have shown that a better understanding of the disease
      may contribute to the improvement of control strategies. This presentation
      focuses mainly on the unique nature of M. ptb within the mycobacteria and the
      central role of the macrophage in pathogenesis and immune response. More details
      can be found in a number of excellent recent reviews (see list of references).

PMID- 12596564
TI  - [The importance of allergic skin test with Johnin, antibody ELISA, cultural fecal
      test as well as vaccination for the sanitation of three chronically
      paratuberculosis-infected dairy herds in Rhineland-Palatinate].
AB  - Three chronically paratuberculosis infected herds were tested for six years twice
      a year (intradermal Johnin test, antibody ELISA (IDEXX Corp.), microbial culture)
      according to a sanitary program. Culling of shedding animals and vaccination of
      calves with NEOPARASEC (Merial Corp.) were part of the program. In course of
      experiment, 1015 samples of 228 non vaccinated cows and 1502 samples of 293
      vaccinated cattle have been tested. 3.8% of the vaccinated animals proved
      positive in microbial culture. Nearly all vaccinated calves developed granulomas
      sized from hazelnut to loaf at the injection site. Positive reactions in
      intradermal test as well as in antibody ELISA were found in very young calves.
      24.3%, 33.7%, 25.9%, respectively of the non vaccinated animals were identified
      as shedders of M. avium subsp. paratuberculosis (MAP) by microbial culture. In
      the first and in the second herd most shedders of MAP were found in the first
      herd examination (66.7%, 42.9%, respectively), whereas in the third herd they
      were detected in the fifth examination (31.0%). At the beginning, 17.9% of non
      vaccinated animals proved positive in intradermal test, 14.4% in antibody ELISA.
      Afterwards, the number of positive test results decreased but increased again
      towards the end of the experiment. 48.5% of the 66 shedders showed positive
      reactions in intradermal test, 57.6% in antibody ELISA, 77.3% in at least one of
      these both tests. Antibodies in ELISA were found in rising frequency from two
      years before the time of shedding. 50.0% of the shedders reacted positive in
      ELISA at the time of shedding. In selected shedders first positive results were
      found at the age of about two years. Unfortunately, only incomplete hygienic
      measures were realized by the farmers. Under field conditions the realisation of
      attending sanitary programs is difficult. MAP is spread mainly by buying of
      animals, therefore a certification program for paratuberculosis free herds is
      urgently necessary as well as an improvement of diagnostic methods.

PMID- 12596565
TI  - [Diagnosis of paratuberculosis].
AB  - Diagnostics of paratuberculosis infection is a difficult and complex field, that
      causes confusion, lack of understanding and frustration in practitioners,
      veterinary officers and last but not least farmers. In this review the various
      diagnostic approaches with their potentials, advantages and disadvantages and
      their limits are discussed.

PMID- 12596566
TI  - [Fifteen years of paratuberculosis eradication programs. Experiences from the
      Lower Saxony Animal Epidemic Finance Office].
AB  - 15 years of systematic paratuberculosis control programs in Lower Saxony were
      reported and critically judged. The proposed measures were considered with
      respect to suitability and enforceability.

PMID- 12596567
TI  - [Paratuberculosis eradication programs in Northrhine-Westfalia].
AB  - Since 1993 a voluntary eradication program for bovine paratuberculosis is
      established in Northrhine-Westfalia. After an effectivity control of the
      serological diagnostics it is combined with the fecal culture since August of
      2000. Parallel use of both methods is necessary for a successful eradication. It
      could be monitored that a high percentage of the newly bought cattle in the herds
      participating in the eradication program was considered positive. Since
      paratuberculosis eradication is time and cost extensive besides intensive
      eradication programs the spread of the disease must be stopped.

PMID- 12596569
TI  - [Evidence-based medicine and fundamental science].

PMID- 12596568
TI  - [Bacteriological investigations about paratuberculosis in dairy herds in
      Switzerland].
AB  - In Switzerland clinical bovine paratuberculosis is registered sporadically with
      on average seven outbreaks per year. Our present studies are aimed to investigate
      the prevalence of Mycobacterium avium ssp. paratuberculosis (MAP)-infections in
      the Swiss cattle population and, therefore methods to culture MAP from bovine
      feces as well as a commercially available ELISA to detect MAP-specific antibodies
      are evaluated by using fecal samples and blood sera from herds with cases of
      clinical paratuberculosis. A series of molecular methods i.e. PCR-coupled RFLP
      analysis of the IS1311-insertion element of M. avium, PCR-coupled RFLP-analysis
      of the mycobacterial rpoB-gene, and DNA analysis of the mycobacterial 16S rRNA
      gene are used to identify mycobacterial isolates grown from bovine feces. Up to
      now, MAP was detected by culture in 12 of 155 (7.7%) animals from herds with
      paratuberculosis. A rather striking result is the finding of atypical
      mycobacteria in feces of 75 cattle (48.3%). Among these isolates, M. avium ssp.
      avium, M. thermoresistibile, and M. hassiacum/M. buckleii have been identified so
      far.

PMID- 12596571
TI  - [New molecules in 2002].

PMID- 12596570
TI  - [Vaccinations for the traveler].
AB  - Long distance journeys are more and more frequent. Beside malaria prophylaxis,
      the general practitioner shall consider several points. Vaccinations against
      tetanus, diphtheria and (for a few years at least) polio should be done every ten
      years. Hepatitis A vaccine shall often be done (with > 20 years protection) but
      typhoid fever vaccine shall be limited to advanturous and/or long stays. Yellow
      fever vaccine (10 years validity) is only administrated in specialised centers;
      this is the only mandatory vaccine for certain african or south american
      countries. In certains instances, one shall consider vaccination against
      hepatitis B, meningococcal meningitis or, less often, against rabies, central
      european or japanese encephalitis. The vaccine against cholera (numerous side
      effects and poor efficacy) is no more available.

PMID- 12596572
TI  - Implementation of the caco-2 cell culture model as a predictive tool for the oral
      absorption of drugs. In-house evaluation procedures.
AB  - The Caco-2 cell culture model is widely used during drug development and lead
      optimization as a predictive tool for the oral absorption of drugs. In order to
      improve the reliability and quality of the results of Caco-2 experiments and to
      ensure that the system being used is functionally and enzymatically
      representative for the intestinal mucosa, it is important to perform a validation
      of the implemented Caco-2 system. In this paper, we summarize evaluation
      techniques to guarantee the in-house validity of the model. Theophyllin and
      sodium fluorescein are used as model compounds to evaluate passive transcellular
      and passive paracellular transport, respectively. Phenylalanine serves as a
      substrate to demonstrate active carrier mechanisms. Aminopeptidase and dipeptidyl
      peptidase are two brush border enzymes present in an active form in the Caco-2
      culture model. The presence of an active efflux carrier mechanism is demonstrated
      with cyclosporin A as a substrate.

PMID- 12596573
TI  - [Comparative studies of total extraperitoneal hernioplasty in combined spinal
      epidural anesthesia versus balanced general anesthesia].
AB  - To appraise the clinical impact of combined spinal-epidural anaesthesia (CSE) in
      patients undergoing total extraperitoneal laparoscopic hernia repair (TEPP), we
      performed a prospective study in 40 patients. These patients were randomized to
      receive either CSE (n = 20) or a balanced general anaesthesia (BGA) with
      controlled ventilation (n = 20). The aim of the study was to determine the impact
      of the intraoperative gas insufflation on compensatory respiratory reactions
      during regional anaesthesia. Therefore, blood gas samples were drawn and
      additional parameters were assessed as follows: noninvasive haemodynamic, lactate
      and glucose levels, differential blood count, and the patients' level of comfort
      during the perioperative setting, which was determined by a questionnaire. In our
      study it was clarified that the respiratory compensation of extraperitoneal gas
      insufflation is not decreased by regional anaesthesia. The haemodynamic state of
      the patients was stabilized by early interventions. In addition--there was no
      evidence that the anaesthesia regime used had any influence on the so called
      stress-parameters. Most of the patients with regional anaesthesia showed severe
      agitation often accompanied by chest pain. Hence, regional anaesthesia is not
      recommended in this setting.

PMID- 12596574
TI  - [Postoperative epidural analgesia--current status, indications and management].
AB  - We are reporting on postoperative pain treatment using epidural analgesia in
      1,822 patients, performed between 1995 to 2000, following continuous epidural
      anaesthesia combined with general anaesthesia for operations in various
      specialized areas (general or visceral surgery, vascular and thoraxic surgery,
      gynaecology, urology and orthopaedics). A total of 1,727 of these postoperative
      epidurals were included in a detailed evaluation. The postoperative epidural
      analgesia consisted of a continuous application of 0.25% bupivacain or 0.2%
      ropivacain. These local anaesthetics were administered epidurally in an hourly
      perfusion rate of 7.5 ml. We found "good" pain relief through continuous epidural
      administering of the local anaesthetics in 1,292 patients (74.8%). "Moderate"
      pain relief was achieved in 392 patients (22.7%). Sufentanil had to be epidurally
      administered in addition to local anaesthetics in 262 patients (15.2%) in the
      wake-up room. The sufentanil doses lay between 5 and a maximum 10 micrograms per
      hour. An additional epidural application of morphine-boli in a dose of 3 mg every
      8-12 hours was necessary in 384 patients (22.2%) in the surgical wake-up
      stations. In 392 patients (22.7%), the additional systemic administering of
      antipyretic analgesics such as metamizol or paracetamol or spasmolytica was
      sufficient. In 43 cases (2.5%), sufficient pain relief could not be achieved with
      epidural analgesia even with additive applications of systemic functioning
      pharmaceuticals, so that the postoperative pain therapy had to be completely
      switched to a PCA. The lying time of the epidural catheter was 2-5 days. It was
      shortest with the gynaecological patients and longest with patients from general,
      visceral, thoraxic and vascular surgery areas. An important factor for a
      sufficient epidural analgesia is the exact epidural positioning of the catheter
      tip in the area of the spinal cord segments, which are affected by the operation.
      This reveals the required puncture height. The following side-effects resulting
      from the epidural analgesia were found: blood pressure loss of more than 20% of
      the starting value (21%), temporary bladder voiding disorders (8%), temporary
      sensory disorders of the lower extremities (6.5%), seldom nausea (2.4%) and post
      puncture headaches (1.2%). The most important prerequisites for successful
      postoperative epidural analgesia and thus for increased patient satisfaction are
      correct selection of the insertion height in relation to the planned operation,
      constantly available medical pain service, the inclusion of trained care
      personnel and unequivocal written instructions.

PMID- 12596575
TI  - [Managing anesthesia in the alcoholic patient].
AB  - In most developed countries, alcohol is a socially tolerated drug. Nevertheless,
      its consumption is associated with several negative side-effects during
      anaesthesia. In surgical patients the prevalence of alcoholism exceeds 20%.
      Chronic alcoholism and acute alcoholism have an important impact on perioperative
      morbidity and mortality and especially on anaesthetic risk, due to
      pharmacological interactions, pathophysiological changes and direct
      pharmacological interactivities between alcohol and narcotics. Symptoms of
      alcohol withdrawal are a serious and potentially life-threatening complication
      and should be avoided or the risk for occurrence should at least be reduced.
      Patients with a high risk of developing perioperative symptoms of alcohol
      withdrawal can be detected by laboratory tests and questionnaires. The most
      important implication for anaesthesia is the choice of a rapid sequence induction
      to reduce the risk of aspiration and the maintenance of haemodynamic stability
      and liver perfusion. Maintaining body temperature and providing intensive
      postoperative surveillance and care are necessary. The indications for regional
      anaesthesia are the same as for other patients (cooperativeness, coagulation,
      consent, etc.). In general, awareness of possible interactions can reduce
      perioperative complications and improve postoperative outcome.

PMID- 12596576
TI  - [Study on the change of bFGF in reticular formation of medulla oblongata after
      primary brain-stem injury].
AB  - OBJECTIVE: To study the effect of primary brain-stem injury on the expression of
      basic fibroblast growth factor (bFGF) in the reticular formation of medulla
      oblongata. METHODS: Immunohistochemical SABC was used to study the change of bFGF
      expression in the reticular formation of medulla oblongata after brain-stem
      injury by striking. RESULTS: The numbers of positive cells and positive intensity
      of the study group in the reticular formation of medulla oblongata were
      significantly elevated than those of the control group and the postmortem injury
      group. CONCLUSION: The expression of bFGF is elevated in reticular formation
      after brain-stem injury.

PMID- 12596577
TI  - [The expression of FN-IIIcs in the wound healing and its relationship with injury
      time].
AB  - OBJECTIVE: To research the expression of alternative splicing segment of
      fibronectin-IIIcs in incised wound of skin, to offer the experimental data for
      early injury time judgement. METHODS: Using in situ hybridization with DIG
      labeled anti-sense RNA probe, the expression of FN-IIIcs domain was detected in
      both human and rat skin incised wound. RESULTS: (1) The expression of FN-IIIcs
      improved from the time of 30 min after injury, reached peak at 6 h and then
      reduced gradually. (2) The positive expression cells were mainly distributed in
      hair follicles, sebaceous glands and endothelium, however, in human beings they
      were basement cells of epidermis. CONCLUSION: The expression of FN-IIIcs domain
      would be a supposed useful criteria for early injury time judgement.

PMID- 12596578
TI  - [The in situ hybridization effort estimation between antisense RNA probe and
      random primed DNA probe].
AB  - OBJECTIVE: To estimate the effort between antisense RNA probe and random primed
      DNA probe. METHODS: The in situ hybridization was conducted on parafin section
      from wounding model of rat skin. RESULTS: Although both probes appeared positive
      staining, RNA probes was superior to DNA probes in terms of depth of staining and
      background. CONCLUSION: RNA probe showed more satisfactorily on ISH.

PMID- 12596579
TI  - [An immunohistochemical study on the distribution in organs in cases with
      morphine poisoning].
AB  - OBJECTIVE: To investigate the distribution of mophine in organs in cases with
      morphine poisioning to select ideal organs for immunohistochemical derection.
      METHODS: Localization and half quantitation of morphine in the brain, the kidney,
      the heart, and the liver were studied in 8 cases with morphine poisoning by
      immunohistochemical SP method. RESULTS: Morphine was mainly detected in the
      cytoplasm of certain parenchymal cells of the organs. The distribution varied
      greatly with different cases and organs. In the brain and kidney, morphine
      positive cells could be easily found. CONCLUSION: The kidney and brain may be the
      ideal organs for sampling in suspected morphine poisoning cases with.

PMID- 12596580
TI  - [Immunohistochemical study with depletion of cardiac troponin T in rats on early
      myocardial ischaemia].
AB  - OBJECTIVE: To study the depletion of cardiac troponin T in Rats of early
      myocardial ischaemia. METHODS: Immunohistochemical method (LSAB) was used and the
      depletion area of CTnT in myocardial ischaemia were measured by the computer
      image analysis. RESULTS: There is obviously depletion of CTnT after 15 min in
      myocardial ischaemia of rats, the mean of CTnT depletion of myocardial ischaemic
      group is significant difference compared with that of the control group (P <
      0.01), and the depletion area increased with the prolongagtion of ischaemic time.
      CONCLUSION: The depletion of CTnT is one of sensitive signs of early myocardial
      ischaemia.

PMID- 12596581
TI  - [The experimental study of expression of intercellular adhesion molecule-1 after
      fluid percussion brain injury].
AB  - OBJECTIVE: To determine the changes of intercellular adhesion molecule-1 after
      traumatic brain injury. METHODS: Use the fluid-percussion model to inflict rat
      brain and take the samples at 2, 4, 8, 12, 24 hours after brain injury. The
      samples were studied by immunohistochemistry method combined with image analysis
      by MIAS image analysis system. RESULT: The expression of ICAM-1 upregulates at 2
      hours, reaches peak at 12 hours and falls down at 24 hours after brain injury.
      CONCLUSION: The changes of ICAM-1 in brain can provide a backup for estimation of
      injury time and survival period after brain injury which sustained within 24
      hours.

PMID- 12596582
TI  - [A study of genetic polymorphism of the STR loci D20S85 and D6S477 in Han
      population living in Wuhan].
AB  - OBJECTIVE: The genetic polymorphism of two STR loci, D20S85 and D6S477, were
      studied in 280 unrelated Chinese individuals in Wuhan. METHODS: The PCR amplified
      products were analyzed by PAGE and silver staining. RESULTS: 10 and 9 alleles
      were observed in these two STR loci, and the discriminating power (DP) were
      0.9085 and 0.9127 respectively. No deviations from Hardy-Weinberg equilibrium
      were found. The two STR loci had been successfully applied to individual
      identification and paternity testing. CONCLUSION: The results demonstrated that
      the two loci were useful for forensic identification.

PMID- 12596583
TI  - [Evaluation on the number and value of STR loci applied in paternity
      identification].
AB  - OBJECTIVE: The study was carried out on the evaluation of number and value of STR
      loci applied in paternity identification. METHODS: A total of 13 STR loci,
      divided into four groups, was observed in 102 cases of paternity exclusion and
      100 cases of paternity inclusion. PCR amplified products of 13 STR loci were
      injected into a capillary on the ABI PRISM 310 Genetic Analyzer. GeneScan
      software analyzed the collected data, which can then be imported into Genotyper
      software for genotyping of alleles. RESULTS: At least 3 STR loci
      incompatibilities between alleged father and child were found in all paternity
      exclusion cases of two observed groups which Cumulative Probability of Exclusion
      (CPE) was more than 99.99%, and in all paternity inclusion cases of those same
      observed groups, their Relative Chance of Paternity(RCP) could be over 99.99%.
      CONCLUSION: The exclusion of paternity should be based on at least three STR loci
      incompatibilities in the identification practice. As a criterion for evaluation
      of the number and value of STR loci applied in paternity test, CPE should reach
      99.99%.

PMID- 12596584
TI  - [Screening of benzodizepines and their metabolites in urine].
AB  - OBJECTIVE: Screen seventeen benzodizepines and their metabolitesin urine by
      GC/ECD and GC/MS. METHODS: They were GC (GC/ECD, GC/MS) assay of benzodizepines
      and GC (GC/ECD, GC/MS) assay of benzophenones of acid-hydrolytic products of 1,4
      benzodizepines. RESULTS: The methods were simple and sensitive. The recoverys
      were 60% to 90% of most benzodizepines, linear calibration curves were 20 ng/ml
      200 ng/ml (r > 0.99), and detection limits were 0.5 ng/ml-10 ng/ml. CONCLUSION:
      They methods were evaluated with human urine samples.

PMID- 12596585
TI  - [Stress and hippocampus].
AB  - This review summarizes the present advance of effects of stress on hippocampal
      structure and function and the role of hippocampus in feedback regulation of
      thalamic-pituitary-adrenocortical (HPA) axis during stress. It shows that stress
      can affect hippocampal structure and function, on the other hand, the hippocampus
      can also suppress the stress reaction through the feedback regulation of HPA
      axis, but chronic stress can attenuate this regulation, then significantly impair
      its structure and function.

PMID- 12596586
TI  - [Injury by electrical forces: pathophysiology, biophysics and pathogenesis].
AB  - As the technologic sophistication of generation and distribution of electrical
      energy has grown, so has the general concern about the effects of electric fields
      on human health. There can be no doubt that the significance of electrical trauma
      will continue to grow with our increasing use of power. It is apparent that our
      understanding of the various forms of electric trauma must increase, while we
      continue to promote safety near electrical hazards and develop effective medical
      therapies. Tissue damage as a result of electrical injury occurs by two
      mechanisms which are summative in action and have a variable degree of contribute
      to the ultimate damage produced. Thermal tissue damage occurs as a result of heat
      generated within the tissue (which offer an electrical resistance) secondary to
      the passage of the electrical current. High temperatures can also lead to cell
      membrane components, e.g., phospholipids, to dissolve. Electroportation damage is
      the tissue damage induced secondary to the strong electric field. Transmembrane
      potentials caused by electrical current result in the formation of pore in the
      phospholipid component of the cell membrane resulting in loss of function of the
      cell membrane with consequent cell death.

PMID- 12596587
TI  - [The applying and foreground of quantifying DNA content by image analysis
      technique in determining postmortem interval].
AB  - Image Analysis Technique(IAT) was developed at 1950's, which quantifies the
      changing all the part of image by sampling, processing, quantifying, computing,
      analyzing the information of image. And now it has become a normal quantifying
      technique in biology and medicine research. In the present paper, we reviewed
      briefly the principium of quantifying the DNA content by IAT, the law of
      degradation of DNA in nucleus and the foreground of this method in determining
      PMI in forensic pathology.

PMID- 12596588
TI  - [Study on the relationship between PMI and the concentration of magnesium and
      iron in the vitreous humor of rabbit after death].
AB  - OBJECTIVE: To seek a exact method of estimating postmortem interval (PMI).
      METHODS: This study detected the concentration of magnesium (Mg) and iron (Fe) in
      vitreous humor of rabbit at 96 h after death and explored the relationship
      between their concentration and PMI using a method ICP-MS. RESULTS: The concentra
      tion of Mg in vitreous humor of rabbit at 48 h after death and Fe in vitreous
      humor of rabbit at 6-48 h after death were related to PMI significantly. The
      formulae of the relationship between PMI and Mg concentrations is y = 0.0738x2 +
      0.6997x + 11.45 (within 48 h, R2 = 0.9119). The formulae of the relationship
      between PMI and Fe concentrations is y = 0.0411x2 - 0.3148x + 1.4113 (within 6-48
      h, R2 = 0.9594). CONCLUSION: The concentration of Mg in vitreous humor of rabbit
      at 48 h after death and Fe in vitreous humor of rabbit at 6-48 h after death may
      be as reference indicator to estimate PMI.

PMID- 12596589
TI  - [Study on the relationship between PMI and the concentration of 21 elements in
      vitreous humor of rabbit after death].
AB  - OBJECTIVE: To seek a precise method for estimating postmortem interval (PMI) in
      forensic medicine practice. METHODS: This study detected the concentration of 21
      elements in the vitreous humor of rabbit within 96 hours after death and explored
      the relationship between their concentration and PMI using the method of ICP-MS.
      RESULT: It was shown that the concentration of 9 elements in vitreous humor of
      rabbit within different intervals after death were correlated to PMI available as
      a reference indicator to estimate PMI. CONCLUSION: The changes in the
      concentration of certain elements in vitreous humor of vitreous humor are
      correlated with PMI and determination of such changes can be used to estimate the
      time of death.

PMID- 12596590
TI  - [A quantitative analysis of peptidergic innervation in sinoatrial node in cases
      of sudden manhood death syndrome].
AB  - OBJECTIVE: To study the distribution and proportion of neuropeptide containing
      nervers in the sinus node in cases of sudden manhood death syndrome (SMDS) and to
      explore the mechanism of SMDS. METHODS: Immunohistochemical staining and
      quantitative analysis of neuropeptide Y (NPY) and vasoactive intestinal
      peptide(VIP) in the sinus node in 6 cases of SMDS and in 12 cases of non-cardiac
      death(control group) were achieved by LSAB method and computerized image system.
      RESULTS: As for NPY positive materials, VIP positive materials and the ratio of
      VIP/NPY in the sinus nodes, there were no significant difference between the
      control group and SMDS group. CONCLUSION: The mechanism of SMDS and the
      abnormality of autonomic nervous innervation in the sinoatrial nodes maybe
      incorrelation.

PMID- 12596591
TI  - [The relationship between the postmortem interval and growing of the fly].
AB  - OBJECTIVE: To study the growing of flies on body after different postmortem
      interval. METHODS: In natural environment, time points when flies coming,
      gathering, making eggs, and maggots pupating, emergencing were observed on a
      female body died of disease. RESULTS: The time when flies coming, gathering,
      making eggs, and maggots pupating, changing to chrysalis, and emergencing were
      0.2, 28, 44, 60, 112 and 248 h after one's death, respectively. CONCLUSION: This
      study may be used in PMI estimation.

PMID- 12596592
TI  - [Cell apoptosis in closed cerebellar contusion in rat].
AB  - OBJECTIVE: To observe the cell apoptosis explore closed cerebellar contusion in
      rat. METHODS: SD rats model of contusion was established and apototic cells were
      detected by TUNEL method at 5, 10, 30, 45, 60 min and 2, 4, 6, 8, 12 h, after
      injury. RESULTS: Apototic cells in contusion area appeared at 1 h after closed
      cerebellar contusion, reached the peak at 4-6 h, then decreased and so as
      marginal area where the peak was in 6-8 h. CONCLUSION: The apoptotic index of
      closed contusion of cerebellum in different injury time may provide a new
      sensitive and objective method for the forensic early injury time estimation.

PMID- 12596593
TI  - [The changes of electrocardiogram and serum cardiac troponin I at the early stage
      of crush injury in rats].
AB  - OBJECTIVE: To observe the changes of electrocardiogram and serum cardiac troponin
      I at the early stage of severe crush injury in rats. METHODS: Crush injury was
      produced in Sprague-Dawley rats. The changes of electrocardiogram were recorded
      with the standard II, the serum levels of cardiac troponin I were studied by
      automated chemiluminescence assay. RESULTS: The ST segment elevated considerably
      after crush injury and lasted 24 h, the levels of serum cTnI were much higher
      than those of the control groupes after 6 h of injury. CONCLUSION: Cardiomyocyte
      injury was induced in the early phase of crush injury.

PMID- 12596594
TI  - [Study on forensic expertise of medical tangle].
AB  - OBJECTIVE: To study the characteristics of forensic expertise of medicial tangle,
      and explore the emphases and difficuties of forensic expertise. METHODS: The
      medical defect was classflied into the negliget defect, the technical defect, the
      administive defect, the learned defect and other defect. The 36 cases were
      analised according to the above-mentioned way. RESULTS: 86.11% of the 36 cases
      has the technical defect, 25% has the negliget defect and the administive defect.
      There were significant different between the our expertise opinion and Medical
      Tangle Expertise Committee's conclusion (P < 0.05, P < 0.01). CONCLUSION: The
      forensic expertise of medical tangle play the positive role in deal with the
      medical tangle cases, but there are many problems to further explore in forensic
      expertise.

PMID- 12596595
TI  - [Study on consistency of assessed results according to the Standard of Evaluated
      Injured Severity].
AB  - OBJECTIVE: To explore the consistency of assessed results according to Standard
      of Evaluated Injured Severity, finding out some factors that influenced appraisal
      conclusion. METHODS: 102 cases examined by Beijing Institute of Forensic Medicine
      and Science in 1998 were re-evaluated respectively by nine appraisers. RESULTS:
      The results showed that distinction of appraisal conclusion between appraisers in
      the same institute was small, but in different institute was big. The work
      experience and professional train were important to reduce errors. CONCLUSION:
      Standard of Evaluated Injured Severity strong take on character of profession.
      Veracity of assessed injured severity is related with unitive authoritative
      explanation, training and experience of appraiser.

PMID- 12596596
TI  - [Analysis of duo paternity testing].
AB  - OBJECTIVE: The study was carried out on application of 13 to 15 STR loci in duo
      paternity test. METHODS: The value of PE and CPE were caculated depending on the
      gene frequency of those STR loci in chinese population. The STR loci
      imcopatibilities were analyzed in 104 cases of paternity exclusion. RESULTS: CPE
      of 13 to 15 STR loci could reach 0.9805 to 0.9906. the RCP was over 99.73%. In
      104 cases of paternity exclusion, less than 2 loci imcompetibilities were only
      found in two cases. CONCLUSION: There was a low risky of false paternity
      inclusion in duo paternity test by using of 13 STR loci. If necessary, the
      genetic markers should be added. The RCP of those cases without imcompatibilities
      could all reach paternity inclusion stardand.

PMID- 12596597
TI  - [Column-switching high-performance liquid chromatographic method for the
      determination of morphine and O6-monoacetylmorphine in urine].
AB  - OBJECTIVE: To develop a column-switching high-performance liquid chromatographic
      method for the determination of morphine and O6-monoacetylmorphine in urine.
      METHODS: Urine samples (1.0 ml) were spiked with 1.0 ml borate buffer, after
      centrifugation, 1.0 ml of supernate were injected directly into an extraction
      column (YWG C18 33 mm x 5.0 mm, 10 microns). After a washing step with the
      extraction mobile phase, the retained morphine and O6-monoacetylmorphine were
      flushed into the analytical column (Lichrospher 100 CN 125 mm x 4.0 mm, 5
      microns) with the mobile phase CH3OH-H2O (60:40). The analytical mobile phase is
      CH3OH-phosphate buffer (pH6.86) (22:78). The UV detector was set at lambda 286
      nm. RESULTS: The method shows excellent linearity from 50 to 1,600 ng/ml for
      morphine and from 100 to 1,600 ng/ml for O6-monoacetylmorphine. The linear
      correlation coefficients were > 0.999. The relative standard deviations were <
      4%. The limits of detection were 40 ng/ml for both morphine and O6
      monoacetylmorphine. CONCLUSION: The method described is sensitive, rapid,
      reproducible, and simple.

PMID- 12596598
TI  - [Influence of NF-kappa B on the development and regulation of neural system].
AB  - Nuclear factor-kappa B (NF-kappa B) plays an important role in controlling
      infection, immunity responses, cellar differentiation and apoptosis. It is of
      characteristics especially in neural system. NF-kappa B exist widely in neural
      cells and transfer from plasma into nucleolus through diversified activation
      passages. in addition, NF-kappa B is also a key factor in the development of the
      neural system, anti-apoptosis and modulating the activity of glia cells. It is of
      great significance in the forensic science.

PMID- 12596599
TI  - [Visual electrophysiology and objective visual function].
AB  - This review summarizes objective assessment of visual function using visual
      electrophysiology. Objective assessment of visual acuity using pattern visual
      evoked potential (PVEP) and sweep pattern visual evoked potential (SPVEP),
      objective assessment of visual field using multifocal visual evoked potential
      (MVEP).

PMID- 12596600
TI  - [The unusual typing of short tandem repeats].
AB  - Short tandem repeats (STRs) have been widely used in forensic sciences such as
      stain analysis and paternity testing. Although most of STR typing could give the
      reliable and clear results, some unusual typing have been observed in forensic
      practice. The anomalous typing could result from a lot of causes, including DNA
      genetic variation, poor quality or quantity of DNA template, different typing
      system or method, nonspecific reaction in PCR or anomalous electrophoresis
      migration. The unusual results may disturb the right interpretation of STR
      typing.

PMID- 12596601
TI  - [The mast cell and trauma].
AB  - Mast cell(MC) takes an important role in trauma and the process of wound healing,
      and the pathophysiology reaction has a relationship to the time since trauma,
      which is helpful to determine the post-trauma and postmortem interval, and to
      distinguish the wound shaped whether before or after death. In this paper, the
      role of MC and its chemic medium in the process of wound healing, scar shaping,
      postburns inflammatory response, healing of bone fracture, as well as the
      signification for forensic medicine and the progress of researching in this field
      were reviewed.

PMID- 12596602
TI  - [The research and application of vascular endothelial factor].
AB  - Vascular endothelial growth factor (VEGF) is a mult-effective catokines on the
      endothelial cells specificly. It promotes the endothelial cells to split multiply
      proliferate and metastasis. It increases vascular permeability and accelerates
      new vascular generation. VEGF participates many physiological and pathological
      processes. It has achieved more clinical application and will have extensive
      applicative prospect.

PMID- 12596603
TI  - ESRD-associated cutaneous manifestations in a hemodialysis population.
AB  - Cutaneous manifestations occurring in patients with end stage renal disease
      (ESRD) can indicate systemic problems that have significant morbidity and
      mortality risks. Skin changes are sometimes a consequence of the disease that
      caused the renal failure or may be an ESRD manifestation. Pruritus is the most
      prevalent ESRD cutaneous complaint, but its pathogenesis is not understood. The
      pathophysiology, presentation, and nursing implications of perforating
      dermatosis, metastatic calcification, polytetraflouroethylene graft infection,
      and lichen planus are discussed with corresponding case reports.

PMID- 12596604
TI  - Advancing chronic kidney disease care: new imperatives for recognition and
      intervention.
AB  - Chronic kidney disease (CKD) affects over 6.2 million people in the U.S. and most
      commonly results from diabetes and/or hypertension. Patients with CKD have an
      increased risk of anemia and hypertension. Anemia occurs early in CKD and can be
      effectively treated with epoetin alfa. Hypertension can be managed with lifestyle
      modifications and medications. Nurses play a vital role in managing these
      patients by providing early CKD/anemia screening and intervention, education,
      patient monitoring, and support for patients and caregivers.

PMID- 12596605
TI  - Hemodialysis patients' symptom experiences: effects on physical and mental
      functioning.
AB  - Dialysis patients experience numerous symptoms, some serious in terms of medical
      outcomes and all serious in terms of potential reductions in functioning and well
      being. This cross-sectional study used self-reports of hemodialysis patients to
      catalogue symptoms; hypothesizing that frequently experienced symptoms,
      regardless of acuity, negatively affect functioning and well-being. Data were
      collected from 307 randomly selected hemodialysis patients from 14 dialysis
      facilities. Twenty-two of the 47 symptoms queried had mean experience scores of >
      or = 1 on a scale of 0-4, that is, were experienced by patients at least "a
      little of the time." Seventeen of these 22 symptoms were significantly correlated
      (< or = .01) with the SF-36 Physical Component Summary (PCS) scale, Mental
      Component Summary (MCS) scale, or both. All but four of these 17 symptoms (dry
      mouth, itchy skin, lack of appetite, and restless legs) clustered around
      fatigue/sleep, sexual concerns, or mobility. Linear multiple regression showed
      age, diabetes, the fatigue/sleep and mobility clusters, and itchy skin to be
      negatively associated with the PCS (p < or = .01). The fatigue/sleep cluster was
      also negatively associated with the MCS. Because previous research has shown the
      PCS and MCS to be associated with morbidity and mortality, management of common,
      non-acute symptoms may have long-term benefits for hemodialysis patients.

PMID- 12596606
TI  - Spirituality characteristics of women following renal transplantation.
AB  - End stage renal disease (ESRD) is a potentially terminal condition that causes
      patients to consider their mortality. Post research has shown that prayer and
      religious coping are associated with better posttransplant adjustment and that
      individuals with life-threatening illnesses have higher levels of spirituality
      than healthy individuals. Few studies, however, have examined the spirituality
      characteristics of kidney transplant recipients. This study examined the
      spiritual perspectives and spiritual well-being of 28 women who had a functioning
      allograft 18-24 months after receiving a first kidney transplant. Measurement by
      the Spiritual Perspective Scale (SPS) and Spiritual Well-Being (SWB) Scale scores
      indicated high levels of spirituality and moderate correlation between spiritual
      perspective and spiritual well-being. Although older participants had higher
      levels of spiritual perspective, there were no associations between age and
      spiritual well-being, nor difference in spiritual perspective and well-being by
      race, education, or employment status. Thus, particularly for the aging,
      spirituality may be a valuable psychological resource that should be supported in
      women posttransplant.

PMID- 12596607
TI  - Anemia management in patients with chronic conditions that affect erythropoiesis.
      Case study of the anemic patients.
AB  - Anemia management programs typically strive to maintain hemoglobin (Hb) levels in
      the target range of 11 to 12 g/dL recommended by the National Kidney Foundation's
      Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Although nephrology
      clinicians are constantly alert for conditions that cause hyporesponse to Epoetin
      alfa therapy, management protocols generally focus on assessing and managing
      acute disorders that affect the production of red blood cells. A more difficult
      clinical challenge is how to systematically manage patients with conditions that
      chronically affect the erythropoietic response and are intractable to routine
      therapies. This article addresses the etiology and management of chronic
      conditions that require a specialized anemia management approach to ensure that
      patients can achieve targeted Hb levels and associated clinical and quality of
      life benefits. Examples include chronic inflammatory disorders, severe secondary
      hyperparathyroidism, malignancies, human immunodeficiency virus (HIV), and kidney
      transplant failure.

PMID- 12596608
TI  - Caring for the renal failure patient: optimizing iron therapy.
AB  - The effectiveness of anemia management in patients with end stage renal disease
      (ESRD) has increased over the past 4 years. However, approximately 26% of treated
      patients still do not meet the minimum hemoglobin (Hgb) value of 11 g/dl that is
      recommended by the K/DOQI Clinical Practice Guidelines (National Kidney
      Foundation [NKF], 2001). One of the main obstacles to good patient outcome may be
      iron deficiency, which is common in both the predialysis and dialysis period.
      Since iron is needed for Hgb synthesis, iron depletion exacerbated anemia and
      reduces the response to recombinant erythropoietin (rEPO) therapy. Health care
      providers can significantly improve patient outcome by addressing iron deficiency
      more rigorously. A good starting point is the establishment of an iron deficiency
      management protocol that includes early evaluation of iron status and aggressive
      iron therapy. Iron therapy, in turn, can be optimized by administering safe and
      effective iron supplements and by implementing maintenance iron regimens to
      prevent the recurrence of iron deficiency. By making these simple improvements to
      their treatment approach, clinicians can enhance the effectiveness of anemia
      management in patients with ESRD.

PMID- 12596609
TI  - Conservative management of chylothorax with autoinfusion of pleural fluid during
      hemodialysis.
AB  - Utilizing this new procedure in an outpatient nephrology setting, we were able to
      maintain E.T.'s positive nitrogen balance, prevent infection, and minimize
      respiratory distress. In addition, his mother was involved in all decisions and
      was supportive to her son and the nursing staff. After E.T.'s AVF matured, the
      central venous catheter was removed and the superior vena cava dilated. The
      chylothorax resolved itself without further interventions. Chest x-rays were
      clear. E.T. remained asymptomatic, and 6 months later he received a successful
      renal transplant.

PMID- 12596610
TI  - Cleansing agents used for hemodialysis catheter care.

PMID- 12596612
TI  - Pearls and pitfalls in the airway management.

PMID- 12596611
TI  - The T.E.A.M. approach.

PMID- 12596613
TI  - The tracheal detecting-bulb: a new device to distinguish tracheal from esophageal
      intubation.
AB  - BACKGROUND: The tracheal detecting-bulb (TDB) is a diagnostic tool for
      confirmation of tracheal intubation. Capnography is also accepted as a standard
      way for such confirmation. The purpose of this investigation was to determine
      whether the results by TDB agreed with those by capnography. METHODS: Four
      hundred patients were allocated to three separate studies. In 200 consecutive
      patients of study 1, tracheal intubation was first confirmed with the TDB
      followed by capnography. In study 2, 100 patients had the esophagus intentionally
      intubated, and confirmation was performed likewise as in study 1. The tube was
      then removed, the trachea was intubated, and confirmation tests followed. Study 3
      involved 100 patients and was carried out in a double-blind, randomized manner.
      The tube was intentionally inserted into either the esophagus (n = 42) or trachea
      (n = 58), and confirmation tests immediately followed. RESULTS: In study 1, the
      rhythmic expansion-contraction of TDB was evident in 173 patients, and always
      agreed with capnographic reading; In 27 instances, the latex bulb of TDB remained
      collapsed or was scantily filled without the turning-up of capnographic reading
      as counterchecked, indicating esophageal intubation. In study 2, regardless of
      esophageal or tracheal intubation, agreement between TDB and capnogram was 100%.
      In study 3, the agreement between the two detecting instruments was 100% too. In
      the 400 patients studied, the results from the TDB were in complete accord with
      those of capnogram. The sensitivity, specificity, and predictive value of the TDB
      in all of these studies were 100%. CONCLUSIONS: The TDB is a valuable diagnostic
      technique for confirming tracheal intubation as it could correctly detect
      esophageal or tracheal intubation of the tracheal tube in all our 400 patients.
      The results of using TDB agree with the results of using capnography.

PMID- 12596614
TI  - Fentanyl-induced coughing and airway hyperresponsiveness.
AB  - BACKGROUND: The tussive effect of fentanyl, in sharp contrast to the antitussive
      effect that common opioids have, is not rarely seen in clinical anesthesia.
      Pretreatment with beta 2 agonist inhalation could dramatically suppress fentanyl
      induced coughing. We hypothesized that airway hyperresponsiveness might exist in
      large proportion of the subjects who had experienced fentanyl-induced coughing
      during previous anesthesia. METHODS: We designed a case-controlled matching study
      to investigate the correlation between fentanyl-induced coughing and airway
      hyperresponsiveness. Twenty-six consecutive subjects (ASA I-III), who experienced
      fentanyl-induced coughing during anesthesia in our hospital from 1999 to 2000,
      were enrolled in this study as the fentanyl-cough group. In all the subjects
      baseline spirometry was first obtained. Airway responsiveness was evaluated with
      either PC20 of methacholine challenge test or bronchodilator test. After matching
      age and sex, another 26 subjects without history of fentanyl-induced coughing
      during previous anesthesia were also enrolled in the study as the control group.
      RESULTS: The proportion of airway hyperresponsiveness in fentanyl-cough group and
      control group was 30.77% and 19.23% respectively. After pairing of these two
      groups, McNemar test revealed no significant difference in the proportion of
      airway hyperresponsiveness between these two groups (P = 0.257). CONCLUSIONS:
      From the analysis of the present study, we cannot prove that there is a direct
      correlation between fentanyl-induced coughing and airway hyperresponsiveness.

PMID- 12596615
TI  - The effect of acupuncture on the acute withdrawal symptoms from rapid opiate
      detoxification.
AB  - BACKGROUND: Rapid Opiate Detoxification (ROD) is among the best treatments for
      substance abuse. Unfortunately this method is associated with severe withdrawal
      reaction. The effect of body acupuncture has not been clearly identified during
      ROD. This study was designed to evaluate the effect of acupuncture on the
      severity of withdrawal reaction during ROD. METHODS: Forty adult male subjects
      addicted to opioids and scheduled for ROD by naloxone were randomly divided into
      acupuncture and control groups. In the acupuncture group during three consecutive
      days immediately before induction of ROD, body acupuncture was performed while in
      the control group it was exempted. Severity of withdrawal reaction was assessed
      having recourse to Clinical Institute Narcotic Assessment (CINA) Score and
      compared between two groups. RESULTS: After induction of ROD, CINA score raised
      significantly during the consecutive days in both groups compared with baseline
      values but the rise was significantly lower in acupuncture group. CONCLUSIONS:
      The result of this study shows that body acupuncture reduces the severity of
      withdrawal symptoms associated with rapid opiate detoxification and it is
      recommended that this nonpharmacologic method of treatment should be included in
      ROD program.

PMID- 12596616
TI  - Tracheal intubation condition--a comparison between one minute after rocuronium
      alone, one minute after rocuronium combined with atracurium and one minute after
      atracurium with rocuronium at one minute priming interval.
AB  - BACKGROUND: Rocuronium, a monoquaternary steroid analogue of vecuronium, is
      designed to provide a rapid onset of action. Experimentally, it has been shown
      that two non-depolarizing neuromuscular relaxants administered together can
      produce either a neuromuscular block of a size expected to be the sum of the
      individual doses (additive effect) or a larger neuromuscular block (synergistic
      effect). Experimental observations have suggested that during onset rocuronium
      acts synergistically with other nondepolarizing agents, but that at a steady
      state the combined action is additive. METHODS: To investigate whether rocuronium
      can speed up the onset of atracurium for intubation, 120 patients who consented
      to receive elective surgery requiring tracheal intubation were randomly assigned
      to 3 equally divided groups to receive one of the following three different
      combinations of muscle relaxants: twice ED95 of rocuronium (0.6 mg/kg group 1),
      an equipotent mixture of ED95 of rocuronium and atracurium (0.3 mg/kg and 0.25
      mg/kg respectively, group 2), and rocuronium 0.1 mg/kg to prime atracurium 0.42
      mg/kg at 1 min interval. Intubation conditions were assessed 1 minute after
      intravenous muscle relaxant injection, and scored as good, acceptable and poor
      based on four clinical evaluators: the ease of laryngoscopy (score of 1-3), the
      relaxation of vocal cord (1-3), the degree of coughing (1-3), and movement of
      extremity (1-3). Adding up together, intubation condition that scored 4-5 was
      considered to be good, 6-7 acceptable, and 8-12 poor. RESULTS: The conditions
      produced in the rocuronium and the mixture groups were similar and both were
      moderately better than those of the priming group. Good intubation conditions
      were achieved in 58% patients of the rocuronium group, 63% of the mixture group
      and 43% of the priming group. By Pearson Chi-square test, the comparisons did not
      show statistical significance between groups. CONCLUSIONS: Statistically,
      rocuronium alone, mixture of equipotent atracurium and rocuronium, and using
      rocuronium to prime atracurium all provided similar onset for satisfactory
      intubation.

PMID- 12596617
TI  - Personnel exposure to waste sevoflurane and nitrous oxide during general
      anesthesia with cuffed endotracheal tube.
AB  - BACKGROUND: Waste anesthetic gases may have adverse effects on the health of
      operating room personnel. To reduce the risk of exposure, the United States
      National Institute of Occupational Safety and Health (US-NIOSH) recommends a time
      weighted average (TWA) of 25 ppm (part-per-million) for nitrous oxide (N2O) and a
      ceiling of 2 ppm for sevoflurane (SEV). This study investigated the
      concentrations of these two gases in the atmosphere of operating room to which
      the working personnel (anesthetists) were exposed during anesthetic practice.
      METHODS: An extractive Fourier transform infrared (FTIR) spectrometer, with an
      optical path length of 10 meters, was used to monitor the concentrations of waste
      general anesthetics in the operating rooms. The FTIR in application could
      simultaneously determine the concentrations of several gases in a near real-time
      manner, which helped to accurately obtain the varying concentrations of gases in
      different anesthetic condition. The sampling Teflon tube of the FTIR was
      conveniently installed in the breathing zone of the anesthetic personnel to
      obtain the personal exposure concentrations of N2O and SEV. RESULTS: Nitrous
      oxide (N2O) and sevoflurane (SEV) concentrations for five surgeries in four
      different operating rooms were determined. In normal condition during
      maintenance, the SEV concentrations as measured were less than 2 ppm but the
      average N2O concentration was greater than 25 ppm. In addition, in three abnormal
      or specific conditions, the N2O and SEV concentrations increased dramatically.
      Firstly, at the end of maintenance (right before emergence), peak concentrations
      of 751 ppm for N2O and 26 ppm for SEV were measured. These unusually high
      concentrations resulted from flushing the tubing of the anesthetic machine to
      speed up the emergence of wakefulness of the patient from anesthesia. Secondly,
      when the cuff of the endotracheal tube was not well inflated or unserviceable,
      peak concentrations of 631 ppm for N2O and 32 ppm for SEV were measured. Thirdly,
      malfunction of or loose connection (or disconnection) between the anesthetic
      machine and the exhaust venting system of operating theater almost doubled the
      N2O and SEV concentrations. CONCLUSIONS: To decrease the exposure of the
      operating personnel to waste anesthetics, minimization of the use of N2O is
      recommended. Besides, the three extraordinary conditions as disclosed in this
      study were tubing flushing, illy managed endotracheal tube cuff and disconnection
      of scarvenging system, the first of which sometimes is unavoidable but the last
      two of which should be avoided.

PMID- 12596618
TI  - The analgesic effect of nalbuphine and its long-acting prodrug, nalbuphine
      pivalate, in rats.
AB  - BACKGROUND: Nalbuphine is an opioid-analgesic with agonist-antagonist properties.
      Recently, we have synthesized a nalbuphine prodrug, nalbuphine pivalate. The aim
      of the present study was to evaluate the analgesic effect and the analgesic
      duration of this prodrug. METHODS: Forty-eight male Sprague-Dawley rats (4
      groups, n = 12 in each group) were used. Rats in group 1 received nalbuphine HCl
      25 mumol/kg (in saline) intramuscular injection; rats in group 2 received
      nalbuphine pivalate 25 mumol/kg (in sesame oil) intramuscular injection, whereas
      those in groups 3 and 4 received saline and sesame oil respectively. The
      analgesic effects of testing agents were evaluated using the cold ethanol tail
      flick test (-30 degrees C). RESULTS: Both nalbuphine HCl and nalbuphine pivalate
      demonstrated significant analgesic effects. The analgesic duration of nalbuphine
      HCl was 2 h while that of nalbuphine pivalate was 30 h. CONCLUSIONS: Nalbuphine
      pivalate has a very long duration of analgesic action. This fascinating finding
      is worth further evaluation.

PMID- 12596619
TI  - Oral clonidine reduces myocardial ischemia in patients with coronary artery
      disease undergoing noncardiac surgery.
AB  - BACKGROUND: To access the clinical effect of clonidine on reduction of myocardial
      ischemia events in patients with history of coronary artery disease undergoing
      noncardiac surgeries. METHODS: Sixty ASA class III patients with coronary artery
      disease were allotted at random to two groups in a prospective, double-blind
      study to receive either clonidine (3 micrograms/kg) or placebo (control group) 90
      minutes before arrival at the operating room. Continuous EKG monitoring (Holter
      monitor) was performed to analyze the ST segment in lead II, V2 and V5 during the
      preoperative (since late hours the night before operation), intraoperative and
      early postoperative periods (total monitoring time = 24 hours). The episode of
      myocardial ischemia defined as the magnitude of ST segment depression of at least
      1 mm, occurring 60 ms after the J point and persisting for three minutes or more
      was recorded. Perioperative hemodynamic data were analyzed with two-way ANOVA
      with repeated measures. Student's t-test for unpaired data was used for analysis
      of demographics. Chi-square test was used for ST segment changes. Results are
      expressed as mean +/- SD and P < 0.05 was considered to be statistically
      significant. RESULTS: In the control group, 9 patients (30%) were noted to have
      episodes of ischemia preoperatively, 7 patients (23.3%) intraoperatively, and 12
      patients (40%) postoperatively. The occurrence of myocardial ischemia peaked in
      the early postoperative period (P < 0.05). On the contrary, in the clonidine
      group, 10 patients (33.3%) saw ischemic episodes preoperatively, 3 patients (10%)
      intraoperatively and 5 patients (16.7%) postoperatively. The incidence of
      myocardial ischemia in clonidine group was significantly lower than that in
      placebo group in intraoperative and postoperative periods. The mean arterial
      pressure was significantly lower in some clonidine-treated patients during
      perioperative periods (P < 0.05). A number of patients in clonidine group
      suffered from drowsiness (66.7%) after operation (P < 0.05), but they could be
      easily aroused. In regard to dryness of mouth, nausea and vomiting clonidine and
      control groups did not differ much (P > 0.05). Demerol consumption was
      significantly lower in clonidine group (43.7 +/- 4.6 mg) than in control group
      (76.3 +/- 3.7 mg, P < 0.05). CONCLUSIONS: We conclude that premedication with
      oral clonidine can significantly reduce the incidence of perioperative myocardial
      ischemia in patients with CAD undergoing noncardiac surgeries. The incidence of
      myocardial ischemia in these patients is rather high during perioperative period,
      which deserves our exceptional caution.

PMID- 12596620
TI  - Metastatic hepatocellular carcinoma of the right atrium causing right ventricular
      outflow tract obstruction during induction of anesthesia--a case report.
AB  - Metastatic hepatocellular carcinoma (HCC) to the right atrium occurs rarely and
      may lead to lethal perioperative complications. A 61-year-old female who was
      about to undergo operation for resection of a right intraatrial tumor thought
      possibly to be metastatic hepatocellular carcinoma met with sudden protrusion of
      the tumor from the right atrial wall that sank into the right ventricle during
      induction of anesthesia. Right ventricular outflow tract obstruction developed
      and was quickly diagnosed by transesophageal echocardiography. Emergent
      cardiopulmonary bypass was rushed on the spot and the surgery was completed
      smoothly. Here we discuss the possible causes of the event and we recommend that
      special attention should be paid to the anesthetic techniques and proper
      precaution should be taken in the face of such a risky surgery.

PMID- 12596621
TI  - Endotracheal tube fire induced by electrocautery during tracheostomy--a case
      report.
AB  - Airway fire resulting from ignition of the endotracheal tube (ETT) caused by
      electrocautery during tracheostomy is a severe and possibly fatal event, and
      should be avoided. An 88-year-old male because of respiratory failure received
      elective tracheostomy for ventilatory support on which prolonged dependence was
      anticipated. Unfortunately, flame was noted to jet out from the trachea incision
      just after a single burst of electrocautery to coagulate a bleeder in the trachea
      tissue nearby the incision. After primary management, including extinguishing the
      flame and evaluation of the tracheal injury by bronchoscope, a tracheostomy tube
      was inserted smoothly without causing hypoxemia or hemodynamic instability. The
      patient stood this ordeal of fire well without related sequelae and was returned
      from the intensive care unit (ICU) to the general ward two weeks later. From this
      accident, we recommend that, besides emphasis on lowering of the inspired oxygen
      concentration (FiO2) and careful use of electrocautery during the tracheostomy
      procedure, special attention should be paid to the integrality of ETT cuff. It
      serves as a barrier to prevent oxygen leaking out from the trachea to be exposed
      to the sparks of electrocautery while the surgical procedure is under way, and
      thus it plays a significant role in the avoidance of airway fire induced by
      electrocautery.

PMID- 12596622
TI  - Hyperparathyroidism and bone disease after renal transplantation.
AB  - Metabolic bone disease is one of the most frequent complications of chronic renal
      failure. Numerous disorders leading to the metabolic bone disease can be reversed
      by successful renal transplantation. However, in some patients, in spite of
      satisfactory renal function, some disorders may persist for months after
      successful transplantation, e.g. increased parathyroid hormone secretion.
      Besides, drugs used in immunossuppressive therapy may cause metabolic bone
      disease or reduction of of bone mass. Therefore, significant loss of mass takes
      place in the majority of patients during the first six months. Among drugs used
      in the prevention of bone disease after transplantation of solid organs the most
      important role have biphosphonates and vitamin D, i.e. calcitriol.

PMID- 12596624
TI  - Rhegmatogenous retinal detachment and seasonal variations.
AB  - Seasonal variations of rhegmatogenous retinal detachment (RRD) have been reported
      in only several studies, mostly from Central and northern Europe. In this study,
      seasonal incidence of RRD was determined and compared with sunlight exposure per
      season in the Mediterranean region of south Europe. The study was based on a
      retrospective review of medical records on 280 eyes of 272 consecutive hospital
      patients in the district of Split, Croatia, who were treated for primary
      nontraumatic phakic RRD over a 12-year period (1988-1999). The number of eyes
      with RRD recorded per season was 79 in summer, 71 in winter, 67 in spring and 63
      in autumn. The average number of sunshine hours in Split was 1001 in summer, 698
      in spring, 576 in autumn and 457 in winter. No seasonal variations in the
      occurrence of RRD and no correlation with the mean duration of sunlight exposure
      per season were found.

PMID- 12596623
TI  - Randomized trial of azithromycin in the prophylaxis of Mediterranean spotted
      fever.
AB  - A randomized clinical trial was undertaken to compare clinical and serologic
      parameters of the efficacy of one-dose azithromycin in the prophylaxis of
      Mediterranean spotted fever (MSF) in 122 persons with a tick bite history.
      Antibodies to Rickettsia conorii (R. conorii) were detected by indirect
      immunofluorescence (IFA) assay in 55 (45.1%) of 122 subjects. Positive result was
      obtained in 19 (31.1%) of 61 subjects with azithromycin prophylaxis and in 36
      (59.0%) of 61 subjects without prophylaxis. Clinical signs and symptoms of MSF
      were recorded in 6 (9.8%) and asymptomatic infection in 30 (49.2%) of 61 subjects
      without prophylaxis. In subjects with prophylaxis, clinical signs of the disease
      were not recorded at all, whereas asymptomatic infection was detected in 19
      (31.1%) of 61 subjects. Based on the results obtained in our study, we assume
      that a single dose of azithromycin is promising in MSF prevention.

PMID- 12596625
TI  - Manifold significance of serum eosinophil cationic protein in asthmatic children.
AB  - Asthma is the result of complex interaction between different cells, mediators
      and nervous system that leads to an inflammatory response accompanied by
      increased bronchial hyperactivity. Its clinical manifestations include recurrent
      cough, wheezing and difficult breathing. The purpose of this study was to
      establish the possibility of diagnosing inflammation in asthmatic patients based
      on the assessment of serum eosinophil cationic protein (ECP), and of following
      the efficacy of asthmatic treatment by the levels of inflammation mediators. In a
      prospective study, 134 children aged 1 to 18 (mean 8) years underwent serum ECP
      assessment. Experimental group included 87 patients with asthma, 56 boys and 31
      girls, mean age 9.1 (range 2-17) years. Control group included patients with
      recurrent non-allergic disorders, 27 boys and 20 girls aged 1-16 (mean 6.1)
      years. Serum ECP was assessed using the Pharmacia CAP system ECP-FEIA method,
      i.e. fluoroimmunoassay test for quantitative assessment of serum ECP levels.
      Serum values of ECP were significantly higher in asthmatics than in controls (p =
      0.001). Our results showed that increased levels of serum ECP to significantly
      correlate with increased eosinophil (p = 0.018) and immunoglobulin E (p = 0.003)
      levels. Increased ECP levels reflect the degree of inflammation and correlate
      with the clinical picture severity in asthmatic patients. Assessment of serum ECP
      levels can reveal eosinophilic activity, and indirectly detect immunologic
      inflammation in asthmatics. It is possible to follow the dynamics of immunologic
      inflammation during the course of treatment as well as treatment efficacy.

PMID- 12596626
TI  - Fetal shoulder dystocia.
AB  - Shoulder dystocia is an unpredictable obstetric complication with the incidence
      of 0.15% to 2%. An increase in the incidence of shoulder dystocia has been
      recorded over the last 20 years, probably just because it has now been regularly
      registered at maternity wards as an obstetric complication. The risk factors for
      shoulder dystocia include fetal macrosomia, fetal malformations and tumors,
      maternal adiposity, excessive weight gain during pregnancy, diabetes mellitus,
      pathologic pelvis, multiparity, short maternal stature, advanced maternal age,
      postterm pregnancy, so-called midforceps delivery or vacuum extraction, prolonged
      delivery stage II, oxytocin labor induction, premature fetal expression according
      to Kristeller, and previous shoulder dystocia in macrosomatic children. The
      sequels of shoulder dystocia and obstetric maneuvers for incarcerated shoulder
      release include clavicular fracture, brachial plexus lesions, sternocleidomastoid
      muscle distension with or without hematoma, diaphragmatic paralysis, Horner's
      syndrome, peripartal asphyxia and consequential cerebral lesions (cerebral
      palsy), and peripartal death. Maternal complications due to shoulder dystocia are
      postpartal hemorrhage, cervical and vaginal lacerations, frequent infections
      during the puerperium, symphysiolysis and rupture of the uterus, and secondary
      cesarean section with related complications due to unsuccessful obstetric
      procedures or as continuation of Zavanelli's maneuver. McRoberts' maneuver (or
      Gaskin maneuver) is recommended as the initial procedure for shoulder release in
      case of shoulder dystocia. If it fails, other obstetric procedures such as
      Resnik's suprapubic pressure and Woods' grip with posteriorly placed arm release
      should be used, always with gross lateral episiotomy. The performance of all
      these obstetric procedures requires skilfull and highly experienced obstetrician
      and obstetric team as a whole.

PMID- 12596627
TI  - Surgical treatment of mediastinal parathyroid adenoma.
AB  - Ectopic parathyroid adenoma is a frequent cause of persistent or recurrent
      hyperparathyroidism after parathyroidectomy in patients with chronic renal
      failure on dialysis. An unusual anatomic localization of parathyroid adenoma may
      make the diagnosis and surgery difficult. In a 41-year-old woman with chronic
      renal failure, increased serum level of parathyroid hormone and symptoms of
      progressive renal osteodystrophy, mediastinal parathyroid adenoma was detected in
      the aorticopulmonary window by 99m Tc sesta MIBI scintigraphy and transmission
      computed tomography. Extirpation of adenoma, sized 3 x 2 cm, was performed
      through a left thoracotomy. Serum parathormone level returned to normal and the
      patient steadily recovered.

PMID- 12596628
TI  - Retropharyngeal abscess and acute inflammation of the maxillary sinus: transoral
      procedure as a surgical method of treatment.
AB  - A previously healthy man, 65 years of age, was hospitalized for clinical symptoms
      and signs of retropharyngeal abscess. Computed tomography showed an abscess of
      the retropharyngeal space and the presence of liquid content in the paranasal
      sinuses. The patient was completely treated by the administration of combined
      antibiotics, biopsy procedure and aspiration of the contents by the
      retropharyngeal transoral procedure.

PMID- 12596629
TI  - Inertial deposition effects: a study of aerosol mechanics in the trachea using
      laser Doppler velocimetry and fluorescent dye.
AB  - This study characterizes the axial velocity and axial turbulence intensity
      patterns noted in the tracheal portion of a cadaver-based throat model at two
      different steady flow rates (18.1 and 41.1 LPM.) This characterization was
      performed using Phase Doppler Interferometry (Laser Doppler Velocimetry).
      Deposition, as assessed qualitatively using fluorescent dye, is related to the
      position of the laryngeal jet within the trachea. The position of the jet is
      dependent on the downstream conditions of the model. It is proposed therefore
      that lung/airway conditions may have important effects on aerosol deposition
      within the throat. There is no correspondence noted between regions of high axial
      turbulence intensity and deposition.

PMID- 12596630
TI  - Analytical study on bioheat transfer problems with spatial or transient heating
      on skin surface or inside biological bodies.
AB  - Several closed form analytical solutions to the bioheat transfer problems with
      space or transient heating on skin surface or inside biological bodies were
      obtained using Green's function method. The solutions were applied to study
      several selected typical bioheat transfer processes, which are often encountered
      in cancer hyperthermia, laser surgery, thermal comfort analysis, and tissue
      thermal parameter estimation. Thus a straightforward way to quantitatively
      interpret the temperature behavior of living tissues subject to constant,
      sinusoidal, step, point or stochastic heatings etc. both in volume and on
      boundary were established. Further solution to the three-dimensional bioheat
      transfer problems was also given to illustrate the versatility of the present
      method. Implementations of this study to the practical problems were addressed.

PMID- 12596631
TI  - Capillary-elastic instabilities of liquid-lined lung airways.
AB  - To model the competition between capillary and elastic forces in controlling the
      shape of a small lung airway and its interior liquid lining, we compute the
      equilibrium configurations of a liquid-lined, externally pressurized, buckled
      elastic tube. We impose axial uniformity and assume that the liquid wets the tube
      wall with zero contact angle. Non-zero surface tension has a profound effect on
      the tube's quasi-steady inflation-deflation characteristics. At low liquid
      volumes, hysteresis arises through two distinct mechanisms, depending on the
      buckling wavenumber. Sufficient compression always leads to abrupt and
      irreversible collapse and flooding of the tube; flooding is promoted by
      increasing liquid volumes or surface tension. The model captures mechanisms
      whereby capillary-elastic instabilities can lead to airway closure.

PMID- 12596633
TI  - Low background, pulsatile, in vitro flow circuit for modeling coronary implant
      thrombosis.
AB  - We have developed an in vitro method for creating pulsatile flows to mimic
      coronary type flow patterns on a beat-to-beat basis. The flow is created by
      accelerating fluid loops about an axis, inducing relative wall motion. Using this
      technique, a variety of oscillating flow patterns can be generated and modulated.
      Such flow generation offers the potential to monitor sensitive, flow-dependent,
      biological parameters like thrombosis while minimizing background disturbances
      from pump action and circuit effects. We examined this potential by measuring the
      loop occlusion time for loops stented with stainless steel 7-9 NIR stents and
      stentless control loops.

PMID- 12596632
TI  - Experimental measurements of the temperature variation along artery-vein pairs
      from 200 to 1000 microns diameter in rat hind limb.
AB  - Theoretical studies have indicated that a significant fraction of all blood
      tissue heat transfer occurs in artery-vein pairs whose arterial diameter varies
      between 200 and 1000 microns. In this study, we have developed a new in vivo
      technique in which it is possible to make the first direct measurements of the
      countercurrent thermal equilibration that occurs along thermally significant
      vessels of this size. Fine wire thermocouples were attached by superglue to the
      femoral arteries and veins and their subsequent branches in rats and the axial
      temperature variation in each vessel was measured under different physiological
      conditions. Unlike the blood vessels < 200 microns in diameter, where the blood
      rapidly equilibrates with the surrounding tissue, we found that the thermal
      equilibration length of blood vessels between 200 microns and 1000 microns in
      diameter is longer than or at least equivalent to the vessel length. It is shown
      that the axial arterial temperature decays from 44% to 76% of the total core-skin
      temperature difference along blood vessels of this size, and this decay depends
      strongly on the local blood perfusion rate and the vascular geometry. Our
      experimental measurements also showed that the SAV venous blood recaptured up to
      41% of the total heat released from its countercurrent artery under normal
      conditions. The contribution of countercurrent heat exchange is significantly
      reduced in these larger thermally significant vessels for hyperemic conditions as
      predicted by previous theoretical analyses. Results from this study, when
      combined with previous analyses of vessel pairs less than 200 microns diameter,
      enable one estimate the arterial supply temperature and the correction
      coefficient in the modified perfusion source term developed by the authors.

PMID- 12596634
TI  - Infrared imaging of 2-D temperature distribution during cryogen spray cooling.
AB  - Cryogen spray cooling (CSC) is used in conjunction with pulsed laser irradiation
      for treatment of dermatologic indications. The main goal of this study was to
      determine the radial temperature distribution created by CSC and evaluate the
      importance of radial temperature gradients upon the subsequent analysis of tissue
      cooling throughout the skin. Since direct measurement of surface temperatures
      during CSC are hindered by the formation of a liquid cryogen layer, temperature
      distributions were estimated using a thin, black aluminum sheet. An infrared
      focal plane array camera was used to determine the 2-D backside temperature
      distribution during a cryogen spurt, which preliminary measurements have shown is
      a good indicator of the front-side temperature distribution. The measured
      temperature distribution was approximately gaussian in shape. Next, the transient
      temperature distributions in skin were calculated for two cases: 1) the standard
      1-D solution which assumes a uniform cooling temperature distribution, and 2) a 2
      D solution using a nonuniform surface cooling temperature distribution based upon
      the back-side infrared temperature measurements. At the end of a 100-ms cryogen
      spurt, calculations showed that, for the two cases, large discrepancies in
      temperatures at the surface and at a 60-micron depth were found at radii greater
      than 2.5 mm. These results suggest that it is necessary to consider radial
      temperature gradients during cryogen spray cooling of tissue.

PMID- 12596635
TI  - Injection of highly supersaturated oxygen solutions without nucleation.
AB  - It is possible to inject highly supersaturated aqueous solutions of gas through a
      small capillary into an aqueous environment without the formation of significant
      gas bubbles. Such a technique has considerable potential therapeutic value in the
      treatment, for example, of heart attacks and strokes. The present paper is the
      second in a series (see Brereton et al. [1]) investigating the basic phenomenon
      behind this surprising effect. Recent experiments clearly demonstrate that the
      nucleation, when it does occur, results from heterogeneous nucleation on the
      interior surface of the distal end of the capillary. This paper describes the
      effects of the treatment of this interior surface on the nucleation processes and
      the results of high speed video observations of the phenomena. A heterogeneous
      nucleation model is presented which is in accord with the experimental
      observations.

PMID- 12596636
TI  - Two-dimensional maps of short-term albumin uptake by the immature and mature
      rabbit aortic wall around branch points.
AB  - In children, aortic lipid deposition develops in triangular regions of the wall
      downstream of branch points, whilst in adults these regions are particularly free
      of disease. Comparable age-related patterns occur in rabbit aortas. They may be
      explained by patterns of wall permeability to circulating macromolecules: along
      the longitudinal midline through branches, permeability is greater downstream
      than upstream in immature rabbits, but is greater upstream at later ages. Here we
      have mapped permeability in detail around such branches, not just along the
      midline. Short-term uptake of rhodamine-labeled albumin, measured using digital
      imaging fluorescence microscopy of serial sections, was greatest in an
      approximately triangular region downstream of immature branches, but in mature
      animals it was greater upstream, particularly away from the midline, and in
      streaks to the side of branches. Hence the maps are consistent with earlier
      permeability data and closely resemble the patterns of disease.

PMID- 12596637
TI  - Local head roughening as a factor contributing to variability of total hip wear:
      a finite element analysis.
AB  - Large inter-patient variability in wear rate and wear direction have been a
      ubiquitous attribute of total hip arthroplasty (THA) cohorts. Since patients at
      the high end of the wear spectrum are of particular concern for osteolysis and
      loosening, it is important to understand why some individuals experience wear at
      a rate far in excess of their cohort average. An established computational model
      of polyethylene wear was used to test the hypothesis that, other factors being
      equal, clinically typical variability in regions of localized femoral head
      roughening could account for much of the variability observed clinically in both
      wear magnitude and wear direction. The model implemented the Archard
      abrasive/adhesive wear relationship, which incorporates contact stress, sliding
      distance, and (implicitly) bearing surface tribology. Systematic trials were
      conducted to explore the influences of head roughening severity, roughened area
      size, and roughened area location. The results showed that, given the postulated
      wear factor elevations, head roughening variability (conservatively) typical of
      retrieval specimens led to approximately a 30 degrees variation in wear
      direction, and approximately a 7-fold variation in volumetric wear rate. Since
      these data show that randomness in head scratching can account for otherwise
      difficult-to-explain variations in wear direction and wear rate, third-body
      debris may be a key factor causing excessive wear in the most problematic subset
      of the THA population.

PMID- 12596638
TI  - Biaxial failure behavior of bovine tibial trabecular bone.
AB  - Multiaxial failure properties of trabecular bone are important for modeling of
      whole bone fracture and can provide insight into structure-function
      relationships. There is currently no consensus on the most appropriate form of
      multiaxial yield criterion for trabecular bone. Using experimentally validated,
      high-resolution, non-linear finite element models, biaxial plain strain boundary
      conditions were applied to seven bovine tibial specimens. The dependence of
      multiaxial yield properties on volume fraction was investigated to quantify the
      interspecimen heterogeneity in yield stresses and strains. Two specimens were
      further analyzed to determine the yield properties for a wide range of biaxial
      strain loading conditions. The locations and quantities of tissue level yielding
      were compared for on-axis, transverse, and biaxial apparent level yielding to
      elucidate the micromechanical failure mechanisms. As reported for uniaxial
      loading of trabecular bone, the yield strains in multiaxial loading did not
      depend on volume fraction, whereas the yield stresses did. Micromechanical
      analysis indicated that the failure mechanisms in the on-axis and transverse
      loading directions were mostly independent. Consistent with this, the biaxial
      yield properties were best described by independent curves for on-axis and
      transverse loading. These findings establish that the multiaxial failure of
      trabecular bone is predominantly governed by the strain along the loading
      direction, requiring separate analytical expressions for each orthotropic axis to
      capture the apparent level yield behavior.

PMID- 12596639
TI  - Spatial micromovements of uncemented femoral components after torsional loads.
AB  - A novel method is presented which permits to assess implanted femoral components
      with regards to location of fixation and initial stability under cyclic torsional
      loads. The measurement apparatus tracks the spatial movement at several sites of
      stem and bone, allowing quantitative analysis of the micromotions and twisting of
      stem and bone, and the location of torque (force) transfer. Four types of
      prostheses were compared, which revealed striking differences in torque transfer.
      Our results for synthetic femurs are consistent with in vivo data on the
      osseointegration and radiolucensies observed for the stem types of this study.
      The method can be used to quantitatively compare various stem designs and
      implantation techniques.

PMID- 12596640
TI  - Accuracy of elastic property measurement in mandibular cortical bone is improved
      by using cylindrical specimens.
AB  - Ultrasonic determination of elastic properties in human craniofacial cortical
      bone is problematic because of a lack of information about the principal material
      axes, and because the cortex is often thinner than in long bones. This study
      investigated solutions that permit reasonable determination of elastic properties
      in the human mandible. We tested whether ultrasonic velocities could be reliably
      measured in cylindrical samples of aluminum and mandibular bone, and the effects
      of reduced specimen thickness. Results indicted that (1) varying shape had
      minimal effects on ultrasonic velocities or derived elastic properties, and (2)
      ultrasonic velocities have relatively increased measurement error as propagation
      distances decreased. The increased error in velocity measurements of mandibular
      cortical specimens of less than 1.2 mm in thickness should be considered when
      assessing the reliability of single measurements.

PMID- 12596641
TI  - Manipulation of remodeling pathways to enhance the mechanical properties of a
      tissue engineered blood vessel.
AB  - There is a current need for a small diameter vascular graft due to the limited
      supply of autogenous grafts and the failure of synthetic grafts due to thrombosis
      and/or intimal hyperplasia. The use of living cells and tissues to fabricate a
      small diameter graft (i.e., tissue engineered blood vessel, TEBV) could be useful
      given the endothelialization potential and biocompatibility benefits of such a
      graft. However, while sufficient strength has been attained in a TEBV, coordinate
      compliance has yet to be fine-tuned. In this study we investigate the effects of
      biological response modifiers, retinoic acid (RA) and ascorbic acid (AA) on TEBV
      biomechanics as a function of time and subsequently correlate observed RA/AA
      induced changes in TEBV mechanics with alterations in smooth muscle cell (SMC)
      biochemistry. TEBVs were constructed using a fibrillar type I collagen network
      populated by human aortic smooth muscle cells (AoSMC). Following construction
      this TEBV was treated with 0.3 mM AA and 0.1 mM RA (concentrations found to
      induce changes in VSMC phenotype). Ultimate tensile stress (UTS), rate of
      relaxation (RR) and elastic efficiency (EE) of RA/AA treated and untreated TEBVs
      were measured following 1, 7, 15, 30, 45, and 60 days of treatment. At
      corresponding time points, the effect of these treatments on collagen and elastin
      protein synthesis and mRNA expression was examined. RA/AA treated TEBV strength
      increased and stiffness decreased compared to controls as a function of time.
      Relative collagen synthesis in treated TEBVs exceeded control levels by nearly
      two-fold at 15 and 30 days of incubation. RA/AA treated collagen gene expression
      followed a similar trend. Relative elastin synthesis was also greater in treated
      TEBVs as compared to untreated TEBVs at 15 and 30 days of incubation and
      correspondingly elastin mRNA expression was significantly elevated at 15 days of
      incubation. These data provide evidence that RA/AA treated TEBVs exhibit
      mechanical properties which more closely mimic those of a native vessel than
      their untreated counterparts and that changes in extracellular matrix composition
      and matrix gene expression in the presence of RA/AA treatment may play an
      important role in the development of said mechanical properties.

PMID- 12596642
TI  - Strain measurement in coronary arteries using intravascular ultrasound and
      deformable images.
AB  - Atherosclerotic plaque rupture is responsible for the majority of myocardial
      infarctions and acute coronary syndromes. Rupture is initiated by mechanical
      failure of the plaque cap, and thus study of the deformation of the plaque in the
      artery can elucidate the events that lead to myocardial infarction. Intravascular
      ultrasound (IVUS) provides high resolution in vitro and in vivo cross-sectional
      images of blood vessels. To extract the deformation field from sequences of IVUS
      images, a registration process must be performed to correlate material points
      between image pairs. The objective of this study was to determine the efficacy of
      an image registration technique termed Warping to determine strains in plaques
      and coronary arteries from paired IVUS images representing two different states
      of deformation. The Warping technique uses pointwise differences in pixel
      intensities between image pairs to generate a distributed body force that acts to
      deform a finite element model. The strain distribution estimated by image-based
      Warping showed excellent agreement with a known forward finite element solution,
      representing the gold standard, from which the displaced image was created. The
      Warping technique had a low sensitivity to changes in material parameters or
      material model and had a low dependency on the noise present in the images. The
      Warping analysis was also able to produce accurate strain distributions when the
      constitutive model used for the Warping analysis and the forward analysis was
      different. The results of this study demonstrate that Warping in conjunction with
      in vivo IVUS imaging will determine the change in the strain distribution
      resulting from physiological loading and may be useful as a diagnostic tool for
      predicting the likelihood of plaque rupture through the determination of the
      relative stiffness of the plaque constituents.

PMID- 12596643
TI  - Advanced bioreactor with controlled application of multi-dimensional strain for
      tissue engineering.
AB  - Advanced bioreactors are essential for meeting the complex requirements of in
      vitro engineering functional skeletal tissues. To address this need, we have
      developed a computer controlled bench-top bioreactor system with capability to
      apply complex concurrent mechanical strains to three-dimensional matrices
      independently housed in 24 reactor vessels, in conjunction with enhanced
      environmental and fluidic control. We demonstrate the potential of this new
      system to address needs in tissue engineering, specifically toward the
      development of a tissue engineered anterior cruciate ligament from human bone
      marrow stromal cells (hBMSC), where complex mechanical and biochemical
      environment control is essential to tissue function. Well-controlled mechanical
      strains (resolution of < 0.1 micron for translational and < 0.1 degree for
      rotational strain) and dissolved oxygen tension (between 0%-95% +/- 1%) could be
      applied to the developing tissue, while maintaining temperature at 37 +/- 0.2
      degrees C about developing tissue over prolonged periods of operation. A total of
      48 reactor vessels containing cell culture medium and silk fiber matrices were
      run for up to 21 days under 90 degrees rotational and 2 mm translational
      deformations at 0.0167 Hz with only one succumbing to contamination due to a leak
      at an medium outlet port. Twenty-four silk fiber matrices seeded with human bone
      marrow stromal cells (hBMSCs) housed within reactor vessels were maintained at
      constant temperature (37 +/- 0.2 degrees C), pH (7.4 +/- 0.02), and pO2 (20 +/-
      0.5%) over 14 days in culture. The system supported cell spreading and growth on
      the silk fiber matrices based on SEM characterization, as well as the
      differentiation of the cells into ligament-like cells and tissue (Altman et al.,
      2001).

PMID- 12596644
TI  - The axial injury tolerance of the human foot/ankle complex and the effect of
      Achilles tension.
AB  - Axial loading of the foot/ankle complex is an important injury mechanism in
      vehicular trauma that is responsible for severe injuries such as calcaneal and
      tibial pilon fractures. Axial loading may be applied to the leg externally, by
      the toepan and/or pedals, as well as internally, by active muscle tension applied
      through the Achilles tendon during pre-impact bracing. The objectives of this
      study were to investigate the effect of Achilles tension on fracture mode and to
      empirically model the axial loading tolerance of the foot/ankle complex. Blunt
      axial impact tests were performed on forty-three (43) isolated lower extremities
      with and without experimentally simulated Achilles tension. The primary fracture
      mode was calcaneal fracture in both groups. However, fracture initiated at the
      distal tibia more frequently with the addition of Achilles tension (p < 0.05).
      Acoustic sensors mounted to the bone demonstrated that fracture initiated at the
      time of peak local axial force. A survival analysis was performed on the injury
      data set using a Weibull regression model with specimen age, gender, body mass,
      and peak Achilles tension as predictor variables (R2 = 0.90). A closed-form
      survivor function was developed to predict the risk of fracture to the foot/ankle
      complex in terms of axial tibial force. The axial tibial force associated with a
      50% risk of injury ranged from 3.7 kN for a 65 year-old 5th percentile female to
      8.3 kN for a 45 year-old 50th percentile male, assuming no Achilles tension. The
      survivor function presented here may be used to estimate the risk of foot/ankle
      fracture that a blunt axial impact would pose to a human based on the peak tibial
      axial force measured by an anthropomorphic test device.

PMID- 12596645
TI  - The effect of vastus medialis forces on patello-femoral contact: a model-based
      study.
AB  - A mathematical model of the patello-femoral joint was introduced to investigate
      the impact of the vastus medialis (longus, obliquus) forces on the lateral
      contact force levels. In the model, the quadriceps were represented as five
      separate forces: vastus lateralis, vastus intermedius, rectus femoris, vastus
      medialis longus (VML), and obliquus (VMO). By varying the relative force
      generation ratios of the quadriceps heads, the patello-femoral contact forces
      were estimated. We sought to analytically determine the range of forces in the
      VMO and VML that cause a reduction or an increase of lateral contact forces,
      often the cause of patello-femoral pain. Our results indicated that increased
      contact forces are more dependent on combinations of muscle forces than solely
      VMO weakness. Moreover, our simulation data showed that the contact force levels
      are also highly dependent on the knee flexion angle. These findings suggest that
      training targeted to reduce contact forces through certain joint angles could
      actually result in a significant increase of the contact forces through other
      joint angles.

PMID- 12596646
TI  - In vitro measurement of the restraining role of the anterior cruciate ligament
      during walking and stair ascent.
AB  - The study aimed to test the hypothesis that the restraining role of the anterior
      cruciate ligament (ACL) of the knee is significant during the activities of
      normal walking and stair ascent. The role of the ACL was determined from the
      effect of ACL excision on tibiofemoral displacement patterns measured in vitro
      for fresh-frozen knee specimens subjected to simulated knee kinetics of walking
      (n = 12) and stair ascent (n = 7). The knee kinetics were simulated using a newly
      developed dynamic simulator able to replicate the sagittal-plane knee kinetics
      with reasonable accuracy while ensuring unconstrained tibiofemoral kinematics.
      The displacements were measured using a calibrated six degree-of-freedom
      electromechanical goniometer. For the simulation of the walking cycle, two types
      of knee flexion/extension moment patterns were used: the more common "biphasic"
      pattern, and an extensor muscle force intensive pattern. For both of these
      patterns, the restraining role of the ACL to tibial anterior translation was
      found to be significant throughout the stance phase and in the terminal swing
      phase, when the knee angle was in the range of 4 degrees to 30 degrees. The
      effect of ACL excision was an increase in tibial anterior translation by 4 mm to
      5 mm. For the stair ascent cycle, however, the restraining role of the ACL was
      significant only during the terminal stance phase, and not during the initial and
      middle segments of the phase. Although, in these segments, the knee moments were
      comparable to that in walking, the knee angle was in the range of 60 degrees to
      70 degrees. These results have been shown to be consistent with available data on
      knee mechanics and ACL function measured under static loading conditions.

PMID- 12596647
TI  - Survival of biological cells deformed in a narrow gap.
AB  - Recent studies show that during slow freezing of biological cells, the cells may
      be also injured by not only chemical damage but also mechanical damage induced by
      ice crystal compression. A new experimental procedure is developed to quantify
      cell destruction by deformation with two parallel surfaces. The viability of
      cells (prostatic carcinoma cells, 17.5 microns in mean diameter) is measured as a
      function of gap size ranging from 3.5 microns to 16.2 microns at 0 degree C, 23
      degrees C and 37 degrees C. The viability at a smaller gap size is significantly
      lower at 37 degrees C than at 23 degrees C, while the difference between 0 degree
      C and 23 degrees C is much smaller. This suggests that deformation damage is
      related to the deformation of the cytoskeleton rather than the mechanical
      properties of the lipid membrane.

PMID- 12596648
TI  - Simulation of progressive deformities in adolescent idiopathic scoliosis using a
      biomechanical model integrating vertebral growth modulation.
AB  - While the etiology and pathogenesis of adolescent idiopathic scoliosis are still
      not well understood, it is generally recognized that it progresses within a
      biomechanical process involving asymmetrical loading of the spine and vertebral
      growth modulation. This study intends to develop a finite element model
      incorporating vertebral growth and growth modulation in order to represent the
      progression of scoliotic deformities. The biomechanical model was based on
      experimental and clinical observations, and was formulated with variables
      integrating a biomechanical stimulus of growth modulation along directions
      perpendicular (x) and parallel (y, z) to the growth plates, a sensitivity factor
      beta to that stimulus and time. It was integrated into a finite element model of
      the thoracic and lumbar spine, which was personalized to the geometry of a female
      subject without spinal deformity. An imbalance of 2 mm in the right direction at
      the 8th thoracic vertebra was imposed and two simulations were performed: one
      with only growth modulation perpendicular to growth plates (Sim1), and the other
      one with additional components in the transverse plane (Sim2). Semi-quantitative
      characterization of the scoliotic deformities at each growth cycle was made using
      regional scoliotic descriptors (thoracic Cobb angle and kyphosis) and local
      scoliotic descriptors (wedging angle and axial rotation of the thoracic apical
      vertebra). In all simulations, spinal profiles corresponded to clinically
      observable configurations. The Cobb angle increased non-linearly from 0.3 degree
      to 34 degrees (Sim1) and 20 degrees (Sim2) from the first to last growth cycle,
      adequately reproducing the amplifying thoracic scoliotic curve. The sagittal
      thoracic profile (kyphosis) remained quite constant. Similarly to clinical and
      experimental observations, vertebral wedging angle of the thoracic apex
      progressed from 2.6 degrees to 10.7 degrees (Sim1) and 7.8 degrees (Sim2) with
      curve progression. Concomitantly, vertebral rotation of the thoracic apex
      increased of 10 degrees (Sim1) and 6 degrees (Sim2) clockwise, adequately
      reproducing the evolution of axial rotation reported in several studies. Similar
      trends but of lesser magnitude (Sim2) suggests that growth modulation parallel to
      growth plates tend to counteract the growth modulation effects in longitudinal
      direction. Overall, the developed model adequately represents the self-sustaining
      progression of vertebral and spinal scoliotic deformities. This study
      demonstrates the feasibility of the modeling approach, and compared to other
      biomechanical studies of scoliosis it achieves a more complete representation of
      the scoliotic spine.

PMID- 12596649
TI  - Apparatus for measuring the swelling dependent electrical conductivity of charged
      hydrated soft tissues.
AB  - This paper describes a new apparatus and method for measuring swelling dependent
      electrical conductivity of charged hydrated soft tissues. The apparatus was
      calibrated using a conductivity standard. Swelling dependent specific
      conductivity of porcine annulus fibrosis (AF) samples was determined. The
      conductivity values for porcine AF were similar to those for human and bovine
      articular cartilage found in the literature. Results revealed a significant
      linear correlation between specific conductivity and water content for porcine AF
      tissues tested in phosphate buffered saline (PBS).

PMID- 12596651
TI  - Pattern of articles published in the Ethiopian Medical Journal.
AB  - Five Hundred and Thirty Nine articles published between January 1984 and December
      2000 in the Ethiopian Medical Journal were analysed to assess the research
      pattern and the citations of published articles. Hand-in-hand search of the
      journals and the Science Citation Index database were used. Majority (69%) of the
      articles were original articles. The median number of authors per article was 2
      with a range of 9 (Maximum 10 and Minimum 1). Majority of first authors were
      affiliated to teaching institutions (69.6%). Foreign nationals were first authors
      in 19.9% and co-authors in 26.7% of the articles. Multiple authored articles [OR
      (95% CI) = 1.17 (1.03-1.33)], original articles [OR (95% CI) = 12.0 (4.43-32.48)
      and articles dealing with intestinal parasites [OR (95% CI) = 3.88 (1.24-12.08)]
      were more likely to be cited. Although, encouraging efforts were seen in
      addressing issues of public health importance in the last five years (1996-2000)
      of the study period, the findings of the study suggest that there is still a need
      to address them in a more vigorous way. It was also recommended efforts should be
      initiated to improve the citation of articles published by the Ethiopian Medical
      Journal and enhance the publication of editorials and brief communications.

PMID- 12596652
TI  - Semen quality of suspected infertile Ethiopians at Family Guidance Association of
      Ethiopia (FGAE) Central Clinic, Addis Ababa: a retrospective review.
AB  - Abnormal semen quality is often associated with male infertility. The objective
      of this retrospective study was to determine the quality of semen in suspected
      infertile Ethiopians. All individual infertility records from Jan. 1, 1991 to
      June 30, 1995 were retrieved and the first semen analysis results of 914 subjects
      were analyzed. Other information like demographic data and VDRL test results were
      also collected. Ninety males (10%) came themselves first for infertility
      investigation while the rest were approached through their female partners. Town
      dwellers were 89% and 61% had secondary and above educational level, but only
      11.2% gave history of use of fertility period. There were 913 semen specimen
      examined since one was aspermic. Of the total, only 30% semen specimens were
      normal in all the parameters. The remaining (70%) had abnormalities in one or
      more parameters; like azoospermia 26%, asthenozoospermia 31%, hypovolemia 47% and
      their combinations. Among the spermatozoa identified sample group (673),
      asthenozoospermia and oligospermia make 42% and 11% respectively. The frequent
      association of hypooligospermia with other parameter abnormalities was noted. The
      review indicated poor quality of semen parameters but needs further research
      under quality controlled standard analysis for international comparison.

PMID- 12596653
TI  - Efficacy of alebendazole and mebendazole in the treatment of Ascaris and
      Trichuris infections.
AB  - This study was conducted to evaluate the efficacy of 100 mg mebendazole
      administered twice a day for three consecutive days and a single dose of 400 mg
      albendazole for the treatment of single or mixed Ascaris lumbricoides and
      Trichuris trichiura infections. Both drugs were found to be highly effective
      against Ascaris lumbricoides infection, with cure rate of over 96% and egg
      reduction of over 99.8%. However, the efficacy of the two drugs against Trichuris
      trichiura infection was low. Mebendazole appeared to be more effective against
      Trichuris trichiura in that it exhibited a cure rate of 34.7% and egg reduction
      of 92.3% as opposed to albendazole, which exhibited a cure rate and egg reduction
      rate of 13.9% and 63.4%, respectively. The two drugs appeared to have little
      effect on Schistosoma mansoni infection. More complaints were reported by
      individuals treated with albendazole than with mebendazole. In conclusion,
      mebendazole appears to be safer and more effective for the treatment of single or
      mixed infections with Trichuris trichiura and Ascaris lumbricoides as compared to
      albendazole.

PMID- 12596654
TI  - Some factors affecting prevalence of and immune responses to Schistosoma mansoni
      in schoolchildren in Gorgora, northwest Ethiopia.
AB  - There are population variations in human immune responses to infection with
      Schistosoma mansoni prior to and following treatment. The aims of the present
      study were a) to study some of the factors correlating with antibody levels
      against the parasite infection, b) to determine whether there were changes in
      antibody responses to the parasite in infected young people following drug
      treatment, and c) to identify some of the social, demographic and clinical
      factors associated with infection in this age group. The study population
      comprised 10 to 14 year old children attending Gorgora Primary School. One
      hundred sixty fife of the 325 children screened by Kato smear were found to be
      excreting S. mansoni eggs, a prevalence of 50.8%. The infected children were
      treated with Praziquantel, and examined for infection six weeks later. Levels of
      IgG and IgA antiworm antibodies were determined by ELISA from blood samples drawn
      prior to and six weeks after treatment. IgG antibody titres in the infected
      children were higher in the older children and were higher in males than in
      females. Antibody titres did not show significant change six weeks after
      treatment. A significantly higher proportion of the boys is infected, and the
      infected boys had higher egg counts than the infected girls. There was no
      correlation between egg excretion and any of the clinical symptoms measured. The
      age of the children significantly affected prevalence, whereas sex and swimming
      habit had only marginal effects. Place of residence, clinical profiles and
      presence of other parasites did not affect prevalence. Male sex and older age
      were associated with higher IgG titer to parasite antigens.

PMID- 12596655
TI  - Isolation of potential bacterial pathogens from the stool of HIV-infected and HIV
      non-infected patients and their antmicrobial susceptibility patterns in Jimma
      Hospital, south west Ethiopia.
AB  - Diarrhea is a major clinical problem in HIV-infected patients. There is a need to
      monitor antimicrobial susceptibility patterns of enteric bacterial pathogens in
      order to ensure appropriate treatment and control of infections. The objectives
      of this study was to identify and determine the magnitude of potential enteric
      pathogens including Salmonella, Shigella, Campylobacter and other species in HIV
      infected and HIV-non-infected patients with diarrhea, to evaluate the current
      antimicrobial susceptibility pattern of the clinical isolates and the association
      of enteric bacterial pathogens in HIV infected patients with diarrhea. A cross
      sectional study was conducted from Feb-July 2001 on 372 consecutive HIV
      seropositive and seronegative patients presenting at Jimma hospital for different
      illnesses. Patients were selected based on their serological tests for HIV.
      Sample of faeces specimens were collected and inoculated onto standard culture
      media as well as onto Skirrow's medium for isolation of Campylobacter species.
      Salmonella and Shigella species were tested for antimicrobial susceptibility
      using disc agar diffusion technique recommended by Kirby-Bauer. Stool specimens
      were also smeared and stained by Zehl-Neelson staining technique for the
      identification of Mycobacterium species. Among the 99 HIV-infected patients with
      diarrhea, 25 (25.0%) of them had enteric bacteria among which 8(8.1%) were
      Salmonella, 4(4.0%) Shigella and 13(13.1%) Campylobacter species. Mycobacterium
      species were identified in 3(3.0%) of stool specimens obtained from HIV-infected
      patients with diarrhea and another 3 species were detected in HIV-infected
      patient without diarrhea. Salmonella species were isolated with higher prevalence
      in HIV-infected than in HIV non-infected patients. These Salmonella isolates were
      100% susceptible to Amikacin, Gentamicin, Nalidixic acid and Kanamycin while
      Shigella isolates were 100% susceptible for Gentamycin and Kanamycin only. Unlike
      Salmonella, Shigella and Campylobacter species showed higher prevalence rates in
      HIV non-infected patients. Enteric bacterial pathogens account for about one
      fourth diarrhea in HIV infected patients in Jimma hospital. The finding of this
      investigation also confirmed earlier observations of wide spread resistance to
      the commonly used drugs in this region.

PMID- 12596656
TI  - Mothers' knowledge and belief on breast feeding.
AB  - It is believed that breastfeeding is universally practiced, however, mothers'
      knowledge and belief towards breastfeeding and related conditions is not well
      known. A cross-sectional survey was thus conducted in 1998 in Adigrat town, to
      assess the knowledge and belief of mothers towards breastfeeding. The study was
      carried-out on 317 mother-child pairs of 0-2 years old children. The conventional
      cluster sampling technique was utilized to select the study subjects. Almost all
      mothers, 308(92%) of them considered human milk as the best milk for good child
      growth compared to cow's milk and/or formula milk. A higher proportion, 253 (80%)
      of mothers considered breast milk alone sufficient enough to feed a baby up to
      the age of 6 months. The majority, 310 (97%) suggested not to breast feed when a
      mother gets pregnant. Three quarters of mothers preferred not to breast feed when
      the mother gets sick. The majority, 288 (91%) of mothers suggested not to breast
      feed when the child gets sick. In conclusion though mothers value breast milk as
      the best child feed, their knowledge and belief towards breastfeeding the child
      when the baby/mother gets sick, and the mother gets pregnant is very poor. These
      are potentially harmful beliefs, which could lead to the dangerous practice of
      abrupt cessation. These harmful beliefs should be well addressed and minimized
      through continuous health education.

PMID- 12596657
TI  - Sociodemographic differentials of adult death in a rural population.
AB  - Mortality rates in this country are very high, but most of the deaths occur
      unattended by a health worker and hence pass unrecorded. As a result, there is a
      critical lack of information to make sound judgement on what kind of
      interventions are needed to reduce the high toll of death. This case-control
      study was conducted in the Meskan and Mareko District, in the ten kebeles that
      are under continuous demographic surveillance by the Butajira Rural Health
      Program (BRHP). Included in the study were 515 cases, of which 49.3% were females
      and 50.7% were males, and 785 controls, of which 52.1% were females and 47.9%
      males. The most important sociodemographic factors that were found to influence
      adult death were single marital status (OR 1.63; 95% CI: 1.13, 2.35), having no
      educated person in the family (OR 1.91; 95% CI 1.11, 3.29), not having gainful
      occupation (OR 1.40; 95% CI 1.01, 1.82), and perceived poor and very poor
      economic status (OR 1.97; 95% CI 1.31, 2.94 and OR 2.98, 95% CI 1.73, 5.13,
      respectively). The male sex (OR 1.46; 95% CI 1.09, 1.95) and living in the rural
      lowlands (OR 1.54; 95% CI 1.03, 2.31) are also significantly associated with
      adult mortality. This study revealed that many of the factors associated with
      adult mortality are related to poor socio-economic conditions and to the
      prevailing under development of the rural areas.

PMID- 12596658
TI  - Satisfaction on outpatient services in hospitals of the Amhara Region.
AB  - A cross sectional survey was conducted to assess patients' satisfaction on
      outpatient services in the hospitals of the Amara Region. A total of 898 patients
      from nine hospitals were interviewed on exit. The majority (95.9%) had come due
      to illness, and of which, 53.2% had illnesses that lasted for more than 30 days.
      Among those who were sick, 47.5% were non-paying (free) patients. Long waiting
      hours during registration, visiting of doctors after registration, laboratory
      procedures, and revisiting of the doctors for evaluation with laboratory results
      and obtaining drugs from pharmacies were associated with dissatisfaction. When
      logistic regression was applied, waiting time for registration, physician
      consultation/examination, obtaining the prescribed drugs from the pharmacies, and
      overall time taken to receive prescriptions were associated with dissatisfaction.
      Among the sociodemographic factors, age was associated with dissatisfaction. More
      than one-third of the patients did not get the medications prescribed in the
      hospital pharmacies. Failure to find the prescribed drugs was associated with
      dissatisfaction. Unnecessary patient delays should be reduced to the minimum by
      assessing hospitals' processes. Ensuring drug supply with facilitated
      administrative processes is recommended.

PMID- 12596659
TI  - Multifocal vertebral tuberculosis with the involvement of the ribs case report.
AB  - A case of multifocal vertebral tuberculosis with lytic involvement of multiple
      ribs and cold abscess is presented. The lungs were normal and the radiographic
      appearance of the skeletal lesions mimicked secondary metastasis of unknown
      primary site, malignant lymphoma and multiple myeloma. HIV serology was negative.
      Tuberculosis should be high in the differential diagnosis of multiple destructive
      bone lesions especially in patients from regions where tuberculosis is endemic.
      The patient's response to standard antituberculous treatment was favorable.
      Medline data base search revealed that multifocal osteoarticular tuberculosis is
      not associated with HIV infection unlike other forms of extrapulmonary
      tuberculosis.

PMID- 12596662
TI  - HIV-1 vaccine research and development in Ethiopia.

PMID- 12596660
TI  - Posterior fossa tumor presenting with bilateral proptosis and blindness.
AB  - It is very unusual for a posterior fossa tumor to present with proptosis. A 24
      years old female patient who had a CT Scan proven posterior fossa tumor presented
      with severe headache, bilateral proptosis and blindness is reported. The rarity
      of the cause of proptosis and blindness and also the difficulty in reaching at
      the clinical diagnosis is discussed.

PMID- 12596663
TI  - [Selection for disease and epidemic resistance in domestic ruminants and swine by
      indicator traits, marker and causal genes--a review. Part 2: Special
      immunogenetics of sheep and goats with particular regard for endoparasitoses,
      scrapie, foot rot and maedi-visna virus infection].
AB  - The introduction of the first part deals with immunogenetic investigations on the
      field of life-stock. The main chapter is outlined as a tabular overview of
      current opportunities of the application of indicator traits as well as marker
      and causal genes in breeding for disease resistance in cattle, sheep, goats and
      swine. In the discussion of the second part, emphasis was laied on diseases of
      small ruminants in central and western Europe with special respect of
      endoparasitoses, scrapie, foot-rot and maedi-visna virus infection. Indicator
      traits are discussed with respect of their advantages and disadvantages. The
      rigorous selection on specific traits is connected with an increase of the number
      of homozygotes. In contrary, pathogens do undergo mutations, thus escaping the
      host's immune system. Out of this point of view it is advisable, to set on
      selection very cautiously. The role of technologies of modern immunogenetics is
      pointed out in respect of constructing disease resistant animals.

PMID- 12596664
TI  - [Effects of muscle needle biopsy on parameters of humoral and cellular immunity
      in pigs].
AB  - The shot biopsy is a common experimental technique for the collection of samples
      to investigate muscle tissue characteristics or to determine meat quality
      features in pigs. Its application seems to be also possible in interdisciplinary
      research projects investigating animal stress, behaviour, and welfare. The
      present study on 12 group-housed pigs (age: 12 weeks, weight: 29.3 kg) shows the
      influence of this wound-causing technique on different humoral and cell-mediated
      parameters of the immune system at 1, 3, 5, and 9 days after biopsy compared to
      the initially investigated levels before. An enhancement of the blood
      sedimentation rate and both the IgG and the cellular immune response in vivo
      (leukocytes, lymphocytes) as well as in vitro (ConA) was observed. Furthermore,
      there were signs of a secondary wound infection 5 days after biopsies were taken
      possibly caused by mutual oral manipulation of the animals. We conclude that the
      muscle shot biopsy technique can be used on group-housed pigs as a method to
      investigate muscle physiological characteristics. The technique, however, induces
      immunological reactions which may interfere with stress-induced immune reactions.

PMID- 12596665
TI  - [Kinetics and persistence of neutralizing antibodies against bovine viral
      diarrhea virus-1 and -2 and border disease virus after two step vaccination of
      cattle].
AB  - The aim of the study was the assessment of rise and persistence of neutralizing
      antibodies (nAb) to bovine viral diarrhea virus (BVDV) and border disease virus
      (BDV) after a two step vaccination using an inactivated BVDV/BDV (Mucobovin) and
      a modified live BVDV vaccine (Vacoviron). In a first experiment eight heifers
      were kept in isolation and were serologically surveyed regularly over a three
      year period after vaccination. The same experiment was done with 80 vaccinated
      cattle kept under field conditions. Neutralizing antibody titres were monitored
      using homologous as well as heterologous BVDV and one BDV strain, respectively.
      Maximum titres were obtained two to three months after vaccination. During the
      three years of monitoring the antibody titres decreased but never fell below the
      detection limit. This slow antibody regression demonstrates that a single two
      step vaccination elicited high nAb titres which persist over at least three
      years. These results might serve as a decision tool when considering the
      necessity and time of revaccination of cattle, which have been vaccinated using
      the two step method.

PMID- 12596666
TI  - Computed tomographic pelvimetry in German shepherd dogs.
AB  - Pelvimetry was performed on a computed tomographic scanner using dorsal and
      lateral scout-view images of 10 adult German shepherd dogs. The vertical and
      transverse diameters of the pelvis were measured and the pelvic inlet and pelvic
      outlet areas were also calculated. No significant correlations between the pelvic
      measurements and body weight, age and sex were found. Although the conjugata
      vera, diameter verticalis, diameter sacralis, sagittal diameter and the distance
      between the two medial tubera ischiadica were longer in females, no significant
      statistical difference was found between male and female animals for all
      measurements. It is proposed that the computed tomographic pelvimetry should be
      preferred for the sensitive measurements when the normal standards are determined
      for different animal species and the cost is reduced to an acceptable level.

PMID- 12596667
TI  - Study on skin diseases in sheep from northern Ethiopia.
AB  - A study was conducted to determine the cause and prevalence of skin diseases in
      local sheep from northern Ethiopia. Of 520 sheep examined 174 (33%) had skin
      diseases of different causes. The identified causes were lice infestation due to
      Damalina ovis and Linognatus africanus (21%), sheep pox (8%), sarcoptic mange
      (Sarcoptic Scab. var. ovis) (4%), dermatophilosis due to Dermatophilus
      congolensis (3%), and orf (contagious ecthyma) (3%). There was no statistically
      significant (P > 0.05) association of any of the skin diseases with age and sex
      of the sheep examined. The occurrence and spread of the diseases were associated
      with poor management, climatic factors, feed scarcity and inadequate veterinary
      services. The increasing threat of skin diseases to the development of sheep
      production warranting an urgent control intervention is indicated.

PMID- 12596668
TI  - [Case report. Treatment of the gillworm disease (Dactylogyrosis) of some South
      American cichlids and catfish].
AB  - The infection with gillworms (Dactylogyrus sp.) causes severe problems in the
      keeping and breeding of tropical ornamental fishes, e.g. Discus (Symphisodon
      aequifasciata). Treatment of gillworm disease with different drugs has been shown
      in the past to be insufficient. Therefore, the effectiveness of a long-term use
      of praziquantel was evaluated in ornamental fish. Cumulative doses up to 10 mg
      praziquantel/l water were tolerated without side-effects by Angel Fish
      (Pterophyllum scalare), Discus, and a variety of catfish species (Ancistrus sp.,
      Corydoras sp.). It was found appropriate to start with a dosage of 2.5 mg/l and
      to add the same dosage every other day several times. All adult parasites and
      larvae were killed by this treatment. For the complete elimination of the
      Dactylogyridae-population in a closed aquarium system, 3 therapy-cycles
      (duration: 5-6 d, accumulated dosage: 2.5 mg/l/d) prooved to be effective. It was
      important to interrupt the therapy-cycles with intervals without medication (1 to
      4 weeks).

PMID- 12596669
TI  - [Case report. Phenprocoumon (Marcumar, Falithrom) as an unusual reason for
      coumarin poisoning in a dog].
AB  - Coumarin poisoning in dogs is not unusual and is in most cases caused by
      warfarin, a coumarin derivative which is used as a rodenticide. Competitive
      inhibition of vitamin K with an incomplete synthesis of the coagulation factors
      II, VII, IX and X can lead to a significant bleeding tendency. We observed a 3
      year old male West Highland White Terrier with a reduced general condition and
      dyspnoea together with a massive haemothorax. Administration of vitamin K1 (3
      mg/kg) led to a rapid improvement of the condition. Coagulation analysis revealed
      a prolonged activated recalcification time (ARCT), prothrombin time (PT) and aPTT
      with uncharacteristic thrombin time (TT); factor II, VII and X activities were
      reduced while factor V activity was normal, all of which are characteristic for
      coumarin poisoning. HPLC did not reveal the presence of warfarin but of
      phenoprocoumon, a drug used for thromboembolic prophylaxis in humans. This
      observation has not been described for dogs to date.

PMID- 12596670
TI  - Congenital melanoma in a heifer.
AB  - The clinical, intra-operative and pathological findings taken from a case of
      melanoma in a 9-month-old female Holstein Friesian heifer are reported here. The
      tumor, hanging on the right side of the thorax, was present at birth and
      increased in size with time. Muscular invasion by tumoral tissue was detected
      during surgery. Histological and cytological data indicated that the neoplasia
      (melanocytoma) was benign but the prognosis, related to the invasiveness of this
      neoplasm, was considered reserved. Melanoma is a rare tumor in cattle, often
      congenital, although already reported in pigs and in horses.

PMID- 12596671
TI  - [The dilemma after whiplash trauma: exercise or immobilization?].

PMID- 12596672
TI  - [Therapy must address the pain. Don't deny the whiplash trauma patient the neck
      brace! (interview by Michael Koczorek)].

PMID- 12596673
TI  - [Arteriosclerosis: how plaque heals].

PMID- 12596674
TI  - [Patients with implanted defibrillators. Increased arrhythmia attacks following
      November 9 1901].

PMID- 12596675
TI  - [Every 10th patient is afflicted. Dangerous tachycardia in patients with cardiac
      pacemakers].

PMID- 12596676
TI  - [Patient with acute dyspnea. Heart disease or lung disease? Natriuretic peptide
      type B clarifies diagnosis].

PMID- 12596677
TI  - [Welcome cardiac protection. With 1 to 2 drinks daily, C-reactive protein
      decreases].

PMID- 12596678
TI  - [35,000 fatalities a year due to colorectal carcinoma. Intestinal cancer can be
      prevented!].

PMID- 12596679
TI  - [Screening for prevention of colorectal carcinoma. Who, when, how?].
AB  - Long-term survival of patients with colon carcinoma is largely determined by the
      timing of the diagnosis. For the identification of early colorectal carcinoma, it
      is of particular importance to detect and remove local precursor lesions (polyps)
      by means of effective screening, before they undergo malignant degeneration. The
      gold standard for such screening continues to be colonoscopy, followed by
      sigmoidoscopy, which latter, however, leaves large segments of the proximal
      uninspected. Additional--though less sensitive and more complicated--current
      screening techniques are the test for occult blood in the stools and the barium
      Doppler contrast examination, and, possibly in the near future, virtual
      colonoscopy and genetic testing for tumor DNA in the stools. Detailed screening
      recommendations are to be found in the guidelines issued by the German Society
      for Digestive and Metabolic Diseases. A prerequisite for effective prevention of
      colorectal carcinoma is the provision of information to, and motivation of, both
      the population and the individual patient, to participate in screening measures.

PMID- 12596680
TI  - [Cancer prevention with the endoscope. Search not only for polyps!].
AB  - Through the rigorous application of polypectomy, the colon carcinoma rate can be
      clearly reduced (66%). The term "polyp" comprises epithelial (hyperplastic or
      neoplastic) and nonepithelial causes. The majority of carcinomas in the colon
      develop from adenomatous tissue (adenoma-carcinoma sequence). Pedunculated
      adenomas (90% of all polyps) are removed with the high-frequency diathermy snare.
      In some cases, flat (sessile) polyps can be elevated by injections placed below
      them, and then removed with the diathermy snare (strip biopsy). In the event of
      larger or large-area flat polyps that cannot be removed with the snare, piecemeal
      resection is applied. The excision alone of adenomas with a stage I carcinoma is
      carried out only in so-called low-risk situations. Flat neoplasms make particular
      demands of the endoscopist, since they often appear merely as a reddish area, but
      may already have invaded the submucosa when diagnosed. For classification and,
      where indicated, endoscopic resection, the recommendations of the Japanese
      Society of Gastroenterological Endoscopy are applied.

PMID- 12596681
TI  - [Endoscopy of the small intestine without tube or enema? A video capsule makes it
      possible].
AB  - The diagnosis of unclear bleeding in the small bowel remains a
      gastroenterological problem. To date, the diagnostic approach routinely employed
      has been roentgen Sellink. With such newer techniques as magnetic resonance
      tomography (MRT) substantially more diagnostic information can now be obtained. A
      recent new development is capsule endoscopy, which is intended for use when
      conventional endoscopic examinations fail to identify the source of bleeding.
      Using this new option in the Ludwigshafen Klinikum the small bowel lesions were
      discovered in 81% of the 26 patients in whom they had been previously remained
      undetected. At present, the patients have to bear the cost of this examination
      themselves.

PMID- 12596682
TI  - [Flush and dyspnea after alcohol drinking. Is it a "wine allergy"?].

PMID- 12596683
TI  - [Exanthema after streptococcal infection in childhood. This can also be psoriasis
      (interview by Dr. Ina Schicker)].

PMID- 12596684
TI  - [Cerebrovascular insufficiency--1. How to reduce the risk of stroke].
AB  - Extracranial stenosis of the carotid artery may lead to cerebral ischemic events
      and stroke. For this reason, such symptoms as transient ischemic attacks (TIA),
      unilateral syndrome or amaurosis fugax, the arteries feeding the brain should be
      investigated. In addition to bilateral palpation and auscultation of the
      arteries, modern ultrasonographic methods have an important role to play. The aim
      of treatment is secondary prevention of ischemic stroke, and possibly even to
      achieve regression of the vascular lesion. This necessitates the elimination of
      atherogenic risk factors. Particularly suitable as preventive medication, are
      platelet aggregation inhibitors, such as, acetylsalicylic acid and clopidogrel,
      which can also be applied postoperatively and postinterventionally to prevent
      recurrence.

PMID- 12596685
TI  - [Cerebrovascular insufficiency--2. When is surgery indicated?].
AB  - For the vascular-surgical treatment of cerebrovascular insufficiency, prior
      staging is essential. In stage I only the 80-89% asymptomatic stenosis should be
      operated on. Using this approach, the stroke risk decreases significantly in
      comparison with conservative treatment. Stage II disease is the domain of
      vascular surgery. In stage II a and b, an operation makes sense only
      exceptionally in the noncomatose patient and within the first 6 hours following
      the event. Prior to disobliteration of stage IV stenoses, CT and MRI findings
      need to be considered. In the presence of a contralateral high-grade stenosis of
      the internal carotid, surgery is recommended here too. The classical method is
      carotid disobliteration with patchplasty. Possible alternativeas are eversion
      endarterectomy and carotid bifurcation-plasty.

PMID- 12596686
TI  - [39. Thoracic pain: not always from the heart].

PMID- 12596687
TI  - Malaria situation in the People's Republic of China in 2000.

PMID- 12596688
TI  - Drug record discrepancies in an outpatient electronic medical record: frequency,
      type, and potential impact on patient care at a hemodialysis center.
AB  - BACKGROUND: Patients who require hemodialysis take many drugs. Electronic drug
      records may be discrepant with what patients are actually taking. Record
      discrepancies are a potential source of drug-related problems. We sought to
      determine the extent to which drug record discrepancies occur in a hemodialysis
      population. METHODS: This was a prospective observational study of patients
      enrolled in a pharmacist clinic at an outpatient hemodialysis center from August
      December 2001. Patients participated in monthly drug interviews conducted by a
      pharmacist, during which patient drug use was determined. Data collected
      consisted of patient demographics, drug type, and number of drugs. Drug record
      discrepancies were classified and assigned a potential drug-related problem.
      Results were compared with the electronic drug record. Patients with documented
      drug record discrepancies were compared with those patients for whom no
      discrepancy was identified. RESULTS: Over the 5-month period, 215 drug interviews
      were conducted in 63 patients. One hundred thirteen drug record discrepancies
      were identified in 38 patients (60%). Discrepancies (mean +/- SD 1.7 +/- 1.3,
      range 1-7) were identified during 65 drug interviews (30.2%). Electronic drug
      records were discrepant by one drug record, two drug records, and more than two
      drug records 60.0%, 26.2%, and 13.8% of the time, respectively. Drug record
      discrepancies placed patients at risk for adverse drug events and dosing errors
      in 49.6% and 34.5%, respectively, of 113 discrepancies. Patient age negatively
      correlated with the number of drug record discrepancies identified (r = -0.27, p
      = 0.04). CONCLUSIONS: Drug record discrepancies occur frequently among patients
      undergoing hemodialysis. Incorporation of a pharmacist into the patient care team
      may increase the accuracy of the electronic drug record and avert unnecessary
      drug-related problems.

PMID- 12596689
TI  - [Fundamental aspects of extreme aging].
AB  - Major developments in molecular biology in invertebrates have recently shown the
      determining effect of genetics on aging. The first finding was that artificial
      selection can highlight the genetic aspect of the aging process, demonstrating
      the polygenetic property of longevity. Another finding showed that certain gene
      transfers can modulate the lifespan of an organism. Recent progress has been made
      in three fields: genetic markers of aging, biological basis of cell maintenance,
      and hereditary factors contributing to late onset genetic disease. These new
      developments open new avenues of research in clinical biology. In regard to
      genetic markers of aging, it has been demonstrated that the ends of the
      chromosomes, telomeres, play a role in cell senescence. Telomeres can be viewed
      as markers of aging. Shortened telomeres are associated with replicative
      senescence and antitumor action. DNA anomalies are also more frequent: simple or
      double breaks, additions and base substitutions. Data on the biological basis of
      cell maintenance obtained in invertebrates show the polygenetic property of aging
      involving four significant mechanisms, control of metabolism, resistance to
      stress, chromatin-dependent gene regulation of genetic homeostasis. Finally,
      recent studies have shown that late onset hereditary diseases would be linked
      with particular genes, some of which have been identified. Two non-exclusive
      mechanisms could be involved: an adaptive mechanism involving gene selection
      during the evolutionary process, for example in obesity; and non-adaptive
      accumulation of gene expression during the post-reproductive phase, for example
      in Alzheimer's disease. These findings open a new era for the biology of aging.

PMID- 12596690
TI  - [Psychoses: a new lecture for new practices. Proceedings of a workshop. Cannes,
      France, 25-26 January 2002].

PMID- 12596691
TI  - [Neoplasm markers useful for diagnosis and monitoring of colonic neoplasms].
AB  - Serum tumor markers: CEA, CA 19-9, AFP, TPS may be helpful in early diagnosis of
      colorectal cancer, in the initial assessment of the extent of the disease, and in
      monitoring of the tumor growth or tumor volume reduction once cancer has been
      diagnosed and treatment started. Recent studies have focused on a new substances
      (candidates for tumour markers) of colorectal cancer.

PMID- 12596692
TI  - Defining moments of history.
AB  - In the life of a nation, as in the life of a man, there are moments that have
      changed the entire course of its eventful history by the totally unexpected
      happening at an inordinate time. The defining moments of history are almost
      always inconspicuous situations that plays its assertive role in determining the
      final outcome of a grand design without in itself seeking prominence or due
      acknowledgement. This is very true when an individual is involved in the process.

PMID- 12596694
TI  - Neuromuscular evaluation of post-orthodontic stability: an experimental protocol.
AB  - To prevent relapse after orthodontic treatment, retention is often considered
      indispensable. Soft tissues are thought to have a significant influence on dental
      movements. To quantify the influence of masticatory muscles on post-treatment
      relapse, and in an attempt to avoid unnecessary procedures, 2 male orthodontic
      patients (13 and 30 years old at debonding) were followed up. The patients
      completed 2 years of fixed orthodontic treatment and received no post-orthodontic
      retention. After 1 week and again after 6 months, alginate impressions of dental
      arches and a surface electromyographic (EMG) assessment of the masseter and
      temporalis muscles during maximum voluntary clenching were performed. The younger
      patient received surface EMG monitoring once a month for the first 6 months and
      at the 1-year follow-up appointment. Arch dimensions and the 3-dimensional
      inclination of the facial axis of the clinical crown (FACC) were measured using a
      computerized digitizer. Symmetry in muscular contraction was measured by the
      percentage overlapping coefficient (POC), and potential lateral displacing
      components were assessed by the torque coefficient (TC). At the 6-month follow
      up, no clinical modifications were observed. Quantitative evaluation assessed
      that arch dimensions had changed slightly (up to 1 mm). While the adolescent
      patient had no modifications in FACC inclinations, the 30-year-old patient showed
      significant alterations (up to 18 degrees). In all examinations of the adolescent
      patient, POC was higher than 86% and TC was lower than 10%. In the adult, POC was
      inside the normal range, while all TCs were higher than 10.5%. The larger TC
      measured in the adult may explain the larger modifications in the 3-dimensional
      position of his dental crowns. In conclusion, a surface EMG assessment may help
      in the detection of patients who might need post-orthodontic retention.

PMID- 12596693
TI  - [The care of HIV-positive women in the pregnancy-puerperal period: nurses'
      perceptions].
AB  - The present study has as its objective to identify the perceptions of nursing
      professionals, who work in the field of women's health, regarding the care of HIV
      positive pregnant women. This is an exploratory study with a qualitative
      approach. The participants of the study were eight nurses who work in the
      obstetric clinic of Hospital de Clinicas in Porto Alegre. Data were collected
      through semi-structured interviews, which were analyzed according to the theme
      content proposal of Minayo (1996). The themes identified in the interview were
      human care, professional practice, duality-HIV X Care and being an HIV positive
      women: the view of nursing. The study motivates professionals who care for HIV
      positive patients to reflect on strategies for a multidisciplinary and continuous
      care. It also emphasizes the importance of respecting individuals so that the
      objective can be achieved.

PMID- 12596695
TI  - Elliptic Fourier analysis of facial profiles during growth and development.
AB  - The quantitative analysis of facial soft tissues is of overwhelming importance
      for orthodontic patients. To assess the normal age-related variations in shape,
      soft tissue facial profiles were studied in 96 healthy male children 3 to 11
      years of age and 16 young men (age 18). Standardized left-side photographs were
      taken of each subject, and facial profiles were traced between trichion and
      cervical point. The line joining the 2 landmarks was set as the baseline, and
      each outline was automatically digitized and mathematically reconstructed by a 30
      harmonic elliptic Fourier series expansion. The same soft tissue profile was
      traced and digitized from the Bolton standards of comparable age. All profiles
      were standardized to the same area, and shape modifications were quantified by
      calculating the morphologic distance between the Fourier reconstructions of each
      facial profile and of (1) the 18-year-old Bolton standard (MD-18) and (2) the age
      related Bolton standard. Descriptive statistics were computed for each age class.
      On average, MD-18 was 7.23 at 3 years of age, increased between 6 and 9 years of
      age, and decreased hereafter, reaching 6.86 at 18 years of age. Within-group
      variability peaked at 8 years of age, and was minimal at 6 and 18 years of age.
      The current soft tissue child profiles seemed different from the profile obtained
      from the Bolton standards.

PMID- 12596696
TI  - [Current trends in pneumology 2002 -- Part 1].

PMID- 12596697
TI  - [Chylothorax in B-cell lymphoma].

PMID- 12596698
TI  - [Improvement of survival time in malignant pleural mesothelioma?].

PMID- 12596700
TI  - Letters from the trenches. By Caveman.

PMID- 12596699
TI  - [Re: Burgmer M, Freyberger HJ. Diagnosis-related groups in psychiatry and
      psychotherapeutic medicine -- the significance of a prospective payment system].

PMID- 12596701
TI  - Literature review.

PMID- 12596702
TI  - Going up.

PMID- 12596703
TI  - Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric study of
      bis(imidazole-1-carboxylate) endfunctionalized polymers,.
AB  - A detailed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric (MALDI
      TOF MS) investigation of polyethylene glycol (PEG), polypropylene glycol (PPG)
      and polyisobutylene (PIB) bis(imidazole-1-carboxylate) esters is reported. The MS
      spectra of PPG and PIBb is (imidazole-1-carboxylate) esters recorded in the
      reflectron mode showed the presence of two additional series of peaks compared to
      those recorded in the linear mode, while in the case of PEG bis(imidazole-1
      carboxylate) only one additional peak series appeared in the reflectron MS
      spectra. These additional series were attributed to the formation of fragment
      ions by the loss of one and two end groups in the first field-free region of the
      instrument. The neutral losses for the three polymers were also supported by
      using the post-source decay method (PSD). The observation of decreasing mass
      difference between the adjacent peaks from two series of polymeric ions with the
      increase of oligomer mass indicates the presence of PSD ions in a reflectron
      MALDI spectrum. The relationship between the mass of the precursor ions and those
      of the PSD ions and neutral loss are also discussed.

PMID- 12596704
TI  - The elephant in the room: evolution, behavioralism, and counteradvertising in the
      coming war against obesity.

PMID- 12596705
TI  - The slow poisoning of Bangladesh: metals in drinking water.

PMID- 12596706
TI  - Dawn of Ayurveda during the reign of Nizam VII of Hyderabad.
AB  - Mir Osman Ali Khan Bahadur, the Nizam VII ruled the Hyderabad State for about 38
      years. In those days Ayurveda was flourishing in the state due to efforts of many
      Ayurvedic physicians, scholastic teachers, distinguished patrons and well-wishes
      who worked together with devotional spirit to make Ayurveda available to the
      people of the state to provide care for the diseases. Nizam Ayurveda Vaidya Sangh
      started Nizam Ayurvedic college and Nizam Ayurvedic Sadar Dawakhana in Hyderabad
      city under their management in the year 1934 as a private institution, which was
      inaugurated in the same year by Azam Jah Bahadur, the Prince of Berar. Consequent
      upon the inauguration, the Nizam Government accorded sanction of an amount of Rs.
      200/- per month for Ayurveda. Thus the seed of Ayurveda was sown during the reign
      of Nizam VII in the Hyderabad state.

PMID- 12596707
TI  - Medical manuscripts in Sri Venkateshwara University Oriental Research Institute,
      Tirupathi, A. P.
AB  - Sri Venkateshwara Oriental Research Institute, Tirupati, was founded in 1939,
      with an object of collecting old, rare and important manuscripts from all parts
      of the state to conserve and publish the same for the benefit of coming
      generations. The total number of the manuscripts preserved in the Institute is
      10,672, classified under 45 different heads out of which 137 manuscripts are
      related to medicine.

PMID- 12596708
TI  - Patient information. Bell's palsy.

PMID- 12596709
TI  - Preventing inpatient suicide.

PMID- 12596710
TI  - 2002 Donald E. Cummings Memorial Award: "Human inhalation toxicology.".

PMID- 12596711
TI  - ELPAT program report: background and current status.

PMID- 12596712
TI  - Health insurance reform: security standards. Final rule.
AB  - This final rule adopts standards for the security of electronic protected health
      information to be implemented by health plans, health care clearinghouses, and
      certain health care providers. The use of the security standards will improve the
      Medicare and Medicaid programs, and other Federal health programs and private
      health programs, and the effectiveness and efficiency of the health care industry
      in general by establishing a level of protection for certain electronic health
      information. This final rule implements some of the requirements of the
      Administrative Simplification subtitle of the Health Insurance Portability and
      Accountability Act of 1996 (HIPAA).

PMID- 12596713
TI  - Health insurance reform: modifications to electronic data transaction standards
      and code sets. Final rule.
AB  - In this final rule, we respond to public comments received and finalize
      provisions applicable to electronic data transaction standards from two related
      proposed rules published in the May 31, 2002, Federal Register. We are also
      adopting proposed modifications to implementation specifications for health care
      entities and others. In addition, we are adopting modifications to implementation
      specifications for several electronic transaction standards that were omitted
      from the May 31, 2002, proposed rules.

PMID- 12596714
TI  - [Dobutamine was approved for stress echocardiography indications].

PMID- 12596715
TI  - [Molecular basis of heart failure and dilated cardiomyopathy].
AB  - Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure.
      Several prospective studies have shown that about 25-30% of all cases are of
      familial etiology. The most common mode of inheritance is autosomal dominant.
      Less frequently is inheritance as an X-chromosomal trait. Examination of families
      has identified nine disease genes so far. The penetrance of the identified
      mutations is highly variable and age-dependent. Many relatives of patients with
      DCM show only minor cardiac abnormalities, and it is unknown whether they
      progress to full cardiomyopathy in later life. Knowledge of the DCM disease genes
      led to the new hypothesis that DCM is a disease of myocardial generation or
      transmission of force. Better understanding of the expression and function of
      disease genes may lead to new diagnostic and therapeutic tools.

PMID- 12596716
TI  - [From relational medicine to allocation medicine? Statement of Prof. Dr. Jorg
      Dietrich Hoppe, President of the German Federal Physicians Committee].

PMID- 12596717
TI  - An international study of the interobserver variation between interpretations of
      vaginal smear criteria of bacterial vaginosis.
AB  - An international workshop on vaginal smear-based diagnosis of bacterial vaginosis
      was organized where 13 investigators scoring 258 slides with smears from vaginal
      fluid. Interobserver reproducibility of interpretations of Nugent scores,
      Hay/Ison scores and wet smear scores for the diagnosis of bacterial vaginosis was
      shown to be high. Detailed analysis of individual scoring results however
      indicated that basic standards of quality control to ensure robust individual
      readings of slides must be adhered to.

PMID- 12596719
TI  - HIV type 1 diversity in France, 1999-2001: molecular characterization of non-B
      HIV type 1 subtypes and potential impact on susceptibility to antiretroviral
      drugs.
AB  - Non-B HIV-1 samples collected in France between 1999 and 2001 were sequenced in
      the env, reverse transcriptase (RT), and protease genes (1) to characterize
      further the non-B strains circulating in the country, (2) to assess the
      importance of recombination, and (3) to describe the polymorphism of RT and
      protease genes and appreciate a possible impact on susceptibility to
      antiretroviral (ARV) drugs. The results show that, within a background of
      CRF02_AG predominance, there is a high genetic diversity of non-B isolates,
      including intersubtype recombinants. There is an extensive polymorphism of
      protease and RT genes compared with B consensus sequences; we have so far no data
      indicating that these non-B isolates may have reduced sensitivity to ARV drugs.

PMID- 12596720
TI  - Genetic analysis of culture-negative UNAIDS subtype C samples.
AB  - To help in the vaccine development, WHO-UNAIDS launched a program for the
      isolation and characterization of subtype C viruses, the most prevalent HIV-1
      subtype in the world. Isolates were obtained from Brazil, China, India, Israel,
      and South Africa, countries in which these strains are circulating. In this study
      we genetically characterized a set of samples displaying the culture-negative
      phenotype by sequencing the nucleotides of three genomic regions: the p17 region
      of the gag gene, the C2V3C3 fragment of the env gene, and the nef gene. The
      association of the culture-negative phenotype with the nef gene was studied, and
      we found a significant accumulation of gene alterations. Except for one B/C
      recombinant from India, the samples studied formed a monophylogenetic subtype C
      clade, although samples from Brazil formed a statistically significant,
      independent subcluster in two of the three genes analyzed.

PMID- 12596723
TI  - [Allergic rhinitis and allergic asthma: SIT saves costs].

PMID- 12596722
TI  - HIV type 1 subtypes among bar and hotel workers in Moshi, Tanzania.
AB  - The HIV-1 prevalence among bar and hotel workers in Tanzania suggests they are a
      high-risk group for HIV-1 infection. We determined the HIV-1 subtype of 3'-p24/5'
      p7 gag and C2-C5 env sequences from 40 individuals representing this population
      in Moshi. Genetic patterns composed of A(gag)-A(env), C(gag)-C(env), and D(gag)
      D(env) were found in 19 (48.0%), 8 (20.0%), and 3 (8.0%) samples, respectively.
      The remaining 10 samples (25%) had different subtypes in gag and env, indicative
      of intersubtype recombinants. Among these recombinants, two contained sequences
      from HIV-1 subsubtype A2, a new genetic variant in Tanzania. Five bar and hotel
      workers may have been infected with viruses from a common source, based on
      phylogenetic analysis. The information obtained by surveillance of HIV-1 subtypes
      in a high-risk population should be useful in the design and evaluation of
      behavioral, therapeutic, and vaccine trial interventions aimed at reducing HIV-1
      transmission.

PMID- 12596725
TI  - Genetic evolution of human immunodeficiency virus type 1 in two spouses
      responding successfully to highly active antiretroviral therapy.
AB  - The current case study provided an unusual setting to track the evolution of HIV
      1 envelope gene over a maximum period of 6 years in two asymptomatic spouses
      undergoing suppressive highly active antiretroviral therapy. For this purpose,
      proviral DNA samples taken from uncultured peripheral blood mononuclear cells and
      spanning the C2-V5 regions of env were analyzed at three sampling points per
      subject. Two distinct topological patterns were observed in the phylogenetic
      reconstructions of the genetically linked sequences of the couple: an
      intermingled pattern and a sequentially shifting pattern in the virus populations
      of the male index case and his spouse, respectively. Application of three
      evolutionary models for the amino acid-encoded sites, using the maximum
      likelihood approach, indicated the operation of positive selection in the region
      only at the second time point in the woman, before receiving therapy. These
      findings reinforce the evidence of a crucial role for host-selective constraints
      on HIV-1 env evolution in vivo.

PMID- 12596727
TI  - Characterization of gag gene of plasma HIV type 1 in combination therapy-treated
      AIDS patients with high viral load and stable CD4+ T cell counts.
AB  - Many AIDS patients retain a high CD4+ T cell count despite a significant increase
      in polymerase chain reaction (PCR)-determined viral load after various periods of
      treatment by combination therapy. Our study involved 10 such AIDS patients who
      showed this discordance. In this study, we characterized changes in the gag gene
      of HIV-1 isolated from the plasma of such patients. Viral RNA was extracted from
      plasma samples and the gag gene was amplified by reverse transcription-PCR. The
      PCR product was cloned and three clones from each patient were sequenced. All the
      sequences were aligned and compared with similar HIV-1 isolated from nontreated
      AIDS patients. Several kinds of changes were observed in the sequences including
      substitutions, frameshifts, and deletions. One patient showed a frameshift due to
      a missing G residue in the capsid-encoding region of the gene whereas another
      patient had virus with two different deletions. Such changes are probably due to
      combination therapy.

PMID- 12596728
TI  - Emergence of complex and diverse CRF02-AG/CRF06-cpx recombinant HIV type 1
      strains in Niger, West Africa.
AB  - On the basis of partial env and gag subtyping, we documented that the majority of
      HIV-1 strains circulating in Niger were CRF02-AG (54.3%) or CRF06-cpx (18.1%) and
      that 9% of the samples were possible recombinants between CRF02 and CRF06. To
      determine in more detail the precise structure of these viruses we sequenced the
      full-length genomes for three such strains (97NE-003, 00NE-036, and 00NE-095).
      From the bootscan and phylogenetic tree analysis it is evident that the new
      viruses are the result of recombination events between CRF02-AG and CRF06-cpx
      strains. Importantly, each virus had a different complex recombinant structure
      with multiple breakpoints, leading to viruses with complex mosaic patterns.

PMID- 12596729
TI  - Mapping of a resistance gene effective against Karnal bunt pathogen of wheat.
AB  - A set of 130 wheat recombinant inbred lines (RILs) developed from a cross between
      parents susceptible (WL711) and resistant (HD29) to Karnal bunt (caused by
      Tilletia indica), were screened for 3 years with the pathogen populations
      prevalent in northern India. When 90 simple sequence repeats (SSRs) and 81
      amplified fragment length polymorphism (AFLP) loci were mapped on the RILs,
      markers on chromosomes 2A, 4B and 7B accounted collectively for about one-third
      of the variation in the disease reaction. The genomic region of largest effect,
      identified on the long arm of chromosome 4B, reduced Karnal bunt disease by half
      in three different experiments and accounted for up to 25% of the phenotypic
      variation for KB reaction. A closely linked SSR marker, GWM538, may be useful in
      marker-assisted selection for Karnal bunt resistance in wheat.

PMID- 12596730
TI  - Guidelines for childhood obesity prevention programs: promoting healthy weight in
      children.
AB  - These guidelines for obesity prevention programs encourage a health-centered,
      rather than weight-centered, approach that focuses on the whole child,
      physically, mentally, and socially. The emphasis is on living actively, eating in
      normal and healthful ways, and creating a nurturing environment that helps
      children recognize their own worth and respects cultural foodways and family
      traditions. It is recognized that obesity, eating disorders, hazardous weight
      loss, nutrient deficiencies, size discrimination, and body hatred are all
      interrelated and need to be addressed in comprehensive ways that do no harm.

PMID- 12596731
TI  - Aldehyde sealer.

PMID- 12596732
TI  - Hypersensitivity.

PMID- 12596733
TI  - Peas and Qs.

PMID- 12596734
TI  - DUWL disinfection.

PMID- 12596735
TI  - Evidence for continuing warfarin during dental extractions.

PMID- 12596736
TI  - Rasayana therapy in classical literature of Ayurveda: a review.
AB  - Ayurveda is a science of life, therefore it is the science, by the knowledge of
      which life may be prolonged. It is human nature to aspire for longevity and this
      desire is found practically among all the peoples of the world. Accordingly if
      longevity is desired, there must be a system of rejuvenation for one who keeps on
      remaining young. Rasayana therapy has been described for this person in Ayurveda
      as a systematic and scientific medical discipline and great results were claimed
      by this therapy. Hence the Rasayana therapy has been reviewed in the various
      headings giving its uses, definition, types and formulations etc.

PMID- 12596737
TI  - Genes, development and evolution of the placenta.
AB  - Through studies of transgenic and mutant mice, it is possible to describe
      molecular pathways that control the development of all major trophoblast cell
      subtypes and structures of the placenta. For example, the proliferation of
      trophoblast stem cells is dependent on FGF signalling and downstream
      transcription factors Cdx2, Eomes and Err2. Several bHLH transcription factors
      regulate the progression from trophoblast stem cells to spongiotrophoblast and to
      trophoblast giant cells (Id1/2, Mash2, Hand1, Stra13). Intercellular actions
      critical for maintaining stable precursor cell populations are dependent on the
      gap junction protein Cx31 and the growth factor Nodal. Differentiation towards
      syncytiotrophoblast as well as the initiation of chorioallantoic (villous)
      morphogenesis is regulated by the Gcm1 transcription factor, and subsequent
      labyrinth development is dependent on Wnt, HGF and FGF signalling. These insights
      suggest that most of the genes that evolved to regulate placental development are
      either identical to ones used in other organ systems (e.g., FGF and epithelial
      branching morphogenesis), were co-opted to take on new functions (e.g., AP
      2gamma, Dlx3, Hand1), or arose via gene duplication to take on a specialized
      placental function (e.g., Gcm1, Mash2). Many of the human orthologues of these
      critical genes show restricted expression patterns that are consistent with a
      conserved function. Such information is aiding the comparison of the human and
      mouse placenta. In addition, the prospect of a conserved function clearly
      suggests potential mechanisms for explaining complications of human placental
      development.

PMID- 12596738
TI  - Warfarin and extractions.

PMID- 12596739
TI  - Corpus Hippocraticum 'on the sacred disease'.
AB  - The Hippocratic Corpus was attributed to all branches of healing including
      internal medicine, surgery, and obstetrics. The Hippocratic collection of
      treatises (or corpus) was mostly written between 430 and 330 B.C. and some are
      later works. Some 600 years after Hippocrates, the Corpus were further
      systematized by Galen and later still by the Persian Islamic physician Avicenna
      and others. The Corpus provides an insight into the origin and development of
      rational medicine in the west.

PMID- 12596740
TI  - The role of Galen in the development and progress of medical sciences.
AB  - Early Roman medicine was a mixture of religion and witchcraft, but as time went
      by, it became more influenced by the Greek medical sciences, which were more
      developed. The most famous Greek physician during the Roman period was Galen (129
      200 AD). In the 4th century A. D. The Byzantine physicians of the Emperor Julian,
      made the Galenic writings available to ordinary practitioners, and so Greek
      medicine spread throughout Syria and was carried by the Nestorians into Persia,
      where it became available to the Islamic World.

PMID- 12596741
TI  - The long journey.

PMID- 12596742
TI  - The terms Khalisa and dar-bahara in Jahangir's dastur -ul- amal and his
      physicians.
AB  - After his accession Jahangir passed twelve orders (dastur-ul-amal). According to
      the tenth order hospitals were to be built in all the big cities and physicians
      were to be appointed and expenditure for this purpose were to be made from
      "Khalisa" establishment. The term 'Khalisa' has been translated as royal treasury
      by scholars. But according to the Encyclopaedia of Islam the term means crown
      land. Jahangir's yearly income from his crown-land was fifty crores of rupees. So
      he in all probability ordered money to be spent from his personal fund. According
      to the fifth order, Jahangir forbade manufacture and sale of dar-bahara (rice
      spirit). It has been suggested that probably the right term was 'dil-bahara'
      (exhilarating drink) because Jahanir the emperor would know title of rice-spirit
      a cheap drink meant for poor people. But in the history of the fourth year of his
      reign Jahangir says that he forbade the sale of bhang and buza (rice-spirit) in
      the market as those were injurious for health and he gave stringent orders for
      the abolition of gambling. So Jahangir was anxious for the physical and moral
      health of his subjects.

PMID- 12596743
TI  - Gujjar Bakarwals: the eco-friendly tribals of Jammu and Kashmir since centuries.
AB  - According to the ecological approach, health represents the adjustment of the
      human organism to his environment. The man of today is living in a highly
      complicated environment and his health problem is more complicated as he is
      becoming more ingenious. But, there are people who with their strong social
      structure are living in healthly relatiomshi with their environment and are
      enjoying the transformation of their rich genetic potentialities into phenotypic
      realities since centuries. They are Gujjar Bakarwal tribals of Jammu and Kashmir.
      Here, in this article, the traditionally hard life style of these tribals with
      reference to their social, physical and biological environment factors which make
      them eco-friendly has been discussed.

PMID- 12596744
TI  - Sown a seed of Ayurveda in the Nizam dominion.
AB  - In the name of Trillinga Ayurveda Vidya Peetham a seed for Ayurveda with a school
      & free Ayurveda dispensary along with a Sanskrit school was sowed at Warangal by
      some eminent devoted private practitioners of Ayurveda and Philanthropists. The
      city of Warangal is a historical place and once a capital of Kakatiya Kingdom,
      though it was part and parcel of Nizam dominion. In fact such steps taken by
      Private Organisations for establishment of Ayurvedic system of Medicine in
      Hyderabad and in Andhra region at Bejwada is appreciable.

PMID- 12596745
TI  - Knowledge and practices of a control authority: impact on the environment and
      food safety.
AB  - This study investigates the practices and knowledge of a Control Authority
      dealing with the environment and the safety and control of hawker foods.
      Experience and background education are used as likely determinants of food
      safety practices and knowledge of the control authority. A total of 60
      questionnaires were distributed to the Health Inspectors (HIs) in the Hawkers'
      and Health Departments, City Hall, Kuala Lumpur. The return rate was 93%. The
      structured questionnaire contained 14 main food safety practices and knowledge
      constructs. Significance was found pertaining to knowledge of HIs with different
      experience backgrounds but experience was not demonstrated to impact on practices
      of HIs. However, education was noted to have significantly but inconsistently
      influenced certain Practices and Knowledge scores of HIs. A Pearson bivariate
      coefficient characterised an association between food safety practices and
      knowledge of the control authority. The findings: (1) highlight the actual
      shortcomings in the staff resources relating to environmental health, food
      safety, foodborne illnesses and their control, and (2) provide information on the
      control aspect within the hawker micro-industry with the view of protecting the
      public from health hazards arising from the hawkers' practices and consumption of
      hawker foods.

PMID- 12596746
TI  - [Protocol of the Session of the Working Team on Sonography on 9/11/2002 on the
      occasion of the 58th Meeting of the DGVS (German Society for Digestive and
      Metabolic Diseases) in Bonn. (Chairman: Prof. Dr. W.F. Caspary, Frankfurt)].

PMID- 12596747
TI  - Public use of automated external defibrillators.

PMID- 12596748
TI  - A man with a prosthetic aortic valve and subacute calf pain.

PMID- 12596749
TI  - Controlling tuberculosis in India.

PMID- 12596750
TI  - Initial management of glycemia in type 2 diabetes.

PMID- 12596751
TI  - Nondiabetic kidney disease.

PMID- 12596752
TI  - Testing medications in children.

PMID- 12596753
TI  - Random sample (DOPPS) versus census-based (registry) approaches to kidney disease
      research.
AB  - This review describes advantages and limitations of registries that base their
      analyses on the census of all patients. Registries may utilize the random sample
      approach to enrich their data for more detailed and informative research. The
      Dialysis Outcomes and Practice Pattern Study (DOPPS) and its random sample
      approach is discussed here in detail, with examples on the value of this method.
      The DOPPS is currently being expanded to allow for even more valuable studies.
      This methodology can also be applied to large countries that do not have an
      existing registry, as it is an effective way of collecting detailed information
      at a relatively low cost that is representative of the country or population as a
      whole.

PMID- 12596754
TI  - Integrated vascular access management.
AB  - Nephrologists need to deal with the problem of vascular access management in the
      same manner as the other major problems that affect our dialysis patients. We
      need to become experts in vascular access and we need to occupy a pivotal
      position in directing the decisions that are made that affect dialysis patient
      welfare. An integrated vascular access management strategy is required.
      Optimally, there should be four components to this strategy - evidence-based
      policies and procedures, a dedicated vascular access facility, committed vascular
      access surgeons and the availability of committed vascular access
      interventionalists. In many respects this is the approach that offers the best in
      quality of patient care and is also the most economic to deliver.

PMID- 12596755
TI  - Hemodialysis vascular access dysfunction: from pathophysiology to novel
      therapies.
AB  - Hemodialysis vascular access dysfunction is a major cause of morbidity and
      hospitalization in the hemodialysis population at a cost of over USD 1 billion
      per annum. Most hemodialysis grafts fail due to a venous stenosis (venous
      neointimal hyperplasia) which then results in thrombosis of the graft. Despite
      the magnitude of the clinical problem there are currently no effective therapies
      for this condition. The current review (a) describes the pathogenesis and
      pathology of venous stenosis in dialysis access grafts and (b) discusses the
      development and application of novel therapeutic interventions for this difficult
      clinical problem. Special emphasis is laid on the fact that PTFE dialysis access
      grafts could be the ideal clinical model for testing out novel local therapies to
      block neointimal hyperplasia.

PMID- 12596756
TI  - Improving vascular access outcomes: a systems approach to eliminating structural
      barriers.
AB  - Maximizing AV fistula creation, regular access monitoring, prompt outpatient
      interventions and minimizing catheter use are well-accepted approaches for
      vascular access management. Systemic barriers impede the application of these
      strategies. A misaligned reimbursement system coupled with educational deficits
      and a lack of accountability has contributed to the institutionalization of
      substandard vascular access care. The hallmark of performance management is to
      create systems in which incentives are aligned to produce desired behaviors.
      Realigning reimbursement through a combination of pre-ESRD funding, enhancements
      to the composite rate to reward outcomes and cover vascular access monitoring and
      updated reimbursement for outpatient vascular access procedures would improve
      care and decrease unnecessary hospitalizations. This should be coupled with
      clearly defined outcome standards and accountability incorporated into hospital
      accreditation and credentialing. Capitation may provide alternative solutions. A
      two-phased approach including reimbursement reform while exploring capitation
      represents a prudent course with the best likelihood of success.

PMID- 12596757
TI  - Assays for parathyroid hormone and their use in patients with end-stage renal
      disease.
AB  - New second-generation immunometric PTH assays have been developed. The assays
      measure full-length biologically active PTH(1-84) exclusively and do not detect
      amino-terminally-truncated PTH fragments, a feature that distinguishes them from
      first-generation immunometric PTH assays. Although few studies have been done
      thus far, second-generation immunometric PTH assays have not been shown to be
      superior to first-generation assays for the diagnostic assessment of patients
      with renal osteodystrophy. Plasma PTH levels obtained using first-generation
      immunometric PTH assays continue to provide the most definitive guide to the
      management of renal bone disease because they are supported by abundant bone
      histology data. Additional work is needed to further characterize the utility of
      second-generation immunometric PTH assays as predictors of bone histology in
      patients with ESRD.

PMID- 12596758
TI  - Anemia in chronic kidney disease and congestive heart failure.
AB  - Anemia is seen in chronic kidney insufficiency (CKI), dialysis patients,
      congestive heart failure (CHF), and renal transplantation. Anemia can lead to
      progressive cardiac damage as well as progressive renal damage. It is not
      generally appreciated that CHF itself may be a very common contributor to both
      the production of anemia as well as to the progression of the renal failure.
      Correction of the anemia with erythropoietin and, as necessary, intravenous iron,
      may prevent the deterioration of both the heart and the kidneys. We suggest that
      there is a triangular relationship, a vicious circle, between CHF, CKI and anemia
      where each of these three can both cause and be caused by the other. We call this
      syndrome the cardio-renal anemia (CRA) syndrome. All physicians, especially
      cardiologists and internists who treat CKI and CHF, should be made aware of the
      dangers of anemia in CKI and CHF and should work with nephrologists to correct
      it.

PMID- 12596759
TI  - Methods and reproducibility of measurement of resistivity in the calf using
      regional bioimpedance analysis.
AB  - The usefulness of regional bioimpedance analysis (RBIA) in determining the dry
      weight in dialysis patients is currently being investigated. The aim of this
      study was to evaluate the reproducibility of measurement of resistivity in the
      calf. METHODS: Twenty-five normal subjects and 10 patients undergoing regular
      hemodialysis were studied. Four electrodes inserted into a blood pressure cuff
      were placed on the calf. Bioimpedance was continuously measured over 3- to 5-min
      periods (Xitron Hydra). After a resting period of 1 min, cuff pressure was
      increased to above the systolic blood pressure (SBP) for a few seconds to expel
      excess ECF fluid and then deflated. The effect on recordings of moving the
      electrodes 2 cm higher and then 2 cm lower than the normal position was studied
      in 8 normal subjects. In a second study of reproducibility, post-dialysis
      measurements were made twice in 10 patients who maintained the same post-dialysis
      target weight throughout the study period. RESULTS: The mean resting resistivity
      rho(0) in normal subjects was 532.6 +/- 95 omega.cm rising to 583.9 +/- 99.7
      omega.cm when cuff pressure was applied rho(p). The average values of rho(0) and
      rho(p) in patients post-dialysis were 489 +/- 74 and 537 +/- 77 respectively
      showing that there were no significant differences in rho(0) and rho(p) between
      normal subjects and patients post-dialysis. The mean values of change in
      resistivity when the electrodes were shifted between the lowest and highest
      positions on the calf were -3.66 +/- 4.45 and -1.44 +/- 3.82%, respectively.
      Repeat measurement of resistivity in patients post-dialysis varied by 2.04 +/-
      2.29% while post-dialysis body weight varied by 0.17 +/- 0.47%. CONCLUSION: In
      this study, resistivity measurement by RBIA at the calf showed similar levels of
      fluid loading in patients post-dialysis as in normal subjects. This study also
      showed that change in electrode position resulted in a mean change in resistivity
      of <5% and repeated measurements showed a change in resistivity <3% while body
      weight changes were <0.2%. This technique appears to have an acceptable level of
      reproducibility for its application to the assessment of patient hydration.

PMID- 12596760
TI  - Chronic kidney disease and the transplant recipient.
AB  - The recent Kidney Disease Outcomes Quality Initiative (K/DOQI) classification of
      chronic kidney disease (CKD) includes transplant recipients. Although there are
      important differences between kidney transplant recipients (KTRs) and patients
      with native kidney disease, the inclusion of KTRs along with other CKD patients
      is an important step to improve long-term outcomes among transplant recipients.
      In this article we discuss the applicability of the K/DOQI classification of CKD
      to transplant recipients and the importance of premature patient death with graft
      function as a cause of graft loss. The implementation of a comprehensive program
      of CKD care beginning prior to transplantation and continuing after graft failure
      is discussed as a strategy to improve patient outcomes and specific areas of
      concern for KTRs are highlighted.

PMID- 12596761
TI  - [Low vision: provision of the visually handicapped with magnifying aids. II.
      Matching and prescription].

PMID- 12596762
TI  - Unionization of health care professionals.

PMID- 12596763
TI  - Genetic diversity within honeybee colonies prevents severe infections and
      promotes colony growth.
AB  - Multiple mating by social insect queens increases the genetic diversity among
      colony members, thereby reducing intracolony relatedness and lowering the
      potential inclusive fitness gains of altruistic workers. Increased genetic
      diversity may be adaptive, however, by reducing the prevalence of disease within
      a nest. Honeybees, whose queens have the highest levels of multiple mating among
      social insects, were investigated to determine whether genetic variation helps to
      prevent chronic infections. I instrumentally inseminated honeybee queens with
      semen that was either genetically similar (from one male) or genetically diverse
      (from multiple males), and then inoculated their colonies with spores of
      Ascosphaera apis, a fungal pathogen that kills developing brood. I show that
      genetically diverse colonies had a lower variance in disease prevalence than
      genetically similar colonies, which suggests that genetic diversity may benefit
      colonies by preventing severe infections.

PMID- 12596764
TI  - Ayurvedic literature in Urdu.
AB  - Urdu is a distinct literary language began to develop in India during Mughal
      empire. Lots of people read, write and speak, this language in Indian
      subcontinent. This brief article will shed light on the seven rare books in Urdu
      compiled and published in the period from 19th century to the first half of the
      current century. Some books may not have high value but the struggle of the
      scholars, is appreciable.

PMID- 12596765
TI  - Medicine in the Holy Bible.
AB  - The study of history of medical science from non-medical sources needs no
      apology. At first sight the discussion of what was thought in the past rather
      than what is known now appears to be of merely anti-quarian value. The Hebrews
      can be proud of having preserved in the Old Testament many old medical practices
      and traditions which throw light on ancient medicine in general and on Hebrew
      medical practices in particular. The Bible is a genuinely documented book
      presenting the wisdom, medical knowledge and the culture of a nomadic race.

PMID- 12596766
TI  - Incorporating Web design and development into dietetics education.

PMID- 12596767
TI  - Collaboration in education: freshmen interest groups.

PMID- 12596769
TI  - [Pacemaker to treat depression].

PMID- 12596770
TI  - [Tularemia ("rabbit plague")].

PMID- 12596771
TI  - Observations by G-banding and multicolor spectral karyotyping in a salivary gland
      basal cell adenoma.

PMID- 12596774
TI  - [Can prostatic carcinoma cause polyneuropathy?].

PMID- 12596775
TI  - Association of caries experience in 12-year-old children in Heidelberg, Germany
      and Montpellier, France with different caries preventive measures.

PMID- 12596776
TI  - [In which hepatic diseases does encephalopathy develop?].

PMID- 12596778
TI  - [Gene chips and predictive medicine: Where is gene diagnostics standing today?].

PMID- 12596779
TI  - [Smallpox].

PMID- 12596780
TI  - [HIV patients exposed to infarct risk, too].

PMID- 12596781
TI  - [Stroke: from blow of fate to treatable emergency].

PMID- 12596782
TI  - The ever-elusive liberal education.

PMID- 12596783
TI  - Death due to intravenous application of enteral feed.
AB  - A 6-month-old male infant was treated with intravenous infusions and enteral feed
      via a naso-gastric tube. Accidentally, enteral feed containing pureed carrots
      diluted with water was injected intravenously and the child died immediately.
      Carrot material could be found in the pulmonary blood vessels and in various
      organs of the systemic circulation.

PMID- 12596784
TI  - Fatal accident caused by isoflurane abuse.
AB  - A fatal accident after isoflurane abuse is presented in this report. A hospital
      employee was found dead in the operating area with a plastic bag over his head.
      In his locker an almost empty bottle of isoflurane was found. Autopsy revealed
      signs of asphyxiation and toxicological examination revealed nordazepam and
      isoflurane in non-toxic concentrations in the blood. Quantification of the
      anaesthetic was also carried out in urine, gastric contents, liver, kidney and
      brain samples, and in addition, oxazepam, prothipendyl and metabolites of
      midazolam and prothipendyl were found in the urine. Although the drug problems of
      the deceased were known before, no efforts had been made to restrict access to
      these drugs.

PMID- 12596785
TI  - The complexity of complex diseases.

PMID- 12596786
TI  - Technical notes for age estimation using the femur: influence of various
      analytical conditions on D-aspartic acid contents.
AB  - In order to make a better estimate of the individual age using bone samples, we
      evaluated the effects of various criteria on the analytical measurement of D
      aspartic acid contents. Using compact bone from a male femur, we varied six
      analytical conditions (sample volume, sample particle size, hydrolysis
      temperature, hydrolysis time, hydrochloric acid volume during hydrolysis, and
      hydrochloric acid concentration during hydrolysis). D-form/L-form ratios were
      affected most by hydrolysis temperature (estimated age differences were 3.03
      years/ degrees C), followed in order by hydrochloric acid volume (1.44 years/ml)
      and hydrochloric acid concentration (0.69 years/0.1 M). Larger sample particle
      sizes and hydrochloric acid volumes during hydrolysis tended to result in lower
      racemization rates. Nonetheless, within a range of 5-50 mg, sampling volume did
      not affect the detected D-aspartic acid contents. Since the racemization reaction
      rate in femur compact bone is slower than in dentin, bone samples seem to be more
      greatly influenced by analytic conditions than dentin. Tests must therefore be
      performed with caution, especially with regard to the hydrolysis temperature,
      hydrochloric acid volume and concentration when estimating age using femur
      samples.

PMID- 12596787
TI  - 2002 William Allan Award Address. Inherited human diseases: victories,
      challenges, disappointments.

PMID- 12596789
TI  - 2002 ASHG Award for Excellence in Education. Education: a joint effort.

PMID- 12596788
TI  - Sequence structure and population data of two X-linked markers: DXS7423 and
      DXS8377.
AB  - DXS7423 and DXS8377 are two microsatellite markers located in the q28 band of
      chromosome X. We developed a protocol to amplify both markers in a single
      reaction, sequenced the most common alleles and studied allele frequencies in a
      Spanish population sample. DXS7423 allele variability was due to different
      numbers of (TCCA) repeats and five different alleles were found with apparent
      sizes between 181 and 197 bp. The probability of discrimination (PD) was 87% for
      female samples, and the expected probability of exclusion (PE) was 71%. DXS8377
      appeared as a highly polymorphic marker with variable numbers of (CTC), (TCC) and
      (TTC) repeats. We found 18 alleles of different sizes (204-258 bp) and the PD and
      PE were 99% and 93%, respectively. These data suggest that DXS7423 and DXS8377
      can be very useful markers for genetic forensic studies.

PMID- 12596790
TI  - 2002 Curt Stern Award Address. Genomic disorders recombination-based disease
      resulting from genomic architecture.

PMID- 12596791
TI  - Commentary: How to derive causes from correlations in educational studies.

PMID- 12596792
TI  - Simulation-based P values: response to North et al.

PMID- 12596793
TI  - Temperature change in the apical 2 mm of gutta-percha during the continuous wave
      technique.

PMID- 12596794
TI  - On estimating P values by the Monte Carlo method.

PMID- 12596795
TI  - A note on calculation of empirical P values from Monte Carlo procedure.

PMID- 12596796
TI  - Confirmatory evidence for linkage of relative hand skill to 2p12-q11.

PMID- 12596797
TI  - Self help smoking cessation in pregnancy. What does work in Doncaster.

PMID- 12596798
TI  - Dynamic changes of MRI in brain abscesses.

PMID- 12596800
TI  - Copying letters to patients. Copying letters can help avoid communications
      nightmare.

PMID- 12596799
TI  - Thromboembolic events after endovascular treatment of ruptured intracranial
      aneurysms in two patients with antiphospholipid-antibody syndrome.

PMID- 12596801
TI  - Concluding remarks. C0X-2-selective inhibition: a new advance in pain management.

PMID- 12596802
TI  - Nuclear medicine and radiology: where are they going?

PMID- 12596803
TI  - Resistance of stratospheric and mesospheric micro-organisms to extreme factors.
AB  - Studies of the stratosphere and mesosphere, by means of special analysers
      installed on meteorological rockets, have thrown more light on our knowledge of
      the upper boundary of the biosphere. The presence of the following micro
      organisms was registered at heights of 49-77 km: Aspergillus niger, Penicillium
      notatum, Circinella muscae, Papulaspora anomala, Mycobacterium luteum and
      Micrococcus albus. The isolated micro-organisms were subjected to the action of
      gamma-irradiation, high vacuum and UV radiation in order to evaluate the quality
      of sterilization by gamma-rays (3.2-3.5 Mrad) prior to sampling and the
      resistance of these micro-organisms to physical factors of the stratosphere and
      mesosphere. No species with high radio-resistance were detected among the
      isolated cultures. The D10 index for fungal spores and bacterial vegetative
      cells, freeze-dried or suspended in a physiological solution, did not exceed 290
      krad. These data confirm that sterilization of the analyser with gamma-rays
      assured the purity of biological experiments during sampling. The isolated micro
      organisms were found to be very resistant to high vacuum (10(-9) mmHg) and UV
      radiation, with the exception of the pigmentless Micrococcus albus. This evidence
      shows that pigmented micro-organisms can survive in the earth's atmosphere at
      high altitudes.

PMID- 12596804
TI  - Evidence for propagation of aerobic bacteria in particles suspended in gaseous
      atmospheres.
AB  - One factor involved in the possibility that airborne microbes might contaminate
      the Jovian atmosphere, is whether microbes have the capacity to propagate in air.
      Prior to these studies, the evidence was that the airborne state was lethal to
      microbes. By mixing an aerosol of aerobic bacteria with another containing 14C
      glucose, we were able to detect the presence of 14CO2, showing that the airborne
      cells were metabolically active. In the same type of experiment, we were able to
      show that thymidine was incorporated into the acid-insoluble fraction of samples,
      indicating the formation of DNA. Finally, we were able to show, both by an
      increase in numbers of viable cells and a parallel increase in particle numbers,
      that at least two new generations of cells could occur. As of this writing,
      evidence for propagation of anaerobic bacteria has been negative.

PMID- 12596805
TI  - Physiology of xerophytic micro-organisms growing under Martian conditions.
AB  - The main factor limiting growth of terrestrial organisms under Martian conditions
      is the low humidity; therefore the biology of xerophytic micro-organisms has been
      studied. We found earlier that Bacillus megaterium var. halotolerant and
      Mycococcus ruber could survive and grow under Martian conditions. In this work,
      we studied the zone of tolerance of these and some other micro-organisms towards
      various levels of water activity, and the toxicity of substances which were used
      to control this activity. A technique for quantitative evaluation of the
      xerophytic nature of micro-organisms is proposed. The technique is based on
      quantitative evaluation by gas chromatography of carbon dioxide evolved in the
      course of growth of micro-organisms on media with different values of water
      activity.

PMID- 12596806
TI  - Isolation and characterization of omnitherms and facultative anaerobes from Cape
      Canaveral soil samples.
AB  - In a bacterial population profile of interplanetary spacecraft environments based
      upon temperature and oxygen requirements, several isolates demonstrated the
      ability to grow over a temperature range from 3 degrees C to 55 degrees C, and
      most grew aerobically and anaerobically. Because of the adaptability of these
      organisms, they may be of significance to planetary contamination. To verify that
      these were actively growing in this range of temperatures, they were streaked
      onto trypticase soy agar (TSA) and incubated at the extreme temperatures (3
      degrees C and 55 degrees C). Isolated colonies were transferred to fresh TSA and
      immediately incubated at the opposite extreme temperatures. Almost all of the
      isolates grew quite well at both temperatures. Because these have been
      subcultured numerous times and still possess the ability to grow over a broad
      temperature range, this appears to be a stable characteristic. Many of these
      isolates possess the ability to grow anaerobically at 3, 32 and 55 degrees C. All
      of these organisms are sporeformers, and data are presented concerning their heat
      resistance and biochemical activity.

PMID- 12596807
TI  - Determinations of microbial loads associated with microscopic-size particles of
      Kennedy Space Center soil.
AB  - Plate counts for six fractions, of micrometer-size, of Kennedy Space Center soil
      provided estimates of aerobic, mesophilic, heterotrophic, microbial loads on
      single soil particles. Analyses included unheated particles, particles subjected
      to wet heat at 80 degrees C for 20 min, and particles subjected to dry heat at
      110 degrees C for 1 hr. Unheated particles yielded mean counts ranging from 6
      colonies per particle for the smallest (44-53 micrometers) soil fraction to
      approximately 55 colonies per particle for the largest size (105-125 micrometers)
      soil fraction tested. Mean counts for heat-resistant forms ranged from 2 colonies
      per particle for the smaller particles to 12-15 colonies for the largest
      particles analyzed.

PMID- 12596808
TI  - Morphology of extremely heat-resistant spores from Bacillus sp. ATCC 27380 by
      scanning and transmission electron microscopy.
AB  - Bacillus sp. ATCC 27380 is a recently discovered aerobic mesophile, isolated from
      surface soil, that produces spores with extreme resistance to dry heat: the
      length of time to 90% kill is 139 hr at 125 degrees C and 13-17 hr at 138 degrees
      C. Values for spores from other known species range from 5 to 100 min. The
      molecular basis for this extreme heat resistance is unknown. We report a
      structural analysis of the internal and external mature spore morphology obtained
      by both scanning and transmission electron microscopy. Both modes of microscopy
      delineate a morel-like structure characterized by irregular, but distinct,
      polygonal ridges suggestive of extreme dehydration. Some spores also possess an
      appendage resembling the bun of a brioche. This bun-like body is possibly unique
      to this species. In cross section the spore exhibits a many-layered structure,
      each layer with a characteristic fine structure. These morphological characters
      do not suffice to explain the observed resistance to dry heat at extreme
      temperatures. They do form a basis for the chemical characterizations which will
      be necessary to understand this heat resistance at the molecular level. The
      concept of "solid state spore" is put forward as a generalization that may be
      useful towards understanding this resistance.

PMID- 12596809
TI  - Life and the outer planets I. Performance of terrestrial organisms in ammonia
      rich systems.
AB  - Survival and growth of organisms has been demonstrated at 298 degrees K in NH3
      atmospheres, including ammonia-methane mixtures. Included are bacteria such as
      Clostridium perfringens, Pseudomonas aeruginosa, fungi such as Penicillium
      notatum and Torula utilis. Although the biological response in onion and other
      species of Allium is limited to germination, standard metabolic poisons were
      active even in 15 M aqueous NH3, at 250 degrees K. The most extreme example of
      compatibility between NH3-rich environments and terrestrial life was the
      retention of metabolic capabilities by conidia of Penicillium after 6 months at
      233 degrees K in a liquid ammonia-glycerol medium. Tritiated thymidine, uridine
      and amino acids were incorporated by these conidia unless subjected to intense
      gamma-radiation. Observations spanning the past decade suggest that the analogies
      between H2O and NH3 as solvent media or -OH and -NH2, as functional groups are
      probably valid. Chemical-biological evolution similar to early terrestrial
      evolution could be compatible with chemical conditions presumed to exist on the
      outer planets and some of their satellites.

PMID- 12596810
TI  - Life and the outer planets. II. Enzyme activity in ammonia-water systems and
      other exotic media at various temperatures.
AB  - Enzyme activities are customarily measured in aqueous solutions. Activity and
      thermodynamic parameters are based upon behavior in these solutions although they
      in no way represent the highly structured internal surface system of the cell.
      Actual environmental limits for enzyme action may be greater than generally
      assumed. Peroxidase, catalase, urease and amylase retain activity in drastically
      modified aqueous and nonaqueous media, including aprotic solvents. Examples
      include formic acid, methanol, formamide, nitromethane, 10 M LiCl and 15 M
      aqueous ammonia. Temperatures as low as 225-233 degrees K permit activity in some
      media. Ammonia-rich environments are compatible with some forms of terrestrial
      life. Enzyme activity in these exotic media and conditions is relevant to
      chemical evolution on Jupiter and similar planetary systems.

PMID- 12596811
TI  - Anaerobic utilization of phosphite/phosphine as a sole source of phosphorus:
      implication to growth in the Jovian environment.
AB  - The objective of the investigation was to isolate anaerobic micro-organisms which
      had the ability to utilize inorganic phosphorus in forms other than phosphate.
      The first part of this investigation was to isolate from Cape Canaveral soil
      micro-organisms capable of utilizing phosphite as their phosphorus source under
      anaerobic conditions. In an attempt to demonstrate this ability, a medium was
      prepared which contained hypophosphite as the phosphorus source. This was
      inoculated with soil samples, and growth was subcultured at least four times. To
      verify that these isolates could use hypophosphite, they were inoculated into
      defined hypophosphite medium, and samples were removed periodically and killed
      with formalin. Growth was determined by turbidity measurements and the sample was
      then filtered. The filtrate was separated by chromatography and the total amounts
      of hypophosphite, phosphate and phosphate in the filtrate were measured. By this
      procedure it appeared that the hypophosphite level began decreasing after 14 hr
      of incubation suggesting utilization of the hypophosphite under anaerobic
      conditions. The third part of this investigation used labeled (32P) hypophosphite
      in a defined medium; the cells were then lysed and the metabolic compounds
      separated by the use of paper chromatography and autoradiograms, demonstrating
      the presence of 32P in intermediate metabolic compounds. Similar investigations
      are now being performed with phosphine as the phosphorus source.

PMID- 12596812
TI  - Satellite studies on the use of electric fields for shielding biological objects
      against cosmic rays.
AB  - The paper presents the results of measurements of conduction currents in strong
      electric fields of an electrostatic radiation shield apparatus aboard the Cosmos
      690 artificial satellite. Power, dose and weight-size characteristics were
      calculated for an electrostatic shield and it was concluded that with available
      high-voltage technology it is possible to create an efficient low-weight
      electrostatic shield against cosmic radiation for biological objects. The
      development of an electric field system for in-flight radiation protection of
      biological objects could solve a number of other technological problems, such as
      protection of equipment and instruments against electric inductions, discharges
      and surface breakdowns.

PMID- 12596813
TI  - Role of nuclear stars in the light flashes observed on Skylab 4.
AB  - The astronauts on Skylab 4 observed bursts of intense visual light-flash activity
      when their spacecraft passed through the portion of the earth's inner trapped
      radiation belt known as the South Atlantic Anomaly (SAA). Two experimental
      sessions were carried out on board Skylab 4 under the auspices of Pinsky et al.
      who compare the flash rates with the measured flux of Z > or = 1 particles that
      would pass through the astronaut's eyes. They concluded that the flash rates,
      which became as great as 20/min, were anomalously high. We explored a number of
      alternative explanations for the anomalous flash rates that would be consistent
      with the accepted SAA flux values and the laboratory data on particle induced
      visual sensations and found that when one includes the effect of nuclear
      interactions in and near the retina which result in star formation (the emission
      of slow protons, neutrons and alpha particles form the nucleus in an evaporation
      like process) the apparent anomaly is removed.

PMID- 12596814
TI  - Assignment of particle tracks to spores of Bacillus subtilis on silver chloride
      detectors.
AB  - In Biostack III B, flown in the Apollo-Soyuz Test Project, AgCl detectors were
      used to study ionizing effects of HZE particles on spores of Bacillus subtilis or
      eggs of Artemia salina. The tracks of these particles inside the detectors are
      used to extrapolate the path of the particle near the biological objects which
      are fixed at the detector surface. The closest distance to the geometric centre
      of the object, the so-called impact parameter, is determined with a mean accuracy
      of 0.3 micrometers for 1 micrometers spores. From knowledge of the lateral
      distribution of the energy transferred by primary and secondary ionization
      effects of the particle, the energy deposit and its localization at the objects
      can be determined. We describe some technical aspects of a video-electronic
      scanning system, Quantimet 720, which has been adjusted to the particular
      requirements of these experiments. The main improvements achieved are increased
      precision of coordinate measurements, objective focusing of the microscopic image
      combined with measurements of the density profile of particle tracks, and finally
      speeding up of the measurements by automatic data transfer.

PMID- 12596815
TI  - Continuous 30-day measurements utilizing the monkey metabolism pod.
AB  - We have previously described a fibreglass pod system which makes possible
      quantitative physiological measurements to study the effects of weightlessness on
      10-14-kg adult monkeys maintained in comfortable restraint under space flight
      conditions. Recent improvements in the system have allowed continuous
      measurements to be made of respiratory gas exchange, cardiovascular function, and
      mineral balance for periods of up to 30 days on pig-tailed monkeys. It has also
      been possible to operate two pods which share one set of instrumentation, thereby
      permitting simultaneous measurements to be made on two animals by commutating
      signal outputs from the pods. In principle, more than two pods could be operated
      in this fashion. The system is compatible with Spacelab design. Representative
      physiological data from ground tests of' the system are presented.

PMID- 12596816
TI  - Dynamics of sleep patterns during prolonged simulated weightlessness.
AB  - Subjects immersed for 6 days in water, simulating weightlessness, exhibited
      marked changes in the total time spent in sleep and in the percentage of that
      time spent in each sleep stage. The length of time spent in Stage 4 deep sleep
      and in REM sleep decreased in the first half of the 6-day immersion period.
      During the latter half of the immersion period, a clear adaptive response was
      observed in the sleep patterns: the sequential appearance of the different stages
      of sleep and the percentage of time spent in the six stages of sleep showed a
      clear approach to the pre-immersion data. During the 3-day post-immersion period,
      the patterns approached the normal pre-immersion levels, although there was some
      overshoot or a negative phase period characterizing this approach. By the sixth
      day of immersion, the percentage of time spent in each stage of sleep had
      returned to near normal pre-immersion values, but the total time spent in sleep
      was still somewhat less than normal. This fact suggests that, once adapted to a
      condition of weightlessness, the sleep requirement may be less than during normal
      ambulatory life. During the post-immersion period, the pattern of Stage 4 sleep
      at early evening, midnight and dawn showed no special reactive characteristics,
      but rather a clear recovery towards the original pattern. On the other hand, at
      the duration of REM sleep, it overshot the pre-immersion values at the beginning
      of the post-immersion period, and then returned to the original pattern. These
      experiments suggest that some of the changes in sleep patterns which are observed
      under conditions simulating weightlessness may be adaptive.

PMID- 12596817
TI  - The effect of low light intensity on the maintenance of circadian synchrony in
      human subjects.
AB  - The light-intensity threshold for humans is not known. In past space flights
      owing to power restrictions, light intensities have been minimal and reported to
      be as low as 15 ft. c. This study was conducted to determine whether the light
      (L)/dark (D) environment of 16L : 8D at the relatively low light intensity of 15
      ft. c. was adequate for the maintenance of circadian synchrony in human subjects.
      Six healthy male subjects aged 20-23 years were exposed for 21 days to a 16L : 8D
      photoperiod. During the first 7 days the light intensity was 100 ft. c.; it was
      reduced to 15 ft. c. during the next 7 days and increased again to 100 ft. c.
      during the last 7 days of the study. Rectal temperature (RT) and heart rate (HR)
      were recorded continuously throughout the 21 days of the study. In the 100 ft. c.
      16L : 8D the RT and HR rhythms remained stable and circadian throughout. When the
      light intensity was decreased to 15 ft. c. the periodicity of the HR rhythm was
      significantly decreased and this rhythm showed marked instability. In contrast
      the period of the RT rhythm did not change but a consistent phase delay occurred
      due to a delay in the lights-on associated rise in RT. These divergent effects on
      these two rhythms in internal desynchronization and performance decrement during
      the 15 ft. c. exposure. The data emphasize the need for establishing accurately
      the minimal lighting requirements for the maintenance of circadian rhythms of
      humans in confined environments.

PMID- 12596818
TI  - Nutations of sunflower seedlings on tilted clinostats.
AB  - The kinetics of hypocotyl nutations in Helianthus annuus L. were measured on
      plants which were rotated on clinostats with axes of rotation inclined at various
      angles, alpha, away from the vertical. The g-force component acting in the
      direction of the plant axis was taken as g cos alpha. The average period and
      average amplitude of nutation were constant for all such axially directed g
      forces between 1.0 and 0.2 g (vertical to about 80 degrees inclination). On the
      horizontal clinostat (90 degrees inclination) nutation was neither initiated nor
      sustained. The g-force just sufficient fully to activate nutational oscillations
      should be sought in the range of the g-force parameter, 0 < g < 0.2.

PMID- 12596819
TI  - Apollo-Soyuz Test Project on biorhythm of zone-forming fungi: preliminary work.
AB  - The purpose of the experiment was to study general and local effects of space
      flight factors on the rhythm of cellular activity and on the morphological and
      genetic properties of biological objects. The Pushchino strain, Actinomyces
      levoris Kras 17-225A-IBFM, isolated at the Institute of Biological Physics,
      Moscow, was chosen as the main biological object. Under appropriate conditions it
      gives distinct and continuous rings of spore formation reflecting its intrinsic
      high degree of synchronism in changing its reproduction forms seen with the
      unaided eye as transparent rings (vegetative growth) alternate with convex white
      rings (spore-formation growth). As an additional test object, a film culture of
      bacteriophage T4Br+ developed at the institute was used. The strains were placed
      together in one bioblock together with plastic detectors for detecting nuclear
      particles. The film culture of bacteriophage enabled us to amplify the area of
      registration of local radiation effects by studying the genetic effects of these:
      frequency of mutations, induced radiation, their spectrum, subsequent
      revertability under the action of chemical mutagens with known mechanisms of
      action on DNA molecules.

PMID- 12596820
TI  - Fistula between rectum and duplicated vagina in an infant with anorectal
      malformation and biliary atresia.

PMID- 12596821
TI  - Listing of educational programs in occupational therapy.

PMID- 12596822
TI  - Clinical experts on Rett disorder.

PMID- 12596823
TI  - Allergic contact dermatitis from occupational propyl gallate exposure.

PMID- 12596824
TI  - [Analysis and correction of leg deformities. 2. Correction].

PMID- 12596825
TI  - [Judgment of the efficacy of digital image diagnosis and ROC analysis].

PMID- 12596826
TI  - [Basic methodologies for evaluation of digital radiography].

PMID- 12596827
TI  - [Image evaluation of flat panel detector].

PMID- 12596829
TI  - [Image quality evaluations of CRT displays from the point of view of device
      characteristics].

PMID- 12596828
TI  - [Image evaluation of CRT's--special reference to physical and psychophysical
      evaluation].

PMID- 12596830
TI  - [Image evaluation in computed tomography].

PMID- 12596831
TI  - [Image quality assessment in magnetic resonance imaging].

PMID- 12596833
TI  - In a virtual world, let's not lose the person.

PMID- 12596834
TI  - Androgen therapy for menopausal women.
AB  - The cohort of menopausal women has dramatically increased in size. Along with the
      drop in endogenous estrogen during this transition, there is also a drop in
      endogenous testosterone. This drop in endogenous testosterone is particularly
      marked in women experiencing chemical and surgical menopause and can lead to
      diminished sexual desire and lack of feelings of well-being. The nurse
      practitioner is in an ideal position to identify these quality-of-life problems
      and provide appropriate androgen therapy as needed.

PMID- 12596835
TI  - Adult survivors of childhood sexual abuse: suggestions for perinatal caregivers.
AB  - As many as 1 in 4 women are survivors of childhood sexual abuse. This traumatic
      life event profoundly influences the care that advanced practice nurses provide
      throughout the life cycle, and particularly the care that is provided during
      times of physical and emotional stress. Despite the prevalence of sexual abuse,
      there has been little research on the experiences of survivors during the
      perinatal period, and few suggestions for interventions. This article reviews the
      literature on the implications of sexual abuse on a woman's experience of
      pregnancy, birth, and breastfeeding. It emphasizes the importance of routine
      screening for abuse, as well as assessment of a survivor's stage in the recovery
      process. Finally, this article suggests topics for appropriate perinatal
      anticipatory guidance for women who have a history of sexual abuse.

PMID- 12596836
TI  - Appendicitis during pregnancy.
AB  - Appendicitis during pregnancy is a serious medical condition that requires
      diagnostic accuracy. If diagnosis is delayed, there is an increased incidence of
      perforation and peritonitis, which can lead to fetal and maternal mortality and
      morbidity. Since appendicitis is the leading reason for surgery during pregnancy,
      healthcare providers must be aware of the signs and symptoms of this disease
      (Allen, Helling, & Langenfeld, 1989; Weingold, 1983). Pregnancy often blunts the
      symptoms, making diagnosis difficult (Sharp, 1994; Weingold, 1983). This article
      discusses the incidence of appendicitis in pregnancy, the signs and symptoms, as
      well as laboratory and radiologic tests used in diagnosis. The risks to the
      mother and fetus, along with surgical and medical interventions, are also
      discussed.

PMID- 12596837
TI  - Historical analysis of the Ebola virus: prospective implications for primary care
      nursing today.
AB  - Ebola continues to attract worldwide attention as a highly lethal virus of
      unknown origin that leaves victims bleeding to death and has no known vaccine or
      cure. The purpose of this historical research was to review and analyze the
      primary and secondary sources available on Ebola for use by primary care nurses
      in the event of future outbreaks. A rich resource of history has been well
      documented by some of the original physicians, virologists, and members of
      international teams, but nothing was found to be documented by nurses during
      these outbreaks. Multiple themes emerged including the origins of the viral
      strains of Ebola, transmission factors, epidemiology, virology, nonhuman and
      genetic research, treatment, and clinical implications. This research will
      provide primary care nurses with historical information about Ebola to help in
      future treatment options and algorithm development.

PMID- 12596838
TI  - Seeking a healthy baby: Hispanic women's views of pregnancy and prenatal care.
AB  - The goal of this study was to develop a grounded theory of pregnancy and prenatal
      care for a cohort of Hispanic women residing in an industrial city in the
      Northeast. Twenty-one women, of predominantly Puerto Rican and Dominican
      heritage, participated in in-depth interviews lasting 30-50 minutes in which they
      shared their views of pregnancies and prenatal care including cultural influences
      on pregnancy, social support, initiation of prenatal care, and interest and
      participation in perinatal education. The core category, seeking a healthy baby,
      emerged from the data using a constant comparison analysis method. The women
      enhanced their chances of achieving the goal of having a healthy baby three ways:
      (1) caring for self by having a positive attitude, viewing pregnancy as normal,
      seeking education, eating healthily, balancing activity and rest, having good
      habits, and initiating and continuing prenatal care; (2) receiving support from
      their network in the form of receiving advice, listening to problems and
      concerns, and providing housing, babysitting, financial aid, and transportation;
      and (3) accepting care from providers in Western and folk medicine.

PMID- 12596839
TI  - Children witnessing domestic violence: a developmental approach.
AB  - Over the past 30 years, domestic violence has been brought to the forefront of
      society's consciousness as a number of studies have defined it, identified
      prevalence and causal factors, and described intervention initiatives. Children
      who witness domestic violence are at risk for developing behavioral and emotional
      problems. These behaviors depend on the age of the child, the duration of the
      violence, whether the child is also being directly abused, the fierceness of the
      violence, and if the child remains in the abusive environment. The purpose of
      this paper was to review the literature and theoretical frameworks associated
      with children who are witnessing domestic violence from a developmental
      perspective and to determine if in their clinical practices expert pediatric
      nurse practitioners (PNPs) are seeing these behaviors in witnessing children.
      Twenty-eight PNPs returned a four-question survey tool describing behaviors in
      the four developmental categories: infancy, preschool, school-aged, and
      adolescence. Their descriptions were similar to data recorded in the literature,
      with extreme behaviors of aggression and withdrawal observed in all age groups.
      PNPs are in a position to identify the presence of domestic violence if they are
      sensitive to the behaviors displayed by witnessing children.

PMID- 12596840
TI  - Women with HSV and HPV: a strategy to increase self-esteem.
AB  - This study tested the impact of the use of a self-help module on knowledge of
      disease and the cognitive perceptual variables of self-esteem, self-concept,
      satisfaction with intimate relationships and body image in young adult women with
      herpes simplex virus (HSV) or human papillomavirus (HPV) infections. In this
      prospective, experimental study, 40 HSV-positive and 58 HPV-positive women were
      randomly assigned to the intervention or routine counseling groups. Analysis of
      covariance was used to test for treatment differences. The HSV intervention
      groups had greater satisfaction with intimate relationships after the
      intervention and a greater increase in self-esteem, but no effect of the
      intervention was found for the HPV groups. Pre- and posttest mean change scores
      were compared for the separate groups using t-test analysis. Although scores on
      the knowledge of disease tests were high for the subjects, they reported engaging
      in risky sexual behaviors. The findings indicate that the use of a self-help
      module to assist HSV-infected women with the psychological impact of this disease
      may be an effective strategy to enhance adjustment, but knowledge did not deter
      risk-taking behavior.

PMID- 12596841
TI  - Nurses in Israel: the struggle for regulating the profession.
AB  - To date (1998), Israel does not have a nurses' law. Israel has 6 million
      inhabitants, approximately 15,000 physicians, and 33,000 nurses--a ratio of 180
      nurses per 100,0000 inhabitants. Since the 1970s, drafts for a nurses' law have
      been formulated to set a legal framework for the profession, as is customary in
      many other countries. This framework would define the particularities of nursing
      as a profession, who may practice it, levels of training, recognized areas of
      specialization, and expertise in the operation of specific medical equipment and
      various nursing duties. Between 1993 and 1996, drafts for legislation were
      deliberated a number of times by committees appointed by the Ministry of Health
      but were not passed. Many elements opposed the drafts: the physicians and both
      the nurses' union and the midwives' union--the latter being a separate and an
      independent professional body from the nurses' organization.

PMID- 12596842
TI  - Using improved access to medical knowledge to enhance patient care.

PMID- 12596843
TI  - Properties of chlorogenic acid quinone: relationship between browning and the
      formation of hydrogen peroxide from a quinone solution.
AB  - Chlorogenic acid is the major polyphenol in foods derived from plants and is a
      good substrate for polyphenol oxidase. Chlorogenic acid quinone (CQA-Q), which is
      an oxidative product of chlorogenic acid by polyphenol oxidase, is an important
      intermediate compound in enzymatic browning. CQA-Q was prepared, and its
      properties and the relationship with browning were examined. The quinone solution
      was yellow or orange, and its molecular absorption coefficient was estimated to
      be 1.7 x 10(3) for 325 nm and 9.7 x 10(2) for 400 nm in an acidic aqueous
      solution. Chlorogenic acid and H2O2 were spontaneously generated in the CQA-Q
      solution as the yellowish color of the solution gradually faded. A pale colored
      polymer was the major product in the reaction solution. Amino acids such as
      lysine and arginine added to CQA-Q solution did not repress the fading of the
      yellowish color of the solution. We concluded from these results that CQA-Q
      itself and a mixture of CQA-Q and amino acids did not form intensive brown
      pigments in the acidic aqueous solution. H2O2 spontaneously formed in the CQA-Q
      solution, and other polyphenols might have played an important role in the
      formation of the brown color by enzymatic browning.

PMID- 12596844
TI  - Cystatin C in milk basic protein (MBP) and its inhibitory effect on bone
      resorption in vitro.
AB  - A cystein protease inhibitor was identified in the basic fraction of bovine milk.
      We have reported in our previous study that the milk basic protein (MBP) fraction
      suppressed osteoclast-mediated bone resorption in vitro. Since osteoclasts
      secreted cystein protease to digest collagen in the bone matrix, we identified
      the cystein protease inhibitor in MBP. A 12-kDa inhibitor was purified from MBP
      by papain affinity gel chromatography and subsequent Hi-Load Superdex 75 gel
      filtration chromatography. The N-terminal sequence of the 18 amino acid residues
      of the inhibitor corresponded to bovine cystatin C. The 12-kDa cystein protease
      inhibitor in MBP therefore seemed to be cystatin C. Purified cystatin suppressed
      bone resorption with the use of isolated osteoclasts in vitro. Cystatin in MBP is
      suggested as one of the factors inhibiting bone resorption.

PMID- 12596845
TI  - Enzyme inhibitors to increase poly-3-hydroxybutyrate production by transgenic
      tobacco.
AB  - Chemical regulation of secondary-metabolite synthesis was investigated through
      the improvement of poly-3-hydroxybutyrate (PHB) production in transgenic tobacco
      plants by the use of enzyme inhibitors. Two tobacco lines, BC3 and rCAB8, that
      produce PHB in both the cytosol and plastids were used. An acetyl-CoA carboxylase
      inhibitor, D-(+)-Quizalofop-ethyl, increased PHB accumulation in both lines 2
      fold. The accumulation rate of plastidial PHB in the rCAB8 line was 2.5-fold
      higher than that of cytosolic PHB in the BC3 line. A specific inhibitor of 3
      hydroxy-3-methylglutaryl-CoA reductase, mevastatin, also increased PHB
      accumulation but only in the BC3 line. These results indicated that chemical
      regulation of the native metabolic flows by the specific enzyme inhibitors
      increased secondary-metabolite production in the transgenic tobacco plants we
      used.

PMID- 12596846
TI  - New estimation method for fatty acid composition in oil using near infrared
      spectroscopy.
AB  - The absorption bands of cis-unsaturation and the carbon chain length of the fatty
      acid moieties in oil appear in the near infrared (NIR) wavelength region,
      especially around 1600-1800 nm. Using this region, a new estimation method for
      fatty acid composition analysis is proposed. Because the differences of the
      original NIR spectra are miniscule even in this region, the second derivative NIR
      spectra were examined in order to estimate the fatty acid composition in oil
      exclusively from the spectral patterns obtained. The parameters for calculating
      the second derivative NIR spectra were examined to make the spectral difference
      clearer. In any parameter, the absorption band was shifted to the shorter
      wavelength region when the unsaturation in fatty acid moieties increased, and it
      was shifted to the longer wavelength region when the carbon chain length
      increased. When the parameters were correct, this NIR method can estimate the
      fatty acid composition roughly, but simply, easily, and sometimes
      nondestructively.

PMID- 12596847
TI  - Induced volatiles in elicitor-treated and rice blast fungus-inoculated rice
      leaves.
AB  - The volatiles released from elicitor (copper chloride, jasmonic acid, UV, L
      methionine and chitosan oligomer)-treated and rice blast fungus-inoculated rice
      leaves were collected by the solid-phase microextraction technique and analyzed
      by GC-MS. (Z)-3-Hexen-1-ol, monoterpenes, methyl salicylate, and sesquiterpenes
      were identified as elicitor-induced volatiles by a comparison of their GC
      retention times and mass spectra with those of authentic compounds. The different
      elicitors resulted in some qualitative and quantitative differences in the
      production of volatiles. Monoterpenes and sesquiterpenes were identified as the
      rice blast fungus-induced volatiles.

PMID- 12596848
TI  - Comparison of C-S lyase in Lentinus edodes and Allium sativum.
AB  - The characteristics of C-S lyase in Lentinus edodes (shiitake) were compared with
      those in Allium sativum (garlic). C-S lyase mRNA from shiitake was hybridized
      with the garlic C-S lyase cDNA fragment, being almost the same length as that
      from garlic. The isoelectric point of the C-S lyase from shiitake was between pH
      4 and 5, while that from garlic was over a wider range between pH 4 and 8.
      Different from the C-S lyase from garlic, that from shiitake was not a
      glycoprotein without being stained by PAS, and was not bound to the anti-garlic C
      S lyase antibody. Similar to garlic C-S lyase, shiitake C-S lyase comprised a
      homodimer, and its molecular mass was 84 kDa. However, the N-terminal amino acid
      sequences of each subunit of shiitake C-S lyase were totally different from those
      of garlic C-S lyase.

PMID- 12596849
TI  - Transcriptional regulators of the 51D surface protein gene of Paramecium
      tetraurelia.
AB  - The alpha-51D gene encodes surface protein 51D, which specifies serotype 51D of
      Paramecium tetraurelia stock 51. Previously, we isolated the gene as one
      expressed at much higher levels in a short-lived mutant than in its parental wild
      type stock and characterized its expression to be up-regulated with increased
      clonal age of the wild-type stock. Here we investigated the transcriptional
      mechanism for the serotype expression in light of its possible causal
      relationship to the Paramecium clonal life span. DNA-protein binding analyses of
      the upstream of the alpha-51D gene identified a stretch of DNA sequence that
      interacted specifically with macronuclear proteins prepared from the 51D
      expressing mutant. The DNA sequence was mapped to the 23 bp between -310 and 
      288, counting from the initiation position of 51D transcription. A protein with a
      binding ability for this DNA element was purified to homogeneity from the
      macronuclear proteins by chromatography using the specific DNA-protein
      interaction. In vitro transcriptional analyses showed that both the purified
      protein and its target domain are essential for increased synthesis of the 51D
      transcript. These results showed that the DNA-protein interaction is required for
      induction of the 51D expression in the mutant. However, aged wild-type paramecia,
      in which the serotype is also highly expressed, lacked the same specific
      transcriptional activity as detected in the mutant, suggesting another DNA
      protein interaction involved in the 51D up-regulation.

PMID- 12596850
TI  - Oxidative stability of polyunsaturated fatty acid in phosphatidylcholine
      liposomes.
AB  - Synthesized PCs containing docosahexaenoic acid (DHA), arachidonic acid (AA),
      linoleic acid (LA), and palmitic acid (PA) at known positions in the glycerol
      moiety were oxidized in liposomes, bulk, and organic solvent. In bulk and organic
      solvent, the oxidative stability of PC decreased with increasing degrees of
      unsaturation. However, the degree of unsaturation had little effect on the
      stability of PC in liposomes. The oxidative stability of PC in liposomes would be
      affected by the chemical reactivity based on the degree of unsaturation and by
      the conformation of fatty acyl component in PC bilayers. When the oxidative
      stability of 1-PA-2-LA-PC or 1-PA-2-AA-PC was compared with that of a 1:1 (mol
      ratio) mixture of 1,2-diPA-PC + 1,2-diLA-PC, or 1,2-diPA-PC + 1,2-diAA-PC,
      respectively, the former PC was more oxidatively stable than that of the latter
      PC mixture in all oxidation systems, although the degree of unsaturation of 1-PA
      2-PUFA-PC was the same as that of the corresponding mixture of diPA-PC + diPUFA
      PC. The higher oxidative stability of 1-PA-2-PUFA-PC than that of a corresponding
      mixture of diPA-PC + diPUFA-PC in liposomes was suggested to be due to the
      different conformation of PC bilayers and the different rate of hydrogen
      abstraction by free radicals from intermolecular and intramolecular acyl groups.

PMID- 12596851
TI  - Characterization of a cellobiose phosphorylase from a hyperthermophilic
      eubacterium, Thermotoga maritima MSB8.
AB  - The cepA putative gene encoding a cellobiose phosphorylase of Thermotoga maritima
      MSB8 was cloned, expressed in Escherichia coli BL21-codonplus-RIL and
      characterized in detail. The maximal enzyme activity was observed at pH 6.2 and
      80 degrees C. The energy of activation was 74 kJ/mol. The enzyme was stable for
      30 min at 70 degrees C in the pH range of 6-8. The enzyme phosphorolyzed
      cellobiose in an random-ordered bi bi mechanism with the random binding of
      cellobiose and phosphate followed by the ordered release of D-glucose and alpha-D
      glucose-1-phosphate. The Km for cellobiose and phosphate were 0.29 and 0.15 mM
      respectively, and the kcat was 5.4 s(-1). In the synthetic reaction, D-glucose, D
      mannose, 2-deoxy-D-glucose, D-glucosamine, D-xylose, and 6-deoxy-D-glucose were
      found to act as glucosyl acceptors. Methyl-beta-D-glucoside also acted as a
      substrate for the enzyme and is reported here for the first time as a substrate
      for cellobiose phosphorylases. D-Xylose had the highest (40 s(-1)) kcat followed
      by 6-deoxy-D-glucose (17 s(-1)) and 2-deoxy-D-glucose (16 s(-1)). The natural
      substrate, D-glucose with the kcat of 8.0 s(-1) had the highest (1.1 x 10(4) M(
      1) s(-1)) kcat/Km compared with other glucosyl acceptors. D-Glucose, a substrate
      of cellobiose phosphorylase, acted as a competitive inhibitor of the other
      substrate, alpha-D-glucose-1-phosphate, at higher concentrations.

PMID- 12596852
TI  - Mutant luciferase enzymes from fireflies with increased resistance to
      benzalkonium chloride.
AB  - Benzalkonium chloride (BAC), used to extract intracellular ATP, interferes with
      subsequent firefly luciferase-luciferin assays. There was a significant
      difference among wild-type luciferases with respect to BAC resistance. Luciola
      lateralis luciferase (LlL) was the most tolerant, followed by Luciola cruciata
      luciferase (LcL) and Photinus pyralis luciferase. Random mutagenesis of
      thermostable mutants of LcL showed that the Glu490Lys mutation contributes to
      improved resistance to BAC. The corresponding Glu490Lys mutation was introduced
      into thermostable mutants of LlL by site-directed mutagenesis. Kinetic analysis
      demonstrated that the resultant LlL-217L490K mutant, having both an Ala217Leu and
      a Glu490Lys mutation, showed the highest resistance to BAC, with an initial
      remaining bioluminescence intensity of 87.4% and a decay rate per minute of 29.6%
      in the presence of 0.1% BAC. The Glu490Lys mutation was responsible for increased
      resistance to inactivation but not inhibition by BAC. The LlL-217L490K had
      identical thermostability and pH stability to the parental thermostable mutant.
      From these results, it was concluded that the LlL-217L490K enzyme is advantageous
      for hygiene monitoring and biomass assays based on the ATP-bioluminescence
      methodology. This is the first report demonstrating improved resistance to BAC of
      the firefly luciferase enzyme.

PMID- 12596853
TI  - Cloning of the maltose phosphorylase gene from Bacillus sp. strain RK-1 and
      efficient production of the cloned gene and the trehalose phosphorylase gene from
      Bacillus stearothermophilus SK-1 in Bacillus subtilis.
AB  - The maltose phosphorylase (MPase) gene of Bacillus sp. strain RK-1 was cloned by
      PCR with oligonucleotide primers designed on the basis of a partial N-terminal
      amino acid sequence of the purified enzyme. The MPase gene consisted of 2,655 bp
      encoding a theoretical protein with a Mr of 88,460, and had no secretion signal
      sequence, although most of the MPase activity was detected in the culture
      supernatant of RK-1. This cloned MPase gene and the trehalose phosphorylase
      (TPase) gene from Bacillus stearothermophilus SK-1 were efficiently expressed
      intracellularly under the control of the Bacillus amyloliquefaciens alpha-amylase
      promoter in Bacillus subtilis. The production yields were estimated to be more
      than 2 g of enzyme per liter of medium, about 250 times the production of the
      original strains, in a simple shake flask. About 60% of maltose was converted
      into trehalose by the simultaneous action of both enzymes produced in B.
      subtilis.

PMID- 12596854
TI  - Cloning and nucleotide sequence of the glutamate decarboxylase-encoding gene gadA
      from Aspergillus oryzae.
AB  - We cloned a genomic DNA encoding the glutamate decarboxylase (GAD) from
      Aspergillus oryzae using a 200-bp DNA fragment as the probe. This DNA fragment
      was amplified by the reverse transcription polymerase chain reaction with mRNA of
      A. oryzae as the template and degenerate primers designed from the conserved
      amino acid sequence of Escherichia coli GAD and Arabidopsis thaliana GAD.
      Nucleotide sequencing analysis showed that the cloned gene (designated gadA)
      encoded 514 amino acid residues and contained three introns. Southern
      hybridization showed that the gadA gene was on a 6.0-kb SacI fragment and that
      there was a single copy in the A. oryzae chromosome. The cloned gene was
      functional, because one transformant of A. oryzae containing multiple copies of
      the gadA gene had 10-fold the GAD activity and a 12-fold increase in gamma
      aminobutyric acid production compared with the control strain.

PMID- 12596855
TI  - Synthesis of 27-oxo, 27-hydroxymilbemycins A3 and A4 and novel 27
      alkoxymilbemycins A3 and A4 from milbemycins A3 and A4 and their acaricidal
      activities.
AB  - 27-Oxomilbemycins A3 and A4 and 27-hydroxymilbemycins A3 and A4 were identified
      as metabolites in soil metabolism studies of milbemycins A3 and A4. Chemical
      derivation methods were developed to synthesize 27-oxomilbemycins A3 and A4 and
      27-hydroxymilbemycins A3 and A4 from milbemycins A3 and A4. In addition, 27
      alkoxymilbemycin derivatives were also synthesized from the same precursors. Some
      of the synthesized compounds displayed satisfactory acaricidal activity against
      the organophosphorus-sensitive two-spotted spider mite (Tetranychus urticae), but
      did not have superior activity to corresponding milbemycins A3 and A4.

PMID- 12596856
TI  - Novel enzymatic method for the production of xylitol from D-arabitol by
      Gluconobacter oxydans.
AB  - Microorganisms capable of producing xylitol from D-arabitol were screened for. Of
      the 420 strains tested, three bacteria, belonging to the genera Acetobacter and
      Gluconobacter, produced xylitol from D-arabitol when intact cells were used as
      the enzyme source. Among them, Gluconobacter oxydans ATCC 621 produced 29.2 g/l
      xylitol from 52.4 g/l D-arabitol after incubation for 27 h. The production of
      xylitol was increased by the addition of 5% (v/v) ethanol and 5 g/l D-glucose to
      the reaction mixture. Under these conditions, 51.4 g/l xylitol was obtained from
      52.4 g/l D-arabitol, a yield of 98%, after incubation for 27 h. This conversion
      consisted of two successive reactions, conversion of D-arabitol to D-xylulose by
      a membrane-bound D-arabitol dehydrogenase, and conversion of D-xylulose to
      xylitol by a soluble NAD-dependent xylitol dehydrogenase. Use of disruptants of
      the membrane-bound alcohol dehydrogenase genes suggested that NADH was generated
      via NAD-dependent soluble alcohol dehydrogenase.

PMID- 12596857
TI  - A new polypeptide toxin from the nematocyst venom of an Okinawan sea anemone
      Phyllodiscus semoni (Japanese name "unbachi-isoginchaku").
AB  - The venomous sea anemone Phyllodiscus semoni causes cases of severe stinging. We
      isolated Phyllodiscus semoni toxin 20A (PsTX-20A), a hemolytic and lethal
      polypeptide (20 kDa), from the nematocyst venom of this species for the first
      time. Furthermore, we sequenced the cDNA encoding PsTX-20A. The deduced amino
      acid sequence of PsTX-20A showed that this toxin was a new member of the
      actinoporin family, which consists of several cytolytic polypeptides originating
      from sea anemones. PsTX-20A showed lethal toxicity to the shrimp Palaemon
      paucidens when administered via intraperitoneal injection (LD50, 50 microg/kg)
      and hemolytic activity toward 0.8% sheep red blood cells (ED50, 80 ng/ml).

PMID- 12596858
TI  - Isoflavone aglycon produced by culture of soybean extracts with basidiomycetes
      and its anti-angiogenic activity.
AB  - Soybean extracts (SBE) containing isoflavone glycosides were cultured with
      Ganoderma lucidum mycelia producing beta-glucosidase. The anti-angiogenic effects
      of the cultivated product, containing rich in genistein, named GCP (genistein
      combined polysaccharide), were assessed with chick chorioallantoic membranes
      (CAM) and a mouse dorsal air-sac model. Beta-glucosidase produced by the mycelia
      converted the isoflavone glycosides into aglycons. A test of volunteers showed
      that serum concentrations of genistein in the subjects treated with GCP (n = 4)
      at 3 h after administration were significantly higher than those in the subjects
      treated with SBE (n = 4). GCP inhibited angiogenesis in CAM, and the activity of
      GCP was greater than that of SBE. GCP inhibited the formation of new vessels
      induced by colon carcinoma cells in vivo.

PMID- 12596859
TI  - Incorporation and accumulation of docosahexaenoic acid from the medium by Pichia
      methanolica HA-32.
AB  - Yeast species were screened for the incorporation and accumulation of
      docosahexaenoic acid (DHA) with a yeast-malt medium containing 0.5% free fatty
      acid prepared from fish oil (DHA, 28% of total fatty acids in fish oil). The most
      suitable strain was Pichia methanolica HA-32. The optimum cultivation conditions
      for the accumulation of lipids and incorporation of DHA were as follows: 5%
      glucose, 20% yeast extract, and 3% free fatty acid in the medium, at pH 6.0 and
      with incubated at 25 degrees C for 3 days. Under these conditions, about 200 mg
      of total lipids and 60 mg of DHA were recovered from 1 g of dry cells. The
      accumulation of DHA in cells increased in conjunction with the amount of yeast
      extract added to the medium. Vitamin B groups and minerals also had an effect on
      the accumulation of DHA. Choline and K2HPO4, which caused browning of the medium,
      promoted the accumulation of DHA in cells.

PMID- 12596860
TI  - Gene cloning, purification, and characterization of 2,3-diaminopropionate ammonia
      lyase from Escherichia coli.
AB  - 2,3-Diaminopropionate ammonia-lyase (DAPAL), which catalyzes alpha,beta
      elimination of 2,3-diaminopropionate regardless of its stereochemistry, was
      purified from Salmonella typhimurium. We cloned the Escherichia coli ygeX gene
      encoding a putative DAPAL and purified the gene product to homogeneity. The
      protein obtained contained pyridoxal 5'-phosphate and was composed of two
      identical subunits with a calculated molecular weight of 43,327. It catalyzed the
      alpha,beta-elimination of both D- and L-2,3-diaminopropionate. The results
      confirmed that ygeX encoded DAPAL. The enzyme acted on D-serine, but its
      catalytic efficiency was only 0.5% that with D-2,3-diaminopropionate. The
      enzymologic properties of E. coli DAPAL resembled those of Salmonella DAPAL,
      except that L-serine, D-and L-beta-Cl-alanine were inert as substrates of the
      enzyme from E. coli. DAPAL had significant sequence similarity with the catalytic
      domain of L-threonine dehydratase, which is a member of the fold-type II group of
      pyridoxal phosphate enzymes, together with D-serine dehydratase and mammalian
      serine racemase.

PMID- 12596861
TI  - Zinc is involved in the expression of a nuclear-encoded alternative oxidase gene
      in the yeast Hansenula anomala.
AB  - When Hansenula anomala cells were treated by the combined addition of pyrithione,
      a zinc ionophore, and metal chelating agents such as EDTA and N,N,N',N'
      tetrakis(2-pyridylmethyl)ethylenediamine, the antimycin A3-dependent induction of
      cyanide-resistant respiratory activity was suppressed. Among the chelators we
      tested, Zn-saturated EDTA failed to sustain the inhibitory effect, and added zinc
      ions restored the induction in the treated cells. Further, the antimycin A3
      inducible mRNA level of the nuclear-encoded alternative oxidase gene detected by
      reverse transcriptase-PCR was significantly decreased by the treatment, and
      recovered to the level of untreated cells upon the addition of zinc ions. These
      results suggest that the treatment with pyrithione plus chelator resulted in an
      intracellular zinc-deficiency, which suppressed the expression of the nuclear
      encoded alternative oxidase gene. The added zinc ions reversibly restored the
      expression, indicating that zinc is involved in the alternative oxidase gene
      expression.

PMID- 12596862
TI  - Old Yellow Enzyme from Candida macedoniensis catalyzes the stereospecific
      reduction of the C=C bond of ketoisophorone.
AB  - Microorganisms were screened for ones that reduced 3,5,5-trimethyl-2-cyclohexene
      1,4-dione (ketoisophorone; KIP), and several strains were found to produce (6R)
      2,2,6-trimethylcyclohexane-1,4-dione (levodione). The enzyme catalyzing the
      reduction of the C=C bond of KIP to yield (6R)-levodione was isolated from
      Candida macedoniensis AKU4588. The results of primary structural analysis and its
      enzymatic properties suggested that the enzyme might be an Old Yellow Enzyme
      family protein.

PMID- 12596863
TI  - Novel S-benzylisothiourea compound that induces spherical cells in Escherichia
      coli probably by acting on a rod-shape-determining protein(s) other than
      penicillin-binding protein 2.
AB  - Random screening for inhibitors of chromosome partitioning in Escherichia coli
      was done by the anucleate cell blue assay. A novel S-benzylisothiourea
      derivative, S-(3,4-dichlorobenzyl)isothiourea, tentatively named A22, was found
      to induce spherical cells and spherical anucleate cells in E. coli. Mecillinam, a
      specific inhibitor of penicillin-binding protein 2, which induces spherical cells
      in E. coli, also caused anucleate cell production. Spherical cells induced by
      treatment with either A22 or mecillinam varied in size, and anucleate cells
      seemed to be more frequent among the smaller cells. These results suggest that
      loss of the rod shape in E. coli leads to asymmetric cell division that results
      in production of anucleate cells. No competition was observed even in the
      presence of a 10-fold excess A22 in an in vitro assay of 14C-penicillin G
      binding, but mecillinam specifically inhibited binding of 14C-penicillin G to
      penicillin-binding protein 2. Simultaneous treatment with mecillinam and
      cephalexin, a specific inhibitor of penicillin-binding protein 3, induced lysis
      of E. coli cells, but a combination of A22 and cephalexin did not. These results
      suggest that the target molecule(s) of A22 was not penicillin-binding protein 2.
      A22 may act on a rod-shape-determining protein(s) other than penicillin-binding
      protein 2, such as RodA or MreB.

PMID- 12596864
TI  - His-to-Asp phosphorelay circuitry for regulation of sexual development in
      Schizosaccharomyces pombe.
AB  - The fission yeast Schizosaccharomyces pombe has three histidine kinases
      (Phk1/Mak2, Phk2/Mak3, and Phk3/Mak1), and two response regulators (Mcs4 and
      Prr1). The results of recent extensive studies on the S. pombe His-to-Asp
      phosphorelay circuitry suggested that it is involved in oxidative stress
      responses through the transcriptional regulation of several scavenger genes for
      toxic free radicals. The functions of these histidine kinases have not yet been
      fully characterized. Here we characterize a homothallic (h90) mutant lacking the
      genes for all the histidine kinases, with special reference to sexual
      development. Homothallic phk1/2/3delta cells underwent mating precociously in a
      nitrogen-deficient medium. Surprisingly, the mutant cells underwent mating even
      in a nitrogen-sufficient medium, under which conditions wild-type cells did so
      rarely if at all. Under anaerobic (or microaerobic) growth conditions, wild-type
      cells did not undergo sexual development even in a nitrogen-deficient medium, but
      the homothallic phk1/2/3delta cells mated efficiently. Oxidative reagents such as
      H2O2 induced sexual development in wild-type cells grown anaerobically. On the
      basis of these results, we propose the novel view that the S. pombe His-to-Asp
      phosphorelay, initiated by the Phk histidine kinases, is crucial for regulation
      of sexual development. This Phk-mediated signaling pathway is linked to the well
      documented canonical pathway for induction of the sexual development, in that
      both converge at the initiation of meiosis through activation of ste11+, mam2+,
      and mei2+ transcription.

PMID- 12596865
TI  - Use of shark collagen for cell culture and zymography.
AB  - The uses of shark collagen as a matrix for cell culture and as a substrate for
      zymography were investigated. Fibroblasts were cultured on a gel matrix of shark
      type I collagen at 30 degrees C. The collagen gel had contracted by 4 days of
      incubation. Individual fibroblasts were visible against the transparent
      background of the contracted collagen as long, lean star-shaped cells. The matrix
      metalloproteinases (MMPs) from fibroblasts secreted from the medium more easily
      digested shark gelatin than pig gelatin. MMP-2, -9, and that of potential form
      were recognizable in the zymographic gel of shark gelatin.

PMID- 12596866
TI  - Antifungal activities of N-arylbenzenesulfonamides against phytopathogens and
      control efficacy on wheat leaf rust and cabbage club root diseases.
AB  - A set of N-arylbenzenesulfonamides with various substituents at the arylamine and
      benzenesulfonyl positions were prepared, and their antifungal properties were
      measured in vitro against such plant pathogenic fungi as Pythium ultimum,
      Phytophthora capsici, Rhizoctonia solani, and Botrytis cinerea. Compounds 3, 4,
      8, 9, 10, 14, 16, 18, 20, 21, 24 and 27 had antifungal activity over a broad
      spectrum of the phytopathogenic fungi tested, where 50% of inhibition (ED50) was
      in the range of 3-15 microg/ml. Based on the in vitro activity, six derivatives
      (3, 4, 10, 18, 21 and 27) were selected and tested further for their fungicidal
      efficacy in vivo. The fungicidal efficacy of 10, 21 and 27 had a disease control
      value of over 85% at 50 microg/ml against wheat leaf rust, while that of 4 was
      selective against cabbage club root disease.

PMID- 12596867
TI  - Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519
      to glutamate receptors.
AB  - In an investigation of the mechanisms of the neuroprotective effects of theanine
      (gamma-glutamylethylamide) in brain ischemia, inhibition by theanine of the
      binding of [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid
      (AMPA), [3H]kainate, and [3H](E)-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1-H
      indole-2-carboxylic acid (MDL 105,519) to glutamate receptors was studied in
      terms of its possible inhibiting effects on the three receptor subtypes (AMPA,
      kainate, and NMDA glycine), with rat cortical neurons. Theanine bound the three
      receptors, but its IC50 of theanine was 80- to 30,000-fold less than that of L
      glutamic acid.

PMID- 12596868
TI  - Identification of a toxic mechanism of the plasticizers, phtahlic acid esters,
      which are putative endocrine disrupters: time-dependent increase in quinolinic
      acid and its metabolites in rats fed di(2-ethylhexyl)phthalate.
AB  - We have reported that the administration of di(2-ethylhexyl)phthalate (DEHP)
      increased the formations of quinolinic acid (QA) and its lower metabolites on the
      tryptophan-niacin pathway. To discover the mechanism involved in disruption of
      the tryptophan-niacin pathway by DEHP, we assessed the daily urinary excretion of
      QA and its lower metabolites, and enzyme activities on the tryptophan-niacin
      pathway. Rats were fed with a niacin-free, 20% casein diet or the same diet
      supplemented with 0.1% DEHP or 0.043% phthalic acid and 0.067% 2-ethylhexanol
      added for 21 days. Feeding of DEHP increased the urinary excretions of QA and its
      lower metabolites in a time-dependent manner, and the increase of these
      excretions reached a peak at 11 days, but feeding of phthalic acid and 2
      ethylhexanol had no effect. Feeding of DEHP, however, did not affect any enzyme
      activity including alpha-amino-beta-carboxymuconate-epsilon-semialdehyde
      decarboxylase (ACMSD), affecting the formation of QA, on the tryptophan-niacin
      pathway.

PMID- 12596869
TI  - Identification of (3S, 9R)- and (3S, 9S)-megastigma-6,7-dien-3,5,9-triol 9-O-beta
      D-glucopyranosides as damascenone progenitors in the flowers of Rosa damascena
      Mill.
AB  - The progenitors of damascenone (1), the most intensive C13-norisoprenoid volatile
      aroma constituent of rose essential oil, were surveyed in the flowers of Rosa
      damascena Mill. Besides 9-O-beta-D-glucopyranosyl-3-hydroxy-7,8-didehydro-beta
      ionol (4b), a stable progenitor already isolated from the residual water after
      steam distillation of flowers of R. damascena Mill., two labile progenitors were
      identified to be (3S, 9R)- and (3S, 9S)-megastigma-6,7-dien-3,5,9-triol 9-O-beta
      D-glucopyranosides (2b) based on their synthesis and HPLC-MS analytical data.
      Compound 2b gave damascenone (1), 3-hydroxy-beta-damascone (3) and 4b upon
      heating under acidic conditions.

PMID- 12596870
TI  - Labdane-type diterpene dialdehyde, pungent principle of myoga, Zingiber mioga
      Roscoe.
AB  - The pungent principle of myoga (Zingiber mioga Roscoe) was identified as (E)
      8beta(17)-epoxylabd-12-ene-15,16-dial (miogadial) on the basis of its physical
      and spectroscopic properties (MS, NMR, IR, and UV). Galanal A and B, isolated as
      well as miogadial, had no hot taste. Reduced miogadial also was tasteless. The
      pungency of miogadial depended on the presence of alphabeta-unsaturated-1,4
      dialdehyde group.

PMID- 12596871
TI  - Effects of added dietary taurine on erythrocyte lipids and oxidative stress in
      rabbits fed a high cholesterol diet.
AB  - Lipid peroxidation leads to damage of polyunsaturated fatty acids of membrane
      phospholipids. The contribution of oxidative stress to hypercholesterolemia
      induced hemolytic anemia and the effects of addition of taurine on erythrocyte
      lipid composition, oxidative stress, and hematological data were studied in
      rabbits fed on a high cholesterol (HC) diet (1%, w/w) for 2 months. The effects
      of taurine on erythrocyte hemolysis and H2O2-induced lipid peroxidation were
      investigated in normal rabbit erythrocytes in vitro. The HC diet resulted in
      increases in plasma lipids and lipid peroxide levels as well as increases in
      cholesterol levels and the cholesterol:phospholipid ratio in the erythrocytes.
      This diet caused a hemolytic anemia, but lipid peroxide levels remained unchanged
      in the erythrocytes of the rabbits. Taurine (2.5%, w/w) added to the food has an
      ameliorating effect on plasma lipids and lipid peroxide levels in rabbits fed on
      a HC diet. This treatment also caused decreases in elevated erythrocyte
      cholesterol levels and cholesterol:phospholipid ratio due to the HC diet, but it
      did not prevent the hemolytic anemia and did not change erythrocyte lipid
      peroxide levels. In addition, in an in vitro study, taurine did not protect
      erythrocytes against H2O2-induced hemolysis or lipid peroxidation. These results
      show that the HC diet causes hemolytic anemia without any changes in erythrocyte
      lipid peroxidation, and taurine treatment was not effective against hemolytic
      anemia caused by the HC diet.

PMID- 12596872
TI  - Substrate inhibition of L-cysteine alpha,beta-elimination reaction catalyzed by L
      cystathionine gamma-lyase of Saccharomyces cerevisiae.
AB  - The alpha,beta-elimination of L-cysteine catalyzed by Saccharomyces cerevisiae L
      cystathionine gamma-lyase (EC 4.4.1.1) was inhibited by the substrate. The
      absorption spectrum of the holoenzyme in the presence of L-cysteine showed that
      the substrate inhibition observed in this reaction was due mainly to removal of
      the cofactor.

PMID- 12596873
TI  - Effects of voluntary resistance exercise on heme biosynthesis in rats given
      glucocorticoid-injections.
AB  - To identify the effects of a tower-climbing exercise on bone marrow heme
      biosynthesis and hematological status in rats given glucocorticoid-injections as
      a model of aging, 29 male Sprague-Dawley rats, 10 weeks of age, were assigned to
      three groups: a saline control (C, n = 9), a glucocorticoid-sedentary (GS, n =
      10) group, and a glucocorticoid-exercise (GE, n = 10) group. The GS and GE groups
      were given 2 mg/kg prednisolone daily, and the C group was given 2 ml of saline
      daily, subcutaneously. Each group was meal-fed commercial rat chow
      isoenergetically and given free access to water for 8 weeks. The GE group were
      allowed to climb a 200-cm tower to drink water from a bottle set at the top of
      it. Weight gain during the 8-week experimental period was greater in the C group
      than in the GS and GE groups. The gastrocnemius and tibialis anterior muscles
      were heavier in the C group than in other groups. The hematological parameters
      were not influenced by glucocorticoid administration with or without climbing
      exercise. Bone marrow delta-aminolevulinic acid dehydratase activity was
      significantly higher in the GE group than in the C group. These results suggest
      that 8 weeks of climbing exercise increases heme biosynthesis without alteration
      of hematological status in rats given glucocorticoid-injections. Resistance
      exercise may be a preventive therapy for iron-deficiency anemia associated with
      aging.

PMID- 12596874
TI  - Isolation of three main sericin components from the cocoon of the silkworm,
      Bombyx mori.
AB  - To characterize the sericin components of the cocoon of silkworm Bombyx mori,
      fresh cocoon shells were dissolved in saturated aqueous lithium thiocyanate
      containing 2-mercaptoethanol, and fractionated by ethanol precipitation. Cocoon
      sericin was found to mainly consist of three polypeptides having molecular masses
      of the 400, 250, and 150 kDa estimated by SDS-PAGE, which corresponds to the
      sericin present in the middle, anterior, and posterior part of the middle silk
      gland. The amino acid compositions of the 400 and 150 kDa components were similar
      to each other, but that of the 250 kDa component was different. This suggests
      differences in the coding gene and properties of the 250 kDa sericin from the
      other two.

PMID- 12596875
TI  - Molecular characterization of the gene encoding rice allene oxide synthase and
      its expression.
AB  - The gene encoding rice allene oxide synthase, OsAOS, was intronless and had
      nucleotide sequences with the high GC content of 67%. Deduced amino acid
      sequences had very high similarity with other AOS proteins, in particular 74%
      similarity to barley, characterized by the conserved motifs of P450 cytochrome of
      the CYP74A family. Purified recombinant rice AOS protein expressed in Escherichia
      coli converted 13-hydroperoxylinolenic acid to allene oxide. Several restriction
      enzyme digestions and Southern analysis showed that OsAOS was likely to have two
      copies in its genome. The basal level of OsAOS expression was detected in various
      tissues and the transcription level was increased by jasmonate treatment.

PMID- 12596876
TI  - Biotransformation of the mycotoxin, zearalenone, to a non-estrogenic compound by
      a fungal strain of Clonostachys sp.
AB  - Zearalenones are mycotoxins with estrogenic activity consisting of a resorcinol
      moiety fused to a 14-membered macrocyclic lactone and are produced by various
      Fusarium species. We found that Clonostachys rosea IFO 7063 was effectively
      capable of converting zearalenone (1) to cleavage product (2), 1-(3,5
      dihydroxyphenyl)-10'-hydroxy-1'E-undecene-6'-one. Moreover, cleavage product 2
      did not show potent estrogenic activity like that of 1 and 17beta-estradiol in
      the human breast cancer MCF-7 cell proliferation assay.

PMID- 12596877
TI  - OsRALyase1, a putative F-box protein identified in rice, Oryza sativa, with
      enzyme activity identical to that of wheat RALyase.
AB  - A rice gene, OsRALyase1, encoding a product similar to wheat ribosomal RNA
      apurinic site specific lyase (RALyase), was isolated and expressed in vitro. An
      open reading frame of the gene predicted a protein of 476 amino acid residues
      with 75% identity to RALyase and contained an F-box-like motif in its amino
      terminal region. The rice gene product expressed in a wheat-germ protein
      expression system had the same characteristics as its wheat counterpart, cleaving
      a specific depurinated site of the 28S rRNA sarcin-ricin domain.

PMID- 12596878
TI  - Design of a fluorescent electrophoretic mobility shift assay improved for the
      quantitative and multiple analysis of protein-DNA complexes.
AB  - We describe a protocol for the fluorescent electrophoretic mobility shift assay
      improved for the quantitative analysis of protein-DNA complexes. Fluorescent
      labeled oligonucleotide probes incubated with nuclear proteins were followed by
      electrophoresis. The signals for protein-DNA complexes were measured and
      normalized with fluorescent-labeled marker using fragment analysis software. This
      assay proved reliable measurement and multiple detection of DNA binding proteins.

PMID- 12596879
TI  - Identification of an indispensable amino acid for ppGpp synthesis of Escherichia
      coli SpoT protein.
AB  - Amino acid substitutions were introduced into a structurally flexible and highly
      conserved region of Escherichia coli SpoT protein. SpoT protein changed from Asp
      to Ala at the 293rd position did not restore cell growth of E. coli CF8295 (delta
      relA, delta spoT) and did not accumulate ppGpp in the cell, suggesting that the
      Asp293 is indispensable for ppGpp synthesis of the protein.

PMID- 12596880
TI  - Further stabilization of earthworm serine protease by chemical modification and
      immobilization.
AB  - Earthworm serine protease is more stable and is less affected by organic solvents
      and detergent than other proteases. However, it is inactivated, probably by
      autolysis, at 60 degrees C or above under alkaline conditions. Further
      stabilization was managed by chemical modification of the enzyme with 1-ethyl-3
      (3-dimethylaminopropyl)carbodiimide and phenylglyoxal to protect the activity
      from the autolytic inactivation. Stabilization was possible also under acidic
      conditions, in which the stability of the enzyme was rather low, by
      immobilization with folded sheet mesoporous material. Thus, further stabilization
      of the enzyme has been achieved by chemical modification or immobilization.

PMID- 12596881
TI  - Antisense suppression of collagen VI synthesis results in reduced expression of
      collagen I in normal human osteoblast-like cells.
AB  - A transient increase in collagen VI expression precedes the accumulation of
      collagen I associated with interleukin-4 (IL-4)-induced mineralization in human
      osteoblast-like cells. Transfection with an antisense oligonucleotide specific
      for alpha1(VI) collagen mRNA was shown to attenuate mRNA levels of collagens VI
      and I. Incubating IL-4 treated cells with anti-collagen VI antiserum decreased
      expression of alpha1(I) mRNA. The results suggest that collagen VI may regulate
      collagen I expression in the early phase of IL-4-induced mineralization.

PMID- 12596882
TI  - Novel hydroquinone as a matrix metallo-proteinase inhibitor from the mushroom,
      Piptoporus betulinus.
AB  - The novel hydroquinone, (E)-2-(4-hydroxy-3-methyl-2-butenyl)-hydroquinone, and
      known compound, polyporenic acid C, were isolated as matrix metallo-proteinase
      inhibitors from the mushroom, Piptoporus betulinus.

PMID- 12596883
TI  - Inhibition of the bacterial surface protein anchoring transpeptidase sortase by
      medicinal plants.
AB  - Inhibition by medicinal plant extracts of a recombinant sortase was evaluated for
      antibacterial drug discovery. The coding region of sortase, a transpeptidase that
      cleaves surface proteins of gram-positive bacteria, was amplified by PCR from the
      chromosome of Staphylococcus aureus ATCC 6538p with the exception of an N
      terminal membrane anchor sequence, expressed in Escherichia coli, and purified by
      metal chelate affinity chromatography. The purified sortase had maximum activity
      at pH 7.5 and was stable at 20-45 degrees C for the cleavage of a synthetic
      fluorophore substrate. The enzyme inhibitory activity in medicinal plants was
      also evaluated for antibacterial drug discovery. Among 80 medicinal plants
      tested, Cocculus trilobus, Fritillaria verticillata, Liriope platyphylla, and
      Rhus verniciflua had strong inhibitory activity. The extract with the greatest
      activity was the ethyl acetate fraction derived from the rhizome of Cocculus
      trilobus (IC50 = 1.52 microg/ml).

PMID- 12596884
TI  - Cloning, sequencing, and overexpression in Escherichia coli of a phenylserine
      dehydratase gene from Ralstonia pickettii PS22.
AB  - The structural gene coding for phenylserine dehydratase from Ralstonia pickettii
      PS22 was cloned into Escherichia coli cells, and the nucleotide sequence was
      identified. The predicted amino acid sequence had high sequence similarity to
      biodegradative and biosynthetic threonine dehydratases from E. coli and serine
      dehydratase from human liver. Transformed E. coli cells overproduced phenylserine
      dehydratase, and the recombinant enzyme was purified to homogeneity with a high
      yield and characterized.

PMID- 12596885
TI  - Mechanism of action of hypotensive prostaglandins in patients with essential
      hypertension.
AB  - Despite extensive investigation, the biological mechanisms causing essential
      hypertension (EHT) remain unclear. To clarify the means by which hypotensive
      prostaglandins (Hypo-PGs, mainly PGE1 and PGE2) act in patients with EHT, the
      interaction between intravenously infused Hypo-PGs and pressor substances such as
      an adrenergic neurotransmitter, noradrenaline (NA) and angiotensin II (AII) was
      examined both in patients with EHT and in perfused isolated rabbit ear artery
      preparations. In patients with EHT, Hypo-PGs were shown to reduce the pressor
      responses to intravenously infused NA or AII, although no significant difference
      was found between the pressor responses to NA under basal conditions and the
      responses during intravenous infusion of Hypo-PGs. Animal studies were undertaken
      to investigate the inhibitory action of Hypo-PGs on the vasoconstrictive
      responses to electrical stimulation of the perivascular sympathetic nerves (VSNS)
      and to exogenous NA at pre- and postjunctional sites in blood vessel walls. The
      suppressive action of Hypo-PGs on the response to VSNS was shown to be more
      potent than that to their action on the response to exogenous NA. Thus, it was
      concluded that the hypotensive action of intravenously infused Hypo-PGs in
      patients with EHT may be more dependent on prejunctional sites than on the
      postjunctional sites in the walls of blood vessels.

PMID- 12596886
TI  - Intimal changes in varicose veins: an ultrastructural study.
AB  - In order to study the structural changes in the intimal layer of varicose veins,
      we prospectively collected a total of 23 vein specimens from both the normal
      proximal thigh long saphenous (LSV) in 3 young trauma patients and from the
      unstripped proximal LSV near the sapheno-femoral junction and the distal calf
      blowouts in 10 primary varicose veins patients. Paraffin sections stained with
      hematoxylin and eosin were examined under the light microscope while ultra-thin
      sections were examined under the transmission electron microscope (TEM). Compared
      with the normal control LSV, varicose vein sections showed increase in the
      diameter of the lumen, hypertrophy of the wall and elongation and invagination of
      the intima. Along these invaginations, endothelial cells were compressed,
      elongated and thinned out. The cells also showed progressive degeneration and
      were finally lost into the lumen, leaving only the basal lamina to form the
      luminal surface. This invited blood components like platelets and red blood cells
      to stick to the bare intima and to penetrate through the wall. This may form the
      basis of the clinical condition of superficial thrombophlebitis, which sometimes
      complicates cases of varicose veins. In conclusion, varicose veins showed
      increased diameter of the lumen and hypertrophy, elongation and invagination of
      the intima. There was marked degeneration of the endothelial cells and
      desquamation of the endothelial layer.

PMID- 12596887
TI  - Smooth muscle changes in the cephalic vein of renal failure patients before use
      as an arteriovenous fistula (AVF).
AB  - Complications in arteriovenous fistula (AVF) occur in up to 35% of renal failure
      patients on hemodialysis. The most frequent complication is thrombosis, usually
      from stenotic lesions in the venous outflow system. To study the pre-existing
      smooth muscle changes in the cephalic vein of these patients, we prospectively
      collected a total of 17 cephalic vein specimens from 3 normal controls and 14
      renal failure patients undergoing primary AVF construction on the chosen limb.
      After preparation, ultrathin sections were stained with uranyl and lead acetate
      and were examined under the transmission electron microscope (TEM). Compared with
      the normal controls, abnormal fibrous infiltration of the intima and the media
      and varying degrees of smooth muscle degenerative changes were observed in all
      the cephalic vein sections of renal failure patients. Smooth muscle cells (SMCs)
      lost their normal fusiform shape and were widely separated by increased amount of
      irregularly disposed, extracellular collagen fibers. Other cellular abnormalities
      included irregular cell membrane, granular cytoplasm, Peri- and Paranuclear
      vacuoles and mega mitochondria. SMCs also showed morphological expression of
      phagocytosis of collagen and elastic fibers as a sign of remodeling of the vein
      wall. In conclusion, pre-existing wall and smooth muscle changes were observed in
      all the cephalic vein sections of renal failure patients, which may contribute to
      the later complications of AVFs.

PMID- 12596888
TI  - Nitric oxide (NO) primarily accounts for endothelium-dependent component of beta
      adrenoceptor-activated smooth muscle relaxation of mouse aorta in response to
      isoprenaline.
AB  - Isoprenaline is known to produce vascular relaxation through activation of beta
      adrenoceptors. In recent years, beta-adrenoceptor-activated vascular relaxation
      has been the focus of pharmacological study in terms of both the receptor
      subtypes and the intracellular signaling mechanisms which trigger smooth muscle
      mechanical functions. In addition, the possible contribution of the endothelium
      to beta-adrenoceptor-activated relaxation of vascular beds has provoked
      considerable discussion, with consensus still to be established. In the present
      study, we examined the effects of isoprenaline on isolated mouse aortic smooth
      muscles to determine whether the presence of the endothelium plays a substantial
      role in the relaxation it produces. A possible role for nitric oxide (NO) as a
      primary endothelium-derived factor released in response to isoprenaline was also
      elucidated pharmaco-mechanically. In isolated thoracic and abdominal aortae pre
      contracted with phenylephrine (3 x 10(-7)-10(-6) M), isoprenaline elicited
      relaxation in a concentration-dependent fashion (10(-9)-10(-5) M). In endothelium
      denuded preparations, isoprenaline-elicited relaxation was reduced to 40-50% of
      the response obtained in endothelium-intact preparations. In the preparations
      treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 3 x 10(-4) M; an NO
      synthase inhibitor) or 1H-[1,2,4]-oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10(-5)
      M; a soluble guanylyl cyclase inhibitor), isoprenaline-elicited relaxation was
      attenuated almost to the same degree as the response in endothelium-denuded
      preparations. The degree of endothelium-dependency in isoprenaline-elicited
      relaxation was largely diminished when treated with propranolol (3 x 10(-6) M).
      The present findings indicate that isoprenaline substantially relaxes the mouse
      aorta with both endothelium-dependent and -independent mechanisms. The
      endothelium-dependent component seems to correspond to about 50% of the
      isoprenaline-elicited relaxation, and is almost entirely due to endothelium
      derived NO. Activation of propranolol (3 x 10(-6) M)-inhibitable beta
      adrenoceptors seems to be primarily responsible for the NO-mediated endothelium
      dependent pathway in isoprenaline-elicited relaxant response of mouse aorta.

PMID- 12596889
TI  - Effects of chronic administration of L-arginine on vasoactive responses induced
      by endothelin-1 and its plasma level in streptozotocin-induced diabetic rats.
AB  - To investigate the mechanism underlying increased endothelin-1 (ET-1) release in
      diabetic rats, we administered L-arginine chronically to streptozotocin (STZ)
      induced diabetic rats. The plasma concentrations of glucose, ET-1 and NOx (NO2- +
      NO3-) were all significantly raised at 10 weeks after the STZ injection. Chronic
      administration of L-arginine resulted in a significantly higher plasma NOx
      concentration and a significantly lower plasma ET-1 level at 10 weeks compared
      with the untreated diabetic group. ET-1 induced a biphasic
      vasodilator/vasoconstrictor response in the perfused isolated mesenteric arterial
      beds from all groups. The vasodilatation was significantly greater in diabetic
      rats than in age-matched controls. Chronic oral L-arginine administration had no
      significant effect on the enhanced ET-1-induced vasodilatation seen in the
      untreated diabetic rats. The vasoconstrictions induced by ET-1 and methoxamine
      were significantly attenuated in STZ-diabetic rats. The attenuated
      vasoconstrictor response to ET-1, but not that to methoxamine, was further
      attenuated by chronic treatment with L-arginine. We conclude that since chronic L
      arginine administration not only reduced the increase in plasma ET-1 levels but
      also further attenuated the ET-1-induced vasoconstriction without affecting the
      change in vasodilatation, chronic L-arginine administration could be valuable for
      the treatment of the symptoms of diabetic mellitus related to ET-1.

PMID- 12596890
TI  - Functional contribution of voltage-dependent and Ca2+ activated K+ (BK(Ca))
      channels to the relaxation of guinea-pig aorta in response to natriuretic
      peptides.
AB  - We examined the relaxant effects of natriuretic peptide family on the isolated
      guinea-pig aorta to determine the receptor subtype which primarily mediates this
      vascular relaxation, with particular attention to the apparent contribution of
      voltage-dependent and Ca2+-activated KS (BK(Ca)) channels to the response. Three
      endogenous natriuretic peptide ligands (natriuretic peptide, ANP; brain
      natriuretic peptide, BNP; C-type natriuretic peptide, CNP) produced a
      concentration-dependent relaxation in de-endothelialized guinea-pig aorta pre
      contracted by noradrenaline (NA), with a potency order of ANP > or = BNP >> CNP.
      Although the relaxations elicited by these three natriuretic peptide ligands were
      significantly diminished by iberiotoxin (IbTx, 10(-7) M), a selective BK(Ca)
      channel blocker, the inhibitory effect of IbTx was most pronounced for the CNP
      induced relaxation; when estimated at 10(-7) M of each peptide, the apparent
      extent of BK(Ca) channel contribution to the total relaxant response was
      approximately 60% for CNP > approximately 20% for either ANP or BNP. Supporting
      the substantial role of BK(Ca) channels in the vascular responses, high-KCl (80
      mM) potently suppressed the relaxations induced by these natriuretic peptide
      ligands. The relaxant response to 8-Bromo-cyclic GMP, a membrane permeable cyclic
      GMP analogue, was also diminished by IbTx (10(-7) M) and high-KCl (80 mM), which
      indicates the key role of cyclic GMP in the BK(Ca) channel-mediated, natriuretic
      peptide-elicited vascular relaxation. These results indicate that the A-type
      receptor (NPR-A, which is more selective for ANP and BNP) rather than the B-type
      receptor (NPR-B, which is more selective for CNP) predominates in the guinea-pig
      aorta as the natriuretic peptide receptor which mediates this vascular smooth
      muscle relaxation. Although activation of BK(Ca) channels substantially
      contributes to both NPR-A- and NPR-B-activated relaxations, particularly in the
      NPR-B-activated relaxation, this K channel may function as a primary relaxant
      mediator in this conduit artery.

PMID- 12596891
TI  - Endothelium-dependent relaxation in pulmonary arteries of L-NAME-treated Wistar
      and stroke-prone spontaneously hypertensive rats.
AB  - To evaluate whether the elevated blood pressure induced by chronic treatment with
      N(omega)-nitro-L-arginine methyl ester (L-NAME) contributes to an impairment of
      endothelium-dependent relaxation (EDR), the effects of chronic treatment of
      Wistar rats with L-NAME on systolic blood pressure, pulmonary arterial blood
      pressure and EDR of the pulmonary arteries were studied and compared with those
      of stroke-prone spontaneously hypertensive rats (SHRSP). While the systolic blood
      pressure (SBP) of Wistar rats was increased above that of controls by chronic
      treatment with L-NAME, it was still significantly lower than that of SHRSP.
      Chronic treatment with L-NAME did not affect pulmonary arterial blood pressure.
      On the other hand, the pulmonary arterial blood pressure of SHRSP was slightly
      but significantly higher than that of the control normotensive Wistar Kyoto rats
      (WKY). EDR in response to acetylcholine in the pulmonary artery of L-NAME-treated
      rats was significantly smaller than that in control Wistar rats. The EDR markedly
      increased in the presence of L-arginine and completely disappeared in the
      presence of N(omega)-nitro-L-arginine. Indomethacin hardly affected EDR. In
      preparations from SHRSP, the EDR was not different from that in those from WKY.
      Relaxation induced by sodium nitroprusside was identical in all preparations.
      Elevation of SBP and the impairment of EDR observed in L-NAME-treated rats
      recovered two weeks following cessation of treatment. These results suggest that
      the impaired EDR in the pulmonary artery of L-NAME-treated rats is not due to an
      L-NAME-induced increase in blood pressure but due to the inhibition of nitric
      oxide synthase by the drug remaining in the endothelium.

PMID- 12596892
TI  - The beta2- and beta3-adrenoceptor-mediated relaxation induced by fenoterol in
      guinea pig taenia caecum.
AB  - Fenoterol, a beta2-adrenoceptor selective agonist, belongs to the
      arylethanolamine class. To understand the receptor subtypes responsible for beta
      adrenoceptor-mediated relaxation of guinea pig taenia caecum, we investigated the
      effect of fenoterol. Fenoterol caused concentration-dependent relaxation of the
      guinea pig taenia caecum. Propranolol, bupranolol and butoxamine produced shifts
      of the concentration-response curve for fenoterol. Schild regression analyses
      carried out for propranolol, butoxamine and bupranolol against fenoterol gave pA2
      values of 8.41, 6.33 and 8.44, respectively. However, in the presence of 3 x 10(
      4) M atenolol, 10(-4) M butoxamine and 10(-6) M phentolamine to block the beta1-,
      beta2- and a-adrenoceptor effects, respectively, Schild regression analysis
      carried out for bupranolol against fenoterol gave pA2 values of 5.80. These
      results suggest that the relaxant response to fenoterol in the guinea pig taenia
      caecum is mediated by both the beta2- and the beta3-adrenoceptors.

PMID- 12596893
TI  - A history of ovine pulmonary adenocarcinoma (jaagsiekte) and experiments leading
      to the deduction of the JSRV nucleotide sequence.
AB  - Jaagsiekte (JS), a contagious cancer affecting the lungs of sheep has been called
      many names over the years. At a recent workshop in Missilac, France it was agreed
      that the disease would be called ovine pulmonary adenocarcinoma (OPA). The
      disease is caused by an infectious retrovirus called jaagsiekte sheep retrovirus
      (JSRV). This chapter focuses on the early research that led up to the isolation,
      cloning and sequencing of the exogenous infectious form of JSRV and the
      demonstration that it has an endogenous counter part that is present in all
      sheep. As there was no in vitro production source of the virus much of the early
      research focused on the in vivo production and purification of the virus to
      obtain sufficient material to use to identify the viral proteins and purify the
      viral genetic material. Typically, new born lambs were inoculated intra
      tracheally with concentrated lung lavage from previously infected sheep lungs.
      The optimal purification involved the concentration of lung lavage of freshly
      slaughtered sheep, an extraction with organic solvent, and final purification by
      both rate zonal and isopycnic centrifugation. Monoclonal and polyclonal
      antibodies were made against the purified fractions. The polyclonal antibodies
      were not very specific and the monoclonal antibodies proved to be against
      antigens expressed in high concentrations in response to any lung pathology. The
      genomic RNA of the virus was isolated from ex vivo purified materials, and cloned
      as a collection of cDNAs. The full length sequence was assembled by walking
      through the cDNA clones. The genome of the exogenous virus is 7462 bases and has
      the classical gag, pol, env genome arrangement and is flanked by a long terminal
      repeat (LTR) on each end. An additional open reading frame (ORF) was observed in
      the viral genome and has been called orfX. A function has not been determined for
      this ORF. JSRV is classified as a betaretrovirus, with gag and pol closely
      related to D type retrovirus, whereas env is related to the B type viruses such
      as the human endogenous retrovirus HERV-K. An interesting finding was that the
      exogenous infectious virus had an endogenous counter part which is present in the
      genomes of all sheep and goats. It is estimated that there are between 15 and 20
      endogenous loci per sheep genome. No circulating antibodies have been found in
      OPA-affected sheep. It is suggested that the endogenous JSRV transcripts are
      expressed at an early age and are cause for the clonal elimination of JSRV
      specific T cells during T-cell ontogeny. Histopathologically the sheep disease
      resembles human bronchiolar alveolar carcinoma and has been identified as a
      natural out bred animal model that could be used to study the human disease.

PMID- 12596894
TI  - Pathology of ovine pulmonary adenocarcinoma.
AB  - Clinical, gross pathology, histopathology and electron microscopy of the ovine
      pulmonary adenocarcinoma (OPA, jaagsiekte) either natural or experimentally
      induced in sheep, goat and moufflon are described. OPA is caused by an oncogenic
      betaretrovirus,jaagsiekte sheep retrovirus (JSRV). Most natural cases of OPA
      appear in animals 1-4 years old. There is no evidence of sex or breed
      susceptibility. Sheep affected by OPA show an afebrile respiratory illness
      associated with loss of weight. A very characteristic clinical sign is moist
      rales caused by the accumulation of fluid in the respiratory airways which is
      discharged from the nostrils when the head is lowered. Gross lesions are confined
      to the lungs but occasionally thoracic or extrathoracic structures are also
      affected. Two pathologic forms of OPA are currently recognized, classical and
      atypical. In classical forms the neoplastic lesions occurs particularly in the
      cranioventral parts of all lung lobes. They are diffuse or nodular, light grey or
      light purple in colour. On the cut surface the tumour is moist, and frothy fluid
      may pour from the airways on slight pressure. Atypical forms tend to be more
      nodular in both early and advanced tumours. They are pearly white in colour, very
      hard in consistency, very well demarcated from the surrounding parenchyma and
      their surface is dry. Histology of the lung sections reveals the presence of
      several foci of epithelial cell neoplastic proliferation in both alveolar or
      bronchiolar regions. The tumours, derived from type II pneumocytes and Clara
      cells, proliferate into mostly papillary but also acinar or occasionally solid
      growths. The tumour generally shows a benign histological pattern but intra- and
      extrathoracic metastases have been detected in some cases. Several considerations
      suggest that the tumour should be classified as an adenocarcinoma of the lung.
      The histology of atypical OPA is similar to that of the classical disease, with
      an increase in the stromal reaction accompanying the epithelial proliferations.
      Pathological features of OPA induced experimentally in sheep, or of OPA in goats
      and moufflon are similar to those described in sheep. Detailed electron
      microscopy of tumour material confirms that type II pneumocytes and Clara
      bronchiolar epithelial cells are the origin of the neoplasia. Also included in
      this chapter is a description of the morphology of the viral particles associated
      with OPA.

PMID- 12596895
TI  - Natural history of JSRV in sheep.
AB  - Ovine pulmonary adenocarcinoma (OPA) is a contagious lung tumour of sheep and,
      rarely, goats that arises from two types of secretory epithelial cell that retain
      their luxury function of surfactant synthesis and secretion. It is classified as
      a low-grade adenocarcinoma and is viewed as a good model for epithelial neoplasia
      because of its morphological resemblance to the human lung tumour,
      bronchioloalveolar adenocarcinoma. OPA is present in most of the sheep rearing
      areas of the globe and, in affected flocks, tumours are present in a high
      proportion of sheep. OPA is associated with the ovine retrovirus, jaagsiekte
      sheep retrovirus (JSRV), and is transmissible only with inocula that contain
      JSRV. All sheep contain JSRV-related endogenous viruses, but JSRV is an exogenous
      virus that is associated exclusively with OPA. JSRV is detected consistently in
      the lung fluid, tumour and lymphoid tissues of sheep affected by both natural and
      experimental OPA or unaffected in-contact flockmates and never in sheep from
      unaffected flocks with no history of the tumour. JSRV replicates principally in
      the epithelial tumour cells, but also establishes a disseminated infection of
      several lymphoid cell types, including peripheral blood leukocytes (PBLs).
      Longitudinal studies in flocks with endemic OPA have revealed JSRV in PBLs before
      the onset of clinical OPA and even in the absence of discernible lung tumour. The
      prevalence of JSRV infection is 40%-80%, although only 30% of sheep appear to
      develop OPA lesions. A unique feature of OPA is the absence of a specific humoral
      immune response to JSRV, despite the highly productive infection in the lungs and
      the disseminated lymphoid infection. This feature is associated with reduced
      responsiveness to some mitogens, although the phenotypic profile of the
      peripheral blood remains unaltered. The reduced response is an early and
      sustained event during infection and may indicate that the failure of infected
      sheep to produce specific antibodies to JSRV is a direct consequence of
      infection.

PMID- 12596896
TI  - Molecular biology of jaagsiekte sheep retrovirus.
AB  - Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary
      adenocarcinoma (OPA), a contagious lung cancer of sheep. Until recently, research
      on JSRV/OPA was hampered by the lack of a tissue culture system for the
      propagation of the virus. Historically, pathological samples (lung fluid)
      collected from sheep affected by OPA were the only source of infectious JSRV.
      Thus studies on the JSRV/OPA system were conducted only where field isolates of
      OPA cases were readily available. In the past 10 years, the deduction of the JSRV
      sequence (York et al. 1991; York 1992), the isolation of an infectious and
      oncogenic JSRV molecular clone (JSRV21) (Palmarini et al. 1999a) and the
      establishment of a rapid method to produce infectious virus in vitro (Palmarini
      et al. 1999a) sparked many studies at the molecular level that strengthened past
      observations and revealed new properties of this unique virus. Here, we will
      review the data accumulated so far on the molecular biology of JSRV using the
      infectious and oncogenic JSRV21 molecular clone as virus of reference.

PMID- 12596897
TI  - Endogenous retroviruses related to jaagsiekte sheep retrovirus.
AB  - Ovine betaretroviruses consist of exogenous viruses [jaagsiekte sheep retrovirus
      (JSRV) and enzootic nasal tumor virus, (ENTV)] associated with neoplastic
      diseases of the respiratory tract and 15-20 endogenous viruses (enJSRV) stably
      integrated in the ovine and caprine genome. Phylogenetic analysis of this group
      of retroviruses suggests that the enJSRV can be considered as 'modern' endogenous
      retroviruses with active, exogenous counterparts. Sequence analysis of JSRV, ENTV
      and enJSRV suggests that enJSRV do not directly contribute to the pathogenesis of
      ovine pulmonary adenocarcinoma (OPA) or enzootic nasal tumor through large-scale
      recombination events, but small-scale recombination or complementation of gene
      function cannot be excluded; experiments involving enJSRV-free sheep, which have
      not been found, would be needed to investigate this possibility. Evidence of
      expression of enJSRV structural proteins in tissues of the reproductive tract and
      lung implies that they do not have a primary role in disease. However,
      experimental exploitation of exogenous/endogenous retrovirus sequence differences
      by producing chimeras has been useful in establishing the determinants of JSRV
      Env-induced transformation. Even if enJSRV do not have a direct role in OPA,
      their expression during ontogeny or in neonatal life may impact the likelihood of
      exogenous JSRV infection and disease outcome via the induction of immunological
      tolerance. Aside from any role in disease, enJSRV loci may serve as useful
      genetic markers in the sheep and their frequent expression in the reproductive
      tract of the ewe may portend an important physiologic role in sheep.

PMID- 12596898
TI  - Transformation and oncogenesis by jaagsiekte sheep retrovirus.
AB  - Jaagsiekte sheep retrovirus (JSRV) is an exogenous retrovirus of sheep that
      induces a contagious lung cancer, ovine pulmonary adenocarcinoma (OPA). JSRV is a
      potent carcinogen in the experimental setting, inducing end-stage tumors at
      around 6 weeks of age when newborn lambs are inoculated intratracheally. Despite
      this rapid oncogenesis, inspection of the JSRV genome sequence does not reveal
      any obvious viral oncogenes. In this review, recent advances in studies of JSRV
      oncogenic transformation are described. Molecular cloning of an infectious and
      oncogenic JSRV provirus was instrumental in the studies. DNA transfection of JSRV
      proviral DNA into mouse NIH3T3 cells results in morphological transformation,
      indicating that the JSRV genome carries an oncogene. Further experiments
      identified the JSRV envelope protein as the transforming gene, and a PI3 kinase
      docking site in the cytoplasmic tail of the transmembrane (TM) protein was shown
      to be necessary for transformation. Avian DF-1 cells infected with an avian
      retroviral vector (RCAS) expressing the JSRV envelope protein also undergo
      tumorigenic transformation. Possible mechanisms of transformation are discussed,
      and a cooperating role for insertional activation of proto-oncogenes in
      tumorigenesis is also considered. The transforming potential of the JSRV envelope
      protein may be necessary for JSRV infection and replication in vivo.

PMID- 12596899
TI  - Identification of Hyal2 as the cell-surface receptor for jaagsiekte sheep
      retrovirus and ovine nasal adenocarcinoma virus.
AB  - Jaagsiekte sheep retrovirus (JSRV) and ovine nasal adenocarcinoma virus (ONAV)
      replicate in the airway and cause epithelial cell tumors through the activity of
      their envelope (Env) proteins. Identification of the receptor(s) that mediate
      cell entry by these viruses is crucial to understanding the oncogenic activity of
      Env and for the development of gene therapy vectors based on these viruses that
      are capable of targeting airway cells. To identify the viral receptor(s) and to
      further study the biology of JSRV and ONAV, we developed retroviral vectors
      containing Moloney murine leukemia virus components and the Env proteins of JSRV
      or ONAV. We used a new technique involving positional cloning by phenotypic
      mapping in radiation hybrid cells to identify and clone the human receptor for
      JSRV, Hyal2, which also serves as the receptor for ONAV. Hyal2 is a
      glycosylphosphatidylinositol-anchored cell-surface protein that has low
      hyaluronidase activity and is a member of a large family that includes sperm
      hyaluronidase (Spam) and serum hyaluronidase (Hyal1). Hyal2 is located in a
      region of human chromosome 3p21.3 that is often deleted in lung cancer,
      suggesting that it may be a tumor suppressor. However, its role in JSRV or ONAV
      tumorigenesis, if any, is still unclear. JSRV vectors are capable of transducing
      various human cells, and are being further evaluated for gene therapy purposes.

PMID- 12596900
TI  - Enzootic nasal adenocarcinoma of sheep and goats.
AB  - Enzootic nasal adenocarcinoma is a contagious tumour of the mucosal nasal glands
      affecting young adult sheep or goats. The disease occurs naturally in all
      continents except Australia and New Zealand. Clinical signs include continuous
      nasal discharge, respiratory distress, exophthalmos and skull deformations. The
      tumour is classified histologically as a low-grade adenocarcinoma. Nasal glands
      of both respiratory and olfactory muosal glands seem to be the origin of the
      neoplasia. It has been experimentally transmitted in sheep and goats using either
      tumour extracts or concentrated nasal fluids. Two distinct retroviruses are
      implicated in the aetiology of the neoplasia one in sheep (ONAV) and one in goats
      (CNAV). We suggest that jaagsiekte sheep retrovirus (JSRV), ONAV, CNAV, and their
      endogenous counterparts represent a unique family of retroviruses. The
      similarities between these viruses suggests that any control strategies,
      including vaccination, may be appropriate to both diseases. The differences,
      however, represent a unique resource for delineating the function of individual
      regions of the virus. It is intriguing that whilst ONAV and CNAV appear to be as
      different to each other as they are to JSRV, that they have very similar disease
      pathologies, distinct from that of OPA. Additionally, all three exogenous viruses
      manage to avoid instigating any apparent immune response. Whether this is indeed
      a result of tolerance induced by the endogenous counterparts or whether the
      viruses themselves have unique immunosuppressive properties will be an important
      finding.

PMID- 12596901
TI  - Pathology of human bronchioloalveolar carcinoma and its relationship to the ovine
      disease.
AB  - Lung cancer is a leading cause of cancer with a poor prognosis.
      Bronchioloalveolar carcinoma (BAC) is a rare tumor that has always intrigued
      physicians. Since the last World Health Organization classification the pathology
      has been clarified; BAC per se is an adenocarcinoma with a pure
      bronchioloalveolar growth pattern and appears as an in situ alveolar
      adenocarcinoma. More usually BAC is a clinically recognizable entity presenting
      as multi-focal nodules evolving towards pneumonia associated with pulmonary
      shunting. Pathology is that of a multifocal mixed adenocarcinoma:
      bronchioloalveolar and papillar. Whatever the stage, survival is better than in
      other forms of non-small cell lung cancer (NSCLC). The true frequency of BAC is
      unknown, although it is a rare form of lung cancer; smoking cannot be excluded as
      a risk factor. It appears that p53 and ras genes are less often mutated than in
      other lung adenocarcinomas, suggesting that the cellular mechanisms involved are
      different. Ovine pulmonary adenocarcinoma (OPA) presents with the same symptoms
      as BAC in humans and is caused by a betaretrovirus Jaagsiekte sheep retrovirus.
      Very early on, clinical and histological similarities with human BAC were
      stressed. A recent series of OPA described, according to the third edition of the
      WHO classification for human lung cancer, mixed adenocarcinoma, BAC and papillary
      and/or acinar carcinoma. An immunohistochemical study suggested that some human
      pulmonary tumors (including BAC) may be associated with a Jaagsiekte sheep
      retrovirus-related retrovirus,but so far no molecular study has confirmed this
      observation. Thus, OPA is an exquisite model of carcinogenesis for human lung
      adenocarcinomas.

PMID- 12596902
TI  - Nucleosome assembly and remodeling.
AB  - Packaging of the eukaryotic genome into chromatin functions not only to constrain
      the genome within the boundaries of the cell nucleus but also to permit dynamic
      and broad-ranging changes related to many important biological phenomena.
      Therefore, chromatin assembly is a process that affects DNA replication, repair,
      and gene expression. Chromatin structure is linked to transcriptional regulation,
      and recent studies show how chromatin is altered so as to facilitate
      transcription. In addition, modification of chromatin structure is an important
      regulatory mechanism. Here I review the mechanism of chromatin assembly in vitro
      and the changes of chromatin structure related to transcriptional activation.

PMID- 12596904
TI  - HP1 complexes and heterochromatin assembly.
AB  - Since its discovery almost two decades ago, heterochromatin protein 1 (HP1) has
      emerged as a major player in the transcriptional regulation of both
      heterochromatic and euchromatic genes as well as the mechanics of chromosome
      segregation and the functional and structural organization of the interphase
      nucleus. Recent years have brought the identification of a myriad of HP1
      interacting proteins. Each of these is discussed in relationship to its role in
      heterochromatin assembly and HP1 function. The breadth of functions represented
      by HP1-interacting proteins testifies to its pivotal role in the daily operations
      of the nucleus.

PMID- 12596905
TI  - SMC protein complexes and the maintenance of chromosome integrity.
AB  - Structural maintenance of chromosomes (SMC) family proteins have attracted much
      attention for their unique protein structure and critical roles in mitotic
      chromosome organization. Elegant genetic and biochemical studies in yeast and
      Xenopus identified two different SMC heterodimers in two conserved multiprotein
      complexes termed 'condensin' and 'cohesin'. These complexes are required for
      mitotic chromosome condensation and sister chromatid cohesion, respectively, both
      of which are prerequisite to accurate segregation of chromosomes. Although
      structurally similar, the SMC proteins in condensin and cohesin appear to have
      distinct functions, whose specificity and cell cycle regulation are critically
      determined by their interactions with unique sets of associated proteins. Recent
      studies of subcellular localization of SMC proteins and SMC-containing complexes,
      identification of their interactions with other cellular factors, and discovery
      of new SMC family members have uncovered unexpected roles for SMC proteins and
      SMC-containing complexes in different aspects of genome functions and chromosome
      organization beyond mitosis, all of which are critical for the maintenance of
      chromosome integrity.

PMID- 12596903
TI  - Chromatin proteins are determinants of centromere function.
AB  - Recent advances in the identification of molecular components of centromeres have
      demonstrated a crucial role for chromatin proteins in determining both centromere
      identity and the stability of kinetochore-microtubule attachments. Although we
      are far from a complete understanding of the establishment and propagation of
      centromeres, this review seeks to highlight the contribution of histones, histone
      deposition factors, histone modifying enzymes, and heterochromatin proteins to
      the assembly of this sophisticated, highly specialized chromatin structure.
      First, an overview of DNA sequence elements at centromeric regions will be
      presented. We will then discuss the contribution of chromatin to kinetochore
      function in budding yeast, and pericentric heterochromatin domains in other
      eukaryotic systems. We will conclude with discussion of specialized nucleosomes
      that direct kinetochore assembly and propagation of centromere-defining chromatin
      domains.

PMID- 12596906
TI  - Selective gene regulation by SWI/SNF-related chromatin remodeling factors.
AB  - Chromatin is a highly dynamic structure that plays a key role in the
      orchestration of gene expression patterns during cellular differentiation and
      development. The packaging of DNA into chromatin generates a barrier to the
      transcription machinery. The two main strategies by which cells alleviate
      chromatin-mediated repression are through the action of ATP-dependent chromatin
      remodeling complexes and enzymes that covalently modify the histones. Various
      signaling pathways impinge upon the targeting and activity of these enzymes,
      thereby controlling gene expression in response to physiological and
      developmental cues. Chromatin structure also underlies many so-called epigenetic
      phenomena, leading to the mitotically stable propagation of differential
      expression of genetic information. Here, we will focus on the role of SWI/SNF
      related ATP-dependent chromatin remodeling complexes in developmental gene
      regulation. First, we compare different models for how remodelers can act in a
      gene-selective manner, and either cooperate or antagonize other chromatin
      modulating systems in the cell. Next, we discuss their functioning during the
      control of developmental gene expression programs.

PMID- 12596907
TI  - The SWI/SNF family of ATP-dependent chromatin remodelers: similar mechanisms for
      diverse functions.
AB  - The SWI/SNF family of complexes utilizes the energy of ATP hydrolysis to remodel
      chromatin structures, thereby allowing transcription factors to gain access to
      DNA. Recent studies suggest that these remodelers also participate in other DNA
      metabolic reactions such as replication and viral integration, and even in
      control of cell growth and tumor suppression. The SWI/SNF remodelers can be
      classified into at least two distinct subfamilies: one includes human BAF (also
      known as hSWI/SNF-A) and yeast SWI/SNF; the other comprises human PBAF (hSWI/SNF
      B) and yeast RSC. Although both types of complexes have similar subunit
      composition and chromatin remodeling activity in vitro, they cannot replace each
      other during transcription mediated by specific activators. Thus, each remodeler
      probably works with a specific set of activators during gene activation. The
      availability of distinct types of remodelers can allow cells to regulate
      expression of a specific group of genes by modulating the activity of
      corresponding remodelers.

PMID- 12596908
TI  - Changing the DNA landscape: putting a SPN on chromatin.
AB  - In eukaryotic cells, transcription and replication each occur on DNA templates
      that are incorporated into nucleosomes. Formation of chromatin generally limits
      accessibility of specific DNA sequences and inhibits progression of polymerases
      as they copy information from the DNA. The processes that select sites for
      initiating either transcription or replication are therefore strongly influenced
      by factors that modulate the properties of chromatin proteins. Further, in order
      to elongate their products, both DNA and RNA polymerases must be able to overcome
      the inhibition presented by chromatin (Lipford and Bell 2001; Workman and
      Kingston 1998). One way to adjust the properties of chromatin proteins is to
      covalently modify them by adding or removing chemical moieties. Both histone and
      non-histone chromatin proteins are altered by acetylation, methylation, and other
      changes, and the 'nucleosome modifying' complexes that perform these reactions
      are important components of pathways of transcriptional regulation (Cote 2002;
      Orphanides and Reinberg 2000; Roth et al. 2001; Strahl and Allis 2000; Workman
      and Kingston 1998). Another way to alter the effects of nucleosomes is to change
      the position of the histone octamers relative to specific DNA sequences
      (Orphanides and Reinberg 2000; Verrijzer 2002; Wang 2002; Workman and Kingston
      1998). Since the ability of a sequence to be bound by specific proteins can vary
      significantly whether the sequence is in the linkers between nucleosomes or at
      various positions within a nucleosome, 'nucleosome remodeling' complexes that
      rearrange nucleosome positioning are also important regulators of transcription.
      Since the DNA replication machinery has to encounter many of the same challenges
      posed by chromatin, it seems likely that modifying and remodeling complexes also
      act during duplication of the genome, but most of the current information on
      these factors relates to regulation of transcription. This chapter describes the
      factor known variously as FACT in humans, where it promotes elongation of RNA
      polymerase II on nucleosomal templates in vitro (Orphanides et al. 1998, 1999),
      DUF in frogs, where it is needed for DNA replication in oocyte extracts (Okuhara
      et al. 1999), and CP or SPN in yeast, where it is linked in vivo to both
      transcription and replication (Brewster et al. 2001; Formosa et al. 2001). Like
      the nucleosome modifying and remodeling complexes, it is broadly conserved among
      eukaryotes, affects a wide range of processes that utilize chromatin, and
      directly alters the properties of nucleosomes. However, it does not have
      nucleosome modifying or standard ATP-dependent remodeling activity, and therefore
      represents a third class of chromatin modulating factors. It is also presently
      unique in the extensive connections it displays with both transcription and
      replication: FACT/DUF/CP/SPN appears to modify nucleosomes in a way that is
      directly important for the efficient functioning of both RNA polymerases and DNA
      polymerases. While less is known about the mechanisms it uses to promote its
      functions than for other factors that affect chromatin, it is clearly an
      essential part of the complex mixture of activities that modulate access to DNA
      within chromatin. Physical and genetic interactions suggest that FACT/DUF/CP/SPN
      affects multiple pathways within replication and transcription as a member of
      several distinct complexes. Some of the interactions are easy to assimilate into
      models for replication or transcription, such as direct binding to DNA polymerase
      alpha (Wittmeyer and Formosa 1997; Wittmeyer et al. 1999), association with
      nucleosome modifying complexes (John et al. 2000), and interaction with factors
      that participate in elongation of RNA Polymerase II (Gavin et al. 2002; Squazzo
      et al. 2002). Others are more surprising such as an association with the 19S
      complex that regulates the function of the 20S proteasome (Ferdous et al. 2001;
      Xu et al. 1995), and the indication that FACT/DUF/CP/SPN can act as a specificity
      factor for casein kinase II (Keller et al. 2001). This chapter reviews the varied
      approaches that have each revealed different aspects of the function of
      FACT/DUF/CP/SPN, and presents a picture of a factor that can both alter
      nucleosomes and orchestrate the assembly or activity of a broad range of
      complexes that act upon chromatin.

PMID- 12596909
TI  - The MYST family of histone acetyltransferases.
AB  - Multiple chromatin modifying proteins and multisubunit complexes have been
      characterized in recent years. Histone acetyltransferase (HAT) activities have
      been the most thoroughly studied, both biochemically and functionally. This
      review sums up the current knowledge on a specific group of proteins that is
      extremely well conserved throughout evolution, the MYST family of histone
      acetyltransferases. These proteins play critical roles in various nuclear
      functions and the control of cell proliferation.

PMID- 12596910
TI  - N-CoR-HDAC corepressor complexes: roles in transcriptional regulation by nuclear
      hormone receptors.
AB  - Many nuclear hormone receptors (NHRs) actively repress the expression of their
      primary response genes through the recruitment of transcriptional corepressor
      complexes to regulated promoters. N-CoR and the highly related SMRT were
      originally isolated and characterized by their ability to interact
      exclusivelywith the unliganded forms of NHRs and confer transcriptional
      repression. Recently, both the N-CoR and SMRT corepressors have been found to
      exist in vivo in multiple, distinct macromolecular complexes. While these
      corepressor complexes differ in overall composition, a general theme is that they
      contain histone deacetylase enzymatic activity. Several of these complexes
      contain additional transcriptional corepressor proteins with functional ties to
      chromatin structure. Together, these data suggest that modulation of chromatin
      structure plays a central role in N-CoR mediated transcriptional repression from
      unliganded NHRs.

PMID- 12596911
TI  - The NuRD complex: linking histone modification to nucleosome remodeling.
AB  - ATP-dependent nucleosome remodeling and core histone tail modifications play
      important roles in chromatin function. Purification and characterization of the
      NuRD/Mi-2 complex, which possesses both nucleosome remodeling and histone
      deacetylase activities, suggests that ATP-dependent nucleosome remodeling and
      histone tail modification can be coupled. Recent studies indicate that NuRD is an
      integral part of the MeCP1 complex, suggesting that nucleosome remodeling and
      histone deacetylation play important roles in methylated DNA silencing. Studies
      in Caenorhabditis elegans have revealed important functions of the NuRD complex
      in embryonic patterning and Ras signaling. Accumulating evidence indicates that
      NuRD may regulate transcription of specific genes by interacting with specific
      transcriptional factors. In addition, it may also participate in genome-wide
      transcriptional regulation through an association with histone tails.

PMID- 12596913
TI  - The calcium gradient along the rod outer segment.
AB  - Vertebrate photoreceptor outer segments renew themselves by growing new membrane
      near the base and shedding old membrane at the tip. Parallel to the resulting age
      gradient along the outer segment there have also been observed gradients of
      membrane composition, rhodopsin phosphorylation, cGMP regeneration,
      responsiveness to light and others. This chapter describes the calcium gradient
      which has been found to exist along the outer segment. The concentration of
      calcium which increases towards the tip is due to an increase in buffered
      calcium. Since calcium is involved in a network of regulatory processes this
      gradient has implications for the transduction cascade as it affects the light
      response, as well as on disc shedding and other functions of the outer segments.

PMID- 12596912
TI  - Calcium and phototransduction.
AB  - Visual phototransduction, the conversion of incoming light to an electrical
      signal, takes place in the outer segments of the rod and cone photoreceptor
      cells. Light reduces the concentration of cGMP, which, in darkness, keeps open
      cationic channels present in the plasma membrane of the outer segment. Ca2+ plays
      an important role in phototransduction by modulating the cGMP-gated channels as
      well as cGMP synthesis and breakdown. Ca2+ is involved in a negative feedback
      that is essential for photoreceptor adaptation to background illumination. The
      effects of Ca2+ on the different components of rod phototransduction have been
      characterized and can quantitatively account for the steady state responses of
      the rod cell to background illumination. The propagation of the Ca2+ feedback
      signal from the periphery toward the center of the outer segment depends on the
      Ca2+ diffusion coefficient, which has a value of 15 +/- 1 microm2 s(-1). This
      value shows that diffusion of Ca2+ in the radial direction is quite slow
      providing a significant barrier in the propagation of the feedback signal. Also,
      because the diffusion coefficient of Ca2+ is much smaller than that of cGMP, the
      decline of Ca2+ in the longitudinal direction lags behind the propagation of
      excitation by the decline of cGMP.

PMID- 12596914
TI  - The time course of light adaptation in vertebrate retinal rods.
AB  - The photoresponse of a rod wanes over time in steady illumination, as light loses
      its efficacy in generating the response. Such desensitization is adaptive because
      it extends the range of ambient light levels over which the rod signals changes
      in light intensity by several orders of magnitude. Adaptation begins to unfold
      rapidly after the onset of light with a time constant of approximately 1 s,
      causing the rod's sensitivity to steady light to decrease by nearly two log
      units. Thereafter, a much slower phase of adaptation evolves with a time constant
      of 9 s. During this phase the rod's sensitivity decreases by an additional log
      unit. Both phases are dependent upon the light-induced fall in intracellular
      Ca2+. The fast phase of light adaptation can be attributed to Ca2+ feedback
      processes regulating the lifetime ofphotoactivated rhodopsin, cGMP synthesis and
      sensitivity of the cGMP-gated channel to cGMP. Although the mechanism(s) of the
      slow phase is not yet known, it appears to include further regulation of the
      lifetime of photoactivated rhodopsin.

PMID- 12596915
TI  - S-modulin.
AB  - S-Modulin is a Ca2+-binding protein found in frog rod photoreceptors (1,2) and
      its bovine homologue is known as recoverin (3,4). In the Ca2+-bound form, S
      modulin inhibits rhodopsin phosphorylation5 through inhibition of rhodopsin
      kinase. (6-9) Because rhodopsin phosphorylation is the quench mechanism of light
      activated rhodopsin (R*), (10,11) the inhibition of the phosphorylation by S
      modulin probably contributes to increase the lifetime of R* to result in
      sustained hydrolysis of cGMP5. The Ca2+ concentration decreases in the light in
      vertebrate photoreceptors, (12-14) and this decrease is essential for light
      adaptation. (15,16) Thus, S-modulin is expected to regulate the lifetime of R*
      and thereby regulate the extent and the time course of hydrolysis of cGMP
      depending on the intensity of background light. With this mechanism, S-modulin is
      believed to regulate the waveform of a photoresponse and the efficiency of the
      light in the generation of a photoresponse.

PMID- 12596916
TI  - Ca2+-dependent control of rhodopsin phosphorylation: recoverin and rhodopsin
      kinase.
AB  - Over many years until the middle of the 1980s, the main problem in vision
      research had been the mechanism of transducing the visual signal from
      photobleached rhodopsin to the cationic channels in the plasma membrane of a
      photoreceptor to trigger the electrophysiological response of the cell. After
      cGMP was proven to be the secondary messenger, the main intriguing question has
      become the mechanisms of negative feedback in photoreceptors to modulate their
      response to varying conditions of illumination. Although the mechanisms of light
      adaptation are not completely understood, it is obvious that Ca2+ plays a crucial
      role in these mechanisms and that the effects of Ca2+ can be mediated by several
      Ca2+-binding proteins. One of them is recoverin. The leading candidate for the
      role of an intracellular target for recoverin is believed to be rhodopsin kinase,
      a member of a family of G-protein-coupled receptor kinases. The present review
      considers recoverin, rhodopsin kinase and their interrelationships in the in
      vitro as well as in vivo contexts.

PMID- 12596917
TI  - Recoverin and rhodopsin kinase.
AB  - The majority of proteins involved in vertebrate phototransduction are expressed
      specifically in photoreceptors. Recoverin and rhodopsin kinase are expressed
      primarily in retinal photoreceptors and they interact with each other in a Ca2+
      dependent manner. This Ca2+-dependent interaction has been studied extensively in
      vitro. Experiments utilizing animal models and electrophysiological approaches
      have started to provide important insight regarding its invivo function.
      Recoverin can be viewed as a negative regulator of rhodopsin kinase in vertebrate
      phototransduction. This interaction imparts a negative feedback loop at the
      receptor level and may play an important role in light adaptation and in
      recovery.

PMID- 12596918
TI  - Pathological roles of recoverin in cancer-associated retinopathy.
AB  - Cancer associated retinopathy (CAR) is an ocular manifestation of paraneoplastic
      syndrome clinically characterized by progressive visual impairment similar to
      retinitis pigmentosa. As a possible mechanism causing the retinal degeneration,
      the presence of serum autoantibodies against recoverin and other retinal antigens
      are involved. The molecular pathology in CAR by anti-recoverin antibody is
      considered to occur in the following steps: Firstly, recoverin aberrantly
      expressed in cancerous tissues is recognized by immunocytes by some unknown
      mechanisms and then a specific antibody toward recoverin is produced. Secondly,
      the anti-recoverin antibody reaches the retina via the peripheral circulation and
      is taken up into photoreceptor cells. Lastly, the antibody blocks recoverin
      function (inhibition of rhodopsin phosphorylation in a calcium dependent manner),
      and enhancement of rhodopsin phosphorylation induces retinal apoptosis.

PMID- 12596919
TI  - RGS9-1 phosphorylation and Ca2+.
AB  - The duration of photoresponses in vertebrate rods and cones is controlled at the
      level of GTP hydrolysis by a GTPase accelerating protein (GAP) whose catalytic
      core is provided by RGS9-1. RGS9-1 is in turn regulated by phosphorylation on
      serine 475, in a reaction that is dependent on Ca2+. In living mice, the level of
      phosphorylation at this site is reduced by light. Thus RGS9-1 phosphorylation
      provides a potential mechanism by which light-regulated changes in intracellular
      [Ca2+] may feed back on phototransduction through effects on the lifetime of
      activated G protein and cGMP phosphodiesterase.

PMID- 12596920
TI  - Phosphorylation by cyclin-dependent protein kinase 5 of the regulatory subunit
      (Pgamma) of retinal cgmp phosphodiesterase (PDE6): its implications in
      phototransduction.
AB  - Cyclic GMP phosphodiesterase (PDE6) is a key enzyme in vertebrate retinal
      phototransduction. After GTP/GDP exchange on the a subunit of transducin (Talpha)
      by illuminated rhodopsin, the GTP-bound form Talpha (GTP/Talpha) interacts with
      the regulatory subunit (Pgamma) of PDE6 to activate cGMP hydrolytic activity. The
      regulatory mechanism of PDE6 has been believed to be a typical G protein-mediated
      signal transduction process. We found that cyclin-dependent protein kinase 5
      (Cdk5) phosphorylates Pgamma complexed with GTP/Talpha in vitro and in vivo.
      Phosphorylated Py dissociates from GTP/Talpha without GTP hydrolysis and
      interacts effectively with catalytic subunits of PDE6 to inhibit the enzyme
      activity. These observations provide new twists to the current model of retinal
      phototransduction. In this article, in addition to the details of Py
      phosphorylation by Cdk5, we review previous studies implying the Pgamma
      phosphorylation and the turnoff of PDE6 without GTP hydrolysis and indicate the
      direction for future studies of Py phosphorylation, including the possible
      involvement of Ca2+/Ca2+-binding proteins.

PMID- 12596921
TI  - Centrins, a novel group of Ca2+-binding proteins in vertebrate photoreceptor
      cells.
AB  - Changes in the intracellular Ca2+-concentration affect the visual signal
      transduction cascade directly or more often indirectly through Ca2+-binding
      proteins. Here we review recent findings on centrins in photoreceptor cells of
      the mammalian retina. Centrins are members of a highly conserved subgroup of the
      EF-hand superfamily of Ca2+-binding proteins commonly associated with centrosome
      related structures. In vertebrate photoreceptor cells, centrins are also
      prominent components in the connecting cilium linking the light sensitive outer
      segment with the biosynthetically active inner segment compartment. Recent
      findings demonstrate that Ca2+-activated centrin forms a complex with the visual
      G-protein transducin in photoreceptor cells. This Ca2+-dependent assembly of G
      proteins with centrin is a novel aspect of the supply of signaling proteins in
      sensory cells, and a potential link between molecular translocations and signal
      transduction in general.

PMID- 12596922
TI  - Tuning outer segment Ca2+ homeostasis to phototransduction in rods and cones.
AB  - Cone photoreceptors respond to light with less sensitivity, faster kinetics and
      adapt over a much wider range of intensities than do rods. These differences can
      be explained, in part, by the quantitative differences in the molecular processes
      that regulate the cytoplasmic free Ca2+ concentration in the outer segment of
      both receptor types. Ca2+ concentration is regulated through the kinetic balance
      between the ions' influx and efflux and the action of intracellular buffers.
      Influx is passive and mediated by the cyclic-GMP gated ion channels. In cones,
      Ca2+ ions carry about 35% of the ionic current flowing through the channels in
      darkness. In rods, in contrast, this fraction is about 20%. We present a kinetic
      rate model of the ion channels that helps explain the differences in their Ca2+
      fractional flux. In cones, but not in rods, the cGMP-sensitivity of the cyclic
      GMP-gated ion channels changes with Ca2+ at the concentrations expected in dark
      adapted photoreceptors. Ca2+ efflux is active and mediated by a Na+ and K+
      dependent exchanger. The rate of Ca2+ clearance mediated by the exchanger in
      cones, regardless of the absolute size of their outer segment is of the order of
      tens of milliseconds. In rod outer segments, and again independently of their
      size, Ca2+ clearance rate is of the order of hundreds of milliseconds to seconds.
      We investigate the functional consequences of these differences in Ca2+
      homeostasis using computational models of the phototransduction signal in rods
      and cones. Consistent with experimental observation, differences in Ca2+
      homeostasis can make the cone's flash response faster and less sensitive to light
      than that of rods. In the simulations, however, changing Ca2+ homeostasis is not
      sufficient to recreate authentic cone responses. Accelerating the rate of
      inactivation (but NOT activation) of the enzymes of the transduction cascade, in
      addition, to changes in Ca2+ homeostasis are needed to explain the differences
      between rod and cone photosignals. The large gain and precise kinetic control of
      the electrical photoresponse of rod and cone retinal receptors suggested a long
      time back that phototransduction is mediated by cytoplasmic second messengers
      that, in turn, control membrane ionic conductance. (1) The unquestionable
      identification of cyclic GMP as the phototransduction messenger, however, did not
      come until the mid 1980's with the discovery that the light-regulated membrane
      conductance in both rods and cones is gated by this nucleotide (2-4) and is, in
      fact, an ion channel. (7) The cyclic nucleotide gated (CNG) channels, now we
      know, are not just the compliant targets of light-dependent change in cytoplasmic
      cGMP, but actively participate in the regulation transduction through Ca2+
      feedback signals. The precise magnitude and time course of the concentration
      changes of cGMP and Ca2+ in either rods or cones remains controversial. It is
      clear, however, that whereas cGMP directly controls the opening and closing of
      the plasma membrane channels, Ca2+ controls the light-sensitivity and kinetics of
      the transduction signal. (8,9) The modulatory role of Ca2+ is particularly
      apparent in the process of light adaptation: in light-adapted rods or cones, the
      transduction signal generated by a given flash is lower in sensitivity and faster
      in time course than in dark-adapted cells. Light adaptation is compromised if
      Ca2+ concentration changes are attenuated by cytopiasmic Ca2+ buffers (8,10,11)
      and does not occur if Ca2+ concentration changes are prevented by manipulation of
      the solution bathing the cells. (2,4) Several Ca2+-dependent biochemical
      reactions have been identified in photoreceptors, among them: 1. ATP-dependent
      deactivation. (15,16) 2 Phodopsin phospshorylation, through the action of
      recoverin (S-modulin). (17-19) 3. Catalytic activity of guanylyl cyclase, (20-22)
      through the action of GCAP proteins. (23,24,25) 4. cGMP-sensitivity of the CNG
      channels. (26-29,30) A challenge in contemporary phototransduction research is to
      understand the details of these reactions and their role in the control of the
      phototransduction signal. Transduction signals in cone photoreceptors are faster,
      lower in light sensitivity, and more robust in their adaptation features than
      those in rods (for review see refs. 31;32). A detailed molecular explanation for
      these differences is not at hand. However, biochemical and electrophysiological
      (33) studies indicate that the elements in the light-activated pathway that
      hydrolyzes cGMP are quantitatively similar in their function in rods and cones
      and unlikely to account for the functional differences. Also, within the limited
      exploration completed todate, the Ca2+-dependence of guanylyl cyclase (34) and
      visual pigment phosphorylation (19) do not differ in rods and cones. On the other
      hand, data accumulated over the past few years indicate that cytoplasmic Ca2+
      homeostasis, while controlled through essentially identical mechanisms it is
      quantitatively very different in its features in the two photoreceptor types.
      Both Ca2+ influx through CNG channels and the rate of Ca2+ clearance from the
      outer segment differ between the two receptor cells. Also, the Ca2+-dependent
      modulation of cGMP sensitivity is larger in extent in cones than in rods. Most
      significantly, the concentration range of this Ca2+ dependence overlaps the
      physiological range of light-dependent changes in cytoplasmic Ca2+ level in
      cones, but not in rods. We briefly review some of the evidence that supports
      these assertions and we then provide a quantitative analysis of the possible
      significance of these known differences. We conclude that while differences in
      Ca2+ homeostasis contribute importantly to explaining the differences between the
      two receptor types, they are alone not sufficient to explain the differences in
      the photoreceptor's response. It is likely that Ca2+-independent inactivation of
      the transduction cascade enzymes is more rapid in cones than in rods.

PMID- 12596923
TI  - Regulation of the rod photoreceptor cyclic nucleotide-gated channel.
AB  - The cGMP-gated channel of rod photoreceptors plays a key role in
      phototransduction by controlling the flow of cations into the outer segment in
      response to light-induced changes in cGMP. The channel is a heterotetramer
      composed of alpha-subunits required for channel activity and beta-subunits that
      are important in modulating the activity of channel. Earlier studies have shown
      that exogenous calmodulin binds to the beta-subunit of the channel and modulates
      the sensitivity of the channel for cGMP in a calcium dependent manner. In
      addition unidentified Ca2+-dependent endogenous proteins have been reported to
      modulate the activity of the frog rod channel. In this paper, we investigated
      whether endogenous calmodulin and other Ca2+ binding proteins interact with and
      modulate the cGMP-gated channel in bovine rod outer segments. Using
      immunoaffinity techniques in conjunction with ion flux assays, we show that
      endogenous calmodulin, but not other Ca2+ dependent proteins, binds and modulates
      the rod cGMP-gated channel in bovine rod outer segments. We also show that the
      beta-subunit of the channel is phosphorylated by endogenous and exogenous casein
      kinase 2. This posttranslational modification, however, does not alter the
      sensitivity of the channel for cGMP.

PMID- 12596924
TI  - Ca2+-channels in the RPE.
AB  - The retinal pigment epithelium closely interacts with photoreceptors and helps to
      maintain the activity of photoreceptors. Investigations using patch-clamp
      techniques on cultured or freshly isolated retinal pigment epithelial cells from
      various species demonstrated the expression of voltage-dependent Ca2+ channels
      with characteristics of L-type channels. Since retinal pigment epithelial cells
      rarely display changes of the membrane potential which lead to the activation of
      these Ca2+ channels, their function seemed to be unclear. Recent findings shed
      light onto the possible role of these Ca2+ channels. First of all, the subtype of
      these ion channels could be identified as neuroendocrine subtype of L-type
      channels. Recent studies demonstrated that the neuroendocrine subtype of L-type
      channels is regulated by serine/ threonine kinases and protein tyrosine kinases.
      These phosphorylation-dependent regulatory mechanisms lead to Ca2+ fluxes into
      the cell which are independent of changes in the membrane potential and induced
      by a shift in the voltage-dependence ofthese ion channels. The regulation
      modality implied that L-type Ca2+ channels play an important role in signal
      transduction pathways which are important for a communication between retinal
      pigment epithelium and photoreceptors. L-type Ca2+ channels in the retinal
      pigment epithelium seem to be involved in the regulation of secretion of various
      factors, in growth factor-dependent intracellular signalling and in the
      regulation of the phagocytosis of photoreceptor outer membranes. Thus, voltage
      dependent Ca2+ channels in the retinal pigment epithelium are of importance for
      the function of photoreceptors.

PMID- 12596925
TI  - The retinal rod and cone Na+/Ca2+-K+ exchangers.
AB  - The past few years has seen significant progress in our understanding of the
      retinal rod and cone Na+/Ca2+-K+ exchanger (NCKX) genes. The human rod and cone
      NCKX genes were localized to chromosomes 15q22 and 9p22, respectively. In situ
      hybridization localized the rod and cone NCKX transcripts in both human and
      chicken retinas: rod NCKX transcripts were found only in the inner segments of
      rods, whereas cone NCKX transcripts were found in a subset of retinal ganglion
      cells as well as in the inner segments of cones. We identified two sets of
      putative transmembrane spanning segments (TM's) as the only sequence elements
      strongly conserved between the rod and cone NCKX cDNAs, as well as between
      mammalian NCKX cDNAs and NCKX cDNAs cloned from lower organisms (C. elegans and
      Drosophila). The two sets of TM's make up less than onethird of the rod NCKX
      sequence and less than half of the cone NCKX sequence. Basic cation binding
      properties as inferred from an analysis of 45Ca transport rates and NCKX currents
      were very similar for all our NCKX clones, implying that conserved residues
      within the two sets of TM's contain all the residues involved in cation binding
      and cation transport.

PMID- 12596926
TI  - The complex of cGMP-gated channel and Na+/Ca2+, K+ exchanger in rod
      photoreceptors.
AB  - Ca2+ is an important signal ion in photoreceptors for recovery after excitation
      and light adaptation. It enters the outer segment as a minor fraction of the dark
      current through cGMP-gated channels and is extruded in the same cell compartment
      by Na+/Ca2+, K+ exchange. Channel and exchanger are located exclusively in the
      plasma membrane, but not in the cytoplasmic membrane stack, the discs, which
      contain the visual pigment rhodopsin. The channel consists presumably of two
      alpha-subunits and two beta-subunits, whereas the exchanger is a monomeric
      protein. Recently, considerable evidence has been accumulated indicating that
      both proteins form a complex which is bound to peripherin/rds, an integral
      protein of the disc rim. This review focuses on the complex of cGMP-gated channel
      and Na+/Ca2+, K+ exchanger. The possibility of direct functional interaction
      between channel and exchanger is discussed. Furthermore, the consequences of
      different subunit arrangements of the channel for the channel-exchanger complex
      are considered. Finally, a Ca2+ diffusion model is presented which examines the
      possibility that Ca2+ currents are locally restricted to the close vicinity of
      the channel.

PMID- 12596927
TI  - Regulation of voltage-sensitive Ca2+ channels in bipolar cells by divalent
      cations and polyamines.
AB  - Ca2+ plays a key role in intracellular signal transduction in neurons but in
      excess it can lead to cell death. Thus its entry into cells is highly regulated
      by both extrinsic and intrinsic mechanisms. Little is known of the regulation of
      Ca2+ entry into retinal neurons. Here we describe the role of divalent cations
      and polyamines as intrinsic modulators of Ca2+ entry into retinal bipolar cells.
      Cone-dominant (small) bipolar cells of the white bass retina were studied using
      whole cell patch clamp techniques. With biophysical and pharmacological tools it
      was determined that these cells expressed a Ca2+ current similar to an L-type
      current. This current was very susceptible to blockage by divalent cations
      including Ca2+. In addition, when tested with the polyamines, spermine,
      spermidine and putrescine, only spermine effectively inhibited the current. When
      the dose response curve was fit with the Hill function we found an EC50 of 28
      microM and a Hill-coefficient of about 2. Our results indicate that divalent
      cations and the polyamine, spermine, are effective modulators of calcium entry
      into cone-dominated bipolar cells. The in vivo regulation of the concentrations
      of these molecules provides an exquisitely sensitive mechanism for regulating
      Ca2+ entry into bipolar cells under different conditions.

PMID- 12596928
TI  - Site-directed and natural mutations in studying functional domains in guanylyl
      cyclase activating proteins (GCAPs).
AB  - Guanylyl cyclase activating proteins (GCAPs) are Ca2+-binding proteins of the EF
      hand superfamily, through which the intracellular calcium regulates cGMP
      synthesis in vertebrate photoreceptors. GCAPs play an essential role in the
      calcium feedback mechanism that controls recovery and light adaptation of rods
      and cones. Moreover, mutations in at least one of the GCAPs have already been
      linked to two forms of congenital human retinal diseases. The GCAPs represent a
      separate small subfamily among the EF-hand proteins that are structurally similar
      to recoverin, but demonstrate a number of unique regulatory properties. When in
      the Ca2+-free conformation (as in light-adapted photoreceptors), GCAPs stimulate
      photoreceptor membrane guanylyl cyclase (retGC), but when the intracellular free
      Ca2+ concentrations ([Ca2+]free) rise (as in dark-adapted photoreceptors), GCAPs
      turn into retGC inhibitors. In GCAPs, site-directed mutagenesis has been
      successfully used to identify a number of structural elements that contribute to
      their specific function as guanylyl cyclase regulators. These elements include EF
      hand Ca2+-binding loops and various other regions in the GCAP primary structure
      involved in multiple protein-protein interactions within the retGC/GCAP complex.

PMID- 12596929
TI  - Calmodulin and Ca2+-binding proteins (CaBPs): variations on a theme.
AB  - Ca2+ is a ubiquitous second messenger that frequently exerts its effects through
      Ca2+-binding proteins. In response to changes in the intracellular [Ca2+], Ca2+
      binding proteins modulate the cellular activities of enzymes, channels and
      structural proteins. Multiple Ca2+-binding proteins are expressed in the retina
      and, in most cases, in a unique cellular and sub-cellular manner. CaBPs are
      retinal Ca2+-binding proteins displaying a high similarity to calmodulin (CaM).
      CaBPs are able to mimic some of the interactions of CaM with effector enzymes,
      although their physiological role has not yet been resolved. CaBPs could be cell
      type specific proteins that play a key role in the Ca2+ signaling of specialized
      retinal neurons.

PMID- 12596930
TI  - GCAPs: Ca2+-sensitive regulators of retGC.
AB  - Lowered concentration of Ca2+ ions, resulting from illumination of the
      photoreceptor cell, is the signal for resynthesis of cGMP by retina-specific
      guanylyl cyclase (retGC). This Ca2+-dependent activation of retGC is mediated by
      Ca2+-binding proteins named GCAPs (guanylyl cyclase-activating proteins) and
      contributes to the recovery of photoreceptor cell to the dark state. Three
      different GCAPs (GCAP1, GCAP2 and GCAP3) are identified in vertebrate retina to
      date. In this chapter we describe their discovery, methods of purification,
      properties, and possible modes of action.

PMID- 12596931
TI  - Structure and membrane-targeting mechanism of retinal Ca2+-binding proteins,
      recoverin and GCAP-2.
AB  - Recoverin and the guanylate cyclase activating proteins (GCAPs) are calcium
      sensing proteins in retinal rod and cone cells that belong to the EF-hand
      superfamily and serve as important calcium sensors in vision. Recoverin and the
      OCAP proteins are myristoylated at their amino-terminus and are targeted to
      retinal disc membranes by a myristoyl switch. Here, we present the three
      dimensional, atomic-resolution structures of recombinant myristoylated recoverin
      containing 0, 1 and 2 calcium ions (Ca2+) bound and unmyristoylated GCAP-2 with 3
      Ca2+ bound as determined by nuclear magnetic resonance. The Ca2+-induced
      structural changes in these proteins are important for elucidating their membrane
      targeting mechanisms and for understanding the molecular mechanism of Ca2+
      sensitive regulation of phototransduction.

PMID- 12596932
TI  - Target recognition of guanylate cyclase by guanylate cyclase-activating proteins.
AB  - Guanylate cyclase-activating proteins (GCAPs) control the activity of membrane
      bound guanylate cyclases in vertebrate photoreceptor cells. They form a permanent
      complex with guanylate cyclase 1 (ROS-GC1) at low and high Ca2+-concentrations.
      Five different target regions of GCAP-1 have been identified in ROS-GC1 at rather
      distant sites. These findings could indicate a multipoint attachment site for
      GCAP-1 or, alternatively, the presence of transient binding sites with short
      contact to GCAP-1. In addition some data are consistent with the operation of one
      or more transducer units, that represent regulatory regions without being direct
      binding sites. A permanent ROS-GC1/GCAP-1 complex is physiologically significant,
      since it allows a very short response time of cyclase activity when the
      intracellular Ca2+-concentration changes. Thereby, activation of cyclase
      participates in speeding up the recovery of the photoresponse after illumination
      and restores the circulating dark current.

PMID- 12596933
TI  - Mouse models to study GCAP functions in intact photoreceptors.
AB  - In photoreceptor cells cGMP is the second messenger that transduces light into an
      electrical response. Regulation of cGMP synthesis by Ca2+ is one of the key
      mechanisms by which Ca2+ exerts negative feedback to the phototransduction
      cascade in the process of light adaptation. This Ca2+ feedback to retinal
      guanylyl cyclases (Ret-GCs) is conferred by the guanylate cyclase-activating
      proteins (GCAPs). Mutations in GCAP1 that disrupt the Ca2+ regulation of Ret-GCs
      in vitro have been associated with severe human vision disorders. This chapter
      focuses on recent data obtained from biochemical and electrophysiological studies
      of GCAP1/GCAP2 knockout mice and other GCAP transgenic mice, addressing: 1. the
      quantitative aspects of the Ca2+-feedback to Ret-GCs in regulating the light
      sensitivity and adaptation in intact rods; 2. functional differences between
      GCAP1 and GCAP2 in intact rod photoreceptors; and 3. whether GCAP mutants with
      impaired Ca2+ binding lead to retinal disease in vivo by constitutive activation
      of Ret-GCs and elevation of intracellular cGMP, as predicted from in vitro
      studies.

PMID- 12596934
TI  - Calcium-dependent activation of guanylate cyclase by S100b.
AB  - Calcium concentration in the dark-adapted retinal rod outer segment is in the 200
      to 600 nM range, and the guanylate cyclase of rod outer segments is thought to be
      activated in response to a fall in calcium concentration triggered by light.
      Calcium-binding proteins that mediate such activation, i.e., activation in the
      absence of or presence of low nanomolar calcium concentrations, have been
      identified and termed GCAPs (Guanaylate Cyclase Activating Proteins). In the
      course of our search for GCAP-like proteins in bovine retina, we isolated a
      protein fraction that stimulated rod outer segment cyclase activity at calcium
      concentrations higher than those in dark-adapted rod outer segments. We purified
      the protein responsible for this calcium-dependent stimulation of cyclase
      activity and found it to be of 6-7 kDa molecular weight as judged by
      electrophoresis under denaturing conditions and about 40 kDa by gel filtration
      analysis. Maximum stimulation of cyclase activity was observed at 3-4 micromolar
      concentration of the protein. It required about 1.5 micromolar free calcium
      concentration for half-maximal activation of the enzyme. Partial amino acid
      sequencing of peptide fragments of the activator suggested that the protein was
      identical with S100b, a previously described calcium-binding protein. Further
      characterization with antibody specific for S100b supported this possibility.
      However, the protein isolated in our laboratory and termed CD-GCAP (Calcium
      Dependent Guanylate Cyclase Activator Protein) was found to differ significantly
      from commercially available S100b in the magnitude and calcium dependence of
      cyclase activation. It was also found to be inactivated by hydroxylamine while
      S100b was resistant. Investigation into these differences showed that
      purification methods had a significant influence on the properties of the
      activator, producing a less active (S100b) or more active (CD-GCAP) protein, but
      that it was, otherwise, one and the same protein. We conclude from this study
      that rod outer segment guanylate cyclase, unlike any cyclase known so far, is
      capable of activation by two different types of calcium-binding proteins, one
      that activates in response to a decrease in calcium concentration, and the other,
      described here, which activates in response to an increase in calcium
      concentration. We hypothesize that this cyclase and others like it will be
      colocalized with one or the other type of activator depending upon the
      physiological requirement, i.e., activation in response to decreasing or
      increasing calcium concentration.

PMID- 12596935
TI  - Role of cadherins in Ca2+-mediated cell adhesion and inherited photoreceptor
      degeneration.

PMID- 12596936
TI  - Guanylate cyclase activating proteins, guanylate cyclase and disease.
AB  - A range of cone and cone-rod dystrophies (CORD) have been observed in man, caused
      by mutations in retinal guanylate cyclase 1 (RetGC1) and guanylate cyclase
      activating protein 1 (GCAP 1). The CORD causing mutations in RetGC1 are located
      at a mutation "hot spot" within the dimerisation domain, where R838 is the key
      residue. Three disease causing mutations have been found in human GCAP1,
      resulting in cone or cone-rod degeneration. All three mutations are dominant in
      their effect although the mechanism by which the P50L mutation exerts its
      influence remains unclear although it might act due to a haplo-insufficiency,
      arising from increased susceptibility to protease activity and increased thermal
      instability. In contrast, loss of Ca2+ sensitivity appears to be the main cause
      of the diseased state for the Y99C and E155G mutations. The cone and cone-rod
      dystrophies that are caused by mutations in RetGC1 or GCAP1 arise from a
      perturbation of the delicate balance of Ca2+ and cGMP within the photoreceptor
      cells and it is this disruption that is believed to cause cell death. The
      diseases caused by mutations in RetGC1 and GCAP1 prominently affect cones,
      consistent with the higher concentrations of these proteins in cone cells.

PMID- 12596937
TI  - Using mutant mice to study the role of voltage-gated calcium channels in the
      retina.
AB  - Neuronal voltage-gated calcium channels (VGCCs) are critical to numerous cellular
      functions including synaptogenesis and neurotransmitter release. Mutations in
      individual subunits of VGCCs are known to result in a wide array of neurological
      disorders including episodic ataxia, epilepsy, and migraines. The
      characterization of these disorders has focused on channel function within the
      brain. However, a defect in the retina-specific alpha1F subunit of an L-type VGCC
      results is a loss of visual sensitivity or the incomplete form of X-linked
      congenital stationary night blindness (CSNB2). Based on the electroretinographic
      phenotype of these patients this channel type is localized to the axon terminal
      of photoreceptor cells and results in a loss of signal transmission from
      photoreceptors to bipolar cells. A mouse with a deletion of the beta2 subunit of
      VGCCs in the central nervous system was recently shown to have a similar
      phenotype as CSNB2 patients. The identification of the role of VGCCs in this
      disorder highlights the potential association of other VGCC mutations with
      retinal disorders. The study of the role of these channels in normal retinal
      function may also be elucidated by the characterization of retinal structure and
      visual function in the numerous knockout, transgenic, and naturally occurring
      mouse mutants currently available.

PMID- 12596938
TI  - Caldendrins in the inner retina.
AB  - Caldendrin is the first member of a novel family of Ca2+-binding proteins
      (CaBPs). Its unique two-domain structure is composed of a calmodulin-homologous
      teminus and an unrelated N-terminal part. The latter is thought to mediate the
      tight association of caldendrin with the subsynaptic cytoskeleton. Caldendrin is
      expressed in forebrain regions with a laminar cytoarchitecture as well as in the
      inner retina where it is localized to OFF cone bipolar and a subset of amacrine
      and ganlion cells. In addition, caldendrin is prominently present in processes
      and synapses of the inner plexiform layer. Thus, caldendrin-immunoreactivity is
      displayed by ubpopulations of most retinal cell classes, with the exception of
      glial cells. Caldendrin is most likely involved in dendritic Ca2+-signaling, one
      of the functions of its close relative, calmodulin. However, several lines of
      evidence suggest that due to its unique properties caldendrin might not merely
      substitute for calmodulin. t is speculated that either the specific enrichment in
      cellular micro-compartments like the postsynaptic cytomatrix, the unique two
      domain structure or the altered distribution of surface charges renders
      caldendrin specific for distinct binding partners or certain Ca2+-triggered
      signaling events.

PMID- 12596939
TI  - Calcium channels at the photoreceptor synapse.
AB  - Presynaptic Ca2+ channels mediate early stages of visual information processing
      in photoreceptors by facilitating the release of neurotransmitter and by
      receiving modulatory input that alters transmission. Two types of L-type Ca2+
      channels, composed of alpha1F and alpha1D subunits and having similar biophysical
      andpharmacological properties, appear to form the principle voltage-dependent
      Ca2+ influx pathways in rods and cones, respectively. The role played by these
      channels in neurotransmitter release at these graded potential, non-spiking
      synapses, has been well described. The channels mediate sustained glutamate
      release in darkness where the cells rest at potentials near -40 mV, and signal
      increases in light intensity as the cells hyperpolarize negative to this value.
      Synaptic modulation and integration mediated by these channels has not yet been
      as fully described but appears to involve GABA, nitric oxide (NO), glutamate, and
      dopamine. Ca2+ permeable cyclic nucleotide gated (CNG) channels appear to have
      supporting roles at the photoreceptor output synapse and may transduce NO signals
      from other cells by either directly permitting Ca2+ influx or by providing
      depolarizing influences that gate voltage dependent Ca2+ channels.

PMID- 12596940
TI  - On bipolar cells: following in the footsteps of phototransduction.
AB  - The electrical signals resulting from phototransduction are decomposed by bipolar
      cells and then encoded into spike trains by ganglion cells. The signal
      decomposition by bipolar cells includes formation of ON and OFF pathways and
      separation of tonic and phasic signals. The decomposition is accomplished by post
      synaptic receptors in the ON and OFF bipolar cells. This chapter focuses on these
      phenomena in ON bipolar cells and the role of metabotropic glutamate receptors in
      these processes.

PMID- 12596941
TI  - Ca2+ regulation of Drosophila phototransduction.
AB  - Drosophila vision research has benefited from simultaneous application of
      genetic, molecular, electrophysiological analyses. The work establishes an
      essential role of Ca2+ in regulation of phototransduction. Many different
      proteins are the targets of Ca2+ regulation and these proteins act at multiple
      steps of the process. These targets include proteins involved in the rhodopsin
      cycle, proteins responsible for intermediate steps of phototransduction, and the
      TRP and TRPL light-gated channels. The regulation of these phototransduction
      components by Ca2+ occurs in three different ways. First, the presence of
      Ca2+/calmodulin-binding sites in phototransduction-mediating proteins places
      these proteins under Ca2+ control. Second, a protein kinase C regulated by Ca2+
      phosphorylates proteins to modulate their activity. Finally, some proteins
      contain Ca2+-binding sites and apparently are directly regulated by Ca2+. Here I
      review the photoreceptor proteins regulated by Ca2+, and summarize current views
      on the roles of these proteins in the Drosophila photoresponse.

PMID- 12596942
TI  - Simultaneous roles for Ca2+ in excitation and adaptation of Limulus ventral
      photoreceptors.
AB  - The ventral photoreceptors of Limulus have been one of the main preparations for
      the study of invertebrate phototransduction. The study of ventral photoreceptors
      has revealed that they have remarkable performance characteristics, most notably
      the very large amplification of the transduction process. This amplification is
      critically dependent upon the coupling of photoactivated rhodopsin to the
      phosphoinositide cascade, resulting in the release of Ca2+ from intracellular
      stores. The consequent elevation of Ca2+ within the photoreceptor's cytosol is
      amongst the most rapid and dramatic known to be activated by the phosphoinositide
      cascade. This review summarizes the evidence that intracellular Ca2+ is a key
      regulator of transduction in Limulus photoreceptors. The mechanisms that regulate
      Ca2+ as well as the possible targets of the action of Ca2+ are reviewed. Ca2+
      elevation is critical for triggering both excitation and adaptation processes in
      the photoreceptor. The question of how a single second messenger can produce
      these two opposing effects is of obvious interest and is a topic dealt with
      throughout this review.

PMID- 12596943
TI  - Calcium homeostasis in fly photoreceptor cells.
AB  - In fly photoreceptor cells, two processes dominate the Ca2+ homeostasis: light
      induced Ca2+ influx through members of the TRP family of ion channels, and Ca2+
      extrusion by Na+/Ca2+ exchange. Ca2+ release from intracellular stores is
      quantitatively insignificant. Both, the light-activated channels and the Ca2+
      extruding exchangers are located in or close to the rhabdomeric microvilli, small
      protrusions of the plasma membrane. The microvilli also contain the molecular
      machinery necessary for generating quantum bumps, short electrical responses
      caused by the absorption of a single photon. Due to this anatomical arrangement,
      the light-induced Ca2+ influx results in two separate Ca2+ signals that have
      different functions: a global, homogeneous increase of the Ca2+ concentration in
      the cell body, and rapid but large amplitude Ca2+ transients in the microvilli.
      The global rise of the Ca2+ concentration mediates light adaptation, via
      regulatory actions on the phototransduction cascade, the voltage-gated K+
      channels and small pigment granules controlling the light intensity. The local
      Ca2+ transients in the microvilli are responsible for shaping the quantum bumps
      into fast, all-or-nothing events. They achieve this by facilitating strongly the
      phototransduction cascade at early stages ofthe light response and subsequently
      inhibiting it. Many molecular targets of these feedback mechanisms have been
      identified and characterized due to the availability of numerous Drosophila
      mutant showing defects in the phototransduction.

PMID- 12596944
TI  - Photoreceptor degeneration and Ca2+ influx through light-activated channels of
      Drosophila.
AB  - We discuss in this chapter the role of Ca2+ homeostasis in maintaining the
      structural integrity of photoreceptor cells in Drosophila. Both insufficient and
      excessive amounts of Ca2+ in photoreceptor cells appear to lead to cell
      degeneration. Because one of the two classes of light-sensitive channels in
      Drosophila photoreceptors is highly Ca2+-permeable, how well this class of
      channels functions can profoundly affect Ca2+ homeostasis. We will begin by
      reviewing Drosophila phototransduction, emphasizing what is known about the
      mechanism of activation of light-sensitive channels. We will then describe Ca2+
      entry through light-sensitive channels and the presumed mechanisms by which too
      little and too much Ca2+ entry can both cause photoreceptor degeneration. We will
      conclude the chapter with discussions of two examples of mutations known to cause
      unregulated Ca2+ entry through light-sensitive channels, leading to massive
      photoreceptor degeneration.

PMID- 12596945
TI  - The TRP calcium channel and retinal degeneration.
AB  - The Drosophila light activated channel TRP is the founding member of a large and
      diverse family of channel proteins that is conserved throughout evolution. These
      channels are Ca2+ permeable and have been implicated as important component of
      cellular Ca2+ homeostasis in neuronal and non-neuronal cells. The power of the
      molecular genetics of Drosophila has yielded several mutants in which
      constitutive activity of TRP leads to a rapid retinal degeneration in the dark.
      Metabolic stress activates rapidly and reversibly the TRP channels in the dark in
      a constitutive manner by a still unknown mechanism. The link of TRP gating to the
      metabolic state of the cell is shared also by mammalian homologues of TRP and
      makes cells expressing TRP extremely vulnerable to metabolic stress, a mechanism
      that may underlie retinal degeneration and neuronal cell death.

PMID- 12596946
TI  - Public health and the United Nations system for development in Morocco.
AB  - This paper reviews the work of the United Nations specialized agencies and
      programmes within the framework of their cooperation in the area of public health
      in Morocco.

PMID- 12596947
TI  - Kawasaki syndrome: the Iranian experience.
AB  - Experience with 50 cases of Kawasaki syndrome in the Islamic Republic of Iran is
      presented. The syndrome occurred mostly in winter and spring with a 2.1:1
      male:female ratio. In 72% of cases, the disease occurred between 1 and 5 years of
      age, and 80% had an antecedent viral or bacterial illness. Eight patents (16%)
      had microbiological evidence of infection and 19 (38%) had clinical evidence.
      Five patients had clinical and radiological evidence of sinusitis. Leukocytosis,
      neutrophilia, bandaemia, elevated erythrocyte sedimentation rate, positive C
      reactive protein, reversed albumin/globulin ratio and increased antistreptolysin
      O titre were other indications of infection and inflammation. Male gender,
      prolonged fever, white blood cell count > 15,000/mm3 and absolute granulocyte
      count > 10,000/mm3 were significant risk factors for the development of coronary
      artery disease (10 patients).

PMID- 12596948
TI  - Topical ciprofloxacin versus topical gentamicin for chronic otitis media.
AB  - We compared the therapeutic efficiency of ciprofloxacin hydrochloride and
      gentamicin sulfate in the treatment of chronic otitis media. A total of 88
      patients aged 9-62 years with chronic suppurative media were randomly placed into
      two groups. In the first group, 48 patients (54.5%) received topical
      ciprofloxacin hydrochloride, while in the second group 40 patients (45.5%)
      received local gentamicin sulfate. Of the 48 patients who received ciprofloxacin
      hydrochloride, 42 (87.5%) were cured, while in 6 patients (12.5%) the treatment
      failed. In the gentamicin group, 12 (30%) of the patients were cured, while 28
      patients showed no clinical or bacteriological improvement. Topical ciprofloxacin
      is safe and more efficacious and efficient than topical gentamicin in the
      treatment of acute exacerbation of chronic suppurative otitis media.

PMID- 12596949
TI  - Job satisfaction of female Saudi nurses.
AB  - This study aimed to assess the degree of satisfaction of 233 Saudi female nurses
      with their work and to study the factors that might increase their satisfaction.
      Data were collected through a self-administered questionnaire. More than 87% and
      92% of nurses were satisfied with their work place and the role assigned
      respectively. The majority of them preferred one-shift duty because of social and
      family obligations. To increase their satisfaction there is a need to improve the
      social attitude towards the nursing profession and to provide more comfortable
      working conditions.

PMID- 12596950
TI  - Etiology of toe-web disease in Al-Ain, United Arab Emirates: bacteriological and
      mycological studies.
AB  - We examined and sampled 45 patients with toe-web intertrigo for bacteriological
      and mycological studies. Prominent isolated pathogens were the genus Candida
      (57.7%), genus Aspergillus (28.8%), Pseudomonas aeruginosa (26.7%) and coliforms
      (24.4%). Dermatophytes scored 4.4% (Trichophyton rubrum). There were 43 patents
      (95.5%) who presented with marked hyperkeratosis and maceration of the toe-webs
      involved. The tradition of the Emirati population of sitting cross-legged may,
      over time, induce in the toe-webs of overweight individuals a macerated pressure
      reaction hyperkeratosis that is colonized by environmental germs. T. rubrum and
      T. mentagrophytes are uncommon in the Al-Ain environment and this may explain the
      rarity of dermatophytes in toe-web intertrigo in our study.

PMID- 12596951
TI  - Prevalence of missed hyperglycaemia among Jordan University Hospital mortality
      discharges, 1995-97.
AB  - To study the prevalence of recognized and unrecognized hyperglycaemia (defined as
      fasting blood glucose > or = 140 mg/dL and/or random blood glucose > or = 200
      mg/dL on two or more occasions), data were collected from Jordan University
      Hospital on all hospital deaths in those > or = 20 years of age, for the years
      1995-97. The prevalence of diagnosed diabetes was 35.3% and 19.2% were missed
      cases of hyperglycaemia; of the missed cases, 65.7% had a blood glucose level >
      250 mg/dL. Thus, the prevalence of missed hyperglycaemia among hospitalized
      patients is high, and greater vigilance needs to be exercised by physicians and
      other health professionals in reviewing laboratory results, especially those
      related to diabetes.

PMID- 12596952
TI  - [Profile of first year dental students in Tunisia].
AB  - The aim of this study was to assess social conditions, school history,
      professional choices and oral health status of first-year dental students
      1998/1999. We included 155 Tunisian students, 18-22 years old. There was a higher
      proportion of female students (58%) whose average age (18.9 years) was younger
      than the males. We found that 79% came from urban environments and 41% from
      middle socioeconomic background. Also 48% had parents who had a high level of
      education. Dental studies were the first choice for 50% of the students and they
      were looking for prestige and security. Concerning oral heath status, 88% of the
      students had periodontal problems and 70% had caries. More information for
      students about the options available to them at university and greater efforts
      from teachers to motivate students in oral hygiene are needed.

PMID- 12596953
TI  - Palatal rugae area: a landmark for analysis of pre- and post-orthodontically
      treated adult Egyptian patients.
AB  - We aimed to evaluate the stability of the palatal rugae area before and after
      orthodontic treatment in adult Egyptian patients, and to suggest whether it could
      be used in superimposition in order to analyse orthodontic treatment change.
      Fifty pre- and post-dental casts of orthodontically treated adult Egyptian
      patients were collected from the clinic of the Orthodontic Department the
      University of Cairo. All patients were indicated to have symmetrical extraction
      of first premolars. The casts were scanned and analysed. The most reliable points
      were found to be the lateral third rugae points, which could be used as reference
      points for cast superimposition.

PMID- 12596954
TI  - Diabetes mellitus in an urban Palestinian population: prevalence and associated
      factors.
AB  - We investigated the prevalence of diabetes and associated factors in a cross
      sectional survey of an urban Palestinian population of 492 men and women aged 30
      65 years. The oral glucose tolerance test was used to diagnose diabetes and
      impaired glucose tolerance. World Health Organization-recommended survey
      protocols were followed. Diabetes was found in 12.0% of the survey population
      (including 9.4% previously diagnosed), and impaired glucose tolerance in 5.9%.
      Logistic regression analysis controlling for age and sex revealed body mass
      index, waist-to-hip ratio and family history of diabetes to be significantly
      independently associated with diabetes.

PMID- 12596955
TI  - Thyroid functional status in leprosy patients in Sudan.
AB  - We studied 45 adult patients with untreated lepromatous leprosy and borderline
      leprosy, presenting at clinics in Khartoum and Omdurman, to assess clinical and
      biochemical effects of the disease on thyroid function. A matching control group
      of 30 subjects, without symptoms or signs of thyroid disease, were included for
      comparison. Thyroxine, triiodothyronine and thyrotrophin levels were within
      normal range. Mean serum thyroxine was low in both groups (significant in
      lepromatous leprosy patients only). Mean serum triiodothyronine was high in both
      groups (significant in neither group). Mean thyrotrophin was significantly higher
      in both groups compared with controls.

PMID- 12596956
TI  - Estimation of tuberculosis incidence and mortality in Egypt using epidemiological
      models.
AB  - To estimate tuberculosis incidence in Egypt, data were collected from national
      tuberculosis case notification records, vital registration statistics, tuberculin
      surveys and treatment outcomes. An important source of information was the
      national comprehensive tuberculin survey results, which estimated a 55.2% case
      detection rate and a 65.6% case notification rate. The data suggest that only two
      thirds of actual cases are being identified and treated by the national
      programme. The figures for expected versus reported deaths from tuberculosis in
      Egypt in 1996 suggest underreporting to be almost 80%.

PMID- 12596957
TI  - Anticardiolipin antibodies in women with recurrent abortion.
AB  - The present study sought to determine whether the level of anticardiolipin
      antibodies in women with recurrent abortion differed from that in the general
      population. Enzyme-linked immunosorbent assay was used for detection of
      anticardiolipin antibodies in a group of 26 patients defined as habitual aborters
      (at least three consecutive spontaneous abortions), and in a control group of 26
      patients each of whom had had at least one live birth without pregnancy wastage.
      A high level of anticardiolipin antibody activity was detected among 19.23% of
      the habitual aborters but in none of the controls, indicating an association
      between anticardiolipin antibody level and habitual abortion.

PMID- 12596958
TI  - Colposcopy, cervical cytology and human papillomavirus detection as screening
      tools for cervical cancer.
AB  - A cohort of 77 women referred for routine screening or investigation of Pap test
      abnormality underwent colposcopic examination. Pap-stained liquid-based
      preparations were diagnosed and categorized according to the Bethesda system.
      Residual material on the sampling device was used to detect high-risk oncogenic
      human papillomavirus DNA. Although the colposcopic failure rate was higher than
      that of cytology, no lesion was missed when both methods were used together. High
      risk types were recorded in 24% of patients with atypical squamous cells of
      undetermined significance, 45% with low-grade squamous intraepithelial lesions
      and 79% with high-grade squamous intraepithelial lesions--indicating that the
      efficacy of cytological screening can be improved by papillomavirus detection.

PMID- 12596959
TI  - Forceps or vacuum extraction: a comparison of maternal and neonatal morbidity.
AB  - To compare maternal and neonatal morbidity associated with forceps and vacuum
      delivery, data on 150 women delivered by forceps and 420 delivered by vacuum
      extraction between 1995 and 1999 at Queen Ala Hospital, Jordan were compared.
      Data included parity, gestational age, infant birthweight, Apgar score,
      presentation and station of fetal head, indications for forceps and vacuum
      deliveries, delivery success rate, and maternal and neonatal morbidity. Maternal
      birth canal and genital tract lacerations were significantly more common in
      forceps delivery, and there was significantly increased morbidity in infants
      delivered by vacuum extraction (caput, jaundice, cephalohaematoma). Serous
      neonatal morbidity was rare for both groups.

PMID- 12596960
TI  - Effects of salted food consumption on urinary iodine and thyroid function tests
      in two provinces in the Islamic Republic of Iran.
AB  - We evaluated sources of difference in urinary iodine between two neighbouring
      Iranian provinces, Gilan and Mazandaran. In the cities of Rasht (Gilan) and Sari
      (Mazandaran), 340 and 343 participants respectively were selected by cluster
      sampling. Urinary iodine in Rasht was significantly higher than in Sari (31
      microg/dL versus 21 microg/dL). Sodium and potassium urine levels in Rasht were
      also higher than Sari. Mean daily intake of iodized salt and thyroid function
      tests were not significantly different. Average annual consumption of some salted
      foods was significantly higher in Rasht than Sari. We conclude that higher
      consumption of salted foods in Rasht is responsible for an increase in urinary
      iodine.

PMID- 12596961
TI  - An inhibitor of Staphylococcus aureus exfoliative toxin.
AB  - We describe here an inhibitor of Staphylococcus aureus exfoliative toxin. The
      toxin was extracted from an S. aureus strain isolated from a case of
      staphylococcus scalded skin syndrome. The activity of the toxin was compared in
      tryptic soy broth and brain heart infusion broth. Both supported growth of S.
      aureus but the culture filtrate of brain heart infusion broth lacked exfoliative
      toxin activity. Furthermore it appeared to contain a substance that neutralized
      the action of exfoliative toxin. This suggests the possibility of a treatment for
      staphylococcal scalded skin syndrome and bullous impetigo.

PMID- 12596962
TI  - Seroepidemiological survey of rubella immunity among three populations in Shiraz,
      Islamic Republic of Iran.
AB  - We used indirect ELISA assay to test 1193 sera for rubella IgG and IgM antibodies
      in a seroepidemiological survey of three age- and gender-differentiated sample
      populations in Shiraz: 203 children aged 2-7 years, 255 paired mothers and
      neonates (cord blood) and 480 women aged 14-70 years. Seropositivity among women
      aged 14-70 years was 96.2%. No IgM positive case was found among the 255 tested
      cord blood samples. Seropositivity among the 203 children was 97.0% (much higher
      than previously reported). This may be due to rubella epidemics, which tend to
      occur every 6-10 years. The impact of introducing rubella vaccination is
      discussed.

PMID- 12596963
TI  - Reproductive tract infections among married women in Upper Egypt.
AB  - In a house-to-house survey using cluster sampling, 1344 married women from urban
      and rural areas of Upper Egypt (Minia, Assiut and Sohag) were interviewed and
      examined to study the magnitude and determinants of reproductive tract
      infections. Overall prevalence was found to be 52.8%, with the most prevalent
      forms being Candida albicans (28.0%), Trichomonas vaginalis (8.7%), Aspergillus
      species (7.4%), streptococci (4.6%) and Chlamydia trachomatis (4.2%).
      Multivariate analysis identified certain groups of women at high risk of
      developing reproductive tract infections (those currently using an intrauterine
      device, those who regularly practised internal vaginal washing). Discriminant
      analysis showed that symptoms were of low discriminating value. There is a great
      need to increase community and women's understanding of reproductive tract
      infections.

PMID- 12596964
TI  - Hepatitis B infection in Yemenis in Sana'a: pattern and risk factors.
AB  - A cross-sectional seroepidemiological study was conducted among 2652 individuals
      (age range: 1 month-95 years; median 23 years) who presented at Sana'a Central
      Health Laboratory in response to a campaign to control hepatitis B virus.
      Screening was carried out by reverse passive haemagglutination. Specificity of
      positive samples was determined by enzyme immunoassay. Of 2321 participants, 7.4%
      were carriers of hepatitis B surface antigen. Risk factors determined by
      bivariate analysis were age, sex, residence, exposure to cutting and puncturing
      tools and blood transfusion. Multivariate analysis revealed age to be the best
      predictor of the carrier rate of hepatitis B virus.

PMID- 12596965
TI  - Kikuchi histiocytic necrotizing lymphadenitis: clinicopathological and
      immunohistochemical study.
AB  - Clinical, morphological and immunohistochemical features of 10 cases having the
      lymphnodal histological pattern of Kikuchi disease were examined. Two of these
      were diagnosed as systemic lupus erythematosus (SLE). Morphologically, Kikuchi
      disease and SLE were nearly indistinguishable. Plasma cells, neutrophilic
      infiltration, haematoxyphilic bodies and vasculitis were not useful in
      differentiating the conditions. Kikuchi lymphadenitis and malignant lymphoma
      however could be differentiated histologically. Morphological features that
      exclude malignancy included: polymorphous nature of cellular infiltrate, absence
      of abnormal mitosis, preservation of sinusoidal pattern on intervening areas and
      presence of extracellular and intracellular karyorrhectic debris.

PMID- 12596966
TI  - Pattern of dietary behaviour and obesity in Ahwaz, Islamic Republic of Iran.
AB  - To study behavioural factors associated with diet and to investigate body mass
      index distribution, a cross-sectional survey was carried out in Ahwaz. A
      composite dietary behaviour score obtained from self-reported responses to a 24
      item food-frequency questionnaire was used to categorize eating habits as
      more/less healthy. Responders were 1600 heads of households from 150,000 randomly
      selected residences. Less healthy diets were shown to be associated with age and
      economic status, and greater obesity with women and age (reversed after ages > 65
      years). Interventions targeted at less healthy eaters need to be evidence-based,
      and further research into factors determining access to healthy diets in
      developing communities is required.

PMID- 12596967
TI  - Alphafetoprotein in screening for congenital hypothyroidism.
AB  - This study was conducted on 500 full-term neonates and 25 older patients with
      congenital hypothyroidism (CH), newly or previously diagnosed. Alphafetoprotein
      (AFP) was elevated in two neonates. In one, persistent elevation of AFP and
      thyroid stimulating hormone (TSH) with low thyroxine (T4) were found (congenital
      hypothyroidism). In the other, AFP, TSH and T4 levels normalized (transient
      hypothyroidism). The mean AFP level in new CH patients was significantly higher
      than in previously diagnosed patients, and was higher in CH patients than in
      controls. Significant relationships were found between AFP and T4, AFP and TSH,
      and AFP and age. AFP is a sensitive indicator of thyroid status and can be used
      as a screening test for hypothyroidism from the first day of life and in follow
      up of CH patients.

PMID- 12596968
TI  - Experimental conversion of virulent RH Toxoplasma gondii tachyzoites in vitro.
AB  - We aimed to induce conversion of RH-stain tachyzoites to bradyzoites by changing
      the pH of the culture medium. Alkalization of the medium to pH 8 induced
      morphological changes in the cultured tachyzoites. The majority of the organism
      increased in size and changed from a regular crescent shape to a rounded or ovoid
      shape. Cyst-like structures were formed. Using a computerized image analyser,
      significant differences in the size of the whole organisms and in their nuclei
      were observed compared to the control group. The converted organisms also showed
      significant differences from the control group by quantitative DNA analysis, and
      did not infect mice.

PMID- 12596970
TI  - Indigenous practices of Saudi girls in Riyadh during their menstrual period.
AB  - The objective of this study was to identify the indigenous menstrual hygiene
      practice of Saudi girls in Riyadh. A total of 600 girls aged from 11 years to 18
      years were selected from outpatient clinics at three different hospitals in
      Riyadh. Data were collected using a structured interview. The results revealed
      that nearly two-thirds of the girls avoided certain foods, drinks and activities,
      including showering and performing perineal care, and practised several
      indigenous rituals during the period. Mother, religious books and sisters were
      the main sources of the girls' infomation. The study suggests that nurses and
      health care providers should use all available opportunities to educate young
      girls about menstruation.

PMID- 12596969
TI  - Urodynamic changes following intrathecal administration of morphine and fentanyl
      to dogs.
AB  - The effect of intrathecal (i.t.) injection of morphine and fentanyl on the
      urinary bladder was studied by ascending cystogram in 18 anaesthetized dogs.
      Examinations were performed before and 60 and 120 minutes after i.t. injection of
      saline (group I), 0.03 mg/kg morphine (group II) and 1.5 microg/kg fentanyl
      (group III). A significant increase in maximal volume and compliance and a
      decrease in voiding pressure were observed, indicating relaxation of the detrusor
      muscle after i.t. administration of morphine or fentanyl. I.t. morphine produced
      greater and more prolonged bladder relaxation than i.t. fentanyl. We conclude
      that i.t. morphine and fentanyl cause variable degrees of urinary retention. As
      fentanyl produced milder and shorter bladder relaxation than morphine, it may be
      useful in patients with urinary disturbances.

PMID- 12596971
TI  - Nutritional status of Yemeni schoolchildren in Al-Mahweet Governorate.
AB  - The nutritional status of 948 children selected randomly from Al-Mahweet
      Governorate schools was investigated. Age range was 5-18 years with a mean of
      10.6 +/- 2.8 years. Among the children, 3.4% had depleted iron and 43.4% had
      below average skin-fold thickness. Approximately half of the children were either
      stunted or chronically underweight and 1 child in 20 was underfed. Depleted fat
      stores affected two-fifths of the children and approximately one-fifth were
      anaemic. Urban residents scored significantly higher on nutritional parameters
      than rural children. Serum ferritin levels were significantly greater among males
      than females whereas mean height-for-age, weight-for-age and skin-fold thickness
      were lower.

PMID- 12596972
TI  - BCG vaccine and post-BCG complications among infants in Gaza Strip, 1999.
AB  - The relationship between post-BCG complications and the practices of
      administration and/or use of certain batches of BCG vaccine was investigated. A
      questionnaire were given to nurses administering BCG vaccination. An abstraction
      sheet was used to analyse cases with BCG complications among infants (n = 552)
      and schoolchildren (n = 97). The rate of complications was 14.7/1000 among
      infants and 2.5/1000 among schoolchildren in 1997. The complications rate was
      19.1/1000 at UNRWA and 8.3/1000 at governmental health services. It was found
      that a single batch of BCG 2611-11 combined with incorrect administering of the
      vaccine was responsible for this outbreak of complications. Therefore, the
      establishment of a surveillance system to monitor adverse events following
      immunization is needed.

PMID- 12596973
TI  - Predictors of surgery outcome for colorectal carcinoma in the United Arab
      Emirates.
AB  - In this retrospective study, 72 patients with colorectal cancer were followed up
      for a mean period of 28.2 months. Predictors of recurrence and survival were
      determined using standard analyses. Univariate analyses identified a group of
      patients with a shorter time to recurrence. The mean overall survival time was
      63.2 +/- 7.7 months and survival time was shorter for younger patients with
      palliative resection, lymph node metastasis and peritoneal nodules. In
      multivariate Cox proportional hazards analysis, the hazard ratio for positive
      lymph nodes was 2.54 (95% CI: 1.36-4.79) compared to negative nodes, and for
      Dukes' stages A and B compared to stage C it was 0.45 (95% CI: 0.25-0.81).

PMID- 12596974
TI  - Molecular diagnosis of spinal muscular atrophy in Egyptians.
AB  - This study was carried out with 33 spinal muscular atrophy (SMA) patients. DNA
      molecular studies of the SMA gene on the long arm of chromosome 5 (5q11.2q13.3)
      revealed homozygous deletion of exon 7 in 55% of cases, 36% of whom also had a
      homozygous delition of exon 8. The adult patients were heterozygous for an
      abnormal size exon 8. The remaining patients had either compound heterozygote
      deletion of exons 7 and 8 or were normal for both. There may therefore be 5q
      unlinked SMA or SMA due to other mutations. Detection of deletions of SMA exons 7
      and 8 is a powerful diagnostic test in patients with SMA, but other mutations
      among Egyptians must also be sought.

PMID- 12596975
TI  - A study of 235 cases of human brucellosis in Sana'a, Republic of Yemen.
AB  - We studied the clinical characteristics of brucellosis among all patients with
      brucellosis referred to the Central Health Laboratory from the main hospitals in
      Sana'a during a 2-year period (1992-93) (235 adults and children). A history was
      taken from each patient and clinical examination, general laboratory tests and
      brucellosis laboratory tests carried out. The overall clinical picture of
      brucellosis in this study is very similar to that reported by other workers in
      this geographical area. Awareness of the presenting features and the realization
      that brucellosis should be part of the differential diagnosis of febrile patients
      with enlarged liver, spleen and lymph nodes will lead to an increasing index of
      suspicion for this disease.

PMID- 12596976
TI  - [The quality of partially treated drinking-water produced in Sana'a City].
AB  - We assessed the quality of partially treated drinking water in 30 private
      establishments in Sana'a City, Republic of Yemen. We also compared the assessed
      water with the quality of 43 private wells and 18 estate wells. Microbiological
      examinations showed that 83% of the samples were contaminated; 50% with fecal
      coliforms and 33% with total coliforms. Concentration of mineral exceeded nominal
      values in 7% of the samples for nitrates, 10% for iron salts and in 20% of the
      samples for fluorides. In 33% of the samples, fluoride concentrations were lower
      than normal. Only 16.7% of the samples were found microbiologically and
      chemically potable.

PMID- 12596977
TI  - Cancer mortality in Benghazi, Libyan Arab Jamahiriya, 1991-96.
AB  - We present a descriptive study of 1221 cancer deaths among Libyans in Benghazi
      for the period 1991-96. The cancer mortality rates per 10(5) person-years at risk
      for males, females and both sexes were 39.8, 26.5 and 33.3 respectively. The age
      standardized cancer death rate per 10(5) standard world population was 91.5, 60.0
      and 76.5 respectively. The 10 most common cancer deaths by site (comprising 67.7%
      of the total), in descending order of frequency, were: trachea, bronchus and
      lung, blood (leukaemia), colon/rectum, other lymphatic and haemo-poietic tissue
      (lymphomas), stomach, breast, prostate, liver, bladder, and larynx. The results
      point to the necessity for conducting comprehensive prospective studies,
      initiating a cancer registry and establishing a national cancer control
      programme.

PMID- 12596978
TI  - A critical review of the infectious diseases surveillance system in the Gaza
      Strip.
AB  - The development and strengthening of national surveillance systems is a key part
      of communicable disease control. This review article describes and evaluates the
      Palestinian surveillance system and discusses the role of the epidemiology
      departments and other health providers in Gaza Strip in reporting infectious
      diseases, considers the use of the data collected, and makes recommendations for
      strengthening infectious diseases surveillance. Underreporting of infectious
      diseases remains a major problem in communicable diseases surveillance.
      Recommendations include the unification of the reporting forms between different
      health providers, increased involvement of health providers in reporting of
      infectious diseases, and complete separation of surveillance and clinical
      activities in epidemiology departments.

PMID- 12596979
TI  - Community health sciences and the legacy of Ibn Ridwan at the Aga Khan
      University.
AB  - This report briefly describes the Aga Khan University with particular reference
      to the Department of Community Health Sciences which was recently rehoused in the
      new Ibn Ridwan building. The building was named after Ibn Ridwan because of his
      significant contribution to community health, and some details of his life are
      given.

PMID- 12596980
TI  - Successful thrombolysis of mitral valve prosthesis by streptokinase during
      pregnancy.

PMID- 12596981
TI  - Measuring inequities in health in Egypt.

PMID- 12596982
TI  - Regional data on causes of death and burden of disease.

PMID- 12596983
TI  - Bibliography of articles on diabetes mellitus published in the Eastern
      Mediterranean health journal.

PMID- 12596984
TI  - Monte Carlo determination of age-dependent steady-state dose to red bone marrow
      and bone from 14C exposure.
AB  - Monte Carlo simulations were carried out to calculate the age-dependent dose from
      the beta decay of 14C to marrow and bone on the basis of a steady-state specific
      activity model. A model of the trabecular cavity containing spherical fat cells
      in a square lattice surrounded by haemopoietic tissue was employed. The age
      dependent 14C dose to haemopoietic (red) marrow was estimated taking account of
      the change in the fat cell size with fat fraction. Allowances were made for the
      change in the percentage cellularity and distribution of active marrow in the
      whole skeleton as a function of age. Age-dependent changes in trabecular cavity
      size and bone composition were found to have only a small effect on dose. Dose
      rates were estimated under steady-state conditions, for food ingested with a 14C
      specific activity of 1 Bq g(-1) of C. The equivalent dose rate to the
      haemopoietic tissue of a 20 year-old adult is 77 microSv a(-1), and 39 microSv a(
      1) for a 3-month-old infant. Similarly, the equivalent dose rate to the bone
      surfaces of an adult is 48 microSv a(-1), and 38 microSv a(-1) for an infant.
      Therefore, the equivalent dose rate to marrow and bone stem cells increases with
      age under steady state conditions.

PMID- 12596985
TI  - Estimating mixed field effects: an application supporting the lack of a non
      linear component for chromosome aberration induction by neutrons.
AB  - The action of neutron fields on biological structures was investigated on the
      basis of chromosome aberration induction in human cells. Available experimental
      data on aberration induction by neutrons and their interaction products were
      reviewed. Present criteria adopted in neutron radiation protection were
      discussed. The linear coefficient alpha and the quadratic coefficient beta
      describing dose-response curves for dicentric chromosomes induced by neutrons of
      different energies were calculated via integration of experimental data on
      dicentric induction by photons and charged particles into the Monte Carlo
      transport code FLUKA. The predicted values of the linear coefficients for neutron
      beams of different energies showed good agreement with the corresponding
      experimental values, whereas the data themselves indicated that the neutron
      quadratic coefficient cannot be obtained by 'averaging' the beta values of recoil
      ions and other nuclear reaction products. This supports the hypothesis that
      neutron induced aberrations increase substantially linearly with dose, a question
      that has been object of debate for a long time and is still open.

PMID- 12596986
TI  - Energy and directional response for the Harshaw dosemeter holders 8814 and 8891,
      and its effect on the appropriate radiation qualities for absolute calibration.
AB  - The personal dosimetry laboratory at the Norwegian radiation protection authority
      utilises a two-element dosemeter card for measuring Hp(10) and Hp(0.07), in a
      Harshaw dosemeter holder type 8814. Energy and directional responses for photons
      and betas for this holder have been assessed, as well as for the new Harshaw
      holder type 8891. The energy response characteristics for the 12-1250 keV photon
      energy range, in terms of TL output per unit Hp(10) and Hp(0.07) have been
      evaluated. The maximum over-response to under-response ratio for the Hp(10)
      element was found to be 1.46 for the new type 8891 holder, as compared to 1.55
      for the older type 8814. The new holder also displays a more favourable
      directional response for this element. For the Hp(0.07) element, no significant
      differences with regard to energy or directional responses were found. Selecting
      radiation energy for absolute calibration of the Hp(10) and Hp(0.07) elements are
      discussed.

PMID- 12596987
TI  - Premature chromosome condensation associated with fluorescence in situ
      hybridisation detects cytogenetic abnormalities after a CT scan: evaluaton of the
      low-dose effect.
AB  - The purpose of this study was to assess the cytogenetic effects of the X ray
      irradiation used during a CT scan in order to estimate the mean absorbed dose in
      circulating lymphocytes. Chromosomal aberrations were scored in blood lymphocytes
      of ten patients undergoing CT scans, by applying fluorescence in situ
      hybridisation (FISH) to metaphase cells and premature chromosome condensation
      (PCC) with chromosomes 1, 3 and 4 painting probes immediately after exposure.
      This generated a dosimetric index that reflects the dose to the circulating
      lymphocytes. By using PCC a significant increase in the frequency of chromosomal
      fragment was observed immediately after a CT scan. However, no significant
      increase in chromosomal aberration was detected in metaphase cells. The mean
      dosimetric index immediately after exposure was 0.057 Gy (95% CI: 0.052-0.082
      Gy). This dosimetric index depends essentially on the size of the examined and
      exposed blood volumes. This dose is in close agreement with the dose length
      product (DLP) (Gy cm) (R = 0.80). It should be kept in mind when justifying
      requests for diagnostic CT scan especially in young patients. The presence of
      chromosomal fragments after a CT scan indicated the cytogenetic effect of a low
      dose. PCC associated with chromosome painting is a method for detecting the
      cytogenetic effect of a low dose immediately after exposure.

PMID- 12596988
TI  - Radiation doses to neonates during X ray computed tomography examinations.
AB  - As the survival rate of newborns has increased, the number of X ray computed
      tomography (CT) examinations performed on neonates has been increasing. The
      exposure doses from CT examinations are known to be higher than those from
      conventional radiography. Although radiation sensitivity of neonates is higher
      than that of adults, there are few reports on dose estimates of neonates in CT
      examinations. Four cylindrical phantoms and one neonatal phantom have been
      developed to estimate doses to neonates during CT examinations. Using these
      phantoms and glass dosemeters, absorbed doses were measured. Estimated exposure
      doses to neonates were higher than those to adults, and our results suggest a
      need to optimise carefully CT examinations in newborns.

PMID- 12596989
TI  - A method for evaluating the entrance surface dose from the measurement of
      exposure and half value layer in intraoral radiography using a
      radiophotoluminescent dosemeter.
AB  - A method for measuring entrance surface dose in intraoral radiography for
      nationwide survey for the determination of guidance levels was developed using a
      commercially available radiophotoluminescent dosemeter (RPLD) system. From the
      ratio of the readings of the RPLD detectors. with and without a 1 mm thick
      aluminium filter, half value layer (HVL) and the energy dependency correction
      factor were derived. HVL and exposure for intraoral radiography were obtained
      with uncertainties of +/- 0.11 mmAl (SD) and +/- 2.1% (CV), respectively. This
      has been achieved by calibration at various beam qualities used in intraoral
      radiography. The HVLs and outputs of intraoral radiography units were measured by
      means of the mailed RPLD holders and also by ionisation chambers in 19 dental
      schools in Japan. Results obtained from the two methods of measurement agreed
      well for both HVLs and outputs.

PMID- 12596990
TI  - Analysis of occupational doses of workers on the dose registry of the Federal
      Radiation Protection Service in 2000 and 2001.
AB  - In 2000 and 2001 about 279 and 221 radiation workers, respectively, were
      monitored by the Federal Radiation Protection Service, University of Ibadan, in
      Nigeria. The distribution of the occupational doses shows that the majority of
      workers received doses below 4 mSv in each of the two years. The radiation
      workers in the two years are classified into two occupational categories:
      medicine and industry. The mean annual effective doses, collective doses and the
      collective dose distribution ratios for workers in each category and the entire
      monitored workers were calculated. The mean annual effective doses were compared
      with their corresponding worldwide values quoted by UNSCEAR. In each of the two
      years, a few workers in industry received doses higher than 50 mSv. The
      collective dose distribution ratio was found to be about 0.49, which is very
      close to the highest value of 0.5 in the range of values considered by UNSCEAR as
      normal for this parameter. This suggests that extra measures have to be taken,
      particularly in industry, to ensure that the proportion of workers at risk does
      not go outside this normal range. The occupational doses were also modelled by
      both the log-normal and Weibull distributions. Both distributions were found to
      describe the data in almost the same way.

PMID- 12596991
TI  - Evaluation of systematic errors in thyroid monitoring.
AB  - In this manuscript the thyroid is described by a new model. Efficiencies of a
      NaI(Tl) detector, for 364 keV photons, are calculated using Monte Carlo
      simulation. Contributions from thyroid size, detector placement and tissue
      overlay thickness, to the efficiency uncertainty, are evaluated considering the
      thyroid of a 12 year old subject as a limit for the adult thyroid. For a shielded
      3" x 3" NaI(Tl) detector, placed at 20 cm from the neck, a contribution of 18% to
      the efficiency uncertainty was found.

PMID- 12596992
TI  - Instrument performance of a radon measuring system with the alpha-track detection
      technique.
AB  - An instrument performance test has been carried out for a radon measuring system
      made in Hungary. The system measures radon using the alpha-track detection
      technique. It consists of three parts: the passive detector, the etching unit and
      the evaluation unit. A CR-39 detector is used as the radiation detector. Alpha
      track reading and data analysis are carried out after chemical etching. The
      following subjects were examined in the present study: (1) radon sensitivity, (2)
      performance of etching and evaluation processes and (3) thoron sensitivity. The
      radon sensitivity of 6.9 x 10(-4) mm(-2) (Bq m(-3) d)(-1) was acceptable for
      practical application. The thoron sensitivity was estimated to be as low as 3.3 x
      10(-5) mm(-2) (Bq m(-3) d)(-1) from the experimental study.

PMID- 12596993
TI  - A representative survey of indoor radon in the sixteen regions in Mexico City.
AB  - Mexico City, also called Federal District, covers an area of 1504 km(2), and has
      more than 8 million inhabitants. It is located more than 2200 m above sea level
      in a zone of high seismic activity, and founded on an ancient lake. At present it
      is one of the most crowded and contaminated cities in the world, with thermal
      inversions. Chemical contaminants and aerosol particles in the environmental air
      are high most of the year. Due to these geological, environmental and
      socioeconomic conditions, Federal District presents very peculiar
      characteristics, which are important for understanding the distribution and
      measurements of indoor radon concentration. In this work the results of 3 year
      (1998-2000) measurements of indoor radon levels in the Federal District are
      presented. For the detector distribution and measurements, the actual political
      administrative divisions of the Federal District, consisting of 16 very well
      defined zones, was used. Nuclear track detection methodology was selected for the
      measurement, with a passive device close-end-cup system with CR-39 (Lantrack)
      polycarbonate as the detection material, with one step chemical etching,
      following a very well established protocol developed at the Instituto de Fisica,
      UNAM. Calibration was carried out at the Oak Ridge National Laboratory, and
      verification at the Instituto de Fisica chamber. The results show that the
      arithmetical mean values of the indoor radon concentration for each region of the
      Federal District follow a non-homogenous distribution.

PMID- 12596994
TI  - Comments on 'Estimation of X ray overexposure in a childhood leukaemia cluster by
      means of chromosome aberration analysis'.

PMID- 12596995
TI  - Adenoviral vectors: production and purification.

PMID- 12596996
TI  - Gutted adenoviral vectors for gene transfer to muscle.

PMID- 12596997
TI  - Dual vector expansion of the recombinant AAV packaging capacity.

PMID- 12596998
TI  - Lentivirus vector-mediated gene transfer to cardiomyocytes.

PMID- 12596999
TI  - Cell therapy in the heart: cell production, transplantation, and applications.

PMID- 12597000
TI  - Cardiac cell transplantation: protocols and applications.

PMID- 12597001
TI  - Cell grafting for cardiac repair.

PMID- 12597002
TI  - Suppressor tRNAs: protocols and applications for cardiac gene transfer.

PMID- 12597003
TI  - Antisense oligonucleotides: design, construction, and applications to cardiac
      allograft transfer.

PMID- 12597004
TI  - Theoretical and technical considerations for gene transfer into vascularized
      cardiac transplants.

PMID- 12597005
TI  - Isolation, culture, and gene transfer of adult canine cardiac myocytes.

PMID- 12597006
TI  - Myofilament protein phosphorylation by PKC in genetically engineered adult
      cardiac myocytes.

PMID- 12597007
TI  - Embryonic and neonatal cardiac gene transfer in vivo.

PMID- 12597008
TI  - Efficient viral gene transfer to rodent hearts in vivo.

PMID- 12597009
TI  - Direct gene transfer to the adult rodent myocardium in vivo.

PMID- 12597010
TI  - Adenovirus-mediated gene transfer to cardiac myocytes in vivo using catheter
      based procedures.

PMID- 12597011
TI  - Coronary perfusion cocktails for in vivo gene transfer.

PMID- 12597012
TI  - Modification of in vivo cardiac performance by intracoronary gene transfer of
      beta-adrenergic receptor signaling components.

PMID- 12597013
TI  - Protocols for hemodynamic assessment of transgenic mice in vivo.

PMID- 12597014
TI  - In quest of thyroid hormone function in mature mammalian brain.
AB  - Thyroid hormones (TH) have important functions in maturation, differentiation and
      metabolism during developmental periods in almost all types of tissues including
      brain of vertebrate animals. In humans' thyroid malfunction in early
      developmental stages cause severe neuropsychological abnormalities due to
      defective gene expression via nuclear receptor activation. However, role of TH in
      adult mammalian brain is lacking and unclear mainly because it was considered for
      a long time as a TH unresponsive tissue. Although adult brain contains a
      substantial number of TH nuclear receptors, no functional properties could be
      attributed. Recent findings suggest that T3 is distributed, concentrated,
      metabolized and binds to specific membrane sites within adult brain. In mature
      humans TH also reversibly regulates various neuropsychological symptoms produced
      in mature condition. This review discusses development of recent concepts and
      literature on role of TH and its importance in neuronal function in adult
      mammalian brain.

PMID- 12597015
TI  - Retinoic acid--a player that rules the game of life and death in neutrophils.
AB  - Neutrophils are the most prevalent white blood cells in the circulation. They
      represent the first line of defense against invading microorganisms and have been
      implicated in the pathogenesis of a number of human diseases. In response to
      various factors, the pluripotent stem cells in bone marrow differentiate into
      mature neutrophils, enter the blood stream, and die within 24 hr via apoptosis.
      Numerous defects can occur during the process of neutrophils' differentiation
      that can manifest in the form of a variety of clinical disorders. Retinoids
      (Vitamin A and analogues), in general, and all-trans retinoic acid (tRA), in
      particular, play a critical role during differentiation of neutrophils. tRA can
      directly modulate gene expression via binding to its nuclear receptors, which in
      turn, can activate transcription of genes that are essential for differentiation
      of immature cells to neutrophils. Involvement of retinoic acid receptor in
      pathogenesis of acute promyelocytic leukemia (APL), reflects an important role
      played by this receptor in differentiation of immature myeloid cells to
      neutrophils. This review summarizes evidence on involvement of retinoic acid
      mediated events in differentiation process of neutrophils and their subsequent
      apoptosis.

PMID- 12597016
TI  - Role of adenosine in drug-induced catatonia in mice.
AB  - Parkinson's disease is one of the most common neurodegenerative disorders
      affecting large majority of population who are older than age of 65. Apart from
      dopamine, acetylcholine and glutamate, adenosinc has also been identified in the
      basal ganglia. Adenosine modulates the release of a variety of neurotransmitters
      including dopamine. In order to establish adenosine-dopamine interactions in drug
      induced catatonia we studied the effect of adenosine in drug-induced catatonia in
      mice. In the present study adenosine dose dependently produced catatonia when
      assessed on rota-rod and bar tests in mice. Adenosine also potentiated the
      catatonic effect of perphenazine. L-dopa plus carbidopa or OR-486 (a potent
      centrally acting COMT inhibitor) completely reversed adenosine-induced catatonia.
      Since reversal by scopolamine of adenosine-induced catatonia was not to the same
      extent as with l-dopa and OR-486 it appears that catecholamines particularly
      dopamine rather than cholinergic modulation is more important in adenosine
      induced catatonia. The motor dysfunction (catatonia) could be easily assessed
      using rota-rod test apparatus in mice.

PMID- 12597017
TI  - Expression of adenosine deaminase and 5'-nucleotidase in artificially induced
      deciduoma in rat and hamster.
AB  - Enzymes adenosine deaminase (ADA) and 5-nucleotidase (5-'NT) are known to play
      active role in tissue/cell proliferation and differentiation. To validate this
      the two enzymes were studied in artificially induced deciduoma of rat and
      hamster. The deciduoma was induced by traumatizing one of the uterine horns of
      progesterone primed animals. Non traumatized horn served as control. The animals
      were later maintained on progesterone, given alone (Gr.I) or conjointly with
      estrogen (Gr.II). The weight of each uterine horn was recorded to determine the
      formation of deciduoma. There was no marked difference between the weights of
      traumatized and control horn on day 2 post-traumatization (PT), but a progressive
      rise was noticed after this day in both species. The ADA activity however
      differed, day and species wise. While in the rats of Gr.I it was low in the
      traumatized horn on all the days, in the hamsters it was remarkably high from day
      2 to 6 PT. In the rats of Gr.II also the activity though was low in the
      traumatized horn, but on day 2 and 4 only; on day 6 and 7 PT it increased
      markedly. In hamster, on the contrary, again the enzyme activity was remarkably
      high on all the three days. The 5'-NT activity, however, did not show any marked
      difference between the two horns under Gr.I and II in both species. It was rather
      high in the control horn of each group. The results suggest: (I) the progesterone
      alone though produces a significant rise in the uterine weight of traumatized
      horn in both species, the ADA activity increases only in hamster, (2) under the
      conjoint treatment also the enzyme activity remains high in hamster; and (3) the
      activity of enzyme 5'-NT does not alter during the deciduoma formation in both
      the species.

PMID- 12597018
TI  - Protective effect of Gingko biloba extract against doxorubicin-induced
      cardiotoxicity in mice.
AB  - Doxorubicin (DXR) causes dose dependent cardiotoxicity in experimental animals
      and in humans. In chronic doxorubicin cardiotoxicity model mice, the role of G.
      biloba extract (Gbe) which has an antioxidant property, was investigated.
      Doxorubicin treated animals showed higher mortality (68%), increased ascites,
      marked bradycardia, prolongation of ST and QT intervals and widening of QRS
      complex. Myocardial SOD and glutathione peroxidase activity were decreased and
      lipid peroxidation was increased. Ultrastructure of heart of DXR treated animals
      showed loss of myofibrils, swelling of mitochondria, vacuolization of
      mitochondria. G. biloba extract significantly protected the mice from cardiotoxic
      effects of doxorubicin as evidenced by lowered mortality, ascites, myocardial
      lipid peroxidation, normalization of antioxidant enzymes, reversal of ECG changes
      and minimal ultrastructural damage of the heart. The results indicate that
      administration of G. biloba extract protected mice from doxorubicin-induced
      cardiotoxicity.

PMID- 12597019
TI  - Antioxidant and hypolipidaemic activity of a herbal formulation--liposem.
AB  - The efficacy of Liposem, a polyherbal formulation, as an antioxidant and
      hypolipidaemic drug was evaluated in diet induced hyperlipidaemia in rats. The
      methanolic extract of Liposem was found to scavenge hydroxyl and superoxide free
      radicals, the IC50 required being 70.5 and 45.0 microg respectively. The lipid
      peroxidation in rat liver homogenate induced by Fe2+ ascorbate system was also
      found inhibited (50%) by 273.5 microg of the extract. The hypolipidaemic effect
      was assessed by serum lipid profile in dietary hyperlipidaemic rats and found to
      have decreased dose dependently in all the four different concentrations of
      administration (100, 200, 300 and 400 mg/kg body wt). Liposem significantly
      raised high-density lipoprotein (HDL) cholesterol and the HDL/low density
      lipoprotein + very low-density lipoprotein (VLDL+LDL) ratio. The atherogenic
      index and the reduction in body weight were significant, indicating the
      effectiveness against hyperlipidaemia and obesity. These results reveal the
      therapeutic potential of Liposem against the vascular intimal damage and diet
      induced hyperlipidaemia leading to the various types of cardio vascular diseases.

PMID- 12597020
TI  - Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on
      alloxan induced diabetes mellitus in rats and its relation with antioxidant
      potential.
AB  - Methanolic extract of P. amarus was found to have potential anti-oxidant activity
      as it could inhibit lipid peroxidation, and scavenge hydroxyl and superoxide
      radicals in vitro. The amount required for 50% inhibition of lipid peroxide
      formation was 104 microg/ml and the concentrations needed to scavenge hydroxyl
      and superoxide radicals were 117 and 19 microg/ml respectively. The extract was
      found to reduce the blood sugar in alloxan diabetic rats at 4th hr by 6% at a
      dose level of 200 mg/kg body wt and 18.7% at a concentration of 1000 mg/kg body
      wt. Continued administration of the extract for 15 days produced significant (P <
      0.001) reduction in blood sugar. On 18th day after alloxan administration values
      were almost similar to normal in the group taking 1000 mg/kg body wt.

PMID- 12597021
TI  - Immunopotentiating activity of abrin, a lectin from Abrus precatorius Linn.
AB  - A non-toxic dose of abrin, (1.25 microg/kg body wt) consecutively for five days
      in normal mice stimulated specific humoral responses. A noticeable increase was
      observed in total leucocyte count, lymphocytosis, weights of spleen and thymus,
      circulating antibody titre, antibody forming cells, bone marrow cellularity and
      alpha-esterase positive bone marrow cells. The results suggest that abrin can
      potentiate the humoral immune response of the host.

PMID- 12597022
TI  - Effects of dried fish on antioxidant levels in rat liver.
AB  - Short-term feeding studies were carried out to investigate the effect of
      ingestion of salted dried fish on alterations in tissue lipid peroxidation and
      modulation of the activities of detoxification enzymes in liver in order to study
      the induction of oxidative stress. Rats were fed diets with either 5, 10 and 20%
      dried mackerel for 4 weeks and levels of antioxidants in liver were estimated.
      The results showed that the fish intake at 10 and 20% dietary level reduced
      glutathione with a reciprocal increase in thiobarbituric acid reactive substances
      and a concomitant decrease in antioxidant vitamins A and C contents in liver. A
      significant decline in the activities of hepatic glutathione peroxidase and
      glutathione reductase were also observed at these levels of fish consumption.
      Kidney gamma-glutamyl transpeptidase activity on the other hand was increased
      abnormally at 20% fish intake. The results suggested that the dried fish
      consumption at higher concentrations (at 10 and 20%) for a short period caused
      lowering of the activities of antioxidative enzymes thereby inducing oxidative
      stress in rat liver.

PMID- 12597023
TI  - Hormonal implication in Bracon-venom-induced paralysation of the host larva of
      Corcyra cephalonica (Lepidoptera: Pyralidae).
AB  - To facilitate oviposition, the ectoparasite Bracon hebetor, injects its venom, a
      paralysing toxin, to the host Corcyra larva that ultimately dies without showing
      any metamorphic change, even if allowed to remain unparasitised. At the initial
      stage of venom injection the rate of heartbeat of the host becomes abruptly high.
      This has been explained from the synergistic action of the substances of poison
      gland and calyx. The paralysed larvae subsequent to envenomization die within 240
      hr. Application of hydroprene as single dose or with a booster dose after
      paralysation mostly increases the survival period considering heart beat as the
      index. The predicted value of survival period (714.4 hr), determined from a
      fitted equation obtained from the relationship between heart beat and survival
      period, indicates that a 100 microg treatment/larva with a booster dose of 50
      microg/larva most effectively lengthens the period. It is concluded that the
      venom-induced physiological dysfunction of the immobilised larvae, as indicated
      in the rate of heart beat and survival period, though can be recovered to some
      extent after the application of juvenoids, there cannot occur any metamorphic
      change of these larvae. The parasitoid, therefore, succeeds in completing its
      development and metamorphosis by arresting the development of its host through an
      indirect hormonal suppression. The findings indicate an endocrine implication in
      host-parasite relationship in insect.

PMID- 12597024
TI  - A rapid hypochlorite method for extraction of polyhydroxy alkanoates from
      bacterial cells.
AB  - A new method has been standardized for extraction of polyhydroxy alkanoates from
      the bacteria, using sodium hypochlorite. This method is simple and quick as
      compared to the existing methods. Statistical analysis has proved the method to
      be reliable and reproducible.

PMID- 12597025
TI  - Solid state cultivation of Curvularia lunata for transformation of rifamycin B to
      S.
AB  - Biotransformation of rifamycin B to rifamycin S using two strains of C. lunata
      namely NCIM 716 and NMU grown on various solid substrates viz., grass, paper,
      jowar/wheat straw, bran and bagasse was studied. Almost complete
      biotransformation efficiency of rifamycin B at 0. 06 mM concentration was
      observed within 24 hr. Among these two strains, C. lunata NMU showed 90% of
      biotransformation and higher rate of cellulose utilization on solid substrates
      vis-a-vis reference strain. Cellulase activity of both strains was also studied
      for exoglucanase, endoglucanase and beta-glucosidase. Column bioreactor studies
      with bagasse revealed further improvement in biotransformation efficiency of C.
      lunata NMU.

PMID- 12597026
TI  - Pigment analysis and ammonia excretion in herbicide tolerant cyanobacteria.
AB  - Isolation of cyanobacteria was attempted from herbicide applied rice soils. The
      predominant genera were Westiellopsis followed by Anabaena, Nostoc and
      Oscillatoria. The herbicide tolerance was further tested by growing the
      cyanobacterial cultures in BG-11 medium supplemented with varying concentrations
      of the commonly used rice herbicide, viz butachlor under in vitro condition. The
      chlorophyll-a, phycobiliproteins and ammonia excretion were assessed at periodic
      intervals. Westiellopsis showed the maximum tolerance followed by Anabaena,
      Nostoc and Oscillatoria.

PMID- 12597027
TI  - Bioassay of three sulphur containing compounds as rat attractant admixed in
      cereal-based bait against Rattus rattus Linn.
AB  - Three sulphur containing compounds, carbon disulphide, dimethyl disulphide and
      dimethyl sulphide were bioassayed for preference after admixing them in cereal
      base as ready bait block for use against commensal rat, R. rattus (wild type) in
      four way choice chamber system. Rat preference for different baits was also
      studied with automatic recording animal activity meter. Rats exhibited
      attractancy to the baits at 0.005% concentration of all the three compounds while
      at 0.01% concentration they have showed repellency. Dimethyl sulphide at 0.005%
      concentration showed better attractancy towards both sexes of rat.

PMID- 12597028
TI  - Changes in free polyamines and related enzymes during stipule and pod wall
      development in Pisum sativum.
AB  - Level of free polyamines, their key metabolic enzymes, and other features related
      to ageing were examined during stipule and pod wall development in pea (Pisum
      sativum). Free polyamine titre (per unit fresh mass) in both the organs, the
      specific activities of arginine decarboxylase and ornithine decarboxylase in the
      pod wall, gradually decreased with maturation. In stipule, these enzymes attained
      peak activity at 15 days after pod emergence and declined thereafter. Ornithine
      decarboxylase activity was greater in pod wall than in stipule; while, arginine
      decarboxylase activity was higher in stipule. Activity of degradative enzyme
      diamine oxidase increased with the onset of senescence in both the organs.
      Chlorophyll and electrical conductance had a inverse relationship throughout the
      experimental period, whereas, the chlorophyll content was directly related with
      polyamine levels in both stipule and pod wall during aging. On the other hand,
      protein and RNA contents were positively correlated with free polyamines
      throughout the test period in stipule, but in the pod wall this was true only for
      the later stages of development.

PMID- 12597029
TI  - Micropropagation of Terminalia arjuna Roxb. from cotyledonary nodes.
AB  - Cotyledonary node explants excised from 21 day old seedlings of T. arjuna
      produced multiple shoots when cultured on full strength MS or modified MS (1/2
      strength major salts and Fe-EDTA) medium supplemented with different
      concentrations (0.1-1.0 mg/l) of BAP. Maximum 8.9 shoots/explant could be
      recorded after 30 days of inoculation on modified MS medium supplemented with BAP
      (0.5 mg/l). A proliferating shoot culture was established by reculturing the
      original cotyledonary nodes (2-3 times) on shoot multiplication medium after each
      harvest of the newly formed shoots. Shoots (each having 2-3 nodes/shoot) thus
      obtained were also used as a source of nodal explant that gave rise to 1-2 shoots
      when cultured on modified MS+BAP (0.5 mg/l) medium. Thus, 45-55 shoots could be
      obtained after 60 days of culture initiation from a single cotyledonary node.
      About 88% shoots rooted well after 15 hr pulse treatment with IBA (1 mg/l) in
      liquid MS medium followed by transfer to modified MS medium without IBA. About
      80% of these plantlets were successfully acclimatized in plastic pots containing
      sand and soil mixture and 70% plantlets transferred in the field those survived
      even after 6 months of transplantation.

PMID- 12597030
TI  - Effect of zinc on antioxidant response in maize (Zea mays L.) leaves.
AB  - Maize (Zea mays L. cv kanaujia) plants grown with Zn [10 (control), 0.1 (low) and
      20 microM (high)], were investigated for concentration of antioxidants and
      activities of antioxidative enzymes in leaves. Young leaves of low Zn plants
      developed whitish-necrotic spots. Leaves of both low and high Zn plants showed
      decrease in chlorophyll concentration and accumulation of lipid peroxides,
      ascorbate and dehydroascorbate, associated with a decrease in the activity of
      ascorbate peroxidase and superoxide dismutase. Low and high Zn, however, showed
      diverse effect on glutathione reductase. While low Zn increased the activity of
      glutathione reductase, high Zn decreased its activity. Zinc effect on
      antioxidative constituents suggested Zn involvement in sustaining the
      antioxidative defense system in maize leaves.

PMID- 12597031
TI  - Effect of external electrical field on mobile water fraction and physiological
      processes in wheat (Triticum aestivum) leaves.
AB  - Experiments were conducted to study the effect of external electric field on
      physiological processes, moisture content and mobile water fraction in wheat
      leaves. Application of electric field increased the stomatal resistance
      immediately and it continued to increase upto 10 min. Photosynthesis and
      respiration of leaves decreased with the application of external electric field.
      Leaf moisture content and mobile fraction of water measured as relaxation times
      were marginally increased with electric field. Closure of stomata, in spite of
      maintaining higher leaf moisture content of the leaf with external electric
      field, suggested that electric field might have regulated stomatal movement
      through hormones or ion flux across the cells.

PMID- 12597032
TI  - Fishmeal extract agar--a new antibiotic sensitivity test medium.
AB  - Fishmeal extract agar is a new antibiotic sensitivity test medium. It is simpler
      and cheaper than Mueller-Hinton agar and comparable in its efficacy to the
      latter. It can also be used for isolation of moderately fastidious and non
      fastidious bacteria from clinical specimens. Fishmeal extract broth can be used
      as a base for biochemical tests used for the identification of bacterial
      isolates.

PMID- 12597033
TI  - Acephate induced oxidative damage in erythrocytes.
AB  - The effect of oral administration of acephate (360 mg/kg body weight), for 15
      days, daily, was investigated on the erythrocytes of male rats. Activities of
      acetyl cholinesterase and glucose-6-phosphate dehydrogenase decreased, while
      those of glutathione-s-transferase and glutathione reductase increased. Decreased
      glutathione content and increased lipid peroxidation suggest that there was
      increased oxidative stress in the erythrocytes of treated animals. Increased
      cholesterol/phospholipid ratio in the erythrocyte membranes and morphological
      changes in RBCs (scanning electron microscopy studies) were observed in acephate
      treated animals. The results clearly suggest that acephate induced oxidative
      stress in erythrocytes leads to morphological changes.

PMID- 12597034
TI  - Photobiodegradation of pyridine by Rhodopseudomonas palustris JA1.
AB  - A purple non-sulfur bacterium isolated from dairy effluent was identified as Rps.
      palustris JA1. This organism was able to grow on pyridine as sole source of
      carbon in a light dependent anaerobic process with a doubling time of 30 h.
      Intermediates of pyridine photobiodegradation were identified as glycine and
      malonate, produced in stoichiometric molar ratios with simultaneous utilization,
      yielding biomass.

PMID- 12597035
TI  - The cellular basis of bacterial infection.
AB  - Innate and adaptive immune responses are responsible for the prevention of and
      recovery from bacterial infections. Fully immunocompetent humans make adaptations
      to the pathogens within their environment. Bacterial pathogens are capable of
      responding to immune adaptations to avoid destruction and elimination.
      Examination of the bacterial mechanisms of evasion has revealed the evolution of
      many elegant systems capable of thwarting host defenses. Undoubtedly, more
      mechanisms have yet to be discovered. A major concern as bacteria become more
      antibiotic resistant is whether human immune adaptation can evolve sufficiently
      to keep pace with bacterial evolution of evasion mechanisms.

PMID- 12597036
TI  - The cellular basis of septic shock.
AB  - Severe sepsis and septic shock are among the most complex and challenging
      conditions treated by critical care practitioners. Although the pathophysiology
      of severe sepsis and septic shock is not fully understood, bacteria and immune
      responses are known to trigger the release of cytokines. These cytokines initiate
      a cascade of events that lead to illness behaviors such as fever, anorexia, and
      sleepiness, as well as a host of physiologic events such as activation of the
      coagulation cascade, vasodilation, hypotension, and increased vessel
      permeability. As research advances the understanding of severe sepsis and septic
      shock, practitioners must become aware of the cellular basis of events so that
      treatments can be implemented knowledgeably and evaluated.

PMID- 12597037
TI  - The role of the critical care nurse in the assessment and management of the
      patient with severe sepsis.
AB  - Sepsis with acute organ dysfunction is common, frequently fatal, and expensive.
      The critical care nurse is involved in the continuous bedside care of the
      critically ill patient; consequently, he or she has the opportunity to prevent
      sepsis through infection control practices and general nursing care, to identify
      patients at risk for the disease, to monitor these patients for the clinical
      signs of sepsis, and to detect developing organ dysfunction as a manifestation of
      severe sepsis. In addition, the nurse is responsible for monitoring the patient's
      response to organ support measures and specific antisepsis interventions. The
      role of the critical care nurse in the assessment and management of severe sepsis
      is significant and can greatly improve outcomes for the patient with this
      disease. Drotrecogin alfa (activated) is a promising new therapy in the treatment
      of severe sepsis. Nurses caring for patients with this disease need to understand
      the issues related to the administration of drotrecogin alfa (activated) and the
      monitoring of patients receiving this drug to promote optimal and appropriate use
      of this innovative therapy.

PMID- 12597038
TI  - Neonatal bacterial sepsis.
AB  - Neonatal bacterial infection is a significant cause of morbidity and mortality
      despite improved survival of premature newborns, better understanding of the
      pathophysiology of sepsis, advances in supportive care, and more potent
      antibacterial agents. Early recognition and implementation of appropriate therapy
      offers the best outcome, and careful assessment of the newborn is essential.
      Current methods to detect signs of sepsis and to identify the causative
      microorganism are not 100% sensitive and precise. Continued research on other
      indicators may yield better diagnostic methods and therapy in the future.
      Research is necessary to identify the most sensitive markers for diagnosis of
      sepsis and methods of immune enhancement that are safe and effective.

PMID- 12597039
TI  - Stress in families of children with sepsis.
AB  - With the understanding that parents are the vital link to the child, nurses can
      develop plans of care based on research. Family functioning must be assessed as
      families attempt to deal with the stress involved in the hospitalization of a
      child with sepsis. Instruments and surveys may be helpful in developing a plan of
      care. These plans of care can have a major impact on the successful coping of
      parents. The stress of hospitalization may have long-term effects on children and
      families. Future research is needed to develop additional interventions that can
      be applied while the child is hospitalized and after discharge to aid the family
      in coping with stress.

PMID- 12597040
TI  - Sex differences in infection and sepsis.
AB  - Sex and gender-based differences in responses to infection and sepsis are
      evident. Estrogens increase immune function, sometimes to the point of inducing
      autoimmune disease. Testosterone suppresses immune function, sometimes leading to
      a worsened outcome following traumatic injury. Therapies using sex hormones to
      improve outcomes after sepsis and hemorrhagic shock and to reduce exacerbations
      of autoimmune diseases are being studied. Differences in sex hormone levels may
      not tell the whole story. Studies of immune function in girls and boys before
      puberty may be helpful. Differences found early might indicate that factors other
      than estrogen and androgen levels are contributing. Variations in societal role
      acculturation and exposures that are gender based also may be involved.
      Clinicians must consider sex and gender when attempting to determine the risk of
      infection, sepsis, and immune dysfunction in populations. Clinical applications
      of sex and gender differences are just beginning to occur with the genesis of sex
      hormone-based treatments. The large-scale efficacy of such treatments has yet to
      be reported. Innovative strategies based on sex or gender differences in immune
      responses may soon be available and may lead to essential data for clinical
      decision making. The impact of sex and gender differences on long-term health
      outcomes remains to be seen.

PMID- 12597041
TI  - Pelvic inflammatory disease and sepsis.
AB  - Pelvic inflammatory disease affects approximately 1 million women per year in the
      United States alone and has a variety of causative organisms. Because the
      diagnosis of PID is based on clinical judgment, health care providers need to be
      guided by the CDC recommendations for diagnosing and treating PID. Because
      presenting symptoms are often vague, the health care provider should assess
      female patients for risky behaviors that may lead to PID and should use screening
      data when making clinical judgments and differential diagnoses. Whenever
      possible, female patients with PID should be treated as outpatients. If diagnosis
      and treatment are not performed in a timely manner, PID may cause sepsis, septic
      shock, and even death. Even if they survive, as many as 15% to 20% of these women
      experience long-term sequelae of PID, such as ectopic pregnancy, tubo-ovarian
      abscess, infertility, dyspareunia, and chronic pelvic pain. The best treatments
      for PID are interventions that lead to prevention and early detection. The
      critical care nurse has an important role in recognizing the variables that may
      lead to PID-related sepsis and in encouraging health-seeking and health
      maintenance behaviors among women with these diagnoses.

PMID- 12597042
TI  - Malnutrition, infection, and sepsis in acute and chronic illness.
AB  - Optimal nutritional status contributes to health maintenance and the prevention
      of infection. The function of healthy cells is maintained by the provision of
      adequate nutrition. When nutrient availability is disrupted, primary and
      secondary malnutrition develop. Malnutrition contributes to a cascade of adverse
      metabolic events that compromise the immune system and impair the body's ability
      to adapt, recover, and survive. Malnutrition is treated by the early delivery of
      essential nutrients in an effective and comprehensive manner. Nurses are
      challenged to understand the importance of adequate nutritional support in the
      prevention of infection, multiple organ failure, and sepsis.

PMID- 12597043
TI  - The role of early enteral nutrition in protecting premature infants from sepsis.
AB  - Care of critically ill, preterm infants is a major challenge. Because of their
      small size and complex health problems, preterm infants require long-term
      hospitalization in the intensive care unit where they are exposed to serious
      microorganisms and other antigens that can overwhelm their immature immune
      systems. As smaller and more fragile preterm infants are surviving NICU care,
      these infants are at increased risk for nosocomial infections. Although modern
      antimicrobial agents are invaluable in the management of infection, they can
      result in biologic stress to the immature physiology of the preterm infant.
      Nonpharmacologic strategies to enhance the immunocompetence of the preterm immune
      systems provide another alternative in the management of these infants. Because
      the gastrointestinal tract is one of the largest immune organs within the body,
      strategies to maximize its immune functions can improve the outcome of these
      infants and help prevent or minimize the risk of infection. One such strategy is
      the early introduction of enteral feedings designed to stimulate or prime the
      gut. Early introduction of enteral feedings in the acutely ill preterm infant
      appears to be well tolerated in a variety of small clinical studies. Although the
      studies vary considerably in design and variables measured, collectively they
      show a solid trend toward improved outcomes. By preventing the negative
      consequences of a prolonged period of NPO, early enteral feedings promote the
      normal processes of the gut as a physical, mechanical, physiologic, and
      immunologic barrier. A solid understanding of the pathophysiology of prolonged
      NPO status and the physiology of the gut's immune properties enables critical
      care nurses to improve care of these vulnerable NICU patients.

PMID- 12597044
TI  - Economics of antibiotic administration.
AB  - This article examines several elements of antibiotic administration that make it
      worthy of policy analysis, including microbial resistance, contagion, competing
      brand and generic drugs, and formulary restrictions by insurers and hospitals.
      These topics are explored using two concepts from health economics, cost
      effectiveness and externalities, revealing theoretical and empirical evidence
      that society may not be using antibiotics as efficiently as it could.

PMID- 12597045
TI  - Infections in the heart transplant recipient.
AB  - The overall incidence of infection after transplantation has decreased with
      improved immunosuppressive agents, increased knowledge and use of prophylaxis,
      and better detection and treatment of infection. Nevertheless, infection
      continues to be a major cause of morbidity and mortality in heart transplant
      recipients. The knowledgeable nurse in any setting who cares for a transplant
      recipient must be aware of the lifelong susceptibility to common and
      opportunistic infections. The transplant recipient and his or her family must
      also be aware of the risks of early opportunistic infection. Infection is a
      lifelong concern for all persons on immunosuppressant medications, and the
      individual must learn appropriate precautions to reduce this risk. Hand washing
      and avoidance of infected individuals are the most important self-care actions
      that the transplant patient should adopt. Recipients must also learn to monitor
      for subtle signs of infection. The nurse is responsible for teaching self-care to
      patients and family members. Ultimately, a team effort by the patient, family,
      nurses, and physicians can reduce the risk of infection in this vulnerable
      population.

PMID- 12597046
TI  - Sepsis and treatment-induced immunosuppression in the patient with cancer.
AB  - Treatment for cancer is frequently an assault to the immune system. The
      immunosuppression that results significantly increases the patient's risk for
      infection. In this patient population, infection can quickly progress to sepsis,
      septic shock, and death. A high index of suspicion during nursing assessments is
      a critical strategy in early identification of infections. In addition, judicious
      adherence to infection control measures, appropriate use of prophylactic agents,
      and immediate employment of broad-spectrum antibiotics that are empirically based
      are essential strategies to maximize the patient's likelihood for survival.

PMID- 12597047
TI  - Are plants vectors for transmission of infection in acute care?
AB  - This article reviews relevant research that sheds light on the role of plants and
      flowers in hospital-acquired infections. After a review of a survey of acute care
      hospital policies, evidence-based practice recommendations intended to reduce
      nosocomial infections in acute and critical care are provided.

PMID- 12597048
TI  - The influence of diabetes mellitus on postoperative infections.
AB  - Clinicians and researchers are linking elevated glucose levels with potential
      infectious outcomes. Physiologic processes to fight foreign agents are
      potentially impaired during periods of hyperglycemia. Some of these responses,
      such as immune function and the inflammatory response, are impaired when they are
      needed most, such as during the recovery from surgical procedures. Investigators
      have demonstrated the importance of control of serum glucose postoperatively.
      Outcomes are improved when tighter glycemic control is practiced. The current
      literature challenges practitioners to become more cognizant of serum glucose in
      surgical patients and patients who are critically ill, implementing protocols to
      gain tighter control of serum glucose in any patient may be appropriate. Further
      investigation of glycemic control in surgical and other populations will
      reinforce research findings in this area. Studies should be performed on surgical
      patients who are particularly vulnerable to DM, glycemic alterations, and
      postoperative infections, such as patients undergoing peripheral vascular
      surgery. Further investigations are also needed on the role of hyperglycemia and
      outcomes in nondiabetic individuals, and on the similarities or differences in
      glycemic control in types 1 and 2 DM. To increase the generalizability of the
      study findings, definitions used across studies, such as the type of diabetes,
      should be standardized. When these studies determine optimal glycemic control
      practices in a variety of patient populations, clinicians will be able to
      determine the best practice guidelines to optimize patient care and limit adverse
      infectious outcomes.

PMID- 12597049
TI  - Inherited metabolic disorders and seizures in infancy.

PMID- 12597050
TI  - Classification of infantile seizures: implications for identification and
      treatment of inborn errors of metabolism.
AB  - Metabolic disorders constitute an important cause of neurologic disease,
      including infantile epilepsy. The inability to characterize seizures and epilepsy
      syndromes precisely in infants impedes the recognition of features suggestive of
      specific underlying metabolic and neurodegenerative etiologies. Classification
      systems using simple descriptions of ictal behaviors can be reliably applied and
      may aid in the recognition of these disorders. Myoclonic seizures in infancy in
      particular suggest an inborn error of metabolism. In addition, certain epileptic
      syndromes are known to be associated with metabolic disorders, including some
      forms of neonatal seizures, West's syndrome, early myoclonic encephalopathy, and
      early infantile epileptic encephalopathy. Occasionally, there are distinctive
      electroencephalographic patterns that may suggest a specific metabolic disease.
      Earlier recognition of metabolic disorders may be accomplished by careful study
      of clinical and electrographic characteristics. There are important treatment
      considerations associated with these disorders.

PMID- 12597051
TI  - Infantile epileptic syndromes and metabolic etiologies.
AB  - Inherited metabolic disorders can cause onset of epilepsy in the first year of
      life. Epilepsy rarely dominates the clinical presentation, which is more
      frequently associated with other neurologic symptoms, such as mental retardation,
      hypotonia and/or dystonia, or vigilance disturbances. The pathogenesis of
      seizures is multifaceted; inherited metabolic disorder can affect the balance
      between excitatory and inhibitory chemical mediators, eliminate an energetic
      substrate at the cerebral level, cause in utero brain malformation, or provoke
      acute brain lesions. Some clinical disorders that strongly suggest particular
      metabolic etiologies can be identified. For example, specific clinical signs and
      findings on electroencephalogram (EEG) are characteristic of pyridoxine-dependent
      seizures, and inherited metabolic disorders associated with early myoclonic
      encephalopathy are well defined. In most cases, however, epilepsy secondary to
      inherited metabolic disorders presents with polymorphic clinical and EEG features
      that are difficult to classify into precise epileptic syndromes. Common
      characteristics of these seizures include onset in the first months of life;
      usually partial, multifocal; simple partial motor semiology; successive
      appearance of tonic seizures, spasms, and massive myoclonus; and resistance to
      antiepilepsy drugs. Inherited metabolic disorders must be considered in patients
      presenting with epilepsy and progressive neurologic worsening.

PMID- 12597052
TI  - Glucose transporter 1 deficiency syndrome and other glycolytic defects.
AB  - Glucose transporter 1 deficiency syndrome is emblematic of a brain energy failure
      syndrome. Energy failure also results from other genetically determined metabolic
      disorders, such as hypoglycemic syndromes, hypoketonemic syndromes associated
      with fatty acid oxidation defects, glycolytic enzymopathies, and mitochondrial
      defects. Glucose transporter 1 deficiency syndrome is particularly illustrative
      of this group of disorders and produces an infantile-onset epileptic
      encephalopathy that responds to a ketogenic diet. The electroencephalographic
      correlate is distinctive and emerges as a 2.5- to 4-Hz spike-wave discharge in
      late infancy to early childhood. Infantile apnea and oscillatory eye movements
      reminiscent of opsoclonus may be the earliest signs of this condition. Mutations
      of the GLUT1 gene are causative and transmitted as an autosomal dominant trait.
      Thioctic acid is a glucose transporter 1 activator, whereas barbiturates and
      methylxanthines are glucose transporter 1 inhibitors. The ketogenic diet is
      effective treatment for glucose transporter 1 deficiency syndrome and pyruvate
      dehydrogenase deficiency. It also should benefit patients with neurologic
      symptoms resulting from a glycolytic enzymopathy.

PMID- 12597053
TI  - Defects of pyruvate metabolism and the Krebs cycle.
AB  - Seizures and metabolic disease are frequently associated, either indirectly as a
      consequence of the metabolically caused brain dysgenesis or directly by the
      metabolic derangement. This article describes defects in pyruvate metabolism
      (pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency) and Krebs
      cycle defects such as fumarase deficiency. Clinical characterizations and
      diagnostic strategies have been developed for each of these diseases. In
      contrast, very little is known about the specific epileptic features in these
      disorders. In females with a pyruvate dehydrogenase deficiency E1alpha owing to
      the mutation in the subunit E1alpha of the pyruvate dehydrogenase complex West's
      syndrome associated with large ventricles and corpus callosum agenesis on
      magnetic resonance imaging can be the main feature of the disease. In fumarase
      deficiency, prenatal brain dysgenesis is the most prominent feature of the
      disease. Diagnosis of these disorders requires measurements of lactate and
      pyruvate in plasma and cerebrospinal fluid, analysis of amino acids in plasma and
      organic acids in urine, and neuroradiologic investigations. Further biochemical
      and molecular analysis leads to a definitive diagnosis and opens the way to
      adequate treatment, genetic counseling, and prenatal diagnosis.

PMID- 12597054
TI  - Mitochondrial disorders.
AB  - Mitochondrial disorders associated with defects in the respiratory chain can be
      attributable to mutations in the mitochondrial genome (mitochondrial DNA) or the
      nuclear genome (nuclear DNA). Because the brain is highly dependent on oxidative
      metabolism, encephalopathy is a common presentation, and epilepsy is a clinical
      hallmark of many of these conditions. Although most mutations in mitochondrial
      DNA do not present in infancy, a few mutations in the adenosine triphosphatase
      gene cause maternally inherited Leigh disease and infantile epilepsy. Early-onset
      epilepsy is more commonly associated with defects of nuclear genes encoding
      subunits of respiratory chain complexes or proteins needed for the correct
      assembly and functioning of the complexes. These defects generally cause
      autosomal recessive Leigh disease. In this review, the frequency and types of
      epilepsy (particularly early-onset seizures) are compared according to a genetic
      classification of the mitochondrial disorders.

PMID- 12597055
TI  - Value of lumbar puncture in the diagnosis of infantile epilepsy and folinic acid
      responsive seizures.
AB  - Seizures are one of the most frequently occurring neurologic phenomena in
      childhood; an inborn error of metabolism should always be considered in the
      diagnostic workup of patients with seizures after more common causes have been
      excluded. Many of the known inborn metabolic errors associated with seizures can
      be detected by metabolite measurement in urine or blood. It is now recognized,
      however, that there are several conditions in which peripheral metabolite
      profiles remain normal. Abnormal metabolism is indicated only by the accumulation
      or absence of specific metabolites within the central nervous system. Some of
      these disorders can be detected by in vivo magnetic resonance spectroscopy. More
      often, an etiology can be ascertained only by analysis of specific metabolites in
      cerebrospinal fluid. This review describes the utility of cerebrospinal fluid
      metabolite analysis in the differential diagnosis of inborn errors of metabolism
      that lead to infantile epilepsy. These include disorders of central nervous
      system energy metabolism, creatine synthesis and transport, serine biosynthesis,
      and glucose transport, together with defects affecting the gamma-aminobutyric
      acid (GABA), catecholamine, and serotonin neurotransmitter systems. In addition,
      information is provided regarding detection of an early-onset seizure disorder
      that responds to folinic acid.

PMID- 12597056
TI  - Role of carnitine and fatty acid oxidation and its defects in infantile epilepsy.
AB  - Defects in fatty acid oxidation are a source of major morbidity and are
      potentially rapidly fatal. Fatty acid oxidation defects encompass a spectrum of
      clinical disorders, including recurrent hypoglycemic, hypoketotic encephalopathy
      or Reye-like syndrome in infancy with secondary seizures and potential
      developmental delay, progressive lipid storage myopathy, recurrent myoglobinuria,
      neuropathy, and progressive cardiomyopathy. As all of the known conditions are
      inherited as autosomal recessive diseases, there is often a family history of
      sudden infant death syndrome in siblings. Early recognition and prompt initiation
      of therapy and the institution of preventive measures may be life saving and
      significantly decrease long-term morbidity, particularly with respect to central
      nervous system sequelae. Seizures may be the result of cerebral bioenergetic
      failure associated with acute episodes of hypoglycemic, hypoketotic
      encephalopathy, or hypoxic-ischemic encephalopathy in the context of cardiac
      arrhythmias and/or cardiomyopathy. This review provides an overview of the fatty
      acid oxidation pathway and the central role of carnitine, as well as a discussion
      of normal fasting adaptation and the critical metabolic adaptations that occur at
      birth. The increased vulnerability of infants and young children to fasting and
      defective fatty acid oxidation is discussed in the context of the heightened
      bioenergetic demands of the developing brain. Clinical and laboratory features of
      specific genetic defects in fatty acid oxidation, approaches to diagnosis, and
      current treatment methodologies are described. Indications for carnitine
      supplementation in childhood epilepsy are also discussed.

PMID- 12597057
TI  - Genetic disorders of gamma-aminobutyric acid, glycine, and serine as causes of
      epilepsy.
AB  - Genetic disorders of gamma-aminobutyric acid (GABA), glycine, and serine
      metabolism and of the GABA and glycine receptors are causes of epilepsy with
      variable responsiveness to treatment. Pyridoxine-dependent convulsions and the
      GABA(A) receptor defects are pure epileptic disorders that respond well to
      treatment. The convulsions associated with 3-phosphoglycerate dehydrogenase
      deficiency can be completely abolished with amino acid therapy. Epilepsy is a
      major symptom in succinic semialdehyde dehydrogenase deficiency. The convulsions
      in these disorders are not responsive or are only partially responsive to
      treatment.

PMID- 12597058
TI  - Inborn errors of creatine metabolism and epilepsy: clinical features, diagnosis,
      and treatment.
AB  - Creatine metabolism disorders have so far been described at the level of two
      synthetic steps, guanidinoacetate N-methyltransferase and arginine:glycine
      amidinotransferase, and at the level of the creatine transporter 1.
      Guanidinoacetate N-methyltransferase and arginine:glycine amidinotransferase
      deficiency respond positively to substitutive treatment with creatine
      monohydrate. Guanidinoacetate N-methyltransferase deficiency results in a severe
      neurologic disease (age of onset 3 months to 2 years) characterized by
      developmental arrest, neurologic deterioration, movement disorders, mental
      retardation, autistic-like behavior, and epilepsy. Severe early-onset epilepsy
      with pleomorphic seizures is a key symptom of this disorder. Data suggest that in
      patients with guanidinoacetate N-methyltransferase deficiency, epilepsy and
      associated electroencephalographic abnormalities are more responsive to creatine
      supplementation than to conventional antiepilepsy drugs. Arginine:glycine
      amidinotransferase and creatine transporter 1 mainly present with mental
      retardation and severe language disorder. All cases of creatine disorders
      reported to date have been detected by brain proton magnetic resonance
      spectroscopy, an expensive technique not routinely used in pediatric neurology. A
      potential diagnostic strategy to select patients for evaluation using proton
      magnetic resonance spectroscopy is proposed in this review.

PMID- 12597059
TI  - Metabolic evaluation of infantile epilepsy: summary recommendations of the Amalfi
      Group.
AB  - The purpose of this symposium was to bring together the disciplines of clinical
      neurology and metabolic investigation and to present the most up-to-date
      information about specific metabolic disorders associated with infantile
      epilepsy. Understanding the etiology of seizures is the key to rational
      intervention. It is only with this insight that progress in the treatment of
      these patients can be made. In the past, many infantile epileptic syndromes were
      described by their clinical features, without understanding of the underlying
      pathophysiology. In the future, it is hoped that the genetic and metabolic bases
      of these syndromes will be more completely defined such that reliable diagnostic
      and effective treatment methods are available. Most of the tests listed in Table
      2 should not be performed without due consideration of the history, clinical
      findings, and results of prior studies. This article is intended to aid
      clinicians in reviewing potential metabolic diagnoses and to approaching
      metabolic evaluations in an economical, logical, and comprehensive manner.
      Although the field of metabolic diseases may be in its infancy, many of these
      disorders can be identified and treated. The task for investigators is to provide
      the armamentarium of diagnostic tools to clinicians to ensure that a metabolic
      disorder is not overlooked. There must be a common ground that links clinicians
      and basic researchers in an evolving and collaborative manner.

PMID- 12597060
TI  - Venous thromboembolic events in an orthopaedic practice.

PMID- 12597061
TI  - A meta-analysis of fondaparinux versus enoxaparin in the prevention of venous
      thromboembolism after major orthopaedic surgery.
AB  - A worldwide phase III program, consisting of four randomized, double-blind trials
      in patients undergoing surgery for hip fracture, in elective hip replacement
      surgery patients and in elective major knee surgery patients, was conducted to
      compare the benefit-to-risk ratio of a subcutaneous 2.5-mg once-daily regimen of
      fondaparinux, a synthetic selective factor Xa inhibitor, starting postoperatively
      with enoxaparin in preventing venous thromboembolism. The overall incidence of
      venous thromboembolism up to day 11 was reduced from 13.7% in the enoxaparin
      group to 6.8% in the fondaparinux group with a common odds reduction of 55.2% in
      favor of fondaparinux (95% confidence interval: 45.8-63.1%, p = 10(-17)). This
      superior efficacy of fondaparinux was also demonstrated for proximal deep vein
      thrombosis with a reduction of 57.4%. The overall incidence of clinically
      relevant bleeding was low and did not differ between the two groups. The benefit
      of fondaparinux was consistent across all types of surgery and all subgroups.

PMID- 12597062
TI  - Thrombosis prophylaxis in orthopedic surgery: current clinical considerations.
AB  - Thrombosis prophylaxis in orthopedic surgery is an important consideration in
      order to avoid the morbidity and mortality of venous thromboembolism (VTE).
      Patients who do not receive prophylaxis, or receive inadequate prophylaxis, may
      be at risk for clinical or fatal pulmonary emboli, and a fatality, although rare,
      may be the first sign of a VTE. Although the surgeon may have corrected the
      patient's orthopedic problem, a symptomatic or asymptomatic venous thrombosis may
      become a new threat to the patient's quality of life. This problem places such
      patients at risk for recurrent VTE, as well as post-thrombotic syndrome, a
      progressive, lifelong disability. Methods of prophylaxis that prevent the most
      clots result in the fewest venous thromboembolic events, but no one method of
      prophylaxis is suitable for all patients. In order to select the appropriate
      modality, a careful risk assessment of each patient is necessary. Those at low or
      moderate risk levels do not require the same modalities that may be used in a
      patient with a previous history of thrombosis or with many risk factors. The
      purpose of this brief review is to examine the complications associated with
      venous thromboembolism and to discuss, in detail, the risk of thrombosis in
      orthopedic patients. In addition, thrombosis prophylaxis modalities are discussed
      and suggestions made based on current Chest Consensus Guidelines and FDA-approved
      products.

PMID- 12597063
TI  - A new antithrombotic strategy, the selective inhibition of coagulation factors,
      and its importance to the orthopedic specialist.
AB  - Traditional anticoagulant drugs including vitamin K antagonists and heparins have
      several limitations. Despite their use, the burden of venous thromboembolism
      remains high, particularly in patients undergoing major orthopedic surgery. A new
      strategy for the design of new antithrombotic drugs is based on selective
      inhibition of a specific coagulation factor. Fondaparinux is a synthetic
      selective inhibitor of factor Xa, which is critically positioned at the start of
      the common pathway of the coagulation system. Its pharmacokinetic profile allows
      for once-daily administration without the need for laboratory monitoring or dose
      adjustment. Fondaparinux has demonstrated its efficacy compared to a widely used
      low-molecular-weight heparin in a number of thromboprophylaxis trials after major
      orthopedic surgery and is approved for use in this setting.

PMID- 12597064
TI  - Proximal femoral fractures.
AB  - Fractures of the proximal femur include fractures of the head, neck,
      intertrochanteric, and subtrochanteric regions. Head fractures commonly accompany
      dislocations. Neck fractures and intertrochanteric fractures occur with greatest
      frequency in elderly patients with a low bone mineral density and are produced by
      low-energy mechanisms. Subtrochanteric fractures occur in a predominantly strong
      cortical osseous region which is exposed to large compressive stresses. Implants
      used to address these fractures must be able to accommodate significant loads
      while the fractures consolidate. Complications secondary to these injuries
      produce significant morbidity and include infection, nonunion, malunion,
      decubitus ulcers, fat emboli, deep venous thrombosis, pulmonary embolus,
      pneumonia, myocardial infarction, stroke, and death.

PMID- 12597065
TI  - Minimally invasive total hip replacement and perioperative management: early
      experience.
AB  - "Minimally invasive" total hip replacement has been promoted in the popular media
      and advertising despite a lack of peer-reviewed data. This article presents the
      author's early experience and preliminary outcomes with this new and potentially
      useful approach to total hip replacement.

PMID- 12597066
TI  - History of total knee replacement.
AB  - In the early 1970s, the condylar knee was developed independently in the United
      States and overseas. The concept of replacing the tibiofemoral condylar surfaces
      with cemented fixation, along with preservation of the cruciate ligaments, was
      developed and refined. To correct severe knee deformities, the condylar knee with
      posterior cruciate-sacrificing design was introduced, also in the early 1970s. By
      1974, replacing the patellofemoral joint and either preserving or sacrificing the
      cruciate ligaments had become standard practice. Subsequently, condylar knee
      designs were improved to include modularity and noncemented fixation, with use of
      universal instrumentation. Today, over 19 companies in the United States
      distribute total knee implants of three different types: cruciate-preserving,
      cruciate-substituting, and TC-III. Six major companies are actively involved in
      designing mobile-bearing knees. Future developments, such as navigation-guided
      surgery, enhanced kinematics, and wear-resistant bearing surfaces with better
      fixation, promise a consistent evolution for the total knee replacement.

PMID- 12597067
TI  - Range of motion after arthroplasty for the stiff osteoarthritic knee.
AB  - In 28 of 1656 total knee arthroplasties (TKAs) (1.7%) performed for
      osteoarthritis at this institution, the preoperative arc of motion was 60 degrees
      or less (average 47.5 degrees; range, 20-60 degrees). The outcome of 22 of the 28
      TKAs (21 patients) is reported at a mean follow-up of 52.9 months (range, 24-144
      months). Eighty-two percent of the cases were managed with standard soft-tissue
      releases and posterior cruciate-retaining implants and 18% with a cruciate
      substituting design. The joint score rose from 28.8 to 82.2 and the Knee Society
      Score from 24.6 to 77 points. The mean postoperative arc of motion improved by 46
      degrees-93.5 degrees. At latest follow-up, 68.2% of knees achieved maximal
      flexion of 90 degrees or more. Manipulation was performed in 22.7%. Complications
      were minimal. A functionally useful range of motion is possible after total knee
      arthroplasty in the majority of stiff osteoarthritic knees, often without the
      need for posterior cruciate substitution.

PMID- 12597068
TI  - Influence of slight to moderate risk for birth hypoxia on acquisition of
      cognitive and language function in the preterm infant: a cross-sectional
      comparison with preterm-birth controls.
AB  - The cognitive and language performance of a group of 26 preterm-birth preschool
      and early school-age children with slight to moderate risk for perinatal hypoxia
      was compared with the performance of a preterm-birth comparison group of 26
      children. Despite the relatively small discrepancy in degree of risk, the
      cognitive performance of the 2 groups diverged significantly. When data for
      children with known perinatal arterial pH were combined, a curvilinear
      (quadratic) regression model provided the best fit. Increasing acidosis was
      linearly related to decreases in cognitive skills, with the bend in the curve
      occurring well within the normal range of pH values. Hence, in the preterm
      infant, even minor risk for birth hypoxia may result in discernible deviation
      from the expected developmental trajectory.

PMID- 12597069
TI  - The contribution of recollection and familiarity to recognition memory: a study
      of the effects of test format and aging.
AB  - Whether the format of a recognition memory task influences the contribution of
      recollection and familiarity to performance is a matter of debate. The authors
      investigated this issue by comparing the performance of 64 young (mean age = 21.7
      years; mean education = 14.5 years) and 62 older participants (mean age = 64.4
      years; mean education = 14.2 years) on a yes-no and a forced-choice recognition
      task for unfamiliar faces using the remember-know-guess procedure. Familiarity
      contributed more to forced-choice than to yes-no performance. Moreover, older
      participants, who showed a decrease in recollection together with an increase in
      familiarity, performed better on the forced-choice task than on the yes-no task,
      whereas younger participants showed the opposite pattern.

PMID- 12597070
TI  - Large sexual-orientation-related differences in performance on mental rotation
      and judgment of line orientation tasks.
AB  - This study examined the performance of heterosexual and homosexual men and women
      on 2 tests of spatial processing, mental rotation (MR) and Benton Judgment of
      Line Orientation (JLO). The sample comprised 60 heterosexual men, 60 heterosexual
      women, 60 homosexual men, and 60 homosexual women. There were significant main
      effects of gender (men achieving higher scores overall) and Gender x Sexual
      Orientation interactions. Decomposing these interactions revealed large
      differences between the male groups in favor of heterosexual men on JLO and MR
      performance. There was a modest difference between the female groups on MR total
      correct scores in favor of homosexual women but no differences in MR percentage
      correct. The evidence suggests possible variations in the parietal cortex between
      homosexual and heterosexual persons.

PMID- 12597071
TI  - Dichotic ear advantages in adults with Down's syndrome predict speech production
      errors.
AB  - Intellectually challenged adults, with and without Down's syndrome (DS), pointed
      to drawings of animals following the dichotic presentation of animal names.
      Although there were no reliable ear differences between the 2 groups, there was
      tremendous between-persons variability within the group of participants with DS.
      Moreover, left-ear advantages in persons with DS were associated with more speech
      production errors when participants either read or repeated a string of 1
      syllable words. This was not true for control participants. The relationship
      between ear advantage and speech errors in persons with DS could reflect their
      unique pattern of cerebral specialization and brain development.

PMID- 12597072
TI  - Face and emotion recognition deficits in Turner syndrome: a possible role for X
      linked genes in amygdala development.
AB  - Face recognition is thought to rely on configural visual processing. Where face
      recognition impairments have been identified, qualitatively delayed or anomalous
      configural processing has also been found. A group of women with Turner syndrome
      (TS) with monosomy for a single maternal X chromosome (45, Xm) showed an
      impairment in face recognition skills compared with normally developing women.
      However, normal configural face-processing abilities were apparent. The ability
      to recognize facial expressions of emotion, particularly fear, was also impaired
      in this TS subgroup. Face recognition and fear recognition accuracy were
      significantly correlated in the female control group but not in women with TS.
      The authors therefore suggest that anomalies in amygdala function may be a
      neurological feature of TS of this karyotype.

PMID- 12597073
TI  - Aspects of social and emotional competence in adult attention
      deficit/hyperactivity disorder.
AB  - Social and emotional competence were evaluated using self-report and behavioral
      measures in adults with attention-deficit/hyperactivity disorder (ADHD) and
      controls. Adults with ADHD viewed themselves as less socially competent but more
      sensitive toward violations of social norms than controls. Films depicting
      emotional interactions were used to assess linguistic properties of free recall
      and perceived emotional intensity. Although adults with ADHD used more words to
      describe the scenes, they used fewer emotion-related words, despite rating the
      emotions depicted as more intense than did controls. In contrast, no group
      differences for words depicting social or cognitive processes were observed.
      Overall, adults with ADHD appear more aware of their problems in social versus
      emotional skills. Findings may have implications for improving the psychosocial
      functioning of these adults.

PMID- 12597074
TI  - Material-specific memory in temporal lobe epilepsy: effects of seizure laterality
      and language dominance.
AB  - This study investigated the effects of seizure laterality and language dominance
      on material-specific memory in temporal lobe epilepsy (TLE). Left TLE (LTLE)
      patients with left-hemisphere language dominance (LHLD) showed significantly
      higher nonverbal than verbal memory capacity, whereas right TLE patients with
      LHLD showed significantly better verbal than nonverbal memory capacity. LTLE
      patients with non-left-hemisphere language dominance (NLHLD) showed significantly
      better verbal memory capacity compared with LTLE patients with LHLD. Thus,
      selective verbal or nonverbal memory deficits that are dependent on side of
      seizure onset were apparent in patients with LHLD but not in patients with NLHLD.
      Relative sparing of verbal memory capacity in LTLE patients with NLHLD may
      reflect interhemispheric reorganization of verbal memory function.

PMID- 12597075
TI  - Effect of manipulation and irrelevant noise on working memory capacity of
      patients with Alzheimer's dementia.
AB  - The effect of manipulation and distracting noise on immediate serial recall was
      measured in patients with dementia of the Alzheimer type (DAT), neurologically
      healthy elderly individuals, and young adults. In Experiment 1, the authors
      compared serial word recall with word recall in alphabetical order. Alphabetical
      recall requires the active manipulation of the contents of working memory.
      Findings indicated that DAT patients were severely impaired in the alphabetical
      recall task, whereas the performance of neurologically healthy elderly
      participants was comparable with the performance of young adult participants. In
      Experiment 2, the authors investigated the effect of different irrelevant
      auditory backgrounds on immediate digit recall. In this task, both elderly
      participants and DAT patients performed similarly to the group of young adult
      participants, indicating comparable efficacy to resist auditory distraction.

PMID- 12597076
TI  - Discourse analysis of logical memory recall in normal aging and in dementia of
      the Alzheimer type.
AB  - This study examined the nature of errors in prose recall made in dementia
      compared with normal aging. Responses by 48 young adults, 47 nondemented older
      adults, and 70 people with very mild or mild Alzheimer's disease to the Logical
      Memory subtest of the Wechsler Memory Scale were examined in a propositional
      analysis. Compared with young adults, healthy older adults showed good immediate
      recall but deficits in retention over a delay. Demented individuals made errors
      of omission, not commission, at immediate recall. These errors probably reflect
      difficulty with attentional control rather than memory per se. In terms of
      clinical implications, veridical scoring of the Logical Memory subtest provides
      more sensitive detection of very mild dementia of the Alzheimer type than the
      current standard criteria for scoring.

PMID- 12597077
TI  - Cerebral hemodynamics during discrimination of prosodic and semantic emotion in
      speech studied by transcranial doppler ultrasonography.
AB  - Simultaneous measurement of blood flow velocity (BFV) in the middle cerebral
      arteries was achieved by transcranial Doppler ultrasonography in 36 right-handed
      volunteers who were instructed to identify the emotion conveyed by prosody or
      semantics of a number of sentences. The tasks were performed under 2 levels of
      interference: neutral versus discordant affective value of the modality that had
      to be ignored. A multivariate analysis of variance showed a significant bilateral
      increase in BFV during the discordant conditions reflecting increased attentional
      demand. A significant left-hemispheric lateralization of BFV was observed as
      emotional semantics were labeled. When attention was shifted to affective
      prosody, the lateralization effect disappeared as a result of a marked increase
      in right-hemispheric BFV.

PMID- 12597078
TI  - What does the object decision task measure? Reflections on the basis of evidence
      from semantic dementia.
AB  - The authors investigated the impact of semantic knowledge on visual object
      analysis by assessing the performance of patients with semantic dementia on a
      different-views object matching test and on 2 object decision tests differing,
      for example, in whether the nonreal items were nonsense objects or chimeras of 2
      real objects. On average, the patients scored normally on both the object
      matching and the object decision test including nonsense objects but were
      impaired on the object decision test including chimeras; this latter was also the
      only visual object test that correlated significantly with degree of semantic
      impairment. These findings demonstrate that object decision is not a single task
      or ability and that it is not necessarily independent of conceptual knowledge.

PMID- 12597079
TI  - Absence of size congruency effects in amnesic patients' recognition: a failure of
      perceptually based recollection.
AB  - This study examined the status of recollection in amnesia when recollection is
      supported by perceptual rather than conceptual processes. Two experiments
      investigated the size congruency effect-the advantage in recognition of patterns
      presented in the same size, rather than in different sizes-at study and test. In
      Experiment 1, the authors used a remember-know paradigm in nonamnesic individuals
      and demonstrated that the size congruency effect was due to enhanced
      recollection. In Experiment 2, the authors examined whether amnesic patients
      would show a size congruency effect when their overall level of performance was
      matched to that of controls. Amnesic patients failed to show a size congruency
      effect. These findings provide evidence for a disproportionate disruption in
      recollection compared with familiarity in amnesia, even when recollection is
      supported by perceptual processes.

PMID- 12597080
TI  - Category learning deficits in Parkinson's disease.
AB  - Sixteen patients with Parkinson's disease (PD), 15 older controls (OCs), and 109
      younger controls (YCs) were compared in 2 category-learning tasks. Participants
      attempted to assign colored geometric figures to 1 of 2 categories. In rule-based
      tasks, category membership was defined by an explicit rule that was easy to
      verbalize, whereas in information-integration tasks, there was no salient verbal
      rule and accuracy was maximized only if information from 3 stimulus components
      was integrated at some predecisional stage. The YCs performed the best on both
      tasks. The PD patients were highly impaired compared with the OCs, in the rule
      based categorization task but were not different from the OCs in the information
      integration task. These results support the hypothesis that learning in these 2
      tasks is mediated by functionally separate systems.

PMID- 12597081
TI  - Moderate hypoglycemia impairs multiple memory functions in healthy adults.
AB  - The effects of acute insulin-induced hypoglycemia on short-term, delayed, and
      working memory were examined in healthy adults. A hyperinsulinemic glucose clamp
      was used to maintain arterialized blood glucose at either 4.5 (euglycemia) or 2.5
      (hypoglycemia) mmol/L on 2 separate occasions in 16 healthy volunteers. Tests of
      immediate and delayed verbal memory, immediate and delayed visual memory, and
      working memory were administered during each experimental condition. All memory
      systems were impaired during acute hypoglycemia, with working memory and delayed
      memory being particularly susceptible. These findings are informative concerning
      the metabolic basis of adequate memory function and are of practical importance
      to people with insulin-treated diabetes, in whom hypoglycemia is common.

PMID- 12597082
TI  - Syntactic comprehension in Parkinson's disease: investigating early automatic and
      late integrational processes using event-related brain potentials.
AB  - Parkinson's disease (PD) has been associated with a general impairment of
      procedures and with an impairment of syntactic procedures in particular. The
      present study investigated comprehension processes in PD using event-related
      brain potentials (ERPs). PD patients and controls listened to sentences that were
      either correct or syntactically or semantically incorrect. The language-related
      ERP component correlated with semantic processes (N400) was present in both
      groups. In the syntactic domain, early automatic processes (early negativity)
      appeared normal in PD, whereas late integrational processes (P600) were modulated
      by this disease. The present findings suggest that the basal ganglia primarily do
      not support early automatic syntactic processes during comprehension but rather
      support processes of syntactic integration.

PMID- 12597083
TI  - Effects of Alzheimer's disease on the recognition of novel versus familiar words:
      neuropsychological and clinico-metabolic data.
AB  - This study explored recognition memory performance for novel versus familiar
      words in Alzheimer's disease (AD) patients and normal controls (NCs), using an
      adaptation of E. Tulving and N. Kroll's (1995) procedure. Results showed that
      both groups exhibited more hits and more false alarms for familiar than for novel
      words. The groups did not differ in the recognition of familiar words, reflecting
      preserved familiarity processes in AD. However, AD patients made more false
      alarms than NCs in the recognition of novel words, reflecting impairment of
      recollection processes in AD. A positron emission tomography analysis of clinico
      metabolic correlations in AD patients showed a correlation between recognition of
      novel words and right hippocampal activity, whereas recognition of familiar words
      was more related to metabolic activity in the left posterior orbitofrontal
      cortex.

PMID- 12597084
TI  - Developmental changes in line bisection: a result of callosal maturation?
AB  - Normal adults tend to bisect horizontal lines to the left of the objective
      middle, especially when using the left hand. This bias has been attributed to the
      dominance of the right hemisphere in spatial attention. The authors investigated
      the effect of hand use and line position in visual line bisection in right-handed
      children and adults, classified into 4 different age groups: 10-12, 13-15, 18-21,
      and 24-53 years (N = 98). All 4 groups showed the characteristic leftward bias
      when using the left hand. When using the right hand, the youngest group showed a
      rightward bias, whereas the other 3 groups all showed a leftward bias. This
      suggests a shift from contralateral to right-hemispheric control during puberty
      and may reflect maturation of the corpus callosum.

PMID- 12597085
TI  - Serotonin levels influence patterns of repetition priming.
AB  - Repetition priming in a word-stem completion task was examined in a group of
      control subjects and in a group of experimental subjects under conditions of
      acute tryptophan depletion (T-) and tryptophan augmentation (T+). Experimental
      subjects ingested amino acid compounds that depleted or loaded the body with
      tryptophan, and word-stem completion priming performance was measured. Results
      indicate differential effects of T- and T+ manipulations on word-stem completion
      priming. In the control group, both specific-visual and amodal priming were
      observed. Conversely, in the T+ condition, specific-visual priming, but no amodal
      priming, was observed, whereas in the T- condition, amodal priming, but no
      specific-visual priming, was observed. The authors conclude that serotonin (5
      hydroxytryptamine) plays a critical role in repetition priming by helping to
      modulate which neural systems contribute to priming effects.

PMID- 12597086
TI  - Inhibitory control following perinatal brain injury.
AB  - Evidence from developmental, lesion, and neuroimaging studies indicates that the
      prefrontal cortex plays a major role in executive abilities, including inhibitory
      control. Proficient executive performance, however, relies not only on the
      integrity of the prefrontal cortex but also on its interactions with other brain
      regions. In the current study, the authors focused on the effect that early
      damage to the white matter tracts interconnecting prefrontal and other brain
      regions has on inhibitory control. Data were collected from 13 children with
      bilateral spastic cerebral palsy and from a control group of 20 children with no
      history of neurologic compromise. Converging evidence from 3 separate paradigms
      is presented that strongly suggests these children experience impairments in
      inhibitory control. Findings are discussed within the context of current
      cognitive and neuroanatomical models of inhibition.

PMID- 12597087
TI  - Magnetic resonance imaging and the neonate.
AB  - Over the past decade, advances in neuroimaging have given birth to a new field of
      diagnostic pediatric neurologic assessment that includes magnetic resonance
      imaging (MRI). This invaluable tool helps medical professionals to resolve many
      clinical and research questions related to neonatal neurodevelopment that other
      imaging technology cannot explain. Nurses and others who accompany infants to MRI
      would benefit from a better understanding of early neurodevelopment and of the
      neuroimaging procedure. Knowing the advantages and disadvantages of MRI
      techniques can help nurses be better patient advocates, parent liaisons, and
      caregivers to infants having MRI scans.

PMID- 12597088
TI  - Prenatal cocaine exposure and neonatal/infant outcomes.
AB  - Illegal drug use throughout the nation is a problem of epidemic proportion. Of
      particular concern is drug use among pregnant women. In most cases, these women
      have little hope of achieving a better life for themselves or their children.
      Illegal drugs, cocaine in particular, can have devastating effects on the
      neonate. These effects can last well into childhood and can exhibit themselves in
      academic, social, and family situations. Challenges for the neonatal nurse
      include early identification of these infants and use of available resources.
      This article addresses prenatal cocaine use and support services for drug
      dependent women, effects of cocaine during the neonatal period, possible neonatal
      and infant outcomes, and implications for nursing practice.

PMID- 12597089
TI  - Using knowledge to cope with stress in the NICU: how parents integrate learning
      to read the physiologic and behavioral cues of the infant.
AB  - Parental stress in the NICU has at least a short-term impact on the establishment
      of the parent-child relationship and potential repercussions on long-term child
      development outcomes. One way to help parents mitigate stress is to help them
      learn what they need to know about their infant's condition and care. In this
      article, we examine how learning to read the infant's physiologic and behavioral
      cues helps parents cope with stress. We view parental learning as a process in
      which parents target specific domains of information for learning according to
      the temporal relevance of the domain to their concerns. It is important that we
      recognize the fluidity of the process and anticipate what parents need to learn
      at different times during hospitalization. The NICU staff assumes a crucial role
      in reducing parental stress by delivering information that is relevant to the
      parents' needs and by helping parents understand this information.

PMID- 12597090
TI  - Timing of the newborn first bath: a replication.
AB  - PURPOSE: To evaluate the effects on thermoregulation of bathing a healthy newborn
      within the first hour of life compared to bathing four to six hours after birth.
      DESIGN: Quasi-experimental. SETTING: Newborn nursery of a 30-bed obstetric unit
      in an urban university hospital. SAMPLE: Fifty-one healthy term newborns with a
      minimum axillary temperature of 36.5 degrees C (97.7 degrees F). INTERVENTION:
      Newborns in an experimental group were bathed within the first hour of birth;
      those in a control group were bathed at the standard four to six hours of age.
      MAIN OUTCOME VARIABLE: Axillary temperatures were measured before the bath,
      immediately after the bath, one hour later, and two hours later. RESULTS:
      Axillary temperatures as measured at four different times did not differ
      significantly between infants bathed within one hour of birth and those bathed
      four to six hours after birth. CONCLUSIONS: A flexible bathing time is
      recommended according to the characteristics and stability of the newborn and to
      family desires.

PMID- 12597091
TI  - The hypotonic infant: case study of central core disease.
AB  - Causes of hypotonia in the newborn can be broadly categorized into two
      classifications. Hypotonia with a supraspinal origin may be seen with systemic
      disease, hypoxic ischemic encephalopathy, cerebral malformations, syndromes (for
      example: Down, Prader-Willi, Lowe, Zellweger, Smith-Lemli-Opitz), and c-spine
      injury. Disorders of the motor unit that present with hypotonia in the newborn
      period include SMA, congenital myotonic dystrophy, congenital myasthenia gravis,
      and congenital myopathies. Central core disease is one of the classic congenital
      myopathies that can be differentiated based on characteristic histologic
      findings. Muscle fiber samples from patients with central core disease possess
      distinct morphology that can be diagnostic. Many infants may not exhibit muscle
      weakness in the newborn period, although there have been rare cases of profound
      hypotonia and respiratory failure. Clearly, muscle biopsy is the gold standard
      and is indicated for any infant with marked hypotonia that is not thought to be
      supraspinal in origin.

PMID- 12597092
TI  - Perinatal brain injury in the premature infant.

PMID- 12597093
TI  - Imaging pitfalls in the postoperative head and neck.
AB  - It may well be that imaging of the post-treatment head and neck is among the most
      difficult tasks faced by the radiologist. Pitfalls are everywhere, and
      opportunities for error endless. In this manuscript, an attempt is made to
      categorize many of the various types of pitfalls that exist in imaging the
      operated head and neck patient. The radiologist can avoid error by remembering
      certain common postoperative appearances and not misinterpreting them as
      abnormal, by having available baseline postoperative studies, and by gaining
      experience in this very challenging aspect of head and neck radiology.

PMID- 12597094
TI  - Imaging of postoperative middle ear, mastoid, and external auditory canal.

PMID- 12597095
TI  - Clinical evaluation of postoperative sinonasal surgical patients.
AB  - Rhinosinusitis is a very common upper respiratory illness. Functional endoscopic
      sinus surgery has been successfully utilized in the surgical treatment of
      medically refractory rhinosinusitis. The endoscopic approach has also been
      extended to various skull base lesion and sinonasal neoplasms. This paper
      provides a brief overview of the clinical aspect of evaluating sinonasal surgical
      patients. Judicious use of nasal endoscopy and importance of CT imaging of the
      sinuses are discussed. Emphasis is placed on establishing communication between
      the sinus surgeon and radiologist to facilitate evaluation of the sinonasal
      surgical patients. liming and specific types of imaging studies before any
      revision sinus surgery are discussed. Major complications associated with
      endoscopic sinus surgery are reviewed.

PMID- 12597096
TI  - Sinusitis: postoperative changes and surgical complications.
AB  - Functional endoscopic sinus surgery (FESS) is the standard of care for the
      surgical management of sinonasal inflammatory disease. This group of procedures
      focuses on the sinus outflow tract, and is designed to improve sinus function by
      restoring sinonasal physiology. Use of the monocular endoscope is associated with
      a range of unique surgical complications that often require cross-sectional
      imaging. Many patients considering sinus surgery today have had surgical
      procedures in the past that were directed at removing diseased mucosa, rather
      than improving sinus drainage, and have a different appearance on CT. This report
      addresses the spectrum of surgical changes found on postoperative imaging of the
      paranasal sinuses, and the surgical complications that may occur during
      endoscopic sinus surgery.

PMID- 12597097
TI  - Flap reconstruction in the head and neck: expected appearance, complications, and
      recurrent disease.

PMID- 12597098
TI  - FRONTLINE--psychoanalysis in the closet or a new beginning?

PMID- 12597099
TI  - Disasters, psychiatry, and psychodynamics.
AB  - The unique experience of Disaster Psychiatry Outreach, a voluntary organization
      devoted to providing psychiatric assistance to people affected by disasters,
      provides a valuable substrate for exploring the role of psychodynamics in the
      human experience of disaster and trauma. This article offers a theoretical
      framework for such an experience that takes into account personal meaning, ego
      psychology and defenses, and grief work and suggests how to employ this framework
      in the setting of a disaster by way of examples from the events of Sept. 11. A
      useful clinical construct for future disaster work known as the "trauma tent" is
      ultimately proposed, as are novel applications of psychodynamics toward the
      prevention and mitigation of manmade and natural disasters.

PMID- 12597100
TI  - Terrorism, our world and our way of life.
AB  - In this article, the author touches on a variety of threads relevant to a
      psychoanalytic approach to terrorism. He begins with a personal September 11
      recollection, and then goes on to share some thoughts about terrorism from the
      vantage point of a citizen who retired from active military duty a little over a
      year ago. He then speculates about a possible psychoanalytic understanding of
      terrorists and their motivation, while acknowledging that terrorists too are
      individuals, and that no hypothesis can apply to an entire group, across the
      border. To illustrate his points, the author shares some vignettes from
      literature, biography, and philosophy. He then reflects on our post-September 11
      roles as psychoanalysts or psychodynamic psychiatrists, but also as Americans.

PMID- 12597101
TI  - Walter Bonime's legacy: principal contributions.
AB  - Walter Bonime is best known for his influential book, The Clinical Use of Dreams,
      published in 1962. Though Bonime embraced a neo-Freudian orientation, The
      Clinical Use of Dreams is remarkable for an absence of theoretical discussions,
      emphasizing instead a detailed practical approach, aided by illustrative
      vignettes. His particular emphases are on collaboration in the discovery of
      meaning and the importance of recognizing feeling representations in dreams.
      Further writings focussed on character disorders with depressive and paranoid
      symptomatology, vividly describing the typical underlying neurotic character
      structures. An outstanding article, co-authored with his wife Florence Bonime,
      criticizes the usual obscurity of psychoanalytic writings and suggests that
      conceptual abstractions be well balanced by clinical illustrations. Bonime's
      style is an exemplary model for such balanced writings.

PMID- 12597102
TI  - A clinical focus on feeling in dreams.
AB  - This article, a posthumous presentation of a work in progress of Walter Bonime,
      one of the maverick thinkers of psychoanalysis of the 20th century, gives us a
      clear picture of a step-by-step use of feelings in dreams to facilitate the
      working through process in psychoanalysis. Through a series of dreams occurring
      during a finite period of the working through process the author shows us how he
      utilizes the feelings in the dreams to facilitate associations. By connecting
      past dreams with the actual one being discussed plus writing about his own
      associations to present and past dreams, while using confrontation and
      clarification Bonime gives us a clear picture of his day-to-day creative process
      of collaboration with his patient. As an incomplete work, still in its draft
      form, this article has the richness of a work in progress. It allows us a clear
      view of the work of a seasoned, innovative, engaged, and committed analyst with a
      patient through time, work mainly anchored in his deep understanding of the human
      psyche, his creative use of dreams, and his commitment to helping the other
      evolve into his/ her best sense of self.

PMID- 12597103
TI  - Dreams and creativity--collaborative psychoanalytic work.
AB  - Walter Bonime's contributions to the understanding and interpretation of dreams
      highlight collaboration and creative effort as essential to achieve appropriate
      attunement and effective emotional growth. The authors incorporate the
      theoretical constructs and technical recommendations of Bonime into their
      clinical work with artists. They describe how creative psychoanalytic work with
      artists' dreams can promote productivity, spontaneity, emotional growth, and
      facilitate conflict resolution, functional regression, and affective regulation.
      Psychoanalytic theories on creativity and the creative personality are reviewed
      and case material is presented to illustrate some of the technical aspects of the
      collaborative interpretation of artists' dreams. The authors propose that the
      process of dream interpretation may also foster the functional regression
      characteristic of creative work and motivate artists to more freely create works
      of art. The critic's transference is defined, and with examples the authors show
      how the exploration of this transference may lead to decreased resistance by
      allowing a reparative experience to exist within the analytic setting.

PMID- 12597104
TI  - A royal road from homelessness--the clinical use of dreams.
AB  - The author discusses the use of a dynamic psychotherapy technique, specifically
      dream exploration, in his work with New York City's homeless. Given the short
      amount of time clinically available in working with this population, discussing
      the patient's dreams was found to quickly get to the most pressing here-and-now
      issues. The psychiatrist's interest in the patient's creation of the dream was
      also noted to enhance the therapeutic relationship and the patient's compliance
      thereby improving the chances of a successful therapeutic outcome.

PMID- 12597105
TI  - Interpersonal psychoanalysis' radical facade.
AB  - The participant-observation model initiated the relational turn, as well as the
      shift from modernism to postmodernism in psychoanalysis. This two-person,
      coparticipant conceptualization of the psychoanalytic situation moved
      psychoanalysis from the realm of alleged objective science toward
      intersubjectivity and hermeneutics. From this perspective, the analyst as
      subjective other is constantly engaged affectively with the patient in ways that
      are very often out of awareness. Analyst and patient both, for better or for
      worse, are believed to unwittingly influence one another. This description of the
      analytic dyad has led many to mistakingly conclude that interpersonal
      psychoanalysts advocate wittinly affective expressiveness, often in the form of
      deliberate self-disclosure of feelings, as part of a standard analytic stance.
      Upon closer examination, radical interventions are no more emblematic of
      interpersonal analysts than they are of analysts from most other traditions,
      though the interpersonalists have indeed expanded what had theretofore been a
      rather narrow repertoire of interventions.

PMID- 12597106
TI  - "Speak to me as to thy thinkings" commentary on 'Interpersonal psychoanalysis'
      radical facade" by Irwin Hirsch.
AB  - This article has two purposes. First, a rebuttal to those writers, including
      Irwin Hirsch, who criticize the current emphasis by relational analysts on the
      value of affective openness and affective honesty, particularly with regard to
      their use of clinical vignettes that vividly portray the analyst's use of self
      revelation--as if these illustrations were revealing an endorsement of a naive
      and mindless invasion of the patient's psyche. The second, and perhaps more
      important purpose, is to illuminate something I feel is obscured by Hirsch's
      framing the topic of the analyst's "spontaneity" in the context of analytic
      politics--that an analyst's self-revelation in language is increasingly
      understood to be not simply "allowable," but a necessary part of the clinical
      process. Language does not make it less spontaneous nor part of what Hirsch calls
      a "standardized technique." Its most powerful therapeutic contribution is in
      facilitating linguistic symbolization of dissociated, enacted, subsymbolic
      experience that is immune to self-reflective cognition, immune to internal
      conflict, and thereby unavailable to interpretation until it becomes relationally
      accessible to language and thought. Both neuroscience and cognitive research
      support the need for a revised theory of therapeutic action consistent with the
      growing recognition of the human mind as a nonlinear, self-organizing dynamic
      system-a system in which normal maturation as well as therapeutic repair depends,
      developmentally, on an ineffable coming together of two minds in an unpredictable
      way. From this vantage point, the analyst's self-revelation contributes to the
      coconstruction of an alive intersubjective space through an ongoing process of
      engagement between two subjectivities, making the analyst's subjective openness
      as potentially negotiable as any other aspect of the patient/analyst
      relationship, rather than an unrepairable "intrusion" into a self-contained
      psyche.

PMID- 12597107
TI  - A Lacanian explanation of Karon's and Villemoes's successful psychodynamic
      approaches to schizophrenia.
AB  - In this article I use Lacan's early theory of schizophrenia as corrected by the
      School of Leuven. Early in his career Lacan argued that schizophrenic people have
      a defective relation to language. Vergote and several of his students--all from
      Leuven--point out that schizophrenics also have a defective relation to their
      bodies. Lacan calls the defective relation to language a defect in the symbolic
      and he calls defective relations to the body a defect in the imaginary. Repairing
      defects in the symbolic requires introducing in the emotional life of the patient
      the paternal function of the law. Repairing the imaginary requires the more
      maternal help of mirroring, affirming, and holding. I underline that the two
      forms of healing that need to occur in the treatment of schizophrenics seem
      contradictory. I then proceed to demonstrate that two therapists, Bertram Karon-
      a non-Lacanian--and Palle Villemoes--a Lacanian-artfully combine the two
      contradictory strategies which are theoretically required. The remainder of the
      article is then devoted to a summary and a discussion of the different methods
      developed by these two therapists. I demonstrate that both do healing work at the
      imaginary level and the symbolic level. Sometimes these two therapists explicitly
      point out that they make a shift in their healing work with the patient;
      sometimes they do not alert the reader that they do so. I claim that in the work
      of both therapists it is the contradictory work at the level of the imaginary and
      of the symbolic that is healing, not the therapeutic intervention at the
      imaginary alone or at the symbolic alone.

PMID- 12597108
TI  - Ego-structuring psychotherapy.
AB  - Psychoanalysis regards psychosis as an early disturbance in the development of
      the personality, specifically, of the ego. The disturbance occurs during that
      period prior to the castration complex and thus before the phase when the
      ordering of relations becomes oedipal. Responsible for this disturbance is,
      according to Freud, foreclosure (verwerfung) of an important factor that normally
      accomplishes the primal repression (urverdrangung) and which renders repression
      proper (verdrangung) out of the question. According to Lacan this factor is the
      Name of the Father, which instigates the metaphorical dimension as such and,
      thereby, makes language come into action through a pact between the subject and
      the Other. In psychosis, Lacan postulates a foreclosure of the Name of the
      Father, which hinders the unconscious, structured as a language, from
      safeguarding the ego and the world, that is, the imaginary. Ego-structuring
      psychotherapy brings the Name of the Father into effect, enabling the psychotic
      person to become linguistically structured; consequently, a world view develops
      in the person and he or she becomes a historically determined person engaged in
      fulfilling a plan for life.

PMID- 12597109
TI  - The biology of dream formation: a review and critique.
AB  - There is great interest in brain function as a result of the new laboratory and
      imaging techniques in the neurosciences. Psychoanalysis has embraced these
      contributions without adequate assessment of whether they bridge the mind/brain
      divide and provide answers to the questions psychoanalysts ask. A review and
      critique of the biological theories of dreaming highlights their limitations and
      points out they do not address the semantics, meaning, and content of dreaming
      nor the pragmatics of dreaming, its function. At best these theories attempt to
      provide the syntax of dreaming, the form dreaming takes. Brain biology cannot
      provide the transduction rules to go from neuronal firing to the psychological
      experience of dreaming or other mind states.

PMID- 12597110
TI  - Psychoanalytic peregrinations IV: what is phenomenology?
AB  - This article proposes to clarify the use of phenomenology as a complementary
      approach to the psychoanalytic process. Because phenomenology is defined and used
      differently by many different authors, it is here specifically juxtaposed to the
      DSM-IV approach for purposes of comparison and elucidation. Phenomenology
      attempts to complement the objectivation and mathematization of reality by the
      sciences with allowing things to speak for themselves. This requires an attitude
      of acceptance of whatever appears from the patient in the consulting room without
      filtering it through judgements or presuppositions that we are all taught in our
      training. So, for example, such concepts as "empathic linkage," the
      "infectiousness" of anxiety, the "feel" of the schizophrenic ambiance as
      described by various authors come across more directly in an encounter based on
      the phenomenologic approach. This can be used in addition to DSM-IV and other
      approaches to gain new information. A brief review of how phenomenology arose and
      the use of it by certain well-known thinkers is presented.

PMID- 12597111
TI  - Commonalities between the Isaac and Oedipus myths: a speculation.
AB  - From a detailed view of the myth of the binding of Isaac, a speculation emerges
      that Isaac may have had incest with his mother, Sarah. This would explain the
      death of Sarah shortly thereafter, his absent virility for twenty years, and his
      blindness. The commonalities with the Oedipus myth are outlined, along with the
      themes of filicide, patricide, guilt, punishment, and expiation. This suggests
      that they are the same myth, with some slight variations. The continued interest
      in both myths may be due to their utility as cautionary tales to teach control of
      hostile impulses in parents and children. While the outcome in the Oedipus myth
      is tragic, it is hopeful in the Isaac myth.

PMID- 12597112
TI  - Isaac versus Oedipus: an alternative view.
AB  - Max Sugar (2002) argues for the essential similarity of the legends of Oedipus
      and Isaac with regard to the common themes of filicide, patricide, guilt,
      punishment, and expiation. Sugar does point out, however, that while the outcome
      in the Oedipus myth is tragic, it is hopeful in the narrative of Isaac. This
      article, in contrast, argues that this distinction between tragedy and
      hopefulness is not incidental and indeed stems out of the essential differences
      between the legends of Oedipus and Isaac, which themselves reflect the opposing
      life views emerging from Athens and Jerusalem. Indeed, we will argue for viewing
      the Akedah (the binding of Isaac) as a Biblical alternative to the Oedipus
      Complex, rather than simply an extension of it, and as the basis for a Biblical
      psychology and psychotherapy.

PMID- 12597113
TI  - Financial limitations of managed care can actually enhance the therapeutic
      process through metaphor and reality testing.

PMID- 12597114
TI  - Simulating the effect of quarantine on the spread of the 1918-19 flu in central
      Canada.
AB  - Quarantine is often proposed and sometimes used to control the spread of
      infectious diseases through a human population. Yet there is usually little or no
      information on the effectiveness of attempting to quarantine humans that is not
      of an anecdotal or conjectural nature. This paper describes how a compartmental
      model for the geographic spread of infectious diseases can be used to address the
      potential effectiveness of human quarantine. The model is applied to data from
      the historical record in central Canada around the time of the 1918-19 influenza
      epidemic. Information on the daily mobility patterns of individuals engaged in
      the fur trade throughout the region prior to, during, and immediately after the
      epidemic are used to determine whether rates of travel were affected by informal
      quarantine policies imposed by community leaders. The model is then used to
      assess the impact of observed differences in travel on the spread of the
      epidemic. Results show that when mobility rates are very low, as in this region,
      quarantine practices must be highly effective before they alter disease patterns
      significantly. Simulation results suggest, though, that effectiveness varies
      depending on when the limitation on travel between communities is implemented and
      how long it lasts, and that a policy of introducing quarantine at the earliest
      possible time may not always lead to the greatest reduction in cases of a
      disease.

PMID- 12597115
TI  - A model for the emergence of adaptive subsystems.
AB  - We investigate the interaction of learning and evolution in a changing
      environment. A stable learning capability is regarded as an emergent adaptive
      system evolved by natural selection of genetic variants. We consider the
      evolution of an asexual population. Each genotype can have 'fixed' and 'flexible'
      alleles. The former express themselves as synaptic connections that remain
      unchanged during ontogeny and the latter as synapses that can be adjusted through
      a learning algorithm. Evolution is modelled using genetic algorithms and the
      changing environment is represented by two optimal synaptic patterns that
      alternate a fixed number of times during the 'life' of the individuals. The
      amplitude of the change is related to the Hamming distance between the two
      optimal patterns and the rate of change to the frequency with which both exchange
      roles. This model is an extension of that of Hinton and Nowlan in which the
      fitness is given by a probabilistic measure of the Hamming distance to the
      optimum. We find that two types of evolutionary pathways are possible depending
      upon how difficult (costly) it is to cope with the changes of the environment. In
      one case the population loses the learning ability, and the individuals inherit
      fixed synapses that are optimal in only one of the environmental states. In the
      other case a flexible subsystem emerges that allows the individuals to adapt to
      the changes of the environment. The model helps us to understand how an adaptive
      subsystem can emerge as the result of the tradeoff between the exploitation of a
      congenital structure and the exploration of the adaptive capabilities practised
      by learning.

PMID- 12597116
TI  - From sphere to torus: a topological view of the metazoan body plan.
AB  - From the viewpoint of mathematical topology, membrane systems in intact living
      cells can be described as closed and orientable surfaces, i.e., as surfaces with
      two sides and no boundary lines so that an 'inside' and an 'outside' can be
      distinguished. Usually, biomembranes represent topological spheres, often one
      embedded in another one. Toroidal membranes are occasionally observed, e.g., in
      specialized structures of plant cells like the prolamellar body. Here, we propose
      that rules analogous to those that govern the topology of biomembranes hold for
      the epithelial cell sheets that cover anatomically external as well as internal
      surfaces of multicellular animals. We suggest to study the emergence of
      morphological complexity during metazoan development using concepts from
      mathematical topology, and propose experimental analyses of those topological
      transitions that appear to be relevant in development and evolution.

PMID- 12597117
TI  - Competitive exclusion and coexistence of universal grammars.
AB  - Universal grammar (UG) is a list of innate constraints that specify the set of
      grammars that can be learned by the child during primary language acquisition. UG
      of the human brain has been shaped by evolution. Evolution requires variation.
      Hence, we have to postulate and study variation of UG. We investigate
      evolutionary dynamics and language acquisition in the context of multiple UGs. We
      provide examples for competitive exclusion and stable coexistence of different
      UGs. More specific UGs admit fewer candidate grammars, and less specific UGs
      admit more candidate grammars. We will analyze conditions for more specific UGs
      to outcompete less specific UGs and vice versa. An interesting finding is that
      less specific UGs can resist invasion by more specific UGs if learning is more
      accurate. In other words, accurate learning stabilizes UGs that admit large
      numbers of candidate grammars.

PMID- 12597118
TI  - Analysis of the signal transduction properties of a module of spatial sensing in
      eukaryotic chemotaxis.
AB  - The movement of cells in response to a gradient in chemical concentration-known
      as chemotaxis-is crucial for the proper functioning of uni- and multicellular
      organisms. How a cell senses the chemical concentration gradient surrounding it,
      and what signal is transmitted to its motion apparatus is known as gradient
      sensing. The ability of a cell to sense gradients persists even when the cell is
      immobilized (i.e., its motion apparatus is deactivated). This suggests that
      important features of gradient sensing can be studied in isolation, decoupling
      this phenomenon from the movement of the cell. A mathematical model for gradient
      sensing in Dictyostelium cells and neutrophils was recently proposed. This
      consists of an adaptation/spatial sensing module. This spatial sensing module
      feeds into an amplification module, magnifying the effects of the former. In this
      paper, we analyze the spatial sensing module in detail and examine its signal
      transduction properties. We examine the response of this module to several inputs
      of experimental and biological relevance.

PMID- 12597119
TI  - Limiting relationships between selection and recombination.
AB  - It is difficult to directly observe processes like natural selection at the
      genetic level, but relatively easy to estimate genetic frequencies in
      populations. As a result, genetic frequency data are widely used to make
      inferences about the underlying evolutionary processes. However, multiple
      processes can generate the same patterns of frequency data, making such
      inferences weak. By studying the limits to the underlying processes, one can make
      inferences from frequency data by asking how strong selection (or some other
      process of interest) would have to be to generate the observed pattern. Here we
      present results of a study of the limits to the relationship between selection
      and recombination in two-locus, two-allele systems in which we found the limiting
      relationships for over 30000 sets of parameters, effectively covering the range
      of two-locus, two-allele problems. Our analysis relates T(min)--the minimum time
      for a population to evolve from the initial to the final conditions--to the
      strengths of selection and recombination, the amount of linkage disequilibrium,
      and the Nei distance between the initial and final conditions. T(min) can be
      large with either large disequilibrium and small Nei distance, or the reverse.
      The behavior of T(min) provides information about the limiting relationships
      between selection and recombination. Our methods allow evolutionary inferences
      from frequency data when deterministic processes like selection and recombination
      are operating; in this sense they complement methods based entirely on drift.

PMID- 12597120
TI  - Interspecific influence on mobility and Turing instability.
AB  - In this paper we formulate a multi-patch multi-species model in which the per
      capita emigration rate of one species depends on the density of some other
      species. We then focus on Turing instability to examine if and when this cross
      emigration response has crucial effects. We find that the type of interaction
      matters greatly. In the case of competition a cross-emigration response promotes
      pattern formation by exercising a destabilizing influence; in particular, it may
      lead to diffusive instability provided that the response is sufficiently strong,
      which contrasts sharply with the well-known fact that the standard competition
      system does not exhibit Turing instability. In the case of prey-predator or
      activator-inhibitor interaction it acts against pattern formation by exerting a
      stabilizing effect; in particular, the diffusive instability, even though it may
      happen in a standard system, never occurs when the response is sufficiently
      strong. We conclude that the cross-emigration response is an important factor
      that should not be ignored when pattern formation is the issue.

PMID- 12597121
TI  - Multiple stable periodic solutions in a model for hormonal control of the
      menstrual cycle.
AB  - This study presents a nonlinear system of delay differential equations to model
      the concentrations of five hormones important for regulation and maintenance of
      the menstrual cycle. Linear model components for the ovaries and pituitary were
      previously analyzed and reported separately. Results for the integrated model are
      now presented here. This model predicts serum levels of ovarian and pituitary
      hormones which agree with data in the literature for normally cycling women. In
      addition, the model indicates the existence and stability of an abnormal cycle.
      Hence, the model may be used to simulate the effects of external hormone
      therapies on abnormally cycling women as well as the effects of exogenous
      compounds on normally cycling women. Such simulations may be helpful in
      understanding the role of xenobiotics in fertility problems, in predicting
      successful hormone therapies, and for testing hormonal methods of birth control.

PMID- 12597122
TI  - Stability properties of elementary dynamic models of membrane transport.
AB  - Living cells are characterized by their capacity to maintain a stable steady
      state. For instance, cells are able to conserve their volume, internal ionic
      composition and electrical potential difference across the plasma membrane within
      values compatible with the overall cell functions. The dynamics of these cellular
      variables is described by complex integrated models of membrane transport. Some
      clues for the understanding of the processes involved in global cellular
      homeostasis may be obtained by the study of the local stability properties of
      some partial cellular processes. As an example of this approach, I perform, in
      this study, the neighborhood stability analysis of some elementary integrated
      models of membrane transport. In essence, the models describe the rate of change
      of the intracellular concentration of a ligand subject to active and passive
      transport across the plasma membrane of an ideal cell. The ligand can be ionic or
      nonionic, and it can affect the cell volume or the plasma membrane potential. The
      fundamental finding of this study is that, within the physiological range, the
      steady states are asymptotically stable. This basic property is a necessary
      consequence of the general forms of the expressions employed to describe the
      active and passive fluxes of the transported ligand.

PMID- 12597123
TI  - Modern laser scanning microscopy in biology, biotechnology and medicine.
AB  - Laser microscopic techniques currently used in morphology and cell biology
      represent highly sensitive tools for detecting biomolecules within their natural
      environment. Use of the fluorescence-, reflectance- and transmission modes of
      confocal laser scanning microscopes (CLSM) equipped with He-Ne- and Ar+-ion
      lasers for CeIV and DAB based detection of endogenous or immunobound enzymatic
      activities in tissue sections (vibratome, cryostat, paraffin and semithin plastic
      sections) opens a wide range of interesting new possibilities in cellular and
      molecular biology. Increased resolution power, blur-free confocal imaging, higher
      sensitivity, optical sectioning capability and 3D-image analysis provide a large
      quantity of valuable information about biological objects specimens. The new
      infrared multiphoton laser scanning microscopy (NIR-LSM) is increasingly becoming
      the optical tool of choice for (a) fluorescence imaging of cellular and
      subcellular components with high spatial and temporal resolution, (b)
      fluorescence resonance energy transfer between physiologically relevant molecular
      species involving protein-protein interactions, (c) nanoprocessing within living
      cells and tissues, with varied applications in (d) photochemistry and (e) medical
      diagnostics as well. Both, CLSM and NIR-LSM as modern microscopical strategies
      are indispensable in basic research and will prove to be invaluable for clinical
      diagnostic studies and therapy in the near future.

PMID- 12597124
TI  - Ultrastructure and immunocytochemical characteristics of cells in the octopus
      cell area of the rat cochlear nucleus: comparison with multipolar cells.
AB  - Cells in the octopus cell area of the rat ventral cochlear nucleus have been
      connected to the monaural interpretation of spectral patterns of sound such as
      those derived from speech. This is possible by their fast onset of firing after
      each octopus cell and its dendrites have been contacted by many auditory fibres
      carrying different frequencies. The cytological characteristics that make these
      large cells able to perform such a function have been studied with
      ultrastructural immunocytochemistry for glycine, GABA and glutamate, and compared
      to that of other multipolar neurons of other regions of the ventral cochlear
      nucleus. Cells in the octopus cell area have an ultrastructure similar to large
      giant D-multipolar neurons present in other areas of the cochlear nucleus, from
      which they differ by the presence of a larger excitatory axo-somatic synaptic
      input and larger mitochondria. Octopus cells are glycine and GABA negative, and
      glutamate positive with different degree. Large octopus cells receive more axo
      somatic boutons than smaller octopus cells. Fusiform octopus cells are found
      sparsely within the intermediate acoustic striae. These cells are large to giant
      excitatory neurons (23-35 microm) with 62-85% of their irregular perimeter
      covered with large axo-somatic synaptic boutons. Most boutons contain round
      vesicles and are glycine and GABA negative but glutamate positive. The latter
      excitatory boutons represent about 70% of the input to octopus cells. Glycine
      positive boutons with flat and pleomorphic vesicles account for 9-10% of the
      input while GABA-ergic boutons with pleomorphic vesicles represent about 20% of
      the synaptic input. Other few, multipolar cells within the rat octopus cell area
      are surrounded by more inhibitory than excitatory terminals which contain flat
      and pleomorphic vesicles, a feature distinctive from that of true octopus cells.
      The latter resemble multipolar cells seen outside the octopus cell area that
      project to the contralateral inferior colliculus and cochlear nucleus. Based on
      this study, two types of large multipolar cells are present in the octopus cell
      area: 1) those that receive about 70% of axo-somatic R boutons and stain more
      intensely for glutamate may correspond to pure onset neurons (Oi); 2) those with
      less than 33% of R axosomatic boutons, with less immunoreactivity to glutamate
      and sometimes glycine positive may represent the onset chopper neurons (Oc). In
      the octopus cell area the first type appears more prevalent. The present study
      suggests that octopus cells are a special type of excitatory D-multipolar neuron
      confined to the octopus cell area and mainly innervated by glutamatergic cochlear
      nerve terminals.

PMID- 12597125
TI  - Expression of neuropeptides and growth-associated protein 43 (GAP-43) in
      cutaneous and mucosal nerve structures of the adult rat lower lip after mental
      nerve section.
AB  - The reinnervation of the adult rat lower lip has been investigated after
      unilateral section of the mental nerve. Rats were sacrificed at 4, 7, 9, 14, 30,
      and 90 days after the operation. A further group of animals with section of the
      mental nerve and block of the alveolar nerve regeneration, was sacrificed at 14
      days. Specimens were processed for immunocytochemistry with antibodies against
      PGP 9.5, GAP-43 or neuropeptides (CGRP, SP and VIP). Four days after nerve
      section, axonal degeneration seems evident in the mental nerve branches and
      inside skin and mucosa. GAP-43 immunoreactivity is intense in the mental nerve 7
      days after nerve section and it reaches its maximal expression and distribution
      in peripheral nerve fibres at 14 days. At 30 days, the decline in its expression
      is associated with the increase of PGP9.5-, SP-, and CGRP immunopositivity. VIP
      is observed only in perivascular fibres at all times observed. Present results
      suggest that, after sensory denervation of the rat lip, nerve fibres in skin and
      mucosa remain at lower density than normal. The different time courses in the
      expression of neuropeptides and GAP-43 suggest a possible early involvement of
      GAP-43 in peripheral nerve regeneration.

PMID- 12597126
TI  - Morphological changes in collagen fiber during development of human fetal parotid
      and submandibular glands.
AB  - Parotid and submandibular glands from human fetuses (16, 20, 24, 28, 32 weeks of
      gestation) were examined under a scanning electron microscope. Changes were found
      in the arrangement of collagen fibers in the connective tissue surrounding the
      salivary gland. In particular, several layers around the salivary gland were
      formed by a collagen network structure. These structures, although in varied
      arrangements, were recognizable in each stage of fetal growth. They are thought
      to play the role of a "cushion" against pressure created by accumulation of
      granules because of the reflex activity of myoepithelial cells during secretion.
      These structural changes are related to the mechanical performance of granule
      formation in the salivary gland and secretion during the development of the
      fetus.

PMID- 12597127
TI  - The neglected maxillary process of the palatine bone.
AB  - In most recent anatomy textbooks as well as in the latest anatomical
      nomenclature, the maxillary process of the palatine bone is not mentioned at all.
      The maxillary process is, however with rare exceptions, always present as an
      important part of the closure of the hiatus sinus maxillaris. In our material
      consisting of 200 disarticulated, macerated skull bones and 25 specimens of
      maxillary sinus, the maxillary process was missing in only 5 cases (2.2%). This
      process develops in the second year of life and displays different shapes. It can
      be long and slender or wide and round shaped. Its upper margin is more or less
      concave, corresponding to the margin of the hiatus over which it is bent. Its
      inferior margin can be smooth or irregular. In instances in which maxillary sinus
      is double, the os palatinum has two maxillary processes, so that both sinuses are
      partly closed with the maxillary process of the palatine bone.

PMID- 12597128
TI  - Estrogen receptor expression and synthesis in the human internal thoracic artery.
AB  - The inhibition of vascular smooth muscle cell proliferation is mediated through
      two intracellular estrogen receptors (ERs), ER-alpha and ER-beta. Deletion
      variants of ER-alpha have been decribed for cultures of smooth muscle cells. The
      internal thoracic artery is frequently used as coronary artery bypass graft, yet
      neither has it been studied for the expression of ER subtypes nor for the
      synthesis of the ERs in morphologically hetergeneous smooth muscle cells. Using
      nested RT-PCR, we have demonstrated the mRNA for ER-alpha splicing variants in
      intact human internal thoracic arteries. The 7A deletion variant occurred in 8
      out of 12 cases, the full-length transcript in three cases. The full-length
      transcript was always found for the ER-beta. Immunolocalization revealed ER
      positive nuclei in the desmin-positive subset of smooth muscle cells, but not in
      cytokeratin (CK)-positive cells of the thickened intima. Morphological evidence
      is presented suggesting that ER synthesis is high in the tunica media when cell
      proliferation of smooth muscle cells is increased. We conclude that, in internal
      thoracic arteries, the 7A deletion variant of ER-a occurs in 75%, whereas the
      full-length transcript is found in all cases. The significance remains unclear.

PMID- 12597129
TI  - Topographical and histological examination of osteophytes taken from arthrotic
      femoral heads.
AB  - Until now it is not known whether osteophytes of the femoral head develop because
      of pathological joint alterations or arise from normal remodeling processes
      secondary to osteoarthrosis. Firstly, we analysed the topographical localization
      of osteophytes. We then compared the extracellular matrix components of
      macroscopically normal cartilage from the margin of osteophytes with osteophytic
      cartilage from weight bearing and non-weight bearing zones by histochemical
      staining of low and heavily sulfated glycosaminoglycans. For examination 65
      femoral heads were taken during endoprosthetic hip surgery. Osteophytes from
      different locations and macroscopically normal cartilage from the margin of
      osteophytes were excised, decalcified and embedded in paraplast. A lateral or
      medial localization of osteophytes (47 cases) was more common than a ventral or
      dorsal position (18 cases). Histochemical staining for low and heavily sulfated
      glycosaminoglycans from normal cartilage at the rim of osteophytes was stronger
      in the unmineralized cartilaginous zones compared to the mineralized
      cartilaginous zone. Weight bearing zones of osteophytic cartilage, on the other
      hand, showed an even distribution of the two differently sulfated
      glycosaminoglycans. Surprisingly, non-weight bearing zones of osteophytic
      cartilage showed a weaker staining for low and especially for heavily sulfated
      glycosaminoglycans in the superficial cartilage layer than in the deep cartilage
      layer. Altogether, osteophytic cartilage can be regarded as a reparative
      phenomenon for two reasons: Firstly, osteophytes arise very often at the weight
      bearing lateral and medial femoral head. Secondly, despite local differences in
      osteophytic cartilage, the same types of glycosaminoglycans are synthesized as in
      normal cartilage at the margin of osteophytes.

PMID- 12597130
TI  - Distribution of collagen fibers in the aggregated lymphoid follicles of swine
      terminal ileum.
AB  - The arrangement of the collagen bundles was studied in the Peyer's patches of
      swine terminal ileum, by means of light microscopy (using silver-impregnation
      technique and picrosirius F3BA staining) and scanning electron microscopy (after
      NaOH-maceration). The lymphoid tissue forms a large and continuous patch along
      the antimesenteric border. The follicles are disposed mainly in the tela
      submucosa and sometimes they reached in the tunica mucosa surface (follicle/dome
      structures). Some follicles are located in the lamina propria of the tunica
      mucosa. Light microscopy showed black and brown-stained fibers, and yellow and
      red, and green-stained fibers, respectively by silver impregnation technique and
      picrosirius red staining, in the tela submucosa. In this tela, by scanning
      electron microscopy, the collagen fibers appeared as thick bundles forming a
      network of parallel layers. This network was denser in the interfollicular than
      in the follicular area, and formed a capsule surrounding the lymphoid follicles.
      Our results pointed out that a clear correspondence exists between the findings
      of currently used light microscopy techniques and the scanning electron
      microscopy after alkali-water maceration method. The arrangement of the collagen
      fibers in the antimesenteric border of the tela submucosa suggested a functional
      compartmentalization within the aggregated lymphoid follicles. This could
      facilitate the antigen-to-cell and cell-to-cell interaction during the immune
      response and thus create a suitable microenvironment for an active cell
      metabolism. The tunica mucosa showed a porous structure and its frequent gaps
      were likely the sites through which lymphocytes and other cells could freely
      migrate thus participating in the immunological activities of these structures.

PMID- 12597131
TI  - Isolated flexor muscles of the little toe in the feet of an individual with
      atrophied or lacking 4th head of the M. extensor digitorum brevis and lacking the
      4th tendon of the M. extensor digitorum longus.
AB  - While dissecting the body of a 75-year-old male we observed variations in the Mm.
      flexor digitorum brevis and longus of both feet. In the left foot, the 4th tendon
      of the M. flexor digitorum brevis was atrophied and the respective tendon of the
      M. flexor digitorum longus to the little toe was absent. In the right foot, the
      4th tendons of both the Mm. flexor digitorum brevis and longus to the little toe
      were absent. The lacking deep flexor tendon to the little toe in the left foot
      was replaced by an isolated flexor muscle originating from the medial and lateral
      processes of the calcaneal tuberosity, which additionally had connections to the
      tendinous plate of the M. flexor digitorum longus and the M. quadratus plantae.
      The absent superficial and deep flexor tendons to the little toe in the right
      foot were replaced by an isolated flexor muscle arising from the M. quadratus
      plantae distal from the medial process of the calcaneal tuberosity. The tendon of
      both isolated flexor muscles inserted in the distal phalanx of the little toe.
      The left isolated flexor muscle for the little toe had connections to the M.
      flexor digitorum longus and the M. quadratus plantae. From these results it seems
      likely that the M. quadratus plantae could be regarded as additional flexor head
      (caput breve or plantare) of the M. flexor digitorum longus as is described in
      classic textbooks. In the individual's lifetime the described variation perhaps
      led to the possibility of an isolated flexion of the little toe.

PMID- 12597132
TI  - Derivation of the anterior belly of the digastric muscle receiving twigs from the
      mylohyoid and facial nerves.
AB  - The anterior belly of the digastric muscle is usually supplied by the mylohyoid
      nerve, and in general anatomy textbooks, the anterior belly is invariably
      described as receiving no other nerve except the mylohyoid nerve. In fact,
      however, it is sometimes supplied by a branch of the facial nerve in addition to
      the mylohyoid nerve. Such cases were found in 8 bodies or 9 head sides among 539
      bodies or 1078 head sides of Japanese subjects. Those nine cases were
      investigated in detail and it was clarified that they had the following three
      characteristics in common: (1) the twig originating from the facial nerve appears
      as the twig of the stylohyoid branch in most cases, (2) the twig from the facial
      nerve enters the anterior belly on its lower (shallow) surface and the twig of
      the mylohyoid nerve on its upper (deep) surface, (3) the twig of the mylohyoid
      nerve is distributed to the deep region and the twig of the stylohyoid branch is
      distributed to the shallow region of the anterior belly. From these results, it
      was concluded that the anterior belly, receiving the twigs of the mylohyoid and
      facial nerves, had been formed by secondarily combining the most ventral and
      rostral part of the primordium of the stylohyoid muscle in the second branchial
      arch with the caudal part of the primordium of the anterior belly in the first
      branchial arch.

PMID- 12597133
TI  - Anatomical study of distribution of valves of the cutaneous veins of adult's
      limbs.
AB  - Since the cutaneous veins of the four limbs have been used as autogenous grafts
      in the treatment of cardiovascular disorders, knowledge of distribution of the
      valves is increasingly required depending upon the use. In the gross anatomical
      study of distribution of valves of the trunci venae, there has been argument
      about locational relationships between the venous roots and the valves in the
      vicinity of the roots and the inter-valvular distance. However, there have been
      only few reports discussing detailed information about valves of the cutaneous
      veins of the four limbs. The authors observed patterns of distribution of the
      cutaneous venous valves of the four limbs of cadavers prepared for practice in
      anatomy. The following parts were excised from each cadaver: the cephalic,
      basilic, and the great saphenous veins, which originate from the acral venous
      network and flow into the proximal deep veins, and the venous roots communicating
      with these veins. An incision was made on each excised vein in the direction of
      the long axis under observation with a stereoscopic microscope, and the inter
      valvular distance and the distance between the valve and the orifice of venous
      root in the vicinity of the valve were measured. The inter-valvular distance
      varied with type of the truncus venae, and it varied according to area even in
      the same truncus venae.

PMID- 12597134
TI  - Tumor microenvironment: what have we learned studying the immune response in this
      puzzling battlefield?
AB  - Recent developments hallmark the progress in the understanding of tumor
      immunology and related therapeutic strategies. The administration of interleukin
      2 (IL-2) to patients with cancer has shown that immune manipulation can mediate
      the regression of established cancers. The identification of the genes encoding
      cancer antigens and the development of means for effectively immunizing against
      these antigens has opened new avenues for the development of active immunization
      of patients with cancer. However, an efficient immune response against tumor
      comprises an intricate molecular network still poorly understood. Only when the
      code governing immune responsiveness of cancer will be deciphered, new
      therapeutic strategies could be designed to fit biologically defined mechanisms
      of immune rejection of cancer. In this review, we propose that the mechanisms
      regulating tumor rejection in response to vaccination will be more efficiently
      identified by following the evolution of treatment induced events within the
      tumor microenvironment taking advantage of recently developed technological
      tools. As a model, we will discuss the observed immune response to tumor antigen 
      specific immunization and its relationship with the systemic administration of IL
      2.

PMID- 12597135
TI  - Radiotherapy after prostatectomy.
AB  - AIMS AND BACKGROUND: The role of radiotherapy after prostatectomy is
      controversial. This paper tries to give some guidelines for everyday practice
      through an analysis of literature data. METHODS: The potential role of
      radiotherapy in the adjuvant and salvage setting is discussed. We also report and
      interpret available literature data for both settings. RESULTS: As regards an
      increase in or detectable prostate-specific antigen (PSA) after radical
      prostatectomy, about 40-50% of patients are rendered bNED with local salvage
      radiotherapy, but only 10-50% are long-term (5 years) biochemically controlled. A
      timely salvage treatment is crucial to optimize control probability. As regards
      adjuvant radiotherapy for undetectable postoperative PSA in patients at high risk
      of failure as judged on pathology, results are more encouraging. Recent data
      report bNED rates > 70% at 5 years. CONCLUSIONS: Although results are far from
      satisfactory, salvage radiotherapy should be considered for every patient with an
      increased or detectable PSA after surgery. Adjuvant radiotherapy seems preferable
      to salvage radiotherapy for patients at high (> 30%) risk of failure.

PMID- 12597136
TI  - Smoking in Italy, 2002.
AB  - AIMS AND BACKGROUND: To update estimates of smoking prevalence in Italy to the
      year 2002. METHODS: Population-based, face-to-face survey conducted by the DOXA
      (the Italian Branch of the Gallup International Association) in March-April 2002
      on 3,238 individuals aged 15 or over, representative of the whole Italian
      population. RESULTS: Overall, 26.6% of Italian adults were current cigarette
      smokers (31.1% of men, 22.3% of women); 19.9% of men and 10.4% of women smoked 15
      or more cigarettes per day. Ex-smokers were 15.2% (21.9% of men, 9.0% of women).
      There was no appreciable difference with reference to geographic area or
      education in men, but more educated women were more frequently smokers (28%).
      Compared to 2001, reported smoking prevalence declined by 3.7% in men and 1.3% in
      women, and the fall was evident in various age groups, including the youngest one
      (15-24 years). However, part of the fall is likely due to increased
      underreporting, since these survey figures are appreciably underestimated as
      compared to sale data. Among ex-smokers, 84% had stopped without support. Among
      smokers, 37% had tried at least once to stop. Using the Fagerstrom questionnaire,
      69.5% of smokers were classified as low or very low dependent, whereas only 20.0%
      of smokers were classified as high or very high dependent. Women, younger and
      elderly, as well as more educated smokers of both sexes tended to be less
      dependent. CONCLUSIONS: Self-reported smoking prevalence tends to decline in
      Italy, although the overall figure (26.6% of Italian adults) remains considerably
      higher than the USA and several Western European countries.

PMID- 12597137
TI  - Cervical cancer epidemiology in Friuli Venezia Giulia.
AB  - AIMS AND BACKGROUND: Until 1998 there was opportunistic screening in Friuli
      Venezia Giulia (FVG). Beginning in 1999, formal screening efforts were organized.
      The regional cancer registry was established in 1998, and data on incidence was
      collected for the period 1995-98. The scope of this study is to provide baseline
      data on the incidence of invasive cervical cancer in FVG for further examination
      of trends in incidence and of the effectiveness of screening efforts. METHODS:
      Data from the regional cancer registry database was examined and linked with data
      from the regional pap smear screening database. RESULTS: The incidence of
      cervical cancer in FVG was 8.6 per 100,000. Most women were diagnosed in stages I
      and II. Most cervical cancers (80%) were squamous cell. Opportunistic screening
      in FVG reached 39.8% of the total female population. Analysis by local health
      unit showed heterogeneous data. CONCLUSIONS: FVG has one of the highest incidence
      rates of cervical cancer in Italy. Approximately 1/3 of the diagnoses were in
      women over the age of 65. Pap smear screening prior to the formal program covered
      a low percentage of the female population. Screening efforts in the future should
      focus on screening coverage in the older female population.

PMID- 12597138
TI  - Incidence and survival cancer trends in children and adolescents in the Provinces
      of Florence and Prato (Central Italy), 1985-1997.
AB  - AIMS AND BACKGROUND: The incidence of childhood and adolescent cancers has been
      increasing during the last decades in most Western countries. Improvements in
      cancer survival rates have also been observed according to the availability of
      more efficient therapies. METHODS AND STUDY DESIGN: A total of 518 cancer cases
      (age, 0-19 years) incident in the period 1985-1997 in the Tuscany Cancer Registry
      area, corresponding to the Provinces of Florence and Prato (Central Italy), were
      analyzed. Incidence rates and estimated annual percentage change were computed
      according to sex, 5-year age groups and diagnostic groups of the International
      Classification for Childhood Cancer. All patients were actively followed at
      31.12.1998, and 5-year survival rates were computed for cases diagnosed in 1985
      1990 and 1991-1997. RESULTS: Overall age-standardized incidence rates were
      186.7/10(6) for males and 175.4 for females. In 1991-1997, standardized incident
      rates were 50.8 for leukemias, 44.6 for lymphomas, and 34.3 for CNS tumors. There
      was a marked increasing trend for lymphomas that grew at a yearly rate of +12.1%
      and less evident increasing tendency for leukemias, CNS tumors and carcinomas.
      The overall survival rate was 88% at one year, 78% at 3 years, and 74% at 5
      years. A slight improving tendency in survival was evident over time.
      CONCLUSIONS: The study pointed out that in the examined area, during 1985-1997,
      there was a significant increasing incidence trend for lymphomas. Survival rates
      were as high as in other Western countries - evidence of the high level of
      diagnostic and treatment services in the area.

PMID- 12597139
TI  - Locally advanced breast cancer in the elderly: a major challenge requiring
      effective and appropriate treatment.
AB  - AIMS AND BACKGROUND: Breast cancer is the most common tumor in women. As the
      population above 65 years increases, breast cancer will be a more substantial
      problem for elderly patients. This work reports our experience in the management
      of stage III and IV locally advanced breast cancer. METHODS: Nineteen patients
      over 65 years of age (mean, 70.3 years) with stage III and IV breast cancers,
      treated between 1990 and 2000, are considered. The management and outcome are
      evaluated. RESULTS: Nine patients had stage IIIA breast cancer, 7 stage IIIB and
      3 stage IV. Sixteen underwent Madden mastectomy and 3 simple mastectomy. Patients
      at stage IIIB and 1 patient at stage IV with T4 tumor received neo-adjuvant
      chemotherapy. There were no significant postoperative complications. Sixteen
      patients were given tamoxifen and 10 patients adjuvant chemotherapy. Patients
      were followed for a median of 36.7 months (range, 6-72 months). In 8 patients
      with stage IlIl disease, metastasis developed. Two patients had local recurrence
      of disease. Of the patients at stage IIIA, 6 were free from disease (one died
      from unrelated causes) and 3 had recurrent disease (2 died). Of the patients at
      stage IIIB, 2 are disease free and 5 had recurrent disease and died. Of the
      patients at stage IV, only one is alive. CONCLUSIONS: Stage and individual
      characteristics of elderly women influence management. Patients should be managed
      adequately since most of them are fit enough to undergo treatment.

PMID- 12597140
TI  - Weekly paclitaxel in metastatic breast cancer patients: a phase II study.
AB  - AIMS ANID BACKGROUND: Paclitaxel, a microtubule inhibitor, is one of the most
      active drugs in metastatic breast cancer. A weekly schedule, at a median dose
      intensity of 91 mg/m2, is effective and has less side effects than a 3-week
      schedule. In this phase II study, we evaluated the toxicity and the activity of
      weekly 1 hr paclitaxel infusions in metastatic breast cancer patients. STUDY
      DESIGN: Between February 1999 and February 2001, 26 patients with metastatic
      breast cancer were treated with weekly paclitaxel (60-90 mg/m2/1 hour iv
      infusion/weekly). The treatment was planned to continue until disease progression
      or prohibitive toxicity; in patients with responsive or stable disease,
      paclitaxel was stopped after 6 months of therapy. RESULTS: At a median follow-up
      of 18.7 months (range, 6.8-30.8), all patients are assessable for response and
      toxicity. We obtained 8 partial responses (30.8%), 8 stable disease (30.8%) and
      10 disease progression (38.4.%). The overall response was 30.8% (95% CI, 13.1
      48.5). The median duration of response was 7.6 months (range, 1.8-12.4); median
      time to progression was 4.86 months (range, 1.4-12.4); median overall survival
      was 9.9 months (range, 1.7-29.2+). Treatment was well tolerated. Hematological
      toxicity was mild and only one patient developed grade 3 anemia. Two patients
      experienced grade 3 cardiovascular toxicity; both had received anthracycline
      based regimens. CONCLUSIONS: In our experience, weekly administration of
      paclitaxel shows a substantial degree of activity even in pretreated metastatic
      breast cancer patients. The toxicity profile is favorable.

PMID- 12597141
TI  - Neoadjuvant chemotherapy with taxotere-epirubicin-5-fluorouracil (TEF) in local
      regionally advanced breast cancer: a preliminary report.
AB  - AIMS AND BACKGROUND: Sixty-three patients with local-regionally advanced breast
      cancer were treated with neoadjuvant chemotherapy consisting of docetaxel
      (Taxotere), epirubicin, and 5-fluorouracil (TEF). METHODS AND STUDY DESIGN:
      Preoperatively, patients received four cycles of Taxotere (80 mg/m2), epirubicin
      (60 mg/m2), and 5-fluorouracil (500 mg/m2), repeated every 21 days. Following
      completion of four cycles of chemotherapy, appropriate surgery was performed.
      After the surgery, patients received one cycle of the TEF chemotherapy regimen;
      following chemotherapy, radiotherapy was applied, and at the end two more cycles
      of TEF chemotherapy regimen were given. RESULTS: Sixty-three patients with
      locally advanced breast cancer were treated. Three patients were excluded from
      the study before the evaluation of response. Median age of the patients was 50
      years (range, 25-77). Twenty-seven and 33 patients were premenopausal and
      postmenopausal, respectively. Thirty-nine patients were in stage IIIA and 21 in
      stage IIIB. Complete and partial responses were observed in 15 (25%) and 42 (70%)
      of the patients following four cycles of preoperative TEF chemotherapy regimen,
      respectively. Overall response was 95%, and primary lesion progressed only in 3
      (5%) patients. The mean disease-free survival was 15.9 +/- 6.8 (range, 3.5-28)
      months and the mean overall survival was 18.6 +/- 7.2 (range, 5-30) months. The
      most frequent side effects were nausea-vomiting, mucositis, alopecia and
      leukopenia. CONCLUSIONS: TEF therapy is a treatment with a high overall response
      rate and toxicities similar to other taxotere combinations. A longer follow-up of
      patients is necessary for the determination of disease-free survival and overall
      survival.

PMID- 12597142
TI  - Recurrence after treatment by loop electrosurgical excision procedure (LEEP) of
      high-grade cervical intraepithelial neoplasia.
AB  - PURPOSE: To evaluate the recurrence rate of high-grade CIN treated by loop
      electrosurgical excision procedure (LEEP) and the optimal follow-up schedule.
      METHOD: 622 cases of CIN2/3 consecutively treated by LEEP in the Florence
      screening program, with 66.5 months average follow-up (range, 6-195 months), were
      evaluated. Recurrence was defined as histological evidence of high-grade CIN.
      RESULTS: The average recurrence rate was 9.1% (52 cases). Recurrence was
      significantly associated to increasing age (chi2 = 12.73, df = 3, P < 001), CIN
      grade (10.5 vs 6.1%, chi2 = 3.37, df = 1, P = 0.067), and time interval, with the
      risk of developing a recurrence highest in the first year (7.4%, 95% confidence
      interval, 5.3-9.5%.), and rare beyond the third year. Multivariate analysis
      confirmed a significant independent association of age (particularly over age 40)
      and CIN grade to the risk of recurrence. CONCLUSIONS: LEEP is an effective
      procedure for the treatment of high-grade CIN. Most recurrences after LEEP occur
      in the first 3 years, and non-recurrent cases at that date may stop intensive
      follow-up and return to current cytological screening every 3 years.

PMID- 12597143
TI  - Analysis of the evolution in the management of endometrial cancer in Italy: a CTF
      study.
AB  - OBJECTIVE: In 1994 we mailed questionnaires to referral centers in Italy in order
      to evaluate the different opinions concerning aspects of endometrial cancer
      treatment, which is still controversial. The data processing showed a significant
      nonhomogeneity in disease management and prompted the Italian Society of
      Gynecologic Oncology to define guidelines for endometrial cancer adjuvant
      treatment. In 2001, we mailed again the same questionnaire to the same referral
      Centers in Italy. The aim of the second enquiry was the evaluation of changes in
      endometrial cancer management and the effective impact of the guidelines
      published. METHODS: The enquiry used the same questionnaires mailed in 1994;
      actually, we mailed those questionnaires to the same referral centers in Italy
      twice: in December 2000 and March 2001. The results of both the enquiries were
      collected in a relational data base, and the statistical evaluations were
      calculated using SPSS-statistics (Window ver. 8). RESULTS: Endometrial cancer
      treatment consists in abdominal hysterectomy and bilateral salpingo-oophorectomy.
      The unique relevant difference as to 1994 consists in the systemic performing of
      peritoneal cytology in endometrial cancer staging. Unlike the previous enquiry,
      adjuvant radiotherapy is not systematically performed in disease at stage Ic
      because of the substantial absence of confirmed data demonstrating a real benefit
      in terms of survival rate. The comparison between the two enquiries shows a
      significant change in medical planning and diversification attitude according to
      patient age and menopausal state. The disease management changes in patients over
      75 years old, mainly with respect to surgery and primary therapy. CONCLUSIONS: We
      noted a resistance of many centers to accept some trends actually widespread in
      the literature but not yet performed in practical clinical.

PMID- 12597144
TI  - Paclitaxel and carboplatin in neo-adjuvant and concomitant chemoradiotherapy in
      locally advanced head and neck squamous cell carcinoma.
AB  - AIM AND BACKGROUND: To evaluate feasibility of neoadjuvant chemotherapy (NA-CT)
      followed by CT + radiotherapy (RT) in locally advanced or unresectable head and
      neck squamous cell carcinoma (HNSCC). METHODS: 22 HNSCC patients were enrolled
      (18 males, 4 females; median age, 59.5 years; median ECOG PS, 1). Sites of
      disease: oral cavity, 18.2%; oropharynx, 40.9%; hypopharynx, 18.2%; larynx, 4.6%,
      multiple sites, 18.2%. T (tumor) category: T2, 13.6%; T3, 31.8%; T4, 54.5%. N
      (nodes) category: NO, 9.1%; N1, 18.1%; N2, 40.9%; N3, 31.8%. Stage: III, 4.6%;
      IVA, 63.6%; IVB, 31.8%. Induction carboplatin (AUC = 6) and paclitaxel (200
      mg/m2) x 3 cycles (q21 days) were given. Responders received definitive
      radiotherapy with concurrent carboplatin (35 mg/m2/day from days 1 to 5 in weeks
      1, 3, 5 and 7) and paclitaxel (50 mg/m2 on days 10, 24 and 38). Patients with
      node involvement were suggested to undergo postradiotherapy neck dissection.
      RESULTS: NA-CT. 97% of planned chemotherapy cycles were administered. Prevalent
      toxicity was hematologic: 50% G4 neutropenia and 31.8% G3, one neutropenic fever.
      All patients had alopecia. Complete responses in T and N were 4 (18.2%) and 3
      (15%), respectively. Partial responses were 13(59%) and 9 (45%). There was 1
      progressive disease. CT + RT. 79.9% of planned cycles of CT were administered. In
      19 patients (86.4%) more than 50% of planned cycles of CT were completed. Median
      dose of RT was 70.2 Gy on T/N+ and 54 Gy on NO. Limiting toxicity was mucositis
      in 77.3%, followed by neutropenia (59.1% G3-G4). Median weight loss was
      4.9%.18.2% of patients required hospitalization. Complete responses in T and N
      were 15 (68.1%) and 8 (40%), respectively. Partial responses were 5 (22.7%) and 7
      (35%). CONCLUSIONS: The preliminary results of this study are encouraging,
      despite the toxicity. Adequate follow-up is required to evaluate efficacy in
      terms of local-regional control and overall survival.

PMID- 12597146
TI  - Postoperative irradiation in localized renal cell carcinoma: the Rambam Medical
      Center experience.
AB  - OBJECTIVE: This study evaluated the results of postoperative adjuvant
      radiotherapy in patients with localized renal cell carcinoma (RCC). PATIENTS:
      Eighty-six patients (median age, 60 years) with RCC treated by radical
      nephrectomy were evaluated for the efficacy of postoperative radiotherapy. Twenty
      four percent of patients had stage T2, 35% T3a, 36% T3b and 5% T4 disease.
      Seventy-seven percent had clear cell carcinomas and 23% granular cell or spindle
      and mixed cell carcinomas. Radiotherapy was given to the renal bed and adjacent
      lymphatic basin at a median dose of 46 Gy. RESULTS: Thirty-two (37%) patients
      relapsed: 27 (84%) had systemic relapse only and five (16%) had local and
      systemic relapse; all patients of the latter group had stage T3b disease. The 10
      year disease-free and overall survival was 40% and 42%, respectively. Tumor
      invasion of the renal vessels and stage of disease were correlated with survival.
      Side effects of radiotherapy were mainly gastrointestinal, but one patient who
      received right abdominal irradiation died because of liver failure. CONCLUSION:
      The results of our study are comparable with those reported in the literature.
      Since postoperative irradiation did not improve the survival of patients with RCC
      and showed toxicity, it is not recommended.

PMID- 12597145
TI  - Hormono-radiotherapy in prostatic carcinoma: prognostic factors and implications
      for combined modality treatment.
AB  - The aim of this study was to evaluate the prognostic role of several clinical
      variables in a patient population undergoing neoadjuvant hormonotherapy (NHT)
      with external beam radiotherapy (ERT) to identify subsets of patients with an
      unfavorable prognosis who require intensified therapy. Eighty-four patients (mean
      age, 68.2 +/- 6.1 years; range, 52-81 years) underwent ERT (45 Gy to pelvic
      volume; 65 Gy mean dose to prostate volume) and NHT (oral flutamide: 250 mg three
      times daily for 30 days; LH-RH analogue: one vial every 28 days starting two
      months before radiotherapy and for its entire duration). The distribution
      according to clinical stage was T2: 46.4%, T3: 50.0%, T4: 3.6%. The distribution
      according to the Gleason score was grade 2-4: 17.9%; grade 5-7: 53.6%; grade 8
      10: 28.5%. The distribution according to pretreatment PSA levels (in ng/mL) was 0
      4: 5.9%; 4-10: 26.2%; 10-20:16.7%; > or = 20: 51.2%. With a median follow-up of
      36 months, 3.6% of patients died; hematogenous metastases and local disease
      progression were found in 16.7% and 6% of patients, respectively. Overall, the
      incidence of disease progression was 17.9%. 32.9% of patients showed biochemical
      failure during followup. Overall, metastasis-free, local progression-free and
      biochemical failure-free actuarial survival at five years was 89.2%, 66.5%, 85.0%
      and 41.9%, respectively. At univariate analysis (log-rank) clinical stage (cT)
      was shown to be significantly correlated with the incidence of metastasis (P =
      0.0004), local progression (P < 0.0001) and disease-free survival (P = 0.0005).
      At multivariate analysis (Cox) the correlations between clinical stage and
      metastasis (P = 0.0175), local progression (P = 0.0200) and disease-free survival
      (P = 0.0175) were confirmed. Gleason score and pretreatment PSA levels did not
      show any significant correlation with these endpoints. These results confirm the
      indications of the recent literature, which, in prostate carcinoma at higher
      clinical stages, suggest the use of prolonged hormonal therapy after
      radiotherapy.

PMID- 12597147
TI  - Are international guidelines for the prescription of adjuvant treatment for early
      breast cancer followed in clinical practice? Results of a population-based study
      on 1547 patients.
AB  - AIMS AND BACKGROUND: The results of several randomized trials and meta-analyses
      have been reported on adjuvant treatment for early breast cancer and treatment
      guidelines have been defined accordingly, but detailed data are lacking on the
      appropriateness of treatment prescription in clinical practice. METHODS: We
      performed a prospective, observational, multicenter study to monitor the
      prescription, delivery and effectiveness of radiotherapy following conservative
      surgery for early breast cancer; 1610 patients treated with postoperative
      radiation to the breast in 1997 were entered by 12 centers in Lombardy, Italy.
      Here we report the results of a secondary analysis focused on the prescription of
      medical adjuvant treatment (1547 eligible patients). RESULTS: Chemotherapy only
      was prescribed to 526 patients (33%), hormonal therapy only to 539 (33%), and
      both treatments to 85 patients (5%); 460 women (29%) received no medical adjuvant
      treatment. We compared the collected data with guidelines defined in 1995 by the
      St Gallen Consensus Conference. Undertreatment was most frequent in node-negative
      patients at intermediate/high risk, no treatment (instead of tamoxifen or
      chemotherapy) being prescribed in 21-45% of cases. Node-negative patients at low
      risk, on the other hand, were overtreated with tamoxifen in 31% of cases. In node
      positive, premenopausal women compliance with guidelines was far better, with a
      91-96% rate of chemotherapy prescription. In node-positive, postmenopausal,
      estrogen receptor-positive patients chemotherapy was unduly prescribed in as many
      as 56% of cases. Comparison of clinical practice with the next version of the
      guidelines (1998) showed a somewhat better compliance. CONCLUSIONS: Despite the
      availability of official and authoritative guidelines, adjuvant treatment
      prescription for early breast cancer in Lombardy in 1997 was suboptimal,
      especially in well-defined subgroups of patients.

PMID- 12597148
TI  - Preliminary study on radioimmunodiagnosis of experimental tumor models using
      technetium-99m-labeled anti-C-erbB-2 monoclonal antibody.
AB  - AIMS AND BACKGROUND: One of the great challenges of oncology is to improve
      methods for early tumor detection. Diagnosis of premalignant lesions and early
      stage primary tumors is crucial for the success of cancer therapy and increased
      survival rates. Growth factor receptors localized to the cell membrane play a
      vital role in cancer. Monoclonal antibodies labeled with radioisotopes have been
      used extensively for radioimmunodiagnosis and radioimmunotherapy of various
      malignancies. A preliminary study on immunoscintigraphy was carried out on animal
      tumor models using 99mTc-labeled monoclonal antibody CIBCgp185 generated against
      the CerbB-2 oncoprotein with a view to develop technologies for in vivo
      radioimmunodetection and localization of human breast cancer. METHODS: Mammary
      tumor xenografts induced using BT474 cells, a breast carcinoma cell line showing
      overexpression of C-erbB-2, were used for immunoscintigraphic studies. RESULTS:
      Scintigrams showed high radiolabel uptake by the tumor tissue of the mice
      belonging to the experimental group, whereas in control animals no radiolabel
      uptake was visualized. Biodistribution studies correlated well with scintiscans.
      CONCLUSIONS: The results indicate the potential application of this monoclonal
      antibody for in vivo diagnosis of occult malignancies of tumors with
      overexpression of C-erbB-2.

PMID- 12597149
TI  - Chemoprevention of prostate carcinogenesis by DFMO and/or finasteride treatment
      in male Wistar rats.
AB  - In the present study the chemopreventive activities of DFMO, the irreversible
      inhibitor of ornithine decarboxylase, and finasteride, the inhibitor of prostatic
      5a-reductase, against the development of chemically induced prostate
      adenocarcinoma by methylnitrosourea/testosterone propionate in male Wistar rats
      were investigated. According to histological examination, oral administration of
      DFMO and finasteride, either alone or combined, for two months to MNU/TP
      inoculated rats reduced the tumor incidence to 11.11%, 10% and 10%, respectively,
      compared to tumored controls (64.3%). DFMO and/or finasteride treatment resulted
      in significant reductions in the wet weight of the prostate gland and seminal
      vesicles and its ratio relative to the total body weight, as well as the levels
      of prostate total protein, DNA, RNA and DNA/RNA ratio, compared to tumored
      controls. However, the effect of the combined treatment was of no statistical
      significance compared to single DFMO or finasteride treatment, as demonstrated by
      the non-significant differences between the mean values of most of the studied
      parameters. The tumor chemopreventive activity and the prostate growth inhibitory
      effect of DFMO and finasteride were due to suppression of prostate polyamine
      synthesis. ANOVA test revealed that the relative weight of the prostate as well
      as blood and tissue polyamine levels could be used as significant endpoint
      biomarkers for DFMO and finasteride as cancer chemopreventive agents.

PMID- 12597150
TI  - Inhibition of growth of human nasopharyngeal cancer xenografts in SCID mice by
      arsenic trioxide.
AB  - AIMS AND BACKGROUND: It is known that arsenic trioxide (As2O3) can induce
      clinical remission in patients suffering from acute promyelocytic leukemia. It
      has been suggested that the agent might also be effective against other
      malignancies. This study was done to explore the efficacy of As2O3 in the
      treatment of human nasopharyngeal cancer xenografts in SCID (severe combined
      immunodeficiency) mice. METHODS: Human nasopharyngeal cancer cells from the CSNE
      1 cell line were implanted subcutaneously into SCID mice to produce tumors. The
      tumor inhibitory rate in vivo was assessed after intraperitoneal administration
      of As2O3. Histopathological changes in the tumor tissues and the toxicity of
      As2O3 to the liver, heart and kidneys of the host mice were also investigated.
      RESULTS: At doses of 1 mg/kg and 5 mg/kg As2O3 induced apoptosis in
      nasopharyngeal carcinoma cells. At 5 mg/kg As2O3 also induced cancer cell
      differentiation, it reduced the PCNA expression, and inhibited tumor growth. The
      tumor growth inhibitory rate in this experimental group was 76.02%. No
      nephrotoxicity was observed histologically at these dose levels but some
      pathological changes in liver and cardiac tissues were found. As2O3 proved lethal
      to the SCID mice at a dose of 10 mg/kg. CONCLUSION: As2O3 has an inhibitory
      effect on human nasopharyngeal carcinoma xenografts in SCID mice. The mechanism
      of antitumor activity may be due, at least in part, to the induction of apoptosis
      and differentiation in cancer cells.

PMID- 12597151
TI  - Atrial fibrillation during adjuvant chemotherapy with docetaxel: a case report.
AB  - A 46-year-old woman had an episode of atrial fibrillation during infusion of
      docetaxel as adjuvant chemotherapy for an infiltrating ductal carcinoma of the
      breast. All cardiological tests performed before treatment were normal and there
      was no evidence of thyroid dysfunction nor any objective or anamnestic data
      indicating acute or chronic cardiovascular disease. None of the drugs
      administered has ever shown any proarrhythmic activity. In controlled clinical
      trials docetaxel was found to have a very low cardiotoxicity.

PMID- 12597152
TI  - Primary non-Hodgkin's lymphoma of the lacrimal sac: a case report.
AB  - Primary non-Hodgkin's lymphoma of the lacrimal sac is an extremely rare
      presentation of orbital localization of lymphoma. We present a 45-year-old male
      patient with primary NHL of the lacrimal sac, stage IE, who was treated with
      surgery and radiotherapy. Fourteen months after the end of radiotherapy the
      patient is free of disease and does not show any treatment-related toxicity.

PMID- 12597153
TI  - Axillary metastasis as first symptom of occult breast cancer: a case report.
AB  - Axillary lymph node metastasis from an occult breast carcinoma is a rare
      occurrence. We report this condition in a 59-year-old woman who presented with a
      swelling in the right axilla. No breast mass was clinically evident. Mammography,
      ultrasonography and multiple random fine-needle breast biopsies yielded no
      pathological findings. No extramammary primary lesions were present. Axillary
      sampling was performed and histological examination revealed the presence of
      metastatic adenocarcinoma in three of the 12 dissected lymph nodes. Estrogen
      receptors were positive and immunohistochemistry pointed to a breast origin. All
      these data were suggestive of occult breast cancer. The patient refused any
      further treatment but accepted clinical and radiological follow-up. Eight years
      later mammography revealed in the same breast a 10-mm nodule containing
      microcalcifications, which was not evident at physical examination. The patient
      underwent a lumpectomy. Intraoperative histology was positive for breast
      carcinoma and complete axillary clearance was performed. Histological examination
      revealed a lobular invasive breast carcinoma and the presence of micrometastasis
      in one of the 23 removed lymph nodes. The patient was given radiotherapy to the
      breast and axilla and tamoxifen. At present, one year after the appearance of the
      primary tumor, she is free of disease. Based on this case report we suggest an
      eclectic approach in the management of patients with axillary metastasis from
      occult breast cancer, depending on the clinical, pathological and biological
      findings.

PMID- 12597154
TI  - Pancreatic involvement from heavily pretreated small cell lung cancer
      successfully treated with transcatheter intra-arterial chemotherapy: a case
      report with local and systemic disease control.
AB  - This is a case report on pancreatic metastases from small cell lung cancer
      successfully treated by transcatheter arterial infusion of chemotherapy. The
      patient showed partial regression of pancreatic and thoracic disease. To our
      knowledge this is the first reported case of small cell lung cancer with
      pancreatic involvement treated with the transcatheter arterial infusion
      procedure; it represents an example of integrated treatments that may be
      considered for patients with pancreatic involvement from small cell lung cancer
      even if heavily pretreated.

PMID- 12597155
TI  - A clinical case report of priapism treated with external RT.
AB  - The aim of this short communication is to present an extremely uncommon case of
      penile metastases from rectal adenocarcinoma treated with an external beam
      radiotherapy technique. A 76-year-old man affected by very painful priapism from
      penile metastases was treated with radiotherapy (30 Gy) for symptom relief. In
      the course of the radiotherapy treatment the patient reported gradual and
      continuous pain reduction. One month after the end of radiotherapy both the
      priapism and the pain had disappeared. Although the long-term prognosis remains
      poor, good quality of life was achieved in this patient.

PMID- 12597156
TI  - [4th National Conference of Medical Oncology. Evolution of the technology and
      clinical objectives of antitumor therapy].

PMID- 12597157
TI  - [Mesenchymal stem cells: biology and clinical applications].

PMID- 12597158
TI  - [Evolution of the parameters indicating response to drug therapy: from regression
      to complete control of the disease and the symptoms].

PMID- 12597159
TI  - [Rationales for the integration of molecular and conventional therapies].

PMID- 12597160
TI  - [Utilization of hemopoietic cytokines].

PMID- 12597161
TI  - [Cellular therapies in 2002].

PMID- 12597162
TI  - [4th National Conference of the Italian Association of Medical Oncology. From
      research to clinical practice: the role of topotecan in oncology].

PMID- 12597164
TI  - Acoustic ray chaos and billiard system in Hamiltonian formalism.

PMID- 12597163
TI  - [2nd CPMP of the European Union recommends the approval of pegylated liposomal
      doxorubicin in the treatment of metastatic breast cancer].

PMID- 12597165
TI  - A mixed finite element method for acoustic wave propagation in moving fluids
      based on an Eulerian-Lagrangian description.
AB  - A nonstandard wave equation, established by Galbrun in 1931, is used to study
      sound propagation in nonuniform flows. Galbrun's equation describes exactly the
      same physical phenomenon as the linearized Euler's equations (LEE) but is derived
      from an Eulerian-Lagrangian description and written only in term of the
      Lagrangian perturbation of the displacement. This equation has interesting
      properties and may be a good alternative to the LEE: only acoustic displacement
      is involved (even in nonhomentropic cases), it provides exact expressions of
      acoustic intensity and energy, and boundary conditions are easily expressed
      because acoustic displacement whose normal component is continuous appears
      explicitly. In this paper, Galbrun's equation is solved using a finite element
      method in the axisymmetric case. With standard finite elements, the direct
      displacement-based variational formulation gives some corrupted results. Instead,
      a mixed finite element satisfying the inf-sup condition is proposed to avoid this
      problem. A first set of results is compared with semianalytical solutions for a
      straight duct containing a sheared flow (obtained from Pridmore-Brown's
      equation). A second set of results concerns a more complex duct geometry with a
      potential flow and is compared to results obtained from a multiple-scale method
      (which is an adaptation for the incompressible case of Rienstra's recent work).

PMID- 12597166
TI  - Measurement of surface wave transmission coefficient across surface-breaking
      cracks and notches in concrete.
AB  - In this paper, a technique for measuring a surface wave transmission coefficient
      across surface-breaking cracks and notches in a heterogeneous but globally
      isotropic material (concrete) is presented. Once the transmission coefficient
      across a surface discontinuity is known, its depth may be estimated. There are
      many difficulties in measuring the transmission coefficient experimentally owing
      to effects of wave path dependence, unknown characteristics of the receiver and
      the wave source, and the variation of impact event or receiver coupling. To
      eliminate the undesired effects, a self-calibrating measurement scheme is applied
      to obtain the surface wave transmission coefficient across notches and surface
      breaking cracks in concrete. The obtained signal transmission coefficient is not
      affected by the experimental setup or the heterogeneous nature of the material.
      The testing scheme is described and experimental results obtained from concrete
      specimens with notches and surface-breaking cracks are presented. Repeatable and
      reliable measurements of surface wave transmission coefficient are obtained,
      which demonstrate a strong relation to normalized discontinuity depth. A
      numerical study using the boundary element method is presented, which verifies
      the experimental findings.

PMID- 12597167
TI  - Numerical investigation and electro-acoustic modeling of measurement methods for
      the in-duct acoustical source parameters.
AB  - It is known that the direct method yields different results from the indirect (or
      load) method in measuring the in-duct acoustic source parameters of fluid
      machines. The load method usually comes up with a negative source resistance,
      although a fairly accurate prediction of radiated noise can be obtained from any
      method. This study is focused on the effect of the time-varying nature of fluid
      machines on the output results of two typical measurement methods. For this
      purpose, a simplified fluid machine consisting of a reservoir, a valve, and an
      exhaust pipe is considered as representing a typical periodic, time-varying
      system and the measurement situations are simulated by using the method of
      characteristics. The equivalent circuits for such simulations are also analyzed
      by considering the system as having a linear time-varying source. It is found
      that the results from the load method are quite sensitive to the change of
      cylinder pressure or valve profile, in contrast to those from the direct method.
      In the load method, the source admittance turns out to be predominantly dependent
      on the valve admittance at the calculation frequency as well as the valve and
      load admittances at other frequencies. In the direct method, however, the source
      resistance is always positive and the source admittance depends mainly upon the
      zeroth order of valve admittance.

PMID- 12597168
TI  - Energy radiated by a point acoustic dipole that reverses its uniform velocity
      along its rectilinear path.
AB  - This work extends a mathematical approach developed recently for monopoles to
      describe the sound energy radiated by a rectilinearly moving dipole that changes
      direction along its trajectory. Although the dipole travels with constant speed,
      it undergoes acceleration by reversing its direction during a finite time
      interval along its path. This work determines the joint angular and frequency
      distribution of the radiated energy, its angular distribution, and the total
      radiated energy output. Results for the radiated energy are systematized by
      expressing the radiation integrals in terms of hypergeometric functions. This
      procedure simplifies the evaluations, particularly at low Mach numbers, and
      permits the comparison of results to the earlier monopole case.

PMID- 12597169
TI  - Nonlinear scattering of acoustic waves by natural and artificially generated
      subsurface bubble layers in sea.
AB  - The paper describes nonlinear effects due to a biharmonic acoustic signal
      scattering from air bubbles in the sea. The results of field experiments in a
      shallow sea are presented. Two waves radiated at frequencies 30 and 31-37 kHz
      generated backscattered signals at sum and difference frequencies in a bubble
      layer. A motorboat propeller was used to generate bubbles with different
      concentrations at different times, up to the return to the natural subsurface
      layer. Theoretical consideration is given for these effects. The experimental
      data are in a reasonably good agreement with theoretical predictions.

PMID- 12597170
TI  - The sound-speed gradient and refraction in the near-ground atmosphere.
AB  - A systematic description of sound refraction in the near-ground atmosphere is
      developed by modeling the effective sound-speed gradient with Monin-Obukhov
      similarity theory. The resulting gradient equation can be recast in a form
      involving just three nondimensional variables. The first is the ratio of a sound
      speed scale (representing the strength of the turbulent fluctuations in the sound
      speed) to the friction velocity. The second is the ratio of the actual height to
      a transitional height where contributions from the near-ground wind-speed
      gradients and the adiabatic lapse rate are roughly balanced. The third is simply
      the cosine of the angle between the propagation direction and mean wind
      direction. When the magnitude of the sound-speed scale/friction velocity ratio is
      large, refraction is unconditionally upward or downward, depending on sign of the
      ratio. A small value for this ratio indicates nearly neutral atmospheric
      stratification, for which refraction is determined by the wind direction for
      small values of the nondimensional height and is upward for larger values. The
      contribution to refraction from air humidity is determined as a function of the
      Bowen ratio and found to be significant over wet surfaces. Weather conditions
      appropriate for measurement of sound pressure levels are also discussed.

PMID- 12597171
TI  - Complex reflection phase gradient as an inversion parameter for the prediction of
      shallow water propagation and the characterization of sea-bottoms.
AB  - In this paper a quantity is proposed, referred to as the complex reflection phase
      gradient, whose use in a matched field inversion procedure allows for the rapid
      extraction of first order geo-acoustic information about the sea-bottom. It is
      based on the observation that at low grazing angles the reflection phase and
      bottom loss for a wide range of sea-bottom types commonly exhibits an approximate
      linear relationship to the vertical component of the acoustic wave number at the
      seabed. The real part of this quantity specifies the rate at which the reflection
      phase varies with vertical acoustic wave number while the imaginary part
      quantifies the rate of change of bottom loss. Despite being defined with just two
      real parameters it is shown that it provides an accurate prediction of the sound
      field for a wide range of bottom types. In addition, its measurement permits an
      estimate to be made for the input impedance to the seabed in the zero grazing
      angle limit and, in the case of a homogeneous elastic half-space of known
      density, the compressional and shear wave speed. The main advantage of the two
      parameter seabottom representation is that each parameter is readily inverted
      from comparatively few acoustic pressure measurements. The usefulness of the
      technique is illustrated by the results from computer simulated acoustic pressure
      measurements made at just eleven sensors in a simple shallow water channel, and
      results from a 10 cm deep laboratory channel at frequencies between 10 kHz and 75
      kHz.

PMID- 12597172
TI  - The contribution of bubbles to high-frequency sea surface backscatter: a 24-h
      time series of field measurements.
AB  - Measurements of acoustic sea surface backscattering, wind speed, and surface wave
      spectra were made continually over a 24-h period in an experiment conducted in 26
      m of water near the Dry Tortugus collection of islands off south Florida in
      February 1995. The backscattering measurements were made at a frequency of 30 kHz
      and a sea surface grazing angle of 20 degrees; a time series of the decibel
      equivalent of this variable, called SS20, was studied in terms of its dependence
      on environmental variables. On occasion reliable estimates of scattering in the
      grazing range 15 degrees-27 degrees were also obtained during the 24 hours. The
      scattering data exhibited evidence, in terms of scattering level and grazing
      angle dependence, of scattering from near-surface bubbles rather than scattering
      from the rough air-sea interface. The scattering data were compared with a model
      for sigma(b), the apparent backscattering cross section per unit area due to
      bubble scattering, that is driven by a parameter, beta1, equal to the depth
      integrated extinction cross section per unit volume. Using an empirical model for
      beta1 based on data from a 1977 experiment conducted in pelagic waters, model
      predictions agreed reasonably well with the 1995 measurements presented here.
      Additional model-data comparisons were made using four measurements from a 1992
      experiment conducted in pelagic waters. Finally, the 24-h time series of acoustic
      scattering exhibited a hysteresis effect, wherein for a given wind speed, there
      was a tendency for the scattering level to be higher if prior winds had been
      falling. A better understanding of this effect is essential to reduce uncertainty
      in model predictions.

PMID- 12597173
TI  - Low frequency coupled mode sound propagation over a continental shelf.
AB  - A two-way integral equation coupled mode method is applied to a continental shelf
      ocean waveguide proposed for a special session devoted to range-dependent
      acoustic modeling at the 141st meeting of the Acoustical Society of America. The
      coupled mode solution includes both sediment trapped and continuum modes. The
      continuum is approximated by a finite number of leaky modes but neglects the
      branch cut contribution. Mode coupling matrix elements and the range evolution of
      the modal amplitudes show the nature of the mode coupling. Transmission loss
      versus range at 100 Hz predicted by the integral equation approach is compared to
      the transmission loss predicted by a wide angle parabolic equation method. While
      there is very good agreement, one observes small differences that can be
      interpreted as backscattering predicted by the integral equation solution.

PMID- 12597174
TI  - Spectral integral representations of monostatic backscattering from three
      dimensional distributions of sediment volume inhomogeneities.
AB  - A theory is developed for generating short time, monostatic reverberation
      realizations caused by three-dimensionally distributed volume inhomogeneities in
      stratified media. A wave number integral approach to treating the propagation to
      and from the scatterers, combined with a two-dimensional spectral representation
      of the azimuthally averaged scatterer realizations and a novel numerical
      implementation, combine to yield an efficient, high fidelity reverberation
      simulator for predicting monostatic backscatter from horizontally stratified
      sediments.

PMID- 12597175
TI  - Modal analysis of broadband acoustic receptions at 3515-km range in the North
      Pacific using short-time Fourier techniques.
AB  - In 1995-1996 the Acoustic Thermometry of Ocean Climate (ATOC) experiment provided
      an opportunity to study long-range broadband transmissions over a series of
      months using mode-resolving vertical arrays. A 75-Hz source off the California
      coast transmitted broadband pulses to receiving arrays in the North Pacific,
      located at ranges of 3515 and 5171 km. This paper develops a short-time Fourier
      transform (STFT) processor for estimating the signals propagating in the lowest
      modes of the ocean waveguide and applies it to analyze data from the ATOC
      experiment. The STFT provides a convenient framework for examining processing
      issues associated with broadband signals. In particular, this paper discusses the
      required frequency resolution for mode estimation, analyzes the broadband
      performance of two standard modal beamforming algorithms, and explores the
      time/frequency tradeoffs inherent in broadband mode processing. Short-time
      Fourier analysis of the ATOC receptions at 3515 km reveals a complicated arrival
      structure in modes 1-10. This structure is characterized by frequency-selective
      fading and a high degree of temporal variability. At this range the first ten
      modes have equal average powers, and the magnitude-squared coherence between the
      modes is effectively zero. The coherence times of the peaks in the STFT mode
      estimates are on the order of 5.5 min. An analysis of mean arrival times yields
      modal dispersion curves and indicates that there are statistically significant
      shifts in travel time over 5 months of ATOC transmissions.

PMID- 12597176
TI  - The balanced electromagnetic separation transducer a new bone conduction
      transducer.
AB  - Conventional bone conduction transducers, which are relatively large, suffer from
      poor performance at low frequencies. A new type of electro-dynamic transducer,
      the balanced electromagnetic separation transducer (BEST), was developed to
      improve the performance of the conventional transducers. By using a balanced
      suspension principle, the quadratic distortion forces, as well as the static
      forces between the vibrating parts, are principally counterbalanced. Both the
      distortion and the size of the transducer can therefore be considerably reduced.
      Moreover, the static and dynamic magnetic fluxes are separated, except in the air
      gap regions, giving a more efficient transducer. For example, in comparison with
      a conventional B71 transducer, a prototype of the BEST has: Lower total harmonic
      distortion (THD), by 20-25 dB, and improved sensitivity by 10-20 dB for 100 to
      1000 Hz and by 2-10 dB for 1 to 10 kHz. From a clinical point of view, the BEST
      offers a chance to measure bone thresholds, at 250 and 500 Hz, which are reliable
      at hearing levels not possible before. For example, at 250 Hz the BEST has 23 dB
      higher sensitivity than the B71; the THD is improved from 61% (B71) to 3.3%
      (BEST) at 40 dB HL (ISO 389-3, 1994).

PMID- 12597177
TI  - Numerical homogenization techniques applied to piezoelectric composites.
AB  - With the recent availability of piezoelectric fibers, the design and the analysis
      of piezoelectric composites needs new modeling tools. Therefore, a numerical
      homogenization technique has been developed, based on the ATILA finite element
      code, that combines two techniques: one relying upon the representative volume
      element (RVE) the other relying upon the wave propagation (WP). The combination
      of the two methods allows the whole tensor of the homogenized properties of the
      piezoelectric composite to be found. Considering a fiber embedded in epoxy, the
      numerical results are compared to the results obtained using previous analytical
      models, thus validating the models. Even if the method is presented in a
      particular case, its extension to any piezoelectric composite is straightforward.

PMID- 12597178
TI  - Reduced models for the medium-frequency dynamics of stochastic systems.
AB  - In this paper, a frequency domain vibration analysis procedure of a randomly
      parametered structural system is described for the medium-frequency range. In
      this frequency range, both traditional modal analysis and statistical energy
      analysis (SEA) procedures well-suited for low- and high-frequency vibration
      analysis respectively, lead to computational and conceptual difficulties. The
      uncertainty in the structural system can be attributed to various reasons such as
      the coupling of the primary structure with a variety of secondary systems for
      which conventional modeling is not practical. The methodology presented in the
      paper consists of coupling probabilistic reduction methods with dynamical
      reduction methods. In particular, the Karhunen-Loeve and Polynomial Chaos
      decompositions of stochastic processes are coupled with an operator decomposition
      scheme based on the spectrum of an energy operator adapted to the frequency band
      of interest.

PMID- 12597179
TI  - Radial vibrations of orthotropic laminated hollow spheres.
AB  - The three-dimensional elasticity problem of the radial vibrations of a composite
      hollow spherical shell laminated of spherically orthotropic layers is considered.
      After formulating the equations, the exact determinantal equation from which the
      frequencies of vibration can be extracted is developed. Some calculated results
      for combinations of isotropic and orthotropic materials indicate the sensitivity
      of the frequencies to the geometry and material make up of the shells.

PMID- 12597180
TI  - Active control of acoustic reflection, absorption, and transmission using thin
      panel speakers.
AB  - This paper explores the development of thin panels that can be controlled
      electronically so as to provide surfaces with desired reflection coefficients.
      Such panels can be used as either perfect reflectors or absorbers. They can also
      be designed to be transmission blockers that block the propagation of sound. The
      development of the control system is based on the use of wave separation
      algorithms that separate incident sound from reflected sound. In order to obtain
      a desired reflection coefficient, the reflected sound is controlled to
      appropriate levels. The incident sound is used as an acoustic reference for
      feedforward control and has the important property of being isolated from the
      action of the control system speaker. In order to use a panel as a transmission
      blocker, the acoustic pressure behind the panel is driven to zero. The use of the
      incident signal as a reference again plays a key role in successfully reducing
      broadband transmission of sound. The panels themselves are constructed using
      poster board and small rare-earth actuators. Detailed experimental results are
      presented showing the efficacy of the algorithms in achieving real-time control
      of reflection or transmission. The panels are able to effectively block
      transmission of broadband sound. Practical applications for these panels include
      enclosures for noisy machinery, noise-absorbing wallpaper, the development of
      sound walls, and the development of noise-blocking glass windows.

PMID- 12597181
TI  - Evaluation of the risk of noise-induced hearing loss among unscreened male
      industrial workers.
AB  - Variability in background risk and distribution of various risk factors for
      hearing loss may explain some of the diversity in excess risk of noise-induced
      hearing loss (NIHL). This paper examines the impact of various risk factors on
      excess risk estimates of NIHL using data from the 1968-1972 NIOSH Occupational
      Noise and Hearing Survey (ONHS). Previous analyses of a subset of these data
      focused on 1172 highly "screened" workers. In the current analysis, an additional
      894 white males (609 noise-exposed and 285 controls), who were excluded for
      various reasons (i.e., nonoccupational noise exposure, otologic or medical
      conditions affecting hearing, prior occupational noise exposure) have been added
      2066) to assess excess risk of noise-induced material impairment in an unscreened
      population. Data are analyzed by age, duration of exposure, and sound level (8-h
      TWA) for four different definitions of noise-induced hearing impairment, defined
      as the binaural pure-tone average (PTA) hearing threshold level greater than 25
      dB for the following frequencies: (a) 1-4 kHz (PTA1234), (b) 1-3 kHz (PTA123),
      (c) 0.5, 1, and 2 kHz (PTA512), and (d) 3, 4, and 6 kHz (PTA346). Results
      indicate that populations with higher background risks of hearing loss may show
      lower excess risks attributable to noise relative to highly screened populations.
      Estimates of lifetime excess risk of hearing impairment were found to be
      significantly different between screened and unscreened population for noise
      levels greater than 90 dBA. Predicted age-related risk of material hearing
      impairment in the ONHS unscreened population was similar to that predicted from
      Annex B and C of ANSI S3.44 for ages less than 60 years. Results underscore the
      importance of understanding differential risk patterns for hearing loss and the
      use of appropriate reference (control) populations when evaluating risk of noise
      induced hearing impairment among contemporary industrial populations.

PMID- 12597182
TI  - Anechoic chamber qualification: traverse method, inverse square law analysis
      method, and nature of test signal.
AB  - Qualification of anechoic chambers is intended to demonstrate that the chamber
      supports the intended free-field environment within some permissible tolerance
      bounds. Key qualification issues include the method used to obtain traverse data,
      the analysis method for the data, and the use of pure tone or broadband noise as
      the chamber excitation signal. This paper evaluates the relative merits of
      continuous versus discrete traverses, of fixed versus optimal reference analysis
      of the traverse data, and of the use of pure tone versus broadband signals. The
      current practice of using widely space discrete sampling along a traverse is
      shown to inadequately sample the complexity of the sound field extant with pure
      tone traverses, but is suitable for broadband traverses. Continuous traverses,
      with spatial resolution on the order of 15% of the wavelength at the frequency of
      interest, are shown to be necessary to fully resolve the spatial complexity of
      pure tone qualifications. The use of an optimal reference method for computing
      the deviations from inverse square law is shown to significantly improve the
      apparent performance of the chamber for pure tone qualifications. Finally, the
      use of broadband noise as the test signal, as compared to pure tone traverses
      over the same span, is demonstrated to be a marginal indicator of chamber
      performance.

PMID- 12597183
TI  - Adaptation in a revised inner-hair cell model.
AB  - A revised computational model of the inner-hair cell (IHC) and auditory-nerve
      (AN) complex was recently presented [Sumner et al., J. Acoust. Soc. Am. 111, 2178
      2188 (2002)]. One key improvement is that the model reproduces the rate-intensity
      functions of low- (LSR), medium- (MSR), and high-spontaneous rate (HSR) fibers in
      the guinea-pig. Here we describe the adaptation characteristics of the model, and
      how they vary with model fiber type. Adaptation of the revised model for a HSR
      fiber is in line with an earlier version of the model [Meddis and Hewitt, J.
      Acoust. Soc. Am. 90, 904-917 (1991)]. In guinea-pig, poststimulus time histograms
      (PSTH) have been found to show less adaptation in LSR fibers. Evidence from
      chinchilla suggests that this is due to chronic adaptation resulting from short
      interstimulus intervals, and that fully recovered LSR fibers actually show more
      adaptation. However, the model is able to account for both variations of PSTH
      shape when fully recovered from adaptation. Interstimulus interval can also
      affect recovery in the model. The model is further tested against data previously
      used to evaluate models of AN adaptation. The tests are (i) recovery from
      adaptation of spontaneous rate and (ii) the recovery of response to acoustic
      stimuli ("forward masking"), (iii) the response to stimulus increments and (iv)
      decrements, and (v) the conservation of transient components. A HSR model fiber
      performs similarly to the earlier version of the model. However, there is
      considerable variation in response to increments and decrements between different
      model fibers.

PMID- 12597184
TI  - Factors contributing to bone conduction: the outer ear.
AB  - The ear canal sound pressure and the malleus umbo velocity with bone conduction
      (BC) stimulation were measured in nine ears from five cadaver heads in the
      frequency range 0.1 to 10 kHz. The measurements were conducted with both open and
      occluded ear canals, before and after resection of the lower jaw, in a canal with
      the cartilage and soft tissues removed, and with the tympanic membrane (TM)
      removed. The sound pressure was about 10 dB greater in an intact ear canal than
      when the cartilage part of the canal had been removed. The occlusion effect was
      close to 20 dB for the low frequencies in an intact ear canal; this effect
      diminished with sectioning of the canal. At higher frequencies, the resonance
      properties of the ear canal determined the effect of occluding the ear canal.
      Sectioning of the lower jaw did not significantly alter the sound pressure in the
      ear canal. The sound radiated from the TM into the ear canal was investigated in
      four temporal bone specimens; this sound is significantly lower than the sound
      pressure in an intact ear canal with BC stimulation. The malleus umbo velocity
      with air conduction stimulation was investigated in nine temporal bone specimens
      and compared with the umbo velocity obtained with BC stimulation in the cadaver
      heads. The results show that for a normal open ear canal, the sound pressure in
      the ear canal with BC stimulation is not significant for BC hearing. At threshold
      levels and for frequencies below 2 kHz, the sound in the ear canal caused by BC
      stimulation is about 10 dB lower than air conduction hearing thresholds; this
      difference increases at higher frequencies. However, with the ear canal occluded,
      BC hearing is dominated by the sound pressure in the outer ear canal for
      frequencies between 0.4 and 1.2 kHz.

PMID- 12597185
TI  - Differential responses to acoustic damage and furosemide in auditory brainstem
      and otoacoustic emission measures.
AB  - Characteristics of distortion product otoacoustic emissions (DPOAEs) and auditory
      brainstem responses (ABRs) were measured in Mongolian gerbil before and after the
      introduction of two different auditory dysfunctions: (1) acoustic damage with a
      high-intensity tone, or (2) furosemide intoxication. The goal was to find
      emission parameters and measures that best differentiated between the two
      dysfunctions, e.g., at a given ABR threshold elevation. Emission input-output or
      "growth" functions were used (frequencies f1 and f2, f2/f1 = 1.21) with equal
      levels, L1 = L2, and unequal levels, with L1 = L2 + 20 dB. The best parametric
      choice was found to be unequal stimulus levels, and the best measure was found to
      be the change in the emission threshold level, delta x. The emission threshold
      was defined as the stimulus level required to reach a criterion emission
      amplitude, in this case -10 dB SPL. (The next best measure was the change in
      emission amplitude at high stimulus levels, specifically that measured at L1 x L2
      = 90 x 70 dB SPL.) For an ABR threshold shift of 20 dB or more, there was
      essentially no overlap in the emission threshold measures for the two conditions,
      sound damage or furosemide. The dividing line between the two distributions
      increased slowly with the change in ABR threshold, delta ABR, and was given by
      delta x(t) = 0.6 delta ABR + 8 dB. For a given delta ABR, if the shift in
      emission threshold was more than the calculated dividing line value, delta x(t),
      the auditory dysfunction was due to acoustic damage, if less, it was due to
      furosemide.

PMID- 12597186
TI  - Patterns of phoneme perception errors by listeners with cochlear implants as a
      function of overall speech perception ability.
AB  - Many studies have noted great variability in speech perception ability among
      postlingually deafened adults with cochlear implants. This study examined phoneme
      misperceptions for 30 cochlear implant listeners using either the Nucleus-22 or
      Clarion version 1.2 device to examine whether listeners with better overall
      speech perception differed qualitatively from poorer listeners in their
      perception of vowel and consonant features. In the first analysis, simple
      regressions were used to predict the mean percent-correct scores for consonants
      and vowels for the better group of listeners from those of the poorer group. A
      strong relationship between the two groups was found for consonant
      identification, and a weak, nonsignificant relationship was found for vowel
      identification. In the second analysis, it was found that less information was
      transmitted for consonant and vowel features to the poorer listeners than to the
      better listeners; however, the pattern of information transmission was similar
      across groups. Taken together, results suggest that the performance difference
      between the two groups is primarily quantitative. The results underscore the
      importance of examining individuals' perception of individual phoneme features
      when attempting to relate speech perception to other predictor variables.

PMID- 12597187
TI  - The importance of cochlear processing for the formation of auditory brainstem and
      frequency following responses.
AB  - A model for the generation of auditory brainstem responses (ABR) and frequency
      following responses (FFRs) is presented. The model is based on the concept
      introduced by Goldstein and Kiang [J. Acoust. Soc. Am. 30, 107-114 (1958)] that
      evoked potentials recorded at remote electrodes can theoretically be given by
      convolution of an elementary unit waveform (unitary response) with the
      instantaneous discharge rate function for the corresponding unit. In the present
      study, the nonlinear computational auditory-nerve model recently developed by
      Heinz et al. [ARLO 2(3), 91-96 (2001)] was used to calculate the instantaneous
      discharge rate ri(t) for fibers i in the frequency range from 0.1 and 10 kHz. The
      summed activity across frequency was convolved with a unitary response which is
      assumed to reflect contributions from different cell populations within the
      auditory brainstem, recorded at a given pair of electrodes on the scalp.
      Predicted potential patterns are compared with experimental data for a number of
      stimulus and level conditions. Clicks, chirps as defined in Dau et al. [J.
      Acoust. Soc. Am. 107, 1530-1540 (2000)], long-duration stimuli comprising the
      chirp, as well as tones and slowly varying tonal sweeps were considered. The
      results demonstrate the importance of considering the effects of the basilar
      membrane traveling wave and auditory-nerve processing for the formation of ABR
      and FFR. Specifically, the results support the hypothesis that the FFR to low
      frequency tones represents synchronized activity mainly stemming from mid- and
      high-frequency units at more basal sites, and not from units tuned to frequencies
      around the signal frequency.

PMID- 12597188
TI  - Cochlear nonlinearity between 500 and 8000 Hz in listeners with normal hearing.
AB  - Cochlear nonlinearity was estimated over a wide range of center frequencies and
      levels in listeners with normal hearing, using a forward-masking method. For a
      fixed low-level probe, the masker level required to mask the probe was measured
      as a function of the masker-probe interval, to produce a temporal masking curve
      (TMC). TMCs were measured for probe frequencies of 500, 1000, 2000, 4000, and
      8000 Hz, and for masker frequencies 0.5, 0.7, 0.9, 1.0 (on frequency), 1.1, and
      1.6 times the probe frequency. Across the range of probe frequencies, the TMCs
      for on-frequency maskers showed two or three segments with clearly distinct
      slopes. If it is assumed that the rate of decay of the internal effect of the
      masker is constant across level and frequency, the variations in the slopes of
      the TMCs can be attributed to variations in cochlear compression. Compression
      ratio estimates for on-frequency maskers were between 3:1 and 5:1 across the
      range of probe frequencies. Compression did not decrease at low frequencies. The
      slopes of the TMCs for the lowest frequency probe (500 Hz) did not change with
      masker frequency. This suggests that compression extends over a wide range of
      stimulus frequencies relative to characteristic frequency in the apical region of
      the cochlea.

PMID- 12597189
TI  - Understanding speech in modulated interference: cochlear implant users and normal
      hearing listeners.
AB  - Many competing noises in real environments are modulated or fluctuating in level.
      Listeners with normal hearing are able to take advantage of temporal gaps in
      fluctuating maskers. Listeners with sensorineural hearing loss show less benefit
      from modulated maskers. Cochlear implant users may be more adversely affected by
      modulated maskers because of their limited spectral resolution and by their
      reliance on envelope-based signal-processing strategies of implant processors.
      The current study evaluated cochlear implant users' ability to understand
      sentences in the presence of modulated speech-shaped noise. Normal-hearing
      listeners served as a comparison group. Listeners repeated IEEE sentences in
      quiet, steady noise, and modulated noise maskers. Maskers were presented at
      varying signal-to-noise ratios (SNRs) at six modulation rates varying from 1 to
      32 Hz. Results suggested that normal-hearing listeners obtain significant release
      from masking from modulated maskers, especially at 8-Hz masker modulation
      frequency. In contrast, cochlear implant users experience very little release
      from masking from modulated maskers. The data suggest, in fact, that they may
      show negative effects of modulated maskers at syllabic modulation rates (2-4 Hz).
      Similar patterns of results were obtained from implant listeners using three
      different devices with different speech-processor strategies. The lack of release
      from masking occurs in implant listeners independent of their device
      characteristics, and may be attributable to the nature of implant processing
      strategies and/or the lack of spectral detail in processed stimuli.

PMID- 12597190
TI  - Cochlear toughening, protection, and potentiation of noise-induced trauma by non
      Gaussian noise.
AB  - An interrupted noise exposure of sufficient intensity, presented on a daily
      repeating cycle, produces a threshold shift (TS) following the first day of
      exposure. TSs measured on subsequent days of the exposure sequence have been
      shown to decrease relative to the initial TS. This reduction of TS, despite the
      continuing daily exposure regime, has been called a cochlear toughening effect
      and the exposures referred to as toughening exposures. Four groups of chinchillas
      were exposed to one of four different noises presented on an interrupted (6 h/day
      for 20 days) or noninterrupted (24 h/day for 5 days) schedule. The exposures had
      equivalent total energy, an overall level of 100 dB(A) SPL, and approximately the
      same flat, broadband long-term spectrum. The noises differed primarily in their
      temporal structures; two were Gaussian and two were non-Gausssian, nonstationary.
      Brainstem auditory evoked potentials were used to estimate hearing thresholds and
      surface preparation histology was used to determine sensory cell loss. The
      experimental results presented here show that: (1) Exposures to interrupted high
      level, non-Gaussian signals produce a toughening effect comparable to that
      produced by an equivalent interrupted Gaussian noise. (2) Toughening, whether
      produced by Gaussian or non-Gaussian noise, results in reduced trauma compared to
      the equivalent uninterrupted noise, and (3) that both continuous and interrupted
      non-Gaussian exposures produce more trauma than do energy and spectrally
      equivalent Gaussian noises. Over the course of the 20-day exposure, the pattern
      of TS following each day's exposure could exhibit a variety of configurations.
      These results do not support the equal energy hypothesis as a unifying principal
      for estimating the potential of a noise exposure to produce hearing loss.

PMID- 12597191
TI  - Perception of the low pitch of frequency-shifted complexes.
AB  - When all of the components in a harmonic complex tone are shifted in frequency by
      delta f, the pitch of the complex shifts roughly in proportion to delta f. For
      tones with a small number of components, the shift is usually somewhat larger
      than predicted from pitch theories, which has been attributed to the influence of
      combination tones [Smoorenburg, J. Acoust. Soc. Am. 48, 924-941 (1970)].
      Experiment 1 assessed whether combination tones influence the pitch of complex
      tones with more than five harmonics, by using noise to mask the combination
      tones. The matching stimulus was a harmonic complex. Test complexes were bandpass
      filtered with passbands centered on harmonic numbers 5 (resolved), 11
      (intermediate), or 16 (unresolved) and fundamental frequencies (FOs) were 100,
      200, or 400 Hz. For the intermediate and unresolved conditions, the matching
      stimuli were filtered with the same passband to minimize differences in the
      excitation patterns of the test and matching stimuli. For the resolved condition,
      the matching stimulus had a passband centered above that of the test stimulus, to
      avoid common partials. For resolved and intermediate conditions, pitch shifts
      were observed that could generally be predicted from the frequencies of the
      partials. The shifts were unaffected by addition of noise to mask combination
      tones. For the unresolved condition, no pitch shift was observed, which suggests
      that pitch is not based on temporal fine structure for stimuli containing only
      high unresolved harmonics. Experiment 2 used three-component complexes resembling
      those of Schouten [J. Acoust. Soc. Am. 34, 1418-1424 (1962)]. Nominal harmonic
      numbers were 3, 4, 5 (resolved), 8, 9, 10 (intermediate), or 13, 14, 15
      (unresolved) and F0s were 50, 100, 200, or 400 Hz. Clear shifts in the matches
      were found for all conditions, including unresolved. For the latter, subjects may
      have matched the "center of gravity" of the excitation patterns of the test and
      matching stimuli.

PMID- 12597192
TI  - Modulation rate discrimination for unresolved components: temporal cues related
      to fine structure and envelope.
AB  - The present study investigated the hypothesis that the cues for modulation rate
      discrimination for unresolved spectral components differ as a function of the
      spectral region occupied by the stimuli. Specifically, it was hypothesized that
      when components occupy relatively low spectral regions, phase locking both to the
      fine structure and to the envelope are useful cues. However, as the spectral
      region occupied by the components increases, phase locking to the fine structure
      becomes less robust, whereas phase locking to the envelope remains as a
      potentially strong cue. Observers were asked to detect a decrease in modulation
      rate for carrier frequencies between 1500 and 6000 Hz. Both amplitude-modulated
      (AM) and quasifrequency-modulated (QFM) tones were used in order to produce
      stimuli having strong and weak envelope cues, respectively. Although there were
      marked individual differences, the results showed an interaction between
      modulation type and spectral region, with AM and QFM performance being relatively
      similar at low spectral region, but with QFM showing a steeper reduction in
      performance as the spectral region of the carrier frequency increased. Overall,
      the data are consistent with an interpretation that pitch perception for
      unresolved components depends upon both fine structure and envelope cues, and
      that the relative importance of these cues depends upon the spectral region
      occupied by the stimuli.

PMID- 12597193
TI  - A mechanical model of vocal-fold collision with high spatial and temporal
      resolution.
AB  - The tissue mechanics governing vocal-fold closure and collision during phonation
      are modeled in order to evaluate the role of elastic forces in glottal closure
      and in the development of stresses that may be a risk factor for pathology
      development. The model is a nonlinear dynamic contact problem that incorporates a
      three-dimensional, linear elastic, finite-element representation of a single
      vocal fold, a rigid midline surface, and quasistatic air pressure boundary
      conditions. Qualitative behavior of the model agrees with observations of glottal
      closure during normal voice production. The predicted relationship between
      subglottal pressure and peak collision force agrees with published experimental
      measurements. Accurate predictions of tissue dynamics during collision suggest
      that elastic forces play an important role during glottal closure and are an
      important determinant of aerodynamic variables that are associated with voice
      quality. Model predictions of contact force between the vocal folds are directly
      proportional to compressive stress (r2 = 0.79), vertical shear stress (r2 =
      0.69), and Von Mises stress (r2 = 0.83) in the tissue. These results guide the
      interpretation of experimental measurements by relating them to a quantity that
      is important in tissue damage.

PMID- 12597194
TI  - Effects of disfluencies, predictability, and utterance position on word form
      variation in English conversation.
AB  - Function words, especially frequently occurring ones such as (the, that, and, and
      of), vary widely in pronunciation. Understanding this variation is essential both
      for cognitive modeling of lexical production and for computer speech recognition
      and synthesis. This study investigates which factors affect the forms of function
      words, especially whether they have a fuller pronunciation (e.g., thi, thaet,
      aend, inverted-v v) or a more reduced or lenited pronunciation (e.g., thax,
      thixt, n, ax). It is based on over 8000 occurrences of the ten most frequent
      English function words in a 4-h sample from conversations from the Switchboard
      corpus. Ordinary linear and logistic regression models were used to examine
      variation in the length of the words, in the form of their vowel (basic, full, or
      reduced), and whether final obstruents were present or not. For all these
      measures, after controlling for segmental context, rate of speech, and other
      important factors, there are strong independent effects that made high-frequency
      monosyllabic function words more likely to be longer or have a fuller form (1)
      when neighboring disfluencies (such as filled pauses uh and um) indicate that the
      speaker was encountering problems in planning the utterance; (2) when the word is
      unexpected, i.e., less predictable in context; (3) when the word is either
      utterance initial or utterance final. Looking at the phenomenon in a different
      way, frequent function words are more likely to be shorter and to have less-full
      forms in fluent speech, in predictable positions or multiword collocations, and
      utterance internally. Also considered are other factors such as sex (women are
      more likely to use fuller forms, even after controlling for rate of speech, for
      example), and some of the differences among the ten function words in their
      response to the factors.

PMID- 12597195
TI  - Accuracy and variability of acoustic measures of voicing onset.
AB  - Five commonly used methods for determining the onset of voicing of syllable
      initial stop consonants were compared. The speech and glottal activity of 16
      native speakers of Cantonese with normal voice quality were investigated during
      the production of consonant vowel (CV) syllables in Cantonese. Syllables
      consisted of the initial consonants /ph/, /th/, /kh/, /p/, /t/, and /k/ followed
      by the vowel /a/. All syllables had a high level tone, and were all real words in
      Cantonese. Measurements of voicing onset were made based on the onset of
      periodicity in the acoustic waveform, and on spectrographic measures of the onset
      of a voicing bar (f0), the onset of the first formant (F1), second formant (F2),
      and third formant (F3). These measurements were then compared against the onset
      of glottal opening as determined by electroglottography. Both accuracy and
      variability of each measure were calculated. Results suggest that the presence of
      aspiration in a syllable decreased the accuracy and increased the variability of
      spectrogram-based measurements, but did not strongly affect measurements made
      from the acoustic waveform. Overall, the acoustic waveform provided the most
      accurate estimate of voicing onset; measurements made from the amplitude waveform
      were also the least variable of the five measures. These results can be explained
      as a consequence of differences in spectral tilt of the voicing source in breathy
      versus modal phonation.

PMID- 12597196
TI  - Acoustic and perceptual evaluation of Mandarin tone productions before and after
      perceptual training.
AB  - Training American listeners to perceive Mandarin tones has been shown to be
      effective, with trainees' identification improving by 21%. Improvement also
      generalized to new stimuli and new talkers, and was retained when tested six
      months after training [Y. Wang et al., J. Acoust. Soc. Am. 106, 3649-3658
      (1999)]. The present study investigates whether the tone contrasts gained
      perceptually transferred to production. Before their perception pretest and after
      their post-test, the trainees were recorded producing a list of Mandarin words.
      Their productions were first judged by native Mandarin listeners in an
      identification task. Identification of trainees' post-test tone productions
      improved by 18% relative to their pretest productions, indicating significant
      tone production improvement after perceptual training. Acoustic analyses of the
      pre- and post-training productions further reveal the nature of the improvement,
      showing that post-training tone contours approximate native norms to a greater
      degree than pretraining tone contours. Furthermore, pitch height and pitch
      contour are not mastered in parallel, with the former being more resistant to
      improvement than the latter. These results are discussed in terms of the
      relationship between non-native tone perception and production as well as
      learning at the suprasegmental level.

PMID- 12597197
TI  - A narrow band pattern-matching model of vowel perception.
AB  - The purpose of this paper is to propose and evaluate a new model of vowel
      perception which assumes that vowel identity is recognized by a template-matching
      process involving the comparison of narrow band input spectra with a set of
      smoothed spectral-shape templates that are learned through ordinary exposure to
      speech. In the present simulation of this process, the input spectra are computed
      over a sufficiently long window to resolve individual harmonics of voiced speech.
      Prior to template creation and pattern matching, the narrow band spectra are
      amplitude equalized by a spectrum-level normalization process, and the
      information-bearing spectral peaks are enhanced by a "flooring" procedure that
      zeroes out spectral values below a threshold function consisting of a center
      weighted running average of spectral amplitudes. Templates for each vowel
      category are created simply by averaging the narrow band spectra of like vowels
      spoken by a panel of talkers. In the present implementation, separate templates
      are used for men, women, and children. The pattern matching is implemented with a
      simple city-block distance measure given by the sum of the channel-by-channel
      differences between the narrow band input spectrum (level-equalized and floored)
      and each vowel template. Spectral movement is taken into account by computing the
      distance measure at several points throughout the course of the vowel. The input
      spectrum is assigned to the vowel template that results in the smallest
      difference accumulated over the sequence of spectral slices. The model was
      evaluated using a large database consisting of 12 vowels in /hVd/ context spoken
      by 45 men, 48 women, and 46 children. The narrow band model classified vowels in
      this database with a degree of accuracy (91.4%) approaching that of human
      listeners.

PMID- 12597198
TI  - Evaluating the function of phonetic perceptual phenomena within speech
      recognition: an examination of the perception of /d/-/t/ by adult cochlear
      implant users.
AB  - This study examined whether cochlear implant users must perceive differences
      along phonetic continua in the same way as do normal hearing listeners (i.e.,
      sharp identification functions, poor within-category sensitivity, high between
      category sensitivity) in order to recognize speech accurately. Adult
      postlingually deafened cochlear implant users, who were heterogeneous in terms of
      their implants and processing strategies, were tested on two phonetic perception
      tasks using a synthetic /da/-/ta/ continuum (phoneme identification and
      discrimination) and two speech recognition tasks using natural recordings from
      ten talkers (open-set word recognition and forced-choice /d/-/t/ recognition).
      Cochlear implant users tended to have identification boundaries and sensitivity
      peaks at voice onset times (VOT) that were longer than found for normal-hearing
      individuals. Sensitivity peak locations were significantly correlated with
      individual differences in cochlear implant performance; individuals who had a /d/
      /t/ sensitivity peak near normal-hearing peak locations were most accurate at
      recognizing natural recordings of words and syllables. However, speech
      recognition was not strongly related to identification boundary locations or to
      overall levels of discrimination performance. The results suggest that perceptual
      sensitivity affects speech recognition accuracy, but that many cochlear implant
      users are able to accurately recognize speech without having typical normal
      hearing patterns of phonetic perception.

PMID- 12597199
TI  - The effects of short-term training for spectrally mismatched noise-band speech.
AB  - The present study examined the effects of short-term perceptual training on
      normal-hearing listeners' ability to adapt to spectrally altered speech patterns.
      Using noise-band vocoder processing, acoustic information was spectrally
      distorted by shifting speech information from one frequency region to another.
      Six subjects were tested with spectrally shifted sentences after five days of
      practice with upwardly shifted training sentences. Training with upwardly shifted
      sentences significantly improved recognition of upwardly shifted speech;
      recognition of downwardly shifted speech was nearly unchanged. Three subjects
      were later trained with downwardly shifted speech. Results showed that the mean
      improvement was comparable to that observed with the upwardly shifted training.
      In this retrain and retest condition, performance was largely unchanged for
      upwardly shifted sentence recognition, suggesting that these listeners had
      retained some of the improved speech perception resulting from the previous
      training. The results suggest that listeners are able to partially adapt to a
      spectral shift in acoustic speech patterns over the short-term, given sufficient
      training. However, the improvement was localized to where the spectral shift was
      trained, as no change in performance was observed for spectrally altered speech
      outside of the trained regions.

PMID- 12597200
TI  - Simulations of tonotopically mapped speech processors for cochlear implant
      electrodes varying in insertion depth.
AB  - It has been claimed that speech recognition with a cochlear implant is dependent
      on the frequency alignment of analysis bands in the speech processor with
      characteristic frequencies (CFs) at electrode locations. However, the most apical
      electrode location can often have a CF of 1 kHz or more. The use of filters
      aligned in frequency to relatively basal electrode arrays leads to the loss of
      lower frequency speech information. This study simulates a frequency-aligned
      speech processor and common array insertion depths to assess this significance of
      this loss. Noise-excited vocoders simulated processors driving eight electrodes 2
      mm apart. Analysis filters always had center frequencies matching the CFs of the
      simulated stimulation sites. The simulated insertion depth of the most apical
      electrode was varied in 2-mm steps between 25 mm (CF 502 Hz) and 17 mm (CF 1851
      Hz) from the cochlear base. Identification of consonants, vowels, and words in
      sentences all showed a significant decline between each of the three more basal
      simulated electrode configurations. Thus, if implant processors used analysis
      filters frequency-aligned to electrode CFs, patients whose most apical electrode
      is 19 mm (CF 1.3 kHz) or less from the cochlear base would suffer a significant
      loss of speech information.

PMID- 12597201
TI  - Reed vibration in lingual organ pipes without the resonators.
AB  - Vibrations of plucked and blown reeds of lingual organ pipes without the
      resonators have been investigated. Three rather surprising phenomena are
      observed: the frequency of the reed plucked by hand is shifted upwards for large
      amplitude plucking, the blown frequency is significantly higher than the plucked
      one, and peaks halfway between the harmonics of the fundamental frequency appear
      in the spectrum of the reed velocity. The dependence of the plucked frequency on
      the length of the reed reveals that the vibrating length at small vibrations is 3
      mm shorter than the apparent free length. The frequency shift for large-amplitude
      plucking is explained by the periodic change of the vibrating length during the
      oscillation. Reed vibrations of the blown pipe can be described by a physical
      model based on the assumption of air flow between the reed and the shallot.
      Aerodynamic effects may generate and sustain the oscillation of the reed without
      acoustic feedback. The appearance of subharmonics is explained by taking into
      account the periodic modulation of the stress in the reed material by the sound
      field. Therefore, a parametric instability appears in the differential equation
      of vibration, leading to the appearance of subharmonics.

PMID- 12597202
TI  - Time-domain simulation of sound production of the sho.
AB  - A physical model based on the sound production mechanism of the sho is proposed
      with intention of applying it to sound synthesis. Time-domain simulation was done
      using this model, and effects of the tube length and blowing pressure on the
      sounding frequency and sounds spectra were investigated. The reed vibration,
      pressure variation inside the tube, and threshold blowing pressure for
      oscillation were measured by artificially blowing air into the sho. The
      experimental results are in acceptable agreement with simulation results in terms
      of the relationships between tube length and threshold pressure and between tube
      length and the sounding frequency. In addition, recorded sound waveforms and
      simulated ones have a common feature in the sense that high-frequency components
      of their spectra increase with increasing blowing pressure. Further, it is
      concluded that a sho reed acts as an "outward-striking valve."

PMID- 12597203
TI  - The effect of superior auditory skills on vocal accuracy.
AB  - The relationship between auditory perception and vocal production has been
      typically investigated by evaluating the effect of either altered or degraded
      auditory feedback on speech production in either normal hearing or hearing
      impaired individuals. Our goal in the present study was to examine this
      relationship in individuals with superior auditory abilities. Thirteen
      professional musicians and thirteen nonmusicians, with no vocal or singing
      training, participated in this study. For vocal production accuracy, subjects
      were presented with three tones. They were asked to reproduce the pitch using the
      vowel /a/. This procedure was repeated three times. The fundamental frequency of
      each production was measured using an autocorrelation pitch detection algorithm
      designed for this study. The musicians' superior auditory abilities (compared to
      the nonmusicians) were established in a frequency discrimination task reported
      elsewhere. Results indicate that (a) musicians had better vocal production
      accuracy than nonmusicians (production errors of 1/2 a semitone compared to 1.3
      semitones, respectively); (b) frequency discrimination thresholds explain 43% of
      the variance of the production data, and (c) all subjects with superior frequency
      discrimination thresholds showed accurate vocal production; the reverse
      relationship, however, does not hold true. In this study we provide empirical
      evidence to the importance of auditory feedback on vocal production in listeners
      with superior auditory skills.

PMID- 12597204
TI  - Surface response of a viscoelastic medium to subsurface acoustic sources with
      application to medical diagnosis.
AB  - The response at the surface of an isotropic viscoelastic medium to buried
      fundamental acoustic sources is studied theoretically, computationally and
      experimentally. Finite and infinitesimal monopole and dipole sources within the
      low audible frequency range (40-400 Hz) are considered. Analytical and numerical
      integral solutions that account for compression, shear and surface wave response
      to the buried sources are formulated and compared with numerical finite element
      simulations and experimental studies on finite dimension phantom models. It is
      found that at low audible frequencies, compression and shear wave propagation
      from point sources can both be significant, with shear wave effects becoming less
      significant as frequency increases. Additionally, it is shown that simple closed
      form analytical approximations based on an infinite medium model agree well with
      numerically obtained "exact" half-space solutions for the frequency range and
      material of interest in this study. The focus here is on developing a better
      understanding of how biological soft tissue affects the transmission of vibro
      acoustic energy from biological acoustic sources below the skin surface, whose
      typical spectral content is in the low audible frequency range. Examples include
      sound radiated from pulmonary, gastro-intestinal and cardiovascular system
      functions, such as breath sounds, bowel sounds and vascular bruits, respectively.

PMID- 12597205
TI  - Prediction of backscatter coefficient in trabecular bones using a numerical model
      of three-dimensional microstructure.
AB  - A model of ultrasonic backscattering for cancellous bone saturated by water is
      proposed. This model assumes that scattering is caused by the solid trabeculae
      and describes the cancellous bone as a weak scattering medium. The backscatter
      coefficient is related to the spatial Fourier transform of bone microarchitecture
      and to the density and compressibility fluctuations between the solid trabeculae
      and the saturating fluid. The computations of the model make use of three
      dimensional numerical images of bone microarchitecture, obtained by tomographic
      reconstructions with a 10 microm spatial resolution. With this model, the
      predictions of the frequency dependence and of the magnitude of the backscatter
      coefficient are reasonably accurate. The theoretical predictions are compared to
      experimental data obtained on 19 specimens. An accuracy error of approximately 1
      dB was found (difference between the averaged experimental values and theoretical
      predictions). One limit of the model may come from inaccurate values of
      trabecular bone characteristics needed for the computations (density and
      longitudinal velocity), which are yet to be precisely determined for human
      trabecular bone. However, the model is only slightly sensitive to variations of
      bone material properties. It was found that an accuracy error of 2.2 dB at
      maximum resulted from inaccurate a priori values of bone material properties. A
      computation of the elastic mean free path in the medium suggests that multiple
      scattering plays a minor role in the working frequency bandwidth (0.4-1.2 MHz).
      It follows from these results that a weak scattering medium model may be
      appropriate to describe scattering from trabecular bone.

PMID- 12597206
TI  - Audiogram of a striped dolphin (Stenella coeruleoalba).
AB  - The underwater hearing sensitivity of a striped dolphin was measured in a pool
      using standard psycho-acoustic techniques. The go/no-go response paradigm and up
      down staircase psychometric method were used. Auditory sensitivity was measured
      by using 12 narrow-band frequency-modulated signals having center frequencies
      between 0.5 and 160 kHz. The 50% detection threshold was determined for each
      frequency. The resulting audiogram for this animal was U-shaped, with hearing
      capabilities from 0.5 to 160 kHz (8 1/3 oct). Maximum sensitivity (42 dB re 1
      microPa) occurred at 64 kHz. The range of most sensitive hearing (defined as the
      frequency range with sensitivities within 10 dB of maximum sensitivity) was from
      29 to 123 kHz (approximately 2 oct). The animal's hearing became less sensitive
      below 32 kHz and above 120 kHz. Sensitivity decreased by about 8 dB per octave
      below 1 kHz and fell sharply at a rate of about 390 dB per octave above 140 kHz.

PMID- 12597207
TI  - Discrimination of complex synthetic echoes by an echolocating bottlenose dolphin.
AB  - Bottlenose dolphins (Tursiops truncatus) detect and discriminate underwater
      objects by interrogating the environment with their native echolocation
      capabilities. Study of dolphins' ability to detect complex (multihighlight)
      signals in noise suggest echolocation object detection using an approximate 265
      micros energy integration time window sensitive to the echo region of highest
      energy or containing the highlight with highest energy. Backscatter from many
      real objects contains multiple highlights, distributed over multiple integration
      windows and with varying amplitude relationships. This study used synthetic
      echoes with complex highlight structures to test whether high-amplitude initial
      highlights would interfere with discrimination of low-amplitude trailing
      highlights. A dolphin was trained to discriminate two-highlight synthetic echoes
      using differences in the center frequencies of the second highlights. The energy
      ratio (delta dB) and the timing relationship (delta T) between the first and
      second highlights were manipulated. An iso-sensitivity function was derived using
      a factorial design testing delta dB at -10, -15, -20, and -25 dB and delta T at
      10, 20, 40, and 80 micros. The results suggest that the animal processed multiple
      echo highlights as separable analyzable features in the discrimination task,
      perhaps perceived through differences in spectral rippling across the duration of
      the echoes.

PMID- 12597208
TI  - Development of form and function in peripheral auditory structures of the
      zebrafish (Danio rerio).
AB  - Investigations of the development of auditory form and function have, with a few
      exceptions, thus far been largely restricted to birds and mammals, making it
      difficult to postulate evolutionary hypotheses. Teleost fishes represent useful
      models for developmental investigations of the auditory system due to their often
      extensive period of posthatching development and the diversity of auditory
      specializations in this group. Using the auditory brainstem response and
      morphological techniques we investigated the development of auditory form and
      function in zebrafish (Danio rerio) ranging in size from 10 to 45 mm total
      length. We found no difference in auditory sensitivity, response latency, or
      response amplitude with development, but we did find an expansion of maximum
      detectable frequency from 200 Hz at 10 mm to 4000 Hz at 45 mm TL. The expansion
      of frequency range coincided with the development of Weberian ossicles in
      zebrafish, suggesting that changes in hearing ability in this species are driven
      more by development of auxiliary specializations than by the ear itself. We
      propose a model for the development of zebrafish hearing wherein the Weberian
      ossicles gradually increase the range of frequencies available to the inner ear,
      much as middle ear development increases frequency range in mammals.

PMID- 12597209
TI  - The effect of a low-frequency sound source (acoustic thermometry of the ocean
      climate) on the diving behavior of juvenile northern elephant seals, Mirounga
      angustirostris.
AB  - Changes in the diving behavior of individual free-ranging juvenile northern
      elephant seals, Mirounga angustirostris, exposed to the acoustic thermometry of
      the ocean climate (ATOC) sound source were examined using data loggers. Data
      loggers were attached to the animals and measured swim speed, maximum depth of
      dive, dive duration, surface interval, descent and ascent rate, and descent and
      ascent angle along with sound pressure level (SPL). The ATOC sound source was at
      a depth of 939 m and transmitted at 195 dB re: 1 microPa at 1 m centered at 75 Hz
      with a 37.5-Hz bandwidth. Sound pressure levels (SPL) measured at the seal during
      transmissions averaged 128 dB and ranged from 118 to 137 dB re: 1 microPa for the
      60-90 Hz band, in comparison to ambient levels of 87-107 dB within this band. In
      no case did an animal end its dive or show any other obvious change in behavior
      upon exposure to the ATOC sound. Subtle changes in diving behavior were detected,
      however. During exposure, deviations in descent rate were greater than 1 s.d. of
      the control mean in 9 of 14 seals. Dive depth increased and descent velocity
      increased in three animals, ascent velocity decreased in two animals, ascent rate
      increased in one animal and decreased in another, and dive duration decreased in
      only one animal. There was a highly significant positive correlation between SPL
      and descent rate. The biological significance of these subtle changes is likely
      to be minimal. This is the first study to quantify behavioral responses of an
      animal underwater with simultaneous measurements of SPL of anthropogenic sounds
      recorded at the animal.

PMID- 12597210
TI  - Simulation of ultrasonic focus aberration and correction through human tissue.
AB  - Ultrasonic focusing in two dimensions has been investigated by calculating the
      propagation of ultrasonic pulses through cross-sectional models of human
      abdominal wall and breast. Propagation calculations used a full-wave k-space
      method that accounts for spatial variations in density, sound speed, and
      frequency-dependent absorption and includes perfectly matched layer absorbing
      boundary conditions. To obtain a distorted receive wavefront, propagation from a
      point source through the tissue path was computed. Receive focusing used an
      angular spectrum method. Transmit focusing was accomplished by propagating a
      pressure wavefront from a virtual array through the tissue path. As well as
      uncompensated focusing, focusing that employed time-shift compensation and time
      shift compensation after backpropagation was investigated in both transmit and
      receive and time reversal was investigated for transmit focusing in addition. The
      results indicate, consistent with measurements, that breast causes greater focus
      degradation than abdominal wall. The investigated compensation methods corrected
      the receive focus better than the transmit focus. Time-shift compensation after
      backpropagation improved the focus from that obtained using time-shift
      compensation alone but the improvement was less in transmit focusing than in
      receive focusing. Transmit focusing by time reversal resulted in lower sidelobes
      but larger mainlobes than the other investigated transmit focus compensation
      methods.

PMID- 12597211
TI  - Wrong-site surgery.

PMID- 12597212
TI  - "Deadman theory".

PMID- 12597213
TI  - The health of our profession.

PMID- 12597214
TI  - Ankle fixation.

PMID- 12597216
TI  - Suture V technique: a method for supplementing soft-tissue interference fixation
      of anterior cruciate ligament grafts.

PMID- 12597215
TI  - Radiologic case study. Stress-induced osteolysis of the distal clavicle.
AB  - Repetitive stress-induced osteolysis of the distal clavicle occurs in athletes
      who engage in upper extremity weight strengthening exercises and occupational
      overuse. Repetitive microtrauma is believed to cause microfractures and bone
      resorption with local pain. Conservative treatment usually is effective. If
      conservative treatment is unsuccessful. excellent outcomes can be expected after
      open or arthroscopic resection of the distal clavicle.

PMID- 12597217
TI  - Functional rating for knee arthroplasty: comparison of three scoring systems.
AB  - This study evaluated the reliability of three rating systems for total knee
      arthroplasty. Twenty-nine patients were assessed by six observers with the
      American Knee Society Score, the British Orthopaedic Association Score, and the
      Oxford 12-item questionnaire. The inter- and intraobserver variations were
      calculated for the American Knee Society Score and the British Orthopaedic
      Association Score, as was the reproducibility of the Oxford 12-item
      questionnaire. Components of the scores were evaluated for agreement using Kappa
      statistics. The British Orthopaedic Association Score had smaller interobserver
      variation compared to the American Knee Society Score, and the greatest
      reproducibility of the three systems. This was attributed to the equal weighting
      of its component variables. The Oxford 12-item questionnaire, a self-administered
      questionnaire that eliminates interobserver error, emerged as the most reliable
      system. Observer experience affected the reliability of the American Knee Society
      Score and the British Orthopaedic Association Score. Subjective variables were
      more reliable and reproducible than the objective components.

PMID- 12597218
TI  - Decreased range of motion following acute versus chronic anterior cruciate
      ligament reconstruction.
AB  - Eighty patients with acute anterior cruciate ligament (ACL) reconstruction were
      compared to 80 patients with chronic ACL reconstruction. Before reconstruction,
      all patients had 0 degrees-120 degrees active motion, performed a straight leg
      raise without loss of extension, and demonstrated good quadriceps control. At 3
      months, 4 acute patients had decreased range of motion (<10 degrees-120 degrees),
      but none at 6 or 12 months, and did not require repeat surgery. One chronic
      patient had decreased range of motion at 3 and 6 months and 1 patient had
      decreased range of motion at 1 year; both patients required operative
      intervention. Using these specific preoperative criteria, no increased incidence
      of decreased range of motion was found when an ACL reconstruction was performed
      within 3 weeks of injury.

PMID- 12597219
TI  - Refracture following plate removal in supracondylar-intercondylar femur
      fractures.
AB  - In a study of 41 supracondylar-intercondylar femur fractures treated with open
      reduction and plate fixation, 15 patients requested plate removal due to lateral
      knee pain over the hardware. A refracture of the distal femur occurred within 10
      weeks of hardware removal in 4 (27%) of 15 patients. All refractures occurred
      during normal functional activities. Patients who request hardware removal
      following union of a distal femur fracture treated with open reduction and
      plating should be informed of the possibility of refracture.

PMID- 12597220
TI  - Idiopathic osteoarthritis of the hip: incidence, classification, and natural
      history of 272 cases.
AB  - Long-term clinical and radiographic data of 210 patients (272 hips) with
      idiopathic hip osteoarthritis were reviewed. Of the 272 hips, 218 (80%) were
      eccentric and 54 (20%) were concentric. In eccentric hips, the femoral head
      migrated superolaterally or superomedially, because of the eccentric development
      of the degenerative changes, which had deteriorated rapidly. Hips with eccentric
      idiopathic osteoarthritis underwent total hip arthroplasty (THA) at an average of
      4 years after symptom onset. In concentric hips, the femoral head migrated
      medially, causing progressive thinning of the medial wall of the acetabulum, and
      degenerative changes progressed slowly. Hips with concentric idiopathic
      osteoarthritis underwent THA at an average of 10 years after symptom onset.

PMID- 12597221
TI  - The role of measured resistance exercises in adolescent scoliosis.
AB  - Twenty adolescent patients (18 girls and 2 boys) with scoliosis ranging from 15
      degrees-41 degrees in their major curve were treated with a progressive resistive
      training program for torso rotation. All patients demonstrated an asymmetry of
      rotation strength measured on specialized equipment, and surface electrode
      electromyograms showed inhibition of lumbar paraspinal muscles. Sixteen of 20
      patients demonstrated curve reduction, and no patient showed an increase in
      curve.

PMID- 12597222
TI  - Overdiagnosed sciatica and stenosis, underdiagnosed hip arthritis.
AB  - A retrospective analysis of 43 consecutive patients with hip osteoarthritis was
      performed. Twenty-four patients had previously been diagnosed with hip
      osteoarthritis, and 19 were treated solely for coexistent spine-related disorders
      without recognition of hip osteoarthritis. Four of 19 patients had previous
      spinal surgery for sciatica or spinal stenosis, 6 of 19 had epidural injections,
      17 of 19 had magnetic resonance imaging or computed tomography, and 3 of 19 had
      electrodiagnostic studies.

PMID- 12597223
TI  - Giant cell-rich osteosarcoma.

PMID- 12597224
TI  - Intramedullary nailing of distal tibial fractures: a technique to prevent
      malalignment.

PMID- 12597225
TI  - Osteochondroma of the upper cervical spine presenting as vertigo.

PMID- 12597226
TI  - Congenital medial dislocation of the patella.

PMID- 12597227
TI  - Chronic back pain caused by an abdominal aortic aneurysm: case report and review
      of the literature.

PMID- 12597228
TI  - An unusual reverse wringer injury: traumatic forearm flexor muscle herniation
      through the first web space.

PMID- 12597229
TI  - The treatment of chronic scapholunate dissociation: an evidence-based assessment
      of the literature.

PMID- 12597230
TI  - Extended thromboprophylaxis after hip or knee replacement.
AB  - Early discharge from the hospital after total joint arthroplasty has increased
      the need for extended outpatient thromboprophylaxis. Multiple controlled clinical
      trials and several meta-analyses of these data have examined various agents in
      different regimens. These data indicate that extended prophylaxis with a low
      molecular-weight heparin after knee or hip arthroplasty significantly reduces the
      number of venous thromboembolic episodes with no increases in major bleeding. The
      data also show that > 98% of patients given long-term low-molecular-weight
      heparin prophylaxis remain free from symptomatic deep venous thrombosis and
      pulmonary embolism. Therefore, to minimize patient risk safely and cost
      effectively, extended prophylaxis with low-molecular-weight heparin once-daily
      for 4 weeks after surgery should be considered for patients undergoing total
      joint arthroplasty.

PMID- 12597231
TI  - Managing thromboembolic risk in hip and knee arthroplasty: state of the art.
AB  - Deep vein thrombosis and pulmonary embolism are major causes of morbidity and
      mortality after knee and hip arthroplasty in the United States. Although patients
      frequently receive prophylaxis for thromboembolism postarthroplasty, surgeons
      vary in their choice of modality and often use suboptimal strategies due to the
      possibility of provoking postoperative bleeding. This article discusses the
      rationale for the prevention of venous thromboembolism and offers an overview of
      clinical recommendations for prophylaxis in knee and hip replacement surgery.
      Supporting medical evidence for these recommendations is described. A summary of
      current prophylactic regimens and discussion of duration of therapy are also
      presented.

PMID- 12597232
TI  - The risk of venous thromboembolism in non-large-joint surgeries.
AB  - The risk of venous thromboembolism, particularly deep venous thrombosis, after
      knee arthroscopy, surgically assisted arthroscopy, or treatment of lower
      extremity fracture may be substantial in patients with factors known to increase
      the risk of postoperative thromboembolism. Few prospective studies have examined
      the effect of prophylaxis in these patient populations. However, results suggest
      that routine administration of a low-molecular-weight heparin reduces the rate of
      deep venous thrombosis in such patients. Additional clinical studies are
      necessary to determine whether the benefits of prophylaxis outweigh its risks and
      whether it is cost-effective. Until such data are available, risk for deep venous
      thrombosis must be assessed in all patients undergoing an orthopedic procedure.
      Thromboprophylaxis with pharmacologic agents may be considered in those at high
      risk.

PMID- 12597233
TI  - Thromboprophylaxis and neuraxial anesthesia.
AB  - Spinal hematoma is a rare and potentially catastrophic complication of spinal or
      epidural anesthesia. Risk factors include traumatic needle/catheter placement,
      sustained anticoagulation in an indwelling neuraxial catheter, and catheter
      removal during therapeutic levels of anticoagulation. Generally, a patient's
      coagulation status should be optimized at the time of spinal or epidural
      needle/catheter placement, and the level of anticoagulation should be monitored
      during epidural catheterization. Signs of cord compression, such as severe back
      pain, progression of numbness or weakness, and bowel and bladder dysfunction,
      warrant immediate radiographic evaluation. A delay in diagnosis and intervention
      of spinal hematoma may lead to irreversible cord ischemia.

PMID- 12597234
TI  - Bleeding associated with thromboprophylaxis: a multifactorial issue.
AB  - Although postoperative bleeding is a legitimate concern when anticoagulant agents
      are used in thromboprophylaxis during total joint arthroplasty, the incidence of
      bleeding reported in clinical trials must be evaluated. Postoperative bleeding is
      a multifactorial effect that may be influenced by variables such as preoperative
      risk factors; the protocol, timing, and dose of the anticoagulant; and the
      surgical procedure and technique, as well as by the specific anticoagulant used.
      Because the reported rates of bleeding associated with various anticoagulants are
      low and the risks of venous thromboembolism in the absence of prophylaxis are
      high, thromboprophylaxis is a safe and effective strategy for reducing morbidity
      and mortality in patients undergoing total joint arthroplasty.

PMID- 12597235
TI  - Religious involvement and the forgiving personality.
AB  - The relationship between religious involvement and forgiveness was assessed in
      three samples of Western Europeans living in a social environment dominated by
      the Catholic tradition. The samples comprised nonbelievers/nonattendees,
      believers/nonattendees, believers/regular attendees, and religious people. Age
      and religious involvement were shown to affect the willingness to forgive in an
      interactive way: The effect of religious involvement was stronger for the elderly
      group. We also found that what made the difference in the willingness to forgive
      was mainly the social commitment to religion (attendance in church and the taking
      of vows), not mere personal beliefs. In addition, age and religious involvement
      were found to affect blockage towards forgiveness in an additive way.

PMID- 12597236
TI  - Relationship quality, trait similarity, and self-other agreement on personality
      ratings in college roommates.
AB  - Previous research has shown that the level of self-other agreement for
      personality trait ratings increases with the length of acquaintanceship between
      the target and the informant. These findings emerge exclusively from studies of
      well-acquainted pairs in natural relationships and relative strangers interacting
      in laboratory and classroom settings. The present study examines self-other
      correlations for trait ratings using the NEO Five Factor Inventory (NEO-FFI;
      Costa & McCrae, 1992) with 103 pairs of previously unacquainted female college
      roommates. Assessments were obtained at approximately 2 weeks and again at
      approximately 15 weeks subsequent to the roommates' initial introduction. Self
      other correlations increased for all five NEO-FFI scores and agreement
      correlations for Conscientiousness were significantly higher than for
      Extraversion at both occasions. Differences in relationship quality did not
      moderate self-other agreement for any of the traits. However, better relationship
      quality was associated with higher other-ratings of Extraversion, Agreeableness,
      and Conscientiousness and lower other-ratings of Neuroticism after controlling
      for self-ratings on the same trait. Higher similarity in self-ratings of
      Neuroticism and Openness was associated with higher self-other agreement for
      these ratings, and similarity in Conscientiousness was associated with higher
      relationship quality. These results are considered in light of existing theories
      of differential trait observability and the effects of unique contexts on trait
      perception.

PMID- 12597237
TI  - Personality judgments in adolescents' families: the perceiver, the target, their
      relationship, and the family.
AB  - The present study investigated whether personality judgments involve different
      processes in a family setting than in a nonfamily setting. We used the Social
      Relations Model to distinguish the effects of perceiver, target, perceiver-target
      relationship, and family on personality judgments. Family members of families
      with adolescents judged their own and the other members' Big Five factors.
      Judgments were found to depend on the relevance of personality factors within the
      family setting: Agreeableness and Conscientiousness were judged most
      consistently. Large relationship variance indicated that parents adjust their
      judgments to the target family member; large perceiver variance indicated that
      adolescents judge family members' personalities rather similarly. However, a
      comparison of self- and other-judgments showed adolescents' judgments to be no
      more related to their self-perceptions than parents' judgments. We concluded that
      the relevance of personality factors may differ on specific tasks within a
      setting.

PMID- 12597238
TI  - Unity versus multiplicity: a conceptual analysis of the term "self" and its use
      in personality theories.
AB  - There is no single answer to the unity-multiplicity problem regarding the self
      for the simple reason that the term "self" is used by too many different
      theorists in too many different ways. In fact, there are several important
      substantive topic areas that need to be distinguished and studied scientifically.
      The topic areas I examine in this article are reflexivity, unit coherence,
      agency, and subjectivity. Each of these areas will be evaluated in terms of what
      it contributes to, and can be interpreted in terms of, the unity-multiplicity
      issue. It is proposed that we need a more differentiated technical vocabulary if
      we are to better understand the phenomena we are examining. Matching our
      technical vocabulary to this empirical detail sharpens the questions being asked
      and places the empirical facts in better focus. A more elaborate framework of
      conceptual differentiation provides a better basis for developing an integrated
      theory.

PMID- 12597239
TI  - The structure of the self-concept and its relation to psychological adjustment.
AB  - Research on the relation between the structure of the self-concept and
      psychological adjustment has produced seemingly inconsistent findings. Some
      research suggests that greater pluralism in self-concept structure enhances
      adjustment, whereas other research suggests that greater unity in the structure
      enhances adjustment. Four studies examined the relations among measures of self
      concept structure and their relations with adjustment. The measures of self
      concept structure included two that we viewed as reflecting self-concept
      pluralism (self-complexity and self-concept compartmentalization) and four that
      we viewed as reflecting self-concept unity (self-concept differentiation, self
      concept clarity, self-discrepancies, and the average correlation among
      participants' self-aspects). The measures of self-concept pluralism were
      unrelated to one another, were unrelated to the measures of self-concept unity,
      and were unrelated to the measures of adjustment. The measures of self-concept
      unity were moderately related to one another and were moderately related to the
      measures of adjustment.

PMID- 12597240
TI  - Effective management of patients with dyslipidemia.
AB  - Coronary heart disease (CHD) is the leading cause of morbidity and mortality in
      the United States. A direct relationship has been demonstrated between
      dyslipidemia and the risk for developing CHD. Improving lipid status has been
      clearly demonstrated to reduce the morbidity and mortality associated with lipid
      disorders. The recently published National Cholesterol Education Program Adult
      Treatment Panel III (NCEP ATP III) guidelines and revised Health Plan Employer
      Data and Information Set (HEDIS) performance measures have placed added emphasis
      on screening and treatment of lipid disorders and global risk for CHD. Current
      ATP III and HEDIS cholesterol screening and goal measures are targeting more
      Americans for cholesterol-lowering therapy. This review summarizes the
      implications of the HEDIS performance measures and the ATP III guidelines,
      reviews the economic benefits of lowering cholesterol, and identifies optimal
      cholesterol levels. In addition, the challenges associated with patients who have
      suboptimal control and patients with poor compliance are discussed, as these
      factors significantly increase CHD morbidity, mortality, and cost of disease. In
      addition, lipid-lowering drug therapies are reviewed, and a lipid-lowering agent
      currently in phase 3 development, rosuvastatin, is introduced.

PMID- 12597241
TI  - Relationship of health status and social support to the life satisfaction of
      older adults.
AB  - We examined the relationship of health factors and social support to life
      satisfaction in older adults dwelling in a rural town. The gender difference in
      variables related to life satisfaction was also discussed in this study. One
      hundred and forty-two older adults (86 females and 56 males) who completed a self
      administered questionnaire and participated in a health examination in 1998 or
      1999 comprised the study participants. The t-test and chi-square test were used
      to assess the differences between the two genders. Correlation measure and
      multiple regression analysis were used to assess the relationship between life
      satisfaction and other health related or socially related factors for each
      gender. Significant gender differences were observed in living status and several
      health related factors. According to the results of the multiple regression
      analyses, life satisfaction was related to mental health and age in females,
      while it was related to mental health status and social support from others in
      males. Gender differences in the variables associated with life satisfaction were
      observed among the community-dwelling older adults. These data suggest the
      importance of mental health for older adults. When preparing health promotion
      strategies for older adults, results of gender differences as they related to
      social support and life satisfaction should be applied in practice.

PMID- 12597242
TI  - Role of mitochondrial NADH shuttle system in acute amylase secretion by
      acetylcholine from mouse pancreatic acinar cells.
AB  - Using the mice that lack mitochondrial glycerol-3-phosphate dehydrogenase
      (mGPDH), a rate limiting enzyme of the glycerol-phosphate NADH shuttle, we
      investigated the role of the NADH shuttle system in amylase secretion in response
      to acetylcholine (ACh) in pancreatic acinar cells. The pancreatic acinar cells of
      mGPDH-deficient mice were not different in histology and immunohistochemistry
      from those of wild-type mice. In both types of pancreatic acinar cells from wild
      type and mGPDH-deficient mice, ACh similarly potentiated amylase secretion,
      measured in 30 minutes after the ACh stimulation. A 30 minutes pre-treatment of
      wild-type cells with aminooxyacetate (AOA), an inhibitor of aspartate
      aminotransferases of the malate-aspartate NADH shuttle, did not change the rate
      of ACh-induced amylase secretion, measured in the following 30 minutes. In also
      mGPDH-deficient cells treated with AOA, thus in this situation all mitochondrial
      NADH shuttles being dysfunctioning, ACh induced amylase release in a similar
      amount to that in AOA-untreated cells. The basal levels of intracellular Ca2+
      concentration ([Ca2+]i), the ACh-stimulated levels of [Ca2+]i and Ca2+
      oscillation patterns in response to ACh were similar in wild-type and mGPDH
      deficient cells, and the AOA-treatment did not affect these [Ca2+]i responses.
      The levels of intracellular concentration of ATP before and during stimulation
      with ACh were similar in wild-type and mGPDH-defficient cells. In only AOA
      treated mGPDH-deficient cells, the level of ATP decreased after the ACh
      stimulation. These results suggest that acute response of amylase secretion to
      ACh from mouse pancreatic acinar cells does not require simultaneous functioning
      of the mitochondrial NADH shuttle system, although the supply of intracellular
      ATP decreases during the ACh stimulation.

PMID- 12597243
TI  - Odor perception in patients with multiple chemical sensitivity.
AB  - Since symptoms typical for multiple chemical sensitivity (MCS) are induced by
      exposure to low levels of chemicals, we hypothesize that MCS represents an
      impaired recognition of odors or an increased emotional reaction to common odors.
      Twenty-five subjects with MCS, 20 women and 5 men, and 50 gender-and-age matched
      controls participated in this study. The University of Pennsylvania Smell
      Identification Test (UPSIT) and the Cross-Cultural Smell Identification Test (CC
      SIT) were administered. In addition to selecting the most probable odor among the
      four, the subjects were asked their impression of each odor. Odor identifiability
      evaluated by the scores of two tests, were almost equal in MCS and control
      groups. The mean CC-SIT odor per person with pleasant feeling was lower in MCS
      than in controls. The mean odor per person creating an unpleasant sensation was
      higher in MCS than in the controls. Gingerbread was the only odor making MCS
      subjects more pleasant than the controls. Nine out of 40 UPSIT odors were felt as
      unpleasant by MCS subjects more than by controls. This study indicates that MCS
      subjects are able to identify the odors equally as well as the controls but feel
      unpleasant to a larger number of odors than the controls. Despite unknown
      mechanisms of the altered odor perception in MCS, the application of these tests
      for diagnostic procedure of MCS is proposed.

PMID- 12597244
TI  - Skin disease among staff in a large Korean nursing home.
AB  - Although previous studies have documented reasonably high rates of skin disease
      among nursing home staff, the prevalence among Korean workers is not well known.
      For this investigation we selected a large Korean nursing home and distributed a
      skin disease questionnaire to all staff. Questions included job title, job
      description, employment history, working hours, patient contact and the
      occurrence of skin disease over the past 12 months. Workers who reported a
      dermatological problem then underwent skin examinations conducted by specialist
      occupational physicians and a dermatologist. Contact dermatitis was the most
      common skin disease detected, with 4.8% of staff currently suffering from it and
      6.0% reporting it in the previous 12-month period. Tinea pedis was another common
      condition, affecting 3.6% on our examination day. However, only two-thirds of
      them (2.4%) recounted a past history of tinea pedis. Scabies was diagnosed among
      2.4% of staff and reported as a previous infection by 6.0%. Overall, the
      prevalence of dermatitis and scabies were quite low when compared to previous
      studies, while fungal infection rates were similar to other investigations.
      Further research into this growing occupational demographic is indicated.

PMID- 12597245
TI  - Single nucleotide polymorphisms in the 3' untranslated region of vascular
      endothelial growth factor gene in Japanese population with or without renal cell
      carcinoma.
AB  - We investigated native Japanese subjects whether C702T, C936T and G1612A
      polymorphisms in the 3' untranslated region (3'-UTR) of vascular endothelial
      growth factor (VEGF) gene are associated with the risk of renal cell carcinoma
      (RCC). Genomic DNAs from 145 RCC patients and 145 healthy controls were examined
      by polymerase chain reaction-based restriction fragment length polymorphism.
      Variant allele frequencies of C702T, C936T and G1612A were 0.00, 0.20 and 0.13 in
      the controls, respectively. The C702T and G1612A allele frequencies were
      significantly different between the Japanese population and the Caucasian
      population reported elsewhere. For each of C936T and G1612A polymorphisms, there
      was no statistically significant difference in the distribution of genotype
      frequencies between the cases and controls. Odds ratios and 95% confidence
      intervals computed by logistic regression analyses were not statistically
      significant. Stratification for the RCC cases according to pathological cell
      subtype, grade or stage failed to reveal any significant heterogeneity with
      respect to the genotype of each VEGF polymorphism. We revealed that there are
      significant ethnic differences in the C702T and G1612A allele frequencies, but
      suggested that C702T, C936T and G1612A polymorphisms in the 3'-UTR of VEGF gene
      are not associated with the risk of RCC, at least in Japanese population.

PMID- 12597246
TI  - Superoxide dismutase activity and glutathione system in erythrocytes of men with
      Behchet's disease.
AB  - In order to clarify whether erythrocyte superoxide dismutase (SOD) activity and
      glutathione system including reduced glutathione (GSH), glutathione peroxidase (G
      Px), glutathione reductase (G-Red), glutathione S-transferase (GST) are impaired
      in men with Behchet's disease (BD) at the first diagnosed time, erythrocyte SOD
      activity, GSH level, activities of G-Px, G-Red and GST were determined in men
      with new diagnosed BD. Erythrocyte GSH level, G-Px and G-Red activities were
      found to be lower, SOD activity was found to be higher in the patients as
      compared the controls. There was no significant difference between patients and
      controls for GST activity. Significant positive correlations between GSH and G
      Px, GSH and G-Red; significant negative correlations between GSH and SOD, G-Px
      and SOD, G-Red and SOD were determined. It was concluded that erythrocyte SOD
      activity and glutathione system are altered in men with new diagnosed BD. It was
      concluded that these alterations may be a contributory factor for tissue damage
      associated with BD.

PMID- 12597247
TI  - Stability of electron-beam energy monitor for quality assurance of the electron
      beam energy from radiotherapy accelerators.
AB  - Information on electron energy is important in planning radiation therapy using
      electrons. The Geske 3405 electron beam energy monitor (Geske monitor, PTW
      Nuclear Associates, Carle Place, NY, USA) is a device containing nine ionization
      chambers for checking the energy of the electron beams produced by radiotherapy
      accelerators. We wondered whether this might increase the likelihood of
      ionization chamber trouble. In spite of the importance of the stability of such a
      quality assurance (QA) device, there are no reports on the stability of values
      measured with a Geske monitor. The purpose of this paper was therefore to
      describe the stability of a Geske monitor. It was found that the largest
      coefficient of variation (CV) of the Geske monitor measurements was approximately
      0.96% over a 21-week period. In conclusion, the stability of Geske monitor
      measurements of the energy of electron beams from a linear accelerator was
      excellent.

PMID- 12597248
TI  - Central nervous system lipomas.
AB  - The lipomas of the central nervous system are rare lesions of congenital origin
      and are located in the medial line and especially in corpus callosum.
      Intramedullary spinal lipomas can be seen in the life span of 30 years of age and
      most frequently coincide with initial puberty period. Magnetic resonance imaging
      and computerized tomography together with clinical trials are of crucial
      importance for diagnosis. The first case: A two-year-aged girl who had lipoma in
      quadrigeminal cistern and who suffered from encephalocraniocutaneous lipomatosis
      has been clinically studied. The fascial lipoma of the patient has been excised
      subtotally by the Plastic Surgeons; then the patient has underwent
      supracerebellar infratentorial operation where the intracranial lipoma has been
      excised by our team. The histopathology has been reported to be consisting of
      peripheric nerve tissue and calcification. The second case: A twenty-year-aged
      man with intramedullary lipoma localized between T1-T4 has been given our
      clinical trials. T1-T5 total laminectomy and subtotal excision were made for this
      patient. Due to the fact that the lipomas of central nervous system are rarely
      seen and are involved in nervous and calcific tissues except for fatty tissues
      they can be mistaken for hamartomatous masses. The total excision of the lipomas
      of central nervous system and especially the spinal intramedullary lipomas are
      quite difficult to be excised since they are tightly entangled with the neural
      tissue. So any attempt for total excision would be dangerous. Operation for
      decompression and biopsy is of primary concern.

PMID- 12597249
TI  - Determination of saponins and alkaloids in Caulophyllum thalictroides (blue
      cohosh) by high-performance liquid chromatography and evaporative light
      scattering detection.
AB  - The roots of Caulophyllum thalictroides, traditionally used for the treatment of
      menstrual difficulties and as an aid in childbirth, contain saponins, which are
      considered to be responsible for the uterine stimulant effects, together with
      teratogenic alkaloids. An HPLC method has been developed which permits the
      determination of the triterpene saponins in the plant and also the separation of
      four alkaloids. The best results were obtained with a C-12 stationary phase using
      ammonium acetate buffer (pH 8.0) and acetonitrile as mobile phase. Owing to their
      low UV absorbance, the saponins were detected by evaporative light scattering,
      whereas the alkaloids were monitored by UV at 310 nm. The identities of the
      compounds were confirmed in an LC-MS experiment. Different plant samples and
      commercial products have been analysed using the described method, and remarkable
      qualitative and quantitative variations were revealed. Comparing the daily uptake
      of total saponins, a difference of greater than 100-fold was observed within the
      various products; the alkaloid content on the other hand was more uniform.

PMID- 12597250
TI  - Fungitoxic phenols from carnation (Dianthus caryophyllus) effective against
      Fusarium oxysporum f. sp. dianthi.
AB  - The phenol compositions of two cultivars of carnation (Dianthus caryophyllus)
      namely "Gloriana" and "Roland", which are partially and highly resistant,
      respectively, to Fusarium oxysporum f. sp. dianthi have been investigated with
      the aim of determining if endogenous phenols could have an anti-fungal effect
      against the pathogen. Analyses were performed on healthy and F. oxysporum
      inoculated in vitro tissues, and on in vivo plants. Two benzoic acid derivatives,
      protocatechuic acid (3,4-dihydroxybenzoic acid) and vanillic acid (4-hydroxy-3
      methoxybenzoic acid), were found within healthy and inoculated tissues of both
      cultivars, together with the flavonol glycoside peltatoside (3-[6-O-(alpha-L
      arabinopyranosyl)-beta-D-glucopyranosyl] quercetin). These molecules proved to be
      only slightly inhibitory towards the pathogen. 2,6-Dimethoxybenzoic acid was
      detected in small amounts only in the inoculated cultivar "Gloriana", while the
      highly resistant cultivar "Roland" showed the presence of the flavone datiscetin
      (3,5,7,2'-tetrahydroxyflavone). The latter compound exhibited an appreciable
      fungitoxic activity towards F. oxysporum f. sp. dianthi.

PMID- 12597251
TI  - HPLC isolation of the anti-plasmodially active bisbenzylisoquinone alkaloids
      present in roots of Cissampelos mucronata.
AB  - The methanolic extract of dried, powdered Cissampelos mucronata roots possesses
      significant in vitro activity against Plasmodium falciparum. In order to enable
      further pharmacological testing, the substances responsible for the observed
      activity were purified, mainly by HPLC, using various stationary and mobile
      phases. The active principles were determined to be a series of
      bisbenzylisoquinoline alkaloids, a group of natural products for which one of the
      first routine preparative HPLC separation methods is described.

PMID- 12597253
TI  - Determination of the absolute configuration of 6-alkylated alpha-pyrones from
      Ravensara crassifolia by LC-NMR.
AB  - The absolute configuration of asymmetric centres of two alpha-pyrones isolated
      from Ravensara crassifolia was determined using the Mosher method. The
      conventional analysis of the purified ester derivatives by 1H-NMR was replaced by
      a rapid and sensitive method in which the alpha-pyrones were analysed under
      isocratic reversed-phase LC-NMR conditions prior to and after derivatisation
      reactions. Comparison of the LC-1H-NMR spectra of the actual alpha-pyrones with
      those of the corresponding Mosher's esters recorded in the
      acetonitrile:deuterated water solvent system exhibited shifts comparable with
      those obtained using conventional deuterated solvents. Based on the shifts
      recorded, determination of the absolute configuration was possible by application
      of Mosher rules. The use of LC-NMR has permitted a direct analysis of crude
      reaction mixtures containing less than 50 microg of the starting material.
      Completion of the reaction was checked by LC-MS and the crude reaction mixture
      was analysed by stop-flow LC-NMR. This methodology seems very promising for the
      determination at the micro-scale level of the absolute configuration of natural
      products which are available only in very small amounts.

PMID- 12597252
TI  - Analysis of volatile fractions of Schisandra chinensis (Turcz.) Baill. using GC
      MS and chemometric resolution.
AB  - The two-dimensional data obtained from GC-MS has been used qualitatively and
      quantitatively to determine the components of the volatile fractions of
      Schisandra chinensis obtained by six different extraction methods. Sub-window
      factor analysis (SFA) was employed to confirm the identities of components
      determined in different samples. With the help of SFA, and other chemometric
      techniques, peak purity in the chromatograms was determined, and overlapping
      peaks were resolved to yield a pure chromatographic profile and mass spectrum for
      each component. It is demonstrated that the accuracy of qualitative and
      quantitative analysis may be greatly enhanced using chemometric resolution
      methods, such methods being particularly valuable with respect to the analysis of
      complex samples such as traditional Chinese medicines. It is further demonstrated
      that different extraction methods give rise to volatile fractions of S. chinensis
      which differ qualitatively and quantitatively in their composition.

PMID- 12597254
TI  - Identification and characterisation of the chinese herb Langdu by LC-MS/MS
      analysis.
AB  - An LC-MS/MS method has been developed for the identification of three species of
      herb used as the traditional Chinese medicine Langdu, namely Stellera chamaejasme
      L., Euphorbia ebracteolata Hayata and E. fischeriana Steud. As these herbs
      contain different mixtures of marker compounds, they could be unambiguously
      differentiated from each other by comparing their respective characteristic
      segmental multiple reaction monitoring profiles. The profiles indicated that S.
      chamaejasme contained daphnetin, skimmetine, stellerin, chamaechromone and
      neochamaejasmin, E. fischeriana contained ebracteolata compound B, ingenol,
      jolkinolide B and fischeriana A, whilst E. ebracteolata contained ebracteolata
      compounds B and C along with ingenol. These results were confirmed from the
      respective MS/MS spectra. The method has been successfully applied to
      differentiate these herbs from the related species Alocasia macrorrhiza (L.)
      Schott and E. kansui Liou.

PMID- 12597255
TI  - Guaiacylglycerol-7'-O-methyl 8'-vanillic acid ether and related compounds from
      Boreava orientalis.
AB  - The threo and erythro forms of guaiacylglycerol-7'-O-methyl 8'-vanillic acid
      ethers, threo and erythro guaiacylglycerol 8'-vanillin ethers, and threo
      guaiacylglycerol 8'-(4-hydroxymethyl-2-methoxyphenyl) ether have been isolated
      from fruits of Boreava orientalis. Structural determinations were made on the
      basis of UV, MS, 1H- and 13C-NMR spectral data, including two-dimensional shift
      correlation. The relative configurations were assigned on the basis of 1H-NMR
      chemical shifts.

PMID- 12597257
TI  - Current awareness in phytochemical analysis.

PMID- 12597256
TI  - HPLC-NMR/HPLC-MS analysis of the bark extract of Stauranthus perforatus.
AB  - A combination of HPLC-MS and HPLC-NMR techniques has been used to analyse the
      cytotoxic fractions of the dichloromethane extract of bark of Stauranthus
      perforatus. Six furanocoumarins (byakangelicol, heraclenin, heraclenol,
      imperatorin, isopimpinellin and xanthotoxin) and nine quinoline alkaloids (two
      known compounds, veprisine and 5-hydroxy-1-methyl-2-phenyl-4-quinolone, along
      with seven novel compounds, stauranthine, 3',4'-dihydroxy-3',4'-dihydroveprisine,
      3',4'-dihydroxy-3',4'-dihydrostauranthine, 3',6'-dihydroxy-3',6'
      dihydroveprisine, 3',6'-dihydroxy-3',6'-dihydrostauranthine, 6'-hydroxy-3'
      ketoveprisine and 6'-hydroxy-3'-ketostauranthine) have been identified in the
      fractions.

PMID- 12597258
TI  - Hawthorn.
AB  - Crataegus monogyna Jacq (Lindm), C. laevigata (Poir) DC, or related Crataegus
      species, collectively known as hawthorn, have been used in the treatment of
      cardiovascular diseases. Clinical studies have found that standardized extracts
      show promise as adjunctive agents for the treatment of left ventricular
      dysfunction. Other trials consistently demonstrate its ability to improve
      exercise tolerance and symptoms of mild to moderate heart failure. Preliminary
      evidence indicates that it improves left ventricular performance, as measured by
      ejection fraction. In order to properly use hawthorn in the treatment of heart
      failure, a large, controlled, multicenter trial in which mortality serves as the
      primary endpoint is needed.

PMID- 12597259
TI  - Coenzyme Q10 and cardiovascular disease: a review.
AB  - This article provides a comprehensive review of 30 years of research on the use
      of coenzyme Q10 in prevention and treatment of cardiovascular disease. This
      endogenous antioxidant has potential for use in prevention and treatment of
      cardiovascular disease, particularly hypertension, hyperlipidemia, coronary
      artery disease, and heart failure. It appears that levels of coenzyme Q10 are
      decreased during therapy with HMG-CoA reductase inhibitors, gemfibrozil,
      Adriamycin, and certain beta blockers. Further clinical trials are warranted, but
      because of its low toxicity it may be appropriate to recommend coenzyme Q10 to
      select patients as an adjunct to conventional treatment.

PMID- 12597260
TI  - Ginkgo biloba for the prevention and treatment of cardiovascular disease: a
      review of the literature.
AB  - Results from clinical trials demonstrate that standardized leaf extracts of
      Ginkgo biloba (SGB extract) reduce the symptoms of age-associated memory
      impairment and dementia, including Alzheimer's disease, and may be of benefit in
      treating intermittent claudication. In addition, preliminary results suggest that
      SGB extract may be useful in preventing and treating cardiovascular disease
      (CVD). particularly ischemic cardiac syndrome. Since many patients with
      cardiovascular disease are already taking anticoagulants and antiplatelet drugs,
      self-medication with SGB extract is not recommended without the advice of their
      physician. Although SGB extracts look promising for preventing and treating CVD,
      well-controlled clinical trials are needed before clinical recommendations can be
      made.

PMID- 12597261
TI  - Cardiovascular benefits of garlic (Allium sativum L).
AB  - Although garlic is believed to have health-promoting benefits, many of the
      claimed benefits are not supported by good scientific studies. This review
      critically examined current scientific literature concerning claims of
      cardiovascular benefits from regular consumption of garlic or garlic
      preparations. The vast majority of recent randomized, placebo-controlled studies
      do not support a role for garlic in lowering blood lipids. There also is
      insufficient evidence to support a role in reducing blood pressure. While there
      have been indications of antiatherosclerotic effects associated with garlic
      consumption, there are insufficient data in humans. Investigation of
      antithrombotic effects of garlic consumption appears to hold promise, but too few
      data exist to draw firm conclusions.

PMID- 12597262
TI  - The cardiovascular effects of soy products.
AB  - In human clinical intervention trials, soy product consumption reduced levels of
      total cholesterol and low-density lipoprotein cholesterol (LDL-C). In October
      1999, the US Food and Drug Administration approved a health claim for the
      relationship between consumption of soy protein and reduced risk of coronary
      heart disease. This article provides an overview of the cardiovascular effects of
      various soy products, including their effects on blood lipids, LDL-C oxidation,
      blood pressure, and vascular reactivity. Potential mechanisms of effect are
      discussed, emphasizing human clinical intervention trials. Soy consumption
      improves plasma lipids, although this effect appears to be more pronounced in
      individuals with elevated cholesterol. Soy and its associated isoflavones also
      reduce LDL oxidation and improve vascular reactivity.

PMID- 12597263
TI  - Herbal interactions with cardiovascular drugs.
AB  - The prevalence of herb-drug interactions has been exaggerated. Nonetheless, some
      herbs, including garlic, ginkgo, ginseng, and St John's wort, can have a
      significant influence on concurrently administered drugs. Herbal medicines may
      mimic, decrease, or increase the action of prescribed drugs. This can be
      especially important for drugs with narrow therapeutic windows and in sensitive
      patient populations such as older adults, the chronically ill, and those with
      compromised immune systems.

PMID- 12597264
TI  - Outcome measurement: evaluating evidence for managing patients with acute
      coronary syndromes.
AB  - Evidence-based practice has been proposed as a means to improve the quality of
      care and decrease unwarranted variability in practice, but evaluating clinical
      trial data as evidence for practice is made more difficult because practice
      changes rapidly. This article reviews current clinical trial data on the
      management of patients with acute coronary syndromes, but the same principles can
      be used when evaluating alternative medicines. Current evidence supports risk
      stratification, early treatment with glycoprotein IIb/IIIa inhibitors, and an
      early invasive strategy in patients who are at intermediate to high risk. In
      addition, cholesterol-lowering statins should be initiated early in the patient's
      hospitalization.

PMID- 12597265
TI  - The "t" word.

PMID- 12597266
TI  - The numbers game: the impact factor and all that jazz.

PMID- 12597267
TI  - An evolutionary perspective of sex-typed toy preferences: pink, blue, and the
      brain.
AB  - Large sex differences in children's toy preferences are attributed to gender
      group identification and social learning. The proposal outlined in this paper is
      that contemporary conceptual categories of "masculine" or "feminine" toys are
      also influenced by evolved perceptual categories of male-preferred and female
      preferred objects. Research on children exposed prenatally to atypical levels of
      androgens and research on typically developing infants suggest sex-dimorphic
      preferences exist for object features, such as movement or color/form. The
      evolution and neurobiology of mammalian visual processing--and recent findings on
      sex-dimorphic toy preferences in nonhuman primates--suggest further that an
      innate bias for processing object movement or color/form may contribute to
      behaviors with differential adaptive significance for males and females. In this
      way, preferences for objects such as toys may indicate a biological preparedness
      for a "masculine" or "feminine" gender role-one that develops more fully as early
      perceptual preferences are coupled with object experiences imposed by
      contemporary gender socialization.

PMID- 12597268
TI  - Same-sex sexuality and quality of life: findings from the Netherlands Mental
      Health Survey and Incidence Study.
AB  - This study assessed differences in quality of life (QL) between homosexual and
      heterosexual people and attempted to identify factors accounting for observed
      differences. Data were collected in a representative sample of the Dutch
      population aged 18-64 (N = 7,076). Classification as heterosexual or homosexual
      was based upon reported sexual behavior in the preceding year; 84.8% of the total
      sample (N = 5,998) could be classified: 2.8% of 2,878 sexually active men and
      1.4% of 3,120 sexually active women had had same-sex partners. Differences in QL
      were tested by analysis of variance. Factors accounting for observed differences
      in QL were identified by selecting determinants of QL on which homosexual and
      heterosexual people differed and including them with same-sex sexuality in
      multiple regression analyses. Homosexual men, but not women, differed from their
      heterosexual counterparts on various dimensions of QL. Lesser QL in homosexual
      men was predominantly explained by self-esteem and mastery. Same-sex sexuality
      contributed independently to some of the observed differences. Although same-sex
      sexuality is related to QL in men, the lack of association in women suggests that
      the link is mediated by other factors, indicating the need to explore in what
      respect the situation of homosexual men and women differs. This study also
      suggests the importance of finding out how lower sense of self-esteem and of
      mastery come about in homosexual men.

PMID- 12597269
TI  - Finger-length ratios in female monozygotic twins discordant for sexual
      orientation.
AB  - The second to fourth finger digit ratio (2D:4D ratio) is a sex-dimorphic
      characteristic in humans that may reflect relative levels of first trimester
      prenatal sex hormones. Low interdigital ratio has been associated with high
      levels of androgens. It has been reported in unrelated women that low 2D:4D ratio
      is associated with lesbian sexual orientation, but because of the nature of those
      samples, it was not possible to conclude whether lower ratio (and hypothetically,
      higher androgen levels) in lesbians are due to differences in genetics as opposed
      to differences in environment. To test the hypothesis that low 2D:4D in lesbians
      is due to differences in environment, interdigital ratio data were analyzed in a
      sample of female monozygotic (MZ) twins discordant for sexual orientation (1 twin
      was lesbian, the other was heterosexual; n = 7 pairs). A control group of female
      MZ twins concordant for sexual orientation (both twins were lesbian) was used as
      a comparison (n = 5 pairs). In the twins discordant for sexual orientation, the
      lesbian twins had significantly lower 2D:4D ratios on both the right and left
      hands than their heterosexual cotwins. There were no significant differences for
      either hand in the twins concordant for sexual orientation. Because MZ twins
      share virtually the same genes, differences in 2D:4D ratio suggest that low 2D:4D
      ratio is a result of differences in prenatal environment.

PMID- 12597270
TI  - Masculine somatotype and hirsuteness as determinants of sexual attractiveness to
      women.
AB  - Five questionnaire studies asked women to rate the attractiveness of outline
      drawings of male figures that varied in somatotype, body proportions, symmetry,
      and in distribution of trunk hair. In Study 1, back-posed figures of mesomorphic
      (muscular) somatotypes were rated as most attractive, followed by average,
      ectomorphic (slim), and endomorphic (heavily built) figures by both British and
      Sri Lankan women. In Study 2, computer morphing of somatotypes to produce an
      intergraded series resulted in a graded response in terms of perceived
      attractiveness which mirrored the findings of Study 1. In Study 3, back-posed
      figures were manipulated in order to change waist-to-hip ratios (WHR) and waist
      to-shoulder ratios (WSR). A WHR of 0.8-0.9 and a WSR of 0.6 were rated as most
      attractive and these effects were more pronounced when modeling mesomorphic
      figures. In Study 4, symmetric figures of a mesomorphic somatotype were rated as
      less attractive than a normal (asymmetric) version of the same man. Study 5
      showed that presence of trunk hair had a marked, positive effect upon women's
      ratings of attractiveness for both mesomorphic and endomorphic male figures.
      Women also judged figures with trunk hair as being older and they consistently
      rated endomorphic figures as being older than mesomorphs. These results are
      consistent with effects of sexual selection upon visual signals that advertise
      health, physical prowess, age, and underlying endocrine condition in the human
      male.

PMID- 12597271
TI  - Sexual initiation among adolescent girls and boys: trends and differentials in
      sub-Saharan Africa.
AB  - This paper examined trends in adolescent sexual initiation in sub-Saharan Africa,
      with emphasis on differentials in social determinants across gender and contexts.
      Data were drawn from Demographic and Health Surveys in 8 countries that had at
      least 2 surveys conducted approximately 5 years apart, each with distinct
      questionnaires for women and men of reproductive age regardless of marital
      status. The data were useful both for testing of substantive hypotheses about the
      correlates of adolescent sexual intercourse as well as for elaborating sexual
      health interventions in contexts of development. The main analytical tool was
      multivariate logistic models using a generalized estimating equation to consider
      the probability of a young man or young woman having first intercourse during
      adolescence. In some countries, observed declines over time in the proportion of
      adolescents having had sex were not statistically significant after taking into
      account changes in background characteristics, especially education. Important
      gender differentials were also found. While secondary schooling was associated
      with lower probability of early sex among girls in all countries, the
      relationship was often in the opposite direction among boys. Influences of other
      sociodemographic and community status variables were generally less important.

PMID- 12597272
TI  - Does quality of marital sex decline with duration?
AB  - Does the quality of marital sex increase or decrease with marital duration?
      Previous research assumes that it decreases; however, there is no empirical
      evidence of declining quality of marital sex with duration in the literature.
      This study theoretically and empirically examines how the quality of marital sex
      changes with duration. Theoretically, two effects may influence the change of
      quality of marital sex: the effect of diminishing marginal utility (the marginal
      utility of consuming a good or service diminishes as the consumption of that good
      or service increases) and the effect of the investment in the marriage-specific
      human capital (including the "partner specific" skills that enhance the enjoyment
      of marital sex and the knowledge about the spouse's sexual preferences, desires,
      and habits). The quality of marital sex could either increase or decrease
      depending on which effect is dominant. The multivariate analysis of the National
      Health and Social Life Survey data shows that marital duration has a small and
      negative effect on the quality of marital sex. The gender difference in the
      quality of marital sex is discussed.

PMID- 12597273
TI  - The meaning of heterosexual intercourse among women with female orgasmic
      disorder.
AB  - The present studies attempt to portray the unique profile of the subjective
      meaning of heterosexual intercourse in women with Female Orgasmic Disorder (FOD).
      In Studies 1 and 2, the Meaning of Heterosexual Intercourse Scale for Women
      (MHISW) was developed. In Study 3, the MHISW was administered to 36 self-referred
      women with FOD, 26 nonreferred women with FOD, and 36 sexually functional women.
      Findings indicated that self-referred women with FOD scored higher than both
      nonreferred women with FOD and sexually functional women on factors with an
      aversive nature related to feelings of alienation and anxieties, whereas
      nonreferred women with FOD scored higher on few of these aversive factors in
      comparison with sexually functional women. Interestingly, sexually functional
      women scored higher than women with FOD on only a limited number of factors with
      relational and instrumental positive connotations. The contribution of the
      findings to the understanding FOD was discussed.

PMID- 12597274
TI  - Alexithymia is inversely associated with women's frequency of vaginal
      intercourse.
AB  - The study examined the relation between frequency of penile-vaginal intercourse
      (FSI; contrasted with other sexual behavior) and alexithymia (difficulty
      recognizing, identifying, and communicating emotions, reduced fantasy capacity,
      and an externally oriented cognitive style). To minimize response bias, persons
      scoring above the 86th percentile on the Eysenck Personality Inventory Lie scale
      were excluded. Participants (54 female and 39 male healthy young adults)
      completed the German version of the Toronto Alexithymia Scale (TAS-20), and
      provided both recall and diary measures of FSI, partner sex without vaginal
      intercourse, and masturbation. For women, TAS-20 scores were inversely associated
      with both recall and diary measures of FSI but not other sexual behavior. For
      men, TAS-20 scores were unrelated to all sexual behavior measures. Thus, for
      normal women but not men, alexithymia was specifically associated with lower FSI.
      Results are discussed in terms of the unique nature of penile-vaginal
      intercourse, emotional integration and sexuality, and both less alexithymia and
      greater FSI being associated with indices of better physical and psychological
      health.

PMID- 12597275
TI  - Complete genomic sequence of nitrogen-fixing symbiotic bacterium Bradyrhizobium
      japonicum USDA110.
AB  - The complete nucleotide sequence of the genome of a symbiotic bacterium
      Bradyrhizobium japonicum USDA110 was determined. The genome of B. japonicum was a
      single circular chromosome 9,105,828 bp in length with an average GC content of
      64.1%. No plasmid was detected. The chromosome comprises 8317 potential protein
      coding genes, one set of rRNA genes and 50 tRNA genes. Fifty-two percent of the
      potential protein genes showed sequence similarity to genes of known function and
      30% to hypothetical genes. The remaining 18% had no apparent similarity to
      reported genes. Thirty-four percent of the B. japonicum genes showed significant
      sequence similarity to those of both Mesorhizobium loti and Sinorhizobium
      meliloti, while 23% were unique to this species. A presumptive symbiosis island
      681 kb in length, which includes a 410-kb symbiotic region previously reported by
      Gottfert et al., was identified. Six hundred fifty-five putative protein-coding
      genes were assigned in this region, and the functions of 301 genes, including
      those related to symbiotic nitrogen fixation and DNA transmission, were deduced.
      A total of 167 genes for transposases/104 copies of insertion sequences were
      identified in the genome. It was remarkable that 100 out of 167 transposase genes
      are located in the presumptive symbiotic island. DNA segments of 4 to 97 kb
      inserted into tRNA genes were found at 14 locations in the genome, which
      generates partial duplication of the target tRNA genes. These observations
      suggest plasticity of the B. japonicum genome, which is probably due to complex
      genome rearrangements such as horizontal transfer and insertion of various DNA
      elements, and to homologous recombination.

PMID- 12597276
TI  - Development and mapping of 2240 new SSR markers for rice (Oryza sativa L.).
AB  - A total of 2414 new di-, tri- and tetra-nucleotide non-redundant SSR primer
      pairs, representing 2240 unique marker loci, have been developed and
      experimentally validated for rice (Oryza sativa L.). Duplicate primer pairs are
      reported for 7% (174) of the loci. The majority (92%) of primer pairs were
      developed in regions flanking perfect repeats > or = 24 bp in length. Using
      electronic PCR (e-PCR) to align primer pairs against 3284 publicly sequenced rice
      BAC and PAC clones (representing about 83% of the total rice genome), 65% of the
      SSR markers hit a BAC or PAC clone containing at least one genetically mapped
      marker and could be mapped by proxy. Additional information based on genetic
      mapping and "nearest marker" information provided the basis for locating a total
      of 1825 (81%) of the newly designed markers along rice chromosomes. Fifty-six SSR
      markers (2.8%) hit BAC clones on two or more different chromosomes and appeared
      to be multiple copy. The largest proportion of SSRs in this data set correspond
      to poly(GA) motifs (36%), followed by poly(AT) (15%) and poly(CCG) (8%) motifs.
      AT-rich microsatellites had the longest average repeat tracts, while GC-rich
      motifs were the shortest. In combination with the pool of 500 previously mapped
      SSR markers, this release makes available a total of 2740 experimentally
      confirmed SSR markers for rice, or approximately one SSR every 157 kb.

PMID- 12597277
TI  - Abundant poly(A)-bearing RNAs that lack open reading frames in
      Schizosaccharomyces pombe.
AB  - We report here that 6.9% (68/987) of randomly selected cDNA clones from an S.
      pombe cDNA library lack apparently long open reading frames which we denote prl.
      One of them, prl1, was examined further because multiple bands were observed when
      it was used as a probe in northern blot analysis. These multiple bands appear to
      be derived from overlapping transcripts from both DNA strands, including non
      coding RNAs and antisense RNAs in addition to mRNA. Such mechanisms may increase
      the transcriptional variation in S. pombe cells.

PMID- 12597278
TI  - Isolation of actin-encoding cDNAs from symbiotic corals.
AB  - A cDNA (named LGfact) encoding actin was identified in planular larvae of the
      scleractinian coral Galaxea fascicularis, using the reverse transcription
      polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE)
      techniques. RNA from the adult coral that was inhabited by symbiotic dinophytes
      was subjected to a similar RT-PCR, and a cDNA fragment, named AGfact-p, was found
      to encode an actin form distinct from LGfact. In an expression study, LGfact
      transcripts were present at similar levels in asymbiotic larvae and symbiotic
      adults, indicating that LGfact was expressed by the host. On the other hand, the
      expression of AGfact-p was detected in adults but not in larvae. Partial cDNA
      sequences of orthologues of LGfact and AGfact-p were detected in another
      scleractinian coral, Favites chinensis. A sequence identical to a part of AFcact
      p (an AGfact-p orthologue) was amplified from the genomic DNA extracted from
      asymbiotic larvae of F. chinensis, strongly suggesting that AFcact-p was a coral
      actin cDNA. Thus, we presume that A Gfact-p encodes an adult-specific form of
      actin in the host. A partial actin-encoding cDNA sequence (named Syact-p)
      obtained from Symbiodinium sp. did not exhibit high levels of similarity to the
      coral actin sequences.

PMID- 12597279
TI  - Complete genomic sequence of nitrogen-fixing symbiotic bacterium Bradyrhizobium
      japonicum USDA110 (supplement).

PMID- 12597280
TI  - Development and mapping of 2240 new SSR markers for rice (Oryza sativa L.)
      (supplement).

PMID- 12597281
TI  - Management of bilateral arytenoid cartilage fixation versus recurrent laryngeal
      nerve paralysis.
AB  - Bilateral arytenoid cartilage fixation (ACF) closely resembles vocal cord
      immobility due to recurrent laryngeal nerve paralysis (RLNP). This study sought
      to determine the etiologic differences between these two entities and to derive
      conclusions about treatment. The charts of 218 consecutive adult patients with
      immobility of both vocal cords requiring surgery for airway restoration were
      reviewed. The results of laryngeal electromyography and laryngotracheoscopy were
      used to distinguish ACF from RLNP. In 186 patients (85.3%), RLNP was identified.
      Of these, 154 paralyses (82.8%) were caused by surgical interventions, 5 (2.7%)
      were caused by previous intubation, 16 (8.6%) were caused by various
      malignancies, and 7 (3.8%) were neurogenic. In 4 patients (2.2%), the cause
      remained unclear. We identified ACF in 32 patients. The etiologic factors
      included previous long-term intubation in 22 patients (68.8%), short-term
      intubation in 3 patients (9.4%), Wegener's granulomatosis in 3 patients (9.4%),
      rheumatoid arthritis in 2 patients (6.3%), previous laryngeal surgery in 1
      patient (3.1%), and caustic ingestion in 1 patient (3.1%). Additional second-site
      airway stenosis was found in 10 of the RLNP patients (5.4%) and in 15 of the ACF
      patients (46.9%). All RLNP patients had endoscopic surgery without temporary
      tracheotomy. Eighteen ACF patients required open surgery, and 4 were managed
      endoscopically but required temporary tracheotomy. The etiologic factors were
      significantly different for the two entities under study. Additional sites of
      stenosis were more frequent in ACF patients. Stenosis due to RLNP could be
      managed endoscopically without preliminary tracheotomy, while ACF frequently
      required open surgery and temporary tracheotomy.

PMID- 12597282
TI  - Monitoring of laryngopharyngeal reflux: influence of meals and beverages.
AB  - Ambulatory 24-hour double-probe pH monitoring seems to be the best test to
      measure reflux. Artifacts caused by intake of acid foods and beverages have to be
      excluded, necessitating a time-consuming manual review of the 24-hour data.
      Dietary restrictions used to bypass these artifacts would interfere with the
      normal daily life situation. Therefore, the influence of food and beverages
      ingested during the monitoring period was studied. Data from 252 patients who
      underwent double-probe pH monitoring were analyzed, first by visual inspection of
      the 24-hour tracing and second by leaving out the intake periods. As to the
      registration of gastroesophageal reflux, the inclusion or omission of meals and
      beverages hardly influenced the data. However, the registration of
      laryngopharyngeal reflux was severely biased by intake of food and beverages and
      other artifacts. Leaving out meals and beverages did not correct for all
      artifacts. Therefore, we recommend review of each laryngopharyngeal pH drop.

PMID- 12597283
TI  - Compact endoscopy of the larynx.
AB  - In order to improve preoperative assessment of suspected precancerous and
      cancerous lesions of the larynx, we examined 83 patients by compact endoscopy
      (combination of autofluorescence and contact endoscopy) during microlaryngoscopy
      in a pilot study. The intraoperative findings were related to histopathologic
      examination. Cancerous laryngeal mucosa was illuminated during autofluorescence
      endoscopy by use of blue filtered light (D-light AF system) for optical
      demarcation of the lesion. After staining the mucosa with methylene blue (1%), we
      performed contact endoscopy. During autofluorescence examination of the
      endolaryngeal mucosa, the appearance of precancerous and cancerous lesions varied
      between opaque light areas and darker reddish areas. By contact endoscopy, it was
      possible to observe the cells, nuclei, and cytoplasm, as well as different
      degrees of abnormality. Histopathologic findings of 83 patients revealed
      laryngeal dysplasia (grade I in 29 patients, grade II in 15, and grade III or
      carcinoma in situ in 8) and laryngeal cancer (31 patients). In 73 cases (88%),
      the findings of compact endoscopy corresponded to those of histopathology. In 5
      cases, epithelial lesions were overestimated because of inflammation and
      scarring, and 5 cases were underestimated because of hyperkeratotic thickening of
      the mucosa covering basal epithelial layers with focal dysplasia of grades II and
      III, carcinoma in situ, and microinvasive cancer. We conclude that compact
      endoscopy enables the laryngologist to assess laryngeal cancer and its preceding
      lesions more accurately during microlaryngoscopy.

PMID- 12597284
TI  - Modeling measured glottal volume velocity waveforms.
AB  - The source-filter theory of speech production describes a glottal energy source
      (volume velocity waveform) that is filtered by the vocal tract and radiates from
      the mouth as phonation. The characteristics of the volume velocity waveform, the
      source that drives phonation, have been estimated, but never directly measured at
      the glottis. To accomplish this measurement, constant temperature anemometer
      probes were used in an in vivo canine constant pressure model of phonation. A 3
      probe array was positioned supraglottically, and an endoscopic camera was
      positioned subglottically. Simultaneous recordings of airflow velocity (using
      anemometry) and glottal area (using stroboscopy) were made in 3 animals. Glottal
      airflow velocities and areas were combined to produce direct measurements of
      glottal volume velocity waveforms. The anterior and middle parts of the glottis
      contributed significantly to the volume velocity waveform, with less contribution
      from the posterior part of the glottis. The measured volume velocity waveforms
      were successfully fitted to a well-known laryngeal airflow model. A noninvasive
      measured volume velocity waveform holds promise for future clinical use.

PMID- 12597285
TI  - Expression of epidermal growth factor receptor and its ligands in chronic
      sinusitis.
AB  - The epidermal growth factor receptor (EGF-R) system plays a crucial role in mucus
      production in vitro and in rats. However, the role of the EGF-R system in humans
      is not known. We compared the localization of EGF-R and its ligands (epidermal
      growth factor and transforming growth factor alpha) in the epithelia of sinuses
      with chronic sinusitis and in those of healthy controls. Immunohistochemical
      techniques were employed to identify the presence of EGF-R and its ligands in the
      sinus mucosa. We found EGF-R in goblet cells, basal cells, and submucosal gland
      cells, but not in ciliated cells. Immunoreactivity for both epidermal growth
      factor and transforming growth factor alpha was found in the epithelial cells and
      inflammatory cells and in some submucosal gland cells. There was stronger
      staining of EGF-R and its ligand proteins in chronic sinusitis specimens than in
      controls. The interrelated localization of EGF-R and its ligands suggests a role
      in mucus production in the epithelium of the sinus mucosa.

PMID- 12597286
TI  - Comparison of virtual and conventional endoscopy of nose and paranasal sinuses.
AB  - We compared computed tomographic virtual rhinosinus endoscopy (VRS) and
      conventional fiberoptic endoscopy (FE) for the detection of inflammatory
      obstructive rhinosinusal disease. We recruited 158 patients; 100 (group A) had
      inflammatory-obstructive rhinosinus disease, and 58 (group B) had a history of
      rhinosinus surgery. All patients underwent VRS within 2 to 6 hours of FE, and VRS
      was able to demonstrate the anatomic details of the nasal fossa and rhinopharynx
      with a high correspondence to FE. A satisfying representation of anatomic detail
      was found in both groups A and B. The VRS was able to visualize invasiveness of
      the endosinusal cavities, which was not accessible to FE. The VRS is a fast,
      relatively easy, and noninvasive technique that could be integrated into FE or
      used as an alternative when FE is unfeasible. Because of the ability to explore
      the sinus cavity, we suggest that virtual rhinosinusoscopy should be considered
      as the appropriate term, instead of virtual rhinoscopy.

PMID- 12597287
TI  - Physiologic effects of open and closed tracheostomy tubes on the pharyngeal
      swallow.
AB  - Studies linking aspiration and dysphagia to an open tracheostomy tube exemplify
      the possibility that the larynx may have an influence on oropharyngeal swallow
      function. Experiments addressing the effects of tracheostomy tube occlusion
      during the swallow have looked at the presence and severity of aspiration, but
      few have included measurements that capture the changes in swallowing physiology.
      Also, hypotheses for the importance of near-normal subglottic air pressure during
      the swallow have not been offered to date. As such, the aim of this study was to
      compare the depth of laryngeal penetration, bolus speed, and duration of
      pharyngeal muscle contraction during the swallow in individuals with tracheostomy
      tubes while their tubes were open and closed. The results of this series of
      experiments indicate that within the same tracheostomized patient, pharyngeal
      swallowing physiology is measurably different in the absence of subglottic air
      pressure (open tube) as compared to the closed tube condition.

PMID- 12597288
TI  - Congenital conductive hearing loss in dyschondrosteosis.
AB  - Conductive hearing loss was detected in a boy with a previous diagnosis of
      dyschondrosteosis. Dyschondrosteosis is a rare inherited condition characterized
      by mesomelic dwarfism and Madelung's deformity. The syndrome can be caused by
      mutations in the SHOX gene, and in that case, the pattern of inheritance is
      pseudoautosomal dominant. Indeed, SHOX mutation analysis in our patient revealed
      a deletion. The combination of dyschondrosteosis and conductive hearing loss has
      been reported in 2 previous cases. In our patient, exploratory tympanotomy
      revealed ankylosis of the stapes and a malformed incus. A substantial gain in
      hearing threshold was obtained by a stapedectomy in combination with a
      malleovestibulopexy.

PMID- 12597289
TI  - From the roots of rhinology: the reconstruction of nasal injuries by Hippocrates.
AB  - The goal of this report is to describe the therapeutic methods and surgical
      techniques used by Hippocrates (5th century BC) in the treatment of nasal
      injuries. We studied the original Greek texts of the (generally considered
      genuine) Hippocratic book Mochlicon and, especially, the analytical On Joints. We
      identified the treatments and techniques applied to the restoration of injured
      noses. We found that Hippocrates classified nasal injuries, from simple
      contusions of soft tissues to complicated fractures. Hippocrates provided
      detailed instructions for each case, from poultice application and bandaging to
      reconstruction and reshaping of the nasal bones in cases of fractures and
      deviation. Hippocrates' texts reflect the interest of the classical period in
      nasal injuries, a common enough accident in athletics. Hippocratic conservative
      and surgical management for each form of injury was adopted by later physicians
      and influenced European medicine.

PMID- 12597290
TI  - Effects of nimodipine on quinine ototoxicity.
AB  - The compound action potential (CAP) in response to a click train stimulus was
      recorded at the round window of guinea pigs. Administration of quinine
      hydrochloride (200 mg/kg) significantly elevated the CAP thresholds by 5 to 25 dB
      (p < .05), and the CAP waveform elicited by the click train stimulus was
      abnormal. The amplitude of the CAP elicited by the second click was bigger than
      that elicited by the first click. These changes may be caused by an abnormally
      broadened N1 response to the first click in the click train. In contrast, CAP
      waveforms elicited by the second and subsequent clicks appeared normal. After
      administration of nimodipine (2 mg/kg), the CAP thresholds and waveforms elicited
      by the click train stimulus were unchanged. Simultaneous administration of both
      quinine (200 mg/kg) and nimodipine (2 mg/kg) resulted in the same
      electrophysiological changes as those induced by quinine alone. These results
      suggest that nimodipine prevents neither the deterioration in the CAP nor the
      abnormal properties in the response to a click train stimulus.

PMID- 12597291
TI  - Cytolysis of eosinophils in nasal secretions.
AB  - It is still unknown how eosinophils degranulate in nasal mucus. Currently,
      cytolysis is being reevaluated as the mode of degranulation of eosinophils in
      allergic nasal mucosa. To examine whether eosinophils migrating to the nasal
      mucus degranulate by cytolysis, we sampled nasal mucus from 9 patients with nasal
      allergy and observed it under electron and light microscopes. Both intact and
      necrotic eosinophils were observed in the nasal mucus. Although the total
      eosinophil count in the nasal mucus was not correlated with the frequency of
      sneezes, there was a significant correlation (p = .0025) between the rate of
      eosinophil lysis and the frequency of sneezes. Whereas extracellular release of
      eosinophil peroxidase was not detected from the eosinophils with intact cell
      membranes, large quantities of eosinophil peroxidase were found outside the
      eosinophils with injured cell membranes. We concluded that eosinophils migrating
      to the nasal mucus degranulate mainly by cytolysis, and that granular proteins
      released from the necrotic eosinophils into the nasal mucus are one of the
      important factors causing hypersensitivity in the nasal mucosa.

PMID- 12597292
TI  - Vocal outcome after endoscopic cordectomies for Tis and T1 glottic carcinomas.
AB  - A cohort of 101 patients with previously untreated glottic cancer (15 Tis, 66
      T1a, and 20 T1b) who underwent endoscopic CO2 laser excision between January 1995
      and December 1997 was prospectively analyzed. The depth and extension of the
      excision were graded according to the European Laryngological Society
      Classification including 5 types of cordectomy. All patients were subsequently
      examined every 2 months for a period ranging from 30 to 66 months (mean, 48
      months). The rates of 5-year overall survival, disease-free survival, ultimate
      local control with laser alone, and laryngeal preservation were 85%, 87%, 93%,
      and 95%, respectively. Sixty-nine patients underwent, at least 1 year after
      surgery, videolaryngostroboscopy combined with perceptual and objective
      evaluation of the voice, and spirometry. Acoustic parameters were compared with
      those obtained in a matched control group by Kruskal-Wallis test. No
      statistically significant difference was found (p > .05) between patients
      submitted to subepithelial (type I) and subligamental (type II) cordectomies and
      controls.

PMID- 12597293
TI  - Medialization laryngoplasty with Gore-Tex for voice restoration secondary to
      glottal incompetence: indications and observations.
AB  - Gore-Tex has been used as an effective implant for medialization laryngoplasty in
      the management of paralytic dysphonia; however, reporting of large patient
      cohorts has been limited. Furthermore, the use of Gore-Tex in the treatment of
      glottal incompetence secondary to soft tissue defects has not yet been described.
      Finally, a number of the procedural nuances of using Gore-Tex have not been
      elucidated. A prospective investigation was done on 142 patients who underwent
      152 Gore-Tex medialization laryngoplasties in 183 vocal folds from December 1997
      to March 2002. The primary diagnoses prompting the 152 procedures were paralysis
      in 94, paresis in 18, cancer reconstruction in 14, sulcus vocalis in 6, atrophy
      in 3, trauma defect in 5, arytenoid dislocation in 3, bilateral paralysis in 3,
      bilateral paresis in 1, parkinsonism in 4, and neurologic aerodynamic
      dissociation in 1. One patient who underwent reconstruction of a complex cancer
      defect required endoscopic removal of the Gore-Tex because of persistent
      granulation. Clinical observations reveal that Gore-Tex is a versatile implant
      that is ideally suited for phonosurgical reconstruction of aerodynamic glottal
      incompetence secondary to a variety of causes. Gore-Tex was especially useful for
      medialization of complex anatomic soft tissue defects such as those resulting
      from cancer resection, trauma, atrophy, and sulcus vocalis. There was superior
      ease in handling, placement, and in vivo adjustability.

PMID- 12597294
TI  - Facial nerve schwannoma.
AB  - Facial nerve schwannomas are clinically challenging tumors. This is a case study
      of a young woman with an extensive facial nerve schwannoma. The clinical
      presentation, radiographic diagnosis, pathological confirmation, and treatment
      options for this relatively rare tumor are discussed.

PMID- 12597295
TI  - Pseudoaneurysm of the superior thyroid artery following radiotherapy for
      hypopharyngeal cancer.
AB  - Carotid blowout syndrome is a devastating complication in head and neck cancer
      patients that is attributed to multifocal, iatrogenic arteriopathy following
      radical surgery or irradiation. Pseudoaneurysms of the carotid artery or its
      small branches are the most frequently recognized of these vascular lesions. We
      present a case of a ruptured pseudoaneurysm of the superior thyroid artery that
      was probably induced by radiation vasculopathy and was successfully treated by
      embolization therapy.

PMID- 12597296
TI  - Natural history of sigmoid sinus thrombosis.
AB  - To demonstrate the evolution of sigmoid sinus thrombosis, we performed a
      prospective observational study on a 6-year-old girl who presented with
      mastoiditis, epidural abscess, and occipital osteomyelitis from multiple drug
      resistant Streptococcus pneumoniae. She underwent mastoidectomy and partial
      occipital craniectomy. This procedure produced a window in the occipital bone
      that allowed serial ultrasonography of the sigmoid sinus during medical
      treatment. Computed tomography was performed, followed by weekly Doppler
      ultrasonography used to monitor resolution of sigmoid sinus thrombosis. The
      natural history of a treated episode of sigmoid sinus thrombosis was illustrated.
      Venous occlusion resolved over a 4- to 6-week period without surgical drainage or
      venous anticoagulants. Collateral flow, reversal of normal venous flow, and
      ultimate return to normal venous transport characterized the period of
      resolution. We conclude that an occluded sigmoid sinus from mastoiditis can
      naturally recanalize. Aberrant venous flow can be demonstrated during the period
      of resolution. This case supports a conservative approach to management of the
      occluded sinus and suggests that 4 to 6 weeks of antibiotic therapy after removal
      of perisinus infection is sufficient for cure.

PMID- 12597297
TI  - Bilateral bifid inferior turbinates.

PMID- 12597298
TI  - Glycogenosis type VII (Tarui's disease): diagnostic considerations and late
      sequelae.

PMID- 12597299
TI  - If the shoe fits... Leading into the second century at Wake Forest University
      School of Medicine.

PMID- 12597300
TI  - Private southern institution serves as model for minority medical education.

PMID- 12597301
TI  - Wake Forest University international medicine.

PMID- 12597302
TI  - Effect of spirituality on successful recovery from spinal surgery.
AB  - BACKGROUND: Many patients believe prayer helps them recover from health problems.
      Benefits of spirituality on other illnesses and surgical procedures have been
      reported. It is unknown whether patients with strong spiritual beliefs have a
      greater propensity for successful recovery from spinal surgery. METHODS: In this
      study, 188 patients having spinal surgery completed the visual analog pain scale
      (VAS) and the Oswestry functional capacity questionnaire (OSW) before and after
      operation, and the scores were used to assess surgical outcome. Degree of
      spirituality was assessed using the INSPIRIT survey. RESULTS: Paired t test
      revealed significant improvements in both the VAS and OSW outcome measures.
      Linear regression analysis revealed no correlation between change in either VAS
      or OSW. CONCLUSIONS: These results suggest that recovery from spinal surgery may
      be more dependent on proper patient selection and surgical technique than on
      patient spiritual beliefs.

PMID- 12597303
TI  - Medical spirituality: defining domains and boundaries.
AB  - The rapidly accumulating evidence that personal spirituality has important
      influences on health care outcomes is somewhat difficult to integrate into daily
      medical practice, in part because accepting it requires adjustments to the
      standard biomedical worldview, and in part because it challenges established
      boundaries between chaplaincy and evidence-based medicine. We propose that the
      recognition of medical spirituality as a distinct, interdisciplinary field of
      interest, with its own well-developed body of clinical evidence, clinical skill,
      clinical ethics, and with well-defined clinical boundaries, can help overcome
      much of the current confusion about how to integrate the new knowledge, and help
      pre-empt developing "turf" issues. The new field would contribute significantly
      to reframing the worldview of healing practice, consistent with the evidence
      based approach.

PMID- 12597304
TI  - Evidence-based medicine in internal medicine clerkships: a national survey.
AB  - BACKGROUND: Although evidence-based medicine (EBM) has become widely accepted,
      the extent of its implementation during clinical clerkships is not well
      described. This study was done to characterize the implementation of formal EBM
      curricula in internal medicine clerkships. METHODS: In 1999, the Clerkship
      Directors in Internal Medicine surveyed its membership from 123 medical schools.
      The EBM section of the four-part survey addressed implementation, teaching and
      evaluation techniques, and barriers to implementing EBM. RESULTS: Survey response
      was 89%. Of 109 respondents, 38.5% reported having a formal EBM curriculum at
      some time during the third year and/or fourth year. Variability existed in
      curricular materials and evaluation tools used. The most common barriers to
      implementing EBM were lack of time and inadequately trained faculty. CONCLUSIONS:
      Evidence-based medicine has been formally incorporated into relatively few
      internal medicine clerkships. Faculty development programs in conjunction with
      innovative teaching methods may help overcome these barriers.

PMID- 12597305
TI  - Health care providers' duty to warn.
AB  - Since the fifth century BC, physicians have sworn to uphold the Hippocratic Oath
      that includes the statement, "Whatever, in connection with my professional
      service, ... I see or hear, in the life of men, which ought not be spoken abroad,
      I will not divulge, as reckoning that all such should be kept secret." However,
      health care and provider responsibility have evolved so as to make this more
      difficult for physicians to uphold. We discuss growing issues surrounding health
      care providers' ability to maintain patient confidentiality and to perform their
      responsibilities, and their "duty to warn and/or protect" third parties.
      Particular Tennessee cases heard on appeal show a change in the health care
      enviromnent relative to provider liability to third parties.

PMID- 12597306
TI  - Familial Mediterranean fever.
AB  - BACKGROUND: The pathogenesis of familial Mediterranean fever (FMF) is unknown,
      and since no specific laboratory test is yet available, the diagnosis of FMF
      remains clinical. The purpose of this study was to review clinical
      characteristics of patients with FMF. METHODS: A total of 96 patients with FMF
      were evaluated either retrospectively (for those diagnosed before 1997) or
      prospectively (for those after 1997). RESULTS: The records of 54 male and 42
      female patients were studied. All patients were Turks. Family history was
      positive in 72 patients (75%). Involved site was peritoneum in 73 (76%), joints
      in 65 (68%), and pleura in 16 (17%). Febrile myalgia occurred in 3 patients (3%),
      and erysipelas-like skin lesions were observed in 2 (2%). Fever was found in 93
      patients (97%). Reactive systemic (AA) amyloidosis was found in 38 patients
      (40%). CONCLUSIONS: Diagnostic problems persist despite increased understanding
      of the pathogenesis of FMF. Amyloidosis, the most important complication of FMF,
      is often seen.

PMID- 12597307
TI  - Surgical treatment of parotid tumors in the general community hospital.
AB  - We reviewed 51 consecutive parotidectomies done at a general community hospital
      and gathered data on age and sex of the patients, length of stay in the hospital,
      perioperative outcome, complications, and surgical pathology. Statistical method
      included logistic regression and ANOVA to determine relationship and dependence
      of the variables. There were 24 male and 27 female patients. Thirty-six (70.6%)
      of the parotid tumors were benign. There were no major complications. Treatment
      of parotid tumors in the community hospital is feasible and safe if basic
      guidelines are implemented. The epidemiology of parotid tumors in the relatively
      smaller hospital should resemble that reported in the literature. Our data
      suggest that parotid malignancy may occur more frequently in elderly men and that
      length of stay in the hospital may be longer for patients having surgery for
      malignant than for benign parotid tumors.

PMID- 12597308
TI  - Bacterial contamination of paper currency.
AB  - One-dollar bills were collected from the general community in western Ohio to
      survey for bacterial contamination. Pathogenic or potentially pathogenic
      organisms were isolated from 94% of the bills. These results suggest a high rate
      of bacterial contamination of one-dollar bills.

PMID- 12597309
TI  - Characteristics and outcomes of patients with Goodpasture's syndrome.
AB  - BACKGROUND: Goodpasture's syndrome is a rare disorder characterized by pulmonary
      hemorrhage, glomerulonephritis, and antiglomerular basement membrane antibodies.
      METHODS: Case reports of Goodpasture's syndrome between 1993 and 2000 were
      identified using MEDLINE. Each case was reviewed for clinical manifestations,
      laboratory features, pathophysiology, treatment options, and outcomes. RESULTS:
      Eighty-five cases of Goodpasture's syndrome were reported in the English language
      literature. The mean age of patients in this review was 44 years. Most patients
      had multiple risk factors. Smoking was strongly associated with pulmonary
      hemorrhage. Most patients presented with hemoptysis and crackles. More than 90%
      had antiglomerular basement membrane antibodies, and 80% had crescenteric
      glomerulonephritis on renal biopsy. CONCLUSION: Most patients were treated with
      immunosuppression and plasma exchange and were alive at follow-up. Patients with
      either pulmonary or renal signs and symptoms should be evaluated for
      Goodpasture's syndrome, since early diagnosis allows prompt treatment and
      improved outcome.

PMID- 12597310
TI  - Risk factors for gallstone disease in a hospital-based study.
AB  - BACKGROUND: We investigated the risk factors for gallstone disease in Taiwan.
      METHODS: We retrospectively analyzed medical records of patients receiving
      periodic health examination at China Medical College Hospital from January to
      December 2000. A detailed history, physical examination, biochemical
      measurements, and abdominal ultrasonography were done. RESULTS: The 602 men
      (58.6%) and 426 women (41.4%) had a mean age of 49.2 +/- 12.8 years (range, 18 to
      87). The prevalence of gallstone disease was 7.8% in women and 6.5% in men. After
      controlling for other covariates, multivariate logistic regression analysis
      showed that with a reference group aged less than 40 years as a comparison, both
      men and women aged 65 or older were more likely to have gallstone disease.
      CONCLUSIONS: Age in both sexes and hepatitis C virus infection in women were
      found to be risk factors for gallstone disease in our study population.

PMID- 12597311
TI  - Work, social, and family disabilities of subjects with anxiety and depression.
AB  - BACKGROUND: Functional impairment scales are increasingly used to evaluate
      subjects with a variety of mental disorders. METHODS: We evaluated the work,
      social, and family disabilities of 228 subjects with 6 common anxiety and
      depressive disorders, as assessed by the Sheehan Disability Scale (major
      depression, panic disorder, generalized anxiety disorder, social phobia,
      obsessive-compulsive disorder, and mixed anxiety and depression). RESULTS:
      Subjects in the 6 diagnostic groups had significantly higher work, social, and
      family disability scores than control subjects, with the exception of the social
      phobia and panic disorder subjects' scores for family disability. Those with
      depressive disorders tended to have significantly higher family disability scores
      than the anxiety disorder subjects. CONCLUSION: Subjects with both anxiety and
      depressive disorders from primary care clinics and from chronic psychiatric and
      medical populations need further evaluation and treatment of the disabilities to
      decrease the personal, family, and economic burdens of these disorders.

PMID- 12597312
TI  - Systematic review of clinical trials examining the effects of religion on health.
AB  - Using MEDLINE, (limited to the English language and the reference lists of the
      randomized controlled trials (RCTs), we assessed the impact of religion on health
      outcomes via systematic, critical review of the medical literature. All RCTs
      published from 1966 to 1999 and all non-RCTs published from 1996 to 1999 that
      assessed a relationship between religion and measurable health outcome were
      examined. We excluded studies dealing with non-religious spirituality, ethical
      issues, coping, well-being, or life satisfaction. We used the Canadian Medical
      Association Journal's guidelines for systematic review of the medical literature
      to evaluate each manuscript. Nine RCTs and 25 non-RCTs met these
      inclusion/exclusion criteria. Randomized controlled trials showed that
      intercessory prayer may improvehealth outcomes in patients admitted to a coronary
      care unit but showed no effect on alcohol abuse. Islamic-based psychotherapy
      speeds recovery from anxiety and depression in Muslims. Non-RCTs indicate that
      religious activities appear to benefit blood pressure, immune function,
      depression, and mortality.

PMID- 12597313
TI  - Neurologic and cardiac progression of glycogenosis type VII over an eight-year
      period.
AB  - Little is known about the progression of phosphofructokinase deficiency
      (glycogenosis type VII, Tarui's disease). We describe a 66-year-old woman who had
      this disease diagnosed in 1997. Initial manifestations had included simple
      partial seizures since 1977, anginal chest pain since 1982, and muscle cramps
      since 1983. To prevent recurrent myocardial infarction, anticoagulation therapy
      with phenprocumon was initiated. Cardiac involvement progressed over an 8-year
      period, manifesting as low-voltage electrocardiogram (ECG), ectopic
      supraventricular tachycardia, thickened mitral valve, mitral valve insufficiency,
      enlarged left atrium, left ventricular hypertrophy, and diastolic dysfunction.
      Progression of neurologic involvement manifested as complex partial seizures,
      double vision, reduced tendon reflexes, central facial palsy,
      bradydiadochokinesia, and distal weakness of the upper extremities.
      Discontinuance of oral anticoagulation after 19 years, initiation of enalapril
      therapy, and administration of carbamazepine markedly improved the patient's
      condition.

PMID- 12597314
TI  - Microscopic polyangiitis in a pregnant woman.
AB  - Patients who have vasculitis in pregnancy generally have a grim prognosis.
      Vasculitis occurring during pregnancy may have a more aggressive course and
      require more aggressive treatment than vasculitis occurring at other times. A 29
      year-old woman who presented in the 16th week of her third intrauterine pregnancy
      was diagnosed as having active microscopic polyangiitis. Therapy consisting of
      high-dose methylprednisolone and cyclophosphamide was instituted, but the patient
      died of pulmonary infection due to methicillin-resistant Staphylococcus aureus.

PMID- 12597315
TI  - Celecoxib-induced upper gastrointestinal hemorrhage and ulceration.
AB  - COX-2 inhibitors are a new class of nonsteroidal anti-inflammatory drugs with a
      reported benefit of less gastric and duodenal ulceration and hemorrhage. We
      describe a 67-year-old man taking a higher than usual dose of celecoxib
      (Celebrex) for osteoarthritis with resultant gastric erosions, ulceration, and a
      significant gastrointestinal (GI) hemorrhage.

PMID- 12597316
TI  - Conservative management of lumbar disk herniations in adolescents.

PMID- 12597317
TI  - Adult T-cell leukemia/lymphoma presenting as obstructive jaundice with complete
      resolution of jaundice after chemotherapy.

PMID- 12597318
TI  - Hematoma and enoxaparin use.

PMID- 12597319
TI  - Volvulus of the transverse colon.

PMID- 12597320
TI  - Extreme leukocytosis without hematologic malignancy.

PMID- 12597322
TI  - Aberrometry: clinical and research applications.

PMID- 12597321
TI  - Paraneoplastic gaze palsies in a patient with negative anti-Hu and anti-Yo
      antibody tests.

PMID- 12597323
TI  - Postoperative LASIK visual aberrations and treatment with InterWave-guided
      multipass, multistage correction.
AB  - Visual aberrations such as glare and halo have been well documented after laser
      in-situ keratomileusis (LASIK). These are more likely in patients with higher
      refractive errors and large pupil diameters. We present a patient with good
      Snellen acuity but functional impairment by visual aberrations after LASIK. These
      symptoms resolved after an InterWave-guided LASIK multipass, multistage
      enhancement treatment to correct spherical aberrations.

PMID- 12597324
TI  - Visual acuity as a function of Zernike mode and level of root mean square error.
AB  - BACKGROUND: The coefficients of normalized Zernike expansion are orthogonal and
      reflect the relative contribution of each mode to the total root mean square
      (RMS) wavefront error. The relationship between the level of RMS wavefront error
      within a mode and its effect on visual performance is unknown. PURPOSE: To
      determine for various levels of RMS wavefront error how each mode of the
      normalized Zernike expansion for the second, third, and fourth orders affect high
      and low-contrast acuity. METHODS: Three healthy optimally corrected cyclopleged
      subjects read aberrated and unaberrated high- and low-contrast logarithm of the
      minimum angle of resolution acuity charts monocularly through a 3-mm artificial
      pupil. Acuity was defined by the total number of letters read correctly up to the
      fifth miss. Aberrated and unaberrated charts were generated using a program
      called CTView. Six levels of RMS wavefront error were used (0.00, 0.05, 0.10,
      0.15, 0.20, and 0.25 microm). Each level of RMS error was loaded into each mode
      of the second, third, and fourth radial orders individually for a total of 72
      charts. Data were normalized by subject, and the normalized data were averaged
      across subjects. RESULTS: Across modes and within each mode as the level of RMS
      wavefront error increased above 0.05 microm of RMS wavefront error, visual acuity
      decreased in a linear fashion. Slopes of the linear fits varied depending on the
      mode. Modes near the center of the Zernike pyramid had steeper slopes than those
      near the edge. CONCLUSIONS: Increasing the RMS error within any single mode of
      the normalized Zernike expansion decreases visual acuity in a linear fashion. The
      slope of the best fitting linear equation varies with Zernike mode. Slopes near
      the center of the Zernike pyramid are steeper than those near the edge. Although
      the normalized Zernike expansion parcels RMS error orthogonally, the resulting
      effects on visual performance as measured by visual acuity are not orthogonal.
      New metrics of the combined effects of the optical and the neural transfer
      functions that are predictive of visual performance need to be developed.

PMID- 12597325
TI  - Spatially resolved wavefront aberrations of ophthalmic progressive-power lenses
      in normal viewing conditions.
AB  - PURPOSE: To measure the wavefront aberration at different locations in
      progressive-power lenses (PPL's) isolated and in situ (PPL's plus eye). METHODS:
      A Hartmann-Shack wavefront sensor was used to measure progressive-power lenses
      and human eyes either independently or in combination. In each selected zone, the
      lens was placed and tilted accordingly to simulate natural viewing conditions. We
      measured 21 relevant locations across an isolated PPL (plano lens of power
      addition of 2 D). In six of the locations, the wavefront aberration of the eye
      plus PPL were obtained in two ways: (1) by direct measurement of the system and
      (2) by adding the individual wavefront aberrations of the eye and the lens for
      each appropriate zone. In every case, we obtained the wavefront aberration as
      Zernike polynomials expansions, the root mean square error, the point-spread
      function, and the Strehl ratio. RESULTS: Along the corridor of the PPL, third
      order coma and trefoil, and astigmatism were the dominant aberrations. In areas
      of the PPL outside the corridor, astigmatism increased, whereas other aberrations
      remained similar to the lens center. Small differences were found between the
      direct and calculated methods used to obtain the wavefront aberration of the eye
      with the lens, and the possible sources of errors were discussed. In some lenses
      zones, the aberrations of the lens may be compensated by the particular
      aberrations of the eye, yielding improved optical performance over that present
      in the lens alone. CONCLUSIONS: We designed and built a wavefront sensor to
      perform spatially resolved aberration measurements in ophthalmic lenses, in
      particular in PPL's, either isolated or in combination with the eye. The
      aberrations appearing in the PPL were compared with those in normal aged eyes.

PMID- 12597326
TI  - On-eye measurement of optical performance of rigid gas permeable contact lenses
      based on ocular and corneal aberrometry.
AB  - PURPOSE: Our aim was to obtain a complete description of the interactions of
      rigid gas permeable (RGP) contact lenses with the optics of normal eyes. METHODS:
      We measured total and anterior-surface aberrations in four subjects, who were all
      long-term RGP contact lens wearers. The anterior-surface wave aberration was
      obtained from videokeratographic elevation maps, and ocular wave aberration was
      measured with a laser ray-tracing technique. Measurements were performed with and
      without their own spherical contact lenses. RESULTS: With this methodology, we
      evaluated the optical performance with RGP lenses compared with the natural
      optics. We estimated the contribution of the anterior surface of the contact
      lens, the internal ocular optics, flexure, and the tear lens aberrations to the
      optical performance of eyes wearing RGP contact lenses. We found that in three of
      four subjects, the contact lens significantly improved the natural optics of the
      eye. For the subject with higher dominance of corneal aberrations, root mean
      square (second-order and higher) decreased from 1.36 microm to 0.46 microm. Third
      and higher-order aberrations decreased from 0.77 microm to 0.39 microm. The
      internal optics and lens flexure imposed limits on aberration compensation.
      Spherical RGP contact lenses did not produce spherical aberration potentially due
      to a compensatory role of the tear lens. CONCLUSIONS: Aberration measurements are
      useful to understand the fitting of contact lenses and the interaction with tear,
      cornea, and internal optics of the eye. Aberrometry can help to choose the best
      standard RGP lens parameters to improve the optics of individual eyes.

PMID- 12597327
TI  - On- and off-eye spherical aberration of soft contact lenses and consequent
      changes of effective lens power.
AB  - BACKGROUND: Soft contact lenses produce a significant level of spherical
      aberration affecting their power on-eye. A simple model assuming that a thin soft
      contact lens aligns to the cornea predicts that these effects are similar on-eye
      and off-eye. METHODS: The wavefront aberration for 17 eyes and 33 soft contact
      lenses on-eye was measured with a Shack-Hartmann wavefront sensor. The Zernike
      coefficients describing the on-eye spherical aberration of the soft contact lens
      were compared with off-eye ray-tracing results. Paraxial and effective lens power
      changes were determined. RESULTS: The model predicts the on-eye spherical
      aberration of soft contact lenses closely. The resulting power change for a +/-
      7.00 D spherical soft contact lens is +/- 0.5 D for a 6-mm pupil diameter and +/-
      0.1 D for a 3-mm pupil diameter. Power change is negligible for soft contact
      lenses corrected for off-eye spherical aberration. CONCLUSIONS: For thin soft
      contact lenses, the level of spherical aberration and the consequent power change
      is similar on-eye and off-eye. Soft contact lenses corrected for spherical
      aberration in air will be expected to be aberration-free on-eye and produce only
      negligibly small power changes. For soft contact lenses without aberration
      correction, for higher levels of ametropia and large pupils, the soft contact
      lens power should be determined with trial lenses with their power and p value
      similar to the prescribed lens. The benefit of soft contact lenses corrected for
      spherical aberration depends on the level of ocular spherical aberration.

PMID- 12597328
TI  - Monochromatic wavefront aberrations in the human eye with contact lenses.
AB  - PURPOSE: The aim of this study was to investigate the effect of contact lenses on
      the optical performance of the eye by measuring wavefront aberrations for the
      eyes with or without contact lenses. METHOD: A sensitive aberrometer was used to
      measure wavefront aberrations for 54 eyes in 27 subjects for three conditions:
      with no contact lens (non-CL), with soft-contact lenses (soft-CL) and with rigid
      gas permeable contact lenses (RGP-CL). The root mean square (RMS) value of the
      wavefront aberrations and Zernike aberrations were calculated. RESULTS: A change
      in the RMS values of wavefront aberrations with CL wear was observed for every
      eye. The change in wavefront aberrations with CL wearing was found to vary
      substantially from individual to individual. Relative to the mean RMS value of
      the group for the non-CL condition, the mean RMS value was increased for the soft
      CL condition and was significantly reduced for the RGP-CL condition. A
      significant increase in mean RMS for the soft-CL condition was found when
      astigmatisms were removed. Although soft-CL wearing resulted in significant
      increases in higher orders of Zernike aberrations (fourth, fifth, and higher),
      the RGP-CL condition led to a significant decrease in second-order Zernike
      aberrations. For the eyes with low wavefront aberrations in the non-CL condition,
      either soft-CL wearing or RGP-CL wearing results in increases in the RMS values.
      CONCLUSION: Contact lens wearing, either with soft lenses or the RGP lenses,
      causes changes in the wavefront aberrations of the eye. The changes in wavefront
      aberrations vary substantially from eye to eye. Although soft-CL wearing tends to
      induce more higher-order aberrations, RGP-CL effectively reduces the
      astigmatisms. Both soft-CL and RGP-CL induce more aberrations for the eyes that
      have low wavefront aberrations. The change in wavefront aberrations due to
      contact lens wearing may explain the changes in visual performance for contact
      lens wearers reported previously.

PMID- 12597329
TI  - Repeatability of ocular wavefront measurement.
AB  - PURPOSE: To assess the repeatability of measurements of ocular aberrations using
      wavefront sensing in a small group of observers and to assess the potential
      effect of measurement error on custom corneal correction due to this variability.
      METHOD: A Shack-Hartmann wavefront sensor was used to measure the ocular
      wavefront in nine eyes. Head position was stabilized using a dental bite bar, and
      the pupil was centred using a cathode ray tube monitor and circular grating.
      Twenty Shack-Hartmann images were collected for each measurement. Each observer
      had three sets of measurements taken; the first and the second after careful
      alignment and the final after regrasping the bite bar in the same position as for
      the second measurement, but without pupil realignment. The modulation transfer
      functions for each set were calculated, and the effect of best-aligned custom
      treatments on the modulation transfer function was estimated. RESULTS: There were
      highly statistically significant differences in a large number of Zernike modes
      between the three sets of measurements. The modulation transfer functions
      calculated for the residual wavefronts after aligned custom treatment were below
      the diffraction limit. The root mean square wavefront errors were consistently
      better for the residual wavefronts obtained using the realigned data than using
      data taken without pupil realignment. CONCLUSIONS: Sequential measurement of
      ocular aberrations shows statistically significant differences in a large number
      of Zernike modes. If aberrations determined by a single measurement are to be
      used in a custom correction, the resulting modulation transfer function is likely
      to remain below the diffraction limit. Pupil realignment is critical in reduction
      of the residual root mean square wavefront values to a minimum.

PMID- 12597330
TI  - Wavefront aberration and its relationship to the accommodative stimulus-response
      function in myopic subjects.
AB  - BACKGROUND: Autorefractors are increasingly used in myopia research because they
      are convenient tools to investigate aspects of the accommodation response. The
      degree to which the autorefractor measures are affected by ocular aberrations has
      been highlighted by studies that have shown changes in aberration levels through
      different parts of the pupil and with accommodation. We have compared
      accommodative accuracy as measured with a Shin-Nippon SRW 5000 autorefractor with
      wavefront error as measured with a Hartmann-Shack wavefront sensor to investigate
      how factors such as accommodation demand, ocular aberrations, and pupil size can
      influence autorefractor measures. METHODS: Accommodation stimulus-response curves
      were determined (using negative lenses) for 30 young healthy subjects (20 myopic
      [-0.75 to -6.00 D] and 10 emmetropic). Accommodation levels ranged from 0 to 4 D
      in 1 D steps. Wavefront aberrations were also determined for the same
      accommodation levels using a Hartmann-Shack wavefront sensor for both the
      subjects' natural pupil sizes and for a 2.9-mm pupil. RESULTS: For all subjects,
      there was a consistent increase in negative spherical aberration with increases
      in accommodative stimulus. However, there was no consistent change in paraxial
      spherocylindrical refractive correction with accommodation stimulus. For the
      emmetropic subjects, accommodation error as measured with the autorefractor was
      statistically similar to the total spherocylindrical correction for the eye as
      estimated by the Hartmann-Shack wavefront sensor, but only for a 2.9-mm pupil
      (the pupil size utilized by the autorefractor). For the myopic subjects,
      accommodation error as measured with the autorefractor was statistically similar
      to the higher-order aberrations, but only when measured for a natural pupil size.
      CONCLUSIONS: The relationship between the accommodation accuracy as measured with
      the autorefractor and the total wavefront aberration as measured with a Hartmann
      Shack wavefront sensor is largely influenced by the higher-order (fourth and
      above) aberration levels. For the emmetropic subjects, the errors measured by the
      two methods agree when adjusted to measure at similar pupil sizes. For the myopic
      subjects with similar pupil sizes, however, the Hartmann-Shack wavefront sensor
      underestimates the accommodation error at higher accommodation levels (2 to 4 D)
      compared with the autorefractor.

PMID- 12597331
TI  - Corneal aberrations and reading.
AB  - PURPOSE: To investigate the effects of eyelid pressure on corneal shape and
      corneal aberrations during reading. METHODS: Twenty young subjects with normal
      ocular health were recruited for the study. The experiment was conducted early in
      the morning, with subjects instructed not to perform any prolonged reading before
      the experiment. Corneal topography of one eye was measured with a
      videokeratoscope before reading and then again after a 60-min reading task. The
      natural position of the eyelids was photographed in primary gaze and during the
      reading task. RESULTS: Twelve of the 20 corneas showed significant changes in
      central topography immediately after reading. The location of the changes
      corresponded closely to the position and angle of the subject's eyelids during
      reading. The change in shape was best described as a wave-like distortion that
      significantly altered some corneal wavefront Zernike coefficients. There was a
      significant correlation between the changes in primary vertical coma and trefoil
      (along 30 degrees). Within the central 6 mm of the cornea, there were significant
      changes in the root mean square error, overall refractive power, and astigmatism.
      CONCLUSIONS: The changes we observed in corneal topography appear to be directly
      related to the force exerted by the eyelids during reading. Because the cornea is
      the major light-refracting surface of the eye, the optical characteristics of
      some eyes can be significantly changed during reading by the force of the
      eyelids. These findings may have important implications for the definition of
      refractive status and may also aid in the understanding of the relationship
      between reading and the development of refractive errors.

PMID- 12597332
TI  - Optical quality of the eye with the Artisan phakic lens for the correction of
      high myopia.
AB  - PURPOSE: To evaluate the optical quality of the eye before and after the
      insertion of an Artisan phakic intraocular lens for the treatment of high myopia.
      METHODS: Consecutive patients implanted with the Artisan lens by a single surgeon
      between June 2001 and April 2002 were enrolled prospectively. One eye per subject
      was tested. The wavefront aberration was calculated from images recorded with a
      Hartmann-Shack sensor. This wavefront aberration was expressed as a Zernike
      polynomial expansion from the third up to the seventh order. Root mean square
      wavefront error was used as a parameter of optical quality. Point-spread function
      and modulation transfer function were also computed from the wavefront
      aberration. RESULTS: The mean age of the four patients (four eyes) was 46 +/- 11
      years. The preoperative mean spherical equivalent was -14.13 +/- 3.19 D (range, 
      20.50 to -9.75 D), with a best-corrected visual acuity of 20/25 or better in
      three of the four eyes. No complications were encountered. Postoperatively, the
      mean spherical equivalent was -0.22 +/- 0.30 D (range, -0.75 to +0.38 D). An
      uncorrected visual acuity of 20/40 or better was observed in three eyes. Overall,
      for each combination of order (third, fourth, and fifth to seventh) and pupil
      size (3, 4, and 5 mm), the mean postoperative root mean square values for the
      four subjects were lower than the mean preoperative values. However, because of
      the small size of the study population (four patients), this improvement did not
      reach a statistically significant level. CONCLUSIONS: Preliminary data using the
      Hartmann-Shack wavefront sensor have not revealed a tendency toward deterioration
      of the optical performance after the insertion of an Artisan lens for the
      treatment of high myopia. The Hartmann-Shack sensor was a useful tool for the
      objective assessment of the image optical quality of eyes with a phakic
      intraocular lens.

PMID- 12597333
TI  - A new measure for optical performance.
AB  - Because diffraction and aberration affect the performance of the optical system,
      a new metric is advanced that emphasizes the link between these three aspects. In
      general, the modulation transfer function is used as a measure for contrast
      sensitivity reduction, whereas the root mean square error is often used to
      quantify the optical quality of the system. However, for a given object,
      wavefront aberrations can alter the output image very differently even though
      they have the same root mean square error and modulation transfer function
      profile. A distinction between coherent and incoherent illumination is made, and
      a new measure, called optical transfer error, is defined to characterize optical
      performance complementarily to root mean square and modulation transfer function.
      The optical transfer error measures the optical excellence in terms of the shape
      of the wavefront as well as the theoretical performance results. Several
      illustrations are presented to better discuss optical performance.

PMID- 12597334
TI  - Angiogenesis and some prognostic parameters of invasive ductal breast carcinoma
      in women.
AB  - The purpose of the study was to correlate angiogenesis parameters (microvessel
      count, area and perimeter) with some clinical and morphological factors in 251
      invasive ductal breast carcinomas in women. Endothelium was stained with antiCD31
      antibody, and measurements were made using a computerised image analysis in the
      whole study population and separately for two subgroups with and without
      metastases to axillary lymph nodes. High angiogenesis parameters in primary
      tumours were associated with older age, large tumour diameter, high grade and the
      associations were statistically significant. Furthermore the microvessel density
      was significantly higher in tumours metastasising to lymph nodes as compared with
      tumours without metastases. Microvessel perimeter was found to be the most useful
      of vessel parameters analysed. The correlation between angiogenesis and some
      clinical and morphological parameters, especially lymph node status may indicate
      the prognostic value of angiogenesis in invasive ductal breast carcinomas.

PMID- 12597335
TI  - Genetic analysis of HER-2/neu gene amplification in paraffin embedded tumour
      tissue in women with breast cancer.
AB  - In recent years several novel prognostic determinants of breast cancer have been
      identified, including HER-2/neu. The oncogene called HER-2/neu or c-erbB-2
      located at 17q21 encodes a 185-kD transmembrane glycoprotein, p185. The HER-2/neu
      gene is frequently overexpressed in human breast cancers as a result of gene
      amplification and/or elevated transcription. In this study we investigated the
      association between the presence of HER-2/neu gene ampliflcation and appearance
      and/or progression of breast cancer. Paraffin embedded tumour tissue was obtained
      from 82 women with breast cancer. Blood samples from age matched healthy women
      served as control (n = 50). The amplification of HER-2/neu gene was determined by
      PCR amplification using appropriate primers. The amplification of HER-2/neu gene
      was significantly higher in women with breast cancer as compared with control (P
      < 0.05). Additionally, there were differences in the amplification status between
      node-positive and node-negative breast cancer patients. The results suggest that
      the presence of amplification of HER-2/neu gene may be linked with the appearance
      and/or progression of breast cancer.

PMID- 12597336
TI  - The expression of tumorigenesis markers in oral papilloma.
AB  - Oral papilloma is the most frequent benign tumor of the oral cavity but its
      biological potential for malignant transformation is still to be evaluated. The
      alteration of apoptosis and uncontrolled cell proliferation is considered to be
      an important factor in oral tumorigenesis. The aim of our study was to evaluate
      by immunohistochemistry P53, Bcl-2, CD44 and PCNA expression in oral papillomas
      with and without dysplasia. We examined a series of 55 oral papillomas, including
      12(21.8%) cases of papillomas with epithelial dysplasia. Staining patterns were
      correlated with sex, age, tumor location, size and presence or absence of
      epithelial dysplasia. P53 showed positive reaction in 70.9%, PCNA in 80%, CD44 in
      50.9% and Bcl-2 in 21.8% of papillomas. There was no correlation between sex,
      age, tumor size, location and presence of dysplastic epithelium in papillomas. We
      observed a statistically significant correlation between Bcl-2, CD44 expression
      and presence of epithelial dysplasia in papillomas. Coexistence of PCNA and P53
      positive immunostaining was observed. Papillomas with overexpression of P53 and
      PCNA showed negative reaction for CD44 protein. The results of our study suggest
      that overexpression of P53 and PCNA might be an early event in oral
      tumorigenesis, whereas CD44 and Bcl-2 are potential markers of epithelial
      dysplasia in oral papillomas.

PMID- 12597337
TI  - Effect of melatonin on cytotoxic effects of daunorubicin on myocardium and on
      transplantable Morris hepatoma in rats.
AB  - In the course of anthracyclin administration, melatonin acts as an effective
      scavenger of oxygen free radicals and exerts cardio- and nephroprotective
      effects. The present study aimed at corroborating cytostatic effectiveness of
      daunorubicin, applied in parallel with melatonin, in rats with transplanted
      Morris hepatoma. The percentage of tumour cells, which manifested traits of
      necrosis was recorded and extent of apoptosis was evaluated in tumour cells and
      in cells of myocardium. Daunorubicin administration was followed by a significant
      increase in necrosis and apoptosis in tumour cells and by intensified apoptosis
      in myocardium cells. Melatonin administered in parallel with daunorubicin
      decreased the extent of necrosis in tumour cells and reduced the proportion of
      apoptotic cardiomyocytes.

PMID- 12597338
TI  - The influence of BMOV [bis(maltolato)oxovanadium(IV)] on biochemical and
      morphological alterations characteristic for streptozotocin-diabetic rat liver
      Golgi complexes.
AB  - The activity of galactosyltransferase (GalT), the Golgi apparatus marker enzyme,
      together with the morphology of this organelle in rat liver, are so
      characteristic that we have used them for twenty years as a test of
      streptozotocin-diabetes, and of the efficacy of different drugs.
      Bis(maltolato)oxovanadium(IV) (BMOV), an oral vanadium complex with anti-diabetic
      properties, best of these drugs, was seen to reverse the previously found
      biochemical and morphological changes. Four groups of diabetic rats were studied
      in different conditions: 1) untreated diabetes (D group), 2) pre-treatment with
      BMOV for two days, to accustom the animals to the taste of vanadium solution and
      to verify possible cytoprotection of the drug, followed by the induction of
      diabetes c. 3 weeks later (pVD group). The third group--3) consisted of the rats,
      in which STZ-diabetes was induced followed by treatment of diabetic animals with
      1.8 mmol BMOV in 0.5% NaCl for seven days (D+V group). The fourth group--4)
      consisted of the animals treated as pVD group, followed by induction of diabetes
      three weeks later and treatment with BMOV (pVD+V group) for seven days. In
      agreement with other investigators, the reduction of body weight was seen in all
      diabetic rats. Vanadium treatment caused the greatest body weight reduction.
      Liquid and food intake was lower in both groups at seven days after treatment
      with BMOV. Major biochemical alterations in yields of Golgi-rich membrane
      fraction were found in D, pVD and pVD+V groups. They were significantly lower (p
      < 0.01) than in D+V group. A significantly lower activity of GalT (total activity
      and calculated in nmol transferred per h and per g of liver) was found in the
      three groups of diabetic rats in comparison with D+V group (p < 0.01 or p <
      0.001). GalT activities, as well as the yield of Golgi fraction in D+V group,
      were similar to the previously obtained in control or control vanadium treated
      groups. A major morphological alteration was observed in D and pVD+V groups
      (characteristic semicircular or arched Golgi apparatus--AG). In the pVD group a
      different structure of AG was seen: short terminally dilated cisternae, sometimes
      only semicircular and arched. In rats treated 7 days with BMOV (the D+V group)
      the "normalisation" of morphology of liver AG was noted.

PMID- 12597339
TI  - The influence of nitric oxide synthesis modulation on the pancreatic acinar cells
      in caerulein-induced acute pancreatitis. An ultrastructural and morphometric
      study.
AB  - The goal of our study was to evaluate the influence of NO synthesis modulation on
      the ultrastructural changes in the pancreatic acinar cells in connection with
      morphometric assessment of the volume and numerical densities of mitochondria
      (Vvm, Nvm) and zymogen granules (Vvz, Nvz) in caerulein-induced acute
      pancreatitis (AP). During AP induction rats were treated with L-arginine-
      substrate for NO synthesis, N(G)-nitro-L-arginine (L-NNA)--NO synthase inhibitor,
      gliceryl trinitrate (NTG)--NO donor, L-arginine+L-NNA or saline. This study
      demonstrated that administration of L-NNA leads to the formation of numerous,
      large autophagosomes and mitochondria oedema in pancreatic acinar cells.
      Treatment with L-arginine or NTG during AP induction resulted in a diminution of
      the ultrastructural changes with a concomitant increase of Vvz. Vvm and Nvm were
      significantly lower in the L-arginine treated group compared to the untreated AP.
      The results indicate that: L-NNA enhances damage to acinar cells which may be
      indicative of a protective role for endogenous NO in oedematous AP. The
      application of L-arginine or NTG decreases the damage to acinar cells evaluated
      ultrastructurally, suggesting the morphological changes accompanying the onset of
      AP in rats after the administration of either substrate for endogenous NO
      synthesis or exogenous NO donor follow a favourable course.

PMID- 12597340
TI  - Immunofluorescence in situ and the serologic indices of Chlamydia pneumoniae
      infection in patients with an abdominal aortic aneurysm.
AB  - The aim of the study was to evaluate the frequency of Chlamydia pneumoniae
      infection in patients with abdominal aortic aneurysm (AAA) using selected
      methods. The histological specimens of aneurysm wall were evaluated, the method
      of immunofluorescence was used to reveal the antigen in the wall of AAA and the
      titers of specific antibodies of IgG, IgM and IgA classes in blood plasma were
      marked. Atherosclerotic changes in the aneurysm wall were found in all patients.
      In 20(87%) patients the C. pneumoniae antigen was seen in the wall of abdominal
      aneurysm using the indirect immunofluorescence method. A significant relation
      between the method of direct C. pneumoniae diagnosis, aneurysm symptoms and
      histologically detected inflammation in its wall was confirmed. Serologic markers
      of the chronic C. pneumoniae infection were seen in 20(87%) out of 23 patients
      and in 6(30%) out of 20 subjects of the control group and this difference was
      statistically significant. It was observed, that all patients with serologic
      indices of active C. pneumoniae infection, had symptomatic aneurysm. The presence
      of Chlamydia pneumoniae in the wall of AAA as well as the occurrence of serologic
      indices of the chronic infection in these patients can confirm the hypothesis of
      the relation between the infection with this microorganism and the development of
      the disease.

PMID- 12597341
TI  - Asynchronous collecting duct carcinoma of the kidney and pulmonary
      adenocarcinoma. A case report.
AB  - Collecting duct carcinoma (CDC) is a rare renal malignancy accounting for about
      0.4-2.6% of cases. We report a case of CDC in a 61-year-old woman previously
      operated on for pulmonary adenocarcinoma. On histological examination and
      immunohistochemical research diagnosis of asynchronous primary bronchial
      carcinoma and renal CDC was made. The authors review the available literature on
      CDC and differential diagnosis of metastatic versus primary renal carcinomas.

PMID- 12597342
TI  - EBV-positive lymphoepithelial carcinoma of salivary gland in a woman of a non
      endemic area--a case report.
AB  - Lymphoepithelial carcinoma of the salivary glands is a very rare malignancy
      comprising not more than 0.4% of all salivary gland neoplasms in the non-endemic
      areas. In contrast it is much more frequent among native Greenlanders, North
      American Inuit (Eskimo) and Southern Chinese people living in Hong Kong. We
      report a case of a 74-year-old woman of Polish origin diagnosed with a
      lymphoepithelial carcinoma of the right parotid gland. The neoplastic cells were
      negative for EBV latent membrane protein (LMP-1), but in situ hybridisation for
      EBV mRNA (EBER) demonstrated positivity in almost all epithelial cells. No signs
      of EBV infection were found in the reactive lymphocytic component. The patient
      was treated with radiotherapy.

PMID- 12597343
TI  - Pluribus unum of primary gastric antigen-dependent lymphomas.
AB  - The paper presents start-of-art knowledge of primary gastric B-cell lymphomas.
      Despite the progress of the investigations, a lot of questions remain still
      unanswered and many doubts wait for explanation.

PMID- 12597344
TI  - Dendritic cell therapy of cancer: can it fulfill its promise?

PMID- 12597345
TI  - Gemcitabine in transitional cell carcinoma of the urothelium.
AB  - Gemcitabine has become one of the key drugs in the treatment of patients with
      locally advanced and metastatic transitional cell carcinoma of the urothelium.
      The overall response rate for single-agent gemcitabine is 25% with a complete
      response rate of 9% and toxicity is mild-to-modest. The overall response rate for
      gemcitabine combined with cisplatin (GC) in Phase II studies is 47% with a
      complete response rate of 18% and a median survival ranging from 12.5 to 14.3
      months. A randomized Phase III study comparing GC and methotrexate, vinblastine,
      adriamycin and cisplatin (MVAC) has demonstrated similar efficacy with respect to
      response, time-to-progression and overall survival, whereas GC is associated with
      less toxicity than MVAC. Thus, GC is now considered a standard of care for
      patients with locally advanced and metastatic urothelial cancer. Other promising
      combinations include gemcitabine together with one of the taxanes with or without
      cisplatin.

PMID- 12597346
TI  - Management of clinical stage I nonseminomatous germ-cell testis tumors.
AB  - Nonseminomatous germ-cell tumors of the testis, the most common cancer in young
      adult males, are highly curable. Clinical Stage I disease represents almost a
      third of the patients. Three treatment strategies are currently available:
      surveillance, postorchiectomy chemotherapy and retroperitoneal lymph node
      dissection. Factors predictive of extratesticular involvement have been
      described, thus making it possible to tailor treatment to risk. New imaging
      procedures also permit staging and prediction of outcome. Decision-making is
      shared between the patient and his oncologist. Economic issues are better
      understood but should be further studied.

PMID- 12597347
TI  - Second-line chemotherapy of epithelial ovarian cancer.
AB  - Despite the high objective response rate of advanced epithelial ovarian cancer to
      front-line chemotherapy, the majority of women with this condition ultimately
      progress or recur after achieving an initial response and are potential
      candidates for a second-line treatment approach. A number of antineoplastic
      agents have demonstrated sufficient biological activity to be considered a
      rational treatment strategy in this clinical setting. In selecting an 'optimal'
      management approach for a particular patient the oncologist must consider a
      number of issues, including the toxicity of the available drugs, the side effects
      previously experienced by the individual, convenience, cost and patient choice.

PMID- 12597348
TI  - Optimal therapy and management of endometrial cancer.
AB  - Carcinoma of the endometrium is the most common malignancy of the female genital
      tract. Fortunately, this neoplasm presents with abnormal clinical symptoms in its
      early stages. The majority of cases will be detected at a curable stage when the
      neoplasm is still confined to the uterus. Given this fact, surgical removal of
      the involved organ remains the cornerstone of treatment for this disease. Certain
      pathologic risk factors for recurrence have been identified and are the basis for
      which adjuvant therapy is recommended. Controversy in management exists as to the
      approach and extent of primary surgery as well as the indications for adjuvant
      therapy. Management of this disease is reviewed.

PMID- 12597349
TI  - Chemotherapy for trophoblastic disease: current standards.
AB  - Gestational trophoblastic diseases comprise a rare spectrum of disorders in which
      the normal regulatory mechanisms controlling the behavior of trophoblastic tissue
      are lost. They vary from the benign complete and partial hydatidiform moles to
      the frankly malignant choriocarcinoma and placental site trophoblastic tumors.
      The majority will be cured by suction curettage, followed by human chorionic
      gonadotrphin screening but some will go on to need chemotherapy. The majority of
      patients will be cured even despite the presence of metastatic disease. Patients
      should have their treatment stratified according to various prognostic factors in
      order to ensure firstly their disease is eliminated and secondly to reduce the
      incidence of long-term treatment complications.

PMID- 12597350
TI  - Screening for ovarian cancer.
AB  - Ovarian cancer frequently presents late, when chances for long-term survival are
      poor. The increased survival advantage for patients diagnosed with early-stage
      ovarian cancer suggests that screening to detect early-stage disease might have
      an impact on disease mortality. Attempts are being made to develop effective
      screening procedures for early ovarian cancer in symptom-free women, using a
      variety of serum tumor markers, proteomic patterns, and ovarian morphological and
      vascular features. Two distinct screening strategies have emerged, one utilizing
      transvaginal scanning as the primary test, and the other involving measurement of
      the serum tumor marker CA125 as the primary test with transvaginal
      ultrasonography as the secondary test (multimodal screening). Large randomized
      trials are now underway to provide definitive data on the impact of screening on
      mortality and address morbidity, health economics and psychosocial issues.

PMID- 12597351
TI  - Immunotherapy for colorectal cancer.
AB  - There have been significant improvements in the diagnosis and treatment of
      colorectal cancer over the past 15 years. However, some 30% of patients with
      colorectal cancer have disseminated disease at presentation, and furthermore, 50%
      of patients initially believed to be cured by surgery subsequently relapse and
      die of the disease. Novel treatment concepts based on understanding the molecular
      signatures that separate tumor from normal epithelium, such as immunotherapy, are
      aimed at abolishing microscopic residual disease post standard treatment. The
      authors provide an overview of progress in the development of specific and
      nonspecific immunotherapies and explain why definition of end-points and early
      translation of immunotherapy into the adjuvant field are key to effective use of
      such agents in the clinical setting.

PMID- 12597352
TI  - Past, current and future protocols for combined modality therapy in childhood
      medulloblastoma.
AB  - Radiotherapy plays a major role in the management of brain tumors, together with
      surgical resection and more recently, chemotherapy. Improved efficacy of
      radiotherapy, ranging from novel techniques of radiotherapy to combination with
      (new) chemotherapeutic drugs or agents that selectively target tumor cells, are
      currently being explored and offer some hope for improvement of the prognosis of
      primary brain tumors. This approach might also enable reducing radiation doses,
      thereby potentially decreasing the risk of severe late effects in pediatric brain
      tumor patients. This review will evaluate past, current and future treatment
      approaches of combined modality therapy in childhood medulloblastoma.

PMID- 12597353
TI  - Chemoprevention of lung cancer: soon daily practice?
AB  - The statistics on lung cancer survival remain disappointing and form a powerful
      argument to develop new methods to control this most deadly form of cancer in
      both men and women. Chemoprevention is one of these new approaches. While
      carcinogens from cigarette smoke form an essential link between nicotine
      addiction and lung cancer, several investigations confirm that dietary and
      genetically determined factors play an important role in modulating the
      individual susceptibility and are linked to the chemoprevention approach. In
      spite of a large abundance of positive preclinical observations, most experiences
      with potential chemopreventive agents, such as retinoids and antioxidants in
      individuals at risk for lung cancer have been so far negative. Moreover, beta
      carotene was associated with an increased lung cancer incidence in two large
      randomized studies, as a consequence of a negative interaction with smoking. On
      the other hand, recent progress in molecular biology has led to the discovery of
      specific approaches to chemoprevention and there considerable optimism regarding
      the potential of molecules and antibodies that target specific receptors or
      mutations. Epidermal growth factor receptor blocking agents, farnesyltransferase
      and cyclooxygenase inhibitors and 9-cis retinoic acid have been identified as
      promising candidates for studies in high risk populations. After more than 20
      years of worldwide research, the prospects for effective lung cancer treatment
      are better than ever.

PMID- 12597354
TI  - Treatment for cancer-related fatigue: an update.
AB  - Cancer-related fatigue is now a recognized phenomenon with an established
      diagnosis. Fatigue is the most common symptom experienced by cancer patients and
      in many cases, the challenge of alleviating its severity is daunting for the
      clinician. Occasionally, the clinician may be fortunate and discover a reversible
      cause of fatigue for which there is a readily available treatment. Most of the
      time, however, the etiology of cancer-related fatigue is multifactorial or
      treatment-related with unknown pathophysiologic abnormalities and the clinician
      must resort to a variety of modalities to attempt to relieve the fatigue.
      Research of cancer-related fatigue treatment is in its infancy and future
      clinical trials examining the effects of various pharmacologic and
      nonpharmacologic therapies for cancer-related fatigue are needed. The development
      of effective therapies for the treatment of cancer-related fatigue could
      profoundly affect the lives of many cancer patients.

PMID- 12597355
TI  - Antibody-based therapeutics in oncology.
AB  - The recent clinical and commercial success of anticancer antibodies, such as
      rituximab (Rituxan) and trastuzumab (Herceptin) has created great interest in
      antibody-based therapeutics for hematopoietic malignancies and solid tumors.
      Given the likely lower toxicity for antibodies versus small molecules, the
      potential increase in efficacy by conjugation to radioisotopes and other cellular
      toxins and the ability to characterize the target with clinical laboratory
      diagnostics to improve the drug's clinical performance, it is anticipated that
      current and future antibody therapeutics will find substantial roles alone and in
      combination therapy strategies for the treatment of patients with cancer. It is
      also likely that conjugation strategies will add new radiolabeled and toxin
      linked products to the market to complement the recent approvals of ibritumomab
      tiuxetan (Zevalin) and gemtuzumab ozogamycin (Mylotarg). However, although there
      are a large number of agents in both early and later stages of clinical
      development, only a handful will make it through regulatory approval and become
      successful products. This review considers the structure of anticancer
      therapeutic antibodies, the techniques used to reduce their antigenicity, factors
      that influence efficacy and toxicity, conjugation with isotopes and toxins and
      antibody target validation.

PMID- 12597356
TI  - Fecal microbial diversity in a strict vegetarian as determined by molecular
      analysis and cultivation.
AB  - Fecal microbial diversity in a strictly vegetarian woman was determined by the
      16S rDNA library method, terminal restriction fragment length polymorphism (T
      RFLP) analysis and a culture-based method. The 16S rDNA library was generated
      from extracted fecal DNA, using bacteria-specific primers. Randomly selected
      clones were partially sequenced. T-RFLP analysis was performed using amplified
      16S rDNA. The lengths of T-RF were analyzed after digestion by HhaI and MspI. The
      cultivated bacterial isolates were used for partial sequencing of 16S rDNA. Among
      183 clones obtained, approximately 29% of the clones belonged to 13 known
      species. About 71% of the remaining clones were novel "phylotypes" (at least 98%
      similarity of clone sequence). A total of 55 species or phylotypes were
      identified among the 16S rDNA library, while the cultivated isolates included 22
      species or phylotypes. In addition, many new phylotypes were detected from the
      16S rDNA library. The 16S rDNA library and isolates commonly included the
      Bacteroides group, Bifidobacterium group, and Clostridium rRNA clusters IV, XIVa,
      XVI and XVIII. T-RFLP analysis revealed the major composition of the vegetarian
      gut microbiota were Clostridium rRNA subcluster XIVa and Clostridium rRNA cluster
      XVIII. The dominant feature of this strictly vegetarian gut microbiota was the
      detection of many Clostridium rRNA subcluster XIVa and C. ramosum (Clostridium
      rRNA cluster XVIII).

PMID- 12597358
TI  - Identification of the pathogenic Aspergillus species by nested PCR using a
      mixture of specific primers to DNA topoisomerase II gene.
AB  - For PCR-based identification of Aspergillus species, a common primer of the DNA
      topoisomerase II genes of Candida, Aspergillus and Penicillium, and species
      specific primers of the genomic sequences of DNA topoisomerase II of A.
      fumigatus, A. niger, A. flavus (A. oryzae), A. nidulans and A. terreus were
      tested for their specificities in PCR amplifications. The method consisted of
      amplification of the genomic DNA topoisomerase II gene by a common primer set,
      followed by a second PCR with a primer mix consisting of 5 species-specific
      primer pairs for each Aspergillus species. By using the common primer pair, a DNA
      fragment of approximately 1,200 bp was amplified from the Aspergillus and
      Penicillium genomic DNAs. Using each species-specific primer pair, unique sizes
      of PCR products were amplified, all of which corresponded to a species of
      Aspergillus even in the presence of DNAs of several fungal species. The
      sensitivity of A. fumigatus to the nested PCR was found to be 100 fg of DNA in
      the reaction mixture. In the nested PCR obtained by using the primer mix (PsIV),
      the specific DNA fragment of A. fumigatus was amplified from clinical specimens.
      These results suggest that this nested PCR method is rapid, simple and available
      as a tool for identification of pathogenic Aspergillus to a species level.

PMID- 12597357
TI  - Molecular epidemiology of Salmonella enterica serovar Enteritidis isolated in
      Taiwan.
AB  - Incidence of Salmonella enterica serovar Enteritidis infection seems to be on the
      rise in Taiwan, and therefore, the characteristics of the isolate, including
      genotypes, were epidemiologically investigated. Of the 71 clinical strains
      isolated in 1997-1999, 61 (86%) remained susceptible to the eight antibiotics
      tested, while the remaining ten, eight of which were isolated in 1999, were
      resistant to one to three of the agents including three multiply resistant
      strains. The majority, 69 or 97% of the isolates, harbored a 60-kb spvC gene
      carrying virulence plasmid and 12 of them harbored one or two additional various
      sized plasmids. Strains with more than one plasmid were isolated mostly in 1999.
      Pulse-field gel electrophoresis (PFGE) revealed three major genotypes (Types A, B
      and C), in which type A was the predominant type. Of the 68 Type A, which
      contained 8 subtypes, 59 (83%) belonged to only two subtypes. Similar results
      were obtained with a PCR-based typing method, the infrequent-restriction-site
      (IRS) PCR. All four methods detected types that were rarely seen before and most
      of these were of recent isolates, indicating that these unusual types were new or
      strains of foreign origin. Though all four methods discriminated types well, PFGE
      and IRS-PCR showed higher sensitivity for classification. Between the two, the
      latter, though less discriminatory than PFGE, seems the method of choice, since
      it is simpler, less time-consuming and above all easy to perform.

PMID- 12597359
TI  - Construction and in vitro properties of chimeric simian and human
      immunodeficiency virus with the human TNF-alpha gene.
AB  - Tumor necrosis factor-alpha (TNF-alpha) has been reported to be involved in the
      development and progression of acquired immunodeficiency syndrome (AIDS). To
      study the role of this cytokine in AIDS pathogenesis, we constructed a chimeric
      simian and human immunodeficiency virus (SHIV) having the human TNF-alpha gene
      (SHIV-TNF) and characterized its properties in vitro. SHIV-TNF replicated both in
      M8166, a human T cell line, and in monkey peripheral blood mononuclear cells
      (PBMCs). Along with SHIV-TNF replication, TNF-alpha was detected in the culture
      supernatant by ELISA. The maximum expression level of TNF-alpha reached 120 ng/ml
      in M8166 cells, and 2.5 ng/ml in monkey PBMCs. The expressed TNF was biologically
      active, as shown by a cytotoxic assay using TNF-sensitive L929 mouse fibroblasts.
      This activity was detected at least until 10 passages of SHIV-TNF (74 days after
      the initial infection). In monkey PBMCs, SHIV-TNF replicated much better than the
      parental SHIV-NI. Flow cytometric analysis showed that the death of monkey PBMCs
      infected with SHIV-TNF was severer than that caused by the parental SHIV-NI.
      These results suggest that SHIV-TNF would be useful for inducing the disease in a
      monkey model, which may contribute to a better understanding of the role of TNF
      alpha in AIDS etiology.

PMID- 12597360
TI  - Human immunodeficiency virus type 1 neutralization by a single molecule of V3
      targeted antibody.
AB  - Human immunodeficiency virus type-1 (HIV-1) infection generally provokes antibody
      responses to the viral envelope glycoprotein. Two major regions of gp120, the
      third variable (V3) domain and the CD4-binding site, have been identified as
      neutralization targets. The precise mechanism of HIV-1 neutralization by
      antibodies against the V3 domain is still unknown. It is shown that by kinetic
      neutralization studies, one molecule of V3-targeted monoclonal antibody (0.5beta)
      is enough to neutralize one virion. This antibody, which neutralized more than
      99% of the virus, inhibited the binding of the virus to cells by 42%. HIV-1
      pseudotyped with G glycoprotein from vesicular stomatitis virus was also
      neutralized by 0.5beta, suggesting that the antibody did not inhibit the viral
      attachment but caused some alteration in the envelope. These results indicate
      that the antibody plays an additional role on steric change of the envelope
      involved in inhibition of viral entry.

PMID- 12597361
TI  - Distribution of rat C5a anaphylatoxin receptor.
AB  - The anaphylatoxin, complement 5a (C5a), plays a key role in mediating various
      inflammatory reactions following complement activation. Several investigators
      have reported that C5a receptor (C5aR) is expressed in non-myeloid cells under
      certain conditions or in different cell lines. In our study, the abundance of
      C5aR-positive myeloid cells in rats depended on the organs examined. C5aR was
      usually expressed at the site of exposure to pathogens, such as in salivary gland
      or lung, and was up-regulated in liver in the inflammatory state induced by
      lipopolysaccharide (LPS) administration. Furthermore, the increased expression of
      C5aR antigen was not accompanied by an increase in C5aR mRNA in Kupffer cells
      following LPS challenge.

PMID- 12597362
TI  - Distribution of Aeromonas hydrophila serogroups in different clinical samples and
      the development of polyclonal antibodies for rapid identification of the genus
      Aeromonas by direct agglutination.
AB  - We characterized a collection of 256 Aeromonas hydrophila strains isolated from
      blood, discharge and stool for their serogroup designation. Of these, 2.3% were
      untypable and 15.2% were rough strains. Among the typable strains, about 50%
      comprised serogroups O:11, O:16, O:18, O:34 and O:83. To develop rapid
      differentiation of Aeromonas from other oxidase-positive bacteria, antisera
      against Aeromonas were produced to establish a direct, genus-specific,
      agglutination test. It was found that among 105 isolates of Aeromonas, 102 showed
      positive results with the agglutination test. The calculated sensitivity and
      specificity were 97.1% and 90.7%, respectively.

PMID- 12597363
TI  - Extracellular proteinase and phospholipase activity of three genotypic strains of
      a human pathogenic yeast, Candida albicans.
AB  - Strains of a human pathogenic yeast, Candida albicans, have (A) intronless, (B)
      intron-containing, and (C) a mixture of intron-containing and intronless 26S rRNA
      genes. To elucidate the significance of these three genotypes in pathogenesis, we
      measured two major virulence factors, extracellular proteinase and phospholipase
      activity, in 56 clinical isolates of C. albicans, and investigated the
      relationship between genotype and enzymatic activity. The genotype B strains had
      significantly higher proteinase and phospholipase activities than genotypes A or
      C. These results suggest that to understand the pathogenesis of C. albicans, the
      genotypes should be considered.

PMID- 12597364
TI  - Identification of genetic determinants that regulate tumorigenicity of Friend
      murine leukemia virus in rats.
AB  - A neuropathogenic variant of Friend murine leukemia virus (FrMLV), clone A8, has
      been shown to cause thymoma and infiltration of leukemic cells to organs at 7-8
      weeks post-infection in rats with a more rapid progression than clone 57. We have
      previously reported that the determinant for induction of aggressive leukemia in
      rats is located in the ClaI-AatII fragment containing the long terminal repeat
      (LTR) and the 5' half of the 5' leader sequence of A8 virus. Further studies of
      chimeric viruses restricted the determinant for the induction of thymoma to only
      the 0.6-kb ClaI-KpnI fragment of A8. This fragment contains a 0.1 kb region of
      the 3' terminus of the env gene, the intergenic region, the U3, and the 5' half
      of the R region in the LTR. Major differences in the fragment between A8 and 57
      viruses were found in the U3 region, especially in the enhancer motifs. These
      results indicate that the enhancer region of A8-LTR contributes to the
      manifestation of thymoma with rapid progression in rats.

PMID- 12597366
TI  - Leptin as a predictor of carcass composition in beef cattle.
AB  - Our objective was to determine if serum concentrations of leptin could be used to
      predict carcass composition and merit in feedlot finished cattle. Two different
      groups of crossbred Bos taurus steers and heifers were managed under feedlot
      conditions near Miles City, MT. The first group consisted of 88 1/2 Red Angus,
      1/4 Charolais, and 1/4 Tarentaise composite gene combination steers (CGC)
      harvested at the ConAgra processing facility in Greeley, CO. The second group
      (Lean Beef Project; LB) consisted of 91 F2 steers and heifers born to Limousin,
      Hereford, or Piedmontese by CGC F1 cows crossed to F1 bulls of similar breed
      composition and harvested at a local processing facility in Miles City, MT. Blood
      samples were collected approximately 24 h before harvest (CGC) or approximately 3
      d before and at harvest (LB). No differences in serum concentrations of leptin
      were detected (P > 0.10) between Hereford, Limousin, or Piedmontese F2 calves nor
      between LB steers and heifers. Positive correlations (P < 0.01) existed between
      serum leptin and marbling score (r = 0.35 and 0.50), fat depth measured between
      the 12th and 13th rib (r = 0.34 and 0.46), kidney, pelvic, and heart fat (KPH) (r
      = 0.42 and 0.46), and quality grade (r = 0.36 and 0.49) in CGC and LB cattle,
      respectively. Serum leptin was also positively correlated with calculated yield
      grade for CGC steers (r = 0. 19; P = 0. 10) and LB cattle (r = 0.52; P < 0.01).
      Longissimus area was not correlated with serum leptin in CGC steers (r = 0.12; P
      > 0.10). However, a negative correlation existed between longissimus area and
      serum leptin in the LB cattle (r = -0.45; P < 0.01). Serum concentrations of
      leptin were significantly associated with carcass composition (marbling, back fat
      depth, and KPH fat) and quality grade in both groups of cattle studied and may
      provide an additional indicator of fat content in feedlot cattle.

PMID- 12597365
TI  - Development of a mucosal complex vaccine against oral Salmonella infection in
      mice.
AB  - We examined the immunogenicity of a Salmonella enterica complex vaccine (CV),
      consisting of flagellin and polysome purified from serotype Typhimurium LT2. CV
      plus cholera toxin (CT), in three oral doses given at 7-day intervals, conferred
      complete protection on C57BL/6 mice against lethal oral infection with a wild
      type strain. It elicited mucosal IgA > IgG2a > IgG1 and systemic IgG2a > IgG1 >
      IgA antibodies to flagellin and polysome, and delayed footpad response (DFR) to
      both antigens. In Peyer's patches (PPs) and lamina propria (LP), IgA was produced
      under a Th1-dominant environment; CD4+T cells from produced interleukin (IL)-2,
      interferon (IFN)-gamma, and IL-10 by stimulation with salmonella extract. On the
      same protocol, flagellin plus CT induced flagellin-specific mucosal and systemic
      IgA and IgG1 antibodies, CD4+T cells producing IL-10 and IFN-gamma in PPs and LP,
      and only minimal levels of flagellin-specific DFR. Polysome plus CT induced
      polysome-specific mucosal and systemic IgG2a in addition to IgG1 and IgA
      antibodies, CD4+T cells producing IFN-gamma and IL-2 in PPs and LP, and polysome
      specific DFR. These two vaccines, however, conferred at most 50-60% survival
      rates. Our results suggest that polysomes in CV provide effective adjuvant
      activity for the induction of both mucosal and systemic Th1-biased responses
      toward flagellin.

PMID- 12597367
TI  - Effect of boar exposure at time of insemination on factors influencing fertility
      in gilts.
AB  - The effect of boar exposure during artificial insemination (AI) on semen
      backflow, fertilization, and embryo quality was evaluated. Gilts (approximately
      170 d) were induced into estrus with PG600, and ovulation was synchronized using
      hCG 72 h later. Estrus detection was initiated after PG600 and continued at 12-h
      intervals. At estrus, gilts were allotted to receive boar exposure (BE, n = 20)
      or no boar exposure (NBE, n = 20) during AI. Gilts receiving NBE were identified
      to be in estrus prior to AI and the boar was then removed for 1 h, whereas gilts
      in the BE group received 15 min of exposure during AI. Insemination occurred in
      crates at 12 and 24 h after onset of estrus with 3 x 10(9) sperm/80 mL. Backflow
      was collected continuously with samples taken at time 0, (during AI), and at
      0.25, 0.5, 0.75, 1, 2, 4, and 8 h after first and second AI. The effect of
      treatment was evaluated for time of insemination (min), backflow (mL), and sperm
      in backflow samples. Oviducts were flushed 2 d after first AI to evaluate the
      effect oftreatment on fertilization rate, accessory sperm numbers on embryos
      (scored 1 to 5), and embryo quality. There was no effect of first or second AI;
      therefore, data were pooled. Average duration of AI was 3.7 +/- 0.2 min and was
      not influenced by BE (P < 0.10). However, during the initial stage of AI, BE
      reduced the volume of semen (18.6 vs 32.4 +/- 3 mL) and the number of sperm lost
      (0.8 vs 1.3 +/- 0.15 x 10(9) sperm) compared to NBE (P < 0.05). There was a
      treatment x time effect (P < 0.05) for volume of backflow. By 45 min, the BE
      gilts lost more volume (9.0 vs 3.6 mL) compared to the NBE group, but sperm loss
      did not differ. Between 1 and 8 h after AI, neither volume nor sperm loss was
      influenced by treatment. By 8 h, total leakage (65 vs 63 mL) and total sperm loss
      (1.6 x 10(9) vs 1.8 x 10(9) sperm) were not influenced by BE (P > 0.10). However,
      more accessory sperm (P < 0.01) were found on embryos for the NBE (> or = 11
      sperm/embryo) compared to BE embryos (< or = 10 sperm/embryo). Despite this
      observation, percentages of fertilized embryos (99.5 +/- 0.5 %) and number of
      embryos (11.5 +/- 0.1) were not different (P > 0.10). In conclusion, AI in the
      presence of a mature boar did not affect total semen leakage, sperm loss,
      fertilized embryos, or embryo quality. The importance of boar exposure during
      insemination was evident from less leakage during insemination, but had no effect
      on fertility; this suggests that the elimination of boar exposure during AI may
      not be deleterious to reproductive performance.

PMID- 12597368
TI  - Ractopamine treatment biases in the prediction of pork carcass composition.
AB  - Carcass and live measurements of 45 barrows were used to evaluate the magnitude
      of ractopamine (RAC) treatment prediction biases for measures of carcass
      composition. Barrows (body weight = 69.6 kg) were allotted by weight to three
      dietary treatments and fed to an average body weight of 114 kg. Treatments were:
      1) 16% crude protein, 0.82% lysine control diet (CON); 2) control diet + 20 ppm
      RAC (RAC16); 3) a phase feeding sequence with 20 ppm RAC (RAC-P) consisting of
      18% crude protein (1.08% lysine) during wk 1 and 4, 20% crude protein (1.22%
      lysine) during wk 2 and 3, 16% crude protein (0.94% lysine) during wk 6, and 16%
      crude protein (0.82% lysine) during wk 6. The four lean cuts from the right side
      of the carcasses (n = 15/treatment) were dissected into lean and fat tissue. The
      other cut soft tissue was collected from the jowl, ribs, and belly. Proximate
      analyses were completed on these three tissue pools and a sample of fat tissue
      from the other cut soft tissue. Prediction equations were developed for each of
      five measures of carcass composition: fat-free lean, lipid-free soft tissue,
      dissected lean in the four lean cuts, total carcass fat tissue, and soft-tissue
      lipid mass. Ractopamine treatment biases were found for equations in which
      midline backfat, ribbed carcass, and live ultrasonic measures were used as single
      technology sets of measurements. Prediction equations from live or carcass
      measurements underpredicted the lean mass of the RAC-P pigs and underpredicted
      the lean mass of the CON pigs. Only 20 to 50% of the true difference in fat-free
      lean mass or lipid-free soft-tissue mass between the control pigs and pigs fed
      RAC was predicted from equations including standard carcass measurements. The
      soft-tissue lipid and total carcass fat mass of RAC-P pigs was overpredicted from
      the carcass and live ultrasound measurements. Prediction equations including
      standard carcass measurements with dissected ham lean alone or with dissected
      loin lean reduced the residual standard deviation and magnitude of biases for the
      three measures of carcass leanmass. Prediction equations including the percentage
      of lipid of the other cut soft tissue improved residual standard deviation and
      reduced the magnitude of biases for total carcass fat mass and soft-tissue lipid.
      Prediction equations for easily obtained carcass or live ultrasound measures will
      only partially predict the true effect of RAC to increase carcass leanness.
      Accurate prediction of the carcass composition of RAC-fed pigs requires some
      partial dissection, chemical analysis, or alternative technologies.

PMID- 12597369
TI  - Ovarian cyclicity in thyroid-suppressed ewes treated with propylthiouracil
      immediately before onset of seasonal anestrus.
AB  - Two experiments were conducted to determine if propylthiouracil (PTU)-induced
      thyroid suppression immediately before onset of anestrus would extend the
      breeding season in mature ewes. In Exp. 1, twice-weekly serum concentrations of
      progesterone indicated that all ewes were cyclic before initiation of treatment.
      Beginning on d 0 (January 17), ewes received 0 (n = 4), 20 (n = 5), or 40 (n = 5)
      mg of PTU x kg(-1) of body weight (BW) x (-1) for 35 d. Blood samples were
      collected regularly throughout the trial and serum thyroxine and progesterone
      were quantified. Ewe BW were similar (P > 0.90) among treatments before the
      experiment began (mean = 78.2 +/- 4.5 kg). Likewise, serum concentrations of
      thyroxine averaged 86.5 +/- 8.0 ng/mL on d 0. After 11 d of PTU treatment, serum
      thyroxine was 90.2,75.2, and 44.2 +/- 14.0 ng/mL in ewes receiving 0, 20, and 40
      mg of PTU/kg BW, respectively (linear effect, P = 0.04). On d 20, thyroxine
      values in the three respective groups were 73.0, 51.1, and 16.1 +/- 12.9 ng/mL
      (linear effect, P < 0.01). Fourteen days after PTU treatment ended, serum
      thyroxine did not differ (P = 0.53) among the three respective groups (71.4,73.3,
      and 57.5 +/- 11.8 ng/mL). Ewes receiving PTU tended to weigh less on d 42 (84.2,
      78.2, and 71.8 +/- 5.1 kg for ewes treated with 0, 20, and 40 mg PTU/kg,
      respectively; linear effect, P = 0.10). Day of onset of anestrus was designated
      as the day on which serum progesterone decreased and remained below 1 ng/mL. Ewes
      treated with 0, 20, or 40 mg of PTU/kg BW became anestrous on d 16,40, and 81 (+/
      12) of the experiment, respectively (linear effect, P < 0.01). At the time the
      35-d treatment period ended, 25, 60, and 100% of ewes receiving 0, 20, or 40 mg
      of PTU/kg exhibited normal estrous cycles. In Exp. 2, ewes received 0, 20, or 40
      mg of PTU/kg BW for 14 d. The dose was then decreased to 0, 10, and 20 mg of
      PTU/kg BW for the remaining 21 d. Serum thyroxine decreased to concentrations
      below 20 ng/mL by d 9 after initiation of PTU treatment. Ewe weights did not
      differ throughout the trial and no BW loss was observed. The average day that
      each group entered anestrus was similar to those in Exp 1. Large doses of PTU
      dramatically lower serum thyroxine and this effect appears to inhibit onset of
      anestrus in ewes.

PMID- 12597370
TI  - Estimation of genetic parameters for ultrasound-predicted percentage of
      intramuscular fat in Angus cattle using random regression models.
AB  - The present study included 3,358 observations of 675 bulls and heifers from the
      Iowa State University beef cattle breeding project. Data were collected over a 3
      yr period between 1998 and 2000. Each year, cattle were scanned four to six times
      for ultrasound-predicted percentage of intramuscular fat (UPFAT) and other
      ultrasound traits, starting at a minimum age of 28 wk. The objective of the
      current study was to estimate variance components, heritability, and
      repeatability of UPFAT in young bulls and heifers. Data were subjected to random
      regression animal models that included fixed effects of contemporary group, fixed
      Legendre polynomial of age at measurement, and random regression coefficients on
      Legendre polynomial of age at measurement for animals' direct genetic and direct
      permanent environmental effects. Phenotypic and genetic models involving
      different levels of polynomial fit for the animal component were considered. A
      model fitting a linear effect of Legendre polynomial of age at a measurement for
      animal direct genetic and direct permanent environmental effects and a
      homogeneous error variance described the present data adequately. Heritability of
      UPFAT ranged from 0.32 at 28 wk of age to a maximum of 0.53 at 63 wk.
      Repeatability of UPFAT increased from a minimum of 0.60 at ages of 28 to 39 wk to
      a maximum of 0.80 at ages 61 to 63 wk. Heritability and repeatability of yearling
      UPFAT were 0.50 and 0.71, respectively. With the exception of minor differences
      at earlier ages, fitting heterogeneous error variances did not have an effect on
      genetic parameter estimates for most ages of measurement. The present results
      showed an optimal heritability and repeatability of UPFAT measures around 52 wk
      and through at least 63 wk of age. This suggested that differences in UPFAT
      measures during this period also are good measures of differences in marbling
      genetic potential of Angus cattle.

PMID- 12597371
TI  - Genetic parameters and trends for litter traits in U.S. Yorkshire, Duroc,
      Hampshire, and Landrace pigs.
AB  - Records on 251,296 Yorkshire, 75,262 Duroc, 83,338 Hampshire, and 53,234 Landrace
      litters born between 1984 and April of 1999 in herds on the National Swine
      Registry Swine Testing and Genetic Evaluation System were analyzed. Animal model
      and restricted maximum likelihood procedures were used to estimate variances of
      animal genetic (a), maternal genetic (m), permanent environmental, and service
      sire, and the covariances between a and m for number born alive (NBA), litter
      weight at 21 d (L21WT), and number weaned (NW). Fixed effects of contemporary
      groups were included in the analysis. Based on a single-trait model, estimates of
      heritabilities were 0.10, 0.09, 0.08, and 0.08 for NBA; 0.08, 0.07, 0.08, and
      0.09 for L21WT; and 0.05, 0.07, 0.05, and 0.05 for NW in the Yorkshire, Duroc,
      Hampshire, and Landrace breeds, respectively. Estimates of maternal genetic
      effects were low and ranged from 0.00 to 0.02 for all traits and all breeds.
      Estimates of permanent environmental effects ranged from 0.03 to 0.08. Estimates
      of service sire effects ranged from 0.02 to 0.05. A bivariate analysis was used
      to estimate the genetic correlations among traits. Average genetic correlations
      over the four breeds were 0.13, 0.15, and 0.71 for NBA with L21WT, NBA with NW,
      and L21WT with NW, respectively. Average genetic trends were 0.018 pigs/yr, 0.114
      kg/yr, and 0.004 pigs/yr for NBA, L21WT, and NW, respectively. Although estimates
      of heritabilities for litter traits were low and similar across breeds, genetic
      variances for litter traits were sufficiently large to indicate that litter
      traits could be improved through selection. This study presents the first set of
      breed-specific estimates of genetic parameters available from large numbers of
      field records. It provides information for use in national genetic evaluations.

PMID- 12597372
TI  - Estimated genetic parameters for palatability traits of steaks from Brahman
      cattle.
AB  - Heritabilities and genetic and phenotypic correlations were estimated from
      carcass and beef palatability data collected from Brahman calves (n = 504) born
      in central Florida from 1996 to 2000. Traits evaluated included Warner-Bratzler
      shear force (after 7, 14, and 21 d of aging), panel tenderness score, connective
      tissue amount, juiciness, flavor intensity, and off flavor (after 14 d of aging),
      percentages of raw and cooked lipids, and milligrams per gram of muscle
      calpastatin activity. Parameters were estimated using an animal model and
      derivative-free restricted maximum likelihood procedures. Estimated
      heritabilities for d 7, 14, and 21 shear force were 0.14,0.14, and 0.06,
      respectively, indicating that improvement in these traits by selection would be
      slow. Estimated heritabilities of sensory panel attributes were 0.11, 0.12, 0.05,
      0.04, and 0.01 for tenderness, connective tissue amount, juiciness, flavor
      intensity, and off flavor, respectively. The estimated heritabilities for
      percentages of raw and cooked lipids, and calpastatin activity were 0.34, 0.17,
      and 0.07, respectively. Most of the estimated genetic correlations among
      palatability traits and for palatability traits with fat thickness, marbling
      score, and loin muscle area were consistent with other estimates from the
      literature. Results indicated that improvement in tenderness based on selection
      for favorable shear force, sensory panel tenderness, or calpastatin activity
      would be slow; therefore, postslaughter intervention programs should also be
      considered.

PMID- 12597373
TI  - Models with cytoplasmic effects for birth, weaning, and fleece weights, and
      litter size at birth for a population of Targhee sheep.
AB  - Fifteen models were compared for the birth weight of 33,994 lambs recorded at the
      U.S. Sheep Experimental Station (1950 to 1998). The initial intent was to
      estimate fractions of variance due to cytoplasmic line (c2; n = 892) and sire by
      cytoplasmic line interaction (sc2; n = 17,557). The basic model included direct
      genetic (fractional variance, a2; n = 35,684), maternal genetic (m2, with
      correlation r-am), and maternal permanent environmental (p2; n = 8,418) effects.
      The model with sc2 was significantly better than the basic model with and without
      c2. When other random effects were added, sc2 became zero. Significant effects
      were associated with random dam x year (dy2; n = 24,801), sire x dam (sd2; n =
      23,924), and dam x number born (dn2; n = 12,944) interaction effects. Estimates
      with all effects in the model were a2, 0.24; m2, 0.19; r-am, 0.11; p2, 0.05; c2,
      0.00; dn2, 0.04; dy2, 0.06; sd2, 0.05; sc2, 0.00. Estimates for a2, m2, and r-am
      were the same for all models. Estimate of p2 changed when other effects were
      added to the model. Largest estimates for nongenetic effects were: p2, 0.08; c2,
      0.00; dy2, 0.13; sd2, 0.11; and sc2, 0.04. Regardless of whether Westell groups
      (n = 91) were in the model, estimates were similar. For weaning weight (120-d, n
      = 32,715), estimates of variances of effects added to the basic model were all
      near zero (a2, 0.18; m2, 0.12; r-am, -0.01; p2, 0.06). For number born (NB, n =
      37,020) and fleece weight (FW, n = 36,197), animal permanent environmental
      effects were added to the model (ap2; n = 9,871 and 9,760) and r-am was dropped.
      For these traits, effects not in the basic model had small variances. Nonzero
      estimates with full model were a2, 0.10; ap2, 0.01; dy2, 0.02; and sc2, 0.01 for
      NB, and a2, 0.54; m2, 0.02; ap2, 0.02; dy2, 0.04; and sc2, 0.02 for FW.
      Cytoplasmic effects were not important. The addition of unusual random effects to
      the model did not change estimates for the basic parameters. Although some of
      these effects were significant, especially for BW, the effects on genetic
      evaluations are likely to be small.

PMID- 12597374
TI  - Identification of mitochondrial DNA substitutions related to meat quality in
      Japanese Black cattle.
AB  - Complete sequences of mitochondrial (mt) genomes of eight Japanese Black cattle
      were determined to investigate the relationships between mt deoxyribonucleic acid
      (DNA) displacement loop (D-loop) types and other mtDNA regions and to identify
      the variation in the coding region that may influence the economic traits. The
      survey of mitochondrial sequences in the encoding region revealed 14
      substitutions including six antonymous substitutions and one in 16S ribosomal
      ribonucleic acid (rRNA). Three methods of polymorphic DNA analyses (polymerase
      chain reaction [PCR]-restriction fragment length polymorphism [RFLP], mismatch
      PCR-RFLP, PCR-single-strand conformation polymorphism [SSCP]) were performed on
      these seven candidate substitutions (base pair [bp] 2,232, 12,158, 12,908,
      13,310, 14,122, 14,140, and 14,565) for 202 Japanese Black cattle. The
      substitution of bp 13,310 was observed in all samples, but not in the reference
      sequence, indicating that this is a minor substitution or a sequencing mistake in
      the reference sequence. The substitutions at bp 14,122, 14,140, and 14,565 were
      observed in only a few samples, suggesting that these were also minor
      substitutions. The substitutions at bp 2,232 (16S rRNA), 12,158, and 12,908
      (reduced nicotinamide adenine dinucleotide-ubiquinone oxidoreductase chain-5)
      were closely related to mitochondrial D-loop types that have previously been
      related to differences in the carcass traits of Japanese Black cattle. Evaluation
      of the effects on six carcass traits with mixed model procedures suggests that
      the bp 2,232 substitution affects longissimus muscle area and beef marbling
      score. The substitution at bp 2,232 is a strong candidate for the mitochondrial
      effect on meat quality.

PMID- 12597375
TI  - Correlated response in placental efficiency in swine selected for an index of
      components of lifter size.
AB  - The objective of this study was to evaluate correlated response in placental
      efficiency to selection for components of litter size. Fourteen generations of
      selection had resulted in a difference between lines of three fully formed
      piglets at birth. Gilts from a line selected for an index of components of litter
      size (S, n = 33) and a randomly selected control (C, n = 27) were observed at
      farrowing. At delivery, the umbilical cord of each piglet was double tagged with
      identically numbered mouse ear tags to allow the piglet's weight to be matched to
      the corresponding placental weight. Litter size, placental weight, birth weight,
      and placental vascularity were recorded. Litter size was higher (12.0 +/- 0.7 vs
      7.9 +/- 0.7) in S than in C (P < 0.001). Line differences in placental
      vascularity were not significant with or without adjustment for litter size (P =
      0.45 and 0.39, respectively). Correlated response to selection for components of
      litter size resulted in a reduced birth weight (S 82.6% of C, P < 0.001) and a
      reduced placental weight (S 90.9% of C, P = 0.11). After adjusting for litter
      size, line differences in neither placental weight nor birth weight were
      significant (P = 0.40 and 0.07, respectively), which indicates that the reduction
      in birth weight was, for the most part, due to the increase in litter size. The
      result of the difference in the magnitude of the change for both weights was that
      placental efficiency, measured as the ratio of birth weight:placental weight was
      0.43 higher in C (P = 0.05). Adjustment for litter size increased the difference
      in placental efficiency to 0.52 (P = 0.02). Since a significant difference in
      litter size favoring the selected line was observed, we hypothesize that this
      physiological response was achieved through mechanisms other than improved
      placental efficiency.

PMID- 12597376
TI  - Evidence of a major gene influencing hair length and heat tolerance in Bos taurus
      cattle.
AB  - Evidence was found that supports the existence of a major gene (designated as the
      slick hair gene), dominant in mode of inheritance, that is responsible for
      producing a very short, sleek hair coat. Cattle with slick hair were observed to
      maintain lower rectal temperatures (RT). The gene is found in Senepol cattle and
      criollo (Spanish origin) breeds in Central and South America. This gene is also
      found in a Venezuelan composite breed, the Carora, formed from the Brown Swiss
      and a Venezuelan criollo breed. Two sets of backcross matings of normal-haired
      sire breeds to Senepol crossbred dams assumed to be heterozygous for the slick
      hair gene resulted in ratios of slick to normal-haired progeny that did not
      significantly differ from 1:1. Data from Carora x Holstein crossbred cows in
      Venezuela also support the concept of a major gene that is responsible for the
      slick hair coat of the Carora breed. Cows that were 75% Holstein: 25% Carora in
      breed composition segregated with a ratio that did not differ from 1:1, as would
      be expected from a backcross matinginvolving a dominant gene. The effect of the
      slick hair gene on RT depended on the degree of heat stress and appeared to be
      affected by age and/or lactation status. The decreased RT observed for slick
      haired crossbred calves compared to normal-haired contemporaries ranged from 0.18
      to 0.4 degrees C. An even larger decrease in RT (0.61 degrees C; P < 0.01) was
      observed in lactating Carora x Holstein F1 crossbred cows, even though it did not
      appear that these cows were under severe heat stress. The improved
      thermotolerance of crossbred calves due to their slick hair coats did not result
      in increased weaning weights, possibly because both the slick and normal-haired
      calves were being nursed by slick-haired dams. There were indications that the
      slick-haired calves grew faster immediately following weaning and that their
      growth during the cooler months of the year was not compromised significantly by
      their reduced quantity of hair. In the Carora x Holstein crossbred cows there was
      a positive effect of slick hair on milk yield under dry, tropical conditions.

PMID- 12597377
TI  - Serum urea concentration as a predictor of dietary lysine requirement in selected
      lines of pigs.
AB  - Serum urea concentrations were measured in Large White pigs from lines
      divergently selected for components of efficient lean growth rate and performance
      tested over three 14-d test periods starting at 30, 50, and 75 kg. Two methods of
      performance testing were used. Phase-fed pigs were fed to appetite isoenergetic
      diets differing in total lysine:energy ratio (0.58, 0.69, 0.81, 0.91, 1.01, 1.12,
      and 1.23 g/MJ of digestible energy), whereas diet-choice pigs were offered a
      choice of the 0.69 and 1.12 lysine:energy diets. Between test periods, all
      animals were fed one diet: 0.91 g of lysine/MJ of digestible energy. The study
      consisted of 230 boars and gilts with 150 pigs performance tested on phase
      feeding and 80 pigs on diet-choice. The line selected for high lean food
      conversion had lower urea concentrations on each diet than the line selected for
      high lean growth rate, despite similar predicted lysine balances. Efficiency of
      lean growth rather than the rate of lean growth may be a better selection
      strategy in the context of nitrogen excretion. Urea concentrations at the end of
      each test period were correlated with lysine intake (0.33, 0.48 and 0.65;
      standard error, 0.08) and predicted lysine balance (0.39,0.44, and 0.64), but
      were uncorrelated with predicted lysine for protein deposition (0.01, 0.08, and
      0.08) and maintenance. Urea concentration at the end of a test period was not a
      useful predictor of protein deposition, even after accounting for pretest
      variation in urea concentration and food intake during test. The expected
      response pattern of serum urea concentration to diets differing in total
      lysine:energy would be nonlinear, with the point of inflection occurring at the
      required dietary total lysine:energy for each genotype. However, there was no
      evidence of such an inflection point such that the prediction of lysine
      requirement from urea concentration was not possible for the selection lines in
      the study.

PMID- 12597378
TI  - The impact of data structure on genetic (co)variance components of early growth
      in sheep, estimated using an animal model with maternal effects.
AB  - Several studies have noted high negative correlations between maternal genetic
      and direct additive effects and their influence on additive and maternal
      heritability of early growth traits in sheep. Multigeneration data from the
      Suffolk Sire Reference Scheme (SSRS) were used to investigate the effect of data
      structure on estimates of direct and maternal (co)variances for lamb 8-wk weight.
      In all analyses the additive, maternal genetic, maternal environmental, and
      residual effects were fitted along with the covariance between direct and
      maternal additive effects. The contributions of particular genetic relationships
      to the estimates were studied by analyzing subsets of the SSRS data. A further
      eight subsets were formed having 10% or 50% of the dams with their own records
      and having one or two, three or four, five or six, and more than six offspring
      per dam. Analysis of data having only 10% of the dams with their own record and
      one or two offspring records yielded a high negative correlation (-0.99) between
      direct and maternal genetic effects. However, the seven other data sets with more
      records per dam or a higher proportion of dams with their own records produced
      values of -0.35 to -0.51. Data structure and the number of dams and granddams
      with records are important determinants of estimated direct and maternal effects
      in early growth traits.

PMID- 12597379
TI  - Large round bale feeder design affects hay utilization and beef cow behavior.
AB  - One hundred sixty beef cows (631 +/- 78 kg) were used to evaluate the quantity of
      hay loss and feeding behaviors from different round bale feeders. Twenty cows
      were allotted by weight and body condition score to one of eight pens with four
      feeder designs: cone, ring, trailer, or cradle. All feeder types provided
      approximately 37 cm of linear feeder space per animal. Alfalfa and orchardgrass
      round bales were weighed and sampled before feeding. Hay that fell onto the
      concrete surrounding the feeder was considered waste and was collected and
      sampled daily. At the end of a 7-d period, each feeder type was assigned to a
      different pen for a second 7-d period. On four consecutive days in each period,
      animal behavior was recorded using a time-lapse video system. Data were collected
      from 5-min observational intervals from the video tapes every 0.5 h each day.
      Feeder access, occupancy rate, and occurrence of agonistic interactions were
      recorded. Dry matter hay waste was 3.5, 6.1, 11.4, and 14.6% for the cone, ring,
      trailer, and cradle feeders, respectively. Calculated dry matter intake of hay
      ranged from 1.8 to 2.0% of body weight and was not different among feeder type (P
      < 0.05). Percentage of organic matter, neutral detergent fiber, acid detergent
      fiber, and crude protein were all lower and acid detergent lignin was higher in
      the recovered waste compared to the hay fed (P < 0.05). Cows feeding from the
      cradle feeder had nearly three times the agonistic interactions and four times
      the frequency of entrances compared to cows feeding from the other feeder types
      (P < 0.05). Feed losses were positively correlated with agonistic interactions,
      frequency of regular and irregular entrances, and feeder occupancy rate (P <
      0.05). Agonistic interactions by cows and frequency of feeder entrances differed
      among feeders and were correlated to feeder design induced feed losses.

PMID- 12597380
TI  - Fenceline contact of beef calves with their dams at weaning reduces the negative
      effects of separation on behavior and growth rate.
AB  - The purpose of this study was to examine the hypothesis that fenceline contact
      between beef calves and cows at weaning reduces indices of behavioral distress
      and associated temporary reductions in weight gain. One hundred Angus/Hereford
      cross calves were randomly assigned to five treatments for 7 d in each of 3 yr to
      determine the effect of different weaning techniques on their behavior and
      subsequent growth. Treatments were 1) fenceline separation from dams on pasture
      (F-P), 2) total separation from dams on pasture (S-P), 3) total separation from
      dams in a drylot (corral) preconditioned to hay (S-D-P), 4) total separation from
      dams in a drylot not preconditioned to hay (S-D-NP), and 5) nonweaned controls on
      pasture (C-P). At the end of the 7-d postweaning period, all calves were placed
      on pasture in large groups. Calves were weighed weekly for 10 wk. In the days
      following weaning, F-P and C-P calves spent more time eating (grazing or eating
      hay) than S-P and S-D-NP calves (P < 0.05). The S-P calves spent more time
      walking (pacing) than calves in the other four treatments (P < 0.05), which did
      not differ. The S-P calves also spent less time lying down than C-P, F-P, and S-D
      P calves (P < 0.05); S-P and S-D-NP calves did not differ in lying time. The F-P
      calves vocalized less than S-P and S-D-NP calves (P < 0.05). In general,
      treatment differences were greatest during the first 3 d following weaning with d
      2 (20 to 30 h after weaning) showing the greatest disparity. The F-P calves spent
      approximately 60% of their time within 3 m of the fence separating them from
      their dams during the first 2 d following weaning, whereas F-P cows spent about
      40% of their time within 3 m of the fence during this period. Postweaning
      cumulative body weight gains of the F-P calves were greater than the gains
      recorded for the calves in the three totally separated treatments (which did not
      differ). The F-P calves gained 95% more weight than the average calf in the three
      totally separated treatments in the first 2 wk and were still heavier at 10 wk
      (21.4 vs 11.0 kg, respectively, at 2 wk and 50.0 vs 38.2 kg, respectively, at 10
      wk; P < 0.05). It was concluded that providing fenceline contact between beef
      calves and cows for 7 d following weaning reduces behavioral indices of distress
      seen in the totally separated calves. In addition, fenceline contact with dams at
      weaning minimizes losses in weight gain in the days following separation. Totally
      separated calves did not compensate for these early losses in weight gain even
      after 10 wk.

PMID- 12597381
TI  - Stereoselectivity of porcine beta-adrenergic receptors for ractopamine
      stereoisomers.
AB  - Ractopamine HCl is a beta-adrenergic receptor ((betaAR) ligand approved for use
      in swine to enhance carcass leanness. Ractopamine is produced commercially as a
      mixture of four stereoisomers (RR, RS, SR, SS). In order to determine which
      stereoisomers are active in the pig and whether they exhibit betaAR subtype
      selectivity, receptor affinity and adenylyl cyclase activation were determined
      using cloned porcine beta1- and beta2AR expressed in Chinese hamster ovary (CHO)
      cells. Dissociation constants (Kd) were determined by competitive displacement of
      [125I]iodocyanopindolol binding by ractopamine stereoisomers. The RR isomer had
      the highest affinity for both beta1- and betaAR (Kd of 29 and 26 nM,
      respectively). Dissociation constants for the other stereoisomers were higher (RS
      = 463 and 78 nM, SR = 3,230 and 831 nM, SS = 16,600 and 3,530 nM for the beta1-
      and beta2AR, respectively) relative to the RR stereoisomer. Isoproterenol
      stimulated adenylyl cyclase activity 600% relative to basal rates in CHO cells,
      regardless of betaAR subtype. Ractopamine stereoisomers did not significantly (P
      > 0.05) stimulate adenylyl cyclase through the beta1AR at moderate (near Kd) or
      high (10(-4) M) concentrations. In contrast, the RR isomer increased adenylyl
      cyclase activity 200 to 300% relative to basal rates through the beta2AR at
      moderate and hiconcentrations; the SR stereoisomer increased adenylyl cyclase
      activity nearly 100%. Neither the RS nor SS stereoisomers were effective in
      activating adenylyl cyclase activity through the beta2AR. A pattern of
      stereoselective activation similar to that for adenylyl cyclase also was
      exhibited for lipolysis using porcine adipocytes. The RR stereoisomer was equal
      to isoproterenol in stimulating lipolysis, whereas the SR isomer was 50% as
      effective; the RS and SR stereoisomers did not stimulate lipolysis in porcine
      adipocytes. The porcine betaAR exhibited stereoselectivity toward ractopamine
      stereoisomers with the RR isomer exhibiting the highest affinity for the (beta1-
      and beta2AR. In contrast, ractopamine stereoisomers seemed to be more effective
      at eliciting adenosine cyclic 3',5'-phosphate responses from beta2AR than
      beta1AR. The RR isomer ilikely the functional stereoisomer of ractopamine, but
      its effectiveness may be compromised by the presence of competing isomers, in
      particular the RS stereoisomer.

PMID- 12597382
TI  - Dietary manipulation of pro- and macroglycogen in porcine skeletal muscle.
AB  - The aim of the study was to investigate how feeding-induced changes in muscle
      glycogen stores affect the ratio of between the glycogen pools, pro- and
      macroglycogen. Pro- and macroglycogen content were determined in longissumus
      muscle from slaughter pigs subjected to a feeding strategy known to reduce total
      glycogen stores. Furthermore, early postslaughter glycolysis of the two glycogen
      forms was determined. The feeding strategy involved a diet (GLYRED diet) with a
      low digestible carbohydrate (5%)/high fat (18%) content, which was fed to the
      pigs the last 3 wk before harvest. A control group was fed a standard pig diet
      (49% digestible carbohydrate/5% fat). Total glycogen was reduced by 48 micromol/g
      dry weight (d.w.) in GLYRED pigs during the 3-wk feeding period. This was mainly
      due to a reduction in macroglycogen of 42 micromol/g d.w. During postmortem
      glycolysis the proglycogen appeared to be degraded in favor of macroglycogen.
      Moreover, total glycogen was degraded to a larger extent in muscle from the
      control pigs compared with muscle from GLYRED pigs. This difference was due to a
      significantly greater degradation of proglycogen in the control pigs. In
      conclusion, the results support earlier studies suggesting that proglycogen and
      macroglycogen are different glycogen pools that have different functions.
      Furthermore, the results show that the muscle glycogen pools can be manipulated
      through diet and that proglycogen is degraded in favor of macroglycogen under the
      anaerobic conditions postmortem.

PMID- 12597383
TI  - Effects of implant regimens (trenbolone acetate-estradiol administered alone or
      in combination with zeranol) and vitamin D3 on fresh beef color and quality.
AB  - In the first oftwo experiments, 123 calf-fed steers were used over a 2-yr period
      to evaluate the effects of trenbolone acetate (TBA)-based implants administered
      alone or in combination with zeranol implants on fresh beef muscle quality,
      color, and physiological maturity of the carcass. Implant treatments decreased (P
      < 0.05) a* values (d 0 and d 3 of retail display) and b* values (d 0, d 1, and d
      3 of retail display) after 14 d of aging. Carcasses from cattle initially
      implanted with Revalor-S and reimplanted with Revalor-S on d 60 of the finishing
      period showed increased lean and bone maturity scores and ash content of the 9th
      to 11th thoracic buttons and Warner-Bratzler shear force values (WBS) compared to
      those initially implanted with Ralgro and subsequently reimplanted with Revalor-S
      or control cattle. In addition, implants decreased (P < 0.05) marbling,
      percentage of the carcasses grading Choice, and kidney, pelvic, and heart fat
      (KPH). Implant treatments increased (P < 0.05) ADG, hot carcass weights, and
      longissimus muscle (LM) area. In the second experiment over a 2-yr period, 166
      steers fed as yearlings were allotted to one of two implant treatments and one of
      two vitamin D3 preharvest supplementation treatments. Implanted steers had
      heavier (P < 0.05) final body weights and higher (P < 0.05) ADG, less (P < 0.05)
      KPH fat, and larger (P < 0.05) LM. Also, implanted steers had more (P < 0.05)
      advanced bone maturity scores, higher (P < 0.05) ash content of the 9th to 11th
      thoracic buttons, and higher (P < 0.05) WBS values on 5-d postmortem loin steaks.
      Vitamin D3 feeding decreased (P < 0.05) final live weight, ADG (P < 0.05), and LM
      (P < 0.05), but did not significantly improve WBS values. In Experiment 2,
      neither implant treatment nor vitamin D3 supplementation had significant effects
      on L*, a*, or b* values of muscles in steaks before or during simulated retail
      display.

PMID- 12597384
TI  - Beef customer satisfaction: trained sensory panel ratings and Warner-Bratzler
      shear force values.
AB  - Trained sensory panel ratings and Warner-Bratzler shear force (WBS) values from
      the Beef Customer Satisfaction study are reported. Carcasses were chosen to fit
      into USDA quality grades of Top Choice (upper two-thirds of USDA Choice), Low
      Choice, High Select, and Low Select. A trained, descriptive attribute panel
      evaluated top loin, top sirloin, and top round steaks for muscle fiber
      tenderness, connective tissue amount, overall tenderness, juiciness, flavor
      intensity, cooked beef flavor intensity, and cooked beef fat flavor intensity.
      Four steaks from each of the three cuts from each carcass were assigned randomly
      to one of four cooking endpoint temperature treatments (60, 65, 70, or 75 degrees
      C) for WBS determination. For all trained panel measures of tenderness and WBS,
      regardless of USDA quality grade, top loin steaks were rated higher than top
      sirloin steaks, which were rated higher than top round steaks (P < 0.05). There
      were significant interactions between USDA quality grade and cut for most of the
      trained sensory panel traits: USDA quality grade influenced ratings for top loin
      steaks more than ratings for top round steaks or top sirloin steaks. Three
      interactions were significant for WBS values: USDA quality grade x endpoint
      temperature (P = 0.02), USDA quality grade x cut (P = 0.0007), and cut x endpoint
      temperature (P = 0.0001). With the exception of High Select, WBS values increased
      (P < 0.05) for each grade with increasing endpoint temperature. Choice top loin
      and top round steaks had lower (P < 0.05) WBS values than Select steaks of the
      same cut; however, only Top Choice top sirloin steaks differed (P < 0.05) from
      the other USDA grades. As endpoint temperatures increased, WBS values for top
      sirloin steaks increased substantially compared to the other cuts. When cooked to
      60 degrees C, top sirloin steaks were closer to top loin steaks in WBS values,
      when cooked to 75 degrees C, top sirloin steaks were closer to top round steaks
      in WBS values. Simple correlation coefficients between consumer ratings and
      trained sensory muscle fiber tenderness, connective tissue amount, overall
      tenderness, juiciness, flavor intensity, and cooked beef fat flavor were
      significant (P < 0.05), but values were low. While relationships exist between
      consumer and trained sensory measures, it is difficult to predict from objective
      data how consumers will rate meat at home.

PMID- 12597385
TI  - On-line prediction of yield grade, longissimus muscle area, preliminary yield
      grade, adjusted preliminary yield grade, and marbling score using the MARC beef
      carcass image analysis system.
AB  - The present experiment was conducted to evaluate the ability of the U.S. Meat
      Animal Research Center's beef carcass image analysis system to predict calculated
      yield grade, longissimus muscle area, preliminary yield grade, adjusted
      preliminary yield grade, and marbling score under commercial beef processing
      conditions. In two commercial beef-processing facilities, image analysis was
      conducted on 800 carcasses on the beef-grading chain immediately after the
      conventional USDA beef quality and yield grades were applied. Carcasses were
      blocked by plant and observed calculated yield grade. The carcasses were then
      separated, with 400 carcasses assigned to a calibration data set that was used to
      develop regression equations, and the remaining 400 carcasses assigned to a
      prediction data set used to validate the regression equations. Prediction
      equations, which included image analysis variables and hot carcass weight,
      accounted for 90, 88, 90, 88, and 76% of the variation in calculated yield grade,
      longissimus muscle area, preliminary yield grade, adjusted preliminary yield
      grade, and marbling score, respectively, in the prediction data set. In
      comparison, the official USDA yield grade as applied by online graders accounted
      for 73% of the variation in calculated yield grade. The technology described
      herein could be used by the beef industry to more accurately determine beef yield
      grades; however, this system does not provide an accurate enough prediction of
      marbling score to be used without USDA grader interaction for USDA quality
      grading.

PMID- 12597386
TI  - Effects of postexsanguination vascular infusion of cattle with a solution of
      saccharides, sodium chloride, and phosphates or with calcium chloride on quality
      and sensory traits of steaks and ground beef.
AB  - Grain-finished Hereford x Angus steers (n = 36) were assigned to one of three
      treatmentgroups. Immediately after jugular exsanguination, 12 steers were infused
      at 10% of live weight via the left carotid artery with a solution developed by
      MPSC, Inc. (St. Paul, MN) consisting of 98.52% water, 0.97% saccharides, 0.23%
      sodium chloride, and 0.28% phosphate blend (MPSC); 12 steers were infused at 10%
      of live weight with 0.30 M CaCl2 (CaCl2); and 12 steers were exsanguinated
      conventionally and served as noninfused controls (CON). Declines in pH for three
      muscles were measured. CaCl2-infused carcasses exhibited extensive muscle
      contraction at the time of cooler entry. Carcasses were graded at 24 h postmortem
      and fabricated at 48 h postmortem. Longissimus lumborum (LL), semitendinosus
      (ST), and quadriceps femoris (QF) muscles were removed, vacuum packaged, and
      stored at 2 degrees C until 14 d postmortem. Then, 2.54-cm-thick steaks were cut
      from the LL and ST for shear force and sensory evaluations. Ground beef was
      formulated from the QF to contain 20% fat. Steers infused with MPSC and CaCl2 had
      4.0 and 2.3% higher dressing percentage points, respectively, than CON steers.
      Calcium concentrations of the LL muscle for CaCl2- and MPSC-infused carcasses, as
      well as the CON carcasses, were 892.0, 158.9, and 216.6 ppm, respectively. For
      the TB and longissimus thoracis muscles, pH decline was more rapid for CaCl2- and
      MPSC-infused carcasses than for CON carcasses, but there were no differences in
      24-h pH. Warner-Bratzler shear force values were much higher (P < 0.05), and
      descriptive attribute sensory panel tenderness scores much lower (P < 0.05), for
      the LL from CaCl2-infused carcasses than for MPSC-infused and CON carcasses.
      Flavor intensity of the LL of CaCl2-infused carcasses was reduced (P < 0.05);
      however, overall tenderness and flavor of the ST were unaffected (P > 0.05) by
      CaCl2 infusion. Beef flavor identification, brown-roasted flavor, and
      bloody/serumy flavor were lowest and soapy/chemical flavor was highest (P < 0.05)
      for both freshly cooked and warmed-over LL from CaCl2-infused carcasses. There
      were no distinct meat quality advantages for infusing cattle with a solution of
      saccharides, sodium chloride, and phosphates. Infusion with 0.30 M CaCl2
      increased dressing percentage, but caused severe muscle contraction early
      postmortem, decreased LL tenderness markedly, and reduced flavor of LL steaks and
      ground beef.

PMID- 12597387
TI  - Serum concentrations of leptin in six genetic lines of swine and relationship
      with growth and carcass characteristics.
AB  - The objective of this study was to evaluate the relationship between serum
      concentrations of the hormone leptin with growth and carcass traits insix
      distinct breeds of pigs entered into the 2000 National Barrow Show Sire Progeny
      Test. Breeds evaluated were Berkshire (n = 131), Chester White (n = 33), Duroc (n
      = 40), Landrace (n = 23), Poland China (n = 26), and Yorkshire (n = 41). Serum
      samples were collected and assayed for concentrations of leptin at entry into
      test (On-Test Leptin) at 34 +/- 6.7 kg of live weight and again 24 h prior to
      harvest (Off-Test Leptin) at 111 +/- 3.1 kg of live weight. Carcass measurements
      taken included hot carcass weight, carcass length, backfat, longissimus muscle
      area (LMA), longissimus pH, Hunter L-value, chemically determined intramuscular
      fat (IMF), and subjective color, marbling, and firmness scores. Average daily
      gain, IMF percentages, and water-holding capacity (WHC) were also determined. On
      Test Leptin concentrations were not different (P > 0.10) between swine breeds;
      however, Off-Test Leptin concentrations did differ (P < 0.001) across genotype.
      Berkshire had the greatest Off-Test Leptin concentrations (6.58 +/- 0.43 ng/mL),
      and Duroc and Yorkshire had the lowest (3.49 and 3.96 +/- 0.68 ng/mL;
      respectively). In addition, Off-Test Leptin concentrations were correlated with
      average daily gain (r = 0.29; P < 0.001), last-rib fat thickness (r = 0.48; P <
      0.001), 10th rib backfat (r = 0.52; P < 0.001), LMA (r = -0.33; P < 0.001),
      percent fat-free carcass lean (r = -0.51; P < 0.001), and WHC (r = 0.15; P <
      0.05). Off-Test Leptin concentrations also differed by gender, with barrows
      having greater (P < 0.001) serum concentrations of leptin than gilts (6.55 +/-
      0.48 vs 3.35 +/- 0.44). Differences exist between breeds of pigs in a manner
      consistent with breed-specific traits for growth, leanness, and quality; thus,
      leptin may serve as a useful marker for selection or identification of specific
      growth and carcass traits.

PMID- 12597388
TI  - Effect of feather meal on live animal performance and carcass quality and
      composition of growing-finishing swine.
AB  - A total of 252 crossbred pigs were used in two experiments to determine the
      effect of feeding hydrolyzed feather meal (FM) during the growing-finishing
      period on animal performance, carcass composition, and pork quality. All pigs
      were blocked by weight, and dietary treatments were assigned randomly to pens
      within blocks. In Exp. 1, 24 pens were randomly assigned to one of three dietary
      treatments: 1) control corn-soybean meal starter, grower, and finisher diets
      devoid of FM; 2) control diets formulated with 3% FM; and 3) control diets
      formulated with 6% FM. During the starter phase, there was a quadratic decrease
      in average daily gain (P < 0.06) and gain:feed (P < 0.01) with increasing FM, and
      during the grower-II phase, gain:feed increased linearly (P < 0.07) with
      increasing FM inclusion level. However, dietary FM had no effects (P > 0.10) on
      performance during the grower-I phase, finisher phase, or in the overall trial.
      Moreover, carcasses from pigs fed 3% FM had greater (P < 0.05) average backfat
      depth than carcasses of pigs fed 0 and 6% FM, but FM did not affect (P > 0.10)
      ham or carcass lean composition. In Exp. 2, 24 pens were randomly allotted to one
      of four dietary treatments: 1) positive control corn-soybean meal-based starter,
      grower, and finisher diets; 2) negative control corn-soybean meal- and wheat
      middlings-based starter, grower, and finisher diets; 3) negative control diets
      formulated with 3% FM; and 4) negative control diets formulated with 6% FM.
      Dietary FM had no effect (P > 0.10) on average daily gain, average daily feed
      intake, or gain:feed during any phase of the experiment. Ham weight decreased
      linearly (P < 0.04), whereas ham lean weight increased linearly (P < 0.09), with
      increasing levels of FM in the diet. Pork from pigs fed 3% FM tended (quadratic
      effect, P < 0.10) to receive higher Japanese color scores than pork from pigs fed
      either negative control or 6% FM diets. Moreover, pork color became lighter (P c
      0.08), less red (P < 0.001), and less yellow (P < 0.003) as FM level was
      increased in swine diets. Results from these two experiments indicate that as
      much as 6% FM can be incorporated into isolysinic diets of growing-finishing pigs
      without adversely impacting animal performance, carcass composition, or pork
      quality.

PMID- 12597389
TI  - Effects of dietary fermentable carbohydrates on behavior and heat production in
      group-housed sows.
AB  - The effects of dietary nonstarch polysaccharides (NSP) on behavior and heat
      production in group-housed sows were studied. Twelve groups of six nonpregnant
      sows were fed one of four experimental diets that were similar in composition
      except for starch and NSP contents. Exchanging sugar beet pulp silage (SBPS) for
      tapioca created the difference in dietary starch and NSP ratio. On a dry matter
      (DM) basis, diets contained 0, 10, 20, or 30% SBPS. Sows were group-housed.
      Intake of fermentable NSP (fNSP) for diets containing 0, 10, 20, or 30% SBPS
      averaged 7.06, 9.18, 11.61, and 13.73 g x kg(-0.75) d(-1), respectively. Sows
      were fed, once a day at 0800. Dry matter intake for diets containing 0, 10, 20,
      or 30% SBPS, averaged 38.05, 38.38, 38.53, and 38.35 g x kg(-075) x d(-1),
      respectively, and ME intake averaged 523, 518, 514, and 493 kJ x kg(-0.75) x d(
      1), respectively. On average, sows spent 177 min/d on physical activity, of which
      8.8% was spent on eating. Time spent in physical activity was affected by diet (P
      = 0.005). Sows fed 0 or 10% SBPS spent more time on physical activity than sows
      fed 20 or 30% SBPS (P = 0.002). Energy cost of physical activity averaged 464 kJ
      x kg(-0.75) x d(-1) (standard estimated mean of 31) and was similar for diets (P
      = 0.679). Total heat production (HP) and activity-related heat production (AHP)
      were affected by diet (P < 0.05). Sows tended to be quieter when fNSP intake
      increased (P = 0.063). The effect of fNSP intake on HP and AHP was not constant
      during the day. During the night period, fNSP intake did not affect HP and AHP (P
      > 0.10). During the day period, increased fNSP intake decreased HP (P = 0.006)
      and tended to decrease AHP (P = 0.062). During eating, increased fNSP intake
      increased HP (P = 0.012) and tended to increase AHP (P = 0.074). Despite similar
      DMI, sows fed 0 or 10% SBPS spent less time eating than sows fed 20 or 30% SBPS
      (P = 0.009). Feed consumption rate was higher (P = 0.003) in groups fed 0 or 10%
      SBPS than in groups fed 20 or 30% SBPS. Feed consumption rate decreased by 0.19 g
      DM x kg(-0.75). min(-1) (P = 0.003) for each gram of fNSP intake. The energy
      saving effect of physical activity on the NE value of fNSP from SBPS ranged
      between 2.3 and 3.7 kJ/g of fNSP intake. In conclusion, intake of fNSP from SBPS
      affected energy expenditure for physical activity (P = 0.063); however, this
      effect was not constant during the day.

PMID- 12597390
TI  - Effect of chromium propionate and metabolizable energy on growth, carcass traits,
      and pork quality of growing-finishing pigs.
AB  - An experiment was conducted to evaluate the dietary effects of Cr propionate
      (CrProp) and metabolizable energy (ME) on growth, carcass traits, and pork
      quality of growing-finishing pigs. One hundred forty-four Cambrough-22 barrows
      were allotted to four dietary treatments in a randomized complete block design
      (six replicates of six pigs per replicate; average initial and final body weight
      were 27 and 113 kg, respectively). The dietary treatments were: 1) corn-soybean
      meal basal (B; low ME), 2) B + 200 ppb of Cr (as CrProp), 3) B + 200 kcal ME/kg
      (4.5% added fat; high ME), or 4) B + 200 kcal ME/kg + 200 ppb of Cr. At trial
      termination, three pigs per replicate were killed to determine dietary effects on
      carcass traits and pork quality. Overall average daily gain, average daily feed
      intake, and gain:feed ratio were not affected (P > 0.10) by diet. During the
      early growing period, average daily gain was increased in pigs fed the CrProp-low
      ME diets, but decreased in pigs fed the CrProp-high ME diets (Cr x ME, P < 0.04).
      Feed intake was increased (P < 0.05) in pigs fed the high-ME diets during the
      early growing period. Forty-five min and 24 h pH were not affected (P > 0.10) by
      diet. The CIE L* tended (P = 0.07) to be increased and shear force tended (P =
      0.06) to be decreased in pigs fed high-ME diets. Subjective marbling was
      increased (P < 0.03) and longissimus muscle percentage moisture and thaw loss
      were decreased (P < 0.04) in pigs fed CrProp. Chromium propionate had no
      consistent effect on growth and carcass traits in this experiment; however,
      CrProp did affect some aspects of pork quality.

PMID- 12597391
TI  - Chronic metabolic acid load induced by changes in dietary electrolyte balance
      increased chloride retention but did not compromise bone in growing swine.
AB  - The effects of chronic dietary acid loads on shifts in bone mineral reserves and
      physiological concentrations of cations and anions in extracellular fluids were
      assessed in growing swine. Four trials were conducted with a total of 38 (8.16 +/
      0.30 kg, mean +/- SEM) Large White x Landrace x Duroc pigs randomly assigned to
      one of three dietary treatments. Semipurified diets, fed for 13 to 17 d, provided
      an analyzed dietary electrolyte balance (dEB, meq/kg diet = Na+ + K+ - Cl-) of 
      35, 112, and 212 for the acidogenic, control, and alkalinogenic diets,
      respectively. Growth performance, arterial blood gas, serum chemistry, urine pH,
      mineral balance, bone mineral content gain, bone-breaking strength, bone ash, and
      percentage of bone ash were determined. Dietary treatments created a range of
      metabolic acid loads without affecting (P > 0.10) growth or feed intake. Urine pH
      was 5.71, 6.02, and 7.65 +/- 0.48 (mean +/- SEM) and arterial blood pH was 7.478,
      7.485, and 7.526 +/- 0.006 for pigs fed acidogenic, control, and alkalinogenic
      treatments, respectively. A lower dEB resulted in an increased (P < 0.001)
      apparent Cl- retention (106.6, 55.4, and 41.2 +/- 6.3 meq/d), of which only 1.6%
      was accounted for by expansion of the extracellular fluid Cl- pool as calculated
      from serum Cl- (105.5, 103.4, 101.6 +/- 0.94 meq/L (mean +/- SEM) for pigs fed
      acidogenic, control, and alkalinogenic treatments, respectively. A lower dEB did
      not decrease (P > 0.10) bone mineral content gain, bone-breaking strength, bone
      ash, percentage of bone ash, or calcium and phosphate balance. In conclusion,
      bone mineral (phosphate) was not depleted to buffer the dietary acid load in
      growing pigs over a 3-wk period.

PMID- 12597392
TI  - Impact of energy intake and pregnancy status on rate and efficiency of gain and
      backfat changes of sows postweaning.
AB  - A collaborative study was conducted to evaluate factors related to determining
      optimal feeding and management programs for increasing net returns from marketing
      cull sows. A total of 269 multiparous sows averaging 192 kg of body weight were
      weaned, moved to individual gestation crates, and assigned to one of eight
      treatment combinations in a 2 x 2 x 2 factorial arrangement for a 42-d
      postweaning feeding experiment. Factors included limited (L) (1.8 kg/sow/d) or ad
      libitum (AL) access to feed during wk 1 postweaning, a corn-soybean meal (corn)
      or barley-sunflower meal (barley) diet, and pregnant or nonpregnant status. All
      sows were provided ad libitum access to feed from wk 2 to 6 postweaning. Gain and
      feed intake (FI) data were collected weekly for each sow and used to calculate
      gain:feed (G/F). Ultrasonic backfat (BF) data were collected on d 0, 21, and 42
      postweaning. Sows on the AL treatment had greater FI (P < 0.05) but similar gain
      (P = 0.80) for the 42-d postweaning period compared to sows on the L treatment.
      Most of this response was due to lower sow body weight loss during wk 1
      postweaning (P < 0.01) when sows were provided AL (-7.2 kg) vs L (-13.2 kg)
      access to feed. Sows fed the corn diet had higher gain (P < 0.01), improved G/F
      (P < 0.01), and increased BF (P < 0.01) over the 42-d feeding period than sows
      fed barley. The corn diet resulted in less sow BW loss (P < 0.01) during wk 1 (
      8.8 kg) than the barley diet (-11.6 kg). Pregnant sows had higher gain, FI, G/ F,
      and BF (P < 0.01) than nonpregnant sows over the 42-d feeding period. Most of
      this advantage occurred during wk 4 postweaning when FI and gain of nonpregnant
      sows was lower (P < 0.01) than for pregnant sows. An economic analysis indicated
      that, when cull sow prices are relatively high and feed prices are moderate to
      low, maintaining and managing cull sows for an additional 6 wk postweaning may be
      economically advantageous compared to 0 or 3 wk. Pregnant sows fed the corn diet
      produced the greatest economic return. These results suggest that mating sows as
      they return to estrus postweaning and providing ad libitum access to a corn
      soybean meal diet improves growth performance and feed efficiency, and may
      thereby provide increased returns when marketing cull sows.

PMID- 12597393
TI  - Effect of ambient temperature on mammary gland metabolism in lactating sows.
AB  - Two groups of three multiparous Large White x Landrace sows were used to
      investigate the direct effect of ambient temperature on mammary gland metabolism.
      Sows from the first group were exposed to temperatures of 28 degrees C between d
      8 and 14 of lactation, and 20 degrees C between d 15 and 21; treatments were
      reversed in the second group. Four to six d after farrowing, an ultrasonic blood
      flow probe was implanted around the right external pudic artery and catheters
      were fitted in the right anterior mammary vein and in the carotid artery. After
      surgery all sows were fed 3.8 kg/d of a lactation diet. The arteriovenous (AV,
      mg/L) plasma samples were obtained every 30 min between 0915 and 1545 on d 5 of
      exposure to ambient temperature; the same day, milk samples were collected at
      1630. Additional arterial samples were obtained between 1000 and 1100 on d 1, 4,
      and 6 of exposure. Milk yield was estimated from the body weight gain of the
      litter. Elevated temperature tended to reduce BW loss (2.44 vs 1.82 kg/d, P <
      0.10), but did not affect milk yield (11.0 kg/d). Glucagon and leptin arterial
      concentrations increased (12 and 8%, respectively; P < 0.10), but thyroxin and
      triiodothyronine concentrations decreased (26 and 16%, respectively; P < 0.01)
      between 20 and 28 degrees C. Expressed as a percentage of total nutrients, AV
      difference, glucose, amino acids, triglycerides (TG), free fatty acids, and
      lactate A-V differences represented 60, 20, 11, 8, and 1%, respectively. Exposure
      to 28 degrees C increased the extraction rate of glucose, TG, and a-amino acid N
      (13, 8, and 2.5%, respectively; P < 0.10). The extraction rates of essential and
      nonessential amino acids were not affected by temperature. The right pudic artery
      mammary blood flow increased (872 vs 945 mL/min, P < 0.05) between 20 and 28
      degrees C, whereas milk yield was unaffected by temperature. It is suggested that
      this apparent inefficiency of the sow mammary gland in hot conditions could be
      related to an increase of proportion of blood flow irrigating skin capillaries in
      order to dissipate body heat.

PMID- 12597394
TI  - Evaluation of vaccination against methyllycaconitine toxicity in mice.
AB  - The purpose of this study was to determine whether larkspur toxins conjugated to
      protein carriers would promote active immunity in mice. Mice were injected with
      several larkspur toxin-protein conjugates or adjuvant alone to determine whether
      the resulting immunological response altered animal susceptibility to
      methyllycaconitine, the major toxic larkspur alkaloid. Although vaccinations
      increased the calculated lethal dose 50% (LD50) for intravenous
      methyllycaconitine toxicity, overlapping confidence intervals did not provide
      evidence of differences between the vaccinated and control groups. In the
      lycoctonine conjugate (LYC)-vaccinated group, mouse survival was related (P =
      0.001) to serum titers for methyllycaconitine doses up to 4.5 mg/kg of body
      weight. When mice withlow antibody titers were removed from the vaccinated groups
      in which titer was related to survival, the recalculated LD50 estimates were 20%
      greater than the LD50 of the control group. However, the 95% confidence intervals
      of the recalculated LD50 groups overlapped with the control groups. Overall,
      these results suggest that vaccination altered methyllycaconitine toxicity in
      mice and that vaccination may be useful in decreasing the effects of larkspur
      toxins in animals. Additional studies are warranted to continue development of
      potential larkspur vaccines for livestock.

PMID- 12597395
TI  - Effects of butyrate on apoptosis in the pig colon and its consequences for
      skatole formation and tissue accumulation.
AB  - Evidence exists that butyrate inhibits apoptosis of colon crypt cells in vivo so
      that less tryptophan from cell debris is available for skatole formation by
      microbes in the pig colon. In this study, potato starch containing a high
      proportion of resistant starch was fed to test the hypothesis that increased
      butyrate formation will occur in the colon and contribute to reduced epithelial
      cell apoptosis, thus leading to reduced skatole formation and absorption. Two
      groups of six barrows were provided with catheters in the jugular vein and fed
      either a ration with pregelatinized starch (high ileal digestibility; controls)
      or potato starch (low ileal digestibility; PS) as the main carbohydrate. All pigs
      were fed 31 MJ of metabolizable energy and 381 g of crude protein per day. The
      controls were fed for 19 d. The PS group received the same control ration for 10
      d, and then changed to the PS ration. The total feeding period of PS consisted of
      a 5 d adaptation period followed by another 19 d. In the continously sampled
      feces, pH, short chain fatty acids, and skatole were determined. Skatole was
      additionally measured in blood plasma that was sampled daily. After killing
      barrows at the end of the feeding period, fat tissue for skatole measurement and
      colon tissue for histological quantification of mitosis and apoptosis were
      obtained. Feeding potato starch led to a rapid 2.2 fold increase of fecal
      butyrate when compared both with the control period of the PS group and the
      control group (P < 0.001). PS feeding resulted in a decrease in pH from 7.3 to
      5.3 (P < 0.001) and apoptosis from 2.06 cells/crypt to 0.90 cells (P < 0.01),
      whereas there was no change in mitosis. Consequently, skatole decreased both in
      feces (controls vs PS group: 120.0 vs 1.9 microg/g; P < 0.001) and in blood
      plasma (1.6 vs 0.2 ng/mL; P < 0.001). The mean concentration of skatole in fat
      tissue was 167 ng/g tissue in controls, and below the detection limit (0.8 ng/g)
      in the PS group (P < 0.001). It is concluded that butyrate-dependent inhibition
      of apoptosis in the colon due to potato starch feeding efficiently inhibits
      skatole production in barrows. Because of the depressed skatole levels, improved
      sensory quality of pork is possible.

PMID- 12597396
TI  - Plasma gonadotropins and ovarian hormones during the estrous cycle in high
      compared to low ovulation rate gilts.
AB  - Mature gilts classified by low (12 to 16 corpora lutea [CL], n = 6) or high (17
      to 26 CL, n = 5) ovulation rate (OR) were compared for plasma follicle
      stimulating hormone (FSH), luteinizing hormone (LH), progesterone, estradiol
      17beta, and inhibin during an estrous cycle. Gilts were checked for estrus at 8-h
      intervals beginning on d 18. Blood samples were collected at 8-h intervals
      beginning on d 18 of the third estrous cycle and continued for one complete
      estrous cycle. Analysis for FSH and LH was performed on samples collected at 8-h
      intervals and for ovarian hormones on samples collected at 24-h intervals. The
      data were standardized to the peak of LH at fourth (d 0) and fifth estrus for the
      follicular phase and analyzed in discrete periods during the periovulatory (-1,
      0, +1 d relative to LH peak), early-luteal (d 1 to 5), mid-luteal (d 6 to 10),
      late-luteal (11 to 15), periluteolytic (-1, 0, +1 d relative to progesterone
      decline), and follicular (5 d prior to fifth estrus) phases of the estrous cycle.
      The number of CL during the sampling estrous cycle was greater (P < 0.005) for
      the high vs low OR gilts (18.8 vs 14.3) and again (P < 0.001) in the cycle
      subsequent to hormone measurement (20.9 vs 14.7). For high-OR gilts, FSH was
      greater during the ovulatory period (P = 0.002), the mid- (P < 0.05) and late
      luteal phases (P = 0.01), and tended to be elevated during the early-luteal (P =
      0.06), but not the luteolytic or follicular periods. LH was greater in high-OR
      gilts during the ovulatory period (P < 0.005), but not at other periods during
      the cycle. In high-OR gilts, progesterone was greater in the mid, late, and
      ovulatory phases (P < 0.005), but not in the follicular, ovulatory, and early
      luteal phases. Concentrations of estradiol-17beta were not different between OR
      groups during the cycle. Inhibin was greater for the high OR group (P < 0.005)
      during the early, mid, late, luteolytic, and follicular phases (P < 0.001). The
      duration of the follicular phase (from last baseline estrogen value to the LH
      peak) was 6.5 +/- 0.5 d and was not affected by OR group. These results indicate
      that elevated concentrations of both FSH and LH are associated with increased
      ovulation rate during the ovulatory phase, but that only elevated FSH during much
      of the luteal phase is associated with increased ovulation rate. Of the ovarian
      hormones, both inhibin and progesterone are highly related to greater ovulation
      rates. These findings could aid in understanding how ovulation rate is controlled
      in pigs.

PMID- 12597397
TI  - Age at puberty, total fat and conjugated linoleic acid content of carcass, and
      circulating metabolic hormones in beef heifers fed a diet high in linoleic acid
      beginning at four months of age.
AB  - In the current study, we hypothesized that diets high in linoleic acid would
      increase conjugated linoleic acid (CLA) tissue content, reduce adiposity and
      leptin production, and result in an increase in the age at puberty in heifers.
      Heifers were weaned and blocked by body weight (heavy, n = 10, and light, n = 10)
      and allocated randomly within block to receive isocaloric and isonitrogenous
      diets with either added fat (HF, n = 10) or no added fat (C, n = 10) from 4 mo of
      age until post-pubertal slaughter. Whole sunflower seed (55% oil; 70% linoleic
      acid) was used as the fat source in HF diets and provided 5% added fat from the
      start of the study until heifers weighed 250 +/- 8 kg, at which time added fat
      was increased to 7% of dry matter until slaughter. Body weights were recorded
      weekly, and blood samples were collected weekly for total cholesterol and hormone
      analyses. Puberty was confirmed based on serum concentrations of progesterone and
      ultrasonographic confirmation of corpora lutea. Heifers were slaughtered at 325
      +/- 10 d of age, and longissimus muscle between the 9th and 11th rib was
      collected and analyzed to estimate carcass composition. Subcutaneous and kidney,
      pelvic, and heart fat were collected at slaughter for fatty acid analyses. The HF
      heavy group tended (P < 0.10) to reach puberty later than all other groups, and
      one HF light heifer did not reach puberty during the study. Linoleic acid and cis
      9, trans-11 CLA tissue contents were higher (P < 0.03) in HF heifers than
      controls, but neither total carcass fat nor percentage of dry matter differed by
      dietary group, although the percentage of protein tended (P < 0.10) to be lower
      in HF heifers. Mean serum concentrations of leptin did not differ due to diet;
      however, leptin increased (P < 0.01) linearly as puberty approached. Circulating
      concentrations of growth hormone and insulin-like growth factor I increased or
      remained relatively constant between wk 2 to 10 of feeding, and then declined (P
      < 0.01) until the onset of puberty. Serum IGF-I was lower (P < 0.01) in heifers
      receiving the HF diet. Mean serum concentrations of insulin and total cholesterol
      increased (P < 0.01) with time in both groups, but only total cholesterol was
      increased by the HF diet (P < 0.05). Results indicate that diets high in linoleic
      acid fed to growing beef heifers beginning early in life have little or no effect
      on total carcass fat, circulating leptin, or age at puberty despite measurable
      increases in CLA accumulation.

PMID- 12597398
TI  - Influence of estradiol, progesterone, and nutrition on concentrations of
      gonadotropins and GnRH receptors, and abundance of mRNA for GnRH receptors and
      gonadotropin subunits in pituitary glands of beef cows.
AB  - Nutritionally induced anovulatory cows (n = 28) were used to determine the effect
      of steroids on regulation of synthesis and secretion of gonadotropins.
      Anovulatory cows were ovariectomized and received intravaginal inserts containing
      estradiol (E2), progesterone (P4), E2 and P4 (E2P4), or a sham intravaginal
      insert (C) for 7 d. Concentrations of luteinizing hormone (LH) and follicle
      stimulating hormone (FSH) were quantified in serum and E2 and P4 were quantified
      in plasma. Cows were exsanguinated within 1 to 2 h after removal of intravaginal
      inserts and pituitary glands were collected and stored at -80 degrees C until
      messenger ribonucleic acid (mRNA) for gonadotropin-releasing hormone receptor
      (GnRH-R) and gonadotropin subunits, pituitary content of GnRH-R, and LH and FSH
      were quantified. Pituitary glands from five proestrous cows were harvested to
      compare gonadotropin characteristics between ovariectomized, anovulatory cows and
      intact cows. Plasma concentrations of E2 were greater (P < 0.05) in E2-treated
      cows than in sham-treated cows. Concentrations of P4 were greater (P < 0.05) in
      cows treated with P4 than in sham-treated cows. Mean serum concentrations of LH
      and FSH were not significantly influenced by steroid treatments. However,
      frequency of LH pulses of ovariectomized, nutritionally induced anovulatory cows
      was increased (P < 0.05) by treatment with E2 and amplitude of LH pulses was
      greater (P < 0.05) in cows treated with E2 or P4 than in cows treated with E2P4
      or sham-treated. Quantity of mRNA for LHbeta in the pituitary gland was greater
      when cows were treated with P4. Concentrations of LH in the pituitary gland were
      not affected by steroid treatments; however, pituitary concentrations of FSH were
      less (P < 0.1) in E2 cows than in sham-treated cows. The number of GnRH-R was
      increased (P < 0.05) in cows treated with E2, but P4 treatment did not influence
      the number of GnRH-R. Abundance of mRNA for GnRH-R, common alpha-subunit, and
      FSHbeta were not affected by treatments. Pituitary concentrations of LH were
      greater (P < 0.05) and concentrations of FSH were less (P < 0.05) in proestrous
      cows than in ovariectomized, anovulatory cows treated with or without steroids.
      Abundance of mRNA for GnRH-R, common alpha-subunit, LHbeta and FSHbeta were
      similar for proestrous and anovulatory cows. We conclude that treatment of
      nutritionally induced anovulatory cows with progesterone and estradiol may cause
      pulsatile secretion of LH.

PMID- 12597399
TI  - Effects of prolactin administered to a perfused area of the skin of Angora goats.
AB  - It is suspected that prolactin may affect mohair growth; therefore, effects of
      infusing prolactin on mohair growth were investigated using a skin perfusion
      technique. Seven Angora wethers (average body weight, 30 +/- 3 kg) were implanted
      bilaterally with silicon catheters into the superficial branches of the deep
      circumflex iliac artery and vein. For the first 14 d of the experiment, animals
      were infused (2.4 mL/h) with prolactin (one side) or control (other side) into
      the deep circumflex iliac arteries. The infusion rate of prolactin was 2.21 mg/d
      and was calculated to triple prolactin blood concentration in the perfused
      region. The area of skin supplied by the deep circumflex iliac artery was
      approximately 240 cm2. Two weeks after the cessation of infusions, 100-cm2 areas
      within the perfused regions were shorn to determine mohair growth. Greasy and
      clean mohair production was decreased (P < 0.05) by prolactin compared with
      control (3.79 vs 4.62 and 3.02 vs 3.67 g/[100 cm2 x 28 d], respectively). Oxygen
      satura tion in blood hemoglobin from the deep circumflex iliac veins was greater
      (P < 0.02) on the side infused with prolactin than on the control side (75.1 vs
      68.2%). Higher concentrations of methionine, lysine, valine, isoleucine, and
      leucine were observed in blood of the deep circumflex iliac vein on the side
      infused with prolactin vs that infused with control (P < 0.05). In conclusion,
      direct skin infusion with prolactin decreased mohair fiber synthesis by the skin
      and may have concomitantly lessened oxygen consumption. Thus, effects of
      increasing prolactin concentration approximately two-fold in the skin on mohair
      fiber growth may not be limited to simple competition for nutrients between skin
      and other tissues such as the mammary gland.

PMID- 12597400
TI  - Role of ovarian progesterone and potential role of prostaglandin F2alpha and
      prostaglandin E2 in modulating the uterine response to infectious bacteria in
      postpartum ewes.
AB  - In sheep and cattle, the postpartum uterus is resistant to bacterial challenge
      until after corpora lutea develop. A 2 x 2 factorial arrangement of treatments
      was used to determine whether prostaglandins may mediate the effects of
      progesterone in transforming the postpartum uterus from resistant to susceptible.
      On d 14 postpartum, ewes (n = 6/group) were ovariectomized or sham
      ovariectomized, and the vena cava was catheterized for daily collection of
      uteroovarian-enriched blood. From d 15 to 20, ewes received twice daily
      intramuscular injections of progesterone in sesame oil or plain sesame oil. On d
      20, each uterus received 75 x 10(7) cfu of Arcanobacterium pyogenes and 35 x
      10(7) cfu of Escherichia coli. Uteri were collected on d 25 and examined for
      signs of infection. For each blood sample, unstimulated and mitogen-stimulated
      lymphocyte proliferation was measured as [3H]thymidine incorporation, smears were
      prepared for differential white blood cell (WBC) counts, and progesterone,
      prostaglandin F2alpha, (PGF2alpha), and prostaglandin E2 (PGE2) were quantified.
      All 12 progesterone-treated, but only two of the 12 oil-treated, ewes developed
      uterine infections (P < 0.001). Progesterone treatment increased (P < 0.001; 3.1
      vs 1.5 ng/mL) and ovariectomy decreased (P < 0.001; 3.7 vs 0.9 ng/mL) vena caval
      progesterone. Progesterone treatment reduced (P < 0.01) PGF2alpha, (303.9 vs
      801.3 pg/mL), and PGF2alpha was greater (P < 0.05) before than after inoculation
      (626.4 vs 478.8 pg/mL). The PGE2 concentration was greater in progesterone
      treated, ovary-intact ewes than in ewes in the other groups (ovariectomy x
      progesterone treatment; P < 0.01). Ovariectomy increased (P < 0.005; 4.4 vs 2.9
      pmol) and progesterone treatment decreased (P < 0.05; 3.2 vs 4.1 pmol)
      concanavalin A-stimulated lymphocyte proliferation. Ovariectomy increased
      lipopolysaccharides-stimulated proliferation (P < 0.05; 2.4 vs 1.9 pmol). For
      neutrophils per 100 WBC, the ovariectomy x progesterone and progesterone x period
      interactions were significant (P < 0.01). The ovariectomy x progesterone
      interaction was significant (P < 0.01) for lymphocytes per 100 WBC. Ovariectomy
      decreased monocytes (P < 0.001; 10 vs 13) and increased eosinophils (P < 0.001;
      10 vs 5) per 100 WBC. Progesterone makes the postpartum uterus in ewes
      susceptible to infection, but ovariectomy allows ewes to remain resistant;
      uterine prostaglandins may mediate this change. This model creates opportunities
      to determine the mechanisms responsible for the shift from resistance to
      susceptible.

PMID- 12597401
TI  - Liquid supplement and forage intake by range beef cows.
AB  - One hundred eighty crossbred cows were assigned to one of six native range
      pastures during two winters to evaluate forage and supplement intake as affected
      by liquid supplement (yr 1: 50% crude protein, 84% from urea; yr 2: 57% crude
      protein, 91% from urea) delivery method and cow age (2, 3, 4, 5, or 6 yr).
      Treatments were: 1) no supplement (Control); 2) a lick-wheel feeder containing
      liquid supplement (ADLIB); and 3) a computer-controlled lick-wheel feeder that
      dispensed 0.9 kg x cow(-1) x d(-1) of liquid supplement (average 0.5 kg of dry
      matter x cow(-1) x d(-1); Restricted). Each treatment was applied to two
      pastures. Forage digestibility was increased (P = 0.03) by supplementation.
      Supplemented cows lost less (P = 0.05) body condition than unsupplemented cows
      (average -0.3 vs -0.6). Blood urea nitrogen (BUN) was highest (P = 0.001) for
      ADLIB (8.7 mg/dL), intermediate for Restricted (6.2 mg/dL), and lowest for
      Control (2.3 mg/dL). Forage DMI was 31% higher (P = 0.01) in 1995 than in 1996,
      and was increased (P = 0.02) by supplementation both years. Cows supplemented
      with ADLIB consumed 23% more forage dry matter than Control cows, whereas
      Restricted cows consumed 21% more dry matter than ADLIB cows. Supplement intake
      by cows on ADLIB was greater (P = 0.001) than by cows on Restricted in both
      years. Supplement intake was lowest (P = 0.002) by 2-yr-old cows, intermediate by
      3-yr-olds, and greatest by 4-, 5-, and 6-yr-old cows. Variation in supplement
      intake by individual cows was higher (P = 0.09) for cows in the Restricted
      treatment (coefficient of variation [CV] = 117%) than those on ADLIB (CV = 68%)
      during the first year, but did not differ between supplement treatments (average
      CV = 62%) in the second year. The proportions of cows consuming less than 0.3
      kg/d of supplement dry matter intake (DMI) and consuming less than the target
      amount of supplement (0.5 kg DMI) were less (P = 0.001) for ADLIB than for
      Restricted during both years. ADLIB cows spent more (P = 0.001) time at the
      supplement feeder and had more (P < 0.002) supplement feeding bouts than
      Restricted cows during both years. During the first year, 2- and 3-yr-old cows
      spent less (P < 0.01) time at the feeder and had fewer feeding bouts per day than
      6-yr-old cows. Age had no effect (P > 0.24) on feeding behavior during the second
      year. Supplementation of beef cows grazing winter range with 50 to 57% crude
      protein liquid supplement increased forage digestibility and intake. Restricting
      supplement access increased forage consumption and variability of supplement
      intake.

PMID- 12597402
TI  - Effects of supplemental energy and/or degradable intake protein on performance,
      grazing behavior, intake, digestibility, and fecal and blood indices by beef
      steers grazed on dormant native tallgrass prairie.
AB  - To evaluate the effects of balancing total diet degradable intake protein with
      dietary total digestible nutrients (TDN), we conducted two studies during 2 yr
      with 100 (302 +/- 8 kg initial BW) mixed-breed yearling steers and 12 ruminally
      cannulated steers (526 +/- 28 kg). Steers individually received one of four
      supplements 5 d/wk while grazing dormant native tallgrass prairie. Supplements
      included: 1) corn and soybean meal, balanced for total diet degradable intake
      protein in relation to total diet TDN (CRSBM), 2) corn and soybean hulls, equal
      in supplemental TDN to CRSBM (CORN), 3) soybean meal, equal in supplemental
      degradable intake protein to CRSBM (SBM), or 4) a cottonseed hull-based control
      supplement (CONT). At each feeding (5 d/wk), steers consumed 13.6, 13.6, or 4.2 g
      of dry matter/kg of body weight, or 178 g of DM, respectively, of supplement.
      Steers fed CRSBM had greater (P < 0.01) average daily gain than cattle fed CORN
      or SBM. Feeding soybean meal (CRSBM, SBM) resulted in improved (P < 0.01)
      efficiency of supplement. Grazing time, intensity, and harvesting efficiency were
      reduced (P < 0.05) by corn supplementation (CRSBM and CORN), whereas the number
      of grazing bouts per day was increased (P < 0.08). Intake and digestibility of
      forage organic matter were reduced (P < 0.01) for steers supplemented with corn
      (CORN and CRSBM) vs cattle not fed corn (SBM and CONT). Total diet digestibility
      (P < 0.12) and digestible organic matter intake (P < 0.01) were greater for CRSBM
      fed steers than for cattle fed either CORN or SBM. Steers fed CRSBM had greater
      (P < 0.01) fecal nitrogen and serum insulin than cattle fed CORN or SBM. Corn-fed
      cattle had lesser (P < 0.01) fecal pH and ADF concentrations than steers not
      consuming grain. Cattle fed supplements with soybean meal (CRSBM and SBM) had
      greater (P < 0.01) serum urea nitrogen than steers fed supplements without
      soybean meal (CORN, CONT). Supplemented steers grazing dormant tallgrass prairie
      had a greater rate of gain, with the greatest response in animal performance
      occurring when grain supplements were balanced for total diet degradable intake
      protein in relation to total diet TDN. These results lead us to suggest that
      grain-supplemented cattle grazing dormant tallgrass prairie require a balance of
      total diet degradable intake protein in relation to total diet TDN to optimize
      animal performance.

PMID- 12597403
TI  - Effects of breed (Angus vs Simmental) and copper and zinc source on mineral
      status of steers fed high dietary iron.
AB  - Forty-four Angus (n = 24) and Simmental (n = 20) steers, averaging 301 kg
      initially, were used to determine the effects of breed and Cu and Zn source (SO4
      or proteinate (Prot) form) on Cu and Zn status of steers fed high dietary iron
      (Fe). Steers were stratified by weight within breed and randomly assigned to
      treatments. Treatments consisted of: 1) CuSO4 + ZnSO4 ,2) CuSO4 + ZnProt, 3)
      CuProt + ZnSO4, and 4) CuProt + ZnProt. Copper and Zn sources were added to
      provide 5 mg Cu and 25 mg supplemental Zn/kg DM. All steers were individually fed
      a corn silage-based diet supplemented with 1,000 mg Fe (from FeSO4)/kg DM. Liver
      biopsy samples were obtained at the beginning and end of the 149-d study. Serum
      samples were collected initially and at 28-d intervals for determination of
      ceruloplasmin activity and Zn and Cu concentrations. Copper and Zn source did not
      affect performance, serum or liver Cu and Zn concentrations, or ceruloplasmin
      activity. Copper status decreased (P < 0.01) in all steers with time, and
      increasing the level of supplemental Cu from 5 to 10 mg/kg DM on d 84 did not
      prevent further drops in serum Cu and ceruloplasmin. Simmental steers had lower
      (P < 0.05) serum and liver Cu concentrations, and serum ceruloplasmin activity
      throughout the study. These results indicate that neither CuSO4 nor CuProt were
      effective at the supplemental concentrations evaluated in alleviating the adverse
      effect of high Fe on Cu status. Simmental steers had lower Cu status than Angus,
      suggesting a higher Cu requirement.

PMID- 12597404
TI  - Effects of 9,10 anthraquinone on ruminal fermentation, total-tract digestion, and
      blood metabolite concentrations in sheep.
AB  - The objective of this study was to evaluate the effects of adding 9,10
      anthraquinone, a known inhibitor of methanogenesis and sulfate reduction, on
      blood metabolites, digestibility, and distribution of gas in sheep. In all
      experiments, we fed a complete pelleted diet that contained 17.5% crude protein
      and 24.5% acid detergent fiber. In an 8-wk study, feeding up to 66 ppm (dry
      matter basis) of 9,10 anthraquinone had no adverse effects on blood metabolites
      including indicators of normal enzyme function, mineral concentrations, and
      hematological measurements. Feeding 9,10 anthraquinone had no effect on average
      daily gain, although sheep fed a diet containing 66 ppm of 9,10 anthraquinone
      numerically gained the least weight. The ruminal molar proportions of acetic acid
      were decreased (P < 0.05) and the molar proportions of propionic acid were
      increased (P < 0.05) in sheep fed 1.5 and 66 ppm 9,10 anthraquinone when compared
      to those fed an unsupplemented diet. In a digestion trial, 9,10 anthraquinone (33
      and 66 ppm) had no effect on the apparent digestion of nutrients in the total
      gastrointestinal tract. In a metabolism study, ruminal gasses were collected by
      rumenocentesis and analyzed for methane and hydrogen concentrations. Feeding 500
      ppm of 9,10 anthraquinone to sheep resulted in a decrease (P < 0.07) in the
      concentration of methane, but an increase (P < 0.05) in hydrogen concentration of
      ruminal gas throughout the 19 d of feeding. There was no indication of ruminal
      adaptation throughout this time. These results are the first to show that 9,10
      anthraquinone can partially inhibit in vivo rumen methanogenesis, which supports
      previous in vitro findings. In addition, at the concentrations used in this
      study, 9,10 anthraquinone was not toxic to ruminants.

PMID- 12597405
TI  - Effects of urea infusion and ruminal degradable protein concentration on
      microbial growth, digestibility, and fermentation in continuous culture.
AB  - The effects of urea and rumen-degradable protein (RDP) on microbial growth,
      digestibility, and fermentation were examined using dual-flow continuous culture.
      The experimental design was a 4 x 4 Latin square with a 2 x 2 factorial
      arrangement of treatments. Factors were urea infusion (0.4 g/L of artificial
      saliva) and RDP concentration, and the treatments were as follows: 1) low RDP (8%
      of dietary dry matter) without urea (LDNU), 2) high RDP (11% of dietary dry
      matter) without urea (HDNU), 3) low RDP (8% of dietary dry matter) with urea
      (LDU), and 4) high RDP (11% of dietary dry matter) with urea (HDU). The LDNU
      (i.e., negative control) and HDNU treatments were formulated to be nitrogen
      limiting. Results indicated that infusion of urea increased all digestibility
      measurements (P < 0.05), which in turn increased (P < 0.05) volatile fatty acid,
      NH3 nitrogen, trichloroacetic acid-soluble nitrogen, and soluble protein
      concentrations. Increasing dietary RDP improved dry matter and organic matter
      digestibility (P < 0.05) but did not alter acid detergent fiber or nonfiber
      carbohydrate digestibilities (P > 0.05). Isobutyrate concentration decreased (P =
      0.05) with increased RDP. Increased dietary RDP increased crude protein
      degradation and soluble protein concentration (P < 0.05), but NH3 nitrogen,
      trichloroacetic acid-soluble nitrogen, and peptide nitrogen were unaffected by
      changing RDP levels. Microbial growth efficiency was 19.9, 24.9, 28.0, and 32.2 g
      N/g organic matter truly digested for LDNU, HDNU, LDU, and HDU, respectively, and
      was significantly improved both by urea infusion (P = 0.002) and increased RDP
      concentration (P = 0.021). The interactions of urea and RDP (P < 0.05) were
      explained by the high digestibility of neutral detergent fiber, nonstructural
      carbohydrate, and especially hemicellulose, with the HDNU treatment. The results
      of this study indicated that hemicellulose-degrading bacteria were able to
      effectively compete with nonstructural carbohydrate-degrading bacteria for
      available peptide and amino acid nitrogen. Further, the extent of protein
      degradation was dependent on the availability of NH3 nitrogen in the system.

PMID- 12597406
TI  - Emergency declared: exotic Newcastle disease found in commercial poultry farms.

PMID- 12597407
TI  - A profession at the crossroads?

PMID- 12597408
TI  - Is AMDUCA enough? Animal Medicinal Drug Use Clarification Act.

PMID- 12597409
TI  - Several take issue with commentary on racial diversity.

PMID- 12597410
TI  - Several take issue with commentary on racial diversity.

PMID- 12597411
TI  - Several take issue with commentary on racial diversity.

PMID- 12597412
TI  - High-dose glucosamine associated with polyuria and polydipsia in a dog.

PMID- 12597413
TI  - Observations on perceived shortage of food animal veterinarians.

PMID- 12597414
TI  - No significant difference: use of statistical methods for testing equivalence in
      clinical veterinary literature.

PMID- 12597415
TI  - What is your diagnosis? Pericardial effusion with a clot in the pericardial space
      likely caused by left atrial rupture secondary to mitral regurgitation.

PMID- 12597416
TI  - Plague: a veterinary perspective.

PMID- 12597417
TI  - Isolation of Staphylococcus schleiferi from dogs with pyoderma.
AB  - OBJECTIVE: To determine frequency with which Staphylococcus schleiferi could be
      isolated from dogs with pyoderma and antimicrobial susceptibility patterns of
      isolates that were obtained. DESIGN: Prospective study. ANIMALS: 54 dogs with a
      first (n = 14) or recurrent (40) episode of pyoderma. PROCEDURE: Specimens were
      obtained and submitted for bacterial culture. Isolates were identified as S
      schleiferi on the basis of growth and biochemical characteristics. Two isolates
      were submitted for DNA sequencing to confirm identification. Methicillin
      susceptibility was determined by means of disk diffusion with oxacillin
      impregnated disks. RESULTS: 3 of 14 dogs examined because of a first episode of
      pyoderma and 12 of 40 dogs examined because of a recurrent episode of pyoderma
      were receiving antimicrobials at the time of specimen collection. Staphylococcus
      schleiferi was not isolated from any dog with first-time pyoderma but was
      isolated from 5 dogs with recurrent pyoderma that were not receiving
      antimicrobials at the time of specimen collection and 10 dogs with recurrent
      pyoderma that were receiving antimicrobials. Nine isolates were identified as S
      schleiferi subsp schleiferi, and 6 were identified as S schleiferi subsp
      coagulans. All S schleiferi subsp schleiferi isolates were resistant to
      methicillin, but only 2 S schleiferi subsp coagulans isolates were. Two
      methicillin-resistant isolates were also resistant to fluoroquinolones, and 1
      isolate had intermediate susceptibility to fluoroquinolones. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results suggest that S schleiferi subsp schleiferi and S
      schleiferi subsp coagulans may be isolated from dogs with recurrent pyoderma.
      Although isolates from dogs with pyoderma were frequently resistant to
      methicillin, multiple drug resistance was uncommon.

PMID- 12597418
TI  - Use of portocaval venografts with ameroid constrictor placement and hepatic
      lobectomy for treatment of intralobular intrahepatic portocaval shunts in four
      dogs.
AB  - Liver lobectomy for complete attenuation of intrahepatic portosystemic shunts
      appears to be a safe and effective surgical treatment. When the intrahepatic
      shunt vessel can be definitively palpated within a liver lobe or its presence
      confirmed portographically, liver lobectomy represents a technically simple and
      effective method of complete shunt attenuation. To maintain portal pressure at an
      acceptable value after lobectomy, an extrahepatic portocaval shunt vessel can be
      created by use of an external jugular vein graft. A second shunt vessel can be
      created if portal pressure remains increased after placement of 1 shunt. Gradual
      and safe attenuation of the shunt vessel is achieved by placement of an ameroid
      constrictor on the extrahepatic graft at the time of the initial surgery.

PMID- 12597419
TI  - Clinical, clinicopathologic, and radiographic findings in dogs with
      coccidioidomycosis: 24 cases (1995-2000).
AB  - OBJECTIVE: To determine clinical, clinicopathologic, and radiographic
      abnormalities in dogs with coccidioidomycosis. DESIGN: Retrospective case series.
      ANIMALS: 24 dogs. PROCEDURE: Clinical information and results of
      clinicopathologic testing were obtained from medical records. Thoracic
      radiographs were reviewed to characterize abnormalities. RESULTS: Dogs ranged
      from 1 to 10 years old at the time of diagnosis, with 12 dogs being between 1 and
      3 years old. Historical complaints included cough, lameness, signs of head or
      neck pain, and difficulty breathing. Mild anemia, neutrophilia, and monocytosis
      were common. All dogs had hypoalbuminemia, and 8 of 15 had hyperglobulinemia.
      Thoracic radiographs of 19 dogs were reviewed. Pulmonary infiltrates were seen in
      13 dogs, with an interstitial pattern of infiltration being most common. Hilar
      lymphadenopathy was seen radiographically in 10 dogs. Serum from 20 dogs was
      tested for antibodies against Coccidioides immitis. One dog was positive for IgM
      antibodies, 5 were positive for IgM and IgG antibodies, and 14 were positive for
      IgG antibodies. Quantitative IgG titers measured in 14 dogs ranged from 1:2 to
      1:128 (median and mode, 1:32). In 6 dogs, histologic examination of biopsy
      samples revealed fungal spherules ranging from 8 to 70 microm in diameter.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in dogs,
      coccidioidomycosis may be associated with a wide spectrum of nonspecific
      respiratory and musculoskeletal abnormalities. The chronic nature of the disease
      makes diagnosis difficult, even in regions in which the organism is endemic.

PMID- 12597420
TI  - Evaluation of equine breeding farm characteristics as risk factors for
      development of Rhodococcus equi pneumonia in foals.
AB  - OBJECTIVE: To identify farm characteristics as risk factors for the development
      of Rhodococcus equi pneumonia in foals. DESIGN: Prospective matched case-control
      study. ANIMALS: 2,764 foals on 64 equine breeding farms with 9,991 horses.
      PROCEDURE: During 1997, participating veterinarians completed paired data
      collection forms, 1 for a farm with > or = 1 foal with R equi pneumonia and 1 for
      an unaffected control farm. Matched data were compared by use of conditional
      logistic regression analysis. RESULTS: Farm characteristics found in bivariate
      analyses to be associated with increased risk for pneumonia caused by R equi in
      foals included > 200 farm acres, > or = 60 acres used in the husbandry of horses,
      > 160 horses, > or = 10 mares housed permanently on the farm (resident mares), >
      17 foals, > 0.25 foals/acre, and the presence of transient mares (mares brought
      temporarily to the farm for breeding or foaling) and their foals. Affected farms
      were significantly more likely to be > 200 acres in size and have > or = 10
      resident dam-foal pairs, whereas control farms were significantly more likely to
      have > or = 75% of their dam-foal pairs housed permanently on the farm.
      CONCLUSIONS AND CLINICAL RELEVANCE: Breeding farms with large acreage, a large
      number of mares and foals, high foal density, and a population of transient mares
      and foals are at high risk for foals developing pneumonia caused by R equi.

PMID- 12597421
TI  - Evaluation of equine breeding farm management and preventative health practices
      as risk factors for development of Rhodococcus equi pneumonia in foals.
AB  - OBJECTIVE: To determine whether foal management practices, environmental
      management, and preventative health practices are risk factors for development of
      Rhodococcus equi pneumonia in foals. DESIGN: Prospective matched case-control
      study. ANIMALS: 2,764 foals on 64 equine breeding farms with 9,991 horses.
      PROCEDURE: During 1997, participating veterinarians completed paired data
      collection forms for comparison; 1 for an affected farm (containing > or = 1 foal
      with pneumonia caused by R equi) and 1 for a control farm. Information collected
      pertained to stabling facilities, environmental management, foal husbandry, and
      preventative equine health practices. RESULTS: Matched farm data compared by use
      of conditional logistic regression indicated that personnel on affected farms
      were more likely to attend foal births, test foals for adequacy of passive
      immunity, administer plasma or other treatments to foals to supplement serum
      immunoglobulin concentrations, administer hyperimmune plasma prophylactically to
      foals, vaccinate mares and foals against Streptococcus equi infection, and use
      multiple anthelmintics in deworming programs. Affected farms were also more
      likely to have foals that developed other respiratory tract disorders and were
      approximately 4 times as likely to have dirt floors in stalls used for housing
      foals as were control farms. CONCLUSIONS AND CLINICAL RELEVANCE: Rhodococcus equi
      pneumonia does not appear to be associated with poor farm management or a lack of
      attention to preventative health practices. Housing foals in stalls with dirt
      floors may increase the risk for development of R equi pneumonia.

PMID- 12597422
TI  - Malignant Sertoli cell tumor in the retained abdominal testis of a unilaterally
      cryptorchid horse.
AB  - A 13-year-old Morgan gelding was evaluated because of a mass in the caudal region
      of the abdomen. The horse had been presumed to be a gelding, but necropsy
      findings revealed a retained testis in the right retroperitoneal space.
      Histologically, the retained testis contained neoplastic cells; metastases were
      identified in the liver, spleen, lungs, and sublumbar lymph nodes.
      Immunohistochemical examination of the testis and metastatic tissues confirmed
      the diagnosis of malignant Sertoli cell tumor. Testicular neoplasms are
      infrequently reported in stallions. Seminomas are most commonly reported, whereas
      Sertoli cell tumors are considered to be rare. Typical biological behavior of
      Sertoli cell tumors in horses is unknown. To the authors' knowledge, there have
      been 2 reports of Sertoli cell tumors in horses; the tumors developed in
      descended testes, and 1 tumor was malignant.

PMID- 12597423
TI  - Stress fractures of the tibia and humerus in Thoroughbred racehorses: 99 cases
      (1992-2000).
AB  - OBJECTIVE: To determine clinical characteristics of and outcome in Thoroughbred
      racehorses with tibial or humeral stress fractures. DESIGN: Retrospective study.
      ANIMALS: 99 Thoroughbreds with tibial or humeral stress fractures. PROCEDURE:
      Information obtained from the medical records included history, signalment, and
      clinical, radiographic, and scintigraphic findings. Outcome was determined by
      interviewing trainers, performing follow-up examinations, and analyzing race
      records. RESULTS: Seventy-four tibial stress fractures were identified in 61
      Thoroughbreds, and 48 humeral stress fractures were identified in 39
      Thoroughbreds (1 horse was included in both groups). Tibial stress fractures
      occurred most commonly in 2-year-old or unraced horses. Fractures were located in
      1 of 3 sites in the tibia (most commonly, the caudolateral cortex of the mid
      diaphysis) and 1 of 4 sites in the humerus (most commonly, the caudodistal
      cortex). Forty-four of 58 (76%) tibial stress fractures and 18 of 32 (56%)
      humeral stress fractures were identified radiographically. Humeral stress
      fractures involving the caudodistal cortex were not detected radiographically.
      Treatment consisted of rest and exercise restriction, and 49 of 61 (80%) horses
      with tibial stress fractures and 30 of 39 (77%) horses with humeral stress
      fractures returned to racing. Humeral stress fractures recurred in 6 horses.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that in Thoroughbred
      racehorses, tibial stress fractures occurred most commonly in unraced 2 year
      olds, whereas humeral fractures occurred most commonly in older horses that had
      raced previously. The prognosis for racing following treatment was good.

PMID- 12597424
TI  - Toxicologic pathology: looking ahead.
AB  - The field of toxicologic pathology is being impacted, as are other fields of
      science and medicine, by rapid transitions to take advantage of new science and
      technology. The new technology represents great opportunities to advance our
      understanding of toxicology and pathology to exciting new levels, but it also
      poses new challenges. We must be seriously engaged in that transition to assure
      that the outcome reflects the knowledge and discipline that are hallmarks of
      today's decision-making process in areas of product development and approval. New
      expertise will be required to deal with new issues. How well and how rapidly we
      adapt as the field moves from "...icities" to "...omics" will, at least in part,
      determine the role of toxicologic pathologists in the product development and
      approval processes of the future.

PMID- 12597425
TI  - Factors affecting the interpretation of canine and nonhuman primate clinical
      pathology.
AB  - Interpreting canine and nonhuman primate clinical pathology data from preclinical
      studies can be challenging. Relatively few animals are tested (typically beagles
      and macaques), and they often undergo study-related procedures (eg, sample
      collection for pharmacokinetic analysis) that can affect clinical pathology test
      results. Data interpretation requires an understanding of the significance of
      each test, species differences for each test, normal interanimal and intraanimal
      variability, the effects of study design variables, and supporting data from
      other disciplines. Interpretation of hematology, coagulation, clinical chemistry,
      and urinalysis parameters are discussed, with emphasis on species peculiarities
      and study design variables that may affect clinical pathology test results.

PMID- 12597426
TI  - The dog's role in the preclinical assessment of QT interval prolongation.
AB  - During the development of a new therapeutic, few pharmacodyamic outcomes
      currently receive as much scrutiny as the effect of a potential medication on the
      electrocardiographic QT interval. The recent withdrawal from marketing of several
      drugs due to potential drug-related cardiac arrhythmias have greatly increased
      concern about drug-related changes on the QT interval. In order to reduce the
      incidence of these idiosyncratic episodes, regulatory agencies have suggested
      that sponsors use more rigorous methodology during the safety evaluation of new
      pharmaceuticals. Along with enhanced electrocardiographic assessments during
      clinical trials, advanced preclinical examinations of effect on QT interval and
      ventricular repolarization have become de rigueur. In this arena, the beagle dog
      is the preclinical species often associated with the most reliable predictivity
      for human safety assessment. To this end, canine models of cardiovascular safety
      assessment are discussed along with the relevance of these assays to human
      electrocardiography.

PMID- 12597427
TI  - Issues related to the use of canines in toxicologic pathology--issues with
      pharmacokinetics and metabolism.
AB  - The dog is a commonly used animal model by virtue of its size, well-characterized
      physiology, and ease of handling. For these reasons and others, dogs are also
      useful in pharmacokinetic and metabolism studies during the development of both
      human and veterinary pharmaceutical products. In comparison with humans, or with
      other animals, dogs have some unique physiologic attributes that can affect the
      disposition of drugs. Species differences in gastrointestinal physiology,
      metabolism, renal function, and protein binding can affect the correlation of the
      pharmacokinetics and toxicology of dogs with those of other species. With the use
      of relevant examples, this article will provide an introduction to
      characteristics of dog physiology and their impact on pharmacokinetics,
      metabolism, drug disposition, toxicity, and dose selection.

PMID- 12597428
TI  - Differentiating spontaneous from drug-induced vascular injury in the dog.
AB  - When vascular injury is observed in dogs used in preclinical toxicology studies,
      careful evaluation of the lesions is warranted, especially when differentiating
      drug-induced vascular changes from spontaneous findings, such as idiopathic
      canine polyarteritis. The clinical signs as well as the nature and distribution
      of lesions can often be distinguishing, as is the case with vasoactive drugs,
      including vasodilators and/or positive inotropes (hydralazine, minoxidil,
      endothelin receptor antagonists, and phosphodiesterase III inhibitors). For most
      types of vasodilator-induced vascular injury, the lesion is often restricted to
      coronary arteries, whereas in idiopathic canine polyarteritis, arterial lesions
      not only involve coronary arteries, but also medium to small arteries of other
      organs. In addition, the nature of the changes in vessels yields important clues.
      Medial and adventitial hemorrhage is generally associated with vasodilator
      induced arterial lesion, whereas hemorrhage is generally absent in idiopathic
      polyarteritis. Although idiopathic canine polyarteritis can generally be
      differentiated from vasoactive-induced vascular injury in dogs, there are
      increasing incidences of this type of polyarteritis in dogs receiving any 1 of a
      number of unrelated classes of compounds, suggestive of an exacerbation of the
      spontaneous disease. Therefore, in order to differentiate drug-induced injury
      from idiopathic canine polyarteritis, it is critical that examination of the
      vascular pathology be conducted with good understanding of clinical,
      pharmacological, and mechanistic data associated with the drug.

PMID- 12597429
TI  - Evaluation of large-sized brains for neurotoxic endpoints.
AB  - Sampling of large-sized brains (eg, dog, primate) for microscopic examination is
      frequently inadequate to detect localized neurotoxic injury. Furthermore, the
      examination of H&E-stained sections alone will often be insufficient for the
      detection of subtle neuropathogic alteration. It is imperative for any
      pathologist evaluating brain sections to have knowledge of microscopic
      neuroanatomy and to also have some understanding of basic neurochemistry. When a
      focus of degeneration is detected within the brain, the pathologist needs to
      ascertain not only the specific anatomic location of this focus but also the
      neuroanatomic regions that project to and receive output from the injured focus.
      Because of the complexity of brain circuitry and the fact that the brain contains
      many distinctive neuron populations, many more brain sections are required for
      adequate microscopic evaluation than for any other body organ. Deciding which and
      how many areas should be examined, microscopically, from a large size brain is
      often problematic. Although any sampling protocol will be influenced by what is
      known about the test chemical, it has been well established that certain regions
      of the brain (eg, hippocampus and other components of the limbic system, basal
      ganglia, Purkinje neurons) are more susceptible than others to a variety of
      physical, metabolic, and chemical insults. Knowledge of these regional
      sensitivities will assist in guiding the pathologist in the development of an
      adequate sampling protocol.

PMID- 12597430
TI  - Myelodysplasia: differentiating neoplastic from nonneoplastic syndromes of
      ineffective hematopoiesis in dogs.
AB  - In the context of human hematopathology, the terms myelodysplasia and
      Myelodysplastic Syndromes (MDS) are applied to disorders of hematopoiesis that
      are clonal, neoplastic, and, in most forms, manifested as ineffective
      hematopoiesis with characteristic morphologic abnormalities in multiple cell
      lines. Studies of human patients have provided the conceptual framework that MDS
      evolve from a multipotential hematopoietic stem cell (CFU-GEMM) that has
      undergone neoplastic transformation as the result of acquired genetic mutations.
      The diagnosis of MDS in human patients is based largely on morphologic
      examination of marrow but can be confirmed by detection of cytogenetic
      abnormalities. Spontaneous, neoplastic myelodysplasia occurs in dogs, but rarely.
      Nonneoplastic syndromes of ineffective hematopoiesis are more common in dogs, can
      resemble MDS, and are probably immune mediated in many cases. Drugs and their
      metabolites are potential causes of dysmorphic maturation and ineffective
      hematopoiesis. Without methods to confirm clonality by cytogenetic analysis, the
      diagnosis of neoplastic myelodysplasia in dogs is based onlight microscopic
      examination of bone marrow smears. This paper discusses and illustrates the
      characteristic morphologic and cytochemical features of neoplastic myelodysplasia
      and nonneoplastic ineffective hematopoiesis in dogs.

PMID- 12597431
TI  - Issues related to the use of fish models in toxicologic pathology: session
      introduction.
AB  - Ready or not, fish models are "here to stay." No longer are fish confined to a
      few specialized laboratories, nor are they exclusively the purview of zoologists
      or environmental toxicologists. In fact, the institution that does not house at
      least 1 fish facility is probably not at the forefront of cutting edge research.
      In toxicologic pathology, fish models are increasingly being used to provide high
      animal numbers at relatively low cost in carcinogenicity testing and
      developmental research, and to provide mechanistic information on fundamental
      cellular processes. In this session, we attempt to provide some perspective for
      the pathologist that is faced with planning or performing experiments or testing
      protocols using fish models, or with reading or interpreting fish studies. First,
      we cover how to approach fish studies from the contract laboratory standpoint,
      including sectioning, quality control, and GLP considerations. Then, we discuss
      specifics on the use of the rainbow trout, zebrafish, and Japanese medaka models.
      The rainbow trout has a rich history in carcinogenicity and mechanistic cancer
      research. Similarly, the 2 workhorses in the small fish category, zebrafish and
      medaka, have found their way into many laboratories doing developmental biology
      and genomics research as well as carcinogenicity testing. Some fascinating
      genetically altered fish models have been developed with both of these species.
      This manuscript provides a session overview of the use of small fish models in
      toxicologic pathology, along with some historical perspective on how these models
      have played a role in the current state of the science.

PMID- 12597432
TI  - Good laboratory practice considerations in the use of fish models.
AB  - In the late 1970's, Good Laboratory Practice Regulations (GLP) were instituted by
      agencies such as the USFDA, the USEPA, and the OECD to provide a system for the
      monitoring of animal studies submitted in support of the safety of regulated
      products. Although GLP regulations are regularly employed in laboratory mammal
      projects, they have been comparatively under-utilized in aquatic animal research.
      This situation is changing due to the continuing emergence of fish as
      toxicological and pharmaceutical test subjects, human and animal disease models,
      genetically-engineered food sources, and environmental sentinels. The application
      of GLP principles to aquatic animal studies poses a variety of challenges,
      especially in the areas of Study Protocol design and the creation of Standard
      Operating Procedures (SOP's). This presentation will highlight differences
      between mammalian and fish studies in the application of GLP principles, and
      identify specific concerns associated with the formulation of SOP's for fish
      projects.

PMID- 12597433
TI  - The rainbow trout (Oncorhynchus mykiss) tumor model: recent applications in low
      dose exposures to tumor initiators and promoters.
AB  - The rainbow trout has been utilized as a model for human carcinogenesis for a
      number of years. Trout are relatively inexpensive to maintain and exhibit (over
      the 9-12-month tumor assay period) very low spontaneous tumor backgrounds. One of
      the most powerful applications of this model is the design and conduct of large
      scale tumor studies requiring thousands of animals that address statistically
      challenging questions of dose-response. Two recent examples of such applications
      include our studies on I3C as a tumor promoter and DBP as a tumor initiator. I3C
      was shown to promote AFB1-initiated liver cancer at doses near those recommended
      for supplementation in humans. Further studies are required to determine if the
      mechanisms responsible for promotion in trout can be extrapolated to humans. In
      the second example, we report results from the largest animal tumor study ever
      conducted. A total of 42,000 trout were utilized to measure DBP carcinogenesis
      down to incidences of 1 in 5,000. The dose response model deviated significantly
      from linearity although the existence of a threshold could not be statistically
      established. Extrapolation of the data model predicts a DBP dose producing 1 in
      10(6) cancers that is 1,000-fold higher than predicted by the conservative linear
      model. If these results can be confirmed with other carcinogens (genotoxic and
      perhaps nongenotoxic) and other targets, this could have a significant impact on
      the utilization of animal tumor data in human risk assessment.

PMID- 12597435
TI  - Use of the Japanese medaka (Oryzias latipes) and guppy (Poecilia reticulata) in
      carcinogenesis testing under national toxicology program protocols.
AB  - A need exists for whole animal toxicity, mutagenesis, and carcinogenesis models
      that are alternative to the traditional rodent test models and that are
      economical, sensitive, and scientifically acceptable. Among small fish models,
      the Japanese medaka (Oryzias latipes) is preeminent for investigating effects of
      carcinogenic and/or toxic waterborne hazards to humans. The guppy (Poecilia
      reticulata), although less widely used, is valuable as a comparison species. Both
      species are easy to maintain and handle in the laboratory and there is a large
      body of background information on their responsiveness to a range of classes of
      carcinogens. There are considerable data on the occurrence of background diseases
      and on spontaneous neoplastic lesions, both of which occur relatively rarely.
      With few modifications, the medaka and guppy are amenable to carcinogenicity
      testing under the rigid standards established by the National Toxicology Program
      (NTP) for rodent tests. The advantages of the small fish in carcinogenesis
      studies are best realized in long-term studies that involve environmentally
      realistic exposures. Studies to identify chronic effects can be conducted in
      about 12 months, near the life span of medaka in our laboratory. Practically, 9
      month studies are optimal but shorter study cycles and a variety of
      exposure/growout and initiation/promotion scenarios are available. Studies on 3
      compounds tested in medaka under NTP protocols are under review and preliminary
      analysis indicates that chronic carcinogenicity bioassays with medaka, guppy, and
      potentially with other small fish species are feasible and scientifically valid.

PMID- 12597436
TI  - A primer of primate pathology: lesions and nonlesions.
AB  - Nonhuman primates are important laboratory animals for biomedical, pharmacology,
      and toxicology research. To effectively use primates as models, their gross and
      histologic anatomy, physiology and natural history, as well as common health
      problems and the source from which the primate is obtained, must be known and
      understood by pathologists involved in study design and/or interpretation. The
      first very important lesson in the "primer" is: there is no such thing as a
      generic monkey. Brand names (ie, species and subspecies) are important. Several
      taxonomic groups of primates are used in research including: prosimians, such as
      galagos and lemurs; New World monkeys, particularily marmosets; Old World
      monkeys, especially macaques and baboons; and the chimpanzee, an African ape.
      Differences between taxa are exemplified by the glucocorticoid resistance of New
      World monkeys compared to Old World monkeys, which results in the requirement for
      Vitamin D3 and their high circulating levels of steroids such as cortisone and
      progesterone. Differences in ovarian histology between Old and New World monkeys
      probably relate to steroid receptor biology as well. There are also variations in
      disease manifestations, even among closely related primate species such as rhesus
      and cynomolgus macaques (cynos). For example type D retrovirus infection is
      accompanied by lymphomas in cynos, but not rhesus. The second important lesson in
      this "primer" is: "not test article related" does not always mean "normal."
      Lymphoid nodules in bone marrow or salivary gland, a common background finding in
      macaques, often signal the presence of type D retrovirus. Other histologic
      changes and normal anatomic variations may be confusing to individuals not
      routinely examining primate tissues. The objective of this paper is to
      familiarize pathologists with the use of primates in research as well as lesions
      and nonlesions (normal anatomy or physiology) of primates that may influence
      study design and confound interpretation.

PMID- 12597437
TI  - Simian retrovirus infections: potential confounding variables in primate
      toxicology studies.
AB  - Various species of nonhuman primates are natural hosts for 6 exogenous
      retroviruses, including gibbon-ape leukemia virus (GaLV), simian sarcoma virus,
      simian T-lymphotropic virus (STLV), simian immunodeficiency virus (SIV), simian
      type D retrovirus (SRV), and simian foamy virus (SFV). These viruses establish
      persistent infections with a broad spectrum of pathogenic potential, ranging from
      highly pathogenic to nonpathogenic, depending on various host, virus, and
      environmental factors. Latent or subclinical infections are common, and various
      procedures associated with experimental protocols may lead to virus reactivation
      and disease. Adverse effects on toxicologic research by undetected retroviral
      infections can occur in several ways, including loss of experimental subjects
      (and statistical power) due to increased morbidity and mortality. In addition,
      results may be confounded by virus-induced clinical abnormalities, histologic
      lesions, alteration of physiologic parameters and responses, and interference
      with in vitro assays and/or destruction of primary cell cultures. Key clinical
      and epidemiological features of several important retroviruses are reviewed, with
      emphasis on viruses infecting species of macaques most commonly used as research
      subjects in primate toxicology studies. Examples of actual and potential
      confounding of toxicologic studies by retroviruses are discussed, including
      altered cytokine profiles in healthy STLV carriers, and clinical and pathological
      abnormalities induced by SRV infection. Adequate prestudy viral screening is
      critical to exclude retrovirus-infected primates from toxicologic research
      protocols and prevent potential confounding of research results.

PMID- 12597438
TI  - Immune modulator studies in primates: the utility of flow cytometry and
      immunohistochemistry in the identification and characterization of
      immunotoxicity.
AB  - Exposure to natural environmental products, biopharmaceuticals, or
      investigational adjuvants has the potential to negatively impact the immune
      system, resulting in either up- or downregulation of immune function
      (immunomodulation). Many current protocols for primate toxicologic testing call
      for the evaluation of changes in immune cell number (peripheral blood or tissue),
      alterations in the weights of immune system organs (lymph nodes, spleen, thymus),
      and/or increases in the overall incidence of infections or neoplasms; these data
      are relied upon to suggest altered immune function. However, these are
      informative only when clear differences in frequency and/or severity of effects
      can be distinguished across control and dosed groups. In the absence of such
      distinct morphologic or clinical pathologic changes, the identification of
      potential immunomodulatory effects can present a much greater challenge.
      Additional evaluations may be needed to detect altered immune system integrity;
      these are based on in vivo assessments in primates of cellular or humoral
      responsiveness. Immunomodulatory effects can be characterized by in vitro or in
      vivo immune function tests: these tests require prestudy planning to integrate
      assessments into ongoing toxicology programs. These methods also involve
      specialized training and equipment, particularly if the intent is to evaluate
      parameters in a GLP laboratory setting. In primate toxicology, the added costs
      required to perform a complete functional analysis of the immune system can be
      substantial, but may be warranted depending on the clinical development plans.
      Two analytical methods that are easily incorporated into the standard toxicology
      profile in primates are flow cytometry and immunohistochemistry. Flow cytometry
      (FC) is used to assess changes in the relative distribution of immune cell marker
      expression, and where marker expression is known to fluctuate with the state of
      cell activation, can also provide information on functional attributes of immune
      cells. Immunohistochemistry (IHC) provides a means to evaluate similar
      characteristics of immune cells within tissue sections. Used together, FC and IHC
      can aid in the identification of changes in immune system that may not be
      apparent by traditional testing procedures (such as H&E staining), thus aiding in
      the characterization of immune system alterations. This presentation focused on
      the utility of flow cytometry and immunohistochemistry in a standard primate
      toxicology evaluation, with representative examples showing the benefits of these
      technologies in the diagnosis of potential immunomodulatory effects.

PMID- 12597439
TI  - Oligodeoxynucleotide studies in primates: antisense and immune stimulatory
      indications.
AB  - Antisense oligodeoxynucleotide compounds (AS ODN) are being developed as
      therapeutics for various disease indications. Their safety and pharmacokinetics
      are most commonly evaluated in rodents and nonhuman primates. Traditional AS ODN
      are short, single strands of DNA, and they target specific mRNA sequences. Plasma
      clearance of AS ODN is rapid, broad tissue distribution occurs, and elimination
      is by nuclease metabolism. Structural modifications to AS ODN have been made to
      enhance their efficacy and improve their safety. A number of class effects are
      observed with AS ODN that are unrelated to the specific targeted mRNA sequence.
      Acute effects include activation of the alternative complement pathway and
      inhibition of the intrinsic coagulation pathway. In monkeys, rodents, and dogs
      given repeated doses of AS ODN, accumulation of AS ODN and/or metabolites occurs
      in the form of basophilic granules in various tissues, including the kidney,
      lymph nodes and liver. A new potential therapeutic application of ODN is that of
      immune stimulation. Immunostimulatory ODN (IS ODN) are being investigated for use
      in treating cancer, infectious disease, and allergy. For the development of both
      AS and IS ODN, primates will continue to be important for safety assessment.

PMID- 12597440
TI  - The common marmoset (Callithrix jacchus) as a model in toxicology.
AB  - The common marmoset, Callithrix jacchus, is the smallest nonhuman primate
      commonly used in biomedical research. Marmoset characteristics and propensities
      have enabled them to be used in a wide range of research as a model of human
      disease, physiology, drug metabolism, general toxicology, and reproductive
      biology. This paper provides a general overview of the marmoset with special
      emphasis on the benefits and disadvantages of this species as a model for
      inclusion in preclinical drug development programmes. In view of its small size
      in comparison with other nonrodent species marmosets have become of value for
      toxicology studies with biotechnology products where compound supply is limited.
      In general toxicology studies, marmosets have been successfully used to meet
      regulatory endpoints also for specific investigatory purposes. The widespread use
      of this species has allowed extensive background information to become available
      and a summary of the most frequently measured parameters are presented. Marmosets
      apparently represent an interesting animal model for comparative research on
      primate reproductive physiology. However, several basic aspects of reproductive
      processes exhibit cardinal discrepancies to those described for macaques and
      human. Thus, from the viewpoint of reproductive toxicology, the relevance of the
      marmoset primate model for human reproduction remains unclear to date and further
      research is obviously needed. Given our current knowledge of marmoset
      reproductive features, the use of this animal model cannot be recommended for
      reproductive toxicology assessment.

PMID- 12597441
TI  - Toxicology and new social ethics for animals.
AB  - The issue of animal treatment has emerged as a major social concern over the past
      three decades. This ramified in a new ethic for animal treatment that goes beyond
      concern about cruelty and attempts to eliminate animal pain and suffering,
      whatever its source. This is evidenced by laws governing animal research in many
      countries. Insofar as toxicology can entail significant and prolonged animal
      suffering, it is at loggerheads with this new ethic. Ways are suggested for the
      toxicological community to put itself in harmony with the ethic and thereby
      preserve its autonomy.

PMID- 12597442
TI  - Environmental enrichment of nonhuman primates, dogs and rabbits used in
      toxicology studies.
AB  - The increasing emphasis on the provision of environmental enrichment to
      laboratory animals, vis-a-vis the USDA Animal Welfare Regulations, the Guide for
      the Care and Use of Laboratory Animals (NRC 1996), and a potential forthcoming
      policy from the USDA on the subject, can be difficult to accommodate in a
      toxicology research environment. A summary will be provided of current
      requirements and recommendations. Then, strategies for meeting regulatory
      requirements will be described for non-rodent animals used in toxicology
      research. These strategies will address methods of both social enrichment, such
      as pair or group housing, as well as non-social enrichment, such as cage
      furniture, food enrichments, and toys. In addition, the value of positive
      interactions with staff (e.g., through training paradigms or socialization
      programs) will also be discussed. Apparent in the discussion of these strategies
      will be an overarching recognition of the necessity to avoid introducing
      confounding variables into the research project and to avoid compromising animal
      health. The roles of the Institutional Animal Care and Use Committee (IACUC) and
      the attending veterinarian in helping scientists balance animal well-being, the
      scientific enterprise and the regulatory environment will be described.

PMID- 12597443
TI  - Multifocal ductal cell hyperplasia in the submandibular salivary glands of Wistar
      rats chronically treated with a novel steroidal compound.
AB  - A high incidence of multifocal ductal hyperplasia was observed in the
      submandibular salivary gland of rats treated for 26 weeks with a high dose of a
      novel synthetic steroid with combined estrogenic and progestagenic properties.
      Hyperplastic foci consisted of microcystic duct-like structures lined by a single
      or multilayered epithelium, sometimes showing a tendency towards a cribiform
      growth pattern. The hyperplastic ducts wereembedded in a collagen-rich stroma and
      surrounded by numerous myoepithelial cells. Immunohistochemical methods used for
      the detection of estrogen- and progesterone receptors revealed that progesterone
      receptors were abundantly present in the nucleus of epithelial cells within the
      lesions, exclusively. Estrogen receptors could not be detected in both the normal
      tissue and hyperplasic foci. The morphological, ultrastructural, and
      immunohistochemical characteristics strongly suggest that these hyperplastic
      lesions originated from the intercalated ducts. The rodent-specific granular duct
      cell was not involved in the pathogenesis as was clearly demonstrated by the lack
      of immunoreactive epidermal growth factor within the lesions. Lesions were not
      observed in studies with progestagens and estrogens alone or with other combined
      estrogen/progestagen compounds, suggesting that the specific ratio of estrogenic
      and progestagenic activity of the present steroid had played an important role in
      the development of ductal hyperplasia in this study. Lesions of the intercalated
      ducts, as described in this study, have not been reported before in the
      literature.

PMID- 12597444
TI  - Pentachlorophenol (but not phenobarbital) promotes intrahepatic biliary cysts
      induced by diethylnitrosamine to cholangio cystic neoplasms in B6C3F1 mice
      possibly due to oxidative stress.
AB  - Administration of diethylnitrosamine (DEN) to B6C3F1 mice at low dose (20 ppm) in
      drinking water for long duration resulted in formation of multifocal cystic
      biliary lesions in the liver. To investigate the potential of the lesions to be
      promoted to neoplasias by chemicals, we examined the effects of 2 different types
      of hepatocarcinogenesis promoters, pentachlorophenol (PCP) and phenobarbital (PB)
      in B6C3F1 mice. Two weeks' exposure to PCP at a concentration of 600 ppm in the
      diet increased 8-oxodeoxyguanosine (8-oxodG) levels in liver nuclear DNA, and
      cell proliferation quantified by bromodeoxyuridine (BrdU) incorporation in
      epithelial cells of intrahepatic bile ducts as well as hepatocytes. In mice
      initiated with DEN at 20 ppm in the drinking water for the first 13 weeks
      followed, after a 4-week recovery interval, by PCP at a concentration of 600 ppm
      in the diet for 25 weeks, cystic atypical hyperplasias, cholangiomas, and
      cholangiocarcinomas were present at statistically significant higher incidences.
      In contrast, neoplasia did not occur in animals treated with 500 ppm PB, and
      there were no elevations in 8-oxodG levels or increases in the proliferation of
      biliary epithelium, although proliferation was increased in hepatocytes. These
      findings suggest that oxidative stress due to PCP might exert a promoting action
      on the biliary cystic lesions produced by DEN.

PMID- 12597445
TI  - Safety evaluation of recombinant staphylokinase in rhesus monkeys.
AB  - Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial
      origin. The objective of this study was to assess the toxicity of rSTAR
      administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at
      the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were
      thickening of the skin in all animals and mild hematoma formation in three dosage
      groups at the injection sites. There were no effects on body weight, absolute or
      relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated
      that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild
      hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and
      bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts,
      hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2.
      Significant prolongtion of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases
      in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent
      increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity
      were observed in the three treated groups. Increased neutralizing rSTAR activity
      diminished the phamacologic effects of rSTAR (ie, prolonged APTT, PT, and TT
      approaching baseline levels at week 2). Histopathological findings included
      hemorrhage, and perivascular inflammatory cell infiltration at the injection
      sites, heptocellular degeneration characterized as cytoplasmic eosinophilia,
      vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma
      within some Bowman's capsules and hyaline casts within the lumen of some renal
      tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte
      hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune
      deposits in glomeruli in the kidneys from the three treated groups were detected.
      These changes were reversible following a 4-week recovery period. In the present
      preclinical evaluation of toxicity in monkeys, rSTAR is well toleratte at doses
      up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone
      marrow.

PMID- 12597446
TI  - Overexpression of aryl hydrocarbon receptor in human lung carcinomas.
AB  - Exposure to polycylic aromatic hydrocarbons (PAH) has been associated with
      increased risk of lung cancer. Aryl hydrocarbon receptor (AhR) is known to play
      an essential role in PAH-induced toxicity. The objectives of this study were to
      identify and evaluate AhR expression in normal human lung tissues and in lung
      carcinomas. AhR protein and mRNA levels in human lung cell lines were evaluated
      with immunoblot and quantitative real-time RT-PCR assays, respectively. AhR
      protein expression was high in cytosol homogenates of adenocarcinoma (AD) cell
      lines and AhR mRNA levels corresponded well with AhR protein levels in these cell
      lines. AhR expression in human lung tissues and carcinomas were examined by means
      of immunohistochemical staining method. In normal lung tissues, immunostaining
      was found in the cytosol of bronchiolar epithelial cells. AhR immunostaining was
      more intense in AD than in squamous cell carcinomas. When AhR expression was
      compared with noral bronchiolar epithelial cells and neoplastic cells in the same
      specimens, the neoplastic cells, especially those of AD, demonstrated an
      increased staining. The upregulation of AhR mRNA expression was also demonstrated
      among 2 of 4 paired tissues with the quantitative real-time RT-PCR assay. Our
      data indicated that AhR expression was upregulated in lung AD and suggested that
      AhR and its expression might play an important role in the development of lung
      AD.

PMID- 12597434
TI  - The state of the art of the zebrafish model for toxicology and toxicologic
      pathology research--advantages and current limitations.
AB  - The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for
      clarification of the roles of specific genes and signaling pathways in
      development. The zebrafish genome will be completely sequenced within the next 1
      2 years. Together with the substantial historical database regarding basic
      developmental biology, toxicology, and gene transfer, the rich foundation of
      molecular genetic and genomic data makes zebrafish a powerful model system for
      clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge
      base on molecular developmental genetics in zebrafish, our database regarding
      infectious and noninfectious diseases and pathologic lesions in zebrafish lags
      far behind the information available on most other domestic mammalian and avian
      species, particularly rodents. Currently, minimal data are available regarding
      spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly
      used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the
      potential of zebrafish as an animal model for understanding human development,
      disease, and toxicology we must greatly advance our knowledge on zebrafish
      diseases and pathology.

PMID- 12597447
TI  - A grading scheme for the assessment of proliferative lesions of the mouse
      prostate in the TRAMP model.
AB  - To improve the precision and consistency of experimental results, we have
      developed a scoring system for proliferative epithelial lesions in the mouse
      prostate based on histological growth patterns observed in individual lobes.
      Severity of proliferative lesions was divided into 6 categories; the grade of the
      most advanced lesion was identified for each lobe and its distribution estimated
      semiquantitatively. A numerical score combining grade and distribution of the
      most advanced lesion in each lobe was assigned and termed the "distribution
      adjusted lesion grade"; the mean of these scores was calculated for each
      treatment group. Using this grading scheme, we assessed lesion development in ad
      libitum-fed and 20%-diet-restricted groups of TRAMP (Transgenic Adenocarcinoma of
      Mouse Prostate) mice that were started on study at 7 weeks of age and sacrificed
      when 11 and 20 weeks old. The anterior, dorsal, lateral, and ventral prostate
      lobes showed clear reductions in lesion severity in diet-restricted TRAMPS at 11
      and 20 weeks. This method for scoring the epithelial pathology of the prostate in
      the TRAMP model with minimal to severe proliferative lesions utilizes the natural
      history of lesion development for assessing the effects of chemical and dietary
      interventions.

PMID- 12597448
TI  - Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines
      using natural anti-oxidant from spinach, NAO--a comparative study of three anti
      oxidants.
AB  - The TRAMP model and human prostatic cancer (PCA) cell lines DU145 and PC3 are
      useful forchemopreventive studies. We compared the efficacy of 3 anti-oxidants [a
      water-soluble natural anti-oxidant. NAO (200 mg/kg). found in spinach leaves;
      epigallocatechin-3 gallate, EGCG (200 mg/kg), a major green tea polyphenol; and N
      acetylcysteine, NAC (125 mg/kg)] plus vehicle in slowing spontaneous tumorigenic
      progression in TRAMP and wild-type male mice. Sacrifices occurred on weeks 5, 9,
      and 13. Prostatic histopathology and oxidative-stress blood markers were
      evaluated. Hyperplasias were ranked by a combination of severity grade and
      distribution (focal, multifocal, and diffuse). The effectivity of each tested
      compound in reducing the severity/focalness of hyperplasia varied from lobe to
      lobe. NAO exerted a significant effect on the dorsal and lateral lobes; NAC, on
      the anterior and ventral lobes, and EGCG, on the ventral lobe. When the most
      severe hyperplasia in all 4 lobes of TRAMPs was evaluated, only NAO reduced
      hyperplasia at weeks 9 and 13. Plasma peroxide levels in TRAMPs were reduced
      following oral administration of NAO or NAC for 13 weeks; EGCG only slightly
      reduced these levels. In NAO-treated DU 145 and PC3 PCA cells, inhibition of
      cellular proliferation occurred in a dose-dependent manner, increasing numbers of
      G1 cells and reducing ROS levels. The anti-oxidative and antiproliferative
      properties of NAO may explain its efficacy in slowing the spontaneous prostatic
      carcinogenic process in the TRAMP and its effects in the cell lines.

PMID- 12597449
TI  - Validation and regulatory acceptance of new carcinogenicity tests.
AB  - The 3 Rs concept, which was developed by Russell and Burch in 1959, was
      implemented into the legal framework in the European Union(EU) for the protection
      of vertebrate animals used for experimental and other scientific purposes, when
      Directive 86/609/EEC was adopted in 1986. To reduce or replace animal testing for
      regulatory purposes, nonanimal tests must be independently validated to prove
      that they can provide information that is relevant and reliable for hazard
      prediction in vivo. At the end of the 1980s, no scientific concept existed for
      the formal validation ofin vitro toxicity tests, so a small group of European and
      American scientists developed a set of principles for experimental validation,
      which was accepted internationally by the OECD in 1996. A major breakthrough was
      the acceptance in the EU of the scientifically validated in vitro toxicity test
      for phototoxic potential in 2000, which was accepted by the OECD at the worldwide
      level in 2002. Taking the progress in the development and validation of
      alternative toxicity tests during the past decade into account, the current
      concepts of developing alternatives to the standard 2-year rodent bioassay for
      carcinogenicity testing are discussed.

PMID- 12597451
TI  - Value of GST-P positive preneoplastic hepatic foci in dose-response studies of
      hepatocarcinogenesis: evidence for practical thresholds with both genotoxic and
      nongenotoxic carcinogens. A review of recent work.
AB  - Recent low-dose carcinogenesis studies, including major group projects are
      reviewed. The prevailing paradigm is that carcinogens, particularly genotoxic
      compounds, have no threshold in exerting their potential for cancer induction.
      However, the nonthreshold hypothesis can be challenged for cancer risk assessment
      in humans. A recent very large-scale cooperative effort in Japan furthermore
      showed that the genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5
      f]quinoxaline, forms DNA adducts and 8-hydroxy-2'-deoxyguanosine at low doses,
      but does not induce glutathione S-transferase placental form (GST-P) positive
      foci as preneoplastic lesions in rat liver (< or = 10 ppm in diet). Moreover,
      very low doses of a N-nitroso compound. diethylnitrosamine (DEN), were also found
      not to significantly induce GST-P positive foci in rat liver (< or = 0.01 ppm in
      drinking water). Given the direct correlation between induction of the
      preneoplastic lesions in the short-term and carcinomas in the longer term with
      different carcinogens, the results imply a practical nonobserved effect level for
      hepatocarcinogenicity. Similar results were also observed with so-called
      nongenotoxic carcinogens such as phenobarbital (PB) and p,p
      dichlorodiphenyltrichloroethane (DDT), which do not exert positive effects on
      lesion development at very low doses. Furthermore, experiments with application
      of PB and DDT after treatment with DEN indicate that at very low doses (< or = 2
      ppm in diet), they may even inhibit the development of GST-P positive foci. The
      data reviewed provide evidence that preneoplastic foci in the liver can be
      employed as end-point lesions in place of tumors and that exposure to very low
      levels of carcinogens, typical of those found in the human environment, does not
      necessarily present as a risk factor.

PMID- 12597450
TI  - Prevalidation of a rat liver foci bioassay (RLFB) based on results from 1600
      rats: a study report.
AB  - A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol
      employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was
      prevalidated in 5 different laboratories. FAH were identified by
      immunohistochemical demonstration of glutathione-S-transferase (placental form,
      GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was
      quantified morphometrically. The four model hepatocarcinogens N
      nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were
      selected according to characteristic differences in their presumed mode of
      action, and tested in a total of 1,600 male and female rats at 2 different dose
      levels. The chemicals were found to differ characteristically in their potency
      and dose-response relationship to induce FAH when given alone or when
      administered following initiation with diethylnitrosamine. The interlaboratory
      variation was small for results obtained with the GSTP-stain and somewhat larger
      with respect to H&E. The assessment of the carcinogenic potential of the four
      chemicals by the different laboratories was in the same range and the nature of
      their dose-response relationships did not differ essentially between
      laboratories. Our results suggest that this RLFB is a sensitive bioassay,
      providing potentially valuable information for risk assessment including the
      classification of carcinogenic chemicals according to their mode of action.

PMID- 12597452
TI  - Mechanisms of promotion and progression of preneoplastic lesions in
      hepatocarcinogenesis by DDT in F344 rats.
AB  - Time-related changes in potential factors involved in hepatocarcinogenesis by DDT
      were investigated in a 4-week and a 2-year feeding studies of p,p'-DDT with F344
      rats. In the 4-week study with males at doses of 50, 160, and 500 ppm, cell
      proliferation and gap junctional intercellular communication (GJIC) were examined
      after 1, 2, 3, 7, 14, and 28 days. Cell proliferation was enhanced within 3 days
      at any dose level, but returned to normal after 7 days, whereas GJIC was
      inhibited throughout the study. In the 2-year study with both sexes at doses of
      5, 50, and 500 ppm, cell proliferation, GJIC, enzyme induction, and oxidative
      stress were investigated after 26, 52, 78, and 104 weeks. Males and females
      showed an inhibition of GJIC and increases in P450 isozymes (CYP2B1 and CYP3A2)
      in a dose-dependent manner at all time points, but no significant change in cell
      proliferation. Lipid peroxide for males at 50 and 500 ppm and 8
      hydroxydeoxyguanosine for both sexes at 500 ppm were elevated throughout the
      study. Histologically, eosinophilic foci and hepatocellular adenomas increased in
      males at 50 ppm and both sexes at 500 ppm. Hepatocellular carcinomas also
      developed in males at 500 ppm. These results indicate that DDT may induce
      eosinophilic foci as a result of oxidative DNA damage and leads them to neoplasms
      in combination with its mitogenic activity and inhibitory effect on GJIC.
      Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.

PMID- 12597453
TI  - Role of connexin32 and beta-catenin in tumor promotion in mouse liver.
AB  - Tumor promoters are nonmutagenic chemicals that increase the probability of
      cancer by accelerating the clonal expansion of cells transformed during tumor
      initiation. The molecular mechanisms underlying this process are only partly
      understood but interference with signaling pathways regulating cell division
      and/or cell death is likely to be important. Ras- and beta-Catenin-dependent
      signaling is important for both of these processes and ras and beta-catenin genes
      are known mutational targets in mouse hepatocarcinogenesis. About 80% of liver
      tumors generated in mice by a promotional regimen including phenobarbital (PB) as
      tumor promoter and N-nitrosodiethylamine (DEN) as initiator showed beta-catenin
      mutations whereas Ha-ras mutations were not detected. By contrast, tumors from
      mice treated with DEN alone showed a approximately 30% Ha-ras mutation prevalence
      but no beta-catenin mutations. This result suggests that PB-mediated promotion in
      mouse liver consists in a positive selection for hepatocytes harboring mutations
      in beta-catenin. The gap junction protein connexin 32 (Cx32) was also found to be
      involved in tumor promotion by PB because Cx32 gene knockout mice were almost
      entirely resistent to the promotional effects of the barbiturate. The link
      between beta-catenin-signaling and Cx32-dependent gap junctional intercellular
      communication, if existent, remains obscure.

PMID- 12597454
TI  - Induction and modulation of hepatic preneoplasia and neoplasia in the rat by
      dehydroepiandrosterone.
AB  - Dehydroepiandrosterone (DHEA), the main adrenal steroid in humans and a precursor
      in androgen and estrogen biosynthesis, acts as a peroxisome proliferator and as a
      hepatocarcinogen in rats. Neoplasms emerge from a
      glycogenotic/amphophilic/basophilic preneoplastic cell lineage. A higher female
      tumor incidence suggests a relevant influence of sex hormones. DHEA enhances
      hepatocarcinogenesis induced by N-nitrosomorpholine (NNM), which is characterized
      by the glycogenotic/basophilic cell lineage. The tumor promoting effect is
      related to an additional amphophilic/basophilic preneoplastic lesion sequence and
      to faster proliferation of the basophilic preneoplastic lesions. Nevertheless,
      hepatocellular carcinomas provided under DHEA treatment seem to have a less
      malignant phenotype compared to tumors induced by NNM only. Further, DHEA
      treatment reduces growth and generation of glycogen storage foci (GSF) in initial
      NNM-treated rats. Thus, DHEA treatment results in both, a growth stimulation of
      the late basophilic lesion type with an additional amphophilic lesion sequence,
      and in a growth inhibition of early preneoplastic lesions, addressing especially
      GSF. DHEA also inhibits the growth of physiologically proliferating liver tissue.
      This might be explained by a DHEA related cellular metabolism, which results in
      significant energy consumption. Additionally, a DHEA-induced alteration of
      cytokine levels might contribute to this growth inhibition as well.

PMID- 12597455
TI  - Different effects of the liver mitogens triiodo-thyronine and ciprofibrate on the
      development of rat hepatocellular carcinoma.
AB  - Previous work has shown that treatment with thyroid hormone (T3) decreased the
      incidence of rat hepatocellular carcinoma (HCC). The present study was designed
      to determine whether the inhibitory effect of T3 on HCC development was limited
      to early steps of the carcinogenetic process or, whether a similar effect could
      also be exerted by starting T3 treatment at later stages. Hepatic nodules were
      induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure
      of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3
      groups: group 1 was maintained on basal diet: group 2 was fed a diet containing 4
      mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA
      administration: group 3 was exposed to cycles of T3 starting 8 months after
      initiation. Results demonstrate that inhibition of HCC development was
      essentially similar in rats exposed to T3 starting either 9 weeks or 8 months
      after initiation (50% inhibition compared to control rats). We have previously
      shown that T3-induced nodule regression and HCC inhibition occurred in spite of
      its mitogenic effect. Therefore, we next wished to determine whether a similar
      antitumoral effect could be exerted by other liver mitogens, such as peroxisome
      proliferators. Rats exposed to the initiation-promotion protocol described
      previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented
      diet, each cycle consisting of 7 days/month: the incidence of HCC and lung
      metastases was determined 13.5 months after initiation. Results showed that
      although treatment with T3 strongly inhibited HCC development (only 31% of T3+
      rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same
      number of HCC as T3-untreated rats. In conclusion, the results of this study
      showed that the anticarcinogenic effect of T3 is maintained also when treatment
      begins late in the process, and its antitumoral property appears to be specific
      and may not be shared by other liver mitogens.

PMID- 12597456
TI  - Biostatistical evaluation of focal hepatic preneoplasia.
AB  - Qualitative analyses of focal hepatic preneoplasia are relatively easy and fast
      but hypothesis tests based on these analyses often lack statistical power.
      Evaluating focal hepatic preneoplasia quantitatively, on the other hand, requires
      more effort but is rewarded by an increased ability to detect differences between
      treatment groups and by the possibility to investigate the mechanism of a
      treatment under study. Due to the stereological problems inherent in the data a
      statistical analysis that concentrates on the evaluation of area fraction will
      provide clear results whereas the analysis of focal transection density and size
      distribution can produce misleading results. In addition, the area fraction is a
      valid variable even in the presence of confluent foci. The number and size
      distribution of focal transections in liver sections cannot be directly
      translated to the number and sizes of foci in the liver. As no general statements
      about the relationship between focal transection density and foci density as well
      as between focal transection size and foci size distribution can be made, there
      is need for a parametric mechanistic model to link the number and size
      distribution of focal transections to those of the underlying foci. The
      stereological problem therefore can be avoided by introducing a model for foci
      appearance and change of volume that then can be used to conclude whether the
      treatment induces foci and whether it changes their volume.

PMID- 12597457
TI  - Relevance of hepatic preneoplasia for human hepatocarcinogenesis.
AB  - Different lesions have been suggested to represent preneoplastic conditions in
      human liver. They include liver cell dysplasia, separated in large-cell change
      (LCC) and small-cell change (SCC), adenomatoid hyperplasia, and the more recently
      identified foci of altered hepatocytes (FAH) and nodules of altered hepatocytes
      (NAH). FAH have been demonstrated to represent preneoplastic lesions in various
      animal models of hepatocarcinogenesis. To demonstrate prevalence and significance
      of FAH in the human liver, the cellular composition, size distribution, and
      proliferation kinetics of these lesions were studied in 163 explanted and
      resected human livers with or without hepatocellular carcinoma (HCC). FAH
      including glycogen-storing foci (GSF), mixed cell foci (MCF), and basophilic cell
      foci were found in 84 of 111 cirrhotic livers, demonstrating higher incidences in
      cases with than without HCC. MCF, predominant in cirrhotic livers of the high
      risk group, were more proliferative, larger and more often involved in formation
      of NAH than GSF. The results suggest that the FAH are preneoplastic lesions, MCF
      being more advanced than GSP. We also investigated the relationship of FAH to
      liver cell dysplasia. Occurrence of SCC, rather than that of LCC, confers FAH an
      increased proliferation activity and higher risk to nodular transformation, and,
      hence, should be considered a precancerous condition. Histological detection of
      FAH and SCC through needle-aspiration liver biopsy can be used for monitoring HCC
      development in high-risk populations, such as HBV carriers with chronic hepatitis
      and/or cirrhosis.

PMID- 12597459
TI  - Priorities for supportive and palliative care in England.

PMID- 12597458
TI  - Significance of hepatic preneoplasia in risk identification and early detection
      of neoplasia.
AB  - Among the different types of liver tumor, hepatocellular neoplasms predominate by
      far in both animals and man. Consequently, preneoplastic foci of altered
      hepatocytes (FAH), preceding both hepatocellular adenomas and carcinomas,
      represent the most prevalent form of hepatic preneoplasia observed in animals for
      a long time, and identified in human chronic liver diseases associated with, or
      predisposing to, hepatocellular carcinomas more recently. Morphological,
      microbiochemical, and molecular biological approaches in situ revealed striking
      similarities in specific changes of the cellular phenotype of preneoplastic FAH
      developing in experimental and human hepatocarcinogenesis, irrespective of
      whether this was elicited by chemicals, hormones, viruses or radiation. The
      advantage of using FAH for risk identification (aiming at primary cancer
      prevention) in long-term and medium-term carcinogenesis bioassays has been well
      documented, but quantitative morphometric approaches appear to be indispensable
      for an appropriate evaluation of both bioassays. The detection of phenotypically
      similar FAH in various animal models and in humans prone to develop or bearing
      hepatocellular carcinomas favors the extrapolation from data obtained in animals
      to humans. Moreover, the recently reported frequent finding of FAH in fine-needle
      biopsies of patients suffering from chronic liver diseases opens new perspectives
      for secondary prevention of human hepatocellular carcinoma.

PMID- 12597460
TI  - Proposal for a new name as well as having the new WHO definition of palliative
      care.

PMID- 12597461
TI  - Quality of life in palliative care: principles and practice.
AB  - In healthcare, most researchers and clinicians agree that quality of life (QOL)
      is related to symptoms, functioning, psychological and social wellbeing, and
      probably to a lesser extent to meaning and fulfillment. This multidimensional
      health-oriented concept has been named health-related quality of life (HRQOL).
      However, during end-of-life care spirituality and existential issues become more
      prominent, as well as family members' perception of quality of care. Outcome
      measures in palliative care require constructs that reflect the specific goals of
      palliative care, such as improving QOL before death, symptom control, family
      support and satisfaction, as well as patients' perceptions of 'purpose' and
      'meaning of life'. It is generally recommended that internationally developed and
      validated patient-rated multidimensional questionnaires should be used when
      assessing HRQOL in research. However, 'multidimensionality', with often more than
      10 possible outcomes, is a threat both to statistical analysis and clinical
      interpretation of data. Preferentially, a more limited number of outcomes based
      upon the research question(s) should be defined prior to data collection in the
      study protocol. The researcher needs to carefully evaluate the content of the
      questionnaire, in addition to other properties, such as the validity and
      reliability, before the final decision is made with regards to which instrument
      to use in a given study.

PMID- 12597462
TI  - Non-invasive ventilation and palliation: experience in a district general
      hospital and a review.
AB  - Non-invasive ventilation (NIV) is increasingly being used in hospitals to treat
      respiratory failure. The use of NIV with palliative intent in a district general
      hospital is described and ten illustrative cases where NIV was used in an attempt
      to palliate symptoms or to 'buy time' are presented. The role of NIV in relieving
      symptoms in various conditions is reviewed and ethical aspects are considered. It
      is suggested that hospital palliative care teams will increasingly see patients
      treated by this technique as it becomes more widely used for exacerbations of
      chronic obstructive airways disease, for relief of breathlessness in the
      terminally ill and for buying time in patient management. Domiciliary teams will
      see increasing numbers of people with motor neurone disease and other conditions
      treated with NIV.

PMID- 12597463
TI  - Caring for the dying: how well prepared are general practitioners? A
      questionnaire study in Wales.
AB  - CONTEXT: General practitioners (GPs) and generalist hospital doctors provide the
      majority of palliative and terminal care in the UK. Studies have revealed
      problems with symptom control and communication in these settings and inadequate
      training for clinical students and junior doctors. OBJECTIVES: To investigate the
      training of GPs in Wales in palliative medicine throughout their careers, with a
      focus on the Welsh Valleys, an area of social deprivation and high levels of
      chronic ill health. To compare these data with those previously obtained from a
      survey of GPs in East Anglia. To develop regression models that enable the
      prediction of less well trained medical students and GPs. METHODS: A postal
      questionnaire survey of a random sample of GPs, stratified by practice location
      (Valleys or elsewhere in Wales). Responders were invited to recall their training
      in five topics of palliative care (pain control, other symptom control, use of
      syringe drivers, communication skills and bereavement care) during four career
      stages (clinical students, junior doctors, GP registrars and GP principals).
      RESULTS: The response rate was 67.6%. Available data enabled evaluation of
      generalizability and response bias. Contrary to an initial hypothesis, no
      significant differences were found between Valleys and non-Valleys responders'
      reported training, although the study was adequately powered. As medical
      students, 27% reported receiving no training in any topic, 75% no training in
      bereavement care and 50% no training in communication skills. Training varied
      across medical schools and was more common for more recent graduates. As junior
      doctors, 25% reported no training in any topic, 75% no training in bereavement
      care and 77% no training in communication skills. The GP registrar year provided
      significantly more coverage of communication, bereavement and syringe drivers
      than the combined preceding 6 years of general professional training. As GP
      principals, a high level of training is reported in all topics. The training
      experience of GPs in Wales is very similar to that previously reported by GPs in
      East Anglia: this lends support to the generalizability of these data. Logistic
      regression analysis indicated that the only predictor of less common training as
      medical students was having qualified less recently. The main predictors of less
      common training as GP principals was having become a GP more recently and not
      being a GP trainer. CONCLUSIONS: There is still some way to go in ensuring that
      medical students, junior hospital doctors and GPs are all adequately trained for
      their important role in caring for dying patients.

PMID- 12597464
TI  - Which depression screening tools should be used in palliative care?
AB  - Depression is a significant symptom for many palliative care patients, but is
      difficult to diagnose and therefore treat. In an effort to improve detection,
      there has been increasing interest in the use of screening tools. Many tools,
      however, have been developed for physically well patients and it is important
      that tools are validated for the populations in which they are used. The present
      study was carried out on behalf of the Association of Palliative Medicine,
      Science Committee, to assess the available evidence for using screening tools in
      palliative care. The single question 'Are you depressed?' was the tool with the
      highest sensitivity and specificity and positive predictive value. Where the
      Hospital Anxiety and Depression Scale and the Edinburgh Depression Scale are
      used, the validated cut-off thresholds for palliative care patients should be
      employed. Patients who report thoughts of self-harm or suicide need prompt
      assessment and evaluation.

PMID- 12597465
TI  - Parenteral antibiotics in a palliative care unit: prospective analysis of current
      practice.
AB  - All patients receiving parenteral antibiotics in a palliative care unit were
      prospectively monitored over a 13-month period. Of 913 consecutive admissions, 41
      patients received 43 courses of parenteral antibiotics. On 27 of 43 occasions,
      the use of parenteral antibiotics was considered helpful (62%), in eight cases it
      was considered unhelpful (19%) and in a further eight cases the outcome could not
      be assessed (19%). The sites of infection for which parenteral antibiotics were
      prescribed included urinary tract infections (37%), lower respiratory tract
      infections (26%), soft tissue/skin or wound infections (16%), purulent terminal
      respiratory secretions (5%) and other (16%). In this sample, urinary tract
      infections were more commonly associated with a positive outcome than other
      indications combined (88% versus 48%, respectively). There appeared to be no
      association between outcome of use and age of the patient (median age 70, range
      37-90), underlying diagnosis (HIV versus advanced malignancy) and reason for
      admission (symptom control versus respite care versus terminal care). However,
      outcomes appeared to vary in this sample according to the palliative care phase
      of the patient at the time parenteral antibiotics were administered. Positive
      outcomes were more common in terminal- (83%) and stable-phase (71 %) patients
      than deteriorating- (58%) or acute-phase (38%) patients. This survey demonstrates
      that in specific circumstances a beneficial role exists for the use of parenteral
      antibiotics in a palliative care setting. The establishment of appropriate
      guidelines is recommended.

PMID- 12597466
TI  - Psychosocial needs in cancer patients related to religious belief.
AB  - In a study of psychosocial needs amongst cancer patients, the possession of a
      religious faith has been identified as a significant factor in determining a
      range of psychosocial needs. Of the 354 respondents to a questionnaire, which
      included a comprehensive psychosocial needs inventory, 83% said they had a
      religious faith, and in general these patients were less reliant on health
      professionals, had less need for information, attached less importance to the
      maintenance of independence and had less need for help with feelings of guilt,
      with their sexuality or with some practical matters than those who said they had
      no religious faith. In addition, they had fewer unmet needs overall (32% compared
      with 52%). The knowledge of a patient's spirituality should help service
      providers to predict aspects of psychosocial need and to respond sensitively and
      appropriately to a patient's experience of cancer.

PMID- 12597467
TI  - The palliative care needs of people with intellectual disabilities: a literature
      review.
AB  - People with intellectual disabilities are among the most disadvantaged groups in
      society. A literature review was conducted aiming to answer the following
      question: What are the palliative care needs of people with intellectual
      disabilities? The literature review covers case histories, morbidity and
      mortality patterns for people with intellectual disabilities, their healthcare
      needs and primary care provision, the way they may present symptoms, their
      conceptualization of illness and death and issues around education and training.
      While the literature review reveals a lack of empirical data around the
      palliative care needs of people with intellectual disabilities, a number of
      potential problem areas are highlighted. These include late presentation of
      illness, difficulties in assessing symptoms, difficulties in understanding the
      illness and its implications and ethical issues around decision making and
      consent to treatment. It is suggested that future studies will need to include
      the views and experiences of people with intellectual disabilities themselves.
      Areas for possible future development include symptom assessment, evaluation of
      current practice and access to services and the development of information and
      training materials.

PMID- 12597469
TI  - The Cochrane Collaboration: pain, palliative and supportive care.

PMID- 12597468
TI  - What is the best way to help caregivers in cancer and palliative care? A
      systematic literature review of interventions and their effectiveness.
AB  - Informal carers in cancer and palliative care are known to have high needs and
      psychological morbidity, yet a literature review identified few targeted
      interventions. This systematic review of interventions for carers of patients
      using home cancer and palliative care services searched Medline, CancerLit,
      Psycinfo and Cinahl databases. The terms used were carer(s), caregiver(s),
      palliative and cancer. Papers that reported interventions for adults actively
      providing informal care for noninstitutionalized cancer and palliative care
      patients were reviewed. Twenty-two interventions were identified, comprising home
      nursing care (four), respite services (three), social networks and activity
      enhancement (two), problem solving and education (three) and group work (10). Of
      these, nine were delivered solely to carers (i.e., were targeted services). Only
      six of the carers' interventions had been evaluated, two of these had used a
      randomized control trial (RCT; grades IB), three employed a single group
      methodology (two prospective grades IIIC and one retrospective grade IIIC) and
      one was evaluated using facilitator feedback. There was a lack of outcome
      evaluation designs, small sample sizes and a reliance on intervention
      descriptions and formative evaluations. Methodological challenges may mean
      alternatives to 'pure' RCTs should be considered. The current evidence
      contributes more to understanding feasibility and acceptability than to
      effectiveness. Practitioners and evaluators must prioritize the further
      development of intervention studies.

PMID- 12597470
TI  - Psychosocial care: setting the research agenda.

PMID- 12597471
TI  - A supportive care model for dialysis patients.

PMID- 12597472
TI  - Monitoring self-reported quality-of-life among patients attending a palliative
      medicine outpatient clinic.

PMID- 12597473
TI  - Inactivation of Escherichia coli O157:H7 and Salmonella by gamma irradiation of
      alfalfa seed intended for production of food sprouts.
AB  - Inonizing irradiation was determined to be a suitable method for the inactivation
      of Salmonella and Escherichia coli O157:H7 on alfalfa seed to be used in the
      production of food sprouts. The radiation D (dose resulting in a 90% reduction of
      viable CFU) values for the inactivation of Salmonella and E. coli O157:H7 on
      alfalfa seeds were higher than the D-values for their inactivation on meat or
      poultry. The average D-value for the inactivation of Salmonella on alfalfa seeds
      was 0.97 +/- 0.03 kGy; the D-values for cocktails of meat isolates and for
      vegetable-associated isolates were not significantly different. The D-values for
      nonoutbreak and outbreak isolates of E. coli O157:H7 on alfalfa seeds were 0.55
      +/- 0.01 and 0.60 +/- 0.01 kGy, respectively. It was determined that the
      relatively high D-values were not due to the low moisture content or the low
      water activity of the seed. The D-values for Salmonella on alfalfa seeds from two
      different sources did not differ significantly, even though there were
      significant differences in seed size and water activity. The increased moisture
      content of the seed after artificial inoculation did not significantly alter the
      D-value for the inactivation of Salmonella. The results of this study demonstrate
      that 3.3- and 2-log inactivations can be achieved with a 2-kGy dose of ionizing
      radiation, which will permit satisfactory commercial yields of sprouts from
      alfalfa seed contaminated with E. coli O157:H7 and Salmonella, respectively.

PMID- 12597474
TI  - Survey of retail alfalfa sprouts and mushrooms for the presence of Escherichia
      coil O157:H7, Salmonella, and Listeria with BAX, and evaluation of this
      polymerase chain reaction-based system with experimentally contaminated samples.
AB  - BAX, a polymerase chain reaction (PCR)-based pathogen detection system, was used
      to survey retail sprouts and mushrooms for contamination with Escherichia coli
      O157:H7, Salmonella, Listeria spp., and Listeria monocytogenes. No Salmonella or
      E. coli O157:H7 was detected in the 202 mushroom and 206 alfalfa sprout samples
      screened. L. monocytogenes was detected in one sprout sample, and seven
      additional sprout samples tested positive for the genus Listeria. BAX also
      detected Listeria species in 17 of the mushroom samples. Only 6 of 850 PCR assays
      (0.7%) failed to amplify control DNA, and therefore reagent failures and the
      inhibition of PCR by plant compounds were rare. The sensitivity of the detection
      system was evaluated by assaying samples inoculated with 10 CFU of each of the
      pathogens. One hundred seventy-two alfalfa sprout samples were inoculated with E.
      coli O157:H7, and two sets of 130 samples were experimentally contaminated with
      Salmonella Enteritidis and L. monocytogenes. The frequency of detection depended
      on the protocols used for inoculation and culturing. Inoculation of samples with
      approximately 10 CFU from frozen stocks yielded detection rates of 87.5 and 94.5%
      for L. monocylogenes and Salmonella Enteritidis, respectively, in mushrooms. The
      corresponding rates for alfalfa sprouts were 94.5 and 76.3%. The E. coli O157:H7
      detection rate was 100% for mushrooms but only 48.6% for sprouts when standard
      BAX culture protocols were used. The substitution of an overnight incubation in
      modified E. coli medium for the 3-h brain heart infusion incubation increased the
      rate of E. coli O157:H7 detection to 75% for experimentally contaminated sprouts.
      The detection rate was 100% when E. coli O157:H7 cells from a fresh overnight
      culture were used for the inoculation. Test sensitivity is therefore influenced
      by the type of produce involved and is probably related to the growth of
      pathogens in the resuscitation and enrichment media.

PMID- 12597475
TI  - Reduction of poliovirus 1, bacteriophages, Salmonella montevideo, and Escherichia
      coli O157:H7 on strawberries by physical and disinfectant washes.
AB  - The efficacy levels of different physical and chemical washing treatments in the
      reduction of viral and bacterial pathogens from inoculated strawberries were
      evaluated. Escherichia coli O157:H7, Salmonella Montevideo, poliovirus 1, and the
      bacteriophages PRD1, phiX174, and MS2 were used as model and surrogate organisms.
      Chemicals readily available to producers and/or consumers were evaluated as
      antimicrobial additives for the production of washes. The gentle agitation of
      contaminated strawberries in water for 2 min led to reductions in microbial
      populations ranging from 41 to 79% and from 62 to 90% at water temperatures of 22
      and 43 degrees C, respectively. Significant reductions (> 98%) in numbers of
      bacteria and viruses were obtained with sodium hypochlorite (50 to 300 ppm of
      free chlorine), Oxine or Carnebon (200 ppm of product generating "stabilized
      chlorine dioxide"), Tsunami (100 ppm of peroxyacetic acid), and Alcide (100 or
      200 ppm of acidified sodium chlorite) washes. Overall, 200 ppm of acidified
      sodium chlorite produced the greatest reductions of microorganisms. Hydrogen
      peroxide (0.5%) was slightly less effective than free chlorine in a strawberry
      wash and caused slight fruit discoloration. Cetylpyridinium chloride (0.1%) was
      effective in the reduction of bacterial species, while trisodium phosphate (1%)
      was effective against viruses. The consumer-oriented produce wash Fit was very
      effective (> 99%) in reducing the numbers of bacteria but not in reducing the
      numbers of viruses. Another wash, Healthy Harvest, was significantly less
      effective than Fit in reducing bacterial pathogens but more effective for
      viruses. The performance of automatic dishwashing detergent was similar to that
      of Healthy Harvest and significantly better than that of liquid dishwashing
      detergent. Solutions containing table salt (2% NaCl) or vinegar (10%) reduced the
      numbers of bacteria by about 90%, whereas only the vinegar wash reduced the
      numbers of viruses significantly (ca. 95%).

PMID- 12597476
TI  - Escherichia coli O157:H7 populations in sheep can be reduced by chlorate
      supplementation.
AB  - Ruminant animals are a natural reservoir of the foodborne pathogen Escherichia
      coli O157:H7. Some foodborne pathogens (e.g., E. coli) are equipped with a
      nitrate reductase that cometabolically reduces chlorate. The intracellular
      reduction of chlorate to chlorite kills nitrate reductase-positive bacteria;
      however, species that do not reduce nitrate are not affected by chlorate.
      Therefore, it has been suggested that ruminants be supplemented with chlorate
      prior to shipment for slaughter in order to reduce foodborne illnesses in human
      consumers. Sheep (n = 14) were fed a high-grain ration and were experimentally
      infected with E. coli O157:H7. These sheep were given an experimental product
      (XCP) containing the equivalent of either 2.5 mM NaNO3 and 100 mM NaCl (control
      sheep; n = 7) or 2.5 mM NaNO3 and 100 mM NaClO3 (chlorate [XCP]-treated sheep; n
      = 7). Control and XCP-treated sheep were treated for 24 h; XCP treatment reduced
      the population of inoculated E. coli O157:H7 (P < 0.05) from 10(2), 10(5), and
      10(5) CFU/g in the rumen, cecum, and rectum, respectively, to < 10(1) CFU/g in
      all three sections of the gastrointestinal tract. The number of sheep testing
      positive for E. coli O157:H7 was significantly reduced by XCP treatment. In a
      similar fashion, total E. coli and coliforms were also reduced (P < 0.05) in all
      three compartments of the intestinal tract. Intestinal pH, total volatile fatty
      acid production, and the acetate/propionate ratio were unaffected by XCP
      treatment. On the basis of these results, it appears that chlorate treatment can
      be an effective method for the reduction of E. coli O157:H7 populations in
      ruminant animals immediately prior to slaughter.

PMID- 12597477
TI  - Comparison of predictive models for growth of parent and green fluorescent
      protein-producing strains of Salmonella.
AB  - The green fluorescent protein (GFP) from the jellyfish Aequorea victoria can be
      expressed in, and used to follow the fate of, Salmonella in microbiologically
      complex ecosystems such as food. As a first step in the evaluation of GFP as a
      tool for the development of predictive models for naturally contaminated food,
      the present study was undertaken to compare the growth kinetics of parent and GFP
      producing strains of Salmonella. A previously established sterile chicken burger
      model system was used to compare the growth kinetics of stationary-phase cells of
      parent and GFP strains of Salmonella Enteritidis, Salmonella Typhimurium, and
      Salmonella Dublin. Growth curves for constant temperatures from 10 to 48 degrees
      C were fit to a two- or three-phase linear model to determine lag time, specific
      growth rate, and maximum population density. Secondary models for the growth
      parameters as a function of temperature were generated and compared between the
      parent and GFP strain pairs. The effects of GFP on the three growth parameters
      were significant and were affected by serotype and incubation temperature. The
      expression of GFP reduced specific growth rate and maximum population density
      while having only a small effect on the lag times of the three serotypes. The
      results of this study indicate that the growth kinetics of the GFP strains tested
      were different from those of the parent strains and thus would not be good marker
      strains for the development of predictive models for naturally contaminated food.

PMID- 12597478
TI  - Efficacy of electrolyzed oxidizing water in inactivating Salmonella on alfalfa
      seeds and sprouts.
AB  - Studies have demonstrated that electrolyzed oxidizing (EO) water is effective in
      reducing foodborne pathogens on fresh produce. This study was undertaken to
      determine the efficacy of EO water and two different forms of chlorinated water
      (chlorine water from Cl2 and Ca(OCl)2 as sources of chlorine) in inactivating
      Salmonella on alfalfa seeds and sprouts. Tengram sets of alfalfa seeds inoculated
      with a five-strain cocktail of Salmonella (6.3 x 10(4) CFU/g) were subjected to
      90 ml of deionized water (control), EO water (84 mg/liter of active chlorine),
      chlorine water (84 mg/liter of active chlorine), and Ca(OCl)2 solutions at 90 and
      20,000 mg/liter of active chlorine for 10 min at 24 +/- 2 degrees C. The
      application of EO water, chlorinated water, and 90 mg/liter of Ca(OCl)2 to
      alfalfa seeds for 10 min reduced initial populations of Salmonella by at least
      1.5 log10 CFU/g. For seed sprouting, alfalfa seeds were soaked in the different
      treatment solutions described above for 3 h. Ca(OCl)2 (20,000 mg/liter of active
      chlorine) was the most effective treatment in reducing the populations of
      Salmonella and non-Salmonella microflora (4.6 and 7.0 log10 CFU/g, respectively).
      However, the use of high concentrations of chlorine generates worker safety
      concerns. Also, the Ca(OCl)2 treatment significantly reduced seed germination
      rates (70% versus 90 to 96%). For alfalfa sprouts, higher bacterial populations
      were recovered from treated sprouts containing seed coats than from sprouts with
      seed coats removed. The effectiveness of EO water improved when soaking
      treatments were applied to sprouts in conjunction with sonication and seed coat
      removal. The combined treatment achieved 2.3- and 1.5-log10 CFU/g greater
      reductions than EO water alone in populations of Salmonella and non-Salmonella
      microflora, respectively. This combination treatment resulted in a 3.3-log10
      CFU/g greater reduction in Salmonella populations than the control (deionized
      water) treatment.

PMID- 12597479
TI  - Filament formation by Salmonella spp. inoculated into liquid food matrices at
      refrigeration temperatures, and growth patterns when warmed.
AB  - In this study, the formation of multicellular filamentous Salmonella cells in
      response to low temperatures was investigated by using isolates of Salmonella
      enterica serovar Enteritidis PT4 and S. enterica serovar Typhimurium DT104 as the
      inocula. The formation of filamentous cells in two liquid food matrices at the
      recommended maximum temperature for refrigeration (8 degrees C) was monitored and
      compared with that in tryptone soya broth. Giemsa staining was performed to
      locate nuclear material within the filaments. Single filaments were warmed on
      agar at 37 degrees C, and the subsequent rate of septation was quantified. For
      all strains tested, > 70% of the Salmonella cells inoculated had become
      filamentous after 4 days in media at 8 degrees C, indicating that filamentation
      could occur during the shelf life of most refrigerated foods. Strains with
      impaired RpoS expression were able to form filaments at 8 degrees C, although
      these filaments tended to be shorter and less numerous. All strains also formed
      filamentous cells at 8 degrees C in retail milk or chicken meat extract.
      Filaments often exceeded 100 microm in length and appeared straight-sided under
      the microscope in media and in foods, and Giemsa staining demonstrated that
      regularly spaced nucleoids were present. This phenotype indicates that an early
      block in cell septation is probably responsible for filamentation. When filaments
      were warmed on agar at 37 degrees C, there was a rapid completion of septation,
      and for one filament, a >200-fold increase in cell number was observed within 4
      h. There are clear public health implications associated with the filamentation
      of Salmonella in contaminated foods at refrigeration temperatures, especially
      when the possibility of rapid septation of filamentous cells upon warming is
      considered.

PMID- 12597480
TI  - Suppression of Salmonella growth by wild-type and large-plaque variants of
      bacteriophage Felix O1 in liquid culture and on chicken frankfurters.
AB  - The bacteriophage Felix O1, a member of Myoviridae, is specific for, and
      possesses a broad host range within, the genus Salmonella. This work explores a
      Felix O1 phage-based intervention for Salmonella enterica serotype Typhimurium
      DT104 that is potentially applicable at several stages of animal production and
      processing. A variant of Felix O1 was obtained that produces a larger, clearer
      plaque phenotype (LP) on Salmonella Typhi than wild-type Felix O1 (WT) does, not
      unlike r mutants of phage T4. LP exhibited slightly more extensive overall
      suppression of Salmonella Typhi in brain heart infusion (BHI) broth, as
      ascertained on the basis of culture turbidity (optical density at 600 nm). Both
      phage variants suppressed log phase BHI broth cultures containing 8.2 x 10(6) CFU
      of Salmonella Typhimurium DT104 per ml. A PFU/CFU ratio of 1.0 was effective for
      WT and LP, whereas increasing the PFU/CFU ratio to 5.0 did not increase
      suppression. Untreated Salmonella-contaminated frankfurters were compared with
      treated samples (PFU/CFU ratio, 1.9 x 10(4)) to test WT and LP for their ability
      to suppress Salmonella growth on chicken frankfurters contaminated with 300 CFU
      of Salmonella Typhimurium DT104. Suppression levels of 1.8 and 2.1 log units were
      achieved with WT and LP, respectively (P = 0.0001), but no difference was found
      between the performances of the two variants (P = 0.5088).

PMID- 12597481
TI  - Identification of Salmonella serovars isolated from live molluscan shellfish and
      their significance in the marine environment.
AB  - A study on the presence of Salmonella spp. in live molluscs was performed, which
      included a description of the different serovars isolated and their relationship
      to the marine environment. A total of 2,980 samples of shellfish from Galicia
      (N.W. Spain) were tested for the presence of Salmonella spp. between September
      1998 and August 2001. The overall incidence of Salmonella was 1.8% and showed a
      slight rise during the 3 years of the study. Mussels and oysters presented a
      higher incidence than clams and cockles, possibly because of their distinct
      growing habitat. A seasonal pattern was noted for the isolation of Salmonella
      spp.: 54% of the isolations were detected from September to November. That nearly
      67% of the total Salmonella was isolated from shellfish with fecal coliform
      levels < 300/100 g (the maximum level criteria in the European Communities
      regulations) supported the view that low levels of fecal coliforms do not
      necessarily indicate the absence of Salmonella. A total of nine serovars were
      found in the 54 Salmonella isolated. Salmonella Senftenberg was the most frequent
      (50%), followed by Salmonella Typhimurium (18%) and Salmonella Agona (17%).
      Salmonella Senftenberg was detected frequently during the year, whereas the
      remaining serovars were detected only on occasional contamination events.

PMID- 12597482
TI  - Survival of Salmonella in waste egg wash water.
AB  - Waste wash waters from chicken egg-processing facilities can harbor high
      densities of bacteria, including salmonellae. For this study, we enumerated total
      coliforms, Escherichia coli, and Salmonella spp. in the egg wash waters of a
      large egg producer. We then determined how long these organisms would survive at
      temperatures of 5, 15, and 25 degrees C. We found that the fraction of
      salmonellae surviving over time at a given temperature was comparable to the
      fraction of indicator organisms that survived. We also found that the survival of
      these organisms varied with temperature, with 16, 8, and < 2 days being required
      for a 90% reduction of Salmonella in waste wash water held at 5, 15, and 25
      degrees C, respectively. Finally, we noted that the response of laboratory
      derived cultures to environmental stresses mimics the response of the indigenous
      microbial population, but individual cells within that population may survive for
      longer periods than laboratory-cultured strains.

PMID- 12597483
TI  - Polymerase chain reaction detection of Listeria monocytogenes on frankfurters
      using oligonucleotide primers targeting the genes encoding internalin AB.
AB  - A polymerase chain reaction (PCR) assay targeting the genes encoding internalin
      AB (inlAB) was developed for detecting Listeria monocytogenes in pure cell
      cultures and on artificially contaminated frankfurters. Four sets of
      oligonucleotide primers were evaluated. The set targeting a 902-bp region of the
      inlAB gene was the most specific. This PCR product was detected in 51 L.
      monocytogenes strains belonging to four different serogroups (1/2a, 1/2b, 1/2c,
      and 4b). In contrast, the PCR product was not detected in other Listeria spp.
      (Listeria innocua, Listeria ivanovii, Listeria seeligeri, Listeria welshimeri, or
      Listeria grayi) or in gram-positive, non-Listeria bacteria, indicating that the
      primer set was highly specific for L monocytogenes. The detection limit of the
      PCR assay was 10(5) CFU per ml of pure cell culture. However, the assay could
      detect as few as 10(1) CFU of L. monocytogenes in 25 g of frankfurter with 16 h
      of enrichment in modified Listeria enrichment broth at 30 degrees C. The total
      assay time including enrichment was approximately 24 h. These results suggest
      that the PCR assay can be used to rapidly detect L. monocytogenes on frankfurters
      and possibly other types of ready-to-eat meat products.

PMID- 12597484
TI  - Lethality of Salmonella and Listeria innocua in fully cooked chicken breast meat
      products during postcook in-package pasteurization.
AB  - The process lethality model was used to predict the thermal kill of Salmonella
      and Listeria innocua in fully cooked and vacuum-packaged chicken breast meat
      during hot-water postprocess pasteurization. Time-temperature profiles of the
      meat samples during treatment and D-values (decimal reduction times) and z-values
      (change in temperature required to change the D-value) for Salmonella and L.
      innocua in the same meat product were used in the prediction of lethality. The
      results of the model prediction were compared with those of the inoculation study
      for the same meat product at a 95% confidence level of up to 10(7) CFU/g for
      Salmonella and L. innocua. The thermal lethality predictions obtained with the
      process lethality model for Salmonella and L. innocua were within the 95%
      confidence level for the experimental data from the inoculation study, suggesting
      that the process lethality model was a useful tool for the determination of the
      kill of Salmonella or L. innocua at up to 10(7) CFU/g in fully cooked chicken
      breast meat products during postprocess pasteurization with hot water.

PMID- 12597485
TI  - Typing of Listeria monocytogenes isolates originating from the food processing
      industry with automated ribotyping and pulsed-field gel electrophoresis.
AB  - A total of 486 Listeria monocytogenes isolates originating from 17 Finnish food
      processing plants (representing meat, poultry, fish, and dairy production) were
      collected and typed by automated ribotyping using EcoRI as the restriction
      enzyme. The isolates were divided into 16 different ribotypes (RTs). Some of
      these isolates (121), representing all EcoRI types and 16 food plants, were
      subjected to ribotyping with the PvuII enzyme, to pulsed-field gel
      electrophoresis (PFGE) typing with AscI and SmaI restriction enzymes, and to
      serotyping with O-antigen antisera. Nineteen ribotypes were generated with PvuII,
      42 macrorestriction patterns were generated with AscI and 24 with SmaI, and three
      serotypes were generated with antisera. When the results were combined, the
      overall number of RTs was 23, and that of the PFGE types was 46. Thus, the
      overall discrimination power of PFGE was higher (discrimination index [DI] 0.966)
      than that of ribotyping (DI 0.906). The most common serotype (90.1% of the
      isolates) was 1/2, and isolates of serotype 4 (3.3%) were rare. There was no
      connection between food sectors and RTs or PFGE types, but PFGE indicated the
      single plants (78.3% of the types) better than ribotyping (56.5%). On the basis
      of its automation and on the availability of identification databases, automated
      ribotyping had some advantages over PFGE. Overall, automated ribotyping can be
      considered a practical and rapid tool when Listeria contamination is suspected
      and when screening a large number of isolates is necessary, e.g., when tracing
      contamination sources. However, in cases of outbreaks, the identical patterns
      must be confirmed by PFGE, which is a more discriminatory method.

PMID- 12597486
TI  - Assessment of control measures to achieve a food safety objective of less than
      100 CFU of Listeria monocytogenes per gram at the point of consumption for fresh
      precut iceberg lettuce.
AB  - The important new concept of the food safety objective (FSO) offers a strategy to
      translate public health risk into a definable goal such as a specified maximum
      frequency or concentration of a hazardous agent in a food at the time of
      consumption that is deemed to provide an appropriate level of health protection.
      For the foodborne pathogen Listeria monocytogenes, there is a proposed FSO of <
      100 CFU/g in ready-to-eat (RTE) products at the time of consumption. Fresh precut
      iceberg lettuce is one of these RTE products. In this study, we worked with a
      commercial manufacturer to evaluate the effectiveness of two antimicrobial
      washing agents (sodium hypochlorite and a mixture of hydrogen peroxide and
      peroxyacetic acid) against L. monocytogenes under simulated fresh precut washing
      conditions and evaluated the growth potential of this pathogen on lettuce
      packaged in a gas-permeable film and stored at 4 or 8 degrees C for 14 days. We
      used the results of this experiment to demonstrate how the commercial
      manufacturer could meet the FSO for L. monocytogenes in fresh precut lettuce
      through the application of performance, process, and microbiological criteria.

PMID- 12597487
TI  - Impact of preheating on the behavior of Listeria monocytogenes in a broth that
      mimics Camembert cheese composition.
AB  - The effect of preheating on the survival of L. monocytogenes in Richard's broth,
      which mimics the composition of Camembert cheese composition, was examined.
      Experiments were carried out to reproduce contamination of cheese with
      environmental heat-stressed cells of L. monocytogenes surviving hot-cleaning
      procedures. Cells in mid-log phase were heated for 30 min at 56 degrees C before
      being inoculated into Richard's broth. The pHs and temperatures of Richard's
      broth were chosen to recreate the conditions of curd dripping (pH 5, 25 degrees
      C), of the beginning of cheese ripening (pH 5, 12 degrees C), and of the
      beginning (pH 5, 4 degrees C) and the end (pH 7, 4 degrees C) of cheese storage.
      Immediately after heat treatment, the viability loss was especially high for
      strain 306715, which exhibited only 0.6% +/- 0.2% survival, compared with 22% +/-
      8.7% for strain EGD. The percentages of the surviving heated cells that were
      injured were 93% +/- 8% for strain 306715 and 98% +/- 3% for strain EGD. The
      destruction of the surviving L. monocytogenes cells was accelerated when they
      encountered the pH and temperature conditions of Camembert cheese during
      manufacturing, ripening, and cold storage (pH 5 at 25, 12, and 4 degrees C,
      respectively). The multiplication of the surviving heated cells was retarded
      under favorable growth conditions similar to those of storage by the distributor
      and the consumer (pH 7 at 4 and 12 degrees C, respectively).

PMID- 12597488
TI  - Establishment of a microbiological profile for an air-chilling poultry operation
      in the United States.
AB  - The microbiological profile of an air-chilling poultry process was investigated
      from the farm through the processing plant. Within a 1-year period, nine broiler
      flocks from four different farm sources were studied. Numbers of total aerobes,
      coliforms, psychrotrophic organisms, E. coli Biotype I (generic E. coli),
      Salmonella spp., and Campylobacter spp. were determined for multiple sampling
      sites on the farm as well as in the processing plant. Farm samples were collected
      the day before the chickens were slaughtered at the plant. The same flock was
      sampled at the plant on the day of slaughter. Sites located before evisceration
      (BE), after evisceration (AE), and after chilling (AC) were sampled. Results
      indicated a positive correlation between contamination of ceca with Salmonella on
      the farm and the presence Salmonella in carcass samples from the plant for all
      three types of sampling sites. The in-plant trend for total aerobes, coliforms,
      and generic E. coli revealed a significant decrease from counts obtained before
      evisceration to those obtained for the (AC) final product when flock variations
      were taken into account. The average coliform counts were 3.91, 3.27, and 2.59
      log10 CFU/ml of rinse for BE, AE, and AC samples, respectively. Generic E. coli
      counts were 3.74, 3.08, and 2.20 log10 CFU/ml of rinse for BE, AE, and AC
      samples, respectively. No reductions in numbers of Campylobacter or Salmonella
      were observed during processing, which suggests that practical intervention
      strategies for lowering pathogen levels are critical on a multilevel basis at the
      farm and in the plant.

PMID- 12597489
TI  - Use of time-temperature integrators and predictive modeling to evaluate
      microbiological quality loss in poultry products.
AB  - The purpose of this study was to characterize the kinetics of the spoilage
      process of chicken drumsticks in order to evaluate the application of an enzyme
      process-based time-temperature integrator (TTI) as a continuous quality monitor
      of poultry products. Shelf life studies were conducted at several temperatures (3
      to 20 degrees C) to characterize (i) the poultry spoilage process as a function
      of total aerobic bacteria and Pseudomonas species populations and (ii) the TTI
      chroma response function. Two types of poultry products were examined: ice-packed
      and chill-packed drumsticks. An enzyme-based TTI with a color change response
      from green to yellow was used. Activation energies for each of the poultry
      products and each of the bacterial populations were as follows: 21.8 +/- 1.6
      kcal/mol (ca. 91.2 +/- 6.7 kJ/mol) for ice-packed drumsticks and total aerobic
      population, 18.8 +/- 4.5 kcal/mol ca. 78.7 +/- 18.8 kJ/mol) for ice-packed
      drumsticks and Pseudomonas spp., 17.0 +/- 2.3 kcal/mol (ca. 71.1 +/- 9.6 kJ/mol)
      for chill-packed drumsticks and total aerobic population, and 14.1 +/- 3.6
      kcal/mol (ca. 59.0 +/- 15.1 kJ/mol) for chill-packed drumsticks and Pseudomonas
      spp. The activation energy calculated for the TTI, 19.1 +/- 1.8 kcal/mol (ca.
      79.9 +/- 7.5 kJ/mol), was determined to be adequately close to that of the
      poultry spoilage process to make effective quality predictions possible. Initial
      bacteria levels on the chicken drumsticks were uniform and not judged as
      important limiting factors in the application of TTIs to poultry products.
      Because the poultry spoilage process was reasonably characterized on the basis of
      Arrhenius kinetics, there is further need to conduct validation studies to
      determine the ability of TTIs to provide a continuous quality monitoring system.

PMID- 12597490
TI  - Evaluation of time-temperature integrators for tracking poultry product quality
      throughout the chill chain.
AB  - The goal of this study was to evaluate the application of one type of time
      temperature integrator (TTI) to monitor the microbiological quality of ice-packed
      raw chicken drumsticks as a function of temperature exposure. A kinetics-based
      model was used to correlate the TTI chroma response to the number of bacteria on
      the drumstick surface under constant- and variable-temperature conditions. Two
      constant-temperature studies (4 and 15 degrees C) and one variable-temperature
      study (4 degrees C for 24 h, 15 degrees C for 24 h, 4 degrees C constant) were
      conducted to evaluate the applicability of the TTI under ideal and worst-case
      situations. During the constant-temperature studies, quality predictions made at
      the midpoint of the product shelf life were accurate within 15% for the observed
      bacterial populations. The accuracy of the TTI was marginal in the initial and
      final stages of the response period. During the variable-temperature study, the
      TTI response demonstrated positive history effects, whereby the observed rate
      constant is affected by previous temperature exposure. After the TTIs had been
      held at 15 degrees C for 24 h, the TTI response rate constant observed during
      subsequent storage at 4 degrees C was higher than what would be predicted for 4
      degrees C. Further work will be needed to develop a continuous TTI-based quality
      monitoring system. However, because the microbiological quality of fresh poultry
      could be reliably predicted with kinetic models, fresh poultry products would be
      excellent candidates for a TTI-based quality monitoring system.

PMID- 12597491
TI  - Bacteriology and storage life of moisture-enhanced pork.
AB  - This study was undertaken to determine the impact of the moisture enhancement
      process on the bacterial contamination and storage life of vacuum-packaged pork
      loins. Bone-in and boneless pork loins injected with brine (sodium chloride,
      sodium phosphate, lemon juice) were obtained from a commercial processing
      facility and stored for 5 weeks in vacuum packaging at 2 and 5 degrees C. At
      weekly intervals, samples were excised to determine numbers of spoilage bacteria
      and pathogens. The loins were subjectively evaluated by a sensory panel to
      quantify appearance and odor acceptability. Moisture-enhanced loins were
      initially contaminated with a population of psychrotrophic bacteria that was
      approximately 2 log units higher than that for noninjected boneless loins. This
      difference was largely due to contamination by larger numbers of pseudomonads in
      the brine-injected loins. There were no significant differences in the initial
      numbers of lactic acid bacteria, Enterobacteriaceae, or Brochothrix
      thermosphacta. Similar trends in spoilage bacterial populations were observed for
      moisture-enhanced loins with bones, but Enterobacteriaceae counts were also found
      to be approximately 1 log unit higher for the injected product. Brine-injected
      loins generally had larger bacterial numbers at each storage time, but there were
      no consistent injection treatment effects on bacterial growth. Brine injection
      did not affect color or odor deterioration, and the storage life for vacuum
      packaged loins was the same as that for noninjected controls. The incidence of
      Listeria monocytogenes was 21% for control loins and 27% for moisture-enhanced
      loins. Although the brine injection process resulted in an increase in bacterial
      contamination, there was no evidence that this contamination would affect the
      storage life of vacuum-packaged loins, and further research is necessary to
      determine the significance of the increased incidence of L. monocytogenes.

PMID- 12597492
TI  - Total mercury and methylmercury content in edible fish from the Mediterranean
      Sea.
AB  - The objective of this study was to determine the current levels of total mercury
      and methylmercury in the muscle tissues of different fish species caught in the
      Mediterranean Sea to ascertain whether these concentrations exceed the maximum
      level stipulated by the European Commission Decision. Total mercury
      concentrations in the muscles of skates ranged from 0.18 to 1.85 mg/kg (wet
      weight) (average, 1.00 mg/kg) while levels of 0.11 to 1.92 mg/kg (wet weight)
      (average, 0.70 mg/kg) and 0.21 to 1.74 mg/kg (wet weight) (average, 0.70 mg/kg)
      were recorded for blue whiting and red mullet, respectively. For 66.7% of long
      nose skate samples, 61.4% of thornback ray samples, 42.8% of winter skate
      samples, and 38% of starry ray samples, the total mercury concentrations exceeded
      the prescribed legal limit (1.0 mg/kg [wet weight]). Concentrations exceeding the
      maximum total mercury level stipulated by the European Commission Decision (0.5
      mg/kg [wet weight]) were observed in 63.6 and 40% of blue whiting and striped
      mullet samples, respectively. Mercury was present in the different species almost
      completely in the methylated form at 55 to 100%. Weekly intakes were estimated
      and compared with the provisional tolerable weekly intake recommended by the
      Joint Food and Agriculture Organization/World Health Organization Expert
      Committee on Food Additives.

PMID- 12597493
TI  - Model studies on the detectability of genetically modified feeds in milk.
AB  - Detecting the use of genetically modified feeds in milk has become important,
      because the voluntary labeling of milk and dairy products as "GMO free" or as
      "organically grown" prohibits the employment of genetically modified organisms
      (GMOs). The aim of this work was to investigate whether a DNA transfer from
      foodstuffs like soya and maize was analytically detectable in cow's milk after
      digestion and transportation via the bloodstream of dairy cows and, thus, whether
      milk could report for the employment of transgene feeds. Blood, milk, urine, and
      feces of dairy cows were examined, and foreign DNA was detected by polymerase
      chain reaction by specifically amplifying a 226-bp fragment of the maize
      invertase gene and a 118-bp fragment of the soya lectin gene. An intravenous
      application of purified plant DNA showed a fast elimination of marker DNA in
      blood or its reduction below the detection limit. With feeding experiments, it
      could be demonstrated that a specific DNA transfer from feeds into milk was not
      detectable. Therefore, foreign DNA in milk cannot serve as an indicator for the
      employment of transgene feeds unless milk is directly contaminated with feed
      components or airborne feed particles.

PMID- 12597494
TI  - Application of a modified culture medium for the simultaneous counting of molds
      and yeasts and detection of aflatoxigenic strains of Aspergillus flavus and
      Aspergillus parasiticus.
AB  - Molds and yeasts from 91 samples of feed and raw materials used in feed
      formulation were enumerated on a new culture medium to which a beta cyclodextrin
      (beta-W7M 1.8-cyclodextrin) had been added. This medium was compared with other
      media normally used in laboratories for the routine analysis of fungi, such as
      Sabouraud agar, malt agar supplemented with 2% dextrose, and potato dextrose
      agar. When a t test for paired data (0.05 significance level, 95% confidence
      interval) was applied, no statistically significant differences between the
      results obtained with the new culture medium and those obtained with the other
      media used to enumerate molds and yeasts were found. For the evaluation of
      contamination due to aflatoxin for all of the samples, Sabouraud agar and yeast
      extract agar, both supplemented with 0.3% beta-W7M 1.8-cyclodextrin, and APA
      (aflatoxin-producing ability) medium were used. Aflatoxin was detected in 21% of
      the feed samples and in 23% of the raw-material samples analyzed, with maximal
      amounts of 2.8 and 6.0 microg of aflatoxin B1 per kg, respectively, being
      detected. In any case, the aflatoxin contents found exceeded the legally
      stipulated limits. The t test for paired data (0.05 significance level, 95%
      confidence interval) did not show statistically significant differences between
      the results obtained with the different culture media used for the detection of
      aflatoxins. The advantage of the new medium developed (Sabouraud agar with 0.3%
      beta-W7M 1.8-cyclodextrin) is that it allows simultaneous fungal enumeration and
      determination (under UV light) of the presence of aflatoxin-producing strains
      without prior isolation and culture procedures involving expensive and/or complex
      specific media and thus saves work, time, and money.

PMID- 12597495
TI  - Determination of ciprofloxacin and nalidixic acid resistance in Campylobacter
      jejuni with a fluorogenic polymerase chain reaction assay.
AB  - A fluorogenic polymerase chain reaction assay for the gyrA gene was used to
      determine the frequency of a Thr-86 mutation in Campylobacter jejuni isolates
      from food animals and humans in northern Thailand and to investigate the
      correlation between this mutation and bacterial resistance to fluoroquinolones.
      Eighty-four isolates of C. jejuni were used: 65 from healthy chickens on farms,
      16 from chickens at the slaughterhouse, 1 from chicken meat at the market, and 1
      from a healthy farm worker. The microbroth dilution technique was used for in
      vitro susceptibility testing. MIC breakpoints established by the National
      Antimicrobial Resistance Monitoring System were used to categorize the resistance
      of C. jejuni to ciprofloxacin and nalidixic acid. Sixty of the 84 C. jejuni
      isolates tested carried the Thr-86 mutation in the gyrA gene. All isolates with
      ciprofloxacin MICs of > or = 2 mg/liter carried the mutation, and no isolates
      with nalidixic acid MICs of < or = 16 mg/liter carried the Thr-86-to-Ile
      mutation. There was a very strong association between ciprofloxacin resistance
      and the presence of the mutation (kappa = 0.971, P < 0.01). The association
      between the presence of the Thr-86-to-Ile mutation and nalidixic acid resistance
      was weaker (kappa 0.859: P < or = 0.01).

PMID- 12597496
TI  - Phage typing of Salmonella enteritidis from different sources in Brazil.
AB  - The occurrence of Salmonella Enteritidis (SE) phage types (PTs) in samples
      collected from healthy and diseased chickens, in outbreaks of human
      gastroenteritis related to the consumption of egg products, in samples of poultry
      meat, in pipped embryos of broiler chickens, in meat meal, in poultry-rearing
      environments, and in many foods (cheese, mayonnaise, cake, and bacon) is
      described for strains isolated from 1995 to 1997 in Brazil. SE strains were
      isolated, and the most common PT was found to be PT 4, followed by PTs 7, 21, 35,
      6, 4a, 8, 30, 6a, 5a, 1, and 1b. Fourteen strains were classified as react-but-do
      not-conform strains, and one strain was not typeable. The results of this study
      demonstrate that PT 4 has a wider distribution among the sources studied than do
      any other SE phage types and is the most important phage type in human
      salmonellosis.

PMID- 12597497
TI  - Prevalence of Listeria spp. in feces and carcasses at a lamb packing plant in
      Brazil.
AB  - The objective of this work was to study the occurrence of Listeria species in
      feces and on dressed and cooled carcasses of lambs at a packing plant in Brazil.
      Listeria spp. were recovered on Oxford and Palcam agars. The 35 fecal samples
      yielded Listeria welshimeri (20%) and Listeria innocua (8.6%). The 69 carcass
      samples yielded L. innocua (34.8%), Listeria monocytogenes (4.3%), and Listeria
      ivanovii (1.5%). More Listeria spp. were recovered with two selective agars than
      with either agar alone.

PMID- 12597498
TI  - Persistence of hepatitis A virus in oysters.
AB  - We investigated the ability of hepatitis A virus (HAV) to persist for up to 6
      weeks in Eastern oysters (Crassostrea virginica). Viral RNA was detected by
      reverse transcription-polymerase chain reaction 6 weeks after 16 h of exposure to
      90,000 PFU (180 PFU/ml of seawater) of HAV. Assaying for infectious virus in
      oysters that received a daily feeding of phytoplankton recovered 3,800, 650, and
      500 PFU of HAV 1, 2, and 3 weeks after contamination with 90,000 PFU of HAV,
      respectively. However, no infectious HAV was isolated from oysters 4, 5, or 6
      weeks after contamination. These results support the position that shellfish
      depuration is insufficient for the complete removal of infectious viruses.
      Extended relay times (in excess of 4 weeks) may be required to produce
      virologically safe shellfish.

PMID- 12597500
TI  - Status of women's health: the need for better access and affordable health
      services.

PMID- 12597499
TI  - Monitoring volatile and nonvolatile amines in dried and salted roes of tuna
      (Thunnus thynnus L.) during manufacture and storage.
AB  - Dried and salted roe, obtained from the reproductive organs of female tuna
      (Thunnus tynnus L.), is a typical fish-based food in the Mediterranean area of
      Spain. In the present study, we monitored the formation of volatile amines
      (trimethyamine nitrogen [TMA-N] and total basic volatile nitrogen [TBVN]) and
      nonvolatile amines (biogenic amines) in dried and salted tuna roe after
      processing and storage for 8 weeks at 4, 20, and 30 degrees C. The salting and
      drying process significantly increased the TBVN, cadaverine, tyramine,
      phenylethylamine, and tryptamine contents, and bacteria with histamine
      decarboxylase activity were detected both in raw and in dried and salted tuna
      roes. During storage of tuna roe, TMA-N and TBVN levels increased significantly
      after the fourth week of storage at 30 degrees C, whereas biogenic amine contents
      remained more or less constant. However, samples stored at 30 degrees C showed
      histamine formation after the first week of storage, with a concentration of < 50
      ppm. The volatile and nonvolatile amine concentrations in tuna roe were below the
      consumer safety limit, with the exception of the total biogenic amine level in
      roe stored at 30 degrees C, which exceeded the European Community's recommended
      limit (300 ppm). These results indicate that in properly stored tuna roe,
      histamine formation will not represent a serious health risk to consumers unless
      the tuna roe has previously been mishandled.

PMID- 12597501
TI  - The fetal origins of disease hypothesis: public health implications for the Asia
      Pacific region.
AB  - There has been rapid development in the Asia-Pacific region, leading to
      improvements in the food supply and nutrition. The high prevalence of low birth
      weight has been a problem in many countries and continues to be a problem in some
      parts of the region. In the past few years an epidemic of obesity and chronic
      disease has emerged. The fetal origins hypothesis links the high prevalence of
      low birth weight and recent increasing obesity to explain the emerging epidemic
      of chronic disease. One public health strategy to challenge this epidemic is the
      promotion of breastfeeding of all infants. Breastfeeding has been shown to
      protect against childhood obesity, and is "dose related", that is, the longer an
      infant is breastfed, the lower the risk of obesity.

PMID- 12597502
TI  - Changes in ante-natal care and family planning in Krakor, Pursat, Cambodia, 1996
      1998.
AB  - This study examines variations in ante-natal care (ANC) and family planning in
      Krakor, Pursat, Cambodia between 1996 and 1998. Population-based survey
      interviews were conducted with a total of 291 women in 1996 and 211 women in
      1998. An intervention strategy designed to enhance the skills and roles of Health
      Centre staff, Village Health Volunteers (VHVs) and Traditional Birth Attendants
      (TBAs) was conducted. Over this timeframe, reported ANC access increased from 37%
      to 47%. Most women delivered their last child at home, usually assisted by a TBA.
      Few women practiced family planning, despite the fact that most reported that
      they did not want any further children. A range of reasons for not practicing
      family planning were found to be highly significant, including the lack of
      available services (p<0.01). The fear of side-effects decreased significantly
      (p<0.01), with the community education provided by the VHVs and TBAs, potentially
      being one contributing factor. The results of this study suggest that continual
      support of VHVs and TBAs will further improve the health of women in Cambodia.

PMID- 12597503
TI  - Utilization of public and private dental services in Sibu, Sarawak: a
      sociodemographic appraisal and types of treatment received.
AB  - This study investigated the sociodemographic profiles of patients attending
      public and private dental clinics and the types of treatment received. Patients
      (n=454) were interviewed using a structured questionnaire at two public and four
      private clinics in Sibu District, Sarawak. Generally, Chinese (74.7%), females
      (60.0%) and urban dwellers (83.7%) were more likely to visit the dentist. Both
      clinics had more females and more Chinese but private clinics had a lower
      percentage of female attendees (53.1% versus 67.0%) but a higher percentage of
      Chinese (85.0% versus 64.5%). Private attendees were younger (mean age of 31.0
      years compared to 41.0 years) and from higher income households (median value of
      MR 2,000 versus MR 900) than public attendees. Treatments were mostly curative
      and a third of the visits were associated with painful conditions. Age (p=0.006),
      gender (p=0.003), ethnicity (p<0.001) and household income (p<0.001) were
      associated with the type of clinic visited. Choice of clinic was not related to
      having painful conditions (p=0.970). To ensure a more affordable and equitable
      distribution of oral healthcare, health planners need to identify disparities in
      the utilization of services and differences between public and private attendees.

PMID- 12597504
TI  - Variation in malaria endemicity in relation to microenvironmental conditions in
      the Admiralty Islands, Papua New Guinea.
AB  - For 197 adults and adolescents in four villages of three small islands in the
      Admiralty Islands, Papua New Guinea, antimalarial antibody titers were examined
      using the indirect fluorescent antibody test (IFAT) and malaria parasites were
      detected by the microtiter plate hybridisation (MPH) method using polymerase
      chain reaction (PCR) technique. The parasite rate (either Plasmodium falciparum
      or P. vivax, or both) averaged 39.2%, varying from 31.1% to 44.8% among the four
      villages due to natural and artificial microenvironmental conditions related to
      breeding sites of mosquitoes (Anopheles farauti). The lack of flat zones owing to
      geomorphological formation contributed to the lowest parasite rate in the
      extremely small island. However, human-modified environments such as a wet-land
      (naturally formed but artificially reformed) and an open well played significant
      roles in other inter-village differences. The present findings imply significant
      roles of microenvironment in diversified malaria prevalence and suggest some ways
      of mitigation of malarial hazards.

PMID- 12597505
TI  - Use of drug sellers by old people in northeast Thailand.
AB  - The paper describes an exploratory study of the use of private drug sellers by
      people age 60 and over in three districts in northeast Thailand. The survey paid
      special attention to problems of under-reporting, and found that respondents
      visited drug sellers two or three times a month--a much higher frequency than
      usually reported. The typical reason for visiting a drug seller was to obtain one
      or two days' worth of modern medicines to treat the symptoms of non-acute
      conditions. The paper discusses ways to improve on current survey methods for
      studying private drug sellers.

PMID- 12597506
TI  - A case-control for the association between change in weight, family history and
      hypertension at different ages.
AB  - To study the association between the changes of weight, family history and
      hypertension at different ages, a pair-matched case-control study was conducted
      in the outpatient service of department of internal medicine in Binjiang Hospital
      of Tianjin from 1994 to 1996. The cases were selected from 312 patients with
      hypertension diagnosed during 1994-1996 and identified newly in the survey. The
      controls were selected from other outpatients of no cardiovascular disease
      histories matched by age and sex. The conditional logistic regression model was
      used. The cases and controls were divided into two age groups under 59 years old,
      60 and older. History of hypertension in the first degree-relatives was linked to
      hypertension, but family history of hypertension of groups under age 59, and at
      60 and older was mainly hypertension history of parents and siblings,
      respectively. Other risk factors of developing hypertension were higher weight or
      body mass index (kg/m2) in the survey, higher degree of weight gain in comparison
      with the basic weight and early age at beginning weight gain in all two groups.
      However, the risk of developing hypertension for increasing weight and obesity
      increased with advancing age groups. The study further indicates that controlling
      body weight, decreasing the degree of weight gain, and delaying the beginning age
      of weight gain all contribute to the lower risk of suffering from hypertension
      and were effective measures of hypertension of the prevention and cure.

PMID- 12597507
TI  - Differing health and health-seeking behaviour: ethnic minorities of the
      Chittagong Hill Tracts, Bangladesh.
AB  - This study investigates the health and health-seeking behaviour of the indigenous
      population of Chittagong Hill Tracts, Bangladesh by surveying 2,550 randomly
      selected households from five major ethnic groups residing in the region. A
      structured questionnaire was used for collecting data. Morbidity prevalence (23%)
      and child malnutrition (19%) was highest among Bangalis. Fever (40%), diarrhoeal
      diseases (37%) and malaria (16%) were the three most common illnesses reported
      among the study population. Around fifteen percent of the Bangalis sought care
      from the paraprofessionals while 'unqualified' allopaths were consulted more
      frequently by the Tripuras, Chakmas and the Marmas (60-70%). Qualified allopaths
      were mostly consulted by the Bangalis (26%). Sex, types of illness, ethnicity,
      household head's education and household's landholding were significant
      predictors of seeking treatment, and allopathic treatment in particular. The
      findings on the differential health and health-seeking behaviour among ethnic
      groups should help in the designing of any future health interventions in the
      area.

PMID- 12597508
TI  - Homebound status in a community-dwelling elderly population in Japan.
AB  - The present study investigated the association between sociodemoraphic profiles,
      health condition and functional disabilities of subjects with a homebound status
      in a rural community setting. The subjects were residents aged 65 years or over
      in a mountain village of Japan. A comprehensive questionnaire was used to obtain
      their data. Among the 1,002 residents, the information of 866 residents (85%),
      who voluntarily completed the entire survey, was obtained for this study. All the
      subjects were native Japanese. Of the 866 subjects investigated, 301 (34.8%) were
      homebound as defined by the parameters of this study. Univariate analysis
      revealed age, female gender, functional impairment (vision, hearing and memory),
      all the ADL impairments, and the use of a portable toilet were associated with
      homebound status. Multivariate analysis revealed that older age, female gender,
      visual and two ADL impairments (moving inside the home and bathing) and use of a
      portable toilet remained significantly related to homebound status. Homebound
      elderly people have more functional limitation and disability related factor than
      their nonhomebound counterparts. Functional impairment, particularly in the
      mobility domain and sensory disturbances, was associated with homebound status.
      These data indicate the importance of assessment in the provision of home care
      for elderly people.

PMID- 12597509
TI  - Evidence-based practice revisited.
AB  - The evidence-based practice (EBP) movement has gathered considerable momentum
      both locally and abroad since first promoted a decade ago. This paper presents an
      updated narrative overview of EBP from the clinical and public health
      perspectives. First, the origins and definition of EBP and how clinicians should
      go about incorporating it into routine practice are described. Reasons for
      adopting the EBP philosophy are outlined and the way to learn the process
      described. The latter can be summarised as the five A's of EBP--assess, ask,
      acquire, appraise and apply. Limitations of the approach and misperceptions about
      its weaknesses are also discussed. Potential solutions are offered and areas for
      future work in the discipline of EBP are highlighted, with particular reference
      to Hong Kong's situation and that of elsewhere in Asia.

PMID- 12597510
TI  - Issues in public health: assuaging concern from contaminated land resulting from
      land use dynamics in Malaysia.
AB  - The anthropogenic disturbance of pristine natural areas caused by land use and
      transformation from one use to another as a result of increased pressure from
      demographic changes and the economics of this shrinking resource can result in
      adverse health hazards for the community. This paper appraises the consequential
      impact of land use dynamics, its assessment and measures required to assuage this
      overlooked public health issue. The anthropogenic impact from land use in
      Malaysia from the industrial sector alone points toward the potential capacity to
      cause adverse health hazards. A deficiency in assessing this impact due to
      limited information has resulted in the inability to establish the extent of this
      problem. Several necessary measures to establish the extent of the problem
      involving ways to characterise contaminated land and the evolution of a strategy
      to resolve it are discussed.

PMID- 12597511
TI  - Emerging and re-emerging diseases in Malaysia.
AB  - Emerging and re-emerging infectious diseases have become a major global problem.
      Malaysia appears to be an epicenter for such infections and in recent years,
      several outbreaks have occurred resulting in loss of lives and economic
      hardships. In this paper, we discussed the outbreaks of leptospirosis,
      enterovirus 71 encephalitis, chikungunya polyarthritis and Nipah encephalitis and
      how a developing country such as Malaysia managed the situation with the help of
      international agencies and organisations. Many valuable lessons were learned and
      by sharing our experience, it is hoped that we will be in a better position to
      handle future outbreaks and prevent their spread to countries in the region.

PMID- 12597512
TI  - Towards a comparative analysis of health systems reforms in the Asia-Pacific
      Region.
AB  - The paper will review a representative selection of health systems reforms
      throughout the Asia-Pacific region to summarise the regional experience, identify
      the key lessons learnt from innovative health reforms and propose policy
      recommendations for sustainable health systems development. Broad descriptive
      trends of health systems reforms will be compared across the Asia-Pacific region
      within the context of rapid demographic, health and socio-economic development.
      More specifically, the study will address the following questions: 1. What are
      the main features of innovative health systems reforms? 2. How have these reforms
      affected the health systems? 3. Are there lessons and other implications from
      these reforms? A common conceptual framework to compare health systems reforms is
      adopted, using a standardised format to report data of national health systems. A
      classification of health systems is constructed by categorising them according to
      the level of development of their respective economies: 1) Developed 2 )High
      Performing 3) Newly Industrialising 4) Transitional, and 5) Developing. A
      typology of common issues, challenges and responses are generalised for these
      health systems at different stages of socio-economic development of individual
      countries. Evaluative criteria are proposed to compare the long-term effects of
      these reforms on national health systems in terms of efficiency, equity, quality
      and sustainability.

PMID- 12597513
TI  - Health care reform and changes: the Malaysian experience.
AB  - Health care reform is an intentional, sustained and systematic process of
      structural change to one or more health subsystems to improve efficiency,
      effectiveness, patient choices and equity. Health care all over the world is
      continuously reforming with time. Health care reform has become an increasingly
      important agenda for policy change in both developed and developing countries
      including Malaysia. This paper provides an overview of the Malaysian health care
      system, its achievements, and issues and challenges leading to ongoing reform
      towards a more efficient and equitable health care system that possess a better
      quality of life for the population.

PMID- 12597514
TI  - Healthcare financing in Malaysia.
AB  - This paper presents an overview of the Malaysian healthcare system and its method
      of financing. The development of the healthcare delivery system in Malaysia is
      commendable. However, the strength and weaknesses of the public healthcare system
      and the financing problems encountered are also discussed. Cost of healthcare and
      funding of both the public and private sectors were also revealed. One must
      optimise the advantages of operating a health financing scheme which is
      affordable and controllable which contribute towards cost-containment and quality
      assurance. Thus, there is a need for the establishment of a National Healthcare
      Financing, a mechanism to sustain the healthcare delivery network and operate it
      as a viable option. A model of the National Health Financing Scheme (NHFS) was
      proposed.

PMID- 12597515
TI  - Role of teleconsultation in moving the healthcare system forward.
AB  - The equitable access to quality healthcare by Malaysians has consistently been
      the primary objective of the Ministry of Health (MOH). The epidemiological
      transition to chronic illnesses, advances in medical technology, escalating
      healthcare costs and rising patient expectations has necessitated the strategic
      use of information systems in healthcare delivery. Malaysia has broken new ground
      by implementing a nationwide network to address inadequate access to healthcare,
      as well as to lower costs and achieve better health outcomes. Teleconsultation
      refers to the electronic transmission of medical information and services from
      one site to another using telecommunication technologies. This technology
      transforms the healthcare system by rapidly matching patient needs with the
      appropriate level of care however geographically remote they may be. Our findings
      suggest that even in these early stages of implementation, teleconsultation has
      led to cost savings, a more efficient allocation of resources, enhanced
      diagnostic options and better health outcomes.

PMID- 12597516
TI  - Changing emphases in public health and medical education in health care reform.
AB  - Globalisation of economies, diseases and disasters with poverty, emerging
      infectious diseases, ageing and chronic conditions, violence and terrorism has
      begun to change the face of public health and medical education. Escalating costs
      of care and increasing poverty have brought urgency to professional training to
      improve efficiency, cut costs and maintain gains in life expectancy and morbidity
      reduction. Technology, genetics research and designer drugs have dramatically
      changed medical practice. Creatively, educational institutions have adopted the
      use of: (1) New educational and communication technologies: internet and health
      informatics; (2) Problem based learning approaches; Integrated Practice and
      Theory Curricula; Research and Problem Solving methodologies and (3) Partnership
      and networking of institutions to synergise new trends (e.g. core competencies).
      Less desirably, changes are inadequate in key areas, e.g., Health Economics,
      Poverty and Health Development, Disaster Management & Bioterrorism and Ethics.
      Institutions have begun to adjust and develop new programs of study to meet
      challenges of emerging diseases, design methodologies to better understand
      complex social and economic determinants of disease, assess the effects of
      violence and address cost containment strategies in health. Besides redesigning
      instruction, professional schools need to conduct research to assess the impact
      of health reform. Such studies will serve as sentinels for the public's health,
      and provide key indicators for improvements in training, service provision and
      policy.

PMID- 12597517
TI  - Multiprofessional and continuing education of health professionals.
AB  - The provision of appropriate education and training for health care workers is
      essential to ensure effective and efficient utilization of their services.
      Organising multiprofessional learning, providing opportunities for continuing
      education and utilising of new trends in medical education facilitates
      achievement of the desired outcome in health care. The delivery of health care is
      a team effort. Thus, it is beneficial that the members of the health care team
      are trained together. Such training would provide opportunity to recognise the
      capabilities and job functions of the fellow health care professionals by the
      trainees. Similarly, by organising continuing education programmes for health
      care workers already in service it would strengthen their confidence and also
      improve the quality of their services. For these purposes, new trends in medical
      education could be utilised.

PMID- 12597518
TI  - Future health: coping with change.
AB  - WHO's Declaration of the "Health for All" (HFA) goal was pronounced in 1978 in
      Alma Ata, and it was planned that HFA would be achieved through primary health
      care programmes and approaches by 2000. However, it is now 2002 and despite the
      technological advancements in medicine, science, and ICT, Health for All is far
      from reality. Instead, more and more conflicts are emerging with lethal
      consequences, such as, bioterrorism, biological agent abuse, global-terrorism,
      and environmental destruction is occurring at a greater scale that we have
      witnessed before. We may have the latest technology and knowledge today, but
      ironically, we are using them to inflict more suffering and pain in the world. In
      the Asia-Pacific, the past 30 years has seen dramatic advancement and lifestyle
      changes. We are now paying a high price for such progress in terms of risk
      factors to the health of the population, such as, ageing diseases, obesity,
      smoking, diabetes, hypertension, and related conditions. The social, political,
      economic and environmental factors appeared to have deterred and negated WHO's
      HFA goal to attain basic human rights and health care for all. The HFA will not
      be achieved in the future if we do not learn from history and start taking
      measures now.

PMID- 12597519
TI  - Asia-Pacific Academic Consortium for Public Health. The APACPH Kazue McLaren
      Leadership Achievement Award.

PMID- 12597520
TI  - Increased plasma plasminogen activator inhibitor-1 levels: a possible marker of
      hypertensive target organ damage.
AB  - High plasma plasminogen-activator inhibitor-1 (PAI-1) concentrations have been
      reported in coronary artery disease and stroke. We therefore, prospectively
      studied the association of PAI-1 with early target organ damage in patients with
      arterial hypertension has not been clearly established. We therefore investigated
      136 subjects, 64 males and 72 females, mean age 50.0 +/- 12.3 years, with newly
      diagnosed essential hypertension who were free of cardiovascular events and were
      not receiving any antihypertensive medication. Plasma PAI-1 levels were measured
      by an ELISA method (STAGO). The study population was divided into two groups,
      group A with PAI-1 levels below 40 ng/mL and group B with more than 40 ng/mL. The
      left ventricular mass was calculated according to the formula of Devereux and was
      normalized by the individual's body surface area (LVM/BSA). Carotid intima-media
      thickness (IMT) was determined by ultrasonography. Microalbuminuria was assessed
      by an immunoturbidimetric method (SERA-PAK). Group A consisted of 89 individuals
      with hypertension (65.4%), 41 males and 48 females and group B of 47 individuals
      with hypertension (34.6%), 21 males and 26 females. Individuals in group B
      exhibited significantly higher LVM/BSA than individuals in group A (155.9 +/-
      23.1 g/m2 vs. 129.7 +/- 32.2g/m2, respectively, p = 0.004) and increased IMT
      (0.97 +/- 0.20mm vs. 0.87 +/- 0.21 mm, respectively, p < 0.001). Microalbumin
      excretion rate was greater in group B than group A (70.9 +/- 84.4 mg/24 hrs vs.
      20.9 +/- 45.1 mg/24 hrs, respectively, p = 0.002). In conclusion, elevated PAI-1
      levels are associated with target organ damage in subjects with newly diagnosed
      arterial hypertension. Thus, it can be postulated that this fibrinolytic
      inhibitor may characterize hypertensives in the early stages of the
      atherothrombotic process.

PMID- 12597521
TI  - NOS II inhibition attenuates post-suspension hypotension in Sprague-Dawley rats.
AB  - The reduction in mean arterial pressure observed in astronauts may be related to
      the impairment of autonomic function and/or excessive production of endothelium
      derived relaxing factors. Here, we examined the role of a nitric oxide synthase
      II (NOS II) inhibitor AMT (2-amino-dihydro-6-methyl-4H-1,3-thiazine) against the
      post-suspension reduction in mean arterial pressure (MAP) in conscious male
      Sprague-Dawley rats. Direct MAP and heart rate were determined prior to tail
      suspension, daily during the 7-day suspension and every 2 hrs post-suspension.
      Prior to release from suspension and at 2 and 4 hrs post-suspension, AMT (0.1
      mg/kg), or saline, were administered intravenously. During the 7-day suspension,
      MAP was not altered, nor were there significant changes in heart rate. The
      reduction in MAP post-suspension in saline-treated rats was associated with
      significant increases in plasma nitric oxide and prostacyclin. 2-Amino-dihydro-6
      methyl4H-1,3-thiazine reduced plasma nitric oxide levels, but not those of
      prostacyclin, attenuated the observed post-suspension reduction in MAP and
      modified the baroreflex sensitivity for heart rate. Thus, the post suspension
      reduction in mean arterial pressure is due, in part, to overproduction of nitric
      oxide, via the NOS II pathway, and alteration in baroreflex activity.

PMID- 12597522
TI  - Biochemical endothelial markers and cardiovascular remodeling in refractory
      arterial hypertension.
AB  - BACKGROUND: Hypertension is the most important and well established risk factor
      for atherosclerosis. The vascular and cardiac remodeling present in refractory
      hypertensive patients are related to endothelial dysfunction, a key factor in
      early atherogenesis and cardiovascular disease. However the mechanistic
      relationship among biochemical endothelial function markers, cardiovascular
      remodeling, and refractory hypertension is unknown. METHODS: We evaluated the
      left ventricular mass and function, carotid thickness, and plasma nitrate/nitrite
      (NO2/NO3), cyclic 3'-5'-guanosine monophosphate (cGMP), and thromboxane B2 (TXB2)
      levels in refractory hypertensive (RH; n = 20) and healthy (CONTROL; n = 20)
      subjects 22-65 years old. Carotid thickness, left ventricular mass index (LVMI),
      and left ventricular fraction ejection (LVFE) were estimated by duplex scan
      ultrasound. Nitrates/nitrites were assayed using the Griess reaction, and plasma
      cGMP and thromboxane B2 were determined by enzymatic immunoassay (EIA). RESULTS:
      Left ventricular mass index was higher in the RH group (138 +/- 20 vs. 108 +/-17
      g/m2, p < 0.001) but there was no significant difference in the ejection fraction
      (67 +/- 5% vs. 69 +/- 4%). Pulse pressure (61 +/- 9 mmHg vs. 46 +/- 10 mmHg) and
      carotid thickness (1.59 +/- 0.22m vs. 1.04 +/- 0.14mm) were significantly higher
      (p < 0.001) in RH patients whereas NO2/NO3, cGMP, and thromboxane B2 plasma
      concentrations were similar in bot groups. CONCLUSION: There was no association
      between cardiovascular remodeling and the particular biochemical markers of
      endothelial function we assessed in refractory hypertensive patients.

PMID- 12597523
TI  - Increased renal angiotensin II AT1 receptor function in obese Zucker rat.
AB  - Angiotensin II (Ang II) via the activation of AT1 receptors and subsequent
      stimulation of the tubular sodium transporters increases sodium and water
      reabsorption in the proximal tubule. An enhanced tubular action of Ang II is
      implicated in obesity related hypertension; however, the mechanism of such a
      phenomenon is unknown. Present study was designed to determine the AT1 receptor
      numbers and function in the proximal tubule of obese and lean Zucker rats. Obese
      Zucker rats were hypertensive and hyperinsulinemic. The plasma renin activity was
      similar in the lean and obese rats. Angiotensin II stimulated the Na,H-exchanger
      (NHE) activity in the proximal tubule, but the stimulatory response was markedly
      greater in obese than in lean rats. Similarly, Ang II caused greater inhibition
      in cAMP accumulation in the proximal tubule of obese compared to lean rats. The
      (125I]sar-Ang II binding revealed a 100% increase in the AT1 receptor number in
      the brush border membrane (BBM) of obese compared to lean rats. The Western blot
      analysis revealed a 36-51% increase in the Gi(alpha)1 and Gi(alpha)3 in the BBM
      of obese compared to lean rats. We conclude that increases in the AT1 receptor
      number and abundance of the Gi(alpha) on BBM may be responsible for the enhanced
      signaling and subsequent greater stimulation of NHE by Ang II in proximal tubules
      of obese rats. The greater stimulation of NHE by Ang II may contribute to the
      increased tubular sodium reabsorption and to the hypertension in obese Zucker
      rats.

PMID- 12597524
TI  - Day/night food consumption in mice is strain and age-dependent.
AB  - Food consumption was measured during the day (lights on) and the night (lights
      off) and compared between one outbred and 9 inbred strains of mice (CBA/Kw, C3H,
      DBA2, KP, BALB/c, C57BL, B10.Amst, B10.BR, B10.BR Y-del) in age groups 30-60, 60
      90, 90-120, and more than 120 days. Outbred mice and animals from B10 sublines
      ate significantly more during nocturnal darkness. Day and night food consumption
      was similar in KP animals. In mice from the remaining strains there was an
      apparent age-related shift from nocturnal towards diurnal eating habits.

PMID- 12597525
TI  - Cytogenetic analysis of a Mediterranean Gobiid fish Gobius paganellus L., 1758
      from Turkey.
AB  - In this study, cytogenetic analysis of Gobius paganellus, a Mediterranean Gobiid
      fish from the southern coast of Turkey, was carried out by modified air-dried
      technique. Phytohemaglutinine pretreatment was performed before the conventional
      air-dried technique to increase the mitotic index. Chromosomes were obtained
      using gill tissue. As a result, it was determined that the diploid chromosome
      number of Gobius paganellus is 2n = 44 (NF = 45), comprising one large
      metacentric and 43 acrocentric chromosomes.

PMID- 12597526
TI  - Karyological notes on six beetle species from Armenia (Coleoptera: Tenebrionidae,
      Cerambycidae, Curculionidae).
AB  - Karyotypic details were studied in males of six beetle species from three
      families, viz. Tenebrionidae: Dailognatha pumila Bdy. (2n = 20, n(male) = 9 +
      Xy(p)), Pachyscelis musiva Menetr. (2n = 18, n(male) = 8 + Xy(p)), Pimelia capito
      Kryn. (2n = 18, n(male) = 8 + Xy(p)); Cerambycidae: Agapanthia walteri Reitt. (2n
      = 20, n(male) = 9+Xy(p)), Agapanthia korostelevi Danilevsky (2n = 20, n(male) = 9
      + Xy(p)); Curculionidae: Phyllobius caucasicus Stierl. (2n = 22, n(male) = 10 +
      Xy(p)). The chromosome number and sex determining system of all beetle species
      are described for the first time. Evolutionary trends in karyotypes of the
      studied beetle groups are briefly discussed.

PMID- 12597527
TI  - Cytogenetic markers for X chromosome in a karyotype of rainbow trout from Rutki
      strain (Poland).
AB  - Cytogenetic or molecular identification of sex chromosomes could help in breeding
      studies in producing monosex fish stocks, estimating success of androgenesis,
      gynogenesis, etc. Among fish species sex chromosomes are recognizable in only a
      few cases. Some populations of rainbow trout Oncorhynchus mykiss show
      morphologically differentiated sex chromosomes. A strain from Rutki, Poland,
      showed a heteromorphic pair of subtelocentric chromosome: presumably of the XY
      type in the male and XX in the female. Restriction endonuclease and DAPI banding
      resulted in a characteristic banding pattern enabling identification of the X
      chromosome.

PMID- 12597528
TI  - Chromosome numbers, C-banding patterns and sperm of some ladybird species from
      Central Europe (Coleoptera, Coccinellidae).
AB  - C-banded karyotypes were studied in the males of seven ladybird species from the
      subfamily Coccinellinae, viz. Adonia variegata (Goeze), Tythaspis sedecimpunctata
      (L.), Coccinella septempunctata (L.), Calvia decemguttata (L.), Calvia
      quatuordecimguttata (L.), Propylea quatuordecimpunctata (L.), Phyllobora
      vigintiduopunctata (L.). All the species, with the exception of Tythaspis
      sedecimpunctata (L.), possess 2n = 20, n(male) = 9 + Xy(p). Tythaspis
      sedecimpunctata (L.), however, has 2n = 24, n(male) = 11+Xy. The examined
      karyotypes show only a paracentromeric position of constitutive heterochromatin
      in all autosomes and the sex chromosome X, while the y heterochromosome is dot
      like and wholly euchromatic. Successive stages of spermiogenesis were analysed.

PMID- 12597529
TI  - Cytological and morphological differences between two species of the genus
      Tettigonia (Orthoptera, Tettigoniidae) from Korea.
AB  - Tettigonia ussuriana and T. dolichopoda maritima differ in the length of tegmina,
      details in venation, and in females in details of the subgenital plate. The two
      species of the genus Tettigonia have the same number and morphology of autosomes
      but a different morphology of the X chromosome: in T. ussuriana it is
      metacentric, whereas in T. dolichopoda maritima acrocentric. In both species,
      euchromatic zones and breaks of one or to chromatids during meiosis and mitosis
      in the X chromosome were observed. Additionally, B chromosomes were noted in most
      individuals of both species.

PMID- 12597530
TI  - Structure of ovaries and formation of egg envelopes in the stonefly, Leuctra
      autumnalis Aubert, 1948 (Plecoptera: Leuctridae). Ultrastructural studies.
AB  - The investigation of ovaries and the formation of egg envelopes of the stonefly
      Leuctra autumnalis was carried out with light and transmission electron
      microscopes. The ovary of the studied species is paired and consists of several
      dozen panoistic ovarioles opening individually to the oviduct. The process of egg
      capsule formation already begins in previtellogenesis. At this time the
      follicular cells secrete precursors of the vitelline envelope. Analysis of the
      presented data suggests that the oocyte itself also takes part in the formation
      of the vitelline envelope during late vitellogenesis. Simultaneously, the
      follicular cells produce precursors of further layers of the egg capsule, i.e.
      two-layered chorion and extrachorion, consisting of two gelatinous layers and a
      flocculent one. The completely developed capsule contains channels, probably
      micropylar ones.

PMID- 12597531
TI  - Studies on some zooplanktonic organisms in the waters of the southern slope of Mt
      Babia Gora (the Carpathians).
AB  - Some predominant zooplanktonic organisms were registered in several water bodies
      of Mt Babia Gora.

PMID- 12597532
TI  - Paramecium novaurelia in the Gorgany Mts (Eastern Carpathians) in Ukraine.
AB  - In the samples collected on the territory of the recently studied region of the
      Eastern Carpathians, i.e. in the Gorgany Mts, the presence of P. novaurelia was
      recorded in the samples collected from the bog situated on the Jablonica Pass at
      an altitude of 100 m. This is the first record of the presence of P. novaurelia
      in the Gorgany Mts.

PMID- 12597533
TI  - DNA polymorphism in various goose lines by RAPD-PCR.
AB  - RAPD markers often primers were used to assess the polymorphism among pooled DNA
      of eight goose lines. The number of bands amplified by each primer ranged from 1
      to 8, within a mean of 2.86. Some bands appeared specific for the line or genetic
      background. RAPD technique is an effective method for generating the polymorphic
      DNA marker in the goose. RAPD patterns from mixed DNA samples can reflect the
      genetic information of populations. The present study indicated that 10
      generations selected for egg production and body weight under various pressure,
      resulted in genetic variation among goose lines as detected by RAPD. Selection
      for meat traits caused greater genetic diversity than selection for egg
      production.

PMID- 12597534
TI  - Separation of megabased-sized DNA molecules of Aspergillus niger using pulsed
      field gel electrophoresis.
AB  - In this study, the chromosomal DNAs were extracted from Aspergillus niger Z10
      wild type strain and these DNAs were separated using the contour clamped
      homogeneous electric field gel electrophoresis (CHEF) system. This system is
      laboratory-made and is operated by a computer program. Total DNAs resolved into
      five distinct chromosomal bands. The size of the chromosomes was estimated as
      being between 3.3 Mb to 6.4 Mb.

PMID- 12597535
TI  - Gene polymorphisms of the renin-angiotensin-aldosterone system and essential
      arterial hypertension in childhood.
AB  - In order to investigate the contribution of candidate genes in the renin
      angiotensin-aldosterone system (RAAS) in pathogenesis of essential arterial
      hypertension (EAH), the I/D polymorphism of ACE gene, the M235T polymorphism of
      the angiotensinogen gene, and the angiotensin II type 1 receptor (AGT,R) A1166C
      gene polymorphism in a group of children with EAH were analyzed. Fifty-scven
      children, aged 8-19 years. with the diagnosis of EAH were included in the
      association study and were compared with 57 subjects with normal blood pressure
      (the control group). Arterial hypertension was defined as systolic/diastolic
      blood pressure measurements higher than 95 age-gender-height percentile of the
      adopted reference values. A trend was found towards an association between the
      M235T angiotensinogen gene polymorphism and EAH in childhood in a dominant model
      (odds ratio (OR) 2.1; 95% confidence interval (CI) 0.9-5.1; P = 0.077), whereas
      the authors failed to demonstrate an association between the ACE I/D gene
      polymorphism, or the A1166C AGT1R gene polymorphism and EAH in childhood.
      Additionally, evidence was found of interaction between the angiotensinogen-TT
      genotype and obesity on the risk of EAH in childhood (OR 19.3; 95% CI 1.1-77.3; P
      = 0.014). In conclusion, the M235T angiotensinogen gene polymorphism is
      considered alone as well as in interaction with obesity to be risk factors for
      EAH in childhood.

PMID- 12597536
TI  - Paramecium biaurelia--relation of strains.
AB  - Inter- and intra-strain crosses were made in Paramecium biaurelia of the P.
      aurelia species complex for studying the relation of strains within the species.
      Altogether ten strains originating from Scotland, Spain, Romania, Czech Republic,
      Ukraine, Italy, Germany, Russia, and Poland (two strains) were studied. A high
      percentage of surviving clones in both generations, F1 (obtained by conjugation)
      and F2 (obtained by autogamy), was observed in strain crosses, indicating a
      strong relation between the strains, and absence of genetic barriers between them
      in P. biaurelia.

PMID- 12597537
TI  - Expression of microinjected reporter gene lacZ during first cleavages of rabbit
      embryos.
AB  - The growing use of reporter genes in a model transgenic system has been a
      fundamental approach of biology, but the strategy of transgenic embryo selection
      prior to transfer to foster mothers may greately increase the efficiency of
      transgenic livestock production. This study was conducted to assess the
      possibility of beta-galactosidase (beta-gal)-labeled transgenic rabbit embryo
      production. Rabbit zygotes were obtained from superovulated females after mating.
      Zygotes were microinjected into male pronuclei with pCMV-lacZ or SV40-lacZ
      constructs; while some embryos were co-injected with the scaffold attachment
      sequences--SAR. Embryos from control non-injected and microinjected groups were
      cultured in vitro. After 24, 48, 72, or 96 h of culture the embryos were stained
      with X-gal for beta-galactosidase. Transgenic embryos produced by pronuclear
      injection showed a discrete pattern of beta-galactosidase expression. The
      percentage of transgenesis with pCMV-lacZalone was 1.5, but with SAR sequences it
      increased to 4.2. In the case of SV40-lacZ construct, the efficiency of
      transgenesis was 2.3% and 4.1%, respectively. The mosaicism was 66.7% for all
      embryos injected with both constructs with or without SAR. The highest numbers of
      100%-transgenic (non-mosaic) embryos were found in the group co-injected with
      SV40-lacZ and SAR. Transgenesis was seen as early as 24 h after injection, in
      four-cell embryos. Most of the microinjected embryos showed delayed development
      as compared with control. It was concluded that lacZ may serve as a reliable
      reporter for early transgenic embryo selection in order to produce transgenic
      animals.

PMID- 12597538
TI  - Adaptations to the air breathing in the posterior intestine of the catfish
      (Corydoras aeneus, Callichthyidae). A histological and ultrastructural study.
AB  - A light and transmission electron microscopic study of the intestine of catfish
      C. aeneus shows that the anterior part of the intestine is a site of digestion
      and absorption and its structure is typical of that of other teleostean fishes.
      However, in this species the thin-walled posterior intestine is adapted to air
      breathing. In this region mucosa is smooth and lined with respiratory epithelium
      with capillary network. Several types of cells are observed in the epithelium:
      flattened respiratory epithelial cells with short microvili, goblet cells, scarce
      epithelial cells with numerous longer microvilli, and two types of endocrine
      cells (EC). The solitary brush cells with several long and thick microvilli
      described here are the first observation of such cells in the gastrointestinal
      tract of fishes. Bodies of respiratory epithelial cells lie between capillaries.
      Their cytoplasm, apart from typical organelles contains dense and lamellar
      bodies, which are a site of accumulation of surfactant. In regions where
      capillaries are covered by thin cytoplasmic sheets of respiratory epithelial
      cells, a thin (0.24-3.00 microm) air-blood barrier is formed, thus enabling gas
      exchange. Epithelial cells with longer microvilli do not participate in the
      formation of the air-blood barrier and are probably responsible for absorbtion.
      EC of the closed type are dispersed within the epithelium. Their cytoplasm
      contains characteristic round or oval dense core vesicles 69 to 230 nm in
      diameter. The role of EC and brush cells in the regulation of processes related
      to absorbtion, and to respiration, is disscused.

PMID- 12597539
TI  - Effect of thyroxine on some digestive enzymes of the adult male toad, Bufo
      melanostictus.
AB  - Thyroxine is known to play an important role during the developmental process of
      amphibians. The present work is designed on the hypothesis that a functional
      relationship exists between the thyroid gland and digestive physiology in the
      adult toad. Three doses of thyroxine (25 microg/100 g; 50 microg/100 g; 100
      microg/100 microg body weight) were orally administered daily to the adult male
      toad, Bufo melanostictus and changes in -amylase, pepsin, trypsin, and esterase
      activities of the different zones of the digestive tract, pancreas and liver were
      observed. The observations were made on 7, 15, and 30 days of thyroxine
      treatment. The result shows that the dose of 25 microg increases the enzyme
      activities in the gastrointestinal tract, liver and pancreas of 7 days treatment.
      However, prolonged treatment with all the doses shows little effect on these
      enzymes. The pattern of changes in the enzymatic activities in the digestive
      tract of the adult male toads show more advanced compartmentalization than that
      of fishes. It is also found that site-specific enzyme production is not
      pronounced in this amphibious vertebrate. It is proposed that a positive
      functional relationship between thyroxine and digestive enzymes exists in the
      adult male toad.

PMID- 12597540
TI  - Active chloride cell density in some tissues of rainbow trout (Oncorhynchus
      mykiss Walbaum, 1792) larvae during the early development stage.
AB  - In this study, active chloride cell density in some tissues (gill arch
      epithelium, skin, and yolk-sac membrane) of rainbow trout (Oncorhynchus mykiss
      Walbaum, 1792) larvae during the early development stage was investigated using a
      vital fluorescence staining technique. It was found that the numbers of active
      chloride cells were very variable, depending on the tissue and age of the larvae.
      Active chloride cells were most abundant in the skin and yolk-sac membrane, but
      less so in the gill arch epithelium of newly hatched larvae. With larval age, the
      density of active chloride cells in the gill epithelium increased, while that in
      the skin and yolk-sac membrane decreased.

PMID- 12597542
TI  - Chromosome C-banding patterns in isolated population of the grasshopper Podisma
      pedesis (L.) (Orthoptera, Acrididae) from the Altai Mts.
AB  - The C-banding patterns in the embryo chromosomes of the grasshopper Podisma
      pedestris (L.) from the Altai Mts are reported. The additional second C
      heterochromatic arms in at least five pairs of autosomes and in the X-chromosome
      were revealed. The paracentromeric, interstitial, and telomeric C-bands were
      observed. The studied population of P. pedestris shows some differences in the
      distribution and amount of the heterochromatin in comparison with European
      populations.

PMID- 12597541
TI  - Phosphatidylserine externalization during bone marrow cell death after treatment
      of mice with WR-2721 and gamma-rays.
AB  - The cell surface exposure of phosphatidylserine (PS) and the plasma membrane
      impairment were assessed in the bone marrow of adult male Swiss mice exposed to a
      single 6 Gy dose of 60 Co gamma-rays, and treated intraperitoneally with the
      aminothiol WR-2721 (Amifostine, S-2-/3-aminopropylamino/ethyl phosphorothioic
      acid), at a dose of 400 mg/kg body weight, 30 min prior to gamma-irradiation. The
      bone marrow cells were stained with a combination of fluoresceinated annexin V
      (annexin V--FITC) and propidium iodide (PI) at 3 h, 7 h, and 24 h after treatment
      of mice with WR-2721 and 60Co gamma-irradiation. The number of early apoptotic
      cells (annexin V--FITC positive/PI negative), and late apoptotic and necrotic
      cells (annexin V--FITC positive/PI positive), was increased at 3 h after exposure
      of mice to 60Co gamma-rays and thereafter declined with the frequency of
      apoptotic and necrotic cells remaining lower in WR-2721 pre-treated mice. Using
      the annexin V--FITC flow cytometric assay, the radioprotective effect of WR-2721
      against induction of apoptosis and necrosis in normal cells of the haematopoietic
      system was shown.

PMID- 12597543
TI  - Novel parasite (nematode) transglutaminase--potential drug target.

PMID- 12597544
TI  - Role of rhizobial biosynthetic pathways of amino acids, nucleotide bases and
      vitamins in symbiosis.
AB  - Rhizobia require the availability of 20 amino acids for the establishment of
      effective symbiosis with legumes. Some of these amino acids are synthesized by
      rhizobium, whereas the remaining are supplied by the host plant. The supply from
      plant appears to be plant-type specific. Alfalfa provides arginine, cysteine,
      isoleucine, valine and tryptophan, and cowpea and soybean provide histidine. The
      production of ornithine and anthranilic acid, the intermediates in the
      biosynthetic pathways of arginine and tryptophan, respectively, seems to be
      essential for effective symbiosis of Sinorhizobium meliloti with alfalfa. The
      expression of ilvC gene of S. meliloti is required for induction of nodules on
      the roots of alfalfa plants. An undiminished metabolic flow through the rhizobial
      pathways for the synthesis of purines and pyrimidines and the synthesis of
      biotin, nicotinic acid, riboflavin and thiamine by rhizobium appear to be
      requirements for normal symbiosis. To the best of our knowledge, this is the
      first review article on the role of rhizobial biosynthetic pathways of amino
      acids, nucleotide bases and vitamins in rhizobium-legume symbiosis. The
      scientific developments of about 35 years in this field have been reviewed.

PMID- 12597545
TI  - Validation of traditional claim of Tulsi, Ocimum sanctum Linn. as a medicinal
      plant.
AB  - In several ancient systems of medicine including Ayurveda, Greek, Roman, Siddha
      and Unani, Ocimum sanctum has vast number of therapeutic applications such as in
      cardiopathy, haemopathy, leucoderma, asthma, bronchitis, catarrhal fever,
      otalgia, hepatopathy, vomiting, lumbago, hiccups, ophthalmia, gastropathy,
      genitourinary disorders, ringworm, verminosis and skin diseases etc. The present
      review incorporates the description of O. sanctum plant, its chemical
      constituents, and various pharmacological activities.

PMID- 12597546
TI  - Short-term androgen deprivation does not alter CaR and VDR mRNA expression in
      duodenal mucosa in male rats.
AB  - Androgen deprivation is associated with decline in intestinal calcium absorption.
      The effect of androgen on CaR and VDR intestinal mucosa has not yet been studied.
      Calcium homeostasis, a real bone mineral density (aBMD, dual energy X-ray
      absorptiometry) and expression of CaR and VDR mRNA in duodenal mucosa of
      orchidectomized (ORX) and sham operated (Sham) adult Sprague Dawley rats at 4
      week have been studied. There was no significant difference in serum calcium,
      alkaline phosphatase, calcidiol and calcitriol levels between both the groups.
      Serum testosterone (T) (ng/dl) and inorganic phosphorous (iP) (mg/dl) levels were
      significantly lower in ORX rats. As compared to sham rats, ORX rats had
      significant decline in in-vitro aBMD at proximal, middle and distal tibia,
      proximal, mid and distal femur and femoral neck (P < 0.05). Northern blot
      analysis revealed no significant alteration in the CaR and VDR mRNA expression in
      duodenal mucosa in ORX rats. CaR and VDR mRNA expression in duodenal mucosa is
      therefore, not affected by physiological concentrations of testosterone in rats.

PMID- 12597547
TI  - Effect of phosphocreatine on H+ extrusion, pHi and dimorphism in Candida
      albicans.
AB  - Candida albicans is an opportunistic pathogen. Its proliferation in human hosts
      is believed to be controlled by immunologic mechanisms. The plasma membrane of
      the fungus possesses an H(+)-ATPase (PM-ATPase) which actively extrudes protons
      to generate an electrochemical gradient which is used in co-transport of
      nutrients. This ATPase is associated with the growth, dimorphism and
      pathogenicity of the fungus. The physiological concentration of phosphocreatine
      (PCr) is 20-35 mM in skeletal muscles. H(+)-extrusion in Candida cells was
      strongly inhibited by PCr; 44% at 20 mM and 69% at 40 mM. H(+)-extrusion was
      stimulated 6.2-fold in the presence of 10 mM glucose. This glucose stimulated
      extrusion was inhibited significantly by PCr; 36% at 20 mM and 53% at 40 mM. The
      intracellular pH pattern of cells destined to differentiate was greatly altered
      in the presence of PCr. Evagination time for control cells was between 90-120
      min. PCr, delayed dimorphism, reduced the population of cells differentiating to
      hyphae and also reduced the length of hyphae after each time interval. Only 60%
      differentiation was observed with 10 mM PCr and 40% for higher PCr concentration
      even after 210 min. Direct interaction of PM-ATPase and PCr has been demonstrated
      by difference spectrum measurement employing stopped flow spectrophotometer. It
      can be concluded that PCr may be playing a significant role in checking growth
      and pathogenesis of C. albicans.

PMID- 12597548
TI  - Control of hyperglycemia and retardation of cataract by mulberry (Morus indica
      L.) leaves in streptozotocin diabetic rats.
AB  - Dried leaf powder of mulberry (M. indica L.) when given along with the diet at
      25% level to streptozotocin induced diabetic male Wistar albino rats for 8 weeks,
      controlled hyperglycemia, glycosuria, albuminuria and retarded onset of
      retinopathy. Untreated diabetic rats showed hyperglycemia, glycosuria,
      albuminuria and developed lenticular opacity after 8 weeks of experimental
      period.

PMID- 12597549
TI  - Growth behaviour and bioproduction of indole acetic acid by a Rhizobium sp.
      isolated from root nodules of a leguminous tree Dalbergia lanceolaria.
AB  - The Rhizobium sp. isolated from healthy and mature root nodules of a leguminous
      tree, Dalbergia lanceolaria Linn. f., preferred mannitol and KNO3 for growth as
      carbon and nitrogen sources, respectively. The bacterium produced a high amount
      (22.3 microg/ml) of indole acetic acid (IAA) from L-tryptophan supplemented basal
      medium. Growth and IAA production started simultaneously. IAA production was
      maximum at 20 hr when the bacteria reached the stationary phase of growth.
      Cultural requirements were optimized for maximum growth and IAA production. The
      IAA production by the Rhizobium sp. was increased by 270.8% over control when the
      medium was supplemented with mannitol (1%,w/v), SDS (1 microg/ml), L-asparagine
      (0.02%,w/v) and biotin (1 microg/ml) in addition to L-tryptophan (2.5 mg/ml). The
      possible role of IAA production in the symbiosis is discussed.

PMID- 12597550
TI  - Secretion of ligninperoxidase by Penicillium citrinum, Fusarium oxysporum and
      Aspergillus terreus.
AB  - Secretion of ligninperoxidase [E.C.1.11.1.7] by Penicillium citrinum, Fusarium
      oxysporum and Aspergillus terreus in liquid culture growth medium has been
      demonstrated. Enzymatic characteristics like Km, pH and temperature optima using
      veratryl alcohol as the organic substrate of ligninperoxidases from above sources
      have been determined. Km values using veratryl alcohol as substrate for enzymes
      from P. citrinum, F. oxysporum and A. terreus were 69, 64 and 60 microM
      respectively. Km values using H2O2 as the variable substrate were 64, 72 and 80
      microM. The pH optima were 4.0, 2.3 and 2.0 respectively. The values of
      temperature optima were 30 degrees, 25 degrees and 22 degrees C for the enzymes
      from P. citrinum, F. oxysporum and A. terreus respectively.

PMID- 12597551
TI  - Effect of low level exposure of lead and cadmium on hepatic estradiol metabolism
      in female rats.
AB  - Toxic effect of metal cations on female reproduction and gonadal functions was
      studied. Adult synchronized female rats were treated intraperitoneally with lead
      acetate and cadmium acetate separately and in combination (0.025, 0.05 and 0.1
      mg/kg body wt) for 15 days. The metabolizing enzymes (17beta-hydroxy steroid
      oxidoreductase and UDP glucoronyl transferase) activities decreased with
      increasing dose showing significant change compared to control. Also, significant
      decrease in cytochrome P450 (CYP450) content was found after the treatment.
      Displacement of zinc bound to metallothionein was more in cadmium treated rats
      compared to other groups. In all these parameters, treatment in combination of
      lead and cadmium showed intermediate results indicating some kind of competition
      between the two metals. But the histological studies showed that combined
      treatment caused more cytotoxic effect than cadmium and lead alone. These results
      indicated that metal cations tested did have a direct inhibitory effect on
      metabolizing enzyme activities.

PMID- 12597552
TI  - Screening of Indian plants for biological activity: Part XVI.
AB  - Alcoholic extracts of 288 of plant materials from 199 plant species have been
      tested for various biological activities including chemotherapeutic and
      pharmacological screening. Biological activities, ranging from moderate to good
      degree, have been observed in 61 plants extracts. Follow up studies have been
      carried out in these extracts and some of them have shown moderate degree of
      activities at this Institute. However, none of the extracts was found to be good
      enough for further development. Results of the present studies, along with
      chemical investigations on different species of similar genera which were
      screened earlier, are also discussed.

PMID- 12597553
TI  - Antimicrobial potentiality of a phenothiazine group of antipsychotic drug
      prochlorperazine.
AB  - The antipsychotic drug, prochlorperazine (Pcp), was tested for its antimicrobial
      efficacy against 103 strains belonging to both gram positive and gram negative
      bacteria. The drug was found to possess maximum activity against Staphylococcus
      aureus, Vibrio cholerae and Shigella spp. Pcp was moderately active against E.
      coli but most of the strains belonging to Bacillus spp, Klebsiella spp,
      Salmonella spp and Lactobacillus spp were found to be resistant to this drug. The
      drug was tested for its mode of antibacterial activity against Shigella
      dysenteriae 1 and it was found to be bacteriostatic in action. In in vivo
      studies, Pcp offered significant protection to Swiss albino mice at
      concentrations of 0.75 micro g/g (P < 0.01) and 1.5 microg/g (P < 0.001) body
      weight when challenged with 50 median lethal dose of Salmonella typhimurium NCTC
      74. Thus the result depicts that prochlorperazine may emerge as a strong
      antimicrobial drug to replace the conventional antibiotics and to overcome the
      problem of drug resistance.

PMID- 12597554
TI  - Synergistic effect of ayurvedic pearl preparation on enhancing effectiveness of
      antibiotics.
AB  - Studies were carried out with ayurvedic preparations derived from pearl, which
      include preparations bhasma and pishti. The synergistic effect to reduce the dose
      of antibiotic was tested against E. coli the test bacterium with ampicillin
      antibiotic by bore well and disks diffusion methods. It was observed that pearl
      preparations do not show any antibacterial activity but when used at 200
      microg/ml concentration with antibiotics, then even at sub-lethal dose, the
      antibiotic has effectively shown the results with reduced contact time. The
      protocol was also tested with the other bacteria like, Pseudomonas aeruginosa.
      Vibrio cholarae, Salmonella typhi, and Staphylococcus aureus and has shown
      similar results. The pearl bhasma synergistic effect was also tested with other
      antibiotics such as erythromycin, kanamycin, and ampicillin.

PMID- 12597555
TI  - SEM study on cytotoxic effect of monocrotophos (MCP) on lungs of rat.
AB  - Monocrotophos (MCP) on oral administration (0.28 mg/100 g of body wt. i.e. 1/5th
      of LD50) to female rats for 15 and 30 days damaged alveolar walls lined by type
      II cells (great alveolar cells); clara cells (non-ciliated cells) lining
      bronchiolar epithelium; and emphysematous lesions due to loss of inter-alveolar
      walls. This led to increase in surface tension in lung due to decrease in
      secretion of surfactant as a result of necrosis of great alveolar cells and clara
      cells resulting in hypoxia. This effect was time dependent. In R group (15 days
      without pesticide after 30 days daily oral treatment), the toxic effects
      mentioned above still persisted which revealed non-repair of necrosis caused by
      MCP.

PMID- 12597556
TI  - Use of RAPD in assessing the genetic variability in Spodoptera litura.
AB  - A polymerase chain reaction based assay to distinguish six different ecotypes of
      the Spodoptera litura, a sporadic insect pest and a predominant defoliator of
      various crops was carried out. A total of 40 random primers were screened to
      reveal the existence of polymorphism between the populations. Among them eight
      showed scorable banding patterns and three primers (OPA-01, OPA-05, OPM-01)
      exhibited distinguishable banding patterns. However, Chengalpattu and Chennai
      populations revealed their closed relatedness and Coimbatore population stood
      distantly from others.

PMID- 12597557
TI  - Entomopoxvirus of cotton bollworm, Helicoverpa armigera (Hbn.).
AB  - Occurrence of an Entomopoxvirus (EPV) from a lepidopteran insect viz;. cotton
      bollworm, H. armigera (HaEPV) along with gross pathological symptoms is reported
      for the first time in India. Histopathological study revealed that the fat body
      being the most favoured site of infection followed by haemocytes and gut
      epithelium. HaEPV was found to be not cross infective to six of the agricultural
      lepidopteran insect pests except for the potato black cutworm, Agrotis segetum
      registering 100% mortality showing typical symptom. Further, safety of HaEPV was
      shown against beneficial insect like mulberry silkworm, Bombyx mori and an useful
      insect general predator, Chrysoperla carnea.

PMID- 12597558
TI  - Mass production of polyhedral occlusion bodies of NPV of Helicoverpa armigera in
      relation to dose, age and larval weight.
AB  - A significant difference was noticed in the yield of polyhedral occlusion bodies
      (POBs) in various larval instars of H. armigera when three different doses of the
      nuclear polyhedrosis virus (NPV) were administered. The yield of POBs from a
      single larva ranged from 0.35 x 10(6) to 25033.33 x 10(6) with a mean of 18422.33
      x 10(6) for fourth instar inoculated. Positive correlation existed between larval
      weight and number of POBs recovered. The regression analysis indicated POBs
      recovered responded with predictable manner to the weight of different larval
      instars and the various concentration of virus administered. The medium lethal
      time increased in the instars of the larva advanced with a minimum of 3.5 and
      maximum of 8 days in the first and fifth instars respectively.

PMID- 12597559
TI  - In vitro regeneration of Acacia catechu Willd. from callus and mature nodal
      explants--an improved method.
AB  - Callus was derived from cultured cotyledons on MS medium supplemented with 2,4-D
      (0.25 mg/l) and NAA (0.25 mg/l). Plantlets were regenerated from the callus and
      nodal explants on MS medium containing BAP (2.0 mg/l) and Kn (2.0 mg/l), and
      further multiplied on the same medium. Addition of adenine sulphate (25.0 mg/l),
      ascorbic acid (20.0 mg/l) and glutamine (150.0 mg/l) in the medium resulted in
      enhanced axillary branching. Multiple shoots formed after 6 weeks were separated
      and subcultured in the fresh medium of same composition. For rhizogenesis,
      microshoots of 2.0-2.5 cm length were dipped in sterilized IAA solution (10 mg/l)
      for 24 hr followed by transfer to half strength MS medium containing activated
      charcoal (0.02%) resulting in rooting (75%) within 8 weeks. The rooted plants
      were transferred to pots containing sterilized soil and sand mixture for
      hardening and 71% survival was recorded. Fifty true to type plantlets of A.
      catechu could be obtained within seven months of culture establishment.

PMID- 12597560
TI  - Cyanobacterial N2 fixation in presence of nitrogen fertilizers.
AB  - Anabaena oryzae ARM 570 was examined for its growth (chlorophyll and protein),
      heterocyst frequency, nitrogenase (acetylene reduction) activity, ammonia
      excretion, and glutamine synthetase and nitrate reductase in response to two
      levels of urea-N vis-a-vis N2-N. Growth of cyanobacterium increased with duration
      of incubation. Reduction in heterocyst frequency (40%) was observed at 30 ppm of
      urea-N, whereas at 60 ppm of urea-N, filaments were completely devoid of
      heterocysts and no nitrogenase activity was observed. Maximum excretion of
      ammonia occurred at 30 ppm of urea-N, which was concomitant with minimum
      glutamine synthetase activity. These results suggested that A. oryzae could be
      effectively utilized in cyanobacterial biofertilizer programme even in the
      presence of combined nitrogen, for improving N-budget in rice cultivation.

PMID- 12597561
TI  - Effect of lead on Na+, K(+)-ATPase activity in Penaeus indicus postlarvae.
AB  - In vivo effect of lead on Na, K(+)-ATPase was studied in plasma
      membrane/mitochondrial fraction of P. indicus post-larvae (PL), exposed to 30
      days to a sublethal concentration (1.44 ppm) of lead. A significant (P < 0.05)
      decrease in the enzyme activity was observed for exposed PL with respect to their
      controls at different intervals except 24hr. Further the substrate (ATP) and ion
      (Na+ and K+)-dependent kinetics of Na+, K(+)-ATPase was studied with the plasma
      membrane/mitochondrial fractions of control and 30 days exposed PL. The apparent
      KM and V(max). values were calculated to determine the nature of inhibition. Both
      the control and exposed PL showed almost the same apparent KM values in the
      presence of different substrate or ion concentrations indicating that lead
      interacts with the enzyme at a different binding site.

PMID- 12597562
TI  - Toxins and bioactive compounds from cyanobacteria and their implications on human
      health.
AB  - Many species of cyanobacteria (blue-green algae) produce secondary metabolites
      with potent biotoxic or cytotoxic properties. These metabolites differ from the
      intermediates and cofactor compounds that are essential for cell structural
      synthesis and energy transduction. The mass growth of cyanobacteria which develop
      in fresh, brackish and, marine waters commonly contain potent toxins.
      Cyanobacterial toxins or cyanotoxins are responsible for or implicated in animal
      poisoning, human gastroenteritis, dermal contact irritations and primary liver
      cancer in humans. These toxins (microcystins, nodularins, saxitoxins, anatoxin-a,
      anatoxin-a(s), cylindrospermopsin) are structurally diverse and their effects
      range from liver damage, including liver cancer to neurotoxicity. Several
      incidents of human illness and more recently, the death of 60 haemodialysis
      patients in Caruaru, Brazil, have been linked to the presence of microcystins in
      water. In response to the growing concern about the non-lethal acute and chronic
      effects of microcystins, World Health Organization has recently set a new
      provisional guideline value for microcystin-LR of 1.0 microg/L in drinking water.
      Cyanobacteria including microcystin-producing strains produce a large number of
      peptide compounds, e.g. micropeptins, cyanopeptolins, microviridin, circinamide,
      aeruginosin, with varying bioactivities and potential pharmacological
      application. This article discusses briefly cyanobacterial toxins and their
      implications on human health.

PMID- 12597563
TI  - Recovery of plasmatic cholinesterase activity in a neotropical fish Prochilodus
      lineatus (Pisces, Curimatidae) exposed to organophosphorous pesticides.
AB  - The objective was to determine the plasmatic enzyme cholinesterase recovery,
      after being inhibited by an organophosphorous in juveniles of Prochilodus
      lineatus. Fish were exposed 12 h to a sublethal concentration of 1 mg/l of
      monocrotophos, and immediately placing in clean water during 12, 24, 48 and 96 h
      to detoxification. After this period, blood was extracted and plasma were used
      for the quantification of cholinesterase. The results showed a enzymatic
      inhibition of 91.9%, 55.1%, 50.4% and 33.4% with 12, 24, 48 and 96 h of recovery,
      respectively. The enzymatic activity spreads to be normalized with the course of
      hours and the degree of inhibition obtained initially was very high and sustained
      in the first 48 h.

PMID- 12597564
TI  - Toxicity of Nerium oleander leaf extract in mice.
AB  - Non-lethal dose of 70% ethanol extract of the Nerium oleander dry leaves (1000
      mg/kg body weight) was subcutaneously injected into male and female mice once a
      week for 9 weeks (total 10 doses). One day after the last injection, final body
      weight gain (relative percentage to the initial body weight) had a tendency, in
      both males and females, towards depression suggesting a metabolic insult at other
      sites than those involved in myocardial function. Multiple exposure of the mice
      to the specified dose failed to express a significant influence on blood
      parameters (WBC, RBC, Hb, HCT, PLT) as well as myocardium. On the other hand, a
      lethal dose (4000 mg/kg body weight) was capable of inducing progressive changes
      in myocardial electrical activity ending up in cardiac arrest. The
      electrocardiogram abnormalities could be brought about by the expected Na+, K(+)
      ATPase inhibition by the cardiac glycosides (cardenolides) content of the lethal
      dose.

PMID- 12597565
TI  - Use of epilithic diatoms to evaluate water quality in the Karasu River of Turkey.
AB  - Epilithic diatom assemblages were used to evaluate water quality in the Karasu
      River basin (Turkey), which was polluted by industrial, agricultural and urban
      wastes. A total of 73 diatom taxa belonging to 22 genera were found from all
      seven sampling stations located in the River basin. The most pollution tolerant
      species Gomphonema parvulum, Nitzchia palea, Navicula cryptocephala were found in
      high densities at the polluted stations. Organic load (COD), biological oxygen
      demand in 5 days (BOD5) and concentrations of nutrients NO3(-)-N, NO2(-)-N,
      NH4(+)-N and PO4(3-)-P) were correlated negatively with dissolved oxygen. Except
      for generic index of diatoms (GI), all diatom indices were correlated
      significantly with COD, BOD5 dissolved oxygen and concentrations of nutrients.
      Saprobity index (SI), trophic diatom index (TDI) and the percentage pollution
      tolerant valves values suggested that the stations III, IV located in the River
      basin were eutrophicated and organically polluted.

PMID- 12597566
TI  - Evaluation of organochlorine insecticide residue levels in locally marketed
      vegetables of Jaipur City, Rajasthan, India.
AB  - Considerable quantities of organochlorine insecticides are still used worldwide
      and their persistent residues are widely distributed throughout the environment.
      Various researchers from different parts of India and abroad have highlighted the
      extent of pollution caused by these insecticides. In view of the above facts the
      present study was conducted during 1993-1996 to investigate the magnitude of
      contamination of organochlorine insecticides in vegetables which were brought for
      sale to the consumers in the local markets of Jaipur city, Rajasthan, India.
      Samples of vegetables (potato, tomato, cabbage, cauliflower, spinach and okra)
      were collected at beginning, middle and end of the seasons with respect to
      different vegetables and organochlorine levels were assessed using Gas Liquid
      Chromatograph (GLC) equipped with Electron Capture Detector (ECD). Most of the
      collected samples were found to be contaminated with residues of DDT and its
      metabolites (DDD, DDE) isomers of HCH (alpha,beta and gamma-HCH), heptachlor,
      heptachlor epoxide and aldrin. Some of the detected insecticides exceeded the
      limit of tolerance prescribed by WHO/FAO.

PMID- 12597567
TI  - Effect of manganese toxicity on pigment content, Hill activity and photosynthetic
      rate of Vigna radiata L. Wilczek seedlings.
AB  - Effect of different concentrations, viz. 10(-4) M, 5 x 10(-4) M, 10(-3) M and 5 x
      10(-3) M of manganese sulphate (MnSO4, 7H2O) on chlorophyll, carotenoid pigment
      content and photosynthesis of mungbean seedlings was examined Progressive
      increase in manganese sulphate concentration upto 5 x 10(-3) M brought about a
      progressive decrease in total chlorophyll and chl a content. Chl b content
      changed very little by excess manganese treatment. Total carotenoid pigment
      content decreased considerably in comparison to control with every concentration
      of manganese sulphate tried here. Hill activity of chloroplasts isolated from
      leaves of mungbean seedling and rate of photosynthesis in terms of CO2 uptake
      showed progressive reduction along with the increase in concentration of the
      manganese.

PMID- 12597568
TI  - Feed utilisation and growth in juveniles of Labeo rohita under the stress of
      endosulfan.
AB  - The objective of the present study is to evaluate the nutrition and growth of
      Labeo rohita under the sublethal stress of endosulfan. It has been observed that
      the feed utilisation and growth were inferior in the fish under the stress of the
      toxicant. It was more so in the test fish under the influence of higher sublethal
      concentration. The food conversion ratio was higher suggesting that the nutrients
      are wasted.

PMID- 12597569
TI  - Retarding fluoride accumulation in Amaranthes viridis through liming and
      implications of phosphorous treatment.
AB  - With an objective to retard fluoride being taken up by the plants from soil, a
      study was carried out on Amaranthes viridis. Four groups of treatment were
      carried out vis-a-vis fluoride alone, fluoride and calcium, fluoride and
      phosphorous and fluoride, calcium and phosphorous together at three different
      concentration levels vis-a-vis 1, 10 and 25 mg/kg soil of each. Sampling was
      carried out first on day 45 and at the end of reproductive phase on leaf and seed
      for accumulation of fluoride in the plants. It was observed that fluoride
      accumulation in plants could be averted through soil amendment by calcium
      treatment in the form of calcium carbonate thereby reducing the risk of human and
      livestock exposure to abnormal levels of fluoride through food chain other than
      protecting plants from getting affected. At the same time, fertilizing the soil
      contaminated with fluoride by superphosphate would aggravate fluoride
      accumulation and exacerbate fluorosis problem in human and livestock through food
      chain. Therefore it is recommended to use acid water-soluble orthophosphate or
      anhydrous dicalcium phosphate or soluble pyrophosphate fertilizers as an
      alternative.

PMID- 12597570
TI  - Bacteriological analysis of a pond water from Gobardanga, West Bengal.
AB  - The present communication deals with the bacteriological examination of a pond
      water, which is being used as one of the sources of drinking water, by multiple
      tube fermentation test to detect the coliform bacteria. The test was performed
      sequentially in three stages: presumptive, confirmed and completed coliform test.
      The results show that as the most probable number (MPN) index per 100 ml is 23,
      that pond water should be treated as nonpotable.

PMID- 12597571
TI  - Toxicological effects on some biochemical parameters of fresh water fish Channa
      punctatus (Bloch.) under the stress of nickel.
AB  - Toxicological effects of some biochemical parameters of freshwater fish Channa
      punctatus (Bloch), under the stress of Nickel (NiSO4. 6H2O), at various
      concentrations of 10, 20, 30 and 40 ppm for 30 days were observed. Gradual
      decrease in the levels of liver protein and liver ascorbic acid due to
      proteolysis and liver glucose breakdown respectively was observed.
      Contradictorily, high liver cholesterol level, may be due to hepatic
      disfunctioning and accumulation in brain. There was also gradual decrease in the
      brain protein level showing significant alterations but the brain ascorbic acid
      level showed no significant alterations. Decrease in the protein and ascorbic
      acid level and increase of cholesterol level thus indicates stressful condition
      of the fish.

PMID- 12597572
TI  - Concentration of organochlorines in Ganges River dolphins from Patna, Bihar.
AB  - Concentrations of DDT, HCH, aldrin and endosulfan were determined in river
      dolphins from the River Ganges, Patna. Among the organochlorines studied in the
      dolphins, DDT concentration was highest followed by HCH. This shows exposure of
      dolphins to these organochlorine pesticides. Presences of organochlorines to
      higher degree in tissues suggest that the river dolphins be at greater risk due
      to pesticidal contamination of the river system.

PMID- 12597573
TI  - Assessment of the pulp and paper mill effluent on growth, yield and nutrient
      quality of wheat (Triticum aestivum L.).
AB  - Assessment of agropotentiality of the effluent coming out from century pulp and
      paper mill, Ghanshyamdham, Lalkua (Uttaranchal) has been made on wheat (Triticum
      aestivum var. UP-2329) crop grown in two soils differing in texture with
      different effluent concentrations. Diluted effluent increased the chlorophyll
      content, plant height, shoot and root biomass, grain yield, protein, carbohydrate
      and lipid contents in wheat grains, while undiluted effluent caused inhibition in
      plant growth resulting in a sharp decline of yield. Pure soil provided better
      growth and yield results than those soil mixed with sand.

PMID- 12597574
TI  - Enzymological aspects of bioconversion of m-dinitrobenzene.
AB  - Three main enzymes, responsible for bioconversion of 1,3 dinitrobenzene (m-DNB)
      by Micrococcus colpogenes MCM B 410, were isolated from the sonicated cell mass,
      grown in presence of m-DNB in a synthetic medium, for 7 days. The soluble
      proteins were separated by differential precipitation and also separated by
      native PAGE. Each fraction obtained from both the protocols, was tested for nitro
      aryl reductase, aryl mono oxygenase and resorcinol 2,3 dioxygenase. The apparent
      molecular weight of the proteins were nitro aryl reductase (30 kDa), aryl mono
      oxygenase (110 kDa) and resorcinol 2,3 di oxygenase (65 kDa).

PMID- 12597575
TI  - Effect of phytohormone pretreatment on metabolic changes in Vigna radiata under
      salt stress.
AB  - Efficiency of pretreatment as foliar spray of indole-3-acetic acid, gibberellic
      acid and kinetin (6-furfuryl aminopurine) each ranging from 10(-7) to 10(-5) M in
      restoring the metabolic alterations imposed by NaCl salinity (E.C. value 4.0 m
      mhos/cm) was investigated in Vigna radiata (L.) Wilczek. Application of NaCl
      resulted in about 7% and 9% decrease in phenol content in mung bean leaf and root
      respectively. In leaf, NaCl caused 40% increase in polyphenol oxidase enzyme
      activity over the control set. This effect was accentuated in root, where
      salinity caused 200% increase in the enzyme activity. In leaf and root of mung
      bean plant, ascorbic acid content decreased about 29% and 31% respectively under
      salinity stress as compared with control. Ascorbic acid oxidase enzyme activity
      increased under stress by about 55% and 23% respectively in leaf and root. It was
      noted that all the three growth regulators used in the present study were able to
      overcome to variable extents the adverse effects of stress imposed by NaCl
      solution.

PMID- 12597576
TI  - Clinical confirmation of trichothecene mycotoxicosis in patient urine.
AB  - The investigations of four Cases involving mold-contaminated buildings and human
      reaction to exposure, documents tests of extracted urine containing trichothecene
      mycotoxins confirming exposure and the diagnosis of mycotoxicosis in humans. In
      each of four Cases, the urine demonstrated antibiotic activity, sulfuric acid
      charring, and protein release. Urine was extracted using ethyl acetate
      40V/60V[EA]. Extracted mycotoxin spotted on (TLC) displayed color and a range of
      (rf) between 0.2-0.6 using various solvents. Extract was re-suspended using 50%
      ethanol V/V to inject mycotoxins into weanling female Sprague-Dawley rats.
      Degeneration and necrosis of the rat's tissue followed. Koch's Postulates
      conditions were fulfilled by isolation of the causative agent, the trichothecene
      mycotoxins and the reproduction of disease. Examination of human tissue within
      the urine extraction group confirms Koch's Postulates and comparative pathology
      confirms inhalation Mycotoxicosis, with severe necrosis of the central nervous
      system and severe scarring within the lungs. Extraction of mycotoxins from human
      patient urine is a very useful confirmatory test to demonstrate exposure and
      identify mycotoxicosis. Low concentrations (6%) of sodium hypochlorite were
      ineffective against the activity of trichothecene mycotoxin. The severity or
      stages of disease directly correlates the level of exposure or poisoning (Patent
      Pending).

PMID- 12597577
TI  - Amelioration of mercurial toxicity by manganese. I. A case study in mung bean
      seedling.
AB  - Mercury, a non essential element renders inhibitory effect on many physiological
      activities of plants even at a low concentration. Plants absorb "Hg" from soil
      through root system. Manganese, an essential element has been found to counter
      the inhibitory effect of mercury mostly by preventing it's uptake from soil. Mung
      bean (Vigna radiata L. Wilczek) cv. Pusa Baisakhi grown in individual (1, 10, 100
      and 1000 ppm) solution of Hg and Mn showed varied uptake of these heavy metals.
      However, in combined solutions (1 : 1, 10 : 1 and 1 : 10 ppm Hg : Mn), mercury
      uptake was mostly prevented in presence of 10 ppm Mn, indicating it's
      ameliorating effect.

PMID- 12597578
TI  - Water quality index and suitability assessment of urban ground water of Hisar and
      Panipat in Haryana.
AB  - Ground water quality in two well-developed cities of Haryana, viz. Hisar and
      Panipat was assessed for drinking purpose based on water quality parameters like
      pH, EC, turbidity, TDS, alkalinity, total hardness, calcium (Ca), magnesium (Mg),
      sodium (Na), potassium (K), chloride (Cl), nitrate (NO3), phosphate (PO4),
      sulphate (SO4) and fluoride (F) with respect to different land-use areas viz.
      residential, industrial, commercial and agricultural. Water quality index based
      on 9 parameters showed that at Panipat, underground water in all the land-use
      zones was fit for consumption (WQI < 50), whereas at Hisar, water in agricultural
      areas was good in quality, but that in other areas varied in magnitude of
      pollution (WQI > 50 to 100).

PMID- 12597579
TI  - Cuscuta hyalina Roth., an insect development inhibitor against common house
      mosquito Culex quinquefasciatus Say.
AB  - A preliminary screening of crude acetone extract of Cuscuta hyalina Roth. was
      conducted against the laboratory reared preadult stages of common house mosquito
      Culex quinquefasciatus (Say) (Diptera: Culicidae). 24 h LC50 of third and fourth
      instar larvae and pupae were 303 ppm, 306.44 ppm and 97.66 ppm respectively. The
      extract completely restrained the adult mosquito emergence at sublethal doses (50
      ppm for third instar and 75 ppm for fourth instar), by disrupting the normal
      morphogenesis. The extract was found to be an effective oviposition deterrent at
      80 ppm. The plant was also found to be effective in suppressing the adult
      emergence when directly sprinkled as dry powder on the water surface.

PMID- 12597580
TI  - The 2001 CDC recommendations for using fluoride to prevent and control dental
      caries in the United States.

PMID- 12597581
TI  - Relative effects of pre- and posteruption water fluoride on caries experience of
      permanent first molars.
AB  - OBJECTIVES: Previous studies have attributed the caries-preventive effects of
      preeruption (PRE) and posteruption (POST) exposure to fluoridated water based on
      data collected before and after the commencement or discontinuation of water
      fluoridation. This study aims to determine the relative pre- and posteruption
      exposure effects of fluoridated water on caries experience of 6-15-year-old
      Australian children based on individual residential histories. METHODS: Parental
      questionnaires covering residential history of participants were linked to their
      oral examinations conducted between June 1991 and May 1992 by the School Dental
      Services of South Australia and Queensland. Percentage of lifetime exposed to
      optimally fluoridated water PRE and POST was calculated with respect to the
      eruption age for first permanent molars. Combined pre- and posteruption
      categories were created to test PRE against POST exposure: PRE & POST = 0, PRE <
      POST, PRE = POST in the range 0-90 percent of lifetime exposure, PRE > POST, and
      PRE & POST > or = 90 percent lifetime exposure. These categories were used as
      indicator variables with PRE and POST = 0 as reference in an analysis of first
      permanent molar DMFS scores. The linear regression model controlled for important
      potential confounders. RESULTS: Participation rates were 69.7 percent in South
      Australia and 55.6 percent in Queensland with 9,690 and 10,195 participants,
      respectively. Pre- and posteruption exposures were strongly correlated (r =. 74;
      P < .01). Compared to the reference, the categories PRE > POST, PRE = POSTin the
      range 0-90 percent, and PRE and POST > or = 90 percent showed significantly lower
      caries levels. CONCLUSIONS: The findings indicated that preeruption exposure was
      required for a caries-preventive effect and that exposure after eruption alone
      did not lower caries levels significantly. However, the maximum caries-preventive
      effects of fluoridated water were achieved by high pre- and posteruption
      exposure.

PMID- 12597582
TI  - Factors influencing the effect of race on established periodontitis prevalence.
AB  - OBJECTIVE: This paper identifies differences in prevalence of established
      periodontitis and evaluates factors that might explain the differences between
      non-Hispanic African Americans (n = 232) and whites (n = 199) in the Detroit
      tricounty area. METHODS: Subjects from a disproportionate probability sample of
      community-dwelling adults were interviewed regarding demographic, psychosocial
      and enabling factors, dental health-related behaviors, and other risk factors,
      and had comprehensive in-home dental examinations. RESULTS: The overall
      prevalence of established periodontitis was 20.8 percent; African Americans
      exhibited a significantly higher prevalence than whites (29.8% vs 17.7%). The
      crude association between race and prevalence of established periodontitis was
      significant (odds ratio [OR] for African Americans = 1.98; 95% confidence
      interval [CI] = 1.17,3.34). After controlling for other covariates, we found the
      effect of race may be modified by dental checkup visit frequency: African
      Americans with dental checkups at least once a year had almost a fourfold higher
      odds of established periodontitis (OR = 3.64; 95% CI = 1.43, 9.24) than their
      white counterparts with dental checkups at least once a year (the referent
      group); while African Americans with a dental checkups once every two years or
      less often were more than fourfold less likely to have established periodontitis
      (OR = 0.22; 95% CI = 0.08, 0.59) than their white counterparts in the referent
      group. CONCLUSIONS: This analysis supports the disparity in periodontal health as
      part of the black:white health disparity when taking other factors into account.
      However, periodontal health disparities may be more complex than previously
      recognized, requiring greater understanding of factors related to dental care
      utilization in future studies evaluating this disparity.

PMID- 12597583
TI  - A national survey of the oral health status of homeless veterans.
AB  - OBJECTIVES: This study reports results from a survey designed to (1) assess the
      oral health needs of a national sample of homeless veterans and (2) compare the
      dental needs of homeless veterans participating in VA-sponsored rehabilitation
      programs with domiciled veterans in VA substance addiction programs. METHODS:
      Homeless veterans enrolled in a nationwide rehabilitation program (n = 1,152)
      completed a survey including questions concerning patients' perceptions of their
      oral health, dental service needs and use, and alcohol and tobacco use. A sample
      of these veterans (n = 281) subsequently received dental exams. A comparison
      group of domiciled veterans enrolled in VA substance abuse programs (n = 339)
      completed a similar survey. A sample of these veterans (n = 150) also received
      dental exams. RESULTS: Sociodemographic variables, patient-reported oral health
      information and risk behaviors, and findings from dental exams described two
      remarkably similar populations. CONCLUSIONS: As expected, the homeless veterans
      exhibited poor oral health, but it was not different from domiciled veterans
      enrolled in substance addiction programs. Lifestyle choices, such as heavy
      drinking and smoking, may contribute more to poor oral health than living
      conditions.

PMID- 12597585
TI  - Early childhood caries-related visits to hospitals for ambulatory surgery in New
      York State.
AB  - OBJECTIVES: The objective of this study was to assess the utilization of
      ambulatory surgery at hospitals for the treatment of early childhood caries in
      New York State. METHODS: Data for this study came from the Statewide Planning and
      Research Cooperative System in New York State. We analyzed 16,149 oral health
      related ambulatory surgeries performed between 1996 and 1999 in children younger
      than 6 years of age. RESULTS: Between 1996 and 1999, the rate of hospitalization
      for dental caries in children younger than 6 years of age ranged from 180 to 193
      cases per 100,000. Approximately two-thirds of the visits by children younger
      than 6 years old were due to dental caries. The highest rate was observed in 3
      year-old children (346.5). The most frequent type of procedure performed was
      placement of stainless steel crowns. Medicaid was the primary source of
      reimbursement. CONCLUSIONS: These data illustrate that, although dental caries is
      preventable, it continues to be a significant problem in young children and
      results in a large number of ambulatory surgery visits.

PMID- 12597584
TI  - The association of early childhood caries and race/ethnicity among California
      preschool children.
AB  - OBJECTIVES: This paper explores the role of race/ethnicity in the occurrence of
      early childhood caries (ECC) among California Head Start (HS) and non-HS
      preschool children. METHODS: Using oral examination and questionnaire data from
      the 1993-94 California Oral Health Needs Assessment of Children, we computed the
      prevalence of ECC using various definitions and fitted logistic regression models
      to explore the effect of race/ethnicity on ECC, separately for HS and non-HS
      children, adjusting for bedtime feeding habits and other covariates. RESULTS:
      Among 2,520 children, the largest proportion with a history of falling asleep
      sipping milk/sweet substance was among Latinos/Hispanics (72% among HS and 65%
      among non-HS) and HS Asians (56%). HS Asians and Latinos/Hispanics had the
      largest prevalence of ECC (30%-33%) and untreated caries (49%-54%). The estimated
      risk for ECC was more than three times higher in HS Asians compared to HS whites
      and among non-HS African Americans and Asians compared to non-HS whites
      controlling for socioeconomic status variables. The risk of ECC was also
      significantly higher among children who fell asleep while sipping milk or any
      sweet substance compared to those who did not. CONCLUSION: Studies of the
      cultural/behavioral patterns that may be specific to ethnic subgroups with the
      highest risk for ECC seem essential to the development of effective prevention
      strategies.

PMID- 12597586
TI  - The relationship between amalgam restorations and mercury levels in male dentists
      and nondental health professionals.
AB  - OBJECTIVES: The objectives of this study were: (1) to compare the mercury levels
      in general dentists with the mercury levels in other health professionals using
      toenail clippings as a biomarker, (2) to identify risk factors associated with
      high mercury levels, and (3) to compare practice characteristics of dentists with
      high and low mercury levels. METHODS: A sample of 579 men was randomly selected
      from the 33,737 men participating in the Health Professionals Follow-up Study who
      had provided toenail samples in 1987. A questionnaire was sent to these male
      subjects in 1991 to obtain information on fish consumption, toothbrushing
      frequency, number of teeth, number of amalgam restorations, general practice or
      specialty status, number of amalgam restorations placed and removed per week,
      mercury storage and handling procedures, and mercury spillage incidents. A
      measure of long-term mercury exposure was obtained from toenail samples using
      neutron activation analysis for the 410 respondents (71% response rate). The 90th
      percentile mercury level in toenails (0.88 ppm) was selected as the threshold for
      elevated toenail mercury level. RESULTS: No relationship was found between the
      number of dental amalgams and toenail mercury levels among general dentists,
      dental specialists, and nondental health professionals. General dentists were
      found to have more than twice the level of mercury in toenails than nondental
      health professionals (mean level = 0.94 vs 0.45) and 60 percent higher than
      dental specialists (mean = 0.59). The combined use of disposable capsules and
      water storage of scrap amalgam appeared to reduce the risk of elevated mercury
      levels. Regardless of professional status, consumption of tuna and saltwater fish
      were the primary exposure factors that were positively associated with toenail
      mercury levels. CONCLUSIONS: As shown by the associations with dental profession
      and fish consumption, the mercury content of toenails is a stable biomarker of
      cumulative long-term mercury exposure. The lack of association between nail
      mercury levels and number of amalgam restorations suggests that avoidance of
      mercury amalgam restorative materials cannot be justified by the presence of
      mercury released from dental amalgams.

PMID- 12597587
TI  - Seropositivity of the rapid plasma reagin (RPR) test in a dental school patient
      population: a retrospective study.
AB  - OBJECTIVES: The purpose of this retrospective study was to determine the
      seropositivity of the rapid plasma reagin (RPR) in a dental school patient
      population. METHODS: Blood was drawn on 20,844 subjects registering for treatment
      at the Louisiana State University School of Dentistry. All subjects who are
      admitted to the dental school are submitted to RPR screening (Macro-Vue-RPR Card,
      Becton Dickinson), blood indices, and serum chemistries. Venereal Disease
      Research Laboratory (VDRL), microhemagglutination assay for Treponema pallidum
      (MHA-TP) and/or fluorescent treponemal absorption test for Treponema pallidum
      (FTA-ABS) were also run on the positive RPR results. RESULTS: Two hundred seventy
      nine (1.34%) of the 20,844 were RPR-positive. Sixty-two subjects (0.30%) of this
      total population from the RPR-positive findings were nonreactive (biological
      false positives or BFP) to the MHA-TP and FTA-ABS. This left 217 (1.04%) subjects
      of the 20,844 screened who were seropositive on both the RPR and the FTA-ABS or
      MHA-TP. CONCLUSIONS: Since this study has not been performed in a dental school
      patient population setting, comparison with other institutions is difficult. The
      authors agree that routine RPR testing is helpful and cost effective to detect
      patients possibly infected with Treponema pallidum in a large patient population.

PMID- 12597588
TI  - Separation and determination of ephedrine and pseudoephedrine by combination of
      flow injection with capillary electrophoresis.
AB  - A simple, rapid, and accurate method for the separation and determination of
      ephedrine and pseudoephedrine using direct UV absorbance detection has been
      developed by the combination of flow injection with capillary electrophoresis for
      the first time. The buffer solution used is a 40 mM borate solution with the pH
      adjusted to 9.5 using a 2 M NaOH solution. The linear calibration range is 50 to
      1000 microg/mL (r = 0.9996) for both analytes, and the recoveries are 91.2-108.2%
      for ephedrine and 92.6-107.3% for pseudoephedrine, respectively. The relative
      standard deviation of the peak area is 1.6% for ephedrine and 1.3% for
      pseudoephedrine (n = 6) at a concentration of 500 microg/mL, respectively. A
      series of samples is injected repeatedly without current interruption and
      subsequent rinsing, and the contents of these two alkaloids in three marketed
      drugs and the medical plant, Ephedra sinica, are determined with satisfactory
      results by this method.

PMID- 12597589
TI  - The role of analogue ions in the ion-pair reversed-phase chromatography of
      quaternary ammonium compounds.
AB  - The choice of analogue ion of the mobile phase additive is shown to significantly
      affect the analysis of quaternary ammonium compounds (QACs) in ion-pair reversed
      phase high-performance liquid chromatography. A series of bromide-containing and
      dodecyl-sulfate-containing mobile phase additives are investigated using two QAC
      probe analytes. In all instances, the quaternary-ammonium-containing mobile phase
      additives perform better than the corresponding sodium-containing additives for
      effective QAC elution. These results indicate that the structure of the analogue
      ion, not just its formal charge, is important in the reversed-phase ion-pair
      chromatography of these compounds. The relative elution order of the QAC probe
      analytes is also influenced by the counter ions of the mobile phase additives,
      with bromide and dodecyl sulfate offering opposite elution orders.

PMID- 12597590
TI  - Quantitative thin-layer chromatographic method of analysis of azithromycin in
      pure and capsule forms.
AB  - A validated stability-indicating thin-layer chromatographic (TLC) method of the
      analysis of azithromycin (AZT) in bulk and capsule forms is developed. Both AZT
      potential impurity and degradation products can be selectively and accurately
      estimated in both raw material and product onto one precoated silica-gel TLC
      plate 60F254. The development system used is n-hexane-ethyl acetate-diethylamine
      (75:25:10, v/v/v). The separated bands are detected as brown to brownish red
      spots after spraying with modified Dragendorff's solution. The Rf values of AZT,
      azaerythromycin A, and the three degradation products are 0.54, 0.35, 0.40, 0.20,
      and 0.12, respectively. The optical densities of the separated spots are found to
      be linear in proportion to the amount used. The stress testing of AZT shows that
      azaerythromycin A is the major impurity and degradation product, accompanied by
      three other unknown degradation products. The stability of AZT is studied under
      accelerated conditions in order to provide a rapid indication of differences that
      might result from a change in the manufacturing process or source of the sample.
      The forced degradation conditions include the effect of heat, moisture, light,
      acid-base hydrolysis, sonication, and oxidation. The compatibility of AZT with
      the excipients used is also studied in the presence and absence of moisture. The
      amounts of AZT and azaerythromycin A are calculated from the corresponding linear
      calibration curve; however, the amounts of any other generated or detected
      unknown impurities are calculated as if it were AZT. This method shows enough
      selectivity, sensitivity, accuracy, precision, linearity-range, and robustness to
      satisfy Federal Drug Administration/International Conference of Harmonization
      regulatory requirements. The method developed can also be used for the purity
      testing of AZT raw material and capsules, content uniformity testing, dissolution
      testing, and stability testing of AZT capsules. The potential impurity profiles
      of both active AZT material and capsule forms are found comparable. The linear
      range of AZT is between 5 and 30 mcg/spot with a limit of quantitation of 2
      mcg/spot. The intraassay relative standard deviation percentage is not more than
      0.54%, and the day-to-day variation is not more than 0.86%, calculated on the
      amounts of AZT RS recovered using different TLC plates.

PMID- 12597591
TI  - Development and validation of a high-performance liquid chromatography
      electrospray ionization-mass spectrometry assay for the determination of zaleplon
      in human plasma.
AB  - In this paper, a sensitive and rapid chromatographic procedure using a selective
      analytical detection method (electrospray ionization-mass spectrometry in
      selected-ion monitoring mode) in combination with a simple and efficient sample
      preparation step is first presented for the determination of zaleplon in human
      plasma. The separation of the analyte, internal standard, and possible endogenous
      compounds are accomplished on a phenomenex Luna 5-microm C8(2) column (250- x 4.6
      mm i.d.) with methanol-water (75:25, v/v) as the mobile phase. In order to
      optimize the mass detection of zaleplon, several parameters such as ionization
      mode, fragmentor voltage, m/z ratios of ions monitored, type of organic modifier,
      and eluent additive in the mobile phase are discussed. An internal standard is
      selected to guarantee the quantitative accuracy. Each analysis takes less than 6
      min. The calibration curve of zaleplon in the range of 0.1-60.0 ng/mL in plasma
      is linear with a correlation coefficient of > 0.9992, and the detection limit
      (s/n = 3) is 0.1 ng/mL. The within- and between-day variations (relative standard
      deviation) in the zaleplon plasma analysis are less than 2.4% (n = 15) and 4.7%
      (n = 15), respectively. The application of this method is demonstrated for the
      analysis of zeleplon plasma samples in a Phase-I human pharmacokinetic study.

PMID- 12597592
TI  - Separation of aliphatic and aromatic acids, aromatic sulfonates, quaternary
      ammonium compounds, and chelating agents on a reversed-phase column without ion
      pairing.
AB  - Cleaning products contain a wide variety of components. These include inorganic
      materials, weak acids, anionic surfactants, cationic surfactants, amphoteric
      compounds, and nonionic materials. The separation of these generally requires the
      use of multichromatographic modes. A system is developed that would give the
      maximum information for a cleaning product in a single chromatographic run. With
      the use of a hydrophobic, high-carbon-loading, and a relatively hydrophobic
      surface reversed-phase packing, such compounds as aromatic sulfonates, quaternary
      ammonium compounds, weak acids, nitrilotriacetic acid, ethylenediaminetetraacetic
      acid, and nonionic materials may be separated in a single run. The mode of
      separation is considered to be a combination of reversed-phase, ion-suppression
      reversed-phase, and adsorption chromatography. The separation is made on a YMC
      Packl ODS-AQl column (4.6 x 250 mm, 120 angstroms). The separation employs a
      gradient run starting with 0.01 N H2SO4 for 10 min followed by a gradient for 15
      min to 100% acetonitrile and continuing for an additional 5 min with 100%
      acetonitrile. The flow rate is 1 mL/min, and the separation is monitored at 210
      nm.

PMID- 12597593
TI  - Stereodifferentiation of chiral compounds using reversed-phase liquid
      chromatography coupled with capillary gas chromatography.
AB  - A method is described for the enantiomeric quantitation of some chiral compounds
      via online coupling of reversed-phase liquid chromatography-gas chromatography.
      The evaluation of some variables affecting the experimentation (i.e., the packing
      material used in the interface, volume of the transferred fraction, desorption
      time, initial temperature of the interface, and purge time) makes it possible to
      optimize the recoveries obtained for some chiral terpenes and lactones using a
      capillary column of beta-cyclodextrin dissolved in OV-1701. The proposed method
      allows the enantiomeric analysis of aqueous matrices obtaining relative standard
      deviations lower than 9% and detection limits ranging from 0.26-0.93 ppm for the
      investigated compounds.

PMID- 12597594
TI  - Determination of limonene oxidation products using SPME and GC-MS.
AB  - Limonene is a common component found in consumer goods ranging from beverages to
      cleaning compounds. Limonene oxidation products, however, have a less desirable
      flavor and fragrance. Early detection of limonene oxide formation would aid
      quality control. A method is developed to determine the concentration of limonene
      oxide in essential oils and beverages using solid-phase microextraction (SPME). A
      headspace sampling technique is used to reduce or eliminate the presence of less
      volatile components. Several different SPME fibers are tested, varying in polymer
      thickness, polymer cross-linking and bonding, and polarity of the polymer. For
      each fiber tested, the sampling time is optimized for reproducible results. The 7
      microm-thick bonded poly(dimethylsiloxane) fiber provides the best results.
      External standards are used for quantitation.

PMID- 12597595
TI  - Study on the determination of polyphenols in tobacco by HPLC coupled with ESI-MS
      after solid-phase extraction.
AB  - A high-performance liquid chromatography method coupled with electrospray
      ionization-mass spectrometry for the determination of polyphenols in tobacco is
      studied. The polyphenols are extracted from a tobacco sample by being refluxed in
      a boiling water bath with 80% methanol and purified by solid-phase extraction
      with a C18 cartridge. The chlorogenic acid, rutin, scopoletin, caffeic acid,
      scopolin, and other polyphenols are satisfactorily separated on a Nova-Pak C18
      chromatographic column (3.9 x 150 mm) with methanol and 0.05 mol/L potassium
      dihydrogen phosphate buffer solution gradient elution as mobile phase at a flow
      rate of 0.5 mL/min. Each of the polyphenols is monitored by photodiode array
      detector at its maximum wavelength: chlorogenic acid, 326.1 nm; rutin, 354.8 nm;
      scopoletin, 344.0 nm; caffeic acid, 323.7 nm; and scopolin, 365.2 nm. The limits
      of detection are: 100 ng/mL for chlorogenic acid, 125 ng/mL for rutin, 60 ng/mL
      for scopoletin, 50 ng/mL for caffeic acid, and 100 ng/mL for scopolin. The key
      polyphenols in tobacco are identified by comparing the retention time, the UV
      spectrum, and the mass spectra with those of the standards. The recovery of
      tobacco polyphenols is 94-105%, and the relative standard deviations are 1.28
      1.49%. This method is successfully applied to qualitatively and quantitatively
      analyze the polyphenols in tobacco with good results.

PMID- 12597596
TI  - Analysis of fatty oil in Semen Ziziphi Spinosae by capillary gas chromatography.
AB  - A simple and fast capillary gas chromatographic (CGC) method with flame
      ionization detection is developed for the analysis of fatty oil in Semen Ziziphi
      Spinosae. After methyl-esterification, eight components are identified by gas
      chromatography-mass spectrometry. The derivatization condition is investigated in
      order to validate this method. Palmitic acid and stearic acid are quantitated
      simultaneously. The limits of detection are 5.024 microg/mL for palmitic acid and
      6.957 microg/mL for stearic acid, respectively. The limits of quantitation are
      16.76 microg/mL for palmitic acid and 23.19 microg/mL for stearic acid,
      respectively. The percent recoveries of palmitic and stearic acid are 97.4% and
      96.6%. CGC is shown to be a quick and informative tool for the analysis of fatty
      oil in Semen Ziziphi Spinosae.

PMID- 12597598
TI  - What is the reason for the difference between the retention indices generated in
      my laboratory and the ones published in the literature?

PMID- 12597599
TI  - How does one do good troubleshooting and do it quickly?

PMID- 12597597
TI  - Automated solid-phase extraction method for the determination of piperaquine in
      plasma by peak compression liquid chromatography.
AB  - A validated bioanalytical method for the determination of piperaquine (PQ) in
      plasma by solid-phase extraction (SPE) and liquid chromatography (LC) using peak
      compression is presented. Protein is precipitated from plasma with acetonitrile
      1% aqueous acetic acid (85:15, v/v). An internal standard (IS) is added to the
      samples before they are loaded onto a strong cation exchanger (Isolute PRS) SPE
      column. PQ and the IS are analyzed by LC on a Zorbax SB-CN column (250 x 4.0 mm)
      with the mobile phase acetonitrile-phosphate buffer [I = 0.1, pH 2.5 (12:88,
      v/v)] and UV detection at 345 nm. Trichloroacetic acid (TCA) is added to the
      samples prior to injection into the chromatography system. PQ elutes in a
      gradient of TCA, which enables peak compression of PQ and significantly higher
      peak efficiency as a result. The intraassay precision for plasma is determined to
      be 5.4% at 3.00 microM and 5.8% at 0.050 microM. The interassay precision for
      plasma is 1.3% at 3.00 microM and 10.0% at 0.050 microM. The lower limit of
      quantitation and the limit of detection are 0.025 and 0.005 microM, respectively.

PMID- 12597600
TI  - Immunization status among children newly enrolled in a health plan: a new
      frontier for quality measurement?
AB  - BACKGROUND: The National Scientific Panel on Immunization Measurement Standards
      recently recommended that the assessment population for the childhood
      immunization measure of the Health Plan Employer Data and Information Set include
      24-month-olds with > or = 6 months of continuous enrollment in a health plan. The
      current inclusion criterion is > or = 12 months of continuous enrollment. The new
      recommendation would expand the assessment population to include children with
      more recent enrollment. OBJECTIVES: To compare the immunization status of
      children enrolled in a large health plan between ages 12 and 17 months vs earlier
      in life and to describe the proportion of children enrolled between ages 12 and
      17 months that could be fully immunized by 24 months. METHODS: All children
      enrolled in a group-model HMO who turned 24 months old during a 12-month study
      were identified for a retrospective cohort study. A computerized immunization
      database was used to identify all vaccines administered to each child, and
      summary measures were created to describe immunization status at selected times.
      The full-text medical records of children who seemed to have no immunizations in
      the computerized database were reviewed. RESULTS: Of the 3448 children in the
      study population, 3130 (91%) enrolled between birth and 11 months of age and 161
      (5%) enrolled between 12 and 17 months of age. Whereas 87% of children who
      enrolled between birth and 11 months of age were fully immunized at age 24
      months, only 57% of those enrolled between 12 and 17 months of age were fully
      immunized at 24 months of age (risk difference, 30%; 95% confidence interval, 24%
      36%; P < .001). Of the 161 children enrolled between 12 and 17 months of age, 68%
      had received all of the immunizations in the primary series. Only 6% of these 161
      children would have been impossible or difficult to fully immunize by age 24
      months using accelerated catch-up vaccination schedules. CONCLUSIONS: Children
      who enrolled in an HMO between 12 and 17 months of age were less likely than
      those who enrolled earlier in life to be fully immunized by age 24 months, but it
      would be feasible to bring almost all of them up to date by that age. Including
      such children in immunization measures, either together with earlier-enrolled
      children or as a separate stratum, would expand the scope of the quality of care
      under evaluation.

PMID- 12597601
TI  - When depression is the diagnosis, what happens to patients and are they
      satisfied?
AB  - OBJECTIVES: To understand the process, outcomes, and patient satisfaction of
      usual primary care for patients given a diagnostic code for depression. STUDY
      DESIGN: Health plan data were used to identify patients with a diagnostic code
      for depression (and no such diagnosis in the preceding 6 months). Patients were
      surveyed by mail soon after the coded visit and again 3 months later about the
      care they had received; their charts were also audited. METHODS: The 274 patients
      in 9 primary care clinics who responded to both surveys reported on their
      personal characteristics, depression symptoms and history, the care received in
      that initial visit, and the follow-up care during the next 3 months. They also
      reported on their satisfaction with various aspects of that care. RESULTS: These
      patients were likely to be given antidepressant medications as their main or only
      treatment. Referral for mental health therapies was not used often, even though
      referral is readily available in this setting; other types of self-management
      recommendations and support were even less frequent. Patient outcomes and levels
      of satisfaction during a 3-month follow-up period were unimpressive. CONCLUSIONS:
      To successfully maintain a key role in the care of this important problem for
      their patients, primary care physicians may need to incorporate a more
      comprehensive and systematic approach to management that involves other team
      members and is more satisfying to patients.

PMID- 12597602
TI  - Healthcare use by veterans treated for diabetes mellitus in the Veterans Affairs
      medical care system.
AB  - OBJECTIVES: To estimate the burden of comorbid conditions and to describe
      patterns of inpatient and outpatient service use by veterans with diabetes
      mellitus. STUDY DESIGN: Retrospective cohort study of 33,481 veterans conducted
      by means of secondary analysis of Department of Veterans Affairs (VA) healthcare
      utilization databases. PATIENTS AND METHODS: The cohort was constructed by
      enrolling all veterans treated in the VA medical care system who had their
      initial VA hospitalization for diabetes mellitus between 1992 and 1997. To
      estimate the typical annual pattern of service use for diabetes mellitus, 1997
      utilization rates per person-year were analyzed based on cohort members surviving
      into 1997. Data on comorbid conditions were obtained from outpatient and
      inpatient contacts. RESULTS: The 3 most prevalent coexisting conditions were
      hypertension (73.4%), ischemic heart disease (35.2%), and alcohol or drug abuse
      disorders (29.5%). In 1997, the typical cohort member followed for 12 months had
      6 primary care visits, 16 other visits for tests or consultations, and 1.3
      unscheduled visits for emergency or urgent care and spent approximately 8 days in
      the hospital. One-year survival was 94.0%. CONCLUSIONS: In the VA medical care
      system, beneficiaries with diabetes mellitus have an extremely heavy burden of
      comorbidities, face a significant risk of dying in a given year (approximately 6%
      in this population), and are heavy users of hospital and outpatient services.

PMID- 12597603
TI  - Medication noncompliance in patients with chronic disease: issues in dialysis and
      renal transplantation.
AB  - For many chronic conditions, poor patient compliance with prescribed medications
      and other aspects of medical treatment can adversely affect the treatment
      outcome. Compliance with long-term treatment for chronic asymptomatic conditions
      such as hypertension is on the order of 50%. Although drugs with a longer
      therapeutic half-life may ease the burden of repeated daily dosing, the efficacy
      of any self-administered medication depends to a large extent on patient
      compliance. This article addresses the compliance issues in patients undergoing
      renal replacement therapy and in those with a successful renal transplant. A
      focused discussion of compliance in dialysis and renal transplant patients is
      followed by a general review of the literature on patient compliance. Many
      factors associated with poor compliance in this patient population are identified
      via a review of the recent literature. The difficulties in monitoring medication
      compliance and the methods used are discussed. Among factors associated with poor
      compliance, the following have been identified in several studies: frequent
      dosing, patient's perception of treatment benefits, poor patient-physician
      communication, lack of motivation, poor socioeconomic background, lack of family
      and social support, and younger age. Many strategies have been suggested to
      improve medication compliance, most without scientific validation. Strategies to
      improve compliance in dialysis and transplant patients are similar to those
      described for other chronic conditions and include simplifying the treatment
      regimen, establishing a partnership with the patient, and increasing awareness
      through education and feedback.

PMID- 12597604
TI  - Restoring trust to managed care, Part 1: A focus on patients.
AB  - Managed care organizations face distrust from patients, many of whom believe the
      organizations disregard their interests. To succeed in a market-driven healthcare
      system, managed care plans must work to restore that trust. A variety of
      strategies are presented to restore patient trust. The next 2 articles of this 3
      part series will examine trust-building strategies targeted at physicians and
      public stakeholders.

PMID- 12597605
TI  - STD prevention and treatment guidelines: a review from a managed care
      perspective.
AB  - OBJECTIVE: To conduct a standardized review of sexually transmitted disease (STD)
      clinical practice guidelines from a managed care perspective. STUDY DESIGN: Eight
      guidelines that address STD prevention and care received dual review on selected
      content and formatting criteria. Content criteria included currency of
      information, coverage of 7 selected STDs, attention to primary prevention areas
      (risk assessment, patient education, counseling), attention to
      system/implementation issues (time/costs/training) of integrating STD practices
      into routine clinical care, and referencing of scientific literature.
      Format/presentation criteria included ease of accessing STD information, clear
      identification of STD recommendations, availability of handbook/pocket versions,
      and availability of online version. Chlamydia screening and treatment
      recommendations were compared for 3 guidelines. RESULTS: The 8 guidelines
      addressed a variety of target populations. Two focused exclusively on STDs. Three
      were current at the time of the review (1998 or later), 2 covered all selected
      STDs, 3 gave considerable emphasis to primary prevention, and 4 cited relevant
      scientific sources. One guideline was classed as having good coverage of
      system/implementation issues. Information for specific STDs was readily located
      and concisely presented in 2 of the guidelines. Four sources had handbook/pocket
      versions, and 5 had on-line versions. Based on these findings, we suggest
      modifications for future versions of these guidelines that may increase their
      usefulness to managed care settings. CONCLUSIONS: Currently available STD
      guidelines potentially can be of great use to managed care providers and
      decisionmakers. The relevance to managed care organizations of a number of
      guidelines could be increased in several areas, particularly by greater focus on
      primary prevention and by providing access to tools and strategies to foster
      integration of STD services into routine clinical care.

PMID- 12597606
TI  - The pathogenesis of atherosclerosis and new opportunities for treatment and
      prevention.
AB  - Atherosclerosis is the most common disease in the industrialised world and by
      2020 is predicted to be the number 1 cause of death worldwide. It is a disease of
      the intima and media of small to medium sized arteries that develop slowly over
      many years. A number of risk factors for atherosclerosis have been identified,
      some of these are reversible and some are not. Most prominent amongst these is an
      elevated level of plasma cholesterol. The lowering of cholesterol reduces the
      risk of heart attacks, strokes and all forms of atherosclerotic vascular disease.
      Nonetheless, 70% of patients go on to get symptomatic disease. The disease
      process sets off an inflammatory response involving the vascular endothelium and
      both T and B cells of the immune system. Adhesion molecules are induced and
      proinflammatory cytokines and growth factors are produced by cells that
      orchestrate the atherosclerotic process. Narrowing the lumen of the artery leads
      to ischaemic symptoms. Within lesions under the influence of proteolytic enzymes
      released from activated macrophages (or foam cells--the hallmark of
      atherosclerosis) the centre of the plaque becomes liquefied to take on it's
      characteristic "gruel" like appearance. The shoulders of such plaque weaken and
      it becomes prone to rupture. Plaque rupture may lead to catastrophic thrombosis
      of coronary or cerebral arteries. The large amounts of tissue factor produced by
      macrophages make this a particularly likely event. On ulcerated plaques adherent
      platelets and thrombus create showers of emboli leading to ischaemic attacks.
      Like the effective treatment of LDL and it's role in the prevention of ischaemic
      attacks there has been a move to develop new drugs that raise HDL. The discovery
      of the role of a new class of ABC transporter, defective in Tangiers disease,
      responsible for cholesterol efflux from peripheral cells including the macrophage
      has created great excitement around ABC1 as a drug target. New areas, new
      possible targets and new genetic and genomic approaches will be discussed.

PMID- 12597607
TI  - Stroke: imaging and differential diagnosis.
AB  - Structural and vascular imaging helps to differentiate haemorrhagic from acute
      ischemic stroke (AIS) and rule out non-stroke causes, as well as identify
      specific subtypes of stroke such as carotid dissection and venous thrombosis.
      However, it is negative in most AIS patients within 3-6 hrs of onset and thus
      does not allow efficient patient classification for management purposes.
      Physiologic neuroimaging with PET, SPECT and combined diffusion- and perfusion
      weighted MR gives access to tissue perfusion and cell function/homeostasis. It
      has near 100% sensitivity in AIS, even in small cortical or brainstem strokes. In
      middle-cerebral artery (MCA) stroke, physiologic imaging also allows
      pathophysiological differentiation into four tissue subtypes: i) already
      irreversibly damaged ("core"); ii) severely hypoperfused ("penumbra"), which
      represents the main target for therapy; iii) mildly hypoperfused ("oligaemia"),
      not at risk of infarction unless secondary complications arise; and iv)
      reperfused/hyperperfused. PET studies have evidenced the penumbra in man, shown
      its largely cortical topography, documented its anticipated impact on both acute
      stage neurological deficit and recovery therefrom, and shown its persistence up
      to 16 hrs after stroke onset in some patients. However, some patients acutely
      exhibit extensive irreversible damage, which places them at considerable risk of
      malignant MCA infarction, and others early spontaneous reperfusion, which is
      almost invariably associated with rapid and complete recovery. Thrombolytics
      and/or neuroprotective agents would therefore be expected to benefit, and hence
      should ideally be reserved to, only those patients in whom a substantial penumbra
      is documented by physiologic neuroimaging, even perhaps beyond the 3 to 6 hrs
      rule. In addition, excluding from thrombolytic therapy those patients with
      substantial necrotic core should avoid many instances of symptomatic haemorrhagic
      transformations. Finally, patients with extensive core might benefit from early
      decompressive surgery, and those with early extensive reperfusion from anti
      inflammatory agents. Overall, therefore, the pathophysiologic heterogeneity
      underlying AIS may account for both the complications from thrombolysis and the
      limited success of clinical trials of neuroprotective agents, despite apparent
      benefit in the laboratory. Pathophysiological diagnosis as afforded by
      neuroimaging should now be incorporated in the design of clinical trials as well
      as in the routine management of stroke.

PMID- 12597608
TI  - Stroke--acute interventions.
AB  - The reduction of blood flow to parts of the brain is the cause of ischemic stroke
      leading to functional deficits and, if prolonged, to irreversible neurological
      and morphological defects. The fast reperfusion, therefore is the most important
      therapeutic strategy and was proven to be effective in clinical trials. Steps to
      intervene with secondary biochemical, molecular, or inflammatory disturbances
      were not successful so far. Since direct therapeutic interventions are limited,
      the general management of the stroke victim is of utmost importance--and was
      shown to be most successful in dedicated stroke units. Acute therapeutic
      interventions in ischemic stroke can only be successful as long as tissue in the
      area of the ischemic compromise is still viable. The area of irreversible damage
      can be identified and distinguished from the penumbral zone, i.e., tissue with
      impaired function but preserved morphology by functional imaging modalities, like
      positron emission tomography (PET) or perfusion-(PW) and diffusion-weighted (DW)
      magnetic resonance imaging (MRI). In such studies it was demonstrated that a
      large portion of the final infarct is irreversibly affected in the first few
      hours in many patients. A considerable tissue volume is viable but critically
      hypoperfused; a smaller portion of the final infarct is sufficiently perfused and
      in this area secondary and delayed biochemical and molecular mechanisms
      contribute to the damage. Based on this concept the improvement of perfusion
      within the time window of opportunity must be the primary goal in treatment of
      ischemic stroke, and neuroprotective and other strategies can only play a
      supportive and additive role. That this is the case can be seen from the results
      of many controlled therapeutic trials, in which up to now only thrombolytic
      therapy with a 3 h time window for systemic and a 6 h time window for
      intraarterial application proved its efficacy, whereas all trials with
      neuroprotective, anti-inflammatory or anti-apoptotic strategies failed. Since the
      direct treatment strategies are limited the acute management of stroke victims is
      of utmost importance: This can be achieved optimally in dedicated stroke units in
      which the outcome was significantly improved over the regular care. It is still
      to be investigated if invasive strategies--e.g., craniectomy and hypothermia--or
      the combination of reperfusion and neuroprotective therapy can improve the
      outcome after ischemic stroke.

PMID- 12597609
TI  - Rehabilitation approaches to stroke.
AB  - This article describes the state of the science in stroke rehabilitation dealing
      with three main topics: (1) General approach to stroke rehabilitation (stroke
      services and stroke units), (2) Neurophysiological and pharmacological
      interventions (facilitation of brain repair mechanisms) and (3) Experimental
      approaches (neuronal transplantation). Stroke rehabilitation is an active process
      beginning during acute hospitalisation, progressing to a systematic program of
      rehabilitation services and continuing after the individual returns to the
      community. There is world-wide consensus that stroke patients should be treated
      at specialised stroke unit with specially trained medical and nursing staff, co
      ordinated multidisciplinary rehabilitation and education programs for patients
      and their families. Stroke Unit has been shown to be associated with a long-term
      reduction of death and of the combined poor outcomes of death and dependency,
      independent of patients age, sex, or variations in stroke unit organisations. No
      study has clearly shown to what extent the beneficial effect is due to specific
      rehabilitation strategies. New imaging studies in stroke patients indicate
      altered post stroke activation patterns, which suggest some functional
      reorganisation. Reorganisation may be the principle process responsible for
      recovery after stroke. It is assumed that different post ischaemic interventions
      like physiotherapy, occupational therapy, speech therapy, electrical stimulation,
      etc. facilitates such changes. Scientific evidence demonstrating the values of
      specific rehabilitation interventions after stroke is limited. Comparisons
      between different methods in current use have so far mostly failed to show that
      any particular physiotherapy, occupational therapy, speech therapy or stroke
      rehabilitation strategy is superior to another. Clinical data are strongly in
      favour of early mobilisation and training. Pharmacological interventions in
      animals revealed that norepinephrine, amphetamine and other alpha-adrenergic
      stimulating drugs can enhance motor performance after unilateral ablation of the
      sensory motor cortex. The clinical data in humans are rather contradictory.
      Neural grafting and neurogenesis are new potential modes of stroke therapy.
      Neural grafting enhanced functional outcome and reduced thalamic atrophy in rats
      only when combined with housing in enriched environments. Recent studies have
      shown that stem cells can differentiate to neurons in the adult human dentate
      gyrus in vivo.

PMID- 12597610
TI  - CADASIL and genetics of cerebral ischaemia.
AB  - Recent advances suggest the existence of several autosomal dominantly inherited
      forms of cerebrovascular disorders. Mutations in diverse genes may induce direct
      pathological changes in intracranial vessels to cause cerebral ischaemic or
      haemorrhagic strokes leading to cognitive impairment and dementia. Similar
      pathology may also be caused by systemic vascular disease resulting from
      mutations and polymorphisms in genes that regulate cardiovascular physiology,
      blood coagulation and metabolic functions. The most common form of familial
      stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with
      subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that
      has been linked to nucleotide substitutions and deletions in the Notch 3 gene.
      The pathogenesis of the disorder or how the mutations lead to cerebral infarcts
      and dementia is not known. However, elucidation of the microvascular pathology
      associated with such genetic disorders not associated with physiological risk
      factors for cardiovascular disease or stroke can bear much light on primary
      vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability.

PMID- 12597611
TI  - Diagnosis and management of vascular cognitive impairment and dementia.
AB  - Vascular dementias (VaDs) are the second most common cause of dementia.
      Cerebrovascular disease (CVD) and stroke relates to high risk of cognitive
      impairment, but also relate to Alzheimer's disease (AD): Vascular cognitive
      impairment (VCI) and dementias extend beyond the traditional multi-infarct
      dementia. Pathophysiology of VaD incorporates interactions between vascular
      etiologies (CVD and vascular risk-factors), changes in the brain (infarcts, white
      matter lesions, atrophy), host factors (age, education) and cognition. Variation
      in defining the cognitive syndrome, in vascular etiologies, and allowable brain
      changes in current criteria have resulted in variable estimates of prevalence, of
      groups of subjects, and of the types and distribution of putative causal brain
      lesions. Should new criteria be developed? Ideally in constructing new criteria
      the diagnostic elements should be tested with prospective studies with clinical
      pathological correlation: replace dogma with data. Meanwhile focus on more
      homogenous subtypes of VaD, and on imaging criteria could be a solution.
      Subcortical ischemic vascular disease and dementia (SIVD) incorporate small
      vessel disease as the chief vascular etiology, lacunar infarct and ischaemic
      white matter lesions as primary type of brain lesions, subcortical location as
      the primary location of lesions, and subcortical syndrome as the primary clinical
      manifestation. It incorporates two clinical entities "Binswanger's disease" and
      "the lacunar state". AD with VaD (mixed dementia) has been underestimated as a
      prevalent cause in the older population. In addition to simple co-existence, VaD
      and AD have closer interaction: several vascular risk factors and vascular brain
      changes relate to clinical manifestation of AD, and they share also common
      pathogenetic mechanisms. Vascular cognitive impairment (VCI) is a category aiming
      to replace the "Alzhemerized" dementia concept in the setting of CVD, and
      substitute it with a spectrum that includes subtle cognitive deficits of vascular
      origin, post-stroke dementia, and the complex group of the vascular dementias. As
      far there is no standard treatment for VaDs, and still little is known on the
      primary prevention (brain at risk for CVD) and secondary prevention (CVD brain at
      risk for VCI/VaD). There is no standard symptomatic treatment for VaD. Recently
      symptomatic cholinergic treatment has shown promise in AD with VaD, as well as
      probable VaD. Future focus should be directed to the distinct etiological and
      pathological factors: the vascular and the AD burden of the brain.

PMID- 12597612
TI  - The genetics of migraine: implication for treatment approaches.
AB  - Migraine is a paroxysmal neurological disorder affecting up to 12% of males and
      24% of females in the general population, demonstrated to have a strong, but
      complex, genetic component. Genetic investigation of migraine bears great promise
      in providing new targets for drug development and optimization of individual
      specific therapy. Better, preferably prophylactic, treatment of migraine patients
      is desired because the presently used drugs are not effective in all patients,
      allow recurrence of the headache in a high percentage of patients and sometimes
      have severe adverse side effects. With the recent identification of the brain
      specific P/Q-type calcium channel gene CACNA1A in the pathogenesis of migraine,
      the first step has been taken to identify primary biochemical pathways leading to
      migraine. Here, we summarize the current knowledge about the genetics of migraine
      and focus on the implication for treatment approaches.

PMID- 12597613
TI  - Does schizophrenia result from developmental or degenerative processes?
AB  - The debate as to whether schizophrenia is a neurodevelopmental or a
      neurodegenerative disorder has its roots in the latter part of the 19th century
      when authorities such as Clouston (1891) posited that at least some insanities
      were "developmental" in origin. These views were soon eclipsed by Kraepelin's
      (1896) concept of dementia praecox as a degenerative disease, and the latter view
      carried not only the day but also much of the 20th century. Then, in the 1980s
      several research groups again began to speculate that schizophrenia might have a
      significant developmental component (Feinberg, 1982-1983; Schulsinger et al.,
      1984; Murray et al., 1985; Murray and Lewis, 1987; Weinberger et al., 1987). What
      became known as the "neurodevelopmental hypothesis" received support from
      neuropathological studies implicating anomalies in early brain development such
      as aberrant migration of neurons. Unfortunately, these studies proved difficult,
      if not impossible, to replicate (Harrison, 1999). The pendulum, therefore, began
      to swing again, and in the latter part of the 1990s came renewed claims that the
      clinical progression of the illness was accompanied by continued cerebral
      ventricular enlargement and reduction in the volumes of certain brain structures.
      Nevertheless, since few doubt that there is a developmental component to
      schizophrenia, the question which we will address in this paper is whether
      schizophrenia is a) simply the final consequence of a cascade of increasing
      developmental deviance (Bramon et al., 2001), or b) whether there is an
      additional brain degeneration following onset of psychosis which is superimposed
      on the developmental impairment (Lieberman, 1999).

PMID- 12597614
TI  - Molecular anatomy of neuronal interactions with special reference to the dopamine
      control of striatal functions.

PMID- 12597615
TI  - Effects of monensin on Na+/K(+)-ATPase and Ca(++)-AtPase activities in chick
      skeletal muscle and myocardium after subacute treatment.
AB  - Chicks were treated at 2 weeks of age with 4,15, 40, 100 and 150 mg/kg of
      monensin, an ionophore used for its anticoccidial and growth-promoting
      properties. In the present immunohistochemical study, the expressions and
      distribution of Na+/K(+)-ATPase and Ca(++)-ATPase were studied in myocardium and
      skeletal muscles (pectoral and quadriceps femoris). We detected an increase of
      Na+/K(+)-ATPase immunostaining with prominent staining of the sarcolemma and a
      slight increase of Ca(+)-ATPase with prominent staining of the sarcoplasma.

PMID- 12597616
TI  - Morphological changes in the frog cerebellar cortex after unilateral section of
      the statoacustic nerve.
AB  - To investigate a possible role of the cerebellum in vestibular compensation that
      follows a lesion to the vestibular apparatus, the morphological changes of the
      cerebellar cortex of adult frogs following unilateral statoacustic nerve section
      was analyzed by means of electron microscopy starting from 3 days after the
      neurectomy for up to 6 months. On the ipsilateral side, massive abnormality was
      found in all layers at early postsurgical intervals. This involved both nerve
      fibers and cell bodies. Fibers often appeared condensed or vacuolated with poorly
      compacted myelin sheath. Cells had electronlucent and vacuolated cytoplasm to
      varying extent. Alterations became less conspicuous after 30 days and after 60
      days altered nerve cells were no longer present. On the contralateral side, only
      a few Purkinje and granule cells were affected at early postsurgical stages. This
      may derive from the fact that, in the frog, some of the vestibular primary
      afferents reach contralateral cerebellar cortex. At 30 days, alterations had
      substantially progressed, and at 60 days they involved all the cortical layers.
      Fiber debris was present in the granular and molecular layers and numerous
      Purkinje cells were electrondense and shrunken. This lateness in alteration may
      be a consequence of the prolonged silence of the vestibular nucleus contralateral
      to the lesion. At 4 and 6 months the tissue architecture was normal.

PMID- 12597617
TI  - The supramedullary cells of the teleost Coris julis (L.): a noradrenergic
      neuronal system.
AB  - This study, carried out on Coris julis (Labridae), is a contribution to the
      immunocytochemical characterization of fish supramedullary neurons. The
      significance of these giant cells has been debated since the beginning of the
      twentieth century. Our research provides the first evidence for a noradrenergic
      feature of this neuronal system. The possible role of supramedullary neurons as
      components of the autonomic nervous system is discussed. Moreover, the present
      results, taken together with our previous studies, surmise that this the first
      known case of colocalization of a neuropeptide (gastrin/CCK-like) and
      noradrenaline in the nervous system of teleosts.

PMID- 12597618
TI  - Comparative immunolocalization of the plasma membrane calcium pump and calbindin
      D28K in chicken retina during embryonic development.
AB  - The immunolocalization of the plasma membrane calcium pump (PMCA) was studied in
      4-week-old chick retina in comparison with calbindin D28K (CaBP) immunostaining.
      We have demonstrated that the monoclonal anti-PMCA antibody SF10 from human
      erythrocyte plasma membrane cross-reacts with a Ca2+ pump epitope of the cells
      from the neural retina. The immunolocalization of both proteins was also studied
      during the embryonic development of the chicken retina. At age 4.5 days, the
      cells of the retina were faintly immunoreactive to PMCA and CaBP antibodies, but
      the lack of cellular aggregation and differentiation did not allow discrimination
      between the two proteins. A clear difference in the localization was seen from
      the tenth day of development through post-hatching with slight variation. PMCA
      localized mainly in the outer and inner plexiform layers, in some cells in the
      ganglion layer, in the nerve fiber layer and slightly in the photoreceptor cells.
      CaBP was intensely stained in cones, cone pedicles and some amacrine cells. The
      number of CaBP positive amacrine cells declined after hatching. A few ganglion
      cells and several nerve fibers were CaBP immunoreactive. The role of these
      proteins in the early stages of retinal development is unknown, but the results
      suggest that Ca2+ homeostasis in the retina is well regulated, probably to avoid
      excessive accumulation of Ca2+, which often leads to neurodegeneration.

PMID- 12597619
TI  - Zinc ions alter morphology and chitin deposition in an ericoid fungus.
AB  - A sterile mycelium PS IV, an ascomycete capable of establishing ericoid
      mycorrhizas, was used to investigate how zinc ions affect the cellular mechanisms
      of fungal growth. A significant reduction of the fungal biomass was observed in
      the presence of millimolar zinc concentrations; this mirrored conspicuous changes
      in hyphal morphology which led to apical swellings and increased branching in the
      subapical parts. Specific probes for fluorescence and electron microscopy
      localised chitin, the main cell wall polysaccharide, on the inner part of the
      fungal wall and on septa in control specimens. In Zn-treated mycelium, hyphal
      walls were thicker and a more intense chitin labelling was detected on the
      transverse walls. A quantitative assay showed a significant increase in the
      amount of chitin in metal-treated hyphae.

PMID- 12597620
TI  - Effects of ageing on peroxidase activity and localization in radish (Raphanus
      sativus L.) seeds.
AB  - Peroxidase activity was assayed in crude extracts of integument, cotyledons and
      embryo axis of radish seeds, deteriorated under accelerated ageing conditions.
      Over five days of ageing, in which germination decreased from 100 to 52%, the
      enzyme activity in integument was higher than that in other seed parts,
      increasing in the first days of ageing and then decreasing sharply in extremely
      aged seeds. Polyacrylamide gel electrophoresis analysis showed four peroxidase
      isoenzymes with MM of 98, 52.5, 32.8 and 29.5 kDa in the embryo axis of unaged
      seeds, and only the 32.8 and 29.5 kDa MM isoforms in the integument and
      cotyledons. In these parts of the seed, only the 29.5 kDa MM isoenzyme increased
      in activity in early days of ageing and decreased there-after. In the embryo
      axis, the 29.5 kDa MM isoenzyme activity increased slowly in the first day of
      ageing, while the 98 and 52.5 kDa MM isoenzyme activities disappeared. A
      cytochemical localization of peroxidase activity in the various tissues showed
      that main differences between unaged and extremely aged seeds occurred in the
      embryo axis.

PMID- 12597621
TI  - LR White is preferable to Unicryl for immunogold detection of fixation-sensitive
      nuclear antigens.
AB  - The purpose of this study was to compare two electron microscopy embedding media 
      LR White and Unicryl - with regard to cell morphologyical and
      immunohistochemical preservation properties for the study of fixation-sensitive
      nuclear antigens. Human cervical carcinoma (HeLa) cells were fixed with 2%
      paraformaldehyde and 0.1% glutaraldehyde, and embedded in parallel in the two
      resins: LR White and Unicryl using; two different polymerization protocols were
      used for each resin. Preservation of fine nuclear structure was good after LR
      White and poor after Unicryl embedding. Immunogold labeling of Sm antigen was
      significantly stronger on LR White sections. Polymerization by UV light resulted
      in stronger and more specific labeling than heat polymerization. These results
      show that LR White is advantageous over Unicryl for the study of nuclear antigens
      requiring delicate aldehyde fixation.

PMID- 12597622
TI  - Use of periodate-lysine-paraformaldehyde for the fixation of multiple antigens in
      human skin biopsies.
AB  - Periodate-lysine-paraformaldehyde (PLP) has been proposed as a fixative for
      glycoprotein antigens which should stabilize periodate oxidized polysaccharide
      chains through lysine mediated crosslinks, either directly or by the
      intermediation of formaldehyde. In spite of premises and attempts reported in the
      literature, this fixative has never become popular for the study of membrane
      antigens of immune system cells, which leads to doubts on its real efficacy. We
      have addressed this issue in biopsies of human skin and found that PLP followed
      by cryoprotection with 30% sucrose and cryosectioning, or PLP fixation of
      isolated epidermal sheets, consistently provided for good preservation of
      morphology and intense labeling of major histocompatibility complex class II
      molecules, CD 1 a, CD4, CD8, E-cadherin, cytokeratins in general, cytokeratin-18
      in particular, and bromodeoxyuridine, incorporated by cycling cells in vitro, and
      for the demonstration of tyrosinase enzyme activity. PLP-fixed, osmicated and
      epon-embedded epidermal sheets proved as good as sheets fixed with a mixture of
      formaldehyde and glutaraldehyde for electron microscopic morphological analysis.
      Also, these sheets were amenable to immunoperoxidase staining of Langerhans cell
      membrane antigen CD1a and keratinocyte membrane antigen E-cadherin before being
      osmicated and prepared for electron microscopy. In a parallel paper, we had also
      shown that oral mucosa biopsies fixed in PLP showed good morphology and
      immunolabeling of CD54, CD80, CD83 and CD86. Therefore, we conclude that PLP can
      be proposed as a multi-task fixative for light and electron microscopic analysis
      of membrane, cytoplasmic and nuclear antigens of immune system cells and
      keratinocytes.

PMID- 12597623
TI  - Nuclear localization of phosphorylated c-Myc protein in human tumor cells.
AB  - Using immunocytochemical techniques at light and electron microscopy, we analysed
      the distribution of phosphorylated c-Myc in actively proliferating human HeLa
      cells. The distribution pattern of c-Myc was also compared with those of other
      ribonucleoprotein (RNP)-containing components (PANA, hnRNP-core proteins,
      fibrillarin) or RNP-associated nuclear proteins (SC-35 splicing factor). Our
      results provide the first evidence that phosphorylated c-Myc accumulates in the
      nucleus of tumor cells, where it colocalizes with fibrillarin, both in the
      nucleolus and in extranucleolar structures.

PMID- 12597624
TI  - Determination of daidzein and genistein in soybean foods by automated on-line in
      tube solid-phase microextraction coupled to high-performance liquid
      chromatography.
AB  - An automated on-line method for the determination of the isoflavones, daidzein
      and genistein, was developed using in-tube solid-phase microextraction coupled to
      high-performance liquid chromatography (in-tube SPME-HPLC). In-tube SPME is a new
      extraction technique for organic compounds in aqueous samples, in which analytes
      are extracted from the sample directly into an open tubular capillary by repeated
      draw/eject cycles of sample solution. Daidzein, genistein and their glucosides
      tested in this study were clearly separated within 8 min by HPLC using an XDB-C8
      column with diode array detection. In order to optimize the extraction of these
      compounds, several in-tube SPME parameters were examined. The glucosides daidzin
      and genistin were analyzed as aglycones after hydrolysis because the glucosides
      were not concentrated by in-tube SPME. The optimum extraction conditions for
      daidzein and genistein were obtained with 20 draw/eject cycles of 40 microl of
      sample using a Supel-Q porous layer open tubular capillary column. The extracted
      compounds were easily desorbed from the capillary by mobile phase flow, and
      carryover was not observed. Using the in-tube SPME-HPLC method, the calibration
      curves of these compounds were linear in the range 5-200 ng/ml, with a
      correlation coefficient above 0.9999 (n = 18), and the detection limits (S/N = 3)
      were 0.4-0.5 ng/ml. This method was successfully applied to the analysis of
      soybean foods without interference peaks. The recoveries of aglycones and
      glucosides spiked into food samples were above 97%.

PMID- 12597625
TI  - Simultaneous extraction of di(2-ethylhexyl) phthalate and nonionic surfactants
      from house dust. Concentrations in floor dust from 15 Danish schools.
AB  - Static extraction, supercritical fluid extraction (SFE), pressurized liquid
      extraction (PLE) and Soxhlet extraction were compared for simultaneous extraction
      of di(2-ethylhexyl) phthalate (DEHP) and nonionic surfactants from house dust.
      Homogenized office floor dust from a vacuum cleaner dust bag ("standard dust")
      was used for the evaluation. One portion of the extracts was used for analysis of
      nonionic surfactants with LC-MS and another portion was used for DEHP analysis
      with GC-MS. The extraction yield of DEHP was comparable for all the methods
      whereas SFE and PLE were the most efficient extraction techniques for the
      nonionic surfactants. The PLE extraction was found most suitable as a routine
      method for simultaneous extraction of both types of compounds and was used in a
      field study of floor dust from 15 Danish schools. The mean concentration of DEHP
      in the school dust samples was approximately 4 times higher than observed in
      other studies of dust from homes in different countries. The concentrations of
      nonionic surfactants were one order of magnitude lower than soap and linear
      alkylbenzene sulfonates measured in other studies of floor dust from offices and
      other public buildings. However, for the first time nonionic surfactants have
      been identified in house dust.

PMID- 12597626
TI  - Retention mechanism of poly(ethylene oxide) in reversed-phase and normal-phase
      liquid chromatography.
AB  - The retention behavior of low- and high-molecular-mass poly(ethylene oxide) (PEO)
      in reversed-phase (RP) and normal-phase (NP) liquid chromatography was
      investigated. In RPLC using a C18 bonded silica stationary phase and an
      acetonitrile-water mixture mobile phase, the sorption process of PEO to the
      stationary phase showed deltaH(o) > 0 and deltaS(o) > 0. Therefore, PEO retention
      in RPLC separation is an energetically unfavorable, entropy-driven process, which
      results in an increase of PEO retention as the temperature increases. In
      addition, at the enthalpy-entropy compensation point the elution volume of PEO
      was very different from the column void volume. These observations are quite
      different from the RPLC retention behavior of many organic polymers. The peculiar
      retention behavior of PEO in RPLC separation can be understood in terms of the
      hydrophobic interaction of this class of typical amphiphilic compounds with the
      non-polar stationary phase, on the one hand, and with the aqueous mobile phase,
      on the other. The entropy gain due to the release of the solvated water molecules
      from the PEO chain and the stationary phase is believed to be responsible for the
      entropy-driven separation process. On the other hand, in NPLC using an amino
      bonded silica stationary phase and an acetonitrile-water mixture mobile phase,
      PEO showed normal enthalpy-driven retention behavior: deltaH(o) < 0 and deltaS(o)
      < 0, with the retention decreasing with increasing temperature and PEO eluting
      near the column void volume at the enthalpy-entropy compensation point.
      Therefore, high-resolution temperature gradient NPLC separation of high-molecular
      mass PEO samples can be achieved with relative ease. The molecular mass
      distribution of high-molecular-mass PEO was found to be much narrower than that
      measured by size-exclusion chromatography.

PMID- 12597627
TI  - Retention mechanism of fatty alcohol ethoxylates in reversed-phase liquid
      chromatography.
AB  - Fatty alcohol ethoxylates (FAEs) are widely used nonionic surfactants that have
      distributions in both alkyl and poly(ethylene oxide) (PEO) chain length.
      Generally, two-dimensional liquid chromatography technique is required for the
      complete characterization of both distributions. By selecting a proper stationary
      and mobile phase condition, however, we can obtain fully resolved chromatograms
      of a FAE sample (Brij 30) with respect to both alkyl and PEO chain length by
      using a single reversed-phase C18 column and aqueous acetonitrile mobile phase.
      FAEs show a peculiar reversed-phase liquid chromatography (RPLC) retention
      behavior with an aqueous-organic mobile phase, the retention mechanism of which
      has not been fully elucidated. For a fixed alkyl chain length, FAEs with higher
      molecular-mass PEO block elutes first and the van't Hoff plot of the retention
      factor shows a curvature. The unique retention behavior can be understood from
      the opposite thermodynamic characteristics associated with RPLC retention of PEO
      block and alkyl chain: the sorption process of PEO to the non-polar stationary
      phase shows deltaH(o) > 0 and deltaS(o) > 0 while the alkyl chain shows deltaH(o)
      < 0 and deltaS(o) < 0 in contrast. The relative magnitude of the two
      contributions can change the elution order of the FAE. Therefore the often found,
      inverted elution order of FAEs (the early elution of FAEs with longer PEO block)
      is due to the positive enthalpic interaction of PEO blocks, which is a
      characteristic of the hydrophobic interaction. And the curvature of the van't
      Hoff plots was analyzed assuming the temperature dependent thermodynamic
      variables.

PMID- 12597628
TI  - Numerical determination of the competitive isotherm of enantiomers.
AB  - A numerical method was developed and used to determine adsorption isotherms in
      chromatography. The numerical parameters of an isotherm model were derived from
      the recorded band profiles of the racemic mixture of the 1-phenyl-1-propanol
      enantiomers, by means of a nonlinear least-squares method. We used the
      equilibrium-dispersive model of chromatography with several isotherm models. The
      numerical constants of the isotherm models were tuned so that the calculated and
      the measured band profiles match as much as possible. We show that this numerical
      inverse method can be applied even without the knowledge of the individual band
      profile of the pure enantiomers. The isotherms determined from the--usually
      unresolved--overloaded band profiles matched extremely well the isotherms
      determined by frontal analysis. Several isotherm models were used and tested-
      such as Langmuir, biLangmuir, Toth, Langmuir-Freundlich. The best-fit isotherm
      was selected by means of statistical evaluation of the results.

PMID- 12597629
TI  - Chemometric comparison of recent chromatographic and electrophoretic methods in a
      quantitative structure-retention and retention-activity relationship context.
AB  - The retention characteristics of 21 basic pharmaceutical substances with a
      considerable difference in hydrophobicity (octanol-water partition coefficients,
      log P, between -0.026 and 6.45) are considered on an immobilized artificial
      membrane column, with a micellar liquid chromatography and a micellar
      electrokinetic capillary chromatography method. Utilising principal component
      analysis (PCA), it is seen that although the main retention principle is the
      same, the above methods as well as more classical RP-HPLC methods vary in
      secondary retention mechanisms. Combining the results of different methods a
      differentiation of the substances into their pharmacological families can be seen
      with PCA. The high correlations of the retention characteristics with log P and a
      biological parameter seem little affected by the method used.

PMID- 12597630
TI  - Prediction of measurement precision of apparatus using a chemometric tool in
      electrochemical detection of high-performance liquid chromatography.
AB  - The relative standard deviation (RSD) of measurements in high-performance liquid
      chromatography with electrochemical detection (HPLC-ECD) was predicted by a
      chemometric tool based on the 1/f fluctuation model which is made up of white
      noise and a Markov process, called the Function of Mutual Information (FUMI)
      theory. FUMI theory can provide aprecise and reliable detection limit from a
      single measurement of noise and signal in HPLC-ECD. To obtain RSD (n = 5) for
      determination of (-)-epicatechin at five concentrations required 12.5 h, while
      the predicted RSD by FUMI theory required only 0.5 h (one measurement). Moreover,
      to trace the source of instrumental noise, power spectra of chromatographic
      baseline were used. Selection of a suitable apparatus in HPLC-ECD system,
      acquisition of RSD, and detection limits for determination of catechins by HPLC
      ECD were simply and easily made by this chemometric tool within a very short
      time. The use of the FUMI theory for the prediction of measuring precision was
      more efficient and the optimization was less time-consuming to be suited for
      determination.

PMID- 12597631
TI  - Simple method for the quantitative examination of extra column band broadening in
      microchromatographic systems.
AB  - In recent years capillary chromatography has gained popularity for trace
      analyses. Most often UV or electrochemical detection is employed because the
      small peak volumes make post-column derivatization challenging. We have developed
      a simple method based on flow injection for determining contributions to peak
      broadening from post-column reactors. The only requirement for application of our
      methodology is that diffusion be in the Taylor regime so that radial
      concentration gradients are relaxed enabling mixing purely by diffusion.

PMID- 12597632
TI  - Cholesterol bonded phase as a separation medium in liquid chromatography.
      Evaluation of properties and applications.
AB  - An extensive survey of the properties and separation capabilities of a
      cholesterol bonded phase is reported. The intermediate hydrophobic/hydrophilic
      properties of the bonded cholesterol material allows this stationary phase to be
      used for both reversed-phase and aqueous normal-phase separations. Interesting
      high selectivity is reported for the structural isomers of some antibiotics. The
      cholesterol bonded material does not display "phase collapse" in high aqueous
      content mobile phases. Variable temperature studies demonstrate that substantial
      structural changes of the bonded moiety occur that might be used to control
      selectivity. Finally, separation of some enantiomers of compounds with a variety
      of chemical structures is reported under reversed-phase conditions indicating
      that the cholesterol material may be chiral stationary phase with a broad range
      of applicability.

PMID- 12597633
TI  - Studies on the separation of hydronium ion using surfactant-modified reversed
      phase stationary phases and eluents containing an acidified electrolyte.
AB  - A further investigation of a chromatographic system allowing determination of
      hydrogen ions is reported. For this purpose an octadecylsilica column dynamically
      modified with sodium dodecylsulfate (SDS) or lithium dodecylsulfate (LDS) was
      used as stationary phase and a slightly acidified electrolyte (usually KCl)-SDS
      solution was used as the eluent. The concentration of SDS, KCl and the acidity of
      the eluent affected the structure of aggregates formed by the molecules of
      dodecylsulfate at the surface of the stationary phase. These aggregates of
      dodecylsulfate were found to be responsible for the appearance of a
      chromatographic peak attributed to the presence of H3O+ ions in a sample. Other
      cations in the sample could be separated in the same manner, permitting the
      simultaneous separation of monovalent cations from H3O+. The detection limit for
      H3O+ ions was 2.25 x 10(-6) M using an eluent comprising 0.3 mM LDS, 50.0 mM KCl
      and 0.10 mM H2SO4. The proposed method is shown to be applicable for the
      determination of free H3O+ ions in aqueous solutions of strong acids.

PMID- 12597634
TI  - Direct chromatographic capture of enzyme from crude homogenate using immobilized
      metal affinity chromatography on a continuous supermacroporous adsorbent.
AB  - A continuous supermacroporous matrix has been developed allowing direct capture
      of enzyme from non-clarified crude cell homogenate at high flow-rates. The
      continuous supermacroporous matrix has been produced by radical co-polymerization
      of acrylamide, allyl glycidyl ether and N,N'-methylene-bis(acrylamide) which
      proceeds in aqueous solution of monomers frozen inside a column (cryo
      polymerization). After thawing, the column contains a continuous matrix having
      interconnected pores of 10-100 microm size. Iminodiacetic acid covalently coupled
      to the cryogel is a rendering possibility for immobilized metal affinity
      chromatographic purification of recombinant His-tagged lactate dehydrogenase,
      (His)6-LDH, originating from thermophilic bacterium Bacillus stearothermophilus,
      but expressed in Escherichia coli. The large pore size of the adsorbent makes it
      possible to process particulate-containing material without blocking the column.
      No preliminary filtration or centrifugation is needed before application of crude
      extract on the supermacroporous column. A total of 210 ml crude homogenate, 75 ml
      of it non-clarified, was processed on a single 5.0 ml supermacroporous column at
      flow speeds up to 12.5 ml/min without noticeable impairment of the column
      properties. Mechanically the cryogel adsorbent is very stable. The continuous
      matrix could easily be removed from the column, dried at 70 degrees C and kept in
      a dry state. After rehydration and reinsertion of the matrix into an empty
      column, (His)6-LDH was purified as efficiently as on the newly prepared column.
      The procedure of manufacturing the supermacroporous continuous cryogel is
      technically simple. Starting materials and initiators are cheap and available and
      are simply mixed and frozen under specified conditions. Altogether these
      qualities reveal that the supermacroporous continuous cryogels is a very
      interesting alternative to existing methods of protein purification from
      particulate-containing crude extracts.

PMID- 12597635
TI  - High-performance liquid chromatography assay for 1-deoxy-D-xylulose 5-phosphate
      synthase activity using fluorescence detection.
AB  - A high-performance liquid chromatography assay for activity of 1-deoxy-D-xylulose
      5-phosphate synthase, an early enzyme in the recently discovered 2-C-methyl-D
      erythritol-4-phosphate pathway, was developed. In this assay, the enzymatic
      product 1-deoxy-D-xylulose was first derivatized with a fluorescent reagent 2
      anthranilic acid, followed by separation using HPLC on a Nova-Pak phenyl column
      with a mobile phase containing CH3CN-water-1-butylamine-tetrahydrofuran-H3PO4
      (2:97:0.125:0.5:0.25, v/v). The eluate was monitored by fluorescence detection at
      an excitation wavelength of 320 nm and an emission wavelength of 425 nm for
      quantitation of the fluorescent derivative. A linear response was obtained
      between 5 and 200 ng of 1-deoxy-D-xylulose. This assay was successfully applied
      to measure the 1-deoxy-D-xylulose 5-phosphate synthase activity in a recombinant
      E. coli overexpressing dxs gene. It demonstrated that this assay is simple,
      sensitive and selective compared to the methods used at present.

PMID- 12597636
TI  - Packing structure and self-heating in capillary electrochromatography.
AB  - The origin of bubble formation during operation of capillary
      electrochromatography (CEC) has been an issue of debate. Ohmic heating resulted
      from current passed through a packed column was proposed as the primary cause.
      However, this explanation has been questioned on the ground that the current
      measured in CEC is much lower than that measured with open-tubular separation
      systems where no bubble formation occurs. To resolve this issue, we carried out a
      theoretical study correlating self-heating of the electrolyte with packing
      structure of the column. We used a bundle of capillary tubes, a bundle of two
      types of capillary tubes and two bundles of capillary tubes connected serially to
      model, respectively, the flow channels in the column of non-porous particles, in
      the column of porous particles and in the column of various packing densities.
      The results from this study indicate that, for columns of homogeneous packing
      density, the heat output is indeed smaller than that in open-tubular columns of
      the same dimensions. In this case, the self-heating cannot be a key factor
      responsible for the bubble formation in CEC. However, for columns of
      heterogeneous packing density, a large excess of heat release may be produced in
      column sections of high packing density and, in turn, over-heating in such
      sections may become the primary cause for the formation of bubbles. It follows
      from this study that preparation of columns of homogeneous packing structure is
      essential to obtain reproducible and bubble-free CEC systems.

PMID- 12597637
TI  - Kinetic study of angiotensin converting enzyme activity by capillary
      electrophoresis after in-line reaction at the capillary inlet.
AB  - The in-capillary reaction of angiotensin converting enzyme (ACE) with the
      tripeptide substrate hippuryl-L-histidyl-L-leucine was studied. ACE activity was
      determined by the quantitation of the product, hippuric acid, at 230 nm. Reaction
      occurred at the capillary inlet during a predetermined waiting period, followed
      by the electrophoretic separation of the compounds. When the set-up was reversed,
      i.e. reaction at the opposite side after short-end injection of enzyme and
      substrate, separation was achieved in less than 5 min. Using the Lineweaver-Burk
      equation, an average Michaelis constant for ACE from rabbit lung was calculated
      to be 1.16 +/- 0.12 mM, a value consistent with previously reported data.

PMID- 12597638
TI  - Quantitation of formate by solid-phase microextraction and gas chromatography-
      mass spectrometry utilizing a [13C]formate internal standard.
AB  - A new method for the analysis of formic acid was developed using gas
      chromatography-electron impact ionization mass spectrometry in the selected ion
      monitoring mode and solid-phase microextraction. Using this method with
      [13C]formic acid as an internal standard, the peak area ratio of [12C]formic
      acid/[13C]formic acid was not affected by differing methanol or sulfuric acid
      concentrations during the esterification and fiber adsorbing step. In comparison,
      the peak area ratio of formic acid/acetonitrile as detected by conventional GC
      with flame ionization detection was greatly affected by methanol or sulfuric acid
      concentrations. The formic acid calibration curve of our method showed excellent
      linearity over the range 5 to 200 microM. The within- and between-run assay
      relative standard deviations for the formic acid concentration were all less than
      1.70%.

PMID- 12597639
TI  - Determination of total petroleum hydrocarbons in soil by dynamic on-line
      supercritical fluid extraction with infrared photometric detection.
AB  - Total petroleum hydrocarbons (TPHs) in soil are determined by on-line dynamic
      supercritical fluid extraction (SFE) using infrared filter photometry detection.
      The filter photometer was constructed in the laboratory using a tungsten lamp, an
      optical notch filter that selects the C-H stretching vibration of the extracted
      organics, an optical chopper with demodulation electronics, and a PbSe detector.
      A modified high-pressure fiber optic flow cell was used to couple the SFE system
      to the photometer. Quantitation of TPHs was accomplished through the construction
      of calibration curves of integrated absorbance of C-H stretching (over time)
      versus concentration. Our studies show that the sensitivity of this system is
      affected by both the optical path length in the high-pressure cell and the SFE
      fluid flow-rate, and detection limits for TPHs are in the mid part-per-million
      range. The results of the application of this on-line SFE-IR instrument to the
      determination of TPHs in real-world samples show good agreement with those
      obtained from standard Soxhlet extraction-IR methods.

PMID- 12597640
TI  - European Working Group on Clinical Cell Analysis (EWGCCA): 6 years on.

PMID- 12597641
TI  - Flow cytometric immunophenotyping of acute lymphoblastic leukemia: is the time
      ready for consensus the guidelines?

PMID- 12597642
TI  - Diagnostic and prognostic value of flow cytometric immunophenotyping in malignant
      hematological diseases.
AB  - Flow cytometry is a diagnostic cell analysis technique with ever increasing
      applications in modern hematological practice. To date immunophenotyping of
      clonal hematological diseases represents one of the primary clinical applications
      of flow cytometry. Immunophenotyping of abnormal cells is now considered a
      fundamental tool to establish the cell lineage assignment and to obtain a more
      precise identification of the various cell subtypes. A number of observations
      have emerged showing strong association between specific immunophenotypes and
      genetic recurrent abnormalities underlying the malignant transformation, with
      prognostic value.

PMID- 12597643
TI  - Clinical validation--the final step in translational medicine! From CD34
      enumeration to probability estimation of autograft quality.

PMID- 12597644
TI  - Quality assessment of autologous hematopoietic blood progenitor and stem cell
      grafting: a prospective registration study.

PMID- 12597646
TI  - Molecular phylogeny of Wolbachia endosymbionts in Southeast Asian mosquitoes
      (Diptera: Culicidae) based on wsp gene sequences.
AB  - Wolbachia are maternally inherited intracellular bacteria that infect a wide
      range of arthropods and nematodes and are associated with various reproductive
      abnormalities in their hosts. Insect-associated Wolbachia form a monophyletic
      clade in the alpha-Proteobacteria and recently have been separated into two
      supergroups (A and B) and 19 groups. Our recent polymerase chain reaction (PCR)
      survey using wsp specific primers indicated that various strains of Wolbachia
      were present in mosquitoes collected from Southeast Asia. Here, we report the
      phylogenetic relationship of the Wolbachia strains found in these mosquitoes
      using wsp gene sequences. Our phylogenetic analysis revealed eight new Wolbachia
      strains, five in the A supergroup and three in the B supergroup. Most of the
      Wolbachia strains present in Southeast Asian mosquitoes belong to the established
      Mors, Con, and Pip groups.

PMID- 12597645
TI  - Intracellular detection of Bcl-2 and p53 proteins by flow cytometry: comparison
      of monoclonal antibodies and sample preparation protocols.
AB  - Several techniques have been proposed for flow cytometric evaluation of
      intracellular antigens. This approach is particularly important for detection at
      the single cell level of proteins which correlate to tumour progression. Bcl-2
      and p53 are two of the most relevant proteins. In the present study we have
      compared five different cell fixation-permeabilisation protocols and nine
      fluorochrome-conjugated (FITC or PE) monoclonal antibodies (mAb): four mAb
      directed against Bcl-2 and five against p53. For detection of Bcl-2 we have
      analysed three Bcl-2 positive cell lines (K562, Daudi and MCF-7), and peripheral
      blood samples obtained from nine healthy subjects. To distinguish internal
      positive (lymphocytes) and negative control cells (granulocytes), it was
      necessary to perform simultaneous detection of surface and intracellular
      antigens. For detection of p53 three cell lines, two p53 positive (Raji and CEM)
      and one p53 negative (HL-60), were analysed. Using these cells we have performed
      a combined analysis of the efficiency of monoclonal antibodies and sample
      preparation techniques. In conclusion, clones 124-FITC and Bcl-2/100-PE (Bcl-2),
      and clones BP53,12-FITC and G59-12-PE (p53) provided the highest specific
      fluorescence intensity of the respective markers independent of cell preparation
      protocols. Importantly, our results show that mAb background may depend on the
      specific fixation/permeabilisation kit and that mAb titration using negative and
      positive control cells is essential to determine the specificity and the
      sensitivity of the mAb used.

PMID- 12597647
TI  - Estimation and comparison of mosquito survival rates with release-recapture
      removal data.
AB  - Methods for the estimation and comparison of survival rates are considered when
      data arises from a release of individuals followed by a sequence of recaptures,
      with recaptured individuals removed from the population. It is shown that
      commonly used methods based on linear regression of the log of recapture numbers
      versus time can lead to substantial errors if individuals are removed from the
      population. A general nonlinear regression approach is proposed combined with
      bootstrap techniques for obtaining confidence intervals and tests of hypotheses.
      Simulations demonstrate that these techniques perform well using data from an
      Aedes aegypit L. mark-release-recapture study in Thailand.

PMID- 12597648
TI  - Infection rates in Dipetalogaster maximus (Reduviidae: Triatominae) by
      Trypanosoma cruzi in the Cape Region, Baja California Sur, Mexico.
AB  - Infection rates of Trypanosoma cruzi Chagas (in the blood-sucking bug
      Dipetalogaster maximus [Uhler]) were determined from specimens collected at 12
      localities in the Cape Region of Baja California Sur, Mexico. Eight collection
      sites were located in the tropical dry forest, two in desert shrub, and two in
      the ecotone between these two communities. Of the 245 D. maximus collected, 65%
      were first and second instar nymphs; 32.6% were third, fourth, and fifth instar
      nymphs; and 2.4% were adults. The highest proportion of specimens came from El
      Fandango (30%) and San Bartolo (23%) canyons and La Cruz hill (12%) in the
      mountain slopes facing the Gulf of California. In feces from individual bugs
      analyzed for T. cruzi, we found an overall infection rate of 7.0%. Infection
      rates increased from 4.1% in second instars to 42.% in fifth instars. High
      infection rates were found in bugs collected from La Poza (38.4%), El Gato
      (27.2%), and El Pedregoso (25%) hills; low infection rates were found in
      specimens from La Cruz hill and San Bartolo canyon. Specimens from some
      collection sites were not infected with T. cruzi.

PMID- 12597649
TI  - Novel growth media for rearing larval horn flies, Haematobia irritans (Diptera:
      Muscidae).
AB  - Experiments were conducted to develop an agar-based medium for rearing immature
      horn flies, Hematobia irritans (L.). Larval survival was determined on sterilized
      manure inoculated with pure and mixed cultures of Acinetobacter sp., Bacillus
      pumilus Meyer & Gottheil, Comamonas acidovorans den Dooren de Jong, Pseudomonas
      mendocina Palleroni, Flavobacterium sp. and Empedobacter breve (Holmes & Owen).
      Rearing larvae on mixed cultures enhanced pupal weight but not survival. Horn fly
      larvae failed to survive when reared on standard bacteriological media inoculated
      with pure and mixed cultures of Acinetobacter sp., P. mendocina, and C.
      acidovorans. Larvae completed development on a minimal medium supplemented with
      alfalfa, egg proteins, and vitamins. Medium with low alfalfa content (30 g
      alfalfa/500 ml minimal medium) had enhanced survival when supplemented with egg
      yolk protein and vitamins. Medium with high alfalfa content (130 g alfalfa/500 ml
      minimal medium) had enhanced survival when supplemented with whole egg protein
      and vitamins. Survival was also favored when media were inoculated with pure
      cultures of Acinetobacter or Acinetobacter mixed with either Pseudomonas or
      Comamonas. Individual plates could support larvae developing from up to 40 eggs,
      and survival was least variable when plates were inoculated with greater numbers
      of eggs. This rearing system shows promise as a means for conducting standardized
      bioassays on a meridic diet.

PMID- 12597650
TI  - Mitochondrial diversity in new world house flies (Diptera: Muscidae).
AB  - Mitochondrial diversity in house flies was examined by using the single-strand
      conformation polymorphism method in house flies, Musca domestica L. sampled in
      six zoogeographical subregions in the New World. The number of haplotypes and
      haplotype diversities were homogeneous among subregions, but a strong spatial
      component was found in the distribution of particular haplotypes. Nei's
      differentiation index among subregions, GRT, was 0.53 and that among populations
      within subregions, GPR, was 0.31. Greater genetic differentiation was found among
      populations in the Nearctic than in the Neotropics. Haplotype frequency
      distributions in two of three Nearctic subregions deviated from that expected
      under the neutral infinite allele model, suggesting the existence of differential
      selection patterns.

PMID- 12597651
TI  - Differences in extent of genetic introgression between sympatric Culex pipiens
      and Culex quinquefasciatus (Diptera: Culicidae) in California and South Africa.
AB  - Comparisons of five morphological characters, 12 enzyme electrophoresis profiles,
      and Wolbachia pipientis infection rates were used to characterize populations of
      members of the Culex pipiens L. complex in California and South Africa. In South
      Africa, male phallosome DV/D ratio, male maxillary palp index, branching of
      siphonal seta 1a, the enzyme locus Mdhp-1, and W. pipientis infection rates
      proved highly diagnostic for separating Culex quinquefasciatus from Cx. pipiens
      phenotypes. In Johannesburg, where sympatric members of the Cx. pipiens complex
      were analyzed as one population, a significant Wahlund Effect was observed in the
      enzyme loci such as Ao, 6-Pgdh, Mdh-2, and Pgm. In California, all populations of
      the Cx. pipiens complex were in Hardy Weinberg equilibrium at all polymorphic
      enzyme loci examined. Additionally, in California, all populations had similar W.
      pipientis infection rates and appeared morphologically identical (except for DV/D
      ratio, in extreme north and south). These findings indicate that in South Africa,
      Cx. pipiens and Cx. quinquefasciatus remain as genetically distinct populations
      and behave as separate species. Conversely, in California, there is considerable
      genetic introgression between Cx. pipiens and Cx. quinquefasciatus, and they
      behave as a single species.

PMID- 12597652
TI  - Biochemical detection of esterases in the adult female integument of
      organophosphate-resistant Boophilus microplus (Acari: Ixodidae).
AB  - Esterase activity was present in the integument of adult female Boophilus
      microplus (Canestrini) ticks that are resistant to organophosphates (OP). Three
      esterases were purified from adult integument, which hydrolyze the substrates p
      nitrophenylacetate and beta-naphthyl acetate after comparison of OP-resistant
      strain and an OP-susceptible strains. The esterases purified by ion-exchange
      chromatography were characterized using different esterase inhibitors; eserine
      sulfate, diethyl p-nitrophenyl phosphate (paraoxon), para-hydroxyl
      mercuribenzoate (pHMB), and diisopropylphosphofluoridate (DFP). All of the
      esterases had a molecular mass of 64 Kd (PAGE), but were characterized based on
      the esterase inhibitor effects as a B-esterase with beta-naphthyl acetate
      affinity, a carboxylesterase with beta-naphthyl acetate and p-nitrophenyl acetate
      affinity, and one A-Esterase (nonspecific esterase) with p-nitrophenyl acetate
      affinity. The described esterases are an important detoxification mechanism in B.
      microplus ticks at the integument. We describe also a microplate biochemical
      assay for the detection of esterase activity in the tick integument, potentially
      a useful tool to detect esterase-mediated OP resistance in B. microplus ticks.

PMID- 12597653
TI  - House-scale evaluation of bifenthrin indoor residual spraying for malaria vector
      control in India.
AB  - In an area of India where the main rural malaria vector, Anopheles culicifacies
      Giles, has developed triple resistance to DDT, HCH, and malathion sprayed indoors
      in antimalaria program, bifenthrin (10% wettable powder) was evaluated in a
      randomized house-scale trial between July 1999 and March 2000. Entomological
      impact of four serial doses of bifenthrin (25, 50, 100, and 200 mg/m2) sprayed in
      rooms in five villages was compared with malathion (2 g/m2) and unsprayed
      control. An. culicifacies was 100% susceptible to bifenthrin (0.1%), but only 57%
      to malathion (5%) test papers. Contact bioassays were carried out on sprayed
      surfaces for 24 wk, and 24 h mortality in An. culicifacies was recorded.
      Bifenthrin 100- and 200-mg doses caused > or = 80% mortality until 24 wk. The 50
      mg dose caused > or = 80% mortality on tin, wood, and mud surfaces for 24 wk, and
      on brick walls for 16 wk. Bifenthrin 25-mg dose produced > or = 80% mortality for
      24 wk on tin, 20 wk on mud walls, 16 wk on brick walls, and 8 wk on wood
      surfaces. Persistence of > or = 80% mortality did not differ for 25- and 50-mg
      doses on any surface except on wood (P < 0.05). Malathion sprayed in three rounds
      of 6 wk apart caused > or = 80% mortality for 16 wk on the brick and mud walls,
      and for 20 wk on the tin and wood surfaces. Bifenthrin 25- and 50-mg doses
      produced a similar impact on the densities of An. culicifacies and other
      mosquitoes but a superior one to malathion or control. Bifenthrin 25-mg dose
      caused least excitorepellency. Overall, efficacy of bifenthrin was superior to
      malathion. Considering the duration of the persistence of significant
      insecticidal action of bifenthrin on the most common surfaces (mud and brick
      walls), least excito-repellency and a relative impact on the mosquito densities,
      the 25-mg dose was the most superior among all the four doses evaluated.

PMID- 12597654
TI  - Development of an in vitro method for the evaluation of candidate repellents
      against Leptotrombidium (Acari: Trombiculidae) chiggers.
AB  - We developed a rapid and economical in vitro procedure with which to evaluate the
      efficacy of candidate repellents against chiggers. The procedure requires only 5
      min and a small number of chiggers to obtain a valid estimate of the median
      effective dose. We used this procedure to evaluate the repellent activity of 11
      compounds against the chigger, Leptotrombidium imphalum Vercammen-Grandjean and
      Langston. Median effective doses were determined for 10 of the 11 compounds. DM
      165-2 (N,N-diethyl-3-flurobenzamide) was the only compound that was significantly
      more effective than deet.

PMID- 12597655
TI  - Efficacy of a new self-supporting low-profile bednet for personal protection
      against Anopheles farauti (Diptera: Culicidae) in a village in Papua New Guinea.
AB  - A new United States (U.S.) self-supporting low-profile bednet was designed by
      Walter Reed Army Institute of Research in collaboration with Breakthrough
      Technologies. The bednet incorporated permethrin-impregnated screening into a
      frame that erected automatically when removed from its bag. The new U.S. bednet
      was compared with the current Australian Defense Force (ADF) mosquito bednet at
      Buka Island, North Solomons Province, Papua New Guinea, in March 1999. At the
      time of the test, Anopheles farauti Laveran was the most abundant biting
      mosquito. Both bednet types provided >97.8% protection compared with an
      unprotected collector. The untreated U.S. Army prototype bednet provided better
      protection than the untreated ADF bednet against mosquitoes entering the bednet
      during the night.

PMID- 12597656
TI  - Spatial and temporal variation in the mosquitoes (Diptera: Culicidae) inhabiting
      waste tires in Nicholas County, West Virginia.
AB  - Larvae of 12 mosquito species were collected from abandoned tire piles at
      peridomestic and forested sites in Nicholas County, WV, from March through
      November of 2001. No larvae were found in March, but the numbers of species
      increased to 10 by July and remained relatively constant, at 9-11 in any given
      month, throughout November. Larvae of Ochlerotatus triseriatus (Say), the most
      commonly encountered species in every month of collection, were significantly
      more likely to be found in forested tire pile sites. Conversely, Culex restuans
      Theobald, Anopheles punctipennis (Say), Cx. territans Walker, and Aedes
      albopictus (Skuse) larvae were significantly more likely to be found in
      peridomestic tire piles. Larvae of the remaining seven species were either found
      in equal proportions at peridomestic and woodland sites, or there were too few
      collections to make statistical inferences. Opportunities for competitive
      interactions between Ae. albopictus and Oc. triseriatus in Nicholas County would
      be minimized because the peak occurrence of the two species differ temporally and
      spatially.

PMID- 12597657
TI  - Antibacterial hemoglobin fragments from the midgut of the soft tick, Ornithodoros
      moubata (Acari: Argasidae).
AB  - Midgut contents of Ornithodoros moubata showed strong antibacterial activity
      against Staphylococcus aureus. A combination of reversed-phase chromatography and
      mass spectrometric analysis was used to isolate two antibacterial peptides from
      the tick midgut lumen. Partial amino acid sequences by Edman degradation of these
      two peptides showed they are identical with the 1-11 and 3-19 portions of rabbit
      a hemoglobin. Host rabbit a hemoglobin appears to be cleaved between Met32 and
      Phe33 to produce these two antibacterial peptides. Isolation of a host bovine
      hemoglobin fragment with antimicrobial activity has been demonstrated in the
      Ixodid tick, Boophilus microplus (Fogaca et al. 1999). Similar immune mechanisms
      in the two major families of ticks, Ixodidae and Argasidae, appear to use the
      hemoglobin of the host as an antimicrobial agent in midgut defense.

PMID- 12597658
TI  - Vector competence of Australian mosquitoes (Diptera: Culicidae) for Japanese
      encephalitis virus.
AB  - Australian mosquitoes were evaluated for their ability to become infected with
      and transmit a Torres Strait strain of Japanese encephalitis virus. Mosquitoes,
      which were obtained from either laboratory colonies and collected using Centers
      for Disease Control and Prevention light traps baited with CO2 and octenol or
      reared from larvae, were infected by feeding on a blood/sucrose solution
      containing 10(4.5 +/- 0.1) porcine stable-equine kidney (PS-EK) tissue culture
      infectious dose50/mosquito of the TS3306 virus strain. After 14 d, infection and
      transmission rates of 100% and 81%, respectively, were obtained for a southeast
      Queensland strain of Culex annulirostris Skuse, and 93% and 61%, respectively,
      for a far north Queensland strain. After 13 or more days, infection and
      transmission rates of > 90% and > or = 50%, respectively, were obtained for
      southeast Queensland strains of Culex sitiens Wiedemann and Culex
      quinquefasciatus Say, and a far north Queensland strain of Culex gelidus
      Theobald. Although infection rates were > 55%, only 17% of Ochlerotatus vigilax
      (Skuse) and no Cx. quinquefasciatus, collected from far north Queensland,
      transmitted virus. North Queensland strains of Aedes aegypti L., Ochlerotatus
      kochi (Donitz), and Verrallina funerea (Theobald) were relatively refractory to
      infection. Vertical transmission was not detected among 673 F1 progeny of Oc.
      vigilax. Results of the current vector competence study, coupled with high field
      isolation rates, host feeding patterns and widespread distribution, confirm the
      status of Cx. annulirostris as the major vector of Japanese encephalitis virus in
      northern Australia. The relative roles of other species in potential Japanese
      encephalitis virus transmission cycles in northern Australia are discussed.

PMID- 12597659
TI  - Lyme disease spirochete, Borrelia burgdorferi endemic at epicenter in Rondeau
      Provincial Park, Ontario.
AB  - The Lyme disease spirochete, Borrelia burgdorferi Johnson, Schmidt, Hyde,
      Steigerwalt, and Brenner was discovered in blacklegged ticks, Ixodes scapularis
      Say at Rondeau Provincial Park, Ontario, Canada During this 2-yr study,
      spirochetes were found in B. burgdorferi-positive I. scapularis larvae attached
      to B. burgdorferi-infected white-footed mice, Peromyscus leucopus Rafinesque.
      Isolates of B. burgdorferi were cultured from blacklegged tick adults, and
      confirmed positive with polymerase chain reaction by targeting OspA and rrf (5S)
      rrl (23S) genes. These findings show an endemic area for B. burgdorferi within an
      established population of L. scapularis at Rondeau Provincial Park.

PMID- 12597660
TI  - Wicking assays for the rapid detection of West Nile and St. Louis encephalitis
      viral antigens in mosquitoes (Diptera: Culicidae).
AB  - The recent outbreaks of West Nile (WN) encephalitis and St. Louis encephalitis
      (SLE) in the United States have highlighted the need for rapid and specific
      methods of detecting arboviral antigens in mosquitoes. We evaluated rapid, field
      usable assays for detecting and differentiating WN and SLE viruses in mosquito
      pools, based on a patent-pending, immunochromatographic technology (VecTest)
      formatted on a dipstick. The device provides results in less than 20 min and can
      be used in laboratories with adequate containment facilities. In laboratory
      assessments, both the SLE and WN virus tests demonstrated sensitivity comparable
      with that of an antigen capture ELISA, but less than can be achieved with Vero
      cell plaque or reverse-transcriptase polymerase chain reaction assays. There was
      no evidence of cross-reaction when tested with high concentrations of
      heterologous flavivirus antigens or with Eastern equine encephalitis or Western
      equine encephalitis viruses. Both the WN and SLE dipstick tests delivered a clear
      positive result with a single positive specimen in a pool of 50 mosquitoes. This
      virus assay technology reduces the time required to obtain test results and will
      allow rapid medical threat assessment and effective targeting of vector control
      measures.

PMID- 12597661
TI  - Detection of Borrelia lonestari in Amblyomma americanum (Acari: Ixodidae) from
      Tennessee.
AB  - Genetic sequences characteristic of Borrelia lonestari (Barbour et al. 1996) were
      detected in two pools of adult Amblyomma americanum (L.) from Tennessee,
      corresponding to an estimated minimum field infection rate of 8.4 infected
      ticks/1000 adults. DNA amplification was conducted using primers derived from the
      B. lonestari flagellin gene that would also amplify Borrelia burgdorferi
      (Johnson, Schmid, Hyde, Steigerwalt, and Brenner). Species-specific, internal
      probes were then used to differentiate between genetic sequences of the
      spirochetes. Subsequent nucleotide sequencing confirmed the presence of B.
      lonestari in A. americanum; B. burgdorferi was not detected. This represents the
      first report of B. lonestari from Tennessee, and suggests that Lyme-like illness
      may occur in Tennessee.

PMID- 12597662
TI  - Host associations and seasonal occurrence of Haemaphysalis leporispalustris,
      Ixodes brunneus, I. cookei, I. dentatus, and I. texanus (Acari: Ixodidae) in
      Southeastern Missouri.
AB  - Hemaphysalis leporispalustris (Packard), Ixodes brunneus Koch, Ixodes cookei
      Packard, Ixodes dentatus Marx, and Ixodes texanus Banks were collected during a 3
      yr study of pathogen-tick-host interactions in southeastern Missouri. H.
      leporispalustris was collected from the eastern cottontail rabbit, Northern
      bobwhite, and Carolina wren, and it was active all year. I. brunneus was
      collected by drag and from passerine birds during December, March, and April. I.
      cookei was collected from raccoons and mink during April, June, September,
      October, and November. I. dentatus was collected from the cottontail rabbit and
      Carolina wren throughout the year. I. texanus was collected from the eastern gray
      squirrel, Virginia opossum, and raccoon throughout the year.

PMID- 12597663
TI  - Occurrence of Dermacentor variabilis (Acari: Ixodidae) around a porcupine
      (Rodentia: Erthethizontidae) carcass at Camp Ripley, Minnesota.
AB  - In May 2000, a dead porcupine (Erethizon dorsatum Culiver) was found on an
      infrequently traveled dirt road at Camp Ripley, MN. The presence of late instar
      Calliphoridae suggested that the porcupine died within the past 4 to 7 d. Adult
      carrion (Silphidae) and rove (Staphylinidae) beetles were observed under the
      carcass. In June, a large number of adult American dog ticks, Dermacentor
      variabilis (Say), were observed questing on the porcupine and the surrounding
      grass. Six zones were established around the carcass, and each zone was sampled
      for ticks once a month from June through September. Ticks were captured in June
      and July, and 93% were captured within 2 m of the carcass. Gases released as part
      of the decomposition process were believed to attract the ticks to the carcass.

PMID- 12597664
TI  - Species-specific primer for identification of Anopheles quadriannulatus sp. B
      (Diptera: Culicidae) from Ethiopia using a multiplex polymerase chain reaction
      assay.
AB  - Anopheles quadriannulatus Theobald historically has been reported from southern
      Africa, Zanzibar islands, and Ethiopia. However, based on evidences of genetic
      incompatibility between crosses of South African and Ethiopian populations, the
      population from Ethiopia was recently reported as a distinct species designated
      as An. quadriannulatus sp. B. An. quadriannulatus sp. A, denoted the southern
      African population. To distinguish the two populations, the IGS (intergenic
      spacer) region of rDNA was sequenced to design a primer specific for An.
      quadriannulatus sp. B. A cocktail polymerase chain reaction (PCR) involving
      Anopheles gambiae Giles universal (UN) primer, the new primer and other primers
      specific for members of the An. gambiae complex produced the expected diagnostic
      products for the respective species. Using extracted DNA and crushed body parts
      as sources of template DNA, this assay was reliably used to identify samples of
      An. quadriannulatus sp. B.

PMID- 12597666
TI  - The taiga tick Ixodes persulcatus (Acari: Ixodidae) in the Sakha Republic
      (Yakutia) of Russia: distributional and reproductive ranges.
AB  - The finding of an unfed adult female of the taiga tick Ixodes persulcatus Schulze
      is reported from the northern part of Eastern Siberia (the central part of the
      Sakha Republic [former Yakutia]) of Russia. This finding supplements other
      reported single findings of the taiga tick in different sites of the central part
      of the Sakha Republic, thus increasing its distributional range. The reproductive
      range of the taiga tick is limited to two separate areas in the southern parts of
      the Republic. The most probable mode of tick introduction northwards from the
      border of the reproductive range is by spring bird migrations from their
      wintering areas to breeding sites. The possibility of the establishment of stable
      tick populations in the areas of introduction is also considered.

PMID- 12597665
TI  - New records and laboratory-rearing data for Ixodes schulzei (Acari: Ixodidae) in
      Brazil.
AB  - Ixodes schulzei Aragao and Fonseca was described from Brazil in 1951 based on
      female ticks collected on wild rats from the states of Rio de Janeiro and Santa
      Catarina. Since that time, there have been no additional reports of I. schulzei
      in the literature. We report two new records of I. schulzei: a female collected
      on the water rat Nectomys squamipes (Brants) from Minas Gerais State, and another
      female from this same host species from Sao Paulo State. This last specimen was
      engorged and oviposited fertile eggs in the laboratory. Larvae hatched from these
      eggs were used for subsequent infestations under laboratory conditions, as were
      nymphs obtained from the engorged larvae. Naive laboratory rats (Rattus
      norvegicus Berkenhout) and wild mice (Calomys callosus Rengger) were used to feed
      ticks. C. callosus was a more suitable host than R. norvegicus, as significantly
      more ticks (P < 0.05) were recovered and successfully molted after feeding on the
      former host species. A significantly (P < 0.05) greater proportion of larvae
      detached from C. callosus during daylight (71.3%) when compared with those that
      detached from R. norvegicus in the same period (54.8%). A total of nine engorged
      nymphs (one from R. norvegicus, and eight from C. callosus) were recovered in the
      infestations. All of them successfully molted to adults, which were all females.
      The male of I. schulzei remains unknown.

PMID- 12597667
TI  - Support families through life's greatest transitions.

PMID- 12597668
TI  - The integration of family health, culture, and nursing: prescriptions and
      practices.

PMID- 12597669
TI  - Successful aging families--a challenge for nurses.
AB  - This nation's view of older-adult families and their care needs reform. Changing
      trends in the longevity of our population will mean changes in family structures
      and relationships. This article examines lessons from studies of successful aging
      to illuminate strategies that may promote successful later-life families. The
      focus is on changes that nurses can make with older-adult families in dispelling
      aging stereotypes, increasing the numbers of nurses educated and specializing in
      the care of older adults, changing the educational approach for new nurses, and
      calling for social policy changes.

PMID- 12597670
TI  - Creating family: a holistic milieu at a geriatric adult day center.
AB  - Many older persons no longer have traditional "family members" to rely on and
      live isolated lives, with little or no contact with either family or community.
      In response to this profound need for family among isolated older adults, the
      Geriatric Adult Day Health Center at The Jewish Home and Hospital in the Bronx,
      New York, created a holistic milieu that involves clients in their care and
      facilitates healing and growth in mind, body, and spirit. The positive experience
      of the group, as members participate in the holistic modalities, strengthens and
      validates each individual. The holistic modalities used in this care model foster
      a sense of family and community that serves as structure and support for healing,
      in an atmosphere of self-responsibility.

PMID- 12597671
TI  - Metaphors, letters, and stories: narrative strategies for family healing.
AB  - This article introduces the reader to the use of narrative strategies in a
      holistic approach to family nursing. It presents congruence with holistic nursing
      practice, narrative theory base, and key elements of narrative therapy. Emphasis
      is on creative adaptation and integration of narrative strategies in a variety of
      clinical situations to promote family healing. Many suggestions for practice and
      some resources for further learning are given.

PMID- 12597672
TI  - Jamaican families.
AB  - The study of the family in the Caribbean originated with European scholars who
      assumed the universality of the patriarchal nuclear family and the primacy of
      this structure to the healthy functioning of society. Matrifocal Caribbean
      families thus were seen as chaotic and disorganized and inadequate to perform the
      essential tasks of the social system. This article provides a more current
      discussion of the Jamaican family. It argues that its structure is the result of
      the agency and adaptation of its members and not the root cause of the increasing
      marginalization of peoples in the developing world. The article focuses on
      families living in poverty and how the family structure supports essential family
      functions, adaptations, and survival.

PMID- 12597673
TI  - Adolescent girls, single-parent fathers, and menarche.
AB  - When adolescent girls reach menarche, they often seek information about
      menstruation from their mothers. More adolescent girls are being raised in single
      father families today and have limited or no contact with their mothers. Thirteen
      adolescent females, who lived with their fathers as the primary caretaker,
      described their menarcheal experience. The participants, who had close
      relationships with their fathers, found it embarrassing to discuss menstruation
      with any male, including their father. They believed their fathers lacked
      credibility regarding menstrual issues, and they experienced an emotional and
      physical distancing from their fathers. Nurses must be aware of the needs of
      single-parent father families, especially menstrual information for both girls
      and their fathers.

PMID- 12597674
TI  - Effects of progressive muscle relaxation on blood pressure and psychosocial
      status for clients with essential hypertension in Taiwan.
AB  - This study examined the effect of progressive muscle relaxation (PMR) on blood
      pressure and psychosocial status in clients with essential hypertension. The
      study, which used a quasi-experimental design, recruited a convenience sample of
      40 subjects from a hypertension outpatient clinic. Twenty subjects received PMR
      training once a week and practiced at home daily for 4 weeks. PMR training had an
      immediate effect, reducing pulse rate 2.35 beats/min, systolic blood pressure
      5.44 mm Hg, and diastolic blood pressure 3.48 mm Hg. After 4 weeks of PMR
      training, further decreases in pulse rate (2.9 beats/min), systolic blood
      pressure (5.1 mm Hg), and diastolic blood pressure (3.1 mm Hg) occurred. PMR
      significantly lowered patients' perception of stress, and it enhanced their
      perception of health. PMR is beneficial for patients with essential hypertension,
      and nurses may use it to enhance their independent function as well as their
      quality of life.

PMID- 12597675
TI  - Spirituality in caregiving and care receiving.
AB  - Spirituality is a part of holistic care for clients and families. This
      qualitative, descriptive study examined spirituality in 60 caregivers and 60 care
      receivers, equally divided between Caucasians and African Americans. Themes were
      coping (subthemes of formal religion and social support) and meaning (subthemes
      of positive attitude, retribution or reward, and all encompassing). Needs of
      caregivers and care receivers include opportunities for formal religion
      (communion, prayer), social support (visiting, respite), and interactions to
      assist them find meaning in their caregiving and care receiving. Implications for
      nurses include collaborating with clergy to support the spiritual needs of
      caregivers and care receivers.

PMID- 12597676
TI  - An integrative approach to eczema (atopic dermatitis).
AB  - This article provides an integrative treatment protocol for eczema (atopic
      dermatitis) using natural therapies. The protocol addresses several primary
      causative factors such as essential fatty acid deficiency and food allergies. In
      addition, it identifies a patented chamomile preparation proven in clinical
      studies to be as effective as hydrocortisone in relieving associated symptoms of
      itching and inflammation while enhancing granulation and epithelialization
      without deleterious side effects associated with long-term use of corticosteroid
      therapy.

PMID- 12597677
TI  - Impact of nasal airway obstruction on dentofacial development and sleep
      disturbances in children: preliminary notes.
AB  - Respiratory disorders in the upper respiratory tract during sleep are most often
      part of a continuous pathological process of long standing. Schematically, three
      clinical syndromes with increasing severity are described: breathing with the
      mouth open, snoring and sleep apneal hypopnea syndrome. Obstructive sleep apnea
      syndrome (OSAS) is a subtle, but severe sleep disorder of early childhood. It is
      often difficult to detect and may have long-term consequences, including failure
      to thrive, behavioral disturbances, developmental delay, and cor pulmonale. These
      conditions always include a functional maxillofacial perturbation, which may be
      associated with a constitutional or acquired morphological disorder. Pediatric
      dentists must be aware of the problems connected with mouth breathing and OSAS
      (obstructive sleep apnea syndrome) in children as any delay in diagnosis and
      treatment may cause prolonged morbidity. They also have a role in the diagnosis
      and co-management of these patients because the signs and symptoms may be
      recognizable in the dental practice. Besides the medical approach itself, the
      treatment sometimes is surgical, always orthopedic: the earlier it is initiated,
      the more effective, simple and unrestraining it is. The aim of this work is to
      focus attention on the early diagnosis and prevention of these pathologies.
      Diagnostic guidelines will be illustrated.

PMID- 12597678
TI  - Occlusal guidance for eruption disturbance of mandibular second premolar: a
      report of three cases.
AB  - This study presents the treatment courses in three impacted cases of mandibular
      second premolars caused by distal inclination of the tooth germs. In all cases,
      the second premolars were surgically exposed, but the traction periods until oral
      emergence differed. The reasons for the differences may be the variation in the
      severity of the distal inclinations of the tooth germs and the calcified
      development of the affected germs at fenestration.

PMID- 12597679
TI  - Use of acellular dermal matrix graft in the treatment of gingival recessions: a
      case report.
AB  - Case presentation in which a 12-years-old boy presented with two large gingival
      recessions on the maxillary central incisors, secondary to a lateral luxation. In
      the surgical procedure, an acellular dermal matrix graft (ADMG) was placed as a
      substitute for a free gingival graft. Twelve months later, complete root coverage
      was achieved, showing that ADMG, a biomaterial recently developed for
      mucogingival surgery, can be successfully used in the treatment of gingival
      recessions in pediatric patients.

PMID- 12597680
TI  - Human enamel veneer restoration in a deciduous tooth: clinical case.
AB  - Trauma to deciduous anterior teeth, frequently occur in children, and the
      treatment is a big challenge for the pediatric dentistry. In these cases, besides
      the pain and discomfort provoked by the injury, both child and parents/persons
      responsible were eager to reconstruct the damage, as soon as possible. In modern
      operative restorative dentistry, no restorative material is able to substitute
      for the human dental enamel in quality, color and resistance. The aim of this
      paper is to relate the treatment of esthetic veneer (facet) of human dental
      enamel in a three-year-old child after trauma that caused concussion and
      accentuated color alteration. Clinical results showed an efficient esthetical
      resolution, revealing it to be a good alternative for treatment of traumatized
      anterior deciduous teeth.

PMID- 12597681
TI  - Three-dimensional evaluation of a rare case with multiple impacted teeth using
      CT.
AB  - A 15-year-old patient is presented with 11 impacted teeth including 2
      supernumerary teeth, who did not exhibit hereditary or clinical disease. The
      patient showed the extruded and lingually inclined lower incisors, the anteriorly
      inclined palatal plane, extremely large curve of Spee, and crowding in the bone.
      A detailed description of the positional relationship between each impacted tooth
      and the neighboring tooth was given using the 3D CT-image.

PMID- 12597682
TI  - Cyclosporin-induced gingival overgrowth in a child treated with CO2 laser
      surgery: a case report.
AB  - A case of a 10 year-old boy with gingival overgrowth due to cyclosporin therapy
      after heart transplantation is described. Different treatment approaches are
      discussed and the surgical effect of CO2 laser is illustrated. The critical role
      of routine professional cleaning and good oral health maintenance for the healthy
      status of the gingival tissue is also emphasized in this paper. Replacement of
      cyclosporin by tacrolimus, another immunosuppressive agent associated with
      minimal to none gingival overgrowth, might be considered in cases with reported
      recurrences.

PMID- 12597683
TI  - Combined aplasia of maxillary first molars and lateral incisors: a case report
      and management.
AB  - Congenital absence of teeth, as the most commonly known developmental dental
      anomaly in man, has a multitude of adverse affects that could be detrimental to
      normal function and esthetics. This report presents a rare case of combined
      agenecies of maxillary permanent first molars and lateral incisors. The
      management plans are highlighted, and phase I orthodontic-restorative treatment
      mechanics and its result are described. The benefits for early orthodontic
      treatment intervention for this case presented here are discussed.

PMID- 12597684
TI  - Management of severe partial hypodontia: case report.
AB  - Hypodontia is characterized by partial or total congenital missing of one or more
      teeth, on one or both dentitions. Heredity is the main etiological factor and the
      principal clinical features are reduction on number, size and form of teeth, and
      late eruption. Removable partial prosthesis, fixed prosthesis, overdentures and
      adhesive prosthesis are alternative treatments; and the indication is type
      dependent. The aim of this study was to describe the clinical case of an eleven
      year-old child with eight missing permanent teeth of idiopathic etiology. The
      patient had facial and skeletal symmetry, normal development and was not related
      to any syndrome. Clinical characteristics: permanent teeth with good periodontal
      conditions (16, 12, 11, 21, 22, 26, 36, 31, 42, 46), primary teeth (53, 63, 64,
      73, 83); overbite and microdontia on teeth 12 and 22. The treatment plan was done
      initially by documenting of the case for teeth analysis (study casting models,
      periapicals and panoramic x-rays, and photographs), and followed by the
      exodontics of teeth 73 and 83. A removable appliance in autocured acrylic resin,
      using teeth in acrylic for maintenance of functional space and occlusion was
      planned and carried out. An anterior track for vertical dimension gain was used
      because of his accentuated overbite. The patient will be monitored until the end
      of the craniofacial growth, when it will be again evaluated and forwarded for the
      final oral rehabilitation. Hypodontia diagnosis and management should be
      performed as early as possible not to interfere with the craniofacial development
      of the child.

PMID- 12597685
TI  - A study of growth changes in the mandible from deciduous to permanent dentition.
AB  - This cross-sectional study investigated mandibular developmental changes in
      untreated normal Taiwanese from the deciduous to permanent dentition. Differences
      in the mean values for ramus height and body length between males and females
      were statistically significant after eruption of the permanent second molars. SNB
      angles significantly increased and gonial and L1-MP angles significantly
      decreased from deciduous to permanent dentition in both sexes. The SN-MP angle in
      females significantly decreased and ramus inclination in males significantly
      increased from the early mixed to permanent dentition.

PMID- 12597686
TI  - An in vitro study of the correlation between clinical and radiographic
      examinations of proximal carious lesions in primary molars.
AB  - The present in vitro study assessed the correlation between clinical and
      interproximal radiographic examinations in diagnosing proximal caries of primary
      molars. A total of 223 mesial and distal surfaces, from 125 primary teeth, were
      evaluated clinically and radiographically. The results demonstrated a strong
      correlation between the increase of depth of radiolucency in radiographic
      examination and the clinical stage of lesions The interproximal radiographic
      examination presented an excellent capability for discriminating surfaces with
      and without cavities in primary molars.

PMID- 12597687
TI  - The developmental stages of the middle phalanx of the third finger (MP3): a sole
      indicator in assessing the skeletal maturity?
AB  - Assessment of skeletal maturity is an integral part of interceptive diagnosis and
      treatment planning. The present day methods of skeletal maturity assessment like
      the hand-wrist radiographs or cervical vertebrae radiographs are expensive,
      require elaborate equipment and accounts for high radiation exposure, especially
      for growing children. The present study was thus undertaken to provide a simple
      and practical method of skeletal maturity assessment using the developmental
      stages of the middle phalanx of the third finger (MP3) as seen on an IOPA film
      taken using a standard dental x-ray machine. The results of the study showed that
      this simple method was highly reliable and could be used as an alternative method
      to assess the skeletal maturity of growing children.

PMID- 12597688
TI  - A SEM investigation of accessory foramina in the furcation areas of primary
      molars.
AB  - The purpose of this study was to determine the prevalence and anatomic
      characteristics of accessory foramina in the external and internal furcation
      areas of primary molars. Sixty human primary molars were divided into two equal
      groups. The teeth of the experimental group showed in previous radiographic
      examination the presence of a radiolucency area confined to the inter-radicular
      region, while the teeth of the control group had no sign of pulpal inflammation
      in the clinical and/or radiographic examination. The specimens were observed by
      scanning electron microscope (SEM). The external furcation area (EFA) showed a
      higher prevalence of accessory foramina than the internal furcation area (IFA)
      (P<0.05). However, the comparison between the two groups did not show
      statistically significant difference (P>0.05). The presence of accessory canals
      should not be considered the only reason for inter-radicular pathological bone
      resorption following pulpal necrosis in deciduous molars.

PMID- 12597689
TI  - Prevalence of gingival stippling in children.
AB  - Gingival stippling is a characteristic of the healthy attached gingiva and its
      diminution or loss has been considered as a sign of gingival disease. The
      clinician however, must take in consideration that its pattern and extent varies
      in different mouth areas, among persons and with age. Reports on the prevalence
      of stippling in children are few and inconsistent. Therefore, the purpose of the
      present study was to describe the prevalence of gingival stippling in children of
      various ages. Fifty-five high quality anterior oral color slides of children (25
      girls and 30 boys) aged 1 to 10 years, were examined for the presence of
      stippling. The average age of the study population was 5.1 years (S. E. = 0.3).
      The overall prevalence of stippling was 56.4%. Analysis of the differences
      between boys and girls in age (t-test) or the prevalence of stippling (Chi
      square) did not indicate statistical significance (p>0.05). Stippling was evident
      from 3 years of age and thereafter, with no particular trend of change with age.
      Stippling was found in 47.2% of the maxillary areas, in 41.7% of the mandibular
      areas and in 26.1% in both arches of the same child. The differences in
      distribution of stippling by gender and arch were not statistically significant
      (Chi square, p>0.05). In conclusion, gingival stippling was found to be a normal
      characteristic in 56.3% of 3 to 10-year-old children, without significant
      differences in prevalence related to arch, gender or age.

PMID- 12597690
TI  - Macroglossia combined with lymphangioma: a case report.
AB  - A four year old white female with a clinical presentation of macroglossia is
      described. Speech disturbances and occasional episodes of traumatic injury to the
      tongue with severe bleeding brought the patient to seek dental care. Lymphangioma
      was diagnosed after incisional biopsy. The differential diagnosis of tongue
      enlargement in children is discussed including review of the literature relevant
      to the diagnosis and treatment of lymphangioma.

PMID- 12597691
TI  - Amelogenesis imperfecta and nephrocalcinosis: a new case of this rare syndrome.
AB  - This article describes a new case of a rare syndrome including enamel agenesis of
      the primary and permanent dentition, delayed or absent eruption of the permanent
      dentition, coronal intra-alveolar resorption and gingival enlargement. Renal
      symptoms include medullary nephrocalcinosis without any apparent cause, and
      evolution to a renal failure. The early diagnosis provided by the oral symptoms
      leads to a better renal prognosis. As a consequence, pediatric dentists should be
      aware of this pathology.

PMID- 12597692
TI  - Tourette's syndrome with rapid deterioration by self-mutilation of the upper lip.
AB  - A case of Tourette's syndrome is presented in a thirteen-year-old boy with
      obsessive-compulsive symptoms including self-mutilation of the upper lip. His
      upper lip injury was caused by complication of picking with fingernail, and self
      biting with the lower anterior teeth. It became rapidly worse and the median part
      of the upper lip collapsed. But the placement of an acrylic splint was able to
      prevent further damage of the upper lip.

PMID- 12597693
TI  - Outcomes of dental procedures performed on children under general anesthesia.
AB  - The purpose of this study was to evaluate the integrity and longevity of
      restorative and pulpal procedures performed on primary teeth under general
      anesthesia (GA). Fifty-four children, who received comprehensive dental treatment
      under general anesthesia between 1993 and 1995, were included. The postoperative
      examination period ranged from 6 to 27 months. Children were examined and the
      quality of the restorations were recorded and evaluated. Behavior problems and
      inability to cooperate were the main reasons for treatment under GA. Results
      showed that restoration of posterior teeth with stainless steel crowns (SSC) were
      more successful (95.5%) when compared to amalgam or composite restorations (50%).
      In the anterior teeth, strip crowns had a success rate similar to that of Class
      III, IV and V composite resin materials. Pulpotomies showed an extremely high
      rate of success (97.1%), while sealants were retained 68.3% of the time. In
      conclusion, SSC are more likely to be successful and last longer than
      multisurface amalgam or composite restorations in children treated under general
      anesthesia. Definitive treatment is more likely to ensure a more positive outcome
      for children treated under general anesthesia due to less frequent complications
      from failed restorations or pulpal procedures.

PMID- 12597694
TI  - Birth weight and gestational age of newborns with cleft lip with or without cleft
      palate and with isolated cleft palate.
AB  - The birth weight and gestational age of 1368 newborns with isolated cleft lip
      with or without cleft palate and 582 with isolated cleft palate were compared to
      those of matched healthy controls. The results indicate that fetuses with oral
      clefts are at elevated risk of having low and very low birth weight, but not of
      having a premature birth. Speculations on a relationship between these findings
      and the presence of oral clefts are presented.

PMID- 12597695
TI  - Are American children's problems still getting worse? A 23-year comparison.
AB  - Child Behavior Checklists were completed in home interviews by parents of 7-16
      year-olds in 1976, 1989, and 1999. Competence scores decreased from 1976 to 1989,
      but increased in 1999. Problem scores increased from 1976 to 1989 and decreased
      in 1999 but remained higher than in 1976. Items, empirically based scales, and
      DSM-oriented scales showed similar patterns for demographically similar
      nonreferred samples assessed in 1976, 1989, and 1999 and for national samples
      that included referred children assessed in 1989 and 1999. For the 114 problem
      items that were common to the 1976, 1989, and 1999 assessments, the Q correlation
      was .98 between the mean scores on the 114 items in 1976 versus 1989 and was .94
      between the mean scores on the 114 items in 1976 vs. 1999. This indicated very
      high stability in the rank ordering of item scores across intervals up to 23
      years. For all children, the 1-year prevalence rate for mental health services
      use was 13.2% in 1989 versus 12.8% in 1999. For children with deviant Total
      Problems scores, the 1989 prevalence for service use was 30.5 versus 26.6% in
      1999. Neither difference was statistically significant.

PMID- 12597696
TI  - Are discrepancies among child, mother, and father reports on children's behavior
      related to parents' psychological symptoms and aspects of parent-child
      relationships?
AB  - Examined whether parents' symptoms and qualitative and quantitative aspects of
      parent-child relationships make unique contributions to mothers' and fathers'
      reports of, and mother-child, father-child, and father-mother discrepancies on,
      children's behavior. Participants were 100 children, aged 10-12, and their
      mothers and fathers. Parents' symptoms and parent-child relationships made unique
      contributions to both parents' ratings of externalizing behavior. Although parent
      child relationship variables were related to both parents' ratings of
      internalizing behavior, only parents' symptoms made unique contributions. On
      mother-child and father-child discrepancies, differences emerged between mother
      and father, and internalizing and externalizing behaviors. Both fathers' and
      mothers' symptoms contributed to father-mother discrepancies on both behavior
      types, with parent-child relationships contributing unique variance to
      discrepancies on internalizing behavior. Results highlight the importance of each
      informant's symptoms and relationship variables in understanding informant
      discrepancies.

PMID- 12597697
TI  - Discriminative validity of the general behavior inventory using youth report.
AB  - The present study investigated the ability of the General Behavior Inventory
      (GBI) to discriminate between diagnostic groups using youth self-report. One
      hundred and ninety-seven youths ages 10-17 years presenting at a midwestern urban
      outpatient clinic specializing in mood disorders completed the GBI as part of the
      intake process. Diagnoses were determined by a structured clinical interview (K
      SADS) administered by either a child and adolescent psychiatrist or a research
      assistant trained to a high level of interrater reliability (kappa > .85). Games
      Howell post hoc tests showed that the diagnostic groups significantly differed on
      the GBI's 2 subscales, Depression and Hypomanic-Biphasic. Logistic regression
      demonstrated that the scales discriminated between bipolar and disruptive
      behavior disorders, unipolar and bipolar depression, and mood and disruptive
      behavior disorders or no diagnosis. Receiver Operating Characteristic (ROC)
      curves further indicated the good diagnostic efficiency of the scales. Results
      indicate that the GBI's subscales might aid in making traditionally difficult
      differential diagnoses, such as between bipolar disorder and Attention Deficit
      Hyperactivity Disorder (ADHD) and between unipolar and bipolar depression.

PMID- 12597698
TI  - Demographic characteristics, social competence, and behavior problems in children
      with gender identity disorder: a cross-national, cross-clinic comparative
      analysis.
AB  - This study examined demographic characteristics, social competence, and behavior
      problems in clinic-referred children with gender identity problems in Toronto,
      Canada (N = 358), and Utrecht, The Netherlands (N = 130). The Toronto sample was,
      on average, about a year younger than the Utrecht sample at referral, had a
      higher percentage of boys, had a higher mean IQ, and was less likely to be living
      with both parents. On the Child Behavior Checklist (CBCL), both groups showed, on
      average, clinical range scores in both social competence and behavior problems. A
      CBCL-derived measure of poor peer relations showed that boys in both clinics had
      worse ratings than did the girls. A multiple regression analysis showed that poor
      peer relations were the strongest predictor of behavior problems in both samples.
      This study-the first cross-national, cross-clinic comparative analysis of
      children with gender identity disorder-found far more similarities than
      differences in both social competence and behavior problems. The most salient
      demographic difference was age at referral. Cross-national differences in factors
      that might influence referral patterns are discussed.

PMID- 12597699
TI  - Understanding adolescent worry: the application of a cognitive model.
AB  - The relationship between worry and 4 cognitive variables, intolerance of
      uncertainty, positive beliefs about worry, negative problem orientation, and
      cognitive avoidance, was examined in an adolescent sample of 528 boys and girls
      aged 14-18. The participants completed questionnaires assessing worry, somatic
      anxiety symptoms, and the variables mentioned above. The results show that (a)
      intolerance of uncertainty, positive beliefs about worry, and negative problem
      orientation each account for a significant amount of variance in adolescent worry
      scores in the multiple regression, and (b) the discriminant function derived from
      the 4 variables is effective in classifying moderate and high worriers into their
      respective groups (72.8% correct classification). Furthermore, analyses
      demonstrate that intolerance of uncertainty has the strongest association with
      worry scores and is the most important variable in discriminating between
      moderate and high adolescent worriers. These results suggest that intolerance of
      uncertainty plays a key role in our understanding of adolescent worry.

PMID- 12597700
TI  - Children's verbalizations and cheating behavior during game playing: the role of
      sociometric status, aggression, and gender.
AB  - The first goal of this study was to investigate sociometric status, aggression,
      and gender differences in children's verbalizations and cheating behavior during
      game playing using a fine-grained observational coding system. The second goal
      was to control for the effects of differential peer treatment and bias on
      children's behavior by observing children in a standardized procedure with
      unfamiliar peer confederates. Participants were 111 second-grade African American
      children, half average and half rejected sociometric status, half aggressive and
      half nonaggressive based on peer nominations, and half boys and half girls.
      Rejected children engaged in more cheating behavior and made more negative and
      argumentative verbalizations than average status children. Boys made more
      negative and argumentative verbalizations than girls. Aggressive children did not
      differ from nonaggressive children, in terms of either verbalizations or cheating
      behavior.

PMID- 12597701
TI  - Emotional competence and aggressive behavior in school-age children.
AB  - Examined emotional competence in 87 children, aged 7-10 years, who varied with
      respect to reports of aggressive behavior to determine whether individual
      differences in emotional competence characterize children with higher levels of
      aggressive behavior. Emotional competence was assessed during a 1-hr lab visit
      that included (a) an observational period consisting of a modified disappointment
      paradigm, (b) assessment of cognitive and language abilities, and (c) 2
      structured emotion interviews. Children with higher levels of aggressive behavior
      exhibited more intense and frequent expressions of anger, both as reported by
      mothers and as observed during the disappointment paradigm. Less sophisticated
      ability to identify the causes of emotion also characterized children with higher
      levels of aggressive behavior. Gender moderated the relation between aggressive
      behavior and type of emotion identified such that reports of happiness (in
      response to receiving a disappointing prize) were associated with lower levels of
      reported aggressive behavior for boys. The value of assessing children's
      emotional competence in the context of an emotionally arousing situation is
      suggested by these findings.

PMID- 12597702
TI  - On-line story representation in boys with attention deficit hyperactivity
      disorder.
AB  - Children with attention deficit hyperactivity disorder (ADHD) face an increased
      risk of poor achievement in school. Thus, knowledge of the cognitive processing
      abilities of children with ADHD is critical to understanding and improving their
      academic performance. Although many studies have focused on the specific nature
      of the attention deficit experienced by children with ADHD, few have examined
      higher order cognitive processing such as comprehension of stories. The present
      study examined the processes of encoding story information, building a story
      representation, and modifying a story representation in boys with ADHD and
      nonreferred boys. Boys were asked to narrate a story from a picture book twice.
      Boys with ADHD showed deficits in representing goals and goal plans in their
      narrations, as compared to nonreferred boys. Boys with ADHD also committed more
      errors than nonreferred boys, but did correct certain types of errors on their
      second telling. Implications are discussed in terms of future research needed to
      identify the cognitive deficits that account for these narrative deficits.

PMID- 12597704
TI  - The effect of chlorhexidine gluconate as an endodontic irrigant on the apical
      seal: long-term results.
AB  - The purpose of this study was to determine whether chlorhexidine gluconate
      (0.12%), used as an endodontic irrigating solution, would affect the apical seal
      of three root canal cements. One hundred, extracted, human, single-canal teeth
      were divided into 9 experimental groups of 10 teeth each, in addition to a
      positive and negative control group of 5 teeth each. The teeth were decoronated
      at the level of the CEJ, accessed, instrumented to a Master apical file #50,
      irrigated with either sterile saline, 5.25% NaOCl, or 0.12% chlorhexidine
      gluconate, and dried using paper points. Obturation was accomplished using
      lateral condensation and one of three endodontic sealers: Roth's 811, AH 26, or
      Sealapex. Postobturation apical leakage was measured at 270- and 360-day
      observation periods using the fluid filtration method. Using the mixed-model
      repeated-measures ANOVA test with Tukey's honest significance difference multiple
      comparison procedure, the results showed the saline-Sealapex combination had
      significantly more leakage (p < 0.05) than either the Peridex-Sealapex or saline
      Roth's combinations at 270 days. No other significant differences were noted
      between any sealer-irrigant combination at 270 days. The saline-Sealapex
      combination had significantly more leakage than the saline-Roth's combination at
      360 days. No other significant differences were noted at 360 days. Under the
      conditions of this study, chlorhexidine gluconate irrigant did not adversely
      affect the apical seal of three root canal cements at 270 and 360 days.

PMID- 12597703
TI  - The effect of methylphenidate on three forms of response inhibition in boys with
      AD/HD.
AB  - The current study was aimed at (a) investigating the effect of three doses
      methylphenidate (MPH) and placebo on inhibition of a prepotent response,
      inhibition of an ongoing response, and interference control in Attention
      Deficit/Hyperactivity Disorder (AD/HD), and (b) studying dose-response relations
      for the three forms of response inhibition. To meet these aims, the following
      tasks were selected: two versions of the Stop Paradigm for inhibition of a
      prepotent response, a Circle Tracing Task and a recently developed Follow Task
      for inhibition of an ongoing response, and the Stroop Color-Word Test and an
      Eriksen Flanker Task for interference control. These tasks were administered to
      23 boys with AD/HD during four treatment conditions: 5 mg MPH, 10 mg MPH, 20 mg
      MPH, and placebo. A pseudorandomized, multiple-blind, placebo-controlled, within
      subject design was used. As hypothesized, inhibitory control in children with
      AD/HD improved under MPH compared to placebo. However, this effect was only
      significant for inhibition of a prepotent response and inhibition of an ongoing
      response (as measured by the Follow Task), but not for interference control. The
      relation between treatment condition and response was linear. However, this
      linear relation was due to improved inhibitory control under MPH compared to
      placebo, because no effects of MPH dose were observed for any of the response
      inhibition measures.

PMID- 12597705
TI  - In vitro evaluation of the cytotoxicity of two root canal sealers on macrophage
      activity.
AB  - Although some studies have been concerned with the cytotoxicity of endodontic
      sealers and their components, few have approached the effects of endodontic
      sealers on macrophage viability and activity. In this study the effect of two
      zinc oxide-eugenol-based sealers, freshly prepared or after setting for 24 h, was
      determined on macrophage activity in vitro. Sealers were placed inside a glass
      capillary tube and added to mouse-elicited macrophage cultures. Sealers did not
      affect macrophage viability; however, adherence to glass and phagocytosis were
      impaired. Moreover, nitric oxide production in response to activation with
      interferon-gamma was diminished, but interleukin-12 production in response to
      Listeria monocytogenes was not altered. Interestingly, freshly mixed and solid
      test samples had similar inhibitory activities. In conclusion, the tested sealers
      did not affect a pro-inflammatory response (interleukin-12 production) but had an
      inhibitory effect on the effector responses measured (phagocytosis and nitric
      oxide production).

PMID- 12597706
TI  - Antibacterial effect of a hydraulic calcium phosphate cement for dental
      applications.
AB  - Calcium hydroxide is currently used in dentistry for endodontic treatment where
      its main advantage consists of its antibacterial and anti-inflammatory potency.
      However, it also has some drawbacks such as pulp necrosis, slight solubility,
      slow and low hardening, and retraction on drying. Since the studies conducted by
      Brown and Chow (IADR 1983, abst. 207), calcium phosphate-based cements (CPC) have
      attracted considerable interest in bone reconstruction because of their good
      osteoconductivity. By mixing calcium bis-dihydrogenphosphate monohydrate (MCPM)
      and calcium oxide with sodium phosphate buffer in the form of liquid phase, we
      obtained a CPC with better mechanical properties than calcium hydroxide. The
      setting reaction produced a mixture of calcium-deficient hydroxyapatite and
      calcium hydroxide, making this cement more suitable for dental applications than
      orthopedic ones. The presence of calcium hydroxide a priori confers antibacterial
      properties to this cement, which were investigated in agar plates (diffusion
      method) against Streptococcus mutans, Lactobacillus acidophilus, Candida albicans
      (clinical isolates) and a preparation of polymicrobial flora isolated from dental
      plaque. The cement samples tested were prepared at calcium-to-phosphate molar
      ratios (Ca/P) ranging from 1.67 to 2.75. A pure calcium hydroxide paste was used
      as reference material. Clear and reproducible bacterial growth inhibition was
      observed for cement samples with Ca/P > or = 2 against all the microorganisms
      tested. MCPM-CaO-based cement is therefore a potential candidate for pulp capping
      and cavity lining.

PMID- 12597708
TI  - Immunohistochemical localization of mu-opioid receptors in human dental pulp.
AB  - Studies in both animal and clinical models suggest that opioids exert their
      analgesic effects not only through activation of receptors in the CNS but also
      through interaction with peripheral opioid receptors. This study evaluated the
      presence and distribution of mu-opioid receptors in human dental pulp. Human
      third molars indicated for extraction were removed, fixed in 4% paraformaldehyde
      and 0.2% picric acid, and decalcified in 10% EDTA and 7.5% polyvinylpyrrolidone.
      The teeth were cut using a cryostat, and the avidin-biotin peroxidase
      immunohistochemistry technique was used. Immunostaining for mu-opioid receptors
      was detected along the nerve bundle of the radicular as well as coronal dental
      pulp. Positive immunostaining was also observed in the individual nerve fibers in
      the coronal region. This demonstration of opiate receptors on pulpal nerve fibers
      suggests a peripheral site in the dental pulp where endogenous or exogenous
      opioids can interact with mu-opioid receptors.

PMID- 12597707
TI  - The effect of extracellular calcium ion on gene expression of bone-related
      proteins in human pulp cells.
AB  - Calcium hydroxide is often used for induction of reparative dentin formation in
      endodontic treatment. However, little is known about the mechanism by which
      calcium hydroxide works. The calcium ion (Ca2+) is an important regulator of cell
      functions. In this study, we examined the effect of extracellular Ca2+ on gene
      expression of bone-related proteins in human cultured pulp cells in serum-free
      conditions. A Ca2+ level elevated by 0.7 mM induced an increase in mRNA
      expression of osteopontin and bone morphogenetic protein (BMP)-2. However, mRNA
      levels of BMP-4 and alkaline phosphatase decreased under the elevated Ca2+
      culture condition. The same concentration of additional magnesium ions had little
      effect on expressions of the examined bone-related protein mRNAs. These findings
      suggest that Ca2+ in Ca(OH)2 specifically modulates osteopontin and BMP-2 levels
      during calcification in pulp.

PMID- 12597709
TI  - Peptostreptococcus micros in primary endodontic infections as detected by 16S
      rDNA-based polymerase chain reaction.
AB  - A 16S rDNA-based polymerase chain reaction (PCR) method was used to detect
      Peptostreptococcus micros in primary root canal infections. Samples were
      collected from 50 teeth having carious lesions, necrotic pulps, and different
      forms of periradicular diseases. DNA extracted from the samples was amplified
      using the PCR assay, which yielded a specific fragment of P. micros 16S rDNA. P.
      micros was detected in 6 of 22 root canals associated with asymptomatic chronic
      periradicular lesions (27.3%), 2 of 8 teeth with acute apical periodontitis
      (25%), and 6 of 20 cases of acute periradicular abscess (30%). In general, P.
      micros was found in 14 of 50 cases (28%). There was no correlation between the
      presence of P. micros and the occurrence of symptoms. Findings suggested that P.
      micros can be involved in the pathogenesis of different forms of periradicular
      lesions.

PMID- 12597710
TI  - Induction of tissue plasminogen activator gene expression by proinflammatory
      cytokines in human pulp and gingival fibroblasts.
AB  - Plasminogen activator converts plasminogen to plasmin, and plasmin activates the
      latent matrix metalloproteinases. Tissue plasminogen activator (t-PA) is one of
      the important proteolysis factors present in human inflamed tissues. However, few
      studies reported on the mechanisms of tissue destruction via a t-PA proteolysis
      pathway in pulpal and periapical diseases. The subsequent reactions leading to
      pulpal and periapical injury after the induction of proinflammatory cytokines
      remains to be elucidated. The aim of this study was to investigate the effects of
      interleukin-1alpha and tumor necrosis factor-alpha on the expression of t-PA mRNA
      gene in cultured human pulp and gingival fibroblasts. The mRNAs for t-PA were
      measured by reverse transcription-polymerase chain reaction at 2, 6, and 24 h.
      The results show that both cytokines induced significantly high levels of t-PA
      mRNA gene expression in human pulp fibroblasts. The peak of t-PA mRNA levels
      induced by both proinflammatory cytokines was at the 6-h incubation period.
      Interleukin-1alpha was found to be more effective in induction of t-PA gene
      expression than tumor necrosis factor-alpha. In addition, a similar induction
      pattern was also found in human gingival fibroblasts. These results indicate that
      proinflammatory cytokines can induce t-PA gene expression and such an effect may
      partially contribute to the destruction of pulpal and periapical tissues through
      dysregulated pericellular proteolysis. An understanding of the mechanism could
      not only further define the role of immune events in pulpal and periapical
      diseases but also have important implication for pharmacological intervention.

PMID- 12597711
TI  - Antibacterial effects of resinous retrograde root filling materials.
AB  - The effect of three resinous retrograde root filling materials on the growth of
      four obligate anaerobic bacteria associated with endodontic infections was
      determined by using the agar diffusion inhibitory test. Samples of the following
      resinous materials (resin-modified, glass-ionomer cement, Fuji II LC; compomer,
      Dyract; and composite resin, Spectrum) were incubated for 1 week with the
      following anaerobic bacteria: Fusobacterium nucleatum, Porphyromonas gingivalis,
      P. endodontalis, and Prevotella intermedia. The freshly mixed and set resinous
      materials were placed into the prepared wells of agar plates inoculated with the
      test microorganisms for 1 week. After the end of the incubation period, the zone
      of growth inhibition was observed and measured. Analysis of variance of the mean
      diameter of the zone of inhibition indicated no statistically significant overall
      differences in the response of the black-pigmented Bacteroides species (p >
      0.05). For F. nucleatum, Spectrum had more antibacterial effect against this
      bacteria than Dyract (p < 0.05). Additionally, Fuji II LC was ineffective against
      F. nucleatum (p < 0.05). However, positive control plates showed bacterial growth
      in all cases. Our data suggest that the antibacterial potency of polymerized
      materials varied considerably, depending on the type and the product tested.

PMID- 12597712
TI  - A comparison of one versus two appointment endodontic therapy in dogs' teeth with
      apical periodontitis.
AB  - This study was conducted to observe the healing process in dogs' teeth with
      apical periodontitis after root canal treatment in one or two appointments.
      Premolars and anterior dogs' teeth had their root canals opened to the oral
      environment for 6 months before being treated. After root canal negotiation they
      were filled by the lateral condensation technique with gutta-percha points and
      Sealapex in one appointment or after a dressing with calcium hydroxide for 7 and
      15 days. Six months after the treatment the animals were killed and the tissues
      prepared for histomorphological analysis. Scores attributed to the different
      histomorphological events were submitted to statistical analysis, which resulted
      in ranking the experimental groups from the best to the worst in the following
      way: (a) calcium hydroxide 14 days; (b) calcium hydroxide 7 days; and (c) one
      appointment. It was concluded that the use of a calcium hydroxide dressing helps
      to achieve better results (p < 0.01) than the treatment in one appointment.

PMID- 12597713
TI  - Effect of fatigue testing on core integrity and post microleakage of teeth
      restored with different post systems.
AB  - The purpose of this study was to evaluate a new nondestructive test system, which
      could test concurrently fatigue and microleakage. Fifty, single-rooted teeth were
      restored with one of the following posts systems and a composite core: titanium
      ParaPost cemented with zinc phosphate cement; CosmoPost; C-Post; Esthetic C-Post;
      and FibreKor post, all cemented with resin cement. Samples were embedded and
      placed in a positioning jig. They were impacted at 45 degrees to the long axis of
      the tooth with a force of 55 N at a frequency of 3 Hz for a total of 100,000
      impacts. After 60,000 impacts, samples were thermocycled. Core integrity and post
      microleakage were evaluated periodically throughout the 100,000 impacts. Samples
      showed no detectable displacement of any of the cores, but the metallic group
      showed a statistically significant increase in microleakage (p < 0.05) at the
      conclusion of the study compared with the nonmetallic groups.

PMID- 12597714
TI  - Fabrication of hard coatings on NiTi instruments.
AB  - The present study was designed to compare the nature of modified surface layers
      obtained by two different procedures on endodontic files made of NiTi alloy: the
      procedures were arc evaporation physical vapor deposition and thermal metal
      organic chemical vapor deposition (MOCVD). Experimental samples were GT Rotary
      Instruments. The first method was based on the physical deposition of elemental
      titanium in the presence of nitrogen. The second technique is a typical MOCVD
      procedure which adopts Ti(Et2N)4 as a titanium and nitrogen precursor. Control
      samples were not exposed to any process. The chemical composition of the surface
      and in-depth layers of each sample were examined by X-ray photoelectron
      spectroscopy and X-ray diffraction measurements. The instruments showed surface
      chemical compositions that were different from those seen in the control group;
      samples treated with the first method show a surface Nitrogen/Titanium ratio of
      1; MOCVD instruments show a surface Nitrogen/Titanium ratio of 1.7; control
      samples show a Nitrogen/Titanium ratio of 0.2. Both techniques can produce a high
      nitrogen concentration on the surface. However, data showed that the
      morphologies, the in-depth nitrogen distribution, and the chemical nature of the
      coatings obtained with the two procedures were different. The paper also reports
      the effects of the two deposition procedures on the nickel/titanium ratio of the
      surface.

PMID- 12597715
TI  - Changes in TrkB-like immunoreactivity in rat trigeminal ganglion after tooth
      injury.
AB  - The purpose of this study was to characterize the impact of tooth injury on the
      distribution of tyrosine receptor kinase B (TrkB) among trigeminal ganglion
      neurons and assess the time course for tooth injury-induced TrkB distribution
      changes. In addition, we sought to further characterize the subpopulation of the
      afferents expressing TrkB receptors. Fifteen adult male Sprague-Dawley rats were
      studied. Pulpal inflammation was induced and ganglia were subsequently harvested
      and processed at different time points. Standard immunohistochemical fluorescence
      techniques were used to visualize TrkB-like immunoreactivity and isolectin B4
      binding. Results indicate that full-length TrkB receptors are present in 36.6% of
      trigeminal ganglion neurons. This percentage decreases for the first 48 h and
      then increases to 41% by 7 days after tooth injury. Finally, TrkB appears to be
      present in a large percentage (54%) of isolectin B4+ neurons, suggesting that it
      is present in nociceptive afferents. These data highlight the fact that even mild
      injury results in sustained changes in nociceptive circuitry and raise the
      possibility that the brain-derived neurotrophic factor/TrkB system may contribute
      to persistent pain after tooth repair.

PMID- 12597716
TI  - Generation of free radicals and/or active oxygen by light or laser irradiation of
      hydrogen peroxide or sodium hypochlorite.
AB  - Generation of free radical and/or active oxygen by light or laser irradiation of
      hydrogen peroxide (H2O2) or sodium hypochlorite (NaClO), which have been used for
      tooth whitening or root canal irrigation, was investigated using electron spin
      resonance spectroscopy combined with a spin-trapping technique. When H2O2 was
      exposed to light or laser radiation, the amount of hydroxyl radical generated
      changed according to the concentration of H2O2 and irradiation time. The amount
      of 5,5-dimethyl-1-pyrrolidone-(2)-oxyl-(1) (DMPO-X) also changed in accordance
      with irradiation time. The amounts of hydroxyl radical generated from H2O2 after
      irradiation were in the order: plasma lamp > halogen lamp > He-Ne laser > Yellow
      He-Ne laser. On the other hand, the amounts of DMPO-X generated from NaClO after
      irradiation were in the order: plasma lamp > Yellow He-Ne laser > halogen lamp >
      He-Ne laser.

PMID- 12597717
TI  - Trephination for acute pain management.
AB  - Surgical trephination can and does provide immediate relief of pain, surgical
      drainage of the infection and related fluids, and in most cases does not require
      supplementary administration of antibiotics and only minimal amounts of
      analgesics. This paper outlines the diagnosis and technique of surgical
      trephination.

PMID- 12597718
TI  - In appreciation of Henry J. Van Hassel.

PMID- 12597719
TI  - Participation of women as authors and editors in journals concerned with mental
      retardation and related topics.
AB  - The present survey determined women's participation in eight journals concerned
      with mental retardation and related topics. The number of female authors was
      recorded for all articles published in these journals from 1991 through 2000. The
      number of women on the editorial board each year, for each journal, also was
      tabulated. For all years and all journals, women were first authors of 41% of
      articles published. Women wrote 34% of single-author articles. Overall, 45% of
      all authors were women. Women constituted 34% of the editorial board members for
      the eight journals combined. In sum, these data suggest that women's contribution
      to the mental retardation literature decreases with the prestige of the activity.

PMID- 12597720
TI  - Adaptive behavior and cognitive function of adults with down syndrome: modeling
      change with age.
AB  - Fifty-eight adults with Down syndrome (ages 31 to 56 years at time of first
      testing, mean age, 43.5) were assessed longitudinally over 10 years for the
      purpose of modeling aging-related change in cognitive function and adaptive
      behavior. Cognitive function was assessed seven times using the Woodcock-Johnson
      Tests of Cognitive Ability-Revised Early Development Battery. Adaptive behavior
      was evaluated five times using the Inventory for Client and Agency Planning.
      Multi-level (hierarchical linear) modeling procedures were used to model change
      with age. Findings provided further evidence of changes in performance with age
      and included selected effects for participants who completed the 10 years of
      study and those who were lost to follow-up as well as for age cohorts.

PMID- 12597721
TI  - Parental opinions about facial plastic surgery for individuals with down
      syndrome.
AB  - Facial plastic surgery is an intervention that some have proposed to improve the
      physical functioning, appearance, and social acceptance of individuals with Down
      syndrome. Our purpose in this study was to examine the opinions of parents of
      children with Down syndrome about this practice. Two hundred and fifty parents
      responded with usable surveys and were generally familiar with the practice, yet
      the majority of respondents did not support the surgery. The literature on this
      topic is reviewed, and related issues are discussed.

PMID- 12597722
TI  - The organization of difference: people with intellectual disabilities and the
      social model of disability.
AB  - In this article I propose that the experience of people categorized as having
      intellectual disabilities is inadequately represented by current disability
      theory, premised, as much of it is, on the socially constructed duality between
      disability and impairment. I argue that representation of intellectual disability
      within the wider world of disability in general will only be achieved by thinking
      of disability on a continuum. This should preserve individual identities while
      reducing categorization and the attendant essentialist versus constructionist
      conflict. Debate can then move to a consideration of what methodologies are
      appropriate to the inquiry.

PMID- 12597723
TI  - Long-term treatment and management of violent tendencies of men with intellectual
      disabilities convicted of assault.
AB  - Success of anger management treatment with individuals who have intellectual
      disabilities convicted of assault-related offenses has not been verified. We
      employed a single case design with repeated measures with 6 such men. Recidivism
      is reported at least 4.5 years and up to 10 years. Modified anger management
      training incorporating cognitive restructuring and arousal reduction was
      employed. Participants showed no uniform reductions in emotional or behavioral
      systems of anger and aggression. Although several retained significant anger
      feelings, there were reductions in the extent to which they would act in an
      aggressive fashion. Five have not re-offended; 1 re-offended within 6 months but
      not in the subsequent 4 years. Anger management treatment seems effective for men
      with intellectual disabilities in the community who have committed socially and
      legally unacceptable acts.

PMID- 12597724
TI  - Eugenics and sterilization in the heartland.

PMID- 12597725
TI  - Observations of a water boy.

PMID- 12597727
TI  - Continuing reduction in populations of large state residential facilities for
      persons with intellectual and developmental disabilities.

PMID- 12597728
TI  - Music listening for maintaining attention of older adults with cognitive
      impairments.
AB  - Twelve older adults with cognitive impairments who were participants in weekly
      community-based group music therapy sessions, 6 older adults in an Alzheimer's
      caregivers' group, and 6 college student volunteers listened to a 3.5 minute
      prepared audiotape of instrumental excerpts of patriotic selections. The tape
      consisted of 7 excerpts ranging from 18 s to 34 s in duration. Each music excerpt
      was followed by a 7-9 s period of silence, a "wait" excerpt. Listeners were
      instructed to move a Continuous Response Digital Interface (CRDI) to the name of
      the music excerpt depicted on the CRDI overlay when they heard a music excerpt.
      Likewise, they were instructed to move the dial to the word "WAIT" when there was
      no music. They were also instructed to maintain the dial position for the
      duration of each music or silence excerpt. Statistical analysis indicated no
      significant differences between the caregivers' and the college students' group
      means for total dial changes, correct and incorrect recognitions, correct and
      incorrect responses to silence excerpts, and reaction times. The mean scores of
      these 2 groups were combined and compared with the mean scores of the group of
      elderly adults with cognitive impairments. The mean total dial changes were
      significantly lower for the listeners with cognitive impairments, resulting in
      significant differences in all of the other response categories except incorrect
      recognitions. In addition, their mean absence of response to silence excerpts was
      significantly higher than their mean absence of responding to music excerpts.
      Their mean reaction time was significantly slower than the comparison group's
      reaction time. To evaluate training effects, 10 of the original 12 music therapy
      participants repeated the listening task with assistance from the therapist
      (treatment) immediately following the first listening (baseline). A week later
      the order was reversed for the 2 listening trials. Statistical and graphic
      analysis of responses between first and second baseline responses indicate
      significant improvement in responses to silence and music excerpts over the 2
      sessions. Applications of the findings to music listening interventions for
      maintaining attention, eliciting social interaction between clients or caregivers
      and their patients, and evaluating this population's affective responses to music
      are discussed.

PMID- 12597729
TI  - Internal versus external locus of control: an analysis of music populations.
AB  - This study investigated the relationship between locus of control and chosen
      field of music specialization. The Nowicki-Strickland Locus of Control Scale was
      designed to assess the construct of locus of control and reinforcement, which is
      defined as the perception of a connection between one's action and its
      consequences; the version of the scale used in this study was specifically
      developed and validated for use with college-aged students by Nowicki (2000).
      This scale was administered to four separate college-aged groups: music therapy
      majors, music education majors, applied music majors, and nonmusic majors who
      also had previous music background and were currently enrolled in a formal
      college music performance organization. Results indicated that there were indeed,
      differences among these populations with music therapy majors evidencing a
      significantly lower internal locus of control. Music education majors and
      nonmajors evidenced a greater internal level and were not significantly different
      from each other, yet both were significantly different from the music therapy
      majors. Music performance majors were also significantly lower in internal
      control compared to the music education and nonmusic majors, but they were not
      significantly different from the music therapy majors. This entire line of
      research has a long history and seems advisable to continue with all music
      populations, especially potential music therapists in order to investigate those
      aspects of self-perception that may help or hinder therapeutic effectiveness.

PMID- 12597730
TI  - Experiences and concerns of students during music therapy practica.
AB  - This phenomenological research study investigated experiences and concerns that
      music therapy students have during their preclinical or practicum experiences.
      Interviews with students were intended to lead to an understanding of these
      experiences as the students perceived them. Eight students enrolled in
      undergraduate music therapy practica participated in open-ended interviews over
      the period of a year, with most students being interviewed 3 times. Six areas of
      interest emerged from the analysis: challenges encountered by students, means of
      dealing with challenges, involvement with clients, areas of learning, supervision
      issues, and structure of practicum. These areas and subcategories under them are
      presented along with transcriptions from the interviews to illustrate the points.
      Implications of the research for education and clinical training are discussed.

PMID- 12597731
TI  - Collaboration and consultation: a survey of board certified music therapists.
AB  - The purpose of this study was to examine the consultation and collaboration
      practices of board certified music therapists (MT-BC) in order to establish a
      baseline of service provision for this profession. Board certified music
      therapists who are members of the American Music Therapy Association (n = 2039)
      were asked to complete a survey regarding collaboration and consultation in their
      professional practice. Specific areas of investigation included (a) population(s)
      with whom the MT-BC works and site of service delivery, (b) selfidentification as
      a collaborator and/or a consultant (c) populations with whom the MT-BC
      collaborates, and (d) frequency, methods, purpose, locations, and personnel for
      whom they provide consultative services. Responses (n = 873, 42.8%) from each of
      the 8 regions designated by the American Music Therapy Association (AMTA)
      indicated a significantly higher report of collaboration versus consultation
      among music therapists. Implications for music therapy education and need for
      further research are discussed.

PMID- 12597732
TI  - A piece of my mind. The cross-cover resident.

PMID- 12597733
TI  - Current and emerging infectious risks of blood transfusions.

PMID- 12597735
TI  - Panel endorses limited role for CRP tests.

PMID- 12597734
TI  - Many questions, few answers for testosterone replacement therapy.

PMID- 12597736
TI  - Syphilis outbreak sparks concerns.

PMID- 12597737
TI  - Shared decision making about withdrawing treatment.

PMID- 12597739
TI  - Bone densitometry testing in nonwhite patients.

PMID- 12597741
TI  - Vitamins and hormone therapy for coronary atherosclerosis.

PMID- 12597742
TI  - Negative-pressure ventilation.

PMID- 12597744
TI  - Idiopathic vs hereditary pancreatitis.

PMID- 12597745
TI  - Idiopathic vs hereditary pancreatitis.

PMID- 12597748
TI  - Intensivist consultation and outcomes in critically ill patients.

PMID- 12597749
TI  - Intensivist consultation and outcomes in critically ill patients.

PMID- 12597750
TI  - Alcohol consumption and expenditures for underage drinking and adult excessive
      drinking.
AB  - CONTEXT: Although estimates of the amount and proportion of alcohol consumed by
      underage and adult drinkers have been reported, more accurate estimates are
      possible and the economic impact has not been explored. OBJECTIVES: To provide
      accurate estimates of underage and adult excessive drinking and to describe
      consumer expenditures linked to underage and adult excessive drinking. DESIGN AND
      SETTING: Information was obtained from national data sets, including 1999
      versions of the National Household Survey of Drug Abuse, the Youth Risk Behavior
      Survey (YRBS), the Behavior Risk Factor Surveillance System (BRFSS), 2000 US
      Census, and national data on consumption and consumer expenditures for alcohol,
      published by Adams Business Research. PARTICIPANTS: A total of 217 192 persons
      aged 12 years or older across 3 data sources. MAIN OUTCOME MEASURES: Amount as a
      proportion of total alcohol consumed and proportion of consumer expenditures on
      alcohol among underage (12-20 years) and adult excessive (> or =21 years)
      drinkers. RESULTS: The proportion of 12- to 20-year-olds who drink was estimated
      to be 50.0% using data from the YRBS; the proportion of adults aged 21 or older
      who drink was estimated to be 52.8% using data from the BRFSS. The estimated
      total number of drinks consumed per month was 4.21 billion; underage drinkers
      consumed 19.7% of this total. The amount of adult drinking that was excessive (>2
      drinks per day) was 30.4%. Consumer expenditure on alcohol in the United States
      in 1999 was $116.2 billion; of that, $22.5 billion was attributed to underage
      drinking and $34.4 billion was attributed to adult excessive drinking.
      CONCLUSION: These data suggest that underage drinkers and adult excessive
      drinkers are responsible for 50.1% of alcohol consumption and 48.9% of consumer
      expenditure.

PMID- 12597751
TI  - Impact of quality improvement efforts on race and sex disparities in
      hemodialysis.
AB  - CONTEXT: By improving the process of care, quality improvement efforts have the
      potential to reduce race and sex disparities. However, little is known about
      whether reductions actually occur. National quality improvement activities
      targeting hemodialysis patients provide an opportunity to examine this issue.
      OBJECTIVE: To determine the effect of quality improvement efforts on race and sex
      disparities among hemodialysis patients. DESIGN, SETTING, AND SUBJECTS:
      Longitudinal study of 58 700 randomly selected hemodialysis patients from
      throughout the United States in 1993 through 2000. INTERVENTION: Medicare-funded
      quality improvement project involving monitoring of patient outcomes, feedback of
      performance data, and education of clinicians at dialysis centers. MAIN OUTCOME
      MEASURES: Changes in hemodialysis dose (Kt/V), anemia management (hemoglobin
      level), and nutritional status (albumin level). RESULTS: The proportion of all
      patients with an adequate hemodialysis dose increased 2-fold. In 1993, 46% of
      white patients and 36% of black patients received an adequate hemodialysis dose
      compared with 2000 when the proportions were 87% and 84%, respectively. Thus, the
      gap between white and black patients decreased from 10% to 3% (P<.001). The gap
      between female and male patients decreased from 23% to 9% over the same period (P
      =.008). The proportion of all patients with adequate hemoglobin levels increased
      3-fold. The proportion of all patients with adequate albumin levels remained
      unchanged. Race and sex disparities in anemia management and nutritional status
      did not change significantly. CONCLUSIONS: Quality improvement efforts have a
      variable impact on race and sex disparities in health outcomes. Further work is
      needed to determine how quality improvement methods can be targeted to reduce
      health disparities.

PMID- 12597752
TI  - Patients' and physicians' attitudes regarding the disclosure of medical errors.
AB  - CONTEXT: Despite the best efforts of health care practitioners, medical errors
      are inevitable. Disclosure of errors to patients is desired by patients and
      recommended by ethicists and professional organizations, but little is known
      about how patients and physicians think medical errors should be discussed.
      OBJECTIVE: To determine patients' and physicians' attitudes about error
      disclosure. DESIGN, SETTING, AND PARTICIPANTS: Thirteen focus groups were
      organized, including 6 groups of adult patients, 4 groups of academic and
      community physicians, and 3 groups of both physicians and patients. A total of 52
      patients and 46 physicians participated. MAIN OUTCOME MEASURES: Qualitative
      analysis of focus group transcripts to determine the attitudes of patients and
      physicians about medical error disclosure; whether physicians disclose the
      information patients desire; and patients' and physicians' emotional needs when
      an error occurs and whether these needs are met. RESULTS: Both patients and
      physicians had unmet needs following errors. Patients wanted disclosure of all
      harmful errors and sought information about what happened, why the error
      happened, how the error's consequences will be mitigated, and how recurrences
      will be prevented. Physicians agreed that harmful errors should be disclosed but
      "choose their words carefully" when telling patients about errors. Although
      physicians disclosed the adverse event, they often avoided stating that an error
      occurred, why the error happened, or how recurrences would be prevented. Patients
      also desired emotional support from physicians following errors, including an
      apology. However, physicians worried that an apology might create legal
      liability. Physicians were also upset when errors happen but were unsure where to
      seek emotional support. CONCLUSIONS: Physicians may not be providing the
      information or emotional support that patients seek following harmful medical
      errors. Physicians should strive to meet patients' desires for an apology and for
      information on the nature, cause, and prevention of errors. Institutions should
      also address the emotional needs of practitioners who are involved in medical
      errors.

PMID- 12597753
TI  - Maternal immunity and prevention of congenital cytomegalovirus infection.
AB  - CONTEXT: Vaccine development to prevent congenital cytomegalovirus (CMV)
      infection has been impeded by the uncertainty over whether maternal immunity
      protects the fetus. OBJECTIVE: To determine whether the presence of maternal
      antibodies to CMV significantly reduces the risk of congenital CMV infection in
      future pregnancies. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 3461
      multiparous women from a population with a high rate of congenital CMV infection
      who delivered newborns screened for congenital CMV infection between 1993 and
      1998, and whose cord serum specimen from a previous delivery could be retrieved
      and tested for antibody to CMV. MAIN OUTCOME MEASURE: Congenital CMV infection
      according to maternal immune status, age, race, parity, and socioeconomic status.
      RESULTS: Of 604 newborns born to initially seronegative mothers, congenital CMV
      infection occurred in 18 (3.0%). In contrast, of 2857 newborns born to immune
      mothers, congenital CMV infection occurred in 29 (1.0%) Two factors,
      preconception maternal immunity (adjusted risk ratio, 0.31; 95% confidence
      interval, 0.17-0.58) and maternal age of 25 years or older (adjusted risk ratio,
      0.19; 95% confidence interval, 0.07-0.49), were highly protective against
      congenital CMV infection. No other factors were associated with a reduction in
      the risk of congenital CMV infection. CONCLUSION: Naturally acquired immunity
      results in a 69% reduction in the risk of congenital CMV infection in future
      pregnancies.

PMID- 12597754
TI  - BCG vaccination and risk of atopy.
AB  - CONTEXT: It has been suggested that BCG vaccination may protect against
      development of allergic diseases, particularly when given just after birth. BCG
      vaccination was given routinely to all infants in Greenland until 1990, when it
      was withdrawn from the vaccination program. Whether this resulted in an increased
      prevalence of atopy in children born after the stop of BCG vaccination is
      unknown. OBJECTIVE: To determine whether BCG vaccination and age at BCG
      vaccination are associated with development of atopy. DESIGN, SETTING, AND
      PARTICIPANTS: Cross-sectional study among schoolchildren aged 8 to 16 years in 4
      towns on the northwest coast of Greenland. Participants had a blood sample drawn
      and information on BCG vaccination was obtained during 2 periods, November 1998
      and November 2001. A total of 1686 children (79% of available children)
      participated, 1575 of whom had complete information on vaccination status. Atopy
      was defined as a positive test result in an assay that tests for IgE specific
      against the most common inhalant allergens in serum. MAIN OUTCOME MEASURES: Odds
      ratio (OR) of atopy in BCG-vaccinated compared with unvaccinated children and OR
      according to age at vaccination. RESULTS: The risk of atopy was the same in BCG
      vaccinated compared with unvaccinated children after adjustment for confounders
      (OR, 1.03; 95% confidence interval, 0.72-1.48). The risk of atopy in BCG
      vaccinated children was not associated with age at vaccination (P =.17).
      CONCLUSIONS: BCG vaccination administered to infants is not associated with
      reduced risk of development of atopy.

PMID- 12597755
TI  - A 57-year-old man with osteoarthritis of the knee.

PMID- 12597756
TI  - A 44-year-old woman with borderline personality disorder, 1 year later.

PMID- 12597757
TI  - Measuring blood pressure accurately: new and persistent challenges.

PMID- 12597758
TI  - Public health implications of excessive alcohol consumption.

PMID- 12597759
TI  - Improving quality and reducing disparities: toward a common pathway.

PMID- 12597760
TI  - Advanced access: reducing waiting and delays in primary care.
AB  - Delay of care is a persistent and undesirable feature of current health care
      systems. Although delay seems to be inevitable and linked to resource
      limitations, it often is neither. Rather, it is usually the result of unplanned,
      irrational scheduling and resource allocation. Application of queuing theory and
      principles of industrial engineering, adapted appropriately to clinical settings,
      can reduce delay substantially, even in small practices, without requiring
      additional resources. One model, sometimes referred to as advanced access, has
      increasingly been shown to reduce waiting times in primary care. The core
      principle of advanced access is that patients calling to schedule a physician
      visit are offered an appointment the same day. Advanced access is not sustainable
      if patient demand for appointments is permanently greater than physician capacity
      to offer appointments. Six elements of advanced access are important in its
      application balancing supply and demand, reducing backlog, reducing the variety
      of appointment types, developing contingency plans for unusual circumstances,
      working to adjust demand profiles, and increasing the availability of bottleneck
      resources. Although these principles are powerful, they are counter to deeply
      held beliefs and established practices in health care organizations. Adopting
      these principles requires strong leadership investment and support.

PMID- 12597761
TI  - Improving timely access to primary care: case studies of the advanced access
      model.
AB  - The advanced access model of patient scheduling is based on the core principle
      that if the capacity to provide patient appointments balances the demand for
      appointments, patients calling to see their physician are offered an appointment
      the same day. The accompanying article in the series "Innovations in Primary
      Care" presents the theory behind advanced access scheduling. In this article we
      describe 4 case studies of primary care practices that successfully implemented
      advanced access and 3 examples of practices that were unable to achieve advanced
      access despite considerable efforts. The lessons of these case studies should be
      useful for primary care practices desiring to improve timely access to care and
      wishing to avoid the pitfalls that can derail this innovation.

PMID- 12597762
TI  - JAMA patient page. Osteoarthritis of the knee.

PMID- 12597764
TI  - Editorial: reverse subspecialization?: is it time to separate ophthalmic
      pediatrics and strabology?

PMID- 12597765
TI  - The phoropter trapeze. A portable refractive support for remote clinics.
AB  - A trapeze was engineered using inexpensive pre-threaded commercial polyvinyl
      chloride ("PVC") plumbing pipe. This was suspended from a convenient overhead
      point and the phoropter was clamped to it. It was stabilized by the patient
      holding on two attached handles. Illustrated in photographs.

PMID- 12597766
TI  - Internuclear ophthalmoplegia (INO): an unusual presentation of neuropsychiatric
      lupus erythematosus.
AB  - BACKGROUND AND PURPOSE: INO in SLE is uncommon, affecting < 5% of hospitalized
      SLE patients. A MEDLINE search 1966-2001 revealed only 22 reported cases. INO
      also rarely presents with diplopia. We report such a case. CASE REPORT: A 35 year
      old woman with long standing SLE developed the abrupt onset of diplopia, vertigo
      and ataxia. Physical examination was remarkable only for the neurologic
      examination with a left INO and abnormal cerebellar testing. Treatment with
      corticosteroids and intravenous cyclophosphamide resulted in resolution of her
      cerebellar and ocular symptoms.

PMID- 12597767
TI  - Fixation linked hypotropia in high myopia. A report of two similar cases.
AB  - Fixation linked hypotropia has rarely been reported. We hereby present two cases
      of fixation linked hypotropia associated with amblyopia and high myopia in the
      deviating eye.

PMID- 12597768
TI  - V-pattern esotropia: a review; and a study of the outcome after bilateral
      recession of the inferior oblique muscle: a retrospective study of 78 consecutive
      patients.
AB  - BACKGROUND: A V-pattern esotropia with bilateral overaction of the inferior
      oblique (IO) is a common finding. The clinical characteristics of this condition
      in a large series are not available. Also, data is lacking about the surgical
      outcome of graded bilateral inferior oblique recessions. Lastly, it is not known
      whether patients with a V pattern below 15 prism diopters (pd) should have IO
      weakening when horizontal eye muscle surgery is to be performed. SUBJECTS AND
      METHODS: Seventy-eight consecutive patients without complicating factors were
      fully evaluated and submitted to bilateral graded recessions of the IO. In Group
      1, 59 patients had a V pattern of 15 pd or more; 55 were also operated for a
      horizontal imbalance. In Group 2, 19 patients in whom a horizontal surgery was
      required and who also had a V pattern of less than 15 pd, also had a bilateral
      graded recession of the IO performed. RESULTS: Preoperative findings: In Group 1,
      the distribution of V patterns showed 88.1% in the range 15 to 35 pd. A bilateral
      overaction of the IO, a bilateral underaction of the superior oblique (SO), and
      elevation in adduction OU were present in 62.7% of the patients. A vertical
      imbalance was observed in 20.3%. In Group 2, a bilateral overaction of the IO, a
      bilateral underaction of the SO, and elevation in adduction OU were noticed in
      42.1% of the patients. A vertical deviation was seen in 26.3%. After surgery, in
      Group 1, 83% had less than 15 pd of V pattern or less than 10 pd of A pattern.
      Surgery reduced a presurgical vertical imbalance, but created a vertical
      deviation in some cases devoid of hypertropia before surgery. After surgery in
      Group 2, a full correction or undercorrection was obtained in 63.1% of the
      patients and an overcorrection to an A pattern in 21.0% Surgery was also prone to
      induce a vertical deviation. Binocularity: There was an improvement of the
      fusional status with surgery, (ascertained with the Worth Four Dot Test and major
      amblyoscope measurement), in patients of both Groups 1 and 2. CONCLUSION: In V
      pattern esotropia cases of 15 pd or more the vast majority were in the range 15
      35 pd. Overaction of both IO, underaction of both SO, and elevation in adduction
      OU constituted a triad of co-occurrent signs present in a significant number of
      patients. A vertical imbalance was detected in 1/5 of the cases. A good outcome
      (collapse of the V pattern) was obtained with bilateral graded recession of the
      IO, but this surgery can create a vertical imbalance. In cases of V pattern less
      than 15 pd, and requiring horizontal surgery, weakening of both IO's can be
      advised.

PMID- 12597770
TI  - A case of acute loss of binocular vision and stereoscopic depth perception. (The
      misery of acute monovision, having been binocular for 68 years).
AB  - PURPOSE: There are few personal reports in the literature, by knowledgeable
      vision scientists, of the loss of binocular vision. This case is reported. CASE
      REPORT: This 68 year old retired pediatric ophthalmologist suffered an almost
      total loss of vision, OD, as a result of a sudden massive hemorrhage into the
      vitreous body from a bridging retinal vessel, which remained after repair of a
      spontaneous large horseshoe retinal tear. This caused significant problems with
      both remaining monocular vision, cognition, and space perception. It was
      surprisingly disabling. A diary is included. RESULT: The author now appreciates
      better: 1. that the overlap and cross compensation of monocular vision is quite
      significant; 2. that monocular depth perception may be impaired by any type of
      intervening optical media; 3. that a two dimensional world is very different and
      vastly inferior to a three dimensional world. COMMENT: Such problems are not
      ordinarily expected or described in these circumstances, but considering what is
      in the literature, they may be more common and serious than assumed by eye care
      professionals, and should be taken into consideration in rendering eye care in
      similar situations. Loss of binocular vision results in a significant handicap
      even when the vision remaining in the good dominant eye is normal. It is truly
      remarkable to this victim that so many mature patients are willing to accept this
      situation in the form of surgical or optical monovision to avoid spectacles for
      presbyopia.

PMID- 12597771
TI  - The recombinant C-terminus of the human MUC2 mucin forms dimers in Chinese
      hamster ovary cells and heterodimers with full-length MUC2 in LS 174T cells.
AB  - The entire cDNA corresponding to the C-terminal cysteine-rich domain of the human
      MUC2 apomucin, after the serine- and threonine-rich tandem repeat, was expressed
      in Chinese-hamster ovary-K1 cells and in the human colon carcinoma cell line, LS
      174T. The C-terminus was expressed as a fusion protein with the green fluorescent
      protein and mycTag sequences and the murine immunoglobulin kappa-chain signal
      sequence to direct the protein to the secretory pathway. Pulse-chase studies
      showed a rapid conversion of the C-terminal monomer into a dimer in both Chinese
      hamster ovary-K1 and LS 174T cells. Disulphide-bond-stabilized dimers secreted
      into the media of both cell lines had a higher apparent molecular mass compared
      with the intracellular forms. The MUC2 C-terminus was purified from the spent
      culture medium and visualized by molecular electron microscopy. The dimer nature
      of the molecule was visible clearly and revealed that each monomer was attached
      to the other by a large globular domain. Gold-labelled antibodies against the
      mycTag or green fluorescent protein revealed that these were localized to the
      ends opposite to the parts responsible for the dimerization. The C-terminus
      expressed in LS 174T cells formed heterodimers with the full-length wild-type
      MUC2, but not with the MUC5AC mucin, normally expressed in LS 174T cells. The
      homodimers of the MUC2 C-termini were secreted continuously from the LS 174T
      cells, but no wild-type MUC2 secretion has been observed from these cells. This
      suggests that the information for sorting the MUC2 mucin into the regulated
      secretory pathway in cells having this ability is present in parts other than the
      C-terminus of MUC2.

PMID- 12597772
TI  - Caenorhabditis elegans pseudouridine synthase 1 activity in vivo: tRNA is a
      substrate, but not U2 small nuclear RNA.
AB  - The formation of pseudouridine (Psi) from uridine is post-transcriptional and
      catalysed by pseudouridine synthases, several of which have been characterized
      from eukaryotes. Pseudouridine synthase 1 (Pus1p) has been well characterized
      from yeast and mice. In yeast, Pus1p has been shown to have dual substrate
      specificity, modifying uridines in tRNAs and at position 44 in U2 small nuclear
      RNA (U2 snRNA). In order to study the in vivo activity of a metazoan Pus1p, a
      knockout of the gene coding for the homologue of Pus1p in Caenorhabditis elegans
      was obtained. The deletion encompasses the first two putative exons and includes
      the essential aspartate that is required for activity in truA pseudouridine
      synthases. The locations of most modified nucleotides on small RNAs in C. elegans
      are not known, and the positions of Psi were determined on four tRNAs and U2
      snRNA. The uridine at position 27 of tRNA(Val) (AAC), a putative Pus1p
      modification site, was converted into Psi in the wild-type worms, but the
      tRNA(Val) (AAC) from mutant worms lacked the modification. Psi formation at
      positions 13, 32, 38 and 39, all of which should be modified by other
      pseudouridine synthases, was not affected by the loss of Pus1p. The absence of
      Pus1p in C. elegans had no effect on the modification of U2 snRNA in vivo, even
      though worm U2 snRNA has a Psi at position 45 (the equivalent of yeast U2 snRNA
      position 44) and at four other positions. This result was unexpected, given the
      known dual specificity of yeast Pus1p.

PMID- 12597773
TI  - Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1.
AB  - The nucleotide sequence data reported in this paper will appear in EMBL
      Nucleotide Sequence Database under the accession number AJ 544720. The
      mitochondrial sterol 27-hydroxylase (CYP27A1) is a multifunctional cytochrome
      P450 enzyme that catalyses important hydroxylations in the biosynthesis of bile
      acids and bioactivation of vitamin D(3). Previous results [Babiker, Andersson,
      Lund, Xiu, Deeb, Reshef, Leitersdorf, Diczfalusy and Bj orkhem (1997) J. Biol.
      Chem. 272, 26253-26261] suggest that CYP27A1 plays an important role in
      cholesterol homoeostasis and affects atherogenesis. In the present study, the
      regulation of the human CYP27A1 gene by growth hormone (GH), insulin-like growth
      factor-1 (IGF-1), dexamethasone, thyroid hormones and PMA was studied. HepG2
      cells were transfected transiently with luciferase reporter gene constructs
      containing DNA fragments flanking the 5'-region of the human CYP27A1 gene. GH,
      IGF-1 and dexamethasone increased the promoter activity by 2-3-fold, whereas
      thyroxine (T(4)) and PMA repressed the activity significantly when measured with
      luciferase activity expressed in the cells. The endogenous CYP27A1 enzyme
      activity in the cells was stimulated by GH, IGF-1 and dexamethasone, whereas T(4)
      and PMA inhibited the activity. Experiments with progressive deletion/luciferase
      reporter gene constructs indicated that the response elements for GH may be
      localized in a region upstream to position -1094 bp. The putative response
      elements for dexamethasone were mapped to positions between -792 and -1095 bp.
      The -451 bp fragment of the human CYP27A1 gene was found to confer the activation
      by IGF-1, and the inhibition by T(4) and PMA. Results of the present study
      suggest that CYP27A1 is regulated in human cells by hormones and signal
      transduction pathways.

PMID- 12597775
TI  - Effect of Pluronic-block copolymers on the reduction of serum-mediated inhibition
      of gene transfer of polyethyleneimine-DNA complexes.
AB  - Serum stability of non-viral vectors is a crucial factor for successful in vivo
      gene delivery. Pluronic-block copolymers consisting of hydrophilic ethylene oxide
      and hydrophobic propylene oxide blocks were tested to prevent the reduction of
      serum-mediated inhibition of gene transfer of polyethyleneimine (PEI)-DNA
      complexes in NIH/3T3 cells. The order of hydrophilic-lipophilic balance (HLB) of
      six different types of Pluronics used in this study was
      F68>F127>P105>P94>L122>L61. Transfection activities of NIH/3T3 cells with PEI-DNA
      complexes containing Pluronics with higher HLB showed marked improvement of gene
      expression levels in serum media from 10 to 50% fetal bovine serum compared with
      PEI-DNA complexes alone. Also, higher concentrations (1 and 3%) of Pluronics with
      higher HLB in the PEI/DNA dispersion provided a stronger steric hindrance in
      resisting serum components than those obtained in a lower concentration (0.1%).
      These results suggested that non-viral vectors incorporated with higher HLB of
      Pluronics may be used as potential vehicles for in vivo delivery of DNA.

PMID- 12597774
TI  - Characterization of SUMO-conjugating enzyme mutants in Schizosaccharomyces pombe
      identifies a dominant-negative allele that severely reduces SUMO conjugation.
AB  - The phenotypes of mutants defective in the Schizosaccharomyces pombe SUMO (small,
      ubiquitin-like modifier)-conjugating enzyme Hus5 (the homologue of Ubc9) show
      that it is required for recovery from S-phase arrest. Unlike the case with
      ubiquitination, where ligases are required, SUMO-conjugating enzymes are
      sufficient for substrate recognition and conjugation of SUMO on to target
      proteins, at least in vitro. Thus SUMO-conjugating enzymes are likely to be
      important regulators of sumoylation. Here, we report on the characterization of
      two hus5 alleles. Although hus5.17 and hus5.62 respond in a similar manner to UV
      and ionizing radiation, they have different responses to the DNA-synthesis
      inhibitor, hydroxyurea. In addition, SUMO (Pmt3) is mislocalized in hus5.17
      cells, but not in hus5.62 mutant cells. The mutations in hus5.62 and hus5.17 map
      to Ala(129) and the 5' splice site of intron 2 respectively. We have
      characterized the Hus5.62 protein and shown, in vitro, that it still interacts
      with SUMO and at least one protein, Rad22, which is a SUMO-modified target. The
      Hus5.62 protein is also capable of forming a thioester link with SUMO, but it
      does not function in sumoylation assays, either in the modification of Rad22 or
      in SUMO chain formation. When overexpressed in wild-type S. pombe cells, the
      Hus5.62 protein has a dominant-negative effect on sumoylation.

PMID- 12597776
TI  - Obstetric prognosis in sisters of preeclamptic women - implications for genetic
      linkage studies.
AB  - BACKGROUND: To investigate obstetric prognosis in sisters of preeclamptic women.
      METHODS: We identified consecutive 635 sib pairs from the Birth Registry data of
      Kuopio University Hospital who had their first delivery between January 1989 and
      December 1999 in our institution. Of these, in 530 pairs both sisters had non
      preeclamptic pregnancies (the reference group), in 63 pairs one of the sisters
      had preeclampsia and the unaffected sisters were studied (study group I). In 42
      pairs both sister's first delivery was affected (study group II). Pregnancy
      outcome measures in these groups were compared. RESULTS: Unaffected sisters of
      the index patients had uncompromised fetal growth in their pregnancies, and
      overall, as good obstetric outcomes as in the reference group. The data on
      affected sisters of the index patients showed an increased prematurity rate, and
      increased incidences of low birth weight and small-for-gestational age infants,
      as expected. CONCLUSION: Unaffected sisters of the index patients had no signs of
      utero-placental insufficiency and they were at low risk with regard to adverse
      obstetric outcome, whereas affected sisters were high-risk. Clinically, affected
      versus unaffected status appears to be clear-cut in first-degree relatives
      regardless of their genetic susceptibility and unaffected sisters do not need
      special antepartum surveillance.

PMID- 12597777
TI  - The bradykinin BK2 receptor mediates angiotensin II receptor type 2 stimulated
      rat duodenal mucosal alkaline secretion.
AB  - BACKGROUND: This study investigates bradykinin and nitric oxide as potential
      mediators of AT2-receptor-stimulated duodenal mucosal alkaline secretion.
      Duodenal mucosal alkaline secretion was measured in methohexital- and alpha
      chloralose-anaesthetised rats by means of in situ pH-stat titration.
      Immunohistochemistry and Western blot were used to identify the BK2 receptors.
      RESULTS: The AT2 receptor agonist CGP42112A (0.1 microg kg(-1) min(-1))
      administered intravenously increased the duodenal mucosal alkaline secretion by
      approximately 50 %. This increase was sensitive to the selective BK2 receptor
      blocker HOE140 (100 ng/kg i.v.), but not to luminal administration of the NOS
      blocker L-NAME (0.3 mM). Mean arterial pressure did not differ between groups
      during the procedures. Immunohistochemistry showed a distinct staining of the
      crypt epithelium and a moderate staining of basal cytoplasm in villus
      enterocytes. CONCLUSION: The results suggest that the AT2-receptor-stimulated
      alkaline secretion is mediated via BK2 receptors located in the duodenal cryptal
      mucosal epithelium.

PMID- 12597778
TI  - Chemical and biomechanical characterization of hyperhomocysteinemic bone disease
      in an animal model.
AB  - BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by
      cystathionine beta-synthase (CBS) deficiency and characterized by distinctive
      alterations of bone growth and skeletal development. Skeletal changes include a
      reduction in bone density, making it a potentially attractive model for the study
      of idiopathic osteoporosis. METHODS: To investigate this aspect of
      hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl
      homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n =
      10), and studied biochemical, biomechanical and morphologic effects of this
      nutritional intervention. RESULTS: hCySH-fed animals grew faster and had longer
      tibiae at the end of the study. Plasma levels of hCySH, methionine,
      cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and
      other indices of osteoblast metabolism were not different. Radiographs of the
      lower limbs showed generalized osteopenia and accelerated epiphyseal ossification
      with distinct metaphyseal and suprametaphyseal lucencies similar to those found
      in human homocystinurics. Although biomechanical testing of the tibiae, including
      maximal load to failure and bone stiffness, indicated stronger bone, strength was
      proportional to the increased length and cortical thickness in the hCySH
      supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed
      no difference in mineral content, but there were higher Ca2+/PO4(3-) and lower
      Ca2+/CO3(2-) molar ratios than in controls. Mineral crystallization was
      unchanged. CONCLUSION: In this chick model, hyperhomocysteinemia causes greater
      radial and longitudinal bone growth, despite normal indices of bone formation.
      Although there is also evidence for an abnormal matrix and altered bone
      composition, our finding of normal biomechanical bone strength, once corrected
      for altered morphometry, suggests that any increase in the risk of long bone
      fracture in human hyperhomocysteinemic disease is small. We also conclude that
      the hCySH-supplemented chick is a promising model for study of the connective
      tissue abnormalities associated with homocystinuria and an important alternative
      model to the CBS knock-out mouse.

PMID- 12597779
TI  - The PALM Technique: histological findings of masked phototherapeutic keratectomy
      on rabbit corneas.
AB  - BACKGROUND: To compare the corneal healing response between conventional and
      phototherapeutic keratectomy through a masking agent, in rabbit corneas. METHODS:
      24 adult rabbits underwent phototherapeutic keratectomy. Animals were divided in
      two groups: 12 received photoablation through a masking agent (PALM gel) and the
      remaining 12 received conventional phototherapeutic keratectomy of equal depth
      and served as control. Light and transmission electron microscopy was performed
      in specimens of both groups obtained: immediately after, four hours, one week,
      one, three and six months after treatment. RESULTS: Reepitheliazation was
      complete within five days in all eyes. Light and transmission electron microscopy
      did not reveal any differences of the healing process in the experimental eyes
      compared to the controls. CONCLUSION: Photoablation through the PALM technique
      did not result any evident alterations of the reepithelisation and stromal
      healing process.

PMID- 12597780
TI  - Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides
      in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus.
AB  - BACKGROUND: Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is
      considered to be a T cell mediated disease in which TH1 and Tc autoreactive cells
      attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM,
      glutamic acid decarboxylase (GAD) 65 appears to play a key role in the
      development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the
      experimental model for this disease. It has been shown that shifting the immune
      response to this antigen from TH1 towards TH2, via the administration of GAD65
      peptides to young NOD mice, can suppress the progression to overt T1DM.
      Accordingly, various protocols of "peptide immunotherapy" of T1DM are under
      investigation. However, in mice with experimental autoimmune encephalomyelitis
      (EAE), another autoimmune TH1 mediated disease that mimics human multiple
      sclerosis, anaphylactic shock can occur when the mice are challenged with certain
      myelin self peptides that initially were administered with adjuvant to induce the
      disease. RESULTS: Here we show that NOD mice, that spontaneously develop T1DM,
      can develop fatal anaphylactic reactions upon challenge with preparations of
      immunodominant GAD65 self peptides after immunization with these peptides to
      modify the development of T1DM. CONCLUSIONS: These findings document severe
      anaphylaxis to self peptide preparations used in an attempt to devise
      immunotherapy for a spontaneous autoimmune disease. Taken together with the
      findings in EAE, these results suggest that peptide therapies designed to induce
      a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to
      the therapeutic peptides.

PMID- 12597781
TI  - Human CD81 directly enhances Th1 and Th2 cell activation, but preferentially
      induces proliferation of Th2 cells upon long-term stimulation.
AB  - BACKGROUND: CD81, a cell-surface protein of the tetraspanin superfamily, has been
      shown to costimulate T cell activation in murine T cells, and is involved in
      development of Th2 immune responses in mice. RESULTS: Here it is shown that
      stimulation of CD81 on human T cells can enhance T cell activation by antigen or
      superantigen, causing an increase in the early activation marker CD69, and
      increasing the number of cytokine-producing and proliferating T cells.
      Interestingly, CD81 costimulates cytokine production by T cells producing both
      Th1 and Th2 cytokines. Although human CD81 is highly expressed on non-T as well
      as T cells, CD81 costimulation appears to act directly on T cells. Pre-incubation
      of purified T cells with anti-CD81 antibody is sufficient to increase T cell
      activation, while pre-incubation of non-T cells is not. However, long-term
      polyclonal stimulation of T cells by anti-CD3 antibody, in the presence of CD81
      costimulation, biases T cells towards the production of IL-4 and not IFNgamma.
      This is accomplished by a preferential proliferation of IL-4-producing cells.
      CONCLUSION: Thus, signalling through CD81 on T cells costimulates both Th1 and
      Th2 cells, but increases the number of Th2 cells during long-term activation.

PMID- 12597783
TI  - Automated analysis of SEM X-ray spectral images: a powerful new microanalysis
      tool.
AB  - Spectral imaging in the scanning electron microscope (SEM) equipped with an
      energy-dispersive X-ray (EDX) analyzer has the potential to be a powerful tool
      for chemical phase identification, but the large data sets have, in the past,
      proved too large to efficiently analyze. In the present work, we describe the
      application of a new automated, unbiased, multivariate statistical analysis
      technique to very large X-ray spectral image data sets. The method, based in part
      on principal components analysis, returns physically accurate (all positive)
      component spectra and images in a few minutes on a standard personal computer.
      The efficacy of the technique for microanalysis is illustrated by the analysis of
      complex multi-phase materials, particulates, a diffusion couple, and a single
      pixel-detection problem.

PMID- 12597784
TI  - A simple low-vacuum environmental cell.
AB  - The environmental cell device discussed in this paper provides a modest low
      vacuum scanning electron microscopy (SEM) capability to a standard SEM without
      requiring additional pumping. This environmental cell confines a volume of low
      vacuum in contact with the sample surface using a container that has an aperture
      for admitting the primary electron beam. The aperture is large enough to permit a
      limited field of view of the sample, and small enough to limit the outflow of gas
      into the SEM chamber to that which can be accommodated by the standard SEM
      pumping system. This environmental cell also functions as a gaseous detector
      device.

PMID- 12597785
TI  - A single-tilt TEM stereomicroscopy technique for crystalline materials.
AB  - A new single-tilt technique for performing TEM stereomicroscopy of strain fields
      in crystalline materials has been developed. The technique is a weak beam
      technique that involves changing the value of g and/or s g while tilting across a
      set of Kikuchi bands. The primary benefit of the technique is it can be used with
      single-tilt TEM specimen holders including many specialty holders such as in situ
      straining, heating, and cooling holders. Standard stereo-TEM techniques are
      almost always limited to holders allowing two degrees of rotational freedom
      (i.e., double-tilt or tilt/rotation holders). An additional benefit of the new
      technique is that it eliminates the need to focus with the specimen height
      control. These advantages make it useful for stereo viewing or for quantitative
      stereomicroscopy provided necessary consideration is given to errors that may
      result from the technique.

PMID- 12597786
TI  - Electron ionization cross sections for atomic subshells.
AB  - Ionization of atoms is the first step in many analytical procedures. The cross
      section for ionizing a particular atomic shell is essential for calculating the
      magnitude of analytical signals. Calculations using atomic wave functions for
      various shells of all elements relevant for X-ray microanalysis over a range of
      electron energies up to 400 keV were performed. The calculations for high
      energies above threshold can be considerably simplified by using the mathematical
      form of the Bethe ridge that dominates the scattering in this region. Corrections
      for exchange at low energies above threshold are incorporated in these
      calculations. A selection of results showing the effects of different
      approximations on ionization cross sections for K, L, and M shells is presented.

PMID- 12597787
TI  - The role of microscopy in understanding atherosclerotic lysosomal lipid
      metabolism.
AB  - Microscopy has played a critical role in first identifying and then defining the
      role of lysosomes in formation of atherosclerotic foam cells. We review the
      evidence implicating lysosomal lipid accumulation as a factor in the pathogenesis
      of atherosclerosis with reference to the role of microscopy. In addition, we
      explore mechanisms by which lysosomal lipid engorgement occurs. Low density
      lipoproteins which have become modified are the major source of lipid for foam
      cell formation. These altered lipoproteins are taken into the cell via receptor
      mediated endocytosis and delivered to lysosomes. Under normal conditions, lipids
      from these lipoproteins are metabolized and do not accumulate in lysosomes. In
      the atherosclerotic foam cell, this normal metabolism is inhibited so that
      cholesterol and cholesteryl esters accumulate in lysosomes. Studies of cultured
      cells incubated with modified lipoproteins suggests this abnormal metabolism
      occurs in two steps. Initially, hydrolysis of lipoprotein cholesteryl esters
      occurs normally, but the resultant free cholesterol cannot exit the lysosome.
      Further lysosomal cholesterol accumulation inhibits hydrolysis, producing a
      mixture of cholesterol and cholesteryl esters within swollen lysosomes. Various
      lipoprotein modifications can produce this lysosomal engorgement in vitro and it
      remains to be seen which modifications are most important in vivo.

PMID- 12597788
TI  - Apoptosis process in mouse Leydig cells during postnatal development.
AB  - The development of Leydig cells in mammals has been widely described as a
      biphasic pattern with two temporally mature Leydig cell populations, fetal stage
      followed by the adult generation beginning at puberty. In the present study,
      mouse Leydig cells were examined for apoptosis during postnatal testis
      development using electron microscopy and in situ DNA fragmentation by terminal
      deoxynucleotidyl transferase staining (TdT). Both the morphological study and the
      DNA fragmentation analysis showed that cellular death by apoptosis did not occur
      in Leydig cells during the neonatal, prepubertal, puberty, and adult periods.
      From these results, we suggest that the remaining fetal Leydig cells in the
      neonatal testis are associated with the involution or degeneration processes. In
      contrast, in the prepubertal and puberty stages, fragmentation of apoptotic DNA
      was detected in germ cells present in some seminiferous tubules.

PMID- 12597791
TI  - Problem Solving Using In Situ Transmission Electron Microscopy: Introduction.

PMID- 12597789
TI  - Simultaneous mechanical loading and confocal reflection microscopy for three
      dimensional microbiomechanical analysis of biomaterials and tissue constructs.
AB  - At present, mechanisms by which specific structural and mechanical properties of
      the three-dimensional extracellular matrix microenvironment influence cell
      behavior are not known. Lack of such knowledge precludes formulation of
      engineered scaffolds or tissue constructs that would deliver specific growth
      inductive signals required for improved tissue restoration. This article
      describes a new mechanical loading-imaging technique that allows investigations
      of structural-mechanical properties of biomaterials as well as the structural
      mechanical basis of cell-scaffold interactions at a microscopic level and in
      three dimensions. The technique is based upon the integration of a modified,
      miniature mechanical loading instrument with a confocal microscope. Confocal
      microscopy is conducted in a reflection and/or fluorescence mode for selective
      visualization of load-induced changes to the scaffold and any resident cells,
      while maintaining each specimen in a "live," fully hydrated state. This
      innovative technique offers several advantages over current biomechanics
      methodologies, including simultaneous visualization of scaffold and/or cell
      microstructure in three dimensions during mechanical loading; quantification of
      macroscopic mechanical parameters including true stress and strain; and the
      ability to perform multiple analyses on the same specimen. This technique was
      used to determine the structural-mechanical properties of three very different
      biological materials: a reconstituted collagen matrix, a tissue-derived
      biomaterial, and a tissue construct representing cells and matrix.

PMID- 12597792
TI  - In Situ Environmental Cell-Transmission Electron Microscopy Study of Microbial
      Reduction of Chromium(VI) Using Electron Energy Loss Spectroscopy.
AB  - Reduction of Cr(VI) by the bacterium, Shewanella oneidensis (previously
      classified Shewanella putrefaciens strain MR-1), was studied by absorption
      spectrophotometry and in situ, environmental cell-transmission electron
      microscopy (EC-TEM) coupled with electron energy loss spectroscopy (EELS).
      Bacteria from rinsed cultures were placed directly in the environmental cell of
      the transmission electron microscope and examined under 100 Torr pressure. Bright
      field EC-TEM images show two distinct populations of S. oneidensis in incubated
      cultures containing Cr(VI)O2- 4: those that exhibit low image contrast and
      heavily precipitate-encrusted cells exhibiting high image contrast. Several EELS
      techniques were applied to determine the oxidation state of Cr associated with
      encrusted cells. The encrusted cells are shown to contain a reduced form of Cr in
      oxidation state +3 or lower. These results demonstrate the capability to
      determine the chemistry and valence state of reduction products associated with
      unfixed, hydrated bacteria in an environmental cell transmission electron
      microscope.

PMID- 12597793
TI  - Surface Kinetics of Copper Oxidation Investigated by In Situ Ultra-high Vacuum
      Transmission Electron Microscopy.
AB  - We review our studies of the initial oxidation stages of Cu(001) thin films as
      investigated by in situ ultra-high vacuum transmission electron microscopy. We
      present our observations of surface reconstruction and the nucleation to
      coalescence of copper oxide during in situ oxidation in O2. We have proposed a
      semi-quantitative model, where oxygen surface diffusion is the dominant mechanism
      of the initial oxidation stages of Cu. We have also investigated the effect of
      water vapor on copper oxidation. We have observed that the presence of water
      vapor in the oxidizing atmosphere retards the rate of Cu oxidation and Cu2O is
      reduced when exposed directly to steam.

PMID- 12597794
TI  - Design and Applications of Environmental Cell Transmission Electron Microscope
      for In Situ Observations of Gas-Solid Reactions.
AB  - The environmental transmission electron microscopy (E-TEM) is a budding technique
      for in situ study of gas-solid chemical reactions with numerous applications.
      Recent improvements in the design have made it possible not only to obtain atomic
      level information but also the chemical information during the reaction by
      incorporating an imaging filter or electron energy-loss spectrometer to an E-TEM.
      We have been involved in modifying a couple of microscopes to incorporate
      environmental cells in order to convert them into E-TEMs. These microscopes have
      been used to obtain atomic level information of the structural and chemical
      changes during dynamic processes by in situ electron diffraction, high-resolution
      imaging, and electron energy-loss spectroscopy. The applications include, but are
      not limited to, oxidation, reduction, polymerization, nitridation,
      dehydroxylation, hydroxylation, chemical vapor deposition, etc. We report recent
      developments in the design and application along with the limitations of an E
      TEM.

PMID- 12597795
TI  - Development of a Nanoindenter for In Situ Transmission Electron Microscopy.
AB  - In situ transmission electron microscopy is an established experimental technique
      that permits direct observation of the dynamics and mechanisms of dislocation
      motion and deformation behavior. In this article, we detail the development of a
      novel specimen goniometer that allows real-time observations of the mechanical
      response of materials to indentation loads. The technology of the scanning
      tunneling microscope is adopted to allow nanometer-scale positioning of a sharp,
      conductive diamond tip onto the edge of an electron-transparent sample. This
      allows application of loads to nanometer-scale material volumes coupled with
      simultaneous imaging of the material's response. The emphasis in this report is
      qualitative and technique oriented, with particular attention given to sample
      geometry and other technical requirements. Examples of the deformation of
      aluminum and titanium carbide as well as the fracture of silicon will be
      presented.

PMID- 12597796
TI  - Verification of Layered Structures in SnO2/Metal-based Gas Sensors by X-ray
      Microanalysis: Comparison with X-ray Photoelectron Spectroscopy.
AB  - The depth profile of thin film layers on bulk substrate, avoiding the cross
      sectioning of samples, is commonly performed by techniques such as X-ray
      photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES), and
      secondary ion mass spectroscopy (SIMS). Techniques based on X-ray emission
      intensity measurements by energy dispersive spectroscopy (EDS), with conventional
      matrix or ZAF correction, are normally applied to cross-sectioned samples. This
      article compares XPS with surface X-ray intensity measurements by EDS, carried
      out with a more realistic X-ray generation and absorption model, known as the
      pi(rho Z) model. The pi(rho Z) approach has been adopted together with Monte
      Carlo simulation for the proper selection of SEM accelerating voltages, in
      conjunction with the analysis of SEM morphological images for thin film density
      correction. The method discussed hereafter and compared with the XPS technique,
      has advantages of higher lateral resolution, non-destructive elemental analyses,
      morphological visualization, low cost, and faster performance. This methodology
      has been followed to verify the layered structure of SnO2/metal-based gas
      sensors. X-ray intensities were measured using an EDS ultra-thin window detector.
      Two different porous layers, 25-nm thick of SnO2 and 10-nm thick of Cu, were
      detected, showing better agreement with their nominal thickness compared to
      results obtained using XPS measurements where porosity affects XPS data. If
      confirmed to be reliable and as effective as XPS depth profiling, this technique
      may be adopted for process quality control purposes.

PMID- 12597797
TI  - Atomic Force Microscopy and Scanning Electron Microscopy Reveal Genome-dependent
      Ultrastructure of Seed Surface.
AB  - Both scanning electron microscopy (SEM) and contact mode imaging via atomic force
      microscopy (AFM) have been utilized to elucidate the ultrastructure of mung bean
      seed surfaces. The results indicate: 1) that AFM is useful in the examination of
      seed surface ultrastructure ex-vaccuo without the need for additional complex
      preparative procedures; and 2) that both the cotyledon and seed coat of different
      strains of mung beans bear specific ultrastructural details unique to each
      strain. To our knowledge, these are the first AFM images of seed surfaces.

PMID- 12597798
TI  - Improved Technique for Electron Microscope Visualization of Yeast Membrane
      Structure.
AB  - Yeast cells represent a powerful model system in cell biology mainly due to their
      amenability to genetic manipulations. Increasingly, studies focus on mutant genes
      resulting in alterations of cellular structures and organelles. To ascertain the
      phenotypic changes involved, it is often desirable to use the resolving power of
      electron microscopy. In contrast to higher eukaryotic cells, yeast cells are
      particularly difficult to preserve mainly due to the presence of a thick cell
      wall that acts as a barrier against diffusion of fixatives. Although several
      procedures are targeted to overcome these difficulties, none of them have become
      established as a standard procedure. As a consequence, electron microscopy is
      still not used routinely as a tool in yeast cell biology. This prompted us to
      develop an easy-to-follow protocol for yeast transmission electron microscopy
      that should be useful in all cases where membrane integrity and organelle
      morphology is emphasized. One means of making the yeast cytoplasm more attainable
      to fixation and staining solutions is by enzymatic digestion of the cell wall.
      Following this approach, we were able to reliably preserve yeast cells and their
      cellular organelles. Enzymatic treatment with zymolyase 20T to partially remove
      the yeast cell wall allowed the fixation, preservation, and visualization of the
      yeast cytoplasm revealing detailed ultrastructure. The advancement of this
      technique is demonstrated with mitochondria as a model organelle. Our studies on
      various yeast mutants clearly show the power of the enzymatic digestion technique
      in visualizing subtle changes of membrane structure and organelle morphology.

PMID- 12597799
TI  - Cytoskeleton Methods and Protocols. Methods in Molecular Biology Series.

PMID- 12597800
TI  - Soft X-rays and Extreme Ultraviolet Radiation: Principles and.

PMID- 12597802
TI  - News and Commentary.

PMID- 12597803
TI  - Accurate Recording and Measurement of Electron Diffraction Data in Structural and
      Difference Fourier Studies of Proteins.
AB  - Many of the techniques that have been developed in X-ray crystallography are
      being applied in electron crystallographic studies of proteins. Electron
      crystallography has the advantage of measuring structure factor phases directly
      from high resolution images with an accuracy substantially higher than is common
      in X-ray crystallography. However, electron diffraction amplitudes are often not
      as precise as those obtained in X-ray work. We discuss here some approaches to
      maximizing the reliability of the diffraction amplitudes through choice of
      exposure and data processing schemes. With accurate measurement of diffraction
      data, Fourier difference methods can be used in electron crystallographic studies
      of small, localized changes of proteins that exist in two-dimensional crystals.
      The mathematical basis for the power of these methods in detecting small changes
      is reviewed. We then discuss several issues related to optimizing the quality of
      the diffraction data and derive an expression for the best exposure for recording
      diffraction patterns. An application of Fourier difference maps in localizing
      drug binding sites on the protein tubulin is discussed.

PMID- 12597804
TI  - Site-specific Transmission Electron Microscope Characterization of Micrometer
      sized Particles Using the Focused Ion Beam Lift-out Technique.
AB  - Micrometer sized particles have been studied to show that a high-quality
      transmission electron microscope (TEM) specimen can be produced, without the use
      of embedding media, from a site-specific region of chosen particles using the
      focused ion beam (FIB) lift-out (LO) technique. The uniqueness of this technique
      is that site-specific TEM LO specimens may be obtained from particles and from
      regions which are smaller than the conventional approximately 10-20 &mgr;m x 5
      &mgr;m x approximately 0.1 &mgr;m dimensions of the LO specimen. The innovative
      FIB LO procedures are described in detail and TEM images of electron transparent
      specimens obtained from specific micrometer-sized particles are presented.

PMID- 12597806
TI  - News and Commentary.

PMID- 12597807
TI  - Web-based Simulation for Contrast Transfer Function and Envelope Functions.
AB  - We have implemented a Web-based simulation program for the contrast transfer
      function and envelope functions in Java and JavaScript. The simulation provides
      interactive controls of all the parameters in those functions. In addition to the
      predefined functions, users can easily define new functions that use any of the
      parameters in the preset functions. The most useful feature of this new
      simulation program is the convenient, universal accessibility through Web
      browsers on any computer platform that supports Java, such as Netscape and
      Internet Explorer.

PMID- 12597808
TI  - Differential Image Distortion Correction.
AB  - Imaging techniques often suffer from distortion effects. Former methods of
      reducing these distortions have been based either on improving the imaging
      technique (i.e., to avoid distortions) or on the use of reference samples (i.e.,
      to determine the distortion field by imaging of a known structure. We present a
      novel method of correcting image distortion by evaluating the imaged position
      changes due to two small sample position shifts. The algorithm allows us to
      calculate a vector field, which enables us to determine the "undistorted"
      position of any point of the image. The presented method has very low
      presuppositions about the sample, requires no reference samples, and is
      applicable to any type of image distortion. In addition to the presentation of
      the method's theoretical basis and a description of the computational method, we
      present corrected secondary ion mass spectroscopy (SIMS) images of a regular
      structure (a copper grid) as well as a stochastic distribution (sodium
      impurities) to show the results of empirical data.

PMID- 12597809
TI  - Improved X-ray Spectrum Simulation for Electron Microprobe Analysis.
AB  - The accurate calculation of characteristic peak intensity is essential for
      interpreting X-ray spectra in electron microprobe analysis. Conventionally, the
      measured intensity from a standard of known composition is used as a reference to
      simplify the calculation. However, if no such standard is available, then all
      factors influencing X-ray generation and X-ray detection efficiency must be
      included. If the intensity and energy distribution of the background radiation
      can also be calculated, the investigator can simulate an entire spectrum from an
      assumed composition, gaining powerful benefits in setting up an experiment and in
      confirming the results. The study presented here demonstrates a fast method of
      spectrum simulation, suitable for energy-dispersive spectroscopy (EDS), and
      assesses the accuracy using 309 spectra from samples of known composition. These
      include K, L, and M lines from elements of atomic number 6-92, excited by beam
      energies in the range of 5-30 keV. The RMS error between 360 measured and
      calculated peak intensities was found to be 7.1%. Central to the method is the
      use of the ratio of peak intensity/total background intensity, which allows
      spectra to be compared from instruments of differing collection efficiency,
      thereby easing the collection of data over a wide range of conditions.

PMID- 12597810
TI  - Scattering Cross Sections in Electron Microscopy and Analysis.
AB  - The scattering cross section is the fundamental measure of the strength of a
      scattering interaction. All scattering in electron microscopy arises from the
      Coulomb interaction, and scattering cross sections, whether elastic or inelastic,
      will therefore all have common features. Simple forms of both elastic and
      inelastic cross sections are reviewed in the context of high resolution and
      analytical microscopy. Some recent developments, such as the calculation of Fano
      resonances in electron energy loss spectra of transition metals and rare earth
      elements are also discussed.

PMID- 12597811
TI  - Scanning Probe Microscope Observation of Recorded Marks in Phase Change Disks.
AB  - This is the first report on observation of phase change recorded marks by use of
      the scanning probe microscope (SPM). The amorphous mark and crystalline blank
      were clearly observed by surface potential mode (SPoM) that visualized the
      surface potential difference among phases or materials. SPoM observation has an
      advantage over conventional transmission electron microscope (TEM) observation in
      that the sample preparation is much easier, and that amorphous mark and
      crystalline blank are clearly distinguished. The possibility of a novel readout
      method of phase change disks, and the possibility of the novel medium with a
      surface potential detection method are also proposed.

PMID- 12597812
TI  - Evidence for 9R-SiC?
AB  - Complementary to our first paper on the origin of threefold contrast on SiC high
      resolution transmission electron microscopy (HRTEM) images, we now provide an
      example of threefold contrast produced by a stacking layer sequence which
      corresponds to one unit cell of the 9R polytype.

PMID- 12597814
TI  - News and Commentary.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597813
TI  - Protein Localization by Fluorescence Microscopy: A PracticalApproach, edited by
      Victoria J. Allan.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597815
TI  - TelePresence Confocal Laser Scanning Microscopy.
AB  - The advent of the Internet has allowed the development of remote access
      capabilities to a growing variety and number of microscopy systems. To date, the
      confocal microscope has not been included among these systems. At the California
      State University (CSU) Confocal Microscopy Core Facility, we have established a
      remote access confocal laser scanning microscope facility that allows users with
      virtually any type of computer platform to connect to our system. Our Leica TCS
      NT confocal system is accessible to any authorized user via the Internet by using
      a free software program called VNC (Virtual Network Computing). Once connectivity
      is established, remote users are able to control virtually all the functions to
      conduct real-time image analysis and quantitative assessments of their specimen.
      They can also move the motorized stage to view different regions of their
      specimen by using a software program associated with the stage. At the end of the
      session, all files generated during the session can be downloaded to the user's
      computer from a link on the CSU confocal website. A number of safeguard features
      have been developed to ensure security and privacy of data acquired during a
      remote session.

PMID- 12597816
TI  - Vascular Corrosion Casting: Review of Advantages and Limitations in the
      Application of Some Simple Quantitative Methods.
AB  - Vascular corrosion casting has been used for about 40 years to produce replicas
      of normal and abnormal vasculature and microvasculature of various tissues and
      organs that could be viewed at the ultrastructural level. In combination with
      scanning electron microscopy (SEM), the primary application of corrosion casting
      has been to describe the morphology and anatomical distribution of blood vessels
      in these tissues. However, such replicas should also contain quantitative
      information about that vasculature. This report summarizes some simple
      quantitative applications of vascular corrosion casting. Casts were prepared by
      infusing Mercox resin or diluted Mercox resin into the vasculature. Surrounding
      tissues were removed with KOH, hot water, and formic acid, and the resulting
      dried casts were observed with routine SEM. The orientation, size, and frequency
      of vascular endothelial cells were determined from endothelial nuclear imprints
      on various cast surfaces. Vascular volumes of heart, lung, and avian salt gland
      were calculated using tissue and resin densities, and weights. Changes in
      vascular volume and functional capillary density in an experimentally induced
      emphysema model were estimated from confocal images of casts. Clearly, corrosion
      casts lend themselves to quantitative analysis. However, because blood vessels
      differ in their compliances, in their responses to the toxicity of casting
      resins, and in their response to varying conditions of corrosion casting
      procedures, it is prudent to use care in interpreting this quantitative data.
      Some of the applications and limitations of quantitative methodology with
      corrosion casts are reviewed here.

PMID- 12597817
TI  - Three-dimensional Analysis of Laser Scanning Confocal Microscope Sections Reveals
      an Array of Microtubules in the Cleavage Furrow of Sea Urchin Eggs.
AB  - Our recent observation that microtubules (MTs) are required for completion of
      division (abscission) led us to analyze MT organization during cytokinesis.
      Although many studies of MTs in sea urchin eggs have been done, computer-aided
      analysis of optical sections described herein reveals a new MT assemblage, which
      we call furrow MTs. This assemblage comprises bundles of MTs that lie in the
      cleavage furrow. Furrow MTs become apparent when the furrow has progressed
      approximately one-third of the way through the egg and persist to abscission.
      Furrow MTs are 8-24-&mgr;m long and arc across the base of the cleavage furrow.
      Acetylated tubulin is localized primarily in the furrow suggesting a distinct MT
      population. Three-dimensional analysis of optical sections suggests that furrow
      MTs are spatially distinct from midbody and astral MTs.

PMID- 12597818
TI  - Chemical Etching Technique for the Investigation of Melt-crystallized Isotactic
      Polypropylene Spherulite and Lamellar Morphology by Scanning Electron Microscopy.
AB  - The spherulitic and lamellar morphologies of melt crystallized isotactic
      polypropylene (iPP) have been investigated according to various crystallization
      temperatures and times. In this study, an appropriate chemical etching condition
      for the observation of iPP morphology by scanning electron microscopy (SEM) is
      determined. The optimum etchant formulation is 3 wt% potassium permanganate with
      the mixed solvent of sulfuric acid and phosphoric acid. The morphologies after
      etching reveal the microstructure of iPP clearly, such as the characterization of
      alpha/beta spherulites and the different lamellar growth patterns.

PMID- 12597820
TI  - News and Commentary.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597819
TI  - Method for Cross-sectional Thin Specimen Preparation from a Specific Site Using a
      Combination of a Focused Ion Beam System and Intermediate Voltage Electron
      Microscope and Its Application to the Characterization of a Precipitate in a
      Steel.
AB  - In this study, we discuss a method for cross-sectional thin specimen preparation
      from a specific site using a combination of a focused ion beam (FIB) system and
      an intermediate voltage transmission electron microscope (TEM). A FIB-TEM
      compatible specimen holder was newly developed for the method. The thinning of
      the specimen using the FIB system and the observation of inside structure of the
      ion milled area in a TEM to localize a specific site were alternately carried
      out. The TEM fitted with both scanning transmitted electron detector and
      secondary electron detector enabled us to localize the specific site in a halfway
      milled specimen with the positional accuracy of better than 0.1 &mgr;m. The
      method was applied to the characterization of a precipitate in a steel. A
      submicron large precipitate was thinned exactly at its center for the
      characterization by a high-resolution electron microscopy and an elemental
      mapping.

PMID- 12597821
TI  - Fifty Years of Electron Probe Microanalysis: A Celebration Honoring Raimond
      Castaing-Introduction.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597822
TI  - Keynote Address: The Time of Pioneers.
AB  - This article, dedicated to the memory of the late professor Raimond Castaing,
      will evoke the birth and the first developments of electron probe microanalysis
      in France.

PMID- 12597823
TI  - The Golden Age of Microanalysis.
AB  - The history of electron probe analysis in the USA in its first two decades is
      reviewed, with reference to the personalities which were involved, the
      development of instrumentation and theory, and the technical problems and
      limitations of that era.

PMID- 12597824
TI  - Development of Electron Probe Instrumentation during Those Early Days When
      Professor Castaing Visited Japan.
AB  - The development of the electron probe microanalyzer (EPMA) in Japan in the early
      1960s, when Prof. R. Castaing visited Japan, is briefly outlined. In 1955, a
      review article was published by Prof. G. Shinoda in Oyobutsuri, the most popular
      journal in Japan, in which the EPMA was introduced. In 1957, a research group at
      the University of Tokyo started to develop an EPMA with a Grant-in-Aid for
      Developmental Research. Their research results led to the funding of a 2-year
      Grant-in-Aid for Cooperative Research Project (April 1960 to March 1962), which
      was chaired by Prof. Y. Sakaki. Prof. G. Shinoda who became the chairman of that
      project in April of 1962 led that group for another year until March of 1963. It
      was just after the start of the project that Prof. R. Castaing visited Japan in
      September of 1960 as a representative of the French Mission Culturelle. This
      visit gave a great push forward for the commercial development of EPMA
      instruments in Japan. The first three commercial EPMA instruments from Hitachi,
      JEOL, and Akashi Ltds. were installed in Tohoku, Osaka, and Waseda Universities
      in 1962, 1963, and 1964, respectively. Photographs of those first commercial EPMA
      systems, together with a brief description of the activities of the cooperative
      research projects, are presented.

PMID- 12597825
TI  - X-ray Crystal Spectrometers and Monochromators in Microanalysis.
AB  - Castaing's successful implementation and application of the electron probe
      microanalyzer in 1950 stimulated a flurry of development activity around the
      world. The later versions of this instrument represented a truly international
      effort, with significant contributions by scientists from Europe, Asia, and North
      America. If the probe-forming system of the instrument was its heart, the X-ray
      wavelength spectrometer was its soul. This article reviews some of the history of
      spectrometer developments-through the "golden years" of microprobe development,
      namely the dozen or so years following the publication of Castaing's thesis, to
      the present. The basic physics of spectrometer and crystal design is reviewed.
      Early experimental devices, such as those developed by Castaing, Borovskii,
      Wittry, Duncumb, and Ogilvie are reported. Examples of commercial spectrometers
      such as those by ARL, MAC, Microspec, and Peak are described. Recent developments
      such as the combination of grazing-incidence optics with flat crystal
      spectrometers are noted, and the properties and uses of doubly curved crystals
      are discussed. Finally, the continued development of doubly curved crystal
      configurations, such as the "Wittry geometry" for scanning monochromators, and
      point-to-point focusing diffractors for producing small monochromatic X-ray
      probes to provide improved detection limits for microanalysis are considered.

PMID- 12597826
TI  - Today's and Tomorrow's Instruments.
AB  - This article will discuss the importance of Raimond Castaing's thesis on the
      genesis of a nondestructive and truly quantitative microanalytical method that
      assisted the scientific community in moving forward in the development of
      microanalytical instruments. I will also share with you my recollection of the
      decades of improvement in the electron probe microanalyzer (EPMA), that has
      allowed us to reach our present level of instrument sophistication, and I will
      explore with you my thoughts on the future evolution of this technique. To
      conclude, I will present the current status of related microanalysis techniques
      developed under Castaing in Orsay in the 1960s, as Castaing's interest in
      microanalysis was not limited to electron probe microanalysis alone.

PMID- 12597827
TI  - Wavelength Dispersive Spectrometer and Energy Dispersive Spectrometer Automation:
      Past and Future Development.
AB  - As part of the Microbeam Analysis Society (MAS) symposium marking 50 years of
      electron microprobe analysis, this article reviews the important advances made
      over the decades to the automation of data collection and computerized analysis
      of data from the electron microprobe. Out of many innovations that contributed to
      the advance of microprobe automation, we have chosen to focus on a few
      developments that the authors feel represent the major trends in advancement of
      the "state of the art" of this instrumentation. After providing brief summaries
      of the three generations of advances in the hardware and software of automation
      systems, several key applications developments are described, followed by our
      prediction of which current developments may impact the future automation of the
      microprobe.

PMID- 12597828
TI  - Fundamental Constants for Quantitative X-ray Microanalysis.
AB  - Quantitative X-ray microanalysis requires the use of many fundamental constants
      related to the interaction of the electron beam with the sample. The current
      state of our knowledge of such constants in the particular areas of electron
      stopping power, X-ray ionization cross-sections, X-ray fluorescence yield, and
      the electron backscattering yield, is examined. It is found that, in every case,
      the quality and quantity of data available is poor, and that there are major gaps
      remaining to be filled.

PMID- 12597829
TI  - Minimizing Errors in Electron Microprobe Analysis.
AB  - Errors in quantitative electron microprobe analysis arise from many sources
      including those associated with sampling, specimen preparation, instrument
      operation, data collection, and analysis. The relative magnitudes of some of
      these factors are assessed for a sample of NiAl used to demonstrate important
      concerns in the analysis of even a relatively simple system measured under
      standard operating conditions. The results presented are intended to serve more
      as a guideline for developing an analytical strategy than as a detailed error
      propagation model that includes all possible sources of variability and
      inaccuracy. The use of a variety of tools to assess errors is demonstrated. It is
      also shown that, as sample characteristics depart from those under which many of
      the quantitative methods were developed, errors can increase significantly.

PMID- 12597830
TI  - Castaing's Electron Microprobe and Its Impact on Materials Science.
AB  - The development of the electron microprobe by Raymond Castaing provided a great
      stimulus to materials science at a critical time in its history. For the first
      time, accurate elemental analysis could be performed with a spatial resolution of
      1 &mgr;m, well within the dimensions of many microstructural features. The impact
      of the microprobe occurred across the entire spectrum of materials science and
      engineering. Contributions to the basic infrastructure of materials science
      included more accurate and efficient determination of phase diagrams and
      diffusion coefficients. The study of the microstructure of alloys was greatly
      enhanced by electron microprobe characterization of major, minor, and trace
      phases, including contamination. Finally, the electron microprobe has proven to
      be a critical tool for materials engineering, particularly to study failures,
      which often begin on a micro-scale and then propagate to the macro-scale with
      catastrophic results.

PMID- 12597831
TI  - A Few Examples of Electron Microanalysis of Art Objects at the Boston Museum of
      Fine Arts.
AB  - Examples of a few objects are presented, where the electron microprobe has proved
      that it can provide the conservator and the curator with information that will
      help in evaluating the authenticity of a particular art object. They will also
      obtain a better understanding of how an object was fabricated and what materials
      it was made from. The results of the analysis of paint samples, samples from
      metal artifacts, as well as specimens from marble sculptures, are described.

PMID- 12597832
TI  - Application of Electron Probe Microanalysis to the Study of Geological and
      Planetary Materials.
AB  - The impact of electron probe microanalysis on the study of geological and
      planetary materials has been tremendous. Electron microprobes evolved into
      routine analytical instruments in geological research laboratories as instrument
      capabilities improved and applications to geologic/planetary materials expanded.
      The contributions of electron probe microanalysis to the characterization of
      minerals, both terrestrial and extraterrestrial, and to other significant
      geological research, such as light element analysis, trace element analysis, and
      element mapping, is described.

PMID- 12597833
TI  - Biological X-ray Microanalysis: The Past, Present Practices, and Future
      Prospects.
AB  - Abrief description is given of the events surrounding the development of
      biological X-ray microanalysis during the last 30 years, with particular emphasis
      on the contribution made by research workers in Cambridge, UK. There then follows
      a broad review of some applications of biological X-ray microanalysis. A more
      detailed consideration is given to the main thrust of current procedures and
      applications that are, for convenience, considered as four different kinds of
      samples. Thin frozen dried sections which are analyzed at ambient temperatures in
      a transmission electron microscope (TEM); semithin frozen dried sections which
      are analyzed at low temperature in a scanning transmission electron microscope
      (STEM); thick frozen hydrated sections which are analyzed at low temperature in a
      scanning electron microscope (SEM), and bulk samples which are analyzed at low
      temperature in the same type of instrument. A brief outline is given of the
      advantages and disadvantages of performing low-voltage, low-temperature X-ray
      microanalysis on frozen hydrated bulk biological material. The article concludes
      with a consideration of alternative approaches to in situ analysis using either
      high-energy beams or visible and near-visible photons.

PMID- 12597834
TI  - News and Commentary.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597835
TI  - Principles and Techniques of Electron Microscopy: Biological Applications, Fourth
      Edition, by M. A. Hayat.
AB  - FATAL ERROR -- Missing abstract.

PMID- 12597851
TI  - Addictive drugs and stress trigger a common change at VTA synapses.
AB  - In this issue of Neuron, Saal et al. find that exposure to any of five addictive
      drugs or exposure to a brief stressor produces a shared cellular modification of
      excitatory synapses in the ventral tegmental area (VTA). This common response may
      represent a starting point for dissecting early changes that underlie addiction.

PMID- 12597852
TI  - Filling the interstices: ghrelin neurons plug several holes in regulation of
      energy balance.
AB  - Of several circulating hormones that act on hypothalamus to affect body energy
      balance, only ghrelin is also expressed in hypothalamic neurons. From the studies
      of Horvath and colleagues appearing in this issue of Neuron, it appears that
      neuronal ghrelin acts presynaptically to stimulate release of the orexigenic
      peptide, neuropeptide Y, and other neurotransmitters, thus defining a new and
      subtle modulatory circuit.

PMID- 12597853
TI  - Sunrise at the synapse: the FMRP mRNP shaping the synaptic interface.
AB  - Recent studies provide new insight into the mechanistic function of Fragile X
      Mental Retardation Protein (FMRP), paving the way to understanding the biological
      basis of Fragile X Syndrome. While it has been known for several years that there
      are spine defects associated with the absence of the mRNA binding protein FMRP,
      it has been unclear how its absence may lead to specific synaptic defects that
      underlie the learning and cognitive impairments in Fragile X. One hypothesis
      under study is that FMRP may play a key role in the regulation of dendritically
      localized mRNAs, at subsynaptic sites where regulation of local protein synthesis
      may influence synaptic structure and plasticity. This review highlights recent
      progress to identify the specific mRNA targets of FMRP and assess defects in mRNA
      regulation that occur in cells lacking FMRP. In addition, exciting new studies on
      Fmr1 knockout mice and mutant flies have begun to elucidate a key role for FMRP
      in synaptic growth, structure, and long-term plasticity.

PMID- 12597854
TI  - Metalloproteases: carving out a role in axon guidance.
AB  - Two families of metalloproteases, the matrix metalloproteases (MMPs) and the A
      Disintegrin and Metalloproteases (ADAMs), have recently been implicated in the
      formation of neural connections in the developing central nervous system.
      Invertebrate and vertebrate axons fail to extend and/or make pathfinding errors
      when metalloprotease function is inhibited or absent. Culture studies suggest
      that this requirement for metalloprotease activity results from their ability to
      cleave ligands, or their receptors, so as to activate or inhibit specific axon
      extension or guidance signaling pathways.

PMID- 12597855
TI  - Neuronal plasticity in thalamocortical networks during sleep and waking
      oscillations.
AB  - Spontaneous brain oscillations during states of vigilance are associated with
      neuronal plasticity due to rhythmic spike bursts and spike trains fired by
      thalamic and neocortical neurons during low-frequency rhythms that characterize
      slow-wave sleep and fast rhythms occurring during waking and REM sleep.
      Intracellular recordings from thalamic and related cortical neurons in vivo
      demonstrate that, during natural slow-wave sleep oscillations or their
      experimental models, both thalamic and cortical neurons progressively enhance
      their responsiveness. This potentiation lasts for several minutes after the end
      of oscillatory periods. Cortical neurons display self-sustained activity, similar
      to responses evoked during previous epochs of stimulation, despite the fact that
      thalamic neurons remain under a powerful hyperpolarizing pressure. These data
      suggest that, far from being a quiescent state during which the cortex and
      subcortical structures are globally inhibited, slow-wave sleep may consolidate
      memory traces acquired during wakefulness in corticothalamic networks. Similar
      phenomena occur as a consequence of fast oscillations during brain-activated
      states.

PMID- 12597856
TI  - Drugs of abuse and stress trigger a common synaptic adaptation in dopamine
      neurons.
AB  - Drug seeking and drug self-administration in both animals and humans can be
      triggered by drugs of abuse themselves or by stressful events. Here, we
      demonstrate that in vivo administration of drugs of abuse with different
      molecular mechanisms of action as well as acute stress both increase strength at
      excitatory synapses on midbrain dopamine neurons. Psychoactive drugs with minimal
      abuse potential do not cause this change. The synaptic effects of stress, but not
      of cocaine, are blocked by the glucocorticoid receptor antagonist RU486. These
      results suggest that plasticity at excitatory synapses on dopamine neurons may be
      a key neural adaptation contributing to addiction and its interactions with
      stress and thus may be an attractive therapeutic target for reducing the risk of
      addiction.

PMID- 12597857
TI  - The formation of highly soluble oligomers of alpha-synuclein is regulated by
      fatty acids and enhanced in Parkinson's disease.
AB  - Accumulation of misfolded proteins as insoluble aggregates occurs in several
      neurodegenerative diseases. In Parkinson's disease (PD) and dementia with Lewy
      bodies (DLB), alpha-synuclein (alpha S) accumulates in insoluble inclusions. To
      identify soluble alpha S oligomers that precede insoluble aggregates, we probed
      the cytosols of mesencephalic neuronal (MES) cells, normal and alpha S-transgenic
      mouse brains, and normal, PD, and DLB human brains. All contained highly soluble
      oligomers of alpha S whose detection was enhanced by delipidation. Exposure of
      living MES neurons to polyunsaturated fatty acids (PUFAs) increased alpha S
      oligomer levels, whereas saturated FAs decreased them. PUFAs directly promoted
      oligomerization of recombinant alphaS. Transgenic mice accumulated soluble
      oligomers with age. PD and DLB brains had elevated amounts of the soluble, lipid
      dependent oligomers. We conclude that alpha S interacts with PUFAs in vivo to
      promote the formation of highly soluble oligomers that precede the insoluble
      alpha S aggregates associated with neurodegeneration.

PMID- 12597858
TI  - In vivo time-lapse imaging of cell divisions during neurogenesis in the
      developing zebrafish retina.
AB  - Two-photon excitation microscopy was used to reconstruct cell divisions in living
      zebrafish embryonic retinas. Contrary to proposed models for vertebrate
      asymmetric divisions, no apico-basal cell divisions take place in the zebrafish
      retina during the generation of postmitotic neurons. However, a surprising shift
      in the orientation of cell division from central-peripheral to circumferential
      occurs within the plane of the ventricular surface. In the sonic you (syu) and
      lakritz (lak) mutants, the shift from central-peripheral to circumferential
      divisions is absent or delayed, correlating with the delay in neuronal
      differentiation and neurogenesis in these mutants. The reconstructions here show
      that mitotic cells always remain in contact with the opposite basal surface by
      means of a thin basal process that can be inherited asymmetrically.

PMID- 12597859
TI  - Two distinct mechanisms target membrane proteins to the axonal surface.
AB  - We have investigated the trafficking of two endogenous axonal membrane proteins,
      VAMP2 and NgCAM, in order to elucidate the cellular events that underlie their
      polarization. We found that VAMP2 is delivered to the surface of both axons and
      dendrites, but preferentially endocytosed from the dendritic membrane. A mutation
      in the cytoplasmic domain of VAMP2 that inhibits endocytosis abolished its axonal
      polarization. In contrast, the targeting of NgCAM depends on sequences in its
      ectodomain, which mediate its sorting into carriers that preferentially deliver
      their cargo proteins to the axonal membrane. These observations show that neurons
      use two distinct mechanisms to polarize proteins to the axonal domain: selective
      retention in the case of VAMP2, selective delivery in the case of NgCAM.

PMID- 12597860
TI  - Rapid and differential regulation of AMPA and kainate receptors at hippocampal
      mossy fibre synapses by PICK1 and GRIP.
AB  - We identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and
      PSD95, as interactors with the kainate receptor (KAR) subunits GluR5(2b,)
      GluR5(2c), and GluR6. Of these, we show that both GRIP and PICK1 interactions are
      required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses.
      In addition, PKC alpha can phosphorylate ct-GluR5(2b) at residues S880 and S886,
      and PKC activity is required to maintain KAR-mediated synaptic responses. We
      propose that PICK1 targets PKC alpha to phosphorylate KARs, causing their
      stabilization at the synapse by an interaction with GRIP. Importantly, this
      mechanism is not involved in the constitutive recycling of AMPA receptors since
      blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR
      mediated synaptic transmission at the same population of synapses.

PMID- 12597861
TI  - Presynaptic cyclic nucleotide-gated ion channels modulate neurotransmission in
      the mammalian olfactory bulb.
AB  - Cyclic nucleotide-gated channels (CNGCs) on the dendritic cilia of olfactory
      receptor neurons (ORNs) are critical for sensory transduction in the olfactory
      system. Do CNGCs also play a role in the axons and/or nerve terminals of ORNs? We
      find that the cyclic nucleotides cAMP and cGMP can both facilitate and depress
      synaptic transmission between olfactory nerve fibers and their targets in
      olfactory bulb glomeruli. Cyclic nucleotides increase intracellular Ca(2+) in ORN
      terminals and enhance spontaneous transmitter release; at higher concentrations,
      cyclic nucleotides depress evoked transmission by altering olfactory nerve
      excitability. Cyclic nucleotides have no effect on transmission or nerve
      excitability, however, in mice lacking olfactory CNGCs. Taken together, our
      results identify a novel role for presynaptic CNGCs in modulating
      neurotransmission.

PMID- 12597862
TI  - The distribution and mechanism of action of ghrelin in the CNS demonstrates a
      novel hypothalamic circuit regulating energy homeostasis.
AB  - The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and
      humans via hypothalamic actions. We discovered expression of ghrelin in a
      previously uncharacterized group of neurons adjacent to the third ventricle
      between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei.
      These neurons send efferents onto key hypothalamic circuits, including those
      producing neuropeptide Y (NPY), Agouti-related protein (AGRP),
      proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH).
      Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY
      neurons. Using electrophysiological recordings, we found that ghrelin stimulated
      the activity of arcuate NPY neurons and mimicked the effect of NPY in the
      paraventricular nucleus of the hypothalamus (PVH). We propose that at these
      sites, release of ghrelin may stimulate the release of orexigenic peptides and
      neurotransmitters, thus representing a novel regulatory circuit controlling
      energy homeostasis.

PMID- 12597863
TI  - Orientation and direction selectivity of synaptic inputs in visual cortical
      neurons: a diversity of combinations produces spike tuning.
AB  - This intracellular study investigates synaptic mechanisms of orientation and
      direction selectivity in cat area 17. Visually evoked inhibition was analyzed in
      88 cells by detecting spike suppression, hyperpolarization, and reduction of
      trial-to-trial variability of membrane potential. In 25 of these cells,
      inhibition visibility was enhanced by depolarization and spike inactivation and
      by direct measurement of synaptic conductances. We conclude that excitatory and
      inhibitory inputs share the tuning preference of spiking output in 60% of cases,
      whereas inhibition is tuned to a different orientation in 40% of cases. For this
      latter type of cells, conductance measurements showed that excitation shared
      either the preference of the spiking output or that of the inhibition. This
      diversity of input combinations may reflect inhomogeneities in functional
      intracortical connectivity regulated by correlation-based activity-dependent
      processes.

PMID- 12597864
TI  - Representation of color stimuli in awake macaque primary visual cortex.
AB  - We investigated the responses of single neurons in primary visual cortex (area
      V1) of awake monkeys to chromatic stimuli. Chromatic tuning properties,
      determined for homogeneous color patches presented on a neutral gray background,
      varied strongly between cells. The continuum of preferred chromaticities and
      tuning widths indicated a distributed representation of color signals in V1. When
      stimuli were presented on colored backgrounds, chromatic tuning was different in
      most neurons, and the changes in tuning were consistent with some degree of
      sensitivity of the neurons to the chromatic contrast between stimulus and
      background. Quantitatively, the average response changes matched the magnitudes
      of color induction effects measured in human subjects under corresponding
      stimulus conditions.

PMID- 12597865
TI  - At least at the level of inferior temporal cortex, the stereo correspondence
      problem is solved.
AB  - Stereoscopic vision requires the correspondence problem to be solved, i.e.,
      discarding "false" matches between images of the two eyes, while keeping correct
      ones. To advance our understanding of the underlying neuronal mechanisms, we
      compared single neuron responses to correlated and anticorrelated random dot
      stereograms (RDSs). Inferior temporal neurons, which respond selectively to
      disparity-defined three-dimensional shapes, showed robust selectivity for
      correlated RDSs portraying concave or convex surfaces, but unlike neurons in
      areas V1, MT/V5, and MST, were not selective for anticorrelated RDSs. These
      results show that the correspondence problem is solved at least in far
      extrastriate cortex, as it is in the monkey's perception.

PMID- 12597866
TI  - Coding of natural scenes in primary visual cortex.
AB  - Natural scene coding in ferret visual cortex was investigated using a new
      technique for multi-site recording of neuronal activity from the cortical
      surface. Surface recordings accurately reflected radially aligned layer 2/3
      activity. At individual sites, evoked activity to natural scenes was weakly
      correlated with the local image contrast structure falling within the cells'
      classical receptive field. However, a population code, derived from activity
      integrated across cortical sites having retinotopically overlapping receptive
      fields, correlated strongly with the local image contrast structure. Cell
      responses demonstrated high lifetime sparseness, population sparseness, and high
      dispersal values, implying efficient neural coding in terms of information
      processing. These results indicate that while cells at an individual cortical
      site do not provide a reliable estimate of the local contrast structure in
      natural scenes, cell activity integrated across distributed cortical sites is
      closely related to this structure in the form of a sparse and dispersed code.

PMID- 12597867
TI  - A supramodal number representation in human intraparietal cortex.
AB  - The triple-code theory of numerical processing postulates an abstract-semantic
      "number sense." Neuropsychology points to intraparietal cortex as a potential
      substrate, but previous functional neuroimaging studies did not dissociate the
      representation of numerical magnitude from task-driven effects on intraparietal
      activation. In an event-related fMRI study, we presented numbers, letters, and
      colors in the visual and auditory modality, asking subjects to respond to target
      items within each category. In the absence of explicit magnitude processing,
      numbers compared with letters and colors across modalities activated a bilateral
      region in the horizontal intraparietal sulcus. This stimulus-driven number
      specific intraparietal response supports the idea of a supramodal number
      representation that is automatically accessed by presentation of numbers and may
      code magnitude information.

PMID- 12597868
TI  - Some like it sticky: targeting of the rice gene Waxy.
AB  - For the first time, a gene function can be knocked out by homologous
      recombination in a monocot plant species. Fertile rice plants with the desired
      change in their genome can be obtained reproducibly. Although the absolute
      frequency of targeting does not exceed that of previous experiments in dicots,
      the use of a negative selectable marker at both extremities of the targeting
      construct reduces the amount of screening and excludes ectopic targeting, an
      unwanted by-product of gene targeting.

PMID- 12597869
TI  - DNA-RNA-protein gang together in silence.
AB  - Two recent reports demonstrate interdependence between DNA and histone
      methylation in Arabidopsis. ddm1 (decrease in DNA methylation 1) mutants switch
      histone methylation from a form associated with inactive chromatin to a form
      connected to actively transcribed genomic regions. The loss of DNA methylation
      and shift in histone methylation cause transcriptional derepression of
      heterochromatic regions. In a related report, small RNAs in Schizosaccharomyces
      pombe mark histone methylation to form heterochromatin, suggesting that
      methylation systems work alongside RNA metabolism.

PMID- 12597870
TI  - Ligand mimicry? Plant-parasitic nematode polypeptide with similarity to CLAVATA3.

PMID- 12597871
TI  - Phytocalpains: orthologous calcium-dependent cysteine proteinases.
AB  - A single calcium-dependent cysteine protease (calpain) gene, essential for
      aleurone cell development, has been identified recently in maize, although this
      activity had been described previously in Arabidopsis and maize roots associated
      with anoxia-induced root-tip death. Calpain genes are ubiquitous in animals and
      there are up to 12 paralogous genes in humans that exhibit molecular diversity
      outside of their catalytic domain. Calpain orthologous genes have been identified
      in 11 plant species. Like their animal counterparts, phytocalpains have
      significant homology within the catalytic domain, but lack the conserved calcium
      binding domain IV, and some members have an N-terminal transmembrane receptor
      like domain.

PMID- 12597872
TI  - Origin of sucrose metabolism in higher plants: when, how and why?
AB  - Since the discovery of sucrose biosynthesis, considerable advances have been made
      in understanding its regulation and crucial role in the functional biology of
      plants. However, important aspects of this metabolism are still an enigma.
      Studies in cyanobacteria and the publication of the sequences of several complete
      genomes have recently significantly increased our knowledge of the structures of
      proteins involved in sucrose metabolism and given us new insights into their
      origin and further evolution.

PMID- 12597873
TI  - Plant biotechnology and breeding: allied for years to come.
AB  - Plant metabolic engineering is lagging behind other kinds of genetic manipulation
      of plants. Creating metabolic pathways or improving their yields requires a
      better understanding of plant metabolism and of its regulation. Metabolic Control
      Analysis provides an interpretation of experimental failures and a guide for
      manipulators. It suggests also that there might be intrinsic limits to raising
      yields in already abundant products. At present, these limits can be dealt with
      more effectively by plant breeding.

PMID- 12597874
TI  - Evolutionary change in flowers and inflorescences: evidence from naturally
      occurring terata.
AB  - Records of naturally occurring, heritable floral abnormalities considerably
      enhance our understanding of floral evolution. Peloric mutants, frequent in
      natural populations of orchids and mints, have radially symmetric flowers but
      occur in species characterized by bilaterally symmetric flowers. Three
      distributions of peloric flowers across an inflorescence are: (1) complete (all
      flowers peloric, as in the cycloidea mutant of Antirrhinum), (2) scattered (with
      both peloric and zygomorphic flowers, as in the epigenetic cycloidea mutant of
      Linaria), and (3) terminal (only the terminal flower peloric, as in the
      centroradialis mutant of Antirrhinum). Genetic relationships between lateral and
      terminal peloria, and between peloric and pseudopeloric flowers, remain
      ambiguous. Complete peloria probably caused occasional evolutionary reversals
      from zygomorphy to actinomorphy, whereas the 'terminal-flower effect' is a less
      likely cause of floral evolution.

PMID- 12597875
TI  - First glance at the plant APC/C, a highly conserved ubiquitin-protein ligase.
AB  - The anaphase-promoting complex or cyclosome (APC/C) is a cell-cycle-regulated
      ubiquitin-protein ligase that has been extensively studied in both fungal and
      animal cells. Many APC/C protein targets have been identified, and their
      sequential degradation during the cell cycle is essential for chromatid
      separation and mitotic exit. APC/C-dependent ubiquitylation of proteins not
      involved in cell-cycle progression has also been documented in animal cells. By
      contrast, the plant APC/C's structure and functions remained unexplored until
      recently. Here, we discuss recent developments in this field and explore the
      Arabidopsis genome sequence to identify plant APC/C components. Details of the
      APC/C ubiquitylation pathway in Arabidopsis are also available on a website that
      will be regularly updated.

PMID- 12597876
TI  - Re-engineering plant gene targeting.
AB  - The genome sequence of Arabidopsis is complete and the genomes of plants
      representing legumes (Medicago truncatula) and grasses (rice) will soon follow.
      The rate at which new genes have been discovered has far outstripped the pace at
      which their function is determined. The greatest hurdle that plant biologists
      face in assigning gene function and in crop improvement is the lack of efficient
      and robust technologies to generate gene replacements or targeted gene knockouts.
      Many of the factors underlying these events remain to be elucidated. This review
      addresses the current status of plant gene targeting and what is known about the
      associated plant DNA repair mechanisms.

PMID- 12597877
TI  - Purification and characterization of the deoxynucleoside monophosphate kinase of
      bacteriophage T5.
AB  - Deoxynucleoside monophosphate kinase (dNMP kinase) of bacteriophage T5 (EC
      2.7.4.13) was purified to apparent homogeneity from phage-infected Escherichia
      coli cells. Electrophoresis in sodium dodecyl sulfate-polyacrylamide gel showed
      that the enzyme has a molecular mass of about 29 kDa. The molecular mass of dNMP
      kinase estimated by analytical equilibrium ultracentrifugation turned out to be
      29.14 +/- 3.03 kDa. These data suggest that the enzyme exists in solution as a
      monomer. The isoelectric point of dNMP kinase was found to be 4.2. The N-terminal
      amino acid sequence, comprising 21 amino acids, was determined to be
      VLVGLHGEAGSGKDGVAKLII. A comparison of this amino acid sequence and those of
      known enzymes with a similar function suggests the presence of a nucleotide
      binding site in the sequenced region.

PMID- 12597878
TI  - Expression and purification of the anticomplementary peptide Sh-CRIT-ed1
      (formerly Sh-TOR-ed1) as a tetramultimer in Escherichia coli.
AB  - Many complement inhibitors found in plants and other organisms have been
      recognized as an antiinflammatory drug. Sh-CRIT-ed1 is a complement inhibitory
      peptide, present on the Schistosoma parasite surface. In the present study, we
      expressed chemically synthesized oligonucleotides encoding Sh-CRIT-ed1 with an
      additional hexahistidine codon at the C-terminus and purified in Escherichia coli
      BL21. The cloned gene, which was multimerized four times in pBlue-script II KS
      (+) at the isoschizomer sites (BamHI, BglII), was named Sh4, and expressed in E.
      coli BL21 harboring pGEX-KG. The fusion protein (GST-Sh4) was purified with high
      yield successively by affinity chromatographies of glutathione-Sepharose 4B and
      Ni-NTA-agarose. Recombinant Sh-CRIT-ed1 was obtained readily by thrombin
      digestion and CNBr cleavage of GST-Sh4, and the yield was 9.03 mg from 1-liter
      culture of E. coli BL21 harboring pGEX-Sh4. The recombinant Sh-CRIT-ed1 showed
      strong anticomplementary activity (IC(50) = 6.02 microM) by complement haemolysis
      assay.

PMID- 12597879
TI  - Expression, purification, and PC1-mediated processing of (H10D, P28K, and K29P)
      human proinsulin.
AB  - Our previous methods for the generation of recombinant human proinsulin were
      inadequate in terms of reproducibility and yield. In addition, it was difficult
      to perform structure/function studies on proinsulin because of its tendency to
      form hexamers. We have developed an improved procedure, which overcomes many of
      the technical purification problems, and results in a potentially monomeric
      version of modified proinsulin. Inclusion bodies were prepared using a commercial
      bacterial lysis solution. The inclusion bodies were solubilized and the fusion
      protein's affinity tag was removed by chemical cleavage. The polypeptide was then
      reduced and transferred into a refolding buffer. Following an overnight
      incubation, only a single form of proinsulin was detected using analytical
      reversed-phase high-performance liquid chromatography. The refolded (H10D, P28K,
      and K29P)-human proinsulin (DKP-hPI) was subjected to a final purification step
      using reversed-phase chromatography. The method is reproducible and produces
      milligram quantities of purified DKP-hPI from a single liter of bacterial
      culture. The final product is greater than 95% pure and is suitable for use as a
      substrate for the propeptide convertase PC1.

PMID- 12597880
TI  - Expression of a soluble and activatable form of bovine procarboxypeptidase A in
      Escherichia coli.
AB  - Bovine pancreatic procarboxypeptidase A has been overexpressed in a soluble and
      activatable form in Escherichia coli. When the protein was expressed under the
      control of bacteriophage T7 promoter in E. coli ADA494 (a thioredoxin reductase
      deficient bacteria), a thioredoxin fusion protein was produced at relatively high
      level in the cytoplasm (4 mg/L culture medium). Although the recombinant protein
      essentially accumulated as inclusion bodies, as much as 30% of the fusion protein
      was recovered in a soluble form at low growth temperature and could therefore be
      purified to homogeneity in a single-step procedure by metal-affinity
      chromatography. The recombinant precursor form of bovine carboxypeptidase A was
      recognized by a monoclonal antibody directed against purified bovine pancreatic
      carboxypeptidase A. Moreover, upon tryptic activation it gave rise to an enzyme,
      the N-terminal sequence, molecular size,and specific activity of which were
      comparable to those of the enzyme derived from the native precursor purified from
      bovine pancreas.

PMID- 12597881
TI  - Methylotrophic yeast Pichia pastoris as a host for production of ATP
      diphosphohydrolase (apyrase) from potato tubers (Solanum tuberosum).
AB  - ATP-diphosphohydrolase (apyrase) catalyzes the hydrolysis of phosphoanhydride
      bonds of nucleoside tri- and di-phosphates in the presence of divalent cations.
      This enzyme has broad substrate specificity for nucleotides, which makes it an
      ideal enzyme for different biotechnical applications, such as DNA sequencing and
      platelet-aggregation inhibition. The only commercially available apyrase is
      isolated from potato tubers. To avoid batch-to-batch variations in activity and
      quality, we decided to produce a recombinant enzyme. The methylotrophic yeast
      Pichia pastoris was chosen as an eukaryotic expression host. The coding sequence
      of potato apyrase, without the signal peptide, was cloned into the YpDC541 vector
      to create a fusion with the alpha-mating secretion signal of Saccharomyces
      cerevisiae. The gene was placed under the control of the methanol-inducible
      alcohol oxidase promoter. The YpDC541-apyrase construct was integrated into P.
      pastoris strain SMD1168. Methanol induction resulted in secretion of apyrase to a
      level of 1mg/L. The biologically active recombinant apyrase was purified by
      hydrophobic interaction and ion exchange chromatography. According to SDS-PAGE
      and Western blot analysis, the purified enzyme showed to be hyperglycosylated. By
      enzymatic removal of N-glycans, a single band corresponding to a molecular mass
      of 48kDa was detected. The recombinant apyrase was found to function well when it
      was used in combination with the Pyrosequencing technology.

PMID- 12597882
TI  - Stimulation of peripheral blood mononuclear cells with lipopolysaccharide induces
      expression of the plasma protein alpha2-macroglobulin.
AB  - The human alpha(2)-macroglobulin gene is approximately 48 kb in size and consists
      of 36 exons, which encode the 180 kDa subunit of this large tetrameric protein.
      In this investigation, a procedure of sequencing human alpha(2)-macroglobulin
      mRNA, using mRNA from lipopolysaccharide-stimulated peripheral blood mononuclear
      cells as template in RT-PCR, was developed. Incubation of peripheral blood
      mononuclear cell populations with lipopolysaccharide induced alpha(2)
      macroglobulin mRNA expression reaching levels detectable by RT-PCR. Extracted
      human alpha(2)-macroglobulin mRNA was used to determine the nucleotide sequence
      of a 500 bp DNA segment encoding the most C-terminal, receptor-binding part of
      the protein, using alpha(2)-macroglobulin specific primers. The sequence obtained
      matched the earlier published sequence of human alpha(2)-macroglobulin, except
      for three point mutations, i.e., cytosine for guanine, cytosine for thymidine and
      thymidine for adenine substitutions at positions 4369, 4423, and 4511,
      respectively. None of these alterations, however, affect the amino acid sequence
      of the protein. In conclusion, we demonstrate a new, improved, approach to
      sequence human alpha(2)-macroglobulin mRNA by overexpressing the protein in
      peripheral blood mononuclear cells. This procedure may be useful in the search
      for mutations in alpha(2)-macroglobulin, examining its role in the pathogenesis
      of human diseases.

PMID- 12597883
TI  - Production of native recombinant human midkine in the yeast, Pichia pastoris.
AB  - Recombinant human midkine (rh-midkine) was efficiently produced in Pichia
      pastoris using the pre-pro secretion signal of yeast alpha-mating factor under
      the control of the AOX1 promoter. The pep4 host SMD1168 was used. The expression
      was induced at pH 3 and 20 degrees C in high cell-density fermentation and
      approximately 360 mg rh-midkine was secreted into 1L of medium. The authentic
      midkine could be obtained after one-step purification. Mass spectrometry of
      purified rh-midkine demonstrated a single large signal for the molecular ion [M +
      H](+) at 13241.2 m/z. This mass is identical to the authentic, unmodified human
      midkine. The precursor of rh-midkine was correctly processed in P. pastoris
      cells, yielding mature rh-midkine. Mass spectrometry detected no yeast-specific O
      mannosylations in the purified midkine preparations. The circular dichroic
      spectrum indicated only a negative Cotton effect at 215 nm. Only beta-structures
      were indicated for the rh-midkine molecule in solution. Purified rh-midkine was
      active in a cell-proliferation assay.

PMID- 12597884
TI  - Expression of an antitumor-analgesic peptide from the venom of Chinese scorpion
      Buthus martensii karsch in Escherichia coli.
AB  - The gene encoding a putative mature antitumor-analgesic peptide (AGAP) from the
      venom of the Chinese scorpion Buthus martensii Karsch was obtained by polymerase
      chain reaction (PCR) according to its cDNA sequence and expressed in Escherichia
      coli. While most of the recombinant AGAP was expressed in the form of insoluble
      inclusion body. The recombinant AGAP was purified to homogeneity by metal
      chelating affinity chromatography. Pharmaceutical tests showed that the
      recombinant AGAP has both analgesic and antitumor activities on mice.

PMID- 12597885
TI  - Expression of recombinant human GM2-activator protein in insect cells:
      purification and characterization by mass spectrometry.
AB  - The GM2-activator protein (GM2AP) is a small non-enzymatic cofactor assisting the
      enzyme beta-hexosaminidase A in the lysosomal degradation of ganglioside GM2.
      Mutations in the gene encoding this glycoprotein lead to a fatal neurological
      disorder, the AB variant of GM2-gangliosidoses. In this paper, we describe the
      overexpression of GM2AP in Sf21 cells using both the baculovirus expression
      vector system (BEVS) and a non-lytic, plasmid-based insect cell expression system
      (InsectSelect). For the BEVS, the cDNA encoding human GM2AP-preproprotein was
      cloned in the expression vector pAcMP3. The recombinant virus generated by
      cotransfection with linearized baculovirus DNA was used to infect Sf21 cells. For
      the non-lytic expression system, the cDNA of GM2AP was inserted into the vector
      pIZ/V5-His, which was used for the constitutive expression in stably transformed
      Sf21 cells. As it was shown by immunoblot analysis of the cell culture
      supernatant, in both expression systems the GM2AP precursor protein was
      efficiently secreted into the medium. Following expression in the BEVS, the GM2AP
      was purified by sequential chromatography on Ni-NTA-agarose and Con A-Sepharose,
      resulting in a yield of up to 9 mg purified protein from 1L of cell culture
      supernatant. Following expression in stably transformed insect cells, the
      secreted protein was first concentrated by cation-exchange and purified by metal
      ion affinity chromatography, with a yield of 0.1 mg/L cell culture supernatant.
      The biological activity of the recombinant protein was demonstrated by its
      ability to stimulate the hexosaminidase A-catalyzed degradation of ganglioside
      GM2, and the homogeneity and glycosylation were assessed by ESI-TOF mass
      spectrometry. While the protein expression in the BEVS led to partly glycosylated
      and partly non-glycosylated protein, the stably transformed cells produced only
      glycosylated protein. In both expression systems, the glycosylation was found to
      be identical and corresponded to the structure (GlcNAc)(2)Fuc(Man)(3).

PMID- 12597886
TI  - Expression and purification of a biologically active basic fibroblast growth
      factor fusion protein.
AB  - Basic fibroblast growth factor (bFGF) is a potent mitogen of many cell types and
      plays an important role in angiogenesis. To help identify proteins that bind to
      bFGF and mediate its intracellular transport and signaling, we overexpressed and
      purified a bFGF fusion protein in Escherichia coli. The fusion protein consists
      of bFGF fused to the C-terminus of glutathione S-transferase (GST). The GST-bFGF
      fusion protein was purified using SP-Sepharose and glutathione-Sepharose affinity
      chromatography. The ability of the purified GST-bFGF to stimulate the growth of
      human umbilical vein endothelial cells (HUVECs) was equivalent to that of
      purified recombinant 18 kDa bFGF.

PMID- 12597887
TI  - Expression, oxidative refolding, and characterization of six-histidine-tagged
      recombinant human LECT2, a 16-kDa chemotactic protein with three disulfide bonds.
AB  - Human LECT2 is a 16-kDa chemotactic protein that consists of 133 amino acids and
      three intramolecular disulfide bonds. Here, we present the oxidative refolding of
      (His)(6)-LECT2, an N-terminally (His)(6)-tagged recombinant protein of human
      LECT2. (His)(6)-LECT2 was overproduced in Escherichia coli in the form of
      insoluble aggregates, solubilized with 8 M urea in the presence of 10 mM DTT, and
      purified and refolded on Ni-NTA agarose by lowering the urea concentration before
      the elution. This process, however, gave a mixture of oligomers of (His)(6)-LECT2
      as well as the monomer, whose composition was as low as 36%. The oligomers formed
      as a result of incorrect intermolecular disulfide bonds. After the refolding on
      Ni-NTA agarose (step 1), the disulfide bonds were shuffled using a glutathione
      redox buffer (step 2) and the remaining thiols were completely oxidized (step 3)
      to improve the yield of correctly folded, monomeric (His)(6)-LECT2. The monomer
      composition was significantly improved to 81% by the three-step refolding method
      and the monomer thus obtained was shown to have the same conformation as the
      authentic LECT2 produced in CHO cells by CD and NMR spectroscopies. The yield of
      (His)(6)-LECT2 was 1.0 mg/L E. coli culture and was 16 times as high as that in
      our previous report, in which (His)(6)-LECT2 was purified from the soluble
      fractions of E. coli cell lysates.

PMID- 12597888
TI  - A bicistronic expression system for bacterial production of authentic human
      interleukin-18.
AB  - Interleukin-18 (IL-18) is activated and released from immune effector cells to
      stimulate acquired and innate immune responses involving T and natural killer
      (NK) cells. The release of IL-18 from mammalian cells is linked to its
      proteolytic activation by caspases including interleukin 1 converting enzyme
      (ICE). The absence of a signal peptide sequence and the requirement for coupled
      activation and cellular release have presented challenges for the large-scale
      recombinant production of IL-18. In this study, we have explored methods for the
      direct production of authentic human IL-18 toward the development of a large
      scale production system. Expression of mature IL-18 directly in Escherichia coli
      with a methionine initiating codon leads to the production of MetIL-18 that is
      dramatically less potent in bioassays than IL-18 produced as a pro-peptide and
      activated in vitro. To produce an authentic IL-18, we have devised a bicistronic
      expression system for the coupled transcription and translation of ProIL-18 with
      caspase-1 (ICE) or caspase-4 (ICE-rel II, TX, ICH-2). Mature IL-18 with an
      authentic N-terminus was produced and has a biological activity and potency
      comparable to that of in vitro processed mature IL-18. Optimization of this
      system for the maximal production yields can be accomplished by modulating the
      temperature, to affect the rate of caspase activation and to favor the
      accumulation of ProIL-18, prior to its proteolytic processing by activated
      caspase. The effect of temperature is particularly profound for the caspase-4 co
      expression process, enabling optimized production levels of over 150 mg/L in
      shake flasks at 25 degrees C. An alternative bicistronic expression design
      utilizing a precise ubiquitin IL-18 fusion, processed by co-expressed
      ubiquitinase, was also successfully used to generate fully active IL-18, thereby
      demonstrating that the pro-sequence of IL-18 is not required for recombinant IL
      18 production.

PMID- 12597889
TI  - Expression, purification, and inhibition of in vitro proteolysis of human AMPD2
      (isoform L) recombinant enzymes.
AB  - AMP deaminase (AMPD) is a multigene family in higher eukaryotes whose three
      members encode tetrameric isoforms that catalyze the deamination of AMP to IMP.
      AMPD polypeptides share conserved C-terminal catalytic domains of approximately
      550 amino acids, whereas divergent N-terminal domains of approximately 200-330
      amino acids may confer isoform-specific properties to each enzyme. However, AMPD
      polypeptides are subject to limited N-terminal proteolysis during purification
      and subsequent storage at 4 degrees C. This presents a technical challenge to
      studies aimed at determining the structural and functional significance of these
      divergent sequences. This study describes the recombinant overexpression of three
      naturally occurring human AMPD2 proteins, 1A/2, 1B/2, and 1B/3, that differ by N
      terminal extensions of 47-128 amino acids, resulting from the use of multiple
      promoters and alternative splicing events. A survey of protease inhibitors
      reveals that E-64 and leupeptin are able to maintain the subunit structure of
      each AMPD2 protein when they are included in extraction and storage buffers. Gel
      filtration chromatography of these three purified AMPD2 enzymes comprised of
      intact subunits reveals that each migrates faster than expected, resulting in
      observed molecular masses significantly greater than those predicted for native
      tetrameric structures. However, chemical crosslinking analysis indicates four
      subunits per AMPD2 molecule, confirming that these enzymes have a native
      tetrameric structure. These combined results suggest that AMPD2 N-terminal
      extensions may exist as extended structures in solution.

PMID- 12597890
TI  - Expression, purification, and characterization of an unstable lysozyme mutant in
      Pichia pastoris.
AB  - To investigate the expression and purification of an unstable heterologous
      protein in Pichia pastoris, the cDNA of H5-lysozyme, a hen egg lysozyme mutant
      with a hydrophobic pentapeptide (Phe-Phe-Val-Ala-Pro) fused to the carboxyl
      terminus, was integrated into the genome of P. pastoris. It was found that medium
      composition, induction time, and fermenter type were important factors for the
      expression of H5-lysozyme. Substantially active H5-lysozyme was secreted by
      induction with methanol when the prepro-sequence of alpha-factor was used as
      secretion signal sequence. The amount secreted was 422-fold greater than that
      observed with Saccharomyces cerevisiae. Recombinant H5-lysozyme was recovered and
      purified by cation-exchange chromatography directly from fermentation broth. The
      mutant lysozyme showed bactericidal activity against Gram-positive as well as
      Gram-negative bacteria.

PMID- 12597891
TI  - Expression, purification, and functional analysis of the C-terminal domain of
      Herbaspirillum seropedicae NifA protein.
AB  - The Herbaspirillum seropedicae NifA protein is responsible for nif gene
      expression. The C-terminal domain of the H. seropedicae NifA protein, fused to a
      His-Tag sequence (His-Tag-C-terminal), was over-expressed and purified by metal
      affinity chromatography to yield a highly purified and active protein. Band-shift
      assays showed that the NifA His-Tag-C-terminal bound specifically to the H.
      seropedicae nifB promoter region in vitro. In vivo analysis showed that this
      protein inhibited the Central + C-terminal domains of NifA protein from
      activating the nifH promoter of K. pneumoniae in Escherichia coli, indicating
      that the protein must be bound to the NifA-binding site (UAS site) at the nifH
      promoter region to activate transcription.

PMID- 12597892
TI  - Purification and characterization of delta3Trx-1, a splicing variant of human
      thioredoxin-1 lacking exon 3.
AB  - Thioredoxins comprise a growing family of proteins that function as general
      protein-disulfide reductases and are maintained in their reduced active form by
      the flavoenzyme thioredoxin reductase. Human Trx-1 is mainly a cytosolic protein,
      although it has been shown to translocate into the nucleus upon certain stimuli
      and can also be secreted. We report here the expression and characterization of
      delta3Trx-1, a splicing variant of human Trx-1, lacking exon 3, which spans from
      residues 44 to 63 in the wild-type protein. Structure-based prediction of this
      splicing form indicates that delta3Trx-1 lacks helix alpha2 and strand beta3,
      which are implicated in substrate positioning and three-dimensional stabilization
      of the active site residues. Recombinant human delta3Trx-1 is recognized by
      polyclonal antibodies raised against full-length human Trx-1. However, delta3Trx
      1 retains no enzymatic activity either with DTT or thioredoxin reductase and
      NADPH as reducing systems. Delta3Trx-1 competes with full-length Trx-1 for the
      interaction with thioredoxin reductase. The absence of helix alpha2 and strand
      beta3 in delta3Trx-1 is consistent with the lack of enzymatic activity and its
      potential dominant negative properties.

PMID- 12597893
TI  - Expression and purification of the Bacillus anthracis protective antigen domain
      4.
AB  - The protective antigen (PA) of Bacillus anthracis plays a crucial role in the
      pathogenesis of the anthrax disease. The fourth domain of PA (PA-D4) is
      responsible for initial binding of the anthrax toxin to the cellular receptor,
      and thus, is an attractive target for structure-based drug therapies. A synthetic
      gene for PA-D4 has been prepared by recursive PCR. PA-D4 has been expressed as a
      fusion protein in Escherichia coli. PA-D4 has been purified to near homogeneity
      and its identity has been verified by mass spectrometry. The recombinant PA-D4
      exhibits CD and NMR spectra that suggest that it is folded and amenable for
      biophysical studies. Moreover, recombinant PA-D4 binds to HeLa cells, which
      suggests that recombinant PA-D4 is functional to bind to its cellular receptor.

PMID- 12597894
TI  - Relationship between self-association of insulin and its secretion efficiency in
      yeast.
AB  - The folding stability of insulin is positively correlated with the expression
      yield of the precursor expressed in yeast. Insulin assembles into dimers and
      hexamers in a concentration-dependent manner and amino acid substitutions that
      impair the ability of insulin to associate into dimers concomitantly decrease the
      expression yield (excluding substitutions that enhance folding stability). In
      contrast, introduction of an amino substitution that enhances the self
      association of insulin improved the yeast expression yield. In the monomeric
      state the majority of the non-polar residues of insulin are exposed to the
      solvent and assembly into dimers and hexamers shields these from contact with the
      solvent. It is proposed that self-association enhances the flux of insulin
      through the secretory pathway by increasing the hydrophilicity, decreasing the
      surface area as well as decreasing the molar concentration in the secretory
      pathway.

PMID- 12597895
TI  - Expression, purification, and characterization of metallothionein-A from rainbow
      trout.
AB  - Recombinant metallothionein A (MT-A) from rainbow trout has been successfully
      produced in milligram quantities in Escherichia coli. cDNA has been subcloned
      into pGEX-6P.1 vector, in-frame with a sequence encoding an N-terminal
      glutathione-S-transferase (GST) tail. Purification to electrophoretic homogeneity
      has been obtained by affinity chromatography using GSH-Sepharose. After enzymatic
      cleavage of GST tail, the MT-A moiety shows a molecular weight, corresponding to
      the expected one (6630 Da). The final yield of the entire expression and
      purification process was about 5 mg of pure metallothionein per liter of
      bacterial culture. The effects of different reducing and alkylating agents have
      been evaluated at the level of the formation of higher molecular weight
      aggregates. To investigate the metal-binding ability of the recombinant MT-A, we
      carried out a spectrophotometrical titration with cadmium ions. Finally, we
      checked the metal dissociation by recording the UV absorbance of the protein as a
      function of the environmental pH.

PMID- 12597896
TI  - Cloning, over-expression, purification, and characterisation of N
      acetylneuraminate synthase from Streptococcus agalactiae.
AB  - N-acetylneuraminate synthase (NeuAc-synthase; E.C. 4.1.3.19) is one of the two
      enzymes responsible for sialic acid (N-acetylneuraminic acid) synthesis in
      bacteria. Potential genes encoding NeuAc synthase in Streptococcus agalactiae and
      Bacillus subtilis were identified from a BLAST search of the EMBL/GenBank/DDBJ
      database using the E. coli neuB gene sequence as a probe and the genes cloned and
      expressed at high level in Escherichia coli. The neuB gene of S. agalactiae was
      shown to encode an active NeuAc synthase, whereas the spsE gene product from B.
      subtilis did not have this activity. Expression of the native S. agalactiae neuB
      gene product enzyme in E. coli resulted in a product that was prone to
      proteolysis during purification so the protein was tagged with a hexa-histidine
      tag at its N-terminus and the enzyme was rapidly purified to homogeneity by
      ammonium sulphate fractionation and Ni-chelating affinity chromatography in two
      steps. Measurement of the subunit molecular mass by electrospray ionisation mass
      spectrometry (M(r) = 38, 987 +/- 3) and of the native molecular mass by gel
      filtration chromatography (M(r) = 78,000) clearly demonstrated that the enzyme is
      dimeric. The effects of EDTA, temperature, and pH on the activity of the S.
      agalactiae NeuAc synthase were examined. Enzyme activity was maximal at pH 7 and
      was dependent on the presence of metal ions such as Mg(2+), Mn(2+) or Co(2+). The
      purified enzyme was inhibited by the reagent phenylglyoxal and the substrates N
      acetyl mannosamine or phosphoenol pyruvate afforded protection against this
      inhibition, suggesting that one or more arginine residues are involved in
      substrate recognition and binding. The ease of expression and the properties of
      the enzyme should now permit a thorough study of the specificity of the enzyme
      and provide the prerequisites for attempts to alter this specificity by directed
      evolution for the production of novel sialic acid analogues.

PMID- 12597897
TI  - Identification and characterization of a second NMN adenylyltransferase gene in
      Saccharomyces cerevisiae.
AB  - The enzyme nicotinamide mononucleotide (NMN) adenylyltransferase (NMNAT) (EC
      2.7.7.1) catalyzes the transfer of the adenylyl moiety of ATP to NMN to form
      NAD(+). On the basis of a remarkable structural similarity with previously
      described Saccharomyces cerevisiae NMNAT (yNMNAT-1), the YGR010-encoded protein
      was identified as a second isoform of yeast NMNAT (yNMNAT-2). The YGR010 gene was
      isolated, cloned into a T7-based vector, and successfully expressed in
      Escherichia coli BL21 cells, yielding high level of NMN adenylyltransferase
      activity. The purification procedure reported in this paper, consisting of two
      chromatographic steps, allowed the isolation of 3mg of electrophoretically
      homogeneous yNMNAT-2 from 1 liter of E. coli culture. Under SDS/PAGE, the
      recombinant protein resulted in a single polypeptide of 46 kDa, in agreement with
      the molecular mass of the hypothetical protein encoded by YGR010 gene. The N
      terminal sequence of the purified recombinant yNMNAT-2 exactly corresponds to the
      predicted sequence. Molecular and kinetic properties of recombinant yNMNAT-2 are
      reported and compared with those already known for yNMNAT-1.

PMID- 12597898
TI  - Mistranslational errors associated with the rare arginine codon CGG in
      Escherichia coli.
AB  - In Escherichia coli, CGG is a rare arginine codon occurring at a frequency of
      0.54% in all E. coli mRNAs or 9.8% when an arginine residue is encoded for. When
      present in high numbers or in clusters in highly expressed recombinant mRNA, rare
      codons can cause expression problems compromising product yield and translational
      fidelity. The coding region for an N-terminally polyhistidine tagged p27 protease
      domain from Herpes Simplex Virus 2 (HSV-2) contains 11 of these rare arginine
      codons, with 3 occurring in tandem near the C-terminus of the protein. When
      expressed in E. coli, the majority of the recombinant material produced had an
      apparent molecular mass of 31 kDa by SDS-PAGE gels or 3 kDa higher than
      predicted. Detailed biochemical analysis was performed on chemical and enzymatic
      digests of the protein and peptide fragments were characterized by Edman and
      MS/MS sequencing approaches. Two major species were isolated comprising +1
      frameshift events at both the second and third CGG codons in the triplet cluster.
      Translation proceeded in the missense frame to the next termination codon. In
      addition, significant levels of glutamine misincorporating for arginine were
      discovered, suggesting second base misreading of CGG as CAG. Coexpression of the
      argX gene, which encodes the cognate tRNA for CGG codons, largely eliminated both
      the frameshift and misincorporation events, and increased expression levels of
      authentic product by up to 7-fold. We conclude that supplementation of the rare
      arginyl tRNA(CGG) levels by coexpression of the argX gene can largely alleviate
      the CGG codon bias present in E. coli, allowing for efficient and accurate
      translation of heterologous gene products.

PMID- 12597899
TI  - Purification and renaturation of Dictyostelium recombinant alkaline phosphatase
      by continuous elution electrophoresis.
AB  - A 1583 bp fragment of Dictyostelium alp cDNA (94% of the gene) was cloned in
      pET32a+. The enzyme was expressed in an inactive form in the inclusion body of
      the expression host BL21-CodonPlus (DE3)-RIL. The recombinant ALP constituted
      more than 50% of the total protein in the inclusion body and 25-30% of the total
      protein in the expression host after 3 h induction with IPTG at 37 degrees C. A
      continuous elution polyacrylamide gel electrophoresis procedure was used to
      purify the recombinant enzyme. This technique yielded a homogeneous protein that
      retained enzymatic activity after dialysis without further treatment. A yield of
      5mg per liter of culture broth was obtained with a specific activity of
      approximately 0.7 nmol/min/mg protein (0.7 mU/mg). Immunoinhibition studies using
      a polyclonal antibody produced against the recombinant protein showed complete
      inhibition of enzymatic activity when the enzyme was preincubated with the
      antibody at a 1:1000 dilution. The enzyme exhibited a pH optimum of approximately
      9.0. The substrate specificity indicated that the Dictyostelium enzyme is a
      typical broad range alkaline phosphatase.

PMID- 12597900
TI  - One-step purification and refolding of recombinant photoprotein aequorin by
      immobilized metal-ion affinity chromatography.
AB  - A hexahistidine tag was fused to the N-terminus of apoaequorin. A suitable vector
      encoding the fusion protein was constructed and used for transformation of
      Escherichia coli JM109 cells. Apoaequorin was overexpressed under the control of
      tac promoter. It was found, however, that most of the protein existed in the form
      of inclusion bodies. Inclusion bodies were solubilized with urea, followed by
      purification and refolding of (His)(6)-apoaequorin in a single chromatographic
      step by immobilized metal-ion affinity chromatography using Ni(2+)
      nitrilotriacetic acid agarose. The purity, as determined by SDS-PAGE analysis,
      was greater than 80%. The yield was 0.7-1 mg apoaequorin from a 50 ml bacterial
      culture. The kinetics of light emission of purified aequorin upon addition of
      Ca(2+) was typical of the commercial aequorin. The luminescence of the purified
      aequorin was a linear function of its concentration extending over six orders of
      magnitude. As low as 0.5 attomoles purified aequorin gave a signal-to-noise ratio
      of 1.8.

PMID- 12597901
TI  - Gene therapy for asthma.
AB  - The accessibility of the airway epithelium and the limitations of current
      treatments for asthma make the disease a logical target for gene therapy. Study
      of the immunopathology of chronic airway inflammation has recently identified
      several pathways that lead to the maladaptive, antigen-induced polarization of
      CD4+ T cells to a type-2 phenotype. This polarization is thought to lead to IgE
      production and eosinophil recruitment and activation that is associated with
      epithelial cell injury and airway hyper-reactivity. Gene transfer to the
      bronchial epithelium has been used in experimental models to redirect these
      pathways toward a less injurious, type-1 phenotype. This mini-review highlights
      recent mechanism-based immunomodulatory and supportive gene transfer approaches
      to treat animal models of asthma. Although substantial hurdles to airway gene
      transfer remain, gene transfer offers the possibility of interrupting the
      pathophysiology of airway inflammation. Doing so can be expected to yield long
      lasting protection from bronchospastic challenge and reduced dependence on
      inhaled and oral medications.

PMID- 12597902
TI  - Immune gene therapy for kidney cancer: the search for a magic trigger.

PMID- 12597903
TI  - Treatment of experimental asthma by long-term gene therapy directed against IL-4
      and IL-13.
AB  - The clinical manifestations of allergic asthma are believed to result from a
      dysregulated, T helper 2 lymphocyte (Th2)-biased response to antigen. Although
      asthma symptoms can be controlled acutely, there is a need for a therapy that
      will address the underlying immune dysfunction and provide continuous control of
      chronic airway inflammation. The Th2-type cytokines, IL-13 and IL-4, have been
      demonstrated to play a crucial role in asthma pathogenesis and their selective
      neutralization results in the alleviation of asthmatic symptoms in mouse models.
      The activity of both of these cytokines can be inhibited by a mutant IL-4
      protein, IL-4 receptor antagonist (IL-4RA), and thus, continual IL-4RA therapy
      might be beneficial in treatment of chronic asthma. To explore the potential
      utility of long-term gene therapy for the treatment of asthma we used a
      recombinant adeno-associated virus (AAV) vector to deliver and provide sustained
      expression of IL-4RA in vivo. We show that AAV-mediated delivery of IL-4RA to the
      airways of mice reduces airway hyperresponsiveness (AHR) and airway eosinophilia
      triggered by either IL-13 or IL-4. Furthermore, AAV-delivered IL-4RA, expressed
      either systemically or in the airways of mice following allergen sensitization,
      significantly inhibited development of airway eosinophilia and mucus production
      and reduced the levels of asthma-associated Th2 cytokines and AHR in the
      experimental mouse model of allergic asthma. Thus, gene therapy can be a
      potential therapeutic option to treat and control chronic airway inflammation and
      asthmatic symptoms.

PMID- 12597904
TI  - A canine conditionally replicating adenovirus for evaluating oncolytic
      virotherapy in a syngeneic animal model.
AB  - Oncolytic adenoviruses, which selectively replicate in and subsequently kill
      cancer cells, have emerged as a promising approach for treatment of tumors
      resistant to other modalities. Although preclinical results have been exciting,
      single-agent clinical efficacy has been less impressive heretofore. The
      immunogenicity of adenoviruses, and consequent premature abrogation of
      replication, may have been a partial reason. Improving the oncolytic potency of
      agents has been hampered by the inability to study host-vector interactions in
      immune-competent systems, since human serotype adenoviruses do not productively
      replicate in animal tissues. Therefore, approaches such as immunomodulation,
      which could result in sustained replication and subsequently increased oncolysis,
      have not been studied. Utilizing the osteocalcin promoter for restricting the
      replication of a canine adenovirus to dog osteosarcoma cells, we generated and
      tested the first nonhuman oncolytic adenovirus. This virus effectively killed
      canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo.
      Canine osteosarcoma is the most frequent malignant disease in large dogs, with
      over 8000 cases in the United States annually, and there is no curative
      treatment. Therefore, immunomodulation for increased oncolytic potency could be
      studied with clinical trials in this population. This could eventually translate
      into human trials.

PMID- 12597905
TI  - Systemic administration of a recombinant adenovirus encoding a HSA-Angiostatin
      kringle 1-3 conjugate inhibits MDA-MB-231 tumor growth and metastasis in a
      transgenic model of spontaneous eye cancer.
AB  - We previously reported that intratumoral injection of AdK3, a recombinant
      adenovirus encoding human angiostatin kringle (K) 1 to 3, inhibits tumor
      vascularization and tumor growth. To reduce the serum clearance of this factor,
      we constructed an adenovirus (AdK3-HSA) that carries a chimeric gene encoding a
      fusion protein between angiostatin K1-3 and human serum albumin (HSA). This
      conjugate inhibited endothelial cell proliferation as efficiently as K1-3. K3-HSA
      serum concentrations in immunodeficient mice systemically injected with AdK3-HSA
      were dramatically higher than in AdK3-injected mice. Furthermore, the growth of
      MDA-MB-231 tumors grafted into nude mice that had been injected intravenously
      with AdK3-HSA was inhibited by 79% (versus 17% with AdK3). In TRP-1/SV40 Tag
      transgenic mice, which spontaneously develop eye tumors with brain metastases,
      intravenous injections of AdK3-HSA in newborn mice blocked metastatic
      dissemination efficiently and significantly, and prolonged survival by 3 weeks.
      After 2 months, only 46% of AdK3-HSA-treated animals developed micrometastases,
      whereas 94% of the AdCO1-injected group displayed numerous macrometastases.
      Nevertheless, ocular tumor growth was not modified because of impaired diffusion
      of the conjugate in the eye compartment. Our results show that HSA genetic
      coupling is an efficient way to increase the pharmacokinetics of circulating
      angiogenic inhibitors and thus their antitumoral activity.

PMID- 12597906
TI  - IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene
      therapy approach.
AB  - While human prostate cancers and cell lines express Fas, most of these cell lines
      are resistant to Fas-mediated death. In the present studies we addressed the
      ability of IFN-gamma to influence Fas-mediated cell death in prostate cancer
      cells. In vitro exposure of the human cell lines LNCaP and PC3 and the mouse cell
      line RM-1 to agonist anti-Fas antibody and/or soluble Fas ligand resulted in
      killing of only PC3 cells. However, preincubation with IFN-gamma resulted in
      synergistic killing in all three cell lines. In vitro treatment of RM-1 with a
      replication-incompetent adenovirus expressing mouse FasL (Ad.FasL) resulted in
      maximal cell kill near 40%, which correlated with baseline Fas expression. The
      addition of IFN-gamma enhanced cell kill to a degree consistent with the
      resulting higher levels of Fas and maintained synergistic killing at very low
      doses of vector. Co-inoculation of orthotopic RM-1 primary tumors with Ad.mFasL
      and an adenovirus expressing mouse IL-12 (Ad.mIL-12) to drive host production of
      IFN-gamma negated the survival advantage of Ad.mIL-12 alone. However, the
      staggered injection of Ad.mIL-12 and Ad.FasL achieved almost threefold higher
      levels of apoptosis in primary tumor tissue and doubled median survival.
      Therefore, IFN-gamma is capable of bestowing increased sensitivity to Fas
      mediated cell death in prostate cancer cells and, in a gene therapy approach, may
      define a powerful tool to treat prostate cancers.

PMID- 12597907
TI  - Long-term correction of glycogen storage disease type II with a hybrid Ad-AAV
      vector.
AB  - We administered an adenovirus-adeno-associated virus (Ad-AAV) vector encoding
      human acid alpha-glucosidase (hGAA) to acid alpha-glucosidase-knockout (GAA-KO)
      mice on day 3 of life by gastrocnemius injection. In contrast to previous results
      for muscle-targeted Ad vector in adult GAA-KO mice, the muscles of the hindlimb
      showed reduced glycogen content and persistent hGAA for as long as 6 months after
      neonatal Ad-AAV vector administration. Not only the injected gastrocnemius
      muscles, but also the hamstrings and quadriceps muscles produced therapeutic
      levels of hGAA as a result of widespread transduction with the Ad-AAV vector;
      moreover, hGAA activity was 50-fold elevated as compared to normal mice. Vector
      RNA was detected in the hindlimb muscles, the hearts, and the livers by northern
      blot analysis and/or by RT-PCR for as long as 6 months. The low levels of hGAA
      detected in the heart were attributable to transduction with the Ad-AAV vector,
      not to secretion of hGAA by the injected muscle and uptake by the heart. Finally,
      although an antibody response to hGAA was present, it did not prevent the
      correction of glycogen storage in the skeletal muscle of GAA-KO mice.

PMID- 12597908
TI  - Novel Semliki Forest virus vectors with reduced cytotoxicity and temperature
      sensitivity for long-term enhancement of transgene expression.
AB  - Alphaviral vectors inhibit host cell protein synthesis and are cytotoxic. To
      overcome these limitations, we modified the nonstructural protein-2 (nsP2) gene
      in the Semliki Forest virus (SFV) vector, pSFV1. Packaging of SFV replicons with
      two point mutations in nsP2 resulted in high-titer recombinant SFV(PD) particles.
      SFV(PD) led to more efficient host cell protein synthesis, exhibited reduced
      cytotoxicity and improved cell survival, and allowed greater and prolonged
      transgene expression than the original vector, SFV. In dissociated hippocampal
      neurons and organotypic rat hippocampal slices, SFV(PD) infection preserved
      neuronal morphology and synaptic function more efficiently than SFV. Combination
      of the two point mutations with a replication-persistent mutation in nsP2
      resulted in a highly temperature-sensitive vector, SFV(PD713P), which efficiently
      transduced neurons in hippocampal slice cultures. At 31 degrees C, SFV(PD713P)
      allowed continuous transgene expression in BHK cells, at amounts comparable to
      SFV(PD). These new SFV mutants are expected to substantially broaden the
      application of alphaviral vectors in neurons and other mammalian cells.

PMID- 12597909
TI  - Negative-strand RNA viral vectors: intravenous application of Sendai virus
      vectors for the systemic delivery of therapeutic genes.
AB  - Treatment by gene replacement is critical in the field of gene therapy. Suitable
      vectors for the delivery of therapeutic genes have to be generated and tested in
      preclinical settings. Recently, extraordinary features for a local gene delivery
      by Sendai virus vectors (SeVV) have been reported for different tissues. Here we
      show that direct intravenous application of SeVV in mice is not only feasible and
      safe, but it results in the secretion of therapeutic proteins to the circulation,
      for example, human clotting Factor IX (hFIX). In vitro characterization of first
      generation SeVV demonstrated that secreted amounts of hFIX were at least
      comparable to published results for retroviral or adeno-associated viral vectors.
      Furthermore, as a consideration for application in humans, SeVV transduction led
      to efficient hFIX synthesis in primary human hepatocytes, and SeVV-encoded hFIX
      proteins could be shown to be functionally active in the human clotting cascade.
      In conclusion, our investigations demonstrate for the first time that intravenous
      administration of negative-strand RNA viral vectors may become a useful tool for
      the wide area of gene replacement requirements.

PMID- 12597910
TI  - Helper-free HSV-1 amplicons elicit a markedly less robust innate immune response
      in the CNS.
AB  - The development and implementation of direct gene transfer technologies for the
      study and treatment of chronic CNS disorders inherently requires consideration of
      vector safety. Virus-based vectors represent the most efficient modalities but
      harbor the potential to induce vigorous innate and adaptive immune responses when
      administered in vivo. These responses can arise because of virus particle
      components, resultant viral gene expression, and/or transgene expression. In the
      current study, we describe the innate responses elicited upon stereotactic
      delivery of herpes simplex virus type 1-based amplicon vectors. C57BL/6 mice were
      injected with sterile saline, beta-galactosidase-expressing amplicon (HSVlac)
      packaged by a conventional helper virus-based technique, or helper virus-free
      HSVlac. After killing the mice at either 1 or 5 days after transduction, we
      analyzed them by immunocytochemistry and quantitative RT-PCR for various
      chemokine, cytokine, and adhesion molecule gene transcripts. All injections
      induced inflammation, with blood/brain barrier opening on day 1 that was enhanced
      with both amplicon preparations as compared with saline controls. By day 5, mRNA
      levels for the pro-inflammatory cytokines (IL-1beta, TNF-alpha, IFN-gamma),
      chemokines (MCP-1, IP-10), and an adhesion molecule (ICAM-1) had returned to
      baseline in saline-injected mice and to near-baseline levels in helper virus-free
      amplicon groups. In contrast, mice injected with helper virus-packaged amplicon
      stocks elicited elevated inflammatory molecule expression and immune cell
      infiltration even at day 5. In aggregate, we demonstrate that helper virus-free
      amplicon preparations exhibit a safer innate immune response profile, presumably
      as a result of the absence of helper virus gene expression, and provide support
      for future amplicon-based CNS gene transfer strategies.

PMID- 12597911
TI  - Simultaneous inhibition of GSK3alpha and GSK3beta using hairpin siRNA expression
      vectors.
AB  - Short interfering RNAs (siRNAs) can mediate sequence-specific inhibition of gene
      expression in mammalian cells. We and others have recently developed expression
      vector-based systems for synthesizing siRNAs or hairpin siRNAs in mammalian
      cells. Expression vector-based RNA interference (RNAi) effectively suppresses
      expression of target genes and is likely to be a powerful tool for analysis of
      gene function. Here we compare inhibition by vectors expressing hairpin siRNA
      designs either with different loop sequences connecting the two siRNA strands, or
      with duplex regions of different lengths. Our results suggest that lengthening
      the 19-nucleotide duplex region of a relatively ineffective hairpin siRNA can
      increase inhibition, but increasing the length of an effective 19-nt hairpin
      siRNA does not increase inhibition. We also demonstrate that hairpin siRNA
      vectors can be used to inhibit two target genes simultaneously. We have targeted
      glycogen synthase kinase-3alpha (GSK-3alpha) and GSK-3beta, two related kinases
      involved in the regulation of a variety of cellular processes and also implicated
      in the pathogenesis of several human diseases. Inhibition of either GSK-3alpha or
      GSK-3beta by transfection of hairpin siRNA vectors leads to elevated expression
      of the GSK-3 target beta-catenin, whereas inhibition of both kinases further
      increases beta-catenin expression. Our results suggest that vector-based siRNA
      inhibition may be useful for dissecting the functional roles of GSK-3alpha and
      GSK-3beta in somatic cells. The ability to inhibit two or more genes
      simultaneously with hairpin siRNA expression vectors should facilitate studies of
      gene function in mammalian cells.

PMID- 12597912
TI  - Localized expression of small RNA inhibitors in human cells.
AB  - Several types of small RNAs have been proposed as gene expression repressors with
      great potential for use in gene therapy. RNA polymerase III (pol III) provides an
      ideal means of expressing small RNAs in cells because its normal products are
      small, highly structured RNAs that are found in a variety of subcellular
      compartments. We have designed cassettes that use human pol III promoters for the
      high-level expression of small RNAs in the cytoplasm, nucleoplasm, and nucleolus.
      The levels and subcellular destinations of the transcripts are compared for
      transcripts expressed using the U6 small nuclear RNA (snRNA), 5S ribosomal RNA
      (rRNA), and the 7SL RNA component of the signal recognition particle. The most
      effective location for a particular inhibitory RNA is not necessarily
      predictable; thus these cassettes allow testing of the same RNA insert in
      multiple subcellular locations. Several small interfering RNA (siRNA) inserts
      were tested for efficacy. An siRNA insert that reduces lamin expression when
      transcribed from the U6 snRNA promoter in the nucleus has no effect on lamin
      expression when transcribed from 5S rRNA and 7SL RNA-based cassettes and found in
      the nucleolus and cytoplasm. To test further the generality of U6-driven siRNA
      inhibitors, siRNAs targeting HIV were tested by co-transfection with provirus in
      cell culture. Although the degree of HIV-1 inhibition varied among inserts,
      results show that the U6 cassette provides a means of expressing an siRNA-like
      inhibitor of HIV gene expression.

PMID- 12597913
TI  - Efficiency of chimeraplast gene targeting by direct nuclear injection using a GFP
      recovery assay.
AB  - Traditional RNA-DNA chimeric oligonucleotides (chimeraplasts), composed of a
      continuous stretch of RNA and DNA residues in a duplex conformation, have been
      shown to correct single-base mutations in episomal and genomic DNA both in vitro
      and in vivo. In the current study, we have compared the efficiency of single-base
      pair correction between a traditionally designed chimeraplast (covalently linked
      duplex) and hybrid chimeraplasts (noncovalent duplexes formed from stretches of
      RNA and DNA nucleotides synthesized individually and hybridized in vitro). Six
      hybrid chimeraplasts of identical length were constructed with various lengths of
      target homology and strand location of the desired nucleotide change. These
      constructs were evaluated for their ability to correct a point mutation in the
      gene encoding recombinant enhanced green fluorescent protein (eGFP) that rendered
      the protein nonfluorescent. A plasmid encoding this mutant eGFP gene and a
      chimeraplast were co-introduced directly into the nuclei of primary fibroblasts
      by microinjection. As shown by the recovery of eGFP fluorescence, three of the
      six hybrid chimeraplasts demonstrated the ability to mediate gene correction (0.4
      2.4%). Covalent joining of RNA and DNA strands in chimeraplasts was not necessary
      for correction of DNA mutations. However, the strand placement of the desired
      nucleotide change and the length of nonhomologous sequences flanking target
      nucleotides played a crucial role in the efficiency of chimeraplast-mediated gene
      correction. Despite the ability of certain chimeraplast designs to correct point
      mutations in episomal plasmids, targeted correction of integrated copies of the
      mutant eGFP transgene was unsuccessful in primary fibroblasts. These results
      demonstrate that, although chimeraplasts are fairly effective at targeting
      episomal DNA in primary cells, further optimization is required to increase the
      efficiency for targeting integrated genes.

PMID- 12597914
TI  - Molecular weight-dependent gene transfection activity of unmodified and
      galactosylated polyethyleneimine on hepatoma cells and mouse liver.
AB  - To optimize a receptor-mediated and cell-selective gene transfer with
      polyethyleneimine (PEI)-based vector, we synthesized three galactosylated PEIs
      (Gal-PEI) with different molecular weights (PEI(1800), PEI(10,000), and
      PEI(70,000)) and investigated their potential as a targetable vector to
      asialoglycoprotein receptor-positive cells. All PEI derivatives formed complexes
      with plasmid DNA (pDNA), whereas the particle size of the complex became smaller
      on increasing the molecular weight of PEI. Transfection efficiency in HepG2 cells
      with PEI was highest with PEI(1800); efficiency was next highest with
      PEI(10,000), although the cellular association was similar. After
      galactosylation, Gal(19)-PEI(10,000)/pDNA and Gal(120)-PEI(70,000)/pDNA showed
      considerable agglutination with a galactose-recognizing lectin, but Gal(9)
      PEI(1800) did not, suggesting that galactose units on the Gal(9)-PEI(1800)-pDNA
      complex are not sufficiently available for recognition. Gal(19)-PEI(10,000)-pDNA
      and Gal(120)-PEI(70,000)-pDNA complexes showed galactose-inhibitable transgene
      expression in HepG2 cells. Transfection efficiency was greatest with Gal(19)
      PEI(10,000)/pDNA, a result that highlights the importance of obtaining a balance
      between the cytotoxicity and the transfection activity, both of which are found
      to be a function of the molecular weight of PEI. After intraportal injection,
      however, Gal(153)-PEI(70,000)/pDNA having a low N/P ratio was most effective,
      suggesting that additional variables, such as the size of the complex, are
      important for in vivo gene transfer to hepatocytes.

PMID- 12597915
TI  - Particle assembly incorporating a VP22-BH3 fusion protein, facilitating
      intracellular delivery, regulated release, and apoptosis.
AB  - Previously we showed that addition of purified VP22, a structural protein of
      herpes simplex virus, to short oligonucleotides (ODN) induced the spontaneous
      assembly of novel particles incorporating both protein and ODN. These particles
      were not toxic, entered cells, and resided stably in the cytoplasm. Surprisingly
      the particles could be activated by light in a regulated synchronous manner to
      release ODN and protein to the cell cytosol and nuclei. Here we construct a
      fusion protein containing a short peptide from the proapoptotic BH3 domain family
      member Bak. The BH3-VP22 protein was recruited into particles that entered cells
      and remained stable in the cytoplasm without toxicity. Light activation rapidly
      disrupted the particles, a process captured in living cells by time-lapse
      microscopy, and this synchronized regulated release resulted in subsequent cell
      death by apoptosis. In control experiments, particles containing a mutant BH3
      peptide, although indistinguishable in cell uptake and regulated release, showed
      no apoptotic effect. Regulated release of VP22-based particles may find
      application in mechanistic analysis of apoptotic pathways, in cell-based
      screening assays both of peptides and of oligonucleotides, or as therapeutic
      agents incorporating specific additional components.

PMID- 12597916
TI  - Construction of an rtTA2(s)-m2/tts(kid)-based transcription regulatory switch
      that displays no basal activity, good inducibility, and high responsiveness to
      doxycycline in mice and non-human primates.
AB  - The tetracycline (Tc)-dependent system in its "on" version (rtTA system) displays
      a baseline activity in the uninduced state, severely limiting its potential
      applicability in human gene therapy. So far, two different strategies to
      circumvent this limitation have been described. On one side, co-expression of the
      tetracycline regulated repressor tTS(kid) has proved capable of substantially
      reducing the baseline activity of rtTA. On the other, novel versions of the
      activator, namely rtTA2(s)-S2 and rtTA2(s)-M2, with a lower basal activity have
      been engineered. We have combined these two approaches by co-expressing TS(kid)
      with the novel transactivators. Bicistronic vectors were constructed that co
      express TS(kid) with rtTA, rtTA2(s)-S2, or rtTA2(s) M2, through an internal
      ribosome entry site (plasmids IRES-A, IRES-S2, and IRES-M2, respectively). IRES
      M2 proved to be the most effective construct EX VIVO: it displayed a negligible
      basal activity, > 1000 fold inducibility, and high responsiveness to doxycycline
      (Dox). Upon delivery as plasmid DNA in mouse muscles, IRES-M2 facilitated 1000
      fold induction of serum alkaline phosphatase (SEAP) gene expression and long
      term, stringent, and strictly Dox-dose-dependent regulation of erythropoietin
      (Epo) gene expression. Tight regulation of the gene encoding SEAP was
      demonstrated also in non-human primates. Notably, the system was induced in
      animals by Dox-dosing regimens comparable to those used in humans.

PMID- 12597917
TI  - Stable genetic modification of human embryonic stem cells by lentiviral vectors.
AB  - Human embryonic stem (hES) cells are pluripotent cells derived from the inner
      cell mass of the early preimplantation embryo. An efficient strategy for stable
      genetic modification of hES cells may be highly valuable for manipulating the
      cells in vitro and may promote the study of hES cell biology, human
      embryogenesis, and the development of cell-based therapies. Here, we demonstrate
      that vectors derived from self-inactivating (SIN) human immunodeficiency virus
      type 1 (HIV-1) are efficient tools for stable genetic modification of hES cells.
      Transduction of hES cells by a modified vector derived from SIN HIV-1 and
      containing the woodchuck hepatitis regulatory element (WPRE) and the central
      polypurine tract (cPPT) sequence facilitated stable transgene expression during
      prolonged (38 weeks) undifferentiated proliferation in vitro. Southern blot
      analysis revealed that the viral vector had integrated into the host cells' DNA.
      Transgene expression was maintained throughout differentiation into progeny of
      all three germ layers both in vitro and in vivo in teratomas. Thus, the
      transduced hES cells retained the capability for self-renewal and their
      pluripotent potential. Genetic modification of hES cells by lentiviral vectors
      provides a powerful tool for basic and applied research in the area of human ES
      cells.

PMID- 12597922
TI  - Vascular endothelial growth factors and angiogenesis in eye disease.
AB  - The vascular endothelial growth factor (VEGF) family of growth factors controls
      pathological angiogenesis and increased vascular permeability in important eye
      diseases such as diabetic retinopathy (DR) and age-related macular degeneration
      (AMD). The purpose of this review is to develop new insights into the cell
      biology of VEGFs and vascular cells in angiogenesis and vascular leakage in
      general, and to provide the rationale and possible pitfalls of inhibition of
      VEGFs as a therapy for ocular disease. From the literature it is clear that
      overexpression of VEGFs and their receptors VEGFR-1, VEGFR-2 and VEGFR-3 is
      causing increased microvascular permeability and angiogenesis in eye conditions
      such as DR and AMD. When we focus on the VEGF receptors, recent findings suggest
      a role of VEGFR-1 as a functional receptor for placenta growth factor (PlGF) and
      vascular endothelial growth factor-A (VEGF)-A in pericytes and vascular smooth
      muscle cells in vivo rather than in endothelial cells, and strongly suggest
      involvement of pericytes in early phases of angiogenesis. In addition, the
      evidence pointing to distinct functions of VEGFs in physiology in and outside the
      vasculature is reviewed. The cellular distribution of VEGFR-1, VEGFR-2 and VEGFR
      3 suggests various specific functions of the VEGF family in normal retina, both
      in the retinal vasculature and in neuronal elements. Furthermore, we focus on
      recent findings that VEGFs secreted by epithelia, including the retinal pigment
      epithelium (RPE), are likely to mediate paracrine vascular survival signals for
      adjacent endothelia. In the choroid, derailment of this paracrine relation and
      overexpression of VEGF-A by RPE may explain the pathogenesis of subretinal
      neovascularisation in AMD. On the other hand, this paracrine relation and other
      physiological functions of VEGFs may be endangered by therapeutic VEGF
      inhibition, as is currently used in several clinical trials in DR and AMD.

PMID- 12597923
TI  - Color opponency in horizontal cells of the vertebrate retina.
AB  - Chromaticity (C-type) horizontal cells have been studied extensively for more
      than 40 years since the first recording of such units in the fish retina. C-type
      horizontal cells are seen in almost every retina of cold-blooded species that
      contains at least two different spectral types of cone. These cells are
      characterized by photoresponses of polarity that depends upon the wavelength of
      the stimulating light. There are two basic varieties of chromaticity horizontal
      cells, biphasic or triphasic cells. Biphasic cells are characterized by one
      wavelength in which response polarity reverses and triphasic cells have two
      wavelengths where response polarity reverses. The neuronal network underlying the
      genesis of color opponency in C-type horizontal cells has been the subject of
      debate for many years. It is generally accepted now that cones feed-forward
      excitatory inputs to horizontal cells which in turn exert inhibitory effects on
      the cones by negative feedback pathways. C-type horizontal cells belonging to the
      same class are interconnected via gap junctions to form a tight syncytium.
      However, the spatial properties of these cells depend upon the polarity of the
      photoresponse because the membrane resistances of the syncytium change with
      different inputs. Thus, color opponency in C-type horizontal cells depends on the
      spatial properties of the stimulating light in addition to its dependence upon
      wavelength, intensity and ambient illumination. The functional role of C-type
      horizontal cells is to influence the spatial-chromatic organization of the
      receptive fields of proximal neurons. Thus, the responsiveness of bipolar cells
      and ganglion cells to surround illumination depend to a great extent upon the
      horizontal cells. However, the exact mode whereby horizontal cells can affect the
      organization of the proximal neurons has yet to be elucidated.

PMID- 12597924
TI  - Identity and regulation of ion transport mechanisms in the corneal endothelium.
AB  - Corneal transparency is dependent on regulation of the hydration of the corneal
      stroma. Water is driven into the cornea across the epithelial and endothelial
      cell layers by the stromal swelling pressure. This fluid leak into the cornea is
      counterbalanced by the corneal fluid pump, which is predominantly attributed to
      the ion and fluid transport capacity of the endothelial cell layer. Primary and
      secondary active transport mechanisms are responsible for generating a net ion
      flux from the stromal to anterior chamber side of the endothelium; however, the
      identity and location of all the components of this transport system are not
      known. The endothelial fluid pump is dependent on the presence of Cl(-) and
      HCO(3)(-), and can be slowed by carbonic anhydrase inhibitors. A number of anion
      transport mechanisms have been identified and characterized in the endothelium,
      including basolateral Na(+)/2HCO(3)(-) cotransport, Na(+)/K(+)/2Cl(-)
      cotransport, Cl(-)/HCO(3)(-) exchange, and apical anion channels permeable to
      both Cl(-) and HCO(3)(-). Furthermore, there is evidence for a carbonic anhydrase
      mediated CO(2)-diffusive mode of apical HCO(3)(-) flux. These findings are
      incorporated into a new model of transendothelial anion transport, which suggests
      that there are a number of alternate pathways for anion transport. There have
      been few studies on activation of signal transduction pathways that could
      stimulate endothelial fluid transport. Interestingly, recent studies show that
      multiple autocrine signaling pathways are in place that could be upregulated
      during physical stimulation and may be responsible for maintaining basal levels
      of fluid secretion.

PMID- 12597925
TI  - Retinal vascular development and oxygen-induced retinopathy: a role for
      adenosine.
AB  - Adenosine is a ubiquitous molecule that is produced predominantly by catabolism
      of adenosine triphosphate. Levels of this nucleoside increase dramatically with
      ischemia and elevated tissue activity. Adenosine levels are high in inner retina
      during retinal vascular development in postnatal dog. The source appears to be
      the ectoenzyme 5' nucleotidase, which is prominent at this time in the innermost
      process of Muller cells. One of the adenosine receptors, A(2A), is present on
      endothelial cell precursors, angioblasts, and endothelial cells in formed blood
      vessels in neonatal dog. These observations suggest that adenosine is important
      in retinal vascular development. Oxygen-induced retinopathy (OIR) is a model for
      human retinopathy of prematurity (ROP). The initial event in OIR is induced by
      exposure of the developing retina to high oxygen. Vascular development is halted
      and over 60% of the retinal vasculature is lost during this stage of the disease
      in dog, which is called vaso-obliteration. 5' nucleotidase is dramatically
      reduced during vaso-obliteration, resulting in a sharp decline in adenosine. When
      animals are returned to room air, the retina is hypoxic because of the lack of
      blood vessels, oxygen consumption is increased due to neuronal development, and
      systemic levels of oxygen have returned to normal. At this time, 5' nucleotidase
      activity and adenosine levels are elevated well beyond normal levels. This stage
      of OIR is the vasoproliferative stage and A(2A) expression and endothelial cell
      proliferation are very elevated compared to control animals. Florid preretinal
      neovascularization forms, which has high levels of adenosine and A(2A) receptors.
      Therefore, adenosine and its A(2A) receptor appear to be important in canine OIR.
      This work suggests that adenosine and its receptors may be a therapeutic target
      in OIR. This hypothesis is supported by recent studies in mouse (Mino et al.,
      Invest. Ophthalmol. Vis. Sci. 42(13) (2001) 3320), which demonstrated that
      targeting one of the A(2) receptors can inhibit formation of neovascularization
      in OIR.

PMID- 12597927
TI  - Urologic aspects of andropause.

PMID- 12597928
TI  - Benign prostatic hyperplasia: a progressive disease of aging men.

PMID- 12597929
TI  - Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml
      total psa range: preliminary analysis.
AB  - OBJECTIVES: To determine the clinical utility of using proenzyme prostate
      specific antigen (pPSA) for early detection of prostate cancer in the 2.5 to 4.0
      ng/mL total PSA range. pPSA, the precursor form of PSA that contains a 7 amino
      acid leader peptide, and truncated forms such as [-2]pPSA and [-4]pPSA can be
      measured in serum by research immunoassay. METHODS: Archival serum from 119 men
      (noncancer, 88; cancer, 31), obtained before biopsy and in the total PSA range of
      2.5 to 4.0 ng/mL, were assayed for total PSA, free PSA (fPSA), and pPSA. pPSA was
      defined as the sum of the [-2], [-4], and [-7] forms, and the percent pPSA
      (%pPSA) was defined as pPSA/fPSA. RESULTS: pPSA averaged 4.6% +/- 0.4% (SEM) of
      total PSA and 39.3% +/- 3.5% of fPSA. PSA and %fPSA values were similar between
      the noncancer and cancer groups, and %pPSA tended to be higher in the cancer
      group (50.1% +/- 4.4%) compared with the noncancer group (35.5% +/- 6.7%; P =
      0.07). Using receiver operating characteristic analysis to assess clinical
      utility, the area under the curve for %pPSA was 0.688 compared with 0.567 for
      %fPSA. At a fixed sensitivity of 75%, the specificity was significantly greater
      for %pPSA at 59% compared with %fPSA at 33% (P <0.0001). CONCLUSIONS: In the 2.5
      to 4.0 ng/mL total PSA range, 75% of cancers can potentially be detected with 59%
      of unnecessary biopsies being spared using %pPSA; use of %fPSA would result in
      sparing only 33% of unnecessary biopsies. A large prospective clinical trial is
      needed to confirm these preliminary findings.

PMID- 12597930
TI  - Detection and isolation of prostate cancer cells from peripheral blood and bone
      marrow.
AB  - OBJECTIVES: To detect and isolate disseminated prostate cancer cells because
      significant effort has been directed toward defining the characteristics of the
      primary tumor that predict progression, but little progress has been made on
      evaluating the disseminated prostate cancer cell. Prostate-specific antigen (PSA)
      reverse transcriptase-polymerase chain reaction results in the bone marrow (BM)
      and peripheral blood (PB) of men with prostate cancer suggest many have
      disseminated cancer cells. METHODS: Disseminated epithelial cells were isolated
      from the BM and PB using Miltenyi antibody-coated paramagnetic microparticle
      technology. In the two-step selection process, anti-CD45 and anti-CD61 were used
      for negative selection, and anti-human epithelial antigen was used for positive
      selection. Cells were then stained for Ber-EP4 (a distinct epitope of the human
      epithelial antigen) and PSA. PSA reverse transcriptase-polymerase chain reaction
      was performed on an enriched aliquot. RESULTS: The normal controls were negative.
      Before prostatectomy, PSA-expressing epithelial cells were detected in 54% of BM
      and 24% of PB samples. At a median of 4 months after prostatectomy, PSA
      expressing cells were detected in 33% of BM and 9% of PB specimens from men
      without evidence of disease. In men more than 5 years after prostatectomy, PSA
      expressing cells were detected in the BM of 4 (29%) of 14, 2 of whom subsequently
      developed evidence of disease recurrence. CONCLUSIONS: The findings suggest that
      dissemination of cells is an early event in prostate cancer that is insufficient
      for the development of metastases. Isolation will allow interrogation of the
      phenotype and genotype of the cells.

PMID- 12597931
TI  - Music decreases anxiety and provides sedation in extracorporeal shock wave
      lithotripsy.
AB  - OBJECTIVES: To evaluate the efficacy of music on sedation in extracorporeal shock
      wave lithotripsy (ESWL) treatment to compare its anxiolytic effects with those of
      midazolam. METHODS: Ninety-eight urolithiasis patients were randomly divided into
      two groups. Hemodynamic parameters, including mean arterial pressure, heart rate,
      respiration rate, and oxygen saturation, were recorded in all patients. In 50
      patients (group 1), 2 mg of midazolam was administered intravenously 5 minutes
      before ESWL. In group 2 (n = 48), music chosen by the patients was listened to
      with a headset and continued during the treatment. The visual analog scale (0 to
      100 mm), Observer's Assessment of Alertness/Sedation Scale, State and Trait
      Anxiety Inventory-Trait Anxiety test, and State and Trait Anxiety Inventory-State
      Anxiety test were administered for the evaluation of pain, sedation level, and
      patient anxiety. RESULTS: For the hemodynamic parameters, a statistically
      significant decrease in mean arterial pressure was noted at the end of the ESWL
      procedure in group 2 and in oxygen saturation from the 10th minute to the end of
      the treatment in group 1. Although the visual analog scale, Observer's Assessment
      of Alertness/Sedation Scale, and State and Trait Anxiety Inventory-State Anxiety
      test did not show statistically significant differences, the State and Trait
      Anxiety Inventory-Trait Anxiety score was found to be lower in the music group
      (group 2) than in the midazolam group (group 1). CONCLUSIONS: With the anxiolytic
      effects of music, ESWL can be performed more effectively with the patient in a
      comfortable state. Listening to music by patients during the ESWL session is a
      feasible and convenient alternative to sedatives and anxiolytics.

PMID- 12597932
TI  - Mechanism of continence after repair of post-traumatic posterior urethral
      strictures.
AB  - OBJECTIVES: To determine the mechanism of urinary continence after repair of post
      traumatic posterior urethral strictures by perineal anastomotic urethroplasty.
      METHODS: Two groups of male patients were enrolled in this study. Group 1
      consisted of 8 patients (mean age 31 years) who had undergone bulboprostatic
      anastomotic urethroplasty for strictures complicating a pelvic fracture urethral
      disruption. Group 2 consisted of 8 patients (mean age 32.5 years) with a normal
      urethra who were used as controls. All 16 patients underwent urethral pressure
      profilometry both at rest and with cough and hold maneuvers. RESULTS: In group I,
      urethral pressure profilometry showed much lower mean maximal urethral pressures
      and maximal urethral closure pressures, as well as a much shorter mean functional
      profile length than in group 2 (48 and 39 cm H(2)O versus 75 and 65 cm H(2)O and
      2.4 versus 4 cm, respectively, P <0.0003). On cough maneuver, intra-abdominal
      pressure changes were transmitted along the entire functional profile length in
      group 1 and only along its first part in group 2. The hold maneuver increased
      urethral pressure in 5 patients (65%) in group 1 and in all 8 patients (100%) in
      group 2. CONCLUSIONS: Continence after anastomotic urethroplasty for post
      traumatic posterior urethral strictures is maintained solely by the proximal
      urethral mechanism. Transmission of intra-abdominal pressure changes and
      contraction of pelvic floor musculature may augment urethral closure in these
      cases during stress conditions.

PMID- 12597933
TI  - Management of failed primary intervention for ureteropelvic junction obstruction:
      12-year, single-center experience.
AB  - OBJECTIVES: To compare contemporary endourologic and open surgical management of
      failed primary intervention for ureteropelvic junction obstruction, specifically
      in regard to immediate and long-term results and complications. METHODS: Since
      1989, 48 patients have undergone management of failed primary intervention for
      ureteropelvic junction obstruction. Of these, 42 patients (21 females and 21
      males; age range 16 to 68 years, mean age 34.9) underwent follow-up evaluations.
      These 42 patients constitute the present study group. The mode of secondary
      intervention was determined by individual upper tract anatomy, concurrent medical
      conditions, and informed patient preference. Secondary intervention included open
      operative repair (n = 20) or percutaneous (n = 11), ureteroscopic (n = 5), or
      retrograde cautery wire balloon (n = 6) endopyelotomy. Success was defined as
      symptomatic relief and improved calicectasis on radiographic evaluation at latest
      follow-up. RESULTS: Follow-up ranged from 6 to 148 months (mean 47.7).
      Endourologic intervention was associated with a mean hospital stay of 2.3 nights
      and a complication rate of 13.6%. The long-term success rate of these endoscopic
      approaches was 59.1% overall, including a 71.4% success rate after a failed open
      operative procedure and a 37.5% success rate after a failed endourologic
      procedure. In contrast, open operative salvage was associated with a mean stay of
      4.3 nights and a 15% complication rate. The success of open operative salvage was
      95% overall, including 94.1% after failed endourologic intervention and 100%
      after failed open operative intervention. CONCLUSIONS: Endourologic intervention
      for failed primary management of ureteropelvic junction obstruction is associated
      with a short hospital stay and low rate of complications. Such intervention
      provides acceptable success rates in the setting of prior failed open operative
      intervention. However, when endourologic salvage was used for prior failed
      endourologic intervention, the success rates were limited. This suggests that
      intrinsic factors such as crossing vessels or periureteral fibrosis may play a
      role in limiting the utility of such procedures in this setting. In contrast,
      open operative salvage after any prior failed intervention for ureteropelvic
      junction obstruction provides excellent functional results without any increase
      in morbidity, with, in this contemporary series, an acceptably short hospital
      stay. These data should help urologists and patients make well-informed treatment
      decisions.

PMID- 12597934
TI  - Association of energy intake with prostate cancer in a long-term aging study:
      Baltimore Longitudinal Study of Aging (United States).
AB  - OBJECTIVES: To examine the association of total energy intake and macronutrient
      contributors to energy with prostate cancer risk among men in the Baltimore
      Longitudinal Study of Aging. METHODS: In the Baltimore Longitudinal Study of
      Aging cohort, 444 men completed at least one food frequency questionnaire (FFQ).
      At their earliest FFQ completion, men were 45 to 92 years old. The total number
      of prostate cancer cases (n = 68) consisted of men who were diagnosed with cancer
      before their FFQ completion (n = 46) and those who were diagnosed after their FFQ
      completion (n = 22). Multiple logistic regression analysis was used to calculate
      the odds ratio of prostate cancer and its 95% confidence interval. RESULTS: Total
      energy intake was positively associated with prostate cancer. Compared with the
      lowest quintile of energy intake, the odds ratio for the highest quintile was
      3.79 (95% confidence interval 1.52 to 9.48, P TREND = 0.002). Energy-adjusted
      intakes of protein, fat, and carbohydrates were not statistically significantly
      associated with prostate cancer risk. CONCLUSIONS: This analysis, in which we
      used current energy intake as a surrogate for past prediagnostic intake, suggests
      a higher risk of prostate cancer with increased energy intake.

PMID- 12597935
TI  - Cross-cultural validation of the UCLA prostate cancer index.
AB  - OBJECTIVES: To explore the impact of cross-cultural differences on University of
      California, Los Angeles, Prostate Cancer Index (PCI) reliability and validity,
      which is unknown. The PCI represents the most widely used prostate cancer
      specific health-related quality-of-life assessment tool. METHODS: The PCI sexual
      and urinary scales, the RAND SF-36 survey, and the Prostate Outcomes Research
      Team (PORT) prostate cancer treatment complication profile were self
      administered. The principal sample consisted of 2415 men (anglophone 256,
      francophone 2159) treated with radical prostatectomy in Quebec between 1988 and
      1996. An additional 35 men (anglophone 17, francophone 18) formed the retest
      sample. RESULTS: The PCI demonstrated excellent internal consistency and test
      retest reliability in tests based on the entire cohort and in tests addressing
      the two linguistically different groups. The instrument showed a lack of
      convergence with the SF-36 scales, confirming the distinctness of the generic and
      prostate cancer-specific constructs. The PCI sexual scales converged with the
      aggregate PORT sexual items (r = 0.8), and the PCI urinary scales were strongly
      related to the aggregate PORT urinary items (r = 0.7). Convergence between PCI
      urinary bother and function was strong (r = 0.8), but only moderate convergence
      was noted between PCI sexual bother and function (r = 0.4). The relation between
      bother and function in both urinary and sexual domains was weaker in anglophone
      participants relative to their francophone counterparts. CONCLUSIONS: The PCI is
      reliable and, at best, only modestly affected by cultural differences when
      administered to culturally distinct English-speaking men or when translated into
      French.

PMID- 12597936
TI  - Educating African-American men about prostate cancer: impact on awareness and
      knowledge.
AB  - OBJECTIVES: To determine whether an education program on prostate cancer could
      improve awareness and knowledge among African-American men. African-American men
      have the world's highest incidence of prostate cancer and more than twice the
      mortality compared with white men. Screening programs for prostate cancer have
      not been successful in attracting African-American participation. One explanation
      is a poor awareness and knowledge about the disease among this high-risk
      population. METHODS: We surveyed 900 African-American adults attending prostate
      cancer education seminars in community settings throughout Illinois between March
      1998 and January 2001. Participants were asked to complete a multiple-choice
      questionnaire on topics related to prostate cancer. The main outcome measures
      were a change in awareness and knowledge of prostate cancer after the 1-hour
      educational seminar. RESULTS: The mean survey score improved from 26.0% before
      the seminar to 73.3% after it (P <0.0001). Every multiple-choice question was
      answered correctly more often after the seminar than before it. Increasing levels
      of education and income were associated with higher before and after scores (P
      <0.001). Men achieved a significantly greater score improvement (mean 48.1%)
      compared with women (mean 41.1%; P = 0.006). Previous screening for prostate
      cancer was reported by 23% of the participants. Using logistic regression
      analyses, higher levels of education and income correlated with higher rates of
      screening. After the seminar, 63.1% stated the intention to undergo screening.
      CONCLUSIONS: Our results demonstrate that prostate cancer awareness and knowledge
      can improve dramatically after a 1-hour seminar on the topic. Additional studies
      to evaluate the long-term retention of knowledge and impact on behavior are
      warranted.

PMID- 12597937
TI  - Number of metastatic sites rather than location dictates overall survival of
      patients with node-negative metastatic renal cell carcinoma.
AB  - OBJECTIVES: To perform a retrospective study to determine whether survival and
      immunotherapy response are related to the site of metastases (lung versus bone)
      and to the number of organ sites involved (one versus multiple). The most common
      sites of metastatic renal cell carcinoma (mRCC) are the lung and bone. METHODS:
      The records of 434 patients with mRCC were reviewed. Patients with pathologic
      evidence of nodal involvement were excluded, leaving 120 patients with mRCC to
      lung only, 33 patients to bone only, and 144 patients with multiple organ
      involvement. The response rates to immunotherapy and overall survival were
      compared. The variables evaluated in statistical analyses included Eastern
      Cooperative Oncology Group score, grade, 1997 tumor stage, and multiple organ
      involvement. RESULTS: The median survival for patients with lung only and bone
      only mRCC was 27 months; patients with multiple organ involvement had a median
      survival of 11 months. In patients who underwent nephrectomy followed by
      immunotherapy, the median survival time was 31, 31, and 13 months in the lung,
      bone, and multiple sites groups, respectively. The response rate to immunotherapy
      after nephrectomy was 44%, 20%, and 14% in the lung, bone, and multiple organ
      groups, respectively. Multivariate analysis confirmed that metastatic disease to
      more than one organ site was associated with poor prognosis (2.05 risk ratio, P
      <0.001). CONCLUSIONS: Patients with mRCC to only one organ site fared
      significantly better than patients who had evidence of disease in multiple
      organs. Survival in patients with disease limited to the lung was similar to that
      of patients whose disease was limited to bone.

PMID- 12597938
TI  - Laparoscopic adult donor nephrectomy for pediatric renal transplantation.
AB  - To evaluate retrospectively our laparoscopic adult donor nephrectomy experience
      for pediatric transplantation. Since February 1995, 7 adult donors have undergone
      laparoscopic donor nephrectomy for pediatric renal transplantation (recipients
      younger than 18 years and weighing less than 30 kg). The outcomes of these donors
      and pediatric recipients were evaluated. The 7 laparoscopic renal donors had a
      median operative time of 306 minutes, median allograft warm ischemia time of 275
      seconds, median blood loss of 200 mL, median hospital stay of 3 days, and 14.2%
      overall complication rate. No graft loss or patient mortality occurred. The
      pediatric recipients of the laparoscopic live-donor allografts had a median
      creatinine clearance level of 52.1, 52.1, 44, and 41.1 mL/min at 3, 6, 12, and 18
      months, respectively. The overall complication rate was 14.2%. The 1 and 2-year
      graft survival rates were 100%. No mortality occurred in the pediatric
      recipients. Laparoscopic donor nephrectomy is well tolerated by the adult donors
      and appears to provide acceptable recipient and allograft outcomes in the
      pediatric population.

PMID- 12597939
TI  - Impact of renal artery multiplicity on outcomes of renal donors and recipients in
      laparoscopic donor nephrectomy.
AB  - OBJECTIVES: To review our laparoscopic donor nephrectomy experience to determine
      the impact of multiple renal arteries on renal donor and recipient outcomes.
      Multiple renal arteries can present a challenge during live laparoscopic donor
      nephrectomy. METHODS: During a 6-year period, 353 patients underwent laparoscopic
      donor nephrectomy and an equal number of patients underwent living-related renal
      transplantation. A retrospective chart review was performed to evaluate the renal
      donors and recipients associated with the laparoscopic procedure. RESULTS:
      Laparoscopic donor nephrectomies were associated with one renal artery in 277
      cases (78.5%), two renal arteries in 71 cases (20.1%), and three renal arteries
      in 5 cases (1.4%). A left-sided procedure was most commonly performed in all
      three groups. The operative and renal allograft warm ischemia times increased
      with the number of renal arteries, but the differences were not statistically
      significant. The renal artery anatomy did not have a significant association with
      intraoperative blood loss, postoperative hospital stay, or complication rate in
      the donor group. Regarding the transplant recipients, renal artery multiplicity
      had no significant association with the complication rate, 1-year graft survival,
      or creatinine clearance levels at 1, 2, or 3 days or at 3, 6, or 12 months
      postoperatively. CONCLUSIONS: With meticulous procurement and reconstructive
      transplantation techniques, the presence of multiple renal arteries in
      laparoscopic donor nephrectomy does not have a significant impact on the outcomes
      of the renal donors or recipients.

PMID- 12597940
TI  - Urinary incontinence after continent urinary diversion using cecal wrap or
      plicated ileum: a patient questionnaire review.
AB  - OBJECTIVES: To evaluate the clinical and urodynamic results of a tapered-cecal
      wrap (TCW) versus a tapered-plicated ileal (TPI) anti-incontinence mechanism.
      METHODS: Of 54 consecutive patients who had undergone continent urinary
      diversions, 33 (17 with TCW and 16 with TPI) were evaluated. The primary disease
      that prompted diversion included bladder cancer (84%), neurogenic bladder (12%),
      and interstitial cystitis (3%). All patients were evaluated using a telephone
      questionnaire regarding ease of catheterization, degree of continence, occurrence
      of postoperative complications, and overall satisfaction in relation to their
      stoma. In addition, 6 patients in the TPI group and 5 in the TCW group underwent
      enterocystometry and outlet pressure recording. The mean follow-up was 30 months
      for the TCW group and 48 months for the TPI group. RESULTS: The overall
      functional continence rate was 100% for the TCW group and 81.3% for the TPI
      group. Transient difficulty with catheterization occurred in 35.3% of the TCW
      group and 18.7% of the TPI group. No differences were observed in the occurrence
      of postoperative complications. Urodynamics demonstrated a statistically
      significant increase in maximal outlet pressure with the reservoir full in the
      TCW group that was not noted in the TPI group. CONCLUSIONS: The addition of a
      cecal wrap to the efferent limb results in significantly improved continence.
      This was supported urodynamically with demonstration of an increase in maximal
      outlet pressure with the reservoir full in the TCW group. No difference in the
      surgical complication rate or long-term difficulty with catheterization was
      observed.

PMID- 12597941
TI  - Whole bladder photodynamic therapy with 5-aminolevulinic acid using a white light
      source.
AB  - OBJECTIVES: To determine whether whole bladder photodynamic therapy after
      intravesical administration of 5-aminolevulinic acid using a white light source
      would destroy urothelial carcinoma. We sought to define the optimal target group
      of patients for this therapy. The side effects of treatment were also assessed.
      METHODS: We performed whole bladder photodynamic therapy with 100 J/cm(2) white
      light 2 to 4.5 hours after intravesical administration of 17% 5-aminolevulinic
      acid in 12 patients with recurring, multifocal, Stage pTa, grade I to III,
      urothelial tumors of the bladder and carcinoma in situ. RESULTS: Immediately
      after whole bladder irradiation, histologic examination of biopsies taken from
      flat suspicious lesions showed no viable cells; remnants of malignant cells were
      found in papillary tumors. Of the 12 patients, 11 returned for follow-up
      examination. At a median follow-up of 18 months (range 3 to 25), 3 of the 7
      patients with carcinoma in situ and 2 of the 4 patients with papillary tumors
      were free of disease. In all patients, urinary frequency and urgency subsided
      within 3 weeks. No decreased bladder capacity or systemic side effects were
      observed. CONCLUSIONS: Our preliminary data show that whole bladder photodynamic
      therapy with intravesically applied 5-aminolevulinic acid using a white light
      source is effective in destroying flat malignant lesions of the bladder such as
      carcinoma in situ. The procedure is easy to perform and is not associated with
      any major side effects. The findings warrant long-term and multicenter studies.

PMID- 12597942
TI  - Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for
      patients with recurrent superficial bladder cancer: a single-center study.
AB  - OBJECTIVES: Photodynamic therapy (PDT) is an effective treatment option for
      patients with superficial bladder cancer uncontrolled by transurethral resection
      and/or intravesical bacille Calmette-Guerin (BCG) immunotherapy alone. We
      determined the efficacy and side effects of PDT in patients with recurrent
      superficial bladder cancer. METHODS: Between April 1994 and July 2001, PDT was
      performed in 31 patients (23 men and 8 women). 5-Aminolevulinic acid (50 mL) in a
      3% concentration was instilled intravesically. Patients were instructed to hold
      the solution as long as possible and were irradiated transurethrally with a mean
      light dose of 3.9 W using laser light emitting a wavelength of 633 nm for a mean
      time of 1260 seconds. RESULTS: The mean patient age at the procedure was 70.2
      years. At an average follow-up of 23.7 months (range 1 to 73), 16 patients were
      free of tumor recurrence; 15 patients had developed tumor recurrence after a mean
      of 8.3 months. Of 10 patients with prior BCG treatment, 4 were free of tumor
      recurrence. Treatment was well tolerated, with the only side effect being dysuria
      due to urinary tract infection in 4 patients and hematuria in 7 patients. No
      phototoxic skin reactions were observed. CONCLUSIONS: PDT represents a safe,
      effective, and less-invasive treatment for patients with recurrent superficial
      bladder cancer. Because of the favorable side-effect profile, PDT can also be
      applied to patients with comorbidity precluding surgical treatment. Furthermore,
      PDT represents a second-line treatment for patients with tumor recurrence after
      BCG failure.

PMID- 12597943
TI  - Radical cystectomy for bladder cancer after definitive prostate cancer treatment.
AB  - OBJECTIVES: To review our perioperative experience with patients presenting with
      high-risk bladder cancer who had undergone prior therapy for prostate cancer.
      With the increase in diagnosis and subsequent treatment of prostate cancer, more
      patients presenting with high-risk bladder cancer have undergone prior therapy
      for prostate cancer. Radical cystectomy in these patients can be technically
      challenging and may be associated with added morbidity. METHODS: A retrospective
      review of 458 patients treated with radical cystectomy between January 1993 and
      January 2002 revealed 29 patients (mean age 72 years) who had received definitive
      treatment for prostate cancer prior to cystectomy for bladder carcinoma. The
      initial treatment in this cohort was radical prostatectomy or external beam
      radiotherapy in 12 (41%) and 17 (59%) men, respectively. Cystectomy was performed
      for transitional cell carcinoma in 25 (86%), small cell carcinoma in 2 (6%), and
      sarcoma in 2 (6%) patients. RESULTS: At the time of cystectomy, the mean blood
      loss was 1175 mL (range 275 to 3500), and the median length of hospitalization
      was 8 days (range 4 to 23). No intraoperative or perioperative deaths occurred in
      this cohort. Twenty-seven early complications were identified in 16 (55%) of 29
      patients; no rectal injuries occurred. Patients with prior radiotherapy had a
      higher rate of extravesical bladder carcinoma (60%) than those patients treated
      with prior prostatectomy (33%). An orthotopic neobladder diversion was created in
      5 patients (17%). CONCLUSIONS: Patients with bladder cancer previously treated
      for prostate cancer with external beam radiotherapy or radical prostatectomy have
      an increased risk of perioperative complications compared with patients
      undergoing cystectomy without prior therapy. This risk is not prohibitive, and
      radical cystectomy should remain the treatment of choice for high-risk bladder
      cancer in this population. Furthermore, orthotopic urinary diversion may be a
      reasonable option and should be considered in select patients.

PMID- 12597946
TI  - Frequency of sexual activity and prostatic health: fact or fairy tale?
AB  - OBJECTIVES: To evaluate whether the symptoms associated with benign prostatic
      hyperplasia can be aggravated by infrequent sex, which has been suggested
      historically, using cross-sectional data from the Olmsted County Study of Urinary
      Symptoms and Health Status Among Men. METHODS: In 1989 and 1990, 2115 white men
      between the ages of 40 and 79 years were recruited from a random sample of
      Olmsted County residents (55% participation rate). During follow-up, these men
      completed a self-administered questionnaire that assessed lower urinary tract
      symptom severity, and 81% reported the frequency of ejaculation during the
      previous month. RESULTS: Overall, men who reported ejaculating at least once a
      week were less likely to have moderate to severe (International Prostate Symptom
      Score greater than 7) symptoms than men reporting no ejaculations (odds ratio
      0.62, 95% confidence interval 0.51 to 0.75). The dose-response relation was
      strong, with men who reported more frequent ejaculations having the lowest
      prevalence of moderate to severe symptoms. Similar associations were seen for
      peak urinary flow rates, prostate volume, and health-related quality of life. The
      associations with urologic measures did not exist within the age decade, however.
      Thus, after adjusting for age, the odds ratio for ejaculation frequency and
      symptom severity was 0.99 (95% confidence interval 0.79 to 1.24) and was similar
      for peak urinary flow rates and prostate volume. CONCLUSIONS: These cross
      sectional data suggest that the frequency of ejaculation has no effect on lower
      urinary tract symptoms, peak urinary flow rates, or prostate volume; the apparent
      protective association appears to be an artifact caused by the confounding
      effects of age.

PMID- 12597947
TI  - Long-term treatment with finasteride in men with symptomatic benign prostatic
      hyperplasia: 10-year follow-up.
AB  - OBJECTIVES: To evaluate the safety and efficacy of finasteride 5 mg during a 10
      year period in men with enlarged prostates from a single center who participated
      in the double-blind and extension phases of the multicenter, Phase III, North
      American benign prostatic hyperplasia (BPH) trial. It is important that the long
      term safety and efficacy of drugs intended for chronic administration in men with
      BPH be well understood. METHODS: The Phase III North American BPH trial involved
      a 1-year, placebo-controlled, double-blind study, followed by a 5-year open
      extension with finasteride 5 mg/day. The trial enrolled men with symptomatic BPH,
      an enlarged prostate on digital rectal examination, and no evidence of prostate
      cancer. Of the 46 patients originally enrolled from our institution, 43 were
      randomized to receive finasteride or placebo, of whom 41 (95%) completed the
      double-blind study and entered the 5-year extension. Thirty (73%) of these 41
      patients completed the 5-year extension. Patients continued to be followed up by
      their physicians for an additional 5 years, for a total follow-up of at least 10
      years. RESULTS: Twenty-four (56%) of the original 43 patients randomized to
      finasteride or placebo were judged as successfully treated during the 10-year
      finasteride follow-up (17 patients taking finasteride alone at 10 years and 7
      patients who were taking finasteride alone when they discontinued during the 10
      year follow-up for reasons not related to finasteride treatment). Altogether, 22
      (51%) of the original 43 randomized patients continued finasteride treatment at
      10 years (17 taking finasteride alone, 4 taking finasteride plus an alpha
      blocker, and 1 taking finasteride for treatment of hematuria). Finasteride was
      well tolerated, with no new adverse experiences occurring with increasing
      duration of exposure to the drug. CONCLUSIONS: This long-term follow-up study has
      demonstrated that appropriately selected patients with symptomatic BPH and
      enlarged prostates are likely to have a long-term response to taking finasteride
      5 mg daily.

PMID- 12597948
TI  - Correlation of preoperative levels of IGF-I and IGFBP-3 with pathologic
      parameters and clinical outcome in patients with bladder cancer.
AB  - OBJECTIVES: To test the hypothesis that plasma insulin growth factor (IGF)-I or
      IGF binding protein (BP)-3 levels would differ between patients with bladder
      cancer and healthy controls and whether preoperative plasma IGF-I or IGFBP-3
      could predict the pathologic characteristics and clinical outcome of patients
      with bladder cancer undergoing radical cystectomy. The IGFs are mitogens that
      have been shown to play a significant role in regulating proliferation and
      differentiation of bladder cancer cells. METHODS: The study group consisted of 51
      patients who underwent radical cystectomy (median follow-up 45.7 months). The
      preoperative plasma levels of IGF-I and IGFBP-3 were measured using DSL-enzyme
      linked immunosorbent assays. The IGF-I and IGFBP-3 levels were also measured in
      44 healthy men. RESULTS: The plasma IGF-I and IGFBP-3 levels in patients with
      bladder cancer were not significantly different from those in healthy subjects (P
      >or=0.339). In a preoperative model that included clinical grade, clinical stage,
      and either IGF-I or IGFBP-3, none of the parameters was associated with either
      metastases to lymph nodes or clinical outcome. However, in an alternative model
      that included both IGF-I and IGFBP-3 in addition to clinical stage and grade,
      only a lower preoperative plasma IGFBP-3 level was associated with metastases to
      regional lymph nodes, bladder cancer progression, and survival (P = 0.047, 0.050,
      and 0.040, respectively). CONCLUSIONS: We found no association between
      preoperative plasma IGF-I and bladder cancer characteristics or outcome, limiting
      the clinical utility of IGF-I. In contrast, a lower preoperative plasma level of
      IGFBP-3 was associated with lymph node metastasis and poorer clinical outcome
      after radical cystectomy when adjusted for IGF-I level.

PMID- 12597949
TI  - Defining the ideal cutpoint for determining PSA recurrence after radical
      prostatectomy. Prostate-specific antigen.
AB  - OBJECTIVES: To determine the ideal cutpoint for defining prostate-specific
      antigen (PSA) recurrence after radical prostatectomy (RP). Although various
      cutpoints have been used, a recent study suggested that 0.4 ng/mL may be the most
      appropriate. METHODS: A retrospective survey of 358 men undergoing RP at the West
      Los Angeles Veterans Affairs Medical Center between 1991 and 2001 was undertaken.
      The 3-year and 5-year risk of PSA recurrence was estimated by Kaplan-Meier
      analyses using various cutpoints of postoperative PSA to define recurrence:
      greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, and
      greater than 0.5 ng/mL. The 1 and 3-year risk of PSA progression after a
      detectable PSA level (PSA rising to a higher cutpoint) was evaluated for each
      definition of PSA recurrence using Kaplan-Meier analyses. Multivariate analysis
      using a Cox proportional hazards model was used to determine the clinical
      variables that were significant independent predictors of PSA recurrence at each
      cutpoint. RESULTS: For patients with a detectable postoperative PSA value from
      0.11 to 0.2 ng/mL, the 1 and 3-year risk of PSA progression was 64% (95%
      confidence interval [CI] 46% to 82%) and 93% (95% CI 74% to 99%), respectively.
      For patients with a PSA value from 0.21 to 0.3 ng/mL, the 1 and 3-year risk of
      PSA progression was 86% (95% CI 69% to 97%) and 100% (95% CI 87% to 100%),
      respectively. The use of higher PSA cutpoints to define recurrence resulted in a
      lower 5-year risk of PSA recurrence. The 5-year risk of PSA recurrence using a
      greater than 0.1 ng/mL cutpoint resulted in a 43% (95% CI 36% to 50%) risk of
      recurrence compared with only 23% (95% CI 18% to 30%) for a greater than 0.5
      ng/mL cutpoint. In multivariate analysis, PSA and biopsy Gleason score were
      significant independent predictors of biochemical recurrence, regardless of the
      definition of PSA recurrence used (P <or=0.002). CONCLUSIONS: PSA and biopsy
      Gleason score were significant predictors of biochemical failure, regardless of
      the definition of failure used. However, the definition of PSA recurrence
      dramatically affected the perceived success of therapy. Patients with a
      postoperative PSA value greater than 0.2 ng/mL are at very high risk of
      developing an additional rise in PSA. On the basis of this finding, a PSA value
      greater than 0.2 ng/mL is an appropriate cutpoint to define PSA recurrence after
      RP.

PMID- 12597950
TI  - Relationship between serum prostate-specific antigen and calculated epithelial
      volume.
AB  - OBJECTIVES: To estimate the relationship between serum prostate-specific antigen
      (PSA) and prostatic epithelial volume, a new simple method for measuring
      epithelial volume was developed and its efficacy evaluated in patients with
      benign prostatic hyperplasia. METHODS: Between March 1998 and June 2001, 122
      patients without prostate cancer in the transurethral resected specimen were
      enrolled in this study. Of the 122 patients, 55 had a serum PSA level of 4.0
      ng/mL or greater and negative sextant biopsies before surgery. First, we measured
      the epithelium/glandular lumen ratio by computer image analysis in 20 specimens.
      Second, we measured the percentage of glandular lumen in all 122 patients. The
      prostatic epithelial volume was then calculated as follows: calculated epithelium
      volume (in cubic centimeters) = epithelium/glandular lumen ratio percentage of
      glandularlumen x total prostate volume (in cubic centimeters). RESULTS: The
      epithelium/glandular lumen ratio was 1.01 in the 20 specimens. In the 122
      patients with benign prostatic hyperplasia, the calculated epithelial volume
      correlated more strongly with the serum PSA level than did the total prostate
      volume, transition zone volume, or percentage of epithelium (gamma = 0.672, P
      <0.0001). The mean PSA level per calculated epithelial volume was 1.27
      ng/mL/cm(3). The calculated epithelial volumes from the biopsy specimens
      correlated significantly with those from transurethral resection specimens (gamma
      = 0.956, P <0.0001). CONCLUSIONS: Serum PSA levels correlated significantly with
      prostatic epithelial volumes in patients with benign prostatic hyperplasia. The
      method of measuring prostatic epithelial volume used in this study is very
      convenient for clinical practice.

PMID- 12597951
TI  - Similar age-specific PSA, complexed PSA, and percent cPSA levels among African
      American and white men of southern Louisiana. Prostate-specific antigen.
AB  - OBJECTIVES: To determine the mean and median complexed prostate-specific antigen
      (cPSA) levels in a predominantly African-American population and to explore
      whether differences in cPSA exist between the races. Differences in total PSA
      (tPSA) levels between age-matched African-American and white men have been
      reported by several groups. Age-specific cPSA levels, however, have not been
      thoroughly evaluated and reported among African-American populations. METHODS: We
      prospectively evaluated the serum cPSA, tPSA, and percent cPSA levels by the
      Bayer Immuno 1 assay as a function of age among 1755 African-American and 630
      white men in southern Louisiana presenting to a prostate cancer screening
      program. All men had a normal digital rectal examination or biopsy-proven benign
      pathologic findings. The intragroup and intergroup statistical analyses were
      carried out for each decade of age. RESULTS: The median cPSA level for African
      American men aged 40 to 49, 50 to 59, and 60 to 69 years old was 0.45, 0.61, and
      0.84 ng/mL, respectively. These did not differ significantly from those of age
      matched white men. Also, no difference was found in the mean or median tPSA
      between the races. The percent cPSA values showed a trend for lower levels in
      African Americans. CONCLUSIONS: These findings suggest that no significant
      difference exists between cPSA or tPSA levels in African-American and white men
      without prostate cancer. Genetic and epigenetic factors distinct to this region
      may account for this observation and thus need further evaluation.

PMID- 12597952
TI  - Biochemical recurrence without PSA progression characterizes a subset of patients
      after radical prostatectomy. Prostate-specific antigen.
AB  - OBJECTIVES: To characterize a subset of patients with biochemical recurrence
      after radical prostatectomy but with little, if any, subsequent rise in serum
      prostate-specific antigen (PSA) and no clinical progression during long-term
      follow-up. METHODS: Of a series of 600 patients, 158 with biochemical recurrence
      after radical prostatectomy were examined. We identified a subset with measurable
      serum PSA levels during long-term follow-up, but with very low PSA velocity and
      no clinical recurrence. Serum PSA was measured with the ultrasensitive TOSOH
      assay with a PSA recurrence defined as a serum PSA of 0.07 ng/mL or greater.
      RESULTS: We identified 14 patients (8.8% of biochemical recurrences) with a
      detectable serum PSA level after radical prostatectomy yet without clinical or
      PSA progression at a mean follow-up after radical prostatectomy of 10.3 years.
      The mean time to PSA recurrence was 5.8 years, and the mean PSA velocity after
      recurrence was 0.028 ng/mL/yr. No clinical or pathologic features were found that
      could be used to identify this subset of patients. CONCLUSIONS: A subset of
      patients with biochemical recurrence after radical prostatectomy will not exhibit
      a progressive rise in serum PSA or clinical progression at 10 years follow-up.
      This suggests that serum PSA kinetics should be observed after biochemical
      recurrence before adjuvant hormonal therapy or radiotherapy.

PMID- 12597953
TI  - Location of positive surgical margins after retropubic, perineal, and
      laparoscopic radical prostatectomy for organ-confined prostate cancer.
AB  - OBJECTIVES: To evaluate and compare the location of positive surgical margins
      after retropubic, perineal, and laparoscopic radical prostatectomy for organ
      confined prostate cancer (pT2). METHODS: From 1988 to 2001, 538 patients
      underwent radical prostatectomy for clinically localized prostate cancer. Patient
      age at surgery, clinical stage, preoperative prostate-specific antigen, and
      Gleason score of positive biopsies were noted. Postoperatively, specimen weight,
      final Gleason score, and capsular, seminal vesicle, and lymph node status, as
      well as tumor volume, were studied. The incidence and location of positive
      margins and the pathologic stage were noted according to the surgical approach.
      RESULTS: A total of 371 patients (69.5%) had organ-confined tumors. Of the 371
      patients, 116 underwent the retropubic, 86 the perineal, and 169 the laparoscopic
      approach, and positive surgical margins were noted in 22 (18.9%), 12 (13.9%), and
      32 (18.9%) patients, respectively. Positive surgical margins were reported in 72
      specimen locations, 32 (44.4%) at the apex, 17 (23.6%) at the bladder neck, and
      29 (31.9%) posterolaterally. The distribution for the retropubic, perineal, and
      laparoscopic approaches was apex in 50%, 33.3%, and 44.4%, bladder neck in 29.1%,
      41.7%, and 13.9%, and posterolaterally in 20.8%, 25%, and 41.6%, respectively.
      CONCLUSIONS: In our series, each approach had a specific high-risk location of
      positive margins: the apex for the retropubic, the bladder neck for the perineal,
      and posterolaterally for the laparoscopic approach. Improvements in the surgical
      techniques should take these specific locations under consideration to decrease
      the incidence of positive surgical margins.

PMID- 12597954
TI  - A structured literature review to determine the use of the American Society for
      Therapeutic Radiology and Oncology consensus definition of biochemical failure.
AB  - OBJECTIVES: The American Society for Therapeutic Radiology and Oncology consensus
      definition (ACD) of biochemical failure after radiotherapy for prostate cancer
      requires three consecutive prostate-specific antigen increases from a nadir
      value. The members of the Consensus Panel recognized that the timing and
      frequency of prostate-specific antigen determinations could affect the
      comparability among different reports if this definition was used. For this
      reason, the Consensus Panel members recommended three guidelines for studies
      presented for publication (publication guidelines [PGs]). The present analysis
      examined the extent to which the ACD has been used in the peer-reviewed published
      literature and how frequently the PGs have been followed. METHODS: A structured
      literature review of 10 relevant journals was done. The inclusion criteria for
      the literature review required publication in calendar year 1999 or 2000;
      treatment with external beam radiotherapy and/or brachytherapy for previously
      untreated, nonmetastatic prostate cancer; and the use of a prostate-specific
      antigen-defined disease-free endpoint. A standardized checklist was created and
      completed by both of the authors. We independently reviewed each publication to
      determine whether the ACD of biochemical failure was used and whether the PGs
      were followed. Discrepancies between us were resolved by joint review of each
      publication in question to achieve a consensus. RESULTS: Fifty-seven articles met
      the inclusion criteria. The median number of patients in the articles reviewed
      was 302 (range 22 to 2222). The ACD was followed in 37 (64.9%) of 57 articles.
      None of the reviewed articles followed all three PGs. In five articles (8.7%),
      two of the three PGs were followed. The vast majority of the articles reviewed
      (52 of 57, 91.3%) followed one or none of the PGs recommended by the Consensus
      Panel. CONCLUSIONS: The ACD was used in two thirds of peer-reviewed published
      articles. The PGs were followed much less frequently. Consistent standards of
      reporting have not been uniformly applied to peer-reviewed manuscripts.

PMID- 12597955
TI  - Herpes simplex virus, cytomegalovirus, and papillomavirus DNA are not found in
      patients with chronic pelvic pain syndrome undergoing radical prostatectomy for
      localized prostate cancer.
AB  - OBJECTIVES: To study the possible involvement of viruses in chronic pelvic pain
      syndrome (CPPS) using polymerase chain reaction. Among other factors, the
      involvement of viruses in CPPS has been speculated, but few studies have
      investigated this. METHODS: Consecutive patients with localized prostate cancer
      for whom radical prostatectomy was considered were evaluated for symptoms of CPPS
      using the National Institutes of Health Chronic-Prostatitis Symptom Index. Ten
      patients with moderate to severe symptoms and 10 without symptoms were included
      in the study. The presence of herpes simplex virus (types 1 and 2),
      cytomegalovirus, and human papillomavirus DNA was investigated by polymerase
      chain reaction in prostatic tissue samples obtained at radical prostatectomy.
      RESULTS: All the samples were negative for the viral sequences tested.
      CONCLUSIONS: A viral etiology could not be demonstrated in CPPS. In addition, no
      association of the viruses with prostate cancer could be found.

PMID- 12597956
TI  - Why patients choose prostatectomy or brachytherapy for localized prostate cancer:
      results of a descriptive survey.
AB  - OBJECTIVES: Limited data exist as to the reasons patients have for deciding among
      potentially curative treatment choices in clinically localized prostate cancer.
      Therefore, we carried out a descriptive pilot study to determine such
      motivations, sources of information, and other variables that influence how such
      patients choose between radical prostatectomy (RP) and brachytherapy (BT).
      METHODS: Three hundred fifty-one men with clinically localized Stage T1c-T3
      adenocarcinoma of the prostate were treated by RP or palladium-103 BT, either
      alone (BTM) or in combination with external radiotherapy (BTC). On June 1, 2000,
      patients were mailed a questionnaire, and cross-sectional analysis of the
      returned questionnaires was carried out. RESULTS: Of 351 men, 262 (74.6%)
      responded to the survey; 65% chose treatment on the basis of evidence or an
      impression that it was the best procedure to cure their cancer. The possible side
      effects were also an important motivation for choosing a procedure. BTC patients
      listed the risk of urinary incontinence as the most disturbing and both RP and
      BTM patients listed sexual dysfunction. The most common unpleasant surprise for
      all treatment groups was bowel or bladder dysfunction. The most common pleasant
      surprise was a quick recovery. Urologists were the most important source of
      information and the major factor influencing the treatment decision.
      Surprisingly, spouses and fellow patients were relatively minor influences in
      this process. CONCLUSIONS: The results from this pilot study indicate that other
      factors beyond "cancer cure" are very important patient treatment decisions. In
      addition, by examining post-treatment "surprises," our data will allow the
      development of improved educational approaches to aid decision making.

PMID- 12597957
TI  - Gross hematuria after prostate brachytherapy.
AB  - OBJECTIVES: To summarize the clinical course of postimplant gross hematuria
      occurring past the perioperative period. METHODS: From 1998 to 2000, 226 patients
      were treated for prostate carcinoma by implant alone or implant with supplemental
      external beam radiotherapy, using palladium-103 or iodine-125. Of these 226
      patients, 9 had incomplete follow-up information and 2 died of causes other than
      prostate cancer. As a part of their routine follow-up, the remaining 215 patients
      were regularly mailed self-reporting questionnaires regarding urinary
      incontinence and hematuria. Postimplant computed tomography-based dosimetry was
      available for 211 (98%) of 215 patients. Dosimetric parameters were recorded for
      each patient using standardized methods. The rates of hematuria resolution were
      calculated using the product-limit (Kaplan-Meier) method. Statistical
      significance was determined using unpaired t testing. RESULTS: Twenty-seven
      patients (13%) reported at least one episode of gross hematuria occurring more
      than 1 week after prostate implantation. The onset and duration of bleeding
      varied widely. Eleven patients reported only a single, isolated episode, and 16
      patients reported multiple episodes, ranging from isolated sporadic to multiple
      times per day. No patient required a blood transfusion. The median time from the
      first episode of hematuria to resolution was 3 months. Of the 27 patients who
      reported hematuria, 88% had resolved by 24 months from time of first bleeding.
      Hematuria was unrelated to the maximal or mean urethral dose. CONCLUSIONS: Gross
      hematuria after brachytherapy resolves spontaneously in nearly all patients.
      Nonetheless, in patients without a recent workup for a genitourinary malignancy
      other than prostate cancer, a hematuria workup is reasonable. Because of the
      retrospective nature of this study and the highly variable presentation and
      clinical course of postimplant gross hematuria, we are unable to make firmer
      conclusions or recommendations regarding the role of follow-up urinalysis, urine
      cytology, anticoagulant medication, or supplemental beam radiation. Such an
      analysis will require a more controlled, prospective study of a large implant
      patient population.

PMID- 12597958
TI  - Outcomes after radical retropubic prostatectomy.
AB  - OBJECTIVES: To determine whether urinary incontinence after radical retropubic
      prostatectomy (RRP) for prostate cancer is improved by the preservation of the
      puboprostatic ligaments or bladder neck; whether impotency is reduced by the
      preservation of the neurovascular bundles; and whether positive surgical margins
      are a risk with more precise bladder neck and apical dissection. METHODS: RRP was
      performed sequentially in three groups using tennis racquet reconstruction,
      bladder neck preservation, or bladder neck and puboprostatic ligament
      preservation, and continence and surgical margin status were assessed. Also,
      recovery of potency and surgical margin status were evaluated when both, one, or
      no neurovascular bundles were preserved. RESULTS: A total of 244 patients had a
      social continence rate of 90%, 100%, and 89% after tennis racquet reconstruction,
      bladder neck preservation, or bladder neck and puboprostatic ligament
      preservation, respectively. The mean time to recovery of continence was similar
      for tennis racquet reconstruction (2.3 months) and bladder neck preservation (2.9
      months) but was longer (P <0.05) for bladder neck and puboprostatic ligament
      preservation (4.3 months). Although 9% of cases had positive margins, no margins
      were positive only at the bladder neck. Of a total of 188 patients potent
      preoperatively, 72% underwent bilateral nerve-sparing surgery. All men younger
      than 50 years old, 87% of men aged 50 to 59 years, 70% of men aged 60 to 69
      years, and 38% of men older than 70 years of age were potent. The surgical
      margins were positive in 9% of patients who underwent bilateral nerve-sparing
      surgery, and the site of margin positivity was the apex only in 3% of patients.
      CONCLUSIONS: Neurovascular bundle and bladder neck preservation decrease
      morbidity and rarely risk margin positivity. Bladder neck plus puboprostatic
      ligament preservation delays and does not improve overall continence.

PMID- 12597959
TI  - Retrieval and cryopreservation of sperm from spermatocele fluid.
AB  - OBJECTIVES: To evaluate the amount, motility, and viability of sperm in fluid
      aspirated from naturally occurring spermatoceles and to investigate the effect of
      cryopreservation of sperm retrieved from spermatoceles. Assisted reproductive
      technologies have led to successful pregnancies and deliveries using sperm
      harvested from the epididymis and/or testis of infertile men. METHODS: Aspiration
      of spermatocele fluid and analysis of the fluid obtained was performed on 20
      patients before elective spermatocelectomy. Randomly selected samples (n = 5)
      were washed using a 70% Percoll gradient, and repeated semen analysis was
      performed. The washed specimens were cryopreserved in liquid nitrogen, and
      repeated semen analysis was performed on the thawed specimens. RESULTS: All
      spermatoceles (n = 20) had viable sperm present (count range 54 x 10(4) to 326 x
      10(6)) and 16 (80%) of 20 contained motile sperm. The average percentage of
      motile sperm was 5%. The average sperm motility and average percent viability of
      sperm recovered after Percoll gradient improved compared with sperm in the
      initial spermatocele aspirates (motility 5%, range 0% to 25% and viability 36%,
      range 2% to 91% before Percoll vs. motility 13%, range 2% to 38% and viability
      39%, range 10% to 92% after Percoll). Sperm retrieved after cryopreservation
      demonstrated reduced motility and viability; however, motile and viable sperm
      were recovered from all washed and cryopreserved samples. CONCLUSIONS: Our
      results suggest that spermatocele fluid may contain sufficient numbers of sperm
      for use with assisted reproductive technologies. Motile and viable sperm can be
      recovered after cryopreservation and storage of sperm obtained from a
      spermatocele. Spermatocele fluid may be an additional source of sperm for
      assisted reproductive technologies.

PMID- 12597960
TI  - "Onco-tese": testicular sperm extraction in azoospermic cancer patients before
      chemotherapy-new guidelines?
AB  - OBJECTIVES: To examine the usefulness of pretreatment testicular sperm extraction
      because some patients have tumor-induced azoospermia. In view of the high cure
      rates for testicular germ cell tumors and malignant lymphomas, increasing
      clinical importance is attached to protecting fertility. High-dose cytostatic
      therapy may be expected to cause long-term infertility. Thus, the standard
      procedure for fertility protection is cryopreservation of ejaculated spermatozoa
      before therapy. METHODS: Contralateral testicular biopsies were taken from 14
      azoospermic patients with malignant testicular germ cell tumors. In addition, 17
      patients with malignant lymphomas underwent unilateral (n = 6) or bilateral (n =
      11) testicular biopsy. The tissue specimens were cryopreserved, and the
      histologic workup was performed at the same time. RESULTS: Of the 14 patients
      with malignant testicular germ cell tumors, 6 had spermatozoa in their testicular
      biopsies. Sertoli cell-only syndrome was found in 5 patients, and 3 had
      maturation arrest without detection of spermatozoa. Successful sperm recovery was
      possible in 8 of the 17 patients with malignant lymphoma, 4 had Sertoli cell-only
      syndrome, and 5 had maturation arrest. None of the patients had evidence of
      secondary wound healing or treatment delay because of the testicular biopsy.
      CONCLUSIONS: Our results show that testicular sperm extraction is a useful
      technique for obtaining spermatozoa before cytotoxic therapy in azoospermic
      cancer patients. This procedure should be considered as an option for fertility
      preservation in azoospermic cancer patients, because high cumulative cytostatic
      doses can cause irreversible fertility alterations.

PMID- 12597961
TI  - Penile hemodynamics in hypogonadal men with micropenis.
AB  - OBJECTIVES: To document the penile vascular and erectile response to
      intracavernous injection (ICI) of vasoactive agent in hypogonadal men with
      micropenis. METHODS: A total of 15, previously untreated, hypogonadal men with
      micropenis (stretched penis length less than 2.5 SD below the mean of the normal
      population) underwent a detailed urologic and endocrinologic evaluation. Their
      mean age was 21.2 +/- 4.2 years. Penile hemodynamics were assessed by color
      Doppler ultrasonography before and after ICI of 5 microg of prostaglandin E(1)
      combined with manual genital self-stimulation. RESULTS: Endocrinologic evaluation
      revealed that hypogonadism was hypogonadotropic in 10 (66.7%) and
      hypergonadotropic in 5 (33.3%). Karyotype analysis showed 46XY in all. Their mean
      stretched penile length was 6.2 +/- 1.4 cm (range 3 to 7.5) and increased to a
      mean of 6.96 +/- 1.5 cm (range 4 to 8.5) after ICI. The serum free testosterone
      levels ranged from 0.2 to 3.2 pg/mL (mean 1.9 +/- 0.92). None had had any
      previous sexual experience, and 14 (93.3%) reported a history of nocturnal
      erections. Penile color Doppler ultrasonography demonstrated a normal penile
      vascular system in 7 (46.7%) and penile arterial insufficiency in 4 (28.6%). All
      11 of these patients (73.3%) achieved an adequate erectile response to ICI
      combined with manual stimulation. Mixed vascular disease was observed in the
      remaining 4 patients (28.8%), and they did not have a sufficient erectile
      response to ICI. Color Doppler ultrasonography revealed similar results in the
      hypogonadotropic and hypergonadotropic men. CONCLUSIONS: Our data suggest that
      the erectile response to ICI combined with manual genital self-stimulation is
      effective in most hypogonadal men having a micropenis with low serum androgen
      levels.

PMID- 12597962
TI  - Incidence of erectile dysfunction in men 40 to 69 years old: results from a
      population-based cohort study in Brazil.
AB  - OBJECTIVES: To estimate the incidence of erectile dysfunction (ED) in Brazilian
      men 40 to 69 years old at study entry during an average 2-year follow-up and
      study the effect of age, socioeconomic status, and medical conditions on the risk
      of developing ED. METHODS: We analyzed data from a randomly sampled cohort of men
      living in Salvador, Bahia (Brazil), a racially diverse city with a population of
      2.3 million. A total of 602 men completed the baseline interview in 1998 and 501
      completed follow-up in 2000. The analysis sample consisted of 428 (83.4%) of 513
      men without ED at baseline. The men were interviewed in person, using a
      standardized questionnaire, and ED was assessed by a single global self-rating
      question. RESULTS: The crude incidence rate for ED was 65.6 cases per 1000 person
      years (95% confidence interval 49.6 to 85.2). The incidence rate increased with
      age and was 33.3, 53.7, and 189.5 cases per 1000 person-years for men 40 to 49,
      50 to 59, and 60 to 69 years old, respectively. The age-adjusted risk of
      developing new-onset ED was higher for men with lower education, diabetes,
      hypertension, and benign prostatic hyperplasia. Population projections for men 40
      to 69 years old suggest that approximately 68,600 new cases of ED in Bahia and
      1,025,600 in Brazil would be expected annually. CONCLUSIONS: The incidence of ED
      in Brazilian men was 2.5-fold higher than that in the Massachusetts Male Aging
      Study (26/1000 person-years) and increased with age, lower education, diabetes,
      hypertension, and benign prostatic hyperplasia.

PMID- 12597963
TI  - Prospective long-term results and quality-of-life assessment after Dura-II penile
      prosthesis placement.
AB  - OBJECTIVES: To evaluate prospectively the long-term device reliability and
      patient satisfaction after Dura-II malleable penile prosthesis implantation.
      METHODS: Between 1992 and 1996, 94 patients underwent Dura-II implantation for
      erectile dysfunction. Patients were prospectively examined and completed
      standardized questionnaires regarding sexual activity, prosthesis function,
      intercourse satisfaction, and overall quality of life. An independent
      statistician analyzed these data. RESULTS: The mean patient age was 63 years, and
      the mean patient follow-up was 5.7 years. Eighty-five patients were available for
      long-term evaluation. Fourteen patients died during the follow-up period. One
      patient was lost to follow-up, and eight prostheses (9%) were explanted; however,
      no mechanical defects were found in the explanted prostheses. Seventy-six percent
      and 87% of patients reported satisfactory rigidity and ease of concealing the
      device, respectively. Seventy-six percent of patients remained sexually active
      during the evaluation period, and 87% of patients reported that the prosthesis
      improved their overall quality of life. Eighty-five percent would undergo the
      implant surgery again, and 88% percent of patients would recommend the Dura-II
      prosthesis to a friend. CONCLUSIONS: The Dura-II malleable penile prosthesis
      provides good rigidity, ability to conceal the device, and mechanical
      reliability, as demonstrated by the results of this long-term study. Most
      patients stated they would have the prosthesis placed again and would recommend
      it to a friend.

PMID- 12597964
TI  - Infant vesicoureteral reflux: a comparison between patients presenting with a
      prenatal diagnosis and those presenting with a urinary tract infection.
AB  - OBJECTIVES: To evaluate the severity, laterality, and gender distribution of
      infant vesicoureteral reflux (VUR) and its potential impact on renal outcome, we
      compared patients presenting fetally (FDR group) and those presenting with a
      urinary tract infection (INF group). METHODS: A retrospective review of 202
      patients with the diagnosis of VUR before 6 months of age was performed. The
      grade of VUR, gender, laterality, initial renal scarring, breakthrough urinary
      tract infections, new renal scarring, and surgical intervention were compared
      between the INF group (n = 146) and FDR group (n = 56). RESULTS: The male/female
      ratio in the FDR group was 1.67:1 compared with 0.60:1 in the INF group. The FDR
      group had more unilateral VUR than the INF group (P <0.001), and no significant
      difference was found between the two groups in terms of VUR grade distribution (P
      = 0.13), percentage of initial damage (28% of FDR patients versus 23% of INF
      patients), or clinical course. In either group, boys and girls exhibited a very
      similar distribution of grade and renal damage. CONCLUSIONS: Our findings do not
      support the commonly held belief that fetally diagnosed reflux is an
      overwhelmingly male, bilateral, and high-grade phenomenon. Few differences were
      observed between infants diagnosed fetally and those diagnosed subsequent to
      urinary tract infection. Once diagnosed, from either group, infant reflux has
      neither great morbidity nor a frequent need for surgery.

PMID- 12597967
TI  - Management of recurrent urethral fistulas after hypospadias repair.
AB  - OBJECTIVES: To report on our experience in the management of recurrent
      urethrocutaneous fistulas in order to understand the etiology and outcome of
      secondary repair of the failed fistula closure. METHODS: We reviewed the records
      of 28 patients between 28 months and 19 years of age, who underwent surgery
      between January 1990 and December 1998. In all patients, urethrocutaneous
      fistulas developed postoperatively, and the number of operations for their
      closure ranged from 2 to 15 attempts. In 17 children, a single large fistula was
      present, and in 11 children, multiple fistulas were present. The causes of
      failure were believed to be the awkward fistula site in 12 (coronal fistulas),
      urethral diverticula in 7, and distal urethral strictures in 4. In 5 children,
      the cause of fistula formation was unclear. RESULTS: The 12 coronal fistulas were
      converted into coronal hypospadias. Thereafter, the urethral plate was
      tubularized using a wider strip (Thiersch tube) with (n = 3) or without (n = 9) a
      relaxing midline incision (Reddy-Snodgrass). Of the 12 repairs, 11 were
      successful; 1 child developed wound separation, resulting in a megameatus that
      was subsequently corrected. In 7 children, the cause of the fistula was a
      urethral diverticulum, which was excised and closed in multiple layers. All were
      successful (voiding well and no stricture or fistula). In 4 children (1 with
      multiple fistulas), the distal urethra was stenotic, and repair of the fistula
      included repair of the stricture using an island onlay flap in 2 and a buccal
      mucosal graft in 2. All 4 patients achieved a successful outcome. Dartos flaps
      were used to cover the repair in 18 patients, and tunica vaginalis flaps were
      used in 6 children. CONCLUSIONS: Recurrent urethral fistula after hypospadias
      repair may be a manifestation of another problem, such as urethral stricture
      and/or urethral diverticulum. Intraoperative calibration of the distal urethra
      and distension of the repaired hypospadias to search for a diverticulum are
      recommended. Coronal fistulas are best repaired by converting them into coronal
      hypospadias, followed by tubularization of the urethral plate with or without a
      dorsal midline relaxing incision. In resurfacing the operative site, the
      traditional transposition flaps (Y-V and advancement) may be unreliable, because
      their vascularity may be compromised by previous surgery. The hairless scrotal
      island or rotation scrotal flap is more reliable for these cases.

PMID- 12597968
TI  - One-stage circumferential buccal mucosa graft urethroplasty for bulbous stricture
      repair.
AB  - A one-stage onlay urethroplasty, using a buccal mucosa graft, is presented for
      patients with bulbous strictures in whom the urethral mucosa is seriously
      involved in the disease. Of 40 patients who underwent a dorsal buccal mucosa
      graft urethroplasty for bulbous urethral strictures, 5 required complete removal
      of the urethral mucosa and its replacement by a buccal mucosa graft. All these
      patients had undergone previous urethrotomy with a false passage inside the
      bulbous urethra and had a suprapubic tube in place. The goal of removal and
      replacement of the urethral mucosa in each case was to create a new, wide
      urethral mucosal bed to promote successful one-stage reconstruction. All patients
      voided spontaneously without problems after removal of the catheter. After 4
      months, the mean peak flow was 21 mL/s. After 6 months, urethroscopy did not show
      any stricture recurrence. None of the patients required instrumentation or
      dilation. In patients with bulbous urethral strictures and false passage into the
      mucosa and spongiosum tissues, the complete removal and replacement of the
      urethral mucosa using a circumferential buccal mucosa graft promotes successful
      one-stage urethral reconstruction.

PMID- 12597969
TI  - Prostate cancer metastatic to skin.

PMID- 12597970
TI  - Aphallia with congenital urethrorectal fistula.

PMID- 12597971
TI  - Congenital posterior urethral polyp in a boy.

PMID- 12597972
TI  - Lateral gluteal myonecrosis in a patient undergoing partial nephrectomy in the
      modified flank position.
AB  - This is the first report of postoperative rhabdomyolysis occurring in a patient
      positioned in the "modified flank position," with the kidney rest positioned
      under the top of the iliac crest. The patient was treated with aggressive
      intravenous fluid hydration and hyperbaric oxygen therapy with maintenance of
      normal renal function and near complete recovery of gluteal muscle function.

PMID- 12597973
TI  - Hormone-refractory prostate cancer responding to capecitabine.
AB  - A 66-year-old male patient with advanced prostate cancer presented with bony
      metastases, including pathologic fractures and hepatosplenomegaly. The patient
      responded to luteinizing hormone-releasing hormone agonists for more than 1 year.
      A clear progression while taking luteinizing hormone-releasing hormone agonists
      manifested as a progressive rise in prostate-specific antigen, alkaline
      phosphatase, hepatosplenomegaly, and myelophthisic pancytopenia. We administered
      capecitabine for 5 months with a complete clinical response. At last follow-up,
      the patient's liver function tests and prostate-specific antigen level have
      normalized. Liver size by computed tomography and blood counts both improved. To
      our knowledge, no previous case reports of capecitabine in the treatment of
      prostate cancer have been published.

PMID- 12597974
TI  - Multilocular cystic renal cell carcinoma with osseous metaplasia in a 25-year-old
      woman.
AB  - Multilocular cystic renal cell carcinoma, clear cell type, accounts for less than
      1% of all renal tumors. It is characterized by variably sized, noncommunicating
      cysts separated by irregular, thick, and fibrous septa covered with clear cells
      microscopically. We report a case of a markedly calcified multilocular renal cell
      carcinoma, clear cell type, with diffuse osseous metaplasia.

PMID- 12597975
TI  - Percutaneous nephrolithotomy of an intrathoracic kidney.
AB  - We present a 35-year-old woman with symptomatic urolithiasis in an intrathoracic
      kidney. Percutaneous nephrolithotomy was successfully performed after
      ureteroscopy failed because of the unusual length of the ureter associated with
      the kidney position. We report the first case of percutaneous nephrolithotomy of
      an intrathoracic kidney.

PMID- 12597976
TI  - "Urological cold shower"--a novel treatment for intraoperative erection.
AB  - Intraoperative penile tumescence during endoscopic surgery is a troublesome
      complication and a challenge to the urologist. We describe a novel, convenient,
      safe, and readily available technique. We used an intracavernosal injection of
      epinephrine using a standard dental syringe and a cartridge of lidocaine 2% and
      epinephrine 1:80,000 to induce detumescence reliably.

PMID- 12597977
TI  - Deep venous thrombosis due to compression of external iliac vein by the penile
      prosthesis reservoir.
AB  - Penile implant surgery has a high rate of success and a very high patient
      satisfaction rate. Compression of the external iliac vein by the reservoir of the
      penile implant is an extremely rare occurrence. We describe a case of deep vein
      thrombosis due to compression of the external iliac vein, which required
      replacement of the penile implant reservoir.

PMID- 12597978
TI  - Osteomyelitis of the pubis: a complication of a chronic indwelling catheter.
AB  - Pubic osteomyelitis typically occurs after pelvic surgery or trauma. We present a
      case of pubic osteomyelitis ensuing from a chronic indwelling (for 8 years)
      urethral catheter in a 40-year-old woman. She presented initially with fever of
      unknown origin, and broad-spectrum antimicrobial therapy was initiated. Computed
      tomography of the abdomen and pelvis ultimately revealed cortical destruction of
      the pubic symphysis, and open biopsy confirmed osteomyelitis. Osteomyelitis of
      the pubis is a rare entity that typically results from bacteremia, trauma, or the
      spread of an adjacent focus of infection from previous pelvic surgery. To our
      knowledge, this is the first report of pubic osteomyelitis resulting from a
      chronic indwelling urethral catheter.

PMID- 12597979
TI  - Primary renal lymphoma of mucosa-associated lymphoid tissue.
AB  - Mucosa-associated lymphoid tissue-type lymphomas have recently been recognized as
      a distinctive form of B-cell malignant lymphoma. In contrast to other types of
      low-grade lymphomas, these tumors have a tendency to be localized at diagnosis
      and to be curable with local therapy. We report an unusual case of primary
      localized low-grade lymphoma of mucosa-associated lymphoid tissue arising in the
      kidney. The patient underwent radical nephrectomy and was free of disease at 28
      months of follow-up without additional treatment. Once properly staged and
      classified, lymphoma of mucosa-associated lymphoid tissue involving the kidney
      can be managed by radical nephrectomy and follow-up.

PMID- 12597980
TI  - Prostate adenocarcinoma presenting with inguinal lymphadenopathy.
AB  - The lymphatic spread of prostate adenocarcinoma most often involves the iliac,
      obturator, and hypogastric nodes. Inguinal lymphadenopathy is very rare during
      the early stages of this disease, especially in the absence of pelvic
      lymphadenopathy or other metastases. We present a case of prostate adenocarcinoma
      with inguinal node involvement during the initial presentation, emphasizing the
      importance of a complete physical examination and the consideration of other
      concurrent diseases.

PMID- 12597981
TI  - Mortality from grossly encrusted bilateral pyelitis, ureteritis, and cystitis by
      Corynebacterium group D2.
AB  - This is the first report of death due to gross encrustations of the entire upper
      urinary tract and bladder by Corynebacterium group D2 in a man with no history of
      renal transplantation or prolonged catheterizations. This case demonstrates that
      debilitated patients with a prior endoscopic procedure are at risk for this
      disease process. Prolonged treatment with appropriate antibiotics, acidification
      of the urine, and removal of crusts is essential for proper management.

PMID- 12597982
TI  - BAY 41-2272: a stimulator of soluble guanylyl cyclase induces nitric oxide
      dependent penile erection in vivo.
AB  - OBJECTIVES: To determine the effectiveness of BAY 41-2272 on penile erections in
      an in vivo rabbit model. The nitric oxide (NO)-dependent increase of
      intracellular cyclic guanosine monophosphate (cGMP) by cGMP-phosphodiesterase
      (PDE5) inhibition has been shown to be an effective mechanism in the treatment of
      erectile dysfunction. Direct, NO-independent stimulation of soluble guanylyl
      cyclase should also lead to elevated cGMP levels in tissues and could be an
      attractive alternative therapeutic option for the treatment of erectile
      dysfunction. BAY 41-2272 is a novel non-NO-based direct stimulator of soluble
      guanylyl cyclase that activates purified enzyme in a synergistic fashion with NO.
      METHODS: BAY 41-2272 was administered to conscious rabbits intravenously (IV) and
      orally (PO). Erection was assessed in a time-dependent manner by measuring the
      length of the uncovered penile mucosa. Erections were evaluated in the absence
      and presence of NO (with intravenous sodium nitroprusside [SNP] as the NO donor).
      RESULTS: BAY 41-2272 only induced weak penile erections in conscious rabbits
      after IV (1 mg/kg) and PO (10 mg/kg) administration in the absence of an NO
      donor. However, the efficacy of BAY 41-2272 was potentiated by the simultaneous
      administration of SNP. Through simultaneous SNP administration, the effective
      doses of BAY 41-2272 were reduced significantly (minimal effective dose 0.1 mg/kg
      IV and 1 mg/kg PO). CONCLUSIONS: The results of this study clearly demonstrated
      the effect of BAY 41-2272 on penile erection in the conscious rabbit model after
      PO and IV administration. The time-course and onset of erection was concurrent
      with the stimulation by exogenous NO (SNP), suggesting that this new
      pharmacologic mechanism of soluble guanylyl cyclase stimulation could be used in
      the treatment of erectile dysfunction. Because the effect is increased by SNP, it
      can be expected that BAY 41-2272 would have enhanced activity during sexual
      arousal, when NO is produced endogenously.

PMID- 12597983
TI  - Preclinical evaluation of a radiosensitizing effect of gemcitabine in p53 mutant
      and p53 wild type bladder cancer cells.
AB  - OBJECTIVES: Despite clinical use, the radiosensitizing effect of gemcitabine
      (2'2'-difluorodeoxycytidine) in human transitional cell carcinoma (TCC) has not
      been shown to date. We investigated gemcitabine as a radiosensitizer for human
      TCC cells. METHODS: Monolayer cultures of RT112 (G1, p53 wild type), RT4 (G1-G2,
      p53 wild type), T24 (G3, p53, mutant type), and SUP (G4, p53 mutant type) cells
      were incubated in medium with gemcitabine. Electron beam radiation was applied
      alone, simultaneous, or 3, 6, 12, and 24 hours after gemcitabine. Jurkat leukemia
      cells were used as controls for radiation toxicity. Cell survival was determined
      6, 12, 24, 48, and 72 hours after radiation by microculture tetrazolium assay.
      DNA damage was evaluated by flow cytometric assessment of poly(ADP-ribose)
      polymerase, and apoptosis was determined by terminal-deoxynucleotidyltransferase
      mediated dUTP nick-end labeling and flow cytometric assessment after annexin-V
      and propidium iodide labeling. RESULTS: In all TCC cell lines, radiation alone
      caused only little and insignificant growth inhibitory effects at 10 Gy.
      Gemcitabine alone had a dose-dependent cytotoxic and apoptosis inducing effect on
      all TCC cell lines independent of p53 status. Assays combining radiation with
      gemcitabine in different dose and time schedules demonstrated no radiosensitizing
      effect in TCC cells. CONCLUSIONS: Gemcitabine is effective in TCC cell lines
      independent of p53 status. A radiosensitizing effect could not be demonstrated.
      Again, p53 status was not predictive of the radioresponse in the bladder cancer
      cell lines. Clinical studies with gemcitabine and radiotherapy might nevertheless
      yield different results but should be performed with utmost caution.

PMID- 12597984
TI  - Effect of Pygeum africanum tadenan on micturition and prostate growth of the rat
      secondary to coadministered treatment and post-treatment with
      dihydrotestosterone.
AB  - OBJECTIVES: Pretreatment with oral tadenan (TAD) has been shown to possess a
      protective effect on bladder dysfunction-induced obstruction. We evaluated the
      functional influence of cotreatment and post-treatment with oral TAD on the
      frequency/volume characteristics of micturition of conscious rats stimulated with
      exogenous dihydrotestosterone (DHT) to induce experimental prostate growth.
      METHODS: Studies were done on 36 adult Sprague-Dawley male rats, treated daily
      for 6 weeks and grouped as follows: group 1, sesame oil during weeks 1 and 2,
      peanut oil during weeks 3 to 6; group 2, DHT (1.25 mg/kg subcutaneously)
      dissolved in sesame oil as vehicle during weeks 1 and 2 and peanut oil during
      weeks 3 to 6; group 3, DHT (1.25 mg/kg subcutaneously) dissolved in sesame oil as
      vehicle and TAD (100 mg/kg orally) in peanut oil during weeks 1 and 2 and TAD
      during weeks 3 to 6; and group 4, DHT in sesame oil during weeks 1 and 2 and TAD
      in peanut oil during weeks 3 to 6. The characteristics of frequency/volume were
      monitored biweekly and at the sixth week. RESULTS: Controls showed no significant
      changes from baseline values in volume or frequency during the entire study
      period. DHT treatment produced a significant increase in frequency (1.9 +/- 0.3
      to 3.0 +/- 0.4/hr) and a significant decrease in volume (1.8 +/- 0.3 to 1.2 +/-
      0.1 mL). In groups 3 and 4, no significant changes occurred in frequency or
      volume. By the sixth week of observation, the effects of DHT treatment decreased
      to control values in all groups. A significant increase in prostatic weight (1191
      +/- 11 to 1434 +/- 17 mg/kg) was produced by DHT treatment and TAD cotreatment
      suppressed growth to 1390 +/- 8.4 mg/kg. CONCLUSIONS: TAD cotreatment or post
      treatment suppressed the effects of DHT on micturition, and TAD cotreatment
      regressed a developing increase in prostatic weight. Post-treatment TAD
      administration did not reduce already established growth.

PMID- 12597985
TI  - Effects of various nitric oxide-donating drugs on adrenergic tension of human
      seminal vesicles in vitro.
AB  - OBJECTIVES: To evaluate the effects of the nitric oxide (NO)-donating compounds
      sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO), S-nitroso-N
      acetylcysteine (SNAC), S-nitroso-N-acetylcysteine-ethylester (SNACET), and
      linsidomine (SIN-1) on the adrenergic tension of isolated human seminal vesicle
      strip preparations. The significance of the NO-cyclic guanosine monophosphate
      (cGMP) pathway in the regulation of smooth muscle tone in the human genitourinary
      tract has been well established. However, information on the significance of NO
      mediated signal transduction in the functional control of the mammalian seminal
      vesicles is still sparse. METHODS: Seminal vesicle strip preparations were
      applied to an organ bath system under standard conditions. Tension was induced by
      the addition of 10 microM norepinephrine. After stable tension plateaus had been
      reached, the drugs were added in a cumulative manner (0.01 to 100 microM) and the
      isometric responses of the tissue registered. The effects of the compounds on the
      phasic contractility of the tissue preparations were also evaluated. The adenylyl
      cyclase-stimulating agent forskolin was used as a reference compound known to
      interfere with the cyclic adenosine monophosphate pathway. RESULTS: Adrenergic
      tension was dose dependently attenuated by the drugs. The rank order of potency,
      from greater to lesser, was GSNO, SNAC, SNP, SIN-1, forskolin, and SNACET. The
      rank order (from greater to lesser) with regard to the inhibitory effects of the
      compounds on the frequency of phasic contractions of the tissue induced by the
      addition of norepinephrine was GSNO, SNAC, SNP, and SIN-1; the effects of SIN-1,
      forskolin, and SNACET on the frequency of contractions were nearly equipotent.
      CONCLUSIONS: Our results strongly support the hypothesis that the contractility
      of the human seminal vesicle is under the control of the NO-cGMP pathway. This
      finding may give a rationale for the use of S-nitrosothiols, such as GSNO and
      SNAC, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation
      (premature ejaculation).

PMID- 12597986
TI  - Determination of percent area density of epithelial and stromal components in
      development of prostatic hyperplasia in spontaneously hypertensive rats.
AB  - OBJECTIVES: To determine the percent area density of epithelial and stromal
      components in the development of prostatic hyperplasia in spontaneously
      hypertensive (SH) rats. METHODS: The ventral lobes of prostates obtained from
      male SH rats and their normotensive counterparts, Wistar Kyoto (WKY) rats, were
      examined histopathologically at 15, 29, 40, and 54 weeks of age (5 SH and WKY
      rats each at each age group). The degree of prostatic hyperplasia was evaluated
      with a score-chart protocol, histoscore. The percent area density of epithelium
      and stroma of the ventral prostate were determined using a computerized image
      analysis system. RESULTS: Definite lesions of hyperplastic changes were
      demonstrated in the ventral prostate of SH rats from 15 to 54 weeks. In
      comparison with WKY rats, SH rats showed a significantly increased degree of
      prostatic hyperplasia as reflected by the histoscore values. Furthermore, the
      histoscore of the ventral prostate of SH rats increased with age (from 21.7 +/-
      0.7 at 15 weeks to 26.1 +/- 0.4 at 54 weeks). The percent area density of
      epithelium and stroma were significantly increased in SH rats, and the ratio of
      stroma to epithelium ranged from 1:2.94 to 1:3.50 in SH rats but was maintained
      at 1:1.15 to 1:1.19 in WKY rats during the observation period. CONCLUSIONS: The
      hyperplastic changes of the ventral prostate may develop with advancing age in SH
      rats. The development of prostatic hyperplasia may result from both epithelial
      and stromal proliferation and may be predominantly expressed as a glandular type
      in SH rats.

PMID- 12597987
TI  - Bare naked baskets: optimizing ureteroscopic stone extraction.

PMID- 12597989
TI  - Inactivation of creatine kinase during the interaction of mefenamic acid with
      horseradish peroxidase and hydrogen peroxide: participation by the mefenamic acid
      radical.
AB  - Creatine kinase (CK) was used as a marker molecule to examine the side effects of
      damage to tissues by mefenamic acid, an effective drug to treat rheumatic and
      arthritic diseases, with horseradish peroxidase and hydrogen peroxide (HRP
      H(2)O(2)). Mefenamic acid inactivated CK during its interaction with HRP
      H(2)O(2). Also, diphenylamine and flufenamic acid caused a loss of CK activity,
      indicating the imino group, not substituent groups, in the phenyl rings have a
      crucial role in CK inactivation. Rapid change in mefenamic acid spectra was
      detected, suggesting that mefenamic acid is efficiently oxidized by HRP-H(2)O(2).
      Peroxidases oxidize xenobiotics to free radicals by a one-electron transfer.
      However, direct detection of mefenamic acid radicals by electron spin resonance
      (ESR) was unsuccessful. Reduced glutathione and 5,5-dimethyl-1-pyrroline-1-oxide
      (DMPO) in the reaction mixture containing mefenamic acid with HRP-H(2)O(2)
      produced ESR signals consistent with a DMPO-glutathionyl radical adduct. These
      results suggest that inactivation of CK is probably caused through formation of
      mefenamic acid radicals. Sulfhydryl groups and tryptophan residues of CK were
      diminished by mefenamic acid with HRP-H(2)O(2). Other SH enzymes, including
      alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, were very
      sensitive to mefenamic acid with HRP-H(2)O(2). Inactivation of SH enzymes may
      explain some deleterious actions of mefenamic acid.

PMID- 12597990
TI  - Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon.
AB  - Hypoxia-induced neuronal damage and glutamate release were investigated in a N(2)
      or in xenon-atmosphere for embryonic rat cortical neurons; cellular damage and
      glutamate over-release were observed in N(2)-treated cells whereas xenon
      protected the cells from the hypoxic insult. The protective effect of xenon was
      strongly reduced by pre-incubating neurons with the calcium-chelator BAPTA-AM
      indicating a role for calcium in this process. The results demonstrate (a) the
      neuroprotective properties of xenon, suggest (b) a relationship between the
      prevention of neurotransmitter release in a hypoxic situation and neuroprotection
      and present (c) evidence that such neuroprotection may be based on yet other
      xenon-dependent mechanisms.

PMID- 12597991
TI  - Effects of changing heart rate on electrophysiological and hemodynamic function
      in the dog.
AB  - Cardiovascular parameters were measured in dogs after RR interval was changed
      from 0.25 s to 1.2 s with atropine and graded doses of zatebradine, an I(f)
      channel blocker. Left ventricular (LV) pre-ejection period (PEP), systemic
      vascular resistance, tau (an estimate of myocardial stiffness), PQ, QTc,
      dLVP/dt(max) and dLVP/dt(min), aortic pressure, and right atrial pressure did not
      change when each parameter was plotted against RR interval (r(2)'s < or = 0.5).
      LV end-diastolic pressure, stroke volume index, LV ejection time (ET), and QT all
      increased either linearly or curvilinearly as RR interval prolonged. Cardiac
      output index and PEP/ET decreased curvilinearly. When heart rate (HR) was fixed
      by pacing, and graded doses of zatebradine were given, changes in cardiovascular
      function were minimal. Thus zatebradine affects cardiovascular function
      principally by changing HR and not by affecting function directly. This study
      provides data on the effects of changing HR, alone, on cardiovascular parameters
      measured frequently during pharmacological and toxicological studies. It should
      prove useful when physiological variables, including HR, change, and there is
      need to know what change in HR, alone, contributes.

PMID- 12597992
TI  - K-ATP opener-mediated attenuation of spontaneous bladder contractions in ligature
      intact, partial bladder outlet obstructed rats.
AB  - Symptoms of urinary frequency and urgency secondary to benign prostatic
      obstruction are common in elderly men. In many patients, these symptoms
      correspond to the urodynamic finding of involuntary detrusor contractions during
      filling cystometry (i.e., detrusor instability). Spontaneous non-voiding
      contractions during filling can be modeled in animals by subchronic, partial
      urethral obstruction. However, many investigators remove the obstructive ligature
      a few days prior to cystometrical evaluation (which may not be an ideal
      representation of the clinical situation where obstruction is still present), and
      all perform cystometry within 3 days post-bladder catheterization surgery (i.e.,
      while considerable wound healing is present). In the current study, we evaluated
      the effects, after oral dosing, of three structurally diverse ATP-sensitive
      potassium channel openers (KCOs) on spontaneous contractions secondary to
      obstruction in rats with an intact obstructive ligature at the time of testing
      and 2 weeks post-bladder catheterization. ZD6169, WAY-133537 and a novel
      dihydropyridine KCO, A-278637, all significantly decreased spontaneous bladder
      contractions at 30 min post-dosing (p.o.). However, only ZD6169 (10 micromol/kg)
      and A-278637 (3 micromol/kg) attenuated such bladder contractions at doses that
      did not concurrently, significantly affect mean arterial blood pressure and heart
      rate. These data confirm the efficacy of KCOs to inhibit unstable contractions in
      obstructed rats, and they further demonstrate the positive effect of a novel,
      bladder-selective KCO, A-278637, in an animal model with potentially less
      artifact than in previous such models.

PMID- 12597993
TI  - Comparison of the effects of specific and nonspecific inhibition of nitric oxide
      synthase on morphine analgesia, tolerance and dependence in mice.
AB  - The effects of L-Canavanine, a selective inducible nitric oxide synthase (NOS)
      inhibitor and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS
      inhibitor, on pain threshold and morphine induced analgesia, tolerance and
      dependence in mice were investigated and compared. Morphine was administered by
      subcutaneous implantation of a pellet containing 40 mg free base and withdrawal
      was precipitated by intraperitoneal (i.p.) injection of naloxone (2 mg/kg). L
      Canavanine (200 mg/kg, i.p.) did not affect the pain threshold, morphine-induced
      analgesia and the induction and expression phases of morphine tolerance and
      dependence. L-NAME (20 mg/kg, i.p.) significantly (p < 0.05) enhanced the pain
      threshold, potentiated morphine-induced analgesia and attenuated the expression
      phase of morphine dependence which has been characterized by withdrawal signs and
      body weight loss, but did not modify the induction phase of morphine tolerance
      and dependence. It is concluded that constitutive NOS isoforms which were
      inhibited by L-NAME may be involved specifically in the mechanisms of morphine
      induced analgesia, tolerance and dependence.

PMID- 12597994
TI  - Interaction of serum proteins with CYP isoforms in human liver microsomes:
      inhibitory effects of human and bovine albumin, alpha-globulins, alpha-1-acid
      glycoproteins and gamma-globulins on CYP2C19 and CYP2D6.
AB  - The effects of serum proteins on the in vitro hydroxylation pathways of
      mephenytoin (CYP2C19) and debrisoquine (CYP2D6) were studied to enhance the
      predictability of in vivo drug metabolism from in vitro assays. Both CYP
      substrates are known to be weakly bound to albumin and the applicability of the
      free drug hypothesis was further appraised. Since bovine serum albumin (BSA) is
      used widely in in vitro assays, a comparison between human and bovine proteins
      was made. Four major serum proteins were studied: albumin, alpha1-acid
      glycoprotein (AGP), alpha- and gamma-globulins. Human serum albumin (HSA)
      inhibited both CYP activities about 20% more than BSA. The addition of human
      alpha-globulins, but not the bovine protein, resulted in marked reduction of 86%
      and 41% in CYP2C19 and CYP2D6 activities, respectively. This reduction of
      activity was strikingly greater than the fraction bound (14 and 22%,
      respectively). The inhibition was of the competitive type and the Ki values of
      human alpha-globulins on CYP2C19 and CYP2D6 were found to be 0.45% (4.5 mg/ml)
      and 3.5% (35 mg/ml), respectively. The effect of both human and bovine gamma
      globulins on CYP isoforms was negligible. The Ki values of human and bovine AGP
      for CYP2C19 were 1.84% (420 microM) and 0.93% (210 microM), respectively. For
      HSA, human alpha-globulins and human and bovine AGP, the strongly decreased CYP
      activities in vitro cannot be explained by the free drug hypothesis. A direct
      interaction of these serum proteins with CYP enzymes is postulated. Differential
      effects of bovine and human serum proteins and CYP specific inhibition were
      observed.

PMID- 12597995
TI  - Lack of adrenomedullin on antigen-induced bronchoconstriction in guinea pigs in
      vivo.
AB  - Antigen challenge can provoke acute bronchoconstriction, recognized as immediate
      asthmatic response (IAR), but the evolving events in this reaction are not well
      defined. Recently, a novel peptide, designated adrenomedullin, was isolated from
      human pheochromocytoma, and has been shown to have potent systemic and pulmonary
      vasodilator activity.The purpose of this study was to elucidate the influence of
      adrenomedullin in the development of IAR. Passively sensitized guinea pigs were
      anesthetized and treated with diphenhydramine hydrochloride, and then
      artificially ventilated. Ovalbumin was inhaled after an intravenous
      administration of adrenomedullin. Other studies were performed in naive guinea
      pigs to investigate the airway responses to inhaled methacholine or histamine
      after an intravenous administration of adrenomedullin. Antigen challenge caused
      bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the
      antigen-induced bronchoconstriction in sensitized guinea pigs or the dose
      dependent responses to inhaled methacholine or histamine in naive animals in
      spite of its vasodilating effect. We conclude that an intravenous administration
      of adrenomedullin does not influence antigen-induced bronchoconstriction or
      bronchial responsiveness to inhaled methacholine or histamine in vivo.

PMID- 12597996
TI  - Changes in the expression of steroid metabolism-related genes in rat adrenal
      glands during selective REM sleep deprivation.
AB  - Selective REM sleep deprivation was carried out under the conditions designed to
      minimize the adverse influence of environmental conditions and restricted
      movement, and the influence of REM sleep deprivation on adrenocortical steroid
      metabolism was investigated by measuring the steady-state levels of mRNAs
      encoding steroid metabolism-related genes, steroidogenic acute regulatory protein
      (StAR), cholesterol side-chain cleavage enzyme cytochrome P450 (P450scc) and
      steroid 5alpha-reductase (5alpha-R), in rat adrenal glands. Selective REM sleep
      deprivation caused a significant decrease in StAR mRNA and an increase in 5alpha
      R mRNA levels without any notable change in P450scc mRNA levels in the adrenal
      gland. In contrast, non-selective sleep disturbance, resulting in the partial
      reductions of non-REM and REM sleep, tended to increase both StAR and P450scc
      mRNA levels without any statistical significance. These results indicate that REM
      sleep deprivation by itself may affect the expression of steroid metabolism
      related genes in the adrenal gland, suggesting a possible relation between REM
      sleep and adrenocortical steroid metabolism.

PMID- 12597997
TI  - Effects of amphetamine on steroidogenesis in MA-10 mouse Leydig tumor cells.
AB  - Amphetamine influences plasma and testicular testosterone levels. However, there
      is no evidence that amphetamine can directly influence Leydig cell functions. In
      the present study, a MA-10 mouse Leydig tumor cell line was used to determine
      whether and how amphetamine affected Leydig cell steroidogenesis. MA-10 cells
      were treated with different concentrations of amphetamine without or with human
      chorionic gonadotropin (hCG) and/or enzyme precursors over different time
      durations. Steroid production, enzyme activities and StAR protein expression were
      determined. Amphetamine alone had no any effect on MA-10 cell steroidogenesis.
      However, amphetamine (10(-11)M and 10(-10)M) significantly enhanced hCG-treated
      progesterone production at 3 hr in MA-10 cells (p < 0.05). Furthermore,
      amphetamine significantly induced more progesterone production upon treatment
      with 22R-hydroxycholesterol (p < 0.05), a precursor of P450 side-chain cleavage
      enzyme (P450scc). However, amphetamine did not induce more progesterone
      production when treated with pregnenolone (p > 0.05), a precursor of 3beta
      hydroxysteroid dehydrogenase. In addition, the expressions of StAR protein and
      P450scc enzyme were not significantly different between hCG alone and hCG plus
      amphetamine treatment in MA-10 cells (p > 0.05). These results suggested that
      amphetamine enhanced hCG-induced progesterone production in MA-10 cells by
      increasing P450scc activity without influencing StAR protein and P450scc enzyme
      expression or 3beta-HSD enzyme activity.

PMID- 12597998
TI  - Decreases of ganglioside GM3 in streptozotocin-induced diabetic glomeruli of
      rats.
AB  - Ganglioside GM(3) (NeuAcalpha3Galbeta4Glcbeta1Cer) is known to regulate the
      proliferation of many cell types and to maintain the charge-selective filtration
      barrier of glomeruli. Based on these, this study examined whether altered
      expression of ganglioside GM(3) was pathologically related with glomerular
      hypertrophy and proteinuria occurring in diabetic human and rat kidneys. Diabetic
      rats were produced by intraperitoneal injection of streptozotocin (80 mg/kg,
      I.P.). At 15 days after the induction of diabetes, glomerular volume and fibrotic
      matrix were dramatically elevated, whereas glomerular sialic acid contents were
      significantly reduced compared with control. Based upon mobility on high
      performance thin-layer chromatography (HPTLC) and reactivity to anti-GM(3)
      monoclonal antibody, normal glomeruli showed a complex ganglioside pattern that
      consisted of six different components of gangliosides, mainly GM(3), and diabetes
      caused a severe reduction of these gangliosides with apparent changes in the
      composition of major ganglioside GM(3). Semi-quantitative analysis by HPTLC
      showed that ganglioside GM(3) was reduced to 57% of control in diabetic
      glomeruli. A prominent immunofluorescence microscopy showed a dramatic
      disappearance of GM(3) expression in diabetic glomeruli. These results indicate
      that diabetic glomeruli can be characterized by decreases of glomerular sialic
      acid content and ganglioside GM(3) expression, which may cause loss of charge
      selective filtration barrier in renal glomeruli. These changes may be account, at
      least in part, for the development of glomerular hypertrophy and proteinuria seen
      in the early stage of diabetic glomerulopathy.

PMID- 12597999
TI  - Characterization of flue gas cleaning residues from European solid waste
      incinerators: assessment of various Ca-based sorbent processes.
AB  - For the first time, a set of samples of European flue gas cleaning residues,
      mainly from the incineration of municipal solid waste (MSW), has undergone a
      mineralogical study. The residues are the result of the neutralization of acid
      flue gases by lime, the predominant method adopted in Europe, using dry and semi
      dry washing processes. The study protocol combines physico-chemical analytical
      techniques (XRD, FTIR, DSC/TGA) and global chemical analysis enabling
      identification of the chemical composition of the main constituents, particularly
      chlorinated Ca-based phases, as well as establishment of modal distributions of
      the represented phases, both crystalline and amorphous. The samples are slightly
      hydrated and values vary for trapped Cl, S and even CO(2). The main crystalline
      phases are NaCl, KCl, CaSO(4), CaCO(3), Ca(OH)(2) and calcium hydroxychloride
      CaOHCl. CaOHCl is the main chlorine phase, regardless of the treatment process,
      filtration mode, and specific surface of the Ca-based sorbent. This phase
      develops during neutralization of HCl by excess lime present according to the
      reaction Ca(OH)(2)+HCl-->CaOHCl+H(2)O, to the detriment of a complete yield
      involving the two lime OH groups with formation of CaCl(2).2H(2)O. In addition,
      it seems that gas temperatures above 150 degrees C increase competition between
      lime-based neutralization of HCl, SO(2) acid flue gases and CO(2) trapping, thus
      reducing washing efficiency.

PMID- 12598000
TI  - Occurrence of alkylphenol polyethoxylates in the St. Lawrence River and their
      bioconcentration by mussels (Elliptio complanata).
AB  - A study was conducted in 1999 to determine the occurrence of alkylphenol
      polyethoxylates in the St. Lawrence River and their bioconcentration by mussels
      (Elliptio complanata). Concentrations of selected contaminants were measured in
      surface water, municipal effluent, sediments and mussels. Analyses were performed
      on 4-tert-octylphenol (4-t-OP), 4-n-nonylphenol (4-n-NP), nonylphenol
      polyethoxylates (NP(1-16)EO), nonylphenol-mono and di-ethoxycarboxylic acids
      (NP(1)EC and NP(2)EC), and octylphenol-mono and di-ethoxycarboxylic acids
      (OP(1)EC and OP(2)EC). Mussels (Elliptio complanata) taken from a reference lake
      were placed in cages and submerged for 62 days at two sites in the St. Lawrence
      River, 1.5 km upstream and 5 km downstream of the outfall of a municipal
      wastewater treatment plant. The results showed that many of the target chemicals
      were present in all matrices studied: in water, at ppt and ppb levels, and
      reaching ppm levels in sediments and mussels. Concentrations of these
      contaminants were higher in matrices sampled at the downstream site than in those
      drawn at the site upstream of the Montreal effluent outfall, especially in
      sediments. Likewise, the slight, but not significant, bioconcentration of certain
      alkylphenol polyethoxylates (AP(n)EO) in the mussels was more noticeable at the
      downstream site than at the upstream site.

PMID- 12598001
TI  - Characterisation of odorants emissions from landfills by SPME and GC/MS.
AB  - Odorous compounds from a landfill have been characterised by gas-chromatography
      mass-spectrometry, identifying about 100 volatile organic compounds. Air samples
      from different landfill sites and from the environment have been analysed after a
      solid-phase microextraction on a three-phase fiber, DVB/Carboxen/PDMS, which
      allowed a preconcentration and the chromatographic data obtained from the most
      significant emission sources have been submitted to chemometric analysis in order
      to better establish specific markers of olfactory pollution. For example limonene
      was a typical tracer of fresh wastes, while p-cymene was characteristic of
      leachate and biogas. By the developed analytical procedure it has been evaluated
      the efficiency of a scrubber plant utilised in the landfill in order to remove
      malodour compounds. The average removal efficiency was not very high (about
      23.5%) due to scarce ability in removing low polarity compounds. Furthermore, it
      has been demonstrated the suitability of a microgas chromatograph for the
      continuous on-site monitoring of air pollution in order to rapidly individuate
      emission sources of olfactive nuisances.

PMID- 12598002
TI  - Comparison of the adsorption of lead, cadmium, copper, zinc and barium to
      freshwater surface coatings.
AB  - Measurements were made regarding the adsorption of lead, cadmium, copper, zinc
      and barium to freshwater surface coatings (biofilms and associated minerals),
      which were collected in Nanhu Lake in Jilin Province, PR China, in order to
      investigate the variability of adsorption capacities of these heavy metals
      mentioned in the above surface coatings. The adsorption of lead and other heavy
      metals to the biofilms was observed to decrease in the following order: copper,
      lead, zinc, cadmium, and barium. Generally, the values of Gamma(max) (the maximum
      adsorption, micromol/m(2)) increased with the standard electrode potential of
      metal elements used and were recorded as 166.7, 40.0, 29.4, 10.8, and 1.8 for
      copper, lead, zinc, cadmium and barium, respectively. The values of 1/Gamma(max)
      increased linearly with the decrease in values of the standard electrode
      potential of metal elements with a significant correlation (n=5, p=0.01) and
      increased linearly with the increase in values of covalent radius of metal
      elements with a significant correlation (n=5, p=0.05). This indicates that
      standard electrode potential and covalent radius were two of the principal
      characteristics of metals employed, causing the variation of lead and other heavy
      metal adsorption to the surface coatings.

PMID- 12598003
TI  - A rainwater quality monitoring network: a preliminary study of the composition of
      rainwater in Galicia (NW Spain).
AB  - A network consisting of 17 sampling stations strategically distributed in the
      geographical area of Galicia (NW Spain) was set up in January 1999 in order to
      monitorice the ionic rainwater quality in this Spanish region which has an area
      approximately 29.575 km(2) and a population of 2.8 million. This paper presents
      the preliminary results of the exploratory study on the ionic rainfall
      composition in this area during the first year. In each rainwater sample
      collected chloride, sulphate, nitrite, nitrate, phosphate, sodium, potassium,
      magnesium, calcium and ammonium were measured, as were pH, conductivity and
      precipitation-volume. An univariate study according to the location of each
      sampling site was performed. Multivariate chemometric techniques, such as
      principal component analysis and cluster analysis, were applied to the complete
      data set (consisting of 630 observations) in order to elucidate the factors
      affecting the ionic composition of rainwater.

PMID- 12598004
TI  - Leaching characteristics of polycyclic aromatic hydrocarbons (PAHs) from spiked
      sandy soil.
AB  - In order to evaluate the factors affecting leachability of hydrophobic organic
      pollutants (HOPs), we performed leaching tests under a variety of conditions
      using sandy soil contaminated with phenanthrene and pyrene. The results obtained
      were: (1) the shaking time, temperature, and dissolved humic matter (DHM, as
      coexisting matter) increased leachability; (2) ionic strength reduced
      leachability; and (3) the liquid-to-solid ratio and pH level had no effect on
      leaching concentration of HOPs. In DHM-added leaching tests assuming equilibrium
      with HOPs, DHM, and solid matrix, the partitioning (binding) coefficient of HOPs
      to DHM was accurately calculated with the equations proposed in this study. While
      we recommend taking into consideration the coexistence of DHM, it is difficult to
      use universally because its properties differ according to origin and extracting
      method. It is therefore reasonable to use an alternative reagent having an effect
      similar to that of DHM.

PMID- 12598005
TI  - Investigation on downwind short-range transport of pesticides after application
      in agricultural crops.
AB  - For the assessment of potential risks from total exposure to both spray drift and
      volatilised pesticides, field experiments in barley were carried out with
      insecticide application in May and June 2000. Pesticide concentrations in the air
      at the edge of the treated plot and at various distances in downwind direction
      were determined. The concentrations at 10 m distance were 0.29 and 0.58
      microg/m(3) (lindane), 0.07 and 0.12 microg/m(3) (parathion) or <0.02 and 0.04
      microg/m(3) (pirimicarb) after 1 d. To quantify the exposure of aquatic
      ecosystems, water containers simulating surface waters were placed in downwind
      direction of the plot at distances of 10 and 50 m. Lindane as the most volatile
      and most persistent of the investigated active substances showed the highest
      entries in surface water with 35 and 153 microg/m(2) after 1 d at a distance of
      10 m, attributable to a larger extent to deposition of volatilised compound than
      to spray drift when drift reducing nozzles were used. Similar results were
      obtained for parathion, but at a lower level. Mainly due to its photolytic
      instability in water, pirimicarb decayed in surface water, where a maximum
      deposition was measured 2 h after application.

PMID- 12598006
TI  - Trace metals in Antarctic copepods from the Weddell Sea (Antarctica).
AB  - The concentrations of Cd, Co, Cu, Ni, Pb and Zn were determined in the Antarctic
      copepods Rhincalanus gigas (Brady, 1883), Calanus propinquus (Brady, 1883),
      Calanoides acutus (Giesbrecht, 1902), Metridia curticauda (Giesbrecht, 1889) and
      Metridia gerlachei (Giesbrecht, 1902). Samples were taken at seven different
      stations between 18.01.1999 and 19.02.1999. Metal concentrations in biological
      tissue were determined by graphite furnace atomic absorption spectroscopy (GFAAS)
      with Zeeman background correction and by flame AAS (air-acetylene) with deuterium
      background correction. We found high mean Cd concentrations in the Metridia
      species of about 10 microg Cd g(-1) and 3-6 microg Cd g(-1) in the other
      copepods. Co and Pb concentrations were low in all species investigated (<0.1
      microg Co g(-1) and <1 microg Pb g(-1)). Zn concentrations were high in M.
      gerlachei and R. gigas (518 and 430 microg Zn g(-1)). In comparison to copepods
      from Arctic Seas (Fram Strait, Greenland Sea) and the North Sea, Cd and Cu
      concentrations appear higher in Antarctic copepods, while Ni and Pb
      concentrations are similar in both polar regions and Pb concentrations are higher
      in the North Sea. Variability between species and different regions are
      discussed.

PMID- 12598007
TI  - Biological oxidation of arsenite: batch reactor experiments in presence of
      kutnahorite and chabazite.
AB  - Arsenic represents a threat to all living organisms due to its toxicity which
      depends on its speciation. This element is carcinogenic, teratogenic and is
      certainly one of the most important contaminants affecting millions of people
      around the world. Abiotic and biotic processes control its speciation and
      distribution in the environment. We have previously shown that a new bacterial
      strain named ULPAs1 performed oxidation of As(III) (1.33 mM) to As(V) in batch
      cultures. In order to develop new methods to remove arsenic from contaminated
      effluents or waste, by bacterial oxidation of As(III) to As(V) followed by its
      sorption, the conservation of oxidative properties of ULPAs1 was investigated
      when cultivated in batch reactors in the presence of two solid phases, chabazite
      and kutnahorite, already used as microorganisms immobilizing materials in
      biological remediation processes. In parallel, the retention efficiency of these
      solid phases toward arsenic ions and particularly arsenate was studied. Pure
      quartz sand was used as a reference material. Kutnahorite efficiently sorbed
      As(V), chabazite alone performed As(III) oxidation and pure quartz sand did not
      sorb arsenic at all. The arsenite oxidative properties of ULPAs1 were conserved
      when cultivated in the presence of quartz or chabazite.

PMID- 12598008
TI  - Trace metal behaviour in the Conwy estuary, North Wales.
AB  - The distribution of trace metals Zn, Ni, Mn, Fe, Cu, Pb, Cd and Cr between
      suspended particulate matter (SPM) and water in the Conwy estuary, North Wales,
      has been studied in three surveys in 1998. Dissolved Cu and Mn showed some
      monthly variations. Most of the dissolved trace metals displayed a negative
      association with salinity, indicating rivers as a major source of inputs for
      them. Particulate Zn, Mn and Fe showed a decreasing concentration seaward, whilst
      the levels of Ni, Cu, Cr and Pb increased with salinity. SPM concentration was
      the most important variable significantly related to trace metal concentrations
      in SPM, with an inverse relationship between the two parameters. This was
      explained by the relative enrichment of trace metals in fine particles at low SPM
      concentrations and relative depletion of trace metals in coarse particles at high
      SPM concentrations. Particulate Zn, Mn and Pb were dominated by the fraction
      available to acetic acid (non-detrital), whilst particulate Ni, Fe and Cr were
      dominated by the fraction available to nitric acid (detrital). The partition
      coefficient of trace metals between SPM and water declined with increasing SPM
      concentration, consistent with the so-called "particle concentration effect".
      Such a phenomenon may be explained by the presence of fine particles (including
      colloids) enriched with trace metals at low SPM concentrations, and the salinity
      induced desorption.

PMID- 12598009
TI  - Generation of cyanide ion by the reaction of phenol with nitrous acid in
      wastewater.
AB  - It was found that phenol reacts with nitrous acid to produce cyanide ions.
      Cyanide ion generation is attributed to the conversion of phenol to nitrosophenol
      through the well-known nitrosation reaction, and decomposition of benzoquinonoxim
      to form cyanide and aliphatic compound.

PMID- 12598013
TI  - Mechanical heart valve prostheses: identification and evaluation.

PMID- 12598015
TI  - Idiopathic intimal hyperplasia of small arteries and arterioles affecting
      intestines and myocardium.
AB  - We report the case of a 52-year-old woman dying from a noninflammatory, occlusive
      vasculopathy. Histology showed marked intimal hyperplasia of small arteries of
      the intestines and myocardium with subsequent infarction of myocardium, large
      intestine and gallbladder. A comprehensive work up including laboratory studies,
      clinical investigations and postmortem failed to assign this condition to any of
      the known vascular diseases.

PMID- 12598014
TI  - Hypoplastic left heart syndrome myocytes are differentiated but possess a unique
      phenotype.
AB  - INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is the term used to describe
      a group of congenital malformations characterized by marked underdevelopment of
      the left side of the heart. HLHS accounts for nearly 25% of cardiac deaths in the
      first year of life. Although much has been reported regarding diagnosis, gross
      morphology and surgical treatment, no information on gene expression in HLHS
      myocytes is available. METHODS: We examined heart tissue from patients with HLHS
      using routine histology, immunohistochemistry, quantitative polymerase chain
      reaction (PCR), two-dimensional (2-D) gel electrophoresis and protein
      identification by mass spectrometry. RESULTS: Histologic examination of right and
      left ventricles from HLHS patients revealed characteristic features of myocyte
      differentiation, including striations and intercalated disc formation.
      Immunohistochemical staining using antibody to N-cadherin demonstrated clear
      development of intercalated discs between myocytes. However, many of the myocytes
      contained scant cytoplasm and were grouped in small, disorganized bundles
      separated by abundant connective tissue and dilated, thin-walled vessels.
      Quantitative PCR analysis demonstrated that both left and right ventricular
      tissue from HLHS hearts expressed the fetal or "heart failure" gene expression
      pattern. Two-dimensional gel electrophoresis and protein identification by mass
      spectrometry also confirmed that myocytes from HLHS ventricles were
      differentiated but expressed the fetal isoform of some cardiac specific proteins.
      However, HLHS myocytes in all of the heart samples (n=21) were inappropriately
      expressing platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD31), a
      member of the cell adhesion molecule (CAM) family that has a primary role in the
      regulation of tissue morphogenesis. These findings indicate that myocytes from
      HLHS syndrome patients, while differentiated, have a unique gene expression
      pattern.

PMID- 12598016
TI  - Apoptosis of myocytes and proliferation markers as prognostic factors in end
      stage dilated cardiomyopathy.
AB  - INTRODUCTION: The aim of the study was to evaluate the role of apoptosis,
      proliferation markers, volume density of interstitium, and myofibril volume
      fraction for the prognosis in patients with end-stage dilated cardiomyopathy
      (DCM). METHODS: Endomyocardial biopsy was performed during open-heart surgery in
      56 patients with end-stage DCM. Patients were divided into two groups, one group
      with shorter survival (24+/-9 months, mean+/-S.D.) and another group with
      survival of more than 7 years after operation. The TUNEL method was used for the
      detection of apoptosis, and immunohistochemical methods were used for the
      evaluation of inhibitor of apoptosis (bcl-2) and proliferation markers (PCNA and
      Ki-67). RESULTS: The increased percentage of apoptotic myocytes, decreased
      expression of bcl-2, and decreased expression of PCNA and Ki-67 antigen was found
      in the group with early mortality compared to that with longer survival.
      Myofibril volume fraction was lower and volume density of interstitium was higher
      in the group with early mortality compared to that with longer survival.
      CONCLUSION: Apoptosis, bcl-2 expression, and proliferation activity of myocytes,
      myofibril volume fraction, and volume density of interstitial tissue might be
      useful in predicting the prognosis (progressive vs. nonprogressive form) of
      patients with heart failure due to DCM.

PMID- 12598017
TI  - Mechanisms of restenosis after coronary intervention: difference between plain
      old balloon angioplasty and stenting.
AB  - BACKGROUND: Restenosis after coronary intervention remains an unsolved and
      important clinical problem. We histologically examined the mechanism of
      restenosis after both balloon injury and stenting. METHODS: Coronary arteries of
      swine were subjected to balloon injury and stenting. Next, just after stenting or
      at 7, 14, or 28 days, the animals were sacrificed for the evaluation by
      morphometric analysis, histological observation, and immunostaining. RESULTS: The
      neointimal area peaked at 14 days in the balloon injury group (BG) and increased
      linearly up to 28 days in the stent group (SG). At 28 days, the total vascular
      area in the BG was reduced to 78% of the control values. In the SG, the total
      vascular area remained enlarged. According to the phenotypic analysis, the
      vascular smooth muscle cells (VSMCs) in the neointimal area at 28 days were the
      contractile type in the BG and the synthetic type in the SG. Proliferating cell
      nuclear antigen (PCNA) and macrophage-positive cells were not observed in
      neointima in the BG at 28 days, whereas they were observed around the stent
      struts in the SG. In addition, numerous inflammatory cells, such as neutrophils
      and eosinophils, were also present in the SG. CONCLUSIONS: Restenosis after
      balloon injury consisted of arterial remodeling and neointimal hyperplasia,
      whereas that after stenting consisted mostly of neointimal hyperplasia. The
      neointimal area in the SG lasted longer than that in the BG. Continuous
      inflammation may be an important factor in the restenosis of stenting.

PMID- 12598018
TI  - Increased vulnerability to ischemia/reperfusion-induced ventricular
      tachyarrhythmias by pre-ischemic inhibition of nitric oxide synthase in isolated
      rat hearts.
AB  - INTRODUCTION: The relationship between vulnerability to reperfusion-induced
      ventricular tachyarrhythmias, such as ventricular tachycardia (VT) and
      fibrillation (VF), and the endogenous activity of nitric oxide synthase (NOS) has
      not been well documented. The objective of the present study was to clarify
      whether the vulnerability to reperfusion-induced VT/VF changes with preishemic,
      sustained inhibition of NOS. METHODS: The experiments were performed using
      Langendorff-perfused isolated rat hearts, in which left ventricular pressure
      (LVP) and left ventricular cardiomyograms (LVCMGs) were measured. RESULTS: A pre
      ischemic, sustained inhibition of NOS resulted in an increased vulnerability to
      reperfusion-induced VT/VF, and the increase was markedly attenuated by co
      treatment with L-arginine or by post-ischemic treatment with 2,4-diamino-6
      hydroxypyrimidine (DAHP), an inhibitor of tetrahydrobiopterin (BH(4)) synthesis.
      We then tried to elucidate whether nitric oxide (NO) and superoxide were produced
      during reperfusion, and ATP-sensitive potassium channels (K(ATP)), especially
      mitochondrial ATP-sensitive potassium channels (mitoK(ATP)), are involved in the
      increased vulnerability. Post-ischemic inhibition of NOS and treatment with a NO
      scavenger attenuated the increased vulnerability to reperfusion-induced VT/VF,
      but post-ischemic treatment with a superoxide scavenger did not. In addition,
      post-ischemic treatment with S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO
      donor, or with diazoxide, a selective opener of mitoK(ATP), increased the VT/VF
      duration during reperfusion. The increased vulnerability to VT/VF was attenuated
      by the treatment with a selective mitoK(ATP) blocker. CONCLUSION: The results
      suggest that a pre-ischemic, sustained inhibition of NOS increases the
      vulnerability to reperfusion-induced VT/VF, and the NO-mitoK(ATP) pathway is one
      of the possible factors contributing to the increased vulnerability to VT/VF.

PMID- 12598021
TI  - General principles of MDCT.
AB  - Multidetector CT (MDCT, multislice CT, multidetector-row CT, multisection CT)
      represents a breakthrough in CT technology. It has transformed CT from an
      transaxial cross-sectional technique into a true 3D imaging modality that allows
      for arbitrary cut planes as well as excellent 3D displays of the data volume.
      Multislice CT scanners provide a huge gain in performance that can be used to
      reduce scan time, to reduce section collimation, or to increase scan length
      substantially. The following article will provide an overview of the principles
      of multislice CT scanning. It describes the various detector systems and gives an
      introduction to the most important acquisition and reconstruction parameters. The
      article describes how reconstruction of thick multiplanar reformations can be
      used to take advantage of the 3D capabilities of multislice CT while keep
      radiation exposure to a minimum.

PMID- 12598022
TI  - Brain perfusion CT in acute stroke: current status.
AB  - Dynamic perfusion CT has become a widely accepted imaging modality for the
      diagnostic workup of acute stroke patients. Although compared with standard
      spiral CT the use of multislice CT has broadened the range from which perfusion
      data may be derived in a single scan run. The advent of multidetector row
      technology has not really overcome the limited 3D capability of this technique.
      Multidetector CT angiography (CTA) of the cerebral arteries may in part
      compensate for this by providing additional information about the cerebrovascular
      status. This article describes the basics of cerebral contrast bolus scanning
      with a special focus on optimization of contrast/noise in order to ensure high
      quality perfusion maps. Dedicated scan protocols including low tube voltage (80
      kV) as well as the use of highly concentrated contrast media are amongst the
      requirements to achieve optimum contrast signal from the short bolus passage
      through the brain. Advanced pre and postprocessing algorithms may help reduce the
      noise level, which may become critical in unconscious stroke victims. Two
      theoretical concepts have been described for the calculation of tissue perfusion
      from contrast bolus studies, both of which can be equally employed for brain
      perfusion imaging. For each perfusion model there are some profound limitations
      regarding the validity of perfusion values derived from ischemic brain areas.
      This makes the use of absolute quantitative cerebral blood flow (CBF) values for
      the discrimination of the infarct core from periinfarct ischemia questionable.
      Multiparameter imaging using maps of CBF, cerebral blood volume (CBV), and a time
      parameter of the local bolus transit enables analyzing of the cerebral perfusion
      status in detail. Perfusion CT exceeds plain CT in depicting cerebral
      hypoperfusion at its earliest stage yielding a sensitivity of about 90% for the
      detection of embolic and hemodynamic lesions within cerebral hemispheres.
      Qualitative assessment of brain perfusion can be further enhanced by adding
      relative perfusion indices from regions of interest. Multislice CTA using a
      collimation of 4 x 1 mm and high pitch factors allows for isotropic scanning of
      the brain supplying arteries from the aortic arch to the vertex in a single run.
      Various image processing modalities such as multiplanar reformations, curved
      planar reconstructions, maximum intensity projections, and volume rendering
      techniques are available to deal with the extensive data and to bring out those
      vascular lesions, which are of relevance for individual stroke. With the advent
      of multidetector CT advanced stroke protocols combining plain CT, perfusion CT
      and CTA can routinely be accomplished within a very short timespan thus ensuring
      the role of CT in the diagnostic workup of acute stroke.

PMID- 12598023
TI  - Head and neck imaging with MDCT.
AB  - Multi-slice CT (MDCT) is rapidly becoming the new standard in radiological
      imaging. Although its advantages in cardiovascular, thoracic and abdominal
      imaging are evident, the extent of its usefulness for imaging the head and neck
      has yet to be clarified. Because of the shorter examination time motion artifacts
      are reduced, phonation-studies are possible. Due to the thin-slicing and nearly
      isotropic multiplanar reconstruction (MPR) examination in only one plane is
      necessary, saving both time and radiation exposure. The shorter examination
      requires the use of higher concentrated contrast medium (400 mg of iodine/ml).
      The use of such a contrast medium produces a higher degree of contrast
      enhancement and provides a 5-10% higher contrast between the surrounding normal
      and pathological tissue, but is more time critical. MPRs are easily done in any
      plane within seconds and enables also three-dimensional visualization, what helps
      in the use of minimal invasive therapy, training and teaching and provides a way
      of handling the hundreds of images acquired during scanning.

PMID- 12598024
TI  - Angio-CT: heart and coronary arteries.
AB  - Despite a multitude of different medical and interventional strategies to treat
      coronary artery disease (CAD), the natural course of CAD is a relentless
      progression. The current gold-standard to assess the degree of stenosis is
      coronary angiography. In Germany alone, the total number of angiographic
      procedures rose by 45% from 1995 to 2000, while the fraction of interventional
      procedures remained almost constantly low at about 30% [Z. Kardiol. 90 (2001)
      665]. Although coronary angiography has become a safe procedure with only a small
      risk associated, the inconvenience for the patient as well as the economic burden
      have fueled the quest to find an alternative, non-invasive method to visualize
      and assess coronary arteries. The following article will explore the application
      of computed tomography (CT) coronary angiography for detection of stenoses, and
      the issue of imaging of non-calcified and unstable plaques with MDCT.

PMID- 12598025
TI  - 3-D imaging with MDCT.
AB  - Without doubt, the greatest challenge of multidetector-row CT is dealing with
      'data explosion'. For our carotid/intracranial CT angiograms, we routinely have
      375 images to review (300 mm coverage reconstructed every 0.8 mm); for aortic
      studies we have 450-500 images ( approximately 600 mm coverage reconstructed
      every 1.3 mm); and for a study of the lower extremity inflow and run-off, we may
      generate 900-1000 transverse reconstructions. While we could reconstruct fewer
      images for these data, experience with single-detector row CT scanners indicates
      that longitudinal resolution and disease detection is improved when at least 50%
      overlap of cross-sections is generated [Radiology 200 (1996) 312]. If we are to
      optimize our clinical protocols and take full advantage of these CT scanners, we
      will need to change the way that we interpret, transfer, and store CT data. Film
      is no longer a viable option. Workstation based review of transverse
      reconstructions for interpretation is a necessity, but the workstations must
      improve to provide efficient access to these data, and we must have a way of
      providing our clinicians with images that can be transported to clinics and the
      operating room. Alternative visualization and analysis using volumetric tools,
      including 3-D visualization must evolve from luxury to necessity. We cannot rest
      on historical precedent to interpret these near isotropically sampled volumetric
      data using transverse reconstructions alone [Radiology 173 (1989) 527]. Although
      the tools for volumetric analysis on 3-D workstations have evolved over recent
      years, they have probably not yet evolved to a level that routine interpretation
      can be performed as efficiently and accurately as transverse section review. Both
      hardware and software developments must occur. While current computer
      workstations and visualization software are certainly adequate for assessing
      these MDCT data volumetrically, the process is very time consuming. What follows
      are a description of current workstation capabilities and a brief discussion of
      where development needs to go to facilitate the complete integration of
      volumetric analysis into the interpretive process of CT data.

PMID- 12598026
TI  - MDCT imaging of the aorta and peripheral vessels.
AB  - Since its clinical introduction in 1991, volumetric CT scanning using spiral or
      helical scanners has resulted in a revolution for diagnostic imaging. Helical CT
      has improved over the past 8 years with faster gantry rotation, more powerful X
      ray tubes, and improved interpolation algorithms, but the greatest advance has
      been the recent introduction of multi detector-row CT (MDCT) scanners [J. Comput.
      Assist. Tomogr. 23 (1999) S83]. Currently capable of acquiring four channels of
      helical data simultaneously, MDCT scanners have achieved the greatest incremental
      gain in scan speed since the development of helical CT and have profound
      implications for clinical CT scanning. Fundamental advantages of MDCT include
      substantially shorter acquisition times, retrospective creation of thinner or
      thicker sections from the same raw data, and improved three-dimensional (3-D)
      rendering with diminished helical artifacts. While these features will likely be
      important to many applications of CT scanning, including the characterization of
      focal lung and liver lesions through the creation of thin sections
      retrospectively, the greatest impact has been on CT angiography. The implication
      for CT angiography is that scans can be performed approximately three-times
      faster than is possible with the fastest single-detector CT scanner. For example
      a 1.25 mm nominal thick section (1.6 mm effective section thickness) can be
      acquired with a table speed of 9.4 mm/s, and a 2.5 mm nominal thick section (3.2
      mm effective section thickness) can be acquired with an 18.8 mm/s table speed.
      The advantages of MDCT for imaging the vascular system can be broken down into
      three fundamental improvements over single detector-row CT scanners speed
      (faster), distance (longer), and section thickness (better). The focus of this
      article will be how multidetector-row CT technology has substantially improved
      aortoiliac and lower extremity arterial imaging.

PMID- 12598027
TI  - Liver imaging with MDCT and high concentration contrast media.
AB  - Liver imaging has advanced greatly over the last 10 years with helical CT
      capability and more recently the addition of multidetector-row CT (MDCT).
      Multidetector CT technology facilitates imaging at faster speeds with improved
      image quality and less breathing artifact [Abdom. Imaging 25 (2000) 643].
      Exquisite three-dimensional data sets can be obtained with thin collimation
      providing improved lesion detection, multiplanar imaging, and the ability to
      perform CT angiography of the liver and mesenteric vessels. New challenges arise
      with this advance in technology including safety considerations. The radiation
      dose to the patient has increased with MDCT and this is compounded by the ability
      to perform multi-phase liver imaging. Furthermore, issues of contrast media
      administration require reconsideration including optimal timing and rate of
      administration, the total volume of contrast needed and the ideal iodine
      concentration of the contrast media. Recently, the use of high concentration
      contrast media (HCCM) has been explored and study results to date will be
      reviewed.

PMID- 12598028
TI  - Use of high concentration contrast media (HCCM): principles and rationale--body
      CT.
AB  - Numerous complex pharmacokinetic interrelationships affect the use of contrast
      media for computed tomography (CT) imaging. The volume, concentration, and rate
      of injection, all affect the degree of enhancement that is achieved with an
      injection of contrast material. In addition, the injection technique, whether the
      contrast is infused with a constant injection rate (uniphasic injection) or
      whether the rate is altered during the injection (multiphasic injection) also
      affect the magnitude and duration of contrast enhancement. In body CT imaging,
      the liver poses unique challenges in managing the use of intravenous contrast
      material because of its dual blood supply and the need to complete imaging before
      equilibrium occurs between the intravascular and extravascular compartments. The
      magnitude of hepatic enhancement that is ultimately achieved is related primarily
      to the amount of iodinated contrast material that accumulates in the
      extravascular space within the target organ, independent of the speed of the CT
      scanner. The key determinant of the onset of the equilibrium phase is the
      injection duration. Given that a high injection flow rate (4-5 ml/s) is desirable
      for arterial phase imaging, the injection duration is maintained with use of an
      appropriate contrast volume. Thus, modifications of total iodine dose are best
      done with alterations in contrast concentration. The magnitude of arterial
      enhancement that is achieved is related to both the concentration and rate of
      contrast administration. The speed of the scanner determines its ability to
      record image data during the most advantageous time period, the peak of arterial
      enhancement. Thus, rapid imaging is particularly advantageous for optimal
      contrast use in CT angiography as well as in multiphasic imaging of the
      parenchymal organs.

PMID- 12598030
TI  - Renal MDCT.
AB  - Multidetector CT has expanded the utility of CT by improving longitudinal
      resolution and acquisition speed. Applications include diagnosis of renal
      vascular and parenchymal injuries, renal tumor diagnosis and staging, the
      emerging field of CT urography and CT angiography. This summary review
      illustrates MDCT approaches to the evaluation of trauma, suspected tumor and
      imaging of the urinary tract and discusses other applications in renal
      inflammatory disease, urolithiasis and renal anomalies.

PMID- 12598029
TI  - Multislice helical CT of the pancreas and spleen.
AB  - Multislice helical CT (MSCT) with its multidetector technology and faster
      rotation times, has led to new dimensions in spatial and temporal resolution in
      CT imaging. In contrast to single-slice CT, smaller slice collimations can be
      applied that lead to almost isotropic voxels and allow high quality multiplanar
      and 3-D image reconstructions. The high speed of multislice CT can be used to
      reduce the time needed to cover a given volume, to increase the spatial
      resolution along the z-axis by applying thinner slice collimations, and to cover
      longer anatomic volumes. The speed of MSCT allows organ imaging in clearly
      defined perfusion phases, e.g. the arterial, parenchymal, and portal venous
      perfusion phases. Contrast agents with higher iodine concentrations (400 mg
      iodine per ml compared with 300 mg iodine per ml) lead to higher contrast
      enhancement of the pancreas (arterial+portal venous phases), the kidneys
      (arterial+portal venous phases), the spleen (arterial phase), the wall of the
      small intestine (arterial+portal venous phases), the larger and smaller arteries
      (arterial phase), and the portal vein (portal venous phase). All of these
      advancements lead to improved visualization of small structures and of various
      pathologies, such as pancreatic tumors, liver metastases, vessel infiltration,
      and vascular diseases.

PMID- 12598031
TI  - Multiple detector-row CT angiography of the renal and mesenteric vessels.
AB  - Computed tomography angiography (CTA) of the abdomen with multiple detector-row
      computed tomography (MD-CT) is an effective technique for minimally invasive
      imaging of the renal arteries and the visceral vasculature. This article reviews
      the clinical and technical aspects of MD-CT angiography in terms of image
      acquisition and reconstruction parameters, contrast medium application, and three
      dimensional visualization with special attention to renal and mesenteric vascular
      imaging. Because of its high sensitivity to detect renal artery stenosis on the
      one hand, and because a normal renal CTA virtually excludes the presence of a
      significant renal artery stenosis on the other hand, renal CTA plays a useful
      role in the management of patients with suspected renovascular hypertension.
      Mesenteric CTA is a useful tool for visualizing normal vascular anatomy and its
      variants-particularly in the setting of organ transplantation. Vascular
      pathology, e.g. atherosclerotic disease (abdominal angina), or aneurysms of the
      visceral arteries are reliably assessed with CTA. Mesenteric CTA is an invaluable
      adjunct to abdominal CT in the setting of abdominal emergencies, because of its
      ability to detect the causes of acute intestinal ischemia (superior mesenteric
      artery embolism or thrombosis, superior mesenteric vein thrombosis). Accurate
      timing of the CTA acquisition and the subsequent parenchymal phase acquisition
      relative to the contrast medium transit time is critical to obtain excellent
      image quality in double-pass abdominal CT acquisitions.

PMID- 12598032
TI  - Use of high concentration contrast media: principles and rationale-vascular
      district.
AB  - Optimal contrast medium delivery remains a crucial issue in CT angiography and it
      will become even more critical with continuously evolving, faster CT scanner
      technology. This review article first explains the fundamentals of arterial
      enhancement using mathematical models of early contrast medium dynamics. The
      relationship of contrast medium volume, injection flow rates and injection
      duration are explicitly illustrated. Next, current techniques of contrast medium
      application are reviewed, with particular attention to methods of accurate timing
      of the scanning delay (test-bolus and automated bolus triggering), tools for
      automated saline-flushing of the veins (double-syringe power injectors) and the
      use of high-concentration contrast medium. From there, rational CT angiographic
      injection protocols for a wide range of selectable acquisition times for 4-, 8-
      and 16-channel MDCT are proposed.

PMID- 12598034
TI  - Exploring membrane organization and dynamics by the wavelength-selective
      fluorescence approach.
AB  - Wavelength-selective fluorescence comprises a set of approaches based on the red
      edge effect in fluorescence spectroscopy which can be used to directly monitor
      the environment and dynamics around a fluorophore in a complex biological system.
      A shift in the wavelength of maximum fluorescence emission toward higher
      wavelengths, caused by a shift in the excitation wavelength toward the red edge
      of absorption band, is termed red edge excitation shift (REES). This effect is
      mostly observed with polar fluorophores in motionally restricted media such as
      very viscous solutions or condensed phases where the dipolar relaxation time for
      the solvent shell around a fluorophore is comparable to or longer than its
      fluorescence lifetime. REES arises from slow rates of solvent relaxation
      (reorientation) around an excited state fluorophore which is a function of the
      motional restriction imposed on the solvent molecules in the immediate vicinity
      of the fluorophore. Utilizing this approach, it becomes possible to probe the
      mobility parameters of the environment itself (which is represented by the
      relaxing solvent molecules) using the fluorophore merely as a reporter group.
      Further, since the ubiquitous solvent for biological systems is water, the
      information obtained in such cases will come from the otherwise 'optically
      silent' water molecules. This makes REES and related techniques extremely useful
      since hydration plays a crucial modulatory role in a large number of important
      cellular events, including lipid-protein interactions and ion transport. The
      interfacial region in membranes, characterized by unique motional and dielectric
      characteristics, represents an appropriate environment for displaying wavelength
      selective fluorescence effects. The application of REES and related techniques
      (wavelength-selective fluorescence approach) as a powerful tool to monitor the
      organization and dynamics of probes and peptides bound to membranes, micelles,
      and reverse micelles is discussed.

PMID- 12598035
TI  - The peculiar thermo-structural behavior of the anionic lipid DMPG.
AB  - Aqueous dispersions of the anionic phospholipid dimyristoyl phosphatidylglycerol
      (DMPG), around 100 mM ionic strength, are known to exhibit a thermal behavior
      similar to that of the largely studied lipid dimyristoyl phosphatidylcholine
      (DMPC), which undergoes a gel to liquid crystalline phase transition at 23
      degrees C, well characterized by differential scanning calorimetry (DSC), and
      other methods. However, at low ionic strength, DMPG has been shown to present a
      large gel-fluid transition region, ranging from 18 to 35 degrees C. This
      intermediate phase is optically transparent and characterized by a continuous
      change in membrane packing. Structural properties of the DMPG gel-fluid
      transition region will be discussed, based on results obtained by several
      techniques: electron spin resonance (ESR) of spin labels at the membrane surface
      and intercalated at different depths in the bilayer; light scattering; DSC; small
      angle X-ray scattering (SAXS); and fluorescence spectroscopy of probes in the
      bilayer.

PMID- 12598036
TI  - The arrangement of cholesterol in membranes and binding of NAP-22.
AB  - Cholesterol forms crystals when the mol fraction of sterol in a membrane bilayer
      exceeds a certain value. The solubility limit of cholesterol is very dependent on
      the nature of the phospholipid with which it is mixed. NMR methods have proven
      useful in quantifying the amount of cholesterol monohydrate crystals present in
      mixtures with phospholipids. A protein, NAP-22, present in high abundance in the
      synaptic cell membrane and synaptic vesicle, promotes the formation of
      cholesterol crystallites in lipid mixtures in which cholesterol would be
      completely dissolved in the membrane in the absence of protein. This finding,
      along with effects of the protein on the phase transitions of mixtures of
      phosphatidylcholine (PC) and cholesterol indicate that NAP-22 facilitates the
      formation of cholesterol-rich domains. This protein will bind only to membranes
      of PC that contain either cholesterol or phosphatidylethanolamine (PE). The
      process requires the presence of a myristoyl group on the N-terminus of NAP-22.
      The phenomenon also does not occur with a 19 amino acid myristoylated peptide
      corresponding to the amino terminal segment of NAP-22. The basis of the
      selectivity of NAP-22 for interacting with membranes of specific composition is
      suggested to be due to the accessibility of the myristoyl group.

PMID- 12598037
TI  - Stabilization of membranes in human platelets freeze-dried with trehalose.
AB  - Human blood platelets are normally stored in blood banks for 3-5 days, after
      which they are discarded. We have launched an effort at developing means for
      preserving the platelets for long term storage. In previous studies we have shown
      that trehalose can be used to preserve biological membranes and proteins during
      drying and have provided evidence concerning the mechanism. A myth has grown up
      about special properties of trehalose, which we discuss here and clarify some of
      what is fact and what is misconception. We have found a simple way of introducing
      this sugar into the cytoplasm of platelets and have successfully freeze-dried the
      trehalose-loaded platelets, with very promising results. We present evidence that
      membrane microdomains are maintained intact in the platelets freeze-dried with
      trehalose. Finally, we propose a possible mechanism by which the microdomains are
      preserved.

PMID- 12598038
TI  - Regulation of lipases by lipid-lipid interactions: implications for lipid
      mediated signaling in cells.
AB  - Lipases are extracellular peripheral proteins that act at the surface of lipid
      emulsions stabilized, typically, by phospholipids. At a critical composition
      lipase activity toward substrates in phospholipid monolayers is discontinuously
      switched on by a small increase in substrate mole fraction. This occurs in part
      because lipase binding is inhibited by phospholipids. Binding of the lipase
      cofactor, colipase, is also inhibited by phospholipids. The initial rate of
      colipase binding increases abruptly at a substrate mole fraction that is
      approximately half the critical composition for lipase activity and just above
      that in substrate-phospholipid complexes. Moreover, complex collapse areas show
      an approximately 1:1 correlation with phospholipid excluded areas determined from
      an analysis of colipase adsorption rates. Thus, complexes inhibit colipase
      binding rate. Additionally, the switching of lipase activity likely occurs when
      uncomplexed substrate becomes the majority species in the interface. Lipase
      substrates, e.g. diacylglycerols, are typically the same lipids generated in the
      cytoplasmic surface of the plasma membrane of stimulated cells. As colipase
      binding is nonspecific and complexes involving lipase substrates form on the
      basis of lipid-lipid interactions alone, complexes should form in the plasma
      membrane of stimulated cells and may regulate protein translocation to the
      membrane.

PMID- 12598039
TI  - Bilayer interfacial properties modulate the binding of amphipathic peptides.
AB  - The free energy of transfer (DeltaG degrees ) from water to lipid bilayers was
      measured for two amphipathic peptides, the presequence of the mitochondrial
      peptide rhodanese (MPR) and melittin. Experiments were designed to determine the
      effects on peptide partitioning of the addition of lipids that produce structural
      modifications to the bilayer/water interface. In particular, the addition of
      cholesterol or the cholesterol analog 6-ketocholestanol increases the bilayer
      area compressibility modulus, indicating that these molecules modify lipid-lipid
      interactions in the plane of the bilayer. The addition of 6-ketocholestanol or
      lipids with attached polyethylene glycol chains (PEG-lipids) modify the effective
      thickness of the interfacial region; 6-ketocholestanol increases the width of
      hydrophilic headgroup region in the direction of the acyl chains whereas the
      protruding PEG chains of PEG-lipids increase the structural width of the
      headgroup region into the surrounding aqueous phase. The incorporation of PEG
      lipids with PEG molecular weights of 2000 or 5000 had no appreciable effect on
      peptide partitioning that could not be accounted for by the presence of surface
      charge. However, for both MPR and melittin DeltaG degrees decreased linearly with
      increasing bilayer compressibility modulus, demonstrating the importance of
      bilayer mechanical properties in the binding of amphipathic peptides.

PMID- 12598040
TI  - Interaction of peptides with binary phospholipid membranes: application of
      fluorescence methodologies.
AB  - The application of fluorescence methodologies to obtain information about the
      extent, dynamics and topology of peptide interaction with binary phospholipid
      (mainly zwitterionic/anionic) mixtures is reviewed. First, general approaches
      based on peptide (tryptophan residues) fluorescence properties that give
      information about its partition, location and dynamics will be presented. Then,
      methodologies based on membrane probes fluorescence that report the influence of
      peptide binding and/or incorporation on the lateral organization (phase
      separation) of membrane phospholipids will be described. Specific examples taken
      from the literature that illustrate both situations are presented as well as
      formalisms for data analysis. It is shown that steady-state and time-resolved
      fluorescence data (particularly important in the case of fluorescence resonance
      energy transfer studies) give complementary information, allowing a molecular
      picture of peptide interaction with biphasic systems to be drawn.

PMID- 12598041
TI  - Binding of sea anemone pore-forming toxins sticholysins I and II to interfaces-
      modulation of conformation and activity, and lipid-protein interaction.
AB  - Sticholysins I and II (St I and St II) are water-soluble toxins produced by the
      sea anemone Stichodactyla helianthus. St I and St II bind to biological and model
      membranes containing sphingomyelin (SM), forming oligomeric pores that lead to
      leakage of internal contents. Here we describe functional and structural studies
      of the toxins aiming at the understanding at a molecular level of their mechanism
      of binding, as well as their effects on membrane permeabilization. St I and St II
      caused potassium leakage from red blood cells and temperature-dependent
      hemolysis, the activation energy of the process being lower for the latter toxin.
      Protein intrinsic fluorescence measurements provided evidence for toxin binding
      to model membranes composed of 1:1 (mol:mol) egg phosphatidyl choline (ePC):SM.
      The fluorescence intensity increased and the maximum emission wavelength
      decreased as a result of binding. The changes were quantitatively different for
      both toxins. Circular dichroism spectra showed that both St I and St II exhibit a
      high content of beta-sheet structure and that binding to model membranes did not
      alter the toxin's conformation to a large extent. Changing the lipid composition
      by adding 5 mol% of negatively charged phosphatidic acid (PA) or phosphatidyl
      glycerol (PG) had small, but detectable, effects on protein conformation. The
      influence of lipid composition on toxin-induced membrane permeabilization was
      assessed by means of fluorescence measurements of calcein leakage. The effect was
      larger for ePC:SM bilayers containing 5 mol% of negative curvature-inducing
      lipids. Electron paramagnetic resonance (EPR) spectra of intercalated fatty acid
      spin probes carrying the nitroxide moiety at different carbons (5, 7, 12, and 16)
      evidenced the occurrence of lipid-protein interaction. Upon addition of the
      toxins, two-component spectra were observed for the probe labeled at C-12. The
      broader component, corresponding to a population of strongly immobilized spin
      probes, was ascribed to boundary lipid. The contribution of this component to the
      total spectrum was larger for St II than for St I. Moreover, it was clearly
      detectable for the C-12-labeled probe, but it was absent when the label was at C
      16, indicating a lack of lipid-protein interaction close to the lipid terminal
      methyl group. This effect could be either due to the fact that the toxins do not
      span the whole bilayer thickness or to the formation of a toroidal pore leading
      to the preferential interaction with acyl chain carbons closer to the
      phospholipids head groups.

PMID- 12598042
TI  - Interaction of antimicrobial peptides from Australian amphibians with lipid
      membranes.
AB  - Solid-state NMR and CD spectroscopy were used to study the effect of
      antimicrobial peptides (aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1)
      from Australian tree frogs on phospholipid membranes. 31P NMR results revealed
      some effect on the phospholipid headgroups when the peptides interact with
      DMPC/DHPC (dimyristoylphosphatidylcholine/dihexanoylphosphatidylcholine) bicelles
      and aligned DMPC multilayers. 2H NMR showed a small effect of the peptides on the
      acyl chains of DMPC in bicelles or aligned multilayers, suggesting interaction
      with the membrane surface for the shorter peptides and partial insertion for the
      longer peptides. 15N NMR of selectively labelled peptides in aligned membranes
      and oriented CD spectra indicated an alpha-helical conformation with helix long
      axis approximately 50 degrees to the bilayer surface at high peptide
      concentrations. The peptides did not appear to insert deeply into PC membranes,
      which may explain why these positively charged peptides preferentially lyse
      bacterial rather than eucaryotic cells.

PMID- 12598043
TI  - Detection of structural and functional asymmetries in P-glycoprotein by combining
      mutagenesis and H/D exchange measurements.
AB  - During the last few years, Attenuated Total Reflection Fourier Transform Infrared
      spectroscopy (ATR-FTIR) has become one of the most powerful methods to determine
      the structure of biological materials and in particular of components of
      biological membranes, like proteins which cannot be studied by X-ray
      crystallography and NMR. Indeed, ATR-FTIR method requires little amount of
      material, gives valuable information about the secondary structure, orientation
      and tertiary structure changes in peptides and proteins. Moreover, this technique
      can be used in the presence of lipids and hence provides an excellent tool to
      study membrane proteins in their natural environment. In this review, we describe
      how structural information about the catalytic cycle of membrane proteins can be
      gained by combining ATR-FTIR spectroscopy and mutagenesis. In particular, results
      obtained about the structure and function of the nucleotide binding domains (NBD)
      of P-glycoprotein (Pgp), a multidrug transporter involved in cancer cells
      resistance to chemotherapy, are described.

PMID- 12598044
TI  - Direct observation of lipid domains in free standing bilayers: from simple to
      complex lipid mixtures.
AB  - The direct observation of temperature-dependent lipid phase equilibria, using two
      photon excitation fluorescence microscopy on giant unilamellar vesicles (GUVs)
      composed of different lipid mixtures, provides novel information about the
      physical characteristics of lipid domain coexistence. Physical characteristics
      such as shape, size, and time evolution of different lipid domains are not
      directly accessible from the traditional experimental approaches that employ
      either small and large unilamellar vesicles or multilamellar vesicles. In this
      short presentation, I will address the most relevant findings reported from our
      laboratory, regarding the direct observation of lipid domain coexistence at the
      level of single vesicles in artificial and natural lipid mixtures. In addition,
      key points concerning our experimental approach will be discussed. The unique
      advantages of the fluorescent probe 6-dodecanoyl-2-dimethylamino-naphthalene
      (LAURDAN) under the two-photon excitation fluorescence microscopy will be
      particularly addressed, especially, the possibility to obtain information about
      the phase-state of different lipid domains directly from the fluorescent images.

PMID- 12598045
TI  - Ceramide modulates the lipid membrane organization at molecular and
      supramolecular levels.
AB  - The role of lipids in membranes has changed rapidly from static to dynamic and
      emphasized their involvement in information transduction, linking temporal and
      topological structuring through compositionally driven effects. Ceramide has been
      described as an important modulator of different membrane functions. In mixtures
      with ganglioside GM1, the condensation induced by ceramide increases
      intermolecular interactions, leading to an increase of the phase transition
      temperature and size of the self-assembled structure. In mixtures with
      phosphatidylcholines, ceramide segregates laterally in the gel state, forming
      domains whose thickness depend on global concentration and chain asymmetry of the
      sphingolipid.

PMID- 12598046
TI  - Dehydration of carbonyls and phosphates of phosphatidylcholines determines the
      lytic action of lysoderivatives.
AB  - The purpose of this study was to correlate the effectiveness of the lysoPC to
      disrupt bilayers with the effects of trehalose and sucrose on the hydration sites
      of a lipid bilayer. The vibration frequencies of carbonyls and phosphates was
      measured at 18 degrees C for different ratios of monomyristoylphosphatidylcholine
      and dimyristoylphosphatidylcholine vesicles prepared in water, sucrose and
      trehalose. The disruption point of the bilayer, evaluated by following the
      changes in the turbidity of the suspension of unilamellar vesicles, was decreased
      when the vesicles were prepared in 100 mM sucrose. The increase of the lytic
      action is directly related to the extent of hydration of the carbonyl
      populations. It is interpreted that the insertion of the sucrose molecule in the
      interface causes local changes in interfacial structure, such as the dehydration
      of the second population of the carbonyls that may be identified as defects of
      packing. In contrast, the insertion of trehalose by replacing water
      simultaneously at the carbonyls and the phosphates does not cause defects of
      packing. For this reason, the lytic action is produced at a concentration very
      similar to that found in water.

PMID- 12598047
TI  - Al(3+)-mediated changes on membrane fluidity affects the activity of PI-PLC but
      not of PLC.
AB  - We investigated whether Al(3+)-mediated changes in membrane fluidity can affect
      the activity of prokaryotic enzymes phospholipase C (PLC) and phospholipase C
      phosphatidyl inositol specific (PI-PLC) in liposomes of phosphatidyl choline
      (PC), PC:phosphatidyl inositol (PI), or PC and polyphosphoinositides (PPI).
      Al(3+) (10-100 microM) promoted membrane rigidification, evaluated with the
      probes 1,6-diphenyl-1,3,5-hexatriene and Laurdan, and followed the order:
      PC:PPI>PC:PI>PC. Al(3+) (25 and 50 microM) did not affect PLC-mediated hydrolysis
      of PC, PI and PIP(2), but stimulated PIP hydrolysis (48.6%). PI-PLC did not
      affect PC, PI, and PIP concentrations, but caused a 67% decrease in PIP(2).
      Al(3+) significantly inhibited PIP(2) hydrolysis in a concentration-dependent (25
      50 microM) manner. Results suggest that the inhibition of PIP(2) hydrolysis by
      Al(3+) could be partially due to a higher lipid packing induced by Al(3+) which
      could affect the interaction between the enzyme and its substrate.

PMID- 12598048
TI  - Detergent resistant domains in erythrocyte membranes survive after cell
      cholesterol depletion: an EPR spin label study.
AB  - We use electron paramagnetic resonance (EPR) with liposoluble spin labels in
      order to study the lipid structures obtained after Triton X-100 extraction of
      erythrocyte membranes. The apparent order profile in these detergent resistant
      membranes (DRM) is very similar to that of the parent membrane, although with
      higher absolute values, consistent with a liquid-ordered state. DRM could also be
      obtained from erythrocytes previously depleted in a 40% of their membrane
      cholesterol, in apparent opposition to the phenomenon of raft disruption reported
      by other authors. However, the protein profile of these samples showed important
      differences with that of DRM from untreated cells. The analysis of our results
      suggests that the effect of Triton X-100 on cholesterol depleted erythrocytes is
      limited to the solubilization of raft proteins, without disrupting the lipid
      matrix of DRM.

PMID- 12598049
TI  - Surface behavior, microheterogeneity and adsorption equilibrium of myelin at the
      air-water interface.
AB  - Interfacial films of whole myelin membrane adsorb at the air-water interface from
      myelin vesicles. The films show a liquid state and their equilibrium spreading
      pressure is equal to the collapse pressure (about 47 mN/m). The films appear
      microheterogeneous as seen by epifluorescence microscopy, consisting in two
      liquid phases over all the adsorption isotherm, starting with rounded liquid
      expanded domains (low surface pressure) immersed in a cholesterol enriched phase
      and reaching a fractal pattern at high surface pressure similar to those
      previously observed by compressing the film. Vesicles adsorb to the interfacial
      film mainly at the lateral interfaces. The high surface pressure at equilibrium
      (almost equal to the collapse pressure) indicates the formation of surface
      multilayers, also shown by fluorescence microscopy.

PMID- 12598050
TI  - Effect of polar head groups on the activity of aspartyl protease adsorbed to
      lipid membranes.
AB  - The proteolytic activity of an aspartyl protease of Mucor miehei was correlated
      with the adsorption of the protease to lipid vesicles. It was observed that the
      presence of phosphatidylethanolamines (PE's) in the membrane increased the enzyme
      activity in a 20% in the gel phase and 10% in the fluid phase. The effects of
      protease on the surface pressure of monolayers composed by
      dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC),
      dimyristoyl phosphatidylethanolamine (DMPE) were measured at constant temperature
      as a function of the surface pressure. At low surface pressures, the major
      changes were induced by protease on DOPC and DMPC monolayers. However, the effect
      were much lower when the monolayer was composed by DMPE. The low hydration and
      strong head-head interaction between the phosphates and the amine groups of
      adjacent PE's would result in an area per molecule much lower in PE than in
      phosphatidylcholine (PC) in concordance with the lower penetration in PE.
      Protease adsorption on PE membranes increases the proteolytic activity in which
      condition is less susceptible to inhibition by pepstatin. However, PC's do not
      alter the enzyme activity being the action of inhibitor unaffected.

PMID- 12598051
TI  - Acyl chains are responsible for the irreversibility in the Escherichia coli alpha
      hemolysin binding to membranes.
AB  - Hemolysin (HlyA) is an extracellular protein secreted by uropathogenic strains of
      Escherichia coli. The mature HlyA is able to bind to mammalian target cell
      membranes including those of the immune system, causing lysis. The lytic activity
      is absolutely dependent upon the Hlyc-dependent acylation of Prohemolysin. In
      this paper we show, through Trp fluorescence studies and denaturation in
      Guanidine hydrochloride, that the acylation is responsible for the loose
      conformation of the active protein, necessary to transform it from soluble to
      membrane-bound form. Previous studies showed that toxin binding to the bilayers
      occurs in, at least two ways, a reversible adsorption and irreversible insertion.
      We demonstrated that the irreversibility is due to the acyl chains in the HlyA,
      as shown by the protein transfer from multilamellar liposomes composed of
      palmitoyl-oleoyl-phosphatidylcholine (POPC) to large unilamellar vesicles
      containing POPC-doxyl as protein fluorescence quencher.

PMID- 12598052
TI  - Characterization of diacetylenic liposomes as carriers for oral vaccines.
AB  - In order to evaluate liposomes as vehicle for oral vaccines the characterization
      and stability of polymerized and non-polymerized liposomes were examined.
      Mixtures of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3 phosphocholine) (DC8,9PC)
      with saturated 1,2-dimiristoyl-sn-glycero-3-phosphocholine in molar ratio 1:1
      were used. Saturated and non-saturated lipids were combined to give a chemically
      modified membrane by UV polymerization derived from DC8,9PC. Characterization was
      carried out by electronic microscopy, differential scanning calorimetry (DSC) and
      by hydrophobicity factor (HF). The stability towards the digestive tract
      (including saliva): acidic solutions, bile and pancreatin are compared to buffer
      pH 7.4, measuring the release of Glucose-6-phosphate or bovine plasma albumin
      entrapment. The polymerized liposomes showed further augmentation of the HF and
      the size. DSC showed phase separation and lower Tt if compared to data obtained
      for DC8,9PC. The HF, as main factor is discussed in relation to in vitro
      stability, suggesting that polymerized and non-polymerized liposomes would serve
      effectively as an oral delivery vehicle.

PMID- 12598053
TI  - Nursing home admission of female Alzheimer's patients: family care aspects.
AB  - This study examined patterns of nursing home admission for males and females with
      Alzheimer's disease. It also examined reasons why women may be less likely to
      remain in home and family-based care. A 2-year, four-wave follow-up study was
      conducted among 573 patients and their family caregivers. Results from logistic
      regression analyses showed that females and males were institutionalized for
      different reasons. Men were institutionalized primarily for medical and
      caregiving need factors. Women showed less physical and less cognitive
      impairment, and their model of placement showed more importance of family
      caregiving patterns.

PMID- 12598054
TI  - Sexual behavior and condom practices among Los Angeles women.
AB  - BACKGROUND: The sociodemographic correlates of the number of recent sexual
      partners and condom use are investigated in a population-based sample of 1,178
      unmarried women living in Los Angeles County. RESULTS: Asian Americans, foreign
      born, and older women are less likely to be sexually active and that more
      educated and previously married women are more likely. Among the sexually active
      (n = 909), Hispanic women and older women are less likely to have multiple
      partners, and younger and previously married women more are more likely. African
      American women and younger women are more likely to use condoms; older and
      previously married women are less likely. CONCLUSIONS: Results from this study
      indicate that women-centered primary and secondary prevention efforts may benefit
      from targeting women not previously considered, such as women of post
      reproductive age and divorced women.

PMID- 12598055
TI  - Intimate partner violence and substance abuse among minority women receiving care
      from an inner-city emergency department.
AB  - A woman's drug and alcohol use has been found to increase her risk of
      experiencing intimate partner violence (IPV). OBJECTIVE: The study describes the
      rates of lifetime and current IPV among women awaiting care in an emergency
      department and explores the association between IPV and having a drug abuse
      problem, and IPV and having an alcohol abuse problem, after controlling for
      demographic factors and history of childhood victimization. METHODS: Face-to-face
      interviews were conducted with 143 low-level triaged women recruited from an
      inner-city emergency department. RESULTS: Nearly one-half reported ever
      experiencing IPV, and over 18% reported IPV during the year before the interview.
      A higher proportion of abused women reported a history of regular crack, cocaine,
      or heroin use and visiting shooting galleries or crack houses. Participants who
      were physically abused by their partner during the past year (15%, n = 21) were
      more likely than nonabused women (85%, n = 122) to report higher scores on the
      Alcohol Use Disorders Identification Test (AUDIT) (4.9 vs. 2.4), a measure of
      alcohol-related problems, and the Drug Abuse Severity Test (DAST) (3.0 vs. 1.3),
      a measure of drug-related problems. Sexually abused women (6%, n = 9) were more
      likely than their counterparts (94%, n = 134) to have significantly higher AUDIT
      scores (6.4 vs. 2.5). The findings have implications for how the intersecting
      public health problems of IPV and substance abuse should be taken into
      consideration in research and patient care protocols in emergency departments.

PMID- 12598056
TI  - A survey of attitudes and experiences of women with heart disease.
AB  - OBJECTIVE: Cardiovascular disease is the leading cause of death in women, but
      little is known about the attitudes and experiences of the 6.4 million American
      women who have a diagnosis of heart disease. We assessed the knowledge,
      attitudes, and experiences of women with heart disease and the effect of the
      disease on their lives. SUBJECTS: A total of 204 women with a self-reported
      diagnosis of heart disease were the subjects. METHODS: A telephone survey with
      open-ended questions was used to ask women about their diagnoses, symptoms,
      interactions with the health care system, knowledge of risks and symptoms,
      satisfaction with care, and the effect of the disease on their lifestyle,
      psychosocial well-being, finances, interpersonal relationships, and spirituality.
      RESULTS: Most of the women (73%) had a diagnosis of coronary artery disease
      (CAD), with the remainder having diagnoses of other cardiac diseases. Most women
      took multiple medications and had undergone several diagnostic and therapeutic
      interventions. Almost half the women had been unaware that they were at risk of
      CAD and, after the condition was diagnosed, almost one-fourth of the respondents
      did not seek additional information about their diagnosis or treatment options
      from their physicians. More than half expressed dissatisfaction with their health
      care, most often because of physician-related knowledge and communication
      problems. Many women reported that they were unable or unwilling to make
      appropriate lifestyle changes after the diagnosis was made because of
      insufficient social, medical, or educational support. Educational opportunities
      may have been limited because less than 60% of women with CAD received cardiac
      rehabilitation services. Respondents reported significant changes in their
      interpersonal relationships, mental health, and financial and spiritual well
      being as a result of having heart disease. CONCLUSION: Heart disease affects many
      aspects of women's lives. A significant percentage of surveyed women continue to
      have adverse consequences long after the diagnosis is made. Furthermore, proven
      beneficial lifestyle changes may not be implemented, most likely because of
      dissatisfaction with care, lack of educational and rehabilitative resources,
      symptoms of depression and anxiety, and suboptimal social support. This study
      identifies several problems that may help explain why women with heart disease
      have poorer medical outcomes than men with heart disease. Further investigation
      and better definition of these problems may help improve outcomes among women.

PMID- 12598057
TI  - Coping styles and personality domains related to menopausal stress.
AB  - PURPOSE: Examine the role of coping styles and personality domains in
      relationship to stress associated with menopause. DATA/INFORMATION: Data are from
      170 women ages 45 to 54 who completed a mailed questionnaire and a telephone
      interview that assessed women's stress associated with menopause, coping style,
      personality, menopausal symptoms, depressive symptoms, and use of hormone
      replacement therapy. RESULTS: Rating menopause as stressful was associated with
      higher levels of neuroticism, seeking social support, and avoidance, and lower
      levels of agreeableness in unadjusted analyses. In a multivariate model,
      menopausal symptoms, seeking social support, and neuroticism accounted for 21% of
      the variance in rating menopause as stressful. CONCLUSIONS: Health care providers
      treating women going through menopause should be aware that the stress response
      to the menopause transition is multifactorial and is associated with women's
      individual personalities and coping styles.

PMID- 12598058
TI  - Does pornography influence young women's sexual behavior?
AB  - Young women (n = 1,000), visiting a family planning clinic in Stockholm, Sweden,
      answered a questionnaire about their sexual behavior and if they had seen
      pornography. Four out of five had consumed pornography, and one-third of these
      believed that pornography had impacted their sexual behavior. As many as 47% had
      experienced anal intercourse, which was significantly more common among older
      women (51%) than among teenagers (31%). The majority valued anal intercourse as a
      negative experience. As the use of a condom was low (40%) when having anal
      intercourse, the consequences for the spread of sexually transmitted diseases
      should be considered.

PMID- 12598059
TI  - Long-term follow-up of coronary artery disease presenting in young adults.
AB  - OBJECTIVES: This study evaluated long-term survival and predictors of elevated
      risk for young adults diagnosed with coronary artery disease (CAD). BACKGROUND:
      Coronary artery disease is rarely seen in young adults. Traditional cardiac risk
      factors have been studied in small series; however, many questions exist.
      METHODS: We identified 843 patients under age 40 with CAD diagnosed by coronary
      angiography from 1975 to 1985. Death, hypertension, gender, family history, prior
      myocardial infarction (MI), diabetes, heart failure, angina class, number of
      diseased vessels, ejection fraction (EF), Q-wave infarction, in-hospital death,
      and initial therapy were studied. Patients were followed for 15 years. RESULTS:
      The mean age was 35 for women (n = 94) and 36 for men (n = 729). The average EF
      was 55%. Fifty-eight percent of the subjects had single-vessel disease, and 10%
      were diabetic. The strongest predictors of long-term mortality were a prior MI
      (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.00 to 1.73), New York
      Heart Association class II heart failure (HR 1.75, 95% CI 1.03 to 2.97), and
      active tobacco use (HR 1.59, 95% CI 1.14 to 2.21). Revascularization, rather than
      medical therapy, was associated with lower mortality (coronary angioplasty: HR
      0.51, 95% CI 0.32 to 0.81; coronary artery bypass graft: HR 0.68, 95% CI 0.50 to
      0.94). Overall mortality was 30% at 15 years. Patients with diabetes had 15-year
      mortality of 65%. Those with prior MI had 15-year mortality of 45%, and patients
      with an EF <30% a mortality of 83% at 15 years. CONCLUSIONS: Coronary disease in
      young adults can carry a poor long-term prognosis. A prior MI, diabetes, active
      tobacco abuse, and lower EF predict a significantly higher mortality.

PMID- 12598060
TI  - Coronary artery disease in young adults.

PMID- 12598061
TI  - Prediction of clinical outcome after mechanical revascularization in acute
      myocardial infarction by markers of myocardial reperfusion.
AB  - OBJECTIVES: We sought to evaluate and compare recently suggested parameters of
      reperfusion after angioplasty in acute myocardial infarction (AMI) for risk
      stratification during long-term follow-up. BACKGROUND: Abnormal myocardial
      perfusion has a detrimental impact on survival. Several parameters of reperfusion
      have been evaluated in controlled study populations for risk stratification.
      METHODS: In 253 consecutive patients undergoing intervention in AMI on a native
      coronary vessel, angiographic myocardial blush grade (MBG), corrected TIMI
      (thrombolysis in myocardial infarction) frame count (CTFC) and persistent ST
      segment elevation (STE) were determined to evaluate reperfusion. This was a high
      risk population, including referral for treatment failure at a primary center in
      29.2%, failed thrombolysis in 22.1% and cardiogenic shock in 13.4% of cases.
      RESULTS: In addition to age, patient referral, LBBB and heart rate on admission,
      MBG 0 to 1 (odds ratio [OR] = 3.23, p < 0.001), CTFC (OR = 1.01, p = 0.015) and
      persistent STE >2 leads (OR = 3.46, p = 0.010) were univariate predictors of
      mortality during a 22.1 +/- 15.6 months follow-up. Myocardial blush grade 0 to 1
      (OR = 2.17, p = 0.033) and persistent STE (OR = 3.61, p = 0.017) persisted as
      independent predictors of mortality, whereas CTFC failed. Differences in
      mortality between reperfusion groups at 30 days remained throughout the complete
      follow-up. In sequential Cox models, the predictive power of clinical data alone
      for mortality (model chi-squared 55.8) was strengthened by adding MBG (model chi
      squared 64.2) and ECG postintervention (model chi-squared 69.2). CONCLUSIONS:
      Myocardial blush grade 0 to 1 and persistent STE are independent predictors for
      long-term mortality after angioplasty in AMI. Corrected TIMI frame count is a
      less powerful predictor. Combining both parameters to consider quality of
      reperfusion in the myocardium at risk and extent of the infarct zone increases
      the predictive power.

PMID- 12598062
TI  - Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene
      with coronary vasomotor dysfunction and myocardial infarction.
AB  - OBJECTIVES: The purpose of this study was to test the hypothesis that
      polymorphisms in the promoter region of the glutamate-cysteine ligase catalytic
      subunit (GCLC) gene may be associated with coronary endothelial vasomotor
      dysfunction and myocardial infarction (MI). BACKGROUND: Glutamate-cysteine ligase
      is a rate-limiting enzyme for synthesis of glutathione (GSH) that plays a crucial
      role in the intracellular antioxidant defense systems. Oxidants transcriptionally
      upregulate the GCLC gene for GSH synthesis, providing a protective mechanism
      against oxidant-induced endothelial dysfunction or activation, which plays a
      pathogenetic role in cardiovascular diseases. METHODS: The association of the
      possible polymorphisms with coronary arterial diameter responses to acetylcholine
      was determined in 62 male subjects. The frequency of polymorphisms was compared
      between 255 male patients with MI and 179 male control subjects. RESULTS: We
      found a polymorphism (-129C/T) in which the T allele showed lower promoter
      activity (50% to 60% of the activity of the C allele) in response to H(2)O(2) in
      human endothelial cells. Endothelium-dependent dilation of coronary arteries was
      impaired in subjects with the -129T allele (n = 31), as compared with the age
      matched subjects without the -129T allele (n = 31). The T allele was highly
      frequent in patients with MI as compared with control subjects, and it was a
      significant risk factor for MI, independent of traditional coronary risk factors
      (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.08 to 3.03; p = 0.03).
      CONCLUSIONS: The -129T polymorphism of the GCLC gene may suppress the GCLC gene
      induction response to an oxidant, and it is implicated in coronary endothelial
      vasomotor dysfunction and MI.

PMID- 12598063
TI  - Combined role of the Lewis antigenic system, Chlamydia pneumoniae, and C-reactive
      protein in unstable angina.
AB  - OBJECTIVES: The goal of this study was to assess the prognostic role of the Lewis
      antigenic system, Chlamydia pneumoniae (CP) seropositivity (CP+), and C-reactive
      protein (CRP) levels in unstable angina (UA). BACKGROUND: The role of CP
      infection in acute coronary syndromes is contradictory. The Lewis antigenic
      system, a genetically determined blood group system associated with infections
      and several disorders, including ischemic heart disease, might influence the
      susceptibility to CP infection, inflammatory response, and risk of cardiac
      ischemic events. METHODS: The CRP levels, Lewis antigens, and CP+ were measured
      in 54 patients with Braunwald's class IIIB UA. All patients were followed up for
      one year, and the occurrence of new coronary events (coronary death, myocardial
      infarction, and recurrence of instability) were recorded. RESULTS: Twenty-five
      coronary events occurred during follow-up. At univariate analysis CRP >3 mg/l
      (CRP+) (p = 0.0056), Lewis antigen b (Leb+) (p = 0.028), and the combination of
      Leb+ and CP+ (p = 0.006) and of CRP+ and Leb+ (p = 0.003) were associated with
      new coronary events, while CP+ alone was not. At multivariate analysis, CRP+ (p =
      0.008) and combined Leb+CP+ (p = 0.03) were independent predictors of worse
      outcome. The event rate was 64% in CRP+ patients, 67% in Leb+CP+ patients, and
      86% in CRP+Leb+CP+ patients. Combined Leb+CP+, but not Leb+ and CP+ alone, was
      related to CRP levels (p = 0.03). Among CP+ patients, CRP levels were higher in
      Leb+ than Leb- (p = 0.028). CONCLUSIONS: Our data demonstrate that in UA the
      Lewis antigenic system plays an important role, probably determining individual
      susceptibility to the detrimental effects of CP infection and by determining an
      enhanced inflammatory response.

PMID- 12598064
TI  - The outcome of percutaneous coronary intervention in patients with in-stent
      restenosis who failed intracoronary radiation therapy.
AB  - OBJECTIVES: This study reports the outcome of patients who failed intracoronary
      radiation therapy (IRT) for the treatment of in-stent restenosis (ISR).
      BACKGROUND: Intracoronary radiation therapy has demonstrated a reduction in the
      recurrence rate of restenosis for patients with ISR. However, 10% to 30% of these
      patients require repeat intervention to the irradiated site. METHODS: Of 961
      patients who were assigned to gamma or beta radiation for the treatment of
      diffuse ISR, we evaluated the outcome of 282 (29%) consecutive patients who
      failed IRT and compared them with the 679 (71%) patients who had successful IRT.
      For patients who failed radiation, the mean time to the first target vessel
      revascularization (TVR) was 173 +/- 127 days after the index procedure and the
      total duration of follow-up was 494 +/- 304 days. RESULTS: Patients who failed
      IRT were younger (60 +/- 10 vs. 63 +/- 11 years, p = 0.002) and had a higher
      incidence of restenting (51% vs. 41%, p = 0.003). The majority (55%) of the
      restenotic lesions after IRT failure were focal (< or =10 mm), with a mean lesion
      length of 11.9 +/- 1.9 mm. Of the 257 patients who had subsequent TVR after
      failed IRT, 68 (26%) underwent coronary artery bypass grafting and 189 (74%)
      underwent percutaneous coronary intervention using balloon in 61%, restenting in
      26%, atheroablation in 11%, and the cutting balloon in 2% of cases. At six
      months, 6% of patients died, 1% had Q-wave MI, 17% had repeat TVR, and the
      overall rate of major adverse cardiac events was 21%. CONCLUSIONS: The
      predominant angiographic pattern of lesions in patients who failed IRT is focal
      restenosis, with these lesions responding well to conventional revascularization
      methods.

PMID- 12598065
TI  - Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and
      enoxaparin on thrombin generation and platelet activation in healthy male
      subjects.
AB  - OBJECTIVES: The effects of ximelagatran, an oral direct thrombin inhibitor (DTI),
      recombinant hirudin (r-hirudin) and enoxaparin on thrombin generation and
      platelet activation were studied in humans. BACKGROUND: Recombinant hirudin
      (parenteral DTI) and enoxaparin (low molecular weight heparin) have been
      demonstrated to be clinically effective in acute coronary syndromes. Ximelagatran
      is currently under investigation for the prevention and treatment of
      thromboembolism. The shed blood model allows for the study of thrombin generation
      and platelet activation in humans in vivo. METHODS: This was an open-label,
      parallel-group study involving 120 healthy male volunteers randomized to receive
      one of three oral doses of ximelagatran (15, 30 or 60 mg), r-hirudin
      (intravenous) or enoxaparin (subcutaneous) at doses demonstrated to be clinically
      effective in acute coronary syndromes, or to serve as a control. Thrombin
      generation (prothrombin fragment 1+2 [F1+2] and thrombin-antithrombin complex
      [TAT]) and platelet activation (beta-thromboglobulin [beta-TG]) biomarkers were
      studied using a shed blood model involving blood collection from skin incisions
      made using standardized bleeding time devices. RESULTS: Oral ximelagatran,
      intravenous r-hirudin and subcutaneous enoxaparin rapidly and significantly (p <
      0.05) decreased F1+2, TAT and beta-TG levels in shed blood, indicating inhibition
      of thrombin generation and platelet activation. Statistically significant
      concentration (melagatran, the active form of ximelagatran)-response
      relationships for F1+2 (p = 0.005), TAT (p = 0.005) and beta-TG (p < 0.001)
      levels, with IC(50)s of 0.376 (F1+2), 0.163 (TAT) and 0.115 (beta-TG) micromol/l,
      were detected. Melagatran showed dose-proportional pharmacokinetics with low
      variability. All drugs were well tolerated. CONCLUSIONS: Oral administration of
      the DTI ximelagatran resulted in a rapid inhibition of both thrombin generation
      and platelet activation in a concentration-dependent manner using a human shed
      blood model. The inhibition of thrombin generation by 60 mg ximelagatran was
      comparable to that observed with doses of r-hirudin and enoxaparin demonstrated
      to be effective for the treatment of acute coronary syndromes.

PMID- 12598066
TI  - Ongoing right ventricular hemodynamics in heart failure: clinical value of
      measurements derived from an implantable monitoring system.
AB  - OBJECTIVES: This study examined the characteristics of continuously measured
      right ventricular (RV) hemodynamic information derived from an implantable
      hemodynamic monitor (IHM) in heart failure patients. BACKGROUND: Hemodynamic
      monitoring might improve the day-to-day management of patients with chronic heart
      failure (CHF). Little is known about the characteristics of long-term hemodynamic
      information in patients with CHF or how such information relates to meaningful
      clinical events. METHODS: Thirty-two patients with CHF received a permanent RV
      IHM system similar to a single-lead pacemaker. Right ventricular systolic and
      diastolic pressures, heart rate, and pressure derivatives were continuously
      measured for nine months without using the data for clinical decision-making or
      management of patients. Data were then made available to clinical providers, and
      the patients were followed up for 17 months. Pressure characteristics during
      optimal volume, clinically determined volume-overload exacerbations, and volume
      depletion events were examined. The effect of IHM on hospitalizations was
      examined using the patients' historical controls. RESULTS: Long-term RV pressure
      measurements had either marked variability or minimal time-related changes.
      During 36 volume-overload events, RV systolic pressures increased by 25 +/- 4% (p
      < 0.05) and heart rate increased by 11 +/- 2% (p < 0.05). Pressure increases
      occurred in 9 of 12 events 4 +/- 2 days before the exacerbations requiring
      hospitalization. Hospitalizations before using IHM data for clinical management
      averaged 1.08 per patient year and decreased to 0.47 per patient-year (57%
      reduction, p < 0.01) after hemodynamic data were used. CONCLUSIONS: Long-term
      ambulatory pressure measurements from an IHM may be helpful in guiding day-to-day
      clinical management, with a potentially favorable impact on CHF hospitalizations.

PMID- 12598067
TI  - Monitoring heart failure hemodynamics with an implanted device: its potential to
      improve outcome.

PMID- 12598068
TI  - Effect of spironolactone on cardiac sympathetic nerve activity and left
      ventricular remodeling in patients with dilated cardiomyopathy.
AB  - OBJECTIVES: We sought to evaluate the effects of spironolactone on cardiac
      sympathetic nerve activity and left ventricular (LV) remodeling in patients with
      dilated cardiomyopathy (DCM). BACKGROUND: Aldosterone prevents the uptake of
      norepinephrine and promotes structural remodeling of the heart. Spironolactone,
      an aldosterone receptor blocker, improves LV remodeling in patients with DCM, but
      its influence on cardiac sympathetic nerve activity has not been determined.
      METHODS: We selected 30 patients with DCM who were treated with an angiotensin
      converting enzyme inhibitor and a loop diuretic. Fifteen patients were assigned
      to receive spironolactone additionally, whereas the remaining 15 patients
      continued their current regimen. The delayed heart/mediastinum (H/M) count ratio,
      delayed total defect score (TDS), and washout rate (WR) were determined from
      iodine-123 ((123)I)-meta-iodobenzylguanidine (MIBG) images before and six months
      after treatment. The left ventricular end-diastolic volume (LVEDV) and left
      ventricular ejection fraction (LVEF) were determined by echocardiography, and New
      York Heart Association (NYHA) functional class was estimated. RESULTS: In the
      spironolactone group, the TDS decreased from 36 +/- 9 to 24 +/- 13 (p < 0.0001),
      the H/M ratio increased from 1.64 +/- 0.20 to 1.86 +/- 0.27 (p < 0.0001), and WR
      decreased from 55 +/- 12% to 41 +/- 15% (p < 0.0005). In addition, the LVEDV
      decreased from 187 +/- 26 to 154 +/- 41 ml (p < 0.005), and LVEF increased from
      33 +/- 6% to 39 +/- 6% (p < 0.005). However, there were no significant changes in
      these parameters in the control group. There was a significant correlation
      between changes in the (123)I-MIBG findings and changes in LVEDV with
      spironolactone treatment (TDS: r = 0.684, p = 0.0038; H/M ratio: r = -0.878, p <
      0.0001; and WR: r = 0.737, p = 0.0011). The NYHA functional class improved in
      both groups but showed a greater improvement in the spironolactone group than in
      the control group (p < 0.01). CONCLUSIONS: Spironolactone improves cardiac
      sympathetic nerve activity and LV remodeling in patients with DCM.

PMID- 12598069
TI  - Atriobiventricular pacing improves exercise capacity in patients with heart
      failure and intraventricular conduction delay.
AB  - OBJECTIVES: We sought to assess the efficacy of biventricular pacing with respect
      to both peak and submaximal measures of exercise in patients with New York Heart
      Association class III heart failure (HF) and intraventricular conduction delay in
      a randomized, blinded study. BACKGROUND: Submaximal and maximal changes in
      exercise capacity need evaluating in this patient population with this novel
      therapy. METHODS: Graded exercise and 6-min walk tests were performed in patients
      randomized to three months each of active (atrio-biventricular) and inactive
      pacing. Minute ventilation (VE), oxygen uptake (VO(2)), ventilated carbon dioxide
      (VCO(2)) and heart rate were measured in patients achieving a respiratory
      quotient >1 (n = 30). Oxygen pulse, anaerobic threshold (AT) and ventilatory
      efficiency (VE/VCO(2)) were calculated. RESULTS: Active biventricular pacing
      increased peak VO(2) (15.8 +/- 4.3 vs. 14.4 +/- 4.6 ml/kg/min, p = 0.02),
      exercise time (501 +/- 223 s vs. 437 +/- 233 s, p < 0.001) and oxygen pulse (9.3
      +/- 2.8 vs. 8.1 +/- 3.1 ml/beat, p < 0.01) compared with inactive pacing. The
      submaximal measures of exercise capacity significantly increased with active
      pacing: AT (11.2 +/- 4.1 ml/kg/min vs. 9.5 +/- 2.3 ml/kg/min, p = 0.02) and 6-min
      walk (414 +/- 94 m vs. 359 +/- 94 m, p = 0.001). Minute ventilation/ventilated
      carbon dioxide improved (32 +/- 9 vs. 36 +/- 11, p = 0.03) with normalization of
      the VE/VCO(2) slope in 59% of patients (chi-square test, p = 0.002) with active
      pacing. CONCLUSIONS: Biventricular pacing may improve maximal and submaximal
      exercise capacity in patients with advanced HF and intraventricular conduction
      delay.

PMID- 12598070
TI  - Stress echo results predict mortality: a large-scale multicenter prospective
      international study.
AB  - OBJECTIVES: The purpose of this study was to assess the long-term value of
      pharmacologic stress echocardiography with either dipyridamole or dobutamine
      (DET) for prediction of cardiac death in patients with proven or suspected
      coronary artery disease (CAD). BACKGROUND: Stress echocardiography is an
      established, cost-effective technique for the detection of CAD. METHODS: From the
      Echo Persantine International Cooperative-Echo Dobutamine International
      Cooperative data bank, 7,333 patients (5,452 males; 59 +/- 10 years) underwent
      pharmacologic stress echocardiography with either high-dose dipyridamole (0.84
      mg/kg over 10 min) (n = 4,984) or high-dose dobutamine (up to 40 microg/kg/3 min)
      (n = 2,349) for diagnostic purposes. Patients were followed up for a mean of 2.6
      years (range 1 to 206 months). RESULTS: The DET was positive for myocardial
      ischemia in 2,854 (35%) patients and negative in 4,479 (61%) patients. During the
      follow-up there were 161 cardiac deaths (sudden death and fatal myocardial
      infarction) (2.1% of the total population). Kaplan-Meier survival estimates
      showed a significantly better outcome for those patients with a negative
      pharmacologic stress echocardiography test compared with those with a positive
      test (92 vs. 71.2%, p = 0.0000). CONCLUSIONS: Pharmacologic stress
      echocardiography with either dipyridamole or dobutamine is effective in
      predicting cardiac death during a long-term follow-up. A negative stress
      echocardiography test result is related to a favorable outcome.

PMID- 12598071
TI  - Prognostic value of predischarge dobutamine stress echocardiography in chest pain
      patients with a negative cardiac troponin T.
AB  - OBJECTIVES: We prospectively studied the prognostic value of predischarge
      dobutamine stress echocardiography (DSE) in low-risk chest pain patients with a
      normal or nondiagnostic electrocardiogram (ECG) and a negative serial troponin T.
      BACKGROUND: Noninvasive stress testing is recommended before discharge or within
      72 h in patients with low-risk chest pain. The prognostic value of immediate DSE
      has not been studied in a blinded, prospective fashion. METHODS: Patients
      presenting at the emergency room within 6 h of symptom onset and a normal or
      nondiagnostic ECG were eligible. Dobutamine stress echocardiography was performed
      after unstable coronary artery disease was ruled out by a standard rule-out
      protocol and a negative serial troponin T; the occurrence of any new wall motion
      abnormality was considered positive. Results were kept blinded. End points were
      cardiac death, myocardial infarction, rehospitalization for unstable angina or
      revascularization. RESULTS: In total, 377 patients were included. There were 2
      deaths, 2 myocardial infarctions, 8 rehospitalization for unstable angina, and 10
      revascularizations at six-month follow-up. The end points occurred in 8/26
      (30.8%) patients with a positive versus 14/351 (4.0%) patients with a negative
      DSE (odds ratio, 10.7; 95% confidence interval, 4.0 to 28.8; p < 0.0001). By
      multivariate analysis, DSE remained a predictor of end points (p < 0.0001).
      CONCLUSIONS: A predischarge DSE had important, independent prognostic value in
      low-risk, troponin negative, chest pain patients.

PMID- 12598072
TI  - Spontaneous echo contrast videodensity is flow-related and is dependent on the
      relative concentrations of fibrinogen and red blood cells.
AB  - OBJECTIVES: The purposes of the present study were to: 1) determine whether
      fibrinogen (Fg) is the plasma protein responsible for spontaneous echo contrast
      (SEC), and 2) investigate modulators of SEC. BACKGROUND: Spontaneous echo
      contrast has been linked to the development of thromboemboli. The blood products
      and their interaction responsible for SEC formation have not been fully
      elucidated. METHODS: Blood echogenicity was examined with the use of quantitative
      videodensitometry over a controlled range of flow velocities in an in vitro
      model. Human blood samples were analyzed in a manner to methodically eliminate
      individual blood components from whole blood to determine which components are
      responsible for the formation of SEC. RESULTS: The videodensity (VD) of whole
      blood was found to be flow-dependent, with higher VD at lower flow rates, and
      correlated with visually dense SEC. The following blood products produced faint
      VD values: washed red blood cells (wRBCs), platelet-depleted plasma, Fg,
      defibrinated plasma, wRBCs plus defibrinated plasma, and physiologic saline. The
      VD of wRBCs increased incrementally as increasing concentrations of Fg were
      added. At each hematocrit (Hct) range, as Fg concentration increased, the SEC
      became denser, and the VD level also increased until a plateau level was reached
      that was distinct for each Hct. The addition of sialic acid, which inhibits RBC
      RBC aggregation, decreased the amount of SEC, even in the presence of Fg.
      CONCLUSION: These results demonstrated that Fg-mediated RBC aggregation may be
      responsible for SEC generation. Furthermore, a unique stoichiometric relationship
      exists between Fg and RBC concentrations that is necessary for blood
      echogenicity.

PMID- 12598073
TI  - Echocardiographic detection of early diabetic myocardial disease.
AB  - OBJECTIVES: We sought to determine whether disturbances of myocardial
      contractility and reflectivity could be detected in diabetic patients without
      overt heart disease and whether these changes were independent and incremental to
      left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular (LV) dysfunction
      is associated with diabetes mellitus, but LVH is common in this population and
      the relationship between diabetic LV dysfunction and LVH is unclear. METHODS: We
      studied 186 patients with normal ejection fraction and no evidence of CAD: 48
      with diabetes mellitus only (DM group), 45 with LVH only (LVH group), 45 with
      both diabetes and LVH (DH group), and 48 normal controls. Peak strain and strain
      rate of six walls in apical four-chamber, long-axis, and two-chamber views were
      evaluated and averaged for each patient. Calibrated integrated backscatter (IB)
      was assessed by comparison of the septal or posterior wall with pericardial IB
      intensity. RESULTS: All patient groups (DM, DH, LVH) showed reduced systolic
      function compared with controls, evidenced by lower peak strain (p < 0.001) and
      strain rate (p = 0.005). Calibrated IB, signifying myocardial reflectivity, was
      greater in each patient group than in controls (p < 0.05). Peak strain and strain
      rate were significantly lower in the DH group than in those in the DM alone (p <
      0.03) or LVH alone (p = 0.01) groups. CONCLUSIONS: Diabetic patients without
      overt heart disease demonstrate evidence of systolic dysfunction and increased
      myocardial reflectivity. Although these changes are similar to those caused by
      LVH, they are independent and incremental to the effects of LVH.

PMID- 12598074
TI  - Myocardial perfusion and viability by positron emission tomography in infants and
      children with coronary abnormalities: correlation with echocardiography, coronary
      angiography, and histopathology.
AB  - OBJECTIVES: This study was designed to assess the feasibility and accuracy of
      positron emission tomography (PET) imaging in infants and children. BACKGROUND:
      Positron emission tomography is employed in adults for the evaluation of
      myocardial perfusion and the detection of myocardial viability. METHODS:
      Perfusion and metabolism findings on PET in infants and children with suspected
      coronary abnormalities (age 14 days to 12 years old, mean 3.3 +/- 4.0 years) were
      correlated with findings on coronary angiography, echocardiography, and
      myocardial histopathology. The segmental myocardial uptake of the flow tracer
      (13)N-ammonia and of the glucose tracer (18)F-deoxyglucose ((18)FDG) was graded
      on a five-point scale and compared with the angiographic perfusion score, with
      regional wall motion, and the presence of fibrosis. RESULTS: There was an
      agreement of r = 0.72 (p < 0.05) between regional myocardial perfusion and
      angiography. The correlation of histopathologic changes with normal, moderately,
      and severely reduced segmental (13)N-ammonia uptake was 87%, 60%, and 75%,
      respectively. Segmental myocardial (18)FDG uptake and histopathologic findings
      were concordant in 48 (79%) of 64 segments without fibrosis; absence of viability
      by perfusion and metabolism imaging correlated with the presence of fibrosis in
      21 (84%) of 25 segments. CONCLUSIONS: The observed agreements between the
      findings on PET perfusion and metabolism imaging with those on coronary
      angiography, echocardiography, and histopathology support the utility and
      accuracy of PET for characterizing myocardial perfusion abnormalities and
      viability in pediatric patients.

PMID- 12598075
TI  - Advances for treating in-hospital cardiac arrest: safety and effectiveness of a
      new automatic external cardioverter-defibrillator.
AB  - OBJECTIVES: The purpose of this study was to prospectively analyze the
      performance and safety of a new programmable, fully automatic external
      cardioverter-defibrillator (AECD) in a European multicenter trial. BACKGROUND
      Although, the response time to cardiac arrest (CA) is a major determinant of
      mortality and morbidity, in-hospital strategies have not significantly changed
      during the last 30 years. METHODS: Patients (n = 117) at risk of CA in monitored
      wards (n = 51) and patients undergoing electrophysiologic testing or implantable
      cardioverter-defibrillator (ICD) implantation (n = 66) were enrolled. The
      accuracy of the automatic response of the device to any change of rhythm (lasting
      >1 s and >4 beats) was confirmed by reviewing the simultaneously recorded Holter
      data and the programmed parameters. RESULTS: During 1,240 h, 1,988 episodes of
      rhythm changes were documented. A total of 115 episodes lasted > or =10 s or
      needed treatment (pacing, n = 32; ICD, n = 51; AECD, n = 35) for termination. The
      device detected ventricular tachyarrhythmias with a sensitivity of 100% and
      specificity of 97.6% (true negatives, n = 1,454; true positives, n = 499; false
      positives, n = 35; false negatives, n = 0). The false positives were all caused
      by T-wave oversensing during ventricular pacing. There were no complications or
      adverse events. The mean response time was 14.4 s for those episodes needing a
      full charge of the capacitor. CONCLUSIONS: This new AECD is safe and effective in
      detecting, monitoring, and treating spontaneous arrhythmias. This fully automatic
      device shortens the response time to treatment, and it is likely that it will
      significantly improve the outcome of patients with in-hospital CA.

PMID- 12598076
TI  - Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT
      syndrome.
AB  - OBJECTIVES: This study was designed to test the hypothesis that epinephrine
      infusion may be a provocative test able to unmask nonpenetrant KCNQ1 mutation
      carriers. BACKGROUND: The LQT1 form of congenital long QT syndrome is associated
      with high vulnerability to sympathetic stimulation and appears with incomplete
      penetrance. METHODS: The 12-lead electrocardiographic parameters before and after
      epinephrine infusion were compared among 19 mutation carriers with a baseline
      corrected QT interval (QTc) of > or =460 ms (Group I), 15 mutation carriers with
      a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls
      (Group IV). RESULTS: The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak
      end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger
      in Group I than in the other three groups. Epinephrine (0.1 microg/kg/min)
      increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in
      Groups I and II, but not in Groups III and IV. The sensitivity and specificity of
      QTce measurements to identify mutation carriers were 59% (20/34) and 100%
      (27/27), respectively, before epinephrine, and the sensitivity was substantially
      improved to 91% (31/34) without the expense of specificity (100%, 27/27) after
      epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were
      significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers
      in Groups I and II, and the prolongation of the mean QTce with epinephrine was
      significantly larger in symptomatic patients. CONCLUSIONS: Epinephrine challenge
      is a powerful test to establish electrocardiographic diagnosis in silent LQT1
      mutation carriers, thus allowing implementation of prophylactic measures aimed at
      reducing sudden cardiac death.

PMID- 12598077
TI  - Haploinsufficiency in combination with aging causes SCN5A-linked hereditary
      Lenegre disease.
AB  - OBJECTIVES: The goal of this study was to investigate the genotype-to-phenotype
      relationship between SCN5A gene mutation and progressive cardiac conduction
      defect in order to gain insights into the pathophysiologic mechanisms of the
      disease. BACKGROUND: Progressive cardiac conduction defect is a frequent disease
      commonly attributed to degeneration and fibrosis of the His bundle and its
      branches. In a French family, we have identified a splicing mutation in the SCN5A
      gene leading to hereditary progressive cardiac conduction defect. METHODS: We
      have extended the size of the pedigree and phenotyped and genotyped all family
      members, and also investigated in vitro the functional consequences of the
      mutation. RESULTS: Among 65 potentially affected members, 25 individuals were
      carriers of the IVS.22+2 T-->C SCN5A mutation. In relation to aging, gene
      carriers exhibit various types of conduction defects. P-wave, PR, and QRS
      duration increased progressively with age in gene carriers and in noncarriers.
      Whatever the age, conduction parameters were longer in gene carriers. The
      widening in the QRS complex with aging was more pronounced in gene carriers older
      than 40 years. Functional studies show that the IVS.22+2 T-->C SCN5A mutation
      lead to exon 22 skipping and to a complete loss of function of the affected
      allele, but to a normal trafficking of the mutated gene product. CONCLUSIONS: Our
      findings demonstrate that hereditary Lenegre disease is caused by a
      haploinsufficiency mechanism, which in combination with aging leads to
      progressive alteration in conduction velocity.

PMID- 12598078
TI  - Fibrinolysis of mechanical prosthetic valve thrombosis: a single-center study of
      127 cases.
AB  - OBJECTIVES: This study was designed to analyze the results of fibrinolytic
      treatment (FT) in a large single-center group of patients with prosthetic heart
      valve thrombosis (PHVT). BACKGROUND: Fibrinolytic treatment of PHVT represents an
      alternative to surgery, but is still controversial because of the risk of
      embolism. METHODS: A total of 110 consecutive patients presenting with 127
      instances of PHVT received FT between 1978 and 2001. The diagnosis of PHVT was
      established mainly by fluoroscopy and/or echocardiography. The first fibrinolytic
      agent used was streptokinase (SK) in 49 cases, urokinase (UK) in 41 cases, and
      recombinant tissue-type plasminogen activator (rtPA) in 37 cases. A second FT was
      consecutively infused in 38 patients (30%) and a third FT in 11 others. The
      efficacy of FT was assessed from hemodynamic parameters derived from echographic
      examinations as well as on clinical grounds. RESULTS: Complete resolution of
      hemodynamic abnormalities was seen in 90/127 patients, partial resolution in
      22/127 patients, and no change in 15/127 patients after one or more consecutive
      fibrinolytic regimens. When SK or rtPA were used as the first fibrinolytic agent,
      they appeared significantly superior to UK in terms of valve reopening. Fifteen
      patients died. Severe hemorrhagic complications were observed in six patients.
      Nineteen documented embolic events occurred during FT. Finally, PHVT recurred in
      24 patients, 17 of whom were retreated with lytic agents. CONCLUSIONS: These
      results indicate that FT is effective in most cases of PHVT, regardless of
      prosthesis or site involved. However, embolism, hemorrhage, and death were not
      uncommon after lytic therapy of left-sided PHVT, limiting its application to
      patients at high risk with alternative treatment.

PMID- 12598079
TI  - The thrombosed prosthetic valve: current recommendations based on evidence from
      the literature.

PMID- 12598080
TI  - Vascular function and carotid intimal-medial thickness in children with insulin
      dependent diabetes mellitus.
AB  - OBJECTIVES: The objective of this study was to evaluate endothelium-dependent
      vasodilation and carotid intimal-medial thickness (IMT) in children with insulin
      dependent diabetes mellitus. BACKGROUND: Diabetes mellitus is an established risk
      factor for atherosclerosis. Vascular complications of diabetes are not clinically
      evident in diabetic children. However, preclinical atherosclerosis is more common
      in young subjects exposed to cardiovascular risk factors. Endothelial function
      and carotid IMT, known to be abnormal in preclinical atherosclerosis, have not
      been studied concurrently in a pediatric population exposed to a risk factor for
      atherosclerosis. METHODS: We studied 31 diabetic teenagers (age 15.0 +/- 2.4
      years; duration of diabetes 6.8 +/- 3.9 years) and 35 age-matched healthy
      children (age 15.7 +/- 2.7 years). Using high-resolution vascular ultrasound, we
      compared carotid IMT and brachial artery responses to reactive hyperemia
      (endothelium-dependent vasodilation) and to sublingual nitroglycerin (endothelium
      independent vasodilation). RESULTS: There was no difference in baseline brachial
      artery diameter between the two groups. Endothelium-dependent vasodilation was
      significantly lower in diabetic children compared with healthy children (4.2 +/-
      3.8% vs. 8.2 +/- 4.2%, p < 0.001). There was no difference in endothelium
      independent vasodilation (17 +/- 6% vs. 18 +/- 6%, p = NS) or mean carotid IMT
      between the groups (0.33 +/- 0.05 vs. 0.32 +/- 0.08 mm, p = NS). Endothelium
      dependent brachial vasodilation correlated with blood glucose levels (r = 0.58, p
      = 0.001) and was weakly and inversely related to the duration of diabetes (r = 
      0.4, p = 0.02), total cholesterol, and low-density lipoprotein cholesterol
      levels. CONCLUSIONS: Endothelial function is impaired in children with diabetes
      mellitus within the first decade of its onset and precedes an increase in carotid
      IMT. The relative timing of these events is important in the evaluation of
      strategies to prevent progression of atherosclerosis and other vascular
      complications in this patient population.

PMID- 12598081
TI  - Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in
      hypertension due to endogenous angiotensin II.
AB  - OBJECTIVES: We investigated if endothelin (ET)-1 and the renin-angiotensin
      aldosterone system play a role in cardiac fibrosis. BACKGROUND: Angiotensin II
      (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are
      incompletely understood. METHODS: Four-week-old transgenic (mRen2)27 rat (TGRen2)
      received for four weeks a placebo, the mixed ET(A)/ET(B) endothelin receptor
      antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist
      irbesartan, the ET(A) endothelin receptor antagonist BMS-182874, and a combined
      treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius
      red-stained serial sections of the left ventricle (LV) with a photomicroscope
      equipped with specific software and assessed the gene expression of procollagen
      alpha1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1
      (TGFbeta1), endothelin converting enzyme, and ET(B) receptor. RESULTS: In the
      placebo group, hypertension was associated with LV hypertrophy and cardiac
      fibrosis (LV weight: 4.0 +/- 0.3 mg/g body weight; collagen density: 2.21 +/-
      0.16%), which were all prevented with irbesartan (2.3 +/- 0.1, 1.30 +/- 0.13, p <
      0.001), but not with BMS-182874 (4.0 +/- 0.2, 2.41 +/- 0.22). Bosentan also
      prevented fibrosis (1.39 +/- 0.18) but not hypertension and LV hypertrophy (3.38
      +/- 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy
      (2.9 +/- 0.1) but not fibrosis (2.52 +/- 0.16). Collagen density correlated (r =
      0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy,
      the gene expression of ANP and ET(B) but not that of TGFbeta1 and procollagen
      alpha1(I) was increased. CONCLUSIONS: In Ang II-dependent hypertension, cardiac
      fibrosis was associated with LV hypertrophy and was hindered by both mixed
      ET(A)/ET(B) blockade and AT-1 blockade. Only the latter treatment prevented both
      hypertension and LV hypertrophy. Thus, there is a dissociation between the
      mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1,
      respectively.

PMID- 12598082
TI  - Phasic coronary blood flow velocity pattern and flow reserve in the atrium:
      regulation of left atrial myocardial perfusion.
AB  - OBJECTIVES: The purpose of this study was to assess rest and stress atrial
      coronary blood flow (CBF) velocity and flow reserve. BACKGROUND: Because of the
      limitations of the methods used until now for assessing myocardial perfusion (MP)
      in the small mass of atrial tissue, data are lacking for human atrial MP.
      METHODS: Seventeen patients with suitable coronary anatomy underwent CBF velocity
      measurements with the use of a Doppler guide wire in the proximal left circumflex
      coronary artery (LCx) and left atrial circumflex branch (LACB), at baseline and
      after adenosine administration. All measurements were performed at resting heart
      rate and at 100 and 120 beats/min. RESULTS: Coronary blood flow velocity in the
      LACB showed a predominant systolic pattern in contrast to the diastolic pattern
      of the LCx. There was a disproportionate increase in baseline time-averaged peak
      coronary flow velocity (cm/s) between the LACB and LCx during the two levels of
      pacing-induced stress (16.8 +/- 5.5 vs. 16.2 +/- 5.1 at rest; 22.9 +/- 7.9 vs.
      18.4 +/- 5.2 at 100 beats/min; and 27.1 +/- 8.0 vs. 20.4 +/- 5.1 at 120
      beats/min; significant interaction, p < 0.001), but there were no significant
      differences in coronary flow reserve (CFR). CONCLUSIONS: Coronary blood flow in
      the left atrium is out of phase with that in the ventricular myocardium, showing
      a predominant systolic pattern. Although atrial and ventricular CFR show no
      significant differences at rest and with two levels of stress, the
      disproportionate increase in atrial blood flow velocity during stress indicates a
      peculiarity of atrial perfusion regulation.

PMID- 12598083
TI  - Connexin43 as a determinant of myocardial infarct size following coronary
      occlusion in mice.
AB  - OBJECTIVES: The purpose of this study was to define the role of cell-cell
      coupling as an independent determinant of infarct size following coronary
      occlusion. BACKGROUND: Electrical uncoupling induced by acute ischemia enhances
      arrhythmogenesis, but it may also protect the heart by limiting intercellular
      spread of chemical mediators of injury. METHODS: The left anterior descending
      coronary artery was ligated in wild-type (Cx43(+/+)) mice and Cx43-deficient
      (Cx43(+/-)) mice that are heterozygous for a null allele in the gene encoding the
      major gap junction channel protein, connexin43 (Cx43). Ventricular remodeling and
      infarct size were compared in both groups. RESULTS: Echocardiography at 1 and 10
      weeks after infarction showed that left ventricular end-diastolic volume and mass
      increased and ejection fraction decreased in proportion to infarct size in both
      Cx43(+/-) and Cx43(+/+) hearts. However, infarct size measured histologically in
      healing infarcts (eight days after infarction) was 29% smaller in Cx43(+/-)
      hearts (17 +/- 14% of total left ventricular area, n = 30) than in Cx43(+/+)
      hearts (24 +/- 15%, n = 23; p = 0.037). Fully healed infarcts were smaller than
      healing infarcts, owing to resorption of necrotic tissue and maturation of scar,
      but infarct size at 10 weeks after coronary occlusion was still smaller (by 50%)
      in Cx43(+/-) hearts (6 +/- 5%, n = 9) compared with Cx43(+/+) hearts (12 +/- 7%,
      n = 17; p = 0.037). CONCLUSIONS: Cx43-deficient mice develop smaller infarcts
      than wild-type mice following coronary ligation. New therapies designed to
      decrease the risk of arrhythmias by enhancing intercellular communication could
      lead to larger infarcts caused by persistent coronary occlusion.

PMID- 12598084
TI  - ACC/AHA clinical competence statement on echocardiography: a report of the
      American College of Cardiology/American Heart Association/American College of
      Physicians-American Society of Internal Medicine Task Force on Clinical
      Competence.

PMID- 12598085
TI  - Abnormal cellularity in asymptomatic relatives of patients with idiopathic
      dilated cardiomyopathy.

PMID- 12598087
TI  - Efficacy of biventricular pacing in congestive heart failure.

PMID- 12598090
TI  - Observation and characterization of colloids derived from leached cement
      hydrates.
AB  - The possibility of colloid generation from cement hydrates in a cementitious
      repository environment has been investigated through leaching experiments.
      Pulverized samples of High Flyash and Silica fume-content Cement (HFSC) and 1:9
      ordinary portland cement/blast furnace slag (1:9 OPC/BFS) hydrate were leached in
      low-salinity groundwater at three solid-to-liquid (S/L) mass ratios (1:5, 1:50
      and 1:100), and two temperatures (20 and 60 degrees C) for durations of nearly 2
      and 8 months. Detailed characterization of colloid populations has been
      undertaken by TEM coupled with X-ray analysis. In addition, the surface charge
      and stability behavior of colloids have been investigated. The colloid
      concentrations in HFSC hydrate leachates generated at 20 and 60 degrees C show
      similar trends with S/L ratio. The colloid concentrations of leachates with the
      lower S/L ratio (1:50 and 1:100) are in the range of 10(11)-10(12) particles per
      liter. The majority of these particles are composed predominantly of Si, Ca, and
      Al; the mean particle size is less than 100 nm. The lowest colloid concentrations
      are found in the leachates with the highest S/L ratios, and the colloid
      populations tend to be dominated by larger particles. HFSC-derived colloid
      stability is due to a high negative zeta potential at alkaline pH values,
      combined with a calcium concentration that is below the critical coagulation
      concentration (CCC) for the colloids. A preliminary interpretation of HFSC
      derived colloid stability based on classical DLVO theory provides a semi
      quantitative explanation of the dependence of colloid populations on the S/L
      ratio in the leaching experiments.

PMID- 12598091
TI  - Generation and stability of bentonite colloids at the bentonite/granite interface
      of a deep geological radioactive waste repository.
AB  - The possible mechanisms of colloid generation at the near field/far field
      interface of a radioactive repository have been investigated by means of novel
      column experiments simulating the granite/bentonite boundary, both in dynamic and
      in quasi-static water flow conditions. It has been shown that solid particles and
      colloids can be detached from the bulk and mobilised by the water flow. The
      higher the flow rate, the higher the concentration of particles found in the
      water, according to an erosion process. However, the gel formation and the
      intrinsic tactoid structure of the clay play an important role in the submicron
      particle generation even in the compacted clay and in a confined system. In fact,
      once a bentonite gel is formed, in the regions where the clay is contacted with
      water, clay colloids can be formed even in quasi-static flow conditions. The
      potential relevance of these colloids in radionuclide transport has been studied
      by evaluating their stability in different chemical environments. The coagulation
      kinetics of natural bentonite colloids was experimentally studied as a function
      of the ionic strength and pH, by means of time-resolved light scattering
      techniques. It has been shown that these colloids are very stable in low saline
      (approximately 1 x 10(-3) M) and alkaline (pH > or = 8) waters.

PMID- 12598092
TI  - Eu3+ uptake by calcite: preliminary results from coprecipitation experiments and
      observations with surface-sensitive techniques.
AB  - A lack of information in databases for contamination risk assessment about the
      transport behaviour of the trivalent f-orbital elements in groundwater systems
      where calcite is at equilibrium motivated this study of Eu(3+) uptake. The free
      drift technique was used to examine the effects of Eu(3+) concentration, presence
      of Na(+) or K(+) and temperature, as well as calcite nucleation and precipitation
      kinetics, on the partitioning of calcite. Changes in surface composition and
      morphology resulting from exposure of single crystals of Iceland spar to Eu(3+)
      bearing solutions were observed with X-ray photoelectron spectroscopy (XPS) and
      atomic force microscopy (AFM). First results confirm that calcite has high
      affinity for Eu(3+). Rates of nucleation and precipitation strongly affect the
      extent of uptake but the presence of Na(+) and K(+) has no effect, suggesting
      formation of solid solution as CaCO(3)-EuOHCO(3). Surface-sensitive techniques
      prove that Eu(3+) is adsorbed to calcite even when the surface is dissolving and
      adsorption is not accompanied by precipitation of a separate Eu(3+)-solid phase.
      Adsorbed Eu modifies calcite's dissolution behaviour, roughening terraces and
      rounding step edges, and producing surface morphology where some surface sites
      appear blocked. Results imply that Eu(3+) concentrations in natural calcites are
      limited by Eu(3+) availability rather than by a lack of ability to fit into
      calcite's atomic structure. This behaviour can probably be expected for other
      trivalent rare Earth elements (REE), actinides and fission products whose
      behaviour is similar to that of Eu(3+). These elements are likely to be
      incorporated within the calcite bulk in systems where it is precipitating and the
      demonstrated strong partitioning ensures some uptake even where calcite is at or
      under saturation.

PMID- 12598093
TI  - Diffusion of tritiated water and 22Na+ through non-degraded hardened cement
      pastes.
AB  - Diffusion experiments through hardened cement pastes (HCP) using tritiated water
      (HTO) and 22Na(+), considered to be conservative tracers, have been carried out
      in triplicates in a glove box under a controlled nitrogen atmosphere. Each
      experiment consisted of a through-diffusion test followed by an out-diffusion
      test. The experimental data were inversely modelled applying an automated
      Marquardt-Levenberg procedure. The analysis of the through-diffusion data allowed
      the extraction of values for the effective diffusion coefficients, D(e), and the
      rock capacity factor, alpha. Good agreement between measured and calculated
      tracer breakthrough curves was achieved using both a simple diffusion model
      without sorption and a diffusion/linear sorption model. The best-fit K(d)-values
      were found to be consistent with R(d)-values measured in previous batch-sorption
      experiments. The best-fit values from the through-diffusion tests were then used
      to predict the results of subsequent out-diffusion experiments. Good agreement
      between experimental data and predictions was achieved only for the case of
      linear sorption. Isotopic exchange can only partially account for both the amount
      of tracer taken up in the batch-sorption tests and the measured retardation in
      the diffusion experiments and, hence, additional mechanisms have to be invoked to
      explain the data.

PMID- 12598094
TI  - Simultaneous estimation of effective and apparent diffusion coefficients in
      compacted bentonite.
AB  - Effective diffusion coefficients (D(e)) are usually measured by means of "through
      diffusion" experiments in which steady state is reached, and the "time-lag"
      methods are used to estimate the apparent diffusion coefficient (D(a)). For
      sorbing radionuclides (as caesium), the time needed to reach steady-state
      conditions is very large, and the precision in D(a) determinations is not
      satisfactory. In this paper, a method that allows determining simultaneously
      effective and apparent diffusion coefficients in compacted bentonite without
      reaching steady-state conditions is described. Basically, this method consists of
      an "in-diffusion" experiment in which the concentration profile in the bentonite
      sample is used to estimate D(a), and the temporal evolution of the solute
      concentration in the reservoir is used to estimate D(e). This method has several
      advantages over the typical "through-diffusion" experiments, in particular: (a)
      experiment duration is significantly shorter, (b) D(a) values are measured with
      greater precision and (c) it is not necessary to maintain a constant solute
      concentration in the reservoir. This new method has been used to estimate the
      effective and apparent diffusion coefficients for caesium in FEBEX bentonite and
      in order to validate it, the results have been compared with results previously
      obtained with standard methods. Experimental results have been satisfactorily
      modelled using a simple model of diffusion in porewater and the measured value of
      D(e)(Cs) is very similar to D(e)(HTO) in the same bentonite. There is no evidence
      of "surface diffusion" in FEBEX bentonite for caesium.

PMID- 12598095
TI  - Diffusion of HTO, 36Cl- and 125I- in Opalinus Clay samples from Mont Terri.
      Effect of confining pressure.
AB  - Diffusion coefficients (T=23 +/- 2 degrees C) and accessible porosities for HTO,
      36Cl(-) and 125I(-) were measured on Opalinus Clay (OPA) samples from the Mont
      Terri Underground Rock Laboratory (URL) using the through-diffusion technique.
      The direction of transport (diffusion) was perpendicular to bedding. Special
      cells that allowed the application of confining pressure were designed and
      constructed. The pressures ranged from 1 to 5 MPa, the latter value simulating
      the overburden at the Mont Terri URL (about 200 m). The test solution used in the
      experiments was a synthetic version of the Opalinus Clay pore water, which has
      Na(+) and Cl(-) as the main components (I=0.42 M). The measured values of the
      effective diffusion coefficients (D(e)) and rock capacity factors (alpha) are:
      D(e)=1.2-1.5 x 10(-11) m(2) s(-1) and alpha=0.09-0.11 for HTO, D(e)=4.0-5.5 x 10(
      12) m(2) s(-1) and alpha=0.05 for 36Cl(-) and D(e)=3.2-4.6 x 10(-12) m(2) s(-1)
      and alpha=0.07-0.10 for 125I(-). For non-sorbing tracers (HTO, 36Cl) the rock
      capacity factor alpha is equal to the diffusion-accessible porosity epsilon. The
      experimental results showed that pressure only had a small effect on the value of
      the diffusion coefficients. Increasing the pressure from 1 to 5 MPa resulted in a
      decrease of the diffusion coefficient of approximately 17% for HTO, approximately
      28% for 36Cl(-) and approximately 30% for 125I(-). Moreover, the diffusion
      coefficients for 36Cl(-) and 125I(-) are smaller than for HTO, which is
      consistent with an effect arising from anion exclusion. The diffusion
      coefficients of HTO and 125I(-) measured in this study are in good agreement with
      recent measurements at three other laboratories performed within the framework of
      a laboratory comparison exercise. The values of the diffusion-accessible
      porosities show a larger degree of scatter.

PMID- 12598096
TI  - Effect of silica sand on activation energy for diffusion of sodium ions in
      montmorillonite and silica sand mixture.
AB  - The effect of silica sand on the diffusion of sodium ions in mixtures of
      montmorillonite and silica sand was studied by measuring the apparent diffusion
      coefficients, activation energies for diffusion, and the basal spacing of the
      mixed samples. These diffusion experiments suggest that the apparent diffusion
      coefficients of sodium ions in the mixed samples were almost the same as those of
      pure montmorillonite samples having the same partial dry densities of
      montmorillonite. The activation energy dependence for diffusion of sodium ions on
      the partial dry density was different between the mixed samples and the pure
      montmorillonite samples. The activation energy increased by adding silica sand at
      the partial dry density of 1.0 Mg m(-3), and decreased by adding silica sand at
      the partial dry densities higher than 1.2 Mg m(-3). A change in the XRD profile
      was observed after adding silica sand at the partial dry density of 1.6 Mg m(-3).
      Here, a three-water-layer hydrate state of montmorillonite was found in the mixed
      sample whereas only a two-water-layer hydrate state was observed in the pure
      montmorillonite sample. These experimental results suggest that silica sand
      changed the montmorillonite microstructure in the mixed samples, which then
      altered the sodium-ion diffusion process.

PMID- 12598097
TI  - Study of the contaminant transport into granite microfractures using nuclear ion
      beam techniques.
AB  - Hydrated bentonite is a very plastic material and it is expected to enter in the
      rock microfractures at the granite/bentonite boundary of a deep geological high
      level waste repository. This process is enhanced by the high swelling pressure of
      the clay. Since bentonite has a very good sorption capability for many
      radionuclides, the displacement of the clay might lead to a "clay-mediated"
      contaminant transport into the rock. The aim of this work is to study the
      contaminant transport into granite microfractures using nuclear ion beam
      techniques, and to determine to what extent the clay can favour it. To do so,
      bentonite previously doped with uranium, cesium and europium was put in contact
      with the surface of granite sheets. Granite sheets contacted with non-doped
      bentonite and with radionuclide solutions were also prepared as references. This
      allowed analysing the differences in the diffusion behaviour of the three
      systems: clay, radionuclides and clay plus radionuclides. A combination of
      Rutherford backscattering spectrometry (RBS) and other nuclear ion-beam
      techniques such as particle-induced X-ray emission (PIXE) and microPIXE was used
      to study the depth and lateral distribution of clay and contaminants inside
      granite. It was also tried to evaluate not only the diffusion depth and diffusion
      coefficients but also the different areas of the granite where the diffusants
      have a preferential access.

PMID- 12598098
TI  - Formation factor logging by electrical methods. Comparison of formation factor
      logs obtained in situ and in the laboratory.
AB  - In this paper, a new in situ method for obtaining the formation factor, which is
      essential for the matrix diffusion, is described and tested in intrusive igneous
      rock. The method is based on electrical resistivity measurements in rock where
      the pore water and rock resistivities are essential parameters. The method is
      based on electromigration instead of diffusion as in traditional diffusion
      experiments. In previous works, quantitative formation factors of rock have been
      obtained by electrical methods in the laboratory. Here, a similar approach is
      used in situ. An in situ logging campaign was performed by SKB during 2000 in the
      1700-m-deep borehole KLX02 in Laxemar, Sweden. The rock resistivity was measured
      with the slimhole Dual Laterolog from Antares. The groundwater resistivity was
      measured with the Difference Flow Meter from Posiva. A formation factor log was
      obtained with the maximum vertical resolution of 10 cm. In order to validate the
      log, 100 rock samples were taken from the bore core, and a formation factor log
      was obtained by using electrical methods in the laboratory. Both direct current
      (DC) and alternating current (AC) were used. The measurements on the core
      confirmed that the in situ log was quantitative, but with a possible systematic
      error. The in situ formation factors were on average about 1/3 to 1/5 of the
      laboratory formation factors, depending on depth.

PMID- 12598099
TI  - Modelling of silica diffusion experiments with 32Si in Boom Clay.
AB  - A mathematical model describing the dissolution of nuclear glass directly
      disposed in clay combines a first-order dissolution rate law with the diffusion
      of dissolved silica in clay. According to this model, the main parameters
      describing the long-term dissolution of the glass are etaR, the product of the
      diffusion accessible porosity eta and the retardation factor R, and the apparent
      diffusion coefficient D(app) of dissolved silica in clay. For determining the
      migration parameters needed for long-term predictions, four Through-Diffusion (T
      D) experiments and one percolation test have been performed on undisturbed clay
      cores. In the Through-Diffusion experiments, the concentration decrease after
      injection of 32Si (radioactive labelled silica) was measured in the inlet
      compartment. At the end of the T-D experiments, the clay cores were cut in thin
      slices and the activity of labelled silica in each slice was determined. The
      measured activity profiles for these four clay cores are well reproducible. Since
      no labelled silica could be detected in the outlet compartments, the Through
      Diffusion experiments are fitted by two In-Diffusion models: one model assuming
      linear and reversible sorption equilibrium and a second model taking into account
      sorption kinetics. Although the kinetic model provides better fits, due to the
      sufficiently long duration of the experiments, both models give approximately
      similar values for the fit parameters. The single percolation test leads to an
      apparent diffusion coefficient value about two to three times lower than those of
      the Through-Diffusion tests. Therefore, dissolved silica appears to be strongly
      retarded in Boom Clay. A retardation factor R between 100 and 300 was determined.
      The corresponding in situ distribution coefficient K(d) is in the range 25-75
      cm(3) g(-1). The apparent diffusion coefficient of dissolved silica in Boom Clay
      is estimated between 2 x 10(-13) and 7 x 10(-13) m(2) s(-1). The pore diffusion
      coefficient is in the range from 6 x 10(-11) to 1 x 10(-10) m(2) s(-1).

PMID- 12598100
TI  - Influence of the mode of matrix porosity determination on matrix diffusion
      calculations.
AB  - The theoretical basis for matrix diffusion in fractured rocks and the methodology
      for the determination of diffusion coefficients in the laboratory are well
      established. One significant problem, however, remains in that it is difficult to
      quantify the degree of sample disturbance affecting the geometrical, geophysical
      and hydraulic properties of the rock matrix. A new technique, with in situ rock
      impregnation with resin, for examining the diffusion-accessible rock matrix has
      been developed and successfully adopted to the rock matrix behind a water
      conducting fracture in host crystalline rocks at Nagra's Grimsel Test Site in
      Switzerland and JNC's Kamaishi In Situ Test Site in Japan. In line with the
      results of a large number of natural analogue and laboratory studies, the
      existence of an in situ interconnected pore network was substantiated. Matrix
      porosities determined on the laboratory samples from both the sites are 1.5-3
      times higher than in situ values, irrespective of the technique applied. On the
      Grimsel granodiorite matrix, matrix porosity existing in situ and artefacts of
      stress release and physical disturbance, induced by sampling and sample
      preparation, were clearly distinguished, allowing in situ porosity to be
      quantified. Laboratory work with conventional techniques tends to overestimate
      the porosity of the rock matrix, hence leading to an overestimation of in situ
      matrix diffusion. The implications of these differences to a repository
      performance assessment are assessed with a couple of examples from existing
      assessments, and recommendations for future approaches to the examination of in
      situ matrix porosity are made.

PMID- 12598101
TI  - Diffusivity measurement of heavy ions in Wyoming montmorillonite gels by X-ray
      computed tomography.
AB  - Medical X-ray computed tomography (CT) was applied to the measurement of the
      diffusion coefficients of heavy ions in an artificial barrier material for the
      disposal of nuclear wastes. Cs(+), Sr(2+), I(-), and Br(-) are the heavy ions
      measured and the barrier used is the water-rich gel of Wyoming montmorillonite
      (86.5-100 wt.% H(2)O). X-ray CT yields an inevitable artifact (beam-hardening) in
      the obtained images. Before the diffusion experiments, the polychromatic primary
      X-ray spectrum of the CT scanner was measured by a CdZnTe detector, and the
      effects of the artifact were examined for an aqueous CsCl solution sample. The
      results show that the beam-hardening artifact derived from the polychromatic
      photon energy distribution can be suppressed by applying a special image
      reconstruction method assuming the chemical composition of samples. The transient
      one-dimensional diffusion of heavy ions in a plastic container filled with the
      gel was imaged nondestructively by the X-ray CT scanner with an in-plane
      resolution of 0.31 mm and slice thickness of 2 mm. The results show that
      diffusivities decrease with increasing clay weight fraction. The degree of the
      diffusivity decrease was high for cations (Cs(+) and Sr(2+)) and low for anions
      (I(-) and Br(-)). The quantitative decomposition of the contribution of the
      geometrical tortuosity and of the sorption to the diffusivity was performed by
      subtracting the diffusivity of nonsorbing I(-) from the measured diffusivities.
      The results show that the contribution of the sorption is large for Cs(+), Sr(2+)
      and small for Br(-). Because X-ray CT allows nondestructive and quick
      measurements of diffusivities, the technique would be useful particularly for
      measuring the diffusive migration of harmful radioactive elements.

PMID- 12598102
TI  - Solute transport in crystalline rocks at Aspo--I: geological basis and model
      calibration.
AB  - Water-conducting faults and fractures were studied in the granite-hosted Aspo
      Hard Rock Laboratory (SE Sweden). On a scale of decametres and larger, steeply
      dipping faults dominate and contain a variety of different fault rocks
      (mylonites, cataclasites, fault gouges). On a smaller scale, somewhat less
      regular fracture patterns were found. Conceptual models of the fault and fracture
      geometries and of the properties of rock types adjacent to fractures were derived
      and used as input for the modelling of in situ dipole tracer tests that were
      conducted in the framework of the Tracer Retention Understanding Experiment (TRUE
      1) on a scale of metres. After the identification of all relevant transport and
      retardation processes, blind predictions of the breakthroughs of conservative to
      moderately sorbing tracers were calculated and then compared with the
      experimental data. This paper provides the geological basis and model
      calibration, while the predictive and inverse modelling work is the topic of the
      companion paper [J. Contam. Hydrol. 61 (2003) 175]. The TRUE-1 experimental
      volume is highly fractured and contains the same types of fault rocks and
      alterations as on the decametric scale. The experimental flow field was modelled
      on the basis of a 2D-streamtube formalism with an underlying homogeneous and
      isotropic transmissivity field. Tracer transport was modelled using the dual
      porosity medium approach, which is linked to the flow model by the flow porosity.
      Given the substantial pumping rates in the extraction borehole, the transport
      domain has a maximum width of a few centimetres only. It is concluded that both
      the uncertainty with regard to the length of individual fractures and the
      detailed geometry of the network along the flowpath between injection and
      extraction boreholes are not critical because flow is largely one-dimensional,
      whether through a single fracture or a network. Process identification and model
      calibration were based on a single uranine breakthrough (test PDT3), which
      clearly showed that matrix diffusion had to be included in the model even over
      the short experimental time scales, evidenced by a characteristic shape of the
      trailing edge of the breakthrough curve. Using the geological information and
      therefore considering limited matrix diffusion into a thin fault gouge horizon
      resulted in a good fit to the experiment. On the other hand, fresh granite was
      found not to interact noticeably with the tracers over the time scales of the
      experiments. While fracture-filling gouge materials are very efficient in
      retarding tracers over short periods of time (hours-days), their volume is very
      small and, with time progressing, retardation will be dominated by altered wall
      rock and, finally, by fresh granite. In such rocks, both porosity (and therefore
      the effective diffusion coefficient) and sorption K(d)s are more than one order
      of magnitude smaller compared to fault gouge, thus indicating that long-term
      retardation is expected to occur but to be less pronounced.

PMID- 12598103
TI  - Solute transport in crystalline rocks at Aspo--II: blind predictions, inverse
      modelling and lessons learnt from test STT1.
AB  - Based on the results from detailed structural and petrological characterisation
      and on up-scaled laboratory values for sorption and diffusion, blind predictions
      were made for the STT1 dipole tracer test performed in the Swedish Aspo Hard Rock
      Laboratory. The tracers used were nonsorbing, such as uranine and tritiated
      water, weakly sorbing 22Na(+), 85Sr(2+), 47Ca(2+)and more strongly sorbing
      86Rb(+), 133Ba(2+), 137Cs(+). Our model consists of two parts: (1) a flow part
      based on a 2D-streamtube formalism accounting for the natural background flow
      field and with an underlying homogeneous and isotropic transmissivity field and
      (2) a transport part in terms of the dual porosity medium approach which is
      linked to the flow part by the flow porosity. The calibration of the model was
      done using the data from one single uranine breakthrough (PDT3). The study
      clearly showed that matrix diffusion into a highly porous material, fault gouge,
      had to be included in our model evidenced by the characteristic shape of the
      breakthrough curve and in line with geological observations. After the disclosure
      of the measurements, it turned out that, in spite of the simplicity of our model,
      the prediction for the nonsorbing and weakly sorbing tracers was fairly good. The
      blind prediction for the more strongly sorbing tracers was in general less
      accurate. The reason for the good predictions is deemed to be the result of the
      choice of a model structure strongly based on geological observation. The
      breakthrough curves were inversely modelled to determine in situ values for the
      transport parameters and to draw consequences on the model structure applied. For
      good fits, only one additional fracture family in contact with cataclasite had to
      be taken into account, but no new transport mechanisms had to be invoked. The in
      situ values for the effective diffusion coefficient for fault gouge are a factor
      of 2-15 larger than the laboratory data. For cataclasite, both data sets have
      values comparable to laboratory data. The extracted K(d) values for the weakly
      sorbing tracers are larger than Swedish laboratory data by a factor of 25-60, but
      agree within a factor of 3-5 for the more strongly sorbing nuclides. The reason
      for the inconsistency concerning K(d)s is the use of fresh granite in the
      laboratory studies, whereas tracers in the field experiments interact only with
      fracture fault gouge and to a lesser extent with cataclasite both being
      mineralogically very different (e.g. clay-bearing) from the intact wall rock.

PMID- 12598104
TI  - In situ diffusion experiment in granite: phase I.
AB  - A program of in situ experiments, supported by laboratory studies, was initiated
      to study diffusion in sparsely fractured rock (SFR), with a goal of developing an
      understanding of diffusion processes within intact crystalline rock. Phase I of
      the in situ diffusion experiment was started in 1996, with the purpose of
      developing a methodology for estimating diffusion parameter values. Four in situ
      diffusion experiments, using a conservative iodide tracer, were performed in
      highly stressed SFR at a depth of 450 m in the Underground Research Laboratory
      (URL). The experiments, performed over a 2 year period, yielded rock permeability
      estimates of 2 x 10(-21) m(2) and effective diffusion coefficients varying from
      2.1 x 10(-14) to 1.9 x 10(-13) m(2)/s, which were estimated using the MOTIF code.
      The in situ diffusion profiles reveal a characteristic "dog leg" pattern, with
      iodide concentrations decreasing rapidly within a centimeter of the open borehole
      wall. It is hypothesized that this is an artifact of local stress redistribution
      and creation of a zone of increased constrictivity close to the borehole wall. A
      comparison of estimated in situ and laboratory diffusivities and permeabilities
      provides evidence that the physical properties of rock samples removed from high
      stress regimes change. As a result of the lessons learnt during Phase I, a Phase
      II in situ program has been initiated to improve our general understanding of
      diffusion in SFR.

PMID- 12598105
TI  - Characterisation of HTO diffusion properties by an in situ tracer experiment in
      Opalinus clay at Mont Terri.
AB  - A long-term single borehole diffusion experiment using tritiated water as tracer
      was carried out in Opalinus clay, an argillaceous rock formation that is
      accessible at the Mont Terri Underground Research Laboratory, situated in the
      Swiss Jura. The tracer was diluted in reconstituted formation water and
      introduced into a packed-off section of a borehole located in saturated rock.
      Pressure in this interval was maintained equal to the pore pressure of the
      surrounding rock in order to prevent any hydraulic gradient around the borehole
      and to avoid advective transport processes. The evolution of the tracer
      concentration in the injection system was monitored over time. After 1 year of
      diffusion, the claystone surrounding the interval was retrieved by overcoring the
      whole borehole and packer system, and by an adjacent oblique borehole. Compressed
      air was used as drilling fluid to reduce rock disturbances. The recovered
      overcore was sampled along profiles perpendicular to the borehole wall with a
      view to determining the tracer-concentration profiles in the rock. To avoid
      further evaporation of tritiated water, subsamples were immediately transferred
      into polyethylene bottles and disaggregated by adding a known amount of tracer
      free water. Fifteen profiles were determined and showed a decreasing tracer
      concentration with distance into the rock. The pore-water contents were constant
      along those profiles, confirming that only very little water was lost during
      overcoring operations. The evolution of tritium-tracer concentration in the
      injection system over time and in situ profiles were interpreted with a 3-D
      numerical simulation of the experiment. That allowed for the identification of
      the transport parameters (orthotropic diffusion tensor and porosity) by
      minimising the relative quadratic error between the experimental and simulated
      data. The fitting is good and the results are consistent with data obtained on
      drill-core samples. The result of tritiated water is discussed regarding (1) the
      potential effect of mechanical and/or chemical disturbances around the injection
      borehole and (2) the specific behaviour of tritiated water.

PMID- 12598106
TI  - Swedish-German actinide migration experiment at ASPO hard rock laboratory.
AB  - Within the scope of a bilateral cooperation between Svensk Karnbranslehantering
      (SKB) and Forschungszentrum Karlsruhe, Institut fur Nukleare Entsorgung (FZK
      INE), an actinide migration experiment is currently being performed at the Aspo
      Hard Rock Laboratory (HRL) in Sweden. This paper covers laboratory and in situ
      investigations on actinide migration in single-fractured granite core samples.
      For the in situ experiment, the CHEMLAB 2 probe developed by SKB was used. The
      experimental setup as well as the breakthrough of inert tracers and of the
      actinides Am, Np and Pu are presented. The breakthrough curves of inert tracers
      were analyzed to determine hydraulic properties of the fractured samples.
      Postmortem analyses of the solid samples were performed to characterize the flow
      path and the sorbed actinides. After cutting the cores, the abraded material was
      analyzed with respect to sorbed actinides. The slices were scanned optically to
      visualize the flow path. Effective volumes and inner surface areas were measured.
      In the experiments, only breakthrough of Np(V) was observed. In each experiment,
      the recovery of Np(V) was < or = 40%. Breakthrough of Am(III) and Pu(IV) as well
      as of Np(IV) was not observed.

PMID- 12598107
TI  - Release of uranium from rock matrix--a record of glacial meltwater intrusions?
AB  - Uranium release observed in a rock matrix around water-carrying fractures was
      studied using U-series disequilibrium (USD) modelling and mass balance
      calculations. Several release scenarios were tested, with specific attention to
      the glacial aspects. The release appears to have occurred in two or three violent
      episodes during the last 300 ky. A release after the last glaciation can be
      excluded on mass flow grounds. Continuous release for more than 300 ky can be
      excluded on radioactive disequilibrium grounds. Repeated inflows of oxic glacial
      meltwater seem to have triggered the release episodes.

PMID- 12598108
TI  - Uranium transport around the reactor zone at Bangombe and Okelobondo (Oklo):
      examples of hydrogeological and geochemical model integration and data
      evaluation.
AB  - The sites at Bangombe and Okelobondo (Oklo) in Gabon provide a unique opportunity
      to study the behaviour of products from natural nuclear reactions in the vicinity
      of reactor zones which were active around two billion years ago. The Commission
      of the European Communities initiated the Oklo Natural Analogue Programme. One of
      the principal aims was to study indications of present time migration of elements
      from the reactor zones under ambient conditions. The hydrogeological and
      hydrochemical data from the Oklo sites were modelled in order to better
      understand the geochemical behaviour of radionuclides in the natural system, by
      using independent models and by comparing the modelling outcome. Two modelling
      approaches were used: M3 code (hydrochemical mixing and mass balance model),
      developed by the Swedish Nuclear Fuel and Waste Management Company (SKB) and
      HYTEC (reactive transport model) developed by Ecole des Mines de Paris. Two
      different reactor zones were studied: Bangombe, a shallow site, the reactor being
      at 11 m depth, and OK84 at Okelobondo, situated at about 450 m depth, more
      comparable with a real repository location. This allowed the validation of
      modelling tools in two different sedimentary environments: one shallow, with a
      more homogeneous layering situated in an area of meteoric alteration, and the
      other offering the opportunity to study radionuclide migration from the reaction
      zone over a distance of 450 m through very heterogeneous sedimentary layers. The
      modeling results indicate that the chemical reactions retarding radionuclide
      transport are very different at the two sites. At Bangombe, the decomposition of
      organic material consumes oxygen and at Okelobondo the oxygen is consumed by
      inorganic reactions resulting, in both cases, in uranium retardation. Both
      modelling approaches (statistic with M3 code and deterministic with HYTEC code)
      could describe this situation. The goal of this exercise is to test codes which
      can help to describe and understand the processes taking place at the sites,
      validate the models with in situ data, and thus build confidence in the tools
      used for future site characterization. Ultimately, this allows identifying and
      selecting processes and parameters that can be used as input into repository
      performance assessment calculations and modelling exercises.

PMID- 12598109
TI  - Geochemical evaluation of different groundwater-host rock systems for radioactive
      waste disposal.
AB  - The geochemical suitability of a deep bedrock repository for radioactive waste
      disposal is determined by the composition of geomatrix and groundwater. Both
      influence radionuclide solubility, chemical buffer capacity and radionuclide
      retention. They also determine the chemical compatibility of waste forms,
      containers and backfill materials. Evaluation of different groundwater-host rock
      systems is performed by modeling the geochemical environments and the resulting
      radionuclide concentrations. In order to demonstrate the evaluation method, model
      calculations are applied to data sets available for various geological formations
      such as granite, clay and rocksalt. The saturation state of the groundwater
      geomatrix system is found to be fundamental for the evaluation process. Hence,
      calculations are performed to determine if groundwater is in equilibrium with
      mineral phases of the geological formation. In addition, corrosion of waste forms
      in different groundwater is examined by means of reaction path modeling. The
      corrosion reactions change the solution compositions and pH, resulting in
      significant changes of radionuclide solubilities. The results demonstrate that
      geochemical modeling of saturation state and compatibility of the host formation
      environment with the radioactive waste proves to be a feasible tool for
      evaluation of various sites considered as deep underground repositories.

PMID- 12598110
TI  - RES3T-Rossendorf expert system for surface and sorption thermodynamics.
AB  - This paper presents a digitized version of a thermodynamic sorption database,
      implemented as a relational database with MS Access. It is mineral-specific and
      can therefore be used for additive models of complex solid phases such as rocks
      or soils. An integrated user interface helps users to access selected mineral and
      sorption data, to extract internally consistent data sets for sorption modeling,
      and to export them in formats suitable for other modeling software. Data records
      comprise mineral properties, specific surface area values, surface binding sites'
      characteristics, sorption ligand information, and surface complexation reactions.
      An extensive bibliography is included, providing links not only to the above
      listed data, but also to background information concerning surface complexation
      model theories, evidence for surface species, and sorption experimental
      techniques.

PMID- 12598111
TI  - Modeling diffusion and adsorption in compacted bentonite: a critical review.
AB  - The current way of describing diffusive transport through compacted clays is a
      simple diffusion model coupled to a linear adsorption coefficient (K(d)). To fit
      the observed results of cation diffusion, this model is usually extended with an
      adjustable "surface diffusion" coefficient. Description of the negative
      adsorption of anions calls for a further adjustment through the use of an
      "effective porosity". The final model thus includes many fitting parameters. This
      is inconvenient where predictive modeling is called for (e.g., for waste
      confinement using compacted clay liners). The diffusion/adsorption models in
      current use have been derived from the common hydrogeological equation of
      advection/dispersion/adsorption. However, certain simplifications were also
      borrowed without questioning their applicability to the case of compacted clays.
      Among these simplifications, the assumption that the volume of the adsorbed phase
      is negligible should be discussed. We propose a modified diffusion/adsorption
      model that accounts for the volume of the adsorbed phase. It suggests that
      diffusion through highly compacted clay takes place through the interlayers
      (i.e., in the adsorbed phase). Quantitative prediction of the diffusive flux will
      necessitate more detailed descriptions of surface reactivity and of the mobility
      of interlayer species.

PMID- 12598112
TI  - Intercomparison of reactive transport models applied to UO2 oxidative dissolution
      and uranium migration.
AB  - Oxidative dissolution of uranium dioxide (UO(2)) and the subsequent migration of
      uranium in a subsurface environment and an underground waste disposal have been
      simulated with reactive transport models. In these systems, hydrogeological and
      chemical processes are closely entangled and their interdependency has been
      analyzed in detail, notably with respect to redox reactions, kinetics of
      mineralogical evolution and hydrodynamic migration of species of interest.
      Different codes, where among CASTEM, CHEMTRAP and HYTEC, have been used as an
      intercomparison and verification exercise. Although the agreement between codes
      is satisfactory, it is shown that the discretization method of the transport
      equation (i.e. finite elements (FE) versus mixed-hybrid FE and finite
      differences) and the sequential coupling scheme may lead to systematic
      discrepancies.

PMID- 12598113
TI  - Sensitivity analysis of radionuclide migration in compacted bentonite: a
      mechanistic model approach.
AB  - Mechanistic model calculations for the migration of Cs, Ra, Am and Pb in
      compacted bentonite have been carried out to evaluate sensitivities with respect
      to different parameter variations. A surface chemical speciation/electric double
      layer model is used to calculate: (i) porewater composition and radionuclide
      speciation in solution and at the bentonite surface, yielding the distribution of
      mobile and sorbed species and (ii) interaction of diffusing species with
      negatively charged pore walls to obtain diffusion parameters. The basic scenario
      considers the interaction of compacted bentonite with a fresh-type groundwater;
      variations include the presence of bentonite impurities and saline groundwater.
      It is shown that these scenarios result in significant variations of porewater
      composition that affect migration via three mechanisms that can partly compensate
      each other: (1) effects on sorption through radionuclide complexation in
      solution, and competition of major cations for surface sites; (2) changes in
      radionuclide solution speciation leading to different diffusing species under
      different conditions; (3) effects on diffusion through changes in the electric
      double layer properties of the clay pores as a function of ionic strength.

PMID- 12598114
TI  - Porewater chemistry in compacted re-saturated MX-80 bentonite.
AB  - Bentonites of various types are being investigated in many countries as backfill
      materials in high-level radioactive waste disposal concepts. Being able to
      understand the chemistry of the porewater in compacted bentonite is very
      important since it is critical to predicting radionuclide solubilities and to the
      synthesis of sorption data bases, and hence to repository safety studies. In this
      paper, porewater compositions in compacted bentonites are calculated, taking into
      consideration such factors as montmorillonite swelling, semi-permeable membrane
      effects, very low "free water" volumes, and the highly effective buffering
      characteristics of the exchangeable cations and the amphoteric edge sites. The
      former buffer the cation concentrations and the latter fix the pH in the
      porewater of a re-saturated bentonite. The above considerations are used in
      conjunction with previously measured physico-chemical characterisation data on MX
      80 powder to calculate porewater compositions in compacted bentonites. For the MX
      80 material specified, the porewaters calculated for initial dry densities
      between 1200 and 1600 kg m(-3) had relatively high ionic strengths (I
      approximately 0.3 M), similar cation concentrations and a pH equal to 8.0. The
      porewaters changed from being Na(2)SO(4)-rich at 1200 kg m(-3) to a
      NaCl/Na(2)SO(4) type water at 1600 kg m(-3).

PMID- 12598115
TI  - Interpretation of out-diffusion experiments on crystalline rocks using random
      walk modeling.
AB  - Matrix diffusion in saturated rocks with very low permeability is one of the
      major mechanisms of solute transport. Laboratory out-diffusion experiments on
      rock samples may provide an estimate of the bulk diffusion coefficient. However,
      numerous results have shown that this average parameter does not really depict
      the complex mechanism of diffusion as a function of the internal heterogeneity of
      crystalline rocks. Two-dimensional images of the porosity distribution in a
      granite sample were obtained by impregnation with a radioactive resin and
      autoradiography. Some examples based on these images and synthetic images were
      used to perform numerical simulations of out-diffusion using two different random
      walk methods. The simulated shapes of the out-diffusion curves depend on the
      spatial distribution of the porosity and on the pore connectivity with the border
      of the sample. Such relations might explain the multiple nested slopes or the
      convex shapes often observed on real experimental curves.

PMID- 12598116
TI  - Prediction of some in situ tracer tests with sorbing tracers using independent
      data.
AB  - Some recent converging tracer tests with sorbing tracers at the Aspo Hard Rock
      Laboratory in Sweden, the TRUE tests, have been predicted using only laboratory
      data and hydraulic data from borehole measurements. No model parameters were
      adjusted to obtain a better fit with the experiments. The independent data were
      fracture frequency and transmissivity data obtained in the field and laboratory
      data on sorption and matrix diffusion. Transmissivity measurements in five
      boreholes in the rock volume containing the region surrounding the injection and
      collection points show that there is a high frequency of water conducting
      fractures. Of 162 packed off sections with 0.5 m packer distances, 112 were found
      to have a transmissivity above the detection limit. The specific flow-wetted
      surface (FWS) of the rock mass could be estimated from these data. The
      transmissivities were found to be reasonably well described by a lognormal
      distribution. Laboratory data on diffusion and sorption properties together with
      the hydraulic data were used to "predict" the residence time distribution (RTD)
      of the sorbing tracers. The results were compared with the experimental
      breakthrough curves. In these experiments, the water residence time is very small
      compared to the residence time of the sorbing tracers due to their diffusion and
      sorption within the rock matrix. We thus could neglect the influence of the water
      residence time in our predictions. Therefore, no information on water residence
      times or on "dispersion" was needed. The dispersion of the sorbing tracers is
      caused by the different sorbing tracer residence times in different pathways. The
      sorbing tracer residence time is determined by the ratio of flowrate to the flow
      wetted surface in the different pathways and not by the water residence time.
      Assuming a three-dimensional flow pattern and using the observed fracture
      frequency and flowrate distribution, breakthrough curves for three strongly
      sorbing tracers were predicted. Only the laboratory data, the transmissivity
      measurements and the pumping flowrate were used in the predictions. No
      information on the water residence time as obtained by the nonsorbing tracers was
      used. The predictions were surprisingly accurate.

PMID- 12598117
TI  - Determination of the flow-wetted surface in fractured media.
AB  - Diffusion and sorption in the rock matrix are important retardation mechanisms
      for radionuclide transport in fractured media. For the conditions existing in a
      deep repository in crystalline rock, interaction with the rock matrix is
      controlled by the water flowrate in the fractures and the surface area in contact
      with the flowing water (the so-called "flow-wetted surface" (FWS)). The flow
      wetted surface may be determined from the frequency of open fractures
      intersecting a borehole. The choice of packer distance used in these hydraulic
      measurements is crucial, however, since several open fractures may be found in
      one packer interval. The use of a packer distance that is too large may result in
      a considerable underestimation of the flow-wetted surface. This is especially
      important in zones with a high frequency of open fractures (fracture zones) where
      a small packer distance is a fundamental requirement. A large volume of hydraulic
      data has been compiled in Sweden from measurements using quite small packer
      distances. Over the last decade, the most common packer distance used for the
      hydraulic tests has been 3 m, although some new measurements using a shorter
      packer distance have also been performed. In several cases, the resolution of
      these measurements has been less than 0.5 m. All these data have been analysed in
      detail. From these data, the flow-wetted surface has been calculated and compared
      with the flow-wetted surface estimated in earlier studies. The results show the
      importance of using a small packer distance for carrying out borehole
      transmissivity measurements.

PMID- 12598119
TI  - Modelling of nonreactive tracer dipole tests in a shear zone at the Grimsel test
      site.
AB  - The investigation of the migration of a high pH plume in a fractured shear zone
      is foreseen by a long-term experiment at the Grimsel rock laboratory. In order to
      characterise the initial conditions for the long-term experiment and to evaluate
      an optimal hydraulic in situ set-up, several dipole experiments with nonreacting
      tracers have been performed. The dipole experiments differ in geometry, pumping
      rates and orientation to the background water flow. Several single and double
      porosity models have been applied to fit the results of these dipole tracer tests
      in order to extract values for some transport parameters and discriminate for
      certain transport processes. A two-dimensional porous medium approach was
      successfully used to fit tracer breakthrough curves measured for a dipole
      experiment. A model based on a one-dimensional dual porous medium approach was
      also successful, although the applied hydraulic dipole, with similar injection
      and extraction rates, suggests the existence of an extended two-dimensional flow
      field. For the two-dimensional porous medium approach, tracer breakthrough could
      only be fitted with a complex flow field geometry within the heterogeneous
      fractured shear zone. The heterogeneity was generated by heterogeneous porosity
      and hydraulic permeability distributions. Predictions for further dipole
      geometries and a sorbing tracer have been calculated by means of both models
      using the flow and transport parameters deduced from fits for a single dipole
      experiment. This allows for comparison with the measured breakthrough of sorbing
      tracers. The foreseen experiment with sorbing (radionuclide) tracers will help
      decide on the appropriate approach that should be used to describe such dipole
      experiments in this shear zone. Additionally, the migration and spreading of a
      solution with high pH has been calculated taking into account mineral dissolution
      and precipitation in a two-dimensional porous medium approach in order to
      estimate the amount and character of the mineral reactions induced by the
      interaction between the high pH solution and the rock.

PMID- 12598118
TI  - A sensibility analysis of model selection in modeling the reactive transport of
      cesium in crushed granite.
AB  - We performed a sensibility analysis of model selection in modeling the reactive
      transport of cesium in crushed granite through model calibration and validation.
      Based on some solid phase analysis data and kinetic batch experimental results,
      we hypothesized three two-site sorption models in the LEHGC reactive transport
      model to fit the breakthrough curves (BTCs) from the corresponding column
      experiments. The analysis of breakthrough curves shows that both the empirical
      two-site kinetic linear sorption model and the semi-mechanistic/semi-empirical
      two-site kinetic surface complexation model, regardless of their complexity, can
      match our experimental data fairly well under given test conditions. A numerical
      experiment to further compare the two models shows that they behave differently
      when the pore velocity is not of the same order of magnitude as our test
      velocities. This result indicates that further investigations to help determine a
      better model are needed. We suggest that a multistage column experiment, which
      tests over the whole range of practical flow velocities, should be conducted to
      help alleviate inadequate hypothesized models.

PMID- 12598120
TI  - Geochemical modelling of bentonite porewater in high-level waste repositories.
AB  - The description of the geochemical properties of the bentonite backfill that
      serves as engineered barrier for nuclear repositories is a central issue for
      performance assessment since these play a large role in determining the fate of
      contaminants released from the waste. In this study the porewater chemistry of
      bentonite was assessed with a thermodynamic modelling approach that includes ion
      exchange, surface complexation and mineral equilibrium reactions. The focus was
      to identify the geochemical reactions controlling the major ion chemistry and
      acid-base properties and to explore parameter uncertainties specifically at high
      compaction degrees. First, the adequacy of the approach was tested with two
      distinct surface complexation models by describing recent experimental data
      performed at highly varying solid/liquid ratios and ionic strengths. The results
      indicate adequate prediction of the entire experimental data set. Second, the
      modelling was extended to repository conditions, taking as an example the current
      Swiss concept for high-level waste where the compacted bentonite backfill is
      surrounded by argillaceous rock. The main reactions controlling major ion
      chemistry were found to be calcite equilibrium and concurrent Na-Ca exchange
      reactions and de-protonation of functional surface groups. Third, a sensitivity
      analysis of the main model parameters was performed. The results thereof indicate
      a remarkable robustness of the model with regard to parameter uncertainties. The
      bentonite system is characterised by a large acid-base buffering capacity which
      leads to stable pH-conditions. The uncertainty in pH was found to be mainly
      induced by the pCO(2) of the surrounding host rock. The results of a simple
      diffusion-reaction model indicate only minor changes of porewater composition
      with time, which is primarily due to the geochemical similarities of the
      bentonite and the argillaceous host rock. Overall, the results show the
      usefulness of simple thermodynamic models to describe porewater chemistry of
      expandable clays although significant uncertainties with regard to the effects of
      swelling and physico-chemical properties of the interstitial water remain.

PMID- 12598121
TI  - An analytical model for the interpretation of pulse injection experiments
      performed for testing the spatial variability of clay formations.
AB  - This paper presents an analytical model to describe pulse injection experiments.
      This model solves the advection-diffusion equation while taking into account back
      diffusion from the clay core to the inlet and from the outlet to the clay core.
      In most analytical models, back diffusion is neglected. For sufficiently high
      Peclet numbers, this is a good approximation. However, in experiments where the
      Peclet number is low, back diffusion is important and must be taken into account.
      An additional advantage of the present model is that both concentration and flux
      are conserved at the inlet and at the outlet of the clay core. This model is used
      to fit pulse injection experiments with iodide and tritiated water (HTO) in clay
      cores. The (new) model is required for fitting the experimental results since in
      clay layers advection is very slow leading to a low Peclet number. The
      experiments are performed on clay cores taken from different depths from the Boom
      Clay and the Ypres Clay layer under the site of the nuclear power plant of Doel
      (Belgium). The quality of all fits is excellent and the obtained parameter values
      are coherent. For HTO, the fitted value for the diffusion accessible porosity is
      consistent with measurements of the water content in Ypres Clay cores. In both
      types of clays, the apparent diffusion coefficient at zero flow is between 10(
      10) and 2 x 10(-10) m(2)/s for iodide and between 2 x 10(-10) and 3 x 10(-10)
      m(2)/s for HTO. The dispersion length is in the order of 10(-3) m. The average
      value for the diffusion accessible porosity is between 0.35 and 0.4 for HTO and
      between 0.2 and 0.25 for iodide.

PMID- 12598122
TI  - High-affinity ammonium transporters and nitrogen sensing in mycorrhizas.
AB  - Most terrestrial plants live in mutualistic symbiosis with root-infecting
      mycorrhizal fungi. This association requires a molecular dialogue between the two
      partners. However, the nature of the chemical signals that induce hyphal
      differentiation are not well characterized and the mechanisms for signal
      reception are still unknown. In addition to its role in ammonium scavenging, the
      Mep2 protein from Saccharomyces cerevisiae has been proposed to act as an
      ammonium sensor that is essential for pseudohyphal differentiation in response to
      ammonium limitation. We propose that the high-affinity ammonium transporters from
      mycorrhizal fungi act in a similar manner to sense the environment and induce,
      via as-yet-unidentified signal transduction cascades, the switch in the mode of
      fungal growth observed during the formation of mycorrhiza.

PMID- 12598123
TI  - The HIV-TSG101 interface: recent advances in a budding field.
AB  - Efficient budding of HIV from the plasma membrane requires a small peptide motif,
      Pro-Thr/Ser-Ala-Pro (PTAP), located near the amino terminus of the p6 Gag
      protein. Studies from several laboratories have demonstrated that the ability of
      p6 to stimulate HIV budding requires a direct interaction between the PTAP motif
      and the host endosomal sorting protein TSG101. The structure of the PTAP-TSG101
      binding site has recently been solved, providing valuable insights into this
      crucial protein-protein interaction.

PMID- 12598124
TI  - Did the loss of sigma factors initiate pseudogene accumulation in M. leprae?
AB  - Pseudogenes are non-functional regions in the genome that have arisen as a
      consequence of accumulating mutations that either result in the premature
      termination of proteins during protein synthesis or the disruption of
      transcription. There have been various discussions of the origins of pseudogenes
      and the models for their formation, but there has been little input on how
      pseudogenes could have accumulated in an organism. In this brief communication, I
      propose a two-step model for the accretion of pseudogenes in the Mycobacterium
      leprae genome, triggered by the loss of different sets of sigma factors at
      different time points during the course of evolution.

PMID- 12598125
TI  - Genome-specific higher-order background models to improve motif detection.
AB  - Motif detection based on Gibbs sampling is a common procedure used to retrieve
      regulatory motifs in silico. Using a species-specific background model was
      previously shown to increase the robustness of the algorithm. Here, we
      demonstrate that selecting a non-species-adapted background model can have an
      adverse effect on the results of motif detection. The large differences in the
      average nucleotide composition of prokaryotic sequences exacerbate the problem of
      exchanging background models. Therefore, we have developed complex background
      models for all prokaryotic species with available genome sequences.

PMID- 12598126
TI  - The building blocks of pathogenicity.

PMID- 12598127
TI  - Bacterial signal transduction: a FHAscinating glimpse at the origins of phospho
      dependent signal transduction.

PMID- 12598128
TI  - URA3 as a selectable marker for disruption and virulence assessment of Candida
      albicans genes.
AB  - The ability to generate isogenic sets of strains with mutations in a gene of
      interest but not in other genes by repeated use of the URA3 marker (Ura-blaster
      methodology) has advanced our understanding of the relationships between gene
      structure and function in Candida albicans. Common applications of Ura-blaster
      technology result in different genomic positions for the URA3 gene in strains
      complemented for the gene of interest compared with mutant strains. Studies using
      animal models of systemic candidiasis pointed to possible differences in URA3
      gene expression, depending on its genomic location, which confounded
      interpretation of the role of the gene of interest in lethality. Positional
      effects on URA3 expression can be avoided by placement at a common locus in all
      strains used for comparison.

PMID- 12598129
TI  - Converting bacteria to organelles: evolution of mitochondrial protein sorting.
AB  - During the evolution of mitochondria from free-living alpha-proteobacteria, many
      bacterial genes were transferred into the nuclear genome of eukaryotic cells.
      This required the development of both targeting signals on the respective
      polypeptides and protein translocation machineries (translocases) in the
      mitochondrial membranes. Most components of these translocases have no obvious
      homologies to bacterial proteins or proteins found in other organelles. Membrane
      integration of many inner membrane proteins, however, apparently occurs via a
      conserved sorting pathway whose components and characteristics resemble protein
      translocation in bacteria. Consistent with this, the topogenic signals of these
      mitochondrial inner membrane proteins mimic those of bacterial proteins. The
      requirement for post-translational transport to their final destination has
      placed considerable constraints on the evolution of mitochondrial protein
      sequences.

PMID- 12598130
TI  - The basis of persistent bacterial infections.
AB  - Selected bacterial pathogens, such as Helicobacter pylori and Mycobacterium
      tuberculosis, establish persistent infections in mammalian hosts despite
      activating inflammatory and antimicrobial responses. The strategies used to
      overcome host defense responses vary with the anatomical location of the
      infection but often rely on deliberate manipulations of the host cell responses.
      Phylogenetically unrelated bacteria can share similar strategies for the
      establishment of persistence and, in selected examples, one even can define
      homologous "persistence" genes. Such observations suggest that persistent
      infection is a specific phase in infection pathogenesis rather than a fortuitous
      imbalance in the host-pathogen interaction.

PMID- 12598131
TI  - The role of porins in neisserial pathogenesis and immunity.
AB  - Neisseria meningitidis and Neisseria gonorrhoeae are Gram-negative pathogenic
      bacteria responsible for bacterial meningitis and septicemia, and the sexually
      transmitted disease gonorrhea, respectively. Porins are the most represented
      outer membrane proteins in the pathogenic Neisseria species, functioning as pores
      for the exchange of ions, and are characterized by a trimeric beta-barrel
      structure. Neisserial porins have been shown to act as adjuvants in the immune
      response via activation of B cells and other antigen-presenting cells (APCs).
      Their effect on the immune response is mediated by upregulation of the
      costimulatory molecule B7-2 (CD86) on the surface of APCs, an effect that is Toll
      like receptor 2- and MyD88-dependent. The effect of neisserial porins on the
      immune system also involves interaction with components of the complement
      cascade. Furthermore, neisserial porins co-localize with mitochondria of target
      cells, where they appear to modulate apoptosis.

PMID- 12598132
TI  - Bacterial coaggregation: an integral process in the development of multi-species
      biofilms.
AB  - Coaggregation is a process by which genetically distinct bacteria become attached
      to one another via specific molecules. Cumulative evidence suggests that such
      adhesion influences the development of complex multi-species biofilms. Once
      thought to occur exclusively between dental plaque bacteria, there are increasing
      reports of coaggregation between bacteria from other biofilm communities in
      several diverse habitats. A general role for coaggregation in the formation of
      multi-species biofilms is discussed.

PMID- 12598133
TI  - A positive result for AIDS.

PMID- 12598134
TI  - How well do health programmes reach the poor?

PMID- 12598135
TI  - Treatment options for genetically determined immunodeficiency.

PMID- 12598136
TI  - Parsing an enigma: the pharmacodynamics of aspirin resistance.

PMID- 12598137
TI  - Diabetes: prevention needed.

PMID- 12598138
TI  - Interferons in relapsing remitting multiple sclerosis: a systematic review.
AB  - BACKGROUND: Recombinant interferons have been approved by many national
      regulatory agencies for treatment of relapsing remitting multiple sclerosis, but
      widespread discussion continues about their true effectiveness, benefits, side
      effects, and costs. METHODS: With the Cochrane Collaboration methodology, we
      reviewed all published, randomised, placebo-controlled trials of recombinant
      interferons undertaken in patients with relapsing remitting multiple sclerosis
      between 1993 and 2002. Our primary aim was to find out whether recombinant
      interferons reduced the number of patients who had clinical exacerbations and
      disease progression, compared with placebo. FINDINGS: The seven trials that met
      our criteria included 1215 randomised patients: data from 667 (55%) were
      available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up.
      Interferon seemed to reduce the number of patients who had exacerbations during
      the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results
      at 2 years' follow-up were not robust and were difficult to interpret because of
      the many dropouts. Although the number of patients who had exacerbations (0.81,
      0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell
      significantly in the protocol analysis, results were inconclusive after
      sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression
      (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and
      admissions to hospital were reduced in the interferon group. Similarly, MRI
      outcome data could not be analysed quantitatively. Side-effects were common, and
      acute toxic effects adversely affected quality of life. INTERPRETATION:
      Recombinant interferons slightly reduce the number of patients who have
      exacerbations during first year of treatment. Their clinical effect beyond 1 year
      is uncertain and new trials are needed to assess their long-term effectiveness
      and side-effects.

PMID- 12598139
TI  - Long-term survival and transplantation of haemopoietic stem cells for
      immunodeficiencies: report of the European experience 1968-99.
AB  - BACKGROUND: Transplantation of allogeneic haemopoietic stem cells can cure
      several primary immunodeficiencies. This European report focuses on the long-term
      results of such procedures done between 1968 and December, 1999, for primary
      immunodeficiencies. METHODS: The report includes data from 37 centres in 18
      countries, which participated in a European registry for stem-cell
      transplantation in severe combined immuno deficiencies (SCID) and in other
      immunodeficiency disorders (non-SCID). 1082 transplants in 919 patients were
      studied (566 in 475 SCID patients, 512 in 444 non-SCID patients; four procedures
      excluded owing to insufficient data). Minimum follow-up of 6 months was required.
      FINDINGS: In SCID, 3-year survival with sustained engraftment was significantly
      better after HLA-identical than after mismatched transplantation (77% vs 54%;
      p=0.002) and survival improved over time. In HLA-mismatched stem-cell
      transplantation, B(-) SCID had poorer prognosis than B(+) SCID. However,
      improvement with time occurred in both SCID phenotypes. In non-SCID, 3-year
      survival after genotypically HLA-matched, phenotypically HLA-matched, HLA
      mismatched related, and unrelated-donor transplantation was 71%, 42%, 42%, and
      59%, respectively (p=0.0006). Acute graft versus host disease predicted poor
      prognosis whatever the donor origin except in related HLA-identical
      transplantation in SCID. INTERPRETATION: The improvement in survival over time
      indicates more effective prevention and treatment of disease-related and
      procedure-related complications--eg, infections and graft versus host disease. An
      important factor is better prevention of graft versus host disease in the HLA-non
      identical setting by use of more efficient methods of T-cell depletion. For non
      SCID, stem-cell transplantation can provide a cure, and grafts from unrelated
      donors are almost as beneficial as those from genetically HLA-identical
      relatives.

PMID- 12598140
TI  - Persistent left superior vena cava.

PMID- 12598141
TI  - Inequities among the very poor: health care for children in rural southern
      Tanzania.
AB  - BACKGROUND: Few studies have been done to assess socioeconomic inequities in
      health in African countries. We sought evidence of inequities in health care by
      sex and socioeconomic status for young children living in a poor rural area of
      southern Tanzania. METHODS: In a baseline household survey in Tanzania early in
      the implementation phase of integrated management of childhood illness (IMCI), we
      included cluster samples of 2006 children younger than 5 years in four rural
      districts. Questions focused on the extent to which carers' knowledge of illness,
      care-seeking outside the home, and care in health facilities were consistent with
      IMCI guidelines and messages. We used principal components analysis to develop a
      relative index of household socioeconomic status, with weighted scores of
      information on income sources, education of the household head, and household
      assets. FINDINGS: 1026 (52%) of 1968 children reported having been ill in the 2
      weeks before the survey. Carers of 415 (41%) of 1014 of these children had sought
      care first from an appropriate provider. 71 (26%) carers from families in the
      wealthiest quintile knew > or =2 danger signs compared with 48 (20%) of those
      from the poorest (p=0.03 for linear trend across quintiles) and wealthier
      families were more likely to bring their sick children to a health facility
      (p=0.02). Their children were more likely than poorer children to have received
      antimalarials, and antibiotics for pneumonia (p=0.0001 and 0.0048, respectively).
      INTERPRETATION: Care-seeking behaviour is worse in poorer than in relatively rich
      families, even within a rural society that might easily be assumed to be
      uniformly poor.

PMID- 12598142
TI  - Genetic associations in large versus small studies: an empirical assessment.
AB  - BACKGROUND: Advances in human genetics could help us to assess prognosis on an
      individual basis and to optimise the management of complex diseases. However,
      different studies on the same genetic association sometimes have discrepant
      results. Our aim was to assess how often large studies arrive at different
      conclusions than smaller studies, and whether this situation arises more
      frequently when findings of first published studies disagree with those of
      subsequent research. METHODS: We examined the results of 55 meta-analyses (579
      study comparisons) of genetic associations and tested whether the magnitude of
      the genetic effect differs in large versus smaller studies. FINDINGS: We noted
      significant between-study heterogeneity in 26 (47%) meta-analyses. The magnitude
      of the genetic effect differed significantly in large versus smaller studies in
      ten (18%), 20 (36%), and 21 (38%) meta-analyses with tests of rank correlation,
      regression on SE, and regression on inverse of variance, respectively. The
      largest studies generally yielded more conservative results than the complete
      meta-analyses, which included all studies (p=0.005). In 14 (26%) meta-analyses
      the proposed association was significantly stronger in the first studies than in
      subsequent research. Only in nine (16%) meta-analyses was the genetic association
      significant and replicated without hints of heterogeneity or bias. There was
      little concordance in first versus subsequent discrepancies, and large versus
      small discrepancies. INTERPRETATION: Genuine heterogeneity and bias could affect
      the results of genetic association studies. Genetic risk factors for complex
      diseases should be assessed cautiously and, if possible, using large scale
      evidence.

PMID- 12598143
TI  - An organic cause of neuropsychiatric illness in adolescence.

PMID- 12598144
TI  - Effect of ibuprofen on cardioprotective effect of aspirin.
AB  - Treatment with ibuprofen might limit the cardioprotective effects of aspirin. We
      aimed to assess whether patients with known cardiovascular disease who take low
      dose aspirin and ibuprofen have increased risk of cardiovascular mortality. We
      studied 7107 patients who were discharged after first admission for
      cardiovascular disease between April, 1989, and April, 1997, and who were
      prescribed low-dose aspirin (<325 mg/day) and survived for at least 1 month.
      Compared with those who used aspirin alone, patients taking aspirin plus
      ibuprofen had an increased risk of all-cause mortality (adjusted hazard ratio
      1.93, 95% CI 1.30-2.87, p=0.0011) and cardiovascular mortality (1.73, 1.05-2.84,
      p=0.0305). Our finding lends support to the hypothesis that ibuprofen may
      interact with the cardioprotective effects of aspirin, at least in patients with
      established cardiovascular disease.

PMID- 12598146
TI  - The effect of providing fansidar (sulfadoxine-pyrimethamine) in schools on
      mortality in school-age children in Malawi.
AB  - Malaria is a major cause of death in school-age (5-18 years) children in Malawi.
      Save the Children Federation helped schools in Mangochi District, Malawi, to
      obtain pupil-treatment kits, which enabled teachers to dispense sulfadoxine
      pyrimethamine tablets according to national guidelines. The overall and malaria
      specific mortality rates were calculated for the 3 years before and 2 years after
      the intervention was introduced; rates dropped from 2.2 to 1.44 deaths/1000
      student-years and from 1.28 to 0.44 deaths/1000 student-years, respectively.
      School-based interventions could play a part in mitigating malaria.

PMID- 12598145
TI  - Migration of human keratinocytes in plasma and serum and wound re
      epithelialisation.
AB  - When skin is wounded, human keratinocytes at the wound edge stop differentiating
      and start migrating to resurface the wound. How this change takes place is
      unclear. Because keratinocytes at the wound edge are for the first time
      surrounded by serum rather than plasma, serum could contain some migration
      promoting factor or factors that is absent in plasma. We did standard computer
      assisted in-vitro migration assays of human keratinocytes in the presence of
      either human plasma or serum. We also did a semiquantitative western blot
      analysis to determine if p38 mitogen-activated protein kinase (p38MAPK) was
      activated by either serum or plasma. Our results showed that keratinocytes
      migrating on collagen in the presence of serum produced migration indices in the
      range of 28, whereas those in the presence of plasma were about 12--the same
      level as control assays without either serum or plasma. We also showed that
      induced keratinocyte polarisation, activation of p38MAPK, and production of
      matrix metalloprotease 9 are possible mechanisms for promotion of re
      epithelialisation of skin wounds by human serum.

PMID- 12598147
TI  - Improve trials in poor nations, say EC's ethics advisers.

PMID- 12598148
TI  - From standing start to human genome sequence in 50 years.

PMID- 12598151
TI  - Netherlands shocked by widespread insurance fraud by medical professionals and
      patients.

PMID- 12598149
TI  - Project seeks to "fast track" rotavirus vaccine.

PMID- 12598152
TI  - Consortium uses RNAi to uncover genes' function.

PMID- 12598154
TI  - South Africa pledges AIDS drugs.

PMID- 12598155
TI  - Brazil launches initiative to eliminate hunger.

PMID- 12598156
TI  - Churg-Strauss syndrome.
AB  - Churg-Strauss syndrome is a rare diffuse vasculitis that is almost invariably
      accompanied by severe asthma. Although overall prognosis is good, and treatment
      with prednisone alone or in combination with immunosuppressive drugs is usually
      successful, severe asthma typically persists. Diffuse organ involvement of Churg
      Strauss syndrome, especially cardiovascular and rare involvement of the CNS and
      renal system, suggests a poorer prognosis than usual, and can be fatal. The cause
      of Churg-Strauss syndrome is unknown, but its characteristic histological
      findings and association with asthma distinguish it from other vasculitides.
      Controversy surrounds the use of asthma drugs-especially antileukotrienes--and
      development of the disorder. We review the epidemiological evidence for an
      association of drug treatment with Churg-Strauss syndrome, the diverse diagnostic
      and pathological criteria for this syndrome, and treatment options.

PMID- 12598157
TI  - Neonatal hip screening.
AB  - CONTEXT: A "missed" case of congenital hip dislocation (CDH) can be a disaster
      for the patient and the outcome may be poor. Considerable resources are expended
      on screening programmes to identify appropriate cases early but a recent change
      in terminology to developmental dysplasia of the hip (DDH) and a realisation that
      neonatal hip maturation is poorly understood has made it difficult to know who
      should be screened and why. STARTING POINT: Neonatal hip screening is well
      established although some experts feel that the effectiveness of clinical let
      alone ultrasound screening programmes is unproven. Several European countries
      undertake population screening, while selective screening occurs in 93% of UK
      units. K Holen and colleagues recently reported (J Bone Joint Surg 2002; 84-B:
      886-90) a prospective randomised trial of just over 15 500 newborn babies in
      which they compare universal and selective screening programmes. With a follow-up
      of 6-11 years, one late-detected hip dysplasia was seen in the universal group
      compared with six in the selective group (not statistically significant). These
      investigators found, on the background of an excellent clinical programme, no
      additional benefit from universal screening and thus advocate selective
      screening. WHERE NEXT: The aims of a screening programme must be defined, then
      evaluated. A consideration of costs can never take into account family pain and
      distress. The results of the universal screening programme in Coventry, UK, are
      impressive and significantly better than results from other UK centres. If the
      Coventry results are the gold standard, then it is necessary to work out how this
      can be achieved elsewhere rather than worry about whether it is unachievable.

PMID- 12598158
TI  - Population stratification and spurious allelic association.
AB  - Great efforts and expense have been expended in attempts to detect genetic
      polymorphisms contributing to susceptibility to complex human disease.
      Concomitantly, technology for detection and scoring of single nucleotide
      polymorphisms (SNPs) has undergone rapid development, extensive catalogues of
      SNPs across the genome have been constructed, and SNPs have been increasingly
      used as a means for investigation of the genetic causes of complex human
      diseases. For many diseases, population-based studies of unrelated individuals-
      in which case-control and cohort studies serve as standard designs for genetic
      association analysis--can be the most practical and powerful approach. However,
      extensive debate has arisen about optimum study design, and considerable concern
      has been expressed that these approaches are prone to population stratification,
      which can lead to biased or spurious results. Over the past decade, a great shift
      has been noted, away from case-control and cohort studies, towards family-based
      association designs. These designs have fewer problems with population
      stratification but have greater genotyping and sampling requirements, and data
      can be difficult or impossible to gather. We discuss past evidence for population
      stratification on genotype-phenotype association studies, review methods to
      detect and account for it, and present suggestions for future study design and
      analysis.

PMID- 12598159
TI  - Alzheimer's disease and angiogenesis.
AB  - Despite enormous investigative efforts, the pathological basis for Alzheimer's
      disease remains unclear. Suggested mechanisms for the disorder include cerebral
      hypoperfusion, inflammation, gene polymorphisms, and molecular lesions in the
      brain. In this Hypothesis, we argue that the vascular endothelial cell has a
      central role in the progressive destruction of cortical neurons in Alzheimer's
      disease. In Alzheimer's disease, the brain endothelium secretes the precursor
      substrate for the beta-amyloid plaque and a neurotoxic peptide that selectively
      kills cortical neurons. Large populations of endothelial cells are activated by
      angiogenesis due to brain hypoxia and inflammation. Results of epidemiological
      studies have shown that long-term use of non-steroidal anti-inflammatory drugs,
      statins, histamine H2-receptor blockers, or calcium-channel blockers seems to
      prevent Alzheimer's disease. We think this benefit is largely due to these drugs'
      ability to inhibit angiogenesis. If Alzheimer's disease is an angiogenesis
      dependent disorder, then development of antiangiogenic drugs targeting the
      abnormal brain endothelial cell might be able to prevent and treat this disease.
      We suggest several laboratory and clinical approaches for testing our hypothesis.

PMID- 12598160
TI  - How international are the editorial boards of leading psychiatry journals?

PMID- 12598161
TI  - Increased nitric oxide production and protection from malaria.

PMID- 12598162
TI  - Increased nitric oxide production and protection from malaria.

PMID- 12598164
TI  - Rethinking the HIV counselling and testing model in the USA.

PMID- 12598165
TI  - WHO Framework Convention on Tobacco Control.

PMID- 12598166
TI  - Hormones for coronary disease.

PMID- 12598167
TI  - Hormones for coronary disease.

PMID- 12598168
TI  - Hormones for coronary disease.

PMID- 12598169
TI  - Patent protection: a need for value-based patents.

PMID- 12598170
TI  - Physicians and patent law.

PMID- 12598171
TI  - The SoS trial.

PMID- 12598172
TI  - Infections and cancer in Uganda.

PMID- 12598173
TI  - The SoS trial.

PMID- 12598174
TI  - The SoS trial.

PMID- 12598176
TI  - Treating hyperkalaemia.

PMID- 12598177
TI  - Valgus or varus cello pathology?

PMID- 12598179
TI  - Practice-based CME.

PMID- 12598181
TI  - HIV no match for microbicides.

PMID- 12598182
TI  - Special K.

PMID- 12598183
TI  - Marianne J Legato.

PMID- 12598184
TI  - Evolutionary self-organising modelling of a municipal wastewater treatment plant.
AB  - Building predictive models for highly time varying and complex multivariable
      aspects of the wastewater treatment plant is important both for understanding the
      dynamics of this complex system, and in the development of optimal control
      support and management schemes. This paper presents a new approach, which is
      called genetic programming as a self-organising modelling tool, to model dynamic
      performance of municipal activated-sludge wastewater treatment plants. Genetic
      programming evolves several process models automatically based on methods of
      natural selection ('survival of the fittest'), that could predict the dynamics of
      MLSS and suspended solids in the effluent. The predictive accuracy of the genetic
      programming approach was compared with a nonlinear state-space model with neural
      network and a well-known IAWQ ASM2. The genetic programming system evolved some
      models that were an improvement over the neural network and ASM2 and showed that
      the transparency of the model evolved may allow inferences about underlying
      processes to be made. This work demonstrates that dynamic nonlinear processes in
      the wastewater treatment plant may be successfully modelled through the use of
      evolutionary model induction algorithms in GP technique. Further, our results
      show that genetic programming can work as a cost-effective intelligent modelling
      tool, enabling us to create prototype process models quickly and inexpensively
      instead of an engineer developing the process model.

PMID- 12598185
TI  - Quantitative structure-activity relationships for estrogen receptor binding
      affinity of phenolic chemicals.
AB  - The estrogen receptor (ER) binding affinities of 25 compounds including 15
      industrial phenolic chemicals, two phytoestrogens, three natural steroids and one
      man-made steroid were detected by a binding competition assay. The 17 industrial
      phenolic chemicals were selected as objective compounds because they are possibly
      released from epoxy and polyester-styrene resins used in lacquer coatings of
      concrete tank and lining of steel pipe in water supply system. A quantitative
      structure-activity relationship (QSAR) for structurally diverse phenols, nine
      alkylphenols with only one alkyl group, four hydroxyl biphenyls, bisphenol A and
      four natural and man-made estrogens was established by applying a quantum
      chemical modeling method. Logarithm of octanol-water coefficient (logPow),
      molecular volume (V(m)), and energies of the highest occupied molecular orbital (
      epsilon (HOMO)) and lowest unoccupied molecular orbital ( epsilon (LUMO)) were
      selected as hydrophobic, steric (V(m)), and electronic chemical descriptors,
      respectively. Chemicals capable of ER binding had large V(m) and high epsilon
      (HOMO), while the effects of logPow and epsilon (LUMO) on the binding affinity
      could not be identified. The QSAR made successful predictions for the three
      phytoestrogens. Also, the successful prediction of ER-binding affinity for
      biochanin A, another phytoestrogen, two indicators of pH (phenolphthalin and
      phenolphthalein) and one alkylphenolic chemical with three alkyl groups (4-methyl
      2,6-di-butyl-phenol), by amending the V(m) in the above-mentioned QSAR according
      to the electron-density distribution (or HOMO density) is an additional step in
      the elucidation of chemical steric and electronic parameters for predicting the
      binding affinities of phenolic compounds.

PMID- 12598186
TI  - Photocatalytic degradation of nitrobenzene using titanium dioxide and
      concentrated solar radiation: chemical effects and scaleup.
AB  - Photocatalytic degradation of nitrobenzene (NB) using titanium dioxide (Degussa P
      25) as photocatalyst and concentrated solar radiation has been studied. The
      effects of various factors, such as the presence of anions common in the
      industrial wastewater, the initial pH and the addition of FeSO(4), were
      investigated. The intermediates detected were o, p,m-nitrophenols and dihhydroxy
      derivatives indicating that degradation proceeds via z.rad;OH radicals.
      Degradation of NB was studied in three reactors of different diameters to
      ascertain the effect of photon penetration depth on the degradation.

PMID- 12598187
TI  - The anoxic extractive membrane bioreactor.
AB  - The extractive membrane bioreactor (EMB) employs a dense silicone rubber membrane
      to selectively extract hydrophobic organic compounds from industrial wastewaters
      into a bioreactor in order to biodegrade them. The major drawback of the EMB is
      excess biofilm growth on the membrane, which limits mass transfer and creates
      oxygen limitations. In this work, nitrate has been used as an electron acceptor
      instead of oxygen. Due to the high solubility of nitrate in water, it is
      hypothesised that nitrate penetrates the whole biofilm, preventing the formation
      of inactive zones of bacteria. Four experiments have been performed with toluene
      as a model substrate under anoxic conditions. The effect of nitrate
      concentrations on the biofilm and on the toluene flux have been investigated. In
      addition, the production of soluble microbial products (SMPs), and bacterial
      hydrophobicity were studied. Under high nitrate concentrations, the performance
      of the anoxic EMB was stable and no biofilm was formed. The bacteria metabolised
      toluene, and the toluene flux remained approximately constant. Conversely, at low
      nitrate concentration, a decrease in pollutant flux concomitant with biofilm
      growth was observed. The production of SMPs increased under limiting nitrate
      concentrations, but the hydrophobicity of the suspended bacteria remained
      constant. However, the bacterial hydrophobicity of the attached cells was
      significantly greater than that of the suspended cells.

PMID- 12598188
TI  - Kinetic modeling of a mixed culture of Pseudomonas denitrificans and Bacillus
      subtilis under aerobic and anoxic operating conditions.
AB  - The kinetics of biological denitrification have been studied and several models,
      with varying degree of complexity, to be used for design purposes have been
      presented in the recent years. However, most of these kinetic studies were
      performed with mixed (and not well defined) microbial systems, such as activated
      sludge. In the present work, kinetic experiments were carried out in order to
      study the dynamic characteristics of a defined mixed culture of the denitrifiers
      Pseudomonas denitrificans and Bacillus subtilis under anoxic and aerobic
      conditions in a defined synthetic medium involving a mixture of organic
      substrates, in the presence of nitrates and/or nitrites. Denitrification was
      assumed to occur by the consecutive reduction of nitrates to nitrites and then to
      nitrogen gas without accumulation of intermediate gaseous products. The behavior
      of these defined mixed cultures was predicted using a kinetic model based on the
      kinetic models that have already been developed for each bacterium separately and
      the predictions were compared with the results from mixed culture experiments.
      The overall mathematical model that was developed and validated in the present
      work is capable of describing the behavior of the mixed culture in the above
      conditions, i.e. the nitrates and nitrites reduction kinetics, the cell growth,
      and the organic carbon utilization rates.

PMID- 12598189
TI  - Identification and quantification of nitrogen removal in a rotating biological
      contactor by 15N tracer techniques.
AB  - High autotrophic nitrogen removal rates of 858mg NL(-1) day(-1) or 1.55g Nm(-2)
      day(-1) were obtained in a lab-scale rotating biological contactor treating an
      ammonium rich influent. It was postulated that ammonium was removed as dinitrogen
      gas by a sequence of aerobic ammonium oxidation to nitrite taking place in the
      outer biofilm layer and anaerobic ammonium oxidation with nitrite as electron
      acceptor occuring in the deeper biofilm layer. Chemical evidence for anaerobic
      ammonium oxidation within intact biofilm sludge from a lab-scale rotating
      biological contactor could be provided, without direct identification of
      responsible organisms catalysing this reaction. 15N tracer techniques were used
      for identification and quantification of nitrogen transformations. In batch tests
      with biofilm sludge at dissolved oxygen concentrations lower than 0.1mgL(-1),
      ammonium and nitrite did react in a stoichiometric ratio of 1:1.43 thereby
      forming dinitrogen. 15N isotope dilution calculations revealed that anaerobic
      ammonium oxidation was the major nitrogen transformation leading to concomitant
      ammonium and nitrite removal. Isotopic analysis of the produced biogas showed
      that both ammonium-N and nitrite-N were incorporated in N(2).

PMID- 12598190
TI  - Toxicity of di-(2-ethylhexyl) phthalate on the anaerobic digestion of wastewater
      sludge.
AB  - Previous studies on the microbial degradation of individual phthalic acid esters
      (PAEs) have demonstrated that the compounds with short ester hydrocarbon chains
      are easily biodegraded and mineralized, but PAEs with long ester chains are less
      susceptible to degradation and some of them are considered recalcitrant.
      Moreover, they inhibit methanogenesis. However, studies have not been made on the
      effect of feeding a combination of recalcitrant and biodegradable PAEs into
      anaerobic digesters treating wastewater sludge. The present study was conducted
      with wastewater sludge from the Los Angeles Bureau of Sanitation's Hyperion
      Treatment Plant. Di (2-ethylhexyl) phthalate (DEHP), the most common persistent
      PAE found in wastewater, and di-n-butyl phthalate (DBP), a common PAE with short
      ester chains, were sorbed into the sludge fed to a bench-scale digester for a
      period of 12 weeks. DEHP degradation was always poor, and accumulation of DEHP
      was correlated with inhibition of the microbial degradation of DBP and with
      process instability of the test digester. Inhibition of the DBP removal was
      completely reversed after DEHP addition was discontinued, but biogas production
      never recovered to the level observed in a control digester. Other process
      parameters of digester performance were not affected by DEHP accumulation. These
      results are similar to the toxic effects of long chain fatty acids on sludge
      digestion, suggesting that DEHP or its degradation products affect all the
      microbial populations in the anaerobic bioreactor. Our results imply that high
      levels of DEHP or other recalcitrant PAEs in wastewater sludge are likely to
      compromise methanogenesis and removal of biodegradable PAEs in sludge digesters.

PMID- 12598191
TI  - Performance predictions of mature experimental constructed wetlands which treat
      urban water receiving high loads of lead and copper.
AB  - The treatment efficiencies of vertical-flow wetland filters containing
      macrophytes and granular media of different adsorption capacities were
      investigated. Different concentrations of lead and copper sulphate were added to
      urban stream inflow water in order to simulate pre-treated (pH adjustment
      assumed) mine wastewater. After 1 year of operation, the metal mass load rate was
      increased by a factor of approximately 4.6. No breakthrough of metals was
      recorded. The use of macrophytes and adsorption media did not enhance heavy metal
      reduction significantly after 13 months of operation. A correlation analysis
      indicated strong positive correlations between conductivity on one side and other
      variables including temperature, total solids, dissolved oxygen and the redox
      potential on the other side. Some expensive or time-consuming variables (e.g.,
      biochemical oxygen demand) can be predicted with less expensive ones (e.g.,
      dissolved oxygen and temperature). The associated absolute mean errors were <10%.

PMID- 12598192
TI  - Preliminary testing of a rapid coupled methodology for quantitation/viability
      determination of helminth eggs in raw and treated wastewater.
AB  - The use of raw and treated wastewater for irrigation of crops is a common
      practice in Mexico. In force since January 1997, the Water Quality Norms for
      helminth ova refer only to the number of eggs that can be present in the
      irrigation water, and ignore the assessment of viability because the conventional
      techniques are not suitable for routine application. However, since viability is
      of prime importance in the epidemiology of parasitic infections, work was done
      for the development of a rapid and reliable method to detect a metabolic activity
      or a physiological characteristic related to viability. As a result, a vital
      staining procedure was developed and validated, and it was coupled with two rapid
      quantitative procedures previously assessed, therefore, permitting the
      determination of the total number of helminth eggs and, simultaneously, the
      viable and non-viable fraction. The average recovering efficiency of the rapid
      quantitative methods is 54% for raw wastewater and 77% for treated wastewater;
      the staining technique for viability is equally reliable (within the 95%
      confidence limits) as the conventional in vitro procedure; the overall test takes
      from 4 to6 h to be completed when processing up to four samples at the same time,
      and the cost per sample (for unrecoverable materials) ranges from US$2.50 to
      $4.00.

PMID- 12598193
TI  - Phthalates, nonylphenols and LAS in an alternately operated wastewater treatment
      plant--fate modelling based on measured concentrations in wastewater and sludge.
AB  - The performance of an alternately operated activated sludge wastewater treatment
      plant (WWTP) has been investigated with respect to six phthalates, nonylphenol
      (NP) and nonylphenol diethoxylate (NPDE) and linear alkylbenzene sulphonates
      (LAS). Samples of raw sewage, primary and secondary sludge and treated water were
      collected during an 8-day period in May 1999 and analysed for dissolved and
      sorbed substances. To evaluate the system performance with respect to substance
      removal through biodegradation and sorption to sludge the measured data were
      applied in a model describing the different bioreactors as one single reactor,
      corresponding to the concepts of, e.g. SimpleTreat. The most abundant of the
      investigated phthalates was di-(2-ethylhexyl)-phthalate (DEHP) with a measured
      mean inlet flow of 240g/day. Two percent of this amount was found in the treated
      water, 70% was biodegraded and 28% was found in the sludge. For LAS the mean
      inlet flow was 20,300g/day, of which less than 1% was found in the treated water,
      84% was biodegraded and 15% was found in the sludge. The mean inlet flow of NP
      and NPDE was 44 and 590g/day, of which 4% and 2% was found in the treated water,
      80% was biodegraded for both substances, and 16% and 18% was found in the sludge,
      respectively. The WWTP removal of the investigated substances was thus high
      compared to other studies of conventional activated sludge WWTPs. The simple
      model set-up presents a strong tool for predicting substance removal and system
      sensitivity related to changes in the inlet conditions, such as concentrations
      and flow. Furthermore, it allows the inclusion of complex alternately operated
      WWTPs in risk assessment tools such as e.g. SimpleTreat.

PMID- 12598194
TI  - Biokinetic modeling of in situ bioremediation of BTX compounds-impact of process
      variables and scaleup implications.
AB  - The impact of three process parameters, i.e. ground water velocity, oxygen-to-BTX
      mass ratio, and benzene, toluene and xylene (BTX) concentrations on first-order
      biodegradation kinetics in a pilot-scale in situ bioremediation system was
      assessed. Generally, first-order biodegradation coefficients decreased with
      ground water velocity, and increased with hydrogen peroxide dose and BTX
      concentration. First-order biodegradation rate coefficients for benzene, toluene,
      and o-xylene varied from 0.3 to 0.81, 0.24 to 0.72, and 0.21 to 0.63 d(-1),
      respectively. Biomass-specific first-order rate coefficients were insensitive to
      ground water velocity, and decreased with increasing BTX concentrations. At
      10mg/l BTX concentration, the specific first-order coefficients increased with
      peroxide dose. However, at the 50mg/l BTX concentration and a peroxide dose of
      1020 mg/l, a 30-70% reduction in specific first-order biodegradation coefficients
      was observed. BTX biodegradation kinetics in this pilot-scale system were
      approximately one-to-two orders of magnitude slower than in soil microcosms and
      mixed culture bioreactors, and about 200-300% higher than full-scale systems.

PMID- 12598195
TI  - Electrochemical regeneration of Fe2+ in Fenton oxidation processes.
AB  - This study is to establish optimal conditions for the minimization of iron sludge
      produced in Fenton oxidation processes by electro-regenerating Fe(2+) with
      constant potential (CPM) or constant current mode (CCM). Results indicate that
      the optimal cathodic potential for Fe(2+) regeneration is -0.1 V vs. the
      saturated calomel electrode (SCE) in terms of current efficiency. Keeping the
      initial Fe(3+) concentration ([Fe(3+)](0)) constant, the average current density
      produced at -0.1 V vs. SCE (CPM) is approximately equal to the optimal current
      density applied in the CCM. The suitable pH range is below the pH value
      determined by Fe(3+) hydrolysis. As expected, increasing cathode surface area and
      solution temperature notably increases Fe(2+) regeneration rate. At the optimal
      potential, the average current density increases linearly with [Fe(3+)](0),
      exhibiting a slope of 8.48 x 10(-3)(A/m(2))(mg/L)(-1). The average current
      efficiency varies with [Fe(3+)](0), e.g., 75% and 96-98% at 100 and > or = 500
      mg/L [Fe(3+)](0), respectively. Once reaching 75% of Fe(2+) regeneration
      capacity, further regeneration becomes difficult due to Fe(3+) mass transfer
      limitation. Fe(2+) can also be effectively regenerated by dissolving iron sludge
      at low pH (usually </=1). The unit energy consumption is 2.0-3.0 k Wh per kg
      Fe(2+) regenerated.

PMID- 12598196
TI  - Geochemistry of some rare earth elements in groundwater, Vierlingsbeek, The
      Netherlands.
AB  - Groundwater samples were taken from seven bore holes at depths ranging from 2 to
      41m nearby drinking water pumping station Vierlingsbeek, The Netherlands and
      analysed for Y, La, Ce, Pr, Nd, Sm and Eu. Shale-normalized patterns were
      generally flat and showed that the observed rare earth elements (REE) were
      probably of natural origin. In the shallow groundwaters the REEs were light REE
      (LREE) enriched, probably caused by binding of LREEs to colloids. To improve
      understanding of the behaviour of the REE, two approaches were used: calculations
      of the speciation and a statistical approach. For the speciation calculations,
      complexation and precipitation reactions including inorganic and dissolved
      organic carbon (DOC) compounds, were taken into account. The REE speciation
      showed REE(3+), REE(SO(4))(+), REE(CO(3))(+) and REE(DOC) being the major
      species. Dissolution of pure REE precipitates and REE-enriched solid phases did
      not account for the observed REEs in groundwater. Regulation of REE
      concentrations by adsorption-desorption processes to Fe(III)(OH)(3) and Al(OH)(3)
      minerals, which were calculated to be present in nearly all groundwaters, is a
      probable explanation. The statistical approach (multiple linear regression)
      showed that pH is by far the most significant groundwater characteristic which
      contributes to the variation in REE concentrations. Also DOC, SO(4), Fe and Al
      contributed significantly, although to a much lesser extent, to the variation in
      REE concentrations. This is in line with the calculated REE-species in solution
      and REE-adsorption to iron and aluminium (hydr)oxides. Regression equations
      including only pH, were derived to predict REE concentrations in groundwater.
      External validation showed that these regression equations were reasonably
      successful to predict REE concentrations of groundwater of another drinking water
      pumping station in quite different region of The Netherlands.

PMID- 12598197
TI  - Biofilm responses to ageing and to a high phosphate load in a bench-scale
      drinking water system.
AB  - The effects of ageing and of phosphate load on drinking water biofilms developed
      on a polycarbonate substratum in the pseudo-equilibrium state have been
      evaluated. Phosphate was added in an amount higher than the stochiometric
      nutrient requirements of bacteria, at concentrations commonly applied in a
      drinking water distribution system for corrosion control. Multiple parameters
      were monitored: heterotrophic plate counts (HPCs), total direct counts (TDCs) and
      potential exoproteolytic activity (PEPA) in order to characterise changes in
      bacterial biofilms. The total carbohydrate, amino acid and phosphate contents of
      biofilms were analysed to characterise and monitor the biochemical composition of
      the biofilm.The three enumeration methods showed that a pseudo-equilibrium state
      was reached after 7 weeks of colonisation after which, the bacterial growth rate
      in the biofilm was 0.1 log per week on average. Bulk phosphate addition doubled
      the phosphate in the biofilm, but did not affect the other biological,
      physiological or chemical parameters measured. Polysaccharides increased in the
      biofilm with ageing and the dynamics of individual carbohydrate synthesis also
      varied with the age of the biofilm. Once pseudo-equilibrium, it was found that
      the total proteins were globally constant, whereas the spectra of some individual
      amino acids of the proteins had significantly changed.

PMID- 12598198
TI  - Identification methods for Legionella from environmental samples.
AB  - Laboratories responsible for Legionella diagnostics around the world use a number
      of different culturing methods of non-equivalent sensitivities and specificities,
      to detect Legionella species in environmental samples. Specific countries usually
      standardize and use one approved method. For example, laboratories in Australia
      use the Australian Standard (AS) method and those in Europe, the International
      Standard method (ISO). However, no standard culturing methods have been
      established in South Africa to date. As a result, there is uncertainty about the
      true prevalence and most common species of Legionella present in the South
      African environment. In an attempt to provide guidelines for the development of a
      standard method specific for South Africa, the ISO, AS and a most probable number
      method were evaluated and compared. In addition, the effect of sample re
      incubation with autochthonous amoebae on culture outcome was studied. Samples
      were collected from four environments, representing industrial water, mine water
      and biofilm. The samples were concentrated by membrane filtration and divided
      into three portions and cultured without pretreatment, after acid treatment and
      after heat treatment, on four culture media namely alphaBCYE, BMPA, MWY and GVPC
      agar. A selective approach, incorporating heat treatment, but not acid treatment,
      combined with culture on alphaBCYE and GVPC or MWY, was most appropriate for
      legionellae detection in the samples evaluated. Legionellae were cultured from
      82% of the environmental samples we evaluated. In 54% of the samples tested,
      legionellae were present in numbers equal to or exceeding 10(2) colony-forming
      units per milliliter (cfu/ml). Legionella pneumophila serogroups (SGs) 1-14 were
      the most prevalent species and were present as single, or a combination of two or
      more SGs in a number of samples tested. Re-incubation of sample concentrates with
      autochthonous amoebae improved the culturability of legionellae in 50% of
      cultures on alphaBCYE and 25% on GVPC.

PMID- 12598199
TI  - Nitrification with high nitrite accumulation for the treatment of wastewater with
      high ammonia concentration.
AB  - The objective of this paper was to determine the best conditions for partial
      nitrification with nitrite accumulation of simulated industrial wastewater with
      high ammonia concentration, lowering the total oxygen needed in the nitrification
      step, which may mean great saving in aeration. Dissolved oxygen (DO)
      concentration and pH were selected as operational parameters to study the
      possibility of nitrite accumulation not affecting overall ammonia removal. A 2.5L
      activated sludge reactor was operated in nitrification mode, feeding a synthetic
      wastewater simulating an industrial wastewater with high ammonia concentration.
      During the start-up a pH of 7.85 and a DO of 5.5mg/L were used. The reactor was
      operated until stable operation was achieved at final nitrogen loading rate (NLR)
      of 3.3kgN- NH(4)(+)/m(3)d with an influent ammonia concentration of 610mg N
      NH(4)(+)/L. The influence of pH was studied in continuous operation in the range
      of 6.15-9.05, changing the reactor pH in steps until ammonia accumulation
      (complete nitrification inhibition) took place. The influence of DO was studied
      in the same mode, changing the DO in steps from 5.5 to 0.5mg/L. The pH was not a
      useful operational parameter in order to accumulate nitrite, because in the range
      of pH 6.45-8.95 complete nitrification to nitrate occurs. At pH lower than 6.45
      and higher than 8.95 complete inhibition of nitrification takes place. Setting DO
      concentration in the reactor at 0.7mg/L, it was possible to accumulate more than
      65% of the loaded ammonia nitrogen as nitrite with a 98% ammonia conversion.
      Below 0.5mg/L of DO ammonia was accumulated and over a DO of 1.7mg/L complete
      nitrification to nitrate was achieved. In conclusion, it is possible under the
      conditions of this study, to treat high ammonia synthetic wastewater achieving an
      accumulation of at least 65% of the loaded nitrogen as nitrite, operating at a DO
      around 0.7mg/L. This represents a reduction close to 20% in the oxygen necessary,
      and therefore a considerable saving in aeration.

PMID- 12598200
TI  - Competition for oxygen by iron and 2,4,6-trichlorophenol oxidizing bacteria in
      boreal groundwater.
AB  - Kinetics of simultaneous iron and 2,4,6-trichlorophenol (TCP) oxidation by
      groundwater enriched cultures were studied in order to reveal the competition for
      oxygen in aerobic in situ bioremediation of boreal groundwater. Chemical iron
      oxidation at near neutral pH in synthetic groundwater depended by the first order
      on the concentrations of ferrous iron and dissolved oxygen and by the second
      order on pH. The chemical iron oxidation rate constant was on average 2.2 x
      10(13)mol(-2)L(2)atm(-1)min(-1). Chemical iron oxidation was insignificantly
      affected by natural organic matter, 2,4,6-tri-, 2,3,4,6-tetra- or
      pentachlorophenol in groundwater. Biological oxidation of iron followed zero
      order kinetics. At pH of 6.3 and dissolved oxygen (DO) concentration of 11.5 mgL(
      1), the rate of biological iron oxidation was 3.8 x 10(-4)mmolL(-1)min(-1) and up
      to one order of magnitude higher than the chemical oxidation rate, 5.2 x 10(-6)
      mmolL(-1)min(-1). Biological oxidation of iron was completely inhibited by
      pentachlorophenol at 23 micro mol-1. With a groundwater enriched culture, oxygen
      was consumed at higher rates by 2,4,6-TCP oxidizers (2.5-7.6 x 10(-5)mmolDOL(
      1)min(-1)) than the iron oxidizing bacteria (0.8-3.1 x 10(-5) mmolDOL(-1)min(-1))
      at both low and saturated DO-concentrations. The results indicate that in situ
      iron oxidation is predominantly biogenic in the studied boreal aquifer. 2,4,6-TCP
      degrading bacteria consumed DO at higher rates than the iron oxidizing bacteria
      and thereby, favour bioremediation of the polychlorophenol contaminated
      groundwater.

PMID- 12598201
TI  - Removal of bis(2-ethylhexyl) phthalate at a sewage treatment plant.
AB  - Bis(2-ethylhexyl) phthalate (DEHP) concentrations were measured at different
      stages in a full-scale sewage treatment plant (STP) and mass balances were
      calculated. The DEHP load to treatment process coming from the sewer system and
      the internal load comprising returned supernatants and filtrate from sludge
      treatment and excess secondary sludge were at the same level. The DEHP removal
      efficiency from the water phase at the STP was on average 94% of sewage DEHP, the
      main removal process being sorption to primary and secondary sludges. On average
      29% of DEHP was calculated to be removed in the biological nitrifying
      denitrifying activated sludge process, which was much less than expected from
      laboratory biodegradation studies described in literature. Monoethylhexyl
      phthalate, the primary biotransformation product of DEHP, was not detected at any
      treatment stage. Approximately 32% of DEHP in sewage was removed during anaerobic
      digestion of the sludge, while 32% remained in the digested and dewatered sludge.

PMID- 12598202
TI  - Estimating sludge loadings to land based on trace metal sorption in soil: effect
      of dissolved organo-metallic complexes.
AB  - This paper describes the results of research examining the effect of dissolved
      organo-metallic complexes of copper (Cu) and zinc (Zn) from sewage sludge
      leachate on sorption by a humic-gley soil A-horizon, and the influence of such
      complexes on resultant sludge loading estimates. Sorption was described with
      Linear, Freundlich or Langmuir equations, and compared between a sample of sludge
      leachate (containing 97.4% of Cu and 63.2% of Zn as dissolved organo-metallic
      complexes) and a reference solution (which mimicked the leachate, except for a
      lack of dissolved organic material). This comparison revealed that dissolved
      organo-metallic complexes significantly depressed Cu and Zn sorption in the study
      soil. The isotherm equations were then used to estimate sludge-derived Cu and Zn
      loadings to soil in order to result in an "allowable" output concentration from
      the soil solution to the surrounding environment. These loadings, together with
      soil bulk density and "availability" of sludge Cu and Zn, were incorporated in a
      preliminary model to estimate sludge application rates which are acceptable in
      terms of off-site movement of these metals through leaching losses. In the
      absence of dissolved organo-metallic complexes (sorption from the reference
      solution), levels of Cu and Zn sorption in the study soil indicated a sludge
      application rate of approximately 3500 kg/ha. However, when Cu and Zn sorption
      from the sludge leachate with dissolved organo-metallic complexes was considered,
      calculated loading rates were reduced to approximately 690 kg-sludge/ha. This
      suggests that for sludge loading estimates based on soil sorption characteristics
      to be relevant to environmental protection, the sorption depressing effect of
      dissolved organo-metallic complexes should be quantitatively considered.

PMID- 12598203
TI  - Model experiments on the microbial removal of chromium from contaminated
      groundwater.
AB  - A bacterial consortium with representatives of sulfate-reducing and denitrifying
      bacteria was selectively enriched. Model experiments under microaerobic
      conditions showed that it precipitated chromium from Cr (VI)-containing waters
      (area of a former electroplating factory, Leipzig, Germany) by two different
      mechanisms: by sulfate reduction and precipitation as sulfide, and by some direct
      reduction. Sulfate reduction needed fatty acids as organic substrates and
      resulted at the first stage in no sulfide accumulation. In the absence of the
      fatty acids but with straw as organic substrate, the direct reduction of chromium
      was observed without sulfate reduction. In this case Cr (VI)-reduction rate
      correlated with that of the denitrification.

PMID- 12598204
TI  - Application of two-stage fuzzy set theory to river quality evaluation in Taiwan.
AB  - An indicator model for evaluating trends in river quality using a two-stage fuzzy
      set theory to condense efficiently monitoring data is proposed. This candidate
      data reduction method uses fuzzy set theory in two analysis stages and constructs
      two different kinds of membership degree functions to produce an aggregate
      indicator of water quality. First, membership functions of the standard River
      pollution index (RPI) indicators, DO, BOD(5), SS, and NH(3)-N are constructed as
      piecewise linear distributions on the interval [0,1], with the critical variables
      normalized in four degrees of membership (0, 0.33, 0.67 and 1). The extension of
      the convergence of the fuzzy c-means (FCM) methodology is then used to construct
      a second membership set from the same normalized variables as used in the RPI
      estimations. Weighted sums of the similarity degrees derived from the extensions
      of FCM are used to construct an alternate overall index, the River quality index
      (RQI). The RQI provides for more logical analysis of disparate surveillance data
      than the RPI, resulting in a more systematic, less ambiguous approach to data
      integration and interpretation. In addition, this proposed alternative provides a
      more sensitive indication of changes in quality than the RPI. Finally, a case
      study of the Keeling River is presented to illustrate the application and
      advantages of the RQI.

PMID- 12598205
TI  - Arsenic removal by zero-valent iron: field, laboratory and modeling studies.
AB  - Field and laboratory studies were conducted to elucidate the design factors and
      mechanisms of arsenic removal from contaminated ground water using zero-valent
      iron. Large scale, field pilot experiments demonstrated for more than 8 months
      that iron filing filters can efficiently remove arsenite from aqueous solutions
      to levels less than 10 micro g/L. The maximum arsenic accumulation measured was
      4.4 mg As/g of media. The iron filing filters leached significant quantities of
      iron (73% of the iron was leached). A critical design parameter of the system was
      found to be the hydraulic detention time of the water in the filter. TCLP
      analyses of the spent media indicated that the arsenic concentration in the
      leachate was two orders of magnitude lower than the 5mg/L of TCLP for arsenic.
      Spectroscopic and laboratory arsenic leaching studies (alkaline extraction and
      TCLP) suggest that the arsenic surface precipitate is related to sulfur. The
      aging process (due to the longevity of the removal mechanism) makes the
      precipitation process virtually irreversible. A mathematical model was developed
      to simulate the removal process using a partitioning coefficient and a mass
      transfer process. Calibration of these parameters using the data for three
      columns revealed that the equilibrium-partitioning coefficient was the same for
      all three columns while the mass transfer coefficient was a function of the flow
      rate. The calibrated mass transfer coefficients are similar to those reported in
      the literature if they are normalized to the surface area of the media.

PMID- 12598206
TI  - Lake sedimentary evidence of phosphorus, iron and manganese mobilisation from
      intensively fertilised soils.
AB  - A study of historical P inputs to Friary Lough, Co. Tyrone, Northern Ireland used
      a multi-sediment core approach. One of the sediment cores taken from the littoral
      zone at 2.5m water depth showed exceptionally high P, Fe and Mn concentrations
      below 20 cm sediment depth. Concentrations increased to 14 mg Pg(-1), 238 mg Feg(
      1) and 35 mg Mng(-1) in the sediment profile and compared with deep basin maxima
      of 7 mg Pg(-1), 70 mg Feg(-1) and 2 mg Mng(-1) in surface sediments at 8.5m water
      depth. It is proposed that the high concentrations in the littoral zone core are
      due to post-depositional intrusion of chemical-rich local groundwater from soils
      in adjacent fields that are excessively fertilised with organic slurry. Soil
      analyses showed Olsen-P concentrations in these fields up to 125 mgkg(-1) at the
      soil surface (0-7.5 cm) and 39 mgkg(-1) in the sub-soil at 20 cm depth. We
      suggest that the mobilisation of P, Fe and Mn is due to leaching following P
      saturation and/or the loss of P absorbing chemicals due to prolonged reduction
      and complexing in wet soils. Further work will explore this relationship and the
      nature of the hydrological pathways through soil.

PMID- 12598207
TI  - Scale-up of anaerobic digestion of the biowaste fraction from domestic wastes.
AB  - In the City of Karlsruhe/Germany anaerobic digestion of 7200 ta(-1) of separately
      collected biowaste has proven its feasibility at an organic loading rate (OLR) of
      up to 8.5 kg CODm(-3)d(-1). An extension of biowaste collection over the whole
      city area would increase the amount of biowaste to 12,000 ta(-1), leading to an
      OLR of the existing anaerobic reactor of up to 15 kg CODm(-3)d(-1). To test,
      whether the increased amount of biowaste could be stabilized in the existing
      plant, biowaste suspensions were digested in a laboratory reactor at a maximum
      OLR, that exceeded the future OLR of the full-scale plant. The laboratory reactor
      was started with effluent of the full-scale biowaste digester. Like in full
      scale, biowaste suspension from the hydropulper was added in a fed-batch mode.
      The elimination of organic material (measured as COD, chemical oxygen demand) and
      the volumetric gas production were linearly increasing with the OLR from 4.3 to
      19 kg CODm(-3)d(-1). Thus, safe operation of the full-scale plant at an OLR of 15
      kg CODm(-3)d(-1) should be possible, leaving still some reserve capacity. To
      determine the metabolic reserves for fatty acid degradation during digestion at
      an OLR of 10 kg CODm(-3)d(-1), digester effluent was supplemented with either 40
      mmoll(-1) acetate, propionate, i-butyrate or n-butyrate. Results of these batch
      assays indicated a rapid degradation of all fatty acids and fatty acid conversion
      rates, that would allow a stable anaerobic fermentation at 15 kg CODm(-3)d(
      1)OLR. On the basis of the laboratory results the OLR of the full-scale methane
      reactor was increased to 15 kg CODm(-3)d(-1). After 7 months, results of full
      scale digestion were still consistent with the previously obtained laboratory
      results.

PMID- 12598208
TI  - The management of severe falciparum malaria.

PMID- 12598209
TI  - Can continuous positive airway pressure be self-titrated?

PMID- 12598210
TI  - Sputum induction: simpler, cheaper, and safer--but is it better?

PMID- 12598211
TI  - Nosology for our day: its application to chronic obstructive pulmonary disease.

PMID- 12598212
TI  - Effect of inspiratory flow pattern and inspiratory to expiratory ratio on
      nonlinear elastic behavior in patients with acute lung injury.
AB  - Ventilatory modes employing different inspiratory flow patterns and inspiratory
      to expiratory ratios may alter lung strain in acute lung injury patients. To
      determine whether variations in lung strain existed between pressure-controlled,
      volume-controlled, and pressure-controlled inverse ratio modes of ventilation, we
      randomly applied each for 30 minutes in 18 acute lung injury patients, keeping
      tidal volume, respiratory rate, fractional inspired oxygen, and total positive
      end-expiratory pressure constant. After each mode, a multiple linear regression
      analysis of dynamic airway pressure and airflow was performed with a volume
      dependent single compartment model of the equation of motion, and an index of
      nonlinear elastic behavior was calculated. In five additional patients,
      concurrent dynamic computerized axial tomography scanning at juxtadiaphragmatic
      and subcarinal levels was added. Although static mechanics, oxygenation, and
      hemodynamics were no different between pressure-controlled, volume-controlled,
      and pressure-controlled inverse ratio ventilation, we found significant
      differences in nonlinear behavior. This was least with pressure-controlled
      followed by volume-controlled ventilation, and pressure-controlled inverse ratio
      ventilation had the greatest nonlinear elastic behavior. Dynamic computerized
      axial tomography analysis revealed more overinflated units in the left subcarinal
      slice with pressure-controlled inverse ratio ventilation. Ventilator flow pattern
      and inspiratory to expiratory ratio independently influence lung strain in acute
      lung injury; however, further studies are needed to determine the biologic
      significance.

PMID- 12598213
TI  - Contribution of the intensive care unit environment to sleep disruption in
      mechanically ventilated patients and healthy subjects.
AB  - Recent studies have challenged the traditional hypothesis that excessive
      environmental noise is central to the etiology of sleep disruption in the
      intensive care unit (ICU). We characterized potentially disruptive ICU noise
      stimuli and patient-care activities and determined their relative contributions
      to sleep disruption. Furthermore, we studied the effect of noise in isolation by
      placing healthy subjects in the ICU in both normal and noise-reduced locations.
      Seven mechanically ventilated patients and six healthy subjects were studied by
      continuous 24-hour polysomnography with time-synchronized environmental
      monitoring. Sound elevations occurred 36.5 +/- 20.1 times per hour of sleep and
      were responsible for 20.9 +/- 11.3% of total arousals and awakenings. Patient
      care activities occurred 7.8 +/- 4.2 times per hour of sleep and were responsible
      for 7.1 +/- 4.4% of total arousals and awakenings. Healthy subjects slept
      relatively well in the typically loud ICU environment and experienced a
      quantitative, but not qualitative, improvement in sleep in a noise-reduced,
      single-patient ICU room. Our data indicate that noise and patient-care activities
      account for less than 30% of arousals and awakenings and suggest that other
      elements of the critically ill patient's environment or treatment should be
      investigated in the pathogenesis of ICU sleep disruption.

PMID- 12598214
TI  - Can patients with obstructive sleep apnea titrate their own continuous positive
      airway pressure?
AB  - Manual continuous positive airway pressure (CPAP) titration in a sleep laboratory
      is costly and limits access for diagnostic studies. Many factors affect CPAP
      compliance, but education and support, rather than in-laboratory CPAP titration,
      appear to be pivotal. Self-adjustment of CPAP at home will provide equal or
      superior efficacy in the treatment of obstructive sleep apnea (OSA) as compared
      with in-laboratory titration. A randomized, single-blind, two-period crossover
      trial of CPAP treatment at the in-laboratory-determined optimal pressure versus
      at-home self-adjustment of CPAP (starting pressure based on prediction equation).
      Eighteen CPAP-naive patients (16 males, 50 +/- 15 years old, apnea hypopnea index
      40 +/- 20) with a new diagnosis of OSA were tested. Testing was performed before
      and after CPAP treatment in each of two 5-week study limbs. CPAP, compliance with
      CPAP treatment, the Sleep Apnea Quality of Life Index, the Functional Outcomes of
      Sleep Questionnaire score, the Epworth sleepiness scale score, sleep
      architecture, sleep apnea severity, and maintenance of wakefulness tests were
      performed. Both modes of CPAP treatment significantly improved objective and
      subjective measures of OSA, but they did not differ in efficacy. Home self
      titration of CPAP is as effective as in-laboratory manual titration in the
      management of patients with OSA.

PMID- 12598215
TI  - Yield of sputum induction in the diagnosis of pleural tuberculosis.
AB  - We prospectively evaluated the diagnostic yield of acid-fast bacilli smear and
      culture for Mycobacterium tuberculosis using sputum induction (SI) in the workup
      of patients with suspected pleural tuberculosis (TB) who were unable to produce
      sputum spontaneously. Of the 113 patients studied, a final diagnosis of pleural
      TB was made in 84 patients (71 HIV seronegative) and a final diagnosis of another
      disease in 29 patients. Histopathologic examination of the pleural biopsy tissue
      had the highest diagnostic yield (78%; 66/84). The bacteriologic yield was 62%
      (52/84) for the pleural tissue, 12% (10/84) for pleural fluid, and 52% (44/84)
      for sputum cultures obtained by SI. The yield of SI culture for M. tuberculosis
      was 55% (35/64) in patients with a normal radiograph (except for the pleural
      effusion) and 45% (9/20) in those with evidence of parenchymal disease suggestive
      of pulmonary TB (p = 0.6). The yield of sputum cultures obtained by SI is high in
      patients suspected of having pleural TB even in those cases with no pulmonary
      parenchymal abnormalities on the chest radiograph.

PMID- 12598216
TI  - Desmopressin therapy for massive hemoptysis associated with severe leptospirosis.
AB  - Massive hemoptysis in patients with severe leptospirosis is often resistant to
      conventional therapies and can rapidly become fatal. Desmopressin is a fast
      acting blood-saving agent used in various hereditary and acquired clotting
      disorders. We used desmopressin infusions to treat massive pulmonary hemorrhage
      in six leptospirosis patients with respiratory failure, shock, and multiple organ
      dysfunction. Hemoptysis ceased rapidly in every case, and five patients finally
      recovered. Two additional patients with less severe hemoptysis were also
      successfully treated.

PMID- 12598217
TI  - Accuracy of the preoperative assessment in predicting pulmonary risk after
      nonthoracic surgery.
AB  - We examined the accuracy of preoperative assessment in predicting postoperative
      pulmonary risk in a prospective cohort of 272 consecutive patients referred for
      evaluation before nonthoracic surgery. Outcomes were assessed by an independent
      investigator who was blinded to the preoperative data. There were 22 (8%)
      postoperative pulmonary complications. Statistically significant predictors of
      pulmonary complications (all p < or = 0.005) were as follows: hypercapnea of 45
      mm Hg or more (odds ratio, 61.0), a FVC of less than 1.5 L/minute (odds ratio,
      11.1), a maximal laryngeal height of 4 cm or less (odds ratio, 6.9), a forced
      expiratory time of 9 seconds or more (odds ratio, 5.7), smoking of 40 pack-years
      or more (odds ratio, 5.7), and a body mass index of 30 or more (odds ratio, 4.1).
      Multiple regression analyses revealed three preoperative clinical factors that
      are independently associated with pulmonary complications: an age of 65 years or
      more (odds ratio, 1.8; p = 0.02), smoking of 40 pack-years or more (odds ratio,
      1.9; p = 0.02), and maximum laryngeal height of 4 cm or less (odds ratio, 2.0; p
      = 0.007). Thus, preoperative factors can identify those patients referred to
      pulmonologists or internists who are at increased risk for pulmonary
      complications after nonthoracic surgery.

PMID- 12598218
TI  - Impaired pulmonary inflammatory responses are a prominent feature of
      streptococcal pneumonia in mice with experimental emphysema.
AB  - Little is known about why patients with chronic obstructive pulmonary disease are
      susceptible to bacterial infections. Using an animal model of pulmonary
      emphysema, we investigated the inflammatory responses to bacterial infection.
      After intratracheal infection with Streptococcus pneumoniae (10(3)-10(7)
      cfu/mouse), the control mice did not die. However, the mice with emphysema died
      in a dose-dependent manner. Bronchoalveolar lavage fluid, examined 24 hours after
      infection showed that the numbers of total cells and neutrophils, in addition to
      murine tumor necrosis factor-alpha and macrophage inflammatory protein-2
      concentrations, were significantly less in the mice with emphysema compared with
      the control mice. Histopathologic findings revealed that the alveoli were filled
      with inflammatory cells and exudate in the control mice but not in the mice with
      emphysema. Seventy-two hours after infection, serum cytokine levels were
      significantly higher in the mice with emphysema, and significant numbers of S.
      pneumoniae were detected in both the whole lung tissues and the blood of mice
      with emphysema. These findings suggest that the inflammatory response in mice
      with emphysema was impaired at the site of bacterial infection despite the
      bacteremia, which accelerated severe systemic inflammatory responses.
      Accordingly, intra-alveolar but not systemic immune responses to bacterial
      infection were impaired in the presence of experimental emphysema.

PMID- 12598219
TI  - Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb
      lung.
AB  - Subtraction hybridization was performed to explore changes in gene expression in
      the fetal lung after 20 mg of intra-amniotic (IA) endotoxin. Interferon-gamma
      inducible 10-kd protein (IP-10) and monokine induced by interferon-gamma (MIG)
      constituted 20% of 102 endotoxin-induced clones identified in the preterm lamb
      lung. IP-10 (CXCL10) and MIG (CXCL9) are T-cell chemoattractants that have
      angiostatic properties. Both IP-10 and MIG mRNA were induced 30- to 40-fold in
      the fetal lung at 1 to 2 days after IA endotoxin. Intense IP-10 mRNA expression
      was detected by in situ hybridization in the bronchiolar and peribronchiolar
      areas and the vascular endothelium after IA endotoxin at all time points tested.
      MIG mRNA expression was detected initially focally in infiltrating neutrophils
      (15 hours after IA endotoxin) and later in the bronchiolar and peribronchiolar
      areas and vascular endothelium (1 day after IA endotoxin). In contrast to
      endotoxin, IA tumor necrosis factor-alpha or interleukin-1 alpha did not induce
      IP-10 or MIG mRNA in the lung. IA endotoxin also caused a modest induction of IP
      10 and MIG mRNA in the jejunum, liver, and spleen. The IP-10 and MIG receptor
      CXCR3 was detected in the bronchiolar epithelium of preterm lambs by
      immunostaining. IP-10 and MIG are potent angiostatic chemokines that may
      contribute to lung injury and altered pulmonary vascular development in the
      preterm exposed to chorioamnionitis.

PMID- 12598220
TI  - American Thoracic Society Statement: Occupational contribution to the burden of
      airway disease.

PMID- 12598221
TI  - Meta-analysis of tidal volumes in ARDS.

PMID- 12598222
TI  - "Acidopnea" and the dictionary.

PMID- 12598223
TI  - Ipratropium and lung health study.

PMID- 12598224
TI  - Dilution of respiratory solutes in exhaled condensates.

PMID- 12598225
TI  - Mitogen-activated protein kinases mediate peroxynitrite-induced cell death in
      human bronchial epithelial cells.
AB  - Peroxynitrite, formed by the reaction of nitric oxide (NO. ) with superoxide
      anions (O(2)(-).), may play a role in the pathophysiology of inflammation. The
      effects of 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, on the
      human bronchial epithelial cell line BEAS-2B, were examined. SIN-1 exposure
      resulted in cell death in a time- and dose-dependent manner. Depletion of
      intracellular glutathione increased the vulnerability of the cells. Pretreatment
      with Mn(III)tetrakis(N-methyl-4'-pyridyl)porphyrin (MnTMPyP) or hydroxocobalamin
      (HC), O(2)(-). and NO. scavengers, respectively, reduced significantly SIN-1
      induced cell death (18.66 +/- 3.57 vs. 77.01 +/- 14.07 or 82.20 +/- 9.64, % cell
      viability SIN-1 vs. MnTMPyP or HC). Moreover, the mitogen-activated protein
      kinases (MAPK) p44/42 (ERK), p38, and p54/46 (JNK) were also activated in a time-
      and concentration-dependent manner. PD-98059 and SB-239063, specific inhibitors
      of ERK and p38 MAPK pathways, failed to protect cells against 1 mM SIN-1.
      However, PD-98059 partially inhibited (60% cell survival) SIN-1 effects at < or
      =0.25 mM, and this was increased with the inclusion of SB-239063. Therefore,
      MAPKs may mediate signal transduction pathways induced by peroxynitrite in lung
      epithelial cells leading to cell death.

PMID- 12598226
TI  - Laser-assisted microdissection and real-time PCR detect anti-inflammatory effect
      of perfluorocarbon.
AB  - The aim of this study was to identify cell types involved in the anti
      inflammatory effect of ventilation with perfluorocarbon in vivo. Fifteen
      anesthetized, surfactant-depleted piglets received either aerosolized
      perfluorocarbon (Aerosol-PFC), partial liquid ventilation (rLV) at functional
      residual capacity (FRC) volume (FRC-PLV), or intermittent mandatory ventilation
      (control). After laser-assisted microdissection of different lung cell types,
      mRNA expression of IL-8 and ICAM-1 was determined using TaqMan real-time PCR
      normalized to hypoxanthine phosphoribosyltransferase (HPRT). IL-8 mRNA expression
      (means +/- SE; control vs. Aerosol-PFC) was 356 +/- 142 copies IL-8 mRNA/copy
      HPRT mRNA vs. 3.5 +/- 1.8 in alveolar macrophages (P <0.01); 208 +/- 108 vs. 2.7
      +/- 0.8 in bronchiolar epithelial cells (P <0.05); 26 +/- 11 vs. 0.7 +/- 0.2 in
      alveolar septum cells (P <0.01); 2.8 +/- 1.0 vs. 0.8 +/- 0.4 in bronchiolar
      smooth muscle cells (P <0.05); and 1.1 +/- 0.4 vs. 0.2 +/- 0.05 in vascular
      smooth muscle cells (P <0.05). With FRC-PLV, IL-8/HPRT mRNA expression was
      significantly lower in macrophages, bronchiolar epithelial, and vascular smooth
      muscle cells. ICAM-1 mRNA expression in vascular endothelial cells remained
      unchanged. Predominantly, alveolar macrophages and bronchiolar epithelial cells
      were involved in the inflammatory pulmonary process. The anti-inflammatory effect
      of Aerosol-PFC was most pronounced.

PMID- 12598227
TI  - Release of biologically active TGF-beta1 by alveolar epithelial cells results in
      pulmonary fibrosis.
AB  - Idiopathic pulmonary fibrosis (IPF) is a progressive fatal fibrotic lung disease.
      Transforming growth factor (TGF)-beta1 is present in a biologically active
      conformation in the epithelial cells lining lesions with advanced IPF. To
      determine the role of aberrant expression of biologically active TGF-beta1 by
      alveolar epithelial cells (AECs), the AECs of explanted normal rat lungs were
      transfected with the TGF-beta1 gene using the retrovirus pMX-L-s223,225-TGF
      beta1. In situ hybridization using a digoxigenin-labeled cDNA of the puromycin
      resistance gene contained in the pMX demonstrated that pMX-L-s233,225-TGF-beta1
      was selectively transfected into AECs of the explants. Conditioned media
      overlying explants obtained 7 days after being treated with pMX-L-s223,225-TGF
      beta1 contained 14.5 +/- 3.15 pg/ml of active TGF-beta1. With the use of Masson's
      trichrome staining of explant sections obtained 14 days after transfection, there
      were lesions similar to those in IPF, characterized by type II AEC hyperplasia,
      interstitial thickening, extensive increase in interstitial and subepithelial
      collagen, an increase in the number of fibroblasts, and areas resembling
      fibroblast buds. Collagens I, III, IV, and V and fibronectin were increased in
      explants treated with pMX-L-s223,225-TGF-beta1. The findings in the current study
      suggest that IPF may be a disorder of epithelial cells and not inflammatory
      cells.

PMID- 12598228
TI  - Impaired synthesis of prostaglandin E2 by lung fibroblasts and alveolar
      epithelial cells from GM-CSF-/- mice: implications for fibroproliferation.
AB  - Prostaglandin E(2) (PGE(2)) is a potent suppressor of fibroblast activity. We
      previously reported that bleomycin-induced pulmonary fibrosis was exaggerated in
      granulocyte-macrophage colony-stimulating factor knockout (GM-CSF(-/-)) mice
      compared with wild-type (GM-CSF(+/+)) mice and that increased fibrosis was
      associated with decreased PGE(2) levels in lung homogenates and alveolar
      macrophage cultures. Pulmonary fibroblasts and alveolar epithelial cells (AECs)
      represent additional cellular sources of PGE(2) within the lung. Therefore, we
      examined fibroblasts and AECs from GM-CSF(-/-) mice, and we found that they
      elaborated significantly less PGE(2) than did cells from GM-CSF(+/+) mice. This
      defect was associated with reduced expression of cyclooxygenase-1 and -2 (COX-1
      and COX-2), key enzymes in the biosynthesis of PGE(2). Additionally,
      proliferation of GM-CSF(-/-) fibroblasts was greater than that of GM-CSF(+/+)
      fibroblasts, and GM-CSF(-/-) AECs were impaired in their ability to inhibit
      fibroblast proliferation in coculture. The addition of GM-CSF to fibroblasts from
      GM-CSF(-/-) mice increased PGE(2) production and decreased proliferation.
      Similarly, AECs isolated from GM-CSF(-/-) mice with transgenic expression of GM
      CSF under the surfactant protein C promoter (SpC-GM mice) produced more PGE(2)
      than did AEC from control mice. Finally, SpC-GM mice were protected from
      fluorescein isothiocyanate-induced pulmonary fibrosis. In conclusion, these data
      demonstrate that GM-CSF regulates PGE(2) production in pulmonary fibroblasts and
      AECs and thus plays an important role in limiting fibroproliferation.

PMID- 12598229
TI  - Knockout of Kir6.2 negates ischemic preconditioning-induced protection of
      myocardial energetics.
AB  - Although ischemic preconditioning induces bioenergetic tolerance and thereby
      remodels energy metabolism that is crucial for postischemic recovery of the
      heart, the molecular components associated with preservation of cellular energy
      production, transfer, and utilization are not fully understood. Here myocardial
      bioenergetic dynamics were assessed by (18)O-assisted (31)P-NMR spectroscopy in
      control or preconditioned hearts from wild-type (WT) or Kir6.2-knockout (Kir6.2
      KO) mice that lack metabolism-sensing sarcolemmal ATP-sensitive K(+) (K(ATP))
      channels. In WT vs. Kir6.2-KO hearts, preconditioning induced a significantly
      higher total ATP turnover (232 +/- 20 vs. 155 +/- 15 nmol x mg protein(-1) x min(
      1)), ATP synthesis rate (58 +/- 3 vs. 46 +/- 3% (18)O labeling of gamma-ATP), and
      ATP consumption rate (51 +/- 4 vs. 31 +/- 4% (18)O labeling of P(i)) after
      ischemia-reperfusion. Moreover, preconditioning preserved cardiac creatine kinase
      catalyzed phosphotransfer in WT (234 +/- 26 nmol x mg protein(-1) x min(-1)) but
      not Kir6.2-KO (133 +/- 18 nmol x mg protein(-1) x min(-1)) hearts. In contrast
      with WT hearts, preconditioning failed to preserve contractile recovery in Kir6.2
      KO hearts, as tight coupling between postischemic performance and high-energy
      phosphoryl transfer was compromised in the K(ATP)-channel-deficient myocardium.
      Thus intact K(ATP) channels are integral in ischemic preconditioning-induced
      protection of cellular energetic dynamics and associated cardiac performance.

PMID- 12598230
TI  - NOS inhibition accelerates atherogenesis: reversal by exercise.
AB  - In this study, we assessed the effects of chronic exercise training (12 wk) on
      atherosclerotic lesion formation in hypercholesterolemic apolipoprotein E
      deficient mice (n = 31). At the age of 9 wk, mice were assigned to the following
      groups: sedentary (Sed; n = 9); exercise (Ex; n = 12); sedentary and oral NG
      nitro-L-arginine (L-NNA, Sed-NA; n = 4), or exercise and oral L-NNA (Ex-NA; n =
      6). Chronic exercise training was performed on a treadmill for 12 wk (6 times/wk
      and twice for 1 h/day) at a final speed of 22 m/min, and an 8 degrees grade. L
      NNA was discontinued 5 days before final treadmill testing. The farthest distance
      run to exhaustion was observed in Ex-NA mice (Sed: 306 +/- 32 m; Ex: 640 +/- 87;
      Sed-NA: 451 +/- 109 m; Ex-NA: 820 +/- 49 m; all P < 0.05). Lesion formation was
      assessed in the proximal ascending aorta by dissection microscopy after oil red O
      staining. The aortas of Sed-NA mice manifested a threefold increase in lesion
      formation compared with the other groups. This L-NNA-induced lesion formation was
      reduced by chronic exercise training (Sed, 786 +/- 144; Ex, 780 +/- 206; Sed-NA,
      2,147 +/- 522; Ex-NA, 851 +/- 253; Sed-NA vs. all other groups: P < 0.001). In
      conclusion, treatment with oral L-NNA (an nitric oxide synthase antagonist) leads
      to accelerated atherogenesis in genetically determined hypercholesterolemic mice.
      This adverse effect can be overcome by chronic exercise training.

PMID- 12598231
TI  - Mechanisms of Arg-Pro-Pro-Gly-Phe inhibition of thrombin.
AB  - Investigations determined the mechanism(s) by which Arg-Pro-Pro-Gly-Phe (RPPGF)
      inhibits thrombin-induced platelet activation. High concentrations of RPPGF
      inhibit thrombin-induced coagulant activity. RPPGF binds to the active site of
      thrombin by forming a parallel beta-strand with Ser214-Gly216 and interacts with
      His57, Asp189, and Ser195 of the catalytic triad. RPPGF competitively inhibits
      alpha-thrombin from hydrolyzing Sar-Pro-Arg-paranitroanilide with a Ki = 1.75 +/-
      0.03 mM. Other mechanisms were sought to explain why RPPGF inhibits thrombin
      activation of platelets at concentrations below that which inhibits its active
      site. Soluble RPPGF blocks biotinylated NATLDPRSFLLR of the thrombin cleavage
      site on protease-activated receptor (PAR)1 from binding to the peptide RPPGC
      (IC50 = 20 microM). The soluble recombinant extracellular domain of PAR1
      (rPAR1EC) blocks biotinylated RPPGF binding to rPAR1EC (IC50 = 50 microM) bound
      to microtiter plates, but rPAR1EC deletion mutants missing the sequence LDPR or
      PRSF do not. RPPGF and related forms prevent the thrombin-like enzyme
      thrombocytin from proteolyzing rPAR1EC at concentrations that do not block
      thrombocytin's active site. These studies indicate that RPPGF is a bifunctional
      inhibitor of thrombin: it binds to PAR1 to prevent thrombin cleavage at Arg41 and
      interacts with the active site of alpha-thrombin.

PMID- 12598232
TI  - Plasticity of KIR channels in human smooth muscle cells from internal thoracic
      artery.
AB  - Inwardly rectifying K(+) (K(IR)) currents are present in some, but not all,
      vascular smooth muscles. We used patch-clamp methods to examine plasticity of
      this current by comparing contractile and proliferative phenotypes of a clonal
      human vascular smooth muscle cell line. Hyperpolarization of cells under voltage
      clamp elicited a large inward current that was selective for K(+) and blocked by
      Ba(2+). Current density was greater in proliferative compared with contractile
      cells (-4.5 +/- 0.9 and -1.4 +/- 0.3 pA/pF, respectively; P < 0.001). RT-PCR of
      mRNA from proliferative cells identified transcripts for Kir2.1 and Kir2.2 but
      not Kir2.3 potassium channels. Western blot analysis demonstrated greater
      expression of Kir2.1 protein in proliferative cells, consistent with the higher
      current density. Proliferative cells displayed a more negative membrane potential
      than contractile cells (-71 +/- 2 and -35 +/- 4 mV, respectively; P < 0.001).
      Ba(2+) depolarized all cells, whereas small increases in extracellular K(+)
      concentration elicited hyperpolarization only in contractile cells. Ba(2+)
      inhibited [(3)H]thymidine incorporation, indicating a possible role for K(IR)
      channels in the regulation of proliferation. The phenotype-dependent plasticity
      of K(IR) channels may have relevance to vascular remodeling.

PMID- 12598233
TI  - High plasma norepinephrine attenuates the dynamic heart rate response to vagal
      stimulation.
AB  - To better understand the pathophysiological significance of high plasma
      norepinephrine (NE) concentration in regulating heart rate (HR), we examined the
      interactions between high plasma NE and dynamic vagal control of HR. In
      anesthetized rabbits with sinoaortic denervation and vagotomy, using a binary
      white noise sequence (0-10 Hz) for 10 min, we stimulated the right vagus and
      estimated the transfer function from vagal stimulation to HR response. The
      transfer function approximated a first-order low-pass filter with pure delay.
      Infusion of NE (100 microg. kg(-1) x h(-1) iv) attenuated the dynamic gain from
      6.2 +/- 0.8 to 3.9 +/- 1.2 beats x min(-1) x Hz(-1) (n = 7, P < 0.05) without
      affecting the corner frequency or pure delay. Simultaneous intravenous
      administration of phentolamine (1 mg x kg(-1) x h(-1)) and NE (100 microg x kg(
      1) x h(-1)) abolished the inhibitory effect of NE on the dynamic gain (6.3 +/-
      0.8 vs. 6.4 +/- 1.3 beats x min(-1) x Hz(-1), not significant, n = 7). The
      inhibitory effect of NE at infusion rates of 10, 50, and 100 microg x kg(-1) x h(
      1) on dynamic vagal control of HR was dose-dependent (n = 5). In conclusion, high
      plasma NE attenuated the dynamic HR response to vagal stimulation, probably via
      activation of alpha-adrenergic receptors on the preganglionic and/or
      postganglionic cardiac vagal nerve terminals.

PMID- 12598234
TI  - Tissue window chamber system for validation of implanted oxygen sensors.
AB  - An experimental system is described for validating electrochemical oxygen sensors
      implanted in tissues. The system is a modified hamster window chamber in which a
      thin layer of vascularized tissue is held between two plates, one plate having an
      observation window and the other plate having an array of oxygen sensors. This
      arrangement permits simultaneous recording of oxygen sensor signals and
      nondestructive visualization of the tissue adjacent to the sensors over periods
      of 1 mo or more, without the inhibitory effects of anesthesia. The system
      provides a means for study of the effects of spatial and temporal oxygen
      distributions on the sensor signals and adaptation of the tissue structure over
      time. Examples are given of sensor recordings and images of tissues with
      implanted oxygen sensor arrays.

PMID- 12598235
TI  - Relative contribution of vasodilator prostanoids, NO, and KATP channels to human
      forearm metabolic vasodilation.
AB  - Isolated ATP-sensitive K(+) (K(ATP)) channel inhibition with glibenclamide does
      not alter exercise-induced forearm metabolic vasodilation. Whether forearm
      metabolic vasodilation would be influenced by K(ATP) channel inhibition in the
      setting of impaired nitric oxide (NO)- and prostanoid-mediated vasodilation is
      unknown. Thirty-seven healthy subjects were recruited. Forearm blood flow (FBF)
      was assessed using venous occlusion plethysmography, and functional hyperemic
      blood flow (FHBF) was induced by isotonic wrist exercise. Infusion of N(G)
      monomethyl-l-arginine (l-NMMA), aspirin, or the combination reduced resting FBF
      compared with vehicle (P < 0.05). Addition of glibenclamide to l-NMMA, aspirin,
      or the combination did not further reduce resting FBF. l-NMMA decreased peak FHBF
      by 26%, and volume was restored after 5 min (P < 0.05). Aspirin reduced peak FHBF
      by 13%, and volume repaid after 5 min (P < 0.05). Coinfusion of l-NMMA and
      aspirin reduced peak FHBF by 21% (P < 0.01), and volume was restored after 5 min
      (P < 0.05). Addition of glibenclamide to l-NMMA and aspirin did not further
      decrease FHBF. Vascular K(ATP) channel blockade with glibenclamide does not
      affect resting FBF or FHBF in the setting of NO and vasodilator prostanoid
      inhibition.

PMID- 12598236
TI  - Postcardiac surgery complications: association of acute renal dysfunction and
      atrial fibrillation.
AB  - Postoperative creatinine increase is associated with adverse outcome after
      cardiac surgery. Although postoperative stroke and renal dysfunction are
      associated after cardiac surgery, suggesting a common systemic insult, a similar
      assessment of atrial fibrillation and renal dysfunction has not been performed.
      Therefore, we tested the hypothesis that patients with new-onset atrial
      fibrillation complicating coronary bypass surgery have a greater postoperative
      creatinine increase. Data were obtained for 453 elective coronary bypass surgery
      patients with no history of atrial fibrillation. Multivariate regression analyses
      of factors associated with peak fractional change in creatinine demonstrated a
      two-way interaction between age and atrial fibrillation (variable estimate, -1.1;
      P = 0.002). Similar results were obtained in a secondary multivariate model
      analyzing factors associated with peak postoperative creatinine (variable
      estimate, -0.01; P = 0.04). We confirmed our hypothesis that patients with new
      onset atrial fibrillation are more likely to have acute renal dysfunction after
      cardiac surgery. The association of atrial fibrillation and creatinine increase
      diminishes with advancing age. These data are consistent with a common
      pathophysiology that contributes in an age-dependent fashion to the etiology of
      both acute renal dysfunction and atrial fibrillation after coronary bypass
      surgery. IMPLICATIONS: We found an independent association between new-onset
      atrial fibrillation and postoperative creatinine increase that is influenced by
      age. The degree to which atrial fibrillation is associated with postoperative
      creatinine increase diminishes with advancing age. This interaction suggests that
      a common etiology for these two complications may be more important in younger
      patients.

PMID- 12598237
TI  - Comparison of alpha-stat and pH-stat cardiopulmonary bypass in relation to
      jugular venous oxygen saturation and cerebral glucose-oxygen utilization.
AB  - Jugular venous oxygen saturation (SJVO(2)) reflects the balance between cerebral
      blood flow and metabolism. This study was designed to compare the effects of two
      different acid-base strategies on jugular venous desaturation (SJVO(2) <50%) and
      cerebral arteriovenous oxygen-glucose use. We performed a prospective, randomized
      study in 52 patients undergoing cardiopulmonary bypass (CPB) at 27 degrees C with
      either alpha-stat (n = 26) or pH-stat (n = 26) management. A retrograde internal
      jugular vein catheter was inserted, and blood samples were obtained at intervals
      during CPB. There were no differences in preoperative variables between the
      groups. SJVO(2) was significantly higher in the pH-stat group (at 30 min CPB:
      86.2% +/- 6.1% versus 70.6% +/- 9.3%; P < 0.001). The differences in
      arteriovenous oxygen and glucose were smaller in the pH-stat group (at 30 min
      CPB: 1.9 +/- 0.82 mL/dL versus 3.98 +/- 1.12 mL/dL; P < 0.001; and 3.67 +/- 2.8
      mL/dL versus 10.1 +/- 5.2 mL/dL; P < 0.001, respectively). All episodes of
      desaturation occurred during rewarming, and the difference in the incidence of
      desaturation between the two groups was not significant. All patients left the
      hospital in good condition. Compared with alpha-stat, the pH-stat strategy
      promotes an increase in SJVO(2) and a decrease in arteriovenous oxygen and
      arteriovenous glucose differences. These findings indicate an increased cerebral
      supply with pH-stat; however, this strategy does not eliminate jugular venous
      desaturation during CPB. IMPLICATIONS: A prospective, randomized study in 52
      patients during cardiopulmonary bypass revealed that pH-stat increased jugular
      venous oxygen saturation and decreased arteriovenous oxygen-glucose differences.
      There was no difference in the incidence of jugular venous desaturation. These
      findings suggest an increased cerebral blood flow with no protection against
      jugular venous desaturation during pH-stat.

PMID- 12598238
TI  - Changes in cerebral microcirculation during and after abdominal aortic cross
      clamping in rabbits: the role of thromboxane A2 receptor.
AB  - Little is known about any changes in cerebral hemodynamics, during and after
      abdominal aortic cross-clamping and unclamping, especially in the cerebral
      microcirculation. We studied the effects of abdominal aortic cross-clamping and
      unclamping on cerebral pial vessel diameter in the presence or absence of the
      thromboxane (Tx)A(2) receptor antagonist using a closed cranial window in 27
      rabbits. Although infrarenal aortic cross-clamping did not affect pial vessel
      diameter, release of a 20-min aortic cross-clamp caused pial arterioles to dilate
      and then constrict. A significant constriction persisted for at least 60 min
      (maximum, -17% for large [> or =75 micro m] and -28% for small arterioles [<75
      micro m] compared with baseline). Topical administration of a TxA(2) receptor
      antagonist, seratrodast, at 10(-7) M and 10(-6) M, significantly attenuated the
      constriction of large and small arterioles (at 60 min, -9% and -13% constriction
      for 10(-7) M, and -6% and -7% for 10(-6) M). Release of a 20-min aortic cross
      clamp induced a sustained pial arteriolar constriction. Because this unclamping
      induced vasoconstriction was attenuated by topical administration of seratrodast,
      it was likely partially mediated via the washout of TxA(2) produced in the
      ischemic region during the clamp and after cross-clamp release. IMPLICATIONS:
      Abdominal aortic unclamping after a 20-min clamp caused an initial dilation
      followed by a sustained constriction of pial arterioles. Seratrodast, a
      thromboxane A(2) receptor antagonist, attenuated the vasoconstriction suggesting
      that it is at least partly mediated by thromboxane A(2) washed out from the
      region rendered ischemic by clamping.

PMID- 12598239
TI  - Dexmedetomidine decreases perioperative myocardial lactate release in dogs.
AB  - The sympatholytic effect of the alpha(2)-adrenergic agonist dexmedetomidine may
      decrease emergence-related myocardial ischemic load in patients. However, a
      direct measure of myocardial ischemia, such as myocardial lactate release, is
      difficult to obtain in patients. Therefore, we studied mongrel dogs and measured
      myocardial lactate release, myocardial oxygen supply, hemodynamic variables, and
      neurohumoral indices of the stress response. After the induction of a
      standardized degree of borderline myocardial ischemia, either dexmedetomidine
      (dexmed group, n = 9) or normal saline (control group, n = 9) was infused.
      Measurements were repeated at the end of the anesthetic period and every 10 min
      during the 90-min emergence period. In the dexmed group, the cumulative emergence
      related lactate release was 46% less than in the control group (95% confidence
      interval, 20%-80%; P = 0.02). Simultaneously, dexmedetomidine increased the endo
      /epicardial blood flow ratio by 35% (control group, 0.4 +/- 0.1; dexmed group,
      0.6 +/- 0.1; P = 0.03). These antiischemic effects of dexmedetomidine were
      accompanied by reduced plasma concentrations of norepinephrine (126 versus 577
      pg/mL) and epinephrine (158 versus 1909 pg/mL) and a slower heart rate (123 +/- 6
      versus 160 +/- 10 bpm, dexmed versus control). The antiischemic effect of
      dexmedetomidine started before emergence, as evidenced by a decreased prevalence
      of myocardial lactate release at that time (zero of eight dogs in the dexmed
      group and four of seven dogs in the control group had lactate release before
      emergence; P = 0.03). IMPLICATIONS: Dexmedetomidine decreases plasma
      catecholamines and heart rate during emergence from anesthesia. In dogs with a
      coronary stenosis, these sympatholytic effects decrease myocardial lactate
      release and, therefore, minimize emergence-related myocardial ischemia.

PMID- 12598240
TI  - Short-term administration of ethanol does not affect functional recovery from
      myocardial stunning in awake dogs.
AB  - Chronic ingestion of small doses of ethanol protects the myocardium from ischemic
      damage. It was demonstrated that short-term administration of ethanol (SAE)
      enhances the recovery of stunned myocardium in acutely instrumented, anesthetized
      dogs. It is unclear whether this beneficial effect of SAE also occurs in awake
      dogs. Therefore, we investigated the effects of SAE on regional myocardial
      stunning in awake dogs. Thirty-six dogs were chronically instrumented for
      measurement of heart rate, left atrial, aortic, and left ventricular pressure,
      left systolic ventricular contactility (dP/dt(max)) and diastolic ventricular
      function (dP/dt(min)), and regional myocardial wall-thickening fraction (WTF).
      Occluders around the left anterior descending (LAD) artery allowed the induction
      of reversible ischemia in the LAD-perfused myocardium. The dogs were assigned to
      one of three groups that differed in the dose of ethanol administered in the
      ethanol experiment (I, 0.125 g/kg [n = 12]; II, 0.25 g/kg [n = 12]; III, 0.5 g/kg
      [n = 12]). In each group, the dogs underwent two ischemic episodes (randomized
      crossover fashion; separate days): 10 min of LAD occlusion after the application
      of ethanol IV over 30 min (ethanol group) and without ethanol (control). WTF and
      hemodynamic variables were measured at baseline and at predetermined time points
      until complete recovery of myocardial stunning occurred. LAD-ischemia led to a
      significant decrease of LAD-WTF in all groups. There was no difference in WTF and
      hemodynamic variables with or without SAE during reperfusion. We conclude that
      SAE (0.125 g/kg, 0.25 g/kg, and 0.5 g/kg) does not significantly affect
      myocardial stunning in conscious dogs. IMPLICATIONS: In contrast to previous
      experiments in anesthetized dogs, short-term administration of ethanol does not
      alter myocardial stunning in conscious dogs.

PMID- 12598241
TI  - Mexiletine differentially modulates vasorelaxation mediated by adenosine
      triphosphate-sensitive K+ channels in aortas from normotensive and hypertensive
      rats.
AB  - The modification of vasodilation through adenosine triphosphate (ATP)-sensitive
      K(+) channels induced by antiarrhythmic drugs has not been studied in chronic
      hypertension. We designed the present study to examine whether mexiletine
      modulates vasorelaxation via these channels in hypertensive rat aortas.
      Normotensive and hypertensive rat aortas without endothelium were suspended for
      isometric force recording. Mexiletine (3 x 10(-5) M) increased vasorelaxation
      induced by levcromakalim (10(-8)-10(-5) M) in normotensive, but not hypertensive,
      rat aortas. Mexiletine (10(-5) to 3 x 10(-5) M) also augmented vasorelaxation to
      sodium nitroprusside (10(-10)-10(-5) M) only in normotensive rat aortas, whereas
      mexiletine (3 x 10(-5) M) did not affect this vasodilation in aortas treated with
      an ATP-sensitive K(+) channel antagonist glibenclamide (10(-5) M). A nitric oxide
      scavenger (carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; 10(-3)
      M) abolished augmented vasorelaxation to sodium nitroprusside induced by
      mexiletine (3 x 10(-5) M) in normotensive rat aortas, whereas a soluble guanylate
      cyclase inhibitor (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; 10(-5) M)
      failed to alter this augmentation of vasorelaxation. These results suggest that
      mexiletine induces augmentation of vasodilation via ATP-sensitive K(+) channels
      activated by the opener as well as a nitric oxide donor only in normotensive rat
      aortas. The vasodilator effects of mexiletine are partly caused by the soluble
      guanylate cyclase-independent action of nitric oxide on these channels.
      IMPLICATIONS: Mexiletine induces augmentation of vasodilation mediated by
      adenosine triphosphate (ATP)-sensitive K(+) channels activated by the opener as
      well as a nitric oxide donor in normotensive, but not hypertensive, rat aortas,
      partly by the soluble guanylate cyclase-independent action of nitric oxide on ATP
      sensitive K(+) channels of vascular smooth muscle cells.

PMID- 12598242
TI  - Treatment of life-threatening hyperkalemia using hemoconcentration in parallel to
      venovenous bypass during orthotopic liver transplantation.
AB  - IMPLICATIONS: The elimination of potassium in patients with end-stage kidney
      failure is limited. An increase in potassium concentrations can lead to lethal
      arrhythmias. In the described case, a large potassium concentration was treated
      during a liver transplantation using a new technical approach.

PMID- 12598243
TI  - Carbon dioxide embolism diagnosed by transesophageal echocardiography during
      endoscopic vein harvesting for coronary artery bypass grafting.
AB  - IMPLICATIONS: We describe a case of massive carbon dioxide embolism with an
      abrupt decrease in arterial blood pressure and continuous mixed venous oxygen
      saturation during endoscopic vein harvesting that was immediately diagnosed by
      intraoperative transesophageal echocardiography.

PMID- 12598244
TI  - Patient-controlled epidural analgesia in children: can they do it?
AB  - Extensive clinical experience and many studies support the use of i.v. patient
      controlled analgesia (i.v. PCA) and regional anesthesia techniques for the
      treatment of postoperative pain in children. In contrast, little has been
      reported about the ability of children to use patient-controlled epidural
      analgesia (PCEA) or about the efficacy of this technique. We report a descriptive
      analysis of prospectively recorded data in 128 children (132 procedures) in whom
      PCEA was used for acute postoperative pain control. Satisfactory analgesia was
      obtained in 119 patients (90.1%) for up to 103 h with no episodes of desaturation
      and without clinical evidence of toxicity or serious adverse effects. Analgesia
      was satisfactory with the initial settings in 89 patients; in 38 others, this was
      achieved with changes in PCEA settings or solution. Five patients were switched
      to i.v. PCA because of inadequate analgesia. Eight patients with satisfactory
      analgesia were converted to i.v. PCA because of adverse effects. Children as
      young as 5 yr had the cognitive ability to understand and the willingness to use
      PCEA, consistent with reported use of i.v. PCA. Careful attention should be paid
      to the total hourly local anesthetic dose to avoid exceeding the recommended
      limits. Our prospectively collected data demonstrate that PCEA provides
      satisfactory analgesia with a small incidence of adverse side effects in children
      and should be considered along with other strategies in pediatric postoperative
      pain management. IMPLICATIONS: A descriptive analysis of prospectively recorded
      data in 132 children receiving patient-controlled epidural analgesia for
      postoperative pain relief demonstrates satisfactory analgesia without serious
      toxicity or side effects in children as young as 5 yr. This modality should be
      considered as another strategy in pediatric postoperative pain management.

PMID- 12598245
TI  - An unusual cause of arterial desaturation in the premature infant undergoing
      patent ductus arteriosus ligation.
AB  - IMPLICATIONS: A premature infant undergoing ligation of a patent ductus
      arteriosus had arterial desaturation during surgical retraction, which was caused
      by a previously unrecognized vascular ring anomaly.

PMID- 12598246
TI  - Case series: IV regional anesthesia with ketorolac and lidocaine: is it effective
      for the management of complex regional pain syndrome 1 in children and
      adolescents?
AB  - IMPLICATIONS: We report our experience with ketorolac/lidocaine IV regional
      anesthesia (Bier block) (IVRA) in two adolescents with complex regional pain
      syndrome 1. IVRA resulted in complete resolution of symptoms.

PMID- 12598247
TI  - Single-lung ventilation with a cuffed endotracheal tube in a child with a left
      mainstem bronchus disruption.
AB  - IMPLICATIONS: We report a case of management of ventilation during operative
      repair of a traumatic left mainstem bronchial disruption in a pediatric patient.
      With the use of a conventional cuffed endotracheal tube, with the cuff partially
      in the right mainstem bronchus and partially in the trachea, we successfully
      managed the case with single-lung ventilation.

PMID- 12598248
TI  - Nitroglycerin for fetal surgery: fetoscopy and ex utero intrapartum treatment
      procedure with malignant hyperthermia precautions.
AB  - IMPLICATIONS: We report the administration of two anesthetics to a patient
      potentially at risk for malignant hyperthermia undergoing fetal surgery and an ex
      utero intrapartum treatment procedure. Management of anesthesia and
      intraoperative uterine relaxation with i.v. nitroglycerin to avoid volatile
      anesthetics are discussed.

PMID- 12598249
TI  - A comparison of airway responses during desflurane and sevoflurane administration
      via a laryngeal mask airway for maintenance of anesthesia.
AB  - IMPLICATIONS: Although sevoflurane is less pungent than desflurane at larger
      concentrations, neither anesthetic seems to irritate the airway when administered
      at the smaller concentrations often used during maintenance of anesthesia. Both
      anesthetics may be delivered effectively via a laryngeal mask airway, with
      minimal evidence of airway irritation.

PMID- 12598250
TI  - GABA(A) receptor blockade antagonizes the immobilizing action of propofol but not
      ketamine or isoflurane in a dose-related manner.
AB  - The enhancing action of propofol on gamma-amino-n-butyric acid subtype A
      (GABA(A)) receptors purportedly underlies its anesthetic effects. However, a
      recent study found that a GABA(A) antagonist did not alter the capacity of
      propofol to depress the righting reflex. We examined whether the noncompetitive
      GABA(A) antagonist picrotoxin and the competitive GABA(A) antagonist gabazine
      affected a different anesthetic response, immobility in response to a noxious
      stimulus (a tail clamp in rats), produced by propofol. This effect was compared
      with that seen with ketamine and isoflurane. Picrotoxin increased the 50%
      effective dose (ED(50)) for propofol by approximately 379%; gabazine increased it
      by 362%, and both antagonists acted in a dose-related manner with no apparent
      ceiling effect (i.e., no limit). Picrotoxin maximally increased the ED(50) for
      ketamine by approximately 40%-50%, whereas gabazine increased it by 50%-60%. The
      isoflurane minimum alveolar anesthetic concentration increased by approximately
      60% with the picrotoxin and 70% with the gabazine infusion. The ED(50) for
      propofol was also antagonized by strychnine, a non-GABAergic glycine receptor
      antagonist and convulsant, to determine whether excitation of the central nervous
      system by a non-GABAergic mechanism could account for the increases in propofol
      ED(50) observed. Because strychnine only increased the immobilizing ED(50) of
      propofol by approximately 50%, GABA(A) receptor antagonism accounted for the
      results seen with picrotoxin and gabazine. We conclude that GABA(A) antagonism
      can influence the ED(50) for immobility of propofol and the non-GABAergic
      anesthetic ketamine, although to a different degree, reflecting physiologic
      antagonism for ketamine (i.e., an indirect effect via a modulatory effect on the
      neural circuitry underlying immobility) versus physiologic and pharmacologic
      antagonism for propofol (i.e., a direct effect by antagonism of propofol's
      mechanism of action). This study also suggests that the immobilizing action of
      isoflurane probably does not involve the GABA(A) receptor because antagonism of
      GABA(A) receptors for animals anesthetized with isoflurane produces results
      quantitatively and qualitatively similar to ketamine and markedly different from
      propofol. IMPLICATIONS: IV picrotoxin and gabazine antagonized the immobilizing
      action of propofol in a dose-related manner, whereas antagonism of the
      immobilizing action of ketamine and isoflurane was similar, smaller than for
      propofol, and not dose-related. These results are consistent with a role for
      gamma-amino-n-butyric acid subtype A receptors in mediating propofol anesthesia
      but not ketamine or isoflurane anesthesia.

PMID- 12598251
TI  - The effect of propofol on the interaction of platelets with leukocytes and
      erythrocytes in surgical patients.
AB  - We tested the antiplatelet effect described for propofol in vitro in surgical
      patients. Platelet aggregation induced by adenosine diphosphate, collagen, and
      arachidonic acid was tested in samples of whole blood, platelet-rich plasma
      (PRP), PRP with red blood cells, and PRP with leukocytes. Also measured were
      platelet production of thromboxane (Tx)B(2) and leukocyte production of 6-keto
      prostaglandin F(1 alpha) (a stable metabolite of prostacyclin) and plasma levels
      of nitrites + nitrates (indicator of nitric oxide production). Anesthesia was
      induced with a bolus IV injection of sodium thiopental 4 mg/kg (n = 10), with a
      bolus dose of 2.5 mg/kg of propofol (n = 20), or with propofol total IV
      anesthesia (n = 20). Sodium thiopental did not modify any of the analytical
      values. In patients who received a bolus injection of propofol, platelet
      aggregation was significantly reduced in whole blood and in PRP + leukocytes.
      Platelet production of TxB(2) was reduced by 35%; the inhibition of 6-keto
      prostaglandin F(1 alpha) was not statistically significant. Plasma levels of
      nitrites + nitrates increased by 37%; this change correlated significantly with
      the decrease in systolic and diastolic blood pressure (both P < 0.05). Similar
      changes, albeit of larger magnitude, were seen in patients who were given total
      IV anesthesia with propofol. In conclusion, propofol inhibited platelet
      aggregation in surgical patients mainly as a result of the inhibition of Tx
      synthesis and the increase in nitric oxide production. These effects are thought
      to be related to the hypotensive effect of this anesthetic. IMPLICATIONS: In
      vitro experiments have shown that propofol inhibits platelet aggregation and
      increases nitric oxide production. This study shows that doses habitually used to
      induce or maintain anesthesia also have these effects. These findings have
      potential applications for patients at increased risk for bleeding and may partly
      explain the hypotensive effect of propofol.

PMID- 12598252
TI  - Changes in consciousness, conceptual memory, and quantitative
      electroencephalographical measures during recovery from sevoflurane- and
      remifentanil-based anesthesia.
AB  - It is unclear whether opioid-induced changes in electroencephalogram (EEG) or
      auditory evoked potentials (AEPs) reliably correspond with consciousness. We
      examined the correlation between 1) the clinically assessed state of
      consciousness, 2) implicit and explicit memory (by use of word pairs), and 3)
      various measures of EEG and AEP-bispectral index (BIS), A-Line ARX AEP index,
      spectral entropy, and entropy of the singular value decomposition (SVDEN; a
      measure of the complexity of the EEG). We studied 21 women during a two-stage
      awakening (sevoflurane washout followed by remifentanil washout) after anesthesia
      for gynecological surgery. All were amnesic, and 19 were unresponsive to verbal
      command with remifentanil alone. In six patients, BIS decreased paradoxically as
      the remifentanil concentration decreased; this was caused by a low-amplitude EEG,
      which was misinterpreted by the Aspect algorithm as burst suppression. Most of
      the EEG/AEP variables were sensitive to the decrease in sevoflurane and the
      recovery of consciousness, but not to the effects of decreasing remifentanil
      concentrations. SVDEN was the only variable that demonstrated significant
      increases for both the sevoflurane and remifentanil washout phases. With the
      prediction probability statistic during remifentanil washout, SVDEN = 0.79,
      spectral entropy = 0.81, A-Line ARX AEP index = 0.63, and BIS = 0.58. Entropy
      measures appear to be worthy of further clinical evaluation in a larger series of
      patients. SVDEN may be a useful variable for assessing anesthetic and analgesic
      effects on the central nervous system. IMPLICATIONS: During the recovery phase
      from a remifentanil-based anesthetic, the bispectral index is not reliably
      predictive of the depth of consciousness, because of suppression ratio artifacts.
      Entropy measures of the electroencephalogram show promise, but there is still no
      gold standard to estimate anesthetic depth.

PMID- 12598253
TI  - Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by
      small-dose ketamine in humans.
AB  - Adding a small dose of ketamine to opioids may increase the analgesic effect and
      prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this
      randomized, double-blinded, placebo-controlled crossover study, we investigated
      the effect of remifentanil combined with small concentrations of ketamine on
      different experimental pain models. Pain detection thresholds to single and
      repeated IM electrical stimulation and to repeated transcutaneous electrical
      stimulation, pressure pain tolerance threshold, and sedative, respiratory, and
      cardiovascular side effects were assessed in 14 healthy volunteers. Saline,
      remifentanil alone, and remifentanil combined with ketamine at target plasma
      concentrations of 50 or 100 ng/mL were administered in four study sessions. The
      ketamine infusion was started after baseline testing at a constant target
      concentration. Remifentanil was started after testing with ketamine alone at an
      initial target concentration of 1 ng/mL and then increased to 2 ng/mL and
      decreased to 1 ng/mL. The last test series were started 10 min after
      discontinuation of remifentanil. Acute remifentanil-induced hyperalgesia and
      tolerance were detected only by the pressure pain test and were not suppressed by
      ketamine. Remifentanil alone induced significant analgesia with all pain tests.
      Ketamine further increased the remifentanil effect only on IM electrical pain.
      Remifentanil at a 2 ng/mL target concentration induced a slight respiratory
      depression that was antagonized by ketamine. We conclude that ketamine effects on
      opioid analgesia are pain-modality specific. IMPLICATIONS: Coadministration of
      ketamine and morphine for pain relief is still controversial. Our experimental
      pain study with volunteers showed that ketamine enhances opioid analgesia without
      increasing sedation and reduces respiratory depression. Opioid-induced
      hyperalgesia and tolerance were not affected by ketamine and depended on the type
      of nociceptive stimulus. This may explain the conflicting results on opioid
      tolerance in previous studies.

PMID- 12598254
TI  - Modulation of myofilament Ca2+ densitivity by delta- and kappa-opioid agonists in
      intact guinea pig hearts.
AB  - We investigated whether delta- and kappa-opioid agonists alter myocardial
      function, intracellular Ca(2+) concentration ([Ca(2+)](i)), and myofilament
      Ca(2+) sensitivity in intact guinea pig beating hearts and whether these effects
      are mediated by an opioid receptor. Intact guinea pig hearts were perfused with
      modified Krebs Ringer solution containing delta- (TAN-67) and kappa- (ICI-199441)
      opioid agonists in the absence and presence of delta- (BNTX) and kappa- (nor-BNI)
      opioid antagonists, respectively, while functional variables and [Ca(2+)](i) were
      recorded. TAN-67 (1 microM) and ICI-199441 (1 microM) decreased heart rate (P <
      0.05). TAN-67 (1 microM) and ICI-199441 (1 micro M) decreased available
      [Ca(2+)](i) without changing developed left ventricular pressure (LVP) (P <
      0.05). TAN-67 (1 microM) and ICI-199441 (1 microM) also caused a leftward shift
      in the curve of developed LVP as a function of available [Ca(2+)](i) (P < 0.05).
      ICI-199441 (1 microM) produced a steeper slope in the relation curve compared
      with baseline (P < 0.05). BNTX (1 microM) and nor-BNI (1 microM) blocked the
      effects of TAN-67 and ICI-199441, respectively. delta- and kappa-opioid agonists
      enhance myofilament Ca(2+) sensitivity despite decreasing available [Ca(2+)](i)
      in intact isolated guinea pig hearts, and these effects are mediated by delta-
      and kappa-opioid receptor stimulation. IMPLICATIONS: Our results indicate that
      delta- and kappa-opioid agonists enhance myofilament Ca(2+) sensitivity despite
      decreasing available intracellular Ca(2+) concentrations in intact isolated
      guinea pig beating hearts, and these effects are mediated by delta- and kappa
      opioid receptor stimulation.

PMID- 12598255
TI  - The postoperative effects of halothane versus isoflurane on hepatic artery and
      portal vein blood flow in humans.
AB  - Animal studies have shown that halothane decreases total hepatic blood flow
      (THBF) by reducing both arterial (HABF) and portal (PVBF) inflow, whereas
      isoflurane appears to preserve them. In this study we assessed the effect of
      halothane and isoflurane on HABF and PVBF in surgical patients by using the
      pulsed Doppler technique. A validation study was conducted in six cynomolgus
      monkeys to compare the values of THBF obtained by the pulsed Doppler and
      indocyanine green clearance methods. Subsequently, six patients (ASA status I and
      II) undergoing elective open cholecystectomy were studied after surgery by using
      implanted pulsed Doppler probes. THBF and liver flow partition were compared
      during 1% halothane and 1.5% isoflurane (end-tidal concentrations). In the animal
      study, there was good agreement between the techniques (Bland and Altmann
      representation). In flunitrazepam-anesthetized patients, THBF was 1120 +/- 284
      mL/min. Compared with this baseline and for a similar mean arterial blood
      pressure decrease (10%), THBF was maintained with isoflurane, whereas it
      decreased by 36% (P < 0.05) under halothane. With isoflurane, PVBF increased
      (25%; P = 0.067) with a maintained HABF. With halothane, both PVBF (-44%; P <
      0.05) and HABF (-20%; P < 0.05) were reduced. Halothane acted mainly as a
      vasoconstrictor of the hepatic circulation, whereas isoflurane was a vasodilator,
      confirming the beneficial effect of isoflurane on hepatic oxygen supply.
      IMPLICATIONS: Volatile anesthetics may alter liver circulation with serious
      adverse effects. Using implanted pulsed Doppler probes in six anesthetized
      patients, we showed that halothane acted mainly as a vasoconstrictor of the liver
      vascular bed, whereas isoflurane was a vasodilator, confirming the beneficial
      effect of isoflurane on liver oxygen supply.

PMID- 12598256
TI  - Gamma-aminobutyric acid neuropharmacological investigations on narcosis produced
      by nitrogen, argon, or nitrous oxide.
AB  - Inhaled anesthetics, including the gaseous anesthetics nitrous oxide and xenon,
      are thought to act by interacting directly with ion-channel receptors. In
      contrast, little is known about the mechanism of action of inert gases that show
      only narcotic potency at high pressures, such as nitrogen or argon. In the
      present study, we investigated the effects of selective gamma-aminobutyric acid
      (GABA) receptor antagonists on narcosis produced by nitrogen, argon, and nitrous
      oxide. Pretreatment with the competitive GABA(A) receptor antagonist gabazine
      (0.2 nmol) but not the GABA(B) receptor antagonist 2-hydroxysaclofen (10 nmol)
      increased the nitrogen and argon threshold pressure for loss-of-righting-reflex
      (P < 0.005) but had no effect on nitrous oxide narcosis. Pretreatment with the
      GABA(A) benzodiazepine receptor antagonist flumazenil (5 nmol) also increased the
      narcosis threshold pressure of argon (P < 0.025). Given that neither 2
      hydroxysaclofen, gabazine, nor flumazenil at the doses used induced
      hyperexcitability, our results support a selective antagonism by gabazine and
      flumazenil of the narcotic action of nitrogen and argon. Some mechanisms of
      nitrogen and argon narcotic action might be similar to those of clinical inhaled
      anesthetics. IMPLICATIONS: We studied the effects in the rat of gamma
      aminobutyric acid (GABA) receptor antagonists on narcosis induced by nitrogen and
      argon that act only at high pressures. Our results show that the GABA (A)
      receptor may play a significant role, suggesting that some mechanisms might be
      similar to those of clinical inhaled anesthetics.

PMID- 12598257
TI  - The effect of vecuronium is enhanced by a large rather than a modest dose of
      gentamicin as compared with no preoperative gentamicin.
AB  - We compared the effect of two doses of gentamicin versus no gentamicin (NG) given
      before surgery on the neuromuscular relaxant effect of vecuronium. Seventy
      patients (intraabdominal procedures) were randomly allocated to receive
      preoperative large-dose (4 mg/kg) gentamicin (LD), a modest dose (1.2 mg/kg) of
      gentamicin (MD), or NG. No more than one dose of gentamicin was given before the
      vecuronium administration. Serum gentamicin levels, the time for 25% recovery of
      the first twitch in the train-of-four after a bolus of vecuronium, and the time
      from cessation of the vecuronium infusion to extubation of the trachea were
      estimated. Serum gentamicin levels were higher (P < 0.001) for LD than MD. The
      time for 25% recovery of the first twitch after the vecuronium bolus was slightly
      longer with LD than MD (P = 0.06) and longer in LD than NG (P = 0.001) (42.9 +/-
      23.6 min versus 36.2 +/- 17 min and 27.4 +/- 9 min, respectively). The time to
      extubation was similar with LD and MD and longer for LD than NG (P = 0.008) (34.7
      +/- 19.2 min versus 27.4 +/- 19.3 min and 19.4 +/- 10.1 min, respectively). The
      differences in these times were insignificant between MD and NG. Gentamicin
      administered as a LD rather than MD enhanced the neuromuscular blockade of
      vecuronium as compared with NG given before surgery. IMPLICATIONS: We
      demonstrated that the neuromuscular relaxant effect of vecuronium is enhanced by
      a large (4 mg/kg) rather than a modest (1.2 mg/kg) dose of gentamicin as compared
      with no gentamicin given before surgery.

PMID- 12598258
TI  - The induction of apoptosis by local anesthetics: a comparison between lidocaine
      and ropivacaine.
AB  - IMPLICATIONS: This study suggests that lidocaine can induce apoptosis (detected
      by dual staining with Annexin V and propidium iodide) on T-cell line cultures in
      a time-dependent manner. This was not observed with ropivacaine.

PMID- 12598259
TI  - Carbon monoxide production from sevoflurane breakdown: modeling of exposures
      under clinical conditions.
AB  - Isoflurane, enflurane, sevoflurane, and especially desflurane produce carbon
      monoxide (CO) during reaction with desiccated absorbents. Of these, sevoflurane
      is the least studied. We investigated the dependence of CO production from
      sevoflurane on absorbent temperature, minute ventilation (VE), and fresh gas flow
      rates. We measured absorbent temperature and in vitro CO concentrations when
      desiccated Baralyme reacted with 1 minimum alveolar anesthetic concentration of
      (2.1%) sevoflurane at 2.3-, 5.0-, and 10.0-L VE. Mathematical modeling of
      carboxyhemoglobin concentrations was performed using an existing iterative
      method. Rapid breakdown of sevoflurane prevented the attainment of 1 minimum
      alveolar anesthetic concentration with low fresh gas flow rates. CO
      concentrations increased with VE and with absorbent temperatures exceeding 80
      degrees C, but concentrations decreased with higher fresh gas flow rates. Average
      CO concentrations were 150 and 600 ppm at 2.3- and 5.0-L VE; however, at 10 L,
      over 11,000 ppm of CO were produced followed by an explosion and fire. Methanol
      and formaldehyde were present and may have contributed to the flammable mixture
      but were not quantitated. Mathematical modeling of exposures indicates that in
      average cases, only patients < or =25 kg, or severely anemic patients, are at
      risk of carboxyhemoglobin concentrations >10% during the first 60 min of
      anesthesia. IMPLICATIONS: Sevoflurane breakdown in desiccated absorbents is
      expected to result in only mild carbon monoxide (CO) exposure. Completely dry
      absorbent and high minute ventilation rates may degrade sevoflurane to extremely
      large CO concentrations. Serious CO poisoning or spontaneous ignition of
      flammable gases within the breathing circuit are possible in extreme
      circumstances.

PMID- 12598260
TI  - Intravenous droperidol causes a reduction in the bispectral index in propofol
      sedated patients during spinal anesthesia.
AB  - We investigated the effect of IV droperidol on the bispectral index (BIS) in
      conscious and propofol-sedated patients during spinal anesthesia. Thirty minutes
      after the induction of spinal anesthesia, 20 patients were given 2 mg of
      droperidol IV without administration of other sedatives (conscious group).
      Another group of patients were sedated with a propofol infusion to maintain BIS
      at 60 +/- 5 and were administered IV saline (placebo group; n = 20), droperidol 1
      mg (dro-1 group; n = 20), or droperidol 2 mg (dro-2 group; n = 20) in a
      randomized order and in a double-blinded fashion. Although BIS remained the same
      in the conscious and placebo groups, it significantly decreased after
      administration of droperidol in the dro-1 and dro-2 groups. The decrease in BIS
      was significantly larger in the dro-2 group than in the dro-1 group. These
      results suggest that an antiemetic dose of droperidol enhances the hypnotic
      effect of propofol in a dose-dependent manner during spinal anesthesia.
      IMPLICATIONS: An antiemetic dose of IV droperidol causes a decrease in the
      bispectral index in patients sedated with propofol during spinal anesthesia. We
      conclude that droperidol may enhance the hypnotic effect of propofol.

PMID- 12598261
TI  - Intrathecal administration of morphine, but not small dose, induced spastic
      paraparesis after a noninjurious interval of aortic occlusion in rats.
AB  - We sought to investigate the dose-response relationship for the effect of
      intrathecal morphine on the transient spastic paraparesis after short-lasting
      spinal ischemia in rats. Spinal ischemia was induced by aortic occlusion for 6
      min with a balloon catheter in rats previously implanted with an intrathecal
      catheter for drug delivery. After ischemia, the animals were allowed to recover,
      and 3, 10, or 30 microg of morphine or saline was injected intrathecally at 30
      min after reperfusion. In a separate group, the quantal bioassay for the effect
      of intrathecal morphine on neurological function after ischemia was performed to
      calculate 50% effective dose values for inducing paraparesis at 2 h of
      reperfusion. Subsequently, histopathology of the spinal cord was assessed at 48 h
      of reperfusion. Intrathecal injection of 30 or 10 micro g of morphine, but 3
      micro g of neither morphine nor saline, caused a progressive development of
      hindlimb spasticity. The 50% effective dose values for inducing paraparesis were
      16.1 +/- 1.5 microg in assessing behavioral analysis at 2 h after intrathecal
      morphine. Histopathological analysis of spinal cords in the 30- microg group
      revealed the presence of dark-staining alpha-motoneurons in lumbosacral segments.
      We conclude that spinal administration of a large dose of morphine after
      transient aortic occlusion may be associated with a potential risk of paraparesis
      and the corresponding development of neurological dysfunction. Careful attention
      should be paid when intrathecal morphine is used for pain control after
      thoracoabdominal aortic aneurysm repair. IMPLICATIONS: Spinal administration of
      large-dose morphine after transient aortic occlusion may be associated with a
      potential risk of irreversible spinal neuronal degeneration and the corresponding
      development of neurological dysfunction.

PMID- 12598262
TI  - Continuous intrathecal clonidine and tizanidine in conscious dogs: analgesic and
      hemodynamic effects.
AB  - Alpha-2-adrenergic agonists, such as clonidine, produce antinociception in animal
      pain models after intrathecal administration. However, clinical usage is limited
      by cardiovascular side effects. To investigate alternative alpha(2)-adrenergic
      agonists as analgesics, we implanted six dogs with an intrathecal catheter and
      infusion pump. After baseline saline infusion, animals received clonidine or
      tizanidine (crossover study) each week at escalating doses of 125-750 microg/h.
      Analgesia, blood pressure, heart rate, respiratory rate, sedation, and
      coordination were evaluated. A 28-day safety study was performed with another
      nine dogs receiving intrathecal tizanidine (3 or 6 mg/d) or saline. Equal doses
      of clonidine and tizanidine produce the same antinociception in thermal
      withdrawal tests. Blood pressure was reduced with 125-500 microg/h of clonidine,
      but not with tizanidine at any dose. Clonidine 250 microg/h reduced heart rate by
      45.8%, and five of six animals had bradyarrhythmias (marked bradycardia), whereas
      tizanidine decreased heart rate by 15.1% without arrhythmias, even at the largest
      dose. Respiratory rate decreased with 250 microg/h of clonidine and larger doses.
      Sedation or incoordination occurred only at the largest dose for either drug. The
      safety study indicated that 3 mg/d of tizanidine in dogs produced no side effects
      or histopathologic changes. Tizanidine may be a useful alternative in patients
      experiencing cardiovascular side effects with intrathecal infusion of clonidine.
      IMPLICATIONS: Clonidine is an effective spinal analgesic, but it is dose-limited
      by cardiovascular side effects. We compared the analgesic properties and side
      effects of clonidine with those of a similar drug, tizanidine. Continuous spinal
      infusion of tizanidine produced similar analgesia as clonidine, but with fewer
      adverse effects on blood pressure and heart rate.

PMID- 12598263
TI  - The effects of intrathecal tramadol on spinal somatosensory-evoked potentials and
      motor-evoked responses in rats.
AB  - Tramadol has been proven to exert a local anesthetic-type effect on peripheral
      nerves in both clinical and laboratory studies. In this study, we evaluated the
      effects of tramadol on sensory and motor neural conduction when administered
      intrathecally in the rat. Tramadol (0, 1, or 2 mg) was administered through an
      intrathecal catheter. Spinal somatosensory-evoked potentials (SSEPs) were
      recorded at the thoracolumbar junction after stimulation of the sciatic nerve. An
      evoked compound muscle action potential (CMAP) was recorded in the intrinsic
      muscles of the foot in response to electric stimulation of the lower thoracic
      (T1213) interspinous space. Both SSEP and CMAP were obtained before drug
      application as the pretreatment baseline and at 5, 15, and 30 min after
      treatment, and at 30- or 60-min intervals thereafter for another 4.5 h. SSEP was
      averaged from 20 responses, whereas CMAP was obtained from a single stimulation.
      Reproducible SSEPs and CMAP were consistently recorded in all rats. Intrathecal
      tramadol dose-dependently reduced the amplitude and delayed the latency in both
      SSEPs and CMAP. Generally, the suppressive effects occurred immediately after
      injection and recovered over 2 h. Combined administration with 20 micro g of
      intrathecal naloxone did not attenuate the inhibition of spinal SSEPs. We
      conclude that intrathecal tramadol causes a dose-related suppressive effect on
      both sensory and motor neural conduction in the spinal cord. IMPLICATIONS: Spinal
      somatosensory-evoked potentials and evoked compound muscle action potential were
      used to evaluate the effects of intrathecal tramadol on sensory and motor neural
      conduction. Intrathecal tramadol dose-dependently reduced the amplitude and
      delayed the latency of both spinal somatosensory-evoked potentials and compound
      muscle action potential. These results indicate that tramadol exerts a dose
      related central neural blockade.

PMID- 12598264
TI  - A single small dose of postoperative ketamine provides rapid and sustained
      improvement in morphine analgesia in the presence of morphine-resistant pain.
AB  - It is a common clinical observation that postoperative pain may be resistant to
      morphine. The analgesic potentials of ketamine have also been well documented. In
      this study, we evaluated the effects of postoperative coadministration of small
      doses of ketamine and morphine on pain intensity, SpO(2), and subjectively rated
      variables in surgical patients who underwent standardized general anesthesia and
      complained of pain (> or =6 of 10 on a visual analog scale [VAS]) despite >0.1
      mg/kg of i.v. morphine administration within 30 min. Patients randomly received
      up to three boluses of 30 microg/kg of morphine plus saline (MS; n = 114) or 15
      microg/kg of morphine plus 250 microg/kg of ketamine (MK; n = 131) within 10 min
      in a double-blinded manner. The MS group's pain VAS scores were 5.5 +/- 1.18 and
      3.8 +/- 0.9 after 10 and 120 min, respectively, after 2.52 +/- 0.56 injections,
      versus the MK group's VAS scores of 2.94 +/- 1.28 and 1.47 +/- 0.65, respectively
      (P < 0.001), after 1.35 +/- 0.56 injections (P < 0.001). The 10-min level of
      wakefulness (1-10 VAS) in the MS group was significantly (P < 0.001) less (6.1 +/
      1.5) than the MK group's (8.37 +/- 1.19). SpO(2) decreased by 0.26% in the MS
      group but increased by 1.71% in the MK patients at the 10-min time point (P <
      0.001). Thirty MS versus nine MK patients (P < 0.001) experienced
      nausea/vomiting; nine MK patients sustained a 2-min light-headed sensation, and
      one patient had a weird dream after the second drug injection. IMPLICATIONS: A
      small-dose ketamine and morphine regimen interrupted severe postoperative pain
      that was not relieved previously by morphine. Ketamine reduced morphine
      consumption and provided rapid and sustained improvement in morphine analgesia
      and in subjective feelings of well-being, without unacceptable side effects.

PMID- 12598265
TI  - Continuous epidural infusion of large concentration/small volume versus small
      concentration/large volume of levobupivacaine for postoperative analgesia.
AB  - In this randomized study, we evaluated the quality of postoperative analgesia and
      the incidence of side effects of continuous thoracic epidural levobupivacaine 15
      mg/h in 2 different concentrations: 0.5%, 3 mL/h (n = 33) or 0.15%, 10 mL/h (n =
      27). The following variables were registered within 48 h: sensory block, pain
      scores, rescue morphine consumption, motor blockade, hemodynamics, sedation,
      nausea and vomiting, and patient satisfaction. The two groups were similar with
      regard to demographics, cephalad level of sensory block, quality of analgesia,
      morphine consumption, side effects, and high satisfaction rate. Motor blockade
      was weaker in the 0.5% group (P = 0.025), with a significantly increased
      hemodynamic stability, compared with the 0.15% group (P = 0.004). In conclusion,
      the same dose of levobupivacaine provides an equal quality of analgesia in small-
      or large-volume continuous epidural infusion and decreases the incidence of motor
      blockade and hemodynamic repercussions. This is in accordance with the assumption
      that the total dose of local anesthetics determines the spread and quality of
      analgesia. IMPLICATIONS: We demonstrated that a large concentration/small volume
      of levobupivacaine given as a continuous thoracic epidural infusion provided an
      equal quality of postoperative analgesia as a small-concentration/large-volume
      infusion and induced less motor blockade and fewer hemodynamic repercussions.

PMID- 12598266
TI  - Organizational factors affect comparisons of the clinical productivity of
      academic anesthesiology departments.
AB  - Productivity measurements based on "per operating room (OR) site" and "per case"
      are not influenced by staffing ratios and have permitted meaningful comparisons
      among small samples of both academic and private-practice anesthesiology groups.
      These comparisons have suggested that a larger sample would allow for clinical
      groups to be compared using a number of different variables (including type of
      hospital, number of OR sites, type of surgical staff, or other organizational
      characteristics), which may permit more focused benchmarking. In this study, we
      used such grouping variables to compare clinical productivity in a broad survey
      of academic anesthesiology programs. Descriptive, billing, and staffing data were
      collected for 1 fiscal or calendar year from 37 academic anesthesiology
      departments representing 58 hospitals. Descriptive data included types of
      surgical staff (e.g., academic versus private practice) and hospital centers
      (e.g., academic medical centers and ambulatory surgical centers [ASCs]). Billing
      and staffing data included total number of cases performed, total American
      Society of Anesthesiologists units (tASA) billed, total time units billed (15-min
      units), and daily number of anesthetizing sites staffed (OR sites). Measurements
      of total productivity (tASA/OR site), billed hours per OR site per day (h/OR/d),
      surgical duration (h/case), hourly billing productivity (tASA/h), and base
      units/case were compared. These comparisons were made according to type of
      hospital, number of OR sites, and type of surgical staff. The ASCs had
      significantly less tASA/OR site, fewer h/OR/d, and less h/case than non-ASC
      hospitals. Community hospitals had significantly less h/OR/d and h/case than
      academic medical centers and indigent hospitals and a larger percentage of
      private-practice or mixed surgical staff. Academic staffs had significantly less
      tASA/h and significantly more h/case. tASA/h correlated highly with h/case (r = 
      0.68). This study showed that the hospitals at which academic anesthesiology
      groups provide care are not all the same from a clinical productivity
      perspective. By grouping based on type of hospital, number of OR sites, and type
      of surgical staff, academic anesthesiology departments (and hospitals) can be
      better compared by using clinical productivity measurements based on "per OR
      site" and "per case" measurements (tASA/OR, billed h/OR/d, h/case, tASA/h, and
      base/case). IMPLICATIONS: Organizational factors, including type of hospital,
      number of operating rooms, and type of surgical staff, influence the clinical
      productivity of academic anesthesiology departments. Reporting quartile data by
      focused grouping variables allows anesthesiology groups to compare their clinical
      productivity with groups practicing in similar clinical settings.

PMID- 12598267
TI  - Inclusion of turnover time does not influence identification of surgical services
      that over- and underutilize allocated block time.
AB  - Allocation of operating room (OR) block time is an ongoing challenge for OR
      managers. In this study, we sought to determine whether inclusion or exclusion of
      turnover time in comparisons of block utilization would identify different
      surgical services as under- or overused. For a 13-mo period, we evaluated data
      extracted from the OR information system of a large academic medical center.
      During that time period, 15 surgical services performed 12,245 surgical
      procedures. Allocated block hours, number of first cases performed, total number
      of cases, and average case durations were determined. The average turnover time
      for each service was determined by a manual, case-by-case review of data from 1
      mo. Raw utilization (RU; case durations only) and adjusted utilization (AU; case
      duration plus turnover time) were calculated for each service. Turnover time was
      credited to the service performing surgery after room turnover. Case du-ration
      was limited to surgeries performed during resource hours. Two indices of
      utilization (i.e., the usage rate of the service divided by the overall use of
      all ORs in the suite) were used to compare services: the RU or AU Index (RUI or
      AUI). Outliers were services with indices that were >1.15 or <0.85. The RUI
      identified three services as underutilizers and one service as an overutilizer.
      Using the AUI, the same outliers were identified, and no new services were
      identified. Examining the changes in index (between AUI and RUI), the percentage
      of to-follow cases highly correlated with changes in index (r(2) = 0.60); the
      average turnover time did not (r(2) = 0.002). Inclusion of turnover time did not
      change the services that were identified as under- and overutilizer.
      IMPLICATIONS: Turnover time is difficult to determine from existing operating
      room information systems. This study determined the use of block time with and
      without turnover time for each surgical service in a large academic hospital.
      Turnover time did not change identification of surgical services that over- (one
      service) or underused (three services) allocated block time.

PMID- 12598268
TI  - Nerve gas terrorism: a grim challenge to anesthesiologists.
AB  - IMPLICATIONS: The 1995 Tokyo subway strike proved nerve gas to be a fearsome
      terrorist weapon of mass destruction. Because the clear liquid is easily hidden
      until released, rescuers must aid nonbreathing casualties near instantly.
      Anesthesiologists are uniquely qualified to train these rescue squads and to
      manage nerve gas victims in the hospital.

PMID- 12598269
TI  - Predictor of core hypothermia and the surgical intensive care unit.
AB  - Inadvertent postoperative core hypothermia is associated with multiple
      physiological effects, especially in patients admitted to the intensive care unit
      (ICU). Despite previous reports of the relationship between patient, surgical,
      and anesthetic factors and immediate postoperative core hypothermia, this
      information might need to be reconsidered in the light of progress in surgery,
      anesthetic, and warming techniques. We designed this prospective study of 194
      postgeneral surgical patients to assess the incidence, predictive factors, and
      outcome of core hypothermia (tympanic membrane core temperature [Tc] <36.0
      degrees C) at the time of admission to the general ICU in a large tertiary
      university medical center from December 2000 to March 2001. The following
      variables were studied: age, sex, body weight, body surface area, preoperative
      body temperature, ASA physical status, history of diabetic neuropathy, emergency
      surgery, surgical subspecialty performing surgery, type of surgery, type of
      anesthesia (general, regional, or combined epidural and general), temperature
      monitoring, use of a forced air warming technique, amount of fluid and blood
      replacement, duration of anesthesia, duration of surgery, and the ambient
      operating room temperature. Other outcomes, i.e., length of ICU stay and
      mortality, were also assessed. The incidence of core hypothermia was 57.1%,
      41.3%, and 28.3% according to the definition of Tc <36.0 degrees C, <35.5 degrees
      C, and <35.0 degrees C, respectively. Multiple logistic regression showed the
      following risk factors for core hypothermia: high ASA physical status (odds
      ratio, 2.87; 95% confidence interval [CI], 0.82-10.03 for ASA II; odds ratio,
      8.35; 95% CI, 1.67-41.88 for ASA >II), magnitude of surgical procedure (odds
      ratio, 6.60; 95% CI, 1.66-26.19 for medium surgery; odds ratio, 22.23; 95% CI,
      5.41-91.36 for major surgery), use of combined epidural and general anesthesia
      (odds ratio, 3.39; 95% CI, 1.05-10.88), and duration of surgery >2 h (odds ratio,
      4.50; 95% CI, 1.48-13.68). Not using temperature monitoring seems to be a risk
      factor as well (odds ratio, 3.00; 95% CI, 0.87-10.12). Significant protective
      factors against core hypothermia were heavier body weight (odds ratio, 0.94; 95%
      CI, 0.89-0.98), higher preoperative body temperature (odds ratio, 0.31; 95% CI,
      0.15-0.65), and warmer ambient operating room temperature (odds ratio, 0.67; 95%
      CI, 0.51-0.88). In conclusion, the incidence of core hypothermia (Tc <36.0
      degrees C) at the time of admission to the general ICU is still frequent. To
      reduce the incidence, more efforts and concern should be taken to prevent core
      hypothermia, especially in the patient with high ASA physical status, undergoing
      more intensive and lengthy surgery, and using combined epidural and general
      anesthesia. IMPLICATIONS: In an effort to decrease the frequent incidence of core
      hypothermia at the time of admission to the general surgical intensive care unit,
      this prospective study showed that high ASA physical status, the use of a
      combined epidural and general anesthesia, surgery lasting longer than 2 h, and
      extensive surgery were the important risk factors, whereas heavier body weight,
      higher preoperative body temperature, and warmer ambient operating room
      temperature were important protective factors.

PMID- 12598270
TI  - Sequential use of midazolam and propofol for long-term sedation in postoperative
      mechanically ventilated patients.
AB  - Acute withdrawal syndromes, including agitation and a long weaning time, are
      common adverse effects after long-term sedation with midazolam. We performed this
      study to determine whether the sequential use of midazolam and propofol could
      reduce adverse effects as compared with midazolam alone. We studied 26 patients
      receiving mechanical ventilation for three or more days after surgery. Patients
      were randomly assigned to two groups. In Group M, patients were sedated with
      midazolam alone. In Group M-P, midazolam was switched to propofol approximately
      24 h before the expected stopping of sedation. The level of sedation was
      maintained at 4 or 5 on the Ramsay sedation scale. The sedation agitation scale
      was evaluated for 24 h after extubation. The recovery time from stopping of
      sedation to extubation was significantly shorter in Group M-P (1.3 +/- 0.4 h)
      compared with Group M (4.0 +/- 2.4 h). The incidence of agitation in Group M-P
      (8%) was significantly less frequent than that in Group M (54%). The results
      indicate that sequential use of midazolam and propofol for long-term sedation
      could reduce the incidence of agitation compared with midazolam alone.
      IMPLICATIONS: Our study indicates that sequential use of midazolam and propofol
      could reduce the incidence of agitation compared with midazolam alone.

PMID- 12598271
TI  - Lack of evidence for apoptosis as a cause of delayed onset paraplegia after
      spinal cord ischemia in rabbits.
AB  - The mechanisms for delayed onset paraplegia after transient spinal cord ischemia
      are not fully understood. We investigated whether apoptotic motor neuron death is
      involved in its development. Spinal cord ischemia was induced for 15 min by
      occlusion of the abdominal aorta in rabbits. At 8, 24, or 48 h after reperfusion,
      hind limb motor function was assessed, and the lumbar spinal cord was examined
      morphologically (hematoxylin-eosin and terminal deoxynucleotidyl transferase
      mediated deoxyuridine triphosphate-biotin nick-end labeling staining) and
      biochemically (breakdown products of alpha-fodrin and patterns of DNA changes).
      At each time point, 14 rabbits were studied (7 for histopathology and 7 for
      biochemical analysis). Six rabbits served as sham controls. Delayed motor
      dysfunction developed in two thirds of the rabbits. The motor neurons in the
      rabbits with motor dysfunction (not paraplegia) showed swelling and a finely
      granular dispersed Nissl substance. In paraplegic rabbits, destruction of the
      gray matter and prominent inflammatory cell infiltration were observed. No
      apoptotic motor neuron was found in any rabbit. There was neither detectable
      increase in a caspase-3-mediated breakdown product of alpha-fodrin, nor DNA
      laddering in any rabbit. The results suggest that apoptosis has a negligible role
      in the pathophysiology of delayed paraplegia in the spinal cord ischemia model
      examined. IMPLICATIONS: Although the possibility of apoptotic motor neuron death
      cannot be completely excluded, delayed onset paraplegia after transient spinal
      cord ischemia is largely associated with necrotic cell death.

PMID- 12598272
TI  - Noninvasive estimation of cerebral perfusion pressure and zero flow pressure in
      healthy volunteers: the effects of changes in end-tidal carbon dioxide.
AB  - Zero flow pressure (ZFP) in the cerebral circulation is defined as the arterial
      pressure at which flow ceases. Noninvasive methods of estimating cerebral
      perfusion pressure (CPP) and ZFP using transcranial Doppler ultrasonography have
      been described. There is a paucity of normal physiological data related to
      changes in estimated CPP (eCPP) and ZFP induced by changes in carbon dioxide
      (CO(2)). We studied the effects of CO(2) on eCPP and ZFP in 17 healthy
      volunteers. After baseline measurements of middle cerebral artery blood-flow
      velocity and blood pressure, subjects voluntarily hyperventilated to decrease
      their end-tidal CO(2) (PE'CO(2)) by approximately 7.5 mm Hg, and then they
      increased their PE'CO(2) by approximately 7.5 mm Hg by breathing through a
      Mapleson D circuit. Blood-flow velocity and blood pressure were recorded at each
      stage. The eCPP and ZFP were calculated by using established formulas, and the
      results were analyzed with analysis of variance. With increasing PE'CO(2), eCPP
      increased from 50.67 mm Hg (8.33 mm Hg) (mean [SD]) to 60.87 mm Hg (9.28 mm Hg)
      (20% increase; P < 0.001), with a corresponding decrease in ZFP (P = 0.017);
      hypocapnia resulted in the opposite effects on eCPP and ZFP. These results
      indicate physiological changes in eCPP and ZFP that can be expected from changes
      in CO(2) in subjects without any neurological disorder. IMPLICATIONS: Increasing
      end-tidal CO(2) increases the estimated cerebral perfusion pressure and vice
      versa. These results are opposite to those expected from the known effects of
      CO(2) on intracranial pressure. Thus, we support the suggestion that, in the
      absence of intracranial hypertension, vascular tone remains a major determinant
      of effective downstream pressure and cerebral perfusion.

PMID- 12598273
TI  - Intrathecal fentanyl, sufentanil, or placebo combined with hyperbaric mepivacaine
      2% for parturients undergoing elective cesarean delivery.
AB  - Worldwide, long-acting bupivacaine is the most popular local anesthetic for
      spinal anesthesia in parturients undergoing elective cesarean delivery. With
      advances in surgical techniques, e.g., the Misgav Ladach method, and shorter
      duration of surgery, the local anesthetic mepivacaine, with an intermediate
      duration of action, may be a reasonable alternative. Our aim in the present study
      was to evaluate the effects of 2% hyperbaric mepivacaine alone, or combined with
      either intrathecal fentanyl (5 and 10 microg), or sufentanil (2.5 and 5 microg),
      on sensory, motor, and analgesic block characteristics, hemodynamic variables,
      and neonatal outcome in a randomized, prospective, and double-blinded study (n =
      100, 20 parturients per group, singleton pregnancy, >37 wk of gestation). No
      parturient experienced intraoperative pain. The average duration of motor block
      Bromage 3 in all groups was 68 min, and resolution time to Bromage 0 was 118 min.
      Maximal cephalad sensory block level was T3-6 and could be established within 6
      min. Complete analgesia was significantly prolonged in all groups receiving
      intrathecal opioids, yet, with sufentanil 5 microg, even the duration of
      effective analgesia was significantly extended. Neonatal outcome was not affected
      by intrathecal opioid administration. In conclusion, 2% hyperbaric mepivacaine is
      a feasible local anesthetic for spinal anesthesia in parturients undergoing
      elective cesarean delivery, particularly with short duration of surgery.
      IMPLICATIONS: Sensory, motor, and analgesic block characteristics of the local
      anesthetic mepivacaine alone or combined with intrathecal opioids were studied in
      parturients undergoing elective cesarean delivery in a randomized, double-blinded
      clinical trial. Mepivacaine was found to be an acceptable local anesthetic for
      spinal anesthesia in parturients undergoing cesarean delivery. In combination
      with sufentanil 5 microg, complete and effective analgesia were significantly
      prolonged.

PMID- 12598274
TI  - Anaphylactoid reaction to hydroxyethylstarch during cesarean delivery in a
      patient with HELLP syndrome.
AB  - IMPLICATIONS: This case report describes an allergic reaction attributed to
      colloid administration before a semi-urgent cesarean delivery. The most
      challenging part of this event was related to the anesthetic and obstetric
      treatment options to avoid further compromise of both mother and fetus.

PMID- 12598275
TI  - An evaluation of the supraclavicular plumb-bob technique for brachial plexus
      block by magnetic resonance imaging.
AB  - Partly based on magnetic resonance imaging studies, the "plumb-bob" approach for
      brachial plexus block was designed to minimize the risk of pneumothorax.
      Nevertheless, the risk of pneumothorax has remained a concern. We analyzed
      magnetic resonance images from 10 volunteers to determine whether the risk of
      pneumothorax was decreased with this method. The recommended initial needle
      direction is anteroposterior through the junction between the lateral-most part
      of the sternocleidomastoid muscle and the superior edge of the clavicle. If the
      initial placement is not successful, the brachial plexus may be sought in sectors
      20 degrees -30 degrees cephalad or caudad to the anteroposterior line in a
      sagittal plane through the insertion point. We found that the anteroposterior
      line reached the pleura in 6 of 10 volunteers without prior contact with the
      subclavian artery or the brachial plexus, but always with contact with the
      subclavian vein. To reach the middle of the brachial plexus, a mean cephalad
      redirection of the simulated needle by 21 degrees was required (range from 41
      degrees cephalad to 15 degrees caudad in one case). We conclude that the risk of
      contacting the pleura and the subclavian vessels may be reduced by initially
      directing the needle 45 degrees cephalad instead of anteroposterior. If the
      brachial plexus is not contacted, the angle should be gradually reduced.
      IMPLICATIONS: In magnetic resonance images of volunteers, simulated needle passes
      with the "plumb-bob" approach to the supraclavicular brachial plexus block were
      analyzed for precision and risk profile. To avoid needle contact with the lung,
      the subclavian vein, and the subclavian artery, our results suggest a change in
      the method's initial needle direction.

PMID- 12598276
TI  - Infragluteal-parabiceps sciatic nerve block: an evaluation of a novel approach
      using a single-injection technique.
AB  - Clinical use of the sciatic nerve block (SNB) has been limited by technical
      difficulties in performing the block using standard approaches, substantial
      patient discomfort during the procedure, or the need for two injections to block
      the tibial and peroneal nerves. In this report, we describe a single-injection
      method for SNB using an infragluteal-parabiceps approach, where the nerve is
      located along the lateral border of the biceps femoris muscle. SNB was performed
      in the prone or lateral decubitus position. The needle was positioned (average
      depth, 56 +/- 15 mm) to the point where plantar flexion (53%) or inversion (45%)
      of the ipsilateral foot was obtained at < or =0.4 mA. Levobupivacaine 0.625% with
      epinephrine (1:200:000) was administered at a dose of 0.4 mL/kg. The procedure
      was completed in 6 +/- 3 min. Discomfort during block placement was treated with
      fentanyl 50-100 microg in 24% of patients. Complete sensory loss and motor
      paralysis occurred in 92% of subjects at a median time of 10 (range, 5-25) min
      after injection. Compared with plantar flexion, foot inversion was associated
      with a more frequent incidence (86% versus 100%), and shorter latency for both
      sensory loss and motor paralysis of the peroneal, tibial, and sural nerves. There
      were no immediate or delayed complications. We conclude that the infragluteal
      parabiceps approach to SNB is reliable, efficient, safe, and well tolerated by
      patients. IMPLICATIONS: Sciatic nerve block using the infragluteal-parabiceps
      approach produces sensory loss and motor paralysis after a single 0.4 mL/kg
      injection of levobupivacaine 0.625% with epinephrine (1:200,000) in >90% of
      patients. The approach is reliable, uses consistent soft-tissue landmarks, is not
      typically painful, and does not produce significant complications.

PMID- 12598277
TI  - The effect of spinal bupivacaine in combination with either epidural clonidine
      and/or 0.5% bupivacaine administered at the incision site on postoperative
      outcome in patients undergoing lumbar laminectomy.
AB  - Spinal anesthesia has numerous advantages over general anesthesia for patients
      undergoing lumbar laminectomy and microdisk surgery. In this study, we evaluated
      the addition of epidural clonidine and/or bupivacaine, injected at the incision
      site, on postoperative outcome variables in patients undergoing lower spine
      procedures using spinal anesthesia. One hundred twenty patients having lumbar
      spine surgery received bupivacaine spinal anesthesia supplemented by 150 microg
      of epidural clonidine with or without incisional bupivacaine, epidural placebo
      plus incisional bupivacaine, or placebo with incisional saline. Demographic data,
      intraoperative hemodynamics, blood loss, pain, nausea, urinary retention,
      hospital discharge, and other variables were compared by using either analysis of
      variance or chi(2) analysis. Demographics were similar. IV fluids, blood loss,
      incidence of intraoperative bradycardia, and hypotension were not different among
      groups. Postanesthesia care unit pain scores were lower and demand for analgesics
      was less in patients who received both the clonidine and subcutaneous
      bupivacaine. Patients who received epidural clonidine also had improved
      postoperative hemodynamics. Hospital discharge, urinary retention, and other
      variables were not different. We conclude that epidural clonidine as a supplement
      to spinal anesthesia produced no perioperative complications and improved
      postoperative pain and hemodynamic stability in patients undergoing lower spine
      procedures. IMPLICATIONS: Spinal anesthesia with supplemental epidural clonidine
      in combination with incision site subcutaneous bupivacaine was evaluated both
      intra- and postoperatively and compared with spinal anesthesia alone for lower
      lumbar spine procedures. Both epidural clonidine and subcutaneous incisional
      bupivacaine, added to spinal anesthesia for lumbar spine surgery, improves pain
      relief and reduces the need for postoperative opioids with their associated side
      effects.

PMID- 12598278
TI  - A comparison of hyperbaric 1% and 3% solutions of small-dose lidocaine in spinal
      anesthesia.
AB  - We examined whether the concentration of hyperbaric lidocaine affected the
      regression of motor block when the dose of lidocaine was kept constant at 30 mg.
      We also examined the spread, duration, and regression of sensory block. Sixty
      five patients (ASA physical status I or II), scheduled for elective perineum or
      lower limb surgery, were enrolled in this study. Patients received spinal
      anesthesia with 1 mL of 3% lidocaine or 3 mL of 1% lidocaine. Adequate level of
      block was obtained for surgery in 63 of 65 patients. Whereas the administration
      of 3 mL of hyperbaric 1% lidocaine solution produced a level of sensory block
      similar to that produced by the administration of 1 mL of hyperbaric 3% lidocaine
      solution in spinal anesthesia, the administration of 3 mL of hyperbaric 1%
      lidocaine solution resulted in shorter times to full motor recovery and to
      urination and produced less motor block compared with 1 mL of hyperbaric 3%
      lidocaine solution. Two patients receiving 1% lidocaine and four patients
      receiving 3% lidocaine required IV ephedrine because of hypotension. Our results
      showed the clinical advantages of hyperbaric 1% lidocaine spinal anesthesia
      compared with hyperbaric 3% lidocaine spinal anesthesia for surgery of short
      duration. IMPLICATIONS: When the dose of lidocaine was kept constant at 30 mg,
      hyperbaric 1% lidocaine solution resulted in shorter times for recovery from
      motor block and to urination than did hyperbaric 3% lidocaine solution. Levels of
      sensory block were similar. Therefore, the more dilute lidocaine for spinal
      anesthesia may be suitable for day-care surgery and short duration surgery.

PMID- 12598279
TI  - Pressure applied on the extra 1 acupuncture point reduces bispectral index values
      and stress in volunteers.
AB  - We investigated the effect of pressure application on the acupuncture point
      "extra 1" and on a control point on the bispectral index (BIS) values and on
      stress in 25 volunteers. In each volunteer, pressure was applied on the extra 1
      point for 10 min and on a control point for 5 min on different days and in a
      randomized manner. The BIS value was recorded before applying pressure on the
      extra 1 point, during pressure application every 30 s for 10 min, and after
      pressure release. Regarding the control point, BIS values were recorded for 5
      instead of 10 min during pressure application because acupressure on that point
      was associated with an unpleasant feeling. Each volunteer was asked to score
      stress before and after pressure application from 0 to 10. The BIS values were
      significantly reduced 2.5, 5, 7.5, and 10 min during pressure application on the
      extra 1 point (P < 0.001 for each comparison, respectively) and returned to the
      baseline values after pressure release. Pressure application on the control point
      decreased BIS values (P < 0.01 and P < 0.05 at 2.5 and 5 min, respectively).
      However, these values were maintained close to 90% and were significantly higher
      than those obtained during pressure on the extra 1 point (P < 0.001 and P < 0.001
      for the 2.5- and 5-min comparisons). The verbal sedation score values obtained
      after pressure application on the extra 1 point were also lower when compared
      with the values obtained after pressure application on the control point (P <
      0.001). IMPLICATIONS: This crossover study investigated the effect of pressure
      application on the acupuncture "extra 1" point in healthy volunteers. Acupressure
      applied for 10 min on the extra 1 point significantly reduced the BIS values and
      the verbal stress score when compared with acupressure applied on a control
      point.

PMID- 12598280
TI  - Hemodynamic responses among three tracheal intubation devices in normotensive and
      hypertensive patients.
AB  - We compare hemodynamic responses in normotensive and hypertensive anesthetized
      paralyzed patients among three intubation devices: the Macintosh laryngoscope
      (LS), the Trachlight lightwand (LW), and the intubating laryngeal mask airway
      Fastrach (ILM). Seventy-five normotensive and 75 hypertensive patients were
      randomly assigned to each intubation device (n = 25). Noninvasive systolic blood
      pressure (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were
      recorded immediately preinduction, immediately preintubation, and every minute
      for the first 5 min after the successful intubation. The number of intubation
      attempts, the time to successful intubation, and any airway injuries were
      recorded. Pharyngolaryngeal morbidity was assessed 18-24 h after surgery by a
      blinded investigator. In all groups, there was a reduction in SBP and DBP but no
      change in HR immediately preintubation compared with baseline values. In all
      groups, HR increased, but there were no increases in SBP and DBP other than in
      DBP in the LS/hypertensive group after intubation compared with baseline values.
      In normotensive patients, there were no differences in any hemodynamic variables
      among the three devices. In hypertensive patients, SBP and DBP in the LS group
      were significantly higher than the ILM and LW groups for 2 min after intubation,
      but there were no differences in HR among the devices. The number of intubation
      attempts was similar among groups, but intubation time was longer for the ILM
      group. The incidence of airway injury was more frequent for the ILM than the LS
      and LW groups (16% versus 0% versus 0%). There were no differences in
      pharyngolaryngeal morbidity among groups. We conclude that both the ILM and the
      LW attenuated the hemodynamic stress response to tracheal intubation compared
      with the LS in hypertensive, but not in normotensive, anesthetized paralyzed
      patients. IMPLICATIONS: Both the intubating laryngeal mask airway Fastrach and
      the Trachlight lightwand attenuate the hemodynamic stress response to tracheal
      intubation compared with the Macintosh laryngoscope in hypertensive, but not in
      normotensive, anesthetized paralyzed patients.

PMID- 12598281
TI  - Flexible lightwand-guided intubation using the intubating laryngeal mask airway
      in the supine, right, and left lateral positions in healthy patients by
      experienced users.
AB  - IMPLICATIONS: Flexible lightwand-guided intubation with the intubating laryngeal
      mask airway is equally effective in the supine, right, and left lateral positions
      in healthy patients by experienced users.

PMID- 12598282
TI  - Visual loss and ophthalmoplegia after shoulder surgery.
AB  - IMPLICATIONS: Ophthalmic complications can occur after a variety of non-ocular
      surgery. The etiology of postoperative visual loss and eye movement dysfunction
      is complex and multifactorial. In many cases, more than one perioperative factor
      may be associated with an adverse ophthalmic outcome.

PMID- 12598283
TI  - The Society for Ambulatory Anesthesia: 17th annual meeting report.

PMID- 12598284
TI  - Epidural steroid injections.

PMID- 12598285
TI  - Subdural hygroma: a rare complication of spinal anesthesia diagnosed after a
      grand mal convulsion.

PMID- 12598287
TI  - Insufficiency in thermometer data.

PMID- 12598286
TI  - Cholinergic transmission not involved in the anesthetic state, but deranged.

PMID- 12598288
TI  - A promising technique for treating circulatory arrest associated coagulopathy.

PMID- 12598289
TI  - A fractured clavicle and vascular compression: a non-orthopedic indication of
      figure-of-eight bandage.

PMID- 12598290
TI  - Reduction of operating room anesthetic gas contamination.

PMID- 12598291
TI  - Class zero airway and laryngoscopy.

PMID- 12598292
TI  - General anesthesia or phrenic nerve block for treatment of chronic hiccups?

PMID- 12598293
TI  - Vascular injury secondary to dilator insertion during internal jugular vein
      cannulation.

PMID- 12598294
TI  - Bring the doctor to the patient...the German "Notarzt" system.

PMID- 12598295
TI  - System failures.

PMID- 12598296
TI  - Hanging by a thread--the tooth solution.

PMID- 12598297
TI  - Hypnosis first, then dissociation.

PMID- 12598298
TI  - Intubation in morbidly obese patients.

PMID- 12598299
TI  - Rewarming rate, diabetes, jugular bulb saturation, and cognitive outcome from
      CABG surgery.

PMID- 12598300
TI  - Renal dysfunction and cognitive function after coronary artery bypass graft
      surgery.

PMID- 12598301
TI  - Proteus syndrome: a concern for the anesthesiologist.

PMID- 12598303
TI  - Serrated adenoma of the colorectum: a lesion with teeth.

PMID- 12598304
TI  - Stress and the hair follicle: exploring the connections.

PMID- 12598305
TI  - Persistent localization of activated extracellular signal-regulated kinases
      (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis.
AB  - Asbestos fibers up-regulate the extracellular signal-regulated kinase (ERK1/2)
      pathway in mesothelial and pulmonary epithelial cells in vitro, but the cell-type
      expression patterns and intracellular localization of activated, ie,
      phosphorylated, ERK in the lung after inhalation of asbestos are unclear. C57/BL6
      mice were exposed to 7-mg/m(3) air of crocidolite asbestos for 5 and 30 days, the
      times required for the development of epithelial cell hyperplasia and fibrotic
      lesions, respectively. Exposure to asbestos caused striking increases in both
      unphosphorylated and phosphorylated ERK (p-ERK), which were most marked at 30
      days and co-localized in bronchiolar and alveolar epithelial cells using an
      antibody to cytokeratin. Alveolar macrophages, detected with an anti-macrophage
      antibody, did not express p-ERK. p-ERK was localized at the apical cell surface
      of bronchiolar and alveolar type II epithelial cells exposed to asbestos fibers,
      and was most marked in areas of epithelial hyperplasia in association with
      fibrotic lesions. Because translocation of p-ERK to the nucleus is associated
      with activation of early response genes and transcription factors, laser scanning
      cytometry was used to determine the kinetics of activation and nuclear
      translocation of p-ERK in an alveolar type II epithelial cell line in vitro after
      exposure to asbestos or the ERK stimuli, epidermal growth factor, or H(2)O(2).
      Results showed that cytoplasmic to nuclear translocation of p-ERK occurred in a
      protracted manner in cells exposed to asbestos. The immunolocalization of p-ERK
      at the membrane surface, a site of initial exposure to asbestos fibers, and the
      chronic activation of p-ERK in epithelial cells at sites of fibrogenesis are
      consistent with the concept that epithelial cell signaling through the ERK
      pathway contributes to remodeling of the lung during the development of pulmonary
      fibrosis.

PMID- 12598307
TI  - Overexpression of the anti-apoptotic caspase-2 short isoform in macrophage
      derived foam cells of human atherosclerotic plaques.
AB  - Apoptosis or programmed cell death is a cellular suicide mechanism that
      frequently occurs in advanced human atherosclerotic plaques. Caspases, a family
      of cysteine proteases, have been identified as important effectors of the death
      machinery. In this study, we report strong caspase-2 immunoreactivity in foam
      cells of macrophage-origin around the necrotic core of advanced human
      atherosclerotic plaques. In contrast, smooth muscle cells (SMCs) and macrophages
      in the fibrous cap as well as endothelial cells, medial SMCs, and SMCs from
      mammary arteries are negative for caspase-2. Caspase-2-positive macrophages were
      isolated from human plaques by laser capture microdissection and were then
      analyzed by Western blotting. A single band of approximately 35 kd corresponding
      with the precursor of the short, anti-apoptotic isoform of caspase-2 (caspase-2S)
      could be identified. Treatment of human U937 macrophages with the DNA strand
      breaking agents etoposide or camptothecin stimulated caspase-2S expression. Since
      atherosclerotic plaques contain a high number of DNA strand breaks, our results
      provide evidence for a survival factor in macrophage-derived foam cells of human
      atherosclerotic plaques that might be up-regulated in response to DNA damage.

PMID- 12598306
TI  - Transcription profiling of platelet-derived growth factor-B-deficient mouse
      embryos identifies RGS5 as a novel marker for pericytes and vascular smooth
      muscle cells.
AB  - All blood capillaries consist of endothelial tubes surrounded by mural cells
      referred to as pericytes. The origin, recruitment, and function of the pericytes
      is poorly understood, but the importance of these cells is underscored by the
      severe cardiovascular defects in mice genetically devoid of factors regulating
      pericyte recruitment to embryonic vessels, and by the association between
      pericyte loss and microangiopathy in diabetes mellitus. A general problem in the
      study of pericytes is the shortage of markers for these cells. To identify new
      markers for pericytes, we have taken advantage of the platelet-derived growth
      factor (PDGF)-B knockout mouse model, in which developing blood vessels in the
      central nervous system are almost completely devoid of pericytes. Using cDNA
      microarrays, we analyzed the gene expression in PDGF-B null embryos in comparison
      with corresponding wild-type embryos and searched for down-regulated genes. The
      most down-regulated gene present on our microarray was RGS5, a member of the RGS
      family of GTPase-activating proteins for G proteins. In situ hybridization
      identified RGS5 expression in brain pericytes, and in pericytes and vascular
      smooth muscle cells in certain other, but not all, locations. Absence of RGS5
      expression in PDGF-B and PDGFR beta-null embryos correlated with pericyte loss in
      these mice. Residual RGS5 expression in rare pericytes suggested that RGS5 is a
      pericyte marker expressed independently of PDGF-B/R beta signaling. With RGS5 as
      a proof-of-principle, our data demonstrate the usefulness of microarray analysis
      of mouse models for abnormal pericyte development in the identification of new
      pericyte-specific markers.

PMID- 12598308
TI  - One-step detection of c-kit point mutations using peptide nucleic acid-mediated
      polymerase chain reaction clamping and hybridization probes.
AB  - The prognostic significance of somatic activating codon 816 c-kit mutations in
      pediatric urticaria pigmentosa has not yet been established in detail. Detection
      of such mutations in archival paraffin-embedded biopsies is usually hampered by
      an abundance of surrounding normal cells. Here we describe a method for the
      selective amplification and specific detection of c-kit mutation Asp816-->Val in
      complete tissue sections cut from up to 24-year-old paraffin blocks. Peptide
      nucleic acid-mediated polymerase chain reaction clamping of the wild-type allele
      was combined with on-line mutation detection using oligonucleotide hybridization
      probes. In DNA extracted from HMC-1 cells heterozygously carrying the c-kit
      mutation Asp816-->Val, the one-tube assay allowed specific detection of this
      mutation in a more than 1000-fold excess of normal background DNA within 1 hour
      and without the need for additional analytical steps. In a series of 38 cases
      with pediatric urticaria pigmentosa we detected c-kit codons 815 and 816
      mutations in 16 cases. Mutation detection did not correlate with clinical outcome
      after a mean follow-up of 11.2 years. In conclusion, the procedure described may
      represent an ideal screening tool for all kinds of clinical applications, using
      point mutations as markers of, for example, early events in carcinogenesis,
      circulating metastatic tumor cells, and minimal residual disease.

PMID- 12598309
TI  - Expression of p16 protein identifies a distinct entity of tonsillar carcinomas
      associated with human papillomavirus.
AB  - Recent analyses of head and neck squamous cell carcinomas revealed frequent
      infections by oncogenic human papillomavirus (HPV) type 16 in tonsillar
      carcinomas. Concerning involvement of risk factors, clinical course of the
      disease, and prognosis there are strong indications arguing that the HPV-positive
      tonsillar carcinomas may represent a separate tumor entity. Looking for a
      surrogate marker, which in further epidemiological studies could replace the
      laborious and expensive HPV detection and typing we analyzed p16 protein
      expression in 34 tonsillar carcinoma for correlation to HPV status and load of
      viral DNA. p16 has been shown to be of diagnostic value for clinical evaluation
      of cervical dysplasia. We found 53% of the tested tonsillar carcinomas to be HPV
      positive. Fifty-six percent of all tumors tested were immunohistochemically
      positive for the p16 protein. In 16 of 18 of the HPV-positive carcinomas diffuse
      p16 expression was observed. In contrast, only one of the HPV-negative carcinomas
      showed focal p16 staining (P < 0.001). As determined by laser-assisted
      microdissection and quantitative real-time polymerase chain reaction, p16
      expression correlated with the presence of HPV-DNA in the individual tumor
      specimens. Clinical outcome analysis revealed significant correlation of p16
      expression with increased disease-free survival (P = 0.02). These data indicate
      that p16 is a technically simple immunohistological marker, applicable for
      routine pathological histology, and its prognostic value for survival is fully
      equivalent to HPV-DNA detection.

PMID- 12598310
TI  - Expression profiling of mouse endometrial cancers microdissected from ethanol
      fixed, paraffin-embedded tissues.
AB  - Expression-profiling studies have helped define genetic changes associated with
      carcinogenesis. Determining which alterations in gene expression are causally
      associated with cancer and which result from the general dysregulation in gene
      expression that is characteristic of malignancies remains a problem.
      Transcriptional profiling of early lesions (small cancers or precancers) holds
      promise for identifying biologically important changes in gene expression. There
      are, however, technical barriers to the study of small tumors. The total number
      of cells available for analysis is limiting. It is also often difficult to
      distinguish cancer cells from normal proliferating cells in frozen sections that
      are typically used as a source of RNA. Here we describe an ethanol fixation and
      paraffin-embedding protocol that preserves tissue architecture and cellular
      morphology of the mouse endometrium, and allows for the recovery of high-quality
      RNA from microdissected cells. We performed GeneChip expression profiling using
      RNA from 800 to 4400 cells microdissected from ethanol-fixed, paraffin-embedded
      uteri. Endometrial adenocarcinomas exhibited changes in the levels of a number of
      messages known to be abnormally expressed in cancer, and differential expression
      of additional transcripts not previously implicated in carcinogenesis. We
      confirmed increased Amd1 expression in RNAs from mouse endometrial carcinomas
      that were hybridized to GeneChips and validated overexpression of this transcript
      in additional tumors.

PMID- 12598311
TI  - High-resolution analysis of paraffin-embedded and formalin-fixed prostate tumors
      using comparative genomic hybridization to genomic microarrays.
AB  - We have used prostate cancer, the most commonly diagnosed noncutaneous neoplasm
      among men, to investigate the feasibility of performing genomic array analyses of
      archival tissue. Prostate-specific antigen and a biopsy Gleason grade have not
      proven to be accurate in predicting clinical outcome, yet they remain the only
      accepted biomarkers for prostate cancer. It is likely that distinct spectra of
      genomic alterations underlie these phenotypic differences, and that once
      identified, may be used to differentiate between indolent and aggressive tumors.
      Array comparative genomic hybridization allows quantitative detection and mapping
      of copy number aberrations in tumors and subsequent associations to be made with
      clinical outcome. Archived tissues are needed to have patients with sufficient
      clinical follow-up. In this report, 20 formalin-fixed and paraffin-embedded
      prostate cancer samples originating from 1986 to 1996 were studied. We present a
      straightforward protocol and demonstrate the utility of archived tissue for array
      comparative genomic hybridization with a 2400 element BAC array that provides
      high-resolution detection of both deletions and amplifications.

PMID- 12598312
TI  - Macrophage recognition and phagocytosis of apoptotic fibroblasts is critically
      dependent on fibroblast-derived thrombospondin 1 and CD36.
AB  - The induction of fibroblast apoptosis and their clearance by phagocytes is
      essential for normal wound healing and prevention of scarring. However, little is
      known about the clearance of apoptotic fibroblasts and whether apoptotic cells
      are active participants in the recruitment and activation of phagocytes. In this
      study, we provide the first evidence that apoptotic fibroblasts actively release
      increased amounts of thrombospondin (TSP1) to actively recruit macrophages.
      Expression of TSP1 and its receptor CD36 was increased on the surface of
      apoptotic fibroblasts. By chemical cross-linking and immunoprecipitation we show
      that TSP1 and CD36 were directly associated. This was confirmed by confocal
      microscopy. Blockade of either CD36 or TSP1 on apoptotic fibroblasts inhibited
      phagocytosis. Blockade of alpha v beta 3 integrins as well as CD36 and TSP1 on
      macrophages inhibited phagocytosis. In contrast, phosphatidylserine or lectins
      were not involved. These findings suggest that apoptotic fibroblasts release TSP1
      as a signal to recruit macrophages while the up-regulated expression of the
      CD36/TSP1 complex on their cell surface may form a ligand bridging the fibroblast
      to a complex consisting of alpha v beta 3/CD36/TSP1 on macrophages. These results
      establish fundamental mechanisms for the clearance of apoptotic fibroblasts and
      may provide insights into the processes involved in normal wound repair.

PMID- 12598313
TI  - Studies on the molecular pathogenesis of extraskeletal myxoid chondrosarcoma
      cytogenetic, molecular genetic, and cDNA microarray analyses.
AB  - Extraskeletal myxoid chondrosarcomas (EMCs) are characterized by recurrent
      chromosome translocations resulting in fusions of the nuclear receptor TEC to
      various NH(2)-terminal partners. Here we describe the phenotypic, cytogenetic,
      and molecular genetic characteristics of a series of 10 EMCs. Using spectral
      karyotyping and fluorescence in situ hybridization, clonal chromosome
      abnormalities were detected in all but one tumor. A t(9;22)(q22;q12)
      translocation was found in three cases; a del(22)(q12-13)in one case; and variant
      translocations, including t(9;17)(q22;q11-12), t(7;9;17)(q32;q22;q11), and
      t(9;15)(q22;q21), were detected in one case each. Recurrent, secondary
      abnormalities, including trisomy 1q, 7, 8, 12, and 19, were found in seven
      tumors. All tumors contained translocation-generated or cryptic gene fusions,
      including EWS-TEC (five cases, of which one was a novel fusion), TAF2N-TEC (four
      cases), and TCF12-TEC (one case). cDNA microarray analysis of the gene expression
      patterns of two EMCs and a myxoid liposarcoma reference tumor revealed a
      remarkably distinct and uniform expression profile in both EMCs despite the fact
      that they had different histologies and expressed different fusion transcripts.
      The most differentially expressed gene in both tumors was CHI3L1, which encodes a
      secreted glycoprotein (YKL-40) previously implicated in various pathological
      conditions of extracellular matrix degradation as well as in cancer. Our findings
      suggests that EMC exhibits a tumor-specific gene expression profile, including
      overexpression of several cancer-related genes as well as genes implicated in
      chondrogenesis and neural-neuroendocrine differentiation, thus distinguishing it
      from other soft tissue sarcomas.

PMID- 12598314
TI  - Inducible nitric oxide synthase expression in human colorectal cancer:
      correlation with tumor angiogenesis.
AB  - To investigate the potential involvement of the nitric oxide (NO) pathway in
      colorectal carcinogenesis, we correlated the expression and the activity of
      inducible nitric oxide synthase (iNOS) with the degree of tumor angiogenesis in
      human colorectal cancer. Tumor samples and adjacent normal mucosa were obtained
      from 46 surgical specimens. Immunohistochemical expression of iNOS, vascular
      endothelial growth factor (VEGF), and CD31 was analyzed on paraffin-embedded
      tissue sections. iNOS activity and cyclic GMP levels were assessed by specific
      biochemical assays. iNOS protein expression was determined by Western blot
      analysis. iNOS and VEGF mRNA levels were evaluated using Northern blot analysis.
      Both iNOS and VEGF expressions correlated significantly with intratumor
      microvessel density (r(s) = 0.31, P = 0.02 and r(s) = 0.67, P < 0.0001,
      respectively). A significant correlation was also found between iNOS and VEGF
      expression (P = 0.001). iNOS activity and cyclic GMP production were
      significantly higher in the cancer specimens than in the normal mucosa (P <
      0.0001 and P < 0.0001, respectively), as well as in metastatic tumors than in
      nonmetastatic ones (P = 0.002 and P = 0.04, respectively). Western and Northern
      blot analyses confirmed the up-regulation of the iNOS protein and gene in the
      tumor specimens as compared with normal mucosa. NO seems to play a role in
      colorectal cancer growth by promoting tumor angiogenesis.

PMID- 12598315
TI  - Stress inhibits hair growth in mice by induction of premature catagen development
      and deleterious perifollicular inflammatory events via neuropeptide substance P
      dependent pathways.
AB  - It has been much disputed whether or not stress can cause hair loss (telogen
      effluvium) in a clinically relevant manner. Despite the paramount psychosocial
      importance of hair in human society, this central, yet enigmatic and
      controversial problem of clinically applied stress research has not been
      systematically studied in appropriate animal models. We now show that
      psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo,
      ie, prematurely terminates the normal duration of active hair growth (anagen) in
      mice. Further, inflammatory events deleterious to the HF are present in the HF
      environment of stressed mice (perifollicular macrophage cluster, excessive mast
      cell activation). This provides the first solid pathophysiological mechanism for
      how stress may actually cause telogen effluvium, ie, by hair cycle manipulation
      and neuroimmunological events that combine to terminate anagen. Furthermore, we
      show that most of these hair growth-inhibitory effects of stress can be
      reproduced by the proteotypic stress-related neuropeptide substance P in
      nonstressed mice, and can be counteracted effectively by co-administration of a
      specific substance P receptor antagonist in stressed mice. This offers the first
      convincing rationale how stress-induced hair loss in men may be pharmacologically
      managed effectively.

PMID- 12598316
TI  - Frequent CpG island methylation in serrated adenomas of the colorectum.
AB  - Serrated adenomas are characterized by a saw-toothed growth pattern with
      epithelial dysplasia (intraepithelial neoplasia). The CpG island methylator
      phenotype (CIMP) is a recently described mechanism for tumorigenesis in
      colorectal carcinomas and adenomas characterized by methylation of multiple CpG
      islands. The role of these epigenetic alterations in the pathogenesis of serrated
      adenomas is not clear. We therefore evaluated CIMP in 22 sporadic serrated
      adenomas and 6 serrated adenomas with multiple (6 to 10) hyperplastic polyps,
      including 5 with admixed hyperplastic glands and adenomatous glands, and compared
      the results with 34 conventional adenomas. Bisulfite methylation-specific
      polymerase chain reaction was used for the p16 and hMLH1 genes, and three MINT
      (methylated in tumor) loci (MINT1, MINT2, and MINT31). Patients with sporadic
      serrated adenomas had a higher frequency of hyperplastic polyps (1.3 +/- 1.6) as
      compared to patients with tubular adenomas (0.4 +/- 0.9, P = 0.02). Mean number
      of methylated sites was significantly higher in sporadic serrated adenomas (2.0
      +/- 1.7) than in tubular adenomas (0.8 +/- 0.9, P = 0.00001). Sporadic serrated
      adenomas had significantly more frequent methylation of MINT1 (48%, 10 of 22) and
      MINT2 (71%, 15 of 21) than tubular adenomas (9%, 3 of 34, P = 0.001; and 18%, 6
      of 34, P = 0.0001), respectively. Concordant methylation of two or more sites
      (CIMP-high) was also more frequent in sporadic serrated adenomas (68%, 15 of 22)
      than in tubular adenomas (18%, 6 of 34, P = 0.0005). All five serrated adenomas
      with admixed hyperplastic glands and adenomatous glands were CIMP-high. Our
      results indicate that CpG island methylation is common in sporadic serrated
      adenomas and may play an important role in their pathogenesis.

PMID- 12598317
TI  - Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral
      sclerosis.
AB  - Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration
      of the motor neurons in the cerebral cortex, brain stem, and spinal cord.
      However, the mechanisms that regulate the initiation and/or progression of motor
      neuron loss in this disease remain enigmatic. Cell-cycle proteins and
      transcriptional regulators such as cyclins, cyclin-associated kinases, the
      retinoblastoma gene product (pRb), and E2F-1 function during cellular
      proliferation, differentiation, and cell death pathways. Recent data has
      implicated increased expression and activation of various cell-cycle proteins in
      neuronal cell death. We have examined the expression and subcellular distribution
      of G(1) to S phase cell-cycle regulators in the spinal cord, motor cortex, and
      sensory cortex from clinically and neuropathologically diagnosed sporadic ALS
      cases and age-matched controls. Our results indicate hyperphosphorylation of the
      retinoblastoma protein in motor neurons during ALS, concurrent with increased
      levels of cyclin D, and redistribution of E2F-1 into the cytoplasm of motor
      neurons and glia. These data suggest that G(1) to S phase activation occurs
      during ALS and may participate in molecular mechanisms regulating motor neuron
      death.

PMID- 12598318
TI  - AIM inhibits apoptosis of T cells and NKT cells in Corynebacterium-induced
      granuloma formation in mice.
AB  - Apoptosis inhibitor expressed by macrophages (AIM) inhibits apoptosis of
      CD4(+)CD8(+) (CD4/CD8) double-positive thymocytes, and supports the viability of
      these cells on the thymic selection. However, pleiotropic functions of AIM have
      been suggested. In this study, heat-killed Corynebacterium parvum (C. parvum) was
      injected into mice carrying the homozygous mutation (AIM(-/-)) and wild-type
      (AIM(+/+)) mice, to investigate the role of AIM in the formation of hepatic
      granulomas. In AIM(-/-) mice, the size and the number of hepatic granulomas were
      larger, and the resorption of granulomas was more delayed than in AIM(+/+) mice.
      The production of interleukin-12 was more prominent in AIM(-/-) mice than in
      AIM(+/+) mice. In the liver of AIM(+/+) mice, expression of AIM messenger
      ribonucleic acid (mRNA) increased after C. parvum injection. In situ
      hybridization demonstrated that AIM mRNA was expressed in Kupffer cells and
      exudate macrophages in the liver, especially in granulomas. Larger numbers of T
      cells and natural killer T (NKT) cells underwent apoptosis in the granulomas of
      AIM(-/-) mice, suggesting that AIM prevents apoptosis of NKT cells and T cells in
      C. parvum-induced inflammation. Recombinant AIM (rAIM) protein significantly
      inhibited apoptosis of NKT cells and T cells obtained from C. parvum-stimulated
      livers in vitro. These results indicate that AIM functions to induce resistance
      to apoptosis within NKT cells and T cells, and supports the host defense in
      granulomatous inflammation.

PMID- 12598319
TI  - Dystroglycan expression is frequently reduced in human breast and colon cancers
      and is associated with tumor progression.
AB  - Dystroglycan (DG) is an adhesion molecule responsible for crucial interactions
      between extracellular matrix and cytoplasmic compartment. It is formed by two
      subunits, alpha-DG (extracellular) and beta-DG (transmembrane), that bind to
      laminin in the matrix and dystrophin in the cytoskeleton, respectively. In this
      study we evaluated by Western blot analysis the expression of DG in a series of
      human cancer cell lines of various histogenetic origin and in a series of human
      primary colon and breast cancers. Decreased expression of DG was observed in most
      of the cell lines and in both types of tumors and correlated with higher tumor
      grade and stage. Analysis of the mRNA levels suggested that expression of DG
      protein is likely regulated at a posttranscriptional level. Evaluation of alpha
      DG expression by immunostaining in a series of archival cases of primary breast
      carcinomas confirmed that alpha-DG expression is lost in a significant fraction
      of tumors (66%). Loss of DG staining correlated with higher tumor stage (P =
      0.022), positivity for p53 (P = 0.033), and high proliferation index (P = 0.045).
      A significant correlation was also observed between loss of alpha-DG and overall
      survival (P = 0.013 by log-rank test) in an univariate analysis. These data
      indicate that DG expression is frequently lost in human malignancies and suggest
      that this glycoprotein might play an important role in human tumor development
      and progression.

PMID- 12598320
TI  - Expression of B-lymphocyte-associated transcription factors in human T-cell
      neoplasms.
AB  - In this study we have investigated the expression of three B-cell-associated
      transcription factors in normal lymphoid tissue and in T-cell neoplasms (three
      cell lines, and more than 50 biopsy samples). Nuclear OCT-1 immunoreactivity was
      seen in normal B cells, in many extrafollicular T cells, and in a heterogeneous
      pattern (ranging in intensity from weak to moderate) in most T-cell neoplasms.
      OCT-2 immunostaining was primarily restricted in normal lymphoid tissue to B
      cells, and was absent from most T-cell neoplasms. In contrast, immunostaining for
      BOB-1/OCA-B--essentially restricted to B cells in normal lymphoid tissue, with
      the exception of activated T-lymphocytes--was seen in all of the T-cell lines
      tested and the majority of the tumor cells in all categories of T-cell lymphoma.
      Thus labeling for each of these three B-cell-associated transcription factors can
      be seen to varying degrees in T-cell neoplasms. However, the high frequency of
      BOB-1 expression in T-cell neoplasms, in contrast to its absence from resting
      peripheral T cells, suggests that its expression might be a prerequisite for
      neoplastic transformation, and prompts a search for the transcriptional target(s)
      of this factor in T cells.

PMID- 12598321
TI  - Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo
      expression of the alpha 6(IV) collagen chain in a canine model of Alport
      syndrome.
AB  - X-linked Alport syndrome is a progressive renal disease caused by mutations in
      the COL4A5 gene, which encodes the alpha 5(IV) collagen chain. As an initial step
      toward gene therapy for Alport syndrome, we report on the expression of
      recombinant alpha 5(IV) collagen in vitro and in vivo. A full-length cDNA
      encoding canine alpha 5(IV) collagen was cloned and expressed in vitro by
      transfection of HEK293 cells that synthesize the alpha1(IV) and alpha2(IV), but
      not the alpha 3(IV) to alpha 6(IV) collagen chains. By Northern blotting, an
      alpha 5(IV) mRNA transcript of 5.2 kb was expressed and the recombinant protein
      was detected by immunocytochemistry. The chain was secreted into the medium as a
      190-kd monomer; no triple helical species were detected. Transfected cells
      synthesized an extracellular matrix containing the alpha1(IV) and alpha2(IV)
      chains but the recombinant alpha 5(IV) chain was not incorporated. These findings
      are consistent with the concept that the alpha 5(IV) chain requires one or more
      of the alpha 3(IV), alpha 4(IV), or alpha 6(IV) chains for triple helical
      assembly. In vivo studies were performed in dogs with X-linked Alport syndrome.
      An adenoviral vector containing the alpha 5(IV) transgene was injected into
      bladder smooth muscle that lacks both the alpha 5(IV) and alpha 6(IV) chains in
      these animals. At 5 weeks after injection, there was expression of both the alpha
      5(IV) and alpha 6(IV) chains by smooth muscle cells at the injection site in a
      basement membrane distribution. Thus, this recombinant alpha 5(IV) chain is
      capable of restoring expression of a second alpha(IV) chain that requires the
      presence of the alpha 5(IV) chain for incorporation into collagen trimers. This
      vector will serve as a useful tool to further explore gene therapy for Alport
      syndrome.

PMID- 12598322
TI  - Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN
      (CD209) in the decidua of early human pregnancy.
AB  - Intact human pregnancy can be regarded as an immunological paradox in that the
      maternal immune system accepts the allogeneic embryo without general
      immunosuppression. Because dendritic cell (DC) subsets could be involved in
      peripheral tolerance, the uterine mucosa (decidua) was investigated for DC
      populations. Here we describe the detailed immunohistochemical and functional
      characterization of HLA-DR-positive antigen-presenting cells (APCs) in early
      pregnancy decidua. In contrast to classical macrophages and CD83(+) DCs, which
      were found in comparable numbers in decidua and nonpregnant endometrium, only
      decidua harbored a significant population of HLA-DR(+)/DC-SIGN(+) APCs further
      phenotyped as CD14(+)/CD4(+)/CD68(+/-)/CD83(-)/CD25(-). These cells exhibited a
      remarkable proliferation rate (9.2 to 9.8% of all CD209(+) cells) by double
      staining with Ki67 and proliferating cell nuclear antigen. Unique within the DC
      family, the majority of DC-SIGN(+) decidual APCs were observed in situ to have
      intimate contact with CD56(+)/CD16(-)/ICAM-3(+) decidual natural killer cells,
      another pregnancy-restricted cell population. In vitro, freshly isolated
      CD14(+)/DC-SIGN(+) decidual cells efficiently took up antigen, but could not
      stimulate naive allogeneic T cells at all. Treatment with an inflammatory
      cytokine cocktail resulted in down-regulation of antigen uptake capacity and
      evolving capacity to effectively stimulate resting T cells. Fluorescence
      activated cell sorting analysis confirmed the maturation of CD14(+)/DC-SIGN(+)
      decidual cells into CD25(+)/CD83(+) mature DCs. In summary, this is the first
      identification of a uterine immature DC population expressing DC-SIGN, that
      appears only in pregnancy-associated tissue, has a high proliferation rate, and a
      conspicuous association with a natural killer subset.

PMID- 12598323
TI  - PTOV-1, a novel protein overexpressed in prostate cancer, shuttles between the
      cytoplasm and the nucleus and promotes entry into the S phase of the cell
      division cycle.
AB  - PTOV1 was recently identified as a novel gene and protein during a differential
      display screening for genes overexpressed in prostate cancer. The PTOV1 protein
      consists of two novel protein domains arranged in tandem, without significant
      similarities to known protein motifs. By immunohistochemical analysis, we have
      found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of
      samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors
      correlated significantly with proliferative index, as assessed by Ki67
      immunoreactivity, and associated with a nuclear localization of the protein,
      suggesting a functional relationship between PTOV1 overexpression, proliferative
      status, and nuclear localization. In quiescent cultured prostate tumor cells,
      PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum
      stimulation, PTOV1 partially translocated to the nucleus at the beginning of the
      S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection
      of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S
      phase of the cell cycle, as shown by double fluorescent imaging for green
      fluorescent protein and for Ki67, and also by flow cytometry. This was
      accompanied by greatly increased levels of cyclin D1 protein in the transfected
      cells. These observations suggest that overexpression of PTOV1 can contribute to
      the proliferative status of prostate tumor cells and thus to their biological
      behavior.

PMID- 12598324
TI  - Expression of protease-activated receptor-1, -2, -3, and -4 in control and
      experimentally inflamed mouse bladder.
AB  - Inflammation underlines all major bladder pathologies and represents a defense
      reaction to injury involving a mandatory participation of mast cells and sensory
      nerves. Mast cells are particularly frequent in close proximity to epithelial
      surfaces where they are strategically located in the bladder and release their
      mediators in response to inflammation. Tryptase is specifically produced by mast
      cells and modulates inflammation by activating protease-activated receptors
      (PARs). We recently found that PAR-4 mRNA is up-regulated in experimental bladder
      inflammation regardless of the initiating stimulus. Because it has been reported
      that PAR-1, PAR-2, and PAR-3 may also be involved in the processes of
      inflammation, we used immunohistochemistry to characterize the expression of all
      known PARs in normal, acute, and chronic inflamed mouse bladder. We found that
      all four PARs are present in the control mouse bladder, and follow a unique
      distribution. All four PARs are co-expressed in the urothelium, whereas PAR-1 and
      PAR-2 are predominant in the detrusor muscle, and PAR-4 is expressed in
      peripheral nerves and plexus cell bodies. The strong expression of PARs in the
      detrusor muscle indicates the need for studies on the role of these receptors in
      motility whereas the presence of PAR-4 in nerves may indicate its participation
      in neurogenic inflammation. In addition, PARs are differentially modulated during
      inflammation. PAR-1 and PAR-2 are down-regulated in acute inflammation whereas
      PAR-3 and PAR-4 are up-regulated. Bladder fibroblasts were found to present a
      clear demarcation in PAR expression secondary to acute and chronic inflammation.
      Our findings provide evidence of participation of PARs in the urinary system,
      provide a working model for mast cell tryptase signaling in the mouse bladder,
      and evoke testable hypotheses regarding the roles of PARs in bladder
      inflammation. It is timely to understand the role of tryptase signaling and PARs
      in the context of bladder biology.

PMID- 12598325
TI  - Gene expression patterns in renal cell carcinoma assessed by complementary DNA
      microarray.
AB  - Renal cell carcinoma comprises several histological types with different clinical
      behavior. Accurate pathological characterization is important in the clinical
      management of these tumors. We describe gene expression profiles in 41 renal
      tumors determined by using DNA microarrays containing 22,648 unique cDNAs
      representing 17,083 different UniGene Clusters, including 7230 characterized
      human genes. Differences in the patterns of gene expression among the different
      tumor types were readily apparent; hierarchical cluster analysis of the tumor
      samples segregated histologically distinct tumor types solely based on their gene
      expression patterns. Conventional renal cell carcinomas with clear cells showed a
      highly distinctive pattern of gene expression. Papillary carcinomas formed a
      tightly clustered group, as did tumors arising from the distal nephron and the
      normal kidney samples. Surprisingly, conventional renal cell carcinomas with
      granular cytoplasm were heterogeneous, and did not resemble any of the
      conventional carcinomas with clear cytoplasm in their pattern of gene expression.
      Characterization of renal cell carcinomas based on gene expression patterns
      provides a revised classification of these tumors and has the potential to supply
      significant biological and clinical insights.

PMID- 12598326
TI  - Divergent roles for p55 and p75 TNF-alpha receptors in the induction of
      plasminogen activator inhibitor-1.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is elevated in obesity and in acute
      inflammatory states, and contributes to the elevated plasminogen activator
      inhibitor-1 (PAI-1) levels associated with these conditions. Mice genetically
      deficient in the p55 and p75 TNF-alpha receptors were used to study the roles of
      these receptors in the expression of PAI-1 in obese (ob/ob) mice, and in lean
      mice following acute stimulation with TNF-alpha. In ob/ob mice, p55 and p75 tumor
      necrosis factor-alpha receptors (TNFRs) act cooperatively to induce PAI-1 mRNA in
      most tissues, including the adipose tissue, kidney, heart, and liver. However, in
      lean mice, TNF-alpha-induced PAI-1 expression is mediated primarily by the p55
      TNFR. Interestingly, PAI-1 mRNA expression in all tissues of the TNF-alpha
      treated p75-deficient lean mice was significantly higher than that observed in
      TNF-alpha-treated wild-type mice. These observations suggest that the p75 TNFR
      may play a role in attenuating TNF-alpha-induced PAI-1 mRNA expression in acute
      inflammatory conditions. Our observation that soluble p75 TNFR was elevated in
      the plasma of TNF-alpha-treated mice in comparison to untreated mice supports
      this hypothesis. These studies thus provide insights into the TNF-alpha receptors
      involved in mediating and modulating the expression of PAI-1 in acute and chronic
      (eg, obesity) inflammatory states associated with elevated TNF-alpha.

PMID- 12598327
TI  - Short-term exposure of cartilage to blood results in chondrocyte apoptosis.
AB  - Studies have shown that joint bleeding leads to cartilage degradation independent
      of concurrent synovitis. We hypothesized that the blood-induced cartilage damage
      is because of increased chondrocyte apoptosis after short-term exposure of whole
      blood or isolated mononuclear cells plus red blood cells to cartilage. Human
      cartilage tissue samples were co-cultured for 4 days with whole blood (50% v/v)
      or with mononuclear cells plus red blood cells (50% v/v equivalents). Cartilage
      matrix proteoglycan synthesis ((35)SO(4)(2-) incorporation) was determined after
      4 days as well as at day 16 (after a 12-day recovery period in the absence of any
      additions). To test the involvement of apoptosis a specific caspase-3 inhibitor
      (acDEVDcho, 0 to 500 micro mol/L) as well as a pan-caspase inhibitor (zVADfmk, 0
      to 500 micro mol/L) were added. Chondrocyte apoptosis was evaluated by
      immunohistochemical staining of single-strand DNA and by terminal dUTP nick-end
      labeling. Cartilage co-cultured with whole blood as well as mononuclear cells
      plus red blood cells induced a long-term inhibition of proteoglycan synthesis
      (74% and 78% inhibition on day 16, respectively). Immunohistochemistry showed a
      threefold increase in apoptotic chondrocytes in cultures with 50% whole blood as
      well as with mononuclear cells plus red blood cells. Both the specific caspase-3
      inhibitor and the pan-caspase inhibitor partially restored proteoglycan synthesis
      in the cartilage after blood exposure. This effect was accompanied by a decrease
      in the number of apoptotic chondrocytes. These data suggest that a single joint
      hemorrhage (a 4-day exposure of cartilage to 50% v/v blood) results in induction
      of chondrocyte apoptosis, responsible for the observed inability of the
      chondrocytes to restore the proteoglycan synthesis during recovery from a short
      term exposure to blood. This reduced restoration could eventually lead to
      cartilage degeneration and ultimately joint destruction.

PMID- 12598328
TI  - Lack of platelet endothelial cell adhesion molecule-1 attenuates foreign body
      inflammation because of decreased angiogenesis.
AB  - Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a 130-kd member
      of the immunoglobulin superfamily of proteins, expressed on endothelial cells,
      leukocytes, and platelets. Antibody-blocking studies have implicated it in
      modulating leukocyte transmigration and angiogenesis. However, the generation of
      the PECAM-1 knockout mouse has shown that its function can be compensated for by
      similarly acting proteins because most acute inflammatory models proceed in a
      comparable manner in wild-type and knockout animals. We decided to examine the
      function of PECAM-1 in the chronic process of foreign body inflammation. We show
      that PECAM-1-deficient mice exhibit attenuated neutrophil infiltration in and
      around a subcutaneous polyvinyl acetyl implant. Bone marrow engraftment studies
      indicate that the lack of CD31 expression on the endothelium determines the
      diminished leukocyte accumulation in the knockout implants. Specifically, we find
      that decreased angiogenesis (as manifested by lower vessel density, decreased
      hemoglobin content, and less laminin deposition) correlates with lower neutrophil
      accumulation in the knockout animals. This study indicates that the absence of
      endothelial PECAM-1 results in decreased angiogenesis and therefore in diminished
      delivery of leukocytes to the foreign body implants.

PMID- 12598329
TI  - Expression of keratin K2e in cutaneous and oral lesions: association with
      keratinocyte activation, proliferation, and keratinization.
AB  - The cytoskeleton in keratinocytes is a complex of highly homologous structural
      proteins derived from two families of type I and type II polypeptides. Keratin
      K2e is a type II polypeptide that is expressed in epidermis late in
      differentiation. Here we report the influence of keratinocyte activation,
      proliferation, and keratinization on K2e expression in samples of cutaneous and
      oral lesions. The normal expression of K2e in the upper spinous and granular
      layers of interfollicular epidermis is increased in keloid scars but showed
      distinct down-regulation in psoriasis and hypertrophic scars where keratinocytes
      are known to undergo activation. Unlike normal and psoriatic skin, K2e expression
      in hypertrophic and keloid scars began in the deepest suprabasal layer. In
      cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor
      islands but the overlying epidermis showed strong expression. No significant K2e
      expression in nonkeratinized or keratinized oral epithelia, including buccal
      mucosa, lateral border of tongue and gingiva was detected. In oral lichen planus
      K2e expression was undetectable, but in benign keratoses of lingual mucosa
      induction of K2e along with K1 and K10 was observed. In mild-to-moderate oral
      dysplasia with orthokeratinization, K2e was highly expressed compared with
      parakeratinized areas but in severe dysplasia as well as in oral squamous cell
      carcinoma, K2e expression was undetectable. Taken together, the data suggest that
      K2e expression in skin is sensitive to keratinocyte activation but its up
      regulation in oral lesions is a reflection of the degree of orthokeratinization.

PMID- 12598330
TI  - Structural and functional changes in heparan sulfate proteoglycan expression
      associated with the myofibroblastic phenotype.
AB  - The principal cells implicated as the source of the extracellular matrix in areas
      of progressive fibrosis are fibroblasts with the phenotypic appearance of
      myofibroblasts. This report describes differences in heparan sulfate proteoglycan
      expression between myofibroblasts and normal fibroblasts, associated with
      impaired responses to fibroblast growth factor-2 (FGF-2). Although both cell
      types responded to platelet-derived growth factor, myofibroblasts, unlike
      fibroblasts, did not proliferate to FGF-2. A response was acquired, however, when
      myofibroblasts were incubated with FGF-2 in the presence of heparan sulfate (HS)
      and heparin. Selective digestion with pronase, NaOH/NaBH(4), heparinase I, or low
      pH nitrous acid showed that each HS-glycosaminoglycan region comprised a pronase
      resistant peptide separating two HS chains. The HS-glycosaminoglycan chains from
      myofibroblasts were larger (K(av), 0.32; molecular weight, 50 kd) than those from
      fibroblasts (K(av), 0.4; molecular weight, 33 kd), although their disaccharide
      composition was identical. The chains from myofibroblasts, however, contained
      three, compared to two, heparinase 1-resistant sequences separated by larger
      contiguous areas of low sulfation. Furthermore, although there was no difference
      in FGF-2-binding affinity between the two cell types, the chains secreted by
      myofibroblasts had twice the binding capacity of those from fibroblasts. Thus, it
      is likely that the difference in response to FGF-2 is because of a difference in
      FGF-2 sequestration and receptor interaction with FGF-2-HS complexes. A
      comparative investigation into HS fine structure is being undertaken to examine
      these findings in more detail.

PMID- 12598331
TI  - cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage
      hepatitis C virus-induced cirrhosis.
AB  - Hepatocellular carcinoma is a common malignancy causing significant morbidity and
      mortality worldwide. In this study we use expression microarray technology to
      identify novel genes that consistently displayed altered expression levels in the
      earliest identifiable precursors to hepatocellular carcinoma, dysplastic and
      macroregenerative nodules. The gene expression profiles from nine patients with
      end-stage hepatitis C cirrhosis that contained a combined 11 dysplastic or
      macroregenerative nodules were compared to the patient's matched cirrhotic liver
      tissue. A total of 53 genes were consistently dysregulated in the patient liver
      specimens. Six of seven genes were validated by quantitative real-time reverse
      transcriptase-polymerase chain reaction, or by immunohistochemical studies
      performed on an independent set of lesions. The novel genes, including caveolin
      1, semaphorin E, and FMS-like tyrosine kinase 3 ligand, have putative roles in
      carcinogenesis but have not been reported in hepatocellular carcinogenesis.
      Microarray expression analysis of dysplastic and macroregenerative liver nodules
      provide insight into the earliest changes in hepatocellular carcinogenesis.

PMID- 12598332
TI  - Changes in myotonic dystrophy protein kinase levels and muscle development in
      congenital myotonic dystrophy.
AB  - Myotonic dystrophy (DM1) is caused by the expansion of a CTG repeat in the
      noncoding region of a protein kinase, DMPK, expressed in skeletal and cardiac
      muscles. The aim of the present study was to determine the effects of very large
      CTG expansions on DMPK expression and skeletal muscle development. In fetuses
      suffering from the severe congenital form of DM1 with large CTG expansions (1800
      to 3700 repeats), the skeletal muscle level of DMPK was reduced to 57% of control
      levels and a similar reduction was observed in cultured DM1 muscle cells relative
      to control cultures. These results are consistent with greatly reduced DMPK
      expression from the mutant allele and normal expression from the unaffected
      allele in this autosomal dominant disorder. In normal fetuses, DMPK protein
      levels increased dramatically between 9 and 16 weeks and remained high throughout
      the remaining gestation period. DM1 fetuses showed impaired skeletal muscle
      development, characterized by a persistence of embryonic and fetal myosin heavy
      chains and almost total absence of slow myosin heavy chains at the end of
      gestation. DMPK expression, however, was similar in both fast and slow fibers
      from normal adult muscle. The reduced DMPK and the delayed slow fiber maturation
      in congenital DM1 may be two separate consequences of nuclear retention of DMPK
      RNA transcripts with expanded CUG repeats.

PMID- 12598333
TI  - Specific binding of an antigen-antibody complex to apoptotic human neutrophils.
AB  - Examination of apoptotic cell surface molecules has so far failed to reveal cell
      type-specific membrane alterations that serve as a signal for phagocytosis. In
      the present study we have identified a novel murine monoclonal antibody, BOB93,
      which bound to the surface of apoptotic neutrophils but not to apoptotic
      lymphocytes. BOB93 binding to apoptotic neutrophils was dependent on the presence
      of the sialoglycoprotein fetuin, a constituent of bovine serum. We demonstrate
      that fetuin is the antigen for BOB93, and that BOB93 and fetuin form a complex in
      solution that is necessary and sufficient for binding to apoptotic neutrophils.
      Individuals who were homozygous for an adenine nucleotide at position 519 of the
      gene for the immune complex receptor Fc gamma RIIA exhibited markedly reduced
      binding of BOB93/fetuin. This report is the first to provide evidence that
      antigen-antibody complexes bind specifically to apoptotic neutrophils and
      implicates apoptosis-associated changes in Fc gamma receptor function.

PMID- 12598335
TI  - Kindling status in sprague-dawley rats induced by pentylenetetrazole: involvement
      of a critical development period.
AB  - Kindled seizures are widely used as a model for epileptogenesis. Although the
      achievement of kindling criterion is known to require time to develop, the
      precise developmental period has not been identified. We now report that optimal
      achievement of the kindling criterion in the Sprague-Dawley rat is associated
      with a critical inter-stimulus interval of 24 to 26 days. We show that highly
      efficient kindling can be achieved with only two subconvulsive doses of
      pentylenetetrazole so long as they are given 25 days apart. Using Northern blot
      hybridization we show that the increased seizure susceptibility at 25 days
      coincides with an increased expression of the plasticity-associated proteins,
      growth-associated protein-43 (GAP-43), microtubule-associated protein 1B (MAP1B),
      and tissue plasminogen activator (tPA) mRNAs in the hippocampus. By in situ
      hybridization and immunocytochemistry on tissue sections, we also show an
      increased expression for GAP-43 in the polymorphic layer of the dentate gyrus,
      mossy fibers, and pyramidal cells in the CA3 region of the hippocampus. The
      demonstration of a long, defined developmental interval for inducing the kindling
      criterion should enable a dissection of the cellular and genetic events
      underlying this phenomenon in the rat.

PMID- 12598336
TI  - Immunomodulation in colorectal cancer: disappointment or promise?

PMID- 12598334
TI  - Full-length telomerase reverse transcriptase messenger RNA is an independent
      prognostic factor in neuroblastoma.
AB  - Telomerase activity (TA) is the most recently recognized prognostic factor in
      neuroblastoma, and its outstanding predictive power was documented by several
      studies. However, TA measurements require fresh tumor tissue that is not always
      available in daily clinical practice. We previously described a reverse
      transcriptase-polymerase chain reaction assay that we used to investigate the
      possible prognostic relevance of the telomerase catalytic subunit, hTERT, at the
      mRNA level. Because hTERT mRNA undergoes alternative splicing as a regulatory
      mechanism of TA, we discriminated between truncated and full-length hTERT
      transcripts. In a retrospective study on 124 neuroblastomas, 56 (45.2%) tumors
      showed spliced hTERT transcripts, whereas 30 (24.2%) contained full-length hTERT
      transcripts. The presence of both spliced and full-length hTERT transcripts was
      significantly associated with MYCN amplification. hTERT in general showed no
      correlation to other prognostic factors, ie, International Neuroblastoma Staging
      System stage, International Neuroblastoma Pathology classification grade, or age
      at diagnosis, whereas the presence of full-length transcripts was significantly
      associated with higher stages. The presence of any hTERT transcripts carried no
      significant prognostic information, yet full-length hTERT transcripts were highly
      predictive of poor outcome (P < 0.0001). In a multivariate analysis, full-length
      hTERT transcripts and International Neuroblastoma Pathology classification grade
      emerged as the sole independent predictors of event-free survival, with relative
      risks of 10.0 and 3.9, respectively. The strong statistical correlation of full
      length hTERT transcripts with clinical outcome in neuroblastoma suggests that the
      reverse transcriptase-polymerase chain reaction analysis of hTERT transcripts may
      be equatable to TA measurements. Because this assay is well suited for archival
      material, it could become a useful adjunct in evaluating the prognosis of
      individual neuroblastoma cases.

PMID- 12598337
TI  - More on the regulation of tobacco smoke: how we got here and where next.
AB  - The modern cigarette is unnecessarily dangerous. Despite being lower in tar
      yield, and consequently in squamo-carcinogenic polyaromatic hydrocarbons such as
      benzo[a]pyrene, the nitrosamine yields are often higher than they need to be.
      Also, reductions in tar levels have not led to the consequential reductions in
      mortality that were anticipated several decades ago. The modern cigarette is also
      smoother, easier to smoke and to learn how to smoke, highly addictive and
      facilitates compensatory smoking. Compensatory smoking leads to excess inhalation
      of carcinogens and toxins in the hunt for nicotine. Its labelling is misleading
      in that supposedly low-yielding cigarettes may, due to compensation occurring as
      a result of cigarette design, lead to inhalation of much higher amounts of
      nicotine, carcinogens and toxins than the smoker is led to expect. Regulation of
      the product is needed to provide the persistent smoker with a cigarette lower in
      risk, accurately labelled, providing a relatively consistent and known dose of
      nicotine, and less likely to facilitate compensatory smoking. This will not
      produce a safe cigarette but should result in a reduction in harm if seriously
      implemented.

PMID- 12598338
TI  - Adjuvant therapy of cutaneous melanoma: the interferon debate.
AB  - Despite the use of a variety of cytotoxic and immunotherapeutic agents in
      adjuvant trials in patients following resection of high-risk early cutaneous
      melanoma, only interferon-alpha2b (IFN-alpha) has shown reproducible efficacy.
      High-dose IFN-alpha (HDI) is superior to observation in prolonging relapse-free
      survival. There is still no formal proof of a statistically significant advantage
      of HDI in prolonging overall survival. For this reason the continued use of
      observation-only control arms is justified and desirable in adjuvant melanoma
      trials, and, wherever possible, patients with resected high-risk and intermediate
      risk melanoma should be entered on these studies. The toxicity of HDI is high,
      but the majority of patients complete treatment with dose modification and nearly
      all toxicity is rapidly reversible. There is now a useful body of information on
      the supportive care of patients receiving HDI, and data on cost and quality
      adjusted time without symptoms and toxicity (Q-TwiST) to support its use in
      certain high-risk patients. Interim results from a trial of intermediate-dose IFN
      alpha are promising. These, and ongoing studies of pegylated IFN-alpha, and of
      shorter induction-only HDI promise refinements in treatment which may improve
      efficacy:toxicity ratios.

PMID- 12598339
TI  - Primary chemotherapy followed by anterior craniofacial resection and radiotherapy
      for paranasal cancer.
AB  - BACKGROUND: To study prospectively the activity of primary chemotherapy with
      cisplatin, fluorouracil and leucovorin (PFL) in patients with paranasal cancer
      receiving surgery and postoperative radiotherapy. PATIENTS AND METHODS: Forty
      nine patients, previously untreated, with resectable paranasal carcinoma were
      enrolled. PFL (leucovorin 250 mg/m2/day for 5 days as a 120 h continuous infusion
      (c.i.), 5-fluorouracil 800 mg/m2/day from day 2 as a 96 h c.i. and cisplatin 100
      mg/m2 day 2 q 3 weeks) was planned for five courses. RESULTS: Thirty-two patients
      (65%) completed three or more chemotherapy courses. Two deaths from thrombotic
      events were observed after the first cycle. Eight cardiac toxicities were
      recorded during chemotherapy causing treatment discontinuation. Objective
      response to PFL was observed in 21 patients [43%; 95% confidence interval (CI)
      29% to 58%], including four complete responses (CRs) (8%; 95% CI 2% to 20%) and
      17 partial responses (PRs) (35%). Pathological complete remission (pCR) was
      achieved in eight of 49 patients (16%). At 3 years, overall survival was 69% and
      event-free survival 57%. Overall and event-free survival in patients achieving
      pCR is 100%. CONCLUSIONS: PFL is active in paranasal cancer. Patients who attain
      a pathological complete remission have a favorable prognosis. Cardiovascular
      complications represent the limiting toxicity. Primary chemotherapy combined with
      surgery-sparing treatment approaches deserves further investigation.

PMID- 12598340
TI  - Results of randomised phase II studies comparing S16020 with methotrexate in
      patients with recurrent head and neck cancer.
AB  - BACKGROUND: The purpose of this study was to carry out two randomised phase II
      trials of S16020, a new olivacine derivative, tested as a single agent in
      patients with recurrent head and neck cancer, using methotrexate as the control
      arm to validate the results. PATIENTS AND METHODS: S16020 at either 80 or 100
      mg/m2 was administered as a 3-h infusion every 3 weeks. Methotrexate, 40 or 50
      mg/m2, was given by bolus injection, weekly for a minimum of 6 weeks. In total,
      36 patients were entered in the randomised studies (25 in an initial study, 11 in
      a confirmatory study) of whom 24 received S16020 and 12 received methotrexate.
      RESULTS: A scheduled interim analysis showed one patient having a non-confirmed
      objective response with S16020 and three patients having a confirmed objective
      response with methotrexate. In the methotrexate group, there were no patients
      with severe non-haematological toxicity. With S16020, there was a high incidence
      of severe non-haematological toxicities, including asthenia, oedema of the face,
      oedema and pain at the tumour sites and erythematous rash; consequently, both
      studies were stopped. CONCLUSIONS: Both studies were stopped due to the poor
      anticipated benefit/risk ratio for S16020, although time to progression and
      overall survival time were similar in both treatment arms.

PMID- 12598341
TI  - Surgical adjuvant therapy of rectal carcinoma: a controlled evaluation of
      leucovorin, 5-fluorouracil and radiation therapy with or without interferon
      alpha2b.
AB  - BACKGROUND: The aim of this study was to determine whether the efficacy of the
      combination of 5-fluorouracil (5-FU), leucovorin (LV) and radiation therapy (RT)
      could be improved by the addition of interferon-alpha2b (IFN-alpha) in patients
      who have had a 'curative' resection, for rectal adenocarcinoma (Dukes' B2/C; T3
      N0, T4 N0, N1-3). PATIENTS AND METHODS: A total of 207 eligible patients with a
      performance status of 0 or 1 were randomized postoperatively between days 21 and
      70 to one of the two treatment groups: group A, LV 20 mg/m2 i.v. bolus and 5-FU
      425 mg/m2 i.v. days 1-5 and 29-33, LV 20 mg/m2 and 5-FU 400 mg/m2 days 57-60 and
      85-88, LV 20 mg/m2 and 5-FU 380 mg/m2 days 1-5 and 29-33 with the second day 1
      occurring 28 days after the completion of RT (45 Gy); group B, LV, 5-FU and RT as
      in group A, and IFN-alpha 5 x 10(6) IU s.c. three times during each week
      chemotherapy is given. RESULTS: 104 patients were randomized into group A and 103
      into group B. There was no statistically significant difference in either disease
      free survival or overall survival between the two groups. Toxicity was also the
      same, except for the flu-like syndrome associated with the IFN-alpha
      administration. CONCLUSIONS: There was no difference in efficacy between the two
      combinations. Toxicity was greater with the LV + 5-FU + IFN-alpha regimen because
      of the flu-like syndrome.

PMID- 12598342
TI  - Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously
      platinum-treated patients with advanced gastric cancer.
AB  - BACKGROUND: Oxaliplatin shows preclinical activity in many cancer cell lines that
      are resistant to cisplatin, and also has synergism with 5-fluorouracil (5-FU). We
      undertook this study to evaluate the efficacy and toxicities of a combined
      oxaliplatin, 5-FU and leucovorin (LV) continuous infusion regimen in patients
      with advanced gastric cancer who progressed during or after treatment with 5-FU
      and platinum compounds. PATIENTS AND METHODS: Twenty-six patients with advanced
      gastric cancer, whose disease progressed while receiving, or after discontinuing,
      chemotherapy with a 5-FU and platinum regimen, were enrolled in this study.
      Treatment comprised oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by
      bolus 5-FU (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4-3.0 g/m2
      concurrently with LV 150 mg/m2. Cycles were repeated at 2-week intervals.
      RESULTS: Of the 23 evaluable patients, there were six partial responses (response
      rate 26%). All responding patients were among those who entered into this trial
      immediately after failure of previous chemotherapy with 5-FU and cisplatin. The
      median time to progression was 4.3 months and the median overall survival was 7.3
      months. The most common hematologic toxicity was grade 1-2 anemia in 39 cycles
      (39%). No grade 4 leukopenia or thrombocytopenia were observed. The most common
      non-hematologic toxicity was nausea/vomiting (33%). Peripheral neuropathy of
      grade 1 or 2 was noted (27%), but there was no grade 3 or 4 neurotoxicity.
      CONCLUSIONS: This phase II study of oxaliplatin, 5-FU and LV continuous infusion
      showed activity in previously platinum-treated patients with advanced gastric
      cancer, with acceptable toxicities.

PMID- 12598343
TI  - Treatment of pancreatic cancer with a combination of irinotecan (CPT-11) and
      gemcitabine: a multicenter phase II study by the Greek Cooperative Group for
      Pancreatic Cancer.
AB  - BACKGROUND: The efficacy and toxicity of gemcitabine (GEM) and irinotecan (CPT
      11) is evaluated in previously untreated patients with inoperable or metastatic
      pancreatic cancer. PATIENTS AND METHODS: From January 1999 to July 2001, 60
      patients with pancreatic cancer (85% stage IV) were enrolled in a two-step
      extended phase II trial. Patients were treated with gemcitabine (1,000 mg/m2 on
      days 1 and 8) and CPT-11 (300 mg/m2 on day 8) in cycles of 3 weeks. No
      prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG
      CSF) was initially planned. RESULTS: In an intention-to-treat analysis one (1.7%)
      complete and 14 (23.3%) partial responses were achieved [objective response rate
      (ORR) 24.7%; 95% confidence interval 14.04% to 35.96%]. Twenty-two (36.7%) and 23
      (38.3%) patients had stable and progressive disease, respectively. The median
      duration of response was 5 months, the median time to tumor progression (TTP) was
      7 months and the median overall survival 7 months. One-year survival was 22.5%.
      Pain improvement and asthenia during treatment were observed in 45% and 43% of
      patients, respectively; weight gain occurred in 19.5% of patients. Grade 3 anemia
      occurred in three (5%) patients who required transfusion of six packed red blood
      cell (RBC) units. Ten (16.7%) additional patients with grade 2 anemia were
      treated with recombinant erythropoietin. Grade 3 thrombocytopenia occurred in
      seven (11.7%) patients and grades 3 and 4 neutropenia in 27 (45%). Ten patients
      developed febrile neutropenia, two of whom died due to sepsis. Prophylactic use
      of rhG-CSF was eventually required in 93 (28.3%) of 329 administered cycles.
      Other toxicities were mild. CONCLUSIONS: The combination of gemcitabine and
      irinotecan is an active chemotherapy regimen against pancreatic cancer with a 25%
      ORR. Toxicity was acceptable for the great majority of patients but with a high
      percentage of hematopoietic growth factor administration.

PMID- 12598344
TI  - 5-Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in
      curatively resected stage III colon cancer: long-term follow-up results of the
      adjCCA-01 trial.
AB  - BACKGROUND: Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and
      leucovorin in curatively resected stage III colon cancer significantly reduces
      the risk of cancer recurrences and improves survival. The impact of 5-FU plus
      leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up
      study in comparison with the effects of 5-FU plus levamisole in the prospective
      multicenter trial adjCCA-01. PATIENTS AND METHODS: Patients with a curatively
      resected stage III (International Union Against Cancer) colon cancer were
      stratified according to tumor, node and grading category and randomly assigned to
      receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface
      area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days,
      plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel
      scheme; arm B). RESULTS: Six hundred and eighty (96.9%) of 702 patients enrolled
      into this study were eligible. To date, 261 patients have died, 117 on arm A and
      144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU
      plus leucovorin combination significantly improved disease-free survival [79.8
      months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly
      increased median overall survival (88.9 months in arm A versus 78.6 months in arm
      B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus
      leucovorin was generally well tolerated; only a minority of patients experienced
      grade 3 and 4 toxicities. CONCLUSIONS: After curative resection of a stage III
      colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well
      tolerated. This long-term follow-up study demonstrates that adjuvant treatment
      with 5-FU plus leucovorin given for 12 cycles is significantly more effective
      than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and
      improving survival.

PMID- 12598345
TI  - Cancer physicians' attitudes toward colorectal cancer follow-up.
AB  - BACKGROUND: The optimal follow-up strategy for colorectal cancer is unknown.
      MATERIALS AND METHODS: We surveyed all Canadian radiation oncologists, medical
      oncologists and surgeons specializing in colorectal cancer to assess their
      recommendations for follow-up after potentially curative treatment, the beliefs
      and attitudes underlying these practices, and the cost implications of different
      follow-up strategies. RESULTS: One hundred and sixty practitioners (58%) returned
      completed surveys. Most recommended clinical assessments every 3-4 months in the
      first 2 years including carcino-embryonic antigen testing, gradually decreasing
      in frequency over 5 years. Ninety per cent recommend a surveillance colonoscopy
      in the first year. The majority felt that specialist involvement in follow-up was
      important because of the increased opportunities for patients to contribute to
      research (76%) and teaching (73%). About half felt that specialists were more
      efficient at providing follow-up than primary care physicians, but these same
      physicians recommended significantly longer and more expensive follow-up routines
      on average than others. Primary care physicians were felt to be important allies,
      especially in managing the psychosocial concerns of patients. CONCLUSIONS:
      Surveillance practices are generally in keeping with published recommendations.
      Most specialists feel that they should remain involved in follow-up, but this may
      result in increased resource utilization.

PMID- 12598346
TI  - Locally advanced/inflammatory breast cancers treated with intensive epirubicin
      based neoadjuvant chemotherapy: are there molecular markers in the primary tumour
      that predict for 5-year clinical outcome?
AB  - BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a
      heterogeneous disease. Molecular markers may help to understand this
      heterogeneity. This paper reports the results of a study assessing the potential
      prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR
      expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK
      trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or
      histological diagnosis of LABC were randomised into a trial comparing two
      anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard
      locoregional therapy. Survival was comparable in both arms. We collected and
      analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258
      patients that had a histological diagnosis. RESULTS: Of the patients included in
      this molecular marker study 114 relapsed and 91 died. In the multivariate
      analysis p53 positivity was associated with a shorter progression-free survival
      [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall
      survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a
      longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS:
      p53 was an independent factor predicting for survival. In order to clarify
      whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is
      being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast
      from frozen tumour samples.

PMID- 12598347
TI  - Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the
      elderly: long-term results of the phase III randomized controlled multicenter
      GRETA trial.
AB  - BACKGROUND: To evaluate the efficacy of tamoxifen as primary treatment in women
      aged over 70 years with operable breast cancer versus surgery followed by
      adjuvant tamoxifen. PATIENTS AND METHODS: Patients randomly received tamoxifen
      alone (160 mg day 1, then 20 mg/day) for 5 years or surgery followed by tamoxifen
      (20 mg/day) for 5 years. Overall survival was the main study end point; secondary
      objectives included breast cancer survival and local control of the disease.
      RESULTS: Between 1987 and 1992, 239 patients were assigned to surgery plus
      tamoxifen and 235 to tamoxifen alone. Treatment arms were comparable for tumor
      size, clinical nodal status and performance status. At a median follow-up of 80
      months 274 patients had died. No difference between groups had emerged in overall
      and breast cancer survival. There were 27 local progressions in the surgery plus
      tamoxifen group and 106 in the tamoxifen-alone group (P = 0.0001). In the surgery
      plus tamoxifen group, no difference in overall survival had emerged according to
      the extension of operation. CONCLUSIONS: The long-term results of the study
      confirm the 3-year interim analysis already reported. Surgery (radical or
      minimal) followed by adjuvant tamoxifen does not modify overall and breast cancer
      survival as compared with tamoxifen alone in early breast cancer of older women.
      Because of the high rate of local progressions with tamoxifen alone, minimal
      surgery followed by tamoxifen appears to be the appropriate treatment in such
      patients. More extensive surgery is not useful. Tamoxifen alone is an adequate
      alternative treatment in very old or frail patients.

PMID- 12598348
TI  - Communication, quality of life and age: results of a 5-year prospective study in
      breast cancer patients.
AB  - BACKGROUND: Previous studies have employed short follow-up periods or examined
      only certain aspects of quality of life (QoL). This study aimed to examine the
      effect of communication on breast cancer patients' QoL and to investigate the
      role of age in this relationship. PATIENTS AND METHODS: In a prospective,
      observational study breast cancer patients were sent questionnaires, including
      the European Organisation for Research and Treatment of Cancer QLQ-C30, over 5
      years. RESULTS: Forty-five per cent of the sample reported that some aspect of
      the communication they received was unclear and 59% wanted to speak with medical
      staff more. Patients under 50 years rated social and psychological help as more
      important, they were more aware of such services, had greater contact with
      support groups but were less satisfied with the information they received.
      Seventeen of the 27 QoL variables were significantly worse (P <0.01), up to 4
      years after diagnosis, for those patients reporting unclear information. For
      patients over 50 years, QoL was significantly (P <0.001) worse when communication
      was unsatisfactory. Operation method or arm problems did not mitigate the
      association between communication and QoL. CONCLUSIONS: Communication is clearly
      a vital clinical skill that may play a role in patient QoL.

PMID- 12598349
TI  - Correlation of p53 status with outcome of neoadjuvant chemotherapy using
      paclitaxel and doxorubicin in stage IIIB breast cancer.
AB  - BACKGROUND: The role of p53 in modulating apoptosis has suggested that it may
      affect efficacy of anticancer agents. We prospectively evaluated p53 alterations
      in 73 patients with locally advanced breast cancer (IIIB) submitted to
      neoadjuvant chemotherapy. PATIENTS AND METHODS: Patients received three cycles of
      paclitaxel (175 mg/m2) and doxorubicin (60 mg/m2) every 21 days. Tumor sections
      were analyzed before treatment for altered patterns of p53 expression using
      immunohistochemistry and DNA sequencing. RESULTS: An overall response rate of
      83.5% was obtained, including 15.1% complete pathological responses. The regimen
      was well tolerated with 17.7% grade 2/3 nausea and 12.8% grade 3/4 leukopenia.
      There was a statistically significant correlation between response and expression
      of p53. Of the 25 patients who obtained a complete clinical response, two were
      classified as positive (P = 0.004, chi-square). Of 11 patients who obtained a
      complete pathological remission, one was positive (P = 0.099, chi-square).
      Discussion The combination is highly effective in locally advanced breast cancer.
      A negative expression of p53 indicates a higher chance of responding to this
      regimen. The p53 status may be used as a biological marker to identify those
      patients who would benefit from more aggressive treatments.

PMID- 12598350
TI  - A randomized phase II study of alternating and sequential regimens of docetaxel
      and doxorubicin as first-line chemotherapy for metastatic breast cancer.
AB  - BACKGROUND: This phase II study evaluated the feasibility and efficacy of
      alternating and sequential regimens of docetaxel and doxorubicin as first-line
      chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with
      MBC requiring first-line chemotherapy for progressive disease (n = 106) were
      randomized and received 3-weekly monotherapy with docetaxel (T, 100 mg/m2, 1-h
      i.v. infusion) and doxorubicin (A, 75 mg/m2, 20-30-min i.v. infusion) either on a
      cycle-by-cycle alternating basis (ATATATAT, n = 51) or sequentially each for four
      cycles (TTTTAAAA, n = 55). RESULTS: For both regimens, the median number of
      cycles administered was the maximum of eight. The alternating and sequential
      groups achieved similar objective tumor response rates (60% and 67%,
      respectively) and similar median duration of response (47 and 44 weeks,
      respectively). With a median follow-up of 31 months, median survival times were
      estimated at 20 and 26 months in the alternating and sequential groups,
      respectively. No unexpected toxicities were reported. Compared with alternating
      therapy, patients receiving sequential therapy were more likely to complete the
      planned eight chemotherapy cycles (69% versus 63%), and had a lower incidence of
      febrile neutropenia (2% versus 14%). CONCLUSIONS: Alternating and sequential
      docetaxel-doxorubicin regimens are viable alternatives to simultaneous
      combination therapy in MBC, with sequential therapy achieving slightly higher
      response rates and improved tolerability compared with alternating therapy.

PMID- 12598352
TI  - Docetaxel and carboplatin is an active regimen in advanced non-small-cell lung
      cancer: a phase II study in Caucasian and Asian patients.
AB  - BACKGROUND: The purpose of this study was to report response rates, survival and
      toxicity in advanced non-small-cell lung cancer (NSCLC) following docetaxel and
      carboplatin, and to explore potential differences in these end points between
      Caucasian and Asian patients. PATIENTS AND METHODS: Sixty-eight patients of good
      performance status with Stage IIIB or IV NSCLC were entered on a phase II study
      at three sites in Australia and Singapore. Docetaxel 75 mg/m2 and carboplatin AUC
      6 were given every 3 weeks. Response to treatment and toxicity were graded by
      standard criteria. The Kaplan-Meier method was used to estimate survival rates,
      and subgroups compared by the log-rank test. Cox's proportional hazards
      regression was used to determine which potentially explanatory variables
      independently affected the outcome. RESULTS: The response rate was 39% (95%
      confidence interval 27% to 52%), and 42% in evaluable patients. Response occurred
      in 65% of Asian and 31% of Caucasian patients (P = 0.01). Ethnicity was the only
      significant predictor of response in multivariate analysis. The 1-year survival
      rate was 53%. Performance status (P = 0.021), ethnicity (P = 0.035) and presence
      of bone or liver metastases (P = 0.011) were independent predictors of overall
      survival. Neutropenia (grade IV in 73% of patients), febrile neutropenia (26%
      patients) and diarrhea (grade III/IV in 11% of patients) were the major treatment
      related toxicities. A high rate (three of six) of febrile neutropenia in
      Singapore, including one treatment-related death in the initial patients treated,
      resulted in a reduction in the carboplatin dose to AUC 4.5 at that site.
      CONCLUSIONS: This regimen is active in advanced NSCLC. The potential impact of
      ethnicity on efficacy and toxicity of treatment requires further investigation.

PMID- 12598351
TI  - Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive
      results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.
AB  - BACKGROUND: Combination chemotherapy yields better response rates which do not
      always lead to a survival advantage. The aim of this study was to investigate
      whether the reported differences in the efficacy and toxicity of monotherapy with
      doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial
      adenocarcinoma lead to significant advantage in favour of the combination.
      PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or
      recurrent endometrial adenocarcinoma and were chemo-naive. Treatment consisted of
      either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4
      weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1
      years. The combination DOX-CDDP was more toxic than DOX alone. Haematological
      toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus
      30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72%
      versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP
      provided a significantly higher response rate than single agent DOX (P <0.001).
      Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and
      26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7
      PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7
      months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed
      that WHO performance status was statistically significant as a prognostic factor
      for survival, and stratifying for this factor, treatment effect reaches
      significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024).
      CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP
      results in higher but acceptable toxicity. The response rate produced is
      significantly higher, and a modest survival benefit is achieved with this
      combination regimen, especially in patients with a good performance status.

PMID- 12598353
TI  - ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung
      cancer: a phase II study.
AB  - BACKGROUND: The purpose of this study was to evaluate ALIMTA (pemetrexed
      disodium, LY231514), a multi-targeted antifolate with first-line activity against
      non-small-cell lung cancer (NSCLC), in a second-line setting. PATIENTS AND
      METHODS: Patients with NSCLC were eligible for this phase II study if they had
      progressive disease within 3 months after first-line chemotherapy or progression
      while being treated with first-line chemotherapy. In 81 patients studied, two
      cohorts of patients were assigned based on whether the first-line therapy had
      included a platinum regimen. ALIMTA was administered at 500 mg/m2 by 10-min
      intravenous infusion once every 21 days. RESULTS: The response rate in the 79
      evaluable patients with poor prognostic features was 8.9% [95% confidence
      interval (CI) 2.6% to 15.1%]. The response rate in the platinum-pretreated group
      was 4.5% and 14.1% in the non-platinum-pretreated group. The median duration of
      response was 6.8 months (95% CI 3.4-7.8 months, 0% censoring). The median
      survival time was 5.7 months (95% CI 4.0-8.3 months, 7.6% censoring). The
      probability of survival for at least 6 months was estimated to be 48%. The median
      time to disease progression was 2 months (95% CI 1.4-2.8 months, 0% censoring).
      The principal toxicity was myelosuppression, which was reversible. CONCLUSIONS:
      ALIMTA is active in a second-line setting in non-platinum-pretreated NSCLC
      patients progressing within 3 months of first-line chemotherapy. This study
      demonstrates that it is possible to evaluate new drugs against NSCLC in a second
      line setting.

PMID- 12598354
TI  - Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer
      therapy.
AB  - BACKGROUND: The role that growth factors and their receptors play in human cancer
      growth and progression makes them interesting targets for novel treatment
      modalities. Our approach consisted of active immunotherapy with the epidermal
      growth factor (EGF). Two pilot clinical trials were conducted to examine the
      safety and immunogenicity of a five-dose immunization protocol and to compare
      different adjuvants and treatment designs. PATIENTS AND METHODS: Forty patients
      with advanced non-small-cell lung cancer were enrolled in both trials. They were
      randomized to be treated with aluminum hydroxide or montanide ISA 51 as adjuvants
      in the EGF vaccine preparation. The use of cyclophosphamide prevaccination
      treatment was evaluated in the second trial. RESULTS: Pooled data from both
      trials showed that the use of montanide as adjuvant increased the percentage of
      good antibody responders (GAR). Cyclophosphamide prevaccination treatment did not
      provoke improvements in antibody response. GAR had a significant increase in
      survival as compared with poor antibody responders. Response duration was also
      related to a significant improvement in survival rates. CONCLUSIONS: Vaccination
      with five doses of EGF vaccine is safe and immunogenic. Montanide ISA 51
      increased the percentage of GAR. There is a direct relationship between anti-EGF
      antibody titers and immune response duration with survival time.

PMID- 12598355
TI  - Soluble intercellular adhesion molecule-1 (s-ICAM-1/s-CD54) in diffuse large B
      cell lymphoma: association with clinical characteristics and outcome.
AB  - BACKGROUND: High serum levels of soluble intercellular adhesion molecule-1(s-ICAM
      1/s-CD54) have been associated with adverse clinical features and poor outcome in
      chronic lymphocytic leukemia, Hodgkin's disease and non-Hodgkin's lymphoma, but
      their value in the different subtypes of non-Hodgkin's lymphoma has not been well
      addressed. PATIENTS AND METHODS: Our aim was to study the serum levels of s-ICAM
      1 in diffuse large B-cell lymphoma (DLBCL) and to correlate them with clinical
      characteristics and outcome. We analyzed the serum levels of s-ICAM-1 in a series
      of 55 patients with DLBCL diagnosed in a single institution. s-ICAM-1 levels were
      quantified by an immunoenzymatic assay. Median age was 62 years (range 22-96); 29
      (53%) were male. Twenty-eight (51%) presented with advanced clinical stage
      (III/IV), 32 (58%) had extranodal involvement, 28 (51%) had high serum lactate
      dehydrogenase (LDH) and 23 (43%) had high beta2-microglobulin levels. All
      patients received anthracycline-containing regimens. Correlation between clinical
      variables and s-ICAM-1 levels were tested with the Mann-Whitney U-test and
      survival was plotted by the Kaplan-Meier method, and curves compared with the log
      rank test. RESULTS: Serum levels of s-ICAM-1 were significantly increased in
      patients with DLBCL compared with normal controls (589 +/- 487 versus 279 +/- 65
      ng/ml, respectively; P <0.001). Higher levels of s-ICAM-1 were present in
      patients with B symptoms, advanced stage and increased LDH and beta2
      microglobulin. s-ICAM-1 levels also correlated with achievement of a complete
      response. Patients with s-ICAM-1 over 668 ng/ml had a shorter time to treatment
      failure (TTF) (3-year TTF, 59% versus 20%, respectively; P = 0.01) and overall
      survival (OS) (3-year OS, 58% versus 22%, respectively; P = 0.04) than the
      remainders. When only low and low-intermediate risk patients in the international
      prognostic index score were considered, those with s-ICAM-1 over 668 ng/ml also
      had worse TTF and OS. CONCLUSIONS: In DLBCL, s-ICAM-1 levels correlated with high
      tumor burden and lymphoma dissemination and may contribute to assessment of
      prognosis.

PMID- 12598356
TI  - CD34+-selected versus unmanipulated autologous stem cell transplantation in
      multiple myeloma: impact on dendritic and immune recovery and on complications
      due to infection.
AB  - BACKGROUND: Large-scale CD34+ enrichment has been demonstrated a safe method in
      autologous transplantation for multiple myeloma. However, the high CD34+
      enrichment and the consequent plasma cell purging result in concomitant T-cell
      and dendritic-cell (DC) depletion, theoretically increasing the risk of life
      threatening infections. PATIENTS AND METHODS: We evaluated immunological and
      dendritic reconstitution in 72 myeloma patients who had undergone CD34+-selected
      (n = 45) and unmanipulated (n = 27) stem cell transplant, and its correlation
      with infections. RESULTS: Haematological recovery occurred promptly in all
      patients. Only a slight delay in platelet recovery to >50 x 10(9)/l was observed
      in patients receiving CD34+-enriched graft. Natural killer (NK) cell count
      recovered in all patients within 2 months and B-cell count had recovered by 6
      months post-transplant in both groups. CD3 cells remained lower than normal in
      both groups. CD8 cells increased above the normal level, reaching a peak at day
      90, and lowered to normal level within 1 year post-transplant. CD4 lymphocytes
      remained <50% of normal, especially in selected patients. In both groups, both
      DC1 and DC2 counts were already significantly lower than in normal individuals
      before conditioning therapy. Pre-conditioning levels of DC1 were reached in
      unmanipulated patients at day 30 and became normal at 6 months. In selected
      patients, DC1 pre-transplant level was observed at day 60 and was maintained
      thereafter. DC2 recovery showed a similar trend. In unselected patients, DC2
      count increased to pre-conditioning level at haematological recovery and was
      normal after 1 year. In selected transplants, DC2 increased more slowly than DC1
      in the same patients: pre-transplant level was detected at day 90 but was still
      significantly lower than normal 1 year after transplant. The incidence of
      infection was similar in both groups. Sepsis had Gram+ aetiology in the majority
      of cases. After engraftment only viral infections were recorded, mostly due to
      herpes reactivation, with no difference between groups. DISCUSSION: In spite of a
      delay in immune recovery, CD34 enrichment is not associated with a significant
      increase of complications due to infection. Relatively fast NK cell recovery to
      pre-transplant levels and the presence of functionally efficient DCs can justify
      the low incidence of infections.

PMID- 12598357
TI  - An open phase I study assessing the feasibility of the triple combination:
      oxaliplatin plus irinotecan plus leucovorin/ 5-fluorouracil every 2 weeks in
      patients with advanced solid tumors.
AB  - BACKGROUND: The aim of this study was to determine the maximum-tolerated dose
      (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5
      fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid
      tumors. PATIENTS AND METHODS: The trial was designed to evaluate escalating doses
      of oxaliplatin and irinotecan, starting at 60 mg/m2 and 90 mg/m2, respectively,
      given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as
      follows: folinic acid 200 mg/m2 followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22
      h continuous infusion, every 2 weeks. The second cohort of patients was treated
      at the recommended dose for oxaliplatin and irinotecan with the simplified LV5FU
      regimen: on day 1, a 2-h infusion of folinic acid (400 mg/m2), followed by a 10
      min intravenous bolus of 5-FU (400 mg/m2), followed by a continuous infusion of 5
      FU (2400 mg/m2) over 46 h. RESULTS: Thirty-four patients were treated at the
      following dose levels (oxaliplatin/irinotecan mg/m2): 60/90, 60/120, 85/120,
      85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the
      recommended dose with the simplified LV5FU scheme. The MTD was reached at dose
      level 85/220 mg/m2 but the recommended dose chosen for the second step was 85/180
      mg/m2 to keep a better compliance with the biweekly schedule. Main grade 3/4
      toxicities per patient included the following: neutropenia in 78% (febrile
      episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral
      neuropathy in 37% (Levi's scale). Antitumor activity was observed at almost all
      dose levels. Most objective responses were observed in digestive malignancies,
      since 10 out of 11 were obtained in five colorectal cancers, two pancreatic
      cancers, two cholangiocarcinoma and one gastric cancer. CONCLUSION: The
      recommended dose for the triple association is 85/180 mg/m2 of oxaliplatin and
      irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity
      in gastrointestinal malignancies should be evaluated in phase II studies in
      different tumor types.

PMID- 12598358
TI  - Mortality from major cancer sites in the European Union, 1955-1998.
AB  - After long-term rises, over the last decade age-standardised mortality from most
      common cancer sites has fallen in the European Union (EU). For males, the fall
      was 11% for lung and intestines, 12% for bladder, 6% for oral cavity and pharynx,
      and 5% for oesophagus. For females, the fall was 7% for breast and 21% for
      intestines. There were also persisting declines in stomach cancer (30% in both
      sexes), uterus (mainly cervix, -26%) and leukaemias (-10%). Mortality rates for
      other common neoplasms, including pancreas for both sexes, prostate and ovary,
      tended to stabilise. The only unfavourable trends were observed for female lung
      cancer (+15%). Lung cancer rates in women from the EU are approximately one-third
      of those in the USA, and 50% lower than breast cancer rates in the EU. Lung
      cancer rates in European women have also tended to stabilise below the age of 75
      years. Thus, effective interventions on tobacco control could, in principle,
      avoid a major lung cancer epidemic in European women.

PMID- 12598361
TI  - Comment on the symposium article "Fertility after treatment for Hodgkin's
      disease", by Z. Blumenfeld, E. Dann, I. Avivi et al. (Ann Oncol 2002; 13 Suppl 1:
      138-147).

PMID- 12598359
TI  - Skin testing and hypersensitivity reactions to oxaliplatin.

PMID- 12598362
TI  - Interaction between paclitaxel and warfarin.

PMID- 12598363
TI  - Severe hepatic toxicity due to thalidomide in relapsed multiple myeloma.

PMID- 12598364
TI  - Cations as hydrogen bond donors: a view of electrostatic interactions in DNA.
AB  - Cations are bound to nucleic acids in a solvated state. High-resolution X-ray
      diffraction studies of oligonucleotides provide a detailed view of Mg2+, and
      occasionally other ions bound to DNA. In a survey of several such structures,
      certain general observations emerge. First, cations bind preferentially to the
      guanine base in the major groove or to phosphate group oxygen atoms. Second,
      cations interact with DNA most frequently via water molecules in their primary
      solvation shell, direct ion-DNA contacts being only rarely observed. Thus, the
      solvated ions should be viewed as hydrogen bond donors in addition to point
      charges. Finally, ion interaction sites are readily exchangeable: The same site
      may be occupied by any ion, including spermine, as well as by a water molecule.

PMID- 12598365
TI  - New insight into site-specific recombination from Flp recombinase-DNA structures.
AB  - The lamba integrase, or tyrosine-based family of site-specific recombinases,
      plays an important role in a variety of biological processes by inserting,
      excising, and inverting DNA segments. Flp, encoded by the yeast 2-mum plasmid, is
      the best-characterized eukaryotic member of this family and is responsible for
      maintaining the copy number of this plasmid. Over the past several years,
      structural and biochemical studies have shed light on the details of a common
      catalytic scheme utilized by these enzymes with interesting variations under
      different biological contexts. The emergence of new Flp structures and solution
      data provides insights not only into its unique mechanism of active site assembly
      and activity regulation but also into the specific contributions of certain
      protein residues to catalysis.

PMID- 12598366
TI  - Protein analysis by hydrogen exchange mass spectrometry.
AB  - Mass spectrometry has provided a powerful method for monitoring hydrogen exchange
      of protein backbone amides with deuterium from solvent. In comparison to popular
      NMR approaches, mass spectrometry has the advantages of higher sensitivity, wider
      coverage of sequence, and the ability to analyze larger proteins. Proteolytic
      fragmentation of proteins following the exchange reaction provides moderate
      structural resolution, in some cases enabling measurements from single amides.
      The technique has provided new insight into protein-protein and protein-ligand
      interfaces, as well as conformational changes during protein folding or
      denaturation. In addition, recent studies illustrate the utility of hydrogen
      exchange mass spectrometry toward detecting protein motions relevant to
      allostery, covalent modifications, and enzyme function.

PMID- 12598367
TI  - Structure and function of the calcium pump.
AB  - Active transport of cations is achieved by a large family of ATP-dependent ion
      pumps, known as P-type ATPases. Various members of this family have been targets
      of structural and functional investigations for over four decades. Recently,
      atomic structures have been determined for Ca2+-ATPase by X-ray crystallography,
      which not only reveal the architecture of these molecules but also offer the
      opportunity to understand the structural mechanisms by which the energy of ATP is
      coupled to calcium transport across the membrane. This energy coupling is
      accomplished by large-scale conformational changes. The transmembrane domain
      undergoes plastic deformations under the influence of calcium binding at the
      transport site. Cytoplasmic domains undergo dramatic rigid-body movements that
      deliver substrates to the catalytic site and that establish new domain
      interfaces. By comparing various structures and correlating functional data, we
      can now begin to associate the chemical changes constituting the reaction cycle
      with structural changes in these domains.

PMID- 12598369
TI  - X-ray crystallographic analysis of lipid-protein interactions in the
      bacteriorhodopsin purple membrane.
AB  - The past decade has witnessed increasingly detailed insights into the structural
      mechanism of the bacteriorhodopsin photocycle. Concurrently, there has been much
      progress within our knowledge pertaining to the lipids of the purple membrane,
      including the discovery of new lipids and the overall effort to localize and
      identify each lipid within the purple membrane. Therefore, there is a need to
      classify this information to generalize the findings. We discuss the properties
      and roles of haloarchaeal lipids and present the structural data as individual
      case studies. Lipid-protein interactions are discussed in the context of
      structure-function relationships. A brief discussion of the possibility that
      bacteriorhodopsin functions as a light-driven inward hydroxide pump rather than
      an outward proton pump is also presented.

PMID- 12598368
TI  - Nucleic acid recognition by OB-fold proteins.
AB  - The OB-fold domain is a compact structural motif frequently used for nucleic acid
      recognition. Structural comparison of all OB-fold/nucleic acid complexes solved
      to date confirms the low degree of sequence similarity among members of this
      family while highlighting several structural sequence determinants common to most
      of these OB-folds. Loops connecting the secondary structural elements in the OB
      fold core are extremely variable in length and in functional detail. However,
      certain features of ligand binding are conserved among OB-fold complexes,
      including the location of the binding surface, the polarity of the nucleic acid
      with respect to the OB-fold, and particular nucleic acid-protein interactions
      commonly used for recognition of single-stranded and unusually structured nucleic
      acids. Intriguingly, the observation of shared nucleic acid polarity may shed
      light on the longstanding question concerning OB-fold origins, indicating that it
      is unlikely that members of this family arose via convergent evolution.

PMID- 12598370
TI  - The power and prospects of fluorescence microscopies and spectroscopies.
AB  - Recent years have witnessed a renaissance of fluorescence microscopy techniques
      and applications, from live-animal multiphoton confocal microscopy to single
      molecule fluorescence spectroscopy and imaging in living cells. These
      achievements have been made possible not so much because of improvements in
      microscope design, but rather because of development of new detectors, accessible
      continuous wave and pulsed laser sources, sophisticated multiparameter analysis
      on one hand, and the development of new probes and labeling chemistries on the
      other. This review tracks the lineage of ideas and the evolution of thinking that
      have led to the actual developments, and presents a comprehensive overview of the
      field, with emphasis put on our laboratory's interest in single-molecule
      microscopy and spectroscopy.

PMID- 12598371
TI  - The British Association of Perinatal Medicine: the first 25 years (1976-2000).

PMID- 12598373
TI  - Biologic therapies for juvenile arthritis.
AB  - A group of therapies with exciting potential has emerged for children and young
      people with severe juvenile idiopathic arthritis (JIA) uncontrolled by
      conventional disease modifying drugs. Theoretical understanding from molecular
      biologic research has identified specific targets within pathophysiological
      pathways that control rheumatoid arthritis (RA) and JIA. This review identifies
      the pathways of autoimmunity to begin to show how biologic agents have been
      produced to replicate, mimic, or block culpable molecules and so promote or
      inhibit cellular activity or proliferation. Of these agents, cytokine antagonists
      have shown greatest promise, and early clinical studies of tumour necrosis factor
      (TNF) blockade have identified dramatic clinical benefit in many children with
      JIA. However, as will also be discussed, overlap of pathways within a complex
      immune system makes clinical response unpredictable and raises additional ethical
      and administrative concerns.

PMID- 12598374
TI  - Disseminated congenital neuroblastoma presenting at birth.

PMID- 12598375
TI  - Intra-articular corticosteroid injections in juvenile idiopathic arthritis.
AB  - Therapeutic intervention with intra-articular steroid injections in juvenile
      idiopathic arthritis (JIA) has evolved from experience with adults with
      inflammatory joint disease, with the earliest report being published in 1951. The
      technique has subsequently been introduced into paediatric rheumatology practice,
      although much of the evidence supporting its use remains anecdotal or based on
      open, non-controlled studies. This review examines the body of evidence relating
      to many aspects of treating children with JIA with intra-articular steroids, and
      is approached from both a medical and a physiotherapy perspective. Where
      appropriate, important areas for future research are identified and discussed.

PMID- 12598376
TI  - Use of methotrexate in juvenile idiopathic arthritis.
AB  - Methotrexate (MTX) has transformed the outlook for children with juvenile
      idiopathic arthritis (JIA). Most of the evidence from uncontrolled clinical
      trials suggests that MTX is an effective agent for treating active JIA. Data from
      controlled clinical trials suggests that MTX has statistically significant
      effects on patient centred disability measures in JIA patients with active
      arthritis. Although we would like a much larger study directed evidence base for
      our use of the drug, the studies that have been done are sound and have been
      followed by a change in clinical expectations and advice that speak of
      qualitative evidence from clinical practice, confirming the scientifically
      acquired data. Randomised controlled multicentre trials using sufficient numbers
      of patients, including functional assessment and quality of life measures, are
      needed to confirm the long term efficacy and safety of MTX in JIA.

PMID- 12598379
TI  - Diagnosis of Prader-Willi syndrome.

PMID- 12598377
TI  - Autologous haematopoietic stem cell transplantation in juvenile idiopathic
      arthritis.

PMID- 12598378
TI  - Hib vaccination in infants born prematurely.
AB  - AIMS: To document the immunogenicity and persistence of antibody to polyribosyl
      ribitol phosphate (PRP) as well as the clinical protection against invasive
      Haemophilus influenzae type b (Hib) disease in premature infants immunised at the
      routine schedule. METHODS: Blood was obtained at 2, 5, 12, and 64 months of age
      from a cohort of prematurely born infants (<or=32 weeks gestation). Anti-PRP
      antibody concentrations were compared with those of a control cohort of infants
      born at full term and vaccinated at the same schedule. Hib vaccine failures
      occurring between October 1992 and October 2000 were reported by paediatricians
      through an active, prospective, national survey in the UK and Republic of
      Ireland. The number of prematurely born children with vaccine failure was
      compared with the corresponding number born at term. RESULTS: Twenty seven
      prematurely born infants were followed to 5 years of age. Compared with term
      infants they had a significantly lower geometric mean concentration of anti-PRP
      antibody and/or a significantly lower proportion above one or both of the
      conventional protective antibody concentrations (0.15 and 1.0 micro g/ml) at all
      ages. A total of 165 cases of invasive Hib disease were identified over eight
      years of national surveillance. Eighteen were premature (<37 weeks);
      approximately 12 would be expected. The relative risk of UK premature infants
      developing disease compared with term infants was 1.5 (95% CI 0.9 to 2.6).
      CONCLUSIONS: Premature infants develop lower antibody concentrations than term
      infants following Hib conjugate vaccination. Premature infants may also have an
      increased risk of clinical vaccine failure, but interpretation is limited by the
      small number of premature infants developing invasive Hib disease over eight
      years of national surveillance. Overall, vaccination with Hib conjugate vaccines
      affords a high level of protection to premature babies.

PMID- 12598380
TI  - Pneumococcal nasopharyngeal carriage in children following heptavalent
      pneumococcal conjugate vaccination in infancy.
AB  - AIMS: To ascertain whether the reduction in nasopharyngeal carriage of vaccine
      serotypes induced by pneumococcal conjugate vaccine (PnCV) administered to
      infants persists beyond the age of 2 years. METHODS: Non-randomised, unblinded
      controlled study of 2-5 year old children who had received three doses of
      heptavalent PnCV (7VPnCV) in infancy and 23-valent pneumococcal polysaccharide
      vaccine at 13 months, and unimmunised controls. Nasopharyngeal swabs were taken
      in summer (150 vaccinated subjects, 126 controls) and winter (143 vaccinated
      subjects, 188 controls). The swabs were cultured and serotyped for Streptococcus
      pneumoniae. RESULTS: Carriage rates (vaccinated subjects: 24.7% and 43.4%;
      controls: 27.0% and 41.0%, in summer and winter respectively) and carriage of
      vaccine serotypes (subjects: 10.0% and 30.0%; controls: 13.5% and 31.5%, in
      summer and winter respectively) were similar in the two groups. CONCLUSIONS:
      Effects of vaccination in infancy on rates of nasal carriage of pneumococcus and
      serotype replacement in children living in a largely unvaccinated population are
      no longer evident by 2-5 years of age.

PMID- 12598381
TI  - Bacterial susceptibility to oral antibiotics in community acquired urinary tract
      infection.
AB  - BACKGROUND: The most common oral antibiotics used in the treatment of urinary
      tract infection (UTI) are sulphonamides and cephalosporins, but emerging
      resistance is not unusual. AIMS: To assess the change in susceptibility of
      urinary pathogens to oral antibiotics during the past decade in children with
      community acquired UTI. METHODS: The study sample included two groups of children
      with a first community acquired UTI: 142 children enrolled in 1991 and 124
      enrolled in 1999. UTI was diagnosed by properly collected urine specimen
      (suprapubic aspiration, transurethral catheterisation, or midstream specimen in
      circumcised males) in symptomatic patients. Antimicrobial susceptibility of the
      isolates was compared between the two groups. RESULTS: The pathogens recovered in
      the two groups were similar: in 1991--E coli 86%, Klebsiella 6%, others 8%; in
      1999--E coli 82%, Klebsiella 13%, and others 5%. A slight but generalised
      decrease in bacterial susceptibility to common antibiotics in the two groups was
      shown: ampicillin 35% versus 30%; cephalexin 82% versus 63% (p < 0.001);
      nitrofurantoin 93% versus 92%. The only exception was co-trimoxazole, 60% versus
      69%. Overall resistance to antibiotics in 1999 was as follows: ampicillin 70%,
      cephalexin 37%, co-trimoxazole 31%, amoxicillin-clavulanate 24%, nitrofurantoin
      8%, cefuroxime-axetil 5%, nalidixic acid 3%. CONCLUSIONS: This study shows a
      slight but generalised decrease in bacterial susceptibility to common oral
      antibiotics in the past decade in our population. Empirical initial treatment
      with co-trimoxazole or cephalexin is inadequate in approximately one third of UTI
      cases. A larger number of pathogens may be empirically treated with amoxicillin
      clavulanate (24% resistance); 95% of organisms are susceptible to cefuroxime
      axetil.

PMID- 12598382
TI  - Long term follow up of serostatus after maternofetal parvovirus B19 infection.
AB  - BACKGROUND: Maternofetal parvovirus B19 infection may result in fetal hydrops or
      abortion. Chronic infection has been associated with long term complications
      (polyarthritis, persistent aplastic anaemia, hepatitis). In pregnancy maternal
      immunosuppression caused by a TH2 dominant response to viral antigens has been
      observed. There is little information on long term reactivity to intrauterine
      infection. AIMS: To assess the serological status in children and their mothers
      after maternofetal parvovirus B19 infection and development of fetal hydrops.
      METHODS: A total of 18 children and their mothers, and 54 age matched control
      infants were studied. Main outcome measures were parvovirus B19 DNA, specific IgM
      and IgG against the virus proteins VP1/VP2, and NS-1 in venous blood. RESULTS:
      Parvovirus B19 DNA and antiparvovirus B19 (IgM) were undetectable in all sera. A
      significant larger proportion of maternal sera compared to study children's sera
      contained IgG against the non-structural protein NS-1. Mean levels of VP1/VP2 IgG
      antibodies were significantly lower in the children than in their mothers (48
      (36) v 197 (95) IU/ml). There was no history of chronic arthritis in mothers and
      children. Five women had subsequent acute but transient arthritis postpartum,
      which was not correlated with antibodies against NS-1. CONCLUSIONS: Serological
      evidence of persistent infection after maternofetal parvovirus B19 disease could
      not be detected. Increased maternal prevalence of anti NS-1 (IgG) and increased
      levels of antiparvovirus B19 (IgG) may reflect prolonged viraemia compared to
      fetal disease.

PMID- 12598383
TI  - Bacterial infections, immune overload, and MMR vaccine. Measles, mumps, and
      rubella.
AB  - Combined measles, mumps, and rubella (MMR) vaccine did not increase the risk of
      hospitalisation with invasive bacterial infection in the three months after
      vaccination; rather there was a protective effect. These results provide no
      support for the concept of "immunological overload" induced by multiple antigen
      vaccinations, nor calls for single antigen vaccines.

PMID- 12598384
TI  - Breast feeding and respiratory morbidity in infancy: a birth cohort study.
AB  - AIM: To examine the relation between the duration of breast feeding and morbidity
      as a result of respiratory illness and infection in the first year of life.
      METHODS: Prospective birth cohort study of 2602 live born children ascertained
      through antenatal clinics at the major tertiary obstetric hospital in Perth,
      Western Australia. Main outcome measures were hospital, doctor, or clinic visits,
      and hospital admissions for respiratory illness and infection in the first year
      of life. Main exposure measures were the duration of predominant breast feeding
      (defined as the age other milk was introduced) and partial (any) breast feeding
      (defined as the age breast feeding was stopped). Main confounders were gender,
      gestational age less than 37 weeks, smoking in pregnancy, older siblings,
      maternal education, and maternal age. RESULTS: Hospital, doctor, or clinic visits
      for four or more upper respiratory tract infections were significantly greater if
      predominant breast feeding was stopped before 2 months or partial breast feeding
      was stopped before 6 months. Predominant breast feeding for less than six months
      was associated with an increased risk for two or more hospital, doctor, or clinic
      visits and hospital admission for wheezing lower respiratory illness. Breast
      feeding for less than eight months was associated with a significantly increased
      risk for two or more hospital, doctor, or clinic visits or hospital admissions
      because of wheezing lower respiratory illnesses. CONCLUSIONS: Predominant breast
      feeding for at least six months and partial breast feeding for up to one year may
      reduce the prevalence and subsequent morbidity of respiratory illness and
      infection in infancy.

PMID- 12598385
TI  - Treatment compliance, passive smoking, and asthma control: a three year cohort
      study.
AB  - AIMS: To study the role of treatment compliance and parents' smoking on asthma
      control in children with recently diagnosed mild or moderate persistent asthma
      who were prescribed inhaled anti-inflammatory treatment. METHODS: Prospective
      cohort study of 167 children aged 6-12 years (64% boys). Patients were examined
      at inclusion and followed up for three years with a visit every four months. Peak
      expiratory flow (PEF) was measured twice a day during the week before each visit.
      Two control criteria were monitored: (1) symptom control = having diurnal or
      nocturnal exacerbations less than once a week and no symptoms between
      exacerbations, at all visits; and (2) PEF control = daily PEF variability <20% on
      each of the seven days before each visit. RESULTS: Symptom control was achieved
      by 25.1% of children and PEF control by 53.3%. Symptom control was positively
      related to having understood the way in which the medication worked and taking
      the prescribed doses (odds ratios (OR) = 3.38 and 4.82 respectively). It was
      inversely related to smoking within the home (OR = 0.34). PEF control was
      positively related to taking the prescribed doses (OR = 3.58). It was less
      frequently achieved if the mother smoked within the home (OR = 0.34).
      CONCLUSIONS: Results suggest that, to maximise the benefits of available asthma
      medication and to improve health outcomes, further efforts should be made to
      convince the parents of asthmatic children not to smoke in the house, and to
      improve compliance by increasing the patients' understanding of the disease and
      its treatment.

PMID- 12598386
TI  - Public health trials.

PMID- 12598387
TI  - Towards evidence based medicine for paediatricians.

PMID- 12598388
TI  - Can traffic calming measures achieve the Children's Fund objective of reducing
      inequalities in child health?

PMID- 12598389
TI  - Should verrucas be covered while swimming?

PMID- 12598391
TI  - Desperately seeking asylum.

PMID- 12598390
TI  - What is the normal range of blood glucose concentrations in healthy term
      newborns?

PMID- 12598392
TI  - Prevention of severe hypoglycaemia in type I diabetes: a randomised controlled
      population study.
AB  - AIMS: To investigate use of targeted self study material in type I diabetes
      patient education regarding dissemination, perceived patient benefit, and
      prevention of severe hypoglycaemia. METHODS: In a randomised 1:1:1 controlled
      study, 332 patients with type I diabetes (aged 2.6-18.9 years) were studied; 313
      completed clinical follow up, 261 completed endpoint questionnaire. The
      intervention group received videotapes and a brochure designed to review skills
      for self control and treatment, aimed at preventing severe hypoglycaemia. Two
      control groups received a videotape and brochure with general diabetes
      information, or traditional treatment only, respectively. RESULTS: Yearly
      incidence of severe hypoglycaemia decreased from 42% to 27% in the intervention
      group, but not in controls. HbA1c remained unchanged. Levels of use ranged from 1
      to 20 times (median 2); 40-49% had shown the materials to friends, relatives,
      school staff, sports coaches, etc (there was little difference between
      intervention and control groups). Higher benefit and learning levels resulted
      from the intervention material, especially in patients with severe hypoglycaemia.
      CONCLUSIONS: Mass distributed pedagogical devices such as high quality video
      programmes and brochures may contribute to the prevention of severe
      hypoglycaemia. Such self study materials can reach high dissemination levels and
      constitute a cost effective complement to regular visits to a diabetes team and
      to other types of education. The findings may have implications for other topics,
      other ages, and other diagnosis groups.

PMID- 12598393
TI  - Bronchodilation in infants with malacia or recurrent wheeze.
AB  - BACKGROUND: Controversy remains regarding the effectiveness of bronchodilators in
      wheezy infants. AIMS: To assess the effect of inhaled beta(2) agonists on lung
      function in infants with malacia or recurrent wheeze, and to determine whether a
      negative effect of beta(2) agonists on forced expiratory flow (V'(maxFRC)) is
      more pronounced in infants with airway malacia, compared to infants with wheeze.
      METHODS: We retrospectively analysed lung function data of 27 infants: eight with
      malacia, 19 with recurrent wheeze. Mean (SD) age was 51 (18) weeks. Mean
      V'(maxFRC) (in Z score) was assessed before and after inhalation of beta(2)
      agonists. RESULTS: Baseline V'(maxFRC) was below reference values for both
      groups. Following inhalation of beta(2) agonists the mean (95% CI) change in mean
      V'(maxFRC) in Z scores was -0.10 (-0.26 to 0.05) and -0.33 (-0.55 to -0.11) for
      the malacia and wheeze group, respectively. CONCLUSIONS: In infants with wheeze,
      inhaled beta(2) agonists caused a significant reduction in mean V'(maxFRC).
      Infants with malacia were not more likely to worsen after beta(2) agonists than
      were infants with recurrent wheeze.

PMID- 12598394
TI  - Parental reporting of smelly urine and urinary tract infection.
AB  - BACKGROUND: Parents often report that young children have "smelly urine" or a
      particular urinary odour. There is little evidence that these observations are
      relevant to the diagnosis of urinary tract infection (UTI). AIMS: To determine
      whether parental reporting of smelly urine is of any relevance to the diagnosis
      of UTI in children less than 6 years of age. METHODS: Parents whose children were
      having urine collected as part of their admission to a large district hospital
      were given a simple questionnaire to complete regarding the current smell of
      their child's urine. Parents were asked whether their child's urine smelled
      different from usual or had a particular smell. Microscopy and culture results of
      the child's urine were compared to their parent's questionnaire answers to see if
      there was a association between parental reporting of a different or particular
      urine smell and a diagnosis of UTI. RESULTS: One hundred and ten questionnaires
      and urine samples were obtained. Fifty two per cent of parents thought that their
      child's urine smelled different from usual or had a particular smell. Only 6.4%
      of children were diagnosed as having a UTI. There was no statistically
      significant association between parental reporting of abnormal urine smell and
      diagnosis of UTI. CONCLUSION: In determining whether a young child has a UTI,
      asking parents about urine smell is unlikely to be of benefit.

PMID- 12598395
TI  - General anaesthesia or conscious sedation for painful procedures in childhood
      cancer: the family's perspective.
AB  - BACKGROUND: Until recently, midazolam sedation was routinely used in our
      institution for bone marrow aspirates and lumbar punctures in children with
      cancer. It has been perceived by many doctors and nurses as being well tolerated
      by children and their families. AIM: To compare the efficacy of inhalational
      general anaesthesia and midazolam sedation for these procedures. METHODS: A total
      of 96 children with neoplastic disorders, who received either inhalational
      general anaesthesia with sevoflurane, nitrous oxide, and oxygen (GA) or sedation
      with oral or nasal midazolam (SED) as part of their routine preparation for
      procedures were studied. The experiences of these children were examined during
      their current procedure and during their first ever procedure. Main outcome
      measures were the degree of physical restraint used on the child, and the levels
      of distress and pain experienced by the child during the current procedure and
      during the first procedure. The family's preference for future procedures was
      also determined. RESULTS: During 102 procedures under GA, restraint was needed on
      four occasions (4%) when the anaesthetic mask was first applied, minimal pain was
      reported, and children were reported as distressed about 25% of the time. During
      80 SED procedures, restraint was required in 94%, firm restraint was required in
      66%, the child could not be restrained in 14%, median pain score was 6 (scale 0
      (no pain) to 6 (maximum pain)), and 90% of the parents reported distress in their
      child. Ninety per cent of families wanted GA for future procedures. Many families
      reported dissatisfaction with the sedation regime and raised concerns about the
      restraint used on their child. CONCLUSIONS: This general anaesthetic regime
      minimised the need for restraint and was associated with low levels of pain and
      distress. The sedation regime, by contrast, was much less effective. There was a
      significant disparity between the perceptions of health professionals and those
      of families with respect to how children coped with painful procedures.

PMID- 12598397
TI  - Craniosynostosis due to premature closing of the sagittal suture.

PMID- 12598396
TI  - Role of itraconazole in haematology/oncology.
AB  - The antifungal agents most frequently used in prophylaxis and treatment are
      amphotericin B (and its new lipid forms) and azoles such as fluconazole,
      itraconazole, and more recently voriconazole. This review assesses the role of
      itraconazole in paediatric haematology/oncology practice. Its broader spectrum of
      activity and availability in oral and intravenous forms allow a flexible approach
      in the management of fungal infections.

PMID- 12598398
TI  - Congenital adrenal hypoplasia presenting as a chronic respiratory condition.
AB  - We describe two children with oxygen dependence, which resolved when congenital
      adrenal hypoplasia was diagnosed and treatment initiated. Chronic respiratory
      distress can be a symptom of adrenal hypoplasia and this should be taken into
      consideration when investigating a child with unexplained chronic respiratory
      difficulties. Respiratory symptoms resolve very quickly when the underlying
      condition is recognised and treated.

PMID- 12598399
TI  - Birth prevalence of Prader-Willi syndrome in Australia.
AB  - This is the first population based study to estimate the birth prevalence of DNA
      proven Prader-Willi syndrome. Thirty infants were reported to the Australian
      Paediatric Surveillance Unit between 1998 and 2000, a prevalence of 4 per 100,000
      live births or approximately 1/25,000 live births per annum.

PMID- 12598400
TI  - A Rapunzel with a difference.

PMID- 12598401
TI  - Female sexual health care in cystic fibrosis.
AB  - Fifty five teenage girls with cystic fibrosis and their mothers were interviewed
      to assess the provision of sexual health information. Parents were the most
      common source of information for adolescents. The cystic fibrosis doctor was
      identified as the key resource for parents. Yet few parents had spoken to their
      doctor about these issues, and 96% requested more information. This information
      was wanted before puberty by mothers, and from puberty onwards by girls.

PMID- 12598402
TI  - Can mild head injury cause ischaemic stroke?
AB  - Five cases of ischaemic stroke preceded by minor head trauma in children are
      described. All patients had striatocapsular infarction. Three had no
      cerebrovascular abnormality; two had turbulent flow in the proximal middle
      cerebral artery. None of the patients had evidence of arterial dissection or any
      other risk factors for stroke. All made an excellent neurological recovery.
      Possible mechanisms include mechanical disruption to the flow in the perforating
      branches of the middle cerebral artery, intimal trauma and subsequent thrombosis,
      or arterial spasm induced by trauma. The specific susceptibility in affected
      children remains unexplained; both genetic and environmental factors (for
      example, previous chickenpox) may be implicated.

PMID- 12598403
TI  - Mycoplasma pneumoniae associated organising pneumonia in a 10 year old boy.
AB  - We describe a 10 year old boy with organising pneumonia associated with acute
      Mycoplasma pneumoniae infection. The diagnosis of organising pneumonia was made
      by open lung biopsy and the M pneumoniae infection was proven serologically.
      Antibiotic and long term corticosteroid treatment resulted in steadily improving
      pulmonary function monitored by spirometry. The introduction of anti-inflammatory
      treatment with NSAIDs/immunosuppressive agents in order to spare steroids was
      well tolerated and resulted in further improvement of the pulmonary function. To
      our knowledge this is the first documented case of Mycoplasma pneumoniae
      associated organising pneumonia to be reported in a child.

PMID- 12598404
TI  - Time for a randomised controlled trial of empyema treatment?

PMID- 12598406
TI  - Questions on questionnaire development.

PMID- 12598408
TI  - The CB1 receptor antagonist SR141716A selectively increases monoaminergic
      neurotransmission in the medial prefrontal cortex: implications for therapeutic
      actions.
AB  - 1. In order to explore potential therapeutic implications of cannabinoid
      antagonists, the effects of the prototypical cannabinoid antagonist SR141716A on
      monoamine efflux from the medial prefrontal cortex and the nucleus accumbens of
      the rat were investigated by in vivo microdialysis. 2. SR141716A moderately
      increased serotonin efflux and concentrations of its metabolite 5-HIAA, both in
      the medial prefrontal cortex and the nucleus accumbens, and increased
      norepinephrine, dopamine and their metabolites in the medial prefrontal cortex.
      In contrast, it had no effect on norepinephrine, dopamine and their metabolites
      in the nucleus accumbens. 3. At the same doses, SR141716A increased acetylcholine
      efflux in the medial prefrontal cortex, in agreement with previous studies;
      contrary to the effects in cortex, SR141716A had no effect on acetylcholine
      efflux in the nucleus accumbens. 4. The efficacy of SR141716A in the
      psychostimulant-induced hyperlocomotion and the forced swimming paradigms was
      also explored in mice. SR141716A attenuated phenylcyclidine- and d-amphetamine
      induced hyperlocomotion, without affecting locomotor activity when administered
      alone, and decreased immobility in the forced swimming test. 5. These results
      suggest that the cortical selectivity in the release of catecholamines, dopamine
      in particular, induced by the cannabinoid antagonist SR141716A, its
      procholinergic properties, together with its mild stimulatory effects on
      serotonin and norepinephrine efflux make similar compounds unique candidates for
      the treatment of psychosis, affective and cognitive disorders.

PMID- 12598409
TI  - Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension
      in spontaneously hypertensive rats: a pharmacologic and autoradiographic study.
AB  - 1. The role of nigral tachykinin NK(1), NK(2) and NK(3) receptors in central
      cardiovascular regulation was studied by measuring the effects of selective
      agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR)
      after bilateral microinjection into the substantia nigra of spontaneously
      hypertensive rats (SHR). Quantitative in vitro autoradiography was also performed
      in the midbrain of SHR and Wistar-Kyoto (WKY) with the NK(3) receptor ligand
      [(125)I]-HPP-Senktide. 2. Tachycardia was elicited by the NK(1)
      ([Sar(9),Met(O(2))(11)]SP) and NK(2) ([betaAla(8)]NKA(4-10)) agonists at 25 and
      100 pmol while the NK(3) agonist (senktide, 50 and 100 pmol) had no significant
      effect. The three agonists had no effect on behaviour, and increases in MAP were
      elicited by the NK(1) agonist only. 3. Whereas antagonists at NK(1) (RP 67580,
      500 pmol) and NK(2) (SR 48968, 500 pmol) receptors had no significant effect on
      MAP and HR, the NK(3) antagonist (R-820, 500 pmol) reduced MAP for over 3 h in
      SHR. That anti-hypertensive effect did not occur after intracerebroventricular or
      intravenous injection of R-820. Also, R-820 had no cardiovascular effect in WKY.
      4. The affinity (K(D): 0.7 nM) and densities of specific NK(3) receptor binding
      sites measured in the substantia nigra, ventral tegmental area, hippocampus and
      amygdala were not significantly different in SHR and WKY. 5. It is concluded that
      endogenous tachykinins exert a tonic activity on NK(3) receptors in the
      substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin
      NK(3) receptors may represent a promising therapeutic target in the treatment of
      arterial hypertension.

PMID- 12598407
TI  - Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion
      injury and preconditioning.
AB  - There appears to be a controversy in the study of myocardial ischaemia
      reperfusion injury and preconditioning whether nitric oxide (NO) plays a
      protective or detrimental role. A number of findings and the interpretation of
      the results to date do not support such a controversy. An understanding of the
      latest developments in NO, superoxide (O(2)(-)*) and peroxynitrite (ONOO(-))
      biology, as well as the various ischaemic animal models utilized is necessary to
      resolve the apparent controversy. NO is an important cardioprotective molecule
      via its vasodilator, antioxidant, antiplatelet, and antineutrophil actions and it
      is essential for normal heart function. However, NO is detrimental if it combines
      with O(2)(-)* to form ONOO(-) which rapidly decomposes to highly reactive oxidant
      species. There is a critical balance between cellular concentrations of NO, O(2)(
      )*, and superoxide dismutase which physiologically favour NO production but in
      pathological conditions such as ischaemia and reperfusion result in ONOO(-)
      formation. In contrast, exposure of the heart to brief episode(s) of ischaemia
      markedly enhances its ability to withstand a subsequent ischaemic injury. The
      triggering of this endogenous cardioprotective mechanism known as preconditioning
      requires both NO and O(2)(-)* synthesis. However, preconditioning in turn
      attenuates the overproduction of NO, O(2)(-)* and ONOO(-) during a subsequent
      episode of ischaemia and reperfusion, thereby protecting the heart. Here we
      review the roles of NO, O(2)(-)*, and ONOO(-) in both ischaemia-reperfusion
      injury and preconditioning.

PMID- 12598410
TI  - Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti
      absorptive effect via the VPAC1 receptor in a human enterocyte-like cell line
      (Caco-2).
AB  - 1. Optimal dipeptide and peptidomimetic drug transport across the intestinal
      mucosal surface is dependent upon the co-operative functional activity of the
      di/tripeptide transporter hPepT1 and the Na(+)/H(+) exchanger NHE3. The ability
      of the anti-absorptive enteric neuropeptide VIP (vasoactive intestinal peptide)
      to modulate dipeptide uptake was determined using human intestinal (Caco-2)
      epithelial cell monolayers. 2. Uptake of glycylsarcosine (Gly-Sar) across the
      apical membrane of Caco-2 cell monolayers is inhibited by basolateral exposure to
      either VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), or the
      VPAC(1) receptor agonist [(11,22,28)Ala]-VIP. Inhibition of Gly-Sar uptake is
      observed only in the presence of extracellular Na(+). Reverse-transcription
      polymerase chain reaction (RT-PCR) demonstrates that VPAC(1) mRNA is expressed in
      Caco-2 cells whereas VPAC(2) mRNA is not detected. 3. The VIP-induced inhibition
      of Gly-Sar uptake is abolished in the presence of the protein kinase A (PKA)
      inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5
      isoquinolinesulfonamide.2HCl). 4. (22)Na(+) uptake across the apical membrane is
      inhibited by the selective NHE3 inhibitor S1611. Experiments with BCECF [2',7'
      bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that
      VIP reduces the NHE3-dependent recovery of intracellular pH (pH(i)) after
      dipeptide-induced acidification. Western blot of Caco-2 cell protein demonstrates
      expression of the NHE regulatory factor NHERF1 (expression of which is thought to
      be required for PKA-mediated inhibition of NHE3). 5. VIP has no effect on Gly-Sar
      uptake in the presence of S1611 suggesting that VIP and S1611 both modulate
      dipeptide uptake via the same mechanism. 6. These observations demonstrate that
      VIP (and PACAP) modulate activity of the H(+)/dipeptide transporter hPepT1 in a
      Na(+)-dependent manner consistent with the modulation being indirect through
      inhibition of NHE3.

PMID- 12598411
TI  - Thrombin-induced conversion of fibrinogen to fibrin results in rapid platelet
      trapping which is not dependent on platelet activation or GPIb.
AB  - 1. Activation of human platelets by thrombin is mediated by the proteolytic
      cleavage of two G-protein coupled protease-activated receptors, PAR-1 and PAR-4.
      However, thrombin also binds specifically to the platelet surface glycoprotein
      GPIb. It has been claimed that thrombin can induce aggregation of platelets via a
      novel GPIb-mediated pathway, which is independent of PAR activation and
      fibrinogen binding to alpha(IIb)beta(3) integrin, but dependent upon polymerizing
      fibrin and the generation of intracellular signals. 2. In the presence of both
      fibrinogen and the alpha(IIb)beta(3) receptor antagonist lotrafiban, thrombin
      induced a biphasic platelet aggregation response. The initial primary response
      was small but consistent and associated with the release of platelet granules.
      The delayed secondary response was more substantial and was abolished by the
      fibrin polymerization blocking peptide GPRP. 3. Cleavage of the extracellular
      portion of GPIb by mocarhagin partially inhibited thrombin-induced
      alpha(IIb)beta(3)-dependent aggregation and release, but had no effect on the
      secondary fibrin-dependent response. 4. Fixing of the platelets abolished
      alpha(IIb)beta(3)-dependent aggregation and release of adenine nucleotides,
      whereas the fibrin-dependent response remained, indicating that platelet
      activation and intracellular signalling are not necessary for this secondary
      'aggregation'. 5. In conclusion, the secondary fibrin-dependent 'aggregation'
      response observed in the presence of fibrinogen and lotrafiban is a platelet
      trapping phenomenon dependent primarily on the conversion of soluble fibrinogen
      to polymerizing fibrin by thrombin.

PMID- 12598413
TI  - Selective blockade of endothelial Ca2+-activated small- and intermediate
      conductance K+-channels suppresses EDHF-mediated vasodilation.
AB  - 1. Activation of Ca(2+)-activated K(+)-channels (K(Ca)) has been suggested to
      play a key role in endothelium-derived hyperpolarizing factor (EDHF)-mediated
      vasodilation. However, due to the low selectivity of commonly used K(Ca)-channel
      blockers it is still elusive which endothelial K(Ca)-subtypes mediate
      hyperpolarization and thus initiate EDHF-mediated vasodilation. 2. Using the non
      cytochrome P450 blocking clotrimazole-derivatives, 1-[(2-chlorophenyl)
      diphenylmethyl]-1H-pyrazole (TRAM-34) and 2-(2-chlorophenyl)-2,2
      diphenylacetonitrile (TRAM-39) as highly selective IK1-inhibitors, we
      investigated the role of the intermediate-conductance K(Ca) (rIK1) in endothelial
      hyperpolarization and EDHF-mediated vasodilation. 3. Expression and function of
      rIK1 and small-conductance K(Ca) (rSK3) were demonstrated in situ in single
      endothelial cells of rat carotid arteries (CA). rIK1-currents were blocked by
      TRAM-34 or TRAM-39, while rSK3 was blocked by apamin. In current-clamp
      experiments, endothelial hyperpolarization in response to acetylcholine was
      abolished by the combination of apamin and TRAM-34. 4. In phenylephrine
      preconstricted CA, acetylcholine-induced NO and prostacyclin-independent
      vasodilation was almost completely blocked by ChTX, CLT, TRAM-34, or TRAM-39 in
      combination with the SK3-blocker apamin. Apamin, TRAM-34, and CLT alone or
      sulphaphenzole, a blocker of the cytochrome P450 isoform 2C9, were ineffective in
      blocking the EDHF-response. 5. In experiments without blocking NO and
      prostacyclin synthesis, the combined blockade of SK3 and IK1 reduced endothelium
      dependent vasodilation. 6. In conclusion, the use of selective IK1-inhibitors
      together with the SK3-blocker apamin revealed that activation of both K(Ca), rIK1
      and rSK3 is crucial in mediating endothelial hyperpolarization and generation of
      the EDHF-signal while the cytochrome P450 pathway seems to play a minor or no
      role in rat CA.

PMID- 12598412
TI  - Differential engagements of glutamate and GABA receptors in cardiovascular
      actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of rats.
AB  - 1. We evaluated in Sprague-Dawley rats anaesthetized with propofol the engagement
      of soluble guanylyl cyclase (sGC)/cGMP cascade, glutamatergic and GABAergic
      neurotransmission in the cardiovascular actions of endogenous nitric oxide (NO)
      at the rostral ventrolateral medulla (RVLM). 2. Microinjection bilaterally into
      the RVLM of a selective iNOS inhibitor, S-methylisothiourea (SMT, 250 pmoles), or
      a selective nNOS inhibitor, 7-nitroindazole (7-NI, 5 pmoles), induced
      respectively an enhancement or a reduction in systemic arterial pressure, heart
      rate and power density of the vasomotor components in the spectrum of arterial
      blood pressure signals, our experimental index for sympathetic neurogenic
      vasomotor tone. 3. The cardiovascular actions of SMT or 7-NI in the RVLM were
      significantly antagonized by co-administration into the RVLM of the sGC
      inhibitor, 1H-[1,2,4]Oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 250 or 500
      pmoles). 4. The cardiovascular excitatory effects after blockade of endogenous
      iNOS activity were significantly attenuated when N-methyl-D-aspartate (NMDA)
      receptor antagonist, dizocilpine (20 or 50 pmoles), or non-NMDA receptor
      antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (250 or 500 pmoles), was co
      microinjected bilaterally into the RVLM. 5. On the other hand, the cardiovascular
      depressive responses to blockade of endogenous nNOS activity were significantly
      antagonized on co-administration of GABA(A) receptor antagonist, bicuculline
      methiodine (5 or 10 pmoles), but not GABA(B) receptor antagonist, 2-hydroxy
      saclofen (50 or 100 pmoles). 6. We conclude that the cardiovascular actions of
      endogenous NO in the RVLM engage the sGC/cGMP pathway. In addition, whereas NO
      derived from nNOS induced sympathoexcitation via both NMDA and non-NMDA receptors
      in the RVLM, NO generated by iNOS elicited sympathoinhibition via GABA(A)
      receptors.

PMID- 12598414
TI  - Characterization of the anticonvulsant profile and enantioselective
      pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in
      rodents.
AB  - 1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic
      acid. The purpose of this study was to evaluate the anticonvulsant activity of
      PID in rodent models of partial, secondarily generalized and sound-induced
      generalized seizures which focus on different methods of seizure induction, both
      acute stimuli, and following short-term plastic changes as a result of kindling,
      and to assess enantioselectivity and enantiomer-enantiomer interactions in the
      pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in
      rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was
      evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal
      kindled rat, and in the Frings audiogenic seizure susceptible mouse. The
      pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice
      (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures
      with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(
      1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA,
      respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg
      kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID,
      (R)-PID and racemic PID also blocked generalized seizures in the Frings mice
      (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In
      the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented
      the secondarily generalized seizure, whereas racemic PID also blocked the
      expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic
      PID also significantly increased the seizure threshold in this model. 5.
      Mechanistic studies showed that PID did not affect voltage-sensitive sodium
      channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of
      PID was enantioselective following i.p. administration of individual enantiomers
      to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID.
      In rats and mice, no enantioselectivity in the pharmacokinetics of PID was
      observed following administration of the racemate, which may be due to enantiomer
      enantiomer interaction. 7. This study demonstrated that PID has both
      enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant
      potency of (R)-PID in comparison to (S)-PID may be due to its more favorable
      pharmacokinetic profile. The enhanced efficacy of the racemate over the
      individual enantiomers in the kindled rat may be explained by a pharmacokinetic
      enantiomer-enantiomer interaction in rats. This study also showed the importance
      of studying the pharmacokinetics and pharmacodynamics of chiral drugs following
      administration of the individual enantiomers as well as the racemic mixture.

PMID- 12598415
TI  - Group III metabotropic glutamate receptors as autoreceptors in the cerebellar
      cortex.
AB  - 1. Group III metabotropic glutamate receptors (mGluRs) of the subtype 4a are
      localized within presynaptic active zones of cerebellar parallel fibre (PF)
      Purkinje cell (PC) synapses. In order to investigate the conditions necessary for
      group III mGluR autoreceptor-activation by synaptically released glutamate, we
      characterized the effects of selective agonists and antagonists on excitatory
      postsynaptic currents (EPSCs) evoked by several distinct PF stimulation patterns.
      2. The group III mGluR-selective agonist L-AP4 depressed evoked EPSCs at PF-PC
      synapses in rat brain slices with an EC(50) of 2.4 microM and maximum inhibition
      of 80%. This L-AP4-induced depression was antagonized by the group III mGluR
      selective antagonist MSOP with an estimated equilibrium dissaciation constant of
      12.5 microM. 3. Paired-pulse or four-pulse PF stimulations did not activate
      presynaptic group III mGluRs as revealed by the lack of effect of 1 mM MSOP on
      relative test EPSC amplitudes with latencies of 250-500 ms. The potentiation of a
      test EPSC evoked 200-500 ms after a short tetanic burst (100 Hz for 60 ms), was
      also unchanged in the presence of MSOP. 4. Endogenous autoreceptor-activation was
      revealed only during prolonged stimulation trains (10 Hz for 4.4 s), where, in
      the presence of 1 mM MSOP, the EPSC amplitudes were enhanced by 15%. 5. These
      observations support an autoreceptor function of group III mGluRs and a role in
      short-term synaptic plasticity at PF synapses. However, the low to moderate
      activation levels observed, despite the close spatial relation with glutamate
      release sites, suggests that additional mechanisms regulate receptor activation.

PMID- 12598416
TI  - Activation of c-fos expression in the heart after morphine but not U-50,488H
      withdrawal.
AB  - 1. In the present work we have studied in the heart the expression of Fos, the
      protein product of the c-fos proto-oncogene and the adaptive changes in
      noradrenergic neurons after naloxone or nor-binaltorphimine (nor-BNI)
      administration to morphine or U-50,488H pretreated rats. 2. Male rats were
      implanted with placebo (naive) or morphine (tolerant/dependent) pellets for 7
      days. On day 8 rats received saline s.c., naloxone (5 mg kg(-1) s.c.) or nor-BNI
      (5 mg kg(-1) i.p.). Other groups of rats were rendered tolerant/dependent on U
      50,488H by injecting the drug twice daily (15 mg kg(-1) i.p.) for 4 days. Control
      animals received saline. On day 5 the animals were injected with vehicle i.p. or
      nor-BNI (5 mg kg(-1) i.p.). 3. Using immunohistochemical staining of Fos, present
      results indicate that morphine withdrawal induced marked Fos immunoreactivity
      (Fos-IR) within the cardiomyocyte nuclei. Moreover, Western blots analysis
      revealed a peak expression of c-fos in right and left ventricle after naloxone
      induced withdrawal in parallel with an increase in noradrenaline (NA) turnover.
      4. However, after nor-BNI administration to rats chronically treated with U
      50,488H, we found a decrease in the NA turnover. In addition, the administration
      of nor-BNI to rats chronically treated with U-50,488H or morphine did not induce
      modifications in the Fos-IR, in the heart. 5. These results demonstrated that
      morphine withdrawal induces the expression of Fos protein, as well as an
      enhancement of noradrenergic activity in the heart. In contrast to morphine U
      50,488 withdrawal produces no changes in Fos-IR in parallel with a decrease in NA
      turnover, indicating that the kappa-opioid receptors are not involved in the
      molecular adaptive mechanisms responsible for the development of opioid
      dependence in the heart.

PMID- 12598417
TI  - Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in
      human blood cells.
AB  - 1. Acetaminophen, an analgesic and antipyretic drug with weak antiinflammatory
      properties, has been suggested to act as a tissue-selective inhibitor of
      prostaglandin H synthases (PGHSs) (e.g. COX-1 and COX-2) through its reducing
      activity, that is influenced by the different cellular levels of peroxides. 2. We
      have studied the effects of acetaminophen on inducible and constitutive
      prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate
      between the inhibitory effect of the drug on PGHS-isozymes vs PGE-synthases
      (PGESs), parallel measurements of PGE(2) and thromboxane (TX) B(2) were carried
      out. Since antioxidant enzymes and cofactors, present in plasma, may affect
      acetaminophen-dependent inhibition of prostanoids, comparative experiments in
      whole blood vs isolated monocytes were performed. 3. Acetaminophen inhibited LPS
      induced whole blood PGE(2) and TXB(2) production, in a concentration-dependent
      fashion [IC(50) microM (95% confidence intervals): 44 (27-70) and 94 (79-112),
      respectively]. Therapeutic plasma concentrations (100 and 300 microM) of the drug
      more profoundly reduced PGE(2) than TXB(2) (71 +/- 3 vs 54 +/- 4 and 95 +/- 0.8
      vs 78 +/- 2%, respectively, mean +/- s.e.mean, n = 6, P < 0.01). 4. Differently,
      in isolated monocytes stimulated with LPS, both PGE(2) and TXB(2) production was
      maximally reduced by only 60%. 5 At 100 and 300 microM, the drug caused a similar
      and incomplete inhibition of platelet PGE(2) and TXB(2) production during whole
      blood clotting (45 +/- 4 vs 54 +/- 4 and 75 +/- 2 vs 75 +/- 1%, respectively,
      mean +/- s.e.mean, n = 4). 6 In conclusion, therapeutic concentrations of
      acetaminophen caused an incomplete inhibition of platelet COX-1 and monocyte COX
      2 but in the presence of plasma, the drug almost completely suppressed inducible
      PGE(2) biosynthesis through its inhibitory effects on both COX-2 and inducible
      PGES.

PMID- 12598418
TI  - A possible mechanism for improvement by a cognition-enhancer nefiracetam of
      spatial memory function and cAMP-mediated signal transduction system in sustained
      cerebral ischaemia in rats.
AB  - 1. Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine
      monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding
      protein (CREB) signal transduction system may be linked to learning and memory
      function. 2. The effects of nefiracetam, which has been developed as a cognition
      enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction
      system in rats with sustained cerebral ischaemia were examined. 3. Microsphere
      embolism (ME)-induced sustained cerebral ischaemia was produced by injection of
      700 microspheres (48 micro m in diameter) into the right hemisphere of rats.
      Daily oral administration of nefiracetam (10 mg kg(-1) day(-1)) was started from
      15 h after the operation. 4. The delayed treatment with nefiracetam attenuated
      the ME-induced prolongation of the escape latency in the water maze task that was
      examined on day 7 to 9 after ME, but it did not reduce the infarct size. 5. ME
      decreased Ca(2+)/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content,
      cytosolic PKA Cbeta level, nuclear PKA Calpha and Cbeta levels, and reduced the
      phosphorylation and DNA-binding activity of CREB in the nucleus in the right
      parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in
      these variables did not occur by the delayed treatment with nefiracetam. 6. These
      results suggest that nefiracetam preserved cognitive function, or prevented
      cognitive dysfunction, after sustained cerebral ischaemia and that the effect is,
      in part, attributable to the prevention of the ischaemia-induced impairment of
      the AC/cAMP/PKA/CREB signal transduction pathway.

PMID- 12598419
TI  - Expression of prostanoid receptors in human ductus arteriosus.
AB  - 1. Prostaglandins play a major role in maintaining ductal patency in utero.
      Ductal tone is regulated by both locally released and circulating vasodilatory
      prostaglandins. In infants with ductus arteriosus-dependent congenital heart
      disease, ductal patency is maintained by intravenous administration of
      prostaglandin (PG) E(1). Little information is available regarding the expression
      of prostaglandin receptors in man. 2. By means of RT-PCR and immunohistochemistry
      we studied the expression of the PGI(2) receptor (IP), the four different PGE(2)
      receptors (EP1, EP2, EP3 and EP4), and the receptors for thromboxane (Tx) A(2)
      (TP), PGD(2) (DP) and PGF(2alpha) (FP) in the ductus arteriosus of three newborn
      infants with ductus arteriosus-dependent congenital heart disease and intravenous
      infusion of PGE(1) and of one 8 month old child with a patent ductus arteriosus.
      3. The EP3, EP4, FP, IP and TP receptor were markedly expressed at the mRNA and
      protein level, whereas the EP2 receptor was weakly expressed and the EP1 receptor
      was detected in two out of four tissue specimens only. The DP receptor was not
      detected in any of the samples. The most pronounced expression, which was located
      in the media of the ductus arteriosus, was observed for the EP4 and TP receptors
      followed by IP and FP receptor protein. 4. These data indicate that ductal
      patency during the infusion of PGE(1) in infants with ductus arteriosus-dependent
      congenital heart disease might be mediated by the EP4 and IP receptor. The data
      further suggest that a heterogeneous population of prostanoid receptors may
      contribute to the regulation of ductus arteriosus tone in humans.

PMID- 12598420
TI  - G protein-coupled receptor kinase 6 (GRK6) selectively regulates endogenous
      secretin receptor responsiveness in NG108-15 cells.
AB  - 1. To determine the role of G protein-coupled receptor kinases (GRKs) in the
      regulation of endogenous secretin receptor responsiveness, we have transiently
      overexpressed both wild-type (WT) and dominant negative mutant (DNM) GRKs in
      NG108-15 mouse neuroblastoma x rat glioma hybrid cells and investigated the
      effects of this on agonist-stimulated adenylyl cyclase activity. 2.
      Overexpression of WT GRK6 selectively inhibited secretin-stimulated cyclic AMP
      accumulation (fold stimulation of cyclic AMP above basal following 15 min
      incubation with 100 nM secretin was 12.1+/-2.0 and 6.2+/- 0.8 in control and WT
      GRK overexpressing cells, respectively) without affecting cyclic AMP responses
      mediated by the adenosine A(2) receptor agonist 5'-(N-ethylcarboxamido) adenosine
      (NECA) or the prostanoid-IP receptor agonist iloprost, or the direct activator of
      adenylyl cyclase, forskolin. On the other hand DNM GRK6 (Lys(215)Arg)
      overexpression produced the opposite effect--a selective increase in the secretin
      stimulated cyclic AMP response was observed in cells overexpressing DNM GRK6
      compared to plasmid-transfected cells (fold stimulation of cyclic AMP above basal
      following 15 min incubation with 100 nM secretin was 12.6+/-2.7 and 29.6+/-5.6
      for control and DNM GRK6-overexpressing cells, respectively). 3. Overexpression
      of WT GRK5 likewise inhibited the secretin-stimulated cyclic AMP response,
      however, this effect was not as selective as with GRK6, since adenosine A(2)
      receptor responsiveness was also suppressed by GRK5 overexpression. Unlike DNM
      GRK6, overexpression of DNM GRK5 failed to modulate secretin or A(2) adenosine
      receptor signalling suggesting that endogenous GRK5 is unlikely to regulate
      desensitization of these receptors in NG108-15 cells. 4. Overexpression of WT
      GRK2 did not affect secretin-stimulated cyclic AMP accumulation. Instead, GRK2
      overexpression selectively inhibited A(2) adenosine receptor responsiveness,
      confirming our previous findings. 5. Together these results suggest a selective
      role of endogenous GRK6 in regulating secretin receptor responsiveness in NG108
      15 cells. In addition, these data indicate that GRKs exert a surprising degree of
      selectivity in the regulation of natively expressed GPCR responses.

PMID- 12598421
TI  - Comparison of human recombinant adenosine A2B receptor function assessed by Fluo
      3-AM fluorometry and microphysiometry.
AB  - 1. The aim of this study was to establish the utility of a fluorometric imaging
      plate reader (FLIPR) assay to assess human adenosine A(2B) receptor function by
      characterizing its receptor pharmacology and comparing this profile to that
      obtained using a microphysiometer. 2. FLIPR was used, in conjunction with a
      Ca(2+)-sensitive dye (Fluo-3-AM), to measure rapid rises in intracellular calcium
      in a Chinese Hamster Ovary (CHO-K1) cell line stably transfected with both the
      human A(2B) receptor and a promiscuous G(alpha16) protein. Microphysiometry was
      used to measure rapid changes in the rate of extracellular acidification in a
      Human Embryonic Kidney (HEK-293) cell line also stably transfected with human
      A(2B) receptor. 3. Activation of A(2B) receptors by various ligands caused a
      concentration-dependent increase in both the intracellular calcium concentration
      and the extracellular acidification rate in the cells tested, with a similar rank
      order of potency for agonists: NECA > N(6)-Benzyl NECA > adenosine > or = R-PIA >
      CPA > S-PIA > CHA > CGS 21680. No comparable effects were observed in the non
      transfected control cell lines. 4. The rank order of potency of the agonists
      examined was the same in all studies, whereas absolute potency and efficacy
      varied. Thus, all compounds exhibited greater potency in FLIPR than the
      microphysiometer and the efficacies obtained with CHO-K1 + G(alpha16) + A(2B)
      cell line and FLIPR were greater than those obtained with HEK-293 + A(2B) cell
      line in the microphysiometer. 5. ZM-241385 was the most potent of a range of
      adenosine antagonists tested with a pA(2) of 8.0 in both the FLIPR and
      microphysiometer assays. 6. In conclusion, the profile of the responses to both
      A(2B) receptor agonists and antagonists in FLIPR were similar to those obtained
      by the microphysiometer, although both potency and efficacy values were higher in
      the FLIPR assay. With this caveat in mind, this study shows that FLIPR coupled
      with a cell line transfected with both the human A(2B) receptor and a promiscuous
      G(alpha16) protein provides a useful, high throughput method for the assessment
      of A(2B) receptor function.

PMID- 12598422
TI  - The cyclopentenone prostaglandin 15-deoxy-delta(12,14)- PGJ2 attenuates the
      development of colon injury caused by dinitrobenzene sulphonic acid in the rat.
AB  - 1. Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative
      stress, leukocyte infiltration, and increased expression of the adhesion
      molecules intercellular adhesion molecule 1 (ICAM-1) in the colon. Recent
      evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy
      delta(12,14)-PGJ(2) (15d- PGJ(2)) functions as an early anti-inflammatory signal.
      2. The aim of the present paper is to investigate the effects of 15d-PGJ(2) in
      rats subjected to experimental colitis. 3. Colitis was induced in rats by intra
      colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d-PGJ(2) was
      administered daily as intraperitoneal injection (20 or 40 microg kg(-1)). On day
      4, animals were sacrificed and tissues were taken for histological and
      biochemical analysis. 4. 15d-PGJ(2) significantly reduced the degree of
      haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d
      PGJ(2) also caused a substantial reduction of (i) the degree of colonic injury,
      (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in
      the tissue levels of malondialdehyde (MDA) and (iv) of the pro-inflammatory
      cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL
      1beta). 5. Furthermore, 15d-PGJ(2) reduced the increase in immunohistochemical
      staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and
      (iii) poly (ADP-ribose) polymerase (PARP), as well as (iv) the increased
      expression of ICAM-1 caused by DNBS in the colon. 6. Electrophoresis mobility
      shift assay (EMSA) of inflamed colon revealed that 15d- PGJ(2) also caused a
      substantial reduction of the activation of nuclear factor-kappaB (NF-kappaB).
      Furthermore, 15d-PGJ(2) stimulates the activation of heat shock protein 72
      (hsp72) in the inflamed colon, as assessed by Western blot analysis. 7. In
      conclusion, 15d-PGJ(2) reduces the development of experimental colitis.

PMID- 12598423
TI  - Spinal amino acid release and repeated withdrawal in spinal morphine tolerant
      rats.
AB  - 1. We used spinal microdialysis in awake rats to investigate whether the repeated
      withdrawal with naloxone during continuous spinal infusion of morphine would lead
      to a progressively greater spinal glutamate release and a more pronounced
      intrathecal tolerance. 2. Rats received lumbar intrathecal (IT) infusion of
      morphine (IT-M: 20 nmol microl(-1) h(-1)) or saline (IT-S: 1 microl h(-1))
      continuously for 3 days. Both groups were further subdivided to receive
      intraperitoneal (i.p.) injection of naloxone (IP-N: 0.6 mg kg(-1)) or saline (IP
      S: 3 ml kg(-1)) every 24 h after the beginning of IT infusion. Daily thermal
      escape latencies, withdrawal signs, the resting basal release of spinal amino
      acids before IP injection and the release immediately after the injection
      (evoked) were measured. 3. Rats receiving IT morphine showed a maximum increase
      in thermal escape latency on day 1, after which this value declined, with the
      fastest decline observed in IT morphine + IP naloxone group. On day 1, no
      significant difference was observed among groups in the resting basal release of
      amino acids. Rats in IT morphine + i.p. naloxone group displayed a progressive
      increase in this value. The release was not significantly altered in other
      groups. 4. For the IT-M + IP-N group, basal resting dialysate concentrations of
      Glu, Asp and Tau rose steadily over the 3-day infusion interval. No change in
      basal resting release was noted for any other treatment. 5. Evoked release (after
      i.p. naloxone) in IT-M animals displayed a progressive increase over the three
      repeated exposures. Evoked release did not change significantly in other
      treatment groups. 6. The degree of precipitated withdrawal significantly
      correlated with the increase in glutamate acutely evoked by i.p. injection. 7.
      The present results show that periodic transient withdrawal of spinal opiate
      agonist activity leads to a progressive increase in glutamate outflow and
      withdrawal signs, in a manner consistent with an enhanced development of spinal
      tolerance.

PMID- 12598424
TI  - CC chemokines induce P-selectin-dependent neutrophil rolling and recruitment in
      vivo: intermediary role of mast cells.
AB  - 1. Based on in vitro chemotaxis experiments, it is widely held that CC
      chemokines, such as macrophage inflammatory protein-1alpha (MIP-1alpha) and
      macrophage chemotactic protein-1 (MCP-1) mainly support lymphocyte trafficking.
      2. The objective of the present study was to examine the role of MIP-1alpha and
      MCP-1 in neutrophil recruitment in vivo by use of intravital microscopy of the
      mouse cremaster microcirculation. 3. MIP-1alpha and MCP-1 caused a dose-dependent
      increase in leukocyte rolling, adhesion and recruitment. Indeed, neutrophils
      comprised more than 85% of the leukocyte response to MIP-1alpha and MCP-1. An
      anti-P-selectin antibody reduced MIP-1alpha and MCP-1-provoked leukocyte rolling
      by more than 94%. Concomitantly, firm adhesion and extravasation of neutrophils
      in response to MIP-1alpha and MCP-1 challenge were significantly decreased by
      more than 78 and 84%, respectively. In contrast, an anti-E-selectin antibody had
      no influence on CC chemokine-induced neutrophil recruitment. 4. Flow cytometric
      analysis revealed that MIP-1alpha and MCP-1 had no effect on P-selectin
      expression on endothelial cells, suggesting that neutrophil recruitment elicited
      by CC chemokines in vivo is not mediated via a direct effect on the endothelium
      but rather via an indirect effect involving activation of an intermediary tissue
      cell. Indeed, it was found that MIP-1alpha-induced neutrophil accumulation was
      significantly decreased by 58% in mast cell-deficient mice. 5. These findings
      demonstrate that CC chemokines trigger P-selectin-dependent rolling and tissue
      recruitment of neutrophils via tissue mast cells in vivo and suggest that CC
      chemokines may also be important targets in neutrophil-mediated tissue damage in
      multicellular organs.

PMID- 12598428
TI  - Hiding in plain view.

PMID- 12598425
TI  - The ACh-induced contraction in rat aortas is mediated by the Cys Lt1 receptor via
      intracellular calcium mobilization in smooth muscle cells.
AB  - 1. Our previously published data indicate that an endogenously produced 5
      lipoxygenase metabolite can strongly contract isolated endothelium-preserved rat
      aortic strips when cyclo-oxygenase isoenzymes are inhibited. Therefore, we
      decided to investigate if cysteinyl-containing leukotrienes (Cys Lts) are
      involved in this endothelium-dependent contraction. 2. The isometric contraction
      of endothelium-preserved rat aortic strips was recorded in preparations
      preincubated with 5 microM indomethacin and precontracted with phenylephrine,
      adjusting resting tension at 0.7 g. Acetylcholine (ACh) contracted control
      strips. Montelukast and MK-571, selective type 1 Cys Lts receptor (Cys Lt(1))
      antagonists and the Cys Lt(1)/Cys Lt(2) (type 2 Cys Lts receptor) antagonist
      BAYu9773 dose-dependently prevented ACh-induced contraction, their IC(50)s being
      2.2, 3.1 and 7.9 nM respectively. The leukotriene B4 receptor antagonist U75302
      was far less potent (IC(50) 1.5 microM). 3. In rat aorta smooth muscle cells
      (RASMs), Western blot analysis showed the presence of Cys Lt(1) and Cys Lt(2)
      receptors, the Cys Lt(1) receptor being predominantly expressed. 4. In fura-2
      loaded RASMs, LTD4 (0.01-100 nM) and LTC4 (200-800 nM) dose-dependently increased
      intracellular calcium concentration ([Ca(2+)](i)). Montelukast (1-100 nM) reduced
      LTD4-induced [Ca(2+)](i) increase, its IC(50) being approximately 10 nM. BAY
      u9773 exhibited significantly low effectiveness. 5. LTD4 (10 nM) induced a
      redistribution of smooth muscle actin fibres throughout the cytoplasm as
      visualized by confocal microscopy. 6. In conclusion, Cys Lt(1) activation by
      endogenously produced Cys Lts, can contract rat aortas, while Cys Lt(2) only
      marginally influences aortic tone. Intracellularly, this effect is mediated by an
      increase in [Ca(2+)](i). Therefore, Cys Lts, by inducing vascular contraction,
      can contribute to systemic hypertension.

PMID- 12598429
TI  - Simultaneous bilateral cataract surgery.

PMID- 12598430
TI  - Amblyopia therapy.

PMID- 12598431
TI  - Public opinion on weekend and evening outpatient clinics.

PMID- 12598432
TI  - Utilities associated with diabetic retinopathy: results from a Canadian sample.
AB  - BACKGROUND/AIMS: To report patient based utilities, using the time trade-off
      technique, associated with visual loss secondary to diabetic retinopathy in a
      sample of Canadian patients. In addition, to compare these utility values with a
      sample collected in a similar manner in a tertiary care practice in the United
      States. METHODS: A cross sectional study of eligible patients with diabetic
      retinopathy presenting to a tertiary facility was performed. Demographic and
      clinical variables (including Snellen visual acuity), and utilities were
      collected both through chart review and standardised interviews with diabetic
      patients. RESULTS: 221 patients with diabetic retinopathy were eligible for this
      study and completed the interview. The mean age was 63.5 (SD 12.5) years, and
      48.4% were female. Over 35% of the sample had visual acuity in the affected eye
      of 6/60 or worse. The mean utility for the sample was 0.79 (SD 0.23). The mean
      utility from this sample did not differ significantly from that obtained from a
      series of patients with diabetic retinopathy who were referred to a tertiary
      facility in the United States (mean 0.77, SD 0.21, p=0.313). Our cross border
      comparison had a power of 95% to detect a difference in utility of 0.1 between
      the two groups. CONCLUSION: On average, Canadian patients with diabetic
      retinopathy were willing to trade off over 20% of their remaining lifespan in
      order to eliminate their ocular disease. The mean utility obtained from our
      sample of Canadian patients with diabetic retinopathy was not statistically
      different from that obtained from a similar sample of American patients.

PMID- 12598433
TI  - Childhood blindness in India: a population based perspective.
AB  - AIM: To estimate the prevalence and causes of blindness in children in the
      southern Indian state of Andhra Pradesh. METHODS: These data were obtained as
      part of two population based studies in which 6935 children <or=15 years of age
      participated. Blindness was defined as presenting distance visual acuity <6/60 in
      the better eye. RESULTS: The prevalence of childhood blindness was 0.17% (95%
      confidence interval 0.09 to 0.30). Treatable refractive error caused 33.3% of the
      blindness, followed by 16.6% due to preventable causes (8.3% each due to vitamin
      A deficiency and amblyopia after cataract surgery). The major causes of the
      remaining blindness included congenital eye anomalies (16.7%) and retinal
      degeneration (16.7%). CONCLUSION: In the context of Vision 2020, the priorities
      for action to reduce childhood blindness in India are refractive error, cataract
      related amblyopia, and corneal diseases.

PMID- 12598434
TI  - Sutureless cataract surgery with nucleus extraction: outcome of a prospective
      study in Nepal.
AB  - AIM: To report the short and medium term outcome of a prospective series of
      sutureless manual extracapsular cataract extractions (ECCE) at a high volume
      surgical centre in Nepal. METHODS: Cataract surgery was carried out, on eyes with
      no co-existing diseases, in 500 consecutive patients who were likely to return
      for follow up. The technique involved sclerocorneal tunnel, capsulotomy,
      hydrodissection, nucleus extraction with a bent needle tip hook, and posterior
      chamber intraocular lens (PC-IOL) implantation according to biometry findings.
      Surgical complications, visual acuity at discharge, 6 weeks, and 1 year follow
      up, and surgically induced astigmatism are reported. RESULTS: The uncorrected
      visual acuity at discharge was 6/18 or better in 76.8% of eyes, and declined to
      70.5% at 6 weeks' follow up, and 64.9% at 1 year. The best corrected visual
      acuity was 6/18 or better in 96.2% of eyes at 6 weeks and in 95.9% at 1 year.
      Poor visual outcome (<6/60) occurred in less than 2%. Intraoperative
      complications included 47 (9.4%) eyes with hyphaema, and one eye (0.2%) with
      posterior capsule rupture and vitreous in the anterior chamber. Surgery led to an
      increase in against the rule astigmatism, which was the major cause of
      uncorrected visual acuity less than 6/18. Six weeks postoperatively, 85.5% of
      eyes had against the rule astigmatism, with a mean induced cylinder of 1.41 D (SD
      0.8). There was a further small increase in against the rule astigmatism of 0.66
      D (SD 0.41) between 6 weeks and 1 year. The mean duration of surgery was 4
      minutes and the average cost of consumables, including the IOL, was less than
      $10. CONCLUSION: Rapid recovery of good vision can be achieved with sutureless
      manual ECCE at low cost in areas where there is a need for high volume cataract
      surgery. Further work is required to reduce significant postoperative
      astigmatism, which was the major cause of uncorrected acuity less than 6/18.

PMID- 12598435
TI  - Screening for primary angle closure in Mongolia: a randomised controlled trial to
      determine whether screening and prophylactic treatment will reduce the incidence
      of primary angle closure glaucoma in an east Asian population.
AB  - AIM: To describe the methods used and initial results of a prospective study
      designed to determine whether screening and prophylactic treatment will reduce
      the incidence of primary angle closure glaucoma (PACG) in Mongolia. METHODS: A
      total of 4725 individuals aged 50 years and above were recruited to the study and
      randomised to intervention or control groups. All subjects had non-mydriatic
      optic disc examination. The intervention arm had measurement of anterior chamber
      depth (ACD) by A-scan ultrasound and intraocular pressure (IOP) with Tonopen.
      Gonioscopy was performed on test positive cases (ACD <2.53 mm or IOP >or=24 mm Hg
      either eye). Those with occludable angles were offered laser iridotomy. Primary
      outcome will be incidence of PACG at 5 year follow up. RESULTS: Glaucoma was
      diagnosed in 128 (2.7%) subjects. Of the remaining 4597, 2293 were randomised to
      intervention. Intervention as allocated was received by 2280 (99.4%) individuals.
      160 (23.4%) of 685 test positive cases had occludable angles, of which 156 were
      treated with iridotomy. CONCLUSIONS: This trial is a further step in determining
      whether screening and prophylactic treatment for primary angle closure in east
      Asian populations will reduce the incidence of glaucoma.

PMID- 12598436
TI  - Retinal neovascular markers in retinopathy of prematurity: aetiological
      implications.
AB  - AIM: (1) To determine if expression of the blood-tissue barrier associated
      glucose transporter GLUT1 is preserved by the neovasculature of retinopathy of
      prematurity (ROP), in contrast with the reported loss of GLUT1 expression in
      preretinal vessels of proliferative diabetic retinopathy. (2) To compare the
      vascular immunophenotype of ROP to juvenile haemangioma, another perinatal
      neovascular disorder that has recently been shown to express placental type
      vascular antigens, including GLUT1 and Lewis Y antigen. METHODS: A retrospective
      case report was carried out. Immunoreactivities for GLUT1 and Lewis Y antigen
      were assessed in a human eye with stage 3 ROP and compared with those in a
      control (paediatric) eye. The presence or absence of endothelial GLUT1 and Lewis
      Y immunoreactivity was determined in preretinal and intraretinal vessels.
      RESULTS: Immunoreactivity was positive for GLUT1 and negative for Lewis Y in the
      intraretinal and preretinal neovasculature of the ROP affected eye and in the
      normal retinal vessels of the control eye. CONCLUSIONS: Retention of
      immunoreactivity for GLUT1 distinguishes ROP from proliferative diabetic
      retinopathy. Furthermore, absence of Lewis Y antigen co-expression distinguishes
      ROP from juvenile haemangioma, a perinatal form of GLUT1 positive
      neovascularisation that has recently been linked to placental vasculature.

PMID- 12598437
TI  - A technique for reconstruction of upper lid marginal defects.
AB  - BACKGROUND/AIMS: Reconstruction of large full thickness upper lid defects that
      cannot be closed directly often rely on utilising the lower lid. An example is
      the Cutler Beard procedure. A one stage technique for repair of large horizontal
      upper lid defects utilising local posterior and anterior lamella advancement
      flaps is described and the results reported. METHOD: Eight cases with upper lid
      defects repaired utilising this technique were reviewed retrospectively. The
      procedures were carried out by one surgeon. The upper lid lesions were removed
      under frozen section control. The mean follow up time was 35 months. RESULTS: All
      patients had a good cosmetic result. One patient had a recurrence of the upper
      lid lesion. Two patients complained of corneal irritation from lanugo hairs. The
      technique was modified to prevent this complication. CONCLUSIONS: Large upper lid
      marginal defects can be readily repaired using the technique described with local
      advancement flaps with no significant complications.

PMID- 12598438
TI  - Blindness: how to assess numbers and causes?
AB  - BACKGROUND: Traditionally, blindness surveys have modelled themselves on the
      "gold standard" of a census and examination of a whole population. Blindness,
      however, is a relatively rare condition even in badly affected communities;
      hence, large sample sizes are required to gain adequate estimates of prevalence,
      particularly by cause. METHODS: Three assessments of blindness prevalence and
      aetiology in the same communities are reported. One involved asking individuals
      questions concerning their visual status during a census (perceived visual
      status, PVD), one involved examination of all ostensibly visually disabled people
      presenting to a central point within each community (examination of the visually
      disabled, EVD), and the final assessment involved a gold standard examination of
      the whole population (whole community examination, WCE). RESULTS: In a population
      of 8139 the blindness prevalence was 2.7% PVS, 3.6% EVD, and 3.1% WCE. Attributed
      causes of blindness were not representative in the PVS except for cataract. The
      END yielded cause specific estimates not far from those found at WE except for a
      relative under-representation of glaucoma and optic atrophy. CONCLUSION: Since
      cataract is, by a significant margin, the most common cause of blindness in the
      world such a simple method as asking individuals if they are blind and what they
      believe to be the cause may yield adequate estimates of the problem for planning
      eye care strategies for this condition. Alternatively, an ophthalmologist
      visiting villages and examining allcomers for visual disability may provide
      reasonably accurate cause specific prevalence estimates without the expense of a
      major blindness survey.

PMID- 12598439
TI  - Bilateral same day phacoemulsification: 220 cases retrospectively reviewed.
AB  - BACKGROUND/AIMS: The relative frequency, basic patient data, results, and
      complications of planned same day bilateral phacoemulsification were studied from
      April 1999 to May 2001 at the Department of Ophthalmology, Linkoping University
      Hospital, Sweden. METHODS: Retrospective study of patient records (n=220)
      regarding preoperative and postoperative visual acuity, applied indications,
      concurrent disease, preoperative, peroperative, and postoperative complications,
      and number of unplanned postoperative visits. The monthly rate of bilateral
      phacoemulsification to all cataract procedures was monitored. RESULTS: Mean
      corrected preoperative visual acuity was 0.27 (worse eye) and 0.39 (better eye),
      and postoperatively (all eyes) 0.71. Visual acuity was 0.5 or better in 78% of
      eyes. Preoperative considerations included type of cataract, to avoid
      anisometropia, social circumstances, and concurrent eye disease. Reasons for
      unplanned postoperative visits included secondary cataract (n=10), iritis (n=6),
      corneal oedema (n=3), cortex in the anterior chamber (n=2), and unilateral
      endophthalmitis (n=2). During the study period, 10.5% of patients were operated
      upon bilaterally on the same day. CONCLUSIONS: Same day bilateral
      phacoemulsification was found to be a safe and cost effective way of rapidly
      rehabilitating selected cataract patients. The patient must be informed of the
      added potential risks as well as the benefits of the procedure.

PMID- 12598440
TI  - Differences in the management of amblyopia between European countries.
AB  - BACKGROUND: Amblyopia treatment is not standardised and differences between
      centres and countries have not been systematically investigated. This survey
      compares the different patterns of orthoptic treatment of amblyopia in the United
      Kingdom (UK) and three German speaking countries (GSC). METHODS: Questionnaires
      were sent to orthoptists in the UK and the GSC asking for their preferred choices
      of treatment of amblyopia between the ages of 6 months to 10 years. RESULTS: The
      following significant differences in management of amblyopia were found: (1) the
      number of hours of occlusion per week was higher in the GSC, p<0.0001, (2)
      orthoptists in the GSC treat amblyopia up to an older age. Orthoptists in the GSC
      and in the UK predicted similar treatment outcomes. CONCLUSION: Orthoptists in
      the GSC usually treat patients more intensively and for longer, while the
      prediction of visual outcome does not differ significantly between countries.
      These results highlight the lack of standardisation in the treatment of the
      various types of amblyopia.

PMID- 12598441
TI  - Effect of non-steroidal anti-inflammatory ophthalmic solution on intraocular
      pressure reduction by latanoprost.
AB  - AIM: To investigate the effects of a non-steroidal anti-inflammatory drug (NSAID)
      ophthalmic solution on latanoprost induced intraocular pressure (IOP) reduction
      using normal volunteers. METHODS: This study was conducted as a prospective and
      observer masked clinical trial. 13 normal volunteers were enrolled. After
      measurement of basal IOP and ophthalmic examination, latanoprost ophthalmic
      solution was initially administered to both eyes once daily. Four weeks later, an
      NSAID ophthalmic solution, sodium 2-amino-3-(4-bromobenzoyl) phenylacetate
      sesquihydrate (refer to bromfenac sodium hydrate), was co-administered to one
      randomly selected eye (NSAID group) twice daily for 2 weeks. The other eye was
      employed as a control (non-NSAID group). After withdrawal of the NSAID ophthalmic
      solution, latanoprost ophthalmic solution was continuously administered for
      another 2 weeks and was then withdrawn. After a 4 week washout, only bromfenac
      sodium hydrate ophthalmic solution was administered to the eyes of the NSAID
      group for 2 weeks. During the study period, ophthalmic examination, including IOP
      measurement was performed in an observer masked fashion. RESULTS: Before
      initiation of bromfenac sodium hydrate, baseline IOPs of the non-NSAID group and
      the NSAID group were 15.73 (SD 1.97) mm Hg and 15.86 (2.06) mm Hg, respectively
      (p=0.88). Although latanoprost ophthalmic solution significantly reduced IOP in
      both groups, co-administration of bromfenac sodium hydrate significantly
      inhibited latanoprost induced IOP reduction compared with the non-NSAID group.
      The IOPs of the non-NSAID and NSAID groups were 10.18 (1.17) mm Hg and 11.63
      (1.35) mm Hg with a 2 week co-administration, respectively (p <0.01). Withdrawal
      of bromfenac sodium hydrate ophthalmic solution diminished the difference between
      the two groups. Re-administration of bromfenac sodium ophthalmic solution only
      did not affect IOP. CONCLUSION: These results indicate that NSAID ophthalmic
      solution may interfere with IOP reduction by latanoprost ophthalmic solution in
      normal volunteers and that we should take this into account when treating
      patients with glaucoma using latanoprost ophthalmic solution.

PMID- 12598442
TI  - Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with
      primary congenital glaucoma.
AB  - AIM: To investigate the phenotypes associated with cytochrome P4501B1 gene
      (CYP1B1) mutations in Japanese patients with primary congenital glaucoma (PCG).
      METHODS: 66 Japanese patients with PCG were screened for sequence mutations in
      the CYP1B1 gene using single strand conformation polymorphism analysis followed
      by automated DNA sequencing. 11 cases had a CYP1B1 mutation in both alleles (the
      mutation group) and 21 cases did not have a CYP1B1 mutation (the "no mutation"
      group). The clinical features, such as age of onset, sex, intraocular pressure,
      and Descemet's membrane rupture, of the two groups were compared. RESULTS: The
      clinical symptoms and signs did not differ for the two groups. The mean age at
      onset was 1.7 months in the mutation group and 3.1 months in the no mutation
      group, and the male:female ratio was 6:5 in the mutation group and 19:2 in the no
      mutation group. Both of these differences were statistically significant.
      CONCLUSIONS: In clinically diagnosed cases of PCG, a subgroup shows a CYP1B1 gene
      mutation. Age at onset was earlier in PCG patients with CYP1B1 mutations than in
      patients without mutations. Women were more prevalent among patients with
      mutations than those without mutations.

PMID- 12598443
TI  - Influence of factor V Leiden on the development of neovascularisation secondary
      to central retinal vein occlusion.
AB  - AIMS: To investigate if the presence of factor V Leiden has an influence on the
      prognosis in central retinal vein occlusion (CRVO). METHODS: 166 patients with
      CRVO were studied retrospectively. They were tested for factor V Leiden using DNA
      analysis. The presence of the mutation was studied in correlation with the
      development of neovascular complications 1 year after the thrombotic event.
      RESULTS: 56 of 166 patients (34%) developed neovascular complications after 1
      year. In the patients who had the studied mutation 11 of 20 (55%) had developed
      neovascular complications after 1 year, compared to 45 of 146 patients (31%) in
      the group without factor V Leiden (p=0.04). CONCLUSION: The presence of factor V
      Leiden seems to enhance the risk of developing neovascular complications in CRVO.

PMID- 12598444
TI  - CNV subtype in first eyes predicts severity of ARM in fellow eyes.
AB  - AIM: To examine the relation between the type of choroidal neovascularisation
      (CNV) in the first eye and age related maculopathy (ARM) severity in the fellow
      eye. METHODS: Colour fundus photographs and fluorescein angiograms from 67
      subjects with a clinical diagnosis of CNV in one eye were scrutinised. CNV was
      classified as wholly classic, predominantly classic, minimally classic, or occult
      based on the proportion of classic leakage within the lesion. ARM changes in the
      fellow eye were assigned a severity stage using the system described by the
      Rotterdam Eye Study. Logistic regression analysis was employed to examine the
      association between CNV subtype and ARM stage. RESULTS: Of subjects with classic
      or predominantly classic CNV in the first eye 78% exhibited least no or early ARM
      features in the fellow eye. By contrast, 85% of subjects with minimally classic
      or occult CNV in the first eye exhibited more advanced ARM features in the fellow
      eye. Kruskall-Wallis one way ANOVA by ranks showed that this was highly
      significant (p = 0.002). Logistic regression analysis showed that as the
      proportion of occult CNV increased in the first eye, fellow eyes of subjects in
      this category were more likely to have been assigned to a higher ARM stage (p =
      0.019). The area occupied by the CNV in the first eye also influenced severity of
      ARM changes in the fellow eye. CONCLUSION: The type and extent of CNV in the
      first affected eye has a distinct relation to ARM severity in the fellow eye.
      Fellow eyes of subjects with minimally classic or occult CNV in the first
      affected eye show widespread ARM changes suggestive of retinal pigment epithelial
      dysfunction. These findings suggest that classic CNV may be focal disease while
      occult CNV is essentially a more widespread retinal pigment epithelial disorder.

PMID- 12598445
TI  - How big is the burden of visual loss caused by age related macular degeneration
      in the United Kingdom?
AB  - AIMS: To predict the burden of blindness, partial sight, and visual impairment
      (binocular visual acuity 6/18 or less) due to late stage age related macular
      degeneration (AMD) in the ageing population of the United Kingdom. METHODS: A
      systematic review, followed by a request for data, was used to establish a pooled
      prevalence of AMD and corresponding visual loss. Prevalence figures were applied
      to the UK population. Using UK population trends, the future burden of AMD over
      the coming decade was established. RESULTS: Pooled data from six studies showed
      that the prevalence of visual loss caused by AMD increased exponentially from the
      age of 70-85 years of age, with 3.5% (95% CI 3.0 to 4.1) having visual impairment
      beyond the age of 75 years. The authors estimate that there are currently 214 000
      (95% CI 151 000 to 310 000) with visual impairment caused by AMD (suitable for
      registration). This number is expected to increase to 239 000 (95% CI 168 000 to
      346 000) by the year 2011. Currently there are 172 000 (95% CI 106 000 to 279
      000) and 245 000 (95% CI 163 000 to 364 000) with geographical and neovascular
      AMD, respectively. CONCLUSIONS: Estimates of visual impairment agree with
      official statistics for the number registered partially sighted or blind, caused
      by AMD, and are well below other figures often cited. Although these estimates
      are associated with wide confidence intervals (CI) and a number of caveats, they
      represent the best available data, which can be used to guide health and social
      care provision for older people in the UK setting. Implications for low vision
      services are outlined.

PMID- 12598446
TI  - Vitrectomy with silicone oil infusion in severe diabetic retinopathy.
AB  - AIMS: To determine the results of pars plana vitrectomy (PPV) and silicone oil
      infusion (SOI) in severe proliferative diabetic retinopathy (PDR). METHODS: The
      records of 23 eyes (21 patients: 12 males, nine females) with PDR who had
      undergone PPV and SOI were reviewed retrospectively. RESULTS: Average follow up
      was 5.4 months (range 1-25). Surgical indications were tractional retinal
      detachment (TRD) (17.4%), traction-rhegmatogenous retinal detachment (TRRD)
      (8.7%), TRD with vitreous haemorrhage (VH) (48%), TRD with neovascular glaucoma
      (NVG) (8.6%), TRD with fibrinoid syndrome (FS) (17.3%). With one operation, the
      retinal reattachment rate was 17/23 (74%). Among these 23 eyes, 11 (48%) had
      previously failed vitrectomy, and the retina was attached in 8/11 (73%) with a
      single procedure. With additional surgery employing PPV and SOI, the final
      reattachment rate was 20/23 (87%). The only cases with intraocular pressure <5 mm
      Hg had retinal detachment. Postoperative visual acuity (VA) improved in 10 eyes
      (44%), was unchanged in three (12%), and decreased in 10 eyes (44%). CONCLUSION:
      SO tamponade is useful in severely diseased eyes with PDR, even in the presence
      of rubeosis iridis (RI) and NVG, FS, or in cases with previously failed
      vitrectomy, especially in the presence of RI.

PMID- 12598447
TI  - Acutance, an objective measure of retinal nerve fibre image clarity.
AB  - BACKGROUND/AIMS: The interpretation of high contrast retinal nerve fibre layer
      (RNFL) images in glaucoma can be confounded by the presence of image blur; it can
      be difficult to discern diffuse axon loss in a poor quality image. One solution
      is to provide an objective measure of the image quality based on features in the
      image other than the RNFL. In this study the authors have developed an objective
      method to quantify the clarity of RNFL images, comparing it with a subjective
      image grading system. METHODS: Digitally acquired, monochrome retinal images were
      taken from 58 eyes (one image per eye) with a Topcon 50 IX retinal camera. Image
      resolution was 1320 x 1032 pixels at 8 bits per pixel. Image sharpness was
      subjectively graded by two masked experienced observers on a scale 1 to 5
      relative to a reference set of RNFL images. Software algorithms were developed
      using Matlab (5.2) to calculate the acutance, an objective measure of the
      physical characteristics that underlie the subjective impression of sharpness in
      an image. RESULTS: Acutance values could be calculated for all the images. The
      Pearson correlation coefficients of the log of the acutance for each image and
      the subjective grades of observer 1 and observer 2 were 0.90 (p<0.001, n=58) and
      0.84 (p<0.001, n=58) respectively. CONCLUSIONS: These data suggest that acutance
      may provide a useful objective measure of image quality, which correlates well
      with the subjective impression of the digital retinal image sharpness. Objective
      measures of image quality should help in the discrimination of diffuse retinal
      nerve fibre loss from image blur in patients with diffuse glaucomatous damage.

PMID- 12598448
TI  - Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.
AB  - AIM: The role of neoadjuvant chemotherapy was studied when first line enucleation
      cannot be safely performed in unilateral extensive retinoblastoma (major
      buphthalmia or radiologically detectable optic nerve involvement). METHODS: Six
      patients, referred for unilateral retinoblastoma, presented with major
      buphthalmia (two) or optic nerve invasion (four): they were treated by
      neoadjuvant chemotherapy using etoposide and carboplatin. RESULTS: Good tumour
      response was observed in the two patients with buphthalmia and in three of four
      cases with optic nerve involvement. Meningeal progressive disease was observed in
      the last patient. The five patients without disease progression were then
      operated on: anterior enucleation in the patients with buphthalmia and
      enucleation via a double neurosurgical and ophthalmological approach with
      prechiasmatic optic nerve section in the other three cases. Postoperative
      chemotherapy was performed in these five patients. Local radiotherapy to the
      chiasmatic region and posterior part of the optic canal was necessary in only one
      patient. The non-operated patient died with disease progression 6 months after
      the diagnosis. The other five patients are alive with a follow up of 12, 15, 21,
      36, and 40 months after stopping treatment. CONCLUSION: Neoadjuvant chemotherapy
      can be useful in extensive unilateral retinoblastoma with buphthalmia and/or
      radiological optic nerve invasion at diagnosis.

PMID- 12598449
TI  - High resolution magnetic resonance imaging of retinoblastoma.
AB  - BACKGROUND/AIMS: Diagnosis of retinoblastoma is mainly based on indirect
      ophthalmoscopy, but additional imaging techniques are indispensable for the
      staging of the disease. A new high resolution magnetic resonance imaging (MRI)
      technique for the examination of the eye was evaluated. A new surface coil with a
      diameter of 5 cm allows a field of view of 60 mm with an in-plane resolution of
      0.8 mm. We compared preoperative MRI scans with the histology after enucleation
      in 21 cases of retinoblastoma. Parameters studied were appearance of
      retinoblastoma, choroidal and scleral infiltration, extraocular extension, optic
      nerve infiltration, and vitreous seeding. RESULTS: All retinoblastomas could be
      visualised as hypointense to vitreous on T2 weighted images and slightly
      hyperintense to vitreous on plain T1 weighted images with a moderate enhancement
      after contrast application. Histology revealed seven cases with infiltration of
      the optic disc or optic nerve. Preoperative MRI scans depict juxtapapillary
      tumour masses, but it was impossible to differentiate between a juxtapapillary
      retinoblastoma, a prelaminar infiltration of the optic disc, or a just
      postlaminar optic nerve infiltration. In five of 14 cases with a proved tumour
      infiltration of the choroid, MRI scans showed an inhomogeneous contrast
      enhancement of the choroid in enhanced T1 weighted sequences beneath the
      retinoblastoma. Whether this sign is specific for a choroidal infiltration or is
      just an artefact remains unclear. High resolution MRI scans did not allow the
      exclusion of this form of intraocular tumour extension. All nine cases with
      proved vitreous seeding were not detected by MRI scans. None of these cases
      showed scleral infiltration or orbital tumour extension. Therefore, it is not
      possible to judge the rank of this technique in detecting orbital tumour growth.
      CONCLUSION: The new MRI technique is of limited value in visualisation of
      prelaminar or postlaminar infiltration of the optic nerve. Advanced choroidal
      infiltration might be visualised by contrast enhanced T1 weighted MRI scans, but
      the available spatial resolution did not allow the exclusion this critical form
      of tumour growth by MRI scans. Nevertheless, high resolution MRI with the new
      surface coil has superior contrast and spatial resolution compared to computed
      tomograph (CT) or other available imaging techniques. MRI cannot replace CT in
      detecting tumour calcification but with increasing experience with this new
      technique it should be possible to renounce CT scans in the majority of cases of
      retinoblastoma.

PMID- 12598451
TI  - Utility values and myopia in teenage school students.
AB  - AIM: To ascertain the utility values of myopic teenage students in Singapore.
      METHODS: Children (n=699) aged 15-18 years with myopia (spherical equivalent (SE)
      at least -0.5 dioptres (D)) in two high schools in Singapore were recruited.
      Information on time trade-off (years of life willing to sacrifice for treatment
      of myopia) and standard gamble for blindness (risk of blindness from therapy
      willing to sacrifice for treatment of myopia) utility values, demographic, and
      socioeconomic status data were obtained. RESULTS: The time trade-off and standard
      gamble for blindness utility values were 0.93 (95% confidence interval (CI) 0.93
      to 0.94) and 0.85 (95% CI 0.84 to 0.86), respectively. Children with presenting
      better eye logMAR visual acuity >0.3 had lower time trade-off utility values
      (mean 0.92 versus mean 0.94), after adjusting for race and sex. There were dose
      response relations between standard gamble for blindness values and total family
      income, as well as both utility values and educational stream (all p values for
      trend <0.01), after controlling for the same factors. CONCLUSION: The utility
      values in myopic students were higher for teenagers with better presenting visual
      acuity, children who wore spectacles or contact lenses, higher total family
      income, more "academic" schooling stream, and who were non-Muslims.

PMID- 12598450
TI  - The familial contribution to non-syndromic ocular coloboma in south India.
AB  - AIMS: To identify the proportion of familial cases of isolated ocular
      colobomatous malformations in a case series from south India. METHODS: Children
      with ocular coloboma without systemic features were recruited from multiple
      sources in Andhra Pradesh, India. Their families were traced, pedigrees drawn,
      and family members examined. RESULTS: 56 probands, 25 females (44.6%) and 31
      males (57.4%) with a colobomatous malformation were identified. In 12 cases
      (21.4%) another family member was affected. The risk to siblings was 3.8%. The
      parents were consanguineous in 25 cases (44.6%). CONCLUSIONS: 21.4% of cases of
      isolated ocular coloboma in this highly consanguineous population of south India
      were familial, with both autosomal dominant and autosomal recessive mechanisms
      likely in different families.

PMID- 12598452
TI  - Mechanisms of staurosporine induced apoptosis in a human corneal endothelial cell
      line.
AB  - BACKGROUND: Apoptosis very probably plays a key part in endothelial cell loss
      during corneal storage in organ culture as well as hypothermic storage. However,
      the mechanisms underlying endothelial apoptosis are poorly understood. The
      response of a human corneal endothelial cell (HCEC) line to staurosporine, a
      known inducer of apoptosis, was investigated to gain insights into the
      intracellular modulators that participate in endothelial cell death. METHODS:
      Immortalised HCECs were studied after 3, 6, 12, and 24 hours of incubation with
      0.2 micro M staurosporine. Cell shedding was monitored. Hoechst 33342 fluorescent
      DNA staining combined with propidium iodide was used for apoptosis/necrosis
      quantification and morphological examination. The caspase-3 active form was
      assessed using western blot, proteolytic activity detection, and
      immunocytochemistry. The cleaved form of poly(ADP-ribose) polymerase (PARP) was
      assessed using immunocytochemistry and western blot. The ultrastructural features
      of cells were screened after 12 hours with staurosporine or vehicle. RESULTS: The
      specific apoptotic nature of staurosporine induced HCEC death was confirmed. The
      ultrastructural features of staurosporine treated cells were typical of
      apoptosis. HCEC shedding and DNA condensation increased with time. Caspase-3
      activity was detected as early as 3 hours after exposure with staurosporine,
      peaking at 12 hours of incubation. The presence of cleaved PARP after 3 hours
      confirmed caspase-3 activation. CONCLUSIONS: These data suggest strongly that
      HCEC cell death induced by staurosporine is apoptosis. The main consequence of
      HCEC apoptosis is shedding. Staurosporine induced apoptosis of endothelial cells
      involves activation of caspase-3, and could be a useful model to study strategies
      of cell death inhibition.

PMID- 12598454
TI  - Hyaluronan synthase in trabecular meshwork cells.
AB  - BACKGROUND/AIMS: Hyaluronan is present in the trabecular meshwork where it is
      involved in the pathophysiology of aqueous outflow environment. In this study,
      the expression and regulation of hyaluronan synthase (HAS), which is the enzyme
      synthesising hyaluronan, in trabecular meshwork cells were investigated. METHODS:
      Cultured bovine trabecular meshwork cells (BTMCs) were used. HAS expression in
      BTMCs was examined by RT-PCR. The effects of transforming growth factor beta (TGF
      beta) and platelet derived growth factor BB (PDGF-BB) on HAS expression in BTMCs
      were examined by quantitative RT-PCR. The HAS2 expression by TGF-beta and PDGF-BB
      at the protein level was also confirmed immunohistochemically. The production of
      hyaluronan from BTMCs was detected by high performance liquid chromatography
      (HPLC). RESULTS: Three HAS isoforms were expressed in BTMCs at the mRNA level.
      Among HAS isoforms, only the expression of HAS2 mRNA was increased by the
      administration of TGF-beta or PDGF-BB. HAS2 upregulation by these growth factors
      was also confirmed at the protein level. Further, hyaluronan production from
      BTMCs was stimulated by TGF-beta or PDGF-BB. CONCLUSION: Expression of HAS in
      trabecular meshwork may maintain the hyaluronan content in the aqueous outflow
      pathway. Its production is regulated by TGF-beta and PDGF-BB. The regulation of
      the expression of HAS in trabecular meshwork might be useful for modulating the
      aqueous outflow environment.

PMID- 12598456
TI  - Ophthalmodynamometric estimation of cerebrospinal fluid pressure in pseudotumour
      cerebri.

PMID- 12598453
TI  - 8-Isoprostaglandin F2a and ascorbic acid concentration in the aqueous humour of
      patients with exfoliation syndrome.
AB  - BACKGROUND/AIMS: The authors investigated the concentrations of 8
      isoprostaglandin F(2a), a marker of oxidative stress in vivo, and ascorbic acid,
      a protectant against oxidative damage, in the aqueous humour of patients with
      exfoliation syndrome (XFS) and cataract and compared the results with those in
      age matched patients with cataract, but without XFS, to determine whether XFS is
      associated with increased oxidative stress. METHODS: Aqueous humour was aspirated
      at the beginning of phacoemulsification cataract surgery from 27 eyes of 27
      cataract patients with XFS and 27 eyes of 27 age matched cataract patients
      without XFS. 8-Isoprostaglandin F(2a)concentration in the aqueous was determined
      with a commercial immunoassay; ascorbic acid concentration was measured with a
      microplate assay method. RESULTS: The mean concentration of 8-isoprostaglandin
      F(2a)in the aqueous from patients with XFS (2429 (SD 2940) pg/ml; range 400-10500
      pg/ml) was significantly higher than that measured in the aqueous of age matched
      control patients (529.1 (226.8) pg/ml; range 325-1000 pg/ml); (p = 0.0028).
      Furthermore, mean ascorbic acid concentration in XFS patients (0.75 (0.39) mM;
      range 0.28-1.70 mM) was significantly lower than that found in control patients
      (1.19 (0.47) mM; range 0.53-2.4 mM); (p = 0.0005). There was a reverse
      correlation between 8-isoprostaglandin F(2a)and ascorbic acid concentration.
      CONCLUSION: 8-Isoprostaglandin F(2a)was significantly increased in the aqueous of
      patients with XFS, and ascorbic acid was decreased, providing evidence of a role
      for free radical induced oxidative damage in the pathobiology of XFS.

PMID- 12598455
TI  - Intravitreal injection of triamcinolone acetonide as treatment for chronic
      uveitis.

PMID- 12598457
TI  - Treatment of atopic blepharitis by controlling eyelid skin water retention
      ability with ceramide gel application.

PMID- 12598458
TI  - Morning glory disc anomaly: an atypical case.

PMID- 12598459
TI  - An unusual tumour of the lacrimal gland.

PMID- 12598460
TI  - Idiopathic anterior hyaloid vessels.

PMID- 12598461
TI  - Paravertebral primitive neuroectodermal tumour presenting with Horner's syndrome.

PMID- 12598462
TI  - Iris pigment epithelial cyst induced by topical administration of latanoprost.

PMID- 12598463
TI  - Association of keratoconus and Avellino corneal dystrophy.

PMID- 12598464
TI  - Presence of vitronectin in neovascularised cornea of patient with gelatinous drop
      like dystrophy.

PMID- 12598465
TI  - Factor XII deficiency and recurrent sixth nerve palsy.

PMID- 12598466
TI  - Unilateral proptosis: the role of medical history.

PMID- 12598467
TI  - Unusual presentation of cat scratch disease in HIV+ patient.

PMID- 12598468
TI  - Simultaneous translocation of the macula and underlying retinal pigment
      epithelium during macular translocation surgery in a patient with long standing
      myopic neovascular maculopathy.

PMID- 12598469
TI  - Fungal and bacterial chronic endophthalmitis following cataract surgery.

PMID- 12598470
TI  - Surgical performance for specialties undertaking temporal artery biopsies: who
      should perform them?

PMID- 12598471
TI  - Trabeculectomy augmented with antimetabolites with a viscocanalostomy technique
      for the management of open angle glaucoma.

PMID- 12598472
TI  - Major complications of endoscopic sinus surgery: a comment.

PMID- 12598473
TI  - Management of age related macular degeneration: still room for improvement.

PMID- 12598474
TI  - Standardised clinical photography in ophthalmic plastic surgery.

PMID- 12598475
TI  - Argon laser and trichiasis.

PMID- 12598476
TI  - Mechanism of ophthalmic artery occlusion following pars plana vitrectomy.

PMID- 12598477
TI  - Dynamics of corneal endothelial cell death in organ culture.

PMID- 12598478
TI  - Entonox as an analgesic agent.

PMID- 12598480
TI  - Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated
      by PAF and LTB4.
AB  - Systemic hypoxia produces a rapid microvascular inflammatory response
      characterized by increased reactive oxygen species (ROS) levels, leukocyte
      endothelial adherence and emigration, and increased vascular permeability. The
      lipid inflammatory mediator leukotriene B(4) (LTB(4)) is involved in the early
      hypoxia-induced responses (ROS generation and leukocyte adherence). Whether other
      lipid inflammatory mediators participate in this phenomenon is not known. The
      objective of these experiments was to study the role of platelet-activating
      factor (PAF) in the microvascular inflammatory response to hypoxia and its
      potential interactions with LTB(4) in this response. Intravital microscopy was
      used to examine mesenteric venules of anesthetized rats. We found that WEB-2086,
      a PAF receptor antagonist, completely prevented the increase in ROS levels and
      leukocyte adherence during a brief reduction in inspired Po(2) to anesthetized
      rats; administration of either WEB-2086 or the LTB(4) antagonist LTB(4)-DMA
      attenuated leukocyte emigration and the increase in vascular permeability to the
      same extent during prolonged systemic hypoxia in conscious rats. Furthermore, no
      additive effect was observed in either response when both antagonists were
      administered simultaneously. This study demonstrates a role for PAF in the rapid
      microvascular inflammatory response to hypoxia, as well as contributions of PAF
      and LTB(4) to the slowly developing responses observed during sustained hypoxia.
      The incomplete blockade of the hypoxia-induced increases in vascular permeability
      and leukocyte emigration by combined administration of both antagonists indicates
      that factors in addition to LTB(4) and PAF participate in these phenomena.

PMID- 12598481
TI  - One- and two-year change in body composition as measured by DXA in a population
      based cohort of older men and women.
AB  - Changing body composition has been suggested as a pathway to explain age-related
      functional decline. No data are available on the expected changes in body
      composition as measured by dual-energy X-ray absorptiometry (DXA) in a population
      based cohort of older persons. Body composition data at baseline, 1-yr follow-up,
      and 2-yr follow-up was measured by DXA in 2,040 well-functioning black and white
      men and women aged 70-79 yr, participants of the Health, Aging, and Body
      Composition Study. After 2 yr, a small decline in total body mass was observed
      (men: -0.3%, women: -0.4%). Among men, fat-free mass and appendicular lean soft
      tissue mass (ALST) decreased by -1.1 and -0.8%, respectively, which was masked by
      a simultaneous increase in total fat mass (+2.0%). Among women, a decline in fat
      free mass was observed after 2 yr only (-0.6%) with no change in ALST and body
      fat mass. After 2 yr, the decline in ALST was greater in blacks than whites.
      Change in total body mass was associated with change in ALST (r = +0.58 to +0.70;
      P < 0.0001). Among participants who lost total body mass, men lost relatively
      more ALST than women, and blacks lost relatively more ALST than whites. In
      conclusion, the mean change in body composition after a 1- to 2-yr follow-up was
      1-2% with a high interindividual variability. Loss of ALST was greater in men
      compared with women, and greater in blacks compared with whites, suggesting that
      men and blacks may be more prone to muscle loss.

PMID- 12598482
TI  - Addition of inspiratory resistance increases the amplitude of the slow component
      of O2 uptake kinetics.
AB  - The contribution of respiratory muscle work to the development of the O(2)
      consumption (Vo(2)) slow component is a point of controversy because it has been
      shown that the increased ventilation in hypoxia is not associated with a
      concomitant increase in Vo(2) slow component. The first purpose of this study was
      thus to test the hypothesis of a direct relationship between respiratory muscle
      work and Vo(2) slow component by manipulating inspiratory resistance. Because the
      conditions for a Vo(2) slow component specific to respiratory muscle can be
      reached during intense exercise, the second purpose was to determine whether
      respiratory muscles behave like limb muscles during heavy exercise. Ten trained
      subjects performed two 8-min constant-load heavy cycling exercises with and
      without a threshold valve in random order. Vo(2) was measured breath by breath by
      using a fast gas exchange analyzer, and the Vo(2) response was modeled after
      removal of the cardiodynamic phase by using two monoexponential functions. As
      anticipated, when total work was slightly increased with loaded inspiratory
      resistance, slight increases in base Vo(2), the primary phase amplitude, and peak
      Vo(2) were noted (14.2%, P < 0.01; 3.5%, P > 0.05; and 8.3%, P < 0.01,
      respectively). The bootstrap method revealed small coefficients of variation for
      the model parameter, including the slow-component amplitude and delay (15 and
      19%, respectively), indicating an accurate determination for this critical
      parameter. The amplitude of the Vo(2) slow component displayed a 27% increase
      from 8.1 +/- 3.6 to 10.3 +/- 3.4 ml. min(-1). kg(-1) (P < 0.01) with the addition
      of inspiratory resistance. Taken together, this increase and the lack of any
      differences in minute volume and ventilatory parameters between the two
      experimental conditions suggest the occurrence of a Vo(2) slow component specific
      to the respiratory muscles in loaded condition.

PMID- 12598483
TI  - Prolonged head-down tilt exposure reduces maximal cutaneous vasodilator and
      sweating capacity in humans.
AB  - Cutaneous vasodilation and sweat rate are reduced during a thermal challenge
      after simulated and actual microgravity exposure. The effects of microgravity
      exposure on cutaneous vasodilator capacity and on sweat gland function are
      unknown. The purpose of this study was to test the hypothesis that simulated
      microgravity exposure, using the 6 degrees head-down tilt (HDT) bed rest model,
      reduces maximal forearm cutaneous vascular conductance (FVC) and sweat gland
      function and that exercise during HDT preserves these responses. To test these
      hypotheses, 20 subjects were exposed to 14 days of strict HDT bed rest. Twelve of
      those subjects exercised (supine cycle ergometry) at 75% of pre-bed rest heart
      rate maximum for 90 min/day throughout HDT bed rest. Before and after HDT bed
      rest, maximal FVC was measured, via plethysmography, by heating the entire
      forearm to 42 degrees C for 45 min. Sweat gland function was assessed by
      administering 1 x 10(-6) to 2 M acetylcholine (9 doses) via intradermal
      microdialysis while simultaneously monitoring sweat rate over the microdialysis
      membranes. In the nonexercise group, maximal FVC and maximal stimulated sweat
      rate were significantly reduced after HDT bed rest. In contrast, these responses
      were unchanged in the exercise group. These data suggest that 14 days of
      simulated microgravity exposure, using the HDT bed rest model, reduces cutaneous
      vasodilator and sweating capacity, whereas aerobic exercise training during HDT
      bed rest preserves these responses.

PMID- 12598484
TI  - Assessment of upper airway stabilizing forces with the use of phrenic nerve
      stimulation in conscious humans.
AB  - Phrenic nerve stimulation (PNS) applied at end-expiration allows the
      investigation of passive upper airway (UA) dynamic during wakefulness. Assuming
      that phasic UA dilating/stabilizing forces should modify the UA properties when
      twitches are applied during inspiration, we compared the UA dynamic responses to
      expiratory and inspiratory twitches (2 s and 200 ms after expiratory and
      inspiratory onset, respectively) in nine men (mean age 28 yr). This procedure was
      repeated with a 2-cm mouth opening provided with a closed mouthpiece. The
      percentage of flow-limited (FL) twitches was significantly higher when PNS was
      realized during expiration than during inspiration. Maximal inspiratory flow
      (Vi(max)) of FL twitches was significantly higher for inspiratory twitches (1,383
      +/- 42 and 1,185 +/- 40 ml/s). With mouth aperture, Vi(max) decreased with an
      increase in the corresponding pharyngeal resistance values, and the percentage of
      twitch with a FL regimen increased but only for inspiratory twitches. We conclude
      that 1) UA dynamics are significantly influenced by the inspiratory/expiratory
      timing at which PNS is applied, 2) the improvement in UA dynamic properties
      observed from expiratory to inspiratory PNS characterizes the overall inspiratory
      stabilizing effects, and 3) mouth aperture alters the stability of UA structures
      during inspiration.

PMID- 12598485
TI  - Small airway morphology and lung function in the transition from normality to
      chronic airway obstruction.
AB  - This study investigated the relationships between pathological changes in small
      airways (<6 mm perimeter) and lung function in 22 nonasthmatic subjects (20
      smokers) undergoing lung resection for peripheral lesions. Preoperative pulmonary
      function tests revealed airway obstruction [ratio of forced expiratory volume in
      1 s to forced vital capacity (FEV1/FVC) < 70%] in 12 subjects and normal lung
      function in 10. When all subjects were considered together, total airway wall
      thickness was significantly correlated with FEV1/FVC (r2 = 0.25), reactivity to
      methacholine (r2 = 0.26), and slope of linear regression of FVC against FEV1
      values recorded during the methacholine challenge (r2 = 0.56). Loss of
      peribronchiolar alveolar attachments was significantly associated (r2 = 0.25)
      with a bronchoconstrictor effect of deep inhalation, as assessed from a maximal
      to-partial expiratory flow ratio <1, but not with airway responses to
      methacholine. No significant correlation was found between airway smooth muscle
      thickness and lung function measurements. In conclusion, this study suggests that
      thickening of the airway wall is a major mechanism for airway closure, whereas
      loss of airway-to-lung interdependence may contribute to the bronchoconstrictor
      effect of deep inhalation in the transition from normal lung function to airway
      obstruction in nonasthmatic smokers.

PMID- 12598486
TI  - Effects of physical training on cortical bone at midtibia assessed by peripheral
      QCT.
AB  - Effects of long-term exercise on volumetric bone mineral density (vBMD), bone
      mineral content, bone geometric properties, and the strength indexes of bone were
      examined in a cross-sectional study of athletes and controls. Tibias of 25
      jumpers (13 women), 30 swimmers (15 women), and 25 controls (15 women), aged 18
      23 yr, were scanned at midsite by using peripheral quantitative computed
      tomography. The cortical vBMD of female athletes was lower than that of the
      controls (2.00 +/- 0.05, 1.90 +/- 0.08, and 1.92 +/- 0.12 g/cm3, respectively,
      for controls, swimmers, and jumpers). On the other hand, periosteal areas of male
      jumpers and female athletes were greater than that of controls (460 +/- 50, 483
      +/- 46, and 512 +/- 55 mm2, respectively, for male controls, swimmers, and
      jumpers, and 283 +/- 52, 341 +/- 73, and 378 +/- 75 mm2, respectively, for female
      controls, swimmers, and jumpers). The endocortical area of female swimmers was
      greater than that of controls (103 +/- 29, 148 +/- 52, and 135 +/- 54 mm2,
      respectively, for controls, swimmers, and jumpers). The polar moment of inertia
      and strength strain index of male jumpers and female athletes were significantly
      greater than those of controls, except for the difference in strength strain
      index between male jumpers and controls. We conclude that the improvement of
      mechanical properties of young adult bone in response to long-term exercise is
      related to geometric adaptation and not to vBMD.

PMID- 12598487
TI  - Muscle temperature transients before, during, and after exercise measured using
      an intramuscular multisensor probe.
AB  - Seven subjects (1 woman) performed an incremental isotonic test on a Kin-Com
      isokinetic apparatus to determine their maximal oxygen consumption during
      bilateral knee extensions (Vo(2 sp)). A multisensor thermal probe was inserted
      into the left vastus medialis (middiaphysis) under ultrasound guidance. The
      deepest sensor (tip) was located approximately 10 mm from the femur and deep
      femoral artery (T(mu 10)), with additional sensors located 15 (T(mu 25)) and 30
      mm (T(mu 40)) from the tip. Esophageal temperature (T(es)) was measured as an
      index of core temperature. Subjects rested in an upright seated position for 60
      min in an ambient condition of 22 degrees C. They then performed 15 min of
      isolated bilateral knee extensions (60% of Vo(2 sp)) on a Kin-Com, followed by 60
      min of recovery. Resting T(es) was 36.80 degrees C, whereas T(mu 10), T(mu 25),
      and T(mu 40) were 36.14, 35.86, and 35.01 degrees C, respectively. Exercise
      resulted in a T(es) increase of 0.55 degrees C above preexercise resting, whereas
      muscle temperature of the exercising leg increased by 2.00, 2.37, and 3.20
      degrees C for T(mu 10), T(mu 25), and T(mu 40), respectively. Postexercise T(es)
      showed a rapid decrease followed by a prolonged sustained elevation approximately
      0.3 degrees C above resting. Muscle temperature decreased gradually over the
      course of recovery, with values remaining significantly elevated by 0.92, 1.05,
      and 1.77 degrees C for T(mu 10), T(mu 25), and T(mu 40), respectively, at end of
      recovery (P < 0.05). These results suggest that the transfer of residual heat
      from previously active musculature may contribute to the sustained elevation in
      postexercise T(es).

PMID- 12598488
TI  - Cardiovascular responses to apneic facial immersion during altered cardiac
      filling.
AB  - The hypothesis that reduced cardiac filling, as a result of lower body negative
      pressure (LBNP) and postexercise hypotension (PEH), would attenuate the reflex
      changes to heart rate (HR), skin blood flow (SkBF), and mean arterial pressure
      (MAP) normally induced by facial immersion was tested. The purpose of this study
      was to investigate the cardiovascular control mechanisms associated with apneic
      facial immersion during different cardiovascular challenges. Six subjects
      randomly performed 30-s apneic facial immersions in 6.0 +/- 1.2 degrees C water
      under the following conditions: 1) -20 mmHg LBNP, 2) +40 mmHg lower body positive
      pressure (LBPP), 3) during a period of PEH, and 4) normal resting (control).
      Measurements included SkBF at one acral (distal phalanx of the thumb) and one
      nonacral region of skin (ventral forearm), HR, and MAP. Facial immersion reduced
      HR and SkBF at both sites and increased MAP under all conditions (P < 0.05).
      Reduced cardiac filling during LBNP and PEH significantly attenuated the absolute
      HR nadir observed during the control immersion (P < 0.05). The LBPP condition did
      not result in a lower HR nadir than control but did result in a nadir
      significantly lower than that of the LBNP and PEH conditions (P < 0.05). No
      differences were observed in either SkBF or MAP between conditions; however, the
      magnitude of SkBF reduction was greater at the acral site than at the nonacral
      site for all conditions (P < 0.05). These results suggest that the cardiac
      parasympathetic response during facial immersion can be attenuated when cardiac
      filling is compromised.

PMID- 12598489
TI  - Dissociation between skeletal muscle microvascular PO2 and hypoxia-induced
      microvascular inflammation.
AB  - Systemic hypoxia (SHx) produces microvascular inflammation in mesenteric,
      cremasteric, and pial microcirculations. In anesthetized rats, SHx lowers
      arterial blood pressure (MABP), which may alter microvascular blood flow and
      microvascular Po(2) (Pm(O(2))) and influence SHx-induced leukocyte-endothelial
      adherence (LEA). These experiments attempted to determine the individual
      contributions of the decreases in Pm(O(2)), venular blood flow and shear rate,
      and MABP to the hypoxia-induced increase in LEA. Cremaster microcirculation of
      anesthetized rats was visualized by intravital microscopy. Pm(O(2)) was measured
      by a phosphorescence-quenching method. SHx [inspired Po(2) of 70 Torr for 10 min,
      MABP of 65 +/- 3 mmHg, arterial Po(2) (Pa(O(2))) of 33 +/- 1 Torr] and cremaster
      ischemia (MABP of 111 +/- 7 mmHg, Pa(O(2)) of 86 +/- 3 Torr) produced similar
      Pm(O(2)): 7 +/- 2 and 6 +/- 2 Torr, respectively. However, LEA increased only in
      SHx (1.9 +/- 0.9 vs. 11.2 +/- 1.1 leukocytes/100 microm, control vs. SHx, P <
      0.05). Phentolamine-induced hypotension (MABP of 55 +/- 4 mmHg) in normoxia
      lowered Pm(O(2)) to 26 +/- 6 Torr but did not increase LEA. Cremaster
      equilibration with 95% N(2)-5% CO(2) during air breathing (Pa(O(2)) of 80 +/- 1
      Torr) lowered Pm(O(2)) to 6 +/- 1 Torr but did not increase LEA. On the other
      hand, when cremaster Pm(O(2)) was maintained at 60-70 Torr during SHx (Pa(O(2))
      of 35 +/- 1 Torr), LEA increased from 2.1 +/- 1.1 to 11.1 +/- 1.5 leukocytes/100
      microm (P < 0.05). The results show a dissociation between Pm(O(2)) and LEA and
      support the idea that SHx results in the release of a mediator responsible for
      the inflammatory response.

PMID- 12598490
TI  - Alterations in EEG activity and sleep after influenza viral infection in GHRH
      receptor-deficient mice.
AB  - Viral infections induce excess non-rapid eye movement sleep (NREMS) in mice.
      Growth hormone-releasing hormone receptor (GHRH receptor) was previously
      identified as a candidate gene responsible for NREMS responses to influenza
      challenge in mice. The dwarf lit/lit mouse with a nonfunctional GHRH receptor was
      used to assess the role of the GHRH receptor in viral-induced NREMS. After
      influenza A virus infection the duration and intensity [electroencephalogram
      (EEG) delta power] of NREMS increased in heterozygous mice with the normal
      phenotype, whereas NREMS and EEG delta power decreased in homozygous lit/lit
      mice. Lit/lit mice developed a pathological state with EEG slow waves and
      enhanced muscle tone. Other influenza-induced responses (decreases in rapid eye
      movement sleep, changes in the EEG high-frequency bands during the various stages
      of vigilance, hypothermia, and decreased motor activity) did not differ between
      the heterozygous and lit/lit mice. GH replacement failed to normalize the NREMS
      responses in the lit/lit mice after influenza inoculation. Decreases in NREMS
      paralleled hypothermia in the lit/lit mice. Lung virus levels were similar in the
      two mouse strains. Lit/lit mice had a higher death rate after influenza challenge
      than the heterozygotes. In conclusion, GHRH signaling is involved in the NREMS
      response to influenza infection.

PMID- 12598491
TI  - Vitamin K--what, why, and when.
AB  - Policies for giving babies vitamin K prophylactically at birth have been
      dictated, over the last 60 years, more by what manufacturers decided on
      commercial grounds to put on the market, than by any informed understanding of
      what babies actually need, or how it can most easily be given. By a pure fluke a
      1 mg IM dose, designed to prevent early vitamin deficiency bleeding
      ("haemorrhagic disease of the newborn") has been found to protect against late
      deficiency bleeding-a condition unrecognised at the time this policy took hold.
      Alternative strategies for oral prophylaxis are now opening up (see pp 109 and
      113), but these are also, at the moment, dictated more by what the manufacturers
      choose to provide than by what would make for ease of delivery either in poor
      countries, or in the developed world.

PMID- 12598492
TI  - Oxygen administration in infants.
AB  - The main methods of oxygen administration to infants are reviewed. Some methods
      are more economical and therefore more useful in developing countries. All the
      methods have potential complications and therefore need to be carefully
      supervised.

PMID- 12598493
TI  - A ten year, multicentre study of coagulase negative staphylococcal infections in
      Australasian neonatal units.
AB  - OBJECTIVE: To study late onset systemic infections with coagulase negative
      staphylococci. METHODS: Prospective longitudinal study of coagulase negative
      staphylococcal infection in 18 Australasian neonatal nurseries. RESULTS: From
      1991 to 2000 inclusive, there were 1281 cases of coagulase negative
      staphylococcal (CoNS) sepsis, comprising 57.1% of all late onset infections. The
      male/female ratio was 1.27:1 (p < 0.05). The incidence of CoNS sepsis was 3.46
      episodes per 1000 live births. Most infected babies (71%) were 24-29 weeks
      gestation at birth (mode 26 weeks). The first positive culture was day 7-14 in
      49% of babies (mode 10 days). Five cases of meningitis were reported, an
      incidence of 0.4% of all CoNS infections. Twenty nine babies (2.3%) had
      concurrent necrotising enterocolitis and CoNS septicaemia. Four babies (0.3%)
      died from CoNS infection, but CoNS infection possibly contributed to the death of
      an additional 20 babies (1.6%). The mortality directly attributable to CoNS
      infection was significantly lower than that from late onset infections with
      Staphylococcus aureus (13.1%; relative risk (RR) = 36.1 (95% confidence interval
      (CI) 13.0 to 100.2) or with Gram negative bacilli (14.2%; RR = 45.5 (95% CI 16.8
      to 123.3)). CONCLUSIONS: CoNS are currently responsible for most late onset
      neonatal infections. Most infected babies are < 30 weeks gestation at birth, and
      usually present between 7 and 14 days of age. CoNS infections may be associated
      with necrotising enterocolitis, although causality is unproven. Neonatal CoNS
      infections are relatively benign: meningitis is rare and mortality low compared
      with infection from other organisms. Over-vigorous attempts to reduce the
      incidence of CoNS infections using prophylactic antibiotics are not advisable.

PMID- 12598494
TI  - Infant to staff ratios and risk of mortality in very low birthweight infants.
AB  - OBJECTIVES: To assess the effect that infant to staff ratios, in the first three
      days of life, have on the survival to hospital discharge of very low birthweight
      infants (<1500 g), having adjusted for initial risk and unit workload. DESIGN: In
      a retrospective analysis of a cohort of patients, the number of infants per nurse
      per shift were averaged for the first three days after admission and related to
      risk of mortality by logistic regression analysis. Infant to staff ratio was
      divided into terciles of low (1.16-1.58), medium (1.59-1.70), and high (1.71
      1.97) infants per staff member. SUBJECTS: 692 very low birthweight infants
      admitted to the Intensive Care Nursery, Royal Women's Hospital, Brisbane over a
      four year period from January 1996 to December 1999. MAIN OUTCOME MEASURES:
      Survival to hospital discharge, adjusted for initial risk using the Clinical Risk
      Index for Babies (CRIB) score, and adjusted for unit workload using dependency
      scores. RESULTS: There were 80 deaths among the 692 babies analysed for the study
      period. The odds of mortality, adjusted for initial risk and infant dependency
      scores (unit workload), were improved by 82% when an infant/staff ratio of
      greater than 1.71 occurred, suggesting improved survival with the highest
      infant/staff ratio. The low and medium staffing levels corresponded with similar
      odds ratios for mortality. CONCLUSIONS: Infants exposed to higher infant to staff
      ratios have an improved adjusted risk of survival to hospital discharge.

PMID- 12598495
TI  - Comparison of meconium and neonatal hair analysis for detection of gestational
      exposure to drugs of abuse.
AB  - BACKGROUND: Meconium and hair are two biological markers of in utero exposure to
      illicit drugs. OBJECTIVE: To compare the sensitivity of the two tests for
      different drugs. SETTING: Motherisk laboratory which tests in utero drug exposure
      in Toronto. METHODS: Cocaine, benzoylecgonine, opiates, cannabis,
      benzodiazepines, methadone, and barbiturates were measured in pairs of hair and
      meconium samples from the same neonates. RESULTS: Meconium was marginally more
      sensitive than neonatal hair for detection of cocaine and cannabis, possibly
      because it may detect second trimester exposure whereas hair grows only during
      the third trimester of pregnancy. There was a significant correlation between
      hair and meconium concentrations of cocaine, cannabis, and opiates. CONCLUSION:
      In cases of clinical suspicion and a negative neonatal urine test, both meconium
      and hair are effective biological markers of in utero illicit drug exposure.
      Meconium may be more sensitive, but neonatal hair is available for three months
      whereas meconium is available for only one or two days. In contrast, the use of
      meconium, being a discarded material, is more acceptable to some parents than
      hair testing, which entails cutting scalp hair from the newborn.

PMID- 12598496
TI  - Cognitive development at 5.5 years of children with chronic lung disease of
      prematurity.
AB  - BACKGROUND: Preterm infants with chronic lung disease (CLD) had impaired
      cognitive development and poorer eye-hand coordination at 10 months of age. AIMS:
      To study whether this effect of CLD persisted until school age and whether the
      severity of CLD affected outcome. METHOD: Cognition and visual-motor skills were
      examined (Wechsler preschool and primary scale of intelligence, and tests from
      the Nepsy scale) in 60 very preterm children, without intraventricular
      haemorrhage or periventricular leucomalacia, at 5.5 years of age. Thirty two
      children suffered from CLD and 28 were controls. RESULTS: The groups did not
      differ significantly in cognitive outcome. Children with CLD and controls
      attained a full scale intelligence quotient (IQ) of 94.4 and 99.1, a verbal IQ of
      99.6 and 101.5, and a performance IQ of 90.9 and 96.7 respectively. Similarly, no
      difference was found in tests of eye-hand control. However, the children with the
      most severe form of CLD had significantly lower performance (84.8) and full
      scale(87.6) IQs and worse visual-motor performance than the controls. CLD grade
      III, together with the need for glasses or lenses, had a significant impact on
      the explained variance. CONCLUSIONS: At school age, children born very preterm
      and who experienced severe CLD had deficits in cognition, visual-motor
      perception, and performance. The findings suggest a need to consider intervention
      programmes for such infants.

PMID- 12598497
TI  - Faecal elastase 1 levels in premature and full term infants.
AB  - BACKGROUND: Determination of faecal elastase 1 (FE1) is a simple, relatively
      inexpensive, non-invasive, highly specific and sensitive test for determining
      pancreatic function. Secretion of pancreatic enzymes varies during infancy, but
      there are almost no specific data on the ontogeny of elastase 1 in human babies.
      AIM: To study FE1 levels in preterm and term babies, and to determine the
      possible effect of gestational and postconceptual age on these levels. METHODS:
      Serial stool samples were collected and tested for FE1 level from 77 premature
      and full term infants. FE1 levels were determined by a commercially available
      enzyme linked immunosorbent assay (ELISA) kit. RESULTS: A total of 232 stool
      samples were collected from 77 neonates. The FE1 level measured in the first
      stool sample (meconium) was below normal (200 micro g/g stool) in all samples
      regardless of gestational age. Sixty three neonates had at least two samples
      tested for FE1 level. The mean (SD) level of FE1 in sample 1 was 45.9 (51.1)
      micro g/g stool and was significantly (p < 0.001) lower than in sample 2 (243.0
      (164.9) micro g/g stool). The lower the gestational age of the newborn, the more
      time it took for FE1 to reach normal levels. CONCLUSIONS: FE1 levels in meconium
      are low, and studies in meconium should be avoided if pancreatic sufficiency is
      to be determined. FE1 reaches normal levels by day 3 in term newborns and by 2
      weeks in infants born before 28 weeks gestation. Normal levels are reached sooner
      in infants of more advanced gestational age who start enteral feeding earlier.

PMID- 12598498
TI  - Oral mixed micellar vitamin K for prevention of late vitamin K deficiency
      bleeding.
AB  - OBJECTIVE: To determine whether the use of mixed micellar vitamin K improves the
      efficacy of the 3 x 2 mg oral vitamin K prophylaxis schedule. DESIGN: Nationwide
      active surveillance for vitamin K deficiency bleeding (VKDB) complemented with
      two surveys on the use of the mixed micellar preparation in hospitals and by
      paediatricians. SETTING AND PATIENTS: Infants in Germany in 1997-2000.
      INTERVENTION: Prophylaxis with three oral doses of 2 mg mixed micellar vitamin K.
      MAIN OUTCOME MEASURE: Confirmed VKDB between day 8 and week 12 and no condition
      requiring specific vitamin K supplementation known before the onset of bleeding.
      RESULTS: Twenty nine reports met the case definition: seven had not received any
      vitamin K prophylaxis; for three, vitamin K prophylaxis was unknown; two had
      insufficient vitamin K prophylaxis for their age; 17 had been given the
      recommended doses. The mixed micellar preparation had been given to seven, other
      preparations to nine, and one had been given both. These cases did not differ
      with respect to the site of bleeding and cholestasis detected at bleeding.
      Estimates of the use of the mixed micellar preparation in birth hospitals and by
      paediatricians yielded 1 817 769 newborns exposed to the mixed micellar
      preparation and 1 320 926 newborns exposed to other preparations. The rate of
      late VKDB was 0.44/100 000 (95% confidence interval (CI) 0.19 to 0.87) in
      children given mixed micellar vitamin K compared with 0.76/100 000 (95% CI 0.36
      to 1.39) in children given other preparations. CONCLUSION: Mixed micellar vitamin
      K did not significantly improve the efficacy of the 3 x 2 mg oral vitamin K
      prophylaxis schedule.

PMID- 12598500
TI  - Plasma bilirubin level and oxidative stress in preterm infants.
AB  - OBJECTIVE: To assess the hypothesis that changes in plasma total bilirubin levels
      (Btot) can influence the antioxidant system and oxidative stress in preterm
      infants. METHODS: Twenty two healthy preterm infants who presented with visible
      non-haemolytic hyperbilirubinaemia were studied at the mean (SD) age of 3.7 (1.5)
      days. Btot, plasma total hydroperoxide concentration (TH), plasma protein SH
      group concentration, and total antioxidant capacity of the plasma (TAC) were
      measured at study entry and after 24 hours. RESULTS: Btot did not correlate with
      TH, TAC, or protein SH group concentration, but a significant correlation was
      found between TH and TAC, TH and protein SH groups, and TAC and protein SH
      groups, both at study entry and after 24 hours. CONCLUSION: The decrease in
      plasma bilirubin was contemporary with an increase in plasma antioxidant capacity
      and decrease in oxidative stress in preterm infants. This may be the result of
      the pro-oxidant effect of haem oxygenase, mediated by iron release, which may
      outcompete the antioxidant properties of bilirubin.

PMID- 12598499
TI  - Intestinal absorption of mixed micellar phylloquinone (vitamin K1) is unreliable
      in infants with conjugated hyperbilirubinaemia: implications for oral prophylaxis
      of vitamin K deficiency bleeding.
AB  - OBJECTIVE: To compare the pharmacokinetics and efficacy of oral versus
      intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic
      liver disease, a known risk factor for vitamin K deficiency bleeding. DESIGN:
      Prospective randomised controlled study. SETTING: Paediatric Liver Unit.
      PATIENTS: Forty four infants less than 6 months of age with conjugated
      hyperbilirubinaemia. MAIN OUTCOME MEASURES: Serum concentrations of vitamin K(1)
      and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of
      vitamin K status) before and for up to four days after a single dose of mixed
      micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24
      hours after oral K(1) with those from 14 healthy newborns given the same dose.
      RESULTS: At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and
      eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K
      deficiency. Median serum K(1) concentrations were similar in the oral and
      intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours
      after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the
      latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml)
      of serum K(1) compared unfavourably with the much higher levels (median 77, range
      11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested
      impaired and erratic intestinal absorption in cholestatic infants. The severity
      of malabsorption was such that only 4/24 (17%) achieved an incremental rise in
      serum K(1) > 10 ng/ml. CONCLUSIONS: The intestinal absorption of mixed micellar
      K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the
      strong association between cholestasis and late vitamin K deficiency bleeding,
      these data provide an explanation for the failure of some oral vitamin K(1)
      prophylaxis regimens in infants with latent cholestasis.

PMID- 12598501
TI  - Progress in treatment and outcome for children with neonatal haemochromatosis.
AB  - AIM: To evaluate the role of antioxidant treatment and liver transplantation in
      the management of neonatal haemochromatosis. METHODS: A retrospective review was
      performed of eight infants with acute liver failure and raised ferritin levels
      between 1990 and 1998. From 1994, treatment with an antioxidant cocktail (vitamin
      E, N-acetylcysteine, selenium, prostaglandin E1, and desferrioxamine) was begun
      once the diagnosis was suspected. Pathological and other findings were reviewed,
      and outcome before and after antioxidant treatment was evaluated. RESULTS: Median
      age at presentation was 4 days with median ferritin levels of 4180 micro g/l
      (range 1650-40 000 micro g/l; normal range 110-503 micro g/l). Three infants
      presented before 1994. One infant died before liver transplantation from acute
      liver failure and one from neurological damage after transplantation. The third
      patient underwent successful transplantation at day 13 and remains well on follow
      up 8 years later. From 1994, five patients received antioxidant treatment, of
      whom two responded: both responders started antioxidants earlier (by day 5) than
      non-responders and had lower peak ferritin levels (< 4200 micro g/l) and a milder
      phenotype. Treatment was continued until ferritin levels were < 500 micro g/l.
      Both children remain well with mean follow up of 42 months, with no recurrence of
      iron overload. One child showed a partial response to treatment and survived long
      enough for a liver transplant, but died from graft failure after the transplant.
      Two children did not respond to antioxidant treatment; both had multiorgan
      failure and were not listed for transplantation. Only three of the eight patients
      survived (37.5%) over this time period. CONCLUSION: Neonatal haemochromatosis can
      be a fatal disease with > 60% mortality. Early treatment with antioxidant
      cocktail is beneficial and may be curative in those who present with milder
      phenotype. Liver transplantation should always be considered at an early stage in
      non-responders and in children with more severe acute liver failure.

PMID- 12598502
TI  - Pilot investigation of hypothermia in neonates receiving extracorporeal membrane
      oxygenation.
AB  - BACKGROUND: Infants requiring extracorporeal membrane oxygenation (ECMO) support
      represent a high risk group in terms of cerebral injury. Mild hypothermia both
      during and after cerebral hypoxic ischaemia appears to be a promising strategy
      for offering neuroprotection. OBJECTIVE: To investigate whether mild hypothermia
      was both feasible and safe in infants receiving ECMO as a prelude to any formal
      assessment of this approach in a randomised trial. METHODS: Twenty infants (body
      weight less than 5 kg) with severe cardiopulmonary insufficiency, referred for
      ECMO support at Glenfield Hospital, Leicester, were enrolled in this study.
      Twenty consecutive infants (compromising four groups of five) were studied.
      Baseline data were obtained from a control group who were run throughout their
      course at 37 degrees C. The patients in the next group were managed with a core
      temperature of 36 degrees C for the first 12 hours of their ECMO run, before
      being warmed up to 37 degrees C. After successful completion, the next group of
      five were cared for at 35 degrees C for the first 12 hours, and, there having
      been no previous complications, the final group were cared for at 34 degrees C
      for the first 12 hours. Patients were assessed clinically and biologically. In
      addition to routine laboratory tests, cytokines (interleukin 6, interleukin 8,
      tumour necrosis factor alpha, and C reactive protein) were measured and
      coagulation tests (D-dimer, thrombin-antithrombin III complex, plasmin-alpha(2)
      antiplasmin complex) were performed serially for five days. RESULTS: There were
      no significant differences among the four groups in gestational age, birth
      weight, age at the time of ECMO, Apgar scores at one and five minutes, pH before
      cannulation, oxygenation index, duration of ECMO, and survival rate to discharge
      from hospital. No adverse effects of mild hypothermia were found on patient
      management during ECMO. Laboratory data for up to five days of ECMO also showed
      no difference among the four groups. CONCLUSION: Mild hypothermia (34 degrees C)
      for the initial 12 hours of an ECMO run is feasible.

PMID- 12598503
TI  - Maternal and umbilical cord erythrocyte omega-3 and omega-6 fatty acids and
      haemorheology in singleton and twin pregnancies.
AB  - BACKGROUND: Being devoid of both nuclei and mitochondria, mature human
      erythrocytes provide an opportunity to study membrane structure and function
      outwith the restrictions of genetic control. With its unique rapid increase in
      vascularisation, pregnancy is considered the most opportune period in which to
      investigate blood rheology. METHODS: Maternal and fetal (cord) bloods were
      retained at delivery from 32 (25 singleton and seven twin) normal pregnancies at
      two maternity hospitals in the Glasgow area over a nine month period. Erythrocyte
      fatty acid compositions were assessed by mass spectroscopy, and corresponding
      membrane deformabilities measured by ultrafiltration through a membrane of 5
      micro m diameter pore size, to mimic placental microcirculation. RESULTS:
      Significant direct correlations (Spearman rank) were found between erythrocyte
      membrane omega-3 docosahexaenoic acid concentrations and corresponding
      deformabilities in maternal and cord blood from both singleton and twin
      pregnancies, whereas greater omega-6 arachidonic acid content was associated with
      increased maternal membrane rigidity. Membrane concentrations of omega-3 fatty
      acids only correlated strongly both within and between maternal and cord bloods.
      Mean cord erythrocyte docosahexaenoic acid concentration was higher than maternal
      in singletons but lower in twins. When maternal erythrocyte concentrations
      exceeded about 7% (of total fatty acids), resistance to erythrocyte flow was
      virtually eliminated. CONCLUSIONS: It may be that a greater maternal intake of
      docosahexaenoic acid should be encouraged in some pregnancies for optimal tissue
      perfusion. Fetal demand for docosahexaenoic acid may not be entirely satisfied in
      multiple pregnancies.

PMID- 12598505
TI  - Effect of a change in global metabolic rate on peripheral oxygen consumption in
      neonates.
AB  - AIM: To evaluate the effect of an induced change in global metabolic rate on
      peripheral oxygen consumption (VO(2)) in healthy full term neonates. SUBJECTS AND
      METHODS: Twenty four healthy full term neonates were studied. Peripheral VO(2)
      was measured by near infrared spectroscopy (NIRS) using arterial occlusion and
      measurement of the oxyhaemoglobin (HbO(2)) decrement slope. Global VO(2) was
      measured by open circuit calorimetry. Global and peripheral VO(2) were measured
      in each neonate before and after a routine bath. Abdominal and forearm skin
      temperatures were also recorded. RESULTS: Nineteen neonates completed the study.
      Global VO(2) increased by 30.7% (p = 0.001), and peripheral VO(2) by 23.1% (p =
      0.001). A correlation between the fractional changes in global and peripheral
      VO(2) was apparent (r = 0.76, p = 0.001). Abdominal skin temperature decreased by
      0.8 degrees C (p = 0.001), and forearm skin temperature by 0.6 degrees C (p =
      0.04). CONCLUSIONS: Measurement of peripheral VO(2) using NIRS with arterial
      occlusion is responsive to conditions that increase global metabolic rate. Any
      change in global VO(2) must be taken into consideration during the interpretation
      of peripheral VO(2) measurements in neonates.

PMID- 12598504
TI  - Effect of limb cooling on peripheral and global oxygen consumption in neonates.
AB  - AIM: To evaluate peripheral oxygen consumption (VO(2)) measurements using near
      infrared spectroscopy (NIRS) with arterial occlusion in healthy term neonates by
      studying the effect of limb cooling on peripheral and global VO(2). SUBJECTS AND
      METHODS: Twenty two healthy term neonates were studied. Peripheral VO(2) was
      measured by NIRS using arterial occlusion and measurement of the oxyhaemoglobin
      (HbO(2)) decrement slope. Global VO(2) was measured by open circuit calorimetry.
      Global and peripheral VO(2) was measured in each neonate before and after limb
      cooling. RESULTS: In 10 neonates, a fall in forearm temperature of 2.2 degrees C
      (mild cooling) decreased forearm VO(2) by 19.6% (p < 0.01). Global VO(2) did not
      change. In 12 neonates, a fall in forearm temperature of 4 degrees C (moderate
      cooling) decreased forearm VO(2) by 34.7% (p < 0.01). Global VO(2) increased by
      17.6% (p < 0.05). CONCLUSIONS: The NIRS arterial occlusion method is able to
      measure changes in peripheral VO(2) induced by limb cooling. The changes are more
      pronounced with moderate limb cooling when a concomitant rise in global VO(2) is
      observed. Change in peripheral temperature must be taken into consideration in
      the interpretation of peripheral VO(2) measurements in neonates.

PMID- 12598506
TI  - Neonatal murmurs: are senior house officers good enough?
AB  - AIM: To show that, given appropriate guidelines, senior house officers (SHOs)
      have the clinical skills required to assess neonatal murmurs. METHODS: Neonatal
      SHOs identified babies with a cardiac murmur at routine neonatal examination. The
      SHOs assessed whether the murmur was significant or innocent and decided between
      immediate further assessment or echocardiogram as an outpatient. RESULTS: A total
      of 112 babies had murmurs at routine neonatal examination. The incidence of
      cardiac murmurs was 13.8 per 1000. Twelve babies were referred for immediate
      further assessment. Eleven had structurally abnormal hearts. One had a normal
      heart with pulmonary hypoplasia. One hundred babies were referred, and 78
      attended for outpatient follow up. Of these, the SHO assessed nine babies as
      having a significant murmur and 69 as having an innocent murmur. Twenty two
      babies failed to attend for follow up; all were thought to have innocent murmurs.
      Of the nine murmurs assessed as significant, four were confirmed as such and five
      were found to be innocent. Of the 91 murmurs assessed as innocent, 63 were proven
      to be innocent, six had abnormalities on echocardiogram, and 22 defaulted to
      follow up. Five of the serious murmurs were small ventricular septal defects,
      which had resolved by 6 months of age; the other had mild pulmonary stenosis.
      None of these babies were clinically symptomatic at outpatient review.
      CONCLUSION: Given appropriate guidelines, SHOs have the skills to assess the
      significance of, and decide on appropriate management for, neonatal murmurs.
      Electrocardiograms and chest radiographs are not necessary.

PMID- 12598507
TI  - Brachial artery pseudoaneurysm in a premature infant.
AB  - A case of brachial artery pseudoaneurysm in a premature infant is reported. The
      lesion was surgically resected, and arterial continuity restored by end to end
      anastomosis. The postoperative period and follow up were uneventful.

PMID- 12598508
TI  - Early dialysis in a neonate with intrauterine lisinopril exposure.
AB  - In general, angiotensin converting enzyme (ACE) inhibitors should be discontinued
      in pregnancy, as they can induce an ACE fetopathy. For the treatment of the
      latter, early peritoneal dialysis is recommended for in utero exposure to
      captopril and enalapril, although the outcome is poor. Early peritoneal dialysis
      has not previously been reported for lisinopril induced multiorgan failure. A
      case is reported in which treatment was given on postnatal day 3. The patient
      recovered from oligoanuria to almost normal renal function, and heart, brain, and
      musculoskeletal injury was reversible. This is despite relatively poor clearance
      of the drug through peritoneal dialysis. Analysis of the pharmacokinetic data
      suggests that haemodialysis or haemofiltration would be more efficacious for
      removal of the drug, and these treatments should be performed if available.

PMID- 12598509
TI  - Andreas Vesalius (1514-1564), Padua, and the fetal "shunts".
AB  - Three remarkable medical anatomists working in Padua during the 16th century
      described the anatomy of the fetal cardiovascular system, thus laying the
      foundation for William Harvey's discovery and description of the fetal
      circulation in the following century.

PMID- 12598510
TI  - Serum S-100 protein does not correlate with cerebral ultrasound scans in preterm
      infants.

PMID- 12598511
TI  - Neonatal sepsis in Peshawar: author's reply.

PMID- 12598512
TI  - Neonatal shaken baby syndrome--lessons to be learned.

PMID- 12598513
TI  - Neonatal shaken baby syndrome--historical inexactitudes.

PMID- 12598514
TI  - SIDS, smoking, and arousal thresholds: conclusions not supported by data.

PMID- 12598515
TI  - Swallowing induced supraventricular tachycardia in a neonate.

PMID- 12598516
TI  - Decreasing oxygen saturation in very early preterm newborn infants after
      transfusion.

PMID- 12598517
TI  - Risks of treating infected neonatal lines.

PMID- 12598518
TI  - Management of mothers of neonates with vertically transmitted sexually
      transmitted infections.

PMID- 12598520
TI  - Promiscuous coupling at receptor-Galpha fusion proteins. The receptor of one
      covalent complex interacts with the alpha-subunit of another.
AB  - Fusion proteins between heptahelical receptors (GPCR) and G protein alpha
      subunits show enhanced signaling efficiency in transfected cells. This is
      believed to be the result of molecular proximity, because the interaction between
      linked modules of one protein chain, if not constrained by structure, should be
      strongly favored compared with the same in which partners react as free species.
      To test this assumption we made a series of fusion proteins (type 1 and 4 opioid
      receptors with G(o) and beta(2) adrenergic and dopamine 1 receptors with G(sL))
      and some mutated analogs carrying different tags and defective GPCR or Galpha
      subunits. Using cotransfection experiments with readout protocols able to
      distinguish activation at fused and non-fused alpha-subunits, we found that both
      the GPCR and the Galpha limb of one fusion protein can freely interact with non
      fused proteins and the tethered partners of a neighboring fusion complex.
      Moreover, a bulky polyanionic inhibitor can suppress with identical potency
      receptor-Galpha interaction, either when occurring between latched domains of a
      fused system or separate elements of distinct molecules, indicating that the
      binding surfaces are equally accessible in both cases. These data demonstrate
      that there is no entropy drive from the linked condition of fusion proteins and
      suggest that their signaling may result from the GPCR of one complex interacting
      with the alpha-subunit of another. Moreover, the enhanced coupling efficiency
      commonly observed for fusion proteins is not due to the receptor tether, but to
      the transmembrane helix that anchors Galpha to the membrane.

PMID- 12598521
TI  - Ligand selectivity of gonadotropin receptors. Role of the beta-strands of
      extracellular leucine-rich repeats 3 and 6 of the human luteinizing hormone
      receptor.
AB  - The difference in hormone selectivity between the human follicle-stimulating
      hormone receptor (hFSH-R) and human luteinizing hormone/chorionic gonadotropin
      receptor (hLH-R) is determined by their approximately 350 amino acid-long N
      terminal receptor exodomains that allow the mutually exclusive binding of human
      follicle-stimulating hormone (hFSH) and human luteinizing hormone (hLH) when
      these hormones are present in physiological concentrations. The exodomains of
      each of these receptors consist of a nine-leucine-rich repeat-containing
      subdomain (LRR subdomain) flanked by N- and C-terminal cysteine-rich subdomains.
      Chimeric receptors, in which the structural subdomains of the hFSH-R exodomain
      were substituted with those of the hLH-R, showed a similar high responsiveness to
      human chorionic gonadotropin (hCG) and hLH as long as they harbored the LRR
      subdomain of the hLH-R. In addition, these chimeric receptors showed no
      responsiveness to hFSH. The LRR subdomains of the gonadotropin receptor
      exodomains are predicted to adopt a horseshoe-like conformation, of which the
      hormone-binding concave surface is composed of nine parallel beta-strands.
      Receptors in which individual beta-strands of the hFSH-R were replaced with the
      corresponding hLH-R sequences revealed that hCG and hLH selectivity is
      predominantly determined by hLH-R beta-strands 3 and 6. A mutant receptor in
      which the hFSH-R beta-strands 3 and 6 were substituted simultaneously with their
      hLH-R counterparts displayed a responsiveness to hCG and hLH similar to that of
      the wild type hLH-R. Responsiveness to hFSH was not affected by most beta-strand
      substitutions, suggesting the involvement of multiple low-impact determinants for
      this hormone.

PMID- 12598522
TI  - A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1
      fibroblasts.
AB  - The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is
      best known for its role in T lymphocyte activation. However, it has become
      increasingly apparent that this signaling pathway is also involved in the
      regulation of cell growth and development in a wide variety of different tissues
      and cell types. Here we have investigated the effects of sustained NFATc1
      signaling on the growth and differentiation of the murine 3T3-L1 preadipocyte
      cell line. Remarkably, we find that expression of a constitutively active NFATc1
      mutant (caNFATc1) in these immortalized cells inhibits their differentiation into
      mature adipocytes and causes them to adopt a transformed cell phenotype,
      including loss of contact-mediated growth inhibition, reduced serum growth
      requirements, protection from growth factor withdrawal-induced apoptosis, and
      formation of colonies in semisolid media. Furthermore, we find that caNFATc1
      expressing cells acquire growth factor autonomy and are able to proliferate even
      in the complete absence of serum. We provide evidence that this growth factor
      independence is caused by the NFATc1-dependent production of a soluble heat
      labile autocrine factor that is capable of promoting the growth and survival of
      wild type 3T3-L1 cells as well as potently inhibiting their differentiation into
      mature adipocytes. Finally, we demonstrate that cells expressing caNFATc1 form
      tumors in nude mice. Taken together, these results indicate that deregulated
      NFATc1 activity is able to induce the immortalized 3T3-L1 preadipocyte cell line
      to acquire the well established hallmarks of cellular transformation and thereby
      provide direct evidence for the oncogenic potential of the NFATc1 transcription
      factor.

PMID- 12598523
TI  - Notch activation suppresses fibroblast growth factor-dependent cellular
      transformation.
AB  - Aberrant activations of the Notch and fibroblast growth factor receptor (FGFR)
      signaling pathways have been correlated with neoplastic growth in humans and
      other mammals. Here we report that the suppression of Notch signaling in NIH 3T3
      cells by the expression of either the extracellular domain of the Notch ligand
      Jagged1 or dominant-negative forms of Notch1 and Notch2 results in the appearance
      of an exaggerated fibroblast growth factor (FGF)-dependent transformed phenotype
      characterized by anchorage-independent growth in soft agar. Anchorage-independent
      growth exhibited by Notch-repressed NIH 3T3 cells may result from prolonged FGFR
      stimulation caused by both an increase in the expression of prototypic and
      oncogenic FGF gene family members and the nonclassical export of FGF1 into the
      extracellular compartment. Interestingly, FGF exerts a negative effect on Notch
      by suppressing CSL (CBF-1/RBP-Jk/KBF2 in mammals, Su(H) in Drosophila and
      Xenopus, and Lag-2 in Caenorhabditis elegans)-dependent transcription, and the
      ectopic expression of constitutively active forms of Notch1 or Notch2 abrogates
      FGF1 release and the phenotypic effects of FGFR stimulation. These data suggest
      that communication between the Notch and FGFR pathways may represent an important
      reciprocal autoregulatory mechanism for the regulation of normal cell growth.

PMID- 12598524
TI  - Characterization of the human lung CYP2F1 gene and identification of a novel lung
      specific binding motif.
AB  - The CYP2F1 gene encodes a cytochrome P450 enzyme capable of bioactivating a
      number of pulmonary-selective toxicants. The expression of CYP2F1 is highly
      tissue-selective; the highest expression is observed in the lung with little or
      no hepatic expression. The objective of these studies was to elucidate the
      mechanisms that govern the unique tissue-specific regulation of CYP2F1. Cosmid
      and bacterial artificial chromosome clones were screened and sequenced to
      identify a gene that spanned 14 kbp containing 10 exons, including an
      untranslated exon 1. Primer extension analysis and 5'-rapid amplification of cDNA
      ends were used to identify the transcription start site. Several sequences
      homologous to known cis-elements were identified in the 5'-upstream region of the
      CYP2F1 promoter. Transient transfection studies with luciferase reporter
      constructs demonstrated a significant functional lung cell-specific CYP2F1
      promoter region (from position -129 to +115). DNase footprinting analysis of 1.6
      kbp of the upstream sequence with nuclear extracts from human lung tissues
      revealed one strong DNA-protein complex at -152 to -182. This nuclear protein
      (called lung-specific factor, LSF) was present only in lung but not liver or
      heart tissues. Competitive electrophoretic mobility shift assays characterized a
      DNA consensus site, within the LSF-binding domain, that was highly similar to two
      E box motifs, but no known "E box" trans-factors were identified. These studies
      identified a novel LSF and its consensus sequence that may control tissue
      specific expression of CYP2F1.

PMID- 12598525
TI  - Recruitment and activation of phospholipase Cgamma1 by vascular endothelial
      growth factor receptor-2 are required for tubulogenesis and differentiation of
      endothelial cells.
AB  - Vascular endothelial growth factor-mediated angiogenic signal transduction relay
      is achieved by coordinated induction of endothelial cell proliferation,
      migration, and differentiation. These complex cellular processes are most likely
      controlled by activation of both cooperative and antagonistic signals by vascular
      endothelial growth factor receptors (VEGFRs). Here, we investigated the
      contribution of tyrosine-phosphorylated residues of VEGFR-2/fetal liver kinase-1
      to endothelial cell proliferation and differentiation and activation of signaling
      proteins. Mutation of tyrosine 1006 of VEGFR-2 to phenylalanine severely impaired
      the ability of this receptor to stimulate endothelial cell differentiation and
      tubulogenesis. Paradoxically, the mutant receptor stimulated endothelial cell
      proliferation far better than the wild-type receptor. Further analysis showed
      that tyrosine 1006 is responsible for phospholipase Cgamma1 (PLCgamma1)
      activation and intracellular calcium release in endothelial cells. Activation of
      PLCgamma1 was selectively mediated by tyrosine 1006. Mutation of tyrosines 799,
      820, 949, 994, 1080, 1173, and 1221 had no measurable effect on the ability of
      VEGFR-2 to stimulate PLCgamma1 activation. Association of VEGFR-2 with PLCgamma1
      was mainly established between tyrosine 1006 and the C-terminal SH2 domain of
      PLCgamma1 in vitro and in vivo. Taken together, the results indicate that
      phosphorylation of tyrosine 1006 is essential for VEGFR-2-mediated PLCgamma1
      activation, calcium flux, and cell differentiation. More importantly, VEGFR-2
      mediated endothelial cell proliferation is inversely correlated with the ability
      of VEGFR-2 to associate with and activate PLCgamma1.

PMID- 12598527
TI  - VEGF162, a new heparin-binding vascular endothelial growth factor splice form
      that is expressed in transformed human cells.
AB  - The splice forms of vascular endothelial growth factor (VEGF) differ in
      biological properties such as the receptor types that they recognize and their
      interaction with heparan sulfate proteoglycans. We have identified a new VEGF
      mRNA splice form encoding a VEGF species containing 162 amino acids (VEGF(162))
      in human A431 ovarian carcinoma cells. This novel mRNA contains the peptides
      encoded by exons 1-5, 6A, 6B, and 8 of the VEGF gene. Recombinant VEGF(162) is
      biologically active. It induces proliferation of endothelial cells in vitro and
      angiogenesis in vivo as determined by the alginate bead assay. VEGF(162) binds
      less efficiently than VEGF(145) but more efficiently than VEGF(165) to a natural
      basement membrane produced by corneal endothelial cells. VEGF(138), an artificial
      VEGF form that contains exon 6B but lacks exons 6A and 7, did not bind to this
      basement membrane at all, indicating that exon 6B probably interferes with the
      interaction of exon 6A with heparin and heparan sulfate proteoglycans.

PMID- 12598526
TI  - Mitofusin-2 determines mitochondrial network architecture and mitochondrial
      metabolism. A novel regulatory mechanism altered in obesity.
AB  - In many cells and specially in muscle, mitochondria form elongated filaments or a
      branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane
      protein that participates in mitochondrial fusion in mammalian cells, is induced
      during myogenesis and contributes to the maintenance and operation of the
      mitochondrial network. Repression of Mfn2 caused morphological and functional
      fragmentation of the mitochondrial network into independent clusters.
      Concomitantly, repression of Mfn2 reduced glucose oxidation, mitochondrial
      membrane potential, cell respiration, and mitochondrial proton leak. We also show
      that the Mfn2-dependent mechanism of mitochondrial control is disturbed in
      obesity by reduced Mfn2 expression. In all, our data indicate that Mfn2
      expression is crucial in mitochondrial metabolism through the maintenance of the
      mitochondrial network architecture, and reduced Mfn2 expression may explain some
      of the metabolic alterations associated with obesity.

PMID- 12598528
TI  - Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype
      of Neu-induced mammary tumor cells.
AB  - Few tyrosine phosphatases support, rather than inhibit, survival of tumor cells.
      We present genetic evidence that receptor-type protein-tyrosine phosphatase
      (RPTP)-epsilon performs such a function, as cells from mammary epithelial tumors
      induced by activated Neu in mice genetically lacking RPTPepsilon appeared
      morphologically less transformed and exhibited reduced proliferation. We show
      that at the molecular level, RPTPepsilon activates Src, a known collaborator of
      Neu in mammary tumorigenesis. Lack of RPTPepsilon reduced Src activity and
      altered Src phosphorylation in tumor cells; RPTPepsilon dephosphorylated and
      activated Src; and Src bound a substrate-trapping mutant of RPTPepsilon. The
      altered morphology of tumor cells lacking RPTPepsilon was corrected by exogenous
      Src and exogenous RPTPepsilon or RPTPalpha; exogenous activated Src corrected
      also the growth rate phenotype. Together, these results suggest that the altered
      morphology of RPTPepsilon-deficient tumor cells is caused by reduced Src
      activity, caused, in turn, by lack of RPTPepsilon. Unexpectedly, the phenotype of
      RPTPepsilon-deficient tumor cells occurs despite expression of the related
      RPTPalpha, indicating that endogenous RPTPalpha does not compensate for the
      absence of RPTPepsilon in this case. We conclude that RPTPepsilon is a
      physiological activator of Src in Neu-induced mammary tumors and suggest that
      pharmacological inhibition of phosphatases that activate Src may be useful to
      augment direct pharmacological inhibition of Src.

PMID- 12598529
TI  - Post-translational modification of Bid has differential effects on its
      susceptibility to cleavage by caspase 8 or caspase 3.
AB  - Bid is instrumental in death receptor-mediated apoptosis where it is cleaved by
      caspase 8 at aspartate 60 and aspartate 75 to generate truncated Bid (tBID) forms
      that facilitate release of mitochondrial cytochrome c. Bid is also cleaved at
      these sites by caspase 3 that is activated downstream of cytochrome c release
      after diverse apoptotic stimuli. In this context, tBid may amplify the apoptotic
      process. Bid is phosphorylated in vitro by casein kinases that regulate its
      cleavage by caspase 8 (Desagher, S., Osen-Sand, A., Montessuit, S., Magnenat, E.,
      Vilbois, F., Hochmann, A., Journot, L. Antonsson, A., and Martinou, J.-C. (2001)
      Mol. Cell 8, 601-611). Using a Bid decapeptide substrate, we observed that
      phosphorylation at threonine 59 inhibited cleavage by caspase 8. This was also
      seen when recombinant Bid (rBid) and Bid isolated from murine kidney were
      incubated with casein kinase II. However, there were differences in the
      susceptibility of rBid and isolated Bid to cleavage by caspases 3 and 8. Caspase
      8 cleaved rBid to generate two C-terminal products, p15 and p13 tBid, but
      produced only p15 tBid from isolated Bid. Contrary to rBid, isolated Bid was
      resistant to cleavage by caspase 3, yet was readily cleaved within the cytosolic
      milieu. Our data suggest that one or more distinct cellular mechanisms regulate
      Bid cleavage by caspases 8 and 3 in situ.

PMID- 12598530
TI  - The low density lipoprotein receptor-related protein complexes with cell surface
      heparan sulfate proteoglycans to regulate proteoglycan-mediated lipoprotein
      catabolism.
AB  - It has been proposed that clearance of cholesterol-enriched very low density
      lipoprotein (VLDL) particles occurs through a multistep process beginning with
      their initial binding to cell-surface heparan sulfate proteoglycans (HSPG),
      followed by their uptake into cells by a receptor-mediated process that utilizes
      members of the low density lipoprotein receptor (LDLR) family, including the low
      density lipoprotein receptor-related protein (LRP). We have further explored the
      relationship between HSPG binding of VLDL and its subsequent internalization by
      focusing on the LRP pathway using a cell line deficient in LDLR. In this study,
      we show that LRP and HSPG are part of a co-immunoprecipitable complex at the cell
      surface demonstrating a novel association for these two cell surface receptors.
      Cell surface binding assays show that this complex can be disrupted by an LRP
      specific ligand binding antagonist, which in turn leads to increased VLDL binding
      and degradation. The increase in VLDL binding results from an increase in the
      availability of HSPG sites as treatment with heparinase or competitors of
      glycosaminoglycan chain addition eliminated the augmented binding. From these
      results we propose a model whereby LRP regulates the availability of VLDL binding
      sites at the cell surface by complexing with HSPG. Once HSPG dissociates from
      LRP, it is then able to bind and internalize VLDL independent of LRP endocytic
      activity. We conclude that HSPG and LRP together participate in VLDL clearance by
      means of a synergistic relationship.

PMID- 12598531
TI  - UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with
      NRAGE.
AB  - The UNC5Hs are axon guidance receptors that mediate netrin-1-dependent
      chemorepulsion, and dependence receptors that mediate netrin-1-independent
      apoptosis. Here, we report an interaction between UNC5H1 and NRAGE. Our
      experiments show that this interaction is responsible for apoptosis induced by
      UNC5H1, and this level of apoptosis is greater than the amount induced by either
      UNC5H2 or UNC5H3. We mapped the NRAGE binding domain of UNC5H1 to its ZU-5 domain
      and show that this region, in addition to an adjacent PEST sequence, is required
      for UNC5H1-mediated apoptosis. Chimeric UNC5H2 and UNC5H3 receptors, containing
      the NRAGE binding domain and PEST sequence of UNC5H1, bind NRAGE and cause
      increased levels of apoptosis. UNC5H1 expression does not induce apoptosis in
      differentiated PC12 cells, which down-regulate NRAGE, but induces apoptosis in
      native PC12 cells that endogenously express high levels of NRAGE and in
      differentiated PC12 cells when NRAGE is overexpressed. Together, these results
      demonstrate a mechanism for UNC5H1-mediated apoptosis that requires an
      interaction with the MAGE protein NRAGE.

PMID- 12598532
TI  - Polyglutamine expansion induces a protein-damaging stress connecting heat shock
      protein 70 to the JNK pathway.
AB  - Polyglutamine diseases, including Huntington's disease, designate a group of nine
      neurodegenerative disorders characterized by the presence of a toxic
      polyglutamine expansion in specific target proteins. Using cell and mouse models,
      we have shown that expanded polyglutamine led to activation of the stress kinase
      JNK and the transcription factor AP-1, which are implicated in neuronal death.
      Polyglutamine expansion-induced stress shared common features with protein
      damaging stress such as heat shock, because activation of JNK involved inhibition
      of JNK phosphatase activities. Indeed, expanded polyglutamine impaired the
      solubility of the dual-specificity JNK phosphatase M3/6. Aggregation of M3/6 by
      polyglutamine expansion appeared to be indirect, because M3/6 was not recruited
      into polyglutamine inclusions. The heat shock protein HSP70, which is known to
      inhibit JNK during the heat shock response, suppressed polyglutamine-mediated
      aggregation of M3/6 and activation of JNK. Interestingly, levels of HSP70 were
      down-regulated by polyglutamine expansion. We suggest that reduction of HSP70 by
      expanded polyglutamine is implicated in aggregation and inhibition of M3/6 and in
      activation of JNK and AP-1.

PMID- 12598533
TI  - Parkinsonian mimetics induce aspects of unfolded protein response in death of
      dopaminergic neurons.
AB  - Genes associated with Parkinson's disease (PD) have suggested a role for
      ubiquitin-proteasome dysfunction and aberrant protein degradation in this
      disorder. Inasmuch as oxidative stress has also been implicated in PD, the
      present study examined transcriptional changes mediated by the Parkinsonism
      inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium
      (MPP+) in a dopaminergic cell line. Microarray analysis of RNA isolated from
      toxin treated samples revealed that the stress-induced transcription factor
      CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP+. Treatment
      with 6-OHDA also induced a large number of genes involved in endoplasmic
      reticulum stress and unfolded protein response (UPR) such as ER chaperones and
      elements of the ubiquitin-proteasome system. Reverse transcription-PCR, Western
      blotting, and immunocytochemical approaches were used to quantify and temporally
      order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not
      MPP+, significantly increased hallmarks of UPR such as BiP, c-Jun, and processed
      Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and
      eIF2 alpha, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is
      capable of triggering multiple pathways associated with UPR, whereas MPP+
      exhibits a more restricted response. The involvement of UPR in these widely used
      neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction
      in PD.

PMID- 12598534
TI  - Induction of nonmuscle myosin heavy chain II-C by butyrate in RAW 264.7 mouse
      macrophages.
AB  - RAW 264.7 macrophages express nonmuscle myosin heavy chain II-A as the only
      significant nonmuscle myosin heavy chain isoform, with expression of nonmuscle
      myosin heavy chain II-B and II-C low or absent. Treatment of the cells with
      sodium butyrate, an inhibitor of histone deacetylase, led to the dose-dependent
      induction of nonmuscle myosin heavy chain II-C. Trichostatin A, another inhibitor
      of histone deacetylase, also induced nonmuscle myosin heavy chain II-C. Induction
      of nonmuscle myosin heavy chain II-C in response to these histone deacetylase
      inhibitors was attenuated by mithramycin, an inhibitor of Sp1 binding to GC-rich
      DNA sequences. Bacterial lipopolysaccharide alone had no effect on basal
      nonmuscle myosin heavy chain II-C expression, but attenuated butyrate-mediated
      induction of nonmuscle myosin heavy chain II-C. The effects of lipopolysaccharide
      were mimicked by the nitric oxide donors sodium nitroprusside and spermine
      NONOate, suggesting a role for nitric oxide in the lipopolysaccharide-mediated
      down-regulation of nonmuscle myosin heavy chain II-C induction. This was
      supported by experiments with the inducible nitric-oxide synthase inhibitor
      1400W, which partially blocked the lipopolysaccharide-mediated attenuation of
      nonmuscle myosin heavy chain induction. 8-Bromo-cGMP had no effect on nonmuscle
      myosin heavy chain induction, consistent with a cGMP-independent mechanism for
      nitric oxide-mediated inhibition of nonmuscle myosin heavy chain II-C induction.

PMID- 12598535
TI  - Hydrogen peroxide formation and actin filament reorganization by Cdc42 are
      essential for ethanol-induced in vitro angiogenesis.
AB  - This report focuses on the identification of the molecular mechanisms of ethanol
      induced in vitro angiogenesis. The manipulation of angiogenesis is an important
      therapeutic approach for the treatment of cancer, cardiovascular diseases, and
      chronic inflammation. Our results showed that ethanol stimulation altered the
      integrity of actin filaments and increased the formation of lamellipodia and
      filopodia in SVEC4-10 cells. Further experiments demonstrated that ethanol
      stimulation increased cell migration and invasion and induced in vitro
      angiogenesis in SVEC4-10 cells. Mechanistically, ethanol stimulation activated
      Cdc42 and produced H(2)O(2) a reactive oxygen species intermediate in SVEC4-10
      cells. Measuring the time course of Cdc42 activation and H(2)O(2) production upon
      ethanol stimulation revealed that the Cdc42 activation and the increase of
      H(2)O(2) lasted more than 3 h, which indicates the mechanisms of the long
      duration effects of ethanol on the cells. Furthermore, either overexpression of a
      constitutive dominant negative Cdc42 or inhibition of H(2)O(2) production
      abrogated the effects of ethanol on SVEC4-10 cells, indicating that both the
      activation of Cdc42 and the production of H(2)O(2) are essential for the actions
      of ethanol. Interestingly, we also found that overexpression of a constitutive
      dominant positive Cdc42 itself was sufficient to produce H(2)O(2) and to induce
      in vitro angiogenesis. Taken together, our results suggest that ethanol
      stimulation can induce H(2)O(2) production through the activation of Cdc42, which
      results in reorganizing actin filaments and increasing cell motility and in vitro
      angiogenesis.

PMID- 12598536
TI  - Platelet-derived growth factor (PDGF)-C, a PDGF family member with a vascular
      endothelial growth factor-like structure.
AB  - Platelet-derived growth factor (PDGF)-C is a novel member of the PDGF family that
      binds to PDGF alphaalpha and alphabeta receptors. The growth factor domain of
      PDGF-C (GFD-PDGF-C) was expressed in high yields in Escherichia coli and was
      purified and refolded from inclusion bodies obtaining a biologically active
      growth factor with dimeric structure. The GFD-PDGF-C contains 12 cysteine
      residues, and Ellman assay analysis indicates that it contains three
      intramonomeric disulfide bonds, which is in accordance with GFD-PDGF-C being a
      member of the cystine knot superfamily of growth factors. The recombinant GFD
      PDGF-C was characterized by CD, fluorescence, NMR, and infrared spectroscopy.
      Together, our data indicate that GFD-PDGF-C is a highly thermostable protein that
      contains mostly beta-sheet secondary structure and some (6%) alpha-helix
      structure. The structural model of PDGF-C, obtained by homology-based molecular
      modeling using the structural representatives of this family of growth factors,
      shows that GFD-PDGF-C has a higher structural homology to the vascular
      endothelial growth factor than to PDGF-B. The modeled structure can give further
      insights into the function and specificity of this molecule.

PMID- 12598537
TI  - DNA (cytosine-N4-)- and -(adenine-N6-)-methyltransferases have different kinetic
      mechanisms but the same reaction route. A comparison of M.BamHI and T4 Dam.
AB  - We studied the kinetics of methyl group transfer by the BamHI DNA-(cytosine-N(4)
      )-methyltransferase (MTase) from Bacillus amyloliquefaciens to a 20-mer
      oligodeoxynucleotide duplex containing the palindromic recognition site GGATCC.
      Under steady state conditions the BamHI MTase displayed a simple kinetic behavior
      toward the 20-mer duplex. There was no apparent substrate inhibition at
      concentrations much higher than the K(m) for either DNA (100-fold higher) or S
      adenosyl-l-methionine (AdoMet) (20-fold higher); this indicates that dead-end
      complexes did not form in the course of the methylation reaction. The DNA
      methylation rate was analyzed as a function of both substrate and product
      concentrations. It was found to exhibit product inhibition patterns consistent
      with a steady state random bi-bi mechanism in which the dominant order of
      substrate binding and product release (methylated DNA, DNA(Me), and S-adenosyl-l
      homocysteine, AdoHcy) was Ado-Met DNA DNA(Me) AdoHcy. The M.BamHI kinetic scheme
      was compared with that for the T4 Dam (adenine-N(6)-)-MTase. The two differed
      with respect to an effector action of substrates and in the rate-limiting step of
      the reaction (product inhibition patterns are the same for the both MTases). From
      this we conclude that the common chemical step in the methylation reaction,
      methyl transfer from AdoMet to a free exocyclic amino group, is not sufficient to
      dictate a common kinetic scheme even though both MTases follow the same reaction
      route.

PMID- 12598538
TI  - The C terminus of the Escherichia coli RecA protein modulates the DNA binding
      competition with single-stranded DNA-binding protein.
AB  - The nucleation step of Escherichia coli RecA filament formation on single
      stranded DNA (ssDNA) is strongly inhibited by prebound E. coli ssDNA-binding
      protein (SSB). The capacity of RecA protein to displace SSB is dramatically
      enhanced in RecA proteins with C-terminal deletions. The displacement of SSB by
      RecA protein is progressively improved when 6, 13, and 17 C-terminal amino acids
      are removed from the RecA protein relative to the full-length protein. The C
      terminal deletion mutants also more readily displace yeast replication protein A
      than does the full-length protein. Thus, the RecA protein has an inherent and
      robust capacity to displace SSB from ssDNA. However, the displacement function is
      suppressed by the RecA C terminus, providing another example of a RecA activity
      with C-terminal modulation. RecADeltaC17 also has an enhanced capacity relative
      to wild-type RecA protein to bind ssDNA containing secondary structure. Added
      Mg(2+) enhances the ability of wild-type RecA and the RecA C-terminal deletion
      mutants to compete with SSB and replication protein A. The overall binding of
      RecADeltaC17 mutant protein to linear ssDNA is increased further by the mutation
      E38K, previously shown to enhance SSB displacement from ssDNA. The double mutant
      RecADeltaC17/E38K displaces SSB somewhat better than either individual mutant
      protein under some conditions and exhibits a higher steady-state level of binding
      to linear ssDNA under all conditions.

PMID- 12598540
TI  - The International Dental Research Agenda--The FDI World Dental Federation.

PMID- 12598539
TI  - C-terminal deletions of the Escherichia coli RecA protein. Characterization of in
      vivo and in vitro effects.
AB  - A set of C-terminal deletion mutants of the RecA protein of Escherichia coli,
      progressively removing 6, 13, 17, and 25 amino acid residues, has been generated,
      expressed, and purified. In vivo, the deletion of 13 to 17 C-terminal residues
      results in increased sensitivity to mitomycin C. In vitro, the deletions enhance
      binding to duplex DNA as previously observed. We demonstrate that much of this
      enhancement involves the deletion of residues between positions 339 and 346. In
      addition, the C-terminal deletions cause a substantial upward shift in the pH
      reaction profile of DNA strand exchange reactions. The C-terminal deletions of
      more than 13 amino acid residues result in strong inhibition of DNA strand
      exchange below pH 7, where the wild-type protein promotes a proficient reaction.
      However, at the same time, the deletion of 13-17 C-terminal residues eliminates
      the reduction in DNA strand exchange seen with the wild-type protein at pH values
      between 7.5 and 9. The results suggest the existence of extensive interactions,
      possibly involving multiple salt bridges, between the C terminus and other parts
      of the protein. These interactions affect the pK(a) of key groups involved in DNA
      strand exchange as well as the direct binding of RecA protein to duplex DNA.

PMID- 12598541
TI  - The junctional epithelium: from strength to defense.

PMID- 12598542
TI  - Oral clefts and syndromic forms of tooth agenesis as models for genetics of
      isolated tooth agenesis.
AB  - Genetic defects responsible for tooth agenesis are only now beginning to be
      uncovered. MSX1 and PAX9 have been associated with tooth agenesis in mice and
      humans, but interestingly for humans, these genes are associated with specific
      missing teeth. Mouse models also show that specific genes contribute to the
      development of specific types of teeth. A precise description of the phenotype
      specifying which teeth are missing has become fundamental. Mendelian segregation
      can be identified in families with tooth agenesis, but heterogenous or multiple
      genes may be responsible for the development of specific types of teeth agenesis
      in humans. Data from animal models are still very complex, and the human
      embryology is still poorly understood. Oral clefts and syndromic forms of tooth
      agenesis may be the best models for isolated tooth agenesis. In the future, a
      precise description of the missing teeth in syndromes involving tooth agenesis
      may be useful.

PMID- 12598543
TI  - Gene expression of growth differentiation factors in the developing periodontium
      of rat molars.
AB  - Growth and differentiation factors (GDF) 5, 6, and 7 are known to play roles in
      tendon and ligament formation, and are therefore probably involved in the
      formation of periodontal ligament. In this study, we sought to determine temporal
      and spatial expression of GDF-5, -6, and -7 mRNA in developing periodontal tissue
      of rat molars using in situ hybridization. GDF gene expression in the periodontal
      ligament was first detected in cells associated with the initial process of
      periodontal ligament fiber bundle formation. Gene signals were also detected in
      cells located along the alveolar bone and cementum surfaces, the insertion sites
      of periodontal ligaments, during the course of root formation. GDF expression in
      these cells were down-regulated after completion of root formation. Our results
      appeared to suggest the involvement of GDF-5, -6, and -7 in the formation of the
      dental attachment apparatus.

PMID- 12598544
TI  - Expression of bone morphogenetic proteins and Msx genes during root formation.
AB  - Like crown development, root formation is also regulated by interactions between
      epithelial and mesenchymml tissues. Bone morphogenetic proteins (BMPs), together
      with the transcription factors Msx1 and Msx2, play important roles in these
      interactions during early tooth morphogenesis. To investigate the involvement of
      this signaling pathway in root development, we analyzed the expression patterns
      of Bmp2, Bmp3, Bmp4, and Bmp7 as well as Msx1 and Msx2 in the roots of mouse
      molars. Bmp4 was expressed in the apical mesenchyme and Msx2 in the root sheath.
      However, Bmps were not detected in the root sheath epithelium, and Msx
      transcripts were absent from the underlying mesenchyme. These findings indicate
      that this Bmp signaling pathway, required for tooth initiation, does not regulate
      root development, but we suggest that root shape may be regulated by a mechanism
      similar to that regulating crown shape in cap-stage tooth germs. Msx2 expression
      continued in the epithelial cell rests of Malassez, and the nearby cementoblasts
      intensely expressed Bmp3, which may regulate some functions of the fragmented
      epithelium.

PMID- 12598545
TI  - Expression of vascular endothelial growth factor and the effects on bone
      remodeling during experimental tooth movement.
AB  - Vascular endothelial growth factor (VEGF) has an ability to induce functional
      osteoclasts as well as neovascularization. We recently reported that the number
      of osteoclasts was enhanced by the injection of recombinant human VEGF (rhVEGF)
      with the application of mechanical force for experimental tooth movement. In this
      study, the expression of VEGF was detected in osteoblasts on the tension side of
      the alveolar bone. Moreover, the rate of tooth movement was significantly
      increased in the rhVEGF injection groups compared with the controls. These
      results suggested that VEGF, highly expressed by mechanical stimuli, enhances the
      number of osteoclasts as a paracrine factor, and that the amount of tooth
      movement is accelerated by both endogenous VEGF and injected rhVEGF.

PMID- 12598546
TI  - NF-kappaB activation and iNOS expression in the synovial membrane of rat
      temporomandibular joints after induced synovitis.
AB  - NF-kappaB plays a pivotal role in pathogenesis in general arthritis. However, the
      participation of NF-kappaB in inflammation of the temporomandibular joint (TMJ)
      is poorly understood. We examined NF-kappaB expression in rat TMJs with synovitis
      induced by condyle hypermobility. By immunohistochemistry, NF-kappaB
      immunoreactivity was found mainly in the cytoplasm, not the nucleus, of the
      synovial lining cells of induced-synovitis and control TMJs. Southwestern
      histochemistry, a new method for detecting transcription factors, showed greater
      NF-kappaB expression in the nucleus of the synovial lining cells in the
      hypertrophic synovium than in control synovium. Increased numbers of the synovial
      lining cells with immunoreactivity for inducible nitric oxide synthase (iNOS),
      which is transcriptionally regulated by NF-kappaB, were also seen in the inflamed
      synovium. These findings indicate that excess mechanical stress increases NF
      kappaB activation in the TMJ and suggest that active NF-kappaB is involved in the
      progression of TMJ inflammation.

PMID- 12598547
TI  - The interleukin-1 polymorphism, smoking, and the risk of periodontal disease in
      the population-based SHIP study.
AB  - Several studies have shown a role for interleukin-1 gene cluster polymorphisms in
      the risk assessment for periodontal diseases. In the Study of Health in Pomerania
      (SHIP), 3148 subjects were randomly selected from the population and assessed for
      a broad range of diseases and environmental/behavioral risk factors. From the
      complete study group in the age 40 to 60 years, N = 1085 subjects were genotyped
      for the interleukin-1 genotype composite polymorphism in relation to periodontal
      parameters. The study objective was to elucidate the gene-environment interaction
      between the risk factors smoking and IL-1 polymorphism. An increased risk of
      periodontal disease was found for IL-1 genotype-positive smokers: odds ratio
      adjusted for age, sex, education, and plaque OR = 2.50 (95% C.I. 1.21 to 5.13; p
      = 0.013). This was not the case with subjects who never smoked: OR = 1.09 (0.73
      1.62; p = 0.676). These results support the hypothesis of gene-environmental
      interaction in periodontitis.

PMID- 12598548
TI  - Optimism and life satisfaction as determinants for dental and general health
      behavior-oral health habits linked to cardiovascular risk factors.
AB  - Oral infections and cardiovascular diseases share common biological and
      behavioral risk factors. Psychosocial determinants could act as a link between
      general health behavior and dental health behavior. Our objective was to study
      optimism and life satisfaction as determinants of general and dental health
      behavior and to evaluate whether these are connected with cardiovascular risk
      factors and dental diseases. The 1966 Northern Finland Birth Cohort (N = 12,058)
      is a general population birth cohort. In a postal questionnaire, respondents (N =
      8690) were asked about their health behavior and dental status. Cardiovascular
      risk factors were assessed in health examinations (N = 6033). Generalized linear
      regression models were used in analysis. The results showed that health
      orientation increases with strengthening life satisfaction and optimism. Dental
      health behavior and general health behavior were associated with both
      cardiovascular risk factors and self-reported dental diseases, which support the
      assumption that they share a common behavioral background.

PMID- 12598549
TI  - Unification of the "burst" and "linear" theories of periodontal disease
      progression: a multilevel manifestation of the same phenomenon.
AB  - Previously, burst and linear theories for periodontal disease progression were
      proposed based on different but limited statistical methods of analysis.
      Multilevel modeling provides a new approach, yielding a more comprehensive model.
      Random coefficient models were used to analyze longitudinal periodontal data
      consisting of repeated measures (level 1), sites (level 2), teeth (level 3), and
      subjects (level 4). Large negative and highly significant correlations between
      random linear and quadratic time coefficients indicated that subjects and teeth
      with greater-than-average linear change experienced decelerated variation.
      Conversely, subjects and teeth with less-than-average linear change experienced
      accelerated variation. Change therefore exhibited a dynamic regression to the
      mean at the tooth and subject levels. Since no equilibrium was attained
      throughout the study, changes were cyclical. When considered as a multilevel
      system, the "linear" and "burst" theories of periodontal disease progression are
      a manifestation of the same phenomenon: Some sites improve while others progress,
      in a cyclical manner.

PMID- 12598550
TI  - Retention in plaque and remineralization of enamel lesions by various forms of
      calcium in a mouthrinse or sugar-free chewing gum.
AB  - Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) nanocomplexes
      incorporated into sugar-free chewing gum have been shown to remineralize enamel
      subsurface lesions in situ. The aim of this study was to compare the ability of
      CPP-ACP, with that of other forms of calcium, to be retained in supragingival
      plaque and remineralize enamel subsurface lesions in situ when delivered in a
      mouthrinse or sugar-free gum in randomized, double-blind trials. In the
      mouthrinse study, only the CPP-ACP-containing mouthrinse significantly increased
      plaque calcium and inorganic phosphate levels, and the CPP were immunolocalized
      to the surfaces of bacterial cells as well as the intercellular matrix. In the
      chewing gum studies, the gum containing the CPP-ACP, although not containing the
      most calcium per piece of gum, produced the highest level of enamel
      remineralization independent of gum-chewing frequency and duration. The CPP could
      be detected in plaque extracts 3 hrs after subjects chewed the CPP-ACP-containing
      gum. The results showed that CPP-ACP were superior to other forms of calcium in
      remineralizing enamel subsurface lesions.

PMID- 12598551
TI  - Human masticatory muscle forces during static biting.
AB  - Muscle forces determine joint loads, but the objectives governing the mix of
      muscle forces involved are unknown. This study tested the hypothesis that
      masticatory muscle forces exerted during static biting are consistent with
      objectives of minimization of joint loads (MJL) or muscle effort (MME). To do
      this, we compared numerical model predictions with data measured from six
      subjects. Biting tasks which produced moments on molar and incisor teeth were
      modeled based on MJL or MME. The slope of predicted vs. electromyographic (EMG)
      data for an individual was compared with a perfect match slope of 1.00.
      Predictions based on MME matched best with EMG activity for molar biting (slopes,
      0.89-1.16). Predictions from either or both models matched EMG results for
      incisor biting (best-match slopes, 0.95-1.07). Muscle forces during isometric
      biting appear to be consistent with objectives of MJL or MME, depending on the
      individual, biting location, and moment.

PMID- 12598552
TI  - Association between serum albumin and root caries in community-dwelling older
      adults.
AB  - Recently, associations between dental diseases and the general health condition
      have been reported. The purpose of this study was to evaluate, by serum albumin
      concentrations, the relationship between the general health condition and root
      caries. We randomly selected 763 individuals (600 70-year-olds and 163 80-year
      olds) living in Niigata City, Japan. The variables body composition, blood
      measurements, daily nutrient intakes, and root caries were measured. The
      relationship between root caries and serum albumin concentration was evaluated.
      The differences in serum albumin concentrations between subjects with untreated
      root caries (DT = 0 and DT > 3) were 75.56 mg/dL in 70-year-olds and 202.97 mg/dL
      in 80-year-olds (p < 0.05, ANOVA). The findings of the present study indicated
      that a relationship between root caries and serum albumin concentration in these
      elderly subjects is highly possible.

PMID- 12598553
TI  - Increased preventive practices lead to greater tooth retention.
AB  - Prior research has rarely examined the impact of ADA-recommended preventive
      practices on tooth retention. We hypothesized that better oral hygiene leads to
      increased tooth retention. We examined the association of cross-sectional and
      long-term assessments of preventive practices, as well as various combinations of
      hygiene practices, with tooth retention. Among 736 male participants in the VA
      Dental Longitudinal Study, we utilized cross-sectional and longitudinal self
      reports of toothbrushing, dental floss use, annual prophylaxis, and combinations
      of such behaviors, and examined their association with clinically assessed
      numbers of teeth. Baseline and long-term hygiene behaviors (except brushing) were
      associated with an increased baseline number of teeth and decreased subsequent
      tooth loss. Use of multiple hygiene behaviors was associated with greater tooth
      retention, cross-sectionally and longitudinally. Adherence to ADA recommendations
      for preventive care leads to better oral health, and consistently practicing
      preventive behaviors over the long term confers greater benefits than doing so
      over the short term.

PMID- 12598554
TI  - Dynamic shear properties of the temporomandibular joint disc.
AB  - Shear stress might be an important factor associated with fatigue failure and
      damage of the temporomandibular joint disc. Little information, however, is
      available on the dynamic behavior of the disc in shear. Since the disc is an
      anisotropic and viscoelastic structure, in the present study the dependency of
      the dynamic shear behavior on the direction and frequency of loading was
      examined. Ten porcine discs were used for dynamic shear tests. Shear stress was
      applied in both anteroposterior (A-P test) and mediolateral (M-L test)
      directions. The dynamic moduli increased as the loading frequency increased. The
      dynamic elasticity was significantly larger in the A-P test than in the M-L test,
      although the dynamic viscosity was similar in both tests. The present results
      suggest that non-linearities, compression/shear coupling, and intrinsic
      viscoelasticity affect the shear material behavior of the disc, which might have
      important implications for the transmission of load in the temporomandibular
      joint.

PMID- 12598555
TI  - Persistent acute inflammation at the implant-abutment interface.
AB  - The inflammatory response adjacent to implants has not been well-investigated and
      may influence peri-implant tissue levels. The purpose of this study was to
      assess, histomorphometrically, (1) the timing of abutment connection and (2) the
      influence of a microgap. Three implant designs were placed in the mandibles of
      dogs. Two-piece implants were placed at the alveolar crest and abutments
      connected either at initial surgery (non-submerged) or three months later
      (submerged). The third implant was one-piece. Adjacent interstitial tissues were
      analyzed. Both two-piece implants resulted in a peak of inflammatory cells
      approximately 0.50 mm coronal to the microgap and consisted primarily of
      neutrophilic polymorphonuclear leukocytes. For one-piece implants, no such peak
      was observed. Also, significantly greater bone loss was observed for both two
      piece implants compared with one-piece implants. In summary, the absence of an
      implant-abutment interface (microgap) at the bone crest was associated with
      reduced peri-implant inflammatory cell accumulation and minimal bone loss.

PMID- 12598557
TI  - Neurotoxicity of dental amalgam is mediated by zinc.
AB  - The use of dental amalgam is controversial largely because it contains mercury.
      We tested whether amalgam caused toxicity in neuronal cultures and whether that
      toxicity was caused by mercury. In this study, we used cortical cell cultures to
      show for the first time that amalgam causes nerve cell toxicity in culture.
      However, the toxicity was not blocked by the mercury chelator, 2,3
      dimercaptopropane-1-sulphonate (DMPS), but was blocked by the metal chelator,
      calcium disodium ethylenediaminetetraacetate (CaEDTA). DMPS was an effective
      mercury chelator in this system, since it blocked mercury toxicity. Of the
      components that comprise amalgam (mercury, zinc, tin, copper, and silver), only
      zinc neurotoxicity was blocked by CaEDTA. These results indicate that amalgam is
      toxic to nerve cells in culture by releasing zinc. While zinc is known to be
      neurotoxic, ingestion of zinc is not a major concern because zinc levels in the
      body are tightly regulated.

PMID- 12598556
TI  - Lifetime prediction of all-ceramic bridges by computational methods.
AB  - There has been limited use of ceramic materials for all-ceramic posterior
      bridges. Major reasons are the low strength, the strength scatter, and the time
      dependent strength decrease of ceramics due to slow crack growth. The objective
      of this study was to predict the long-term failure probability and loading
      capability of all-ceramic bridges (Empress 1, Empress 2, In-Ceram Alumina, and
      ZrO(2)) by computational techniques. The lifetimes of different bridge model
      designs were predicted by means of the NASA post-processor CARES. Bridges made of
      zirconia showed a very high mechanical long-term reliability. Empress I and
      InCeram Alumina seem to be insufficient as posterior bridge materials based on
      this prediction. The lifetime of the all-ceramic bridges can be significantly
      increased by improving the design in the connector area. We conclude that
      computational techniques can help to judge a ceramic material and a specific
      ceramic bridge design with respect to mechanical reliability before clinical use.

PMID- 12598558
TI  - Plant culture: thirteen seasonal pieces. March--say it is ashboughs.

PMID- 12598559
TI  - Radiation measurement for plant ecophysiology.
AB  - The principles of radiation physics for plant ecophysiological studies are
      outlined with an emphasis on choosing appropriate sensors for specific purposes
      such as for studies of photosynthesis, UV-B damage or canopy energy balance.
      Remote sensing, both from the ground and from aircraft or satellites, is
      increasingly being used as a tool for the study of plant canopies. Therefore,
      relevant terminology and applications are discussed, including the use of remote
      sensing for the determination of canopy structural properties and the use of
      thermal remote sensing for the measurement of canopy temperature, for example, in
      energy balance studies.

PMID- 12598560
TI  - A comparison of manual and automated systems for soil CO2 flux measurements:
      trade-offs between spatial and temporal resolution.
AB  - Soil respiration is affected by distributions of roots and soil carbon substrates
      and by temperature and soil water content, all of which vary spatially and
      temporally. The objective of this paper was to compare a manual system for
      measuring soil respiration in a temperate forest, which had a greater spatial
      distribution of measurements (n=12), but poorer temporal resolution (once per
      week), with an automated system which had poorer spatial distribution (n=3) but
      superior temporal frequency of measurements (hourly). Soil respiration was
      measured between 18 June and 21 August, 2002, at the Harvard Forest in central
      Massachusetts, USA. The fluxes measured within 1 h of each other by these systems
      were not significantly different. However, extrapolations of the mid-morning
      manual measurements to daily flux values were consistently lower (averaging 13%
      lower) than the daily estimates obtained from summing the 24 hourly measurements
      of the automated system. On the other hand, seasonal flux estimates obtained by
      interpolating between weekly manual sampling dates or by summing the hourly
      automated measurements were nearly identical. Underestimates by interpolated
      weekly manual measurements during some periods were cancelled by overestimates
      during other periods. Hence, a weekly sampling schedule may be sufficient to
      capture the most important variation of seasonal efflux of CO(2) from the soil.
      The larger number of chambers that could be measured with the manual system
      (larger n) resulted in a smaller 95% confidence interval for characterizing
      spatial variability within the study area on most dates. However, the greater
      sampling frequency of the automated system revealed rapid responses of soil
      respiration to wetting events, which permitted better empirical modelling of the
      effects of soil temperature and moisture on soil respiration than could have been
      achieved with the manual sampling system. Most of the positive residuals of a
      function that predicts soil respiration based on temperature were from fluxes
      measured within 12 h of a rain event, and the residuals were positively
      correlated with water content of the O horizon. The automated system also
      demonstrated that Q(10) values calculated for diel variation in soil temperature
      over a few days were not significantly different than Q(10) values for the entire
      3 month summer sampling period. In summary, a manual system of numerous,
      spatially well-distributed flux chambers measured on a weekly basis may be
      adequate for measuring seasonal fluxes and may maximize confidence in the
      characterization of spatial variance. The high temporal frequency of measurements
      afforded by automation greatly improves the ability to measure and model the
      effects of rapidly varying water content and temperature. When the two approaches
      can be combined, the temporal representativeness of the manual measurements can
      be tested with the automated measurements and the spatial representativeness of
      the automated measurements can be tested by the manual measurements.

PMID- 12598561
TI  - The role of two isoenzymes of alpha-amylase of Araucaria araucana (Araucariaceae)
      on the digestion of starch granules during germination.
AB  - Starch is the principal reserve of Araucaria araucana seeds, and it is hydrolysed
      during germination mainly by alpha-amylase. There are several alpha-amylase
      isoenzymes whose patterns change in the embryo and in the megagametophyte from
      the one observed in quiescent seeds (T(0)) to a different one observed 90 h after
      imbibition (T(90)). The objective of this research was to study the roles of two
      purified alpha-amylase isoenzymes by in vitro digestion of starch granules
      extracted from the tissues at two times of imbibition: one is abundant in
      quiescent seeds and the other is abundant after 90 h of imbibition. The
      isoenzymes digested the starch granules of their own stage of germination better,
      since the isoenzyme T(0) digested starch granules mainly from quiescent seeds,
      while the isoenzyme T(90) digested starch mainly at 90 h of imbibition. The sizes
      of the starch granule and the tissue from which these granules originated make a
      difference to digestion by the isoenzymes. Embryonic isoenzyme T(0) digested
      large embryonic starch granules better than small and medium-sized granules, and
      better than those isolated from megagametophytes. Similarly isoenzyme T(90)
      digested small embryonic starch granules better than medium-sized and large
      granules, and better than those isolated from megagametophytes. However, a
      mixture of partially purified megagametophytic isoenzymes T(0) and T(90) digested
      the megagametophytic granules better than those isolated from embryos. Studies of
      in vitro sequential digestion of starch granules with these isoenzymes
      corroborated their specificity. The isoenzyme T(90) digested starch granules
      previously digested by the isoenzyme T(0). This suggests that in vivo these two
      isoenzymes may act sequentially in starch granule digestion.

PMID- 12598562
TI  - Uncleaved legumin in developing maize endosperm: identification, accumulation and
      putative subcellular localization.
AB  - While identifying proteins present in the cytoskeleton and protein body fractions
      from maize (Zea mays L.) endosperm, a 51 kDa protein was discovered in a fraction
      containing small (approximately 200 nm in diameter) protein bodies. Based on
      partial amino acid sequences of V8 protease fragments, degenerate primers were
      made and fragments of cDNA encoding these partial sequences were cloned. Using 3'
      and 5' PCR, a full-length cDNA encoding this 51 kDa protein was obtained, which
      was identified as legumin-1. In other plants, this protein is generally cleaved
      into 20 and 35 kDa subunits after synthesis. However, SDS-PAGE of both the native
      and denatured protein indicates that cleavage does not occur in corn endosperm,
      even though the cleavage site (asparagine) is conserved. The lack of cleavage is
      presumably because the canonical cleavage sequence downstream from the cleavage
      site is almost totally absent. levels of transcript and encoded protein were
      compared in all three varieties and it was shown that both are more abundant in
      wild-type maize than in opaque-2 or sweet corn. Finally, using TEM, it was shown
      that the protein apparently occurs in morphologically distinct protein bodies,
      very similar to the protein bodies in legumes.

PMID- 12598563
TI  - Mitochondrial and peroxisomal manganese superoxide dismutase: differential
      expression during leaf senescence.
AB  - In pea (Pisum sativum L.) leaves, manganese superoxide dismutase (Mn-SOD) is
      mainly localized in mitochondria as well as in peroxisomes. In this work, the
      effect of leaf senescence on the peroxisomal and mitochondrial Mn-SOD was studied
      in detached leaves from pea plants which were incubated in the dark at 25 degrees
      C for 3-11 d. Northern blots hybridized with a cDNA encoding mitochondrial Mn-SOD
      from pea leaves and a mitochondrial Mn-SOD transit peptide-specific probe showed
      increased Mn-SOD transcript levels during leaf senescence, due in part to in
      creased mitochondrial Mn-SOD mRNA. Recombinantly-expressed mitochondrial Mn-SOD
      was used to raise polyclonal antibodies which cross-reacted with Mn-SOD in
      peroxisomes purified from pea leaves. Western blot assays of crude extracts with
      the antibodies to pea mitochondrial Mn-SOD showed that the levels of total Mn-SOD
      protein gradually increased with leaf senescence. By native PAGE, the total Mn
      SOD activity of pea leaves increased with senescence. EM immunocytochemistry was
      used to distinguish mitochondrial and peroxisomal Mn-SOD in senescent leaves.
      Increased Mn-SOD labelling in mitochondria was intensified, whereas the
      immunogold labelling of peroxisomes did not change with senescence. Overall,
      these results show that mitochondrial and peroxisomal Mn-SOD expression is
      regulated differently. The expression of mitochondrial Mn-SOD is induced during
      the senescence of pea leaves, whereas peroxisomal Mn-SOD could be post
      translationally activated. Previously described results showing decreased
      mitochondrial Mn-SOD activity and increased peroxisomal Mn-SOD activity may be
      reflective of post-translational events regulating enzymatic activity during leaf
      senescence.

PMID- 12598564
TI  - Reactive oxygen species production in association with suberization: evidence for
      an NADPH-dependent oxidase.
AB  - In response to wounding, potato tubers generate reactive oxygen species (ROS) in
      association with suberization. Immediately following wounding, an initial burst
      of ROS occurs, reaching a maximum within 30 to 60 min. In addition to this
      initial oxidative burst, at least three other massive bursts occur at 42, 63 and
      100 h post-wounding. These latter bursts are associated with wound healing and
      are probably involved in the oxidative cross-linking of suberin poly(phenolics).
      The source of ROS is likely to be a plasma membrane NADPH-dependent oxidase
      immunorelated to the human phagocyte plasma membrane oxidase. The initial
      oxidative burst does not appear to be dependent on new protein synthesis, but the
      subsequent bursts are associated with an increase in oxidase protein components.
      Oxidase activity is enhanced in vitro by hydroxycinnamic acids and conjugates
      associated with the wound healing response in potato.

PMID- 12598565
TI  - The first 238 amino acids of the human lamin B receptor are targeted to the
      nuclear envelope in plants.
AB  - In plants, the nuclear envelope (NE) is one of the least characterized cellular
      structures. In particular, little is known about its dynamics during the cell
      cycle. This is due to the absence of specific markers for in vivo studies. To
      generate such an in vivo marker, the suitability of the human lamin B receptor
      (LBR) was tested. When the first 238 amino acids of the LBR, fused to the green
      fluorescent protein (GFP), were expressed in tobacco plants, fluorescence
      accumulated only at the NE of leaf epidermal cells. This was confirmed by
      electron microscopy. The protein was shown to be membrane-integral by phase
      separation. Distribution of fluorescence was compared with two ER markers, GFP
      calnexin and GFP-HDEL. While co-localization of all three markers was noted at
      the NE, only LBR-GFP was specific to the NE, while the other two also showed
      fluorescence of the cortical ER. These results suggest that common targeting
      mechanisms to those in animals and fungi exist in plants to direct and locate
      proteins to the NE. This chimaeric construct is the first available fluorescent
      integral membrane protein marker to be targeted exclusively to the plant NE and
      it provides a novel opportunity to investigate the dynamics of this membrane
      system in vivo. With it, the cell cycle was followed in tobacco BY-2 cells stably
      expressing the fusion protein. The interphase labelling of the NE altered in
      metaphase into an ER-like meshwork, suggesting the dispersal of the NE to ER as
      in animal cells. Finally, the meshwork of fluorescent membranes was lost and new
      fluorescent NE formed around the daughter nuclei.

PMID- 12598566
TI  - A cathepsin B-like cysteine protease gene from Hordeum vulgare (gene CatB)
      induced by GA in aleurone cells is under circadian control in leaves.
AB  - A barley cDNA clone encoding a putative cysteine protease with sequence homology
      to cathepsin B from mammalian cells has been characterized. This barley gene
      (CatB) is ubiquitously expressed, its mRNA being detected in leaves and roots,
      immature, mature and germinating embryos, in developing endosperms, and in
      aleurones upon germination, as assessed by northern blot analysis. The CatB mRNA
      expression in leaves increased by cold shock (6 degrees C), was not affected by
      wounding, and was under circadian control. These transcripts increased in the
      aleurone upon germination, whereas those for a cystatin encoding gene (Icy), that
      inhibits commercial cathepsin B in vitro, decreased. Gibberellin (GA) treatment
      of isolated barley aleurones induced and abscisic acid (ABA) repressed the steady
      state levels of CatB mRNA, while Icy expression had an opposite pattern of mRNA
      accumulation in aleurones treated with GA. No response to GA or ABA was detected
      in leaves.

PMID- 12598567
TI  - Transcriptional activation of phosphoenolpyruvate carboxylase by phosphorus
      deficiency in tobacco.
AB  - Phosphoenolpyruvate carboxylase (PEPC), which catalyses the carboxylation of
      phosphoenolpyruvate using HCO(3)(-) to generate oxaloacetic acid, is an important
      enzyme in the primary metabolism of plants. Although the PEPC genes (ppc)
      comprise only a small gene family, the function of each gene is not clear, except
      for roles in C(4) photosynthesis and CAM. Three PEPC genes (Nsppc1-3) from the
      C(3) plant Nicotiana sylvestris were used to investigate their roles and
      regulation in a C(3) plant, and their regulation by phosphorus depletion in
      particular. First, the induction of PEPC by phosphorus depletion was confirmed.
      Next, Nsppc1 was determined to be mainly responsive to phosphorus deficiency at
      the transcriptional level. Further studies using transgenic tobacco harbouring a
      chimeric gene consisting of the 2.0 kb promoter region of Nsppc1 and the beta
      glucuronidase (GUS) reporter showed that PEPC is transcriptionally induced. It
      was also found that sucrose had a synergistic effect on the induction of PEPC by
      phosphorus deficiency. A series of transgenic tobacco containing 5'-deletion
      mutants of Nsppc1 promoter::GUS fusion revealed that the -539 to -442 bp Nsppc1
      promoter region, relative to the translation start site, was necessary for the
      response to phosphorus deficiency. Gain-of-function analysis using a construct
      containing three tandem repeats of the -539 to -442 bp region confirmed that this
      region was sufficient to induce the phosphorus-deficiency response in tobacco.

PMID- 12598569
TI  - The micromorphology and protein characterization of rubber particles in Ficus
      carica, Ficus benghalensis and Hevea brasiliensis.
AB  - Rubber biosynthesis takes place on the surface of rubber particles. These
      particles are surrounded by a monolayer membrane in which the rubber transferase
      is anchored. In order to gain better insight into whether rubber particles from
      different plant species share common structural characteristics, the
      micromorphology of rubber particles from Ficus carica, Ficus benghalensis, and
      Hevea brasiliensis was examined by electron microscopy. Rubber particles of all
      three species were spherical in shape, and the size of rubber particles of H.
      brasiliensis was much smaller than those of F. carica and F. benghalensis. In
      addition, investigations were undertaken to compare the cross-reactivity of the
      antibody raised against either the H. brasiliensis small rubber particle protein
      (SRPP) which is suggested to be involved in rubber biosynthesis, or the cis
      prenyltransferase (CPT) which has an activity similar to rubber transferase. Both
      western analysis and TEM-immunogold labelling studies showed that rubber
      particles of F. carica and F. benghalensis do not contain the SRPP. None of the
      rubber particles in F. carica, F. benghalensis and H. brasiliensis contained the
      CPT, suggesting that the CPT itself could not catalyse the formation of high
      molecular weight rubber. These results indicate that rubber particles in the
      three different plant species investigated share some degree of similarity in
      architecture, and that the SRPP and CPT themselves are not the core proteins
      necessary for rubber biosynthesis.

PMID- 12598568
TI  - A Tudor protein with multiple SNc domains from pea seedlings: cellular
      localization, partial characterization, sequence analysis, and phylogenetic
      relationships.
AB  - A major high molecular weight protein (HMP) in the cytoskeletal fraction from pea
      has been purified. A combination of chromatographic techniques and protease
      fragment analysis also facilitated the isolation of the encoding cDNA, disclosing
      the sequence of the complete open reading frame. The protein possesses four
      complete N-terminal Staphylococcal nuclease (SNc) domains, a central Tudor domain
      and a partial SNc domain at the C-terminus, which may act as a coiled-coil
      cytoskeleton interaction motif. Cell fractionation studies showed that the
      protein was abundant in the cytoskeleton fraction in dark-grown pea seedlings,
      but essentially was absent from the nucleus. Gel filtration column chromatography
      indicated that the native protein exists as a dimer, while isoelectric focusing
      suggested that there were at least four HMP isotypes. The protein co-eluted with
      ribosomes from a heparin affinity column in vitro, consistent with
      ribosome/polysome interactions in vivo. Significantly, sequence analysis of the C
      terminal SNc motif may accurately predict nuclear versus cytoplasmic localization
      resulting in potentially very different functional roles for this protein family
      in different organisms. An antibody to HMP from peas was also raised and an HMP
      with a similar molecular mass was detected in the cytoskeleton fractions and to a
      lesser extent in the nuclear fraction (250 g pellet) from rice and wheat
      seedlings.

PMID- 12598570
TI  - One-step analysis of seed storage data and the longevity of Arabidopsis thaliana
      seeds.
AB  - Seeds of two ecotypes of Arabidopsis thaliana, NW20 and N1601, were aged over a
      range of saturated salt solutions at temperatures between 6 degrees C and 55
      degrees C. For each ecotype, the results from 37 storage experiments were
      summarized using the Ellis and Roberts viability equations and a modified version
      of these equations which allows for a proportion of 'non-respondents'. For both
      models, two approaches were taken in order to model the effect of moisture
      content (MC) and temperature on seed longevity. The first, a two-step approach,
      involved fitting individual survival curves and then multiple regression analysis
      of the fitted parameters on moisture content and temperature. For the second
      approach, the full viability models were fitted in one step, including the
      multiple regression for the effects of MC and temperature within the generalized
      linear model used to describe each survival curve. This one-step approach takes
      into account the full variability of the data and provides the best predictions
      of seed longevity based on the original assumptions of the Ellis and Roberts
      viability equations. As a consequence of taking into account all the variation,
      this one-step approach is more sensitive and thus more likely to detect changes
      due to reducing the number of parameters in the model as being significant.
      Whilst both approaches indicated that seeds from the two Arabidopsis ecotypes
      have the same response to MC and temperature, parameter values did differ between
      the approaches, with the one-step approach providing the better fit. The best
      model for these two ecotypes, from the one-step approach, confirmed a quadratic
      relationship between temperature and longevity, but the magnitude of the non
      linearity is not as large as indicated by the universal value for the quadratic
      term.

PMID- 12598571
TI  - Changes in phosphorylation of 50 and 53 kDa soluble proteins in graviresponding
      oat (Avena sativa) shoots.
AB  - The present work indicates that phosphorylation of a 50 kDa soluble protein is
      involved in the gravitropic response in graviresponsive pulvini of oat (Avena
      sativa) stems. This 50 kDa protein shows a differential pattern of
      phosphorylation between lower and upper halves of pulvini both in vivo and in
      vitro. The differential phosphorylation of this protein is detected only when
      stem segments are gravistimulated for short and long time periods. The
      differential phosphorylation of the 50 kDa protein occurs as early as 5 min after
      the initiation of gravistimulation. This corresponds closely to the presentation
      time of 5.2 min. This differential phosphorylation pattern was changed by
      treatments with cycloheximide, implying that a newly-synthesized protein is
      involved in the differential phosphorylation during the gravitropic response. An
      autophosphorylation experiment shows that the 50 kDa protein has kinase activity.
      The phosphorylation patterns of a 53 kDa protein were similar to those of the 50
      kDa protein, but were only expressed in vitro. These findings indicate that the
      differential phosphorylation of the 50 (and 53 kDa) soluble proteins in
      graviresponding oat shoots may be an important component of the gravity signal
      transduction pathway.

PMID- 12598572
TI  - Expression of a putative high-affinity NO3- transporter and of an H+-ATPase in
      relation to whole plant nitrate transport physiology in two maize genotypes
      differently responsive to low nitrogen availability.
AB  - Two maize genotypes differently responsive to nitrogen availability were
      characterized for their efficiency in nitrate accumulation via both the LATS (Low
      Affinity Transport System) and HATS (High-Affinity Transport System) nitrate
      uptake systems. In addition, a full-length cDNA encoding a putative high-affinity
      nitrate transporter (ZmNrt2.1) was isolated and its expression evaluated in both
      the roots and leaves of the two maize genotypes, together with the expression of
      a maize H(+)-ATPase isoform (Mha1). The data showed the importance of the iHATS
      (Inducible High-Affinity System) system efficiency as a physiological marker of
      adaptation to low input and suggested that the transcript accumulation of
      ZmNrt2.1 might be a key step for the regulation of iHATS. However, ZmNrt2.1
      transcription cannot account for the differences found between the two hybrids in
      terms of the activity of their respective iHATS and, as a consequence, of their
      adaptation to low input. Therefore, the involvement of some other transporter(s)
      or of some post-transcriptional/post-translational mechanism of regulation
      affecting the efficiency of iHATS may be hypothesized. In addition, the data
      suggest that the transcription of the Mha1 gene may also be involved in the
      global efficiency of the iHATS system.

PMID- 12598573
TI  - 14-3-3 isoforms and pattern formation during barley microspore embryogenesis.
AB  - The members of the 14-3-3 isoform family have been shown to be developmentally
      regulated during animal embryogenesis, where they take part in cell
      differentiation processes. 14-3-3 isoform-specific expression patterns were
      studied in plant embryogenic processes, using barley (Hordeum vulgare L.)
      microspore embryogenesis as a model system. After embryogenesis induction by
      stress, microspores with enlarged morphology showed higher viability than non
      enlarged ones. Following microspore culture, cell division was only observed
      among the enlarged microspores. Western blot and immunolocalization of three
      barley 14-3-3 isoforms, 14-3-3A, 14-3-3B and 14-3-3C were carried out using
      isoform-specific antibodies. The level of 14-3-3C protein was higher in enlarged
      microspores than in non-enlarged ones. A processed form of 14-3-3A was associated
      with the death pathway of the non-enlarged microspores. In the early
      embryogenesis stage, 14-3-3 subcellular localization differed among dividing and
      non-dividing microspores and the microspore-derived multicellular structures
      showed a polarized expression pattern of 14-3-3C and a higher 14-3-3A signal in
      epidermis primordia. In the late embryogenesis stage, 14-3-3C was specifically
      expressed underneath the L(1) layer of the shoot apical meristem and in the
      scutellum of embryo-like structures (ELSs). 14-3-3C was also expressed in the
      scutellum and underneath the L(1) layer of the shoot apical meristem of 21 d
      after pollination (DAP) zygotic embryos. These results reveal that 14-3-3A
      processing and 14-3-3C isoform tissue-specific expression are closely related to
      cell fate and initiation of specific cell type differentiation, providing a new
      insight into the study of 14-3-3 proteins in plant embryogenesis.

PMID- 12598574
TI  - Identification of dehydration-responsive cysteine proteases during post-harvest
      senescence of broccoli florets.
AB  - Harvest-induced senescence of broccoli results in tissue wilting and sepal
      chlorosis. As senescence progresses, chlorophyll and protein levels in floret
      tissues decline and endo-protease activity (measured with azo-casein) increases.
      Protease activity increased from 24 h after harvest for tissues held in air at 20
      degrees C. Activity was lower in floret tissues from branchlets that had been
      held in solutions of sucrose (2% w/v) or under high carbon dioxide, low oxygen
      (10% CO(2), 5% O(2)) conditions. Four protease-active protein bands were
      identified in senescing floret tissue by zymography, and the use of chemical
      inhibitors of protease action suggests that some 44% of protease activity in
      senescing floret tissue 72 h after harvest is due to the action of cysteine and
      serine proteases. Four putative cysteine protease cDNAs have been isolated from
      broccoli floret tissue (BoCP1, BoCP2, BoCP3, BoCP4). The cDNAs are most similar
      (73-89% at the amino acid level) to dehydration-responsive cysteine proteases
      previously isolated from Arabidopsis thaliana (RD19, RD21). The mRNAs encoded by
      the broccoli cDNAs are expressed in floret tissue during harvest-induced
      senescence with mRNA accumulating within 6 h of harvest for BoCP1, 12 h of
      harvest for BoCP4 and within 24 h of harvest for BoCP2 and BoCP3. Induction of
      the cDNAs is differentially delayed when broccoli branchlets are held in
      solutions of water or sucrose. In addition, the expression of BoCP1 and BoCP3 is
      inhibited in tissue held in atmospheres of high carbon dioxide/low oxygen (10%
      CO(2), 5% O(2)). The putative cysteine protease mRNAs are expressed before
      measurable increases in endo-protease activity, loss of protein, chlorophyll or
      tissue chlorosis.

PMID- 12598575
TI  - Mechanisms of seed ageing under different storage conditions for Vigna radiata
      (L.) Wilczek: lipid peroxidation, sugar hydrolysis, Maillard reactions and their
      relationship to glass state transition.
AB  - Two primary biochemical reactions in seed ageing (lipid peroxidation and non
      enzymatic protein glycosylation with reducing sugars) have been studied under
      different seed water contents and storage temperatures, and the role of the
      glassy state in retarding biochemical deterioration examined. The viability loss
      of Vigna radiata seeds during storage is associated with Maillard reactions;
      however, the contribution of primary biochemical reactions varies under different
      storage conditions. Biochemical deterioration and viability loss are greatly
      retarded in seeds stored below a high critical temperature (approximately 40
      degrees C above glass transition temperature). This high critical temperature
      corresponds to the cross-over temperature (T(c)) of glass transition where
      molecular dynamics changes from a solid-like system to a normal liquid system.
      The data show that seed ageing slows down significantly, even before seed tissue
      enters into the glassy state.

PMID- 12598576
TI  - Powdery mildew (Sphaerotheca fuliginea) resistance in melon is selectable at the
      haploid level.
AB  - The major cause of powdery mildew in melons (Cucumis melo L.) is the fungus
      Sphaerotheca fuliginea. There are several cultivar- and season-specific races of
      this fungus. In order to control powdery mildew, it is important to introduce
      resistance to fungal infection into new cultivars during melon breeding. Haploid
      breeding is a powerful tool for the production of pure lines. In this study, it
      was investigated whether powdery mildew resistance could be manifested at the
      haploid level from two disease-resistant melon lines, PMR 45 and WMR 29. the
      effects of various races of S. fuliginea on diploid and haploid plants of PMR 45
      and WMR 29 and of a disease-susceptible line, Fuyu 3 were measured. The responses
      of haploid and diploid plants to powdery mildew were identical. In addition,
      haploids that were generated from hybrids between Fuyu 3 and disease-resistant
      lines were examined. Seven out of 13 haploids from a Fuyu 3xPMR 45 cross and 10
      out of 12 haploids from a Fuyu 3xWMR 29 cross were classified as resistant plants
      because they showed the same responses as their disease-resistant diploid parents
      to the various fungal races. These results indicate that resistance in PMR 45 and
      WMR 29 is selectable at the haploid level. All of the plant responses were
      observed by microscopy. A possible mechanism for generating powdery mildew
      resistance in two different melon lines is discussed.

PMID- 12598577
TI  - Malate metabolism and reactions of oxidoreduction in cold-hardened winter rye
      (Secale cereale L.) leaves.
AB  - In cold-hardened leaves (CHL) of winter rye (Secale cereale L.) much higher
      levels of malate were detected by (13)C-NMR than in non-hardened leaves (NHL). As
      this was not observed previously, malate metabolism of CHL was studied in more
      detail by biochemical assays. The activities of several enzymes of malate
      metabolism, NADP-malate dehydrogenase, NAD-malate dehydrogenase,
      phosphoenolpyruvate carboxylase, and NADP-malic enzyme, were also increased in
      CHL. Short exposures to low temperature of 1-3 d did not induce increases in the
      malate content or in the activities of enzymes of malate metabolism in mature
      NHL. The malate content and the enzyme activities declined within 1-2 d after a
      transfer of CHL from their growing temperature of 4 degrees C to 22 degrees C.
      The malate content was further increased when CHL were exposed to a higher light
      intensity at 4 degrees C. In CO(2)-free air the malate content of CHL strongly
      declined at 4 degrees C. Malate may thus serve as an additional carbon sink and
      as a CO(2)-store in CHL. It may further function as a vacuolar osmolyte balancing
      increased concentrations of soluble sugars previously observed in the cytosol of
      CHL. Malate was not used as a source of reductants when CHL were exposed to photo
      oxidative stress by treatment with paraquat. However, the activities of enzymes
      of the oxidative pentose phosphate pathway were markedly increased in CHL and may
      serve as non-photosynthetic sources of NADPH and thus contribute to the
      previously observed superior capacity of CHL of winter rye to maintain their
      antioxidants in a reduced state in the presence of paraquat.

PMID- 12598578
TI  - Leghaemoglobin oxygenation gradients in alfalfa and yellow sweetclover nodules.
AB  - Respiration in support of N(2) fixation by rhizobia in legume root nodules
      depends on an adequate supply of O(2), but excessive O(2) can damage nitrogenase,
      the key enzyme. The movement of O(2) into and within the nodule is driven by
      gradients in the concentration of O(2) or in the oxygenation of the O(2)-carrier,
      leghaemoglobin. Steeper gradients may increase flux to the sites of respiration,
      but gradients also raise the possibility of inadequate O(2) in some nodule zones
      and excessive O(2) in others. No detailed study of O(2) gradients in the interior
      of nodules has been published previously. Spectral changes in leghaemoglobin with
      oxygenation, previously used to measure the average O(2) status of the nodule
      interior, were used to map longitudinal gradients in O(2) and in respiratory
      capacity in the elongated nodules of alfalfa (Medicago sativa L.) and sweetclover
      (Melilotus officinalis L.). Variability among nodules under air in the magnitude
      and direction of internal O(2) gradients was seen in both species. Despite
      consistently higher respiratory capacity near the meristematic tip, a majority of
      nodules had higher O(2) towards the tip than towards the base. These results
      contrast with a previous report, apparently based on limited data, but they are
      consistent with anatomical and tracer studies showing higher gas permeability
      near the tip.

PMID- 12598579
TI  - Tissular localization of coumarins in the green alga Dasycladus vermicularis
      (Scopoli) Krasser: a photoprotective role?
AB  - Cell distribution of coumarins, a group of UV-absorbing substances, was analysed
      by epifluorescence optical microscopy in the green macroalga Dasycladus
      vermicularis. Maximal concentration of 3,6,7-trihydroxycoumarin (THC), which
      corresponds to almost 100% of the total coumarins in D. vermicularis, was found
      in the apical part of the thallus, which is more exposed to solar radiation. At a
      cell level, two blue, highly fluorescent layers, corresponding to a large
      accumulation of THC, were found in the internal part of the cell wall and around
      the vacuolar membrane. The percentage of UV radiation absorbed by each THC layer
      could be measured from the in vitro total thallus concentration of THC and
      histological measurements of the layers. The THC layer close to the cell wall
      absorbed 88% of the incident irradiance at 346 nm (corresponding to the maximum
      of absorbance of THC in the UVA region), while that close to the vacuole membrane
      absorbed 87.5%. These results agree with the hypothesis of a natural sunscreen
      role, significantly reducing harmful UV radiation reaching the cell. Owing to the
      release of this substance into the medium under different stress conditions, its
      capacity as a UV filter for other macroalgae has been tested. The ecological
      relevance of the release process of this UV-absorbing substance in specific
      environments is discussed.

PMID- 12598580
TI  - Greenhouse and field testing of transgenic wheat plants stably expressing genes
      for thaumatin-like protein, chitinase and glucanase against Fusarium graminearum.
AB  - Genes encoding pathogenesis-related (PR-) proteins isolated from a cDNA library
      of Fusarium graminearum-infected wheat spikes of scab-resistant cultivar 'Sumai
      3' were transformed into susceptible spring wheat, 'Bobwhite' using a biolistic
      transformation protocol, with the goal of enhancing levels of resistance against
      scab. Twenty-four putative transgenic lines expressing either a single PR-protein
      gene or combinations thereof were regenerated. Transgene expression in a majority
      of these lines (20) was completely silenced in the T(1) or T(2) generations. Four
      transgenic wheat lines showed stable inheritance and expression of either a
      single transgene or transgene combinations up to four generations. One line co
      expressing a chitinase and beta-1,3-glucanase gene combination, when bioassayed
      against scab showed a delay in the spread of the infection (type II resistance)
      under greenhouse conditions. This line and a second transgenic line expressing a
      rice thaumatin-like protein gene (tlp) which had moderate resistance to scab in
      previous greenhouse trials, along with susceptible and resistance checks were
      evaluated for resistance to scab under field conditions. None of the transgenic
      lines had resistance to scab in the field under conditions of strong pathogen,
      suggesting these plants lacked effective resistance to initial infection (type I
      resistance) under these conditions. As far as is known, this is the first report
      of field evaluation of transgenic wheat expressing genes for PR-proteins against
      disease resistance.

PMID- 12598581
TI  - Ubiquitous expression of a gene encoding for uncoupling protein isolated from the
      thermogenic inflorescence of the dead horse arum Helicodiceros muscivorus.
AB  - Uncoupling proteins (UCPs) are a family of mitochondrial inner membrane proteins
      that have been implicated in heat production in mammalian cells. The
      inflorescences of several members of the arum lily family (Araceae) have also
      been shown to produce heat during flowering, but the involvement of UCP-mediated
      heat production in plants is not known. In this work a gene has been isolated
      termed HmUCPa that encodes for a putative uncoupling protein from Helicodiceros
      muscivorus, a highly thermogenic arum lily. RT-PCR analysis revealed that the
      expression of HmUCPa was ubiquitously found, both in thermogenic male florets and
      appendix, and the non-thermogenic female florets, spathe and club-shaped organs
      of the spadix. These results suggest that HmUCPa is not primarily involved in
      organ-specific heat production in H. muscivorus.

PMID- 12598582
TI  - Isolation of two plastid division ftsZ genes from Chlamydomonas reinhardtii and
      its evolutionary implication for the role of FtsZ in plastid division.
AB  - In order to elucidate the origin of the plastid division gene ftsZ in green plant
      lineage, and to understand the significance of this divergence for the function
      of FtsZ proteins in plants, two full-length cDNAs (accession numbers AF449446 and
      AB084236) were isolated from Chlamydomonas reinhardtii, a base species of green
      plant lineage. A phylogenetic analysis based on amino acid sequences of
      eukaryotic FtsZs reveals that an ancient duplication of the ftsZ gene occurred
      after the endosymbiotic event. The ancient duplication implies that two ftsZ
      families might play an indispensable role at the early endosymbiotic stage.

PMID- 12598583
TI  - Zea mays ZmMybst1 cDNA, encodes a single Myb-repeat protein with the VASHAQKYF
      motif.
AB  - A cDNA clone from a 4 DAP dissected maize embryo sac encoding a novel Zea mays
      single-repeat Myb protein is reported here. This full-length cDNA contains an ORF
      of 948 bp. The gene ZmMybst1 contains two introns (1166 and 706 bp) and is a
      single copy gene. The ZmMybst1 protein shares high sequence identity with the
      potato Mybst1 protein (58%). Northern blot, RT-PCR and electronic northern
      analysis shows that ZmMybst1 is expressed in endosperm between 4 and 30 DAP,
      coinciding with the period of aleurone cell differentiation and development.

PMID- 12598584
TI  - Energy storage during stretch of active single fibres from frog skeletal muscle.
AB  - Heat production and force were measured during tetani of single muscle fibres
      from anterior tibialis of frog. During stimulation fibres were either kept under
      isometric conditions, or were stretched or allowed to shorten (at constant
      velocity) after isometric force had reached its plateau value. The energy change
      was evaluated as the sum of heat and work (work = integral of force with respect
      to length change). Net energy absorption occurred during stretch at velocities
      greater than about 0.35 L0 s-1 (L0 is fibre length at resting sarcomere length
      2.10 microm). Heat produced by 1 mm segments of the fibre was measured
      simultaneously and separately; energy absorption is not an artefact due to patchy
      heat production. The maximum energy absorption, 0.092 +/- 0.002 P0L0 (mean +/-
      S.E.M., n = 8; where P0 is isometric force at L0), occurred during the fastest
      stretches (1.64 L0 s-1) and amounted to more than half of the work done on the
      fibre. Energy absorption occurred in two phases. The amount in the first phase,
      0.027 +/- 0.003 P0L0 (n = 32), was independent of velocity beyond 0.18 L0 s-1.
      The quantity absorbed in the second phase increased with velocity and did not
      reach a limiting value in the range of velocities used. After stretch, energy was
      produced in excess of the isometric rate, probably from dissipation of the stored
      energy. About 34 % (0.031 P0L0/0.092 P0L0) of the maximum absorbed energy could
      be stored elastically (in crossbridges, tendons, thick, thin and titin filaments)
      and by redistribution of crossbridge states. The remaining energy could have been
      stored in stretching transverse, elastic connections between myofibrils.

PMID- 12598586
TI  - Concordant expression of KChIP2 mRNA, protein and transient outward current
      throughout the canine ventricle.
AB  - Expression of the transient outward K+ current (Ito) was analysed in nine
      different regions of the canine ventricle. In addition to the previously
      described transmural gradients in the right and left ventricular free walls, an
      inverted U-shaped pattern of Ito expression was observed in the interventricular
      septum. The mRNA and protein expression for the K+ channel beta subunit KChIP2
      were examined in the same tissues. The KChIP2 protein levels closely matched mRNA
      expression in all regions of the ventricle and paralleled the density of Ito. The
      global pattern of gene expression in human epicardial and endocardial tissue was
      examined using microarrays. Only 0.1 % of the genes expressed in the human
      ventricle displayed the same expression pattern as the KChIP2 gene in left
      ventricle. It is unlikely, therefore, that the reported distribution of KChIP2
      protein within the ventricle can be explained by a cross-reaction of the anti
      KChIP2 antibody with a different protein. It is concluded that transcriptional
      regulation of the KChIP2 gene is a primary determinant of Ito expression in
      heart.

PMID- 12598585
TI  - Alpha 1-adrenoceptor-activated cation currents in neurones acutely isolated from
      rat cardiac parasympathetic ganglia.
AB  - The noradrenaline (NA)-induced cation current was investigated in neurones
      freshly isolated from rat cardiac parasympathetic ganglia using the nystatin
      perforated patch recording configuration. Under current-clamp conditions, NA
      depolarized the membrane, eliciting repetitive action potentials. NA evoked an
      inward cation current under voltage-clamp conditions at a holding potential of 
      60 mV. The NA-induced current was inhibited by extracellular Ca2+ or Mg2+, with a
      half-maximal concentration of 13 microM for Ca2+ and 1.2 mM for Mg2+. Cirazoline
      mimicked the NA response, and prazosin and WB-4101 inhibited the NA-induced
      current, suggesting the contribution of an alpha1-adrenoceptor. The NA-induced
      current was inhibited by U73122, a phospholipase C (PLC) inhibitor. The membrane
      permeable IP3 receptor blocker xestospongin-C also blocked the NA-induced
      current. Furthermore, pretreatment with thapsigargin and BAPTA-AM could inhibit
      the NA response while KN-62, phorbol 12-myristate 13-acetate (PMA) and
      staurosporine had no effect. These results suggest that NA activates the
      extracellular Ca2+- and Mg2+-sensitive cation channels via alpha 1-adrenoceptors
      in neurones freshly isolated from rat cardiac parasympathetic ganglia. This
      activation mechanism also involves phosphoinositide breakdown, release of Ca2+
      from intracellular Ca2+ stores and calmodulin. The cation channels activated by
      NA may play an important role in neuronal membrane depolarization in rat cardiac
      ganglia.

PMID- 12598587
TI  - Damage to developing mouse skeletal muscle myotubes in culture: protective effect
      of heat shock proteins.
AB  - Damage to skeletal muscle occurs following excessive exercise, upon reperfusion
      following ischaemia and in disease states, such as muscular dystrophy. Key
      mechanisms by which damage is thought to occur include a loss of intracellular
      calcium homeostasis, loss of energy supply to the cell, increased activity of
      oxidising free radical-mediated reactions and activation of apoptosis pathways.
      An increased cellular content of heat shock proteins (HSPs) has been shown to
      protect skeletal muscle against some forms of damage, although the mechanistic
      basis of this protection is not clearly understood. The aim of this study was to
      establish a cell culture-based model of damage to C2C12 skeletal muscle cells
      using the calcium ionophore, A23187 and the mitochondrial uncoupler, 2,4
      dinitrophenol (DNP) as damaging agents. Treatment of cells with 1 mM DNP for 60
      min resulted in the release of 63.5 % of intracellular creatine kinase (CK)
      activity over the 3 h experimental period. Treatment of cells with 10 microM
      A23187 for 30 min resulted in the release of 47.9 % of CK activity. Exposure of
      myotubes to a period of hyperthermia resulted in a significant increase in their
      content of HSP25, HSP60, HSC70 (heat shock cognate) and HSP70. This increase in
      HSPs was associated with significant protection against both DNP-induced and
      A23187-induced damage to the myotubes. These results indicate that an increased
      content of HSPs may provide protection against the muscle damage that occurs by a
      pathological increase in intracellular calcium or uncoupling of the mitochondrial
      respiratory chain.

PMID- 12598588
TI  - Modulation of slow waves by hyperpolarization with potassium channel openers in
      antral smooth muscle of the guinea-pig stomach.
AB  - Modulation of spontaneous electrical activities (slow waves, pacemaker potentials
      and follower potentials) in response to hyperpolarization produced by the ATP
      sensitive K+ channel openers (KCOs) pinacidil or nicorandil was investigated in
      smooth muscle tissues of the guinea-pig stomach antrum. With hyperpolarization,
      the amplitude of slow waves and follower potentials was reduced and that of
      pacemaker potentials was increased, with a minor modulation of their frequency.
      The attenuation of slow waves was associated with an inhibition of the 1st
      component and abolition of the 2nd component. All these actions of KCOs were
      antagonized by glibenclamide. An increase in the extracellular K+ concentration
      prevented the KCO-induced hyperpolarization with partial restoration of slow
      waves, suggesting that the inhibition was produced mainly by a decrease in
      membrane resistance. Exposure of tissues to KCOs for a long period of time (> 20
      min) resulted in the reappearance of slow waves displaying both 1st and 2nd
      components. The 2nd component of the slow wave, which displayed a slower
      recovery, was inhibited again by 5-hydroxydecanoic acid, an inhibitor of
      mitochondrial ATP-sensitive K+ channels. Noradrenaline hyperpolarized the
      membrane by activating apamin-sensitive K+ channels and increased the amplitude
      and frequency of slow waves through activation of alpha 1-adrenoceptors, actions
      different from those of KCOs. Thus, inhibition of slow waves by KCOs may be
      primarily related to the decrease in amplitude of a passive electrotonic
      component, possibly due to a reduction of the input resistance. The
      hyperpolarization shifted the threshold potential for generation of the 2nd
      component of slow waves to negative levels, presumably due to modulation of
      mitochondrial functions.

PMID- 12598589
TI  - Protective effect of prone posture against hypergravity-induced arterial
      hypoxaemia in humans.
AB  - Patients with acute respiratory distress syndrome have increased lung tissue
      weight and therefore an increased hydrostatic pressure gradient down the lung.
      Also, they have a better arterial oxygenation in prone (face down) than in supine
      (face up) posture. We hypothesized that this effect of the direction of gravity
      also existed in healthy humans, when increased hydrostatic gradients were induced
      by hypergravity. Ten healthy subjects were studied in a human centrifuge while
      exposed to 1 or 5 G in anterio-posterior (supine) or posterio-anterior (prone)
      direction. We measured blood gases using remote-controlled sampling and gas
      exchange by mass spectrometry. Hypergravity led to marked impairments of arterial
      oxygenation in both postures and more so in supine posture. At 5 G, the arterial
      oxygen saturation was 84.6 +/- 1.2 % (mean +/- S.E.M.) in supine and 89.7 +/- 1.4
      % in prone posture (P < 0.001 for supine vs. prone). Ventilation and alveolar PO2
      were increased at 5 G and did not differ between postures. The alveolar-to
      arterial PO2 difference increased at 5 G to 8.0 +/- 0.2 kPa and 6.6 +/- 0.3 kPa
      in supine and prone postures (P = 0.003). Arterial oxygenation was less impaired
      in prone during hypergravity due to a better-preserved alveolo-arterial oxygen
      transport. We speculate that mammals have developed a cardiopulmonary structure
      that favours function with the gravitational vector in the posterio-anterior
      direction.

PMID- 12598590
TI  - Myogenin induces higher oxidative capacity in pre-existing mouse muscle fibres
      after somatic DNA transfer.
AB  - Muscle is a permanent tissue, and in the adult pronounced changes can occur in
      pre-existing fibres without the formation of new fibres. Thus, the mechanisms
      responsible for phenotype transformation in the adult might be distinct from
      mechanisms regulating muscle differentiation during muscle formation and growth.
      Myogenin is a muscle-specific, basic helix-loop-helix transcription factor that
      is important during early muscle differentiation. It is also expressed in the
      adult, where its role is unknown. In this study we have overexpressed myogenin in
      glycolytic fibres of normal adult mice by electroporation and single-cell
      intracellular injection of expression vectors. Myogenin had no effects on myosin
      heavy chain fibre type, but induced a considerable increase in succinate
      dehydrogenase and NADH dehydrogenase activity, with some type IIb fibres reaching
      the levels observed histochemically in normal type IIx and IIa fibres. mRNA
      levels for malate dehydrogenase were similarly altered. The size of the fibres
      overexpressing myogenin was reduced by 30-50 %. Thus, the transfected fibres
      acquired a phenotype reminiscent of the phenotype obtained by endurance training
      in man and other animals, with a higher oxidative capacity and smaller size. We
      conclude that myogenin can alter pre-existing glycolytic fibres in the intact
      adult animal.

PMID- 12598591
TI  - Mechanism of the distance-dependent scaling of Schaffer collateral synapses in
      rat CA1 pyramidal neurons.
AB  - Schaffer collateral axons form excitatory synapses that are distributed across
      much of the dendritic arborization of hippocampal CA1 pyramidal neurons.
      Remarkably, AMPA-receptor-mediated miniature EPSP amplitudes at the soma are
      relatively independent of synapse location, despite widely different degrees of
      dendritic filtering. A progressive increase with distance in synaptic conductance
      is thought to produce this amplitude normalization. In this study we examined the
      mechanism(s) responsible for spatial scaling by making whole-cell recordings from
      the apical dendrites of CA1 pyramidal neurons. We found no evidence to suggest
      that there is any location dependence to the range of cleft glutamate
      concentrations found at Schaffer collateral synapses. Furthermore, we observed
      that release probability (Pr), paired-pulse facilitation and the size of the
      readily releasable vesicular pool are not dependent on synapse location. Thus,
      there do not appear to be any changes in the fundamental presynaptic properties
      of Schaffer collateral synapses that could account for distance-dependent
      scaling. On the other hand, two-photon uncaging of 4-methoxy-7-nitroindolinyl
      caged L-glutamate onto isolated dendritic spines shows that the number of
      postsynaptic AMPA receptors per spine increases with distance from the soma. We
      conclude, therefore, that the main synaptic mechanism involved in the production
      of distance-dependent scaling of Schaffer collateral synapses is an elevated
      postsynaptic AMPA receptor density.

PMID- 12598594
TI  - Colour and form in the early stages of cortical processing.

PMID- 12598592
TI  - Regulation of Cl- secretion by alpha2-adrenergic receptors in mouse colonic
      epithelium.
AB  - Previous studies have shown that alpha2 adrenoceptor (alpha2AR) agonists inhibit
      electrolyte secretion in colonic epithelia, but little is known about the
      molecular mechanisms involved in this process. In this study we examined the
      effect of alpha2AR activation on transepithelial anion secretion across isolated
      murine colonic epithelium. We found that alpha2AR agonists, UK 14,304, clonidine
      and medetomidine were potent inhibitors of anion secretion, especially in the
      proximal colon. Short circuit current measurements (Isc) in colonic epithelia
      from normal and cystic fibrosis (CF) mice showed that alpha2AR agonists inhibited
      basal cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl-
      secretion but had no effect on CFTR activation by cAMP-dependent phosphorylation.
      Apical administration of an ionophore, nystatin (90 microg ml-1), was used to
      investigate the effect of UK 14,304 on basolateral K+ transport. The Na+-K+
      ATPase current, measured as ouabain-sensitive current in the absence of ion
      gradients, was unaltered by pretreatment of the tissue with UK 14,304 (1 microM).
      In the presence of a basolaterally directed K+ gradient, UK 14,304 significantly
      reduced nystatin-activated Isc indicating that activation of alpha2ARs inhibits
      basolateral K+ channels. Studies with selective K+ channel inhibitors and openers
      showed that alpha2AR agonists inhibited KATP channels that were tonically active
      in mouse colonic epithelia. RT-PCR and pharmacological studies suggested that
      these channels could be similar to vascular smooth muscle KATP channels
      comprising Kir6.1/SUR2B or Kir6.2/SUR2B subunits. Inhibition of anion secretion
      by alpha2AR agonists required activation of pertussis toxin-sensitive Gi/o
      proteins, but did not involve classical second messengers, such as cAMP or Ca2+.
      In summary, alpha2ARs inhibit anion secretion in colonic epithelia by acting on
      basolateral KATP channels, through a process that does not involve classical
      second messengers.

PMID- 12598593
TI  - Hypotonic stimulation of the Na+ active transport in frog skeletal muscle: role
      of the cytoskeleton.
AB  - Hypotonicity produces a marked activation of the Na+ pump in frog sartorius
      muscle. The increase in net Na+ efflux under hypotonic conditions occurs despite
      the reductions in [Na+]i that are due to fibre swelling and Na+ loss. The pump
      density (ouabain binding) increases not only upon reduction of the medium osmotic
      pressure (pi) from its normal value (pi = 1) to one-half (pi = 0.5), but also in
      muscles that are returned to pi = 1 after equilibration in pi = 2 medium. The
      equilibration in pi = 2 medium does not affect pump density. Ouabain-binding
      increments cannot be ascribed to a rise in the Na+-K+ exchange rate of a fixed
      number of pumps: they also occurred in the continued presence of a saturating
      concentration of ouabain (50 microM). Under those conditions, the pi = 1 pi = 0.5
      transfer produced a 43 % increase in pump sites, while the pi = 2 pi = 1 transfer
      induced a rise of 46 %. Actinomycin D did not alter the stimulation of Na+
      extrusion elicited by hypotonicity, suggesting that de novo synthesis of pumps
      was not involved in the increase of the apparent number of pump sites. Disruption
      of microtubules by colchicine (100 microM) and intermediate filaments by
      acrylamide (4 mM) did not alter the hypotonic effect. Likewise, genistein (100
      microM), a specific inhibitor of tyrosine kinase, did not affect significantly
      the hypotonic response. Microfilament-disrupting agents like cytochalasin B (5
      microM) and latrunculin B (10 microM) reduced the increase in Na+ efflux induced
      by pi = 1 pi = 0.5 transfer by about 35 % and 72 %, respectively. Latrunculin B
      reduced the increases in pump density generated by pi = 1 pi = 0.5 and pi = 2 pi
      = 1 transfers by about 79 % and 91 %, respectively. The results suggest that the
      membrane stretch due to hypotonic fibre volume increase would promote a
      microfilament-mediated insertion of submembranous spare Na+ pumps in the
      sarcolemma and, consequently, the rise in active Na+ transport.

PMID- 12598595
TI  - Dynamic modulation of inspiratory drive currents by protein kinase A and protein
      phosphatases in functionally active motoneurons.
AB  - Plasticity underlying adaptive, long-term changes in breathing behavior is
      hypothesized to be attributable to the modulation of respiratory motoneurons by
      intracellular second-messenger cascades. In quiescent preparations, protein
      kinases, including cAMP-dependent protein kinase A (PKA), potentiate
      glutamatergic inputs. However, the dynamic role of protein kinases or
      phosphatases in functionally active and behaviorally relevant preparations
      largely remains to be established. Rhythmic inspiratory drive to motoneurons
      innervating inspiratory muscles is mediated by the release of glutamate acting
      predominantly on AMPA receptors. In rhythmically active brainstem slices from
      neonatal rats, we investigated whether synaptic AMPA receptor function could be
      modulated by changes in intracellular PKA activity, affecting inspiratory drive
      in hypoglossal (XII) motoneurons. Intracellular perfusion of the catalytic
      subunit of PKA potentiated endogenous synaptic and (exogenously applied) AMPA
      induced currents in XII motoneurons. Conversely, when a peptide inhibitor of PKA
      was perfused intracellularly, inspiratory drive currents were depressed.
      Intracellular perfusion with microcystin, a potent phosphatase 1 and 2a
      inhibitor, increased both endogenous and exogenous AMPA receptor-mediated
      currents, further supporting a role of phosphorylation in modulating motoneuronal
      excitability affecting behaviorally relevant synaptic inputs. These findings
      suggest that PKA is constitutively active in XII motoneurons in vitro. Thus,
      endogenous synaptic AMPA currents in XII motoneurons are influenced by
      phosphorylation, specifically by PKA, and dephosphorylation. The role of this
      modulation may be to keep the activity of motoneurons within a dynamic range that
      aids in responding to different physiological challenges affecting breathing,
      such as exercise, hypoxia, and sleep.

PMID- 12598596
TI  - Foveal versus full-field visual stabilization strategies for translational and
      rotational head movements.
AB  - Because we view the world from a constantly shifting platform when our head and
      body move in space, vestibular and visuomotor reflexes are critical to maintain
      visual acuity. In contrast to the phylogenetically old rotational vestibulo
      ocular reflex (RVOR), it has been proposed that the translational vestibulo
      ocular reflex (TVOR) represents a newly developed vestibular-driven mechanism
      that is important for foveal vision and stereopsis. To investigate the hypothesis
      that the function of the TVOR is indeed related to foveal (as opposed to full
      field) image stabilization, we compared the three-dimensional ocular kinematics
      during lateral translation and rotational movements with those during pursuit of
      a small moving target in four rhesus monkeys. Specifically, we tested whether
      TVOR rotation axes tilt with eye position as in visually driven systems such as
      pursuit, or whether they stay relatively fixed in the head as in the RVOR. We
      found a significant dependence of three-dimensional eye velocity on eye position
      that was independent of viewing distance and viewing conditions (full-field,
      single target, or complete darkness). The slopes for this eye-position dependence
      averaged 0.7 +/- 0.07 for the TVOR, compared with 0.6 +/- 0.07 for visually
      guided pursuit eye movements and 0.18 +/- 0.09 for the RVOR. Because the
      torsional tilt versus vertical gaze slopes during translation were slightly
      higher than those during pursuit, three-dimensional eye movements during
      translation could partly reflect a compromise between the two different solutions
      for foveal gaze control, that of Listing's law and minimum velocity strategies.
      These results with respect to three-dimensional kinematics provide additional
      support for a functional difference in the two vestibular-driven mechanisms for
      visual stability during rotations and translations and establish clearly the
      functional goal of the TVOR as that for foveal visual acuity.

PMID- 12598597
TI  - Central modulatory neurons control fuel selection in flight muscle of migratory
      locust.
AB  - Insect flight is one of the most intense and energy-demanding physiological
      activities. High carbohydrate oxidation rates are necessary for take-off, but, to
      spare the limited carbohydrate reserves, long-distance flyers, such as locusts,
      soon switch to lipid as the main fuel. We demonstrate that before a flight,
      locust muscles are metabolically poised for take-off by the release of octopamine
      from central modulatory dorsal unpaired median (DUM) neurons, which increases the
      levels of the potent glycolytic activator fructose 2,6-bisphosphate in flight
      muscle. Because DUM neurons innervating the flight muscles are active during rest
      but selectively inhibited during flight, they stimulate carbohydrate catabolism
      during take-off but tend to decrease muscle glycolysis during prolonged flight.
      cAMP-dependent protein kinase A is necessary but not sufficient for signal
      transduction, suggesting parallel control via a calcium-dependent pathway. Locust
      flight is the first reported instance of a direct and specific involvement of
      neuronal activity in the control of muscle glycolysis in working muscle during
      exercise.

PMID- 12598598
TI  - Hippocampal theta in the newborn rat is revealed under conditions that promote
      REM sleep.
AB  - Hippocampal theta activity, a high-amplitude, slow (4-12 Hz) oscillation that
      occurs in a variety of behavioral contexts, is thought to emerge in infant rats
      only after 1 week of age. However, we report here that unanesthetized 2- and 4-d
      old rats with electrodes implanted in the CA1 field of the hippocampus and tested
      in thermoneutral conditions exhibit theta activity. Moreover, this infant theta
      is characterized by the same neuronal bursting pattern and power spectrum that
      characterize theta in adults. Simultaneous measures of behavior and neck muscle
      tone indicated that bouts of theta occurred predominantly during periods of
      muscle atonia (with or without concurrent myoclonic twitching), indicative of REM
      sleep. In contrast, sharp waves were accompanied by startles (i.e., simultaneous
      and vigorous movement of all four limbs). These findings underscore the need for
      comprehensive in vivo investigations of the pharmacology, neural substrates, and
      behavioral correlates of hippocampal field activity in neonates.

PMID- 12598599
TI  - The role of synaptic GTPase-activating protein in neuronal development and
      synaptic plasticity.
AB  - Synaptic GTPase-activating protein (SynGAP) is a neuronal RasGAP (Ras GTPase
      activating protein) that is selectively expressed in brain and highly enriched at
      excitatory synapses, where it negatively regulates Ras activity and its
      downstream signaling pathways. To investigate the physiological role of SynGAP in
      the brain, we have generated mutant mice lacking the SynGAP protein. These mice
      exhibit postnatal lethality, indicating that SynGAP plays a critical role during
      neuronal development. In addition, cell biological experiments show that neuronal
      cultures from mutant mice have more synaptic AMPA receptor clusters, suggesting
      that SynGAP regulates glutamate receptor synaptic targeting. Moreover,
      electrophysiological studies demonstrated that heterozygous mutant mice have a
      specific defect in hippocampal long-term potentiation (LTP). These studies show
      that the regulation of synaptic Ras signaling by SynGAP is important for proper
      neuronal development and glutamate receptor trafficking and is critical for the
      induction of LTP.

PMID- 12598600
TI  - Protein synthesis is required for synaptic immunity to depotentiation.
AB  - De novo protein synthesis and transcription are necessary for the expression of
      long-lasting synaptic potentiation [long-term potentiation (LTP)] in hippocampal
      area CA1 and for the consolidation of long-term memory. The stability of LTP and
      its longevity require macromolecular synthesis at later stages, but a specific
      role for early protein synthesis has not been identified. Using
      electrophysiological recording methods in mouse hippocampal slices, we show that
      multiple trains of high-frequency stimulation provide immediate synaptic immunity
      to depotentiation. This immunity to depotentiation is dependent on the amount of
      synaptic stimulation used to induce LTP, it is input specific, and it is
      prevented by inhibitors of protein synthesis. We propose that local translation
      mediates input-specific synaptic immunity against depotentiation. We also present
      evidence suggesting that, in addition to translation, products of transcription
      can provide cell-wide immunity to depotentiation via heterosynaptic transfer of
      synaptic immunity between distinct pathways in area CA1. Protein synthesis and
      transcription may importantly regulate long-term storage of information by
      conferring synaptic immunity to depotentiation at previously potentiated
      synapses.

PMID- 12598601
TI  - Modulation of the kv3.1b potassium channel isoform adjusts the fidelity of the
      firing pattern of auditory neurons.
AB  - Neurons of the medial nucleus of the trapezoid body, which transmit auditory
      information that is used to compute the location of sounds in space, are capable
      of firing at high frequencies with great temporal precision. We found that
      elimination of the Kv3.1 gene in mice results in the loss of a high-threshold
      component of potassium current and failure of the neurons to follow high
      frequency stimulation. A partial decrease in Kv3.1 current can be produced in
      wild-type neurons of the medial nucleus of the trapezoid body by activation of
      protein kinase C. Paradoxically, activation of protein kinase C increases
      temporal fidelity and the number of action potentials that are evoked by
      intermediate frequencies of stimulation. Computer simulations confirm that a
      partial decrease in Kv3.1 current is sufficient to increase the accuracy of
      response at intermediate frequencies while impairing responses at high
      frequencies. We further establish that, of the two isoforms of the Kv3.1
      potassium channel that are expressed in these neurons, Kv3.1a and Kv3.1b, the
      decrease in Kv3.1 current is mediated by selective phosphorylation of the Kv3.1b
      isoform. Using site-directed mutagenesis, we identify a specific C-terminal
      phosphorylation site responsible for the observed difference in response of the
      two isoforms to protein kinase C activation. Our results suggest that modulation
      of Kv3.1 by phosphorylation allows auditory neurons to tune their responses to
      different patterns of sensory stimulation.

PMID- 12598603
TI  - Studies of NMDA receptor function and stoichiometry with truncated and tandem
      subunits.
AB  - The subunits that compose eukaryotic glutamate ion channel receptors have three
      transmembrane domains (TMs) and terminate with intracellular tails that are
      important for controlling channel expression and localization. Truncation of NMDA
      receptor subunits before the final TM showed that this TM and intracellular tail
      region are necessary to form functional channels. However, it is shown here that
      these truncated subunits may be partially rescued by coexpressing the final TM
      and tail as a separate protein. The whole-cell currents so produced are somewhat
      lower than with full-length subunits, and they do not show the sag characteristic
      of currents from channels containing NR1 and NR2A subunits in the continued
      presence of an agonist. In addition, these truncated subunits were joined to full
      length subunits to generate tandems. The functional expression of these tandems
      confirmed the tetrameric structure of NMDA receptors and also suggested that the
      subunits making up NMDA receptors are arranged as a dimer of dimers in the
      receptors with a 1-1-2-2 orientation of the subunits in the channel, and not in
      an alternating pattern of subunits around the pore. These results may redirect
      future studies into the mechanism of binding and gating in these receptors toward
      schemes including dimers, and may also be relevant to studies of glutamate
      receptor ion channels in general.

PMID- 12598602
TI  - Postsynaptic application of a peptide inhibitor of cAMP-dependent protein kinase
      blocks expression of long-lasting synaptic potentiation in hippocampal neurons.
AB  - Multiple trains of high-frequency synaptic stimulation evoke long-term
      potentiation (LTP) of synaptic transmission in hippocampal area CA1, which has
      been correlated with hippocampal long-term memory and requires the activation of
      cAMP-dependent protein kinase (PKA). To assess whether postsynaptic PKA is
      necessary for the expression of LTP, we made prolonged whole-cell voltage-clamp
      recordings from CA1 pyramidal neurons in mouse hippocampal slices during
      postsynaptic infusion of cell-impermeant modulators of PKA. Repeated stimulation
      (four 100 Hz trains at 5 min intervals) of the Schaffer collateral pathway
      increased synaptically evoked EPSCs for up to 2 hr. The postsynaptic infusion of
      either a cell-permeant PKA inhibitor (Rp-cAMPS) or a cell-impermeant PKA
      inhibitor (PKI(6-22)) did not alter post-tetanic peak potentiation, but it caused
      significant decay of EPSCs to pretetanization amplitudes within 1.5 hr. In
      contrast, postsynaptic infusion of PKI(6-22) did not alter a more modest,
      decaying form of LTP evoked by a single 100 Hz train. Paired-pulse facilitation
      was unchanged during most of the duration of LTP, suggesting that postsynaptic
      mechanisms, including PKA activation, are involved in the expression of LTP
      induced by multitrain stimulation. The postsynaptic infusion of a constitutively
      active isoform of the PKA catalytic subunit (Calpha) into CA1 pyramidal neurons
      increased EPSC sizes to elicit long-lasting synaptic facilitation. Thus,
      mimicking the activation of PKA in postsynaptic CA1 pyramidal neurons is
      sufficient for inducing persistent synaptic facilitation. Activation of
      apostsynaptic PKA is necessary for the expression of LTP in CA1 pyramidal neurons
      and is sufficient for initiating persistent synaptic facilitation.

PMID- 12598604
TI  - Muscarinic potentiation of GABA(A) receptor currents is gated by insulin
      signaling in the prefrontal cortex.
AB  - Cholinergic neurotransmission and insulin signaling in cognitive areas, such as
      the prefrontal cortex (PFC), play a key role in regulating learning and memory.
      However, the cellular mechanisms by which this regulation occurs are unclear.
      Because GABAergic inhibition in the PFC controls the timing of neuronal activity
      during cognitive operations, we examined the potential regulation of GABA
      transmission by cholinergic and insulin signaling in PFC pyramidal neurons.
      Activation of muscarinic acetylcholine receptors (mAChRs) with carbachol produced
      an enhancement of GABA(A) receptor currents in acutely dissociated cells after a
      short treatment with insulin. Inhibiting phosphoinositide-3 kinase (PI3K), a
      downstream target of insulin signaling, eliminated this effect as well as the
      carbachol-induced enhancement of GABAergic miniature IPSC amplitudes in PFC
      slices. The muscarinic potentiation of GABA(A) currents was blocked by PKC
      inhibitors, broad-spectrum protein tyrosine kinase inhibitors, and specific
      inhibitors of the nonreceptor tyrosine kinase Src. Additionally, muscarinic
      receptors in PFC slices activated PKC and the focal adhesion kinase Pyk2 (a
      potential molecular link between PKC and Src) in a PI3K-dependent manner.
      Together, our results show that mAChR activation in PFC pyramidal neurons
      enhances GABA(A) receptor functions through a PKC-dependent, Src-mediated
      signaling cascade that is gated by an insulin/PI3K pathway. Given the
      significance of GABAergic transmission in regulating PFC functions, our results
      provide a novel mechanism for understanding the role of cholinergic systems and
      insulin signaling in learning and memory.

PMID- 12598606
TI  - Subunit-dependent modulation of kainate receptors by extracellular protons and
      polyamines.
AB  - Synaptic activity causes significant fluctuations in proton concentrations in the
      brain. Changes in pH can affect neuronal excitability by acting on ligand-gated
      channels, including those gated by glutamate. We show here a subunit-dependent
      regulation of native and recombinant kainate receptors by physiologically
      relevant proton concentrations. The effect of protons on kainate receptors is
      voltage-independent and subunit dependent, with GluR5(Q), GluR6(Q), GluR6(R), and
      GluR6(R)/KA2 receptors being inhibited and GluR6(R)/KA1 receptors being
      potentiated. Mutation of two acidic residues (E396 and E397) to neutral amino
      acids significantly reduces the proton sensitivity of the GluR6(Q) receptor,
      suggesting that these residues influence proton inhibition. The endogenous
      polyamine spermine potentiated GluR6(R) kainate currents in a pH-dependent
      manner, producing an acidic shift in the IC(50) for proton inhibition. Spermine
      potentiation of GluR6(R) is voltage independent, does not affect receptor
      desensitization, and only slightly shifts the agonist affinity of the receptor.
      These results suggest that, similar to its action on NMDA receptors, spermine
      potentiates kainate receptors by relieving proton inhibition of the receptor.
      Furthermore, they suggest that fluctuations in brain pH during both normal and
      pathological processes could regulate synaptic transmission and plasticity
      mediated by kainate receptors.

PMID- 12598605
TI  - Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.
AB  - Neuropathic pain is a common and often incapacitating clinical problem for which
      little useful therapy is presently available. Painful peripheral neuropathies can
      have many etiologies, among which are trauma, viral infections, exposure to
      radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers
      generally experience both pain at rest and exaggerated, painful sensitivity to
      light touch. Spontaneous firing of injured nerves is believed to play a critical
      role in the induction and maintenance of neuropathic pain syndromes. Using a well
      characterized nerve ligation model in the rat, we demonstrate that
      hyperpolarization-activated, cyclic nucleotide-modulated (HCN) "pacemaker"
      channels play a previously unrecognized role in both touch-related pain and
      spontaneous neuronal discharge originating in the damaged dorsal root ganglion.
      HCN channels, particularly HCN1, are abundantly expressed in rat primary afferent
      somata. Nerve injury markedly increases pacemaker currents in large-diameter
      dorsal root ganglion neurons and results in pacemaker-driven spontaneous action
      potentials in the ligated nerve. Pharmacological blockade of HCN activity using
      the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch
      and decreases the firing frequency of ectopic discharges originating in Abeta and
      Adelta fibers by 90 and 40%, respectively, without conduction blockade. These
      findings suggest novel insights into the molecular basis of pain and the
      possibility of new, specific, effective pharmacological therapies.

PMID- 12598607
TI  - Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5
      activator by phosphorylation.
AB  - Cyclin-dependent kinase 5 (Cdk5), a cdc2-related kinase expressed in postmitotic
      neurons, is activated by association with a brain-specific activator, p35. It has
      been suggested that the conversion of p35 to p25 by the protease calpain is
      involved in neuronal cell death. However, p35 protein is turned over rapidly via
      proteasomal degradation in living neurons. In this study we show that the
      phosphorylation of p35 by Cdk5 suppresses the cleavage to p25 by calpain, whereas
      phosphorylation facilitates the proteasomal degradation of p35. The
      phosphorylation site in p35 that might be involved in preventing calpain cleavage
      was distinct from the phosphorylation site involved in facilitating proteasomal
      degradation. A phosphorylated form of p35 that was resistant to cleavage by
      calpain was more prevalent in the fetal brain, whereas the unphosphorylated form
      of p35 occurred in the adult brain. These results suggest that the
      phosphorylation of p35 serves as a protective mechanism that suppresses the
      generation of p25 in developing brains.

PMID- 12598608
TI  - Involvement of the neurotensin receptor-3 in the neurotensin-induced migration of
      human microglia.
AB  - Microglia motility plays a crucial role in response to lesion or exocytotoxic
      damage of the cerebral tissue. We used two in vitro assays, a wound-healing model
      and a chemotaxis assay, to show that the neuropeptide neurotensin elicited the
      migration of the human microglial cell line C13NJ by a mechanism dependent on
      both phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein
      (MAP) kinase pathways. The effect of neurotensin on cell migration was blocked by
      the neurotensin receptor-3 propeptide, a selective ligand of this receptor. We
      demonstrate, by using RT-PCR, photoaffinity labeling, and Western blot analysis,
      that the type I neurotensin receptor-3 was the only known neurotensin receptor
      expressed in these microglial cells and that its activation led to the
      phosphorylation of both extracellular signal-regulating kinases 1/2 and Akt.
      Furthermore, the effect of neurotensin on cell migration was preceded by a
      profound modification of the F-actin cytoskeleton, particularly by the rapid
      formation of numerous cell filopodia. Both the motility and the filopodia
      appearance induced by neurotensin were totally blocked by selective inhibitors of
      MAP kinases or PI 3-kinase pathways. This demonstrates that the neurotensin
      receptor-3 is functional and mediates the migratory actions of neurotensin.

PMID- 12598609
TI  - Modulation of spike-mediated synaptic transmission by presynaptic background Ca2+
      in leech heart interneurons.
AB  - At the core of the rhythmically active leech heartbeat central pattern generator
      are pairs of mutually inhibitory interneurons. Synaptic transmission between
      these interneurons consists of spike-mediated and graded components, both of
      which wax and wane on a cycle-by-cycle basis. Low-threshold Ca2+ currents gate
      the graded component. Ca imaging experiments indicate that these low-threshold
      currents are widespread in the neurons and that they contribute to neuron-wide
      changes in internal background Ca2+ concentration (Ivanov and Calabrese, 2000).
      During normal rhythmic activity, background Ca2+ concentration oscillates, and
      thus graded synaptic transmission waxes and wanes as the neurons move from the
      depolarized to the inhibited phases of their activity. Here we show that in
      addition to gating graded transmitter release, the background Ca2+ concentration
      changes evoked by low-threshold Ca2+ currents modulate spike-mediated synaptic
      transmission. We develop stimulation paradigms to simulate the changes in
      baseline membrane potential that accompany rhythmic bursting. Using Ca imaging
      and electrophysiological measurements, we show that the strength of spike
      mediated synaptic transmission follows the changes in background Ca2+
      concentration that these baseline potential changes evoke and that it does not
      depend on previous spike activity. Moreover, we show using internal EGTA and
      photo-release of caged Ca2+ and caged Ca2+ chelator that changes in internal Ca2+
      concentration modulate spike-mediated synaptic transmission. Thus activity
      dependent changes in background Ca2+, which have been implicated in homeostatic
      regulation of intrinsic membrane currents and synaptic strength, may also
      regulate synaptic transmission in an immediate way to modulate synaptic strength
      cycle by cycle in rhythmically active networks.

PMID- 12598610
TI  - Amino-acid residues involved in glutamate receptor 6 kainate receptor gating and
      desensitization.
AB  - The glutamate receptor (GluR) agonist-binding site consists of amino acid
      residues in the extracellular S1 and S2 segments in the N-terminal and M3-M4 loop
      regions, respectively. Molecular and atomic level structural analyses have
      identified specific S1 and S2 residues that interact directly with ligands,
      interact with one another in a dimeric configuration, and influence channel
      gating and desensitization properties of AMPA receptors. Other studies suggest
      that KA receptor gating and desensitization may differ mechanistically. In
      particular, a leucine (L) to tyrosine (Y) mutation in the S1 segment of AMPA
      receptors is sufficient to block desensitization, whereas KA receptors naturally
      contain a tyrosine residue at the equivalent position (Y751 in GluR6) but retain
      the fast-desensitizing phenotype. We hypothesized that KA receptor
      desensitization is preserved by a compensatory substitution in the S2 segment. We
      generated a series of GluR6 mutants that converted individual S2 domain residues
      to their AMPA receptor equivalents. Various S2 mutations had effects on the
      kinetics of desensitization and recovery from desensitization, but no single
      amino acid substitution was found to block desensitization, as in the L/Y mutant
      AMPA receptors, or to prevent desensitization to KA. Other mutations designed to
      neutralize residues thought to interact across the dimer interface had dramatic
      effects on channel gating and desensitization. These results are consistent with
      a close but imperfect structural homology between AMPA and KA receptors and
      support the role of conserved S1S2 domain interactions at the dimer interface in
      GluR channel function.

PMID- 12598611
TI  - Synergistic dopaminergic neurotoxicity of the pesticide rotenone and inflammogen
      lipopolysaccharide: relevance to the etiology of Parkinson's disease.
AB  - Parkinson's disease (PD) is characterized by a progressive degeneration of the
      nigrostriatal dopaminergic pathway resulting in movement disorders. Although its
      etiology remains unknown, PD may be the final outcome of interactions among
      multiple factors, including exposure to environmental toxins and the occurrence
      of inflammation in the brain. In this study, using primary mesencephalic
      cultures, we observed that nontoxic or minimally toxic concentrations of the
      pesticide rotenone (0.5 nm) and the inflammogen lipopolysaccharide (LPS) (0.5
      ng/ml) synergistically induced dopaminergic neurodegeneration. The synergistic
      neurotoxicity of rotenone and LPS was observed when the two agents were applied
      either simultaneously or in tandem. Mechanistically, microglial NADPH oxidase
      mediated generation of reactive oxygen species appeared to be a key contributor
      to the synergistic dopaminergic neurotoxicity. This conclusion was based on the
      following observations. First, inhibition of NADPH oxidase or scavenging of free
      radicals afforded significant neuroprotection. Second, rotenone and LPS
      synergistically stimulated the NADPH oxidase-mediated release of the superoxide
      free radical. Third and most importantly, rotenone and LPS failed to induce the
      synergistic neurotoxicity as well as the production of superoxide in cultures
      from NADPH oxidase-deficient animals. This is the first demonstration that low
      concentrations of a pesticide and an inflammogen work in synergy to induce a
      selective degeneration of dopaminergic neurons. Findings from this study may be
      highly relevant to the elucidation of the multifactorial etiology of PD and the
      discovery of effective therapeutic agents for the treatment of the disease.

PMID- 12598612
TI  - Cyclin-dependent kinase activity is required for apoptotic death but not
      inclusion formation in cortical neurons after proteasomal inhibition.
AB  - Growing evidence suggests that the proteasome may be dysfunctional in a number of
      neurodegenerative disorders, including Lewy body diseases. We have reported
      previously that application of pharmacological inhibitors of the proteasome to
      cultured cortical neurons leads to apoptotic death and formation of ubiquitinated
      cytoplasmic inclusions. A number of cell cycle regulatory proteins are known to
      be degraded by the proteasome. In light of the emerging role of aberrant cell
      cycle activation in neuronal cell death, we have assessed the involvement of cell
      cycle components in the effects induced by proteasomal inhibitors in cortical
      neurons. Death and mitochondrial dysfunction induced by lactacystin and other
      pharmacological inhibitors of the proteasome were prevented by flavopiridol, a
      specific inhibitor of cyclin-dependent kinases (Cdks). Molecular expression of
      the Cdk inhibitors p16 or p27, or of dominant-negative Cdk2, Cdk4, or Cdk6 was
      also protective against lactacystin-induced death. Flavopiridol blocked the
      induction of retinoblastoma protein (pRb) phosphorylation that occurred after
      lactacystin application, and expression of a mutant pRb that lacked
      phosphorylation sites was neuroprotective. These results suggest that in cortical
      neurons, proteasomal inhibition leads to a cell death pathway that is dependent
      on Cdk activation and pRb inactivation. Although cyclins D1 and E were
      sequestered within the ubiquitinated inclusions formed at late time points after
      lactacystin application, the formation of ubiquitinated inclusions was unaffected
      by Cdk inhibition. This suggests that there are parallel pathways regulating
      neuronal death and inclusion formation elicited by proteasomal inhibition in
      cortical neurons.

PMID- 12598613
TI  - Intracellular cross talk and physical interaction between two classes of
      neurotransmitter-gated channels.
AB  - Fast chemical communications in the nervous system are mediated by several
      classes of receptor channels believed to be independent functionally and
      physically. We show here that concurrent activation of P2X2 ATP-gated channels
      and 5-HT3 serotonin-gated channels leads to functional interaction and
      nonadditive currents (47-73% of the predicted sum) in mammalian myenteric neurons
      as well as in Xenopus oocytes or transfected human embryonic kidney (HEK) 293
      cell heterologous systems. We also show that these two cation channels
      coimmunoprecipitate constitutively and are associated in clusters. In
      heterologous systems, the inhibitory cross talk between P2X2 and 5-HT3 receptors
      is disrupted when the intracellular C-terminal domain of the P2X2 receptor
      subunit is deleted and when minigenes coding for P2X2 or 5-HT3A receptor subunit
      cytoplasmic domains are overexpressed. Injection of fusion proteins containing
      the C-terminal domain of P2X2 receptors in myenteric neurons also disrupts the
      functional interaction between native P2X2 and 5-HT3 receptors. Therefore,
      activity-dependent intracellular coupling of distinct receptor channels underlies
      ionotropic cross talks that may significantly contribute to the regulation of
      neuronal excitability and synaptic plasticity.

PMID- 12598614
TI  - blue cheese mutations define a novel, conserved gene involved in progressive
      neural degeneration.
AB  - A common feature of many human neurodegenerative diseases is the accumulation of
      insoluble ubiquitin-containing protein aggregates in the CNS. Although Drosophila
      has been helpful in understanding several human neurodegenerative disorders, a
      loss-of-function mutation has not been identified that leads to insoluble CNS
      protein aggregates. The study of Drosophila mutations may identify unique
      components that are associated with human degenerative diseases. The Drosophila
      blue cheese (bchs) gene defines such a novel degenerative pathway. bchs mutants
      have a reduced adult life span with the age-dependent formation of protein
      aggregates throughout the neuropil of the CNS. These inclusions contain insoluble
      ubiquitinated proteins and amyloid precursor-like protein. Progressive loss of
      CNS size and morphology along with extensive neuronal apoptosis occurs in aged
      bchs mutants. BCHS protein is widely expressed in the cytoplasm of CNS neurons
      and is present over the entire length of axonal projections. BCHS is nearly 3500
      amino acids in size, with the last 1000 amino acids consisting of three
      functional protein motifs implicated in vesicle transport and protein processing.
      This region along with previously unidentified proteins encoded in the human,
      mouse, and nematode genomes shows striking homology along the full length of the
      BCHS protein. The high degree of conservation between Drosophila and human bchs
      suggests that study of the functional pathway of BCHS and associated mutant
      phenotype may provide useful insights into human neurodegenerative disorders.

PMID- 12598615
TI  - The H+-coupled electrogenic lysosomal amino acid transporter LYAAT1 localizes to
      the axon and plasma membrane of hippocampal neurons.
AB  - Recent work has identified a lysosomal protein that transports neutral amino
      acids (LYAAT1). We now show that LYAAT1 mediates H+ cotransport with a
      stoichiometry of 1 H+/1 amino acid, consistent with a role in the active efflux
      of amino acids from lysosomes. In neurons, however, LYAAT1 localizes to axonal
      processes as well as lysosomes. In axons LYAAT1 fails to colocalize with synaptic
      markers. Rather, axonal LYAAT1 colocalizes with the exocyst, suggesting a role
      for membranes expressing LYAAT1 in specifying sites for exocytosis. A protease
      protection assay and measurements of intracellular pH further indicate abundant
      expression at the plasma membrane, raising the possibility of physiological roles
      for LYAAT1 on the cell surface as well as in lysosomes.

PMID- 12598616
TI  - Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha
      subunit mutants.
AB  - The Na+/K+ ATPase asymmetrically distributes sodium and potassium ions across the
      plasma membrane to generate and maintain the membrane potential in many cell
      types. Although these pumps have been hypothesized to be involved in various
      human neurological disorders, including seizures and neurodegeneration, direct
      genetic evidence has been lacking. Here, we describe novel mutations in the
      Drosophila gene encoding the alpha (catalytic) subunit of the Na+/K+ ATPase that
      lead to behavioral abnormalities, reduced life span, and severe neuronal
      hyperexcitability. These phenotypes parallel the occurrence of extensive, age
      dependent neurodegeneration. We have also discovered that the ATPalpha
      transcripts undergo alternative splicing that substantially increases the
      diversity of potential proteins. Our data show that maintenance of neuronal
      viability is dependent on normal sodium pump activity and establish Drosophila as
      a useful model for investigating the role of the pump in human neurodegenerative
      and seizure disorders.

PMID- 12598617
TI  - GTPase regulators and photoresponses in cones of the eastern chipmunk.
AB  - Vertebrate cone and rod photoreceptor cells use similar mechanisms to transduce
      light signals into electrical signals, but their responses to light differ in
      sensitivity and kinetics. To assess the role of G-protein GTP hydrolysis kinetics
      in mammalian cone photoresponses, we have characterized photoresponses and GTPase
      regulatory components of cones and rods from the cone-dominant retina of the
      eastern chipmunk. Sensitivity, based on the stimulus strength required for a half
      maximum response, of the M-cone population was 38-fold lower than that of the
      rods. The relatively lower cone sensitivity could be attributed in part to lower
      amplification in the rising phase and in part to faster recovery kinetics. At a
      molecular level, cloning of chipmunk cDNA and expression of recombinant proteins
      provided standards for quantitative immunoblot analysis of proteins involved in
      GTPase acceleration. The ratio of the cGMP-phosphodiesterase inhibitory subunit
      gamma to cone pigment, 1:68, was similar to the levels observed for ratios to
      rhodopsin in bovine retina, 1:76, or mouse retina, 1:65. In contrast, the ratio
      to pigment of the GTPase-accelerating protein RGS9-1 was 1:62, more than 10 times
      higher than ratios observed in rod-dominant retinas. Immunoprecipitation
      experiments revealed that, in contrast to rods, RGS9-1 in chipmunk retina is
      associated with both the short and long isoforms of its partner subunit G(beta5).
      The much higher levels of the GTPase-accelerating protein complex in cones,
      compared with rods, suggest a role for GTPase acceleration in obtaining rapid
      photoresponse kinetics.

PMID- 12598618
TI  - Spatiotemporal dynamics of sensory responses in layer 2/3 of rat barrel cortex
      measured in vivo by voltage-sensitive dye imaging combined with whole-cell
      voltage recordings and neuron reconstructions.
AB  - The spatiotemporal dynamics of the sensory response in layer 2/3 of primary
      somatosensory cortex evoked by a single brief whisker deflection was investigated
      by simultaneous voltage-sensitive dye (VSD) imaging and whole-cell (WC) voltage
      recordings in the anesthetized rat combined with reconstructions of dendritic and
      axonal arbors of L2/3 pyramids. Single and dual WC recordings from pyramidal
      cells indicated a strong correlation between the local VSD population response
      and the simultaneously measured subthreshold postsynaptic potential changes in
      both amplitude and time course. The earliest VSD response was detected 10-12 msec
      after whisker deflection centered above the barrel isomorphic to the stimulated
      principal whisker. It was restricted horizontally to the size of a single barrel
      column coextensive with the dendritic arbor of barrel-column-related pyramids in
      L2/3. The horizontal spread of excitation remained confined to a single barrel
      column with weak whisker deflection. With intermediate deflections, excitation
      spread into adjacent barrel-columns, propagating twofold more rapidly along the
      rows of the barrel field than across the arcs, consistent with the preferred
      axonal arborizations in L2/3 of reconstructed pyramidal neurons. Finally, larger
      whisker deflections evoked excitation spreading over the entire barrel field
      within approximately 50 msec before subsiding over the next approximately 250
      msec. Thus the subthreshold cortical map representing a whisker deflection is
      dynamic on the millisecond time scale and strongly depends on stimulus strength.
      The sequential spatiotemporal activation of the excitatory neuronal network in
      L2/3 by a simple sensory stimulus can thus be accounted for primarily by the
      columnar restriction of L4 to L2/3 excitatory connections and the axonal field of
      barrel-related pyramids.

PMID- 12598619
TI  - Novel espin actin-bundling proteins are localized to Purkinje cell dendritic
      spines and bind the Src homology 3 adapter protein insulin receptor substrate
      p53.
AB  - We identified a group of actin-binding-bundling proteins that are expressed in
      cerebellar Purkinje cells (PCs) but are not detected in other neurons of the CNS.
      These proteins are novel isoforms of the actin-bundling protein espin that arise
      through the use of a unique site for transcriptional initiation and differential
      splicing. Light and electron microscopic localization studies demonstrated that
      these espin isoforms are enriched in the dendritic spines of PCs. They were
      detected in the head and neck and in association with the postsynaptic density
      (PSD) of dendritic spines in synaptic contact with parallel or climbing fibers.
      They were also highly enriched in PSD fractions isolated from cerebellum. The PC
      espins efficiently bound and bundled actin filaments in vitro, and these
      activities were not inhibited by Ca2+. When expressed in transfected neuronal
      cell lines, the PC espins colocalized with actin filaments and elicited the
      formation of coarse cytoplasmic actin bundles. The insulin receptor substrate p53
      (IRSp53), an Src homology 3 (SH3) adapter protein and regulator of the actin
      cytoskeleton, was identified as an espin-binding protein in yeast two-hybrid
      screens. Cotransfection studies and pull-down assays showed that this interaction
      was direct and required the N-terminal proline-rich peptide of the PC espins.
      Thus, the PC espins exhibit the properties of modular actin-bundling proteins
      with the potential to influence the organization and dynamics of the actin
      cytoskeleton in PC dendritic spines and to participate in multiprotein complexes
      involving SH3 domain-containing proteins, such as IRSp53.

PMID- 12598620
TI  - P2X7 receptor-mediated release of excitatory amino acids from astrocytes.
AB  - Astrocyte glutamate release can modulate synaptic activity and participate in
      brain intercellular signaling. P2X7 receptors form large ion channels when
      activated by ATP or other ligands. Here we show that P2X7 receptors provide a
      route for excitatory amino acid release from astrocytes. Studies were performed
      using murine cortical astrocyte cultures. ATP produced an inward current in patch
      clamped astrocytes with properties characteristic of P2X7 receptor activation:
      the current was amplified in low divalent cation medium, blocked by pyridoxal
      phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), and more potently activated
      by 3'-O-(4-benzoyl)benzoyl ATP (BzATP) than by ATP itself. Measurement of current
      reversal potentials showed the relative BzATP-induced permeabilities to different
      substrates to be Na+, 1 > Cl-, 0.34 > N-methyl-D-glucamine, 0.27 > L-glutamate,
      0.15 approximately D-aspartate, 0.16. Astrocytes exposed to BzATP also became
      permeable to Lucifer yellow, indicating a large channel opening. Release of L
      glutamate and D-aspartate through P2X7 channels was confirmed using radiolabeled
      tracers. As with the inward current, release of glutamate and D-aspartate was
      induced by BzATP more potently than ATP, amplified in Ca2+/Mg2+-free medium, and
      blocked by PPADS or oxidized ATP. Efflux through P2X7 channels is a previously
      unrecognized route of ligand-stimulated, nonvesicular astrocyte glutamate
      release.

PMID- 12598621
TI  - Bulk membrane retrieval in the synaptic terminal of retinal bipolar cells.
AB  - The mechanism of bulk membrane uptake at the synapse remains poorly defined,
      although exocytosis of synaptic vesicles is followed by compensatory membrane
      retrieval into both small vesicles and large cisternas or vacuoles. We
      investigated bulk retrieval in the presynaptic terminal of retinal bipolar cells.
      Fluorescence imaging of the membrane dye FM1-43 indicated that Ca2+-triggered
      exocytosis was followed by endocytosis into small vesicles and larger vacuoles
      that could be selectively labeled using large fluorescent dextrans. Disruption of
      actin filaments with cytochalasin D or latrunculin B inhibited the formation and
      transport of vacuoles, but exocytosis and endocytosis continued at normal rates.
      Bulk retrieval was linked to remodeling of the actin network, and both processes
      were inhibited by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, an inhibitor
      of phosphatidylinositol 3-kinase (PI 3-kinase). The regulation of F-actin
      dynamics by Ca2+ and PI 3-kinase therefore played an important role in
      compensatory endocytosis at this synapse, but this role was confined to bulk
      membrane uptake. Capacitance measurements demonstrated that fast endocytosis and
      refilling of the rapidly releasable pool of vesicles were not dependent on F
      actin or PI 3-kinase activity. The basic properties of bulk membrane retrieval at
      this synapse were very similar to macropinocytosis described in non-neural cells.
      Bulk retrieval did not play an essential role in maintaining the vesicle cycle
      during maintained stimulation, but we suggest that it may play a role in the
      structural plasticity of this synaptic terminal.

PMID- 12598622
TI  - Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1.
AB  - The vanilloid receptor [transient receptor potential (TRP)V1, also known as VR1]
      is a member of the TRP channel family. These receptors share a significant
      sequence homology, a similar predicted structure with six transmembrane-spanning
      domains (S1-S6), a pore-forming region between S5 and S6, and the cytoplasmically
      oriented C- and N-terminal regions. Although structural/functional studies have
      identified some of the key amino acids influencing the gating of the TRPV1 ion
      channel, the possible contributions of terminal regions to vanilloid receptor
      function remain elusive. In the present study, C-terminal truncations of rat
      TRPV1 have been constructed to characterize the contribution of the cytoplasmic C
      terminal region to TRPV1 function and to delineate the minimum amount of C tail
      necessary to form a functional channel. The truncation of 31 residues was
      sufficient to induce changes in functional properties of TRPV1 channel. More
      pronounced effects of C-terminal truncation were seen in mutants lacking the
      final 72 aa. These changes were characterized by a decline of capsaicin-, pH-,
      and heat-sensitivity; progressive reduction of the activation thermal threshold
      (from 41.5 to 28.6 degrees C); and slowing of the activation rate of heat-evoked
      membrane currents (Q10 from 25.6 to 4.7). The voltage-induced currents of the
      truncated mutants exhibited a slower onset, markedly reduced outward
      rectification, and significantly smaller peak tail current amplitudes. Truncation
      of the entire TRPV1 C-terminal domain (155 residues) resulted in a nonfunctional
      channel. These results indicate that the cytoplasmic COOH-terminal domain
      strongly influences the TRPV1 channel activity, and that the distal half of this
      structural domain confers specific thermal sensitivity.

PMID- 12598623
TI  - Target-derived trophic effect on skeletal muscle innervation in senescent mice.
AB  - In the present work, we tested the hypothesis that target-derived insulin-like
      growth factor-1 (IGF-1) prevents alterations in neuromuscular innervation in
      aging mammals. To explore this hypothesis, we studied senescent wild-type mice as
      a model of deficient IGF-1 secretion and signaling and S1S2 transgenic mice as a
      tool to investigate the role of sustained overexpression of IGF-1 in striated
      muscle in neuromuscular innervation. The analysis of the nerve terminal in
      extensor digitorum longus muscles from senescent mice showed that the decrease in
      the percentage of cholinesterase-stained zones (CSZ) exhibiting nerve terminal
      branching, number of nerve branches at the CSZ, and nerve branch points was
      partially or completely reversed by sustained overexpression of IGF-1 in skeletal
      muscle. Target-derived IGF-1 also prevented age-related decreases in the
      postterminal alpha-bungarotoxin immunostained area, as well as the reduction in
      the number and length of postsynaptic folds, and area and density of postsynaptic
      folds studied with electron microscopy. Overexpression of IGF-1 in skeletal
      muscle may account for the lack of age-dependent switch in muscle fiber type
      composition recorded in senescent mice. In summary, the use of the S1S2 IGF-1
      transgenic mouse model allowed us to provide morphological evidence for the role
      of target-derived IGF-1 in spinal cord motor neurons in senescent mice.

PMID- 12598625
TI  - Honeycomb-like mosaic at the border of layers 1 and 2 in the cerebral cortex.
AB  - In this report, we present evidence of a small-scale modularity (<100 microm) at
      the border of layers 1 and 2 in neocortical areas. The modularity is best seen in
      tangential sections, with double-labeling immunohistochemistry to reveal
      overlapping or complementary relationships of different markers. The pattern is
      overall like a reticulum or mosaic but is described as a "honeycomb," in which
      the walls and hollows are composed of distinct afferent and dendritic systems. We
      demonstrate the main components of the honeycomb in rat visual cortex. These are
      as follows: (1) zinc-enriched, corticocortical terminations in the walls, and in
      the hollows, thalamocortical terminations (labeled by antibody against vesicular
      glutamate transporter 2 and by cytochrome oxidase); (2) parvalbumin-dense
      neuropil in the walls that partly colocalizes with elevated levels of glutamate
      receptors 2/3, NMDAR receptor 1, and calbindin; and (3) dendritic subpopulations
      preferentially situated within the walls (dendrites of layer 2 neurons) or
      hollows (dendrites of deeper neurons in layers 3 and 5). Because the
      micromodularity is restricted to layers 2 and 1b, without extending into layer 3,
      this may be another indication of a laminar-specific substructure at different
      spatial scales within cortical columns. The suggestion is that corticocortical
      and thalamocortical terminations constitute parallel circuits at the level of
      layer 2, where they are segregated in association with distinct dendritic
      systems. Results from parvalbumin staining show that the honeycomb mosaic is not
      limited to rat visual cortex but can be recognized at the layer 1-2 border in
      other areas and species.

PMID- 12598624
TI  - A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and
      is required for normal axon pathfinding.
AB  - Altering the concentrations of cyclic nucleotides within nerve cells can
      dramatically change their responses to axonal guidance cues, but the
      physiological signals that might induce such alterations are unknown. Here we
      show that the chemokine stromal cell-derived factor 1 (SDF-1) reduces the
      repellent activities of slit-2 on cultured retinal ganglion cell axons, of
      semaphorin 3A on dorsal root ganglion sensory axons, and of semaphorin 3C on
      sympathetic axons. This is a modulatory effect because SDF-1 has no detectable
      attractive or repellent effects on retinal or DRG axons by itself. This
      modulation is mediated through CXCR4, the receptor of SDF-1, and a pertussis
      toxin-sensitive G-protein-coupled signaling pathway that induces an elevation of
      cAMP. The spinal cords of CXCR4 mutant mice contain hyperfasciculated and
      aberrantly projecting axons. These results suggest that SDF-1 plays an essential
      role in modulating axonal responsiveness to various known guidance cues through a
      cyclic nucleotide-dependent signaling pathway.

PMID- 12598626
TI  - Ectopic photoreceptors and cone bipolar cells in the developing and mature
      retina.
AB  - An antibody against recoverin, the calcium-binding protein, labels
      photoreceptors, cone bipolar cells, and a subpopulation of cells in the ganglion
      cell layer. In the present study, we sought to establish the origin and identity
      of the cells expressing recoverin in the ganglion cell layer of the rat retina.
      By double labeling with rhodopsin, we demonstrate that early in development some
      of the recoverin-positive cells in the ganglion cell layer are photoreceptors.
      During the first postnatal week, these rhodopsin-positive cells are eliminated
      from the ganglion cell layer, but such neurons remain in the inner nuclear layer
      well into the first postnatal month. Another contingent of recoverin-positive
      cells, with morphological features equivalent to those of bipolar cells, is
      present in the postnatal retina, and approximately 50% of these neurons survive
      to maturity. The incidence of such cells in the ganglion cell layer was not
      affected by early transection of the optic nerve, a manipulation that causes
      rapid loss of retinal ganglion cells. These recoverin-positive cells were not
      double-labeled by cell-specific markers expressed by photoreceptors, rod bipolar
      cells, or horizontal and amacrine cells. Based on their staining with recoverin
      and salient morphological features, these ectopic profiles in the ganglion cell
      layer are most likely cone bipolar cells. Collectively, the results provide
      evidence for photoreceptors in the ganglion cell and inner nuclear layers of the
      developing retina, and a more permanent subpopulation of cone bipolar cells
      displaced to the ganglion cell layer.

PMID- 12598627
TI  - Distorted odor maps in the olfactory bulb of semaphorin 3A-deficient mice.
AB  - Semaphorin 3A (Sema3A) repels growing olfactory axons that express neuropilin-1
      (NP-1), a receptor for Sema3A. The Sema3A-mediated axon guidance seems to be
      essential for the formation of the glomerular sensory map in the olfactory bulb
      (OB). To understand whether and how Sema3A is involved in sensory map formation,
      we examined the glomerular map in the OB of adult Sema3A-deficient mice. In wild
      type mice, NP-1-positive glomeruli form the lateral and medial bands and avoid
      the anteromedial and ventral regions of the OB. In the Sema3A-deficient OB, NP-1
      positive glomeruli spread over the entire OB, and we consistently found the
      ectopic arrangement of NP-1-positive glomeruli in the anteromedial and ventral
      regions. In addition, a specific subset of NP-1-negative and olfactory cell
      adhesion molecule-positive glomeruli, especially those in the anteromedial
      region, disappeared from the mutant OB. These results show a critical role for
      Sema3A in the spatial arrangement of glomeruli in the OB. Optical imaging from
      the dorsal OB showed that the distorted glomerular map conserved molecular
      feature domains. However, the positions of the domains were shifted, which
      suggests a secondary rearrangement of the glomerular map in the Sema3A-deficient
      OB.

PMID- 12598628
TI  - Nonpsychotropic cannabinoid receptors regulate microglial cell migration.
AB  - During neuroinflammation, activated microglial cells migrate toward dying
      neurons, where they exacerbate local cell damage. The signaling molecules that
      trigger microglial cell migration are poorly understood. In this paper, we show
      that pathological overstimulation of neurons by glutamate plus carbachol
      dramatically increases the production of the endocannabinoid 2
      arachidonylglycerol (2-AG) but only slightly increases the production of
      anandamide and does not affect the production of two putative endocannabinoids,
      homo-gamma-linolenylethanolamide and docosatetraenylethanolamide. We further show
      that pathological stimulation of microglial cells with ATP also increases the
      production of 2-AG without affecting the amount of other endocannabinoids. Using
      a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell
      migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol
      sensitive receptors, with subsequent activation of the extracellular signal
      regulated kinase 1/2 signal transduction pathway. It is important to note that
      cannabinol and cannabidiol, two nonpsychotropic ingredients present in the
      marijuana plant, prevent the 2-AG-induced cell migration by antagonizing the CB2
      and abnormal-cannabidiol-sensitive receptors, respectively. Finally, we show that
      microglial cells express CB2 receptors at the leading edge of lamellipodia, which
      is consistent with the involvement of microglial cells in cell migration. Our
      study identifies a cannabinoid signaling system regulating microglial cell
      migration. Because this signaling system is likely to be involved in recruiting
      microglial cells toward dying neurons, we propose that cannabinol and cannabidiol
      are promising nonpsychotropic therapeutics to prevent the recruitment of these
      cells at neuroinflammatory lesion sites.

PMID- 12598629
TI  - Steroid-induced dendritic regression reduces anatomical contacts between neurons
      during synaptic weakening and the developmental loss of a behavior.
AB  - Steroid hormones alter dendritic architecture in many animals, but the exact
      relationship between dendritic anatomy, synaptic strength, and behavioral
      expression is typically unknown. In larvae of the moth Manduca sexta, the tip of
      each abdominal proleg (locomotory appendage) bears an array of mechanosensory
      hairs, each innervated by a planta hair sensory neuron (PH-SN). In the CNS, PH-SN
      axons make monosynaptic, excitatory nicotinic cholinergic connections with
      accessory planta retractor (APR) motoneurons. These synapses mediate a proleg
      withdrawal reflex behavior that is lost at pupation. The prepupal peak of
      ecdysteroids (molting hormones) triggers the regression of APR dendrites and a
      >80% reduction in the amplitude of EPSPs produced in APRs by PH-SNs that
      innervate posterior planta hairs. The present study tested the hypothesis that a
      decrease in the number of synaptic contacts from PH-SNs to APRs contributes to
      this synaptic weakening. Pairs of PH-SNs and APRs were fluorescently labeled in
      larvae and pupae, and the number of indistinguishably close anatomical contacts
      (putative synapses) was counted by confocal laser scanning microscopy. During APR
      dendritic regression, the mean number of contacts from posterior PH-SNs decreased
      by approximately 80%, whereas the size of individual contacts did not change
      detectably and the axonal arbors of PH-SNs did not regress. These results suggest
      that the steroid-induced regression of motoneuron dendrites physically
      disconnects the motoneurons from the synaptic terminals of sensory neurons,
      producing synaptic weakening and the developmental loss of the proleg withdrawal
      reflex behavior at pupation.

PMID- 12598630
TI  - Rho kinase inhibition enhances axonal regeneration in the injured CNS.
AB  - Myelin-associated inhibitors limit axonal regeneration in the injured brain and
      spinal cord. A common target of many neurite outgrowth inhibitors is the Rho
      family of small GTPases. Activation of Rho and a downstream effector of Rho,
      p160ROCK, inhibits neurite outgrowth. Here, we demonstrate that Rho is directly
      activated by the myelin-associated inhibitor Nogo-66. Using a binding assay to
      measure Rho activity, we detected increased levels of GTP Rho in PC12 and dorsal
      root ganglion (DRG) cell lysates after Nogo-66 stimulation. Rho activity levels
      were not affected by Amino-Nogo stimulation. Rho inactivation with C3 transferase
      promotes neurite outgrowth of chick DRG neurons in vitro, but with the delivery
      method used here, it fails to promote neurite outgrowth after corticospinal tract
      (CST) lesions in the adult rat. Inhibition of p160ROCK with Y-27632 also promotes
      neurite outgrowth on myelin-associated inhibitors in vitro. Furthermore, Y-27632
      enhances sprouting of CST fibers in vivo and accelerates locomotor recovery after
      CST lesions in adult rats.

PMID- 12598631
TI  - Neurotrophin-3 expressed in situ induces axonal plasticity in the adult injured
      spinal cord.
AB  - The mammalian CNS lacks the ability to effectively compensate for injury by the
      regeneration of damaged axons or axonal plasticity of intact axons. However,
      reports suggest that molecular or cellular manipulations can induce compensatory
      processes that could support regeneration or plasticity after trauma. We tested
      whether local, sustained release of the neurotrophic factor neurotrophin-3 (NT-3)
      would support axonal plasticity in the spinal cord distal to the site of injury
      in rats. The corticospinal tract (CST) was cut unilaterally at the level of the
      medulla. This avoided excessive inflammation, secondary cell death, vascular
      disruption, and the release of inhibitory molecules in the lumbar spinal cord. A
      replication-defective adenoviral vector (Adv) carrying the NT-3 gene (Adv.EFalpha
      NT3) was delivered to the spinal motoneurons by retrograde transport through the
      sciatic nerve. Retrograde transport of the adenoviral vectors avoided the
      inflammatory response that would be associated with direct injection into the
      spinal cord. Transduction of spinal motoneurons with Adv.EFalpha-NT3 resulted in
      a significant increase in the concentration of NT-3 in the L3-L6 region of the
      spinal cord for up to 3 weeks. In animals with a CST lesion, this local
      expression of NT-3 induced growth of axons from the intact CST across the midline
      to the denervated side. If the CST remained intact, overexpression of NT-3 did
      not lead to an increase in the number of axons crossing the midline. These data
      demonstrate that local, sustained expression of NT-3 will support axonal
      plasticity of intact CST axons after trauma-induced denervation.

PMID- 12598632
TI  - Sleep-related consolidation of a visuomotor skill: brain mechanisms as assessed
      by functional magnetic resonance imaging.
AB  - Subjects were trained on a pursuit task in which the target trajectory was
      predictable only on the horizontal axis. Half of them were sleep deprived on the
      first post-training night (n = 13). Three days later, functional magnetic
      resonance imaging revealed task-related increases in brain responses to the
      learned trajectory, as compared with a new trajectory. In the sleeping group (n =
      12) as compared with the sleep-deprived group, subjects' performance was
      improved, and their brain activity was greater in the superior temporal sulcus
      (STS). Increased functional connectivity was observed between the STS and the
      cerebellum and between the supplementary eye field and the frontal eye field.
      These differences indicate sleep-related plastic changes during motor skill
      learning in areas involved in smooth pursuit eye movements.

PMID- 12598634
TI  - Human cortical object recognition from a visual motion flowfield.
AB  - Moving dots can evoke a percept of the spatial structure of a three-dimensional
      object in the absence of other visual cues. This phenomenon, called structure
      from motion (SFM), suggests that the motion flowfield represented in the dorsal
      stream can form the basis of object recognition performed in the ventral stream.
      SFM processing is likely to contribute to object perception whenever there is
      relative motion between the observer and the object viewed. Here we investigate
      the motion flowfield component of object recognition with functional magnetic
      resonance imaging. Our SFM stimuli encoded face surfaces and random three
      dimensional control shapes with matched curvature properties. We used two
      different types of an SFM stimulus with the dots either fixed to the surface of
      the object or moving on it. Despite the radically different encoding of surface
      structure in the two types of SFM, both elicited strong surface percepts and
      involved the same network of cortical regions. From early visual areas, this
      network extends dorsally into the human motion complex and parietal regions and
      ventrally into object-related cortex. The SFM stimuli elicited a face-selective
      response in the fusiform face area. The human motion complex appears to have a
      central role in SFM object recognition, not merely representing the motion
      flowfield but also the surface structure of the motion-defined object. The motion
      complex and a region in the intraparietal sulcus reflected the motion state of
      the SFM-implicit object, responding more strongly when the implicit object was in
      motion than when it was stationary.

PMID- 12598633
TI  - Phase resetting light pulses induce Per1 and persistent spike activity in a
      subpopulation of biological clock neurons.
AB  - The endogenous circadian clock of the mammalian suprachiasmatic nucleus (SCN) can
      be reset by light to synchronize the biological clock of the brain with the
      external environment. This process involves induction of immediate-early genes
      such as the circadian clock gene Period1 (Per1) and results in a stable shift in
      the timing of behavioral and physiological rhythms on subsequent days. The
      mechanisms by which gene activation permanently alters the phase of clock neuron
      activity are unknown. To study the relationship between acute gene activation and
      persistent changes in the neurophysiology of SCN neurons, we recorded from SCN
      neurons marked with a dynamic green fluorescent protein (GFP) reporter of Per1
      gene activity. Phase-resetting light pulses resulted in Per1 induction in a
      distinct subset of SCN neurons that also exhibited a persistent increase in
      action potential frequency 3-5 hr after a light pulse. By simultaneously
      quantifying Per1 gene activation and spike frequency in individual neurons, we
      found that the degree of Per1 induction was highly correlated with neuronal spike
      frequency on a cell-by-cell basis. Increased neuronal activity was mediated by
      membrane potential depolarization as a result of a reduction in outward potassium
      current. Double-label immunocytochemistry revealed that vasoactive intestinal
      peptide (VIP)-expressing cells, but not arginine vasopressin (AVP)-expressing
      cells, exhibited significant Per1 induction by light pulses. Rhythmic GFP
      expression occurred in both VIP and AVP neurons. Our results indicate that the
      steps that link acute molecular events to permanent changes in clock phase
      involve persistent suppression of potassium current, downstream of Per1 gene
      induction, in a specific subset of Per1-expressing neurons enriched for VIP.

PMID- 12598635
TI  - A neural basis for auditory feedback control of vocal pitch.
AB  - Hearing one's own voice is essential for the production of correct vocalization
      patterns in many birds and mammals, including humans. Bats, for instance, adjust
      temporal, spectral, and intensity parameters of their echolocation calls by
      precisely monitoring the characteristics of the returning echo signals. However,
      neuronal substrates and mechanisms for auditory feedback control of vocalizations
      are still mostly unknown in any vertebrate. We used echolocating horseshoe bats
      to investigate the role of the midbrain and hindbrain tegmentum for the control
      of call frequencies in response to changing auditory feedback. These bats
      accurately control the frequency of their echolocation calls through auditory
      feedback both when the bat is at rest [resting frequency (RF)] and when it is
      flying and compensating for changes in echo frequency caused by flight-induced
      Doppler shifts [Doppler shift compensation (DSC)]. We iontophoretically injected
      various GABAergic and glutamatergic transmitter agonists and antagonists into the
      brainstem tegmentum. We found that within the parabrachial nuclei and the
      immediately adjacent tegmentum, excitatory effects caused by application of the
      glutamate agonist AMPA or the GABA(A) antagonist bicuculline raised RF and the
      frequency of calls emitted during DSC. Bicuculline application routinely blocked
      DSC altogether. Alternately, inhibitory effects caused by application of either
      the GABA(A) agonist muscimol or the AMPA antagonist CNQX lowered call frequencies
      emitted at rest and during DSC. Such an audio-vocal feedback mechanism might
      share basic aspects with audio-vocal feedback controlling the pitch of
      vocalizations in other mammals, including the involuntary response to "pitch
      shifted feedback" in humans.

PMID- 12598636
TI  - A novel functional neuron group for respiratory rhythm generation in the ventral
      medulla.
AB  - We visualized respiratory neuron activity covering the entire ventral medulla
      using optical recordings in a newborn rat brainstem-spinal cord preparation
      stained with voltage-sensitive dye. We measured optical signals from several
      seconds before to several seconds after the inspiratory phase using the
      inspiratory motor nerve discharge as the trigger signal; we averaged the optical
      signals of 50-150 respiratory cycles to obtain an optical image correlating
      particularly to inspiratory activity. The optical images we obtained from the
      ventral approach indicated that neuron activity first appeared during the
      respiratory cycle in the limited region of the rostral ventrolateral medulla
      (RVLM), preceding the onset of inspiratory activity by approximately 500 msec.
      During the inspiratory phase, plateau activity appeared in the more caudal
      ventrolateral medulla at the level of the most rostral roots of the XIIth nerve.
      Comparison with electrophysiological recordings from respiratory neurons in the
      RVLM suggested that the optical signals preceding the inspiratory burst reflect
      preinspiratory neuron activity in this area. This RVLM area was determined to be
      ventrolateral to the facial nucleus and close to the ventral surface. We referred
      to this functional neuron group as the para-facial respiratory group (pFRG).
      Partial, bilateral electrical lesioning of the pFRG significantly reduced the
      respiratory frequency, together with changes in the spatiotemporal pattern of
      respiratory neuron activity. Our findings suggest that the pFRG comprises a
      neuronal population that is involved in the primary respiratory rhythm generation
      in the rostrocaudally extending respiratory neuron network of the medulla.

PMID- 12598637
TI  - Orexin neurons express a functional pancreatic polypeptide Y4 receptor.
AB  - The receptor subtypes that mediate the effects of neuropeptide Y (NPY) on food
      intake have not been clearly defined. The NPY Y4 receptor has been identified
      recently as a potential mediator of the regulation of food intake. The purpose of
      the present study was to characterize the central site of action of the Y4
      receptor using a combination of neuroanatomical and physiological approaches.
      Using immunocytochemistry, Y4-like immunoreactivity was found to be colocalized
      with orexin cell bodies in the lateral hypothalamic area (LHA) and orexin fibers
      throughout the brain. In situ hybridization confirmed the expression of Y4 mRNA
      in orexin neurons. To determine the functional interaction between Y4 receptors
      and orexin neurons, we examined the effects of rat pancreatic polypeptide (rPP),
      a Y4-selective ligand, or NPY, a nonselective ligand, administered directly into
      the LHA on the stimulation of food and water intake and c-Fos expression. Both
      rPP and NPY significantly increased food and water intake when they were
      administered into the LHA, although NPY was a more potent stimulator of food
      intake. Furthermore, both NPY and rPP significantly stimulated c-Fos expression
      in the LHA. However, whereas rPP stimulated c-Fos expression in orexin neurons,
      NPY did not. Neither rPP nor NPY stimulated c-Fos in melanin-concentrating
      hormone neurons, but both activated neurons of an unknown phenotype in the LHA.
      These results suggest that a functional Y4 receptor is expressed on orexin
      neurons and that these neurons are activated in response to a ligand with high
      affinity for the Y4 receptor (rPP). Although these data suggest a role for
      central Y4 receptors, the endogenous ligand for this receptor has yet to be
      clearly established.

PMID- 12598638
TI  - Behavioral effects of high-strength static magnetic fields on rats.
AB  - Advances in magnetic resonance imaging are driving the development of more
      powerful and higher-resolution machines with high-strength static magnetic
      fields. The behavioral effects of high-strength magnetic fields are largely
      uncharacterized, although restraint within a 9.4 T magnetic field is sufficient
      to induce a conditioned taste aversion (CTA) and induce brainstem expression of c
      Fos in rats. To determine whether the behavioral effects of static magnetic
      fields are dependent on field strength, duration of exposure, and orientation
      with the field, rats were restrained within the bore of 7 or 14 T superconducting
      magnets for variable durations. Behavioral effects were assessed by scoring
      locomotor activity after release from the magnetic field and measuring CTA
      acquisition after pairing intake of a palatable glucose and saccharin (G+S)
      solution with magnetic field exposure. Magnetic field exposure at either 7 or 14
      T suppressed rearing and induced tight circling. The direction of the circling
      was dependent on the rat's orientation within the magnetic field: if exposed head
      up, rats circled counterclockwise; if exposed head-down, rats circled clockwise.
      CTA was induced after three pairings of taste and 30 min of 7 T exposure or after
      a single pairing of G+S and 1 min of 14 T exposure. These results suggest that
      magnetic field exposure has graded effects on rat behavior. We hypothesize that
      restraint with high-strength magnetic fields causes vestibular stimulation
      resulting in locomotor circling and CTA acquisition.

PMID- 12598639
TI  - Slow Na+ inactivation and variance adaptation in salamander retinal ganglion
      cells.
AB  - The retina adapts to the temporal contrast of the light inputs. One component of
      contrast adaptation is intrinsic to retinal ganglion cells: temporal contrast
      affects the variance of the synaptic inputs to ganglion cells, which alters the
      gain of spike generation. Here we show that slow Na+ inactivation is sufficient
      to produce the observed variance adaptation. Slow inactivation caused the Na+
      current available for spike generation to depend on the past history of activity,
      both action potentials and subthreshold voltage variations. Recovery from slow
      inactivation required several hundred milliseconds. Increased current variance
      caused the threshold for spike generation to increase, presumably because of the
      decrease in available Na+ current. Simulations indicated that slow Na+
      inactivation could account for the observed decrease in excitability. This
      suggests a simple picture of how ganglion cells contribute to contrast
      adaptation: (1) increasing contrast causes an increase in input current variance
      that raises the spike rate, and (2) the increased spike rate reduces the
      available Na+ current through slow inactivation, which feeds back to reduce
      excitability. Cells throughout the nervous system face similar problems of
      accommodating a large range of input signals; furthermore, the Na+ currents of
      many cells exhibit slow inactivation. Thus, adaptation mediated by feedback
      modulation of the Na+ current through slow inactivation could serve as a general
      mechanism to control excitability in spiking neurons.

PMID- 12598640
TI  - Time-dependent relationship between the dorsal hippocampus and the prefrontal
      cortex in spatial memory.
AB  - The prefrontal cortex and the dorsal hippocampus have been studied extensively
      for their significant roles in spatial working memory. A possible time-dependent
      functional relationship between the prefrontal cortex and the dorsal hippocampus
      in spatial working memory was tested. A combined lesion and pharmacological
      inactivation technique targeting both the dorsal hippocampus and the medial
      prefrontal cortex was used (i.e., axon-sparing lesions of the dorsal hippocampus
      combined with reversible inactivation of the medial prefrontal cortex, or vice
      versa, within a subject). A delayed nonmatching-to-place task on a radial eight
      arm maze with short-term (i.e., 10 sec) versus intermediate-term (i.e., 5 min)
      delays was used as a behavioral paradigm. Here we report that the dorsal
      hippocampus and the medial prefrontal cortex process short-term spatial memory in
      parallel, serving as a compensatory mechanism for each other. The role of the
      dorsal hippocampus, however, becomes highlighted as the time-window for memory
      (i.e., delay) shifts from short-term to a delay period (i.e., intermediate-term)
      exceeding the short-term range. The results indicate that the time window of
      memory is a key factor in dissociating multiple memory systems.

PMID- 12598641
TI  - A dynamic dendritic refractory period regulates burst discharge in the
      electrosensory lobe of weakly electric fish.
AB  - Na+-dependent spikes initiate in the soma or axon hillock region and actively
      backpropagate into the dendritic arbor of many central neurons. Inward currents
      underlying spike discharge are offset by outward K+ currents that repolarize a
      spike and establish a refractory period to temporarily prevent spike discharge.
      We show in a sensory neuron that somatic and dendritic K+ channels differentially
      control burst discharge by regulating the extent to which backpropagating
      dendritic spikes can re-excite the soma. During repetitive discharge a
      progressive broadening of dendritic spikes promotes a dynamic increase in
      dendritic spike refractory period. A leaky integrate-and-fire model shows that
      spike bursts are terminated when a decreasing somatic interspike interval and an
      increasing dendritic spike refractory period synergistically act to block
      backpropagation. The time required for the somatic interspike interval to
      intersect with dendritic refractory period determines burst frequency, a time
      that is regulated by somatic and dendritic spike repolarization. Thus, K+
      channels involved in spike repolarization can efficiently control the pattern of
      spike output by establishing a soma-dendritic interaction that invokes dynamic
      shifts in dendritic spike properties.

PMID- 12598642
TI  - Single neurons in CA1 hippocampus encode trace interval duration during trace
      heart rate (fear) conditioning in rabbit.
AB  - This study sought to determine whether CA1 hippocampal neurons encode the
      duration of the trace interval during trace fear conditioning. Single neurons
      were recorded extracellularly in the CA1 of rabbits during and after a single
      trace fear classical conditioning session. Trace fear conditioning trials
      consisted of an auditory conditioned stimulus (CS; 3 sec) and a fear-producing
      shock unconditioned stimulus (US; 0.5 sec) separated by a silent trace interval.
      One group of rabbits was trained using a 10 sec trace interval (n = 5), and
      another group was trained using a 20 sec trace interval (n = 4). These groups
      were compared with pseudoconditioning control rabbits (n = 5 and n = 4,
      respectively) that received unpaired CSs and USs. One day after trace and pseudo
      fear conditioning rabbits received a CS-alone retention session in which no USs
      were presented. The trace conditioned groups showed larger bradycardiac-fear
      responses on CS-alone trials compared with the pseudoconditioning groups. A
      significant percentage of CA1 neurons from the 10 and 20 sec trace groups (24 and
      28%, respectively) showed maximal firing on CS-alone retention trials timed to 10
      sec (+/-1.5 sec) and 20 sec (+/-2.0 sec) after CS offset, respectively. These
      latencies were similar to the duration of the trace interval used on previous CS
      trace-US trials. Timed CA1 firing was not seen in pseudoconditioning control
      animals, suggesting that a subset of CA1 neurons encoded the trace interval
      duration. The percentage of neurons encoding trace duration was largest when
      rabbits exhibited significant fear responses to the CS, suggesting that trace
      encoding was related to the strength of the CS and US association.

PMID- 12598643
TI  - Changes in inhibitory amino acid release linked to pontine-induced atonia: an in
      vivo microdialysis study.
AB  - We hypothesized that cessation of brainstem monoaminergic systems and an
      activation of brainstem inhibitory systems are both involved in pontine
      inhibitory area (PIA) stimulation-induced muscle atonia. In our previous study
      (Lai et al., 2001), we found a decrease in norepinephrine and serotonin release
      in motoneuron pools during PIA stimulation-induced muscle tone suppression. We
      now demonstrate an increase in inhibitory amino acid release in motor nuclei
      during PIA stimulation in the decerebrate cat using in vivo microdialysis and
      HPLC analysis techniques. Microinjection of acetylcholine into the PIA elicited
      muscle atonia and simultaneously produced a significant increase in both glycine
      and GABA release in both the hypoglossal nucleus and the lumbar ventral horn.
      Glycine release increased by 74% in the hypoglossal nucleus and 50% in the spinal
      cord. GABA release increased by 31% in the hypoglossal nucleus and 64% in the
      spinal cord during atonia induced by cholinergic stimulation of the PIA. As with
      cholinergic stimulation, 300 msec train electrical stimulation of the PIA
      elicited a significant increase in glycine release in the hypoglossal nucleus and
      ventral horn. GABA release was significantly increased in the hypoglossal nucleus
      but not in the spinal cord during electrical stimulation of the PIA. Glutamate
      release in the motor nuclei was not significantly altered during atonia induced
      by electrical or acetylcholine stimulation of the PIA. We suggest that both
      glycine and GABA play important roles in the regulation of upper airway and
      postural muscle tone. A combination of decreased monoamine and increased
      inhibitory amino acid release in motoneuron pools causes PIA-induced atonia and
      may be involved in atonia linked to rapid eye-movement sleep.

PMID- 12598645
TI  - Selective killing of cancer cells by beta -lapachone: direct checkpoint
      activation as a strategy against cancer.
AB  - Most chemotherapeutic drugs kill cancer cells by indirectly activating checkpoint
      mediated apoptosis after creating nonselective damage to DNA or microtubules,
      which accounts for their toxicity toward normal cells. We seek to target cancer
      cells by directly activating checkpoint regulators without creating such damage.
      Here, we show that beta-lapachone selectively induces apoptosis in cancer cells
      without causing the death of nontransformed cells in culture. This unusual
      selectivity against cancer cells is preceded by activation of S-phase checkpoint
      and selective induction of E2F1, a regulator of checkpoint-mediated apoptosis.
      This study suggests direct checkpoint activation as a strategy against cancer.

PMID- 12598644
TI  - Bacillus thuringiensis crystal proteins that target nematodes.
AB  - Bacillus thuringiensis (Bt) crystal proteins are pore-forming toxins used as
      insecticides around the world. Previously, the extent to which these proteins
      might also target the invertebrate phylum Nematoda has been mostly ignored. We
      have expressed seven different crystal toxin proteins from two largely unstudied
      Bt crystal protein subfamilies. By assaying their toxicity on diverse free-living
      nematode species, we demonstrate that four of these crystal proteins are active
      against multiple nematode species and that each nematode species tested is
      susceptible to at least one toxin. We also demonstrate that a rat intestinal
      nematode is susceptible to some of the nematicidal crystal proteins, indicating
      these may hold promise in controlling vertebrate-parasitic nematodes. Toxicity in
      nematodes correlates with damage to the intestine, consistent with the mechanism
      of crystal toxin action in insects. Structure-function analyses indicate that one
      novel nematicidal crystal protein can be engineered to a small 43-kDa active
      core. These data demonstrate that at least two Bt crystal protein subfamilies
      contain nematicidal toxins.

PMID- 12598646
TI  - Retroevolution of lambda Cro toward a stable monomer.
AB  - The Cro protein from bacteriophage lambda has a dimeric alpha+beta fold that
      evolved from an ancestral all-alpha monomer. The sequence mutations responsible
      for this dramatic structural evolution are unknown. Here we use analysis of
      sequence alignments to show that Ala-33, a small side chain in the hydrophobic
      "ball-and-socket" dimer interface of lambda Cro, was a much larger tryptophan
      side chain at a previous point in evolution. The retroevolutionary lambda Cro
      A33W mutant shows a 10-fold reduction in dimerization affinity relative to the
      wild type as well as a large increase in monomer thermal stability (Delta T(m) >
      10 degrees C), apparently due to partial filling of the hydrophobic socket from
      within the same monomer. An additional mutation in the dimer interface, F58D,
      almost completely abolishes detectable dimerization while maintaining the high
      monomer stability. The secondary structure content of the monomerized versions of
      lambda Cro is similar to that of the wild-type protein, and the tertiary
      structure of the monomer appears relatively well defined. These results (i)
      support a model in which the ball-and-socket dimer interface of lambda Cro was
      created by altered volume mutations within a limited branch of the Cro lineage
      and (ii) suggest the possibility that the evolution of the alpha+beta dimer from
      an all-alpha monomer proceeded through an alpha+beta monomer intermediate.

PMID- 12598647
TI  - Type I polyketide synthase requiring a discrete acyltransferase for polyketide
      biosynthesis.
AB  - Type I polyketide synthases (PKSs) are multifunctional enzymes that are organized
      into modules, each of which minimally contains a beta-ketoacyl synthase, an
      acyltransferase (AT), and an acyl carrier protein. Here we report that the
      leinamycin (LNM) biosynthetic gene cluster from Streptomyces atroolivaceus S-140
      consists of two PKS genes, lnmI and lnmJ, that encode six PKS modules, none of
      which contain the cognate AT domain. The only AT activity identified within the
      lnm gene cluster is a discrete AT protein encoded by lnmG. Inactivation of lnmG,
      lnmI, or lnmJ in vivo abolished LNM biosynthesis. Biochemical characterization of
      LnmG in vitro showed that it efficiently and specifically loaded malonyl CoA to
      all six PKS modules. These findings unveiled a previously unknown PKS
      architecture that is characterized by a discrete, iteratively acting AT protein
      that loads the extender units in trans to "AT-less" multifunctional type I PKS
      proteins for polyketide biosynthesis. This PKS structure provides opportunities
      for PKS engineering as exemplified by overexpressing lnmG to improve LNM
      production.

PMID- 12598648
TI  - MecA, an adaptor protein necessary for ClpC chaperone activity.
AB  - ClpC of Bacillus subtilis is an ATP-dependent HSP100Clp protein involved in
      general stress survival. A complex of ClpC with the protease ClpP and the adaptor
      protein MecA also controls competence development by regulated proteolysis of the
      transcription factor ComK. We investigated the in vitro chaperone activity of
      ClpC and found that the presence of MecA was crucial for the major chaperone
      activities of ClpC. In particular, MecA enabled ClpC to solubilize and refold
      aggregated proteins. Finally, in the presence of ClpP, MecA allowed the ClpC
      dependent degradation of unfolded or heat-aggregated proteins. This study
      demonstrates that adaptor proteins like MecA through interaction with their
      cognate ClpC proteins can have a dual role in the protein quality-control network
      by rescuing, or together with ClpP, by degrading, aggregated proteins. MecA can
      thereby coordinate substrate targeting with ClpC activation, adding another layer
      to the regulation of HSP100/Clp protein activity.

PMID- 12598649
TI  - IL-15 availability conditions homeostasis of peripheral natural killer T cells.
AB  - Steady-state numbers of peripheral lymphocyte are tightly controlled. For
      conventional T cells, signals delivered through the interaction of the T cell
      receptor (TCR) with antigen-loaded MHC molecules are required for the peripheral
      survival of naive T cells and for their homeostatic expansion in lymphopenic
      hosts. Cytokines, including IL-7, are also essential for survival of peripheral
      naive T cells. CD1d-restricted, V alpha 14(+) natural killer (NK)-T cells are a
      specialized autoreactive T subset with immunoregulatory activity. The relative
      roles of TCR engagement and cytokine signaling in the peripheral homeostasis of V
      alpha 14(+) NK-T cells were investigated. After adoptive transfer, the survival
      and expansion of peripheral V alpha 14(+) NK-T cells was independent of CD1d
      expression in the host. In contrast, IL-15 (but not IL-7) was required for
      maintenance of peripheral CD1d-reactive V alpha 14(+) T cells. Comparison of V
      alpha 14(+) T cell transfers into NK-proficient vs. deficient hosts suggests that
      NK-T cells and NK cells compete for peripheral resources. Our results indicate
      that IL-15 maintains the homeostasis of peripheral V alpha 14(+) NK-T cells. In
      contrast, TCR "tickling" of NK-T cells, if it occurs under steady-state
      conditions, does not by itself provide a sufficient signal for their peripheral
      survival.

PMID- 12598650
TI  - Phase locking between human primary and secondary somatosensory cortices.
AB  - Unilateral stimulation of human peripheral nerves activates the primary
      somatosensory cortex (SI) contralaterally and the secondary somatosensory cortex
      (SII) bilaterally. We aimed at characterizing phase locking between SI and SII in
      response to electric stimuli applied once every 3 s to the right median nerve at
      the wrist; phase locking between brain regions has been proposed to either
      reflect joined processing or information exchange. Ongoing neuromagnetic activity
      of healthy volunteers was recorded with 204 planar gradiometers covering the
      whole scalp. After selecting a sensor maximally sensitive to activity in the left
      (contralateral) SI, phase locking between this sensor and the other 203 sensors
      was examined from single trial data. Statistically significant phase locking was
      found at approximately 20 Hz, 80-90 ms after the stimuli between the left SI and
      the right SII in 9 of 10 subjects. Sensors with high phase-locking values over
      the left SI and right SII were separated by sensors with no phase-locked activity
      over the scalp midline, indicating that the phase locking was not caused by the
      sensors seeing activity from the same sources. The observed SI-SII phase locking
      would not be reflected in the evoked responses because a considerable part of it
      was not time-locked to the stimuli. Thus, our finding reveals a unique
      interaction in the sensorimotor system.

PMID- 12598651
TI  - IL-1 is required for tumor invasiveness and angiogenesis.
AB  - Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1
      alpha are required for in vivo angiogenesis and invasiveness of different tumor
      cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16
      melanoma cells were not observed compared with WT mice. Angiogenesis was assessed
      by the recruitment of blood vessel networks into Matrigel plugs containing B16
      melanoma cells; vascularization of the plugs was present in WT mice, but was
      absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing
      Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response.
      Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs
      in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs.
      In IL-1 alpha KO mice, local tumor development and induction of an angiogenic
      response in Matrigel plugs was less pronounced than in WT mice, but significantly
      higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL
      1 beta were not restricted to the melanoma model, but were also observed in DA/3
      mammary and prostate cancer cell models. In addition to the in vivo findings, IL
      1 contributed to the production of vascular endothelial cell growth factor and
      tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells.
      Host-derived IL-1 seems to control tumor angiogenesis and invasiveness.
      Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here,
      suggest a possible therapeutic role in cancer, in addition to its current use in
      rheumatoid arthritis.

PMID- 12598653
TI  - Hemese, a hemocyte-specific transmembrane protein, affects the cellular immune
      response in Drosophila.
AB  - We have identified a previously undescribed transmembrane protein, Hemese, from
      Drosophila melanogaster blood cells (hemocytes), by using a monoclonal pan
      hemocyte antibody. Heavy glycosylation is suggested by the heterogeneous size
      distribution, ranging between 37 and 70 kDa. Hemese expression is restricted to
      the cell surfaces of hemocytes of all classes, and to the hematopoietic organs.
      The sequence of the corresponding gene, Hemese (He), predicts a glycophorin-like
      protein of 15 kDa, excluding an N-terminal signal peptide, with a single
      hydrophobic transmembrane region. The extracellular region consists mainly of
      Ser/Thr-rich sequence of low complexity, with several potential O-glycosylation
      sites. Hemese contains phosphotyrosine and the cytoplasmic region has potential
      phosphorylation sites, suggesting an involvement in signal transduction.
      Depletion of Hemese by RNA interference has no obvious effect under normal
      conditions, but the cellular response to parasitic wasps is much enhanced. This
      finding indicates that Hemese plays a modulatory role in the activation or
      recruitment of the hemocytes.

PMID- 12598654
TI  - Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and
      the molecular basis of its regulation.
AB  - The retinoblastoma tumor suppressor protein (pRb) regulates the cell cycle,
      facilitates differentiation, and restrains apoptosis. Furthermore, dysfunctional
      pRb is thought to be involved in the development of most human malignancies. Many
      of the functions of pRb are mediated by its regulation of the E2F transcription
      factors. To understand the structural basis for this regulation, we have
      determined the crystal structure of a fragment of E2F in complex with the pocket
      domain of the tumor suppressor protein. The pRb pocket, comprising the A and B
      cyclin-like domains, is the major focus of tumourigenic mutations in the protein.
      The fragment of E2F used in our structural studies, residues 409-426 of E2F-1,
      represents the core of the pRb-binding region of the transcription factor. The
      structure shows that E2F binds at the interface of the A and B domains of the
      pocket making extensive interactions with conserved residues from both. We show
      by solution studies that a second site, probably contained within the "marked
      box" region of E2F, is responsible for additional interactions with the pRb
      pocket but is insufficient for complex formation on its own. In addition, we show
      that the interaction of the core binding fragment of E2F with pRb is inhibited by
      phosphorylation of the tumor suppressor protein by CDK2cyclin DE. Finally, our
      data reveal that the tight binding of the human papillomavirus E7 oncoprotein to
      pRb prevents subsequent interactions with the marked box region of E2F but not
      with its core binding region.

PMID- 12598655
TI  - Evidence for rotation of V1-ATPase.
AB  - V(o)V(1)-ATPase is responsible for acidification of eukaryotic intracellular
      compartments and ATP synthesis of Archaea and some eubacteria. From the
      similarity to F(o)F(1)-ATP synthase, V(o)V(1)-ATPase has been assumed to be a
      rotary motor, but to date there are no experimental data to support this. Here we
      visualized the rotation of single molecules of V(1)-ATPase, a catalytic
      subcomplex of V(o)V(1)-ATPase. V(1)-ATPase from Thermus thermophilus was
      immobilized onto a glass surface, and a bead was attached to the D or F subunit
      through the biotin-streptavidin linkage. In both cases we observed ATP-dependent
      rotations of beads, the direction of which was always counterclockwise viewed
      from the membrane side. Given that three ATP molecules are hydrolyzed per one
      revolution, rates of rotation agree consistently with rates of ATP hydrolysis at
      saturating ATP concentrations. This study provides experimental evidence that
      V(o)V(1)-ATPase is a rotary motor and that both D and F subunits constitute a
      rotor shaft.

PMID- 12598656
TI  - Interdomain zinc site on human albumin.
AB  - Albumin is the major transport protein in blood for Zn(2+), a metal ion required
      for physiological processes and recruited by various drugs and toxins. However,
      the Zn(2+)-binding site(s) on albumin is ill-defined. We have analyzed the 18 x
      ray crystal structures of human albumin in the PDB and identified a potential
      five-coordinate Zn site at the interface of domains I and II consisting of N
      ligands from His-67 and His-247 and O ligands from Asn-99, Asp-249, and H(2)O,
      which are the same amino acid ligands as those in the zinc enzymes calcineurin,
      endonucleotidase, and purple acid phosphatase. The site is preformed in
      unliganded apo-albumin and highly conserved in mammalian albumins. We have used
      (111)Cd NMR as a probe for Zn(2+) binding to recombinant human albumin. We show
      that His-67 --> Ala (His67Ala) mutation strongly perturbs Cd(2+) binding, whereas
      the mutations Cys34Ala, or His39Leu and Tyr84Phe (residues which may H-bond to
      Cys-34) have no effect. Weak Cl(-) binding to the fifth coordination site of
      Cd(2+) was demonstrated. Cd(2+) binding was dramatically affected by high fatty
      acid loading of albumin. Analysis of the x-ray structures suggests that fatty
      acid binding to site 2 triggers a spring-lock mechanism, which disengages the
      upper (His-67Asn-99) and lower (His-247Asp-249) halves of the metal site. These
      findings provide a possible mechanism whereby fatty acids (and perhaps other
      small molecules) could influence the transport and delivery of zinc in blood.

PMID- 12598657
TI  - Gonadotrophin-releasing hormone drives melatonin receptor down-regulation in the
      developing pituitary gland.
AB  - Melatonin is produced nocturnally by the pineal gland and is a neurochemical
      representation of time. It regulates neuroendocrine target tissues through G
      protein-coupled receptors, of which MT(1) is the predominant subtype. These
      receptors are transiently expressed in several fetal and neonatal tissues,
      suggesting distinct roles for melatonin in development and that specific
      developmental cues define time windows for melatonin sensitivity. We have
      investigated MT(1) gene expression in the rat pituitary gland. MT(1) mRNA is
      confined to the pars tuberalis region of the adult pituitary, but in neonates
      extends into the ventral pars distalis and colocalizes with luteinizing hormone
      beta-subunit (LH beta) expression. This accounts for the well documented
      transient sensitivity of rat gonadotrophs to melatonin in the neonatal period.
      Analysis of an upstream fragment of the rat MT(1) gene revealed multiple putative
      response elements for the transcription factor pituitary homeobox-1 (Pitx-1),
      which is expressed in the anterior pituitary from Rathke's pouch formation. A
      Pitx-1 expression vector potently stimulated expression of both MT(1)-luciferase
      and LH beta-luciferase reporter constructs in COS-7 cells. Interestingly,
      transcription factors that synergize with Pitx-1 to trans-activate gonadotroph
      associated genes did not potentiate Pitx-1-induced MT(1)-luciferase activity.
      Moreover, the transcription factor, early growth response factor-1, which is
      induced by gonadotrophin-releasing hormone (GnRH) and trans-activates LH beta
      expression, attenuated Pitx-1-induced MT(1)-luciferase activity. Finally,
      pituitary MT(1) gene expression was 4-fold higher in hypogonadal (hpg) mice,
      which do not synthesize GnRH, than in their wild-type littermates. These data
      suggest that establishment of a mature hypothalamic GnRH input drives the
      postnatal decline in pituitary MT(1) gene expression.

PMID- 12598658
TI  - Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from
      colon cancer cells.
AB  - Up-regulation of cyclooxygenase-2 (COX-2) and overproduction of prostaglandins
      have been implicated in the initiation and/or progression of colon cancer.
      However, it is uncertain in which cells and how COX-2 is induced initially in the
      tumor microenvironment. We found that a conditioned medium of the colon cancer
      cell line, LS 180, contained a factor to induce COX-2 in human peripheral blood
      mononuclear cells. This factor was purified biochemically and revealed to be
      mucins. A small amount of mucins (approximately 100 ng of protein per ml) could
      elevate prostaglandin E2 production by monocytes. The mucins induced COX-2 mRNA
      and protein levels of monocytes in a dose- and time-dependent manner, indicating
      a COX-2-mediated pathway. We also have examined immunohistochemically the
      localization of COX-2 protein and mucins in human colorectal cancer tissues. It
      is noteworthy that COX-2-expressing macrophages were located around the region in
      which mucins were detectable, suggesting that COX-2 also was induced by mucins in
      vivo. These results suggest that mucins produced by colon cancer cells play a
      critical role in the initial induction of COX-2 in the tumor microenvironment.

PMID- 12598660
TI  - The long and winding road from silica exposure to silicosis and other health
      effects.

PMID- 12598659
TI  - Non-heme iron enzymes: contrasts to heme catalysis.
AB  - Non-heme iron enzymes catalyze a wide range of O(2) reactions, paralleling those
      of heme systems. Non-heme iron active sites are, however, much more difficult to
      study because they do not exhibit the intense spectral features characteristic of
      the porphyrin ligand. A spectroscopic methodology was developed that provides
      significant mechanistic insight into the reactivity of non-heme ferrous active
      sites. These studies reveal a general mechanistic strategy used by these enzymes
      and differences in substrate and cofactor interactions dependent on their
      requirement for activation by iron. Contributions to O(2) activation have been
      elucidated for non-heme relative to heme ligand sets, and major differences in
      reactivity are defined with respect to the heterolytic and homolytic cleavage of
      O-O bonds.

PMID- 12598661
TI  - Quantitative relations between exposure to respirable quartz and risk of
      silicosis.
AB  - AIMS: To reanalyse exposure-response data from a Scottish colliery to gain a more
      detailed knowledge of the relations between exposure to quartz and risks of
      silicosis in coal miners, and hence inform the debate on an appropriate
      occupational standard for respirable quartz. METHODS: Detailed data on working
      times at different quartz concentrations were combined to produce exposure
      profiles for miners who had provided a full chest radiograph at a follow up
      survey. Logistic regression methods were used to model profusion of radiographic
      abnormalities category 2/1+, and a general exposure index was used to compare
      different quartz exposure measures in these models. RESULTS: Results in 371 men
      aged 50-74 indicated that cumulative quartz exposure at higher concentrations
      resulted in proportionally greater risks of abnormalities. One g x h x m(-3) of
      cumulative exposure at quartz concentrations greater than 2 mg x m(-3) was
      estimated to have equivalent risks to 3 g x h x m(-3) at lower concentrations.
      The timing of exposure relative to follow up appeared less important, although
      the study had limited power to compare different lag periods between exposure and
      effect. CONCLUSIONS: Quantification of the risks of silicosis should take account
      of variations in quartz exposure intensity, particularly for exposure to
      concentrations of greater than 1 or 2 mg.m(-3), even if exposure is for
      relatively short periods. The risks of silicosis over a working lifetime can rise
      dramatically with even brief exposure to such high quartz concentrations. Risk
      estimates are given, to inform choice of control limits.

PMID- 12598662
TI  - Follow up of mortality and incidence of cancer 1952-98 in men from the UK who
      participated in the UK's atmospheric nuclear weapon tests and experimental
      programmes.
AB  - AIMS: To extend and analyse follow up of mortality and cancer incidence among men
      who took part in the UK's atmospheric nuclear weapon tests and experimental
      programmes 40-50 years ago, with particular reference to multiple myeloma and
      leukaemia. METHODS: A total of 21,357 servicemen and male civilians from the UK
      who participated in the tests and a control group of 22,333 male controls were
      followed over the period 1952-98. Analyses were conducted of mortality from
      various causes, and of mortality and incidence for 27 types of cancer. RESULTS:
      Rates of mortality from all causes continued to be similar among test
      participants and controls with the longer follow up, with standardised mortality
      ratios (SMRs) of 89 and 88 respectively over the full follow up period. For all
      cancers, the corresponding SMRs were 93 for participants and 92 for controls.
      Mortality from multiple myeloma was consistent with national rates both for
      participants and controls, and the relative risk (RR) of myeloma incidence among
      participants relative to controls was 1.14 (90% CI 0.74 to 1.74) over the full
      follow up period and 0.79 (90% CI 0.45 to 1.38) during the extended period of
      follow up (1991-98). Over the full follow up period, leukaemia mortality among
      participants was consistent with national rates, while rates among controls were
      significantly lower, and there was a suggestion of a raised risk among test
      participants relative to controls (RR 1.45, 90% CI 0.96 to 2.17); the
      corresponding RR for leukaemia incidence was 1.33 (90% CI 0.97 to 1.84). After
      excluding chronic lymphatic leukaemia (CLL), which is not thought to be radiation
      inducible, the RR of leukaemia mortality increased to 1.83 (90% CI 1.15 to 2.93),
      while that for incidence was little changed. Analysis of subgroups of
      participants with greater potential for exposure provided little evidence of
      increased risks, although the numbers of men involved were smaller and the
      statistical power was therefore less. Among other types of cancer, only for liver
      cancer incidence was there evidence of differences in rates between participants
      and controls in both the earlier and in the additional period of follow up.
      Mortality rates among test participants from causes other than cancer were
      generally similar to those among the controls. CONCLUSIONS: Overall levels of
      mortality and cancer incidence in UK nuclear weapons test participants have
      continued to be similar to those in a matched control group, and overall
      mortality has remained lower than expected from national rates. There was no
      evidence of an increased raised risk of multiple myeloma among test participants
      in recent years, and the suggestion in the first analysis of this study of a
      raised myeloma risk is likely to have been a chance finding. There was some
      evidence of a raised risk of leukaemia other than CLL among test participants
      relative to controls, particularly in the early years after the tests, although a
      small risk may have persisted more recently. This could be a chance finding, in
      view of low rates among the controls and the generally small radiation doses
      recorded for test participants. However, the possibility that test participation
      caused a small absolute risk of leukaemia other than CLL cannot be ruled out.

PMID- 12598664
TI  - Mental health of British farmers.
AB  - AIMS: To estimate the prevalence of neurotic symptoms in a sample of British
      farmers, to investigate whether farming characteristics are associated with
      psychiatric morbidity, and to test the hypothesis that British farmers have a
      higher prevalence of depression and thoughts of life not worth living than the
      British household population. METHODS: A total of 425 farmers from Hereford,
      Norwich, and Preston completed the Revised Clinical Interview Schedule (CIS-R) by
      computer between March and July 1999. The comparison cohort consisted of 9830
      private householders aged 16-64 from the Office of Population Censuses and
      Surveys National Psychiatric Morbidity Surveys of Great Britain carried out in
      1993 in which the CIS-R was administered. All analyses used the commands
      developed specifically for survey data available in Stata version 6.0. RESULTS:
      Taking a threshold of an overall score of 12 or more on the CIS-R, only 6% of
      farmers reported clinically relevant psychiatric morbidity. Psychiatric morbidity
      was not significantly associated with farm type or size in this study. Farmers
      reported a lower prevalence of psychiatric morbidity than the general population
      but were more likely to report thinking that life is not worth living,
      particularly after the low prevalence of psychiatric morbidity had been taken
      into account (odds ratio 2.56, 95% CI 1.39 to 4.69). When restricting the
      comparison to only rural or semirural householders, this increased risk was even
      more pronounced (odds ratio 3.26, 95% CI 1.51 to 7.02). CONCLUSIONS: The relation
      between depression and suicidal ideation seems to be quite different among
      farmers and the general population and warrants further investigation. We have
      shown it is possible to measure mental health systematically in a sample of
      British farmers. This study should be repeated in the aftermath of the foot and
      mouth crisis.

PMID- 12598663
TI  - Effect of trihalomethane exposure on fetal development.
AB  - AIMS: To examine the effect of trimester specific and pregnancy average total
      trihalomethane (TTHM) exposure on infant birth weight, low birth weight, and
      intrauterine growth retardation in term births, as well as gestational age and
      preterm delivery in all births. METHODS: Cross sectional analysis of 56 513
      singleton infants born to residents of Massachusetts during 1990. City specific
      aggregate data were used to estimate maternal exposure to TTHM concentration;
      individual maternal information was used to adjust for confounding. RESULTS:
      Increased pregnancy average and second trimester TTHM exposure were associated
      with small for gestational age and reductions in birth weight after adjusting for
      potential confounding variables. Compared to </=60 micro g/l, pregnancy average
      TTHM exposure over 80 micro g/l was associated with a 32 g reduction in birth
      weight. There was a 23 g reduction in birth weight in infants born to mothers
      exposed to greater than 80 micro g/l TTHM during the second trimester. For each
      20 micro g/l increase in TTHM, the estimated reduction in birth was 2.8 g for
      pregnancy average exposure and 2.6 g for second trimester exposure. An increased
      risk of small for gestational age births was found for pregnancy average (odds
      ratio (OR) 1.14; 95% CI 1.02 to 1.26) and second trimester (OR 1.13, 95% CI 1.03
      to 1.24) TTHM levels greater than 80 micro g/l. There was no evidence of an
      association between preterm delivery and increased TTHM levels, but there were
      slight increases in gestational duration associated with TTHM concentrations.
      CONCLUSIONS: Maternal exposure to THMs may be associated with fetal growth
      retardation. Our findings are consistent with most previous work, although we
      generally found smaller effects of TTHMs on low birth weight and intrauterine
      growth retardation.

PMID- 12598665
TI  - Lymphohaematopoietic system cancer incidence in an urban area near a coke oven
      plant: an ecological investigation.
AB  - AIMS: To evaluate the incidence risk of lymphohaematopoietic cancers for the 1986
      94 period in Cornigliano, a district of Genoa (Italy), where a coke oven is
      located a few hundred metres from the residential area. METHODS: The whole of
      Genoa and one of its 25 districts (Rivarolo) were selected as controls. The trend
      of risk around the coke oven was evaluated via Stone's method, while the
      geographic pattern of such risks across the Cornigliano district was evaluated by
      computing full Bayes estimates of standardised incidence ratio (FBE-SIR).
      RESULTS: In males, elevated relative risks (RR) were observed for all
      lymphohaematopoietic cancers (RR 1.7 v Rivarolo and 1.6 v Genoa), for NHL (RR 2.4
      v Rivarolo and 1.7 v Genoa), and for leukaemia (RR 2.4 v Rivarolo and 1.9 v
      Genoa). In females, statistically non-significant RR were observed. In males no
      excess of risk was found close to the coke oven. In females, a rising risk for
      NHL was observed approaching the plant, although statistical significance was not
      reached, while the risk for leukaemia was not evaluable due to the small number
      of cases. Analysis of the geographic pattern of risk suggested the presence of a
      cluster of NHL in both sexes in the eastern part of the district, where a foundry
      had been operational until the early 1980s. A cluster of leukaemia cases was
      observed in males in a northern part of the area, where no major sources of
      benzene seemed to be present. CONCLUSIONS: The estimated risks seem to be
      slightly or not at all related to the distance from the coke oven. The
      statistically significant higher risks observed in males for NHL and leukaemia,
      and the clusters of leukaemia in males and of NHL in both sexes deserve further
      investigations in order to trace the exposures associated with such risks.

PMID- 12598667
TI  - Coverage of work related fatalities in Australia by compensation and occupational
      health and safety agencies.
AB  - AIMS: To determine the levels of coverage of work related traumatic deaths by
      official occupational health and safety (OHS) and compensation agencies in
      Australia, to allow better understanding and interpretation of officially
      available statistics. METHODS: The analysis was part of a much larger study of
      all work related fatalities that occurred in Australia during the four year
      period 1989 to 1992 inclusive and which was based on information from coroners'
      files. For the current study, State, Territory, and Commonwealth OHS and
      compensation agencies were asked to supply unit record information for all deaths
      identified by the jurisdictions as being due to non-suicide traumatic causes and
      which were identified by them as being work related, using whatever definitions
      the agencies were using at the relevant time. This information was matched to
      cases identified during the main study. RESULTS: The percentage of working deaths
      not covered by any agency was 34%. Only 35% of working deaths were covered by an
      OHS agency, while 57% were covered by a compensation agency. The OHS agencies had
      minimal coverage of work related deaths that occurred on the road (to workers
      (8%) or commuters (3%)), whereas the compensation system covered these deaths
      better than those of workers in incidents that occurred in a workplace (65%
      versus 53%). There was virtually no coverage of bystanders (less than 8%) by
      either type of agency. There was marked variation in the level of coverage
      depending on the industry, occupation, and employment status of the workers, and
      the type of injury event involved in the incident. CONCLUSIONS: When using data
      from official sources, the significant limitations in coverage identified in this
      paper need to be taken into account. Future surveillance, arising from a
      computerised National Coroners Information System, should result in improved
      coverage of work related traumatic deaths in Australia.

PMID- 12598668
TI  - Radiographic (ILO) readings predict arterial oxygen desaturation during exercise
      in subjects with asbestosis.
AB  - BACKGROUND: Exercise impairment is common in subjects with asbestosis. Arterial
      oxygen desaturation during exercise is an important contributor to exercise
      limitation. The International Labour Office (ILO) classification of plain chest
      radiographs correlates with resting pulmonary function, but its value in
      predicting abnormal ventilatory responses to exercise, including desaturation,
      has not been explored. AIMS: To determine in subjects with asbestosis (1) if
      radiographic profusion scores and the extent of small irregular shadows on plain
      chest radiographs correlate with resting lung function and abnormal ventilatory
      responses to exercise; and (2) if radiographic scores add value to resting lung
      function tests in predicting abnormal ventilatory responses to exercise. METHODS:
      Thirty eight male subjects with asbestosis were included. Plain chest radiographs
      were read according to the ILO classification independently by three observers.
      All subjects underwent assessment of lung function and an incremental exercise
      test. RESULTS: Profusion scores and number of affected zones correlated
      significantly with the percentage predicted values of single breath diffusing
      capacity (DLCO), forced vital capacity (FVC), and total lung capacity (TLC).
      Arterial oxygen desaturation occurred in 29% of the subjects. The severity of
      desaturation correlated significantly with profusion and the number of affected
      zones. The combined use of number of affected zones, FEV(1)/FVC ratio and DLCO
      predicted desaturation during exercise with an explained variance of 41%.
      VO(2)max was significantly related only to DLCO but was not predicted by the ILO
      score. CONCLUSION: Arterial oxygen desaturation correlated with the profusion and
      extent of parenchymal abnormality on chest radiographs. The addition of
      morphological indices to physiological measurements is valuable for predicting
      oxygen desaturation during exercise but not for VO(2)max. Refinement of the
      radiographic scoring system and the addition of more sophisticated imaging
      techniques may further improve the predictive power.

PMID- 12598669
TI  - Volcanic ash and respiratory symptoms in children on the island of Montserrat,
      British West Indies.
AB  - BACKGROUND: In July 1995 the volcano on the West Indian island of Montserrat
      erupted after being inactive for several hundred years. Since then, clouds of ash
      have been released intermittently from the volcano. Some of this ash is <10 micro
      m in diameter and therefore respirable. Concerns were raised that the particles
      might cause respiratory problems. AIMS: To evaluate whether ashfalls had any
      effect on the respiratory health of children in Montserrat. METHODS: A survey of
      asthma diagnoses, respiratory symptoms, exercise induced bronchoconstriction
      (EIB), and current and previous exposure to volcanic ash was carried out in
      schools in Montserrat during February 1998. RESULTS: Questionnaire information
      was available for nearly 80% of the 443 children on the school rolls. The
      prevalence of wheeze symptoms in the previous 12 months was 18% in children aged
      12 years and under and 16% in children aged 13 years and over. In children aged
      12 and under, the prevalence of wheeze was greater in those who had ever been
      heavily or moderately exposed to volcanic ash compared with the group who had
      only ever been exposed to low levels (wheeze in last 12 months: odds ratio (OR)
      4.30; wheeze ever: OR 3.45). The prevalence of EIB in 8-12 year olds was about
      four times higher in those who were currently heavily exposed to volcanic ash (OR
      3.85) compared to those currently exposed to low levels. CONCLUSIONS: Volcanic
      ash emissions adversely affected the respiratory health of Montserrat children.
      The findings emphasise the need to limit exposures of children to volcanic ash
      and ensure the appropriate management of respiratory symptoms.

PMID- 12598670
TI  - Memory one month after acute carbon monoxide intoxication: a prospective study.
AB  - BACKGROUND: Serious delayed neuropsychological sequelae may complicate carbon
      monoxide intoxication. The existence of minor manifestations, especially memory
      disturbances, is not well documented. AIMS: To study several memory functions
      after carbon monoxide intoxication. METHODS: In a prospective study, 32 poisoned
      patients without risk factors for cognitive disturbances were compared to 32
      paired control subjects one month after acute carbon monoxide intoxication (blood
      carbon monoxide concentration at least 1.0 mmol/l), who had been treated with
      standard conventional therapy. Psychometric tests included Buschke's verbal
      memory testing, verbal digit span, Corsi's visuospatial span, reaction times,
      Stroop's colours decoding test, and verbal fluency test. RESULTS: (1) Memory
      functions in poisoned subjects were not worse than in the control group and were
      even better in some areas: learning, word recall, and quality of learning by
      Buschke's verbal memory testing. Attention was also better in the patients, in
      whom visual reaction time was shorter than in controls. (2) Results of several
      memory functions-quality of learning and immediate visual memory-were positively
      correlated with the initial carbon monoxide level. CONCLUSIONS: In a highly
      selected subset of patients devoid of risk factors for memory impairment, memory,
      objectively evaluated by psychometric testing, was not worse one month after
      carbon monoxide intoxication in patients undergoing standard treatment than in
      paired control subjects.

PMID- 12598671
TI  - Pain tolerance in upper limb disorders: findings from a community survey.
AB  - AIMS: To test the hypothesis that non-specific upper limb pain arises from
      altered pain perception with reduced tolerance of sensory stimuli. METHODS:
      Subjects undergoing clinical examination as part of a community based survey of
      upper limb disorders were invited to return for an assessment of pain tolerance.
      A standardised algorithm was used to classify the 94 participants according to
      whether they had specific upper limb disorders (n = 22), non-specific arm pain (n
      = 15), or no arm pain (n = 57). Pain tolerance was assessed at three anatomical
      sites in each arm in response to electrocutaneous stimulation with alternating
      currents up to a maximum of 10 mA at three frequencies (5, 250, and 2,000 Hz). A
      proportional odds model was used to compare pain tolerance thresholds according
      to sex, age, and diagnosis. RESULTS: Women were less tolerant of pain than men
      (OR 0.13) and tolerance also declined with age (OR for one year increase in age
      0.97). After allowance for sex and age, there was no indication that pain
      tolerance was lower in subjects with non-specific arm pain than in those with
      specific upper limb disorders or those who had no arm pain. CONCLUSIONS: The
      study hypothesis was not supported. However, before the hypothesis is dismissed,
      it should be tested further in patients with more severe and disabling arm pain.

PMID- 12598672
TI  - Relation between colour vision loss and occupational styrene exposure.

PMID- 12598673
TI  - Letter from Shanghai.

PMID- 12598674
TI  - Are personal and static samples related?

PMID- 12598675
TI  - Mental ill health in workers: observations from a few Indian populations.

PMID- 12598676
TI  - Competence at the workplace.

PMID- 12598677
TI  - Confounding and confounders.

PMID- 12598678
TI  - New insights into the diversity and function of neuronal immunoglobulin
      superfamily molecules.
AB  - Immunoglobulin superfamily (IgSF) proteins are implicated in diverse steps of
      brain development, including neuronal migration, axon pathfinding, target
      recognition and synapse formation, as well as in the maintenance and function of
      neuronal networks in the adult. We provide here a review of recent findings on
      the diversity and the role of transmembrane and secreted members of IgSF proteins
      in the nervous system. We illustrate that the complexity of IgSF protein function
      results from various different levels of regulation including regulation of gene
      expression, protein localization, and protein interactions.

PMID- 12598680
TI  - Selectivity in neurotrophin signaling: theme and variations.
AB  - Neurotrophins are a family of growth factors critical for the development and
      functioning of the nervous system. Although originally identified as neuronal
      survival factors, neurotrophins elicit many biological effects, ranging from
      proliferation to synaptic modulation to axonal pathfinding. Recent data indicate
      that the nature of the signaling cascades activated by neurotrophins, and the
      biological responses that ensue, are specified not only by the ligand itself but
      also by the temporal pattern and spatial location of stimulation. Studies on
      neurotrophin signaling have revealed variations in the Ras/MAP kinase, PI3
      kinase, and phospholipase C pathways, which transmit spatial and temporal
      information. The anatomy of neurons makes them particularly appropriate for
      studying how the location and tempo of stimulation determine the signal cascades
      that are activated by receptor tyrosine kinases such as the Trk receptors. These
      signaling variations may represent a general mechanism eliciting specificity in
      growth factor responses.

PMID- 12598681
TI  - Vege and Mar: two novel hAT MITE families from Drosophila willistoni.
AB  - Two novel families of miniature inverted repeat transposable elements (MITEs),
      Vege and Mar, are described from Drosophila willistoni. Based on their
      structures, both element families are hypothesized to belong to the hAT
      superfamily of transposable elements. Both elements have perfect, inverted
      terminal repeats and 8-bp target site duplications and were found to have
      inserted within fixed copies of nonautonomous P elements. Vege is present in all
      studied D. willistoni populations and appears to have a relatively low copy
      number. Mar was identified in only a single D. willistoni population, and its
      copy number is presently unknown. Although MITEs occupy relatively large
      proportions of the genomes of a broad range of organisms, this may be their first
      unambiguous identification in any species of the genus Drosophila.

PMID- 12598682
TI  - Evidence for positive selection on the floral scent gene isoeugenol-O
      methyltransferase.
AB  - Isoeugenol-O-methyltransferase (IEMT) is an enzyme involved in the production of
      the floral volatile compounds methyl eugenol and methyl isoeugenol in Clarkia
      breweri (Onagraceae). IEMT likely evolved by gene duplication from caffeic acid-O
      methyltransferase followed by amino acid divergence, leading to the acquisition
      of its novel function. To investigate the selective context under which IEMT
      evolved, maximum likelihood methods that estimate variable d(N)/d(S) ratios among
      lineages, among sites, and among a combination of both lineages and sites were
      utilized. Statistically significant support was obtained for a hypothesis of
      positive selection driving the evolution of IEMT since its origin. Subsequent
      Bayesian analyses identified several sites in IEMT that have experienced positive
      selection. Most of these positions are in the active site of IEMT and have been
      shown by site-directed mutagenesis to have large effects on substrate
      specificity. Although the selective agent is unknown, the adaptive evolution of
      this gene may have resulted in increased effectiveness of pollinator attraction
      or herbivore repellence.

PMID- 12598683
TI  - Accumulation of Spock and Worf, two novel non-LTR retrotransposons, on the neo-Y
      chromosome of Drosophila miranda.
AB  - Transposable elements constitute a major fraction of eukaryotic genomes. Here, I
      characterize two novel non-LTR retrotransposons, cloned from the neo-Y chromosome
      of Drosophila miranda. Worf is 4.1 kb in size and shows homology to the T1-2 non
      LTR transposon characterized in Anopheles. Spock is 4.9 kb in size and shows
      similarity to the Doc element of D. melanogaster. Southern blot analysis of both
      elements yielded stronger signals for male DNA. In situ hybridization to polytene
      chromosomes revealed that both elements are accumulating on the neo-Y chromosome
      of D. miranda. PCR analysis was conducted to investigate the frequency of spock
      and worf and of the previously identified transposons, TRIM and TRAM, at
      individual chromosomal sites among 12 strains of D. miranda. Contrary to the
      observation that element frequencies are usually kept low at individual sites in
      Drosophila, the four transposons investigated are fixed at their genomic
      locations on the neo-Y chromosome. These results support the hypothesis that
      transposons accumulate in nonrecombining regions and may be one cause of the
      heteromorphism of sex chromosomes.

PMID- 12598684
TI  - Identifying site-specific substitution rates.
AB  - A maximum likelihood framework for estimating site-specific substitution rates is
      presented that does not require any prior assumptions about the rate
      distribution. We show that, when the branching pattern of the underlying tree is
      known, the analysis of pairs of positions is sufficient to estimate site-specific
      rates. In the abscense of a known topology, we introduce an iterative procedure
      to estimate simultaneously the branching pattern, the branch lengths, and site
      specific substitution rates. Simulations show that the evolutionary rate of fast
      evolving sites can be reliably inferred and that the accuracy of rate estimates
      depends mainly on the number of sequences in the data set. Thus, large sets of
      aligned sequences are necessary for reliable site-specific rate estimates. The
      method is applied to the complete mitochondrial DNA sequence of 53 humans,
      providing a complete picture of the site-specific substitution rates in human
      mitochondrial DNA.

PMID- 12598679
TI  - Breathing: rhythmicity, plasticity, chemosensitivity.
AB  - Breathing is a vital behavior that is particularly amenable to experimental
      investigation. We review recent progress on three problems of broad interest. (i)
      Where and how is respiratory rhythm generated? The preBotzinger Complex is a
      critical site, whereas pacemaker neurons may not be essential. The possibility
      that coupled oscillators are involved is considered. (ii) What are the mechanisms
      that underlie the plasticity necessary for adaptive changes in breathing?
      Serotonin-dependent long-term facilitation following intermittent hypoxia is an
      important example of such plasticity, and a model that can account for this
      adaptive behavior is discussed. (iii) Where and how are the regulated variables
      CO2 and pH sensed? These sensors are essential if breathing is to be appropriate
      for metabolism. Neurons with appropriate chemosensitivity are spread throughout
      the brainstem; their individual properties and collective role are just beginning
      to be understood.

PMID- 12598685
TI  - Recurrent exon shuffling between distant P-element families.
AB  - Two independent stationary P-related neogenes had been previously described in
      the Drosophila obscura species group and in the Drosophila montium species
      subgroup. In Drosophila melanogaster, P-transposable elements can encode an 87
      kDa transposase and a 66 kDa repressor, but the P-neogenes have only conserved
      the capacity to encode a 66 kDa repressor-like protein specified by the first
      three exons. We have previously analyzed the genomic modifications associated
      with the transition of a P-element into the montium P-neogene, the coding
      capacity of which has been conserved for around 20 Myr ( Nouaud, D., and D.
      Anxolabehere. 1997. Mol. Biol. Evol. 14:1132-1144). Here we show that the P
      neogene of some species of the montium subgroup presents a new structure
      involving the capture of an additional exon from a very distant P-element
      subfamily. This additional exon is inserted either upstream or downstream of the
      first exon of the P-neogene. As a result of alternative splicing, these modified
      neogenes can produce, in addition to the repressor-like protein, a new protein
      which differs only by the NH2-terminal region. We hypothesize that this protein
      diversity within an organism results in a functional diversification due to the
      selective advantage associated with the domestication of the P-neogene in these
      species. Moreover, the autonomous P-element which provides the additional exons
      is still present in the genome. Its nucleotide sequence is more than 45% distant
      from the previously defined P-type element (M-type, O-type, T-type) and defines a
      new P-type element subfamily referred to as the K-type.

PMID- 12598686
TI  - Positive selection on an acrosomal sperm protein, M7 lysin, in three species of
      the mussel genus Mytilus.
AB  - Marine invertebrate sperm proteins are particularly interesting because they are
      characterized by positive selection and are likely to be involved in prezyogotic
      isolation and, thus, speciation. Here, we present the first survey of
      interspecific and intraspecific variation of a bivalve sperm protein among a
      group of species that regularly hybridize in nature. M7 lysin is found in sperm
      acrosomes of mussels and dissolves the egg vitelline coat, permitting
      fertilization. We sequenced multiple alleles of the mature protein-coding region
      of M7 lysin from allopatric populations of mussels in the Mytilus edulis species
      group (M. edulis, M. galloprovincialis, and M. trossulus). A significant McDonald
      Kreitman test showed an excess of fixed amino acid replacing substitutions
      between species, consistent with positive selection. In addition, Kolmogorov
      Smirnov tests showed significant heterogeneity in polymorphism to divergence
      ratios for both synonymous variation and combined synonymous and nonsynonymous
      variation within M. galloprovincialis. These results indicate that there has been
      adaptive evolution at M7 lysin and, furthermore, show that positive selection on
      sperm proteins can occur even when postzygotic reproductive isolation is
      incomplete.

PMID- 12598687
TI  - Gene genealogies when the sample size exceeds the effective size of the
      population.
AB  - We study the properties of gene genealogies for large samples using a continuous
      approximation introduced by R. A. Fisher. We show that the major effect of large
      sample size, relative to the effective size of the population, is to increase the
      proportion of polymorphisms at which the mutant type is found in a single copy in
      the sample. We derive analytical expressions for the expected number of these
      singleton polymorphisms and for the total number of polymorphic, or segregating,
      sites that are valid even when the sample size is much greater than the effective
      size of the population. We use simulations to assess the accuracy of these
      predictions and to investigate other aspects of large-sample genealogies. Lastly,
      we apply our results to some data from Pacific oysters sampled from British
      Columbia. This illustrates that, when large samples are available, it is possible
      to estimate the mutation rate and the effective population size separately, in
      contrast to the case of small samples in which only the product of the mutation
      rate and the effective population size can be estimated.

PMID- 12598688
TI  - Reconstructing the evolutionary history of China: a caveat about inferences drawn
      from ancient DNA.
AB  - The decipherment of the meager information provided by short fragments of ancient
      mitochondrial DNA (mtDNA) is notoriously difficult but is regarded as a most
      promising way toward reconstructing the past from the genetic perspective. By
      haplogroup-specific hypervariable segment (HVS) motif search and matching or near
      matching with available modern data sets, most of the ancient mtDNAs can be
      tentatively assigned to haplogroups, which are often subcontinent specific.
      Further typing for mtDNA haplogroup-diagnostic coding region polymorphisms,
      however, is indispensable for establishing the geographic/genetic affinities of
      ancient samples with less ambiguity. In the present study, we sequenced a
      fragment (approximately 982 bp) of the mtDNA control region in 76 Han individuals
      from Taian, Shandong, China, and we combined these data with previously reported
      samples from Zibo and Qingdao, Shandong. The reanalysis of two previously
      published ancient mtDNA population data sets from Linzi (same province) then
      indicates that the ancient populations had features in common with the modern
      populations from south China rather than any specific affinity to the European
      mtDNA pool. Our results highlight that ancient mtDNA data obtained under
      different sampling schemes and subject to potential contamination can easily
      create the impression of drastic spatiotemporal changes in the genetic structure
      of a regional population during the past few thousand years if inappropriate
      methods of data analysis are employed.

PMID- 12598689
TI  - Evolution of bindin in the pantropical sea urchin Tripneustes: comparisons to
      bindin of other genera.
AB  - Bindin, a sea urchin sperm protein, mediates sperm-egg attachment and membrane
      fusion and is thus important in species recognition and speciation. Patterns of
      bindin variation differed among three genera that had been studied previously. In
      two genera of the superorder Camarodonta, Echinometra and Strongylocentrotus,
      both of which contain sympatric species, bindin is highly variable within and
      between species; a region of the molecule evolves at high rates under strong
      positive selection. In Arbacia, which belongs to the superorder Stirodonta and
      whose extant species are all allopatric, bindin variation is low, and there is no
      evidence of positive selection. We cloned and sequenced bindin from Tripneustes,
      a sea urchin that belongs to the Camarodonta but whose three species are found in
      different oceans. Worldwide sampling of bindin alleles shows that the bindin of
      Tripneustes (1) contains the highly conserved core characteristic of all other
      bindins characterized to date, (2) has an intron in the same position, and (3)
      has approximately the same length. Its structure is more like that of bindin from
      other camarodont sea urchins than to bindin from the stirodont ARBACIA: The
      resemblances to other camarodonts include a glycine-rich repeat structure
      upstream of the core and lack of a hydrophobic domain 3' of the core, a
      characteristic of Arbacia bindin. Yet the mode of evolution of Tripneustes bindin
      is more like that of Arbacia. Differences between bindins of the Caribbean
      Tripneustes ventricosus and the eastern Pacific T. depressus, separated for 3 my
      by the Isthmus of Panama, are limited to four amino acid changes and a single
      indel. There are no fixed amino acid differences or indels between T. depressus
      from the eastern Pacific and T. gratilla from the Indo-Pacific. Bindin of
      Tripneustes, like that of Arbacia, also shows no evidence of diversifying
      selection that would manifest itself in a higher proportion of amino acid
      replacements than of silent nucleotide substitutions. When the rate of
      intrageneric bindin divergence is standardized by dividing it by cytochrome
      oxidase I (COI) divergence, Tripneustes and Arbacia show a lower ratio of bindin
      to COI substitutions between the species of each genus than exists between the
      species of either Echinometra or Strongylocentrotus. Thus, mode of bindin
      evolution is not correlated with phylogenetic affinities or molecular structure,
      but rather with whether the species in a genus are allopatric or sympatric. For a
      molecule involved in gametic recognition, this would suggest a pattern of
      evolution via reinforcement. However, in bindin the process that gave rise to
      this pattern is not likely to have been selection to avoid hybridization, because
      there is no excess of amino acid replacements between species versus within
      species in the bindins of Echinometra and Strongylocentrotus, as would have been
      expected if specific recognition were the driving force in their evolution. We
      suggest instead that the pattern of reinforcement is a secondary effect of the
      ability of species with rapidly evolving bindins to coexist in sympatry.

PMID- 12598690
TI  - The effect of single nucleotide polymorphism identification strategies on
      estimates of linkage disequilibrium.
AB  - At present there is tremendous interest in characterizing the magnitude and
      distribution of linkage disequilibrium (LD) throughout the human genome, which
      will provide the necessary foundation for genome-wide LD analyses and facilitate
      detailed evolutionary studies. To this end, a human high-density single
      nucleotide polymorphism (SNP) marker map has been constructed. Many of the SNPs
      on this map, however, were identified by sampling a small number of chromosomes
      from a single population, and inferences drawn from studies using such SNPs may
      be influenced by ascertainment bias (AB). Through extensive simulations, we have
      found that AB is a potentially significant problem in estimating and comparing LD
      within and between populations. Specifically, the magnitude of AB is a function
      of the SNP discovery strategy, number of chromosomes used for SNP discovery,
      population genetic characteristics of the particular genomic region considered,
      amount of gene flow between populations, and demographic history of the
      populations. We demonstrate that a balanced SNP discovery strategy (where equal
      numbers of chromosomes are sampled from multiple subpopulations) is the optimal
      study design for generating broadly applicable SNP resources. Finally, we
      validate our theoretical predictions by comparing our results to publicly
      available data from ten genes sequenced in 24 African American and 23 European
      American individuals.

PMID- 12598691
TI  - Paternal leakage of mitochondrial DNA in the great tit (Parus major).
AB  - Animal mitochondrial DNA is normally inherited clonally from a mother to all her
      offspring. Mitochondrial heteroplasmy, the occurrence of more than one
      mitochondrial haplotype within an individual, can be generated by relatively
      common somatic mutations within an individual, by heteroplasmy of the oocytes, or
      by paternal leakage of mitochondria during fertilization of an egg. This
      biparental inheritance has so far been reported only in mice, mussels,
      Drosophila, and humans. Here we present evidence that paternal leakage occurs in
      a bird, the great tit Parus major. The major and minor subspecies groups of the
      great tit mix in the middle Amur Valley in far-eastern Siberia, where we found a
      bird that possessed the very distinct haplotypes of the two groups. To our
      knowledge this is the first report of paternal leakage in birds.

PMID- 12598692
TI  - Comparison of Bayesian and maximum likelihood bootstrap measures of phylogenetic
      reliability.
AB  - Owing to the exponential growth of genome databases, phylogenetic trees are now
      widely used to test a variety of evolutionary hypotheses. Nevertheless,
      computation time burden limits the application of methods such as maximum
      likelihood nonparametric bootstrap to assess reliability of evolutionary trees.
      As an alternative, the much faster Bayesian inference of phylogeny, which
      expresses branch support as posterior probabilities, has been introduced.
      However, marked discrepancies exist between nonparametric bootstrap proportions
      and Bayesian posterior probabilities, leading to difficulties in the
      interpretation of sometimes strongly conflicting results. As an attempt to
      reconcile these two indices of node reliability, we apply the nonparametric
      bootstrap resampling procedure to the Bayesian approach. The correlation between
      posterior probabilities, bootstrap maximum likelihood percentages, and
      bootstrapped posterior probabilities was studied for eight highly diverse
      empirical data sets and were also investigated using experimental simulation. Our
      results show that the relation between posterior probabilities and bootstrapped
      maximum likelihood percentages is highly variable but that very strong
      correlations always exist when Bayesian node support is estimated on bootstrapped
      character matrices. Moreover, simulations corroborate empirical observations in
      suggesting that, being more conservative, the bootstrap approach might be less
      prone to strongly supporting a false phylogenetic hypothesis. Thus, apparent
      conflicts in topology recovered by the Bayesian approach were reduced after
      bootstrapping. Both posterior probabilities and bootstrap supports are of great
      interest to phylogeny as potential upper and lower bounds of node reliability,
      but they are surely not interchangeable and cannot be directly compared.

PMID- 12598693
TI  - Bayes or bootstrap? A simulation study comparing the performance of Bayesian
      Markov chain Monte Carlo sampling and bootstrapping in assessing phylogenetic
      confidence.
AB  - Bayesian Markov chain Monte Carlo sampling has become increasingly popular in
      phylogenetics as a method for both estimating the maximum likelihood topology and
      for assessing nodal confidence. Despite the growing use of posterior
      probabilities, the relationship between the Bayesian measure of confidence and
      the most commonly used confidence measure in phylogenetics, the nonparametric
      bootstrap proportion, is poorly understood. We used computer simulation to
      investigate the behavior of three phylogenetic confidence methods: Bayesian
      posterior probabilities calculated via Markov chain Monte Carlo sampling (BMCMC
      PP), maximum likelihood bootstrap proportion (ML-BP), and maximum parsimony
      bootstrap proportion (MP-BP). We simulated the evolution of DNA sequence on 17
      taxon topologies under 18 evolutionary scenarios and examined the performance of
      these methods in assigning confidence to correct monophyletic and incorrect
      monophyletic groups, and we examined the effects of increasing character number
      on support value. BMCMC-PP and ML-BP were often strongly correlated with one
      another but could provide substantially different estimates of support on short
      internodes. In contrast, BMCMC-PP correlated poorly with MP-BP across most of the
      simulation conditions that we examined. For a given threshold value, more correct
      monophyletic groups were supported by BMCMC-PP than by either ML-BP or MP-BP.
      When threshold values were chosen that fixed the rate of accepting incorrect
      monophyletic relationship as true at 5%, all three methods recovered most of the
      correct relationships on the simulated topologies, although BMCMC-PP and ML-BP
      performed better than MP-BP. BMCMC-PP was usually a less biased predictor of
      phylogenetic accuracy than either bootstrapping method. BMCMC-PP provided high
      support values for correct topological bipartitions with fewer characters than
      was needed for nonparametric bootstrap.

PMID- 12598694
TI  - Parallel evolution of ligand specificity between LacI/GalR family repressors and
      periplasmic sugar-binding proteins.
AB  - The bacterial LacI/GalR family repressors such as lactose operon repressor
      (LacI), purine nucleotide synthesis repressor (PurR), and trehalose operon
      repressor (TreR) consist of not only the N-terminal helix-turn-helix DNA-binding
      domain but also the C-terminal ligand-binding domain that is structurally
      homologous to periplasmic sugar-binding proteins. These structural features imply
      that the repressor family evolved by acquiring the DNA-binding domain in the N
      terminal of an ancestral periplasmic binding protein (PBP). Phylogenetic analysis
      of the LacI/GalR family repressors and their PBP homologues revealed that the
      acquisition of the DNA-binding domain occurred first in the family, and ligand
      specificity then evolved. The phylogenetic tree also indicates that the
      acquisition occurred only once before the divergence of the major lineages of
      eubacteria, and that the LacI/GalR and the PBP families have since undergone
      extensive gene duplication/loss independently along the evolutionary lineages.
      Multiple alignments of the repressors and PBPs furthermore revealed that
      repressors and PBPs with the same ligand specificity have the same or similar
      residues in their binding sites. This result, together with the phylogenetic
      relationship, demonstrates that the repressors and the PBPs individually acquired
      the same ligand specificity by homoplasious replacement, even though their genes
      are encoded in the same operon.

PMID- 12598695
TI  - Compositional evolution of noncoding DNA in the human and chimpanzee genomes.
AB  - We have examined the compositional evolution of noncoding DNA in the primate
      genome by comparison of lineage-specific substitutions observed in 1.8 Mb of
      genomic alignments of human, chimpanzee, and baboon with 6542 human single
      nucleotide polymorphisms (SNPs) rooted using chimpanzee sequence. The pattern of
      compositional evolution, measured in terms of the numbers of GC-->AT and AT-->GC
      changes, differs significantly between fixed and polymorphic sites, and indicates
      that there is a bias toward fixation of AT-->GC mutations, which could result
      from weak directional selection or biased gene conversion in favor of high GC
      content. Comparison of the frequency distributions of a subset of the SNPs
      revealed no significant difference between GC-->AT and AT-->GC polymorphisms,
      although AT-->GC polymorphisms in regions of high GC segregate at slightly higher
      frequencies on average than GC-->AT polymorphisms, which is consistent with a
      fixation bias favoring high GC in these regions. However, the substitution data
      suggest that this fixation bias is relatively weak, because the compositional
      structure of the human and chimpanzee genomes is becoming homogenized, with
      regions of high GC decreasing in GC content and regions of low GC increasing in
      GC content. The rate and pattern of nucleotide substitution in 333 Alu repeats
      within the human-chimpanzee-baboon alignments are not significantly affected by
      the GC content of the region in which they are inserted, providing further
      evidence that, since the time of the human-chimpanzee ancestor, there has been
      little or no regional variation in mutation bias.

PMID- 12598696
TI  - Molecular phylogeny of early vertebrates: monophyly of the agnathans as revealed
      by sequences of 35 genes.
AB  - Extant vertebrates are divided into three major groups: hagfishes (Hyperotreti,
      myxinoids), lampreys (Hyperoartia, petromyzontids), and jawed vertebrates
      (Gnathostomata). The phylogenetic relationships among the groups and within the
      jawed vertebrates are controversial, for both morphological and molecular studies
      have rendered themselves to conflicting interpretations. Here, we use the
      sequences of 35 nuclear protein-encoding genes to provide definitive evidence for
      the monophyly of the Agnatha (jawless vertebrates, a group encompassing the
      hagfishes and lampreys). Our analyses also give a strong support for the
      separation of Chondrichthyes (cartilaginous fishes) before the divergence of
      Osteichthyes (bony fishes) from the other gnathostomes.

PMID- 12598697
TI  - The question of outcomes.

PMID- 12598698
TI  - A look at the purpose and outcomes of colostomy irrigation.

PMID- 12598699
TI  - Assessing quality of life in patients with chronic leg ulceration using the
      Medical Outcomes Short Form-36 questionnaire.
AB  - Clinician awareness of the importance of recognizing, assessing, and ultimately
      addressing the negative impact of chronic wounds on patient quality of life is
      increasing. One hundred, eighteen (118) patients (average age 78 years)
      participated in a study to evaluate the use of the Medical Outcomes Short Form-36
      for assessing the health-related quality of life of patients with chronic leg
      ulceration. Most patients (104, 88%) were treated at home by community nurses. A
      medical history was obtained and patients completed the Short Form-36
      questionnaire at baseline and after 12 weeks of receiving standard ulcer care.
      Published normative data were used to ascertain the effect of leg ulcers on
      health-related quality of life. Short Form-36 responsiveness was determined by
      comparing baseline and 12-week scores. Results suggest that the questionnaire is
      reliable for five of eight Short Form-36 domains (alpha > 0.8), with the
      remainder alpha > 0.7. Compared to age-sex adjusted published normative scores,
      patients with leg ulcers had significantly lower mean scores in the following
      domains: role-emotional (d = 28.6, P <0.001), social functioning (d = 22.8, P
      <0.001), role-functioning (d = 20.8, P <0.001), role-physical (d = 20.7, P
      <0.001), and bodily pain (d = 12.3, P <0.001). Short Form-36 scores barely
      changed between baseline and the 12-week assessment, but bodily pain improved in
      the 31 patients whose ulcers healed during that time (d = 14.6, P = 0.006; SRM =
      0.60). Pain did not improve in patients whose ulcers remained open (d = -2.1, P =
      0.45). Compared to patients whose ulcers did not heal, patients with healed
      ulcers experienced greater improvements in the following domains: body pain (d =
      16.8, P = 0.003), mental health (d = 9.4, P = 0.013), role-physical (d = 19.7, P
      = 0.06), role-emotional (d = 17.2, P = 0.12), and vitality (d = 9.0, P = 0.052).
      The results of this study suggest that leg ulcers reduce patient quality of life
      and that the Short Form-36 can be used to ascertain their impact

PMID- 12598700
TI  - The chronic wound and the family.
AB  - Stressful life events, such as coping with a chronic wound, often compel families
      to reorganize their style of functioning. The Family Stress Theory, developed by
      Professor Reuben Hill, provides one explanation for the family's adjustment
      process as it faces a crisis event. The effects of caregiving on families and
      their health are just beginning to be understood, and only a few studies have
      explored the experiences of families caring for people with chronic wounds.
      However, application of the Family Stress Theory and available research may help
      clinicians understand how families react and respond to health alterations and
      guide practice when the family is an integral part of the intervention.

PMID- 12598701
TI  - Quality of life in patients with stomas: the Montreux Study.
AB  - Ostomy surgery profoundly affects a person's life. To determine the extent of the
      effect, the Stoma Care Quality of Life Index instrument was developed from a
      quality-of-life index. After ascertaining its validity and reliability, the
      instrument was used to measure patient quality of life in a European-wide study
      (16 countries). Six hundred, eighteen (618) stoma care nurses recruited 4,739
      patients following stoma surgery. The self-administered questionnaire was
      completed immediately following surgery and after 3,6, 9, and 12 months. The mean
      age of patients was 61.6 years (+/- 13.4 years), 53.7% were men, and the majority
      (66.5%) had a colostomy. Stoma Care Quality of Life Index scores were fairly
      consistent in all patients throughout Europe immediately following surgery. While
      scores improved steadily over time, only the difference between the postoperative
      and 3-month scores was significant (P < 0.001). Stoma Care Quality of Life Index
      scores were significantly higher in patients who were satisfied with the care
      received than in those who were not satisfied. Similarly, patients who had a good
      relationship with the stoma care nurse and felt confident about changing the
      appliance had significantly higher Stoma Care Quality of Life Index scores than
      those who did not have a good relationship or feel confident. The results of this
      study suggest that stoma patient quality of life can be assessed, that it changes
      over time, and that patient access to specialist ostomy care nurses is
      particularly important during the first 3 to 6 months following surgery.

PMID- 12598702
TI  - Medicare issues new policy on electrical stimulation.

PMID- 12598703
TI  - The international league of dermatological societies: global dermatology on the
      move.

PMID- 12598704
TI  - Growth factors, signal transduction, and cellular responses.
AB  - The extraordinary advances in the field of growth factors and signal transduction
      have created new and promising therapeutic interventions. We intend to explain
      the difficult nomenclatures associated with growth factors and their mechanisms
      of action.

PMID- 12598705
TI  - The induction of heme oxygenase-1 by exogenous nitric oxide in ex vivo normal
      human skin.
AB  - Gaseous carbon monoxide (CO) has received attention as a neurotransmitter and as
      a material involved in persistent dilatation of vessels. CO is released by heme
      oxygenase (HO) during the process from heme to bilirubin or biliverdin. Many
      reports have revealed that exogenous nitric oxide (NO) can induce HO-1 in vitro,
      which is the induced isoform of HO. In the present study, we attempted an ex vivo
      system as an explant culture. A quantitative analysis was performed in
      combination with a reverse transcription-competitive polymerase chain reaction
      method, which proved to be very accurate, as well as a qualitative analysis with
      an immunohistochemistry. With this system we confirmed the induction of HO-1 mRNA
      and protein by exogenous NO in normal human skin. Our results concluded that this
      ex vivo system was very useful, because skin samples could be handled easily
      under conditions close to the in vivo situation.

PMID- 12598706
TI  - Demonstration of TARC and CCR4 mRNA expression and distribution using in situ RT
      PCR in the lesional skin of atopic dermatitis.
AB  - Thymus- and activation-regulated chemokine (TARC/CCL17) and its receptor, CC
      chemokine receptor 4 (CCR4), have been proven to be involved in a number of
      allergic diseases, especially atopic dermatitis (AD). The purpose of this study
      was to examine the expression and distribution of TARC and CCR4 mRNAs in samples
      of AD (n=15, acute lesions 8, chronic lesions 7) and normal skin (n=6). The
      expression and distribution of TARC and CCR4 mRNAs were detected with the in situ
      reverse transcription (RT) -polymerase chain reaction (PCR) technique. TARC mRNA
      was expressed in epidermal keratinocytes, dermal endothelial cells and
      infiltrating cells. CCR4 mRNA was expressed in dermal endothelial cells and
      infiltrating cells. In acute AD lesional skin, there were more positive cells,
      and the staining intensity was stronger than in chronic lesions (p<0.05). The
      distribution of positive cells was as follows: In the epidermis, keratinocytes in
      the basal layer showed the strongest staining, and keratinocytes in the spinous
      layer showed moderate staining; the superficial area showed faint staining. In
      the dermis, infiltrating cells located in the superficial area of the dermis
      showed the strongest staining, positive staining intensity became weaker and the
      percentage of positive cells became less as the location became deeper. There
      were no positive cells in normal skin. These data further substantiate the role
      of TARC/CCR4 in the pathogenesis of AD.

PMID- 12598707
TI  - Prognostic value of Ki-67, CD31 and epidermal growth factor receptor expression
      in basal cell carcinoma.
AB  - Recurrence of basal cell carcinoma following treatment is common, and the
      majority of recurrences appear in the first 3 years. We examined the original
      tumors of 26 basal cell carcinoma cases, 14 of whom had a recurrence after an
      average of 3.7 years, and 12 of whom had no recurrence during an average of 4.4
      years follow-up. Using immunohistochemistry, we tested for Ki-67, CD31 and
      epidermal growth factor receptor expressions in the tumor tissue. The percentages
      of expression for Ki-67, CD31 and epidermal growth factor receptor were
      significantly higher in the recurrent tumors than in the non-recurrent ones.
      Expression of Ki-67 and CD31 was 271.57 +/- 17.91 and 58.1 +/- 9.37 for the
      recurrent group and 187.08 +/- 21.48 and 23.9 +/- 5.45 for non-recurrent group
      respectively (p<0.0001; p<0.0001). Expression of epidermal growth factor receptor
      was positive in all basal cell carcinoma cells. The staining intensity was strong
      in 57% of recurrent and 8.3% of non-recurrent tumors (p=0.014). These results
      show that Ki-67, CD31 and epidermal growth factor receptor expression differ
      between basal cell carcinomas which later recur and those that do not recur.

PMID- 12598708
TI  - Relative frequency of the different types of cutaneous T cell and natural killer
      cell lymphomas in Korea based on the proposed WHO classification and the EORTC
      classification.
AB  - The R.E.A.L. classification was largely adopted recently by the proposed WHO
      classification. The usefulness of this classification in cutaneous T cell and
      natural killer (NK) cell lymphomas in Korea was evaluated compared to that of the
      European Organization for Research and Treatment of Cancer (EORTC)
      classification. Overall, 78 patients with cutaneous T cell and NK cell lymphomas
      were diagnosed in Asan Medical Center in the 1990's. The clinical records, slides
      of H&E and immunohistochemical stainings were reviewed. By the proposed WHO
      classification, mycosis fungoides (20 cases), lymphomatoid papulosis (13 cases),
      nasal type NK/T-cell lymphoma (10 cases), CD30+ anaplastic large cell lymphoma (8
      cases), subcutaneous panniculitis-like T-cell lymphoma (6 cases), peripheral T
      cell lymphoma, unspecified (3 cases), Sezary syndrome (1 case) and blastic NK
      cell lymphoma (1 case) comprised the primary cases. Secondary or undetermined
      cases included peripheral T-cell lymphoma, unspecified (10 cases), nasal type
      NK/T-cell lymphoma (5 cases), and angioimmunoblastic T-cell lymphoma (1 case).
      EORTC classification for cutaneous T cell and NK cell lymphomas did not include
      nasal and nasal type NK/T-cell lymphomas, unspecified non-pleomorphic T-cell
      lymphoma, undetermined cases among primary or secondary ones and some rare types
      of skin lymphomas which can be classified by WHO. The WHO classification is more
      useful for skin lymphomas in Korea since it encompassed all the various types of
      skin T cell and NK cell lymphomas in Korea.

PMID- 12598709
TI  - Seborrheic Keratosis-like lesions in patients with epidermodysplasia
      verruciformis.
AB  - Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by
      disseminated infection by human papillomavirus (HPV) and malignant transformation
      of the lesions in about half of the patients. Two phenotypes of EV have been
      described according to their propensity to develop malignant tumors. The benign
      form of EV presents a singular type of lesions comprised of flat warts widely
      disseminated. The malignant form of EV is highly polymorphic and presents as
      malignant skin tumors, predominantly basal and squamous cell carcinomas, on sun
      exposed sites. The seborrheic keratosis-like (SK) lesions in patients of EV have
      been reported to be associated with the malignant phenotype. In this work, we
      documented the behavior of SK-like lesions in nine patients with EV, through
      clinical observations as well as histological and immunohistochemical findings.
      We suggest that the HPV infection may promote the occurrence of SK-like lesions
      in EV patients. Despite the fact that we did not observe any malignant
      transformation of these lesions in our series of patients, this possibility was
      not completely excluded.

PMID- 12598710
TI  - Stevens-Johnson syndrome with idiopathic thrombocytopenic purpura treated with
      dexamethasone pulse therapy.
AB  - Stevens-Johnson syndrome (SJS) is a severe, episodic, acute, mucocutaneous
      hypersensitivity reaction often caused by drugs. We herewith report a case of SJS
      with idiopathic thrombocytopenic purpura (ITP) that did not respond to daily oral
      prednisolone therapy. When treated with dexamethasone pulse therapy, the response
      was found to be very good. Therefore, we concluded that dexamethasone pulse
      therapy can be a good and an effective alternative therapy for treatment of such
      patients. However, to establish its role, further trials in more patients are
      needed.

PMID- 12598711
TI  - Bullous pyoderma gangrenosum complicated by disseminated intravascular
      coagulation with subsequent myelodysplastic syndrome (chronic myelomonocytic
      leukemia).
AB  - A 33-year-old woman developed a bullous PG precursing a chronic myelomonocytic
      leukemia (CMML) complicated by life-threatening, disseminated, intravascular
      coagulation after administration of systemic corticosteroids in combination with
      immunosuppressant and antibiotic agents. Although the association between PG and
      leukemia, as well as the coincidence of disseminated intravascular coagulation
      (DIC) and leukemia, is well known, a premonitoring effect of PG in combination
      with DIC preceding the diagnosis of chronic myelomonocytic leukemia in the same
      patient has not been reported recently.

PMID- 12598712
TI  - Pentoxifylline in the treatment of erythema nodosum leprosum.
AB  - Erythema nodosum leprosum (ENL) is a well-known serious complication affecting
      10% of lepromatous multibacillary leprosy patients. In the chronic form, its
      morbidity may be considerable. Thalidomide and systemic steroids are the two
      current effective drugs for the management of ENL. However, their use in endemic
      countries is often difficult and hazardous, and a search for new therapies is
      needed. We report our experience on the effects of pentoxifylline, a
      methylxanthine derivative, which has recently been suggested as a possible
      effective treatment for ENL attacks.

PMID- 12598714
TI  - A case of ductal apocrine carcinoma in the left axilla with tubular apocrine
      adenoma in the right axilla.

PMID- 12598713
TI  - A case of baboon syndrome associated with group a streptococcal infection.
AB  - We described a 21-year-old Japanese patient with sore throat, fever, and diffuse
      erythema on the neck, trunk, and limbs. Erythema markedly appeared on the neck,
      axillary, antecubital, and popliteal fossae. However, other skin signs of scarlet
      fever such as red strawberry tongue and linear petechial eruption did not appear.
      Before his visit to our clinic, he had been diagnosed as pharyngitis and treated
      with cefaclor 750 mg daily for six days. However, the symptoms did not improve.
      Oral prednisolone of 20 mg daily rapidly improved all the symptoms. Pharyngeal
      culture grew Streptococcus pyogenes that was sensitive to cefaclor. Laboratory
      findings showed elevated serum levels of antibody against streptolysin O.
      Together with the distribution of erythema, culture of Streptococcal pyogenes,
      and elevated anti-streptolysin O titer, the diagnosis of baboon syndrome
      associated with streptococcal infection was made. This seems to be the first
      report of baboon syndrome due to streptococcal infection.

PMID- 12598715
TI  - Plasma IL-13 levels in patients with atopic dermatitis.

PMID- 12598716
TI  - [Molecular mechanisms of allergic airway inflammation in asthma].

PMID- 12598717
TI  - [Willingness to pay and quality of life in patients with Japanese-cedar
      pollinosis].
AB  - Seasonal allergic rhinitis (SAR) is one of the world's most common health
      problems because it's a high-cost, high-prevalence disease. In this study, we
      investigated patients' willingness to pay (WTP) for prevention and cure from most
      common SAR, Japanese-cedar pollinosis. Two hundred and forty patients with
      Japanese-cedar pollinosis, who visited 4 clinics in Osaka and were measured QOL
      by the SF-36 Questionnaire (Japanese version) during pollen season, were mailed
      WTP questionnaire in off-season in 1998. Completed questionnaires were sent back
      by 175 patients. Most patients (83.5%) were willing to pay less than 10,000 yen.
      Patients with longer duration of disease or severer nasal symptom tended to be
      more willing to pay. In contrast, no association was found between WTP and sex,
      age, occupation and comorbid condition. There were significant impairments in
      five of eight QOL dimensions in patients of Much-WTP in comparison with Less-WTP.
      Patients with mild symptom had significant higher medication cost than those with
      less mild symptom. We conclude that effective treatment, even if it costs much,
      can satisfy patients and may help to reduce indirect costs as well as to lessen
      the impact of Japanese-cedar pollinosis on QOL for both patient and society.

PMID- 12598718
TI  - [Pollen dispersion of Japanese cedar and Japanese cypress in Kagawa Medical
      University of Kagawa Prefecture].
AB  - We installed the Durham sampler on the roof (27.4 m on the ground) of Kagawa
      Medical University in 1989 to survey pollen dispersion in Kagawa prefecture and
      have investigated the pollen survey from 1989 to 2001. We examined the
      correlation between the annual variations in the pollen counts of Japanese cedar
      (Cryptomeria japonica) and Cupressaceae, mainly Japanese cypress (Chamaecyparis
      obtusa) and annual changes in meteorological conditions. The sum of these pollen
      counts correlated with the highest temperature from 11 July to 10 August in
      Kagawa prefecture. However, it is difficult to determine the pollen dispersion
      only based on meteorological factors. Other factors giving influences on the
      pollen dispersion need to be further analyzed in the future.

PMID- 12598719
TI  - [Effects of administration of bifidobacteria on fecal microflora and clinical
      symptoms in infants with atopic dermatitis].
AB  - Fifteen children with atopic dermatitis who had Bifidobacterium-deficient
      microflora were selected for this study. Eight subjects in the bifidobacteria
      administered group were given oral administration of lyophilized bifidobacteria
      (Bifidobacterium breve M-16V strain). The changes in fecal microflora and
      clinical symptoms were compared with the control group. In the bifidobacteria
      administered group, the proportion of Bifidobacterium in the fecal microflora was
      increased (P=0.0173) and the proportion of aerobic bacteria was decreased
      (P=0.0499) after 1 month of administration. Furthermore, significant improvement
      of allergic symptoms (P=0.0176 in cutaneous symptom score, P=0.0117 in total
      allergic score) was also observed in the bifidobacteria-administered group. The
      tendency of allergic symptom improvement in the bifidobacteria-administered group
      was remarkable compared with the control group; however there was no correlation
      between changes in fecal microflora and allergic symptoms.

PMID- 12598721
TI  - [A case of near-fatal asthma caused by defecation].

PMID- 12598720
TI  - [An evaluation of the acceptance of budesonide turbuhaler by older Japanese
      patients with bronchial asthma when changed from fluticasone propionate (FP) or
      beclomethasone dipropionate (BDP)].
AB  - Although the clinical reputation of the inhaled steroid budesonide(R) (BUD) has
      become well established in Europe and the USA, we found that in clinical practice
      many older Japanese patients were resistant to changing to this form of inhaled
      steroid from fluticasone propionate (FP) or beclomethasone dipropionate (BDP).
      This study was accordingly designed to evaluate the acceptability and clinical
      efficacy of budesonide in older Japanese patients with bronchial asthma. METHODS:
      Forty-five Japanese asthma patients aged over 65 (22 using FP and 23 using BDP)
      were changed to BUD inhalation from their existing inhaled steroid. After two
      weeks, patients were questioned as to their acceptance of BUD, their inhalation
      technique was checked, and the duration of inhalation required to dispense the
      drug and peak expiratory flow (PEF) was measured. The rate of pharyngeal
      candidiasis was also assessed, both before and after changing to BUD. RESULTS:
      Most of the patients in both groups considered BUD inhalation to be easy and
      could quickly learn to use the Turbuhaler. However, as no sensation of drug
      inhalation was generally experienced, over 70% of patients felt anxious about
      whether they had successfully inhaled the medication. Furthermore, there were
      various misunderstandings in correct inhaler technique. Although there were no
      significant differences in PEF or in the rate of pharyngeal candidiasis before
      and after changing to BUD administration, side effects occurred in about 40% of
      both groups. In patients aged 65-74, 50.0% of patients who had previously been
      taking FP and 38.9% of those who had previously been taking BDP intended to
      continue BUD inhalation, while in patients over 75, only 8.3% of former users of
      FP and 20.0% of former users of BDP intended to continue using BUD. CONCLUSION:
      In older patients, factors influencing satisfaction with inhaled medication
      include not only ease of use and time needed to become accustomed to a new
      delivery method, but also the important issue of satisfaction with the sensation
      of drug inhalation.

PMID- 12598722
TI  - K+ channel activation and low-threshold Ca2+ spike of rat cerebellar Purkinje
      cells in vitro.
AB  - Using the whole-cell configuration of the patch-clamp recording method, we
      analyzed the role of K+ conductances in determining the characteristics of the
      dendritically-initiated low-threshold Ca+ spike (LTS) recorded at the somatic
      level of rat cerebellar Purkinje cells (PCs) in slice cultures. Blockade of tetra
      ethyl-ammonium-(TEA)- and 4-aminopyridine-(4-AP)-sensitive K+ channels increased
      the amplitude of the LTS. This effect was prominent with 4-AP, which promotes the
      fast-decaying component of the LTS. Surprisingly, a shortening of the LTS was
      induced by the blockade of K+ channel activity instead of a broadening of spikes
      as generally observed. We propose that, when propagating to the soma, TEA- and 4
      AP-sensitive K+ channel activity affects the electrical properties of dendrites
      such that the LTS is attenuated and slowed down.

PMID- 12598723
TI  - Unaltered expression of Bcl-2 and TAG-1/axonin-1 precedes sensory apoptosis in
      Brn3a knockout mice.
AB  - Mice lacking the POU-domain transcription factor Brn3a exhibit growth defects in
      trigeminal axons, undergo extensive sensory cell death in late gestation, and die
      at birth. Based on tissue culture studies, the mediator of apoptosis Bcl-2 has
      been suggested as a target of Brn3a regulation which could affect sensory
      viability in these mice. In addition, Bcl-2 and the neural cell adhesion molecule
      TAG-1/axonin-1 have both been implicated in sensory axon guidance. In this study
      we examined wild-type and Brn3a knockout embryos for alterations in the
      expression of these genes. Trigeminal ganglia were harvested from embryonic day
      13.5 mouse embryos, and Bcl-2 and TAG-1 expression were measured by RT-PCR. TAG-1
      expression was also examined in the embryonic trigeminal and dorsal root ganglia
      by immunohistochemistry. The developing trigeminal ganglia of Brn3a knockout mice
      exhibit similar levels of Bcl-2 and TAG-1 mRNA expression. Immunohistochemical
      staining of TAG-1 also appeared to be quantitatively similar in the sensory axons
      of wild-type and knockout embryos. It is unlikely that Bcl-2 is a regulatory
      target of Brn3a, or that either of these factors mediates the defects in axon
      guidance and neuronal survival observed in the sensory ganglia of Brn3a knockout
      mice.

PMID- 12598724
TI  - Neural response to pleasant stimuli in anhedonia: an fMRI study.
AB  - The aim of this study was to investigate the neural correlates of affect
      processing in depressed anhedonic patients and healthy controls. Whole brain
      functional magnetic resonance imaging scans were obtained from seven females with
      a diagnosis of chronic unipolar major depression and high levels of anhedonia,
      and seven healthy females, while they were presented with positive valence and
      neutral images. Patients, compared to controls, showed decreased activation in
      medial frontal cortex, and increased activation in inferior frontal cortex,
      anterior cingulate, thalamus, putamen and insula. Reduced activation in medial
      frontal cortex may underlie abnormal positive affect processing in patients.
      Increases in neural activation in putamen and thalamus, previously found in
      transient sadness, and anterior cingulate could point to an involvement of these
      structures in anhedonia.

PMID- 12598725
TI  - Activation of caspase-12, an endoplasmic reticulum resident caspase, after
      permanent focal ischemia in rat.
AB  - The endoplasmic reticulum (ER) is emerging as a contributory component of cell
      death after ischemia. Since caspase-12 has been localized to the ER and is a
      novel signal for apoptosis, we examined the message levels and protein expression
      of caspase-12 after cerebral ischemia in vivo. Animals underwent permanent middle
      cerebral artery occlusion (MCAO) and were sacrificed 24 h after ischemia. Protein
      analysis revealed a significant increase in caspase-12 and a corresponding up
      regulation of caspase-12 mRNA in the ischemia group compared with that in the
      sham group. Immunohistochemical analysis revealed diffuse positive immunostaining
      of caspase-12 throughout the striatum and cerebral cortex in animals that
      underwent ischemia, with more intense caspase-12 immunostaining in the striatum
      than in the cortex after ischemia. These results demonstrate that cerebral
      ischemia initiates an ER-based stress response that results in the
      transcriptional up-regulation and corresponding increased expression of caspase
      12 protein, and may provide a new area for therapeutic intervention to ameliorate
      outcomes following stroke.

PMID- 12598726
TI  - Extracellular and intracellular glutathione protects astrocytes from Zn2+-induced
      cell death.
AB  - Free Zn(2+) is released in excess at excitatory synapses in pathological
      conditions including transient global and focal cerebral ischemia, which causes
      neuronal and glial cell death. In the current study, we explored the mechanism
      underlying Zn(2+)-induced cell death in primary cortical astroglial cultures.
      Chronic treatment with 30-35 microM Zn(2+) led to the death of 70-95% of
      astrocytes within 18 h, preceded by Zn(2+) influx. Extracellular glutathione
      (GSH; 100 microM) completely blocked the Zn(2+) influx and Zn(2+) toxicity. The
      Zn(2+) toxicity was also inhibited when intracellular GSH was increased.
      Conversely, it was aggravated when intracellular GSH was depleted by buthionine
      sulfoximine (BSO). Consistently, the level of cellular GSH was notably decreased
      with a concurrent increase in oxidized GSH in Zn(2+)-treated astrocytes. These
      results suggest that the disruption of proper maintenance of thiol homeostasis is
      a mechanism underlying Zn(2+) toxicity in primary cortical astrocytes.

PMID- 12598727
TI  - Decreased potassium channel IK1 and its regulator neurotrophin-3 (NT-3) in
      inflamed human bowel.
AB  - Calcium-activated potassium currents of intermediate conductance (IK1) have been
      described in the rodent enteric nervous system, where they may regulate
      afterhyperpolarisation of intrinsic primary afferent neurons. Using specific
      antibodies for immuno-cytochemistry, we now report IK1-like immunoreactivity for
      the first time in enteric neurons of human colon, and a significant decrease of
      IK1-positive cells in myenteric plexus in inflamed colon from patients with
      Crohn's disease and ulcerative colitis (p = 0.031). Neurotrophin-3 (NT-3), which
      regulates IK1 expression, was also observed in fewer neurons of the myenteric
      ganglia in Crohn's bowel (p = 0.048), and in inflamed colonic extracts by Western
      blotting (p = 0.004); the numbers of neurons expressing the NT-3 high affinity
      receptor trk C were unchanged. Our findings may explain the diarrhoea and colicky
      abdominal pain produced by inflammatory bowel disease, and by IK1-blocking
      pyridine drugs prescribed for neuromuscular disorders.

PMID- 12598728
TI  - Short-term depression at primary afferent synapses in rat substantia gelatinosa
      region.
AB  - Short-term synaptic depression is a widespread and predominant mechanism
      underlying the process of neural information. To study the short-term depression
      at primary afferent synapses between Adelta fibers and substantia gelatinosa (SG)
      neurons in the spinal cord, transverse spinal cord slices with dorsal root
      attached were made from young rats. With whole-cell voltage-clamp method, Adelta
      fiber elicited excitatory post-synaptic currents (EPSCs) were recorded from SG
      neurons visualized by infrared microscope. Using the normalized peak amplitudes
      of EPSCs, the existence of short-term depression was examined at all six stimulus
      frequencies ranging from 0.5 to 20 Hz. Both paired-pulse and steady-state
      depressions became greater with the increasing stimulus frequency. External
      calcium concentration could significantly affect the degrees of paired-pulse and
      steady-state depressions, with paired-pulse depression more affected. Application
      of NMDA receptor antagonist had no significant effect on this depression. These
      results indicated that short-term synaptic depression exists at primary afferent
      neurotransmission in spinal cord and results from the presynaptic reduction in
      the number of quanta of transmitter released by impulses.

PMID- 12598729
TI  - Newborn pig nociceptin/orphanin FQ activates protein tyrosine kinase and mitogen
      activated protein kinase to impair NMDA cerebrovasodilation after ischemia.
AB  - This study characterized the contributions of protein tyrosine kinase and mitogen
      activated protein kinase in nociceptin/orphanin FQ induced impairment of NMDA
      dilation after cerebral hypoxia/ischemia in anesthetized newborn pigs equipped
      with a closed cranial window. Topical nociceptin/orphanin FQ, in a concentration
      observed after hypoxia/ischemia, impaired NMDA pial artery vasodilation. Co
      administration either of the protein tyrosine kinase inhibitor genistein or the
      mitogen activated protein kinase inhibitor U0126 with nociceptin/orphanin FQ
      partially prevented the inhibition of NMDA dilation compared to that observed in
      their absence. After exposure to hypoxia/ischemia, pial artery dilation in
      response to NMDA was reversed to vasoconstriction but pretreatment with either
      genistein or U0126 partially protected such impairment. These data show that
      protein tyrosine kinase and mitogen activated protein kinase activation
      contribute to nociceptin/orphanin FQ induced impairment of NMDA dilation. These
      data suggest that protein tyrosine and mitogen activated protein kinase are
      involved in the mechanism by which nociceptin/orphanin FQ impairs NMDA dilation
      following hypoxia/ischemia.

PMID- 12598730
TI  - Corpus callosum: musician and gender effects.
AB  - Previously we found that musicians have significantly larger anterior corpus
      callosum (CC). In the current study, we intended to replicate and extend our
      previous results using a new and larger sample of gender-matched subjects (56
      right-handed professional musicians and 56 age- and handedness-matched controls).
      We found a significant gender x musicianship interaction for anterior and
      posterior CC size; male musicians had a larger anterior CC than non-musicians,
      while females did not show a significant effect of musicianship. The lack of a
      significant effect in females may be due to a tendency for a more symmetric brain
      organization and a disproportionately high representation of absolute pitch (AP)
      musicians among females. Although a direct causal effect between musicianship and
      alterations in the midsagittal CC size cannot be established, it is likely that
      the early commencement and continuous practice of bimanual motor training serves
      as an external trigger that can influence midsagittal CC size through changes in
      the actual callosal fiber composition and in the degree of myelinization, which
      will have implications for interhemispheric connectivity.

PMID- 12598731
TI  - Kindling suppresses primed-burst-induced long-term potentiation in hippocampal
      CA1.
AB  - In a previous study, we showed that partial hippocampal kindling in rats, a model
      of temporal lobe epilepsy, reduced the efficacy of presynaptic GABA(B) receptors
      in the CA1 area of hippocampal slices. In this study, we show that long-term
      potentiation (LTP) induced by theta-frequency primed bursts was suppressed in
      kindled as compared to control rats, but not in the presence of the GABA(B)
      receptor antagonists CGP35348 or CGP55845A. This is original evidence that LTP is
      suppressed by pathophysiological downregulation of GABA(B) autoreceptors. Control
      of postsynaptic inhibition by presynaptic GABA(B) receptors may provide a
      compensatory mechanism for controlling paroxysmal activity, with a side effect of
      blocking synaptic plasticity.

PMID- 12598732
TI  - Reduced NMDA-induced apoptosis in neurons lacking ataxia telangiectasia mutated
      protein.
AB  - Apoptosis is an important route to neuronal death in experimental models of
      stroke, the leading neurological cause of death and disability. Here we explore a
      role for ataxia telangiectasia mutated protein (ATM), an activator of p53, in a
      primary cortical culture model of stroke. NMDA-induced apoptosis was reduced in
      cultures derived from mice with targeted deletions in the ATM gene. In addition,
      NMDA-induced caspase-3 activity was abolished in cultures lacking two functioning
      copies of the ATM gene. These data provide evidence to suggest that, in primary
      cortical culture, NMDA-induced apoptosis is partially mediated through ATM. They
      provide further evidence to support the hypothesis that DNA damage is one route
      to apoptosis following neuronal injury.

PMID- 12598733
TI  - Altered short-term hippocampal synaptic plasticity in mutant alpha-synuclein
      transgenic mice.
AB  - Hippocampal synaptic plasticity was studied in transgenic mice over-expressing
      human alpha-synuclein containing the A30P Parkinson's disease mutation. Medial
      perforant path-dentate granule cell synapses showed enhanced paired-pulse
      depression (PPD) for short interpulse intervals (< 200 ms), without differences
      in basal transmission. Extracellular calcium reduction failed to rescue the
      enhanced PPD. Paired-pulse facilitation in the CA1 region was normal in slices
      from transgenic mice, but enhanced synaptic depression was revealed upon
      repetitive stimulation of the Schaffer collaterals. Long-term potentiation in the
      CA1 field was not impaired in slices from transgenic mice. These results suggest
      that mutant alpha-synuclein accumulation impairs short-term changes in synaptic
      strength when neurotransmitter availability is limited due to enhanced release
      probability or repetitive synaptic activity.

PMID- 12598734
TI  - Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue
      syndrome.
AB  - Fatigue is a common symptom of neurological diseases that affect basal ganglia
      function. We used proton magnetic resonance spectroscopy ((1)H MRS) to study the
      metabolic functions of the basal ganglia in chronic fatigue syndrome (CFS) to
      test the hypothesis that fatigue in CFS may have a neurogenic component. (1)H MRS
      of left basal ganglia was carried out in eight non-psychiatric patients with CFS
      and their results were compared to age- and sex-matched healthy asymptomatic
      healthy controls. A highly significant increase in the spectra from choline
      containing compounds was seen in the CFS patient group (p < 0.001). In the
      absence of regional structural or inflammatory pathology, increased choline
      resonance in CFS may be an indicator of higher cell membrane turnover due to
      gliosis or altered intramembrane signalling.

PMID- 12598735
TI  - Nitric oxide synthase inhibition lowers activity of neurons with meningeal input
      in the rat spinal trigeminal nucleus.
AB  - Nitric oxide is thought to control transmitter release and neuronal activity in
      the spinal dorsal horn and the spinal trigeminal nucleus, where nociceptive
      information from extra- and intracranial tissues is processed. Extracellular
      impulse activity was recorded from neurons in the rat spinal trigeminal nucleus
      with afferent input from the cranial dura mater. In contrast to the inactive
      isomer D-NAME, infusion of the nitric oxide synthase inhibitor L-NAME (20 mg/kg)
      significantly reduced neuronal activity and increased systemic blood pressure. It
      is concluded that nitric oxide production contributes to the ongoing activity of
      sensitized neurons in the spinal trigeminal nucleus. The results suggest that
      nitric oxide may be involved in the generation and maintenance of primary
      headaches such as migraine.

PMID- 12598736
TI  - Altered rapid eye movement sleep timing in serotonin transporter knockout mice.
AB  - The monoamine neurotransmitter serotonin has long been implicated in development
      and maintenance of sleep patterns, yet the role of the serotonin transporter
      (SERT) in these processes has not been evaluated in detail. We report that
      genetically engineered SERT knockout mice exhibit more REM sleep (REMS) than wild
      type littermates (11 vs 7% of recording time under baseline conditions) and
      display more frequent REMS bouts that last longer. This phenotype resembles the
      previously reported long-term effect of repeated treatment with SERT inhibitor
      compounds rather than the acute REMS suppressing effect of treatment with such
      compounds, and is thus likely to reflect neuroadaptations to the absence of SERT,
      rather than an acute effect of its absence in the adult. While
      electroencephalographic (EEG) spectra did not differ between SERT knockout and
      wild type mice during non-REM sleep (NREMS) or REMS, the dynamics of the EEG
      during the transition from NREMS to REMS differed between the genotypes. The
      surge in EEG power in both the 6-9 Hz and 10-16 Hz ranges that occurs just prior
      to the onset of REMS (pre-REMS power surge) is of greater magnitude in SERT
      knockout mice than in wild type littermate controls. This observation contrasts
      with the reduced magnitude pre-REMS power surge observed in rats subjected to
      REMS deprivation relative to yoked controls. These results indicate that the pre
      REMS power surge is influenced by REMS history and by monoaminergic transmission.
      Genetic differences in serotonin systems and developmental exposure to SERT
      blockers are likely to exert effects on REMS.

PMID- 12598737
TI  - Prenatal morphine exposure decreases analgesia but not K+ channel activation.
AB  - The present study has investigated the possible supraspinal adaptive changes
      induced by prenatal administration of morphine, including morphine-induced
      supraspinal antinociception in vivo, the density and binding affinity of mu
      opioid receptors in the brain and the cellular action of morphine in brain slices
      in vitro. The cellular action of morphine was assessed by its activation of K+
      channels in the ventrolateral periaqueductal gray (PAG), a crucial area for the
      supraspinal analgesic effect of morphine. Female rats were treated with morphine
      7 days before mating at 2 mg/kg. The treatment was continued during pregnancy and
      after delivery at doses which increased by 1 mg/kg every 2 weeks. Experiments
      were conducted in the offspring at p14 days. Prenatal morphine exposure induced
      tolerance to supraspinal morphine-induced tail-flick response. The binding
      affinity and maximal binding of [(3)H]DAMGO in whole brain were not significant
      different between the morphine- or saline-treated dams. Autoradiographic analysis
      shows that the mu-opioid receptor density was decreased in the striatum, thalamus
      and amygdala but not in the midbrain, nucleus accumbens, hippocampus or cortex in
      morphine offspring. In ventrolateral PAG neurons, morphine activated inwardly
      rectifying K+ channels in 59% of recorded neurons of morphine offspring. Neither
      the magnitude of K channel activation nor the percentage of sensitive neurons was
      different between the saline- and morphine-treated offspring. It is concluded
      that prenatal morphine exposure induces tolerance to supraspinal analgesia and
      this tolerance is not attributed to a change in the mu-opioid receptor density or
      the receptor-function coupling efficiency in the midbrain periaqueductal gray.

PMID- 12598738
TI  - Mobile phone use facilitates memory in male, but not female, subjects.
AB  - In the present study we report on the effects of mobile phone exposure on short-
      and long-term memory in male and female subjects. Subjects were university
      undergraduate students, and consisted of right-handed, males (n = 33) and females
      (n = 29). Individuals were randomly assigned to one of three experimental
      conditions: no phone exposure; inactive phone exposure; and active phone
      exposure. They were provided with a series of words to learn, structured in a two
      dimensional shape, and given 3 min to memorise the words. After a 12 min
      distraction task, they were then asked to draw the shape (spatial) and place the
      correct words (semantic) into the appropriate boxes. One week later the same
      subjects were brought back to again redraw the shape and words. Error scores were
      determined and analysed by non-parametric techniques. The results show that males
      exposed to an active phone made fewer spatial errors than those exposed to an
      active phone condition, while females were largely unaffected. These results
      further indicate that mobile phone exposure has functional consequences for human
      subjects, and these effects appear to be sex-dependent.

PMID- 12598739
TI  - Cortical activations associated with auditorily paced finger tapping.
AB  - We investigated neuromagnetic responses during an auditorily paced
      synchronization task using a 122-channel whole-head neuromagnetometer. Eight
      healthy right handed subjects were asked to synchronize left and right unilateral
      finger taps to a regular binaural pacing signal. Synchronization of the right
      hand with an auditory pacing signal is known to be associated with three tap
      related neuromagnetic sources localized in the contralateral primary sensorimotor
      cortex. While the first source represents the neuromagnetic correlate of the
      motor command the second one reflects somatosensory feedback due to the finger
      movement. The functional meaning of the third source, which is also localized in
      the primary somatosensory cortex is still unclear. On the one hand this source
      represents a neuromagnetic correlate of somatosensory feedback due to the finger
      tap. On the other hand it has been suggested that the function of this source
      could additionally represent a cognitive process, which enables the subject to
      monitor the time distance between taps and clicks. The aim of the present study
      was to elucidate the function of this source, which would fundamentally reform
      the meaning of the primary somatosensory cortex in the timing of movements with
      respect to external events. The data of the present study demonstrate that the
      three sources in the contralateral sensorimotor cortex are stronger related to
      the tap than to the click. This result contradicts the assumption of a cognitive
      process localized in the primary somatosensory cortex. Thus, activation in the
      primary somatosensory cortex most likely represents exclusively somatosensory
      feedback and no further cognitive processes.

PMID- 12598740
TI  - Naloxone depresses cocaine self-administration and delays its initiation on the
      following day.
AB  - While dopamine mechanisms play a crucial role in cocaine-taking behavior, the
      contribution of endogenous opioid systems is less clear. We assessed the effects
      of opioid receptor blockade by naloxone (1 mg/kg, s.c.) on the daily performance
      and subsequent initiation of cocaine self-administration in trained rats.
      Naloxone decreased self-administration rate by approximately half, with the
      effect varying from complete blockade to no change. On the day following naloxone
      treatment, the latencies from the drug availability cue to the first self
      administration were consistently longer than before naloxone treatment.
      Measurement of brain temperature and behavioral observations suggested a lower
      than normal level of motivational arousal as a factor for slow initiation of
      cocaine-taking behavior. After the first drug infusion, however, performance was
      uniformly normal. These data suggest endogenous opioid systems play a role in
      cocaine-taking behavior and indicate a residual inhibitory consequence of
      naloxone treatment on the initiation of this behavior.

PMID- 12598741
TI  - Glycogen synthase kinase-3 beta-mediated tau phosphorylation in cultured cell
      lines.
AB  - To study further the role of glycogen synthase kinase-3beta on tau
      phosphorylation, glycogen synthase kinase-3beta and tau expression vectors were
      co-transfected into CHO-K1, COS-7 and SH-SY5Y cell. Tau phosphorylation was
      assessed by phosphorylation-dependent antibodies AT-8, AT-180, AT-270 and PHF-1.
      The AT-270 and AT-8 epitopes were consistently phosphorylated by glycogen
      synthase kinase-3beta in the three cell lines. Phosphorylation on AT-180 epitope
      was significant in CHO-K1 and SH-SY5Y cells while PHF-1 epitope was hyper
      phosphorylated only in SH-SY5Y cells. We also found that lithium induces
      phosphorylation of the serine 9 residue of glycogen synthase kinase-3beta
      together with inhibition of tau phosphorylation on PHF-1 epitope in all the three
      cell lines. This suggests a novel mechanism whereby lithium-mediated inhibition
      of GSK-3beta activity influences tau phosphorylation.

PMID- 12598742
TI  - The role of spectral change detectors in temporal order judgment of tones.
AB  - Human listeners can judge the temporal order of acoustic events quite accurately
      in certain conditions. We hypothesized that this accuracy is realized by coding
      temporal order as a single neural code of spectral change in the auditory system.
      To test this hypothesis, we examined whether adaptation to linear frequency
      glides affects subsequent temporal order judgment of brief tones. We found that
      the point of subjective simultaneity between two tones shifted depending on the
      direction of spectral change of the adaptor, as predicted by the hypothesis. The
      amount of aftereffect was significantly reduced when adaptor and test tones were
      presented in different frequency regions or to different ears, suggesting that
      the relevant neural units exist predominantly in a frequency-selective monaural
      pathway.

PMID- 12598743
TI  - Screening and characterization of human single-chain Fv antibody against beta
      amyloid peptide 40.
AB  - Expression of single-chain variable fragment antibody on the surface of
      filamentous bacteriophage is widely used to make antibodies with pre-defined
      specificities. Using direct selection on solid phase-bound amyloid-beta 40
      peptide, which is a main pathogenic feature of Alzheimer's disease, we obtained
      single-chain Fv antibody with specific binding activity. The binding epitope of
      the antibody is located between amino acids 1 and 16 of the peptide antigen. DNA
      sequencing showed that the gene coding for the single chain Fv antibody consists
      of 768 bp, and the complementarity-determining regions were deduced.

PMID- 12598744
TI  - Effect of AD-5423 on animal models of schizophrenia: phencyclidine-induced
      behavioral changes in mice.
AB  - The antipsychotic efficacy of AD-5423, which has the properties of both a
      serotonin 5-HT(2) and a dopamine D(2) receptor antagonist, was evaluated using
      animal models of schizophrenia. Sensitization to phencyclidine (PCP)-induced
      hyperlocomotion is considered a model of the positive symptoms of schizophrenia,
      and was significantly antagonized by AD-5423 and haloperidol. The PCP-induced
      enhancement of immobility induced by the forced swimming test, a model of the
      negative symptoms of schizophrenia, was attenuated by AD-5423 but not by
      haloperidol. Since this attenuated effect of AD-5423 was antagonized by DOI, a
      serotonin 5-HT(2) receptor agonist, it is postulated to be mediated by serotonin
      5-HT(2) receptors. These findings suggest that AD-5423 would be clinically
      effective against both the positive and negative symptoms of schizophrenia.

PMID- 12598745
TI  - Neuromagnetic gamma-band activity in the primary and secondary somatosensory
      areas.
AB  - To evaluate the gamma-band activity related to somatosensory processing, we
      recorded neuromagnetic signals from seven healthy subjects. The source power
      changes evoked by electrical stimulation of the median nerve were estimated with
      synthetic aperture magnetometry (SAM). Source power in the low gamma band (40 Hz)
      decreased in the contralateral primary somatosensory cortex (SI) for a few
      hundred milliseconds (i.e. middle and long latency) and then increased inversely.
      Source power in the high gamma band (70-90 Hz) increased simultaneously both in
      the contralateral SI and contra/ipsilateral secondary somatosensory cortex (SII)
      in 80-180 ms. These results suggest that low and high gamma oscillations work
      under independent mechanisms during somatosensory processing. In particular, high
      gamma oscillations may play an essential role in making a functional connection
      between SI and SII.

PMID- 12598746
TI  - Axotomy induces cytochrome c release in retinal ganglion cells.
AB  - Activation of caspase-3 and -9 has been implicated in the death of axotomized
      retinal ganglion cells (RGCs). The upstream pathways involved in the activation
      of these caspases, however, remain unknown. The aim of the current study is to
      examine the role of cytochrome c release in axotomized RGC death using immuno
      histochemistry. We found that while only a low level of cytochrome c
      immunoreactivity was evident in normal retina, cytochrome c immunoreactivity
      increased markedly at 1 day post-axotomy, peaked at 3 days post-axotomy, and
      decreased thereafter. In addition, cytochrome c immunoreactivity localized almost
      exclusively to RGCs, suggesting that the cytochrome c release observed was injury
      related. Our data indicate that cytochrome c release potentially contributes to
      the death of axotomized RGCs.

PMID- 12598747
TI  - Antisaccade deficit after anterior cingulate cortex resection.
AB  - Suppression of unwanted reflexive saccades is a crucial process allowing to
      sustain voluntary fixation, when required. This inhibition process, which is
      mainly controlled by the dorsolateral prefrontal cortex, may also involve other
      cortical and subcortical structures. We prospectively studied the effect of
      frontal cortical resections involving adjacent regions to the anterior cingulate
      cortex on the ability to inhibit reflexive saccades. This lesion study included
      six patients undergoing resection of frontal low grade gliomas, studied prior and
      after surgery with electro-oculography, using the antisaccade paradigm. Lesions
      were normalized and mapped in Talairach space allowing to detail the structures
      whose lesions were associated with antisaccade deficits. In three of the six
      patients significant early post-operative antisaccade errors were associated with
      resection of a common critical region, mainly involving the posterior part of the
      anterior cingulate cortex. This same region was spared in the three remaining
      patients with no antisaccade deficit, suggesting that the anterior cingulate
      cortex, known as the cingulate eye field, could play a role in suppression of
      unwanted saccades.

PMID- 12598748
TI  - The effect of caspase inhibitors and neurotrophic factors on damaged retinal
      ganglion cells.
AB  - To elucidate the role of caspase inhibitors and neurotrophic factors in retinal
      ganglion cell (RGC) death and regeneration, we cultured mouse retinal explants in
      the presence of caspase-1, -3, -8, or -9 inhibitors, brain-derived neurotrophic
      factor (BDNF) and ciliary neurotrophic factor (CNTF) in serum-free culture media.
      We quantified apoptosis by TUNEL staining in RGCs and assessed the number of
      regenerating neurites. Apoptosis of RGCs treated with all caspase inhibitors or
      with neurotrophic factors was significantly reduced and the number of
      regenerating neurites was significantly greater than controls (p < 0.05). Our
      findings indicate that caspase-1, -3, -8, -9 play a critical role in explanted
      RGC death and may be ideal targets of neuroprotection and regeneration of damaged
      RGCs.

PMID- 12598749
TI  - Balloon dilation-assisted laparoscopic heller myotomy and Dor fundoplication.
AB  - Two methods are currently used in the treatment of achalasia: endoscopic balloon
      dilation and surgical Heller myotomy. Laparoscopy has come into use in achalasia
      surgery, and good outcomes have been achieved. This study included 11 patients
      (mean age, 30.7 years). Balloon dilation-assisted laparoscopic Heller myotomy and
      Dor fundoplication were performed in all patients. A 36-F orogastric tube was
      placed under visualization. The balloon of the tube was placed in the
      esophagogastric junction. After laparoscopic cardiomyotomy, the balloon was
      removed and Dor fundoplication was performed. The mean operative time was 90
      minutes. The patients were discharged on the second and third postoperative days
      (mean [standard deviation], 3 +/- 0.46). One month after the operation, the
      patients were tested with barium swallowing, and no complications or recurrences
      were observed. Laparoscopic distal esophagomyotomy combined with partial
      fundoplication may be the surgical approach of choice in achalasia because it is
      safer, provides good to excellent relief of symptoms and excellent cosmetic
      results, involves a shorter hospital stay, and is easy to execute. Balloon
      dilation makes myotomy easier because it separates the muscle fibers. Placing and
      insufflation of the balloon become safer because the entire procedure is executed
      under visualization; thus, excessive dilation is avoided.

PMID- 12598750
TI  - Complications of laparoscopic fundoplication in the elderly.
AB  - Our objective was to assess the complications of laparoscopic fundoplication in
      77 patients older than 70 years of age. The indications for surgery were (1)
      complications of reflux esophagitis (n = 17), (2) large hiatal hernia (n = 10),
      (3) asthma and bronchitis (n = 7), (4) the need for other surgery (n = 13), and
      (5) a patient's desire to discontinue medical treatment that was controlling
      reflux esophagitis (n = 30). Operative time varied from 34 to 250 minutes (mean
      [standard deviation], 116 +/- 20). Hospital stay varied from 12 hours to 19 days
      (mean, 1.2). No patient needed conversion to open operation. Intraoperative
      complications were observed in 4 patients (5.2%): left pneumothorax in 2, major
      operative bleeding in 1, and minor spleen lesion in 1. The most common
      postoperative complications were gas-bloating syndrome and dysphagia. Gastric
      ulcer was diagnosed in two. Other postoperative complications included acute
      delirium, acute urinary retention, and acute ischemia of the lower extremity. One
      patient died of congestive heart failure. It is concluded that laparoscopic
      fundoplication is an effective procedure for treating geriatric patients with
      reflux esophagitis and may be performed with low morbidity and mortality rates.

PMID- 12598751
TI  - Laparoscopic radiofrequency ablation of unresectable liver malignancies:
      feasibility and clinical outcome.
AB  - Radiofrequency ablation (RFA) is a safe and effective treatment in patients with
      unresectable liver malignancies. Since there is little information on its optimal
      approach, the feasibility, clinical outcome, and efficacy of laparoscopic RFA
      need further investigation. Twenty-three consecutive patients with unresectable
      hepatic malignancies were treated with RFA. RFA was performed percutaneously in 5
      patients (5 tumors; median maximum diameter of 25 mm [range, 20-73]), via
      laparotomy in 9 (28 tumors; median maximum diameter of 38 mm [5-90]), and via
      laparoscopy in 9 (16 tumors; median maximum diameter of 35 mm [8-58]). Mortality
      and intraoperative complication rates were 0. In the laparoscopy and laparotomy
      groups, mean blood loss was 13 mL versus 421 mL and mean hospital stay was 5.7
      versus 11.2 days, respectively (P = 0.0008 and P = 0.04). Postoperative
      complications occurred in one patient after laparoscopic RFA and in three after
      RFA via laparotomy. After a median follow-up of 12.2 months, local recurrence
      occurred in 2 patients (laparoscopic RFA, 1; percutaneous RFA, 1), and new
      hepatic tumors developed in 7 (laparoscopic RFA, 2/9; RFA via laparotomy, 5/9).
      Laparoscopic RFA is a safe and feasible treatment modality to achieve tumor
      destruction in selected patients with unresectable hepatic malignancies.

PMID- 12598752
TI  - Laparoscopic treatment of ventral hernias: prospective evaluation.
AB  - We describe 50 patients who recently underwent laparoscopic surgery. Early
      results, complications, and follow-up data were collected prospectively. Of 50
      patients, 34 had an incisional hernia, whereas 16 had a primary defect. Three
      trocars were inserted. EndoShears or Ultracision was used for tissue
      manipulation. The prosthetic mesh used was an expanded polytetrafluoroethylene
      (ePTFE) mesh, inserted through the first trocar and fixed with a helicoidal
      stapler. Patients were followed-up in the outpatient clinic (mean, 14 months).
      Every operation was successfully completed, and mean operative time was 103
      minutes. There were two small bowel injuries (4%) repaired by minilaparotomy.
      Postoperative pain was limited. Bowel movements, ambulation, and discharge were
      prompt. We noted 4 cases of urinary retention (8%), 8 seromas (16%), and 1
      prolonged ileus, which resolved on day 5 spontaneously. Mean postoperative stay
      was 4 days. One patient was readmitted after 4 weeks because of incomplete
      obstruction, resolved conservatively. There has been only 1 recurrence (2%), 8
      months after the operation. The technique appears safe and efficacious.

PMID- 12598753
TI  - 100 cases of endoscopic thyroidectomy: breast approach.
AB  - Neck surgery is one of the newest fields of endoscopic surgical application. One
      hundred patients underwent endoscopic thyroidectomy. We used 3 incisions: 1 on
      both upper circumareolar areas and 1 approximately 3 cm below the clavicle on the
      tumor side. Subplatysmal and subcutaneous operative space was created with CO2
      insufflation at 6 mm Hg of pressure. The thyroidal vessels and the parenchyma of
      the gland were dissected and divided with ultrasonic scalpel and commonly used
      laparoscopic instruments. The mean (+/-SD) operation time was 136 +/- 10 minutes
      before the year 2000 and 67 +/- 9 in the year 2000 (P < 0.05). There were six
      cases of conversion to conventional thyroidectomy. Postoperative complications
      occurred in five cases. There was no subcutaneous emphysema. The patients were
      satisfied with the cosmetic result. On the basis of our experience with these 100
      patients, we believe that endoscopic thyroidectomy is feasible and safe for
      resection of thyroid tumors. Thus, this procedure will provide another surgical
      technique for treatment of thyroid tumors, with maximized cosmetic effect.(2)

PMID- 12598754
TI  - Hand-assisted laparoscopic total gastrectomy.
AB  - Although the standard method to manage gastric cancer is still radical
      gastrectomy, minimally invasive surgery is of great interest in early gastric
      cancer because of its potential impact on improving the quality of life, if the
      disease is curable. With its degree of technical difficulty, laparoscopic total
      gastrectomy has not yet met with widespread acceptance. However, using a hand
      access device, a total gastrectomy and Roux-en-Y esophagojejunostomy with a D1
      plus alpha lymph node dissection and omentectomy with an Ultrashear was performed
      in its entirety. The operation took 6 hours, and the blood loss was 500 mL. The
      patient recovered uneventfully and was discharged on the 16th postoperative day.
      In terms of recovery and quality of life, laparoscopic total gastrectomy is a
      technically feasible and reasonable option for the management of early gastric
      cancer in the proximal stomach, especially when an endoscopic mucosal resection
      is not indicated.

PMID- 12598755
TI  - Laparoscopic reintervention for residual gallstone disease.
AB  - Laparoscopic reintervention is being increasingly performed in patients who have
      previously undergone surgery for gallstone disease. A few patients with
      gallbladder remnants or a cystic duct stump with residual stones have recurrent
      symptoms of biliary disease. Patients with bile duct injuries were excluded from
      the study. We reviewed our experience in treating such patients over a 4-year
      period, January 1998 through December 2001. Five patients underwent laparoscopic
      reintervention after previous surgery for gallstone disease performed elsewhere
      during the period mentioned above. Of these 5 patients, 3 had impacted stones in
      gallbladder remnants (laparoscopic cholecystectomy, 2; open cholecystectomy, 1)
      and 2 had recurrent symptoms after cholecystolithotomy and tube cholecystostomy
      (conventional surgery) performed elsewhere. Laparoscopic excision of the gall
      bladder remnants was done in 3 patients and a formal laparoscopic cholecystectomy
      was done in 2 patients who had previously undergone cholecystolithotomy and tube
      cholecystostomy. The mean operating time was 42 minutes. No drainage was required
      postoperatively. All patients were symptom-free during a mean follow-up of 2.3
      years (range, 7 months to 4 years). Reintervention may be required for patients
      with residual gallstones whose symptoms recur after gallbladder surgery such as
      cholecystectomy, subtotal cholecystectomy, and tube cholecystostomy. It is safe
      and feasible to remove the gallbladder or gallbladder remnants in such patients
      laparoscopically.

PMID- 12598756
TI  - Laparoscopically assisted surgery for congenital gastric or duodenal diaphragm in
      children.
AB  - Presented are our recent experiences with successful laparoscopically assisted
      surgery in two children with congenital gastric or duodenal diaphragm.
      Laparoscopy was used as an adjunct in performing the following surgical
      procedures: (1) inspection of the entire bowel, (2) identification and evaluation
      of the involved site, and (3) mobilization and exteriorization of the involved
      site. A minimal transverse incision was made for exteriorization. Extracorporeal
      removal of the diaphragm was followed by pyloroplasty or duodenoplasty. Each
      patient had a rapid and uncomplicated recovery with complete resolution of the
      symptoms. Laparoscopically assisted surgery may be a valuable modality in
      pediatric patients with congenital gastric or duodenal diaphragm. It allows
      better assessment of the entire bowel, minimizing the disfiguring and morbid
      abdominal incisions, without impeding the effectiveness of the planned operation.
      Avoidance of full-scale laparotomy may decrease the risk of future adhesions.
      These advantages seem attractive especially for children with longer life
      expectancy.

PMID- 12598757
TI  - Adult intussusception due to inverted Meckel's diverticulum: laparoscopic
      approach.
AB  - Nowadays, laparoscopy appears to be an attractive alternative to conventional
      surgery in the management of small bowel obstruction. Adult intussusception is an
      unusual cause of intestinal obstruction, and a wide range of pathologic
      conditions can result with intussusception. In this report, we present a very
      rare case of intussusception secondary to inverted Meckel's diverticulum in an
      adult who underwent laparoscopic surgery. The diagnostic modalities and surgical
      management of intussusception are discussed.

PMID- 12598758
TI  - Lower gastrointestinal bleeding from ileostomy takedown site 2 years after
      operation.
AB  - This case involves a 31-year-old man who presented with lower gastrointestinal
      bleeding from a perianastomotic ulcer 2 years after surgery. This report reviews
      the literature and suggests that perianastomotic ulcers may be underrecognized as
      delayed complications of side-to-side small bowel anastomosis. This report also
      demonstrates the value of push enteroscopy via the rectum in making the
      diagnosis.

PMID- 12598759
TI  - Laparoscopic splenectomy for Evans syndrome.
AB  - Evans syndrome is a rare, chronic, sometimes fatal immunologic disorder defined
      as Coombs' positive hemolytic anemia and immune thrombocytopenia without an
      underlying etiology. This syndrome has a variable clinical course, and the
      benefit of splenectomy is unknown. This report reviews the clinical outcome of
      laparoscopic splenectomy for Evans syndrome. A retrospective review was conducted
      of patients undergoing laparoscopic splenectomy for autoimmune hemolytic anemia
      and concomitant immune thrombocytopenic purpura at the Cleveland Clinic
      Foundation from August 1995 through August 2001. Data were collected in a
      prospective database and included demographic characteristics of the patients,
      surgical indications, operative details, and postoperative follow-up information.
      Five patients underwent laparoscopic splenectomy for Evans syndrome. At mean
      follow-up of 18 months (range, 1-31) after laparoscopic splenectomy, two patients
      had normal platelet counts (>100,000/microL) and required no further medical
      therapy. Two patients did not respond to laparoscopic splenectomy and are still
      undergoing medical therapy. One patient initially responded to laparoscopic
      splenectomy but became thrombocytopenic at 18 months and required further medical
      therapy. After 2 months of further medical treatment, this patient is currently
      (at month 10) in remission. Laparoscopic splenectomy for Evans syndrome is safe
      and technically feasible. The clinical outcome of splenectomy for patients with
      Evans syndrome is unpredictable. This select cohort of patients requires
      extensive long-term follow-up to determine the merits of splenectomy.

PMID- 12598760
TI  - Iliac artery pseudoaneurysm as a complication of laparoscopic rectopexy.
AB  - The occurrence of arterial pseudoaneurysms after laparoscopic cholecystectomy in
      the right hepatic artery, common hepatic artery, and cystic artery has been well
      documented. We describe a case of pseudoaneurysm of the common iliac artery
      presenting after laparoscopic stapled mesh rectopexy. As the benefits of minimal
      access surgery are extended to more and more procedures, surgeons should
      recognize the possibility of such a complication.

PMID- 12598761
TI  - Laparoscopic parastomal hernia repair.
AB  - Parastomal hernia is a common complication of ostomy construction. The morbidity
      and recurrence rates associated with repair can be quite high. Among the various
      approaches to repair, the lowest recurrence rates are associated with the use of
      mesh. We report a case in which a parastomal hernia was repaired
      laparoscopically. By employing this minimally invasive approach, our patient
      avoided the morbidity associated with laparotomy for intraperitoneal mesh
      placement.

PMID- 12598762
TI  - Richter's hernia in the laparoscopic era: four case reports and review of the
      literature.
AB  - Richter's hernia can occur at trocar sites after laparoscopic procedures, and 10
      mm or larger ports are the usual culprits. Most surgeons now routinely close the
      fascia of these sites to prevent herniation. The usual presentation is of crampy
      abdominal pain with nausea and vomiting. Treatment is reduction of the bowel that
      is incarcerated and then repair of the fascial defect. We describe four cases of
      Richter's hernia after laparoscopy, two that were repaired by open procedure and
      two that were repaired laparoscopically, and review the literature. A
      laparoscopic hernia repair is acceptable treatment at the time of diagnosis,
      especially in the obese patient, as long as the incarcerated bowel is not
      compromised or frankly ischemic.

PMID- 12598763
TI  - Laparoscopic bilateral hand-assisted nephrectomy: end-stage renal disease from
      tuberculosis, an unusual indication for nephrectomy before transplantation.
AB  - The purpose of the study was to sterilize renal tuberculous foci in a
      pretransplantation patient with a laparoscopic hand-assisted approach and to
      verify the feasibility of bilateral nephrectomy for this indication. This case
      report is the first description of hand-assisted laparoscopic bilateral
      nephrectomy for this pathologic condition. The 33-year-old patient had end-stage
      renal disease from renal tuberculosis. A commercially available hand-assistance
      device was used through a midline 8-cm supraumbilical incision and with four
      ports. The procedure was successfully completed. The total operative time was 3
      hours and 40 minutes. Estimated blood loss was 250 mL. The postoperative course
      was uneventful, and clinical follow-up at 3 weeks revealed a successful outcome.
      Hand-assisted bilateral laparoscopic nephrectomy in patients with chronic renal
      failure from tuberculosis represents a viable option because it is feasible and
      effective. The hand-assisted approach increases the safety of the procedure while
      retaining all the advantages of minimally invasive surgery.

PMID- 12598764
TI  - Laparoscopically assisted reversal of Hartmann's procedure.

PMID- 12598765
TI  - Laparoscopic management of splenic cysts.

PMID- 12598766
TI  - Recent observations on HIV type-1 infection in the genital tract of men and
      women.

PMID- 12598767
TI  - Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by
      HLA alloantigen recognition.
AB  - OBJECTIVE: This study was performed to determine whether ribonucleases (RNases)
      contribute to the soluble HIV-1 inhibitory activity that results from the
      recognition of HLA alloantigens. DESIGN AND METHODS: Supernatants from mixed
      lymphocyte reactions of peripheral blood mononuclear cells from healthy HLA
      discordant individuals exhibited HIV-1 inhibitory activity (alloantigen
      stimulated factors; ASF). These supernatants were tested for their sensitivity to
      heating (90 degrees C for 3 min), and for the presence of three RNases belonging
      to the RNase A superfamily: eosinophil-derived neurotoxin (EDN); RNase A; and
      angiogenin. Polyclonal antibodies specific for these RNases were used for Western
      blot analysis of the ASF, as well as for blocking the HIV-1 inhibitory activity
      of ASF. In addition, an RNase inhibitor (RI) was used to determine whether the
      anti-viral activity of ASF was due to RNase activity. RESULTS: HIV-1 inhibitory
      activity of ASF was: (i). resistant to heat treatment; (ii). blocked by 58% with
      an antibody specific for EDN, but not with antibodies against RNase A or
      angiogenin; and (iii) blocked by 65-100% with an RI. Moreover, Western blot
      analysis with an anti-EDN antibody detected EDN in the ASF. CONCLUSION: These
      findings indicate that the majority of the soluble HIV-1 inhibitory activity
      contained in the supernatants of mixed lymphocyte reactions is due to EDN or a
      closely related RNase.

PMID- 12598768
TI  - Inability of natural killer cells to destroy autologous HIV-infected T
      lymphocytes.
AB  - OBJECTIVE: Determine whether natural killer (NK) cells are capable of killing HIV
      infected autologous primary T-cell blasts. DESIGN: The ability of NK cells to
      kill HIV-infected primary T-cell blasts, whose cell surface major
      histocompatibility complex (MHC) class I molecules was decreased, was evaluated
      in a lytic assay. METHODS: Phytohemagglutinin-treated CD4+ T cells were infected
      with HIV-1. Infected cells were separated from uninfected cells by removal of
      CD4+ T cells. The NK cells were isolated from peripheral blood mononuclear cells
      (PBMC) of the same donor as the CD4+ T cells by immunomagnetic bead separation.
      The NK cells isolated from PBMC were then used as effector cells and the HIV
      infected T-cell blasts were used as target cells in a lytic assay. RESULTS: It
      was demonstrated that HIV infection of primary CD4+ T cells results in a 61-68%
      reduction in surface expression of MHC class I molecules. Despite the decreased
      MHC class I expression the NK cells were incapable of lysing autologous HIV
      infected T-cell blasts, yet were effective in the lysis of the NK cell sensitive
      cell line, K562. The inability of NK cells to lyse HIV-infected T-cell blasts is
      not dependent on the strain of HIV used to infected the CD4+ T cell CONCLUSION:
      These studies indicate that despite drastic decreases in MHC class I molecule
      expression, HIV-infected T-cell blasts can evade destruction by autologous NK
      cells.

PMID- 12598769
TI  - Interferon-alpha restores HIV-induced alteration of natural killer cell perforin
      expression in vivo.
AB  - OBJECTIVE: The percentage and the activity of natural killer (NK) cells are known
      to be decreased in HIV-infected patients. However, the mechanisms responsible for
      this NK deficiency are poorly understood. Because of the role of NK cells in the
      host defence against microbial infections, this defect contributes to the virus
      induced immune deficiency. The aim of the present study was to better understand
      this defect in order to be able to restore NK function in HIV infection. DESIGN
      AND METHODS: The expression of the cytolytic mediators perforin and granzyme A
      was analysed by flow cytometry, the lytic activity of peripheral blood NK cells
      of HIV-infected patients was analysed by cytotoxic assay, and the expression of
      perforin was followed during administration of interferon (IFN)alpha attached to
      polyethylene glycol (PEG)-IFNalpha. RESULTS: The lytic activity and the
      expression of perforin and granzyme A was low in NK cells of infected individuals
      in comparison with normal control volunteers. In both groups NK cytotoxic
      capacity was linked to perforin expression. The low perforin expression in HIV
      infected subjects negatively correlated with HIV RNA plasma level. administration
      of PEG-IFNalpha restored perforin expression even in patients whose viral load
      was not reduced by this treatment. CONCLUSIONS: These results suggest that HIV
      induced NK deficiency could be partly mediated by a defect in perforin and
      granzyme A expression, and that PEG-IFNalpha could be used in infected subjects
      to directly improve their natural immunity in addition to eventually reducing
      their viraemia.

PMID- 12598770
TI  - Perforin expression in T cells and virological response to PEG-interferon alpha2b
      in HIV-1 infection.
AB  - OBJECTIVE AND DESIGN: Interferon alpha (IFNalpha), which is known to directly
      inhibit the HIV-1 replicative cycle and to increase the activity of cytotoxic T
      lymphocytes (CTL), is being tested as an anti-HIV agent. As CTL play a major role
      in immune defence against HIV, we wanted to further characterize CTL activity and
      the effect of IFNalpha on it. METHODS: We followed by flow cytometry the
      intracellular expression of the key mediator of cytotoxicity, perforin, in
      peripheral blood T cells of patients treated with IFNalpha. RESULTS: We observed
      that the percentage of T cells harbouring perforin was higher in infected
      subjects than in non-infected controls. Administration of IFNalpha2b attached to
      polyethylene glycol increased this perforin expression further and reduced viral
      load (P = 0.010). The increase in the percentage of T cells expressing perforin
      correlated with IFNalpha-induced decrease in viral load (r, 0.753; P = 0.003). In
      addition, the level of perforin expression before IFNalpha administration was
      inversely correlated with viral load remaining after IFNalpha administration (r, 
      0.647; P= 0.017). CONCLUSION: The pre-therapeutic percentage of perforin-positive
      T cells might be a predictive marker of the virological response to IFNalpha in
      HIV-1-infected patients.

PMID- 12598772
TI  - Impaired production of cytokines is an independent predictor of mortality in HIV
      1-infected patients.
AB  - OBJECTIVES: With regard to the natural history of HIV-1 infection this study
      investigated whether whole-blood culture cytokine production was associated with
      mortality in HIV-1-infected patients. DESIGN AND METHODS: One hundred and seven
      HIV-1-infected patients stratified according to the Centers for Disease Control
      and Prevention criteria and 65 controls participated. The 24-h
      phytohaemagglutinin and lipopolysaccharide-stimulated whole-blood culture
      production of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma,
      interleukin (IL) receptor antagonist (-ra), IL-1beta, IL-12, IL-10, IL-2 and
      soluble (s) IL-2 receptor (-r)alpha were studied and progression was evaluated
      using Kaplan-Meier method and Cox proportional-hazards models. RESULTS: Compared
      with controls, asymptomatic patients had increased production of IL-1beta and IL
      12 (both P< 0.05), unchanged production of TNF-alpha, IFN-gamma and IL-1ra and
      notably reduced production of IL-10, IL-2 and sIL2-ralpha (all P< 0.05). HIV
      progression led to a progressive decline in whole-blood culture production of TNF
      alpha, IFN-gamma, IL-1ra, IL-1beta, IL-12, IL-10 and IL-2 (all P< 0.0001). Low
      production of these cytokines were all associated with increased mortality risk
      in the patients (log-rank test, all P < 0.01, univariate Cox, all P< 0.001).
      Furthermore, low production of TNF-alpha, IL-1beta, IL-12 and IL-10 independently
      predicted mortality after adjusting for other known prognostic variables
      (multivariate Cox, all P< 0.05). CONCLUSIONS: Preserved capacity of blood cells
      to produce cytokines was associated with prolonged survival in HIV-1-infected
      patients indicating a clinical significance of impaired cytokine production in
      HIV-1 infection.

PMID- 12598771
TI  - HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin
      D.
AB  - BACKGROUND: A high prevalence of bone demineralization occurs in people living
      with HIV/AIDS. The contribution of HIV itself and its treatment is still unclear.
      Protease inhibitors (PIs) are potent inhibitors of the cytochrome p450 enzyme
      system. Three cytochrome p450 mixed function oxygenases control serum levels of
      1,25-dihydroxyvitamin D (1,25(OH) D ), which is responsible for vitamin D actions
      in target tissues including bone. The 25- and 1alpha-hydroxylases regulate
      1,25(OH) D synthesis and 24-hydroxylase 1,25(OH) D catabolism. OBJECTIVE: To
      assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair
      the activity of the main enzymes involved in 1,25(OH) D homeostasis. DESIGN AND
      METHODS: Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP
      1) cell lines, expressing 25-hydroxylase and 1alpha-hydroxylase, respectively.
      The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH)
      D. Conversion rates of vitamin D to 25-hydroxyvitamin D [25(OH)D ]; 25(OH)D to
      1,25(OH) D or 24,25(OH) D, and 1,25(OH) D degradation were quantified in
      untreated and HIV-PI-treated cells after C -cartridge extraction and high
      performance liquid chromatography purification of 25(OH)D - 24,25(OH) D - and
      1,25(OH) D fractions. RESULTS: The PIs impair hepatocyte 25(OH)D - and macrophage
      1,25(OH) D synthesis in a reversible, dose-dependent manner. Furthermore, PIs
      inhibit 1,25(OH) D -degradation in macrophages with lower potency than that
      elicited on 1alpha-hydroxylase. Thus, reduced macrophage 1,25(OH) D production is
      the net effect of PIs action. CONCLUSIONS: In intact cells, HIV-PIs markedly
      suppress the activities of 25- and 1alpha-hydroxylase, which are critical in
      1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase,
      responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in
      inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D
      production could contribute to the bone demineralization in HIV patients.

PMID- 12598773
TI  - Mucosal and systemic HIV-1-specific immunity in HIV-1-exposed but uninfected
      heterosexual men.
AB  - BACKGROUND: Despite multiple, repeated exposures to HIV-1, some individuals never
      seroconvert. Mucosal and systemic immune correlates of this condition have been
      analysed in HIV-1-exposed women but no data are available concerning mucosal
      immunity and HIV-1-specific immune responses in exposed but uninfected men.
      DESIGN: We analysed cellular and humoral immune parameters in peripheral
      lymphocytes, seminal fluid and urethral swabs of 14 recently HIV-1-exposed
      seonegative (ESN) heterosexual men, seven HIV-seropositive patients and seven
      healthy controls. RESULTS: HIV-1-specific IgA were detected in urethral swabs of
      11 out of 14 ESN and of six out of seven HIV-seropositive patients; Env- and Gag
      specific IFNgamma-producing CD4 and CD8 peripheral lymphocytes were present in
      ESN and HIV-seropositive patients; seminal lymphocytes, but not peripheral blood
      lymphocytes, of ESN were enriched in activated populations (CD8CD38RO and
      CD4CD25). p24-specific cytotoxic T lymphocytes were correlated with the
      percentage of CD4 in the HIV-seropositive partners. High urethral concentrations
      of HIV-1-specific IgA were seen in those ESN with the most recent unprotected
      sexual episode. CONCLUSIONS: This is the first report of HIV-specific mucosal
      immunity in ESN men. These data add to the body of knowledge of the immune
      correlates present in exposed, uninfected individuals and might be important in
      vaccine design.

PMID- 12598774
TI  - Usefulness of total lymphocyte count in monitoring highly active antiretroviral
      therapy in resource-limited settings.
AB  - OBJECTIVE: To assess the usefulness of total lymphocyte count (TLC) for
      monitoring HIV-infected patients receiving highly active antiretroviral therapy.
      DESIGN Observational cohort study. METHODS: Correlation between difference
      (Delta) from baseline at week 4, 8, 12 and 48 in TLC, CD4 cell count and viral
      load was determined in patients initiating HAART in phase III clinical trials
      between 1995 and 2001 at the HIV Clinical Research Unit, Somerset Hospital, Cape
      Town. RESULTS: The study included 266 patients. At weeks 4, 8, 12 and 48, median
      increase in TLC was 30, 52, 139 and 219 cells x 10 /l, median increase in CD4
      cell count was 8, 48, 88, and 145 cells x 10 /l, and median decrease in viral
      load was -1.6, -2.2, -2.5 and -2.7 log copies/ml, respectively. The correlation
      between all pairs of DeltaTLC and DeltaCD4 cell counts was significant (r, 0.61;
      P < 0.0001), but between DeltaTLC and Delta viral load it was not (r, -0.014; P=
      0.73). However, the correlation between median viral load reduction and median
      increase in both DeltaCD4 cell count (r, -0.96; P< 0.0001) and DeltaTLC (r, 
      0.89; P< 0.0001) was significant. The slope of DeltaCD4 cell count was [52.493 +
      0.14(DeltaTLC)]. Sensitivity and specificity of an increase or decrease from
      baseline in TLC for similar trend in CD4 cell count during follow-up were 83.4%
      and 87.3% respectively. CONCLUSION: TLC correlated well with changes in CD4 cell
      count and at a group level with viral load changes. TLC may have a role in
      inexpensive monitoring of the immunological response to highly active
      antiretroviral therapy in a resource-constrained setting.

PMID- 12598775
TI  - A phase I/II study of nevirapine for pre-exposure prophylaxis of HIV-1
      transmission in uninfected subjects at high risk.
AB  - OBJECTIVE: To evaluate the safety, tolerability, and trough levels of three pre
      exposure prophylaxis regimens of nevirapine among HIV-1-uninfected subjects at
      high risk for HIV-1 infection. METHODS: A phase I/II trial (HIVHOP 101) in which
      33 such uninfected subjects received a 200 mg tablet of nevirapine once weekly
      (cohort A, n = 12), twice weekly (cohort B, n = 12), or every other day (cohort
      C, n = 9) for 12 weeks. Clinical signs/symptoms, laboratory parameters, and
      nevirapine trough levels were assessed at entry and at 1, 2, 4, 6, 9, and 12
      weeks, with a follow-up sample at 16 weeks. RESULTS: No subject experienced
      clinical symptoms attributed to nevirapine, including rash. There were no
      significant changes in liver enzyme levels from baseline to week 12 in the three
      cohorts, except for glutamyl transpeptidase in cohort B. Median nevirapine trough
      levels at weeks 1 and 12 were 119 ng/ml (range, < 25-205) and 135 ng/ml (range, <
      25-1065), respectively, for cohort A, 569 ng/ml (range, 135-2641) and 431 ng/ml
      (range, 42-2454) for cohort B, and 1942 ng/ml (range, 1214-2482) and 943 ng/ml
      (range, 262-5281) for cohort C. No subject became HIV-1 antibody positive by week
      16. CONCLUSIONS: A single dose of nevirapine taken once weekly, twice weekly, or
      every other day for 12 weeks was safely tolerated by the subjects in this small
      study, and resulted in nevirapine levels well above the IC (inhibitory
      concentration of 50%: 10 ng/ml) over the 12-week period in nearly all evaluable
      subjects. (50)

PMID- 12598776
TI  - Significant levels of intracellular stavudine triphosphate are found in HIV
      infected zidovudine-treated patients.
AB  - DESIGN AND OBJECTIVE: It has been previously shown that zidovudine (ZDV) and its
      phosphorylated metabolites can be chemically reduced into the corresponding
      stavudine (d4T) forms in solution. The aim of this study was to search for
      intracellular d4T-triphosphate (TP) in patients receiving ZDV therapy as part of
      highly active antiretroviral therapy and to examine the ratio of concentrations
      of d4T-TP : ZDV-TP in these patients. METHODS: Seven ml of blood were sampled
      between 0.5 and 13.7 h after the last ZDV dosing in 31 patients. Peripheral blood
      mononuclear cells (PBMC) were separated using Vacutainer CPT tubes. Intracellular
      d4T-TP and ZDV-TP concentrations were determined by a newly developed high
      performance liquid chromatography/tandem mass spectrometry method. RESULTS:
      Intracellular d4T-TP was found in all ZDV-treated patients. d4T-TP concentrations
      ranged between 3 and 38.5 fmol/1 x 10 cells and represented between 0.03 and 0.37
      of the corresponding ZDV-TP concentrations. These d4T-TP concentrations are in
      the lower range of those measured in d4T-treated patients. The intracellular
      transformation of ZDV into d4T-TP was also observed during experiments in cells
      cultured in the presence of ZDV. d4T-TP was never detected in PBMC from patients
      treated with neither ZDV nor d4T. CONCLUSION: Significant levels of d4T-TP can be
      measured in PBMC from patients receiving ZDV therapy. This observation sheds new
      light on the cross resistance observed between ZDV and d4T and indicates that, in
      patients treated with ZDV, d4T-TP could participate in the antiretroviral
      activity and/or toxicity of the drug.

PMID- 12598777
TI  - Highly active antiretroviral therapy corrects hematopoiesis in HIV-1 infected
      patients: interest for peripheral blood stem cell-based gene therapy.
AB  - OBJECTIVES: To study, in asymptomatic HIV-1-infected (HIV+) patients, whether
      peripheral blood hematopoietic progenitor/stem cells (PBPC) mobilized by
      granulocyte colony stimulating factor (G-CSF), can be used as a source of cells
      for retroviral gene therapy. DESIGN: PBPC from two groups of HIV+ patients
      (treated or untreated by highly active antiretroviral therapy) and from
      seronegative donors were mobilized with G-CSF. METHODS: PBPC collected by
      leukapheresis were enriched for CD34 cells, immunophenotypically and functionally
      characterized, cultured and infected with retroviral vectors. HIV proviral
      integration was studied on fresh and cultured cells. RESULTS: G-CSF moderately
      and transiently increased the viral load in untreated patients only, and induced
      in both groups of HIV+ patients mobilization of percentages and numbers of CD34
      cells comparable to those of seronegative volunteers. The most immature CD34 cell
      subset, the clonogenic progenitor and long-term culture initiating cells were
      significantly decreased in leukapheresis products and CD34-enriched fractions
      from untreated HIV+ patients but not in those from treated HIV+ patients. Cell
      cycle activation and growth factor responses of CD34 cells from both groups of
      HIV+ patients were not different from those of the control group. Culture and
      retroviral infection of CD34 cells from HIV+ patients did not enhance HIV
      replication, and yielded transduction levels similar to those obtained using CD34
      cells from seronegative donors. CONCLUSIONS: G-CSF-mobilized PBPC can be safely
      used for HIV retroviral gene therapy in asymptomatic treated patients while
      highly active antiretroviral therapy would control the G-CSF-induced increase in
      viral load and correct the defective hematopoiesis observed in untreated
      patients, without inhibiting the retroviral transduction of PBPC.

PMID- 12598778
TI  - Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving
      cotrimoxazole prophylaxis in Abidjan, Cote d'Ivoire.
AB  - BACKGROUND: WHO/UNAIDS recommended that cotrimoxazole should be prescribed in
      Africa in HIV-infected adults with CD4 cell counts < 500 x 10 /l, while closely
      monitoring bacterial diseases in as many settings as possible. METHODS:
      Prospective cohort study, describing bacterial morbidity in adults receiving
      cotrimoxazole prophylaxis (960 mg daily) between April 1996 and June 2000 in
      Abidjan, Cote d'Ivoire. RESULTS: Four-hundred and forty-eight adults (median
      baseline CD4 cell count 251 x 10 /l) were followed for a median time of 26
      months. The rates of overall bacterial diseases and of serious bacterial diseases
      with hospital admission were 36.8/100 person-years (PY) and 11.3/100 PY,
      respectively. Bacterial diseases were the first causes of hospital admissions,
      followed by non-specific enteritis (10.2/100 PY), acute unexplained fever
      (8.4/100 PY), and tuberculosis (3.6/100 PY). Among serious bacterial diseases,
      the most frequent were enteritis (3.0/100 PY), invasive urogenital infections
      (2.5/100 PY), pneumonia (2.3/100 PY), bacteraemia with no focus (2.0/100 PY),
      upper respiratory tract infections (1.6/100 PY) and cutaneous infections (0.6/100
      PY). Compared with patients with baseline CD4+ cell counts >or= 200 x 10 /l,
      other patients had an adjusted hazard ratio of serious bacterial diseases of 3.05
      (95% confidence interval, 2.00-4.67; < 0.001). Seventy-five bacterial strains
      were isolated during serious episodes including 29 non-, 14, 12 spp, and 12.
      DISCUSSION: Though with a medium-term rate half that of the short-term rate
      estimated under placebo before 1998 (26.1/100 PY), serious bacterial morbidity
      remains the first cause of hospital admission in adults receiving cotrimoxazole
      in this setting.

PMID- 12598779
TI  - The effect of dual infection with HIV and malaria on pregnancy outcome in western
      Kenya.
AB  - OBJECTIVE: To determine the effect of dual infection with HIV and malaria on
      birth outcomes and maternal anaemia among women delivering at a large public
      hospital in Kisumu, western Kenya. SUBJECTS AND METHODS: Data on obstetric and
      neonatal characteristics, maternal and placental parasitaemia, and postpartum
      haemoglobin levels were collected from women enrolled in a cohort study of the
      interaction between malaria and HIV during pregnancy. RESULTS: Between 1996 and
      1999, data were available from 2466 singleton deliveries. The maternal HIV
      seroprevalence was 24.3%, and at delivery 22.0% of the women had evidence of
      malaria. Low birthweight, preterm delivery (PTD), intrauterine growth retardation
      (IUGR) and maternal anaemia (haemoglobin < 8 g/dl) occurred in 4.6, 6.7, 9.8 and
      13.8% of deliveries, respectively. Maternal HIV, in the absence of malaria, was
      associated with a 99 g (95% CI 52-145) reduction in mean birthweight among all
      gravidae. Malaria was associated with both IUGR and PTD, resulting in a reduction
      in mean birthweight of 145 g (95% CI 82-209) among HIV-seronegative and 206 g
      (95% CI 115-298) among HIV-seropositive primigravidae, but not among
      multigravidae. Both HIV and malaria were significant risk factors for postpartum
      maternal anaemia, and HIV-seropositive women with malaria were twice as likely to
      have anaemia than HIV-seronegative women with or without malaria. CONCLUSION:
      Women with dual infection are at particular risk of adverse birth outcomes. In
      areas with a moderate or high prevalence of HIV and malaria, all pregnant women
      should be the focus of malaria and anaemia control efforts to improve birth
      outcomes.

PMID- 12598781
TI  - Sexual networks of pregnant women with and without HIV infection.
AB  - OBJECTIVES: To determine the relationship of HIV infection in pregnant women to
      sexual network size and other risk factors. DESIGN: Case-control study of women
      attending the public maternity hospital in Lima, Peru. METHODS: We interviewed 75
      HIV-seropositive women, 41 of their most recent male partners, and two control
      groups totaling 137 uninfected pregnant women and 70 of their most recent male
      partners. Each woman's sexual network size was estimated through second and third
      generation partnerships over the past year, 5 years and lifetime. RESULTS: Few
      HIV-seropositive women reported behavioral risk factors for HIV infection, but
      79% of male partners were HIV seropositive. Risk factors in male partners
      included sex with a female sex worker (FSW) or with another man (MSM). The mean 5
      year sexual network sizes through the second generation (8.4 persons for HIV
      seropositive women, and 2.5 and 1.9 for women in the two control groups)
      predicted HIV in the women, independently of her own number of partners. These
      differences were largely attributable to the number of partners reported by male
      partners. Using data from concurrent studies of FSW and MSM, estimates of 5-year
      sexual network sizes through the third-generation, excluding contacts with FSW
      which were protected by consistent condom use, were 672 persons for HIV
      seropositive women, and 160 and 224 for women in the two control groups.
      CONCLUSIONS: HIV infection risk among pregnant women in Lima depends largely on
      their male partners' risk behaviors. Even monogamous women had very large sexual
      networks.

PMID- 12598780
TI  - HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya.
AB  - OBJECTIVE: To study the importance of HIV infection for malaria in pregnancy in
      Kisumu, Kenya. SUBJECTS AND METHODS: Healthy women with an uncomplicated
      pregnancy of 32 weeks or more attending the prenatal clinic in the Provincial
      Hospital between June 1996 and March 1999 were tested for HIV and malaria after
      consent had been obtained. For participating women who delivered in the same
      hospital, a blood smear of the mother and the placenta were obtained. RESULTS: In
      the third trimester, 5093 women consented to testing: the prevalence of malaria
      and HIV was 20.1 and 24.9%, respectively. Among the 2502 screened women who
      delivered in the hospital, the prevalence of HIV, peripheral parasitaemia and
      placental malaria was 24.5, 15.2, and 19.0%, respectively. Compared with HIV
      seronegative women, HIV-seropositive women were more likely to be parasitaemic,
      to have higher parasite densities, and to be febrile when parasitaemic. Placental
      infections in HIV-seropositive women were more likely to be chronic, as indicated
      by the presence of moderate to heavy pigment depositions. When adjusted by age,
      the typical gravidity-specific pattern of malaria in pregnancy disappeared in HIV
      seropositive women; HIV-seropositive primigravidae had a similar risk of malaria
      as HIV-seropositive multigravidae. The excess malaria attributable to HIV in the
      third trimester increased from 34.6% among HIV-seropositive primigravidae, to
      41.5% among HIV-seropositive secundigravidae, and 50.7% among HIV-seropositive
      gravidae with three or more pregnancies. CONCLUSION: HIV infection alters
      patterns of malaria in pregnant women; in areas with both infections, all
      pregnant women should use malaria prevention.

PMID- 12598782
TI  - Determinants and prevalence of HIV infection in pregnant Peruvian women.
AB  - OBJECTIVES: To determine age-specific seroprevalence, risk factors, and risk
      markers for heterosexually-acquired HIV infection among pregnant women. DESIGN:
      Cross-sectional study of 12436 consecutive pregnant women in Lima, Peru in 1996
      1997. METHODS: Standardized interviews, serologic tests for HIV and syphilis,
      bivariate and multivariate analysis. RESULTS: HIV seropositivity was confirmed in
      58 women (0.5%). Only 22.6% were married, and only 12% of HIV infected women
      reported >or=2 sex partners ever. In multivariate analyses HIV infection was
      associated with: short duration of current relationship; two risk behaviors of
      women themselves (early onset of sexual activity and number of past sexual
      relationships); women's perceptions of two risk behaviors of partners (partner is
      a 'womanizer,' and partner uses illegal drugs); inadequate prenatal care; and
      four additional risk factors or markers (history of sexually transmitted disease,
      tuberculosis, or abortion in the women; and diagnosis of HIV/AIDS in a partner).
      CONCLUSIONS: HIV infection was related both to women's own risk behaviors and to
      the perceived risk behaviors of their sexual partners. Underlying societal
      factors related to heterosexual HIV infection, including deferral of marriage,
      warrant further study.

PMID- 12598783
TI  - Trial and error: cross-trial comparisons of antiretroviral regimens.

PMID- 12598784
TI  - Induction of HIV-1 long terminal repeat-mediated transcription by Neisseria
      gonorrhoeae.
AB  - Gonorrhoea enhances the transmission of HIV through increased viral shedding and
      the increased probability of seroconversion among previously HIV-negative
      individuals. However, the mechanism(s) underlying these influences remain poorly
      understood. We demonstrated that exposure to Neisseria gonorrhoeae induces the
      nuclear factor kappa B-dependent transcription from the HIV-1 long terminal
      repeat in derivatives of the Jurkat CD4 T cell line. These data suggest that
      gonococcal infection directly impacts HIV-1 transmission through the localized
      stimulation of viral expression.

PMID- 12598785
TI  - Different subtype distributions in two cities in Myanmar: evidence for
      independent clusters of HIV-1 transmission.
AB  - A molecular epidemiological investigation was conducted in two major cities in
      Myanmar (Yangon and Mandalay). The study revealed a unique predominance of HIV-1
      subtype B' (Thailand variant of subtype B) among injecting drug users in Yangon,
      indicating the strong founder effect of this variant. In contrast, multiple
      lineages of HIV-1 strains were found in Mandalay, leading to the evolution of
      various forms of intersubtype recombinants. The results showed independent
      clusters of HIV-1 transmission in Myanmar.

PMID- 12598786
TI  - Interleukin-2-associated viral breakthroughs induce HIV-1-specific CD4 T cell
      responses in patients on fully suppressive highly active antiretroviral therapy.
AB  - The combination of intermittent subcutaneous IL-2 and highly active
      antiretroviral therapy in individuals infected with HIV-1 has been shown to have
      a beneficial quantitative effect on the CD4 T cell count. We observed IL-2
      associated viral load 'blips' inducing HIV-1-specific lymphoproliferative
      responses at 24 weeks in such individuals. This immunotherapeutic approach,
      utilizing autologous virus as autovaccination, may be a viable, safer alternative
      to structured treatment interruption and potentially more efficacious than
      therapeutic vaccines.

PMID- 12598787
TI  - Real-time quantitation of HIV-1 p24 and SIV p27 using fluorescence-linked antigen
      quantification assays.
AB  - We developed fluorescence-linked antigen quantification (FLAQ) assays for HIV-1
      and SIV antigen quantitation. The assays utilize polystyrene microspheres coated
      with monoclonal antibodies against HIV-1 Gag p24 or SIV Gag p27, which are
      incubated with unknown samples, flourochrome-conjugated detector antibody, and
      lysing agent. The fluorescence of individual microspheres is measured using flow
      cytometry. The speed, simplicity, and wide dynamic range of FIAQ assays makes
      them superior to enzyme-linked immunosorbent assays for many applications
      performed in research laboratories.

PMID- 12598788
TI  - The impact on health-related quality of life of treatment interruptions in HIV-1
      infected patients.
AB  - To examine health-related quality of life (HRQOL) before, during and after
      treatment interruptions (TI) in antiretroviral therapy, we analysed results from
      Medical Outcomes Study HIV health surveys on 50 HIV-1-infected patients. HRQOL
      scores decreased during a TI but increased after re-initiating treatment,
      although scores remained lower than those preceding the TI. The reasons for a TI
      differentially affected HRQOL. The findings suggest that TI should be based on
      medical decisions and not used to increase HRQOL.

PMID- 12598789
TI  - Co-administration of rifampin and nevirapine in HIV-infected patients with
      tuberculosis.

PMID- 12598790
TI  - Concurrent use of bupropion with CYP2B6 inhibitors, nelfinavir, ritonavir and
      efavirenz: a case series.

PMID- 12598791
TI  - Remission of disseminated infection caused by Encephalocytozoon intestinalis with
      highly active antiretroviral therapy.

PMID- 12598792
TI  - Non-consented HIV testing by Belgian general practitioners.

PMID- 12598794
TI  - Environmental epidemiology and risk factors for autoimmune disease.
AB  - It has long been recognized that environmental influences play an important role
      in the risk of developing chronic rheumatic disease. Defining specific pathogenic
      environmental mediators that may trigger the development or progression of
      autoimmune disease remains a focus of increasing investigative effort. Factors
      promoting disease may not be identical to factors that influence the severity or
      progression of the disorder. Human monozygotic twin studies, animal studies, and
      genetic models demonstrate that genetic influences strongly determine whether one
      will develop autoimmunity, however, genes affecting the metabolism of exogenous
      agents that may trigger disease expression have only recently drawn attention. In
      this article the authors review recent reports that advance our understanding of
      previously recognized environmental risk factors and challenge accepted beliefs
      that increased estrogenic exposures predate the incidence of autoimmune
      disorders, systemic lupus erythematosus in particular.

PMID- 12598795
TI  - Clinical epidemiology: diagnostic and prognostic tests.
AB  - Recent studies of diagnostic and prognostic tests have commonly examined
      serological tests and new imaging techniques. Antifilaggrin antibodies have been
      found to be highly specific for the diagnosis of rheumatoid arthritis (RA), but
      uncertainty remains about the sensitivity of this test, particularly in early RA.
      Magnetic resonance imaging and ultrasound continue to be explored as methods to
      detect synovitis and erosions in RA. Several recent studies have confirmed the
      association between the human leukocyte antigen DRB1 shared epitope and worse
      radiographic outcomes in patients with RA. Interlaboratory variation in detecting
      autoantibodies remains a concern, as does overuse of tests for antineutrophil
      cytoplasmic autoantibodies.

PMID- 12598796
TI  - Social epidemiology and rheumatic disease.
AB  - Social epidemiology, a subdiscipline of epidemiology, aims to identify
      socioenvironmental exposures that may be related to a broad range of health
      status outcomes. The strong association throughout the developed world between
      lower levels of individual socioeconomic status and poorer health outcomes from
      many diseases, including arthritis, is well established. Although not yet well
      studied in arthritis, recent data suggest that community social determinants, the
      socioeconomic environment of an individual's neighborhood, may be operant in this
      regard as well. It is of considerable interest that the association of community
      social determinants with health outcomes appears to be independent of an
      individual's socioeconomic status, at least in some clinical situations. Both
      Healthy People 2010 and the National Arthritis Action Plan place high priority on
      reducing disparities in health outcomes in the United States. Development of
      effective prevention strategies will require (1) precise recognition of
      individual and community variables that are associated with health outcomes and
      (2) evaluation of the putative mediating mechanisms.

PMID- 12598797
TI  - Genetic epidemiology: disease susceptibility and severity.
AB  - Genetic factors are increasingly recognized to have an important contribution to
      the occurrence of both inflammatory and noninflammatory rheumatic disease.
      Although identifying the specific genetic mechanisms involved in the rheumatic
      diseases continues to present considerable challenges, the prospect of
      identifying individual gene action has been brought closer by a number of recent
      developments. These include newer approaches to phenotype definition, refinements
      in statistical tools for analysis, and the advent of newer technologies,
      including the use of microarrays. In this article, we review some of these
      developments together with the recent literature on the contribution of both
      broad and specific genetic factors to the spectrum of rheumatic disease. We also
      consider contemporary opinions on the potential impact of genetic discoveries to
      human health.

PMID- 12598798
TI  - Pharmacoepidemiology and rheumatic diseases: 2001-2002.
AB  - Pharmacoepidemiology is the branch of epidemiology that focuses on medications
      and their outcomes, including both adverse events and intended consequences. Such
      studies have become more prominent in rheumatology as the number of new
      medications has grown and prescribing databases have become more available. In
      the past year, the potential cardiovascular complications associated with
      selective COX-2 inhibitors have become an important concern. A number of pooled
      analyses suggest the possibility of an increased risk of acute myocardial
      infarction, and studies of naproxen have found a possible protective effect.
      Accumulating evidence supports the contention that early initiation of disease
      modifying antirheumatid drug therapy improves outcomes of patients with
      rheumatoid arthritis. Open-label extensions of biologic therapies found continued
      benefits extending several years with the TNF-alpha antagonists, but concerns
      have arisen regarding tuberculosis and central nervous system demyelination with
      these agents. Data continue to be published quantifying the risk of osteoporosis
      associated with glucocorticoids, and the association between biphosphonate
      therapy and upper gastrointestinal events appears to be less of a concern that
      originally described.

PMID- 12598799
TI  - Cost-effectiveness, cost-utility, and cost-benefit studies in rheumatology: a
      review of the literature, 2001-2002.
AB  - Economic analyses of prevention and treatment interventions in rheumatology are
      potentially powerful tools for evaluating many complex decisions facing clinical
      and public policy makers. Cost-effectiveness, cost-utility, and cost-benefit
      analyses allow for the assessment of the trade-offs between expended resources
      and expected health benefits. This review describes 12 cost-effectiveness
      analyses done in the past year. Each relates to a different intervention for a
      variety of rheumatologic conditions including osteoporosis, rheumatoid arthritis,
      the use of cyclooxygenase-II inhibitors, infected total joint replacements, back
      pain, and Lyme disease. While cost-effectiveness analyses of the use of the new
      biologic agents in rheumatoid arthritis have been presented at national meetings,
      these have yet to be published. Proper use of cost-effectiveness analysis could
      provide valuable evidence about treatment decisions for clinical and public
      policy makers in rheumatology.

PMID- 12598801
TI  - Effectiveness and cost-effectiveness of comprehensive rehabilitation programs.
AB  - Comprehensive rehabilitation involving multidisciplinary involvement of
      healthcare professionals is available to patients with rheumatic diseases.
      Studies were reviewed on the effectiveness of such programs for patients with
      chronic low back pain, widespread pain, and rheumatoid arthritis. When effects on
      the various outcome measures are demonstrated, improvements can only with
      difficulty be attributed to a specific component of a comprehensive program.
      Economic analyses for the effectiveness of comprehensive programs are scarce, but
      are needed by policy makers to allow optimal allocation of resources. Preferably
      the overall performance of comprehensive rehabilitation programs, not the
      individual components, should be evaluated.

PMID- 12598802
TI  - Effectiveness and safety of strengthening, aerobic, and coordination exercises
      for patients with osteoarthritis.
AB  - Exercise has generated interest as an important nonpharmacological treatment for
      symptomatic osteoarthritis (OA) of the hip and knee. Effect sizes in exercise
      interventions are small to moderate for pain and functional improvements and are
      similar to those observed for improvement in pain for nonsteroidal anti
      inflammatory drugs (NSAIDS). However, in contrast to NSAIDS, exercise
      interventions are safe and improve function through a direct effect on muscle
      strength and function. Both aerobic and strengthening exercises seem to be
      equally effective in regard to pain and function in patients with OA. In obese
      patients with OA, a combination of diet and exercise may be advantageous for
      optimal benefits in health-related quality-of-life and physical function. This
      article will focus on recent (September 2001-August 2002) randomized controlled
      trials with exercise as an intervention in patients with OA.

PMID- 12598803
TI  - What can rehabilitation interventions achieve in patients with primary
      fibromyalgia?
AB  - Symptoms of primary fibromyalgia (FM) persist for years, independent of applied
      therapy. That is the sad reality we have to deal with. But is that really true?
      The following review is a scan of literature from September 1, 2001 to August 31,
      2002, concerning rehabilitation interventions for patients with FM, to find
      progress in this field and to ascertain state-of-the-art treatment strategies for
      the disease. The main problem when treating patients with FM successfully is the
      heterogeneity of the patients' group. Several investigators determined subgroups
      within FM patients diagnosed by the 1990 American College of Rheumatology
      classification criteria of FM. Therefore, uniform recommendations for treatment
      cannot be given. Current treatment recommendations for FM include reassurance and
      explanation of the nature of the illness, evaluation and eradication of
      mechanical stressors as far as possible, symptomatic analgesic drug treatment,
      moderate individually adapted physical exercises, and adjuvant psychotherapeutic
      support in an interdisciplinary setting. Individually adapted measures are highly
      emphasized to differentially treat FM subgroups, as far as identified. This
      review will focus on these points on the one hand, and provide an overview about
      the current symptomatically-oriented therapy on the other hand. This all occurs
      against the background of an unknown etiology of the disease so far. Experimental
      approaches will be noted as well. The demonstration of a long-term effective
      intervention for managing the symptoms associated with FM is needed.

PMID- 12598804
TI  - Complementary medicine.
AB  - Complementary medicine has become an important subject for rheumatologists, not
      least because many patients try complementary treatments. Recent clinical trials
      yield promising results. In particular, evidence suggests that several herbal
      medicines and dietary supplements can alleviate the pain of osteoarthritis and
      rheumatoid arthritis. Clearly, rigorous testing of complementary treatments is
      possible, and considering their popularity, should be encouraged.

PMID- 12598805
TI  - Psychoeducational interventions in rheumatic diseases: a review of papers
      published from September 2001 to August 2002.
AB  - A large number of psychoeducational intervention studies have been developed for
      use with patients with rheumatic disease. The interventions vary considerably in
      the components they include and in the extent of the benefits they find. Recent
      meta-analyses of studies in rheumatoid arthritis (RA) report moderate short-term
      benefits, but it remains necessary to further examine which components are most
      important in bringing about change. A significant recent development in
      psychoeducational interventions is the move toward a generic intervention-the
      Chronic Disease Self-Management Program (CDSMP). A randomized controlled trial of
      this program has been performed, but statistical analysis for arthritis have not
      been reported separately.

PMID- 12598806
TI  - Effectiveness and practice variation of rehabilitation after joint replacement.
AB  - Early mobilization is the gold standard for achieving functional mobility after
      arthroplasty. The value of additional interventions to improve range of motion
      during the immediate inpatient period is not proven. Home is the preferred
      discharge destination and yields similar outcomes compared with inpatient
      rehabilitation. It is possible to improve outcomes related to physical activity
      by implementing exercise programs carried out at home or in groups. Knee
      arthroplasty possibly requires more rehabilitation than hip arthroplasty to
      achieve optimal outcomes. To enable firm conclusions on the effectiveness of
      rehabilitation after joint replacement, future studies have to consider
      methodological issues such as outcomes evaluated and number of patients included
      to ensure sufficient power.

PMID- 12598808
TI  - Reliability and validity of judgments of sound quality in elderly hearing aid
      wearers.
AB  - OBJECTIVE: The aim of the present study was to evaluate a particular sound
      quality rating procedure, referred to here as the Judgments of Sound Quality
      (JSQ) test, for potential use as an outcome measure with elderly hearing aid
      wearers. The validity and reliability of the JSQ as an outcome measure were
      determined for unaided and aided listening conditions. DESIGN: A repeated
      measures design was employed with two primary independent variables, each with
      two values: 1) aided condition (aided versus unaided listening); and 2) trial
      (test versus retest). Sixteen elderly, hearing-impaired hearing aid users
      participated in the study. The participants provided ratings on eight dimensions
      of sound quality (softness, brightness, clarity, fullness, nearness, loudness,
      spaciousness, and total impression) under four stimulus conditions (speech at 65
      dB SPL with a +8 dB signal-to-noise ratio, speech at 65 dB SPL in quiet, music at
      90 dB SPL, and music at 75 dB SPL). Test and retest ratings were obtained in both
      unaided and aided conditions. RESULTS: No significant differences were found
      between median test and retest scores on the JSQ. The median ratings for each
      sound-quality dimension were found to have moderate test-retest reliability, with
      test-retest correlations (r) ranging from 0.20 to 0.73 (median r value = 0.58)
      for the unaided listening condition, and from 0.23 to 0.85 (median r value =
      0.51) for the aided listening condition. Test validity was established through
      significant differences in JSQ ratings for various stimulus pairs (e.g., speech
      in quiet versus speech in noise). In addition, significant differences were
      observed between unaided and aided ratings for the dimensions of clarity,
      nearness, loudness, and total impression with aided JSQ ratings approaching
      normative "ideal" values established previously. CONCLUSIONS: The JSQ appears to
      be a potentially useful measure of hearing aid outcome, especially when using
      group data to document the benefits of amplification. Additional efforts should
      be directed at improving the reliability of the JSQ, however, before application
      to hearing aid wearers on an individual basis.

PMID- 12598809
TI  - Comparison of speech processing strategies used in the Clarion implant processor.
AB  - OBJECTIVE: To evaluate the performance of the various speech processing
      strategies supported by the Clarion S-Series implant processor. DESIGN: Five
      different speech-processing strategies [the Continuous Interleaved Sampler (CIS),
      the Simultaneous Analog Stimulation (SAS), the Paired Pulsatile Sampler (PPS),
      the Quadruple Pulsatile Sampler (QPS) and the hybrid (HYB) strategies] were
      implemented on the Clarion Research Interface platform. These speech-processing
      strategies varied in the degree of electrode simultaneity, with the SAS strategy
      being fully simultaneous (all electrodes are stimulated at the same time), the
      PPS and QPS strategies being partially simultaneous and the CIS strategy being
      completely sequential. In the hybrid strategy, some electrodes were stimulated
      using SAS, and some were stimulated using CIS. Nine Clarion CIS users were fitted
      with the above speech processing strategies and tested on vowel, consonant and
      word recognition in quiet. RESULTS: There were no statistically significant
      differences in the mean group performance between the CIS and SAS strategies on
      vowel and sentence recognition. A statistically significant difference was found
      only on consonant recognition. Individual results, however, indicated that most
      subjects performed worse with the SAS strategy compared with the CIS strategy on
      all tests. About 33% of the cochlear implant users benefited from the PPS and QPS
      strategies on consonant and word recognition. CONCLUSIONS: If temporal
      information were the primary factor in speech recognition with cochlear implants
      then SAS should consistently produce higher speech recognition scores than CIS.
      That was not the case, however, because most CIS users performed significantly
      worse with the SAS strategy on all speech tests. Hence, there seems to be a trade
      off between improving the temporal resolution with an increasing number of
      simultaneous channels and introducing distortions from electrical-field
      interactions. Performance for some CI users improved when the number of
      simultaneous channels increased to two (PPS strategy) and four (QPS strategy).
      The improvement with the PPS and QPS strategies must be due to the higher rates
      of stimulation. The above results suggest that CIS users are less likely to
      benefit with the SAS strategy, and they are more likely to benefit from the PPS
      and QPS strategies, which provide higher rates of stimulation with small
      probability of channel interaction.

PMID- 12598810
TI  - Distortion product otoacoustic emission response characteristics in older adults.
AB  - OBJECTIVE: The primary purpose of this study was to determine the distortion
      product otoacoustic emission (DPOAE) and noise response characteristics in a
      large sample of older adults. Another purpose was to evaluate how specific
      absolute DPOAE levels or DPOAE/Noise ratios differentiated hearing status in
      these individuals. DESIGN: A cross-sectional design was utilized for this study.
      As a part of the Epidemiology of Hearing Loss Study (EHLS), DPOAEs were measured
      in 937 of the 3,429 participants aged 48 to 92 yr. The DPOAE and noise response
      characteristics were evaluated at 1,000, 2,000, 4,000, and 8,000 Hz. Absolute
      DPOAE level and DPOAE/Noise ratios were measured in the participants. The DPOAE
      data were compared with individual pure-tone frequencies (1,000, 2,000, 4,000,
      and 8,000 Hz) in the participants to investigate how DPOAE responses
      differentiated ears with normal hearing from impaired ears. Sensitivity,
      specificity, positive and negative predictive values, and accuracies were
      calculated for various absolute DPOAE levels and DPOAE/Noise ratios. RESULTS: Due
      to the considerable overlap between DPOAE responses and the noise levels at 1,000
      Hz, this frequency was not used for any analyses. Sensitivity and specificity
      were calculated for various DPOAE responses. Sensitivity and specificity varied
      by frequency for absolute DPOAE levels and DPOAE/Noise ratios. Receiver operator
      characteristic (ROC) analyses were used to determine which DPOAE responses
      differentiated normal hearing from hearing loss. The ROC analyses demonstrated
      that -6 dB SPL at 2,000 Hz, -14 dB SPL at 4,000 Hz, and -22 dB SPL at 8,000 Hz
      and a +9 dB DPOAE/Noise ratio at each of these frequencies yielded the highest
      discrimination. CONCLUSIONS: Sensitivity and specificity varied by DPOAE response
      characteristics and frequency. The decision as to which DPOAE response criterion
      used should be based on careful consideration of objectives and the possible
      consequences of misdiagnosis. The results of this study support the use of DPOAEs
      as a clinical measure for older adults.

PMID- 12598811
TI  - Effects of aging on speech sound discrimination in the Mongolian gerbil.
AB  - The of this study was to examine the hypothesis that aging would adversely effect
      speech sound discrimination in the Mongolian gerbil, as assessed by behavioral
      techniques. The involved measuring difference limens (DLs) for frequency changes
      along three synthetic speech continua (vowel, liquid, stop-consonant) in 25
      gerbils as a function of age up to 36 mo. Absolute thresholds were also measured
      in the aging gerbils to verify normal hearing. The indicated no adverse effects
      of aging on the DLs for any of the speech continua. Thus the was that "intrinsic"
      aging processes in the gerbil, considered apart from "extrinsic" insulting
      factors, are not detrimental to speech discrimination, at least under quiet
      conditions. The clinical implications for humans are that the deficits typically
      observed in elderly humans for speech sound discrimination may be insult-related,
      and not the result of normal aging processes.

PMID- 12598812
TI  - Hearing levels in infants and young children in relation to testing technique,
      age group, and the presence or absence of middle-ear effusion.
AB  - OBJECTIVE: As part of a prospective study of possible effects of early-life
      otitis media on speech, language, cognition, and psychosocial development, we
      evaluated hearing both during episodes of middle-ear effusion (MEE) and when MEE
      was not present. The objective of this report is to describe age-specific hearing
      threshold levels in relation to the presence or absence of MEE in a large sample
      of young children. DESIGN: Participants were 1,055 children drawn from a sample
      of 6,350 children who were enrolled in the larger study by 2 mo of age. Otologic
      evaluation of each child was conducted at least monthly. The protocol of the
      larger study called for hearing evaluations 1) after 8 wk of continuous
      unilateral or bilateral MEE and every 4 wk thereafter until one test had been
      conducted when MEE was no longer present; 2) immediately before developmental
      testing; and 3) in a sample of children without MEE to obtain age-specific
      normative data. RESULTS: Results are presented by testing technique, age group,
      and middle-ear condition. In general, hearing threshold levels were highest in
      the youngest children tested with visual reinforcement audiometry and lowest in
      the oldest children tested with conventional audiometry. In general also,
      thresholds were lowest in children with normal middle-ear status, intermediate in
      children with unilateral MEE, and highest in children with bilateral MEE. On
      average, the presence of bilateral MEE was associated with hearing threshold
      levels 10 to 15 dB higher than the normative values for the corresponding age
      group. CONCLUSIONS: In infants and young children, audiometric results are
      influenced by testing technique, age group, and the presence or absence of
      effusion in each ear.

PMID- 12598813
TI  - Longitudinal changes in children's speech and voice physiology after cochlear
      implantation.
AB  - OBJECTIVES: The purposes of this investigation were 1) to describe speech/voice
      physiological characteristics of prelingually deafened children before and after
      cochlear implantation and determine whether they fall into a range that would be
      considered deviant, 2) to determine whether selected deviant articulatory and
      phonatory behaviors of children with cochlear implants persist despite long-term
      cochlear implant use and continued participation in aural rehabilitation
      services, and 3) to determine whether further development of deviant articulatory
      and phonatory behaviors occurs postimplantation. DESIGN: Seven prelingually
      deafened children who received cochlear implants after 5 yr of age were followed
      from shortly before implantation until 5 to 6 yr postimplantation. These children
      received their early education in a Total Communication environment and used the
      Nucleus 22-electrode cochlear implant. All of them initially used the MPEAK
      speech processing strategy, and five of them eventually upgraded to the SPEAK
      speech processing strategy. Speech/voice physiological measurements that were
      obtained periodically from the children included intraoral air pressure (P(o)),
      nasal and phonatory air flow, voice onset time (VOT), and fundamental frequency
      (F(o)). Data from the deaf children were compared with a database from 56
      children with normal hearing to determine when the deaf children exhibited
      "deviant" speech/voice behaviors. Speech/voice behaviors were considered
      "deviant" if they never occurred for children with normal hearing or were
      associated with z-scores that were outside the range of +/-2.0. RESULTS: The deaf
      children showed a wide range of deviant speech and voice behaviors both pre- and
      post-cochlear implant. The most frequently occurring atypical behaviors were use
      of negative P(o), high P(o) for [b, m], long and short VOT for [p], and high
      F(o). Some deviant behaviors improved post-cochlear implant. However, deviant
      behaviors often persisted for several years post-cochlear implant. There was
      considerable evidence of further development of deviant behaviors post-cochlear
      implant. All of the deaf children demonstrated deviancy on at least two of our
      measures at the last data collection interval (5 to 6 yr post-cochlear implant).
      CONCLUSIONS: Children who received cochlear implants after 5 yr of age and who
      were educated in a Total Communication setting showed persistence and further
      development of deviant speech/voice behaviors for several years post-cochlear
      implant. Although our findings cannot be generalized to other populations of
      children with cochlear implants (i.e., those who were implanted earlier, those
      educated in auditory-oral programs), it seems wisest at the present time not to
      assume that children's deviant speech/voice behaviors will remit spontaneously
      with continued cochlear implant use. Our data provide an important comparative
      database for future investigations of pediatric cochlear implant users who have
      had shorter periods of auditory deprivation and who have received cochlear
      implants with more current technological features. Longitudinal Changes in
      Children's Speech and Voice Physiology after Cochlear Implantation

PMID- 12598814
TI  - Audibility-index predictions of normal-hearing and hearing-impaired listeners'
      performance on the connected speech test.
AB  - OBJECTIVE: In a previous study (Sherbecoe & Studebaker, 2002), we derived a
      frequency-importance function and a transfer function for the audio compact disc
      version of the Connected Speech Test (CST). The current investigation evaluated
      the validity of these audibility-index (AI) functions based on how well they
      predicted data from four published studies that presented the CST to normal
      hearing and hearing-impaired subjects. DESIGN: AI values were calculated for the
      test conditions received by 78 normal-hearing and 72 hearing-impaired subjects
      from the selected studies. The observed CST scores and AI values for these
      conditions/subjects were then plotted and the dispersion of the data compared to
      the expected range based on critical differences. The AI values for the
      conditions/subjects were also converted into expected CST scores and subtracted
      from their corresponding observed scores to determine the distribution of the
      resulting difference scores and the relationship between the difference scores
      and subject age. RESULTS: Good predictions were obtained for normal-hearing
      subjects who had been tested under audio-only conditions but not those who had
      received audiovisual tests. The expected scores for the latter subjects were too
      low when the AI accounted only for audibility and too high when it included the
      correction for visual cues from ANSI S3.5-1997. All of the hearing-impaired
      subjects had been tested under audio-only conditions. In their case, the mean
      difference between the observed and the expected scores was comparable with the
      audio-only mean for the normal-hearing subjects when the AI included corrections
      for speech level distortion and hearing loss desensitization. However, the
      hearing-impaired subject data had greater variability. The predictions for these
      subjects also decreased in accuracy when subject age increased beyond 70 yr
      despite the application of an AI correction for age. CONCLUSIONS: The results of
      this study suggest that the AI functions derived for the CST satisfactorily
      predict the scores of normal-hearing subjects when they listen in speech babble
      under audio-only conditions but not when they receive visual cues. To obtain
      accurate predictions for the audiovisual form of the CST, it will be necessary to
      develop new ANSI-style AI correction equations for visual cues or new AI
      functions based on audiovisual test scores. If the current AI functions are used
      to predict the scores of hearing-impaired listeners tested under audio-only
      conditions, the AI should include corrections for the effects of speech level and
      hearing loss. A correction for subject age also could be applied, if it seems
      appropriate to do so. In either case, however, the predictions are still likely
      to be less accurate than the predictions for normal-hearing subjects. This may be
      because speech recognition deficits in people with hearing loss are not due
      solely to diminished audibility. Hearing-impaired subjects, particularly if they
      are elderly, also may be more susceptible to masking effects or other factors not
      accounted for by the AI.

PMID- 12598815
TI  - Trends in age of identification and intervention in infants with hearing loss.
AB  - OBJECTIVE: In 1993, 11 hospitals in the United States were known to screen more
      than 90% of newborns for hearing loss. By 2000, approximately 1,000 hospitals
      reported screening at least 90% of their babies. This study was designed to
      identify trends in the age of identification and intervention for infants and
      young children with hearing loss in light of expanded implementation of newborn
      hearing screening. DESIGN: Parents of children under 6 yr of age with a confirmed
      hearing loss were surveyed. The survey instrument was designed to investigate
      three questions: 1) is the age of identification and intervention earlier for
      babies whose hearing is screened at birth compared with those whose hearing is
      not screened; 2) when hearing is screened at birth, do ages of diagnosis of
      hearing loss and intervention meet the guide-lines established in 2000, by the
      Joint Committee on Infant Hearing (Reference Note 1), and 3) what are the
      barriers to timely identification and intervention? Six hundred fifty-seven
      parents received the mailing. RESULTS: Responses of 151 parents of children with
      hearing loss, born between 1996 and 2000, were analyzed. Parents from 41 states
      provided information. Approximately half the children reported on were screened
      for hearing loss at birth. Age of identification and hearing aid fitting varied
      substantially based on degree of hearing loss and whether the cause of hearing
      loss was known or unknown; however, diagnosis and intervention occurred at an
      earlier age for infants screened at birth. Findings indicate that when hearing is
      screened at birth, infants with more severe degrees of hearing loss and an
      unknown cause tend to be identified and receive intervention within the 2000
      timelines proposed by the Joint Committee on Infant Hearing. Barriers to timely
      identification and intervention are discussed. CONCLUSIONS: Before widespread
      implementation of newborn hearing screening, age of identification and
      intervention were consistently reported to exceed 2 yr of age. The results
      reported here indicate a trend toward earlier identification and hearing aid
      fitting with the implementation of newborn hearing screening. Although limited to
      literate and English speaking respondents, the study provides supporting evidence
      that newborn hearing screening lowers the ages of identification and
      intervention.

PMID- 12598816
TI  - Meta-analysis of double blind randomized controlled clinical trials of acetyl-L
      carnitine versus placebo in the treatment of mild cognitive impairment and mild
      Alzheimer's disease.
AB  - The efficacy of acetyl-L-carnitine (gamma-trimethyl- beta-acetylbutyrobetaine
      (Alcar) in mild cognitive impairment (MCI) and mild (early) Alzheimer's disease
      (AD) was investigated with a meta-analysis of double-blind, placebo-controlled
      prospective, parallel group comparison studies of at least 3 months duration. The
      duration of the studies was 3, 6 or 12 months and the daily dose varied between
      studies from 1.5-3.0 g/day. An effect size was calculated to reflect the results
      of the variety of measures used in the studies grouped into the categories of
      clinical tests and psychometric tests. The effect sizes from the categories were
      integrated into an overall summary effect size. The effect size for the Clinical
      Global Impression of Change (CGI-CH) was calculated separately. Meta-analysis
      showed a significant advantage for Alcar compared to placebo for the integrated
      summary effect [ES =0.201, 95% confidence interval (CI)=0.107-0.295] and CGI-CH
      (ES =0.32, 95% CI=0.18-0.47). The beneficial effects were seen on both the
      clinical scales and the psychometric tests. The advantage for Alcar was seen by
      the time of the first assessment at 3 months and increased over time. Alcar was
      well tolerated in all studies.

PMID- 12598817
TI  - Chronic treatment with lithium, but not sodium valproate, increases cortical N
      acetyl-aspartate concentrations in euthymic bipolar patients.
AB  - Previous studies have found that treatment with lithium over a 4-week period may
      increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients
      and controls. In view of other findings indicating that NAA concentrations may be
      a good marker for neuronal viability and/or functioning, it has been further
      suggested that some of the long term benefits of lithium may therefore be due to
      actions to improve these neuronal properties. The aim of the present study was to
      utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects
      of both lithium and sodium valproate upon NAA concentrations in treated euthymic
      bipolar patients. In the first part of the study, healthy controls (n =18) were
      compared with euthymic bipolar patients (type I and type II) who were taking
      either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios
      were determined. In the second part, we examined a separate group of euthymic
      bipolar disorder patients taking sodium valproate (n =9) and compared these to
      age- and sex-matched healthy controls (n =11), and we quantified the exact
      concentrations of NAA using an external solution. The results from the first part
      of the study showed that bipolar patients chronically treated with lithium had a
      significant increase in NAA concentrations but, in contrast, there were no
      significant increases in the sodium valproate-treated patients compared to
      controls. The second part of the study also found no effects of sodium valproate
      on NAA concentrations. These findings are the first to compare NAA concentrations
      in euthymic bipolar patients being treated with lithium or sodium valproate. The
      results support suggestions that longer-term administration of lithium to bipolar
      patients may increase NAA concentrations. However, the study suggests that
      chronic administration of sodium valproate to patients does not lead to similar
      changes in NAA concentrations. These findings suggest that sodium valproate and
      lithium may not share a common mechanism of action in bipolar disorder involving
      neurotrophic or neuroprotective effects.

PMID- 12598818
TI  - Tolerability of memantine in combination with cholinesterase inhibitors in
      dementia therapy.
AB  - Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA)
      receptor antagonist, has been shown to be effective in dementia, including
      Alzheimer disease (AD). Therefore, its combination with acetylcholinesterase
      inhibitors (AChEIs) is anticipated. We report a postmarketing surveillance study
      conducted among German physicians who, during routine clinical practice, treated
      demented patients with memantine in combination with an AChEI. Most of the 158
      surveyed patients (mean age, 74 years) were diagnosed with AD but other dementias
      were included. Memantine was prescribed at a wide range of daily doses (median,
      20 mg/day) and was combined with donepezil for most patients (84%). Combination
      therapy was well tolerated for nearly all patients (98%) for an average
      observation period of 4 months at stable doses of both antidementia agents. No
      serious adverse drug reaction (ADR) was reported. No ADR or change in blood
      chemistry was experienced by most patients (96% and 81%, respectively); the six
      reported ADRs resolved without sequelae and without drug discontinuation. Global
      clinical status of most patients was judged as improved (54%) or stable (39%)
      over the observation period. These findings particularly suggest that memantine
      in combination with AChEIs is safe and well tolerated.

PMID- 12598819
TI  - The onset and time course of response of negative symptoms to add-on fluvoxamine
      treatment.
AB  - Not enough is known about the propensity of individual negative symptoms to
      respond to treatment and the dynamics of this change. We have previously shown
      that adding the selective serotonin reuptake inhibitor fluvoxamine to
      antipsychotics can improve negative symptoms, and now provide data on the
      response of individual negative symptoms to such treatment. We examined items on
      the Schedule for the Assessment of Negative Symptoms for patients participating
      in two published controlled studies comparing the effect of add-on fluvoxamine
      and placebo on negative symptoms. Using a mixed regression model, we analysed
      item scores at each week of the study to identify the first signs of a treatment
      effect. Potential confounding effects of depressive extrapyramidal and positive
      symptoms were statistically controlled. Eleven of 16 items tested showed
      improvement, five within 2 weeks and a further four within 3 weeks of starting
      treatment. The most rapidly responding items included core negative symptoms such
      as alogia. The propensity for and rate of improvement with fluvoxamine treatment
      differs for the various negative symptoms. Many symptoms, including those
      generally agreed to be core features of the illness such as alogia, improved
      within 2-3 weeks of treatment initiation.

PMID- 12598820
TI  - Amantadine as augmentation therapy in the management of treatment-resistant
      depression.
AB  - Treatment-resistant depression is an important clinical problem presenting a
      major challenge to clinical psychiatry. While several strategies have been
      attempted, including medication switch, antidepressant polypharmacy and various
      augmentative regimens, success remains limited. Amantadine (AMN), an agent
      traditionally used in the treatment and prophylaxis of influenza, is now known to
      exhibit prominent effects at the level of dopaminergic, monoamine oxidase and N
      methyl-D-aspartate systems. The present reports on the efficacy of AMN as
      augmentation to standard antidepressant treatment in patients with treatment
      resistant depression. Eight patients with treatment-resistant depression
      consented to receive AMN, titrated up to a dose of 300 mg, over a period of 4
      weeks in a non-blinded fashion. Improvement in both depression and anxiety scores
      were observed from week 1, with patients exhibiting improvement of depressive
      scores of up to 49% by study completion. Females appeared to exhibit a stronger
      response, and within a shorter period of time. Side-effects reported included dry
      mouth and sedation. AMN appears to demonstrate efficacy as a safe and effective
      augmentative agent in treatment-resistant depression. Further studies are clearly
      mandated to test these preliminary observations in a double-blinded manner.

PMID- 12598821
TI  - Lamotrigine augmentation in unipolar depression.
AB  - A significant number of patients with unipolar depression fail to achieve
      remission after one or a series of antidepressants. We present the results of a
      retrospective chart review of the efficacy and tolerability of lamotrigine as an
      augmentation drug in treatment-resistant unipolar depression. A previous absence
      of a response was defined as the clinically significant presence of depressive
      symptomatology after 6 weeks of treatment with an antidepressant, with at least 3
      weeks at the maximum dose tolerated by the patient. The patients were rated
      retrospectively using the Clinical Global Impression rating scale. Seventy-six
      percent of the patients improved. Gender, age, basal severity of the episode and
      degree of previous non response were not statistically significantly associated
      with response to lamotrigine augmentation. Comorbidity showed a tendency to be
      negatively related with response to lamotrigine. Three patients abandoned the
      treatment with lamotrigine due to side-effects. Complaints were excessive
      somnolence, headache, dizziness, nausea and malaise. Data suggest that
      lamotrigine is a promising drug for treatment-refractory unipolar depression.
      Double-blind studies are necessary to confirm its use as an augmentation agent.

PMID- 12598822
TI  - Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen
      persisting perception disorder with anxiety features.
AB  - An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and
      LSD-like substances is the recurrence of some of the symptoms which appear during
      the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen
      persisting perception disorder (HPPD) is a condition in which the re-experiencing
      of one or more perceptual symptoms causes significant distress or impairment in
      social, occupational or other important areas of functioning and may be extremely
      debilitating. Benzodiazepines are one of the recommended agents for the treatment
      of HPPD but it is unclear which of them may be more helpful. The goal of our
      investigation was to assess the efficacy of clonazepam in the treatment of LSD
      induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of
      HPPD with anxiety features for at least 3 months and were drug free at least 3
      months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued
      for 6 months. They were weekly evaluated during the 2 months of clonazepam
      administration and monthly during the follow-up period using the Clinical Global
      Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients
      reported a significant relief and the presence of only mild symptomatology during
      the clonazepam administration. This improvement was clearly sustained and
      persisted during a 6-month follow-up period. This study suggests that high
      potency benzodiazepines like clonazepam, which has serotonergic properties, may
      be more effective than low-potency benzodiazepines in the treatment of some
      patients with LSD-induced HPPD.

PMID- 12598823
TI  - Plasma levels of homovanillic acid and the response to risperidone in first
      episode untreated acute schizophrenia.
AB  - We have previously reported that risperidone might improve negative symptoms in
      schizophrenia by influencing noradrenergic neurons. In the present study, we
      focused on the clinical efficacy and mechanisms of risperidone towards positive
      symptoms in the acute phase of schizophrenia. Thirty-four patients meeting DSM-IV
      criteria for schizophrenia and treated with risperidone alone were evaluated
      regarding their clinical improvement using the Positive and Negative Syndrome
      Scale (PANSS) before and 2 weeks after risperidone administration, and blood
      samples were also drawn at the same times. Plasma concentrations of homovanillic
      acid (HVA) and 3-methoxy-4-hydroxyphenylglycol were analysed by high-performance
      liquid chromatography with electrochemical detection. Plasma HVA levels in the
      responders to the risperidone treatment (more than 50% improvement in scores of
      positive symptoms in PANSS) were higher than those of non-responders before
      risperidone administration. Furthermore, there was a negative trend between
      changes in plasma HVA levels and improvement of total scores for positive
      symptoms in PANSS. These results suggest that higher levels of plasma HVA before
      risperidone administration might be a predictor of a good response to risperidone
      treatment, and the influence of risperidone on dopaminergic activity might be
      associated with its efficacy in treating symptoms of schizophrenia in the acute
      phase.

PMID- 12598824
TI  - Comorbidity of schizophrenia and galactosemia: effective clozapine treatment with
      weight gain.
AB  - Weight gain with atypical antipsychotics such as clozapine has been hypothesized
      to have a multifactorial genesis. Beside changes in neurotransmitter systems
      caused by antipsychotic-induced receptor blockade, hormonal changes and other
      neuroleptic side-effects (sedation, reduced activity, reduced basal metabolic
      rate, dry mouth) are also discussed. Our unique case report of a patient with
      comorbid galactosemia and schizophrenia is an interesting example of weight gain
      being a positive side-effect of clozapine, not necessarily associated with
      increased appetite and higher caloric intake.

PMID- 12598825
TI  - Replacement of antipsychotic and antiepileptic medication by L-alpha-methyldopa
      in a woman with velocardiofacial syndrome.
AB  - We report the case of a 23-year-old woman with velocardiofacial syndrome (VCFS)
      and a history of psychosis and seizures. She had been treated with conventional
      antipsychotic and antiepileptic drugs for 10 and 3 years, respectively. However,
      she continued to experience occasional hallucinations and paroxysmal jerking of
      the extremities. L-alpha-methyldopa 500 mg b.i.d. (later reduced to 250 mg
      t.i.d.) was added to her regimen. Hallucinations and seizures stopped shortly.
      Over the course of approximately 1 year, the previous medications were
      discontinued without recurrence of psychotic and epileptic symptoms. Eventually,
      improved mental functions and behaviour enabled her transition from living in a
      licensed residential facility to sharing a private residence with a partner. VCFS
      is associated with haploinsufficiency of catecholamine-methyltransferase, leading
      to excessive extraneuronal catecholamine concentrations. Alpha-Methyldopa
      inhibits catecholamine neurotransmission in a variety of ways. It is possible
      that the drug compensated for genetically disturbed catecholamine transmission
      thus achieving beneficial effects in this case.

PMID- 12598826
TI  - [Clinical training in French medical schools: the end of the story?].

PMID- 12598827
TI  - Recommendations for the prevention and management of tuberculosis in patients
      taking infliximab.
AB  - An unusually large number of cases of tuberculosis, often with miliary or
      widespread dissemination, has been reported in patients taking infliximab for
      rheumatoid arthritis or Crohn's disease. Recommendations have been issued in
      France regarding the definition of high-risk patients, the screening methods to
      be used in these patients, and possible prophylactic treatments. The present
      update is also intended to help physicians manage tuberculosis occurring before
      or during infliximab therapy.

PMID- 12598828
TI  - [Calcium needs in hemodialyzed-parathyroidectomized patients].
AB  - Parathyroidectomy changes the homeostasis of calcium balance in patients under
      dialysis for kidney failure. The aim of this work is to value calcium needs in 20
      hemodialysed patients who underwent parathyroidectomy, in the department of
      nephrology of UHC Ibn Rochd of Casablanca from January 1994 to June 1999. These
      patients, 12 women (60%) and 8 men (40%), aged between 14 and 70 years
      (mean=46.10+/-13.62 years). Hungry bone syndrome was noted in 8 patients and
      postoperative hypocalcemia in 15 (75%). Mean minimal serum calcium was 196+/-0.21
      mmol/l, with clinical signs in 6 patients. Mean calcium supplement the first
      postoperative week was 18.1+/-0,54 g/day in the 8 patients with hungry bone
      syndrome and 14.28+/-0,86 g/day in the 12 remaining patients. Between 6 and 18
      months postoperatively, required calcium supplementation was 4.5 to 12 g/day in
      patients with hungry bone syndrome compared with 3 to 6g/day at the remaining
      patients. Mean serum calcium remained stable between 2.16 mmol/l to the 3(rd)
      month and 2.48 mmol/l to the 36(th) month. Postoperative hypocalcemia remains a
      major concern after parathyroidectomy requiring massive substitution with calcium
      and active vitamin D metabolite under close supervision to spare these patients
      from hypercalcemia resulting from parathyroid dysfunction.

PMID- 12598829
TI  - [Immunity, autoimmunity, and the aging process: complex interactions].
AB  - Immune deficiency is not an age-related process, but rather a progressive process
      where predominantly cellular immune response is gradually, but never totally,
      replaced by antibody response. Cellular immune response appears to be associated
      with the intrinsic mechanisms of pathological aging. Cellular immunity resulting
      from induction of macrophage stimulation and cytokine secretion appears to
      involved. These immuno-inflammatory changes mimic the effects of pathological
      aging in the different organs. Are they essential factors or simply accessory
      phenomena? Switching towards an antibody response appears to be a mechanism of
      adaptation rather than a mechanism of deterioration. Immune status provides a
      good means of assessing general status in an elderly subject. An attempt should
      be made to identify the cause of any immune deficiency since age is not in itself
      an underlying cause. Etiological treatment is indicated.

PMID- 12598830
TI  - [Nutrition and immunity in the elderly].
AB  - Global malnutrition (reduced intake or increased requirements for protein and
      calories) is the most common nutritional deficit in the elderly population.
      Micronutrients (vitamins and trace minerals) deficiencies are also common in
      older adults. Malnutrition consequences on immunity are characterized by a
      decrease in cell mediation immunity with a reduction in naive T cells and in
      cytokine production. During infection, the treatment must be specific and after
      infection it has to associate nutritional supplementation and exercise. The lack
      of clear benefit in the use of specific micronutrient should discourage the use
      of high-dose supplementation for an immunologic indication.

PMID- 12598831
TI  - [Central nervous system vasculitis and of the peripheral nerves in the elderly].
AB  - Vasculitis of the nervous system are rare in the elderly. When present, they may
      constitute an urgent diagnosis and a therapeutic emergency. Clinical expression
      is rich and without specificity. Atypical signs (unusual course of dementia,
      systemic signs) or atypical laboratory results (inflammatory syndrome) may
      suggest the diagnosis of vasculitis. However, as multiple comorbidity is the rule
      in elderly subjects, searching for intercurrent factors (e.g. atrial fibrilation
      due to infectious disease causing embolic stroke) may be more contributive than
      searching for proof of a rare disease (vasculitis) with invasive procedures in
      this population. Giant cell (temporal) arteritis is the only vasculitis
      specifically related with age; the vital prognosis of vision may be compromised.
      Corticosterid therapy must be instituted without delay. Periartritis nodosa
      begins in 30% of cases after 60 years of age. The clinical features are the same
      as in younger subjects. Other vasculidis are rare in the elderly. In absence of
      specific studies in this population, therapeutic protocols are the same as in
      younger subjects but may have to be adjusted.

PMID- 12598832
TI  - [Monoclonal gammopathy of undetermined significance].
AB  - Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic
      disorder with serum monoclonal immunoglobulin less than 30 g/l. It preferentially
      affects elderly patients; MGUS prevalence is about 1% in the general population
      and about 10% in patients aged over 80 years. MGUS diagnosis is based on
      elimination of other causes of serum monoclonal immunoglobulin, particularly
      multiple myeloma. Within the 20 years following diagnosis of MGUS, about 25% of
      patients will evolve towards myeloma or other malignant lymphoproliferative
      disorder. No factor has been identified to date which can efficiently predict
      this evolution. Recent data concerning immunophenotype, cytogenetics and
      molecular biology of plasma cells demonstrate the link between MGUS and multiple
      myeloma. MGUS clearly appears now as a plasma cell monoclonal pathology with
      reduced malignity. Soon, new biological data would help to discriminate patients
      with MGUS who will remain asymptomatic life-long from those who will evolve
      towards malignant lymphoproliferative disorder.

PMID- 12598833
TI  - [Treatment of hepatitis C. Paris 27-28 February 2002].

PMID- 12598834
TI  - [Nephrogenic ascites. A case report].
AB  - Nephrogenic ascites is a clinical diagnosis defined as a refractory ascites in
      patients with end-stage renal disease. The exact cause of ascites formation is
      unknown. Patients frequently present with moderate to massive ascites and
      cachexia. The ascitic fluid is an exudate. The diagnosis is one established only
      by exclusion of the others causes of exudative ascites. Only continuous
      ambulatory peritoneal dialysis and renal transplantation appear to be effective
      in controlling ascites formation. The prognosis is dismal. We described here one
      patient case with nephrogenic ascites and review of the literature.

PMID- 12598835
TI  - [Generic carbamazepine-induced subacute adrenal insufficiency?].
AB  - Iatrogenic causes of adrenal insufficiency in Addison's disease are exceptional.
      We report the case of a patient with a history of epilepsy (taking carbamazepine,
      Tegretol LP) and Addison's disease (treated by hydrocortisone (HDC) 30 mg/d,
      Dectancyl 0,5 mg/d, Florinef 50 mg/d). Recent digestive disorders required
      emergency hospitalization. The physical examination was normal and laboratory
      tests showed hyponatremia, hyperkalemia, and elevated serum ACTH. The course was
      rapidly favorable after rehydration and up-titration of the drug regimen. No
      triggering factor was identified, but the Tegretol LP had been replaced for 3
      months by a generic drug with the same quantity of active ingredients and the
      same bioavailability, but with a different excipient (the generic drug was not
      encapsulated). Could these differences have increased the serum level of
      carbamazepine and lead to more rapide HDC metabolism by enzymatic induction?
      Could poorer digestive tolerance have decreased HDC absorption? The hypothesis of
      carbamazepine overdosage is unlikely because the assay remained within the
      therapeutic range and hyperkaliemia would favor adrenal decompensation. In
      conclusion, this single case cannot prove drug interaction but does point out the
      importance of being prudent when modifying a well--tolerated regimen in a patient
      with Addison's disease.

PMID- 12598836
TI  - [Vitamin B12 deficiency-induced moderate hyperhomocysteinemia and venous
      thromboembolism].

PMID- 12598837
TI  - [Biermer's anemia corrected by oral vitamin B12].

PMID- 12598838
TI  - Chronic hypertension in pregnancy.
AB  - Hypertension is the most common medical disorder during pregnancy. Chronic
      hypertension is a serious medical complication in pregnancy with increased
      maternal and perinatal morbidity and mortality. Those who develop uncontrolled
      severe hypertension, those with target organ damage, and those who are poorly
      compliant with prenatal visits are at high risk for poor perinatal outcome.
      Maternal complications include abruptio placenta, stroke, and superimposed pre
      eclampsia. Fetal complications include prematurity, low birth weight, and
      perinatal death. Careful antepartum, intrapartum and postpartum management of
      women with high-risk chronic hypertension in pregnancies may reduce morbidity and
      mortality.

PMID- 12598839
TI  - [The therapy of endometriosis. New prospects].
AB  - Surgery is still the first line of therapy for endometriosis. At present, medical
      therapy is mostly indicated for treatment and prevention of recurrences. Current
      pharmacological regimens induce a hypoestrogenic state; this effect tends, on one
      hand, to inhibit the growth of endometriotic implants while, on the other hand,
      it significantly interferes with the integrity of the hypothalamus-pituitary
      ovarian axis. The aim of this study is to review current knowledge on the new
      experimental therapeutic approaches to the disease. English articles on this
      topic have been searched by Medline. A particular attention has been paid to
      experimental therapeutic interventions supported by in vivo results. Three
      different novel strategies have been identified: 1) To act on estrogenic
      dependence of endometriosis using new drugs such as aromatase inhibitors and
      raloxifene. These drugs may have the advantage to act more specifically on the
      disease. 2) To treat the disease with immuno-modulators and anti-inflammatory
      drugs. These compounds may be helpful in both limiting the growth of
      endometriotic implants and in controlling the symptoms of the disease. 3) To
      prevent adhesion reformation after surgical lysis. Adhesions are an important
      hallmark of endometriosis which cannot be adequately eliminated by surgery. The
      use of barrier and fluid agents after surgical lysis seems to be effective in
      this regard. Results from studies aimed to investigate the effectiveness of these
      approaches are appealing. However, controlled clinical trials are now required to
      appropriately determine their real benefits and their specific indications.

PMID- 12598840
TI  - [Stress urinary incontinence: an overview on actual surgical trends].
AB  - Stress urinary female incontinence (IUS) is an unpleasant symptom describing a
      loss of urine during physical exertion; genuine stress incontinence (GSI) is a
      socially unacceptable, involuntary loss of urine in absence of detrusor activity
      from the urethra associated with sudden cough or strain. The incidence of IUS is
      less than 10% in reproductive-age women but may approach 10-20% in postmenopausal
      women. The IUS pathophysiology is connected with two specific mechanisms: the
      urethral-bladder sliding out of anatomical area involves the normal system of
      endobladder/intraabdominal pressures, with a loss of urine; the second mechanism
      involves the damaged urethral sphincteric function, with a reduction of the
      urethral closure pressure and a urinary loss after minimal physical stimulation.
      The IUS medical therapy is troublesome and often inefficient, and the only
      approved effective measures are the surgical procedures, actually reserved for
      cases of unsuccessful medical therapy; surgical treatments can be classified
      according to the access as: vaginal, abdominal, associated and complex. They
      intend to reposition the urethral-bladder sliding in its normal intra-abdominal
      position, to allow equal transmission of increased intraabdominal pressure to the
      bladder and the proximal urethra. In the scientific literature there are more
      than one hundred surgical procedures for IUS correction, but the IUS surgical
      approach is anyway the actual gold standard therapy.

PMID- 12598842
TI  - [Indications for hormone replacement therapy].
AB  - BACKGROUND: The purpose of the present study is to evaluate indications and
      contraindications, advisability and compliance of hormone replacement therapy
      (HRT) in women in the climacteric who, owing to the cessation of ovarian
      activity, face loss of the state of present and future wellbeing. METHODS: A
      series of 602 women who have attended the Menopause Centre of the II Division of
      the Department of Gynaecology and Obstetrics of the Second University of Naples
      in the period from 1/12/1998 to 10/4/2001. The diagnostic methodology adopted is
      outlined and the reasons for the prescription of HRT indicated. Patients who do
      not present contraindications were assessed in relation to the gravity of the
      climacteric syndrome and the likelihood of a future pathology bound up with the
      lack of estrogens. The intensity of the symptomatology was assessed on the basis
      of Kuppermann's nomogram. RESULTS: The cessation of ovarian activity occurred
      between the ages of 40 and 45 in 16.9% of cases while the percentage was 5.9%
      prior to the age of 40. Cases in which a climacteric syndrome was present
      numbered 147, or 24.2%. Women who present a cardiovascular risk represent a
      noteworthy percentage (27.1%). A high number of women are at osteoporotic risk:
      223, or 37.0%. Although it has a great number of indications, HRT is only
      prescribed in about half the patients. Stress is laid on the caution exercised by
      physicians in prescribing HRT and the diffidence of women in accepting it. Of the
      well-known contraindications to HRT the most common are those relative to the
      mammary risk. CONCLUSIONS: HRT was only prescribed for about half the women who
      came to our attention both as a result of the caution of the physicians who
      consider even relative contraindications peremptory, and because of the
      diffidence of a percentage of women with regard to such therapy. Alternative
      therapies to HRT are in fact a second valid choice, especially in the prevention
      of osteoporosis.

PMID- 12598841
TI  - [Induction of fetal lung maturation in the prevention of hyaline membrane
      disease: the connection with neonatal sepsis].
AB  - BACKGROUND: The aim of this study was to evaluate the effect of antenatal
      maternal corticosteroid treatment on the frequency of neonatal outcomes and
      perinatal infectious morbidity among singleton pregnancies complicated by preterm
      delivery. METHODS: A nonrandomized analysis was performed on 189 neonates of 24
      34 weeks' gestation who were born at the Department of Obstetrics and Gynecology,
      University of Udine, between January 2000 to December 2001. The neonates were
      subdivided into 3 groups: 1) 143 neonates received 2 doses of corticosteroids in
      a 24-hour interval and repeated after 10 days; 2) 26 neonates received 2 doses;
      3) 20 neonates did not receive any treatment. Data were analysed with the Fisher
      exact test. p<0.05 was considered significant. RESULTS: The incidence of
      respiratory distress syndrome (RDS), neonatal mortality and intraventricular
      hemorrhage was respectively 43.4%, 3.2 % and 6.3 %. The rate of early-onset
      neonatal sepsis was 4.9% in the 1st group, 3.9% in the 2nd group and 5% in the
      3rd group. There were no significant differences in the early-onset neonatal
      sepsis and the antenatal corticosteroids treatment. CONCLUSIONS: The single or
      the multiple courses of antenatal steroids did not apparently increase neonatal
      sepsis in patients with preterm delivery.

PMID- 12598843
TI  - [Intraepithelial cervical carcinoma and HIV. Prevalence, risk factors and
      prevention strategies].
AB  - BACKGROUND: The present study analyses cervical dysplastic lesions associated
      with HIV infection by means of cytological, colposcopic and histologic
      examinations, and the diagnostic accuracy of the Pap test. METHODS: Cross
      sectional study. We have studied colposcopic and histologic findings of 115 HIV
      positive women. In 86 patients a cytological examination was also carried out.
      The results were compared with those of a control group consisting of 127 HIV
      negative women in pre-menopause age. RESULTS: The prevalence of cervical
      dysplastic lesions present at colposcopic/bioptic examination was 3.2 times
      greater in HIV+ women than in HIV- women (38% vs 12%, p<0.001) and that of
      lesions of a higher degree 7 times greater. Compared to non-HIV+ women, patients
      who were positive presented more severe dysplastic lesions, a higher frequency of
      HPV-derived lesions and inflammatory pictures. There was also a correlation
      between high incidence of dysplastic cervical lesions and advanced stage of
      immunodepression. The negative predictive value of the Pap test was higher in the
      seronegatives (95%) than in the seropositives (83%, p<0.01). The overall
      agreement between cytology and colposcopy/histology was greater in the seronegati
      ves than in the seropositives (87% vs 74%, p<0.05). CONCLUSIONS: Cervical
      dysplastic lesions in seropositive patients are more frequent and aggressive than
      in HIV negatives and are related both to the degree of immunodepression and to
      the HPV infection. Further, the diagnostic value of the Pap test in association
      with HIV is reduced. These results suggest that in HIV+ patients careful combined
      cytological-colposcopic screening should be adopted, together with an attentive
      cyto-colposcopic follow-up in treated patients.

PMID- 12598844
TI  - [Diagnostic hysteroscopy in abnormal uterine bleeding. Five-years' experience].
AB  - BACKGROUND: Hysteroscopy has acquired a central role in the clinical diagnosis of
      intrauterine pathologies. This study evaluated the feasibility, procedure
      modality, tolerability, complications and diagnostic accuracy of hysteroscopy in
      the management of patients with abnormal uterine bleeding (AUB). METHODS: This
      retrospective study was carried out on 512 women (age range: 38-80 years, mean
      age: 63) with AUB who attended our hysteroscopy outpatient service from January
      1996 to December 2001. After undergoing transvaginal sonography, the patients
      were referred for further diagnostic studies. Ambulatory hysteroscopy without
      premedication was performed using a Hamou hysteroscope and physiological solution
      or CO(2) as distension medium. Guided biopsy with a Novak cannula completed the
      examination. When focal lesions were found, the patients were referred for
      surgical treatment (hysteroscopic resection, hysterectomy, etc.). Hysteroscopic
      and histologic findings were then compared. RESULTS: Locoregional or general
      anaesthesia was required in only 9.3% of cases to complete the examination.
      Overall, the examination was well tolerated; one case of serious complications
      (vagal syndrome which resolved rapidly) and 18 cases of shoulder blade pain were
      recorded. The hysteroscopic picture was normal in 25% of cases, benign pathology
      was diagnosed in 58.6% and suspected malignant neoplasia in 16.4%. Correlation
      rates between hysteroscopic and histologic diagnoses are reported for the various
      hysteroscopic pictures. CONCLUSIONS: Ambulatory hysteroscopy was shown to be a
      simple, safe, well tolerated and reliable procedure in the diagnosis of AUB
      across all age groups. Its widespread use can drastically reduce the need for
      conventional curettage, thereby increasing patient satisfaction and lowering
      costs.

PMID- 12598845
TI  - [Reliability of ultrasound examination confirmed at autopsy in foetuses suffering
      from Dandy-Walker Syndrome].
AB  - BACKGROUND: The Dandy-Walker Syndrome (DWS) is a congenital malformation of the
      structures of the posterior cranial fossa with failure of the Luschka and
      Magendie foramina, which connect the ventricular system to the subarachnoid
      space, to open. In this syndrome, the cerebellar vermis may be absent or
      hypoplastic, the hemispheres small, the encephalic trunk and cervical spinal bone
      marrow flattened, complete or partial absence of cerebellar vermis, cystic
      dilatation of IV ventricle and frequently hydrocephalus. METHODS: We evaluated 56
      cases of fetal malformations of the central nervous system from January 1998 to
      May 2001. Of these 56, 11 regarded the Dandy-Walker Syndrome. Ultrasound
      examinations were carried out at the 9(th) and 10(th) weeks, at the 21(st)-23(rd)
      weeks and at the 31(st) to 34(th) weeks of gestation so as to assess foetal
      anatomy and morphology. RESULTS: The results of the 11 pregnancies with Dandy
      Walker Syndrome were as follows: 3 spontaneous miscarriages (at the 15(th),
      18(th) and 20(th) weeks of gestation), 5 therapeutic abortions, 3 term
      pregnancies. Of the 3 newborns we were only able to follow the clinical course of
      two of them; both newborns underwent an intervention for ventriculo-peritoneal
      fluid derivation. At the moment both babies, aged respectively 30 and 25 months,
      are in good physical, intellectual and behavioural condition. CONCLUSIONS:
      Bearing in mind the notable clinical and socioeconomic importance of this
      malformation, we consider foetal morphological ultrasound to be a valid
      instrument for the correct management of pregnancy. Identification of lesions
      makes use of the comparison of ultrasound data with the results of
      histopathological examinations.

PMID- 12598846
TI  - [Amniotic fluid analysis as a screening test in term and post-term pregnancy].
AB  - BACKGROUND: To verify the hypothesis that isolated oligohydramnios in low-risk
      term or post-term pregnancy does not increase the risk of trauma to the fetus
      compared with a control group. METHODS: This prospective study compared a group
      of patients with low-risk pregnancy and oligohydramnios (AFI = or <50) and a
      control group which on ultrasonography performed 24 hours before delivery had an
      AFI volume >50 and = or <250 mm. The evaluation criteria included incidence of
      induction, modality of delivery and neonatal outcome. Statistical analysis was
      carried out using Student's "t"-test and the data set of categories was compared
      using the chi square test. RESULTS: From January 1997 to April 1999, 105 cases of
      oligohydramnios were compared with a control group (105 patients) matched for
      maternal age, gestation period and parity. The incidence of induction, fetal
      distress and variable deceleration was significantly higher in the group with AFI
      = or <50. The incidence of vacuum extractor, cesarean section, duration of labor
      and late deceleration did not differ between the two groups. No significant
      differences in neonatal outcome were found between the two groups. CONCLUSIONS:
      In patients with oligohydramnios without risk factors, the modality of delivery
      and neonatal outcome do not differ compared with those with normal amniotic fluid
      volume.

PMID- 12598847
TI  - [Primary lymphoma of the uterus. A case report].
AB  - Primary uterine lymphoma is a rare gynecologic cancer. Usually it involves rather
      the cervix than the uterine corpus and most of them are B-cell lymphomas. We
      describe a case of a 43-year old, asymptomatic patient, arrived observed for
      ureter dilatation due to a pelvic mass diagnosed by urography. The history of the
      patient, the presurgical clinical and radiological findings did not reveal any
      sign of uterine lymphoma. These difficulties show that at present it is not
      possible to make any prevention for this kind of cancer. The diagnosis of
      lymphoma was done at frozen section during surgery, but the final diagnosis is
      reached after two weeks. The patient underwent a debulking surgery of the mass,
      ureter cleaning with introduction of ureteral stent and a node sampling was done.
      The correct staging and the surgical and/or medical management of this cancer
      (not yet standardized) are the most important factors to improve the survival of
      these patients.

PMID- 12598848
TI  - [Factor V Leiden mutation. Successful outcome of a pregnancy after heparin
      therapy].
AB  - Several reports have highlighted the significant correlation between maternal
      thromboembolism pathologies, such as factor V Leiden mutation, and the occurrence
      of gestational pathologies. The main causes of thromboembolism pathologies are
      the inherited coagulopathies. The most common genetic predispositions include
      autosomal dominant inheritance coagulative factors deficiencies, such as
      antithrombin III (AT III), C protein (CP), S protein (SP), G20210A mutation,
      hyperomocystinemia and the activated C protein resistance, caused by factor V
      Leiden mutation. Maternal thromboembolism as an inherited coagulopathy
      expression, may be associated with high fetal-maternal morbidity and mortality
      rate. Nowadays, a wide screening is not possible, but the patients with previous
      or familiar deep venous thrombosis episodes should at least undergo very careful
      examinations. In the present case the patient's knowledge of her own status as a
      factor V Leiden mutation carrier , the prophylactic therapy performed, and the
      frequent fetal and maternal monitoring allowed us to avoid the recurrence of the
      dramatic events occurring during her first pregnancy.

PMID- 12598849
TI  - [Effects of tamoxifen and estrogen replacement therapy on lipid metabolism and
      some other cardiovascular risk factors. A prospective study in hysterectomised
      women].
AB  - BACKGROUND: The aim of this clinical study was to evaluate the relationship of
      tamoxifen and the risk factors of cardiovascular disease in hysterectomised
      women. METHODS: Between 1992 and 1998, 93 women were recruited for a prospective
      study with follow-up at 0, 12 and 24 months. All women had an increased risk of
      breast cancer and they were hysterectomised and ovariectomised for a benign
      pathology. They were divided according to the following categories: Group A was
      constituted of 26 (28%) symptomatic patients (hot flushes, depression) who had
      received tamoxifen and oral conjugated estrogens. Group B was constituted of 27
      (29%) symptomatic patients who had received tamoxifen and transdermal 17B
      estradiol. Group C was constitued of 19 (21%) asymptomatic patients who had
      received only tamoxifen. Group D (control) was constitued of 21 (22%)
      asymptomatic patients who had not received any therapy. A venous blood sample for
      total cholesterol levels (T-C), high-density lipoprotein-cholesterol (HDL-C), low
      density lipoprotein-cholesterol (LDL-C), triglycerides (TRG), fibrinogen (FBR),
      platelets (PLT) and antithrombin III (AT III) was taken during follow-up. ANOVA
      (repeated measures) was used to assess statistical significance: p<0.05 was
      considered significant (95% CI). RESULTS: The patients who received tamoxifen
      with or without estrogen replacement therapy showed after 24 months, a reduction
      of T-C, LDL-C and FBR (p<0.01); the HDL-C levels did not vary significantly
      compared to the control group (p=NS); the 26 patients of group A showed an
      increase of HDL-C (p<0.02). We reported an increase of TRG in the patients of
      group A and C (p<0.05); on the contrary, we obtained a significant reduction of
      TRG (p<0.01) in the patients who received tamoxifen and transdermal 17B-estradiol
      (group B). There was no interaction on plateled count (p=NS). CONCLUSIONS: These
      results suggest the administration of tamoxifen in hysterectomised women with a
      high risk of breast cancer and without climateric symptoms. In these patients,
      tamoxifen could reduce coronary heart disease and incidence of breast cancer. The
      symptomatic patients are suggested to receive tamoxifen and transdermal 17B
      estradiol because of the better effects on lipid metabolism.

PMID- 12598850
TI  - [Serious postpartum hemorrhage].

PMID- 12598851
TI  - High-dose chemotherapy: changes in approaches and applications.

PMID- 12598852
TI  - Hematopoietic stem cells and hematopoiesis.
AB  - BACKGROUND: The highly orchestrated process of blood cell development and
      homeostasis is termed "hematopoiesis." Understanding the biology of hematopoietic
      stem cells as well as hematopoiesis is important to developing improved
      treatments for hematologic malignancies, congenital disorders, chemotherapy
      related cytopenias, and blood and marrow transplants. METHODS: The author reviews
      the current state of the art regarding hematopoietic stem cells and
      hematopoiesis. RESULTS: Several new concepts, including stem cell plasticity,
      suggest the possibility that stem cells may have the ability to differentiate
      into other tissues in addition to blood cells. CONCLUSIONS: While much is known
      about hematopoietic stem cells and hematopoiesis, much remains to be clarified
      about the environmental and genetic processes that govern the growth and
      development of the blood system. In addition, careful studies remain to be
      conducted to determine whether hematopoietic stem cells can differentiate into
      extra-hematopoietic tissues.

PMID- 12598853
TI  - Nonmyeloablative allogeneic stem-cell transplantation for hematologic
      malignancies: a systematic review.
AB  - BACKGROUND: Increasingly, clinicians advocate the use of nonmyeloablative
      allogeneic stem-cell transplants (NM-allo-SCTs, "mini-transplants") to manage
      hematologic malignancies. They hypothesize that NM-allo-SCT is equally
      efficacious to standard allo-SCT but produces less regimen-related toxicity.
      METHODS: To analyze available evidence on the benefits and harms of "mini
      transplants," we identified 23 manuscripts, 1 abstract, and 1 letter that
      reported the outcome of mini-transplants in hematologic malignancies. RESULTS:
      Data were compiled on 603 treated patients, with 118 transplants using stem cells
      from matched unrelated donors. All studies were small prospective case series,
      and most lacked concurrent or historical controls. Outcomes of interest were not
      uniformly reported. The studies were heterogeneous and used different patient
      selection criteria, conditioning regimens, and timing of transplant with respect
      to disease status. The transplant-related mortality rate was 32%, the relapse
      rate was 15%, and toxicities included acute and chronic graft-vs-host disease and
      veno-occlusive disease. The aggregate rate of complete remission was 45%.
      Survival at 1 year or longer ranged from 30% to 60% at 1 to 5 years of follow-up.
      All studies reported successful chimerism. CONCLUSIONS: Disease-specific studies
      with longer follow-up are needed to evaluate this potentially promising therapy.

PMID- 12598855
TI  - High-dose chemotherapy in adult patients with germ cell tumors.
AB  - BACKGROUND: Approximately 80% of patients with advanced germ cell tumors (GCTs)
      can be cured with cisplatin-based chemotherapy. Patients with poor-prognosis
      disease have a cure rate of only 50%, whereas patients with first relapse have
      only a 25% chance of prolonged survival and potential cure following standard
      therapy. High-dose chemotherapy (HDC) is being investigated in patients with GCTs
      to improve the results of salvage treatment and in first-line setting for poor
      prognosis disease. METHODS: The authors review the results of the clinical trials
      that have evaluated the role of HDC in GCT patients. Data were obtained using a
      computer-assisted MEDLINE search, and meeting abstracts with clinical relevance
      in this field were hand-searched. Open randomized phase III studies are described
      and examined. RESULTS: Several phase II studies have shown a possible benefit for
      patients with recurrent disease, but the preliminary results of a phase III
      randomized trial did not demonstrate a survival advantage for HDC after three
      courses of standard-dose chemotherapy in the salvage therapy of patients in whom
      first-line treatment has failed. Three prospective, randomized trials are
      evaluating the role of HDC in a first-line setting. CONCLUSIONS: New HDC
      strategies are emerging, involving new drugs (eg, paclitaxel), intensive
      induction regimens, and upfront and/or multiple courses of HDC. The evaluation of
      mature data of randomized trials will better define the role of HDC in this
      disease.

PMID- 12598854
TI  - High-dose chemotherapy for breast cancer: the French PEGASE experience.
AB  - BACKGROUND: Early studies of high-dose chemotherapy (HDC) for breast cancer were
      limited by small numbers and the lack of adequate control groups. The French
      PEGASE Group was founded to perform larger and properly randomized comparative
      studies of this approach. METHODS: The program was created to determine the
      effects of intensive chemotherapy for breast cancer. The seven PEGASE protocols
      addressed HDC as adjuvant therapy (01 and 06) and as treatment for inflammatory
      nonmetastatic disease (02, 05, and 07) and metastatic disease (03 and 04). Two of
      these protocols are ongoing. RESULTS: The PEGASE 01 adjuvant therapy trial showed
      that 3-year disease-free survival was significantly better in the HDC arm but
      overall survival was unchanged. The ongoing phase III 06 trial is studying a
      higher dosage regimen. The HDC trials for metastatic and inflammatory
      nonmetastatic disease are encouraging. CONCLUSIONS: Many clinicians no longer
      subscribe to the concept of HDC for breast cancer. Overall outcomes from
      management of poor-risk breast cancer remain poor, however, and it is possible
      that some selected subgroups of patients may benefit from such an approach.

PMID- 12598856
TI  - Intense immunosuppression and stem-cell transplantation for patients with severe
      rheumatic autoimmune disease: a review.
AB  - BACKGROUND: Intense immunosuppression plus stem-cell transplantation (SCT) has
      emerged as a new treatment modality for patients with refractory, severe
      rheumatic autoimmune disease. Its rationale is based on eliminating
      autoaggressive lymphocytes by lympho- or myeloablative conditioning followed by
      stem-cell rescue. Preclinical studies in animal models of autoimmune disease and
      observations in patients with rheumatoid arthritis (RA) who were cured after
      allogeneic bone marrow transplantation for concomitant hematologic malignancy
      have provided support for the concept. METHODS: The authors reviewed the results
      of recent phase I/II studies and data from the EBMT/EULAR Registry on more than
      400 patients with autoimmune diseases including RA, systemic lupus erythematosus
      (SLE), systemic sclerosis (SSc), and juvenile idiopathic arthritis (JIA).
      RESULTS: Toxicity resulting from stem-cell grafting depended on underlying
      disease and the intensity of the conditioning regimen. Treatment-related
      mortality was low in RA (1.4%) but relatively high (>10%) in patients with JIA,
      SLE, and SSc, possibly related to visceral involvement in these patients. With
      the application of uniform and strict criteria, safety has improved. Long-term
      remissions up to 4 years have been observed in SSc and JIA, while relatively more
      relapses have occurred in patients with SLE and RA. Sensitivity to antirheumatic
      drugs was restored in RA and SLE patients, however, resulting in improved disease
      control. CONCLUSIONS: Intense immunosuppression and SCT may be an effective
      therapy for selected patients with severe rheumatic autoimmune disease. Its
      merits need to be proven via multicenter phase III studies by comparing efficacy
      and safety with conventional therapy.

PMID- 12598857
TI  - Three questions about costs and cancer clinical trials.

PMID- 12598858
TI  - Catheter-related bloodstream infections, part II: specific pathogens and
      prevention.

PMID- 12598859
TI  - Leadership and followership.

PMID- 12598860
TI  - Nursing intervention for grooming of elders with mild cognitive impairments in
      Korea.
AB  - This study explores the effect of behavioral nursing intervention strategies to
      improve the grooming performance of elders with cognitive impairments in Korea.
      Eight residents with mild cognitive impairments were chosen in a special dementia
      care facility. A total of 21 sessions, including baseline, interventions, and
      postinterventions for each resident, were collected in the morning by using
      videotaped recordings of face-washing, toothbrushing, and hair-combing. The
      baselines of these activities and postinterventions were provided by nurse
      assistants, and the interventions were implemented by a trained nurse. The effect
      of Performance of Grooming Tasks (PGT) was determined. The results showed a
      decrease in assistance of PGT scores from 0.86, 0.77, and 0.73 at baseline to
      0.60, 0.45, and 0.57 during intervention and an increase to 0.77, 0.71, and 0.71
      at postintervention. The study showed a significant increase in grooming
      independence of elders with dementia in the nursing home when they were cared for
      with behavioral nursing intervention strategies.

PMID- 12598862
TI  - Practice guidelines for recreation therapy in the care of people with dementia.
AB  - Activity is a basic human need expressed in work and leisure pursuits.
      Unfortunately, people with dementia have a low rate of activity participation
      because of associated physical and cognitive constraints. Recently, the American
      Therapeutic Recreation Association (ATRA) held a consensus meeting to address
      this issue and formulate practice guidelines for recreation therapy in the care
      of people with dementia. The consensus document presents an evidence-based
      intervention theory that draws on the science of two disciplines: nursing and
      recreation therapy. This article reports on the ATRA guidelines and illustrates
      their applicability in a case study of a resident with severe aggression
      associated with dementia.

PMID- 12598863
TI  - An anthropological perspective of Alzheimer disease.
AB  - This article deals with Alzheimer disease (AD) from an anthropological
      perspective. It describes the basis of my research: social representations and
      practices with regard to Alzheimer dementia. An analysis of the sociocultural
      construction of the AD process and the practices of caring for people who have it
      can improve nursing practice in this field. This approach helps us achieve a
      better understanding of this condition and provides a framework for providing
      care in a more appropriate and contextualized way. To achieve this aim, my
      research is based on three points of analysis derived from the main axes: the
      domestic and family context of Alzheimer dementia, the biomedical discourse and
      social construction of the condition, and the loss of self and social death of
      the person with AD.

PMID- 12598864
TI  - Alzheimer disease support group characteristics: A comparison of caregivers.
AB  - Although family members are known to continue to be involved in care after
      admitting a loved one with Alzheimer disease into a long-term care (LTC)
      facility, little research has been done regarding the psychosocial support
      requirements of these caregivers. Of the 55 caregivers surveyed in this study, 13
      had care recipients living in LTC, and 42 had recipients living at home. Results
      were studied to see if differences arose in the needs of these two groups and if
      current support groups met those needs. Data indicated that caregivers with
      relatives in LTC facilities were older and had less interest in receiving
      information on a variety of subjects. However, both groups indicated having
      feelings of reassurance after attending support group meetings.

PMID- 12598865
TI  - Alzheimer disease from a child's perspective.
AB  - Alzheimer disease (AD) directly afflicts several million people in the United
      States, but it also affects millions more who love and care for them. Young
      children are especially vulnerable because of a lack of understanding or
      inability to cope. The progression of AD varies greatly with each individual, but
      the signs and symptoms are common. Children's reactions to these indications
      differ depending on a multitude of variables. Honesty and simplicity are the
      basis for discussing AD with children. Shared experiences between these
      generations can be pleasurable and beneficial as long as certain considerations
      are regarded. The health care provider should include these topics when providing
      holistic care to patients with AD.

PMID- 12598866
TI  - The Care Dependency Scale: an assessment instrument for elderly patients in
      German hospitals.
AB  - The purpose of the study was to examine aspects of reliability and validity of
      the German version of the Care Dependency Scale (CDS), a Dutch assessment
      instrument originally developed for demented and mentally handicapped patients.
      Data of 1806 patients, 60 years or older from a larger sample, collected in 11
      hospitals in Germany, were analyzed. Reliability was determined by Cronbach's
      alpha, showing a very good result with a value of.98. Criterion related validity
      was examined by comparing the data of the CDS with the German nursing personal
      regulation. The scores of the CDS correlate to the scores of the personal
      regulation. The study shows further that most elders are fairly independent and
      care dependency increases with age.

PMID- 12598868
TI  - The geriatric nurse as witness: tips for effective testimony.

PMID- 12598871
TI  - General nurse practitioner guidelines: dementia with Lewy bodies.

PMID- 12598872
TI  - A home care update.

PMID- 12598873
TI  - Maintaining cognitive function with diet.

PMID- 12598874
TI  - Steps taken toward improving dementia treatment during 2002.

PMID- 12598876
TI  - Payment for CPD allowances.

PMID- 12598875
TI  - Modern management of acute myocardial infarction.

PMID- 12598877
TI  - Cutaneous reaction to carbamazepine.

PMID- 12598878
TI  - Irrational therapies.

PMID- 12598879
TI  - Further statistics in dentistry. Part 9: Bayesian statistics.
AB  - Statistics can be defined as the methods used to assimilate data, so that
      guidance can be given, and conclusions drawn, in situations which involve
      uncertainty. In particular, statistical inference is concerned with drawing
      conclusions about particular aspects of a population when that population cannot
      be studied in full. Uncertainty arises here because the totality of the
      information is not available. Instead, to make inferences about the population,
      it is necessary to rely on a sample of data which is selected from the
      population; this sample data may be augmented, in certain circumstances, by
      auxiliary information which is obtained independently of the sample data.
      Clearly, uncertainty lies at the heart of statistics and statistical inference.
      This uncertainty is measured by a probability which therefore forms the crux of
      statistics and must be properly understood in order to interpret a statistical
      analysis.

PMID- 12598880
TI  - Who will provide dental care for housebound people with oral problems?
AB  - There are currently 9(1/2) million people in England and Wales over retirement
      age and nearly 4 million of these are over 75 years. Age itself is not a disease
      and 70% of the population over 65 are functionally independent. However, ageing
      is associated with an increase in the prevalence of chronic disease and
      disability and 20% of people over 65 years are frail and a further 10% are
      functionally dependent, either homebound or institutionalised. The implications
      of this demographic change on oral health has been investigated. Reports show
      oral health for the well elderly is improving, creating a demand for dental
      services, which this group are able to access, but maintenance of oral health and
      access to dental treatment is a problem for disabled elderly people, who, for
      their daily activity are dependent on carers.

PMID- 12598881
TI  - A view from the bodies corporate. 6. Oasis Dental Care Ltd. Interview by F.
      Stuart-Wilson.
AB  - Peter Brook and I finally meet in London on the third attempt at getting together
      for an interview. However, the fates which seemed to conspire against us with
      hindsight seemed to be working for us, as when we do meet before Christmas he is
      able to tell me about not just one, but two major acquisitions. The acquisitions
      of Ora Dental Care and Dencare mean that he is now Group Clinical Director of a
      corporate with 124 sites, making Oasis one of the largest players in the market.

PMID- 12598885
TI  - An investigation into the comparative efficacy of soluble aspirin and solid
      paracetamol in postoperative pain after third molar surgery.
AB  - OBJECTIVE: To compare the efficacy of soluble aspirin 900 mg and paracetamol
      1,000 mg in patients with postoperative pain after third molar surgery. DESIGN: A
      randomised, placebo controlled, double-blind study. SETTING: Day stay units of
      Oral and Maxillofacial Surgery at Cardiff Dental Hospital and Hexham General
      Hospital, Northumberland. SUBJECTS AND METHODS: One hundred and sixty-seven (104
      female) patients who required the removal of their impacted third molars under
      general anaesthesia. INTERVENTION: In the early postoperative period, patients
      were medicated with either a single dose of soluble aspirin 900 mg, solid
      paracetamol 1,000 mg or placebo. MAIN OUTCOME MEASURES: Pain intensity was
      measured on 100 mm visual analogue scales at 0, 5, 10, 15, 20, 30, 45, 60, 90,
      120 and 240 minutes after dosing. Other efficacy variables evaluated included
      time to rescue medication and an overall assessment of the study medication
      efficacy by the patient on completion of the study. RESULTS: One hundred and
      sixty-seven patients consented to take part in the study, but only 153 were
      medicated. Of the 14 patients not treated, 10 failed to develop sufficient pain
      to enter the study, two withdrew consent, one had an adverse reaction to the
      general anaesthetic and one was a protocol violator. Over the four hour
      investigation period, patients treated with soluble aspirin reported
      significantly less pain when compared with those treated with paracetamol (mean
      difference in AUC(0-240) = -2001, 95% CI -3893 to -109, p=0.038) and placebo
      (mean difference in AUC(0-240) = -3470, 95% CI -5719 to -1221, p=0.003).
      Similarly, at 20 and 30 minutes after dosing, patients in the soluble aspirin
      group were reporting significantly less pain than those in the paracetamol
      treatment group (mean difference in pain intensity: at 20 minutes -7.9, 95% CI 
      15.3 to -0.6, p=0.035; at 30 minutes -10.6, 95% CI -18.6 to -2.6, p=0.010). There
      were no significant differences between treatment groups with respect to the
      number of patients requiring rescue medication, however the time to dosing was
      significantly longer for those taking soluble aspirin when compared with placebo
      (hazard ratio 2.34, 95% CI 1.41 to 3.88, p<0.001). CONCLUSION: The findings from
      this study showed that soluble aspirin 900 mg provides significant and more rapid
      analgesia than paracetamol 1,000 mg in the early postoperative period after third
      molar surgery.

PMID- 12598886
TI  - Preventive dentistry: what do Australian patients endorse and recall of smoking
      cessation advice by their dentists?
AB  - OBJECTIVE: To investigate patients' views regarding dentists' smoking cessation
      advice. DESIGN: Survey questionnaire. SETTING: One hundred and thirty five dental
      practices in Sydney Australia. Subjects Two thousand, four hundred and fifty one
      dental patients. RESULTS: One thousand, one hundred and sixty pre-consultation
      questionnaires were obtained (RR=80%), 302 (26%) were self-reported smokers. From
      these, 623 post-consultation questionnaires were returned (RR = 54%). Most
      patients expected dentists to be interested in their smoking status (n =
      847/1160, 73%, 95% CI: 70% to 76%) and to discuss smoking with them (n =
      713/1160, 61%, 95% CI: 59% to 64%), however, smokers were significantly less
      likely to respond as such compared with non-smokers (P < 0.001). Smokers and non
      smokers equally would not change dentist even if asked about their smoking status
      opportunistically (59% versus 62%) (OR = 0.91, 95% CI: 0.67 to 1.22). Less than
      one third of all smokers would try to quit if their dentist suggested they do so
      (n = 90/302, 30%, 95% CI: 25% to 35%). Smokers' recall of quit advice from their
      recent consultation was low (n = 22/124, 18%). CONCLUSIONS: Smoking cessation
      advice by dentists is not self-evidently effective. These findings behove
      interventional research to ascertain efficacy of smoking cessation advice
      delivered by dentists before admonishing changes in routine clinical practice.

PMID- 12598887
TI  - Bridging the gap--vocational trainee to senior house officer: a new induction
      course.
AB  - OBJECTIVES: The objectives of this course were: to develop an induction course
      for vocational trainees taking up first SHO posts; to enable new dental SHOs to
      have enhanced skills from the beginning of the post; to create safe practitioners
      capable of performing SHO duties; and to assess whether such a course is
      perceived to be beneficial by the SHOs, their educational supervisors and
      professional colleagues from medicine, dentistry and nursing. DESIGN: A 5-day
      intensive, interactive course was developed and directed by a consultant
      maxillofacial surgeon, with contributions from a range of professional colleagues
      to teach appropriate knowledge, skills and attitudes. SUBJECTS: Trainees
      completing the VT programme; due to commence SHO posts in the Yorkshire Region.
      EVALUATION METHOD: Detailed daily and end of course questionnaires were
      completed. A post course; in-work evaluation was sought from the trainees,
      educational supervisors and a range of professional colleagues about the validity
      of the course. RESULTS: Daily and end of course evaluations were positive about
      the perceived importance and relevance of the course. After 6 weeks in post the
      SHOs continued to place high value on the course as a preparation for hospital
      practice. Feedback from the supervisors and colleagues indicated that the SHOs
      were performing well, but the influence of the course on performance could not be
      determined in this study. CONCLUSION: It was possible to design and deliver an
      appropriate induction course, which appeared to meet most of the needs of new
      dental SHOs. Feedback indicated the need for modification of some aspects of the
      course.

PMID- 12598891
TI  - A novel protein-mineral interface.
AB  - Transferrins transport Fe3+ and other metal ions in mononuclear-binding sites. We
      present the first evidence that a member of the transferrin superfamily is able
      to recognize multi-nuclear oxo-metal clusters, small mineral fragments that are
      the most abundant forms of many metals in the environment. We show that the
      ferric ion-binding protein from Neisseria gonorrhoeae (nFbp) readily binds
      clusters of Fe3+, Ti4+, Zr4+ or Hf4+ in solution. The 1.7 A resolution crystal
      structure of Hf-nFbp reveals three distinct types of clusters in an open,
      positively charged cleft between two hinged protein domains. A di-tyrosyl cluster
      nucleation motif (Tyr195-Tyr196) is situated at the bottom of this cleft and
      binds either a trinuclear oxo-Hf cluster, which is capped by phosphate, or a
      pentanuclear cluster, which in turn can be capped with phosphate. This first high
      resolution structure of a protein-mineral interface suggests a novel metal-uptake
      mechanism and provides a model for protein-mediated mineralization/dissimilation,
      which plays a critical role in geochemical processes.

PMID- 12598892
TI  - Structure and function of archaeal box C/D sRNP core proteins.
AB  - Nop56p and Nop58p are two core proteins of the box C/D snoRNPs that interact
      concurrently with fibrillarin and snoRNAs to function in enzyme assembly and
      catalysis. Here we report the 2.9 A resolution co-crystal structure of an
      archaeal homolog of Nop56p/Nop58p, Nop5p, in complex with fibrillarin from
      Archaeoglobus fulgidus (AF) and the methyl donor S-adenosyl-L-methionine. The N
      terminal domain of Nop5p forms a complementary surface to fibrillarin that serves
      to anchor the catalytic subunit and to stabilize cofactor binding. A coiled coil
      in Nop5p mediates dimerization of two fibrillarin-Nop5p heterodimers for optimal
      interactions with bipartite box C/D RNAs. Structural analysis and complementary
      biochemical data demonstrate that the conserved C-terminal domain of Nop5p
      harbors RNA-binding sites. A model of box C/D snoRNP assembly is proposed based
      on the presented structural and biochemical data.

PMID- 12598893
TI  - Suppression of experimental autoimmune encephalomyelitis by selective blockade of
      encephalitogenic T-cell infiltration of the central nervous system.
AB  - Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the
      central nervous system (CNS) in which T cells that are reactive with major
      components of myelin sheaths have a central role. The receptor for advanced
      glycation end products (RAGE) is present on T cells, mononuclear phagocytes and
      endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in
      MS and in the related rodent model, experimental autoimmune encephalomyelitis
      (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic
      protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred
      spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR
      alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of
      the CNS by immune and inflammatory cells. Transgenic mice with targeted
      overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP
      induced EAE. These data reinforce the importance of RAGE-ligand interactions in
      modulating properties of CD4+ T cells that infiltrate the CNS.

PMID- 12598894
TI  - Cell-permeable peptides improve cellular uptake and therapeutic gene delivery of
      replication-deficient viruses in cells and in vivo.
AB  - Small polybasic peptides derived from the transduction domains of certain
      proteins, such as the third alpha-helix of the Antennapedia (Antp) homeodomain,
      can cross the cell membrane through a receptor-independent mechanism. These cell
      permeable molecules have been used as 'Trojan horses' to introduce biologically
      active cargo molecules such as DNA, peptides or proteins into cells. Using these
      cell-permeable peptides, we have developed an efficient and simple method to
      increase virally mediated gene delivery and protein expression in vitro and in
      vivo. Here, we show that cell-permeable peptides increase viral cell entry,
      improve gene expression at reduced titers of virus and improve efficacy of
      therapeutically relevant genes in vivo.

PMID- 12598895
TI  - Transcriptional profiling identifies Id2 function in dendritic cell development.
AB  - Dendritic cells (DCs) are potent antigen-presenting cells with a pivotal role in
      antigen-specific immune responses. Here, we found that the helix-loop-helix
      transcription factor Id2 is up-regulated during DC development in vitro and
      crucial for the development of distinct DC subsets in vivo. Id2-/- mice lack
      Langerhans cells (LCs), the cutaneous contingent of DCs, and the splenic
      CD8alpha+ DC subset is markedly reduced. Mice deficient for transforming growth
      factor (TGF)-beta also lack LCs, and we demonstrate here that, in DCs, TGF-beta
      induces Id2 expression. We also show that Id2 represses B cell genes in DCs.
      These findings reveal a TGF-beta-Id2 signaling pathway in DCs and suggest a
      mechanism by which Id2 affects the lineage choice of B cell and DC progenitors.

PMID- 12598896
TI  - An essential role for tripeptidyl peptidase in the generation of an MHC class I
      epitope.
AB  - Most of the peptides presented by major histocompatibility complex (MHC) class I
      molecules require processing by proteasomes. Tripeptidyl peptidase II (TPPII), an
      aminopeptidase with endoproteolytic activity, may also have a role in antigen
      processing. Here, we analyzed the processing and presentation of the
      immunodominant human immunodeficiency virus epitope HIV-Nef(73-82) in human
      dendritic cells. We found that inhibition of proteasome activity did not impair
      Nef(73-82) epitope presentation. In contrast, specific inhibition of TPPII led to
      a reduction of Nef(73-82) epitope presentation. We propose that TPPII can act in
      combination with or independent of the proteasome system and can generate
      epitopes that evade generation by the proteasome-system.

PMID- 12598897
TI  - Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to
      gastric ulcer induction by VacA of Helicobacter pylori.
AB  - The vacuolating cytotoxin VacA produced by Helicobacter pylori causes massive
      cellular vacuolation in vitro and gastric tissue damage in vivo, leading to
      gastric ulcers, when administered intragastrically. Here we report that mice
      deficient in protein tyrosine phosphatase receptor type Z (Ptprz, also called PTP
      zeta or RPTP-beta, encoded by Ptprz) do not show mucosal damage by VacA, although
      VacA is incorporated into the gastric epithelial cells to the same extent as in
      wild-type mice. Primary cultures of gastric epithelial cells from Ptprz+/+ and
      Ptprz-/- mice also showed similar incorporation of VacA, cellular vacuolation and
      reduction in cellular proliferation, but only Ptprz+/+ cells showed marked
      detachment from a reconstituted basement membrane 24 h after treatment with VacA.
      VacA bound to Ptprz, and the levels of tyrosine phosphorylation of the G protein
      coupled receptor kinase-interactor 1 (Git1), a Ptprz substrate, were higher after
      treatment with VacA, indicating that VacA behaves as a ligand for Ptprz.
      Furthermore, pleiotrophin (PTN), an endogenous ligand of Ptprz, also induced
      gastritis specifically in Ptprz+/+ mice when administered orally. Taken together,
      these data indicate that erroneous Ptprz signaling induces gastric ulcers.

PMID- 12598898
TI  - Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan
      syndrome.
AB  - Marfan syndrome is an autosomal dominant disorder of connective tissue caused by
      mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix
      component of extracellular microfibrils. A distinct subgroup of individuals with
      Marfan syndrome have distal airspace enlargement, historically described as
      emphysema, which frequently results in spontaneous lung rupture (pneumothorax;
      refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we
      analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model
      of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal
      period and manifest as a developmental impairment of distal alveolar septation.
      Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with
      the view that early developmental perturbations can predispose to late-onset,
      seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have
      marked dysregulation of transforming growth factor-beta (TGF-beta) activation and
      signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of
      TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data
      indicate that matrix sequestration of cytokines is crucial to their regulated
      activation and signaling and that perturbation of this function can contribute to
      the pathogenesis of disease.

PMID- 12598899
TI  - Extracellular amyloid formation and associated pathology in neural grafts.
AB  - Amyloid precursor protein (APP) processing and the generation of beta-amyloid
      peptide (Abeta) are important in the pathogenesis of Alzheimer's disease.
      Although this has been studied extensively at the molecular and cellular levels,
      much less is known about the mechanisms of amyloid accumulation in vivo. We
      transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the
      neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type
      hosts did not develop amyloid deposits up to 20 months after grafting. In
      contrast, both transgenic and wild-type grafts into young transgenic hosts
      developed amyloid plaques as early as 3 months after grafting. Although largely
      diffuse in nature, some of the amyloid deposits in wild-type grafts were
      congophilic and were surrounded by neuritic changes and gliosis, similar to the
      amyloid-associated pathology previously described in APP23 mice. Our results
      indicate that diffusion of soluble Abeta in the extracellular space is involved
      in the spread of Abeta pathology, and that extracellular amyloid formation can
      lead to neurodegeneration.

PMID- 12598900
TI  - Oxytocin improves long-lasting spatial memory during motherhood through MAP
      kinase cascade.
AB  - Oxytocin is an essential hormone for mammalian labor and lactation. Here, we show
      a new function of oxytocin in causing plastic changes in hippocampal synapses
      during motherhood. In oxytocin-perfused hippocampal slices, one-train tetanus
      stimulation induced long-lasting, long-term potentiation (L-LTP) and
      phosphorylation of cyclic AMP-responsive element binding protein (CREB), and MAP
      kinase inhibitors blocked these inductions. An increase in CREB phosphorylation
      and L-LTP induced by one-train tetanus were observed in the multiparous mouse
      hippocampus without oxytocin application. Furthermore, intracerebroventricular
      injection of oxytocin in virgin mice improved long-term spatial learning in vivo,
      whereas an injection of oxytocin antagonist in multiparous mice significantly
      inhibited the improved spatial memory, L-LTP and CREB phosphorylation. These
      findings indicate that oxytocin is critically involved in improving hippocampus
      dependent learning and memory during motherhood in mice.

PMID- 12598901
TI  - Mutated APC and Asef are involved in the migration of colorectal tumour cells.
AB  - The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and
      familial colorectal tumours. APC binds to beta-catenin, a key component of the
      Wnt signalling pathway, and induces its degradation. APC interacts with
      microtubules and accumulates at their plus ends in membrane protrusions, and
      associates with the plasma membrane in an actin-dependent manner. In addition,
      APC interacts with the Rac-specific guanine nucleotide exchange factor Asef and
      stimulates its activity, thereby regulating the actin cytoskeletal network and
      cell morphology. Here we show that overexpression of Asef decreases E-cadherin
      mediated cell-cell adhesion and promotes the migration of epithelial Madin-Darby
      canine kidney cells. Both of these activities are stimulated by truncated APC
      proteins expressed in colorectal tumour cells. Experiments based on RNA
      interference and dominant-negative mutants show that both Asef and mutated APC
      are required for the migration of colorectal tumour cells expressing truncated
      APC. These results suggest that the APC-Asef complex functions in cell migration
      as well as in E-cadherin-mediated cell-cell adhesion, and that truncated APC
      present in colorectal tumour cells contributes to their aberrant migratory
      properties.

PMID- 12598902
TI  - Redox-dependent downregulation of Rho by Rac.
AB  - Rac and Rho GTPases function as critical regulators of actin cytoskeleton
      remodelling during cell spreading and migration. Here we demonstrate that Rac
      mediated reactive oxygen species (ROS) production results in the downregulation
      of Rho activity. The redox-dependent decrease in Rho activity is required for Rac
      induced formation of membrane ruffles and integrin-mediated cell spreading. The
      pathway linking generation of ROS to downregulation of Rho involves inhibition of
      the low-molecular-weight protein tyrosine phosphatase (LMW-PTP) and then an
      increase in the tyrosine phosphorylation and activation of its target, p190Rho
      GAP. Our findings define a novel mechanism for the coupling of changes in
      cellular redox state to the control of actin cytoskeleton rearrangements by Rho
      GTPases.

PMID- 12598903
TI  - A non-proteolytic function of separase links the onset of anaphase to mitotic
      exit.
AB  - Separase is a protease that triggers chromosome segregation at anaphase onset by
      cleaving cohesin, the chromosomal protein complex responsible for sister
      chromatid cohesion. After anaphase, cells exit from mitosis; that is, they
      complete downregulation of cyclin-dependent kinase activity, undergo cytokinesis
      and enter G1 of the next cell cycle. Here we show that separase activation at the
      onset of anaphase is sufficient to promote release from the nucleolus and
      activation of the budding yeast phosphatase, Cdc14, a key step in mitotic exit.
      The ability of separase to activate Cdc14 is independent of its protease function
      but may involve promoting phosphorylation of the Cdc14 inhibitor Net1. This novel
      separase function is coregulated with its proteolytic activity by the separase
      inhibitor securin. This helps to explain the coupling of anaphase and mitotic
      exit--after securin degradation at anaphase onset, separase cleaves cohesin to
      trigger chromosome segregation and concurrently uses a non-proteolytic mechanism
      to initiate mitotic exit.

PMID- 12598904
TI  - Spontaneous receptor-independent heterotrimeric G-protein signalling in an RGS
      mutant.
AB  - Tripartite G-protein-coupled receptors (GPCRs) represent one of the largest
      groups of signal transducers, transmitting signals from hormones, neuropeptides,
      odorants, food and light. Ligand-bound receptors catalyse GDP/GTP exchange on the
      G-protein alpha-subunit (Galpha), leading to alpha-GTP separation from the
      betagamma subunits and pathway activation. Activating mutations in the receptors
      or G proteins underlie many human diseases, including some cancers, dwarfism and
      premature puberty. Regulators of G-protein signalling (RGS proteins) are known to
      modulate the level and duration of ligand-induced signalling by accelerating the
      intrinsic GTPase activity of the Galpha subunit, and thus reformation of the
      inactive GDP-bound Galpha. Here we find that even in the absence of receptor,
      mutation of the RGS family member Sst2 (refs 6-9) permits spontaneous activation
      of the G-protein-coupled mating pathway in Saccharomyces cerevisiae at levels
      normally seen only in the presence of ligand. Our work demonstrates the
      occurrence of spontaneous tripartite G-protein signalling in vivo and identifies
      a requirement for RGS proteins in preventing such receptor-independent
      activation.

PMID- 12598905
TI  - Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK
      cascade.
AB  - Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes,
      osteoblasts and other cells. Balanced cytodifferentiation of stem cells is
      essential for the formation and maintenance of bone marrow; however, the
      mechanisms that control this balance remain largely unknown. Whereas cytokines
      such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit
      adipogenesis, the ligand-induced transcription factor peroxisome proliferator
      activated receptor-gamma (PPAR-gamma), is a key inducer of adipogenesis.
      Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals
      might occur during adipogenesis. Here we show that the ligand-induced
      transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and
      that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF
      kappaB-inducing kinase (NIK) cascade, a downstream cascade associated with IL-1
      and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation
      function by mitogen-activated protein kinase-induced growth factor signalling
      through phosphorylation of the A/B domain, NF-kappaB blocks PPAR-gamma binding to
      DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC
      2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may
      alter the fate of pluripotent mesenchymal stem cells, directing cellular
      differentiation towards osteoblasts rather than adipocytes by suppressing PPAR
      gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.

PMID- 12598906
TI  - p53RDL1 regulates p53-dependent apoptosis.
AB  - Although a number of targets for p53 have been reported, the mechanism of p53
      dependent apoptosis still remains to be elucidated. Here we report a new p53
      target-gene, designated p53RDL1 (p53-regulated receptor for death and life; also
      termed UNC5B). The p53RDL1 gene product contains a cytoplasmic carboxy-terminal
      death domain that is highly homologous to rat Unc5H2, a dependence receptor
      involved in the regulation of apoptosis, as well as in axon guidance and
      migration of neural cells. We found that p53RDL1 mediated p53-dependent
      apoptosis. Conversely, when p53RDL1 interacted with its ligand, Netrin-1, p53
      dependent apoptosis was blocked. Therefore, p53RDL1 seems to be a previously un
      recognized target of p53 that may define a new pathway for p53-dependent
      apoptosis. We suggest that p53 might regulate the survival of damaged cells by
      balancing the regulation of Netrin-p53RDL1 signalling, and cell death through
      cleavage of p53RDL1 for apoptosis.

PMID- 12598907
TI  - Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by
      DNA damage.
AB  - Cell cycle checkpoints are signal transduction pathways activated after DNA
      damage to protect genomic integrity. Dynamic spatiotemporal coordination is a
      vital, but poorly understood aspect, of these checkpoints. Here, we provide
      evidence for a strikingly different behaviour of Chk2 versus Nbs1, key mediators
      of the ataxia-telangiecatesia-mutated (ATM)-controlled checkpoint pathways
      induced by DNA double-strand breaks (DSBs). In live human cells with DSBs
      restricted to small sub-nuclear areas, Nbs1 was rapidly recruited to the damaged
      regions and underwent a dynamic exchange in the close vicinity of the DSB sites.
      In contrast, Chk2 continued to rapidly move throughout the entire nucleus,
      irrespective of DNA damage and including the DSB-free areas. Although
      phosphorylation of Chk2 by ATM occurred exclusively at the DSB sites, forced
      immobilization of Chk2 to spatially restricted, DSB-containing nuclear areas
      impaired its stimulating effect on p53-dependent transcription. These results
      unravel a dynamic nature of Nbs1 interaction with DSB lesions and identify Chk2
      as a candidate transmitter of the checkpoint signal, allowing for a coordinated
      pan-nuclear response to focal DNA damage.

PMID- 12598908
TI  - An integrated functional genomics screening program reveals a role for BMP-9 in
      glucose homeostasis.
AB  - A coordinated functional genomics program was implemented to identify secreted
      polypeptides with therapeutic applications in the treatment of diabetes. Secreted
      factors were predicted from a diverse expressed-sequence tags (EST) database,
      representing >1,000 cDNA libraries, using a combination of bioinformatic
      algorithms. Subsequently, approximately 8,000 human proteins were screened in
      high-throughput cell-based assays designed to monitor key physiological
      transitions known to be centrally involved in the physiology of type 2 diabetes.
      Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent
      assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in
      hepatocytes and activating Akt kinase in differentiated myotubes. Purified
      recombinant BMP-9 potently inhibited hepatic glucose production and activated
      expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a
      single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels,
      with maximal reduction observed 30 hours after treatment. BMP-9 represents the
      first hepatic factor shown to regulate blood glucose concentration. Using a
      combination of bioinformatic and high-throughput functional analyses, we have
      identified a factor that may be exploited for the treatment of diabetes.

PMID- 12598909
TI  - TIP, a T-cell factor identified using high-throughput screening increases
      survival in a graft-versus-host disease model.
AB  - A coordinated effort combining bioinformatic tools with high-throughput cell
      based screening assays was implemented to identify novel factors involved in T
      cell biology. We generated a unique library of cDNAs encoding predicted secreted
      and transmembrane domain-containing proteins generated by analyzing the Human
      Genome Sciences cDNA database with a combination of two algorithms that predict
      signal peptides. Supernatants from mammalian cells transiently transfected with
      this library were incubated with primary T cells and T-cell lines in several high
      throughput assays. Here we describe the discovery of a T cell factor, TIP (T cell
      immunomodulatory protein), which does not show any homology to proteins with
      known function. Treatment of primary human and murine T cells with TIP in vitro
      resulted in the secretion of IFN-gamma, TNF-alpha, and IL-10, whereas in vivo TIP
      had a protective effect in a mouse acute graft-versus-host disease (GVHD) model.
      Therefore, combining functional genomics with high-throughput cell-based
      screening is a valuable and efficient approach to identifying immunomodulatory
      activities for novel proteins.

PMID- 12598910
TI  - Patterns of beta-catenin expression in gastric carcinoma: clinicopathological
      relevance and mutation analysis.
AB  - Studies on the expression of beta-catenin (beta-ct) in gastric carcinoma have
      provided conflicting results, and the role played by beta-ct mutations in gastric
      carcinogenesis remains unclear. In an attempt to clarify the aforementioned
      issues we undertook the retrospective study of 157 gastric carcinomas by using
      immunohistochemistry and molecular genetics. Reduced/absent membranous beta-ct
      expression was significantly associated with isolated-cell/diffuse histotype both
      in "pure" diffuse gastric carcinomas and in the isolated-cell/diffuse component
      of mixed carcinomas. Cytoplasmic and/or nuclear beta-ct expression was
      particularly prevalent in mixed carcinomas and was significantly associated with
      lymphatic vessel invasion and lymph node metastases. beta-ct mutations were not
      detected in any case. We conclude that the pattern of beta-ct expression is
      closely related to gastric carcinoma histotype. The activation of Wnt/beta-ct
      pathway is associated with mixed gastric carcinoma and with features of clinical
      aggressiveness; the mechanism(s) underlying this pathway in gastric carcinoma are
      not due to beta-ct mutations and remain to be elucidated.

PMID- 12598911
TI  - Immunohistochemical markers of melanocytic tumors.
AB  - While historically detection of premelanosomes by electron microscopic studies
      was the only means possible of confirming melanocytic lineage of a neoplastic
      process, advances in the field of immunohistochemistry have allowed for accurate
      and reliable diagnosis using antibodies to 1 of a number of melanocyte-restricted
      proteins. S-100 was the first such marker exploited by immunohistochemistry;
      subsequently, the HMB45 monoclonal antibody to gp100 became widely used as a
      sensitive and specific melanocytic marker. More recently, antibodies to other
      melanocytic proteins have become available, inciuding the MART-1 gene product and
      microphthalmia transcription factor. This article provides a brief overview of
      these markers in terms of their specificity and sensitivity and offers a
      discussion of tumors with partial melanocytic differentiation.

PMID- 12598912
TI  - Double immunolabeling by the RBM and the PLAP markers for identifying
      intratubular (in situ) germ cell neoplasia of the testis.
AB  - Identification of intratubular germ cell neoplasia (carcinoma in situ, CIS) of
      the testis is a diagnostic challenge, and markers are sorely needed to assist in
      accurately identifying the lesion. RNA-binding motif (RBM) protein, encoded by
      the Y chromosome, is expressed exclusively and consistently in differentiated
      male germ cells, while it is absent in neoplastic germ cells. Another
      immunohistochemical marker, placental alkaline phosphatase (PLAP), is commonly
      used for the detection of undifferentiated germ cells. The current study
      demonstrates that simultaneous use of the immunohistochemical markers, RBM and
      PLAP, by double immunolabeling enhances the accuracy of diagnosing CIS, a
      preinvasive testicular neoplasm.

PMID- 12598913
TI  - Lymphoid progenitor cells in human tonsils.
AB  - To investigate the occurrence of lymphoid progenitor cells in human tonsils, we
      studied tonsils from children and adults by immunohistochemistry by using a panel
      of antibodies to antigens associated with lymphoid progenitor cells, including
      terminal deoxynucleotidyl transferase (TdT), CD10 (CALLA), CD34, CD99
      (p30/32mic2), and CD117 (c-kit), and compared them to reactive lymph nodes.
      Lymphoid progenitor cells, positive for TdT, CD10, and CD99, but not CD34 or
      CD117, were readily identified in tonsils from children and adults (TdT, 14 of
      15; CD10, 15 of 15; CD99, 11 of 15), but were rarely present in lymph nodes (TdT,
      1 of 8; CD10, 1 of 8; CD99, 0 of 8). Lymphoid progenitor cells in tonsils were
      localized to discrete foci at the periphery of lymphoid lobules adjacent to
      fibrous septae. Lymphoid progenitor cells are present in human tonsils, and the
      tonsils are a potential site of postnatal lymphopoiesis. The presence of lymphoid
      progenitor cells in human tonsils should not be confused with lymphoblastic
      lymphoma or leukemia.

PMID- 12598914
TI  - Thymic tissue in the skin: a clue to the diagnosis of the branchio-oculo-facial
      syndrome: report of two cases.
AB  - The branchio-oculo-facial (BOF) syndrome is a rare autosomal dominant disorder
      with a peculiar phenotype related to a combination of craniofacial abnormalities.
      Rare examples presenting with dermal thymic tissue have been described. We are
      reporting 2 children, 15 and 4 months old, respectively, with BOF syndrome in
      whom surgical repair/excision of skin cervical lesions showed thymic tissue. In
      the first patient the thymic tissue was exposed to the surface, without
      epithelial coverage and contained areas suggestive of all stages of thymus
      formation. A dermohypodermal nodule of fully developed thymic tissue
      superficially covered by nonkeratinizing squamous epithelium was found in the
      second patient. Since pharyngeal pouches are not exposed to the surface during
      normal embryogenesis and the thymus originates from the third pharyngeal pouch,
      both examples seem to indicate that in BOF syndrome there is a more complex
      malformation than simply ectopic thymus tissue. Thymic tissue at the skin appears
      to be unique for BOF syndrome and in a given case may provide the clue for the
      accurate diagnosis of the malformation complex.

PMID- 12598915
TI  - Angiogenesis relates to estrogen receptor negativity, c-erbB-2 overexpression and
      early relapse in node-negative ductal carcinoma of the breast.
AB  - Tumor angiogenic activity is an important process linked to tumor growth,
      metastasis, and invasion. In the present study we investigated whether
      intratumoral microvessel density (MVD), as assessed with immunohistochemistry, is
      of prognostic relevance in a series of 77 breast cancer patients with node
      negative disease. The mean MVD in the hot spots ranged from 9 to 106 (median 31)
      vessels per x200 optical field. Patients were grouped into 3 categories of low
      (27 pts), medium (26 pts), and high (24 pts) MVD. Angiogenesis was not related to
      the primary tumor dimensions (T-stage) or the histology differentiation. An
      inverse association of MVD with estrogen receptor (ER) expression was noted
      (p=0.0007), while high MVD was directly related to c-erbB-2 overexpression
      (p=0.04) and high MIB1 proliferation index (p=0.02). In univariate and
      multivariate analysis of relapse-free survival, MVD was the only variable
      significantly and independently linked to relapse. It is concluded that high
      intratumoral angiogenic activity is linked with early relapse in node-negative
      breast cancer.

PMID- 12598916
TI  - Cutaneous malignant melanoma: the great simulator.

PMID- 12598917
TI  - The cutaneous keratocyst: a rare hallmark of the nevoid basal cell carcinoma
      syndrome.

PMID- 12598918
TI  - The juxtaoral organ of Chievitz.

PMID- 12598920
TI  - Pulmonary hyalinizing granuloma associated with Aspergillus infection.
AB  - A 38-year-old immunocompetent man with occupational exposure to Aspergillus
      presented with dyspnea, pleuritic chest pain, and hemoptysis. Chest
      roentgenograms and computed tomography scans demonstrated multiple pulmonary
      nodules bilaterally. An initial set of bronchial washing cultures grew
      Aspergillus fumigatus, serologic testing showed an elevated anti-Aspergillus
      titer, and immunodiffusion testing was positive for antibody against A. fumigatus
      and A. niger. There was no microbiologic or serologic evidence of infection by
      other pathogens, and no clinical or laboratory evidence of autoimmune disease. An
      open lung biopsy was diagnostic of pulmonary hyalinizing granuloma. This novel
      association with Aspergillus infection not only expands the spectrum of pathogens
      linked to pulmonary hyalinizing granuloma but also documents a new pattern of
      lung disease that can be caused by Aspergillus.

PMID- 12598921
TI  - Polymorphous low-grade adenocarcinoma of the vulva and vagina: a tumor resembling
      adenoid cystic carcinoma.
AB  - We report the first case of a polymorphous low-grade adenocarcinoma (PLGA)
      occurring in the vulva and vagina of a 32-year-old woman. This tumor consisted of
      cellular lobules with distinct cribriform, papillary, and cystic patterns. Owing
      to its location and its distinct cribriform pattern, this lesion was initially
      diagnosed as an unusual variant of adenoid cystic carcinoma (ACC). However, this
      diagnosis was revised to PLGA when it was recognized that the cribriform,
      papillary and cystic patterns and their concomitant occurrence in the same lesion
      are characteristic of PLGA. PLGA should be added to the differential diagnosis of
      vulvar and vaginal neoplasia.

PMID- 12598922
TI  - Metastatic pleural mesothelioma presenting with solitary involvement of the
      tongue: report of a new case and review of the literature.
AB  - We report a new case of mesothelioma that presented with an isolated lingual
      metastasis 14 months after initial diagnosis. The patient was a 71-year-old man
      with a history of pleural decortication and chemotherapy for epithelioid
      mesothelioma who recently complained of chronic bleeding from a nodular
      consolidation of tongue. There was no clinical or instrumental evidence of
      extrathoracic tumor spread. Microscopic examination of a lingual biopsy specimen
      revealed nests of atypical polygonal cells with moderate cytoplasm,
      immunopositive for keratins, epithelial membrane antigen, vimentin,
      thrombomodulin, and calretinin. This case provides additional evidence that
      mesothelioma could rarely, but not exceptionally, metastatize, to unusual sites
      such as the tongue. In that location it can mimic primary poorly differentiated
      squamous carcinoma or adenocarcinoma as well as a number of other metastatic
      malignancies. In addition to obvious medicolegal implication, metastatic
      mesothelioma should be correctly recognized so as to avoid useless radical
      treatment.

PMID- 12598923
TI  - Intraosseous rhabdomyosarcoma of the mandible: a case report.
AB  - Rhabdomyosarcoma is the most common soft-tissue sarcoma of the head and neck
      region in children and adolescents. Oral cavity involvement is relatively
      uncommon, with tongue, soft palate, hard palate, and buccal mucosa being the
      sites of predilection. This report presents a rare case of intraosseous oral
      rhabdomyosarcoma arising in the mandibular bone of a 6-year-old child. Clinical,
      radiologic, and histopathologic features and possible pathogenesis are discussed.

PMID- 12598924
TI  - Eccrine syringofibroadenoma arising in peristomal skin: a report of two cases.
AB  - Eccrine syringofibroadenoma (ESFA) is a benign neoplasm arising from the
      intraepidermal portion of eccrine ducts. It is characterized by a distinctive
      histologic pattern of epithelial cells arranged in anastomosing cords surrounded
      by a fibrovascular stroma. Approximately 50 cases of ESFA have been reported, and
      in recent years the lesion has been described occurring in association with other
      skin conditions. We report 2 cases of ESFA arising in abdominal skin adjacent to
      enterostomy sites.

PMID- 12598926
TI  - Synaptic and molecular mechanisms of glutamatergic synapses in pain and memory.
AB  - Glutamate is a fast excitatory transmitter in mammalian brains. Glutamatergic
      synapses are found in central regions related to pain transmission, plasticity
      and modulation. Glutamate NMDA receptors in forebrain structures are well known
      to contribute to the formation and storage of information. Here we propose the
      hypothesis that forebrain NMDA receptors play an important role in persistent
      inflammatory pain by re-enforcing glutamate sensory transmission in the brain.
      Mice with enhanced function of forebrain NMDA receptors demonstrate selective
      enhancement of persistent pain and allodynia. Drugs targeting forebrain NMDA NR2B
      receptors may serve as a new class of medicine to control persistent pain in
      humans.

PMID- 12598927
TI  - Electrophysiological effects of phytoestrogen genistein on spontaneous activity
      of rabbit atrioventricular node cells.
AB  - The purpose of this study was to determine the electrophysiological effects of
      genistein (GST) on spontaneous activity of atrioventricular (AV) node and the
      underlying mechanism(s). Action potentials in AV node cells were recorded using
      intracellular microelectrode technique. GST not only reduced the amplitude of
      action potential (APA), maximal rate of depolarization (V(max)), velocity of
      diastolic (phase 4) depolarization (VDD), and rate of spontaneous firing (RSF),
      but also prolonged 90% duration of action potential (APD(90)) in a concentration
      dependent manner. The effects of GST (50 micromol/L) could be blocked completely
      by pretreatment with Bay K8644 (0.25 micromol/L), an agonist of L-type calcium
      channel. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 0.5
      mmol/L), a nitric oxide (NO) synthase inhibitor, did not affect the effects of
      GST on AV node cells. Elevation of Ca(2+) concentration (5 mmol/L) in superfusate
      antagonized the effects of GST (50 micromol/L). These results suggest that GST
      exerted a negative electrophysiological effects of spontaneous activity of AV
      node cells in rabbits. These effects were likely due to reduction in calcium
      influx, but had no association with NO release.

PMID- 12598928
TI  - [Effects of Mycobacterium tuberculosis infection on the transcriptional
      expression of human macrophage gene encoding ion channels and related regulatory
      elements].
AB  - Expression microarray was employed in this study to investigate whether the ion
      channels and their regulatory elements encoding genes participate in the immune
      response to Mycobacterium tuberculosis infection. The results of a virulent
      strain were compared with those of the clinically isolated strains. The data
      demonstrate that K(+), Na(+), Ca(2+) and Cl(-) channels and their regulatory
      elements, such as the G protein, receptor and second messenger, protein kinase
      and protein phosphatase were involved in the immune reaction. The clinical strain
      affected more types of ion channels and respective regulatory elements. The data
      provides clues for further scrutiny into the role of ion channels and related
      elements in the interaction between Mycobacterium tuberculosis and host
      macrophage.

PMID- 12598929
TI  - [Interleukin-2 induced endothelium-dependent relaxation of rat thoracic aorta].
AB  - Interleukin-2 (IL-2) therapy often results in potentially life-threatening side
      effects including hypotension. However, the mechanism has not been completely
      elucidated. In order to determine whether IL-2 modifies vascular tone, we
      investigated the effect of IL-2 on rat thoracic aorta rings and the underlying
      mechanisms. Effects of IL-2 on the contraction of high KCl and phenylephrine (PE)
      preconstricted rat thoracic aorta with or without endothelium were determined by
      organ bath technique. To explore the mechanism, nitric oxide synthase inhibitor L
      N(G)-nitroarginine methyl ester (L-NAME), guanylyl cyclase inhibitor methylene
      blue, and cyclooxygenase inhibitor indomethacin were used. IL-2 (10-1000 U/ml)
      caused concentration-dependent relaxation of aorta rings preconstricted with PE
      (10 micromol/L) in endothelium-intact rings, but had no effect on KCl (120
      mmol/L) preconstricted rings. Removal of the endothelium, or pretreatment with L
      NAME (0.1 mmol/L) or methylene blue (10 micromol/L) or indomethacin (10
      micromol/L), inhibited the relaxation of IL-2. The results indicate that the
      relaxation by IL-2 in rat aorta ring is endothelium-dependent and is possibly
      mediated by the NO-guanylyl cyclase pathway and cyclooxygenase-dependent pathway.

PMID- 12598930
TI  - [Effect of ginkgolide B on L-type calcium current and cytosolic [Ca2+]i in guinea
      pig ischemic ventricular myocytes].
AB  - With whole-cell variant patch-clamp and laser scanning confocal microscope
      technique, we examined the effect of ginkgolide B (GB) from ginkgo leaves on L
      type calcium current and cytosolic [Ca(2+)](i) in guinea pig ischemic ventricular
      myocytes. The results showed that under normal conditions, at a test voltage of 0
      mV, GB had no significant effect on I(Ca,L); and during ischemia, the peak Ca(2+)
      current reduced by 37.71%, and the I-V curve of I(Ca,L) was shifted upward. 1
      micromol/L GB reversed the change induced by ischemia, a result being
      significantly different from those of the ishemia group (P<0.05).Under control
      condition, 0.1,1,10 micromol/L GB decreased intracellular calcium concentration
      by 10.58%, 17.27% and 16.35% (n=12, 12, 10, P<0.01-0.001), respectively. With
      perfusion of ischemic solution for 12 min, intracellular calcium concentration
      increased by 20.15%. After a 12 min-perfusion of ischemic solution containing 1
      micromol/L nifedipine or 5 mmol/L NiCl2, intracellular calcium concentration
      increased by 18.18% (P>0.05 vs ischemia) and 11% (P<0.05 vs ischemia),
      respectively. After 12 min of perfusion with ischemic solution containing 1
      micromol/L GB, intracellular calcium concentration increased by 9.6% (P<0.05 vs
      ischemia). It is shown that GB could reverse the decrease of I(Ca,L) and
      partially inhibit calcium overload during ischemia.

PMID- 12598931
TI  - [Effects of central histaminergic receptor activation on carotid sinus
      baroreceptor reflex resetting in stressed rats].
AB  - To determine the effect of stress on carotid sinus baroreceptor reflex (CSR) and
      whether or not central histaminergic receptors modulate the CSR under stress, the
      characteristics of CSR were analyzed by using an isolated carotid sinus
      preparation in Wistar rats. Animals were divided into two groups at random:
      unstressed group (n=42) and stressed group (n=41). According to the site of
      microinjection of histaminergic receptor antagonists, each group was subdivided
      into a group of intracerebroventricular injection (i.c.v.) and a group of
      microinjection into the nucleus of the solitary tract (NTS). The volume of
      injection into the lateral cerebroventricle and NTS was 5 microl and 1 micro1,
      respectively. Stressed groups were subjected to unavoidable electric foot-shock
      twice daily for a week, each session of foot-shock lasted 2 hours. The left and
      right carotid sinus regions were isolated from the systemic circulation under
      anesthesia with pentobarbital sodium in all rats. The intracarotid sinus pressure
      (ISP) was altered in a stepwise manner to trigger CSR from 0 to 280 mmHg at every
      step of 40 mmHg and 4 s, and then returned to 0 mmHg in similar steps. ISP and
      mean arterial pressure (MAP) were recorded simultaneously. ISP-MAP relationship
      curve was constructed by fitting to the logistic function with five parameters.
      The CSR parameters and the ISP-MAP relationship curve were separately compared
      statistically. The main results obtained are as follows. (1) Stress significantly
      shifted the ISP-MAP relationship curve upwards and obviously moved the middle
      part of ISP-Gain relationship curve downwards, and decreased the value of the MAP
      range and maximum gain (G(max)), but increased the threshold pressure (TP),
      saturation pressure (SP), set point and ISP at G(max) (ISP(Gmax)). (2) I.c.v. of
      H1 receptor antagonist chlorpheniramine (CHL, 5 microg) or H2 receptor antagonist
      cimetidine (CIM, 15 g) significantly diminished the above-mentioned changes in
      CSR performance induced by stress; the alleviative effect of CIM was less
      remarkable than that of CHL. The responses of CSR in stressed rats to H(1) or
      H(2) receptor antagonists generally occurred 20 min after the administration and
      lasted approximately for 15 min. (3) After microinjection of CHL (0.5 microg) or
      CIM (1.5 microg) into the NTS, the responses of CSR in stressed groups were
      similar to those after i.c.v. injection of CHL or CIM. (4) However,
      microinjection of CHL or CIM into the lateral cerebroventricle or the NTS could
      not completely abolish the stress-induced changes in CSR. These findings suggest
      that stress results in a resetting of CSR, a decrease in reflex sensitivity. The
      stress-induced changes in CSR may be mediated, at least in part, by activating
      the brain histaminergic system. The central histaminergic receptors (H(1) and
      H(2) receptors) may play an important role in the resetting of CSR under stress.
      The descending histaminergic pathway from the hypothalamus to NTS may be involved
      in these effects.

PMID- 12598932
TI  - An electrophysiological study on the anti-ventricular arrhythmic effect of
      adenosine in the guinea pig.
AB  - Using whole-cell patch clamp technique this study investigated the effects of
      adenosine (Ado) on action potential, L-type calcium current (I(Ca.L)), delayed
      afterdepolarizations (DADs), and transient inward current (I(ti)) induced by
      isoproterenol (Iso) in guinea pig isolated single ventricular myocytes. The
      results showed: (1) Ado alone had no significant direct effects on action
      potential and I(Ca.L) in guinea pig ventricular myocytes at 20-100 micromol/L.
      However, Ado significantly attenuated the prolongation of action potential
      duration (APD) and the increase of the peak amplitude of I(Ca.L) induced by Iso.
      Iso (10 nmol/L) markedly increased APD(50) and APD(90) from 340+/-21 ms to 486+/
      28 ms and from 361+/-17 ms to 501+/-29 ms, respectively (P<0.01), and increased
      the amplitude of I(Ca.L) from 6.53+/-1.4 pA/pF to 18.28+/-2.4 pA/pF (P<0.01). The
      peak potential of current-potential relationship shifted to the left. Ado (50
      micromol/L) abbreviated APD(50), APD(90) to 403+/-19 ms and 419+/-26 ms (P<0.01),
      and decreased the peak amplitude of I(Ca.L) to 10.2+/-1.5 pA/pF (P<0.01 vs Iso),
      but did not change resting membrane potential (RMP), action potential amplitude
      (APA), and overshoot (OS). (2) Iso (30 nmol/L) reproducibly elicited DADs with
      100% incidence of DADs under this condition. Ado (50 micromol/L) completely
      inhibited Iso from inducing DADs. Iso (30 nmol/L) elicited I(ti) with 2-second
      depolarizing voltage-clamp pulses rising to +20 mV from a holding potential of 
      40 mV, the incidence of I(ti) being 100%, and the I(ti) was suppressed in the
      presence of Ado (50 micromol/L) with the incidence of I(ti) decreased to 14.3%
      (P<0.05). These data indicate that Ado antagonizes the stimulatory effect of Iso,
      and that the antiarrhythmic mechanism of Ado preventing Iso-induced DADs is due
      to the inhibition of intracellular Ca(2+) overload through attenuating the
      prolongation of APD, the enhance of I(Ca.L) and I(ti).

PMID- 12598933
TI  - [Pituitary adenylate cyclase activating polypeptide protects neuro-2a cells from
      beta amyloid protein cytotoxicity by modulating intracellular calcium].
AB  - MTT analysis and intracellular calcium measurement by using confocal laser
      scanning microscopy were used to study the possible mechanism of protective
      effect of pituitary adenylate cyclase activating polypeptide 27 (PACAP27) from
      beta amyloid protein (Abeta)-induced neurotoxicity. The results showed that
      treatment with PACAP (less than 0.1 micromol/L) increased the survival and
      reproductive ability of neuro-2a cells and protected the neuro-2a cells from
      being injured by Abeta. The protective effect of PACAP27 was reversed by the
      competitive PACAP receptor antagonist PACAP6-27. An increase in intracellular
      calcium was observed when the cells were challenged with Abeta and PACAP. But the
      calcium increase induced by Abeta kept stable for a long time while PACAP caused
      a transient rise in intracellular calcium. The intracellular calcium increase
      induced by Abeta was blocked by pretreatment with PACAP for 10 min. It is
      suggested that the neuroprotective effect of PACAP against neuronal damage
      induced by Abeta may result from its role in inhibiting the sustained rise in
      intracellular calcium.

PMID- 12598934
TI  - [Adenosine protects cardiomyocytes from hypoxia/reoxygenation injury].
AB  - The aim of this study was to investigate the protective effect of adenosine (ADO)
      on cardiomyocytes following hypoxia/reoxygenation (H/R) and its molecular
      mechanism. Primary cultured cardiomyocytes of neonatal rats were divided into two
      groups, namely H/R (control) and ADO (1.0 micromol/L) groups. The morphologic
      changes in cardiomyocytes were observed under an inverted phase-contrast
      microscope. The following parameters of the two groups were determined: lactate
      dehydrogenase (LDH) activity, intracellular calcium concentration and
      malondialdehyde (MDA) content. Tumor necrotic factor (TNF-alpha) assay was
      performed using an ELISA kit and NF-kappaB in the nucleus was analyzed by
      electrophoretic mobility shift assay (EMSA). The results are as follows: (1)
      after H/R injury, cardiomyocytes contracted, tending to get round in shape and
      its pseudopods decreased, while marked morphological changes were not observed in
      ADO group; (2) LDH leakage maintained at a lower level in ADO group than that in
      the control group during H/R (both P<0.01); (3) ADO significantly reduced the
      concentration of calcium in cells and prevented calcium overload during H/R (both
      P<0.01); (4) ADO markedly reduced the content of MDA during H/R (both P<0.01);
      (5) ADO inhibited the production of TNF-alpha during H/R (both P<0.01); and (6)
      ADO down-regulated NF-kappaB binding activity of cardiomyocytes during H/R (both
      P<0.01) The results suggest that (1) exogenous ADO attenuates H/R injury of
      cultured cardiomyocytes; (2) exogenous ADO inhibits the production of TNF-alpha
      after H/R injury; (3) exogenous ADO prevents the activation of NF-kappaB, which
      may be the molecular mechanism of down-regulation of TNF-alpha expression.

PMID- 12598935
TI  - [Influence of nitric oxide on the angiotensin II-activated protein kinase C
      activity in cultured neonatal rat cardiomycytes].
AB  - We examined the effect of endogenous and exogenous nitric oxide (NO) on protein
      kinase C (PKC) activity induced by angiotensin II (Ang II) in cultured neonatal
      rat cardiomyocytes. The results are as follows. The activity of PKC was increased
      by Ang II (0.01-10 micromol/L) in a dose-dependent manner, but decreased by NO
      precursor L-arginine (L-Arg) (10 micromol/L-10 mmol/L) in a dose-dependent manner
      in cultured neonatal rat cardiomyocytes. Pretreatment with L-Arg (100 micromol/L)
      decreased significantly Ang II -activated PKC activity and PKC activity induced
      by phorbol 12-myristate 13-acetate (PMA) ( 10 micromol/L), a PKC activator.
      Pretreatment with N(G)-nitro-L-argingie methyl ester (L-NAME), a nitric oxide
      synthase (NOS) blocker, may inhibit significantly the role of L-Arg on Ang II -
      and PMA-activated PKC activity. The activity of PKC was also decreased by NO
      donor sodium nitroprusside (SNP) (10 micromol/L-1 mmol/L) in a dose-dependent
      manner in cultured neonatal rat cardiomyocytes. Pretreatment with SNP (10
      micromol/L) decreased significantly Ang II - and PMA-activated PKC activity.
      These results indicate that PKC was controlled by both NO and Ang II. PKC may be
      a cross talk between Ang II and NO in cardiomyocytes. NO abolished the activity
      of PKC and impaired PKC downstream signaling transduction pathway cascades.

PMID- 12598936
TI  - [The role of activation of nuclear factor-kappa B of rat brain in the
      pathogenesis of experimental allergic encephalomyelitis].
AB  - To investigate the role of activated nuclear factor-kappaB (NF-kappaB) in
      experimental allergic encephalomyelitis (EAE), the activity and protein
      expression of NF-kappaB p65 in rat brain tissues, which were extracted from EAE
      rats at 1, 7, 14 and 21 d respectively after EAE was induced by CFA-GPSCH, were
      measured with electrophoretic mobility shift assay and immunohistochemistry. The
      relationship between activated NF-kappaB and symptoms of EAE was also
      investigated. The results showed that protein expression level and the activity
      of NF-kappaB were very low in the brain of the control group. After EAE was
      induced, the activity of NF-kappaB and the level of the protein expression in the
      brains increased gradually with the development of symptoms and brain pathology
      of EAE. On d 14, both the activity and the level of protein expression in the
      brains reached a peak, the positive cells of NF-kappaB were mainly located at the
      choroid plexuses and subfornical organ, as well as around the regions of   sleeve
      like   lesion foci, which were coincident with the locations of lesions of EAE.
      The incidence, symptoms, reduction of the body weight and pathology of EAE rats
      brains at the above locations were most significant. On d 21 the activity of NF
      kappaB and level of the protein expression reduced gradually, which was in
      parallel with a gradual alleviation of the symptoms of EAE rats. After a specific
      inhibitor of NF-kappaB, PDTC was applied, the symptoms and pathological lesions
      of EAE rat brain were mitigated markedly. The above results indicate that the
      dynamic changes in the activity and protein expression of NF-kappaB were in
      parallel with the changes in symptoms and pathological lesion of EAE rat brains.
      In conclusion, the activated NF-kappaB in the brain may play a critical role in
      the pathogenesis of EAE, and application of some inhibitors of NF-kappaB, such as
      PDTC, may be one of the effective therapeutic methods for prevention and
      treatment of EAE.

PMID- 12598937
TI  - [Calbindin D-28k-containing neurons receiving visceral and somatic nociceptive
      information in interstitial nucleus of the spinal trigeminal tract project to the
      parabrachial nuclei in the rat].
AB  - The calbindin D-28k (CB)-containing neurons in the interstitial nucleus of the
      spinal trigeminal tract (INV) that receive visceral and orofacial somatic
      nociceptive information and emanate projections to the parabrachial nuclei (PB)
      were investigated by the triple-labeled methods of fluorogold (FG) retrograde
      tracing combined with Fos and CB proteins immunofluorescence histochemistry in
      the rat. The results showed (1) in the perioral stimulation group, a large number
      of FG-retrograde labeled and Fos-immunoreactive neurons were found in the
      paratrigeminal nucleus (PaV) and the dorsal paramarginal nucleus (PaMd) of the
      INV ipsilateral to FG and formalin injection made to the PB and lips,
      respectively, while a lot of CB-immunoreactive neurons were distributed in the
      INV bilaterally; (2) a majority of the FG-retrograde labeled neurons (77.3%) were
      double-labeled with CB, and 40.7% of them were double-labeled with Fos; about
      38.5% of FG/CB double-labeled neurons were FG/CB/Fos triple-labeled in the INV;
      and (3) in the upper alimentary tract stimulation group, the distribution and the
      numbers of FG-retrograde labeled, CB-immunoreactive neurons and FG/CB double
      labeled neurons in the INV were similar to those of the perioral stimulation
      group as described above, except that the Fos immunoreactive neurons were
      distributed in the INV bilaterally, approximately 41.9% of the FG-retrograde
      labeled neurons were FG/Fos double-labeled, and over half (52.0%) of those double
      labeled neurons were FG/CB/Fos triple-labeled. The results indicate that a part
      of CB-containing neurons in the INV receive orofacial somatic and visceral
      nociceptive information and that these neurons sent projections directly to the
      PB. The CB-containing neurons might play an important role in the transmission of
      the peripheral nociceptive information from INV to PB.

PMID- 12598938
TI  - [Construction of pcDNA3.1AM and expression of adrenomedullin in mammalian cells].
AB  - The newly discovered endogenous vasodilating and diuretic peptide adrenomedullin
      (AM) was considered to be of attractive value in clinical treatment of
      hypertension and congestive heart failure. In order to explore the treatment of
      cardiovascular diseases by expressing AM in vivo, AM cDNA was inserted into
      mammalian expressing vector pcDNA3.1, and in vitro expression of AM was carried
      out in cultured K(562) cell line. AM mRNA was amplified by RT-PCR from the total
      RNA isolated from the adrenal glands of rats and was inserted into pcDNA3.1
      vector to form pcDNA3.1AM, the recombinant pcDNA3.1AM was then transferred into
      cultured K(562) cell line by liposome. The expression of AM in pcDNA3.1AM
      transferred cell was identified by RT-PCR and dot immunoblot assay. The results
      demonstrated that there were AM mRNA in the pcDNA3.1AM-transferred K(562) cell
      line and AM peptides in the culturing medium, indicating that the recombinant
      pcDNA3.1AM vector can express AM in mammalian cell line.

PMID- 12598939
TI  - [Angiotensin II contents in plasma, and cardiac and renal tissues of sinoaortic
      denervated rats].
AB  - Our previous data demonstrate that impairment of arterial baroreceptor reflex
      (ABR) plays an independent role in hypertension target organ damage. To elucidate
      the mechanisms responsible for the dysfunction of ABR associated organ damage,
      sinoaortic denervated (SAD) rats were used as an animal model of ABR dysfunction.
      Twenty-four-hour continuous blood pressure (SBP and DBP), blood pressure
      variability (BPV), heart rate (HR) and HR variability (HRV) were measured in
      conscious and unrestrained rats. Angiotensin II (Ang II) in plasma, heart and
      kidney was assayed by raio-immunological assay (RIA) 1 or 18 weeks after
      denervation. In short-term SAD rats, twenty-four-hour mean SBP and DBP increased
      compared with that of sham-operated rats and long-term SAD rats. No significant
      difference in SBP, DBP or HR was found between long-term SAD rats and sham
      operated ones. Compared with the sham-operated rats, long-term SAD rats had
      elevated BPV. No significant change in Ang II levels of caridiac and renal
      tissues was found in short-term SAD rats. In long-term SAD rats, Ang II level of
      plasma was not increased while the Ang II content in the heart and kidney
      increased. Ang II contents of plasma and tissues in long-term SAD rats exposed to
      chronic stress were higher than those in the control rats. These results show (1)
      in short-term SAD rats blood pressure increased, while in long-term SAD rats 24 h
      mean blood pressure did not increase, although BPV elevated in long-term SAD
      rats; (2) in long-term SAD rats, secretion of Ang II in cardiac and renal tissues
      was enhanced and more Ang II released when the animals were exposed to chronic
      stress. These results suggest that elevated BPV and secretion of Ang II may be
      related to the development of organ damage induced by ABR dysfunction.

PMID- 12598940
TI  - [Tissue-specific expression of Na+ -H+ exchanger isoforms at two developmental
      stages of human fetus].
AB  - Na(+)-H(+) exchangers (NHE) are major membrane proteins that have been identified
      as signal transduction mediators in the regulation of cell differentiation and
      important membrane ion transporters in the regulation of the intercellular pH and
      the cell volume. NHE are composed of at least six isoforms and activated in
      growth factor-regulated cell differentiation. However, little is known about the
      differential regulation of NHE expression in the development. In the present
      study, we studied developmental regulation of the expression of NHE isoforms in
      human fetal tissues by comparing the expression of various isoforms between two
      developmental stages, i.e., week 11 (11 W) and week 16 (16 W). The results
      demonstrated that NHE1 transcripts were expressed ubiquitously. In comparison to
      the expression at 16 W, the level of NHE1 transcripts was low and varied
      significantly in a tissue-specific pattern at 11 W, suggesting that the   house
      keeping   function of MHE1 occurs at 11 W or earlier and becomes well established
      at least as early as at 16 W. The tissue-specifically restricted expression of
      NHE2 and NHE3 was regulated at 11 W and 16 W in an opposite tendency, supporting
      the overlapping relationship between NHE2 and NHE3 in the tissue distribution as
      reported in adults. NHE5 expression was relatively ubiquitous at 11 W and became
      restricted in the cerebellum at 16 W, suggesting that the restrictive expression
      of NHE5 in the brain occurs later than that of other isoforms. The present study
      demonstrates a space time-dependent regulation of the tissue-specific expression
      pattern of NHE isoforms during human development between 11 W and 16 W. The
      results also suggest that at 16 W or earlier the expression pattern of developing
      tissues becomes similar to that of adult tissues. The observed developmental
      regulation of NHE expression provides a molecular basis for further study of the
      function and regulation of NHE gene during development.

PMID- 12598941
TI  - [Effect of interleukin-2 on the activity of Ca2+ ATPase and Na+/K+ ATPase of
      sarcoplasmic reticulum and sarcolemma].
AB  - The purpose of the present study was to investigate whether interleukin-2 (IL-2)
      changes the activity of sarcoplasmic reticulum (SR) Ca(2+) ATPase, sarcolemmal
      Ca(2+)ATPase and Na(+)/K(+) ATPase by measuring the Pi liberated from ATP
      hydrolysis with colorimetrical methods. It was shown that the activity of
      Ca(2+)ATPase in SR from IL-2-perfused (10, 40, 200, 800 U/ml) rat heart increased
      dose-dependently. After incubation of the SR with ATP (0.1 approximately 4
      mmol/L), the activity of SR Ca(2+)ATPase increased dose-dependently in the
      control group. In the SR from 200 U/ml IL-2-perfused hearts, the activity of
      Ca(2+)ATPase was much higher than that in the control group. On the other hand,
      incubation of the SR with Ca(2+) (1 approximately 40 micromol/L) increased the
      activity of SR Ca(2+) ATPase in the control group. The activity of SR
      Ca(2+)ATPase of IL-2-perfused hearts was inhibited as the function to Ca(2+).
      Pretreatment with specific kappa-opioid receptor antagonist nor-BNI (10 nmol/L)
      for 5 min attenuated the effect of IL-2 (200 U/ml) on the activity of SR Ca(2+)
      ATPase. After pretreatment with pertussis toxin (PTX, 5 mg/L) or U73122 (5
      micromol/L), IL-2 failed to increase SR Ca(2+)ATPase activity. The activity of SR
      Ca(2+)ATPase was not changed by incubation of SR isolated from normal hearts with
      IL-2. Perfusion of rat heart with IL-2 did not affect the activity of sarcolemmal
      Ca(2+)ATPase and Na(+)/K(+)ATPase. It is concluded that perfusion of rat heart
      with IL-2 increases the activity of SR Ca(2+)ATPase dose-dependently, which is
      mainly mediated by cardiac kappa-opioid receptor pathway including a PTX
      sensitive Gi-protein and phospholipase C. IL-2 increases the activity of SR
      Ca(2+)ATPase as the function to ATP, but inhibits the activity of SR Ca(2+)ATPase
      as the function to Ca(2+). IL-2 has no effect on the activity of sarcolemmal
      Ca(2+)ATPase and Na(+)/K(+)ATPase.

PMID- 12598942
TI  - Kappa-opioid receptor stimulation contributes to aortic artery dilation through
      activation of K(ATP) channel in the rats.
AB  - To investigate the relaxation effect and underlying mechanism of U50,488H (a
      selective kappa-opioid receptor agonist) on aorta in the rat, isolated aortic
      ring was perfused and the tension of the vessel was measured. It was shown: (1)
      kappa-opioid receptor stimulation with U50,488H relaxed rat aorta dose
      dependently; (2) the relaxation effect of U50,488H on aorta was partially
      endothelium-dependent; (3) the relaxation effect of U50,488H was significantly
      attenuated in the presence of glybenclamide and glipizide, two ATP-sensitive K(+)
      channel (K(ATP)) blockers; and (4) the relaxation effect of U50,488H on vessel
      bore no relationship to muscarinic-receptor, beta-adrenoceptor, prostaglandin and
      nitric oxide (NO). These results indicate that kappa-opioid receptor stimulation
      with U50,488H relaxes the aortic artery at least partially via K(ATP) channel in
      the rat.

PMID- 12598943
TI  - Role of unsaturated fatty acids in the enhancement of muscarinic current by
      hyposmotic membrane stretch in guinea pig smooth muscle cells.
AB  - To investigate the function of exogenous unsaturated fatty acids in hyposmotic
      membrane stretch enhancement of muscarinic current (ICCh) in antral circular
      smooth muscle cells of guinea pig, we recorded the membrane current with the
      conventional whole cell patch-clamp technique. I(CCh) elicited by 50 micromol/L
      carbachol (CCh) at the holding potential of 20 mV under isosmotic condition was
      taken as control. Hyposmotic membrane stretch increased I(CCh) to 226.0+/-21.0%.
      When the cells were pretreated with 5 micromol/L arachidonic acid (AA), linoleic
      acid (LA) or oleic acid (OA), I(CCh)was inhibited to 3.8+/-0.6%, 35.2+/-0.8% and
      66.6+/-0.6% respectively. Hyposmotic membrane stretch increased I(CCh) to 106.0+/
      2.5%, 173.2+/-6.8% and 222.1+/-11.0% of the control respectively. Five micromol/L
      AA inhibited hyposmotic membrane stretch-enhanced I(CCh) by 51.2+/-3.8%, while
      the control I(CCh) under isosmotic condition was inhibited by 96.2+/-1.6%. The
      results suggest that unsaturated fatty acids inhibited I(CCh) and the inhibitory
      effect is more significant when the unsaturation degree is increased. However,
      the unsaturated fatty acids are not involved in the increase of I(CCh) induced by
      hyposmotic membrane stretch.

PMID- 12598944
TI  - [MK-801 suppresses dynorphin A (1-17)-induced facilitation of nociceptive
      responses to formalin in rats].
AB  - To explore the facilitation of nociceptive response by dynorphin (Dyn ) A in a
      model of formalin test in rats, the effects of single intrathecal injection
      (i.t.) of normal saline (NS), MK-801 (antagonist of NMDA receptor), naloxone
      (antagonist of opioid receptor), or Dyn A (1-17) were observed, and the effects
      of i.t. MK-801 or naloxone followed by i.t. Dyn A (1-17) were observed as well.
      The nociceptive licking and biting induced by injection of formalin exhibited two
      phases. The first phase lasted for a relatively short period of 3-9 min, and the
      second phase lasted for a relatively longer period after a 3 to 6- min quietness.
      The results showed that there were no differences in the first phase in all
      groups; however, there were differences in the second phase as follows: (1) the
      duration of nociceptive response was significantly increased in Dyn A (1-17)
      group (489.5+/-22.5 s) as compared to that of NS group (344.7+/-12.9 s), MK-801
      group (331.4+/-20.7 s) or naloxone group (352.5+/-18.4 s) (P<0.01 in three
      cases); (2) the duration of nociceptive response was significantly shortened in
      MK-801 plus Dyn A (1-17) group (285.7+/-19.4 s) as compared to that of Dyn A (1
      17) group (P<0.01), but there were no significant differences as compared to that
      of MK-801 group; and (3) there was no significant difference in the second phase
      between naloxone plus Dyn A (1-17) group (473.8+/-17.8 s) and Dyn A (1-17) group,
      but the duration of nociceptive response was longer than that of NS group or
      naloxone group (P<0.01 in both). The results obtained suggest: (1) at the spinal
      cord, Dyn A (1-17) facilitates nociceptive responses; (2) NMDA receptors, but not
      opioid receptors, are possibly involved in the nociception by Dyn A (1-17).

PMID- 12598945
TI  - [Dorsal root reflex from Adelta and C afferent fibers induced by electrical
      stimulation of the sural nerve in rats].
AB  - The purpose of the study was to investigate whether the small fiber-evoked dorsal
      root reflex (DRR) can be obtained by electrical stimulation of the peripheral
      nerve in rats. Fifty-one DRRs were recorded from different kinds of fiber
      filaments in the proximal ends of the cut L(5) dorsal root following electrical
      stimulation of the sural nerve. According to the kind of afferent fibers in the
      sural nerve associated with the DRRs from dorsal root, these DRRs were divided
      into five different types: A(alphabeta) fiber-evoked A(alphabeta).DRR
      (A(alphabeta)- A(alphabeta).DRR), A(betadelta) - A(delta ).DRR, A(betadelta)
      C.DRR, A(alphabetadelta)-C.DRR and C-C.DRR. The results obtained show that the
      DRR can be obtained from either A-fibers (including A(delta )-fibers) or C-fibers
      of dorsal root filaments by stimulation of the sural nerve. It is therefore
      suggested that either A(delta ).DRR or C.DRR can be used as a validity index of
      presynaptic inhibition of the thin primary afferent terminals for investigation
      of the modulation mechanisms of peripheral effectors.

PMID- 12598946
TI  - [Preparation and identification of polyclonal antiserum against angiotensinogen].
AB  - For studying the expression and distribution of angiotensinogen (AGT), the C
      teminus of rat AGT gene was expressed in E.coli. Rabbits were immunized with
      expressed AGT protein and sera from different rabbits were raised. ELISA showed a
      high titre (1:25600) of the antiserum. With the antiserum, Western blotting
      recognized not only the prokaryotic expressed AGT, but also the endogenous AGT
      protein in liver tissue of both rats and humans. Using this antiserum,
      immunohistochemistry showed the expression of AGT protein in islet cells of human
      pancreas as well as in epithelium of human bile duct. These results suggest that
      the prokaryotic expressed AGT protein is an effective immunogen for the
      preparation of anti-AGT antiserum. Our present work provides an important tool
      for study of the pathophysiological role of AGT as well as local renin
      angiotensin system.

PMID- 12598947
TI  - The exercise pressor reflex.
AB  - The exercise pressor reflex is believed to play a role in causing the
      cardiovascular and ventilatory responses to exercise. This review will discuss
      the evidence that the reflex is active in both humans and animals. In addition,
      this review will discuss the nature of the mechanical and metabolic stimuli that
      evoke the exercise pressor reflex. Particular attention will be paid to the
      discharge properties of the thin fiber sensory nerves (i. e., group III and IV
      muscle afferents) whose activation by these mechanical and metabolic stimuli is
      responsible for evoking the reflex. Finally, some current findings and
      controversies will be discussed.

PMID- 12598948
TI  - Breathing control in neurological diseases.
AB  - Control of ventilation depends on a brainstem neuronal network that controls
      activity of the motor neurons innervating the respiratory muscles. This network
      includes the pontine respiratory group and the dorsal and ventral respiratory
      groups in the medulla, which contain neurons that fire primarily during
      inspiration, post-inspiration, or expiration. The ventral respiratory group
      includes the pre-Botzinger complex, which contains neurokinin-1 receptor
      immunoreactive neurons critical for respiratory rhythmogenesis. Structural and
      degenerative disorders affecting this network produce abnormalities of
      respiration, including sleep apnea and various patterns of dysrhythmic breathing,
      not infrequently associated with disturbances of cardiovagal and sympathetic
      vasomotor control. This emphasizes the important interactions between the
      respiratory and cardiovascular control networks in the medulla. Common disorders
      associated with impaired cardiorespiratory control include brainstem stroke or
      compression, syringobulbia, Chiari malformation, high cervical spinal cord
      injuries, and multiple system atrophy. This review focuses on the functional
      organization of the respiratory control network and common causes of impaired
      control of respiration.

PMID- 12598949
TI  - Cardiovascular and respiratory consequences of bilateral involvement of the
      medullary intermediate reticular formation in syringobulbia.
AB  - We studied five patients with clinical and radiological evidence of syringobulbia
      (SB) to determine whether the distribution of lesions in relationship to the
      cardiorespiratory control networks in the medullary intermediate reticular zone
      (IRt) correlates with the presence of abnormalities in autonomic cardiovascular
      and respiratory control in these patients. All patients underwent high resolution
      MRI to characterize the size, volume and distribution of the SB lesions,
      cardiovascular autonomic function testing and polysomnography. One patient with
      bilateral IRt involvement at both the rostral and caudal medulla had orthostatic
      hypotension (OH), absent HR(DB), abnormal Valsalva ratio, exaggerated fall of BP
      during phase II and absent phase IV during VM, and a dramatic fall of BP during
      head up tilt; this patient also had severe obstructive sleep apnea (OSA) and
      exhibited BP drops during each respiratory effort. A second patient, with
      bilateral IRt involvement restricted to the caudal medulla, had less severe
      cardiovascular autonomic dysfunction but also exhibited severe OSA. The other
      three patients had small SB cavities sparing the IRt and had sleep apnea but no
      autonomic dysfunction. Autonomic dysfunction could not be related to the size of
      the syrinx or the degree of atrophy in the cervical spinal cord in any of the
      five patients. Bilateral involvement of the IRt by SB produces cardiovascular
      autonomic failure and sleep apnea. In patients with more restricted lesions,
      autonomic and respiratory dysfunction may be dissociated. Clinico-radiological
      correlations using high resolution MRI assessment of medullary lesions can
      provide insight into the central organization of cardiovascular and respiratory
      control in humans.

PMID- 12598950
TI  - Autonomic control of the heart and renal vascular bed during autonomic
      dysreflexia in high spinal cord injury.
AB  - Autonomic function and hemodynamics were studied in nine spinal cord injured
      (SCI) subjects, at rest and during peripheral afferent stimulation, bladder
      percussion. Nine able-bodied subjects were studied for comparison during
      unstimulated conditions. Spontaneous baroreceptor reflex sensitivity was
      calculated from recordings of ECG and intraarterial blood pressure. An index of
      sympathetic activity was provided by measuring total body noradrenaline (NA)
      spillover by isotope dilution technique. Renal vascular resistance was calculated
      from PAH-clearance.SCI subjects had lower total body NA spillover (1011 +/- 193
      vs 2261 +/- 328 pmol/min, P < 0.01), but similar baroreceptor reflex sensitivity
      and hemodynamics compared to able-bodied subjects at rest. In SCI group, during
      bladder percussion, mean arterial pressure increased (79 +/- 5 vs 113 +/- 8 mm
      Hg, P < 0.01), whereas heart rate was reduced during the first minute of the
      manoeuvre (62 +/- 2 vs 56 +/- 2 bpm, P < 0.05). Baroreceptor reflex sensitivity
      remained unchanged. Total body NA spillover and renal vascular resistance
      increased by 332 % (from 1004 +/- 218 pmol/min, P < 0.05) and 55 % (from 0.078 +/
      0.011 mmHg/ml/min, P < 0.05), respectively.SCI subjects demonstrated lower total
      body sympathetic outflow but normal baroreceptor reflex sensitivity at rest,
      suggesting a balanced autonomic output to the heart. Bladder percussion caused a
      substantial increase in renal vascular resistance and blood pressure, which was
      partly due to marked generalised sympathetic activation. This activation was
      counterbalanced by an increased vagal activity as evidenced by reduction of the
      heart rate.

PMID- 12598951
TI  - Baroreflex sensitivity in essential and secondary hypertension.
AB  - Baroreceptor reflex regulation has been shown to reset towards a higher blood
      pressure level and to operate with reduced sensitivity in hypertension. Whether
      this is secondary to elevated blood pressure or whether it plays a role in the
      development of hypertension is not known. In addition, only limited data exist on
      baroreflex sensitivity (BRS) in patients with long-lasting medically treated
      essential hypertension and in patients who have blood pressure elevation with
      similar severity, but of different etiology. The purpose of this study was to
      examine BRS in patients with different severity and forms of chronic, medically
      treated hypertension. Patients with renovascular hypertension (RVHT, n = 14),
      severe essential hypertension (SEHT, n = 36) and mild essential hypertension
      (MEHT, n = 29) as well as healthy age- and sex-matched control subjects were
      studied. BRS was measured with the phenylephrine method.BRS in the RVHT (3.7 +/-
      0.6 ms/mmHg) and SEHT (7.6 +/- 0.8 ms/mmHg) groups did not differ from each other
      after age, gender and left ventricular mass index were taken into consideration.
      On the contrary, BRS in the RVHT (p = 0.008) and SEHT (p = 0.016) groups were
      lower than in the MEHT (8.5 +/- 1.2 ms/mmHg) group. BRS was also significantly
      reduced in the RVHT (P = 0.004) and SEHT groups (P = 0.006) when compared to the
      healthy age- and sex-matched controls. BRS in the MEHT group did not differ from
      the control subjects. In conclusion, BRS was equally impaired in patients with
      renovascular and severe essential hypertension, which was similar in severity but
      different in etiology. BRS in patients with long-lasting medically treated mild
      essential hypertension did not differ from the healthy subjects. Our study
      suggests that baroreflex dysfunction in hypertensive patients is related to the
      clinical severity of hypertension, rather than its etiology.

PMID- 12598952
TI  - No increased herniation of the cerebellar tonsils in a group of patients with
      orthostatic intolerance.
AB  - Orthostatic intolerance, seen predominantly in young women, is characterized by
      symptoms of lightheadedness, fatigue and palpitations in the upright posture.
      With standing, plasma norepinephrine levels rise dramatically and heart rate
      often increases by more than 30 beats per minute, although blood pressure does
      not usually fall. A theory recently popularized in the media suggests that some
      cases of orthostatic intolerance are related to hindbrain compression, with or
      without a Chiari I malformation. As a preliminary investigation of this
      hypothesis, head or cervical spine MRI scans from 23 females with orthostatic
      intolerance were reviewed. The cerebellar tonsils averaged 0.3 +/- 1.9 mm below
      the foramen magnum. These results were compared to measurements from a control
      group averaging 0.4 +/- 2.6 mm above the foramen magnum (P > 0.05). Tonsillar
      depression of at least 3 mm occurred in 13 % of both the patient group and the
      control group. Tonsillar herniation was not found to influence supine or upright
      blood pressure, heart rate or plasma norepinephrine levels in the patients. We
      conclude that herniation of the cerebellar tonsils is not a common cause of
      orthostatic intolerance. However, the single measurement of tonsillar depression
      might underestimate the number of patients with hindbrain compression.

PMID- 12598953
TI  - Evidence of decreased sympathetic function in children with psychosomatic
      symptoms.
AB  - We investigated cardiovascular autonomic function using power spectral analysis
      of heart rate variation and beat-to-beat finger arterial pressure at rest and
      while standing and correlated these findings with self-reported psychosomatic and
      psychosocial symptoms in 122 schoolchildren. Children with three or more
      psychosomatic and psychosocial symptoms (somatizers) were found to have
      significantly lower blood pressure than children without symptoms. Somatizers had
      the more decreased spectral power of the low frequency (LF) band of arterial
      pressure and RR intervals in the supine position. The high frequency (HF) power
      did not differ between the two groups. Somatizers showed a more marked reduction
      in systolic arterial pressure at the onset of standing than did subjects without
      symptoms but somatizers showed an identical response in systolic arterial
      pressure when compared to subjects without symptoms during the later stage of
      standing. The increases in the LF band of arterial pressure and LF/HF of RR
      intervals during standing were higher in somatizers. These results suggest that
      somatizers have decreased sympathetic modulation. We conclude that psychosomatic
      and psychosocial symptoms in children might be associated with low blood pressure
      and decreased sympathetic modulation.

PMID- 12598954
TI  - Association between vasovagal hypotension and low sympathetic neural activity
      during presyncope.
AB  - Recent studies suggest that an underlying mechanism for susceptibility of
      patients and astronauts to presyncope includes hypoadrenergic responses to
      orthostatic stress. However, data used to reach this conclusion are open to
      various interpretations. In this report, maintenance of sympathetic neural
      activity (MSNA; peroneal nerve microneurography) during -60 mmHg lower body
      negative pressure (LBNP) was associated with maintenance of orthostatic
      tolerance, and disappearance of MSNA was associated with hypotension and pre
      syncope. However, MSNA was substantially higher during progressive increases of
      negative pressure in the presyncopal subject, compared to the non-presyncopal
      subjects. The data from this case report question the notion that orthostatic
      hypotension occurs due to inadequate sympathetic neural activation during
      orthostatic stress in apparently normal, healthy subjects.

PMID- 12598955
TI  - Cajal's contribution to the neurology of breathing.
AB  - Cajal, through his pioneering investigations, was able to characterize the
      location and connections of several brainstem nuclei. This, coupled with previous
      investigations by others, allowed him to formulate a concept of the microscopic
      anatomy of automatic respiration.

PMID- 12598956
TI  - Pediatric surgery in India - a specialty come of age?
AB  - The quality of neonatal surgical care and scientific publications are reliable
      yardsticks that were used to assess the status of pediatric surgery in India. A
      specific questionnaire to assess neonatal care and surgical outcome was mailed to
      all institutes imparting pediatric surgery training. Data were obtained regarding
      the outcome of important neonatal surgical conditions for the year 1998 and a
      PubMed literature search was performed to identify scientific articles between
      1995 and 2000. Though a literature search was done to compile a complete list of
      publications of all the consultants in all the institutes, of the 24
      questionnaires mailed, only 11 (45.8%) institutes provided data. The mean (range)
      annual neonatal admissions in neonatal surgical units was 137 (42-263). The mean
      newborn admissions requiring surgical intervention per surgeon per year was 36
      (17-80). The overall survival was 57.2% (30%-75%), 70.8% (40%-100%), 90.4% (75%
      100%), 74.7% (30%-100%), and 59.1% (0%-100%) for esophageal atresia (EA) with or
      without tracheoesophageal fistula (TEF), congenital diaphragmatic hernia,
      anorectal malformations, intestinal atresia, and abdominal-wall defects,
      respectively. The center that had the lowest survival in EA/TEF and CDH had the
      highest workload per consultant. Between 1995 and 2000, the mean number of
      scientific articles published in indexed journals compiled from all the
      institutes (n = 24) was 10.7 (0-84). In conclusion, this is a preliminary study
      toward setting up national databases of neonatal surgery in different parts of
      the world to set goals for improvement.

PMID- 12598957
TI  - Malignant solid tumours in neonates: an African perspective.
AB  - Malignant tumours in the neonate are distinct pathologically, clinically, and
      therapeutically from those in older children or adults. Behaviour cannot be
      directly implied from the histological appearance, and risk stratification is
      therefore difficult and complex. We review 42 patients seen over a 20-year
      period. Neuroblastoma (NB) was the commonest tumour seen (11), but the soft
      tissue sarcomas were the dominant group (14). The initial management was surgical
      when possible. Chemotherapy, despite appropriate dose reduction, had significant
      morbidity and mortality. Whilst the outcome for congenital fibrosarcoma was good
      (6/7, 86%), there were no survivors amongst 5 patients with rhabdomyosarcoma. In
      the absence of cytogenetic and biochemical markers, risk stratification amongst
      babies with NB was based upon INSS staging. Stage I disease was associated with a
      good prognosis, whilst stage IV disease was uniformly fatal. Stage IVs disease
      had only 50% early survival. Patients with renal tumours, whether nephroblastoma
      or mesoblastic nephroma, did well. Only patients with morphologically immature
      teratomas were included, amongst whom there are 2 of 7 (29%) known survivors, but
      43% have been lost to follow-up and their status is unknown. These figures are
      consistent with other reports from Africa.

PMID- 12598958
TI  - Lost bits: particle shedding with polyvinyl chloride intravenous administration
      sets.
AB  - Silicone particles have been demonstrated in the effluent from silicone
      intravenous (IV) tubing. It has been widely suspected that polyvinyl chloride
      (PVC) particles are also lost. We sought to clarify the situation in a carefully
      controlled laboratory setting using the apparatus and flow rates common in a
      paediatric setting, using scanning electron microscope techniques (SEM), we found
      that particles were indeed shed from IV tubing during use, but they were not PVC.

PMID- 12598959
TI  - Prognostic factors in prenatally-detected posterior urethral valves: a
      multivariate analysis.
AB  - To identify prognostic factors associated with chronic renal insufficiency in
      children with posterior urethral valves (PUV), 22 children with PUV were
      submitted to a systematic protocol and prospectively followed. Prognostic factors
      associated with fetal echography and clinical and laboratory findings were
      studied on admission. Median follow-up was 76 months. The analysis was conducted
      in two steps: in univariate analysis, variables associated with adverse outcome
      were identified by the Kaplan-Meier method. The variables that were significantly
      associated with adverse outcome were then included in a multivariate analysis
      using the Cox model. Eleven patients (50%) developed chronic renal failure (CRF)
      during follow-up. After adjustment by the multivariate model, four factors were
      identified as independent predictors of adverse outcome: oligohydramnios
      (relative risk [RR] = 10.6, 95% CI = 2.7 - 77, P = 0.02), ventilatory support (RR
      = 6, 95% CI = 2 - 24, P = 0.01), urea higher than 40 mg/dl (RR = 3.7, 95% CI =
      0.92 - 15.0, P = 0.06), and bilateral vesicoureteral reflux (VUR) (RR = 6.1, 95%
      CI = 1.25 - 30, P = 0.02). On the other hand, the presence of unilateral VUR was
      a protective factor against the development of CRF or death during follow-up (RR
      = 0.92, 95% CI = 0.87 - 0.98, P = 0.05).

PMID- 12598960
TI  - Concealed penis.
AB  - A small phallus causes great concern regarding genital adequacy. A concealed
      penis, although of normal size, appears small either because it is buried in
      prepubic tissues, enclosed in scrotal tissue penis palmatus (PP), or trapped due
      to phimosis or a scar following circumcision or trauma. From July 1978 to January
      2001 we operated upon 92 boys with concealed penises; 49 had buried penises (BP),
      while PP of varying degrees was noted in 14. Of 29 patients with a trapped penis,
      phimosis was noted in 9, post-circumcision cicatrix (PCC) in 17, radical
      circumcision in 2, and posttraumatic scarring in 1. The BP was corrected at 2-3
      years of age by incising the inner prepuce circumferentially, degloving the penis
      to the penopubic junction, dividing dysgenetic bands, and suturing the dermis of
      the penopubic skin to Buck's fascia with nonabsorbable sutures. Patients with PP
      required displacement of the scrotum in addition to correction of the BP.
      Phimosis was treated by circumcision. Patients with a PCC were recircumcised
      carefully, preserving normal skin, but Z-plasties and Byars flaps were often
      required for skin coverage. After radical circumcision and trauma, vascularized
      flaps were raised to cover the defect. Satisfactory results were obtained in all
      cases although 2 patients with BP required a second operation. The operation
      required to correct a concealed penis has to be tailored to its etiology.

PMID- 12598961
TI  - Histologic study of peritoneal adhesions in children and in a rat model.
AB  - Peritoneal adhesions (PA) represent a major cause of morbidity in pediatric
      surgical patients. The pathogenesis is still largely unknown. A possible role
      could be played by foreign bodies (FB) accidentally contaminating the operative
      field during surgery. We report a histologic study of PA in a rat model and in
      children, investigating the role of FB in their formation. Abdominal adhesions
      were studied in 18 rats. In 6 (group A) we performed a laparotomy and rubbed the
      visceral and parietal peritoneum with a cotton bud. In 6 (group B) we performed a
      minimal laparotomy and injected powdered autologous and heterologous material
      into the peritoneal cavity, avoiding any peritoneal abrasions. In 6 (group C) we
      performed a laparotomy and applied both treatment methods, i.e., rubbing and
      injection of FB. After 1 month, at autopsy rats were classified according to the
      presence and grade of surgical adhesions. Twenty-two PA were also collected from
      seven children undergoing abdominal surgery in whom one or more procedures had
      been previously performed. The adhesions were stained with hematoxylin-eosin and
      Giemsa stains for histologic examination. Adhesions were found in 4 rats of group
      A and all 6 rats of group C. None were identified in group B. Group C rats showed
      a higher grade of adhesions with respect to group A. In both humans and animals
      PA were always found to coexist with microscopic particles of solid substances,
      which were incorporated inside the connective tissue. However, after simple
      injection of FB into the abdominal cavity we did not observe any PA. These data
      suggest that two different stimuli are necessary for adhesion formation: a direct
      lesion of the mesothelial layers and a solid substrate (FB). We underline the
      importance of reducing contamination with FB during surgery. On the basis of
      these considerations, the laparoscopic approach seems to be particularly
      pertinent.

PMID- 12598962
TI  - Effects of melatonin and lactulose on the liver and kidneys in rats with
      obstructive jaundice.
AB  - The negative effects of obstructive jaundice (OJ) on the liver and kidneys cause
      high morbidity and mortality. In this study, the effects of melatonin (M) and
      lactulose (L) on the liver and kidneys were investigated by inducing OJ in 30
      rats in five groups (n = 6): controls, sham, M, L, and M + L. In the treatment
      group, after the rats' biliary canals were tied and cut, 10 mg/kg M IM and 2
      ml/day L p.o. was administered for 7 days. The histopathologic findings in the
      liver and kidneys, tissue malonyl dialdehyde (MDA) levels, and serum biochemistry
      were evaluated. In the M group, pathological histologic findings were less marked
      than in the other groups; investigation of kidney cross-sections revealed no
      significant differences among groups. In the jaundiced rats liver MDA levels were
      significantly higher compared to the control group ( P < 0.001), but no such
      difference was observed in kidney MDA levels ( P > 0.05). L did not cause any
      significant changes in tissue MDA levels. There were no differences among groups
      with regard to serum levels of liver enzymes and bilirubin. Serum urea was
      significantly less in the group that received L ( P < 0.001), but the groups
      showed no significant differences with respect to creatinine values ( P > 0.05).
      The increase in serum total cholesterol was significantly less in the M + L group
      than in the other groups ( P < 0.001). We conclude that in the rats in which
      obstructive jaundice was induced, M administration reduced liver and kidney
      injury, but L and M + L did not lead to significant improvement.

PMID- 12598963
TI  - Can histologic changes of the upper pole justify a conservative approach in
      neonatal duplex ectopic ureterocele?
AB  - The aim of this study was to review the histology of the upper-pole segment in
      patients with duplex-system ectopic ureterocele (DEU) to determine if less
      aggressive surgery is justified in prenatally-diagnosed cases. The study included
      15 consecutive patients with DEU treated between 1991 and 1999. The diagnosis was
      made according to the criteria of the Section on Urology of the American Academy
      of Pediatrics. The histology specimens were assessed for dysplastic,
      inflammatory, and obstructive changes. All 15 patients were surgically treated by
      heminephro-ureterectomy and the surgical specimens were histologically examined.
      Nine cases were diagnosed prenatally; the histology of the upper-pole segment in
      these patients showed segmental renal microcystic dysplasia, chondroid metaplasic
      islands, and an inflammatory tubulointerstitial nephropathy in 6 (66.6%) and
      nephroblastomatosis in 2 (22.2%). The histology of the 6 postnatally-diagnosed
      patients showed segmental multicystic renal dysplasia, inflammatory tubulo
      interstitial nephropathy, and segmental parenchymal scars. The upper-pole
      histology of the prenatally-diagnosed patients did not show any evidence of
      reversible histologic changes. Considering this findings and the good outcome of
      patients treated with upper-pole nephroureterectomy, less aggressive surgery with
      preservation of the upper pole does not seem justified.

PMID- 12598964
TI  - Endotoxemia associated with intussusception and its diagnostic and surgical
      interventions.
AB  - To determine if and when intussusception results in endotoxemia and to evaluate
      whether diagnostic and surgical interventions of intussusception aggravate
      endotoxemia, intussusception was created in seven pigs during general anesthesia
      (ileocolic n = 3, ileo-ileocolic n = 2, ileocolic with silicone ring as leadpoint
      n = 1, ileoileal with silicone ring n = 1). After a period of observation and
      before progression to bowel gangrene, a diagnostic ultrasound study with a saline
      enema was undertaken, followed by a laparotomy and resection of the
      intussusception with a primary bowel anastomosis. Serial blood samples were
      obtained before and at regular intervals after: (1) formation of the
      intussusception; (2) the enema; and (3) resection for endotoxin measurement by
      limulus amebocyte lysate assay. The mean level of endotoxin increased from a pre
      intussusception value of 0.750 EU/ml (range: 0.215-1.281) to a post
      intussusception maximum of 1.482 EU/ml (0.997-2.882, P = 0.009), peaking mostly
      at 2 h after the intussusception. The mean pre-saline-enema level was 1.547 EU/ml
      (0.869-2.677) while the post-enema level was 1.41 EU/ml (0.84-2.468, P = 0.655).
      The mean pre-resection level was 1.470 EU/ml (0.784-2.468) while the post
      resection maximum was (2.130 EU/ml) (0.850-4.381, P = 0.09). It is concluded
      that: (1) even in the absence of bowel gangrene intussusception results in
      significant endotoxemia within 2 h of its formation; (2) gentle saline enemas are
      not associated with endotoxemia; and (3) surgical resection results in a further
      upward surge of endotoxemia. These findings provide a scientific basis for
      improved understanding and management of intussusception.

PMID- 12598965
TI  - Perianal abscess in childhood.
AB  - Perianal abscess (PA) is a common condition encountered in childhood, but its
      optimal primary treatment is uncertain. Treatment of PA by incision and drainage
      (I & D) alone is associated with an unacceptably high recurrence rate, either as
      fistula-in-ano (FIA) or as PA. To identify possible causes of recurrence and
      assess the value of concomitant laying open of a fistulous tract at the time of
      primary incision and drainage, the case notes of all children who presented to
      our institution with a PA between January 1992 and January 1997 were reviewed
      retrospectively. Thirty-three cases were identified (29 boys and 4 girls). A
      fistulous tract was identified and laid open at the time of primary drainage in
      20 cases, whilst 13 were treated by I & D alone. Following primary drainage,
      there were 7 recurrences (21.2%) (FIA 5 and PA 2). All recurrences had been
      primarily treated by drainage alone, whilst there were no recurrences in patients
      who had also undergone fistulotomy at the time of primary drainage. Thus the
      primary treatment of PA in childhood should involve a careful search for a
      coexisting fistula and treatment of this by fistulotomy.

PMID- 12598966
TI  - Conservative management of pneumatosis intestinalis and pneumoperitoneum
      following bone-marrow transplantation.
AB  - Pneumatosis intestinalis (PI), with or without pneumoperitoneum (PP), may
      complicate allogenic bone-marrow transplantation (BMT). The aim of our study was
      to establish the incidence and outcome of this complication following BMT in
      children. A departmental database was used to identify children who underwent BMT
      in the 4-year period up to December 1999. The medical records of children who
      developed PI with or without PP were obtained for further study. All patients
      were managed without recourse to surgery. Conservative management included 7 days
      of intravenous antibiotics and 10 days of intestinal rest supported by parenteral
      nutrition. In the study period, 138 BMTs were carried out. Six children (4%) with
      a total of 7 episodes of PI/PP were identified, 1 boy and 5 girls with a median
      age of 8.5 years (range 0.8-11). Neutropenia was noted in 3 children at the time
      of presentation. Other risk factors identified included alternative BMT donors
      (5/6), steroid therapy (6/7), and graft-versus-host disease (5/6). Organisms were
      isolated from stool cultures sent at the time of diagnosis in 3 out of 7
      instances. Diarrhoea was the predominant presenting symptom. All patients
      recovered from the acute episode, but 5 died at a mean of 12 months from the
      development of PI/PP (range 6-17 months). This mortality of 83% compares with a
      mortality of 33% (43 of 132) for the remainder of children who underwent BMT
      during the study period. Thus, while initial recovery can be anticipated, the
      medium-term mortality in this group of children is high.

PMID- 12598967
TI  - Factors effecting morbidity in typhoid intestinal perforation in children.
AB  - To determine the factors affecting morbidity in patients with typhoid intestinal
      perforation (TIP), 42 patients who had been operated upon for TIP between 1990
      and 2000 were reviewed. The average age was 10.4 years, the male-to-female ratio
      2.5/1. The mean interval from admission to operation was 6 h. Twenty-three
      children had multiple perforations. Primary closure (PC) was performed in 55% of
      the patients, ileostomy in 26%, and resection with anastomosis (RA) in 19%.
      Parenteral nutrition (PN) was available for 22 patients for an average of 9 days.
      Postoperative complications occurred more commonly in patients with delayed
      admission and/or severe peritonitis. Hospitalization was shorter and the
      postoperative complication rate lower in patients who received PN and in those
      who underwent ileostomy. None of the patients developed an enterocutaneous
      fistula. The 2 deaths (4.8%) resulted from overwhelming sepsis. The most
      significant factors affecting morbidity were prolongation of perforation
      operation interval and severe peritonitis. No operative procedure is likely to be
      the best in all cases; therapy should be individualized. Ileostomy appears to be
      an effective procedure, particularly in patients with severe abdominal
      contamination and delayed presentation. The use of PN in addition to standard
      medical and surgical therapy in patients with TIP may be beneficial.

PMID- 12598968
TI  - Exclusion of androgen insensitivity syndrome in girls with inguinal hernias:
      current surgical practice.
AB  - To review the current approach of paediatric surgeons to the exclusion of
      androgen insensitivity syndrome (CAIS) in girls with inguinal hernias (IH), a
      questionnaire was sent to all specialist paediatric surgeons in the United
      Kingdom and Ireland asking if they exclude CAIS, how they exclude it, and what
      they say to parents preoperatively. In all, 32 surgeons responded (29%); 41% made
      no attempt to exclude CAIS because they thought the incidence was too low to
      justify exclusion; 19(59%) excluded CAIS at the time of surgery by assessment of
      the internal genitalia. Only 1 performed karyotyping primarily, and then only for
      bilateral IH. Although most would proceed to karyotyping if the primary
      assessment suggested CAIS, some would not. Of those who exclude CAIS, only 1
      mentions CAIS preoperatively, 6 others mention gonadal inspection, and 12/19
      (63%) make no comment. Thirty-one surgeons agreed to take part in a prospective
      study to define the incidence of CAIS in girls with IH. It is concluded that
      surgeons who exclude CAIS in girls with IH adopt different assessment methods,
      some of which may be unreliable. However, many do not attempt to exclude CAIS,
      believing the incidence to be too low. As the health and medicolegal consequences
      of failing to exclude CAIS may be considerable, surgeons should consider changing
      their practice. A prospective study should be undertaken to determine the
      incidence of CAIS in girls with IH.

PMID- 12598969
TI  - A comparison of the clinical presentation and outcome of focal intestinal
      perforation and necrotizing enterocolitis in very-low-birth-weight neonates.
AB  - There is controversy about the identity of focal intestinal perforation (FIP) and
      necrotizing enterocolitis (NEC). To elucidate the difference between them, we
      reviewed their clinical presentations. Over the last 20 years, 39 very-low-birth
      weight (VLBW) neonates, including 21 extremely-low-birth-weight neonates,
      underwent a laparotomy for intestinal perforation without mechanical causes.
      Nineteen patients had typical findings of NEC, and 8 had FIP. FIP is defined as
      isolated intestinal perforation without gross necrosis. In FIP, the gestational
      age was significantly lower than in NEC (23.8 +/- 1.8 vs 27.0 +/- 2.5 weeks, P <
      0.01). The birth weight (BW) of FIP patients was lower than that of NEC infants
      (635 +/- 134 vs 883 +/- 256 g, P < 0.05). The incidence of coexistent respiratory
      distress syndrome (RDS) was higher in FIP compared to NEC (88% vs 37%, P < 0.05).
      The age at onset was younger in FIP than NEC (7.3 +/- 2.7 vs 14.4 +/- 7.9 days, P
      < 0.05). All patients except 1 had the sites of perforation exteriorized. There
      was a trend toward higher survival in FIP compared to NEC (88% vs 58%, P =
      0.136). Our data clearly show differences in BW, gestational age, and association
      of RDS between FIP and NEC. Based on our data, prematurity and RDS appear to be
      the major etiologic factors of FIP. The present series supports the fact that FIP
      is a definite clinical entity.

PMID- 12598970
TI  - Atypical mycobacterial disease in children: a personal series.
AB  - Atypical mycobacterial disease is common in children in Australia. Over 22 years,
      records were kept prospectively by the senior author. The diagnosis was confirmed
      in 118 patients, either by culture or by the combination of a positive skin test
      plus typical histology. There were 46 boys and 72 girls with a median age at
      diagnosis of 28 months. Most children (n = 56) presented with chronic
      lymphadenitis or abscess formation (n = 55). The duration of illness varied from
      4 days to 18 months. The most common sites affected were the head and neck (n =
      112), with the pre-auricular region and anterior end of the submandibular
      triangle being characteristic. Nine patients had multifocal disease. The aim of
      treatment is to excise as much of the infected tissue as possible: 47 children
      had node excision through a planned incision that was closed primarily, with only
      4 needing a second operation; 42 had excision of a node through the base of the
      superficial part of a collar-stud abscess with 6 recurrences. However, of the 33
      children who had only drainage/curettage of the cavity or node 10 had recurrences
      requiring re-operation. Only 1 patient required a third operation. Morbidity was
      extremely low, with 1 staphylococcal wound infection. No child suffered permanent
      paresis of the mandibular division of the facial nerve. It is our belief that
      surgical excision of both the macroscopically affected and adjacent
      macroscopically unaffected nodes is necessary to achieve cure in the majority of
      cases.

PMID- 12598971
TI  - Intraluminal casein model of necrotizing enterocolitis for assessment of mucosal
      destruction, bacterial translocation, and the effects of allopurinol and N
      acetylcysteine.
AB  - An intraluminal casein model (ICM) of necrotizing enterocolitis (NEC) is able to
      produce small-bowel changes reminiscent of human NEC in neonatal animals. We
      studied bacterial translocation (BT) in NEC induced by using the ICM in neonatal
      piglets. We also studied whether allopurinol (AL) and N-acetylcysteine (NAC) have
      an effect on BT and mucosal changes in the ICM of NEC. Twenty-eight neonatal
      piglets were randomized into four groups. NEC was induced in 21 by injecting
      casein-d-gluconate into a loop of terminal ileum: group Cas (n = 7) had no
      premedication, in group Cas/AL (n = 7) intravenous (i.v.) Al (100 mg/kg), and in
      group Cas/NAC (n = 7) i.v. NAC (200 mg/kg) was given. Group Sham (n = 7) had the
      ileum injected with 0.9% saline with no premedication. Immediately after the
      injection a mesenteric lymph node (MLN) adjacent to the loop was harvested for
      quantitative aerobic bacterial culture; 4 h after the injection another MLN and
      samples of spleen, liver, kidney, and lung were harvested and cultured.
      Comparison of the incidence of samples with positive bacterial cultures and the
      number of colony-forming units (CFU) in samples was made between groups. The
      severity of NEC in the ileum was graded from 0 to 3 according to macroscopic and
      histologic findings. NEC changes in the bowel were most severe in Cas piglets,
      less severe in Cas/NAC piglets ( P < 0.5), and sham piglets had the least severe
      changes ( P < 0.05). piglets with NEC changes in the ileum had a higher incidence
      of BT into the MLN than piglets without NEC changes ( P < 0.05), but the
      difference in CFU was not significant ( P > 0.05). In Cas and Cas/NAC piglets a
      high incidence of BT into the MLN was noted as early at -5 min after casein
      injection. The incidence of BT into the MLN was significantly higher in Cas and
      Cas/NAC piglets than in Sham piglets ( P < 0.05), the difference in CFU being not
      significant ( P > 0.05). BT in Cas/Al piglets was not significantly different
      from that of Cas piglets ( P > 0.05), but less than in Cas/NAC piglets ( P <
      0.05). Four hours after casein injection into the ileum there was significant BT
      into the MLN. Premedication with NAC was associated with less severe NEC changes,
      but neither NAC nor AL significantly affected BT.

PMID- 12598972
TI  - Endorectal pull-through for Hirschsprung's disease: 17-year review of results in
      Ukraine.
AB  - Several surgical procedures are available for the treatment of Hirschsprung's
      disease (HD) the choice often depends on the surgeon's preference. The procedure
      that is most convenient for the surgeon is not necessarily the optimal one for
      the patient, however, and complications and mortality need to be considered. We
      reviewed our series of 275 children operated upon for HD by endorectal pull
      through after Soave-Boley dissection of the seromuscular cuff followed by a hand
      sutured (HSA) (210) or stapled (SA) (65) primary perineal colorectal anastomosis.
      Early postoperative complications were documented in 13 children with a HSA and 5
      with a SA Follow-up was from 6 months to 15 years for HSA patients with and from
      1 month to 3 years after SA. Results were good or satisfactory; there were no
      unsatisfactory results. On long-term follow-up the complication rate after SA
      (13.8%) was comparable to that after HSA (20.5%). The overall complication rate
      on long-term follow-up was 2.91%, which is comparable to results published in the
      literature. The SA is particularly convenient for surgeon, as it allows a simpler
      and shorter operation than with the traditional HSA.

PMID- 12598973
TI  - Relationship of the fistulas to the rectum and genitourinary tract in mouse
      fetuses with high anorectal malformations induced by all-trans retinoic acid.
AB  - Since high anorectal malformations with fistulae in human embryos and fetuses of
      successive developmental stages have not been reported, the embryologic
      relationship between the rectal fistula (RF) and the genitourinary tract (GUT) in
      high anorectal agenesis (ARA) remains to be elucidated. This study investigates
      the developmental relationship between the RF and the GUT in male and female
      fetuses with high ARA using our established model for high ARA with fistula in
      mice. Pregnant mice received all-trans retinoic acid suspended in corn oil (5
      mg/ml) 100 mg/kg i.p. on day 9 of pregnancy. All fetuses were removed from the
      uterus on a single day from days 12 to 18 of pregnancy. The caudal regions were
      analyzed histologically with hematoxylin and eosin staining. All fetuses examined
      had high ARA with fistula. On day 12 of pregnancy, an anomalous communication was
      seen between the urogenital sinus (UGS) and the rectum. In the affected female
      fetuses, on day 14 of pregnancy the paramesonephric (mullerian) ducts and
      mullerian tubercle were located above the rectocloacal fistula (RCF), and on day
      18 of pregnancy the uterovaginal canal was located between the cloaca and the
      RCF. In the male fetuses, on day 14 of pregnancy the junction between the
      mesonephric (wolffian) duct and the UGS was located away from the junction
      between the rectum and the UGS. On day 18 of pregnancy the ejaculatory duct was
      located between the urinary bladder and the rectourethral fistula. The results of
      our experiment clearly show the embryologic relationship between the RF and the
      GUT with high ARA. The anomalous communication between the UGS and the rectum may
      interfere with normal caudal migration along the dorsal wall of the UGS at the
      junction between the UGS and the mesonephric or paramesonephric duct.

PMID- 12598974
TI  - Primary peritonitis in a child caused by Haemophilus parainfluenzae.
AB  - A case of primary peritonitis caused by Haemophilus parainfluenzae in a
      previously healthy child is presented. To our knowledge, this is the first such
      documented case.

PMID- 12598975
TI  - Ruptured adrenocortical carcinoma as a cause of paediatric acute abdomen.
AB  - Adrenocortical carcinoma (ACC) is rare in children. Its presentation is usually
      related to hormonal activity of the tumour. We report a case of childhood ACC
      that presented as an acute abdomen due to tumour rupture. This is the first
      reported case of a ruptured ACC as a cause of paediatric acute abdomen.

PMID- 12598976
TI  - Congenital bowel perforation in twin-to-twin transfusion syndrome.
AB  - Two unrelated survivors of twin-to-twin transfusion syndrome (TTTS) presented
      with intestinal perforation at birth. Both were localised perforations without
      any suggestion of widespread ischaemic disease to the splanchnic bed.
      Histopathology from the perforation site showed evidence of focal ischaemic
      necrosis, presumably from a vascular accident. One infant later died of multiple
      organ failure with major brain damage, but the other survived without long-term
      sequelae. These two cases appear to represent an unreported variation of the
      ischaemic intestinal complications of TTTS.

PMID- 12598977
TI  - Multicystic dysplasia in one-half of a horseshoe kidney with megaureter and lower
      ureteric atresia.
AB  - During evaluation of chronic abdominal pain, a 9-year-old male was found to have
      a horseshoe kidney (HSK) with multicystic dysplasia (MCD) of the left-sided
      component. Attached to the MCD was a very large, tortuous ureter occupying almost
      the whole left side of the abdomen. This ureter on dissection was found to end
      blindly adjacent to the bladder. MCD of one-half of a HSK is an unusual lesion.
      Its association with a large megaureter with juxtavesical atresia is a unique
      event. In HSKs, controversy exists about the need to remove a small dysplastic
      segment. If this segment is associated with a large ureter, as in our case,
      removal is mandatory in order to avoid pain and infection.

PMID- 12598978
TI  - Laparoscopic Kasai portoenterostomy for biliary atresia.
AB  - Conventional surgery for extrahepatic bile-duct atresia (EHBDA) usually requires
      a large, painful, muscle-cutting laparotomy, dislodgment of the liver, and wide
      manipulations, followed by adhesions and possible complications that may disturb
      the postoperative course and hamper liver transplantation (LT). The main role of
      laparoscopy in EHBDA has been for diagnostic purposes. Besides all the advantages
      of minimally-invasive access, it allows excellent visibility and dissection of
      tiny hilar structures. The authors present the first two cases of successful Roux
      en-Y laparoscopic portoenterostomy (LARP) for EHBDA, showing the importance of
      advanced technical skills and a new approach for extracorporeal
      enteroanastomosis. Laparoscopic hilar dissection and portoenterostomy was
      accomplished using four trocars. The umbilical site was used for extracorporeal
      Roux-en-Y enteroenterostomy, in the first case using a laparoscopic stapler and
      in the second a hand-sewn suture. Mean operative time was 190 min, and no
      operative complications were observed. Both girls became anicteric. The first is
      doing well 15 months after the operation with good hepatic function. The other
      was anicteric for 6 months, had one episode of cholangitis, developed an
      umbilical hernia, has shown slow and progressive hepatic failure, and is now
      being evaluated for possible LT. It is concluded that LARP for EHBDA can be done
      safely in infants using an extracorporeal transumbilical enteric anastomosis,
      with several advantages compared with open surgery. The role of LARP in
      facilitating LT is yet to be defined.

PMID- 12598979
TI  - Enterolithiasis with imperforate anus: report of a case.
AB  - A three-year-old child presented with imperforate anus. A local perineal
      procedure was performed at birth, possibly without repairing the fistula. The
      child later presented with severe anal stenosis, which required a divided sigmoid
      colostomy. The child later presented at the age of two years with multiple radio
      opaque shadows in the pelvis. These proved to be enteroliths, which had developed
      in the distal rectal stump possibly due to a large associated recto-urethral
      fistula with associated urinary stasis.

PMID- 12598980
TI  - An unusual neurogenic cystic tumor.
AB  - The presacral cystic teratoma in an infant is reported. The cyst consisted solely
      of central nervous system tissue. This pathologic finding is extremely rare. A
      review of the literature reveals no previous report of a teratoma arising in this
      manner.

PMID- 12598981
TI  - Thoracoscopic sympathectomy using ultrasonic coagulating shears: a technical
      improvement in the treatment of palmar hyperhidrosis.
AB  - Thoracoscopic sympathectomy has emerged in recent years as the treatment of
      choice for primary palmar hyperhidrosis when medical treatment fails.
      Postoperative complications have been reported in large series, however,
      including neurologic problems such as temporary or definitive Horner syndrome and
      peripheral nerve injuries. The authors report the use of ultrasonic coagulating
      scissors instead of electrocautery for the dissection and removal of a segment of
      sympathetic chain in an 11-year-old girl. A bilateral procedure was performed
      sequentially through three 5-mm axillary trocars on each side. The use of
      ultrasonic shears eliminates the risk of distal nerve injury induced by the
      spread of electric current and could possibly reduce the incidence of the above
      mentioned complications.

PMID- 12598982
TI  - A technique to facilitate nursing care in patients with long-gap esophageal
      atresia.

PMID- 12598983
TI  - 180 Degrees rotated intestinal anastomosis for jejunoileal atresia in neonates -
      a preliminary study.
AB  - The authors report the results of a preliminary study of a new technique of 180
      degrees rotated anastomosis carried out as a primary anastomosis for ten neonates
      with jejunoileal atresia. The details of the technique are illustrated. The
      advantages of this technique over the conventional end-to-back anastomosis are
      discussed. A comparative analysis shows improved results compared to the
      conventional anastomosis.

PMID- 12598984
TI  - Rectal biopsy: what is the optimal procedure?
AB  - Rectal suction biopsy (RSB) is a well-known diagnostic procedure for disorders of
      bowel motility such as Hirschsprung's disease (HD). However, there are few
      reports about the optimal method of obtaining rectal tissue. We introduce a new
      technique using Gruenwald's nasal cutting forceps (NCF). From 1986 to 1999, we
      performed 130 sets of rectal biopsies in patients suspected of having HD. In
      group I (1986 to 1994), 68 sets of three-site biopsies (2, 3, and 5 cm above the
      dentate line) were performed using a conventional blind RSB technique. In group
      II (1995 to 1999), 62 sets of one-site biopsies (2 cm above the dentate line)
      were performed using Gruenwald's NCF after anal dilatation during general
      anesthesia. Hematoxylin-eosin staining and acetylcholinesterase histochemistry
      were used to examine all specimens. Biopsy specimens in group II (4.39 +/- 1.07
      mm(2)) were larger than in group I (1.59 +/- 0.39 mm(2)) ( P < 0.01). In 18 cases
      (26 %) in group I, normal and HD bowel could not be differentiated because the
      specimens were too small to detect ganglion cells (i.e., only lamina propria [9
      cases] or a small area of submucosa [9 cases] was present). These cases required
      repeat biopsy. All cases of HD diagnosed in group I (n = 20) were based on the
      findings of biopsies taken at 2 cm; biopsies from 3 and 5 cm did not provide
      additional information. There were 2 cases of post-biopsy hemorrhage in group I.
      In group II, 18 subjects were diagnosed with HD and 39 were confirmed to have
      normal bowel. There were no complications and repeating the biopsy was
      unnecessary. Three cases of hypoganglionosis (1 in group I and 2 in group II)
      were missed because the myenteric plexus abnormalities could not be detected by
      RSB. Intestinal neuronal dysplasia (IND) was diagnosed in 5 cases (2 in group I
      by repeat full-thickness biopsy and 3 in group II by rectal biopsy). We conclude
      that our new technique is advantageous and safe to differentiate between normal
      bowel, HD, and even IND on the basis of a single biopsy taken 2 cm above the
      dentate line. The biopsy can be taken under direct vision and is
      histopathologically accurate.

PMID- 12598985
TI  - Optical-based molecular imaging: contrast agents and potential medical
      applications.
AB  - Laser- and sensitive charge-coupled device technology together with advanced
      mathematical modelling of photon propagation in tissue has prompted the
      development of novel optical imaging technologies. Fast surface-weighted imaging
      modalities, such as fluorescence reflectance imaging (FRI) and 3D quantitative
      fluorescence-mediated tomography have now become available [1, 2]. These
      technical advances are paralleled by a rapid development of a whole range of new
      optical contrasting strategies, which are designed to generate molecular contrast
      within a living organism. The combination of both, technical advances of light
      detection and the refinement of optical contrast media, finally yields a new
      spectrum of tools for in vivo molecular diagnostics. Whereas the technical
      aspects of optical imaging are covered in more detail in a previous review
      article in "European Radiology" [3], this article focuses on new developments in
      optical contrasting strategies and design of optical contrast agents for in vivo
      diagnostics.

PMID- 12598986
TI  - Fine-needle percutaneous transhepatic parenchymal portal venography by using
      carbon dioxide: a pilot study in pigs.
AB  - Our purpose was to evaluate the feasibility and safety of carbon dioxide (CO(2))
      in fine-needle percutaneous transhepatic parenchymal portal venography and its
      potential clinical applications. Three Belgian landrace pigs received fine-needle
      percutaneous transhepatic parenchymal portal venography by using CO(2) as a
      contrast agent. Under fluoroscopic and B-mode ultrasonic guidance, right or left
      lobe of liver was punctured with a 22-G Chiba needle, through which CO(2) was
      injected with a dedicated CO(2) injector at injection rate of 20 ml/s for 20 ml,
      40 ml/s for 40 ml, 40 ml/s for 60 ml, and 40 ml/s for 80 ml, respectively. The
      portal venograms were obtained by use of digital subtraction angiography (DSA)
      system with animal in supine position. In one pig transarterial portal venography
      was performed, in addition, using iodinated contrast agent. The portal vein was
      visualized in each run of venography. Optimal images of portal tree structure up
      to four-order branches were obtained in all those with CO(2) injection rate of 40
      ml/s, which appeared much better in quality than those obtained by cranial
      mesenteric arteriography with iodinated contrast agent. No extravasation of
      CO(2), liver laceration, or any other complication occurred during the
      procedures. The technique we proposed demonstrated optimal portography, which
      appeared to be safe, minimally invasive, less time-consuming, cost-effective, and
      easy to perform, with great potential in clinical applications.

PMID- 12598987
TI  - Deep vein thrombosis of the upper extremity: intra- and interobserver study of
      digital subtraction venography.
AB  - Our objective was to assess the inter-observer and intra-observer agreement in
      the interpretation of digital subtraction venography (DSV) in patients with
      suspected deep vein thrombosis of the upper extremity (DVTUE). Prospectively, 62
      consecutive DSV studies in 54 patients with clinically suspected DVTUE were
      included. Hard copies were presented without demographic data or original report.
      All venograms were read twice, at 3-month intervals, by an interventional
      vascular radiologist (observer 1) and an experienced general radiologist
      (observer 2). Consensus reading took place in the presence of a third experienced
      interventional radiologist. Inter-observer and intra-observer agreement were
      assessed using kappa statistics. Initial reading in 62 venograms showed an inter
      observer agreement of 71% (kappa 0.48). The inter-observer agreement of the
      second reading was 83% (kappa 0.71). The agreement with the consensus report
      ranged from 76 to 94%. The intra-observer agreement for the first and second
      observer was 94% (kappa 0.89) and 76% (kappa 0.56), respectively ( p<0.01).
      Digital subtraction venography has moderate to excellent intra- and inter
      observer agreement, suggesting that digital subtraction venography is reliable
      for the diagnosis of DVTUE.

PMID- 12598988
TI  - Upper limb vein anatomy before hemodialysis fistula creation: cross-sectional
      anatomy using MR venography.
AB  - Preoperative imaging is indicated to discriminate patent, adequate superficial
      veins of the upper limbs undetectable by clinical inspection that could be
      anastomosed for the creation of a durable and functional hemodialysis fistula.
      The aim of this pictorial review is to provide a venous anatomic map of the upper
      limbs using MR venography (MRV) which could help surgeons before creation of
      hemodialysis access fistulas (AVF). At the level of the forearm, the antebrachial
      cephalic vein is the most commonly identified as patent. At the level of the
      elbow and distal arm, the cephalic vein is patent in 80% of normal subjects, and
      less often patent (23-26%) than basilic vein (33-38%) in patients. Overall,
      reading transaxial MR views can help for assessing upper limb vein anatomy before
      creation of a hemodialysis access fistula.

PMID- 12598989
TI  - Preoperative evaluation of malignant liver tumors: comparison of unenhanced and
      SPIO (Resovist)-enhanced MR imaging with biphasic CTAP and intraoperative US.
AB  - The purpose of this study was to evaluate the diagnostic efficacy of iron-oxide
      enhanced MRI vs CT during arterial portography (CTAP) and intraoperative
      ultrasound (IOUS) in detection of liver neoplasms. Seventeen patients with
      malignant focal liver lesions (liver metastases, n=7), hepatocellular carcinomas
      (HCC, n=9), and cholangiocellular carcinoma (CCC, n=1) underwent presurgical
      Resovist-enhanced MRI and CTAP. Two independent observers (A and B) assessed the
      blinded images of unenhanced and iron-oxide-enhanced MRI vs CTAP for the
      presence, number, and location of the liver lesions. These results were compared
      lesion by lesion and segment by segment with the results of intraoperative
      ultrasound ( n=17) serving as the reference standard. Eighty lesions were
      detected by intraoperative ultrasound in 17 patients. In comparison with IOUS
      (lesion-by-lesion analysis) the sensitivity was 86.8% for CTAP, 65% for combined
      unenhanced MR imaging, and 86.8% for combined Resovist-enhanced MRI as well as
      86.8% for the combination of unenhanced and Resovist-enhanced MRI. Compared with
      the sensitivity of combined unenhanced MRI the sensitivity of CTAP as well as the
      sensitivity of combined Resovist-enhanced MRI was significantly higher (p<0.05).
      False-positive results were much higher in CTAP as compared with combined
      unenhanced and SPIO-enhanced MRI. Using the segment-by-segment analysis the
      specificity of combined unenhanced MRI with 100% (96.7-100%) as well as combined
      Resovist-enhanced MRI with 100% (96.7-100%) was significantly higher (p<0.05) in
      comparison with the specificity of CTAP with 91.1% (83.2-96.1%). The accuracy of
      combined unenhanced MRI was 100% (93.2-100%), combined Resovist-enhanced MRI 100%
      (93.6-100%) and of CTAP 85.2% (72.9-93.4%). In the detection of focal liver
      lesions iron-oxide-enhanced MR imaging is superior to unenhanced MRI and similar
      to CTAP.

PMID- 12598990
TI  - Non-invasive quantification of pancreatic exocrine function using secretin
      stimulated MRCP.
AB  - Our objective was to quantify water volume using magnetic resonance
      cholangiopancreatography (MRCP) sequences and apply this to secretin-stimulated
      studies with the aim of quantifying pancreatic exocrine function. A commercially
      available single-shot MRCP sequence was used in conjunction with a body phased
      array coil and a 1.5-T MR system. Signal intensity was measured in samples of
      water, pancreatic, duodenal juice, and secretin-stimulated pancreatic juice. A
      water phantom was made and MR calculated volumes compared with known water
      volumes within the phantom. Changes in small intestinal volume in response to
      secretin were measured in a group of 11 patients with no evidence of pancreatic
      disease. Changes in water volume were plotted over time. The pancreatic duct
      diameter before and after secretin was noted and filling defects were sought. All
      patients also underwent an axial breath-hold T1-weighted gradient-echo sequence
      and the pancreatic parenchyma was evaluated for size and signal intensity. There
      was no difference in the signal intensity of the different juice samples. There
      was excellent correlation between known and calculated MRCP volumes
      (chi(2)=0.99). All patients demonstrated normal duct morphology on MRCP and
      normal pancreatic parenchyma on T1-weighted imaging. The mean flow rate in the
      patient population was 8.1+/-2.5 ml/s over a median of 7 min (range 5-9 min). The
      MRCP sequence can be used to measure water volume. Sequential MRCP measurements
      following secretin permitted calculation of volume change and flow rate. This
      should prove useful as an indicator of pancreatic exocrine function.

PMID- 12598991
TI  - Assessment of the pancreatic and intrapancreatic bile ducts using 0.5-mm
      collimation and multiplanar reformatted images in multislice CT.
AB  - Our objective was to evaluate the ability of multiplanar reformatted (MPR) images
      combined with 0.5-mm axial images to depict the pancreatic and intrapancreatic
      bile ducts and compare the results with those of 0.5-mm axial, 2-mm axial, and 6
      mm axial images alone. Seventy-seven patients without obstruction of the main
      pancreatic ducts (MPD) underwent dual-phase helical scanning of the pancreas
      using multislice computed tomography (MSCT). The MPR images were generated from
      0.5-mm-thick images. Visualization of the pancreatic and intrapancreatic bile
      ducts and their confluence was graded on a four-point scale by a consensus of two
      radiologists. The results for 0.5-mm axial images in early-phase CT, 2-mm axial
      images in early-phase CT, MPR images combined with 0.5-mm axial images in early
      phase CT, and 6-mm axial images in late-phase CT were then compared. The
      relationships of the focal pancreatic lesions with the pancreatic ducts were
      analyzed. The MPR images combined with 0.5-mm axial images were significantly
      superior to the other three types of images for the visualization of the
      pancreatic and intrapancreatic bile ducts and their confluence (p<0.01). The
      depiction rate of the MPD using MPR images combined with 0.5-mm axial images was
      94, 94, 95, and 75%, respectively in the head, neck, body, and tail of the
      pancreas. Accessory pancreatic ducts, intrapancreatic bile ducts, and duct
      confluence were depicted in 48, 99, and 92%, respectively. In comparison with
      evaluation based on axial images alone, the use of MPR images more clearly
      demonstrated the relationship between the lesions and the pancreatic ducts in 14
      of 19 lesions. The MPR images combined with 0.5-mm axial images improve the CT
      depiction of the pancreatic and intrapancreatic bile ducts in comparison with 0.5
      mm axial, 2-mm axial, and 6-mm axial images alone.

PMID- 12598992
TI  - Budd-Chiari syndrome due to prothrombotic disorder: mid-term patency and efficacy
      of endovascular stents.
AB  - Our objective was to evaluate efficacy and patency of metallic stent placement
      for symptomatic Budd-Chiari syndrome (BCS) due to prothrombotic disorders. Eleven
      patients with proved BCS due to prothrombotic disorders were referred for
      endovascular treatment because of refractory ascites (n=9), abdominal pain (n=8),
      jaundice (n=6), and/or gastrointestinal bleeding (n=4). Stents were inserted for
      stenosed hepatic vein (n=7), inferior vena cava (n=2), or mesenterico-caval shunt
      (n=2). Clinical efficacy and stent patency was evaluated by clinical and Doppler
      follow-up. After a mean follow-up of 21 months, 6 patients had fully patent
      stents without reintervention (primary stent patency: 55%). Two patients with
      hepatic vein stenosis had stent thrombosis and died 4 months after procedure.
      Restenosis occurred in 3 cases (2 hepatic vein and 1 mesenterico-caval shunt
      stenosis) and were successfully treated by balloon angioplasty (n=2) and addition
      of new stents (n=1) leading to a 82% secondary stent patency. Of 9 patients with
      patent stent, 7 were asymptomatic (77%) at the end of the study. Stent placement
      is a safe and effective procedure to control of symptomatic BCS. Prothrombotic
      disorder does not seem to jeopardize patency in anticoagulated patients.

PMID- 12598993
TI  - Effect of subcutaneous butylscopolamine administration in the reduction of
      peristaltic artifacts in 1.5-T MR fast abdominal examinations.
AB  - In abdominal MR imaging, ghost artifacts from noncyclic bowel movements can
      reduce the quality of the images. Although pharmacologic suppression of motion is
      effective, no study has being conducted to analyze the influence of drug motion
      suppression on fast breath-hold 1.5-T examinations of the upper abdomen. A
      prospective, randomized, double-blind trial was conducted in 50 patients.
      Patients were randomly distributed into two groups: The control group received
      only an oral solution, whereas the other group received the oral solution plus a
      subcutaneous injection of 20 mg of butylscopolamine 10 min before the MR
      examination. Breath-hold T1-weighted gradient-recalled-echo (GRE) MR images were
      obtained in a 1.5-T superconductive unit. Quantitative image analysis was
      performed with region-of-interest (ROI) measurements of the signal intensity of
      the liver and in background air anterior and lateral to the patient. A
      qualitative analysis of the subjective quality of the T1-weighted images was also
      done, and the adverse reactions were registered. The groups were homogeneous
      regarding age, gender, and weight distribution. No significant differences in the
      signal intensity of the liver and in the incoherent noise measurements were found
      between the two groups. Gastrointestinal noise showed significant differences
      between groups, with lower values for the butylscopolamine group compared with
      the control group. There was also a statistically significant difference in the
      image quality between groups, and optimal studies were only found in the
      butylscopolamine group, where most patients had a good-quality evaluation.
      Regarding adverse events, there were non-significant differences between groups.
      In conclusion, administration of an antiperistaltic agent to reduce the movements
      of the gastrointestinal tract diminishes the motion artifacts generated on MR
      imaging of the abdomen, even at high field strength and with fast imaging
      sequences. Images of the upper abdomen obtained after pharmacologic suppression
      of the gastrointestinal movement are of significantly superior quality.

PMID- 12598994
TI  - CT findings of phytobezoar associated with small bowel obstruction.
AB  - The purpose of this study was to evaluate CT findings of phytobezoar associated
      with small bowel obstruction. We evaluated abdominal CT of 19 patients with
      phytobezoar. Abdominal CT of 6 patients with small bowel feces was included for
      the comparison. On CT we analyzed morphological features of phytobezoars such as
      location, number, size, shape, and the presence or absence of an encapsulating
      wall. The sites of the phytobezoar were in the jejunum in 12 patients (63%) and
      the ileum in 7 (37%). The phytobezoars were single in number in 13 patients (68%)
      and multiple in 6 (32%). The mean short- and long-axis diameters of the
      phytobezoars measured 3.2 cm (range 2.1-5.2 cm) and 5.2 cm (range 2.2-11.0 cm),
      respectively. The phytobezoars were ovoid in 9 patients, round in 6, and tubular
      in 4. On CT, phytobezoars appeared as gas-containing masses in 17 patients (89%)
      and as a solid mass without gas in the remaining 2 patients (11%). An
      encapsulating wall was noted in 6 patients (32%). Small bowel feces were much
      more tubular in shape but did not have encapsulating wall on CT. The CT imaging
      is useful in making the diagnosis of phytobezoar associated with small bowel
      obstruction.

PMID- 12598995
TI  - Diagnostic potential of virtual cystoscopy of the bladder: MRI vs CT. Preliminary
      report.
AB  - The aim of the study was to evaluate the diagnostic potential of the half-Fourier
      acquired single-shot turbo spin echo (HASTE) sequence for MRI cystoscopy compared
      with CT cystoscopy and the gold standard conventional cystoscopy. The MRI- and CT
      cystoscopy was performed in 29 patients with bladder tumors documented at
      cystoscopy and a control group using a 1.5-T unit (6-mm slice thickness) and a
      helical CT (3-mm collimation, pitch 1) after filling the bladder with air. Axial
      MRI and CT images were transferred to a workstation for application of virtual
      cystoscopy and compared with routine cystoscopy. Axial images and virtual
      cystoscopies were read by three readers for size and location of tumors. Forty
      seven tumors were diagnosed at cystoscopy (12<1 cm, 35>/=1 cm). The sensitivity
      for detection of tumors smaller than 1 cm was 88.9% at MRI cystoscopy and 100%
      for tumors of 1 cm or larger. These results were not statistically different from
      the other modalities. Three tumors smaller than 1 cm were not detected at CT
      cystoscopy, four not all identical at MRI cystoscopy. One tumor with a wall
      thickening was detected on axial CT and MR images and CT cystoscopy by all
      observers, but only by two at MRI cystoscopy. The MRI cystoscopy is a diagnostic
      modality with results comparable to conventional and CT cystoscopy.

PMID- 12598996
TI  - Immature teratoma of the ovary: correlation of MR imaging and pathologic
      findings.
AB  - The objectives of this study were to describe MR imaging findings of immature
      teratoma and to correlate imaging findings with histopathologic findings. The MR
      findings of ten patients (age range 12-29 years, mean age 19.0 years) with
      pathologically proven immature teratoma were retrospectively reviewed for tumor
      size, presence and characteristics of fatty content, presence and characteristics
      of solid components, and presence of ascites and implants. The MR findings were
      compared with gross (n=3) and microscopic (n=10) findings. Comparisons between
      relative amounts of solid components and histologic grades were evaluated by
      Spearman rank-order correlation. On MR images all lesions appeared to be fat
      containing tumors with solid components consisting of numerous cysts of various
      sizes. Solid tissue exhibited a wide variety of signal intensities on T2-weighted
      images. Punctate foci of fat were identified in all lesions, whereas fatty fluid
      was observed only in two. Predominant fluid content exhibited signal intensities
      similar to simple fluid in nine lesions. Ascites was observed in six lesions, and
      peritoneal dissemination in three. Pathologic studies confirmed scattered foci of
      adipose tissue in the solid portions of all cases, and revealed numerous cystic
      structure formations in these solid components. The correlation coefficient
      between the amount of solid tissue and the tumor grade was not significant
      (r(s)=0.266). The MR images of immature teratoma tended to show aqueous fluids
      and the solid components consisting of numerous cysts with punctate foci of
      adipose tissue, whereas predominant fluid is sebaceous fluid in the vast majority
      of mature cystic teratomas.

PMID- 12598997
TI  - Low-field MR arthrography of the shoulder joint: technique, indications, and
      clinical results.
AB  - In the age of cost containment and urgent reductions in health care expenditures,
      new options have to be explored to satisfy both diagnostic requirements and
      economic limitations. The introduction of low-field MR systems for assessment of
      joint disorders seemed to be an option for lower costs. The purpose of this
      article is to summarize available experiences with low-field MR arthrography of
      the glenohumeral joint with respect to image quality and diagnostic accuracy in
      detecting labral and rotator cuff lesions. Up to now, there has been only a
      limited number of studies available dealing with low-field MR arthrography of the
      glenohumeral joint. They reveal that, despite a minor image quality in comparison
      with high-field imaging, low-field MR arthrography of the shoulder allows for
      sufficient evaluation of intra- and extra-articular structures in the detection
      of major abnormalities such as glenohumeral instability or rotator cuff disease.
      Furthermore, open-configured MR scanners enable kinematic studies: Besides the
      analysis of normal motion, pathological findings in patients with instabilities
      and impingement syndrome can be delineated. They further offer the possibility
      for performing MR imaging-guided arthrography of the shoulder. This was first
      described using an open C-arm scanner with a vertically oriented magnetic field
      so that MR arthrography may be performed in one setting.

PMID- 12598998
TI  - Respiratory motion artifact suppression in diffusion-weighted MR imaging of the
      spine.
AB  - Diffusion-weighted spin-echo imaging of the spine has been successfully
      implemented for differentiation of benign fracture edema and tumor infiltration
      of the vertebral body. Nevertheless, this technique still suffers from
      insufficient image quality in numerous patients due to motion artifacts. The aim
      of this study was to investigate the impact of variable respiratory motion
      artifact suppression techniques on image quality in diffusion-weighted spin-echo
      imaging of the spine. In addition to phase-encoding reordering, a newly
      implemented right hemi-diaphragmaitc navigator for respiratory gating was used.
      Subjective and objective image quality parameters were compared. Respiratory
      motion artifact suppression has a major impact on image quality in diffusion
      weighted imaging of the spine. Phase-encoding reordering does not enhance image
      quality while right hemi-diaphragmatic respiratory navigator gating significantly
      improves image quality at the cost of data acquisition time. Navigator gating
      should be used if standard spin-echo diffusion-weighted imaging demonstrates
      insufficient image quality.

PMID- 12598999
TI  - The value of fat-suppressed T2 or STIR sequences in distinguishing lipoma from
      well-differentiated liposarcoma.
AB  - The objective of this study was to evaluate the diagnostic value of fat
      suppressed T2-weighted (FS-T2) images or short tau inversion recovery (STIR)
      imaging in distinguishing lipoma from lipoma-like subtype of well-differentiated
      liposarcoma. Spin-echo T1-weighted and STIR or fat-suppression T2-weighted
      sequences were performed in 60 lipomas and 32 lipoma-like well-differentiated
      liposarcomas, histologically proven, looking for thick septa or nodules in T1
      weighted images and linear, nodular, or amorphous hyperintensities on FS-T2/STIR
      sequences. Fourteen lipomas (23.3%) showed thick septa and/or nodules on T1,
      whereas on FS-T2 or STIR sequences only seven (11.7%) displayed hyperintense
      nodules and/or septa. All well-differentiated liposarcomas contained these signs
      on FS-T2 or STIR sequences. The presence of hyperintense septa or nodules in a
      predominantly lipomatous tumor on FS-T2/STIR sequences helps to differentiate
      malignant tumors from lipomas. Employing the presence of hyperintense nodules
      and/or septa as criteria of malignancy specificity was 76.6% and sensitivity
      100%. Overdiagnoses of well-differentiated liposarcoma can occur due to the
      presence of non-lipomatous areas within lipomas.

PMID- 12599000
TI  - Follow-up of breast lesions detected by MRI not biopsied due to absent
      enhancement of contrast medium.
AB  - Our objective was to follow-up patients in whom scheduled MR-guided vacuum
      biopsies for suspicious lesions were aborted due to absent enhancement of
      contrast medium. Thirty-seven of 291 scheduled MR-guided vacuum biopsies were
      aborted. Six cases were lost to follow-up. Two could be unequivocally identified
      and were nevertheless biopsied. In 25 of 29 patients absent enhancement was
      confirmed on subsequent studies without compression. Varying hormonal or
      inflammatory changes between initial MRI and MR-guided vacuum biopsy most
      probably explain the findings. Enhancement re-appeared on short-term follow-up <6
      months without compression in 4 of the 29 patients. Too strong compression during
      MR-guided vacuum biopsy explains the absence of enhancement in these patients. Of
      note, on histology, three of these cases proved malignant. We conclude that short
      term follow-up without compression is necessary and recommended for all lesions
      not visible during scheduled MR-guided vacuum biopsy.

PMID- 12599001
TI  - Stratification of mammographic computerized analysis by BI-RADS categories.
AB  - The Breast Imaging Reporting and Data System (BI-RADS) was implemented to
      standardize characterization of mammographic findings. The purpose of the present
      study was to evaluate in which BI-RADS categories the changes recommended by
      computerized mammographic analysis are most beneficial. Archival cases including,
      170 masses (101 malignant, 69 benign) and 63 clusters of microcalcifications
      (MCs; 36 malignant, 27 benign), were evaluated retrospectively, using the BI-RADS
      categories, by several radiologists, blinded to the pathology results. A
      computerized system then automatically extracted from the digitized mammogram
      features characterizing mammographic lesions, which were used to classify the
      lesions. The results of the computerized classification scheme were compared, by
      receiver operating characteristics (ROC) analysis, to the conventional
      interpretation. In the "low probability of malignancy group" (excluding BI-RADS
      categories 4 and 5), computerized analysis improved the A(z )of the ROC curve
      significantly, from 0.57 to 0.89. In the "high probability of malignancy group"
      (mostly category 5) the computerized analysis yielded an ROC curve with an A(z
      )of 0.99. In the "intermediate probability of malignancy group" computerized
      analysis improved the A(z )significantly, from 0.66 for to 0.83. Pair-wise
      analysis showed that in the latter group the modifications resulting from
      computerized analysis were correct in 83% of cases. Computerized analysis has the
      ability to improve the performance of the radiologists exactly in the BI-RADS
      categories with the greatest difficulties in arriving at a correct diagnosis. It
      increased the performance significantly in the problematic group of "intermediate
      probability of malignancy" and pinpointed all the cases with missed cancers in
      the "low probability" group.

PMID- 12599002
TI  - Macromolecular contrast agents for MR mammography: current status.
AB  - Macromolecular contrast media (MMCM) encompass a new class of diagnostic drugs
      that can be applied with dynamic MRI to extract both physiologic and morphologic
      information in breast lesions. Kinetic analysis of dynamic MMCM-enhanced MR data
      in breast tumor patients provides useful estimates of tumor blood volume and
      microvascular permeability, typically increased in cancer. These tumor
      characteristics can be applied to differentiate benign from malignant lesions, to
      define the angiogenesis status of cancers, and to monitor tumor response to
      therapy. The most immediate challenge to the development of MMCM-enhanced
      mammography is the identification of those candidate compounds that demonstrate
      the requisite long intravascular distribution and have the high tolerance
      necessary for clinical use. Potential mammographic applications and limitations
      of various MMCM, defined by either experimental animal testing or clinical
      testing in patients, are reviewed in this article.

PMID- 12599003
TI  - Dental CT: imaging technique, anatomy, and pathologic conditions of the jaws.
AB  - In addition to conventional imaging methods, dental CT has become an established
      method for anatomic imaging of the jaws prior to dental implant placement. More
      recently, this high-resolution imaging technique has gained importance in
      diagnosing dental-associated diseases of the mandible and maxilla. Since most
      radiologists have had little experience in these areas, many of the CT findings
      remain undescribed. The objective of this review article is to present the
      technique of dental CT, to illustrate the typical appearance of jaw anatomy and
      dental-related diseases of the jaws with dental CT, and to show where it can
      serve as an addition to conventional imaging methods in dental radiology.

PMID- 12599004
TI  - Invasive central nervous system aspergillosis in bone marrow transplantation
      recipients: an overview.
AB  - Invasive central nervous system aspergillosis is being seen with an increased
      frequency, particularly due to the increased number of immunosuppressed patients.
      The major cause of invasive central nervous system aspergillosis is bone marrow
      transplantation. In most cases, aspergillosis develops in the paranasal sinuses
      and in the lungs, and secondarily spreads to the brain. Imaging of cerebral
      aspergillosis may present different patterns depending on the lesion's age and
      the immunologic status of the patient. Lesions of the spinal cord are far less
      common but has been encountered in our series. In this article we review the
      clinical and radiologic features of aspergillosis affecting the central nervous
      system in patients who underwent bone marrow transplantation. Different CT and MR
      patterns are presented, including pertinent clinical and pathologic material.
      Significant morbidity and mortality can be associated with this fungal infection,
      and it is therefore incumbent upon the radiologist to identify intracranial
      aspergillosis as early as possible so that appropriate therapy can be
      administered.

PMID- 12599005
TI  - The non-invasive detection of intracranial aneurysms: are neuroradiologists any
      better than other observers?
AB  - Can non-neuroradiologists detect intracranial aneurysms as well as
      neuroradiologists, using CT and MR angiography? Sixty patients undergoing intra
      arterial digital subtraction angiography (IADSA) to detect aneurysms also
      underwent computed tomographic angiography (CTA) and time-of-flight magnetic
      resonance angiography (MRA). Consensus review of IADSA by two neuroradiologists
      was the reference standard. Two neuroradiologists, a neurosurgeon, a
      neuroradiographer and a general radiologist blinded to IADSA, plain CT and
      clinical data, independently reviewed hard-copy base and reconstructed maximum
      intensity projection images of the CTA and MRA studies. Thirty patients had a
      total of 63 aneurysms, 71.4% were </=5 mm in size. Compared with IADSA, mean
      accuracy per patient for neuroradiologists was CTA 0.87 (95% CI 0.75-0.94), and
      MRA 0.82 (0.70-0.90); for the other observers it was CTA 0.81 (0.75-0.86), and
      MRA 0.78 (0.71-0.84). Sensitivity per aneurysm for neuroradiologists was CTA 0.63
      (0.50-0.75), and MRA 0.43 (0.6-0.74); for the other observers it was CTA 0.52
      (0.44-0.59), and MRA 0.38 (0.31-0.45). Differences between readers and modalities
      were not statistically significant. Agreement with IADSA was "good" for
      neuroradiologists: kappa 0.73 for CTA, and 0.63 for MRA. For the other observers,
      agreement with IADSA was "moderate": kappa 0.59 for CTA, and 0.56 for MRA.
      Neuroradiologists performed consistently better than the other observers,
      although differences did not reach statistical significance.

PMID- 12599006
TI  - Double balloon esophageal catheter for diagnosis of tracheo-esophageal fistula.
AB  - Congenital H-type and recurrent tracheo-esophageal fistulas (TEF) are always
      difficult to diagnose. For a more accurate diagnosis we designed a new double
      balloon catheter, which is a modification of esophageal dilatation balloon. The
      catheter has two balloons to occlude the esophagus proximal and distal to the
      fistula. The fistula can be identified by passing of the contrast material to the
      tracheal tree, which was injected into the esophageal segment between the
      inflated balloons. To prove the efficiency of this catheter, a TEF was created
      surgically in a New Zealand rabbit. On the postoperative fourteenth day the
      catheter was tried and the fistula could be visualized easily by injecting the
      contrast material. We think this technique may be of use in the diagnosis of TEF
      in children.

PMID- 12599007
TI  - Value of F-18 FDG hybrid camera PET and MRI in early takayasu aortitis.
AB  - Takayasu aortitis (TA) is a chronic inflammatory and fibrotic vasculitis of large
      and medium-sized arteries. Early stages of the disease show a panarteritis and
      inflammatory wall thickening of the aorta and its branches, whereas advanced
      (fibrotic) stages comprise stenosis, aneurismatic transformation and occlusion.
      Magnetic resonance imaging visualises early-stage disease with high accuracy and
      is considered to be the method of choice in the diagnosis of TA. The aim of this
      article is the detailed comparison of FDG-PET performed with a hybrid camera and
      MR imaging in five patients with early TA. Five patients (median age 60 years)
      were enrolled during an ongoing prospective study on [18F]2'-deoxy-2-fluoro-D
      glucose (FDG) hybrid camera PET in patients with fever of unknown origin (FUO).
      These patients underwent MR imaging after establishing the diagnosis of TA.
      Abnormal FDG uptake in the wall of the aorta was noted in all patients. The
      bracheocephalic artery and the common carotid arteries were visualized in 3
      cases. Increased uptake of the subclavian artery was found in 3 patients and in 4
      patients pathological uptake was noted in the ilio-femoral vessels. Of 34
      vascular regions studied, 26 (76%) showed elevated FDG uptake. On transversal MR
      images vessel wall thickening and contrast enhancement of the thoracic aorta was
      found in 4 patients (ascending aorta/aortic arch: n=2; descending aorta: n=3;
      abdominal aorta: n=1). Additionally, vessel wall pathologies of the subclavian
      and the common carotid arteries could be shown in 1 patient and in another
      patient in the ilio-femoral arteries. No abnormalities were found using contrast
      enhanced MR angiography. Of 28 vascular regions studied, 9 (32%) showed
      vasculitis on MRI. The FDG-PET is a suitable whole-body screening method in the
      primary diagnosis of early TA, especially in those cases with early disease that
      present with uncharacteristic symptoms such as FUO. Both MRI and MRA remain
      indispensable in the exact determination of the pathomorphological changes and in
      the documentation of complications such as stenosis, aneurismatic transformation
      and occlusion.

PMID- 12599008
TI  - Conceptus radiation dose and risk from chest screen-film radiography.
AB  - The objectives of the present study were to (a) estimate the conceptus radiation
      dose and risks for pregnant women undergoing posteroanterior and anteroposterior
      (AP) chest radiographs, (b) study the conceptus dose as a function of chest
      thickness of the patient undergoing chest radiograph, and (c) investigate the
      possibility of a conceptus to receive a dose of more than 10 mGy, the level above
      which specific measurements of conceptus doses may be necessary.
      Thermoluminescent dosimeters were used for dose measurements in anthropomorphic
      phantoms simulating pregnancy at the three trimesters of gestation. The effect of
      chest thickness on conceptus dose and risk was studied by adding slabs of lucite
      on the anterior and posterior surface of the phantom chest. The conceptus risk
      for radiation-induced childhood fatal cancer and hereditary effects was
      calculated based on appropriate risk factors. The average AP chest dimension
      (d(a)) was estimated for 51 women of childbearing age from chest CT examinations.
      The value of d(a) was estimated to be 22.3 cm (17.4-27.2 cm). The calculated
      maximum conceptus dose was 107 x 10(-3) mGy for AP chest radiographs performed
      during the third trimester of pregnancy with maternal chest thickness of 27.2 cm.
      This calculation was based on dose data obtained from measurements in the
      phantoms and d(a) estimated from the patient group. The corresponding average
      excess of childhood cancer was 10.7 per million patients. The risk for hereditary
      effects was 1.1 per million births. Radiation dose for a conceptus increases
      exponentially as chest thickness increases. The conceptus dose at the third
      trimester is higher than that of the second and first trimesters. The results of
      the current study suggest that chest radiographs carried out in women at any time
      during gestation will result in a negligible increase in risk of radiation
      induced harmful effects to the unborn child. After a properly performed maternal
      chest X-ray, there is no need for individual conceptus dose estimations.

PMID- 12599009
TI  - Resolution requirements for monitor viewing of digital flat-panel detector
      radiographs: a contrast detail analysis.
AB  - With the introduction of digital flat-panel detector systems into clinical
      practice, the still unresolved question of resolution requirements for picture
      archiving communication system (PACS) workstation monitors has gained new
      momentum. This contrast detail analysis was thus performed to define the
      differences in observer performance in the detection of small low-contrast
      objects on clinical 1K and 2K monitor workstations. Images of the CDRAD 2.0
      phantom were acquired at varying exposures on an indirect-type digital flat-panel
      detector. Three observers evaluated a total of 15 images each with respect to the
      threshold contrast for each detail size. The numbers of correctly identified
      objects were determined for all image subsets. No significant difference in the
      correct detection ratio was detected among the observers; however, the difference
      between the two types of workstations (1K vs 2K monitors) despite less than 3%
      was significant at a 95% confidence level. Slight but statistically significant
      differences exist in the detection of low-contrast nodular details visualized on
      1K- and 2K-monitor workstations. Further work is needed to see if this result
      holds true also for comparison of clinical flat-panel detector images and may,
      for example, exert an influence on the diagnostic accuracy of chest X-ray
      readings.

PMID- 12599010
TI  - Value of abdominal CT in the emergency department for patients with abdominal
      pain.
AB  - The purpose of our study is to demonstrate the value of CT in the emergency
      department (ED) for patients with non-traumatic abdominal pain. Between August
      1998 and April 1999, 536 consecutive patients with non-traumatic abdominal pain
      were entered into our study. Using a computer order entry system, physicians were
      asked to identify: (a) their most likely diagnosis; (b) their level of certainty
      in their diagnosis; (c) if they thought CT would be normal or abnormal; (d) their
      treatment plan (prior to knowledge of the CT results); and (e) their role in
      deciding to order CT. This information was correlated with each patient's post-CT
      diagnosis and subsequent management. Pre- and post-CT diagnoses were concordant
      in 200 of 536 (37%) patients. The physicians' certainty in the accuracy of their
      pre-CT diagnosis was less than high in 88% of patients. Prior to CT, the
      management plan included hospital admission for 402 patients. Following CT, only
      312 patients were actually admitted; thus, the net impact of performing CT was to
      obviate the need for hospital admission in 90 of 536 (17%) of patients with
      abdominal pain. Prior to CT, 67 of 536 (13%) of all patients would have undergone
      immediate surgery; however, following CT only 25 (5%) actually required immediate
      surgery. Among patients with the four most common pre-CT diagnoses (appendicitis,
      abscess, diverticulitis, and urinary tract stones) CT had the greatest impact on
      hospital admission and surgical management for patients with suspected
      appendicitis. For patients with suspected appendicitis, CT reduced the hospital
      admission rate in 28% (26 of 91) of patients and changed the surgical management
      in 40% (39 of 91) of patients. Our study demonstrates the advantage of performing
      abdominal CT in the ED for patients with non-traumatic abdominal pain.

PMID- 12599011
TI  - Evaluation of a "no-cost" Internet technology-based system for teleradiology and
      co-operative work.
AB  - The aim of this study was to assess the suitability of a no-cost system based on
      standard Internet technology components for teleradiology. The system was
      composed of free software (communication, DICOM viewer, compression) and standard
      off-the-shelf hardware components. For different image (CR, CT, MR) and network
      types (LAN and ISDN) the File Transfer, Audio and Video Conference, and Co
      operative Work properties were examined and compared with the literature
      referring to standard complete packages and dedicated teleradiology systems. The
      main advantages of the no-cost system are: price; ease of use; independence from
      specific hardware; and potential connection to any possible partner. The
      performance of the File Transfer and the Audio and Video Conference was
      comparable to the other system groups with slight disadvantages in the usability.
      For Co-operative Work the employed "application sharing" technology does not meet
      the clinical requirements, which applies identically to the standard complete
      packages. Here the specialized systems prove superior, although they are
      proprietary. With minimal restraints the evaluated no-cost solution can be used
      for File Transfer and Conference scenarios. The usage for Co-operative Work with
      ISDN is not recommended, unless for the purpose of gaining experience or when
      dealing with small amounts of cases or images.

PMID- 12599013
TI  - The role of angiogenesis in prostate development and the pathogenesis of prostate
      cancer.
AB  - New vessel formation, a highly-regulated, active process commencing in the embryo
      and evident notably during the pubertal growth spurt, is essential for normal
      prostate development. Reactivation of this process in response to physiological
      stimuli, particularly hypoxia in mature tissues, occurs with new vessels forming
      principally from stromal components. Although angiogenesis is complex, putatively
      involving a multitude of angiogenic factors and inhibitors, there is powerful
      evidence of the importance of the VEGF system in the development of both the
      normal prostate and prostate cancer. Recent advances include an understanding of
      how castration acts through the VEGF system to inhibit angiogenesis. Stromal
      endothelial and epithelial-endothelial interactions are just beginning to be
      investigated. A better understanding of how physiological angiogenesis is
      controlled should help to provide further insights into the mechanism of
      disregulated angiogenesis in tumours. Ultimately, new antiangiogenic agents are
      likely to find a role in the management of patients with prostate cancer.

PMID- 12599012
TI  - A comparison of the biodistribution and biokinetics of (99m)Tc-anti-CD66 mAb BW
      250/183 and (99m)Tc-anti-CD45 mAb YTH 24.5 with regard to suitability for
      myeloablative radioimmunotherapy.
AB  - Radioimmunotherapy (RIT) with radiolabelled monoclonal antibodies (mAbs) is an
      effective method of achieving myeloablation in leukaemia patients prior to stem
      cell transplantation (SCT). We wished to compare the approaches of specific
      binding to leukaemic blasts and non-specific binding to benign red marrow cells,
      which results in a myeloablative "cross-fire" effect. Therefore, we prospectively
      evaluated the biodistribution and biokinetics of the anti-CD45 mAb YTH 24.5 and
      the anti-CD66 mAb BW 250/183 with regard to their suitability for myeloablative
      RIT. The red marrow selective anti-CD66 mAb BW 250/183 (IgG1) binds to normal
      granulopoietic cells. In contrast, the anti-CD45 mAb YTH 24.5 (IgG2b) binds to 85
      90% of acute leukaemic blasts and almost all haematopoietic white cells. Patients
      with leukaemic blast infiltration of the marrow <25% and assigned for RIT and SCT
      were included. Twelve patients (eight male, four female; median age 46+/-7 years)
      with AML (5), CML (5) or ALL (2) were examined. Both mAbs were labelled with
      technetium-99m. Within 48 h, 906+/-209 MBq (99m)Tc-anti-CD66 mAb and 760+/-331
      MBq (99m)Tc-anti-CD45 mAb were injected consecutively. Scintigraphic and urinary
      measurements were performed 1, 2, 4 and 24 h after injection. Serum activities
      were evaluated 2, 5, 10, 15, 30 and 60 min and 2, 4 and 24 h after injection.
      Compared with the anti-CD45 mAb, the anti-CD66 mAb showed an approximately
      fourfold higher accumulation in the red marrow, a 2.5-fold lower accumulation in
      the liver and similar accumulation in the kidneys. The serum activity (% of the
      injected dose) initially decreased faster for the anti-CD45 mAb but was similar
      for the two mAbs 24 h after injection: 3.3%+/-1.2% (anti-CD66 mAb) and 2.4%+/
      1.1% (anti-CD45 mAb). The cumulated urinary excretion was 17%+/-6.6% (anti-CD66
      mAb) and 27.3%+/-7.9% (anti-CD45 mAb) 24 h after application. In these patients
      with low tumour load, the anti-CD66 mAb BW 250/183 showed more favourable
      properties in terms of biodistribution and pharmacokinetics. Thus, it appears
      superior to anti-CD45 mAb YTH 24.5 in selectively increasing the marrow dose and
      avoiding extramedullary organ toxicity.

PMID- 12599014
TI  - Treatment of stress urinary incontinence: recent developments in the role of
      urethral injection.
AB  - Stress urinary incontinence is prevalent in adult women and has a considerable
      impact on quality of life. However, it often remains undiagnosed and therefore
      untreated. Non-invasive treatment is likely to be offered in mild cases and may
      entail physiotherapy, minimally invasive devices or pharmacotherapy. Surgical
      intervention is widely considered as the only effective option for more severe
      cases. These strategies are not suitable for all patients, and urethral injection
      represents an alternative, minimally invasive procedure. The choice of the
      bulking agent is the key to the success of this treatment: the most extensively
      studied are silicone, polytetrafluoroethylene and bovine collagen. However,
      doubts regarding the safety and efficacy of these materials has led to the
      development of carbon-coated zirconium beads, calcium hydroxylapatite and
      dextranomer/hyaluronic acid (Dx/HA) copolymer. Of these, the most clinical
      experience has been gained with Dx/HA copolymer. Until 2 years ago, urethral
      injection could only be administered endoscopically. The recent development of
      devices for 'blind' injection has increased the speed and convenience of urethral
      injection, removing the need for surgical facilities. Although few data are yet
      available, it is conceivable that urethral injection administered 'blind' may in
      future be considered as an option for all patients failing non-invasive
      treatment.

PMID- 12599015
TI  - Cellular fibronectin in patients with transitional cell carcinoma of the bladder.
AB  - Various tumor markers for transitional cell carcinoma (TCC) of the bladder have
      been described, but none of them are used in clinical routine. Fibronectin, a
      glycoprotein, seems to play a very important role in both the progression and
      invasion of cancer. The aim of this study was to evaluate cellular fibronectin
      (cFN) in the urine and blood of patients with TCC of the bladder and to determine
      its possible role as a tumor marker and prognostic factor. Morning urine samples
      and blood were collected from 20 patients (8 women, 12 men, mean age 69.9 years)
      before they underwent transurethral resection of bladder tumors (TURB). Twenty
      patients (10 women, 10 men, mean age 63.4 years) with nonmalignant urological
      disorders were recruited as the control group. Determination of cFN in plasma and
      urine was performed by using a newly developed time-resolved fluorescence
      immunoassay (TRFIA). Patients with nonmalignant diseases had mean cFN plasma
      levels of 404 ng/ml (range 181-746 ng/ml). Patients with TCC of the bladder
      showed significantly higher cFN plasma levels of 686 ng/ml (range 274-1999 ng/ml,
      p<0.05). Subdivided according to the TNM system, muscle-invasive bladder tumors
      (n=5) demonstrated higher cFN plasma levels (mean 944 ng/ml) than superficial
      bladder tumors (n=15, mean 463 ng/ml). There were no differences of plasma cFN
      concentrations concerning tumor grade and also no differences in urine levels
      between the different groups. We found a significant difference (p<0.04) of cFN
      plasma levels between patients with TCC of the bladder and the control group. The
      difference in cFN plasma levels between pTa/pT1 and >or=pT2 tumors indicates a
      clinically useful potential of this tumor marker for preoperative staging and
      postoperative follow-up. Our data underline the important but still unclear role
      of cFN as a tumor marker in TCC, and this will be the focus of future studies.

PMID- 12599016
TI  - Involvement of cyclic nucleotides in renal artery smooth muscle relaxation.
AB  - The elevation of vascular smooth muscle tone in the renal arteries during kidney
      transplantation and nephron-sparing surgery plays a major role in postsurgical
      organ dysfunction. Therefore, a better understanding of the intracellular
      mechanisms of contraction and relaxation is of fundamental interest to improve
      urological treatment. The present study was designed to investigate the complex
      intracellular system of cyclic nucleotides involved in the regulation of smooth
      muscle relaxation by using swine renal artery rings in the Schuler organ bath.
      Phenylephrine (PE) induced dose-dependent and fully reversible isometric
      contractions with a threshold concentration of 10 nM and an EC(50) of 804 nM. The
      receptor was identified as alpha(1A)-subtype by the selective antagonist WB4101.
      Increasing the intracellular concentration of cyclic 3':5'-adenosine
      monophosphate (cAMP) by dibutyryl-cAMP (5 mM) and forskolin (5 micro M) resulted
      in a decreased contractiltity of 48.0% and 76.3%, respectively. Elevation of the
      cytosolic content of cyclic 3':5'-guanosine monophosphate (cGMP) using dibutyryl
      cGMP (1 mM), sodium nitroprusside (100 micro M) and SIN-1 (100 micro M) decreased
      the average PE-induced contraction by 16.4%, 41.9% and 62.4%, respectively. The
      unselective phosphodiesterase inhibitors theophylline (1 mM), papaverine (100
      micro M) and IBMX (5 mM) reduced the PE-induced contraction by 37.3%, 93.1% and
      95.5%, respectively. Furthermore, selective inhibition of phosphodiesterases by
      milrinone (PDE(3)-selective) resulted in a decreased contractility by 1.3% (50
      micro M), 29.5% (100 micro M) and 93.5% (5 mM), and using rolipram (PDE(4)
      selective), the PE-induced contraction was inhibited by 57.9% (50 micro M) and
      81.9% (100 micro M). The results suggest the involvement of cAMP and cGMP in the
      relaxation of renal artery smooth muscle cells. Moreover, phosphodiesterases,
      especially PDE(3) and PDE(4), seem to play a critical role in the regulation of
      renal artery smooth muscle tone.

PMID- 12599017
TI  - Effects of an aqueous extract from Phyllantus niruri on calcium oxalate
      crystallization in vitro.
AB  - Phyllanthus niruri is a plant used in Brazilian folk medicine for the treatment
      of urolithiasis. It was previously observed that P. niruri shows no toxicity,
      potentially increases calculus voiding by stone forming patients and inhibits the
      endocytosis of calcium oxalate (CaOx) crystals by MDCK cells. In addition, in a
      rat model of urolithiasis it reduced calculus growth. In the present study, we
      evaluated the effect of an aqueous extract of P. niruri on CaOx crystallization
      in vitro. CaOx precipitation was induced by the addition of 0.1 M sodium oxalate
      to unfiltered urine samples from Wistar rats (n=14) and normal humans (n=18) in
      the presence or absence of P. niruri extract (0.25 mg/ml of urine). The presence
      of CaOx crystals was evaluated immediately and 24 h later. In vitro
      crystallization of human urine produced typical mono- and dihydrated CaOx
      crystals, but only a few typical CaOx crystals were found in rat urine. The
      presence of P. niruri extract did not inhibit CaOx precipitation and even more
      crystals were obtained, although they were significantly smaller than those in
      the control urine. Crystal aggregation observed 24 h after crystallization was
      also inhibited by P. niruri extract. The results showed an inhibitory effect of
      P. niruri extract on CaOx crystal growth and aggregation in human urine,
      suggesting that it may interfere with the early stages of stone formation and may
      represent an alternative form of treatment and/or prevention of urolithiasis

PMID- 12599018
TI  - Rapamycin induces Smad activity in prostate cancer cell lines.
AB  - Rapamycin inhibits the FK506-binding protein 12 (FKBP12)/mammalian target of
      rapamycin (mTOR) complex and causes cell cycle arrest in G1. The precise
      mechanism of growth inhibition by rapamycin is only partly understood. Rapamycin
      led to growth inhibition in the human prostate cancer cell lines LNCaP and PC3
      cells after 72 h, ID50: 93 and 50 nM, respectively. Filter cDNA array analysis
      showed down-regulation by more than 0.75x by rapamycin in PC3 cells and LNCaP
      cells of the following genes: follistatin, eukaryotic initiation factor-4E
      (eIF4E), glucose-6-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH)
      A, ATP synthase, heat shock protein (HSP)-1. Upregulation by more than 1.5x was
      found for: bone morphogenetic protein (BMP)-4, FKBP12, carcinoma embryonic
      antigen (CEA) precursor, eukaryotic initiation factor (eIF)-3 p36 subunit, latent
      transforming growth factor (TGF) beta binding protein (LTBP)1. Rapamycin induced
      BMP4 and reduced follistatin expression in PC3 cells. This resulted in a dose
      dependent nuclear expression of Smad4 and activated the SBE4 Smad-reporter,
      indicating activation of TGFbeta/BMP signaling. Combining rapamycin with PI3K
      inhibition (LY294002) increased growth inhibition. These findings illustrate that
      Smad signaling plays a role in the anticancer effects of rapamycin and show that
      combination with PI3K inhibition improves growth inhibition.

PMID- 12599019
TI  - Ki67, gelsolin and PTEN expression in sarcomatoid renal tumors.
AB  - Sarcomatoid renal tumors differ morphologically and prognostically from other
      renal tumors. Using tissue microarray technology, we show that sarcomatoid renal
      tumors have a distinct protein expression profile for biomarkers Ki67, gelsolin
      and PTEN, when compared with clear-cell and papillary renal tumors. Our results
      confirm the previous reports that Ki67 is highly expressed in sarcomatoid tumors.
      We also show that gelsolin expression differs between the studied tumor types,
      suggesting different roles for gelsolin in the carcinogenesis of different renal
      tumor types.

PMID- 12599020
TI  - Serum levels of basic fibroblast growth factor reflect disseminated disease in
      patients with testicular germ cell tumors.
AB  - The potential role of angiogenesis stimulators in the pathogenesis of different
      tumor entities has been confirmed in several studies. We measured the serum
      levels of basic fibroblast growth factor (bFGF), vascular endothelial growth
      factor (VEGF) and platelet derived growth factor (PDGF) in 51 patients with
      testicular germ cell tumors and in 39 healthy volunteers. Serum concentrations of
      bFGF, VEGF and PDGF-AB were determined by enzyme-linked immunosorbent assay. The
      median serum bFGF level for tumor patients was 3.46 pg/ml (range 0-61.6) compared
      to 0.7 pg/ml (0-11) in the control group (P<0.01). In patients with metastatic
      disease, the median serum bFGF level was 10.3 pg/ml (0-61.6) in contrast to 2.8
      pg/ml (0-50) in patients with localized disease (P<0.01). The median serum VEGF
      and PDGF levels were 270 pg/ml (0-1,903) and 37,837 pg/ml (9,075-108,800),
      respectively, for tumor patients and 200 pg/ml (44-585) and 23,000 pg/ml (4,250
      70,650) in the control group ( P<0.05). Our data suggest that angiogenesis, as
      reflected by serum concentrations of bFGF, VEGF and PDGF, plays a functional role
      in the growth and progression of testicular germ cell tumors.

PMID- 12599021
TI  - Granulocyte colony-stimulating factor for the treatment of biomaterial-associated
      staphylococcal infections in-vitro.
AB  - Staphylococcal infections are a common and severe complication after the
      implantation of a prosthesis. We developed an in-vitro model for biomaterial
      associated infections and studied the effects of human recombinant granulocyte
      colony-stimulating factor (rhuG-CSF; filgrastime) on the eradication of bacteria
      from the surface of biomaterial. Latex beads (25 micro m) were incubated with
      10(7) colony forming units of either a slime producing (DSM 3269) or non-slime
      producing strain (ATCC 14990) of Staphylococcus epidermidis. Infected particles
      were consecutively confronted with effector cells, derived from heparinized whole
      blood samples taken from healthy volunteers, after stimulation with rhuG-CSF
      (5,000 IU/ml, 10,000 IU/ml). Control blood specimens were not stimulated or
      conditioned with normal saline. The results indicate that stimulation with rhuG
      CSF induced an increased rate of phagocytosis and lead to a more rapid reduction
      of adhering bacteria from the surface of the beads. Therefore, the in-vitro data
      suggest that patients with prosthesis infection may profit from an additional
      treatment with rhuG-CSF.

PMID- 12599022
TI  - Botulinum toxin type A may improve bladder function in a rat chemical cystitis
      model.
AB  - The purpose of this study was to investigate the effect of botulinum toxin type A
      on bladder function and histology in a rat chemical cystitis model. The study
      included 41 female Sprague-Dawley rats with chemical cystitis induced by
      intravesical instillation of hydrochloric acid. The acid instillation was
      repeated monthly to maintain chronic inflammation. The treatment group (n=21)
      received 2-3 units of botulinum toxin type A injected into the bladder detrusor
      at the 3, 6, 9 and 12 o'clock positions, and the control group (n=20) underwent
      saline injection into the bladder detrusor at the same positions. Urodynamic
      studies were performed in all rats before the treatment and at death. The rats
      were killed at 1 week, 2 weeks, 1 month and 2 months after treatment. The
      bladders were removed and examined histologically for mast cells and inflammatory
      changes. The cystometric findings showed that, at the beginning and end of the
      experiment, the increases in the maximum bladder capacity and compliance were
      significantly higher in the treatment group than in the control group (P=0.000
      and P=0.025, respectively). The histological studies revealed similar mast cell
      counts and leukocyte infiltration for the treatment and control groups. In
      conclusion, in this rat chemical cystitis model, botulinum toxin type A injected
      into the bladder detrusor led to a functional improvement. Thus, botulinum toxin
      type A injection may be an alternative, minimally invasive choice to other
      surgical treatment options in the treatment of a chronic inflammatory condition
      to improve deteriorated bladder function.

PMID- 12599023
TI  - Systemic administration of MK-801 produces an abnormally persistent latent
      inhibition which is reversed by clozapine but not haloperidol.
AB  - RATIONALE: Latent inhibition (LI) refers to retarded conditioning to a stimulus
      as a consequence of its inconsequential pre-exposure, and disrupted LI in the rat
      is considered to model an attentional deficit in schizophrenia. Blockade of NMDA
      receptor transmission, which produces behavioral effects potentially relevant to
      schizophrenic symptomatology in several animal models, has been reported to spare
      LI. OBJECTIVES: To show that systemic administration of the non-competitive NMDA
      antagonist MK-801 will lead to an abnormally persistent LI which will emerge
      under conditions that disrupt LI in controls, and that this will be reversed by
      the atypical neuroleptic clozapine but not by the typical neuroleptic
      haloperidol, as found for other NMDA antagonist-induced models. METHODS: LI was
      measured in a thirst-motivated conditioned emotional response (CER) procedure by
      comparing suppression of drinking in response to a tone in rats which previously
      received 0 (non-pre-exposed) or 40 tone exposures (pre-exposed) followed by two
      (experiment 1) or five (experiments 2-5) tone - foot shock pairings. RESULTS: MK
      801 at doses of 0.1 and 0.2 mg/kg reduced conditioned suppression while no effect
      on suppression was seen at the 0.05 mg/kg dose. At the latter dose, intact LI was
      seen with parameters that produced LI in controls (40 pre-exposures and two
      conditioning trials). Raising the number of conditioning trials to five disrupted
      LI in control rats, but MK-801-treated rats continued to show LI, and this
      abnormally persistent LI was due to the action of MK-801 in the conditioning
      stage. MK-801-induced LI perseveration was unaffected by both haloperidol (0.1
      mg/kg) and clozapine (5 mg/kg) administered in conditioning, and was reversed by
      clozapine but not by haloperidol administered in pre-exposure. CONCLUSION: MK-801
      induced perseveration of LI is consistent with other reports of perseverative
      behaviors, suggested to be particularly relevant to negative symptoms of
      schizophrenia, following NMDA receptor blockade. We suggest that LI perseveration
      may model impaired attentional set shifting associated with negative symptoms of
      schizophrenia. Moreover, the finding that the action of MK-801 on LI and the
      action of clozapine are exerted in different stages of the LI procedure suggests
      that the MK-801-based LI model may provide a unique screening tool for the
      identification of novel antipsychotic compounds, whereby the schizophrenia
      mimicking LI abnormality is drug-induced, but the detection of the antipsychotic
      action is not dependent on the mechanism of action of the pro-psychotic drug.

PMID- 12599024
TI  - [Material and structure of drainages].
AB  - The long history of surgical drainages stands in contradiction to available and
      reliable data. As of today, closed systems made of silicone are preferable.
      Taking possible complications into consideration and the good results of routine
      operations without drainages, indication for use should be critically evaluated.
      Interdisciplinary research,however, offers the chance of optimizing material and
      surface characteristics, biostability, biocompatibility, and flow rates. New
      drainages with improved performance and reduced side effects may counteract the
      current tendency to do without.

PMID- 12599025
TI  - [Abdominal drainages].
AB  - The use of drainages in abdominal surgery is characterized by tradition and
      personal experience of the surgeon. There are only a few high-quality, randomized
      studies on the use of prophylactic drainages. The risk of postoperative
      mediastinitis leads surgeons to maintain the use of drainages in esophageal
      anastomosis. The use of drainages in gastric and small bowel surgery appears to
      be negligible. There are evidence grade A recommendations for hepatobiliary
      surgery (without biliodigestive anastomosis) to abstain from the use of
      drainages. One prospective, randomized study showed an advantage of surgery
      without drainage in pancreatic resections (and bilioenteric anastomosis). The
      situation is clear for colorectal surgery. Several prospective, randomized
      studies have shown the advantages of avoiding drainages. The use of drainages in
      perforated appendicitis appears to be associated with an increased rate of
      postoperative complications. There are no general recommendations for the use of
      drainages in cases of peritonitis. The few high-quality studies published show
      that the use of drainages in visceral surgery has to be questioned continuously.
      High-quality clinical studies are necessary to obtain evidence-based
      recommendations for the use of drainages in visceral surgery.

PMID- 12599026
TI  - [Thoracic drainage. What is evidence based?].
AB  - Pleural drainage becomes a vital measure to restore physiological conditions in
      cases of loss of pleural negative pressure, regardless its etiology. Therefore,
      it is not surprising that hardly any evidence based publications on this topic
      are available. For the treatment of pleural empyema,the history of pleural
      drainage goes back to antiquity.Nowadays, quite a number of synonymously used
      terms are wrongly employed instead of the correct terms of thoracic or pleural
      drainage. Indications for placing a pleural drainage are: pneumothorax, pleural
      effusion, pleural empyema,hemothorax and chylothorax. As a standard method, it is
      recommended that the pleural drainage be placed in the fifth or sixth intercostal
      space in the anterior axillary line. It is not advisable to use a closed
      insertion with the help of a trocar due to the significantly increased risk of
      injury. The insertion of a pleural drainage when correctly placed is a safe
      procedure; rare typical complications involve the wrong placement of the
      drainage, hemorrhage or infection like pleural empyema. The complication rate,
      however, does not exceed 3%.

PMID- 12599027
TI  - [Drainage in soft tissue surgery. What is "evidence based"?].
AB  - Due to the advanced technical possibilities, there are now up to 30 different
      drainage systems available for soft tissue surgery. The differences between these
      systems involve the mode of drainage (open into the bandage, closed into
      bag/bottle), the kind of suction (gravity drainage, low-vacuum and high-vacuum up
      to 900 mbar) and the material of the tube (PVC, silicone or polyurethane). There
      also exists a marked controversy about the fundamental necessity for drainage
      after surgery. A survey of the literature indicates that there is a distinct
      discrepancy between scientific knowledge and daily routine action. For primarily
      uninfected wounds, the application of an open drainage system,with the secretion
      going directly into the bandage, is obsolete. Gravity drainage systems guarantee
      just as effective secretion drainage in comparison to high vacuum drainage
      according to Redon. In soft tissue wounds, high-vacuum suction leads to the
      sucking in of tissue and blood,whereby comparatively elevated quantities of
      secretion can be produced. During the removal of Redon-drainage, there is
      stronger pain than on the removal of gravity drainage systems consisting of
      silicone or polyurethane. Prophylactic insertion of drainage in uncomplicated
      thyroid surgery and for hernia repair is not necessary. Insertion of drainage for
      up to 72 h is not accompanied by an elevated infection rate. The routine
      microbiological examination of the tip of the drainage tube is not recommended.

PMID- 12599028
TI  - [Drains in trauma surgery].
AB  - Closed suction drains are still commonly used following orthopedic procedures.
      While empirical recommendations predominated until the 1980s,many randomized
      controlled studies concerning the use of drains have been conducted within the
      last 20 years. This article compares studies that have been performed in a
      prospective randomized manner.Numerous investigations have shown that there is no
      positive effect of suction drains with regard to long-term results in aseptic
      orthopedic surgery. This even holds true in the fields of endoprosthetic surgery
      and procedures that are associated with a high incidence of complications, e.g.,
      bone grafting from the iliac crest.Moreover, there is evidence from some studies
      that septic complications are significantly higher in the suction drain
      groups.Evidence-based surgery should call for a very critical indication to use
      suction drains;however, the acceptance of this evidence is very low among
      surgeons up to now.

PMID- 12599029
TI  - [PET examination of metastases of somatic carcinomas via the lymphatic system
      (thyroid gland and breast)].
AB  - We previously showed that advanced visceral cancers (58 rectum cancers) are
      confined in their pattern of lymphatic spread to one caudocranial regional
      pathway and never appear in another one, even in cases of local recurrence. We
      have now investigated PET scan series of 94 somatic cancers (44 thyroid and 50
      breast cancers). They too are confined in their pattern of lymphatic spread to
      paratracheal or ipsi-cervical or axillary pathways. Only when the main pathways
      are removed or blocked do they then force their way into mediastinal or collar
      regions. They never affect visceral regions.

PMID- 12599030
TI  - [Total excision of the mesorectum in cancer of the lower and middle rectum.
      Oncological and functional results].
AB  - INTRODUCTION: The introduction of total mesorectal excision (TME) in the
      treatment of rectal cancer has improved survival rates and decreased recurrence.
      Our objective was to analyse perioperative data as well as the results of the
      follow-up examination. Risk-factors for local recurrence should be identified
      since the indication for adjuvant therapy in "optimal surgery" has to be
      redefined. PATIENTS AND METHODS: Between March 1997 and December 2001, 108
      patients with adenocarcinoma of the lower and middle rectum were operated on by
      three surgeons according to the concept of total mesorectal excision. In 75
      (69.4%) patients,a lower anterior resection and in 32 (29.2%) cases an
      abdominoperineal resection was performed. One patient received a Hartmann's
      resection. There were 15 cases of stage IV (UICC) present and in 53 patients the
      tumor extension was restricted to the wall. Demographic and perioperative data as
      well as the results of the follow-up examination were registered prospectively.
      The median follow-up period amounted to 24 months (2-56). RESULTS: A total of 87
      patients underwent a curative resection. Fourteen lymph nodes were dissected
      (median). Pelvic autonomic nerve preservation was possible in 90 patients. The
      median intraoperative blood loss was 500 ml. As surgical complications,
      anastomotic leakage occurred in 18% of cases, perineal wound infection in 33%,
      and bladder dysfunction (requiring catheterisation) in 5.6%. The overall rate of
      recurrence was 17.5%. The rate of local recurrence was 4.9% and the survival rate
      was 91% over 3 years. Risk factors for local recurrence are N2-disease,
      transmural growth and tumor localisation in the lower third of the rectum.
      CONCLUSIONS: TME offers good oncological and functional results with low
      complication rates for the treatment of cancer in the middle and upper third of
      the rectum. Interdisciplinary multicenter studies are still necessary to redefine
      the place of adjuvant radiation and chemotherapy in cases of cancer in the lower
      two thirds of the rectum and stage III disease.

PMID- 12599031
TI  - [Lymphatic mapping and sentinel lymph node biopsy in gastric cancer].
AB  - INTRODUCTION: Lymphatic mapping and the sentinel lymph node (SLN) concept has
      been validated in malignant melanoma and breast cancer.However, the application
      for other solid tumors is still controversial. One of the most promising
      approaches is selective lymph node staging in gastric cancer.The presented pilot
      study evaluated the feasibility of the radiocolloid technique in gastric cancer
      patients and its value in predicting a positive nodal status. PATIENTS AND
      METHODS: Fifteen patients with gastric cancer (u T(1-3)) underwent endoscopic
      submucosal injection of 0.4 ml 60 MBq (99m)Tc-Nanocis around the tumor 17 (+/-3)
      h prior to surgery. After laparotomy the activity of all 16 (JGCA) lymph node
      stations was measured by a handheld probe. All patients underwent standard
      gastrectomy with systematic D2 lymphadenectomy. After resection the site was
      scanned for residual activity. All sentinel lymph nodes (SLN's) were removed ex
      vivo from the resected specimen and processed for intensified histopathologic
      assessment including serial sections and immunohistochemistry. RESULTS: In 14 of
      15 patients at least one or more SLN's were obtained (93%), the median number of
      SLN's was 3 (1-5). Of the 14 patients, 9 revealed lymph node metastases. In eight
      of the nine patients the sentinel node(s) correctly predicted metastatic lymph
      node invasion. In five cases the lymph node station with positive sentinel
      node(s) was the only positive node station resulting in a sensitivity of 8/9
      (89%). In one case immunohistochemical staining revealed micrometastases leading
      to an upstaging in 1/6 of the initially nodal-negative patients. CONCLUSION:
      Lymphatic mapping and sentinel node biopsy using the radiocolloid technique is
      feasible in gastric cancer. Limited results indicate a correct prediction of the
      nodal status and the potential of upstaging.Further studies seem to be justified
      to evaluate the clinical impact of the method.

PMID- 12599032
TI  - [Prognostic relevance of biological and molecular markers in oncology. Criteria
      for planning and interpreting studies].
AB  - Experts on different specialties (surgery, pathology, molecular biology and
      medical statistics) discussed the evaluation of prognostic factors during a
      workshop. The most important results presented are: (1) the prognostic relevance
      of new biological or molecular markers must be evaluated in a phase-III
      prognostic study. To establish such a marker in the UICC-TNM-classification in at
      least two different centers, two multivariate analyses according to defined
      criteria are necessary; (2) the standards of laboratory methods have to be
      defined, e.g.,which method to apply for RNA-analysis,which materials to used,
      etc; (3) intensive data analysis should be done before using methods of
      multivariate analysis. The criteria for the presentation of survival curves are
      given in detail; (4) in multivariate analysis, the Cox proportional hazard
      regression for survival outcomes is discussed with explanations and examples of
      the terms relative risk, odds-ratio, hazard and relative hazard. The arrangement
      and interpretation of a good prognostic study should be performed as an
      interdisciplinary approach.

PMID- 12599033
TI  - [Local recurrence of breast cancer. Isolated local recurrence located at the skin
      of the latissimus dorsi donor flap after breast reconstruction].
AB  - The reasons for local recurrence of breast cancer are currently unknown.
      Inadequate resection (not RO), undetected multifocal tumors, or absence of
      postoperative radiation are discussed. Secondary multifocal tumors as well as
      ipsilateral secondary tumors have been described as potential origins. Partial
      local recurrences can be considered a sign for general metastasis with an
      isolated local "reproduction" of the initial tumor. In our patient the
      observation of isolated local recurrences of the initial breast cancer, located
      at the skin of the latissimus dorsi donor flap, may be helpful in clarifying the
      ongoing controversial discussion. Our case study shows that the local recurrence
      occurred exactly at the initial location of the primary tumor independent of the
      local epidermal situation. We assume that activated vertical connections exist
      between the fascial lymphatic system and the dermal lymphatic plexus that
      "directed" the way to the body wall.

PMID- 12599034
TI  - [A rare location for extratruncular vascular malformation].
AB  - We report on an undefined tumor of the right ulnar side of the elbow in a 15-year
      old boy. The clinical examination showed painful swelling in the area of the
      ulnar nerve at the right elbow as well as sensory and motor deficits of the right
      hand corresponding to distribution of the ulnar nerve. Ultrasound examination and
      magnetic resonance imaging showed a tumor along the nerve. Subsequent surgical
      therapy included tumor decompression by division of the fascia. The histological
      examination demonstrated a capillary hemangioma that infiltrated the ulnar
      nerve.After surgery, oral glucocorticoid therapy with cortisone (5 mg/kg per day)
      was administered over a period of 4 weeks, alternating between 1 week of therapy
      and 1 week without medication. The result of this combined therapy was a rapid
      diminution of the tumor and an almost complete restitution of the neural
      function.

PMID- 12599035
TI  - [Endoprostheses of the knee joint].

PMID- 12599036
TI  - [Prenatal diagnosis--a persistent forensic risk].

PMID- 12599037
TI  - [Acute left lower quadrant abdominal pain: ultrasonographic differential
      diagnosis].
AB  - Acute left lower quadrant pain is frequently caused by diverticulitis, especially
      in elderly patients. The most common differential diagnoses include renal colic,
      urinary tract infection, gynaecologic disorders, epiploic appendicitis,
      perforated carcinoma, other inflammatory diseases of the colon and diseases of
      the abdominal wall. Because the clinical impression may lead to a false
      diagnosis, further evaluation is necessary. Imaging methods are used to establish
      a correct diagnosis and to differentiate between benign self-limited disorders
      and those which require immediate intervention. Sonography and CT are the imaging
      methods of choice for the examination of patients with left lower quadrant pain.
      Both methods have shown to be accurate in verifying diverticulitis as well as in
      establishing alternative diagnoses. This review reports the sonographic
      appearance of the different entities and refers to other imaging methods if
      necessary.

PMID- 12599038
TI  - [Liability for overlooked malformations. Three recent rulings concerning false
      ultrasound diagnosis].
AB  - It is a grave risk for any physician working in prenatal medicine to be liable
      for an undiagnosed foetal malformation which would have justified an abortion
      according to section 218 a Abs. 2 StGB, making him responsible for compensation
      for the complete cost of upkeep and nursing of a handicapped child. Three recent
      high court rulings concerning the liability for overlooked malformations (amelia)
      have again emphasised this problem and have also demonstrated how carefully the
      courts determine whether a legal abortion would have been justified. In two cases
      this was denied, one of these cases representing a monozygotic twin pregnancy.
      Since an abortion would have almost certainly terminated the life of the healthy
      fetus, the "Bundesgerichtshof" specified stringent requirements as to the degree
      of handicap of the malformed fetus and the degree of additional stress for the
      mother, both of which were denied. A third case was judged differently because
      all four limbs were severely malformed and the mother was seen to be in a very
      unstable psychological state with the possible danger of suicide. Therefore the
      gynaecologist was judged to be liable for an incorrect ultrasound diagnosis (20/5
      gestational week). This court ruling contains remarkable comments regarding the
      burden of proof and the permission for a late abortion. Although this ruling is
      in line with recent jurisdiction, it has yielded a surprisingly critical
      response. this criticism should be levelled not towards the courts, but to the
      legislative body responsible for the consequences of legalising abortion on
      (socio-) medical grounds.

PMID- 12599039
TI  - Fetal ovarian cysts: development and neonatal outcome.
AB  - INTRODUCTION: The aim of the study was to evaluate the outcome of fetal ovarian
      cysts in relation to their size and ultrasonic appearance. METHODS: We
      retrospectively analysed pre- and postnatal charts of 61 infants with a prenatal
      diagnosis of ovarian cysts between 1991 and 2000. RESULTS: In a total of 61
      fetuses 65 ovarian cysts were detected by transabdominal ultrasound: 35 (57 %)
      cysts on the left side, 22 (36 %) on the right side and 4 fetuses (7 %) had
      bilateral cysts. Three patients with uncomplicated cysts were lost to follow-up
      and one fetus with bilateral cysts died in the 27th week of gestation. In 17
      cysts treatment was necessary. 14 cysts (all complicated) were operated after
      delivery because of persistence or enlargement. The histological results were
      either follicular or theca lutein cysts in 12 cases, one lymphangioma and one
      teratoma. Two cysts were aspirated in utero and one after delivery. In the
      remaining 40 fetuses, 43 cysts where only controlled by ultrasound. 8 cysts
      regressed before delivery and 35 cysts after delivery independent of their
      sonographic appearance. The mean diameter of cysts that required treatment was
      significantly different from the mean diameter of cysts that resolved
      spontaneously (6.8 [SD 2.4] cm vs. 3.3 [SD 0.8] cm; p < 0.01). CONCLUSION:
      Complicated cysts which do not regress should be treated either by laparotomy or
      laparoscopically after delivery. Uncomplicated cysts which exceed 5 cm could be
      treated by in utero aspiration or aspiration after delivery to avoid further
      complications. Cysts smaller than 5 cm, presenting the tendency to regress,
      should be left untouched independent of their sonographic appearance.

PMID- 12599040
TI  - [Radio-frequency-ablation (RFA) with wet electrodes in the treatment of primary
      and secondary liver tumours].
AB  - INTRODUCTION: The majority of patients with primary and secondary tumours of the
      liver cannot be treated curatively by surgery. The treatment of these patients
      with radio-frequency thermoablation using perfused needle applicators (wet
      electrodes) was evaluated in a feasibility study. METHOD: Patients with primary
      and secondary tumours of the liver and contraindications against surgery or LTX
      were included into the feasibility study. RFA was performed percutaneously under
      ultrasound guidance. The patients were followed up sonographically and by
      computed tomography. RESULTS: 20 patients (9 male, 11 female) with 35 lesions
      were treated with RFA. 12 patients (22 tumour locations) suffered from HCC and 8
      patients (13 tumour masses) had liver metastases (colorectal, breast, pancreas,
      carcinoid). The median age was 65.6 years (36 to 83 years). The median tumour
      size was 33.5 mm. 59 RFTA applications (1.7 applications per tumour mass) were
      performed. The mean duration of RFTA per patient was 16.2 minutes. During the
      procedure isotonic saline was injected at a mean flow rate of 6.63 ml/min. All
      patients received local anaesthesia. In 33 sessions an additional analgosedation
      was necessary (average dose 63.8 mg Pethidine and 1.4 mg Midazolam). In 2 cases a
      reduction of the haemoglobin level, occurred, necessitating a blood transfusion.
      3/4 of the treated metastases could be eradicated completely. Within a median
      follow-up of 145 days no intrahepatic local recurrence but 4 distant metastases
      occurred. 2/3 of the treated HCC could initially be brought into complete
      remission (CR). After a median follow-up of 329 days 5 of the 8 initially
      successfully treated patients with HCC were still in complete remission. In 3
      cases an intrahepatic local recurrence developed. CONCLUSION: RFA with wet
      electrodes is a safe, effective and inexpensive treatment for primary and
      secondary tumours of the liver, measuring less than 4 cm in diameter.

PMID- 12599041
TI  - [Real-time registration of flow-mediated dilatation for the assessment of
      endothelial function].
AB  - Flow-mediated dilatation (FMD) is used to qualify vascular endothelial function.
      AIM: To evaluate the feasibility of real-time assessment of the stimulus-to
      response (i. e. flow-velocity-to-diameter) relationship, repeated FMD was
      assessed in healthy subjects. METHODS: Brachial artery diameter and flow velocity
      were measured simultaneously in 10 healthy male subjects lying in the supine
      position. These parameters were registered in real-time mode and beat-to-beat by
      means of a 7.5 MHz linear array transducer attached to a custom-built Wall Track
      System and an 8 MHz continuous wave Doppler. RESULTS: Post-ischaemic increase in
      arterial diameter amounted to 5.9 +/- 2.9 % with an average increase in blood
      flow velocity of 487 +/- 174 %. The relative change in diameter was not
      correlated to the relative increase in flow velocity. CONCLUSION: Continuous
      registration of FMD can be performed. Motion artefacts, however, interfere with
      the real-time registration of FMD.

PMID- 12599042
TI  - [Non-thermal non-cavitational effects of ultrasound].
AB  - The non-thermal, non-cavitational (NTNC-) effects of medical ultrasound are based
      essentially on the direct and indirect effects of the sound radiation pressure.
      This article introduces the biophysics of the basic mechanisms and describes
      possible clinical implications using selected examples. It has been determined
      that generally no additional risks ensue through the effects of NTNC used purely
      for diagnostic purposes. Significant effects can only be detected under the
      conditions which prevail during therapeutic exposure. The question as to whether
      the pulse Doppler technique is completely harmless cannot be answered
      conclusively at this time. The synergetic effects between ultrasound and contrast
      media have not yet been examined thoroughly.

PMID- 12599043
TI  - [Lethal rupture of an echinococcal cyst of the liver].
AB  - A 50-year-old man is admitted to the hospital emergency service because of a 24
      hour history of right abdominal pain. Ultrasound examination and laboratory tests
      suggest the perforation of an Echinococcal cyst situated in the subcapsular area
      of the right hepatic lobe. The patient and his family refuse the recommended
      hospitalisation and operation and leave the hospital on their own responsibility.
      60 hours later the patient dies. Post-mortem examination confirms the diagnosis
      of a perforated hydatid cyst of the right hepatic lobe. The cause of death was a
      partly fibrino-purulent, partly nodular peritonitis including the area of liver
      rupture.

PMID- 12599044
TI  - Tale of two epidemics--the continuing challenge of preventing mother-to-child
      transmission of human immunodeficiency virus.

PMID- 12599045
TI  - A multicenter randomized controlled trial of nevirapine versus a combination of
      zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to
      child transmission of human immunodeficiency virus type 1.
AB  - To determine the efficacy and safety of 2 inexpensive and easily deliverable
      antiretroviral (ARV) regimens for the prevention of mother-to-child transmission
      (MTCT) of human immunodeficiency virus (HIV) type 1 during labor and delivery,
      HIV-infected pregnant women were screened at 11 maternity health institutions in
      South Africa and were enrolled in an open-label short course ARV regimen of
      either nevirapine (Nvp) or multiple-dose zidovudine and lamivudine (Zdv/3TC). The
      overall estimated HIV-1 infection rates in 1307 infants by 8 weeks were 12.3%
      (95% confidence interval [CI], 9.7-15.0) for Nvp and 9.3% (95% CI, 7.0-11.6) for
      Zdv/3TC (P=.11). Excluding infections detected within 72 h (intrauterine), new
      HIV-1 infections were detected in 5.7% (95% CI, 3.7-7.8) and 3.6% (95% CI, 2.0
      5.3) of infants in the Nvp and Zdv/3TC groups, respectively, in the 8 weeks after
      birth. There were no drug-related maternal or pediatric serious adverse events.
      Common complications were obstetrical for mothers (Nvp group, 24.3%; Zdv/3TC
      group, 26.3%) and respiratory for infants (Nvp group, 16.1%; Zdv/3TC group,
      17.0%). This study further confirms the efficacy and safety of short-course ARV
      regimens in reducing MTCT rates in developing countries.

PMID- 12599046
TI  - Breast-milk infectivity in human immunodeficiency virus type 1-infected mothers.
AB  - Human immunodeficiency virus type 1 (HIV-1) is transmitted through blood, genital
      secretions, and breast milk. The probability of heterosexual transmission of HIV
      1 per sex act is.0003-.0015, but little is known regarding the risk of
      transmission per breast-milk exposure. We evaluated the probability of breast
      milk transmission of HIV-1 per liter of breast milk ingested and per day of
      breast-feeding in a study of children born to HIV-1-infected mothers. The
      probability of breast-milk transmission of HIV-1 was.00064 per liter ingested
      and.00028 per day of breast-feeding. Breast-milk infectivity was significantly
      higher for mothers with more-advanced disease, as measured by prenatal HIV-1 RNA
      plasma levels and CD4 cell counts. The probability of HIV-1 infection per liter
      of breast milk ingested by an infant is similar in magnitude to the probability
      of heterosexual transmission of HIV-1 per unprotected sex act in adults.

PMID- 12599047
TI  - Longitudinal analysis of human immunodeficiency virus type 1 RNA in breast milk
      and of its relationship to infant infection and maternal disease.
AB  - Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding
      can occur throughout lactation. Defining both fluctuation in breast-milk virus
      level over time and how breast-milk virus correlates with mother-to-child
      transmission is important for establishing effective interventions. We quantified
      breast-milk HIV-1 RNA levels in serial samples collected from 275 women for up to
      2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T
      cell count, and detection of HIV-1 DNA in maternal genital secretions were
      significantly associated with elevated breast-milk HIV-1 RNA. Within women who
      breast-fed, median virus load in colostrum/early milk was significantly higher
      than that in mature breast milk collected 14 days after delivery (P< or =.004).
      Breast-feeding mothers who transmitted HIV-1 to their infants had both
      significantly higher breast-milk viral RNA throughout lactation and more
      consistent viral shedding, compared with mothers who did not transmit HIV-1. In
      breast-feeding women, a 2-fold-increased risk of transmission was associated with
      every 10-fold increase in breast-milk virus load (95% confidence interval, 1.3
      3.0; P<.001). These results indicate that the risk of infant infection from
      breast-feeding is influenced by breast-milk virus load, which is highest early
      after delivery.

PMID- 12599048
TI  - Impact of antiretroviral therapy and changes in virus load on human
      immunodeficiency virus (HIV)-specific T cell responses in primary HIV infection.
AB  - Human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T cell responses
      were evaluated prospectively in a large cohort of subjects with HIV primary
      infection via long-term follow-up examining different virological profiles
      related to different treatment interventions. No correlation was observed between
      baseline virus load and HIV-specific CD4(+) and CD8(+) T cell responses. Highly
      active antiretroviral therapy (HAART)-induced suppression of viremia was
      associated with an increase in CD4(+) T cell proliferative responses. The HIV
      specific proliferative response also increased, at least in the first 18 months,
      in subjects with detectable viremia, either treated or untreated. The magnitude
      of the HIV-specific CD8(+) T cell response decreased with suppression of viremia.
      In subjects with detectable viremia, the breadth and magnitude of the HIV
      specific CD8(+) T cell responses increased progressively. Finally, whether HAART
      was initiated before or after seroconversion had little effect on HIV-specific
      CD4(+) and CD8(+) T cell responses.

PMID- 12599049
TI  - Qualitative change in antibody responses of human immunodeficiency virus-infected
      individuals to pneumococcal capsular polysaccharide vaccination associated with
      highly active antiretroviral therapy.
AB  - Variable region gene family 3 (V(H)3) is the predominant immunoglobulin (Ig) gene
      family used in human antibodies to pneumococcal capsular polysaccharide (PPS).
      This study examined whether highly active antiretroviral therapy (HAART) restores
      the ability of human immunodeficiency virus (HIV)-infected individuals to
      generate a V(H)3-positive response to PPS. The IgM, IgG, and V(H)3 (represented
      by antibodies expressing the determinant recognized by the monoclonal antibody
      D12) responses to PPS were determined for first-time recipients of a 23-valent
      PPS vaccine, both receiving and not receiving HAART, and second-time vaccine
      recipients receiving HAART. The results showed that only the individuals
      receiving HAART manifested a V(H)3-(D12)-positive response to PPS, despite a
      similar IgG response in each group. There was also a negative correlation between
      HIV load and PPS response for the groups receiving HAART. These findings suggest
      that HAART may influence qualitative aspects of the PPS response by restoring
      expression of certain V(H)3 genes used in the normal PPS response.

PMID- 12599050
TI  - Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in
      simian immunodeficiency virus infection.
AB  - Worldwide, the majority of human immunodeficiency virus-1 cases occur through
      heterosexual transmission, yet little is known regarding the phenotype of CD4(+)
      T cells in the vaginal mucosa. In the present study, lymphocytes were compared
      from the lymph nodes, blood, and vagina from uninfected and simian
      immunodeficiency virus (SIV)-infected macaques. In mature female macaques, 54%
      67% of the vaginal CD4(+) T cells expressed C chemokine receptor 5 (CCR5),
      whereas 84%-99% coexpressed CXC chemokine receptor 4. In contrast, only 4.4%
      14.8% of peripheral blood and 2.4%-13% of lymph-node CD4(+) T cells coexpressed
      CCR5. Moreover, CCR5 mean channel fluorescence was significantly higher on CD4
      cells from the vagina, compared with those from blood. In macaques intravenously
      infected with SIV, rapid depletion of CD4(+) T cells was observed in the vagina,
      particularly among the CCR5(+)CD4(+) subset. This demonstrates that large numbers
      of CD4(+) T cells expressing high levels of CCR5 reside within the vagina and
      that these cells are preferentially targeted for elimination by SIV infection.

PMID- 12599051
TI  - Mutations conferring foscarnet resistance in a cohort of patients with acquired
      immunodeficiency syndrome and cytomegalovirus retinitis.
AB  - The clinical significance of cytomegalovirus (CMV) foscarnet resistance was
      studied in patients with acquired immunodeficiency syndrome and CMV retinitis.
      Sequencing of the CMV pol gene was performed in 30 isolates. Phenotypic
      resistance was characterized by the DNA hybridization assay (DHA) in 30 isolates
      and by plaque-reduction assay (PRA) in 18 isolates. Nine isolates had foscarnet
      resistance mutations, including V787L and E756Q that were confirmed by marker
      transfer experiments. Seven of 9 isolates with a 50% inhibitory concentration
      (IC(50)) >600 microM by DHA had genotypic resistance, compared with 2 of 21 with
      an IC(50) < or =600 microM (P=.0005). By PRA, 5 isolates had an IC(50) >400
      microM and genotypic resistance, whereas only 1 of 13 susceptible isolates had
      genotypic resistance (P=.0007). Sixteen of 18 isolates had concordant PRA and DHA
      phenotypes. Among 44 patients treated with foscarnet, drug resistance increased
      the risk of retinitis progression (odds ratio, 14; P=.016). The incidence of
      foscarnet resistance after 6, 9, and 12 months of therapy was 13%, 24%, and 37%,
      respectively.

PMID- 12599052
TI  - Human metapneumovirus infections in young and elderly adults.
AB  - Human metapneumovirus virus (hMPV) is a newly discovered respiratory pathogen
      with limited epidemiological data available. Cohorts of young and older adults
      were prospectively evaluated for hMPV infection during 2 winter seasons. Patients
      hospitalized for cardiopulmonary conditions during that period were also studied.
      Overall, 44 (4.5%) of 984 illnesses were associated with hMPV infection, and 9
      (4.1%) of 217 asymptomatic subjects were infected. There was a significant
      difference in rates of hMPV illnesses between years 1 and 2 (7/452 [1.5%] vs.
      37/532 [7.0%]; P<.0001). In the second year, 11% of hospitalized patients had
      evidence of hMPV infection. Infections occurred in all age groups but were most
      common among young adults. Frail elderly people with hMPV infection frequently
      sought medical attention. In conclusion, hMPV infection occurs in adults of all
      ages and may account for a significant portion of persons hospitalized with
      respiratory infections during some years.

PMID- 12599053
TI  - Horizontal transmission of rhesus monkey rotavirus-based quadrivalent vaccine
      during a phase 3 clinical trial in Caracas, Venezuela.
AB  - During a phase 3 clinical trial of rhesus monkey rotavirus-based quadrivalent
      vaccine in Venezuela, 2207 infants received 3 oral doses of vaccine (4 x 105
      plaque-forming units/dose) or placebo at ages approximately 2, 3, and 4 months;
      219 (14%) of 1537 stools obtained during 1550 diarrheal episodes in
      postvaccination surveillance were rotavirus-positive by enzyme-linked
      immunosorbent assay. With the use of various VP7 and VP4 primers for genotyping
      purposes, 213 of 219 rotavirus-positive stools were analyzed by reverse
      transcription polymerase chain reaction. Twenty-nine (14%) of 213 rotavirus
      positive stools contained at least 2 distinct rotavirus strains: a low-titered
      vaccine strain(s) and a second strain that, when possible, was studied further
      and found to be a wild-type rotavirus strain. The titer of vaccine viruses in 19
      stools that plaqued directly in cell cultures ranged from 10(1) to 10(3) plaque
      forming units/0.5 mL of a 10% stool suspension. Reassortants of vaccine virus and
      wild-type human rotavirus were not detected.

PMID- 12599054
TI  - Transferred herpes simplex virus immunity after stem-cell transplantation:
      clinical implications.
AB  - Herpes simplex virus (HSV) commonly reactivates after stem-cell transplantation
      (SCT), despite acyclovir prophylaxis. Whether HSV-seropositive recipients with
      HSV-seronegative or type-discordant donors had more frequent and severe HSV
      infections than those with HSV type-concordant donors was explored. Banked serum
      samples from HSV-positive SCT recipients and their donors were tested for the
      presence of HSV antibodies. HSV-1-positive SCT recipients from HSV-1-negative
      donors had more frequent and longer episodes than HSV-1-positive SCT recipients
      from HSV-1-positive donors; the proportion of patients receiving antiviral
      treatment for >10% of follow-up days was 27.4% versus 7.2% (P<.001). Both HSV-1
      visceral infection (9.8% vs. 2.2%; P=.001) and acyclovir resistance (5.8% vs.
      1.8%; P=.03) were more common in type-discordant than -concordant patients,
      respectively; these associations were confirmed in multivariable models.
      Serological testing of donors can identify patients who are at highest risk for
      HSV-related morbidity, for whom prolonged prophylaxis or donor vaccination (once
      available) could be considered.

PMID- 12599055
TI  - Inter- and intragenic variations complicate the molecular epidemiology of human
      cytomegalovirus.
AB  - Human cytomegalovirus isolates were analyzed, both by restriction fragment-length
      polymorphism typing and by sequencing for intra- and intergenic variability at 9
      sites on the genome, to determine whether genetic variation influenced disease
      outcome and whether linkage among genes could be identified. Variation at the
      UL55 (glycoprotein B [gB]), UL74 (gO), UL75 (gH), UL115 (gL), US9, and US28 gene
      open-reading frames was studied in relationship to outcome of cytomegalovirus
      disease. Major findings were that (1) on the basis of analysis of only 9 genomic
      sites, it is apparent that an almost infinite number of genetic combinations are
      theoretically possible; (2) genetic linkages are rare; (3) intragenic variability
      may be a complicating factor in molecular epidemiologic studies; and (4) analysis
      of only a single gene from a clinical isolate may not reveal the presence of
      either intragenic variants or mixtures of genotypes.

PMID- 12599056
TI  - Synergistic activation of the serum response element-dependent pathway by
      hepatitis B virus x protein and large-isoform hepatitis delta antigen.
AB  - Hepatitis delta virus (HDV) is a naturally occurring satellite of hepatitis B
      virus (HBV). There are few studies of the effects of the combination of HBV and
      HDV proteins (HDV antigens [HDAgs]) on intracellular signaling pathways. To
      understand the influence of HBV and HDV coinfection on hepatocytes, we
      investigated the effect of HBV proteins and HDAgs on the serum response element
      (SRE)-dependent pathway. Reporter assays revealed that only HBV X protein (HBx),
      alone or with the large isoform of HDAg (LHDAg), synergistically activated the
      SRE-dependent pathway. The effect of HBx and LHDAg on Elk1 or serum response
      factor (SRF) was examined, because both proteins bind to the SRE. HBx activated
      the transcriptional ability of Elk1, whereas LHDAg activated the transcriptional
      ability of SRF. Thus, HBx and LHDAg synergistically activated the SRE-dependent
      pathway. These results may help us understand clinical phenomena in patients
      coinfected with HBV and HDV.

PMID- 12599057
TI  - Gastric mucosal recognition of Helicobacter pylori is independent of Toll-like
      receptor 4.
AB  - Little is known about the interactions between Helicobacter pylori, which
      specializes in colonizing the mucin layer that covers the gastric mucosa, and
      primary gastric epithelial cells. The expression pattern of Toll-like receptors
      (TLRs) in primary gastric epithelial cells and cell lines was compared. Primary
      cells did not express TLR4, whereas all cell lines expressed a nonsignaling form
      of TLR4. Because other cells within the mucosa expressed TLR4, it was next
      investigated whether H. pylori can be recognized by TLR4--they cannot. Moreover,
      H. pylori infection of primary cells induced a regulated production of
      interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha, whereas infection of
      cell lines only resulted in IL-8 production. The cytokine production in all cell
      types was strictly cag dependent. These findings indicate that, although the
      epithelium is important in directing the immune response against H. pylori
      infections, the response is independent of TLR4.

PMID- 12599058
TI  - Bartonella quintana bacteremia and overproduction of interleukin-10: model of
      bacterial persistence in homeless people.
AB  - Chronic asymptomatic bacteremia caused by Bartonella quintana occurs in homeless
      people, but its pathophysiology is unknown. We investigated homeless people with
      bacteremia to determine whether the persistence of B. quintana is associated with
      a specific immune profile. Homeless people without B. quintana infection
      exhibited an inflammatory profile--levels of circulating markers of leukocyte
      activation (soluble interleukin [IL]-2 receptor and neopterin) and cytokines
      released by mononuclear cells (tumor necrosis factor, IL-1beta, IL-6, and IL-10)
      were significantly higher than levels in healthy control subjects. In contrast,
      homeless people with B. quintana bacteremia exhibited specific increases in IL-10
      secretion by mononuclear cells. This overproduction of IL-10 was associated with
      an attenuated inflammatory profile. The depressed inflammatory response was
      specific of bacteremia, because patients with specific antibodies and without
      bacteremia had responses similar to those of homeless people. The overproduction
      of IL-10 and attenuated inflammatory response may account for the persistence of
      B. quintana in homeless people.

PMID- 12599059
TI  - Reinfection, rather than persistent infection, in patients with chronic
      granulomatous disease.
AB  - Chronic granulomatous disease (CGD) is characterized by severe recurrent
      infections with Staphylococcus aureus, certain gram-negative rods, Nocardia
      species, and fungi. When infections with the same species recur, they may
      represent relapses or new infections. We collected organisms from infections that
      occurred between 1992 and 2000 in patients with CGD and determined the
      biochemical phenotypes, in vitro antibiotic susceptibility patterns, and pulsed
      field gel electrophoresis (PFGE) patterns of the organisms causing the initial
      and recurrent infections. Recurrence of infection with Burkholderia cepacia or
      Serratia marcescens was caused by a new strain in 9 of 10 cases (P=.001).
      Recurrent S. aureus infections were caused by new strains in 7 of 8 cases
      (P=.006). In patients with CGD, recurrence of infection with the same bacterial
      species after appropriate antibiotic therapy usually represents new infection.

PMID- 12599060
TI  - Immune mechanisms underlying host susceptibility to infection with group A
      streptococci.
AB  - Different strains of mice differ markedly in their susceptibility to group A
      streptococci (GAS) infection, with BALB/c mice being much more resistant than
      C3H/HeN mice. In this study, we examined the mechanisms underlying host
      resistance/susceptibility to GAS infection in these 2 mouse strains. Resolution
      of GAS infection in BALB/c mice correlated with effective control of bacterial
      proliferation and moderate inflammatory response. In contrast, C3H/HeN mice
      failed to control bacterial growth and, in response to infection, produced a
      vigorous inflammatory reaction that resulted in extensive tissue destruction,
      organ failure, and death. In addition, in response to in vitro stimulation with
      GAS products, spleen cells from C3H/HeN mice had stronger proliferative activity
      and greater IFN-gamma production than did those from BALB/c mice. Therefore, the
      failure to restrict bacterial growth, the concomitant high levels of bacterial
      products, and the genetic predisposition to produce high levels of inflammatory
      mediators seem to be responsible for the susceptibility of C3H/HeN mice to GAS
      infection.

PMID- 12599061
TI  - Immunoglobulin G (IgG) responses to Plasmodium falciparum
      glycosylphosphatidylinositols are short-lived and predominantly of the IgG3
      subclass.
AB  - The induction of neutralizing immunity to Plasmodium falciparum toxins by
      vaccination has been proposed as a preventive strategy to limit the severity of
      malaria. For this approach to be successful, generation of a sustained immune
      response would be necessary. This study shows that immunoglobulin G (IgG)
      subclass responses elicited by the proposed P. falciparum toxin
      glycosylphosphatidylinositol (GPI) in Papua New Guinean subjects 5-60 years old
      predominantly involve IgG(3), with a lesser contribution from IgG(1) and an
      absence of IgG(2) and IgG(4). IgG(3) levels declined sharply within 6 weeks of
      pharmacological clearance of parasitemia in all subjects, whereas a significant
      decrease in IgG(1) levels was seen only in subjects < or =19 years old. Because
      the natural antibody response to P. falciparum GPIs is skewed toward the short
      lived IgG(3) subclass, a vaccination strategy with GPI analogues would likely
      require augmentation by costimulatory molecules, to induce a more persistent anti
      GPI response.

PMID- 12599062
TI  - Toxigenic Vibrio cholerae serogroup O141-associated cholera-like diarrhea and
      bloodstream infection in the United States.
AB  - Toxigenic Vibrio cholerae serogroup O141 has been associated with sporadic
      cholera-like diarrhea and bloodstream infection in the United States. Consumption
      of seafood and proximity to the coast may increase the risk of infection. All V.
      cholerae isolates recovered from stool samples of patients with diarrhea or from
      a normally sterile site should be serogrouped and assessed for cholera toxin
      production. Improved surveillance and case-control studies are needed to further
      characterize illness and risk factors for V. cholerae O141 infection.

PMID- 12599063
TI  - Outbreak of meningococcal disease caused by PorA-deficient meningococci.
AB  - An outbreak of 7 cases of group C meningococcal disease occurred during the last
      week of July and the first week of August 2001 in the southwestern part of The
      Netherlands. Characterization of the 7 patients' isolates by various typing
      methods showed that the isolates were identical, except for the expression of
      PorA. Isolates from 5 patients were PorA deficient. These results show that
      transmission of PorA-deficient meningococci occurs and that PorA-deficient
      meningococci can cause invasive disease. PorA-based meningococcal vaccines may
      provide limited protection.

PMID- 12599064
TI  - Perinatal hepatitis C virus transmission--role of human immunodeficiency virus
      infection and injection drug use.

PMID- 12599066
TI  - Differential expression of human immunodeficiency virus coreceptors, by CEM,
      CEMVBL, and CEM E1000 cells.

PMID- 12599068
TI  - Prognostic factors for chronic active Epstein-Barr virus infection.
AB  - Chronic active Epstein-Barr virus infection (CAEBV) is a high-mortality and high
      morbidity disease. To clarify the prognostic factors, a national survey was
      performed in Japan, and data for 82 patients who met the criteria for CAEBV were
      analyzed. Of these 82 patients, 47 were alive and 35 had already died.
      Multivariate analysis revealed that thromobocytopenia and age at disease onset
      were correlated with mortality. The probability of 5-year survival was 0.45 for
      older patients (onset age, > or = 8 years), 0.94 for younger patients (P<.001),
      0.38 for patients with thrombocytopenia (platelet count < 12 x 10(4)
      platelets/microL at diagnosis), and 0.76 for patients without thrombocytopenia
      (P=.01). Furthermore, patients with T cell infection by EBV had shorter survival
      times than patients with natural killer cell infection (probability of 5-year
      survival, 0.59 vs. 0.87; P<.009). Patients with CAEBV with late onset of disease,
      thrombocytopenia, and T cell infection had significantly poorer outcomes.

PMID- 12599069
TI  - Cytomegalovirus production by infected astrocytes correlates with transforming
      growth factor-beta release.
AB  - Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed
      persons, but its pathogenesis has received little investigative attention. The
      examination of brain tissue from 2 patients with acquired immunodeficiency
      syndrome who had CMV encephalitis showed colocalization of CMV inclusions and
      transforming growth factor (TGF)-beta in cells that contained astrocyte-specific
      glial filaments. To investigate the relationship between CMV and TGF-beta in the
      brain, an ex vivo murine model of CMV-infected astrocytes was established.
      Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine
      (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in
      parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release
      of CMV declined in the presence of antibody to TGF-beta and increased
      substantially after the addition of exogenous TGF-beta. These findings suggest
      that CMV infection of astrocytes induces the production of TGF-beta, which in
      turn enhances productive CMV expression.

PMID- 12599070
TI  - Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection
      against genital HSV-1 or HSV-2 disease in guinea pigs.
AB  - In two recent clinical trials, a vaccine containing herpes simplex virus (HSV)
      type 2 glycoprotein D (gD2) and a novel adjuvant AS04 comprising alum (Al) and 3
      deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women
      significant protection against HSV-2 genital disease (vaccine efficacy, 73% in
      study 1 and 74% in study 2) and limited protection against infection (46% in
      study 1 and 39% in study 2). In the present report, studies in the guinea pig
      model investigated the protection afforded by gD2/AS04 against HSV-1 and HSV-2
      genital herpes and investigated whether immunization could prevent or reduce
      recurrent disease in guinea pigs that developed mucosal infection. Immunization
      with gD2/AS04 conveyed nearly complete protection against primary disease with
      either virus but did not prevent mucosal infection. Guinea pigs immunized with
      gD2/AS04 were significantly better protected against recurrent disease than were
      guinea pigs immunized with a gD2/Al vaccine, which suggests that inclusion of 3
      dMPL improved protection against latent infection.

PMID- 12599071
TI  - Restricted T cell receptor beta-chain variable region protein use by cornea
      derived CD4+ and CD8+ herpes simplex virus-specific T cells in patients with
      herpetic stromal keratitis.
AB  - Herpetic stromal keratitis (HSK) is a T helper type 1 cell-mediated inflammatory
      disease triggered by herpes simplex virus (HSV) infection of the cornea. In
      contrast to animal models of HSK, little is known about the role of T cells in
      human HSK. The phenotypes and repertoires of HSV-specific T cells recovered from
      the corneas of 12 patients with HSK were determined by flow cytometry. Cornea
      derived T cell lines (TCLs) from 10 of the 12 patients contained high numbers of
      HSV-specific T cells. HSV reactivity was HSV type common and involved relatively
      more CD8(+) than CD4(+) T cells. The majority of the TCLs showed restricted T
      cell receptor beta-chain variable region protein (TCRBV) use. T cells expressing
      1 or 2 TCRBVs dominated the HSV-1 reactivity in 3 of 5 TCLs analyzed. The data
      demonstrate that both CD4(+) and CD8(+) T cells may be involved in the HSV
      specific T cell response in the corneas of patients with HSK and suggest that
      restricted TCRBV use by cornea-residing HSV-specific T cells occurs.

PMID- 12599072
TI  - Postnatal human herpesvirus 8 and human immunodeficiency virus type 1 infection
      in mothers and infants from Zambia.
AB  - The specific route and timing of human herpesvirus (HHV) 8 infection in regions
      where Kaposi sarcoma is endemic are not known. HHV-8 infection and any risk
      factors that may be associated with HHV-8, including human immunodeficiency virus
      (HIV) type 1 infection, were monitored during the 12-month postdelivery period
      for 416 mothers and 485 infants from Lusaka, Zambia. HHV-8 incident infection
      rates during this period were 3.2 and 5.3 infections/100 person-years for infants
      and mothers, respectively. HHV-8 infection among infants was not associated with
      HHV-8 or HIV-1 infection in the mother. Among the HHV-8-positive infants, 2 of 12
      tested were found to have HHV-8 DNA in their peripheral blood mononuclear cells
      at birth, which suggests that in utero infection is possible. However, most HHV-8
      positive infants appeared to have acquired infection either intrapartum or
      postpartum. The present study indicates that transmission of HHV-8 to infants can
      occur early and is likely via multiple routes.

PMID- 12599074
TI  - Experimental Pneumocystis carinii pneumonia in simian immunodeficiency virus
      infected rhesus macaques.
AB  - To establish experimental Pneumocystis carinii infection in simian
      immunodeficiency virus (SIV)-infected macaques as a model of acquired
      immunodeficiency syndrome (AIDS)-associated P. carinii pneumonia (PCP), SIV
      infected macaques were inoculated intrabronchially with macaque-derived P.
      carinii, and P. carinii-specific polymerase chain reaction (PCR) and flow
      cytometric analysis of bronchoalveolar lavage fluid were done biweekly for up to
      44 weeks after inoculation. All inoculated animals had a P. carinii-specific PCR
      product after infection. CD8(+) T cells in lung lavage samples from SIV- and P.
      carinii-coinfected animals increased to >90% of total CD3(+) cells, a pattern
      associated with naturally acquired P. carinii infection. Progression of disease
      also was correlated with increased neutrophil infiltration to the lungs. The
      animals had a protracted period of asymptomatic colonization with P. carinii
      before progression to PCP. The development of a model of PCP in SIV-infected
      rhesus macaques provides the means to study AIDS-associated PCP.

PMID- 12599073
TI  - CC chemokine receptor 5 genotype and susceptibility to transmission of human
      immunodeficiency virus type 1 in women.
AB  - The human gene for CC chemokine receptor 5, a coreceptor for human
      immunodeficiency virus type 1 (HIV-1), affects susceptibility to infection. Most
      studies of predominantly male cohorts found that individuals carrying a
      homozygous deleted form of the gene, Delta 32, were protected against
      transmission, but protection did not extend to Delta 32 heterozygotes. The role
      played by this mutation in HIV-1 transmission to women was studied in 2605
      participants in the Women's Interagency HIV Study. The Delta 32 gene frequency
      was 0.026 for HIV-1-seropositive women and 0.040 for HIV-1-seronegative women,
      and statistical analyses showed that Delta 32 heterozygotes were significantly
      less likely to be infected (odds ratio, 0.63 [95% confidence interval, 0.44
      0.90]). The CCR5 Delta 32 heterozygous genotype may confer partial protection
      against HIV-1 infection in women. Because Delta 32 is rare in Africans and
      Asians, it seems plausible that differential genetic susceptibility, in addition
      to social and behavioral factors, may contribute to the rapid heterosexual spread
      of HIV-1 in Africa and Asia.

PMID- 12599075
TI  - Nationwide surveillance of nasopharyngeal Streptococcus pneumoniae isolates from
      children with respiratory infection, Switzerland, 1998-1999.
AB  - The surveillance of pneumococcal antibiotic resistance and serotype distribution
      is hampered by the relatively low numbers of invasive pneumococcal infections. In
      Switzerland, a nationwide sentinel surveillance network was used to assess
      antibiotic resistance and serotype distribution among 1179 pneumococcal isolates
      cultured from 2769 nasopharyngeal swabs obtained from outpatients with acute
      otitis media or pneumonia during 1998 and 1999. The proportion of penicillin
      susceptible pneumococcal isolates overall (87%) and among infants <2 years old
      (81%) was comparable to that of invasive isolates (90% and 81%, respectively).
      The high number of nasopharyngeal isolates allowed for the detection of a rapid
      increase in the number of penicillin-nonsusceptible pneumococcal (PNSP) strains
      in the West region of Switzerland, partly because of an epidemic caused by the
      19F clone of Streptococcus pneumoniae. Clustering of risk factors for the
      carriage of PNSP isolates further explained the geographic variation in
      resistance rates. The nationwide sentinel surveillance of nasopharyngeal
      pneumococcus proved to be valuable for the monitoring of antibiotic resistance,
      risk factors for carriage of PNSP isolates, and serotype distribution and for the
      detection of the emergence of a new epidemic clone.

PMID- 12599076
TI  - Survival of Streptococcus pyogenes within host phagocytic cells: a pathogenic
      mechanism for persistence and systemic invasion.
AB  - Streptococcus pyogenes is generally an extracellular pathogen that can survive
      and persist within the host by circumventing the host defense mechanisms. To
      achieve this, S. pyogenes has developed a number of strategies to circumvent the
      host immune system (e.g., virulence factors directed to prevent phagocytosis). By
      use of a murine model of skin infection, it was shown that survival within host
      phagocytic cells constitutes an additional strategy used by S. pyogenes to evade
      the host defenses and disseminate. Viable microorganisms were isolated from mouse
      phagocytic cells after in vitro or during in vivo infection. The capacity of
      intracellularly located bacteria to establish infection was demonstrated by the
      efficiency of gentamicin-treated neutrophils isolated from infected mice to
      transfer infection when injected intravenously into naive mice. The ability of S.
      pyogenes to exploit the inflammatory response of the host by surviving inside
      phagocytic cells may constitute an additional virulence mechanism of this
      pathogen.

PMID- 12599077
TI  - Intrahost sequence variation in the streptococcal inhibitor of complement gene in
      patients with human pharyngitis.
AB  - Selection of new variants of the streptococcal inhibitor of complement protein
      has been implicated in the perpetuation of epidemics caused by serotype M1
      strains of group A Streptococcus (GAS). The frequency at which new streptococcal
      inhibitor of complement (Sic) variants arise in an infected individual is not
      known. To study this issue, the sic gene was sequenced in 100 isolates cultured
      from throat swabs of each of 20 patients with acute pharyngitis caused by
      serotype M1 GAS. Five patients were infected with GAS populations expressing 2
      Sic variants characterized by deletion of a region of the protein. In contrast,
      no intrahost variation was detected in the number of a pentanucleotide repeat
      (CAAAA) that controls production of a bacterial cell-surface collagen-like
      protein by slipped-strand mispairing. Sic variation occurs at a sufficient
      frequency in vivo to result in mixed infections on the mucosal surface of human
      hosts, potentially contributing to pathogen survival.

PMID- 12599078
TI  - Experimental protection of mice against lethal Staphylococcus aureus infection by
      novel bacteriophage phi MR11.
AB  - The protective effects of bacteriophages were assessed against experimental
      Staphylococcus aureus infection in mice. Of the S. aureus phages isolated in the
      study, phi MR11 was representatively used for all testing, because its host range
      was the most broad and it carries no genes for known toxins or antibiotic
      resistance. Intraperitoneal injections (8 x 10(8) cells) of S. aureus, including
      methicillin-resistant bacteria, caused bacteremia and eventual death in mice. In
      contrast, subsequent intraperitoneal administration of purified phi MR11 (MOI >
      or = 0.1) suppressed S. aureus-induced lethality. This lifesaving effect
      coincided with the rapid appearance of phi MR11 in the circulation, which
      remained at substantial levels until the bacteria were eradicated. Inoculation
      with high-dose phi MR11 alone produced no adverse effects attributable to the
      phage. These results uphold the efficacy of phage therapy against pernicious S.
      aureus infections in humans and suggest that phi MR11 may be a potential
      prototype for gene-modified, advanced therapeutic S. aureus phages.

PMID- 12599079
TI  - Use of the quorum-sensing inhibitor RNAIII-inhibiting peptide to prevent biofilm
      formation in vivo by drug-resistant Staphylococcus epidermidis.
AB  - Staphylococcus epidermidis is a frequent cause of infections associated with
      foreign bodies and indwelling medical devices. The bacteria are capable of
      surviving antibiotic treatment through encapsulation into biofilms. RNAIII
      inhibiting peptide (RIP) is a heptapeptide that inhibits S. aureus pathogenesis
      by disrupting quorum-sensing mechanisms. In this study, RIP inhibited drug
      resistant S. epidermidis biofilm formation through a mechanism similar to that
      evidenced for S. aureus. RIP is synergistic with antibiotics in eliminating 100%
      of graft-associated in vivo S. epidermidis infections, which suggests that RIP
      may be used to coat medical devices to prevent staphylococcal infections.
      Disruption of cell-cell communication can prevent infections associated with
      antibiotic-resistant strains.

PMID- 12599080
TI  - Blocking of responses to endotoxin by E5564 in healthy volunteers with
      experimental endotoxemia.
AB  - E5564 is a second-generation synthetic analogue of the lipid A component of
      endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic
      activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus
      infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a
      mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250
      microg ameliorated or blocked all of the effects of LPS in a dose-dependent
      manner. All E5564 dose groups had statistically significant reductions in
      elevated temperature, heart rate, C-reactive protein levels, white blood cell
      count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6),
      compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an
      LPS antagonist and completely eliminated these signs. E5564 also blocked or
      ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia
      (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a
      human model of clinical sepsis and indicate its potential in the treatment and/or
      prevention of clinical sepsis.

PMID- 12599081
TI  - Assessment in mice of the therapeutic potential of tailored, multivalent Shiga
      toxin carbohydrate ligands.
AB  - The therapeutic potential of 2 soluble multivalent receptor-based inhibitors of
      Shiga toxin (Stx) 1 and Stx2 was determined in mice. One of these, Starfish,
      protected mice when it was injected subcutaneously in admixture with a lethal
      dose of Stx1 but not Stx2. Starfish also reduced the distribution of (125)I-Stx1
      but not (125)I-Stx2 to the murine kidney and brain. A modified version of
      Starfish, called "Daisy," in which the Stx alpha Gal(1,4)beta Gal(1,4)beta Glc
      receptors were installed on the core glucose structure via a modified tethering
      strategy, protected mice against both Stx1 and Stx2. Daisy also protected
      streptomycin-treated mice from Escherichia coli O91:H21 and did not interfere
      with the ability of the murine immune system to produce Stx-specific protective
      antibodies. These results extend the possibility of using soluble carbohydrate
      based receptor inhibitors to prevent Stx-mediated complications arising from
      infections with enterohemorrhagic E. coli serotypes.

PMID- 12599082
TI  - Mucopurulent cervicitis and Mycoplasma genitalium.
AB  - Many cases of mucopurulent cervicitis (MPC) are idiopathic and cannot be
      attributed to the known cervical pathogens Neisseria gonorrhoeae, Chlamydia
      trachomatis, or herpes simplex virus. Because Mycoplasma genitalium is associated
      with nongonoccocal urethritis in men, its role in MPC, the corresponding syndrome
      in women, was investigated. Archived cervical specimens from women recruited in
      the Harborview Sexually Transmitted Disease Clinic in Seattle from 1984 to 1986
      were tested, using polymerase chain reaction, in a study that identified other
      causes of and risk factors for MPC. M. genitalium was detected in 50 (7.0%) of
      719 women. Young age, multiple recent partners, prior miscarriage, smoking,
      menstrual cycle, and douching were positively associated with M. genitalium,
      whereas bacterial vaginosis and cunnilingus were negatively associated. After
      adjustment for age, phase of menstrual cycle, and presence of known cervical
      pathogens, women with M. genitalium had a 3.3-fold greater risk (95% confidence
      interval, 1.7-6.4) of MPC, which suggests that this organism may be a cause of
      MPC.

PMID- 12599083
TI  - Randomized, controlled trial of daily iron supplementation and intermittent
      sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western
      Kenya.
AB  - A randomized, placebo-controlled treatment trial was conducted among 546 anemic
      (hemoglobin concentration, 7-11 g/dL) children aged 2-36 months in an area with
      intense malaria transmission in western Kenya. All children used bednets and
      received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed
      by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and
      daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron
      placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean
      hemoglobin concentration at 12 weeks, compared with that for the double-placebo
      group, was 1.14 g/dL (95% confidence interval [CI], 0.82-1.47 g/dL) greater for
      the IPT+iron group, 0.79 g/dL (95% CI, 0.46-1.10 g/dL) greater for the iron
      group, and 0.17 g/dL (95% CI, -0.15-0.49 g/dL) greater for the IPT group. IPT
      reduced the incidence of malaria parasitemia and clinic visits, but iron did not.
      The combination of IPT and iron supplementation was most effective in the
      treatment of mild anemia. Although IPT prevented malaria, the hematological
      benefit it added to that of a single dose of SP and bednet use was modest.

PMID- 12599084
TI  - Kinetics of antibody responses to Plasmodium falciparum-infected erythrocyte
      variant surface antigens.
AB  - The kinetics of antibody responses to the Plasmodium falciparum malaria parasite
      induced erythrocyte surface antigens (PIESAs) in 26 Kenyan children were examined
      by use of flow cytometry and agglutination assays. Although 19 of the 26 children
      mounted a primary antibody response to PIESAs within 2 weeks of experiencing an
      acute episode and maintained high antibody levels for at least 12 weeks, the
      remaining 7 children had responses that were weak and brief. Resistance to
      reparasitization was decreased in the children with short-lived responses.
      Isotype profiles of responses in 11 of the children studied suggest that they may
      have failed to switch to IgG after the initial IgM response. These data suggest
      that children vary widely in their ability to respond to PIESAs and that, in some
      individuals or with certain PIESA variants, short-lived antibody responses are
      induced that may be associated with poor antibody class switching.

PMID- 12599085
TI  - Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with
      MF59C.1.
AB  - A recombinant human parvovirus B19 vaccine (MEDI-491; MedImmune) composed of the
      VP1 and VP2 capsid proteins and formulated with MF59C.1 adjuvant was evaluated in
      a randomized, double-blind, phase 1 trial. Parvovirus B19-seronegative adults
      (n=24) received either 2.5 or 25 microg MEDI-491 at 0, 1, and 6 months. MEDI-491
      was safe and immunogenic. All volunteers developed neutralizing antibody titers
      that peaked after the third immunization and were sustained through study day
      364.

PMID- 12599086
TI  - Tracking the source of the hepatitis B virus-specific CD8 T cells during
      lamivudine treatment.
AB  - Lamivudine treatment in chronic hepatitis B leads to the reconstitution of virus
      specific T cells in the circulation, but it is not clear whether this is the
      preferential result of T cell efflux from the liver or lymph nodes. To address
      this question, the frequency and function of liver-, lymph node-, and blood
      derived hepatitis B virus (HBV)-specific CD8 T cells were analyzed in patients
      treated with lamivudine and undergoing liver transplantation. HBV-specific CD8 T
      cells, identified in portal lymph nodes, were able to expand in vitro after
      antigen-specific stimulation and displayed a heterogeneous profile of cytokine
      production. These findings suggest that the peripherally reconstituted HBV
      specific CD8 T cells can originate from precursor cells within lymph nodes.

PMID- 12599087
TI  - Transmission fitness of drug-resistant human immunodeficiency virus and the
      prevalence of resistance in the antiretroviral-treated population.
AB  - Although the prevalence of drug-resistant strains in primary human
      immunodeficiency virus (HIV) infection in North America has recently increased,
      their transmission fitness remains unknown. The present study estimated the
      frequency of transmission of drug-resistant HIV from patients receiving
      antiretroviral therapy using retrospective surveys of clinic data. It revealed
      that resistant virus was transmitted only approximately 20% as frequently as
      expected from these patients. Individuals with primary resistance may become a
      significant source of resistant strains.

PMID- 12599088
TI  - Genotype and phenotype at baseline and at failure in human immunodeficiency virus
      infected antiretroviral-naive patients in a randomized trial comparing zidovudine
      and lamivudine plus nelfinavir or nevirapine.
AB  - For the 127 Spanish patients enrolled in the Combine Study, a resistance substudy
      was performed with 100 (79%) plasma samples obtained at baseline and with 18
      samples obtained from 19 patients at the time they experienced treatment failure.
      At baseline, primary mutations to nonnucleoside reverse-transcriptase inhibitors
      and protease inhibitors were not detected, whereas mutations to nucleoside
      reverse-transcriptase inhibitors were observed in 10% of patients. At failure,
      mutations were detected in 7 of 16 patients. An agreement in the results of
      virtual and real phenotypes was observed in the 93 samples in which both tests
      were performed.

PMID- 12599089
TI  - Use of an open-reading frame-specific Campylobacter jejuni DNA microarray as a
      new genotyping tool for studying epidemiologically related isolates.
AB  - Findings from use of an open-reading frame-specific Campylobacter jejuni DNA
      microarray to investigate genetic diversity among clinical isolates associated
      with 5 independent clusters of infection were compared with data from random
      amplified polymeric DNA (RAPD) and Penner serotyping analyses. The DNA microarray
      provides a highly specific epidemiological typing tool for analysis of C. jejuni
      isolates and reveals both divergent and highly conserved gene classes among
      isolates.

PMID- 12599090
TI  - Polyclonal and compartmentalized infection by Mycobacterium tuberculosis in
      patients with both respiratory and extrarespiratory involvement.
AB  - Infection by Mycobacterium tuberculosis (MTB) is assumed to be caused by a single
      strain, and several MTB strains within the same patient are rarely considered.
      The present study analyzes the phenomenon of mixed infections by MTB in a group
      of 50 patients with both respiratory and extrarespiratory tuberculosis. First,
      the proportion of patients with infection by >1 strain was defined, and second,
      the clonal composition of the MTB populations at different infected sites was
      studied. In 3 (6%) of 50 patients, >1 strain was cultured, which indicates that
      mixed infections are not anecdotal. The coinfecting strains were not equally
      distributed at the respiratory and extrarespiratory site, which reflects a
      compartmentalization of the infection. In 1 patient, although 2 strains were
      found at the respiratory site, only 1 of these strains was involved in the
      extrarespiratory infection, which suggests that clonal selection can occur in the
      dissemination of the infection.

PMID- 12599091
TI  - Impairment of antimicrobial activity and nitric oxide production in alveolar
      macrophages from smokers of marijuana and cocaine.
AB  - Human alveolar macrophages (AMs) were recovered from the lungs of healthy
      nonsmokers (NS) or smokers of tobacco (TS), marijuana (MS), or crack cocaine (CS)
      and challenged in vitro with Staphylococcus aureus. AMs from NS and TS exhibited
      potent antibacterial activity that correlated with the production of nitric oxide
      (NO) and induction of NO synthase without the requirement for priming with
      exogenous cytokines. In contrast, AMs from MS and CS exhibited minimal
      antibacterial activity and failed to produce NO unless primed with additional
      cytokines. These results confirm that NO plays a significant role as an effector
      molecule used by normal human AMs, but this capacity is suppressed in AMs from MS
      and CS because of a lack of intrinsic cytokine priming.

PMID- 12599092
TI  - Regulation by granulocyte-macrophage colony-stimulating factor and/or steroids
      given in vivo of proinflammatory cytokine and chemokine production by
      bronchoalveolar macrophages in response to Aspergillus conidia.
AB  - Production of the proinflammatory cytokines interleukin (IL)-1 alpha and tumor
      necrosis factor (TNF)-alpha and of the chemotactic chemokine macrophage
      inflammatory protein (MIP)-1 alpha by bronchoalveolar macrophages (BAMs) from
      mice in response to Aspergillus conidia was tested after in vivo administration
      of saline, dexamethasone, cortisone acetate, granulocyte-macrophage colony
      stimulating factor (GM-CSF), or a combination. Dexamethasone suppressed
      production of IL-1 alpha, TNF-alpha, and MIP-1 alpha; GM-CSF reduced secretion
      slightly but antagonized dexamethasone suppression when the two were given in
      combination. Cortisone acetate gave results similar to dexamethasone, but
      cortisone acetate suppression of BAM responses lasted 7 days, > or = 4 days
      longer than dexamethasone suppression. The effect of GM-CSF on cortisone acetate
      suppression lasted at least 7 days. GM-CSF could promote resistance to conidia by
      maintaining proinflammatory responses.

PMID- 12599093
TI  - Suppression by Candida albicans beta-glucan of cytokine release from activated
      human monocytes and from T cells in the presence of monocytes.
AB  - The effect of a soluble beta-glucan from Candida albicans (CSBG) on cytokine
      production by cultured human peripheral blood mononuclear cells (PBMC) was
      assessed. CSBG induced a slight increase in the spontaneous release of
      proinflammatory cytokines, such as interleukin (IL)-6, but significantly
      suppressed endotoxin-induced IL-6 production in cultures of PBMC and monocytes
      isolated from PBMC. CSBG also suppressed the release of type 1 cytokines, IL-2,
      and interferon-gamma. These findings suggest that CSBG suppresses monocyte
      functions directly and thus suppresses T cell function indirectly. CSBG may play
      a role in the development of candidiasis.

PMID- 12599094
TI  - Immune responses directed against microfilariae correlate with severity of
      clinical onchodermatitis and treatment history.
AB  - The induction of pathological changes in Onchocerca volvulus infections is
      directly related to the presence of the microfilarial stage of this filarial
      nematode. Patients with either of the 2 major forms of the clinical disease
      (i.e., asymptomatic/mild [n=12] and severe [n=16] dermatopathology) were studied.
      The cellular immune responses (cell proliferation) of those with severe disease
      were stronger (stimulation index [SI], 12.3+/-1.9) than those with mild
      dermatopathological effects (SI, 2.9+/-0.6) or control patients (SI, 4.5+/-0.4).
      Cytoadherence antibody responses were greatest (grade 4) in the clinically severe
      group and only weak (grades < or = 1) in the mild group or the control patients.
      Ivermectin treatment was followed by an increase in immune responsiveness in
      those with initially poor responses. Thus, the degree of dermatopathological
      effect is related to the host's immune response against microfilariae, and
      ivermectin augments such responses.

PMID- 12599096
TI  - [Developmental dyslexia].
AB  - Developmental dyslexia makes up an important proportion of the known learning
      disorders. Until the late 1970s most research on dyslexia was carried out by
      educators and educational psychologists, but soon after the publication of some
      dyslexic cases with focal disorders of neuronal migration to the cerebral cortex,
      interest in the neurobiological and neurocognitive underpinnings of dyslexia
      grew, especially in Europe and North America. There are at least two types of
      developmental dyslexia--phonological and surface. Surface dyslexia refers to a
      disorder in which the difficulty lies in reading irregular words, whereas
      phonological dyslexia is characterized by difficulty with pseudowords.
      Phonological dyslexia is the more common of the two types. Surface dyslexia does
      not present a major problem in a language such as Spanish, where the number of
      irregular words is indeed very small. Still, in languages such as English, where
      irregular words are common, the phonological type of developmental dyslexia is
      much more common. Phonologic dyslexics have problems with phonological awareness,
      that is, the conscious knowledge and manipulation of speech sounds, which is the
      most proximate explanation for their difficulty in reading pseudowords. Many, but
      not all, phonologic dyslexics also have problems processing rapidly changing
      sounds, even if not linguistic, and some slow sounds, too. The same group tends
      to have visual problems, especially involving the so-called magnocellular pathway
      of the visual system, which, among others, has the role of analyzing movement.
      Accompanying these perceptual and cognitive deficits, phonologic dyslexics also
      show abnormal brain activation to phonological tasks, as shown in functional
      magnetic resonance studies (figure). In addition, dyslexic brains show focal
      malformations, ectopias and microgyria, of the cerebral cortex, involving mainly
      the left perisylvian region and the word form area in the temporo-occipital
      junction. There are also changes in the composition of neurons in the lateral and
      medial geniculate nuclei of the thalamus. Experimental studies indicate that the
      thalamic changes are a consequence of the focal malformations, and that they are
      responsible for the sound processing deficits. None of these discoveries have
      changed the therapeutic modalities in this condition, but it is hoped that this
      will be the next area of progress.

PMID- 12599097
TI  - [Neuromagnetic correlates of dyslexia].
AB  - Dyslexia was first described over a century ago and since then many theories have
      been put forward to explain it, but we still do not have one single unified
      theory that explains the problem. Furthermore, over the years a great deal of
      research work has also been carried out that relates dyslexia with disorders in
      different brain structures, and yet we still do not have a clear idea of exactly
      which neurophysiological mechanisms are involved. It has been claimed, however,
      that the disorder may be caused by specific deficits in the left frontotemporal
      region or atypical asymmetries in the left perisylvian regions. Lastly,
      neuroimaging techniques, such as functional magnetic resonance or mapping of the
      electrical activity in the brain, have helped to further studies into dyslexia
      over the last decade. Recently, the introduction of magnetoencephalography in the
      study of the brain has opened up a whole new range of possibilities that will
      allow most of the controversial points raised by research into dyslexia using
      neuroimaging techniques to be resolved empirically.

PMID- 12599098
TI  - [Intervention in dyslexic disorders: phonological awareness training].
AB  - Taking into account the systems for the treatment of brain information when
      drawing up a work plan allows us to recreate processing routines that go from
      multisensory perception to motor, oral and cognitive production, which is the
      step prior to executive levels of thought, bottom-up and top-down processing
      systems. In recent years, the use of phonological methods to prevent or resolve
      reading disorders has become the fundamental mainstay in the treatment of
      dyslexia. The work is mainly based on phonological proficiency, which enables the
      patient to detect phonemes (input), to think about them (performance) and to use
      them to build words (output). Daily work with rhymes, the capacity to listen, the
      identification of phrases and words, and handling syllables and phonemes allows
      us to perform a preventive intervention that enhances the capacity to identify
      letters, phonological analysis and the reading of single words. We present the
      different therapeutic models that are most frequently employed. Fast For Word
      (FFW) training helps make progress in phonematic awareness and other linguistic
      skills, such as phonological awareness, semantics, syntax, grammar, working
      memory and event sequencing. With Deco-Fon, a programme for training phonological
      decoding, work is carried out on the auditory discrimination of pure tones,
      letters and consonant clusters, auditory processing speed, auditory and
      phonematic memory, and graphophonological processing, which is fundamental for
      speech, language and reading writing disorders. Hamlet is a programme based on
      categorisation activities for working on phonological conceptualisation. It
      attempts to encourage the analysis of the segments of words, syllables or
      phonemes, and the classification of a certain segment as belonging or not to a
      particular phonological or orthographical category. Therapeutic approaches in the
      early phases of reading are oriented towards two poles based on the basic
      mechanisms underlying the process of learning to read, the grapheme phoneme
      transformation process and global word recognition. The interventionalist
      strategies used at school are focused on the use of cognitive strategy
      techniques. The purpose of these techniques is to teach pupils practical
      strategies or resources aimed at overcoming specific deficiencies.

PMID- 12599099
TI  - [Unsolved problems in research on difficulties of lexical access: a programme for
      the future].
AB  - Difficulties of lexical retrieval are a complex syndrome which is hard to
      delimit. The syndrome implies an unexpected failure in word identification,
      access to meaning, pronunciation and spelling. It affects individuals with normal
      intelligence and interferes significantly with academic achievement and with
      everyday tasks that involve the ability to read. It is estimated that 4% of
      school age children in the USA suffer from it, compared to 2% in Spain. The
      chronic nature of dyslexia and the social and emotional problems that it brings
      about are of considerable concern to education professionals. In this paper we
      attempt an exhaustive review of recent studies on this topic. We use this review
      as a basis to reflect on the repercussions of recent findings for the design of
      effective assessment tasks and intervention techniques.

PMID- 12599100
TI  - [Clinical profiles and transitions in the spectrum of specific language
      impairment in childhood].
AB  - OBJECTIVES: To test the clinical nature and diversity of specific language
      impairment (SLI) in Spanish individuals, in the framework of the
      neuropsycholinguistic model of Chevrie-Muller and the classification of Rapin and
      Allen. PATIENTS AND METHODS: Forty two language impaired children with normal
      intelligence and audition have been followed during a mean period of 3 years 7
      months in preschool and school ages; all of them have participated in an
      intervention program for language abilities. The evolutive neuropsychological
      evaluation at our hospital has comprised measurement of general cognitive
      abilities, formal (phonology, vocabulary, syntax) and pragmatic aspects of
      language. RESULTS: Phonological and syntactic abilities are the better evolutive
      predictors. The group clinical profiles, in general, fill into the clustering
      system proposed by Rapin and Allen, but mixed transitional forms are observed in
      individuals. Also in six patients a transition from one to another clinical form
      have been observed; in these subjects, mixed phonological syntactical syndrome is
      an obligate step during their evolutive changes; these changes can be attributed
      to natural evolutive processes and/or to effects of intervention. CONCLUSION: Our
      results permit hypothesize that the spectrum of SLI is an unique basic disorder
      whose clinical manifestations (interindividual and intraindividual during
      evolution) can be diverse in form and severity. This clinical interpretation is
      reinforced by the results of recent publications showing that members of the same
      familial group with identical genetic mutation had different forms of SLI.

PMID- 12599101
TI  - [The neuromagnetic correlates of language].
AB  - Studies of language using different functional neuroimaging techniques have shown
      the cortical structures to be involved in the functions of language, both in
      control subjects and in patients with different neurological pathologies who are
      to undergo brain surgery. Magnetoencephalography (MEG) is a totally non-invasive
      technique that measures the magnetic fields generated by the flow of
      intracellular current produced in the dendrites of the pyramidal neurones. MEG
      also offers the possibility of lateralizing language, so enabling us to know
      which areas of language lie within the dominant hemisphere and to establish the
      temporal patterns that reveal the organisation, either in sequence or in
      parallel, of the different areas that are activated. This will provide us with a
      deeper understanding of the physiological foundations upholding both language and
      other cognitive processes.

PMID- 12599102
TI  - [Speech therapy intervention in phonological disorders from the psycholinguistic
      paradigm of speech processing].
AB  - The aim of this study is to present a survey of speech therapy intervention in
      phonological disorders (PD). We will examine the concepts of normal phonological
      development and those involved in PD in order to understand how they have been
      dealt with, historically, in speech therapy intervention. Lastly, we will
      describe how evaluation and intervention are carried out from the speech
      processing paradigm. Phonetic phonological skills allow people to decode the
      phonic strings they hear so as to be able to gain access to their phonological
      form and meaning. These abilities also enable them to encode these strings from
      lexical representations to pronounce words. The greater part of their development
      takes place during approximately the first four years of life. Speech processing
      difficulties affect the phonetic phonological skills and occur throughout almost
      all language pathologies, although the effect they exert is not always the same.
      This can range from a lack of the capacity to speak to important problems of
      intelligibility or mild problems with certain phonemes. Their influence on
      learning to read and write has been shown in recent decades. Speech therapy
      intervention began from a model based on articulatory phonetics. In the 70s a
      linguistic model based on the process of speech simplification and phonological
      analysis was added and this gave rise to a marked improvement in the systems used
      for evaluation and intervention. At present we have assumed a psycholinguistic
      model that links the perceptive skills with productive ones and top-down or
      bottom-up processing (from lexical representations to perception or production of
      phonemes and vice-versa).

PMID- 12599103
TI  - [Stereotypic movements].
AB  - Stereotypic movements are repetitive patterns of movement with certain peculiar
      features that make them especially interesting. Their physiopathology and their
      relationship with the neurobehavioural disorders they are frequently associated
      with are unknown. In this paper our aim is to offer a simple analysis of their
      dominant characteristics, their differentiation from other processes and a
      hypothesis of the properties of stereotypic movements, which could all set the
      foundations for research work into their physiopathology.

PMID- 12599104
TI  - [Autism and hyperlexia].
AB  - INTRODUCTION: Hyperlexia is described in children who present alterations or
      retardation in development and is frequently characterised by their teaching
      themselves to read at an early age. This ability to decode words does not
      correlate with their intellectual level and can course with different degrees of
      mental retardation. It is always accompanied by difficulty in establishing social
      relationships. Autism is a disorder that is prototypical of the autistic spectrum
      disorders (ASD), which are essentially characterised by qualitative alterations
      in social interaction, in communication and language development, and in the
      presence of a limited repertory of interests, accompanied by stereotyped or
      peculiar responses. METHOD: The presence of hyperlexia in autistic children is
      more frequent than in other development disorders. This phenomenon is linked with
      the increased skills involving visual memory, visual discrimination and
      motivation/interest towards visually represented material that is to be found in
      people with autism. However, not all autistic individuals present hyperlexia and
      not all children with hyperlexia present autism, although evidence shows that
      hyperlexia is a phenomenon that is observed with greater frequency in autism and
      in ASD. CONCLUSION: Hyperlexia, understood as meaning a little island of ability
      in children with autism and ASD, poses a number of questions and represents an
      important challenge in neuropsychological research in this population.

PMID- 12599105
TI  - [Clinical features of epilepsy in autism spectrum disorders].
AB  - Autism is a rare disease, but is currently in vogue. An incidence of 1/1,000 has
      been estimated for early childhood autism, but in autism spectrum the incidence
      can reach 30/1,000. The clinical characteristics of autism are cognitive language
      disorders, lack of social interaction, obsessive behaviours with stereotypic
      movements and epilepsy. For some authors it is an associated symptom while for
      others it is a cardinal symptom of the disease. Epilepsy in autism, as an
      association, was reported as early as 1944 by Leo Kanner, in describing his
      initial work involving 11 cases and how one of them suffered from epilepsy. In
      1960, the prevalence of epilepsy among autistic patients was evaluated and found
      to be much higher than in the normal population. The figures differ from author
      to author, but really they depend on age: the higher the age, the greater the
      prevalence of epilepsy. It was in fact this detail that drew our attention to
      this issue, and triggered the first questions in our research into autism and
      epilepsy. The series vary from 4 to 86%, depending on the methodology used to
      confirm the epilepsy. In our casuistics, between the ages of 1 and 18 years, 20%
      of these children with autism spectrum disorders suffer some kind of epileptic
      seizures, and 80% suffer what other researchers call subclinical seizures . In
      this paper, the symptomatology of the most important subclinical seizures that
      have been observed in these children is presented; the diseases associated with
      autism are commented on; the concept of primary and secondary autism is
      discussed; we explain why seizures occur in autism and their consequences as a
      neurodevelopmental disorder, and we put forward an interesting hypothesis within
      our general theory of autism. We also comment on the importance that the use of
      functional magnetic images in the study of autism has in our research.

PMID- 12599106
TI  - [Comorbidity in attention deficit hyperactivity disorder].
AB  - In this paper we review the aspects linked with the comorbidity of attention
      deficit hyperactivity disorder (ADHD). The disorders most frequently associated
      with ADHD are: Tourette syndrome, generalised development disorders,
      communication disorders, learning disorders, coordination development disorders,
      behavioural disorders, anxiety disorders, affective disorders and mental
      retardation. From the neurocognitive point of view, the executive functions play
      an important role in ADHD and from the neuroanatomical point of view there is
      involvement of the frontostriatal circuits. The functional model of ADHD based on
      these functions and these structures enables us to understand the comorbidity
      with the above mentioned processes. Given the high rate of comorbidity of ADHD it
      is important to identify the associated problems in order to rationalise the
      psychological approach and pharmacological treatment employed. We also review the
      therapeutic implications that comorbidity entails.

PMID- 12599107
TI  - [The role played by parents in the development and learning of children with
      attention deficit hyperactivity disorder].
AB  - INTRODUCTION: The parents of children with attention deficit hyperactivity
      disorder (ADHD) undergo high levels of stress, frequent quarrels amongst
      themselves and limitations in their social life, which are factors that exert an
      influence on the progress of the disorder and constitute a high priority
      therapeutic goal. AIMS: 1. To analyse the impact ADHD has on family life:
      economy, the relations between parents and children and between brothers and
      sisters, social life, and the feelings and attitudes parents have towards their
      child. 2. To study possible changes in the use of behavioural modification
      techniques and in the attributions/expectations of the parents following a
      programme of counselling. SUBJECTS AND METHODS: In order to accomplish the first
      objective, 36 couples filled in a questionnaire about family impact, and
      percentage analyses were carried out. To achieve the second aim, 28 couples, who
      received counselling in small groups, filled in questionnaires before and after
      the programme, and comparative analyses were performed using the Wilcoxon
      interval test. RESULTS: 89% of parents suffer from stress, 64% feel uncomfortable
      about their child's behaviour, for 68% of them the psychoeducational cost of the
      child is higher, 50% have quarrels with their partner and 44% report that it
      makes it more difficult for their brothers and sisters to take part in
      activities. Significant changes have also been observed in the knowledge parents
      have about the nature of the disorder and the attributions/expectations they have
      about their child, together with improvements in the application of behavioural
      modification techniques. CONCLUSIONS: ADHD exerts a negative effect on the family
      system; parent counselling has proved to be effective in understanding the
      pathology and bringing about positive changes in expectations/attributions.

PMID- 12599108
TI  - [Assessment and intervention of preschool children with attention deficit
      hyperactivity disorder symptoms and disruptive behavior].
AB  - Attention deficit hyperactivity disorder (ADHD) constitutes one of the most
      common childhood syndromes and its negative outcomes on all the child's
      functional domains have been consistently reported in the literature. As a
      result, their early identification is becoming a topic of increasing concern
      among the researchers from the field. However, given that many of the behaviors
      of interest are normative behaviors during this period, diagnosis in preschool
      years is controversial. Specifically, from a developmental perspective, although
      it is well known that high levels of motor activity, poor self control, and lack
      of attention are typical during these years, both expression and intensity of
      these behaviors are markedly higher on the group of ADHD preschool children.
      Consequently, their negative interference with daily living, produce significant
      maladjustments in the child's natural settings. All these ideas justify the need
      of considering and studying the most appropriate assessment techniques to
      reliably identify the deficits of ADHD in preschool children. On the basis of
      these statements, this paper offers a theoretical overview of the most recent
      developments regarding ADHD assessment and intervention techniques directed to
      the prevention of cognitive deficits as well as the achievement of a better
      school and social adjustment of ADHD preschool children.

PMID- 12599109
TI  - [Autoimmune neuropsychiatric disorders associated to infection by streptococcus
      in the paediatric age: PANDAS].
AB  - INTRODUCTION: The acronym PANDAS (Paediatric Autoimmune Neuropsychiatric
      Disorders Associated with Streptococcus) describes the neuropsychiatric disorders
      resulting from an autoimmune response to an infection by streptococcus in
      children. AIMS: The aim of this study was to clinically analyse 38 patients under
      the age of 16 with tics, Tourette syndrome (TS) or obsessive compulsive disorder
      (OCD) and their possible association to an infection caused by group A beta
      haemolytic streptococcus (GABHS). METHOD: We reviewed the medical records at the
      Instituto Neurologico in Valencia (Venezuela) over a 12 year period (1988-2000).
      All the patients met the inclusion criteria set out by the National Institute of
      Mental Health in Bethesda (1997) and the DSM-IV. RESULTS: Onset of the symptoms
      was higher in the group of schoolchildren (n=24), followed by the group of
      preschool children (n=8) and adolescents (n=6). Males were predominant (n=33)
      (86.8%). 17 patients presented chronic tics (44.7%), 13 had transitory tics
      (34.2%) and there were eight cases of TS (21.1%). The most frequently related
      comorbid disorders were: difficulties in learning (n=30) (78.9%), ADHD (n=27)
      (71.1%), OCD 14 (36.8%), sleep disorders (n=14) (36.8%), behavioural disorders
      (n=12) (31.6%), language disorders (n=11) (28.9%), psychomotor disorders (n=10)
      (26.3%) and nocturnal enuresis (n=7) (18.4%). Electroencephalogram patterns were
      abnormal in 72.4% (n=12), and the disorganised pattern was the most frequently
      observed (n=12) (41.4%), followed by a slow diffuse pattern (n= 7) (24.1%) and
      the left centro-parieto-temporal focal paroxysmal specific pattern (n=7) (24.1%).
      Less frequently we found unspecific generalised paroxysmal patterns, in four
      cases (13.8%), and asymmetrical patterns (n=1) (3.4%). The association with an
      infection by streptococcus was shown in two cases, which amounted to 5.2% of the
      sample. CONCLUSIONS: The obtained are similar to those reported in the
      literature. Only 5.2% of the cases were linked to a prior streptococcus
      infection.

PMID- 12599110
TI  - [Adopted children: risk factors and neuropsychological problems].
AB  - In recent years there has been a striking increase in the number of transnational
      adoptions in our country, which follows the trend already observed in other
      developed European countries. Major contributing factors to this phenomenon have
      been the improvements in socioeconomic conditions in our country, the drop in the
      birth rate, with the corresponding decrease in the number of children available
      for adoption, and the disappearance of orphanages. This growing demand can be met
      by developing countries, in which the birth rate is still high and there are only
      limited chances of being able to maintain offspring. The children that are
      adopted come mainly from countries in Central and South America, Eastern Europe
      and Asia. Pathologies that can be expected in adopted children include general
      paediatric conditions, especially infections (which are often autochthonous
      ailments in their own country) and malnutrition, as well as neuropsychological
      and developmental disorders, such as psychomotor retardation, conduct and
      behavioural disorders, which sometimes stem from conflicts arising in the process
      of adaptation, communication problems, which occasionally reflect an autistic
      like disorder, and the problems deriving from the circumstances that condition
      the donation of the child for adoption (perinatal pathology, maternal drug
      addiction and withdrawal symptoms, maternal psychopathology.). The pathology,
      history and prognosis of the adopted child depend on several different factors
      that act in an accumulative fashion. The country of origin plays a decisive role
      in the type of pathology, according to the level of the health care system that
      exists there, the existence of adoption programmes that are regulated by law,
      etc. The child's age at adoption marks the difference in the optimisation of
      their development, if they have early access to a stable family unit. Having
      stayed in institutions and the length of time spent there is a risk factor for
      presenting a neuropsychological pathology. On many occasions the scarce
      information available about the child's medical history makes it more difficult
      to anticipate the appearance of certain problems. The existence of social risk
      factors in the biological families is a conditioning factor in increased
      morbidity. We describe a short series of adopted patients who were attended in
      our Neuropaediatric clinic, and we analyse the above mentioned conditioning
      variables and the most frequent pathologies.

PMID- 12599111
TI  - [Diagnosis and intervention of disability-causing neonatological risk factors].
AB  - INTRODUCTION: Early care attempts to offer children with, or at risk of suffering
      from, development disorders a series of optimising compensatory actions that help
      them to mature properly in all spheres, thus allowing them to reach a maximum
      level of personal development and social integration. In this study we review the
      main instruments used for the diagnosis and prevention of neurological
      disabilities during the pre-and post-natal period. DEVELOPMENT: In this field,
      neuropaediatrics intervenes in a joint, coordinated fashion with neonatology in
      the detection, diagnosis and therapeutic care of the new-born. The progress made
      in diagnostic techniques allows the early detection of anomalies that are
      associated with disability. Neuroimaging (transfontanellar echography,
      computerised tomography (CAT), magnetic resonance imaging, brain SPECT), genetic
      and molecular genetics studies, metabolic neonatal and infection screening,
      neurophysiological techniques and so on will enable earlier and more sensitive
      diagnoses to be made. In addition, throughout the neonatal period the
      obstetrician has the enormous responsibility of diagnosing many processes that
      can be subsidiary to a future disability. CONCLUSIONS: We believe that close
      collaboration between the obstetrician, neonatologist and neuropaediatrician will
      enable the detection and prevention of risk factors that can lead to a
      neurological disability. It is also the neuropaediatrician's duty to take part in
      programmes to monitor the development of children with a biopsychosocial risk, as
      well as participating in the detection of warning signs and in the diagnosis of
      neurological disorders.

PMID- 12599112
TI  - [Multisensory stimulation].
AB  - INTRODUCTION: Diagnosis in early care (EC) involves a global study that covers
      the child's development, their personal history, family and surroundings. The
      specific aims of an intervention programme in EC could be summed up in four
      areas: the prevention of deficits or difficulties, the detection of problems
      linked with a socio-family deficiency or shortages, the stimulation of
      development, and help and assistance for families. Multisensory stimulation (MSS)
      of small children is essential for their future existence. The presentation of
      stimuli must follow a strict schedule; indeed, this observation is so important
      that if the critical moment for incorporating a stimulus is missed, providing the
      stimulus at another time will not have the same effect. METHOD: Intellectual
      development during early childhood was taken into account when defining the
      fundamental aims of a therapeutic intervention programme in EC. To develop
      suitable therapy according to these concepts, an EMS (Snoezelen) room with
      certain special characteristics is required. This room must allow the stimuli
      offered in each moment and under each sensory modality to be controlled.
      CONCLUSION: Applying intervention programmes in a proper, specific and timely
      manner will enable us to accompany each child, as far as is possible in each
      case, in the development of his or her abilities and capabilities.

PMID- 12599113
TI  - [Value of intrathecal baclofen in the treatment of spastic cerebral palsy].
AB  - Spasticity is the most common movement disorder in cerebral palsy. Cerebral
      spasticity has traditionally been treated with physical therapy and orthopedic
      surgery. Oral medications have been used with limited success. Intrathecal
      administration of baclofen may be a valuable alternative in selected patients. We
      comment the patient management and clinical practice guidelines on the use of
      intrathecal baclofen for the treatment of spasticity.

PMID- 12599114
TI  - [Williams syndrome. A summary of cognitive, electrophysiological,
      anatomofunctional, microanatomical and genetic findings].
AB  - Williams syndrome (WS) is the result of a hemideletion of about 17 genes in the
      q11.22-23 region of chromosome 7. Patients with WS show unique phenotypic
      features that include elfin face, heart malformations, calcium metabolism
      problems and learning disorders. The latter consist of mental retardation that is
      characterised by serious difficulties with processing visuospatial tasks, a
      striking ability to easily recognise faces, a relatively developed linguistic
      capacity and sensitiveness to sound, a strong need to establish affective ties
      with other people and a fondness for music. Anatomical studies show a decrease in
      the postero-dorsal parts of both hemispheres of the brain, malformation in the
      central dorsal region and an expansion of the superior temporal gyrus, of the
      amygdala and of the frontal lobe. These macroscopic anomalies are accompanied by
      microscopic anomalies, which consist of changes in the number and size of the
      neurons. Studies on evoked potentials show acoustic hyperexcitability and
      abnormal waves related to language and to faces. Genetic studies in our
      laboratories show that the exact size of the deletion can vary, which means
      partial cases also exist and have partial phenotypes. Combining behavioural,
      electrophysiological, anatomical and genetic reports suggests a problem with the
      posterior dorsal region of the brain, possibly resulting from mistakes in
      establishing the dorsoventral and caudorostral genetico-molecular gradients,
      which specify the cortical regions during development.

PMID- 12599115
TI  - [Aspects of cognition and language in children with fragile X syndrome].
AB  - INTRODUCTION: Fragile X syndrome, which is produced by mutation of a gene in the
      X chromosome, is the most frequent cause of hereditary mental retardation. The
      multisystemic alterations of the disorder are due to the inhibition of the
      expression of the FMR1 gene and to the lack or absence of FMRP protein. Mental
      retardation and autistic spectrum constitute the most serious manifestations of
      the syndrome, but there are numerous neuropsychological disorders that make up
      the cognitive behavioural (CB) phenotype of patients, and the number of clinical
      manifestations they are going to present is also high. AIMS: The aim of the study
      was to evaluate the parameters that can contribute to the elaboration of a set of
      generally agreed guidelines that include early diagnosis and the indispensable
      genetic counselling, as well as a multidisciplinary intervention that
      contemplates, in a global manner, the medical and educational needs of those
      affected. METHODOLOGY: The method used to conduct the study involved an analysis
      of the early manifestations of the disease and the neuropsychological aspects of
      those affected, by means of a study protocol that includes biological and
      pedagogical data together with batteries of standard tests. RESULTS AND
      CONCLUSIONS: Preliminary results confront us with the delay in diagnosis and in
      genetic counselling because the CB phenotype, in which language disorders were
      the most constant element, is not taken as being an early sign of the clinical
      manifestations or as a serious interference factor in the cognitive aspects in
      the progress of the disease.

PMID- 12599116
TI  - [Neuropsychological problems of cerebrovascular pathology in children].
AB  - Cerebrovascular pathology in infancy is, unlike in adults, infrequent. However,
      this must not lead us to think it is unimportant. There are a number of different
      vascular processes that exert an influence to varying degrees on the neurological
      and psychological future of our young patients. These sequelae can be of more or
      less importance and, on some occasions, can be lesions that will accompany them
      throughout the rest of their lives, in spite of the therapeutic methods we have
      available today. We basically differentiate vascular organic lesions that are pre
      established or due to malformations from other causes acquired as a consequence
      of an anomalous situation inherent to other pathologies and that have an
      extravascular origin. The most striking of these, because of their frequency,
      gravity and cellular pathology, are peri/intraventricular haemorrhages (PIVH) in
      those born premature and those weighing very little at birth. The causes from
      malformations remain and are relatively rare with a stable frequency, while the
      number of cases of PIVH has risen sharply in recent years due to different
      causes, the most notable of which is the increase in preterm multiple births, at
      around 30-32 weeks of gestation. This group of the population requires early and
      continuous neuropaediatric monitoring. Some of the sequelae are detected and
      dealt with quickly; others may appear later and will need the joint, coordinated
      attention of neuropaediatricians, psychologists, educators and physiotherapists.

PMID- 12599117
TI  - [Clinical phenotypes of classic Rett syndrome].
AB  - INTRODUCTION: Rett syndrome (RS) is a progressive neurological disorder that is
      diagnosed by essential, supportive and exclusion clinical criteria, and
      development takes place in four stages. It has been shown to be caused by de novo
      mutations of a gene located in the long arm of the dominant X chromosome that
      codes for the methyl CpG binding protein (MECP2). It has been observed that girls
      with classic RS (CRS) present distinguishing nuances with respect to the age of
      onset of the different criteria and as regards the progression of the disorder.
      Taking the ability or failure to walk as a reference, we have established three
      phenotypes. METHOD: Phenotype I. Ambulant CRS, which corresponds to a permanent
      stage III, or a stage III that lasts a long time before going into stage IV. The
      loss of the ability to use the hands in a purposeful way takes place at the age
      of 25.6 months, social withdrawal at 25.4 months, language impairment at 20
      months, stereotypic hand movements at 22.8 months and signs of spasticity appear
      around the age of 8-10 years. Phenotype II. Ambulant CRS. Transitory, which
      corresponds to an early stage IV-A. The first signs of abnormality appear around
      the age of 9-10 months. This is followed by the loss of the purposeful use of the
      hands towards the age of 23.4 months, social withdrawal around 21.4 months,
      language impairment at 20 months, stereotypic hand movements at 25.2 months and
      scoliosis, neuromotor disorders and trophic and vasomotor disorders at the age of
      4-5 years. Phenotype III. Non ambulant CRS, which corresponds to stage IV-B. It
      begins with hypotonia towards the age of 5-6 months, loss of voluntary grasping
      at 17.8 months, social withdrawal at 18 months, language impairment at the age of
      12 months, stereotypic hand movements at 13 months and early onset of motor,
      trophic and vasomotor disorders. Genetic studies were conducted in 12 girls and
      MECP2 gene mutations were found in 10 of them, belonging to the three different
      phenotypes. CONCLUSIONS: We have established three phenotypes in RS according to
      the ability to walk. If walking is not achieved or the ability is lost early on,
      speech loss, social withdrawal and the onset of stereotypic movements, motor,
      trophic and vasomotor disorders all progress more quickly. Mutations in the MECP2
      gene have been found in the three phenotypes. In 16.6% the genotype was normal.
      Greater accuracy is required in the definition of cases of CRS in order to
      establish phenotype genotype correlations.

PMID- 12599118
TI  - [Behavioural phenotypes in Prader-Willi syndrome].
AB  - INTRODUCTION: The behavioural phenotype of Prader-Willi syndrome (PWS) is defined
      by a neurological profile and a characteristic pattern of behavioural disorders
      which include cognitive deficits, learning difficulties and behavioural problems,
      which increase with age, both in number and gravity. METHOD: We review the
      behavioural phenotype of the cases of PWS in the Valencian Community, together
      with their peculiar behaviours, and analyse how these generate family and social
      problems. CONCLUSION: The description of a peculiar behaviour opens up new
      horizons when understanding and treating PWS, both from a pharmacological and
      neuropsychological perspective.

PMID- 12599119
TI  - [Savant or idiot savant syndrome].
AB  - Savant syndrome is currently still very mysterious, yet, thanks to the progress
      made in neuroimaging studies and especially MSI (Magnetic Source Imaging)
      techniques, a little more is now known about it. The theory, formulated many
      years ago, about damage to the left hemisphere of the brain has been supported by
      functional neuroimaging. Its relation to developmental disorders or to autism
      spectrum disorders is far more justified today and can be explained on the basis
      of its neuropathology. We present a study based on a review of the scientific
      literature concerning the syndrome, from the first time it was described back in
      1789 by Benjamin Rush up to the present day. We comment on its epidemiology and
      positive clinical manifestations, involving brilliant artistic talent and
      dazzling memory, but also the negative aspects suffered by these autistic
      patients. The most important theories are discussed together with the clinical
      coincidence with frontotemporal dementia and the responsibility of the right
      hemisphere when there are alterations in the contralateral hemisphere. The latest
      contributions made by Positron Emission Tomography and magnetoencephalography
      will be discussed and a mini-video of a personal case will be projected.

PMID- 12599120
TI  - [Cognitive profiles of borderline intelligence. The boundaries of mental
      retardation].
AB  - Few studies have been conducted on children and teenagers with borderline
      intelligence (BI) as a collective that shares this condition. In this paper we
      discuss the concept of intelligence and analyse the different cognitive profiles
      with which BI can be expressed. We also evaluate how aspects linked to a 'g'
      factor of intelligence and those linked to executive functions are involved.
      Among the former, how fast information is processed may play a significant role
      and would be related to a homogeneous BI profile. On the other hand, executive
      deficits would lead to BI with the passing of the years and would be linked to
      selective deficiencies that are related to learning disorders, language disorders
      and attention deficit hyperactivity disorder. We highlight the need to
      individualise each case in order to determine the most suitable educational
      needs.

PMID- 12599121
TI  - [Symbiosis between paediatric neurology and neuropsychology: personal experience
      and the current panorama].
AB  - OBJECTIVE: To show the possibilities of child neurologist and neuropsychologist
      to share the work on many patients with neurological and behavioral pathologies.
      METHOD: Child neurologists and neuropsychologists have an important work to share
      in the future. Every expert must know what type of disease corresponds to the
      knowledge acquired during the studies in the University School as well as to the
      functions permitted by the authorities, always thinking to get the best results
      to the patients, the families and the surrounding people.

PMID- 12599122
TI  - [The EHSA project: the study of spontaneous subarachnoid haemorrhages in
      Andalusia. Incidence and results].
AB  - AIM: To evaluate the incidence and results of spontaneous subarachnoid
      haemorrhages (SAH) in Andalusia. PATIENTS AND METHODS: We conducted a
      longitudinal prospective study of the cases of SAH attended in 28 hospitals in
      Andalusia over a three month period in 2000. SAH was defined as cases of acute
      haemorrhagic strokes diagnosed by tomography. The gross incidence rate (GR) was
      determined from census information from the Instituto Andaluz de Estad stica.
      Standard rates (SR) were estimated with relation to the European population.
      Results were evaluated on hospital discharge according to the Glasgow Outcome
      Score (GOS) and at 12 months, according the Barthel index (BI). RESULTS: The GR
      per 100,000 inhabitants/year was found to be 5.7 cases and the SR was 5.8. A
      comparison of incidences by province or sex showed no statistically significant
      differences. The period of maximum risk was the age bracket between 55 74 years
      (GR: 14.1). The acute fatality GR and SR rose to 1.9 per 100,000 inhabitants and
      year. Mortality was concentrated in a statistically significant way (p< 0.01)
      among those over the age of 65; sex did not exert any influence, but clinical
      gravity (p< 0.001) and the amount of bleeding did (p< 0.005). CONCLUSIONS: The
      incidence of spontaneous SAH in Andalusia was found to be within the average
      rates. Unfavourable results were high, although similar to those in other series.
      Fatality is significantly associated with factors that cannot be modified
      medically (age, clinical gravity and volume of bleeding)

PMID- 12599123
TI  - [Magnetoencephalographic study in patients with cognitive impairment].
AB  - INTRODUCTION: In early stages, dementia is a neurodegenerative process with
      difficult diagnosis. Although well defined clinically, its neurophysiological,
      neuroradiological and metabolic diagnosis is still unsuccessful. PATIENTS AND
      METHOD: A MEG study using a 148 channel whole head magnetometer (Magnes 2500 WH)
      and evaluation by mini mental state examination (MMSE) was performed in 31
      subjects. Statistical analyses was made to correlate number of dipoles of slow
      waves and neuropsychological variables. RESULTS: The 63.3% (21 patients) show
      slow waves dipoles in temporal lobes (52.3% were bitemporal). Right temporal lobe
      has 119.5 23.3 dipoles (averaged value), and left temporal lobe has 126.2 19.8
      dipoles (averaged value). The 25% (8 patients) shown slow waves dipoles in
      parietals lobes, 5 of them biparietal. Correlation between MMSE averaged scores
      and temporal lobe dipoles was r= 0.84. CONCLUSION: MEG results show that slow
      waves dipoles number in temporal lobes is related with low scores in the mini
      mental state examination. MEG could be a usefully complementary method in
      evaluation and following of degree of cognitive impairment in these patients

PMID- 12599124
TI  - [Thrombosis of the cerebral venous sinuses: a description of its clinical
      features, risk factors and treatment in a hospital of Colombia].
AB  - INTRODUCTION: Thrombosis of the cerebral venous sinuses (TCVS) is an infrequent
      entity that still represents a challenge in health care. PATIENTS AND METHODS: A
      descriptive study involving the evaluation of the medical records of patients
      that met the following criteria: over 18 years of age with a diagnosis of TCVS
      confirmed by CAT scan or cranial MRI, the absence of a history of intracranial
      surgery in the previous six months and absence of a history of intracranial
      infection. RESULTS: A total of 15 patients (14 females and one male) were found
      with an average age of 28.6 years. The time required for the development of the
      most frequent symptoms was 1 10 days (60%). The usual presentation was a syndrome
      of intracranial hypertension with focalisation and encephalopathy. Risk factors
      were identified in 13 patients (87%). TCVS was diagnosed by cranial MRI in the
      case of 14 patients (93%), by CAT scanning in one (7%) and this was also used to
      orient diagnosis in 12 cases (80%). The most frequently affected sinuses were the
      superior longitudinal and transverse, in 10 cases each (66%), and venous
      infarctions were also detected in 10 patients (66%). In the patients in whom we
      were able to evaluate clotting disorders, it was found that the only individual
      who displayed activated protein C resistance was positive, three out of four
      patients had a protein C deficiency and four out of six had an antithrombin III
      deficiency. CONCLUSION: TCVS presents as an intracranial hypertension syndrome
      and it is possible to find risk factors in as many as 85% of the cases.

PMID- 12599125
TI  - [Characterization of a group of patients with cryptococcosis of the central
      nervous system].
AB  - INTRODUCTION: Incidence of cryptococcosis of the central nervous system has risen
      sharply since AIDS became pandemic; from early 1998, the Instituto de Neurologia
      y Neurocirugia in Havana has beaten its own record in the number of cases
      attended. AIM: To describe the clinical epidemiological characteristics of
      patients with this disease who were hospitalised in this centre between 1991 and
      2000. PATIENTS AND METHODS: We present a descriptive study of 16 adult
      individuals who were admitted for this reason. Data on variables related with
      aspects concerning their epidemiology, clinical features, treatment and evolution
      were collected from a review of the clinical records and a survey conducted by
      post. RESULTS: It was found that in no cases did the disease appear as an
      epidemic outbreak, in 75% of the patients there was some kind of link with
      pigeons, none of the patients were HIV positive, and 50% displayed other causes
      of immunosuppression. Clinical behaviour varied and forms of meningitis and
      meningoencephalitis were prevalent; 37.5% of the patients displayed mild forms of
      the disease and 62.5% had more serious forms. The initial symptom in most cases
      was headache. The most constant CSF pattern was a raised protein level in the
      cerebrospinal fluid with scarce cellularity. 87.5% of the patients were cured of
      the disease by treatment involving amphotericin B, in some cases associated with
      fluconazole. Death and the presence of post treatment sequelae were observed in
      patients with serious clinical forms and late diagnoses

PMID- 12599126
TI  - [Gabapentin in the treatment of tremor].
AB  - PATIENTS AND METHODS: We evaluated the efficacy of gabapentin added to basal
      tremor treatment by means of a 16 month non randomized open study conducted at
      our Unit on treated and monitored patients. Efficacy was evaluated by means of
      the following scales: Tremor Scale (TS), Global Disability Examiner Scale (GDE)
      and Global Disability Patient Scale (GDP). For the GDE and GDP scales we
      constructed a dichotomic result evaluation variable (improvement vs. non
      improvement) and adjusted a logistic regression model (independent variables:
      age, gender, tremor duration and number of antitremor drugs associated with
      gabapentin). Two multiregression models were adjusted for the TS (12 month score
      result variable). Model 1: TS (items 1 14) and model 2: TS (items 15 21).
      INDEPENDENT VARIABLES: age, gender, tremor duration, initial test score and
      number of antitremor drugs associated with gabapentin. We studied 63 patients
      aged 59.4 years (SD, 16 years): 34 essential tremor, 16 Parkinson s disease
      tremor, 10 multiple sclerosis tremor, 4 writing tremor and 3 orthostatic tremor.
      RESULTS: At 12 months gabapentin improved the clinical results. The largest
      decrease (absolute terms) was observed in multiple sclerosis tremor, and in
      percentage terms the largest decrease was in orthostatic tremor. Logistic
      regression showed that masculine gender and a shorter tremor duration predicted a
      better result. Multiregression showed association between end and basal score, on
      the one hand, and a better result in males and shorter tremor duration, on the
      other

PMID- 12599127
TI  - [Tetanus in intensive care units].
AB  - INTRODUCTION: Tetanus is medical disease with a high mortality rate, even in high
      tech centres and in Intensive Care Units (ICU). AIMS. To analyse the appearance
      and evolution of tetanus in the ICU at our hospital. PATIENTS AND METHODS: This
      retrospective descriptive study, made up of 26 patients admitted to hospital with
      tetanus in the ICU at the Hospital Escuela during the period between January 1995
      and December 2001, examined the clinico epidemiological of the disease and the
      clinical evolution of the patients. RESULTS: Of the cases reviewed (n= 26), 34.6%
      were females and 65.4% males. The main clinical manifestations were: trismus
      (88%), dysphagia (77%) and cervical rigidity (69%). The incubation period varies
      from 3 days to 4 weeks. Most cases resulted from cut wounds (54%), to a lesser
      extent from excoriations (15%), and one case was associated with gynaecological
      surgery. The entry sites of the injuries were mainly on the upper (42%) and lower
      limbs (34.6%). Three patients had been vaccinated and 17 had not. Six cases were
      not recorded. The chief complications that developed were: dysautonomia (73%) and
      pneumonia (42%). The mortality rate was 69%. CONCLUSION: In spite of having
      suitable equipment available with which to treat tetanus, mortality is high,
      mainly because of dysautonomias. Prevention is therefore the most effective way
      of controlling this disease

PMID- 12599128
TI  - [Ischemic stroke: transesophageal echocardiographic findings].
AB  - INTRODUCTION: Since its initial application in 1976, the transesophageal
      echocardiogram (TEE) has improved the detection of cardiovascular emboligenic
      sources. Even though its indication in patients with stroke is still
      controversial, its use has contributed to the identification of potential embolic
      stroke sources. OBJECTIVE: To describe the transesophageal echocardiographic
      findings in ischemic stroke patients. PATIENTS AND METHODS: We analyzed case
      series of 162 TEE performed on a total of 576 ischemic events dated between
      01/01/99 to 01/05/01. The required information was collected prospectively in the
      Stroke Data Bank of the Neurology Department at Policl nico Bancario in Buenos
      Aires. RESULTS: TEE was carried out in 162 (28.1%) cases. Of theses cases 13%
      belonged to the clinical subtype TACI, 37% to PACI, 17% to POCI, and 37% to LACI
      subtype. Pathologic findings corresponded to cardiac level: spontaneous contrast
      in 29% of the cases, and to aortic level: plaques grade IV in 34% and debris in
      13% of the cases. According to the etiology of ischemic stroke, 67 patients had
      been registered under the diagnosis of lacunar infarct (60 in the anterior region
      and 7 in the posterior region), 93 had been diagnosed medium and grand artery
      infarct (73 in the anterior region and 29 in the posterior region), and 2 had
      remained unclassified. Emboligenic sources were found in 69.5% of TACI, 65% of
      PACI, 52% of POCI, and 53% of LACI. CONCLUSIONS: A high percentage of aortic
      artheroembolic pathology was detected in the population under study. However,
      spontaneous contrast was the echocardiographic phenomenon more frequently
      reported. It is to be pointed out the presence of potential cardiac and/or aortic
      emboligenic sources in 48% of the population with lacunar infarct

PMID- 12599129
TI  - [Non-paraneoplastic limbic encephalitis].
AB  - CASE REPORT: A young patient with epilepsy and limbic encephalitis unrelated to
      neoplasm. RESULTS: The patient in a subacute fashion showed frequent partial
      seizures with neuropsychological deficits mainly in recent memory capability,
      with an no simultaneous affectation of both temporal lobe and adjacent
      structures. After 6 years there was no evidence of underlying malignancy.

PMID- 12599130
TI  - [Unilateral isolated paralysis of the soft palate: a case report and a review of
      the literature].
AB  - INTRODUCTION: Unilateral isolated paralysis of the soft palate is a rare clinical
      entity. CASE REPORT: We describe the case of a 12 year old girl who presented
      acute dysphagia, a nasal voice and regurgitation of liquids into the nose.
      Exploration revealed right velopalatine insufficiency with normal gag reflex and
      pharyngeal sensitivity. All the complementary studies, including magnetic
      resonance, lumbar puncture and viral serology tests, were normal. There are 28
      similar cases in the literature, with the following characteristics: acute onset,
      appearing in infancy (96%), predominance in males (79%), recent respiratory
      infection (35%) and an excellent prognosis for recovery (85%). CONCLUSION: This
      is probably a case of acute cranial mononeuropathy with a viral aetiology

PMID- 12599131
TI  - [Primary intracranial Ewing's sarcoma of the mastoid bone. A case report].
AB  - INTRODUCTION: Ewing s sarcoma (ES) is a tumorous process that is found mainly in
      long bones and the pelvis, but its primary location is not often the intracranial
      zone. CASE REPORT: We report the case of a 5 year old patient who visited surgery
      30 days before hospital admission with increased volume of the left mastoid bone,
      torticollis, balance disorders and discoordinated movements. A computerised
      tomography brain scan confirmed our suspicions of a tumorous lesion that was
      destroying the left mastoid bone, and was invading the projection of the left
      hemispherium cerebri and edges of the brain stem (mid brain). The patient was
      submitted to surgery and a partial excision was performed. A month later, another
      operation was carried out and the patient died after several days in the
      intensive care unit from serious respiratory complications. CONCLUSIONS: The
      tumour marker CD 99 is specifically used to diagnose ES. We think that, when
      faced with a patient suffering from ES, conduct must always be aggressive, with
      early surgery and, later, adjuvant therapy.

PMID- 12599132
TI  - [Cerebral activation during Stroop's test in a case of early focal brain injury].
AB  - INTRODUCTION: Functional magnetic resonance imaging (fMRI) offers an important
      advantage over other functional neuroimaging techniques used with children
      because of its harmlessness. Previous studies conducted with adults with alexia
      suggested two ways the brain can reorganise reading after a brain injury
      affecting the left hemisphere, one contralateral and the other ipsilateral. CASE
      REPORT: We describe a study carried out using fMRI of a 10 year old girl with an
      injury to the left hemisphere caused by a fishing harpoon when she was 6 years
      old. As a result of the accident the girl presented a right hemiparesia. The girl
      s parents and teachers also reported difficulties in the acquisition of reading
      writing and arithmetic, as well as a certain degree of attentional deficit. An
      fMRI exploration was performed while the girl was doing the Stroop test. The
      structural MR images showed left hemisphere cortical lesions in the orbital and
      angular gyrus regions, in addition to the caudate and putamen nuclei, and in the
      inferior longitudinal bundle. The fRMI revealed a strong overactivation of the
      right dorsolateral frontal cortex, in the evaluation of interference, and
      activations of the right angular and bilateral supramarginal gyri, in the
      evaluation of word reading. CONCLUSION: The functional study suggests the
      existence of a reorganisation of reading that is both intra and inter
      hemispheric.

PMID- 12599133
TI  - [Griscelli syndrome in Mexico. Description of a case with neurological
      manifestations].
AB  - INTRODUCTION: Griscelli syndrome is a pathological condition with
      immunodeficiency and is characterised by hepatosplenomegaly, silvery hair,
      progressive neurological deterioration, hypogammaglobulinemia and pancytopenia.
      It is inherited by autosomal recessive transmission and is diagnosed using the
      histopathological findings from a skin biopsy, characterised by hyperpigmentation
      with accumulations of melanin, associated to the manifestations described. CASE
      REPORT: We report on the first case identified in Mexico: the patient, who
      presented silvery hair, hepatosplenomegaly and pancytopenia, was a member of a
      family with two children and had no noteworthy antecedents. From the ninth month
      onwards there was a fast progression of the neurological deterioration, which was
      characterised by epileptic seizures and flaccid quadriparesis that progressed
      quickly to a state of coma. Magnetic resonance imaging revealed demyelination of
      the white matter, mainly in the bilateral frontotemporal area; skin biopsy showed
      hyperpigmentation with accumulations of melanin. CONCLUSIONS: Immunodeficiencies
      are serious problems, but associated with dermatological, haematological and
      neurological data, accompanied by findings obtained by paraclinical
      haematological explorations, by neuroimaging and skin biopsies, it is possible to
      establish the proper diagnosis in order to improve quality of life and the
      progress of the disease. This can be achieved by bone marrow transplant (until
      now the only therapy available) but it must be performed early and not when the
      disease is at an advanced stage, when the possibility of recovery becomes more
      remote

PMID- 12599134
TI  - [Lumbar puncture and early neuroimaging in complex febrile seizures. Report of a
      case of shaken infant syndrome].
AB  - INTRODUCTION: Febrile convulsions are one of the most frequent pathologies seen
      in paediatric emergencies. The diagnosis of febrile seizures is clinico
      evolutionary and is easily established once the acute process is overcome and a
      normal state is restored in the child. The differential diagnosis is established
      with the processes that associate fever and convulsions in children between the
      ages of 1 month and 6 years, many of which require specific treatment. Certain
      complementary examinations, essentially a blood test, lumbar puncture and
      neuroimaging, are needed to identify them. Shaken infant syndrome is a form of
      physical abuse which includes the presence of intracranial traumatic injury,
      retinal haemorrhage and, in general, the absence of other physical signs of
      traumatic injury in the child. CASE REPORT: An 8 month old infant who presented a
      convulsive seizure on the left side of the body which coincided with an axillary
      temperature of 38 C that remitted with intravenous diazepam 40 minutes after
      onset. An early cranial computerised tomography (CT) scan led to a diagnosis of
      shaken infant syndrome. DISCUSSION: This case constitutes an argument in favour
      of performing an early cranial CT scan in complex febrile convulsions and in
      prolonged or partial non provoked seizures. We highlight the risks involved in
      performing a lumbar puncture in the absence of suspected non complicated acute
      bacterial meningitis. The diagnostic usefulness of an early CT scan in diagnosing
      such an important problem as shaken infant syndrome must also be noted, due to
      the risk of repetition and its high morbidity and mortality rates.

PMID- 12599135
TI  - [Exocytosis as the mechanism for neural communication. A view from chromaffin
      cells].
AB  - Exocytosis constitutes the main cellular mechanism for secreting
      neurotransmitters. It entails the fusion of a secretory vesicle with plasma
      membrane, thus promoting the release of its soluble content. Among the cell
      models that have provided insight into molecular machinery underlying the
      succesive steps of exocytosis, adrenal chromaffin cells have taken a prominent
      place. Exocytosis gave support to the classical quantal theory, which maintains
      that neurotransmitters are released as discrete packages from the nerve terminals
      towards the postsynaptic cell. We present here a brief review of the estate of
      our knowlegments about the secretory vesicle traffic towards the cell membrane
      and how exocytosis takes place through the so called SNARE hypothesis. We also
      review the novel mechanisms implicated in the regulation of the late steps of
      exocytosis as well as their possible role as target for drug therapy

PMID- 12599136
TI  - [Neurobiology of addiction to drugs of abuse].
AB  - OBJECTIVE: In this review we study drug addiction from a neurobiological point of
      view, emphasizing the dopamine hypothesis. This is basic to explain how a genetic
      feature is related with an alteration of this neurotransmitter and can connect
      with environmental factors to develop the addiction problem. DEVELOPMENT: Toxic
      addiction is defined as the physical or psychophysiological dependence on a
      special chemical substance, whose suppression arouses deprivation symptoms in the
      person. The study of addiction to different drugs gives us a new approach for
      knowing the strengthening systems. Because even thought we do not know precisely
      the nervous mechanism of these substances that cause pleasure, we suppose that
      they are in the same place as rewarding and strengthening the behaviour
      mechanisms. In this way the dopamine hypothesis has been developed: in this
      hypothesis drug addiction is closely connected with a genetic upset of this
      neurotransmitter, so there is a defect in the reward system. This in turn
      stimulates the substance abuse that increases the brain s dopamine levels.
      CONCLUSION: Knowing the neurobiological mechanisms involved in addiction and its
      relation with dopamine and the reward system can help us understand that problem
      and aid the rational development of treatment

PMID- 12599137
TI  - [A review of sleep disorders in depression].
AB  - AIMS: The main aims of this study are, on the one hand, to report on the current
      state of the art in research into the characteristics of sleep in depression and,
      on the other hand, to analyse the theoretical and practical implications of these
      results. METHOD: We review the main findings regarding the sleep disorders linked
      with depression and offer data about the sensitivity and specificity of these
      measures. The aetiopathogenic meaning of these sleep disorders is also analysed
      and finally we present some of the principal theoretical models put forward to
      explain these data. CONCLUSIONS: A number of studies have observed significant
      alterations in electroencephalographic patterns during sleep in subjects with
      depression. Some of the most commonly mentioned findings involve disorders
      affecting the continuity and duration of sleep, a reduction of phases 3 and 4 of
      sleep, lowered latency in REM (rapid eye movements) sleep, and a longer and more
      intense first period of REM. This technique is presently of limited use as a
      diagnostic tool in depression. The pathophysiological mechanisms governing sleep
      disorders in depression are not yet known, but sleep studies still play an
      important role in research into depression, especially in areas concerning the
      prediction of responses to treatment, the prognosis of relapses, longitudinal
      results, familial studies and in research into aetiological models

PMID- 12599138
TI  - [Neurophysiology in Creutzfeldt-Jakob disease].
AB  - INTRODUCTION: Neurophysiological studies conducted in subjects who it is
      suspected are suffering from Creutzfeldt-Jakob disease (CJD) are usually aimed at
      searching for what is called a typical EEG. However, the EEG is a dynamic test
      and therefore subject to variations in time. Furthermore, there are other kinds
      of neurophysiological tests that may also be of interest, and the lack of typical
      traces in the new variant of the disease forces us to explore other diagnostic
      approaches. METHOD: We performed a clinical EEG correlation in the course of the
      evolution of the disease, in which we observed a significant variability
      throughout the different stages. We then review the neurophysiological studies
      that have been conducted on CJD, in which shortcomings and important
      discrepancies can be seen. CONCLUSION: EEG has proved to be a fundamental element
      in CJD probability diagnosis. It is also found that sleep and waking records,
      obtaining series of EEGs, the detection of poligraphic changes related with
      variations in the degree of consciousness and, lastly, studies conducted by means
      of other neurophysiological techniques associated with clinical data will all
      undoubtedly enable us to achieve higher efficiency in diagnosis

PMID- 12599139
TI  - [Childhood insomnia].
AB  - AIMS: This work reviews the causes of insomnia in children and attempts to show
      the difficulties involved in performing a diagnosis to differentiate it from
      other sleep disorders. METHOD: Insomnia is a disorder in which the sufferer has
      difficulty in falling or staying asleep. There are multifactorial causes involved
      in the aetiology of childhood insomnia. In order to understand and diagnose
      insomnia in childhood it is necessary to have a good knowledge of the mechanisms
      involved in the genesis of sleeping and waking. We must also take the possible
      existence of other types of disorders into consideration. Insomnia appears as an
      imbalance between the systems that maintain the waking state and those that are
      in charge of activating sleep generating systems. In children, this imbalance
      depends on the state of functional immaturity peculiar to each age. Rather than a
      shortage of sleep, childhood insomnia takes the form of a lack of matching
      between the child s own rhythm or need to sleep and his or her family or social
      environment. Insomnia is most frequently caused by environmental, behavioural and
      psychological factors. A correct diagnosis of childhood insomnia has to be based
      on determining a procedure to differentiate it from parasomnias or motor
      disorders affecting waking and sleep. CONCLUSIONS: Identifying the causes of
      childhood insomnia, differentiating it from real insomnia and other sleep
      disorders, and resolving it are no simple matter because of the influence exerted
      by the environment and the child s behaviour on how he or she sleeps.

PMID- 12599140
TI  - [Workshop on electroretinography and visual evoked potentials].
AB  - Studies of vision using electrophysiological techniques are tests which record
      functional alterations in very early phases of a disease. Full field flash ERG
      evaluates the integrity of the cones, rods and bipolar cells. It is obtained by
      photopsic stimulation with Ganzfeld and contact lens corneal electrodes or,
      alternatively, gold leaf or anchor electrodes. Five responses must be obtained:
      that of the rods, a maximum, oscillatory potentials, that of the cones and a
      flicker response. Pattern ERG is a response of the ganglionic cells, which is
      obtained by pattern reversal morphoscopic stimulation, with a bandwidth between 1
      and 60 Hz. The fundamental waves (0.5 5 mV) are P50 (luminance) and N95 (pattern
      specific). This is of great value in the early diagnosis of glaucoma. VEP are
      electrical fields that are recorded in the calcarine cortex. They give
      information about alterations in the optic nerve, chiasm, radiations and cortex.
      Pattern VEP is obtained with a visual angle of between 13 and 14 . The
      fundamental wave P100 is evaluated according to its latency and amplitude, and by
      comparing it with a healthy eye. Flash VEP is only used on patients who do not
      collaborate or who present an opacity of media.

PMID- 12599141
TI  - [The contributions of a neurophysiological study in the diagnosis of patient with
      orthostatic tremor].

PMID- 12599142
TI  - [The missing corpus callosum. An exceptional congenital anomaly].

PMID- 12599143
TI  - [Thrombosis of the cerebral venous sinuses following ligature of the internal
      jugular vein].

PMID- 12599144
TI  - [The portrait of the Mona Lisa. A neurological view].

PMID- 12599145
TI  - [Quantum physics and consciousness].

PMID- 12599146
TI  - [Diagnostic and therapeutic management of pseudo-occlusions of the carotid
      artery].
AB  - AIMS: The aim of this study was to evaluate the diagnostic attitude and the
      results obtained after surgery in cases of pseudo occlusions of the carotid
      artery. PATIENTS AND METHODS: Between 1995 and 2000, 13 cases of pseudo occlusion
      of the internal carotid artery were performed (3.06% of carotid surgery carried
      out). Diagnostic criteria were as follows. Echo Doppler: complete occlusion with
      its origin in the internal carotid artery, damped distal signal; arteriography:
      occlusion with its origin in the internal carotid artery, filiform distal part,
      string sign. Clinical presentation was: 53.84% cerebral infarction, 23.07% TIA
      and 23.07% were asymptomatic. The 13 patients were submitted to echo Doppler and
      nine were examined using arteriography. Two patients were operated on without
      arteriography because of unstable neurological clinical features. A surgical
      exploration was performed in 100% of the cases. RESULTS: In seven cases,
      revascularisation of the internal carotid artery was carried out (53.84%) and in
      six cases it was ligated (46.16%). Echographic monitoring (from 1 4 years,
      average 2 years) showed permeability in the seven revascularised cases; in one
      case restenosis was detected between 31 50% at 2 years follow up. In the clinical
      controls (from 2 months to 4 years, average 30 months), one patient who was not
      revascularised was seen to have symptoms of TIA at one year and two months.
      DISCUSSION: Since neither arteriography nor echo Doppler can predict when it will
      be possible to revascularise the internal carotid artery, and because we did not
      observe an increase in surgical morbidity mortality, we believe surgical
      exploration is useful. In our study 53.84% of the series were successfully
      revascularised.

PMID- 12599147
TI  - [Neurocysticercosis in a paediatric population in Lima: an epidemiological and
      clinical analysis].
AB  - INTRODUCTION: Neurocysticercosis (NCC) in children is a clinical entity that was
      believed to be infrequent but, as methods of diagnosis by means of imaging
      techniques and immunological tests have improved, it has become possible to
      confirm more cases. This disease has been reported as being most prevalent in
      developing countries but over the past few years there has also been an increase
      in the incidence in developed countries. PATIENTS AND METHODS: We examined the
      clinical records of paediatric patients admitted to the Hospital Cayetano
      Heredia, in Lima, Peru, between 1993 and 1998. The statistical analysis was
      performed with the SPSS software package. RESULTS: A sample made up of 52
      patients was obtained (n= 52), of which two were excluded because they were being
      treated at the same time with antituberculosis and anthelmintic drugs. Of these
      50 patients, 22 were males (44%) and 28 females (56%). Average age was 7.86 years
      old (interval: 7 months 15 years). Diagnosis was definite in 26% of them,
      probable in 50% and possible in the remaining 24%. 36% reported that they raised
      pigs at home and had travelled to endemic areas. The convulsive syndrome was the
      most frequent clinical presentation, followed by endocranial hypertension. The
      single lesions were often identified in imaging studies (64.3%). 36.8% of the
      patients were found to be seropositive. 90% of the patients were receiving
      treatment with anticonvulsive drugs and almost 70% with albendazole and
      corticoids. DISCUSSION: This study represents the first attempt to find out more
      about the epidemiological and clinical characteristics of the Peruvian infant
      population who are diagnosed as having NCC. The findings do not differ from those
      obtained in previous studies in other countries.

PMID- 12599148
TI  - [Clinical characteristics of optical neuritis in children].
AB  - OBJECTIVE: To describe the clinical characteristics and the visual prognosis of a
      group of children affected with optic neuritis. PATIENTS AND METHODS: The
      clinical charts of patients under 15 years of age with clinical criteria of optic
      neuritis were revised at the Hospital Universitario San Vicente de Pa l (Medell
      n, Colombia), in a time span from January 1th 1989 to December 31th 2001.
      RESULTS: 16 patients fulfilled the clinical criteria of optic neuritis; 50% were
      male and the overall mean age was 9,4 years. Seven (43,7%) patients had a
      preceding infectious disease two weeks earlier and only one suffered from
      varicella four weeks earlier. Decrease in visual acuity was present in 15 (94%)
      patients; 7 (44%) had headache; 7 (44%) had ocular ache and 25% had both, head
      and ocular ache. Neuritis was found in 28 eyes, of whom 68% had papilledema and
      in 32% the fundoscopic examination was normal. Bilateral affection was present in
      75%. Excellent visual prognosis (20/20) was present in 19 (68%) of affected eyes;
      good (20/20 to 20/50) in 4 (14%), regular (20/50 to 20/100) in 2 (7%) and bad
      (20/200) in 11%. CONCLUSION: In our country the clinical evolution of childhood
      optic neuritis does not differ from that reported in other parts of the world.

PMID- 12599150
TI  - [Familial intracranial aneurysms in Camaguey].
AB  - INTRODUCTION: Genetic etiology in suggested in intracranial aneurysms. Such
      hypothesis is supported on familial aggregation, ocurrence in identical twins or
      associated to genetic diseases like adult polycystic renal disease. OBJECTIVE: To
      identify biological features in familial aneurysms different to sporadic ones.
      PATIENTS AND METHODS: Camag ey province is one of the most ancient in Cuba.
      Motionless population at the beginning had its sources in Spanish and African
      people. It has 800,000 inhabitants. 497 patients with intracranial aneurysms were
      operated at Manuel Ascunce Domenech Hospital between January 1982 and August
      2001. We identified 15 families with intracranial aneurysms. RESULTS: 31 patients
      were operated on of 42 intracranial sacs at the carotid territory. There were 34%
      of multiplicity ant three mirror aneurysms. Three patients (9.7 %) have adult
      polycystic renal disease. 87 % of patients present aneurysms rupture and
      mortality was 32 %. This last figure was related to poor admission clinical
      grade. CONCLUSIONS: Frequency of familial aneurysms was 6.2% Familial
      aggregation, aneurysms between twins associated with genetic linked disease,
      early age rupture, high frequency between women, posterior communicating and
      middle cerebral artery bifurcation preference, mirror aneurysms and high general
      mortality associated to massive intracranial bleeding identified this clusters of
      familial aneurysms and would justify imaginological screening of high risk
      patients before the rupture.

PMID- 12599149
TI  - [Neuropsychological study of 8 to 15-year-old children with lateralised sub
      clinical paroxysmal discharges and poor academic achievement].
AB  - Paroxysmal discharges have been observed in non epileptic children who, at the
      same time, display learning disorders. In this study our aim is to determine
      whether the association between sub clinical discharges (SCD) and learning
      disorders reflects specific neuropsychological deficiencies and, more
      particularly, whether the possible deficits are defined according to the brain
      hemisphere in which the paroxysmal activity is located. Neuropsychological
      evaluation was performed in 17 children between the ages of 8 and 15, with
      unspecific learning disorders, who presented sub clinical paroxysmal discharges
      localised in the left hemisphere (nine cases) or in the right hemisphere (eight
      cases). The children with paroxysmal activity in the left hemisphere obtained
      similar results to those in which it was found on the right, except in the tests
      that evaluate visuo constructive skills, in which their scores were higher, and
      in the executive function tasks, in which they displayed a deficit that was not
      observed in the children with paroxysmal activity in the right hemisphere. We
      interpreted the presence of SCD discharges in the left hemisphere as reflecting a
      slower or more deficient process of brain maturation, which could be compensated
      with a suitable programme of neuropsychological intervention.

PMID- 12599151
TI  - [Topographic disorientation associated with infarction in the territory of the
      right posterior cerebral artery].
AB  - INTRODUCTION: Topographic disorientation is defined as the difficulty to find one
      s way in familiar surroundings. It can be due to an amnesic or agnostic like
      defect, which is known as topographic amnesia or agnosia. This disorder can give
      rise to disability in the life of the patient and may well go undetected unless a
      suitable neuropsychological study is conducted. CASE REPORTS: We report the cases
      of two patients with infarction in the territory of the right posterior cerebral
      artery who began with hemianopsia and topographic disorientation. One of the
      cases was due to a disorder affecting spatial memory and the other was caused by
      errors in visuospatial perception. The battery of tests for studying visuospatial
      perception VOSP was administered. CONCLUSIONS: Occipital lesions are often
      associated with topographic disorientation, especially when it is the right
      hemisphere that is injured. It is important to detect this alteration, which
      makes the patient totally dependent on others even in his or her own home. The
      appearance of an amnesic or agnostic type disorientation can be related with a
      disorder affecting one of the two systems that play a part in the processing of
      visual data. A guided neuropsychological study can provide us with a great deal
      of information about the type of disorder presented by the patient.

PMID- 12599152
TI  - [A rare neurologically originated speech disorder: foreign accent syndrome].
AB  - INTRODUCTION: Foreign accent syndrome (FAS) is an unusual neurological speech
      disorder documented in not more than twenty specific studies. As a consequence of
      a cerebral mainly subcortical injury, the patient s speech is foreign sounding to
      native listeners. As subject cannot avoid this foreign accent, and given its
      abrupt emergence, this disorder usually involves emotional consequences by loss
      of identity and of belonging to a speech community. CASE REPORT: In this paper, a
      case from Castellon de la Plana (Spain) is presented with a injury in right basal
      ganglia and the literature about this topic is revised. CONCLUSIONS: From the
      available data, we describe the main characteristics of the syndrome and discuss
      the possible role of basal ganglia

PMID- 12599153
TI  - [Miller Fisher syndrome in the course of an acute pneumonia by Mycoplasma
      pneumoniae].
AB  - CASE REPORT: We report a patient with Miller Fisher syndrome in the course of an
      acute pneumonia by Mycoplasma pneumoniae. CONCLUSION: Miller Fisher syndrome as a
      neurologic complication of mycoplasmal respiratory disease occurring at infection
      onset is very rare and has not been described previously.

PMID- 12599154
TI  - [Sarcoidosis and idiopathic intracranial hypertension. A case report].
AB  - INTRODUCTION: Sarcoidosis is a multisystemic disease of unknown etiology,
      characterized by non caseating granulomas in different organs. The respiratory
      system is the most frequently involved organ system. Up to 90% of patients with
      sarcoidosis have pulmonary involvement. The neurological involvement is rare and
      only occurs in the 5 7% of the patients. CASE REPORT: We present the case of a 41
      years old woman who had severe headache and a sixth nerve palsy. Diagnosis of
      sarcoidosis was made in association with idiopathic intracranial hypertension
      (IIH). CONCLUSIONS: Sarcoidosis can involve any portion of the nervous system. An
      etiologic association between sarcoidosis and IIH could be identified in this
      case. Treatment with corticosteroids, repeated lumbar punctures and diuretics
      were prescribed and induced a significant clinical improvement.

PMID- 12599155
TI  - [Arterial chemoreceptors: cellular and molecular mechanisms in the adaptative and
      homeostatic function of the carotid body].
AB  - The carotid body is a sensory chemoreceptor organ located in the vicinity of the
      carotid bifurcation. Structurally it is composed of cell clusters formed by
      chemoreceptor and supporting cells. The sensory nerve endings of the carotid
      sinus nerve penetrate the clusters to synapse with chemoreceptor cells. The
      carotid body plays an important role in the control of ventilation during
      hypoxia, hypercapnia and acidosis. Hypoxia and other natural stimuli are detected
      by chemoreceptor cells which upon stimulation increase their rate of release of
      neurotransmitters. Neurotransmitters in turn increase the action potential
      frequency in the carotid sinus nerve which via its central projections to the
      brainstem activates ventilation. This review is devoted to the cellular aspects
      of the function of this chemoreceptor organ. From a brief description of the
      complex structure of the carotid body, we go to present a summary of the main
      prevailing theories concerning the transduction mechanisms for hypoxic and
      acidic/hypercapnic stimuli, with special emphasis on the electrical properties of
      cultured chemoreceptors cells. A special attention is provided to the possible
      significance of reactive oxygen species as mediators of the hypoxic transduction
      cascade. The neurotransmission between chemoreceptor cells and the sensory nerve
      endings is also covered in certain detail. After a brief historical presentation
      of the theories of communication between these two structures, we examine,
      following the classical criteria of neurotransmission, the functional
      significance of acetylcholine, dopamine, substance P and other neurotransmitters
      known to be present in chemoreceptor cells.

PMID- 12599156
TI  - [Acquired immunodeficiency syndrome by vertical transmission: neurological
      disorders].
AB  - INTRODUCTION: Forty million people are currently infected by HIV; of these, 50%
      are women and children. Vertical transmission occurs in 90% of the cases reported
      in the literature and was also observed by the authors of the present study at
      Hospital de Clinicas de Porto Alegre, Brazil, in the follow up of 340 HIV
      positive children since 1985. Transmission can occur during pregnancy
      (intrauterine) or during labor and delivery (intrapartum). In addition, HIV has
      been identified in the breast milk of infected mothers, which represents a
      contraindication for breastfeeding in these cases. Laboratory diagnosis is
      carried out using the following tests: ELISA, Western blot, and indirect
      immunofluorescence. DEVELOPMENT: Neurological manifestations in children may be
      divided into primary neurological diseases and secondary complications. Primary
      neurological diseases include both static encephalopathy, of slow evolution, and
      progressive encephalopathy, which affects neuropsychomotor development. The
      follow up of 340 children with AIDS showed encephalopathy in 32.5% of cases and
      delayed neuropsychomotor development in 42.5%. Opportunistic infections occurred
      in 33.8% of cases (one infant presented meningoencephalitis caused by Trypanosoma
      cruzi). One child presented lymphomas, 2.6% had cerebrovascular accidents, and 5%
      had peripheral neuropathies. Currently, 54 children of those followed since birth
      have over 10 years of age, and of these, 31 (57%) present neurological symptoms
      40% with encephalopathy and 30% with neurological complications; the remaining
      children present educational, behavioral, and developmental difficulties.
      CONCLUSIONS: Several factors have influenced the natural history of AIDS in
      childhood, such as early diagnosis, drug regimen used, social, economic, and
      nutritional conditions, as well as health practices aimed at this population.

PMID- 12599157
TI  - [Acute loss of vision in children].
AB  - The differential diagnosis of acute loss of vision in children includes acute
      loss of vision due to retinal or optic nerve disease, and cortical blindness. The
      retinal disorders which may be mis diagnosed as optic neuritis include Leber
      neuroretinitis, Leber hereditary optic neuropathy, and Stargardt macular
      dystrophy. Retinal changes which evolve in neuroretinitis, and the
      pseudopapilledema in Leber heredity optic neuropathy are helpful in
      differentiating these disorders from optic neuritis. Stargardt macular dystrophy,
      a disorder associated with a variety of mutations, may be mis diagnosed as
      psychogenic visual loss due to the early normal appearance of the retina, and the
      loss of vision over a period of weeks. The differentiation of optic neuritis from
      anterior ischemic optic neuropathy (AION), depends upon the initial appearance of
      the optic disc (in AION either hyperemia due to reperfusion, or swelling and
      pallor if total infarction has occurred). The authors have described children
      with abrupt loss of vision during renal dialysis, whose risk factors for AION
      included systemic hypotension and intra ocular hypertension. Children with
      vigorous treatment of accelerated hypertension, and children with migraine and
      pro thrombotic disorders have also incurred AION. Thus, AION should be suspected
      when acute loss of vision occurs in association with certain ocular and systemic
      risk factors. In children capable of cooperating for visual field examination,
      the typical change in AION is an altitudinal defect, while optic neuritis it is a
      central scotoma. The association of optic neuritis with multiple sclerosis, DeVic
      disease, and with acute demyelinating1 encephalomyelitis require special
      consideration in regard to treatment and prognosis. Acute loss of vision due to
      cerebral cortical insults involves a large differential diagnosis which includes
      vascular, metabolic and infective disease; as well as disorders causing
      transitory blindness such as seizures and migraine

PMID- 12599158
TI  - [Intraventricular haemorrhage in premature newborn babies].
AB  - This work is the product of the checking of the pathogenesis, incidence,
      treatment, and prognostic of the intraventricular hemorrhage in the premature
      newborn. In the revised publications, that include important series of following,
      this pathology is present in 25% of the infants weighing less than 1,500 g, in
      which the mortality and morbidity is greater than that of normal newborns, since
      the development of intraventricular hemorrhage can produce alterations of
      cerebral blood flow in the immature germinal matrix and in the microvascular net.
      In consequence the prevention of the intraventricular hemorrhage is directly
      related with its pathogenesis. It is said that the use of dexamethasone steroids
      in low doses in the prenatal period, and low doses of indomethacin in the
      postnatal period, can give better neuroprotection. The surgical treatment is
      exceptional and has very precise indications, when a progresive hydrocephalus of
      later apparition is proven. Therefore in premature newborns with intraventricular
      hemorrhage the best actual treatment is to use an appropiate pharmacological and
      medical following

PMID- 12599159
TI  - [Indications for neuroendoscopy].
AB  - INTRODUCTION: In order to reduce intracerebral trauma in the diagnosis and
      treatment of intracranial lesions in children, neuroendoscopy is an important
      tool in current neurosurgery. Using this minimally invasive technique
      intraventricular objectives may be approached with little damage caused to
      adjacent structures. OBJECTIVES: There are two aspects to current indications for
      neuroendoscopy. Firstly, diagnosis is achieved by taking intraventricular
      biopsies of cystic lesions and tumours and for anatominical vigilance in
      microsurgical operations. Secondly, there is the therapeutic aspect, especially
      in operations to restore the circulation of cerebrospinal fluid (CSF), correct
      complex hydrocephaly, insert or remove intraventricular shunts, aspiration of
      cysts or haematomas, fenestration of cysts, resection of tumours within or near
      the ventricles. DEVELOPMENT: At the present time in neurosurgical paediatric
      management, neuroendoscopy is a tool used daily in common lesions such as
      hydrocephaly and the identification of intraventricular lesions. It may be safely
      used as a primary method of approach to the lesions or as a complement to open or
      guided surgery to the patient s advantage. We therefore reviewed the literature
      in the light of our own experience in neuroendoscopy since 1996. CONCLUSIONS: The
      formal indications for neuroendoscopy are greater in paediatric neurosurgery. In
      fact, the management of the CSF circulation, and disorders associated with this,
      together with the identification of tumours using minimally invasive methods,
      make this technique directly useful for solving these problems. This is most
      obvious in lesions such as multiseptate complex hydrocephaly, and
      intraventricular tumours and cysts where it is the first surgical option. In the
      short term, thanks to improvements in neuro navigation and frameless stereotaxis,
      its use will be wider and more precise

PMID- 12599160
TI  - [The effect of interictal epileptiform discharges on cognitive function in
      children with idiopathic epilepsy].
AB  - INTRODUCTION: Transient cognitive disorders (CD) in benign rolandic epilepsy
      (BRE), the most common of idiopathic partial epilepsy (IPE), may be secondary to
      interictal epileptiform discharges (IED). OBJECTIVES: To determine incidence and
      risk factors for persistent TC in students with IE before, during and after
      antiepileptic (AE). PATIENTS AND METHODS:  INCLUSION CRITERIA: 6 12 years old,
      IPE, controlled for 2 years with AE, and follow up for 5 years. EVALUATIONS:
      intelligence (Wechsler III), learning (Wechsler), academic level (Woodcock
      Johnson) and attention/behavior (O Conners R). VARIABLES: sex, age of onset,
      seizure type, interval between first seizure and AE onset, EEG results and AE
      type. ANALYSIS: chi square. RESULTS: Fourteen children had decreased learning and
      attention span with impulsivity, hyperactivity, low tolerance and agressivity
      during remission; 12 (85,71%) with temporal lobe epilepsy: 6 (50%) with IED in
      the left dominant hemisphere, 2 (16,67%) with IED in the right temporal lobe in
      left dominant hemisphere children, 2 (16,67%) in both temporal lobes in left
      dominant hemisphere children and 2 (14,29%) with ERB and IED. MRI were normal.
      CONCLUSIONS: Children with idiopathic temporal lobe epilepsy and IED in the left
      dominant hemisphere are at higher risk for CD than children with other types of
      IPE. To control the seizures and to abolish the IED are recommended in an attempt
      to prevent these cognitive disorders

PMID- 12599161
TI  - [The effect of refractory epileptic seizures on cognitive processes].
AB  - A complete definition of all risk factors for intractability and/or mental
      retardation cannot currently be given because epilepsy is not a disease but a
      heterogeneous phenomenon from the physiological, clinical and etiological points
      of view so that no single way of addressing the issue can fit all situations. It
      is quite possible that some risk factors can be specific for subgroups and do not
      apply to the majority of cases. Such subgroups may be small enough to escape
      detection in large prospective studies that uniformly indict a limited number of
      factors mostly related to characteristics of the disease or patients. Yet, even
      factors that are at play only in small groups may be extremely important if they
      can be at the origin of effective preventive measures. This may well be the case
      for vigorous early treatment of complex febrile seizures as there is increasing
      evidence of a close, probably causal, relationship between lengthy early
      convulsions and mesial temporal sclerosis. It may also apply to the prevention of
      cognitive/behavioural deterioration in children with certain types of epilepsy
      even though the evidence in this regard is less strong. Exonerating seizures
      and/or subclinical paroxysmal activity of any responsibility in the production
      and/or aggravation of brain damage is not justified on the basis of known facts
      and vigorous although reasonable treatment of the epilepsies may do more, at
      least in certain forms, than simply decreasing the relapse rate of seizures

PMID- 12599162
TI  - [Cognitive effects of antiepileptic drugs].
AB  - DEVELOPMENT: Traditionally it has been shown that anti epileptic drugs have side
      effects which cause alterations particularly in behaviour and cognition,
      independently from that due to the epilepsy itself. This has caused great
      controversy. Some studies have informed that many of these drug effects are
      caused by the epilepsy rather than the drugs themselves. It is possible that the
      drugs may cause changes in behaviour and cognition, but these also improve when
      the seizures are brought under control. The main problem therefore is to
      determine the methodology which would take these variables into account, since
      many studies do not follow a standard methodology: the various drugs and
      neuropsychological aspects are compared using a large variety of tests.
      CONCLUSIONS: At the present time, using suitable methodology, and double blind
      randomized controlled trials, it has been found that the secondary effects on
      cognition and behaviour are not as severe as had been thought. The drug causing
      most alterations is phenobarbitone and some benzodiazepines, such as clonazepam,
      alter cognitive function to a greater degree. With the newer anti epileptic drugs
      improvement in cognition has been observed due to its mechanism of action and to
      control of the epilepsy.

PMID- 12599164
TI  - [Transcranial Doppler study in patients with parkinsonism].

PMID- 12599165
TI  - [Pseudo-Babinski's sign and pseudo-responses].

PMID- 12599168
TI  - The pharmaceuticals and materials used in common spine interventions.
AB  - Image-guided spine interventions are rapidly increasing in number in the realm of
      the interventional radiologist. Appropriate selection and understanding of the
      pharmaceuticals used in these procedures is necessary to minimize complications
      and maximize successful outcomes.

PMID- 12599169
TI  - Image-guided epidural steroid injections.
AB  - Epidural steroid injection has been proven to be useful in the treatment of acute
      lumbosacral radicular pain syndromes. The use of image guidance significantly
      increases accuracy and decreases complication rates. The technique of performing
      these injections, including translaminar approach, is described in this article.
      Necessary precautions and potential risks are also described.

PMID- 12599170
TI  - Selective nerve root blocks.
AB  - Selective nerve root blocks are an effective way of diagnosing and treating
      radicular pain in many patients. Although traditionally performed under
      fluoroscopic guidance, computed tomography (CT) and CT fluoroscopy have been
      increasingly used to direct needle placement. This article discusses the
      indications and technique of selective nerve root blocks in the cervical,
      thoracic, and lumbar spine, as well as the evidence supporting their use in the
      treatment of patients with radiculopathy and/or back pain.

PMID- 12599171
TI  - Facet blocks and sacroiliac joint injections.
AB  - Facet and sacroiliac joint pathology are not an uncommon cause of back or neck
      pain. Imaging-guided techniques provide ready access to these synovial joints.
      Percutaneous injection of the facet or sacroiliac joints yields important
      diagnostic information as to whether or not the interrogated joint is involved in
      the patient's pain syndrome. The injection of a steroid-anesthetic mixture into
      these joints is capable of providing significant, albeit temporary, pain relief.

PMID- 12599172
TI  - Discography.
AB  - Discography is an image-guided spine procedure that provides diagnostic
      information about the intervertebral disc. This procedure attempts to reproduce a
      patient's back or neck pain profile. Discography is used to confirm or refute the
      presence of a discogenic pain source. Additional morphologic information with
      post-discography computed tomography and manometric measurements of intradiscal
      pressure are further enhancements to this procedure.

PMID- 12599173
TI  - Intradiscal electrothermal therapy in the treatment of discogenic low back pain.

PMID- 12599174
TI  - Percutaneous vertebroplasty: A to Z.
AB  - Percutaneous vertebroplasty has been performed in the United States since 1995,
      and widespread application of the procedure for osteoporotic and neoplastic
      compression fractures or vertebral infiltration has demonstrated remarkable
      efficacy with rare complications. Appropriate patient selection criteria and a
      thorough understanding of safe technique is essential for clinical success;
      imaging studies must be combined with careful physical examination to direct
      treatment to the appropriate level in patients with multiple compression
      deformities. Preoperative consultation with the patient and their family provides
      an opportunity to clarify the patient's treatment expectations and helps to
      anticipate and obviate potential obstacles to treatment.

PMID- 12599175
TI  - Kyphoplasty.
AB  - Kyphoplasty is a relatively new procedure that is indicated for the treatment of
      osteoporotic or pathologic compression fractures of the thoracic and/or lumbar
      spine. This minimally invasive procedure requires imaging guidance. Kyphoplasty
      entails the inflation of a balloon tamp, prior to the injection of opacified
      acrylic bone cement, within the compressed vertebral body in an attempt to
      restore vertebral body height and reduce the associated kyphotic deformity.
      Preliminary studies show that kyphoplasty, like vertebroplasty, provides
      significant pain relief in properly selected patients. Definitive demonstration
      of height restoration and kyphosis correction are still under investigation.

PMID- 12599176
TI  - B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of
      familial B-cell chronic lymphocytic leukemia.
AB  - BACKGROUND: Among all hematologic malignancies, B-cell chronic lymphocytic
      leukemia (BCLL) has the highest familial clustering (three- to sevenfold
      increase), strongly suggesting a genetic component to its etiology. Familial BCLL
      can be used as a model to study the early pathogenesis of this disease. METHODS:
      We examined nine kindreds from the National Cancer Institute's Familial BCLL
      Registry, consisting of 19 affected members with BCLL and 33 clinically
      unaffected first-degree relatives. Flow cytometric immunophenotyping to detect a
      B-cell monoclonal lymphocytosis (BCML) was performed. Monoclonality was confirmed
      by polymerase chain reaction analysis of whole blood DNA. Cell cycle analysis for
      aneuploidy was conducted. RESULTS: In all affected individuals, we observed the
      classic BCLL CD5/CD19/CD20/CD23 immunophenotypic patterns. Six of the 33
      unaffected individuals (18%) had evidence of BCML. Additional individuals (13/33,
      39%) showed some other abnormality, whereas 14 individuals (42%) were normal.
      Based on an estimated prevalence of 0.7% for BCML in the general population, the
      finding of six subjects (18%) with clonal abnormalities in this relatively modest
      sample was significantly greater than expected (i.e., 18% vs. 0.7%, P < 5.7 x 10(
      9)). CONCLUSIONS: Individual components of BCML and other B-cell abnormalities
      were observed in almost half of the apparently unaffected individuals. Our
      findings suggested that BCML may be an early detectable abnormality in BCLL. The
      spectrum of some of these observed abnormalities suggested the involvement of
      different B-cell subpopulations or different pathways in clonal evolution.
      Population-based, longitudinal studies will be required to determine the
      incidence of BCML and other B-cell abnormalities and their relation to disease
      progression in BCLL and other closely related B-cell lymphoproliferative
      disorders.

PMID- 12599177
TI  - Flow cytometry versus histamine release analysis of in vitro basophil
      degranulation in allergy to Hymenoptera venom.
AB  - BACKGROUND: Flow cytometry (FCM) has been proposed for specific allergy in vitro
      testing. We investigated its biological significance for allergy to Hymenoptera
      venoms and compared it with the routinely performed basophil histamine release
      test (HRT). METHODS: Blood samples from 26 allergic and 8 nonallergic donors were
      incubated with venom at serial concentrations. Basophils were analyzed with anti
      CD45-PE-Cyanin 5, Anti-IgE-FITC, and Anti-CD63-Phycoerythrine. HRT was measured
      by radioimmunoassay. RESULTS: FCM was as convenient as HRT for measuring basophil
      reactivity in at least 87% of allergic and 75% of nonallergic subjects. CD63
      outer expression was specifically induced in 91% of releaser subjects (86% on
      HRT) and in 1 of 10 tests in nonallergic donors, or one of six tests (16% on HRT)
      in allergic patients tested with an irrelevant allergen. Both methods were
      concordant in 85.7% of the tests. The three discordant patients had low-grade
      reactions and borderline biological responses on FCM (n = 2) or HRT (n = 1).
      CONCLUSIONS: The dynamic, physiologic significance of CD63, the dose-response
      curve, and dependency on ethylene-diaminetetra acetic acid suggested that both
      tests reflect the same mechanism.

PMID- 12599178
TI  - Vortex disaggregation for flow cytometry allows direct histologic correlation: a
      novel approach for small biopsies and inaspirable bone marrows.
AB  - BACKGROUND: Many approaches to obtaining single cells from tissue for flow
      cytometric immunophenotyping are used; however, these methods result in tissue
      that is too disrupted for subsequent histologic examination. We introduce a new
      technique for cell dissociation of hematopoietic malignancies that preserves
      tissue for histology. This is especially important with small specimens for which
      this type of correlation is critical. METHODS: Fresh tissue from lymph node,
      gastrointestinal (GI) tract, skin, and other soft tissue biopsies, in addition to
      cores of inaspirable bone marrows, were briefly vortexed until the RPMI cell
      culture medium became cloudy. Larger specimens such as lymph nodes were sectioned
      before disaggregating, whereas smaller ones were vortexed in toto. Resultant flow
      cytometric analyses were compared with the histology and, in some cases, the
      immunohistochemistry (IHC) to determine whether the data were concordant. Cell
      suspensions of 104 specimens-composed of 48 lymph nodes, 19 bone marrow cores
      (BMCs), 11 GI biopsies, 11 skin/soft tissue biopsies, and 15 miscellaneous
      specimens-were prepared via vortex disaggregation. RESULTS: Flow cytometric
      analysis of 96 specimens (92.3%) showed adequacy of material and diagnostic
      correlation with the histology and IHC. Of the eight cases (7.7%) that were
      discordant, seven were attributable to significant specimen fibrosis or necrosis.
      With respect to tissue type, this method produced diagnostic cell suspensions for
      most lymph nodes (95.8%), GI biopsies (90.9%), and BMCs (89.5%); however, it was
      less useful for skin/soft tissue samples (81.8%). CONCLUSIONS: Disaggregation of
      tissue for flow cytometric analysis by vortexing appears to provide adequate and
      representative cellular material. This technique is ideal for inaspirable bone
      marrows and small biopsies where tissue preservation for histology is paramount.

PMID- 12599179
TI  - Normal values of CD4 and CD8 lymphocyte subsets in healthy indian adults and the
      effects of sex, age, ethnicity, and smoking.
AB  - BACKGROUND: Information on lymphocyte populations (T, B, and natural killer
      cells) and subpopulations (CD4 and CD8) in India is generally lacking.
      Measurement of T-cell subsets is important in India for evaluating disease stage
      and progression in individuals with the human immunodeficiency virus (HIV).
      Hence, this study was conducted to provide normal ranges of absolute and
      percentage values of CD4 and CD8 T-lymphocyte subsets and the ratio of CD4 to CD8
      in normal Indian adults. METHODS: Flow cytometric analysis (EPICS-XL) was used to
      determine the range of T-lymphocyte subpopulations in normal Indian blood donors
      at Command Hospital and the Armed Forces Medical College, Pune, India. The
      reference population consisted of 94 healthy HIV-seronegative blood donors. T
      lymphocyte subsets were analyzed with two-color immunophenotyping of peripheral
      blood lymphocytes with the use of a lysed whole-blood technique and enumerated.
      RESULTS: For normal values of various blood components, we found mean values of
      2114 cells/microl for total lymphocytes, 865 cells/microl (40.2%) for CD4(+)
      lymphocytes, 552 cells/microl (31.3%) for CD8(+) lymphocytes, and 1.7 for the
      CD4:CD8 ratio. The 95% confidence intervals for the same parameters were 1115
      4009 cells/microl, 430-1740 cells/microl (30.75-49.60%), 218-1396 cells/microl
      (20.06-42.52%), and 0.39-3.02 respectively. Females had significantly higher CD4
      counts (P < 0.05), percentage of CD4 lymphocytes (P < 0.01), and CD4:CD8 ratio (P
      < 0.01). Males had a significantly higher percentage of CD8 lymphocytes (P <
      0.01). They also had higher CD8 counts that did not reach significance. Age,
      ethnicity (Dravidian versus Aryan), smoking, alcohol consumption, and the
      interval between drawing the blood sample and its analysis were factors that did
      not produce statistically significant differences in the T-cell subsets studied.
      CONCLUSIONS: When compared with other published series, the CD4 and CD8 values in
      healthy Indians were no different from those reported in the West. These
      observations have important clinical implications for the use of T-lymphocyte
      subset measurements in India, especially in the management of HIV infection. The
      normal ranges established by this study can be used as a reference for decisions
      made in clinical practice.

PMID- 12599180
TI  - Stability of currently used cytometers facilitates the identification of
      pipetting errors and their volumetric operation: "time" can tell all.

PMID- 12599181
TI  - Importance of CD117 in the evaluation of acute leukemias by flow cytometry.
AB  - BACKGROUND: The issue of which specific antibodies need to be used when
      evaluating acute leukemias by flow cytometry is controversial. METHODS: Recent
      studies have suggested that antibodies against CD117 or c-kit are not essential
      for the assignment of blast lineage by flow cytometry, even though CD117 appears
      to be a very specific marker for myeloid lineage acute leukemias. We report a
      case of acute myeloid leukemia M2 subtype with an 8:21 translocation, where the
      leukemic blasts expressed CD117, CD19, and CD15 but did not show definitive
      expression of the myeloid markers CD13 or CD33. RESULTS AND CONCLUSIONS: This
      study highlights the importance of CD117 when evaluating acute leukemias by flow
      cytometry, which was necessary in this case to suggest that the blasts were
      phenotypically abnormal myeloblasts. In addition, this case presented an unusual
      acute myeloid leukemia phenotype that will likely be encountered by others and
      could be difficult to interpret.

PMID- 12599182
TI  - Prenatal diagnosis of isolated femoral bent bone skeletal dysplasia: problems in
      differential diagnosis and genetic counseling.
AB  - Severe localized and symmetric bowing of the femora, in the absence of other
      significant skeletal or nonskeletal abnormalities, is a rare prenatal ultrasound
      finding. A 38-year-old woman was referred at 19 weeks gestation and ultrasound of
      the fetus showed severe shortening, and marked symmetric bowing of the femora. A
      provisional diagnosis of kyphomelic dysplasia (KD) was made. The patient elected
      termination of pregnancy and post mortem assessments were most consistent with
      kyphomelic dysplasia. KD is bent-bone skeletal dysplasia that, in contrast to
      campomelic dysplasia, involves principally the femora with relative sparing of
      the remainder of the skeleton. KD can be difficult to distinguish, particularly
      from symmetric cases of femoral hypoplasia unusual facies syndrome (FH-UFS), and
      few prenatal diagnoses have been reported. Because KD is thought to an be
      autosomal recessive disorder, the possibility that definitive diagnosis may not
      be possible prenatally, and even by postmortem assessment in cases choosing to
      abort, is an important counseling consideration.

PMID- 12599183
TI  - De novo double translocation 3;13 and 4;8;18 in a patient with mental retardation
      and skeletal abnormalities.
AB  - A de novo, apparently balanced complex chromosome rearrangement (CCR) involving
      five chromosomes and six chromosome breakpoints was found in a child with
      Marfanoid habitus, kyphoscoliosis, axillary pterygium, camptodactyly, joint
      laxity, and mild mental retardation. Fluorescence in situ hybridization (FISH)
      revealed a simple translocation involving chromosomes 3 and 13, and a complex
      rearrangement involving chromosomes 4, 8, and 18 with four breakpoints.

PMID- 12599184
TI  - A series of supernumerary small ring marker autosomes identified by FISH with
      chromosome probe arrays and literature review excluding chromosome 15.
AB  - Seven supernumerary small ring marker autosomes were studied. The pantelomere
      probe (Oncor) in conjunction with scoring for dicentric rings was used to confirm
      ring morphology. The small rings were identified mainly by FISH with chromosome
      probe arrays (Cytocell) containing representations from all 24 chromosomes and
      the rings were derived from chromosomes 7, 8 (three cases), 11, 12, and 14. The
      effectiveness of the array methodology in identifying markers was tested.
      Microsatellite DNA data showed biparental disomy (BPD) was present for the rings
      from chromosomes 7 and 14 thereby excluding UPD, both were de novo but the ring
      14 was of paternal origin. The literature on supernumerary small ring autosomes
      was reviewed excluding chromosome 15. The grade and distribution of mosaicism was
      invoked as the major determinant of the differences in phenotype and, in
      addition, variation was attributed to the possibility of different contributions
      from each chromosome arm. There are 88 published supernumerary small ring cases
      in total, with phenotypic data attributable to the respective rings in 77 cases
      and all chromosomes being represented except chromosome 17. Of the prenatally
      ascertained cases, where there was adequate phenotypic data, 30% had an abnormal
      phenotype attributable to the ring, and there were 44% familial cases in this
      group. Of the postnatally ascertained small rings, 75% had an abnormal phenotype
      attributable to the ring and there were 13% familial cases. This higher
      abnormality rate is concordant with the considerable ascertainment bias of this
      latter group and the prenatal data are recommended for genetic counseling.
      Although data are small there were some differences between the rings derived
      from different chromosomes. Chromosomes 3 and 8 demonstrate the extremes. Of the
      supernumerary small r(8) cases reviewed including the three presently described,
      8/11 had an abnormal phenotype attributable to the marker but of the small r(3)
      cases, only 1/6 had an abnormal phenotype. Two of the present r(8) were studied
      with the GATA4 probe at 8p23.1. The r(8) in case 2 (patient moderately retarded)
      was comprised mostly of an intact 8p whereas the larger r(8) in case 3 (normal
      phenotype) was missing 8p23.1 --> pter and had more of 8q contributing to the
      ring. In other supernumerary rings postnatally ascertained, there is mostly
      insufficient data but there is an abnormal phenotype in 8/11 cases with multiple
      small rings, in 5/6 cases with r(20), and in 5/10 with r(1). A novel origin for
      supernumerary small rings is proposed: that they may originate from incompletely
      digested superfluous (haploid) pronuclei. The small rings presumptively so formed
      may occasionally be transfected into the zygote nucleus. The high proportion (
      approximately 12.5%) of cases with multiple supernumerary small rings almost
      always of different centromeric origin is consistent with this concept.

PMID- 12599185
TI  - Waardenburg syndrome: clinical differentiation between types I and II.
AB  - Here we present the results of a study performed on 59 patients affected by
      Waardenburg syndrome (WS), 30 with the I variant, 21 having the type II, and 8 of
      them being isolated cases without telecanthus. These patients belong to 37
      families; the main contributions and conclusions are based on the detailed study
      of 25 of these families, examined using standard procedures. All patients were
      examined as to the presence of eight cardinal signs important for the diagnosis
      of the condition; from each patient, from many of his/her normal relatives, and
      from a control sample of 300 normal individuals stratified by age and sex, 23
      different craniofacial measurements were obtained. We also estimated, using our
      own data as well those collected from the literature, the frequencies of the
      cardinal signs, based on a total sample of 461 affected individuals with WSI and
      121 with WSII. In order to originate discriminant functions to separate
      individuals affected by one of the two variants, both metric (from craniofacial
      measurements) as well as categoric data (based on the frequencies of the cardinal
      signs or symptoms) were used. Discriminant analysis based on the frequency of the
      eight cardinal signs can improve the separation of WSI patients without
      telecanthus from those presenting the variant II. We present also a Table with
      the conditional probabilities favoring the diagnosis of WSI for suspect subjects
      without telecanthus and any combination of the other seven signs/symptoms. The
      discriminant function based on the four ocular measurements (inner and outer
      intercanthal, interpupillary, and inferior lacrymal distances), on the other
      side, perfectly classifies patients affected by one of the variants of WS, the
      same taking place when the average values of the W index of all affected
      individuals per family are used. The discriminant function based solely in the
      individual W index values of patients correctly classifies 93% of WSII subjects,
      but only 60% of the patients with the I variant of WS.

PMID- 12599187
TI  - Syndromic form of X-linked mental retardation with marked hypotonia in early
      life, severe mental handicap, and difficult adult behavior maps to Xp22.
AB  - An X-linked recessive syndromic form of mental retardation is described in a
      family in which 10 males in four generations were affected. The main
      manifestations were severe to profound intellectual disability, muscular
      hypotonia in childhood, delayed walking, and difficult, aggressive behavior.
      There was a moderate reduction both in occipitofrontal circumference (OFC) and
      height and a similar facial appearance, triangular in shape with a high forehead,
      prominent ears, and a small pointed chin. Linkage analysis located the gene at
      Xp22 with maximum lod scores of 4.8 at theta = 0.0 for markers mapping between
      the closest recombination points at DXS7104 and DXS418. The physical length of
      this region is approximately 6 Mb. Mutations in the GRPR gene and M6b genes were
      excluded by sequence analysis. Nearby genes in which mutations are known to be
      associated with mental retardation (RPS6KA3, STK9, and VCXA, B and C), were
      excluded by position.

PMID- 12599186
TI  - Familial MCA/MR syndrome due to inherited submicroscopic translocation
      t(18;21)(q22.1q21.3) with breakpoint at the Down syndrome critical region.
AB  - We report three generation family that includes two patients with severe mental
      retardation and additional anomalies who have been studied, clinically,
      cytogenetically, and molecular cytogenetically. A clinical diagnosis could not be
      made in the propositus, but facial anomalies of Down syndrome (DS) were
      recognized in the maternal uncle of the propositus. In view of a strong family
      history of recurrent miscarriage, a familial translocation was highly suggestive.
      Standard cytogenetic analysis did not reveal any abnormalities. Fluorescence in
      situ hybridization (FISH) using subtelomeric DNA probes identified a familial
      cryptic translocation of chromosomes 18 and 21, resulting in partial trisomy 21
      and partial monosomy 18q in both patients. FISH analysis of obligate carriers
      demonstrated a balanced translocation between the terminal parts of 18q and 21q.
      Including this family, a total of six different familial cases with cryptic or
      subtle subtelomeric translocations of chromosome 21q has been reported, of which
      three involved terminal parts of chromosome 18q. The remarkable similarity of the
      chromosomal breakpoints of our patients and the described families prompted us to
      refine the breakpoints and to discuss phenotypic differences between these
      patients. Our results reinforce the role of cryptic subtelomeric rearrangements
      in patients with mental retardation associated with physical anomalies and stress
      the importance of FISH technology to supplement routine cytogenetics.

PMID- 12599188
TI  - FISH and cytogenetic characterization of a terminal chromosome 1q deletion:
      clinical case report and phenotypic implications.
AB  - We report a 24-year-old woman with minor facial anomalies, mental retardation,
      seizures, and partial agenesis of the corpus callosum. Cytogenetic analysis
      showed a de novo terminal chromosome 1 long arm deletion. FISH with a panel of
      chromosome 1q42-qter bands-specific BAC and YAC clones located the breakpoint at
      the 1q42-q43 junction, with monosomy restricted to the 1q43 and 1q44 bands. The
      changing craniofacial phenotype of this patient with age is described as part of
      the del(1)(q) syndrome natural history. The patient's features are compared with
      those of other patients with similar deletions, and variable phenotypic findings
      due to different deleted chromosomal segments are discussed.

PMID- 12599189
TI  - Novel perforin mutation in a patient with hemophagocytic lymphohistiocytosis and
      CD45 abnormal splicing.
AB  - Hemophagocytic lymphohistiocytosis (HLH) composes a group of rare heterogenous
      disorders characterized by uncontrolled accumulation and infiltration of
      activated T lymphocytes and macrophages. Cytotoxic T and natural killer cell
      activity is significantly reduced or absent in these patients. Mutations in the
      important mediator of lymphocyte cytotoxicity perforin were identified in a
      number of HLH individuals. Here we report a novel missense mutation thr435met in
      the conserved Ca(2+) binding domain of perforin in a patient with HLH. Prediction
      of the 3-dimensional structure of the thr435met perforin mutant using comparative
      molecular modeling indicates that the protein's ability to bind Ca(2+), and
      therefore its cytolytic function, would be strongly compromised. In addition,
      this patient exhibited abnormal CD45 splicing caused by a C77G mutation in the
      gene encoding CD45 (PTPRC). Our findings suggest a combined role for perforin
      mutation and abnormal CD45 splicing as significant contributory factors in the
      pathogenesis of HLH.

PMID- 12599190
TI  - Submicroscopic terminal deletion of 1p36.3 and Xp23 hidden in complex chromosome
      rearrangements: independent mechanism of telomere restitution on the two
      chromatids.
AB  - In this study, we report two cases each with a complex chromosome rearrangement
      concealing a submicroscopic terminal deletion. The first case had a mos
      46,XX,der(1)t(1;9)(p36.3;p13). ish der(1)(wcp9 +, 1ptel-, 9ptel +, pan tel
      +)[88]/46,XX. ish del(1)(1ptel -, 9ptel -, pan tel +)[12] karyotype. Scrutiny by
      FISH using wcp 9, 1ptel, 9ptel, and pan telomeric probes found a subtelomeric
      1ptel deletion on the der(1) in the abnormal cell line and on a chromosome 1 in
      the apparently normal cell line. The telomere (TTAGGG)n, however, was present on
      the terminal ends of both copies of chromosome 1 in the apparently normal and
      abnormal cell lines. The second case had a de novo mos
      46,X,der(X)t(X;22)(p22.3;q11.2),inv dup(22)(q11.2).ish der(X)(wcpX +,wcp22 +,KAL
      +, STS -,Xptel -,BCR +),inv dup(22)(wcp22 +,TUPLE ++,BCR 
      )[85]/45,X,der(X)t(X;22)(p22.3;q11.2),- 22[15].ish der(X)(wcpX +,wcp22 +, KAL
      +,STS -,Xptel -,BCR +) karyotype. FISH probes identified a terminal Xpter
      deletion, distal to the KAL gene. The two rearrangements are hypothesized to have
      been initiated by a terminal deletion. We propose a model for the formation of
      the rearrangement in Case 1, which invokes independent telomere stabilization of
      the sister chromatids. A terminal deletion 1pter in meiosis, was followed by
      acquiring or regenerating a telomere (TTAGGG)n cap on one chromatid and the other
      chromatid was involved in a translocation with a chromosome 9 chromatid.
      Following segregation of this chromosome the viable cell line survives to form
      the mosaic karyotype. Our findings suggest that subtelomeric deletions should be
      ruled out in cases with complex and simple rearrangements involving the terminal
      regions.

PMID- 12599191
TI  - Sudden infant death syndrome: association with a promoter polymorphism of the
      serotonin transporter gene.
AB  - Serotonergic receptor binding in the arcuate nucleus, n. raphe obscurus, and
      other medullary regions is decreased in sudden infant death syndrome (SIDS)
      cases. Further, a variable tandem repeat sequence polymorphism in the promoter
      region of the serotonin transporter protein (5-HTT) gene has recently been
      associated with risk of SIDS in a Japanese cohort. This polymorphism
      differentially regulates 5-HTT expression, with the long allele (L), the SIDS
      associated allele, being a more effective promoter than the short allele (S). We
      therefore investigated the 5-HTT promoter polymorphism in a cohort of 87 SIDS
      cases (43 African American and 44 Caucasian) and gender/ethnicity-matched
      controls. Significant positive associations were found between SIDS and the 5-HTT
      genotype distribution (P = 0.022), specifically with the L/L genotype (P =
      0.048), and between SIDS and the 5-HTT L allele (P = 0.005). There was also a
      significant negative association between SIDS and the S/S genotype (P = 0.011).
      The comparisons were repeated in the African American and Caucasian subgroups.
      The data patterns were consistent in the subgroups, i.e., the L/L genotype and L
      allele were increased in the cases, but not all subgroup comparisons were
      statistically significant. These results indicate a relationship between SIDS and
      the L allele of the 5-HTT gene in African Americans and Caucasians, and if
      confirmed, will provide an important tool for identifying at-risk individuals and
      estimating the risk of recurrence.

PMID- 12599193
TI  - Prenatal diagnosis of mosaic tetrasomy 10p associated with megacisterna magna,
      echogenic focus of left ventricle, umbilical cord cysts and distal
      arthrogryposis.
AB  - We present the first report of mosaic isochromosome 10p associated with multiple
      congenital anomalies including megacisterna magna, echogenic focus of the left
      ventricle, umbilical cord cysts, and distal arthrogryposis. The most obvious
      anomalies found on prenatal ultrasound were enlarged cisterna magna and lower
      limb flexion contractures which resembled clubfeet. Analyses of GTG-banded
      chromosomes of 42 cells harvested from 32 independent tissue culture colonies
      were examined. Thirty-five cells from 27 colonies had 46 chromosomes and appeared
      to be 46,XX, female karyotype. Seven cells from independent colonies had 47
      chromosomes with abnormal karyotypes. The extra chromosome material was
      identified as isochromosome 10p without involvement of the heterochromatic region
      of the long arm [47,XX,+ i(10p)]. Mosaic tetrasomy 10p was confirmed using
      fluorescent in situ hybridization (FISH) of a 10p-specific probe to metaphase
      chromosomes of this patient.

PMID- 12599192
TI  - Ring chromosome 12 with variable phenotypic features: clinical report and review
      of the literature.
AB  - A ring chromosome 12 (p13; q24.33) was observed in all cells analyzed from
      peripheral blood lymphocytes of a 15-year-old female referred for academic
      difficulties and growth delay. In addition to clinical manifestations generally
      observed with ring chromosome 12 such as growth retardation, mental deficiency,
      microcephaly, the patient had bilateral pseudocamptodactyly of little fingers,
      mild hirsutism, exaggerated lumbar lordosis, and ostium secundum atrial septal
      defect (ASD). The clinical features of reported cases are analyzed. The only
      consistent features were growth retardation and mental deficiency. Breakpoint in
      all the cases has been at the telomeric region with minimal deletion of
      chromosomal material. An account of complex changes at mitosis and meiosis in
      ring chromosome has been given. Examination of 200 metaphases demonstrated 2%
      cell line was showing 45,XX, -12. Serum lactate dehydrogenase (LDH) level was
      normal ruling out overlapping monosomy 12 syndrome.

PMID- 12599194
TI  - Two unique patients with trisomy 18 mosaicism and molecular marker studies.
AB  - We report two unusual patients with trisomy 18 mosaicism presenting with minor
      anomalies and failure to thrive in the first year of life. Chromosome analysis
      showed trisomy 18 in 30/30 peripheral blood lymphocytes in both children.
      Analysis of skin fibroblasts in the first child showed normal female chromosomes
      in 30/30 cells, and the fibroblast karyotype in the second child showed mosaicism
      for tetrasomy 18p, trisomy 18, and normal female chromosomes (karyotype 47,XX,
      +i(18)(p10)[47]/47,XX, +18[9] /46,XX[4]). Trisomy 18 commonly results from
      nondisjunction at maternal meiosis II (MII). Nondisjunction at maternal MII has
      also been postulated to be the initial step in the formation of tetrasomy 18p. In
      our second case, the additional chromosome 18 was the result of maternal
      nondisjunction at MII, consistent with this hypothesis. In the first case,
      nondisjunction at maternal meiosis I (MI) was responsible for the extra
      chromosome 18.

PMID- 12599195
TI  - Zimmermann-Laband syndrome associated with a balanced reciprocal translocation
      t(3;8)(p21.2;q24.3) in mother and daughter: molecular cytogenetic
      characterization of the breakpoint regions.
AB  - Zimmermann-Laband syndrome (ZLS) is a rare disorder characterized by gingival
      fibromatosis, abnormalities of the nose and/or ears, and absence or hypoplasia of
      nails or terminal phalanges of hands and feet. Other more variable features
      include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and
      mental retardation. The genetic basis of ZLS is unknown; autosomal dominant
      inheritance has been suggested. We report an apparently balanced chromosomal
      aberration, 46,XX, t(3;8)(p13-p21.2;q24.1-q24.3), in a family with an affected
      mother and daughter. Using fluorescence in situ hybridization with BAC clones, we
      refined the breakpoints to 3p21.2 and 8q24.3 and, thereby, narrowed down both
      breakpoint regions to approximately 1.5 Mb. Our data provide additional support
      to the assumption that ZLS follows autosomal dominant inheritance. The 3;8
      translocation described here represents a powerful resource to identify the
      causative gene for ZLS that maps most likely to one of the breakpoints.

PMID- 12599196
TI  - Generalized skeletal dysplasia in mother and daughter with 22q11 deletion
      syndrome.

PMID- 12599197
TI  - Microcephalic osteodysplastic primordial short stature type II with cafe-au-lait
      spots and moyamoya disease.

PMID- 12599198
TI  - Screening for cryptic chromosomal abnormalities in patients with mental
      retardation and dysmorphic facial features using telomere FISH probes.

PMID- 12599199
TI  - Analysis of BRCA1 and BRCA2 mutations in an Iranian family with hereditary breast
      and ovarian cancer syndrome.

PMID- 12599200
TI  - Genetic drift. September 11, 3 PM.

PMID- 12599201
TI  - Coming together for blastogenesis.

PMID- 12599202
TI  - Reply to correspondence from Shipkov and Anastassov--"Bilateral Poland anomaly:
      does it exist?".

PMID- 12599203
TI  - Inflammatory mediators and reversible myocardial dysfunction.
AB  - A variety of seemingly unrelated clinical conditions manifest the same effects on
      the heart. These effects include: (1) reversible myocardial dysfunction, (2) beta
      adrenergic desensitization, and (3) activation of inflammatory mediators. We
      provide evidence supporting a role for cytokines, mitogen activated protein
      kinases (MAP kinases), and nitric oxide (NO) as common mediators of reversible
      myocardial dysfunction and beta-adrenergic desensitization. Data from animal
      models and human studies support a pathogenic role for these inflammatory
      mediators in ischemic as well as non-ischemic myocardial dysfunction. It is
      suggested that compensatory cellular programs are activated to provide short-term
      protection from brief periods of ischemia and infection. Continuous activation of
      these compensatory pathways leads to cardiomyopathy and chronic (congestive)
      heart failure. Elucidating the signaling pathways involved has the potential to
      provide the opportunity to exploit the cardioprotective advantages of these
      agents without bearing the burden of excessive stimulation.

PMID- 12599204
TI  - Putative role for EPC-1/PEDF in the G0 growth arrest of human diploid
      fibroblasts.
AB  - EPC-1/PEDF expression is closely associated with reversible growth arrest in
      normal human diploid fibroblast-like (HDF) cells and is diminished with
      proliferative senescence in vitro. EPC-1 expression in HDF cells is induced under
      conditions of density-dependent contact inhibition and growth factor deprivation.
      Antiserum generated against EPC-1 recognizes a secreted protein of approximately
      50 kDa from medium conditioned by early passage HDF cells, but not from senescent
      cells. The addition of EPC-1 antiserum to early population doubling level (PDL)
      cultures near the plateau phase of growth significantly increases the number of
      cells entering DNA synthesis. Affinity purified EPC-1 antibodies alone enhance
      the ability of near plateau-phase early PDL WI-38 cells to synthesize DNA by as
      much as threefold. Further, the addition of recombinant EPC-1 (rEPC-1) to
      logarithmically growing cells resulted in a marked decrease in the ability of
      these cells to enter DNA synthesis. We also demonstrate the loss of EPC-1
      expression in WI-38 and IMR-90 HDF cell lines with both senescence and simian
      virus 40 (SV40) transformation. The loss of EPC-1 expression with SV40
      transformation occurs at the level of steady-state mRNA and protein accumulation
      with genomic EPC-1 sequences grossly intact. Taken together, these results
      suggest that EPC-1 may play a role in the entry of early passage fibroblasts into
      a G(0) state or the maintenance of such a state once reached.

PMID- 12599205
TI  - Hydrocortisone has a protective effect on CyclosporinA-induced cardiotoxicity.
AB  - CyclosporinA (CsA) is an immunosuppressive drug which induces severe adverse
      effects such as cardiotoxicity and nephrotoxicity. In several therapeutic
      protocols CsA is used in association with corticosteroids to obtain better
      therapeutic results. Recently, our studies showed that CsA increases blood
      pressure while inhibit Nitric Oxide (NO) production in vivo. In this study we
      evaluated in rat cardiomyocytes the effects of CsA, used alone or in association
      with Hydrocortisone (HY), on intracellular calcium concentration, NO production
      and lipid peroxidation (MDA level). Our results demonstrated that CsA increased
      intracellular calcium and such effect was dose-dependent. HY used alone, slightly
      decreased intracellular calcium, while dramatically reduced CsA-induced calcium
      fluxes. CsA (3.2 microM) increased lipid peroxidation and this effect was blunted
      by HY. Both CsA and HY inhibited NO production in rat cardiomyocytes acting on
      this pathway synergically. Our results demonstrated that in rat cardiomyocytes,
      CsA toxicity is due to a calcium overload, which in turn induce lipid
      peroxidation and determines oxidative stress-induced cell injury. Treatment with
      HY effectively inhibits CsA-induced toxicity, decreasing lipid peroxidation as
      well as calcium intracellular concentration. Our findings seem to suggest that
      glucocorticoids may be effective in reducing CsA-induced cardiotoxicity at
      concentrations which are consistent with current therapeutic doses.

PMID- 12599207
TI  - Induction of globin mRNA expression by interleukin-3 in a stem cell factor
      dependent SV-40 T-antigen-immortalized multipotent hematopoietic cell line.
AB  - Erythropoiesis requires the stepwise action on immature progenitors of several
      growth factors, including stem cell factor (SCF), interleukin 3 (IL-3), and
      erythropoietin (Epo). Epo is required to sustain proliferation and survival of
      committed progenitors and might further modulate the level of expression of
      several erythroid genes, including globin genes. Here we report a new SCF
      dependent immortalized mouse progenitor cell line (GATA-1 ts SCF) that can also
      grow in either Epo or IL-3 as the sole growth factor. When grown in SCF, these
      cells show an "open" chromatin structure of the beta-globin LCR, but do not
      significantly express globin. However, Epo or IL-3 induce globin expression and
      are required for its maintainance. This effect of IL-3 is unexpected as IL-3 was
      previously reported either to be unable to induce hemoglobinization, or even to
      antagonize it. This suggests that GATA-1 ts SCF cells may have progressed to a
      stage in which globin genes are already poised for expression and only require
      signal(s) that can be elicited by either Epo or IL-3. Through the use of
      inhibitors, we suggest that p38 may be one of the molecules modulating induction
      and maintenance of globin expression.

PMID- 12599206
TI  - Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes
      exposed to ischemia/reperfusion oxidative stress model.
AB  - During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of
      nutrients and successively to radical oxygen species (ROS). In the present study,
      we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose
      depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in
      their standard culture medium to simulate reperfusion. We investigated the
      effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP
      kinases activation to address the role of each event with respect to apoptosis.
      We demonstrate that serum/glucose depletion per se did not induce apoptosis when
      compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways.
      SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis
      while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking
      phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without
      consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were
      analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the
      presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased
      in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest
      that p38MAPK activation primarily mediates ROS-induced apoptosis while
      concomitant JNK activation would represent a scavenger pathway for cells trying
      to escape apoptosis.

PMID- 12599208
TI  - Lamellipodial motility in wounded endothelial cells exposed to physiologic flow
      is associated with different patterns of beta1-integrin and vinculin
      localization.
AB  - Integrins- and cytoskeletal-associated focal adhesion proteins may participate in
      the process of endothelial wound closure, but their relationship in these wounds
      and in the presence of shear forces has not been defined. The goal in this study
      was to test the hypotheses that (1) modulation of beta(1)-integrin in human
      coronary artery endothelial cells (HCAEC) would alter endothelial wound closure
      under shear stress, and (2) beta(1)-integrin association with vinculin would be
      necessary for mediating this closure. HCAEC monolayers were pre-conditioned to
      attain alignment by shearing at 12 dynes/cm(2) for 18 h in a parallel-plate flow
      chamber. Subsequently, they were divided into three groups: (a) control, (b)
      treated with anti-beta(1)-integrin adhesion blocking antibody, or (c) treated
      with anti-beta(1)-integrin adhesion promoting antibody. Next, the monolayers were
      wounded with a metal spatula, and re-sheared at 20 dynes/cm(2) or left static.
      Time-lapse imaging and deconvolution microscopy were then performed for 3 h.
      Immunocytochemistry for beta(1)-integrin expression and vinculin was performed on
      all wounded monolayers. Under shear stress, vinculin localized to the ends of
      stress fibers, while beta(1)-integrin took on an intracellular macroaggregate
      appearance. Treatment with anti-beta(1)-integrin adhesion blocking antibody
      enhanced wound closure, left the vinculin staining at the lamellipodial tips
      unchanged, but was associated with beta(1)-integrin staining at the lateral cell
      edges. Treatment with the anti-beta(1)-integrin adhesion promoting antibody
      retarded wound closure, increased vinculin staining at cell-cell junctions, and
      was associated with a fibrillar pattern of beta(1)-integrin staining. Modulation
      of beta(1)-integrin and changes in beta(1)-integrin and vinculin localization may
      further our understanding of laminar shear stress-induced endothelial repair in
      the coronary circulation.

PMID- 12599209
TI  - Control of hepatocyte DNA synthesis by intracellular pH and its role in the
      action of tumor promoters.
AB  - The mechanisms of tumor promotion in liver by various xenobiotics of diverse
      structure are not well understood. However, these tumor promoters share the
      ability to exert growth-stimulatory effects on hepatocytes. Our laboratory has
      been utilizing normal rat hepatocytes under defined conditions of primary
      cultures, to investigate growth-stimulatory actions of liver tumor promoters. We
      have shown that most, if not all, of the liver tumor promoters tested stimulate
      hepatocyte DNA synthesis when added in combination with epidermal growth factor
      (EGF), insulin, and glucocorticoids. In the present study, we sought evidence for
      the role of the Na(+)/H(+) antiporter and cytoplasmic alkalinization in the
      direct growth-stimulatory actions of tumor promoters on hepatocytes. Hepatocytes
      cultured under conditions (bicarbonate-buffered medium) where intracellular pH
      (pH(i)) was independent of extracellular pH (pH(e)), EGF- and insulin-stimulated
      rates of DNA synthesis were unaffected by modest changes in pH(e). However, under
      conditions (HEPES-buffered medium) where pH(i) varied in a linear fashion with
      pH(e), rates of EGF- and insulin-stimulated DNA synthesis were highly dependent
      on pH(e). Similarly, 12-O-tetradecanoylphorbol-13-acetate (TPA) and alpha
      hexachlorocyclohexane (HCH)-stimulated DNA synthesis were pH(e)-dependent but
      were stimulatory over different pH(e) ranges, suggesting that these promoters may
      act by distinct mechanisms. Chemicals that are capable of inducing rapid
      cytoplasmic alkalinization, ammonium chloride (1 and 15 mM) and monensin (0.5
      microM), were found to stimulate hepatocyte DNA synthesis. The role of the
      Na(+)/H(+) antiport in controlling pH(i) of hepatocytes was demonstrated by
      artificially acidifying 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein
      acetoxymethyl (BCECF)-loaded isolated hepatocytes with 20 mM sodium acetate and
      the use of specific inhibitors. Amiloride and its analogues inhibited pH(i)
      recovery from the acid load in a dose dependent manner and the relative potency
      of these inhibitors paralleled their K(i) values for the Na(+)/H(+) antiport. At
      concentrations that stimulate hepatocyte DNA synthesis, some liver tumor
      promoters phenobarbital (PB) and HCH, were found to cause a rapid rise pH(i) in
      isolated hepatocytes which was sensitive to amiloride and its analogues. Taken
      together, our data suggest that activation of Na(+)/H(+) antiport activity may be
      one mechanism whereby some liver tumor promoters stimulate hepatocytes DNA
      synthesis. This study has implications for the mechanisms of tumor promotion in
      liver carcinogenesis.

PMID- 12599210
TI  - Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the
      differentiation of primary human adult skeletal myoblasts.
AB  - Although muscle satellite cells were identified almost 40 years ago, little is
      known about the induction of their proliferation and differentiation in response
      to physiological/pathological stimuli or to growth factors/cytokines. In order to
      investigate the role of the insulin-like growth factor (IGF)/IGF binding protein
      (IGFBP) system in adult human myoblast differentiation we have developed a
      primary human skeletal muscle cell model. We show that under low serum media
      (LSM) differentiating conditions, the cells secrete IGF binding proteins-2, -3, 
      4 and -5. Intact IGFBP-5 was detected at days 1 and 2 but by day 7 in LSM it was
      removed by proteolysis. IGFBP-4 levels were also decreased at day 7 in the
      presence of IGF-I, potentially by proteolysis. In contrast, we observed that
      IGFBP-3 initially decreased on transfer of cells into LSM but then increased with
      myotube formation. Treatment with 20 ng/ml tumour necrosis factor-alpha
      (TNFalpha), which inhibits myoblast differentiation, blocked IGFBP-3 production
      and secretion whereas 30 ng/ml IGF-I, which stimulates myoblast differentiation,
      increased IGFBP-3 secretion. The TNFalpha-induced decrease in IGFBP-3 production
      and inhibition of differentiation could not be rescued by addition of IGF-I.
      LongR(3)IGF-I, which does not bind to the IGFBPs, had a similar effect on
      differentiation and IGFBP-3 secretion as IGF-I, both with and without TNFalpha,
      confirming that increased IGFBP-3 is not purely due to increased stability
      conferred by binding to IGF-I. Furthermore reduction of IGFBP-3 secretion using
      antisense oligonucleotides led to an inhibition of differentiation. Taken
      together these data indicate that IGFBP-3 supports myoblast differentiation.

PMID- 12599211
TI  - Epidermal growth factor induces an increase in cell adhesion and an arrangement
      of actin skeleton in stress fibres in pituitary cultured cells from infantile
      rats but not adult rats.
AB  - The rat anterior pituitary gland undergoes changes in its cyto-architecture
      during the second and third weeks of postnatal life. However, little is known
      about the factors that regulate these tissue conformational changes. The
      epidermal growth factor (EGF) is one of the growth factors that are synthesized
      by the pituitary gland, and almost all of the pituitary cells have EGF receptors
      (EGFR). In addition to the effects of the EGF on mitosis and differentiation,
      this growth factor can modulate cell adhesion, cell migration, and cytoskeletal
      organization. In this study we focussed our attention in examining the effects of
      EGF on the adhesion of cells to the extracellular matrix and on the actin
      cytoskeletal arrangement of pituitary cells from infantile and adult rats. Our
      results show that in infantile cells the EGF induces cell adhesion with increase
      in cell surface area. The arrangement of actin-F in infantile EGF-treated cells
      was in stress fibers and vinculin acquired a striped shape at the membrane
      border, suggesting the assembly of focal adhesion contacts. In contrast, in adult
      pituitary cells EGF does not induce any change in cell adhesion, and the cells
      maintain a rounded shape with an arrangement of actin-F in thin cortical bands
      even though, immuno-localization of the EGFR was observed in adult cells cultured
      in defined medium. We also looked for the EGFR in membrane preparations from
      infantile and adult pituitaries, and a marked difference in membrane EGFR was
      observed between them, the infantile pituitaries showing a significantly higher
      amount. Our results suggest that in infantile cells EGF induces the assembly of
      focal adhesion contacts, and that in adult cells the receptor of this growth
      factor is uncoupled of the signaling pathway by which a rearrangement of actin
      cytoskeleton occurs.

PMID- 12599212
TI  - Cyclooxygenase and cytochrome P-450 pathways induced by fetal calf serum regulate
      wound closure in 3T6 fibroblast cultures through the effect of prostaglandin E2
      and 12 and 20 hydroxyeicosatetraenoic acids.
AB  - Wound-induced injury of 3T6 fibroblast cultures initiated a repair process
      stimulated by fetal calf serum (FCS) that restored the integrity of cell
      cultures. In these experimental conditions, FCS induced arachidonic acid (AA)
      release and eicosanoid production. Our results show that the inhibition of the
      cyclooxygenase (COX) and/or cytochrome P-450 pathways significantly decreases the
      wound closure, whereas that of the lipoxygenase pathway does not modify the wound
      repair process. Both EP(1) and EP(4) receptors of prostaglandin E(2) (PGE(2))
      mediate PGE(2) stimulated 3T6 fibroblast wound closure. Our data suggest that
      calcium and cAMP are involved in the signaling event induced by PGE(2) during the
      3T6 fibroblast wound repair process. On the other hand, we show that
      ketoconazole, a cytochrome P-450 inhibitor, hinders the wound closure induced by
      FCS in wounded 3T6 fibroblast cultures. 12 and 20 Hydroxyeicosatetraenoic acids
      (HETEs), which are key AA metabolites synthesized by cytochrome P-450, partially
      revert the effects of ketoconazole on the wound repair process. Thus, the COX and
      cytochrome P-450 pathways of the arachidonate cascade are involved in 3T6
      fibroblast wound closure.

PMID- 12599213
TI  - Vanadium-induced apoptosis and pulmonary inflammation in mice: Role of reactive
      oxygen species.
AB  - Pulmonary exposure to metals and metal-containing compounds is associated with
      pulmonary inflammation, cell death, and tissue injury. The present study uses a
      mouse model to investigate vanadium-induced apoptosis and lung inflammation, and
      the role of reactive oxygen species (ROS) in this process. Aspiration of the
      pentavalent form of vanadium, V (V), caused a rapid influx of polymorphonuclear
      leukocytes into the pulmonary airspace with a peak inflammatory response at 6 h
      post-exposure and resolution by 72 h. During this period, the number of apoptotic
      lung cells which were predominantly neutrophils increased considerably with a
      peak response at 24 h accompanied by no or minimum necrosis. After 24 h when the
      V (V)-induced inflammation was in the resolution phase, an increased influx of
      macrophages and engulfment of apoptotic bodies by these phagocytes was observed,
      supporting the role of macrophages in apoptotic cell clearance and resolution of
      V (V)-induced lung inflammation. Electron spin resonance (ESR) studies using
      lavaged alveolar macrophages showed the formation of ROS, including O(2)(*-),
      H(2)O(2), and (*)OH radicals which were confirmed by inhibition with free radical
      scavengers. The mechanism of ROS generation induced by V (V) involved the
      activation of an NADPH oxidase complex and the mitochondrial electron transport
      chain. The ROS scavenger, catalase (H(2)O(2) scavenger), effectively inhibited
      both lung cell apoptosis and the inflammatory response, whereas superoxide
      dismutase (SOD) (O(2)(*-) scavenger) and the metal chelator, deferoxamine
      (inhibitor of (*)OH generation by Fenton-like reactions) had lesser effects.
      These results indicate that multiple oxidative species are involved in V (V)
      induced lung inflammation and apoptosis, and that H(2)O(2) plays a major role in
      this process.

PMID- 12599214
TI  - Lipid factor (bVLF) from bovine vitreous body evokes in EGFR-T17 cells a Ca2+
      dependent K+ current associated with inositol 1,4,5-trisphosphate-independent
      Ca2+ mobilization.
AB  - Bovine vitreous lipid factor (bVLF) is a complex phospholipid isolated from
      bovine vitreous body with strong Ca(2+)-mobilizing activity. In this study, the
      effects of bVLF on membrane potential were investigated in EGFR-T17 fibroblasts
      with the whole-cell patch clamp technique on monolayer cells, as well as with the
      fluorescent dye bis-oxonol as membrane potential-sensitive probe on monolayer and
      suspension cells. bVLF induced a transient hyperpolarization characterized by an
      initial peak and subsequent return to resting membrane potential levels within 1
      2 min. The increase of [Ca(2+)](i) was concomitant with an outward current
      responsible for the hyperpolarizing response. Results with: (a) high [K(+)](o)
      media; (b) the monovalent cation ionophore gramicidin; and (c) substitution of
      K(+) with Cs(+) in the intracellular solution were consistent with the
      involvement of K(+) channels. The bVLF-induced hyperpolarization was blocked by
      the K(+) channel blockers, quinine and tetraethylamonium chloride, and partially
      affected by 4-aminopyridine. The calcium ionophore ionomycin caused a similar
      hyperpolarization as bVLF. When intracellular calcium was buffered by adding
      BAPTA to the pipette solution, bVLF-activated outward current was prevented.
      Moreover, the hyperpolarization response was strongly reduced at low doses (3 nM)
      of specific Ca(2+)-activated K(+) channel blockers, charybdotoxin and
      iberiotoxin. Based on these observations we conclude that bVLF hyperpolarizes the
      cells via the activation of a Ca(2+)-dependent K(+) current. In addition, it was
      observed that bVLF did not have a significant effect on intercellular
      communication measured by a single patch-electrode technique. Thus, membrane
      potential changes appeared to belong to the earliest cellular responses triggered
      by bVLF, and are closely associated with phosphatidic acid-dependent [Ca(2+)](i)
      mobilization.

PMID- 12599215
TI  - CD31 (PECAM-1)-bright cells derived from AC133-positive cells in human peripheral
      blood as endothelial-precursor cells.
AB  - To clarify the process of endothelial differentiation, we isolated AC133(+) cells
      and induced the in vitro differentiation of these cells into endothelial cells.
      AC133(+) cells efficiently differentiated into endothelial cells when the cells
      were cultured on fibronectin-coated dishes in the presence of vascular
      endothelial growth factor. Time-course analysis of the alteration of endothelial
      markers on cultured AC133(+) cells revealed that the expression of CD31 (PECAM-1)
      on AC133(+) cells was the earliest marker among all of the tested markers. Based
      on the hypothesis that CD31 is an early indicator during the endothelial
      differentiation, we examined the relationship between CD31 expression and the
      ability to differentiate into endothelial cells in cells derived from AC133(+)
      cells. CD31-bright cells, which were sorted from cultured AC133(+) cells,
      differentiated more efficiently into endothelial cells than had CD31-positive or
      CD31-negative cells, suggesting that CD31-bright cells may be precursor cells for
      endothelial cells. In the present study, we identified CD31(+) cells derived from
      cultured AC133(+) cells that are able to differentiate to endothelial cells as
      precursor cells.

PMID- 12599216
TI  - Mast cell-mediated apoptosis of endothelial cells in vitro: a paracrine mechanism
      involving TNF-alpha-mediated down-regulation of bcl-2 expression.
AB  - Degranulated mast cells are present in the subendothelial space of eroded (de
      endothelialized) coronary atheromas. Upon degranulation, mast cells secrete into
      the surrounding tissue an array of preformed and newly synthesized mediators,
      including proapoptotic molecules, such as chymase and TNF-alpha. In a co-culture
      system involving rat serosal mast cells and rat cardiac (microvascular)
      endothelial cells, we could show, by means of competitive RT-PCR, immunoblotting,
      immunocytochemistry, annexin staining, flow cytometry, and DNA-laddering, that
      stimulation of mast cells with ensuing degranulation rapidly (within 30 min) down
      regulated the expression of both bcl-2 mRNA and protein, with subsequent
      induction of apoptosis in the endothelial cells. The major effect of bcl-2 down
      regulation resided in the exocytosed granule remnants, a minor effect also being
      present in the granule remnant-free supernatant. No significant changes were
      observed in the expression levels of the pro-apoptotic protein, bax. The mast
      cell-mediated apoptotic effect was partially (70%) dependent on the presence of
      TNF-alpha and involved the translocation of cytochrome C from mitochondria into
      cytoplasm. These results are the first to show that one of the cell types present
      in the atherosclerotic plaques, namely the mast cell, by releasing both granule
      remnant-bound and soluble TNF-alpha, may contribute to the erosion of
      atherosclerotic plaques by inducing apoptosis in adjacent endothelial cells.
      Published 2003 Wiley-Liss, Inc.

PMID- 12599218
TI  - Refined measurement of outcome for adjuvant breast carcinoma therapy.
AB  - BACKGROUND: Traditional nonparametric statistical methods do not provide a
      quantitative measure of the lifetime benefit from adjuvant therapy. This
      deficiency makes it difficult to determine the long-term difference in impact
      between the two treatment arms of a clinical trial. METHODS: To assess the impact
      of breast carcinoma recurrence, parametric survival models were derived from two
      randomized, controlled clinical trials of adjuvant therapy for Stage II breast
      carcinoma. To assess time to death from causes other than breast carcinoma,
      actuarial models derived from 1980 Census data were used. These two models were
      then combined to estimate the mean time to event (MTE) as a function of patient
      age, with the event being either recurrence or death from other causes. The MTE
      was then used to measure the differential benefit between two arms of a clinical
      trial. RESULTS: In the first trial, differences in MTE between treatment groups
      varied from 2.7 years for 35-year-old patients to 1.4 years for 75-year-old
      patients. For this trial, the mechanism of survival benefit was an increase in
      time to recurrence. In the second trial, differences in MTE varied from 7.6 to
      1.6 years over the same age ranges. For this trial, the mechanism of survival
      benefit was an increase in the likelihood of cure, i.e., an increase in the
      asymptote of the curve that represents proportion of patients without relapse.
      CONCLUSIONS: When applied to data from controlled clinical trials, MTE offers a
      quantitative measure of long-term outcome from adjuvant therapy. The greatest
      benefit is achieved when therapy that increases the likelihood of cure is
      provided to young patients.

PMID- 12599217
TI  - Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of
      ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor,
      in head and neck squamous carcinoma cells.
AB  - High expression of the epidermal growth factor receptor (EGFR) has been
      implicated in the development of squamous-cell carcinomas of head and neck
      (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine
      kinase inhibitor) that blocks signal transduction pathways implicated in
      proliferation and survival of cancer cells, and other host-dependent processes
      promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest
      in SCCHN cell lines by inhibiting EGFR-mediated signaling. Cell cycle kinetic
      analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a
      G1 arrest together with a partial G2/M block; this was associated with increased
      expression of both p27(KIP1) and p21(CIP1/WAF1) cyclin-dependent kinase (CDK)
      inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was
      reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this
      effect correlated to the increased amount of p27(KIP1) and p21(CIP1/WAF1)
      proteins associated with CDK2-cyclin-E and CDK2-cyclin-A complexes. In addition,
      ZD1839-induced growth inhibition was significantly reduced in cell transfectants
      expressing p27(KIP1) or p21(CIP1/WAF1) antisense constructs. Overall, these
      results as well as the timing of the effect of ZD1839 on G1 arrest and p27(KIP1)
      and p21(CIP1/WAF1) upregulation, suggest a mechanistic connection between these
      events.

PMID- 12599219
TI  - 5-Year mammography rates and associated factors for older women.
AB  - BACKGROUND: Major national interventions occurred in the early and mid-1990s to
      increase mammography screening rates among older women. The current study
      examined mammography utilization by older women during this period. Relation
      between mammography utilization and demographic measures and health care-related
      factors also were examined. METHODS: A cross-sectional design examined variations
      in mammography during the 5 years between 1993 to 1997 in a representative sample
      of 10,000 female Medicare beneficiaries in Michigan age >or= 65 years in 1993.
      Medicare and census data were used. Separate analyses were performed for having
      undergone any mammogram and, for the 5680 women who had undergone a mammogram,
      the number of mammograms. Relations were examined between mammography utilization
      and 15 demographic variables (e.g., age and African-American race) and health
      care-related variables (e.g., inpatient admissions and number of physicians
      involved in care). RESULTS: In the 5 years 43% of older women had no evidence of
      having undergone a mammogram. Those with any mammogram averaged 2.8 mammograms.
      Meaningful independent predictors of both having undergone a mammogram and having
      more than one mammogram were more physicians involved in care, fewer inpatient
      admissions, and younger age. Having undergone a mammogram also was found to be
      associated with seeing an obstetrician/gynecologist. CONCLUSIONS: Even with
      screening mammography as a covered benefit and after several national
      informational campaigns, the current study found that in 5 years, 60% of older
      women either had not undergone a mammogram or had undergone only 1. Intervention
      efforts should emphasize screening based on functional status, not age. This
      message should be targeted to physicians as well as to older women without claims
      for recent mammograms and who are likely to be in good health.

PMID- 12599220
TI  - Is axillary lymph node dissection necessary in elderly patients with breast
      carcinoma who have a clinically uninvolved axilla?
AB  - BACKGROUND: Axillary dissection in elderly patients with early-stage breast
      carcinoma who do not have palpable axillary lymph nodes is controversial because
      of the associated morbidity of the surgery, reduced life expectancy of the
      patients, and efficacy of hormone therapy in preventing recurrences and axillary
      events. METHODS: The authors performed a retrospective analysis of 671
      consecutive patients with breast carcinoma who were age >or= 70 years and who
      underwent conservative breast surgery with axillary dissection (172 patients) or
      without axillary dissection (499 patients). Tamoxifen always was given. The
      effects of axillary dissection compared with no axillary dissection on breast
      carcinoma mortality and distant metastasis were analyzed using multiple
      proportional-hazards regression models. Because the assignment to axillary
      treatment was nonrandom, covariate adjustments were made for baseline variables
      that influenced the decision to perform axillary dissection and for prognostic
      factors. RESULTS: The crude cumulative incidence curves for breast carcinoma
      mortality and distant metastasis did not appear to differ significantly between
      the two groups (P = 0.530 and P = 0.840, respectively). The crude cumulative
      incidences of axillary lymph node occurrence at 5 years and 10 years were 4.4%
      and 5.9%, respectively (3.1% and 4.1%, respectively, for patients with pT1
      tumors). CONCLUSIONS: Elderly patients with breast carcinoma who have no evidence
      of axillary lymph node involvement may be treated effectively with conservative
      surgery and tamoxifen. Immediate axillary dissection is not necessary but should
      be performed in the small percentage of patients who later develop overt axillary
      lymph node involvement.

PMID- 12599221
TI  - Evaluation of an internet support group for women with primary breast cancer.
AB  - BACKGROUND: Women with breast carcinoma commonly experience psychologic distress
      following their diagnosis. Women who participate in breast cancer support groups
      have reported significant reduction in their psychologic distress and pain and
      improvement in the quality of their lives. Web-based breast cancer social support
      groups are widely used, but little is known of their effectiveness. Preliminary
      evidence suggests that women benefit from their participation in web-based
      support groups. METHODS: Seventy-two women with primary breast carcinoma were
      assigned randomly to a 12-week, web-based, social support group (Bosom Buddies).
      The group was semistructured, moderated by a health care professional, and
      delivered in an asynchronous newsgroup format. RESULTS: The results indicate that
      a web-based support group can be useful in reducing depression and cancer-related
      trauma, as well as perceived stress, among women with primary breast carcinoma.
      The effect sizes ranged from 0.38 to 0.54. Participants perceived a variety of
      benefits and high satisfaction from their participation in the intervention
      CONCLUSIONS: This study demonstrated that the web-based program, Bosom Buddies,
      was effective in reducing participants' scores on depression, perceived stress,
      and cancer-related trauma measures. The effect size of the intervention was in
      the moderate range. Although web-based social support groups offer many
      advantages, this delivery mechanism presents a number of ethical issues that need
      to be addressed.

PMID- 12599222
TI  - Capecitabine in combination with docetaxel and epirubicin in patients with
      previously untreated, advanced breast carcinoma.
AB  - BACKGROUND: The objective of this study was to evaluate the activity and safety
      of oral capecitabine in combination with docetaxel and epirubicin (TEX) as first
      line treatment for patients with locally advanced/metastatic breast carcinoma.
      METHODS: This open-label, Phase II study was conducted at six Italian centers.
      Treatment consisted of epirubicin, 75 mg/m(2) (intravenous bolus), and docetaxel,
      75 mg/m(2) (1-hour infusion), both administered on Day 1, plus oral capecitabine,
      1000 mg/m(2) twice daily, on Days 1-14 of each 3-week treatment cycle. RESULTS: A
      total of 67 patients received 392 cycles of treatment, with a median of 6 cycles
      in patients with Stage III disease (n = 34 patients) and a median of 8 cycles in
      patients with Stage IV disease (n = 33 patients). The objective response rate was
      82%, including complete responses in 21% of patients. A greater proportion of
      patients with Stage III disease achieved tumor responses compared with patients
      who had Stage IV disease (97% vs. 67%, respectively). Among 34 patients with
      Stage III disease, pathologic complete responses were confirmed in 10 patients
      (29%). TEX chemotherapy demonstrated an acceptable safety profile. There was a
      low incidence of Grade 3 adverse events, and Grade 4 adverse events were
      particularly rare (4%). The most common Grade 3-4 adverse event was febrile
      neutropenia, which occurred in 16% of patients. CONCLUSIONS: TEX combination
      therapy has important antitumor activity and an acceptable safety profile in this
      setting. A large, randomized, Phase III trial is ongoing to compare TEX
      chemotherapy with an epirubicin plus docetaxel regimen in patients with
      untreated, advanced breast carcinoma.

PMID- 12599223
TI  - Pure versus follicular variant of papillary thyroid carcinoma: clinical features,
      prognostic factors, treatment, and survival.
AB  - BACKGROUND: The follicular variant of papillary thyroid carcinoma (FVPTC) is a
      common subtype of papillary thyroid carcinoma. Few studies have compared the
      clinical behavior and treatment outcome of patients with FVPTC with the outcome
      of patients with pure papillary carcinoma (PTC). A retrospective study was
      performed to identify the influence of FVPTC compared with PTC on therapeutic
      variables, prognostic variables, and survival. METHODS: A clinicopathologic
      analysis of 243 patients with papillary carcinoma was performed. One hundred
      forty-three tumors were PTC, and 100 tumors were FVPTC. The following variables
      were evaluated: age at diagnosis, tumor size, stage of tumor, treatment, capsular
      invasion, and survival. RESULTS: The median follow-up was 11.5 years. The median
      age was 43 years in the PTC group and 44 years in the FVPTC group. The median
      tumor size, disease stage, and type of initial surgery and iodine 131 ablation
      were similar. More patients had capsular invasion by the tumor and less
      metastases to cervical lymph nodes in the FVPTC group. The actuarial survival of
      patients age < 40 years was higher compared with the survival of patients age >
      50 years in both groups. The 21-year overall actuarial survival was 82% in
      patients with PTC and 86% in patients with FVPTC (P value not significant).
      CONCLUSIONS: The pathologic and clinical behaviors of PTC and FVPTC were
      comparable. Prognostic factors, treatment, and survival also were similar.
      Patients in both groups must be treated identically.

PMID- 12599224
TI  - Prognostic factors in patients with Hurthle cell neoplasms of the thyroid.
AB  - BACKGROUND: Hurthle cell neoplasms, often considered a variant of follicular
      thyroid neoplasms, represent 3% of thyroid carcinomas. Only a handful of
      publications have focused on the biologic behavior, prognostic factors, and
      treatment outcomes of Hurthle cell carcinoma. The objective of the current study
      was to identify the clinical and pathologic features of Hurthle cell carcinomas
      that predict disease progression or death. METHODS: The authors reviewed medical
      records of patients who were treated for Hurthle cell carcinoma (HCC) and Hurthle
      cell adenoma (HCA) at The University of Texas M. D. Anderson Cancer Center from
      March 1944 to February 1995, including follow-up information. The pathologic
      diagnosis was confirmed by one of the authors. RESULTS: The authors identified
      127 patients with Hurthle cell neoplasms, 89 patients with HCC and 38 patients
      with HCA. Seven patients with HCC had foci of anaplastic thyroid carcinoma.
      Survival for this subgroup was worse compared with the overall group and was
      analyzed separately. The HCC group was significantly older (age 51.8 years vs.
      age 43.1. years) and had larger tumors (4.3 cm vs. 2.9 cm) compared with the HCA
      group. No differences were seen in gender or previous radiation exposure. Forty
      percent of patients in the HCC group died of thyroid carcinoma, whereas no
      patients in the HCA group died of the disease. There has been no improvement in
      all-cause and disease specific mortality in the past 5 decades for patients with
      these neoplasms. Conventional staging systems predicted mortality with minor
      differences. Of the patients with known metastasis, 38% showed radioiodine
      uptake. Univariate analysis identified older age, higher disease stage, tumor
      size, extraglandular invasion, multifocality, lymph node disease, distant
      metastasis, extensive surgery, external beam radiation therapy, and chemotherapy
      as factors that were associated with decreased survival. Tumor encapsulation was
      associated with improved survival. Although radioactive iodine treatment had no
      overall effect on survival, subgroup analysis showed that patients who received
      radioactive iodine for adjuvant ablation therapy had better outcomes compared
      either with patients who did not receive radioactive iodine or with patients who
      received radioactive iodine as treatment for residual disease. Multivariate
      analysis indicated that older age and larger tumor size predicted worse survival
      through an association with worse behaving tumors (multifocal, less encapsulated,
      and with extraglandular invasion). The decreased survival in patients with lymph
      node metastases may be explained by its association with distant metastases. The
      association of extensive surgery, external beam radiation therapy, and
      chemotherapy with worse survival also disappeared once those factors were
      analyzed together with other prognostic factors, such as distant metastases.
      CONCLUSIONS: Several clinical and pathologic prognostic factors were identified
      in patients with HCC and HCA. Older age and larger tumor size predicted reduced
      survival. Radioactive iodine therapy may confer a survival benefit when it is
      used for adjuvant ablation therapy, but not when residual disease is present. The
      authors could not demonstrate a survival benefit for the use of extensive
      surgery, external beam radiation therapy, or chemotherapy.

PMID- 12599225
TI  - Cisplatin-based combined modality therapy for anal carcinoma: a wider therapeutic
      index.
AB  - BACKGROUND: Definitive chemoradiation therapy is the standard of care for anal
      carcinoma. The chemotherapy regimen comprising 5-fluorouracil (5-FU) and
      mitomycin-C is the most commonly used among patients with anal carcinoma but
      causes well documented toxicities. In the current study, the authors evaluated
      their experience in treating anal carcinoma with combined modality therapy using
      cisplatin and 5-FU. METHODS: A retrospective analysis was performed of 92
      patients with nonmetastatic squamous cell carcinoma of the anus who were treated
      between 1989 and 1998. The primary tumor and involved lymph nodes received a
      total dose of 55 grays (Gy) administered in more than 30 daily fractions.
      Cisplatin (4 mg/m(2)/day) and 5-FU (250 mg/m(2)/day) were given as a continuous
      infusion, 5 days each week during the entire radiation course. Kaplan-Meier
      methodology was used to determine local control (LC), disease-free survival
      (DFS), and overall survival (OS). RESULTS: Ten patients had T1 or Tx, 43 had T2,
      27 had T3, and 12 patients had T4 disease. There were 21 male and 71 female
      patients. Sixty-five patients (71%) were lymph node negative. With a median
      follow-up duration of 44 months, the actuarial 5-year OS rate was 85%, the DFS
      rate was 77%, and the colostomy-free survival rate was 82%. Local recurrences
      occurred in 16 patients (17%). Distant metastases (DM) occurred in eight patients
      (9%). Advanced T classification (> T2) predicted lower LC and DFS rates. Advanced
      N classification (> N1) predicted worse DFS, OS, and DM rates. Greater than 90%
      of patients completed treatment without significant treatment interruption. Only
      five patients developed acute toxicities of Radiation Therapy Oncology Group
      (RTOG) Grade 4 or higher and only three patients developed chronic toxicities of
      RTOG Grade 4 or higher. CONCLUSIONS: Combined modality therapy with continuous
      infusion of cisplatin and 5-FU is a well tolerated regimen that results in high
      rates of LC, OS, and sphincter preservation. These rates are comparable to the
      best results reported with mitomycin-C and 5-FU. Without the normally severe
      toxicity, cisplatin-based therapy results in a wider therapeutic index.

PMID- 12599226
TI  - Impact of a novel neoadjuvant and adjuvant hormone-deprivation approach on
      quality of life, voiding function, and sexual function after prostate
      brachytherapy.
AB  - BACKGROUND: Data demonstrate a benefit from neoadjuvant and adjuvant hormone
      deprivation therapy with luteinizing hormone-releasing hormone agonists in
      patients who are treated with radiotherapy for localized prostate carcinoma;
      however, this approach has detrimental effects on quality of life (QOL). A cross
      sectional study was undertaken to evaluate the impact on QOL, voiding function,
      and sexual function of an alternative hormone-deprivation approach. METHODS:
      Three hundred fifty patients with clinical T1c-T2b prostate carcinoma were
      treated from March 1997 to August 2000 either with palladium 103 brachytherapy
      (BTM) without hormone therapy or with 8 months of adjuvant and neoadjuvant
      hormone-deprivation therapy with an antiandrogen and finasteride (BTM+H), were
      mailed the Functional Assessment of Cancer Therapy (FACT) global well being QOL
      instrument (FACT-G), the American Urological Association symptom score (AUASS),
      and specific items addressing urinary control and sexual function from validated
      instruments. Differences between treatment groups were assessed as a function of
      time since treatment. RESULTS: Seventy-two percent of patients responded to the
      questionnaire. No differences in overall FACT-G scores, AUASS scores, or AUASS
      subscale scores between the BTM group and the BTM+H group were found. The BTM+H
      group initially had lower personal well being FACT-G subscale scores, more
      urinary incontinence, and lower odds of attaining an erection sufficient for
      intercourse initially, although these differences disappeared with longer follow
      up. CONCLUSIONS: The use of neoadjuvant and adjuvant antiandrogen and finasteride
      with brachytherapy is associated with QOL equal to that of brachytherapy alone
      for the treatment of patients with localized prostate carcinoma, allowing the
      advantages of hormone manipulation in terms of tumor control without its
      downside.

PMID- 12599227
TI  - Elevation of cytokine levels in cachectic patients with prostate carcinoma.
AB  - BACKGROUND: Approximately 60-70% of patients with advanced prostate carcinoma
      (CaP) suffer from cachexia, one of the most devastating conditions associated
      with advanced malignant disease. The pathophysiology of cachexia is
      multifactorial, and several cytokines, such as tumor necrosis factor alpha
      (TNFalpha) and interleukin 1 (IL-1), IL-6, and IL-8, may be involved. The
      objective of the current study was to determine whether cachexia associated with
      advanced CaP is accompanied by increased serum levels of TNFalpha, IL-1beta, IL
      6, and IL-8. METHODS: The levels of TNFalpha, IL-1beta, IL-6, IL-8, and prostate
      specific antigen (PSA) were examined in serum samples from normal donors (n = 10
      donors), from patients with organ-confined CaP (n = 19 patients), from patients
      with advanced CaP without cachexia (n = 17 patients), and from patients with
      cachectic CaP (n = 26 patients). DPC Immulite and Abbott IMx Total-PSA assays
      were used to determine cytokine and PSA levels, respectively. RESULTS: Levels of
      TNFalpha, IL-6, and IL-8 were elevated significantly in the group of patients
      with advanced, cachectic CaP compared with patients who were without cachexia. In
      the cachectic patients, levels of TNFalpha were correlated positively with IL-8,
      and there was no correlation between PSA levels and any of the cytokine levels.
      IL-1beta levels were below the limit of detection in all samples. CONCLUSIONS:
      The current results show that levels of TNFalpha, IL-6, and IL-8 were increased
      in CaP patients with cachexia. Increased levels of these cytokines were not
      correlated with PSA levels, suggesting that they are regulated by a mechanism
      that is independent of PSA synthesis. Additional fundamental research is needed
      to determine the mechanisms involved and to identify potential therapeutic
      targets in patients with cachexia.

PMID- 12599228
TI  - High-dose weekly oral calcitriol in patients with a rising PSA after
      prostatectomy or radiation for prostate carcinoma.
AB  - BACKGROUND: In preclinical systems, calcitriol, the natural vitamin D receptor
      (VDR) ligand, has been found to demonstrate antiproliferative effects, although
      concentrations > 1 nM are required. Unlike daily dosing, weekly administration of
      oral calcitriol can safely achieve such blood calcitriol concentrations. This
      study sought to define the long-term toxicity of this regimen and measure its
      effect on serum prostate specific antigen (PSA) levels in patients with hormone
      naive prostate carcinoma. METHODS: Patients with a rising serum PSA after
      prostatectomy and/or radiation and no prior systemic therapy for prostate
      carcinoma recurrence maintained a reduced calcium diet and received calcitriol
      0.5 microg/kg orally once each week until a maximum of a four-fold increase in
      the PSA. RESULTS: Twenty-two patients received treatment for a median of 10
      months (range, 2-25+ months). Treatment was well tolerated with no Grade >or= 3
      toxicity and no hypercalcemia or renal calculi. No patient had a PSA response
      (50% reduction confirmed 4 weeks later). Three patients (14%, 95% CI 0-28%) had
      confirmed reductions in the PSA ranging from 10% to 47%. Statistically
      significant increases in the PSA doubling time (PSADT) were seen in three
      additional patients and no patient had a shorter PSADT after starting treatment.
      For the entire study population, the median PSADT increased from 7.8 months to
      10.3 months (P = 0.03 by Wilcoxon signed rank test). CONCLUSIONS: Weekly high
      dose calcitriol was found to be safe. The primary efficacy endpoint of 50%
      reduction in the serum PSA was not achieved with this therapy. Randomized studies
      are needed to further examine the impact of this therapy on prostate carcinoma
      progression.

PMID- 12599229
TI  - Caveolin-1 expression is a predictor of recurrence-free survival in pT2N0
      prostate carcinoma diagnosed in Japanese patients.
AB  - BACKGROUND: The authors previously identified elevated caveolin-1 expression in
      human prostate carcinoma and determined that caveolin-1 levels as detected by
      immunohistochemistry of radical prostatectomy specimens offered novel prognostic
      information. A higher incidence of caveolin-1 expression also was reported in
      African-American men compared with white men in the U.S. To explore these
      ethnic/racial differences in caveolin-1 expression further, the authors evaluated
      caveolin-1 expression as a predictive marker in Japanese men with prostate
      carcinoma. METHODS: Immunohistochemical staining with a caveolin-1 specific
      antibody was performed on routinely processed paraffin sections from 152
      consecutively collected radical prostatectomy specimens. The mean patient age was
      64.3 years (range, 49-74 years; median, 64.5 years) and the mean follow-up period
      was 49.5 months (range, 1.3-103.3 months; median, 48.2 months). Caveolin-1
      immunoreactivity was evaluated in association with patient's age; preoperative
      prostate specific antigen level; clinical stage; and pathologic features
      including Gleason score, extraprostatic extension, status of surgical margins,
      seminal vesicle involvement, lymph node involvement, and time to disease
      progression after surgery. RESULTS: Positive caveolin-1 immunostaining was
      detected in 46 of the 152 tumors (30.3%) and was found to be associated
      significantly with a positive surgical margin (P = 0.022). A higher incidence of
      caveolin-1 expression tended to be found in patients with poorly differentiated
      tumors (Gleason score > 7, 6-7, and < 6, 35.0% vs. 34.9% vs. 20.4%, respectively)
      or in patients with extraprostatic extension versus those without extraprostatic
      extension (35.4% vs. 24.7%) or patients with lymph node involvement compared with
      those without lymph node involvement (50% vs. 29.5%), although these differences
      did not reach statistical significance (P = 0.100, P = 0.150, and P = 0.178,
      respectively, by the Spearman correlation test). Kaplan-Meier analysis revealed
      that increased caveolin-1 expression was associated with an increased risk of
      disease progression at 5 years (P = 0.0122 by the log-rank test). In patients
      with organ-confined (pT2N0) disease, univariate Cox proportional hazards
      regression analysis revealed that positive caveolin-1 expression was the only
      significant predictor of disease recurrence after radical prostatectomy (P =
      0.011; hazards ratio = 4.75; and 95% confidence interval, 1.43-15.76).
      CONCLUSIONS: The results of the current study confirm that positive caveolin-1
      expression is associated with clinical markers of disease progression and is
      predictive of poor clinical outcome after surgery in Japanese patients with pT2N0
      prostate carcinoma.

PMID- 12599230
TI  - A randomized trial of liposomal daunorubicin and cytarabine versus liposomal
      daunorubicin and topotecan with or without thalidomide as initial therapy for
      patients with poor prognosis acute myelogenous leukemia or myelodysplastic
      syndrome.
AB  - BACKGROUND: Because angiogenesis may play a role in the pathogenesis of acute
      myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and
      thalidomide (Th) has shown significant anti-angiogenic activity, this study was
      designed to investigate the potential role of Th in the treatment of patients
      with AML and MDS and the possible role of a non-ara-C-containing regimen.
      METHODS: Adults with AML or high-risk MDS and cytogenetic abnormalities other
      than inv (16), t(8;21), -Y or -X were randomized to receive liposomal
      daunorubicin (DNX) and ara-C (DA) or DNX and topotecan (DT). Within each arm,
      patients were randomized to receive chemotherapy alone (DA or DT) or with
      thalidomide (DATh or DTTh). Vascular endothelial growth factor (VEGF) plasma
      levels and microvascular density was measured before and after therapy. Eighty
      four patients (median age, 65 years; range, 27-84 years) were treated. RESULTS:
      None of 11 patients treated with DT or DTTh responded and these arms were closed.
      Seventeen of 37 patients treated with DA and 15 of 36 treated with DATh achieved
      an early complete remission. Median complete response duration was 38 and 34
      weeks (P = 0.57) and median survival 35 and 28 weeks (P = 0.15), respectively.
      Patients with high pretreatment VEGF levels had an inferior survival. There was
      no significant difference in the changes in VEGF levels or microvascular density
      after treatment in patients who did versus those who did not receive thalidomide.
      CONCLUSIONS: The authors concluded that thalidomide in combination with
      chemotherapy does not result in clinical benefit in patients with AML or high
      risk MDS.

PMID- 12599231
TI  - Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and
      cyclophosphamide plus allogeneic transplantation for the treatment of patients
      with leukemias.
AB  - BACKGROUND: Decitabine is a hypomethylating agent that has activity in patients
      with leukemia. The authors combined decitabine with busulfan and cyclophosphamide
      as a conditioning regimen prior to allogeneic hematopoietic stem cell
      transplantation. METHODS: Patients with high-risk acute myeloid leukemia (AML) (n
      = 12 patients); chronic myelomonocytic leukemia (CMML) (n = 1 patient); acute
      lymphocytic leukemia (ALL) (n = 1 patient); or late chronic phase, accelerated,
      or blastic phase chronic myelogenous leukemia (n = 9 patients) were eligible for
      the study. The treatment plan was comprised of busulfan, 12 mg/kg orally;
      cyclophosphamide, 100 mg/kg (n = 4 patients) or 120 mg/kg (n = 19 patients); and
      decitabine, intravenously at 3 dose levels: 400 mg/m(2) (n = 10 patients), 600
      mg/m(2) (n = 8 patients), and 800 mg/m(2) (n = 5 patients). Donors were human
      leukocyte antigen-identical siblings in all cases, and all but one patient
      received peripheral blood stem cells. Graft-versus-host disease (GVHD)
      prophylaxis was tacrolimus based in all but one patient. RESULTS: The median time
      to neutrophil and platelet engraftment was 12.5 days and 17.5 days, respectively.
      Twenty-one patients were engrafted and achieved disease remission. At a median of
      3.3 years posttransplantation, 26% of patients (40% of patients with AML) were
      alive and disease free. The median survival for the group was 17.2 months, and
      the disease free survival for the group was 8.9 months. Causes of death were
      disease recurrence (nine patients), chronic GVHD (four patients), infections
      (three patients), and acute GVHD (one patient). The 100-day mortality rate was
      9%. No decitabine dose-limiting toxicity was documented. The treatment-related
      mortality rate at 3 years was 35%. Responders were treated at all three
      decitabine dose levels, and no dose-response correlation was observed.
      CONCLUSIONS: There was a high response rate with low treatment-related mortality,
      with 26% of patients alive in remission 3.3 years after transplantation.

PMID- 12599232
TI  - Increased telomerase activity is associated with shorter survival in patients
      with chronic phase chronic myeloid leukemia.
AB  - BACKGROUND: Significantly elevated telomerase activity (TA) has been found in
      samples from patients with many malignant hematologic diseases. However, the
      impact of elevated TA on the course of patients with chronic phase chronic
      myeloid leukemia (CP-CML) is unknown. METHODS: Using a modified polymerase chain
      reaction-based telomeric repeat amplification protocol assay, the authors
      measured TA in bone marrow samples from 93 patients with CP-CML and correlated it
      with patient characteristics and survival. TA also was measured in bone marrow
      samples from 29 patients with accelerated/blastic phase CML. RESULTS: Patients
      with accelerated/blastic phase CML were found to have somewhat higher levels of
      TA compared with patients with CP-CML (P = 0.07). Among patients with CP-CML,
      those with high TA progressed to advanced stages of disease sooner (P = 0.05) and
      had a significantly shorter survival (P = 0.04) than patients with low TA. No
      correlation was found between TA and patient age, hemoglobin, platelet and
      leukocyte counts, percentage of peripheral or bone marrow blasts or basophils, or
      bone marrow cellularity. On multivariate analysis, high TA retained its
      significance as a factor associated with shorter patient survival (P = 0.02).
      CONCLUSIONS: The current study data suggest that TA plays a role in the
      propagation of CP-CML and that the potential of telomerase inhibitors in patients
      with CML should be explored, even in those with early phase disease.

PMID- 12599233
TI  - Risk factors for local recurrence of small hepatocellular carcinoma tumors after
      a single session, single application of percutaneous radiofrequency ablation.
AB  - BACKGROUND: The objectives of this study were to clarify risk factors for local
      tumor recurrence and to determine which patients with hepatocellular carcinoma
      (HCC) are most suitable for a single session, single application of percutaneous
      radiofrequency (RF) ablation. METHODS: Fifty-six consecutive patients with 65 HCC
      tumors measuring <or= 3 cm in greatest dimension who received a single session,
      single application of percutaneous RF ablation and who achieved optimal tumor
      ablation, as assessed by an immediate computed tomography scan, were enrolled in
      this study. Six possible factors for local recurrence were analyzed using a Cox
      proportional hazards regression model: tumor size, tumor location, proximity of
      the tumor to intrahepatic large vessels, types of electrodes used, prior
      treatment, and observation of impedance rises. Local recurrence free intervals
      were estimated using the Kaplan-Meier method, and differences between groups were
      compared using the log-rank test. RESULTS: The Kaplan-Meier estimates of overall
      cumulative local recurrence free intervals after a single RF ablation treatment
      were 76% (95% confidence interval [95%CI], 70.9-81.7%) at 12 months and 74%
      (95%CI, 68.2-79.6%) at 15 months. The log-rank test revealed a statistically
      significant difference between the local recurrence free intervals according to
      tumor size (P = 0.001) and tumor location (P < 0.001). Further investigation with
      a Cox regression analysis indicated that a greatest tumor dimension > 2 cm (risk
      ratio [RR], 4.9; 95%CI, 1.3-16.4; P = 0.019) and subcapsular location (RR, 5.2;
      95%CI, 1.7-16.6; P = 0.005) were associated independently with local recurrence.
      The other four factors were not associated with local recurrence in this study.
      CONCLUSIONS: A single session, single application of RF ablation produced
      favorable local control. Patients who have nonsubcapsular HCC tumors measuring
      <or= 2 cm in greatest dimension may be the most suitable candidates for a single
      session, single application of RF ablation.

PMID- 12599234
TI  - Chromosomal aberrations of primary lung adenocarcinomas in nonsmokers.
AB  - BACKGROUND: Lung carcinoma is a common malignancy, and tobacco carcinogenesis is
      the major cause. Studies on individual genes or loci have suggested, that in
      tumors from nonsmokers, different genetic alterations are present compared with
      tumors from smokers. It is possible that distinct genetic pathways may be
      involved. However, the targets remain largely unknown; and, to the authors'
      knowledge, molecular cytogenetics studies on lung carcinomas from nonsmokers have
      not been reported. METHODS: Comparative genomic hybridization (CGH) analysis was
      performed on primary lung adenocarcinoma samples from 32 patients who never
      smoked to identify loci of frequent aberrations. RESULTS: Different extents of
      aberration were found in 31 of the 32 samples studied. The most frequently
      altered locus was gain of 16p (59% of samples) followed by gain of 20q (44% of
      samples), with the minimal overlapping regions at 16p13.1-p13.2 and 20q13.2,
      respectively. Other over-represented loci with > 30% frequency were observed at
      5p (34% of samples), 7p (41% of samples), 8q (31% of samples), 17q (34% of
      samples), and 19q (34% of samples); and high-level DNA amplifications were
      detected at 1q, 7p, 12q, 19q, and 20q. DNA under-representation was observed less
      commonly and included 8p (28% of samples), 9p (22% of samples), 13q (28% of
      samples), and 18q (38% of samples). CONCLUSIONS: The current study identified
      targets of frequent genetic aberration in primary adenocarcinomas from
      nonsmokers. Compared with reported CGH findings in the literature, the current
      findings suggest that DNA gain at 16p is the distinct aberration involved in
      these tumors. Other frequently altered loci involve commonly reported oncogenic
      and tumor suppressor loci, suggesting an overlap with the genetic pathways of
      tobacco-induced lung carcinogenesis.

PMID- 12599235
TI  - Overdiagnosis in chest radiographic screening for lung carcinoma: frequency.
AB  - BACKGROUND: The pattern of results in the Mayo Lung Project (MLP), which is the
      basis for the prevailing recommendations against radiographic screening for lung
      carcinoma, has led to the assertion that up to 50% of the diagnosed cases of
      early-stage disease in that trial may have represented overdiagnosed, indolent
      cases. This finding suggests the possibility of such a high frequency of
      overdiagnosis in chest radiographic lung carcinoma screening in general. In the
      current study, the authors analyzed data from the MLP and its counterpart study
      at Memorial Sloan-Kettering Cancer Center (MSK) to estimate the frequency of
      overdiagnosis in these studies. METHODS: For the cases diagnosed as Stage I in
      the MLP and the MSK studies, the doubling times of tumor volumes were calculated.
      The calculations were based on size measurements recorded by the original
      investigators from chest radiographs taken during the course of each study.
      RESULTS: The median doubling times were 101 days in the MLP and 144 days in the
      MSK, times that are somewhat shorter than those reported in published series of
      adenocarcinoma cases diagnosed outside screening, and only 5% had doubling times
      exceeding 400 days. CONCLUSIONS: The hypothesis that early-stage lung tumors
      diagnosed on chest radiography during lung carcinoma screening may frequently be
      overdiagnosed, indolent cases needs to be rejected.

PMID- 12599236
TI  - Chromosomal anomalies in oligodendroglial tumors are correlated with clinical
      features.
AB  - BACKGROUND: Patients who have oligodendrogliomas (OD) that demonstrate loss of
      both 1p and 19q appear to have a better prognosis after they receive chemotherapy
      and radiotherapy compared with patients who have OD without these
      characteristics. It is unclear whether this improvement in outcome is due only to
      a better response to treatment. The authors investigated the correlation between
      genetic and clinical characteristics of OD in 33 patients who received
      chemotherapy with procarbazine, lomustine, and vincristine for recurrent disease
      after receiving radiotherapy. METHODS: The initial presentation, prior
      treatments, overall survival, and response to chemotherapy were assessed. The 1p
      and 19q status in OD lesions was determined with fluorescence in situ
      hybridization on paraffin embedded, archival material using locus specific
      probes. P53 mutations were assessed by polymerase chain reaction-single-strand
      conformation polymorphism analysis and immunohistochemistry for P53; the
      proliferation index was assessed with the MIB-1 antibody. RESULTS: Patients who
      had OD lesions with a combined loss of 1p and 19q typically presented with low
      grade tumors that manifested with seizures of long-standing duration. In
      contrast, patients who had OD lesions without a combined loss of 1p and 19q
      usually presented with focal deficits that required immediate treatment. Both the
      response rate to chemotherapy and the time to disease progression after
      chemotherapy were significantly better in patients who had a combined loss of 1p
      and 19. Tumors with classic OD morphology more often had a combined loss of 1p
      and 19q, although the genotype was better at identifying patients with
      chemoresponsive tumors. P53 mutations were observed in three tumors, none of
      which had a combined loss of 1p and 19q. CONCLUSIONS: OD lesions with combined a
      loss of 1p and 19q have a more indolent nature compared with OD lesions that do
      not have these losses. Virtually all patients with these tumors present with low
      grade tumors accompanied by seizures and remain stable for prolonged periods.
      Future trials must keep these tumor types apart.

PMID- 12599237
TI  - Extraskeletal myxoid chondrosarcoma: a Multi-Institutional Study of 42 Cases in
      Japan.
AB  - BACKGROUND: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant
      neoplasm. Despite a consensus for the distinct clinicopathologic entity of EMC,
      its clinical features remain controversial. In addition, most studies have
      contained a small number of patients who underwent definitive surgical treatment.
      METHODS: Forty-two cases of EMC, which had been identified from files of eight
      affiliated hospitals and confirmed for histologic diagnosis at the Pathology
      Center, were analyzed for histologic grade, demographics, treatments, outcomes,
      and prognostic factors. The average follow-up period was 7.4 years. RESULTS:
      Included in the study were 20 men and 22 women with a mean age at diagnosis of
      52.1 years. The tumors were located mainly in the lower extremities (69%). Thirty
      three tumors (79%) were classified as Grade 1 and nine as Grade 2 according to
      the modified French System. Overall survival was 100% at 5 years and 88% at 10
      years. Disease-free survival was 45% at 5 years and 36% at 10 years. Inadequate
      initial surgery was defined as a significant risk factor for local recurrence by
      univariate analysis of all 42 patients but not by the analysis of those 30
      patients who had undergone wide tumor excision or amputation. Wide excision led
      to the recurrence rate of 14%. CONCLUSIONS: These findings supported the role of
      wide excision in the local control of EMC, irrespective of the previous excision
      procedure or recurrence. The protracted clinical course of the tumors and the
      presence of patients who had distant metastasis develop after definitive surgery
      of the primary tumor represented EMC as intermediate malignancy.

PMID- 12599238
TI  - Mammography screening among Chinese-American women.
AB  - BACKGROUND: Breast carcinoma is the most common major malignancy among several
      Asian-American populations. This study surveyed mammography screening knowledge
      and practices among Chinese-American women. METHODS: In 1999, the authors
      conducted a cross-sectional, community-based survey in Seattle, Washington.
      Bilingual and bicultural interviewers administered surveys in Mandarin,
      Cantonese, or English at participants' homes. RESULTS: The survey cooperation
      rate (responses among reachable and eligible households) was 72% with 350
      eligible women (age >or= 40 years with no prior history of breast carcinoma or
      double mastectomy). Seventy-four percent of women reported prior mammography
      screening, and 61% of women reported screening in the last 2 years. In
      multivariate analysis, a strong association was found between mammography
      screening and recommendations by physicians and nurses (prior screening: odds
      ratio [OR], 16.0; 95% confidence interval [95% CI], 7.8-35.0; recent screening:
      OR, 7.0; 95% CI, 3.8-13.6). This finding applied to both recent immigrants (< 15
      years in the U.S.) and earlier immigrants (>or= 15 years in the U.S.). Thirty-two
      percent of women reported that the best way to detect breast carcinoma was a
      modality other than mammogram. CONCLUSIONS: The authors recommend a multifaceted
      approach to increase mammography screening by Chinese-American women:
      recommendations from the provider plus targeted education to address the
      effectiveness of screening mammography compared with breast self examination and
      clinical breast examination.

PMID- 12599239
TI  - Socioeconomic status and breast carcinoma survival in four racial/ethnic groups:
      a population-based study.
AB  - BACKGROUND: Although overall survival for invasive breast carcinoma remains high,
      black women experience poorer survival than whites. Less is known about the
      survival of Hispanics and Asians, who may share clinical and socioeconomic risk
      factors similar to blacks. To better understand racial/ethnic survival patterns,
      we investigated the effect of socioeconomic status (SES) and disease stage on
      racial/ethnic differences in breast carcinoma survival in a large population
      based cohort. METHODS: Using data from the Surveillance, Epidemiology, and End
      Results program (SEER), we identified 10,414 white, 940 black, 1100 Hispanic, and
      1180 Asian females diagnosed with breast carcinoma in the Greater San Francisco
      Bay Area between 1988 and 1992. We used the Kaplan-Meier method to generate
      survival rates and Cox proportional hazards regression to estimate the risk of
      death by race/ethnicity, after adjustment for clinical, demographic, and census
      derived SES variables. RESULTS: The 10-year unadjusted survival rates were 81%
      for whites, 69% for blacks, 75% for Hispanics, and 79% for Asians. Adjusting for
      stage decreased the relative risk of mortality for blacks from 1.81 to 1.29; the
      stage-adjusted relative risk for Hispanics (1.11) and Asians (1.02) did not
      differ significantly from whites. Additional adjustment for age, tumor
      characteristics, and treatment factors did little to alter the relative risk in
      blacks; adding blue-collar status to the model further decreased the relative
      risks for blacks to 1.22. Residing in a blue-collar neighborhood was
      independently associated with a 1.16 increase in risk of death. CONCLUSIONS:
      After adjustment for multiple factors, blacks continue to have slight but
      significantly poorer survival after breast carcinoma compared with whites,
      whereas the survival of Hispanics and Asians did not differ from whites.

PMID- 12599240
TI  - A randomized, active-control, pilot trial of front-loaded dosing regimens of
      darbepoetin-alfa for the treatment of patients with anemia during chemotherapy
      for malignant disease.
AB  - BACKGROUND: Anemia in patients receiving chemotherapy can be ameliorated with
      recombinant human erythropoietin (rHuEPO), which is administered one to three
      times per week. Darbepoetin alpha, a new erythropoietic agent, has longer serum
      residence time, allowing it to be administered less frequently. METHODS: Patients
      (n = 127) were randomized to receive study drug for 12 weeks: either rHuEPO
      40,000 U with escalations to 60,000 U for nonresponders or darbepoetin alpha at
      doses of 4.5 microg/kg per week until hemoglobin concentration >or= 12 g/dL, then
      1.5 microg/kg per week (Group 1); 4.5 microg/kg per week for 4 weeks, then 2.25
      microg/kg per week for 8 weeks (Group 2); or 4.5 microg/kg per week for 4 weeks,
      then 3.0 microg/kg every 2 weeks (Group 3). Efficacy was measured using the mean
      change in hemoglobin level, the proportion of patients achieving a hemoglobin
      response, the time to response, and the mean change in Functional Assessment of
      Cancer Therapy-Fatigue Scale scores. Safety was assessed by reports of adverse
      events. RESULTS: Overall, after 4 weeks of treatment, the mean change (95%
      confidence interval [95%CI]) in hemoglobin concentration was 0.53 g/dL (95%CI,
      0.05-1.02 g/dL), 0.70 g/dL (95%CI, 0.11-1.29 g/dL), and 0.90 g/dL (95%CI, 0.47
      1.33 g/dL) in darbepoetin alpha Groups 1, 2, and 3, respectively, and 0.39 g/dL
      (95%CI, - 0.22-1.00 g/dL) in the rHuEPO group. By the end of the study, the mean
      change (95%CI) in hemoglobin concentration was 1.35 g/dL (95%CI, 0.67-2.02 g/dL),
      1.35 g/dL (95%CI, 0.57-2.12 g/dL), and 1.28 g/dL (95%CI, 0.84-1.73 g/dL) in
      darbepoetin alpha Groups 1, 2, and 3, respectively, and 1.03 g/dL (95%CI, 0.53
      1.53 g/dL) in the rHuEPO group. The early erythropoietic response in patients who
      were treated with darbepoetin alpha was associated with an early and maintained
      reduction in patient-reported fatigue. The adverse event profile was comparable
      with all doses of darbepoetin alpha and rHuEPO. CONCLUSIONS: Darbepoetin alpha,
      given as a front-loaded dose for 4 weeks and followed by lower and/or less
      frequent doses, appears to be efficacious and may decrease the time to response
      relative to treatment with rHuEPO.

PMID- 12599241
TI  - Ki-67 expression in breast carcinoma: its association with grading systems,
      clinical parameters, and other prognostic factors--a surrogate marker?
AB  - BACKGROUND: The number of mitoses and, thus, the proliferative capacity of a
      tumor is one of the most crucial variables for tumor grading. The Ki-67 nuclear
      antigen may be considered as an alternative to mitotic counts in grading schemes
      and as a single parameter that can be used in fine-needle aspirates and small
      biopsies. METHODS: Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was
      performed on 434 breast carcinoma specimens from the International Breast Cancer
      Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were
      used to replace the mitotic counts component in the Nottingham grade (NHG) to
      produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single
      parameter. RESULTS: In both the lymph node positive subgroup and the lymph node
      negative subgroup, the NKG and Ki-67 group was correlated significantly with
      Bloom-Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph
      node negative cohort and estrogen receptor status, progesterone receptor status,
      and c-erbB-2 expression in the lymph node positive cohort also were correlated
      significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB
      2 expression in the lymph node positive cohort only. NKG was similar to BRG and
      NHG when it was evaluated for prognostic significance. Patients with higher
      categoric Ki-67 percentages had worse overall and disease free survival in all
      groups except for the untreated, lymph node negative group. CONCLUSIONS: Ki-67
      detection represents a valuable tool and is a good objective substitute for
      mitotic counts when used in a grading system. When it is used alone, Ki-67
      detection provides valuable information, although it is necessary to combine this
      with other parameters in the study of core biopsies and fine-needle aspirates.

PMID- 12599242
TI  - Second malignancies in children with neuroblastoma after combined treatment with
      131I-metaiodobenzylguanidine.
AB  - BACKGROUND: (131)I-metaiodobenzylguanidine ((131)I-MIBG) is selectively taken up
      by cells of neural crest origin, allowing targeted radiotherapy of tumors such as
      neuroblastoma (NB) and pheochromocytoma. Radiotherapy may provide additional
      benefits in the treatment of NB, with moderate side effects such as hematologic
      and thyroid toxicity. However, with longer follow-up, other complications might
      occur. We describe our experience with second cancers occurring in children
      treated with (131)I-MIBG and chemotherapy. METHODS: The clinical records of 119
      consecutive NB cases treated with (131)I-MIBG at a single institution between
      1984 and 2001 were reviewed for the occurrence of a second malignant neoplasm
      (SMN). RESULTS: Overall, five cases of SMN occurred in the study patients. In
      particular, two cases of myeloid leukemia, one of angiomatous fibrous
      histiocytoma, one of malignant schwannoma, and one case of rhabdomyosarcoma were
      detected. The schwannoma and the rhabdomyosarcoma developed within the residual
      neuroblastic mass after first-line therapy. CONCLUSIONS: Should (131)I-MIBG
      treatment become more broadly employed in the therapeutic strategy for
      neuroblastoma, the risk of second cancer will have to be taken into
      consideration. The organization of an international registry of subjects treated
      with (131)I-MIBG might better define the frequency and features of second
      malignancies following this radiometabolic approach.

PMID- 12599243
TI  - Childhood cancer patients' access to cooperative group cancer programs: a
      population-based study.
AB  - BACKGROUND: The Children's Oncology Group (COG), a merger of the Children's
      Cancer Group (CCG) and the Pediatric Oncology Group (POG), conducts clinical
      trials for the treatment of childhood cancer. To assess the feasibility of
      developing a nationwide childhood cancer registry, the authors attempted to
      determine whether COG could serve as a resource for identifying all children with
      cancer. METHODS: A consolidated file of children age < 20 years who were
      diagnosed with cancer between 1992-1997 and registered with either CCG or POG was
      linked with records from the National Cancer Institute's Surveillance,
      Epidemiology and End Results (SEER) Program. Age-specific registration rates and
      age-adjusted registration rates (AARR) were calculated overall and by year of
      diagnosis, gender, race/ethnicity, stage of disease at diagnosis, and type of
      cancer. RESULTS: Of 10,108 children age < 20 years with cancer who were
      identified by the 11 SEER registries between 1992-1997, 5796 were registered with
      CCG or POG. The AARR was 71% for children age < 15 years, 24% for adolescents
      ages 15-19 years, and 57% for children age < 20 years. Registration rates were
      stable over the years studied, varied by geographic region, and were found to be
      higher among children with more advanced disease. Registration rates were highest
      for children with leukemia, hepatic tumors, and renal tumors, and were lowest for
      carcinoma and retinoblastoma. CONCLUSIONS: The results of the current study
      demonstrate that not all children with cancer are registered by the cooperative
      groups; however, a national registry program can be achieved by supplementing
      cases identified through COG with data collected by statewide population-based
      cancer registries. Such a partnership would be mutually beneficial, allowing COG
      to achieve 100% registration of children with cancer and, for the statewide
      cancer registries, improving the timeliness of case-finding and follow-up
      information for cancer outcomes.

PMID- 12599244
TI  - Intraoperative and conformal external-beam radiation therapy with protracted 5
      fluorouracil infusion in patients with locally advanced pancreatic carcinoma.
AB  - BACKGROUND: Chemoradiotherapy is widely used for patients with locally advanced
      pancreatic carcinoma. The purpose of this study was to clarify the efficacy and
      feasibility of chemoradiotherapy with more intensive radiotherapy in these
      patients, using a combination of intraoperative radiotherapy (IORT), conformal
      external-beam radiaotherapy (EBRT), and protracted 5-fluorouracil (5-FU).
      METHODS: Thirty patients with unresectable locally advanced pancreatic carcinoma
      were enrolled in this Phase II study. The treatment consisted of IORT (25 grays
      [Gy]), followed by EBRT (40 Gy in 20 fractions, 5 times per week), and concurrent
      protracted 5-FU infusion (200 mg/m(2)), beginning 2-4 weeks after IORT. The
      authors evaluated the efficacy and adverse effects of this treatment by following
      up patients for 12.0-28.1 months. Survival from the date of IORT was calculated
      using the Kaplan-Meier method. RESULTS: In 11 of the 30 patients, metastatic
      spread was detected in the abdominal cavity at laparotomy. The full EBRT dose was
      administered in 28 of the 30 patients. Of the remaining 2 patients, EBRT was
      terminated at 8 Gy due to progression of brain metastasis and another patient did
      not receive EBRT or chemotherapy due to massive ascites after IORT. The overall
      response rate for primary pancreatic tumor on dynamic computed tomography scan
      was 23.3% (7 partial responses). Grade 3 or 4 toxicity (according to the National
      Cancer Institute Common Toxicity Criteria) was observed in 15 of the 28 patients
      who received the full irradiation dose (53.6%). These included anorexia, nausea,
      emesis, fatigue, leukopenia, and/or elevation of transaminase levels. There were
      no directly treatment-related deaths, but 1 patient died of hepatic failure
      related to late effects of irradiation after 25.6 months. The median survival
      time of the 30 patients was 7.8 months and the 2-year survival rate was 8.1%. The
      median survival time of the 19 patients without metastatic spread in the
      abdominal cavity was 12.9 months and that of the 11 patients with metastatic
      spread was 5.8 months. CONCLUSIONS: The present regimen of chemoradiotherapy is
      not superior to conventional chemoradiotherapy (EBRT and 5-FU) for patients with
      locally advanced pancreatic carcinoma.

PMID- 12599245
TI  - Oral pseudotumor: benign polypoid masses following radiation therapy.
AB  - BACKGROUND: The current study evaluated postirradiation pseudotumor in the oral
      cavity to investigate clinical and pathologic characteristics and incidence
      rates. METHODS: Between 1960 and 1999, 2719 patients with squamous cell carcinoma
      of the oral cavity were treated with radiation therapy at Tokyo Medical and
      Dental University Hospital. Of these, six patients developed clinically polypoid
      tumors pathologically diagnosed as pseudotumors. Histopathology, immunohistology,
      and the clinical courses of these lesions were investigated. RESULTS: Spindled
      fibroblastic cells arranged in whorled patterns were common pathologic features.
      Immunohistochemical results showed reactivity for vimentin and smooth muscle
      actin and nonreactivity for cytokeratin. The latent period from the initial
      radiation therapy to the development of the pseudotumor ranged from 45 to 145
      months (median, 79 months). The overall cumulative incidence of pseudotumor was
      0.22% during the 40 year period. All six patients were cured with simple
      excisions. CONCLUSIONS: Oral carcinoma patients treated with radiation therapy
      may develop pseudotumor in a low frequency with a shorter period than that of
      radiation induced carcinoma/sarcoma. Pseudotumor was curable with surgery.
      Pseudotumor should be added to the list of differential diagnosis for
      postirradiation oral polypoid masses.

PMID- 12599246
TI  - Nitric oxide suppression triggers apoptosis through the FKHRL1 (FOXO3A)/ROCK
      kinase pathway in human breast carcinoma cells.
AB  - BACKGROUND: The winged helix/forkhead transcriptional factor FKHRL1 (FOXO3a)
      triggers apoptosis, but its mode of action is not well understood. ROCK kinase is
      an effector molecule in human breast carcinoma cell apoptosis, but its relation
      to FKHRL1 is unknown. Because the human breast carcinoma T47D cell line releases
      a great amount of nitric oxide (NO), I investigated signaling of FKHRL1/ROCK
      [corrected] kinase during NO suppression. METHODS: Expression of phosphorylated
      FKHRL1 in T47D cells was analyzed using Western blotting. Apoptosis was evaluated
      by flow cytometry. Transfection of FKHRL1-HA wild-type and mutant FKHRL1-HA T32A
      constructs were performed by lipofectamine plus reagent. Measurement of NO
      generation was performed by Griess reaction. RESULTS: Nitric oxide suppression
      promotes FKHRL1 thr-32-enhanced phosphorylation, which was significantly (P <
      0.005) sensitive to Y-27632, a specific inhibitor of the ROCK kinase, but not to
      capase-3 inhibitor or wortnannin, a specific inhibitor of phosphoinositol-3-OH
      kinase (PI3K). Nitric oxide suppression by N-(G)-monomethyl-L-arginine, an
      inhibitor of NO synthase, causes a significant (P < 0.001) increase in the
      apoptosis of T47D cells. However, a significant decrease (P < 0.01) in NO
      generation and a significant (P < 0.01) increase in apoptosis were observed when
      FKHRL1-HA wild-type cells were transfected, which caused increased FKHRL1 thr-32
      phosphorylation. CONCLUSIONS: This novel unknown phenomenon of breast carcinoma
      cell apoptosis was triggered by NO suppression, which promotes FKHRL1 thr-32
      enhanced phosphorylation and initiates signaling of FKHRL1 to ROCK kinase as an
      effector molecule. This apoptotic signalling process is caspase-3 as well as
      PI3K/Akt independent.

PMID- 12599247
TI  - Pathologic analysis of tumor size and lymph node status in
      multifocal/multicentric breast carcinoma.

PMID- 12599251
TI  - Formation of steady-state oxygen gradients in vitro: application to liver
      zonation.
AB  - We have developed a perfusion bioreactor system that allows the formation of
      steady state oxygen gradients in cell culture. In this study, gradients were
      formed in cultures of rat hepatocytes to study the role of oxygen in modulating
      cellular functions. A model of oxygen transport in our flat-plate reactor was
      developed to estimate oxygen distribution at the cell surface. Experimental
      measurements of outlet oxygen concentration from various flow conditions were
      used to validate model predictions. We showed that cell viability was maintained
      over a 24-h period when operating with a physiologic oxygen gradient at the cell
      surface from 76 to 5 mmHg O(2) at the outlet. Oxygen gradients have been
      implicated in the maintenance of regional compartmentalized metabolic and
      detoxification functions in the liver, termed zonation. In this system,
      physiologic oxygen gradients in reactor cultures contributed to a heterogeneous
      distribution of phosphoenolpyruvate carboxykinase (predominantly localized
      upstream) and cytochrome p450 2B (predominantly localized downstream) that
      correlates with the distribution of these enzymes in vivo. The oxygen gradient
      chamber provides a means of probing the oxygen effects in vitro over a continuous
      range of O(2) tensions. In addition, this system serves as an in vitro model of
      zonation that could be further extended to study the role of gradients in
      ischemia-reperfusion injury, toxicity, and bioartificial liver design.

PMID- 12599252
TI  - Effects of intermittent addition of cellulase for production of L-lactic acid
      from wastewater sludge by simultaneous saccharification and fermentation.
AB  - An attempt was made to create L-lactic acid, a precursor of poly-lactic acid,
      which is a biodegradable plastic, from wastewater sludge from the paper
      manufacturing industry. The sludge contained a high percentage of cellulose and
      needed to be hydrolyzed to glucose by the action of the cellulase before being
      treating with lactic acid bacteria. Therefore, a method involving simultaneous
      saccharification and fermentation (SSF) was carried out. The optimum pH of the
      SSF for production of the lactic acid by the newly isolated lactic acid bacterium
      with a high selectively of L-lactic acid was found out to be around pH = 5.0, and
      the optimum temperature to be approximately 40 degrees C. On the basis of the
      measurement of the cell density changes in the lactic acid bacteria, it was
      ascertained that the bacterial activity could continue at a high level for a
      relatively long period of time, and that the L-lactic acid productivity was
      diminished by the rapid deactivation of the cellulase. With the intermittent
      addition of cellulase once daily for the sake of compensating for the cellulase
      deactivation, the L-lactic acid attained a maximum concentration of 16.9 g/L,
      i.e., a 72.2% yield based on the potential glucose contained in the sludge under
      optimum pH and temperature conditions.

PMID- 12599253
TI  - Characterization of an oxygen-dependent inducible promoter, the Escherichia coli
      nar promoter, in gram-negative host strains.
AB  - The Escherichia coli nar promoter is maximally induced under anaerobic conditions
      in the presence of nitrate ion or under anaerobic only conditions, depending on
      the genotype of the E. coli nar promoter. Previously, we found that the E. coli
      nar promoter has some desirable characteristics as an inducible promoter in the
      E. coli host strains. In this study, the E. coli nar promoter with lacZ gene at
      the downstream was cloned onto a broad-host-range Gram-negative vector, pBBR122.
      It was then induced in some other Gram-negative host strains, such as
      Agrobacterium, Pseudomonas, and Rhizobium, to determine whether the E. coli nar
      promoter could be used as an inducible promoter in these strains. From shake
      flask experiments it was found that the wild-type E. coli nar promoter cloned
      onto pBBR122, pNW61, was suppressed under aerobic conditions in an Agrobacterium
      host strain, was partially induced under microaerobic only conditions, and was
      maximally induced under microaerobic conditions in the presence of nitrate ion.
      Whereas the mutant-type E. coli nar promoter cloned onto pBBR122, pNW618, was
      suppressed under aerobic conditions and was maximally induced under microaerobic
      conditions, regardless of the presence of nitrate ion. This kind of induction
      pattern observed for the E. coli nar promoters in the Agrobacterium host strain
      was similar to that observed for the E. coli nar promoters in the E. coli host
      strain. On the other hand, it was found that both of the E. coli nar promoters,
      pNW61 and pNW618, in a Pseudomonas host strain were partially induced under
      aerobic conditions and were maximally induced under microaerobic conditions,
      regardless of the presence of nitrate. Finally, it was found that both of the E.
      coli nar promoters in a Rhizobium host strain were minimally induced, regardless
      of the presence of oxygen or nitrate ion. Similar induction patterns for the
      three strains were also observed from fermentor experiments in which the
      dissolved oxygen (DO) level was tightly controlled. From an evolutionary point of
      view, the results from the three Gram-negative host strains indicate that the E.
      coli nar promoter system, including the promoter and regulatory proteins, was
      best conserved in the Agrobacterium host strain and the least conserved in the
      Rhizobium host strain. From an industrial point of view, the results indicate
      that the E. coli nar promoter system can be used as an oxygen-dependent inducible
      promoter in both Agrobacterium and Pseudomonas host strains.

PMID- 12599254
TI  - Computer simulation of the delivery of etanidazole to brain tumor from PLGA
      wafers: comparison between linear and double burst release systems.
AB  - This paper presents the computer simulation results on the delivery of
      Etanidazole (radiosensitizer) to the brain tumor and examines several factors
      affecting the delivery. The simulation consists of a 3D model of tumor with
      poly(lactide-co-glycolide) (PLGA) wafers with 1% Etanidazole loading implanted in
      the resected cavity. A zero-order release device will produce a concentration
      profile in the tumor which increases with time until the drug in the carrier is
      depleted. This causes toxicity complications during the later stages of drug
      treatment. However, for wafers of similar loading, such release results in a
      higher drug penetration depth and therapeutic index as compared to the double
      drug burst profile. The numerical accuracy of the model was verified by the
      similar results obtained in the two-dimensional and three-dimensional models.

PMID- 12599255
TI  - Effect of low culture temperature on specific productivity, transcription level,
      and heterogeneity of erythropoietin in Chinese hamster ovary cells.
AB  - To determine the effect of low culture temperature on erythropoietin (EPO)
      production in recombinant Chinese hamster ovary (rCHO) cells, rCHO cells
      producing EPO (LGE10-9-27) were cultivated at 30, 33, and 37 degrees C. At a
      culture temperature lower than 37 degrees C cell growth was suppressed, but cell
      viability remained high for a longer culture period. When the culture temperature
      was lowered from 37 degrees C to 33 degrees C, more than a 2.5-fold increase in
      the maximum EPO concentration was achieved. This enhanced EPO production at 33
      degrees C was not just because of the extended culture longevity with the
      decreased release of proteolytic enzymes from dead cells, but mainly because of
      enhanced q(EPO). The q(EPO) at 33 degrees C was 0.35 +/- 0.08 microg/10(6)
      cells/h, which was approximately 4-fold higher than that at 37 degrees C.
      Although the highest q(EPO) of 0.49 +/- 0.14 micro/10(6) cells/h was obtained at
      30 degrees C, the maximum EPO concentration was lowest because the detrimental
      effect of lowering culture temperature on cell growth outweighed its beneficial
      effect on q(EPO). Like q(EPO), the relative EPO mRNA content increased by
      lowering culture temperature, indicating that the increased transcription level
      of EPO was responsible in part for the enhanced q(EPO) at low culture
      temperature. The quality of EPO produced at 33 degrees C in regard to isoform
      pattern, sialic acid content, and in vivo biological activity was comparable to
      or even better than that produced at 37 degrees C. Taken together, the results
      obtained demonstrate the potential of the application of low culture temperature
      to the commercial EPO production in rCHO cells.

PMID- 12599256
TI  - Rheology, oxygen transfer, and molecular weight characteristics of poly(glutamic
      acid) fermentation by Bacillus subtilis.
AB  - Poly(glutamic acid) (PGA) is a water-soluble, biodegradable biopolymer that is
      produced by microbial fermentation. Recent research has shown that PGA can be
      used in drug delivery applications for the controlled release of paclitaxel
      (Taxol) in cancer treatment. A fundamental understanding of the key fermentation
      parameters is necessary to optimize the production and molecular weight
      characteristics of poly(glutamic acid) by Bacillus subtilis for paclitaxel and
      other applications of pharmaceuticals for controlled release. Because of its high
      molecular weight, PGA fermentation broths exhibit non-Newtonian rheology. In this
      article we present experimental results on the batch fermentation kinetics of PGA
      production, mass transfer of oxygen, specific oxygen uptake rate, broth rheology,
      and molecular weight characterization of the PGA biopolymer.

PMID- 12599257
TI  - Quantification of toxic and inhibitory impact of copper and zinc on mixed
      cultures of sulfate-reducing bacteria.
AB  - The adverse effects of copper and zinc on an acetate-utilizing mixed cultures of
      sulfate-reducing bacteria (SRB) at concentrations below the toxic concentration
      (minimum metal concentration at which no sulfate reduction is observed) are
      reported in this paper. Mathematical models were developed to incorporate the
      toxic and inhibitory effects (defined as the reduction in bacterial population
      upon exposure to the metal and the decrease in the metabolic rate of sulfate
      reduction by the SRB, respectively) into the sulfate-reduction biokinetics. The
      characteristic toxicity and inhibition constants were obtained from the
      measurements of bacterial populations and dissolved metal concentrations in serum
      bottle studies conducted at 35 degrees C and pH 6.6. Both copper and zinc had
      toxic and inhibitory effects on SRB. The toxicity constants for copper and zinc
      were 10.6 and 2.9 mM(-1), respectively, indicating that exposure to copper
      resulted in a higher mortality of SRB than did exposure to zinc. The values of
      the inhibition constants were found to be 17.9 +/- 2.5 and 25.2 +/- 1.0 mM(-1)
      for copper and zinc, respectively. This implies that dissolved zinc was slightly
      more inhibitory to SRB than copper. The models presented in the paper can be used
      to predict the response of a sulfate-reduction bioreactor to heavy metals during
      acid mine drainage treatment.

PMID- 12599258
TI  - Aerobic biological treatment of synthetic municipal wastewater in membrane
      coupled bioreactors.
AB  - Membrane-coupled bioreactors (MBRs) offer many benefits compared to conventional
      biological wastewater treatment systems; however, their performance
      characteristics are poorly understood. Laboratory-scale MBRs were used to study
      bacterial adaptations in physiology and community structure. MBRs were fed a
      mixture of starch, gelatin, and polyoxyethylene-sorbitan monooleate to simulate
      the polysaccharide, protein, and lipid components of municipal wastewater.
      Physiological adaptations were detected by measuring ectoenzyme activity while
      structural dynamics were studied by denaturing gradient gel electrophoresis of
      PCR-amplified 16S rRNA gene fragments. As cell biomass accumulated in the MBRs,
      pollutant removal efficiency initially improved and then stabilized with respect
      to effluent concentrations of chemical oxygen demand, protein, and carbohydrate.
      Comparison of the MBR effluent to filtered reactor fluid indicated that a portion
      of the observed pollutant removal was due to filtration by the membrane rather
      than microbial activity. The rates of ectoenzyme-mediated polysaccharide (alpha
      glucosidase) and protein (leucine aminopeptidase) hydrolysis became relatively
      constant once pollutant removal efficiency stabilized. However, the maximum rate
      of lipid hydrolysis (heptanoate esterase) concomitantly increased more than 10
      fold. Similarly, alpha-glucosidase and leucine aminopeptidase ectoenzyme
      affinities were relatively constant, while the heptanoate esterase affinity
      increased more than 30-fold. Community analysis revealed that a substantial
      community shift occurred within the first 7 days of operation. A Flavobacterium
      like bacterial population dominated the community (>50% of total band intensity)
      and continued to do so for the remainder of the experiment.

PMID- 12599259
TI  - Bracketed generic inactivation of rodent retroviruses by low pH treatment for
      monoclonal antibodies and recombinant proteins.
AB  - Viral safety is a predominant concern for monoclonal antibodies (mAbs) and other
      recombinant proteins (RPs) with pharmaceutical applications. Certain commercial
      purification modules, such as nanofiltration and low-pH inactivation, have been
      observed to reliably clear greater than 4 log(10) of large enveloped viruses,
      including endogenous retrovirus. The concept of "bracketed generic clearance" has
      been proposed for these steps if it could be prospectively demonstrated that
      viral log(10) reduction value (LRV) is not impacted by operating parameters that
      can vary, within a reasonable range, between commercial processes. In the case of
      low-pH inactivation, a common step in mAb purification processes employed after
      protein A affinity chromatography, these parameters would include pH, time and
      temperature of incubation, the content of salts, protein concentration,
      aggregates, impurities, model protein pI, and buffer composition. In this report,
      we define bracketed generic clearance conditions, using a prospectively defined
      bracket/matrix approach, where low-pH inactivation consistently achieves >or=4.6
      log(10) clearance of xenotropic murine leukemia virus (X-MLV), a model for rodent
      endogenous retrovirus. The mechanism of retrovirus inactivation by low-pH
      treatment was also investigated.

PMID- 12599260
TI  - Application of hydrophobic interaction displacement chromatography for an
      industrial protein purification.
AB  - Recently it has been established that low molecular weight displacers can be
      successfully employed for the purification of proteins in hydrophobic interaction
      chromatography (HIC) systems. This work investigates the utility of this
      technique for the purification of an industrial protein mixture. The study
      involved the separation of a mixture of three protein forms, that differed in the
      C-terminus, from their aggregate impurities while maintaining the same relative
      ratio of the three protein forms as in the feed. A batch high-throughput
      screening (HTS) technique was employed in concert with fluorescence spectroscopy
      for displacer screening in these HIC systems. This methodology was demonstrated
      to be an effective tool for identifying lead displacer candidates for a
      particular protein/stationary-phase system. In addition, these results indicate
      that surfactants can be employed at concentrations above their CMCs as effective
      displacers. Displacement of the recombinant proteins with PEG-3400 and the
      surfactant Big Chap was shown to increase the productivity as compared to the
      existing step-gradient elution process.

PMID- 12599261
TI  - Characterization of antibody binding to three cancer-related antigens using flow
      cytometry and cell tracking velocimetry.
AB  - Proper antibody labeling is a fundamental step in the positive
      selection/isolation of rare cancer cells using immunomagnetic cell separation
      technology. Using either a two-step or single-step labeling protocol, we examined
      a combination of six different antibodies specific for three different antigens
      (epithelial specific antigen, epithelial membrane antigen, and HER-2/Neu) on two
      different breast cancer cell lines (HCC1954 and MCF-7). When a two-step labeling
      protocol was used (i.e., anti-surface marker-fluoroscein-isothiocyanate [FITC]
      [primary Ab], anti-FITC magnetic colloid [secondary Ab]) saturation of the
      primary antibody was determined using fluorescence intensity measurements from
      flow cytometry (FCM). The saturation of the secondary antibody (or saturation of
      a single-step labeling) was determined using magnetophoretic mobility
      measurements from cell tracking velocimetry (CTV). When the maximum
      magnetophoretic mobility was the primary objective, our results demonstrate that
      the quantities necessary for antibody saturation with respect to fluorescence
      intensity were generally higher than those recommended by the manufacturer. The
      results demonstrate that magnetophoretic mobility varies depending on the types
      of cell lines, primary antibodies, and concentration of secondary magnetic
      colloid-conjugated antibody. It is concluded that saturation studies are a vital
      preparatory step in any separation method involving antibody labeling, especially
      those that require the specificity of rare cell detection.

PMID- 12599262
TI  - Ester synthesis from trimethylammonium alcohols in dry organic media catalyzed by
      immobilized Candida antarctica lipase B.
AB  - Twenty-one different organic solvents were assayed as possible reaction media for
      the synthesis of butyryl esters from trimethylammonium alcohols in dry conditions
      catalyzed by immobilized Candida antarctica lipase B. The reactions were carried
      out following a transesterification kinetic approach, using choline and L
      carnitine as primary and secondary trimethylammonium alcohols, respectively, and
      vinyl butyrate as acyl donor. The synthetic activity of the enzyme was strictly
      dependent on the water content, the position of the hydroxyl group in the
      trimethylammonium molecule, and the Log P parameter of the assayed solvent.
      Anhydrous conditions and a high excess of vinyl butyrate over L-carnitine were
      necessary to synthesize butyryl-L-carnitine. The synthetic reaction rates of
      butyryl choline were practically 100-fold those of butyryl-L-carnitine with all
      the assayed solvents. In both cases, the synthetic activity of the enzyme was
      dependent on the hydrophobicity of the solvent, with the optimal reaction media
      showing a Log P parameter of between -0.5 and 0.5. In all cases, 2-methyl-2
      propanol and 2-methyl-2-butanol were shown to be the best solvents for both their
      high synthetic activity and negligible loss of enzyme activity after 6 days.

PMID- 12599263
TI  - Engineering the aveC gene to enhance the ratio of doramectin to its CHC-B2
      analogue produced in Streptomyces avermitilis.
AB  - Avermectin and its analogues are produced by the actinomycete Streptomyces
      avermitilis and are major commercial products for parasite control in the fields
      of animal health, agriculture, and human infections. Historically, the avermectin
      analogue doramectin (CHC-B1), which is sold commercially as Dectomax is co
      produced during fermentation with the undesired analogue CHC-B2 at a CHC-B2:CHC
      B1 ratio of 1.6:1. Although the identification of the avermectin gene cluster has
      allowed for characterization of most of the biosynthetic pathway, the mechanism
      for determining the avermectin B2:B1 ratio remains unclear. The aveC gene, which
      has an essential role in avermectin biosynthesis, was inactivated by insertional
      inactivation and mutated by site-specific mutagenesis and error-prone PCR.
      Several unrelated mutations were identified that resulted in improved ratios of
      the desirable avermectin analogue CHC-B1, produced relative to the undesired CHC
      B2 fermentation component. High-throughput (HTP) screening of cultures grown on
      solid-phase fermentation plates and analysis using electrospray mass spectrometry
      was implemented to significantly increase screening capability. An aveC gene with
      mutations that result in a 4-fold improvement in the ratio of doramectin to CHC
      B2 was identified. Subsequent integration of the enhanced aveC gene into the
      chromosome of the S. avermitilis production strain demonstrates the successful
      engineering of a specific biosynthetic pathway gene to significantly improve
      fermentation productivity of a commercially important product.

PMID- 12599264
TI  - Effect of specific oxygen uptake rate on Enterobacter aerogenes energetics:
      carbon and reduction degree balances in batch cultivations.
AB  - The effect of oxygen availability on the metabolism of Enterobacter aerogenes
      NCIMB 10102 was studied through batch fermentations of glucose performed
      increasing the specific oxygen uptake rate up to 72.7 mmol(O2) C-mol(DW) (-1) x
      h(-1). The final concentrations of fermentation products of this biosystem (2,3
      butanediol, hydrogen, acetoin, formate, acetate, carbon dioxide, ethanol,
      lactate, succinate, and biomass) were utilized to check the use of simple carbon
      mass and reduction degree balances for the study of microbial energetics even in
      batch cultivations.

PMID- 12599265
TI  - Abstracts of the 72nd Annual Meeting of the American Association of Physical
      Anthropologists, April 2003, Tempe, Arizona, USA.

PMID- 12599272
TI  - A cross-linguistic fMRI study of perception of intonation and emotion in Chinese.
AB  - Conflicting data from neurobehavioral studies of the perception of intonation
      (linguistic) and emotion (affective) in spoken language highlight the need to
      further examine how functional attributes of prosodic stimuli are related to
      hemispheric differences in processing capacity. Because of similarities in their
      acoustic profiles, intonation and emotion permit us to assess to what extent
      hemispheric lateralization of speech prosody depends on functional instead of
      acoustical properties. To examine how the brain processes linguistic and
      affective prosody, an fMRI study was conducted using Chinese, a tone language in
      which both intonation and emotion may be signaled prosodically, in addition to
      lexical tones. Ten Chinese and 10 English subjects were asked to perform
      discrimination judgments of intonation (I: statement, question) and emotion (E:
      happy, angry, sad) presented in semantically neutral Chinese sentences. A
      baseline task required passive listening to the same speech stimuli (S). In
      direct between-group comparisons, the Chinese group showed left-sided
      frontoparietal activation for both intonation (I vs. S) and emotion (E vs. S)
      relative to baseline. When comparing intonation relative to emotion (I vs. E),
      the Chinese group demonstrated prefrontal activation bilaterally; parietal
      activation in the left hemisphere only. The reverse comparison (E vs. I), on the
      other hand, revealed that activation occurred in anterior and posterior
      prefrontal regions of the right hemisphere only. These findings show that some
      aspects of perceptual processing of emotion are dissociable from intonation, and,
      moreover, that they are mediated by the right hemisphere.

PMID- 12599273
TI  - Neural systems of second language reading are shaped by native language.
AB  - Reading in a second language (L2) is a complex task that entails an interaction
      between L2 and the native language (L1). To study the underlying mechanisms, we
      used functional magnetic resonance imaging (fMRI) to visualize Chinese-English
      bilinguals' brain activity in phonological processing of logographic Chinese and
      alphabetic English, two written languages with a sharp contrast in phonology and
      orthography. In Experiment 1, we found that phonological processing of Chinese
      characters recruits a neural system involving left middle frontal and posterior
      parietal gyri, cortical regions that are known to contribute to spatial
      information representation, spatial working memory, and coordination of cognitive
      resources as a central executive system. We assume that the peak activation of
      this system is relevant to the unique feature of Chinese that a logographic
      character has a square configuration that maps onto a monosyllabic unit of
      speech. Equally important, when our bilingual subjects performed a phonological
      task on English words, this neural system was most active, whereas brain areas
      mediating English monolinguals' fine-grained phonemic analysis, as demonstrated
      by Experiment 2, were only weakly activated. This suggests that our bilingual
      subjects were applying their L1 system to L2 reading and that the lack of letter
      to-sound conversion rules in Chinese led Chinese readers to being less capable of
      processing English by recourse to an analytic reading system on which English
      monolinguals rely. Our brain imaging findings lend strongest support to the idea
      that language experience tunes the cortex.

PMID- 12599274
TI  - The time course of brain activity in reading English and Chinese: an ERP study of
      Chinese bilinguals.
AB  - Chinese bilinguals performed a delayed naming task, reading both Chinese
      characters and English words, while EEGs were recorded by a 128-channel system.
      Principle component analysis (PCA) of Event Related Potentials (ERP) from the
      onset of the stimulus suggested a temporal unfolding of graphic, phonological,
      and semantic processing that depended on both language and word frequency. At 150
      msec, Chinese produced an earlier and higher amplitude shift (N150) than English.
      At 250 msec, frequency effects were significant for both Chinese and English, but
      at 450 msec, only the English frequency effect was reliable. Source localization
      analysis by Low Resolution Electromagnetic Tomography (LORETA) showed bilateral
      occipital (left BA 17, right BA 18) visual processing of Chinese characters with
      left occipital only (left BA 17) for English high-frequency words. Low-frequency
      English words showed activation bilaterally, but with a more diffused and
      extended temporal pattern. Right prefrontal area (BA 10) was found to be strongly
      activated in the mid latency (300-400 msec) period of Chinese character naming,
      whereas English word naming showed more medial frontal (BA 8, and 10) activation.
      A post 450-msec visual verification was found to be general for both writing
      systems.

PMID- 12599275
TI  - Developmental aspects of language processing: fMRI of verbal fluency in children
      and adults.
AB  - We examined developmental differences, in location and extent of fMRI language
      activation maps, between adults and children while performing a semantic fluency
      task. We studied 29 adults and 16 children with echo planar imaging BOLD fMRI at
      1.5 T using covert semantic verbal fluency (generation of words to categories
      compared to rest) using a block design. Post task testing was administered to
      assess performance. Individual data were analyzed with an a priori region of
      interest approach from t maps (t = 4) and asymmetry indices (AI). Group studies
      were analyzed using SPM 99 (Wellcome, UK; fixed effect, corrected P < 0.0001). We
      found no significant differences in location or laterality of activation between
      adults and children for a semantic verbal fluency task. Adults activated more
      pixels than children in left inferior frontal gyrus and left middle frontal
      gyrus, but AIs were the similar across ages (r(2) < 0.09). Extent or laterality
      of activation was not affected by performance (r(2) < 0.15). The brain areas that
      process semantic verbal fluency are similar in children and adults. The
      laterality of activation does not change appreciably with age and appears to be
      strongly lateralized by age 7 years.

PMID- 12599276
TI  - Comparison of block and event-related fMRI designs in evaluating the word
      frequency effect.
AB  - Printed word frequency can modulate retrieval effort in a task requiring
      associative semantic judgment. Event-related fMRI, while avoiding stimulus order
      predictability, is in theory statistically less powerful than block designs. We
      compared one event-related and two block designs that evaluated the same semantic
      judgment task and found that similar brain regions demonstrated the word
      frequency effect. Although the responses were lower in amplitude, event-related
      fMRI was able to detect the word frequency effect to a comparable degree compared
      to the block designs. The detection of a frequency effect with the event-related
      design also suggests that stimulus-order predictability may not be as serious a
      concern in block designs as might be supposed.

PMID- 12599277
TI  - Bilateral brain abnormalities associated with dominantly inherited verbal and
      orofacial dyspraxia.
AB  - The KE family is a large three-generational pedigree in which half of the members
      suffer from a verbal and orofacial dyspraxia in association with a point mutation
      in the FOXP2 gene. This report extends previous voxel-based morphometric analyses
      of magnetic resonance imaging (MRI) scans (Watkins et al. [2002] Brain 125:465
      478) using a bilateral conjunction analysis. This searches specifically for areas
      of grey matter density that differ bilaterally in the affected members compared
      with both matched controls and the unaffected family members. 3-D T1-weighted MRI
      datasets of 17 family members (10 affected, 7 unaffected) and matched controls
      were compared. The most significant findings were reduced grey matter density
      bilaterally in the caudate nucleus, the cerebellum, and the left and right
      inferior frontal gyrus in the affected members. In addition, increased grey
      matter density was found bilaterally in the planum temporale. These results
      confirm that a point mutation in FOXP2 is associated with several bilateral grey
      matter abnormalities in both motor and language related regions. The results also
      demonstrate the advantages of using a conjunction analysis when bilateral
      abnormalities are suspected.

PMID- 12599278
TI  - Distinct brain regions associated with syllable and phoneme.
AB  - The syllable and the phoneme are two important units in the phonological
      structure of speech sounds. In the brain mapping literature, it remains unsolved
      as to whether there are separate brain regions mediating the processing of
      syllables and phonemes. Using functional magnetic resonance imaging (fMRI), we
      investigated the neural substrate of these phonological units with Chinese
      subjects. Results revealed that the left middle frontal cortex contributes to
      syllabic processing, whereas the left inferior prefrontal gyri contributes to
      phonemic processing. This pattern of findings offers compelling evidence for
      distinct cortical areas relevant to the representation of syllables and phonemes.

PMID- 12599279
TI  - Involvement of the cerebellum in semantic discrimination: an fMRI study.
AB  - We investigated, using functional magnetic resonance imaging (fMRI), whether
      semantic discrimination, an inner linguistic task without overt articulation, can
      elicit activation in the cerebellum. Six subjects performed three semantic tasks
      with different loads of discrimination while being scanned. All three semantic
      tasks activated distributed brain areas, including the right posterior inferior
      cerebellum. Much stronger activation was found in the cerebellum in more
      difficult tasks, in terms of the activation volume and signal intensity. These
      results suggest that the cerebellum activation is involved in semantic
      discrimination and is modulated by discrimination difficulty.

PMID- 12599280
TI  - Neural basis of the non-attentional processing of briefly presented words.
AB  - The neural basis of the automatic activation of words was investigated in an fMRI
      study. In the study, words were presented briefly (51 or 151 msec) followed by a
      mask. To prevent attentional processing, subjects attended to the masks and not
      the words, and were required to make perceptual judgment about the masks. We
      found that a distributed neural network (including the frontal, temporal,
      occipital, parietal lobes, and the cerebellum) was activated during non
      attentional processing of words in both exposure durations. A significant main
      effect of presentation duration was found in bilateral cerebellum and the right
      fusiform gyrus, suggesting their role in the later (151 msec) processing of
      words. In addition, a significant interaction between presentation duration and
      word frequency was obtained. When the presentation duration was 151 msec, no
      significant difference in activation was found between high- and low-frequency
      words. Alternatively, when the presentation duration was 51 msec, high-frequency
      words evoked significantly greater activation in bilateral fusiform gyri,
      cerebellum, right inferior parietal lobe, medial frontal gyrus (BA 45/46/9), and
      the right temporal-occipital junction (BA 21/37). These results suggest that
      these regions are sensitive to word frequency, and are related to both the
      attentional and non-attentional access of lexical representations.

PMID- 12599281
TI  - Modulation of neural connectivity during tongue movement and reading.
AB  - In a functional magnetic resonance imaging (fMRI) study, a novel connectivity
      analysis method termed within-condition interregional covariance analysis (WICA)
      was introduced for investigation into brain modulation during tongue movement and
      reading Chinese pinyins and logographic characters. We found that performing a
      horizontal tongue movement task generated a specific brain module with
      hierarchical orders of neural computation. Such functional modularity was further
      examined during both overt and silent Chinese reading tasks. Our results showed
      that overt pinyin reading was associated with the following distributed regions
      involved in tongue movement: the primary motor cortex (M1), the supplementary
      motor area (SMA), Broca's area, and Wernicke's area. Furthermore, we have used
      the WICA and demonstrated task-dependent covariance patterns that are strongly
      associated with the M1 mouth/tongue region, in which the Broca-Wernicke pathway
      is implicated in a meaning access procedure based on assembled phonology, while
      the SMA-Broca pathway is implicated in a meaning access procedure based on
      addressed phonology. Our functional connectivity analysis of the neural pathway
      involved in language processing may provide a basis for future studies of the
      dynamic neural network associated with language learning and reading in both
      developmental and disease conditions.

PMID- 12599282
TI  - An fMRI study comparing brain activation between word generation and electrical
      stimulation of language-implicated acupoints.
AB  - We compared the brain activation on functional magnetic resonance imaging (MRI)
      during word generation with the activation during electrical stimulation of two
      language-implicated acupoints in 17 healthy, Mandarin-speaking, Chinese male
      volunteers (age 19-26 years). All subjects were strongly right handed according
      to a handedness inventory. Using a standard functional MRI procedure and a word
      generation paradigm, significant activation was seen in the left and right
      inferior frontal gyri (BA 44, 45) as well as the left superior temporal gyrus (BA
      22, 42). Stronger activation with a larger volume was seen in the left
      hemisphere. Electrical stimulation of either one of the two language-implicated
      acupoints, SJ 8 (11 subjects) and Du 15 (6 subjects), without the word-generation
      paradigm in the same cohort, produced significant activation in the right
      inferior frontal gyrus (BA 44, 46) and in the left and right superior temporal
      gyri (BA 22, 42), respectively. Nevertheless, no activation was seen in the left
      inferior frontal gyrus. In addition, electrical stimulation of the adjacent non
      acupoints did not produce any significant brain activation. Although our results
      support the notion of acupoint-brain activation, applying acupuncture at SJ 8 or
      Du 15 does not activate the typical language areas in the left inferior frontal
      cortex.

PMID- 12599283
TI  - Towards understanding language organisation in the brain using fMRI.
AB  - Functional magnetic resonance imaging (fMRI), which allows non-invasive mapping
      of human cognitive functions, has become an important tool for understanding
      language function. An understanding of component processes and sources of noise
      in the images is contributing to increased confidence in the reproductability of
      studies. This allows clinical applications, e.g., for pre-surgical lateralisation
      of language functions in patients with temporal lobe epilepsy. fMRI is a
      sensitive method for mapping regions involved in language functions. We recently
      have applied it to study the effect of word surface form on reading with a
      comparison of responses to Chinese characters or alphabetical Pinyin.
      Interpretation of fMRI activations must be made with caution; fMRI suggests task
      associated activation, but does not independently confirm that such activity is
      necessary. However, complementary studies can be performed using transcranial
      magnetic stimulation (TMS), which can be used to interfere with brain activity in
      a specific region transiently for characterisation of the behavioural effects. We
      describe how TMS combined with fMRI has confirmed a role for the left inferior
      frontal cortex in semantic processing.

PMID- 12599284
TI  - Management of mandibular osteoradionecrosis corresponding to the severity of
      osteoradionecrosis and the method of radiotherapy.
AB  - PURPOSE: : To demonstrate appropriate treatment methods for mandibular
      osteoradionecrosis (ORN) by evaluating previous results. METHODS: : The
      relationship between the time interval after radiation therapy (RT) and the
      severity of ORN was examined. Eighty-seven patients were classified according to
      the extent of the lesion (grades), and the cure rates were calculated according
      to the RT modality, the grade, and the treatment method for ORN. RESULTS: : The
      later ORN developed and the higher the dose of irradiation, particularly among
      the patients who received external RT, the more it progressed. The initial cure
      rates for conservative management, marginal, and segmental mandibulectomy were
      39.7%, 50%, and 86.7%, respectively. CONCLUSIONS: : Conservative management
      should be limited to early-onset ORN after brachytherapy with or without a low
      dose of external irradiation. Marginal mandibulectomy is appropriate for the late
      onset ORN after brachytherapy with or without low-dose external irradiation.
      Segmental mandibulectomy is required for late-onset ORN after a high dose of
      external irradiation.

PMID- 12599285
TI  - Differentially expressed genes associated with CIS-diamminedichloroplatinum (II)
      resistance in head and neck cancer using differential display and CDNA
      microarray.
AB  - BACKGROUND: The mechanism by which cancer cells become resistant to cis
      Diamminedichloroplatinum (II) (cDDP) is not completely understood. To investigate
      the molecular markers involved in the cDDP resistance, we compared the gene
      expression profiles between a head and neck squamous cell carcinoma (HNSCC) line
      sensitive to cDDP and its cDDP-resistant variant. METHODS: Both a fluorescent
      differential display and a cDNA microarray analysis were applied to distinguish
      the gene profiles between KB, a human HNSCC line, and its cDDP-resistant variant
      (KB/cDDP). These results were confirmed by Northern blot analysis. RESULTS: One
      up-regulated gene, glycoprotein hormone alpha-subunit, and two down-regulated
      genes coding membrane proteins, human folate receptor and tumor-associated
      antigen L6, were identified in KB/cDDP cells. CONCLUSIONS: Our findings suggest
      that development of the cDDP-resistant phenotype is accompanied by alternations
      of gene expression including a glycoprotein hormone and membrane proteins. These
      gene products could be new molecular markers for resistance to cDDP.

PMID- 12599286
TI  - Cervical metastases in upper aerodigestive tract squamous cell carcinoma:
      histopathologic analysis and reporting.
AB  - BACKGROUND: Accurate histopathologic assessment of neck dissections is of
      paramount importance. Retrospective analyses of the distribution of lymph node
      metastases have formed the rationale for elective neck dissection. However,
      standard techniques for examination of neck dissection specimens may have
      difficulty in correctly recognizing node levels and may also miss
      micrometastases, microscopic extracapsular spread, and soft tissue deposits.
      METHODS: Two hundred thirty-seven neck dissections were performed in 173 patients
      with squamous cell carcinoma of the upper aerodigestive tract between August 1995
      and November 2000. The neck dissections were separated into node levels
      peroperatively, sectioned at 6 microm thickness, and stained with hematoxylin and
      eosin. RESULTS: Eleven thousand three hundred forty-nine lymph nodes were
      identified and examined. The mean yield per neck dissection was 50.4 (range, 12
      131); 21.4% had extracapsular spread, 11.0% had soft tissue deposits, and 13.3%
      had both. A third of the metastatic nodes were 3 mm or less in diameter.
      CONCLUSIONS: The accurate pathologic staging of the neck in patients with upper
      aerodigestive tract squamous cell cancer is important for providing prognostic
      information and optimizing the treatment plan for the patient. Accurate staging
      also allows the changing patterns of disease to be monitored and allows equitable
      comparison of patients in clinical trials and among surgical units.

PMID- 12599287
TI  - Generation of vaccine-primed lymphocytes for the treatment of head and neck
      cancer.
AB  - BACKGROUND: This study was performed to assess the ability of autologous tumor
      vaccines to induce T-cell reactivity to squamous cell cancers (SCC). METHODS:
      Irradiated autologous tumor cells admixed with bacillus Calmette-Guerin (BCG)
      were given intradermally in patients with advanced head and neck cancers. Vaccine
      primed lymph node (VPLN) cells were secondarily activated with anti-CD3 mAb and
      expanded in IL-2 for adoptive immunotherapy. A mean (+/- SEM) of 2 (+/-0.6) x
      10(10) anti-CD3-activated cells were administered in conjunction with IL-2 in six
      patients. RESULTS: Anti-CD3-activated VPLN cells secreted IFN-gamma and GM-CSF in
      response to autologous tumor cells but not to allogeneic tumor cells in four of
      five patients analyzed. Both CD4(+) and CD8(+) tumor reactive cells were present
      in the VPLN. There were no significant tumor responses after transfer of the anti
      CD3-activated VPLN. In separate experiments, costimulation of VPLN cells with
      anti-CD3 and anti-CD28 mAb resulted in enhanced cytokine secretion to autologous
      tumor compared with anti-CD3 activation alone. CONCLUSIONS: Both CD4(+) and
      CD8(+) responses can be induced to SCC by autologous tumor vaccination. However,
      additional approaches need to be identified to enhance the therapeutic efficacy
      of this approach.

PMID- 12599288
TI  - Gamma knife radiosurgery for recurrent salivary gland malignancies involving the
      base of skull.
AB  - BACKGROUND: The management of skull base recurrence of salivary gland tumors is
      challenging, because complete surgical resection and fractionated reirradiation
      are seldom possible. Experience is being gained with radiosurgery for this
      indication. METHODS: From 1994-2000, eight patients with 16 skull base
      recurrences of salivary gland tumors underwent Gamma Knife radiosurgery at the
      University of California San Francisco. Local freedom from progression (FFP),
      regional FFP, locoregional FFP, and survival times were measured from the date of
      radiosurgery and estimated using the Kaplan-Meier method. RESULTS: All patients
      experienced symptomatic response, usually pain resolution. The median local FFP,
      regional FFP, locoregional FFP, and survival times were 15.4, 12.0, 10.0, and
      21.2 months, respectively. The 1-year local FFP probabilities are 93% and 59%,
      respectively. Local FFP, allowing for salvage radiosurgery, was 100% at 1 year
      and 75% at 2 years. Five of seven patients with locoregional failure underwent
      repeat radiosurgery, successfully achieving control for an additional 4.4 to 13.4
      months in four patients. One patient had radiation necrosis develop. CONCLUSION:
      Radiosurgery provided good local control and symptomatic relief in patients with
      recurrent salivary gland malignancies involving the base of skull. In patients
      with good performance status, radiosurgery should be considered as salvage
      treatment.

PMID- 12599289
TI  - Intraoperative radiotherapy for head and neck and skull base cancer.
AB  - BACKGROUND: The purpose of this study was to evaluate the use of intraoperative
      electron beam radiotherapy (IORT) as an adjuvant modality in the treatment of
      advanced head and neck and skull base cancer. METHODS: Between 1991 and 1996, 34
      patients with squamous cell carcinoma (SCCA) and 10 patients with non-SCCA were
      enrolled in this prospective nonrandomized clinical trial. Most patients had been
      previously treated with combinations of surgery, external beam radiotherapy, and
      chemotherapy. The most frequent sites treated were the skull base (56%) and the
      neck (44%). IORT was delivered in a dedicated operating room suite with energies
      of 6 to 15 MeV (6 MeV most commonly used) at doses of 12.5 to 22.5 Gy. RESULTS:
      At 2 years overall and disease-free survival was 32% and 21%, respectively, for
      the SCCA patients and 50% and 40%, respectively, for the non-SCCA patients. Tumor
      control rates at 2 years in the IORT field were 46% for the SCCA patients and 52%
      for the non-SCCA patients. For squamous cell histology, survival in patients with
      microscopic residual tumor did not differ from those with no residual tumor, but
      they both had significantly longer disease-free survival than those patients with
      gross residual at the time of IORT (p =.03), with a trend toward longer overall
      survival (p =.09). The only complication directly attributable to IORT was a
      neuropathy in a patient who received an IORT dose of 22.5 Gy (cumulative dose
      130.1 Gy). CONCLUSIONS: IORT at a dose of 12.5 Gy is safe and produces tumor
      control and survival for patients likely to have microscopic residual disease in
      sites difficult to resect such as the skull base.

PMID- 12599290
TI  - Detection of recurrent nasopharyngeal carcinomas with thallium-201 single-photon
      emission computed tomography in patients with indeterminate magnetic resonance
      imaging findings after radiotherapy.
AB  - BACKGROUND: The aim of this study was to evaluate the usefulness of thallium-201
      (Tl-201) single-photon emission CT (SPECT) to detect recurrent nasopharyngeal
      carcinomas (NPC) when MRI findings are indeterminate. METHODS: After
      radiotherapy, 26 NPC patients with indeterminate MRI findings were included in
      this study. MRI, Tl-201, and biopsy were performed at least 4 months after
      radiotherapy and within 1 week. The final results were based on histopathologic
      findings and clinical follow-up after at least 6 months. RESULTS: For detecting
      recurrent NPC in indeterminate MRI findings, the sensitivity, specificity, and
      accuracy of Tl-201 SPECT were 92.3%, 92.3%, and 92.3%, respectively. CONCLUSIONS:
      On the basis of this result, Tl-201 SPECT seems to be effective in detecting
      recurrent NPC when MRI findings are indeterminate.

PMID- 12599291
TI  - Speech and swallowing outcomes in reconstructions of the pharynx and cervical
      esophagus.

PMID- 12599292
TI  - Scintigraphic method to detect silent aspiration during sleep in postsurgical
      patients with oral cancer.
AB  - BACKGROUND: A simple method to detect silent aspiration during sleep has not been
      established in postsurgical oral cancer patients. METHODS: Radioactive paste
      consisting of (99m)TcO(4) (-) and carboxylmethylcellulose was prepared and placed
      in a maxillary prosthesis with a cavity in the palatal space. The patient was
      requested to wear this appliance during sleep, and the following morning the
      patient was subjected to scintigraphic scanning. Both the anterior and posterior
      aspects of the thorax were scanned using a Shimazu Medical gamma camera with
      window settings adjusted to a low energy collimator at 500 kilocounts per image.
      RESULTS: Silent aspiration that had not been detected by videofluoroscopic
      examination was clearly demonstrated by the scintigraphic method, showing
      aspiration of radioactive paste during sleep in the left thorax of the patient.
      CONCLUSIONS: The method reported for establishing aspiration is simple and
      reliable to assess silent aspiration during sleep in patients with oral cancer.

PMID- 12599294
TI  - Global awareness. Multimedia HIV/AIDS awareness blitz begins.

PMID- 12599293
TI  - The effect of radiation therapy on microcystic adnexal carcinoma: a case report.
AB  - BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare, locally aggressive
      tumor. Treatment for this neoplasm typically requires extensive local excision
      leading to morbidity. Therefore, the temptation to use alternative treatment
      options remains high. METHODS: We report one case of a nasal dorsum MAC treated
      with external beam radiation secondary to the patient's poor health status and
      preference. RESULTS: After initial dramatic clinical resolution, the tumor
      recurred in a clinically more extensive and histologically more aggressive form.
      CONCLUSION: On the basis of this case and several detailed in the literature, we
      therefore hypothesize that radiation therapy is not only an ineffective treatment
      for MAC, but evidence exists that this modality may induce conversion to a
      histologically and clinically less favorable neoplasm.

PMID- 12599295
TI  - Smallpox vaccinations trouble gay, legal, medical communities.

PMID- 12599296
TI  - Prevention. N.J. AIDS panel urges needle program, condoms in schools.

PMID- 12599297
TI  - ADA violation. District court rules N.Y. village zoning code discriminatory.

PMID- 12599298
TI  - Disease transmission. Court reverses damages for Samaritan exposed to HIV.

PMID- 12599299
TI  - Smallpox vaccine. Groups provide smallpox risk information to health care
      workers.

PMID- 12599300
TI  - State budgets. Tax cuts threaten AIDS spending, programs in most states.

PMID- 12599301
TI  - Court reverses denial of SSI benefits for HIV-positive man.

PMID- 12599302
TI  - WHO enlisted to break deadlock over drug-access agreement.

PMID- 12599303
TI  - Disability. HIV-positive doctor assessed attorney's fees for dishonesty.

PMID- 12599304
TI  - Senegal stems HIV by keeping network 'hubs' disease-free.

PMID- 12599305
TI  - Leading businesses confront AIDS in Africa.

PMID- 12599306
TI  - Viatical policy. Seller's lack of securities license voids viatical agreement.

PMID- 12599307
TI  - Dermoid cyst as a dumbbell-shaped tumour of the cavernous sinus.

PMID- 12599308
TI  - [Violation of working hours law: a liability case?].

PMID- 12599309
TI  - [Liability of the Chief Physician for coding errors].

PMID- 12599310
TI  - [DRG exercises: perforated duodenal ulcer, peritonitis].

PMID- 12599311
TI  - [Potential effects of the DRGs in vascular surgery. Results of a systematic
      grouping].

PMID- 12599312
TI  - [Extract from the Coalition Agreement on Health Policy].

PMID- 12599313
TI  - [Annual Meeting of the Schleswig-Holstein Section of the BDC (Professional
      Society of German Surgeons), 14 August 2002].

PMID- 12599314
TI  - [To further improve transplantation results].

PMID- 12599315
TI  - [Bone tumors].

PMID- 12599316
TI  - ["Weber syndrome". A new occupational disease of trauma surgeons].

PMID- 12599317
TI  - Profile: Ansgar O. Aasen, M.D., Ph.D. Interview by Vicki Glaser.

PMID- 12599318
TI  - [Rheumatism patients: worse care, more suffering, higher costs!].

PMID- 12599319
TI  - Help me help me help you.

PMID- 12599320
TI  - Congenital malignant peritoneal mesothelioma.

PMID- 12599321
TI  - New BMJ policy on economic evaluations. Will the BMJ return clinical trials if
      submitted without any economic results?

PMID- 12599322
TI  - New BMJ policy on economic evaluations. Economic evaluations should be judged on
      scientific merit.

PMID- 12599323
TI  - New BMJ policy on economic evaluations. Economic evaluations are often based on
      many studies.

PMID- 12599324
TI  - New BMJ policy on economic evaluations. Will the Lancet play ball?

PMID- 12599325
TI  - How to deal with scientific controversy?

PMID- 12599326
TI  - Awarding of the sixth Lucien Appel prize for neuroradiology.

PMID- 12599327
TI  - A chew-and-spit method of corticosteroid delivery.

PMID- 12599328
TI  - Fixed drug eruption due to fluconazole.

PMID- 12599329
TI  - New approaches in targeting intracerebral tumours with 90Y-labelled
      radiopeptides.

PMID- 12599330
TI  - Nuclear medicine technologist training in European countries.

PMID- 12599331
TI  - Preoperative brain mapping using [15O]water activation PET provides evidence on
      altered language networks in an adult brain tumour patient.

PMID- 12599332
TI  - [Circumscribed vasculitis with posterior artery infarct in Hashimoto
      encephalopathy].

PMID- 12599333
TI  - Speaking volumes on volunteering.

PMID- 12599334
TI  - Three cheers for HIPAA.

PMID- 12599335
TI  - Keeping up with hand hygiene recommendations.

PMID- 12599337
TI  - [12 Sonnenberg Guidelines for psychiatric-psychotherapeutic management of migrans
      in Germany].

PMID- 12599336
TI  - [Comments on the contribution, "Immunomodulating staged therapy of multiple
      sclerosis by the Multiple Sclerosis Therapy Consensus Group"].

PMID- 12599338
TI  - Using the microintroducer technique for PICC placement.

PMID- 12599339
TI  - [Off-label use: the case of methylphenidate (Ritalin)].

PMID- 12599340
TI  - Kava: a supplement to avoid.

PMID- 12599341
TI  - The stealth fat.
AB  - Trans fat lurks in a multitude of foods. It's not labeled. And it's bad for your
      heart. Here's how to avoid it.

PMID- 12599342
TI  - Brain death and spontaneous breathing.

PMID- 12599343
TI  - Interfering with nature.
AB  - Certain kinds of medical treatment are often held to be morally unacceptable
      because they are an 'interference with nature'. I suggest a way in which we can
      make sense of such ideas. We can make significant choices only against a
      background of conditions which we regard as 'natural', and these will typically
      include such facts as those of birth and death, of youth and age, and of sexual
      relations. I argue, however, that such ideas, though intelligible, do not
      establish any valid moral objection to, for instance, the use of ovarian tissue
      for assisted conception.

PMID- 12599345
TI  - The survival of the survival lottery.
AB  - In his paper 'The Survival Lottery' John Harris suggested that there could be
      situations where the rational thing to do would be to kill a healthy person and
      harvest his organs for transplantation, thereby saving several lives at the cost
      of one. Anne Maclean claims that such a proposal, far from being rational, does
      not qualify as a moral proposal at all since what it suggests is 'plain murder'.
      I argue that she is correct to claim that the proposal is not uniquely rational
      and that doctors could quite rationally reject it, but that she overreaches
      herself when she holds it not to be a moral proposal at all.

PMID- 12599344
TI  - Tonic in a teapot.
AB  - Here's the latest evidence tea is good for you and, because you have to drink it
      to reap the benefits, our taste tests of 19 green teas.

PMID- 12599347
TI  - The Maryland Health Care Decisions Act: achieving the right balance?

PMID- 12599346
TI  - The changing nature of the bioethics movement.

PMID- 12599348
TI  - Maryland's 1993 Health Care Decisions Act--implications for health care
      practitioners.

PMID- 12599349
TI  - Should families make health care decisions?

PMID- 12599351
TI  - The precarious role of the courts: surrogate health care decisionmaking.

PMID- 12599350
TI  - Who's the patient?

PMID- 12599352
TI  - Particularism in bioethics: balancing secular and religious concerns.

PMID- 12599353
TI  - The new Uniform Health Care Decisions Act: paving a health care decisions
      superhighway?

PMID- 12599354
TI  - The right to refuse life-sustaining medical treatment: national trend and recent
      changes in Maryland law.

PMID- 12599355
TI  - [Dysphagia with hoarseness. Acinar cell carcinoma of the larynx].

PMID- 12599356
TI  - Periodontic and orthodontic treatment in adults.

PMID- 12599357
TI  - Research topics.

PMID- 12599358
TI  - Research topics.

PMID- 12599359
TI  - Board certification.

PMID- 12599360
TI  - A disturbing trend.

PMID- 12599361
TI  - New additions to the federal report on carcinogens.

PMID- 12599362
TI  - Strengthening the fight against infectious disease.

PMID- 12599363
TI  - From the Centers for Disease Control and Prevention. Infant botulism--New York
      City, 2001-2002.

PMID- 12599364
TI  - UNICEF and CDC report on Afghanistan women's health.

PMID- 12599365
TI  - From the Centers for Disease Control and Prevention. Outbreak of botulism type E
      associated with eating a beached whale--western Alaska, July 2002.

PMID- 12599366
TI  - New academic centers for Public Health Preparedness funded.

PMID- 12599369
TI  - Expansion of global access to HIV/AIDS treatment.

PMID- 12599370
TI  - Allocation of medical resources: new CMDS ethics statement.

PMID- 12599371
TI  - Psychiatric disorders among detained youth.

PMID- 12599372
TI  - Innovations ignite Jackson CMDA.

PMID- 12599373
TI  - Bioethics center is an agent of change.

PMID- 12599374
TI  - Decision making in clinical ethics: secular and Christian approaches.

PMID- 12599375
TI  - Doctors should not kill, even condemned prisoners.

PMID- 12599376
TI  - Going public over patient privacy.

PMID- 12599377
TI  - Strengthening the doctor-patient-God relationship.

PMID- 12599378
TI  - Current awareness of NMR in biomedicine.

PMID- 12599379
TI  - Doctors in the lion's den.

PMID- 12599380
TI  - Dialogue: stem cell research.

PMID- 12599381
TI  - The stem cell revolution.

PMID- 12599382
TI  - Latest CMDA ethics statements: alternative/complementary therapy; limits to
      parental authority in medical decision making; unionization.

PMID- 12599383
TI  - Cloning name games: therapeutic cloning is still cloning.

PMID- 12599385
TI  - Cytomegalovirus seropositivity, infectious burden, and coronary artery disease.

PMID- 12599386
TI  - Current bibliography of the history of science and its cultural influences. 2001.

PMID- 12599387
TI  - Doctor-patient communication increases duration of antidepressant therapy.

PMID- 12599388
TI  - New combination treatment for hepatitis C is more beneficial than standard
      therapy, study says.

PMID- 12599389
TI  - HEDIS scores show health plan performance on the rise, but disparities remain.

PMID- 12599391
TI  - How do I respond to autonomic dysreflexia?

PMID- 12599390
TI  - HEDIS score reporting in late 1990s was ineffective, study says.

PMID- 12599392
TI  - Ovine surgery.

PMID- 12599393
TI  - [12th annual congress of the European Respiratory Society].

PMID- 12599394
TI  - "Onco-Mouse II". October 3, 1990--Case No. T19/90--In re President and Fellows of
      Harvard College.

PMID- 12599395
TI  - [Injury prevention in the elderly population].

PMID- 12599396
TI  - Development of a cw-laser-based cavity-ringdown sensor aboard a spacecraft for
      trace air constituents.
AB  - The progress in the development of a sensor for the detection of trace air
      constituents to monitor spacecraft air quality is reported. A continuous-wave
      (cw), external-cavity tunable diode laser centered at 1.55 micrometers is used to
      pump an optical cavity absorption cell in cw-cavity ringdown spectroscopy (cw
      CRDS). Preliminary results are presented that demonstrate the sensitivity,
      selectivity and reproducibility of this method. Detection limits of 2.0 ppm for
      CO, 2.5 ppm for CO2, 1.8 ppm for H2O, 19.4 ppb for NH3, 7.9 ppb for HCN and 4.0
      ppb for C2H2 are calculated.

PMID- 12599397
TI  - Development of a tunable mid-IR difference frequency laser source for highly
      sensitive airborne trace gas detection.
AB  - The development of a compact tunable mid-IR laser system at 3.5 micrometers for
      quantitative airborne spectroscopic trace gas absorption measurements is
      reported. The mid-IR laser system is based on difference frequency generation
      (DFG) in periodically poled LiNbO3 and utilizes optical fiber amplified near-IR
      diode and fiber lasers as pump sources operating at 1083 nm and 1562 nm,
      respectively. This paper describes the optical sensor architecture, performance
      characteristics of individual pump lasers and DFG, as well as its application to
      wavelength modulation spectroscopy employing an astigmatic Herriott multi-pass
      gas absorption cell. This compact system permits detection of formaldehyde with a
      minimal detectable concentration (1 sigma replicate precision) of 74 parts-per
      trillion by volume (pptv) for 1 min of averaging time and was achieved using
      calibrated gas standards, zero air background and rapid dual-beam subtraction.
      This corresponds to a pathlength-normalized replicate fractional absorption
      sensitivity of 2.5 x 10-(10 )cm-1.

PMID- 12599400
TI  - The pathogenetic mechanisms causing anal fissure.

PMID- 12599401
TI  - Chemical sensing with pulsed QC-DFB lasers operating at 15.6 micrometers.
AB  - Pulsed thermoelectrically cooled QC-DFB lasers operating at 15.6 micrometers were
      characterized for spectroscopic gas sensing applications. A new method for
      wavelength scanning based on repetition rate modulation was developed. A non
      wavelength-selective pyroelectric detector was incorporated in the sensor
      configuration giving the advantage of room-temperature operation and low cost.
      Absorption lines of CO2 and H2O were observed in ambient air, providing
      information about the concentration of these species.

PMID- 12599402
TI  - [Quality evaluation and utilization of germplasm resources of Magnolia
      officinalis].
AB  - OBJECTIVES: To lay a theoretical foundation for studies on strategies for
      improvement of Magnolia officinalis and select superior gemplasm resources to
      meet the demand for modernization, industrialization and internationalization of
      Chinese medicine. METHODS: Seeds of Magnolia officinalis from 13 main habitats of
      7 provinces were collected and strewn in a place of Jingning County, Zhejiang. At
      the age of seven, 195 samples were collected from the same height of the trunk of
      15 individual trees of each provenance, and assayed for effective ingredients
      with HPLC. RESULTS: Differences in the content of phenols were significant among
      the seed sources and even greater among individuals within a seed source.
      CONCLUSIONS: 3 seed sources viz. Wufeng, Hefeng and Enshi of Hubei were obviously
      superior to other seed sources on account of high contents of magnolol, honokoiol
      and total phenols. Extension and application of these 3 seed sources is an
      effective path leading to quality improvement of Magnolia officinalis. With great
      differences in the content of phenols existing among individuals within each
      source, there is a big gap between production of medicinal materials by merely
      using superior seed sources of Magnolia officinalis and the demand of stable and
      controllable quality for modernization and internationalization of Chinese
      medicine. But the great difference has laid a material foundation and brought
      about a great potential for genetic improvement of Magnolia officinalis.
      Therefore, the superior individuals within a superior seed source are an
      excellent material for the breeding of Magnolia officinalis.

PMID- 12599403
TI  - [Study on tissue culture of Altingia chingii].
AB  - In the present thesis, suitable medium for callus inducement and growth of
      Altingia chingii were studied by mono-factorial and uniform design. The
      experiments showed that the callus inducement rate of the leaf was higher than
      that of the stem. The basic medium for callus inducement was MS, and the best
      medium for callus growth was MS + 6-BA 2 mg/L + NAA 1 mg/L + Suc 3%. Culturing in
      darkness was much more favorable to callus growth.

PMID- 12599404
TI  - [Medicinal plant resources of Trib. Isopyreae and prospects of exploitation].
AB  - There are 17 species of medicinal plants from Trib. Isopyreae Schrod in China.
      This paper reports their resources, habitats and medicinal properties. On the
      basis of referring to the native and abroad medical studies on the plants from
      same Trilbe, their prospects of exploitation were advised.

PMID- 12599405
TI  - [Study on cross-section morphorlogy of Flos Chrysanthemi from Zhejiang Province
      and comparison with other kinds of Flos Chrysanthemi].
AB  - OBJECTIVE: To identify all kinds of commodity Flos Chrysanthemi. METHOD: The
      cross-section morphorlogy of each part of Hangbaiju was studied and compared with
      other 4 kinds of Flos Chrysanthemi. RESULT: The characters of cross-section
      morphorlogy of each part of Hanghaiju were obtained. And it was found that cross
      section morphology of the commodity Flos Chrysanthemi was different. CONCLUSION:
      It provided evidences for the identification of Hangbaiju with other 4 kinds of
      Flos Chrysanthemi.

PMID- 12599406
TI  - [Study on extraction of active ingredients from Andrographis paniculatal using
      the orthogonal experiment with supercritical carbon dioxide].
AB  - This paper studied the extraction technology of active ingredients from
      Andrographis paniculatal using the orthogonal experiment with supercritical CO2.
      The active ingredients of this extract had higher purity and more stable quality
      than those came from conventional extract technology. And the target ingredients,
      dehydrated andrographolidume and andrographolidume, had higher content.
      Furthermore this method had shorter technology process and saved a great deal of
      solvent than conventional ethanol extraction, which was exactly suitable for
      industrialization manufacture. The optimization condition was: extractor pressure
      25 MPa, extractor temperature 46 degrees C, separator I pressure 6 MPa, separator
      I temperature 65 degrees C, separator II pressure 6 MPa, separator II temperature
      45 degrees C, CO2 rate of flow 40 kg/h.

PMID- 12599407
TI  - [Improvement of learning and memory functions by rice flavoids in mice].
AB  - OBJECTIVE: To observe the effects of rice flavoids (RF) on learning and memory
      functions. METHODS: The step down test and the step through test in mice were
      used. RESULTS: RF could significantly improve the learning and memory ability in
      many dementia models, such as the impairment of acquisition of memory mice
      induced by M-anticholinergic agents like anisodine, the impairment of
      consolidation of memory in mice induced by protein biosynthesis inhibitors like
      actidione, the impairment of retrieval of memory in mice induced by central
      neuron system(CNS) depressants like ethanol, mice after cerebral ischemia
      reperfusion. CONCLUSION: It is suggested that RF can markedly enhance the
      learning and memory ability, and that is significant to prevent and cure the
      senile dementia.

PMID- 12599408
TI  - [Comparative study on pharmacodynamic effects of yinqiao powder decoction and its
      granule].
AB  - OBJECTIVE: To compare the pharmacodynamic effects of Yinqiao Powder on dividual
      decoction, admixture decoction and granule. METHODS: The mouse and rat
      inflammatory models were established by dimethylbenzene and carrageenin
      respectively. The rabbit model was established by typhoid Vi polysaccharide
      bacterin through ear vein and serolysin was induced by chick red cell. The
      effects of different dosage forms on inflammation antipyresis and inhibiting
      serolysin were observed. RESULTS: All three dosage forms of Yinqiao Powder could
      inhibit mouse auricle swelling and rat toe swelling, possessed the antithemic
      action and could accelerate the formation of serolysin(p < 0.01). But there were
      no difference among these three dosage forms in pharmacodynamic effects.
      CONCLUSIONS: Three dosage forms of Yinqiao Powder had the similar effects in
      above-mentioned pharmacodynamic markers.

PMID- 12599409
TI  - [Pharmacodynamic comparison between sanhuang decoction for purging stomach-fire
      and its concentrated granule].
AB  - OBJECTIVE: To discuss the feasibility that a traditional decoction is substituted
      by its concentrated gratnule. METHODS: The effects of the two kinds of decoction
      were compared on mice auricle tumefaction induced by xylene, arresting bleeding
      of mice broken tails and mice alvine creepage. RESULT: There was no remarkable
      difference between two kinds of decoction on pharmacodynamic effects except
      purging action. CONCLUSION: The research and exploitation of classical
      prescription concentrated granule has great signifaction.

PMID- 12599410
TI  - [Study on activating blood and eliminating stasis of guanxin dansheng capsule].
AB  - The effects of Guangxin Dansheng Capsule on activating blood and eliminating
      stasis, regulating vital energy and alleviating pain were observed. The results
      showed that Guanxin Dansheng Capsule possessed obvious protective effects on
      acute cardiac muscle ischemia and could inhibit the aggregation of platelet
      induced by ADP, reduce the amount of oxygen consumed and prolong time of
      haemorrhage.

PMID- 12599411
TI  - [Study on the inclusion compound of qucertin with hydroxypropyl-beta
      cyclodextrin].
AB  - The inclusion compound of qucertin-HP-beta-CD was manufactured by aqueous
      solution-stirring method. The inclusion compound of qucertin-HP-beta-CD was
      confirmed by IR spectroscopy and differential theramal analysis (DTA). The
      results indicated that the inclusion compound of qucertion-HP-beta-CD was formed.
      The content analysis of the inclusion compound showed that the molecular ratio of
      qucertin to HP-beta-CD was 1:1. The solubility of qucertin increased when the
      drug was included by HP-beta-CD, which in water has added from 0.0392 mg/ml to
      34.227 mg/ml.

PMID- 12599412
TI  - [Study on enrichment process of total flavonoids from Euphorbia himifusa with
      macroporous resin].
AB  - OBJECTIVE: To study the optimal technology parameters of the enrichment process
      for total flavonoids of Euphorbia himifusa with macroporous resin. METHODS: The
      enrichment process was studied by orthogonal experiment design using orthogonal
      form L9(3(4)) with the content of total flavonoids from Euphorbia himifusa as
      indexes, and three factors were chosen in this experiment, including the
      saturation of the extract sicca from Euphorbia himifusa, duration of absortion
      and the consistence of alcohol as eluent. RESULTS: The results showed that the
      optimal enrichment process was that 10 ml of the extract of Euphorbia himifusa
      (i.e. lml 75% alcohol contains 0.5 g the extract sicca from Herba Euphorbiae
      Humifusae) was absorbed 30 min with a column of macroporous resin(r 15 mm x H160
      mm) and the total flavonoids was eluted from the macroporous resin with 95%
      alcohol. CONCLUSION: The elutive rate of total flavonoids was above 93% by means
      of the macroporous resin. So this process enriching the total flavonoids of
      Euphorbia himifusa is feasible.

PMID- 12599413
TI  - [Initial study on three-dimensional culture of tenocytes under cyclic mechanical
      stretch].
AB  - OBJECTIVE: To detect the effect of mechanical stretch on shape, alignment,
      proliferation, and metabolism of tendon cells maintained in three-dimensional
      culture. METHODS: A cyclic mechanical strain apparatus for three-dimensional cell
      cultures was developed. Based on the apparatus, a specific stretch pattern (10%
      elongation, 12 stretches/min for 15 min of each hour) was applied to tenocytes
      scaffolding composites. RESULTS: Initial studies demonstrated that the stretch
      mediated effects on cell division, DNA synthesis, and metabolism in such cultures
      were influenced by the amplitude, frequency, periodicity, and duration of the
      applied stretch. After 48 hours' exposure to the stretch, the cell number and
      [3H] thymidine incorporation into DNA were increased, compared with those of the
      nonstretched controls(P < 0.05). Under the stretch pattern, the shape of cells
      changed to oblate and spread to the direction of the stretch. The cyclic stretch
      also caused an increase in collagen synthesis by tendon cells (P < 0.05), which
      was predominant in type I. CONCLUSION: Cyclic mechanical stretches act directly
      to stimulate tendon cell growth and these results are compatible with a
      significant role for stretch in tissue-engineered tendon construction.

PMID- 12599414
TI  - [DST and low/ultralow/colo-anal anastomoses laparoscopically in the treatment of
      low rectal cancer].
AB  - OBJECTIVE: To assess the feasibility and adequacy of double stapling technique
      (DST) and anal sphincter preservation with laparoscopic approach for low rectal
      cancer. METHODS: DST and low/ultralow/coloanal anastomoses were performed
      laparoscopically on 30 patients with low rectal cancer. RESULTS: The 30
      laparoscopic DST and low/ultralow/colo-anal anastomoses with anal sphincter
      preservation were successfully completed, and not one of the cases was converted
      to open procedures. The operation time was 155 min with the ranges from 110 to
      320 min. The operative blood loss was 20 ml with a range between 5 and 80 ml. The
      time of bowel function restoration and post-operative ambulation was 1-2 days
      after the operation. 14 patients had postoperative analgesic requirement. The
      hospital stay varied from 5 to 14 days, averaging 8 days, and there were no
      intraoperative and postoperative complications in the 30 patients. CONCLUSION:
      Laparoscopic DST and low/ultralow/colo-anal anastomoses for low rectal cancer is
      a perspective minimally invasive technique, which is feasible, safe and
      effective. With the use of this technique, surgeons could accomplish higher rates
      of sphincter preservation, more accurate autonomic nerve preservation and good
      micturation with decreased postoperative pain and rapid recovery.

PMID- 12599415
TI  - [Preparation and in vitro killing effect of adriamycin-loaded immunonanosphere
      against hepatoma led by F (ab')2 Fragment of monoclonal antibodies].
AB  - OBJECTIVE: To study the preparation method and in vitro killing effect of
      adriamycin (ADR)-loaded human serum albumin (HSA) immunonanosphere (HAb18 F(ab')2
      ADR-HSA-NP) against hepatoma led by F(ab')2 fragment of human hepatoma specific
      monoclonal antibody HAb18. METHODS: After ADR loaded HSA nanosphere (ADR-HSA-NP)
      was prepared in the emulsifying high temperature solidifying way, HAb18 F(ab')2
      ADR-HSA-NP was prepared using the modified N-succinimidyl 3-(2-pyridyldithio)
      propionate (SPDP) method. In vitro binding characters of HAb18 F(ab')2-ADR-HSA-NP
      and ADR-HSA-NP and hepatoma cell SMMC-7721 were observed under optical microscopy
      and electronic microscopy. In vitro effects of killing hepatoma cell SMMC-7721 of
      two microspheres were determined using the method of 3H-TdR. RESULTS: The
      surfaces of HAb18 F(ab')2-ADR-HSA-NP gave out bright yellow-green fluorescence
      after it was dyed with fluorescent agent, whereas ADR-HSA-NP did not give out
      fluorescence. HAb18 F(ab')2-ADR-HSA-NP could integrate with hepatoma cell SMMC
      7721 and effectively killed hepatoma cell SMMC-7721 with dose dependence, but ADR
      HSA-NP could not obviously integrate and kill SMMC-7721. Neither of the two
      microspheres could bind and kill human large intestine cancer cell SW1116.
      CONCLUSION: HAb18 F(ab')2-ADR-HSA-NP has a good character for in vitro specific
      targeting to bind and kill human hepatoma cell.

PMID- 12599416
TI  - [Study on expression of beta-NGF in myoblasts transfected by PSVCEP NGF-CAT with
      Lipofect AMINE].
AB  - OBJECTIVE: To gain an understanding of the expression of beta-NGF in myoblasts
      transfected by PSVCEP NGF-CAT and the transfecting efficiency of Lipofect AMINE.
      METHODS: PSVCEP NGF-CAT was delivered into cultured myoblasts by Lipofect AMINE.
      Expression of beta-NGF in the transfected myoblasts was detected by
      immunocytochemistry. RESULTS: Lipofect AMINE was evidently engulfed by myoblasts
      at the 6th hour; about 40% myoblasts could be detected with the expression of
      beta-NGF by immunocytochemistry at the 48th hour. CONCLUSION: PSVCEP NGF-CAT can
      express beta-NGF in cultured myoblasts, and Lipofect AMINE is a convenient vector
      for gene transfection with simplicity and efficacy.

PMID- 12599417
TI  - [Study on the biological character of liposome-mediated 99m-technetium labeled
      antisense oligonucleotide for c-myc mRNA].
AB  - OBJECTIVE: To probe the biological character of liposome-mediated 99m-technetium
      labeled antisense oligonucleotide of c-myc mRNA, and lay the foundations for
      clinical research on antisense image or treatment. METHODS: Antisense, sense and
      scrambled oligonucleoyide, each containing 15 bases, were synthesized elsewhere.
      The rates of liposome-entrapped 99mTc-DNA and 99mTc-DNA combination with plasma
      protein were tested through trichloroacetic acid precipitation. BALB/c mice were
      used to test the biodistribution in vivo, and rabbits were used to investigate
      the pharmacokinetics characters. RESULTS: Their rates of combination with plasma
      protein ranged from 34.81% to 70.53%. Reticuloendothelial system played an
      important role in the biodistribution; stomach, blood and intestines were less
      important; other tissues accumulated the least of the liposome-mediated 99mTc
      labeled c-myc oligonucleotides. The pharmacokinetics of liposome-entrapped 99mTc
      DNA fitted the open dithecal model. Their distribution (t1/2 alpha) half time was
      about 2 to 5 minutes, and clearance (t1/2 beta) half time about 100 to 150
      minutes. Plasma clearance was smaller than 2 ml/min. CONCLUSION: The rate of
      99mTc-DNA combination with plasma protein was high. The biological half time of
      liposome-mediated 99mTc-DNA was proper. Plasma clearance was high. So liposome
      mediated 99mTc-DNA is a potential kind of radioactive agent.

PMID- 12599418
TI  - [Inhibitory effect of cationic liposome-mediated antisense c-myb oligonucleotide
      on the growth of glioma].
AB  - OBJECTIVE: To aim at demonstrating whether cationic liposome-mediated antisense c
      myb oligonucleotide(LipoAON) can inhibit the growth of C6 glioma by intravenous
      injection. METHODS: Intracerebral C6 glioma cells were implanted into the left
      caudal nucleus of forty-eight male Wistar rats. There were four groups: LipoAON(n
      = 12), antisense c-myb oligonucleotide (AON; n = 12), cationic liposome (Lipo; n
      = 12), and normal saline (NS; n = 12). Six days after tumor implantation, the
      above-mentioned drugs were injected into the right femoral veins of the rats
      respectively. Two days later, the same drugs were injected into the left femoral
      veins. The appetite, motor and weight of every animal were closely observed
      during the whole experiment. Six rats of each group were respectively killed 4
      days and 10 days after the end of administration. The weight change, pathologic
      examination and immunohistochemical analysis of c-myb expression of the tumor
      were completed. RESULTS: In LipoAON group, the growth of the tumors was
      significantly inhibited in a short time after treatment and c-myb expression was
      down-regulated. But in the AON group and Lipo group, the growth of the tumors was
      not inhibited and c-myb expression was not down-regulated, compared with that in
      NS group. The inhibitory effect of LipoAON on the tumors rapidly declined with
      time and c-myb expression was again up-regulated. CONCLUSION: 1. Cationic
      liposome (LipofectAMINE) as transfection vehicle makes c-myb easily penetrate
      BBTB and enter the tumor. The technique is simple, safe, highly effective for the
      transfection of c-mybAON; 2. LipoAON has marked inhibitory effect on the growth
      of C6 glioma. The AON technical method for inhibiting the expression of c-myb
      oncogene has a research perspective in the treatment of glioma; 3. The inhibitory
      effect of LipoAON on the growth of glioma declines with time. The question about
      how to make c-myb AON have highly effective, sustained and stable expression in
      the tumor still requires further research.

PMID- 12599419
TI  - [The expression of nuclear factor kappa B in cancer cells of human
      adenocarcinoma].
AB  - OBJECTIVE: Nuclear factor kappa B is very important in cis-activation which
      regulates the expression of many genes. This study inquired into the mechanism of
      cancer cell metastasis. METHODS: Immunohistochemical method was used for studying
      the expression of nuclear factor kappa B in cancer cells of human metastasized
      rectum adenocarcinoma. RESULTS: Expressed nuclear factor kappa Bp65 was found in
      the cancer cells of peritumoral tissues and metastasized lymph nodes. The
      reaction product was located in the cytoplasm and cytonucleus. CONCLUSION: The
      findings of this study suggest a strong correlation between the expression of
      nuclear factor kappa B in cancer cells and the metastasis of cancer.

PMID- 12599420
TI  - [Inhibition of constitutively activated Jak3 and induction of apoptosis in NALM-6
      cell line].
AB  - OBJECTIVE: To investigate the relation of Jak3 constitutive activation and acute
      lymphoblastic leukemia(ALL). METHODS: NALM-6 cells were treated with varying
      concentrations of AG490, a Jak3 inhibitor. Apoptosis and proliferation of NALM-6
      cells were tested by flow cytometry (FCM) analysis and MTT assay. RESULTS: With
      the exception of AG490 5 mumol/L, the AG490 10, 15, 20 mumol/L induced a strong
      apoptotic response in NALM-6 cells by FCM analysis(P < 0.05) and significantly
      inhibited the proliferation of NALM-6 cells by MTT assay(P < 0.05). All of the
      effects were dose-dependent. CONCLUSION: Jak3 inhibitor AG490 can inhibit
      proliferation and induce apoptosis in NALM-6 cells, and Jak3 activation is
      associated with pre-B ALL.

PMID- 12599421
TI  - [Alteration of multiple tumor metastatic genes with correlation to metastasis in
      ovarian carcinoma].
AB  - OBJECTIVE: To investigate the expression and mutation of MTA1, nm23H1 and E
      cadherin(E-cad) genes in ovarian carcinoma (OC) in relation to lymph node (LN)
      metastasis. METHODS: A panel of normal ovarian tissues, primary OC specimens and
      corresponding LNS was examined for mRNA expression and mutation of MTA1 and
      nm23H1 and protin expression of E-cad genes by using RT-PCR, RT-PCR-SSCP and
      immunohistochemistry. RESULTS: The frequency of MTA1 over expression was
      100%(7/7) in primary OC with metastasis but only 38.5%(5/13) in those without
      metastasis (P = 0.0103). Overexpression of MTA1 was observed in 87.5%(6/7) of LNS
      with metastasis but in only 23%(3/13) of LNS without metastasis (P = 0.0118). In
      contrast with MTA1, low expression of nm23H1 mRNA was seen in 7 of 7 OC with
      metastasis but only in 4 of 13(30%) of those without metastasis (P = 0.0043). Low
      nm23H1 expression was also seen in 7 of 7 LNS with metastasis but only in 5 of 13
      (38.5%) nonmetastatic LNS (P = 0.0102). Meantime, no expression of E-cad protein
      was observed in 7 of 7 OC with metastasis but in 6 of 13(46.2%) of those without
      metastasis (P = 0.044). In correlation analysis of the three genes, MTA1
      reversely correlated with nm23H1 and E-cad respectively (r = -0.903, -0.803), and
      positive correlation existed between nm23H1 and E-cad (r = 0.724). No mutation of
      MTA1, nm23H1 and was found by SSCP analysis. CONCLUSION: The mRNA expression of
      MTA1, nm23H1 and E-cad is positively and negatively correlated with LN
      metastasis. The expression abnormalities but not the mutations of the three genes
      are frequent events related to LN metastasis of ovarian cancer.

PMID- 12599422
TI  - [Comparative studies on the banding characteristics of insulin receptor in human
      hepatocellular carcinoma and adjacent liver tissues].
AB  - OBJECTIVE: To investigate the expression of insulin receptor in human
      hepatocellular carcinoma and it's adjacent tissue. METHODS: The human
      hepatocellular carcinoma and it's adjacent tissue specimens were obtained from 12
      patients with histologically confirmed hepatocellular carcinoma at surgery and
      were immediately frozen under -80 degrees C. Insulin was radioiodinated using Ch
      T method. Cell membrane fraction of human hepatocellular carcinoma and it's
      adjacent tissue were isolated by sucrose density gradient centrifugation.
      Receptor binding of 125I-insulin to human hepatocellular carcinoma and it's
      adjacent tissue were performed. Binding data were calculated according to
      Scatchard using the ligand program. Statistical comparison was made with the
      paired t-test. RESULTS: The Kd values of human hepatocellular carcinoma and it's
      adjacent tissue were 2.12 +/- 0.62 nmol/L and 2.21 +/- 0.78 nmol/L respectively;
      the values of Bmax were 1.94 +/- 0.64 pmol/mg protein and 1.42 +/- 0.57 pmol/mg
      protein respectively. The Bmax value of human hepatocellular carcinoma was
      significantly higher than that of the adjacent tissue (P < 0.05), whereas the two
      Kd values had little difference (P > 0.05). CONCLUSION: The results of this study
      showed that human hepatocellular carcinoma expressed denser insulin receptors
      than it's adjacent tissue, but there was no significant increase in the affinity
      of the carcinoma to insulin.

PMID- 12599423
TI  - [Construction and identification of recombinant shuttle-plasmid with ESAT-6 from
      Mycobacterium tuberculosis].
AB  - OBJECTIVE: To construct a recombinant BCG secretively expressing ESAT-6 of
      Mycobacterium tuberculosis. METHODS: alpha-antigen(alpha-Ag) signal sequence and
      esat-6 gene were amplified from the genome of Bacille Calmette-Guerin (BCG) and
      Mycobacterium tuberculosis by PCR respectively. esat-6 gene was cloned in E. coli
      BCG shuttle-plasmid pMV261 to get pME. Then a new recombinant plasmid pSME was
      constructed by inserting BCG alpha-Ag signal sequence into pME. RESULTS: The
      cloned genes alpha-Ag signal sequence and esat-6 were correctly inserted into the
      vector pMV261, which was confirmed by restriction endonuclease digestion and PCR
      amplification of pSME. CONCLUSION: pSME was expected to secretively express ESAT
      6 of Mycobacterium tuberculosis in BCG. This study provides the possibility of
      further researches on the development of new anti-tuberculosis vaccine.

PMID- 12599424
TI  - [Effects of wild-type p53 gene transfection on the growth and cisplatin
      sensitivity of cervical cancer cell line HeLa].
AB  - OBJECTIVE: To investigate the effects of human wild-type p53 gene transfection on
      the growth and chemosensitivity of human cervical carcinoma. METHODS: Recombinant
      eukaryotic expression vector pCB6.p53 containing human wild-type p53 cDNA was
      introduced by lipofectamine transfection regent into HeLa cell line. The
      expression of p53 was detected by immunohistochemistry. Cell proliferation was
      measured by methyl thiazolyl tetrazolium after the treatment of cisplatin.
      RESULTS: Expression of p53 was detected by immunohistochemistry. The growth rate
      of p53-transfected HeLa decreased. Wild-type p53-positive HeLa was more sensitive
      to cisplatin, compared with the control cell lines. CONCLUSION: The exogenous
      wild-type p53 expression not only induced great suppression of cell growth but
      also increased chemosensitivity of human cervical carcinoma.

PMID- 12599425
TI  - [Sequential changes of hypoxia-inducible factor 1 alpha in experimental spinal
      cord injury and its significance].
AB  - OBJECTIVE: To investigate the sequential changes of hypoxia-inducible factor 1
      alpha (HIF-1 alpha) in experimental spinal cord(SCI) injury in rats and analyze
      its potential effects on SCI. METHODS: Static compression model of SCI was
      employed in this study. Expressions of HIF-1 alpha were measured with
      immunohistochemical staining. Flow cytometry was used to determine the apoptotic
      ratio and bcl-2 expressions. RESULTS: HIF-1 alpha began to increase one day after
      injury, and reached peak at 3-7 days. Two weeks later, it declined significantly.
      The sequential changes of HIF-1 alpha coincided well with the alterations of
      apoptotic ratio and bcl-2 content. CONCLUSION: HIF-1 alpha may participate in the
      secondary ischemic and hypoxic procedures after spinal cord injury and mediate
      the traumatic apoptosis. Further understanding of HIF-1 alpha may provide new
      therapeutic regimens for SCI.

PMID- 12599426
TI  - [Effect of acupuncture on the expression of NT3 in the process of spinal
      plasticity].
AB  - OBJECTIVE: To explore the change in the expression of NT3 in the process of
      promoting the plasticity of spinal cord by acupuncture. METHODS: Five adult cats
      were subjected to unilateral spared root rhizotomy; their L1-L5, L7-S2 dorsal
      root ganglia (DRG) were sectioned, but L4 was spared. And two groups of acupoints
      [Zusani (St.36) and Xuanzhong (G. B.39); Futu (St.32) and Sanyingjiao (Sp.6)]
      located in hind limb were electro-stimulated for thirty minutes q.d. x 7. At
      seven days, after acupuncture, the L5 segment of spinal cord and spared dorsal
      root ganglion (L6) were taken and made into frozen section 20 microns in
      thickness. Immunohistochemistry (NT3 antibody 1:1500) and in situ hybridization
      (NT3 cRNA probe 1:100) techniques were used. The numbers of positive neuron for
      NT3 and it's mRNA in large, medium, small neuron of L6 DRG and the numbers of
      positive neurons and glia cells for NT3 in lamina II were counted respectively.
      RESULTS: The numbers of positive large, small neurons for NT3 and its mRNA in DRG
      and the number of positive neurons and glia cells for NT3 in lamina II on the
      acupuncture side increased apparently than those on the non-acupuncture side (P <
      0.05). However, the positive signal of NT3 mRNA in lamina II was not seen in our
      study. CONCLUSION: The results indicate that acupuncture promoting the plasticity
      of spinal cord involves both the increase in expression of NT3 in large and small
      neurons of spared DRG and the increase in number of NT3 positive neurons and glia
      cells in spinal lamina II. Moreover, NT3 may play a role in the process of
      promoting the plasticity of spinal cord by acupuncture.

PMID- 12599427
TI  - [Studies on extracellular matrices in rat hepatocarcinogenesis induced by
      diethylnitrosamine].
AB  - OBJECTIVE: The evolution processes of type IV collagen(CN), fibronectin(FN), and
      laminin(LN) in carcinogenesis were studied by the use of diethylnitrosamine
      induced rat hepatocarinogensis model so as to clarify the action of chemical
      carcinogens on the mechanisms of the occurrence and development of hepatocellular
      carcinoma. METHODS: Immunohistochemical technigue and image analysis were used to
      demonstrate the change of the above mentioned three extracellular matrices (ECMs)
      in histopathological foci. RESULTS: There were no ECMs expressed in the altered
      foci, whereas in some neoplastic nodules the ECMs were expressed intensively
      along the capillarized sinusoid. Cellular morphological analysis showed that in
      these nodules the average perimeter and the area of the cell increased
      significantly, but nucleus/cytoplasm ratio decreased significantly as compared
      with the controls. In the nodules with intensive expression of ECMs, cell
      proliferation was active, but in the hepatocellular carcinoma these three ECMs
      diminished or vanished. CONCLUSION: The ECMs play an important role in the
      occurrence and development of hepatocellular carcinoma.

PMID- 12599428
TI  - [Nerve tissue morphological study of tutin microinjection into pontine NPBM in
      two hours].
AB  - OBJECTIVE: To observe whether Tutin microinjection into the pontine NPBM
      respiratory area of rabbit will cause morphological damage to that area two hours
      later. METHODS: At two hours after the microinjection of Tutin into NPBM, the
      experimental effects on respiration came to be remarkable and the physiological
      condition was well, the rabbit was subjected to morphological sampling then. The
      sample was cut into slices for LM (Nissl dyeing) and transmission EM observation
      and photography. RESULTS: Under the LM and EM examination, no remarkable
      morphological damage done by Tutin microinjection into the pontine NPBM was
      observed. By comparing the Tutin-injected side with the other side of NPBM where
      equal normal saline microinjection was given, no apparent morphological
      difference could be found. CONCLUSION: In our experiment condition, there was no
      morphological damage caused by Tutin microinjection into pontine NPBM respiratory
      area of the rabbit.

PMID- 12599429
TI  - [Analysis of serum lipid and apolipoprotein levels in pregnancy-induced
      hypertension and normotensive pregnant women].
AB  - OBJECTIVE: To investigate the serum lipid and apolipoprotein levels in pregnancy
      induced hypertension (PIH or pre-eclampsia), normotensive pregnant women and non
      pregnant women. METHODS: Twenty-eight women with PIH, 31 normatensive and 24 non
      pregnant ones were studied, from whom maternal blood samples were collected.
      Serum lipid levels were measured by enzymatic method and apolipoproteins AI,
      B100, C II, CIII and E levels by radial immunodiffusion kits developed by our
      Lab. RESULTS: 1. Serum TG, apoC II and apoC III were highly increased in
      normotensive pregnant women by 3.5, 2.4 and 2.8 times respectively, when compared
      with those in non-pregnant ones (P < 0.001); serum TC, nHDL-C and apoAI, B100 and
      E were also increased in normotensive pregnant women by 21%, 33%, 55%, 79% and
      77% respectively, when compared with those in non-pregnant ones (P < 0.001).
      TG/HDL-C in normotensive pregnant women was also significantly, higher than that
      in non-pregnant ones(P < 0.01). Serum HDL-C levels remained unchanged in both
      groups. 2. Serum TG, apoC II and apoC III were highly increased in PIH patients
      by 2.3, 4.0 and 2.8 times respectively, when compared with those in non-pregnant
      ones (P < 0.001); serum TC, nHDL-C and apoAI, B100 and E were also increased in
      PIH patients by 27%, 26%, 52%, 90% and 67% respectively, when compared with those
      in non-pregnant ones (P < 0.001) TG/HDL-C in PIH patients was also significantly
      higher than that in non-pregnant ones (P < 0.01). Serum HDL-C levels were
      increased in PIH patients by 29%, when compared with non-pregnant women. Only
      serum HDL-C level in PIH patients was higher than that in normotensive pregnant
      women. No significant differences were seen in other lipid and apolipoprotein
      levels between PIH patients and normotensive pregnant ones. 3. There was no
      significant difference in the levels of serum lipid and apolipoprotein between
      the subgroups of PIH patients according to the severity of the disease.
      CONCLUSION: The increase of serum lipid and apolipoprotein levels in PIH is
      probably not the predictor for pre-eclampsia.

PMID- 12599430
TI  - [The influence of two implant materials on the growth of three subgingival
      predominant bacteria].
AB  - OBJECTIVE: Commercially pure titanium and titanium alloy as dental implants have
      show impressive clinical results. Despite the high success rates, some implants
      do fail. Compared to those studies on osseointegration of implants, the
      information pertaining to their failure is little. Further studies on the
      relationship between implant material and micro-organism are needed. The purpose
      of this investigation is to study the effect of two commonly used implant
      materials Titanium (TA2) and Ti-6AI-4V alloy (TC4) on the growth behaviour of
      three subgingival predominant bacteria Streptococcus sanguis (S. s),
      Porphyromanus gingivalis (P. g), Fusobacterium nucleatum (F. n) and their
      mixture. METHODS: Under anaerobic condition, bacterial suspensions of S.s, P.g,
      F.n and their mixture were incubated together with the two implant materials
      respectively, setting the same bacterial suspensions as controls. After 2, 7 and
      14 days, the bacterial growth amount was assayed by means of clone forming unit
      (CFU) method. The pH value of the bacterial suspension was determined by pH
      Meter. RESULTS: The results showed that there was no difference in amount of
      bacterial growth or pH value between TA2 group and TC4 group (P > 0.05). There
      was also no statistically significant change as to the proportion of individual
      bacteria in bacterial mixture or the pH value of culture suspension. CONCLUSION:
      Under the condition of this investigation, the two studies implant materials have
      no examined influences on the growth of the subgingival bacteria and the pH value
      of their culture environment.

PMID- 12599431
TI  - [Therapeutic effect of high-density lipoprotein of human plasma on rat
      endotoxemia].
AB  - OBJECTIVE: To investigate the therapeutic effect of high-density lipoprotein
      (HDL) of human plasma on rat endotoxemia. METHODS: Rats were divided into 2
      groups randomly, the treated group received bolus intravenous endotoxin (500
      EU/kg), then followed by a bolus HDL (75 mg/kg) intravenously as their blood
      pressure decreased obviously. The control group just received bolus intravenously
      endotoxin (500 EU/kg) without HDL. Blood pressure, survival time, the
      concentration of TNF and the levels of endotoxin in plasma were determined using
      radioimmunoassay and limulus lysate test. RESULTS: The decrease of blood pressure
      was obviously attenuated (P < 0.01), the survival time was significantly
      increased (P < 0.01) and the concentration of plasma TNF was decreased (P < 0.05)
      in the treated group, compared with those in the control group. The levels of
      endotoxin were of no significant difference between the two groups (P > 0.05).
      CONCLUSION: HDL of human plasma has obvious therapeutic effect on rat endotoxemia
      it could enhance the resistance of rats to endotoxemia, and the mechanism therein
      may be related to the inhibition of the release of TNF.

PMID- 12599432
TI  - [Generation of dendritic cells from healthy human peripheral blood].
AB  - OBJECTIVE: To get high quality and sufficient numbers of mature dendritic cells
      (DC) from healthy human peripheral blood. METHODS: Cultured plastic-adherent
      monocytes were isolated from healthy human peripheral blood by use of granulocyte
      monocyte clony-stimulating factor and Interleukin-4 for 7 days without fed with
      fresh medium and cytokine. RESULTS: A large number of DCs with high purity were
      generated. These DCs expressed HLA-I, II molecules, Costimulating molecules and
      adherent molecules highly, showing the characteristics of mature DC. These DCs
      could stimulate proliferation of allogenic T lymphocytes and had active
      endocytosis ability which peaked at the third day in culture but decreased
      afterwards. CONCLUSION: These results provide evidence that CD monocytes isolated
      from peripheral blood monocytes exhibit dendritic cells characteristics and may
      facilitate further studies of DC and its clinical application.

PMID- 12599433
TI  - [The effects of cholecystokinin octapeptide on PKC activity in rat cerebral
      cortex neurocytes].
AB  - OBJECTIVE: To investigate the effects of CCK8 on protein kinase C activity in rat
      cerebral cortex. METHODS: The cerebral cortex neurocytes were isolated and used
      as a model. The effects of CCK8, L-364, 718 and L-365, 260 on PKC activities were
      detected by using a non-radioactive method. RESULTS: CCK8 caused a detectable
      increase in PKC activity at 10(-11) mol/L, and a peak increase of PKC activity
      was observed at 10(-5) mol/L (about 4.5 U/mg protein). PKC activity was increased
      in dose-dependent manner by CCK8(10(-11)-10(-6) mol/L). The CCKB-selective
      receptor antagonist L-365, 260 with a higher efficiency, and the CCKA-selective
      receptor antagonist L-364, 718 with a lower efficiency were able to block a
      maximal effect of CCK8-induced PKC activation. CONCLUSIONS: CCK8 may regulate PKC
      activities in rat cerebral cortex through CCKB receptor.

PMID- 12599434
TI  - [The effects of fluoride-containing trace element agents on the growth of mutants
      of S. mutans].
AB  - OBJECTIVE: To compare the influence of 6 trace element agents containing fluoride
      versus 6 trace element agents not containing fluoride on the growth of mutants of
      S. mutans and detect the interaction between fluoride and trace elements.
      METHODS: Six trace element agents containing fluoride [SnF2, ZnF2, SrF2, LaF2,
      (NH3)2MoF8, NaF] and 6 trace element agents not containing fluoride [SnCl2,
      SrCl2, LaCl2, ZnAc2, (NH3)2MoO4, NaCl] were selected. The continuous anaerobic
      cultivating technique and the absorbency of bacteria liquid and the count of
      bacteria were used to assess the effects of different agents on the growth of S.
      mutans. RESULTS: NaF, SnF2, SnCl2, ZnF2, ZnAc2, (NH3)2MoF8 and (NH3)2MoO4 were
      found to have strong inhibition effects on the growth of mutant of S. mutans(P <
      0.01). SnF2 had more stronger inhibition effects than SnCl2; ZnF2 had more
      stronger inhibition effects than ZnAc2, no significant differences were seen
      between (NH3)2MoF8 and (NH3)2MoO4. SnF2 and ZnF2 had most potent inhibition
      effects(P < 0.01). No significant differences were observed between SrF2, SrCl2,
      LaCl2, LaF2, NaCl and the control groups(P > 0.05). CONCLUSION: The agents
      containing fluoride and trace elements, such as stannum and zinc had the effects
      of prohibiting the growth of mutant of S. mutans, As far as caries prevention is
      concerned, the agents containing both fluoride and trace elements are more
      effective than mono-fluoride, the potential mechanism may be the synergistic
      action between fluoride and trace elements.

PMID- 12599435
TI  - [The immunogenicity and effect of domestic recombinant human growth hormone:
      serum GH-antibody determination and evaluation].
AB  - OBJECTIVE: To investigate the immunogenicity of a domestic recombinant human
      growth hormone (rhGH) preparation and assess its influence on the growth
      promoting effect. METHODS: We developed a specific and sensitive radioimmuno
      precipitation assay to determine the anti-hGH-antibody (GH-Ab) in serum of GH
      deficient (GHD) children treated with rhGH preparation. The study included 61 GHD
      children (49 boys and 12 girls) who were treated with daily subcutaneous
      injections of rhGH (0.1 IU/Kg) before sleep for six months. The patients' height,
      growth velocity and height standard deviation score were measured prior to and
      after treatment. The binding ratio with 125I-hGH and titer of GH-Abs were
      measured by radioimmuno-precipitation assay; the binding capacity and affinity
      (Ka) were analyzed by competitive RIA and Scatchard plot method. RESULTS: Three
      months after rhGH therapy, serum GH-Abs were detected in 29 patients (48%), and
      their GH-Abs were persistently positive till the end of the trial. Serum GH-Ab
      was not detectable in the other 32 patients (52%) during treatment. The GH-Abs
      positive samples, according to the 125I-hGH binding ratio (B/T%), were divided
      into the weakly positive (B/T < 10%, n = 20) and strong positive (B/T > 15%, n =
      9) groups; their binding capacity, affinity (Ka) and titer were (0.1-4.8) pmol/L,
      (1.7 x 10(7)-6.5 x 10(8))L/mol and 1:4-1:8, respectively. They were weak and not
      available to give negative effect to rhGH activity. The height and growth
      velocity as well as height standard deviation score of the GH-Ab positive
      patients presented no decrease during treatment and were not significantly
      different from that of negative patients. CONCLUSION: The domestic rhGH
      preparation certainly had growth-promoting effect on the children with GHD.
      Nearly forty-eight percent patients showed GH-Ab positive in serum, but due to
      the lower titer and binding capacity, the GH-Ab had no negative effect on the
      height velocity of GHD children.

PMID- 12599436
TI  - [Study on the differentiation of K562 cell-line induced by Tanshinone II A].
AB  - OBJECTIVE: To investigate the effect of Tanshinone II A on K562 cell-line and its
      possible mechanism. METHODS: Cell culture, cytomorphology and cytometrics were
      used. RESULTS: The proliferative inhibition of K562 cells induced by Tanshinone
      II A was dose-independent, and the degrees of erythroid differentiation induced
      by 30 nmol/L ACM and 0.5 microgram/ml Tanshinone II A were not statistically
      different (P > 0.05). CONCLUSION: Tanshinone II A has an inhibitive effect on the
      proliferation of K562 cells and an inductive effect on the differentiation of
      erythrocyte series. The mechanisms may be related to the changes of cell cycle
      and gene expressions.

PMID- 12599437
TI  - [A study on apoptosis of nasopharyngeal carcinoma cell line induced by Tanshinone
      II A and its molecular mechanism].
AB  - OBJECTIVE: To assess effect of Tanshinone II A on the apoptosis of human
      nasopharyngeal carcinoma (NPC) cell line CNE-1 and inquire into the mechanism
      there in involved. METHODS: The CNE-1 cells cultured in vitro were treated with
      0.5 microgram/ml Tanshinone II A for 4 days. The morphology of the cells was
      observed by microscopy. The cell growth and proliferation were measured by cell
      counting. The DNA break was examined by gel electrophoresis. The cell cycle,
      apoptosis index (AI) and the expression of apoptosis associated gene were
      analysed by flow cytometry. RESULTS: 0.5 microgram/ml Tanshinone II A could
      induce the apoptosis of CNE-1 cells. In the treatment group, the morphologic
      characteristics of apoptotic cells were observed, the DNA of cells presented
      "ladder" break, the cell growth and proliferation were inhibited obviously, and
      the AI was 16.9% (the AI of control group was 6.4%). The cells were arrested in
      G0/G1 phase and cellular DNA synthesis was inhibited. The expressions of
      apoptosis associated gene fas, bax, p53 and p21 were up-regulated; the expression
      of bcl-2 was down-regulated. CONCLUSION: Tanshinone II A can induce apoptosis of
      human nasopharyngeal carcinoma cells. Its molecular mechanism may relate to
      modulation of the apoptosis associated gene expression.

PMID- 12599438
TI  - [Isolation and purification of antibacterial polypeptides from human LAK cells].
AB  - OBJECTIVE: To isolate and purify new antibiotic peptides from human lymphokine
      activated killer (LAK) cells. METHODS: Preparative Acid-Urea Polyacrylamide Gel
      Electrophoresis and Reverse Phase HPLC were performed to isolate and purify
      polypeptides from the acid extract of human LAK cells. The molecule weight was
      analyzed by Tricine-SDS-PAGE. Radial agar diffusion assay was used to analyze the
      antibacterial activities. RESULTS: Several antibiotic peptides were isolated. Two
      peptides were purified from fractions HLP-2, HLP-3, which had molecular weight of
      around 7.9 x 10(3) u and 4 x 10(3) u and were named HLP-2b and HLP-3a,
      respectively. Four peptides with molecular weight of 7.2 x 10(3) u, 10.4 x 10(3)
      u, 6.2 x 10(3) u and 6.2 x 10(3) u were almost purified and were named HLP-2a,
      HLP-2c, HLP-3b and HLP-3c, respectively. HLP-2b, HLP-2a, HLP-2c, HLP-3b and HLP
      3c all had antimicrobial activities against S. Aureus and C. Albicans, and HLP-3a
      against S. Aureus only. CONCLUSION: Human LAK cells contained a variety of
      antimicrobial peptides.

PMID- 12599439
TI  - [Study on the activities of fluoroquinolones against Staphylococcus aureus and
      the effect of reserpine on these activities].
AB  - OBJECTIVE: To investigate the activities of fluoroquinolones and the effects of
      reserpine on the activities of fluoroquinolones against S. aureus. METHODS: The
      minimal inhibitory concentration (MICs) and the effects of reserpine on MICs of
      fluoroquinolones against S. Aureus were determined using standard agar dilution
      method. RESULTS: Cross resistance to fluoroquinolones was found existing in S.
      aureus, but there was no remarkable multidrug resistance. The MICs of
      fluoroquinolones against many of S. aureus could be decreased by reserpine;
      Obvious decrease in MICs of fluoroquinolones against SA2-16 was observed; The
      decreasing percentage of MICs of fluoroquinolones against resistant strains was
      shown not significantly higher than that of sensitive strains. The decreasing
      percentage of MICs of hydrophilic fluoroquinolones against the strains studied
      was significantly higher than that of hydrophobic fluoroquinolones. CONCLUSIONS:
      Cross resistance to fluoroquinolones has been found existing in S. aureus,
      whereas multidrug resistance is not seen in existence. The efflux of
      fluoroquinolones is normal in S. aureus; the amount of fluoroquinolones effluxed
      is related with the resistance of fluoroquinolones in S. aureus.

PMID- 12599440
TI  - [Expression of human nerve growth factor gene in E. coli].
AB  - OBJECTIVE: To investigate the structure and function of human nerve growth factor
      (beta-NGF) and the gene encoding beta-NGF. METHODS: A pair of specific primers
      (29 mer) for the sequence encoding human beta-NGF was designed and synthesized. A
      380 bp fragment was amplified from human blood genomic DNA by polymerase chain
      reaction, and cloned into pGEM-T Easy vector. The identified insert fragment from
      the recombinant pGEM-T-NGF was directionally ligated with linearized pGEX-5T with
      the compatible termini. E. coli JM 109 was transformed with the expression
      recombinant p5TNGF and induced by IPTG. RESULTS: The cloned DNA fragment was
      identified as the full-length sequence encoding human beta-NGF by restriction
      analysis and DNA sequencing. SDS-PAGE and Western blot revealed the cloned NGF
      gene expressed as a fusion protein (40.5 x 10(3) u) in the cells transformed by
      p5TNGF. The soluble fusion protein was determined to be 503.2 mg/L, accounting
      for 6.8% of the total soluble protein (7.4 g/L) of bacterial cells. This fusion
      protein was found to have antigenic activities of NGF. CONCLUSION: The clone
      containing the full-length sequence encoding human beta-NGF is obtained and
      successfully expressed in E. coli to be of use for studying the biological
      functions of human beta-NGF gene.

PMID- 12599441
TI  - [Study on GSTs activity in trinitrotoluene cataract].
AB  - OBJECTIVE: To direct the relationship between the activity of glutathione S
      transferases(GSTs) and susceptibility to trinitrotoluene cataract (TC). METHODS:
      KMSL method was used to test the activity of GSTs in 154 cases of TC(group A), 41
      cases of non-trinitrotolune cataract (group B), and 40 normal subjects (group B).
      RESULTS: The activity of GSTs in group TC was significantly lower than that in
      the two control groups (P < 0.01). The differences in GSTs activity were highly
      significant between the four stages of TC (P < 0.01), in which the sequence of
      GSTs activity levels from high to low was the stage of observation, stage I,
      stage II, and stage III. Compared to the persons with gst mu gene, the persons
      without gst mu gene had significantly lower GSTs activity (P < 0.01). It was
      found that the GSTs activity of the persons without gst mu gene in TC group was
      significantly lower than that of the persons without gst mu gene in the two
      control groups (P < 0.01), but the differences in GSTs activity between the
      persons with gst mu gene among the three groups were not significant (P > 0.05).
      The most noticeable correlation was observed between GSTs activity gst mu gene
      deletion (r = 0.702, P < 0.01). CONCLUSION: TC and its stages are closely
      correlated with the activity of GSTs.

PMID- 12599442
TI  - [The growth inhibition of colorectal adenoma cells by sulindac and its
      mechanisms].
AB  - OBJECTIVE: This study was conducted to assess the growth inhibition of colorectal
      adenoma cells by sulindac and identify the possible mechanisms. METHODS: The
      colorectal adenoma cells from human sporadic adenomatous polyps were cultured,
      and then treated with sulindac. The cell viability was examined by MTT
      colorimetric assay; the S-phase fraction and the percentage of apoptosis were
      measured by flow cytometry. RESULTS: Following sulindac treatment at different
      concentrations for 24, 48 and 72 hours, reduction of the cell viability was time-
      and dose-dependent. After 48-hour-treatment, S-phase fraction was decreased and
      the percentage of apoptosis was increased; both indexes of all groups except 0.3
      mmol/L group were different from those of controls (P < 0.05). CONCLUSION: These
      data suggested that sulindac could inhibit the growth of the colorectal adenoma
      cells, and its mechanisms might be related to suppressing proliferation and
      inducing apoptosis.

PMID- 12599443
TI  - [The change of nitric oxide to PGE2 ratio in uterine tissues of endotoxin-treated
      pregnant mice].
AB  - OBJECTIVE: To investigate the relationship between preterm labour and the ratio
      of nitric oxide to prostaglandin E2 in uterine tissues. METHODS: Pregnant mice
      were given lipopolysaccharide(LPS), LPS + DETA/NO, LPS + DETA or saline solution
      respectively by intraperitoneal injection on day 16 of gestation. The delivery
      time of each mouse was recorded. Four separate groups of mice were given
      treatment as described. And they were killed at 12 hours after that. Serum
      progesterone, uterine production of nitrite and PGE2 were measured. RESULTS:
      Uterin production of nitrite and PGE2 in LPS-treated mice was significantly
      higher than that in control mice. In contrast the ratio of nitrite to PGE2
      decreased. Accompanied by the fall of serum progesterone level DETA/NO rather
      than DETA could partially reversed the changes. CONCLUSION: Infection can induce
      preterm labor by altering the ratio of nitric oxide to PGE2. Nitric oxide can
      prevent the decrease of nitric oxide to PGE2 ratio possibly by attenuating the
      fall of serum progesterone. And it can prevent LPS-induced preterm labor.

PMID- 12599444
TI  - [Influence of placenta on fetal hypoxia in intrahepatic cholestasis of
      pregnancy].
AB  - OBJECTIVE: To determine the influence of placenta on fetal hypoxia in
      intrahepatic cholestasis of pregnancy (ICP). METHODS: The transfer of oxygen
      across the placental membranes in ICP group (n = 7) was compared with that of
      controls (n = 8) by dual perfusion of the human placental lobule in vitro.
      RESULTS: The oxygen consumption and the volume loss of perfusate from the fetal
      circuit (< 5 ml/h) of placental lobule from women with ICP are similar to
      controls. The rate of oxygen transfer across the placental membranes in ICP was
      similar to controls, too (P < 0.05, Power > 0.08). These findings suggest that
      the transfer of oxygen across the placental membrane in ICP is normal value.
      CONCLUSION: The placenta in ICP has not direct impact on the fetal oxygenation
      just leads to insufficiency of placental oxygen reserve resulting from a
      reduction in the size of the intervilous space.

PMID- 12599445
TI  - [An epidemiological investigation of perinatal teratomas in China].
AB  - OBJECTIVE: To investigate the prevalence rate and epidemiological features of
      teratomas in China. METHODS: From 1987 through 1992, hospital-based cluster
      sampling method was adopted for collecting data. During that period all live or
      still births with 28 weeks of gestation or more were assessed within 7 days after
      delivery. RESULTS: 238 teratoma cases were identified in 4,489,692 births,
      including 198 isolated and 40 associated forms of teratomas. The prevalence rates
      of total teratomas, isolated and associated forms of teratomas were 0. 53/10000,
      0.44/10000, 0.09/10000 respectively. The prevalence rates in urban areas and
      rural areas were 0.46/10000 and 0.66/10000, respectively. The prevalence rates of
      teratomas in male and female births were 0.80/10000 and 0.27/10000
      correspondingly. The ratio of male to female teratomas was 1:2.76. The perinatal
      fatality rate of teratomas was 55.0%. CONCLUSION: The most frequent teratomas
      were isolated forms. Time trends have not been found in the occurrence of
      teratomas. High prevalence in urban areas has been observed, compared to that in
      rural areas. The prevalence of teratomas in female births is three times as high
      as that in male births. In view of the high fatality rate, prenatal diagnosis and
      perinatal management of teratomas should be strengthened.

PMID- 12599446
TI  - [Change and clinical significance of PEF in smokers, COPD and cor pulmonale
      patients].
AB  - OBJECTIVE: To understand the change and clinical significance of PEF in smokers,
      COPD and cor pulmonale patients. METHODS: The F-V curves were measured in 116
      smokers, 90 COPD (43 with chronic bronchitis, 47 with emphysema) and 31 cor
      pulmonale patients in the ameliorated period. The indices selected were FVC, PEF,
      V75, V50 and V25. RESULTS: The PEF% (measured values/predicted values) in smokers
      and chronic bronchitis patients were higher than 84%(i.e. percentages being
      within the normal range); they were 44% and 32% in patients with emphysema and
      cor pulmonale respectively and decreased with the severity of disease. The
      [formula: see text] (%) in smokers and chronic bronchitis patients were 87.7%
      89.7% (again, percentages being within the normal range); they were 70.7% and
      41.9% in patients with emphysema and cor pulmonale respectively and decreased
      with the severity of disease. The phenomenon that decrease was more conspicuous
      in V75% than in PEF% could be explained with the wave-speed theory. CONCLUSION:
      There is clinical significance in the degree of decrease in PEF% and [formula:
      see text] (%).

PMID- 12599447
TI  - [Immunophenotype of acute leukemia and its clinical significance].
AB  - OBJECTIVE: To examine the immunophenotype of adult acute leukemia and analyze its
      clinical significance. METHODS: Immunophenotypes were examined by direct
      immunofluorescence method and flowcytometry in 69 de novo AL. RESULTS: 1. The
      incidence of myeloid antigen expression in 29 adult ALL was 30%. Among them, CD13
      was 10.3% and CD33 was 20.7%, no difference was found in expression of myeloid
      antigens between B-ALL and T-ALL (P > 0.05). Myeloid antigens were expressed much
      more higher in CD34 positive ALL than in CD34 negative ALL (77.8% vs 13.3%, P =
      0.036). CR rate in myeloid antigen positive ALL was lower than in myeloid antigen
      negative ALL (33.3% vs 80%, P = 0.0203). 2. The incidence of lymphoid antigen
      expression in 40 adult AML was 30%. Among them, CD7 was 15%, CD19 12.5% and CD2
      2.5%. CD7 was mainly expressed in M1 and M2 subtypes. Lymphoid antigens were
      expressed higher in CD34 positive AML than in CD34 negative AML (61.1% vs 4.5%, P
      = 0.000125). Though CR rate was lower in lymphoid antigen positive AML than in
      lymphoid antigen negative AML, no significant difference between them was noted
      (50% vs 71.4%, P = 0.126). CONCLUSION: Aberrant antigen expression in adult acute
      leukemia is about 30%. Antigen aberrant is much higher in CD34 positive AL than
      in CD34 negative AL. The CR rate of antigen aberrant AL is lower than that of
      usual AL.

PMID- 12599448
TI  - [The prophylactic effect of BCG polysaccharides nucleic acid on the acute attack
      of chronic obstructive pulmonary disease].
AB  - OBJECTIVE: To investigate the prophylactic effect of BCG polysaccharides nucleic
      acid (BCG-PSN) on patients with chronic obstructive pulmonary disease and inquire
      about the mechanism thereof. METHODS: Sixty patients with chronic obstructive
      pulmonary disease were divided into two groups. In the treatment group, 36
      patients received BCG-PSN 0.5 mg intramuscular injection, quaque die alterna, for
      18 times. All patients revisited the hospital every 2 weeks and were followed up
      for 6 months. The number and days of patients with acute attack in 3 and 6 months
      were assessed. In the treatment group, the blood samples were collected before
      treatment and 3 and 6 months after treatment for the measurement of the blood
      IgA, IgG, IgM, CD3, CD4 and CD8. RESULTS: The number and days of patients with
      acute attack in the treatment group were significantly lower than those in the
      control group. After the treatment by BCG-PSN, blood CD4 and CD4/CD8 were
      significantly increased. CONCLUSION: BCG-PSN increases the patient's cellular
      immunocompetence and thus serves as a good protection against the acute attack of
      chronic obstructive pulmonary disease.

PMID- 12599449
TI  - [The influence of peritoneal dialysis on the pulmonary function of patients with
      end-stage renal disease].
AB  - OBJECTIVE: To demonstrate the change of pulmonary function in patients with end
      stage renal disease(ESRD) before and after peritoneal dialysis (PD). METHODS: In
      this study were measured the forced vital capacity (FVC), maximum breathing
      capacity (MBC), the forced expiratory volume of the first second (FEV1), maximal
      expiratory flow (MEF), maximal mid-expiratory flow rate (MMEF), 25% of maximal
      expiratory flow (V25), and the diffusion of co in lung (DLco) for 50 patients
      with end-stage renal disease and 20 normal subjects. All the indexes were
      determined again in 30 ESRD patients two months after peritoneal dialysis.
      RESULTS: The indexes of pulmonary ventilation (FVC, MBC, FEV1, PEF, MMEF, V25)
      and the pulmonary diffusion DLco were lower in the ESRD patients than in the
      controls. FEV1, PEF, MMEF and V25 were improved markedly after peritoneal
      dialysis in ESRD patients (P < 0.05); FVC, MBC, and DLco were of no change (P >
      0.05). CONCLUSION: The function of pulmonary ventilation and diffusion are
      decreased in patients with ESRD accompanied with airways obstruction. Peritoneal
      dialysis can improve airways obstruction remarkably, but it has no effect on the
      function of pulmonary ventilation and diffusion.

PMID- 12599450
TI  - [A method for rapid and early diagnosis of trisomy 21 using molecular
      techniques].
AB  - OBJECTIVE: Using molecular techniques, we typed 2 short tandem repeat (STR) loci
      on 21 chromosome to establish the method for rapid and accurate diagnosis of
      trisomy 21. METHODS: Genomic DNA samples from 50 individuals diagnosed previously
      by karyotype as trisomy 21 and 40 children with severe mental retardation (IQ <
      50) suspected of trisomy 21 were analyzed for 2 short tandem repeat loci on 21
      chromosome, D21S1435 and D21S2055. Typing was carried out after polymerase chain
      reaction (PCR) and silver staining. The trisomy was identified by the number of
      alleles: 3 alleles bands whose density is same, two alleles bands with one
      obvious higher density compared to the other and one allele band whose density is
      three times than the normal control. RESULTS: All of the complete trisomy 21 were
      detected by this method; the parental source was easily determined. CONCLUSION:
      This method for diagnosing trisomy 21 is rapid and accurate.

PMID- 12599451
TI  - [Using purified conjugated bilirubin as a calibrator for bilirubin measurement].
AB  - OBJECTIVES: To improve the accuracy and precision of the determination of
      bilirubin, especially direct bilirubin (DB), and the standardization of that as
      well. METHODS: Purified conjugated bilirubin (Bc) and ditaurobilirubin(DTB) and
      their diazo products were subjected to absorption spectrum analysis. The diazo
      reaction characters of their calibration solutions were compared by the method of
      Doumas J-G(TB & DB). RESULTS: Bc, DTB and their azopigments were found to have
      the similar absorption spectra with the same lambda max. Their TB standard curves
      almost superposed together all over. Although the slopes of their DB standard
      curves were not markedly different ((YBc = 0.00366X + 0.00933, rBc2 = 0.9977, P <
      0.01; YDTB = 0.00391X + 0.00023, rDTB2 = 0.9987, P < 0.01; Pb1-b2 > 0.05, n1 = n2
      = 5), the DB value measured for Bc differed from that for DTB(n = 5, P < 0.05).
      In addition, the calibrators made from Bc based different matrices, such as HSA,
      BSA and human serum, were significantly different in DB/Bc, but no difference was
      seen among the concentrations. Furthermore, the DB values determined for DTB or
      Bc increased linearly with the corresponding concentrations, respectively, with
      no difference between the slopes (YBc = 0.8300XBc + 1.9463, rBc2 = 0.9977, P <
      0.01; YDTB = 0.8853XDTB-0.0251, rDTB2 = 0.9986, P < 0.01; n1 = n2 = 5, Pb1-b2 >
      0.05). CONCLUSIONS: The results demonstrate that the diazo reaction characters of
      Bc are identified with those of DTB. However, under the condition of DB, Bc
      reacts differently from DTB. This study also indicates that as a calibrator of DB
      based human serum, Bc has the similar constant effect of HCl as serum samples do,
      so it is a more reliable calibrator to eliminate the matrix effects.

PMID- 12599452
TI  - [Determination of IgG content of IVIG by improved rocket immune electrophoresis].
AB  - OBJECTIVE: To establish a specific method for determination of IgG in IVIG.
      METHODS: The IVIG samples were disposed by acylation and analyzed by Rocket
      Immunoelectrophoresis. The amount of the IgG in IVIG was calculated by an IgG
      standard curve. RESULTS: The standard curve by this method has a very good linear
      relationship: r = 0.9967. The reproducibilities with 3 bathes of IVIG samples (n
      = 6) are 5.37% +/- 0.21%, 5.28% +/- 0.39% and 5.80% +/- 0.30%. CONCLUSION: This
      method could be adapted to regular assay in blood products.

PMID- 12599453
TI  - [The primary culture methods of colorectal adenoma cells].
AB  - OBJECTIVE: To improve the primary cell culture methods of colorectal adenomas.
      METHODS: The methods of the in vitro primary cell culture of colorectal adenomas,
      mainly the method for taking and preparing specimen, the methods of culture
      conditions and cells purification, were considered again and improved in this
      study. RESULTS: Of the 32 cases, of polyp, 26 were successfully cultured and 6
      failed. The culture lasted 5-23 days with 50%-95% viscosity of wells. By means of
      immuno-histochemical staining and electromicroscopy, the cultured cells were
      proved to be of epithelial origin. CONCLUSION: The primary culture methods of
      adenoma cells have been improved, but further study on the serial transfer
      culture cell lines is most needed.

PMID- 12599454
TI  - [Quantitative analysis of IGF-1 and its application in the diagnosis of prostate
      cancer].
AB  - OBJECTIVE: To quantify the level of insulin-like growth factor (IGF-1) in serum
      and investigate its role in the diagnosis of prostate cancer. METHODS: IGF-1
      immunoradiometric assay (IRMA) was set up and used to determine serum IGF-1 level
      in patients with prostate cancer (n = 81), benign prostate hyperplasia (BPH, n =
      55), uroepithelial tumor (n = 32) and healthy male controls (n = 84).
      Furthermore, the levels of IGF-1 and prostate-specific antigen (PSA) in 38
      patients with BPH were determined every three months for one year. RESULTS:
      Linearity was well demonstrated for IGF-1 in the range of 8-1000 ng (r = 0.98),
      the lowest limit for detecting IGF-1 being 2 mg/L and the mean recovery for
      detecting IGF-1 being 94.5%. The within-replicate coefficient of variance (CV) of
      IGF-1 detection was 7.2% for a higher level (382.4 mg/L) and 4.2% for a low level
      (32.5 mg/L) of IGF-1. Insulin, growth factor or IGF-2 did not interfere with the
      detection of IGF-1 (< 3 ml/L). There was high level of IGF-1 in patients with
      prostate cancer than in healthy controls, patients with BPH and uroepithelial
      tumor (P < 0.05); the odds ratio and its 95% confidence intervals were 2.86 and
      1.38-5.34, respectively; the specificity and sensitivity of IGF-1 determination
      were 0.68 and 0.58, respectively; furthermore, the level of IGF-1 was increased
      during the development of prostate cancer. CONCLUSIONS: These findings
      demonstrate that IGF-1 may serve prospectively as an important tumor marker in
      the diagnosis and prediction of prostate cancer.

PMID- 12599456
TI  - Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols.
AB  - [formula: see text] The kinetic resolution of racemic epoxides via catalytic
      enantioselective rearrangement to allylic alcohols was investigated. Using the Li
      salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as
      catalyst allowed both epoxides and allylic alcohols to be obtained in an
      enantioenriched form.

PMID- 12599455
TI  - [Simultaneous determination of 13 polycyclic aromatic hydrocarbons in indoor air
      by HPLC].
AB  - OBJECTIVE: To establish a method for the simultaneous determination of 13
      polycyclic aromatic hydrocarbons (PAHs) in indoor air by high performance liquid
      chromatography (HPLC) using methanol/water as mobile phase. METHODS: The
      analytical procedure involves collecting indoor airborne PAHs on quartz fiber
      filter, ultrasonic extraction with methanol, transferring PAHs to methanol after
      blowing off the solvent with nitrogen gas followed with separation and
      quantitation with reverse-phase HPLC using gradient elution and fluorescence
      programmed multiple wavelength shift detection. The separation and determination
      parameters were optimized. PAHs were spiked to evaluate the accuracy of the
      method. RESULTS: The detection limits of 13 PAHs varied from 0.11 to 11.7 pg. The
      recoveries ranged between 80.7% and 112.1%. The within-day (n = 5) and between
      day (n = 6) relative standard deviations were 0.5%-5.5% and 2.4%-9.1%
      respectively. CONCLUSIONS: This method is rapid, economical, accurate, and
      suitable for determining the trace PAHs in indoor air.

PMID- 12599457
TI  - The first catalytic asymmetric addition of dialkylzincs to alpha-ketoesters.
AB  - [formula: see text] The first catalytic, enantioselective addition of organoznic
      reagents to alpha-ketoesters is described. Modular bifunctional salen catalysts
      that contain Lewis acid and Lewis base activating groups accelerate the carbonyl
      addition to a much greater extent than the competing carbonyl reduction. alpha
      Hydroxyesters containing new quaternary stereogenic centers are obtained in high
      yield and moderate enantiomeric excess. Enrichment to 98% ee can be effected by
      recrystallization of the corresponding alpha-hydroxy acid.

PMID- 12599458
TI  - Fluorous, chromatography-free Mitsunobu reaction.
AB  - [formula: see text] The reaction of secondary and primary alcohols with highly
      fluorinated 3,4,5-tris(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12
      heptadecafluorododecan- 1-yloxy)benzoic acid in the presence of Ph3P and DIAD in
      THF at room temperature (fluorous Mitsunobu) resulted in a simple, chromatography
      free isolation protocol with excellent yields (83-96%).

PMID- 12599459
TI  - On the endo/exo stereoselectivity of intramolecular Diels-Alder reactions of
      hexadienylacrylates: an interesting failure of density functional theory.
AB  - [formula: see text] A combined experimental and computational study of endo/exo
      stereoselectivity in a series of IMDA reactions of hexadienylacrylates has found
      that DFT makes erroneous predictions when the endo and exo transition states
      possess differing degrees of conjugation. These problems are overcome by carrying
      out calculations at the MP2 level of theory, which gives remarkably accurate
      Boltzmann distributions of products. These findings are used to predict ways to
      obtain either endo- or exo-cycloadducts exclusively.

PMID- 12599460
TI  - Synthesis of the beta 2 agonist (R)-salmeterol using a sequence of supported
      reagents and scavenging agents.
AB  - [formula: see text] The enantioselective synthesis of (R)-salmeterol has been
      achieved by using a sequence of supported reagents and sequestering agents. The
      saligenin core was installed by a regiospecific alkylation and a chiral
      auxilliary approach was employed to introduce the desired stereochemistry via a
      diastereoselective reduction.

PMID- 12599461
TI  - Cyclization of aryl silanes with unexpected retention of silicon.
AB  - [formula: see text] Intramolecular Friedel-Crafts cyclization of 2-O-benzyl
      ethers at a model pyranose acetal is activated by incorporation of a
      trimethylsilyl group, albeit via unexpected, presumably steric means.

PMID- 12599462
TI  - Highly enantioselective 1,4-addition of diorganozinc reagents to cyclic enones
      using chiral diphosphite ligands derived from H8-binaphthol.
AB  - [formula: see text] High enantioselectivities have been achieved in the 1,4
      addition of dialkylzincs to 2-cyclopentenone, 2-cyclohexenone, and 2
      cycloheptenone with ee values up to 99% by using chiral aryl diphosphite ligands
      derived from H8-binaphthol.

PMID- 12599463
TI  - Direct synthesis of unprotected 4-aryl phenylalanines via the Suzuki reaction
      under microwave irradiation.
AB  - [formula: see text] 4-Aryl phenylalanines were prepared as free amino acids from
      the Suzuki coupling of 4-borono phenylalanine with aryl halides in high yields
      within 5-10 min under microwave irradiation.

PMID- 12599464
TI  - A practical synthesis of meso-monosubstituted, beta-unsubstituted porphyrins.
AB  - [formula: see text] A simple straightforward synthesis for meso-monosubstituted,
      beta-unsubstituted porphyrins is reported. Porphyrins of this type are easily
      prepared by condensation of dipyrromethane, pyrrole-2-carbaldehyde, and the
      desired aromatic or aliphatic aldehyde. The method can be used for a variety of
      functional groups with yields between 2 and 12%. In most cases, the 5, 15
      disubstituted porphyrin is obtained as a second product but can be removed
      easily.

PMID- 12599465
TI  - Diastereoselective titanium enolate aldol reaction for the total synthesis of
      epothilones.
AB  - [formula: see text] The development of a highly diastereoselective addition of
      the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient
      entry to the total synthesis of the epothilone family. The new aldol process is
      robust and tolerates a wide range of functional groups.

PMID- 12599466
TI  - SAR and pH stability of cyano-substituted epothilones.
AB  - [formula: see text] 3-Cyano epothilones 15-18 are the only examples of non
      hydroxy C-3-substituted analogues. Their tubulin binding affinity and
      cytotoxicity provide meaningful structure-activity relationship information on
      the dependence of C-1/C-3 conformation upon activity. 12-Cyano epothilone 24 has
      improved pH stability over epothilone B, and its activity further supports the
      hypothesis that C-12 stereochemistry is not critical for tubulin affinity.

PMID- 12599467
TI  - Isoapoptolidin: structure and activity of the ring-expanded isomer of
      apoptolidin.
AB  - [formula: see text] Apoptolidin (1) is a novel oncolytic lead that induces
      apoptosis in transformed cell lines with exceptional selectivity. We report the
      isolation and characterization of a ring-expanded macrolide isomer of
      apoptolidin: isoapoptolidin (2). The solution conformation of isoapoptolidin is
      described. The rate of isomerization was measured under biologically relevant
      conditions and found to approach equilibrium within the time frame of most cell
      based assays. Isoapoptolidin's ability to inhibit mitochondrial F0F1-ATPase is
      over 10-fold less than that of apoptolidin.

PMID- 12599469
TI  - A mild protocol for allylation and highly diastereoselective syn or anti
      crotylation of aldehydes in biphasic and aqueous media utilizing potassium allyl-
      and crotyltrifluoroborates.
AB  - [formula: see text] Potassium allyl- and crotyltrifluoroborates undergo addition
      to aldehydes in biphasic media as well as water to provide the corresponding
      homoallylic alcohols in high yields (> or = 94%), excellent diastereoselectivity
      (dr > or = 98:2), and without the necessity of any subsequent purification. The
      presence of a phase transfer catalyst (e.g., nBu4NI) significantly accelerates
      the rate of reaction, whereas added fluoride ion retards the reaction.

PMID- 12599468
TI  - Toward a stable apoptolidin derivative: identification of isoapoptolidin and
      selective deglycosylation of apoptolidin.
AB  - [formula: see text] Isoapoptolidin was isolated from crude fermentation extracts
      of the apoptolidin-producing microorganism Nocardiopsis sp. Apoptolidin
      isomerizes to isoapoptolidin upon treatment with methanolic triethylamine to
      establish a 1.4:1 equilibrium mixture of isoapoptolidin and apoptolidin.
      Semisynthesis of a peracetylated and deglycosylated derivative of apoptolidin is
      also described.

PMID- 12599470
TI  - A new method for the preparation of unprotected peptides on biocompatible resins
      with application in combinatorial chemistry.
AB  - [formula: see text] A synthetic strategy for the preparation of side chain free
      peptides on biocompatible solid supports is described. Final peptide detachment
      is afforded in mild basic conditions with no presence of scavengers or other
      additives, thus allowing single peptide-resin beads to be cleaved in mass
      spectrometry sample plates for direct sequencing using MALDI-TOF post-source
      decay. This methodology offers clear advantages for the development of one-bead-
      one-compound combinatorial libraries in addition to parallel and regular
      synthesis of peptides.

PMID- 12599471
TI  - Tandem asymmetric conjugate addition--silylation of enantiomerically enriched
      zinc enolates. Synthetic importance and mechanistic implications.
AB  - [formula: see text] The zinc enolates, resulting from the copper-catalyzed
      enantioselective conjugate addition of dialkyl zinc reagents to cyclic and
      acyclic enones, could be trapped, quantitatively, as silyl enol ethers with
      TMSOTf in apolar solvents or with TMSCI and NEt3. These enantiomerically enriched
      silyl enol ethers were submitted to four synthetic transformations to show their
      synthetic utility. The zinc enolates obtained from acyclic enones were found to
      be configurationally stable, as shown by the stereochemistry of the silyl enol
      ethers.

PMID- 12599472
TI  - Chemoselective esterification of phenolic acids and alcohols.
AB  - [formula: see text] The Mitsunobu reaction can distinguish between alcohol and
      phenol hydroxyls in esterification reactions, providing an expeditious and
      broadly applicable entry into various phenolics and polyphenolics of biomedical
      and nutritional relevance.

PMID- 12599473
TI  - Carbon nucleophiles in the Mitsunobu reaction. Mono- and dialkylation of
      bis(2,2,2-trifluoroethyl) malonates.
AB  - [formula: see text] Simple dialkyl malonate esters, for example diethyl malonate,
      exhibit relatively limited scope as carbon nucleophiles in the Mitsunobu
      dehydrative alkylation reaction. In contrast, bis(2,2,2-trifluoroethyl) malonate
      readily undergoes dehydrative alkylation with primary alcohols, and using only a
      slight excess of malonate gives monoalkylated product in good yield. Some
      secondary alcohols can also be employed, and bis(2,2,2-trifluoroethyl) malonates
      can be used in a second dehydrative alkylation to give dialkylated products in
      good to excellent yield.

PMID- 12599474
TI  - Highly selective entry to the azadirachtin skeleton via a Claisen
      rearrangement/radical cyclization sequence.
AB  - [formula: see text] A highly diastereoselective, microwave-induced Claisen
      rearrangement of an appropriately substituted propargylic enol ether allows the
      formation of the sterically congested C8-C14 bond of azadirachtin. When combined
      with a radical-mediated cyclization of the corresponding allene, this sequence
      offers rapid entry to the framework of azadirachtin.

PMID- 12599475
TI  - A highly fluorous room-temperature ionic liquid exhibiting fluorous biphasic
      behavior and its use in catalyst recycling.
AB  - [formula: see text] A novel fluorous room-temperature ionic liquid, 1-butyl-3
      methyl-imidazolium tetrakis[p-[dimethyl(1H, 1H, 2H, 2H
      perfluorooctyl)silyl]phenyl]-borate (1), was used as a solvent for the
      homogeneous hydrosilylation of 1-octene catalyzed by a fluorous version of
      Wilkinson's catalyst. The catalyst was recycled by biphasic separation with an
      average retention of catalyst activity of 94%. As opposed to other ionic liquids,
      1 exhibits high miscibility with apolar compounds such as alkenes and resembles
      fluorous solvents in its phase behavior with organic solvents.

PMID- 12599476
TI  - Ruthenium-catalyzed ROM-RCM of cycloalkene-yne.
AB  - [formula: see text] ROM-RCM (ring-opening and ring-closing metatheses) of
      cycloalkene-yne was demonstrated using a second-generation ruthenium complex.
      When cycloalkene bearing the alkyne moiety at the C-1 position was reacted with a
      ruthenium-carbene complex under an atmosphere of ethylene, ROM-RCM proceeded
      smoothly to give bicyclic compound and/or dimeric compound in good yields.

PMID- 12599477
TI  - A flexible route to (5R)-thiolactomycin, a naturally occurring inhibitor of fatty
      acid synthesis.
AB  - [formula: see text] A new and efficient asymmetric synthesis of naturally
      occurring (5R)-thiolactomycin (1) using D-alanine as the source of chirality is
      described.

PMID- 12599478
TI  - Rational design of vitamin D3 analogues which selectively restore activity to a
      vitamin D receptor mutant associated with rickets.
AB  - [formula: see text] Vitamin D3-resistant rickets (VDRR) is associated with
      mutations to the Vitamin D receptor (VDR) which effect ligand-dependent
      transactivation. Some VDRR associated mutants directly disrupt ligand binding.
      Using the reported VDR-1,25-dihydroxy vitamin D3 (1,25(OH)2D3) cocrystal
      structure, three 1,25(OH)2D3 analogues were designed to uniquely complement the
      rickets associated mutant VDR(Arg274-->Leu). The three analogues were 17 to 286
      times more potent than 1,25(OH)2D3 with the mutant in cell-based assays and did
      not substantially activate cellular calcium influx.

PMID- 12599479
TI  - 5-amino-2'-deoxyuridine, a novel thymidine analogue for high-resolution
      footprinting of protein-DNA complexes.
AB  - [formula: see text] 5-Amino-2'-deoxyuridine 5'-triphosphate, an analogue of
      deoxythymidine triphosphate, was synthesized and found to be a substrate of Taq
      DNA polymerase. The DNA-borne analogue underwent selective chemical reaction with
      permanganate. The use of 5-amino-dU as an interference probe was validated using
      the Ada protein/ada promoter complex. The performance of 5-amino-dU in
      interference footprints is similar to that of the previously described analogue 5
      hydroxy-dU, but the former is incorporated more readily into DNA during enzymatic
      polymerization.

PMID- 12599480
TI  - Synthesis of 1,3-difluoroaromatics in one pot by addition of difluorocarbene from
      sodium chlorodifluoroacetate to 1,2-substituted cyclobutenes.
AB  - [formula: see text] The synthesis of 1,3-difluoro-2,4-diphenylbenzene has been
      accomplished in one step from 1,2-diphenylcyclobutene using the environmentally
      benign difluorocarbene precursor sodium chlorodifluoroacetate. In addition, the
      preparation of the previously unknown compound 1,3-difluoro-2,4-di-n
      propylbenzene has been accomplished in one step from 1,2-di-n-propylcyclobutene
      using Seyferth's reagent (Ph-Hg-CF3) and sodium chlorodifluoroacetate.

PMID- 12599481
TI  - Synthesis of 2,6-dideoxysugars via ring-closing olefinic metathesis.
AB  - [formula: see text] Grubbs' RuCl2 (=CHPh)(PCy3)2 (catalyst 1) and
      RuCl2(=CHPh)(PCy3)(IMess) (catalyst 2) complexes have been successfully utilized
      in the construction of beta,gamma-unsaturated delta-lactones containing various
      substitution patterns of methyl groups. Asymmetric dihydroxylation followed by
      reduction leads to 3,4-cis-dihydroxy-2,6-dideoxypyranoses, which have proven to
      play very important biological roles as key components of natural products.

PMID- 12599482
TI  - Synthesis of photochromic 1,2-dihetarylethene using regioselective acylation of
      thienopyrroles.
AB  - [formula: see text] The influence of catalysts, acid chlorides, and solvents in
      the acylation of methyl 2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate was
      studied. Conditions for the regioselective acylation processes were found.
      Thienopyrrole-based photochrome was synthesized for the first time.

PMID- 12599483
TI  - Design and development of a common synthetic strategy for a variety of 1-N
      iminosugars.
AB  - [formula: see text] A new synthetic strategy has been developed for a general
      approach toward the synthesis of a variety of 1-N-iminosugar-type glycosidase
      inhibitors utilizing precursors developed by the PET-mediated cyclization of
      alpha-trimethylsilylmethylamine radical cation to a tethered pi-functionality.

PMID- 12599484
TI  - Enantio- and diastereoselective synthesis of cis-2-aryl-3-methoxycarbonyl-2,3
      dihydrobenzofurans via the Rh(II)-catalyzed C-H insertion process.
AB  - [formula: see text] The enantioselective intramolecular C-H insertion reaction of
      aryldiazoacetates has been explored with use of dirhodium(II) carboxylate
      catalysts, which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino
      acids as chiral bridging ligands. Dirhodium tetrakis[N-phthaloyl-(S)-tert
      leucinate], Rh2(S-PTTL)4, has proven to be the catalyst of choice for this
      process, providing exclusively cis-2-aryl-3-methoxycarbonyl-2,3-dihydobenzofurans
      in up to 94% ee.

PMID- 12599486
TI  - A one-pot synthesis of beta-C-glucopyranosides from exo-glucal, p-tolylsulfenyl
      chloride, an alpha-methoxyalkene, and an external nucleophile.
AB  - [formula: see text] beta-C-Glycosides were synthesized in one-pot experiments
      using the following sequence of four reactions: (i) addition of p-TolSCl to an
      alpha-methoxyalkene, (ii) generation of the episulfonium ion from a beta
      (arylsulfanyl)alkyl chloride, (iii) reaction of the episulfonium intermediate
      with benzylated exo-D-glucal to form a cyclic five-membered sulfonium salt, and
      (iv) quenching of the sulfonium salt with the external nucleophile: H2O, CH3OH,
      or NaCNBH3.

PMID- 12599485
TI  - Synthetic and mechanistic studies of the retro-Claisen rearrangement. 4. An
      application to the total synthesis of (+)-Laurenyne.
AB  - [formula: see text] A novel asymmetric total synthesis of marine natural product
      (+)-Laurenyne has been achieved. The key elements of the strategy are the
      sequential metal ion-templated SN2' cyclization affording a highly functionalized
      chiral vinyl cyclobutane and a retro-Claisen rearrangement for the construction
      of an eight-membered ring ether.

PMID- 12599487
TI  - Bleach/acetic acid-promoted chlorinative ring expansion of [2.2.1]- and [2.2.2]
      bicycles.
AB  - [formula: see text] Treatment of vinyl-substituted [2.2.1]- and [2.2.2]
      bicyclocarbinols with NaOCl and AcOH provides [3.2.1]- and [3.2.2]-beta-chloro
      bicycloketones, respectively. For [2.2.2]-bicycles, these chlorinative ring
      expansions are particularly efficient and selective.

PMID- 12599488
TI  - Palladium(II)-catalyzed three-component coupling reaction initiated by
      acetoxypalladation of alkynes: an efficient route to gamma,delta-unsaturated
      carbonyls.
AB  - [formula: see text] A divalent palladium-catalyzed coupling reaction of electron
      deficient alkynes and acrolein or MVK (methyl vinyl ketone) was developed. The
      reaction provides an efficient method to synthesize gamma,delta-unsaturated
      carbonyls. A mechanism involving acetoxypalladation of alkyne, followed by
      insertion of alkene and protonolysis of the C-Pd bond, is proposed. The
      protonolysis of the carbon-palladium bond with the assistance of bidentate
      nitrogen containing ligands is the key step in this tandem reaction.

PMID- 12599489
TI  - [1.1](3,3')-azobenzenophane: novel crystal structure and cis-trans isomerization
      of distorted azobenzene.
AB  - [formula: see text] [1.1](3,3')-Azobenzenophane, in which two azobenzenes are
      cyclically connected by -CH2- chains at the meta positions, has been synthesized.
      The crystal structures of all isomers have been revealed. This is the first
      report on the crystal structure of the cis isomer of macrocyclic azobenzenes. The
      trans,trans isomer was slightly distorted, the trans,cis isomer highly deformed,
      and the cis,cis isomer unstrained. The thermal stability of cis isomers in
      solutions are deducible from the crystal structures.

PMID- 12599490
TI  - A unique spherical molecular host with D2d symmetry. A novel intramolecular
      kinetic equilibrium in metal ion complexation between two crown ethers.
AB  - [formula: see text] A spherical host with D2d symmetry consisting of a
      tetrathia[3.3.3.3]paracyclophane and two 18-crown-6 moieties was synthesized. Its
      crystal structure shows a central cavity with a diameter of 1.96 A and a depth of
      6.75 A. A Na+ ion could rest in the cavity center but prefers core binding to
      external binding in one of the crown units. An intramolecular kinetic equilibrium
      was reached with the Na+ ion switching between the two crown units with an energy
      barrier of 14.1 +/- 3 kcal/mol.

PMID- 12599491
TI  - An approach to serrulatane diterpenes via endo-selective conjugate nucleophilic
      addition to arene-Cr(CO)3 complexes.
AB  - [formula: see text] Starting from a nonracemic planar-chiral arene tricarbonyl
      chromium complex, the serrulatane diterpenoid (+)-20-methoxy-serrulat-14-en-7,8
      diol was synthesized in a highly stereoselective fashion. The key step of the
      synthesis is an endo-selective conjugate nucleophilic addition of lithio
      methylphenyl sulfone to a 1-ethylidene-tetralin-Cr(CO)3 derivative. By employing
      different substrates and nucleophiles it was shown that the surprising and rather
      general endo selectivity must result from a unique complex induced proximity
      effect under participation of the Cr(CO)3 moiety.

PMID- 12599493
TI  - Solution-phase parallel synthesis of carbamates using polymer-bound N
      hydroxysuccinimide.
AB  - [formula: see text] A convenient method for the synthesis of carbamates using
      polymer-supported N-hydroxysuccinimide is described. Various carbamates were
      synthesized in highly pure form without the need for chromatographic
      purification. This new "catch and release"-type solid-phase synthesis should be
      useful for combinatorial synthesis of various carbamates.

PMID- 12599492
TI  - Synthesis of (-)-centrolobine by Prins cyclizations that avoid racemization.
AB  - [formula: see text] The segment-coupling Prins cyclization avoids two of the
      problems common to other Prins cyclization protocols: side-chain exchange and
      partial racemization by reversible 2-oxonia Cope rearrangement. Model studies
      demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy
      ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we
      propose a mechanism for the racemization observed in some intermolecular Prins
      cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine
      highlight the utility of Prins cyclizations.

PMID- 12599494
TI  - The first immobilization of pyridine-bis(oxazoline) chiral ligands.
AB  - [formula: see text] A chiral pyridine-bis(oxazoline) ligand, functionalized with
      a vinyl group in the pyridine ring, can be polymerized with styrene and
      divinylbenzene to obtain supported chiral ligands. As proof of the usefulness of
      this supported ligands, the corresponding ruthenium complexes are catalysts for
      the cyclopropanation reaction of styrene with ethyl diazoacetate with up to 85%
      ee.

PMID- 12599495
TI  - Second-generation synthesis of the polypropionate subunit of callystatin A based
      on regioselective internal alkyne hydrostannation.
AB  - [formula: see text] An improved route to the polypropionate segment of
      callystatin A is described in which the efficient directed hydrostannation of an
      internal alkyne and subsequent iodinolysis provides a key vinylic iodide
      intermediate.

PMID- 12599496
TI  - Solid-phase synthesis of imidazo[1,2-a]pyridine using sodium benzenesulfinate as
      a traceless linker.
AB  - [formula: see text] The preparation of the first library of imidazo[1,2
      a]pyridine derivatives on a solid support is described. A sulfone linker strategy
      was applied in the synthesis. Key steps involved in the solid-phase synthetic
      procedure include (i) alpha-haloketone resin formation by sulfinate-->sulfone
      alkylation, (ii) imidazo[1,2-a]pyridine ring formation by treatment with 2
      aminopyridine, (iii) sulfone anion alkylation, and (iv) traceless product release
      by oxidation-elimination. A library of 12 imidazo[1,2-a]pyridines was
      synthesized.

PMID- 12599497
TI  - Conformational preference and configurational control of highly symmetric
      spirobi[dibenzazepinium] cation.
AB  - [formula: see text] Stereodynamics were detected in solution for salts of the
      simple spirobi[dibenzazepinium] cation in favor of the homochiral (D2) conformer
      as evidenced by chiral TRISPHAT and BINPHAT counterions; asymmetric induction was
      furthermore observed in 1H and 15N NMR spectroscopy.

PMID- 12599498
TI  - Convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin.
AB  - [formula: see text] The convergent synthesis of the ABCDEF-ring system of
      yessotoxin and adriatoxin was accomplished. This efficient convergent strategy
      was performed on the basis of the coupling of the acetylide of the A-ring and the
      triflate of the DEF-ring, oxidation of the alkyne to diketone, intramolecular
      diacetalization, and stereoselective reduction of the diacetal with Et3SiH
      TMSOTf.

PMID- 12599499
TI  - New supported beta-amino alcohols as efficient catalysts for the enantioselective
      addition of diethylzinc to benzaldehyde under flow conditions.
AB  - [formula: see text] Polymeric monoliths 10 containing an amino alcohol moiety
      derived from an industrial waste material represent one of the best ligands for
      the enantioselective catalytic addition of ZnEt2 to benzaldehyde (99% ee), being
      recoverable and usable under flow conditions.

PMID- 12599500
TI  - Enantioselective synthesis of slagenins A-C.
AB  - [formula: see text] An enantioselective synthesis of slagenins A-C (1a-c) is
      described in which their absolute stereochemistries were established. The key
      step in the synthesis involved the efficient condensation of 2-methoxy-dihydro
      furan-3-one 9 and urea to construct the slagenin bicycle core.

PMID- 12599501
TI  - Oxidative aromatization of 1,3,5-trisubstituted pyrazolines and Hantzsch 1,4
      dihydropyridines by Pd/C in acetic acid.
AB  - [formula: see text] 1,3,5-Trisubstituted pyrazolines and Hantzsch 1,4
      dihydropyridines were converted to the corresponding pyrazoles and pyridines
      effectively by the treatment of a catalytic amount of Pd/C in acetic acid.

PMID- 12599502
TI  - Synthesis of the 5-7-6 core of guanacastepenes. Construction of C8 quaternary
      carbon via the inversion of stereochemistry.
AB  - [formula: see text] An efficient and unique route to the 5-7-6 core of
      guanacatepene A (1) is described. The installation of the desired stereochemistry
      at the C8 position was achieved via the desymmetrization of the cyclohexadienone
      by reductive ring closure of the seven-membered ring. That the closure of the
      seven-membered ring produced only the desired isomer is hypothesized to be a
      result of the more stable trans relationship between the C8 and C11 methyl
      groups.

PMID- 12599503
TI  - Synthesis of C-linked glycopyranosyl serines via a chiral glycine enolate
      equivalent.
AB  - [formula: see text] The stereoselective preparation of C-linked D-gluco- and D
      galactopyranosyl L-serines in their alpha and beta forms is herein reported. The
      syntheses require the conversion of the allyl C-glycopyranosides into their
      iodoethyl derivatives, which then undergo substitution with the Williams' chiral
      glycine enolate equivalent. Deprotection and acetylation affords Boc-protected
      amino acids for peptide synthesis.

PMID- 12599504
TI  - Novel thermal reaction of Fischer carbene complexes with imines: synthesis of
      beta-methoxy allylic amine derivatives.
AB  - [formula: see text] Alkyl-substituted chromium Fischer carbene complexes were
      found to react with various N-tosylimines to give beta-methoxy allylic amine
      derivatives under thermal conditions. This result is essentially distinct from
      the photochemical outcome in which beta-lactam derivatives are obtained.

PMID- 12599505
TI  - An electrochemically controllable nanomechanical molecular system utilizing edge
      to-face and face-to-face aromatic interactions.
AB  - [formula: see text] A new molecular system, 2,11
      dithio[4,4]metametaquinocyclophane containing a quinone moiety, was designed and
      synthesized. As the quinone moiety can readily be converted into an aromatic pi
      system (hydroquinone) upon reduction, the nanomechanical molecular cyclophane
      system exhibits a large flapping motion like a molecular flipper from the
      electrochemical redox process. The conformational changes upon reduction and
      oxidation are caused by changes of nonbonding interaction forces (devoid of bond
      formation/breaking) from the edge-to-face to face-to-face aromatic interactions
      and vice versa, respectively.

PMID- 12599506
TI  - Enantiospecific synthesis of the antituberculosis marine sponge metabolite (+)
      puupehenone. The arenol oxidative activation route.
AB  - [formula: see text] The total synthesis of the marine sesquiterpene quinone (+)
      puupehenone, a promising new antituberculosis agent, was achieved in 10 steps
      starting from commercially available (+)-sclareolide. The key feature of this
      synthesis is the construction of the heterocycle via an intramolecular attack of
      the terpenoid-derived C-8 oxygen function onto an oxidatively activated 1,2
      dihydroxyphenyl unit.

PMID- 12599507
TI  - Stereoselective synthesis of L-oliose trisaccharide via iterative alkynol
      cycloisomerization and acid-catalyzed glycosylation.
AB  - [formula: see text] The synthesis of an all-alpha L-oliose diastereomer of
      digitoxin provides valuable insights into the generality and protective-group
      dependence of acid-catalyzed glycosylations of glycals to 2-deoxycarbohydrates.

PMID- 12599508
TI  - Cobalt nanoparticles on charcoal: a versatile catalyst in the Pauson-Khand
      reaction, hydrogenation, and the reductive Pauson-Khand reaction.
AB  - [formula: see text] Dispersions of nanometer-sized cobalt particles with very
      high stability were prepared in charcoal and analyzed by electron microscopy and
      X-ray analysis. The resulting cobalt nanoparticles on charcoal (CNC) were
      successfully used as a catalyst for the carbonylative cycloaddition of alkyne,
      alkene, and carbon monoxide (Pauson-Khand reaction), hydrogenation, and the
      reductive Pauson-Khand reaction.

PMID- 12599509
TI  - Seizing the opportunity.

PMID- 12599510
TI  - Application of nursing diagnoses, interventions, and outcomes to patients
      undergoing abdominal surgery in Korea.
AB  - PURPOSE: To identify nursing diagnoses, interventions, and outcomes used with
      patients undergoing abdominal surgery, and the links among them. METHODS: A
      review of the nursing records of 60 patients undergoing abdominal surgery. Three
      checklists developed by the researchers were used to document nursing diagnoses
      made, interventions specified, and outcomes selected. FINDINGS: Pain was the most
      frequent diagnosis, "pain management" the most frequent intervention, and Pain
      Level the most frequent outcome. Further study is needed with various samples and
      settings. CONCLUSIONS: Most of the suggested NIC-NANDA interventions and NOC
      NANDA outcomes listed in NANDA Nursing Diagnoses: Definitions and Classification,
      1999-2000, were used in this study, but some additional interventions and
      outcomes should be considered for inclusion. PRACTICE IMPLICATIONS: This study
      provides a framework for documenting nurses' work; the results of the study can
      promote more rapid computerization of nursing records.

PMID- 12599511
TI  - Validation of the nursing diagnosis anxiety in adult patients undergoing bone
      marrow transplant.
AB  - PURPOSE: To validate the nursing diagnosis anxiety as experienced by adult
      patients undergoing bone marrow transplant (BMT). METHODS: Using a descriptive,
      longitudinal design, data were collected on the first day of conditioning, 25
      days later, and 100 days post-transplant. Study tools included the State/Trait
      Anxiety Inventory (STAI), the Graphic Anxiety Scale (GAS), and the Defining
      Characteristics Tool (DCT). FINDINGS: A significant positive correlation was
      found between patient STAI and GAS scores and STAI and DCT scores at Times 1 and
      2, between DCT and GAS scores at Time 2, and between patient DCT scores and
      significant other DCT scores at Times 1 and 2. Eighteen critical and supporting
      defining characteristics were identified by the patient, 20 by the significant
      other, and 9 by the nurse. Significant others were found to be a valid resource
      in identification of the patients' level of anxiety, as well as the defining
      characteristics of anxiety. CONCLUSIONS: A tool that consists of the critical and
      supporting defining characteristics of anxiety, as experienced by patients
      undergoing BMT, is recommended for further development and testing. Use of a
      visual analog scale to assess anxiety in clinical environments should be
      considered. PRACTICE IMPLICATIONS: Availability of clinically valid and reliable
      tools to help assess anxiety in this patient population could enhance patient
      outcomes. Recognizing and incorporating significant others' assessment of patient
      anxiety is important data to be considered in the planning and delivery of
      patient care.

PMID- 12599512
TI  - Essential differences between evidence-based nursing and evidence-based medicine.

PMID- 12599513
TI  - [Changes in streptococcal infections].

PMID- 12599514
TI  - [An autopsied case of chronic active Epstein-Barr virus infection complicated in
      systemic lupus erythematosus and antiphospholipid antibody syndrome].
AB  - We have experienced a case of chronic active Epstein-Barr virus infection (CAEBV)
      complicated in systemic lupus erythematosus (SLE) and antiphospholipid antibody
      syndrome (APS). A 35-year-old woman was admitted to our hospital with complaints
      of fever and dyspnea on exertion. She was diagnosed as having SLE on the basis of
      arthritis, oropharyngeal ulcer, lymphopenia, and positive autoantibodies against
      DNA, RNP and SSA. The diagnosis of APS was also made because of positive anti
      cardiolipin IgG antibodies and the existence of multiple pulmonary infarction
      with pulmonary hypertension. The administration of 30 mg/day of prednisolone and
      anti-coagulation significantly improved clinical symptoms. However, she was again
      admitted to the hospital four months later because of progressive liver damage
      and pancytopenia. Increment of prednisolone did not improve the clinical
      situation and she expired because of pulmonary hemorrhage. At autopsy, there were
      a significant increase of histiocytes with hemophagocytosis and a dense
      infiltration of atypical lymphocytes in the liver, spleen, lymph nodes and bone
      marrow. Infiltrated lymphocytes were positive for CD 3 and EBER 1 in
      immunohistochemical staining and EBVmRNA was detected by in situ hybridization.
      Final pathological diagnosis was CAEBV with hemophagocytic syndrome in
      association with lupus nephritis, pulmonary hemorrhage and pulmonary infarction.

PMID- 12599515
TI  - [A case of Sjogren's syndrome with marked lacrimal gland enlargement, atypical
      onset and IgA-M-proteinemia].
AB  - Since July, 1999, a 66 year-old man had been complaining of dry cough. He noticed
      submandibular swelling, lacrimal gland enlargement and dry eye.
      Keratoconjuctivitis sicca was detected by an ophthalmologist. Sjogren's syndrome
      was diagnosed based on microscopic findings of a labial salivary gland biopsy
      although anti-SS-A and anti-SS-B antibodies were negative. Hypergammaglobulinemia
      (IgG 3916 mg/dl) and IgA-M-proteinemia were pointed out. Swelling of mediastinal
      and abdominal lymph nodes was detected together with enlargement of salivary and
      lacrimal glands. We suspected the existence of malignant lymphoma, but a biopsy
      of lacrimal glands showed only lymphocytic and plasma cell infiltration and
      immunohistochemical analysis denied monoclonality of lymphoid line. An
      administration of corticosteroids caused rapid diminution in size of lacrimal and
      submandibular glands and lymph nodes. Clinical symptoms were also improved, but
      IgA-M proteinemia remains. The characteristics of our case were enlargement of
      lacrimal glands, the negativity of anti SS-A and SS-B antibodies, atypical onset
      and M-proteinemia. We discussed about these characteristics of Sjogren's syndrome
      in our case.

PMID- 12599516
TI  - [Anti-neutrophil cytoplasmic autoantibody-associated rapid progressive
      glomerulonephritis complicated with both limited and diffuse scleroderma].
AB  - We report two patients with scleroderma, 73-year-old female and 67-year-old
      female, who developed anti neutrophil cytoplasmic autoantibody (ANCA) associated
      rapid progressive glomerulonephritis (RPGN). Both patients have had a long
      history of scleroderma (23 and 14 years, respectively) when ANCA-associated
      glomerulonephritis occurred. In the first patient, scleroderma was localized in
      both fingers. She has been followed-up as CREST syndrome rather than systemic
      sclerosis. The complaints on admission were leg edema and left chest pain in the
      first patient, and a pyrexia and dyspnea in the second patient. Both patients
      showed pulmonary manifestation (pleural effusion in the first patient,
      interstitial pneumonia and alveolar hemorrhage in the second patient,
      respectively) and rapid progressive glomerulonephritis. Both patients died in
      spite of corticosteroid therapy. Autopsy findings in the second patient
      demonstrated crescentic glomerulonephritis and alveolar hemorrhage. Our cases
      demonstrated that MPO-ANCA associated glomerulonephritis could be associated with
      limited scleroderma as well as systemic scleroderma. In these condition, the
      prognosis will be poor if scleroderma seemed to be stable.

PMID- 12599517
TI  - [Gamma knife radiosurgery for brain metastases].

PMID- 12599518
TI  - [Changes in GABA and neural functions induced by gene targeting of GABA
      synthesizing enzyme, GAD].

PMID- 12599519
TI  - [Long-term treatment of Parkinson's disease patients with selegiline
      hydrochloride (FPF 1100): outcome of 5-year treatment].
AB  - We herein report on the outcome of 5 year-treatment of Parkinson's disease
      patients with selegiline hydrochloride. The subjects participated in this study
      were 10 patients whose treatment had been maintained consecutively by
      administration of this agent even after completion of the Phase II trial (all
      cases under adjunct therapy with L-DOPA/DCI). The daily dose of selegiline
      hydrochloride was 6.6 +/- 2.5 mg in average at the end and/or termination of the
      study. As for L-DOPA, its daily dose decreased from 410 +/- 160 mg to 365 +/- 133
      mg at the 6th month, but the dose reduction level after 9 months was not
      determinable due to an increase in dropouts. Regarding alteration in the scores
      for individual symptoms, improvement in wearing-off symptom was pronounced during
      the treatment period of 3 to 51 months. The Global Improvement Rate and
      Usefulness Rate remained stable during the period of 18 to 30 months treatment
      although these rates declined after 36 months probably because of exacerbation in
      disease conditions. This study may assure tolerability of selegiline
      hydrochloride in a long-term treatment of Parkinson's disease patients.

PMID- 12599521
TI  - [Transient improvement of writing tremor by holding breath in volition: a case
      report].
AB  - We report a 76-year-old Japanese woman who had tremor of her hand during writing.
      Her past and family histories were unremarkable. On neurological examination,
      there was no abnormal finding except the writing tremor and the postural tremor
      of her lips and jaw. Surface EMG studies revealed that regular grouped
      discharges, at a frequency of about 5 Hz, appeared in the wrist flexor and
      extensor muscles soon after she start writing; these grouped discharges were
      inhibited while holding breath. Her postural tremor improved after consumption of
      a small amount of alcohol, suggesting that she had essential tremor. Thus, she
      may be diagnosed as having a variant of essential tremor. On the other hand, this
      tremor may be interpreted as a variant of writer's cramp, since her writing
      tremor transiently improved when she hold breath, just like a trick. In patients
      with dystonia, it is well known that dystonic symptoms can be temporally
      ameliorated by geste movement like a "trick". Although the pathophysiological
      relationship between primary writing tremor and writer's cramp are unclear, the
      unique characters of this tremor may suggest that a focal task-specific tremor
      and essential tremor can co-exist.

PMID- 12599520
TI  - [Consciousness disturbance caused by iodoform absorption in a patient with
      decubitus ulcer topically treated with iodoform-gauze].
AB  - A 76-year-old man with supranuclear palsy, developed consciousness disturbance
      followed by the treatment of decubitus ulcer in the sacral region using iodoform
      gauze. He was semicoma and tachycardia. His pupils were miotic and light reflexes
      were absent. EEG demonstrated diffuse and random slow activities. Plasma
      concentration of free iodine was high (151 micrograms/dl), but the other
      laboratory findings including thyroid functions were normal. He was diagnosed as
      suffering from iodoform poisoning. The symptoms and laboratory abnormalities of
      the patient recovered soon after the removal of iodoform-gauze. Although iodoform
      has been widely used for the treatment of wounds, there are few case reports of
      its side effects, such as consciousness disturbance, delirium, headache and
      tachycardia.

PMID- 12599522
TI  - [A case of thoracic spondylosis presented with an attack of abnormal sensation
      and hyperhydrosis on the upper back].
AB  - A 23-year-old man presented an attack of abnormal sensation and hyperhydrosis on
      his upper back when he was tense or took a bath. This presentation continued for
      a month after commencement of Judo practise. Neurological examination found
      hyperactivity of bilateral deep tendon reflex alone. Magnetic resonance image
      demonstrated that the anterior thoracic spinal cord at the Th 4/5, 5/6 and 7/8
      level were compressed by a bony spur. In our case, limitation of exercise, and
      prescription of adenosine triphosphate disodium and vitamin B led to a favourable
      outcome. Thoracic spondylosis in a young person is rare and there have been no
      standard protocols for the treatment. Thus, further clinical investigations are
      warranted.

PMID- 12599523
TI  - [A case of cervical pyogenic spondylitis difficult to differentiate from
      metastatic spinal tumor].
AB  - A 52-year-old man with medical complications of diabetic mellitus and alcoholic
      liver dysfunction, presented with weakness in the bilateral lower extremities.
      Cervical magnetic resonance images disclosed the lesion extended from
      retropharyngeal space and multiple vertebral bodies to epidural space of the
      spinal canal, which was enhanced by gadolinium. Not only fever elevation during
      clinical course but also inflammatory reaction on selologic examination were not
      identified, so we initially thought the lesion metastatic spinal tumor. In
      researching original foci, his clinical condition worsened with gate disturbance
      and urinary incontinence. Eleven days later after admission, laminectomy from C-5
      to Th-1 and open biopsy of the lesion was performed. The vertebral bodies exposed
      via the right frontal approach were covered by thick whitish membrane. Small
      mount of pus emerged after incision of the membrane, so we diagnosed the lesion
      pyogenic spondylitis. After the operation, high dose antibiotic therapy for 6
      weeks was performed. Follow-up cervical MR imaging 4 months after the operation
      found that the volume of the lesion and compression of the spinal cord were
      reduced. The gate disturbance and urinary incontinence gradually improved, he was
      able to walk with a cane 6 months later.

PMID- 12599524
TI  - [Late-onset nonketotic hyperglycinemia: a case report].
AB  - We report a 66-year-old woman who developed mental deterioration in her school
      days, and progressive gait disturbance, dysarthria and bradykinesia in her 40 s.
      Her parents were consanguineous, and the two of her brothers were suspected to
      have the allied disorder. On physical examination, she was short-statured and
      high-arched palate was observed. Neurological examination revealed dementia,
      abnormal eye movement, dysarthria, spastic paraparesis with hyperreflexia,
      bilateral Babinski signs, cerebellar ataxia and dysuria. Brain MRI showed marked
      hypoplasia of corpus callosum with dilatation of lateral ventricles and cerebral
      sulci and significant cerebellar atrophy. Amino acid analyses showed significant
      elevation of glycine without ketosis in serum, cerebrospinal fluid, and urine,
      which lead us to the diagnosis of late-onset nonketotic hyperglycinemia(NKH). NKH
      is known to be a rare autosomal recessive metabolic disorder primarily caused by
      deficient activity of various components of the mitochondrial glycine cleavage
      system. Onset of the disease occurs most often in early infancy, however, later
      onset variants have been described. Usually, late-onset NKH only manifests mild
      mental deterioration, character change, seizure, ataxia or spastic paraparesis,
      which sometimes makes difficulty in differentiating this disease from other
      hereditary cerebellar ataxia or spastic paraparesis. In addition, many structural
      brain abnormalities have been reported accompanied with NKH, and especially,
      agenesis or hypoplasia of corpus callosum is the most characteristic feature in
      this disease. Therefore, we emphasized that amino acid analyses should be
      considered in any patients who have cerebellar ataxia or spastic paraparesis of
      unknown cause with these neuroradiological findings.

PMID- 12599525
TI  - [A case of calvarial aneurysmal bone cyst: transcranial contrast sonographic
      examination with pulse inversion harmonic imaging method].
AB  - A 31-year-old female came to our hospital complaining of left frontal bulging
      with pain on 10 August 2000. The head x-p showed a radiolucent lesion and bulging
      at the same calvarial site. CT scan and MRI showed fluid-fluid levels, diploic
      cyst, deformity and hypertrophic calvarial change. There was a partial
      hypervascular part of cyst adjacent to the left frontal base by selective left
      external carotid angiography. Harmonic image is a contrast specific imaging
      modality that uses the nonlinear properties of contrast agents by transmitting at
      the fundamental frequency and receiving at multiples of these frequencies. Pulse
      inversion harmonic image(PIHI) using pulse inversion to eliminate and strengthen
      the harmonic frequency is more effective than conventional harmonic imaging.
      Transcranial sonographic examination showed hyper- and hypoechoic appearances in
      the cyst around abnormal hyperechoic appearances of the calvarial site. The
      transcranial contrast sonographic images with PIHI (hereinafter TCIpi)
      demonstrated an enhanced intracystic lower stratum and nearby the diploic part.
      That modality facilitates better visualization than the harmonic imaging method,
      enabling differentiation of vascular from avascular areas. As contrast agents are
      microbubbles, those are restricted in the vascular canal space. So TCIpi findings
      proved to be a blood circulation of the tumor, cyst and neighboring tissue.
      Enhanced areas changed by every minute and disappeared gradually. The findings
      were probably based on the vascular component of the tumor. We obtained images
      similar to those with CT and MRI. The patient underwent on 21 August. The tumor
      was removed along with the surrounding skull component. Fresh and old blood were
      mixed in the cyst. The clinical and pathological diagnosis was aneurysmal bone
      cyst. The postoperative course was uneventful and she was discharged on 29
      August. Aneurysmal bone cyst is a rare calvarial tumor. An diagnostic finding is
      fluid-fluid levels that appear in approximately 30% of aneurysmal bone cysts.
      However, this is not a specific finding and has also been reported to occur in
      osteosarcoma, malignant fibrous histiocytoma, fibrous dysplasia, synovial
      sarcoma, hemangioma and simple bone cyst. Therefore, diagnosis of aneurysmal bone
      cyst is based on a combination of the various imaging applications, clinical and
      pathological findings. Gometz reported that sonographic examination was superior
      to any diagnostic imaging studies for aneurysmal bone cyst. Furthermore, the
      perfusion examination like TCIpi can directly observe blood circulation channels
      in tissue, so the specific enhancement changes of aneurysmal bone cyst could be
      observed. TCIpi is a useful method for diagnosis of aneurysmal bone cyst.

PMID- 12599526
TI  - [beta-lactamase-producing activity and antimicrobial susceptibility of major
      pathogenic bacteria isolated from clinical samples. Japan beta-lactamase Research
      Group].
AB  - beta-Lactamase production and susceptibility to an assortment of antimicrobial
      agents were examined in 9,483 strains of organisms isolated from clinical
      materials obtained from inpatients and outpatients at 104 institutions throughout
      Japan from December 1999 to February 2000. The organisms were Staphylococcus
      aureus, 1,369 strains, including 847 methicillin-resistant (MRSA) strains;
      Enterococcus faecalis, 735 strains; Enterococcus faecium, 302 strains; Moraxella
      (Branhamella) catarrhalis, 730 strains; Haemophilus influenzae, 1,142 strains;
      Escherichia coli, 1,276 strains; Klebsiella pneumoniae, 1,058 strains;
      Enterobacter cloacae, 772 strains; Serratia marcescens, 847 strains; and
      Pseudomonas aeruginosa, 1,252 strains. The 23 antimicrobial agents used were
      ampicillin, sulbactam/ampicillin, clavulanic acid/amoxicillin, oxacillin,
      piperacillin, cefazolin, cefotiam, cefmetazole, cefoperazone,
      sulbactam/cefoperazone, cefotaxime, ceftazidime, cefepime, cefpodoxime, imipenem,
      gentamicin, arbekacin, clarithromycin, minocycline, chloramphenicol, vancomycin,
      teicoplanin, and levofloxacin. Antimicrobial agents appropriate for each organism
      were used. Among S. aureus strains, 61.9% were MRSA, and 62.3% were positive for
      beta-lactamase. Among the MRSA strains, none was resistant to vancomycin or
      teicoplanin, and only 3% were resistant to arbekacin. There was no vancomycin
      resistance in the Enterococcus strains. Only 0.1% of E. faecalis strains were
      ampicillin-resistant. Among the M. catarrhalis strains, 97.5% produced beta
      lactamase, while among the H. influenzae strains, 8.5% produced beta-lactamase
      and 14.5% were beta-lactamase-negative and ampicillin-resistant (BLNAR). Among
      the Enterobacteriaceae and P. aeruginosa strains, there were 20 (E. coli;
      7/1,276, K. pneumoniae; 13/1,058) that produced extended-spectrum beta-lactamases
      (ESBLs), and 11 that produced class B beta-lactamases. Multiple drug resistance
      was advanced in every species, and organisms resistant to 7 or more common
      antimicrobial agents were isolated. The best combination of antimicrobial agent
      and beta-lactamase inhibitor was sulbactam/cefoperazone. Sulbactam/cefoperazone,
      cefepime, and imipenem still have excellent antimicrobial activity. Rates of
      resistance to each antimicrobial agent differed more among institutions than
      among geographical regions.

PMID- 12599527
TI  - [Identification and classification of beta-lactamases in clinical isolates of
      bacteria].
AB  - Emergence of bacterial resistance has rendered ineffective a number of previously
      valuable antibiotic treatments and now threatens the effectiveness of others.
      beta-Lactam resistance is no longer predominantly a hospital-treated problem; it
      has now become an important issue in community medicine. More than 100-beta
      lactamases have been identified and classified according to their structure,
      substrate specificity, and whether they are chromosomal or plasmid-mediated. beta
      Lactamase production is rare among Gram-positive pathogens, important exceptions
      being Staphylococcus aureus and Enterococcus faecalis. By contrast, many Gram
      negative pathogens are beta-lactamase-positive; inducible and/or hyper-productive
      strains are particularly challenging in the clinical setting. Surveillance
      programs have shown that, in general, beta-lactam resistance is on the increase,
      and that the plasmid-mediated beta-lactamase have developed rapidly over past
      decade such as ESBLs and carbapenemases.

PMID- 12599528
TI  - [Antibiotic susceptibility and beta-lactamase activity of pathogenic microbes
      isolated in Miyagi Prefecture between December in 1999 and February in 2000].
AB  - We determined beta-lactamase activity and antimicrobial susceptibility of 556
      strains consisting of 10 species isolated in four medical institutions and one
      microbiological laboratory of Miyagi Prefecture in Japan between December in 1999
      and February in 2000. beta-Lactamase determined by nitrocefin method was positive
      in 68% of S. aureus, in 15% of H. influenzae and in 100% of M. catarrhalis.
      Penicillinase/cephalosporinase determined by acidometry was positive in 9%/10% of
      E. coli, in 17%/2% of K. pneumoniae, in 16%/58% of E. cloacae, in 43%/78% of S.
      marcescens, and in 4%/32% of P. aeruginosa, respectively. Of a total of 298
      strains of Enterobacteriaceae and P. aeruginosa, 25 strains (14 strains of E.
      coli, 10 strains of K. pneumoniae and one strain of S. marcescens) produced class
      A beta-lactamase, two strains of E. cloacae produced class B beta-lactamase, and
      12 strains (one strain of E. coli, four strains of E. cloacae, six strains of S.
      marcescens and one strain of P. aeruginosa) produced class C beta-lactamase.
      According to NCCLS standard, three strains (one strain of E. coli and two strains
      of K. pneumoniae) of ESBL-positive microbes were detected. beta-Lactamase
      negative ampicillin-resistant (BLNAR) strains of H. influenzae were found in
      10/40 (25.0%) of the strains tested.

PMID- 12599529
TI  - [Antimicrobial susceptibility and beta-lactamase producibility of bacteria
      clinically isolated during the period from December 1999 to February 2000].
AB  - Antimicrobial susceptibility and beta-lactamase producibility were tested in 848
      clinical strains collected at 8 hospitals in Kanagawa prefecture during the
      period from December 1999 to February 2000. Positive rates of beta-lactamase used
      the nitrocefin method (Cefinase) were 21.9% of Staphylococcus aureus, 10.0% of
      Haemophilus influenzae, and 99.0% of Moraxella catarrhalis. Furthermore, on the
      acidometric method (P/Case test) penicillinase (PCase), cephalosporinase
      (CEPase), and both of PCase and CEPase were found to be positive in 19.0%, 16.0%,
      and 16.0% for Escherichia coli, 6.2/0/3.1% for Klebsiella pneumoniae,
      0/66.3/26.5% for Enterobacter cloacae, 2.8/57.7/15.5% for Serratia marcescens,
      and 4.0/15.0/22.0% for Pseudomonas aeruginosa, respectively. Based on the
      assessment of minimal inhibitory concentrations (MICs) of antibacterial agents
      among beta-lactamase producing strains, there were 5 strains (4 strains of K.
      pneumoniae and 1 strain of E. coli) that may be ESBLs producing bacteria out of a
      total of 466 strains of Enterobacteriaceae and P. aeruginosa. During this
      process, 1 strain of class-B beta-lactamase-producing E. cloacae was isolated.
      MRSA were found in 79.2% of S. aureus, and BLNAR were found in 8.9% of H.
      influenzae.

PMID- 12599530
TI  - [Antimicrobial susceptibility and beta-lactamase types among clinical isolates
      during January and February 2000 in the Kinki area of Japan].
AB  - We studied antimicrobial susceptibility and beta-lactamase types among clinical
      isolates in the Kinki area of Japan. Eight hundreds isolates of eight organisms
      were collected by seven medical institutions during January and February 2000.
      The rates of beta-lactamase producing by using the chromogenic nitrocephin test
      were 68.0% against Staphylococcus aureus isolates, 6.0% against Haemophilus
      influenzae isolates, 98.0% against Moraxella catarrhalis isolates. The rate of
      beta-lactamase negative ampicillin-resistant H. influenzae was 4.0% (4 out of
      100). The result of beta-lactamase producing by using the acid-metric method were
      as follows the penicillinase and cephalosporinase: 27.0% and 37.0% against
      Escherichia coli isolates, 37.0% and 1.0% against Klebsiella pneumoniae isolates,
      21.8% and 100% against Enterobacter cloacae isolates, 24.2% and 96.0% against
      Serratia marcescens isolates, 7.0% and 22.0% against Pseudomonas aeruginosa
      isolates. We identified beta-lactamase type of each isolate detected by
      polymerase chain reaction: SHV-derived extended-spectrum beta-lactamase (ESBLs)
      (1 isolate of E. coli and 1 isolate of K. pneumoniae), CTX-M-1-derived ESBLs (1
      isolate of K. pneumoniae, 1 of E. cloacae and 4 of S. marcescens), and IMP-1
      derived metallo beta-lactamases (2 isolates of S. marcescens).

PMID- 12599532
TI  - [Drug sensitivity and beta-lactamase producibility of various types of bacteria
      clinically isolated during the period from December 1999 to February 2000].
AB  - beta-Lactamase activity and drug sensitivity were measured in 744 strains from 8
      species of bacteria isolated at medical institutions in Chikugo District of
      Fukuoka Prefecture during the period from December 1999 to February 2000.
      Nitrocefin test revealed that beta-lactamase was positive in 48% of S. aureus, 7%
      of H. influenzae, and 92% of M. catarrhalis, and acidometry revealed that
      penicillinase/cephalosporinase were positive in 13%/14% of E. coli, 22%/8% of K.
      pneumoniae, 47%/97% of E. cloacae, 3%/65% of S. marcescens, and 10%/36% of P.
      aeruginosa. Based on the assessment of the MIC values of various types of
      antibacterial drugs for beta-lactamase-producing strains, there were 11 strains
      (1 strain of K. pneumonia, 6 strains of E. cloacae, and 4 strains of P.
      aeruginosa) of class-B beta-lactamase-producing bacteria out of a total of 496
      strains of Enterobacteriaceae and Pseudomonas aeruginosa. The results of PCR
      analysis suggested that 1 strain of K. pneumonia, 1 strain of E. cloacae, and 4
      strains of P. aeruginosa produced metallo-beta-lactamase. There was no strain (E.
      coli and K. pneumoniae) of ESBL-producing bacteria. BLNAR strains, on the other
      hand, were found in 9% (9/100) of H. influenzae.

PMID- 12599531
TI  - [Beta-lactamase activity and susceptibilities to antibiotics among some species
      of bacteria isolated from medical institution between December 1999 and February
      2000].
AB  - We studied the beta-lactamase activity and susceptibilities to antibiotics in 604
      strains among 10 species of bacteria isolated from 10 medical institutions in
      Tottori and Shimane Prefectures between December 1999 and February 2000. beta
      Lactamase activity was measured by the nitrocefin test and
      penicillinase/cephalosporinase activities were measured by acidometry. beta
      Lactamase activity was detected in 72.1% of S. aureus, 18.8% of H. influenzae,
      and 96.3% of M. catarrhalis. Penicillinase/cephalosporinase activities were
      detected in 17.8%/22.2% of E. coli, 9.7%/0.0% of K. pneumoniae, 18.6%/95.3% of E.
      cloacae, 12.7%/79.4% of S. marcescens, and 7.1%/31.8% of P. aeruginosa. Three of
      72 strains (4.2%) of K. pneumoniae and 5 of 90 strains (5.6%) of E. coli were
      assessed as ESBL-producing bacteria using the NCCLS proposed screening method
      based on routine susceptibility testing results. BLNAR were detected in 13 of 69
      strains (18.8%) of H. influenzae.

PMID- 12599533
TI  - [Antimicrobial susceptibility and prevalence of beta-lactamase producing clinical
      isolates in southern Kyushu. The results of collaborative study from 1999 to
      2000].
AB  - The positivity of beta-lactamase and antimicrobial susceptibility were determined
      in a total of 1,358 clinical isolates at 15 hospitals and clinics in four
      prefectures in southern Kyushu (Okinawa, Miyazaki, Kagoshima and Kumamoto) during
      the period from December 1999 to February 2000. The isolates collected comprised
      of 176 strains of S. aureus, 203 of H. influenzae, 102 of M. catarrhalis, 206 of
      E. coli, 153 of K. pneumoniae, 99 of E. cloacae, 95 of S. marcescens, 201 of P.
      aeruginosa, 79 of E. faecalis, and 44 of E. faecium. The frequency of CPDX
      resistance among E. coli in particular varied geographically, and was found to be
      higher in Kumamoto and Kagoshima. The strains of K. pneumoniae and E. cloacae
      resistant to common antimicrobial agents were particularly found in Kagoshima,
      and one strain of IPM-resistant E. cloacae was isolated in Miyazaki. Also, the
      geographical difference in the frequency of LVFX resistance among the isolates of
      E. cloacae was noted, the results indicating the higher prevalence in Okinawa and
      Kagoshima. Resistant isolates of P. aeruginosa were less common in Kagoshima, and
      four isolates of P. aeruginosa from Miyazaki were found to be resistant to CAZ
      and IPM. None of the isolates of S. aureus and Enterococcus spp. was resistant to
      VCM or TEIC at all. The isolates of E. faecalis resistant at high-level GM (500
      micrograms/ml) and SM (1,000 micrograms/ml) were found in 27.8% and 22.8%, and
      those of E. faecium were 6.8% and 38.6%, respectively. Overall, the ratio of MRSA
      among S. aureus was 67.6%, and three isolates were resistant to ABK with no less
      than 8 micrograms/ml of MIC. The frequency of BLNAR (beta-lactamase-negative,
      ampicillin resistant) among H. influenzae isolated in Okinawa was markedly higher
      (isolation ratio, 37.9%) when compared with other prefectures, and the isolates
      of BLPACR (beta-lactamase-positive, AMPC/CVA resistant) were found only in
      Okinawa with a ratio of 41.6%. A total of 18 strains of ESBL defined by the NCCLS
      criteria (M100-S11) were isolated, eight strains of K. pneumoniae and 10 strains
      of E. coli. Of 18 isolates of ESBL, 13 were from Kagoshima and the remaining five
      were from Kumamoto.

PMID- 12599534
TI  - [Antimicrobial susceptibility and beta-lactamase productivity of recent clinical
      isolates during the period between December 1999 and February 2000].
AB  - Antimicrobial susceptibility testings of 24 antimicrobial agents against 605
      clinical strains belonging to 10 species were carried out according to the micro
      broth dilution method of NCCLS M7-A4. The productivity of beta-lactamase was also
      determined against them isolated at 8 medical facilities in Nagano prefecture,
      Japan during the period between December 1999 and February 2000. When applied the
      nitrocefin method, beta-lactamase productivity was demonstrated to be positive
      for 89.2% of 74 S. aureus, 4.3% of 94 H. influenzae, and 100% of 69 M. (B.)
      catarrhalis isolates. On the other hand, when used the acidometry method,
      penicillinase/cephalosporinase were found to be positive for 21.2%/9.6% of 52 E.
      coli, 29.0%/3.2% of 31 K. pneumoniae, 53.2%/100% of 47 E. cloacae, 0%/11.1% of 99
      S. marcescens, and 25.9%/55.6% of 54 P. aeruginosa isolates, respectively. Among
      the beta-lactamase-producers including P. aeruginosa isolates, only 2 E. coli
      isolates were found to be ESBL-producers. Besides, 9.6% (9/94) of H. influenzae
      isolates were proved to be BLNAR strains.

PMID- 12599536
TI  - [Anatomy and physiology of the prostate].

PMID- 12599538
TI  - [Hormonal regulation and abnormality of the prostate].

PMID- 12599537
TI  - [Hormone receptors in human prostate].

PMID- 12599539
TI  - [Molecular and endocrinological mechanism of benign prostatic hyperplasia and
      prostate cancer].

PMID- 12599541
TI  - [Prostatitis syndrome].

PMID- 12599540
TI  - [Molecular diagnosis and gene therapy for prostate cancer].

PMID- 12599542
TI  - [Summary and characteristics of 'General rule for clinical and pathological
      studies on prostate cancer (the 3rd edition)'].

PMID- 12599543
TI  - [Epidemiological trends of prostate cancer in Japan and international
      comparisons].

PMID- 12599544
TI  - [Natural history of prostate cancer].

PMID- 12599545
TI  - [Statistical analysis of prostate cancer in Japan].

PMID- 12599546
TI  - [Hormone dependency of prostate cancer].

PMID- 12599547
TI  - [Mutations of oncogenes and tumor suppressor genes in prostate neoplasms].

PMID- 12599548
TI  - [The mechanism and predictive factors of hormone-independent recurrence of
      prostate cancer].

PMID- 12599549
TI  - [Histological classification of prostate cancer with clinicopathological
      implication].

PMID- 12599550
TI  - [Staging system for prostate cancers].

PMID- 12599551
TI  - [Clinicopathological features of prostate cancer].

PMID- 12599552
TI  - [Overview of diagnosis of prostate cancer].

PMID- 12599553
TI  - [The use of prostate specific antigen in prostate cancer--prediction for
      treatment failure].

PMID- 12599554
TI  - [PSA density, PSATZ, PSA velocity and PSA doubling time].

PMID- 12599555
TI  - [Free/total PSA ratio].

PMID- 12599556
TI  - [The present status and future directions for standardization of PSA assays in
      PSA gray zone].

PMID- 12599557
TI  - [Clinical usefulness of transrectal ultrasonography in screening and staging for
      prostate cancer].

PMID- 12599558
TI  - [MRI and proton MR spectroscopy for diagnosis of prostatic cancers].

PMID- 12599559
TI  - [Bone scintigraphy for diagnosis of bone metastasis in patients with prostatic
      cancer].

PMID- 12599560
TI  - [Prostatic needle biopsy].

PMID- 12599561
TI  - [Prostate specific membrane antigen (PSMA) as a role of tumor marker].

PMID- 12599562
TI  - [Detection of PSA mRNA and PSMA mRNA by RT-PCR].

PMID- 12599563
TI  - [IGF-1, IGFBP-3, PICP, ICTP].

PMID- 12599564
TI  - [Serum chromogranin A in prostate cancer].

PMID- 12599565
TI  - [Prognostic significance of interleukin-6 in patients with prostate cancer].

PMID- 12599566
TI  - [Treatment strategy for prostate cancer].

PMID- 12599567
TI  - [Characteristics, effects, side effects of the LH-RH agonist].

PMID- 12599568
TI  - [Time to normalization of testosterone after withdrawal of long time LH-RH
      agonist therapy in prostate cancer].

PMID- 12599569
TI  - [Antiandrogen in prostate cancer].

PMID- 12599570
TI  - [Total androgen blockade].

PMID- 12599571
TI  - [Estrogen therapy--high-dose intravenous diethylstilbestrol diphosphate therapy
      for advanced or hormone refractory prostate cancer].

PMID- 12599572
TI  - [Chemotherapy for prostate cancers].

PMID- 12599573
TI  - [Significance of surgical treatment of prostate cancer: problems and measures].

PMID- 12599574
TI  - [Radical retropubic prostatectomy].

PMID- 12599575
TI  - [Radical perineal prostatectomy].

PMID- 12599576
TI  - [Laparoscopic radical prostatectomy].

PMID- 12599577
TI  - [External beam radiotherapy for prostate cancer].

PMID- 12599578
TI  - [Brachytherapy for prostate neoplasms].

PMID- 12599579
TI  - [Heavy charged particle radiation therapy for prostate cancers].

PMID- 12599580
TI  - [Palliative radiotherapy for prostate cancers].

PMID- 12599581
TI  - [Genitourinary and rectal toxicity after radiation therapy for prostate cancer].

PMID- 12599582
TI  - [Multidisciplinary treatment for prostate cancers].

PMID- 12599583
TI  - [Therapy for hormone-refractory prostate cancer].

PMID- 12599584
TI  - [A novel molecular target therapeutics for refractory prostate cancer].

PMID- 12599585
TI  - [The trends in new drugs for the prostate cancer].

PMID- 12599586
TI  - [PSA follow-up after radical prostatectomy].

PMID- 12599587
TI  - [Evaluation of mass screening for prostatic cancer].

PMID- 12599588
TI  - [Prostatectomy and QOL].

PMID- 12599589
TI  - [Management of side effects of endocrine treatment for prostate cancer].

PMID- 12599590
TI  - [Problems of prostate cancer in elderly patients].

PMID- 12599591
TI  - [Clinical guideline for benign prostatic hyperplasia].

PMID- 12599592
TI  - [Epidemiology and natural history of benign prostatic hyperplasia].

PMID- 12599593
TI  - [Criteria for severity of prostatic hyperplasia and the treatment efficacy].

PMID- 12599594
TI  - [Clinical diagnosis of benign prostatic hyperplasia].

PMID- 12599595
TI  - [Image diagnosis of benign prostatic hypertrophy--ultrasonic diagnosis and
      retrograde urethrography].

PMID- 12599596
TI  - [Benign prostatic hyperplasia: value of CT and MRI].

PMID- 12599597
TI  - [Biochemical diagnosis of benign prostatic hyperplasia (including differential
      diagnosis with prostatic carcinoma)].

PMID- 12599598
TI  - [Urodynamic study in patients with prostatic hyperplasia].

PMID- 12599599
TI  - [Alpha 1-adrenoceptor antagonists for treatment of prostatic hyperplsia].

PMID- 12599601
TI  - [Chinese medicine for treatment of patients with prostatic hyperplasia].

PMID- 12599600
TI  - [Hormonal therapy for benign prostatic hyperplasia].

PMID- 12599602
TI  - [BPH pharmacotherapy (miscellaneous)].

PMID- 12599603
TI  - [New agents developed for the treatment of benign prostatic hyperplasia].

PMID- 12599604
TI  - [Open surgery for patients with prostatic hyperplasia].

PMID- 12599605
TI  - [TURP, TUIP for patients with prostatic hyperplasia].

PMID- 12599606
TI  - [Interstitial laser coagulation of the prostate].

PMID- 12599607
TI  - [Transurethral electrovaporization of the prostate].

PMID- 12599608
TI  - [Thermotherapy and hyperthermia for therapy of patients with prostatic
      hyperplasia].

PMID- 12599609
TI  - [Ethanol injection therapy of the prostate for benign prostatic hyperplasia].

PMID- 12599610
TI  - [Other less invasive surgical therapy for BPH (urethral stent)].

PMID- 12599611
TI  - [Quality of life in patients with benign prostatic hyperplasia].

PMID- 12599612
TI  - [The usefulness of clinical pathway on BPH].

PMID- 12599613
TI  - [Cost effectiveness in benign prostate hyperplasia].

PMID- 12599614
TI  - [Definition and classification of prostatitis syndrome].

PMID- 12599615
TI  - [Acute bacterial prostatitis].

PMID- 12599616
TI  - [Treatment of chronic bacterial prostatitis].

PMID- 12599617
TI  - [Chronic nonbacterial prostatitis/chronic pelvic pain syndrome].

PMID- 12599618
TI  - [Asymptomatic inflammatory prostatitis].

PMID- 12599619
TI  - [Cooperative care between urologists and general practitioners].

PMID- 12599620
TI  - [Association of vitamin D receptor gene polymorphism with prostate cancer].

PMID- 12599621
TI  - [Update of familial prostate cancer in Japan].

PMID- 12599623
TI  - [The influence of prostate volume on the diagnostic parameters related to PSA and
      clinicopathological features of prostate cancer].

PMID- 12599622
TI  - [Prospects of genetic polymorphism analyses in prostatic disease].

PMID- 12599624
TI  - [Asthma].

PMID- 12599627
TI  - [COPD].

PMID- 12599634
TI  - [Sleep disorders].

PMID- 12599639
TI  - [Diffuse pulmonary diseases].

PMID- 12599647
TI  - [Bronchial cancer -- mesothelioma].

PMID- 12599652
TI  - [Pulmonary artery hypertension].

PMID- 12599656
TI  - [Lung transplantation].

PMID- 12599660
TI  - [Respiratory tract infectious pathologies].

PMID- 12599664
TI  - [Mucoviscidosis].

PMID- 12599666
TI  - [Imaging of bronchiolitis].

PMID- 12599665
TI  - [Gastroesophageal reflux].

PMID- 12599667
TI  - [Stem cells and the lungs].

PMID- 12599668
TI  - [Respiratory tract diseases].

PMID- 12599671
TI  - [Non-invasive ventilation in acute respiratory failure].

PMID- 12599679
TI  - [Nosocomial pneumopathies in mechanical ventilation].

PMID- 12599683
TI  - [Practice of home ventilation in Europe: the French model].

PMID- 12599684
TI  - [Respiratory failure in Steinert's myotonic dystrophy].

PMID- 12599685
TI  - [Acute respiratory distress syndrome (ARDS): therapeutic features].

PMID- 12599686
TI  - [Non-respiratory resuscitation].

PMID- 12599687
TI  - [Resuscitation of immunodepressed patients].

PMID- 12599688
TI  - [Radiologic clinical cases].

PMID- 12599689
TI  - [Phenological analysis upon yield and quality of Flos Lonicerae].
AB  - Yield and quality of Flos Lonicerae varied in different phenological phase. Yield
      in the first flowering season was the highest. Yield in the last three flowering
      season decreased one by one. The dry weight of one thousand flower buds and
      chlorogenic acid content in the first flowering season were the highest during a
      year, then was the fourth, the second and the third were both the lower. The
      difference of above was related to such biologic factors as days of flower bud
      differentiation, types of flower branch, leaf area, chlorophyll content, and also
      to such climatic factors as air temperature, hours of sunshine and precipitation.

PMID- 12599690
TI  - [Karyotype analysis of Astragalus complanatus chromosome].
AB  - Micrograph were used to analyse the number, karyotype and volume of chromosome of
      Astragalus complanatus. The normal diploid 2n = 16, karyotype formula based on
      Levean publication (1964) was K(2n) = 16 = 10 m + 6 sm. According to the method
      of S.R. Guo, the chromosome relative length was 2n = 16 = 6M2 + 10M1, which
      belonged to "2A" type according to the Stebbins' karyotype classification. The
      total length of chromosome groups was 33.05 microns, total length of long arms
      was 19.76 microns, from Arano's method the AS.K% was 59.79%. The total volume of
      chromosome was 50.6 micron 3.

PMID- 12599691
TI  - [Determination of chemical constituents of the essential oil from Cnidium
      monnieri by GC-MS].
AB  - OBJECTIVE: The chemical components of the essential oil from Cnidium monnieri
      (L.) Cusson were analyzed by GC-MS. METHOD: The essential oil was extracted from
      Cnidium monnieri (L.) Cusson by steam distillation, the components analyzed with
      the different kinds of capillary columns, the optimum separated and analytical
      conditions were researched, the amount of the components from the essential oil
      were determinated by normalization method. The separated components were
      identified by GC-MS. RESULTS: 50 components composed of about 86% of the total
      essential oil were separated and identified. CONCLUSION: The method is reliable
      and stable.

PMID- 12599692
TI  - [Effect of traditional Chinese medicine compounds Aining on the expression of
      apoptosis inducing genes of human gastric cancer cell].
AB  - OBJECTIVE: To investigate the effects of Aining on the genes of the human gastric
      cancer cells. METHODS: Flow cytometry(FMC) was adopted to detect the gene
      expression of the gastric cancer cell in the Aining group, the cisplatin(DDP)
      group and the blank group. RESULTS: Compared with the blank group, the expression
      of c-myc and bcl-2 genes was low, while that of the p53, bax genes was high(P <
      0.01), and the ratio of bax/bcl-2 significantly increased in both the Aining
      group and the cisplatin(DDP) group. CONCLUSIONS: The mechanism of inducing the
      human gastric cancer cells apoptosis by Aining has some relationship with the
      changes of the genes.

PMID- 12599693
TI  - [Estrogen-like effects of puerarin and total isoflavones from Pueraria lobata].
AB  - OBJECTIVE: To study the estrogen-like effects of puerarin and total isoflavones
      from Pueraria lobata (TIP) in vivo. METHODS: Puerarin and TIP were orally
      administrated to ovariectomized rats, infancy or adult mice and estrogen-treated
      mice at the doses of 150, 300 and 600 mg/kg for 5-9 days. The estrogen-like
      effects were measured by viginacytology and uterus or ovary weights. RESULTS:
      Puerarin and TIP significantly promoted uterus growth in ovariectomized rats and
      infancy mice, increased the ratios of keratocytes in vaginal smear in
      ovariectomized rats. The sexual cycle was partially recovered in dose-dependent
      manner. In E2-treated mice, puerarin and TIP obviously inhibited the growth of
      vigina induced by E2. No obvious effect was observed in normal adult mice.
      CONCLUSION: The results showed that puerarin and TIP acted as weak estrogen-like
      effect on estrogen-deficiency animals, while no effect on normal-estrogen level
      ones, but as antiestrogen-like effect in high-estrogen-level ones. These results
      suggested that puerarin and TIP possessed property of partial agonist of estrogen
      receptor.

PMID- 12599694
TI  - [Studies on purgative activity of rhubarb extracts by different technologies].
AB  - OBJECTIVE: To study on purgative activity of rhubarb extracts by solvent
      extraction, SFE-CO2 and SFE-CO2 & residue resin purification. METHODS: The
      effects of the extracts by the three technologies on creepage of mouse small
      intestine and rat large intestine were studied by injecting charcoal ink into the
      intestines. And the volume of the mouse small intestine was observed. The effects
      of the extracts were also studied on water absorption of mouse small intestine
      and large intestine by weighing the intestines. RESULTS: The purgative activity
      of the extracts by the three technologies was SFE-CO2 & residue resin
      purification > solvent extraction > SFE-CO2. CONCLUSION: Extracting different
      polar components separately might get a good result.

PMID- 12599695
TI  - [Preventing and treating effects of "changkun granules" on experimental acute
      renal failure induced by cisplatin in rats].
AB  - OBJECTIVE: To study the preventing and treating effects of "Changkun Granules" in
      experimental acute renal failure(ARF) induced by cisplatin in rats. METHODS: The
      ARF rats were administered the "Changkun Granules". Serum BUN and SCr of all the
      rats were measured and the renal morphology was evaluated. RESULTS: Serum BUN
      level in the "Changkun Granules" group was lower than the one in cisplatin group.
      "Changkun Granules" could also improve renal histology damage. CONCLUSION: The
      results indicated that "Changkun Granules" had certain protective effect on
      experimental ARF.

PMID- 12599696
TI  - [Preventive and therapeutic effects of extract from Rheum palmatum on hepatic
      encephalopathy in rats with acute liver failure].
AB  - OBJECTIVE: To probe the preventive, therapeutic effect and the possible mechanism
      of extract from Rheum palmatum (ERP) on hepatic encephalopathy(HE) in rats with
      acute liver failure. METHODS: HE was induced by the administration of 300 mg
      thioracetamide per kg body weight by gavage on two consecutive days. The effects
      of ERP were observed on neurology test, serum ammonium, serum endotoxin and liver
      impairment. RESULTS: ERP could improve rat neuro-reflexes, decrease the staging
      of HE and rat serum ammonium, endotoxin concentrations, and reduce the liver
      impairment. CONCLUSION: ERP significantly prevents and treats HE in rats with
      thioacetamide-induced acute liver failure.

PMID- 12599697
TI  - [Comparative study between montmorillonite and Smecta on anti-dysentery effect].
AB  - OBJECTIVE: To compare the efficiency of montmorillonite (Mengtuoshi) and Smecta.
      METHODS: The effects on the dysentery mice induced by MgSO4, rhubarb powder and
      castor oil, were observed by given respectively 15.6%, 31.2% Mengtuoshi and 31.2%
      Smecta. And the effects on the over-contracted rabbit intestines were also
      observed. RESULTS: Both Mengtuoshi and Smecta could relieve the over pushing
      speeding of stomach and intestine, and reduce the times of dysentery. CONCLUSION:
      The anti-dysentery effect of Mengtuoshi was similar to Smecta from France and may
      be used as good anti-dysentery drug.

PMID- 12599698
TI  - [Study on preparation of beta-cyclodextrin inclusion compound of volatile oil
      from Aucklandia lappa].
AB  - OBJECTIVE: To study optimum inclusion process conditions for volatile oil from
      Aucklandia lappa. METHODS: The study was carried out with orthogonal design. The
      process conditions were studied by determining the utilization ratio of volatile
      oil from Aucklandia lappa, the oil-bearing rate and extract ratio of inclusion
      compound. RESULTS: The optimum preparation conditions for inclusion were
      established as: oil: beta-CD was 1:8, the inclusion temperature and time were at
      40 degrees C and for 1 h respectively, the utilization ratio of oil is 87.1%.
      CONCLUSION: The method can be used for production of beta-CD on a large scale.

PMID- 12599699
TI  - [Study on aqueous extraction process for preparation of yuxianling granules].
AB  - OBJECTIVE: To optimize the aqueous extraction process for preparation of
      Yuxianling Granules in order to provide a basis for industrial-scale produce.
      METHODS: The amount of extract and the content of ferulic acid were used as
      indexes of the extraction process for Yuxianling Granules. The aqueous extract
      optimum condition of preparation was selected by orthogonal experimental design.
      RESULTS: The optimum extraction condition was adding ten, eight times amount of
      water into crude drug, soaking for 30 min, decocting for 1.5 h, 1.0 h. Both the
      content of ferulic acid and the amount of extract were the highest. CONCLUSION:
      The above extraction process gave the most rational, feasible and satisfactory
      results.

PMID- 12599701
TI  - Louisville nurses win battle. ...but war goes on at Audubon hospital.

PMID- 12599700
TI  - Tenet's fall. Heads roll as questions mount over for-profit chain's 'aggressive
      pricing strategy'.

PMID- 12599702
TI  - Crossing boundaries. Big Pharma stalls discounted Maine Rx drug program.

PMID- 12599703
TI  - RNs press California to finalize ratios. Hospitals step up attack at public
      hearings.

PMID- 12599704
TI  - Key Canadian report rejects privatization.

PMID- 12599705
TI  - Step right up.... Town hall meetings fuel debate, desire for health care reform.

PMID- 12599706
TI  - Witnessing tragedy, celebrating life.

PMID- 12599707
TI  - Code language. What student nurses are taught about whistleblowing.

PMID- 12599708
TI  - [Reminiscence: several significant analyses of nursing care].
AB  - We would like to submit a critical evaluation of different studies on this
      concept. We will demonstrate that these studies suffer from limitations that
      deserve an analytical approach pertaining solely to nursing, and for a better
      understanding and evaluation of treatment results: reminiscence. The goal of this
      article is to illustrate that reminiscence has been little analyzed in regards to
      a conceptual model specific to nursing science. Dr. Neuman's conceptual model
      offers a rich theoretical basis for the application of this practice.

PMID- 12599709
TI  - [Observation].

PMID- 12599710
TI  - [Information to the families of hospitalized patients in recovery: impact of the
      representation of the status of physicians and nurses].
AB  - Doctors and nurses respond to the need of the patients' family for information
      regarding the patients' recovery in Intensive Care. However, their
      dissatisfaction, linked to the perception of contradictory informations delivered
      by the doctor and the nurse, has been observed. Interviews carried out in an
      intensive care unit among patients 'families' has confirmed the influence of the
      representation of the doctor's and nurse's status regarding this perception of
      information. This study has identified the prestigious position held by the
      doctor, reinforced by the events in progress, and which legitimizes an elevated
      level of knowledge and competence for the family. Alternatively, the
      representation of the nurse still relies on an onerous past history which limits
      the emergence of the profession's competences.

PMID- 12599711
TI  - [Expected and received assistance from informal social support for aged people in
      heart surgery].
AB  - This study describes and compares the importance and availability of expected and
      received types of assistance, during the convalescence period at home, from the
      informal social support network, as perceived by older persons undergoing heart
      surgery. The research design is descriptive and comparative. Barrera's conceptual
      framework has been integrated to Roy's model of adaptation. The 45 participants,
      31 men and 14 women with a mean age of 74 years (SD = 3.37 years), underwent
      myocardium revascularisation, valve replacement, or a combination of both
      surgeries. The day before the heart surgery and one month following the hospital
      discharge, the participants completed a French modified and adapted version of
      the "Inventory of Socially Supportive Behaviors" (Lepage, 1984) to identify
      perceived importance and availability of expected and received types of
      assistance (material, physical, emotional, guidance, and feedback) while at home
      on convalescence. Repeated-measure MANOVAs result in significant interactions
      between importance and availability of assistance, and between the day before
      heart surgery and one month following hospital discharge in three categories of
      assistance (emotional, p = 0.002; guidance, p = 0.003; feedback, p = 0.001).
      ANOVAs indicate that older persons perceive, one month after hospital discharge,
      the received assistance as important as anticipated the day before their surgery,
      but its availability is less. It is therefore important for nurses to reevaluate
      and adapt their pre-operative teaching program for older persons, especially as
      pertaining to the significant 15 types of assistance, and according to available
      resources from the informal social support network, and to mobilize the formal
      support network before hospital discharge.

PMID- 12599712
TI  - [Motivation of health care personnel in geriatrics: between attitudes and
      values].
AB  - Motivation in work is a process which implies a willingness to work hard, to
      direct and sustain on a long term basis one's efforts towards the achievement of
      goals and to transform this into obtaining the best performance from the staff.
      This process, supported by the personal and professional values of the individual
      could, as far as the caring staff are concerned, be a matter of attitude: more
      the individual is the author, more he is motivated. To direct the carer towards
      becoming an author, three elements would appear to be particularly influential:
      the desire to increase or at least to maintain the perceived level of prestige
      attached to the job, the variety within the job which enables initiative to be
      used as a matter of routine, the fullfilment of one's professional self, this
      fullfilment being inextricably bound to the notion of project.

PMID- 12599713
TI  - [Evaluation of satisfaction of nurses: development and validation of a new
      analysis tool].
AB  - A new device for the analyses of nurses' satisfaction has been developed and
      validated on two types of general and intensive treatments at the University
      Hospital in Vaudois, Switzerland. A questionnaire has been elaborated for
      identifying the variables linked with characteristics of the nurse's work, as
      well as personal variables of the employer which could have an influence on the
      level of satisfaction. In identifying the sources of satisfaction and
      dissatisfaction, it has been possible to propose recommendations and corrective
      measures in order to improve the level of global satisfaction of the nursing
      team.

PMID- 12599714
TI  - [Role of volunteers and caregivers in an interdisciplinary team].

PMID- 12599715
TI  - [Reduction of human error in health: research, theoretical analysis model, and
      prevention].
AB  - The costs of the errors like human and financial resources are remarkable. This
      research seeks to explore the high risk activities where the study of human error
      led a shrinking of this. The application of this theory can prevent the health
      human error.

PMID- 12599716
TI  - [Bifocal model in the management of respiratory problems. Application in a
      critical care unit].
AB  - The peculiar situations involved in critical care need a complex and efficient
      team work. This induces very often an overlapping of different specific roles,
      due to the complexity of clinical situations. G. Buchechek and J. Mc Closkey
      define nursing interventions as every care treatment by nursing staff, including:
      nurse treatment initiated by nurse diagnosis, physician-initiated treatment, and
      daily tasks, defined as performances, for the patient that it is not
      autosufficient (Nursing interventions: Treatments for potential nursing diagnoses
      1989). Thus, nursing initiative cannot be considered autonomous. The following
      manuscript represents a survey on nursing activities in respiratory care in a
      large hospital of the city of Rome, Italy, which follows the bifocal method of
      nursing care by Lynda J. Carpenito (1983).

PMID- 12599717
TI  - [Pilot training experience in lip-reading skills for nurses in intensive care
      units].
AB  - In the intensive care unit (ICU) of Mestre hospital (Italy) a research was
      carried out to analyse the possibility to improve nurses' lip-reading skills.
      METHODS: A specialized speech therapist organized a 20 hour training course for
      34 health workers in ICU. RESULTS: The participants had a lip-reading test at the
      beginning and at the end of the course and six months later. The final test
      revealed that participants could recognize a greater number of typical words in
      ICU in comparison to the initial test. Yet, after 6 months the skill decreased to
      the level shown at the beginning of the course. On the other hand, the trend
      shows that some participants' skill did not decrease. Neither the starting level
      nor intermediate stage are conditioned by sex, age, profession, and experience.
      In order to measure clinic efficacy, the participants had another test to
      understand if improved lip-reading skill could influence the following variables:
      word comprehension, nurse attitude to communication toward non-speaking people,
      patient emotional status and nurse emotional status. The training course seems to
      have had good effects on nurses' attitudes towards their patients and on their
      communication. Yet, study results do not show if increased lip-reading skills
      have real positive effects on ICU communication and whether this method is better
      than usual communication methods (e.g. mimic or alphabetic board).

PMID- 12599718
TI  - [Criteria used by nurses in choosing the site for intramuscular injections:
      custom or scientific evidence?].
AB  - The nursing literature of the last 20 years recommends the ventrogluteal site how
      the best site for intramuscular injections Beecroft, Redick, 1990, but, the few
      studies done with the aim to discover which is the most frequently used site
      report that the dorsogluteal site is the one preferred from nurses Farley, Joyce,
      Long et al., 1996. The propose of this descriptive study is to understand which
      are the criteria used by nurses when they have to decide which site choose for
      administering an intramuscular injection. 167 Italian nurses, from the province
      of Reggio Emilia, that answered at an anonymous questionnaire, compose the sample
      of this study. The study's outcomes demonstrate that the most frequently site
      used from the nurses is the dorsogluteal. The most frequently principles that
      support this choice are the easier access, the large muscle's bulk, the lower
      sensibility at the pain and the request of the patient. These reasons suggest
      that the nurses are guided, in choose the site for administering an intramuscular
      injection, much more by the customs than the evidence.

PMID- 12599719
TI  - [Proposal for first level nursing degree].
AB  - A project for the organisation of the new nursing degree program starting in
      Italy in 2001/02 is presented (national regulation published 5 June 2001). It is
      the fruit of the work of a group of nursing professors of the University of
      Insubria (Varese, Italy). After the explanation of the criteria which have led to
      the educative objectives construction, the choice of the scientific disciplines
      necessary to reach them has been made. The same educative objective have guided
      the amount of working hours assigned to each discipline and formative activity
      (according to the European credit transfer system). The characteristic elements
      of the project are: the presence of an introductory module among the so called
      "professionalising formative activities"; the centrality of these
      professionalising formative activities; the constant reference to a conceptual
      nursing model; the decision to keep the integrated courses modality beginning
      from the experience gained since 1992; the reduction in number of the integrated
      courses and therefore of the exams.

PMID- 12599721
TI  - [Scientific presentation].
AB  - To give a correct and effective scientific presentation, is an arduous task that
      asks for close examination of basic techniques of communication. This article
      proposes indications and suggestions to help public speakers to be communicators,
      to use visual aids and it explains how to capture the audience attention.

PMID- 12599720
TI  - [Significance of health education in schools. Strategy for the prevention of
      cardiovascular diseases].
AB  - Cardiovascular diseases are the first cause of death in our Country. They mainly
      manifests in adult age but it is the result of initiated lesions since the young
      age and imputable often to errors of behaviours and to non appropriate styles of
      life. The knowledges related to the prevention of some illnesses, allows a
      reduction of the incidence of these, a reduction of the mortality, with
      consequent reduction of the health and social costs related to the care and to
      the rehabilitation. In our educational system, unlike what happens in the most
      greater part of the other European countries, these themes are only partially
      present and however treated in sporadic and insufficient way. For these raisons
      Pronto Cuore onlus Association has decided to start, in collaboration with the
      Regione Lazio, a project of health education to the high schools students
      considering that a more informed population has a longer expectancy of life and a
      better life quality. This job wants to underline the necessity to undertake a
      health education program to teach and inform students and teachers: to recognize
      some factors of risk as principal causes of cardiovascular diseases; to change
      life style; to recognize critical situations and behaviours to be adopted.

PMID- 12599722
TI  - [XXIV Annual Meeting of the WENR].

PMID- 12599723
TI  - [Recommendations on nursing research in Europe].

PMID- 12599724
TI  - Mary "Mother" Bickerdyke.

PMID- 12599725
TI  - Nurse spent time as P.O.W.

PMID- 12599726
TI  - Vietnam: one nurse's story.

PMID- 12599727
TI  - Development of the human cerebral cortex: a histochemical study.
AB  - In recent years, improvement in diagnostic techniques has led to better
      recognition of "disorders of cortical development". These disorders constitute a
      significant cause of epilepsy, mental retardation, developmental delay and
      neurological deficits in childhood, and may also contribute to the pathogenesis
      of psychological and neurodegenerative diseases in adults. Hitherto, however, few
      systematic studies of the human fetal cortex have been performed, and little is
      known about the ontogenetic processes of the neocortex in man. The aim of the
      study is to establish an understanding of the developmental events that occur in
      the second and third trimesters of gestation, by investigating the biochemical
      patterns of development of the human neocortex during this period. The temporal
      and spatial patterns of expression of the neuronal markers gamma-aminobutyric
      acid (GABA), choline acetyltransferase (ChAT), dopamine beta hydroxylase (DBH),
      dopamine receptor DR1 and synaptophysin, as well as the glial cell markers glial
      fibrillary acidic protein (GFAP), S100B and excitatory amino acid transporter
      protein GLT-1 are delineated in the fetal cortex using immunohistochemistry.
      Results of this study showed that different neuronal and glial cell proteins
      follow different developmental patterns and many show inter- or intra-regional
      variations in expression. Details of these patterns are described and discussed.
      The early expression of these proteins suggests that they play important roles in
      the developmental processes of cell proliferation, migration and differentiation.
      Both neurotransmitters and glial cell proteins probably function outside the
      confines of synapses in the fetal brain, as paracrine/autocrine factors. Early
      developmental events seem to be dictated by an innate programme, whereas late
      events may be more susceptible to extrinsic influences. It is hoped that
      knowledge of the normal developmental process can lead to better understanding of
      the causes and mechanisms of "disorders of cortical development", and to better
      treatments.

PMID- 12599728
TI  - Dr. Peter Centre - removing barriers to health care services.

PMID- 12599729
TI  - Share the learning.

PMID- 12599730
TI  - Optimal asthma care.

PMID- 12599731
TI  - Survey: new grads seek support in the workplace.
AB  - The relentless nature of the current nurse shortage, in conjunction with ongoing
      concerns expressed by employers, unions, schools of nursing, and new graduate
      registered nurses themselves about the issues facing new graduate registered
      nurses, prompted RNABC to conduct the New Graduate Nurse Project. The project
      included a mailed survey to, and telephone interviews with, registered nurses who
      graduated from B.C. nursing education programs in 2001. In 2003, RNABC will
      conduct a similar survey of 2002 graduates to compare findings.

PMID- 12599732
TI  - Listening is both complicated and subtle.

PMID- 12599733
TI  - [Fournier syndrome: the perception of the patient].
AB  - The purpose of the present investigation was to identify the perception of the
      Fournier syndrome's patients about their disease and caregivers. Data was
      collected by means of interviews with a structured routine and the analysis was
      based on the Andre's analysis of prose. According to the patients, the syndrome
      causes intense pain, edema, fever and wounds, demanding surgical treatment,
      dressings and bringing physical, economical and familiar problems. The
      caregivers' attitudes and behaviors were described as having more negative
      aspects than good ones. The necessity of a better training of the caregivers in
      the cognitive, psychomotor and affective sense is evident.

PMID- 12599734
TI  - [Loss of spontaneous action: the discomfort of men with acute myocardial
      infarction].
AB  - Considering that comfort and discomfort must be understood in the light of
      patients' interactions during illness and treatment -thus linked to institutions'
      objective factors, grounding rationale, and practices-, this study inquired on
      comfort and discomfort such as experienced by men who had suffered acute
      myocardial infarction (AMI). By resorting to the Symbolic Interactionism and to
      Grounded Theory methodology, data were collected by means of interviews with 13
      men who had suffered AMI, at two health units in the city of Sao Paulo. The
      analysis led to building a theoretical model of such experience, made up by three
      phenomena and essentially prevaded by the discomfort of "undergoing loss of
      spontaneous action." This articles sums up the basic psychosocial process that
      emerges from that experience, and discusses its implications to question the
      clinical model of treatment, pointing to prevention as a further scope of action
      for nurses, besides raising issues to enhance nurse education.

PMID- 12599735
TI  - [Construction of the process leading to burns: the life story of burned
      patients].
AB  - This study aimed at understanding the reasons leading certain people to choose
      burning as a form of self-destruction. It was based on the accounts of two
      patients who, in spite of presenting distinct characteristics, portrayed common
      points in their life histories which may have influenced their decision. The
      identification of mental or psychic disorders in these patients shows the
      importance of the presence of a specialized professional in Mental Health in the
      Burns Unit, since he can provide support to the multiprofessional team and will
      enable the provision of more adequate care and the necessary support to the
      burned patient aiming at his physical and mental recovery.

PMID- 12599736
TI  - [Living the humanized delivery: phenomenological study from the point of view of
      adolescents].
AB  - The purpose of this study was to comprehend the meaning of the humanized
      childbirth experience for teenage parturients. Phenomenology was adopted as the
      way to achieve the essence of the phenomenon. Eight teenagers who were assisted
      at the Sofia Feldman Hospital--a philantropic and non-profit-making institution-
      Belo Horizonte/MG--Brazil--have taken part of this study. Field work and open
      interview were the proceedures used for data collection. The study made it
      possible to seize three categories of analysis: Prechildbirth/Chilbirth--the body
      is being controlled. Prechildbirth/Chilbirth--a combination of pain and pleasure;
      Humanized Childbirth--expected and desired care.

PMID- 12599737
TI  - [Main concepts of the systemic approach in nursing care given to the individual
      and his/her family].
AB  - With the current emphasis in the family question it is important to discuss some
      concepts underlying the systemic approach to the family nursing care, which has
      in the interview with the family its main instrument. In this paper the following
      concepts are discussed: system, human being, family, familiar health, nursing
      intervention, hypotheses, circularity, systemic hypothesis and neutrality. It was
      aimed to supply practical examples that could facilitated the understanding of
      the concepts, as well as its applicability.

PMID- 12599738
TI  - [Social representation of nursing workers who are not nurses (nursing technicians
      and aids) on the work at the intensive care unit in a teaching hospital].
AB  - The study identifies and analyses social representations of Intensive Care Unit
      (ICU) nursing staff about their work and how they express feelings of sorrow and
      pleasure associated to their job. The theoretical and methodological reference
      used by this study was the Theory of Social Representations. Interviews were
      carried out with auxiliary nursing personnel (licensed practical nurse and nurse
      technician). The data were analyzed by analysis-of-content technique, in
      particular the enunciation. The results indicate that ICU units causes much
      suffering, forcing nursing staff to utilize, individually, several defense
      mechanisms traditionally described by psychoanalysis and psychopathology.

PMID- 12599739
TI  - [Assessment of the teaching-learning process: its meaning for students holding a
      high school diploma or equivalent and attending a nursing program].
AB  - This study aimed at gaining an understanding of what the assessment meant to
      students holding a high school diploma or equivalent and attending a nursing
      program. It was carried out at a private nursing school in the city of Sao Paulo,
      Brazil. Data was gathered through a tool containing the following question: "what
      does assessment mean to you as a student of a nursing assistant program"? The
      essays received were classified qualitatively according to the BARDIN frame of
      reference. Results show that students perceive assessment as a set of meanings
      that converge toward what we call the TEACHING-LEARNING PROCESS, EMOTIONAL
      FACTORS and The ROLE OF THE TEACHER.

PMID- 12599740
TI  - [Changes in nursing: the representation of nurses regarding institutional
      mobilization].
AB  - Big changes have been happening in the society. In this study, we had as
      objective to show the nurses' representation about the changes in nursing
      inserted in an institution context. Eighteen nurses at a public, school hospital,
      which is specialized in cardiology were interviewed. Using the analysis of
      content according to Bardin' proposal, we construct a representation' scheme that
      indicates two periods of time, concrete and desirable time, and in order to adapt
      in a new time it happens in a pace between limits and catalysers of changes'
      process, to achieve auto-supported existence as a project to become a new
      professional.

PMID- 12599741
TI  - [Contradictions in speech and practice of nursing in day-care mental health
      services].
AB  - It has been observed nowadays that nurses have not yet consolidated a new
      professional identity in the majority of mental health institutions compromised
      with the implementation of Psychiatric Reform. Therefore, the objective of this
      work is to characterize the nursing care provided in two day-care institutions
      located in the city of Campinas--SP through an exploratory descriptive study of
      qualitative nature. The data analysis show that nursing activities concern mostly
      in fulfilling the client's needs related to the field of Psicho-social
      Reabilitation. Nevertheless, its implementation displays some contradictions wich
      evoke the presence of traces compatible with the former model of assistance.

PMID- 12599742
TI  - [Nosocomial infection and mortality].
AB  - A retrospective study with 69 deaths occurred at a pediatric hospital in 1993 was
      undertaken to identify the relationship of nosocomial infection with death.
      Pneumonia and bloodstream infection were the main site of infection. A higher
      prevalence of gram-negative bacteria was also observed. The hospital infection
      was causally related to death in 30.4% and contributed to death in 50.8% of
      children. The nosocomial infection was causally related to death more frequently
      in patients classified as having a non fatal disease at admission.

PMID- 12599743
TI  - [Reutilization of paraformaldehyde tablets: assessment of their sterilizing
      effect].
AB  - The sterilizing activity of reused Paraformaldehyde tablets was assessed by
      microbiologic monitoring according to the Association of Official Analytical
      Chemists (AOAC) technic required in Brazil to register this class of sanitizing
      substances into the Health Ministry. Previous to the microbiologic tests,
      physical-chemscs assays were done through iodine titration according to the
      Society of Japanese Pharmacopoeia. It was possible, than, to draw a graphic
      showing a curve of the gaseous formaldehyde concentration discharged, at each
      sterilization cycle in relation to the number of reuse of the paraformaldehyde
      tablets. Through this graphic it was possible to chose the adequate moment to
      make the microbiologic analysis. After 12 cycles, the some group of the
      paraformaldehyde tablets kept the sterilizing activity at 3% concentration (3
      g/100 cm3), at 50 degrees C, for 4 hours of exposition time with great relative
      humidity.

PMID- 12599744
TI  - [Survival of patients treated with hemodialysis and estimated expenses in the
      municipality of Ribeirao Preto - SP].
AB  - Using Life Table Method the present study estimated the survival of patients gone
      under hemodialysis, according to age group, from 1997 to 2000, in the Ribeirao
      Preto County. Based in probability of survival it was also estimated the expenses
      referred to the sessions of hemodialysis for patients that are beginning
      treatment. Nearly 60% of patients followed were alive after four years of study,
      show high survival. The results of this study show that the high expenditure with
      hemodialysis refers to the increase of survival of patients and not specifically
      the increase of demand of the therapy.

PMID- 12599745
TI  - Can RN who self-publishes 'abandonment' charge sue?

PMID- 12599746
TI  - RN fails to notify Dr. post-surgery Pt.'s artery is visible. Case on point:
      Taylor v. Interim Healthcare (Raleigh-Durham), 2002 WL 31687556 S.E.2d-NC.

PMID- 12599747
TI  - PA: Substance abuse subject licensed in 31 states: failure to comply with
      agreement-sanctions result.

PMID- 12599748
TI  - LA: Disoriented Alzheimer patient falls from bed: failure to have expert witness
      fatal to Pt.'s case.

PMID- 12599749
TI  - An exception to the 'going to' & 'coming from' rule. Case on point: Hampson v.
      Liberty Northwest Insurance Corp., 2002 MTWCC57 (11/18/02).

PMID- 12599750
TI  - Understanding protein folding with energy landscape theory. Part II: Quantitative
      aspects.

PMID- 12599751
TI  - Biophysical basis of brain activity: implications for neuroimaging.
AB  - In vivo 13C magnetic resonance spectroscopy (MRS) studies of the brain have
      quantitatively assessed rates of glutamate-glutamine cycle (Veye) and glucose
      oxidation (CMRGle(ox)) by detecting 13C label turnover from glucose to glutamate
      and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in
      vivo 13C-MRS results demonstrate that glutamate recycling is a major metabolic
      pathway, inseparable from its actions of neurotransmission. Furthermore, both in
      the awake human and in the anesthetized rat brain, Veye and CMRGle(ox) are
      stoichiometrically related, where more than two thirds of the energy from glucose
      oxidation supports events associated with glutamate neurotransmission. The high
      energy consumption of the brain measured at rest and its quantitative relation to
      neurotransmission reflects a sizeable activity level for the resting brain. The
      high activity of the non-stimulated brain, as measured by cerebral metabolic rate
      of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral
      function that leads to reinterpreting functional imaging data because the large
      baseline signal is commonly discarded in cognitive neuroscience paradigms.
      Changes in energy consumption (delta CMRO2%) can also be obtained from magnetic
      resonance imaging (MRI) experiments, using the blood oxygen level-dependent
      (BOLD) image contrast, provided that all the separate parameters contributing to
      the functional MRI (fMRI) signal are measured. The BOLD-derived delta CMRO2% when
      compared with alterations in neuronal spiking rate (delta v%) during sensory
      stimulation in the rat reveals a stoichiometric relationship, in good agreement
      with 13C-MRS results. Hence fMRI when calibrated so as to provide delta CMRO2%
      can provide high spatial resolution evaluation of neuronal activity. Our studies
      of quantitative measurements of changes in neuroenergetics and neurotransmission
      reveal that a stimulus does not provoke an arbitrary amount of activity in a
      localized region, rather a total level of activity is required where the
      increment is inversely related to the level of activity in the non-stimulated
      condition. These biophysical experiments have established relationships between
      energy consumption and neuronal activity that provide novel insights into the
      nature of brain function and the interpretation of fMRI data.

PMID- 12599752
TI  - Suppression of intestinal crypt cell proliferation and aberrant crypt foci by
      dietary quercetin in rats.
AB  - Quercetin inhibits proliferation of human gastric and colonic cancer cells in
      vitro by suppressing mitosis and increasing apoptosis. Quercetin might therefore
      act as an anticarcinogen in the alimentary tract, but previous findings have been
      inconsistent. We fed rats quercetin at dietary concentrations of 1, 5, 20, and 50
      g/kg. At < or = 20 g/kg, we observed a statistically significant reduction in the
      frequency of crypt cell mitosis in proximal, mid, and distal small intestine and
      in distal colon, amounting to approximately 40% of control at 1 g/kg. There was
      no effect on apoptosis. Quercetin metabolites, but not quercetin aglycone, were
      detected in plasma of rats fed quercetin at 20 and 50 g/kg. In a second
      experiment, rats were fed quercetin at 1 g/kg after treatment with 1,2
      dimethylhydrazine to induce aberrant crypt foci. In dimethylhydrazine-treated and
      control rats, crypt cell mitosis was suppressed at 48 h and 42 days after
      injection, and there was a statistically significant reduction in the number of
      aberrant crypts and larger aberrant crypt foci (> 4 crypts/focus) in the distal
      colon of treated animals. These findings demonstrate that quercetin can inhibit
      intestinal crypt cell proliferation in vivo, but the effect diminishes as the
      level of dietary exposure increases. At low concentrations, dietary quercetin
      inhibits induction of aberrant crypts by a mechanism that does not involve
      increased crypt cell apoptosis.

PMID- 12599753
TI  - [Induction and identification of autotetraploid plant of Platycodon
      grandiflorum].
AB  - The methods and technique of inducing polyploid plants of Platycodon grandiflorum
      were done. Many autotetraploid plant lines were induced by colchicine in vitro
      successfully. The identification of main agronomic characteristics of these
      clonal lines was conduced in the fields. The results showed the giant type
      occurred in tetraploid plants comparing with that in diploid plants. It may show
      prospective way in developing new varieties with high yield and high content of
      useful compounds.

PMID- 12599754
TI  - [The observation and comparison of Pogostemon cablin from different habitats].
AB  - The present work is concerned the observation and comparison among 4 kinds of
      Pogostemon cablin (Blanco.) Benth. from different habitats by some methods, such
      as descriptions identification, microscopical identification and scanning
      electron microscopy. The results provide scientific basis for recognition and
      distinction of Pogostemon cablin varieties.

PMID- 12599755
TI  - [Interrelationship between folk plant medicine of Arhorchin Mongolian and
      Mongolian medicine as well as Chinese herbal medicine].
AB  - Based on the results of investigation of Arhorchin Mongolian folk medicinal
      plants and related knowledge system, the present paper discussed the
      interrelationship between folk plant medicine and Mongolian medicine as well as
      Chinese herbal medicine by the items of plant species, medicinal parts, treating
      disease and administering methods. The results show that there are some
      consistency between folk medicine and Mongolian medicine as well as Chinese
      herbal medicine, and there are also some other inconsistency. Consistency between
      folk medicine and Mongolian medicine may be illustrated the fact that the
      Arhorchin Mongolian folk medicinal knowledge and Mongolian medicine are belongs
      to same system. Consistency between folk medicine and Chinese herbal medicine are
      illustrated the fact that knowledge exchange and cultural infiltration between
      Arhorchin Mongolians and Han nationality. Inconsistency may be illustrated
      richness and exploration value of folk medicinal knowledge.

PMID- 12599756
TI  - [Comparative study on volatile oils in flower and stem of Lonicera japonica].
AB  - OBJECTIVE: To study the volatile oils in flower and stem of Lonicera japonica.
      Thunb. METHOD: GC-MS. RESULTS: 36 constituents are isolated and identified in
      all, of which 28 from Flos Lonicerace and 26 from Caulis Lonicerae. 18 compounds
      are found simultaneously in both crude drugs and they account for 85.23%, 83.42%,
      respectively. Palmatic acid and linoleic acid are the highest principles.
      CONCLUSION: The volatile oils are highly similar to each other.

PMID- 12599757
TI  - [Constituent analysis of essential oils from radix of Angelica acutiloba].
AB  - OBJECTIVE: To analyze the chemical constituents of essential oils from Angelica
      acutiloba Kitagawa cultivated in Sichuan. METHOD: Chemical constituents were
      analyzed by GC-MS. RESULTS: 47 chemical compounds were identified and the total
      content of the identified constituents in the essential oils was 99.02%. The
      percentage of each constituent was given. CONCLUSION: Ligustilide (22.8%) and
      Butylidene phthalide (19.5%) are the main constituents.

PMID- 12599758
TI  - [Effects of xuefuzhuyu decoction on collagen synthesis and proliferation of
      cardiac fibroblasts].
AB  - OBJECTIVE: To study the effects of XueFuZhuYu Decoction (XFZYD) on collagen
      synthesis and proliferation of cardiac fibroblasts and provide academic bases of
      remedying kinds of heart disease aroused by proliferation of cardiac fibroblasts.
      METHODS: By adding medicine directly and serum pharmacological method. RESULTS:
      Compared with the control group, 1 g/ml XFZYD(dilution 1:80) and 10 percent serum
      of rat contained XFZYD could significantly inhibit the collagen synthesis and the
      proliferation of cardiac fibroblasts. Moreover, 1 g/ml XFZYD(dilution 1:80) could
      significantly affect collagen secrtion of cardiac fibroblasts (P < 0.05), up to
      17.9%. CONCLUSION: XFZYD could inhibit both proliferation and collagen secretion
      of cardiac fibroblasts. It could resist cardiac muscle fibrosis.

PMID- 12599759
TI  - [Effect of jinshui-liujun decoction on chronic bronchitis in rats].
AB  - OBJECTIVE: To study of the quality standard about Jinshui Liujun decoction.
      METHODS: The chronic broncitis model of rat was induced by injecting LPS into
      rat's trachea. Then, the number of WBC, SV, PS were detected. RESULTS: Both
      Jinshui Liujun decoction and hesperidin can improve the content of PS and reduce
      the number of WBC. There were statistical difference between the therapeutic
      groups and the model group, and the changes of bronchi between the therapeutic
      group were similar. But the SV of hesperidin group was bigger than Jinshui Liujun
      decoction group, and the PS of hesperidin group was less than Jinshui Liujun
      decoction group. CONCLUSION: It was feasible that the content of hesperidin in
      Jinshui Liujun decoction was as primary quality control index.

PMID- 12599760
TI  - [Comparative study of tissue cultured Dendrobium protocorm with natural
      Dendrobium candidum on immunological function].
AB  - OBJECTIVE: To compare the immunological function and acute toxicity of the tissue
      cultured protocorm from Dendrobium candidum with natural medicinal materials from
      Dendrobium candidum. METHODS: The effect on immunological function was examined
      by counting white blood cells, weighing the weight of immune organs, and using
      carbon granules clearance and lymphocyte transformation test in mice treated with
      cyclophospamide. The acute toxicity was studied by giving maximum tolerated dose.
      RESULTS: The tissue cultured protocorm could increase the quantity of white blood
      cells, the ratios of thymus weight to body weight and spleen weight to body
      weight, promote the function of phagocytes and enhance the lymphocyte
      transformation rate. The mice could tolerate the dose of 54.56 g/kg(dried herbs)
      by oral administration. The functions were similar to those of natural medicinal
      materials from Dendrobium candidum. CONCLUSION: Both tissue cultured protocorm
      and natural medicinal materials from Dendrobium candidum could improve
      immunological function with similar potency. The maximum tolerated dose was 227
      times as high as the effective clinical.

PMID- 12599761
TI  - [Effects of invigorating the kidney and strengthening the bones capsule on
      osteoporosis in ovariectomized rats].
AB  - OBJECTIVE: To study the therapeutic effects of inrigorating the kidney and
      strengthening the bones capsule(IKSBC) on osteoporotic ovariectomized(OVX) rat
      model. METHODS: The concentrations of calcium, phosphorus and ALP in serum of
      ovariectomized rats were determined by clinical biochemical assay, and the right
      hind leg thighbones of ovariectomized rats were reserved for the preparation of
      bone specimens and were studied by bone histomorphometry. RESULTS: After
      treatment with IKSBC, the concentrations of calcium and phosphorus in
      ovariectomized rat serum were increased, the activity of ALP was decreased and
      the percentage of relative trabecular volume was increased significantly as
      compared with that before treatment(P < 0.05). CONCLUSION: IKSBC possesses some
      therapeutic effects on osteoporotic rat model.

PMID- 12599762
TI  - [Study on effects of scutellarin on scavenging reactive oxygen].
AB  - OBJECTIVE: To study the antioxidative effects and its mechanism of scutellarin.
      METHODS: Scavenging effects of scutellarin on hydroxyl radical (OH.) produced
      from 0-phenathroline-ascorbic acid system, super oxide anion radical (O2-.)
      produced from xanthine-xanthine oxidase-luminol system and hydrogen peroxide was
      studied by a chemiluminescence assay. RESULTS: Scutellarin has a significant
      effect on scavenging hydroxyl radicals, super oxide anion radicals, hydrogen
      peroxide, their IC50 are 66 micrograms/ml, 1.3 micrograms/ml and 1.6
      micrograms/ml respectively. CONCLUSION: Scutellarin is an efficiency antioxidant.

PMID- 12599763
TI  - [The effects of dieda zhentong liquid on ear microcirculation of rabbit].
AB  - OBJECTIVE: To observe the effects of Dieda Zhentong Liquid (DDZTL) on ear
      microcirculation of rabbits. METHODS: With microcirculation apparatus, caliber of
      micrangium, velocity and volume of blood flow were detected in experimental
      groups. RESULTS: The volume of blood flow of DDZTL group without Chlorophytum
      laxum haven't an increase compared with that of the group without administering
      the medicinal liquid. Shexiang Shuhuo Essence group, Chlorophytum laxum group,
      high and low dose DDZTL group have an increase. CONCLUSION: DDZTL could improve
      ear microcirculation of rabbit. Chlorophytum laxum maybe play an important role
      in above-mentioned effect.

PMID- 12599764
TI  - [Non-technical causes of fakes existing in Chinese medicinal material markets].
AB  - Non-technical causes of fakes existing in Chinese medicinal materials markets
      come from three aspects. Source of Chinese medicinal materials is complex and it
      is difficult to trace back to a source; lawless add impurities and use inferior
      goods pretending to superior quality and illegally seek for profit; supervising
      department lack strict blow and deterrent force is limitted.

PMID- 12599765
TI  - Organizational ethics need not be an oxymoron.

PMID- 12599766
TI  - Good leadership requires systemic solutions to personnel challenges.

PMID- 12599767
TI  - Nurse recruiting plans in North Carolina count on schools.

PMID- 12599768
TI  - Survey: nurses key to improving satisfaction with surgical department.

PMID- 12599769
TI  - [The pathogeny and treatment of glossopharyngeal neuralgia].
AB  - OBJECTIVE: To investigate the etiopathogensis of glossopharyngeal neuralgia, and
      to research the curative effect of medicine and operation on it. METHOD: The
      microsurgical relationships between glossopharyngeal nerve and the posterior
      inferior cerebellar artery were examined in 30 adults cadavers. Twenty patients
      with glossopharyngeal neuralgia were treated by operation in which the
      glossopharyngeal nerves were observed and sectioned. RESULT: 10 out of the
      glossopharyngeal nerves in 30 adults cadavers were observed contacting with the
      posterior inferior arteries which represented 16.67 percent of all the cases. 8
      of 20 patients were observed that their glossopharyngeal nerve were compressed
      and distorted by the posterior inferior cerebellar arteries. They were cured by
      operations. CONCLUSION: Vascular compression may be one of the causes of
      glossopharyngeal neuralgia, but not the only one. The curative effect of section
      of glossopharyngeal nerve is sure. This paper pointed out that this kind of
      operation should be a choice.

PMID- 12599770
TI  - [Ruby laser arytenoidectomy in the treatment of bilateral vocal cord paralysis].
AB  - OBJECTIVE: To explore endoscopic ruby-laser arytenoidectomy for the treatment of
      bilateral vocal cord paralysis. METHOD: Ten cases with bilateral vocal cord
      paralysis were operated, six were male and four were female, all of whom had Ruby
      laser arytenoidectomy with tracheostomy and anesthesia through intubiting ahead.
      RESULT: There are no complications. During the following three to thirteen
      months, all patients operated breathed well with no synecdochical scar formed in
      the throat and their pronounciation improved apparently. Their glottis are
      broadened more than 4 mm after operation. CONCLUSION: Ruby-laser arytenoidectomy
      is a practicable therapy to bilateral vocal cord paralysis.

PMID- 12599771
TI  - [Selection of methods of rehabilitation for hypopharyngeal defects after
      hypopharyngeal carcinoma removal].
AB  - OBJECTIVE: To explore how to repair hypopharyngeal defects after hypopharyngeal
      carcinoma removal. METHOD: We analysed the methods of stage I rehabilitation for
      hypopharyngeal defects and deglutitory function in 31 cases carried out
      hypopharyngeal carcinoma operation in our department from June, 1996 to June,
      2001. RESULT: 1 case was performed "zero rehabilitation". In 15 of 17 cases
      (88.2%) carried out with direct suture rehabilitation, deglutitory function is
      good. In 6 of 13 cases (46.2%) carried out with tissue graft rehabilitation,
      deglutitory function is good. In 9 of 14 cases carried out with preserved
      laryngeal operation synchronously, deglutitory function is good(all direct suture
      rehabilitation). There were 5 cases with worse deglutitory function(each case
      occured inhalational error, 2 of them were direct suture rehabilitation and 3 of
      them were, issue graft rehabilitation). CONCLUSION: Patients obtain a better
      deglutitory function after direct suture rehabilitation. For total hypopharyngeal
      defects, stomach/intestines pull-up is superior to myocutaneous flap
      transposition. For synchronous preserved laryngeal operation, we should pay more
      attentions in case selection and inhalational error prevention. "Zero
      rehabilitation" is helpful to enhance the indication of surgical treatment for
      hypopharyngeal carcinoma.

PMID- 12599772
TI  - [The diagnosis of ectopic thyroid].
AB  - OBJECTIVE: To explore the diagnosis method of ectopic thyroid. METHOD: 11 cases
      with ectopic thyroid were analyzed. RESULT: 11 cases were diagnosed by 99mTc
      scan, 7 cases were complicated by hypothyroidism, 3 cases were diagnosed by
      ultrasonography and autopsy else. CONCLUSION: 99mTc scan is the best method and
      the biopsy is an accurate method to diagnose ectopic thyroid.

PMID- 12599773
TI  - [Study on voice quality after different layers injured in vocal fold with CO2
      laser microsurgery].
AB  - OBJECTIVE: To investigate the nature of pathological voice after injured in
      different layers of vocal fold with CO2 laser microsurgery. METHOD: 50 cases of
      precancerous lesion (keratosis and leukoplakia) were treated with laser mucosa
      ablation. Glottal carcinoma (Tis-T2) were treated with laser microsurgery in
      mucosal stripping(30 cases) or with laser cordectomy(60 cases). Vocal function
      was examined by acoustic analysis (F0, Jitter, Shimmer, NNE, HNR), aerodynamic
      analysis (MPT, S/Z) and videostroboscopic examination. RESULT: For lesion mucosa
      ablation, hoarseness improved quickly after operation and acoustic analysis
      became normal. There were 18.2% decreased mucosa wave, 16.7% mild-moderate
      supraglottal hyperfunction. For mucosa stripping (cover layers excised), 63.3%
      decreased and 10.0% absented with mucosa wave, 46.7% mild-moderate supraglottal
      hyperfunction, glottal closure was incomplete. Acoustic analysis showed that
      Jitter, Shimmer, F0 different from normal(P < 0.05), HNR significantly different
      from normal(P < 0.01). For cordectomy: Acoustic analysis showed significantly
      worse than normal(P < 0.01), 61.7% mild-moderate supraglottal hyperfunction. The
      ipsilateral mucosa wave was absent, but 30.0% showed mucosa wave of vocal process
      and 13.3% with ventricular fold wave. There was little difference with or without
      vocalis muscle excision in acoustic analysis. To compared with mucosa stripping,
      the NNE, HNR, Jitter, Shimmer of cordectomy group was worse and amplitude was
      higher in cordectomy(P < 0.01). CONCLUSION: Although the acoustic characteristic
      and vibration mode of mucosa ablation and mucosa stripping was distinct to each
      other, within the cover layer injured, vocal function will be good. Once the body
      layer is injured, vocal quality will decrease significantly.

PMID- 12599774
TI  - [Dyspnea analyse and treatment to adult acute epiglottitis].
AB  - OBJECTIVE: To discuss the estimation and treatment of adult acute epiglottitis
      dyspnea. METHOD: 126 adult with acute epiglottitis patients were analyzed.
      RESULT: None of 30 patients undergone epiglotiotomy had asphyxia, inflammation
      diffuse or serious hemorrhage. 8 patients undergone tracheotomy, one patient
      undergone thyroericotomy but died. One of 87 patients with conservative treatment
      died. CONCLUSION: Gaspping, salivating and dyslogia are symbols of severe larynx
      obstruction. Fibrous laryngoscope is the best way of examine. Keeping respiratory
      path open and eliminating epiglottis swelling is the key of treatment.

PMID- 12599775
TI  - [Diagnosis of foreign bodies in trachea and bronchus of children by means of
      coronal CT scan].
AB  - OBJECTIVE: To study the sensitivity, specificity and clinical value of coranal CT
      scan of trachea and bronchus in diagnoing children's foreign body in bronchus.
      METHOD: 30 cases of the children with foreign body in their trachea and bronchus
      were examined by chest X ray (chest X-ray), and by coranal CT scan at the same
      time. (some of them were compared with axial CT scan.) RESULT: The position of
      foreign body in trachea and bronchus was definitely diagnosed by coronal CT scan
      in all cases, of whom, 28 cases with obstructive emphysema; 5 case with
      obstructive pneumonia and 3 cases with obstructive atelectasis. CONCLUSION:
      Coranal CT scan could demonstrate the position of foreign body in trachea and
      bronchus and be helpful in planning surgery.

PMID- 12599776
TI  - [Cause and treatment in difficult decannulation of tracheotomic children].
AB  - OBJECTIVE: To explore the cause of difficult decannulation in tracheotomic
      children and increase the rate of successful decannulation. METHOD: Clinical data
      of 69 cases of difficult decannulation in tracheotomic children were analyzed
      retrospectively. RESULT: 42(60.9%) cases were not cured for their primary
      diseases were not cured in a short time, 14 (20.3%) cases were in improper
      procedure. The location of tracheotomy was too high in 4 (5.8%) cases and
      tracheal stricture in 4(5.8%). In 5(7.2%) cases discharge blocked in airway.
      After treatment decannulation was finished in 49 cases, among them, 15 cases
      remain tracheo-skin fistula. The other 18 cases failed to decannulation, and 2
      cases died of tubal accident. CONCLUSION: The main reason of difficult
      decannulation in tracheotomic children is the primary disease which were not
      fully recovered. The second reason is improper procedure of decannulation.
      Difficulty in decannulation has nothing to do with the age of children.

PMID- 12599777
TI  - [Improvement of the general anesthesia method for microlaryngoscopic surgery with
      self-retaining laryngoscope: a study on 31 cases].
AB  - OBJECTIVE: To investigate the improvement of general anesthesia method for
      microlaryngoscopic surgery with self-retaining laryngoscope. METHOD: 31 cases
      with laryngeal lesion who had undergone the microlaryngoscopic operation with
      self-retaining by anesthesia were reviewed retrospectively from October 1, 1997
      to December 31, 2000. RESULT: All patients undergone the microlaryngoscopic
      surgery and their specimens were examined by pathology, 30 cases were benign
      lesion, 1 case was squamous cell cancer of the vocal cord. Their voice recovers
      very satisfactorily except for 2 patients. There were no recurrence after 6-38
      months follow-up. CONCLUSION: This study suggests that the general aneathesia
      with plastic jet ventilating tube controlling respiratory for microlaryngoscopic
      surgery is easier, more effective and safer than the other methods.

PMID- 12599778
TI  - [Clinical analysis to 36 cases of acute laryngeal damage].
AB  - OBJECTIVE: To research the way to deal with the acute laryngeal damage. METHOD:
      Data of 36 cases with acute laryngeal damage were analyzed. RESULT: Among 36
      cases, there were 10 cases who received non-surgical treatment and their
      phonation was normal except 2 cases who had mild hoarseness. Among 26 cases who
      had been performed operation. 21 had normal phonation after operation. 5 cases
      still had roughness of voice. There were 22 cases with normal respiration but 4
      cases with larynostenosis and difficulty in decannulation. Among these 4 cases, 2
      cases were decannulated respectively after 2 months and 10 years after operation.
      29 cases made of 80% in all were cured and decannulated within 1 month.
      CONCLUSION: Acute laryngeal damage patients should be diagnosed and treated as
      early as possible according to the damage degree so as to recovery the laryngeal
      and tracheal's function and to prevent the sequelae and to increase the cure
      rate.

PMID- 12599779
TI  - [The upper airway CT scan in patients with obstructive sleep apnea syndrome].
AB  - OBJECTIVE: To compare the CT scan results in OSAS patients and normal adults so
      as to explore its value in measuring upper airway structure. METHOD: 53 patients
      with OSAS and 53 normal adults were included in the study. The upper airway from
      roof of nasopharynx to glottis was evaluated with the use of a Phlips Tomoscan AV
      Expander E1 spiral scanner. The area and the dimensions of palate, uvula, lingua
      and epiglottis region was studied, and the thickness of retropharyngeal and
      lateral pharyngeal tissue were evaluated, too. RESULT: There were obviously
      differences between OSAS patients and normal adults in the areas of palate,
      uvula, lingua, and there are differences of dimension and thickness in different
      sites. CONCLUSION: The study suggests that there is a obviously difference
      between the patients with OSAS and normal adult in upper airway by CT scan. The
      anatomic structure of upper airway is one of causes of OSAS.

PMID- 12599780
TI  - [Erosion of the mastoid caused by the external auditory canal cholesteatoma (with
      3 cases reported)].
AB  - OBJECTIVE: To improve the diagnosis and treatment of the external auditory canal
      cholesteatoma (EACC) with erosin into the mastoid. METHOD: The data of 3 patients
      with erosin of the mastoid caused by EACC were analysed retrospectively and
      recent literatures were reviewed. RESULT: In all cases, the cholesteatomas were
      found in the external auditory canal and the mastoid cavity. The disease eroded
      the posterior aspect of the canal wall, and fistulas between the canal and the
      mastoid were found. The fallopian canal was eroded but the facial never and
      labyrinth were intact. All patients were treated with canal wall down
      mastoidectomy. There was no recurrence after 6 months to 9 years follow-up.
      CONCLUSION: EACC was easily misdiagnosed as keratosis obturans(KO). EACC with
      posterior canal wall-mastoid cavity fistula is an extremely rare occurrence.
      Treatment consists of the removal of the cholesteatoma sac and bony sequestra.
      Surgical treatment options can be taken depending on the stage of disease.

PMID- 12599781
TI  - [The expressions of telomerase activity and cyclinD1 protein in laryngeal
      squamous cell carcinoma].
AB  - OBJECTIVE: In order to investigate the telomerase activity and its relationship
      with the overexpression of cyclin D1 protein in laryngeal squamous cell
      carcinomas (LSCC). METHOD: TRAP(Telomeric repeat amplification protocol) assay
      and immunohistochemical method were used respectively to detect the telomerase
      activity and the overexpression of cyclin D1 protein in 38 LSCC and correspondent
      laryngeal mucosa. RESULT: The expressions of telomerase and cyclin D1 protein
      were 82%(31/38), 50%(19/38) respectively in LSCC, both of them were not
      associated with the age of patients, location of tumors, T stage and pathological
      grade(P > 0.05), but there was a significant difference among clnic stages (P <
      0.05) in telomerase activity, no significant difference could be found among
      clinic stages in expression of cyclin D1. 18 out of 31 cases were expressed in
      both of them simultaneously there was significant association between them(P <
      0.05). CONCLUSION: Telomerase is widely activated in LSCC, the overexpression of
      cyclin D1 protein may be one of the most important mechanisms of telomerase
      activation in LSCC.

PMID- 12599782
TI  - [Detection and clinical significance of CYFRA21-1 in serum of laryngeal carcinoma
      patients].
AB  - OBJECTIVE: To study the relationship between the overexpression of CYFRA21-1 in
      the serum of laryngeal cracinoma patients and the associated clinical feature.
      METHOD: The serum level of CYFRA21-1 were determined by ELISA in 25 laryngeal
      carcinoma patients preoperatively and postoperatively. 20 laryngeal benign
      diseases are as control group. RESULT: Positive rate was 60% for serum of CYFRA21
      1 in the laryngeal carcinoma patiens. The mean serum level for CYFRA21-1 in
      laryngeal carcinoma patients preoperatively (5.14 +/- 1.82) micrograms/L was
      significantly elevated than in control group (2.17 +/- 0.68 micrograms/L). The
      Serum level of CYFRA21-1 1 were significantly declined after surgery under normal
      level. Serum level of CYFRA21-1 went up once ogain in 2 recurrence patients.
      There was no correlation between serum level of CYFRA21-1 with age, sex and site
      in the laryngeal carcinoma patients. There were correlations between the serum
      level of CYFRA21-1 with clinical stage, pathological grading and lymphatic
      matatasis. Level of CYFRA21-1 was higher in poorly differentiated. CONCLUSION:
      The study suggests that serem CYFRA21-1 level could be a useful tumor marker for
      diagnosis, progenosis and follow-up after surgery in laryngeal carcinomas.

PMID- 12599783
TI  - [The detection of cytokine and immunoglobulin in sera of children with
      respiratory papillomatosis].
AB  - OBJECTIVE: To investigate the levels and effects of cytokine and immunoglobulin
      on children with respiratory papillomatosis(RP). METHOD: The levels of cytokine
      and immunoglobulin in sera of 23 patients with RP were measured by ELISA and
      immunoassay and were compared with the normal data published by our department of
      Laboratory. RESULT: The levels of cytokine in RP group were significantly higher
      than that of normal group and the levels of immunoglobulin in RP group was
      significantly lower than that of normal group. CONCLUSION: The result shows that
      there are immune deficiency and abnormal immune reponse with cytokine in the RP
      patients.

PMID- 12599784
TI  - [Obstructive sleep apnea of gestational period].
AB  - OBJECTIVE: To explore the influence of obstructive sleep apnea syndrome (OSAS) on
      the pregnant women. METHOD: 465 women in pregnancy were studied by random. The
      snoring rate, the relation with hyper blood pressure and preeclamptism, and the
      influence on infant were observed. RESULT: The magnificent statistics shows total
      snoring rate is 24.7%(115/465). 21.3%(92/442) is after pregnancy, of them, 28.7%
      meet the standard of OSAS, 12.17% with hyper blood pressure, 7.8% with
      preeclamptism, 5.2% infant with aplasia. CONCLUSION: Diseases incidence with OSAS
      is more oboious than that with normal pregnant women. OSAS has a marked1
      influence on pregnancy. Pregnant women with obvious OSAS can be regard as an
      independent factor of high risk pregnancy. We should pay more attentions to them
      in their early stage.

PMID- 12599785
TI  - [Correlation between expression of Fas protein and hair cell apoptosis in basilar
      papilla of chicken].
AB  - OBJECTIVE: To study the relationship between expression of Fas protein and hair
      cell apoptosis following drug ototoxicity in the chicken inner ear. METHOD: The
      damaged chicken inner ear model was developed by a subcutaneous injection of
      kanamycin at a daily dose of 100 mg/(kg.d) for 10 consecutive days. The Fas
      protein positive cells and apoptotic cells were examined by immunohistochemistry
      and TUNEL method at 1, 3, 7, 14, 21 days post-treatment. RESULT: TUNEL positive
      cells were localized to luminal layer of the sensory epithelia in the basilar
      papilla, there were much more apoptosis cells at the seventh day post-treatment.
      Fas positive cells began to increase at the first day post-treatment, and
      expression level of Fas protein increased to its peak at the third day after the
      last injection. At the fourteenth day post-treatment, TUNEL positive cells
      decreased following a low expression of Fas protein in the basilar papilla.
      CONCLUSION: There is a relationship between hair cell apoptosis and high
      expression of Fas protein in chicken inner ear following chronic kanamycin
      ototoxicity, Fas protein may contribute to regulate and control hair cells
      apoptosis.

PMID- 12599786
TI  - [Health care research--current and future challenges].

PMID- 12599787
TI  - [Should physicians perform research?].

PMID- 12599788
TI  - [Conditions and possibilities for health care research in Denmark].
AB  - Public health research is a necessary part of our attempts to control and to
      prevent diseases and to improve health. Epidemiology has probably been the most
      productive part of public health research in Denmark, and the discipline still
      has a lot of growth potential. The medical profession is, however, abandoning the
      full-time research departments, mainly because clinical units are in a position
      to pay higher salaries than research departments. New and important research
      opportunities will be available in the future. To fully take advantage of these
      opportunities, we need better coordination and better management in public health
      research in Denmark. We also need the medical profession to be part of the team.

PMID- 12599790
TI  - [Why should many physicians perform clinical research?].

PMID- 12599789
TI  - [What is required to recruit physicians for research in preclinical fields?].

PMID- 12599791
TI  - [Health research--industry's point of view].

PMID- 12599792
TI  - [General practice research. Research results from hospitals and population
      studies can not be directly transferred to family practice].

PMID- 12599794
TI  - [Peer review of research institutions. Evaluation or facilitation].

PMID- 12599793
TI  - [Research barometer: how is research activity monitored and how is it compared?].
AB  - Recent analyses place Danish health science with the highest scientific impact
      per investment and the greatest share of most-cited papers globally. Several
      fields have international top score impact implying that they achieve more
      frequent citing than the average (Matthew effect). This appears paradoxical in
      view of the drastic reductions in Danish research budgets through the last 20
      years--and the concomitant switch from long-term government grants to short-term
      external/private funding implying that continuity is replaced by demands for
      prompt results. Danish health research has thus proved remarkably robust under
      the steady downward tendency, but it is doubtful how far it will withstand
      current policy without irreversible damage. The methodologies applied in
      assessment of the excellence of research become increasingly sophisticated. They
      are still not completely reliable. At present they are primarily retrospective.
      It is imperative that future instruments monitor the actual research position.

PMID- 12599795
TI  - [Which are the elements of an international evaluation of research? Experiences
      from an evaluation of Swedish psychiatric research].
AB  - INTRODUCTION: In order to ensure the quality of research, it is necessary to
      perform an external evaluation of the quality and structure of the research
      environments on a regular basis and consider them in a national and international
      perspective. MATERIAL AND METHODS: There are several ways of evaluating research.
      The author mentions an audit-like expert evaluation based on his own experience
      from an evaluation of Swedish psychiatric research in 2000. RESULTS AND
      DISCUSSION: A short comparison with Danish psychiatric research is made. One of
      the advantages of this method is that the research evaluation can be carried out
      by the members of the research teams in an open dialogue among peers. This
      procedure makes it possible to focus on weaknesses and strengths with the purpose
      of planning future strategies and organisation in the most appropriate way. An
      obvious limitation, however, is the competence assigned to the expert group whose
      composition is important for the result.

PMID- 12599796
TI  - [Danish research within the field of anesthesia and intensive medicine. Problems
      and visions].
AB  - INTRODUCTION: Danish anaesthesiology research has traditionally done well
      internationally. However, there are signs that the research activity is
      declining. The aim of this article is both to appraise the status of the
      development of research in anaesthesiology and to discuss the problems that face
      Danish anaesthesiology research. MATERIAL AND METHODS: The development of
      research is assessed from the bibliometric literature based on the number of
      publications in journals that use a peer review of the articles, the total
      international exposure, the absolute impact of citations, and finally the
      proportion of publications cited at least once. RESULTS: Unlike countries with
      which we usually compare ourselves, both the total level of research activity and
      the amount of international exposure of research have been declining in Denmark
      over the past 10-15 years. However, the quality of the research appears to be
      improving. CONCLUSION: On the background of debates within the speciality--e.g.
      at various meetings and workshops--the author discusses the reasons for and
      impact of the declining level of research activity. An account is given for what
      is being done within the speciality to promote research, and tangible proposals
      are put forward with a view to promoting research activity further at different
      levels in the Danish Health Service. Finally, attention is drawn to the three
      most important challenges facing Danish anaesthesiology research in the coming
      years, namely the shortage of specialist practitioners, the new medical paradigm
      shift, and the bibliometric methods used for research evaluation.

PMID- 12599797
TI  - [Graduate education--a continuous developmental process].

PMID- 12599798
TI  - [Recruitment of younger researchers--a joint responsibility].

PMID- 12599799
TI  - [Research and the research support system].

PMID- 12599800
TI  - [The Danish basic research grant. Difficult and condemned].

PMID- 12599801
TI  - [From where does the economic support to health research come?].

PMID- 12599802
TI  - [Is there a need of cross-county/regional cooperation concerning research?].

PMID- 12599803
TI  - [The role of sector research institutions in the research].

PMID- 12599804
TI  - [Part time positions clinical work/research. A necessary piece in the overall
      situation].

PMID- 12599805
TI  - [Changing fasting guidelines--sugar water instead of sedatives?].

PMID- 12599806
TI  - [Let scientific misconduct be seen through to prevent it].

PMID- 12599807
TI  - [The committee of patients' complaints and diagnoses].

PMID- 12599808
TI  - [The nursing profession: new creations].

PMID- 12599809
TI  - [Reform of the health and social systems is the greatest challenge in politics.
      Reforms only with the involvement of nurses].

PMID- 12599810
TI  - [The Society has been called upon to support knowledgable student nurses. Nursing
      knowledge is a necessity].

PMID- 12599811
TI  - [Historical nursing research requires an archive].

PMID- 12599812
TI  - [A woman's profession emancipates itself].

PMID- 12599813
TI  - [Wild nurses find a home].

PMID- 12599814
TI  - [The time of the "helping angels". The National Socialist glorification of the
      nurse--which is still used].

PMID- 12599815
TI  - [From the general nursing supervisor to the presidency].

PMID- 12599816
TI  - [The nursing identity crisis].

PMID- 12599818
TI  - [The German Nursing Society deserves importance; interview].

PMID- 12599817
TI  - [The proper proof of interest].

PMID- 12599819
TI  - Distinguishing 'toxins' from 'toxicants'.

PMID- 12599820
TI  - Welders, helpers are exposed to severe burns.

PMID- 12599821
TI  - Ten signs an applicant is a lawsuit waiting to happen.

PMID- 12599822
TI  - 'Making the case': CD or print?

PMID- 12599823
TI  - New ANSI Z9.8 IAQ and HVAC standard.

PMID- 12599824
TI  - New perspectives on accident/incident investigation.

PMID- 12599825
TI  - Growing season. Putting your reward emphasis on leading indicators will improve
      safety and stimulate a cultural shift.

PMID- 12599826
TI  - Better ingredients: the pizza analogy.

PMID- 12599827
TI  - Making safety part of the corporate culture.

PMID- 12599828
TI  - Keeping engagement high and bandwidth low.

PMID- 12599829
TI  - Technology in the fast lane.

PMID- 12599830
TI  - Don't be shocked.

PMID- 12599831
TI  - Lessons the anthrax scare taught us.

PMID- 12599833
TI  - 'Side pushing': when you can't push it or pull it.

PMID- 12599832
TI  - DOJ's authorized equipment purchase list.

PMID- 12599834
TI  - Dangerous postures.

PMID- 12599835
TI  - Effective dermal protection.

PMID- 12599836
TI  - Alternative drug testing update.

PMID- 12599837
TI  - [Transjugular intrahepatic portosystemic shunt (TIPS) in Denmark].

PMID- 12599838
TI  - [Transjugular intrahepatic portosystemic shunt (TIPS) for the treatment of
      complications of portal hypertension in patients with liver cirrhosis].
AB  - Portal hypertension is a main cause for the development of esophago-gastric
      varices, ascites and hepatic nephropathy in liver cirrhosis. Reduction of portal
      pressure by a transjugular intrahepatic portosystemic shunt (TIPS) procedure has
      been possible for the last decade. The treatment reduces the risk for variceal
      bleeding, reduces ascites formation and may improve renal function in hepatic
      nephropathy. Improved survival, however, has not yet been documented.
      Complications comprise procedure related events (puncture of liver capsule,
      bleeding, infection, hemolysis with mortality 1-5%), shunt stenosis (30-80%
      during the first year but reversible), and encephalopathy (30% intermittent, 10%
      chronic). Indications for the procedure are primarily variceal bleeding resistant
      to conventional pharmacologic and endoscopic treatment. Absolute and relative
      contraindications are severe hepatic failure, a history of hepatic
      encephalopathy, infections, respiratory failure, and non-hepatic renal
      insufficiency.

PMID- 12599839
TI  - [TIPS--transjugular intrahepatic portosystemic shunt. Experiences from a recently
      started center].
AB  - The transjugular intrahepatic portosystemic shunt (TIPS) is a percutaneous,
      minimally invasive, method of creating a portosystemic shunt for the treatment of
      portal hypertension. The results of the first 54 TIPS procedures are reported.
      There were no severe procedure-related complications. TIPS implantation was
      successful in 52 patients. Rebleeding was seen in 13% of the patients. Hepatic
      encephalopathy developed in 19%, but only in 11% as a chronic complication. Seven
      out of 9 patients with refractory ascites no longer required paracentesis after
      six months. The cumulative survival for the whole group was 81% after one year
      and 62% after three years.

PMID- 12599840
TI  - [Hereditary pancreatitis].
AB  - Hereditary pancreatitis (HP) is a disease which has been discovered quite
      recently. The inheritance is autosomally dominant with 80% penetrance. It gives
      the same symptoms as acute pancreatitis in early childhood and ends up with
      chronic pancreatitis. In 60% of the patients, a mutation in the trypsinogen gene
      can be demonstrated. The remaining 40% of the HP patients are diagnosed on the
      basis of clinical criteria. The acute and the chronic pancreatitis are treated as
      usual. It is important to recognize the disease because patients with HP have a
      50 times increased risk of developing pancreatic cancer. At the age of 70, 40%
      have developed pancreatic cancer. This risk doubles for cigarette smokers.
      Screening programmes for HP in order to prevent pancreatic cancer are, however,
      expensive and troublesome.

PMID- 12599841
TI  - [Glucosamine and chondroitin sulfate in the treatment of arthritis].
AB  - Glucosamine and chondroitin sulphate are naturally occurring substances used by
      an increasing number of Danish patients with arthritis, although neither of the
      compounds has been approved for sale in Denmark. Both substances can be taken by
      mouth and have no known significant side effects. Glucosamine and chondroitin
      sulphate have been examined in laboratory and animal experiments, and in several
      clinical studies, which have shown some effect on the symptoms of early or
      moderate arthritis. The long-term effect has not been evaluated sufficiently and
      studies of the relation between dose and effect are lacking for both compounds.

PMID- 12599842
TI  - [Bisphosphonate treatment of children and adolescents].

PMID- 12599844
TI  - [The effect of losartan versus atenolol on cardiovascular morbidity and mortality
      in patients with diabetes mellitus in the LIFE-study].
AB  - INTRODUCTION: The most suitable antihypertensive drug to reduce the risk of
      cardiovascular disease in patients with hypertension and diabetes is unclear. In
      a prespecified analysis of the LIFE-study we compared the effects of losartan and
      atenolol on cardiovascular morbidity and mortality in diabetic patients. MATERIAL
      AND METHODS: A total of 1195 patients in the LIFE-study had diabetes at the time
      of the randomisation. The patients were randomised for double-blind treatment
      with losartan versus atenolol. The patients had ECG-verified left ventricular
      hypertrophy, mean age 67 years, blood pressure 177/96 mmHg after two weeks
      placebo run-in period. Patients were followed for at least four years (mean 4.7
      years). The primary composite endpoint was cardiovascular death, stroke or
      myocardial infarction. RESULTS: Blood pressure was reduced to 146/79 and 148/79
      in losartan-treated patients and atenolol-treated patients, respectively. The
      primary endpoint occurred in 103 patients assigned losartan (n = 586) and 139
      assigned atenolol (n = 609). Relative risk reduction 24% (p < 0.031).
      Cardiovascular mortality was reduced by 37% in favour of losartan (p < 0.028),
      and all cause mortality by 39% (p < 0.002). DISCUSSION: Losartan was very
      effective in reducing cardiovascular morbidity and mortality as compared to
      atenolol. These results will have a major impact on the choice of anti
      hypertensive treatment for patients with hypertension and diabetes.

PMID- 12599843
TI  - [The effect of losartan versus atenolol on cardiovascular morbidity and mortality
      in patients with hypertension and ECG-verified left ventricular hypertrophy in
      the LIFE-study].
AB  - INTRODUCTION: Left ventricular hypertrophy is a strong independent predictor of
      risk of cardiovascular morbidity and death. The aim of the LIFE-study was to
      establish whether treatment with the angiotensin-II AT 1-receptor antagonist,
      losartan, reduced cardiovascular events more effectively than treatment with the
      betablocker atenolol in patients with hypertension and left ventricular
      hypertrophy. MATERIAL AND METHODS: The LIFE-study included 9193 patients with
      essential hypertension and ECG-verified left ventricular hypertrophy, age range
      55-80 years, systolic blood pressure in sitting position 160-200 mmHg and/or
      diastolic blood pressure 95-115 mmHg. Patients were randomized to double-blind
      treatment with losartan versus atenolol. They were followed for at least four
      years and until 1040 patients had a primary cardiovascular event (cardiovascular
      death, myocardial infarction or stroke). RESULTS: Blood pressure fell by
      30.2/16.6 and 29.1/16.8 mmHg in the losartan and the atenolol group,
      respectively. The primary composite endpoint occurred in 508 losartan and 588
      atenolol patients (relative risk 0.87, p = 0.021). A total of 232 and 309,
      respectively, had fatal or non-fatal stroke (relative risk 0.75, p = 0.001).
      There was no difference in myocardial infarction. New-onset diabetes was 25% less
      frequent on losartan. Side effects were less on losartan compared to atenolol.
      DISCUSSION: Losartan prevents to a higher degree cardiovascular morbidity and
      death than atenolol for a similar reduction in blood pressure and is better
      tolerated.

PMID- 12599845
TI  - [Strengths and Difficulties Questionnaire (SDQ-Dan). A new instrument for
      psychopathologic screening of children aged 4-16 years].

PMID- 12599846
TI  - [Congenital hydrocephalus--prevalence and prognosis. Mortality and morbidity in a
      population-based study].
AB  - INTRODUCTION: The aim was to describe the prevalence and to estimate the
      prognosis of congenital hydrocephalus (HC) in fetuses and children. MATERIAL AND
      METHODS: Data for the study were taken from the Eurocat Register of Congenital
      Malformations for the County of Funen and from medical records. The study
      includes liveborn, intrauterine deaths, and induced abortions. All cases with HC
      born in the County of Funen in the years 1986-1998 were included. The followup
      period is three years after birth. RESULTS: The prevalence of HC was 0.4/1,000
      births. There were 29 cases of HC, out of which 21 were liveborn. 41% had
      associated malformations, syndromes and/or chromosome abnormalities, and
      mortality of these compared to cases with isolated HC were significantly
      increased (p < 0.05). 18 children had shunt surgery and 12 children had one or
      more reoperations. At the age of three, four children had died, 12 had
      neurological problems related to their HC, and five children were described as
      normal. DISCUSSION: We found high mortality and morbidity in fetuses and children
      with HC. Mortality was significantly increased if associated malformations,
      syndromes and/or chromosome abnormalities were present. After prenatal diagnosis
      of HC it is important to look carefully for other malformations and to perform a
      karyotype before information about the prognosis of the fetus is given to the
      parents.

PMID- 12599847
TI  - [Disability retirement pension for patients with syndrome diagnoses. A registry
      study on the basis of data from the Social Appeal Board].
AB  - INTRODUCTION: Since the early 1990s, disability retirement pension may be granted
      on the basis of a syndrome diagnosis. Before the pension can be granted, local
      public authorities collect information on health and social matters and report to
      The Social Appeal Board. In 1998, a new diagnostic tool was introduced based on
      the International Statistical Classification of Diseases and Related Health
      Problems (ICD-10) diagnoses. The information available in The Social Appeal Board
      has made it possible to study the social consequences of a syndrome diagnosis.
      The purpose of the study was: 1) To estimate the incidence of patients granted
      disability retirement pension with the diagnoses whiplash, fibromyalgia, chronic
      pain disorder, chronic fatigue syndromee, chronic strain syndromee, and pelvic
      syndromee. 2) To estimate changes in the level of pension granted to patients
      with syndromee diagnosis. 3) To compare differences between patients with
      syndromee diagnosis granted disability retirement pension to patients with other
      diagnoses on the following parameters: sex, civil status, income when applying
      for pension, and attempts of rehabilitation. 4) To estimate comorbidity of
      psychiatric diagnosis in patients with syndromee diagnosis. MATERIAL AND METHODS:
      A register study of data on pension reported to The National Social Appeal Board
      in the period July 1st 1998 to December 31st, 2000. RESULTS: Of all patients
      granted pension in the period 8.3 per cent had a syndromee diagnosis, 11 per cent
      of the women and 5 per cent of the men. Both the relative and the absolute number
      of patients with syndromee diagnosis granted a pension were increasing.
      Comorbidity of psychiatric disorders was 3 per cent in the group with syndromee
      diagnosis. More patients with syndromee diagnosis than with other diagnoses had
      received sickness benefits and rehabilitation when pension was granted.
      DISCUSSION: The large number of patients with syndromee diagnosis granted pension
      calls for multidisciplinary prophylactic and treatment initiatives in order to
      reduce the number of patients in need of public support. The results are
      discussed in view of the new Pension's Act which will become effective as from
      January 1st, 2003.

PMID- 12599848
TI  - [An outbreak of allergic contact dermatitis caused by 2-hydroxypropyl
      methacrylate in an anaerobic sealant].
AB  - We report an outbreak of occupational contact dermatitis from an anaerobic
      sealant. This diagnosis was given to 12 out of 48 exposed workers at two Danish
      refrigerator factories. Six workers showed a positive patch test reaction to 2
      hydroxypropyl methacrylate, a constituent of the sealant. Main causes were
      insufficient information from the producer and poor work place hygiene.

PMID- 12599849
TI  - [Clozapine and diabetic ketoacidosis].
AB  - We report a case of diabetic ketoacidosis in a 54-year-old white female with type
      2 diabetes and schizophrenia during clozapine treatment.

PMID- 12599850
TI  - [Picture of the month: hydrocephalus].

PMID- 12599851
TI  - [Does gestational anxiety result in children's attention disorders?].

PMID- 12599852
TI  - [Sexually transmitted infections and sexual violence against women].

PMID- 12599853
TI  - [Chlamydia trachomatis and Neisseria gonorrhoeae in sexually abused children in
      Jutland].

PMID- 12599854
TI  - [Health status of asylum seeking children].

PMID- 12599855
TI  - [Doctors Club 3].

PMID- 12599856
TI  - [Doctors Club 4].

PMID- 12599857
TI  - Rewarding for quality: new incentives emerge to improve healthcare and promote
      best practices.
AB  - When the Institute of Medicine's Committee on Quality of Health Care in America
      released its second report, Crossing the Quality Chasm, last year, criticism was
      leveled at the "toxic reimbursement system" that failed to reward efforts to
      achieve quality care. However, times are changing, and this issue of The Quality
      Letter looks at new ways incentive programs are being implemented and fine-tuned
      at the hospital, health plan, and medical practice level to promote the delivery
      of quality healthcare.

PMID- 12599858
TI  - Leadership by example: IOM report calls for U.S. to become more visible in
      quality arena.
AB  - The federal government--as both a regulator and the largest healthcare purchaser
      in the country--should take advantage of its "influential position" to promote
      quality standards and patient safety for the entire healthcare sector, according
      to a report released this fall by the Institute of Medicine's Committee on
      Enhancing Federal Healthcare Quality Programs.

PMID- 12599859
TI  - Ergonomic principles of safe patient handling.

PMID- 12599860
TI  - Neonatal transitional care program.

PMID- 12599861
TI  - ONS structures: old and new. Organizational structure supports society's mission,
      vision, and values.

PMID- 12599862
TI  - ONS meets with success in key priority areas in 2002.

PMID- 12599863
TI  - ONS participates in American College of Chest Physicians Lung Cancer Guidelines
      Project.

PMID- 12599864
TI  - Health Insurance Portability and Accountability Act protects privacy of medical
      records.

PMID- 12599865
TI  - [The nurse and a patient undergoing an electrophysiological study].

PMID- 12599866
TI  - [Prolonged breastfeeding. A complex process and yet poorly known].

PMID- 12599867
TI  - [Bronchial hygiene. From the traditional manual techniques to the modern
      technological approaches].

PMID- 12599868
TI  - [Impossible Christmas].

PMID- 12599869
TI  - [Troubling destructive repetitive behaviors].

PMID- 12599870
TI  - [Treatment of osteoporosis and fracture prevention].

PMID- 12599871
TI  - [Exclusive and partial breastfeeding].

PMID- 12599872
TI  - [Buttocks dermatitis in infants].

PMID- 12599873
TI  - [Licence to kill. Is it that the "right to die" in the Netherlands has become a
      "duty to die"?].

PMID- 12599874
TI  - [Speaking with one voice].

PMID- 12599875
TI  - [Changed AIDS problem requires new strategies].

PMID- 12599876
TI  - [International AIDS Conference. Call to action].

PMID- 12599877
TI  - [Post-traumatic stress syndrome. After shock and horror in consoling safety].

PMID- 12599878
TI  - [Interdisciplinary cooperation. Medicine and nursing--Siamese twins?].

PMID- 12599879
TI  - [Nomenclature. "Nursing care only becomes visible when we document it"].

PMID- 12599880
TI  - [Nursing home for the aged. From guidelines to concrete nursing care].

PMID- 12599881
TI  - ["With the same voice"].

PMID- 12599882
TI  - [Support for victims of terrorism. "My life has become a nightmare"].

PMID- 12599883
TI  - [Psychological sequelae caused by an act of terrorism. Post-traumatic stress
      disorder--manifestations and symptoms].

PMID- 12599884
TI  - [Help for survivors of trauma. Psychological debriefing].

PMID- 12599885
TI  - [Innovative anti-violence program in Sweden. "Look at what you've done"].

PMID- 12599886
TI  - [Reaffirming commitment in psychiatric nursing. Social behavior training].

PMID- 12599887
TI  - [Working conditions. Does work threaten the health of nurses?].

PMID- 12599888
TI  - [Managing patients with dementia in EMS. Daily challenges for nurses].

PMID- 12599890
TI  - [Midway in the health occupation education reform, an ambitious project.
      Interview by Celine Dekussche].

PMID- 12599891
TI  - [Breast cancer, emergence of a new dialogue with patients].

PMID- 12599892
TI  - [Sexuality for mentally handicapped persons?].

PMID- 12599893
TI  - [Year one of Coordin'Action in Martinique].

PMID- 12599894
TI  - [Reflections on nursing education].

PMID- 12599895
TI  - [Giving sense to functional rehabilitation quality].

PMID- 12599896
TI  - [HIV and hepatitis C seroconversions in nurses].

PMID- 12599897
TI  - [Blood exposure accidents study in Franche-Comte in 2001].

PMID- 12599898
TI  - [HIV infection prophylaxis after exposure].

PMID- 12599899
TI  - [Blood exposure accident prevention and education-action].

PMID- 12599900
TI  - [Evaluation of a prevention measure against blood exposure accidents].

PMID- 12599901
TI  - [Rights and responsibilities in cases of blood exposure accidents].

PMID- 12599902
TI  - [Diabetic foot ulcer].

PMID- 12599903
TI  - Will agenda for change resolve the grading issue?

PMID- 12599904
TI  - As if by magic. Can the government work a miracle and end nursing's chronic
      recruitment problem?

PMID- 12599905
TI  - The importance of good record-keeping for nurses.
AB  - Good record-keeping is a mark of the skilled and safe practitioner, yet
      allegations concerning shortcomings in nurses' record-keeping were the second
      most common category of hearing brought before the UKCC in 2000-2001. The absence
      of accurate records makes it difficult for practitioners to prove they provided
      appropriate care should they be asked to do so in a professional or legal
      hearing. This is particularly pertinent since litigation against health
      professionals is increasing rapidly. This article discusses the importance of
      keeping comprehensive and accurate records of patient care and decisions from the
      perspective of nurses, their patients and colleagues. It also discusses the
      elements of good record-keeping, as well as practices to avoid.

PMID- 12599906
TI  - What you need to know about ... cystic fibrosis.

PMID- 12599907
TI  - Electrocardiogram.

PMID- 12599908
TI  - Diabetes: treatment and complications--the nurse's role.
AB  - Diabetes is treated by insulin (type 1), and by diet and exercise alone or in
      combination with insulin (type 2). The long-term complications of diabetes can be
      devastating in their effects, therefore good glycaemic control must be a target
      for all patients. Nurses have a role in diabetes care as specialists or as part
      of general care. Screening for complications and referral of patients to relevant
      agencies when necessary are important aspects of their work, as is offering
      health promotion advice.

PMID- 12599909
TI  - Anorexia nervosa and the efficacy of an eating disorder service.
AB  - Anorexia nervosa is often a chronic and severe disorder in which morbidity and
      mortality are high. This article describes the treatments used at The Priory
      Hospital's eating disorder service. The findings of an audit and follow-up study
      found that 85 per cent of the anorexic patients were successfully helped to gain
      weight (up to their normal weight) at a rate of about 1 kg per week. In a follow
      up study four years later 80 per cent were doing reasonably well.

PMID- 12599910
TI  - 'It's amazing to see life open up for clients'. Interview by Leona Armstrong.

PMID- 12599911
TI  - Pioneers in treating pain. Interview by Carol Davis.

PMID- 12599912
TI  - Tackling the big issue in Brighton.

PMID- 12599913
TI  - Integrating historical and mechanistic biology enhances the study of adaptation.
AB  - Adding a causal, mechanistic dimension to the study of character evolution will
      increase the strength of inferences regarding the evolutionary history of
      characters and their adaptive consequences. This approach has the advantage of
      illuminating mechanism and testing evolutionary hypotheses rigorously. We
      consider the advantages of combining mechanistic and historical biology in the
      study of behavior, physiology, and development. We present six examples to
      illustrate the advantages: (1) preexisting biases in sound perception in frogs;
      (2) preexisting biases in visual cues in swordtailfishes; (3) exploitation of
      prey location behavior for attraction of mates in water mites; (4) heterospecific
      mating in asexual molly fishes; (5) developmental foundation of morphological
      diversification in amphibian digits; and (6) locomotor performance at low
      temperature and the evolution of nocturnality in geckos. In each of these
      examples, the dominant role of history, combined with organismal integration,
      makes ignoring history a risky proposition.

PMID- 12599914
TI  - When T-helper cells don't help: immunopathology during concomitant infection.
AB  - Disease directly caused by immune system action is known as immunopathology. Many
      factors may lead the immune system to cause rather than cure disease, and
      autoimmune, allergic, and infection-related immunopathological diseases affect
      millions of people worldwide. This review presents an analysis of T-helper cell
      mediated, infection-related immunopathology within the framework of evolutionary
      ecology. A proximate cause of infection-related immunopathology is an error in
      the type of T-helper response induced. Distinct subsets of T-helper cells enable
      different effector mechanisms and therefore work optimally against different
      types of parasites (e.g., extracellular versus intracellular parasites). Immune
      responses that cure rather than cause disease require that the T-helper subset be
      tailored to the parasite. It is thus critical for the immunophenotype to match
      the "environment" of the parasitic infection. As in other cases of adaptive
      plasticity, a mismatch between an organism's phenotype and the selective
      environment can decrease fitness. T-helper response induction may be confounded
      by coinfection of a single host by multiple parasite species. Because of normally
      adaptive feedback loops that lend to polarize T-helper responses, it can become
      impossible for the immune system to mount effective, conflicting responses
      concurrently. Immunophenotype-environment mismatches may thus be inevitable when
      simultaneous, conflicting immune responses are required. An ultimate cause of
      infection-related immunopathology in a multiparasite selection regime is the T
      helper response polarization that can propagate response errors and constrain the
      ability of the immune system to resolve conflicting response requirements. A case
      study is used to illustrate how coinfection can exacerbate immunopathology and to
      frame testable predictions about optimal responses to coinfection (e.g., is the
      observed joint response to coinfection accurately predicted by the average of the
      component single-infection optimal responses, where the single-infection optima
      are weighted by the contribution of each to fitness). The case study includes
      immunological and pathological data from mice infected by Schistosoma mansoni
      alone and by S. mansoni in combination with Toxoplasma gondii. Such data can
      inform hypothesis tests of evolutionary ecological principles, and ecological
      analysis can in turn clarify assumptions about responses to coinfection for a
      greater understanding of the immune system. The synthesis of evolutionary ecology
      and immunology could therefore be of mutual benefit to the two disciplines.

PMID- 12599916
TI  - English-speaking children's comprehension of relative clauses: evidence for
      general-cognitive and language-specific constraints on development.
AB  - Children must possess some ability to process input in a meaningful manner to
      acquire language. The present study reports on data from an experiment
      investigating 3- to 5-year-old English-speaking children's understanding of
      restrictive relative clauses manipulated for embeddedness and focus. The results
      of the study showed that English-speaking children acquire right-branching before
      center-embedded structures. Comparisons made with data from Portuguese-speaking
      children suggest general-cognitive and language-specific constraints on
      development, and with respect to English, a "clause expansion" approach to
      processing in development.

PMID- 12599915
TI  - Individual differences in sentence memory.
AB  - Results from an experiment with two parts are presented in this paper. In part
      one, participants listened to sentences containing two, three, four, or five
      clauses, and were asked questions about the content of the sentences. The results
      of part one demonstrate that an important unit of representation in sentence
      memory is the clause, and not some other component of discourse structure. In
      part two, the same group of participants performed eight different short-term
      storage/working memory tasks. A composite complex span score was computed for
      each participant based on three working memory tasks closely based on Daneman &
      Carpenter's (1980) reading span task. This working memory measure was
      significantly correlated with the participants' performance on the sentence
      memory task in part one. A second working memory measure--N-back--was also
      significantly correlated with the participants' performance on the sentence
      memory task, and there was no correlation between their performance on the
      complex span task and the N-back task. It is therefore concluded that (i) working
      memory consists of a number of dissociable components; and (ii) memory for
      sentences taps into more than one of these working memory components.
      Furthermore, the high correlations of sentence memory with the complex span and
      the N-back tasks (neither of which are language processing tasks) suggests that
      memory for sentences is not simply a result of linguistic experience; rather, it
      is likely that an independent working memory component contributes to
      participants' performance on the sentence memory task.

PMID- 12599917
TI  - Notation systems for transcription: an empirical investigation.
AB  - A 21-syllable question posed by Bernard Shaw in a CNN television interview with
      Margaret Thatcher was presented to 90 participants, either as an audio recording
      or as a typed transcript or as both. Participants were asked to speak it, as
      closely as possible, as Shaw had (or, in conditions without the audio recording,
      as he might have). The typed version was either an ordinary transcript or a
      transcript in one of three transcription systems used currently in research on
      spoken discourse, all of which incorporate notations for prosody. Hence, there
      were nine conditions in all, with five women and five men in each. Contrary to
      the experimental hypothesis, approximations to Shaw's original temporal measures
      of performance were not degraded but were instead improved significantly by the
      addition of a prosodically notated transcript to the audio recording and
      significantly more in the absence of the audio recording. Presentation of the
      ordinary transcript alone produced the worst approximation to Shaw's temporal
      measures. The usefulness, accuracy, and readability of transcripts prepared
      according to detailed notation systems are discussed.

PMID- 12599918
TI  - Processing "d-linked" phrases.
AB  - Linguists draw a distinction between two types of interrogatives: discourse
      linked (d-linked) phrases such as which man, which implies the existence of a set
      of contextually determined entities (men) from which the speaker is asking for a
      choice, and non-d-linked interrogatives such as who, which carry no such
      implication. Two questionnaires and an on-line reading study showed that readers
      prefer a d-linked phrase more than a non-d-linked phrase as the antecedent for a
      pronoun, suggesting that d-linked phrases are immediately instantiated in a
      discourse representation that is checked during the process of pronoun
      interpretation. Comparable difficulty is not observed for non-d-linked
      interrogatives. A questionnaire and an on-line listening study also showed that
      readers and listeners were more willing to accept a grammatical "island
      violation" containing a pronoun when the pronoun's antecedent was a d-linked
      interrogative than when the antecedent was non-d-linked, suggesting that they
      check a discourse representation for the pronoun antecedent. All results suggest
      that d-linked phrases are immediately interpreted in a discourse representation,
      not just in a syntactic representation.

PMID- 12599919
TI  - Reading, syntactic, orthographic, and working memory skills of bilingual Arabic
      English speaking Canadian children.
AB  - This study assessed the reading, language, and memory skills of 56 bilingual Arab
      Canadian children age's 9-14. English was their main instructional language, and
      Arabic was the language spoken at home. All children attended a Heritage Language
      Program in Toronto where they were taught to read and write Arabic. The children
      were administered word and pseudo-word reading, language, and working memory
      tests in English and Arabic. The majority of the children showed at least
      adequate proficiency in both languages. There was a significant relationship
      between the acquisition of word and pseudo-word reading working memory, and
      syntactic awareness skills in the two languages. The poor readers in Arabic had
      lower scores on all linguistic tasks, except the visual task. There were no
      significant differences between bilingual English Arabic children and monolingual
      English-speaking children on the reading, language, and memory tasks. However,
      bilingual English Arabic children who had reading problems in English had higher
      scores on English pseudo-word reading and spelling tasks than monolingual English
      speaking children with reading disabilities, probably because of positive
      transfer from the regular nature of Arabic orthography. In this case,
      bilingualism does not appear to have negative consequences for the development of
      language reading skills in both languages--Arabic and English--despite the
      different nature of the two orthographies.

PMID- 12599920
TI  - [Recent advances and problems in management and treatment of postoperative
      infection in surgery].

PMID- 12599921
TI  - [Prosthetic valve endocarditis: complication following cardiac surgery].
AB  - Prosthetic valve endocarditis (PVE) is a rare but serious complication following
      valve replacement surgery. Early-phase PVE, which occurs within 60 days of valve
      replacement, may be associated with nosocomial or intraoperative infection. The
      primary organism of this type is the Staphylococcus group. Late-phase PVE, which
      usually occurs more than one year after valve replacement, may be caused by a
      mechanism similar to that of native valve endocarditis. The primary causative
      organism of this type would thus be similar to that of native valve endocarditis,
      which is the Streptococcus group. To treat PVE effectively, it is extremely
      important to identify the primary causative organism. If uncontrollable cardiac
      failure or infection occurs, a second valve replacement is absolutely indicated.
      A cryopreserved aortic valve allograft, if available, is the first choice for
      PVE. Features such as cell viability, less compliance mismatch, and
      postantibiotic process could be reasons for the anti-infective characteristics of
      cryopreserved allografts. Currently, allograft valves are not widely available in
      Japan; therefore, conventional prosthetic valves are usually used. The use of
      antibiotic-soaked prosthetic valves or stentless xenograft valves has also been
      attempted. A genetic or tissue engineering approach could open a new era to
      overcome this lethal complication.

PMID- 12599922
TI  - [Management of the aortic graft infection].
AB  - Prosthetic graft infection is a life-threatening complication in aortic surgery.
      Ectopic gas, perigraft fluid collection, and pseudoaneurysm can be detected by CT
      scanning. In cases of graft-enteric fistula, the prosthetic material can
      sometimes be observed using gastroduodenoscopy. Several methods of treatment have
      been attempted clinically. Removal of the infected graft and additional extra
      anatomic bypass are associated with acceptable surgical outcomes, although the
      mortality rates are high because of persistent infection or aortic stump rupture.
      In-situ prosthetic graft replacement or omental transposition has also been
      attempted, although control of the infection has rarely been achieved. In-situ
      replacement with a cyropreserved aortic allograft considered to be resistant
      against infection has recently been performed. The immunological rejection or
      long-term patency rate of aortic allografts is unknown. However, this technique
      appears to be a useful option for the management of aortic graft infection.

PMID- 12599923
TI  - [Postoperative immunocompromised host infection in patients with thoracic
      disease].
AB  - Currently, pneumonia is divided into two categories: community-acquired pneumonia
      and hospital-acquired pneumonia. Postoperative pneumonia is included in the
      hospital-acquired category. In particular, ventilator-associated pneumonia occurs
      frequently in surgical units, and the aspiration of intrapharyngeal fluid causes
      this type of infection. Methicillin-resistant Staphylococcus aureus pneumonia
      also occurs in patients with advanced lung carcinoma, poor performance status,
      and impaired pulmonary function. Empiric therapy plays an important role in
      postoperative patients with severe pulmonary infection.

PMID- 12599924
TI  - [Infectious complications after esophageal surgery].
AB  - The incidence of wound infection, which is an intrasurgical field infection, is
      lower than the incidence of pneumonia, which is an extrasurgical field infection,
      after esophageal cancer surgery. Several trials predicting postoperative
      infectious complications have been reported. One measured the phytohemagglutinin-
      and concanavalin A-induced proliferation of peripheral blood mononuclear cells in
      patients; one measured the white blood cell (WBC) count 2 h after surgery and the
      decrease in WBC count on first postoperative day; and another showed that the
      decrease in serum IgG2 level can predict the occurrence of methicillin-resistant
      Staphylococcus aureus (MRSA) infections. Useful strategies for managing
      infectious complications have also been reported. Applying mupirocin calcium
      hydrate ointment to the nasal cavity decreases the incidence of MRSA infections.
      Autologous blood collection reduces the need for allogeneic transfusion in
      patients undergoing resection of esophageal cancer, and avoidance of allogeneic
      transfusion may reduce the risk of postoperative infection. The total exposure to
      preoperative chemoradiotherapy should be limited to 40 Gy or less to prevent
      postoperative pneumonia.

PMID- 12599925
TI  - [Biliary bacterial infection in liver surgery].
AB  - Hepatectomy for biliary tract carcinoma with obstructive jaundice is associated
      with a higher incidence of postoperative septic complications as compared with
      hepatectomy for hepatocellular carcinoma or metastatic liver cancer. Since most
      bacteria isolated from septic sites are identical to those found in the
      preoperative percutaneous transhepatic biliary drainage (PTBD) bile, bacterial
      colonization in bile appears to be responsible for posthepatectomy septic
      complications in patients with biliary tract carcinoma. Although it remains
      unclear how bile becomes contaminated after bile duct obstruction or why
      preoperative PTBD increases the incidence of biliary infection, bacterial
      translocation via the portal vein, resulting from loss of integrity of the
      intestinal mucosa and change in intestinal microflora, may in part account for
      the mechanisms. Moreover, impaired function of Kupffer cells and altered
      structure and function of hepatocyte tight junctions might also participate in
      the development of postoperative bacteremia in such patients. As septic
      complications and liver failure are profoundly associated with each other, it is
      important to take all measures before surgery to enhance liver function and to
      prevent postoperative septic complications.

PMID- 12599926
TI  - [Infection as a major morbidity in surgical treatment for patients with liver
      cirrhosis].
AB  - The prognosis of patients with liver cirrhosis (LC) has been improved by the
      advanced diagnostic modalities and medical treatment of the disease. During the
      follow-up period, the opportunity for discovery of carcinomas of the liver and
      the other digestive organs is increased in LC patients, who are recognized as a
      compromised hosts with impaired hepatic functional reserve, portal hypertension,
      and depressed reticuloendothelial function. Thus LC patients are susceptible to
      infection as a major form of morbidity after surgical treatment, which can result
      in sepsis and subsequent hepatic failure. Based on the adequate evaluation of
      cancer progression and hepatic functional reserve, a procedure yielding the
      necessary results with the minimum surgical treatment and careful perioperative
      management should be performed for LC patients to avoid critical complications
      such as sepsis and hepatic failure.

PMID- 12599927
TI  - [Infection in liver transplant recipients].
AB  - Despite the advances in liver transplantation, infection continues to be a major
      problem, with an incidence greater than that observed in other solid organ
      transplantations. The risk of infection is largely determined by the patient's
      preoperative condition, operative factors, and the status of immunosuppression.
      Here we describe the current understanding of bacterial, viral, and fungal
      infection in patients who underwent liver transplantation.

PMID- 12599928
TI  - [Endotoxin removal in septic shock].
AB  - Endotoxin adsorption therapy with a column containing polymyxin B-immobilized
      fiber (PMX-DHP) has been widely applied in the treatment of endotoxin-induced
      septic shock in Japan. Recently, the indications for PMX-DHP have been expanded
      as it has become clear that anandamide can be removed from the bloodstream with
      PMX-DHP. On the other hand, continuous hemodiafiltration with a polymethyl
      methacrylate (PMMA) membrane hemofilter(PMMA-CHDF) is performed to remove various
      humoral mediators from the bloodstream in the ICU in many hospitals because it
      has been accepted that those humoral mediators play a more important role in the
      pathogenesis of septic shock than endotoxins. According to our own results, there
      were no differences in the endotoxin removal rate, anandamide removal rate, and
      survival rate with or without PMX-DHP during PMMA-CHDF in the treatment of
      patients with septic shock. These results indicate that there is no need to
      perform PMX-DHP for septic shock as long as PMMA-CHDF is performed, and that the
      indications for PMX-DHP should be circumspectly investigated again.

PMID- 12599929
TI  - [Diagnosis related groups (3). Its future].

PMID- 12599930
TI  - Treatment of non-small-cell lung cancer in older persons.
AB  - The majority of individuals diagnosed with lung cancer in the United States are
      70 years of age and older. Defining appropriate therapy for older patients with
      non-small-cell lung cancer (NSCLC) is becoming a major focus of clinical
      research. In this article, we review the available data on clinical predictors of
      risk and benefit for elderly NSCLC patients receiving treatment via a variety of
      modalities, including surgery, radiotherapy, combined radiotherapy and
      chemotherapy, and chemotherapy alone. The data demonstrate that subgroups of
      elderly patients benefit from appropriately selected treatment. Participation of
      older patients in clinical trials designed to assess efficacy, toxicity, and
      quality-of-life outcomes for recently developed treatment modalities in this
      population is critical.

PMID- 12599932
TI  - New data may alter lymph node biopsy practices in early breast cancer.

PMID- 12599931
TI  - Management of sexual dysfunction after prostate brachytherapy.
AB  - Erectile dysfunction is a common sequela following potentially curative local
      treatment for early-stage carcinoma of the prostate gland. With larger studies
      and longer follow-up, it is clear that erectile dysfunction following prostate
      brachytherapy is more common than previously reported, with a myriad of
      previously unrecognized sexual symptoms. Approximately 50% of patients develop
      erectile dysfunction within 5 years of implantation. Several factors including
      preimplant potency, patient age, the use of supplemental external-beam
      irradiation, radiation dose to the prostate gland, radiation dose to the bulb of
      the penis, and diabetes mellitus appear to exacerbate brachytherapy-related
      erectile dysfunction. The majority of patients with brachytherapy-induced
      erectile dysfunction respond favorably to sildenafil citrate (Viagra). Despite
      reports questioning the potency-sparing advantage associated with brachytherapy,
      recent elucidations of brachytherapy-related erectile dysfunction may result in
      refinement of treatment techniques, an increased likelihood of potency
      preservation, and ultimately, improved quality of life.

PMID- 12599933
TI  - Clinical Trials Referral Resource. Clinical trials in cervical cancer.

PMID- 12599934
TI  - Nonmyeloablative preparative regimens for allogeneic hematopoietic
      transplantation. Biology and current indications.
AB  - High-dose myeloablative therapy with allogeneic hematopoietic transplantation is
      an effective treatment for hematologic malignancies, but this approach is
      associated with a high risk of complications. The use of relatively nontoxic,
      nonmyeloablative, or reduced-intensity preparative regimens still allows
      engraftment and the generation of graft-vs-malignancy effects, is potentially
      curative for susceptible malignancies, and reduces the risk of treatment-related
      morbidity. Two general strategies along these lines have emerged, based on the
      use of (1) immunosuppressive chemotherapeutic drugs, usually a purine analog in
      combination with an alkylating agent, and (2) low-dose total body irradiation,
      alone or in combination with fludarabine (Fludara).

PMID- 12599935
TI  - Evaluating the total costs of cancer. The Northwestern University Costs of Cancer
      Program.
AB  - The Northwestern University Costs of Cancer Program consists of a series of pilot
      studies that address the costs of cancer care. The program is designed to serve
      as a template in preparation for undertaking a large-scale study of a nationally
      representative sample of cancer patients--i.e., in preparation for a cancer costs
      and services utilization study in the future. In this article, we outline the
      theoretical framework associated with a study of cancer costs and summarize
      findings from our ongoing pilot studies in this area.

PMID- 12599936
TI  - Diagnosis of venous thromboembolic disease in cancer patients.
AB  - Venous thromboembolic disease is a common but likely underdiagnosed condition in
      the cancer patient population. Timely and accurate diagnosis of venous
      thromboembolism is imperative due to the unacceptable morbidity and mortality
      associated with a misdiagnosis. Because diagnosis of the condition based on
      clinical grounds alone is unreliable, physicians should select an appropriate
      objective diagnostic test to confirm or refute their clinical impressions.
      Compression duplex ultrasound is the best initial imaging test for both suspected
      upper- and lower-extremity deep venous thrombosis. Magnetic resonance venography
      (MRV) is a valid alternative when ultrasound is inconclusive, but contrast
      venography remains the "gold standard." Suspected pulmonary embolism should be
      initially evaluated by helical (spiral) computed tomography (CT) or
      ventilation/perfusion lung scintigraphy, the former being preferred in cases of
      obvious pulmonary or pleural disease. Indeterminate studies should prompt
      performance of contrast pulmonary angiography. Inferior vena cava thrombosis is
      also best assessed by contrast venography, with MRV and CT reserved as
      alternative imaging modalities. Evidence to date suggests that D-dimer assays
      remain unreliable in excluding venous thromboembolism in cancer patients. A newer
      latex agglutination D-dimer assay may prove to be clinically useful in this
      setting.

PMID- 12599937
TI  - Alzheimer's disease: emerging noncholinergic treatments.
AB  - With population trends skewing toward a larger percentage of elderly, Alzheimer's
      disease is projected to afflict many millions in the United States and around the
      world in the next 50 years. In terms of cost and psychological burden, the
      anticipated burden of this disease on caregivers and society at large is
      staggering. It is hoped that, with the development of new insights into the
      processes of this devastating illness and the development of new medications that
      may interrupt those processes, the projected incidence and impact of AD may be
      modified in the near future.

PMID- 12599938
TI  - Government in Northern Ireland.

PMID- 12599939
TI  - Is breastfeeding education the key to improved breastfeeding rates?

PMID- 12599940
TI  - Baby shops not helping to cut cot deaths.

PMID- 12599941
TI  - Influencing the research agenda.

PMID- 12599942
TI  - Agenda for change: RCM briefing.

PMID- 12599943
TI  - Consultant midwifery: a personal view.

PMID- 12599944
TI  - Should cord pH be performed routinely after normal birth?
AB  - Care of women in labour and how we monitor the wellbeing of baby remains a
      contentious issue. The National Institute for Clinical Excellence (NICE) guidance
      informs us that for low risk women intermittent auscultation is the method of
      choice. It also informs us that cord pH sampling should be performed in those
      cases where there has been fetal blood sampling in labour, caesarean section, or
      instrumental delivery. It does not say that all babies should have their acid
      base or pH determined after birth (NICE, 2001: 29). Nevertheless, in the hospital
      where the author practiced until July 2002 it remains hospital 'policy' to
      perform cord sampling on all babies. The net result influenced how midwives
      practiced, in that many midwives felt unable in the main to go against Trust
      policy. It became even more difficult to encourage midwives to practise
      intermittent auscultation as they felt the new policy made them more fearful of
      not using the cardiotocograph. Even when midwives protested and put forward their
      case, they were forced by fear of blame and litigation to practise defensively
      and not in the best interests of women. Midwives made their concerns known, but
      the practice continues and the issues remain largely unresolved. This paper is an
      account not only of the impact of cord pH sampling on well babies, but also of
      the unequal status of midwifery in relation to medical dominance that still
      persists in the NHS today.

PMID- 12599945
TI  - Crying babies, desperate parents.

PMID- 12599946
TI  - Head cases: an examination of craniosacral therapy.

PMID- 12599947
TI  - Re: Skincare for the newborn.

PMID- 12599948
TI  - Stress distressed.

PMID- 12599949
TI  - 'Real' expertise.

PMID- 12599950
TI  - Who is responsible for child protection?

PMID- 12599951
TI  - Patient benefits of new immunosuppression drugs.

PMID- 12599953
TI  - Managing erectile dysfunction.

PMID- 12599952
TI  - Different cultures but equal needs.
AB  - Many health professionals deal with issues of child protection on a regular or
      occasional basis, so they not only need a good understanding of their duties but
      also an awareness of cultural issues.

PMID- 12599955
TI  - Health-care challenges in rural areas: physical and sociocultural barriers.
AB  - Important health and well-being issues for people living in the countryside
      include zoonotic diseases, accidents and mental health problems. Long distances
      from specialist centres can cause hardship, as can the financial cost.
      Sociocultural barriers to seeking medical help comprise another serious
      challenge. More research is needed in this area to support health staff.

PMID- 12599954
TI  - A comparison of general nurses' and junior doctors' diabetes knowledge.
AB  - People with diabetes may be hospitalised for the condition or another reason.
      Either way, they need special care to avoid diabetes-related complications.
      General ward nurses and trainee doctors were tested on their knowledge of
      diabetes, with poor results in some areas. The questionnaire used could prove a
      useful tool for identifying and addressing these problems.

PMID- 12599956
TI  - An integrated care pathway for fractured neck of femur patients.
AB  - Fractured neck of femur is a common traumatic condition, particularly among older
      women. An acute trust developed an integrated care pathway for these patients,
      led by a consultant and a senior nurse. Multidisciplinary team members were
      trained and outcomes for patients on discharge seem to be improving. But some
      medical staff have been slow to get involved with the project.

PMID- 12599957
TI  - The nursing needs of a patient with a complicated abdominal wound.
AB  - A patient with a complex wound after abdominal surgery had three types of
      treatment--wound manager bags, vacuum-assisted closure and a capillary dressing.
      The patient's self-image was profoundly affected by the size and appearance of
      his wound. But despite the problems the wound healed, thanks to regular
      assessment and a multidisciplinary approach to his care.

PMID- 12599958
TI  - Pain assessment: how far have we come in listening to our patients?
AB  - Nurses have a key part to play in assessing patient's pain. Listening to the
      patient is essential and where communication is a problem, for language or other
      reasons, so is observing patients and talking to those who know them. Various
      pain assessment tools can be useful but nurses should remain open-minded and,
      above all, believe what their patients tell them.

PMID- 12599959
TI  - Safeguarding children: 1. The role of health and other professionals.
AB  - This is the first of a four-part Study paper on child protection. Part 1 reviews
      the concept of child abuse and significant harm and the role of all health-care
      professionals and other key workers in preventing, detecting and reporting such
      harm. Those children who may be at particular risk of harm are described and the
      child-protection process is examined.

PMID- 12599960
TI  - Sedation in the intensive care unit.

PMID- 12599961
TI  - Coronary care units should care for all at-risk cardiac patients.
AB  - Coronary care units have transformed the treatment of many patients whose lives
      are at risk. But many others who should be in these wards are still treated
      elsewhere.

PMID- 12599962
TI  - Acute coronary syndromes: identification and patient care.
AB  - Acute coronary syndromes comprise acute ST-elevation myocardial infarction, non
      ST-elevation myocardial infarction and unstable angina. These three conditions
      share a very similar pathology, although treatments differ. This paper examines
      the pathophysiology, identification, classification and management of these
      conditions.

PMID- 12599963
TI  - Management of a patient admitted with acute non-ST-elevation MI.
AB  - This case study reviews the history, symptoms, management and rehabilitation of a
      patient admitted to accident and emergency with severe chest pain. After other
      conditions had been ruled out he was diagnosed with acute non-ST-elevation
      myocardial infarction. He later underwent a coronary angioplasty.

PMID- 12599964
TI  - Pharmacological treatment of acute coronary syndromes.
AB  - Many trials have examined the efficacy of medications used in acute coronary
      syndromes. This paper reviews those now recommended in patients with unstable
      angina and non-ST-segment elevation myocardial infarction. There are currently
      seven groups of drugs that are used in the management of such patients.

PMID- 12599965
TI  - Home breech birth.

PMID- 12599966
TI  - My birth story.

PMID- 12599967
TI  - All tied up. Tongue tie and its implications for breastfeeding.

PMID- 12599968
TI  - Midwifery basics. Antenatal care--health in pregnancy.
AB  - Joanna is now 20 weeks pregnant. She has been well, although rather nauseous at
      times, but this is now less frequent. Her abdomen is beginning to expand, but she
      is at a stage where it isn't obvious that she is pregnant, and she just feels
      fat. She has felt the tiniest flicker of what she thinks are fetal movements, but
      is not quite sure. Louis, her partner, can not feel anything and finds it all
      rather hard to conceptualise.

PMID- 12599970
TI  - Antenatal education but not as you know it. 3 October 2002, Centennial Centre,
      Birmingham.

PMID- 12599969
TI  - Baby friendly education standards. Aiming to improve breastfeeding training.

PMID- 12599971
TI  - Research appeal.

PMID- 12599972
TI  - Stillbirth.

PMID- 12599973
TI  - Too many 'superbugs'.

PMID- 12599975
TI  - Speak up ... if you dare: raising concerns about colleagues you suspect of bad
      practice is not easy in a working culture that views whistle-blowing as 'telling
      tales'.

PMID- 12599974
TI  - The front line: what are the implications for nurses in the UK if war with Iraq
      becomes a reality?

PMID- 12599976
TI  - Cover plans: as legislation forces a reduction in junior doctors' hours, trusts
      are preparing for nurses to take over some of their roles.

PMID- 12599977
TI  - Number one: Chlamydia is the most common sexually transmitted infection in the
      UK.

PMID- 12599978
TI  - Lifting the lid: despite a litigious culture, there are few regulations governing
      nurses' lifting and moving of patients in the United States.

PMID- 12599979
TI  - Partnership works: the complexity of anorexia demands multidisciplinary care.

PMID- 12599980
TI  - Are you ready? A National Audit Commission report suggests nurses feel ill
      prepared to deal with biochemical attacks.

PMID- 12599981
TI  - Infection control audit of hand hygiene facilities.
AB  - BACKGROUND: The socio-economic costs of healthcare associated infections (HCAIs)
      are continually rising. The focus for reducing the incidence of HCAIs should be
      on maintaining a microbiologically safe environment Hand hygiene is of paramount
      importance in preventing the transmission of infection, as it is a low-tech, low
      cost, effective intervention. Hand hygiene is as important in the non-acute care
      setting as in the acute setting, as community or non-acute patients are often
      admitted to acute facilities. CONCLUSION: This audit, conducted in 2000-2001,
      examined hand hygiene facilities at one non-acute trust. The results confirmed
      that although handwashing is considered the most important factor in preventing
      the spread of infection, it cannot always be carried out successfully if
      facilities are inadequate. Recommendations were made that will encourage safe
      practice, improve service delivery and raise clinical standards.

PMID- 12599982
TI  - An incremental approach to educational development.
AB  - This article examines the implications for education in practice of the document.
      Preparation of Mentors and Teachers (ENB/DoH 2001), and the changes that it
      imposes on those who teach in the practice area. The range of academic and
      clinical skills practitioners require to teach and assess students at differing
      levels of professional practice is explored. The authors discuss the need to
      support teaching. Learning and assessing in the practice area from the pre
      registration stage through to higher level practice. A flexible model of
      educational theory and practice that has the capacity to incorporate a clinical
      component is proposed.

PMID- 12599983
TI  - The nursing management of pain in older people.
AB  - This article examines the complex skills nurses need to manage pain in older
      people and the tools that can help quantify a subjective experience. It also
      examines the pharmacological management of pain and non-pharmacological
      approaches that can support analgesia and help reduce pain.

PMID- 12599984
TI  - 'Loss of self': a psychosocial study of the quality of life of adults with
      diabetic foot ulceration.
AB  - At present, recognition of the importance of psychosocial factors in the care of
      individuals with diabetes is still in its infancy. Understanding of the specific
      psychosocial factors relating to diabetic foot ulceration is embryonic. The study
      reported in this paper begins to raise awareness of psychosocial quality of life
      issues for patients living with diabetic foot ulceration, as narrated by the
      patients themselves. Findings revealed a range of restrictions on daily life that
      profoundly affected the individual's sense of self. These findings have
      implications for patients' adherence to treatment. Implications of these findings
      for health promotion are also reported.

PMID- 12599985
TI  - Medical pathology in patients with leg ulcers: a study carried out in a leg ulcer
      clinic in a day hospital for the elderly.
AB  - This study was undertaken to see if the multiple pathology previously found in
      elderly patients with leg ulcers (other than the ulcer) differed in older and
      younger patients. A retrospective survey of the case notes of 42 consecutive
      patients (19 males, 23 females) admitted to a medically staffed leg ulcer clinic
      based in a geriatric day hospital was carried out. Twenty one patients were aged
      < or = 74 years (including seven aged < or = 59 years) and 21 aged > or = 75
      years. Medical conditions known on referral and illnesses diagnosed during
      attendance were identified. The high incidence of disease in both age groups was
      identical, with 57% of patients with four or more diagnoses. No patient had no
      medical illness in addition to their ulcer. The commonest was cardiovascular
      disease followed by arthritis, obesity and endocrine disease. Nineteen per cent
      of all diagnoses were made at the clinic. Medical treatment, including drug
      reviews, in addition to compression bandaging and other local treatment, was
      found to be helpful for healing the ulcer. Medical input to leg ulcer clinics is
      therefore important.

PMID- 12599986
TI  - Evidence-based practice: justifying changes in clinical practice based upon the
      appraisal of evidence.
AB  - Patients with diabetes are known to be at higher risk of foot ulceration that can
      often lead to limb amputation. Anecdotal evidence suggested that the provision of
      a multidisciplinary foot clinic for patients with diabetes could improve
      outcomes. Although this approach appears common sense the author required
      evidence to support a bid for a change in practice. This paper begins by
      describing some of the origins and principles of evidence based practice and how
      they can be applied in practice. The search for evidence and critical appraisal
      of two papers is explained. The tools used to assist implementation of the change
      in practice are included. The paper concludes with recommendation for changes in
      practice based upon the evidence found.

PMID- 12599987
TI  - Measurement of interface pressure and its role in soft tissue breakdown.

PMID- 12599988
TI  - Measurement of interface pressure and its role in soft tissue breakdown.

PMID- 12599989
TI  - [Vitamin composition of wild onion species].
AB  - The data on vitamins C, B1, B2, A, E and carotenoids content in fresh-cut leaves
      of some species of genus of Allium cultivated in the Main Botanical garden
      (Moscow) are submitted. Their significance as these nutrients source is
      evaluated. Onion leaves usually used as flavor-odour additive (10-20 g) give only
      1-4 per cent of vitamin B group and E daily recommended allowance. At the same
      time this quantity supply with vitamin C (20 per cent of vitamin C daily
      recommended allowance) and carotenoids (20-50 per cent).

PMID- 12599991
TI  - [Clinical evaluation of the usage of iodine-containing food products in the diet
      of children].
AB  - On the basis of clinical supervision came to a conclusion, that the canned food
      meat of chickens with sea cabbage can be recommended for use in a dietotherapy of
      children 1.5-3.5 years with deficiency iodine by a condition.

PMID- 12599990
TI  - [Actual diet of children in orphanages].
AB  - The account of quantitative and qualitative structure of diets of children of
      children's houses has revealed infringements in organisation of mode of a meals,
      and also unbalance of diet on structure of food substances, including on iodine,
      that can promote development of iodine-dependence diseases.

PMID- 12599992
TI  - [The experience of using sterilized milk enriched with beta-carotene in the diet
      of preschool age children in Kursk].
AB  - The results of sterilized milk enriched with beta-carotene usage for nutrition of
      children under school age in Kursk town is presented. 140 weakened children at
      the age of 1.5-7 years old attending the children dispensary were tested within
      the period of 3 years. It was stated that under the influence of beta-carotene in
      the children allowance acute and chronic diseases including diseases of breathe
      organs, blood system and the level of respiratory diseases have been reduced. The
      wide usage of dairy products enriched with beta-carotene in medical-prophylactic
      nutrition of children under school age is recommended.

PMID- 12599993
TI  - [Change of natural antibody levels in patients with cardiovascular diseases by
      the use of anti-atherogenic diets with processed soy product foods].
AB  - It was investigated the influence of a diet supplemented with soy oil and soy
      protein on dynamic of clinic manifestation and immune status patients with IND
      and HBP. The results of investigations indicated that a (?).

PMID- 12599994
TI  - [The use of the combined food products with soy protein in diet therapy for
      patients with diabetes mellitus type 2].
AB  - It was investigated the influence of a diet containing 60, 30 or 45 g/day soy
      protein on clinic-metabolic parameters and nitrogen balance status in type 2
      diabetic patients. As source of soy protein was used combined products containing
      soy protein (Aarhus Olie, Denmark)--oatmeal and buckwheat porridges, biscuits,
      soy beverage and concentrate of soy protein (Danpro-S). The results of
      investigations indicated that increase in diet the quality of soy protein up 60 g
      accompanied reduce of basal levels of glycemia and triglyceridemia. In including
      in diet 30 g soy protein was noted reduce the content of total cholesterol in
      blood serum and stabilization of the hypoglycemic effect of diet. Balance study
      indicated that the protein providing in all levels of substitution of the
      traditional source of protein in products containing soy protein was adequate.

PMID- 12599995
TI  - [The influence of vegetable biologically active food additives on men's health].
AB  - The young people of draft age often have breach of a the dietary, that guite
      often is accompanied by decrease resistance and adaptation of opportunities.
      Application vegetative BAS to food (the beet with selderej) separately or
      especially together with liquid biphidiumbacterin gives good therapeutic effect.

PMID- 12599996
TI  - [Study of clinical efficiency of glycosaminoglucan-containing pharmaceutical in
      osteoarthritis].
AB  - On 58 patients with osteoarthritis the study was carried out clinical efficiency
      of application glicosaminoglicanjcontaing of a preparation at the patients
      reduction of intensity of a pain in rest, at walking and at descent on a ladder.
      The preparation was well combined with medical means of supporting therapy. By
      effects in reception of a preparation is not fixed.

PMID- 12599997
TI  - [Resistant starches and immune system].
AB  - Different absorbtion level is inherent capacities for natural, resistant and
      hydrolized starches to regulate a volume of non-hydrolyzed starches in colon.
      This regulates an interaction with intestinal microflora to produce the short
      chain fatty acids and other bio-active compounds. The T- and B-lymphocyte
      receptors are targets for starches to disrupt the number and density of plasma
      membrane receptors CD3, CD4, and CD8. All starches regulate the expression of
      adhesion molecules LFA-1 and ICAM-1, as well as receptor Mac-1. Maize starch
      increases the level of spontaneous and ceramide-dependent apoptosis in thymic and
      spleen cells of experimental animals.

PMID- 12599998
TI  - [Zinc in human nutrition: actual consumption and bioavailability requirements
      (communication 2)].
AB  - This revue discusses data concerning essential trace element zinc (Zn) dietary
      consumption levels in Russian Federation and some foreign countries. There are
      discussed biochemical criteria of Zn security in humans. It's concluded that zinc
      insufficiency is widely distributed among adult and children population in many
      districts of Russia.

PMID- 12599999
TI  - [Regional features of diet therapy organization under the conditions of health
      care reform].

PMID- 12600000
TI  - Detection of rubella-virus-induced apoptosis in Vero cell cultures with
      hematoxylin and eosin staining.
AB  - In order to facilitate the detection of apoptotic cells (Apo C) in Rubella virus
      (RV) infected cultures in settings of low resources, we compared hematoxylin and
      eosin staining (H&E) with the conventional TUNEL technique, and confirmed our
      findings with DNA electrophoresis and transmission electron microscopy. H&E
      allowed to distinguish Apo C from non-apoptotic cells. The proportion of Apo C in
      infected cultures was proportional to the multiplicity of infection (MOI). At a
      MOI of 10, the percent of Apo C at 3, 4 and 5 days post infection (pi) were 26,
      45 and 47%, respectively, which were significantly reduced when the caspase
      inhibitor z-VAD-fmk was present in the supernatant. By the TUNEL assay, the
      percent of Apo C in RV-infected cultures were lower (0.8, 1.2 and 1.2% at 3, 4
      and 5 days pi, respectively). Our results have shown that H&E staining is an
      easy, rapid, economic and reproducible method to detect Apo C in RV infected Vero
      cells cultures. It is possible that H&E makes evident early stages of apoptosis,
      when an apoptotic cell shows chromatin condensation, nuclear and cytoplasmic
      contraction (but is still attached to the monolayer), while TUNEL detects later
      stages of apoptosis because it needs an extensive DNA fragmentation, when
      apoptotic cells are about to or have already detached from the substratum.

PMID- 12600001
TI  - [Characterization of Rhizobium isolates from acid and alkaline soils in semi-arid
      regions of Pernambuco].
AB  - The genetic variety of the Rhizobium isolates from acid and alkaline soils in the
      semiarid zone of Pernambuco state was evaluated through the use of 17 primers of
      arbitrary sequence. Amplified products were separated by electrophoresis in
      agarose gel at 1.4% and visualized by ethidium bromide coloration. The results
      obtained suggest a high genetic variety of the isolates in relation to the
      standard strain. Data were analyzed by UPGMA (unweighted pair-group method with
      arithmetic average), based on Jaccard's coefficient and visualized through
      dendrograms. The strains isolated from the acid soils were included in one group
      whereas the strains from alkaline soils were located in other three groups.
      Meanwhile, one of the groups formed by strain Isol-14, isolated from acid soils
      is more related to the groups of strains isolated from acid soils than to the
      remaining groups from alkaline soils.

PMID- 12600002
TI  - Fluorescent Pseudomonas species causing post-harvest decay of endives in
      Argentina.
AB  - A post-harvest bacterial decay was observed on ready-to-use French endives in
      Argentina. Affected chicons showed browning and soft-rot of inner leaves and
      marginal necrosis. Physiological and biochemical tests allowed us to identify the
      isolates from endive as Pseudomonas fluorescens bv. III, Pseudomonas fluorescens
      bv. V, and Pseudomonas cichorii. Pathogenicity was verified on RTU healthy
      endives by inoculation with each bacterial species, and also with the mixture of
      the 3 strains. P. cichorii caused dark brown necrosis of the margins of outer
      leaves; both isolates of P. fluorescens caused browning and soft-rotting of inner
      leaves, while the mixture induced all the described symptoms, that were similar
      to those found in natural infection. Identity of bacterial isolates was confirmed
      by RFLP analysis of a PCR-DNA fragment amplified from the 16S rRNA gene. This is
      the first record of a post-harvest decay in endives in Argentina.

PMID- 12600003
TI  - [Campylobacter jejuni and C. coli in aborted swine: comparison between phenotypic
      identification and polyacrylamide gel protein profiles].
AB  - Campylobacter jejuni and Campylobacter coli were isolated from aborted pig
      fetuses which proceeded from different animals and farms between February 2000
      and March 2001. Seven Campylobacter jejuni biotype II, three biotype I and one
      Campylobacter coli biotype I were identified by phenotypic tests and Lior's
      scheme. To corroborate and compare the phenotypic results, 7.5, 10 and 12.5%
      polyacrilamide gel electrophoresis (SDS-PAGE) were used under reducing
      conditions. Characteristic bands of hypervariable dense zone within C. jejuni and
      C. coli species were observed in all the whole cell protein extracts with
      differences in mobility. It was possible to establish differences between
      identical phenotypic Campylobacter isolates and different protein profile from
      fetuses of the same litter. SDS-PAGE is a stable and reproducible method to
      establish differences between Campylobacter strains and is considered applicable
      for the differentiation of the wide variability of Campylobacter species for
      epidemiologic purposes.

PMID- 12600004
TI  - [Development and application of a method for isolating Escherichia coli O157:H7
      in the city of Gualeguaychu].
AB  - Culture media, reagents, and commercial kits were compared on artificially
      contaminated food samples. The objective was to find an isolation method for
      Escherichia coli O157:H7 sensitive, specific and accessible in terms of cost,
      requirements of equipments and qualification of the analyst. The adopted scheme
      consisted in a selective enrichment at 42 degrees C during 18 to 24 h, using an
      appropriate medium, in accordance with the nature of the sample, followed by a
      step of immunomagnetic separation and simultaneous isolation on a chromogenic
      agar and MacConkey sorbitol agar with potassium tellurite and cefixime, during 18
      24 h at 37 degrees C. The presumptive colonies were confirmed as E. coli O157 by
      serological and biochemical tests. Secondly, this methodology was applied to food
      samples, water, bovine gastric content and manure. A total of 410 samples were
      studied: 279 from meat, 54 milk and dairy products, 6 from vegetables, 27 water
      samples and 44 bovine gastric content and manure. The frequency of isolation of
      E. coli O157:H7 was of 3.9%. The phenotypic and genotypic characterization of the
      isolates was performed. A simple isolation methodology for E. coli O157 was
      developed, which proved accessible to food laboratories of lower complexity. This
      methodology allowed the detection of this pathogen in food and environmental
      samples in Gualeguaychu City. The role of water as vehicle of infection was also
      established. The strains harbored the same virulence factors as those recovered
      from human disease.

PMID- 12600005
TI  - [Distribution of Cryptococcus neoformans serotypes associated with human
      infections in Argentina].
AB  - C. neoformans (Cn) causes severe meningitis in immunocompromised patients,
      particularly those with AIDS. Little is known about Cn serotypes associated with
      human infections in Argentina due to the lack of antisera availability. The aim
      of this study was to produce these antisera, to serotype the Argentinean clinical
      isolates of Cn received at our laboratory from 1984 to 2001 and to evaluate the
      agreement of these results with the variety differentiation obtained with
      Canavanine-Glycine-Bromothymol Blue agar (CGB) medium. We studied 123 isolates
      recovered from first episodes of cryptococcosis from HIV-infected patients (85),
      non HIV-infected patients (6) and from other non specified patients (32). Of the
      isolates, 89% (110/123) were serotype A, 4% (5/123) corresponded to serotype D,
      3% (3/129) were serotype AD, 3 isolates were untypable and 2 corresponded to
      serotype B. All the serotyped isolates agreed with the variety determined by CGB
      medium. These results indicate that, in our country, most cryptococcal infections
      in patients with AIDS are associated with serotype A (77/85), which agrees with
      international studies. In patients with other immunosuppressions, this serotype
      may be also predominant, although a low number of isolates were tested (4/6).
      Recovery of Cn serotype B in these clinical isolates suggests that studying the
      variety and their serotypes might be important to detect a probable
      epidemiological alteration.

PMID- 12600006
TI  - [Isolation and identification of Listeria monocytogenes and Listeria spp. in dry
      sausages obtained in markets in the city of La Plata, Argentina].
AB  - A total of 60 samples of dry sausages were analyzed (50 of "salami" and 10 of
      "chorizo" "candelario" type) obtained at random in markets authorized for their
      commercialization, for the purpose of evidencing the presence of bacteria of the
      genus Listeria (Listeria monocytogenes and Listeria spp.). The results obtained
      in salami were the following: 10 (20%) isolates of Listeria spp., were
      characterized: 1 (2%) strain as L. monocytogenes type 1, 7 (14%) strains as L.
      innocua, 2 (4%) strains as L. welshimeri. In chorizo candelario type 6 (60%)
      isolates of Listeria spp., were characterized: 2 (33%) strains as L.
      monocytogenes type 1 and 4 (66%) strains as L. innocua. The total percentages of
      isolations were: 26.6% of Listeria spp., 5% of L. monocytogenes type 1, 18.3% of
      L. innocua and 3.3% of L. welshimeri. In conclusion, we consider that
      methodologies of control must be developed and implemented in order to guarantee
      the inocuity of these products.

PMID- 12600007
TI  - [Detection of vancomycin-resistant Enterococcus faecium: 2 years' experience in a
      high complexity hospital ].
AB  - The presence of vancomycin-resistant enterococci (VRE) in our hospital prompted
      us to apply an appropriate method for assessing its rectal carriage. A screening
      method with bile-esculin azide agar plus different concentrations of vancomycin
      was used. The antimicrobial susceptibility study of enterococci isolated from
      clinical samples was also emphasized. The present study includes the surveillance
      and detection of VRE in our hospital during two years. A total of 260 samples
      corresponding to 138 patients were studied, 158 of them resulting positive. All
      EVR were Van A Enterococcus faecium, with MICs of vancomycin > or = 256
      micrograms/ml. The analysis of susceptibility patterns shows variations with
      chloramphenicol, tetracycline and high level gentamicin concentrations. This
      method was easily applied because materials could be available in any clinical
      microbiology laboratory, and in our hands it has demonstrated to be useful for
      epidemiological surveillance for EVR.

PMID- 12600008
TI  - [Group B streptococcal infections in adults, excluding genital infections].
AB  - Group B streptococcus (GBS) or Streptococcus agalactiae is recognized as a mayor
      cause of neonatal meningitis, sepsis and infections during pregnancy. However, in
      recent years there have been several reports concerning GBS infections in non
      pregnant adult population, specially in immunocompromised hosts and in patients
      with severe underlying diseases such as diabetes mellitus and cancer. We report a
      series of 45 cases which occurred in nonpregnant adult population during a period
      of two years. The average age was 50.8 years and most patients (38/44) had one or
      more risk factors: diabetes mellitus was the most significant underlying disease.
      The most frequent infection localization was skin and soft tissues followed by
      urinary tract infection. Several isolated cases of pneumonia, bacteremia,
      endocarditis, endometritis and peritonitis were observed. GBS infections should
      no longer be exclusively considered as perinatal and peripartum events. New
      clinical presentations are arising in non pregnant adult population with special
      incidence in immunocompromised hosts. We are obliged to keep this in mind and
      remember that SGB may be a possible etiologic agent for infections, particularly
      in skin and soft tissues of diabetic patients.

PMID- 12600009
TI  - [Activity of 14 antimicrobials against Eikenella corrodens].
AB  - Eikenella corrodens is a gram-negative bacillus that colonizes as normal flora of
      the mouth, the upper respiratory tract and the gastrointestinal tract. The aim of
      this study was to determine the susceptibility patterns against fourteen
      antibiotics of 25 E. corrodens strains isolated at our hospital. MICs were
      determined by the agar dilution technique using Mueller-Hinton agar with sheep
      blood (5% v/v) to penicillin, ampicillin, ampicillin-sulbactam, cephalotin,
      cefoxitin, ceftiaxone, colistin, gentamicin, amikacin, erythromycin, rifampin,
      ciprofloxacin and clindamycin. The most active antibiotics were ciprofloxacin and
      ceftriaxone (MIC90 = 0.008 and 0.125 microgram/ml, respectively), whereas
      eritromycin, gentamicin and amikacin showed less activity. Only one strain was
      beta lactamase positive, and it was inhibited by sulbactam. Erithromycin,
      gentamicin and amikacin had poor activity (MIC90 = 16.8 and 64 micrograms/ml,
      respectively), whereas all the strains were uniformly resistant to clindamycin
      (MIC > or = 32 micrograms/ml). We suggest about the need of periodical surveys of
      E. corrodens susceptibility patterns, since strains have been found with
      decreased susceptibility against antibiotics which are currently being used for
      the treatment of infectious diseases.

PMID- 12600010
TI  - [Guidance for rethinking. The lost art of healing].

PMID- 12600011
TI  - [Why health care is loosing its vitality. The gradual change of healthy probands
      into patients].

PMID- 12600012
TI  - [Pathogen spectrum in chronic viral hepatitis--HBV, HCV and new candidates].

PMID- 12600013
TI  - [3M Red Dot electrodes with repositioning potential. One for everything!].

PMID- 12600014
TI  - [Clean and uncomplicated: new VACUETTE--urine container for urine collection].

PMID- 12600015
TI  - [A new drug which saves lives. Sepsis: chaos in the body--recent aspects of
      pathophysiology and therapy].

PMID- 12600016
TI  - [PROWESS--milestone in lowering sepsis mortality].

PMID- 12600018
TI  - [The "old benign holiday"?].

PMID- 12600017
TI  - [Sepsis diagnosis: hemostatic imbalance and role of activated protein C].

PMID- 12600019
TI  - ["Arouse yourself, become light!"].

PMID- 12600020
TI  - [Effects of beech dust extract on lipid peroxidation and expression of ref-1 gene
      of mouse lung tissue].
AB  - In order to explore the effects of beech dust on lipid peroxidation and
      expression of redox-related gene ref-1, the 2-stage model of mouse lung tumor
      short-term induction test is used. The mice exposed to the extract beech dust are
      divided into 3 groups(group of normal lung tissue, group of papillary adenoma and
      group of lung adenoma) with the mice treated with solvents as control. The extent
      of homogenate lipid peroxides is determined by measuring the formation of TBARS,
      and expression of ref-1 measured by immunohistochemistry. The results show that
      1. The formation of TBARS of all groups treated with the beech extracts of beech
      dust is increased compared with the control, and the differences between the
      groups with adenoma and the control are statistically significant (P < 0.01),
      while the P value of that of the group of normal lung tissue is less than 0.05.
      2. Both the control and the group of normal lung tissue treated with the extracts
      are Ref-1-negative, strong nuclear Ref-1 immunostaining is found in the group of
      papillary adenoma, and the cytoplasmic/nuclear expression of Ref-1 is
      significantly enhanced in the group of lung adenoma and group of mixed adenoma.
      It is suggested that the extracts of beech dust toxicity is probably related to
      its altering redox regulation of ref-1 and subsequent disturbance of redox
      status.

PMID- 12600021
TI  - [Dynamics of contents of chemical elements in fetal liver, and its physiological
      and nutritional significance].
AB  - The dynamics of contents of chemical elements in fetal liver, and its
      physiological and nutritional significance are studied. Twenty-one chemical
      elements in livers of fetus from induced abortion aged four to ten months are
      measured and are compared with those in adult. The relativity between the monthly
      average contents of twenty-one elements and fetus month age are analyzed and
      assorted. The results show that the contents of chemical elements of fetus liver
      are not well distributed and are not stable during the stage of fetus growth, and
      even change following the fetus's age. The changing patterns of contents of
      chemical elements of fetus liver can be divided into three types: a marked
      positive relativity of some chemical element contents with the increase in fetus
      age, marked negative relativity with the increase of fetus age, and indefinite
      relativity with the increase of fetus age. In the time period of embryo
      development to fetus to newborn infant, the content of some elements that has
      marked positive relativity with the increase of fetus age varies from low to
      high, indicating an increase of their contents in liver of fetus while supplying
      the need of fetus growth. The content of elements that have marked negative
      relativity with the increase of fetus age varies also from low to high and
      rapidly decreases in per unit tissue, resulting in an increase of the sensitivity
      to deficiency of these elements. The contents of elements that have indistinctive
      relativity with the increase of fetus age may not bring about any impact to fetus
      and newborn infant from the view of physiology and nutrition.

PMID- 12600022
TI  - [Toxicity effects of manganese on PC12 cells].
AB  - In order to study the mechanisms of inhibitory effects of manganese on neurocyte.
      PC12 cells were incubated in culture media with 100, 200 and 500 mmol/L
      manganese(MnCl2) for 24, 48 and 72 h respectively. MTT test, Trypan blue
      exclusion test, malondiadehyde(MDA) colorimetry and DNA gel electrophoresis were
      performed to exam proliferation, lipid peroxidation, and apoptosis of PC12 cells.
      The results of MTT test reveled that manganese (100-500 mmol/L) could inhibit the
      proliferation of PC12 cells. DNA gel electrophoresis showed that the apoptosis of
      the PC12 cells could be induced by manganese (100 mmol/L). It is concluded that
      manganese can inhibit proliferation of PC12 cells, the mechanism includes the
      interference of DNA metabolism, inhibitory of lipid peroxidation, and cell
      apoptosis.

PMID- 12600023
TI  - [Effects of lead on NO, NOS, SOD, MDA in rat cerebral cortex].
AB  - To study the effects of lead exposure on nitric oxide (NO), nitric oxide synthase
      (NOS), super oxide dismutase (SOD) and malondialdehyde (MDA) in cerebral cortex
      of rats, Wistar rats are exposed to lead from drinking 0, 18.4, 184 mg/L lead
      acetate solution respectively. RESULTS: Cerebral cortex NOS activity in low and
      high-dosed lead exposure groups are significantly increased at the time of 7 days
      (P < 0.05), cerebral cortex NOS activity in low-dosed group is significantly
      decreased after 90 days and 30 days in high-dosed group (P < 0.05) as compared
      with that of the controls. Cerebral cortex NO content is markedly decreased in
      low-dosed group after 90 days poisoning and 14 days, 60 days, 90 days in high
      dosed group (P < 0.05). SOD activity in low and high-dosed group is significantly
      decreased after 30 days exposure. MDA content is markedly increased after 14 days
      exposure in high-dosed group. CONCLUSION: It is suggested that the damage of
      cerebral cortex may caused by lead toxicity that results from the changes of NOS
      activity, NO level, SOD activity and MDA content in cerebral cortex.

PMID- 12600024
TI  - [Protective effect of extra metallothioneins from rabbit liver induced by zinc on
      toxicity of lead in rat primary hepatocyte culture].
AB  - Metallothionein (MT), a low-molecular-weight, cysteine-rich, zinc-binding
      protein, has an important effect in the detoxification of various metals.
      However, extra Zn7-MT protects aginst the cellular toxicity of lead in rat
      primary hepatocyte (RPHC) culture has seldom been examined thoroughly. This study
      was therefore designed to determine the effects of extra Zn7-MT on the toxicity
      of lead in rat primary hepatocyte culture. Hepatocytes were grown in monolayer
      culture for 24 h and Zn7-MT was subsequently added for 24 h. RPHC were exposed to
      different concentration of lead for 24 h. Cytotoxicity was assessed by enzyme
      leakage and loss of intracellular K+. Meanwhile, the subcellular distribution and
      accumulation of lead was studied, and the protactive effect on the cellular
      toxicity of lead in RPHC culture in the present of Zn7-MT was investigated. The
      results showed that the toxicity of lead was significantly less in the presence
      of Zn7-MT. The hepatocelluar uptake and accumulation of lead have markedly
      altered. In the cytosol of control cells, the lead was bound mainly to high
      molecular-weight proteins whereas the lead was mainly associated with MT in the
      presence of extra Zn7-MT.

PMID- 12600025
TI  - [Combined effect of lead and cadmium on lipid peroxidation in renal tubular
      epithelial cells of rats].
AB  - In order to observe the combined effects of lead and cadmium on lipid
      peroxidation, the cultured renal tubular epithelial cells (TEC) of rats are used
      to perform 3 x 3 factorial experimental design. In the experimental group (A-H),
      rats are given lead and cadmium respectively for 6 hours at different
      concentrations (A: lead acetate 0.02 mmol/L; B: lead acetate 0.1 mmol/L; C:
      cadmium chloride 0.001 mmol/L; D: cadmium chloride 0.004 mmol/L; E: lead acetate
      0.02 mmol/L + cadmium chloride 0.001 mmol/L; F: lead acetate 0.02 mmol/L +
      cadmium chloride 0.004 mmol/L; G: lead acetate 0.1 mmol/L + cadmium chloride
      0.001 mmol/L; H: lead acetate 0.1 mmol/L + cadmium chloride 0.004 mmol/L). After
      TEC are smashed by supersonic, the concentrations of glutathione (GSH) and
      malondiadehyde (MDA) in cells are analyzed. The same analysis is also done for
      the determination of the activity of glutathione peroxidase(GSH-Px) and
      superoxide dismutase(SOD). In comparison with control group, significant decrease
      in activities of GSH, GSH-Px, SOD in cells treated with lead and cadmium and
      increases of MDA are observed. The data from ANOVA analysis show that the
      interaction between lead and cadmium on GSH, MDA, and SOD in TEC (P < 0.05) is
      demonstrated while no interaction on GSH-Px is shown.

PMID- 12600026
TI  - [Application of microwave dissolution and inductively coupled plasma-MS
      spectrometry for determination of ultra-trace level of lanthanides in human rib].
AB  - A new method for the determination of ultra-trace level of lanthanides such as
      La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm Yb and Lu in human rib is
      explored. Closed-vessel microwave digestion with concentrated HNO3 is used for
      the sample preparation and the digested analyte is directly analyzed by ICP-MS.
      The method is sensitive and accurate and, is efficient for the determination of
      the fourteen lanthanides listed above. Detection limit for various elements
      ranges from 0.0007 microgram/L to 0.005 microgram/L. Calibration plots exhibit
      good linearity with high linear correlation coefficient r > or = 0.997.
      Recoveries of spiked samples ranges from 93.7% to 115.4%. Precision is < 3% RSD.
      Rhodium is used as the internal standard to compensate the signal suppression
      caused by the sample matrix. Isobaric overlap of polyatomic ions caused by matrix
      oxide/hydroxide of barium is corrected by interference correction factor. Two
      standard reference materials, namely "Human Hair GBW07601" and "Wheat Flour
      GBW08503" are used for quality control of the analyzed samples.

PMID- 12600027
TI  - [Study on the effects of cooking oil fume condensate on the DNA integrity].
AB  - The aim of this study was to study the DNA damage mechanisms of cooking oil fumes
      (COF) in vitro. The colorimetric MTT reduction assay was adopted to measure the
      effects of the cytotoxicity of COF condensate on type II pneumocytes from the
      lungs in the rats. The condensate of COF was of the dose-responsive effect on
      cell-inhibit rate to some extent (r = 0.943, P < 0.01). There is distinctive
      cytotoxicity on type II pneumocytes when concentration is higher than 20
      micrograms/ml. The genotoxicities of COF condensate to type II pnemocytes were
      studied by modified alkaline single-cell gel using a electrophoresis(SCGE)
      assay(comet assay), the maximum concentration of condensate is below the
      concentration of cytotoxicity. The results showed that the condensate of COF was
      of the dose-responsive effect on the type II pneumocytes DNA damage to some
      extent(r = 0.918, P < 0.05) at the dosage of 0-5 micrograms/ml. The DNA damage
      reach to the maximum at the dosage of 10 micrograms/ml. The damaged DNA could be
      restored after been cultured for 2 hours. Calf thymus DNA cross-link after the
      administration of COF condensate were measured with ethidium bromide assay. It
      was found that condensate of COF was of the dose-responsive effect on the calf
      thymus DNA cross-links to some extent(r = 0.963, P < 0.01). The above results
      suggested that cooking oil fume condensate could induce DNA damage at much lower
      dosage and result in the increase of DNA cross-links in a certain concentration.

PMID- 12600028
TI  - [Variation of gene at the apolipoprotein C III locus with the changes of serum
      lipid profile in school-aged children].
AB  - The variation of gene at the apolipoprotein C III locus with the changes of serum
      lipids in children was studied. Blood samples were collected from 308 normal
      children aged 7-11 year-old, including of 151 boys and 157 girls. The levels of
      serum lipids profile, including TC, TG, LDL-C, HDL-C, apoB, apoA I and Lp(a) were
      detected. The genome DNA was extracted from blood clot, then ApoB-Xba I gene
      polymorphism were tested by the PCR-RFLP method. The frequency of ApoC III-Sac I
      heterozygote(+/-) was 48.7%, homozygote (+/+) was 7.5%, and allele (+) was 31.8%
      of the 308 children. The frequency of allele(+) was more than the reports in
      Shanghai (12%) and Guassian (6%), and closed to the Japanese (34%). The results
      showed a population and ethnic difference in the inheritance variation. Comparing
      the serum lipids levels among different genotypes, the average TG levels of
      homozygotes(+/+) were more than wildtype (-/+)(1.06 mmol/L vs 0.85 mmol/L, P <
      0.05). The frequency of(+/+) genotype in hypertriglyceridemia group was more than
      control group (30.0% vs 6.7%, P < 0.05); The allele(+) could increase the TG
      level of 0.031 mmol/L. It suggested that the variation of Apolipoprotein C III
      Sac I locus was correlated with the TG level in children.

PMID- 12600029
TI  - [Protective effect of magnesium on the damaged cultured endothelial cells induced
      by oxidized low density lipoprotein].
AB  - The protective effect of magnesium on endothelial cells induced by H2O2 and t
      butyl hydroperoxide and the subsequent alterations of extracellular superoxide
      dismutase (EC-SOD) and cellular selenium-dependent and non-selenium-dependent GSH
      Px are investigated in this study. Low density lipoproteins (LDLs) are isolated
      from poeled healthy human fresh sera by ultracentrifugation. Conjugate diene was
      measured for assessing the susceptibility of LDL to oxidation mediated by Cu2+.
      The extent of LDL modification is determined by measuring the formation of
      thiobarbituric acid reaction substances (TBARS). In addition, human umbilical
      vein endothelial cells are used to assess the effect of magnesium on damage
      induced by oxidized LDL (ox-LDL). The extent of cellular lipid peroxides is
      determined by measuring the formation of TBARS. Results show that (1) the
      presence of Mg2+ resulted in a protracted lag phase at doses of 0.3, 0.6, 1.2 and
      2.4 mmol/L, as well as the presence of Mg2+ at doses of 0.3 and 0.6 mmol/L
      decreases the production of TBARS when LDL is oxidized by the addition of Cu2+;
      (2) the formation of TBARS is significantly reduced in the group of ox-LDL + Mg2+
      at doses of 0.3, 0.6, 1.2 and 2.4 mmol/L. The activity of EC-SOD, GSH-Px with and
      without selenium in the group of ox-LDL + Mg2+ at all doses increases
      significantly compared with ox-LDL group. It is concluded that magnesium inhibits
      LDL oxidation mediated by Cu2+ and protected endothelial cells from lipid
      peroxidation and reinforces the activities of antioxidant enzymes.

PMID- 12600030
TI  - [Study on the anti-carcinogenic effects of three compounds in Kaempferia galanga
      L].
AB  - In order to study the anti-carcinogeneic effect of three compounds isolated from
      Kaempferia galanga L, EBV assay, ear edema test, ornithine decarboxylase (ODC)
      activity and two-stage-carcinogenisis test are applied. The results show that
      both -cis and -trans ethyl-p-methoxycinnamate has inhibitory effect in vitro, and
      also has inhibitory effects in TPA tests or croton oil-induced ear edema, ODC
      activity in specimen of mouse epidermis and extent of papilloma, indicating a
      relatively strong anti-carcinogenic potential of ethyl-p-methoxycinnamate in
      Kaempferia galanga L.

PMID- 12600031
TI  - [Effects of silkworm pupa oil on serum lipids level and platelet function in
      rats].
AB  - To observe the effects of silkworm pupa oil on serum lipids level and platelet
      function in rats, according to serum TG, TC level, 40 male Wistar rats are
      divided into four groups (normal control group, high fat control group, silkworm
      pupa oil group and silkworm pupa oil + VE group). The rats are fed different
      diets and six weeks later, serum lipids level and platelet function are measured.
      The results show that (1) Compared with high fat control group, serum TC, TG, LDL
      C level, AI value, Platelet aggregability, plasma TXB2 level and T/P ratio
      decrease significantly while HDL-C level and 6-k-PGF1 level increase in silkworm
      pupa oil group; (2) Serum TC, LDL-C level, T/P ratio and platelet aggregability
      are significantly lower in silkworm pupa oil + VE group than in silkworm pupa oil
      group. It is suggested that silkworm pupa oil rich in alpha-linolenic acid can
      reduce serum lipids level and inhibit platelet aggregation, which is more
      effective with the supplementation with VE.

PMID- 12600032
TI  - [Studies on the stabilities of bioactive selenocompounds in selenium-enriched
      garlic and onion].
AB  - It is reported that selenium (Se) incorporation into garlic increases the
      bioactivities of garlic. Hence, the chemical changes of selenocompounds during
      processing and storage will influence the bioactive effectiveness of Se-enriched
      garlic. The principal selenocompounds in Se-enriched garlic are water-soluble,
      and several comparative experiments are thus conducted to examine the stabilities
      of the selenocompounds in water extracts of Se-enriched garlic and Se-enriched
      onion. The results show that preparing the garlic powder by freeze-drying
      technique can maintain the chemical properties of the selenium compounds in Se
      enriched garlic. Se-methyl-selenocysteine is unstable in water extract of Se
      enriched garlic when the extract is prepared and stored at room temperature.
      Specific alliinase inhibitor hydroxylamine (NHOH.HCl) effectively prevents the
      loss of Se-methyl-selenocysteine, which suggests that the decomposition of Se
      methyl-selenocysteine may be catalyzed by alliinase. Se-methyl-selenocysteine is
      one of the main bioactive selenocompounds in Se-enriched garlic. The procedures
      of processing and storage should be carefully chosen to prevent the loss of
      selenocompounds and the decrease of the bioactivity of Se-enriched garlic. Se
      enriched onion also contains alliinase and Se-methyl-selenocysteine, but its Se
      methyl-selenocysteine is proved to be stable in the same water extract as that of
      Se-enriched garlic. The stability differences of Se-methyl-selenocysteine in Se
      enriched garlic and onion, the mechanism of selenocompound decomposition and the
      bio-activities of decomposed compounds in Se-enriched garlic need to be further
      studied.

PMID- 12600033
TI  - [Antisense TIF3 reverses the oncogenic potential of CdCl2-transformed BALB/c-3T3
      cells].
AB  - TIF3 (GenBank Accession Number AF 271072) is identified as a novel cadmium-
      responsive proto-oncogene. In order to determine whether the antisense TIF3
      reverses the oncogenic potential of Cd-transformed BALB/c-3T3 cells or not, a
      stable expression system of CdCl2-transformed BALB/c-3T3 cells with the
      expression vector containing TIF3 cDNA in the antisense orientation using calcium
      phosphate and G418 selection protocols is firstly established. Then, the reversal
      of the oncogenic potential of these cells is tested by soft agar and nude mouse
      tumorigenicity assay. The results demonstrated that expression of the antisense
      TIF3 in the CdCl2-transformed BALB/c-3T3 cells results in reversal of the
      transformed phenotype of the cells. This is evidenced by a 25%-70% decrease in
      the number of anchorage-independent colonies growing on soft agar and the
      significant reduced tumorigenic potential of cells in nude mice compared with the
      corresponding controls. In addition to a significant delay in the onset of
      appearance of tumors, a significant reduction in size and a 50.8%-55.1% decrease
      in weight of the tumors are also observed in the mice injected with the TIF3
      antisense expressing cells compared with the corresponding controls. The results
      indicate that antisense TIF3 mRNA expression reverses its oncogenic potential of
      Cd-transformed BALB/c-3T3 cells and may have therapeutic potential to cancer
      induced by cadmium.

PMID- 12600034
TI  - [Influence of calcium content among different calcium agents on absorbing and
      bone density of rats].
AB  - To identify the influence of different calcium contents among different calcium
      agents on absorbing and born density of rats, wistar rats are fed with diet
      containing different contents of calcium of different calcium agents. 3-day
      calcium metabolization experiment is carried out in the fourth week and atomic
      absorption spectrophotometry is applied to measure the calcium content of their
      dejecta and to estimate apparent absorptivity. Rats are killed in the twelfth
      week, and their thighbones are peeled. the results show that there is significant
      difference of the apparent absorptivity with different calcium intake. With the
      same content of calcium from nine kinds of calcium agents, the absorptivity is
      not significant different with an exception of those of active calcium, milk
      powder and oatmeal. Born density from the group of rats, which fed with diet with
      low level, middle level or high level of calcium, is obviously higher than that
      of rats fed with basic diet (P < 0.05). Born density of thighbone of the group of
      rats, which fed with diet with middle or high level of calcium content is not
      significantly different compared with that of rats fed with diet with calcium
      carbonate. The absorptivity of calcium is related with calcium content in diet.
      The effect of absorptivity of calcium agents tested is affirmative, but there is
      no difference of their effect in comparison with the calcium carbonate.

PMID- 12600035
TI  - [Coxsackievirus B3 infection and Keshan disease].
AB  - To study the relationship between the infection of enteroviruses and the etiology
      of keshan disease, we examined the 30 blood samples from the latent-chronic KD
      patients from Mianning, Xider, Derchang county of Sichuan Province with LDE-PCR
      (long distance enterovirus-specific RT PCR), two sensitive and specific ELISAs
      (one for CVB1-6 IgM and the other for CVB1-6 IgG), and three-primer RT PCR
      specific for CVB3. Results show that: 1) The infection rate of enteroviruses in
      the samples from the latent-chronic KD patients is higher than from the control
      group (80% VS 0%, P < 0.01); 2) The CVB1-6 antibody positive rate in latent
      chronic KD is higher than that of the control group (IgM, 33% VS 0%, P < 0.01;
      IgG, 23% VS 0%, P < 0.01); 3) 16.6% (4/24) of enteroviruses positive samples or
      40% (4/10) of CVB1-6 IgM antibody positive samples can be identified as CVB3. So,
      the infection of enter viruses maybe involves in the cause and development of
      latent-chronic keshan disease, and at least we conclude that the mutation of CVB3
      is not the only cause of KD.

PMID- 12600036
TI  - [Study of anti-atherosclerosic effect of grape seed extract and its mechanism].
AB  - In order to observe the anti-atherosclerosic effect of the grape seed extract and
      its mechanism, the 50C57/6J mice are divided randomly into 5 group (normal
      control group, hyperlipidemia model group, low and high grape seed extract
      groups(0.2 mg/gBW, 0.6 mg/gBW), and drug control group(0.2 mg/gBW). After twenty
      one weeks, plasma oxidized low density lipoprotein (OX-LDL), serum nitric oxide
      (NO) and intercellular adhesion molecule-1 (ICAM-1) are measured and the form of
      aortic valves are observed pathologically. The results show that the levels of
      plasma OX-LDL, and ICAM-1 are significantly lower in grape seed extract group
      than those in model group while the levels of NO are higher in grape seed extract
      group than that in model group (P < 0.01). The thickness of aortic valves
      consisting of foam cell and endothelium hyperplasia in grape seed extract group
      is lighter than that of model group. The results indicate that the grape seed
      extract has inhibitary effect on atherosclerosis in C57BL/6J mice, and the
      possible mechanism may be related to inhibition of the increase of OX-LDL, and
      ICAM-1, reduction of the damage of vascular endothelium and protection of the
      function of vascular endothelium.

PMID- 12600037
TI  - [Effects of air pollution from coal-burning on respiratory diseases and symptoms
      in children].
AB  - To study effects of air pollution from coal-burning on children's health of 6-13
      years old, A cross sectional epidemiological study was carried out in three
      places in Taiyuan city with different degrees air pollution by questionnaire and
      testing children's nasal cavity and oral cavity. The result showed that the
      incidence of rhinitis, faucitis and tonsillitis increased significantly with the
      extent of air pollution. The risk of the prevalence of respiratory symptoms and
      diseases were also increased among those children living in the area with heavy
      ambient air pollution.

PMID- 12600039
TI  - [Breakfast practice of students in four cities in China].
AB  - In order to investigate the breakfast practice of Chinese students in four
      cities, and to provide scientific basis for developing School Breakfast Program,
      self-administrated questionnaire is administrated among 7,617 elementary and
      junior students in Guangzhou, Shanghai, Jinan and Haerbin. The results showed
      that 18.9% junior students and 16.6% elementary students did not have breakfast
      everyday and, the nutrition of their breakfasts is inadequate. It is suggested
      that further recognition should be given to the improvement of the breakfast of
      the students.

PMID- 12600038
TI  - [Correlation of arsenic accumulative intake and its health effects to the
      residents in arsenic polluted area. Estimation of arsenic accumulative intake
      level of residents living in arsenic polluted area].
AB  - In order to evaluate arsenic accumulative intake level of residents living in an
      area with arsenic pollution in the air, the level of arsenic accumulative intake
      is measured by calculating residents' accumulative rice consumption and the
      measurement of the level via inhalation. The results show that ignoring the non
      polluted time periods, the highest arsenic accumulative intake level (AAIL)
      appears in residents aged 50 and above who have the highest level of air
      inhalation and rice consumption in comparison with young residents after 32 years
      exposure, and their AAIL detected via inhalation are 591.4 mg for female and
      612.9 for male respectively. There is 3488.74 mg arsenic obtained by their daily
      diet. Total AAIL are 4080.14 mg for female and 4101.66 mg for male respectively,
      being about 80% of estimation level reflected by daily exposure level multiplied
      by total exposure time (day).

PMID- 12600040
TI  - [Effects of dietary intervention on hyperlipidemia in eight communities in
      Beijing].
AB  - Based on the data available from hyperlipidemia screening, 180 participants were
      recruited and divided into intervention group and control group. Dietary
      intervention lasted six months and dietary survey, anthropometry and serum lipid
      determination were performed and analyzed respectively before and after the
      intervention. The results showed the decreases of total calories, fat,
      cholesterol and oil by 13.20%, 24.75%, 24.40% and 22.43% respectively in
      participants of intervention group. The percentages of total calories provided by
      fat, carbohydrate and protein trended to be desirable and the reductions were
      also observed in body weight and BMI. There were 5.61% and 7.06% reductions in
      total serum cholesterol and low-density lipoprotein cholesterol in intervention
      group, while no significant reduction in the control group. These results
      indicated that the community-based dietary intervention could effectively improve
      dietary pattern, control body weight, decrease the level of total serum
      cholesterol and low-density lipoprotein cholesterol.

PMID- 12600041
TI  - [Evaluation of effects of health education on prevention of cardio-cerebro
      vascular diseases in community population].
AB  - A comprehensive community-based intervention with health education as the major
      measure for preventing cardio-cerebro-vascular diseases in selected urban
      residents in Beijing, Shanghai and Changsha cities during the periods of the
      ninth "five-year" plan (1996-2000) was conducted, and its effects on knowledge,
      attitude and behavior (KAB) changes were evaluated by quasi-trial designation.
      Results show that the net KAB level increases by 6.01 scores in three cities and
      by 6.12 scores in patients suffering from hypertension after intervention, and
      these changes in scores are statistically significant. The net percentage of
      hypertension patients who took blood pressure measurement regularly within every
      3 months and the net percentage of them who took anti-hypertension drugs
      regularly for therapy increased by 9.65% and 7.33% respectively after the
      intervention and the former increased was statistically significant. It is
      concluded that health education may promote the improvement of knowledge,
      attitude and behavior changes of participants and is of great importance for
      preventing cardio-cerebro-vascular diseases in communities.

PMID- 12600042
TI  - [Iodine nutritional status of pregnant, lactating women and children in Linxia
      Region of Gansu Province].
AB  - With a staged random cluster sampling method, 55 pregnant women, 75 lactating
      women, 83 3-5 year-old children and 68 neonates were selected from Linxia Region
      of Gansu Province. The median value of urinary iodine was in pregnant women,
      lactating women, 3-5 year-old children, and infants was 295.0, 232.0, 192.5 and
      374.5 micrograms/L respectively, and the percentage of urinary iodine below 100
      micrograms/L was 6.1%, 16.1%, 21.7% and 6.8% respectively. The thyroid volume at
      the 97th percentile for pregnant and lactating women was 24.81 and 24.26 ml. The
      concentration of serum T3 for pregnant women, lactating women and 3-5-year-old
      children, were 87.3%, 78.7%, 80.0%, T4 were 63.7%, 98.7% and 83.1%, and TSH were
      77.3%, 81.2%, 65.9% of normal value respectively. TSH of umbilical blood higher
      than 5 mIU/L was 18.8%. The iodine nutrition status of the population in Linxia
      Region was improved greatly, but iodine deficiency has not been eliminated
      completely.

PMID- 12600043
TI  - [Determination of trace iron by catalytic spectrophotometry with nile blue].
AB  - A new method is developed for the determination of trace iron, which is used to
      catalyze the discoloring reaction of KBrO3 oxidizing nile blue in acid medium in
      the presence of NTA. The kinetics is studied. The method has high sensitivity and
      the range of determination is 0-0.4 microgram/25 mL for iron. The detection limit
      of the method is 4.73 x 10(-10) g/mL. Satisfactory results are obtained for the
      determination of trace iron in food and water.

PMID- 12600044
TI  - [Acute aging model induced by gamma-ray irradiation].
AB  - In order to develop a quick and convenient model of acute induced-aging, gamma
      ray (3.0 Gy/time for 4 min 53 s for 5 days) is used to irradiate a group of rats,
      and galactose (40 mg.kg-1.d-1 for 40 days) is injected into a group of mice. At
      the end of the experiment, the activities of superoxide dismutase (SOD) and
      content of malondiadehycle (MDA) in the serum of experimental animals are
      assayed, showing that the gamma-ray irradiation leads to the reduction of SOD
      activity and an increase in MDA content in the serum of the rats, while galactose
      injection leas to the reduction of SOD activity and an increase in MDA content in
      the serum of the mice. The results from this investigation indicate that an acute
      aging model can be induced by gamma-ray irradiating on rats.

PMID- 12600045
TI  - [A portable analyzer for determination of iodine in human urine].
AB  - A instrument based on principle of ion chromatography and amperometric detector
      for quick determination of iodine in urine are introduced in this paper, which
      covers from signal collection and treatment to data analysis. It presents the
      principle of hardware and software method to obtain the determination by using
      computer technology as well as the method of analysis of chromatogram. The
      instrument possess advantage of single, sensitive and simple. Both of tow stages
      of calibration curve for iodine 20-150 and 200-1500 micrograms/L respectively
      showed good linearity with r > 0.999. The detection limit of iodine was 10
      micrograms/L(signal to noise ratio 3:1). The relative standard deviation was less
      than 5% (n = 4), The relative error of measuring urine reference material was
      less than 3%. Range of iodine in concentration 15 human urine samples by this
      method was 116.0-1079 micrograms/L.

PMID- 12600047
TI  - [Method of separate culture of primary neurons using glial feeder layer].
AB  - In order to obtain primarily cultured neurons that can live longer and are
      healthy, and easy to be isolated and purified, the glial feeder layers are used
      for culturing the primary neurons separated from the glial cells. The result
      shows that this method is reliable and easy to be handled. The cultured neurons
      are pure, and healthy. They can survive longer and have potential to be utilized
      in many relevant studies.

PMID- 12600046
TI  - [Determination of heavy metal in Chinese herbs].
AB  - Microwave digestion system was used in digesting samples. Lead and cadmium were
      determined by graphite furnace atomic absorption spectrometry. Mercury was
      determined by cold vapor atomic absorption spectrometry. Standard reference
      material (NBS1570), spinach powder was used as analysis quality assurance in this
      method, and 264 Chinese herbs (23 species) and standard reference material were
      determined, and satisfactory results were obtained by using this method. Averages
      recovery of lead, cadmium and mercury is 95.0%, 97.5% and 99.2% respectively.
      Limit of detection (LOD) is 0.006 mg/kg, 0.208 microgram/kg and 0.026
      microgram/kg respectively for lead, cadmium and mercury. Limit of quantity (LOQ)
      is 0.019 mg/kg, 0.694 microgram/kg and 0.087 microgram/kg respectively for lead,
      cadmium and mercury. This method is also suitable to determine lead, cadmium and
      mercury in food.

PMID- 12600048
TI  - [Studies on the effect of combined treatment of irradiation with vacuum packaging
      on ready-to-eat meat products contaminated with Listeria monocytogenes and
      spoilage bacteria].
AB  - Altogether one hundred and fifty samples of Beijing roast duck, roast chicken and
      cooked meat products inoculated with approximately 1.5 x 10(3)-2.3 x 10(3) cfu/g
      L. monocytogenes are packed under vacuum and are irradiated with 60Co radiation
      at doses of 1.0, 2.0, 2.5 and 3 kGy. The results showed that L. monocytogenes in
      samples can be eliminated by a dose of 2.5 kGy. The resistance of the model
      strain 54004 to irradiation is stranger than three isolates (X20, G4 and g2). In
      addition, the spoilage bacteria in 150 samples of roast duck, roast chicken and
      cooked meat products can be killed at doses of 10.15 and 20 kGy, respectively.

PMID- 12600049
TI  - [Advances in the detection method of several forbidden rodenticides].
AB  - The progress of detection method of four forbidden rodenticides, including
      fluoroacetamide, sodium fluoroacetate, gliftor and tetramine is reviewed in this
      paper. The technique of sample preparation and gas chromatography are emphasized.

PMID- 12600050
TI  - [Current researches on biological effect of aluminum].
AB  - Aluminum content is generally not high (less that 10 mg/kg) in most foods with
      the exception of a few such as tea, spinach, and so on, that contain more amounts
      of it. However, aluminum content is much high in foods in those aluminum
      containing food additives are used. After drinking water is treated with aluminum
      containing coagulant agent, it's aluminum concentration increases. The aluminum
      intake of residents from cookware in our country is 4 mg/(capit.d). The aluminum
      intake in adults is usually 10 mg/(capit.d), but it will rise up to tens to
      hundreds mg/(capit.d) when residents consume foods with a high aluminum
      concentration or aluminum-containing drugs. Aluminum is absorbed mainly via a
      duodenum, and this can be influenced by multiple factors. Absorbed aluminum is
      discharged primarily by renal excretion. Aluminum accumulation in human body
      might harm central nervous system, bone lesions, and hemopoietic system, and is a
      suspected causal factor to Alzheimer's disease.

PMID- 12600051
TI  - [Revolutions and future directions in food composition studies].
AB  - Food composition studies are not only basic, but also essential for many purposes
      in nutrition, food science, and dietetics. This article reviews the Food
      Composition Revolutions, improving the reporting of food composition data, causes
      of variation between actual and measured diets, and future directions in food
      composition. Food composition experts, nutrition professionals, physician, health
      educators, epidemiologists and editors of journals must pay more attention to all
      of these above.

PMID- 12600052
TI  - [Toxicological effects of clenbuterol in human and animals].
AB  - It is reported that clenbuterol increases the lean- to fat conversion in
      livestock and is an illegal stimulating and growth promoter. Consumption of meat
      containing clenbuterol residues causes adverse health effects in human, reduces
      the performance in exercise and disturbs reproductive system and hormone
      response. The toxicity of clenbuterol and its mechanism is reviewed in this
      paper.

PMID- 12600053
TI  - [Effects of epidermal growth factors on the proliferation and metabolism of A/J
      mouse embryonic palatal cells].
AB  - OBJECTIVE: The purpose of this study was to investigate the effects of epidermal
      growth factors (EGFs) with different concentration on the OD, DNA, protein, and
      PGE2 of A/J mouse embryonic palatal shelves cells (A/J MEPC) isolated from
      embryonic palatal shelves. METHODS: The mouse embryonic palatal shelves cells
      were grown in different 39 pores (or bottles) with 9 gradient concentrations of
      EGF (0.005, 0.010, 0.050, 0.100, 0.500, 1.000, 5.000, 10.000, 50.000 ng/ml), and
      four pores were prepared for the same concentration, then the OD, DNA, protein
      and PGE2 of A/J MEPC were measured after 1 day, 3 days and 5 days. RESULTS: EGFs
      stimulated DNA and PGE2 synthesis of A/J MEPC, and augmented proliferation index
      (PIX). Their effects were very obvious in promoting the proliferation of A/J
      MEPC, when the concentration was 10.000 ng/ml. CONCLUSION: EGF may be important
      in regulating proliferation and metabolism of embryonic palatal shelves cells.

PMID- 12600054
TI  - [A study of alumina powder used in fabrication of GI-II infiltrated ceramic].
AB  - OBJECTIVE: This investigation was to analyze the mechanism of formation of porous
      structure by studying some characteristics of the alumina powder used for GI-II
      Infiltrate Ceramic. METHODS: The alumina powder crystal type was analyzed with X
      diffractometer, and its size distribution was obtained by powder size analysis
      device, and fracture surface of alumina adobe was observed under scanning
      electronic microscope. RESULTS: Alumina crystals were purely alpha type, with
      firmest structure and best stability. Fine powder whose size was smaller than 0.5
      micron occupied 9 wt% (mass) and, coarse powder with sizes between 1 to 3.5
      microns occupied 75 wt% (mass). The SEM graphs of adobe showed that fine powders
      were attached to the surface of coarse powders, dispersed evenly, and alumina
      powders contacted each other firmly. CONCLUSION: The crystal type, size
      distribution and even dispersion of the studied alumina powder contributed to the
      formation of porous structure of alumina sintered body (preform), which was the
      material prerequisite in forming porous preform and one of the key factors to the
      rise of strength of GI-II Infiltrated Ceramic.

PMID- 12600055
TI  - [A study on expression of basic fibroblast growth factors in periodontal tissue
      following orthodontic tooth movement associated with low power laser
      irradiation].
AB  - OBJECTIVE: The purpose of this study was to investigate the effects of low power
      laser on basic fibroblast growth factors (bFGF) expression in periodontal tissue
      during tooth movement. METHODS: 18 white rabbits were randomly divided into 6
      groups with 3 rabbits in each group, including groups of 1, 3, 5, 7, 14 and 21
      days. Under an anesthesia condition by 2% pentobarbital sodium, the stainless
      coil springs were fixed between the first maxillary molar and the incisor
      producing the force of 80 g. The right side of maxilla was considered as the
      experimental group under the irradiation of low power laser with the left side as
      the control groups. The expression of bFGF was investigated half-quantitatively
      through immunohistochemical analysis. RESULTS: The expression of bFGF in
      periodontal tissue with irradiation of low power laser was higher than the
      control side. There were significant differences among the 5, 7, and 14 day
      groups. In the tension area of the experimental side, the expression of bFGF in
      the osteoblastic surface of alveolar bone was characteristically greater than
      that of the control side. CONCLUSION: The laser of low power promotes the
      expression of bFGF in the periodontal tissue and alveolar bone remodeling.

PMID- 12600056
TI  - [A study on the morphological characters of immortalized mandibular condylar
      chondrocyte].
AB  - OBJECTIVE: The purpose of this study was to compare the morphological character
      between immortalized mandibular condylar chondrocyte (IMCC) and primarily
      cultured mandibular condylar chondrocyte (MCC). METHODS: The phase contrast
      microscope, photomicroscope and transmission electron microscope were used to
      observe the morphological character of IMCC and MCC. The highresolution
      pathological image and word report system-1000 (HPIAS-1000) was used to compare
      the size of IMCC and MCC. RESULTS: The phase contrast micrography showed that
      MCCs in primary culture underwent distinct morphological changes with respect to
      shape, size, and density of the cells. The majority of MCCs were in polygonal
      shape earlier in culture, while more fusi-form and spindle-shaped cells were
      found after 4-5 passages. While IMCCs were polygonal-shaped, similar to MCCs.
      Subculture, freezing and recovering had no effect on cellular shape of IMCC.
      Transmission electron microscopy indicated that MCC had chondrocyte-like
      phenotype, while IMCC looked like prechondroblast or immature chondrocyte. Some
      of IMCCs had irregular nucleus, and the proportion of nucleus/cytoplasm changed.
      By analysis of HPIAS-1000, the diameter and area of IMCC were obvious smaller
      than those of MCC (P < 0.01). CONCLUSION: IMCC retain the main morphological
      character of MCC, and also keep a stable phenotype, which belong to immature
      chondrocytes, similar to cells in the proliferative zone.

PMID- 12600057
TI  - [A fundamental study on bioreactions of Sr-HA].
AB  - OBJECTIVE: Sr-HA, a new type of hydroxyapatite biomaterial, was implanted into
      animals to study the bioreaction and character, which would be helpful for the
      further clinical applications in the future. METHODS: Totally 24 rabbits were
      divided into 3 groups. The bone defect of 6 mm x 12 mm x 4 mm was made at both
      mandibular angles of rabbits and Sr-HA of different proportion (10%, 5%, 0) was
      applied to reform the defects. One group of animals were killed randomly at 1, 3
      and 6 months after operation to evaluate the material biological compatibility
      using anatomic, X-ray examination, histological and ECT methods. RESULTS: The
      histological photographs showed that Sr-HA caused little infection around
      implanted area and, almost was not repulsed by hosts. With the degradation of
      biomaterial, there was more apparent new bone growth in the area around Sr-HA
      than that around HA and some ossification can be found in soft tissue nearby.
      Also a tight osteointegrity was gradually got after the operation, according to
      the results of X-ray and, the border between Sr-HA and bone was hardly discovered
      at the 6th month after the operation. A more obvious nuclide assembling was
      observed at the side of Sr-HA by ECT images. With the biodegradation of Sr-HA,
      more new bone was intruded into the spare space of the biomaterial. CONCLUSION:
      Sr-HA has better biocompatibility and higher biodegradation than that of pure HA.
      It holds an excellent osteoinductivity and fair osteoconductivity to some degree
      too. So a more satisfying effect of bone defect rehabilitation was gained with
      the increasing new bone depositing in the free space of the material, when it
      degraded gradually.

PMID- 12600058
TI  - [Effect of Angiogenesis inhibitor (TNP-470) on the morphology of GNM cell line in
      vitro].
AB  - OBJECTIVE: The purpose of this study was to investigate the effect of an
      angiogenesis inhibitor (TNP-470) on the ultra micro-structural morphological
      changes of GNM cell line, which was derived from human oral squamous cell
      carcinomas in vitro. METHODS: The GNM cells were cultured and, the effect of TNP
      470 on ultra micro-structural morphological changes of GNM cells was observed
      under the inverted microscope, the scanning electron microscope (SEM) and the
      transmission electron microscope (TEM). RESULTS: Numerous round cells, shrinkage
      of cellular membrane and dead cells were observed 48 hours after 2 micrograms/ml
      of TNP-470 was added into the GNM cellular suspension. After 72 hours, GNM cells
      became shortened and, the number of microvilli of the cellular surface was
      observed under the SEM and TEM. A large number of GNM cells turned into necrosis,
      accompanying with the destruction of mitochondria and endoplasmic reticula.
      CONCLUSION: TNP-470 has a strong tumor cytotoxic effect on GNM cells, which may
      be due to its destructibility on mitochondria and endoplasmic reticula of GNM
      cells. TNP-470 can alter the surface structure of GNM cell membrane, which
      suggests that TNP-470 may interrupt the metastasis of GNM cells.

PMID- 12600059
TI  - [The character of glial line-cell derived neurotrophic factor mRNA expression in
      a facial nerve-striking model].
AB  - OBJECTIVE: It has been known that glial line-cell derived neurotrophic factor
      (GDNF) has the nutritional and protective effect in motor neurons. In this
      experiment, we investigated the character of GDNF mRNA expression in a facial
      nerve-striking model; combined with other scholars' experimental results; and
      analyzed what role GDNF plays in the regeneration process of injured motor
      nerves. METHODS: We established a striking model in rabbit facial nerves with a
      striking gun with the striking velocity of 10 m/s and the total striking energy
      of 7.5 J. Then we detected the GDNF mRNA expression in facial neurons and axons
      with in situ hybridization on days 3, 7, 14 and 21 after striking. We counted the
      expression numbers of facial neurons and, compared with normal facial neurons and
      peripheral facial nerves. RESULTS: We detected GDNF mRNA expression in the facial
      neurons from day 3 to day 21 after the facial nerve injured by striking. The peak
      of GDNF mRNA expression appeared on the 7th day, and then the expression number
      of facial neurons decreased gradually. A high level expression was also detected
      on day 21. GDNF mRNA expression was not detected neither in Schwann cells nor in
      normal facial neurons from the 3rd day to the 21st day. CONCLUSION: GDNF is a
      kind of neurotrophic growing factor (NGF) that could be activated by injury. The
      character of GDNF mRNA expression was accordant to the process of nerve
      regeneration. These results showed that GDNF plays a very important role in the
      regeneration of injured motor nerves.

PMID- 12600060
TI  - [Immunohistochemical detection of micrometastases in cervical lymph nodes from
      squamous cell carcinoma of tongue in neck dissection specimens].
AB  - OBJECTIVE: The purpose of this study was to explore a feasible method to detect
      the micrometastases. METHODS: Totally 152 cases of negative cervical lymph nodes
      (CLNs) from 30 patients with squamous cell carcinoma in tongue were included in
      this study. The HE-stained slices of the CLN were reexamined by two experienced
      pathologists and, conformed that no carcinoma cells were found. Two slices were
      made from each paraffin specimen and, the slices were stained with the microwave
      immunohistochemical technique with monoclonal antibody CK (AE1/AE3) (DAKO Co.
      Denmark, 1:100). RESULTS: Among these 152 cases 7 (4.6%) positive lymph nodes
      were found in 4(13.3%) patients, and CLN metastases were found in all the
      patients before the surgical treatment. Most of the micro-metastatic nodes
      appeared in the upper deep cervical area, except that one of them was found in
      the submandibular triangle. CONCLUSION: The results suggest that micrometastases
      frequently occurred in negative lymph nodes. The present method may be useful in
      detecting the micrometastases of lymph nodes and in evaluating clinical stages of
      patients with oral cancers.

PMID- 12600061
TI  - [A study of effects of pingyangmycin injection on treatment of lymphangiomas in
      oral, maxillofacial and cervical regions].
AB  - OBJECTIVE: The purpose of this study was to investigate the indication and
      therapeutic effects of Pingyangmycin injection as a primary therapy of
      lymphangiomas in oral, maxillofacial and cervical region. METHODS: A total of 195
      patients (106 males and 89 females) with lymphangiomas in oral and maxillofacial
      regions were treated in the affiliated dental hospital of Sichuan University from
      May 1990 to December 2000. The patients' ages ranged from 0.5 to 46 years. The
      tongue was the most commonly involved site, followed by the cheek and the neck.
      The 200 lymphangiomas (5 patients had 2 lymphangiomas in different sites)
      underwent the therapy of Pingyangmycin, which was injected as with 1 mg/ml in
      saline. The total dose of Pingyangmycin ranged from 5 mg to 70 mg and 5 to 58
      times, 1 time per 2-4 weeks. RESULTS: The curative rate of cystic-type
      lymphangiomas was the highest. Of the 51 cystic lymphangiomas, 110 capillary
      lymphangiomas, 18 cavernous lymphangiomas and 21 combinations of capillary and
      cavenous lymphangiomas, the curative rates were respectively 100% (51), 46.36%
      (51), 16.16% (3) and 19.05% (4), which showed a significant therapeutic effect,
      respectively. And 40(78.43%), 19(17.27%), 2(11.11%) and 0(0%) of them completely
      disappeared. There was no serious side effect with Pingyangmycin-injection
      treatment, such as pulmonary fibrosis. CONCLUSION: The treatment of injection of
      Pingyangmycin is a selective primary method of lymphangiomas, which can reduce
      the size of lymphangiomas, and make them completely disappeared.

PMID- 12600062
TI  - [A quantitatively pathological study on malignant ameloblastomas].
AB  - OBJECTIVE: The purpose of this study was to investigate the role of nuclear
      morphometric parameters, DNA content and Ag-NOR count in the differentiating
      malignant and benign ameloblastomas. METHODS: Totally 17 cases of malignant
      ameloblastomas were examined by using HE, AgNOR and DNA stain methods.
      Morphometric parameters of cell nuclei, DNA content and AgNOR count were
      quantitatively studied by using an image analysis system. RESULTS: Seven
      parameters (area, perimeter, equal diameter, minor diameter, mean diameter, round
      index, axis ratio) out of ten shape factors were significantly different between
      malignant and benign ameloblastoma (P < 0.01). AgNOR count and DNA index in
      malignant ameloblastoma were significantly higher than those in benign
      ameloblastoma (P < 0.01). Logistic regression equation was established, according
      to nuclear morphormetric parameters and DNA index. CONCLUSION: Quantitative
      analysis of DAN content, nuclear morphmetric parameters and AgNOR count may be
      helpful in differentiating malignant and benign ameloblastomas.

PMID- 12600063
TI  - [The evaluation of color for the clinical application of thinner porcelain
      laminate restoration].
AB  - OBJECTIVE: The aim of this study was to evaluate the clinical application of the
      thinner porcelain laminate restoration, which is initiated in the West China
      College of Stomatology, Sichuan University. METHODS: The color of 51 ceramic
      veneers was evaluated using the chromatic instrument and visual observation.
      RESULTS: Among factors affecting the clinical results of the porcelain laminate,
      the hue of ceramic materials and bond composites played a more important role
      than the dentition. The brightness of ceramic materials and bond composites were
      closely correlated with the whole restoration brightness. There was also a close
      correlation between the brightness and the bond composite. CONCLUSION:
      Satisfactory restoration results can be achieved by clinical application of
      thinner porcelain laminate.

PMID- 12600064
TI  - [Flowcytometry DNA analysis of oral and maxillofacial non-Hodgkin's lymphoma].
AB  - OBJECTIVE: The purpose of this study was to investigate the relationship between
      the results of flowcytometry analyses of different clinical stage, location,
      pathologic grade and cell origin of oral and maxillofacial non-Hodgkin's lymphoma
      (NHL), and the diagnostic value of flowcytometry analysis in lymphoma. METHOD:
      This study analyzed 50 oral and maxillofacial NHL cases and 10 reactive lymph
      nodes (formalin fixed and paraffin embedded) by flowcytometry (FCM). RESULTS:
      Reactive lymph nodes were all diploid. The diploid rate of NHL was 54%, and
      aneuploidy rate was 46%. There was statistically significant difference between
      reactive lymph nodes and NHL in the DNA ploidy status and cell cycle data (SPF,
      CV, S + G2/M, DI). The S phase fraction (SPF) and S + G2/M had close relationship
      with the grade of NHL. SPF value and DNA ploidy status had no obvious
      relationship with the prognosis. CONCLUSION: The results suggested that the FCM
      had diagnostic value in NHL, especially when the morphological diagnosis was
      difficult. Although the cell cycle data had no prognostic value, SPF and SPF +
      G2/M can show the proliferative status of NHL, which can help clinical doctor
      select therapeutic method.

PMID- 12600065
TI  - [A longitudinal study of 5 cephalometric plane angles in female children from 7
      to 12 years old].
AB  - OBJECTIVE: The aim of this study was to find the laws of angular changes of 5
      cephalometric planes in children with mixed dentitions. METHODS: Nineteen female
      children were annually examined with X-ray, and the cephalometric analysis was
      performed in continuous 4 years. Of these children, 10 children were investigated
      from the age of 7 years old, and the other 9 children from 9 years old. The two
      groups were longitudinally studied. All of the children were observed almost at
      the same age (9-10 years old) in the two groups, and the results were analyzed
      with mixed longitudinal methods. All data were analyzed with SPSS 8.0 software.
      RESULTS: In the observation period, the angular relationship of FH to BaN remain
      constant among 5 cephalometric planes, and FH to SN was almost in the same
      situation. CONCLUSION: In mixed dentition, the angular relationship of FH, BaN
      and SN barely change.

PMID- 12600066
TI  - [A study of ultrasound images under 3 different functional mandibular positions
      in young females].
AB  - OBJECTIVE: The aim of this study was to establish the average of superfacial
      masseter muscle of young females with normal occlusion, and further supply a clue
      for dentists to evaluate the muscle function of patients with malocclusion.
      METHODS: Totally 31 young females were investigated in this study, whose mean age
      was 21 years and 4 months old. Ultrasound technique was applied to obtain the
      ultrasound parameters of images, including area, width, mean thickness, maximal
      thickness of the cross-section and the length of the vertical-section of the
      masseter muscle under relaxing, maximal clenching and maximal protruding
      condition. The data were analyzed using ANOVA analysis. RESULTS: The mean value
      and standard deviation of every parameter were figured out and it was found that
      there was a significant difference between relaxing and maximal clenching as well
      as maximal protruding. CONCLUSION: The result indicates that ultrasonic technique
      is an effective method for describing superfacial masseter muscle morphology and
      diagnosing its function.

PMID- 12600067
TI  - [Changes in the inferior alveolar vessels and angiogenesis following mandibular
      lengthening with different rates of distraction].
AB  - OBJECTIVE: The purpose of this study was to study the changes in the inferior
      alveolar vessels and angiogenesis following mandibular lengthening with different
      rates of distraction. METHODS: Bilateral mandibular corticotomies were performed
      in 6 goats. The mandibles in 6 goats were lengthened 10.0 mm using a custom-made
      distractor with different rates of distraction (1.0 mm/d[n = 3] and 2.0 mm/d [n =
      3]); the other 2 nondistracted mandibles served as control. The goats with
      distracted mandibles were killed at 2 weeks after completion of distraction. The
      inferior alveolar vessels with distracted calluses were harvested and processed
      for histologic and morphometric evaluation. RESULTS: No pathological changes in
      the inferior alveolar vessels were found following mandibular osteodistraction.
      However, the number of microvessels within distraction gap in the animals
      distracted at a rate of 1.0 mm/day was greater than that in the goats distracted
      using a rate of 2.0 mm/day, and more mature newly formed bone trabeculae was
      observed. CONCLUSION: There were no significant changes in the inferior alveolar
      vessels after mandibular lengthening with distraction osteogenesis, but rapid
      distraction may have adverse effects on the aniogenesis in the distraction gap.

PMID- 12600068
TI  - [Distraction osteogenesis for the repair of cleft palate--an ultrastructural
      study].
AB  - OBJECTIVE: The aim of this study was to explore ultrastructural characters of the
      newly formed bone in the correction of cleft palate (CP) bone defect by
      distraction osteogenesis (DO). METHODS: The CP experimental animal models (12
      cats) were established surgically, and were divided randomly into the
      experimental group (10 cats), in which the hard palate bone defects were
      corrected with DO procedure at the rate of 0.4 mm x 2/day. The specimen retrieval
      with euthanasia was carried out at 2, 4, 6, 8, 12 weeks after completion of
      distraction. Ultrastructural study was then performed; the experimental control
      group (2 cats) was kept for 6 weeks before euthanasia without any correction, the
      other extra 2 cats were used as the negative control. RESULTS: New bone formation
      appeared in early 2 weeks. Exclusively intramembranous bone formation was
      observed in all specimens. The remodeling activities were keep observed
      throughout the period of study, and the bone structure matured gradually till 12
      weeks after the completion of DO. No repair was observed in experimental control
      group. CONCLUSION: The reconstruction of CP bone defect by means of DO could get
      active intramembranous bone formation and remodeling, which adapted to normal
      functional activities.

PMID- 12600069
TI  - [Characteristics of BMP expression and X-ray films in distraction osteogenesis
      for repair of cleft palate--an immunohistochemical and roentgenographic study].
AB  - OBJECTIVE: The purpose of this study was to observe the roentgenographic
      characters of distraction osteogenesis (DO) correction of cleft palate (CP), to
      study the expression of BMP proportional to fixation period time intervals, and
      to explore the new bone formation mechanism in Cleft Palate bone shelf. METHODS:
      12 cats were used to establish the CP animal model surgically, and then were
      assigned randomly to (1) Experimental group (12 cats): CP defects were DO
      repaired at the rate and rhythm of 0.4 mm x 2/day. Specimen retrieval at 2, 4, 6,
      8, 12 weeks after completion of distraction, roentgenography and Anti-BMP
      immunohistochemistry studies were performed; (2) Experimental control group (2
      cats): CP defects without any treatment procedures, and (3) Empty control group
      of 2 cats. RESULTS: Anti-BMP immunohistochemistry study showed positive DAB dye
      in early 2 weeks and most extensively positive expression of BMP in 4 to 6 weeks.
      The expression of BMP wore off gradually through 8 to 12 weeks. The
      roentgenography showed that the newly mineralized bone was developed from the cut
      bone edges bilaterally to the central transparent zone, and the newly formed bone
      bridged the defect area completely at the end of the study. The CP bone defect
      was reconstructed and the distraction gap was filled with de nove osteogenesis.
      No new bone formation was observed in experimental control group. CONCLUSION: The
      process of new bone formation in the distraction area is dynamic. Being
      stimulated primarily, the process was kept highly active till quiescence phase
      finally. The X-ray examination shows that there is distinctively low
      roentgenopeque. Nevertheless, roentgenography is so far a very effective and
      convenient method to evaluate and monitor the DO correction efficiency.

PMID- 12600070
TI  - [The effects of the mechanical stress on the cytoskeleton filament F-actin of
      osteoblast-like cells in vitro].
AB  - OBJECTIVE: Mechanical stimulation alters cell's metabolism, but little is known
      about the effects of mechanical strain on the cytoskeleton of osteoblasts. This
      study was to investigate the changes of F-actin, a cytoskeleton protein of rat
      derived osteoblast-like cell line UMR-106, and to provide theoretical basis for
      further investigation of mechanism of bone-remodeling. METHODS: Centrifugation
      was used to inflict UMR-106 the top-bottom axial stress (225 x g) expected and,
      confocal laser scanning microscope (LSCM) was used to examine the morphological
      changes 15, 30 min, and 1, 4, 6, 12, and 24 hr after undergoing physical strain.
      Unstrained cells were used as the controls respectively. The distribution of F
      actin was observed after immunofluorescent staining and electronic photo was
      scanned for further analysis of osteoblasts' average fluorescence by
      spectrofluorimetric quantification. RESULTS: Except the 24 hr group, the actin
      filaments of the strained osteoblasts were much shorter, more flimsy and tenuous
      than that of untreated osteoblasts and unlike the normal distribution of bundles
      or membrane-like of the control group, and they were arranged without direction.
      Its quantified fluorescence was significantly less than that of the controls. But
      the 24 hr group showed a normal distribution and a stronger fluorescence.
      CONCLUSION: It is concluded that the cytoskeleton of the strained osteoblasts has
      a reduced number of F-actin fibers and a unique abnormal morphology and could
      recover in 24 hr.

PMID- 12600071
TI  - [Experimental research on degradation and biocompatibility of super-high
      molecular-weight poly-DL-lactic acid].
AB  - OBJECTIVE: The super-high-molecular-weight poly-DL-lactic acid (PDLLA), with the
      molecular weight of 900 kD, is a newly emerging biomaterial and potentially used
      in the therapy of bone fracture because of its excellent mechanical property.
      However the biocompatibility of this material has not been reported so far,
      therefore this experiment was designed to examine whether the super-high
      molecular-weight PDLLA was harmful to creatures, when it was implanted in the
      body of animals for a long period. METHODS: The material was prepared in small
      cuboids, with the size of 1.0 mm x 1.5 mm x 2.0 mm, and these blocks were
      implanted into the masseteric space of SD rats and, the activity of the SD-rats
      was monitored continuously. The animals were sacrificed in the 3rd, 6th, 9th,
      12th months after the operation and, the specimens were taken out from the
      animals. The examination included anatomical, pathological and haematological
      methods. The data were analyzed with SPSS 8.0. RESULTS: The wound healed well
      after the operation. Super-high-molecular-weight PDLLA degraded 6 months after
      the implantation. In the 3rd month after the operation, a thin fiber membrane
      around the materials was formed. In the 6th month, the membrane was much thinner
      than that in the 3rd month and completely disappeared in the 9th month. The
      pathological examination showed that slightly inflammatory reaction appeared in
      the tissue around these blocks in the 3rd month, but the inflammatory reactions
      were gradually remitted in the following 6th, 9th and 12th months. Further, the
      haematological examination did not show any abnormity during the 12-month
      observation period. CONCLUSION: The super-high-molecular-weight PDLLA can be
      degrade when it is implanted into the body of creatures, which proves its good
      biocompatibility.

PMID- 12600072
TI  - [A survey on dental knowledge and behavior of mothers and teachers of school
      children].
AB  - OBJECTIVE: The purpose of this survey was to assess dental knowledge and
      behaviors of the teachers and mothers of school children. METHODS: All data was
      collected from 1365 mothers of first grade students and 215 schoolteachers in
      Yichang, Hubei by using questionnaires and, analyzed using SPSS software.
      RESULTS: The level of dental knowledge was higher among schoolteachers than among
      mothers; the mothers were mostly informed through television/book (62.4%/51.5%),
      while teachers received information from various sources, including the dentists
      (75.3%). Most of the children (94.0%) didn't have practical support from their
      parents in daily tooth cleaning. Only 18.9% of them visited the dentist at least
      once per year. CONCLUSION: This finding suggested that we should emphasize oral
      healthy education among mothers and schoolteachers, in order to promote school
      based oral health education program.

PMID- 12600073
TI  - [K. pneumoniea endotoxin induced mice beta-defensin-4 mRNA expression and its
      signaling transduction].
AB  - OBJECTIVE: To investigate the in vivo effects of Klebsiella pneumoniae
      endotoxin(LPS) on beta-defensin expression and the relevant signaling
      transduction pathway. METHODS: A LPS tolerant mouse C3H/HeJ with a point mutation
      at Toll-like receptor-4 (TLR4) gene and its wild type strain C3H/HeN were used in
      this study. C3H/HeJ and C3H/HeN were injected with 4 mg/kg of LPS
      intraperitoneally. The tracheas, lungs and kidneys of the C3H/HeJ and C3H/HeN
      were collected respectively at different LPS-treated time points, and the total
      RNA of each sample was extracted. The expression of mice beta-defensin-3 and/or
      beta-defensin-4 mRNA in these tissues was determined by reverse transcriptase
      polymerase chain reaction (RT-PCR). The sequence of cDNA amplified from the lung
      of C3H/HeN treated by LPS for 24 h was analyzed. By using western blot, p-I kappa
      B alpha (phosphorylated I kappa B alpha) and I kappa B alpha of in the lungs of
      C3H/HeJ and C3H/HeN were detected at different time points after treatment with
      LPS or without LPS. RESULTS: 1. beta-defensin-4 mRNA was detected in the lungs of
      C3H/HeN after 24 h treatment with LPS. In contrast, no signal was determined in
      C3H/HeJ mice with LPS treatment and the C3H/HeN mice without LPS treatment. 2.
      Compared with the control, increas of the p-I kappa B alpha was observed in the
      lungs of C3H/HeN at 4 h after treatment with LPS, while both the p-I kappa B
      alpha and I kappa B alpha contents showed a tendency to go down at 8 h after
      treatment and dramatically decreased at 24 h. But there were no changes in the of
      p-I kappa B alpha and I kappa B alpha content the lungs of C3H/HeJ under the same
      conditions. CONCLUSION: K. pneumoniea endotoxin could induce the expression of
      beta-defensin-4 mRNA in the lung of C3H/HeN, and TLR4-mediated NF-kappa B
      activation signaling pathway may be responsible for this event.

PMID- 12600074
TI  - [DNA sequence analysis and expression of the recombinant plasmid pBX1 from
      Borrelia burgdorferi B31 strain].
AB  - OBJECTIVE: This study was to provide the target antigen for the development of a
      Lyme disease vaccine and serodiagnosis reagent. METHODS: We used the automatic
      DNA sequencing machine (Model 377) to detect the nucleotide sequence of the
      inserted part of the recombinant plasmid pBX1 from Borrelia burgdorferi B31
      strain. The restriction enzyme map of the inserted part of pBX1 was analysed by
      using computer software. The expressed product of pBX1 in E. coli XLI-Blue MRF
      was analysed by using SDS-PAGE and western-blotting. RESULTS: 1. DNA sequencing
      showed that pBX1 contained a 477bp inserted gene fragment, and when it was
      compared with the published sequence of the specific region of the gene of the 83
      kd antigen protein from Borrelia burgdorferi B31 strain, only one amino acid
      codon was different. 2. The restriction enzyme map of the inserted part of pBX1
      was successfully constructed. 3. The recombinant plasmid pBX1 expressed a 29 kd
      fusion protein in E. coli XL1-Blue MRF' after induced with IPTG. The recombinant
      fusion protein could be recongnized by rabbit polyclonal antiserum against
      Borrelia burgdorferi B31 strain. CONCLUSION: A recombinant plasmid which contains
      the gene fragment encoding the specific region of the 83 kd antigen protein from
      Borrelia burgdorferi B31 strain has been successfully constructed. The
      recombinant plasmid can stably express 29 kd fusion protein in E. coli XL1-Blue
      MRF'. These results could serve as a base of further studies on the usefulness of
      the fusion protein in serodiagnosis and vaccine for Lyme disease.

PMID- 12600075
TI  - [The HVR genotypes and their relationship with the resistance of methicillin
      resistant staphylococci].
AB  - OBJECTIVE: To investigate the HVR-PCR genotype of methicillin-resistant
      Staphylococci in local hospitals and compare it with the antibiograms, with aview
      to selecting effective antibacterial agents, moreover, to discuss preliminarily
      its role in molecular epidemiology. METHODS: The minimal inhibitory
      concentrations(MICs) of 86 MRSA, 10 MRSE(Mc'S. epidemidis), 5 MSSE(Mc'S.
      epidemidis), 8 MRSH(Mc'S. haemolyticus) and 5 MSSH(Mc'S. haemolyticus) clinical
      isolates collected from 4 local hospitals were tested by serial two-fold agar
      dilution method; their DNA were extracted by moved basic lytic method, whose
      polymerase chain reaction(PCR) products amplified, based on the size of mec
      associated hypervariable region(HVR) were analyzed by PAG vertical and agarose
      gel electrophoresis. RESULTS: MRSA, MRSE and MRSH were grouped into 4, 3 and 2
      HVR genotypes respectively according to the size of the PCR products. The PCR
      products amplified from 9 of 10 MRSE isolates were the same as the products
      amplified from MRSA isolates. MRSA strains in this study were mainly HVR
      genotypes A and D, which accounted for 52.32% and 39.53%; Genotypes B and C were
      the most multi-drug resistant, but genotype D was multi-sensitive. The I genotype
      of MRSE was multi-drug resistant, but its genotype III was multi-drug sensitive.
      The genotype a of MRSH was more resistant than genotype b. CONCLUSION: These
      results suggest that HVR-PCR genotype method is an easy and fast method for
      epidemiological investigation of nosocomial infections caused by MRSA, and it is
      helpful for clinical selection of antibacterial agents. This method can compare
      the mec determinants of MRSA and Mc'CNSt isolates and hence to search for the
      origin of the mec determinant.

PMID- 12600076
TI  - [Construction of recombinant plasmids containing genes of HBsAg and their
      expression in the eukaryotic cells].
AB  - OBJECTIVE: To construct recombinant plasmids expressing L, M, S and pre-S1-S
      protein of HBsAg. METHODS: Amplifying segments of S, pre-S2-S, pre-S1-pre-S2-S
      genes of HBV by PCR and amplifying segment of pre-S1-S by overlap extension PCR;
      inserting the segments into Rc/CMV and pSG5UTPL/Flag plasmids respectively and
      exploring their expressions by Western-Blot hybridization, identifying the
      inserting segments by sequencing. RESULTS: The sequences of the inserted segments
      were the same as the genes of S, pre-S2-S, pre-S1-pre-S2-S and pre-S1-S and the
      results of Western-Blot hybridization were positive for the aimed proteins.
      CONCLUSION: We have gained 8 recombinant plasmids expressing S, M, L and pre-S1-S
      proteins with high efficacy.

PMID- 12600077
TI  - [Apolipoprotein C III gene Sst I polymorphism in patients with endogenous
      hypertriglyceridemia in Chinese population].
AB  - OBJECTIVE: To investigate the apoC III gene Sst I polymorphism and its
      relationship with serum lipids and apolipoproteins (apo) levels in patients with
      endogenous hypertriglyceridemia in Chinese population. METHODS: The genotype and
      allele frequency of apoC III gene Sst I polymorphism was assayed by polymerase
      chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Serum
      lipids were measured by enzymatic kits and apolipoproteins A I, A II, B100, C II,
      C III and E were measured by RID kits developed by Apolipoprotein Research Unit
      of WCUMS in 176 HTG patients whose fasting serum TG levels were > or = 2.26
      mmol/L and in 199 healthy subjects whose fasting serum TG levels were < 1.82
      mmol/L and TC levels < 6.2 mmol/L from a population of Chinese Han nationality in
      Chengdu area. RESULTS: In both HTG group and control group, S1 allele was the
      major allele and homozygous S1S1 genotype was the most frequent one. The
      frequency of S2 allele was significantly higher than that reported in Caucasians
      (0.289 vs 0.06-0.16, P < 0.05). No differences were found in apoC III gene Sst I
      polymophism in the HTG group when compared with the control group (0.287 vs
      0.289, P > 0.05). The genotype of S2S2 was not associated with higher TG and
      apolipoproteins levels when compared with the genotypes of S1S1 and S1S2 (P >
      0.05). CONCLUSION: These results suggest that the Sst I polymorphism of the apoC
      III gene was not associated with endogenoushypertriglyceridemica in Chinese
      population.

PMID- 12600078
TI  - [Study on apoE gene polymorphism in Chinese type II b hyperlipidemia].
AB  - OBJECTIVE: To study apolipoprotein(apo) E polymorphism and its relationship with
      plasma lipids and apolipoproteins levels in Chinese patients with type II b
      hyperlip oproteinemia. METHODS: apoE genotypes were assayed by polymerase chain
      reaction (PCR)-restriction fragment length polymorphism (RFLP) method, serum
      lipids were determined by enzyme method, and apolipoproteins were measured by
      radial immunodiffusion assay in 74 type II b hyperlipidemia patients whose
      fasting serum lipids levels were TG > or = 2.26 mmol/L, TC > or = 6.21 mmol/L and
      in 230 healthy subjects whose fasting serum lipids levels were TG < 1.82 mmol/L,
      TC < 6.21 mmol/L from a population of Chinese Han nationality in Chengdu area.
      RESULTS: Compared with the control group, the serum TG, TC, LDLC, nHDLC, apoA II,
      apoB100, apoC II, apoC III, apoE levels and TG/HDLC ratio in patients with type
      II b hyperlipidemia were significantly increased(P < 0.001), and the serum HDLC
      levels and apoE/apoC III ratio were significantly decreased (P < 0.05). ApoE3/3
      genotype and allele epsilon 3 frequency in type II b hyperlipidemia group and
      control group were both the highest. In type II b hyperlipidemia group, allele
      epsilon 2 frequency tended to increase and allele epsilon 4 frequency tended to
      decrease as compared with those in the control group (P > 0.05). In type II b
      hyperlipidemia group the genotype of apoE2 was associated with higher serum TG,
      apoC II, apoE levels and apoE/apoC III ratio when compared with the genotype of
      apoE3; the genotype of apoE4 was associated with higher serum TC, nHDLC and apoE
      levels when compared with the genotypes E3 and E2 (P < 0.001). CONCLUSION: The
      alleles epsilon 2 and epsilon 4 are associated with serum TG, TC, nHDLC, apoC II
      and apoE levels to some extent in type II b hyperlipide in Chinese population.

PMID- 12600079
TI  - [Detection of hepatitis C virus from hepatocellular carcinoma and its
      relationship to hepatocarcinogenesis].
AB  - OBJECTIVE: To get an insight of the relationship between hepatitis C Virus (HCV)
      infection and hepatocellular carcinoma (HCC). METHODS: A molecular pathology
      research was performed. Liver specimens from 19 HCC cases with HCV infection only
      were detected for HCV antigen (HCAg) and HCV RNA with monoclonal antibody (McAb)
      against HCV NS3 antigen by means of immuno-histochemistry staining and in situ
      hybridization using Dig-labeled full-length HCV cDNA Probe. RESULTS: In 17 of 19
      (89.5%) cases, positive expression of the antigen was observed; 11 of 19 (57.9%)
      cases were positive for HCV RNA. The viral antigen was expressed in cytoplasm and
      nucleus of para-cancerous hepatocytes and in cancer cells too, while the
      distribution of HCV RNA was only seen in cytoplasm of hepatocyte. CONCLUSION:
      These results strongly support the relationship between HCV infection and the
      occurrence of HCC. The nucleic distribution of HCAg suggests a possible
      interaction between HCAg and the host genome, which may lead to
      hepatocarcinogenosis.

PMID- 12600080
TI  - [Overexpression of cyclin A leads to S-phase arrested apoptosis].
AB  - OBJECTIVE: This study was aimed to gain an insight into the molecular basis of S
      phase arrest associated apoptosis. METHODS: The molecular expressions of Rb,
      cyclin A, cyclin E, CDK2 and CDC2 involved in S-phase progression were
      investigated by westernblot in L-2 and Br1-3pr-1 cells. Furthermore, their
      associated kinase activities were assayed by histone, phosphorylation. RESULTS:
      The results showed that ofter PALA treatment, the expression of cyclin A
      increased and the expression of Bcl-2 decreased in apoptosising L-2 cell as
      compared with those in unapoptosising Br1-3pr-1 cell, but there were no
      significant differences in other molecular expressions and associated kinase
      activities between the above-mentioned L-2 cell and Br1-3pr-1 cell arrested at S
      phase after PALA treatment. CONCLUSION: Cyclin A is a most potential candidate
      for S phase checkpoint element, and it may be able to induce the S phase arrest
      associated apoptosis through the Bcl-2 pathway.

PMID- 12600081
TI  - [The protein expression of p53 and bcl-2 in laryngeal squamous cell carcinoma].
AB  - OBJECTIVE: To detect the relationship of p53 and bcl-2 gene to laryngeal
      carcinoma. METHODS: p53 and bcl-2 protein expressions were examined in the
      specimens of 60 laryngeal carcinomas and 8 vocal cord polyps by
      immunohistochemistry method. RESULTS: Overexpressions of p53 and bcl-2 were found
      in the laryngeal carcinoma specimens; the positive rates of p53 and bcl-2 protein
      expression were 61.7%(37/60) and 43.3%(26/60), respectively. Negative results
      were observed in all the vocal cord polyp specimens. The positive rates of p53
      and bcl-2 expression were related to the histological grade and cervical
      lymphatic metastasis of laryngeal carcinoma but not related to clinical stage and
      tumor types. CONCLUSION: The results of this study support the hypothesis that
      p53 and bcl-2 gene may be involved in the apoptosis of laryngeal carcinoma and
      they may play an important role in the pathogenesis of laryngeal cancer.

PMID- 12600082
TI  - [Adenovirus-mediated Rb gene transfect for head and neck cancer].
AB  - OBJECTIVE: To evaluate the efficacy of Rb gene therapy in head and neck
      carcinoma. METHODS: We investigated the adenovirus-mediated Rb (Ad-Rb) gene
      transfect into human oral squamous cell carcinoma cell line (012) in both in
      vitro and in vivo models. RESULTS: The cells growth curve for 012 tumor cells
      transfect with Ad-Rb became lower after two days transfection and declined
      slightly by six days. Tumor growth in nude mice was also significantly retarded
      following Ad-Rb injection when compared with controls. Ad-Rb expression was
      identified by Western blotting in those tumors injected with Ad-Rb. CONCLUSION:
      These results implicated that the recombinant Rb gene adenovirus vector could
      efficiently transfect and inhibit oral squmous cell carcinoma. It might be an
      important candidate for gene therapy in head and neck cancer.

PMID- 12600083
TI  - [The significance of nuclear factor kappa Bp65 (NF kappa Bp65) expression on the
      vascular endothelial cells of rectum adenocarcinoma of human].
AB  - OBJECTIVE: This study inquired into the mechanism of cancer vascular metastasis.
      METHODS: The immunohistochemical method was adopted in determining the expression
      of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor kappa B (NF
      kappa Bp65) on the peritumoral rectum tissues and metastatic lymph nodes of 8
      patients and on the rectum tissues and lymph nodes of 5 normal human subjects.
      Also, the method of in situ hybridization was employed in detecting the binding
      site of NF kappa Bp65 on vascular endothelial cells. RESULTS: It was found that
      the proteins of ICAM-1 and NF kappa Bp65 were expressed on the vascular
      endothelial cells of the rectum adenocarcinoma patients, and there was a NF kappa
      B binding consensus sequences on ICAM-1 promoter in the vascular endothelial
      cells of the rectum adenocarcinoma patients. When DIG-AKP labeled 38-bp
      oligonucleotide probe was used, there was no expression of ICAM-1 and NF kappa
      Bp65 on the vascular endothelial cells of the normal human lymph node and rectum
      tissues. CONCLUSION: The above data suggest that the activation of ICAM-1
      promoter may critically depend on NF kappa Bp65 homodimers or heterodimers
      binding to a variant kappa B site on the vascular endothelial cells of human
      rectum adenocarcinoma. These may indicate the potential roles of NF kappa B in
      cancer metastasis, thus giving clues to the development of a novel anti
      metastasis strategy.

PMID- 12600084
TI  - [Alterations in the level of calcitonin gene related peptide and endothelin-1 in
      the cirrhotic rat heart].
AB  - OBJECTIVE: To investigate the role of calcitonin gene related peptide(CGRP) and
      endothelin-1 (ET-1) in cirrhotic cardiomyopathy (CCM). METHODS: We measured the
      level of CGRP and ET-1 in the samples of rat heart collected from 15 liver
      cirrhosis rats and 15 controls by using radio immunoassay. RESULTS: The data
      showed that the levels of CGRP (74.2130 +/- 10.3776 pg/mg protein) and ET-1 level
      (1.4780 +/- 0.9235 pg/mg protein) were significantly higher in the cirrhotic rat
      hearts than those in controls (P < 0.05). The increase of ET-1 in the cirrhotic
      rat hearts was closely associated with the severity of liver cirrhosis (P =
      0.004); whereas no significant association was seen between the CGRP
      concentration and the severity of liver cirrhosis (P = 0.307). CONCLUSION: We
      infer that the increasing of CGRP level in the cirrhotic rat heart may be a
      protective or antagonistic reaction to ET-1 or other pathogenic factors for
      cardiac dysfunction. The disturbance of the balance between CGRP and ET-1 in the
      liver cirrhosis rat hearts may contribute to the pathologic process of CCM.

PMID- 12600085
TI  - [TGF beta 1 and ET-1 expression in the peripheral blood of patients with
      cirrhosis].
AB  - OBJECTIVE: The aims of this study were to determine 1. the variation of blood TGF
      beta 1 and ET-1 in patients with liver cirrhosis; 2. the relationship of the
      blood TGF beta 1 and ET-1 with Child degree of liver function and the severity of
      esophageal varices. METHODS: Peripheral blood samples were obtained from 72
      patients and 24 normal controls. The blood levels of TGF beta 1 and ET-1 were
      measured by using a standard bioassay and the radioimmunoassay. RESULTS: TGF beta
      1 level (11.77 +/- 1.32 ng/ml) and ET-1 level (78.37 +/- 17.54 pg/ml) were
      significantly higher in the patients than those in controls(P < 0.05). The
      increase of the ET-1 in the patients is closely associated with Child degree of
      liver function (r = 0.94) and the severity of esophageal varices(r = 0.87). TGF
      beta 1 concentration is not associated with Child degree of liver function (r =
      0.11) and the severity of esophageal varices (r = 0.03). CONCLUSION: TGF beta 1
      and ET-1 may play an important role in the pathophysiologic process of cirrhosis.
      ET-1 concentration may reflect portal hypertension development.

PMID- 12600086
TI  - [The effects of adenosine, interleukin-1 and theophylline on the expression of A2
      adenosine receptor mRNAs in peripheral blood mononuclear cells from asthmatic
      patients].
AB  - OBJECTIVE: To explore the roles of A2a and A2b adenosine receptors(A2aAR and
      A2bAR) in the pathogenesis of bronchial asthma. METHODS: Eleven asthmatics and 11
      healthy subjects were included in this investigation. Peripheral blood
      mononuclear cells(PBMCs) were obtained after density centrifugation on Ficoll
      Hypaque. The expression of A2aAR and A2bAR mRNAs in PBMCs was examined by use of
      the reverse transcription-polymerase chain reaction (RT-PCR) and image pattern
      analysis semiquantitation method. RESULTS: The expression of A2aAR mRNA in PBMCs
      from asthmatics was not enhanced, compared with that of healthy subjects(P >
      0.05). Adenosine or IL-1 or theophylline was not observed to have effect on A2aAR
      mRNA (P > 0.05). A2bAR gene expression in PBMCs was more markedly in patients
      with asthma than in normal individuals (P < 0.05). Adenosine and IL-1
      significantly increased A2bAR mRNAs in asthmatics. Theophylline inhibited A2bAR
      gene expressions. The expression of A2bAR mRNA in PBMCs was positively correlated
      to serum total immunoglobulin E (TIgE) level in asthmatics (r = 0.72, P < 0.01).
      The expressions of A2bAR mRNA elevated by adenosine or IL-1 were correlated
      positively with serum TIgE(r = 0.78 or r = 0.61; P < 0.05) and negatively with
      the forced expiratory volume in first second to predicted value ratio (FEV1%) (r
      = -0.62 or r = -0.81; P < 0.05) in asthmatics. CONCLUSION: These results
      indicated that the expression of A2bAR mRNAs in PBMCs was more remarkable in
      asthmatics than in healthy subjects; that adenosine or IL-1 potentiated the mRNA
      expression of A2bAR in PBMCs in asthmatic patients, which was correlated with
      allergy state and the degree of airway obstruction; and that theophylline might
      antagonize adenosine by inhibiting A2bAR mRNA.

PMID- 12600087
TI  - [Investigation of the effects of various factors affecting apoptosis of chronic
      lymphocytic leukemic cells mediated by P2Z receptors].
AB  - OBJECTIVE: To explore the effects of various factors affecting apoptosis of
      chronic lymphocytic leukemia (CLL) cells mediated by P2Z purinoceptor. METHODS:
      In vitro exposure of CLL cells with P2Z receptors to 1 mmol/L ATP or 0.1 mmol/L
      benzoylbenzoic ATP (BzATP) for 8 h in the presence of 1.0 mmol/L Mg2+ or other
      bivalent cations, 150 mmol/L choline in media, 1, 2, 4 mmol/L EDTA or EGTA, or
      under different temperature. ATP-induced apoptosis was detected by agarose gel
      electrophoresis, TdT assay and flow cytometric analysis (FCA). RESULTS: The
      results showed that 1. Extracellular Mg2+ or Ca2+ stimulated ATP-induced DNA
      fragmentation in a dose-dependent manner, and the compatible evidence was
      provided by the inhibition of ATP-induced DNA fragmentation in the presence of
      EGTA or EDTA; 2. ATP-induced DNA fragmentation was completely inhibited by 1.0
      mmol/L Zn2+; 3. ATP-induced DNA breaks were not affected by Ba2+, Sr2+, Co2+ when
      they were substituted for extracellular Mg2+ or Ca2+; 4. Choline, an inhibitor of
      phospholipase D (PLD) stimulated by ATP through P2Z receptor in human
      lymphocytes, was also a partial inhibitor of ATP-induced DNA fragmentation, and
      the results were confirmed by flow cytometric analysis (FCA); 5. ATP-induced DNA
      fragmentation was completely obliterated when the temperature was lower than 10
      degrees C. CONCLUSION: These results suggest that the endonuclease and PLD may be
      involved in ATP-induced apoptosis in human lymphocytes via P2Z receptor.

PMID- 12600088
TI  - [Expression of apoptosis of the skin lesion and muscle from patients with
      dermatomyositis].
AB  - OBJECTIVE: This study inquired into the relationship between the influence of
      corticosteroid and the expression of apoptosis, Fas and Bcl-2 in muscle from
      patients with dermatomyositis (DM). METHODS: Corticosteroid was given to group A
      (10 DM cases) but not given to group B (12 DM cases). RESULTS: Apoptotic cells
      were detected in situ by terminal deoxynucleotidyl transferase-mediated-dUTP nick
      end labeling (TUNEL). Fas and Bcl-2 expressions was determined with the use of
      immunohistochemical staining in DM. The results showed that more expression of
      apoptosis in keratinocytes, muscle cells and lymphocytes were observed in group
      A. The apoptotic index (AI) of muscle cells and that of lymphocytes were more
      marked in group A than in group B (P < 0.05). Less apoptosis cells were observed
      in two weeks of treatment, and no correlation was found between apoptosis and the
      lesion of skin and muscle. CONCLUSION: The authors suggest that corticosteroid
      may play a role in inducing the apoptosis of keratinocytes, muscle cells and
      lymphocytes, which may be one of the therapeutic mechanisms of corticosteroid.
      The length of administering corticosteroid to the patients seems related to
      apoptosis.

PMID- 12600089
TI  - [The change of nerve growth factor and brain derived neurotrophic factor in
      neurons of cerebral cortex of adult rat following local ischemia].
AB  - OBJECTIVE: To acquire knowledge about the change of nerve growth factor (NGF) and
      brain derived neurotrophic factor (BDNF) in neurons of cerebral cortex of adult
      rat following local ischemia. METHODS: Using specific antiserums of NGF and BDNF
      by immunohistochemical ABC method. RESULTS: NGF-like and BDNF-like
      immunoreactions distributed mainly in the neurons of the third and fifth layers
      in cerebral cortex. After local ischemia, the average gray degrees of NGF and
      BDNF in neurons of cerebral cortex both decreased on the operated side more than
      on the un-operated side. CONCLUSION: This experiment demonstrated that the levels
      of NGF and BDNF in neurons of cerebral cortex following ischemia were upregulated
      apparently, suggesting that NGF and BDNF may play an important role in the
      process of neurons' reaction after ischemia.

PMID- 12600090
TI  - [The effect of AG490 on NK activity and lymphocyte transformation of PBMC].
AB  - OBJECTIVE: To examine the effect of AG490 on NK activity and lymphocyte
      transformation. METHODS: Using MTT colorimetry to detect cell survival, NK
      activity and cell proliferation. RESULTS: AG490 inhibited IL-2 and PHA induced
      peripheral blood mononuclear cell proliferation, and it inhibited NK activation.
      CONCLUSION: As an inhibitor of JAK, AG490 can influence the function of normal
      cells.

PMID- 12600091
TI  - [Study on donor-specific antigens in inducing immunological tolerance].
AB  - OBJECTIVE: To compare the effects of different donor-specific antigens, through
      different pathways, on the inducement of immunological tolerance. METHODS: After
      the establishment of a stable rat cervical heterotopic heart transplantation
      model, donor specific transfusion (DST), donor specific spolenocyte (DSSL) and
      donor specific bone marrow (DSBM) were given to recipients 3-14 days prior to the
      transplantation through peripheral vein, portal vein and intrathymic injection
      respectively. Low dose CsA 5 mg/(kg.d) was given from the 3rd-14th day pre
      transplantation to the 28th day post-transplantation. The survival time of
      cardiac grafts was monitored, meanwhile, the donor specific mixed lymphocyte
      reaction (MLR) and the subsets of T lymphocytes CD8+ were determined. RESULTS:
      DSBM and the administrative pathway of intrathymic injection achieved the best
      effects on the inducement of immunological tolerance and the improvement of graft
      survival. CONCLUSION: The donor specific antigens can induce the donor-specific
      immunological tolerance. It may be a practicable approach for the clinical
      experiments in the future.

PMID- 12600092
TI  - [A comparison between 99mTc-Q3 and 201Tl on clearance and retention properties at
      varying coronary flow rates in isolated rabbit heart].
AB  - OBJECTIVE: This study was intended to investigate and compare technetium-99m-N,
      N'-ethylenebis(acetylacetoneiminato)bis[tris (3-methoxy-1-propyl) phosphine]
      (99mTc-Q3) versus 201Tl on clearance and retention properties at varying coronary
      flow rates in isolated rabbit heart. METHODS: 20 New Zealand White rabbits were
      anaesthetized and excised through a median sternotomy. The hearts were isolated
      and arrested in ice-cold saline. The external perfusion models with isolated
      rabbit hearts were installed and were perfused at flow rates ranging from 0.52 to
      3.75 ml/(g wet wt.min) in the absence of tracer recirculation. Furthermore, 99mTc
      Q3 experimental relations between uptake, clearance and retention were explored
      in comparison with 201Tl. RESULTS: 201Tl net uptake was higher and also more
      affected by flow rates (P < 0.05) as compared with 99mTc-Q3 net uptake. 201Tl
      clearance was faster than 99mTc-Q3 clearance within 4 to 25 minutes after
      radiopharmaceuticals injection in high flow rates group, and 201Tl clearance was
      faster than 99mTc-Q3 clearance within 40 minutes after radiopharmaceuticals
      injection in low flow rates group. 201Tl earlier rapid clearance observed in the
      high flow rates group did not appear in the low flow rates group, but 99mTc-Q3
      did not display early rapid clearance either in the high flow rates group or in
      the low flow rates group. CONCLUSION: Owing to faster clearance, the superiority
      of 201Tl over 99mTc-Q3 as a myocardial perfusion imaging agent would be lost
      entirely within 10 minutes after injection of agent, therefore 99mTc-Q3 is still
      a good myocardial perfusion imaging agent, and further study is worth doing.

PMID- 12600093
TI  - [Study on DNA oxidative damage of O3 aging model in mice].
AB  - OBJECTIVE: This study was aimed to detect the animals' DNA oxidative damage.
      METHODS: A free radical mouse aging model was established by putting the mouse in
      a device for inhaling quantities of ozone (O3). Single cell gel electrophoresis
      (SCGE) was used for assessing the splenolymphocytes' DNA damage. RESULTS: The
      appearance rate of comet and the length grade of DNA migration for the young
      control group (P < 0.05). No significant difference in the degree of DNA damage
      was observed between the O3 model group and the natural aging group(P > 0.05).
      CONCLUSION: The DNA damage of O3 animal model is consistent with that of natural
      aging animal; this animal model DNA damage of O3 animal model is consistent with
      that of natural aging animal; this animal model and the method of SCGE are useful
      for future researches on aging and antiaging medicine.

PMID- 12600094
TI  - [The effect of fluid shear stress on the proliferation of rat primary osteoblast
      like cells in vitro].
AB  - OBJECTIVE: To inquire into the cellular mechanism by which mechanical stress
      regulates bone remodeling and make an attempt at establishing the most suitable
      physiological stress to stimulate bone formation. METHODS: The isolated rat
      primary osteoblast-like cells were exposed to fluid shear stress 2, 4, 8, 12, 14,
      17 and 19 dyn/cm2 for 60 min respectively in the flow chamber. The ability of
      proliferation of cells was studied by flow cytometry. RESULTS: After exposed to
      fluid shear stress, the cells rearranged and the cells' axes were elongated
      following the flow direction. The proliferation indexes (PI) of the cells went up
      with the gradual increase of shear stress. When fluid stress reached 12 dyn/cm2,
      the PI of cells increased significantly (P < 0.05), compared with the control.
      But the PI of cells began to decrease when the fluid stress continued to
      increase, and when fluid stress reached 14 dyn/cm2, the PI of cells decreased
      significantly (P < 0.01), compared with the control. CONCLUSION: The mechanism by
      which mechanical stress regulates bone remodeling is related to the proliferation
      of the osteoblast cells stimulated by stress-induced fluid flow. Low shear stress
      has no marked influence on the proliferation of cells. Medium shear stress (12
      dyn/cm2) can stimulate cells significantly. Major shear stress (14 dyn/cm2) can
      inhibit cells significantly.

PMID- 12600095
TI  - [Growth and osteogenesis characteristics of cultured rat marrow stromal cells
      under bone induction condition].
AB  - OBJECTIVE: To investigate the growth and osteogenesis characteristics of cultured
      rat marrow stromal cells(rMSCs) under bone induction condition. METHODS: rMSCs
      were isolated from adult rat using density gradient separation method. The rMSCs
      attachment formed soon after seeding and grew into colonies with the appearance
      of fibroblastic cells. The osteogenic induction compound of Dex(10(-8) mol/L),
      beta-GP(10 mmol/L) and AA(50 micrograms/ml) was added to different passaged rMSCs
      and the proliferation and osteogenic differentiation of them was observed.
      RESULTS: The induction compound had strong effect on promoting proliferation,
      especially on that of further passaged rMSCs, and its stimulation effect on
      osteogenesis was also well proved with the expression of alkaline phosphatase
      (ALP) rising after one-week induction. Further subculturing from P1 to P6 led to
      the increase of proliferation activity of rMSCs. After three-week induction,
      mineral deposits appeared in the culture. CONCLUSION: The lower expression of ALP
      in P1 rMSCs and the increase of it in further passages or under induction
      condition suggest the rMSCs in our culture system are mainly undifferentiated
      osteoprogenitors.

PMID- 12600096
TI  - [The effects of leptin on proliferation and function of human osteoblast].
AB  - OBJECTIVE: To observe the effect of leptin on osteoblast. METHODS: Human
      osteoblast primary culture was carried out, and the morphology and function of
      osteoblast were observed. The effects of different levels of leptin on osteoblast
      in different days were assessed by MTT colorimetry. Osteocalcin production was
      measured also. RESULTS: Human osteoblasts were fusiform in shape and were
      positive for alkaline phosphatase by histochemical staining, positive for
      osteocalcin by immunofluorescence staining, and positive by Alizarin Reds
      staining after mineralized upon supplementation with ascorbate and beta
      glycerophosphate. On the first, second and third days, the proliferation of
      osteoblast, cultured with different concentrations of leptin, had no changes. The
      leptin-stimulated synthesis of osteocalcin of cells was found to be dose
      dependent (P < 0.05), but not time-dependent (P > 0.05). CONCLUSION: The above
      data indicated that there were no evidences for the effects of leptin on the
      proliferation of human osteoblast, but leptin could enhance the function of human
      osteoblast.

PMID- 12600097
TI  - [Transforming growth factor-beta can induce differentiation of hypertrophic
      chondrocytes into osteoblast-like cells in epiphyseal plate].
AB  - OBJECTIVE: To investigate the effect of transforming growth factor-beta (TGF
      beta) on the differentiation of hypertrophic chondrocytes in epiphyseal plate in
      order to understand its role in the mechanism of bone and cartilage formation.
      METHODS: We observed the effect of TGF-beta in varied time and dosage on the
      differentiation of hypertrophic chondrocytes in embryonic chick femora which were
      cultured in serum-free medium, using histochemical staining to detect the
      expression of alkaline phosphatase (ALP) and immunohistochemical staining to
      detect the expression of type I collagen and fibronectin. RESULTS: TGF-beta
      enabled the chondrocytes to express type I collagen and fibronectin, and it
      enhanced the expression of ALP in hypertrophic zone. Time-effect and dosage
      effect relationships were observed. CONCLUSION: TGF-beta can induce the
      differentiation of hypertrophic chondrocytes into osteoblast-like cells in
      epiphyseal plate of embryonic chick femora. The inducing effect might be closely
      related to time and dosage of TGF-beta.

PMID- 12600098
TI  - [Factors that influence the quality of life of Sichuan population].
AB  - OBJECTIVE: To investigate the risk factors influencing quality of life with the
      aim of providing evidence for valid health promotion measures. METHODS: The
      authors used the short form 36 to assess the quality of life of 2249 residents in
      Sichuan Province. The data of potential risk factors including social economic
      status, culture, chronic condition and personal characteristics were collected.
      The Student t test, variance analysis, and stepwise multivariate regression
      methods were used to test the impacts of different risk factors on quality of
      life. RESULTS: Chronic condition, age, sex, educational level, marital status,
      occupation, personal income, number of family members, number of generation in a
      family, inhabitant places (urban or rural), and way of payment of medical
      expenditure were correlated with all or most of the domains of the short form 36
      in t-test or one-way variance analysis. When the effect of interaction between
      factors were excluded by use of multivariate regression, the chronic condition,
      personal income, inhabitant places, age, and educational level remained to be
      significant risk factors. Marital status also had impacts on a few domains.
      CONCLUSION: The key steps of promoting the quality of life should include the
      prevention and control of chronic conditions, the development of economy, and the
      improvement of people's income and educational level. It is necessary to provide
      norms of the short form 36 stratified by inhabitant's place and age. Further
      research would be needed to provide evidence for the necessity of norms
      stratified by sex.

PMID- 12600099
TI  - [Assessing the quality of life of people with chronic diseases using SF-36].
AB  - OBJECTIVE: To analyze the influence of chronic diseases on the quality of life by
      using short form of 36 (SF-36). METHODS: Four hundred and thirty-eight people
      with chronic diseases were surveyed in a township and a city in Sichuan Province.
      The diseases were classified according to ICD-9 and the quality of life of people
      with chronic diseases of different systems was analyzed. RESULTS: The quality of
      life of people with chronic diseases of different systems was lower than that of
      general people aged 40 or above. The quality of life varied among people with
      chronic diseases of different systems in four fields, namely PF, SF, VT and MH.
      The main diseases that influenced the quality of life were mental disorders,
      infectious and parasitic diseases, the diseases of blood and blood-forming
      organs. CONCLUSION: The chronic diseases have decreased the quality of life. The
      diseases of different systems have had different influences on the quality of
      life. SF-36 is suitable for assessing the quality of life of people with chronic
      diseases. Quality of life should be taken as an important health index in chronic
      disease control and prevention.

PMID- 12600100
TI  - [The psychological effect of clinical examination on women with tubal
      infertility].
AB  - OBJECTIVE: To comprehend the psychological effects in the course of diagnosis and
      treatment of infertility on the sexuality, emotional feeling and marriage of
      women with tubal infertility. METHODS: The study involved 180 hospitalized
      patients who were awaiting tube operation from May to September in the year 2000.
      A survey was made by using questionnaire about sexuality, emotional feeling and
      marriage after infertility examinations. RESULTS: The sexual intercourse
      frequency of 46.2% infertile women decreased and no influences on sexual living
      satisfaction were confirmed during basal body temperature (BBT) examination.
      92.3% to 93.2% of the infertile women were sad after hysterosalpingography(HSG)
      and laparoscopy. 78.9% of them felt remorse when the result of semen examination
      was normal. 56.6% of them would choose in vitro fertilization and embryo
      transfer(IVF-ET); 38.9% of the infertile couples' wedlock would not be stable and
      10.5% of them would be divorced in the case of continuing infertility 2 years
      after tube operation. CONCLUSION: Sexual intercourse in almost half of the
      infertile couples decreased during BBT examination. Most infertile women became
      sad when they were informed of the abnormal results of HSG and laparoscopy and
      the normal results of semen analysis.

PMID- 12600101
TI  - [Biological assessment of sintered titanium alloy for dental crown and bridge by
      means of slip casting].
AB  - OBJECTIVE: To evaluate the biological safety of sintered titanium alloy for
      dental crown and bridge, and provide a sound scientific basis for dental clinical
      practice. METHODS: A series of tests, including acute toxicity test, cytotoxity
      test (agar overlay), sensitization test, oral mucous membrane irritation test,
      haemolysis test and micronucleus test were conducted to examine the dental
      crown/bridge-used titanium alloy which is processed with vacuum-sintered powder
      metallurgy. RESULTS: The haemolysis rate of this material was 2.21% (less than
      5%), an index of good blood compatibility. Cytotoxic effect was not observed in
      cell culture, nor was toxic effect observed in mouse toxicity test. Local mucous
      membrane irritation reaction was not found. No potential mutagenicity of this
      material was noted. CONCLUSION: Dental crown/bridge-used titanium alloy material
      is of reliable was noted biological safety in dental clinical application.

PMID- 12600102
TI  - [Bonding and mechanical interlocking of three kinds of luting cements in
      retention of complete metal crowns].
AB  - OBJECTIVE: To evaluate the effects of bonding and mechanical interlocking of
      three kinds of luting cements in the retention of complete metal crowns. METHODS:
      Zinc phosphate cement (ZP), glass ionomer cement (GI) and polycarboxylate cement
      (PC) are in common use for clinical treatment. In this study, these cements were
      selected to bond the complete crowns to molars in vitro. The retention capacities
      of the complete crowns were tested and compared. And apart from mechanical
      interlocking, the effect of bonding was tested. On this basis the interlocking
      capacity of the cement was calculated. RESULTS: 1. The retention capacities of
      complete metal crowns from the highest to least were: GI > ZP > PC. 2. The
      proportions of mechanical interlocking of ZP, GI and PC in the retention of
      complete metal crowns were 62.6%, 48.3% and 20.1% and the ratios of bonding of
      ZP, GI and PC were 37.4%, 51.7% and 79.9%, respectively. CONCLUSION: The effects
      varied with different cements in the retention of complete metal crowns because
      of the discrepancy in bonding and mechanical interlocking properties. Mechanical
      interlocking plays a prominent role when ZP or GI is used, and the role of
      bonding is apparent in PC.

PMID- 12600103
TI  - [Characterization of alumina adobe and sintered body of GI-infiltrated ceramic].
AB  - OBJECTIVE: This study was conducted to elucidate the mechanism of formation of
      porous structure by investigating the porosity of the alumina adobe and sintered
      body of GI-II Infiltrate Ceramic, and its role in strengthening and toughening
      this kind of ceramic composite. METHODS: The alumina powder size-mass
      distribution was obtained by BI-XDC powder size analysis device; the open pore
      parameters of alumina adobe and sintered body were analyzed using the mercury
      pressure method. Their fracture surfaces were observed under scanning electronic
      microscope. RESULTS: Fine powder had two main size groups of 0.09-0.1 micron and
      0.2-0.5 micron, respectively, and coarse powder, with size between 1.5 to 4.5
      microns, occupied the majority of powder mass. Alumina adobe's pores became
      larger after sintering. The median pore radii of adobe and sintered body were
      0.2531 micron and 0.3081 micron, respectively; the average pore radii changed
      from 0.0956 micron to 0.1102 micron. Under scanning electronic microscope, fine
      alumina powders were fused partially together and their surfaces were blunted,
      but coarse powders did not show such phenomena. CONCLUSION: The alumina size
      distribution contributes to the formation of porous structure of alumina sintered
      body. This porous structure is not only the shape skeleton but also the
      mechanical skeleton of GI-II Infiltrated Ceramic. It plays an important role in
      raising the mechanical properties of this kind of ceramic composite.

PMID- 12600104
TI  - [Effect of decreased bite force on the temporal and spatial expression of type I
      collagen mRNA in rat molar periodontal ligament].
AB  - OBJECTIVE: The aim of this study was to observe the effect of decreased bite
      force on type I collagen mRNA in periodontal ligament (PDL) and probe into the
      molecular mechanism of the change in type I collagen mRNA. METHODS: Animal models
      were established by extracting left maxillary molars of rats. In situ
      hybridization was applied. RESULTS: The results showed that under decreased bite
      force, the expression level of type I collagen mRNA decreased at the sixth hour
      (49.7 +/- 11.1) (P < 0.05), reached the nadir on the second day (23.7 +/- 8.6),
      began to get over on the third day (43.1 +/- 10.3), and reached a relatively high
      level at the second week(56.3 +/- 9.8), but it was still lower than that of the
      normal bite force group (91.4 +/- 16.0)(P < 0.05); the expression of type I
      collagen mRNA near the cementum was higher than that near the alveolar bone.
      CONCLUSION: These results indicate that the expression level of type I collagen
      mRNA is closely related to bite force.

PMID- 12600105
TI  - [Effects of laser welding on ceramic fused to metal].
AB  - OBJECTIVE: This study was aimed to investigate the bonding effect of laser
      welding on ceramic fused to metal. METHODS: Ten laser welded CW-PA ceramo-alloy
      rods were fused with porcelain at fusion zone. The porcelain-metal bond strength
      was measured with pull-through test. SEM examination and EDAX analysis were
      performed. Ten non-welded CW-PA ceramo-alloy pull-rod plates were used as
      comparison. RESULTS: The results showed that the bond strength of laser welded
      sample was 41.32 +/- 6.69 MPa, approaching to 45.71 +/- 9.98 MPa of the non
      welded sample (P > 0.05). The microscope displayed the interface compacted union
      of the two phase boundary. There was no change in the elements and their ratio at
      the fusion zone. CONCLUSION: These results indicate that laser welding does not
      affect ceramic fused to metal.

PMID- 12600106
TI  - [The effects of ethanol on neuromuscular junctions of adult toad].
AB  - OBJECTIVE: To investigate the effects of ethanol on the transmission at the
      neuromuscular junctions(NMJ) and the possible mechanism thereby. METHODS: The
      effects of ethanol on the endplate potential (EPP) and miniature endplate
      potential(MEPP) of sciatic nerve-sartorious muscle preparations of 20 adult toads
      (Bufo bufo gargarizans) were studied in vitro by means of intracellular
      microelectrode recording. RESULTS: Ethanol could cause the changes in EPP
      amplitude so as to influence the transmission at NMJ, and the effects apparently
      depended on the concentration of the ethanol. A proper concentration of ethanol
      could produce a significant increase in EPP amplitude and therefore facilitate
      the transmission at the NMJ. A proper concentration of ethanol also could produce
      a significant increase in MEPP frequency but had no influence on MEPP amplitude.
      CONCLUSION: Ethanol can increase the quantal number of transmitters released from
      presynaptic part. That may be one of the reasons why ethanol can facilitate the
      transmission at the NMJ.

PMID- 12600107
TI  - [Correlation of JNK/SAPK activity and the production of ICAM-1 on renal mesangial
      cells in vitro].
AB  - OBJECTIVE: To observe the activity of c-Jun N-terminal kinase/stress-activated
      protein kinase (JNK/SAPK) and assess the correlation between JNK/SAPK activity
      and ICAM-1 expression on mesangial cells in mesangial proliferative
      glomerulonephritis(MSPGN). METHODS: Seven patients with MSPGN and 6 controls were
      selected for this study. JNK/SAPK activity was detected by immunoprecipitation
      and western blotting; RT-PCR was used to detect ICAM-1 mRNA expression, and flow
      cytometry was used to analyze cell surface ICAM-1 expression. RESULTS: Either in
      spontaneous condition or under the stimulus of TNF alpha, the activity of
      JNK/SAPK on mesangial cells in vitro in MSPGN was higher than that of the
      controls(P < 0.05); the activity of JNK/SAPK in MSPGN was found to have a
      positive correlation with the levels of ICAM-1 mRNA and protein. The levels of
      ICAM-1 mRNA and protein were increased by TNF alpha stimulation while the levels
      ICAM-1 mRNA and protein were decreased by DMAP inhibition (P < 0.01). CONCLUSION:
      JNK/SAPK may have been aberrantly activated in MSPGN, which may involve in the
      overexpression of ICAM-1 in MSPGN.

PMID- 12600108
TI  - [The effects of quercetin and isorhamnetin on oxidative modification of VLDL
      induced by Cu2+].
AB  - OBJECTIVE: To observe the effects of quercetin(Que) and isorhamnetin (Iso) on the
      oxidative modification of very low density lipoprotein (VLDL). METHODS: Human
      VLDL was prepared by one-step ultracentrifuge and oxidized by Cu2+ in vitro; Que
      and Iso in different concentrations were added to VLDL before incubation with
      Cu2+. The MDA, vitamin E contents and the activity of superoxide dismutase(SOD)
      in ox-VLDL were determined. RESULTS: Compared with ox-VLDL group, Que and Iso
      decreased MDA production in a dependent concentration-manner, Que and Iso also
      elevated Vit E level and SOD activity markedly. CONCLUSION: This experiment
      indicates that Que and Iso have similar inhibitory effects on the oxidative
      modification of VLDL.

PMID- 12600109
TI  - [Studies on the triterpenoidal saponins from flowers of Eriobotrya japonica].
AB  - OBJECTIVE: To investigate the chemical composition of the flowers of Eriobotrya
      japonica. METHODS: Four constituents were isolated from the ethanolic extracts of
      flowers of Eriobotrya japonica (Thunb) Lindl and were identified by chemical
      methods and spectroscopic (IR, MS, 1HNMR, 13CNMR). RESULTS: The structures were
      identified as: Oleanolic acid (I), Ursolic acid(II), 2 alpha, 3 alpha, 19 alpha
      Trihydroxyurs-5,12-dien-28-acid (III) and 2 beta, 3 beta, 23 alpha
      Trihydroxyolean-12-en-28-acid (IV). CONCLUSION: The compounds I, II, III and IV
      were obtained from the flowers of Eriobotrya japonica for the first time.

PMID- 12600110
TI  - [Effects of isocarbophos on the integrity of epidermic cell membrane of human
      skin].
AB  - OBJECTIVE: To investigate the effects of isocarbophos, a new and highly effective
      organophosphorus pesticide on the membranes of keratinocytes. METHODS: The
      epidermic cells of human skin cultured in the medium were adopted as a biological
      material. The activity of lactate dehydrogenase (LDH) was used as an indicator.
      We tested the activities of LDH and alkaline phosphatase (ALP) in the medium in
      different isocarbophos dosage conditions. RESULTS: It was found that the activity
      of LDH in the medium decreased with the increase of isocarbophos dosage. The LDH
      activities of the dosage groups were statistically different from those of the
      positive and negative groups. The ALP activities were of no significant
      difference between the groups. CONCLUSION: The above findings reveal that
      isocarbophos does not damage the membranes of keratinocytes directly, however it
      inhibits the LDH of human skin keratinocytes; thus it is suggested that
      isocarbophos like most organophosphorus pesticides used widely can pass through
      the intact human skin and poison the body before the skin is damaged. Therefore,
      protection during work hours is of paramount importance.

PMID- 12600111
TI  - [Relations of electrolytes to the by-product CHCl3 produced in electrochemical
      disinfection].
AB  - OBJECTIVE: To investigate the relation of electrolytes(NaCl, Na2SO4) to the by
      product CHCl3 produced in the electrochemical disinfection process. METHODS:
      Taking filtering water, we used the graphite and Ti (matrix)-Ti as electrodes,
      adjusted the current sample for analysis in different time, and determined the
      production of CHCl3 under different conditions. RESULTS: Na2SO4 had no effect on
      the production of CHCl3 in the electrolysis(P > 0.05). but NaCl had the effect
      and the higher the concentration of Cl- was, the more the production of CHCl3
      increased. The production of CHCl3 increased with the length of electrolysis
      time, and it exceeded the national standard after 10 minutes' electrolysis using
      Ti (matrix)-Ti as electrodes. When graphite was used as electrodes, the
      production of CHCl3 was much less. CONCLUSION: Na2SO4 has no effect on the
      production of CHCl3. Our suggestion is that graphite should be used as the
      electrodes for electrochemical disinfection of drinking water.

PMID- 12600112
TI  - [Randomized controlled trial for the effect of amrinone and aprotinin on
      proinflammatory cytokine release in patients with prosthetic valve replacement
      during perioperative period].
AB  - OBJECTIVE: To explore the effect of amrinone and aprotinin on whole-body
      inflammatory response in the patients with prosthetic valve replacement during
      perioperative period. METHODS: 24 patients undergoing prosthetic valve
      replacement were randomized to control group (group A, n = 8), aprotinin group
      (group B, n = 8) and amrinone combined with aprotinin group (group C, n = 8). In
      the aprotinin group, 3 x 10(6) of aprotinin was added to the priming solution of
      the extracorporeal circulation (ECC). In the amrinone combined with aprotinin
      group 3 x 10(6) of aprotinin was added to the priming solution of the ECC and
      amrinone began with a bolus of 1 mg/kg followed by a maintenance infusion of 8
      micrograms/(kg.min). The control group received an equivalent prime volume
      without aprotinin. Venous blood samples were drawn before the operation, at the
      end of ECC, 1 hour after the end of ECC, and one day after the operation
      respectively. Enzyme-linked immunosorbent assay techniques were used to measure
      each of the cytokines. RESULTS: Before ECC, there were no differences of the
      levels of IL-6 and IL-8 among groups (P > 0.05). After ECC, the levels of IL-6
      and IL-8 increased significantly in all groups (P < 0.05). The levels on day one
      after the operation were still higher than those before the operation in all
      groups (except the level of IL-8 in group C), but no statistical significance was
      observed. (P > 0.05). At 1 hour after the end of ECC, the level of IL-6 in group
      B was lower than that in group A, and the level of IL-6 in group C was lower than
      that in group B, but there was no statistically significant difference (P >
      0.05); At the end of ECC, the level of IL-8 in group B was lower than that in
      group A and the level of IL-8 in group C was lower than that in group B, but no
      significant difference was noted (P > 0.05). It was also observed that the level
      of IL-8 was lower in group C than group A or B at 1 hour after the end of ECC.
      CONCLUSION: Although amrinone and aprotinin have antiinflammatory activity, but
      pump prime only aprotinin or aprotinin combined with amrinone may fall in
      preventing proinflammatory cytokine release (IL-6, IL-8) completely in patients
      with prosthetic valve replacement during ECC perioperative period.

PMID- 12600113
TI  - [The risk of sustained amenorrhea in patients with systemic lupus erythematosus
      receiving intermittent pulse cyclophosphamide therapy].
AB  - OBJECTIVE: To determine the risk of sustained amenorrhea in premenopausal women
      with systemic lupus erythematosus (SLE) receiving intermittent pulse
      cyclophosphamide (CTX) therapy. METHODS: Prospectively comparing the amenorrhea
      rate of 51 cases receiving intermittent pulse cyclophosphamide therapy versus
      that of 22 cases receiving intermittent pulse methylprednisolone (MP) therapy.
      RESULTS: The amenorrhea rate was higher in the CTX group (19.6%) than in the MP
      group (P = 0.025). In the CTX group, the amenorrhea rate of patients aged over 30
      was higher than that of patients aged 30 or below 30 (P = 0.0018). CONCLUSION:
      Pulse CTX therapy in fertile women with SLE is associated with increased rate of
      sustained amenorrhea, and the older the patient is, the higher risk for sustained
      amenorrhea the patient runs.

PMID- 12600114
TI  - [Study on gastric motility and its relevant factors in type 2 diabetes].
AB  - OBJECTIVE: In this study radionuclide semi-liquid gastric emptying (GE) study was
      adopted to test the gastric motility in 129 patients with type 2 diabetes.
      Further study was made to explore the relationship between gastric motility
      disorder of diabetes and the influential factors. METHODS: The variables to be
      measured and analyzed were age, BMI, duration of illness, level of glycemia,
      HbAlc, plasma insulin, motilin, gastrin, glucagon and Mg2+. RESULTS: Of the 129
      cases, 80 had delayed GE with an occurrence of 62.02%, and there was a close
      correlation between gastric motility disorder and the duration of illness, BMI,
      FPG, PPG, serum insulin, motilin levels and HbAlc as well. CONCLUSION: These
      findings imply that gastric motility disorder of diabetes is influenced by
      multiple factors. The results also suggest that gastric motiligy disorder is much
      more common than expected, and radionuclide gastric emptying test is a useful aid
      for the early detection of this clinical entity.

PMID- 12600115
TI  - [A therapeutical approach by administering reduced glutathione to patients with
      uremic anemia].
AB  - OBJECTIVE: To verify the therapeutical effect of exogenous reduced glutathione
      (GSH) on the patients with uremic anemia. METHODS: Forty two patients with uremic
      anemia were randomly divided into treatment group and control group. All patients
      received subcutaneously recombinant human erythropoietin (r-HuEPO) at the dose of
      3000U twice a week for 12 weeks. Each of the patients in the treatment group was
      given intravenously reduced glutathione at the dose of 1200 mg twice a week for
      12 weeks. The measurements of hemoglobin, red blood cells and hematocrit were
      performed. RESULTS: After administration of r-HuEPO, the levels of hemoglobin,
      red blood cells and hematocrit were significantly elevated in both treatment and
      control groups (P < 0.01). The levels of hemoglobin, red blood cells and
      hematocrit in treatment group were elevated much more obviously, compared with
      those in control group (P < 0.05). CONCLUSION: These findings seem to indicate
      that exogenous GSH could enhance the effect of r-HuEPO on uremic anemia, and
      therefore it might represent a useful drug in the treatment and management of
      uremic anemia.

PMID- 12600116
TI  - [Polycystic ovaraian syndrome and hyperinsulinemia].
AB  - OBJECTIVE: To identify the relationship between polycystic ovarian syndrome and
      hyperinsulinemia. METHODS: Age, body height, body weight, serum estradiol,
      progesterone, testosterone, follicle stimulating hormone (FSH), luteinizing
      hormone (LH), prolactin (PRL), triiodothyronine (T3), tetraiodothyronine (T4),
      insulin, oral glucose tolerance test (OGTT), and cortisol were measured in 28
      patients with polycystic ovarian syndrome (PCOS). RESULTS: Sxiteen patients
      (57.1% of total) had hyperinsulinemia. Among them one patient was found diabetic.
      No difference was noted in age, height, body weight, body mass index, serum
      estradiol, progesterone, testosterone, FSH, LH, PRL, T3, T4, cortisol, and
      glucose of OGTT between hyperinsulinemia and non-hyperinsulinemia patients.
      However the LH/FSH ratio (2.4 +/- 1.5) in hyperinsulinemia patients was
      significantly higher than 1.2 +/- 0.6 in non-hyperinsulinemia patients (P =
      0.0125). In addition, the results showed that the fasting serum insulin, insulin
      after OGTT, the insulin/glucose ratio at 30, 120 minutes, 180 minutes, the area
      under curve of and the insulin, insulin resistant index (IRI) were higher in
      hyperinsulinemia pateints than in non-hyperinsulinemia patients respectively.
      Furthermore, the fasting insulin level, insulin/glucose ratio were found to be
      negatively related to insulin sensitivity index and positively related with beta
      cell functioning index. CONCLUSION: Hyperinsulinemia and insulin resistance
      accompany with some of the PCOS patients in China. Further investigations will be
      necessary to clarify the relevant mechanisms.

PMID- 12600117
TI  - [The relationships of the serum concentrations of insulin-like growth factors in
      fetal rats with intrauterine growth retardation].
AB  - OBJECTIVE: To observe the alterations of serum insulin-like growth factor-I,-II
      (IGF-I, IGF-II) in rat fetus and to investigate the relationship of serum IGFs
      with intrauterine growth retardation (IUGR). METHODS: 21 pregnant SD rats were
      randomly divided into control group (n = 9) and experimental group (IUGR group, n
      = 12). On day 14 of gestation, the bilateral uterine arteries and veins of
      experimental group were clamped for 20 minutes to build the rat IUGR models and
      sham surgeries were performed on control group. Fetal serum concentrations of
      IGFs, birth weight, the length and weight of fetal liver, lung, brain and
      placenta of all rats in the two groups were measured and compared. RESULTS: The
      serum concentrations of IGF-I,-II of IUGR group were 117.92 +/- 26.58 ng/ml and
      223.19 +/- 33.35 ng/ml, respectively, which were significantly lower than those
      of control group (234.43 +/- 70.65 ng/ml and 397.74 +/- 23.69 ng/ml,
      respectively, P < 0.01). Likewise, birth weight, the length and weight of liver,
      lung, brain and placenta in IUGR group were significantly lower than those in
      control group (P < 0.05). CONCLUSION: The decrease of fetal serum concentrations
      of IGF-I,-II may be one of the internal factors contributing to fetal IUGR, and
      IGFs may play an important role in fetal growth.

PMID- 12600118
TI  - [A study of prognostic factors of stage IV epithelial ovarian cancer].
AB  - OBJECTIVE: To determine the effects of treatments for stage IV epidermal ovarian
      cancer and detect the prognostic factors. METHODS: 31 cases primarily treated in
      our hospital from 1990 to 1998 were analyzed retrospectively. RESULTS: Univariate
      analysis showed that the number of courses of chemotherapy, the size of residual
      disease, the histologic cell type, and the metastatic site were the significant
      prognostic factors(P < 0.05). Cox proportional hazard model confirmed that two
      factors (the size of residual lesion < or = 2 cm and the cycles of chemotherapy >
      or = 8 decreased the death odds ratio by 0.28 and 0.72 respectively. Three
      factors (lack of operation, presence of supraclavicular lymph node involvement
      and liver involvement) increased the death odds ratio by 14.25 times, 11.44 times
      and 1.85 times respectively (P < 0.05). CONCLUSION: Surgical debulking,
      aggressive and appropriate chemotherapy are important measures to improve
      survival rate for patients with stage IV epithelial ovarian cancer.

PMID- 12600119
TI  - [Effects of gliclazide on blood rheology of diabetes Wistar rat].
AB  - OBJECTIVE: To assess the effects of Gliclazide on blood rheology of alloxan
      induced diabetes Wistar rats. METHODS: Four weeks after the establishment of the
      animal models, Gliclazide was given to the rats by gastrogarage for 8 weeks. A
      comparison was made on the hemorrheologic parameters between the control group
      and the study group. Also a comparative analysis of the study group befor and
      after the administration of Gliclazide was performed. RESULTS: All of the
      parameters related to the blood rheology of alloxan-induced diabetes Wistar rats
      showed significance differences in the controlled comparison and the before-and
      after comparison (P < 0.05). CONCLUSION: Gliclazide can obviously improve the
      blood rheology of diabetic Wistar rats.

PMID- 12600120
TI  - [The photostability of hydrocortisone injection].
AB  - OBJECTIVE: This experiment was designed to make known wether the photostability
      of drugs in daylight can be obtained from lamplight exposure. METHODS: A self
      made cumulative illuminometer via pulse counting method was used for measuring
      cumulative illuminance of daylight to investige the photodegradation of
      Hydrocortisone injection in various lamp light and daylight; the equivalent
      influences of different light sources on the photostability of the injection were
      obtained, and the shelf-life in indoor daylight of the drug was predicted.
      RESULTS: The photodegradation of Hydrocortisone injection obeys zero order
      kinetics: C = C0-kEt; the shelf-life in indoor daylight of the injection in nude
      ampoules was predicted as 36 days and is comparable to 35 days in a long-term
      storage test. CONCLUSION: The photostability of drugs in daylight can be obtained
      from lamplight exposure experiment.

PMID- 12600121
TI  - Not a job for outsiders.

PMID- 12600122
TI  - Through the gate. Progress along the proposed new pay scales will be linked to a
      knowledge and skills framework.

PMID- 12600123
TI  - About time. Will Agenda for Change put an end to unpaid overtime?

PMID- 12600124
TI  - Get to the details.

PMID- 12600125
TI  - Debt trap.

PMID- 12600126
TI  - Plan early, retire happy.

PMID- 12600127
TI  - Peaceful night?

PMID- 12600128
TI  - Implantable cardioverter defibrillators: developing evidence-based care.
AB  - BACKGROUND: In the UK, access to psychological support for people with
      implantable cardioverter defibrillators (ICDs) is arbitrary, despite the fact
      that the National Institute for Clinical Excellence (NICE) recognises that the
      provision of adequate support can positively affect recovery. The author
      evaluates the available literature. CONCLUSION: This review identifies that,
      although a lot of information is available about the effects of ICD technology on
      patients, there have been few systematic evaluations of care interventions that
      aid adjustment to living with an ICD. Equally, it has not yet been established
      whether nurses are equipped to effectively assess and meet the complex care needs
      of this patient population. The development and evaluation of national standards
      of care, in association with ICD patients and their families, is recommended.

PMID- 12600130
TI  - Safe work environments workshop.

PMID- 12600129
TI  - Prevention of constipation through risk management.
AB  - Constipation is a common problem for patients in community and hospital settings.
      It can have significant personal costs for individuals, including discomfort,
      pain, reduced quality of life and other serious physical complications. The
      author explores the prevention of constipation using a risk assessment approach.

PMID- 12600131
TI  - Health plan for Texas: 12 goals. Measurable impact by 2010.

PMID- 12600132
TI  - All that wheezes isn't asthma.... But most that does is!

PMID- 12600133
TI  - A 2-year-old boy with fever and a limp.

PMID- 12600134
TI  - Management of asthma.

PMID- 12600135
TI  - Asthma in the school-aged child.
AB  - Understanding the role of inflammation in childhood asthma has led to major
      changes in the approach to management of this disease. Based on the guidelines
      from the NIH, inhaled long-term control medications that target the underlying
      inflammatory processes in asthma are now recommended as the mainstay of drug
      treatment. Long-term control medications are recommended for all children who
      have asthma symptoms that occur more frequently than twice weekly or nocturnal
      symptoms more than twice monthly. Environmental control measures to decrease
      allergen exposure are important, as is attention to sinusitis and GER. The main
      impediment to improved asthma care is poor patient compliance. Many patients do
      not understand the role and importance of prophylactic medications in asthma
      treatment. Further, inconvenient dosing regimens, difficulties with metered-dose
      inhalers, and fear of potential side effects have all contributed to poor patient
      compliance. Increased efforts at patient education are needed to improve
      adherence to asthma plans. These efforts at improving patient compliance, along
      with improved physician adherence to the guidelines from the NIH, are needed to
      decrease the morbidity and mortality of childhood asthma.

PMID- 12600136
TI  - The wheezing infant: diagnosis and treatment.

PMID- 12600137
TI  - Environmental indoor allergens.

PMID- 12600138
TI  - Asthma delivery devices: age-appropriate use.

PMID- 12600139
TI  - [Renewed and recognizable].

PMID- 12600140
TI  - [Health in the global world].

PMID- 12600141
TI  - [Your problem is my problem].

PMID- 12600143
TI  - [Estrogen therapy in menopause--attitudes and practice patterns].

PMID- 12600142
TI  - [Absolute indications or absolute contraindications seldom appear in medicine.
      Disadvantage or advantage?].

PMID- 12600144
TI  - [Are women underrepresented in medical research projects?].

PMID- 12600145
TI  - [Sleep and development of children and adolescents].

PMID- 12600147
TI  - [Pathology archives--new perspectives on stored tissue material].

PMID- 12600146
TI  - [Acute renal failure during the treatment of heart failure with ACE inhibitors].

PMID- 12600148
TI  - [Research activities within different specialties in Northern Norway].

PMID- 12600149
TI  - [Is waiting time to a consultation with a neurologist shorter for those who don't
      give in?].

PMID- 12600150
TI  - [Cardiovascular adverse effects of cytostatic agents].

PMID- 12600151
TI  - [The total use theory and its significance for alcohol policy].

PMID- 12600152
TI  - [Obligations of health services in work with substance abuse].

PMID- 12600153
TI  - [Alcohol abuse--what are the consequences for family members?].

PMID- 12600154
TI  - [In the beginning there was not the word].

PMID- 12600155
TI  - [Medical truth, what is it?].

PMID- 12600156
TI  - [The intervention center--a tool-box for medicine and technology].

PMID- 12600158
TI  - [Absinthe and the artistic creativeness].

PMID- 12600157
TI  - [HIV/AIDS--a disaster for Africa].

PMID- 12600159
TI  - [Absolutely not true and relatively true about risk reduction].

PMID- 12600160
TI  - [Postpartum hemorrhage and routine prophylaxis].

PMID- 12600161
TI  - [Need of beds in departments of internal medicine].

PMID- 12600162
TI  - [Different advice about non-medical malaria prophylaxis].

PMID- 12600163
TI  - [Pilocarpus in Sjogren's syndrome].

PMID- 12600164
TI  - [The society for control of the filth?].

PMID- 12600165
TI  - [Reorientation therapy is professionally and ethically inexcusable].

PMID- 12600166
TI  - On the fast track to privacy rule compliance.

PMID- 12600167
TI  - Tackling the training mandate. How to get your work force privacy training under
      control and under way.

PMID- 12600168
TI  - Restriction requests pose new challenges. HIM departments should prepare now for
      patient queries.

PMID- 12600169
TI  - By line, by hour: keeping the transcription machine running.

PMID- 12600170
TI  - Success at every level: a career ladder for privacy officers.

PMID- 12600171
TI  - Professional practice solutions...record completion policies.

PMID- 12600172
TI  - Teach your attorney healthcare contracting.

PMID- 12600173
TI  - Practice Brief. Using benchmarking for performance improvement.

PMID- 12600174
TI  - Protecting verbal PHI: a plan.

PMID- 12600176
TI  - The elements of electronic note style.

PMID- 12600177
TI  - Diverse local group collaborates on compliance issues. Workgroup focuses on code
      sets, transactions.

PMID- 12600178
TI  - Major changes for heart failure codes in 2003.

PMID- 12600179
TI  - [Serum level and urinary excretion of RANTES in patients with primary
      glomerulonephritis].
AB  - Proteinuria plays a central role in the progression of glomerular disease, and
      there is growing evidence suggesting that it may determine tubular cell
      activation with release of proinflammatory chemokines and fibrogenic factors,
      leading to interstitial inflammatory reaction. Chemokines are proteins that
      contribute to the migration of leukocytes to sites of tissue injury. C-C
      chemokine receptor 5 is receptor for the C-C chemokine RANTES, which is expressed
      in inflammatory kidney diseases. To better understand the role of RANTES in
      various types of human glomerular diseases, we studied 53 patients with primary
      glomerular diseases (5 minimal change--MC; 4 focal glomerulosclerosis--FS; 4
      membranous nephropathy--MN; 12--mesangial proliferative GN--MesPGN; 18 IgA
      nephropathy--IgAN; 6 membranoproliferative GN-MPGN, and 4 extracapillary GN-ExGN)
      and 10 healthy person. Renal biopsies were evaluated by light and
      immunofluorescence microscopy. RANTES concentrations in serum and urine were
      measured by ELISA (BIOSOURCE international kits). The treatment of patients
      consisted of 3 to 5 i.v. methylprednisolone pulses (1.0 g per single dose,
      average total 1.0 g/20 kg given alternate days) followed by oral prednisone 20 to
      25 mg/day and six monthly i.v. cyclophosphamide 0.6 g/l m2/month. The study
      groups (except FS) showed a significantly higher concentration of RANTES in their
      sera compared with the control. The increase of urinary excretion for RANTES was
      2-fold in patients with MN, and 8-fold in patients with ExGN but in patients with
      FS a significant decrease in urinary RANTES excretion was found. There was no
      significant differences in the urinary excretion of RANTES in other groups
      compared to a control group. In patient groups serum Cr showed significant
      correlations with interstitial volume in renal biopsy. No significant correlation
      was found between serum concentration of RANTES and their urinary excretion and
      other parameters considered (serum creatinine, urinary protein, serum protein
      concentration, and interstitial volume in renal biopsy). In patients with renal
      insufficiency (Cr > 1.3 mg%) and reduction of proteinuria > 50% after 1 year of
      treatment, the serum concentration and urinary secretion of RANTES was higher
      before treatment than in patients with protein reduction < 50%, and in patients
      with renal sufficiency. These results showed that patients with glomerular
      diseases who showed renal insufficiency and reduction of urinary protein after 1
      year of immunosuppressive treatment revealed high levels of serum and urinary
      excretion of RANTES. It was thus suggested that the measurement of serum and
      urinary excretion of RANTES is useful in evaluating the degree of renal injury in
      patients with glomerular diseases after immunosuppressive treatment.

PMID- 12600180
TI  - [Serum level and urinary excretion of soluble Fas (sFas) in patients with primary
      glomerulopathies].
AB  - Fas ligand (Fas-L) is a lethal cytokine that promotes apoptosis, as well as the
      immune and inflammatory responses through cross-linking of the Fas receptor.
      Soluble Fas (sFas) blocks apoptosis by inhibition of binding between Fas and Fas
      L or soluble Fas-L. The aim of the work was to investigate the prognostic
      significance and role of the serum levels and urinary excretion of sFas in
      various types of adult chronic primary glomerular diseases. We studied 53
      patients with primary glomerular diseases (5 minimal change--MC; 4 focal
      glomerulosclerosis--FS; 4 membranous nephropathy--MN; 12--mesangial proliferative
      GN--MesPGN; 18 IgA nephropathy--IgAN; 6 membranoproliferative GN--MPGN, and 4
      extracapillaris GN--ExGN) and 10 healthy persons. Renal biopsies were evaluated
      by light and fluorescence microscopy. Concentrations of sFas were measured by
      ELISA (BIOSOURCE international kits). The treatment of patients consisted of 3 to
      5 i.v. methylprednisolone pulses (1.0 g per single dose, average total 1.0 g/20
      kg given alternate days) followed by oral prednisone 20 to 25 mg/day and six
      monthly i.v. cyclophosphamide 0.6 g/l m2/month. The serum levels and urinary
      excretion of sFas in the patients with MC, and MN were similar to controls.
      However, the serum levels and urinary excretion of sFas were insignificantly
      elevated in patients with MesPGN, MPGN, FS, and ExGN, but significantly elevated
      in patients with IgAN as compared with control and patient groups. In patient
      groups serum Cr showed significant correlations with interstitial volume in renal
      biopsy, and urinary excretion of sFas, but serum levels of sFas with interstitial
      volume. Serum levels and urinary secretion of sFas in patients with renal
      insufficiency (Cr > 1.3 mg%) and reduction of proteinuria < 50% after 1-year
      treatment was higher before treatment than in another patient groups. These
      results suggest that increased serum and urinary excretion of sFas in
      proliferative glomerulonephritis PGN (particularly in IgAN) may inhibit apoptosis
      in glomeruli and may be one of the progressing factors in PGN.

PMID- 12600181
TI  - [Expression of p16INK4a, p15INK4b, p21WAF1/Clip1 cell cycle inhibitors on blastic
      cells in patients with acute myeloblastic leukemia (AML) and acute lymphoblastic
      leukemia (ALL) ].
AB  - Cyclin-dependent kinases (cdk) play the important role in neoplastic
      transformation. Their activity depends on interaction with proteins called
      inhibitors. There are two groups of inhibitors: INK4 (p16INK4a, p15INK4b,
      p18INK4c, p19INK4d) and proteins p21WAF1/Clip1, p27Kip1, p57Kip2. Alteration of
      inhibitors expression was assessed in acute lymphoblastic leukemia (ALL) and in
      acute myeloblastic leukemia (AML), but the results are not clear. The aim of our
      study was to estimate p16INK4a, p15INK-4b, p21WAF1/Clip1 expression in blast
      cells in patients with AML and ALL by cytochemistry method and to compare with
      the result of treatment. Forty-two patients were included in the study, 23 with
      AML and 19 with ALL. Expression of inhibitors was considered as positive when
      detected in > 5% of blast cells. Complete remission (CR) rate in patients with
      positive expression p16INK4a and p15INK4b was statistically significantly higher
      than in patients with negative expression: for p16INK4a chi 2 = 7.78, p < 0.01,
      for p15INK4b, chi 2 with Yates' modification = 3.94, p < 0.05. There was no
      difference in CR rate in patients with positive and negative p21WAF1/Clip1
      expression. Moreover the patients with simultaneous expression of three
      inhibitors reached CR more often than the others: chi 2 = 7.43, p = 0.01 for AML
      and chi 2 = 6.74, p < 0.01 for ALL. Our study indicates that estimation of
      p16INK4a, p15INK4b, p21WAF1/Clip1 expression in blast cells can be used as
      prognostic factor in acute leukemia.

PMID- 12600182
TI  - [Influence of insertion-deletion polymorphism of the angiotensin converting
      enzyme gene on left ventricular hypertrophy in patients with aortic stenosis-
      differences in men and women].
AB  - The role of different parameters (including genetic factors) on the timing and
      extend of left ventricle hypertrophy in patients with aortic stenosis is not
      defined. In our study we analyze the influence of clinical, echocardiographic
      parameters and I/D polymorphism of the angiotensin converting enzyme gene on the
      left ventricle hypertrophy (left ventricle mass index) in this group of patients.
      The study was done with the group of 302 pts with aortic stenosis--120 women and
      182 men; mean age 58 +/- 11 yrs. Stepwise (backward) regression was used to
      assess the influence of the analyzed parameters (age, gender, history of
      hypertension, EF, MGA, presence of significant coronary artery disease and I/D
      ACE polymorphism) on the LVH in the all pts and in the women and the men
      separately. In the whole group the LVMI depends on EF (t = -6.5; p = 0.0001-
      higher LVMI in lower EF), MGA (t = 3.9; p = 0.0001--higher LVMI in higher MGA)
      and gender (t = 2.8; p = 0.005--higher LVMI in men). In women LVMI was related
      with EF (t = -3.6; p = 0.001--higher LVMI in lower EF), age (t = 2.9; p = 0.004-
      higher LVMI in older pts) and MGA (t = 2.5; p = 0.013--higher LVMI in higher
      MGA). In men the LVMI depends on EF (t = -4.8; p = 0.0001--higher LVMI in lower
      EF) and MGA (t = 1.98; p = 0.049--higher LVMI in higher MGA). Significant
      relationship between LVMI and results of I/D ACE polymorphism was observed both
      in women and men. I/D polymorphism relationship with LVMI was divergent in these
      2 groups--association of higher LVMI with lack of DD type of polymorphism in
      women and presence of DD polymorphism in men. CONCLUSIONS: 1. Left ventricle
      hypertrophy in pts aortic stenosis is higher in men than in women. 2. In women
      left ventricle hypertrophy is related with ejection fraction, maximal aortic
      gradient, age and I/D ACE polymorphism; in men it is related to EF, MGA and I/D
      ACE polymorphism. 3. The influence of I/D ACE polymorphism on the left ventricle
      hypertrophy is divergent in women and men--in women related to the lack of DD
      polymorphism, in men related to the presence of DD polymorphism.

PMID- 12600183
TI  - [Seasonal profile of calcium-phosphate metabolism in hemodialysis patients with
      secondary hyperparathyroidism].
AB  - Sunlight UV plays an important role in synthesis of active vitamin D3. Vitamin D3
      concentration depends on seasonal sunlight exposure. It was not state, whether
      these changes may act on secondary hyperparathyroidism (SHP) in hemodialysis (HD)
      patients. The aim of our analysis was to assess the relationship between seasons
      and parameters of Ca-P metabolism in HD patients with SHP. We studied 30 pts (F =
      17, M = 13), aged 20-72 years (mean 49 +/- 13), duration of HD therapy 3-132
      months (mean 54.4 +/- 43.7), treated with alphacalcidol (1 alpha OHD3) due to
      SHP. Blood was collected for PTH, Ca, P concentrations in January (1), April
      (IV), July (VII) and October (X); also doses of CaCO3 and 1 alpha OHD3 were
      analyzed. The day duration was: 7 hours and 51 minutes (I), 12.53 (IV), 16.37
      (VII) and 11.39 (X), respectively. PTH concentration was significantly higher in
      I vs IV (882 +/- 588 vs 691 +/- 511 pg/ml, p < 0.05) and higher in X vs VII (831
      +/- 600 vs 701 +/- 525 pg/ml, p < 0.05), despite drug dosage did not differ.
      Calcium concentration was lower in I vs IV and X, and phosphate concentration was
      lower in I compared to IV, VII i X. These changes suggest presence of seasonal
      rhythm of PTH concentration in HD patients with SHP. When assessing the
      effectiveness of SHP therapy, the season of the year when PTH concentration was
      tested should be taken into account.

PMID- 12600184
TI  - [Expression of Fas receptor and soluble Fas ligand (sFasL) concentration in acute
      leukemia].
AB  - Apoptosis mediated by the interaction of cytotoxic T lymphocyte with blast cell
      via Fas receptor/Fas ligand (FasL) pathway is a one of the mechanisms of
      immunological leukemia surveillance. There is few data on possible blocking of
      Fas receptor by soluble form of Fas (sFasL) present in serum and the role of
      blast cells as the source of this ligand. Forty-eight patients with de novo
      diagnosis of acute leukemia, 32 with myeloblastic (AML) and 16 with acute
      lymphoblastic leukemia (ALL) were studied. Fas expression on bone marrow leukemic
      blasts was determined by flow cytomertic immunofluorescent analysis and serum
      concentration of sFasL assessed at presentation, in remission and in relapse.
      Blasts of all patients expressed Fas at variable degree (0.8 to 100%). Fas
      expression was significantly higher on myelo--than on lymphoblasts. There was no
      relation between degree of Fas expression at diagnosis and remission rate.
      Concentration of sFasL in acute leukemia patients at diagnosis was significantly
      higher than in healthy control group, decreased to normal values in remission and
      rose again in relapse. There was a negative correlation between Fas expression on
      blasts and sFasL concentration at the time of diagnosis. Results obtained suggest
      that blast cells could be the source of soluble FasL in acute leukemia patients
      and that sFasL serum concentration could be used for monitoring of disease
      activity.

PMID- 12600185
TI  - [Gastric emptying disorders in diabetes mellitus].
AB  - OBJECTIVE: 1. To find out the prevalence of gastroperesis and of accelerated
      gastric emptying in long-standing and recently diagnosed diabetic patients. 2.
      and to determine the relationship between the percentage of gastric retention of
      the test meal to the gastric symptoms, degree of metabolic control,
      cardiovascular autonomic neuropathy, and late diabetic complication. RESEARCH
      DESIGN AND METHODS: We studied the gastric emptying of technetium labeled
      digestible solid test meal in 81 diabetic patients (51 long-standing and 30
      recently diagnosed diabetic patients) and in 44 healthy controls. Diabetic
      patients were divided roto 2 groups according to the type and duration of
      diabetes. All patients were evaluated for gastric symptoms, glycemic control,
      peripheral neuropathy, retinopathy and cardiovascular autonomic neuropathy.
      RESULTS: Delayed gastric emptying was found in 21 long-standing diabetic patients
      and in 3 recently diagnosed type 2 diabetic patients. Accelerated gastric
      emptying was found in 10 patients mainly recently diagnosed type 2 diabetic
      patients. The rate of gastric emptying was related to CANP but not gastric
      symptoms or actual glycemic control. CONCLUSIONS: 1. Diabetics gastroparesis is a
      common disorder affecting both type 1 and type 2 long-standing diabetes mellitus
      in about 40% usually in the setting of late diabetic complications and can be
      manifested in recently diagnosed type 2 diabetes mellitus. 2. Accelerated gastric
      emptying is another gastrointestinal disorder manifested in about 20% of recently
      diagnosed diabetic patients (maimy type 2) but can be present in long-standing
      diabetic patients. 3. The rate of gastric emptying is related to cardiovascular
      autonomic neuropathy but not to gastric symptoms or actual metabolic control.

PMID- 12600186
TI  - [Whipple's disease as a complication of chronic lymphocytic leukemia treated with
      fludarabine].
AB  - The case of 53-year-old man who suffered from chronic lymphocytic leukemia since
      1993 was presented. In the 6th year of treatment fludarabine was administered.
      Few days after administration of drug the patient developed watery diarrhoea not
      responding to treatment. We excluded both infectious etiological factors and
      infiltration of intestine in course of chronic lymphocytic leukemia.
      Histopathological examination with monoclonal antibodies and periodic acid-Schiff
      stain (PAS) revealed Whipple's disease as the reason of enteropathy. During 6
      months diarrhoea caused extreme dyselectrolitemia, renal insufficiency and
      finally death of the patient.

PMID- 12600187
TI  - [The role of T helper lymphocytes population: Th1, Th2, and Th3 in human immune
      response].

PMID- 12600188
TI  - [The association between malnutrition, inflammation, and atherosclerosis in
      chronic renal failure].

PMID- 12600189
TI  - [Ischaemic heart disease in patients with systemic lupus erythematosus].

PMID- 12600190
TI  - [Role of receptor activator of nuclear factor kappa B (RANK), its ligand (RANK-L)
      and osteoprotegerin (OPG) in bone metabolism].

PMID- 12600191
TI  - [Role of growth hormone in cardiovascular diseases].

PMID- 12600192
TI  - Mechanistic considerations for general acid-base catalysis by RNA: revisiting the
      mechanism of the hairpin ribozyme.
AB  - Several small ribozymes carry out self-cleavage at a specific phosphodiester bond
      to yield 2',3'-cyclic phosphate and 5'-hydroxyl termini. Prior mechanistic and
      structural studies on the HDV ribozymes led to the proposal that the pK(a) of C75
      is shifted toward neutrality, making it an effective general acid. Recent
      mechanistic studies on the hairpin ribozyme have led to models in which
      protonation of G8 is required for phosphodiester cleavage, either for general
      acid catalysis or for electrostatic stabilization. Inspection of recent crystal
      structures of the hairpin ribozyme, including a complex with a vanadate
      transition state mimic, suggests an alternative model involving general acid-base
      catalysis with G8 serving as the general base and A38 as the general acid. This
      model is consistent with the literature on the hairpin ribozyme, including pH
      rate profiles of wild-type and mutant ribozymes and solvent isotope effects.
      General mechanistic considerations for RNA catalysis suggest that the penalty for
      having general acids and bases with pK(a)s removed from neutrality is not as
      severe as expected. These considerations suggest that general acid-base catalysis
      may be a common mechanistic strategy of RNA enzymes.

PMID- 12600193
TI  - The proton-translocating NADH-quinone oxidoreductase in the respiratory chain:
      the secret unlocked.

PMID- 12600194
TI  - A spring-loaded state of NusG in its functional cycle is suggested by X-ray
      crystallography and supported by site-directed mutants.
AB  - Transcription factor NusG is present in all prokaryotes, and orthologous proteins
      have also been identified in yeast and humans. NusG contains a 27-residue KOW
      motif, found in ribosomal protein L24 where it interacts with rRNA. NusG in
      Escherichia coli (EcNusG) is an essential protein and functions as a regulator of
      Rho-dependent transcription termination, phage lambda N and rRNA transcription
      antitermination, and phage HK022 Nun termination. Relative to EcNusG, Aquifex
      aeolicus NusG (AaNusG) and several other bacterial NusG proteins contain a
      variable insertion sequence of approximately 70 residues in the central region of
      the molecule. Recently, crystal structures of AaNusG in space groups P2(1) and
      I222 have been reported; the authors conclude that there are no conserved dimers
      among the contacting molecules in the crystals [Steiner, T., Kaiser, J. T.,
      Marinkovic, S., Huber, R., and Wahl, M. C. (2002) EMBO J. 21, 4641-4653]. We have
      independently determined the structures of AaNusG also in two crystal forms,
      P2(1) and C222(1), and surprisingly found that AaNusG molecules form domain
      swapped dimers in both crystals. Additionally, polymerization is also observed in
      the P2(1) crystal. A unique "ball-and-socket" junction dominates the
      intermolecular interactions within both oligomers. We believe that this
      interaction is a clue to the function of the molecule and propose a spring-loaded
      state in the functional cycle of NusG. The importance of the ball-and-socket
      junction for the function of NusG is supported by the functional analysis of site
      directed mutants.

PMID- 12600195
TI  - Functional evidence for an intramolecular side chain interaction between residues
      6 and 10 of receptor-bound parathyroid hormone analogues.
AB  - The N-terminal domain of PTH(1-34) is critical for PTH-1 receptor (P1R)
      activation and has been postulated to be alpha-helical when bound to the
      receptor. We investigated the possibility that the side chains of residues 6
      (Gln) and 10 (Gln or Asn) of PTH analogues, which would align on the same face of
      the predicted alpha-helix, could interact and thereby contribute to the PTH/P1R
      interaction process. We utilized PTH(1-11), PTH(1-14), and PTH(1-34) analogues
      substituted with alanine at one or both of these positions and functionally
      evaluated the peptides in cell lines (HKRK-B7 and HKRK-B28) stably expressing the
      P1R, as well as in COS-7 cells transiently expressing either the P1R or a P1R
      construct that lacks the amino-terminal extracellular domain (P1R-DelNt). In HKRK
      B7 cells, the single substitutions of Gln(6) --> Ala and Gln(10) --> Ala reduced
      the cAMP-stimulating potency of [Ala(3),Gln(10),Arg(11)]rPTH(1-11)NH(2)
      approximately 60- and approximately 2-fold, respectively, whereas the combined
      Ala(6,10) substitution resulted in a approximately 2-fold gain in potency,
      relative to the single Ala(6) substitution. Similar effects on P1R-mediated cAMP
      signaling potency and P1R-binding affinity were observed for these substitutions
      in [Aib(1,3),Gln(10),Har(11),Ala(12),Trp(14)]rPTH(1-14)NH(2). Installation of a
      lactam bridge between the Lys(6) and the Glu(10) side chains of
      [Ala(3,12),Lys(6),Glu(10),Har(11),Trp(14)]rPTH(1-14)NH(2) increased signaling
      potency 6-fold, relative to the nonbridged linear analogue. Alanine substitutions
      at positions 6 and/or 10 of [Tyr(34)]hPTH(1-34)NH(2) did not affect signaling
      potency nor binding affinity on the intact P1R; however, Ala(6) abolished PTH(1
      34) signaling on P1R-DelNt, and this effect was reversed by Ala(10). The overall
      data support the hypothesis that the N-terminal portion of PTH is alpha-helical
      when bound to the activation domain of the PTH-1 receptor and they further
      suggest that intrahelical side chain interactions between residues 6 and 10 of
      the ligand can contribute to the receptor interaction process.

PMID- 12600196
TI  - Overexpression of Mdm2 and MdmX fusion proteins alters p53 mediated
      transactivation, ubiquitination, and degradation.
AB  - Mdm2 and MdmX function as cellular regulators of the p53 tumor suppressor
      protein. Mdm2, a p53 inducible protein, negatively regulates p53 by inhibiting
      p53 transcriptional activity and promoting ubiquitin mediated proteasome
      degradation. The Mdm2 ring finger domain has been shown to possess E3 ligase
      activity and to be a necessary domain for targeting p53 degradation. MdmX, a p53
      binding protein sharing a high degree of structural homology with Mdm2, has
      emerged as another negative regulator of the p53 tumor suppressor. MdmX has also
      been shown to block p53 transactivation but unlike Mdm2 cannot induce p53
      degradation. Since MdmX also possesses a ring finger domain that allows MdmX to
      associate with Mdm2, this study focused on elucidating how the ring and zinc
      fingers of these two proteins affected p53 function. We have generated a series
      of fusion proteins between Mdm2 and MdmX by swapping the ring finger domains with
      or without the zinc finger domains and examined how these fusions regulated p53
      induced transactivation, ubiquitination, and degradation. All fusions inhibited
      the transcriptional activity of p53. In the absence of Mdm2, none of the fusion
      proteins could trigger p53 ubiquitination or degradation. However, in a cell line
      with endogenous Hdm2, Mdm2:X fusions containing the ring finger domain with or
      without the zinc finger domain demonstrated p53 ubiquitination presumably through
      stabilization of Hdm2. Additionally, an Mdm2:XZFRF fusion also degraded p53 when
      endogenous Hdm2 was present. Results from immunofluorescence studies suggest that
      p53 is colocalized to the cytoplasm when coexpressed with a Mdm2:X fusion
      (Mdm2:XZFRF) and that this fusion is capable of stabilizing endogenous Hdm2.
      Since none of the fusions triggered p53 ubiquitination in cells lacking Mdm2,
      these results indicate that the E3 ligase domain within the ring finger of Mdm2
      when part of MdmX and the MdmX ring finger fused to Mdm2 were not sufficient to
      trigger p53 ubiquitination, in vivo.

PMID- 12600197
TI  - Structural changes of water in the Schiff base region of bacteriorhodopsin:
      proposal of a hydration switch model.
AB  - In a light-driven proton-pump protein, bacteriorhodopsin (BR), three water
      molecules participate in a pentagonal cluster that stabilizes an electric
      quadrupole buried inside the protein. In low-temperature Fourier transform
      infrared (FTIR) K minus BR spectra, the frequencies of water bands suggest
      extremely strong hydrogen bonding conditions in BR. The three observed water O-D
      stretches, at 2323, 2292, and 2171 cm(-1), are probably associated with water
      that interacts with the negative charges in the Schiff base region. Retinal
      isomerization weakens these hydrogen bonds in the K intermediate, but not in the
      later intermediates such as L, M, and N. In these states, spectral changes of
      water bands appeared only in the >2500 cm(-1) region, which correspond to weak
      hydrogen bonds. This observation suggests that after the K state the water
      molecules in the Schiff base region find a hydrogen bonding acceptor. We propose
      here a model for the mechanism of proton transfer from the Schiff base to Asp85.
      In the "hydration switch model", hydration of a water molecule is switched in the
      M intermediate from Asp85 to Asp212. This will have increased the pK(a) of the
      proton acceptor, and the proton transfer is from the Schiff base to Asp85. The
      present results also suggest that the deprotonated Asp96 in the N intermediate is
      stabilized in a manner different from that of Asp85 in BR.

PMID- 12600198
TI  - Mechanism of flavin mononucleotide cofactor binding to the Desulfovibrio vulgaris
      flavodoxin. 1. Kinetic evidence for cooperative effects associated with the
      binding of inorganic phosphate and the 5'-phosphate moiety of the cofactor.
AB  - The pathway(s) by which the flavin cofactor binds to the apoflavoprotein is the
      subject of some debate. The crystal and NMR structures of several different
      flavodoxins have provided some insight, although there is disagreement about the
      location of the initial interaction between the flavin mononucleotide (FMN) and
      the apoflavodoxin and the degree of protein conformational change associated with
      cofactor binding [Genzor, C. G., Perales-Alcon, A., Sancho, J., and Romero, A.
      (1996) Nat. Struct. Biol. 3, 329-332; Steensma, E., and van Mierlo, C. P. M.
      (1998) J. Mol. Biol. 282, 653-666]. Binding kinetics using stopped-flow
      spectrofluorimetry and phosphate competition studies were used to develop a model
      for flavin binding to the flavodoxin from Desulfovibrio vulgaris. In the presence
      of phosphate, the time course of fluorescence quenching associated with FMN
      binding to apoflavodoxin was biphasic, whereas riboflavin, which lacks the 5'
      phosphate group of FMN, displayed monophasic binding kinetics. When the
      concentration of phosphate in solution was increased, the FMN binding rates of
      the two phases behaved differently; the rate of one phase decreased, while the
      rate of the other increased. A similar increase in the single phase associated
      with riboflavin binding was also observed. This has led to the following model.
      The binding of the flavin isoalloxazine ring to its subsite is dependent on the
      presence of a phosphate group in the phosphate-binding subsite. When phosphate is
      in the buffer solution, FMN can bind in either of two ways: by the initial
      insertion of the 5'-phosphate group followed by ring binding or, when inorganic
      phosphate from solution is bound, the insertion of the isoalloxazine ring first.
      Riboflavin, which lacks the phosphate moiety of FMN, binds only in the presence
      of inorganic phosphate, presumably due to the binding of this group in the
      phosphate-binding subsite. These results suggest that cooperative interactions
      exist between the phosphate subsite and the ring-binding region in the D.
      vulgaris flavodoxin that are necessary for isoalloxazine ring binding.

PMID- 12600199
TI  - Mechanism of flavin mononucleotide cofactor binding to the Desulfovibrio vulgaris
      flavodoxin. 2. Evidence for cooperative conformational changes involving
      tryptophan 60 in the interaction between the phosphate- and ring-binding
      subsites.
AB  - A mechanism has been proposed for the binding of flavin mononucleotide (FMN) and
      riboflavin to the apoflavodoxin from Desulfovibrio vulgaris [Murray, T. A., and
      Swenson, R. P. (2003) Biochemistry 42, 2307-2316]. In this model, the binding of
      the flavin isoalloxazine ring is dependent on the presence of a phosphate moiety
      in the phosphate-binding subsite, suggesting a cooperative interaction between
      that region and the ring-binding subsite. In the absence of inorganic phosphate,
      FMN can bind through the initial association of its 5'-phosphate group in the
      phosphate-binding subsite followed by insertion of the flavin ring. Because
      riboflavin lacks the 5'-phosphate group, it is unable to bind to this apoprotein
      in the absence of inorganic phosphate in solution. However, inorganic phosphate
      can enhance the rate of ring binding by occupying the phosphate-binding subsite.
      In this paper, NMR, near-UV circular dichroism (CD), and fluorescence
      spectroscopy provide evidence for a phosphate-induced conformational change
      within the isoalloxazine ring-binding subsite. Phosphate-dependent changes in the
      chemical shifts of 22 amide groups were observed in (1)H-(15)N HSQC NMR spectra.
      The majority of these groups are proximal to the phosphate-binding subsite or the
      loops that constitute the isoalloxazine ring-binding site. Also, a phosphate
      dependent change in the environment or position of the Trp60 side chain was
      apparent in the NMR data and was confirmed by associated changes in the near-UV
      CD and tryptophan fluorescence spectra when compared to the spectra of the W60A
      mutant. These data suggest that phosphate, either the 5'-phosphate of the FMN or
      inorganic phosphate from solution, facilitates the movement of the side chain of
      Trp60 out of the isoalloxazine ring-binding site and other associated
      conformational changes, creating a population of apoflavodoxin that is capable of
      binding the isoalloxazine ring. This conformational switch may explain why some
      apoflavodoxins cannot bind riboflavin and also supports the "aromatic gate" model
      proposed from the crystal structure of the Anabaena apoflavodoxin [Genzor, C. G.,
      Perales-Alcon, A., Sancho, J., and Romero, A. (1996) Nat. Struct. Biol. 3, 329
      332].

PMID- 12600200
TI  - Minor groove orientation for the (1S,2R,3S,4R)-N2- [1-(1,2,3,4-tetrahydro-2,3,4
      trihydroxybenz[a]anthracenyl)]-2'-deoxyguanosyl adduct in the N-ras codon 12
      sequence.
AB  - The conformation of the trans-anti-(1S,2R,3S,4R)-N(2)-[1-(1,2,3,4-tetrahydro
      2,3,4-trihydroxybenz[a]anthracenyl)]-2'-deoxyguanosyl adduct in
      d(G(1)G(2)C(3)A(4)G(5)X(6)T(7)G(8)G(9)T(10)G(11)).d(C(12)A(13)C(14)C(15)A(16)C(17
      C(18)T(19)G(20)C(21)C(22)), bearing codon 12 of the human N-ras protooncogene
      (underlined), was determined. This adduct had S stereochemistry at the benzylic
      carbon. Its occurrence in DNA is a consequence of trans opening by the
      deoxyguanosine amino group of (1R,2S,3S,4R)-1,2-epoxy-1,2,3,4
      tetrahydrobenz[a]anthracenyl-3,4-diol. The resonance frequencies, relative to the
      unmodified DNA, of the X(6) H1' and H6 protons were shifted downfield, whereas
      those of the C(18) and T(19) H1', H2', H2' ', and H3' deoxyribose protons were
      shifted upfield. The imino and amino resonances exhibited the expected sequential
      connectivities, suggesting no interruption of Watson-Crick pairing. A total of
      426 interproton distances, including nine uniquely assigned BA-DNA distances,
      were used in the restrained molecular dynamics calculations. The refined
      structure showed that the benz[a]anthracene moiety bound in the minor groove, in
      the 5'-direction from the modified site. This was similar to the (+)-trans-anti
      benzo[a]pyrene-N(2)-dG adduct having S stereochemistry at the benzylic carbon
      [Cosman, M., De Los Santos, C., Fiala, R., Hingerty, B. E., Singh, S. B., Ibanez,
      V., Margulis, L. A., Live, D., Geacintov, N. E., Broyde, S., and Patel, D. J.
      (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 1914-1918]. It differed from the (-)
      trans-anti-benzo[c]phenanthrene-N(2)-dG adduct having S stereochemistry at the
      benzylic carbon, which intercalated in the 5'-direction [Lin, C. H., Huang, X.,
      Kolbanovskii, A., Hingerty, B. E., Amin, S., Broyde, S., Geacintov, N. E., and
      Patel, D. J. (2001) J. Mol. Biol. 306, 1059-1080]. The results provided insight
      into how PAH molecular topology modulates adduct structure in duplex DNA.

PMID- 12600201
TI  - Role of base sequence context in conformational equilibria and nucleotide
      excision repair of benzo[a]pyrene diol epoxide-adenine adducts.
AB  - We investigate the influence of base sequence context on the conformations of the
      10S (+)- and 10R (-)-trans-anti-[BP]-N(6)-dA adducts through molecular dynamics
      (MD) simulations with free energy calculations, and relate the structural
      findings to results of nucleotide excision repair (NER) assays in human cell
      extracts. In previous studies, these adducts were studied in the CA*A sequence
      context, and here we report results for the CA*C sequence. Our simulations
      indicate that the base sequence context affects the syn-anti conformational
      equilibrium in the 10S (+) adduct by modulating the barrier heights between these
      states on the energy surface, with a higher barrier in the CA*C case. Our
      nucleotide excision repair assay finds greater NER susceptibilities in the 10S
      (+) adduct for the CA*C sequence context. A structural rationale ties together
      these results. A sequence specific hydrogen bond, accompanied by a significantly
      increased roll and consequent bending in the 10S (+) adduct, has been found in
      our simulations for the CA*C sequence, which could account for the enhanced
      nucleotide excision repair as well as the syn-anti equilibrium difference we
      observe in this isomer and sequence. Such sequence specific differential repair
      could contribute to the existence of mutational hotspots and thereby contribute
      to the complexity of cancer initiation.

PMID- 12600202
TI  - Nucleation of alpha 1-antichymotrypsin polymerization.
AB  - Alpha(1)-antichymotrypsin is an acute phase plasma protein and a member of the
      serpin superfamily. We show here that wildtype alpha(1)-antichymotrypsin forms
      polymers between the reactive center loop of one molecule and the beta-sheet A of
      a second at a rate that is dependent on protein concentration and the temperature
      of the reaction. The rate of polymerization was accelerated by seeding with
      polymers of alpha(1)-antichymotrypsin and a complex of alpha(1)-antichymotrypsin
      with an exogenous reactive loop peptide but not with reactive loop cleaved
      alpha(1)-antichymotrypsin or with polymers of other members of the serpin
      superfamily. Sonication of alpha(1)-antichymotrypsin polymers markedly increased
      the efficacy of seeding such that polymers were able to form under physiological
      conditions. Taken together, these data provide the first demonstration that
      serpin polymerization can result from seeding. This mechanism is analogous to the
      fibrillization of the Abeta(1-42) peptide and may be important in the deposition
      of alpha(1)-antichymotrypsin in the plaques of Alzheimer's disease.

PMID- 12600203
TI  - Energetic and structural analysis of the role of tryptophan 59 in FKBP12.
AB  - Tryptophan 59 forms the seat of the hydrophobic ligand-binding site in the small
      immunophilin FKBP12. Mutating this residue to phenylalanine or leucine stabilizes
      the protein by 2.72 and 2.35 kcal mol(-1), respectively. Here we report the
      stability data and 1.7 A resolution crystal structures of both mutant proteins,
      complexed with the immunosuppressant rapamycin. Both structures show a relatively
      large response to mutation involving a helical bulge at the mutation site and the
      loss of a hydrogen bond that anchors a nearby loop. The increased stability of
      the mutants is probably due to a combination of improved packing and an entropic
      gain at the mutation site. The structures are almost identical to that of wild
      type FKBP12.6, an isoform of FKBP12 that differs by 18 residues, including Trp59,
      in its sequence. Therefore, the structural difference between the two isoforms
      can be attributed almost entirely to the identity of residue 59. It is likely
      that in FKBP12-ligand complexes Trp59 provides added binding energy at the active
      site at the expense of protein stability, a characteristic common to other
      proteins. FKBP12 associates with the ryanodine receptor in skeletal muscle
      (RyR1), while FKBP12.6 selectively binds the ryanodine receptor in cardiac muscle
      (RyR2). The structural response to mutation suggests that residue 59 contributes
      to the specificity of binding between FKBP12 isoforms and ryanodine receptors.

PMID- 12600204
TI  - Interaction of DNA polymerase I (Klenow fragment) with the single-stranded
      template beyond the site of synthesis.
AB  - Cocrystal structures of DNA polymerases from the Pol I (or A) family have
      provided only limited information about the location of the single-stranded
      template beyond the site of nucleotide incorporation, revealing contacts with the
      templating position and its immediate 5' neighbor. No structural information
      exists for template residues more remote from the polymerase active site. Using a
      competition binding assay, we have established that Klenow fragment contacts at
      least the first four unpaired template nucleotides, though the quantitative
      contribution of any single contact is relatively small. Photochemical cross
      linking indicated that the first unpaired template base beyond the primer
      terminus is close to Y766, as expected, and the two following template bases are
      close to F771 on the surface of the fingers subdomain. We have constructed point
      mutations in the region of the fingers subdomain implicated by these experiments.
      Cocrystal structures of family A DNA polymerases predict contacts between the
      template strand and S769, F771, and R841, and our DNA binding assays provide
      evidence for the functional importance of these contacts. Overall, the data are
      most consistent with the template strand following a path over the fingers
      subdomain, close to the side chain of R836 and a neighboring cluster of
      positively charged residues.

PMID- 12600205
TI  - Mechanism of human S-adenosylmethionine decarboxylase proenzyme processing as
      revealed by the structure of the S68A mutant.
AB  - S-Adenosylmethionine decarboxylase (AdoMetDC) is a pyruvoyl-dependent enzyme that
      catalyzes the formation of the aminopropyl group donor in the biosynthesis of the
      polyamines spermidine and spermine. The enzyme is synthesized as a protein
      precursor and is activated by an autocatalytic serinolysis reaction that creates
      the pyruvoyl group. The autoprocessing reaction proceeds via an N --> O acyl
      rearrangement, generating first an oxyoxazolidine anion intermediate followed by
      an ester intermediate. A similar strategy is utilized in self-catalyzed protein
      splicing reactions and in autoproteolytic activation of protein precursors.
      Mutation of Ser68 to alanine in human AdoMetDC prevents processing by removing
      the serine side chain necessary for nucleophilic attack at the adjacent carbonyl
      carbon atom. We have determined the X-ray structure of the S68A mutant and have
      constructed models of the proenzyme and the oxyoxazolidine intermediate.
      Formation of the oxyoxazolidine intermediate is promoted by a hydrogen bond from
      Cys82 and stabilized by a hydrogen bond from Ser229. These observations are
      consistent with mutagenesis studies, which show that the C82S and C82A mutants
      process slowly and that the S229A mutant does not process at all. Donation of a
      proton by His243 to the nitrogen atom of the oxyoxazolidine ring converts the
      oxyoxazolidine anion to the ester intermediate. The absence of a base to activate
      the hydroxyl group of Ser68 suggests that strain may play a role in the cleavage
      reaction. Comparison of AdoMetDC with other self-processing proteins shows no
      common structural features. Comparison to histidine decarboxylase and aspartate
      decarboxylase shows that these pyruvoyl-dependent enzymes evolved different
      catalytic strategies for forming the same cofactor.

PMID- 12600206
TI  - Structure, function, and aggregation of the zinc-free form of the p53 DNA binding
      domain.
AB  - The p53 DNA binding domain (DBD) contains a single bound zinc ion that is
      essential for activity. Zinc remains bound to wild-type DBD at temperatures below
      30 degrees C; however, it rapidly dissociates at physiological temperature. The
      resulting zinc-free protein (apoDBD) is folded and stable. NMR spectra reveal
      that the DNA binding surface is altered in the absence of Zn(2+). Fluorescence
      anisotropy studies show that Zn(2+) removal abolishes site-specific DNA binding
      activity, although full nonspecific DNA binding affinity is retained.
      Surprisingly, the majority of tumorigenic mutations that destabilize DBD do not
      appreciably destabilize apoDBD. The R175H mutation instead substantially
      accelerates the rate of Zn(2+) loss. A considerable fraction of cellular p53 may
      therefore exist in the folded zinc-free form, especially when tumorigenic
      mutations are present. ApoDBD appears to promote aggregation of zinc-bound DBD
      via a nucleation-growth process. These data provide an explanation for the
      dominant negative phenotype exhibited by many mutations. Through a combination of
      induced p53 aggregation and diminished site-specific DNA binding activity, Zn(2+)
      loss may represent a significant inactivation pathway for p53 in the cell.

PMID- 12600207
TI  - Structural characterization of hellethionins from Helleborus purpurascens.
AB  - Thionins are relatively small-sized multiple-cystine peptides that are probably
      involved in the plant defense against pathogens. As such, these peptides
      constitute promising candidates for engineered plant resistance in the
      agricultural industry. More recently, thionins have been proposed as potential
      immunotoxins in tumor therapy. In the search for pharmacologically active natural
      products, a new family of thionins was recently discovered in the roots of
      Helleborus purpurascens that accordingly were termed hellethionins. The
      structural characterization by NMR of one representative member of this family,
      i.e., of hellethionin D, clearly reveals that thionins from different sources
      share a highly conserved overall fold. In fact, the well-defined 3D structure of
      hellethionin D is very similar to those reported so far for viscotoxins,
      purothionins, or crambin, although distinct differences could be detected in the
      C-terminal portion, especially for loop 36-39. These differences may derive from
      the unusual distribution of charged residues in the C-terminal half of the
      peptide sequence compared to other thionins and from the uncommon occurrence of
      four contiguous threonine residues in loop 36-39. As expected, reduction of the
      disulfide bonds in hellethionin D leads to complete unfolding, but upon oxidative
      refolding by air oxygen in the presence of glutathione the correct isomer is
      recovered in high yields, confirming the very robust fold of this class of
      bioactive cystine peptides.

PMID- 12600208
TI  - Bacterial expression and characterization of a novel, soluble, calcium-binding,
      and calcium-activated human nucleotidase.
AB  - A newly discovered human analogue of a bed bug apyrase, which we named hSCAN-1
      for human soluble calcium-activated nucleotidase-1, was expressed in bacteria,
      refolded from inclusion bodies, purified, and characterized. This apyrase, which
      is distinct from the eNTPDases exemplified by the endothelial CD39 (NTPDase1)
      apyrase, is a 38 kDa monomeric enzyme capable of hydrolyzing a variety of
      nucleoside di- and triphosphates, but not monophosphates. Preferred substrates
      include GDP, UDP, and IDP, with a pH optimum for activity between 6 and 7. The
      specific activity and substrate preference of the bacterially expressed enzyme
      closely mimic those of the enzyme expressed in mammalian COS cells, as well as
      the enzyme synthesized in an in vitro bacterial expression system. This suggests
      that glycosylation and other posttranslational modifications that do not occur in
      bacteria are not necessary for nucleotidase activity or proper folding of this
      human apyrase. hSCAN-1 absolutely requires Ca(2+), but not Mg(2+) or other
      divalent cations analyzed, for enzymatic activity. Surprisingly, the activity
      does not increase in a quasi-linear fashion at sub-millimolar Ca(2+)
      concentrations, as would be expected if Ca(2+) were only used as a cosubstrate
      for the nucleotide substrate, but rather follows a sigmoidal curve. The intrinsic
      fluorescence and difference absorption studies of hSCAN-1 in the absence of
      nucleotides revealed Ca(2+)-induced changes in the environment of tryptophan and
      tyrosine residues with half-saturation at about 90 microM Ca(2+). NaCl increased
      the half-saturating Ca(2+) concentration needed for both structural changes
      detected by optical spectroscopy and enzymatic activation of hSCAN-1 detected by
      nucleotidase assay. These results suggest that Ca(2+) triggers a conformational
      change in hSCAN-1, converting the enzymatically inactive protein to the active
      enzyme, in addition to forming the metal-nucleotide substrate complex necessary
      for nucleotidase activity.

PMID- 12600209
TI  - Engineering a catalytic metal binding site into a calcium-independent
      phosphatidylinositol-specific phospholipase C leads to enhanced
      stereoselectivity.
AB  - Eukaryotic phosphatidylinositol-specific phospholipase Cs (PI-PLCs) utilize
      calcium as a cofactor during catalysis, whereas prokaryotic PI-PLCs use a
      spatially conserved guanidinium group from Arg69. In this study, we aimed to
      construct a metal-dependent mutant of a bacterial PI-PLC and characterize the
      catalytic role of the metal ion, seeking an enhanced understanding of the
      functional differences between these two positively charged moieties. The
      following results indicate that a bona fide catalytic metal binding site was
      created by the single arginine-to-aspartate mutation at position 69: (1) The R69D
      mutant was activated by Ca(2+), and the activation was specific for R69D, not for
      other mutants at this position. (2) Titration of R69D with Ca(2+), monitored by
      (15)N-(1)H HSQC (heteronuclear single quantum coherence) NMR, showed that
      addition of Ca(2+) to R69D restores the environment of the catalytic site
      analogous to that attained by the WT enzyme. (3) Upon Ca(2+) activation, the thio
      effect of the S(P)-isomer of the phosphorothioate analogue (k(O)/k(Sp) = 4.4 x
      10(5)) approached a value similar to that of the WT enzyme, suggesting a
      structural and functional similarity between the two positively charged moieties
      (Arg69 and Asp69-Ca(2+)). The R(P)-thio effect (k(O)/k(Rp) = 9.4) is smaller than
      that of the WT enzyme by a factor of 5. Consequently, R69D-Ca(2+) displays higher
      stereoselectivity (k(Rp)/k(Sp) = 47,000) than WT (k(Rp)/k(Sp) = 7600). (4)
      Results from additional mutagenesis analyses suggest that the Ca(2+) binding site
      is comprised of side chains from Asp33, Asp67, Asp69, and Glu117. Our studies
      provide new insight into the mechanism of metal-dependent and metal-independent
      PI-PLCs.

PMID- 12600210
TI  - Metabolic buffering exerted by macromolecular crowding on DNA-DNA interactions:
      origin and physiological significance.
AB  - Crowding, which characterizes the interior of all living cells, has been shown to
      dramatically affect biochemical processes, leading to stabilization of compact
      morphologies, enhanced macromolecular associations, and altered reaction rates.
      Due to the crowding-mediated shift in binding equilibria toward association,
      crowding agents were proposed to act as a metabolic buffer, significantly
      extending the range of intracellular conditions under which interactions occur.
      Crowding may, however, impose a liability because, by greatly and generally
      enhancing macromolecular association, it can lead to irreversible interactions.
      To better understand the physical determinants and physiological consequences of
      crowding-mediated buffering, we studied the effects of crowding, or excluded
      volume, on DNA structures. Results obtained from isothermal titration calorimetry
      (ITC) and UV melting experiments indicate that crowding-induced effects are
      marginal under conditions that a priori favor association of DNA strands but
      become progressively larger when conditions deteriorate. As such, crowding exerts
      "genuine" buffering activity. Unexpectedly, crowding-mediated effects are found
      to include enthalpy terms that favorably contribute to association processes. We
      propose that these enthalpy terms and preferential stabilization derive from a
      reconfiguration of DNA hydration that occurs in dense DNA-rich phases obtained in
      crowded environments.

PMID- 12600211
TI  - Evaluating the potential of fluorinated tyrosines as spectroscopic probes of
      local protein environments: a UV resonance Raman study.
AB  - Ultraviolet resonance Raman (UVRR) studies designed to test the utility of
      fluorinated tyrosines as spectroscopic probes of the local environment are
      presented. Specifically, resonance Raman spectra of 2-fluoro-L-tyrosine and 3
      fluoro-L-tyrosine (3-Y(f)) obtained with 229 nm excitation are reported. In
      contrast to the modest environmental dependence of the tyrosine resonance Raman
      spectrum, the spectrum of 3-Y(f) is found to be extremely dependent on the
      hydrogen bonding strength of the surrounding environment. Preliminary ab initio
      studies suggest that this behavior is due to normal modes having dominant
      contributions from the C-OH and C-F internal coordinates. Hydrogen bonding to the
      solvent perturbs the internal coordinate energetics and/or couplings, thereby
      altering the character of the normal modes and the corresponding transition
      frequencies and/or intensities. In addition to the solvent studies, 3-Y(f) is
      site specifically incorporated into the influenza hemagglutinin (HA) 100-107
      peptide which binds to the Fv fragment of the 17/9 anti-HA(98-108) peptide
      antibody. These studies demonstrate that the spectrum of 3-Y(f) can be monitored
      in the presence of native tyrosine. In summary, the studies presented here
      demonstrate that 3-Y(f) holds exceptional promise as a probe of the protein
      environment.

PMID- 12600212
TI  - Cross-linking of 2-deoxyribonolactone and its beta-elimination product by base
      excision repair enzymes.
AB  - 2-Deoxyribonolactone (3) is produced in DNA as a result of reaction with a
      variety of DNA damaging agents. The lesion undergoes beta-elimination to form a
      second metastable electrophilic product (4). In this study, DNA containing 2
      deoxyribonolactone (3) and its beta-elimination product (4) are generated at
      specific sites using a photolabile nucleotide precursor. 2-Deoxyribonolactone is
      not incised by any of the 8 AP lyases tested. One enzyme, Escherichia coli
      endonuclease III, cross-links to 3, and the lesion strongly inhibits excision of
      typical abasic sites by this enzyme. Two of the enzymes, FPG and NEIL1 known to
      cleave normal abasic sites (1) by effecting beta,delta-elimination form cross
      links to the butenolide lesion (4). The observed results are ascribable to
      characteristics of the enzymes and the lesions. These enzymes are also important
      for the removal of oxidative base lesions. These results suggest that high
      concentrations of 3 and 4 may exert significant effects on the repair of normal
      AP site and oxidative base lesions in cells by reducing the cellular activity of
      these BER enzymes either via cross-linking or competing with binding to the BER
      enzymes.

PMID- 12600213
TI  - Effects of base sequence context on translesion synthesis past a bulky (+)-trans
      anti-B[a]P-N2-dG lesion catalyzed by the Y-family polymerase pol kappa.
AB  - The effects of bases flanking single bulky lesions derived from the binding of a
      benzo[a]pyrene 7,8-diol 9,10-epoxide derivative ((+)-7R,8S,9S,10R stereoisomer)
      to N(2)-guanine (G*) on translesion bypass catalyzed by the Y-family polymerase
      pol kappa (hDinB1) were examined in vitro. The lesions were positioned near the
      middle of six different 43-mer 5'-...XG*Y... sequences (X, Y = C, T, or G, with
      all other bases remaining fixed). The complementary dCTP is preferentially
      inserted opposite G* in all of the sequences; however, the proportions of other
      dNTPs inserted varies as a function of X and Y. The dCTP insertion efficiencies,
      f(ins) = (V(max)/K(m))(ins), are smaller in the XG*Y than in XGY sequences by
      factors of approximately 50-90 (GG*T and GG*C) or 5000-25000 (TG*G and CG*G).
      Remarkably, in XG*Y sequences, f(ins) varies by as much as 3 orders of magnitude,
      being smallest with G flanking the lesions on the 3'-side and highest with G
      flanking the adducts on the 5'-side. One-step primer extension efficiencies just
      beyond the lesions (f(ext)) are generally smaller than f(ins) and also depend on
      base sequence. However, reasonably efficient translesion bypass of the (+)-trans
      [BP]-N(2)-dG adducts is observed in all sequences in running-start experiments
      with full, or nearly full, primer extension being observed under conditions of
      [dNTP] > K(m). The key features here are the relatively robust values of the
      kinetic parameters V(max) that are either diminished to a moderate extent or even
      enhanced in the presence of the (+)-trans-[BP]-N(2)-dG adducts. In contrast to
      the small effects of the lesions on V(max), the apparent K(m) values are orders
      of magnitude greater in XG*Y than in the unmodified XGY sequences. Thus the
      bypass of (+)-trans-[BP]-N(2)-dG adducts under conditions when [dNTP] < K(m) is
      quite inefficient. These considerations may be of importance in vivo where [dNTP]
      <or= K(m), and the translesion bypass of the (+)-trans-[BP]-N(2)-dG by pol kappa
      may be significantly less efficient than in vitro at higher dNTP concentrations.
      The base sequence-dependent features of translesion bypass are discussed in terms
      of the possible conformations of the adducts and the known structural features of
      bypass polymerases.

PMID- 12600214
TI  - X-ray absorption and NMR spectroscopic studies of CopZ, a copper chaperone in
      Bacillus subtilis: the coordination properties of the copper ion.
AB  - XAS studies have been performed, under various experimental conditions, on a
      copper(I)-transporting protein, CopZ, of Bacillus subtilis. The copper(I) ion,
      reduced with dithiothreitol, is three-coordinate with three sulfur donor atoms,
      two of which presumably provided by the protein and one by dithiothreitol. If a
      molar excess of acetate (15 mM; 5:1 respect to CopZ) or citrate (6 mM; 2:1
      respect to CopZ) is present in solution, the EXAFS spectra suggest the presence
      of a dimeric form involving a close contact between Cu(I) ions from two
      molecules, where Cu is still three-coordinate. (1)H and (15)N NMR data provide
      further structural details. If copper reduction is accomplished with ascorbate,
      the data indicate that one oxygen of ascorbate enters in the first-coordination
      sphere of copper, together with two sulfur atoms, in a dimeric form of the
      protein. These results are instructive and have been discussed with respect to
      the molecular basis of copper trafficking.

PMID- 12600215
TI  - Spectroscopic characterization of five- and six-coordinate ferrous-NO heme
      complexes. Evidence for heme Fe-proximal cysteinate bond cleavage in the ferrous
      NO adducts of the Trp-409Tyr/Phe proximal environment mutants of neuronal nitric
      oxide synthase.
AB  - Nitric oxide synthases (NOS) are a family of cysteine thiolate-ligated heme
      containing monooxygenases that catalyze the NADPH-dependent two-step conversion
      of L-arginine to NO and L-citrulline. During the catalysis, a portion of the NOS
      heme forms an inhibitory complex with self-generated NO that is subsequently
      reverted back to NO-free active enzyme under aerobic conditions, suggesting a
      downstream regulator role of NO. Recent studies revealed that mutation of a
      conserved proximal tryptophan-409, which forms one of three hydrogen bonds to the
      heme-coordinated cysteine thiolate, to tyrosine or phenylalanine considerably
      increases the turnover number of neuronal NOS (nNOS). To further understand these
      properties of nNOS on its active site structural level, we have examined the
      oxygenase (heme-containing) domain of the two mutants in close comparison with
      that of wild-type nNOS with UV-visible absorption, magnetic circular dichroism,
      and electron paramagnetic resonance spectroscopy. Among several oxidation and
      ligation states examined, only the ferrous-NO adducts of the two mutants exhibit
      spectra that are markedly distinct from those of parallel derivatives of the wild
      type protein. The spectra of the ferrous-NO mutants are broadly similar to those
      of known five-coordinate ferrous-NO heme complexes, suggesting that these mutants
      are predominantly five coordinate in their ferrous-NO states. The present results
      are indicative of cleavage of the Fe-S bond in the nNOS mutants in their ferrous
      NO state and imply a significant role of the conserved tryptophan in
      stabilization of the Fe-S bond.

PMID- 12600216
TI  - Topology of the retinal cone NCKX2 Na/Ca-K exchanger.
AB  - The Na/Ca-K exchanger (NCKX) is a polytopic membrane protein that plays a
      critical role in Ca(2+) homeostasis in retinal rod and cone photoreceptors. The
      NCKX1 isoform is found in rods, while the NCKX2 isoform is found in cones, in
      retinal ganglion cells, and in various parts of the brain. The topology of the
      Na/Ca-K exchanger is thought to consist of two large hydrophilic loops and two
      sets of transmembrane spanning segments (TMs). The first large hydrophilic loop
      is located extracellularly at the N-terminus; the other is cytoplasmic and
      separates the two sets of TMs. The TMs consist of either five and five membrane
      spanning helices or five and six membrane spanning helices, depending upon the
      predictive algorithm used. Little specific information is yet available on the
      orientation of the various membrane spanning helices and the localization of the
      short loops connecting these helices. In this study, we have determined which of
      the connecting loops are exposed to the extracellular milieu using two different
      methods: accessibility of substituted cysteine residues and insertion of N
      glycosylation sites. The two methods resulted in a consistent NCKX topology in
      which the two sets of TMs each contain five membrane spanning helices. Our new
      model places what was previously membrane spanning helix six in the cytoplasm,
      which places the C-terminus on the extracellular surface. Surprisingly, this NCKX
      topology model is different from the current NCX topology model with respect to
      the C-terminal three membrane helices.

PMID- 12600218
TI  - Specialist nurse management programmes: economic benefits in the management of
      heart failure.
AB  - Chronic heart failure (CHF) is a modern-day epidemic in most developed countries.
      As such, it is both common and costly. Contrary to the impression given by
      clinical trial data, CHF mainly affects older individuals with approximately
      equal numbers of men and women and concurrent disease profiles likely to
      complicate or even prohibit the application of proven treatments. It is within
      this context that there has been an increasing interest in specific CHF
      management programmes designed to limit costly hospital use in typically older
      individuals at high risk for poor quality of life, recurrent readmissions and
      premature death. This paper examines the evidence to suggest that CHF programmes
      involving individualised multidisciplinary post-discharge healthcare, with a
      major focus on specialist nurse management to ensure that the patient receives
      optimal treatment, are clinically and economically effective in reducing the
      typical burden imposed by CHF. These programmes appear to be most effective in
      'high-risk' patients who typically have recurrent readmissions in high-cost
      units. Overall, the literature suggests that these programmes are able to reduce
      recurrent hospital stay by 30-50% relative to usual care (even in the presence of
      gold-standard treatment) in the short to medium term with comparable cost
      benefits. Recent data from a management programme involving a cohort of typically
      older and fragile patients with CHF in Australia showed that at 3 years post
      index admission, hospital utilisation costs were reduced by one-third relative to
      usual care. The potential for enormous cost benefits (both in terms of absolute
      cost savings and in terms of facilitating a more efficient healthcare system) if
      a specialist nurse programme of care was applied in the form of a UK-wide heart
      failure service was also recently examined. Based on year 2000 activity levels,
      it was found that for each specialist heart failure nurse appointed in the UK
      (with a caseload of 200-250 patients per annum), nominal savings of pound 49 000
      per annum could be generated in order to make the healthcare system more
      efficient.

PMID- 12600219
TI  - Health-related quality-of-life assessments in patients with advanced cancer of
      the prostate.
AB  - Health-related quality of life (HR-QOL) research, in general, is developing. It
      is becoming increasingly recognised as being important and knowledge on how to
      assess HR-QOL is spreading. Modern HR-QOL research should assess prevalence and
      severity of symptoms or functions, as well as the bother that symptoms or changes
      in functions inflict and whether this bother affects the overall well-being of
      the patient. In the prostate cancer field, HR-QOL assessments have evolved
      rapidly during the last decade. The importance of HR-QOL and associated research
      in prostate cancer is being more and more appreciated. Most published studies
      concern patients with early prostate cancer; studies in patients with late
      advanced stages are less frequent. In early stages, patients often have no or few
      symptoms from the disease. HR-QOL aspects for these patients are thus often
      associated with anxiety and treatment adverse effects such as changes in sexual,
      urinary and bowel functions. Changes in these functions also often affect HR-QOL
      in patients with more advanced local stages of prostate cancer or metastatic
      disease. Moreover, HR-QOL in these patients is also affected by endocrine
      treatment aiming to castrate the patient. Monotherapy with antiandrogens as
      endocrine treatment may be the treatment alternative that affects HR-QOL the
      least. This alternative may, however, not be as effective as castration. In the
      palliative phase, patients with prostate cancer have problems common to patients
      dying of other cancers. HR-QOL research should be encouraged and the knowledge on
      how HR-QOL can be assessed needs to be disseminated. HR-QOL assessments should be
      as natural in outcomes research as survival assessments. The technology of
      assessing HR-QOL needs to be further investigated and improved particularly with
      respect to the understanding of differences in performance between instruments
      using summary scores and item-specific assessments. Also, we need an increased
      understanding of the mechanisms behind patients' trade-offs and of how
      information should be communicated to patients in order to give the best
      possibilities for making informed treatment decisions.

PMID- 12600221
TI  - Unit costs of inpatient hospital days.
AB  - BACKGROUND: Costs of inpatient days in hospitals are frequently the main drivers
      of total treatment costs, and their unit cost can markedly affect the outcomes of
      an economic evaluation. In many countries, the availability of unit cost data is
      limited and unit costs are often based on data from hospitals participating in
      clinical trials. OBJECTIVE: To provide data about unit costs of inpatient
      hospital days in The Netherlands from a healthcare provider's perspective and to
      give an insight into the extent to which cost categories and total costs differ
      between hospitals. DESIGN: Unit costs were collected from 22 wards and 11
      intensive care units (ICUs) of general and university hospitals involved in
      clinical trials with 'piggybacked' economic evaluations. Direct costs, such as
      costs of nursing and medical materials, were calculated by dividing the annual
      cost per category of the nursing department by the annual number of inpatient
      days. Indirect costs, such as overheads and accommodation, were allocated to the
      nursing departments by applying direct allocation. All costs were expressed in
      1998 euros (EUR). RESULTS: The mean costs per inpatient day were EUR230 (range:
      EUR154-EUR311) in general hospitals and EUR323 (range: EUR209-EUR400) in
      university hospitals. The mean costs per inpatient day in an ICU were EUR1125
      (EUR919-EUR1560). Between 38-48% of the total costs were made up of nursing
      costs. All cost categories showed wide variations between hospitals. CONCLUSIONS:
      The results of this study were used to develop standard costs for inpatient days
      in The Netherlands and may contribute to the comparability and generalisability
      of economic evaluations.

PMID- 12600222
TI  - A study of influenza and influenza-related complications among children in a
      large US health insurance plan database.
AB  - BACKGROUND: Influenza places a substantial burden on the affected individual and
      society. While there are data available on the overall occurrence of influenza in
      children, less information is available on the differential impact of influenza
      on healthcare for previously healthy children and those at high risk of
      developing influenza-related complications. OBJECTIVE: To compare the frequency
      of influenza-related complications in healthy and 'at-risk' children, and
      quantify the associated use of medical resources and costs. DESIGN: Data were
      obtained from a large US-based health insurance plan database. MAIN OUTCOME
      MEASURES AND RESULTS: A total of 23 188 health insurance claims with an influenza
      diagnosis were identified over the 3-year period 1995-1997 (3 247 834 patient
      years). Influenza-related complications were observed in approximately a quarter
      of the total diagnosed cases, with younger children (0-4 years of age) at
      substantially greater risk. 'At-risk' children were more likely to develop
      influenza-related complications than otherwise healthy children. The greatest
      difference in incidence rate in the 0-4 year age group was for asthma (incidence
      rate ratio 8.7, 95% CI 5.2-14.4), and in the 5-14 year age group for asthma
      (incidence rate ratio 8.5, 95% CI 5.2-13.7) and acute sinusitis (incidence rate
      ratio 2.7, 95% CI 1.2-5.4). The average direct medical costs of influenza in
      children under 15 years with complications were more than 3.5 times higher than
      those without. CONCLUSIONS: Measures to prevent and treat influenza-related
      complications are certainly warranted for at-risk children, although the elevated
      incidence rates for several common complications even among healthy children
      should prompt consideration of these measures for all children.

PMID- 12600220
TI  - Cost comparisons of pharmacological strategies in open-heart surgery.
AB  - Open-heart surgery (OHS) is performed to bypass occluded arteries, replace
      malfunctioning cardiac valves or correct congenital abnormalities. The average
      cost of OHS varies from $US25 057-$US79 795 (1997 values). The objective of this
      paper was to review economic studies of pharmacological strategies in open-heart
      surgery. Pharmacological strategies studied include the prevention of
      postoperative complications such as atrial fibrillation (AF), bleeding and
      infection. Modifications in anaesthetic technique have been attempted by using
      agents that promote early extubation. In addition, strategies for postoperative
      management of sedation, analgesia and AF and use of neuromuscular blockers have
      also been compared. The majority of studies in this area have been cost analyses
      with few cost-effectiveness studies performed. Prophylaxis against AF with
      amiodarone is associated with a reduction in AF and was cost-neutral compared
      with placebo. Compared with placebo, prevention of bleeding with
      antifibrinolytics reduces transfusion costs. In direct comparative studies,
      lysine analogues, due to lower drug acquisition costs, offset transfusion costs
      to a greater extent than aprotinin. However, safety concerns with the lysine
      analogues remain. Erythropoietin decreases transfusion requirements and is cost
      effective compared with no intervention when the cost of postoperative bacterial
      complications is included. First- and second-generation cephalosporins prevent
      postoperative infections. Based on drug acquisition cost, the first-generation
      agents are less expensive although when administration costs are included, both
      classes have similar costs. Modifications in anaesthetic technique with short
      acting anaesthetic agents, results in higher drug costs although nursing and
      total hospital costs are typically reduced. For neuromuscular blockers, drug
      acquisition costs are lowest with pancuronium but administration costs and the
      cost of adverse events have not been included in existing analyses. Midazolam
      provides an equivalent level of postoperative sedation to propofol but the
      acquisition cost is lower. The combined use of propofol and midazolam warrants
      further investigation, as its use is associated with lower sedative agent costs
      compared with either agent alone. There is limited data on the economics of
      postoperative analgesia and the management of AF. As the majority of studies to
      date are partial cost analyses, additional studies that include length of stay
      and other hospitalisation data are warranted. In future, cost-effectiveness and
      cost-utility studies, which incorporate quality of life and the cost of adverse
      effects and other longer term costs, should be undertaken.

PMID- 12600223
TI  - Ontario's formulary committee: how recommendations are made.
AB  - BACKGROUND: In 1996, the provincial government in Ontario, Canada required
      pharmaceutical manufacturers seeking to list their products on the provincial
      formulary to provide a formal economic analysis documenting the products' cost
      effectiveness. The provincial formulary lists pharmaceutical products for which
      reimbursement is provided for residents on the Ontario Drug Benefit Program
      (ODB). OBJECTIVE: To describe how listing decisions are made, and specifically
      the role of economic analysis in this process. DESIGN: A qualitative case study
      approach was taken. Data were analysed using the pattern-matching technique. Data
      consisted of meeting transcripts and interviews with committee members, which
      were coded and weighted for analysis using the pattern-matching technique.
      SETTING: Nine meetings of the Drug Quality and Therapeutics Committee (DQTC),
      which makes listing recommendations to the ODB, were observed. PARTICIPANTS:
      Seven individual committee members were interviewed. RESULTS: Complex economic
      analyses (i.e. analyses more involved than a simple cost-consequence analysis)
      played a limited role. The clinical factor dominated the perception of costs.
      Generic and 'me-too' products with no price premium did not require complex
      economic analyses. Poor quality analyses were not useful and the DQTC members'
      lack of in-depth knowledge of health economics influenced the extent to which
      analyses were discussed. The DQTC did discuss economic issues however, and often
      performed informal economic analyses to guide decisions. CONCLUSIONS: Complex
      economic analyses had an impact on provincial drug benefit decisions in a limited
      number of circumstances, principally for expensive innovative products. However,
      the committee did use some form of economic analysis to guide decisions in almost
      all cases, and therefore requesting economic analyses, even simple ones, from
      manufacturers seeking formulary listing is a useful healthcare policy.

PMID- 12600225
TI  - Diagnosis and treatment of patients with pouchitis.
AB  - Pouchitis is the most common long-term complication of ileal pouch-anal
      anastomosis in patients with underlying ulcerative colitis. Clinical symptoms of
      pouchitis are not specific, and they can be caused by other conditions such as
      rectal cuff inflammation and irritable pouch syndrome. Therefore, to make an
      accurate diagnosis, endoscopic evaluation together with symptom assessment is
      necessary. Among five available treat-first and test-first strategies, the
      initial approach with pouch endoscopy without histology was the most cost
      effective strategy for the diagnosis of pouchitis. On the basis of clinical
      course, pouchitis can be classified into acute, relapsing and chronic forms.
      Pouchitis can also be classified into three categories based on the response to
      antibacterial therapy: antibacterial-responsive; antibacterial-dependent; and
      antibacterial-resistant. Metronidazole and ciprofloxacin are both effective in
      treating acute pouchitis. Although antibacterial therapy can induce and maintain
      remission, probiotics such as VSL#3 can also be used as to maintain clinical
      remission and prevent relapse in patients with relapsing or chronic pouchitis.
      For patients with chronic pouchitis that is resistant to antibacterials, therapy
      with anti-inflammatory agents and immunomodulators is often required.

PMID- 12600224
TI  - Clinical potential of sodium-calcium exchanger inhibitors as antiarrhythmic
      agents.
AB  - The Na(+)/Ca(2+) exchanger (NaCaX) plays an important role in calcium handling in
      myocytes, but in the setting of calcium overload NaCaX can also contribute to the
      activation of an arrhythmogenic transient inward current (I(ti)). Therefore,
      approaches to inhibit NaCaX could have potential antiarrhythmic effects in
      pathophysiological states such as heart failure (HF) or myocardial ischaemia and
      reperfusion. NaCaX typically functions in a forward (Ca(2+) extrusion) mode but
      can also function in a reverse (Ca(2+) influx) mode. The determining factors for
      the directionality of NaCaX ion movement are the electrochemical gradients of
      calcium and sodium, and membrane potential (E(m)). In HF, upregulated NaCaX plays
      a dual role: it decreases sarcoplasmic reticulum (SR) calcium load, which leads
      to contractile dysfunction, and it underlies the I(ti) responsible for delayed
      after-depolarisations (DADs) and ventricular arrhythmias. In myocardial ischaemia
      and reperfusion, increases in [Na(+)](i) (as a result of acidosis and activation
      of the Na(+)/H(+) exchanger [NHE]) lead to calcium overload via the NaCaX and
      arrhythmogenesis is probably mediated by I(ti) activation due to NaCaX. As such,
      inhibition of NaCaX could provide a novel therapeutic approach to the prevention
      and treatment of arrhythmias. Unfortunately, it is difficult to assess the
      efficacy of such an approach since there are no specific NaCaX inhibitors.
      Currently available agents are hampered by their nonspecific effects on other ion
      channels and carriers. The potential utility of specific inhibition of forward or
      reverse mode NaCaX as an antiarrhythmic approach in the settings of HF and
      ischaemia/ reperfusion is discussed within the context of current knowledge of
      myocyte calcium and sodium handling. NaCaX is a challenging and complex
      therapeutic target because of the delicate balance of SR calcium load (too little
      contributes to contractile dysfunction and too much leads to calcium overload and
      arrhythmogenesis). Further understanding of NaCaX function, [Na(+)](i) and
      [Ca(2+)](i) in HF and ischaemia/reperfusion, combined with the development and
      assessment of specific NaCaX inhibitors, will ultimately define the potential
      role of NaCaX inhibition in the prevention and treatment of ventricular
      arrhythmias.

PMID- 12600226
TI  - Progestogens with antiandrogenic properties.
AB  - Chlormadinone acetate, cyproterone acetate and dienogest are potent, orally
      active progestogens, which have antiandrogenic instead of partial androgenic
      activity. They act mainly by blocking androgen receptors in target organs, but
      also reduce the activity of skin 5alpha-reductase, the enzyme responsible for
      converting testosterone to the more potent androgen, 5alpha-dihydrotestosterone,
      in sebaceous glands and hair follicles. Chlormadinone acetate and cyproterone
      acetate also suppress gonadotropin secretion, thereby reducing ovarian and
      adrenal androgen production. Combined oral contraceptives (COCs) containing
      antiandrogenic progestogens provide highly effective contraception (gross and
      adjusted Pearl indices: 0-0.7 and 0-0.3, respectively) with excellent cycle
      control. Furthermore, COCs containing 2mg of chlormadinone acetate or cyproterone
      acetate plus 30 or 35 microg of ethinylestradiol produced improvement or
      resolution of seborrhoea in 80% of users, acne in 59-70%, hirsutism in 36% and
      androgen-related alopecia in up to 86%. These COCs are generally well tolerated,
      the main adverse effects being nonspecific or as expected for a COC (headache,
      breast tenderness and nausea). They have no clinically relevant effects on
      metabolic or liver functions or on bodyweight. Effects on mood and libido are
      uncommon (<3.5% and <6% of women, respectively). COCs containing antiandrogenic
      progestogens are likely to be particularly valuable in women with pre-existing
      androgen-related disorders who require contraception. They also increase the
      choice of products available for women with normal skin and hair who are
      concerned about the possibility of developing seborrhoea or acne with other COCs.

PMID- 12600227
TI  - Intramuscular preparations of antipsychotics: uses and relevance in clinical
      practice.
AB  - Intramuscular formulations of antipsychotics can be sub-divided into two groups
      on the basis of their pharmacokinetic features: short-acting preparations and
      long-acting or depot preparations. Short-acting intramuscular formulations are
      used to manage acute psychotic episodes. On the other hand, long-acting
      compounds, also called "depot", are administered as antipsychotic maintenance
      treatment to ensure compliance and to eliminate bioavailability problems related
      to absorption and first pass metabolism. Adverse effects of antipsychotics have
      been studied with particular respect to oral versus short- and long-acting
      intramuscular formulations of the different compounds. For short-term
      intramuscular preparations the main risk with classical compounds are hypotension
      and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot
      formulations are controversial: some studies point out that the incidence of EPS
      is significantly higher in patients receiving depot preparations, whereas others
      show no difference between oral and depot antipsychotics. Studies on the
      strategies for switching patients from oral to depot treatment suggest that this
      procedure is reasonably well tolerated, so that in clinical practice depot
      antipsychotic therapy is usually begun while the oral treatment is still being
      administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics
      and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate
      and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard,
      flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and
      undecylenate, and fluspirilene are reviewed. In addition, the intramuscular
      preparations of atypical antipsychotics and clinical uses are reviewed.
      Olanzapine and ziprasidone are available only as short-acting preparations, while
      risperidone is to date the only novel antipsychotic available as depot
      formulation. To date, acutely ill, agitated psychotic patients have been treated
      with high parenteral doses of typical antipsychotics, which often cause serious
      EPS, especially dystonic reactions. Intramuscular formulations of novel
      antipsychotics (olanzapine and ziprasidone), which appear to have a better
      tolerability profile than typical compounds, showed an equivalent efficacy to
      parenteral typical agents in the acute treatment of psychoses. However,
      parenteral or depot formulations of atypical antipsychotics are not yet widely
      available.

PMID- 12600231
TI  - Stress and radiation-induced activation of multiple intracellular signaling
      pathways.
AB  - Exposure of cells to a variety of stresses induces compensatory activations of
      multiple intracellular signaling pathways. These activations can play critical
      roles in controlling cell survival and repopulation effects in a stress-specific
      and cell type-dependent manner. Some stress-induced signaling pathways are those
      normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other
      pathways activated by stresses such as ionizing radiation include those
      downstream of death receptors, including pro-caspases and the transcription
      factor NFKB. This review will attempt to describe some of the complex network of
      signals induced by ionizing radiation and other cellular stresses in animal
      cells, with particular attention to signaling by growth factor and death
      receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to
      the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro
      caspases and NFKB. The roles of autocrine ligands in the responses of cells and
      bystander cells to radiation and cellular stresses will also be discussed. Based
      on the data currently available, it appears that radiation can simultaneously
      activate multiple signaling pathways in cells. Reactive oxygen and nitrogen
      species may play an important role in this process by inhibiting protein tyrosine
      phosphatase activity. The ability of radiation to activate signaling pathways may
      depend on the expression of growth factor receptors, autocrine factors, RAS
      mutation, and PTEN expression. In other words, just because pathway X is
      activated by radiation in one cell type does not mean that pathway X will be
      activated in a different cell type. Radiation-induced signaling through growth
      factor receptors such as the EGFR may provide radioprotective signals through
      multiple downstream pathways. In some cell types, enhanced basal signaling by
      proto-oncogenes such as RAS may provide a radioprotective signal. In many cell
      types, this may be through PI3K, in others potentially by NFKB or MAPK. Receptor
      signaling is often dependent on autocrine factors, and synthesis of autocrine
      factors will have an impact on the amount of radiation-induced pathway activity.
      For example, cells expressing TGFalpha and HB-EGF will generate protection
      primarily through EGFR. Heregulin and neuregulins will generate protective
      signals through ERBB4/ERBB3. The impact on radiation-induced signaling of other
      autocrine and paracrine ligands such as TGFbeta and interleukin 6 is likely to be
      as complicated as described above for the ERBB receptors.

PMID- 12600228
TI  - Imatinib mesylate: in the treatment of gastrointestinal stromal tumours.
AB  - Imatinib mesylate (imatinib) is an orally administered competitive inhibitor of
      the tyrosine kinases associated with the KIT protein (stem cell factor receptor),
      ABL protein and platelet-derived growth factor receptors. The KIT tyrosine kinase
      is abnormally expressed in gastrointestinal stromal tumour (GIST), a rare
      neoplasm for which there has been no effective systemic therapy. In a randomised,
      nonblind, multicentre study that evaluated imatinib 400 or 600mg once daily in
      147 patients with advanced GIST, confirmed partial responses were achieved in 54%
      of patients overall (median duration of follow-up was 288 days). Stable disease
      was experienced by 28% of patients and the estimated 1-year survival rate was
      88%. Similar response rates were reported in a smaller, dose-escalation study, in
      which objective tumour response was a secondary endpoint. Although nearly all
      patients with GIST treated with imatinib experienced adverse events, most events
      were mild or moderate in nature. Severe or serious adverse events occurred in 21%
      of patients in the larger study, and included gastrointestinal or tumour
      haemorrhage. The control of cellular processes, such as cell growth, division and
      death, involves signal transduction, which commonly involves the transfer of
      phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate
      proteins, by tyrosine kinase enzymes. Activation of oncogenes coding for kinase
      proteins can lead to the production of kinases that are continually active in the
      absence of a normal stimulus,leading to increased cell proliferation and/or
      decreased apoptosis. A major focus of cancer research in recent years has been to
      identify oncogenic molecules and the signal transduction pathways in which they
      are involved, in order to develop specifically targeted drugs. One such drug is
      imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2
      phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine
      kinases associated with platelet-derived growth factor (PDGF) receptors, the
      Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF]
      receptor). Imatinib was initially evaluated for the treatment of chronic myeloid
      leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been
      approved for the treatment of patients with advanced gastrointestinal stromal
      tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed.
      GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal
      cells. They are rare neoplasms, with between 5000 and 10 000 new cases being
      diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract
      but the stomach and small intestine are the most common sites. Symptoms depend on
      the site and size of the tumour, and may include abdominal pain, gastrointestinal
      bleeding or signs of obstruction; small tumours may be asymptomatic. The
      diagnosis of GIST is made by immunohistochemical staining for CD117, a cell
      surface antigen on the extracellular domain of KIT, in conjunction with
      pathological examination of tissue with light microscopy. All GISTs may have some
      degree of malignant potential. They are unresponsive to standard chemotherapy and
      to radiotherapy, and the mainstay of treatment in the past has been surgery.
      However, recurrence rates are high, and there has been no effective systemic
      treatment for unresectable GIST or metastatic disease. For patients in whom
      complete resection is not possible, or in patients with metastatic or recurrent
      disease, the median duration of survival is 9-12 months, and 10-19 months,
      respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to
      90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto
      phosphorylation of tyrosine residues independent of ligand-receptor binding),
      leading to aberrant cell division and tumour growth. Imatinib selectively
      inhibits the tyrosine kinase activity associated with KIT, which forms the
      rationale for evaluating its effects in GIST. Subsequent to initial evidence of
      the clinical efficacy of imatinib in a single patient with progressive,
      metastatic, CD117-positive GIST, formal studies of imatinib in this new
      indication were initiated. This article summarises the pharmacology, efficacy and
      tolerability profile of imatinib in the treatment of patients with advanced GIST.

PMID- 12600232
TI  - Are chromosomal instabilities induced by exposure of cultured normal human cells
      to low- or high-LET radiation?
AB  - Radiation-induced genomic instability has been proposed as a very early, if not
      an initiating, step in radiation carcinogenesis. Numerous studies have
      established the occurrence of radiation-induced chromosomal instability in
      various cells of both human and rodent origin. In many of these studies, however,
      the cells were not "normal" initially, and in many cases they involved tumor
      derived cell lines. The phenomenon clearly would be of even greater interest if
      it were shown to occur generally in cells that are normal at the outset, rather
      than cells that may have been "selected" because of a pre-existing susceptibility
      to induced instability. As a test of the generality of the phenomenon, we studied
      low-passage normal diploid human fibroblasts (AG1521A) to determine whether they
      are susceptible to the induction of chromosomal instability in the progeny of
      surviving cells after exposure in G(0) to low- and high-LET radiation.
      Cytogenetic assays for instability were performed on both mixed populations of
      cells and clones of cells surviving exposure. We found no evidence for the
      induction of such instability as a result of radiation exposure, though we
      observed a senescence-related chromosomal instability in the progeny of both
      irradiated and unirradiated cell populations.

PMID- 12600233
TI  - Possible biomarkers for ionizing radiation exposure in human peripheral blood
      lymphocytes.
AB  - Biomarkers to indicate past exposure to radiation have not been entirely
      satisfactory. Using cDNA microarray hybridization to find new potential
      biomarkers, we identified highly expressed genes in human peripheral blood
      lymphocytes (PBLs) after irradiation 1 Gy ex vivo. The present set of radiation
      markers in PBLs was identified 12 h after radiation. A total of 44 genes were
      identified. However, when RT-PCR was performed with mRNA from the PBLs of five
      individuals, only four genes, including TRAIL receptor 2, DRAL (now known as
      FHL2), cyclin G, and cyclin protein gene, showed greater than 50% agreement
      between gene induction as detected by microarray analysis and by RT-PCR. When
      more than 32 donors were tested for the above four genes, greater than 85%
      agreement was obtained between gene induction measured by microarray analysis and
      by RT-PCR. There was a linear dose-response relationship between 0.5 and 4 Gy 12
      h after irradiation; however, there was less linearity at later times. These
      results suggested that the relative expression levels of genes such as TRAIL
      receptor 2, FHL2, cyclin G, and cyclin protein gene in PBLs may provide estimates
      of radiation exposures.

PMID- 12600234
TI  - Low doses of radiation increase the latency of spontaneous lymphomas and spinal
      osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice.
AB  - Mice heterozygous for Trp53 are radiation-sensitive and cancer-prone,
      spontaneously developing a variety of cancer types. Osteosarcomas in the spine
      lead to paralysis, while lymphomas lead rapidly to death, distinct events that
      provide objective measures of latency. The effects of a single low-dose (10 or
      100 mGy), low-dose-rate (0.5 mGy/min) (60)Co gamma irradiation on lymphoma or
      spinal osteosarcoma frequency and latency, defined as time of death or of onset
      of paralysis, respectively, were examined. Compared to spontaneous lymphomas or
      to spinal osteosarcomas leading to paralysis in unexposed mice, an exposure of 7
      8-week-old Trp53(+/-) mice to 10 or 100 mGy had no significant effect on tumor
      frequency, indicating no effect on tumor initiation. All tumors are therefore
      assumed to be of spontaneous origin. However, a 10-mGy exposure reduced the risk
      of both lymphomas and spinal osteosarcomas by significantly increasing tumor
      latency, indicating that the main in vivo effect of a low-dose exposure is a
      reduction in the rate at which spontaneously initiated cells progress to
      malignancy. The effect of this adaptive response persisted for the entire life
      span of all the animals that developed these tumors. Exposure to 100 mGy delayed
      lymphoma latency longer than the 10-mGy exposure. However, the 100-mGy dose
      increased spinal osteosarcoma risk by decreasing overall latency compared to
      unexposed control mice. That result suggested that this higher dose was in a
      transition zone between reduced and increased risk, but that the dose at which
      the transition occurs varies with the tumor type.

PMID- 12600235
TI  - Tumor oxygenation and acidification are increased in melanoma xenografts after
      exposure to hyperglycemia and meta-iodo-benzylguanidine.
AB  - Tumor oxygen tension and extracellular pH (pH(e)) are physiological parameters
      that can be manipulated to improve current cancer therapies. Many human tumors
      consist of cells that are chronically exposed to low pH(e). Exposure of tumor
      cells in culture to glucose decreases oxygen consumption (oxygen sparing or
      Crabtree effect), and while this effect is absent in low pH-adapted tumor cells,
      it can be restored by combining the respiratory inhibitor meta-iodo
      benzylguanidine (MIBG) with glucose (Burd et al., Cancer Res. 61, 5630-5635,
      2001). The effects of hyperglycemia and MIBG on tumor oxygen tension and on pH(e)
      were investigated in human melanoma xenografts in SCID mice. An oral gavage of 1
      M glucose (2 g/kg) increased the average blood glucose concentration from <140
      mg/dl to approximately 400 mg/dl. Although tumor pH(e) decreased from pH 6.7 to
      pH 6.5 (P < 0.01) after about 60 min, no change in tumor oxygen tension was
      observed. However, when oral glucose and MIBG (15 mg/kg) were administered
      together, oxygen tension increased from 2.8 mmHg to approximately 17 mmHg, and
      tumor pH(e) decreased from pH 6.7 to pH 6.3 (P < 0.01) after about 115 min. In
      conclusion, administration of glucose together with MIBG increases tumor oxygen
      tension and also increases the magnitude and duration of acidification.
      Hyperglycemia plus MIBG has the potential to improve response to radiation
      therapy as well as to hyperthermia and some chemotherapies.

PMID- 12600236
TI  - A mathematical model of tumor oxygen and glucose mass transport and metabolism
      with complex reaction kinetics.
AB  - Hypoxia imparts radioresistance to tumors, and various approaches have been
      developed to enhance oxygenation, thereby improving radiosensitivity. This study
      explores the influence of kinetic and physical factors on substrate metabolism in
      a tumor model, based on a Krogh cylinder. In tissue, aerobic metabolism is
      assumed to depend on glucose and oxygen, represented by the product of Michaelis
      Menten expressions. For the base case, an inlet pO(2) of 40 mmHg, a hypoxic limit
      of 5 mmHg, and a tissue/capillary radius ratio of 10 are used. For purely aerobic
      metabolism, a hypoxic fraction of 0.16 and volume-average pO(2) of 8 mmHg are
      calculated. Reducing the maximum oxygen rate constant by 9%, decreasing the
      tissue cylinder radius by 5%, or increasing the capillary radius by 8% abolishes
      the hypoxic fraction. When a glycolytic term is added, concentration profiles are
      similar to the base case. Using a distribution of tissue/capillary radius ratios
      increases the hypoxic fraction and reduces sensitivity to the oxygen consumption
      rate, compared to the case with a single tissue/capillary radius ratio. This
      model demonstrates that hypoxia is quite sensitive to metabolic rate and
      geometric factors. It also predicts quantitatively the effects of inhibited
      oxygen metabolism and enhanced mass transfer on tumor oxygenation.

PMID- 12600237
TI  - Radiation-induced suppression of the Bmp2 signal transduction pathway in the
      pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of
      heterotopic ossification by radiotherapy.
AB  - Heterotopic ossification is a common complication after total hip replacement.
      Clinical studies showed the effectiveness of radiation for prevention of
      heterotopic ossification. The mechanism of radiotherapy responsible for the
      reduction of heterotopic ossification is unclear. The purpose of this study was
      to study an analogue model showing a time- and dose-dependent effect of
      radiation. Using cells of the defined embryonic mouse cell line C2C12, the
      influence of ionizing radiation on the Bmp-induced signal cascade leading to
      osteogenic differentiation was analyzed. Binding of iodinated Bmp2 to the
      receptors, Smad1 activation, and alkaline phosphatase (ALP) activity were
      determined in cells with or without irradiation. The cytotoxic effect of
      radiotherapy was evaluated using viability tests. Radiotherapy reduced formation
      of the Bmp2/Bmp receptor complex. This effect was dependent on dose. The
      phosphorylation (activation) of Smad1 decreased after irradiation in a time
      dependent manner, whereas the level of total Smads was not influenced by
      radiotherapy. The ALP activity decreased after radiotherapy. A dose of 7 Gy
      delivered 6 h before or after incubation with Bmp resulted in about a 30%
      decrease in ALP activity. No signs of cytotoxic effects were observed within the
      time window studied using doses of 0 to 20 Gy. The time- and dose-dependent
      effect of radiotherapy for prevention of heterotopic ossification known from the
      results of clinical studies has an analogue in the C2C12 cell model. The primary
      mechanism of radiotherapy seems to be an influence on cellular responsiveness to
      the Bmp2-induced osteoblastic differentiation. The results suggest a down
      regulation of the Bmp2/receptor complex.

PMID- 12600238
TI  - Secretion of saliva in X-irradiated rat submandibular glands.
AB  - The mechanism of radiation-induced dysfunction in rat submandibular glands was
      investigated at the cellular level. After X irradiation (single dose, 15 Gy), a
      vacuolation in the acinar cells or an enlargement of the acinar lumen was
      observed as a typical morphological change for 2 weeks. As observed using a video
      enhanced contrast differential interference contrast (VEC-DIC) microscope,
      exocytosis and shrinkage of the acinar cells induced by application of
      pilocarpine (100 microM) were markedly suppressed for 5 days and then recovered
      to 80% of the control levels. Using an immunohistochemical method, no significant
      change was observed in amylase distribution, but a marked loss of aquaporin 5 was
      found in the acinar cells after the irradiation. The extent and time course of
      pilocarpine-induced mobilization of intracellular Ca(2+) did not change after the
      irradiation. We conclude that radiation-induced dysfunction in the salivary
      glands is due to an impairment of exocytosis and a reduction of water secretion.
      The loss of aquaporin 5 and possibly other membrane-fusion proteins in acinar
      cells may be the major mechanism underlying such a dysfunction.

PMID- 12600240
TI  - Evaluation of the effect of ascorbic acid treatment on wound healing in mice
      exposed to different doses of fractionated gamma radiation.
AB  - Alteration of the radiation-induced changes in wound contraction, collagen
      synthesis and wound histology by ascorbic acid was studied in mice exposed to 10,
      16 and 20 Gy of fractionated (2 Gy/fraction) gamma radiation. The animals were
      given double-distilled water or ascorbic acid daily before exposure to 2 Gy/day
      of fractionated irradiation. A full-thickness skin wound was created on the
      dorsum of the irradiated mice, and the progression of wound contraction and
      collagen synthesis were examined and histological evaluations were carried out at
      various times after wounding. Irradiation caused a dose-dependent delay in wound
      contraction, and pretreatment with ascorbic acid resulted in a significant
      increase in wound contraction. The greatest increase in wound contraction was
      observed 6 and 9 days after wounding in both groups. Pretreatment with ascorbic
      acid augmented the synthesis of collagen significantly as revealed by an increase
      in hydroxyproline content. The collagen deposition and fibroblast and vasculature
      densities declined in a dose-dependent manner in groups receiving radiation alone
      as indicated by histological evaluation. Pretreatment with ascorbic acid
      ameliorated the observed effect significantly. These studies demonstrate that
      pretreatment with ascorbic acid resulted in a significant reduction of radiation
      induced delay in wound healing as shown by earlier wound closure and increased
      collagen content and fibroblast and vascular densities.

PMID- 12600239
TI  - Prevention of radiation-induced oral cavity mucositis by plasmid/liposome
      delivery of the human manganese superoxide dismutase (SOD2) transgene.
AB  - Oral cavity mucositis is a major toxicity of radiation therapy for head and neck
      cancer. In the present mouse model studies, we evaluated intraoral administration
      of SOD2-PL complexes 24 h before single-fraction 30-Gy irradiation for the
      prevention of oral cavity mucositis. Expression of the human SOD2 transgene in
      the oral cavity of C3H/HeNsd mice was demonstrated by nested reverse
      transcriptase polymerase chain reaction (RT-PCR). Mice treated intraorally with
      bacterial beta-galactosidase gene-plasmid/liposome (LacZ-PL) or hemagglutinin
      (HA)-manganese superoxide dismutase-plasmid/liposome (HA-SOD2-PL) demonstrated
      LacZ or HA-SOD2 expression, respectively, 24 h after injection. In a second
      strain of mouse, SOD2-PL-treated female athymic nude mice demonstrated
      significantly decreased ulceration at day 5 after 30 Gy, compared to LacZ-PL
      injected, irradiated mice or irradiated controls. No further reduction in
      radiation-induced ulceration was detected in mice treated with both SOD2-PL and
      10 mg/kg of amifostine (WR-2721) 30 min before 30 Gy compared to SOD2-PL alone.
      No significant protection of orthotopically transplanted murine squamous cell
      carcinoma (SCC-VII) tumors was detected in mice that received SOD2-PL treatment
      before 18 Gy. Thus overexpression of human SOD2 in the oral cavity mucosa can
      prevent radiation-induced mucositis with no detectable compromise in the
      therapeutic response of orthotopically transplanted tumors.

PMID- 12600241
TI  - Benchmark studies of the effectiveness of structural and internal materials as
      radiation shielding for the international space station.
AB  - Accelerator-based measurements and model calculations have been used to study the
      heavy-ion radiation transport properties of materials in use on the International
      Space Station (ISS). Samples of the ISS aluminum outer hull were augmented with
      various configurations of internal wall material and polyethylene. The materials
      were bombarded with high-energy iron ions characteristic of a significant part of
      the galactic cosmic-ray (GCR) heavy-ion spectrum. Transmitted primary ions and
      charged fragments produced in nuclear collisions in the materials were measured
      near the beam axis, and a model was used to extrapolate from the data to lower
      beam energies and to a lighter ion. For the materials and ions studied, at
      incident particle energies from 1037 MeV/nucleon down to at least 600
      MeV/nucleon, nuclear fragmentation reduces the average dose and dose equivalent
      per incident ion. At energies below 400 MeV/nucleon, the calculation predicts
      that as material is added, increased ionization energy loss produces increases in
      some dosimetric quantities. These limited results suggest that the addition of
      modest amounts of polyethylene or similar material to the interior of the ISS
      will reduce the dose to ISS crews from space radiation; however, the radiation
      transport properties of ISS materials should be evaluated with a realistic space
      radiation field.

PMID- 12600242
TI  - Germanium oxide enhances the radiosensitivity of cells.
AB  - We investigated here the combined effect of GeO(2) and radiation on cell
      viability. Cells were treated with 0 to 22 mM GeO(2) for 12 h followed by 1 Gy X
      irradiation. A synergistic cytotoxic effect was observed for the combined
      treatment with a dose-dependent reduction of cell viability. Complete survival
      curves showed a 2.3- and 2.75-fold increase in radiosensitivity for 50% cell
      death in the presence of 5 and 15 mM GeO(2), respectively. The increased
      radiosensitivity also occurred when GeO(2) was given either 4 h prior to
      irradiation or immediately after radiation exposure. GeO(2) did not affect the
      total soluble thiol content or the activities of catalase and glutathione S
      transferase. Analysis of the production of reactive oxygen species (ROS) revealed
      that the combined treatment dramatically increased the synthesis of ROS. Addition
      of N-acetyl cysteine (NAC, 20 mM) decreased the production of ROS in cells. NAC,
      however, increased cell viability only slightly after treatment with GeO(2) and
      radiation. Thus increased production of ROS makes little or no contribution to
      the observed death. The combination of GeO(2) and X radiation, however,
      significantly increased the frequency of DNA double-strand breaks (DSBs).
      Notably, the presence of GeO(2) also reduced the efficiency of DNA repair. We
      conclude that treatment with GeO(2) followed by X irradiation increases DNA DSBs
      and cell death.

PMID- 12600243
TI  - Simulation of DNA damage after proton irradiation.
AB  - The biophysical radiation track simulation model PARTRAC was improved by
      implementing new interaction cross sections for protons in water. Computer
      simulated tracks of energy deposition events from protons and their secondary
      electrons were superimposed on a higher-order DNA target model describing the
      spatial coordinates of the whole genome inside a human cell. Induction of DNA
      double-strand breaks was simulated for proton irradiation with LET values between
      1.6 and 70 keV/microm and various reference radiation qualities. The yield of
      DSBs after proton irradiation was found to rise continuously with increasing LET
      up to about 20 DSBs per Gbp and Gy, corresponding to an RBE up to 2.2. About half
      of this increase resulted from a higher yield of DSB clusters associated with
      small fragments below 10 kbp. Exclusion of experimentally unresolved multiple
      DSBs reduced the maximum DSB yield by 30% and shifted it to an LET of about 40
      keV/microm. Simulated fragment size distributions deviated significantly from
      random breakage distributions over the whole size range after irradiation with
      protons with an LET above 10 keV/microm. Determination of DSB yields using
      equations derived for random breakage resulted in an underestimation by up to
      20%. The inclusion of background fragments had only a minor influence on the
      distribution of the DNA fragments induced by radiation. Despite limited numerical
      agreement, the simulations reproduced the trends in proton-induced DNA DSBs and
      fragment induction found in recent experiments.

PMID- 12600244
TI  - Electron and hole transfer from DNA base radicals to oxidized products of guanine
      in DNA.
AB  - An investigation of electron and hole transfer to oxidized guanine bases in DNA
      is reported. Guanine in DNA was preferentially oxidized by Br(2)(*-) at 298 K to
      8-oxo-7,8-dihydro-guanine (8-oxo-G) and higher oxidation products. HPLC-EC
      analysis of irradiated DNA shows that the formation of 8-oxo-G could not be
      increased above the ratio of one 8-oxo-G to 127 +/- 6 bp regardless of dose. 8
      oxo-G can be produced only at low levels because it is further oxidized to other
      species. These oxidation products of guanine have been extensively investigated
      and identified by others. Our electron spin resonance studies suggest that at 77
      K 8-oxo-G is a trap for radiation-produced holes, but certain further oxidation
      products of 8-oxo-G (G(ox)) are found to be efficient electron traps. Gamma
      irradiation of oxidized DNA samples in frozen (D(2)O) aqueous ices and glassy 7 M
      LiBr solutions resulted in radicals formed by electron attachment to the G(ox)
      sites that were monitored by electron spin resonance spectroscopy (ESR) at 77 K.
      These ESR spectra suggest that those oxidation products of 8-oxo-G containing
      alpha-diketo groups account for the electron traps (G(ox)) in oxidized DNA with
      oxaluric acid a likely major trap. Electron transfer from DNA anion radicals to
      G(ox) was followed by monitoring of their ESR signals with time at 77 K. Using
      typical values for the tunneling constant beta estimates of the relative amount
      of G(ox) to base pairs were obtained. Radicals formed by UV photolysis of
      oxidized DNA in 8 M NaClO(4) glassy aqueous solutions were also investigated. The
      8-oxo-G cation accounts for less than 10% of all the radicals observed after
      either gamma irradiation of oxidized DNA in frozen (D(2)O) aqueous solution or UV
      photolysis of oxidized DNA in 8 M NaClO(4) glassy aqueous solutions. We estimate
      hole transfer distances of about 7 +/- 1 bp at 1 min from G(*+) to 8-oxo-G.

PMID- 12600245
TI  - Caffeine could not efficiently sensitize homologous recombination repair
      deficient cells to ionizing radiation-induced killing.
AB  - Caffeine inhibits ATM and ATR, two important checkpoint regulators, abolishes
      ionizing radiation-induced checkpoint response, and radiosensitizes cells.
      Radiation-induced DNA double-strand breaks (DSBs) are repaired by two major
      processes, homologous recombination repair (HRR) and nonhomologous end joining
      (NHEJ). It remains unclear which repair process, HRR or NHEJ, is affected when
      the checkpoint responses are abolished by caffeine. In this study we observed the
      effect of caffeine on gene-targeted DT40 chicken lymphoblast cells. We show that
      caffeine efficiently abolishes S- and G(2)-phase checkpoint responses after
      irradiation in all cell lines tested and greatly radiosensitizes wild-type and
      ATM(-/-) cells, the partially checkpoint-deficient cells. However, caffeine has a
      much smaller radiosensitizing effect on RAD54(-/-) cells and has no effect on
      RAD51-deficient cells. RAD51 and RAD54 are the important factors for HRR. Our
      results indicate that the checkpoint responses abolished by caffeine (S and G(2))
      mainly affect HRR, which results in cell radiosensitization.

PMID- 12600246
TI  - Caffeine-induced radiosensitization is independent of nonhomologous end joining
      of DNA double-strand breaks.
AB  - After exposure to ionizing radiation, proliferating cells actively slow down
      progression through the cell cycle through the activation of checkpoints to
      provide time for repair. Two major complementary DNA double-strand break (DSB)
      repair pathways exist in mammalian cells, homologous recombination repair (HRR)
      and nonhomologous end joining (NHEJ). The relationship between checkpoint
      activation and these two types of DNA DSB repair pathways is not clear. Caffeine,
      as a nonspecific inhibitor of ATM and ATR, abolishes multi-checkpoint responses
      and sensitizes cells to radiation-induced killing. However, it remains unknown
      which DNA repair process, NHEJ or HRR, or both, is affected by caffeine-abolished
      checkpoint responses. We report here that caffeine abolishes the radiation
      induced G(2)-phase checkpoint and efficiently sensitizes both NHEJ-proficient and
      NHEJ-deficient mammalian cells to radiation-induced killing without affecting
      NHEJ. Our results indicate that caffeine-induced radiosensitization occurs by
      affecting an NHEJ-independent process, possibly HRR.

PMID- 12600247
TI  - Low-dose reduction in transformation frequency compared to unirradiated controls:
      the role of hyper-radiosensitivity to cell death.
AB  - Calculations based on plausible parameters taken from the existing experimental
      database, and new measurements on the cell cycle dependence of low-dose hyper
      radiosensitivity (HRS) of non-tumorigenic HeLa x skin fibroblast human hybrid
      cells, provide the first experimental evidence that the selective killing of a
      transformation-sensitive G(2)/M-phase subpopulation as a consequence of low-dose
      HRS could account in part for the observed reduction of induced transformation
      frequencies at low doses to values below that observed spontaneously. However, it
      is clear that other mechanisms associated with classical adaptive response, such
      as induced DNA repair, are also likely to be involved.

PMID- 12600248
TI  - Clinical practice guidelines: a guide to better practice, not a recipe for
      uniformity.

PMID- 12600249
TI  - The epidemiology and causes of cerebral palsy.
AB  - Cerebral palsy is the commonest physical disability in childhood, occurring in
      2.0 to 2.5 per 1000 live births. Although the total number of children with
      cerebral palsy has remained stable or increased slightly since 1970, there has
      been a consistent rise in the proportion of cerebral palsy associated with
      preterm and very preterm births. Known causes of cerebral palsy--whether
      prenatal, perinatal or postnatal--must be distinguished from risk factors or
      associations. Much is known about such risk factors which, alone or in
      combination, may indirectly result in cerebral palsy. Causes and risk factors
      implicated in cerebral palsy are discussed in detail, together with directions
      for future research.

PMID- 12600251
TI  - Secondary and tertiary prevention in the management of low-trauma fracture.
AB  - A significant risk factor for osteoporotic fracture is a previous atraumatic
      fracture. The objective of this study was to investigate whether patients with
      Colles fracture from minimal trauma were subsequently identified, assessed and
      treated for their elevated risk of fracture. Medical records at Sir Charles
      Gairdner Hospital in Perth, Western Australia, from August 1999 to July 2000 were
      audited and 111 patients who had sustained a Colles fracture from minimal trauma
      were identified. Questionnaires were subsequently posted to participants to
      determine whether any assessment or treatment was undertaken outside the hospital
      system. According to documentation in the medical records, 9% (10/111) had their
      bone mineral density assessed, 15% (17/111) were receiving medical therapy for
      osteoporosis, 7% (8/111) had their falls risk assessed and 51% (58/111) were seen
      by a physiotherapist. Of the 58 who received physiotherapy, 76% (44/58) received
      upper limb exercises and 19% (11/58) received lower limb or balance exercises.
      Follow-up questionnaires one to two years after the fracture were returned by 43%
      (48/111) of the sample. By this time, 37% (18/48) had BMD assessed and 27%
      (13/48) were receiving medical therapy for osteoporosis. Thirty-five per cent
      (17/48) of patients recalled being advised to increase their calcium intake. Of
      those who reported more than one fall during the past 12 months, 62% (8/13) had
      been seen by a physiotherapist, 46% (6/13) reported having their balance assessed
      and 54% (7/13) reported having a home visit for assessment of rails etc. Despite
      the availability of effective treatments, a substantial proportion of patients
      with Colles fracture from minimal trauma are not all being identified, assessed
      or treated for their elevated risk of subsequent osteoporotic fracture.

PMID- 12600250
TI  - A randomised trial of weight-bearing versus non-weight-bearing exercise for
      improving physical ability in inpatients after hip fracture.
AB  - The purpose of this study was to assess the effects of weight-bearing and non
      weight-bearing exercise on strength, balance, gait and functional performance
      among older inpatients following hip fracture. Eighty people (mean age 81 years,
      SD 8) undergoing inpatient rehabilitation after fall-related hip fracture were
      randomised to receive two-week programs of either weight-bearing or non-weight
      bearing exercise prescribed by a physiotherapist. Both groups improved markedly
      (in the order of 50%) on measures of physical ability. Overall there was little
      difference between groups in the extent of improvement, however post hoc testing
      identified some additional strength benefits for the non-weight-bearing group-
      non-affected leg hip flexion mean difference in extent of improvement was 9.3 N
      (95% CI 3.7 to 15.0), non-affected leg hip abduction mean difference in extent of
      improvement was 6.5 N (95% CI 0.1 to 12.9). There were also additional functional
      benefits for the weight-bearing group--improved ability to complete a lateral
      step-up on the affected leg with nil or one hand supports (OR 3.4, 95% CI 1.1 to
      12.3) and the need for less supportive walking aids (p = 0.045). Weight-bearing
      and non-weight-bearing exercise programs produce similar effects on strength,
      balance, gait and functional performance among inpatients soon after hip
      fracture.

PMID- 12600252
TI  - The effect of circuit type, volume delivered and "rapid release" on flow rates
      during manual hyperinflation.
AB  - Traditionally, manual hyperinflation has been performed using "rapid release" to
      promote a fast peak expiratory flow rate (PEFR) but rapid release has not been
      described. In addition, it has been demonstrated that different resuscitation
      circuits provide varying degrees of resistance to expiratory flow and it is known
      that a variety of circuits are used in Australia for manual hyperinflation. The
      aim of this study was to document current practice, the effect of rapid release,
      controlling inspiration, different volumes and circuit type on flow rates, and
      the inspiratory to expiratory flow rate (I:E) ratio during manual hyperinflation.
      Using a test lung model, 15 physiotherapists performed 11 trials using the Air
      Viva 2, a Mapleson-C and a Mapleson-F circuit, both with and without rapid
      release, and delivering two volumes. The order of the trials was randomised.
      Rapid release produced a faster PEFR irrespective of circuit type or volume
      delivered. The effect of rapid release, and the absolute PEFR, was less for the
      Air Viva 2 compared with the Mapleson circuits. Expiratory flow rate was faster
      for the larger volume. The theoretically optimal I:E ratio to move secretions was
      achieved delivering the lower target volume with the Mapleson circuits and using
      rapid release.

PMID- 12600253
TI  - Physical activity levels of adolescents with congenital heart disease.
AB  - Regular physical activity prevents chronic disease and moderate to vigorous
      participation provides additional health benefits. Therefore, adolescents with
      congenital heart disease risk developing latent diseases due to real or perceived
      physical activity restrictions. Habitual physical activity levels, psychological
      determinants and advice received were examined by postal survey of 434 West
      Australian adolescents aged 12-18 years with congenital heart disease. Survey
      results (n = 153) were compared with published normative adolescent data. Total
      activity was classified as vigorous, adequate or inadequate according to
      metabolic equivalents, reported frequency and duration. Comparable numbers of
      respondents and healthy peers were active (winter 62% vs 74%; and summer 73% vs
      82% respectively, p = 0.27). However, significantly fewer male respondents were
      classified as vigorously active compared with healthy peers, in both winter (48%
      vs 67%, p < 0.02), and summer (48% vs 69%, p = 0.04). Similar, but non
      significant, trends were found when comparing female respondents with healthy
      peers and for mild versus severe disease groups. Self-efficacy ratings did not
      explain differences in physical activity intensity. Congenital heart disease may
      impact on the intensity of physical activity undertaken by affected adolescents
      thus denying additional health benefits. Physiotherapists could facilitate these
      adolescents to achieve more moderate to vigorous physical activity, to offset
      adult sedentary behaviour.

PMID- 12600254
TI  - The difficult patient in private practice physiotherapy: a qualitative study.
AB  - This qualitative study utilised the nominal group technique to identify a
      typology of the difficult patient in private practice physiotherapy and to
      determine strategies physiotherapists use, and would like to improve, when
      dealing with such patients. The two areas physiotherapists found most difficult
      to manage were behavioural problems of patients and patient expectations. Few
      differences were evident regarding ranking of difficult patient attributes
      between the experienced (n = 19) and less experienced (n = 18) physiotherapists
      except for the categories of pain and diagnosed psychological problems. While
      less experienced physiotherapists ranked the pain category highly, experienced
      physiotherapists did not identify this category. Further, more experienced
      physiotherapists specifically distinguished between patients with diagnosed
      psychological problems and patients with psychosocial concerns, while less
      experienced physiotherapists did not, and placed both these issues into one
      category. To assist in their interaction with difficult patients,
      physiotherapists (n = 37) identified that communication skills and behaviour
      modification techniques were strategies that they would like to learn more about.
      The results of this qualitative study contribute to the evolving literature
      relating to physiotherapist-patient interactions and form a useful basis for
      educational programs directed at improving the therapeutic relationship in
      private practice physiotherapy.

PMID- 12600255
TI  - Cervical manipulation requires advanced technical skills plus sound clinical
      reasoning (Comment on Refshauge K et al, Australian Journal of Physiotherapy 48:
      171-179 and Jull G et al, Australian Journal of Physiotherapy 48: 180-183).

PMID- 12600256
TI  - Spinal manipulation for chronic low back pain--where to from here? (Comment on
      Ferreira et al, Australian Journal of Physiotherapy 48: 277-284).

PMID- 12600258
TI  - Editorial explains why electrophysical agents are still important in
      physiotherapy education. (Comment on Laakso EL et al, Australian Journal of
      Physiotherapy 48: 251-254).

PMID- 12600259
TI  - Selective citation did not advance debate on electrophysical agents. (Comment on
      Laakso EL et al, Australian Journal of Physiotherapy 48: 251-254).

PMID- 12600261
TI  - Signal transduction and protein phosphorylation in smooth muscle contraction.
AB  - Smooth muscles are important constituents of vertebrate organisms that provide
      for contractile activity of internal organs and blood vessels. Basic molecular
      mechanism of both smooth and striated muscle contractility is the force-producing
      ATP-dependent interaction of the major contractile proteins, actin and myosin II
      molecular motor, activated upon elevation of the free intracellular Ca2+
      concentration ([Ca2+](i)). However, whereas striated muscles display a
      proportionality of generated force to the [Ca2+](i) level, smooth muscles feature
      molecular mechanisms that modulate sensitivity of contractile machinery to
      [Ca2+](i). Phosphorylation of proteins that regulate functional activity of
      actomyosin plays an essential role in these modulatory mechanisms. This provides
      an ability for smooth muscle to contract and maintain tension within a broad
      range of [Ca2+](i) and with a low energy cost, unavailable to a striated muscle.
      Detailed exploration of these mechanisms is required to understand the molecular
      organization and functioning of vertebrate contractile systems and for
      development of novel advances for treating cardiovascular and many other
      disorders. This review summarizes the currently known and hypothetical mechanisms
      involved in regulation of smooth muscle Ca2+-sensitivity with a special reference
      to phosphorylation of regulatory proteins of the contractile machinery as a means
      to modulate their activity.

PMID- 12600262
TI  - Molecular mechanisms of the cross-impact of pathological processes in combined
      diabetes and cancer. Research and clinical aspects.
AB  - The mechanisms of interaction and cross-impact of metabolic processes in a
      combined diabetes and cancer condition are discussed. A hypothesis is proposed
      whereby the processes responsible for destruction of the organism in the case of
      diabetes--long-term hyperglycemia and generation of methylglyoxal--may
      substantially impact tumor development. The hypothesis is based on the fact that
      both diabetes and carcinogenesis cause dysfunction of the vital cellular signal
      system regulated by the protein kinase C (PKC) family. Normalization of the PKC
      functional activity in the case of diabetes restrains development of diabetic
      complications and inhibits the processes of tumor growth and metastasizing in
      carcinogenesis. On this basis, an attempt is made to interpret both the
      detrimental and beneficial effects of diabetes on cancer. The resultant effect is
      determined by the type of tumor and the duration and level of hyperglycemia. The
      mechanisms of the impact of diabetes mellitus on cancer are analyzed to develop
      recommendations for combined cancer therapy options.

PMID- 12600263
TI  - Role of tumor necrosis factor alpha and sphingomyelin cycle activation in the
      induction of apoptosis by ischemia/reperfusion of the liver.
AB  - The signal transduction pathways triggering apoptotic mechanisms after
      ischemia/reperfusion may involve TNF-alpha secretion, ceramide generation, and
      initiation of lipid peroxidation. In the present study involvement of the TNF
      alpha, sphingomyelin cycle, and lipid peroxidation in the initiation of apoptosis
      induced in liver cells by ischemia and reperfusion was investigated. Wistar rats
      were subjected to total liver ischemia (for 15, 30 min, and 1 h) followed by
      subsequent reperfusion. Ischemia caused sharp decrease of neutral
      sphingomyelinase activity. Activity of acidic sphingomyelinase initially
      decreased (during 15-30 min ischemia) but then increased (after 1 h of ischemic
      injury). Reperfusion of the ischemic lobe of the liver caused increase in neutral
      sphingomyelinase activity and decrease in acidic sphingomyelinase activity. A
      small amount of TNF-alpha detected by immunoblotting analysis was accumulated in
      the ischemic area of liver rapidly and the content of this cytokine dramatically
      increased after the reperfusion. TNF-alpha is known to induce free radical
      production. We found that the accumulation of TNF and increase of
      sphingomyelinase activity during the development of ischemic/reperfusion injury
      coincided with increase in content of lipid peroxidation products (conjugated
      dienes) and DNA degradation detected by gel electrophoresis. Recently it was
      shown that superoxide radicals are used as signaling molecules within the
      sphingomyelin pathway. This suggests the existence of cross-talk between the
      oxidation system and the sphingomyelin cycle in cells, which may have important
      implications for the initial phase and subsequent development of post-ischemic
      injury.

PMID- 12600264
TI  - Analysis of bispecific monoclonal antibody binding to immobilized antigens using
      an optical biosensor.
AB  - The interaction between two different monoclonal antibodies (Mabs) and their
      corresponding bispecific antibodies (Babs) with immobilized antigens was
      investigated using an optical biosensor (IAsys). The analyzed panel of affinity
      purified antibodies included two parental Mabs (one of which was specific to
      human IgG (hIgG), and another one to horseradish peroxidase (HRP)), as well as
      Babs derived thereof (anti-hIgG/HRP). Babs resulting from the fusion of parental
      hybridomas bear two antigen-binding sites toward two different antigens and thus
      may interact with immobilized antigen through only one antigen-binding site
      (monovalently). Using an IAsys biosensor this study shows that the bivalent
      binding of Mabs predominates over the monovalent binding with immobilized HRP,
      whereas anti-hIgG parental Mabs were bound monovalently to the immobilized hIgG.
      The observed equilibrium association constant (K(ass)) values obtained in our
      last work [1] by solid-phase radioimmunoassay are consistent with those constants
      obtained by IAsys. The K(ass) of anti-HRP Mabs was about 50 times higher than
      that of anti-HRP shoulder of Babs. The dissociation rate constant (k(diss)) for
      anti-HRP shoulder of Babs was 21 times higher than k(diss) for anti-HRP Mabs. The
      comparison of the kinetic parameters for bivalent anti-HRP Mabs and Babs derived
      from anti-Mb/HRP and anti-hIgG/HRP, allowed to calculate that 95% of bound anti
      HRP Mabs are bivalently linked with immobilized HRP, whereas only 5% of bound
      anti-HRP Mabs are monovalently linked. In general, the data obtained indicate
      that Babs bearing an enzyme-binding site may not be efficiently used instead of
      traditional antibody-enzyme conjugates in the case of binding of bivalent Mabs.

PMID- 12600266
TI  - Structure of tanacetan, a pectic polysaccharide from tansy Tanacetum vulgare L.
AB  - Tanacetan TVF was found to have a branched structure with a backbone of linear
      alpha-1,4-D-galacturonan. The ramified regions consist of linear alpha-1,2-L
      rhamno-alpha-1,4-D-galacturonan as the core. The side chains appear to attach to
      the 4-position of the L-rhamnopyranose residues. They are present as single beta
      galactopyranose residues or a branching beta-1,4-galactopyranan bearing 4,6
      substituted beta-D-galactopyranose residues as branched points. In addition, the
      ramified regions contain side chains of a branched alpha-1,5-arabinofuranan
      possessing 2,5- and 3,5-substituted alpha-L-arabinofuranose residues as branching
      points. Some side chains of rhamnogalacturonan appear to be arabinogalactan which
      contains branched sugar chains of alpha-1,5-arabinofuranan attached to the linear
      chains of beta-1,4-galactopyranan by 1,3- and 1,6-linkages. The residues of alpha
      L-arabinofuranose seem to occupy the terminal positions of the arabinogalactan
      side chains.

PMID- 12600265
TI  - Engineering of bacteriophage T4 tail sheath protein.
AB  - Gene product 18 (gp18, 659 amino acids) forms bacteriophage T4 contractile tail
      sheath. Recombinant protein assembles into different length polysheaths during
      expression in the cell, which complicates the preparation of protein crystals for
      its spatial structure determination. To design soluble monomeric gp18 mutants
      unable to form polysheaths and useful for crystallization, we have used Bal31
      nuclease for generation deletions inside gene 18 encoding the Ile507-Gly530
      region. Small deletions in the region of Ile507-Ile522 do not affect the protein
      assembly into polysheaths. Protein synthesis termination occurs because of
      reading frame failure in the location of deletions. Some fragments of gp18
      containing short pseudo-accidental sequence in the C-terminal, while being
      soluble, have lost the ability for polysheath assembly. For the first time we
      succeeded in obtaining crystals of a soluble gp18 fragment containing 510 amino
      acids which, according to trypsin resistance, is similar to native protein
      monomer.

PMID- 12600267
TI  - Study of the spontaneous dissociation of rabbit C-reactive protein.
AB  - C-Reactive protein (CRP) is composed of five identical noncovalently linked
      monomers and characterized as an important acute-phase protein. The CRP subunit
      obtained by denaturing treatments, which is termed modified CRP, has also been
      widely studied. In the current work, we found that there exists some degree of
      natural dissociation of CRP in stock solution. This dissociation is critically
      dependent on the absence of Ca2+. Low pH could enhance the dissociation of CRP,
      while ionic strength has little effect. Anilinonaphthalenesulfonate (ANS)
      fluorescence detections indicate that the exposure of hydrophobic surface
      increases during the dissociation. Acidic pH conditions also induce an increase
      in ANS fluorescence. This suggests that hydrophobic interactions between CRP
      subunits may contribute to the study of its pentameric structure. Surface plasmon
      resonance experiments indicate that monomeric CRP does not specifically bind to
      phosphatidylcholine-containing membrane as native CRP does. Electron microscopy
      shows that monomeric CRP binds to negatively charged lipid through electrostatic
      forces, and such lipid may induce the dissociation of CRP due to the acidic pH in
      the diffuse double layer near the membrane.

PMID- 12600268
TI  - Study of antiproteinase activity of acylated derivatives of Bowman-Birk soybean
      proteinase inhibitor.
AB  - The effect of acylation of Bowman-Birk soybean proteinase inhibitor (BBI) by
      derivatives of various unsaturated fatty acids on inhibition of trypsin, alpha
      chymotrypsin, and human leukocyte elastase was investigated. Inhibition (K(i))
      and kinetic (k(ass), k(diss)) constants of interaction between proteases and
      acylated BBI derivatives were determined. For mono-, di-, and triacylated BBI
      derivatives, insertion of two oleic residues into the BBI molecule was
      demonstrated to be more potent for exhibiting antiproteinase activity.

PMID- 12600269
TI  - Subunit interaction slows the unfolding of the N-terminal domain of creatine
      kinase in urea.
AB  - Fluorescence emission intensity changes with two different excitation wavelengths
      were used to measure the unfolding rate constants of different domains of muscle
      type creatine kinase (CK-MM) according to the heterogeneity of aromatic amino
      acid distributions in the crystal structure of CK-MM. The results were compared
      with those of brain type creatine kinase (CK-BB) and dithio-bis(succinimidyl
      propionate) cross-linked CK-MM. CK-BB differed greatly in its distribution of
      aromatic amino acids in each domain and the unfolding process of cross-linked CK
      MM was not accompanied by the dissociation of the dimer. The N-terminal domain of
      CK-MM was shown to be well protected by subunit interaction during the unfolding
      of CK-MM in 4 M urea. Dissociating the CK dimer in high urea concentration (> or
      = 6 M) eliminated the subunit protection. Subunit interactions are also important
      in preserving secondary structure and forming contracted conformation at low urea
      concentration.

PMID- 12600270
TI  - Kinetic mechanism of mitochondrial NADH:ubiquinone oxidoreductase interaction
      with nucleotide substrates of the transhydrogenase reaction.
AB  - The effects of Tinopals (cationic benzoxazoles) AMS-GX and 5BM-GX on NADH
      oxidase, NADH:ferricyanide reductase, and NADH --> APAD+ transhydrogenase
      reactions and energy-linked NAD+ reduction by succinate, catalyzed by
      NADH:ubiquinone oxidoreductase (Complex I) in submitochondrial particles (SMP),
      were investigated. AMS-GX competes with NADH in NADH-oxidase and
      NADH:ferricyanide reductase reactions (K(i) = 1 micro M). 5BM-GX inhibits those
      reactions with mixed type with respect to NADH (K(i) = 5 micro M) mechanism.
      Neither compound affects reverse electron transfer from succinate to NAD+. The
      type of the Tinopals' effect on the NADH --> APAD+ transhydrogenase reaction,
      occurring with formation of a ternary complex, suggests the ordered binding of
      nucleotides by the enzyme during the reaction: AMS-GX and 5BM-GX inhibit this
      reaction uncompetitively just with respect to one of the substrates (APAD+ and
      NADH, correspondingly). The competition between 5BM-GX and APAD+ confirms that
      NADH is the first substrate bound by the enzyme. Direct and reverse electron
      transfer reactions demonstrate different specificity for NADH and NAD+ analogs:
      the nicotinamide part of the molecule is significant for reduced nucleotide
      binding. The data confirm the model suggesting that during NADH --> APAD+
      reaction, occurring with ternary complex formation, reduced nucleotide interacts
      with the center participating in NADH oxidation, whereas oxidized nucleotide
      reacts with the center binding NAD+ in the reverse electron transfer reaction.

PMID- 12600271
TI  - Activation of C-terminal Src kinase (Csk) by phosphorylation at serine-364
      depends on the Csk-Src homology 3 domain.
AB  - In the present study, we investigate the mechanism for the protein kinase A (PKA)
      mediated activation of C-terminal Src kinase (Csk). Although isolated Csk kinase
      domain was phosphorylated at Ser(364) by PKA to the same stoichiometry as wild
      type Csk, significant activation of the isolated Csk kinase domain by PKA was
      observed only in the presence of the purified Src homology 3 domain (SH3 domain).
      Furthermore, the interaction between the SH3 and kinase domains was facilitated
      by PKA-mediated phosphorylation of the kinase domain, as evaluated by surface
      plasmon resonance. This suggests that an overall structural domain organization
      and interaction between the kinase and SH3 domains are important for the activity
      of Csk and its regulation by PKA.

PMID- 12600272
TI  - Direct binding of a fragment of the Wiskott-Aldrich syndrome protein to the C
      terminal end of the anaphylatoxin C5a receptor.
AB  - Migration of myeloid cells towards a source of chemoattractant, such as the C5a
      anaphylatoxin, is triggered by the activation of a G-protein-coupled receptor. In
      the present study, we have used a yeast two-hybrid approach to find unknown
      partners of the C5a receptor (C5aR). Using the cytosolic C-terminal region of
      C5aR as bait to screen a human leucocyte cDNA library, we identified the Wiskott
      Aldrich syndrome protein (WASP) as a potential partner of C5aR. WASP is known to
      have an essential function in regulating actin dynamics at the cell leading edge.
      The interaction was detected with both the fragment of WASP containing amino
      acids 1-321 (WASP.321) and WASP with its actin-nucleation-promoting domain
      [verprolin-like, central and acidic (VCA) domain] deleted. The interaction
      between C5aR and the WASP.321 was supported further by an in vitro binding assay
      between a radiolabelled WASP.321 fragment and a receptor C-terminus glutathione S
      transferase (GST) fusion protein, as well as by GST pull-down, co
      immunoprecipitation and immunofluorescence experiments. In the yeast two-hybrid
      assay, full-length WASP showed no ability to interact with the C-terminal domain
      of C5aR. This is most probably due to an auto-inhibited conformation imposed by
      the VCA domain. In HEK-293T cells co-transfected with full-length WASP and C5aR,
      only a small amount of WASP was co-precipitated with the receptor. However, in
      the presence of the active form of the GTPase Cdc42 (Cdc42V12), which is thought
      to switch WASP to an active 'open conformation', the amount of WASP associated
      with the receptor was markedly increased. We hypothesize that a transient
      interaction between C5aR and WASP occurs following the stimulation of C5aR and
      Cdc42 activation. This might be one mechanism by which WASP is targeted to the
      plasma membrane and by which actin assembly is spatially controlled in cells
      moving in a gradient of C5a.

PMID- 12600274
TI  - Psoriasin (S100A7) expression is altered during skin tumorigenesis.
AB  - BACKGROUND: Psoriasin (S100A7) expression has previously been associated with
      psoriasiform hyperplasia as well as with tumor progression in breast cancer. Its
      expression profile for different stages of skin lesions is unknown. The aim of
      this study was to determine the relationship between psoriasin (S100A7) and tumor
      progression in skin. METHODS: Psoriasin was assessed by immunohistochemistry and
      levels of expression determined by semi-quantitative scoring in skin biopsies
      from 50 patients. The cohort included normal skin, actinic keratosis, squamous
      carcinoma in-situ, invasive squamous cell carcinoma, and basal cell carcinoma.
      RESULTS: In normal skin, psoriasin was rarely detected in epidermis but was
      expressed in underlying adnexae. In abnormal epidermis psoriasin was frequently
      expressed in abnormal keratinocytes in actinic keratosis, in-situ and invasive
      squamous cell carcinoma, but was rarely observed in the basal epidermal layer or
      in superficial or invasive basal cell carcinoma. The highest levels of expression
      were seen within squamous carcinoma in-situ. Significantly reduced levels of
      expression were observed in both unmatched (p = 0.0001) and matched (p < 0.004)
      invasive squamous cell carcinoma. Psoriasin expression within abnormal squamous
      lesions correlated with mitotic count (r = 0.54, p = 0.0036), however no
      significant relation was found with the intensity of dermal inflammatory cell
      infiltrates assessed within each pathology. CONCLUSION: These results suggest
      that altered psoriasin expression occurs in abnormal epidermis and that
      downregulation may be related to the onset of invasion in squamous cell carcinoma
      in skin.

PMID- 12600275
TI  - Determinants of the clinical course of musculoskeletal complaints in general
      practice: design of a cohort study.
AB  - BACKGROUND: Musculoskeletal complaints are frequent and have large consequences
      for public health. Information about the prognosis after presentation in general
      practice is far from complete. Knowledge about determinants of the clinical
      course of musculoskeletal complaints is essential for management decisions and to
      inform patients about their prognosis. The purpose of this study is to provide
      information about the prognosis of musculoskeletal complaints other than low back
      pain by studying the course of these complaints in general practice and to
      identify determinants of this course. METHODS: Patients of 18 years and older,
      who present in general practice with a new episode of a musculoskeletal complaint
      of the neck, shoulder, elbow, wrist, hand, arm, hip, knee, ankle or foot, are
      recruited by their general practitioner (GP). Participants will receive complaint
      specific questionnaires by mail at baseline and after 3, 6, 12 and 18 months. The
      following putative determinants of the course of the complaints will be
      investigated: sociodemographic characteristics, characteristics of the complaint,
      psychosocial job characteristics, physical workload, physical activity during
      leisure time, pain coping, mood, kinesiophobia, social support, optimism. The
      primary outcomes are perceived recovery, pain, functional status, sick leave and
      overall quality of life.

PMID- 12600273
TI  - Signalling specificity of Ser/Thr protein kinases through docking-site-mediated
      interactions.
AB  - Signal transduction pathways use protein kinases for the modification of protein
      function by phosphorylation. A major question in the field is how protein kinases
      achieve the specificity required to regulate multiple cellular functions. Here we
      review recent studies that illuminate the mechanisms used by three families of
      Ser/Thr protein kinases to achieve substrate specificity. These kinases rely on
      direct docking interactions with substrates, using sites distinct from the
      phospho-acceptor sequences. Docking interactions also contribute to the
      specificity and regulation of protein kinase activities. Mitogen-activated
      protein kinase (MAPK) family members can associate with and phosphorylate
      specific substrates by virtue of minor variations in their docking sequences.
      Interestingly, the same MAPK docking pocket that binds substrates also binds
      docking sequences of positive and negative MAPK regulators. In the case of
      glycogen synthase kinase 3 (GSK3), the presence of a phosphate-binding site
      allows docking of previously phosphorylated (primed) substrates; this docking
      site is also required for the mechanism of GSK3 inhibition by phosphorylation. In
      contrast, non-primed substrates interact with a different region of GSK3.
      Phosphoinositide-dependent protein kinase-1 (PDK1) contains a hydrophobic pocket
      that interacts with a hydrophobic motif present in all known substrates, enabling
      their efficient phosphorylation. Binding of the substrate hydrophobic motifs to
      the pocket in the kinase domain activates PDK1 and other members of the AGC
      family of protein kinases. Finally, the analysis of protein kinase structures
      indicates that the sites used for docking substrates can also bind N- and C
      terminal extensions to the kinase catalytic core and participate in the
      regulation of its activity.

PMID- 12600276
TI  - Effects of aging on vibration detection thresholds at various body regions.
AB  - BACKGROUND: The ability to detect sinusoidal vibrations on the skin surface is
      dependent on the activation of two classes of receptors. The density of such
      receptors varies across the skin surface and is a factor in determining the
      sensory acuity of each skin area. However, the acuity of many sensory systems is
      known to deteriorate with advancing age. The aim of this study was to determine
      if vibrotactile sensibility of several skin surfaces deteriorated equally with
      advancing age. METHODS: Vibration detection thresholds for two frequencies of
      vibration (30 Hz and 200 Hz) were determined using a method of limits protocol,
      in two groups of healthy adults, one group aged 17 to 27 years and the other aged
      55 to 90 years. Sinusoidal vibrations were generated by a computer and delivered
      to the skin surface via the probe (diameter = 2 mm) of a mechanical vibrator.
      Four skin sites (palmar surface of the tip of the middle finger, volar surface of
      the forearm, lateral aspect of the shoulder, cheek just caudal to the zygoma)
      were tested. RESULTS: The fingertip was the most sensitive site for vibrotactile
      detection at both frequencies in a substantial majority of subjects. The older
      group of subjects showed significantly higher detection thresholds for both
      frequencies at all sites, except the fingertip, when compared to young subjects.
      CONCLUSION: The study confirms the deterioration of vibrotactile acuity at
      several skin sites previously reported in the literature. However, there appears
      to be no significant reduction in vibrotactile detection at the fingertips in
      older subjects. This may reflect the high receptor density of this area, or the
      functional importance of vibrotactile sensibility of the fingertips or some
      combination of both of these factors.

PMID- 12600277
TI  - Sequence determinants in human polyadenylation site selection.
AB  - BACKGROUND: Differential polyadenylation is a widespread mechanism in higher
      eukaryotes producing mRNAs with different 3' ends in different contexts. This
      involves several alternative polyadenylation sites in the 3' UTR, each with its
      specific strength. Here, we analyze the vicinity of human polyadenylation signals
      in search of patterns that would help discriminate strong and weak
      polyadenylation sites, or true sites from randomly occurring signals. RESULTS: We
      used human genomic sequences to retrieve the region downstream of polyadenylation
      signals, usually absent from cDNA or mRNA databases. Analyzing 4956 EST-validated
      polyadenylation sites and their -300/+300 nt flanking regions, we clearly
      visualized the upstream (USE) and downstream (DSE) sequence elements, both
      characterized by U-rich (not GU-rich) segments. The presence of a USE and a DSE
      is the main feature distinguishing true polyadenylation sites from randomly
      occurring A(A/U)UAAA hexamers. While USEs are indifferently associated with
      strong and weak poly(A) sites, DSEs are more conspicuous near strong poly(A)
      sites. We then used the region encompassing the hexamer and DSE as a training set
      for poly(A) site identification by the ERPIN program and achieved a prediction
      specificity of 69 to 85% for a sensitivity of 56%. CONCLUSION: The availability
      of complete genomes and large EST sequence databases now permit large-scale
      observation of polyadenylation sites. Both U-rich sequences flanking both sides
      of poly(A) signals contribute to the definition of "true" sites. However, the
      downstream U-rich sequences may also play an enhancing role. Based on this
      information, poly(A) site prediction accuracy was moderately but consistently
      improved compared to the best previously available algorithm.

PMID- 12600278
TI  - STRP screening sets for the human genome at 5 cM density.
AB  - BACKGROUND: Short tandem repeat polymorphisms (STRPs) are powerful tools for gene
      mapping and other applications. A STRP genome scan of 10 cM is usually adequate
      for mapping single gene disorders. However mapping studies involving genetically
      complex disorders and especially association (linkage disequilibrium) often
      require higher STRP density. RESULTS: We report the development of two separate
      10 cM human STRP Screening Sets (Sets 12 and 52) which span all chromosomes. When
      combined, the two Sets contain a total of 782 STRPs, with average STRP spacing of
      4.8 cM, average heterozygosity of 0.72, and total sex-average coverage of 3535
      cM. The current Sets are comprised almost entirely of STRPs based on tri- and
      tetranucleotide repeats. We also report correction of primer sequences for many
      STRPs used in previous Screening Sets. Detailed information for the new Screening
      Sets is available from our web site:
      http://research.marshfieldclinic.org/genetics. CONCLUSION: Our new human STRP
      Screening Sets will improve the quality and cost effectiveness of genotyping for
      gene mapping and other applications.

PMID- 12600280
TI  - A format for databasing and comparison of AFLP fingerprint profiles.
AB  - BACKGROUND: Amplified fragment length polymorphism (AFLP) is a PCR-based
      technique that involves restriction of genomic DNA followed by ligation of
      adaptors to the fragments generated and selective PCR amplification of a subset
      of these fragments. The amplified fragments are separated on a sequencing gel and
      visualized by autoradiography or fluorescent sequencing equipment. AFLP allows
      high-resolution genotyping but the lack of a format for databasing and comparison
      of AFLP fingerprint profiles limits its wider applications in profiling large
      numbers of biological samples. RESULTS: A scheme is described to represent a DNA
      fingerprint profile with a nucleotide sequence-like format in which the
      information line contains the minimal necessary details to interpret an AFLP DNA
      fingerprint profile. They include technique used, information on restriction
      enzymes, primer combination, biological source for DNA materials, fragment sizing
      and annotation. The bodylines contain information on size and relative intensity
      of DNA fragments by a string of defined alphabets or symbols. Algorithms for
      normalizing raw data, binning of fragments and comparing AFLP DNA fingerprint
      profiles are described. Firstly, the peak heights are normalized against their
      average and then represented by five symbols according to their relative
      intensities. Secondly, a binning algorithm based loosely on common springs and
      rubber bands is applied, which positions sequence fragments into their best
      possible integer approximations. A BLAST-like reward-penalty concept is used to
      compare AFLP fingerprint profiles by matching peaks using two metrics: score and
      percentage of similarity. A software package was developed based on our scheme
      and proposed algorithms. Example of use this software is given in evaluating
      novelty of a new tropical orchid cultivar by comparing its AFLP fingerprint
      profile against those of related commercial cultivars in a database. CONCLUSIONS:
      AFLP DNA fingerprint profiles can be databased and compared effectively with
      software developed based on our scheme and algorithms. It will facilitate wider
      use of this DNA fingerprinting technique in areas such as forensic study,
      intellectual property protection for biological materials and biodiversity
      management. Moreover, the same concepts can be applied to databasing and
      comparing DNA fingerprint profiles obtained with other DNA fingerprint
      techniques.

PMID- 12600279
TI  - Control of T lymphocyte morphology by the GTPase Rho.
AB  - BACKGROUND: Rho family GTPase regulation of the actin cytoskeleton governs a
      variety of cell responses. In this report, we have analyzed the role of the
      GTPase Rho in maintenance of the T lymphocyte actin cytoskeleton. RESULTS:
      Inactivation of the GTPase Rho in the human T lymphocytic cell line HPB-ALL does
      not inhibit constitutively high adhesion to the integrin beta1 substrate
      fibronectin. It did however result in the aberrant extension of finger-like
      dendritic processes on the substrates VCAM-1, Fn, and mAb specific to beta1
      integrins. Time-lapse video microscopy demonstrated that C3 induced extensions
      were primarily the result of an altered pseudopod elongation rather than
      retraction. Once the stellate pseudopodia extended, none retracted, and cells
      became completely immobile. Filipodial structures were absent and the dendritic
      like processes in C3 treated cells were rich in filamentous actin.
      Immunolocalization of RhoA in untreated HPB-ALL cells spreading on fibronectin
      demonstrated a diffuse staining pattern within the pseudopodia. In C3 treated
      cells, clusters of RhoA were pronounced and localized within the altered
      extensions. CONCLUSIONS: GTPase Rho is actively involved in the regulation of T
      lymphocyte morphology and motility.

PMID- 12600281
TI  - [Expression of human novel gene CT120 in lung cancer and its effects on cell
      growth].
AB  - BACKGROUND & OBJECTIVE: A novel membrane-associated gene CT120 was isolated from
      chromosome 17p13.3 locus in our laboratory. Its mRNA was not expressed in human
      normal lung tissues, but was abundant in human lung cancer cell line SPC-A-1.
      This study was designed to investigate the differential expression patterns of
      CT120 in different lung cancer and noncancerous tissues using
      immunohistochemistry and to explore the effects of ectopic expression and
      overexpression of CT120 on cell growth in vitro and in vivo. METHODS: A
      polypeptide at the C-terminus of CT120 was selected by bioinformatics, then was
      synthesized and conjugated to KLH (a high molecular carrier). The chicken anti
      CT120 antibody IgY was prepared with the synthesized antigen and was used to
      determine the different expression patterns of CT120 in various tumor cell lines
      and in lung cancer and noncancerous tissues. The effects of ectopic expression of
      CT120 on NIH/3T3 cell growth were investigated through colony formation analysis.
      The effect of overexpression of CT120 on the cell growth of A549 was analyzed
      using growth curve assay and tumor formation assay of transfected cells in nude
      mice. RESULTS: The novel gene CT120 expressed in various tumor cell lines and
      expressed remarkably higher in lung cancers than in noncancerous tissues as well
      as normal lung tissues. Also, it promoted the proliferation of NIH/3T3 and A549
      cells in vitro and in vivo. CONCLUSION: CT120 gene may be a novel candidate gene
      closely related to lung carcinogenesis.

PMID- 12600282
TI  - [Redox reactions of Sep15 and its relationship with tumor development].
AB  - BACKGROUND & OBJECTIVE: Sep15 is a selenium-containing protein identified in
      1998. This protein may be involved in cancer etiology and it may have redox
      function. The objective of this study was to investigate the relationship between
      the redox function of Sep15 and tumor development. METHODS: The full-length DNA
      sequence of Sep15 was obtained by RT-PCR and then recombined to eukaryotic
      expression vector pcDNA3.1(+). The BEL-7402- Sep15 cell line, which expressed the
      high levels of Sep15 by transfecting the cultured hepatocarcinoma cell line BEL
      7402 with pcDNA3.1-Sep15 was generated. From morphologic investigation, cell
      growth curve, clone formation and nude mice tumor growth curve, the relationship
      between Sep15 and hepatocarcinoma cell line BEL-7402 was determined. Furthermore,
      the redox reaction of sep15 was detected by MTT assay. RESULTS: There was no
      distinct effect of transfection of Sep15 gene on BEL-7402-Sep15 cell. The cell
      survival rate was drastically different between BEL-7402-Sep15 cell and both BEL
      7402- pcDNA cell and BEL-7402-Sep15 cell after foreign H2O2 reactive oxygen
      stress (P<0.05). CONCLUSION: Transfecting Sep15 gene did not influence the growth
      characteristics of BEL-7402 cell line and Sep15 may have redox function.

PMID- 12600283
TI  - [Expression of BRD7-interacting proteins,BRD2 and BRD3, in nasopharyngeal
      carcinoma tissues].
AB  - BACKGROUND & OBJECTIVE: BRD7 is a novel gene tightly associated with
      nasopharyngeal carcinoma(NPC) cloned by cDNA representational difference analysis
      (cDNA RDA). Two proteins,BRD2 and BRD3, including bromodomain and interacting
      with BRD7 protein had been screened from human fetal brain cDNA library by yeast
      two-hybrid system. This study was designed to further identify the interactions
      of BRD2 and BRD3 with BRD7 respectively and to investigate the expression and
      action pattern of BRD2 and BRD3 in NPC. METHODS: BRD2 and BRD3 genes were
      respectively co-transformed to yeast Y187 with BRD7 gene, then the yeast
      cotransformers were blotted to nylon membrane. And then the expression of report
      gene Lac Z by beta-Gal was determined and the interactions of BRD2 and BRD3
      proteins with BRD7 protein were identified. Besides,reverse transcription
      polymerase chain reaction (RT- PCR) was used to examine the expression of BRD2
      and BRD3 genes in normal nasopharyngeal epithelium and NPC biopsies, and to
      detect the effect of re-expression of BRD7 gene on the expression of BRD2 and
      BRD3 genes in HNE1 stably transfected BRD7 gene. RESULTS: The yeast transformers
      showed all blue by yeast two-hybrid system, which further identified that BRD2
      and BRD3 proteins could respectively interact with BRD7 protein. Down-expression
      or loss of BRD2 and BRD3 genes were detectable in NPC biopsies. The expression
      levels of BRD2 and BRD3 were increasing with the re-expression of BRD7 gene in
      HNE1 stably transfected with BRD7. CONCLUSION: BRD7 protein could respectively
      interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression
      levels of BRD2 and BRD3 genes in mRNA level to some extent. Each of these three
      homolog proteins might be capable of forming heteromers with the others, which
      play important roles in the suppression of growth of NPC cells.

PMID- 12600284
TI  - [Analysis of suppressive roles of BLU gene at 3p21.3 in nasopharyngeal
      carcinoma].
AB  - BACKGROUND & OBJECTIVE: Nonrandom allelic loss at chromosome 3p21.3 is a common
      and early event in nasopharyngeal carcinoma (NPC), which implicates the presence
      of tumor suppressor genes (TSGs) that may be involved in the pathogenesis of
      NPCs. BLU gene, containing a MYND domain and located at 3p21.3, has been
      considered as a NPC associated candidate tumor suppressor gene (TSG) due to the
      occurrence of loss of its expression and aberrant promoter hypermethylation in
      most NPCs. This study was designed to construct expression vectors containing
      either wild type BLU gene and its mutants and to analyze the effect of BLU gene
      on proliferation of NPC cells by transfection assays. METHODS: The full-length
      cDNA of BLU gene was amplified by RT-PCR. The expression vectors containing
      various BLU mutants were constructed by site-directed mutagenesis by overlapping
      PCR. These mutants include a MYND domain deletion mutant, a Ser402Phe and
      del405Cys, del406Ser mutant, and a Gly160Arg mutant. The wild type BLU gene and
      the MYND domain deletion mutant were transfected into NPC cell lines CNE1 and
      CNE2. The effect on apoptosis was determined by TUNEL assay. Cellular
      proliferation of the stably-transfected cells was examined with cell growth curve
      and by colony formation assays. Tumorigenicity in nude mice of CNE2 stably
      transfected with BLU was investigated. RESULTS: No significant difference in
      apoptosis index (AI) was observed between cells transfected with wild type or
      MYND domain deleted BLU gene and cells transfected with plasmid controls.
      Exogenous expression of wild type BLU gene had no effect on growth rate and
      colony formation ability of CNE1 and CNE2. BLU gene showed no suppressor ability
      in CNE2 tumorigenicity. CONCLUSION: Although BLU gene was frequently altered in
      NPCs, its suppressor role in NPC cells proliferation was not evident. Thus, the
      possibility of BLU gene as a TSG involved in NPC development remained to be
      elucidated by further studies.

PMID- 12600285
TI  - [Expression of a new cloned nitroreductase gene NOR1 and purification of
      expressed product].
AB  - BACKGROUND & OBJECTIVE: NOR(1)is a good candidate of tumor
      suppressor/susceptibility gene associated with nasopharyngeal carcinoma. This
      study was designed to construct the prokaryotic expression vector and to
      investigate the expression of nitroreductase gene NOR(1)in Escherichia coli and
      to purify expressed product. METHODS: Total RNA was subtracted from normal
      nasopharyngeal carcinoma tissue. The full length of NOR(1)gene was amplified by
      reverse transcription-polymerase chain reaction (RT-PCR) and digested with
      BamHIand XhoI restriction endonucleases. The plasmid pGEX-4T-2 was also digested
      with BamHI and XhoI,then the NOR(1)gene was inserted into vector pGEX-4T-2. The
      recombinant expression vector pGEX-4T-2/NOR(1)was identified by sequencing and
      digested with restriction enzymes. E.coli Jm105 transformed with the recombinant
      plasmid was induced by IPTG to express GST fusion protein. The result was
      confirmed by Western blot analysis and the purified targeted protein was obtained
      by affinity chromatography. RESULTS: The 1.25kb NOR(1)gene was successfully
      isolated. After induction, a new anticipated protein of 74 kDa appeared on sodium
      dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE). It existed not only
      in supernatant but also in precipitation of broken bacteria. The result was
      confirmed by Western blot analysis,and the purified targeted protein was obtained
      by affinity chromatography. CONCLUSION: The successes in construction of
      expression vector of NOR(1), expression and purification of GST/NOR(1)fusion
      protein make it possible to prepare for the polyantibodies for NOR(1).

PMID- 12600286
TI  - [Effects of mitogen-activated protein kinase(MAPK) in cell signal transduction of
      chronic myelogenous leukemia cell line K562].
AB  - BACKGROUND & OBJECTIVE: Ras-MAPK signal transduction has been thought to play an
      important role in the carcinogenesis of chronic myelogenous leukemia. In this
      study, the authors investigated the effects and mechanism of mitogen-activated
      protein kinase (MAPK) in cell signal transduction of chronic myelogenous
      leukemia(CML). METHODS: After MAPK antisense oligodeoxynucleotide (ASO) was
      introduced into K562 cell line by liposomal transfection, the effects of ASO on
      K562 cell were evaluated by cell proliferation, DNA synthesis, MAPK protein
      content and MAPK activity. RESULTS: The cell proliferation, DNA synthesis, MAPK
      protein content and MAPK activity were significantly inhibited by MAPK ASO, the
      inhibitory rates were 51.8%, 57.1%, 45.3%, and 61.6%, respectively,with
      significant difference in comparison to the control (P<0.05). CONCLUSION: MAPK
      plays an important role in the signal transduction of CML and MAPK may become a
      new target in the treatment of CML.

PMID- 12600287
TI  - [Cloning and identification of 5'-untranslated region (UTR) and 3'-untranslated
      region of neutrophil gelatinase-associated lipocalin (NGAL) gene from esophageal
      carcinoma cell line SHEEC].
AB  - BACKGROUND & OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) was a
      novel member of the lipocalin family. The authors previously found that NGAL was
      overexpressed in the progress of malignant transformation from human immortalized
      esophageal epithelial cell line SHEE to esophageal carcinoma cell line SHEEC.
      However, the regulation mechanism of NGAL overexpression was not known. The
      objective of this study was to clone 5'-untranslated region(5'-UTR) and
      3'untranslated region (3'-UTR) of NGAL in SHEEC and to analyze their structural
      characters. METHODS: 5'-UTR and 3'-UTR of NGAL were cloned from SHEEC using rapid
      amplification of cDNA ends(RACE). After sequencing the alignment of their
      nucleotides was analyzed by BLAST database of NCBI and the potential cis-acting
      elements in the 3'-UTR were identified by computer analysis. RESULTS: The authors
      cloned and sequenced 69 bp 5'-UTR and 147 bp 3'-UTR of NGAL gene on the basis of
      the previous works and did not find any base pair mutation. CONCLUSION: NGAL gene
      from SHEEC had the entire 5'-UTR and 3'-UTR.

PMID- 12600288
TI  - [Effect of transfection of hEndostatin gene on CNE2 cell xenograft growth in nude
      mice].
AB  - BACKGROUND & OBJECTIVE: Tumor angiogenesis play an important role in growth and
      metastasis of cancer. Angiogenesis inhibitors induce apoptosis in cancer by
      inhibiting tumor angiogenesis and have strong inhibiting effect on both growth
      and metastasis of cancer. This study was designed to explore the effect of
      transfection of human endostatin gene on nasopharyngeal carcinoma CNE2 cells
      xenograft growth in nude mice. METHODS: The plasmids (pBlast-hIL-hEndostatin,
      pBlast-hEndostatin, and pBlast-MCS) were transfected and lipofectin-mediated into
      the CNE2 cell line. The biological activity of secreted hEndostain from gene
      transferred cell lines was determined using MTT method in vitro. Then the
      transfected CNE2 cells were injected into the nude mice and tumorigenicity of
      CNE2 was observed in vivo. RESULTS: The supernatant of CNE2 cell transfected with
      pBlast-hIL-hEndostatin effectively inhibited the growth of endothelial cell
      (ECV304). The volume and the weight of tumor in pBlast-hIL -hEndostatin
      transfecting cells group were less than those in control group (P< 0.01). The
      growth speed of tumor in pBlast-hIL-hEndostatin transfecting cells group was
      slower than that in control group. CONCLUSION: Transfection of hEndostatin gene
      could inhibit CNE2 cell growth in nude mice.

PMID- 12600289
TI  - [Effects of selenium dioxide on regulatory regions P250 of c-fos gene].
AB  - BACKGROUND & OBJECTIVE: This study was designed to investigate the impact of
      selenium dioxide (SeO2) on regulatory regions P250 of c-fos gene and to seek
      possible regulation mechanism. METHODS: HeLa cells were transfected with plasmids
      containing upstream regulating regions of c-fos chloramphenicol acetyl
      transferase (CAT). The cells were cultured in various concentration of selenium
      dioxide. CAT expression in transfected cells was observed. RESULTS: After
      transfected HeLa cells were exposed to selenium dioxide, CAT expression showed
      obvious increase, especially in 10 micromol/L and 30 micromol/L selenium dioxide
      group (P< 0.05). CONCLUSION: Trough affecting regulatory regions P250 of c-fos
      gene, Selenium dioxide plays biological effect of regulating tumor cells.
      Selenium dioxide possibly has anti-tumor effects.

PMID- 12600290
TI  - [Magnetic resonance imaging (MRI) in evaluation of tyrosinase gene expression in
      HepG2 cell].
AB  - BACKGROUND & OBJECTIVE: Gene therapy is the frontier of life science. There is no
      perfect method to evaluate gene expression without invasion at present. Medical
      imaging connecting with molecular biology might be helpful; however, the
      technology is just on the horizon. The authors conducted this study in vitro by
      transferring reporter tyrosinase gene into HepG2 cell to apply magnetic resonance
      imaging (MR) for evaluating gene expression. METHODS: The plasmid of pcDNA3tyr
      carried the full-length cDNA of tyrosinase gene was transfected into HepG2 cell
      by lipofectin, its property of synthesizing melanin was used to produce high
      signal in T1WI MR image and then to evaluate gene expression. Further
      identification were performed with searching melanin granules by Fontana staining
      and searching cDNA of tyrosinase gene using reverse transcription-polymerase
      chain reaction (RT-PCR). RESULTS: (1)The melanin granules were found in HepG2
      cell using Fontana staining. (2)The cDNA fragment of tyrosinase gene was
      detectable in transferred HepG2 cell by RT-PCR. (3)Plasmid of pcDNA3tyr was
      transfected into HepG2 cell and synthesized a large amount of melanin in HepG2
      cell; the synthetic melanin appeared high signal in T1WI MR imaging as same as
      natural melanin and was enough to be detected by MR. And further, the signal
      intensity was positively related to the amount of transferred plasmid.
      CONCLUSION: The fact that synthetic melanin of HepG2 cell can be detected by MR
      demonstrates that medical imaging connecting with molecular biology can be used
      to evaluate the result of gene expression in vitro.

PMID- 12600292
TI  - [Relationship between carcinoembryonic antigen and cyclooxygenase 2 expression
      and colorectal cancer].
AB  - BACKGROUND & OBJECTIVE: Some research showed that carcinoembryonic antigen(CEA)
      related to cell adhesion and cyclooxygenesis 2(COX2) may be related to colorectal
      carcinogenesis. This study was designed to investigate the expression of CEA and
      COX2 to evaluate their effects on the tumorigenesis and progression in the
      colorectal cancer. METHODS: The immunohistochemistry was used to determine the
      expression of CEA and COX2 in the 34 tissues of colorectal cancer,border of
      cancer, normal mucosa,and 19 metastatic lymph nodes. RESULTS: CEA expression
      level had a correlation with the differentiation of the tumor tissue (P< 0.05),
      but had no correlation with lymph node metastasis,Dukes' stage,the patients'
      age,sex,and the location of tumor (P >0.05). The level of COX2 increased in the
      majority of tumor tissues (31/34) and all of the lymph node metastases, but had
      no correlation with the tumor differentiation, stage,location,patients' age and
      sex(P >0.05). There was significant difference of expression of CEA and COX2
      between tumor and nontumor tissues (P< 0.01). CONCLUSION: The abnormal expression
      of CEA and COX2 plays a role in the carcinogenesis and development of colorectal
      cancer.

PMID- 12600291
TI  - [Vascular endothelial growth factor gene expression in nasopharyngeal carcinoma
      cell line induced by hypoxia in vitro].
AB  - BACKGROUND & OBJECTIVE: Hypoxia is a common phenomenon in the tumor
      microenvironment of most solid tumors including human nasopharyngeal neoplasms.
      Hypoxia can induces vascular endothelial growth factor (VEGF) gene expression in
      some tumor cells like glioma cell line C6. The present investigations were
      conducted to study the effect of hypoxia on the VEGF gene expression in cultured
      nasopharyngeal carcinoma (NPC) cell line CNE-2Z in vitro and to discuss its
      impact on tumor metastasis. METHODS: Hypoxic culture model in vitro was
      established to test the VEGF gene expression in CNE-2Z cell line. After cultured
      in the hypoxia circumstance for 24 hours, VEGF expression were tested in mRNA
      level and protein level by RT-PCR and Western-blot analysis, respectively.
      RESULTS: VEGF mRNA isoforms VEGF189, VEGF165, VEGF145,and VEGF121 were identified
      by RT-PCR in cultured CNE-2Z cell line. All of the four VEGF mRNA isoforms
      expression were increased after treated under hypoxia for 24 hours. The mRNA
      level of four VEGF isoforms were 2.67+/-0.30, 2.05+/-0.03, 2.73+/-0.15, and
      1.65+/-0.01 folds as those in normoxic cells,respectively. Western blot analysis
      showed that VEGF protein expression in CNE-2Z cells was 2.20+/-0.07 folds as that
      in normoxic cells. CONCLUSION: VEGF gene expresses in CNE-2Z cell line and can be
      induced by hypoxia in vitro, this mechanism may be involve in metastasis process
      of NPC by inproved neoplasm angiogenesis.

PMID- 12600293
TI  - [Significance of both nuclear and cytosol androgen receptor (AR) in assessment of
      AR status in prostate carcinoma and hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: Androgen receptor (AR) is closely associated with the
      genesis,development,treatment and assessment of prognosis of prostate carcinoma
      (PC) and hepatocellular carcinoma (HCC). How to determine the AR status
      accurately has important clinical significance. This study was designed to
      investigate the significance of androgen receptor(AR) in cell nucleus for
      assessment of the AR status of patients with PC and HCC. METHODS: A total of 94
      PC and 192 HCC tissues were analyzed for the affinity (KD),cytosol AR (AcR) and
      nuclear AR(AnR) using radioligand binding assay(RBA). RESULTS: In 94 PC tissues,
      the Bmax values of AcR and AnR were 58.82+/-34.73 and 543.70+/-249.44 fmol/mg
      protein which were significantly higher than those of the surrounding tissues
      (21.63+/-14.89 and 89.20+/-47.32 fmol/mg protein, P< 0.001). The KD values of AcR
      and AnR were 0.84+/-0.52 and 2.15+/-0.79 nmol/L which were not significantly
      different as compared with the surrounding tissues(0.78+/-0.49 and 2.24+/-0.84
      nmol/L, P >0.50). In 192 HCC tissues, the Bmax values of AcR and AnR were 18.09+/
      16.87 and 59.93+/-34.12 fmol/mg protein, which were significantly higher than
      those of the surrounding tissues (10.87+/-7.60 and 25.54+/-20.10 fmol/mg protein,
      P< 0.001 ). The KD values of AcR and AnR were 0.76+/-0.57 and 1.89+/-0.74
      nmol/L)which were not significantly different as compared with the surrounding
      tissues(0.69+/-0.48 and 1.94+/-0.88 nmol/L, P >0.50). The ratio of AnR/AcR was
      also higher (P< 0.001). Of 94 PC tissues, 48.94% were both AcR and AnR positive,
      being lower than that of the tissues with positive AcR alone (77.66%). Of 192 HCC
      tissues, 34.09% were both AcR and AnR positive, being also lower than that of AcR
      positive alone (56.26%). However, 63.01% of PC and 62.03% of HCC AcR-positive
      tissues were accompanied by AnR-positive. CONCLUSION: Despite the fact that the
      Bmax of both AcR and AnR increased in PC and HCC tissues as compared to the
      surrounding tissues, the AnR showed more significant changes. In assessment of
      the AR status of PC and HCC tissues, it would be more accurate to analyze with
      both AcR and AnR than with AcR alone.

PMID- 12600294
TI  - [Expression of a new lung cancer drug resistance-related gene in lung cancer
      tissues and lung cancer cell strains].
AB  - BACKGROUND & OBJECTIVE: A new drug resistance-related gene fragment which was 494
      bp long was found using suppression subtractive hybridization (SSH) and its full
      length cDNA fragment was cloned by the authors. This study was designed to
      determine the expression of this lung cancer drug resistance-related gene (LCDRG)
      in lung cancer tissues, juxtacancerous tissues, and five lung cancer cell
      strains. METHODS: The expression of LCDRG was determined by semi-quantitative
      reverse transcription-polymerase chain reaction (RT-PCR) method in 38 lung cancer
      tissues,12 juxtacancerous tissues, and 5 lung cancer cell strains. RESULTS: The
      expression of LCDRG in cancer tissues was significantly higher than that in
      juxtacancerous tissue (P< 0.001). There was no significance of the expression
      among adenocarcinoma, brochioloalveolar carcinoma, and squamous carcinoma. In
      lung cancer cell strains, the expression levels of LCDRG in adenocarcinoma cell
      strains SPC-A-1 and A549, big cell lung cancer cell strain H460, small cell lung
      cancer cell strains H446 and SH77 were decreased gradually. CONCLUSION: LCDRG is
      closely related to lung cancer and may be involved in the pathogenesis of lung
      cancer.

PMID- 12600295
TI  - [Significance of screening by iodine staining of endoscopic examination in the
      area of high incidence of esophageal carcinoma].
AB  - BACKGROUND & OBJECTIVE: In order to improve early detection and visualization of
      esophageal premalignant lesion and carcinoma, this study was designed to explore
      significance of the screening by iodine staining of endoscopic examination in the
      area of high incidence of esophageal carcinoma. METHODS: Three screenings were
      completed through endoscopic examination for 3164 persons in high-risk
      population. Esophageal epithelium was stained with iodine in endoscopic
      examination. According to mucosal color and pathological result, esophageal
      carcinoma and premalignant lesion were confirmed. RESULTS: After staining, the
      normal epithelium became brown and precancerous or malignant epithelium
      manifested yellow with sharp margin. (1) 100% early esophageal cancer was iodine
      staining positive, all lesions were grade I to grade II. The incidence rates of
      early esophageal carcinoma and advanced esophageal carcinoma were 1.60%-4.59% and
      0.29%-1.09%, respectively. Early detection rate of esophageal carcinoma was all
      over 75%. (2) 95.6% severe dysplasia were staining positive; 91.3% lesion were
      grade I and grade II in staining. The incidence rate of severe dysplasia was
      4.49%-7.68%. (3) 96.6% moderate dysplasia was positive in iodine staining, 73.3%
      lesion were grade II and grade III. (4) 92.3% mild dysplasia was positive in
      iodine staining; most of lesions were grade III. (5) 0.9% esophagitis and 0.4%
      normal esophageal mucosal were grade I and grade II in iodine staining, most of
      lesion were negative or grade III. CONCLUSION: The results demonstrated that the
      screening with endoscopic staining examination could improve early detection of
      esophageal carcinoma and precancerous lesion. Iodine staining showed highly
      sensitivity and specificity for identifying these precancerous and early squamous
      cancer lesions; it may be helpful for diagnosis of early esophageal carcinoma and
      precancerous lesion.

PMID- 12600296
TI  - [Relationship between expression of matrix metalloproteinase (MMP-9) and tumor
      angiogenesis, cancer cell proliferation, invasion, and metastasis in invasive
      carcinoma of cervix].
AB  - BACKGROUND & OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) might plays an
      important role in regulating processes of tumor angiogenesis, invasion,and
      metastasis. The expression and clinical significance of MMP-9 in early invasive
      carcinoma of cervix was investigated. METHODS: Expression of MMP-9, microvessel
      density (MVD) labeled by CD(34) and proliferation index of cancer cells labeled
      by Ki-67 in 75 cases of early invasive carcinoma of cervix (ICC), 18 cases of
      cervical intraepithelial neoplasm (CIN), and 15 cases of normal cervical
      epithelium (NCE) were detected by immunohistochemistry SP method. RESULTS: MMP-9
      was mainly expressed in the cellular membrane and/or cytoplasm in tumor
      cells,whereas expression of Ki-67 was mainly confined to the nuclei, and that of
      CD(34), to the vascular epithelial cells in tumor stroma. It was shown that
      positive rate of expression of MMP-9,Ki-67, and MVD increased remarkably from NCE
      to CIN,and then to ICC accordingly(P< 0.05). In ICC, MVD was positively related
      to the expression of MMP-9 (r=0.287, P<0.05). The expression of MMP-9 correlated
      with pelvic lymph node metastasis, intravascular and stromal infiltration, FIGO
      staging, histological grading,and Ki-67 expression (P< 0.05 or P< 0.01); but not
      correlated with patients age and histological types (P >0.05). In cases with
      pelvic lymph node metastasis, intravascular and deeper stroma infiltration, FIGO
      staging II, histological grade III and over-expression of Ki-67, positive rate of
      expression of MMP-9 was significantly higher than that in those without the
      conditions mentioned above (P< 0.05). CONCLUSION: In cervical carcinoma, MMP-9
      may play an important role during tumor angiogenesis, proliferation of cancer
      cells, cancer invasion and metastasis. Over-expression of MMP-9 may result in
      great increase of tumor angiogenesis, rapid proliferation of cancer cells, cancer
      invasion and metastasis, but it is not the only decisive factor. Detection
      expression of MMP-9 may be of value in further understanding the biological
      behavior and predicting the prognosis of cervical carcinoma.

PMID- 12600297
TI  - [Angiogenesis and micrometastases of regional lymph node in ovarian cancer].
AB  - BACKGROUND & OBJECTIVE: In many investigation it was demonstrated that intratumor
      microvessel density (IMD) is the best factor for no tumor survival for patients
      with ovarian cancer. Occult axillary node micrometastases as the prognostic
      factor for the patients with breast cancer was proved, but currently no
      literature of the pelvic lymph node micrometastases in ovarian cancer is
      provided. This study try to detect the microvessel density of tumor tissues and
      micrometastases of regional lymph nodes in ovarian cancer and to investigate the
      relationship between these two factors and their prognostic significance.
      METHODS: The sections of ovarian cancer from 39 patients were stained
      immunohistochemically for cytokeratin(CK) and factor VIII-related antigen (F8
      RA). Microvessels on the section were counted by computerized morphometry (40
      fields). Sections of 212 regional lymph nodes from 39 patients were stained also
      with HE and CK. RESULTS: (1)We found 7 lymph node metastases with HE staining in
      39 patients and 12 micrometastases with CK staining.(2) Average value of
      intratumor microvessel density (IMD) in the HE positive group was 48.86+/-16.60
      and was obviously higher than that in the HE negative group (29.16+/-10.02,P<
      0.01). The average IMD was 41.67+/-21.69 in the CK positive group and was also
      obviously higher than that in the CK negative group (28.70+/-10.77,P< 0.05). We
      found 8(50%) micrometastases in 16 patients with higher IMD (> or = 30/40 x
      fields) and only 4(17.4%) micrometastases in 23 patients with lower IMD (< 30/40
      x fields), the difference was significant (P< 0.05). (3)IMD (P=0.03) and regional
      lymph node micrometastases(P=0.04) were the most significant factors to the
      survival time through Cox proportional hezard model analysis,the IMD (P=0.0008)
      and clinical stage (P=0.03) were also the most important factors to predict
      recurrence. CONCLUSION: The study suggests the CK immunohistochemical staining
      could detect the micrometastases in the HE negative lymph node in patients with
      epithelial ovarian cancer. The IMD is closely related to the micrometastases and
      these two factors have prognostic significance in ovarian cancer. The IMD and
      micrometastases could act as independent prognosis factors of patients with
      ovarian cancer.

PMID- 12600298
TI  - [Surgery-predominant comprehensive therapy for 134 patients with small
      hepatocellular carcinoma].
AB  - BACKGROUND & OBJECTIVE: Although surgical resection is the primary choice
      modality in treatment of small hepatocellular carcinoma(HCC), the 5-year
      recurrent rate after resection was as high as 35.4%-43.5%. This study was
      designed to investigate the efficacy of surgery-predominant comprehensive therapy
      for small HCC in reducing the recurrent rate and improving the outcome. METHODS:
      A total of 134 cases of small HCC (< or = 5 cm in diameter) received surgery
      predominant comprehensive treatment in The Affiliated Tumor Hospital, Guangxi
      Medical University from 1985 to 2001. The median age of the patients was 45 years
      old (range,18-70 years). Of 134 cases, 121 were treated with hepatectomy: 16 with
      irregular hepatectomy, 83 with local radical resection, 12 with regular liver
      lobe resection or liver segment resection, 2 with left semi-hepatectomy, and 8
      with hepatectomy and gallbladder resection. In the other 13 cases of
      nonresectable small HCC, they received multimodality treatments by various
      combinations of hepatic artery ligation and anticancer agents by hepatic artery
      infusion, microwave coagulation, ethanol injection into tumor, cryosurgery,radio
      frequency (RF), and hepatic artery chemoembolization therapy. RESULTS: Of 134 HCC
      patients, 90.3% received liver resection and no operative death occurred. For the
      surgery group, the 1-, 3-, 5-, and 10-year survival rates were 89.3%, 74.4%,
      64.6%, and 43.8%, respectively; the 1-, 3-, and 5-year recurrent rates were
      11.9%, 23.8%, and 32.1%, respectively. For the total group,the 1-, 3-,5-, and 10
      year survival rates were 88.8%, 72.2%, 63.4%, and 41.7%, respectively; the 1-, 3
      , and 5-year recurrent rates were 15.9%, 29.1%, and 36.6%, respectively.
      CONCLUSIONS: Surgical resection remains primary choice modality in treatment of
      small HCC; postoperative comprehensive treatment is important for preventing
      tumor recurrence and improving the long-term results.

PMID- 12600299
TI  - [Relationship between computed tomography (CT) manifestations and pathology in
      thyroid carcinoma].
AB  - BACKGROUND & OBJECTIVE: In clinical diagnosis and treatment of thyroid carcinoma,
      the misdiagnosis rate is about 40%-70%and the recurrence is about 30%. This study
      was designed to investigate the relationship between the CT features of thyroid
      carcinoma and its clinical pathology. METHODS: Fourty-six cases of thyroid
      carcinoma, pathologically proven, were retrospectively analyzed for CT and
      histological findings. RESULTS: Of 46 patients with thyroid carcinoma, 31 cases
      showed heterogeneous density, 30 cases showed irregular shape, 37 cases showed
      untidy margin, 16 cases showed peninsular tubercles around the tumor,and 10 cases
      showed no complete enhanced ring around the tumor. 20 cases were detected
      calcifications, including 9 cases fine globular calcifications, 4 cases nodular
      calcifications, 7 cases mixture calcifications. In addition,"calcified nodule in
      cyst sign" were found in 7 cases. 23 cases infiltrated the adjacent structures
      and 15 cases were revealed metastatic lymphadenopathy on the neck. CONCLUSION:
      Some cases of thyroid carcinoma can be diagnosed correctly according to the
      characteristic manifestations on CT. Different pathological types of thyroid
      carcinoma were related to calcification manifestations and adjacent structure
      invasion. CT scan can provide reliable information in selecting therapeutic
      methods.

PMID- 12600300
TI  - [Preliminary study of p16 gene expression in pituitary adenomas].
AB  - BACKGROUND & OBJECTIVE: The inactivation and low expression of tumor suppressor
      gene p16 has been found to play an important role in the tumorigenesis of a wide
      variety of human tumors, but its association with human pituitary adenomas was
      not clear. This study was conducted to investigate the relationship between p16
      gene expression and clinicopathologic features including invasiveness and
      recurrence in pituitary adenoma patients. METHODS: The p16 mRNA and p16 protein
      expression levels were examined using reverse transcription polymerase chain
      reaction (RT-PCR) and Western Blot analysis respectively in 70 pituitary adenomas
      and 10 normal brain tissues. RESULTS: Fifty-two of 70 (74.3%) tumor samples
      presented loss or low p16 mRNA and p16 protein. The invasive and recurrent
      adenomas had higher loss expression rates than noninvasive and nonrecurrent group
      respectively; however, there was no significant difference (P >0.05). Moreover,
      the mean diameter of adenomas without p16 expression was obviously larger than
      that of p16-positive tumors (22.1+/-7.2 mm versus 8.1+/-4.5 mm, P< 0.01). There
      was no association between p16 expression and other clinicopathologic features of
      pituitary adenomas. CONCLUSION: These findings suggested that p16 down-regulation
      may play an important role in the initial tumorigenesis, growth, and biological
      behavior of pituitary adenomas.

PMID- 12600301
TI  - [Effect of retinoic acid (RA) on the T-lymphocyte subsets and T-cell colony of
      patients with colorectal cancer].
AB  - BACKGROUND & OBJECTIVE: Retinoic acid (RA) is the derivative of vitamin A. It can
      inhibit the carcinogenesis and reduce the morbidity of experimental colorectal
      cancer. However, there are few reports about the effect of RA on the T-lymphocyte
      subsets and T-cell colony of patients with colorectal cancer. This study was
      designed to investigate the effect of RA on the function of immune system and
      provide theoretical data for clinical. METHODS: Forty patients with colorectal
      cancer were divided into the RA treating group (n=20) and control group (n=20)
      for prospective study. Peripheral blood in all the patients was preoperatively
      and postoperatively was collected. Subsets (OKT(3), OKT(4), OKT(8)) of T
      lymphocyte were assayed. The ability to form T-cell colony and the IgG, IgM, IgA
      in peripheral blood were also determined. RESULTS: (1) Comparing with
      preoperative in two groups, there was no significant difference on OKT(3). OKT(4)
      and ratio of T4/T8 significantly increased (P< 0.05) and OKT(8) decreased
      progressively postoperatively (P< 0.05). Comparing in two groups, OKT(3), OKT(4)
      and T4/T8 were significantly higher in RA treating group than in the control
      group (P< 0.05); But OKT(8) did not show difference between the two groups (P
      >0.05). (2) The ability to form T-cell colony was significantly lower in RA
      treating group than in the health human group, and higher than in the control
      group (P< 0.05). (3) Comparing with control group, postoperative 1 to 3 months,
      IgG and IgM significantly increased in RA treating group (P< 0.05). IgA did not
      show significant difference. CONCLUSION: Applying RA after radical operation of
      colorectal carcinoma could promote the cellular and humoral immunity and improve
      immune state recover from immunosuppression in the patients with colorectal
      cancer.

PMID- 12600302
TI  - [Multivariate analysis for prognostic predictors in the cN0 squamous cell
      carcinoma of the tongue].
AB  - BACKGROUND & OBJECTIVE: There is controversy in therapy strategy for the cN0
      squamous cell carcinoma of the tongue. The aim of this study was to explore the
      relative factors of prognosis for the cN0 squamous cell carcinoma of the tongue
      and to identify the risk population. METHODS: Cox regression model was used to
      analyze the clinical data of 109 patients with cN0 tongue cancer treated in
      Cancer Center, Sun Yat-sen University from January 1990 to March 1998. The
      prognostic index (PI) of the patients was calculated on basis of the results of
      multivariate analysis. According to the individualized PI, the patients were
      classified to different hazard groups. RESULTS: The 3, 5 years survival rates
      were 74.40%and 69.31%, respectively. Multivariate analysis showed the prognosis
      statistically correlated with T grade, therapy manner of primary tumor,
      differentiation grade, age, and occult neck lymph node metastasis. T stage was
      found to be the most important prognostic factor. The prognosis of the patients
      in comprehensive therapy group is better than that in surgery alone group,
      chemotherapy alone,or radiotherapy alone group. The patients with tongue
      carcinoma in low differentiation group, the older group, or occult neck lymph
      node metastasis group showed a poor prognosis. The patients were divided into
      high-risk group,moderate-risk group, and low-risk group according to the PI value
      and there was significant difference in the survival rates between each two
      groups of the three groups (P< 0.05), and the 5-year survival rates were 83.33%,
      64.12%, and 27.65%, respectively. CONCLUSION: The prognosis of cN0 squamous cell
      carcinoma of the tongue is associated with T grade, therapy manner of primary
      tumor, differentiation grade, age, and occult neck lymph node metastasis. PI
      value could be used to predict the prognosis of the patients with the cN0
      squamous cell carcinoma of the tongue.

PMID- 12600303
TI  - [Multivariate analysis of prognosis of patients with clinical stage I and II
      carcinoma of mobile tongue].
AB  - BACKGROUND & OBJECTIVE: There are many factors affecting the prognosis of the
      patients with clinical stage I and II carcinoma of mobile tongue. This study was
      designed to analyze the most important factors affecting the prognosis. METHODS:
      The data of long period follow-up were analyzed retrospectively for 147 patients
      with clinical stage I and II squamous cell carcinoma of mobile tongue to evaluate
      the contribution of every factors influencing on survival. Survival analysis was
      performed by life table method; comparison among/between groups was performed
      using log-rank test; multivariate analysis was carried out using Cox proportional
      hazard model and Logistic regression model. RESULTS: Univariate analysis showed
      that pathological grade (G2 and G3), status of cervical lymph node, pathological
      stage (stage III and IV), history of alcohol consumption, primary location
      recurrence, regional recurrence, primary location and regional recurrence, and
      cancer recurrence were risk factors of the prognosis of the patients (P< 0.05).
      Multivariate analysis showed that locoregional recurrence (P=0.000) and
      pathological stage (P=0.045) could predict the prognosis. The result of Logistic
      regression model indicated that status of cervical lymph node (P=0.003) and
      history of alcohol consumption (P=0.012) were closely associated with
      locoregional recurrence. CONCLUSION: Locoregional recurrence and pathological
      stage(stage III and IV) are the most important factors affecting the prognosis of
      the patients with clinical stage I and II squamous cell carcinoma of mobile
      tongue. The risk factors affecting locoregional recurrence of the patients are
      positive cervical lymph node and history of alcohol consumption.

PMID- 12600304
TI  - [Review of relationship between tumor necrosis factor genetic polymorphism and
      hematological malignancies].
AB  - Patients with malignant tumor including hematological malignancies have high
      plasma levels of tumor necrosis factor (TNF) and excessive production of TNF is
      associated with polymorphic variation of TNF locus. TNF polymorphism affects TNF
      expression by affecting transcriptional regulation. The aim of this paper was to
      review the correlation between TNF polymorphism and hematological malignancies
      such as lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, acute
      lymphocytic leukemia and multiple myeloma and to make preparation for further
      research of their relationship.

PMID- 12600305
TI  - [Early diagnosis of lung cancer].
AB  - Lung cancer is one of the leading causes of cancer death in mankind, with five
      year survival rate remains 10%. Previous screening trials using chest radiography
      and cytological examination of sputum failed to reach the goal of a diagnostic
      screening test,a decrease in lung cancer mortality. With the development of new
      kinds of technology, there has been a resurgent interest in screening for lung
      cancer. We reviewed recent diagnosis of early detection of lung cancer including
      low-dose CT, Thin-Prep cytology, laser- induced fluorescence endoscope and
      molecular pathology.

PMID- 12600306
TI  - Considering nuclear compartmentalization in the light of nuclear dynamics.
AB  - Many proteins are concentrated in compartments within the nucleus. Chromatin is
      also compartmentalized at different nuclear sites. However, nuclear proteins have
      now been shown to be highly mobile. This review considers the formation and
      function of nuclear compartments in a situation in which proteins are rapidly
      moving through the nuclear volume.

PMID- 12600307
TI  - Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling.
AB  - The centromere is a chromosomal locus that ensures delivery of one copy of each
      chromosome to each daughter at cell division. Efforts to understand the nature
      and specification of the centromere have demonstrated that this central element
      for ensuring inheritance is itself epigenetically determined. The kinetochore,
      the protein complex assembled at each centromere, serves as the attachment site
      for spindle microtubules and the site at which motors generate forces to power
      chromosome movement. Unattached kinetochores are also the signal generators for
      the mitotic checkpoint, which arrests mitosis until all kinetochores have
      correctly attached to spindle microtubules, thereby representing the major cell
      cycle control mechanism protecting against loss of a chromosome (aneuploidy).

PMID- 12600308
TI  - Un menage a quatre: the molecular biology of chromosome segregation in meiosis.
AB  - Sexually reproducing organisms rely on the precise reduction of chromosome number
      during a specialized cell division called meiosis. Whereas mitosis produces
      diploid daughter cells from diploid cells, meiosis generates haploid gametes from
      diploid precursors. The molecular mechanisms controlling chromosome transmission
      during both divisions have started to be delineated. This review focuses on the
      four fundamental differences between mitotic and meiotic chromosome segregation
      that allow the ordered reduction of chromosome number in meiosis: (1) reciprocal
      recombination and formation of chiasmata between homologous chromosomes, (2)
      suppression of sister kinetochore biorientation, (3) protection of centromeric
      cohesion, and (4) inhibition of DNA replication between the two meiotic
      divisions.

PMID- 12600309
TI  - Regulating access to the genome: nucleocytoplasmic transport throughout the cell
      cycle.
AB  - Macromolecular transport between the cytoplasm and the nucleus occurs through the
      nuclear pore complex (NPC) and is mediated by multiple families of soluble
      transport factors. All these transport factors share the ability to translocate
      across the NPC through specific interactions with components of the nuclear pore.
      This review highlights advances in our understanding of the structure and
      function of the NPC and the shuttling transport receptors involved in nuclear
      transport. It discusses recently proposed models for the translocation of
      receptor-cargo complexes through the NPC channel and reviews how the small GTPase
      Ran functions as a positional marker of the genome to regulate multiple important
      aspects of the eukaryotic cell cycle.

PMID- 12600310
TI  - Cellular motility driven by assembly and disassembly of actin filaments.
AB  - Motile cells extend a leading edge by assembling a branched network of actin
      filaments that produces physical force as the polymers grow beneath the plasma
      membrane. A core set of proteins including actin, Arp2/3 complex, profilin,
      capping protein, and ADF/cofilin can reconstitute the process in vitro, and
      mathematical models of the constituent reactions predict the rate of motion.
      Signaling pathways converging on WASp/Scar proteins regulate the activity of
      Arp2/3 complex, which mediates the initiation of new filaments as branches on
      preexisting filaments. After a brief spurt of growth, capping protein terminates
      the elongation of the filaments. After filaments have aged by hydrolysis of their
      bound ATP and dissociation of the gamma phosphate, ADF/cofilin proteins promote
      debranching and depolymerization. Profilin catalyzes the exchange of ADP for ATP,
      refilling the pool of ATP-actin monomers bound to profilin, ready for elongation.

PMID- 12600311
TI  - The molecular motor toolbox for intracellular transport.
AB  - Eukaryotic cells create internal order by using protein motors to transport
      molecules and organelles along cytoskeletal tracks. Recent genomic and functional
      studies suggest that five cargo-carrying motors emerged in primitive eukaryotes
      and have been widely used throughout evolution. The complexity of these "Toolbox"
      motors expanded in higher eukaryotes through gene duplication, alternative
      splicing, and the addition of associated subunits, which enabled new cargoes to
      be transported. Remarkably, fungi, parasites, plants, and animals have distinct
      subsets of Toolbox motors in their genomes, suggesting an underlying diversity of
      strategies for intracellular transport.

PMID- 12600312
TI  - Mitochondria: releasing power for life and unleashing the machineries of death.
AB  - The mitochondrion has long been known both as a chemical powerplant and as a
      cellular compartment housing various biosynthetic pathways. However, studies on
      the function of mitochondria in apoptotic cell death have revealed a versatility
      and complexity of these organelles previously unsuspected. The mechanisms
      proposed for mitochondrial involvement in cell death are diverse and highly
      controversial. In one model, mitochondria are seen as passive containers that can
      be made to leak out cytotoxic proteins. In other scenarios, however, certain more
      or less familiar aspects of mitochondrial physiology, such as oxidative
      phosphorylation, generation of oxygen radicals, dynamic morphological
      rearrangements, calcium overload, and permeability transition, are proposed to
      play crucial roles. In this review, we examine a few promising mechanisms that
      have been gaining attention recently.

PMID- 12600313
TI  - Protein translocons: multifunctional mediators of protein translocation across
      membranes.
AB  - Protein translocation systems consist of complex molecular machines whose
      activities are not limited to unidirectional protein targeting. Protein
      translocons and their associated receptor systems can be viewed as dynamic
      modular units whose interactions, and therefore functions, are regulated in
      response to specific signals. This flexibility allows translocons to interact
      with multiple signal receptor systems to manage the targeting of topologically
      distinct classes of proteins, to mediate targeting to different suborganellar
      compartments, and to respond to stress and developmental cues. Furthermore, the
      activities of translocons are tightly coordinated with downstream events, thereby
      providing a direct link between targeting and protein maturation.

PMID- 12600314
TI  - Membrane domains in the secretory and endocytic pathways.
AB  - Progress in identifying, characterizing, and localizing the constituents of
      distinct membrane bound compartments has revealed a new level of intracellular
      subcompartmentation. Proteins and lipids are not uniformly distributed in a given
      organelle, and subdomains are formed by a combination of hierarchical assembly
      processes and protein exclusion. Thus, functionally distinct specializations of a
      given organelle are physically segregated to a greater extent than previously
      believed.

PMID- 12600315
TI  - Membrane fusion.
AB  - Membrane fusion, one of the most fundamental processes in life, occurs when two
      separate lipid membranes merge into a single continuous bilayer. Fusion reactions
      share common features, but are catalyzed by diverse proteins. These proteins
      mediate the initial recognition of the membranes that are destined for fusion and
      pull the membranes close together to destabilize the lipid/water interface and to
      initiate mixing of the lipids. A single fusion protein may do everything or
      assemblies of protein complexes may be required for intracellular fusion
      reactions to guarantee rigorous regulation in space and time. Cellular fusion
      machines are adapted to fit the needs of different reactions but operate by
      similar principles in order to achieve merging of the bilayers.

PMID- 12600316
TI  - Sticky business: orchestrating cellular signals at adherens junctions.
AB  - Cohesive sheets of epithelial cells are a fundamental feature of multicellular
      organisms and are largely a product of the varied functions of adherens
      junctions. These junctions and their cytoskeletal associations contribute heavily
      to the distinct shapes, polarity, spatially oriented mitotic spindle planes, and
      cellular movements of developing tissues. Deciphering the underlying mechanisms
      that govern these conserved cellular rearrangements is a prerequisite to
      understanding vertebrate morphogenesis.

PMID- 12600317
TI  - Adenylyl cyclase localization regulates streaming during chemotaxis.
AB  - We studied the role of the adenylyl cyclase ACA in Dictyostelium discoideum
      chemotaxis and streaming. In this process, cells orient themselves in a head to
      tail fashion as they are migrating to form aggregates. We show that cells lacking
      ACA are capable of moving up a chemoattractant gradient, but are unable to
      stream. Imaging of ACA-YFP reveals plasma membrane labeling highly enriched at
      the uropod of polarized cells. This localization requires the actin cytoskeleton
      but is independent of the regulator CRAC and the effector PKA. A constitutively
      active mutant of ACA shows dramatically reduced uropod enrichment and has severe
      streaming defects. We propose that the asymmetric distribution of ACA provides a
      compartment from which cAMP is secreted to locally act as a chemoattractant,
      thereby providing a unique mechanism to amplify chemical gradients. This could
      represent a general mechanism that cells use to amplify chemotactic responses.

PMID- 12600318
TI  - Asymmetric loading of Kar9 onto spindle poles and microtubules ensures proper
      spindle alignment.
AB  - Spindle alignment is the process in which the two spindle poles are directed
      toward preselected and opposite cell ends. In budding yeast, the APC-related
      molecule Kar9 is required for proper alignment of the spindle with the mother-bud
      axis. We find that Kar9 localizes to the prospective daughter cell spindle pole.
      Kar9 is transferred from the pole to cytoplasmic microtubules, which are then
      guided in a myosin-dependent manner to the bud. Clb4/Cdc28 kinase phosphorylates
      Kar9 and accumulates on the pole destined to the mother cell. Mutations that
      block phosphorylation at Cdc28 consensus sites result in localization of Kar9 to
      both poles and target them both to the bud. Thus, Clb4/Cdc28 prevents Kar9
      loading on the mother bound pole. In turn, asymmetric distribution of Kar9
      ensures that only one pole orients toward the bud. Our results indicate that Cdk1
      dependent spindle asymmetry ensures proper alignment of the mitotic spindle with
      the cell division axis.

PMID- 12600319
TI  - SAS-4 is a C. elegans centriolar protein that controls centrosome size.
AB  - Centrosomes consist of a centriole pair surrounded by pericentriolar material
      (PCM). Previous work suggested that centrioles are required to organize PCM to
      form a structurally stable organelle. Here, we characterize SAS-4, a centriole
      component in Caenorhabditis elegans. Like tubulin, SAS-4 is incorporated into
      centrioles during their duplication and remains stably associated thereafter. In
      the absence of SAS-4, centriole duplication fails. Partial depletion of SAS-4
      results in structurally defective centrioles that contain reduced levels of SAS-4
      and organize proportionally less PCM. Thus, SAS-4 is a centriole-associated
      component whose amount dictates centrosome size. These results provide novel
      insight into the poorly understood role of centrioles as centrosomal organizers.

PMID- 12600321
TI  - [Early visceral resection for severe corrosive injuries: systematic or
      selective?].

PMID- 12600322
TI  - [Laparoscopic aortoiliac surgery for occlusive disease and or aneurysms].
AB  - The techniques of video-assisted surgery have been recently applied to aortoiliac
      surgery. The choices between first the retroperitoneal approach or the
      transperitoneal approach and the place of video-assisted surgery in relation to
      totally laparoscopic surgery are at the centre of debates. The aim of this
      clarification is to relate the evolution of laparoscopic aortoiliac surgery for
      occlusive disease and aneurysms through a review of the literature on this
      subject.

PMID- 12600324
TI  - [High intensity focused ultrasonic destruction of hepatic parenchyma].
AB  - OBJECTIVE: High intensity focused ultrasound (HIFU) is an effective and precise
      method of focal tumoral destruction since it is associated with imagery. This
      method is widespread for the endorectal treatment of prostatic adenocarcinomas.
      HIFU seem appropriate for the treatment of liver tumors but its use needs to be
      experimentally tested in vivo. The aim of the work is to study the feasibility,
      tolerance and effectiveness of the destruction of porcine liver by HIFU. MATERIAL
      AND METHODS: Ten pigs had liver destruction by HIFU after coeliotomy. Four to 5
      2,3 cm(3) HIFU lesions were performed per animal under ultrasonographic control.
      The study included biological surveillance and an autopsy was performed 4 to 24
      hours later for histological examination of the liver. RESULTS: The destruction
      of the liver was feasible in all cases and the 4 lobes of the liver could be
      treated. The general and biological tolerance of the procedure was excellent.
      Ultrasonographic features of the HIFU lesions were defined. The histological
      examination of the lesions showed well-circumscribed necrosis areas associated
      with cavitation or histological deficiencies of various degrees. CONCLUSION: This
      work demonstrated that liver destruction by HIFU is a feasible and effective
      method with low morbidity. A long-term experimental study is necessary before
      comtemplating its clinical use.

PMID- 12600323
TI  - [Gastric conservation in severe caustic lesions of the digestive tract: is it
      legitimate?].
AB  - OBJECTIVE: To evaluate advantages and drawbacks of a controlled conservative
      management of patients with severe gastric caustic injuries. METHODS: Among 40
      patients with severe caustic gastric burns (> IIb), 28 with stade III lesions
      (mosaic necrosis: n = 10, extensive or circumferential necrosis: n = 18) were
      managed prospectively from 1990 to 1998. Twenty-two patients had associated stage
      III oesophageal lesions and 6 had stage III duodenal lesions. All patients were
      followed up by daily surgical examination. Total gastrectomy with esophageal
      exclusion or stripping was performed in case of perforation. RESULTS: Five
      immediate and 7 secondary total gastrectomies, two associated esophagectomies and
      two jejunal resections were performed. Mortality rate was 18% (5/28). Sixteen
      gastric preservations (60%) were achieved, including 7 complete and 9 partial
      because of gastric stricture. Eighteen esophagoplasties for oesophageal
      strictures or after gastrectomy were performed without mortality. CONCLUSION:
      Stage III caustic injuries of the stomach, when they are not immediately life
      threatening, do not systematically require total gastrectomy. A strict
      conservative attitude can be done with significant morbidity and acceptable
      mortality and significantly raises the numbers of preserved stomach.

PMID- 12600325
TI  - [Women's preferences for early discharge after conservative breast surgery:
      feasibility, patient profile and satisfaction].
AB  - PURPOSE: Ours aims were to assess the feasibility of short stay after
      conservative breast surgery when giving the choice to women, to identify women
      characteristics associated to short (less than 48 hours) or conventional stay and
      to confront satisfaction and anxiety of the two groups. METHODS: Women were able
      to choice the length of stay immediately after surgery. Afterwards they completed
      a questionnaire measuring pain, anxiety and satisfaction. Clinical data
      concerning surgery were also collected. RESULTS: The hospital stay was short for
      114 women (75.5%) and conventional for 37 women (24.5%). Length of stay was
      related to education level (P = 0,021), general health status (ASA score) (P =
      0,003), breast pain (P = 0,001), the number of wound drains (P = 0,005), cancer
      (P = 0,001) and satisfaction about hospitalisation (P = 0,022). Post-surgical
      morbidity was similar between groups, except prolonged axillary drainage more
      frequent in conventional stay group. CONCLUSION: Women often chose a short stay
      after breast conservative surgery. This procedure is feasible routinely without
      heavy complication. Women preference for a short stay is real and could be
      improved by a better organisation, which ensure the continuity of care between
      hospital and home, with satisfaction assessment.

PMID- 12600326
TI  - [Symptomatic bladder or ureteral endometriosis: report of 8 cases and review of
      the literature].
AB  - OBJECTIVES: The aim of this study was to determine the symptoms of bladder and
      ureteral endometriosis and to review the treatment approaches. MATERIALS AND
      METHODS: We conducted a retrospective studyover the period November 1989-July
      2000. We reviewed the medical data of all women with bladder or utereral
      endometriosis who underwent a major surgery (ureteral reimplementation on psoas
      bladder, partial resection of the ureter, partial cystectomy). RESULTS: Eight
      women met the defined selection criterion, three with bladder injuryand five with
      ureteral injury. The only adverse postoperative complication was a passive
      ureteral reflux following ureteral reimplementation on psoas bladder. No
      recurrence on the urinary tract were reported. CONCLUSION: Surgical treatment is
      indicated for patient suffering from symptomatic bladder or ureteral
      endometriosis. Isolated bladder injuries due to endometriosis are mostly treated
      by laparoscopic surgery. Ureteral endometriosis may deteriorate the renal
      function. The initial step of the treatment may include an uterolysis by
      coelioscopy or an ureteral dilatation by ureteroscopy together with a medical
      treatment. The renal function must be closely monitored. In case of persistent or
      recurrent endometriosis, an ureteral resection would be justified.

PMID- 12600327
TI  - [Which type of fundoplication for gastroesophageal reflux disease?].

PMID- 12600328
TI  - [Breast angiosarcomas: three case reports].
AB  - Angiosarcoma is a rare type of breast cancer, it has the worst prognosis of all
      breast malignancies. We report three cases of breast angiosarcoma observed at the
      National Oncology Institute and the Maternity of Orangers. A preoperative
      diagnosis was evoked in one case only, after a local recurrence in the second one
      and histological in the last one. Mastectomy is the reference treatment. The
      development is distinguished by general metastasis. Based on review of
      literature, we analysed the different aspects of this disease.

PMID- 12600329
TI  - [Acute peritonitis: a rare presentation of chylous ascites].
AB  - Chylous ascites is a rare case of peritonitis. We report here a case arising in a
      21-year-old lady.

PMID- 12600330
TI  - [Accessory liver lobe torsion mimicking a pancreatic tumor].
AB  - We report a case of liver accessory lobe torsion. In few published cases, pre
      operative diagnosis was made by radiologic findings for non specific abdominal
      pain. In reported case, only surgery led to diagnosis, whereas pancreatic tumor
      was suspected by ultrasound and tomodensitometry.

PMID- 12600331
TI  - [Feasibility of prosthesis insertion by laparotomy as palliative treatment for
      malignant duodenal stenosis].
AB  - The authors report a preliminary series assessing the feasibility of duodenal
      stenting using a surgical approach. The study included 16 patients with a
      malignant duodenal outlet obstruction for whom a biliaryobstruction necessitated
      a laparotomyor following an endoscopic stenting failure. The stent was efficient
      in 15 patients with a complete relieve of obstruction. These patients could have
      oral intake at the end of the first postoperative week. No stent obstruction
      occurred. The duodenal stenting by laparotomy could be a good alternative to
      palliative gastroenteral anasotomosis.

PMID- 12600332
TI  - [Distal pancreatectomy with "centrifugal" dissection of splenic vessels].
AB  - We describe a technique of distal pancreatectomy beginning with division of
      pancreatic neck before control of splenic vessels. Early neck division allows
      safer vascular control. For distal pancreatectomy, primary section of the neck
      and splenic vessels ligation, combined with division of left gastro-epiploic and
      short gastric vessels, precedes mobilization of a devascularized specimen,
      decreases operative bleeding and seems more logical from a carcinologic point of
      view. Furthermore, this technique could be the first step of left pancreatectomy
      with splenic preservation.

PMID- 12600333
TI  - [Response to S. Benoist and Y. Panis in the article: Mobilization of the left
      colic angle by laparoscopy: operative technique].

PMID- 12600334
TI  - [Response to K. Slim and P.L. Fagniez in the article: Endoscopic, percutaneous
      and laparoscopic treatment of acute biliary pancreatitis].

PMID- 12600336
TI  - Increased musculoskeletal stiffness during load carriage at increasing walking
      speeds maintains constant vertical excursion of the body center of mass.
AB  - The primary objective of this research was to determine changes in body and joint
      stiffness parameters and kinematics of the knee and body center of mass (COM),
      that result from wearing a backpack (BP) with a 40% body weight load at
      increasing speeds of walking. It was hypothesized that there would be speed and
      load-related increases in stiffness that would prevent significant deviations in
      the COM trajectory and in lower-extremity joint angles. Three independent
      biomechanical models employing kinematic data were used to estimate global lower
      extremity stiffness, vertical stiffness and knee joint rotational stiffness in
      the sagittal plane during walking on a treadmill at speeds of 0.6-1.6 ms(-1) in
      0.2 ms(-1) increments in BP and no backpack conditions. Kinematic data were
      collected using an Optotrak, three-dimensional motion analysis system. Knee
      angles and vertical excursion of the COM during the compression (loading phase)
      increased as a function of speed but not load. All three estimates of stiffness
      showed significant increases as a function of both speed and load. Significant
      interaction effects indicated a convergence of load-related stiffness values at
      lower speeds. Results suggested that increases in muscle-mediated stiffness are
      used to maintain a constant vertical excursion of the COM under load across the
      speeds tested, and thereby limit increases in metabolic cost that would occur if
      the COM would travel through greater vertical range of motion.

PMID- 12600337
TI  - Rapid neck muscle adaptation alters the head kinematics of aware and unaware
      subjects undergoing multiple whiplash-like perturbations.
AB  - To examine whether habituation confounds the study of whiplash injury using human
      subjects, we quantified changes in the magnitude and temporal development of the
      neck muscle electromyogram and peak linear and angular head/torso kinematics of
      subjects exposed to sequential whiplash-like perturbations. Forty-four seated
      subjects (23F, 21M) underwent 11 consecutive forward horizontal perturbations
      (peak sled acceleration=1.5 g). Electromyographic (EMG) activity was recorded
      over the sternocleidomastoid (SCM) and cervical paraspinal (PARA) muscles with
      surface electrodes, and head and torso kinematics were measured using linear and
      angular accelerometers and a 3D motion analysis system. EMG onset occurred at
      reflex latencies (67-75 ms in SCM) and did not vary with repeated perturbations.
      EMG amplitude was significantly attenuated by the second perturbation in PARA
      muscles and by the third perturbation in SCM muscles. The mean decrement in EMG
      amplitude between the first trial and the mean of the last five trials was
      between 41% and 64%. Related kinematic changes ranged from a 21% increase in head
      extension angle to a 29% decrease in forward acceleration at the forehead, and
      were also significantly different by the second exposure in some variables.
      Although a wider range of perturbation intensities and inter-perturbation
      intervals need to be studied, the significant changes observed in both muscle and
      kinematic variables by the second perturbation indicated that habituation was a
      potential confounder of whiplash injury studies using repeated perturbations of
      human subjects.

PMID- 12600338
TI  - In vivo forces used to develop design parameters for tissue engineered implants
      for rabbit patellar tendon repair.
AB  - Previous studies in tissue engineering have shown that suspending
      undifferentiated mesenchymal stem cells in collagen gels and wrapping them about
      a suture causes alignment of cells and contraction of constructs in culture in a
      form that is suitable for implantation for tendon repair. Little is known about
      the patterns of these in vivo signals that might improve tendon repair
      biomechanics. Three hypotheses were tested in this study using the rabbit
      patellar tendon (PT) model: (1) peak in vivo forces and the rates of rise and
      fall in these forces will increase significantly with increasing levels of
      activity; (2) the PTs safety factor for all activities will be in the range of
      values found for tendons (2.5-3); (3) rabbits will not "favor" the operated limb
      at the time of evaluation but maintain similar vertical ground reaction forces in
      both limbs during quiet standing (QS). In vivo rabbit PT forces were measured
      during QS and while the animal hopped on a treadmill whose speed (0.04 and 0.13
      m/s) and inclination (0 degrees and 12 degrees) were controlled. Implantable
      force transducers were surgically placed in one PT and data collected three days
      post surgery in each of eight New Zealand White rabbits. Peak tensile forces
      increased significantly with inclination of the treadmill and the rates of rise
      and fall in tendon force increased significantly with both speed and inclination
      (p<0.001). Such design criteria should be useful in mechanically stimulating cell
      gel constructs for tendon repair.

PMID- 12600339
TI  - Early cement damage around a femoral stem is concentrated at the cement/bone
      interface.
AB  - This study aimed to improve understanding of the mechanical aspects of cemented
      implant loosening. After aggressive fatigue loading of stem/cement/femur
      constructs, micro-cracks and stem/bone micro-motions were quantified to answer
      three research questions: Are cracks preferentially associated with the
      stem/cement interface, the cement/bone interface or voids? Is cement damage
      dependent on axial position? Does cement damage correlate with micro-motion
      between the stem and the bone? Eight Charnley Cobra stems were implanted in
      cadaveric femora. Six stem/cement/femur constructs were subjected to "stair
      climbing" loads for 300 kcycles at 2Hz. Loads were normalized by construct
      stiffness to avoid fracture. Two additional constructs were not loaded.
      Transverse sections were cut at 10mm intervals, stained with a fluorescent dye
      penetrant and examined using epi-fluorescence stereomicroscopy. Crack lengths and
      cement areas were recorded for 9 sections per specimen. Crack length-density was
      calculated by dividing summed crack length by cement mantle area. To isolate the
      effect of loading, length-density data were offset by the baseline length-density
      measured in the non-loaded specimens. Significantly more cracks were associated
      with the interdigitated area (35.1%+/-11.6%) and the cement/bone interface
      (31.0%+/-6.2%) than with the stem/cement interface (11.0%+/-5.2%) or voids
      (6.1%+/-4.8%) (p<0.05). Load-induced micro-crack length-density was significantly
      dependent on axial position, increasing proximally (p<0.001). Micro-motions were
      small, all stems rotated internally. Cement damage did not correlate with micro
      motion.

PMID- 12600340
TI  - Non-linear viscoelastic models predict fingertip pulp force-displacement
      characteristics during voluntary tapping.
AB  - We evaluated whether lumped-parameter non-linear viscoelastic models of human
      fingertip tissue can describe fingertip force-displacement characteristics during
      a range of rapid, dynamic tapping tasks. Eight human subjects tapped with their
      index finger on the surface of a rigid load cell while an optical system tracked
      fingertip position using an infra-red LED attached to the fingernail. Four
      different tapping conditions were tested: normal and high-speed taps with a
      relaxed hand, and normal and high-speed taps with the other fingers co
      contracted. A non-linear viscoelastic model comprised of an instantaneous
      stiffness function and viscous relaxation function was capable of predicting
      fingertip tissue force response due to measured pulp compression under these four
      different loading conditions. The model could successfully reconstruct very rapid
      (less than 5 ms) force transients, and forces occurring over time periods greater
      than 100 ms, with errors of 10%. Model parameters varied by less than 20% over
      the four conditions, despite almost 3-fold differences in average forces and 38%
      differences in fingertip velocities. Energy dissipation by the fingertip averaged
      81%, and varied little (<3%) across conditions, despite a 1. 5-fold range of
      energy input. The ability of a lumped-parameter model to describe fingertip force
      displacement characteristics during a range of conditions contributes both to
      understanding the transmission of force through the fingertip to the
      musculoskeletal system and to predicting the stimulation of mechano-receptors
      located within the fingertip.

PMID- 12600341
TI  - Correlation between active and passive isometric force and intramuscular pressure
      in the isolated rabbit tibialis anterior muscle.
AB  - The purpose of this study was to quantify the relationship between intramuscular
      pressure (IMP) and muscle force during isometric muscle contraction of the rabbit
      tibialis anterior (TA) absent the effect of either bone or fascia. To quantify
      this relationship, length-tension experiments were performed on the isolated TA
      of the New Zealand White rabbit (mass=2.5+/-0.5kg, n=12). The knee was fixed in a
      custom jig, the distal tendon of the TA was attached to a servomotor, and a 360
      microm fiber optic pressure transducer was inserted into the TA. The peroneal
      nerve was stimulated to define optimal length (L(0)). The length-tension curve
      was created using 40Hz isometric contractions with 2-min rest intervals between
      each contraction. Measurements began at L(0)-50%L(f) and progressed to
      L(0)+50%L(f), changing the length-tension in 5% L(f) increments after each
      contraction. Qualitatively, the length-tension curve for isometric contractions
      was mimicked by the length-pressure curve for both active and passive conditions.
      Linear regression was performed individually for each animal for the ascending
      and descending limb of the length-tension curve and for active and passive
      conditions. Pressure-force coefficients of determination ranged from 0.138-0.963
      for the active ascending limb and 0.343-0.947 for the active descending limb.
      Passive pressure coefficients of determination ranged from 0.045-0.842 for the
      ascending limb and 0.672-0.982 for the descending limb. These data indicate that
      IMP measurement provide a fairly accurate index of relative muscle force,
      especially at muscle lengths longer than optimal.

PMID- 12600342
TI  - Theories of bipedal walking: an odyssey.
AB  - In this paper six theories of bipedal walking, and the evidence in support of the
      theories, are reviewed. They include: evolution, minimising energy consumption,
      maturation in children, central pattern generators, linking control and effect,
      and robots on two legs. Specifically, the six theories posit that: (1) bipedalism
      is the fundamental evolutionary adaptation that sets hominids--and therefore
      humans--apart from other primates; (2) locomotion is the translation of the
      centre of gravity along a pathway requiring the least expenditure of energy; (3)
      when a young child takes its first few halting steps, his or her biomechanical
      strategy is to minimise the risk of falling; (4) a dedicated network of
      interneurons in the spinal cord generates the rhythm and cyclic pattern of
      electromyographic signals that give rise to bipedal gait; (5) bipedal locomotion
      is generated through global entrainment of the neural system on the one hand, and
      the musculoskeletal system plus environment on the other; and (6) powered dynamic
      gait in a bipedal robot can be realised only through a strategy which is based on
      stability and real-time feedback control. The published record suggests that each
      of the theories has some measure of support. However, it is important to note
      that there are other important theories of locomotion which have not been covered
      in this review. Despite such omissions, this odyssey has explored the wide
      spectrum of bipedal walking, from its origins through to the integration of the
      nervous, muscular and skeletal systems.

PMID- 12600343
TI  - Effects of elastic property of the wall on flow characteristics through arterial
      stenoses.
AB  - Hemodynamic characteristics of blood flow through arterial stenoses are
      numerically investigated in this work. The blood is assumed as a Newtonian fluid
      and the pulsatile nature of flow is modeled by using measured values of the
      flowrate and pressure for the canine femoral artery. An isotropic elastic and
      incompressible material is assumed for the wall at each axial section, but a non
      uniform distribution of the shear modulus in axial direction is used to model the
      high stiffness of the wall at the stenosis location. Full Navier equations for a
      thick wall are used as the governing equations for the wall displacements. A
      continuous grid extending over the flow field and the wall is considered and
      governing equations are transformed for use in the computational domain.
      Discretized forms of the transformed wall and flow equations, which are coupled
      through the boundary conditions at their interface, are obtained by control
      volume method and simultaneously solved using the well-known SIMPLER algorithm.
      To study the effects of wall deformability, solutions are obtained for both rigid
      and elastic walls. The results indicate that deformability of the wall causes an
      increase in the time average of pressure drop, but a decrease in the maximum wall
      shear stress. Displacement and stress distributions in the wall are presented.

PMID- 12600344
TI  - Elastohydrodynamic lubrication analysis of metal-on-metal hip-resurfacing
      prostheses.
AB  - The elastohydrodynamic lubrication analysis was carried out in this study for a
      typical metal-on-metal hip-resurfacing prosthesis under a simple steady-state
      rotation. Both the Reynolds equation and the elasticity equation were coupled and
      solved numerically by the finite difference method. The finite element method was
      used to determine the elastic deformation of both the femoral and the acetabular
      components required for the lubrication analysis. The effect of the radial
      clearance between the femoral head and the acetabular cup on the predicted film
      thickness and pressure distribution was investigated. The predicted minimum
      lubricating film thickness was found to compare favourably with the prediction
      using the Hamrock and Dowson [J. Lubrication Technol. 100 (1978) 236] formula
      based on the assumption of ball-on-plane semi-infinite solids. This implies that
      the non-metallic materials such as bone and cement underlying the metallic
      components have a small effect on the predicted lubrication performance for the
      particular metal-on-metal hip-resurfacing prosthesis considered in this study.
      Under realistic physiological walking conditions, a decrease in the radial
      clearance from 150 to 50 microm resulted in a 137% increase in the predicted
      minimum film thickness from 19 to 45 nm. Consequently, given a surface roughness
      of 0.01 microm for both the metallic femoral and acetabular bearing surfaces, the
      predicted mixed lubrication regime for the larger clearance was changed to a full
      fluid film lubrication regime for the smaller clearance. This clearly highlighted
      the importance of the design and manufacturing parameters on the tribological
      performance of these hard-on-hard hip prostheses.

PMID- 12600345
TI  - Optimised performance of the backward longswing on rings.
AB  - Many elite gymnasts perform the straight arm backward longswing on rings in
      competition. Since points are deducted if gymnasts possess motion on completion
      of the movement, the ability to successfully perform the longswing to a
      stationary final handstand is of great importance. Sprigings et al. (1998) found
      that for a longswing initiated from a still handstand the optimum performance of
      an inelastic planar simulation model resulted in a residual swing of more than 3
      degrees in the final handstand. For the present study, a three-dimensional
      simulation model of a gymnast swinging on rings, incorporating lateral arm
      movements used by gymnasts and mandatory apparatus elasticity, was used to
      investigate the possibility of performing a backward longswing initiated and
      completed in handstands with minimal swing. Root mean square differences between
      the actual and simulated performances for the orientations of the gymnast and
      rings cables, the combined cable tension and the extension of the gymnast were
      3.2 degrees, 1.0 degrees, 270N and 0.05m respectively. The optimised simulated
      performance initiated from a handstand with 2.1 degrees of swing and using
      realistic changes to the gymnast's technique resulted in 0.6 degrees of residual
      swing in the final handstand. The sensitivity of the backward longswing to
      perturbations in the technique used for the optimised performance was determined.
      For a final handstand with minimal residual swing (2 degrees) the changes in body
      configuration must be timed to within 15 ms while a delay of 30 ms will result in
      considerable residual swing (7 degrees).

PMID- 12600346
TI  - In situ chondrocyte deformation with physiological compression of the feline
      patellofemoral joint.
AB  - The mechanical environment is an important factor affecting the maintenance and
      adaptation of articular cartilage, and thus the function of the joint and the
      progression of joint degeneration. Recent evidence suggests that cartilage
      deformation caused by mechanical loading is directly associated with deformation
      and volume changes of chondrocytes. Furthermore, in vitro experiments have shown
      that these changes in the mechanical states of chondrocytes correlate with a
      change in the biosynthetic activity of cartilage cells. The purpose of this study
      was to apply our knowledge of contact forces within the feline patellofemoral
      joint to quantify chondrocyte deformation in situ under loads of physiological
      magnitude. A uniform, static load of physiological magnitude was applied to
      healthy articular cartilage still fully intact and attached to its native bone.
      The compressed cartilage was then chemically fixed to enable the evaluation of
      cartilage strain, chondrocyte deformation and chondrocyte volumetric fraction.
      Patella and femoral groove articular cartilages differ in thickness, chondrocyte
      aspect ratio, and chondrocyte volumetric fraction in both magnitude and depth
      distribution. Furthermore, when subjected to the same compressive loads, changes
      to all of these parameters differ in magnitude and depth distribution between
      patellar and femoral groove articular cartilage. This evidence suggests that
      significant chondrocyte deformation likely occurs during in vivo joint loading,
      and may influence chondrocyte biosynthetic activity. Furthermore, we hypothesise
      that the contrasts between patella and femoral groove cartilages may explain, in
      part, the site-specific progression of osteoarthritis in the patellofemoral joint
      of the feline anterior cruciate ligament transected knee.

PMID- 12600347
TI  - The effect of material characteristics of shoe soles on muscle activation and
      energy aspects during running.
AB  - The purposes of this study were (a) to determine group and individual differences
      in oxygen consumption during heel-toe running and (b) to quantify the differences
      in EMG activity for selected muscle groups of the lower extremities when running
      in shoes with different mechanical heel characteristics. Twenty male runners
      performed heel-toe running using two shoe conditions, one with a mainly elastic
      and a visco-elastic heel. Oxygen consumption was quantified during steady state
      runs of 6 min duration, running slightly above the aerobic threshold providing
      four pairs of oxygen consumption results for comparison. Muscle activity was
      quantified using bipolar surface EMG measurements from the tibialis anterior,
      medial gastrocnemius, vastus medialis and the hamstrings muscle groups. EMG data
      were sampled for 5 s every minute for the 6 min providing 30 trials. EMG data
      were compared for the different conditions using an ANOVA (alpha=0.05). The
      findings of this study showed that changes in the heel material characteristics
      of running shoes were associated with (a) subject specific changes in oxygen
      consumption and (b) subject and muscle specific changes in the intensities of
      muscle activation before heel strike in the lower extremities. It is suggested
      that further study of these phenomena will help understand many aspects of human
      locomotion, including work, performance, fatigue and possible injuries.

PMID- 12600348
TI  - Kinematics, kinetics, and finite element analysis of commonplace maneuvers at
      risk for total hip dislocation.
AB  - Dislocation remains a disturbingly frequent complication of total hip
      arthroplasty (THA). Over the past several years, increasingly rigorous
      biomechanical approaches have been developed for studying dislocation, both
      experimentally and computationally. Realism of the input motion challenge data
      has lagged behind most other aspects of this body of work, and anterior
      dislocation maneuvers remain unstudied. To enhance realism of biomechanical
      studies of dislocation, motion data are here reported for ten THA-aged subjects,
      each repeatedly performing seven maneuvers known to be dislocation-prone. An
      optoelectronic motion tracking system and a recessed force plate captured the
      kinematics and ground reaction forces of these maneuvers. Using an established
      inverse dynamics model to estimate hip joint loading, 354 motion trials were
      evaluated using an existing finite element model of THA dislocation. Worst-case
      scenario THA constructs were simulated (22 mm femoral head, acetabular cup
      orientations at the limit of the accepted safe zone), in order to deliberately
      induce impingement and dislocation. The results showed a high incidence of
      computationally predicted dislocation for all movements studied, but also that
      risk was very maneuver-dependent, with patients being six times more likely to
      dislocate from a low-sit-to-stand maneuver than from stooping. These new motion
      data hopefully will help facilitate systematic efforts to reduce the incidence of
      dislocation.

PMID- 12600349
TI  - New insight into deformation-dependent hydraulic permeability of gels and
      cartilage, and dynamic behavior of agarose gels in confined compression.
AB  - Equilibrium, creep, and dynamic behaviors of agarose gels (2.0-14.8%) in confined
      compression were investigated in this study. The hydraulic permeabilities of gels
      were determined by curve-fitting creep data to the biphasic model (J. Biomech.
      Eng. 102 (1980) 73) and found to be similar in value to those published in the
      literature (AIChE J. 42 (1996) 1220). A new relationship between intrinsic
      permeability and volume fraction of water was found for agarose gel, capable of
      predicting deformation-dependent permeabilities of bovine articular cartilage and
      2% agarose gel published in literature. This relationship is accurate for gels
      and cartilage over a wide range of permeabilities (four orders of magnitude
      variation). The dynamic stiffness of the gels increases with gel concentration
      and loading frequency (0.01-1.0Hz). The increase in dynamic stiffness with
      loading frequency is less pronounced for gels with higher concentrations. The
      results of this study provide a new insight into deformation-dependent
      permeability behavior of agarose gel and cartilage, and are important for
      understanding biological responses of cells to interstitial fluid flow in gel or
      in cartilage under dynamic mechanical loading.

PMID- 12600350
TI  - Normalization of joint moments during gait: a comparison of two techniques.
AB  - Joint moments are commonly used to characterize gait. Factors like height and
      weight influence these moments. This study determined which of two commonly used
      normalization methods, body mass or body weight times height, most reduced the
      effects of height and weight on peak hip, knee, and ankle external moments during
      walking. The effectiveness of each normalization method in reducing gender
      differences was then tested. Gait data from 158 normal subjects were analyzed
      using unnormalized values, body mass normalized values, and body weight times
      height normalized values. Without normalization, height or weight accounted for 7
      82% of the variance in all 10 peak components of the moments. With normalization,
      height and weight accounted for at most 6% of the variance with the exception of
      the hip adduction moment normalized by body weight times height and the ankle
      dorsiflexion moment normalized by body mass. For the hip adduction moment
      normalized by body weight times height, height still accounted for 13% of the
      variance (p<0.001) and for the ankle dorsiflexion moment normalized by body mass,
      22% of the variance (p<0.001). After normalization, significant differences
      between males and females remained for only two out of 10 moments with the body
      weight times height method compared to six out of 10 moments with the body mass
      method. When compared to the unnormalized data, both normalization methods were
      highly effective in reducing height and weight differences. Even for the two
      cases where one normalization method was less effective than the other (hip
      adduction-body weight times height; ankle dorsiflexion-body mass) the
      normalization process reduced the variance ascribed to height or weight by 48%
      and 63%, respectively, as compared to the unnormalized data.

PMID- 12600351
TI  - A model of fracture testing of soft viscoelastic tissues.
AB  - Fracture, or tear, toughness of soft tissues can be computed from the work of
      fracture divided by the area of new crack surface. For soft tissues without
      significant plastic deformation, total work, which can be measured
      experimentally, is composed of the sum of fracture and viscoelastic work. In
      order to deduce fracture work, a method is needed to estimate viscoelastic work.
      Two different methods (Ph.D. Dissertation, University of Minnesota, 2000; J.
      Mater. Sci.: Mater. Med. 12 (2001) 327) have been proposed to estimate
      viscoelastic work in a fracture test of a soft tissue. The relative merits of
      these methods are unknown because the true viscoelastic work in an experiment is
      unknown. In order to characterize the accuracy of these methods, a theoretical
      model of crack propagation of viscoelastic soft tissue in a tensile test is
      presented, from which the exact viscoelastic work is calculated. The material is
      assumed to obey the standard linear solid model. The "exact" solution for the
      viscoelastic work during the fracture is computed from the model and compared
      with the work estimated by the two methods. It was found that both methods tend
      to underestimate the viscoelastic work done, and thus overestimate the fracture
      work and fracture toughness, although the errors were greater with the Fedewa
      method. It was further found that low displacement rates can give rise to a
      "snap" effect, where rapid crack growth can cause a disproportionate amount of
      viscoelastic energy to be dissipated during unloading. This modeling approach may
      be useful in evaluating other experimental methods of soft tissue fracture.

PMID- 12600352
TI  - Estimation of discretization errors in contact pressure measurements.
AB  - Contact pressure measurements in total knee replacements are often made using a
      discrete sensor such as the Tekscan K-Scan sensor. However, no method currently
      exists for predicting the magnitude of sensor discretization errors in contact
      force, peak pressure, average pressure, and contact area, making it difficult to
      evaluate the accuracy of such measurements. This study identifies a non
      dimensional area variable, defined as the ratio of the number of perimeter
      elements to the total number of elements with pressure, which can be used to
      predict these errors. The variable was evaluated by simulating discrete pressure
      sensors subjected to Hertzian and uniform pressure distributions with two
      different calibration procedures. The simulations systematically varied the size
      of the sensor elements, the contact ellipse aspect ratio, and the ellipse's
      location on the sensor grid. In addition, contact pressure measurements made with
      a K-Scan sensor on four different total knee designs were used to evaluate the
      magnitude of discretization errors under practical conditions. The simulations
      predicted a strong power law relationship (r(2)>0.89) between worst-case
      discretization errors and the proposed non-dimensional area variable. In the
      total knee experiments, predicted discretization errors were on the order of 1-4%
      for contact force and peak pressure and 3-9% for average pressure and contact
      area. These errors are comparable to those arising from inserting a sensor into
      the joint space or truncating pressures with pressure sensitive film. The
      reported power law regression coefficients provide a simple way to estimate the
      accuracy of experimental measurements made with discrete pressure sensors when
      the contact patch is approximately elliptical.

PMID- 12600353
TI  - Comment on "A mathematical formula to calculate the theoretical range of motion
      for total hip arthroplasty".

PMID- 12600355
TI  - AIDS in the HAART era: New York's heterogeneous geography.
AB  - During the 1990s, the number of new AIDS cases in New York City, USA, declined
      precipitously. The declines, beginning before highly active antiretroviral
      therapy (HAART) was introduced, were geographically heterogeneous across two New
      York City boroughs analyzed. From 1993 to 1998, zip codes in Lower Manhattan,
      with large white and affluent populations, had declines as much as 55% more than
      the rest of Manhattan. Bronx zip codes underwent still lesser declines. Declines
      also differed within zip codes among subpopulations. White zip code populations
      tended to have greater declines than Latino populations, which in turn tended to
      have greater declines than black populations. According to bivariate and stepwise
      regressions, an array of socioeconomic and community stress variables acted in
      combination on the decline in New York AIDS. Manhattan's declines in total AIDS
      incidence were primarily defined by changes in AIDS incidence for whites and for
      men who have sex with men, racial segregation, and the proportions of households
      in upper income classes and under rent stress. Bronx declines in total AIDS are
      principally explained by a broader range of income classes, and social
      instability as marked by housing overcrowding and cirrhosis and drug mortalities.
      Whatever the combination of proximate causes for the decline in AIDS incidence in
      1990s New York (educational campaigns, HAART, demographic stochasticity), the
      decline was shaped by the city's socioeconomic structure and political and
      ecological history. That structure and history generates the geographically
      defined aggregates of behaviors that promote or impede AIDS decline. Such spatial
      heterogeneity may provide for HIV refugia, areas where the virus can weather the
      epidemic's contraction, a troubling possibility with the accelerating
      microbicidal failures of combination therapies.

PMID- 12600354
TI  - Mortality, inequality and race in American cities and states.
AB  - A number of studies have found that mortality rates are positively correlated
      with income inequality across the cities and states of the US. We argue that this
      correlation is confounded by the effects of racial composition. Across states and
      Metropolitan Statistical Areas (MSAs), the fraction of the population that is
      black is positively correlated with average white incomes, and negatively
      correlated with average black incomes. Between-group income inequality is
      therefore higher where the fraction black is higher, as is income inequality in
      general. Conditional on the fraction black, neither city nor state mortality
      rates are correlated with income inequality. Mortality rates are higher where the
      fraction black is higher, not only because of the mechanical effect of higher
      black mortality rates and lower black incomes, but because white mortality rates
      are higher in places where the fraction black is higher. This result is present
      within census regions, and for all age groups and both sexes (except for boys
      aged 1-9). It is robust to conditioning on income, education, and (in the MSA
      results) on state fixed effects. Although it remains unclear why white mortality
      is related to racial composition, the mechanism working through trust that is
      often proposed to explain the effects of inequality on health is also consistent
      with the evidence on racial composition and mortality.

PMID- 12600356
TI  - Respiratory illness in the Dominican Republic: what are the predictors for health
      services utilization of young children?
AB  - Respiratory illness and diarrhoea continue to be the leading causes of paediatric
      morbidity and mortality in the Dominican Republic. An important first step in
      alleviating this disease burden is to understand patterns and predictors of
      health services utilization for these conditions. This study examines the
      predictors of (a) health services utilization, and (b) public versus private
      sector use, for respiratory illness in the under-five population in the Dominican
      Republic. The DHS-2 dataset (1991) was utilized for analysis. Logistic regression
      models for predicting use and non-use, and for predicting private versus public
      sector use, were constructed using the Andersen Behavioural Model as the
      conceptual framework. Our findings indicate that sex, location and possession
      index quartile are factors that influence the decision to seek care or not for
      respiratory illness in under-fives. In contrast, the choice between the public
      and private sector is determined by location and insurance status. From the
      policy perspective, if the Dominican Republic were to undertake steps to increase
      private insurance coverage, our results indicate that this would lead to
      increased utilization of private sector providers for respiratory illness by
      children having private insurance, but would not have an impact on overall
      utilization (i.e. use vs. non-use). On the other hand, one of the ways to deliver
      cost-effective interventions by the publicly financed system would be to improve
      facilities in the rural areas.

PMID- 12600357
TI  - Quality of care and the demand for health services in Bamako, Mali: the specific
      roles of structural, process, and outcome components.
AB  - The public finance and foreign exchange crisis of the 1980s aggravated the
      unfavourable economic trends in many developing countries and resulted in budget
      cuts in the health sector. Policymakers, following the suggestions of World Bank
      experts, introduced user fees. Economic analysis of the demand for health care in
      these countries focused on the impact of price and income on health service
      utilisation. But the lesson to date from experiences in cost recovery is that
      without visible and fairly immediate improvements in the quality of care, the
      implementation of user fees will cause service utilisation to drop. For this
      reason, the role of quality of health care has been recently a subject of
      investigation in a number of health care demand studies. In spite of using the
      data from both households and facilities, recent studies are quite limited
      because they measure quality only by structural attributes (availability of
      drugs, equipment, number and qualifications of staff, and so on). Structural
      attributes of quality are necessary but not sufficient conditions for demand. A
      unique feature of this study is that it also considers the processes followed by
      practitioners and the outcome of care, to determine simultaneously the respective
      influence of price and quality on decision making. A nested multinomial logit was
      used to examine the choice between six alternatives (self-treatment, modern
      treatment at home, public hospital, public dispensary, for-profit facility and
      non-profit facility). The estimations are based on data from a statistically
      representative sample of 1104 patients from 1191 households and the data from a
      stratified random sample of 42 out of 84 facilities identified. The results
      indicate that omitting the process quality variables from the demand model
      produces a bias not only in the estimated coefficient of the "price" variable but
      also in coefficients of some structural attributes of the quality. The
      simulations suggest that price has a minor effect on utilisation of health
      services, and that health authorities can simultaneously double user fees and
      increase utilisation by emphasising improvement of both the structural and
      process quality of care in public health facilities.

PMID- 12600358
TI  - Generating political will for safe motherhood in Indonesia.
AB  - In 1987 an international conference brought global attention to an issue that
      previously had been ignored: the world's alarmingly high number of maternal
      deaths in childbirth. The conference ended with a declaration calling for a
      reduction in maternal mortality by at least half by the year 2000. As the
      deadline approached, safe motherhood activists lamented the fact that the world
      was nowhere near to achieving this objective. They attributed this failure to a
      variety of causes, but were in agreement that the medical technology was
      available to prevent maternal deaths in childbirth, and the key was generating
      the political will to make such technology widely available to women in
      developing countries.What 'political will' means, however, has been left as an
      unopened black box. What causes governments to give priority to the issue of safe
      motherhood, given that national political systems are burdened with thousands of
      issues to sort through each year? In marked contrast to our extensive knowledge
      about the medical interventions necessary to prevent maternal death, we know
      little about the political interventions necessary to increase the likelihood
      that national leaders pay meaningful attention to the issue. Drawing from a
      scholarly literature on agenda setting, this paper identifies four factors that
      heighten the likelihood that an issue will rise to national-level attention: the
      existence of clear indicators showing that a problem exists; the presence of
      effective political entrepreneurs to push the cause; the organization of
      attention-generating focusing events that promote widespread concern for the
      issue; and the availability of politically palatable policy alternatives that
      enable national leaders to understand that the problem is surmountable. The paper
      presents a case study of the emergence, waning and re-generation of political
      priority for safe motherhood in Indonesia over the decade 1987-1997, to highlight
      how these four factors interacted to raise safe motherhood from near obscurity in
      the country to national-level prominence. While there are contextual factors that
      make this case unique, some elements are applicable to all developing countries.
      The paper draws out these dimensions in the hope that greater knowledge
      surrounding how political will actually has been generated can help shape
      strategic action to address this much neglected global problem.

PMID- 12600359
TI  - A new theory of health promoting schools based on human functioning, school
      organisation and pedagogic practice.
AB  - This paper outlines a novel explanatory frame for understanding how schools may
      intervene in order to promote pupils' health. The new theory is synthesised from
      an Aristotelian interpretation of human functioning and a theory of cultural
      transmission. In keeping with recent influential theoretical developments, it is
      proposed that health has its roots in human functioning. It follows from this
      concept that the promotion of pupils' health is facilitated by the promotion of
      pupil functioning and the primary mechanisms through which schools promote pupil
      functioning and, hence, health, are through the influences of school
      organisation, curriculum development and pedagogic practice on pupil development.
      According to the new theory, good human functioning is dependent on the
      realisation of a number of identified essential human capacities and the meeting
      of identified fundamental human needs. Two essential capacities, the capacity for
      practical reasoning and the capacity for affiliation with other humans, plan and
      organise the other essential capacities. The realisation of these two capacities
      should, it is argued, be the primary focus of health promoting schools.
      Additionally, health promoting schools should ensure that fundamental human needs
      concerning non-useful pain and information about the body are met. A number of
      testable hypotheses are generated from the new theory. Comparisons with existing
      interpretations of health promoting schools indicate there are similarities in
      the actions schools should take to promote health. However, the new theory can,
      uniquely, be used to predict which pupils will enjoy the best health at school
      and in adulthood. Additionally, according to the new theory, schools do not need
      designated health education classes or teaching staff with specialist health
      education roles in order to be health promoting. It is concluded that the new
      theory may have a number of advantages over existing theories at both the policy
      and intervention levels.

PMID- 12600360
TI  - Religion and women's health in Ghana: insights into HIV/AIDs preventive and
      protective behavior.
AB  - Since the late 1970s when the first cases of HIV/AIDS were identified in Africa,
      there has been an upsurge of research on the epidemic. Although religious
      involvement may be germane to AIDS protective and risk behavior, few of these
      studies deal with religion and AIDS. This article contributes to the discourse on
      religion and health in Africa by analysing the interrelationship between religion
      and AIDS behavior in Ghana, a West African country at the early stages of the
      AIDS epidemic, and one where religious activities are more pronounced. We explore
      whether a woman's knowledge of HIV/AIDS is associated with her religious
      affiliation, and whether religious affiliation influences AIDS preventive
      (protective) attitudes. Findings from our analysis of Ghanaian data indicate that
      religious affiliation has a significant effect on knowledge of AIDS. However, we
      did not find religious affiliation to be associated with changes in specific
      protective behavior, particularly the use of condoms. The limitations and
      implications of the study are discussed, promising directions for further
      research on religion and AIDS protective and risk behaviors are also discussed,
      and the design and development of culturally sensitive programs to help in the
      ongoing AIDS prevention efforts in the region are proposed.

PMID- 12600361
TI  - Dimensions of the emerging orphan crisis in sub-Saharan Africa.
AB  - This study uses recent Demographic and Health Survey (DHS) data to examine
      levels, trends, and differentials in orphan prevalence in sub-Saharan Africa. The
      first part of the analysis presents direct estimates of orphan prevalence in 17
      countries during the period 1995-2000. We find a strong correlation between
      orphanhood prevalence and national adult HIV prevalence estimates lending support
      to the interpretation of the orphan crisis as, in large part, AIDS-related. The
      second part of the analysis consists of an in-depth study of trends and age
      patterns in orphan prevalence and welfare in the 1990s for five countries that
      have had widely divergent HIV prevalence levels (Zimbabwe, Kenya, Tanzania,
      Ghana, and Niger). The vulnerability of orphans with respect to their situation
      in households and educational opportunities is evaluated in relation to non
      orphans' experience. The results of the analysis indicate that losing one or both
      parents is significantly associated with diminished chances of being at the
      appropriate grade level for age. Our results are interpreted in the context of
      societal responses to the crisis, and potential recommendations for intervention.

PMID- 12600362
TI  - Motherhood as a vulnerability factor in major depression: the role of negative
      pregnancy experiences.
AB  - Adverse pregnancy experiences were examined retrospectively in relation to adult
      lifetime experience of clinical depression to see whether such experience
      conferred long-term risk for women. The sample consisted of just under 200
      community-based women, half of whom were selected for high depressive-risk on the
      basis of adverse childhood experience. Over two-thirds of these women had
      experienced pregnancy. Adverse pregnancies were classified either in terms of
      loss (adverse non-live pregnancy/births) or in terms of live births in difficult
      circumstances (adverse live pregnancy/births). Intensive life history interviews
      collected details of all pregnancies, childhood neglect/abuse, marital adversity
      and a history of episodes of clinical depression. Both adverse non-live and live
      pregnancy experiences were significantly related to lifetime depression. The
      relationship remained for depression in different time periods and for those
      episodes unrelated to maternity experience. Both types of adverse pregnancy/birth
      experiences were associated with increased rates of marital problems. While
      adverse live pregnancy/births related to prior childhood neglect/abuse, this did
      not hold for those non-live. Logistic regression showed that only adverse non
      live pregnancy/births together with marital adversity and childhood neglect/abuse
      provided the best model for lifetime depression. The findings are discussed in
      terms of lifetime trajectories linking difficult environments, close
      relationships and issues of loss.

PMID- 12600363
TI  - "It's like an addiction first thing...afterwards it's like a habit": daily
      smoking behaviour among people living in areas of deprivation.
AB  - The paper draws on qualitative interviews with a sample of male and female
      smokers who live in areas of disadvantage in Edinburgh, Scotland, to examine
      their perceptions of habit and addiction and the implications for smoking
      behaviour. The paper shows how smokers have a sophisticated understanding of
      these concepts and the way in which they affected their smoking behaviour across
      the course of a 'typical' day. The paper argues that daily contexts which smokers
      inhabit either constrain or facilitate smoking and as such play a central role in
      the way in which they smoke. In contexts where smoking was constrained (by
      externally or self-imposed restrictions) smokers described how they employed
      various strategies to achieve and maintain what they perceived to be a desirable
      level of nicotine intake, such as by anticipatory smoking. Where restrictions on
      smoking were absent, men's and women's smoking appeared remarkably similar.
      However, for the most part, the contexts which men and women inhabited over the
      course of the day differed, with women assuming the largest share of domestic and
      child care responsibilities. Apparent gender differences in smoking behaviour
      appeared to be related to the different daily contexts which men and women
      inhabited. Crucially, the influences on smoking described by respondents in this
      study were closely related to circumstances of socio-economic deprivation.

PMID- 12600364
TI  - Health and safety in policing: lessons from the regulation of CS sprays in the
      UK.
AB  - Recent years have seen the introduction of a wide range of weapons for police
      forces around the world intended to minimise injuries incurred in officer-public
      encounters. In 1996, police forces in England and Wales began trials of CS
      incapacitant sprays. This article reviews the claims and counterclaims
      surrounding the medical implications of the sprays with a view to asking how the
      uncertainties associated with them have been handled in the regulation process.
      This analysis casts considerable doubt on the robustness of the precautions taken
      and demonstrates a continuing failure for relevant government agencies to respond
      and learn from problems identified. Drawing on wider literature regarding the
      health implications of risky technologies, it further asks what policy lessons
      the case of the CS sprays holds for the regulation of weaponry at an
      international level.

PMID- 12600365
TI  - Different frames, different fears: communicating about chlorinated drinking water
      and cancer in the Canadian media.
AB  - Risk issues become complicated when scientific evidence concerning a potential
      environmental exposure is equivocal; particularly when many argue that the public
      health benefits of a policy action outweigh any potential negative health
      effects. Chlorinated drinking water, and chlorinated disinfection byproducts
      (CDBPs) that are formed during the disinfection process, represent a useful case
      study for examining these complications. We conduct a media analysis of
      chlorinated drinking water stories in the Canadian print media from 1977 to 2000.
      We examine media presentations of science compared to framings by scientists,
      regulators, the chlorine industry, water utility representatives, and non
      governmental organizations of the CDBP issue based on key informant interviews.
      We argue that there are two main framings of the debate, each of which are
      powerful in constructing risk perceptions. On the one hand, many frame the debate
      as a 'voluntary' risk: we choose chlorine disinfection to protect against
      microbial risks with a possible adverse consequence of that protection. On the
      other hand, others frame the issue as an 'involuntary' risk: chlorine
      disinfection was a 'choice' imposed by public health and water utility officials;
      a choice that carries a potential cancer risk, and alternative disinfection
      technologies are advocated. We demonstrate these different frames by examining
      metaphorical constructs of water, chlorine and cancer contained within them.

PMID- 12600366
TI  - Implementing participatory intervention and research in communities: lessons from
      the Kahnawake Schools Diabetes Prevention Project in Canada.
AB  - Community public health interventions based on citizen and community
      participation are increasingly discussed as promising avenues for the reduction
      of health inequalities and the promotion of social justice. However, very few
      authors have provided explicit principles and guidelines for planning and
      implementing such interventions, especially when they are linked with research.
      Traditional approaches to public health programming emphasise expert knowledge,
      advanced detailed planning, and the separation of research from intervention.
      Despite the usefulness of these approaches for evaluating targeted narrow-focused
      interventions, they may not be appropriate in community health promotion,
      especially in Aboriginal communities. Using the experience of the Kahnawake
      Schools Diabetes Prevention Project, in Canada, this paper elaborates four
      principles as basic components for an implementation model of community
      programmes. The principles are: (1) the integration of community people and
      researchers as equal partners in every phase of the project, (2) the structural
      and functional integration of the intervention and evaluation research
      components, (3) having a flexible agenda responsive to demands from the broader
      environment, and (4) the creation of a project that represents learning
      opportunities for all those involved. The emerging implementation model for
      community interventions, as exemplified by this project, is one that conceives a
      programme as a dynamic social space, the contours and vision of which are defined
      through an ongoing negotiation process.

PMID- 12600367
TI  - Informal HIV caregiving in a vulnerable population: toward a network resource
      framework.
AB  - For the impoverished and often stigmatized communities most affected by HIV/AIDS,
      needs for informal caregiving present tremendous demands on already limited
      resources. Traditional theoretical frameworks emphasize care needs as driving
      informal caregiving. The proposed theoretical framework emphasizes microsocial
      processes that may affect informal caregiving among economically disadvantaged
      populations. The study examined: (1) network structural factors (homophily) that
      may affect availability of ties and local sociocultural expression of ties
      (social roles, behavioral norms) and (2) the role of financial resources in
      enabling informal caregiving. Low income, African American injection drug using
      persons living with HIV/AIDS (PLHAs) and their primary HIV supporters were
      interviewed. Supporters were predominantly female (71%), consanguineal kin (59%)
      and partners or friends (41%). Compared to the general US population, supporters
      were disproportionately HIV-infected, drug using, African Americans of poor
      health and low socioeconomic status. Supporters who perceived their PLHA tie
      needed informal care, compared to those who perceived no care need, were more
      than twice as likely to report a history of drug use, functional limitation
      (IADLs), higher income, and PLHA's financial reliance. Supporters' reported care
      provision was associated with their financial resources, but not PLHAs' health
      status. PLHAs' reported care receipt was associated only with their health
      status.HIV supporters' reported care provision was affected by financial factors,
      consistent with the proposed theoretical framework, while PLHAs' perceptions of
      care receipt conformed to traditional "needs"-based frameworks of caregiving.
      Results suggest that programs are needed to bolster network financial resources
      of disadvantaged populations affected by HIV to promote and sustain their
      informal HIV caregiving. Findings may aid in the understanding of informal
      caregiving as a social process. Network resource-oriented research may allow for
      ascertainment of community caregiving capacity, and guide the development of
      interventions to promote HIV caregiving in disadvantaged populations.

PMID- 12600368
TI  - Subjective social status: its determinants and its association with measures of
      ill-health in the Whitehall II study.
AB  - The purpose of this study was twofold-(1) investigate the role of subjective
      social status as a predictor of ill-health, with a further exploration of the
      extent to which this relationship could be accounted for by conventional measures
      of socioeconomic position; (2) examine the determinants of a relatively new
      measure of subjective social status used in this study. A 10 rung self-anchoring
      scale was used to measure subjective social status in the Whitehall II study, a
      prospective cohort study of London-based civil service employees. Results
      indicate that subjective status is a strong predictor of ill-health, and that
      education, occupation and income do not explain this relationship fully for all
      the health measures examined. The results provide further support for the
      multidimensional nature of both social inequality and health. Multiple regression
      shows subjective status to be determined by occupational position, education,
      household income, satisfaction with standard of living, and feeling of financial
      security regarding the future. The results suggest that subjective social status
      reflects the cognitive averaging of standard markers of socioeconomic situation
      and is free of psychological biases.

PMID- 12600369
TI  - Sociological influences on antidepressant prescribing.
AB  - This study examined how patient characteristics, physician characteristics, the
      physician's interaction with the health care system, and the physician's
      interaction with the patient influenced whether patients with a depression
      diagnosis received an antidepressant prescription and whether they received a
      SSRI antidepressant, a non-SSRI antidepressant, or both. The 1998 National
      Ambulatory Medical Care Survey (NAMCS), in the USA, was used for the analysis.
      Logistic regression was used to examine what characteristics influenced whether a
      patient with a depression diagnosis received an antidepressant prescription.
      Next, a multinomial logistic regression model was applied to examine the relative
      risk of using one type of antidepressant versus another among antidepressant
      users while correcting for possible sample selections using the Heckman selection
      model. Sixty-seven percent of patients with a depression diagnosis received an
      antidepressant. Patients who were seeing providers who were not primary care
      physicians or psychiatrists, self-paying patients, and patients with neurotic
      depression were significantly less likely to receive an antidepressant
      prescription. Patients with depression listed as their first diagnosis were
      significantly more likely to receive an antidepressant prescription. Patients
      seeing a psychiatrist were more likely than patients seeing a primary care
      physician to receive a non-SSRI antidepressant than a SSRI antidepressant.
      Patients belonging to an HMO that had capitated visits were over four times more
      likely to receive non-SSRI antidepressants than SSRI antidepressants. Patients
      with major depression were significantly more likely to receive a non-SSRI
      antidepressant. Patients with depression as their primary diagnosis and patients
      who saw psychiatrists were significantly more likely to receive both SSRI and non
      SSRI antidepressants rather than just SSRI antidepressants. Patient
      characteristics, physician characteristics, the physician's interaction with the
      health care system, and the physician's interaction with the patient all
      influenced antidepressant prescribing. An especially important finding was that
      insurance status influenced whether patients received an antidepressant. Health
      care providers need to take the time to help patients without insurance obtain
      antidepressant medication if it is needed.

PMID- 12600370
TI  - The impact of attitudes and beliefs on length of benzodiazepine use: a study
      among inexperienced and experienced benzodiazepine users.
AB  - Prolonged benzodiazepine use is a widespread phenomenon in medical practice. In
      the present article, we argue that psychological models may contribute to our
      understanding of benzodiazepine use. This study examined variables derived from
      the theory of planned behaviour and the health belief model in relation to the
      length of benzodiazepine use. Data were collected from a sample of all
      benzodiazepine users with a request for this medicine in the only pharmacy in a
      Dutch community (N=467). Determinants of the length of benzodiazepine use were
      analysed separately for inexperienced and experienced users using structural
      equation modelling (SEM) analyses. For both groups, results showed that the
      intention to use benzodiazepines was a predictor of length of use. Attitudes
      towards benzodiazepine use had an indirect influence on length of use, through
      intentions. Furthermore, a positive attitude toward using benzodiazepines was
      related to the perceived norm of the prescriber. Experienced users were more
      inclined to consume benzodiazepines when they had less control over drug taking.
      In this group, the belief that benzodiazepine use leads to dependence was
      associated with less control over drug taking and a high intention to use the
      drug. In addition, older experienced users reported a higher intention to use the
      drug. For inexperienced users, the perceived attitude of the prescriber towards
      use of the medicine was a strong determinant. Finally, results of SEM-analyses
      showed that the model accounted for far more variance in behaviour for
      experienced users (67%), than for inexperienced users (18%).

PMID- 12600371
TI  - 'Double or quits': perceptions and management of organ transplantation by adults
      with cystic fibrosis.
AB  - Medical sociologists have often considered lay perceptions of the risks of
      medical interventions, yet in many empirical studies respondents are people who
      are not likely to be exposed to a particular intervention. Furthermore, it has
      been well documented that risk perceptions may change over time and with
      diminishing health state. This paper explores perceptions and management of the
      risks of organ transplantation amongst adults with cystic fibrosis (CF), the most
      common autosomal recessive genetic disease in the UK. Although the focus of
      medical research is now on providing gene replacement therapy to this group,
      transplantation is currently the last treatment that an adult with CF can be
      offered when all other treatment has failed to maintain their health. Thirty-one
      respondents with varying degrees of health state from a specialist CF centre were
      interviewed as part of a larger study concerning perceptions of health and risks
      of treatment. Interviews were audiotaped, transcribed and analysed using ATLAS
      ti. During analysis respondents' transcripts were divided into two groups:
      firstly those who did not anticipate needing a transplant in the near future (if
      at all) and secondly those who were currently being considered for
      transplantation, on the transplant list, or who had already received donor
      organs. The paper focuses on themes arising from interview transcripts and finds
      that although the focus of risk differs between the two groups, the influence of
      luck is perceived as strong for both groups and emotion work features heavily in
      those undergoing the transplant process. Contrary to previous research, fears of
      inheriting donor characteristics are not found amongst adults with CF, but rather
      body components are commodified when talking of both giving and receiving organs.

PMID- 12600374
TI  - Ozonation of drinking water: part I. Oxidation kinetics and product formation.
AB  - The oxidation of organic and inorganic compounds during ozonation can occur via
      ozone or OH radicals or a combination thereof. The oxidation pathway is
      determined by the ratio of ozone and OH radical concentrations and the
      corresponding kinetics. A huge database with several hundred rate constants for
      ozone and a few thousand rate constants for OH radicals is available. Ozone is an
      electrophile with a high selectivity. The second-order rate constants for
      oxidation by ozone vary over 10 orders of magnitude, between < 0.1 M(-1)s(-1) and
      about 7 x 10(9) M(-1)s(-1). The reactions of ozone with drinking-water relevant
      inorganic compounds are typically fast and occur by an oxygen atom transfer
      reaction. Organic micropollutants are oxidized with ozone selectively. Ozone
      reacts mainly with double bonds, activated aromatic systems and non-protonated
      amines. In general, electron-donating groups enhance the oxidation by ozone
      whereas electron-withdrawing groups reduce the reaction rates. Furthermore, the
      kinetics of direct ozone reactions depend strongly on the speciation (acid-base,
      metal complexation). The reaction of OH radicals with the majority of inorganic
      and organic compounds is nearly diffusion-controlled. The degree of oxidation by
      ozone and OH radicals is given by the corresponding kinetics. Product formation
      from the ozonation of organic micropollutants in aqueous systems has only been
      established for a few compounds. It is discussed for olefines, amines and
      aromatic compounds.

PMID- 12600375
TI  - Ozonation of drinking water: part II. Disinfection and by-product formation in
      presence of bromide, iodide or chlorine.
AB  - Ozone is an excellent disinfectant and can even be used to inactivate
      microorganisms such as protozoa which are very resistant to conventional
      disinfectants. Proper rate constants for the inactivation of microorganisms are
      only available for six species (E. coli, Bacillus subtilis spores, Rotavirus,
      Giardia lamblia cysts, Giardia muris cysts, Cryptosporidium parvum oocysts). The
      apparent activation energy for the inactivation of bacteria is in the same order
      as most chemical reactions (35-50 kJ mol(-1)), whereas it is much higher for the
      inactivation of protozoa (80 kJ mol(-1)). This requires significantly higher
      ozone exposures at low temperatures to get a similar inactivation for protozoa.
      Even for the inactivation of resistant microorganisms, OH radicals only play a
      minor role. Numerous organic and inorganic ozonation disinfection/oxidation by
      products have been identified. The by-product of main concern is bromate, which
      is formed in bromide-containing waters. A low drinking water standard of 10
      microg l(-1) has been set for bromate. Therefore, disinfection and oxidation
      processes have to be evaluated to fulfil these criteria. In certain cases, when
      bromide concentrations are above about 50 microg l(-1), it may be necessary to
      use control measures to lower bromate formation (lowering of pH, ammonia
      addition). Iodate is the main by-product formed during ozonation of iodide
      containing waters. The reactions involved are direct ozone oxidations. Iodate is
      considered non-problematic because it is transformed back to iodide
      endogenically. Chloride cannot be oxidized during ozonation processes under
      drinking water conditions. Chlorate is only formed if a preoxidation by chlorine
      and/or chlorine dioxide has occurred.

PMID- 12600376
TI  - The influence of silver additives on titania photoactivity in the photooxidation
      of phenol.
AB  - Photodeposition of small amounts of metal silver on the surface of titanium(IV)
      oxide enhances its photoactivity in phenol decomposition. The applied method of
      in situ metal photoreduction resulted in preparing better Ag/TiO(2) systems than
      those already described in literature. Optimum silver loading on titania amounts
      to 0.5 wt%. The photoreaction, which finally leads to total phenol
      mineralization, proceeds via intermediate compounds. Hydroquinone, benzoquinone
      and catechol are the main intermediates determined quantitatively. Photooxidation
      of the compounds competes with the photooxidation of phenol. At higher phenol
      concentration, >6 x 10(-4)mol dm(-3), the rate of the photocatalytic reaction is
      strongly retarded. The photoreaction was conducted in a specially designed, three
      phase fluidal photoreactor.

PMID- 12600377
TI  - Changes in dietary bioaccumulation of tributyltin chloride (TBTCl) in red sea
      bream (Pagrus major) with the concentration in feed.
AB  - The effect of the concentration of tributyltin (TBT) in feed on the dietary
      bioaccumulation of tributyltin chloride (TBTCl) was studied in an 8-week uptake
      experiment and a 4-week elimination experiment using red sea bream (Pagrus
      major). The biomagnification factor (BMF) and the assimilation efficiency (AE)
      decreased from 0.30 to 0.15 and from 13% to 5.9%, respectively, as the TBT
      concentration in feed increased from 1.3 to 20 microg/g. The elimination rate
      constant (k(2)) was independent of the TBT concentration in the fish. Laboratory
      measurements of the BMF and AE of TBTCl underestimate actual field values if
      highly contaminated feed is used. Judging from the BMF and AE, the risk of the
      bioaccumulation of TBTCl through the food chain might be smaller than that of
      polychlorinated biphenyls.

PMID- 12600378
TI  - Continuous electrochemical treatment of phenolic wastewater in a tubular reactor.
AB  - The electrochemical treatment of phenolic wastewater in a continuous tubular
      reactor, constructed from a stainless steel tube with a cylindrical carbon anode
      at the centre, was investigated in this study, being first in literature. The
      effects of residence time on phenol removal was studied at 25 degrees C, 120 g l(
      1) electrolyte concentration for 450 and 3100 mg l(-1) phenol feed concentrations
      with 61.4 and 54.7 mA cm(-2) current densities, respectively. The change in
      phenol concentration and pH of the reaction medium was monitored in every run and
      GC/MS analyses were performed to determine the fate of intermediate products
      formed during the electrochemical reaction in a specified batch run. During the
      electrolysis mono, di- and tri-substituted chlorinated phenol products were
      initially formed and consumed along with phenol thereafter mainly by
      polymerization mechanism. For 10 and 20 min of residence time phenol removal was
      56% and 78%, respectively, with 450 mg l(-1) phenol feed concentration and above
      40 min of residence time all phenol was consumed within the column. For 1, 1.5, 2
      and 3h of residence time, phenol removal achieved was 42%, 71%, 81% and 98%,
      respectively, at 3100 mg l(-1) phenol feed concentration. It is noteworthy that
      more than 95% of the initial phenol was converted into a non-passivating polymer
      without hazardous end products in a comparatively fast and energy-efficient
      process, being a safe treatment.

PMID- 12600379
TI  - Regulatory role of n-propanol in propylene glycol biomethanization under
      overload.
AB  - This work examines the transient response of an anaerobic fluidized bed
      bioreactor to an overload of propylene glycol (PG), the primary component in
      aircraft de-icing waste. Under favorable operating conditions, PG was converted
      to n-propanol (n-PrOH) and propionate (HPr), and subsequently n-PrOH was
      completely converted into HPr. HPr was then fully degraded to methane and carbon
      dioxide via acetate. Under an overload condition, n-PrOH conversion to propionate
      was completely blocked but propionate degradation continued, contrary to free
      energy computations in which n-PrOH should rapidly degrade and HPr should
      accumulate. When the imposed overload condition was relieved, the accumulated n
      PrOH was rapidly converted into propionate. n-PrOH, then, could act as a temporal
      sink for reducing equivalents (XH(2)) and could regulate the overall PG
      methanazation process. n-PrOH should be monitored along with typical VFAs such as
      HPr to avoid sudden VFA accumulation and thus to optimize process performance for
      PG methanization.

PMID- 12600380
TI  - Improvement in capacitive deionization function of activated carbon cloth by
      titania modification.
AB  - Activated carbon cloth (ACC) was modified by the reaction between polar groups on
      its surface and metal alkoxides of titanium, silicon, aluminum and zirconium to
      enhance its capacitive deionization (CDI) performance. Incorporated state of
      metals and surface property of modified ACC were deduced from surface analysis
      results obtained using FE-SEM, XRD, XPS and zeta-potential meter. Titania was
      highly dispersed on the ACC surface with tetrahedral coordination, and the
      incorporated titania was effective to decrease physical adsorption of NaCl and to
      increase electric field adsorption, resulting in a significant enhancement of CDI
      performance. The negligible contribution of silica, alumina and zirconia
      modifications suggested that the small oxidation-reduction potential of titania
      was responsible for the enhancement of the electric field adsorption.
      Reversibility of adsorption and desorption operation on titania-modified ACC were
      also discussed relating to its CDI function.

PMID- 12600381
TI  - The adsorption of basic dyes from aqueous solution on modified peat-resin
      particle.
AB  - Modified peat was prepared by mixing thoroughly raw peat with sulfuric acid, and
      modified peat-resin particle was obtained, by mixing modified peat with solutions
      of polyvinylalcohol (PVA) and formaldehyde. In this paper, the adsorption of
      Basic Magenta and Basic Brilliant Green onto modified peat-resin particle is
      examined. The adsorption isotherm showed that the adsorption of basic dyes on
      modified peat-resin particle deviated from the Langmuir and Freundlich equations.
      The pseudo-first order, pseudo-second order and intraparticle diffusion models
      were used to fit the experimental data. By comparing the standard deviation, it
      was found that the intraparticle diffusion model could be used to well describe
      the adsorption of two basic dyes on modified peat-resin particle. According to
      the change of intraparticle diffusion parameter, the adsorption processes could
      be divided into different stages. The kinetics experiment also indicated that
      initial dye concentrations, particle dose and particle size could affect the
      adsorption processes of basic dyes.

PMID- 12600382
TI  - New method of treating dilute mineral acids using magnesium-aluminum oxide.
AB  - Mineral acids, such as H(3)PO(4), H(2)SO(4), HCl, and HNO(3,) were treated with
      magnesium-aluminum oxide (Mg-Al oxide), which behaved as a neutralizer and
      fixative of anions. Anion removal increased with increasing Mg-Al oxide quantity,
      time, Mg/Al molar ratio, and initial acid concentration. Up to 95% removal of
      anions was achieved in 0.5 N acids using a stoichiometric quantity of
      Mg(0.80)Al(0.20)O(1.10) for H(3)PO(4), 1.75 stoichiometric quantities for
      H(2)SO(4), or 2.5 stoichiometric quantities for HCl or HNO(3) at 20 degrees C
      over a period of 6 h. The final solutions were found to have a pH in the range of
      8-12. Selectivity of acid removal was found to follow the following order:
      H(3)PO(4) > H(2)SO(4) > HCl > HNO(3). The equivalent of acid removal per 1 g of
      Mg-Al oxide decreased as the Mg/Al molar ratio of Mg-Al oxide increased.

PMID- 12600383
TI  - Effects of pH and precipitation on autohydrogenotrophic denitrification using the
      hollow-fiber membrane-biofilm reactor.
AB  - Experiments carried out in a hollow-fiber, membrane-biofilm reactor (HFMBR)
      showed that the optimum pH for autotrophic denitrification was in the range 7.7
      8.6, with the maximum efficiency at 8.4. Increasing the pH above 8.6 caused a
      significant decrease in nitrate removal rate and a dramatic increase in nitrite
      accumulation. The pH rose by 1.2 units when a large buffer was not added,
      suggesting that some field applications may require pH control. Precipitation of
      Ca(2+) occurred in every experiment. Precipitation was the largest sink for
      carbonate, and it also offset alkalinity production by denitrification. Although
      the alkalinity increased in most cases, systems with a high carbonate buffer and
      high pH accentuated precipitation, and the net change in alkalinity was negative.
      The long-term success of field applications of the HFMBR may depend upon the
      interactions among calcium concentration, total carbonate concentration, pH, and
      alkalinity changes.

PMID- 12600384
TI  - Disinfection efficacy of organic chloramines.
AB  - The disinfection efficacies of model organic chloramines were investigated.
      Twenty amino acids and two nucleic acid bases were chlorinated separately with
      sodium hypochlorite at a Cl:N molar ratio of 0.4:1, and were then used to treat
      an E. coli suspension for 60 min. DPD/FAS titration was carried out to obtain the
      concentration of the chlorinated nitrogenous organic compounds as a function of
      time. In addition, membrane introduction mass spectrometry (MIMS) was used to
      quantify inorganic chloramines (mono-, di-, and trichloramine). The results of
      these experiments showed that the organic chloramines examined in this research
      had little or no effect on the viability of E. coli. MIMS analyses demonstrated
      that there was no quantifiable formation of inorganic chloramines when the
      organic nitrogen compounds were chlorinated.

PMID- 12600385
TI  - A critical comparison of respirometric biodegradation tests based on OECD 301 and
      related test methods.
AB  - Biodegradation studies of organic compounds in the aquatic environment gain
      important information for the final fate of chemicals in the environment. A
      decisive role play tests for ready biodegradability (OECD 301) and in this
      context, the respirometric test (OECD 301F). Two different respirometric systems
      (Oxitop and Sapromat) were compared and in two of ten cases (diethylene glycol
      and 2-ethylhexylacrylate) differences were observed indicating that the test
      systems are not always equivalent. For 2-ethylhexylacrylate and cyclohexanone we
      could not state differences in the extent of biodegradation with a municipal and
      industrial inoculum whereas for cyclohexanone the degradation rate was faster
      with a municipal inoculum. Allylthiourea (ATU) proved to be an effective
      inhibitor of nitrification processes and did not affect the heterotrophic
      biodegradation activity. Modelling of biodegradation processes could be
      successfully performed with a first-order and a modified logistic plot.

PMID- 12600386
TI  - Phytoplankton, pelagic community and nutrients in a deep oligotrophic alpine
      lake: ratios as sensitive indicators of the use of P-resources (DRP:DOP:PP and
      TN:TP:SRSi).
AB  - The different use of P-resources between two sites in the deep oligotrophic
      Traunsee was studied by seasonal and vertical patterns of phytoplankton and
      nutrients from 12/1997 to 10/1998. The P-resources were evaluated from the
      proportion between the P-fractions, the dissolved reactive P (DRP), dissolved non
      reactive P (DOP) and particulate organic P (PP) and from the stoichiometry
      between nutrients, the total N (TN), the total P (TP) and soluble reactive Si
      (SRSi). Significant differences between an inshore site impacted by industrial
      tailings (Ebensee Bay, EB) and an open water reference site (Viechtau, VI) were
      evident from vertical profiles of both the P-accumulation (%PP of TP) evaluated
      by DRP:DOP:PP and the distribution of phytoplankton assessed by Si-exhaustion
      (TN:TP:SRSi), but not from the seasonal patterns of phytoplankton composition,
      S:V ratios of the algal community or surface layer nutrient dynamics. Low TP and
      the stable stratification from May to September triggered the relative
      accumulation of epilimnetic P at VI as it was evident from both the higher
      portion of particulate P within TP (%PP of TP) and from the shift towards P
      enrichment in nutrient stoichiometry of TN:TP:SRSi. The predominance of around 55
      52% algal carbon over bacteria at the surface layer to 20m coincided spatially
      with the lowest Si content relative to N and P. The disturbances at the impacted
      site was summarised by: up to 11% less P accumulation by organisms at the
      surface, no stoichiometric shift towards TP in the epilimnion when compared with
      deeper layers and a reduction of the trophogenic zone to the top 10m. Reasons for
      this disturbance are seen in the unstable stratification, turbidity, higher TP
      and the metazoan dominated food chain. Both triple ratios, DRP:DOP:PP and
      TN:TP:SRSi, were sensitive indicators of the use of P-resources by plankton
      communities, while inorganic dissolved fractions (DIN:DRP:SRSi, DIN = dissolved
      inorganic N) provided only insufficient information on nutrient resources in
      Traunsee.

PMID- 12600387
TI  - Occurrence of sessile Pseudomonas oryzihabitans from a karstified chalk aquifer.
AB  - Pseudomonas oryzihabitans is an uncommon pathogen that may cause opportunistic
      infections. Although it has been previously isolated from the environment, the
      source of human infection has not been well documented. In this study, we
      describe the presence of P. oryzihabitans adhering on suspended particulate
      matters recovered from karst groundwaters. The isolated pathogen was capable of
      forming biofilms on silicon supports and clay beads. Adherent P. oryzihabitans
      cells displayed a high resistance to chlorine as compared with the same organisms
      cultured in the planktonic mode. These results demonstrate that aquifer biofilms
      are potential environmental sources for water-born P. oryzihabitans infections
      and that bacterial attachment might affect drinking water purification.

PMID- 12600388
TI  - Removal of ammonium and phosphates from wastewater resulting from the process of
      cochineal extraction using MgO-containing by-product.
AB  - The wastewater produced by the cochineal extract process to obtain the carminic
      acid colouring pigment (carmin red E120) has high concentrations of phosphates
      and ammonium. It is known that both ions can be precipitated with magnesium in
      the form of struvite, MgNH(4)PO(4), or ammonium magnesium phosphate (MAP)
      compounds. In this study, the use of an alternative MgO-containing by-product is
      investigated. The optimal pH, reaction time and solid/liquid ratio have been
      studied. It has been found that the low-grade MgO needed is greater than the
      stoichiometric value for the full removal of ammonium and phosphate as MAP
      compounds. Although the low-grade MgO (LG-MgO) reacts slower than pure MgO, it
      has considerable economic advantages. A batch process has been proposed for the
      removal of ammonium and phosphates from wastewater obtained in cochineal extracts
      processing, previously to biological treatment to diminish the COD.

PMID- 12600389
TI  - Analysis of a municipal wastewater treatment plant using a neural network-based
      pattern analysis.
AB  - This paper addresses the problem of how to capture the complex relationships that
      exist between process variables and to diagnose the dynamic behaviour of a
      municipal wastewater treatment plant (WTP). Due to the complex biological
      reaction mechanisms, the highly time-varying, and multivariable aspects of the
      real WTP, the diagnosis of the WTP are still difficult in practice. The
      application of intelligent techniques, which can analyse the multi-dimensional
      process data using a sophisticated visualisation technique, can be useful for
      analysing and diagnosing the activated-sludge WTP. In this paper, the Kohonen
      Self-Organising Feature Maps (KSOFM) neural network is applied to analyse the
      multi-dimensional process data, and to diagnose the inter-relationship of the
      process variables in a real activated-sludge WTP. By using component planes, some
      detailed local relationships between the process variables, e.g., responses of
      the process variables under different operating conditions, as well as the global
      information is discovered. The operating condition and the inter-relationship
      among the process variables in the WTP have been diagnosed and extracted by the
      information obtained from the clustering analysis of the maps. It is concluded
      that the KSOFM technique provides an effective analysing and diagnosing tool to
      understand the system behaviour and to extract knowledge contained in multi
      dimensional data of a large-scale WTP.

PMID- 12600390
TI  - Adsorption of heavy metals on Na-montmorillonite. Effect of pH and organic
      substances.
AB  - Clays (especially montmorillonite and bentonite) are widely used as barriers in
      landfills to prevent contamination of subsoil and groundwater by leachates
      containing heavy metals. For this reason it is important to study the adsorption
      of metals by these clays. The sorption of seven metals (Cd, Cr, Cu, Mn, Ni, Pb
      and Zn) on Na-montmorillonite was studied as a function of pH and in the presence
      of ligands, forming complexes of different stabilities with the metals of
      interest. The continuous column method was used as it better simulates natural
      conditions. The total capacity of Na-montmorillonite towards these metals was
      determined. The pH variations influence to a higher extent the concentrations of
      Cu, Pb and Cd in the effluent. Moreover the results suggest that complex
      formation hinders the sorption of the metals on the clay, with an increasing
      influence in the order: Mn < or = Pb < or = Cd < or = Zn < Ni < Cu < Cr. The
      evaluation of the total capacity of Na-montmorillonite shows that this clay is a
      good sorbent towards all examined metals.

PMID- 12600391
TI  - Performance of temperature-phased anaerobic digestion (TPAD) system treating
      dairy cattle wastes.
AB  - The performance of temperature-phased anaerobic digestion (TPAD) system in the
      stabilization of dairy cattle wastes at high solids concentrations has never been
      evaluated, though the process has been established as a feasible alternative to
      conventional mesophilic processes for the treatment of municipal wastewater
      sludges. In this study, the TPAD system operating at a retention time of 14 days
      was subjected to varying total solids (TS) concentrations (3.46-14.54%) of dairy
      cattle wastes. At TS concentrations lower than 12.20%, corresponding to system
      volatile solids (VS) loadings in the range of 1.87-5.82 g VS/L/day, the system
      achieved an average VS removal of 40.2%. The maximum VS destruction of 42.6% was
      achieved at a TS concentration of 10.35%. Methane recovery from the wastes was
      consistently within 0.21-0.22 L/g VS fed. There was a drop in the system
      performance with respect to VS removal and methane recovery at TS concentrations
      higher than 10.35%. volatile fatty acid/alkalinity ratios less than 0.35 in the
      thermophilic reactor and 0.10 in the mesophilic reactor were found favorable for
      stable operation of the system. For the entire range of TS concentrations, the
      indicator organism counts in the biosolids were within the limits specified by
      USEPA in 40 CFR Part 503 regulations for Class A designation. After digestion,
      nearly 80-85% of total phosphorus was associated with the biosolids.

PMID- 12600392
TI  - Comparison of total coliform, fecal coliform, and enterococcus bacterial
      indicator response for ocean recreational water quality testing.
AB  - In July 1999, California's ocean recreational bacterial water quality standards
      were changed from a total coliform (TC) test to a standard requiring testing for
      all three bacterial indicators: TC, fecal coliforms (FC), and enterococci (EC).
      To compare the relationship between the bacterial indicators, and the effect that
      changing the standards would have on recreational water regulatory actions, three
      regional studies were conducted along the southern California shoreline from
      Santa Barbara to San Diego, California. Two studies were conducted during dry
      weather and one following a large storm event. In each study, samples were
      collected at over 200 sites which were selected using a stratified random design,
      with strata consisting of open beach areas and rocky shoreline, and areas near
      freshwater outlets that drain land-based runoff. During the dry weather studies,
      samples were collected once per week for 5 weeks. For the storm event study,
      sampling occurred on a single day about 24 h following the storm. The three
      indicator bacteria were measured at each site and the results were compared to
      the single sample standards (TC > 10,000; FC > 400 and EC > 104 MPN or cfu/100
      ml). EC was the indicator that failed the single sample standards most often.
      During the wet weather study, 99% of all standard failures were detected using
      EC, compared with only 56% for FC, and 40% for TC. During the Summer Study, EC
      was again the indicator that failed the single sample standards most often, with
      60% of the failures for EC alone. The increased failure of the EC standard
      occurred consistently regardless of whether the sample was collected at a beach
      or rocky shoreline site, or at a site near a freshwater outlet. Agreement among
      indicators was better during wet weather than during dry weather. During dry
      weather, agreement among indicators was better near freshwater outlets than along
      open shoreline. Cumulatively, our results suggest that replacement of a TC
      standard with an EC standard will lead to a five-fold increase in failures during
      dry weather and a doubling of failures during wet weather. Replacing a TC
      standard with one based on all three indicators will lead to an eight-fold
      increase in failures. Changes in the requirements for water quality testing have
      strong implications for increases in beach closures and restrictions.

PMID- 12600393
TI  - Atrazine sorption on surface soils: time-dependent phase distribution and
      apparent desorption hysteresis.
AB  - Non-equilibrium sorption-desorption behavior of atrazine was studied on two
      surface soils. Impact of sorption contact time was evaluated by interpreting
      temporal variations in Freundlich sorption isotherm parameters n(t) and K(F)(t)
      obtained from the phase distribution relationships. The extent of sorption
      linearity was very similar (n approximately 0.90) for the two soils at all
      sorption contact times. K(F)(t) increased with contact time and stabilized upon
      reaching apparent equilibrium. K(F) for woodland soil was significantly higher
      than that for agricultural soil. The Apparent Hysteresis Index (AHI) parameter
      was used to quantify sorption-desorption hysteresis arising from non-equilibrium
      sorption. AHI was a function of the sorption contact time and correlated well
      with K(F)(t). The woodland soil sorbed more herbicide due to its higher organic
      matter content. However, a larger fraction of the herbicide sorbed to this soil
      was released rapidly (within 24 h) following sorptive uptake. The differences in
      sorption-desorption behavior of atrazine in the two soils appear to be related to
      variations in the type and location of organic matter in the two soils. The
      parameters K(F)(t) and AHI(t) consistently demonstrated the effects that arise
      when batch systems are not brought to equilibrium during sorption studies.

PMID- 12600394
TI  - Use of multidimensional scaling in the selection of wastewater toxicity test
      battery components.
AB  - In aquatic toxicity testing, no single test species is sensitive to all
      toxicants. Therefore, test batteries consisting of several individual assays are
      becoming more common. The organisms in a test battery should be representative of
      the entire system of interest. The results of the assays should be complementary
      to other components in the test battery to avoid redundancy. With the aid of
      multidimensional scaling (MDS), a multivariate statistical method, we examined
      the toxicity data of five bioassays (the continuous Shk1, Polytox, activated
      sludge respiration inhibition, Nitrosomonas, and Tetrahymena assays) that could
      serve as test battery components for the assessment of wastewater toxicity to
      activated sludge. MDS mapped the five assays into a two-dimensional space and
      showed that the Nitrosomonas assay should be included in test batteries plus one
      of the remaining four assays for assessing wastewater toxicity to activated
      sludge.

PMID- 12600395
TI  - Pb scavenging from a freshwater lake by Mn oxides in heterogeneous surface
      coating materials.
AB  - Selective extraction techniques were used to assay the importance of specific
      solid phases in Pb binding by heterogeneous surface coating materials (biofilms)
      in Cayuga Lake, NY. Hydroxylamine hydrochloride (NH(2)OH.HC1) was used to extract
      easily reducible Mn oxides, and sodium dithionite (Na(2)S(2)O(4)) was used to
      extract Mn and Fe oxides in two sets of biofilm samples retrieved from the lake.
      Pb remaining after extraction was removed by extraction with 10% HNO(3),
      determined by analysis of Pb(208) using a sector field mass spectrometer with an
      inductively coupled plasma ion source (ICP-MS), and compared to the total
      extractable Pb. The results indicate that the greatest contribution to total Pb
      binding to the heterogeneous surface coating materials was from Mn oxides. Pb
      adsorption capacity of Mn oxides exceeded that of Fe oxides on a molar basis by
      approximately an order of magnitude. The high reactivity observed for natural Mn
      oxides indicates that they are biogenic in origin, consistent with expectations
      based on the relative biotic and abiotic rates of Mn(II) oxidation under
      circumneutral conditions. Collectively, these results confirm expectations based
      on prior observations of adsorption of added Pb by Cayuga Lake biofilms before
      and after selective extraction, and also confirm predictions for Pb phase
      association in the lake based on the behavior of laboratory surrogates for
      adsorptive surfaces.

PMID- 12600396
TI  - A stochastic model of an ozonation reactor.
AB  - Disinfection of some microorganisms is characterized by a lag-phase (a minimum
      required ozone exposure until disinfection occurs). This phenomenon is easy to
      model in laboratory batch reactors but not in continuous flow mixed reactors.
      This paper introduces a stochastic disinfection model where individual
      microorganisms are followed on their paths through full-scale reactors. Combining
      exponentially distributed transport processes with delayed exponential
      disinfection kinetics for large populations of microorganisms (up to 10,000
      individuals) yields predictions which can be evaluated statistically. It could be
      shown that deterministic models work well for systems with good disinfection
      performance (more than 2 log units reduction of active microorganisms), for
      reactors with poor performance stochastic models have to be applied. It could be
      demonstrated for real reactors that Bacillus subtilis spores are poor surrogates
      for Cryptosporidium parvum oocysts. The differences between the two
      microorganisms are large for reactors that deviate significantly from plug-flow
      behaviour.

PMID- 12600397
TI  - Removal of lead ions from industrial waste water by different types of natural
      materials.
AB  - The adsorption capacity of some natural materials for lead such as animal bone
      powder, active carbon, Nile rose plant powder, commercial carbon and ceramics was
      studied. The V/m ratio has been chosen to be 500 ml/g. The adsorption process was
      affected by various parameters such as contact time, pH and concentration of lead
      solution. The lead uptake percent reaches equilibrium state after 15, 30, 45 and
      120 min for bone powder, active carbon, plant powder and commercial carbon,
      respectively. The uptake percent of lead increased by increasing pH value. The
      sequence of lead uptake percent (% adsorption) at constant pH from certain
      concentration of lead nitrate solution by the different natural materials is in
      the order: bone powder > active carbon > plant powder > commercial carbon. The
      uptake percent of lead is increased by decreasing the concentration of lead at
      constant pH. The capacity of lead adsorbed from nitrate solution by the different
      natural materials increased by increasing pH value. The synthetic and industrial
      waste-water samples were treated by using the different natural materials
      (contact time 3h, pH = 4). The percent removal of lead was 100% by bone powder,
      90% by active carbon, 80% by plant powder and 50% by commercial carbon. There was
      no removal of lead by ceramics. This may be due to the presence of high percent
      of lead in the constituent of ceramics (372 mg/g).

PMID- 12600398
TI  - The emotional reasoning heuristic in children.
AB  - A previous study by Arntz, Rauner, and Van den Hout (1995; Behaviour Research and
      Therapy, 33, 917-925) has shown that adult anxiety patients tend to infer danger
      not only on the basis of objective danger information, but also on the basis of
      anxiety response information. The current study examined whether this so-called
      emotional reasoning phenomenon also occurs in children. Normal primary school
      children (N = 101) first completed scales tapping anxiety disorders symptoms,
      anxiety sensitivity, and trait anxiety. Next, they were asked to rate danger
      levels of scripts in which objective danger versus objective safety and anxiety
      response versus no anxiety response were systematically varied. Evidence was
      found for a general emotional reasoning effect. That is, children's danger
      ratings were not only a function of objective danger information, but also, in
      the case of objective safety scripts, by anxiety response information. This
      emotional reasoning effect was predicted by levels of anxiety sensitivity and
      trait anxiety. More specifically, high levels of anxiety sensitivity and trait
      anxiety were accompanied by a greater tendency to use anxiety-response
      information as an heuristic for assessing dangerousness of safety scripts.
      Implications of these findings are briefly discussed.

PMID- 12600399
TI  - Pre-sleep imagery under the microscope: a comparison of patients with insomnia
      and good sleepers.
AB  - During the pre-sleep period and in the natural home environment patients with
      insomnia (N=20) and good sleepers (N=20) were asked to record when an image came
      to mind by pressing a handheld counter. They then provided an oral description of
      the image and indicated whether the image was 'pleasant', 'unpleasant', or
      'neutral' (responses captured via a voice-activated tape recorder). Subjective
      and objective (actigraphy) estimates of sleep-onset latency (SOL) were recorded.
      On both the handheld counter and the audiotape recording, participants with
      insomnia reported fewer images than the good sleepers. The insomnia group had a
      higher percentage of unpleasant images compared to good sleepers. For the
      insomnia group, but not the good sleeper group, there was a positive correlation
      between unpleasant images and subjective SOL. The insomnia group experienced more
      images regarding 'intimate relationships' and 'sleep' and fewer regarding
      'random/non-connected topics' compared to the good sleeper group. The results are
      discussed with reference to proposals made by Borkovec, Ray and Stober (Cognitive
      Ther. Res., 22, (1998) 561) in the context of generalised anxiety disorder (GAD).

PMID- 12600400
TI  - An examination of the cognitive processes involved in childhood obsessive
      compulsive disorder.
AB  - The cognitive theory of obsessive-compulsive disorder (OCD) is the most widely
      accepted account of the aetiology and maintenance of this disorder in adults.
      This paper investigated whether cognitive processes were evident in a sample of
      children with a primary diagnosis of OCD. Using an idiographic approach, as
      proposed by the Obsessive-Compulsive Cognitions Working Group, this paper
      assessed cognitive appraisals of responsibility, probability, severity, thought
      action fusion, self-doubt and cognitive control. Ratings of these cognitive
      appraisals were obtained across a sample of children with OCD, and were compared
      with ratings from a clinical control group of anxious children and a non-clinic
      control group. It was hypothesised that consistent with the cognitive theory of
      OCD, children in the OCD group would display higher estimations of these
      cognitive processes in comparison to anxious and non-clinic children. Results of
      this investigation provide preliminary support for a cognitive conceptualisation
      of OCD during childhood. OCD children reported significantly higher ratings of
      responsibility, severity, thought action fusion and less cognitive control in
      comparison to non-clinic children. OCD children could also be clearly
      differentiated from anxious children on ratings of cognitive control.
      Implications of this investigation are discussed and directions for future
      research are highlighted.

PMID- 12600401
TI  - Repeated checking causes memory distrust.
AB  - This paper attempts to explain why in obsessive-compulsive disorder (OCD)
      checkers distrust in memory persists despite extensive checking. It is argued
      that: (1) repeated checking increases familiarity with the issues checked; (2)
      increased familiarity promotes conceptual processing which inhibits perceptual
      processing; (3) inhibited perceptual processing makes recollections less vivid
      and detailed and finally; (4) reduction in vividness and detail promotes distrust
      in memory. An interactive computer animation was developed in which participants
      had to perform checking rituals on a virtual gas stove. Two separate experiments
      were carried out with n=39 (Experiment I) and n=40 (Experiment II) healthy
      participants. In both studies, the control group and the experimental group were
      given the same pre-test and post-test on the virtual gas stove. In between, the
      experimental group engaged in 'relevant checking', i.e. checking the gas stove,
      while the control group engaged in 'irrelevant checking', i.e. checking virtual
      light bulbs. In both experiments there were powerful effects of repeated
      'relevant checking': while actual memory accuracy remained unaffected, the
      vividness and detail of the recollections were greatly reduced. Most pertinently,
      in both experiments relevant checking undermined confidence in memory. No such
      effects were observed in the control group. One might argue that the pre
      test/post-test design may have made the control group anticipate a memory
      assessment at the post-test and that this artifact made them relatively alert
      producing memory confidence at post test that was artificially high. A third
      experiment was carried out (n=2 x 20) in which no pre-test was given while, other
      than that, Experiment III was identical to the first two experiments. Results
      confirmed earlier findings: compared to the irrelevant checking control group,
      recollections in the relevant checking group were non-vivid, non-detailed while
      confidence in memory was low. The theory and data suggest an answer to the
      question 'why memory distrust persists despite repetitive checking'. In people
      who check extensively, memory distrust may persist as a result of repetitive
      checking. OCD checking may be motivated by the wish to reduce uncertainty, but
      checking appears to be a counter-productive safety strategy. Rather than reducing
      doubt, checking fosters doubt and ironically increases meta-memory problems.

PMID- 12600402
TI  - The cognitive-behavioural treatment of low self-esteem in psychotic patients: a
      pilot study.
AB  - Low self esteem in individuals with a psychotic disorder is common and may be
      related to poorer clinical outcomes. However, there has been little research on
      devising treatment methods to improve self-esteem either generally or in
      psychotic patients in particular. The aims of this study were to evaluate the
      efficacy of a simple cognitive behavioural intervention to improve self esteem in
      psychotic patients who scored poorly on a self-esteem measure. This pilot study
      was a randomised control trial with a convenience sample of chronic psychotic
      inpatients. The cognitive behavioural self-esteem intervention, as an adjunct to
      treatment as usual (TAU), was compared to TAU alone in patients with psychosis.
      The individual self-esteem intervention as described by Tarrier (The use of
      coping strategies and self-regulation in the treatment of psychosis. (2001))
      consisted of working with participants to elicit positive self-attributes and
      then identify specific behavioural examples to provide evidence of this
      attribute. Emphasis was given to any consequential change in the patient's belief
      that they had the attribute. The results indicated that this cognitive
      behavioural treatment for self-esteem used as an adjunct treatment in psychosis,
      resulted in clinical benefits in terms of increased self-esteem, decreased
      psychotic symptomatology and improved social functioning. These benefits were
      largely maintained at 3-month follow-up.

PMID- 12600403
TI  - Anger, aggression, risky behavior, and crash-related outcomes in three groups of
      drivers.
AB  - High anger drivers who acknowledged problems with driving anger and were
      interested in treatment were compared to high and low anger drivers who did not
      acknowledge problems with driving anger or want treatment. Although high anger
      drivers who acknowledged problems reported greater anger on two measures than
      high anger drivers who did not acknowledge problems, both high anger groups
      tended not to differ from one another and were more frequently and intensely
      angered when driving, reported more aggressive and less adaptive/constructive
      forms of expressing anger while driving, engaged in more aggressive and risky
      behavior on the road, and experienced more of some accident-related outcomes than
      low anger drivers. High anger groups did not differ from each other, but reported
      more trait anxiety and anger and more outward negative and less controlled
      general anger expression than the low anger group. The two groups of high anger
      drivers, however, require different types of interventions given their state of
      readiness for driving anger reduction. Results were also interpreted as
      supportive of the state-trait model of anger and construct validity of the
      Driving Anger Scale.

PMID- 12600404
TI  - Amnesia, flashbacks, nightmares, and dissociation in aging concentration camp
      survivors.
AB  - The current study examined to what extent war memories of Dutch survivors of
      Japanese/Indonesian concentration camps display characteristics that are often
      believed to be typical for traumatic memories. Twenty-nine survivors were
      interviewed about amnesia, flashbacks, nightmares and the sensory quality of
      their most upsetting war memories. In addition, they completed self-report scales
      measuring post-traumatic stress symptoms and dissociation. In contrast to
      prevailing notions, amnesia, flashbacks and nightmares were not typical for this
      sample. Neither were traumatic memories characterized by a particularly strong
      sensory loading. Post-traumatic stress symptoms were not related to dissociative
      experiences. At least for this group of aging survivors, it appears that the
      pathogenic potential of traumatic memories has more to do with their extremely
      aversive content than with a qualitatively different type of organization of
      these memories.

PMID- 12600405
TI  - The correlation between thought-action fusion and religiosity in a normal sample.
AB  - Thought-action fusion (TAF) refers to a set of two cognitive biases that are
      thought to contribute to the inflation of feelings of responsibility for one's
      own thoughts, and thus to the development of obsession. Therefore, insight into
      the origins of TAF is a clinically relevant research topic. The present study
      examined the association between religiosity and TAF. Undergraduate students
      (N=100) completed questionnaires concerning religion, TAF and obsessive
      compulsive complaints. Results indicate that religiosity is, indeed, correlated
      with certain aspects of TAF. Furthermore, correlational patterns differed between
      Catholic and Protestant subsamples.

PMID- 12600406
TI  - Phenomenological validity of an OCD-memory model and the remember/know
      distinction.
AB  - In earlier experiments using interactive computer animation with healthy
      subjects, it was found that displaying compulsive-like repeated checking behavior
      affects memory. That is, checking does not alter actual memory accuracy, but it
      does affect 'meta-memory': as checking continues, recollections are experienced
      as less vivid and less detailed while confidence in memory is undermined. This
      procedure provides a model of OCD checking and suggests that checking is a
      counterproductive strategy to reduce memory distrust. The present experiment was
      carried out to specify the phenomenological quality of memory distrust after
      checking and to see if repeated checking produces a shift in the memory source
      that is used to decide about the outcome of checking: from 'remembering' to
      'knowing' (Tulving, 1985). Using the same interactive computer-animation, the
      earlier findings on vividness, detail and confidence were replicated. In
      addition, it was found that checking made participants endorse quotations from
      OCD patients (Reed, 1985) expressing a specific ambivalence about memory: 'It is
      as though the memory is there, but is isn't definite enough', 'I remember doing
      it in a way, but it's all fuzzy....' And 'I can remember that I've done it. But
      the memory isn't clear somehow'. This finding adds to the validity of the
      experimental model. Furthermore, after checking subjects' beliefs about the
      outcome of checking became based on (general) knowing instead of (specific)
      remembering. It is suggested that OCD checkers feel a general and relatively
      strong need to be certain about the veracity of recollections and that they have
      high standards for memory performance. This may explain earlier findings that OCD
      checkers have a general tendency to distrust their episodic memory. A need for
      certainty and a critical attitude towards memory performance may not be
      problematic or abnormal. It is suggested that clinical problems arise when the
      patient tries to fight memory distrust by repeated checking. The latter does not
      reduce distrust but rather increases distrust and the patient may get trapped in
      a spiral of mutually reinforcing checking behavior and memory distrust.

PMID- 12600410
TI  - Modulation of interleukin-8 and nitric oxide synthase mRNA levels by interferon
      gamma in macrophages stimulated with lignin derivatives and lipopolysaccharides.
AB  - It has been shown that interferon-gamma (IFN-gamma) plays a role in the
      regulation of interleukin-8 (IL-8), nitric oxide (NO), and tumor necrosis factor
      alpha (TNF-alpha) secretion by macrophages stimulated with lignin derivatives,
      such as EP3, and lipopolysaccharides (LPS) [Cytokine 11 (1999) 571]. To examine
      the mechanism by which IFN-gamma affects secretion of these factors, EP3- or LPS
      stimulated macrophages were treated with different concentrations of IFN-gamma,
      and mRNA levels of IL-8, nitric oxide synthase (NOS) and TNF-alpha were
      determined by Northern blot analysis and reverse transcription-polymerase chain
      reaction (RT-PCR). As reported previously, stimulation of macrophages by EP3 or
      LPS dramatically induced the expression of IL-8, NOS, and TNF-alpha mRNAs. IFN
      gamma clearly decreased the level of IL-8 mRNA in stimulated macrophages,
      although it did not affect the IL-8 mRNA level in unstimulated macrophages. In
      contrast, IFN-gamma appeared to increase the level of NOS mRNA both in
      unstimulated and stimulated macrophages. IFN-gamma, which increased the amount of
      TNF-alpha mRNA in unstimulated macrophages, showed no significant effect on the
      high level of TNF-alpha mRNA in stimulated macrophages. These results suggest
      that IFN-gamma causes changes in IL-8 and NO secretion by stimulated macrophages
      through its effects on the level of IL-8 and NO mRNA, respectively. Effects of
      IFN-gamma on TNF-alpha secretion by stimulated macrophages may be mediated by a
      different mechanism.

PMID- 12600411
TI  - Mitochondrial damage prior to apoptosis in furanonaphthoquinone treated lung
      cancer cells.
AB  - The mechanisms of the antitumor reactions of 2-methylnaphtho[2,3-b]furan-4,9
      dione (FNQ3) to human lung adenocarcinoma A549 cells were investigated. A549
      cells that received 1.25 microg/ml FNQ3 (IC(50) at 0.35 microg/ml) developed
      intensive mitochondrial H(2)O(2) production at 1 h. Selective structural
      mitochondrial swelling, alteration of mitochondrial membrane potential, and
      cytochrome c and caspase-9 release from the mitochondria occurred 18-24 h later.
      alpha-Tocopherol inhibited the alteration of both mitochondrial permeability and
      the leakage of procaspase-9. The caspase-9 was then activated in the cytosol. The
      expression of Bcl-2 oncoprotein was suppressed by FNQ3, and resulted in
      apoptosis. The higher dose of 5 microg/ml induced necrosis via severe
      mitochondrial breakage. These results showed that FNQ3 targets the mitochondria
      of A549 cells to produce a reactive oxygen species resulting in apoptosis and
      necrosis.

PMID- 12600412
TI  - The efficacy of a serum carboxyterminal pyridinoline cross-linked telopeptide of
      type I collagen as a quantitative screening marker for bone metastases in
      patients with urological malignancies.
AB  - In order to ascertain whether carboxyterminal pyridinoline cross-linked
      telopeptide of type I collagen (ICTP) might be useful as a serum screening
      parameter for bone metastases from non-prostate urological malignancies as well
      as prostate cancers, as series of 210 patients were examined. In addition to
      ICTP, serum alkaline phosphatase (ALP) and also prostate specific antigen (PSA)
      in the prostate cancer cases were assayed using commercial kits. The areas under
      the receiver operating characteristic (ROC) curves were 0.7846 for ICTP (cut-off
      point 9.6 microg/l), 0.8304 for ALP in prostate cancer cases, and 0.8278 for ICTP
      (cut-off point 10.6 microg/l), and 0.7139 for ALP in non-prostate cancer cases.
      While significance was only observed for ICTP and PSA in prostate cancer cases,
      borderline significance was also evident with ICTP for non-prostate malignancies,
      and with ALP for prostate cancer case. The results suggest that serum ICTP may be
      useful in combination with ALP as a quantitative clinical marker for low cost
      screening for bone metastases in patients with all types of urological
      malignancies.

PMID- 12600414
TI  - Relationship between DNA repair capacity and resistance to genotoxins in four
      human cell lines.
AB  - We have developed fast, reliable and simple fluorescent method to assess and
      compare repair capacity of cells. To this end plasmid pEGFP containing the gene
      for the enhanced green fluorescent protein was damaged in vitro by genotoxic
      agents and introduced into cells by transfection. The repair capacity of the
      cells was determined from the number of fluorescent cells counted with a
      fluorescent microscope 24 h after transfection. The ability of four human tumor
      cell lines--HEK293, HeLa, Namalwa and K562 to repair DNA lesions inflicted by cis
      diamminedichloroplatinum(II), UV light, 8-methoxypsoralen and 4',5'-8
      trimethylpsoralen were determined and compared to the survival rates of the cells
      after treatment with the same genotoxic agents. In most but not all cases, there
      was a good correlation between repair capacity and cell survival. This finding
      indicates that the DNA repair capacity could be used as a biomarker in risk
      assessment and/or drug resistance assays.

PMID- 12600413
TI  - Microsatellite dinucleotide (T-G) repeat: a candidate DNA marker for breast
      metastasis.
AB  - A dinucleotide (T-G) repeat sequence was isolated by comparing DNA from
      metastatic lymph node and matched normal breast samples from a ductal mammary
      carcinoma patient using representational difference analysis (RDA) method. Our
      present study used this metastasis associated DNA sequence (MADS) as a diagnostic
      probe to screen five patient samples by slot blot method. A new approach to
      isolate single cells by microdissection, namely single cell microdissection (SCM)
      was developed to obtain homogeneous population of tumor cells (approximately
      1000) from matched primary tumors and corresponding positive lymph nodes of five
      patients. We isolated DNA from these homogeneous tumor cells and used for the RDA
      and DNA slot blot experiments. The screening of patient samples showed loss of
      this MADS in the transition from primary to metastasis in four out of five cases
      (80%) suggesting its possible role in breast metastasis.

PMID- 12600415
TI  - Evaluation of familial clustering of breast and prostate cancer in the Minnesota
      Breast Cancer Family Study.
AB  - Few studies examining familial clustering of breast and prostate cancer (PC) have
      focused on a clearly defined high-risk population with epidemiologic risk
      factors. We conducted a cohort study of prostate cancer among a subset of 426
      families ascertained through female breast cancer probands. Three groups of males
      were included: 804 relatives in 60 families with four or more breast or ovarian
      cancers, 536 marry-ins in these high-risk families, and 484 relatives in 81
      families where only the proband had breast cancer. A total of 118 prostate
      cancers were reported. The rate of prostate cancer among blood relatives in high
      risk families was significantly lower than among marry-ins (RR = 0.6, 95% C.I.:
      0.4-0.9). The rate of prostate cancer among blood relatives in low-risk families
      was not significantly different from the rate among marry-ins (RR = 0.8, 95%
      C.I.: 0.5-1.2). These results provide little evidence that male relatives in high
      risk breast cancer families are at increased risk of prostate cancer.

PMID- 12600416
TI  - Suppression of mammary gland tumorigenesis in diabetic rats.
AB  - The aim of this study was to compare mammary gland tumorigenesis in diabetic and
      non-diabetic rats. Streptozotocin and N-nitroso-N-methylurea were used to induce
      diabetes and mammary tumors, respectively. A suppression of mammary
      carcinogenesis in diabetic rats was shown by a longer latency period, a lower
      number of tumors per animal and a smaller final tumor volume. An 84% of the
      lesions developed in diabetic animals were benign tumors. Eighty day-old diabetic
      rats had significantly lower plasma levels of total-IGF-I and insulin versus non
      diabetic rats. We postulate that the decrease in the total IGF-I and insulin
      levels during the promotion phase of carcinogenesis in this model plays an
      important role in retarding the tumor development in diabetic animals and in
      favoring the development of benign mammary lesions.

PMID- 12600417
TI  - The MTS assay as an indicator of chemosensitivity/resistance in malignant
      gynaecological tumours.
AB  - The aim of this study was to use the (3-(4,5-dimethylthiazol-2-yl)-5-(3
      carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay
      to determine the response of 17 endometrial and 27 cervical tumours to cytotoxic
      drugs. Tumour samples were taken at surgery and cultured using the explant
      technique. Cells were incubated with chemotherapy drugs. The MTS cytotoxicity
      assay was carried out to ascertain the response to the drugs and correlated
      retrospectively to the clinical outcome. Tumours of similar stage and grade
      displayed heterogeneity in their responses to the drugs. A total of 88 of 90
      tumours (97.8%), including data from an earlier study of 44 ovarian tumour
      samples yielded chemosensitivity data. A total of 45 specimens were evaluable for
      in vitro-in vivo correlations. In vitro sensitivity was associated with clinical
      response in 26 of 30 patients and in vitro resistance with progressive disease or
      death in 14 of 15 patients. A randomised prospective trial should be carried out
      to validate chemosensitivity/resistance testing.

PMID- 12600418
TI  - Specific fatty acids and human colorectal cancer: an overview.
AB  - BACKGROUND: Evidence suggests that dietary fats are associated with risk of
      colorectal cancer. The effect of fats depends not only on the quantity, but also
      on their composition in specific fatty acids. Moreover, fats are peroxidizable,
      and peroxidation products as well as antioxidants play a role in the pathogenic
      process of colorectal cancer. METHODS: The published literature was reviewed for
      the relationship between dietary intake or concentration of specific fatty acids
      in adipose tissue, erythrocytes, plasma or feces in relation to colorectal
      cancer. RESULTS: Increased concentrations of short-chain fatty acids (SCFAs) and
      eicosanopentaenoic acid (EPA) seem to protect against colorectal cancer.
      Increased concentrations of medium-chain fatty acids (MCFAs) and arachidonic acid
      (AA) might be associated with increased risk. Long-chain saturated fatty acids
      (LCSFAs) seem unrelated to colorectal cancer, while the associations between
      monounsaturated fatty acids (MUFAs), trans fatty acids, polyunsaturated fatty
      acids (PUFAs) such as linoleic acid (LA), alpha-linolenic acid (ALA),
      docosahexaenoic acid (DHA), omega-3/omega-6 ratio and colorectal cancer are
      unconvincing. CONCLUSIONS: It is suggested that the substitution of food with
      high MCFAs and AA content by a SCFAs- and EPA-rich diet may contribute to reduced
      risk of colorectal cancer.

PMID- 12600419
TI  - Boswellic acid acetate induces differentiation and apoptosis in highly metastatic
      melanoma and fibrosarcoma cells.
AB  - The aim of the study was to investigate the antitumor and/or preventive effect of
      BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw.
      containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the
      MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study
      the growth inhibition activity of BC-4. Tumor cells migration within a three
      dimensional collagen matrix was recorded by time-lapse videomicroscopy and
      computer-assisted cell tracking. Topoisomerase II was isolated from mouse
      melanoma B16F10 cells and its activity was determined by its ability to cut
      plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases
      (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin
      zymography. BC-4 was a cytostatic compound and could induce the differentiation
      of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and
      inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was
      increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to
      5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also
      inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT
      1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa
      staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited
      the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out
      that BC-4 is a well tolerated substance, exhibiting no significant toxicity or
      side effects, being evaluated currently in China, BC-4 is a good candidate for
      the prevention of primary tumor, invasion and metastasis.

PMID- 12600420
TI  - Effects of hyperthermia and differentiation on cultured Dunn osteosarcoma cells.
AB  - We investigated the characteristics of morphology, DNA synthesis and argyrophilic
      nucleolar organizer regions (AgNORs) on murine Dunn osteosarcoma cells in
      response to heat (42 degrees C, 1 h) or dibutyryl cyclic adenosine 3',5'
      monophosphate (Bt(2)cAMP). The cell morphology changes to a fibroblast-like
      appearance with long and thin protoplastic processes with the reduction of DNA
      synthesis by heat. It is closely similar to a response by Bt(2)cAMP. In the
      presence of 3 mM Bt(2)cAMP, the mean number of AgNORs was significantly decreased
      in 48 h compared with the untreated group. It was increased conversely by heat.
      Among these responsive cells, we can also find many cells stained without
      discrimination by the use of AgNORs staining. The present study provides a new
      clue to support differentiation of osteosarcoma cells from the viewpoint of
      hyperthermia in vitro.

PMID- 12600422
TI  - The value of corpus cavernosum electromyography in erectile dysfunction: current
      status and future prospect.
AB  - In the last decade, several investigators have tried to develop corpus cavernosum
      electromyography (CC-EMG) as a direct clinical method to evaluate the state of
      the penile autonomic innervation and the cavernous smooth muscle. Both basic and
      clinical studies have shown promising results. However, its application as a
      diagnostic tool with clinical relevance was hindered by insufficient knowledge of
      cavernous smooth muscle electrophysiology, lack of standardization, technical and
      practical difficulties and problems in the interpretation of the results.
      Recently, the European Commission created the so-called COST Action B18 (corpus
      cavernosum EMG in erectile dysfunction), aiming to strengthen the coordination of
      the European research groups and give the development of CC-EMG a new impetus.
      This review presents an overview of the physiological background, the current
      status of CC-EMG, and discusses possibilities for further developments.

PMID- 12600423
TI  - A review of condition-specific instruments to assess the impact of urinary
      incontinence on health-related quality of life.
AB  - To date, severity of symptoms of urinary tract conditions, such as overactive
      bladder (OAB) and stress incontinence, have been the main indicators used to
      understand the burden on the patient. However, there is also an impact on
      patients' health-related quality of life (HRQoL) that should also be assessed. A
      literature search was conducted and all HRQoL instruments published in peer
      reviewed journals were evaluated. Ten instruments were identified: general use
      (five); urinary urge (OAB) incontinence (four); and stress incontinence (one).
      Several were identified as valid instruments for assessing HRQoL in urinary
      incontinence patients.

PMID- 12600424
TI  - Costs of prostate cancer, metastatic to the bone, in the Netherlands.
AB  - OBJECTIVE: To quantify medical costs associated with bone metastases in patients
      with prostate cancer. Bone metastases in patients with prostate cancer are
      associated with considerable morbidity, negatively impact quality of life, and
      can add substantially to medical costs, given a median survival of 30-35 months
      from diagnosis of bone metastases. METHODS: A retrospective cost analysis from
      both a community and university hospital in The Netherlands was conducted. Twenty
      eight patient records (14 from each hospital) were investigated to assess the
      impact of skeletal-related events (SREs), including fractures, spinal cord
      compression, and radiotherapy, on total direct medical costs and cost of
      hospitalization. Costs are given in EUROS (Euros). RESULTS: The average total
      cost of treatment was Euros 13,051 per patient over the 24-month follow-up
      period, which includes an average cost of Euros 6973 per patient to treat SREs.
      Treatment of SREs more than doubled total treatment costs. Patients in this
      analysis experienced, on average, one SRE per year, and the cost of SREs varied
      from Euros 1187 to Euros 40,948. CONCLUSIONS: Occurrence of SREs contributes
      significantly to the cost of care for patients with advanced prostate cancer.
      These data suggest that bisphosphonates, which can reduce pain and SREs, may
      reduce healthcare costs.

PMID- 12600425
TI  - A 10-year clinical experience with intermittent hormonal therapy for prostate
      cancer.
AB  - OBJECTIVES: To evaluate, over a 10-year period, the feasibility, efficacy,
      duration of action and adverse effects of intermittent hormonal therapy (IHT) in
      patients with advanced prostate cancer or biochemical recurrence after radical
      treatment. MATERIALS AND METHODS: Two hundred and thirty-three patients with
      prostate cancer have been included in an IHT protocol since 1992. Fifty-five
      patients had already been treated by radical prostatectomy (group A), 35 patients
      had received radiotherapy or a treatment with high-intensity focused ultrasound
      (HIFU) (group B) and 143 patients had not received any previous treatment (group
      C). Three-monthly injection of LHRH analogue combined with a non-steroidal
      antiandrogen was administered during the treatment phase ("on" phase). Treatment
      was stopped ("off" phase) when the PSA level fell below 4 ng/ml, regardless of
      the duration of the "on" phase. Criteria for resumption of hormonal therapy were
      PSA >20 ng/ml, PSA progression slope over the previous three months >5 ng/ml per
      month or recurrence of pain or urinary symptoms. RESULTS: The median follow-up
      was 34.9 months (range: 13-151) and the median initial PSA was 28 ng/ml (range: 1
      433). Five cycles were performed in the patients with the longest follow-up. The
      mean duration of cycles was gradually decreased from 19.6 months to 11.8 months.
      The "on/off" ratio was close to 30% regardless of the cycle or patient group. Ten
      patients (4%) died from their cancer during the study, with a median survival of
      42.2 months. Six patients (2.5%) developed painful symptoms during IHT.
      CONCLUSIONS: IHT ensures medium-term (three years) control of the disease, using
      a treatment resumption criteria of PSA >20 ng/ml and was not associated with
      major complications.

PMID- 12600426
TI  - The value of a second transurethral resection in evaluating patients with bladder
      tumours.
AB  - OBJECTIVES: To evaluate the usefulness of a second transurethral resection for
      superficial and muscle-invasive bladder tumours. METHODS: A review of the
      literature relevant to repeat resection for bladder tumours was conducted using
      Medline Services. RESULTS: Transurethral resection of the bladder has two
      shortcomings: underestimating clinical stage, and overlooking other lesions. A
      second transurethral resection, when performed 2-6 weeks after the initial
      resection, corrects clinical staging errors in 9-49% of cases and detects
      residual tumour in 26-83% of cases. A second resection is particularly warranted
      for T1 tumours since 2-28% of them prove to be muscle-invasive, thus requiring a
      change in management. For muscle-invasive tumours, a second resection may be
      performed only if bladder sparing is being considered, as it helps to exclude the
      presence of tumour sites contra-indicating conservative treatment. CONCLUSIONS: A
      second transurethral bladder resection may be warranted for T1 tumours, and for
      invasive tumours when a bladder preservation is planned.

PMID- 12600427
TI  - A study of the morbidity, mortality and long-term survival following radical
      cystectomy and radical radiotherapy in the treatment of invasive bladder cancer
      in Yorkshire.
AB  - OBJECTIVES: To study the morbidity of radical cystectomy and radical radiotherapy
      in the treatment of patients with invasive carcinoma of the bladder and to report
      the long-term survival following these treatments. PATIENT AND METHODS: 398
      patients with invasive carcinoma of the bladder treated between 1993 and 1996 in
      the Yorkshire region were studied. Of 398 patients studied, 302 patients received
      radical radiotherapy and 96 underwent radical cystectomy. A retrospective review
      of patients' case notes was performed to construct a highly detailed database.
      Crude estimates of survival differences were derived using Kaplan-Meier methods.
      Log-rank tests (or, where appropriate, Wilcoxon tests) were used to test for the
      equality of these survivor functions. These functions were produced as all-cause
      survival. The proportional hazards regression modelling was used to assess the
      impact of definitive treatment on survival. A backwards-stepwise approach was
      used to derive a final predictive model of survival, with likelihood ratio tests
      to assess the statistical significance of variables to be included in the model.
      RESULTS: The patients undergoing radiotherapy were significantly older (mean age:
      71 years versus 66 years), but no difference was identified in the distribution
      of American Society of Anaesthesiologists (ASA) grades in the two treatment
      groups. The stage distribution of cases in the treatment groups was not
      significantly different. Significant treatment delays were observed in both
      treatment groups. The median time from being seen in the clinic to transurethral
      resection of bladder tumour (TURBT) and subsequent radical treatment (cystectomy
      or radiotherapy) was 4.3 and 9 weeks, respectively. Age was the most significant
      independent factor accounting for treatment delays (p < 0.001). The 30-day and 3
      month treatment-associated mortality for radical cystectomy and radiotherapy was
      3.1% and 8.3% and 0.3% and 1.65%. Of the patients who received radiotherapy, 57
      (18.8%) were subsequently subjected to a salvage cystectomy. For these 57
      patients, 30-day and 3-month mortality after the salvage cystectomy were 8.8% and
      15.7%. Gastrointestinal complications were the major source of early morbidity
      after primary and salvage cystectomy. Bowel leakage occurred in 3% following
      radical and 8.7% after salvage cystectomy. Bowel complications (leakage and
      obstruction) were the major cause of death following salvage cystectomy. No
      specific cause was predominant in those undergoing radical cystectomy with
      intestinal anastomotic leakage and urinary leakage accounting for one death each.
      Exacerbation of co-morbid conditions accounted for the remaining causes of
      mortality. Urinary leakage occurred in 4% following both forms of cystectomy.
      Recurrent pyelonephritis and intestinal obstruction were responsible for the
      majority of complications in the follow-up period. Bladder and gastrointestinal
      complications accounted for the majority of complications following radical
      radiotherapy. Some degree of irritative bladder and rectal were noted commonly.
      Severe bladder problems, which rendered the bladder non-functional or required
      surgical correction, occurred in 6.3% of patients. 2.3% of patients underwent
      surgery for bowel obstruction related to radiotherapy induced bowel strictures.
      Following radiotherapy, 43.6% of patients had a recurrence in the bladder at
      varying intervals post-treatment. Of these, 40% had > or =T2 disease. The 5-year
      survival following radiotherapy (with or without salvage cystectomy) was 37.4%
      while 36.5% of patients were alive 5 years after radical cystectomy. There was no
      statistically significant difference in the overall 5-year survival figures
      between the two primary treatments. Tumour stage, ASA grade and sex were the only
      independent predictors of 5-year survival on multivariate analysis. CONCLUSIONS:
      This retrospective regional study shows that there is no significant difference
      in the 5-year survival of patients with invasive bladder cancer treated with
      either radical radiotherapy or radical cystectomy. All forms of radical treatment
      for bladder cancer are associated with a significant treatment-associated
      morbidity and mortality. Gastrointestinal complications were responsible for the
      majority of complications. The treatment-associated mortality at 3 months was two
      or three-fold higher than the 30-day mortality; emphasising its importance as an
      indicator of the true risks of cystectomy. The clinical T stage, the sex and the
      ASA grade of the patient were the only independent predictors of survival. The
      data in this series suggests that radical radiotherapy and radical cystectomy
      should be both considered as valid primary treatment options for the management
      of invasive bladder cancer.

PMID- 12600428
TI  - Comparison of clinical and urodynamic outcome in orthotopic ileocaecal and ileal
      neobladder.
AB  - OBJECTIVE: Aim of this study was to evaluate the clinical and urodynamic results
      in patients who had undergone orthotopic bladder substitution with ileocaecal
      (Mainz pouch procedure) or ileal (Abol-Enein and Ghoneim procedure) segments and
      who had a minimum follow-up of 12 months. METHODS: Mainz pouch procedure (MP) was
      performed in 19 patients (mean age 62.4 years, median follow-up 36 months) and
      Abol-Enein and Ghoneim procedure (AG) in 36 patients (mean age 64.3 years, median
      follow-up 31 months). Complications and urodynamic findings were compared in both
      groups. RESULTS: Complications related to the pouch were (MP and AG groups,
      respectively) ureterointestinal anastomotic stenosis (10.5% versus 5.7%), poucho
      urethral anastomosis stenosis (5.3% versus 5.5%), poucho-ureteral reflux (7.9%
      versus 4.2%), and pyelonephritis (15.8% versus 13.8%). At 12 months
      postoperatively, daytime incontinence rates were 5.3% versus 5.5% and nighttime
      incontinence (twice weekly or more) rates were 21% versus 8.4% in MP and AG
      groups. In urodynamic evaluation, which was performed in 39 patients at 12 months
      postoperatively, both groups showed adequate bladder capacity, the mean values of
      which were 426 +/- 34 ml in MP group and 442+/-27 ml in AG group (p > 0.05). The
      mean value of maximal flow rate was 19.6 +/- 3.7 ml/s in MP group and 16 +/- 6.1
      ml/s in AG group (p > 0.05). The mean residual urinary volume was 37 +/- 8.2 ml
      in MP group and 45 +/- 7.1 ml in AG group (p > 0.05). CONCLUSION: The comparison
      between two types of bladder substitution, namely ileocaecourethrostomy (Mainz
      pouch procedure) and ileal reservoir (Abol-Enein and Ghoneim procedure) has
      demonstrated that urodynamic findings showed no significant difference between
      two groups.

PMID- 12600429
TI  - Surgical and patient reported outcomes of 'clam' augmentation ileocystoplasty in
      spinal cord injured patients.
AB  - OBJECTIVE: To study the outcomes and effectiveness of 'clam' augmentation
      ileocystoplasty in the treatment of suprasacral spinal cord injured patients with
      detrusor hyperreflexia refractory to pharmacological and other conservative
      therapy. METHODS: A retrospective review of spinal injured patients who had
      undergone 'clam' augmentation ileocystoplasty was performed, followed by a
      specifically designed questionnaire/telephone interview to assess patient
      satisfaction and other issues from this specific group of patients with
      suprasacral spinal cord lesions. 32 patients were followed up for a mean of 6.0
      +/- 3.6 years. RESULTS: Complete continence was found in all patients. There was
      a significant improvement in bladder capacity from a mean 143 +/- 81 ml pre
      operatively to 589 +/- 188 ml post-operatively, and the maximum detrusor pressure
      fell from a mean of 108 +/- 43 cm H(2)O to 19 +/- 15 cm H(2)O. Pre-operative
      vesico-ureteric reflux resolved completely in 4 out of 5 patients and improved
      from grade IV to grade II in one, illustrating the need for achieving low bladder
      pressures rather than the performance of an anti-reflux procedure at the time of
      cystoplasty. The use of the questionnaire, designed to evaluate this subset of
      patients after augmentation cystoplasty, highlighted the high levels of
      satisfaction with the operation in this group of patients with 96.2% of patients
      reporting an improvement in quality of life parameters. CONCLUSION: Using an
      appropriate questionnaire we have found high satisfaction rates, in addition to
      successful surgical outcomes, in spinal cord injured patients following
      augmentation cystoplasty. We recommend using this questionnaire as part of the
      work-up and ongoing assessment of spinal injured patients undergoing 'clam'
      augmentation ileocystoplasty.

PMID- 12600430
TI  - C-reactive protein in early detection of bacteriemia and bacteriuria after
      extracorporeal shock wave lithotripsy.
AB  - OBJECTIVES: To evaluate the value of plasma C-reactive protein (CRP) levels in
      early detection of bacteriuria and bacteriemia after extracorporeal shock wave
      lithotripsy (ESWL) of calcium and infection stones. METHODS: A total of 75
      patients who had infection stones (n = 27) and calcium stones (n = 48) were
      included in the study. All patients had sterile urine before ESWL. The mean age
      was 41.6 +/- 4.85 and male/female ratio was 2.12. Blood cultures were obtained
      within 1 hour post-ESWL period. Urine cultures were obtained 3 times just after
      and on the first and seventh day of ESWL. RESULTS: Post-ESWL evaluations showed 3
      positive blood cultures with 2 (2.66%) patients in infection stone and 1 (1.33%)
      patient in calcium stone groups, whereas urine cultures revealed 6 (8%) positive
      results in infection stones and 4 (5.33%) in calcium stones. The patients who had
      positive cultures also had elevated plasma CRP levels when compared to the levels
      in patients with negative cultures (p = 0.000). CONCLUSIONS: Bacteriuria and
      bacteriemia after ESWL have been well-identified entities and may be responsible
      from some of the post-ESWL complications. CRP can be useful for early detection
      of such complications.

PMID- 12600431
TI  - Stone burden in an average Swedish population of stone formers requiring active
      stone removal: how can the stone size be estimated in the clinical routine?
AB  - OBJECTIVE: To get information on the distribution of stone burdens in an average
      and representative group of Swedish stone forming patients requiring active
      removal of stones from the kidneys or ureters and to compare different methods
      for assessing the stone burden. METHODS: A computerised device was used to
      measure the total stone surface area (A(measured)) of 599 stone situations in
      kidneys and ureters in a consecutive group of patients referred to active stone
      removal. These measurements were compared with the large and short transverse
      diameters of the greatest stone, the sum of the largest diameters of the stones,
      the arithmetically calculated surface area (A(calculated)) as well as with the
      stone-types (A-F) previously described. RESULT: There were 483 stone situations
      with one and 116 with more than one stone. The stones were found in 407 men and
      192 women. In 343 cases were the stones on the left side and in 256 on the right
      side. There were 34 staghorn stones. Of the examined stone situations 250 were in
      the kidney and 349 in the ureter. An A(measured) above 300 mm(2) was recorded in
      7% of all stone situations. The corresponding numbers for A(measured) above 200
      mm(2), 500 mm(2) and 700 mm(2) were 13%, 4% and 3%, respectively. When staghorn
      stones were excluded, good correlations were recorded for all variables but the
      best correlation was found between A(measured) and A(calculated). A revision of
      the previously published stone-type subgroups is suggested based on the following
      limits for the stone surface area: A < or = 30 mm(2), B = 31-300 mm(2), C = 301
      700 mm(2) and D > 700 mm(2). CONCLUSION: The distribution of stone situations
      with different stone burden in an average Swedish population is described. With
      the exception of staghorn stones and stones with extremely irregular form an
      acceptable estimate of the stone surface are can be arithmetically derived from
      the length and the width of the stone.

PMID- 12600432
TI  - Urodynamic results of sacral neuromodulation correlate with subjective
      improvement in patients with an overactive bladder.
AB  - OBJECTIVES: Standard urodynamic investigations showed no correlation between the
      efficacy of sacral neuromodulation (SNS) and urodynamic data. Ambulant urodynamic
      investigations (ACM) are presented as more sensitive and reliable in detecting
      and quantifying bladder overactivity. In this study we looked at the correlation
      and results of ambulant urodynamic data and the clinical effects of SNS. METHODS:
      Data of patients with bladder overactivity, who underwent an ACM before and
      during SNS were investigated. Blind analyses of the ACM were performed and the
      detrusor activity index (DAI) was calculated as the degree of bladder
      overactivity of the detrusor. The ACM parameters, before and during SNS, were
      analyzed and correlated to the clinical effect of SNS. RESULTS: In 22 of the 34
      patients a DAI before and during stimulation could be calculated because of
      quality aspects. In all other patients, the other ambulatory urodynamic
      parameters could be analyzed and a significant reduction was found in bladder
      overactivity. A significant correlation (p = 0.03) was found in DAI reduction of
      the ACM before and during SNS as compared to the clinical improvement in
      overactive bladder symptoms. CONCLUSIONS: The objective and subjective results
      show a decrease in bladder overactivity during SNS. During SNS bladder
      instabilities are still present, which is in accordance with the published
      literature. The reduction of the DAI during SNS as compared to before SNS
      correlates significantly to the clinical effect of SNS.

PMID- 12600433
TI  - Body mass index and outcome of tension-free vaginal tape.
AB  - OBJECTIVES: To assess the effectiveness of tension-free vaginal tape (TVT) in
      women with high body mass indices (BMIs). METHODS: Thirty-eight consecutive
      patients with BMIs exceeding 30 who underwent tension-free vaginal tape were
      compared with 149 consecutive patients with BMIs of 30 or less who underwent the
      same procedure. Body mass index was calculated pre-operatively and at follow-up.
      Women were classified as being of normal weight (BMI 20-25), overweight (BMI 26
      30), or obese (BMI >30). Patient characteristics, operative and post-operative
      complications, reported continence rates were analyzed according to BMI. RESULTS:
      There were no significant differences between groups in terms of age, parity,
      menopausal status, previous surgery, type and degree of incontinence. Estimated
      blood loss, operative times, bladder injuries, post-operative urgency and voiding
      disorders did not differ significantly between women with high BMIs and those
      with low BMIs. Women with BMIs exceeding 30 had a significantly higher incidence
      of post-operative urge urinary incontinence (17.9 versus 3.4 and 6.4% p = 0.02)
      without any effects on the objective and subjective cure rates (82 versus 88.7
      and 93% p = 0.1, 71.7 versus 72.1 and 74% p = 0.9). CONCLUSION: We did not find
      pre-operative obesity to be a risk factor for failure of tension-free vaginal
      tape.

PMID- 12600434
TI  - Diagnostic value of magnetic resonance imaging in Peyronie's disease--a
      comparison both with palpation and ultrasound in the evaluation of plaque
      formation.
AB  - OBJECTIVE: To compare the value of magnetic resonance imaging (MRI) with
      palpation and ultrasound in the evaluation of plaque formation in Peyronie's
      disease. METHODS: 57 patients underwent a standardized diagnostic procedure to
      evaluate plaque formation consisting of palpation and ultrasonography (7.5 MHz).
      MRI was performed during flaccidity and during erection induced by Prostaglandin
      E(1) including intravenous application of Gadolinium
      diethylenetriaminepentaacetic acid (Gd-DPTA). RESULTS: With all methods, 93
      plaques have been detected in 57 patients. 85 plaques (91.4%) have been evaluated
      by palpation alone. Using ultrasound, 52 of these 93 plaques (55.9%) were
      detectable. This is equivalent to 61.1% of the palpable plaques. MRI confirmed 58
      of the palpated plaques (68.2%) and exposed 8 primarily not palpable plaques at
      the penile basis. MRI revealed more palpable plaques than ultrasound, but this
      finding was not significant (p = 0.083). By means of sonography, calcification
      was evident in 14 plaques. MRI failed in revealing any calcification. After
      application of Gd-DPTA, 5 of 57 patients (9%) demonstrated contrast enhancement
      indicating local inflammation. None of these patients reported on penile pain.
      CONCLUSIONS: Penile palpation in combination with ultrasound represents the
      method of choice to diagnose plaque formation in Peyronie's disease. MRI provides
      better information on plaque formation at the penile basis. Calcification can
      only be proven by ultrasound, not by MRI. There may be additional information by
      MRI about local inflammation. A prospective study comparing the histological and
      MRI findings should be performed to answer the question, if pain is really
      associated with inflammation.

PMID- 12600435
TI  - The survival effect of prolactin on PC3 prostate cancer cells.
AB  - OBJECTIVES: Recent studies suggest a paracrine/autocrine loop involving prolactin
      (PRL) within the human prostate. The aims of this study were to determine the
      effects of PRL on the growth and survival of prostate cancer cells and the
      intracellular signalling mechanisms underlying such effects. METHODS: The effect
      of PRL on proliferation of LNCaP, PC3 and DU145 was assessed by Coulter counting.
      The effect of PRL on TRAIL-, staurosporine- and flavopiridol-induced apoptosis
      was assessed by Timelapse microscopy and Annexin V binding. The status of the PRL
      receptor (PRL-R) and Akt/PKB (protein kinase B) activity were assessed by Western
      blotting. RESULTS: All three cell lines expressed both the short and long forms
      of the PRL receptor. Although, no significant effect of PRL on the proliferation
      of these cells was found, PRL partially inhibited TRAIL-induced apoptosis in PC3
      cells. PRL also enhanced the phosphorylation of Akt/PKB in these cells.
      CONCLUSIONS: PRL had no significant effect on the proliferation of PC3, DU145 and
      LNCaP, but inhibited TRAIL-induced apoptosis in PC3 cells, possibly via enhanced
      Akt/PKB phosphorylation in PC3 cells. Further investigations are underway to
      determine the survival effect of PRL on the other two prostate cancer cell line.

PMID- 12600436
TI  - Fibroblast growth factors and their receptors in urological cancers: basic
      research and clinical implications.
AB  - Because therapeutical options for advanced urological cancers are limited, the
      understanding of key elements responsible for invasion and metastasis is very
      important. It has been hypothesized that progression to malignant growth is
      associated with a dysregulation of growth factors and/or their receptors. In the
      last few years, signaling pathways of the fibroblast growth factor (FGF) family
      have been subject to intense investigation. Fibroblast growth factors constitute
      one of the largest families of growth and differentiation factors for cells of
      mesodermal and neuroectodermal origin. The family comprises two prototypic
      members, acidic FGF (aFGF) and the basic FGF (bFGF), as well as 21 additionally
      related polypeptide growth factors that have been identified to date. FGFs are
      involved in many biological processes during embryonic development, wound
      healing, hematopoesis, and angiogenesis. In prostate, bladder, and renal cancers,
      FGFs regulate the induction of metalloproteinases (MMP) that degrade
      extracellular matrix proteins, thus facilitating tumor metastasis. Probably due
      to their potent angiogenic properties, aFGF and bFGF have received the most
      attention. However, there is increasing evidence that other FGFs also play
      crucial roles in tumors of the prostate, bladder, kidney, and testis. This review
      will discuss the different elements involved in FGF signaling and summarize the
      present knowledge of their biological and clinical relevance in urological
      cancers.

PMID- 12600438
TI  - Re: Crew JP, Jephcott CR, Reynard JM. Radiation-induced haemorrhagic cystitis.
      Eur Urol 2001;40(2):111-23.

PMID- 12600437
TI  - Joseph-Frederic-Benoit Charriere: master cutler and instrument designer.
AB  - Modern surgery owes its development to the innovations and skill of those
      craftsmen in the early 19th Century. Joseph-Frederic-Benoit Charriere was a
      Parisian Cutler of renowned fame. He pioneered many developments in ether
      administration, urologic and other general surgical instrumentation. He also made
      profound modifications to the syringe, haemostat and aneurysm clip. Charriere,
      most importantly, developed the French (Fr) or Charriere (Ch) gauge system used
      in sizing catheters and endoscopic equipment (1 Charr. = 0.333 mm). His
      contributions were widespread and are still evident today.

PMID- 12600439
TI  - Fundoplication improves disordered esophageal motility.
AB  - Patients with gastroesophageal reflux disease (GERD) and disordered esophageal
      motility are at risk for postoperative dysphagia, and are often treated with
      partial (270-degree) fundoplication as a strategy to minimize postoperative
      swallowing difficulties. Complete (360-degree) fundoplication, however, may
      provide more effective and durable reflux protection over time. Recently we
      reported that postfundoplication dysphagia is uncommon, regardless of
      preoperative manometric status and type of fundoplication. To determine whether
      esophageal function improves after fundoplication, we measured postoperative
      motility in patients in whom disordered esophageal motility had been documented
      before fundoplication. Forty-eight of 262 patients who underwent laparoscopic
      fundoplication between 1995 and 2000 satisfied preoperative manometric criteria
      for disordered esophageal motility (distal esophageal peristaltic amplitude < or
      =30 mm Hg and/or peristaltic frequency < or =80%). Of these, 19 had preoperative
      manometric assessment at our facility and consented to repeat study. Fifteen
      (79%) of these patients had a complete fundoplication and four (21%) had a
      partial fundoplication. Each patient underwent repeat four-channel esophageal
      manometry 29.5 +/- 18.4 months (mean +/- SD) after fundoplication. Distal
      esophageal peristaltic amplitude and peristaltic frequency were compared to
      preoperative data by paired t test. After fundoplication, mean peristaltic
      amplitude in the distal esophagus increased by 47% (56.8 +/- 30.9 mm Hg to 83.5
      +/- 36.5 mm Hg; P < 0.001) and peristaltic frequency improved by 33% (66.4 +/-
      28.7% to 87.6 +/- 16.3%; P < 0.01). Normal esophageal motor function was present
      in 14 patients (74%) after fundoplication, whereas in five patients the
      esophageal motor function remained abnormal (2 improved, 1 worsened, and 2
      remained unchanged). Three patients with preoperative peristaltic frequencies of
      0%, 10%, and 20% improved to 84%, 88%, and 50%, respectively, after
      fundoplication. In most GERD patients with esophageal dysmotility, fundoplication
      improves the amplitude and frequency of esophageal peristalsis, suggesting
      refluxate has an etiologic role in motor dysfunction. These data, along with
      prior data showing that postoperative dysphagia is not common, imply that
      surgeons should apply complete fundoplication liberally in patients with
      disordered preoperative esophageal motility.

PMID- 12600441
TI  - Duodenal reflux produces hyperproliferative epithelial esophagitis--a possible
      precursor to esophageal adenocarcinoma in the rat.
AB  - Esophageal reflux of duodenal contents converts a rat nitrosamine esophageal
      cancer model from squamous cell carcinoma to adenocarcinoma. Further, there was a
      tendency for male rats to have a higher incidence of cancer than female rats.
      However, chemical castration with the gonadotropin-releasing hormone analog
      leuprolide did not protect male or female animals from developing cancer. We have
      identified an early (6-week) hyperproliferative epithelial cell reaction to
      duodenal reflux. We carried out experiments to assess the specificity of duodenal
      reflux in producing the hyperproliferative epithelial precursor lesion. Animals
      underwent specific surgical procedures to produce esophageal reflux of pure
      duodenal contents, mixed gastroduodenal, or bland intestinal contents. A
      hyperproliferative mucosal esophagitis developed in the group with duodenal
      reflux but not in the other groups. Mucosal thickness in the duodenal reflux
      group reached seven times that of normal mucosa at 6 weeks. These results suggest
      that esophageal reflux of duodenal contents plays an important role in the
      pathogenicity of proliferative esophagitis and the potential development of
      esophageal adenocarcinoma.

PMID- 12600440
TI  - Barrett's esophagus with high grade dysplasia: surgical results and long-term
      outcome--an update.
AB  - We updated our surgical results and long-term outcome for prophylactic
      esophagectomy in patients with Barrett's esophagus and high-grade dysplasia (HGD)
      and determined the incidence of occult adenocarcinoma. Sixty consecutive patients
      with HGD who underwent esophagectomy had pre- and postoperative pathology
      examined at our institution from 1982 to 2001. We reviewed medical records to
      determine patient characteristics, surgical approach, operative morbidity and
      mortality, pathology, and length of stay. Patients and/or referring physicians
      were contacted to determine long-term outcome. Fifty-three men (88%) and 7 women
      (12%) were followed up for a median of 4.6 years. Transhiatal esophagectomy was
      performed in the majority of patients (82%). There was one operative death (1.7%)
      and 15 complications (29%). Median length of stay was 9 days. In 18 patients
      (30%), invasive adenocarcinoma was detected in the resected specimen. When
      examined by time periods, 43% (13/30) of patients were diagnosed with occult
      cancer from 1982-1994, whereas 17% (5/30) harbored occult malignancy from 1994
      2001. All patients with adenocarcinoma in the recent interval had stage I
      disease, as opposed to only 61.5% of patients from the earlier study. Operative
      mortality declined from 3.3% to 0% over the two intervals as did mean length of
      stay from 14 days to 10 days. Five-year survival was excellent at 88%. Age and
      amount of preoperative weight loss were preoperative predictors of survival,
      whereas major postoperative complications and stage were postoperative predictors
      of outcome. Barrett's esophagus with high-grade dysplasia continues to be an
      indication for prophylactic esophagectomy. Overall prevalence of occult
      adenocarcinoma remains high. We have demonstrated a declining incidence of occult
      cancer and treatment of earlier stage adenocarcinoma when found in this
      population of patients treated with esophagectomy.

PMID- 12600442
TI  - Preoperative intervention does not affect esophageal muscle histology or patient
      outcomes in patients undergoing laparoscopic Heller myotomy.
AB  - Botox injection and pneumatic dilation are common therapies for achalasia. We
      sought to determine the impact of these preoperative therapies on esophageal
      muscle histology and outcomes after laparoscopic Heller myotomy. A total of 73
      consecutive patients had esophageal muscle biopsies taken from the
      gastroesophageal junction at the time of myotomy between November 1998 and
      November 2001. Muscle fibrosis was graded by a senior pathologist who was blinded
      to preoperative treatments and postoperative outcomes. Patients graded their
      dysphagia and heartburn symptoms before and after myotomy and graded their
      outcomes at follow-up. Patients were grouped according to the preoperative
      endoscopic treatment (dilation, Botox, both, or neither) and the groups were
      compared. Preoperative therapy did not correlate with esophageal fibrosis or
      postoperative outcomes, and the degree of esophageal muscle fibrosis was not
      predictive of outcome. Symptom scores improved significantly for dysphagia (4.5
      +/- 0.9 vs. 1.6 +/- 1.6) and heartburn (2.3 +/- 1.8 vs. 1.5 +/- 1.4) irrespective
      of preoperative therapy or fibrosis. Overall, excellent or good outcomes were
      obtained in 92% of patients at follow-up of 15.7 months +/- 14.4. Successful
      outcomes are highly probable after laparoscopic Heller myotomy regardless of
      preoperative interventions. The amount of fibrosis in the esophageal muscle is
      not related to preoperative intervention and is not predictive of outcomes.

PMID- 12600443
TI  - Cholangitis: bacterial virulence factors that facilitate cholangiovenous reflux
      and tumor necrosis factor-alpha production.
AB  - In previous studies we noted that biliary bacteria produce slime and possess P1
      fimbriae. The presence of gram-negative bacteria killed by complement correlated
      with serious biliary infections and induced more tumor necrosis factor-alpha (TNF
      alpha) production in sera, suggesting a role for cytokine production and
      complement activation in biliary sepsis. This study examined bacterial virulence
      factors that facilitate cholangiovenous reflux (CVR) and TNF-alpha production in
      a rat model. Twenty-one biliary bacteria and two stool isolates were tested for
      slime production, sensitivity to complement killing, and hemolysin production.
      10(7) Bacterial colony-forming units/ml (or saline control) were injected
      retrograde into the common bile ducts of Sprague-Dawley rats at a pressure of 30
      cm H(2)O. Blood was obtained at 5 and 60 minutes after infusion for bacterial
      culture and TNF-alpha assay, respectively. The magnitude of slime production
      correlated inversely with the magnitude of bacterial CVR. Average bacterial
      colony-forming units were 1.4 x 10(5), 6.8 x 10(4), or 2.1 x 10(3) for bacteria
      with slime production 0 to 10, 11 to 99, or more than 100, respectively (P <
      0.0001, analysis of variance). CVR was greater for serum-resistant bacteria (1.2
      x 10(5) vs. 5.5 x 10(4) [P = 0.007, resistant vs. sensitive]), but TNF-alpha
      production was greater in serum-sensitive bacteria. TNF-alpha production as a
      function of bacterial reflux followed a logarithmic curve (R(2) = 0.75) for serum
      sensitive bacteria but was linear (R(2) = 0.60) for serum-resistant bacteria.
      These data show how specific virulence factors explain why some bacterial species
      colonize without causing illness, whereas others colonize and cause sepsis.
      Although slime production was necessary for colonization, too much slime
      inhibited CVR. Although complement killing cleared bacteria from the circulation,
      it was also associated with increased TNF-alpha production, which can lead to
      septic manifestations. The most virulent bacterial species (from patients with
      sepsis) were killed by complement, but they still had significant CVR and were
      associated with increased TNF-alpha production.

PMID- 12600444
TI  - Liver injury during acute pancreatitis: the role of pancreatitis-associated
      ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis.
AB  - We have demonstrated that pancreatitis-associated ascitic fluid contributes to
      hepatocyte injury during acute pancreatitis; a phenomenon independent of ascites'
      enzymatic content and Kupffer cell-derived cytokines. Our aim is to characterize
      the mechanisms of pancreatitis-associated ascitic fluid induced hepatocyte death.
      NIH mice were injected intraperitoneally with pathogen-free pancreatitis
      associated ascitic fluid. Twenty-four hours later, serum AST, ALT, LDH, and
      hepatocyte apoptosis (TUNEL) were measured. Human hepatocytes (CCL-13) were
      treated with pancreatitis-associated ascitic fluid +/-SB203580 or caspase-3
      inhibitor-II. Mitochondrial membrane integrity was determined by DiOC6 staining.
      Apoptosis was measured by TUNEL staining and flow cytometry after dual labeling
      with Annexin-V/7-AAD. Data are mean +/- SEM of triplicates. Pancreatitis
      associated ascitic fluid increased serum AST, ALT, LDH, and apoptotic cells in
      the mouse liver (all P < 0.03 vs. sham). In CCL-13 cells, pancreatitis-associated
      ascitic fluid induced a time and dose-dependent increase in apoptosis, in
      addition to p38-MAPK phosphorylation (P = 0.02 vs. control), caspase-3 cleavage
      (P < 0.03 vs. control) and decreased DiOC6 mitochondrial staining (P < 0.01 vs.
      control). Both caspase-3 inhibitor-II and SB203580 decreased apoptosis, but the
      former had no effect on DiOC6 staining. Pancreatitis-associated ascitic fluid
      induces liver injury and hepatocyte apoptosis by activating p38-MAPK and caspase
      3 dependent pro-apoptotic pathways.

PMID- 12600445
TI  - Pancreaticoduodenectomy: role of interventional radiologists in managing patients
      and complications.
AB  - Although the mortality rate after pancreaticoduodenectomy has decreased, the
      morbidity rate remains high. Major morbidity is often managed with the aid of
      interventional radiologists. The objective of this study was to evaluate the
      cooperative roles of interventional radiologists and pancreatic surgeons in
      complex pancreatic surgery, specifically pancreaticoduodenectomy. Our
      pancreaticoduodenectomy database was reviewed for all patients undergoing
      pancreaticoduodenectomy between January 1, 1995 and December 31, 2000. The
      interventional radiologic procedures for each patient were evaluated. A total of
      1061 patients underwent pancreaticoduodenectomy. The overall mortality and
      morbidity rates were 2.3% and 35%, respectively. Five hundred ninety patients
      (56%) had no interventional radiologic procedures, whereas 471 patients (44%) had
      interventional radiologic procedures. Of those, 342 (32%) had preoperative
      biliary drainage (PBD) and 129 (12%) required postoperative interventional
      radiologic procedures. Percutaneous aspiration/catheter drainage was required in
      84 patients for intra-abdominal abscess, biloma, or lymphocele, with 24 requiring
      two or more abscess drains. Thirty-nine patients underwent postoperative PBD for
      bile leaks due to anastomotic disruption, undrained biliary segments, or T
      tube/bile stent dislodgment. Eighteen patients had hemobilia/gastrointestinal
      bleeding treated by angiography with embolization. The reoperation rate for the
      entire cohort of 1061 patients was 4.1% (n = 43). Nineteen of the 129 patients
      (15%) requiring postoperative radiologic intervention required reoperation.
      Although 4 of 18 patients who required embolization for bleeding subsequently
      required surgical intervention for the same reason, only 4 of 84 patients
      undergoing abscess drainage later required operation for anastomotic disruption
      or unsuccessful percutaneous drainage. As would be expected, the patients who
      required postoperative radiologic intervention (n = 129) had a higher incidence
      of postoperative complications including pancreatic fistula (20% vs. 6%, P <
      0.01), bile leakage (22% vs. 1%, P < 0.01), and wound infection (16% vs. 8%, P <
      0.01). With the complications in these 129 patients, the postoperative mortality
      rate was only 6.2% compared to 1.7% in patients who did not require radiologic
      intervention (n = 932, P < 0.01). The median postoperative length of stay was 15
      days in those patients requiring postoperative radiologic intervention, 10 days
      in those not requiring intervention (P < 0.01; postoperative interventional
      radiology vs. no postoperative interventional radiology), and 29.5 days for
      patients needing reoperation. Interventional radiologists play a critical role in
      the management of some patients undergoing pancreaticoduodenectomy. Although
      complications such as anastomotic leaks, abscess formation, and bleeding can
      result in increased mortality and a longer hospital stay, the skills of the
      interventional radiology team provide expert management of some life-threatening
      complications, thus avoiding reoperation, speeding recovery times, and minimizing
      morbidity.

PMID- 12600447
TI  - Gene transfer of human manganese superoxide dismutase protects small intestinal
      villi from radiation injury.
AB  - Small bowel toxicity represents a major dose-limiting side effect of radiation
      treatment for many malignancies. We examined the effects of overexpressing human
      manganese superoxide dismutase (MnSOD) in the small intestine in mice to prevent
      radiation enteritis. Mice were treated with the human MnSOD gene delivered
      enterally using a nontoxic, replication-defective herpes simplex virus (HSV)-1
      based vector. HSV vectors containing the human MnSOD transgene and green
      fluorescent protein (GFP) transgene, or GFP transgene alone, were constructed and
      injected intraluminally into a 2cm length of small intestine of C3H/HeNsd mice.
      Total body irradiation of 15 Gy was delivered to mice inoculated 24 hours earlier
      with either HSV-MnSOD (10(3) to 10(8) plaque-forming units), control HSV-GFP, or
      no vector. At 24 or 72 hours after irradiation, mice were killed and villi areas
      were measured from appropriate segments of the small intestine. Control
      irradiated mice showed a decreased villi area of 82% by day 3 after irradiation,
      whereas treatment of mice with HSV-MnSOD 10(8) plaque-forming units led to only a
      16% decrease in villi area (P < 0.001) before radiation. Similar findings were
      seen on day 3 and were associated with a significant (P < 0.001) preservation of
      enteric protein content in HSV-MnSOD-treated mice. A dose-dependent effect of
      MnSOD in preventing radiation-induced small bowel injury was evident. These data
      demonstrate that overexpression of human MnSOD via a replication-defective herpes
      viral vector is an efficacious method of protecting the small intestine from
      ionizing radiation damage.

PMID- 12600446
TI  - Evaluation of vascular endothelial growth factor blockade and matrix
      metalloproteinase inhibition as a combination therapy for experimental human
      pancreatic cancer.
AB  - Blockade of vascular endothelial growth factor (VEGF) and inhibition of matrix
      metalloproteinases (MMP) are promising therapies for cancer. This study assessed
      the effects of a neutralizing anti-VEGF antibody (A4.6.1) and an MMP inhibitor
      (BB-94) on pancreatic cancer (PaCa) in vivo. Five million cells of two human PaCa
      cell lines (AsPC-1 and HPAF-2) were injected subcutaneously into nude mice; 1
      mm(3) fragments of the resulting tumors were implanted into the pancreas of other
      mice. Animals were randomized into a control group and three treatment groups:
      A4.6.1 (100 microg intraperitoneally twice weekly); BB-94 (50 mg/kg every other
      day); and combination (A4.6.1 plus BB-94). Treatment was started after 3 days and
      continued for 14 weeks. Tumor volume, local and distant spread (score), and
      ascites were determined at autopsy. Microvessel density as a parameter of
      neoangiogenesis was analyzed in CD31-stained tumor sections. Both monotherapies
      reduced tumor volume (HPAF-2: -89% by A4.6.1 and -75% by BB-94; AsPC-1: -48% by
      A4.6.1 and -72% by BB-94), spread (HPAF-2: -76% by A4.6.1 and -58% by BB-94; AsPC
      1: -32% by A4.6.1 and -54% by BB-94), and microvessel density (HPAF-2: -75% by
      A4.6.1 and -30% by BB-94; AsPC-1: -59% by A4.6.1 and -30% by BB-94), resulting in
      a tendency toward increased survival (HPAF-2: 8 of 8 animals by A4.6.1 or BB-94
      vs. 4 of 8; AsPC-1: 3 of 8 by A4.6.1, 4 of 8 by BB-94 vs. 1 of 8). Combination
      therapy yielded additional effects in the HPAF-2 group with regard to tumor
      volume (-95%) and development of ascites (0 of 8 vs. 2 of 8 by A4.6.1 or BB-94
      vs. 5 of 8 control mice). Both VEGF blockade and MMP inhibition reduce primary
      tumor size, metastasis, and angiogenesis, thereby increasing survival in
      experimental pancreatic cancer. Combination treatment results in additive effects
      in moderately differentiated HPAF-2 tumors.

PMID- 12600448
TI  - Transcriptional activation of the enterocyte differentiation marker intestinal
      alkaline phosphatase is associated with changes in the acetylation state of
      histone H3 at a specific site within its promoter region in vitro.
AB  - Enterocyte differentiation is thought to occur through the transcriptional
      regulation of a small subset of specific genes. A recent growing body of evidence
      indicates that post-translational modifications of chromatin proteins (histones)
      play an important role in the control of gene transcription. Previous work has
      demonstrated that one such modification, histone acetylation, occurs in an in
      vitro model of enterocyte differentiation, butyrate-treated HT-29 cells. In the
      present work, we sought to determine if the epigenetic signal of histone
      acetylation occurs in an identifiable pattern in association with the
      transcriptional activation of the enterocyte differentiation marker gene
      intestinal alkaline phosphatase (IAP). HT-29 cells were maintained under standard
      culture conditions and differentiated with sodium butyrate. The chromatin
      immunoprecipitation (ChIP) assay was used to compare the acetylation state of
      histones associated with specific regions of the IAP promoter in the two cell
      populations (undifferentiated vs. differentiated). Chromatin was extracted from
      cells and cleaved by sonication or enzymatic digestion to obtain fragments of
      approximately 200 to 600 base-pairs, as confirmed by polymerase chain reaction
      using primers designed to amplify the IAP segments of interest. The ChIP assay
      selects DNA sequences that are associated with acetylated histones by
      immunoprecipitation. Unbound segments represent DNA sequences whose histones are
      not acetylated. After immunoprecipitation, sequences were detected by
      radiolabeled polymerase chain reaction, and the relative intensity of the bands
      was quantified by densitometry. The relative acetylation state of histones at
      specific sites was determined by comparing the ratios of bound/unbound segments.
      We determined that in a segment of the IAP promoter between -378 and -303 base
      pairs upstream from the transcriptional start site, the acetylation state of
      histone H3 increased twofold in the differentiated, IAP expressing cells, whereas
      that of histone H4 remained essentially constant. Additionally, at a distant
      site, between -1378 and -1303 base-pairs, the acetylation state of H3 and H4 did
      not change appreciably between the undifferentiated and differentiated cells. We
      conclude that butyrate-induced differentiation is associated with specific and
      localized changes in the histone acetylation state within the IAP promoter. These
      changes within the endogenous IAP gene may underlie its transcriptional
      activation in the context of the enterocyte differentiation program.

PMID- 12600644
TI  - HIV-1 cell entry and advances in viral entry inhibitor therapy.
AB  - Despite the considerable successes of highly active antiretroviral therapy, new
      classes of therapeutic agents are still urgently needed. Unfortunately, the
      emergence of antiviral resistance and drug toxicity remain challenging obstacles
      to successful treatment in many HIV-1-infected individuals. HIV-1 entry is a
      multi-step process that is an attractive target for the development of new
      classes of therapeutic agents. Considerable progress has been made in the
      understanding of HIV-1 cell entry, enabling the design of specific agents that
      can inhibit each step of cellular entry. A number of promising agents have
      commenced clinical trials, including the attachment inhibitor PRO 542, co
      receptor inhibitor AMD3100 and fusion inhibitor T-20. A greater number of HIV-1
      entry inhibitors are in preclinical development. This review outlines the
      mechanisms involved in HIV-1 entry and the sites of action of specific HIV-1
      inhibitors.

PMID- 12600449
TI  - Colonic metaplasia in the ileal pouch is associated with inflammation and is not
      the result of long-term adaptation.
AB  - Ileal pouch-anal anastomosis (IPAA) is the preferred surgical therapy for chronic
      ulcerative colitis (CUC) and familial adenomatous polyposis (FAP). Previous
      studies have demonstrated morphologic changes in pouch mucosa such as villous
      atrophy and crypt hyperplasia. These changes have been labeled "colonic
      metaplasia." The aims of this study were to determine whether these changes
      represent "normal" long-term adaptation of the nondiseased pouch or instead are
      present only in the setting of inflammation. Twenty-four patients were
      identified, greater than 5 years status post-IPAA for CUC, who underwent
      pouchoscopy for surveillance and had no history of pouchitis. Thirty-one patients
      were identified greater than 5 years status post-IPAA for CUC, who had a history
      of pouchitis and had undergone pouchoscopy at least 5 years status post-IPAA.
      Eight patients status post-IPAA for FAP were also identified. Biopsy specimens
      were reevaluated by a single, blinded pathologist for degree of inflammation, the
      presence of villous atrophy and crypt hyperplasia, and evidence of dysplasia.
      Among the patients with CUC, the inflammation score was greater in the pouchitis
      group, 13.2 +/- 1.2, compared to the nonpouchitis group, 4.0 +/- 0.5 (P <
      0.0001). Median colonic metaplasia score was greater in the pouchitis group (4
      [range 2 to 6]) vs. 2 (9 [range 0 to 6]; P < 0.0001). The colonic metaplasia
      score correlated with the inflammation score (Spearman coefficient r = 0.83; P <
      0.0001). In the eight patients with FAP, the inflammation score was 5.1 +/- 0.9
      and the median colonic metaplasia score was 1 (range 0 to 4). There was no
      evidence of dysplasia in any of the biopsy specimens. Patients without a history
      of pouchitis or symptoms of pouchitis have only a minimal degree of villous
      atrophy and crypt hyperplasia. These morphologic changes in the ileal pouch are
      found primarily in the setting of inflammation, and likely represent a reparative
      response.

PMID- 12600645
TI  - HIV, ethnicity and travel: HIV infection in Vietnamese Australians associated
      with injecting drug use.
AB  - BACKGROUND: The movement of people with their constructed identities including
      ethnicity has always been one of the determinants of the human immunodeficiency
      virus (HIV) pandemic. An example of the contributions of travel and ethnicity to
      experiences of HIV can be seen in the Vietnamese community in Australia.
      OBJECTIVES: This paper seeks to describe the contributions of ethnicity and
      travel to the Australian HIV epidemic with particular reference to the evolving
      epidemic within the Vietnamese Australian community. STUDY DESIGN: We reviewed
      the available data on the HIV epidemic in Australia with reference to overseas
      acquisition, ethnicity, the epidemic in the Vietnamese community and the
      determinants of the current patterns of transmission within this community.
      RESULTS: Available data suggests that 20-25% of HIV infections notified in
      Australia are acquired overseas. This proportion is higher in some specific
      categories such as heterosexually acquired infections. Notification rates are no
      higher in Vietnamese Australians than in the general Australian population apart
      from infections associated with injecting drug use (IDU) notified in the state of
      Victoria. The reasons for this increased rate of notification include increased
      vulnerability to blood borne virus infection in Australia and the additional,
      unique risk of frequent travel to Vietnam, a country where IDU carries a high
      risk of HIV infection. CONCLUSIONS: Australia has succeeded in stabilising the
      HIV epidemic partly through successful interventions to limit the spread of
      infection among IDUs. There is now early evidence that HIV transmission may be
      increasing amongst Vietnamese Australian IDUs. Timely responses that help
      Vietnamese Australian IDUs reduce their accumulation of risk are likely to be
      important in determining the level of harm associated with IDU throughout
      Australia.

PMID- 12600646
TI  - The role of Vif during HIV-1 infection: interaction with novel host cellular
      factors.
AB  - BACKGROUND: Current research suggests that human immunodeficiency virus type-1
      (HIV-1) virion infectivity factor (Vif) acts during viral assembly in producer
      cells to ensure infectivity in target cells but the exact mechanism of action has
      not been defined. Vif interacts with Gag, viral protease and RNA and these
      interactions are proposed to be important for correct particle assembly and
      stability of the reverse transcription complex. OBJECTIVES: The existence of
      cells that are either permissive or non-permissive for replication of Vif
      deficient viruses suggests the involvement of host cellular factors in its
      function. Current research suggests an association of Vif with the intermediate
      filament protein, vimentin, and the tyrosine kinase, Hck, but the significance of
      these associations remains to be defined. More recently HP68, a cellular ATP
      binding protein, has been shown to be important for capsid formation and an
      interaction between Vif and HP68 has been shown. Our aim was to further identify
      host cellular factors involved in Vif function. STUDY DESIGN: We have employed
      the yeast 2-hybrid system to identify cellular proteins which interact with HIV-1
      Vif. Sixteen clones were isolated from a high stringency yeast-2-hybrid screen of
      a human leucocyte cDNA library with Vif derived from the T-cell tropic HIV-1
      strain NL4.3. Of these, 8 clones were confirmed as specifically binding Vif,
      fully sequenced and identified via GenBank homology searches. RESULTS: Thus far 3
      of these clones, spermine/spermidine N1-acetyltransferase, Triad 3 and a novel
      gene which we have termed 'novel Vif binding protein', have been characterised
      and represent attractive candidates for mediating Vif action during HIV
      replication. CONCLUSIONS: Through identification and characterisation of cellular
      factors interacting with HIV-1 Vif we hope to unravel the mechanism of action of
      Vif which may ultimately aid therapeutic design.

PMID- 12600647
TI  - Rates of transmission of antiretroviral drug resistant strains of HIV-1.
AB  - BACKGROUND: It is clear that transmission of drug resistant HIV-1 is possible and
      occurs regularly. However, there is a lack of clarity concerning the true rate of
      this transmission in a given population, the impact of combination therapies on
      this rate, and the contribution of transmitted resistant virus to treatment
      failure either in an individual or on a population basis. OBJECTIVES: To provide
      a review of our current understanding of rates of transmission of drug resistant
      HIV-1 in various populations and to report the results of a study conducted to
      determine this rate in Sydney, Australia in the years 1992-2000. STUDY DESIGN: A
      review of the literature combined with a prospective study of antiretroviral drug
      resistance in 130 individuals who were diagnosed with symptomatic primary
      infection at St. Vincent's Hospital, Sydney, Australia between 1992 and 2000.
      Sequencing of reverse transcriptase (RT) and protease (PR) was performed by the
      TruGene HIV-1 genotyping kit (Visible Genetics Inc.). RESULTS: The results found
      in the Sydney population contrast with much of the literature. The prevalence of
      mutations that conferred primary resistance to protease inhibitors (PIs) was only
      0.8% at position V82I. Secondary mutations/polymorphisms were seen in the PR at
      position L10I/V, K20R, M36I, L63P, A71T/V, or V77I in 60%. L63P was the most
      frequently found mutation (46.3%). The incidence of protease-resistant strains of
      HIV in primary HIV-1 infection did not change after the introduction of PIs in
      1996. The distribution of the most common resistance mutations in the RT was as
      follows; M41L (8.5%) and T215Y (8.5%) and K70R (4.8%). The frequency of mutations
      associated with NRTI resistance was significantly lower in the post 1995 samples
      (43.9 vs. 19.1%, P < 0.05). Moreover, both M41L and K70R, but not T215Y, occurred
      with significantly decreased frequency in the post 1995 samples. CONCLUSIONS: In
      contrast to other studies we found no increase in the rate of PR resistance and a
      decrease in the rate of RT resistance in recently transmitted virus over the
      period 1992-2000. The reasons for the differences between these results and those
      reported from elsewhere may relate to treatment regimens used in the transmitting
      population and may have implications for treatment policies in this country.

PMID- 12600648
TI  - False negative HIV-1 proviral DNA polymerase chain reaction in a patient with
      primary infection acquired in Thailand.
AB  - BACKGROUND: Qualitative HIV-1 proviral DNA PCR tests have three main diagnostic
      applications. These include direct detection of viral sequences in the pre
      seroconversion window period which may be positive up to 8 days prior to the
      development of HIV specific antibodies; resolution of indeterminate HIV
      serological tests and in the diagnosis of neonates born to seropositive mothers
      where maternal antibodies may be detectable for up to 15 months past partum.
      METHODS: A total of three serial specimens from a single patient following
      symptomatic primary HIV-1 infection were assessed by commercially available
      serological assays for antibodies to HIV and HIV-1 antigen and nucleic acid
      amplification assays for proviral DNA (Amplicor HIV-1 test, Roche Molecular
      Systems, CA, USA) and RNA (HIV MONITOR ver1.5, Roche Molecular Systems) according
      to manufacturers recommendations. A subsequent modified PCR protocol for HIV
      proviral DNA was performed which included modified primers (SK145/SKCC1B) and
      altered thermal cycling parameters. RESULTS: We describe a case of HIV infection
      acquired in Thailand by heterosexual transmission, where a commercially available
      HIV proviral DNA PCR assay remained negative despite a typical evolving
      serological profile consistent with seroconversion. CONCLUSION: These data
      support the use of HIV DNA PCR tests only as a second line supplemental test to
      licensed standard HIV diagnostic testing strategies, and should be used with care
      in cases where non-B subtype infection is a possibility.

PMID- 12600649
TI  - Epidemiology of hepatitis C virus infection in Australia.
AB  - BACKGROUND: Since the discovery in 1989 of hepatitis C virus (HCV) as the
      infectious agent responsible for the vast majority of post-transfusion non-A non
      B hepatitis the patterns of transmission and clinical consequences of this highly
      prevalent flavivirus have been widely studied. OBJECTIVE: This paper reviews
      available evidence on the epidemiology of HCV infection in Australia, including
      HCV notification data obtained through public health surveillance systems, HCV
      seroprevalence surveys among high risk populations, and models for estimating and
      projecting HCV transmission and long-term consequences of chronic HCV infection.
      RESULTS: Over the period 1990-2000 approximately 160,000 notifications of HCV
      infection were received by State and Territory health jurisdictions making it the
      most commonly notified communicable disease in Australia. Approximately 210,000
      people are estimated to be living with HCV infection in Australia, with an
      estimated 80% having acquired their infection through injecting drug use. Less
      than 500 cases of newly acquired HCV infection are notified each year, however,
      an estimated 16,000 new infections occur annually. Despite the widespread
      introduction of needle and syringe programmes in the late 1980s, HCV transmission
      continues at high levels among current injecting drug users (IDUs) with incidence
      and prevalence estimates of 10-20/100 person years and 50-55%, respectively.
      Levels of HCV transmission are particularly high in both younger and incarcerated
      IDUs. In contrast to HCV infection, prevalence of HIV among current IDUs has
      remained below 2% since 1995. Although a small minority of people with chronic
      HCV infection will develop liver failure or hepatocellular carcinoma, the
      incidence of these advanced disease complications is estimated to double over the
      next decade. CONCLUSION: The epidemic of HCV infection continues to escalate in
      Australia, predominantly through transmission related to injecting drug use. As
      the population of people with chronic HCV infection and progressive liver disease
      expands the public health burden of advanced disease complications will be
      considerable.

PMID- 12600650
TI  - Clinical and virological aspects of hepatitis B co-infection in individuals
      infected with human immunodeficiency virus type-1.
AB  - The improved prognosis of HIV-infection that has occurred since the introduction
      of highly active antiretroviral therapy (HAART) has resulted in renewed emphasis
      being placed on co-morbidities associated with HIV-infection, and chronic viral
      hepatitis in particular. Hepatitis B virus (HBV) infection is an important
      infection in HIV-1 infected individuals because of the influence of HIV-1 co
      infection on the natural history of HBV infection. Antiviral therapies with
      activity against both viruses have enabled targeted therapy in co-infected
      individuals, however, optimism regarding improved prognosis has been tempered by
      the development of antiviral resistant HBV. Emerging new classes of HBV therapies
      herald the possibility of combination HBV therapy.

PMID- 12600651
TI  - Nucleoside analogues and neuropathy in the era of HAART.
AB  - BACKGROUND: Sensory neuropathies occur commonly in the setting of HIV infection.
      Sensory neuropathy (SN) is clearly associated with HIV itself, and in this
      context develops in association with increased macrophage activation in the
      peripheral nervous system. A clinically identical SN may also occur as a
      consequence of exposure to some HIV treatments. In this setting, impaired
      mitochondrial function is thought to play a role in the development of
      neurological dysfunction. OBJECTIVE: This review explores the evidence for the
      neurotoxicity of HIV and HIV treatments, the effect of nucleoside reverse
      transcriptase inhibitors on mitochondria, and the likely associations between
      these. CONCLUSIONS: Dideoxynucleotide drugs are commonly associated with SN. The
      nucleoside reverse transcriptase inhibitors inhibit mitochondrial DNA synthesis
      and may thus exacerbate existing viral-induced nerve damage.

PMID- 12600652
TI  - The role of observational data in monitoring trends in antiretroviral treatment
      and HIV disease stage: results from the Australian HIV observational database.
AB  - OBJECTIVES: To illustrate how human immunodeficiency virus (HIV) observational
      databases may be used to monitor trends in HIV treatment and HIV disease outcomes
      through data reported from the Australian HIV Observational Database (AHOD).
      METHODS: Time trends in the use of antiretroviral treatment, and changes in
      treatment strategies were calculated in patients recruited to AHOD from HIV
      specialist clinics including hospitals, sexual health clinics and general
      practices. These results were then compared to trends reported from other
      observational cohorts. RESULTS: By September 2001, 1961 patients were recruited
      to AHOD. Since entering AHOD, 3% of patients have been diagnosed with an AIDS
      defining illness, and 2% of patients have died, of which, 54% were non-HIV
      related deaths. The proportion of patients receiving antiretroviral therapy
      increased from 66% between January and June 1998 and 77% between July and
      September 2001. The most commonly received treatment regimen was triple therapy
      including a protease inhibitor (PI), ranging between 36% in January and June 1998
      and 31% in July to September 2001. Triple therapy including a non-nucleoside
      reverse transcriptase inhibitor (NNRTI) more than doubled to 32% between July and
      September 2001. The proportion of patients receiving either stavudine (d4T) or
      zidovudine (AZT) treatment regimens decreased from 92% between January and June
      1998 to 76% between July and September 2001. Patients receiving ritonavir in
      combination with another PI increased, as did the proportion of patients
      interrupting therapy for more than 3 months. CONCLUSION: These findings suggest
      there have been changes in the way antiretroviral treatments have been used in
      Australia, and are consistent with the current literature. Furthermore, these
      findings demonstrate the usefulness of observational cohorts as a surveillance
      tool monitoring trends in treatment and disease progression.

PMID- 12600653
TI  - Effect of therapeutic drug monitoring on outcome in antiretroviral experienced
      HIV-infected individuals.
AB  - BACKGROUND: The role of therapeutic drug monitoring (TDM) in the routine
      management of HIV-infected individuals is still unclear, largely due to a lack of
      basic data regarding specific drug concentrations and how they correlate with
      maximal effect and minimal toxicity within given populations. Nevertheless, it
      has a potentially important role to play in the management of HIV-infected
      patients, with the aim of limiting toxicity, optimising antiviral effect and
      decreasing virological failure and emergence of viral resistance. OBJECTIVES: To
      measure serum concentrations of specific antiretroviral drugs in individuals
      changing antiretroviral therapy and assess relationship to virological response.
      STUDY DESIGN: A prospective, non-randomised, 24-week study of 40 antiretroviral
      experienced HIV-infected patients. Subjects had failed their previous
      antiretroviral regimen and were beginning new regimens based on genotypic
      testing. Serum antiretroviral concentrations and virological response was
      measured after initiation of treatment. RESULTS: There was a significant
      correlation between higher concentrations of lopinavir and efavirenz and better
      virological outcome. This was not seen with amprenavir. CONCLUSIONS: Use of TDM
      in this setting helps predict virological response to therapy. Optimal use of TDM
      would require dose adjustment on the basis of a TDM level. Further research is
      necessary to enable this practice to become routine in the management of HIV
      infected patients.

PMID- 12600654
TI  - The first strand transfer reaction of HIV-1 reverse transcription is more
      efficient in infected cells than in cell-free natural endogenous reverse
      transcription reactions.
AB  - BACKGROUND: In the presence of dNTPs, intact HIV-1 virions are capable of reverse
      transcribing at least part of their genome, a process known as natural endogenous
      reverse transcription (NERT). PCR analysis of virion DNA produced by NERT
      revealed that the first strand transfer reaction (1stST) was inefficient in
      intact virions, with minus strand (-) strong stop DNA (ssDNA) copy numbers up to
      200 times higher than post-1stST products measured using primers in U3 and U5.
      This was in marked contrast to the efficiency of 1stST observed in single-round
      cell infection assays, in which (-) ssDNA and U3-U5 copy numbers were
      indistinguishable. OBJECTIVES: To investigate the reasons for the discrepancy in
      first strand transfer efficiency between intact cell-free virus and the infection
      process. STUDY DESIGN: Alterations of both NERT reactions and the conditions of
      cell infection were used to test whether uncoating and/or entry play a role in
      the discrepancy in first strand transfer efficiency. RESULTS AND CONCLUSIONS: The
      difference in 1stST efficiency could not be attributed simply to viral uncoating,
      since addition of very low concentrations of detergent to NERT reactions removed
      the viral envelope without disrupting the reverse transcription complex, and
      these conditions resulted in no improvement in 1stST efficiency. Virus
      pseudotyped with surface glycoproteins from either vesicular stomatitis virus or
      amphotrophic murine leukaemia virus also showed low levels of 1stST in low
      detergent NERT assays and equivalent levels of (-) ssDNA and 1stST in single
      round infections of cells, demonstrating that the gp120-mediated infection
      process did not select for virions capable of carrying out 1stST. These data
      indicate that a post-entry event or factor may be involved in efficient HIV-1
      reverse transcription in vivo.

PMID- 12600655
TI  - Analysis of HIV-1 viral load in seminal plasma samples.
AB  - BACKGROUND: With HIV-1-infected individuals now facing the prospect of relatively
      long and healthy lives, many discordant couples (where the male is HIV-1
      seropositive) are seeking to have children. To assist reducing the risks of
      heterosexual and subsequent vertical transmission in this situation,
      quantification of HIV-1 viral load in seminal plasma may be effective as one of
      several measures to reduce the risk of infecting the mother during insemination,
      potentially providing a better indication of infectivity than blood plasma
      analysis. OBJECTIVE(S): To modify existing molecular methods for the purpose of
      analysing HIV-1 viral load in seminal plasma. METHODS: Two commercial assays for
      HIV-1 RNA quantification were used to assess their sensitivity, specificity and
      precision for quantification of seminal plasma samples. Seminal plasma samples
      were prepared with an additional centrifugation step to aid removal of inhibitors
      to molecular assays. RESULTS: Seminal plasma samples exhibited specificity of
      >95%, equivalent to that reported by the manufacturers of the commercial assays.
      With additional centrifugation, complete inhibition of 2/19 (10%) seminal plasma
      samples was observed using the RT-PCR assay, and inhibition was not apparent in
      the bDNA assay. Quantification of HIV-1 RNA in seminal plasma samples in both
      assays was equivalent to that observed in plasma samples and did not appear to be
      affected by the additional centrifugation step. CONCLUSION: Minor modification of
      the RT-PCR assay procedure by additional centrifugation of seminal plasma
      improved the sensitivity of the assay. Inhibition was not apparent with the bDNA
      assay.

PMID- 12600656
TI  - Defective phagocytosis by human monocyte/macrophages following HIV-1 infection:
      underlying mechanisms and modulation by adjunctive cytokine therapy.
AB  - Defective immunological function of cells of the macrophage lineage contributes
      considerably to the pathogenesis of HIV-1 infection. Impairment of phagocytosis
      of opportunistic pathogens such as Mycobacterium avium complex (MAC),
      Pneumocystis carinii, Toxoplasma gondii or Candida albicans by peripheral blood
      monocytes, tissue macrophages and monocyte-derived macrophages following in vivo
      and in vitro HIV-1 infection is well documented. The development of opportunistic
      infections due to these pathogens in HIV-infected individuals at late stages of
      disease is attributed to defective monocyte/macrophage function. The mechanisms
      whereby HIV-1 impairs phagocytosis are not well known. A number of phagocytic
      receptors normally mediate engulfment of specific opportunistic pathogens by
      cells of macrophage lineage; distinct mechanisms are triggered by pathogen
      receptor binding to promote cytoskeletal rearrangements and engulfment. This
      review focuses on the signalling events occurring during Fcgamma receptor- and
      complement receptor-mediated phagocytosis, and considers the mechanisms by which
      HIV-1 inhibits those signalling events. Since macrophage function is enhanced by
      cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and
      interferon-gamma (IFN-gamma), the use of these immunomodulators is of potential
      interest as adjunctive immunotherapy in immunosuppressed individuals. In this
      review we present examples of clinical applications of GM-CSF and IFN-gamma
      therapy for the treatment of opportunistic infections in HIV-infected individuals
      receiving antiretroviral drugs.

PMID- 12600657
TI  - Photosensitive neurons in mollusks.
AB  - In addition to regular photoreceptors, some invertebrates possess simple
      extraocular photoreceptors. For example, the central ganglia of mollusks contain
      photosensitive neurons. These neurons are located on the dorsal surface of the
      ganglia and based on their electrophysiological properties, it has been
      postulated that they are the internal photoreceptors. However, besides the eye,
      transduction of the light also occurs in these extra-ocular photoreceptors. In
      the present work, we analyse the reactivity of these nerve cells to light and
      describe the underlying mechanism mediating the light-induced response.

PMID- 12600658
TI  - The effect of transdermal corticosterone application on plasma corticosterone
      levels in pregnant Lacerta vivipara.
AB  - Relationships between hormones and behaviour can be explored by altering
      endogenous hormone levels, often through implantation of silastic tubing or
      osmotic pumps filled with a hormone or its agonists or antagonists. However,
      organisms in sensitive life-history stages (such as pregnancy) may be adversely
      affected by the surgical procedures associated with these manipulations,
      necessitating use of non-invasive techniques. We demonstrate that the application
      of a sesame oil-corticosterone mixture to the skin of pregnant female common
      lizards (Lacerta vivipara) elevates plasma levels of the hormone. Pregnant female
      L. vivipara were captured and treated daily for 1-20 days with the sesame oil
      corticosterone mixture (experimental group) or with vehicle only (control group).
      Blood samples were collected and analyzed for corticosterone by radioimmunoassay.
      Baseline plasma corticosterone levels were elevated within 1 h in the
      experimental group. Similar levels ( approximately 145 ng/ml) were found over the
      subsequent 2 days, and by day 5 had risen significantly higher ( approximately
      281.9 ng/ml), where they remained for the duration of the experiment. These
      increases are comparable to those found in other species using related
      techniques. No significant changes in plasma corticosterone levels occurred in
      the control group. Finally, corticosterone levels also were determined for
      untreated females that were captured, held overnight, sampled, and released to
      access to the natural range of basal corticosterone levels. Basal plasma levels
      of corticosterone in pregnant females varied among individuals independently of
      female body size or corpulence.

PMID- 12600659
TI  - Differential cytoplasmic and whole cellular expression of histone H1 within the
      avian bursa of Fabricius.
AB  - Bursal anti-steroidogenic peptide (BASP), purified from the chicken bursa of
      Fabricius (BF), has been previously demonstrated to be a potent and efficacious
      inhibitor of steroid hormone biosynthesis from chicken ovarian, and both
      mammalian and avian adrenal cells in vitro. Other studies have demonstrated that
      BASP can markedly reduce avian and mammalian mitogen-stimulated lymphocyte
      proliferation. Recent studies have indicated that BASP has a structural and
      functional relationship with histone H1. Immunohistochemical studies using a
      monoclonal antibody, which is known to recognize a common histone H1 epitope from
      several plant and animal species identified the protein within the cytoplasm and
      nucleus of distinct cells within both the cortex and medulla of all BF follicles.
      Additionally, epithelial cells within the BF expressed the protein strongly in
      the cytoplasm with reduced nuclear staining. In contrast, the same antibody did
      not recognize the protein in thymus of the same animals. The differential
      expression of histone H1 immunoreactivity within selected cells of the BF may
      support a previous proposed role of histone H1 in extranuclear and extracellular
      signaling in chickens and possibly other species.

PMID- 12600660
TI  - Variation in cottonmouth (Agkistrodon piscivorus leucostoma) resting metabolic
      rates.
AB  - The study of intra- and inter-individual variation in the metabolic response to
      environmental variation can provide mechanistic explanations to large-scale
      ecological and evolutionary patterns. In a study of range-limiting factors,
      variation in resting metabolic rates of cottonmouths (Agkistrodon piscivorus
      leucostoma) was investigated along a latitudinal gradient in southern populations
      and in populations near and at the northern range limit. CO(2) production rates
      of 53 snakes were measured in response to body mass, temperature, time of day,
      latitude of origin, and sex. The within-subjects effects were similar to those
      reported for other pit vipers. Metabolic cold adaptation appears to exist, with
      cottonmouths from northern populations having higher low temperature metabolic
      rates. Calculations suggest that Arkansas cottonmouths allocate almost twice as
      much energy to resting metabolism during non-feeding periods (brumation) as
      Louisiana cottonmouths. While maintenance metabolism alone during brumation is
      more costly near the northern range limit, it is most likely not a limiting
      factor in geographic distribution and may be used to fuel important processes
      other than activity metabolism.

PMID- 12600661
TI  - Comparative ionic flux and gill mucous cell histochemistry: effects of salinity
      and disease status in Atlantic salmon (Salmo salar L.).
AB  - Two experiments were conducted to assess the physiological effects of freshwater
      exposure and amoebic gill disease (AGD) in marine Atlantic salmon (Salmo salar
      L.). The first experiment monitored marine salmon during a 3 h freshwater
      exposure, the standard treatment for AGD in Tasmania. The second experiment
      described the gill mucous cell histochemistry for freshwater adapted and seawater
      acclimated fish (AGD affected and unaffected) for possible correlations to
      ionoregulation. When exposed to freshwater, marine Atlantic salmon experienced a
      minor ionoregulatory dysfunction represented by a net efflux of Cl(-) ions at 3
      h. AGD affected fish experienced the net efflux of Cl(-) ions 1 h sooner, and had
      a significantly greater net efflux of total ammonia. Changes to gill mucous cell
      populations corresponded to differing salinity and the presence of AGD. In AGD
      affected fish, these populations significantly differed between lesion and non
      lesion associated areas of the gill filament. Our results have shown changes in
      the ionoregulatory capacity of Atlantic salmon due to freshwater exposure and
      AGD. Gill mucous cell histochemistry indicates the potential importance of the
      mucous layer in ionoregulation and disease. In comparison to previous studies on
      rainbow trout, these results suggest that Atlantic salmon have a greater short
      term ionoregulatory capacity.

PMID- 12600662
TI  - Transcranial oximetry using fast near infrared spectroscopy can detect failure of
      collateral blood supply in humans.
AB  - We tested the hypothesis that transcranial oximetry by fast scanning near
      infrared spectroscopy can detect local desaturation of hemoglobin in arterial
      vessels of cerebral circulation with impaired blood supply. A total of 74 near
      infrared spectroscopy recordings were taken from the intact skull of humans.
      Perfusion of the hemisphere under the detector was assessed in one of four
      groups: (1) healthy volunteer; (2) patient, unaffected side; (3) patient,
      affected side with intact collateral blood supply; (4) patient, affected side,
      impaired collateral blood supply. Transcranial saturation was 0.90+/-0.01 (all
      values reported as mean+/-S.E.) in healthy volunteers (n=24), 0.92+/-0.008 in the
      unaffected hemisphere of patients (n=23), 0.92+/-0.001 in the affected side if
      collateral supply with blood was intact (n=16). There was no statistical
      significance between these groups. Saturation in affected hemispheres with
      impaired collateral blood supply (n=9) was 0.81+/-0.028, which was significantly
      different from all other groups (P<0.05, one way-ANOVA). We conclude, that
      transcranial pulse oximetry can detect local hypoxia if collateral blood supply
      fails.

PMID- 12600664
TI  - Composition and properties of the soluble organic matrix of the otolith of a
      marine fish: Gadus morhua Linne, 1758 (Teleostei, Gadidae).
AB  - The soluble matrix of the sagittal otolith of the cod Gadus morhua was analyzed
      using UV and IR spectroscopy, liquid chromatography and electrophoresis. This
      matrix is a complex mixture of proteins and glycoproteins, with a large range of
      molecular weights. High weights (>1000 kDa) are shown for the first time in water
      soluble matrix of otolith. However, the 2D denaturing electrophoresis and large
      range of sorting used in high performance liquid chromatography columns do not
      separate the soluble matrix to well-defined molecular weights. The IR data
      indicate that several conformations are present and the main part of the sugars
      is not sulfated. Additionally, electrophoresis data show that the acidity of the
      sugar components is higher than that of the proteins. Despite the relative
      scarcity of literature data, our study of G. morhua suggests that the chemical
      composition of otolith soluble organic matrix may differ among species.

PMID- 12600663
TI  - Effects of neonatal clomiphene citrate on fertility and sexual behavior in male
      rats.
AB  - In order to investigate the participation of estrogen during the period of brain
      sexual differentiation, male rats were treated with clomiphene citrate in the
      neonatal phase. Fertility and sexual behavior were assessed during adult life.
      Sexual maturation, body weight, and wet weight of the testes were unchanged.
      Although the adult male rats treated with clomiphene in the neonatal phase
      presented a significant reduction in the frequency of mounts, 90% of these rats
      were able to mate with normal females, which became pregnant. However, these
      females exhibited a significantly increased number of pre- and post-implantation
      losses. When these adult male rats were castrated and received estrogen, 60%
      presented female sexual behavior (receptive behavior and acceptance of mount).
      Thus, treatment of pups with clomiphene immediately after birth has a long-term
      effect on the reproductive physiology and sexual behavior of male rats.

PMID- 12600666
TI  - Hibernation reduces pancreatic amylase levels in ground squirrels.
AB  - Pancreatic enzyme levels in mammals are influenced by food intake and dietary
      composition. In this study, we examined the activity and expression of pancreatic
      amylase in a hibernating mammal, a natural model for long-term fasting.
      Pancreatic tissues were obtained from summer-active 13-lined ground squirrels and
      hibernating squirrels that had not eaten for at least 6 weeks. Amylase specific
      activity was reduced by approximately 50% in the torpid hibernators compared with
      summer squirrels, and immunoblot analysis revealed that amylase protein
      expression was reduced by approximately 40% in the hibernators. Similar
      reductions in amylase specific activity were observed in interbout euthermic
      hibernators. These results support a strong influence of food intake on
      pancreatic enzyme expression in hibernating mammals. The maintenance of basal
      levels of this key digestive enzyme at approximately 50% of summer values despite
      the extended winter fast likely facilitates the rapid resumption of digestive
      function after terminal arousal in the spring.

PMID- 12600665
TI  - Circadian rhythms of body temperature and liver function in fed and food-deprived
      goats.
AB  - Daily rhythms of body core temperature and liver function were recorded in goats
      maintained under various schedules of lighting and feeding. Concentration of urea
      in the blood was used as an index of digestion-driven hepatic activity, whereas
      concentration of cholesterol served as an index of autonomous hepatic activity.
      Body temperature exhibited robust circadian rhythmicity in the presence and
      absence of a light-dark cycle and/or a feeding regime. The rhythm was more
      responsive to shifts in feeding time than to shifts in the light-dark cycle. Urea
      concentration in the blood exhibited daily rhythmicity only in the presence of a
      daily feeding regime and, therefore, was driven by ingestive and digestive
      processes. The rhythm of cholesterol concentration persisted in the presence or
      absence of a light-dark cycle and/or a feeding regime, except when the feeding
      time was shifted under constant light. However, the cholesterol rhythm did not
      respond either to shifts in the light-dark cycle or, more importantly, to shifts
      in feeding time. Thus, based on this index of hepatic function, the liver cannot
      be identified as the site of the putative food-entrainable pacemaker.

PMID- 12600667
TI  - Free amino acids in the clam Macoma balthica L. (Bivalvia, Mollusca) from
      brackish waters of the southern Baltic Sea.
AB  - Fourteen acidic and neutral free amino acids (FAA) were investigated in soft
      tissue of Macoma balthica from different depth zones of the Gulf of Gdansk
      (Baltic Sea) over a full seasonal cycle. The dry weight of the bivalves and
      physico-chemical parameters of overlying bottom water and surface sediments were
      measured simultaneously at each site. In the brackish waters of the Baltic, the
      main pool of FAA is composed of Ala, Gln, Arg, Gly and Orn which represent
      approximately 80% of the total. Compared to the full saline environments, the
      composition of FAA in the clams from the Baltic differs substantially. The
      differences can be attributed to the lower salinity of the Baltic. In the Baltic,
      Gly appears to play a most important role in regulating intracellular osmolarity
      in the clams, a function performed primarily by Tau in Atlantic and North Sea
      populations. Spatio-temporal variations of the FAA are affected by biotic and
      environmental parameters; their respective influence differs with the amino
      acids. The concentration of Arg depends on its uptake from the external medium.
      However, its level might be temporarily modified by stress-induced metabolic
      transformation (e.g. hydrolysis to Orn) caused by changes in the ambient
      environment. The concentration of Ala increases with depth, probably because of
      physiological adaptations of the animal to diminishing oxygen concentration
      through anaerobic glucose catabolism. Biosynthesis of Ala, similarly to Gln, in
      the shallower zone is generally related to the physiological state of an
      organism. The concentration of Gly is most likely regulated by internal
      mechanisms driven by gonadal development and reproduction.

PMID- 12600668
TI  - Functional voltage-gated Ca2+ channels in muscle fibers of the platyhelminth
      Dugesia tigrina.
AB  - The presence and function of voltage-gated Ca(2+) channels were examined in
      individual muscle fibers freshly dispersed from the triclad turbellarian Dugesia
      tigrina. Individual muscle fibers contracted in response to elevated
      extracellular K(+) in a concentration-dependent fashion. These depolarization
      induced contractions were blocked by extracellular Co(2+) (2.5 mM), suggesting
      that they were dependent on depolarization-induced Ca(2+) influx across the
      sarcolemma. A voltage-gated inward current was apparent in whole cell recordings
      when the outward K(+) current was abolished by replacement of intracellular K(+)
      by Cs(+). This inward current was amplified with increasing concentration (</=10
      mM) of extracellular Ba(2+) and was independent of extracellular Na(+)
      concentration suggesting the current was mediated by voltage-gated Ca(2+)
      channels. Further, and supporting the hypothesis that the inward current was
      mediated by these Ca(2+) channels, the Ba(2+) current was blocked by
      extracellular Co(2+) (2.5 mM) but not by tetrodotoxin (5 microM). Action
      potentials were generated by the muscle fibers in the presence of, but not in the
      absence of, extracellular Ba(2+) (5 mM). These data are the first clear
      demonstration of a voltage-gated Ca(2+) channel current in platyhelminth muscle,
      and they demonstrate a role for Ca(2+) influx in depolarization-induced
      contractions of muscle in these organisms.

PMID- 12600669
TI  - Influence of gender on ethanol-induced ventricular myocyte contractile depression
      in transgenic mice with cardiac overexpression of alcohol dehydrogenase.
AB  - Acute ethanol exposure depresses ventricular contractility and contributes to
      alcoholic cardiomyopathy in both men and women chronically consuming ethanol.
      However, a gender-related difference in the severity of myopathy exists with
      female being more sensitive to ethanol-induced tissue damage. Acetaldehyde (ACA),
      the major oxidized product of ethanol, has been implicated to play a role in the
      pathogenesis and gender-related difference of alcoholic cardiomyopathy, possibly
      due to its direct cardiac effect and interaction with estrogen. This study was
      designed to compare the effects of cardiac overexpression of alcohol
      dehydrogenase (ADH), which converts ethanol into ACA, on the cardiac contractile
      response to ethanol in ventricular myocytes isolated from age-matched adult male
      and female transgenic (ADH) and wild-type (FVB) mice. Mechanical properties were
      measured with an IonOptix SoftEdge system. ACA production was assessed by gas
      chromatography. The ADH myocytes from both genders exhibited similar mechanical
      properties but a higher efficacy to produce ACA compared to FVB myocytes.
      Exposure to ethanol (80-640 mg/dl) for 60 min elicited concentration-dependent
      decrease of cell shortening in both FVB and ADH groups. The ethanol-induced
      depression on cell shortening was significantly augmented in female but not male
      ADH group. ADH transgene did not exacerbate the ethanol-induced inhibition of
      maximal velocity of shortening/relengthening in either gender. In addition,
      neither ethanol nor ADH transgene affect the duration of shortening and
      relengthening in male or female mice. These data suggest that females may be more
      sensitive to ACA-induced cardiac contractile depression than male, which may
      attribute to the gender-related difference of alcoholic cardiomyopathy.

PMID- 12600670
TI  - Carp (Cyprinus carpio) vitellogenin: purification and development of a
      simultaneous chemiluminescent immunoassay.
AB  - Vitellogenin (Vg) was purified from the serum of vitellogenic female carp
      (Cyprinus carpio) by hydroxylapatite column chromatography and gel filtration. Vg
      had an apparent molecular mass of 490 kDa and appeared as two bands corresponding
      to 190 and 156 kDa after SDS-PAGE under reducing conditions. These bands were
      immunoreacted in Western blotting using antiserum against carp lipovitellin (anti
      Lv) which is an egg yolk protein derived from Vg. The amino acid composition of
      carp Vg was similar to previous reports of cyprinids. The chemiluminescent
      immunoassay (CLIA) for carp Vg was developed to quantify serum Vg using purified
      carp Vg and anti-Lv. Its measurable range was from 1.95 to 1000 ng/ml. The
      dilution curve in the CLIA of vitellogenic female serum was parallel to the
      standard curve of purified Vg. The coefficient variations of intra- and inter
      assay were less than 5%, respectively. Furthermore, the assay had cross
      reactivity with the sera of other female cyprinids (crucian carp and Japanese
      dace). In fish diets-experiments, Vg was detected in all fish in the fish meal
      containing soybean (20%) group, but was not detected in almost all of the fish in
      the fish meal-group. This suggests that a soybean based-diet may induce Vg
      production in the serum of cultivated carp.

PMID- 12600671
TI  - High beta-hydroxybutyrate concentration in liver and skeletal muscle of newly
      hatched chicks.
AB  - Characteristic changes in ketone body concentrations in blood, liver, and
      skeletal muscle were investigated in detail in newly hatched chicks. The
      concentration of beta-hydroxybutyrate in the blood was maximal at hatch (0 day),
      markedly decreased to 3 days, then maintained at low levels, up to 14 days of
      age. The concentration of acetoacetate in blood, on the other hand, did not
      change after hatching but remained lower than that of beta-hydroxybutyrate at all
      ages. In liver and muscles, the concentration of beta-hydroxybutyrate changed in
      a manner similar to that in the blood. The muscle to blood ratio of the beta
      hydroxybutyrate concentration on days -1 and 0 was significantly higher than
      those at 1 through 14 days post-hatch. These results show that newly hatched
      chicks have the same high ketone body concentrations in the skeletal muscle,
      blood and liver. It is, hence, suggested that uptake of beta-hydroxybutyrate by
      muscles is substantial or that ketogenesis, if any, occurs in muscles immediately
      before and after hatching of chicks.

PMID- 12600672
TI  - Asparagine-linked oligosaccharide-independent secretion of egg envelope
      glycoprotein ZPC of the Japanese quail (Coturnix japonica).
AB  - In avian species, a glycoprotein homologous to mammalian ZPC is synthesized in
      the granulosa cells of developing follicles. We have previously reported that the
      newly synthesized ZPC (proZPC) in the granulosa cells is cleaved at the consensus
      furin cleavage site to generate mature ZPC prior to secretion. In the present
      study, we examined the role of asparagine (N)-linked oligosaccharides in the
      proteolytic processing of proZPC and the subsequent secretion of ZPC by using
      site-directed mutagenesis of the consensus sequence for N-glycosylation, and
      tunicamycin, an inhibitor for N-glycosylation of glycoprotein. Western blot
      analysis demonstrated that tunicamycin did not block either proteolytic cleavage
      of proZPC or the subsequent ZPC secretion. Moreover, a site-directed mutant that
      possesses a mutated sequence for N-glycosylation was efficiently secreted from
      the cells. These results indicate that proteolytic cleavage of proZPC, and the
      subsequent ZPC secretion occur in the absence of N-linked oligosaccharides.
      Therefore, the addition of N-glycans to ZPC polypeptide is not required for quail
      ZPC secretion.

PMID- 12600673
TI  - Enhanced expression of beta-thymosin mRNA in the ovary of GnRH analog or
      estradiol-17beta-treated paradise fish, Macropodus opercularis.
AB  - cDNA clones were isolated as expressed sequence tags (ESTs) from the ovarian cDNA
      library of Macropodus opercularis. The EST sequences showed similarity with many
      housekeeping genes and ribosomal proteins. One of the ESTs showed similarity to
      beta-thymosin, a 5-kDa polypeptide expressed under different physiological
      conditions. The cDNA corresponding to beta-thymosin of M. opercularis is 368 bp
      in length and codes for a putative polypeptide of 42 amino acids. Multiple
      alignment of the deduced amino acid sequence showed 61% similarity with piscine
      beta-thymosins and 56% similarity with mammalian beta-thymosins. Administration
      of a gonadotropin releasing hormone analog or estradiol-17beta induced an
      increase in the gonadosomatic index, oocyte diameter and also enhanced expression
      of beta-thymosin m-RNA in the recrudizing ovary. This report indicates that both
      GnRH analog and E(2) might induce similar pathways for the differentiation of
      ovarian cells for the maturation of oocytes.

PMID- 12600674
TI  - Effects of potassium deficiency on potassium, polyamines and amino acids in mouse
      tissues.
AB  - Sexual dimorphism in potassium content was found in plasma, kidney, heart and
      skeletal muscle of CD1 mice. We observed that feeding mice with a K(+)-deficient
      diet had an uneven and gender-dependent effect on organ weight and tissue
      potassium concentrations. Treatment produced a marked decrease in plasma,
      pancreas and skeletal muscle K(+) levels in both sexes, and a reduction in
      kidney, liver and heart potassium concentrations in females. Moreover, K(+)
      deficiency produced a 2-3-fold increase in the concentrations of cationic amino
      acids, such as arginine and lysine in both heart and skeletal muscle of the two
      sexes, a slight increase ( approximately 37%) in renal arginine in the male mice.
      The concentrations of these amino acids in plasma and other tissues in both sexes
      remained unaltered. Polyamine levels in heart, liver, skeletal muscle and
      pancreas from male and female mice were not affected by K(+) deficiency. However,
      in the male kidney potassium deficiency was accompanied by an increase of
      putrescine and spermidine concentration, and a reduction of putrescine excretion
      into the urine, even though renal K(+) concentration was not significantly
      affected and ornithine decarboxylase activity was dramatically decreased. The
      general lack of correlation between tissue potassium decrease and the increase in
      organic cations suggests that it is unlikely that the changes observed could be
      related with an attempt of the tissues to compensate for the reduction in
      cellular positive charge produced by the fall in K(+) content. The mechanisms by
      which these changes are produced are discussed, but their physiological
      implications remain to be determined.

PMID- 12600675
TI  - The effects of stress on the association between hsp70 and the glucocorticoid
      receptor in rainbow trout.
AB  - The purpose of this study was to characterize the association between hepatic
      heat shock protein 70 (hsp70) and the glucocorticoid receptor in rainbow trout
      that were exposed to heat stress, cortisol, and beta-naphthoflavone. This study
      is the first to document that the glucocorticoid receptor complex in rainbow
      trout hepatic tissues contains hsp70. Heat stress significantly increased levels
      of total cellular hsp70, and by discerning the association of hsp70 with the
      glucocorticoid receptor, we demonstrated that heat stress significantly increased
      the amount of hsp70 not bound to the glucocorticoid receptor, while significantly
      decreasing the amount of hsp70 bound to the glucocorticoid receptor. By
      calculating the ratio of hsp70 bound to the glucocorticoid receptor, to the total
      number of glucocorticoid receptors, stress (heat stress and cortisol-treatment)
      promoted the association of hsp70 with the glucocorticoid receptor. These
      findings demonstrate a functional and structural link between hsp70 and the
      glucocorticoid receptor in rainbow trout, and raise questions regarding the
      existence of a complex, interrelated stress response that spans all levels of
      biological organization within the whole animal.

PMID- 12600676
TI  - Hepatocyte ploidy in normal young rat.
AB  - The aim of the present study was to examine the relation between hepatocyte size
      and ploidy in Sprague-Dawley rat liver. Therefore, subpopulations of hepatocytes
      of various sizes were separated from the isolated crude hepatocyte population
      either mechanically or by using centrifugal elutriation. Hepatocyte size was
      determined on scanning electron microscopy photographs. Ploidy of hepatocytes was
      assessed by flow cytometry. The crude hepatocyte population was very
      heterogeneous in sizes, with diameters ranging from 8 to 39 microm. Hepatocyte
      ultrastructure was well preserved as demonstrated by transmission electron
      microscopy. The distribution of hepatocytes within the ploidy classes was the
      following: 19.6+/-3.6% diploid, 56.2+/-3.2% tetraploid and 3.4+/-0.6% octoploid
      mononucleated cells. Thus approximately 79% of hepatocytes appeared
      mononucleated. The binucleated hepatocytes (21%) had two diploid nuclei (18.7+/
      2.9%) or two tetraploid nuclei (2.1+/-0.6%). A similar distribution of
      hepatocytes into ploidy classes was obtained in subpopulations of hepatocytes of
      various sizes. Our findings suggest that distribution into ploidy classes is not
      strictly correlated with hepatocyte size. In accordance with previous
      observations, our results on hepatocyte ploidy from periportal or perivenous
      origin using digitonin perfusion, is in favour of the existence of ploidy
      zonation within the rat hepatic lobule.

PMID- 12600677
TI  - Effect of GABAergic blockade on light responses of frog retinal ganglion cells.
AB  - The effect of GABAergic blockade by picrotoxin on ganglion cells (GC) activity
      was investigated in perfused dark adapted eyecups of frog (Rana ridibunda). PT
      had diverse effects on the light responses of GC in contrast to its uniform
      potentiating effect on the amplitude of the ERG b- and d-wave. In some (n=32) of
      PT-sensitive ON-OFF GC the ON and OFF responses were changed in a similar manner
      (both responses were potentiated or both were inhibited), but in the other (n=10)
      the both responses were changed in a different manner. PT influenced
      differentially the activity of OFF GC (n=17) as well. It not only potentiated or
      inhibited their light responses, but changed also the temporal characteristics of
      the responses. Some tonic cells became phasic ones and in some phasic cells a
      late component appeared under the influence of PT. In some cases (n=4) the
      GABAergic blockade changed the apparent cell's type, because of appearance of a
      new type of response (ON or OFF) non-existing before the blockade. Our results
      indicate that the GABAergic interneurons are involved in different networks in
      the inner plexiform layer of frog retina.

PMID- 12600678
TI  - Sex alteration in soft-shell clams (Mya arenaria) in an intertidal zone of the
      Saint Lawrence river (Quebec, Canada).
AB  - The purpose of this study was to verify whether any changes in sex ratio might
      occur in soft-shell clams (Mya arenaria) located in an intertidal harbor zone
      located at the mouth of the Saguenay Fjord in the Saint Lawrence estuary (Baie
      Sainte-Catherine (BSC), Quebec, Canada) likely to be contaminated by organotin
      compounds. Bivalves were harvested at the BSC harbor site and from two reference
      sites. Condition index (weight to length ratio), gonado-somatic index, sex ratio,
      vitellin-like proteins, organotin concentrations in gonad tissue, maturation
      stages of the gonads, the number of estradiol-17beta binding sites and the
      capacity of female gonad extracts to produce estradiol-17beta were determined in
      collected animals. Results showed that sex ratio in clams was significantly
      skewed toward males. Moreover, the condition and gonad-somatic indices, vitellin
      like proteins in female gonads and the capacity of female gonads to produce
      estradiol-17beta were significantly reduced at the harbor site with respect to
      the reference sites. Maturation status of male gonads was clearly delayed at the
      harbor site. Additionally, gonad tissue contained tributyltin (TBT) at an average
      level of 109+/-18 ngSn/gdry wt. at the harbor site while organotins were not
      detected from the reference sites. Finally, female gonads had a higher number of
      unoccupied estradiol binding sites at the harbor site indicating low levels of
      this steroid in this tissue. Overall, this paper is first to report that clams
      collected in the vicinity of a TBT contaminated harbor are subject to
      masculinizing effects which seems to be consistent with biological effects that
      organotins are known to exert toward some other marine invertebrates.

PMID- 12600680
TI  - Quantitative determination of creatine kinase release from herring (Clupea
      harengus) spermatozoa induced by tributyltin.
AB  - Creatine kinase (CK, ATP creatine phosphotransferase, EC 2.7.3.2) is an enzyme
      participating in ATP regeneration, which is the primary source of energy in
      living organisms. We demonstrated that CK from herring spermatozoa has high
      activity ( approximately 452 micromol/min/g of fresh semen) and has a different
      electrophoretic mobility from isoenzymes present in skeletal muscle. In our
      study, we investigated toxic effect of tributyltin (TBT) on herring spermatozoa
      using a specific sperm viability kit to observe live and dead sperm cells with a
      confocal microscope. Treatment of herring spermatozoa with TBT caused a time
      dependent decrease of viability: 35% nonviable cells with 5 microM TBT and more
      than 90% nonviable cells with 10 microM TBT after 6 h exposure. We also monitored
      CK release from damaged spermatozoa into surrounding medium containing different
      concentrations of TBT. The higher concentration of TBT was used the more CK
      release from spermatozoa was observed. We suggest that CK could be a good
      biomarker of sperm cell membranes degradation in the case when lactate
      dehydrogenase release from permeabilized cells is not possible for rapid
      determination of the effect of TBT.

PMID- 12600679
TI  - Mitochondrial, sarcoplasmic membrane integrity and protein degradation in heart
      and skeletal muscle in exercised rats.
AB  - Several different exercise regimens varied in the severity of tissue damage
      induced. Therefore, this study investigated the effects of a single bout of
      exercise versus endurance training in heart and skeletal muscles with different
      predominant fiber types on indices of mitochondrial, endoplasmic reticulum (ER)
      integrity and protein degradation. Male Wistar rats performed different treadmill
      exercise protocols: exhaustive, maximal exhaustive, eccentric, training and
      exhaustive exercise after training. The maximal and eccentric exercises resulted
      in a significant loss of integrity of the sarcoplasmic and ER muscle, while no
      changes were observed in cardiac muscle. Mitochondrial membrane fluidity measured
      by the fluorescence polarization method was significantly increased post-acute
      exercises in heart and oxidative muscles. Regular exercise can stabilize and
      preserve the viscoelastic nature of mitochondrial membranes in both tissues. The
      highest increase in carbonyl content was obtained in heart after exhaustive
      exercise protocol, from 1+/-0.1 to 3.6+/-0.14 nmol mg protein(-1), such increase
      were not found after regular exercise with values significantly decreased.
      Nitrate heart levels showed attenuated generation of nitric oxide after training.
      Muscle protein oxidation was produced in all exhaustive exercises including
      eccentric exercise.

PMID- 12600682
TI  - Cadmium-dependent generation of reactive oxygen species and mitochondrial DNA
      breaks in photosynthetic and non-photosynthetic strains of Euglena gracilis.
AB  - The photosynthetic strain Z of Euglena gracilis is more susceptible to cadmium
      chloride (Cd) than the non-photosynthetic strain SMZ. We investigated the
      correlation of intracellular reactive oxygen species (ROS) levels with Cd-induced
      cellular damage. Flow cytometry with dihydrorhodamine 123 showed that strain Z
      generated higher levels of ROS, probably H(2)O(2) and/or ONOO(-), than strain
      SMZ, and that this difference between the two strains became more pronounced with
      increasing Cd dose. The levels of ROS increased at cytotoxic concentrations of
      Cd, at over 10 microM Cd for Z and 50 microM Cd for SMZ. These results show an
      association of Cd cytotoxicity with ROS generation. Considering that strain SMZ
      is non-photosynthetic, the higher levels of ROS in strain Z might be due to
      blockage of photosynthetic electron flow by Cd. Using terminal
      deoxyribonucleotidyl transferase-mediated dUTP nick end-labeling analysis in
      combination with 4',6-diamidino-2-phenylindole, dihydrochloride staining, we
      observed DNA breaks in the mitochondria of both strains after Cd exposure. The
      results suggest that the mitochondrion is the primary target organelle of Cd in
      E. gracilis cells.

PMID- 12600681
TI  - Role of aromatase and androgen receptor expression in gonadal sex differentiation
      of ZW/ZZ-type frogs, Rana rugosa.
AB  - To elucidate the mechanisms of amphibian gonadal sex differentiation, we examined
      the expression of aromatase and androgen receptor (AR) mRNAs for days 17-31 after
      fertilization. The effects of inhibitors and sex steroid hormones were also
      examined. In ZZ males, expression of AR decreased after day 19, while aromatase
      expression was low throughout the sampling period. Males treated with 17beta
      estradiol (E2) showed increasing aromatase expression after day 21, and formed
      ovaries. AR antagonist treatment also induced high-level aromatase expression and
      ovarian differentiation. In males co-treated with an aromatase inhibitor and E2,
      the undifferentiated gonads developed into testes despite high-level aromatase
      expression. Males treated with androgen and E2 before and during an estrogen
      sensitive period, respectively, also formed testes. In ZW females, AR expression
      persisted at a low-level, while aromatase expression increased after day 18.
      Short-term treatment with an aromatase inhibitor was ineffective in preventing
      ovarian differentiation, whereas long-term treatment resulted in testes
      developing from ovarian structure. Compared with the ZZ males and ZW females, WW
      females did not exhibit detectable expression of AR, suggesting that the active
      AR gene(s) itself, or a putative gene regulating AR gene expression, is located
      on Z chromosomes. From the time lag of aromatase expression between ZW females
      and ZZ males treated with E2 and the effect of AR antagonist, it was found that
      in males elevated AR expression suppresses aromatase expression directly or
      indirectly. Consequently, endogenous androgens, accumulated by blocking estrogen
      biosynthesis, induced testicular differentiation. The gonadogenesis of males is
      dependent on sex hormone, whereas that of females has evolved to hormone
      independence.

PMID- 12600683
TI  - Isolation of pisumin, a novel antifungal protein from legumes of the sugar snap
      pea Pisum sativum var macrocarpon.
AB  - An antifungal protein with a novel N-terminal sequence GVGAAYGCFG and a molecular
      mass of 31 kDa was isolated from the legumes of the sugar snap pea Pisum sativum
      var. macrocarpon. The protein, designated pisumin, exhibited antifungal activity
      against Coprinus comatus and Pleurotus ostreatus and much weaker activity against
      Fusarium oxysporum and Rhizoctonia solani. Pisumin inhibited cell-free
      translation in a rabbit reticulocyte lysate system with an IC(50) of 6 microM.
      Pisumin was similar to other leguminous antifungal proteins in that it was
      adsorbed on Affi-gel blue gel and CM-Sepharose.

PMID- 12600684
TI  - The effects of pulp mill effluent on the sex steroid binding protein in white
      sucker (Catostomus commersoni) and longnose sucker (C catostomus).
AB  - The objective of this study was to characterize the effects of pulp mill effluent
      on the properties of the sex steroid binding protein (SBP) in the plasma of white
      sucker (Catostomus commersoni) and longnose sucker (C. catostomus). SBPs which
      specifically bind estradiol and testosterone with high affinity (k(D)
      approximately 3 nM) and low capacity (B(max) approximately 73-81 nM) were
      identified in both species. Subsequent studies determined if the properties of
      the SBP in white sucker exposed to bleached kraft mill effluent (BKME) at Terrace
      Bay, ON, and in longnose sucker exposed to BKME at Grande Prairie, AB. differed
      from appropriate reference fish. There were no effects of BKME exposure on the
      binding affinity (k(D)) of the SBP in either species, but there was a significant
      increase in the binding capacity (B(max)) of longnose sucker SBP exposed to BKME.
      The livers of nai;ve white sucker exposed to effluent at Terrace Bay or a
      bleached sulfite/groundwood mill in Edmundston, NB, rapidly accumulated compounds
      of differing hydrophobicity that bound to both the white sucker and goldfish
      (Carassius auratus) SBP. Conversely, there was reduced accumulation of SBP
      ligands in the bile of effluent-exposed fish. We have demonstrated that
      constituents present within pulp mill effluent bind to both the white sucker and
      goldfish SBP, and that native species residing downstream of pulp mill effluents
      may experience modifications in the properties of their SBP.

PMID- 12600685
TI  - Comparison of ELISAs for detecting vitellogenin in the fathead minnow (Pimephales
      promelas).
AB  - Measurement of vitellogenin (VTG) concentrations in the fathead minnow
      (Pimephales promelas) is currently being considered and evaluated for screening
      of endocrine active substances. One of the proposed methods, an enzyme-linked
      immunosorbent assay (ELISA) based on VTG from carp (Cyprinus carpio), was
      recently evaluated in an inter-laboratory ring test using whole body homogenates
      from juvenile fathead minnows. The objective of the current study was to compare
      the performance of three different ELISAs for measuring fathead minnow VTG: (1) a
      heterologous carp VTG (cVTG) ELISA used in the ring test, (2) a homologous
      fathead minnow VTG (fVTG) ELISA, and (3) a hybrid ELISA with the antibody
      developed for cVTG, but using fVTG for coating the plates and preparing standard
      curves. VTG was measured in whole body homogenates from juvenile fathead minnows
      exposed to 17alpha-ethynylestradiol (EE(2); 10 ng/l) and whole body homogenates
      and plasma from adult fathead minnows exposed to 17beta-estradiol (E(2); 5 mg/kg;
      i.p.). The cVTG assay showed lower specificity for fathead minnow VTG in whole
      body homogenates and plasma from treated fish, compared to the fVTG assay. VTG
      concentrations in juvenile fathead minnow homogenates from the EE(2)-exposed
      group were approximately 50-fold higher when measured using the fVTG method
      compared to the cVTG method. Use of the homologous fVTG in the hybrid cVTG assay
      yielded VTG concentrations in the range of the fVTG assay but the low specificity
      persisted. The homologous fVTG assay is recommended to achieve accurate
      quantification of VTG levels in fathead minnows.

PMID- 12600687
TI  - Ethanol- and Fe(+2)-induced membrane lipid oxidation is not additive in
      developing chick brains.
AB  - In order to study the effects of exogenous EtOH and/or Fe(+2) on membrane lipid
      peroxidation, exogenous EtOH, FeCl(2), FeCl(2) & EtOH, NaCl and NaCl & EtOH were
      injected into fertile chicken eggs. Controls were either shams or injected with
      saline. These injections were made at 0 days or 0-2 days of development and
      tissue removed at stage 37 (11 days of development). Embryonic exposure to
      exogenous EtOH and/or Fe(+2) promoted decreased brain mass, decreased levels of
      brain membrane polyunsaturated fatty acids, elevated levels of brain lipid
      hydroperoxides, and elevated levels of Fe(+2) within embryonic brain and liver.
      These alterations were more severe in triple-injected embryos (E0-2/E11) as
      compared to single-injected embryos (E0/E11). While exogenous treatments of
      either EtOH and/or FeCl(2) promoted increased levels of endogenous brain Fe(+2),
      the effects were not additive. These observations are consistent with the
      hypothesis that embryonic exposure to exogenous EtOH and/or Fe(+2) promotes brain
      membrane lipid peroxidation.

PMID- 12600686
TI  - Identification of a novel frog RFamide and its effect on the latency of the tail
      flick response of the newt.
AB  - Neuropeptide FF, one of the mammalian PQRFamides, has been reported to affect the
      latency of the tail-flick response in rat. We intended to examine the nociceptive
      effect by the peptide PQRFamides from the comparative aspect. Using the dot
      immunoblot method with antiserum to FMRFamide as an assay system, a peptide
      (frog's nociception-related peptide, fNRP) which has the C-terminal sequence
      PQRFamide was isolated from the brain of the frog, Rana catesbeiana. The
      determined sequence, SIPNLPQRF-NH(2), is the same as that named first (frog
      growth hormone-releasing peptide-gene-related peptide-1: fGRP-RP-1, which is
      encoded in the cDNA of the fGRP precursor. Since the peptide was isolated from
      the frog brain, we tested another amphibian, the newt, which has a tail, by the
      hot beam tail-flick test. Intraperitoneal injection of fNRP significantly
      increased the latency of the pain response (tail-flick) 90 min after
      administration. The effect was blocked by simultaneous administration of 5 mM
      naloxone. The result provides evidence for the interaction of fNRP and opioid
      steps in the analgesia pathways in the newt.

PMID- 12600688
TI  - Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at
      recombinant alpha1beta2gamma2L GABA(A) receptors.
AB  - The sesquiterpene trilactone bilobalide is one of the active constituents of the
      50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning.
      Bilobalide was found to antagonise the direct action of gamma-aminobutyric acid
      (GABA) on recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors. The effect of
      bilobalide on the direct action of GABA at alpha(1)beta(2)gamma(2L) GABA(A)
      receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp
      method was evaluated and compared with the effects of the classical GABA(A)
      receptor competitive antagonist bicuculline and noncompetitive antagonist
      picrotoxinin. Bilobalide (IC(50)=4.6+/-0.5 microM) was almost as potent as
      bicuculline and pictrotoxinin (IC(50)=2.0+/-0.1 and 2.4+/-0.5 microM,
      respectively) at alpha(1)beta(2)gamma(2L) GABA(A) receptors against 40 microM
      GABA (GABA EC(50)). While bilobalide and picrotoxinin were clearly noncompetitive
      antagonists, the potency of bilobalide decreased at high GABA concentrations
      suggesting a component of competitive antagonism.

PMID- 12600689
TI  - Effects of demethylzeylasteral and celastrol on spermatogenic cell Ca2+ channels
      and progesterone-induced sperm acrosome reaction.
AB  - The male antifertility effect of a water-chloroform extract of Tripterygium
      wilfordii Hook. f. (GTW) and several monomers isolated from GTW has attracted
      worldwide interest. In the present study, the effects of two isolated monomers
      from GTW, demethylzeylasteral and celastrol, on the Ca(2+) channels in mouse
      spermatogenic cells and on the sperm acrosome reaction were investigated by whole
      cell patch-clamp recording and chlortetracycline staining methods, respectively.
      The results showed that demethylzeylasteral concentration-dependently and in a
      partially reversible manner inhibited the Ca(2+) current in spermatogenic cells
      with an IC(50) of 8.8 microg/ml. Celastrol decreased the Ca(2+) current in the
      cells time-dependently and irreversibly. The changes in the activation and
      inactivation time constants of Ca(2+) currents after application of these two
      compounds were also examined. Demethylzeylasteral increased both activation and
      inactivation time constants of Ca(2+) currents, and celastrol had no significant
      effect on them. The two compounds also inhibited significantly the sperm acrosome
      reaction initiated by progesterone. These data suggest that inhibition of Ca(2+)
      currents could be responsible for the antifertility activity of these compounds.

PMID- 12600690
TI  - Protection of cortical neurons against oxygen-glucose deprivation and N-methyl-D
      aspartate by DIDS and SITS.
AB  - The Cl(-) channel blockers, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid
      (DIDS) or 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) dose
      dependently protected against oxygen-glucose deprivation in cultured rat cortical
      neurons. DIDS or SITS attenuated oxygen-glucose deprivation-induced increases in
      extracellular glutamate concentrations and intracellular Ca(2+). DIDS or SITS
      provided moderate protection against N-methyl-D-aspartate (NMDA) toxicity and
      decreased NMDA receptor-mediated increases in intracellular Ca(2+). Whole-cell
      NMDA receptor currents were attenuated 39+/-2% and 21+/-3% by 1 mM DIDS and SITS,
      respectively. Other Cl(-) channel blockers as equipotent as DIDS and SITS did not
      decrease oxygen-glucose deprivation- or NMDA-mediated neuronal Ca(2+) influx or
      toxicity. Neurotoxicity by exogenous glutamate was not prevented by SITS and was
      exacerbated by DIDS. Reductions in oxygen-glucose deprivation-induced increases
      in intracellular Ca(2+) levels underlie neuroprotection by DIDS and SITS. This
      was a reflection of lower extracellular [glutamate], direct inhibition of Ca(2+)
      influx through postsynaptic NMDA receptors, and possibly through other protective
      properties associated with DIDS and SITS.

PMID- 12600691
TI  - Diverse effects of monensin on capacitative Ca2+ entry and release of stored Ca2+
      in vascular smooth muscle cells.
AB  - The effects of monensin, an activator of Na(+)/H(+) exchanger (NHE), on
      capacitative Ca(2+) entry (CCE) were investigated using A7r5 cells. Capacitative
      Ca(2+) entry was induced by elevation of extracellular Ca(2+) concentrations of
      A7r5 cells in which stored Ca(2+) had been depleted by previous administration of
      thapsigargin. Capacitative Ca(2+) entry was abolished by pretreatment of the
      cells with SKF-96365 (1-[beta-(3-[4-methoxyphenyl]propoxy)-4-methoxyphenethyl]-1H
      imidazole hydrochloride) but was not affected by pretreatment with verapamil.
      Monensin significantly increased capacitative Ca(2+) entry. On the other hand, 5
      hydroxytryptamine-induced inositol monophosphate accumulation and subsequent
      intracellular Ca(2+) release from its stores were significantly inhibited by
      monensin, while thapsigargin-induced Ca(2+) release was not affected by monensin.
      These results suggest that monensin has diverse actions on capacitative Ca(2+)
      entry and agonist-induced release of stored Ca(2+) in vascular smooth muscle
      cells.

PMID- 12600692
TI  - Adenosine A2A receptor antagonism increases striatal glutamate outflow in
      dopamine-denervated rats.
AB  - The objective of the work was to study, by in vivo microdialysis, the effect of
      the adenosine A(2A) receptor antagonist 7-(2-phenylethyl)-5-amino-2-(2-furyl)
      pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261) on glutamate outflow
      in the striata of unilateral 6-hydroxydopamine-infused rats. Two vertical
      microdialysis probes were implanted bilaterally in both the denervated striatum
      and in the intact striatum. Glutamate concentrations in the dialysate were
      determined by high-performance liquid chromatography (HPLC). Infusion of the
      adenosine A(2A) receptor antagonist SCH 58261 (50 nM), through the microdialysis
      fiber, significantly increased glutamate outflow from the denervated striatum
      while it decreased glutamate outflow from the intact striatum. The opposite
      effects of SCH 58261 on glutamate outflow in the intact and 6-hydroxydopamine
      lesioned striatum might be attributed to blockade of striatal adenosine A(2A)
      receptors located on either striatal indirect output pathways or glutamatergic
      terminals. These results may be relevant to our understanding of the mechanism of
      action of adenosine A(2A) receptor antagonists in Parkinson's disease.

PMID- 12600693
TI  - Increased plasma concentration and brain penetration of methamphetamine in
      behaviorally sensitized rats.
AB  - Exposure to methamphetamine causes behavioral sensitization in experimental
      animals. However, the precise mechanism of this behavioral sensitization has not
      yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic
      properties of methamphetamine in rats behaviorally sensitized to methamphetamine
      following its repeated administration (6 mg/kg, i.p., once a day for 5 days
      followed by a 21-day drug abstinence period). In the sensitized rats,
      methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly
      enhanced, suggesting the successful establishment of behavioral sensitization to
      methamphetamine. Significant increases in the concentrations of methamphetamine
      in plasma and brain dialysate, as well as the delayed disappearance of
      methamphetamine from plasma, were observed in the sensitized rats after
      intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma
      concentration ratio (Kp) of methamphetamine in lung and heart decreased in the
      sensitized rats. The renal excretion of methamphetamine, which is sensitive to
      several cations, was also decreased in the sensitized rats. Moreover, in the
      sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was
      decreased in kidney, brain and heart as measured by reverse transcriptase
      polymerase chain reaction (RT-PCR). Taken together, these results suggest that
      the behavioral outcome of sensitization to methamphetamine might, in part, be due
      to the increased levels of methamphetamine in plasma and brain extracellular
      areas, as well as an altered tissue distribution of methamphetamine associated
      with changes in the cation transport system.

PMID- 12600694
TI  - Cocaine- and amphetamine-regulated transcript peptide produces anxiety-like
      behavior in rodents.
AB  - Cocaine- and amphetamine-regulated transcript (CART) peptide (CART-(55-102)) is
      involved in the suppression of food intake. We now report that CART-(55-102) is
      involved in anxiety in rodents. Intracerebroventricularly administered CART-(55
      102) as well as intraperitoneal administration of N-methyl-beta-carboline-3
      carboxamide (FG-7142), a selective GABA(A)/benzodiazepine receptor inverse
      agonist, reduced time spent in the open arms in the elevated plus-maze task in
      mice. CART-(55-102)-induced anxiogenic-like behavior in this task was attenuated
      by widely prescribed anxiolytics such as diazepam and buspirone. Likewise, CART
      (55-102) and FG-7142 significantly reduced social interaction in mice. Both
      diazepam and buspirone significantly reversed CART-(55-102)-induced anxiogenic
      like behavior in social interaction tests. By contrast, another biologically
      active CART peptide, CART-(62-102), was without effect in the elevated plus-maze
      task in mice. Moreover, intracerebroventricular administration of CART-(55-102)
      markedly increased the firing rate of locus coeruleus neurons in single unit
      recording in anesthetized rats. As CART-(55-102) produced anxiety-like effects in
      rodents, this peptide may possibly be involved in anxiety and stress-related
      behavior.

PMID- 12600695
TI  - Acute effects of antipsychotic drugs on cardiovascular responses to stress.
AB  - The effect of acute treatment with clozapine, risperidone and haloperidol on
      cardiovascular response to open field novelty stress was investigated in rats
      using radio-telemetry and video-tracking analysis. Pretreatment with clozapine
      dose-dependently inhibited the pressor response, tachycardia and increase in
      dP/dt and caused a marked reduction of exploratory locomotor activity. Similar
      effects were observed after risperidone treatment. Haloperidol treatment markedly
      reduced locomotor activity but its cardiovascular effects were limited to a more
      rapid return of heart rate towards baseline levels. These data suggest that
      particularly the atypical antipsychotic drugs, clozapine and risperidone, but not
      the typical antipsychotic, haloperidol, reduce cardiovascular stress responses,
      an effect that could reflect their anxiolytic action. Such anxiolytic effects
      could contribute to the beneficial clinical effects of atypical antipsychotic
      drugs in patients with schizophrenia.

PMID- 12600696
TI  - Involvement of calcitonin gene-related peptide in the depressor effects of
      losartan and perindopril in rats.
AB  - Previous investigations have indicated that calcitonin gene-related peptide
      (CGRP) plays an important role in the regulation of cardiovascular function, and
      that the development of hypertension may be related to the reduction of sensory
      vasodilator nerve actions. In the present study, we examined the effect of
      perindopril, an angiotensin-converting enzyme inhibitor, and losartan, an
      angiotensin II receptor antagonist, on the plasma level and synthesis of CGRP in
      2 kidneys, 1-clip hypertensive rats (2K1C, Goldblatt). In the hypertension group,
      systolic blood pressure and mean artery pressure were raised, and the level of
      CGRP in plasma was slightly raised compared with control groups. Chronic
      treatment with losartan or perindopril significantly increased the plasma
      concentration of CGRP and the expression of CGRP mRNA in dorsal root ganglia in
      the 2K1C, Goldblatt hypertensive rats. These results suggest that the 2K1C,
      Goldblatt hypertensive model has a compensatory increase of sensory nerve
      actions, and that the depressor effects of perindopril or losartan may be related
      to stimulation of the synthesis and release of CGRP in the 2K1C, Goldblatt
      hypertensive rats.

PMID- 12600697
TI  - Pharmacological characterization of the 5-HT1A, 5-HT2 and 5-HT3 receptors in the
      bovine ciliary muscle.
AB  - We aimed to investigate the effects of serotonin (5-hydroxytryptamine, 5-HT) on
      the bovine ciliary muscle and subsequently to characterize and identify the
      subtypes of 5-HT receptors involved in the serotonin-evoked contractility muscle.
      The binding of [3H]ketanserin, [3H]granisetron and [3H]8-hydroxy-2-(di-n
      propylamino)tetralin ([3H]8-OH-DPAT) was analyzed. All labelled compounds bound
      with high affinity to a single site in the membrane preparations studied. The
      affinity (K(d)) of the binding site was 7.5+/-1.2 nM for [3H]ketanserin, 6.9+/
      0.8 nM for [3H]granisetron and 4.4+/-0.31 nM for [3H]8-OH-DPAT. The density of
      receptors (B(max)) was 1062+/-43.0 fmol/mg protein for [3H]ketanserin, 566+/-2.32
      fmol/mg protein for [3H]granisetron and 205+/-4.63 fmol/mg protein for [3H]8-OH
      DPAT. The serotonin-induced contraction appeared to be competitively antagonized
      by ketanserin (0.1, 1 and 10 microM) and ondansetron (0.1, 10 and 100 microM)
      which produced a pA(2) value of 8.5+/-0.12 and 8.0+/-0.19, respectively. 8-OH
      DPAT and 5-carboxamidotryptamine (5-CT) proved to be completely ineffective. We
      conclude that serotonin induces bovine ciliary muscle contraction via 5-HT(2) and
      5-HT(3) receptors while the 5-HT(1A) receptors, although present, do not mediate
      the contractile response.

PMID- 12600698
TI  - Protective effect of edaravone against streptomycin-induced vestibulotoxicity in
      the guinea pig.
AB  - This study investigated alleviation of streptomycin-induced vestibulotoxicity by
      edaravone in guinea pigs. Edaravone, a free radical scavenger, has potent free
      radical quenching action and is used in clinical practice to treat cerebral
      infarction. Streptomycin was administered to the inner ear by osmotic pump for 24
      h, and edaravone (n=8) or saline (n=6) was intraperitoneally injected once a day
      for 7 days. We observed horizontal vestibulo-ocular reflex as a marker of
      postoperative vestibular function. Animals injected with saline showed
      statistically smaller gains than those injected with edaravone. These results
      suggest that edaravone suppresses streptomycin-induced vestibulotoxicity.

PMID- 12600700
TI  - The open field as a paradigm to measure the effects of drugs on anxiety-like
      behaviors: a review.
AB  - The open field is a very popular animal model of anxiety-like behavior. An
      overview of the literature on the action elicited by effective or putative
      anxiolytics in animal subjected to this procedure indicates that classical
      treatments such as benzodiazepine receptor full agonists or 5-HT(1A) receptor
      full or partial agonists elicit an anxiolytic-like effect in this procedure in
      most cases (approximately 2/3). However, compounds (triazolobenzodiazepines such
      as adinazolam and alprazolam, selective serotonin reuptake inhibitors) that have
      a different spectrum of therapeutic efficacy in anxiety disorders such as panic
      attacks, generalized anxiety disorder or obsessive-compulsive disorder were
      poorly effective as anxiolytics in the open field test, suggesting that this
      paradigm may not model features of anxiety disorders. The procedure is also
      relevant for the study of compounds endowed with anxiogenic effects, as such
      effects were detected after treatments with benzodiazepine receptor inverse
      agonists or with corticotropin releasing factor (CRF) receptor agonists.

PMID- 12600701
TI  - A review of 25 years of the social interaction test.
AB  - The social interaction test of anxiety was developed 25 years ago to provide an
      ethologically based test that was sensitive to both anxiolytic and anxiogenic
      effects. It is sensitive to a number of environmental and physiological factors
      that can affect anxiety. It has detected anxiogenic effects of peptides such as
      corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and
      anxiolytic effects of neuropeptide Y and substance P receptor antagonists. It has
      successfully identified neuropharmacological sites of action of anxiogenic
      compounds and drug withdrawal. Effects of compounds acting on the gamma
      aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) systems have been
      extensively investigated after both systemic administration and microinjection
      into specific brain regions. The use of this test has, thus, played a crucial
      role in unravelling the neural basis of anxiety. It is hoped that in the next 25
      years, the test will play a crucial role in determining the genetic basis of
      anxiety disorders.

PMID- 12600702
TI  - The mouse light/dark box test.
AB  - The light/dark test is based on the innate aversion of rodents to brightly
      illuminated areas and on the spontaneous exploratory behaviour of rodents in
      response to mild stressors, that is, novel environment and light. The test
      apparatus consists of a small dark safe compartment (one third) and a large
      illuminated aversive compartment (two thirds). The test was developed with male
      mice. The strain, weight and age may be crucial factors. The extent to which an
      anxiolytic compound can facilitate exploratory activity depends on the baseline
      level in the control group. Differences between the type and severity of external
      stressors might account for the variable results reported by different
      laboratories. The light/dark test may be useful to predict anxiolytic-like or
      anxiogenic-like activity in mice. Transitions have been reported to be an index
      of activity-exploration because of habituation over time, and the time spent in
      each compartment to be a reflection of aversion. Classic anxiolytics
      (benzodiazepines) as well as the newer anxiolytic-like compounds (e.g.
      serotonergic drugs or drugs acting on neuropeptide receptors) can be detected
      using this paradigm. It has the advantages of being quick and easy to use,
      without requiring the prior training of animals.

PMID- 12600703
TI  - The Vogel conflict test: procedural aspects, gamma-aminobutyric acid, glutamate
      and monoamines.
AB  - A multitude of mechanisms are involved in the control of emotion and in the
      response to stress. These incorporate mediators/targets as diverse as gamma
      aminobutyric acid (GABA), excitatory amino acids, monoamines, hormones,
      neurotrophins and various neuropeptides. Behavioural models are indispensable for
      characterization of the neuronal substrates underlying their implication in the
      etiology of anxiety, and of their potential therapeutic pertinence to its
      management. Of considerable significance in this regard are conflict paradigms in
      which the influence of drugs upon conditioned (trained) behaviours is examined.
      For example, the Vogel conflict test, which was introduced some 30 years ago,
      measures the ability of drugs to release the drinking behaviour of water-deprived
      rats exposed to a mild aversive stimulus ("punishment"). This model, of which
      numerous procedural variants are discussed herein, has been widely used in the
      evaluation of potential anxiolytic agents. In particular, it has been exploited
      in the characterization of drugs interacting with GABAergic, glutamatergic and
      monoaminergic networks, the actions of which in the Vogel conflict test are
      summarized in this article. More recently, the effects of drugs acting at
      neuropeptide receptors have been examined with this model. It is concluded that
      the Vogel conflict test is of considerable utility for rapid exploration of the
      actions of anxiolytic (and anxiogenic) drugs. Indeed, in view of its clinical
      relevance, broader exploitation of the Vogel conflict test in the identification
      of novel classes of anxiolytic agents, and in the determination of their
      mechanisms of action, would prove instructive.

PMID- 12600704
TI  - The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety
      and panic.
AB  - The Mouse Defense Test Battery was developed from tests of defensive behaviors in
      rats, reflecting earlier studies of both acute and chronic responses of
      laboratory and wild rodents to threatening stimuli and situations. It measures
      flight, freezing, defensive threat and attack, and risk assessment in response to
      an unconditioned predator stimulus, as well as pretest activity and postthreat
      (conditioned) defensiveness to the test context. Factor analyses of these
      indicate four factors relating to cognitive and emotional aspects of defense,
      flight, and defensiveness to the test context. In the Mouse Defense Test Battery,
      GABA(A)-benzodiazepine anxiolytics produce consistent reductions in defensive
      threat/attack and risk assessment, while panicolytic and panicogenic drugs
      selectively reduce and enhance, respectively, flight. Effects of GABA(A)
      benzodiazepine, serotonin, and neuropeptide ligands in the Mouse Defense Test
      Battery are reviewed. This review suggests that the Mouse Defense Test Battery is
      a sensitive and appropriate tool for preclinical evaluation of drugs potentially
      effective against defense-related disorders such as anxiety and panic.

PMID- 12600706
TI  - Stress-induced vocalisation in adult animals. A valid model of anxiety?
AB  - The post-stimuli anticipatory vocalisations that follow stressful and painful
      conditions are suggested as a quantitative measure of the emotional state of fear
      and anxiety in animal models. Adult rats emit characteristic 22-kHz ultrasound
      vocalisations consisting of 20-30 kHz calls with a mean duration of 300-600 ms as
      response to aversive stimuli (e.g. inescapable electric footshock, acoustic or
      air-puff stimuli, agonistic encounter or withdrawal from treatment with drugs of
      abuse). The vocalisations are accompanied by defensive submissive behaviour and
      signal a refractory, socially withdrawn or helpless state. Furthermore, brain
      structures that are involved in the mediation of anxiety-like behaviour, e.g. the
      dorsal periaqueductal grey and cortical areas, are also important for modulation
      of ultrasonic vocalisation. Benzodiazepines, e.g. diazepam, inhibit shock-induced
      ultrasonic vocalisation although the active doses are generally close to those
      that produce sedation and muscle relaxation. Selective serotonin reuptake
      inhibitors and other antidepressants that preferentially enhance serotonergic
      neurotransmission inhibit footshock-induced ultrasonic vocalisation. The 5-HT(2)
      receptor antagonistic properties of fluoxetine may explain why only partial
      inhibition is achieved. The biphasic dose-response curve of the racemic drug,
      citalopram, may perhaps be ascribed to an attenuating effect of R-citalopram.
      Tricyclic antidepressants, e.g. imipramine, and antidepressants that
      preferentially enhance catecholaminergic neurotransmission, e.g. reboxetine and
      venlafaxine, are inactive. Classical antipsychotics like haloperidol have no or a
      weak inhibitory effect. Serotonin plays a major role in the mediation of
      ultrasonic vocalisation, and in particular 5-HT(1A) and 5-HT(2) receptors are
      found to have a prominent role. Different serotonergic pathways are likely to be
      involved in the mediation of the anxiolytic-like response, e.g. the pathway
      ascending from the dorsal raphe nucleus through the medial forebrain bundle to
      the amygdala and frontal cortex mediating conditioned/learned anxiety and another
      pathway ascending from the dorsal raphe nucleus to the periaqueductal grey
      mediating unconditioned/fight flight anxiety. Dopamine D(2) receptor agonists are
      potent inhibitors of footshock-induced ultrasonic vocalisation. The role of
      dopamine D(1) receptors and adrenoceptors remains to be further elucidated.
      Several other neurotransmitters are involved in the mediation of ultrasonic
      vocalisation, e.g. acetylcholine, histamine and glutamate. There is also a need
      for further studies of how changes in stress-axis function may modulate
      ultrasonic vocalisation and for studies of the effects of chronic drug treatment
      on ultrasonic vocalisation.

PMID- 12600705
TI  - Stress-induced hyperthermia and anxiety: pharmacological validation.
AB  - When mammals, including man, are confronted with a stressful event, their core
      body temperature rises, stress-induced hyperthermia. In mice, the stress-induced
      hyperthermia procedure has been developed to measure antistress or anxiolytic
      like effects of psychoactive drugs. Group-housed and singly housed versions of
      the stress-induced hyperthermia generate comparable results. Because the number
      of animals needed to perform an experiment is much lower in the singly housed
      versus the group-housed procedure, the former is the test of choice for
      pharmacological testing. A typical stress-induced hyperthermia test starts with
      an injection 60 min before the first rectal temperature measurement (T(1)),
      followed by a second temperature measurement (T(2)) 10-15 min later. The
      difference DeltaT (=T(2)-T(1)) is the stress-induced hyperthermia. The procedure
      also measures the intrinsic activity of drugs on the basal body temperature and
      DeltaT is relatively independent from the intrinsic temperature effects of drugs.
      Anxiolytic drugs (benzodiazepines, 5-HT(1A) receptor agonists, alcohol) reduce
      DeltaT suggestive of anxiolytic-like effects. Because the parameter measured for
      anxiety in the stress-induced hyperthermia procedure is not dependent on
      locomotor activity, like in almost all other anxiety tests, the stress-induced
      hyperthermia procedure is an attractive addition to tests in the anxiety field.
      Because the stress-induced hyperthermia is also present with a comparable
      pharmacological profile in females, this procedure has a wide species and gender
      validity. The procedure was applied in various genetically modified mice [5
      HT(1A) and 5-HT(1B) receptor knockout (KO) mice and corticotropin-releasing
      hormone overexpressing (CRH-OE) mice] to study phenotypic influences of the
      various mutations on aspects of anxiety. The stress-induced hyperthermia test in
      singly housed male and female mice appears a useful and extremely simple test to
      measure effects of drugs on certain aspects of anxiety or to help to determine
      phenotypic differences in mutant mice.

PMID- 12600707
TI  - Defensive burying in rodents: ethology, neurobiology and psychopharmacology.
AB  - Defensive burying refers to the typical rodent behavior of displacing bedding
      material with vigorous treading-like movements of their forepaws and shoveling
      movements of their heads directed towards a variety of noxious stimuli that pose
      a near and immediate threat, such as a wall-mounted electrified shock-prod. Since
      its introduction 25 years ago by Pinel and Treit [J. Comp. Physiol. Psychol. 92
      (1978) 708], defensive (shock-prod) burying has been the focus of a considerable
      amount of research effort delineating the methodology/ethology,
      psychopharmacology and neurobiology of this robust and species-specific active
      avoidance or coping response. The present review gives a summary of this research
      with special reference to the behavioral (face and construct) and pharmacological
      (predictive) validity of the shock-prod burying test as an animal model for human
      anxiety. Emphasis is also placed on some recent modifications of the paradigm
      that may increase its utility and reliability as to individual differences in
      expressed emotional coping responses and sensitivity to pharmacological
      treatments. Overall, the behavioral and physiological responses displayed in the
      shock-prod paradigm are expressions of normal and functionally adaptive coping
      patterns and the extremes of either active (i.e., burying) or passive (i.e.,
      freezing) forms of responding in this test cannot simply be regarded as
      inappropriate, maladaptive or pathological. For this reason, the shock-prod
      paradigm is not an animal model for anxiety disorder or for any other psychiatric
      disease, but instead possesses a high degree of face and construct validity for
      normal and functionally adaptive human fear and anxious apprehension. However,
      the apparent good pharmacological validation (predictive validity) of this test
      reinforces the view that normal and pathological anxiety involves, at least
      partly, common neurobiological substrates. Therefore, this paradigm is not only
      suitable for screening potential anxiolytic properties of new drugs, but seems to
      be especially valuable for unraveling the neural circuitry and neurochemical
      mechanisms underlying the generation of active and passive coping responses as
      different expressions of anxiety.

PMID- 12600708
TI  - A robust animal model of state anxiety: fear-potentiated behaviour in the
      elevated plus-maze.
AB  - Fear (i.e., decreased percentage time spent on open-arm exploration) in the
      elevated plus-maze can be potentiated by prior inescapable stressor exposure, but
      not by escapable stress. The use of fear-potentiated plus-maze behaviour has
      several advantages as compared to more traditional animal models of anxiety. (a)
      In contrast to the traditional (spontaneous) elevated plus-maze, which measures
      innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an
      enhanced anxiety state (allostatic state). This "state anxiety" can be defined as
      an unpleasant emotional arousal in face of threatening demands or dangers. A
      cognitive appraisal of threat is a prerequisite for the experience of this type
      of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator
      odour, swim stress, restraint, social defeat, predator stress (cat)), this
      enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more
      severe when rats are isolated in comparison to group housing. (c) Drugs can be
      administered in the absence of the original stressor and after stressor exposure.
      As a consequence, retrieval mechanisms are not affected by drug treatment. (d)
      Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics
      and anxiogenics which act via mechanisms related to the benzodiazepine-gamma
      aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing
      receptor antagonists and glucocorticoid receptor antagonists and serotonin
      receptor agonists/antagonists complex (high predictive validity). (e) Fear
      potentiated plus-maze behaviour is very robust, and experiments can easily be
      replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be
      measured both in males and females. (g) Neural mechanisms involved in contextual
      fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear
      potentiated plus-maze behaviour may be a valuable measure in the understanding of
      neural mechanisms involved in the development of anxiety disorders and in the
      search for novel anxiolytics. Finally, the involvement of corticotropin-releasing
      factor and corticosteroid-corticotropin-releasing factor interactions in the
      production of fear-potentiated plus-maze behaviour are discussed.

PMID- 12600709
TI  - 5-HT1A receptor knockout mouse as a genetic model of anxiety.
AB  - Low levels of the serotonin(1A) (5-HT(1A)) receptor have been repeatedly found in
      mood and anxiety disorders. Stress often exacerbates psychiatric disease and can
      also reduce 5-HT(1A) receptor levels. When receptor deficiency was produced in
      mice by genetic knockout, an anxiety-like phenotype was observed. Anxiety in mice
      is defined as a high level of avoidance of novel and unfamiliar environment and
      increased fear reaction. Other aspects of anxiety such as autonomic activation,
      increased stress responsiveness, and neuroendocrine abnormalities have also been
      described in receptor knockout mice. These data indicate that 5-HT(1A) receptor
      knockout mice represent a genetic animal model of anxiety with both construct and
      face validities. Although the core phenotype of anxiety can be reproduced in
      knockout mice in various inbred and outbred backgrounds, abnormalities in 5-HT
      dynamics and resistance to the anxiolitic drug diazepam have been seen in one but
      not on other genetic backgrounds. This indicates that while the development of
      anxiety is an invariable consequence of receptor deficit, other features induced
      by receptor loss are strongly modulated by other gene(s). Strain-dependent
      variability within the core phenotype does not diminish the value of 5-HT(1A)
      receptor knockout mice as a model of anxiety. Indeed, it is consistent with the
      manifestation of anxiety in genetically heterogeneous human population.

PMID- 12600710
TI  - 5-HT1A receptor knockout mice and mice overexpressing corticotropin-releasing
      hormone in models of anxiety.
AB  - Pharmacological experiments have implicated a role for serotonin (5-HT)(1A)
      receptors in the modulation of anxiety. More recent is the interest in
      corticotropin-releasing hormone (CRH) system as a potential target for the
      treatment of anxiety disorders. However, selective pharmacological tools for the
      CRH system are limited, hampering research in this field. Gene targeting is a
      relatively new approach to study mechanisms underlying anxiety disorders. 5
      HT(1A) receptor knockout (1AKO) mice have been created on three different
      background strains, and two different lines of mice, overexpressing CRH (CRH-OE),
      have been generated. In the present review, behavioural and physiological
      findings reported for 1AKO mice and CRH-OE mice will be reviewed. As behavioural
      phenotyping is often limited to one or two approach avoidance paradigms, we
      extended these observations and also tested 1AKO and CRH-OE mice in a conditioned
      fear paradigm. This paradigm reflects essentially different aspect of anxiety
      than approach avoidance paradigms. 1AKO mice on a 129/Sv background strain showed
      similar freezing as wild-type (WT) mice. In CRH-OE mice, less freezing was
      observed than in the corresponding wild-type mice. The fact that the anxious
      phenotype of these genetically altered mice seems less clear than initially
      reported will be discussed. Rather than studying the direct consequences of
      alterations in the targeted gene, 1AKO and CRH-OE mice seem very valuable to
      study compensatory processes that seem to have taken place in reaction to life
      long changes in gene expression.

PMID- 12600711
TI  - Role of the bed nucleus of the stria terminalis versus the amygdala in fear,
      stress, and anxiety.
AB  - The bed nucleus of the stria terminalis is a limbic forebrain structure that
      receives heavy projections from, among other areas, the basolateral amygdala, and
      projects in turn to hypothalamic and brainstem target areas that mediate many of
      the autonomic and behavioral responses to aversive or threatening stimuli.
      Despite its strategic anatomical position, initial attempts to implicate the bed
      nucleus of the stria terminalis in conditioned fear were largely unsuccessful.
      Recent studies have shown, however, that the bed nucleus of the stria terminalis
      does participate in certain types of anxiety and stress responses. In this work,
      we review these findings and suggest from the emerging pattern of evidence that,
      although the bed nucleus of the stria terminalis may not be necessary for rapid
      onset, short-duration behaviors which occur in response to specific threats, the
      bed nucleus of the stria terminalis may mediate slower-onset, longer-lasting
      responses that frequently accompany sustained threats, and that may persist even
      after threat termination.

PMID- 12600712
TI  - The place of the hippocampus in fear conditioning.
AB  - Pavlovian fear conditioning is a phenomenon amenable to laboratory analysis of
      the neurobiology of fear and the investigation of neural mechanisms of learning
      and memory. Investigators have made much progress in delineating the
      neurocircuitry and neurochemistry of fear conditioning. The place of the
      hippocampus in context fear remains a controversial issue. In this review, we
      examine the evidence that the hippocampus plays a role in fear conditioning. We
      then critically examine hypotheses concerning its exact role in learning and
      memory for cued and context fear conditioning.

PMID- 12600713
TI  - The relevance of neuronal substrates of defense in the midbrain tectum to anxiety
      and stress: empirical and conceptual considerations.
AB  - The medial hypothalamus, amygdala, and dorsal periaqueductal gray constitute the
      main neural substrates for the integration of aversive states in the brain. More
      recently, some regions of the mesencephalon, such as the superior and inferior
      colliculi have also been proposed as part of this system. In fact, fear-like
      behaviors often result when these sites are electrically or chemically
      stimulated. Both the behavioral and autonomic consequences of electrical
      stimulation of the mesencephalic tectum have been shown to be attenuated by minor
      tranquilizers, probably through enhancement of gamma-aminobutyric acid (GABA)
      mediated neurotransmission, which exerts a tonic inhibitory control on the neural
      circuits responsible for the so-called defense behavior repertoire. Besides GABA,
      also 5-hydroxy tryptamine serotonin (5-HT), opioids, neuropeptides, histaminergic
      and excitatory amino acids have all been implicated in the regulation of anxiety
      related behaviors induced by stimulation of midbrain tectum. Efforts have been
      made to characterize how these neurotransmitters interact with each other in the
      organization of these reactions to aversive stimulation. In this review, we
      summarize the evidence linking the brain's defense response systems to the
      concept of fear-anxiety. Furthermore, a case is made for the consideration of the
      relevance of this body of data to the search for the physiological underpinnings
      of depression and its consequences.

PMID- 12600714
TI  - Neuroendocrine pharmacology of stress.
AB  - Exposure to hostile conditions initiates responses organized to enhance the
      probability of survival. These coordinated responses, known as stress responses,
      are composed of alterations in behavior, autonomic function and the secretion of
      multiple hormones. The activation of the renin-angiotensin system and the
      hypothalamic-pituitary-adrenocortical axis plays a pivotal role in the stress
      response. Neuroendocrine components activated by stressors include the increased
      secretion of epinephrine and norepinephrine from the sympathetic nervous system
      and adrenal medulla, the release of corticotropin-releasing factor (CRF) and
      vasopressin from parvicellular neurons into the portal circulation, and seconds
      later, the secretion of pituitary adrenocorticotropin (ACTH), leading to
      secretion of glucocorticoids by the adrenal gland. Corticotropin-releasing factor
      coordinates the endocrine, autonomic, behavioral and immune responses to stress
      and also acts as a neurotransmitter or neuromodulator in the amygdala, dorsal
      raphe nucleus, hippocampus and locus coeruleus, to integrate brain multi-system
      responses to stress. This review discussed the role of classical mediators of the
      stress response, such as corticotropin-releasing factor, vasopressin, serotonin
      (5-hydroxytryptamine or 5-HT) and catecholamines. Also discussed are the roles of
      other neuropeptides/neuromodulators involved in the stress response that have
      previously received little attention, such as substance P, vasoactive intestinal
      polypeptide, neuropeptide Y and cholecystokinin. Anxiolytic drugs of the
      benzodiazepine class and other drugs that affect catecholamine, GABA(A),
      histamine and serotonin receptors have been used to attenuate the neuroendocrine
      response to stressors. The neuroendocrine information for these drugs is still
      incomplete; however, they are a new class of potential antidepressant and
      anxiolytic drugs that offer new therapeutic approaches to treating anxiety
      disorders. The studies described in this review suggest that multiple brain
      mechanisms are responsible for the regulation of each hormone and that not all
      hormones are regulated by the same neural circuits. In particular, the renin
      angiotensin system seems to be regulated by different brain mechanisms than the
      hypothalamic-pituitary-adrenal system. This could be an important survival
      mechanism to ensure that dysfunction of one neurotransmitter system will not
      endanger the appropriate secretion of hormones during exposure to adverse
      conditions. The measurement of several hormones to examine the mechanisms
      underlying the stress response and the effects of drugs and lesions on these
      responses can provide insight into the nature and location of brain circuits and
      neurotransmitter receptors involved in anxiety and stress.

PMID- 12600715
TI  - Is there a future for vaccination as a treatment for Alzheimer's disease?
AB  - Vaccination of APP transgenic mice with Abeta has been shown to prevent amyloid
      deposits. A clinical trial of Abeta vaccination in Alzheimer's disease (AD) was
      halted due to serious neurological complications developing in some patients.
      Such complications were not observed in transgenic mice. Since human APP is not a
      mouse self-protein, vaccination of mice with Abeta should not produce an
      autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q
      poorly recognizes human Abeta so complement activation is much weaker in
      transgenic mice than in AD. Vaccination will increase complement activation
      through formation of antigen-antibody complexes. In mice this will enhance
      phagocytosis. But in AD, where complement is already overactivated, and where the
      senile plaques are relatively insoluble, this stimulation should increase
      production of the membrane attack complex, adding to the autodestruction of
      neurons. The future of vaccination as a therapy for AD will require surmounting
      the problems of autoimmune reactions generally and autotoxic complement
      activation specifically.

PMID- 12600716
TI  - Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's
      disease model.
AB  - We have engineered transgenic Caenorhabditis elegans animals to inducibly express
      the human beta amyloid peptide (Abeta). Gene expression changes resulting from
      Abeta induction have been monitored by cDNA hybridization to glass slide
      microarrays containing probes for almost all known or predicted C. elegans genes.
      Using statistical criteria, we have identified 67 up-regulated and 240 down
      regulated genes. Subsets of these regulated genes have been tested and confirmed
      by quantitative RT-PCR. To investigate whether genes identified in this model
      system also show gene expression changes in Alzheimer's disease (AD) brain, we
      have also used quantitative RT-PCR to examine in post-mortem AD brain tissue
      transcript levels of alphaB-crystallin (CRYAB) and tumor necrosis factor-induced
      protein 1 (TNFAIP1), human homologs of genes found to be robustly induced in the
      transgenic C. elegans model. Both CRYAB and TNFAIP1 show increased transcript
      levels in AD brains, supporting the validity of this approach.

PMID- 12600717
TI  - Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid
      beta-peptide (1-42) in a transgenic Caenorhabditis elegans model.
AB  - Alzheimer's disease is a progressive, neurodegenerative disorder characterized by
      senile plaques and neurofibrillary components. Abeta(1-42) is a principal
      component of senile plaques and is thought to be central to the pathogenesis of
      the disease. The Alzheimer's disease brain is under significant oxidative stress,
      and the Abeta(1-42) peptide is known to cause oxidative stress in vitro. One
      controversy in the amyloid hypothesis is whether or not Abeta plaques are
      required for toxicity. We have employed a temperature-inducible Abeta expression
      system in Caenorhabditis elegans to create a strain of worms, CL4176, in which
      Abeta(1-42) is expressed with a non-permissive temperature of 23 degrees C. The
      CL4176 strain allows examination of the temporal relationship between Abeta
      expression, oxidative stress, and Abeta fibril formation. CL4176 were under
      increased oxidative stress, evidenced by increased protein oxidation indexed by
      increased carbonyl levels, 24 and 32 h after temperature upshift as compared to
      the control strain, CL1175. The increased oxidative stress in CL4176 occurred in
      the absence of Abeta fibril formation, consistent with the notion that the toxic
      species in Abeta toxicity is pre-fibrillar Abeta and not the Abeta fibril. These
      results are discussed with reference to Alzheimer's disease.

PMID- 12600718
TI  - ABCA1 modulates CSF cholesterol levels and influences the age at onset of
      Alzheimer's disease.
AB  - Increased formation of the beta-amyloid peptide (Abeta) is a central event in the
      pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes
      Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates
      cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1
      may influence cholesterol metabolism in the central nervous system (CNS) and,
      thus, interfere with the development of AD. Healthy elderly carriers of the A
      allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the
      ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in
      cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset,
      sporadic AD, this allele was associated with delayed age at onset of the disease
      by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in
      ABCA1 (rs2234886) failed to show significant association with the risk for AD. We
      conclude that genetic variability of ABCA1 influences the development of AD,
      possibly by interfering with CNS cholesterol homeostasis.

PMID- 12600719
TI  - Cyclin C expression is involved in the pathogenesis of Alzheimer's disease.
AB  - The expression of different cell cycle proteins in terminally differentiated
      neurons apparently precedes cell death or contributes to pathogenetic progression
      of Alzheimer's disease (AD). Cyclins and cyclin-dependent kinases (Cdks),
      physiologically involved in mitotic processes of proliferating cells, are
      elevated in neurons prone to dedifferentiation and degeneration. Previously, it
      was shown that even inhibitors of the Cdks as p16(INK4a), p18(INK4c) or p27(KIP1)
      are expressed in neurons of AD patients, indicating a rather complete involvement
      of cell cycle machinery in affected neurons. The aim of this study was to examine
      the involvement of the non-classical cyclin C in the pathogenetic process of AD.
      A marked elevated immunoreactivity of cyclin C was found both in neurons and
      astrocytes in AD. Increased levels of cyclin C RNA were detected by ribonuclease
      protection assay (RPA) in severe AD cases. Colocalization of cyclin C and its
      preferred binding partner, Cdk8, was only observed in astrocytes but not in
      neurons. The present observations suggest different cellular functions of cyclin
      C in neurons and astrocytes in AD.

PMID- 12600720
TI  - Abeta42 generation is toxic to endothelial cells and inhibits eNOS function
      through an Akt/GSK-3beta signaling-dependent mechanism.
AB  - The application of beta-amyloid (Abeta) is cytotoxic to endothelial cells,
      promotes vasoconstriction and impairs nitric oxide (NO) generation or action.
      However, there is no information on the effect of intracellular Abeta on
      endothelial cell biology, although recent studies indicate that neuronal Abeta
      drives Alzheimer's disease pathogenesis. Since the serine-threonine kinase Akt is
      crucial to both neuronal and endothelial cell survival as well as eNOS
      activation, we investigated the effects of Abeta expression on Akt-signaling in
      cultured endothelial cells. Virally-encoded Abeta42 was proapoptotic and
      inhibitory to Akt phosphorylation in human umbilical vein endothelial cells
      (HUVECs). Toxicity was characterized by mitochondrial dysfunction, DNA
      condensation and activation of caspase-3. Substrates downstream of Akt action,
      GSK-3beta and eNOS, are underphosphorylated in the presence of Abeta.
      Constitutive activation of Akt reversed Abeta-induced toxicity and stimulated
      caspase-3 activity, suggesting that inhibition of Akt signaling is functionally
      significant. These Abeta effects were mediated, in part, through the derepression
      of GSK-3beta activation and correlated with reductions in NO production. We
      conclude that intracellular production of Abeta42 is cytotoxic to endothelial
      cells and that disruption of the Akt/GSK-3beta cell signaling pathway is
      involved.

PMID- 12600721
TI  - Variability in memory performance in aged healthy individuals: an fMRI study.
AB  - Episodic memory performance varies in older subjects but underlying biological
      correlates remain as yet ambiguous. We investigated episodic memory in healthy
      older individuals (n=24; mean age: 64.4+/-6.7 years) without subjective memory
      complaints or objective cognitive impairment. Episodic memory was assessed with
      repetitive learning and recall of abstract geometric patterns during fMRI. Group
      analysis of brain activity during initial learning and maximum recall revealed
      hippocampal activation. Correlation analysis of brain activation and task
      performance demonstrated significant hippocampal activity during initial learning
      and maximum recall in a success-dependent manner. Neither age nor gray matter
      densities correlated with hippocampal activation. Functional imaging of episodic
      memory thus permits to detect objectively variability in hippocampal recruitment
      in healthy aged individuals without subjective memory complaints. Correlation
      analysis of brain activation and performance during an episodic memory task may
      be used to determine and follow-up hippocampal malfunction in a very sensitive
      manner.

PMID- 12600722
TI  - Non-invasive localization of P300 sources in normal aging and age-associated
      memory impairment.
AB  - Cognitive event-related potentials were recorded from 17 EEG leads in an auditory
      two-tone paradigm in 43 patients aged 51-79 years with the diagnosis of age
      associated memory impairment (AAMI), in age-and sex-matched normal controls and
      in a control group 10 years older than the AAMI patients. In addition to P300
      latencies, amplitudes and topographies, three-dimensional current density
      distribution utilizing low-resolution brain electromagnetic tomography (LORETA)
      was computed. P300 latency was delayed and P300 amplitude was reduced in both
      AAMI and older subjects. Topographically this amplitude reduction was most
      pronounced frontally. LORETA revealed medial (frontal and parietal) and lateral
      (dorso- and ventrolateral prefrontal, middle/superior temporal, posterior
      superior temporal/inferior parietal) sources. Significant reductions in LORETA
      source strength in normal aging and in AAMI were found mainly medially frontally,
      right dorsolaterally prefrontally and right inferiorly parietally. Since these
      anatomically highly interconnected brain regions in the right hemisphere are part
      of a network associated with sustained attention, the results speak for a decline
      in attentional resource capacity in AAMI patients and elderly subjects.

PMID- 12600723
TI  - Protective effect of the heparin-derived oligosaccharide C3, on AF64A-induced
      cholinergic lesion in rats.
AB  - Alzheimer's disease (AD) literature indicates that glycosaminoglycans (GAGs) may
      prevent proteoglycan-induced amyloid-beta (Abeta) aggregation, decrease Abeta
      induced tau-2 immunoreactivity, and increase the axonal growth and arborization
      of hippocampal neurons. However, there is no information about the impact of GAGs
      on cholinergic lesions. Here, AF64A was administered stereotaxically into the
      lateral ventricles of rats, at doses that are selective for cholinotoxicity (1
      and 2 nmol). The heparin-derived oligosaccharide (HDO), C3 (25mg/kg), was
      administered orally, once daily for 7 days before, and 7 days after AF64A
      administration. Choline acetyltransferase (ChAT) immunohistochemistry revealed
      that C3 administration reduced AF64A-induced cholinergic damage in the septum and
      cingulum bundle. Quantitative neuronal cell counts showed that C3 attenuated, by
      60%, the decrease in cell number in the medial septum. Enzyme analysis showed
      that C3 also significantly restored ChAT (30%) and acetylcholinesterase (AChE)
      enzyme activity (45%), which had been diminished by AF64A. Our data suggest that,
      in addition to its effects of anti-Abeta aggregation, anti-Abeta-induced tau-2
      immunoreactivity, and neurotrophic effects, C3 also effectively reduces AF64A
      induced cholinergic damage; hence it may have potential therapeutic value in AD
      patients.

PMID- 12600724
TI  - Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial
      damage and DA depletion.
AB  - Previous studies showed a synergistic effect of melatonin and deprenyl against
      dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in
      Parkinson's disease (PD), we explored the effects of melatonin plus deprenyl
      administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD
      in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of
      mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced
      by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine
      hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity
      of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and
      inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl
      on catecholamine turnover and mice ambulatory activity. These results suggest a
      dissociation of complex I inhibition from DA depletion in this model of
      Parkinson's disease. The data also support that a combination of melatonin, which
      improves mitochondrial electron transport chain and reduces oxidative damage, and
      deprenyl, which promotes the specific function of the rescued neurons, i.e. DA
      turnover, may be a promising strategy for the treatment of PD.

PMID- 12600725
TI  - Glutathione S-transferase isoenzymatic response to aging in rat cerebral cortex
      and cerebellum.
AB  - Aging is associated with increased oxidant generation. One mechanism involved in
      the defense of oxidative products is the family of glutathione transferases
      (GST). We have analyzed the activity, distribution and expression of GSTP1 and
      GSTA4 isoenzymes in the cerebral cortex and cerebellum of young, adult and aged
      rats. The total GST activity, measured with the universal substrate 1-chloro-2,4
      dinitrobenzene (CDNB), increased only with the maturation process; however GSTA4
      activity, using the specific substrate 4-hydroxynonenal (HNE), did show an age
      dependent increase in both brain regions. Cellular location of GSTA4 in
      astrocytes was not changed except for young cerebral cortex and adult/aged
      cerebellum that also showed immunoreactivity in layer III pyramidal neurons and
      Bergman radial glia, respectively. Distribution of GSTP1 was similar among groups
      and only an increased number of positive oligodendrocytes was found in the
      Purkinje and granular layer of adult/aged cerebellum. The GSTA4 and GSTP1
      expression increased from young to adult/aged brain and GSTA4 even augmented in
      the aged cerebral cortex. These results suggest a GST isoenzymatic response with
      aging, but above all with the maturation process.

PMID- 12600726
TI  - Facial nerve axotomy in aged and young adult rats: analysis of the glial
      response.
AB  - With increasing age, there is a trend towards greater morbidity and injury extent
      with brain injury. Because several reports have suggested that microglia and
      astrocytes have an exacerbated response to brain injury in the aged, we set out
      to explore glial responses to facial nerve axotomy. This model was chosen because
      the glial responses are well-characterized in young rats and there is no
      perturbation of the blood-brain barrier (BBB). Immunohistochemistry was performed
      for glial fibrillary acidic protein (GFAP), leukocyte common antigen, type 3
      complement receptor, and major histocompatability complex classes I and II.
      Quantitative analysis showed that age does not affect the glial response to
      axotomy in the lesioned facial nucleus; however, an aging-related contralateral
      effect with enhanced GFAP-labeling was observed. Interestingly, despite a lack of
      infiltrating neutrophils, a T cell influx was observed in both young and aged
      rats. Overall, these results suggest that neutrophil extravasion and BBB
      breakdown are underappreciated with regards to aging and injury exacerbation.

PMID- 12600727
TI  - The effect of oviductal epithelial cell co-culture during in vitro maturation on
      sow oocyte morphology, fertilization and embryo development.
AB  - In vitro embryo production in the sow is challenged by poor cytoplasmic
      maturation, low sperm penetration and low normal fertilization, leading to the
      development of poor quality blastocysts containing a small number of nuclei. In
      prepubertal gilt oocytes, the presence of porcine oviductal epithelial cells
      (pOECs) during maturation increases cytoplasmic maturation and blastocyst
      development. These aspects, as well as blastocyst quality, may be improved when
      adult sow oocytes are matured with pOEC. Therefore, the effect of the presence of
      pOEC on sow oocyte morphology, fertilization and the progression of embryo
      development was evaluated. The pOEC were cultured in M199 for 18 h, then cultured
      in NCSU23 for 4 h before the oocytes were added. Oocytes from 2 to 6 mm follicles
      were matured in 500 microl NCSU23, with eCG and hCG, for 24 h, and then cultured
      with or without pOEC, in NCSU23 without hormones, for 18 h. In vitro
      fertilization took place in modified Tris-buffered medium, for 6 h, and the
      presumptive zygotes were then cultured for 162 h in NCSU23. Morphology of the IVM
      oocytes was compared to that of immature oocytes and in vivo matured MII oocytes
      from slaughtered sows in estrus. The in vitro matured oocytes had a greater
      diameter and a wider perivitelline space than the immature and in vivo matured
      MII oocytes (P < 0.01). Penetration, polyspermy and pronucleus formation did not
      differ between the pOEC and Control groups, although the total penetration rate
      was higher for the Control oocytes (26% versus 39%; P < 0.01). Fewer blastocysts
      developed in the pOEC group than in the Control group (19% versus 27%; P < 0.01),
      but blastocyst growth was accelerated, leading to a higher percentage of hatched
      blastocysts (3% versus 10%; P < 0.01). Finally, the average blastocyst cell
      number was higher in the pOEC group (47 versus 40; P < 0.05) and a greater
      percentage of blastocysts contained a superior number of nuclei. In conclusion,
      the addition of pOEC during the second half of in vitro maturation resulted in
      fewer blastocysts formed, but of those blastocysts that did form the quality was
      improved.

PMID- 12600728
TI  - Effects of oxytocin on semen release response in African catfish (Clarias
      gariepinus).
AB  - In silurid fishes, semen collection is practically impossible, even after
      hormonal stimulation. Instead, males are killed and testes macerated to obtain
      sperm. To understand the endocrine control of semen release in catfishes, we
      investigated the role of smooth muscle contractors in semen release and semen
      quality of African catfish (Clarias gariepinus). In in vitro experiments, testis
      slices were incubated with oxytocin (1 and 10 IU), isotocin (2 and 20 ug),
      vasopressin (0.2 and 2 ug), epinephrine (1 and 10 ug), PGF2alpha (1 and 10 ug),
      purified Clarias LH (300 ng) and partly purified Clarias pituitary extract
      (containing 300 ng LH). Only oxytocin increased sperm concentration of the medium
      (assessed by optical density measurements) compared to control incubations.
      Oxytocin was then tested in vivo in two groups of fish: normal males, and males
      that had been treated with 17alpha-methyltestosterone during larval stages to
      inhibit seminal vesicle development (MT males). Both groups of fish received two
      doses of carp pituitary suspension (8 and 10 mg/kg, respectively i.m.) with or
      without subsequent oxytocin treatment (5 IU/kg i.v.; cPS-OT treatment and cPS
      treatment, respectively). There was no effect of oxytocin on the number of
      strippable males. Of cPS and cPS-OT treated fish, 87% MT males and 60% normal
      males were strippable. The stripped semen volume was low in both groups but MT
      males produced higher (P < 0.001) hatching rates (63.1%) than did normal males
      (2.1%).

PMID- 12600729
TI  - Effect of recombinant bovine somatotropin on superovulatory response and
      recipient pregnancy rates in a commercial embryo transfer program.
AB  - Recombinant bovine somatotropin (rbST) has been shown to increase follicular
      growth in cattle and some studies have demonstrated an increase in superovulatory
      response for rbST-treated cows. Pregnancy rates have also been shown to increase
      when rbST was administered around the time of insemination or prior to embryo
      transfer. The application of rbST for the purpose of increasing superovulatory
      responses of donor cows and increasing pregnancy rates of recipient heifers was
      tested in a commercial embryo transfer program. In Experiment 1, embryo donor
      cows (n = 56) underwent three cycles of control superovulation (two before and
      one after weaning) and subsequently underwent up to four additional
      superovulations while being treated with either rbST (500 mg sustained-release
      rbST; Posilac, Monsanto, St. Louis, MO; n = 28) or excipient (control; n = 28)
      once every 14 days. In Experiment 2, lactating embryo donor cows (n = 37)
      underwent a control superovulation and then underwent a superovulation while
      lactating and being treated with either rbST (n = 16) or excipient (n = 21). In
      Experiment 3, embryo recipient heifers that were being implanted with either in
      vitro or in vivo produced embryos were treated with either rbST (n = 146) or
      excipient (n = 143) at the time of embryo transfer. Treatment of non-lactating
      (Experiment 1) or lactating (Experiment 2) donor cows with rbST during repeated
      superovulation did not affect the number of corpora lutea, the sum of
      transferable embryos, degenerate embryos, and unfertilized oocytes, or the number
      of transferable embryos. Treatment of recipient heifers with rbST (Experiment 3)
      did not affect pregnancy rates for either in vitro or in vivo produced embryos.
      We conclude that superovulatory response and pregnancy rates (respectively) are
      similar to control for rbST-treated cows undergoing repeated superovulations and
      rbST-treated recipient heifers treated at the time of embryo transfer.

PMID- 12600730
TI  - Abortifacient and endocrine effects of metergoline in beagle bitches during the
      second half of gestation.
AB  - The purpose of this study was to investigate the abortifacient effects of high
      doses of metergoline when administered to pregnant beagle bitches during the
      second half of gestation and to define the endocrine effects of this treatment as
      represented by plasma progesterone and estradiol concentrations. Previously,
      metergoline had been shown to be incompletely luteolytic and induced abortion in
      only one of eight pregnant bitches when 0.4-0.5 mg/kg were administered twice
      daily for 5 days from Days 18 to 20 of diestrus. Nine pregnancies in six beagle
      bitches were used for the present study. Three bitches were treated in each of
      two consecutive pregnant cycles. Metergoline was administered at a dose of 0.6
      mg/kg per os twice daily, starting on Day 28 after the cytological onset of
      diestrus. Abortion was induced in eight of the nine treated pregnancies and
      started after 3-23 days of treatment (mean 12.5 days, S.D. 6.4 days). The
      abortions were completed within 0.5-8 days (mean 2.2 days, S.D. 2.7 days). There
      were no side effects associated with metergoline treatment and none of the
      abortions was associated with complications that required intervention. In the
      single bitch that did not abort, an ovarian granulosa cell tumor was discovered
      when the single fetus had to be removed surgically at term. Plasma progesterone
      concentrations declined after the start of metergoline administration in all
      pregnancies but levels below 4.8 nmol/l were required for successful abortions.
      Plasma estradiol concentrations showed a tendency to decline and fluctuate
      concurrently with the plasma progesterone levels. However, suppression of plasma
      estradiol concentrations by metergoline was not as complete as the suppression of
      progesterone and did not seem a prerequisite for abortion. The hormone profiles
      and treatment period required for abortion tended to be similar for both cycles
      of the three bitches that were treated during two consecutive pregnancies. This
      suggests a bitch effect on the factors that determine the efficacy of metergoline
      to induce abortion. The large variation and length of the treatment period that
      was required until abortion commenced was probably related to the relatively
      early start of treatment compared to other studies. The results of this
      investigation suggest that, similar to other prolactin suppressing ergot
      derivatives, metergoline causes complete luteolysis and can be used to reliably
      induce abortion only during the last 3 weeks of gestation.

PMID- 12600731
TI  - Early pregnancy diagnosis in sheep by progesterone and pregnancy-associated
      glycoprotein tests.
AB  - The aim of this study was to compare the accuracy of the progesterone (P4) and
      pregnancy associated glycoprotein (PAG) tests for determination of early
      pregnancy in sheep. Estrus was synchronized in 182 Awassi x Merino ewes and blood
      samples were collected at Days 0 (day of the insemination), 18, 22, 29, 36, and
      50 after artificial insemination (AI). Plasma P4 concentrations at Days 0 and 18
      were determined by double antibody radioimmunoassay, while PAG concentrations at
      Days 22, 29, 36 and 50 were determined by a heterologous, double-antibody
      radioimmunoassay (RIA) using the bovine PAG 67 kDa subunit as tracer and standard
      and rabbit antiserum raised against a mixture of caprine 55 and 59 kDa PAG
      subunits as the first antibody. The discriminatory value for diagnosis of
      pregnancy by the P4 and the PAG-RIA tests was > or = 1 ng/ml. Based on lambing
      data, the accuracy for diagnosing pregnant (sensitivity) and non-pregnant ewes
      (specificity) and predictivity of both tests were calculated. The sensitivity,
      specificity, positive and negative predictive values for P4 and PAG tests were
      100, 95.4, 81.6, and 100% at Day 18 (P4) and 93.5, 100, 100 and 98.7% at Day 22
      (PAG), respectively. For diagnosis of non-pregnant ewes the PAG test had
      significantly higher specificity than the P4 test (P < 0.05). It is concluded
      that ovine pregnancy can be reliably diagnosed at Day 22 after AI by using a
      heterologous radioimmunoassay of PAG.

PMID- 12600732
TI  - Improvement of a porcine somatic cell nuclear transfer technique by optimizing
      donor cell and recipient oocyte preparations.
AB  - This study was conducted to improve a porcine somatic cell nuclear transfer
      (SCNT) technique by optimizing donor cell and recipient oocyte preparations.
      Adult and fetal fibroblasts, and cumulus and oviduct cells were used as donor
      cells, and in vivo- and in vitro-matured oocytes were employed as recipient
      oocytes. The percentages of fusion and development to the blastocyst stage, the
      ratio of blastocysts to 2-cell embryos, and cell number of blastocysts were
      monitored as experimental parameters. In Experiment 1, donor cells of four
      different types were transferred to enucleated oocytes matured in vitro, and more
      (P < 0.05) blastocysts were derived from SCNT of fetal fibroblasts than from that
      of other cells (15.9% versus 3.1-7.9%). For SCNT using fetal fibroblasts,
      increasing the number of subcultures up to 15 times did not improve developmental
      competence to the blastocyst stage (12.2-16.7%). In Experiment 2, fetal
      fibroblasts were transferred to enucleated oocytes that matured in vivo or in
      vitro. When parthenogenetic activation of both types of oocytes was conducted as
      a preliminary control treatment, a significant increase in blastocyst formation
      was found for in vivo-matured compared with in vitro-matured oocytes (36.4%
      versus 29.5%). However, no improvement was achieved in SCNT using in vivo-matured
      oocytes. In conclusion, the type of donor somatic cell is important for improving
      development after porcine SCNT, and fetal fibroblasts were the most effective
      among examined cells. A system with good reproducibility has been established
      using fetal fibroblasts as the donor karyoplast after subculturing 1-10 times,
      and using both in vivo and in vitro-matured oocytes as the recipient cytoplast.

PMID- 12600733
TI  - Ultrasonographic appearance of clinically healthy testicles and epididymides of
      rams.
AB  - The clinically healthy testicles and epididymides of 31 rams were imaged inside
      and outside the breeding period, by using a real time ultrasound scanner. A
      scanning technique based on multiple imaging planes from the caudal and the
      lateral surface of the genitalia was employed. Optimum imaging was achieved by
      using a 6.0 MHz frequency sector transducer. The testicular parenchyma appeared
      homogeneous with a coarse medium echo-pattern. The mediastinum testis was present
      in 87% of rams and 77% of testicles; its median echogenicity score was 2 (range:
      0-3) among rams aged 13 months or older and 1 among rams aged less than 13 months
      (P = 0.001). The tail of the epididymis was always clearly visible; it appeared
      less echoic than the testicular parenchyma and with a heterogeneous structure.
      The epididymal body was not visible, whilst the epididymal head was consistently
      partially imaged. The pampiniform plexus was clearly imaged as a dome-shaped
      structure masking the upper part of the head of the epididymis. The scrotal
      septum was seen in lateral sonograms as a highly echogenic line between the
      testicles. The scrotal skin formed a thick hyper-echoic peripheral structure.

PMID- 12600734
TI  - Identification of sperm subpopulations with specific motility characteristics in
      stallion ejaculates.
AB  - The aim of this study was to test the presence of separate sperm subpopulations,
      with specific motility characteristics, in stallion ejaculates by using a
      computer-assisted semen motility analysis (CASA) system. Motility data were
      analyzed with a hierarchical clustering of variables based on a correlation or
      covariance matrix to select like parameters of sperm motility descriptors that
      better explain the kinetics of spermatozoa. The statistical analyses clustered
      the whole motile sperm population in both fresh and 24 h stored ejaculates into
      four separate groups. There were significant differences in the distribution of
      the four subpopulations (P < 0.001) as well as in the total sperm number and the
      percentage of total motility (P < 0.01) in fresh semen among the five stallions
      tested. Our results show that separate subpopulations of spermatozoa with
      different motility characteristics coexist in stallion ejaculates. These
      subpopulations were maintained, although with a less-progressive motion pattern,
      after 24 h of storage. The study of subpopulations in ejaculates that have
      confirmed fertilizing capacity showed that the majority of the motile spermatozoa
      in these ejaculates are included in a subpopulation with high progressive
      motility and low linearity, and the ejaculates with proven fertility that have a
      total sperm count > or = 20 x 10(9) spermatozoa/ejaculate show all of their
      motile sperm included in this subpopulation. Our results show that the use of the
      CASA system is a relatively simple approach to the study of sperm subpopulation
      patterns in equine ejaculates.

PMID- 12600735
TI  - Effect of pretreatment with bovine somatotropin (bST) and/or gonadotropin
      releasing hormone (GnRH) on conception rate of dairy cows with ovarian cysts
      subjected to synchronization of ovulation and timed insemination.
AB  - The objective of this study was to determine the effect of pretreatment with
      bovine somatotropin (bST) and/or gonadotropin-releasing hormone (GnRH) 7 days
      prior to initiation of a protocol for synchronization of ovulation and timed
      insemination (Ovsynch) on conception rate (CR) of cows with ovarian cysts. A
      total of 254 lactating dairy cows with ovarian cysts was divided into four groups
      (Day 0). On Day 0, cows in Group 1 (n = 61) were pretreated with 500 mg bST,
      s.q., and 100 microg GnRH, i.m.; cows in Group 2 (n = 73) were pretreated with
      100 microg GnRH, i.m.; cows in Group 3 (n = 59) were pretreated with 500 mg bST,
      s.q.; and cows in Group 4 (n = 61) received no pretreatment. All cows were
      subjected to the Ovsynch protocol 7 days later. All cows previously received
      routine bST treatment every 14 days until milk production decreased to a minimum
      level established by the management of the herd. CR was assessed using logistic
      regression after adjusting for timing of concurrent bST treatment relative to Day
      0, parity, season at time of insemination, and days in milk (DIM) on Day 0. CR
      for cows in Group 3 (12%) was significantly lower (P < 0.05) than that for cows
      in Group 4 (27%), and CR for cows in Group 1 (18%) and Group 2 (15%) tended to be
      lower (P < 0.10) than that for cows in Group 4 (27%). From the results of this
      study, it was concluded that bST pretreatment decreased CR, and pretreatment with
      GnRH, and GnRH with bST tended to decrease CR in lactating dairy cows with
      ovarian cysts concurrently treated with bST and subjected to the Ovsynch
      protocol.

PMID- 12600737
TI  - Effect of follicle-stimulating hormone on nuclear and cytoplasmic maturation of
      sow oocytes in vitro.
AB  - A series of experiments were conducted to evaluate the effects of FSH
      supplementation during IVM on porcine oocyte nuclear maturation, and subsequent
      fertilization, cleavage and embryo development. Cumulus-oocyte complexes (COCs)
      were cultured 40 h without FSH (control), 40 h with FSH (FSH 0-40 h), or 20 h
      with FSH followed by a 20-h culture period without FSH (FSH 0-20 h). Nuclear
      stage of oocytes was assessed at intervals from 12 to 40 h of IVM. Furthermore,
      oocytes were in vitro fertilized, fixed and stained to determine normally
      fertilized and polyspermic oocytes. Additionally, COCs were matured with FSH,
      fertilized and zygotes cultured in NCSU-23. The percentage of cleaved embryos and
      blastocysts were determined and the number of nuclei was counted. The presence of
      FSH during the first 20 h of IVM retarded germinal vesicle breakdown. After 40 h
      of culture 84, 67 and 58% MII oocytes were observed in the FSH 0-20 h, FSH 0-40 h
      and control groups, respectively. After IVF, penetration rates were similar at
      27, 26 and 29%, while the proportion of polyspermic oocytes was 7, 19 and 11% of
      penetrated oocytes for control, FSH 0-40 and FSH 0-20 h groups, respectively.
      Cleavage and blastocyst rates differed among treatments (21, 29 and 38%, and 7,
      15 and 20% for control, FSH 0-40 and FSH 0-20 h groups, respectively). No
      differences in blastocyst cell number were found among groups. Blastocyst rates,
      based on number of cleaved embryos, were 51 and 52% for the FSH 0-40 and FSH 0-20
      h groups, which differed significantly from the control group (31%). The results
      indicate that FSH has a stimulatory effect on nuclear and cytoplasmic maturation
      of sow oocytes. Addition of FSH for the first 20 h of culture was most
      beneficial, based on cleavage and blastocyst development rates.

PMID- 12600736
TI  - Innervation of vas deferens and accessory male genital glands in the water
      buffalo (Bubalus bubalis). Neurochemical characteristics and relationships to the
      reproductive activity.
AB  - Autonomic nerves supplying mammalian male internal genital organs have an
      important role in the regulation of reproductive function. To find out the
      relationships between the neurochemical content of these nerves and the
      reproductive activity, we performed a histochemical and immunohistochemical study
      in a species, the water buffalo, exhibiting a seasonal sexual behaviour. The
      distribution of noradrenergic and nitric oxide synthase (NOS)- and peptide
      containing nerves was evaluated during the mating and non-mating periods. Fresh
      segments of vas deferens and accessory genital glands were collected immediately
      after slaughter and immersed in 4% paraformaldehyde. Frozen sections were
      obtained and processed according to single and double labelling immunofluorescent
      procedures or NADPH-diaphorase histochemistry. During the mating period, a dense
      noradrenergic innervation was observed to supply the vas deferens as well as the
      accessory genital glands. NOS- and peptide-containing nerves were also observed
      but with a lower density. During the non-mating period noradrenergic nerves
      dramatically reduced. In addition, neuropeptide Y (NPY)- and vasoactive
      intestinal peptide (VIP)-containing nerves were also reduced. These findings
      suggest the presence of complex interactions between androgen hormones and the
      autonomic nerve supply in the regulation of male water buffalo reproductive
      functions.

PMID- 12600738
TI  - The 5th EFIS Tatra Immunology Conference on 'Molecular determinants of T cell
      immunity' held in the High Tatra Mountains, Slovakia, September 7-11, 2002.

PMID- 12600739
TI  - Technique for obtaining highly enriched, quiescent immature Langerhans cells
      suitable for ex vivo assays.
AB  - Epidermis and surface epithelium-dendritic cells comprise of immature cells
      termed Langerhans cells (LCs), which express characteristically the Birbeck
      granules, along with surface markers such as CD1a. These cells can capture a
      pathogen and then migrate and differentiate to a more mature stage. During this
      maturation process, dentritic cells express surface markers differentially. In
      physio-pathological models of infection where LCs are involved, it is critically
      important to ensure that the LCs tested in vitro are still immature and are not
      artefactually matured-dentritic cells. For experimental purposes, LCs were
      isolated from skin epidermis obtained from patients undergoing plastic surgery.
      This work thus aimed at collecting fresh LCs ex vivo and at testing the cells for
      phenotypic and functional characteristics of the immature stage. After mechanic
      disruption of the epidermis and proceeding for single cell suspension obtaining,
      two methods for purification were tested in parallel: (a) a positive immuno
      magnetic separation by anti-CD1a-coated beads and (b) a purely mechanic
      purification system based on a three-step Ficoll floatation process. Both systems
      were equally efficient in terms of purification and yield. By using flow
      cytometry phenotyping, we have demonstrated that the use of magnetic beads led to
      some degree of maturation of CD1a(+) LCs, contrary to the repeated Ficoll
      floatation. This work calls attention for the use of certain monoclonal
      antibodies such as anti-CD1a to purify immature dendritic cells as they pre
      activate these cells. Pre-activation would render a number of assays on the early
      events of LC physiology invalid, contrary to the purification of fresh skin
      epidermis LCs by means of a repeated Ficoll floatation.

PMID- 12600740
TI  - Modulation of proliferation, differentiation and cytokine secretion of murine B
      1b cells by proteins of the extracellular matrix.
AB  - At least three B cell subsets, B-1a (Ly-1B), B-1b and B-2, are present in the
      mouse periphery. B-1a and B1-b cells represent a small population in the adult
      spleen and are abundant in the peritonial and pleural cavities. It has been
      demonstrated in our laboratory that B-1b cells spontaneously proliferated in
      stationary cultures of adherent peritonial cells. Further, that these cells
      migrate to a non-specific inflammatory focus. Based on these findings, it was
      investigated whether components of the extracellular matrix (ECM) might
      selectively influence the adherence, proliferation and cytokine production of
      these cells in vitro. Results showed that collagen induced a higher level of B-1b
      cells differentiation into adherent phagocytic cells. It was observed that only
      fibronectin induced higher level of proliferation than other matrix components.
      The analysis of cytokine production has shown that the presence of laminin
      stimulated B-1b cells led to high levels of IL-10 production and fibronectin and
      collagen induced the production of high levels of TNF-alpha. The combination of
      fibronectin, collagen and laminin induced higher levels of IL-1beta. These
      results demonstrate that differentiation, proliferation and cytokine production
      by B-1b cells are markedly influenced by ECM components.

PMID- 12600742
TI  - Effect of BCG vaccination on cytokine mRNA expression in atopic children with
      asthma.
AB  - BACKGROUND: To investigate whether a preexisting T(H2)-type immune response could
      be suppressed by BCG immunization in atopic children with asthma. METHODS AND
      RESULTS: We have used PCR to amplify reverse transcribed (RT) IFN-gamma and IL-5
      mRNA expressed by peripheral blood mononuclear cells (PBMCs) in response to in
      vitro phytohemagglutinin A, purified protein derivative and Dermatophagoides
      pteronyssinus II stimulation from nine atopic children, both before and 8 weeks
      after BCG vaccination. We have demonstrated that IFN-gamma expression was induced
      in response to all stimulants (IFN-gamma/beta-actin) after the vaccination,
      whereas there was no expression before (P<0.001). Although there was a tendency
      to diminish in the expression of IL-5 mRNA in response to the stimulants, only
      PHA rendered a statistically significant decrease after the vaccination.
      CONCLUSIONS: These results provide some evidence of TH1 dominance after BCG
      administration in atopic children.

PMID- 12600741
TI  - Galactoside-specific plant lectin, Viscum album agglutinin-I induces enhanced
      proliferation and apoptosis of murine thymocytes in vivo.
AB  - Galactoside-specific plant lectin, Viscum album agglutinin-I (VAA-I) has been
      shown to act as a biomodulator with proinflammatory and apoptosis-inducing
      effects, however its cellular targets and mechanism of immunobiological action in
      vivo are less well understood. Therefore, in the present work the short- and long
      term in vivo effects of VAA-I on thymocyte subpopulations and peripheral T cells
      were tested using a murine (Balb/c) model. Cell surface CD4/CD8 staining and flow
      cytometry allowed us to follow the changes of thymocyte subpopulations: CD4-CD8-
      double negative (DN), CD4+CD8+ double positive (DP), CD4+ or CD8+ single positive
      (SP) and mature peripheral T cells after single or repeated injections with low
      doses of VAA-I. The apoptosis of the cells was detected by flow cytometry using
      propidium iodide (PI) and Annexin V staining. To detect the short-term effects of
      the lectin, the animals were investigated 24 h after a single injection of 1 or
      30 ng/kg body weight (BW) VAA-I+/-1 mg/kg Dexamethasone (DX). The total number of
      mature CD8+ SP thymocytes increased significantly with an enhancement of the
      ratio of apoptotic cells. In contrast, in the blood samples an elevated CD4/CD8
      ratio was found. In the next trial, Balb/c mice were treated twice weekly with 1
      or 30 ng/kg VAA-I+/-1 mg/kg DX for 3 weeks. The total cell count of thymocytes
      showed significant increases after both doses of VAA-I, but an elevated
      percentage of apoptotic cells was found only after treatment with 30 ng/kg VAA-I.
      SP thymocytes revealed higher increases in lectin-induced apoptosis than DN or DP
      cells. In addition, both lectin doses significantly inhibited the DX-induced
      reduction of all thymocyte subpopulations investigated. In conclusion, our data
      suggest that VAA-I is able to modulate the maturation of thymocytes in vivo.

PMID- 12600743
TI  - Transforming growth factor-beta induces apoptosis in antigen-specific CD4+ T
      cells prepared for adoptive immunotherapy.
AB  - Transforming growth factor-beta (TGF-beta), found at the site of most tumors, has
      been recognized as one of the mechanisms involved in tumor immunological escape.
      To evaluate its impact on adoptive immunotherapy against cancer, we examined the
      susceptibility of tumor-specific T cells to TGF-beta in the setting of these T
      cells being prepared for adoptive transfer. Hepatitis B virus (HBV)-specific
      CD4(+) T cells were ex vivo generated by activating with HBV-transfected
      dendritic cells and selecting with antibodies to CD25 activation molecules, and
      then expanded with antibodies to CD3/CD28. These T cells expressed higher levels
      of the type II TGF-beta receptor than nai;ve T cells and exhibited enhanced
      apoptosis when exposed to TGF-beta. The underlying apoptotic pathway was linked
      to the dissipation of the mitochondrial inner membrane potential and activation
      of caspase-9. The absence of caspase-8 activity in TGF-beta-treated T cells
      suggests that the death receptor system may not be involved in this type of
      apoptosis. Interleukin-2 (IL-2), which is concomitantly administered with tumor
      specific T cells in adoptive immunotherapy, was unable to protect HBV-specific
      CD4(+) T cells from the pro-apoptotic effect of TGF-beta when added
      simultaneously with TGF-beta. Interesting, IL-2-pretreated T cells displayed the
      type II TGF-beta receptor at lower levels and were more resistant to TGF-beta.
      Together, our findings indicate that the effectiveness of adoptive cancer
      immunotherapy may be impaired by tumor-derived TGF-beta and appropriate
      manipulation of exogenous IL-2 might overcome this hurdle.

PMID- 12600745
TI  - Monoclonal antibodies detecting differentiation antigens on human leukocytes.

PMID- 12600744
TI  - Molecular characterization of a human monoclonal antibody to B antigen in ABO
      blood type.
AB  - A human anti-B antibody of clone BT97 was obtained from a healthy individual of
      type A of the ABO blood group without immunization. Cloning was performed by
      means of heterohybridoma formation of cell fusion between human peripheral
      lymphocytes and mouse myeloma cells. The antibody selectively reacted with B
      antigen in flow cytometry using red blood cells and enzyme-linked immunosorbent
      assay. The VH and VL genes of BT97 were derived from the germline genes of DP-47
      and 3p.81A4, respectively, with a couple of somatic mutational events.
      Comparative analysis with other reported anti-A, B and H antibodies revealed that
      the amino acid sequence of the VH region was more homologous than that of the VL
      region. The sequence of BT97 showed complete identity with one anti-H natural
      antibody reported by Marks et al., with the exception of the CDR3 region. It is
      not known whether the homologies include the common properties of the natural
      antibodies; however, a particular germline gene potentially changes to anti-ABH
      antibodies. We think that this method is suitable for cDNA preparation of human
      monoclonal antibodies to blood group antigens and for sequence analysis.

PMID- 12600746
TI  - The Polycomb-group protein ENX-2 interacts with ZAP-70.
AB  - Human ENX-2 is a homologue of Drosophila Enhancer of zeste, which is a member of
      Polycomb-group proteins regulating the expression of homeotic genes as chromatin
      associated proteins. In this study, we demonstrate that ENX-2 plays an important
      role as a signaling molecule involved in T cell receptor-mediated signaling
      pathway. In immunoprecipitation experiments, ENX-2 and zeta associated protein-70
      (ZAP-70) were co-precipitated from T cell lysate. When probed with an anti
      phospho-tyrosine antibody, ENX-2 was found to be phosphorylated on tyrosine. On
      the other hand, ENX-2 was not phosphorylated on tyrosine in the mutant Jurkat
      cell, J.Cam1.6 lacking the activity of lymphocyte protein tyrosine kinase
      p56(lck). The interaction between ENX-2 and ZAP-70 was abolished in the mutant
      cell. Furthermore, in-vitro kinase assay using purified p56(lck) demonstrated
      that ENX-2 became tyrosine phosphorylated by this kinase. These findings show
      that the phosphorylation of ENX-2 is responsible for the interaction between ENX
      2 and ZAP-70.

PMID- 12600747
TI  - Characterization of monoclonal antibodies specific to the transcription factor
      ETS-2 protein.
AB  - ETS-2 is a member of the ETS family of transcription factors. ETS-2 was initially
      characterized as a nuclear oncogene and has been shown to play a role in
      regulation of apoptosis and cell cycle progression. Members of the ETS family
      display high sequence homology, thus, there is considerable controversy
      concerning the specificity of existing ETS-2 polyclonal antibodies that have been
      used to define ETS-2 function. We therefore embarked on the production of ETS-2
      specific monoclonal antibodies. In this report, we describe the production and
      characterization of six antibodies and the localization of their target epitopes
      to distinct domains of the ETS-2 protein. Four antibodies are ETS-2 specific and
      two antibodies cross-react with ETS-1, an ETS family member with the highest
      amino acid sequence homology to ETS-2. This report provides a comprehensive
      evaluation of ETS-2 specific monoclonal antibodies verified using ETS-2 null
      cells. These antibodies can be used for EMSA, Western blotting,
      immunoprecipitation and immunofluorescence staining experiments. Collectively,
      these reagents are invaluable molecular tools that should help better understand
      the biological function of ETS-2.

PMID- 12600748
TI  - Passive immunization of mice pups through oral immunization of dams with a plant
      derived vaccine.
AB  - Passive immunization plays an important role in protecting young mammals against
      pathogens before the maturation of their own immune systems. Although many
      reports have shown active immunization of animals and human through the use of
      plant-derived vaccines, only one report has given evidence of passive
      immunization of offspring through oral immunization of parents using plant
      derived vaccines. In this case, a challenge alone provided the evidence of
      passive immunization and the mechanism through which this occurred was not
      investigated. This report describes the first step in elucidating the mechanism
      of passive immunization of offspring through actively immunizing the female
      parent through an orally delivered, plant-derived vaccine. The authors found
      passive immunization of offspring was caused by transfer of antigen-specific IgG
      through either transplacental transfer or ingesting colostrum. Future studies
      will investigate the roles of transplacental antibody transfer and ingesting
      colostrum in passive immunization and the possible involvement of IgA in this
      immunization route.

PMID- 12600749
TI  - Effect of the Emu IgH enhancer on expression of a GFP reporter gene in
      transfected B cells and transgenic mice.
AB  - Transgenic mice were generated to identify the first B cell maturation stage
      showing expression of an immunoglobulin transcriptional enhancer element (Emu)
      green fluorescent protein (GFP) transgene, and to check the ability of the Emu
      element to behave as a locus control region. Flow cytometry experiments indicated
      that stably transfected 18-81 cells (a murine pre-B cell line) and A20 cells (a
      murine IgM(+) B cell line) maintained a constant GFP expression for several
      months in culture. Contrasting with in vitro results, flow cytometry experiments
      did not highlight GFP(+) B cells in spleen and bone marrow of Emu-GFP transgenic
      mice and no GFP transcripts were detected by Northern blot and reverse
      transcriptase polymerase chain reaction analysis. In transgenic mice, the lack of
      GFP expression seemed related to transgene DNA methylation occurring within all
      organs. Our results show dramatic differences for expression of the Emu-GFP
      transgene in vitro and in vivo. Despite that Emu was reported to efficiently
      control the in vivo expression of other associated transgenes, it is not
      sufficient to sustain GFP expression in transgenic mice and to counteract
      developmental silencing programs that occur in the embryo.

PMID- 12600751
TI  - Impaired thymic output and restricted T-cell repertoire in two infants with
      immunodeficiency and early-onset generalized dermatitis.
AB  - We evaluated the T-cell repertoire and the thymic output in two infants, one with
      Omenn Syndrome (OS) and another with complete DiGeorge Syndrome (DGS), who
      developed generalized dermatitis. The patients shared common T-cell
      abnormalities, as demonstrated by the low response to mitogenic stimulation, by
      an unusual usage of specific T-cell receptor (TCR) segments, and by a reduction
      of TCR diversity in both alpha/beta and gamma/delta populations. Furthermore,
      they both showed an impaired thymic function, as assessed by the low number of
      TCR recombination excision circles, which are formed from excised DNA during the
      rearrangement of TCR genes. These data indicated that generalized erythrodermia
      may be present in different forms of T-cell immunodeficiency and may reflect
      intrinsic defects in either V(D)J recombination or in thymic development, leading
      to the peripheral expansion of T-cell clonotypes, that bear peculiar TCR chains.

PMID- 12600750
TI  - Naturally occurring immune response against bacteria commonly involved in upper
      respiratory tract infections: analysis of the antigen-specific salivary IgA
      levels.
AB  - Lyophilized bacterial lysates, which actively stimulate the immune response, are
      widely used as vaccines or 'biological response modifiers' in subjects with
      recurrent bacterial respiratory infections. Since vaccines are indicated in the
      absence or in the presence of a weak constitutive immune response activity, a
      better knowledge on the 'naturally' occurring antibacterial immune response at
      the oropharingeal level should be helpful. A study was, therefore, designed to
      quantify the presence of salivary IgA directed against surface antigens bacteria
      frequently involved in the pathogenesis of upper respiratory tract infections:
      Klebsiella pneumoniae (KP), Staphylococcus aureus (SA), Streptococcus pyogenes
      (SPy), Morraxella catarrhalis (MC), Haemophylus influenzae (HI), and
      Streptococcus pnumoniae (SPn). In 34 volunteers (21 adults and 13 children),
      salivary fluid was collected and the presence of microorganism-specific IgA
      antibodies evaluated by a novel enzyme immuno-assay. In the whole population only
      29 and 24% of subjects had IgA directed, respectively, to KP and SA, while the
      immune-response against other microbes was detectable in a small population
      ranging from 12 to 15% of all subjects studied. We found higher proportions of
      individuals with strain specific salivary IgA in the adult than in the pediatric
      population for all the microorganism evaluated. In addition, in children, the
      only strain inducing a significant production of specific IgA at oropharingeal
      level was KP. Interestingly, only ten out of 21 adults and two out 13 children
      have at least one significantly high antibody titer against one of the bacteria
      evaluated. Nevertheless, when a group of healthy donors was treated with a
      polyvalent mechanical bacterial lysate (Ismigen t.), the large majority developed
      a specific immune-response in the salivary fluid. These results are thus
      consistent with the good features of the novel enzyme-immunoassay and with a poor
      frequency of naturally induced specific anti-microbe antibodies in children and
      in adults despite the presence on recurrent respiratory infections in their
      clinical history.

PMID- 12600752
TI  - Granulocyte-macrophage colony stimulating factor is an anti-apoptotic cytokine
      for thymic dendritic cells and a significant modulator of their accessory
      function.
AB  - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth-promoting
      factor for myeloid-derived dendritic cells (DC) but not for lymphoid DC. The data
      about its effect on thymic DC (TDC), which are both of lymphoid and myeloid
      origin, are very scarce. Using an in vitro model, we demonstrated in this work
      that GM-CSF significantly increased the survival of rat TDC in culture by
      inhibiting their apoptosis and the effect correlated with up-regulation of Bcl-2
      expression. GM-CSF also stimulated differentiation and maturation of TDC as
      judged by higher expression of MHC class I and II molecules, CD54, CD80 and CD86.
      These changes correlated with stronger stimulatory activity of GM-CSF-pulsed TDC
      in syngeneic thymocyte proliferation assay and MLR. The stimulatory potential of
      TDC was further increased when thymocytes were cultivated with an anti-alphabeta
      TCR (R73) monoclonal antibody (mAb). The influence of unstimulated TDC on
      proliferation of thymocytes was inhibited by anti-CD86 but not anti-CD80 mAb,
      whereas in cultures with GM-CSF-treated TDC both mAbs exerted an additive
      blocking effect. After separation of TDC on CD11b(+) and CD11b(-) we demonstrated
      that GM-CSF inhibited apoptosis and potentiated accessory activity of both TDC
      subsets independently of the myeloid marker expression. Cummulatively, our
      results suggest that GM-CSF is one of the regulatory cytokine involved in
      survival, maturation, differentiation and accessory function of TDC.

PMID- 12600753
TI  - Perforin-dependent killing of tumor cells by Vgamma1Vdelta1-bearing T-cells.
AB  - The T-cell subset expressing Vdelta2 paired primarily with Vgamma2 comprises a
      majority of gammadelta T-cells in human adult peripheral blood and expands
      significantly during a variety of infectious diseases. In contrast, the other
      subset of gammadelta T-cells that express Vdelta1 is rare among circulating T
      cells and its function is poorly understood. Here, we show that a
      Vgamma1Vdelta1(+) T-cell line, 3-D, established from human peripheral blood by
      immortalization with Herpesvirus saimiri was able to specifically recognize tumor
      cells, such as K562 cells, and release cytotoxic granules containing perforin for
      target cell killing. Some tumor cells, including Daudi cells that are known to be
      susceptible to killing by Vdelta2(+) T-cells, were resistant to 3-D killing,
      implicating distinct pathways for tumor cell control by Vdelta1(+) and Vdelta2(+)
      T-cells. The 3-D T-cell receptor (TCR):CD3 complex reconstituted in TCR-deficient
      Jurkat cells was capable of transmitting signals, evidenced by activation of the
      interleukin 2 (IL-2) gene following ligation with anti-CD3 antibody, yet the TCR
      reconstituted cells failed to produce IL-2 in response to the target cells. Thus,
      these results raise the possibility that some Vgamma1Vdelta1(+) T-cells could
      potentially be stimulated and lyse tumor cells via ligation of TCR/CD3
      unassociated molecules.

PMID- 12600754
TI  - COX-3: in the wrong frame in mind.

PMID- 12600755
TI  - Exposure to (226)Ra from consumption of vegetables in the high level natural
      radiation area of Ramsar-Iran.
AB  - The vegetable-to-soil concentration ratio (CR) for (226)Ra and the related
      effective dose were studied in Talesh Mahalleh, a district of the city of Ramsar
      in Iran with a high level of natural radiation (HLNR). Maximum and minimum CR
      were measured in leafy and root vegetables with average values of 1.6 x 10(-2)
      and 4.0 x 10(-3), respectively. The mean effective dose resulting from (226)Ra
      due to consumption of edible vegetables by adults in the critical group in this
      region was estimated to be 72.3 microSv a(-1). This value is about 12 times
      greater than the average of effective dose resulting from this radionuclide due
      to combined intake of all foods and drinking water in normal background areas.

PMID- 12600756
TI  - The use of extraction chromatography resins to concentrate actinides and
      strontium from soil for radiochromatographic analyses.
AB  - An analytical technique utilizing selective extractant resins to concentrate
      strontium and actinides from soil followed by separation with radiochromatography
      was evaluated. The technique was tested using uncontaminated soil samples spiked
      with a radionuclide tracer solution that were either microwave-aided acid
      digested or leached with a strong acid. Extraction of the strontium and actinides
      from the acidified solution was accomplished using a serial arrangement of Sr
      Resin and TRU-Resin columns. The combined eluate solutions from the extraction
      resins were treated with HNO(3) and H(2)O(2) to oxidize residual extractant and
      eluates prior to separation and analysis of the radionuclides by
      radiochromatography. Chromatograms obtained with larger soil mass loadings
      resulted in either incomplete peak resolution of the tracers or had highly
      variable peak elution times, indicative of an ionic interfering constituent(s).
      Better separations (e.g., chromatograms that resolved all radioactive
      constituents) were obtained when the sample mass loading was decreased, but with
      a concurrent decreased sensitivity for the radionuclides. Elemental analyses of
      the soil were conducted to provide data on the ionic constituents in unprocessed
      soil and post-processed soil samples. These results identified aluminum as an
      interfering contributor to the poor performance exhibited by the
      radiochromatographic separations.

PMID- 12600757
TI  - Indoor radon levels and influencing factors in houses of Patras, Greece.
AB  - Measurements of indoor radon concentrations were performed in 28 low-rise houses
      and 30 apartments in Patras area from December 1996 to November 1997, using
      nuclear track detectors. The investigation was focused on the effects of season
      and floor number, as well as on the existence of a basement in low-rise houses on
      indoor radon levels. It was found that the differences in mean radon
      concentrations between adjacent seasons, in a number of 61 selected sampling
      sites distributed in 28 houses, were statistically significant. As expected, a
      maximum was found in winter and a minimum in summer. The differences in mean
      radon concentration on different floors of the same houses were also
      statistically significant and followed a linear decrease from underground to 2nd
      floor. In addition, indoor radon concentrations in the ground floor were found to
      be influenced by the existence or not of a basement. The average annual radon
      concentration was found to be 41 Bq m(-3) for the houses, 28 Bq m(-3) for the
      apartments and 38 Bq m(-3) for all the dwellings. These values lead to an average
      effective dose equivalent of 1.1, 0.7 and 0.9 mSv y(-1), respectively. Residents
      living on the underground in low-rise houses, during winter, where the average
      effective dose equivalent is 2.1 mSv y(-1), attain the higher risk.

PMID- 12600758
TI  - Surface air concentration and deposition of lead-210 in French Guiana: two years
      of continuous monitoring.
AB  - To make up for the lack of data on (210)Pb aerosol deposition in tropical regions
      and to use this radionuclide as an aerosol tracer, a monitoring station was run
      for two years at Petit-Saut, French Guiana. Lead-210 concentration in air at
      ground level was monitored continuously together with atmospheric total
      deposition. The air concentration has a mean value of 0.23+/-0.02 mBq m(-3)
      during both wet and dry seasons, and it is only weakly affected by the
      precipitation mechanism. This result was unexpected in a wet tropical region,
      with a high precipitation rate. In contrast, deposition clearly correlates with
      precipitation for low/moderate rainfall (<15 cm per 15-day), while this
      correlation is masked by strong fluctuations at high rainfall. The estimated mean
      annual deposition over the last ten years is 163+/-75 Bq m(-2) y(-1). This
      provides a procedure for estimating this mean flux at other sites in French
      Guiana.

PMID- 12600759
TI  - Fluctuations of exposure rate at regional radiation monitoring stations in Korea.
AB  - Based on hourly means of exposure rate between August 2000 and July 2001 at nine
      Regional Radiation Monitoring Stations (RRMS) in Korea, we analyzed spatio
      temporal characteristics of exposure rate. The mean and fluctuations of exposure
      rates were 99 and 3.8 nGy h(-1), respectively. The hourly exposure rate over 9
      RRMS indicated a diurnal pattern with the exposure rates reaching a maximum
      between 5:00 and 8:00 a.m. in the early morning and a broad minimum between 4:00
      and 10:00 p.m. in the afternoon. The fluctuations of exposure rate in the inland
      areas were less than 3.2 nGy h(-1), and those of exposure rate in coastal areas
      were larger than 3.9 nGy h(-1). The frequency distribution of exposure rates had
      one peak around the mean and was to be skewed to the right or positively skewed
      and its tails were fatter than those of a normal distribution. The interrelations
      of exposure rates at each station generally decreased with the distance between
      the stations. Empirical orthogonal function (EOF) analysis showed that almost all
      (99.9%) of exposure rate fluctuations were described by simultaneous variations.
      The spatial distribution of the first EOF modes of actual, low-pass (periods
      longer than one month) and high-pass (periods shorter than one month) exposure
      rate series were similar to each other.

PMID- 12600760
TI  - Tritium in surface waters of the Yenisei River basin.
AB  - This paper reports an investigation of the tritium content in the surface waters
      of the Yenisei River basin near the Mining and Chemical Combine (MCC). In 2001
      the maximum tritium concentration in the Yenisei River did not exceed 4 +/- 1 Bq
      l(-1), which is consistent with the data of 1998-99. However, it has been found
      that there are surface waters containing enhanced tritium as compared with the
      background values for the Yenisei River. For instance, in the Ploskii Stream and
      the Shumikha River the maximum tritium concentrations amount to 168 and 81 Bq l(
      1), respectively. The source of tritium in these surface waters is the last
      operating reactor at the MCC, which still uses the Yenisei water as coolant. In
      water and sediment samples of the Bolshaya Tel River (a tributary of the Yenisei
      River) the tritium content turned out to be at least 10 times higher than the
      background values for the Yenisei River. The measurements conducted at the RPA
      RADON (Moscow) revealed not only tritium but also the artificial radionuclide
      (14)C in the Bolshaya Tel samples. The data obtained suggest that the Bolshaya
      Tel River receives the major part of tritium from sediments rather than from the
      water catchment area. This allows the conclusion that there is water exchange
      between the surface waters and the radioactively contaminated underground
      horizons of the "Severny" testing site.

PMID- 12600761
TI  - Validating riverine transport and speciation models using nuclear reactor-derived
      radiocobalt.
AB  - Risk assessment of intentional or accidental discharges of toxic substances into
      river systems requires combined hydraulic and chemical modeling. Periodic
      discharges of known volumes with low radioactivity by the Beznau nuclear reactor
      (Switzerland) serve as validation tracers for both river flow and chemical
      speciation simulation. Validation of the former has been achieved by comparison
      of modeled and measured arrival times of radiocobalt along a 65 km transect with
      a maximum reaction period of 24 hours. Modeled breakthrough curves coincide well
      with measurements collected during three field campaigns, in spite of the fact
      that sorption and sedimentation processes were not activated during simulation.
      This gives indirect evidence of inefficient cobalt sorption. Particle/solution
      distribution measurements carried out during breakthrough allow further
      validation of our speciation approach, which is based on Tableau setup of
      inorganic reactions combined with sorption and organic complexation. Modeled and
      measured speciation results confirm recent observations of enhanced complexation
      of cobalt with dissolved organic substances, which significantly reduces particle
      sorption. The large variability of conditional stability constants for sorption
      and complexation reactions, for sorption site densities, and for organic ligand
      concentrations explains the variability of published particle-solution
      distribution coefficients.

PMID- 12600762
TI  - Modelling the dynamics of fish contamination by Chernobyl radiocaesium: an
      analytical solution based on potassium mass balance.
AB  - After the sudden fallout from the Chernobyl nuclear accident in 1986, activities
      and bioaccumulation factors of radiocaesium ((137)Cs, (134)Cs) fluctuated
      strongly over several years before reaching quasi-equilibrium, with patterns
      significantly differing among organisms. To model these dynamic relaxation
      processes based on ecological mechanisms we developed mass balance equations for
      (137)Cs in an aquatic food chain on the following basis: (a). potassium acts as a
      biogeochemical analogue ("carrier") of caesium; (b). the concentration of
      potassium in fish and other animals is effectively constant; (c). the main source
      of potassium in freshwater fish is the dietary uptake. The model is applicable to
      linear food chains of any number of trophic levels, while solutions evaluated
      here include the following food chain compartments: water, invertebrates (fish
      food), non-piscivorous fish, and piscivorous fish. The activity concentration in
      the water, which is considered as the secondary source of (137)Cs, is described
      by multi-component first-order decay function, although two components (fast and
      slow) are often sufficient to provide agreement with empirical data. In every
      compartment the turnover rate of caesium is considered as a constant over time.
      The analytical solution of the model equations describes the (137)Cs activity
      concentration in every compartment as a series of exponential functions, of which
      some are derived from the source pattern, and the others determined by the
      (137)Cs turnover rate in each food chain compartment. The model was tested with
      post-Chernobyl data from several long-term studies in lakes and provided a
      reasonable description of important radioecological aspects.

PMID- 12600768
TI  - Association behavior of beta-casein.
AB  - The association behavior of beta-casein, a protein with a distinct amphipathic
      character, was studied. beta-Casein exhibits markedly temperature-dependent
      association behavior; at low temperatures (<10-15 degrees C), monomers
      predominate, but as the temperature is increased, monomers associate, via
      hydrophobic bonding, into micelles. beta-Casein micelles have a hydrodynamic
      radius of approximately 12 nm, a radius of gyration of approximately 8.3 nm, and
      an interaction radius of approximately 15 nm. These data are fully consistent
      with a previous fluffy particle. The association behavior of beta-casein is also
      strongly affected by concentration and solvent quality. At low concentrations
      beta-casein exhibits a critical micelle concentration (CMC) of approximately
      0.05%, w/v, at 40 degrees C. In the presence of 6 M urea the temperature
      dependence of beta-casein's association behavior is eliminated, leaving monomers
      predominantly. Temperature-dependent transformations in micelle morphology can be
      explained by changes in solvent quality, i.e., the temperature-protein
      hydrophobicity and temperature-voluminosity profiles of beta-casein. The results
      obtained are consistent with the shell model as developed by Kegeles, in which a
      distribution of micelle sizes is formed. They contrast with the traditional
      description of the micellization of beta-casein by a two-state model or by the
      closed-association model, i.e., monomers if micelles.

PMID- 12600773
TI  - Study of the immobilization of alcohol dehydrogenase on Au-colloid modified gold
      electrode by piezoelectric quartz crystal sensor, cyclic voltammetry, and
      electrochemical impedance techniques.
AB  - The immobilization of alcohol dehydrogenase (ADH) on Au-colloid modified gold
      electrodes has been investigated. Colloidal Au was first self-assembled onto gold
      electrodes through the thiol groups of an 1,6-hexanedithiol monolayer.
      Piezoelectric quartz crystal sensor, cyclic voltammetry, and electrochemical
      impedance techniques were used to investigate the immobilization of ADH on Au
      colloids. The cyclic voltammogram tends to be more irreversible with increased
      ADH concentration. In the impedance spectroscopic study, an obvious difference of
      the electron transfer resistance between the Au-colloid modified electrode and
      the bare gold electrode was observed. Using the piezoelectric quartz crystal
      sensor, the Michaelis constant, K(m), and the maximum initial rate, V(max), of
      the immobilized ADH were estimated as 6.03 x 10(-4) M and 0.63 Hzs (-1),
      respectively. The binding constant of ADH with nicotinamide adenine dinucleotide
      (NAD) was also determined as 1.87 x 10(4) M(-1). Experimental results showed that
      colloidal Au can be used as a biocompatible matrix for enzyme immobilization.

PMID- 12600777
TI  - Estimation of micellization parameters of sodium dodecyl sulfate in water+1
      butanol using the mixed electrolyte model for molar conductance.
AB  - The mixed electrolyte model of Shanks and Franses has been applied to estimate
      the critical micelle concentration, aggregation number, and counterion binding
      constant of sodium dodecyl sulfate in a water + 1-butanol medium from its
      measured conductivity data at 25 degrees C. The surface potential of the ionic
      micelle in this mixed solvent medium was computed by solving the nonlinear
      Poisson-Boltzmann equation. The standard free energy terms of micellization were
      also calculated. The present study confirms further the observation made in the
      previous studies that ionic micelles do not contribute to the ionic strength of a
      surfactant solution, an inference originally made by McBain and coworkers.

PMID- 12600781
TI  - Polymer functionalized submicrometric emulsions as potential synthetic DNA
      vectors.
AB  - Triglyceride-based emulsions were first prepared by a solvent displacement
      procedure which was modified to achieve their functionalization by surface
      deposition of various amphiphilic comb-like copolymers. These emulsions have been
      characterized as regards to hydrodynamic particle size and surface charges using
      dynamic light scattering and electrophoretic mobility measurements. The
      adsorption isotherms of a polydT15 oligonucleotide and a model plasmid showed
      that the process was dependent on the nature of the interfaces, the affinity for
      the nucleic acid increasing with more cationic charges, together with improved
      accessibility. The binding process was found to proceed according to two regimes:
      one at low nucleic acid coverage, independent of the initial plasmid
      concentration, and the second one at high coverage, which was nucleic-acid
      concentration dependent. This behavior was considered to occur because of the
      development of repulsive interactions upon increasing the amount of immobilized
      nucleic acid. The complexation of plasmid complexed at the interface was finally
      investigated using the ethidium bromide displacement technique. The level of
      compaction of plasmid complexed onto the functionalized emulsions was lower than
      that obtained with the parent free polymer.

PMID- 12600782
TI  - Effects of synthetic lipids on solubilization and colloid stability of
      hydrophobic drugs.
AB  - Aqueous miconazole (MCZ) aggregates were solubilized and/or colloidally
      stabilized by bilayer-forming synthetic amphiphiles such as
      dioctadecyldimethylammonium bromide (DODAB) or sodium dihexadecylphosphate (DHP)
      dispersions. Particle sizing, light absorption and scattering from drug
      particles, zeta-potential determination, and drug aggregation kinetics from
      turbidity changes in the presence or absence of lipid dispersions were obtained
      over a range of drug and lipid concentrations. The very low solubility of MCZ in
      water made possible the determination of size distributions for drug particles in
      water and comparison to those in the presence of DODAB or DHP nanosized bilayer
      fragments or entire and closed bilayer vesicles. Large drug aggregates
      disappeared upon incubation with nanosized bilayer fragments produced by
      ultrasonic dispersion with tip. Light-absorption spectra for MCZ in a poor
      solvent (water), in a good organic solvent (methanol), and in different lipid
      dispersions showed that solubilization depended on the presence of bilayer
      fragments. MCZ was poorly soluble in dispersions formed of closed bilayers
      (vesicles) of DODAB or DHP in the gel state and in phosphatidylcholine (PC)
      vesicles in the liquid-crystalline state. Increased hydrophobicity at the borders
      of bilayer fragments explained MCZ solubilization. At [MCZ]>0.4 mM, kinetics of
      drug aggregation, zeta-potential measurements, and size minimization were
      obtained upon addition of minute amounts of oppositely charged bilayer fragments
      ([DHP]=0.05 mM), making possible determination of a remarkable stabilizing effect
      of drug particles by coverage with anionic bilayer fragments. High drug colloid
      stability in the presence of charged bilayer fragments was achieved by two
      different means: (1). at large drug concentrations and small concentrations of
      bilayer fragments, coverage of large drug particles with bilayer fragments; (2).
      at large amounts of bilayer fragments, drug solubilization in its monomeric form
      at the borders of bilayer fragments. Inexpensive, synthetic bilayer fragments
      offered a large area of hydrophobic nanosurfaces dispersed and electrostatically
      stabilized in water, opening new prospects for drug solubilization and colloid
      stabilization of insoluble drug particles.

PMID- 12600784
TI  - A discrete-particle model of blood dynamics in capillary vessels.
AB  - We investigate the mechanism of aggregation of red blood cells (RBC) in capillary
      vessels. We use a discrete-particle model in 3D to model the flow of plasma and
      RBCs within a capillary tube. This model can accurately capture the scales from
      0.001 to 100 microm, far below the scales that can be modeled numerically with
      classical computational fluid dynamics. The flexible viscoelastic red blood cells
      and the walls of the elastic vessel are made up of solid particles held together
      by elastic harmonic forces. The plasma is represented by a system of dissipative
      fluid particles. Modeling has been carried out using 1 to 3 million solid and
      fluid particles. We have modeled the flow of cells with vastly different shapes,
      such as normal and "sickle" cells. The two situations involving a straight
      capillary and a pipe with a choking point have been considered. The cells can
      coagulate in spite of the absence of adhesive forces in the model. We conclude
      that aggregation of red blood cells in capillary vessels can be stimulated by
      depletion forces and hydrodynamic interactions. The cluster of "sickle" cells
      formed in the choking point of the capillary efficiently decelerates the flow,
      while normal cells can pass through. These qualitative results from our first
      numerical results accord well with the laboratory findings.

PMID- 12600787
TI  - Scaling analysis of polyacrylamide gel surfaces synthesized in the presence of
      surfactants.
AB  - Surfaces of polyacrylamide hydrogels synthesized in the presence of surfactants
      were imaged by atomic force microscopy (AFM), and the surface morphology was
      studied by numerical scaling analysis. The gels were formed by polymerizing
      acrylamide plus a cross-linker in the presence of surfactants, which were then
      removed by soaking in distilled water. Gels formed in the presence of over 20%
      surfactant (by weight) formed clear, but became opaque upon removal of the
      surfactants. Other gels formed and remained clear. The surface morphology of the
      gels was studied by several one- and two-dimensional numerical scaling methods.
      The surfaces were found to be self-affine on short length scales, with a
      roughness (Hurst) exponent in the range from 0.85 to 1, crossing over to a
      constant root-mean-square surface width at long scales. Both the crossover length
      between these two regimes and the saturation value of the surface width increased
      significantly with increasing surfactant concentration, coincident with the
      increase in opacity. We propose that the changes in the surface morphology are
      due to a percolation transition in the system of voids formed upon removal of the
      surfactants from the bulk.

PMID- 12600788
TI  - Effects of NaCl on the J-aggregation of two thiacarbocyanine dyes in aqueous
      solutions.
AB  - The effects of NaCl on the aggregation of two typical thiacarbocyanine dyes (3,3'
      di(3-sulfopropyl)-4,5,4',5'-dibenzo-9-phenyl-thiacarbocyanine triethyl ammonium
      salt (Dye 1) and 3,3'-di(3-sulfopropyl)-4,5,4',5'-dibenzo-9-methyl
      thiacarbocyanine triethyl ammonium salt (Dye 2)) in aqueous solution have been
      studied by using absorption spectroscopy, fluorescence spectroscopy, and 1H- and
      23Na-NMR measurements. It is found that the J-aggregation of two dyes can be
      promoted by the addition of NaCl and that the effective coherence length of the J
      aggregate is shorter than that obtained without NaCl. Fluorescence spectra
      demonstrate that the fluorescence intensities of the J-aggregates of two dyes are
      quenched by addition of NaCl. This is consistent with the decrease of the
      effective coherence length of J-aggregates of the two dyes in the presence of
      NaCl. 1H-NMR spectra of two dyes show that the Na(+) ions penetrate into the J
      aggregates and replace the counterion (triethylammonium ions) in two dyes. The
      measurements of the chemical shifts of 23Na nuclei provide further information
      about the interaction between the Na(+) ions and dye anions in the J-aggregates
      of the two dyes. Due to this interaction, the electrostatic repulsion between the
      dye anions in the J-aggregates can be reduced and thus accelerate the aggregation
      of the two dyes in the presence of NaCl. The apparent association constants
      between Na(+) ions and dye molecules in J-aggregates of Dye 1 and Dye 2 estimated
      from the measured chemical shifts of 23Na nuclei are about 2.38 M(-1) and 1.35 M(
      1), respectively.

PMID- 12600791
TI  - Information processing biases among chronic pain patients and ankylosing
      spondylitis patients: the impact of diagnosis.
AB  - The aim of this research was to explore the impact that diagnostic status has on
      information processing biases among chronic pain (CP) and ankylosing spondylitis
      (AS) patients. AS patients, CP patients, and healthy hospital staff controls,
      completed a questionnaire and short computer task. During the computer task
      participants endorsed sensory, depression, illness, and neutral adjectives,
      following a cue question (which facilitated encoding of the adjectives in
      relation to the self). They were then asked to recall the adjectives in a
      surprise memory task. Diagnosed CP patients demonstrated a recall bias away from
      depression related stimuli, whilst the non-diagnosed CP patients did not. The
      results also suggest an association between receipt of a diagnosis and better
      psychological outcome in terms of information processing biasing. It was
      questioned whether the presence of a diagnosis among CP patients who are not
      currently depressed may protect or 'buffer' them against cognitive biasing
      towards classic depression related stimuli. The diagnosed AS group showed a bias
      towards sensory stimuli, perhaps reflecting the presence of an enduring and over
      riding pain schema. The non-pain control group also displayed a sensory bias,
      which was attributed to a frequency effect as a result of working in an
      environment where they were regularly exposed to sensory language. The results
      are discussed in relation to existing literature in this area and implications
      for clinical practice are provided.

PMID- 12600792
TI  - Childhood adversities in patients with fibromyalgia and somatoform pain disorder.
AB  - Primary fibromyalgia is regarded as disorder with a complex symptomatology, and
      no morphological alterations. Findings increasingly point to a dysfunction of the
      central nervous pain processing. The study aims to discuss vulnerability for
      fibromyalgia from a developmental psychopathological perspective. We investigated
      the presence of psychosocial adversities affecting the childhood of adult
      fibromyalgia patients (FM) and compared them to those of patients with somatoform
      pain disorders (SOM) and a control group (CG) with medically explained chronic
      pain. Using the structured biographical interview for pain patients (SBI-P), 38
      FM patients, 71 SOM patients, and 44 CG patients were compared on the basis of 14
      childhood adversities verified as relevant regarding longterm effects for adult
      health by prospective studies. The FM patients show the highest score of
      childhood adversities. In addition to sexual and physical maltreatment, the FM
      patients more frequently reported a poor emotional relationship with both
      parents, a lack of physical affection, experiences of the parents' physical
      quarrels, as well as alcohol or other problems of addiction in the mother,
      separation, and a poor financial situation before the age of 7. These experiences
      were found to a similar extent in the SOM patients, but distinctly less
      frequently in the CG. The results point to early psychosocial adversities as
      holding a similar etiological meaning in fibromyalgia as well as in somatoform
      pain disorders. The potential role of these factors as increasing the
      vulnerability for fibromyalgia is discussed.

PMID- 12600793
TI  - Epidural ketamine potentiates epidural morphine but not fentanyl in acute
      nociception in rats.
AB  - Epidural opioids have been reported to provide superior analgesia in acute pain
      management. Despite the fact that the required doses are low, major side effects
      such as respiratory depression may still occur. In an effort to maximize
      analgesia and to minimize the rate of side effects, epidural NMDA receptor
      antagonists, especially ketamine, may be co-administered with opioids. This study
      investigated whether ketamine had beneficial effects on fentanyl- or morphine
      induced antinociception in an acute pain model in rats. In male Wistar rats, an
      epidural catheter was placed under general anaesthesia. After 1 week the animals
      were subjected to the tail withdrawal reaction (TWR) test. After determination of
      the basal reaction latencies, fentanyl, morphine, ketamine or combinations of an
      opioid with ketamine were administered epidurally. TWR latencies were measured
      for up to 2h after treatment. Both opioids showed a dose related antinociceptive
      effect. Fentanyl had a fast onset and a short duration of action whereas the
      reverse was true for morphine. Ketamine exhibited only limited antinociceptive
      properties. In the combinations, ketamine improved morphine-induced
      antinociception both in terms of maximal possible effect (MPE) as well as in
      duration of action. The combination of fentanyl with ketamine did not result in
      any improvement, neither in terms of MPE nor in duration of action. Moreover,
      increasing doses of ketamine tended to decrease the MPE of various doses of
      fentanyl. These data confirm that ketamine, contrary to opioids, does not possess
      important antinociceptive properties in an acute test such as the TWR test.
      Furthermore, these data indicate that additive drugs such as ketamine may have
      different effects on different opioids.

PMID- 12600794
TI  - Antinociceptive effect in mice of intraperitoneal N-methyl-D-aspartate receptor
      antagonists in the formalin test.
AB  - Although the antinociceptive effect of NMDA antagonists in the formalin test is
      well recognised, these compounds can induce adverse motor effects. The aim of
      this study was to identify the systemic doses of NMDA antagonists that induce
      analgesia without causing side effects. Male Swiss mice (30-40g) received a
      subcutaneous (sc) injection of 1.25% formalin (50 micro l) in the dorsal surface
      of the right hind-paw and, 15min before or after formalin, an ip injection of one
      of the following NMDA receptor antagonists: MK 801 (0.01, 0.025, and 0.05mg/kg),
      memantine (0.1, 0.5, and 1mg/kg), ketamine (0.125, 0.25, and 0.5mg/kg),
      dextromethorphan (5, 10, and 20mg/kg), and CGP 37849 (4, 6, and 8mg/kg). Pain
      related behaviour (licking, lifting, favouring, shaking, and flinching of the
      treated paw) was recorded at 5-min intervals for 60min. The NMDA receptor
      antagonists significantly (p<0.01) and dose-dependently reduced, versus controls,
      nociceptive activity during the second phase of the formalin test (from the 20th
      to the 60thmin): at the highest doses, 97.6+/-0.1% with MK 801; 90.4+/-0.2% with
      memantine; 74.7+/-0.3% with ketamine; 92.8+/-0.4% with dextromethorphan; and
      80.7+/-0.3% with CGP 37849, without affecting coordination. The rank order
      potency of antinociceptive activity of NMDA antagonists was:
      MK801>memantine>ketamine>dextromethorphan>CGP37849. The NMDA antagonists
      administered after formalin (during the analgesic interval) did not affect the
      late phase of the formalin test. In conclusion, systemic administration of NMDA
      receptor antagonists decreases the nociception observed during the late phase of
      the formalin test.

PMID- 12600795
TI  - Psychophysics of phasic and tonic heat pain stimuli by quantitative sensory
      testing in healthy subjects.
AB  - The increased use of quantitative sensory testing in the study of pain raises the
      need to characterize various aspects of psychophysical response to noxious
      stimulation in healthy subjects. The present study aims to address several issues
      regarding the use of heat pain stimuli: (a) Are pain scores for short-term
      repeated phasic stimuli consistent? (b) Does an exposure to tonic heat pain
      stimulus cause sensitization and change the scores for subsequent phasic stimuli?
      and (c) Are pain scores for phasic and tonic heat pain correlated? To address
      these questions, a series of four phasic heat pain stimuli of 47 degrees C were
      given to the forearms of 70 healthy volunteers, over the course of an hour. Pain
      scores by Visual Analog Scale (VAS) were obtained for each stimulus. In 50
      subjects, a tonic heat pain of 70s duration at 47.5 degrees C was given between
      the first and second phasic stimuli. Pain scores were obtained at four points
      along this tonic stimulus. Repeated measures ANOVA and a sensitive post hoc
      analysis indicated that, while the pain perception was reduced on the second,
      nearly immediate trial, subsequent VAS scores of pain perception were not
      different from the first (#1: 35.2+/-19.2; #2: 31.4+/-20.2, #3: 33.0+/-21.6; and
      #4: 33.2+/-20.1, respectively), with strong correlation among the phasic tests.
      The average tonic pain score was 53.7+/-23.1. Administration of tonic pain
      stimuli did not result in different VAS scores of subsequent phasic pain stimuli,
      compared to those subjects who did not receive tonic pain stimuli. Tonic and
      phasic pain were positively correlated (e.g., r=0.45,p<0.001 for the first phasic
      stimuli). However, no relation was found between the level of perceived pain,
      either for phasic or for tonic stimuli, and presence or absence of temporal
      summation during the tonic pain. IN CONCLUSION: (i) phasic pain scores
      assessments at 30' and 60' after baseline is consistent; (ii) tonic heat pain,
      despite relatively high VAS scores, does not cause a change in the scoring of
      subsequent phasic stimuli; and (iii) phasic and tonic pain scores correlate with
      each other. Thus, the normal pattern of pain perception is stable and not altered
      by single tonic pain stimulation.

PMID- 12600796
TI  - Experimental muscle pain and tenderness following infusion of endogenous
      substances in humans.
AB  - Several human models of myofascial pain exist, but none are similar to clinical
      pain. The aim of the present study was to develop a clinically relevant model of
      prolonged human myofascial pain using infusion of the naturally occurring
      endogenous substances. Initially, bradykinin (Bk), serotonin (5-hydroxytryptamine
      (5-HT)), histamine (His), prostaglandin E(2) (PGE(2)), adenosine-tri-phosphate
      (ATP), and their combinations were infused into the trapezius muscle of 36
      healthy subjects in a total of 67 sessions to identify substances, which could
      induce a moderate muscle pain. PGE(2), ATP, and a combination of Bk, 5-HT, His,
      and PGE(2) produced the intended moderate pain. These substances were further
      examined in a randomised, blinded, placebo-controlled dose-finding design in 15
      healthy subjects in 68 sessions. PGE(2) (3, 6, and 12 nmol/ml) induced mild pain
      and tenderness not different from placebo. ATP (9000, 18,000, and 36,000 nmol/ml)
      induced pain of moderate to strong intensity (P=0.04) and the dose of 18,000
      nmol/ml furthermore produced moderate local tenderness (P=0.04). Because of
      unacceptable side effects in subsequent examinations, further studies of ATP in
      humans were suspended. Infusion of the combination of Bk (92 nmol), 5-HT (156
      nmol), His (140 nmol), and PGE(2) (1.95 nmol) produced a moderate pain intensity
      (P=0.04) and mild tenderness (P=0.04) without inducing unacceptable side effects.
      Intramuscular infusion of a combination of Bk, 5-HT, His, and PGE(2) induced a
      prolonged moderate pain and tenderness in healthy humans, and this model may be a
      valuable tool in future studies of the pathophysiological mechanisms of
      myofascial pain.

PMID- 12600798
TI  - Validation of the arthritis self-efficacy short-form scale in German fibromyalgia
      patients.
AB  - Self-efficacy is assumed to account for significant variance in the treatment
      outcome of chronic pain patients. The aim of this study was to provide a German
      version of an approved measure of disease-related self-efficacy in fibromyalgia
      (FM) patients which assesses treatment outcomes and specific differences compared
      to other pain patients. The 8-item short-form of the arthritis self-efficacy
      scale was translated into German (ASES-D) and administered to 148 FM patients and
      53 patients with rheumatoid arthritis (RA). In addition, similar cognitive
      constructs (locus of control, optimism/pessimism, and general self-efficacy) and
      disease-related variables (pain, functioning, depression, and coping) were
      assessed. The instrument was further applied to 43 FM patients who underwent
      interdisciplinary group therapy. Validation methods consisted of correlation,
      principal component analysis and difference testing between the disease groups.
      The instrument met good psychometric properties. Evidence for construct validity
      was provided. Self-efficacy was sensitive to changes and could be used in
      predicting the treatment outcome in FM patients. The German short-form ASES-D is
      a further step toward an internationally comparable assessment of disease-related
      self-efficacy in FM.

PMID- 12600797
TI  - Low-dose diclofenac potassium in the treatment of episodic tension-type headache.
AB  - BACKGROUND: Several clinical trials have demonstrated that low doses of non
      steroidal anti-inflammatory drugs relieve episodic tension-type headache (ETH).
      AIMS: The aims of this placebo-controlled study were to determine whether single
      doses of diclofenac-K 12.5 and 25mg effectively relieve ETH in adults and to
      compare it to ibuprofen 400mg. METHODS: A single-dose multicentre, randomised,
      double-blind, double-dummy, clinical trial was conducted at 22 primary care
      centres in Germany. All subjects had a history of ETH according to the
      classification of the International Headache Society. Of 684 subjects randomised,
      620 used the study drugs for an episode of tension headache occurring within one
      month after enrolment: diclofenac-K 12.5mg (n=160), diclofenac-K 25mg (n=156),
      ibuprofen 400mg (n=151) and placebo (n=153). The primary efficacy variable was
      total pain relief, calculated as the time-weighted sum of the pain relief
      assessments from baseline to the 3h evaluation time (TOTPAR-3). RESULTS: For
      TOTPAR-3, all active treatments were superior to placebo; no statistically
      significant difference between the three active treatments could be detected. A
      similar pattern was also observed with regard to TOTPAR-6 (6h evaluation time), >
      or =50%maxTOTPAR at 3 and 6h, weighted pain intensity difference at 3 and 6h
      (SPID-3; SPID-6), percentage of patients with complete headache relief at 2h, end
      of study global evaluation and time to rescue medication. The number-needed-to
      treat (NNT) at 6h was 4.5 (2.9-9.2) in the ibuprofen 400mg group, 4.0 (2.8-7.3)
      in the diclofenac-K 12.5mg group and 3.9 (2.7-7.1) in the diclofenac-K 25mg
      group. These differences were not statistically significant. CONCLUSION:
      Diclofenac-K, administered as single doses of 12.5 and 25mg effectively relieves
      ETH and is comparable to ibuprofen 400mg.

PMID- 12600799
TI  - Therapeutic approaches to fibromyalgia syndrome in the United Kingdom: a survey
      of occupational therapists and physical therapists.
AB  - BACKGROUND AND PURPOSE: This study sought information from occupational
      therapists (OTs) and physical therapists (PTs) working in rheumatology in the UK
      on their usual methods of treatment and management of patients with fibromyalgia
      syndrome (FMS). METHODS: Data were gathered by self-completion questionnaire on:
      work setting; referrals of FMS patients; usual treatment objectives; assessment
      and treatment approaches; perceived responsiveness of patients; and other
      perceptions of the management of FMS. Most data were in the form of frequency
      counts, with some ordinal scales and open responses. RESULTS: Responses were
      obtained from 142 therapists (71% response rate), of whom 47 OTs and 39 PTs
      managed patients with FMS. The foremost therapeutic objective was increased
      functional ability for OTs, and increased exercise tolerance and general fitness
      for PTs. Pain reduction or management was rated as the second objective for both
      groups. An endurance-based exercise program and energy conservation techniques
      were the most frequently utilized interventions. Patients with FMS were thought
      to be 'moderately responsive' to physical management. Predictors of outcome were
      considered to be largely psychosocial, rather than physical, in nature.
      CONCLUSION: These data provide a preliminary profile of current practice in the
      management of FMS among UK therapists and indicate certain differences in
      approach between OTs and PTs.

PMID- 12600800
TI  - Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative
      analgesic consumption. A meta-analysis with assessment of optimal treatment
      parameters for postoperative pain.
AB  - AIM: We investigated the literature of randomised placebo-controlled trials to
      find out if transcutaneous electrical nerve stimulation (TENS) or acupuncture
      like transcutaneous electrical nerve stimulation (ALTENS) can reduce analgesic
      consumption after surgery. RESULTS: Subgroup analysis for adequate treatment
      (pulse frequency: 1-8Hz [ALTENS] or 25-150Hz [TENS], current intensity: "strong,
      definite, subnoxious, maximal tolerable" or above 15mA, and electrode placement
      in the incision area) were performed. Twenty-one randomised, placebo-controlled
      trials with a total of 1350 patients were identified. For all trials, the mean
      reduction in analgesic consumption after TENS/ALTENS was 26.5% (range -6 to +51%)
      better than placebo. Eleven of the trials compromising 964 patients, had reports
      which stated that a strong, subnoxious electrical stimulation with adequate
      frequency was administered. They reported a mean weighted reduction in analgesic
      consumption of 35.5% (range 14-51%) better than placebo. In nine trials without
      explicit confirmation of sufficient current intensity and adequate frequency, the
      mean weighted analgesic consumption was 4.1% (range -10 to +29%) in favour of
      active treatment. The difference in analgesic consumption was significantly
      (p=0.0002) in favour of adequate stimulation. The median frequencies used in
      trials with optimal treatment was 85Hz for TENS and 2Hz in the only trial that
      investigated ALTENS. CONCLUSION: TENS, administered with a strong, subnoxious
      intensity at an adequate frequency in the wound area, can significantly reduce
      analgesic consumption for postoperative pain.

PMID- 12600801
TI  - The effects of A-fiber pressure block on perception and neurophysiological
      correlates of brief non-painful and painful CO2 laser stimuli in humans.
AB  - This study examined the relative capacity of Adelta- and C-fibers to encode non
      painful and painful brief CO(2) laser stimuli by comparing the effects of
      Adelta/C-fiber activation versus C-fiber activation alone. In nine normal
      subjects, brief CO(2) laser pulses of four different intensities (range 5.8
      10.6mJ/mm(2)) were delivered at random on the first intermetacarpal zone of the
      dorsum of the hand. A-fiber pressure block of the superficial radial nerve was
      performed to fully isolate the activity of C-fibers. Quality and intensity (VAS)
      of percepts, reaction time (RT) and laser-evoked potentials (LEPs) were examined
      in baseline and A-fiber block conditions. During A-fiber block, absolute
      detection threshold increased dramatically from 4.8+/-1.8 to 10.9+/-4.8mJ/mm(2),
      proportion of detected stimuli decreased from 87% to 47% and proportion of pain
      reports from 39% to 10%. The quality of sensations became mainly 'light touch'
      and the 'pricking' sensation almost vanished. The stimulus-VAS curve shifted to
      the right and the slope was reduced. Signal Detection Theory analysis revealed
      that discrimination performance (P(A)) was significantly depressed and that
      response bias (B) evolved from a neutral towards a stoical attitude. Median RT
      increased from 492 to 1355ms. The late LEPs, attributed to the activation of
      Adelta-fibers, disappeared and ultra-late LEPs were recorded at Cz with a
      positivity peaking around 800ms. Collectively, these observations lead to the
      conclusion that Adelta-fibers are the main peripheral mediators for the
      perception of brief CO(2) laser stimuli and that they provide more sensory
      information than C-fibers.

PMID- 12600802
TI  - Pharmacological modulators of voltage-gated calcium channels and their
      therapeutical application.
AB  - Calcium channels (CCs) play an important role in the transduction of action
      potential to the cytosol. An influx of Ca(2+) is essential for muscle
      contraction, neurotransmitter, and hormonal release. Level of cytosolic Ca(2+)
      controls activities of many enzymes and regulatory proteins. Voltage-gated
      calcium channels (VGCCs) serve as sensors for membrane depolarization. Blood
      pressure reduction is due to relaxation of actomyosine filaments in vascular
      smooth muscles. Calcium channel blockers (CCBs) are traditionally used for
      treatment of cardiovascular diseases. Neurotransmitter release from presynaptic
      neurons is triggered by Ca(2+) influx. Blockers of neuronal CCs may be applied
      for pain treatment. Overload of neurons by Ca(2+) is toxic. CCBs may be applied
      for prevention of some neurodegenerative disorders.

PMID- 12600803
TI  - Compartmental analysis of steady-state diaphragm Ca2+ kinetics in chronic
      congestive heart failure.
AB  - An analytic method based on simulation and modeling of long-term 45Ca(2+) efflux
      data was used to estimate steady-state Ca(2+) contents (nmolCa(2+)g(
      1)tissuewetwt.) and exchange fluxes (nmolCa(2+)min(-1)g(-1)tissuewetwt.) for
      extracellular and intracellular compartments in in vitro resting diaphragm from
      congestive heart failure (CHF, n=12) and sham-operated (SHAM, n=10) rats. Left
      hemidiaphragms were excised from experimental animals, loaded with 45Ca(2+) for
      1h, and washed out with 45Ca(2+)-free perfusate for 8h. Tissue from the right
      hemidiaphragm was used to assess single-fiber cross-sectional area (CSA) as well
      as the relative proteolytic activity of Ca(2+)-dependent calpain. Kinetic
      analysis of 45Ca(2+) efflux data revealed that CHF was associated with increased
      Ca(2+) contents of extracellular and intracellular compartments as well as
      increased Ca(2+) exchange fluxes for all compartments. This accounted for the
      model prediction of a 250% increase in total diaphragm Ca(2+). Furthermore,
      single-fiber CSA was decreased 12% and proteolytic activity of calpain was
      increased twofold in CHF diaphragm relative to SHAM. CONCLUSIONS: The kinetic
      data are consistent with the hypothesis that diaphragm Ca(2+) overload in CHF
      required all intercompartmental Ca(2+) fluxes to increase. The potential
      relationships among Ca(2+) overload, increased activity of calpain, and wasting
      of the diaphragm in CHF are discussed.

PMID- 12600804
TI  - Ca2+/calmodulin-dependent protein kinase II delta2 regulates gene expression of
      insulin in INS-1 rat insulinoma cells.
AB  - Ca(2+)/calmodulin-dependent protein kinase II is a member of a broad family of
      ubiquitously expressed Ca(2+) sensing serine/threonine-kinases. Ca(2+)/calmodulin
      dependent protein kinase II is highly expressed in insulin secreting cells and is
      associated with insulin secretory granules and has been proposed to play an
      important role in exocytosis or in insulin granule transport to release sites. To
      elucidate its function the antisense sequence of the major beta-cell subtype,
      Ca(2+)/calmodulin-dependent protein kinase II delta(2), was stably expressed in
      INS-1 rat insulinoma cells. This caused a loss of Ca(2+)/calmodulin-dependent
      protein kinase II delta(2) expression at the mRNA and protein level, while the
      expression of the 95% homologous Ca(2+)/calmodulin-dependent protein kinase II
      gamma and of beta-cell specific proteins such as the homeodomain factor
      pancreatic-duodenal homeobox factor-1 (PDX-1, also referred to as islet/duodenum
      homeobox-1, IDX-1, insulin promoter factor-1, IPF-1 and somatostatin
      transactivating factor-1, STF-1), the glucagon-like peptide-1 (GLP-1) receptor
      and K(ATP)-channels K(IR)6.2/SUR-1 (sulfonylurea receptor-1) was not altered.
      Unexpectedly, the cells showed a large reduction of insulin gene expression,
      which was due to reduced insulin gene transcription. Electrophoretic mobility
      shift assays of PDX-1 binding to the insulin promoter A1 and E2/A3A4 elements
      showed additional bands indicating alterations of PDX-1 complex formation. Stable
      over expression of Ca(2+)/calmodulin-dependent protein kinase II delta(2), by
      contrast, was associated with elevated expression of insulin mRNA. Therefore, we
      conclude that Ca(2+)/calmodulin-dependent protein kinase II delta(2) links fuel
      dependent increases in intracellular Ca(2+) concentrations to transcriptional
      regulation of genes related to the metabolic control of insulin secretion.

PMID- 12600805
TI  - Regulation of outer hair cell cytoskeletal stiffness by intracellular Ca2+:
      underlying mechanism and implications for cochlear mechanics.
AB  - Two Ca(2+)-dependent mechanisms have been proposed to regulate the mechanical
      properties of outer hair cells (OHCs), the sensory-motor receptors of the
      mammalian cochlea. One involves the efferent neurotransmitter, acetylcholine,
      decreasing OHC axial stiffness. The other depends on elevation of intracellular
      free Ca(2+) concentration ([Ca(2+)](i)) resulting in OHC elongation, a process
      known as Ca(2+)-dependent slow motility. Here we provide evidence that both these
      phenomena share a common mechanism. In whole-cell patch-clamp conditions, a fast
      increase of [Ca(2+)](i) by UV-photolysis of caged Ca(2+) or by extracellular
      application of Ca(2+)-ionophore, ionomycin, produced relatively slow (time
      constant approximately 20s) cell elongation. When OHCs were partially collapsed
      by applying minimal negative pressure through the patch pipette, elevation of the
      [Ca(2+)](i) up to millimole levels (estimated by Fura-2) was unable to restore
      the cylindrical shape of the OHC. Stiffness measurements with vibrating elastic
      probes showed that the increase of [Ca(2+)](i) causes a decrease of OHC axial
      stiffness, with time course similar to that of the Ca(2+)-dependent elongation,
      without developing any measurable force. We concluded that, contrary to a
      previous proposal, Ca(2+)-induced OHC elongation is unlikely to be driven by
      circumferential contraction of the lateral wall, but is more likely a passive
      mechanical reaction of the turgid OHC to Ca(2+)-induced decrease of axial
      stiffness. This may be the key phenomenon for controlling gain and operating
      point of the cochlear amplifier.

PMID- 12600807
TI  - NTP, the photoproduct of nifedipine, activates caffeine-sensitive ion channels in
      leech neurons.
AB  - Leech P neurons possess caffeine-sensitive ion channels in intracellular Ca(2+)
      stores and in the plasma membrane. The following results indicate that these
      channels are also activated by 2,6-dimethyl-4-(2-nitrosophenyl)-3,5
      pyridinedicarboxylic acid dimethyl ester (NTP), the photoproduct of the L-type
      Ca(2+) channel-blocker nifedipine: (1) Just like caffeine, NTP evoked Ca(2+)
      influx and intracellular Ca(2+) release, as well as the influx of various other
      divalent cations and that of Na(+). (2) In the presence of high NTP or caffeine
      concentrations the plasma membrane channels close, suggesting desensitization of
      the channel-activating mechanism. (3) Depending on the concentration, NTP and
      caffeine induce cross-desensitization or act additively. (4) NTP was effective in
      the same neurons as caffeine (P, N, Leydig, 101), and it was ineffective in
      neurons in which caffeine was also ineffective (AP, T, L, 8, AE). (5) In Retzius
      neurons, NTP and caffeine evoked intracellular Ca(2+) release but no Ca(2+)
      influx. Despite these parallels, the effects of NTP and caffeine were not
      identical, which may be due to differences in the mechanisms of channel
      activation or desensitization and/or to substance-specific side effects. The
      caffeine-sensitive ion channels were activated by NTP concentrations > or =10
      microM, which is almost three orders of magnitude smaller than the threshold
      concentration of caffeine.

PMID- 12600806
TI  - Quantitative estimate of mitochondrial [Ca2+] in stimulated motor nerve
      terminals.
AB  - Peak values reported for mitochondrial matrix [Ca(2+)] following stimulation have
      ranged from micromolar to near-millimolar in various cells. Measurements using
      fluorescent indicators have traditionally used high-affinity dyes such as rhod-2,
      whose fluorescence would be expected to saturate if matrix [Ca(2+)] approaches
      millimolar levels. To avoid this potential problem, we loaded lizard motor
      terminal mitochondria with the low-affinity indicator rhod-5N (K(d) approximately
      320 microM). During trains of action potentials at 50Hz, matrix fluorescence
      transients (measured as F/F(rest)) increased to a plateau level that was
      maintained throughout the stimulus train. This plateau of matrix [Ca(2+)]
      occurred in spite of evidence that Ca(2+) continued to enter the terminal and
      continued to be sequestered by mitochondria. When the stimulation frequency was
      increased, or when Ca(2+) entry per action potential was increased with the K(+)
      channel blocker 3,4-diaminopyridine (3,4-DAP), or reduced by lowering bath
      [Ca(2+)], the rate of rise of matrix [Ca(2+)] changed, but the plateau amplitude
      remained constant. Calculations demonstrated that the F/F(rest) measured at this
      plateau corresponded to a matrix [Ca(2+)] of approximately 1 microM. The high
      K(d) of rhod-5N ensures that this value is not a result of dye saturation, but
      rather reflects a powerful Ca(2+) buffering mechanism within the matrix of these
      mitochondria.

PMID- 12600808
TI  - Myoclonic encephalopathy caused by chronic bismuth abuse.
AB  - Bismuth (Bi) is used for the treatment of different gastrointestinal symptoms and
      disorders such as gastric ulcers. In Germany, Bi medication is available without
      prescription as over-the-counter-medication even though it can cause severe
      myoclonic encephalopathy if ingested chronically in high doses. We report a 49
      year-old woman with chronic gastric ulcers and 5 years of Bi abuse who developed
      the typical clinical course of Bi encephalopathy. She presented with progressive
      dementia, dysarthria and myoclonic jerks one week after increasing the Bi dosage.
      The EEG showed generalized spike-wave complexes suggesting that the myoclonus was
      epileptic in nature. Bi intake was stopped and valproate was given, which
      decreased the frequency of the myoclonic jerks. Administration of the metal
      chelator D,L-2,3-dimercaptopropane- 1-sulfonic acid (DMPS) led to increased urine
      excretion of Bi, but was accompanied by a clinical deterioration which resulted
      in it being discontinued. The subsequent clinical recovery of the patient was
      documented over 40 days by EEG, video and neuropsychological testing. A time lag
      of two weeks was observed between falling plasma levels and clinical improvement.
      In conclusion, Bi-induced encephalopathy is a differential diagnosis for
      myoclonic encephalopathies. Treatment with metal chelators may aggravate the
      encephalopathy. The over-the-counter availability of medications containing Bi
      should be questioned. (Published with video sequence.)

PMID- 12600809
TI  - Fear, anger and compulsive behavior during seizure: involvement of large scale
      fronto-temporal neural networks.
AB  - Seizure-related, abnormal affective and gestural behavior may involve some of the
      same processes as those underlying non-pathological behavior, but their
      mechanisms remain largely unknown. In this report, we studied a patient in whom
      seizures initially involved the medial temporal region before involving the
      frontal cortex. Seizure semiology of the second part of the seizure included
      marked emotional disturbances (dominated by intense fear and anger) and
      compulsive behavior to bite into something. This patient underwent presurgical
      evaluation including intracerebral electroencephalographic recordings (SEEG,
      stereoelectroencephalography). METHODS: In addition to SEEG examination, we used
      coherence analysis of signals as a means of studying functional coupling between
      different regions of the brain. Two seizures were studied. Coherence values from
      different periods of interest were compared to identify the neural structures
      involved at the onset of seizure activity as well as during the emotional
      behavioral changes. RESULTS: A first network of neural structures was identified
      within the right anterior temporal regions (amygdala, temporal pole, hippocampus,
      temporal neocortex). At the time of intense affective and compulsive changes, and
      by comparison with the first ictal period, a second network was identified
      characterized by significant functional coupling between the amygdala, the orbito
      frontal structures and the frontal opercular region, while a decrease in
      functional coupling between these regions and the dorsolateral region and the
      cingulate gyrus was apparent. CONCLUSION: This study show that the emergence of
      an intense affective and behavioral state during a temporal lobe seizure could be
      related to the involvement of a network of structures including the anterior
      temporal lobe and the orbito-frontal cortex. The decrease of coupling between
      these regions and the lateral prefrontal and cingulate regions could also
      participate in these phenomena.

PMID- 12600810
TI  - Long-term neuropsychological follow-up and nosological considerations in five
      patients with continuous spikes and waves during slow sleep.
AB  - Continuous spikes and waves during slow sleep (CSWSS) is a well-known EEG pattern
      that can be associated with cognitive and behavioural deterioration. We present
      the long-term neuropsychological follow-up and nosological considerations of five
      patients who developed CSWSS during childhood. All five of our patients presented
      CSWSS, although the duration and severity of this pattern varied. The outcome was
      of three basic types: acquired frontal dementia, language deficits and normal.
      Four of our patients were initially diagnosed with Landau-Kleffner syndrome but
      have had markedly diverse outcomes in terms of the severity and type of
      compromise. Our data suggest that the initial diagnosis, according to current
      nosological categories, has almost no prognostic significance, while the length
      and the age of onset of CSWSS, the site of epileptiform activity and the
      individual neuropsychological profile are more useful for identifying the long
      term outcome of patients with CSWSS.

PMID- 12600811
TI  - Epilepsy in children with congenital hemiplegia: correlation between clinical,
      EEG and neuroimaging findings.
AB  - OBJECTIVES: the aim of this retrospective, multicentre study was to investigate
      the relationship between epilepsy, clinical, electroencephalographic (EEG) and
      neuroimaging findings in children with congenital hemiplegia (CH). PATIENTS AND
      METHODS: two hundred and three children with CH were assessed by history,
      neurological and developmental examination. Electroencephalogram (EEG) and CT/MRI
      brain imaging were performed in 150 of them (81/150 had an MRI and 69/150 had a
      CT scan). Patients were re-evaluated every six months for, at least, a two-year
      follow-up period (range 2-14 yrs). RESULTS: the EEG was abnormal in 76% of
      patients; epileptic seizures developed in 38.9% of them. The frequency of
      epilepsy paralleled the degree of EEG abnormality, approaching 85% in patients
      with severe EEG abnormalities and was also closely related to the extent of
      neuroimaging findings (up to 79% in patients with cerebral malformations). The
      prevalence of epilepsy in 12/62 patients (19.4%) with mild hemiplegia was
      significantly lower as compared to 67/141 (47.5%) of patients with moderate or
      severe hemiplegia. 36.7% of the children had their first seizure between the 1st
      and the 5th year of life, and 26.5% during the first year of life. CONCLUSIONS:
      epileptic seizures developed in more than one third of patients with CH, although
      EEG abnormalities were evident in the majority of them. The prevalence of
      epilepsy is closely related to the severity of hemiparesis, the extent of
      neuroimaging findings and the degree of EEG abnormalities. The absence of EEG
      abnormalities and/or normal (or minor) neuroimaging findings was negatively
      related to the occurrence of epilepsy.

PMID- 12600812
TI  - Tolerability of tiagabine: a prospective open-label study.
AB  - Tiagabine was used as add-on therapy in the treatment of epilepsy with partial
      and/or secondarily generalised seizures to evaluate tolerability and efficacy.
      Five hundred and seventy-four patients (299 men and 275 women, mean age 38.1
      years), with refractory partial seizures, were enrolled in this prospective, open
      label study. Tiagabine was added to one (44.1%) or more (up to nine)
      antiepileptic drugs. The median daily dose of tiagabine was 30 mg (mean 29.1, SD
      12.0). The mean duration of follow-up was 94.9   42.7 days. 12.3% of patients
      were completely seizure-free at the end of the observation period. Median total
      seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. Adverse events
      occurred in 78 patients (13.6%). Tiagabine proved to be a well-tolerated AED.

PMID- 12600813
TI  - Ictal bradycardia followed by cardiac asystole: a case report.
AB  - We report on a patient with a 30-year history of left temporal lobe epilepsy who
      presented with ictal bradycardia followed by cardiac asystole. The EEG during the
      ictal period was documented and analyzed. Clinical features and therapeutic
      considerations are discussed.

PMID- 12600814
TI  - Human leukocyte antigen-DR alleles influence the clinical course of pulmonary
      sarcoidosis in Asian Indians.
AB  - Host genetic factors are known to contribute to disease susceptibility and course
      in sarcoidosis. They may also be important in defining the pattern of disease
      presentation and progression, as well as its overall prognosis. We have studied
      human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a
      cohort of Indian patients with sarcoidosis and 275 healthy control subjects from
      north India. Although no specific HLA class I allele association was found among
      sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into
      supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for
      the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with
      control subjects. Among class II alleles, positive association of DRB1*11,
      DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed.
      Clinical follow-up of the patient cohort up to a 5-yr period showed a predominant
      occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset,
      advanced disease on chest radiographs, and chronic course with frequent relapses
      on tapering off the prednisolone treatment. Further, multivariate logistic
      regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and
      DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were
      independent predictors of sarcoidosis. The present findings imply that HLA
      associated genetic factors influence the risk for the development of sarcoidosis
      and disease progression.

PMID- 12600815
TI  - Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor-induced
      adhesion molecule expression on eosinophils by p38 mitogen-activated protein
      kinase and nuclear factor-[kappa] B.
AB  - We investigated the intracellular signaling mechanisms for cytokine interleukin
      (IL)-3, IL-5, or granulocyte-macrophage colony-stimulating factor (GM-CSF)
      induced expression of adhesion molecules including very late antigen 4 (CD49 d),
      macrophage antigen-1 (CD11b), leukocyte function-associated antigen-1
      (CD11a/CD18), intercellular adhesion molecule (ICAM)-1, and ICAM-3 on
      eosinophils. The expression of adhesion molecules and nuclear factor (NF)-kappaB
      pathway was measured by flow cytometry and cDNA expression array, respectively.
      The phosphorylation of inhibitor kappaB-alpha and p38 mitogen-activated protein
      kinase (MAPK) was detected by Western blot, whereas NF-kappaB activity was
      measured by electrophoretic mobility shift assay. IL-3, IL-5, and GM-CSF could
      enhance p38 MAPK and NF-kappaB activity and induce ICAM-1, CD11b, and CD18
      expressions on eosinophils. They could suppress ICAM-3 expression, but had no
      effect on CD49 d expression. Either SB 203580 or MG-132 was able to offset the
      cytokine-induced expression of ICAM-1. Only SB 203580 could reverse the effect on
      CD11b, CD18, and ICAM-3 expressions. Therefore, the expression of ICAM-1 might
      involve both p38 MAPK and NF-kappaB activities, whereas the regulation of CD11b,
      CD18, and ICAM-3 expressions might be mediated through p38 MAPK but not NF
      kappaB. These cytokines therefore play a crucial role, via the p38 MAPK and NF
      kappaB pathways, in the expression of important adhesion molecules on eosinophils
      in allergic inflammation.

PMID- 12600816
TI  - Identification of genes promoting angiogenesis in mouse lung by transcriptional
      profiling.
AB  - A better understanding of the regulation of factors that promote angiogenesis may
      ultimately enable improved therapeutic control of this important process. In our
      previous studies, obstruction of the left pulmonary artery in the mouse
      consistently induced the formation of a new vasculature, which developed from the
      visceral pleura and entered the upper left lung directly within 5-6 days after
      ligation. No new vessels developed to the lower left lung, despite the initial
      ischemic stimulus being identical to that in the upper lung. Using this unique
      model of angiogenesis, we have determined the temporal pattern of differential
      gene expression from two independent regions of the same lung: one where
      angiogenesis is induced, and the other where angiogenesis does not occur.
      Microarray analysis and quantitative real-time RT-PCR were used to compare the
      signals from these two lung regions in the first 3 d following ischemia. The
      findings reveal the important roles of ELR+ CXC chemokines as proangiogenic
      signals. Genes involved in tissue remodeling, inflammation, and injury were also
      upregulated in the proangiogenic upper lung. Results also confirm that lung
      ischemia, rather than hypoxia, is the essential trigger for angiogenesis. These
      altered profiles of expression in the early stage of lung ischemia show potential
      roles and interactions of the most important genes involved in promoting new
      blood vessel formation.

PMID- 12600817
TI  - Particulate matter induces alveolar epithelial cell DNA damage and apoptosis:
      role of free radicals and the mitochondria.
AB  - Airborne particulate matter (PM) increases morbidity and mortality resulting from
      cardiopulmonary diseases including cancer. We hypothesized that PM is genotoxic
      to alveolar epithelial cells (AEC) by causing DNA damage and apoptosis. PM caused
      dose-dependent AEC DNA strand break formation, reductions in mitochondrial
      membrane potential (Delta psi m), caspase 9 activation, and apoptosis. An iron
      chelator and a free radical scavenger prevented these effects. Finally,
      overexpression of Bcl-xl, a mitochondrial anti-apoptotic protein, blocked PM
      induced Delta psi m and DNA fragmentation. We conclude that PM causes AEC DNA
      damage and apoptosis by mechanisms that involve the mitochondria-regulated death
      pathway and the generation of iron-derived free radicals.

PMID- 12600818
TI  - Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator
      protein-1- and nuclear factor-kappaB-mediated gene expression in airway
      epithelial cells.
AB  - In 16HBE14o- human bronchial epithelial cells, maximal tumor necrosis factor
      (TNF)-alpha-induced interleukin (IL)-8 expression depends on the activation of
      two distinct signaling pathways, one constituted in part by activator protein
      (AP)-1 and the other by nuclear factor (NF)-kappaB. We examined the upstream
      signaling intermediates responsible for IL-8 and granulocyte-macrophage colony
      stimulating factor (GM-CSF) expression in this system, hypothesizing that p21 Ras
      and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase
      kinase (MEKK)-1 function as common upstream activators of both the AP-1 and NF
      kappaB pathways. TNF-alpha treatment induced both Ras and MEKK1 activation.
      Dominant-negative forms of Ras (N17Ras) and MEKK1 (MEKK1-KM) each inhibited TNF
      alpha-induced transcription from IL-8 and GM-CSF promoters. Ras was required for
      maximal activation of extracellular signal-regulated kinase (ERK) and Jun amino
      terminal kinase (JNK) as well as AP-1 and NF-kappaB transcriptional activities,
      but not for activation of IkappaB kinase (IKK)-beta, an upstream activator of NF
      kappaB. MEKK1 was required for maximal activation of ERK, JNK, and IKK, as well
      as for maximal AP-1 and NF-kappaB transcriptional activities. We conclude that
      Ras regulates TNF-alpha-induced chemokine expression by activating the AP-1
      pathway and enhancing transcriptional function of NF-kappaB, whereas MEKK1
      activates both the AP-1 and NF-kappaB pathways.

PMID- 12600819
TI  - Inhibition of proteinase 3 by [alpha]1-antitrypsin in vitro predicts very fast
      inhibition in vivo.
AB  - Neutrophil proteinase 3 (Pr3) cleaves elastin and other matrix proteins, and is
      thought to cause lung tissue destruction in emphysema and cystic fibrosis. Its
      deleterious action is theoretically prevented by alpha1-antitrypsin, a serpin
      present in lung secretions. We have evaluated the anti-Pr3 activity of this
      inhibitor to decide whether it may play a physiologic proteolysis-preventing
      function in vivo. We show that (i). the oxidized inhibitor does not inhibit Pr3;
      (ii). the inhibitor competes favorably with elastin for the binding of Pr3, but
      is less efficient for inhibiting elastin-bound proteinase than for complexing
      free enzyme; and (iii). the inhibition takes place in at least two steps: the
      enzyme and the inhibitor first form a high-affinity reversible inhibitory complex
      EI* with an equilibrium dissociation constant K*i of 38 nM; EI* subsequently
      transforms into an irreversible complex EI with a first-order rate constant k2 of
      0.04 s-1. Because the alpha1-antitrypsin concentration in the epithelial lining
      fluid is much higher than K*i, any Pr3 molecule released from neutrophils will be
      taken up as an EI* complex within much less than 1 s, indicating very efficient
      inhibition in vivo.

PMID- 12600820
TI  - Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle
      cell migration.
AB  - Hyperplasia and cell migration of smooth muscle are features of both airway and
      pulmonary vascular diseases. The precise cellular and molecular mechanisms that
      regulate smooth muscle migration in the lungs remain unknown. In this study, we
      examined the effect of cAMP-mobilizing agents and steroids on smooth muscle cell
      migration. Platelet-derived growth factor (PDGF), transforming growth factor
      alpha, vascular endothelial growth factor, and basic fibroblast growth factor
      significantly stimulated cell migration in pulmonary vascular smooth muscle
      (PVSM) cells. Airway smooth muscle (ASM) migration was also stimulated by PDGF,
      transforming growth factor-alpha, and basic fibroblast growth factor, but
      vascular endothelial growth factor was without effect. Interestingly, the smooth
      muscle mitogen thrombin did not stimulate migration of either cell type. Agents
      capable of elevating intracellular cAMP inhibited basal (unstimulated) cell
      migration in both cell types, whereas their effects on PDGF-stimulated migration
      were more variable. Prostaglandin E2, salmeterol, and the phosphodiesterase type
      4 inhibitor cilomolast inhibited basal ASM and PVSM migration by 30-60%.
      Prostaglandin E2 and cilomolast also inhibited PDGF-stimulated migration of ASM
      and PVSM cells, but salmeterol was without effect. Preincubation of ASM cells
      with dexamethasone or fluticasone inhibited basal and PDGF-stimulated migration,
      and enabled an inhibitory effect of salmeterol on PDGF-induced cell migration.
      Steroids alone did not stimulate cAMP production or cAMP/PKA-dependent gene
      transcription (CRE-Luc activity), but slightly augmented salmeterol-stimulated
      CRE-Luc activity. Collectively, these findings demonstrate that cAMP-mobilizing
      agents and steroids modulate human smooth muscle cell migration, likely by
      distinct mechanisms.

PMID- 12600821
TI  - Cytokine-chemokine networks in experimental mycobacterial and schistosomal
      pulmonary granuloma formation.
AB  - Type-1 and type-2 lung granulomas, respectively, elicited by bead immobilized
      Mycobacteria bovis and Schistosoma mansoni egg antigens (Ags) display different
      patterns of chemokine expression. This study tested the hypothesis that chemokine
      expression patterns were related to upstream cytokine signaling. Using
      quantitative transcript analysis, we defined expression profiles for 16
      chemokines and then examined the in vivo effects of neutralizing antibodies
      against interferon-gamma (IFN-gamma), interleukin (IL)-4, IL-10, IL-12, and IL
      13. Transcripts for CXCL2, -5, -9, -10, and -11 and the CCL chemokine, CCL3, and
      lymphotactin (XCL1), were largely enhanced by Th1-related cytokines, IFN-gamma or
      IL-12. Transcripts for CCL11, CCL22, CCL17, and CCL1 were enhanced largely by Th2
      related cytokines, IL-4, IL-10, or IL-13. Transcripts for CCL4, CCL2, CCL8, CCL7,
      and CCL12 were potentially induced by either Th1- or Th2-related cytokines,
      although some of these showed biased expression. IFN-gamma and IL-4 enhanced the
      greatest complement of transcripts, and their neutralization had the greatest
      anti-inflammatory effect on type-1 and type-2 granulomas, respectively. Th1/Th2
      cross-regulation was evident because endogenous Th2 cytokines inhibited type-1,
      whereas Th1 cytokines inhibited type-2 biased chemokines. These findings reveal a
      complex cytokine-chemokine regulatory network that dictates profiles of local
      chemokine expression during T cell-mediated granuloma formation.

PMID- 12600822
TI  - Oxidative stress and apoptosis interact and cause emphysema due to vascular
      endothelial growth factor receptor blockade.
AB  - We have previously demonstrated that a failure of pulmonary endothelial cell
      survival induced by vascular endothelial growth factor (VEGF) receptor blockade
      results in lung alveolar septal cell apoptosis and emphysema. Because apoptosis
      and oxidative stress may be pathobiologically linked, we hypothesized that
      oxidative stress has a central role in alveolar septal cell apoptosis and
      emphysema induced by VEGF receptor blockade. When compared with control animals,
      rats treated with the VEGF receptor blocker SU5416 showed increased alveolar
      enlargement, alveolar septal cell apoptosis, and expression of markers of
      oxidative stress, all of which were prevented by the superoxide dismutase mimetic
      M40419. The preservation of lung structure in SU5416+M40419-treated lungs was
      associated with increased septal cell proliferation, and enhanced phosphorylation
      of the prosurvival and antiapoptotic Akt, when compared with SU5416-treated
      lungs. Consistent with a positive feedback interaction between oxidative stress
      and apoptosis, we found that apoptosis predominated in areas of oxidative stress,
      and that apoptosis blockade by a broad spectrum caspase inhibitor markedly
      reduced the expression of markers of oxidative stress induced by SU5416
      treatment. Oxidative stress and apoptosis, which cause lung cellular destruction
      in emphysema induced by VEGF receptor blockade, may be important mediators common
      to human and experimental emphysema.

PMID- 12600823
TI  - The RhoA/Rho kinase pathway regulates nuclear localization of serum response
      factor.
AB  - RhoA and its downstream target Rho kinase regulate serum response factor (SRF)
      dependent skeletal and smooth muscle gene expression. We previously reported that
      long-term serum deprivation reduces transcription of smooth muscle contractile
      apparatus encoding genes, by redistributing SRF out of the nucleus. Because serum
      components stimulate RhoA activity, these observations suggest the hypothesis
      that the RhoA/Rho kinase pathway regulates SRF-dependent smooth muscle gene
      transcription in part by controlling SRF subcellular localization. Our present
      results support this hypothesis: cotransfection of cultured airway myocytes with
      a plasmid expressing constitutively active RhoAV14 selectively enhanced
      transcription from the SM22 and smooth muscle myosin heavy chain promoters and
      from a purely SRF-dependent promoter, but had no effect on transcription from the
      MSV-LTR promoter or from an AP2-dependent promoter. Conversely, inhibition of the
      RhoA/Rho kinase pathway by cotransfection with a plasmid expressing dominant
      negative RhoAN19, by cotransfection with a plasmid expressing Clostridial C3
      toxin, or by incubation with the Rho kinase inhibitor, Y-27632, all selectively
      reduced SRF-dependent smooth muscle promoter activity. Furthermore, treatment
      with Y-27632 selectively reduced binding of SRF from nuclear extracts to its
      consensus DNA target, selectively reduced nuclear SRF protein content, and
      partially redistributed SRF from nucleus to cytoplasm, as revealed by
      quantitative immunocytochemistry. Treatment of cultured airway myocytes with
      latrunculin B, which reduces actin polymerization, also caused partial
      redistribution of SRF into the cytoplasm. Together, these results demonstrate for
      the first time that the RhoA/Rho kinase pathway controls smooth muscle gene
      transcription in differentiated smooth muscle cells, in part by regulating the
      subcellular localization of SRF. It is conceivable that the RhoA/Rho kinase
      pathway influences SRF localization through its effect on actin polymerization
      dynamics.

PMID- 12600824
TI  - ORFeome-based search of airway epithelial cell-specific novel human [beta]
      defensin genes.
AB  - beta-Defensin is one of the major host defense shields produced by various
      tissues and organs against microbial infection. To date, four human beta
      defensins (DEFBs) gene products that share a consensus six-cysteine motif have
      been discovered. The hidden Markov model (HMM) profile was constructed from the
      common features of those known beta-defensin peptides to search for additional
      novel DEFB genes. A genome-wide search of the profile against ORFeome-based
      peptide databases (e.g., Ensembl project) led to the identification of six new
      DEFB members that also shared the conserved six-cysteine motif. Phylogenetic
      analysis supported a close relationship of these six new members with existing
      DEFB genes. Polymerase Chain Reaction studies of human tissue cDNA panels
      confirmed the expression of all six novel DEFB genes in various tissues. Two of
      them, DEFB106 and DEFB109, were expressed in the lung. A pilot study with cRNA
      probes for in situ hybridization and a synthetic propeptide for the functional
      characterization demonstrated the tissue-/cell-specific expression and the strong
      antimicrobial activity of DEFB106. These results support the utility of ORFeome
      based HMM search in gene discovery for members of a specific gene family. The
      novel DEFB genes identified in this study may significantly contribute to overall
      antimicrobial host defenses.

PMID- 12600825
TI  - Identification of three genes of known function expressed by alveolar epithelial
      type I cells.
AB  - To identify genes of known function expressed by type I (AT1) cells, changes in
      gene expression during transdifferentiation of alveolar epithelial cells (AEC) in
      primary culture from type II (AT2) to type I-like cell phenotype were evaluated.
      Total RNA from AEC on Day 0 or Day 8 was hybridized to a rat microarray for
      screening. Eight upregulated genes on Day 8 were selected for further
      investigation. Northern analysis confirmed upregulation of three of these genes,
      PAI-1, P2X4, and P15INK4B. The corresponding proteins were evaluated in cultured
      AEC and results correlated with expression in AT1 cells. In AEC monolayers, all
      three proteins increased between Day 1 and Day 8. In mixed populations of freshly
      isolated rat lung cells, concurrent labeling with the AT1 cell-specific antibody,
      VIIIB2, localized these proteins to AT1 cells. In whole lung, all three proteins
      were detected in alveolar epithelium in a location consistent with expression in
      AT1 cells. Identification of novel AT1 cell genes of known function suggests an
      active role for AT1 cells in alveolar homeostasis. Furthermore, expression of
      these gene products in AT1-like cells, in freshly isolated AT1 cells, and AT1
      cells in whole lung indicates that AT1-like cells reflect many of the properties
      of AT1 cells in situ.

PMID- 12600826
TI  - The antimicrobial activity of the cathelicidin LL37 is inhibited by F-actin
      bundles and restored by gelsolin.
AB  - Antimicrobial peptides are part of the innate host defense system, and
      inactivation of these peptides is implicated in airway infections in cystic
      fibrosis (CF). The sputum of patients with CF contains anionic polyelectrolytes,
      including F-actin and DNA not found in normal airway fluid. These anionic
      filaments aggregate to contribute to the altered viscoelastic properties of CF
      sputum. We hypothesized that the airway components stabilizing bundles of F-actin
      and DNA are in part cationic antimicrobial agents, and that appropriate
      modification of diseased airway fluid of patients with CF might dissociate these
      bundles and restore antimicrobial activity. We demonstrate that the human
      cathelicidin peptide LL37 forms bundles with F-actin and DNA, which are dissolved
      by gelsolin and DNase, respectively. Coincident with bundle formation,
      antimicrobial activity of LL37 is inhibited by F-actin and DNA. Pseudomonas
      bacteria were killed by low concentrations of LL37, but killing was significantly
      reduced in the presence of F-actin. The actin filament-fragmenting protein
      gelsolin restored bactericidal activity nearly completely. In a growth inhibition
      assay, the effects of F-actin were confirmed, and DNA was also shown to inhibit
      the activity of LL37. When added to CF sputum, gelsolin significantly reduced the
      growth of bacteria, suggesting activation of endogenous antimicrobial factors.
      These findings may have therapeutic implications for treatments previously
      thought to alter only the viscoelastic properties of airway secretions and
      amplify the possible advantage of gelsolin in CF treatment.

PMID- 12600827
TI  - Gene expression in lung adenocarcinomas of smokers and nonsmokers.
AB  - Adenocarcinoma (AC) has become the most frequent type of lung cancer in men and
      women, and is the major form of lung cancer in nonsmokers. Our goal in this paper
      was to determine if AC in smokers and nonsmokers represents the same genetic
      disease. We compared gene expression profiles in resected samples of nonmalignant
      lung tissue and tumor tissue in six never-smokers with AC and in six smokers with
      AC, who were matched for clinical staging and histologic criteria of cell
      differentiation. Results were analyzed using a variety of bioinformatic tools.
      Four times as many genes changed expression in the transition from noninvolved
      lung to tumor in nonsmokers as in smokers, suggesting that AC in nonsmokers
      evolves locally, whereas AC in smokers evolves in a field of genetically altered
      tissue. There were some similarities in gene expression in smokers and
      nonsmokers, but many differences, suggesting different pathways of cell
      transformation and tumor formation. Gene expression in the noninvolved lungs of
      smokers differed from that of nonsmokers, and multidimensional scaling showed
      that noninvolved lungs of smokers groups with tumors rather than noninvolved
      lungs of nonsmokers. In addition, expression of a number of genes correlated with
      smoking intensity. Our findings, although limited by small sample size, suggest
      that additional studies comparing noninvolved to tumor tissue may identify
      pathogenetic mechanisms and therapeutic targets that differ in AC of smokers and
      nonsmokers.

PMID- 12600828
TI  - Heterogeneity of claudin expression by alveolar epithelial cells.
AB  - Claudins are proteins that participate in epithelial barrier function and
      regulate paracellular permeability. By immunohistochemistry of adult rat lung
      sections, claudin-3, claudin-4, and claudin-5 were found to be co-expressed by
      type II alveolar epithelial cells. Claudin-3 and claudin-4 were also co-expressed
      by some alveolar epithelial cells adjacent to type II cells. In contrast, claudin
      5 was expressed throughout the alveolus. Isolated primary rat alveolar epithelial
      cells in culture also expressed claudin-3, claudin-4, and claudin-5, but showed
      little claudin-1 and claudin-2 expression. Claudin expression by isolated cells
      at both the mRNA and protein level varied with time in culture. In particular,
      claudin-3 and claudin-5 co-localized and were distributed around the alveolar
      cell periphery, but claudin-4 expression was heterogeneous. We also found that
      paracellular permeability was increased when cultured alveolar epithelial cells
      were treated with a fatty acid amide, methanandamide. Methanandamide did not
      alter cell viability. Claudin-3, claudin-4, claudin-5, occludin, and zona
      occludens 1 remained localized to cell-cell contact sites at the plasma membrane
      in methanandamide-treated cells, suggesting that plasma membrane localization of
      these junction proteins is not sufficient for maintaining barrier function.
      However, methanandamide-treated cells showed a 12-fold increase in claudin-5
      expression and a 2- to 3-fold increase in claudin-3, consistent with the notion
      that specific changes in claudin expression levels may correlate with changes in
      alveolar epithelial barrier function.

PMID- 12600829
TI  - Associations between toll-like receptors and interleukin-4 in the lungs of
      patients with tuberculosis.
AB  - Toll-like receptors (TLRs) are implicated in the intracellular killing of
      Mycobacterium tuberculosis, and their expression is modulated by interleukin-4
      (IL-4) in vitro. Our aim was to examine the expression of TLRs at the site of
      pathology in tuberculous lung granulomas and to explore the effect of the immune
      response on TLR expression. Immunohistochemistry was performed on lung granulomas
      from nine patients with tuberculosis undergoing lobectomy for haemoptysis. All
      nine patients expressed all of the TLRs studied (TLRs 1-5 and 9), whereas only
      five out of the nine patients had any granulomas positive for IL-4. Statistical
      analysis of TLR and cytokine staining patterns in 183 individual granulomas from
      the nine patients revealed significant associations between pairs of receptors
      and IL-4. A positive association between TLR2 and TLR4 (P < 0.0001) and a
      negative association between TLR2 and IL-4 (P < 0.0001) was observed. The
      associations between TLRs 1, 5, and 9 were significantly different in IL-4
      negative compared with IL-4-positive patients. In conclusion, TLRs are expressed
      by various cell types in the human tuberculous lung, and their expression
      patterns are reflected by differences in the immune response.

PMID- 12600831
TI  - Continuous mechanical contraction modulates expression of alveolar epithelial
      cell phenotype.
AB  - We have previously reported that mechanical distention of alveolar epithelial
      type II cells in culture favored the expression of the type I cell phenotype and
      inhibited the expression of the type II cell phenotype. The objective of the
      present study was to investigate the effects of continuous mechanical contraction
      on the expression of specific markers for the type I and type II cell phenotypes
      in cultured alveolar type II cells. Type II cells were mechanically contracted in
      culture at varying amplitudes and times. Cells were analyzed for mRNA and protein
      content of markers of the type I (RTI40) and type II (surfactant proteins [SPs]
      A, B, and C) phenotypes. Continuous contraction of culture membrane surface area
      by 25% for a duration of 4 h resulted in an 83% increase in SP-A, a 42% increase
      in SP-B, and a 230% increase in SP-C, in comparison with controls. After 12 h of
      contraction, RTI40 mRNA content decreased to 59% of control levels. A minimal
      contraction of 20% of culture membrane surface area was required to modulate
      expression of the type II cell markers. In summary, mechanical contraction favors
      expression of the type II cell phenotype and inhibits expression of the type I
      cell phenotype in a time- and amplitude-dependent manner.

PMID- 12600830
TI  - Mucin biosynthesis: epidermal growth factor downregulates core 2 enzymes in a
      human airway adenocarcinoma cell line.
AB  - Enzymes which exhibit core 2 beta1,6 N-acetylglucosaminyltransferase (C2GnT)
      activity play important roles in physiologic processes including the inflammatory
      response and immune system function, and C2GnT activity is regulated during
      processes, such as T cell activation and cellular differentiation. In this study,
      we have examined the regulation of C2GnT activity in the H292 airway epithelial
      cell line by epidermal growth factor (EGF), which has been previously shown to
      upregulate expression of the airway mucin MUC5AC in this cell line. We found that
      EGF suppressed C2GnT activity in a time- and dose-dependent fashion, and also
      suppressed core 4 beta1,6 N-acetylglucosaminyltransferase (C4GnT) activity.
      Consistent with the suppression of C4GnT activity, Northern blotting results
      showed that EGF preferentially inhibited the M isoform of C2GnT, which forms core
      2, core 4, and blood group I beta1,6 branched carbohydrate structures, while the
      L isoform, which forms only the core 2 structure, was only modestly affected.
      Furthermore, EGF treatment resulted in a shift in the carbohydrate structure of
      FLAG-tagged MUC1 expressed in the cells from core 2-based toward core 1-based
      structures, consistent with the inhibitory effects of EGF on C2GnT. Transforming
      growth factor alpha mimicked the effect of EGF on C2GnT, implicating the EGF
      receptor (EGF-R) in C2GnT suppression, and the EGF-R tyrosine kinase inhibitor
      AG1478 blocked C2GnT suppression, confirming the role of EGF-R in the inhibition
      of C2GnT expression. Also, PD98059, a specific inhibitor of mitogen-activated
      protein kinase/extracellular signal-regulated kinase kinase (MEK)1/2 in the Ras
      mitogen-activated protein kinase pathway, completely blocked the EGF suppressive
      effect, suggesting possible involvement of the Ras-mitogen-activated protein
      kinase pathway in EGF-mediated downregulation of C2GnT. The results of this study
      suggest that exposure of airway cells to EGF may result in remodeling of mucin
      carbohydrate structure, potentially altering the biological properties of the
      cells.

PMID- 12600832
TI  - Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B
      activation.
AB  - Although permissive hypercapnia improves the prognosis of patients with acute
      respiratory distress syndrome, it has not been conclusively determined whether
      hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of
      the lung. The present study was designed to explore the molecular mechanism of HA
      in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial
      cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but
      not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human
      pulmonary artery endothelial cells. Exposure to HA significantly attenuated LPS
      induced NF-kappaB activation through suppressing IkappaB-alpha degradation.
      Isocapnic acidosis and buffered hypercapnia showed qualitatively similar but
      quantitatively smaller effects. HA did not attenuate the LPS-enhanced activation
      of activator protein-1. Following the reduced NF-kappaB activation, HA suppressed
      the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin
      8, resulting in a decrease in both lactate dehydrogenase release into the medium
      and neutrophil adherence to LPS-activated human pulmonary artery endothelial
      cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of
      integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis
      would have anti-inflammatory effects essentially through a mechanism inhibiting
      NF-kappaB activation, leading to downregulation of intercellular adhesion
      molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to
      pulmonary endothelial cells.

PMID- 12600833
TI  - Neutrophil DNA contributes to the antielastase barrier during acute lung
      inflammation.
AB  - During acute lung inflammation, the airspaces are invaded by circulating
      neutrophils. These may then injure tissues through the release of elastase.
      Different natural specific inhibitors such as alpha1-proteinase inhibitor,
      secretory leukocyte proteinase inhibitor, and elafin are nonetheless able to
      counteract the enzymatic activity of elastase. The present study was undertaken
      to assess the role of these different inhibitors in the intrinsic antielastase
      barrier during lipopolysaccharide-induced lung inflammation in mice. Upon
      intranasal administration of lipopolysaccharide to mice, the antielastase
      activity recovered from bronchoalveolar lavage fluids (BALF) increases
      progressively up to 48 h (7-fold) and returns to the basal level within 72 h. By
      contrast, when the same experiments are performed with neutropenic mice
      (pretreatment with an antigranulocyte antibody, or vinblastine), the increase is
      almost totally absent. Ultrafiltration of BALF through 100 kD cutoff membranes
      shows that the activity remains in the retentate, thus ruling out a role for
      native alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and
      elafin. Gel filtration and fraction analysis show that the material eluted with a
      Mr of 600 kD. Agarose gel electrophoresis and ethidium bromide staining reveal
      that the activity corresponds to the presence a large amount of DNA.
      Interestingly, DNase treatment of the active fraction suppresses the antielastase
      activity. Analysis of BALF from patients with acute lung inflammation shows the
      presence of DNA with antielastase activity. We therefore concluded that during
      acute lung inflammation, the recruitment of neutrophils in the airspaces accounts
      for the increased presence of DNA, which in turn contributes to the antielastase
      barrier.

PMID- 12600834
TI  - Reactive nitrogen species block cell cycle re-entry through sustained production
      of hydrogen peroxide.
AB  - Endogenous sources of reactive nitrogen species (RNS) act as second messengers in
      a variety of cell signaling events, whereas environmental sources of RNS like
      nitrogen dioxide (NO2) inhibit cell survival and growth through covalent
      modification of cellular macromolecules. To examine the effects of RNS on cell
      cycle progression, murine type II alveolar C10 cells arrested in G0 by serum
      deprivation were exposed to either NO2 or SIN-1, a generator of RNS, during cell
      cycle re-entry. In serum-stimulated cells, RNS did not prevent the immediate
      early gene response by AP-1, but rather blocked cyclin D1 gene expression,
      resulting cell cycle arrest at the boundary between G0 and G1. Dichlorofluorescin
      diacetate (DCF) fluorescence indicated that RNS induced sustained production of
      intracellular hydrogen peroxide (H2O2), which normally is produced only
      transiently in response to serum growth factors. Loading cells with catalase did
      not diminish the formation of 3-nitrotyrosine on the cell surface, but rather
      prevented enhanced DCF fluorescence and rescued cyclin D1 expression and S phase
      entry. These studies indicate environmental RNS interfere with cell cycle re
      entry through an H2O2-dependent mechanism that influences expression of cyclin D1
      and progression from G0 to the G1 phase of the cell cycle.

PMID- 12600836
TI  - Double-stranded RNA induces the synthesis of specific chemokines by bronchial
      epithelial cells.
AB  - Virus-induced secretion of proinflammatory chemokines (e.g., regulated on
      activation, normal T cells expressed and secreted [RANTES], interleukin [IL]-8)
      by airway epithelial cells helps to initiate antiviral responses and airway
      inflammation by enhancing inflammatory cell recruitment. To define mechanisms for
      virus-induced chemokine secretion, monolayers of nontransformed bronchial
      epithelial cells were transfected or incubated with polydeoxyinosinic
      deoxycytidylic acid (synthetic double-stranded [ds] RNA), rhinovirus dsRNA, or
      single-stranded RNA (ssRNA), and the secretion of selected chemokines was
      determined. Transfection or incubation with dsRNA, but not ssRNA, significantly
      enhanced secretion of RANTES and IL-8, but not eotaxin or macrophage inflammatory
      protein-1alpha. Mechanistically, dsRNA induced and activated dsRNA-dependent
      protein kinase (PKR), and activated nuclear factor-kappaB and p38 mitogen
      activated protein kinase. Furthermore, the PKR inhibitor 2-aminopurine
      significantly blocked dsRNA-induced RANTES and IL-8 secretion, whereas the p38
      mitogen-activated protein kinase inhibitor SB203580 suppressed dsRNA-induced IL
      8, but not RANTES. These findings indicate that dsRNA selectively induce the
      secretion of chemokines such as IL-8 and RANTES, and implicate dsRNA-sensitive
      signaling proteins in this process. Moreover, these data suggest that this may be
      an important mechanism for the selective secretion of chemokines by viruses
      (e.g., rhinovirus, respiratory syncytial virus, influenza) that synthesize dsRNA
      during replication.

PMID- 12600835
TI  - Effects of transforming growth factor-[beta] and budesonide on mitogen-activated
      protein kinase activation and apoptosis in airway epithelial cells.
AB  - Airway epithelial cells play a central role in the inflammatory, apoptotic, and
      remodeling processes associated with asthma. Within this context, a key function
      is exerted by transforming growth factor-beta (TGF-beta), whose biological
      effects are mediated at least in part by mitogen-activated protein kinases
      (MAPKs). The aim of our study was to investigate, in primary cultures of human
      bronchial epithelial cells (HBEC), the effects of TGF-beta (10 ng/ml) on both
      MAPK activation and apoptosis, in the presence or absence of a pretreatment with
      budesonide (10-8 M). MAPK activation was detected by Western blotting, using anti
      phospho-MAPK monoclonal antibodies, which specifically recognize the
      phosphorylated, active forms of these enzymes. Apoptosis was assayed by caspase-3
      activation and fluorescence microscopy, using annexin-V (An-V) and propidium
      iodide (PI) as markers of cell death. Our results show that TGF-beta induced a
      marked ( reverse similar 9-fold) increase in p38 MAPK phosphorylation, and also
      dramatically enhanced cell death, which was completely prevented by specific MAPK
      inhibitors. Both MAPK activation and apoptosis were effectively inhibited by
      budesonide (BUD), thereby suggesting that the powerful antiapoptotic action of
      inhaled glucocorticoids may be very important for their protective role against
      epithelial injury, which represents a key pathogenic event in asthma.

PMID- 12600838
TI  - Whole-grain foods, dietary fiber, and type 2 diabetes: searching for a kernel of
      truth.

PMID- 12600839
TI  - Gamma-tocopherol, the new vitamin E?

PMID- 12600840
TI  - Intakes of fish and marine fatty acids and the risks of cancers of the breast and
      prostate and of other hormone-related cancers: a review of the epidemiologic
      evidence.
AB  - Marine fatty acids, particularly the long-chain eicosapentaenoic and
      docosahexaenoic acids, have been consistently shown to inhibit the proliferation
      of breast and prostate cancer cell lines in vitro and to reduce the risk and
      progression of these tumors in animal experiments. However, whether a high
      consumption of marine fatty acids can reduce the risk of these cancers or other
      hormone-dependent cancers in human populations is unclear. Focusing primarily on
      the results of cohort and case-control studies, we reviewed the current
      epidemiologic literature on the intake of fish and marine fatty acids in relation
      to the major hormone-dependent cancers. Despite the many epidemiologic studies
      that have been published, the evidence from those studies remains unclear. Most
      of the studies did not show an association between fish consumption or marine
      fatty acid intake and the risk of hormone-related cancers. Future epidemiologic
      studies will probably benefit from the assessment of specific fatty acids in the
      diet, including eicosapentaenoic and docosahexaenoic acids, and of the ratio of
      these to n-6 fatty acids, dietary constituents that have not been examined
      individually very often.

PMID- 12600842
TI  - Nutritional risk assessment and obesity in rural older adults: a sex difference.
AB  - BACKGROUND: Many older Americans are overweight or obese, but it is unclear
      whether obesity is associated with other nutritional risk indicators. OBJECTIVE:
      This study investigated sex-associated differences in nutritional risk among
      community-dwelling, rural older adults and determined whether weight status [body
      mass index (BMI; in kg/m(2)) and waist circumference] was related to other
      measures of nutritional risk. DESIGN: This cross-sectional study explored
      relations between weight status and nutritional risk, which was determined on the
      basis of the Level II Screen, overall diet quality, nutrient intakes, and plasma
      biomarkers. RESULTS: Of the 179 subjects, 44% were overweight (BMI 25-29.9) and
      35% were obese (BMI > 30). There were few differences in nutrient intakes between
      older men and women after we controlled for energy intake. In women, BMI was
      directly associated with multiple additional nutritional risk indicators,
      including the number of Level II items (r = 0.30), intakes of fat (r = 0.26) and
      saturated fat (r = 0.21), and homocysteine concentration (r = 0.25). Weight
      status in women was inversely associated with intakes of carbohydrates (r = 
      0.25), fiber (r = -0.35), folate (r = -0.24), magnesium (r = -0.29), iron (r = 
      0.22), and zinc (r = -0.23); Healthy Eating Index scores (r = -0.22); and plasma
      pyridoxal 5' phosphate (r = -0.30). Associations with waist circumference were
      similar. In men, weight status was associated only with plasma cobalamin (r = 
      0.33 for BMI) and pyridoxal 5' phosphate (r = -0.24 for waist circumference).
      CONCLUSIONS: Overweight and obese older women, particularly those living alone,
      may be at greater nutritional risk than are men with a high BMI. Targeted
      nutritional intervention emphasizing nutrient-dense food choices to improve
      dietary patterns may be warranted.

PMID- 12600841
TI  - Blunted lipolytic response to fasting in abdominally obese women: evidence for
      involvement of hyposomatotropism.
AB  - BACKGROUND: Abdominal obesity is associated with a blunted lipolytic response to
      fasting that may contribute to the preservation of adipose tissue mass.
      OBJECTIVE: To further explore the pathophysiology of blunted lipolysis during
      fasting in obesity, we simultaneously measured lipolysis and distinct
      neuroendocrine regulatory hormones in abdominally obese and normal-weight (NW)
      women. DESIGN: Eight abdominally obese [x +/- SD body mass index (BMI; in
      kg/m(2)): 32.1 +/- 2.6] and 6 NW (BMI: 22.7 +/- 1.5) women were studied during
      the last 8 h of a 20-h fast. The glycerol appearance rate and the serum and
      plasma concentrations of insulin, leptin, cortisol, and growth hormone were
      measured regularly. RESULTS: At 13 h of fasting, the mean (+/-SD) glycerol
      appearance rate corrected for fat mass was greater in NW women than in obese
      women (7.2 +/- 1.0 and 5.1 +/- 0.6 micro mol.kg(-1).min(-1), respectively; P =
      0.001). After a 20-h fast, lipolysis increased to 8.9 +/- 1.5 mmol.kg(-1).min(-1)
      in NW women (23%), whereas it did not change significantly in obese women (-2%).
      Fasting decreased insulin concentrations by approximately 30% in both groups, but
      it did not induce significant changes in leptin concentrations. Mean cortisol
      concentrations and urinary catecholamine excretion were comparable in both
      groups. However, mean plasma growth hormone concentrations were higher in NW
      women than in obese women (1.81 +/- 0.98 compared with 0.74 +/- 0.52 mU/L; P =
      0.046). The relative change in lipolysis tended to correlate with mean plasma
      growth hormone concentrations (r = 0.515, P = 0.059). CONCLUSION: Abdominal
      obesity-associated hyposomatotropism may be involved in the blunted increase in
      lipolysis during fasting.

PMID- 12600843
TI  - Addition of inulin to a moderately high-carbohydrate diet reduces hepatic
      lipogenesis and plasma triacylglycerol concentrations in humans.
AB  - BACKGROUND: A high-carbohydrate, low-fat diet is recommended for the prevention
      of atherosclerosis, because it reduces plasma cholesterol concentrations.
      However, such a diet can increase plasma triacylglycerol concentrations--an
      undesirable side effect. The addition of nondigestible carbohydrate could reduce
      the risk of elevated triacylglycerol concentrations. OBJECTIVE: The objective was
      to determine whether the addition of a moderate dose of inulin to a moderately
      high-carbohydrate diet would decrease hepatic lipogenesis and plasma
      triacylglycerol concentrations and have a cholesterol-lowering action. DESIGN:
      Eight healthy subjects were studied twice in a double-blind, randomized, placebo
      controlled crossover study after consuming for 3 wk a moderately high
      carbohydrate, low-fat diet (55% of total energy) plus an oral placebo or 10 g
      high-performance inulin/d. Hepatic lipogenesis and cholesterol synthesis
      (deuterated water method), plasma lipid concentrations, fatty acid synthase,
      acetyl-CoA carboxylase 1, and sterol responsive element binding protein 1c
      messenger RNA concentrations were measured in adipose tissue at the end of the 2
      diet periods. RESULTS: Plasma triacylglycerol concentrations and hepatic
      lipogenesis were lower after inulin than after placebo ingestion (P < 0.05), but
      cholesterol synthesis and plasma cholesterol concentrations were not
      significantly different between the 2 groups. None of the adipose tissue
      messenger RNA concentrations changed significantly after inulin ingestion.
      CONCLUSIONS: The addition of high-performance inulin to a moderately high
      carbohydrate, low-fat diet has a beneficial effect on plasma lipids by decreasing
      hepatic lipogenesis and plasma triacylglycerol concentrations. These results
      support the use of nondigestible carbohydrate for reducing risk factors for
      atherosclerosis.

PMID- 12600844
TI  - Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid
      metabolism in human subjects.
AB  - BACKGROUND: The quantity and type of dietary polyunsaturated fatty acids (PUFAs)
      can alter essential fatty acid metabolism in humans. Diets rich in 20- and 22
      carbon PUFAs may inhibit desaturase expression or activity and decrease the
      synthesis of long-chain unsaturated fatty acids. OBJECTIVE: It was theorized that
      the fat content of a fish-based diet would inhibit the kinetics of the in vivo
      metabolism of n-3 fatty acids compared with a beef-based diet. DESIGN: A
      compartmental model was used to determine the coefficients of the kinetic rate
      constants from the plasma concentration time curves of pentadeuterated (d(5))
      18:3n-3, 20:5n-3, 22:5n-3, and 22:6n-3 of 10 subjects who subsisted on 3 diets
      with different long-chain PUFA contents. For 3 wk, subjects reported their food
      intake from their usual diets and then consumed a beef-based diet for 3 wk and
      then a fish-based diet for an additional 3 wk. Subjects consumed 1 g d(5)-18:3n-3
      ethyl ester at weeks 3, 6, and 9. Blood was drawn over 168 h and the plasma
      analyzed for fatty acids. The coefficients of the kinetic constants of n-3 fatty
      acid metabolism and the percentage utilization of the substrates were determined.
      RESULTS: Across all diets, < 1% of plasma 18:3n-3 was utilized for long-chain
      PUFA synthesis. There was a 70% reduction in the value of the rate constant
      coefficient that regulated transfer of the isotope from the 22:5n-3 compartment
      to 22:6n-3 when the fish-based diet was compared with the beef-based diet. The
      turnover rate of plasma d(5)-22:6n-3 also decreased. CONCLUSIONS: The primary
      effect of a fish-based diet on the kinetics of n-3 metabolism involves processes
      that inhibit the synthesis of 22:6n-3 from 22:5n-3. These processes may involve a
      system of feedback control mechanisms responsive to the plasma concentration of
      22:6n-3.

PMID- 12600845
TI  - Effect of sex and obesity on basal VLDL-triacylglycerol kinetics.
AB  - BACKGROUND: Plasma fatty acid availability is a major regulator of VLDL
      triacylglycerol production. Basal whole-body lipolysis is higher in women than in
      men and is higher in persons with abdominal obesity than in lean individuals.
      OBJECTIVE: Our goal was to determine whether sex and abdominal obesity affect
      VLDL-triacylglycerol kinetics. We hypothesized that basal VLDL-triacylglycerol
      production would be greater in women than in men and greater in obese than in
      lean subjects. DESIGN: VLDL-triacylglycerol kinetics were measured in 20 lean (10
      men, 10 women; body mass index, in kg/m(2): 23 +/- 1) and 20 abdominally obese
      (10 men, 10 women; body mass index: 35 +/- 1) subjects by using a bolus injection
      of [(2)H(5)]glycerol and compartmental modeling analysis. RESULTS: The rate of
      VLDL-triacylglycerol secretion was greater in the lean women than in the lean men
      (5.1 +/- 0.7 and 2.6 +/- 0.3 micro mol x L plasma(-1) x min(-1), respectively; P
      < 0.002). Obesity was associated with increased VLDL-triacylglycerol secretion in
      the men (P < 0.001) but not in the women, which resulted in greater rates of VLDL
      triacylglycerol secretion in the obese men than in the obese women (6.8 +/- 0.5
      and 5.0 +/- 0.5 micro mol x L plasma(-1) x min(-1), respectively; P < 0.05). The
      clearance of VLDL-triacylglycerol from plasma was greater (P < 0.05) in the lean
      women than in the lean men (42 +/- 7 and 27 +/- 4 mL plasma/min, respectively) or
      in the obese men and obese women (28 +/- 3 and 20 +/- 4 mL plasma/min,
      respectively). The plasma VLDL-triacylglycerol concentration was directly related
      to the rate of VLDL-triacylglycerol secretion in the men (R(2) = 0.79, P < 0.001)
      and inversely related to VLDL-triacylglycerol clearance in the women (R(2) =
      0.84, P<0.001). CONCLUSION: Sex and obesity have independent effects on basal
      VLDL-triacylglycerol kinetics.

PMID- 12600846
TI  - Whole-body fat oxidation rate and plasma triacylglycerol concentrations in men
      consuming an ad libitum high-carbohydrate or low-carbohydrate diet.
AB  - BACKGROUND: High-carbohydrate diets may increase plasma triacylglycerol
      concentrations either by increasing production of triacylglycerols or by reducing
      their clearance. OBJECTIVE: We assessed whether the changes in plasma
      triacylglycerol concentrations induced by dietary interventions were associated
      with the changes in whole-body fat oxidation rates. DESIGN: In a parallel study,
      37 healthy male subjects [body mass index (in kg/m(2)): 28 +/- 5, age: 34 +/- 11
      y (x +/- SD)] consumed an ad libitum high-carbohydrate (60% of energy; n = 19) or
      low-carbohydrate (46% of energy), high-fat (41% of energy, 23% as monounsaturated
      fatty acids; n = 18) diet for 7 wk. The following variables were measured before
      and after the dietary interventions: 1) plasma triacylglycerols before and 2, 4,
      6, and 8 h after a meal (containing 40% of daily energy needs and 41% fat); 2)
      indirect calorimetry throughout the 8-h test; and 3) postheparin plasma
      lipoprotein lipase (phLPL) activity at time 8 h of the test. RESULTS: The diets
      induced changes in 1) body weight: -2.5 +/- 2.8 kg (P < 0.01) and -1.7 +/- 3.1 kg
      (P < 0.05) and 2) fasting plasma triacylglycerols: 0.0 +/- 0.4 mmol/L (NS) and 
      0.3 +/- 0.3 mmol/L (P < 0.05) for the high-carbohydrate and the low-carbohydrate
      diets, respectively. In normoinsulinemic subjects (fasting insulin < 100 pmol/L),
      dietary changes in postprandial triacylglycerols were significantly predicted by
      changes in phLPL, body weight, respiratory quotient (or fat oxidation), and the
      type of diet (stepwise multiple linear regression). CONCLUSION: Postprandial
      plasma triacylglycerol concentrations may depend at least partly on fat
      oxidation, body weight, and LPL activity.

PMID- 12600847
TI  - Plasma lipids and lipoproteins in hypercholesterolemic men fed a lipid-lowering
      diet containing lean beef, lean fish, or poultry.
AB  - BACKGROUND: To reach desirable lipid and lipoprotein concentrations, patients
      with hypercholesterolemia are often told to replace the consumption of beef with
      that of fish and poultry. OBJECTIVE: The objective of this study was to compare
      the effects on lipoprotein profiles in hypercholesterolemic men of the
      incorporation of lean beef, poultry (without skin), and lean fish into an
      American Heart Association diet with a high polyunsaturated-to-saturated fatty
      acid ratio and a high fiber content. DESIGN: Three groups of subjects each
      rotated in a crossover design through 3 experimental periods that lasted 26 d
      each. The diets were planned to provide 11 713 kJ/d, of which 18% came from
      protein, 53% from carbohydrate, and 30% from lipids (polyunsaturated-to
      monounsaturated-to-saturated fatty acid ratio: 1.0:1.1:1.0); 268 mg
      cholesterol/d; and 29 g fiber/d. RESULTS: The lean beef, lean fish, and poultry
      diets reduced plasma total and LDL cholesterol by 5-9%, LDL apolipoprotein B by
      16-19%, VLDL triacylglycerols by 22-31%, and the ratio of total cholesterol to
      HDL cholesterol by 6-11%; they also increased the ratio of LDL cholesterol to
      apolipoprotein B by 18-28%. No significant difference was found in these lipid
      variables between the 3 experimental diets. However, the lean fish diet increased
      HDL(2) cholesterol significantly more (P < 0.05) than did the lean beef diet and
      the ratio of HDL(2) to HDL(3) cholesterol significantly more (P < 0.05) than did
      the lean beef and poultry diets. CONCLUSION: The results indicate that an
      American Heart Association diet with a high polyunsaturated-to-saturated fatty
      acid ratio and high fiber content induced numerous favorable changes in coronary
      artery disease risk factors in hypercholesterolemic men, regardless of the
      protein source.

PMID- 12600848
TI  - Is intake of breakfast cereals related to total and cause-specific mortality in
      men?
AB  - BACKGROUND: Prospective studies suggested that substituting whole-grain products
      for refined-grain products lowers the risks of type 2 diabetes and cardiovascular
      disease (CVD) in women. Although breakfast cereals are a major source of whole
      and refined grains, little is known about their direct association with the risk
      of premature mortality. OBJECTIVE: We prospectively evaluated the association
      between whole- and refined-grain breakfast cereal intakes and total and CVD
      specific mortality in a cohort of US men. DESIGN: We examined 86,190 US male
      physicians aged 40-84 y in 1982 who were free of known CVD and cancer at
      baseline. RESULTS: During 5.5 y, we documented 3114 deaths from all causes,
      including 1381 due to CVD (488 myocardial infarctions and 146 strokes). Whole
      grain breakfast cereal intake was inversely associated with total and CVD
      specific mortality, independent of age; body mass index; smoking; alcohol intake;
      physical activity; history of diabetes, hypertension, or high cholesterol; and
      use of multivitamins. Compared with men who rarely or never consumed whole-grain
      cereal, men in the highest category of whole-grain cereal intake (> or = 1
      serving/d) had multivariate-estimated relative risks of total and CVD-specific
      mortality of 0.83 (95% CI: 0.73, 0.94; P for trend < 0.001) and 0.80 (0.66, 0.97;
      P for trend < 0.001), respectively. In contrast, total and refined-grain
      breakfast cereal intakes were not significantly associated with total and CVD
      specific mortality. These findings persisted in analyses stratified by history of
      type 2 diabetes, hypertension, and high cholesterol. CONCLUSIONS: Both total
      mortality and CVD-specific mortality were inversely associated with whole-grain
      but not refined-grain breakfast cereal intake. These prospective data highlight
      the importance of distinguishing whole-grain from refined-grain cereals in the
      prevention of chronic diseases.

PMID- 12600849
TI  - Dietary factors protecting women from urinary tract infection.
AB  - BACKGROUND: Because urinary tract infections (UTIs) are caused by bacteria in the
      stool, dietary factors may affect the risk of contracting a UTI by altering the
      properties of the fecal bacterial flora. OBJECTIVE: We studied dietary and other
      risk factors for UTI in fertile women in a case-control setting. DESIGN: One
      hundred thirty-nine women from a health center for university students or from
      the staff of a university hospital (mean age: 30.5 y) with a diagnosis of an
      acute UTI were compared with 185 age-matched women with no episodes of UTIs
      during the past 5 y. Data on the women's dietary and other lifestyle habits were
      collected by questionnaire. A risk profile for UTI expressed in the form of
      adjusted odds ratios (ORs) with 95% CIs was modeled in logistic regression
      analysis for 107 case-control pairs with all relevant information. RESULTS:
      Frequent consumption of fresh juices, especially berry juices, and fermented milk
      products containing probiotic bacteria was associated with a decreased risk of
      recurrence of UTI: the OR for UTI was 0.66 (95% CI: 0.48, 0.92) per 2 dL juice. A
      preference for berry juice over other juices gave an OR of 0.28 (95% CI: 0.14,
      0.56). Consumption of fermented milk products > or = 3 times/wk gave an OR of
      0.21 (95% CI: 0.06, 0.66) relative to consumption < 1 time/wk. Intercourse
      frequency was associated with an increased risk of UTI (OR for > or = 3 times/wk
      compared with < 1 time/wk: 2.7; 95% CI: 1.16, 6.2). CONCLUSION: Dietary habits
      seem to be an important risk factor for UTI recurrence in fertile women, and
      dietary guidance could be a first step toward prevention.

PMID- 12600850
TI  - Differential effects of saturated and monounsaturated fats on postprandial
      lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes.
AB  - BACKGROUND: Postprandial lipemia is important in the development of coronary
      artery disease because of elevated postprandial triacylglycerol-rich plasma
      lipoproteins and suppressed HDL-cholesterol concentrations. We showed in healthy
      subjects a possible association between postprandial lipid metabolism and the
      responses of the duodenal incretin hormones glucagon-like peptide 1 (GLP-1) and
      gastric inhibitory polypeptide after meals rich in saturated and monounsaturated
      fatty acids (oleic acid), respectively. OBJECTIVE: The objective was to compare
      the postprandial responses (8 h) of glucose, insulin, fatty acids,
      triacylglycerol, gastric inhibitory polypeptide, and GLP-1 to saturated- and
      monounsaturated-rich test meals. DESIGN: Twelve overweight patients with type 2
      diabetes ingested 3 meals randomly: an energy-free soup with 50 g carbohydrate
      (control meal), the control meal plus 100 g butter, and the control meal plus 80
      g olive oil. Triacylglycerol responses were measured in total plasma and in a
      chylomicron-rich and a chylomicron-poor fraction. RESULTS: No significant
      differences in the glucose, insulin, or fatty acid responses to the 2 fat-rich
      meals were seen. The plasma triacylglycerol and chylomicron triacylglycerol
      responses were highest after the butter meal. HDL-cholesterol concentrations
      decreased significantly after the butter meal but did not change significantly
      after the olive oil meal. GLP-1 responses were highest after the olive oil meal.
      CONCLUSIONS: Olive oil induced lower triacylglycerol concentrations and higher
      HDL-cholesterol concentrations than did butter, without eliciting significant
      changes in glucose, insulin, or fatty acids. Furthermore, olive oil induced
      higher concentrations of GLP-1, which may indicate a relation between fatty acid
      composition, incretin responses, and triacylglycerol metabolism postprandially in
      patients with type 2 diabetes.

PMID- 12600851
TI  - Long-term effect of varying the source or amount of dietary carbohydrate on
      postprandial plasma glucose, insulin, triacylglycerol, and free fatty acid
      concentrations in subjects with impaired glucose tolerance.
AB  - BACKGROUND: Reducing the glycemic load (GL) is considered beneficial for managing
      insulin resistance. The GL can be reduced either by reducing carbohydrate intake
      or by reducing the glycemic index (GI). OBJECTIVE: We studied whether these 2
      dietary maneuvers have the same long-term effects on postprandial plasma glucose,
      insulin, triacylglycerol, and free fatty acid (FFA) concentrations in subjects
      with impaired glucose tolerance (IGT). DESIGN: Thirty-four subjects with IGT were
      randomly assigned to high-carbohydrate, high-GI (high-GI); high-carbohydrate, low
      GI (low-GI); and low-carbohydrate, high-monounsaturated fatty acid (MUFA) diets
      for 4 mo. Plasma glucose, insulin, and FFAs were measured from 0800 to 1600 at
      baseline in response to high-GI meals (60% carbohydrate, GI = 61, GL = 63) and
      after 4 mo in response to meals representative of the study diet. RESULTS:
      Carbohydrate intake (% of energy), GI, and GL in the high-GI, low-GI, and MUFA
      groups (breakfast and lunch meals combined), respectively, were 60%, 61, and 63;
      60%, 53, and 55; and 49%, 61, and 52. Compared with the change after 4 mo of the
      high-GI diet, both the low-GI and MUFA diets reduced 0-8-h mean plasma glucose
      concentrations by 0.35 mmol/L (P < 0.05). Mean plasma insulin was approximately
      20% higher (P < 0.05) and FFAs approximately 12% lower (P < 0.05) after the low
      GI diet than after the high-GI diet, with no significant effect of MUFA. Changes
      in 0-8-h mean plasma triacylglycerols in the 3 treatment groups differed
      significantly: -0.14, 0.04, and 0.18 mmol/L, respectively, with the high-GI,
      MUFA, and low-GI diets. CONCLUSIONS: In subjects with IGT, reducing the GI of the
      diet for 4 mo reduced postprandial plasma glucose by the same amount as did
      reducing carbohydrate intake. The 2 dietary maneuvers had different effects on
      postprandial plasma insulin, triacylglycerols, and FFAs.

PMID- 12600852
TI  - Whole-grain and fiber intake and the incidence of type 2 diabetes.
AB  - BACKGROUND: Epidemiologic evidence of a preventive effect of whole grain against
      type 2 diabetes is mainly based on data from women. Information specific to men
      and women is needed. OBJECTIVE: The objective was to study the relation between
      the intake of whole grain and fiber and the subsequent incidence of type 2
      diabetes. DESIGN: The design was a cohort study of 2286 men and 2030 women aged
      40-69 y and initially free of diabetes. Food consumption data were collected from
      1966 through 1972 with the use of a dietary history interview covering the
      habitual diet during the previous year. During a 10-y follow-up, incident type 2
      diabetes cases were identified in 54 men and 102 women from a nationwide
      register. RESULTS: Whole-grain consumption was associated with a reduced risk of
      type 2 diabetes. The relative risk (adjusted for age, sex, geographic area,
      smoking status, body mass index, energy intake, and intakes of vegetables, fruit,
      and berries) between the highest and lowest quartiles of whole-grain consumption
      was 0.65 (95% CI: 0.36, 1.18; P for trend = 0.02). Cereal fiber intake was also
      associated with a reduced risk of type 2 diabetes. The relative risk between the
      extreme quartiles of cereal fiber intake was 0.39 (95% CI: 0.20, 0.77; P = 0.01).
      CONCLUSIONS: An inverse association between whole-grain intake and the risk of
      type 2 diabetes was found. The similar result for cereal fiber intake suggests
      that the whole-grain association is due to cereal fiber or another factor related
      to cereal fiber intake.

PMID- 12600853
TI  - Energy requirements of women of reproductive age.
AB  - BACKGROUND: The energy requirements of women have been based on total energy
      expenditure (TEE) derived from the factorial approach or as multiples of basal
      metabolic rate (BMR). OBJECTIVE: This study was designed to reevaluate the energy
      requirements of healthy, moderately active underweight, normal-weight, and
      overweight women of reproductive age. DESIGN: The energy requirements of 116
      women [n = 13 with a low body mass index (BMI), n = 70 with a normal BMI, and n =
      33 with a high BMI] were estimated from TEE measured by the doubly labeled water
      method. Twenty-four-hour EE and BMR were measured by room respiration
      calorimetry, activity EE was estimated from nonbasal EE as TEE - BMR, and
      physical activity level was calculated as TEE/BMR. Body composition was derived
      from a multicomponent model. Fitness, strength, and physical activity level were
      assessed, and fasting serum indexes were measured. RESULTS: Energy requirements
      differed among the low-BMI (8.9 +/- 0.9 MJ/d), normal-BMI (10.1 +/- 1.4 MJ/d),
      and high-BMI (11.5 +/- 1.9 MJ/d) groups (P = 0.02-0.001, all pairwise
      comparisons). Major predictors of BMR, 24-h EE, and TEE were weight, height, and
      body composition; minor predictors were fasting metabolic profile and fitness.
      Fat-free mass and fat mass accounted for the differences in EE seen between the
      BMI groups. The mean physical activity level of 1.86 suggested that the multiples
      of BMR used to estimate energy requirements have been underestimated. CONCLUSION:
      Recommended energy intakes for healthy, moderately active women of reproductive
      age living in industrialized societies should be revised on the basis of TEE.

PMID- 12600854
TI  - Estimation of energy requirements in a controlled feeding trial.
AB  - BACKGROUND: Estimating energy requirements is a frequent task in clinical
      studies. OBJECTIVE: We examined weight patterns of participants enrolled in a
      clinical trial and evaluated factors that may affect weight stabilization. The
      Harris-Benedict equation and the FAO/WHO equation, used in conjunction with
      physical activity levels estimated with the 7-d Physical Activity Recall, were
      compared for estimating energy expenditure. DESIGN: This was a multicenter,
      randomized controlled feeding trial with participants of the Dietary Approaches
      to Stop Hypertension Trial. For 11 wk, the amount of food participants received
      was adjusted to maintain their body weights as close to their initial weights as
      possible. Change-point regression techniques were used to identify weight-stable
      periods. Factors related to achieving weight stabilization were examined with
      logistic regression. RESULTS: A stable weight was achieved by 86% of the 448
      participants during the run-in period and by 78% during the intervention period.
      Energy intake averaged 11 +/- 2.4 MJ/d (2628 +/- 578 kcal/d), with most
      participants (n = 270) requiring 9-13 MJ/d (2100-3100 kcal/d). The difference
      between predicted and observed intakes was highest at high estimated energy
      intakes, mainly because of high and probably incorrect estimates of the activity
      factor. Participants with lower energy intakes tended to need less adjustment of
      their energy intakes to maintain a stable weight than did participants with
      higher energy intakes. CONCLUSIONS: Weight stabilization is not affected by diet
      composition, sex, race, age, or baseline weight. Either the Harris-Benedict
      equation or the FAO/WHO equation can be used to estimate energy needs. Activity
      factors > 1.7 often lead to overestimation of energy needs.

PMID- 12600856
TI  - Redistribution of vitamin A after iron supplementation in Indonesian infants.
AB  - BACKGROUND: Deficiencies of iron and vitamin A are prevalent worldwide. Single
      micronutrient supplementation is widely used to combat these deficiencies.
      However, micronutrient deficiencies often occur concurrently, and there are many
      interactions between micronutrients. OBJECTIVE: This study investigated
      interactions among 3 important micronutrients--iron, vitamin A, and zinc--when
      they are given as supplements. DESIGN: In a randomized, double-blind, placebo
      controlled supplementation trial, 387 Indonesian infants aged 4 mo were
      supplemented 5 d/wk for 6 mo with 10 mg Fe, 10 mg Zn, 2.4 mg beta-carotene, 10 mg
      each of Fe and Zn, 10 mg Zn + 2.4 mg beta-carotene, or placebo. Complete data on
      micronutrient status, including hemoglobin, ferritin, retinol, zinc, and the
      modified relative dose response (a measure of liver retinol stores), were
      available from 256 infants at the end of the study. RESULTS: Iron-supplemented
      infants had significantly lower plasma retinol concentrations and a significantly
      higher prevalence of vitamin A deficiency, as defined by a plasma retinol
      concentration <0.70 micromol/L, than did the non-supplemented infants. In
      contrast, the modified relative dose response of the iron-supplemented infants
      indicated greater liver stores of vitamin A. Iron supplementation improved iron
      status, and zinc supplementation improved zinc status, but beta-carotene
      supplementation did not significantly improve vitamin A status. CONCLUSIONS: In
      this study, iron supplementation in infants with marginal vitamin A status led to
      lower plasma vitamin A concentrations and simultaneously to greater vitamin A
      liver stores. This implies a redistribution of retinol after iron
      supplementation, which might induce vitamin A deficiency. Therefore, iron
      supplementation in infants should be accompanied by measures to improve vitamin A
      status.

PMID- 12600855
TI  - Gastrointestinal symptoms and blood indicators of copper load in apparently
      healthy adults undergoing controlled copper exposure.
AB  - BACKGROUND: Mild and moderate effects of marginally low and marginally high
      copper exposure are poorly understood in humans. OBJECTIVE: The objective was to
      assess acute gastrointestinal effects and blood markers of copper status in
      apparently healthy adults who underwent controlled copper exposure for 2 mo.
      DESIGN: This was a 2-mo, randomized, controlled, double-blind study of 1365
      apparently healthy adults in whom acute gastrointestinal symptoms (nausea,
      vomiting, diarrhea, and abdominal pain) were assessed as responses to copper
      exposure (<0.01, 2, 4, or 6 mg/L water). Blood markers were measured in 240
      participants at the end of the survey. Subjects with anemia, inflammation, or
      infection were excluded. Serum and erythrocyte copper, peripheral mononuclear
      cell copper, serum ceruloplasmin, the nonceruloplasmin bound copper fraction,
      superoxide dismutase activity, hemoglobin, mean corpuscular volume, serum
      ferritin, and liver enzyme activities were measured. RESULTS: The percentage of
      subjects reporting gastrointestinal symptoms was higher in the 6-mg Cu group than
      in the <0.01-mg Cu group (P < 0.02). One hundred ninety-five subjects fulfilled
      the inclusion criteria for the blood studies. Although a significant relation
      between copper intake and total gastrointestinal symptoms was observed, no
      relation was found between copper intake or reported symptoms and copper-load
      variables. CONCLUSIONS: Gastrointestinal symptoms increased significantly in
      response to 6 mg Cu/L water. No detectable changes were observed in indicators of
      copper status, which suggests competent homeostatic regulation. The results of
      liver function tests remained normal in all subjects. The lack of change in
      superoxide dismutase activity supports the Food and Nutrition Board's latest
      recommendation of 0.9 mg Cu/d for adults.

PMID- 12600857
TI  - Comparison of the effect of low-dose supplementation with L-5
      methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo
      controlled study.
AB  - BACKGROUND: Food fortification with folic acid has been introduced in several
      countries for the prevention of neural tube defects. Fortification has lowered
      total homocysteine (tHcy) concentrations in the US population, a consequence that
      may have health benefits. However, folic acid fortification could mask vitamin B
      12 deficiency. Synthetic L-5-methyltetrahydrofolate (L-MTHF) may be more
      appropriate than folic acid as a fortificant because it is unlikely to mask the
      hematologic indicators of vitamin B-12 deficiency. OBJECTIVE: The objective of
      the study was to compare the effectiveness of 100 micro g folic acid/d with that
      of equimolar L-MTHF in lowering tHcy in healthy volunteers. DESIGN: The study was
      designed as a 24-wk, randomized, placebo-controlled intervention. Free-living
      healthy volunteers (n = 167) were randomly assigned to receive a daily supplement
      containing folic acid (100 microg), L-MTHF (113 microg), or placebo. Blood
      collected at baseline and at 8, 16, and 24 wk was analyzed for tHcy, plasma
      folate, and red blood cell folate (RCF) concentrations. RESULTS: At 24 wk, after
      adjustment for baseline values, mean (95% CI) tHcy was 14.6% (9.3, 19.5%) and
      9.3% (3.7, 14.6%) lower, mean plasma folate was 34% (14, 56%) and 52% (30, 78%)
      higher, and mean RCF was 23% (12, 35%) and 31% (19, 44%) higher in the L-MTHF and
      folic acid groups, respectively, than in the placebo group. L-MTHF was more
      effective than was folic acid in lowering tHcy (P < 0.05). At 24 wk, the
      increases in plasma folate and RCF concentrations did not differ significantly
      between the 2 supplemented groups. CONCLUSION: Low-dose L-MTHF is at least as
      effective as is folic acid in reducing tHcy concentrations in healthy persons.

PMID- 12600858
TI  - Thyroid size and goiter prevalence after introduction of iodized salt: a 5-y
      prospective study in schoolchildren in Cote d'Ivoire.
AB  - BACKGROUND: The long-term goal of salt iodization is elimination of iodine
      deficiency and reduction of the goiter rate to < 5% in school-aged children.
      Normalization of the goiter rate probably indicates disappearance of iodine
      deficiency disorders as a public health problem. However, thyroid size may not
      return to normal for months or years after correction of iodine deficiency.
      OBJECTIVE: We described the time course and pattern of changes in thyroid size
      and goiter rate in response to the introduction of iodized salt in an area of
      severe endemic goiter. DESIGN: In a 5-y prospective study, we measured thyroid
      size by ultrasonography and urinary iodine and thyroid hormone concentrations in
      schoolchildren 6 mo before the introduction of iodized salt and annually for 4 y
      thereafter. RESULTS: Four years after the introduction of iodized salt and
      normalization of the median urinary iodine concentration, mean thyroid size had
      decreased 56% (P < 0.0001). However, 29% of the children remained goitrous, with
      a significant age shift in the distribution of goiter. At baseline, the goiter
      rate was significantly higher in younger (age: 5-9 y) than in older (age: 10-14
      y) children (P < 0.0001). At 2, 3, and 4 y after salt iodization, the goiter rate
      was significantly higher in the older than in the younger children (at 4 y: 52%
      compared with 19%), and the difference increased with time (P < 0.0001).
      CONCLUSION: The goiter rate in school-aged children may remain sharply elevated
      for up to 4 y after successful introduction of iodized salt, primarily because of
      persistent goiter in older children.

PMID- 12600859
TI  - Homocysteine and cognitive function in healthy elderly community dwellers in
      Italy.
AB  - BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are common
      in the elderly and have been suggested to be a risk factor for dementia.
      OBJECTIVE: In an elderly population, we examined the relation between plasma tHcy
      and scores on the Mini-Mental State Examination (MMSE), a commonly used screening
      measure of cognitive impairment in general practice. DESIGN: Fasting plasma tHcy
      concentrations were measured in 650 healthy, cognitively normal Italian community
      dwellers aged > or = 65 y (x +/- SD: 72.8 +/- 6.0 y). Socioeconomic status; serum
      folate, vitamin B-12, and creatinine; other potential dietary and lifestyle
      determinants of tHcy; and conventional vascular disease risk factors were also
      assessed. RESULTS: Subjects with MMSE scores of 26-28 had higher plasma tHcy
      concentrations (12.7 micromol/L; range: 12.2-13.2 micromol/L) than did those with
      scores > 28 (11.9 micromol/L; 11.4-12.3 micromol/L; P < 0.01). Subjects with
      scores of 24-25 had higher plasma tHcy concentrations (14.5 micro mol/L; 13.5
      15.6 micromol/L) than did subjects with scores of 26-28 (P < 0.01) or > 28 (P <
      0.001). The risk of hyperhomocysteinemia (plasma tHcy > 15 micromol/L) was higher
      in subjects with scores of 24-25 (odds ratio: 3.81; 95% CI: 1.9, 7.5) or 26-28
      (odds ratio: 1.96; 95% CI: 1.3, 3.0) than in those with scores > 28. The results
      did not change after adjustment for conventional vascular risk factors and for
      age, medical, dietary, and lifestyle determinants of plasma tHcy. CONCLUSION:
      Elevated plasma tHcy has an independent, graded association with concurrent
      cognitive impairment as measured with the MMSE in healthy elderly community
      dwellers.

PMID- 12600860
TI  - Validation of a soy food-frequency questionnaire and evaluation of correlates of
      plasma isoflavone concentrations in postmenopausal women.
AB  - BACKGROUND: Soy foods may have various health benefits, but little is known about
      the patterns and correlates of soy consumption among postmenopausal women in the
      United States. OBJECTIVE: We assessed the reliability and validity of a soy food
      frequency questionnaire (FFQ) and examined demographic, lifestyle, and dietary
      correlates of plasma isoflavone concentrations in postmenopausal women. DESIGN:
      In this cross-sectional study, soy isoflavone intake and plasma isoflavone
      concentration were analyzed in 96 postmenopausal women aged 50-79 y; the data
      were obtained at 2 visits that were 1 wk apart. Intake was determined with a 20
      item soy FFQ and a comprehensive FFQ that included questions about tofu and
      soymilk. Fasting plasma daidzein and genistein concentrations were determined
      with liquid chromatography-mass spectrometry. RESULTS: Intraclass correlations
      between week 1 and week 2 values were >0.98 for both the soy and comprehensive
      FFQs. Median reported isoflavone intake was <2 mg/d. Pearson's product-moment
      correlation coefficients relating isoflavone intakes with plasma isoflavone
      concentrations ranged from 0.35 to 0.43. Plasma isoflavone concentrations were
      positively associated with age, fiber consumption, servings of fruit and
      vegetables, and dietary supplement use and were inversely associated with
      caffeine consumption; no associations with body mass index, education, dietary
      beliefs, activity level, alcohol intake, or fat intake were observed.
      CONCLUSIONS: Within a population with low soy consumption, the soy FFQ and
      comprehensive FFQ showed good reliability and moderate validity. Associations of
      plasma isoflavone concentrations with other dietary behaviors suggest that these
      compounds may serve as biomarkers of health behaviors in populations with low soy
      consumption.

PMID- 12600861
TI  - Population-based plasma kinetics of an oral dose of [2H4]retinyl acetate among
      preschool-aged, Peruvian children.
AB  - BACKGROUND: The deuterated-retinol-dilution technique provides a quantitative
      estimate of total-body vitamin A (TBVA) stores in adults. To apply the technique
      to children, information on plasma retinol kinetics in this age group is needed.
      OBJECTIVES: We described the plasma retinol kinetics of an oral dose of
      [(2)H(4)]retinyl acetate in a population of Peruvian children (12-24 mo of age)
      in order to examine the relation between TBVA stores and individual plasma
      isotopic ratios 3 d after the dose and to estimate 1) the time required for the
      isotope dose to mix with endogenous vitamin A, 2) the fractional catabolic rate
      for retinol, and 3) TBVA stores. DESIGN: An oral dose of [(2)H(4)]retinyl acetate
      (14 micromol retinol equivalents) was administered to children (n = 107) to
      construct a population-level kinetic curve of the plasma ratio of
      [(2)H(4)]retinol to retinol to estimate equilibration time and the fractional
      catabolic rate. TBVA stores were estimated by using a modification of the isotope
      dilution equation for adults. RESULTS: The dose of [(2)H(4)]retinyl acetate fully
      mixed with endogenous vitamin A 8 d after the dose. The fractional catabolic rate
      was 0.022/d (95% CI: 0.014, 0.030/d). Mean (+/- SD) TBVA stores were estimated as
      0.097 +/- 0.081 mmol (range: 0.016-0.392 mmol). Plasma ratios of [(2)H(4)]retinol
      to retinol 3 d after the dose were correlated with the inverse of estimated TBVA
      stores (r = -0.74, P < 0.0001). CONCLUSIONS: Compared with previous results in
      adults, the equilibration time occurred earlier and the estimated system
      fractional catabolic rate was higher in this population of children. The modified
      isotope dilution equation provided estimates of hepatic vitamin A concentration
      that are similar to values reported in US children at autopsy.

PMID- 12600862
TI  - Effect of the methylenetetrahydrofolate reductase 677C-->T mutation on the
      relations among folate intake and plasma folate and homocysteine concentrations
      in a general population sample.
AB  - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate
      and homocysteine metabolism. The common MTHFR 677C-->T polymorphism decreases the
      enzyme's activity. OBJECTIVE: The objective of the study was to assess the effect
      of the polymorphism on the relations among folate intake, plasma folate
      concentration, and total plasma homocysteine (tHcy) concentration. DESIGN: The
      design was a cross-sectional analysis in a random sample (n = 2051) of a Dutch
      cohort (aged 20-65 y). RESULTS: At a low folate intake (166 micro g/d), folate
      concentrations differed significantly among the genotypes (7.1, 6.2, and 5.4
      nmol/L for the CC, CT, and TT genotypes, respectively; P for all comparisons <
      0.05). At a high folate intake (250 microg/d), folate concentrations in CT and CC
      subjects did not differ significantly (8.3 and 8.6 nmol/L, respectively, but were
      significantly higher (P = 0.2) than those in TT subjects (7.3 nmol/L; P = 0.04).
      At a low folate concentration (4.6 nmol/L), TT subjects had a significantly
      higher (P = 0.0001) tHcy concentration than did CC and CT subjects (20.3 compared
      with 15.0 and 14.1 micromol/L, respectively), whereas at a high folate
      concentration (11.9 nmol/L), the tHcy concentration did not differ significantly
      between genotypes (P > 0.2; <13.1 for all genotypes). The relation between folate
      intake and tHcy concentration had a pattern similar to that of the relation
      between plasma folate and tHcy concentrations. CONCLUSIONS: At any folate intake
      level, TT subjects have lower plasma folate concentrations than do CT and CC
      subjects. Yet, at high plasma folate concentrations, tHcy concentrations in TT
      subjects are as low as those in CT and CC subjects.

PMID- 12600863
TI  - Quantitative assessment of total body stores of vitamin A in adults with the use
      of a 3-d deuterated-retinol-dilution procedure.
AB  - BACKGROUND: The conventional deuterated-retinol-dilution (DRD) technique provides
      a quantitative estimate of total body stores of vitamin A in humans. The
      procedure requires equilibration of serum deuterated retinol with nondeuterated
      retinol after administration of an oral dose of deuterated vitamin A.
      Equilibration takes approximately 3 wk to complete. OBJECTIVE: Our goal was to
      develop a predictive mathematical formula for quantitative assessment of total
      body stores of vitamin A in adults by using a procedure that takes less time to
      perform because serum isotope equilibration is not required, so that blood
      drawing can be done 3 d, instead of approximately 3 wk, after isotope dosing.
      DESIGN: Ratios of serum deuterated to nondeuterated retinol (D:H retinol) were
      determined in Filipino adults (n = 68) 3 and 20 d after an oral dose of 0.015
      mmol [(2)H(4)]retinyl acetate and in Guatemalan adults (n = 15) 3 and 21 d after
      a 0.030-mmol dose. D:H retinol values 20 or 21 d after the isotope dose were used
      in a mathematical formula to obtain quantitative estimates of total body stores
      of vitamin A that were then correlated with serum D:H retinol values 3 d after
      the isotope dose. RESULTS: The relation between these variables was nonlinear and
      was described by the following equation: total body stores of vitamin A (in mmol
      retinol) = 0.00468 x 10(37(isotope dose in mmol))/D:H retinol in serum 3 d after
      the isotope dose. CONCLUSION: A 3-d DRD technique could be used for quantitative
      assessment of total body stores of vitamin A; this technique takes less time than
      does the conventional DRD technique.

PMID- 12600865
TI  - Pregnancy and lactation have no long-term deleterious effect on measures of bone
      mineral in healthy women: a twin study.
AB  - BACKGROUND: The long-term effects of pregnancy and lactation on measures of bone
      mineral in women remain unclear. OBJECTIVE: We studied whether pregnancy or
      lactation has deleterious long-term effects on bone mineral in healthy women.
      DESIGN: We measured bone mineral density (BMD; g/cm(2)) in women aged > or = 18
      y. Analyses were performed on 3 data sets: study 1, 83 female twin pairs (21
      monozygous and 62 dizygous) aged (x +/- SD) 42.2 +/- 15.5 y who were discordant
      for ever having been pregnant beyond 20 wk; study 2, 498 twin pairs aged 42.3 +/-
      15.0 y; and study 3, 1354 individual twins, their siblings, and family members.
      RESULTS: In study 1, there were no significant within-pair differences in
      unadjusted BMD or BMD adjusted for age, height, and fat mass at the lumbar spine
      or total-hip or in total-body bone mineral content (BMC; kg) (paired t tests). In
      study 2, there was no significant within-pair difference in measures of bone
      mineral or body composition related to the within-pair difference in number of
      pregnancies. In study 3, subjects with 1 or 2 (n = 455) and > or = 3 pregnancies
      (n = 473) had higher adjusted lumbar spine BMD (2.9% and 3.8%, respectively; P =
      0.001) and total-body BMC (2.2% and 3.1%; P < 0.001) than did nulliparous women
      (n = 426). Parous women who breast-fed had higher adjusted total-body BMC (2.6%;
      P = 0.005), total-hip BMD (3.2%; P = 0.04), and lower fat mass (10.9%; P = 0.01)
      than did parous non-breast-feeders. CONCLUSION: We found no long-term detrimental
      effect of pregnancy or breast-feeding on bone mineral measures.

PMID- 12600864
TI  - Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms.
AB  - BACKGROUND: Epidemiologic studies have shown an inverse correlation between acute
      coronary events and high intake of dietary vitamin E. Recent clinical studies,
      however, failed to show any beneficial effects of alpha-tocopherol on
      cardiovascular events. Absence of tocopherols other than alpha-tocopherol in the
      clinical studies may account for the conflicting results. OBJECTIVE: This study
      compared the effect of a mixed tocopherol preparation rich in gamma-tocopherol
      with that of alpha-tocopherol on platelet aggregation in humans and addressed the
      potential mechanisms of the effect. DESIGN: Forty-six subjects were randomly
      divided into 3 groups: alpha-tocopherol, mixed tocopherols, and control. ADP and
      phorbol 12-myristate 13-acetate-induced platelet aggregation, nitric oxide (NO)
      release, activation of endothelial constitutive nitric-oxide synthase (ecNOS; EC
      1.14.13.39) and of protein kinase C (PKC), and ecNOS, superoxide dismutase (SOD;
      EC 1.15.1.1), and PKC protein content in platelets were measured before and after
      8 wk of administration of tocopherols. RESULTS: ADP-induced platelet aggregation
      decreased significantly in the mixed tocopherol group but not in the alpha
      tocopherol and control groups. NO release, ecNOS activation, and SOD protein
      content in platelets increased in the tocopherol-treated groups. PKC activation
      in platelets was markedly decreased in the tocopherol-treated groups. Mixed
      tocopherols were more potent than alpha-tocopherol alone in modulating NO release
      and ecNOS activation but not SOD protein content or PKC activation. CONCLUSIONS:
      Mixed tocopherols were more potent in preventing platelet aggregation than was
      alpha-tocopherol alone. Effects of mixed tocopherols were associated with
      increased NO release, ecNOS activation, and SOD protein content in platelets,
      which may contribute to the effect on platelet aggregation.

PMID- 12600866
TI  - Arachidonic acid status during pregnancy is associated with polychlorinated
      biphenyl exposure.
AB  - BACKGROUND: Seafood is an important source of long-chain polyunsaturated fatty
      acids (LCPs), which are essential for normal growth and development. However, the
      nutritional benefits could be limited by polychlorinated biphenyl (PCB)
      contamination. In particular, inhibition of desaturase activities by PCBs may
      affect the maintenance of arachidonic acid (AA) status during development.
      OBJECTIVE: The aim was to evaluate AA status in a birth cohort from a fishing
      community with a high seafood intake and a wide range of PCB exposures. DESIGN:
      We measured LCP concentrations in paired mother and umbilical cord serum samples
      obtained from 182 consecutive births in the Faroe Islands, where PCB-contaminated
      whale blubber forms part of the diet. PCB exposure was determined from maternal
      concentrations. RESULTS: Serum phospholipid AA concentrations averaged 9.14% and
      16.5% (by wt) in maternal and cord serum, respectively. After adjustment for
      gestational age and concentrations of linoleic, alpha-linolenic, and
      eicosapentaenoic acids, a decrease in AA concentrations of 0.17% (by wt) (95% CI:
      0.03%, 0.31%) and 0.31% (by wt) (95% CI: 0.10%, 0.52%) was seen in maternal and
      cord serum, respectively, for each doubling of PCB exposure. CONCLUSIONS:
      Increased PCB exposure was associated with a modest decrease in serum AA
      concentrations, which is in accordance with the experimental evidence of
      desaturase inhibition by PCBs. Such interference with LCP utilization could
      attenuate the beneficial effects of the essential lipids contained in seafood.
      Because AA is of key importance for growth and development, these results suggest
      that this possible mechanism for PCB toxicity deserves to be explored.

PMID- 12600867
TI  - Multiple micronutrient supplementation during pregnancy does not lead to greater
      infant birth size than does iron-only supplementation: a randomized controlled
      trial in a semirural community in Mexico.
AB  - BACKGROUND: Little is known about the benefits of prenatal multivitamin and
      mineral supplements in reducing low birth weight. OBJECTIVE: We conducted a
      randomized, double-blind clinical trial in semirural Mexico to compare the
      effects of multiple micronutrient (MM) supplements with those of iron supplements
      during pregnancy on birth size. DESIGN: Pregnant women (n = 873) were recruited
      before 13 wk of gestation and received supplements 6 d/wk at home, as well as
      routine antenatal care, until delivery. Both supplements contained 60 mg Fe, but
      the MM group also received 1-1.5 times the recommended dietary allowances of
      several micronutrients. RESULTS: At recruitment, the women in the 2 groups were
      not significantly different in age, parity, economic status, height, or
      hemoglobin concentration but differed significantly in marital status (4.6% and
      2.0% of women in the MM and iron-only groups, respectively, were single mothers)
      and mean (+/- SD) body mass index (in kg/m(2); 24.6 +/- 4.3 and 23.8 +/- 3.9 in
      the iron-only and MM groups, respectively). Losses to follow-up (25%) and
      compliance (95%) did not differ significantly between the groups. In intent-to
      treat analyses (MM group: n = 323; iron-only group: n = 322), mean (+/- SD) birth
      weight (2.981 +/- 0.391 and 2.977 +/- 0.393 kg in the MM and iron-only groups,
      respectively) and birth length (48.61 +/- 1.82 and 48.66 +/- 1.83 cm in the MM
      and iron-only groups, respectively) did not differ significantly between the
      groups. CONCLUSION: These findings suggest that MM supplementation during
      pregnancy does not lead to greater infant birth size than does iron-only
      supplementation.

PMID- 12600868
TI  - Programming of lean body mass: a link between birth weight, obesity, and
      cardiovascular disease?
AB  - BACKGROUND: A high birth weight has been suggested to increase the later risk of
      obesity, as measured by body mass index, but, paradoxically, to decrease the
      later propensity to cardiovascular disease. Programming of more lean tissue
      rather than fat mass by a high birth weight might explain this paradox and also
      explain the association of birth weight with later body mass index. This concept
      has been inadequately tested. OBJECTIVE: The objective was to test the hypothesis
      that a high birth weight programs a greater proportion of lean mass in children
      and adolescents. DESIGN: Body fat mass and fat-free mass were assessed by both
      skinfold-thickness measurement and bioelectrical impedance analysis in
      adolescents aged 13-16 y (n = 78) who were part of a study that investigated the
      early origins of cardiovascular disease. Body composition was assessed by dual
      energy X-ray absorptiometry in a separate group of younger children. RESULTS: An
      increase in birth weight of 1 SD was significantly associated with a 0.9-1.4-kg
      (2-3%) increase in fat-free mass in adolescents but not with an increase in fat
      mass. This association was independent of age, sex, height, pubertal stage,
      socioeconomic status, and physical activity. Similar observations were made in
      younger children. CONCLUSIONS: Our data support the hypothesis that fetal growth,
      measured by birth weight, programs lean mass later in life. Our observations may
      therefore explain the association of birth weight with body mass index and have
      implications for the early origins of both obesity and cardiovascular disease.

PMID- 12600869
TI  - Adrenocortical activity in healthy children is associated with fat mass.
AB  - BACKGROUND: Excess endogenous or exogenous cortisol is a potent stimulus for fat
      gain. OBJECTIVE: We examined whether physiologic variations in endogenous
      cortisol secretion may be associated with changes in body composition during
      growth. DESIGN: Anthropometric measurements and 24-h excretion rates of urinary
      free cortisol (UFF) and cortisone (UFE) and the sum of 3 major glucocorticoid
      metabolites (GC), which reflects overall daily cortisol secretion, were
      determined cross-sectionally in healthy preschool (50 boys and 50 girls aged 4-5
      y), late prepubertal (50 boys and 50 girls aged 8-9 y), and pubertal (50 males
      aged 13-14 y and 50 females aged 12-13 y) subjects. RESULTS: Significant positive
      associations (P < 0.001) were found between GC excretion and fat mass, percentage
      body fat, and body mass index by using covariance analysis adjusted for the
      grouping factors sex and age. The relations between GC and indexes of body fat
      remained significant (P < 0.05) even after GC was corrected for individual body
      surface area and the effect of maternal body mass index on fatness was
      considered. No consistent associations with fat indexes were seen for UFF, UFE,
      or the ratio of major urinary cortisol to cortisone metabolites, which reflects
      11 beta-hydroxysteroid dehydrogenase type 1 activity. CONCLUSIONS: Although
      direct effects of UFF and UFE on body composition were not shown, our findings
      strongly suggest that a higher adrenocortical activity is one endocrine-metabolic
      feature of healthy children with higher body fat. Whether urinary GC is a long
      term predictor of fat gain during childhood should be analyzed in future studies.

PMID- 12600870
TI  - Effect of parenteral glutamine supplementation on plasma amino acid
      concentrations in extremely low-birth-weight infants.
AB  - BACKGROUND: Glutamine is one of the most abundant amino acids in both plasma and
      human milk and may be conditionally essential in premature infants. However,
      glutamine is not provided by standard intravenous amino acid solutions.
      OBJECTIVE: We assessed the effect of parenteral glutamine supplementation on
      plasma amino acid concentrations in extremely low-birth-weight infants receiving
      parenteral nutrition (PN). DESIGN: A total of 141 infants with birth weights of
      401-1000 g were randomly assigned to receive a standard intravenous amino acid
      solution that did not contain glutamine or an isonitrogenous amino acid solution
      with 20% of the total amino acids as glutamine. Blood samples were obtained just
      before initiation of study PN and again after the infants had received study PN
      (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d.
      RESULTS: Infants randomly assigned to receive glutamine had mean plasma glutamine
      concentrations that increased significantly and were approximately 30% higher
      than those in the control group in response to PN (425 +/- 182 and 332 +/- 148
      micromol/L for the glutamine and control groups, respectively). There was no
      significant difference between the 2 groups in the relative change in plasma
      glutamate concentration between the baseline and PN samples. In both groups,
      there were significant decreases in plasma phenylalanine and tyrosine between the
      baseline and PN samples; the decrease in tyrosine was greater in the group that
      received glutamine. CONCLUSIONS: In extremely low-birth-weight infants,
      parenteral glutamine supplementation can increase plasma glutamine concentrations
      without apparent biochemical risk. Currently available amino acid solutions are
      likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for
      these infants.

PMID- 12600873
TI  - Racial differences in susceptibility to obesity.

PMID- 12600871
TI  - Membrane peroxidation by lipopolysaccharide and iron-ascorbate adversely affects
      Caco-2 cell function: beneficial role of butyric acid.
AB  - BACKGROUND: Membrane lipid peroxidation may play a role in immune-mediated bowel
      diseases. OBJECTIVE: We examined the effects of lipopolysaccharide (LPS), a
      ubiquitous endotoxin mediator of gram-negative bacteria, alone and in combination
      with iron-ascorbate, on enterocyte function. Furthermore, we assessed the
      antioxidant capacity of butylated hydroxytoluene (BHT) and butyric acid, which
      are known to play a significant role in the welfare of intestinal mucosa. DESIGN:
      Differentiated intestinal Caco-2 cells were used to study the induction of
      membrane peroxidation by LPS (100 micro g/mL) and iron-ascorbate (0.2 and 2
      mmol/L, respectively) and to examine the beneficial effects of BHT and butyric
      acid. RESULTS: A significant dose-dependent increase in malondialdehyde,
      accompanied by lower apical membrane fluidity and significantly decreased sucrase
      activity, was observed when Caco-2 cells were incubated with LPS. LPS also
      augmented paracellular permeability ([(14)C]polyethylene glycol flux),
      prostaglandin E(2) production, and cyclooxygenase-2 (EC 1.14.99.1) expression.
      These abnormalities were exacerbated by the coadministration of iron-ascorbate,
      but most of them were suppressed by butyric acid and BHT. CONCLUSION: Bacterial
      endotoxin and prooxidants may overwhelm antioxidant defenses and become
      deleterious to enterocyte function, whereas butyric acid and BHT may provide
      antioxidant protection.

PMID- 12600875
TI  - Cellular basis of abnormal calcium transients of failing human ventricular
      myocytes.
AB  - Depressed contractility is a central feature of the failing human heart and has
      been attributed to altered [Ca2+]i. This study examined the respective roles of
      the L-type Ca2+ current (ICa), SR Ca2+ uptake, storage and release, Ca2+
      transport via the Na+-Ca2+ exchanger (NCX), and Ca2+ buffering in the altered
      Ca2+ transients of failing human ventricular myocytes. Electrophysiological
      techniques were used to measure and control V(m) and measure I(m), respectively,
      and Fluo-3 was used to measure [Ca2+]i in myocytes from nonfailing (NF) and
      failing (F) human hearts. Ca2+ transients from F myocytes were significantly
      smaller and decayed more slowly than those from NF hearts. Ca2+ uptake rates by
      the SR and the amount of Ca2+ stored in the SR were significantly reduced in F
      myocytes. There were no significant changes in the rate of Ca2+ removal from F
      myocytes by the NCX, in the density of NCX current as a function of [Ca2+]i, ICa
      density, or cellular Ca2+ buffering. However, Ca2+ influx during the late
      portions of the action potential seems able to elevate [Ca2+]i in F but not in NF
      myocytes. A reduction in the rate of net Ca2+ uptake by the SR slows the decay of
      the Ca2+ transient and reduces SR Ca2+ stores. This leads to reduced SR Ca2+
      release, which induces additional Ca2+ influx during the plateau phase of the
      action potential, further slowing the decay of the Ca2+ transient. These changes
      can explain the defective Ca2+ transients of the failing human ventricular
      myocyte.

PMID- 12600876
TI  - Transmural heterogeneity of calcium handling in canine.
AB  - Spatial heterogeneity of the action potential and its influence on arrhythmia
      vulnerability is known. However, heterogeneity of intracellular calcium handling
      and, in particular, its effect on the electrophysiological substrate is less
      clear. Using optical mapping techniques, calcium transients and action potentials
      were recorded simultaneously from ventricular sites across the transmural wall of
      the arterially perfused canine left ventricular wedge preparation during steady
      state baseline pacing and rapid pacing. During baseline pacing, the decay of
      intracellular calcium to diastolic levels and calcium transient duration were
      slower (70%, P<0.005) and longer (20%, P<0.005), respectively, closer to the
      endocardial surface compared with the epicardial surface. Tissue samples isolated
      from the left ventricular wall demonstrate that sarcoplasmic reticulum Ca2+
      ATPase (SERCA2a) expression was significantly less in the subendocardial and
      midmyocardial layers compared with the subepicardial layer. In contrast, no
      significant difference in the transmural expression of Na+-Ca2+ exchanger was
      observed. During rapid pacing, calcium transient alternans and increased levels
      of diastolic intracellular calcium were significantly greater (P<0.01) closer to
      the endocardium (101%+/-62% and 41%+/-15%, respectively) compared with the
      epicardium (12%+/-7% and 12%+/-14%, respectively). In conclusion, cells closer to
      the endocardium exhibit a slower decay of intracellular calcium compared with
      cells near the epicardium, which may be due in part to reduced expression of
      SERCA2a. As a possible consequence, calcium transient alternans and increased
      diastolic levels of intracellular calcium may occur preferentially closer to the
      endocardial surface.

PMID- 12600877
TI  - Wavebreak formation during ventricular fibrillation in the isolated, regionally
      ischemic pig heart.
AB  - Both fixed and dynamic heterogeneities were implicated in the mechanism of
      wavebreak (WB) generation during ventricular fibrillation (VF). However, their
      relative roles remain unclear. We hypothesized that during ischemic VF, the WBs
      are produced primarily because of a fixed heterogeneity; namely, the gradient of
      refractoriness across the ischemic border zone (BZ). Ischemia was induced in 15
      isolated blood-perfused hearts by occluding the left anterior descending coronary
      artery. Simultaneous video imaging (approximately 32x32 mm2) of Di-4-ANEPPS
      fluorescence in the ischemic zone (IZ), the BZ, and the nonischemic zone (NIZ)
      was performed. Dominant-frequency maps were constructed to assess gradients of
      refractoriness during VF. We used singularity points analysis to quantify the
      incidence of WBs per square centimeter per second. During preischemic VF, the
      distribution of WBs was relatively uniform. Ischemia caused an increase of WBs in
      the BZ (from 6.2+/-2.8 to 10.8+/-4.0) and a decrease of WBs in the IZ (from 5.8+/
      2.8 to 2.8+/-1.4), without a significant change in NIZ (from 6.4+/-2.3 to 4.1+/
      1.7). This finding is fully consistent with the dominant-frequency distribution
      during ischemic VF: the average dominant frequency was significantly slower in IZ
      than in NIZ (7.8+/-0.7 versus 10.1+/-1.0 Hz), suggesting a large gradient in
      refractory periods across the BZ. We concluded that acute regional ischemia plays
      a dual role in the maintenance of VF, decreasing the incidence of WB in the IZ
      while increasing it in the BZ. This suggests a predominant role of fixed
      heterogeneities in the formation of WB during VF in acute regional ischemia.

PMID- 12600878
TI  - Glucose regulates monocyte adhesion through endothelial production of interleukin
      8.
AB  - We have shown that glucose increases monocyte adhesion to human aortic
      endothelial cells (HAECs) in vitro.1 In the present study, we examined mechanisms
      by which glucose stimulates monocyte:endothelial interactions. HAECs cultured for
      7 days in 25 mmol/L glucose had a 2-fold elevation in interleukin-8 (IL-8)
      secretion over control cells cultured in 5.5 mmol/L glucose (P<0.001). Use of a
      neutralizing antibody to IL-8 prevented glucose-mediated monocyte adhesion. Both
      glucose and IL-8 activated beta1 integrin on the HAEC surface, suggesting that
      both activate the alpha5beta1 integrin complex on the endothelial surface. The
      alpha5beta1 integrin complex is important for anchoring connecting segment-1
      fibronectin on the HAEC surface for monocyte adhesion. Analysis of the human IL-8
      promoter revealed binding sites for NF-kappaB and AP-1 as well as several aligned
      carbohydrate response elements (also known as E-boxes). Glucose dramatically
      stimulated IL-8 promoter activity. Using mutated IL-8 promoter constructs and
      EMSA, we found that the AP-1 element and the glucose-response element were
      responsible for much of the glucose-mediated activation of IL-8 transcription.
      Interestingly, inhibition of reactive oxygen species (ROS) production through use
      of pharmacological uncouplers of the mitochondrial electron transport chain
      significantly reduced glucose-mediated induction of IL-8 expression. These data
      indicate that glucose regulates monocyte:endothelial interactions through
      stimulation of IL-8 and ROS production and activation of the alpha5beta1 integrin
      complex on HAECs.

PMID- 12600879
TI  - Mast cell-mediated stimulation of angiogenesis: cooperative interaction between
      A2B and A3 adenosine receptors.
AB  - Adenosine is released during tissue injury, ischemia and tumor growth, and
      promotes angiogenesis. Because mast cells accumulate in the proximity of new
      blood vessel development, we examined if they may contribute to adenosine-induced
      angiogenesis. We found that HMC-1 human mast cells express A2A, A2B, and A3
      adenosine receptors. The adenosine agonist NECA (100 micromol/L) increased
      interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and angiopoietin
      2 mRNA expression. NECA-induced secretion of IL-8 and VEGF was verified by ELISA.
      A2B receptors mediate VEGF and IL-8 secretion because neither CGS21680 (selective
      A2A agonist) nor IB-MECA (selective A3 agonist) produced this effect, and it was
      inhibited by the selective A2B antagonist IPDX but not by the selective A2A
      antagonist SCH58261 or the selective A3 antagonist MRS1191. In contrast, the
      selective A3 agonist IB-MECA (EC50 1 nmol/L) stimulated angiopoietin-2
      expression. Conditioned media from NECA-activated HMC-1 stimulated human
      umbilical vein endothelial cell proliferation and migration, and induced
      capillary tube formation. Capillary formation induced by mast cell-conditioned
      media was maximal if both HMC-1 A2B and A3 receptors were activated, whereas
      activation of A2B receptor alone was less effective. Thus, adenosine A2B and A3
      receptors act in a functional cooperative fashion to promote angiogenesis by a
      paracrine mechanism involving the differential expression and secretion of
      angiogenic factors from human mast cells.

PMID- 12600880
TI  - Urokinase-type plasminogen activator plays a critical role in angiotensin II
      induced abdominal aortic aneurysm.
AB  - We have previously demonstrated that urokinase-type plasminogen activator (uPA)
      is highly expressed in the aneurysmal segment of the abdominal aorta (AAA) in
      apolipoprotein E-deficient (apoE-/-) mice treated with angiotensin II (Ang II).
      In the present study, we tested the hypothesis that uPA is essential for AAA
      formation in this model. An osmotic minipump containing Ang II (1.44 mg/kg per
      day) was implanted subcutaneously into 7- to 11-month-old male mice for 1 month.
      Ang II induced AAA in 9 (90%) of 10 hyperlipidemic mice deficient in apoE (apoE-/
      /uPA+/+ mice) but in only 2 (22%) of 9 mice deficient in both apoE and uPA (apoE
      /-/uPA-/- mice) (P<0.05). Although the expansion of the suprarenal aorta was
      significantly less in apoE-/-/uPA-/- mice than in apoE-/-/uPA+/+ mice, the aortic
      diameters of the aorta immediately above or below the suprarenal aorta were
      similar between the 2 groups. Ang II induced AAA in 7 (39%) of 18 strain-matched
      wild-type C57 black/6J control mice. The incidence was significantly higher in
      atherosclerotic apoE-deficient (apoE-/-) mice, in which 8 (100%) of 8 mice
      developed AAA. Only 1 (4%) of 27 uPA-/- mice developed AAA after Ang II
      treatment. We conclude the following: (1) uPA plays an essential role in Ang II
      induced AAA in mice with or without preexisting hyperlipidemia and
      atherosclerosis; (2) uPA deficiency does not affect the diameter of the
      nonaneurysmal portion of the aorta; and (3) atherosclerosis and/or hyperlipidemia
      promotes but is not essential for Ang II-induced AAA formation in this model.

PMID- 12600881
TI  - Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin
      mediated sarcolemmal localization of neuronal Nitric oxide synthase.
AB  - Neuronal nitric oxide synthase (nNOS) is abundantly expressed in skeletal muscle
      where it associates with the dystrophin complex at the sarcolemma by binding to
      the PDZ domain of alpha-syntrophin. Nitric oxide (NO) produced by skeletal muscle
      nNOS is proposed to regulate blood flow in exercising muscle by diffusing from
      the skeletal muscle fibers to the nearby microvessels where it attenuates alpha
      adrenergic vasoconstriction. In the present study, we hypothesized that
      sarcolemmal localization of nNOS is a critical determinant of the vasoregulatory
      effect of skeletal muscle-derived NO. To test this hypothesis, we performed
      experiments in alpha-syntrophin null mice and in transgenic mice expressing a
      mutated alpha-syntrophin lacking the PDZ domain (DeltaPDZ), both of which are
      characterized by reduced sarcolemmal nNOS. We found that modulation of alpha
      adrenergic vasoconstriction was greatly impaired in the contracting muscles of
      the alpha-syntrophin null mice and transgenic DeltaPDZ mice compared with wild
      type mice and transgenic mice expressing full-length alpha-syntrophin. These in
      vivo mouse studies highlight the functional importance of appropriate membrane
      targeting of nNOS by the dystrophin-associated protein alpha-syntrophin and may
      have implications for the development of potential gene therapy strategies to
      treat muscular dystrophy or other muscle-related diseases.

PMID- 12600882
TI  - Sustained reentry in the left ventricle of fibrillating pig hearts.
AB  - It has been proposed that ventricular fibrillation (VF) is driven by sustained
      reentry. However, mapping studies have not detected such "mother rotors" in large
      mammalian hearts. We mapped VF from three 21x12 unipolar electrode arrays in 6
      pigs. Two of the arrays were adjacent to each other on the left-ventricular
      epicardium. Electrode spacing was 2 mm. The third array consisted of 21 needles
      (0.5-mm diameter, 12 electrodes, 1-mm spacing) inserted in a row (2-mm spacing)
      between the epicardial arrays. A total of 88 5-second VF epochs were analyzed
      with automatic reentry detection algorithms. Although intramural reentry was
      sporadically present (29 total occurrences), it was always short-lived with a
      mean life span of 127+/-57 ms. However, in 3 of the 6 animals, sustained
      epicardial reentry (ie, reentry persisting for more than a few cycles) was
      consistently present, often lasting for several seconds. For each epoch, we
      computed indices characterizing (1) the relative duration of reentry on the two
      epicardial arrays (R), (2) the flow of wavefronts between epicardial arrays (W),
      and (3) the relative activation rates of the two epicardial arrays (F). R did not
      correlate with either W or F indicating that rotor-containing regions did not
      produce a net outflow of wavefronts and were not faster than neighboring regions.
      Thus, sustained epicardial, but not intramural, rotors were consistently present
      in some large animal hearts during VF. However, we found no evidence that these
      rotors were responsible for sustaining VF through the mechanisms outlined in the
      mother rotor hypothesis.

PMID- 12600883
TI  - Involvement of the fibroblast growth factor system in adaptive and chemokine
      induced arteriogenesis.
AB  - Fibroblast growth factors (FGFs) have been applied in a variety of therapeutic
      and experimental studies to improve collateral blood flow. However, the
      pathophysiological role and the temporospatial expression of the FGFs and their
      receptors during arteriogenesis have never been elucidated in vivo. Here, we
      report that collateral artery growth in its early phase is associated with an
      increased expression of FGF receptor-1 (FGFR-1) and syndecan-4 on mRNA and
      protein levels as well as with an increased kinase activity of FGFR-1 in a rabbit
      model of arteriogenesis. However, the mRNA levels of FGF-1 and -2 remained
      constant. Our data suggest that these growth factors are supplied by endothelial
      attracted monocytes that, in turn, produce and deliver the FGFs to growing
      collateral arteries. Monocyte chemoattractant protein-1-stimulated arteriogenesis
      was strongly reduced in rabbits by application of the FGF inhibitor
      polyanetholesulfonic acid, indicating that the monocyte-related arteriogenesis
      (as well as the unstimulated adaptation proper) is promoted by FGFs. In summary,
      this study shows that arteriogenesis is associated with an increased expression
      of the FGFRs at the site of the vessel, whereas the growth-promoting ligands are
      supplied by monocytes in a paracrine way.

PMID- 12600884
TI  - Mevastatin can cause G1 arrest and induce apoptosis in pulmonary artery smooth
      muscle cells through a p27Kip1-independent pathway.
AB  - Advanced pulmonary arterial hypertension is characterized by extensive vascular
      remodeling that is usually resistant to vasodilator therapy. Mevastatin is an
      inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate
      limiting step for cholesterol synthesis. HMG-CoA reductase inhibitors have been
      shown to upregulate the cyclin-dependent kinase inhibitor p27Kip1 and to block
      cell proliferation through cholesterol-independent pathways. The aim of this
      study was to determine the effect of mevastatin on DNA synthesis, cell cycle
      progression, and cell proliferation in rat pulmonary artery smooth muscle cells
      (PASMCs). We found that mevastatin induced G1 arrest and decreased DNA synthesis
      in rat PASMCs and did so in association with an increase in both total and cyclin
      E-bound p27Kip1. This caused a marked decrease in cyclin E kinase activity, which
      suggests an important role for p27Kip1 in the ability of mevastatin to induce G1
      arrest. However, in PASMCs lacking functional p27Kip1, mevastatin still decreased
      cyclin E kinase activity, caused G1 arrest, and decreased DNA synthesis. In
      p27Kip1-deficient PASMCs, mevastatin induced a greater reduction of cyclin E
      protein levels (to 35% of control) than in wild-type cells (to 70% of control)
      and also reduced the phosphorylation of cdk2 on threonine 160. Mevastatin also
      caused apoptosis in both wild-type and p27Kip1-deficient PASMCs and was able to
      do so at a dose that did not induce cell cycle arrest. These data suggest that
      HMG-CoA reductase inhibitors can both inhibit cell proliferation and induce
      apoptosis in PASMCs through p27Kip1-independent pathways and may be important
      therapeutic agents in pulmonary arterial hypertension.

PMID- 12600885
TI  - Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but
      not PPARgamma, modulate the expression of genes involved in cardiac lipid
      metabolism.
AB  - Long-chain fatty acids (FA) coordinately induce the expression of a panel of
      genes involved in cellular FA metabolism in cardiac muscle cells, thereby
      promoting their own metabolism. These effects are likely to be mediated by
      peroxisome proliferator-activated receptors (PPARs). Whereas the significance of
      PPARalpha in FA-mediated expression has been demonstrated, the role of the
      PPARbeta/delta and PPARgamma isoforms in cardiac lipid metabolism is unknown. To
      explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes
      were exposed to FA or to ligands specific for either PPARalpha (Wy-14,643),
      PPARbeta/delta (L-165041, GW501516), or PPARgamma (ciglitazone and
      rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes,
      and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was
      determined. Consistent with the PPAR isoform expression pattern, the FA oxidation
      rate increased in cardiomyocytes exposed to PPARalpha and PPARbeta/delta ligands,
      but not to PPARgamma ligands. Likewise, the FA-mediated expression of FA-handling
      proteins was mimicked by PPARalpha and PPARbeta/delta, but not by PPARgamma
      ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only
      express PPARbeta/delta, the FA-induced expression of genes was mimicked by the
      PPARbeta/delta ligand only, indicating that FA also act as ligands for the
      PPARbeta/delta isoform. In cardiomyocytes, MCPT-1 promoter activity was
      unresponsive to PPARgamma ligands. However, addition of PPARalpha and
      PPARbeta/delta ligands dose-dependently induced promoter activity. Collectively,
      the present findings demonstrate that, next to PPARalpha, PPARbeta/delta, but not
      PPARgamma, plays a prominent role in the regulation of cardiac lipid metabolism,
      thereby warranting further research into the role of PPARbeta/delta in cardiac
      disease.

PMID- 12600886
TI  - Deficiency of the cysteine protease cathepsin S impairs microvessel growth.
AB  - During angiogenesis, microvascular endothelial cells (ECs) secrete proteinases
      that permit penetration of the vascular basement membrane as well as the
      interstitial extracellular matrix. This study tested the hypothesis that
      cathepsin S (Cat S) contributes to angiogenesis. Treatment of cultured ECs with
      inflammatory cytokines or angiogenic factors stimulated the expression of Cat S,
      whereas inhibition of Cat S activity reduced microtubule formation by impairing
      cell invasion. ECs from Cat S-deficient mice showed reduced collagenolytic
      activity and impaired invasion of collagens type I and IV. Cat S-deficient mice
      displayed defective microvessel development during wound repair. This abnormal
      angiogenesis occurred despite normal vascular endothelial growth factor and basic
      fibroblast growth factor levels, implying an essential role for extracellular
      matrix degradation by Cat S during microvessel formation. These results
      demonstrate a novel function of endothelium-derived Cat S in angiogenesis.

PMID- 12600887
TI  - Epicardial/Mesothelial cell line retains vasculogenic potential of embryonic
      epicardium.
AB  - Recent work has demonstrated the importance of the epicardium in the development
      of the heart. During embryogenesis, these epithelial cells provide the
      progenitors for the epicardium, coronary smooth muscle, endothelium, and cardiac
      fibroblasts. The epicardium sends important signals to the developing myocardium.
      Still, analysis of these epithelial cells has lagged behind that of other cardiac
      cell types largely because of the lack of a defined experimental cell system in
      which epicardial cell differentiation can be studied. The present report examines
      the developmental potential of a cell line derived from rat epicardial
      mesothelial cells. These analyses demonstrate that the cell line retains many
      characteristics of the intact epithelium, including the ability to form a
      polarized epithelium and express many epicardial genes. Our data show for the
      first time that these cells retain the ability to produce mesenchyme in response
      to specific growth factors and, importantly, to generate smooth muscle cells.
      Thus, this study provides evidence that these cells can serve as an important
      model system for the analysis of the cellular and molecular mechanisms that
      govern epicardial development and function.

PMID- 12600888
TI  - Activation of RhoA and inhibition of myosin phosphatase as important components
      in hypertension in vascular smooth muscle.
AB  - Two mechanisms are proposed to account for the inhibition of myosin phosphatase
      (MP) involved in Ca2+ sensitization of vascular muscle, ie, phosphorylation of
      either MYPT1, a target subunit of MP or CPI-17, an inhibitory phosphoprotein. In
      cultured vascular aorta smooth muscle cells (VSMCs), stimulation with angiotensin
      II activated RhoA, and this was blocked by pretreatment with 8-bromo-cGMP. VSMCs
      stimulated by angiotensin II, endothelin-1, or U-46619 significantly increased
      the phosphorylation levels of both MYPT1 (at Thr696) and CPI-17 (at Thr38). The
      angiotensin II-induced phosphorylation of MYPT1 was completely blocked by 8-bromo
      cGMP or Y-27632 (a Rho-kinase inhibitor), but not by GF109203X (a PKC inhibitor).
      In contrast, phosphorylation of CPI-17 was inhibited only by GF109203X. Y-27632
      dramatically corrected the hypertension in N(omega)-nitro-L-arginine methyl ester
      (L-NAME)-treated rats, and this hypertension also was sensitive to isosorbide
      mononitrate. The level of the active form of RhoA was significantly higher in
      aortas from L-NAME-treated rats. Expression of RhoA, Rho-kinase, MYPT1, CPI-17,
      and myosin light chain kinase were not significantly different in aortas from L
      NAME-treated and control rats. Activation of RhoA without changes in levels of
      other signaling molecules were observed in three other rat models of
      hypertension, ie, stroke-prone spontaneously hypertensive rats, renal
      hypertensive rats, and DOCA-salt rats. These results suggest that independent of
      the cause of hypertension, a common point in downstream signaling and a critical
      component of hypertension is activation of RhoA and subsequent activation of Rho
      kinase.

PMID- 12600889
TI  - Chlamydia pneumoniae induces tissue factor expression in mouse macrophages via
      activation of Egr-1 and the MEK-ERK1/2 pathway.
AB  - Recent studies have suggested that infection with Chlamydia pneumoniae (C
      pneumoniae) may contribute to the instability of atherosclerotic plaques and
      thrombosis and is associated with acute coronary events. Tissue factor (TF), a
      potent prothrombotic molecule, is expressed by macrophages and other cell types
      within atherosclerotic lesions and plays an essential role in thrombus formation
      after plaque rupture. Therefore the effects of C pneumoniae on induction of TF
      expression in macrophages were investigated. Infection of RAW mouse macrophages
      with C pneumoniae induced a time-dependent increase in procoagulant activity,
      expression of TF protein, and TF mRNA. C pneumoniae infection stimulated
      increased binding of nuclear proteins to the consensus DNA sequence for Egr-1, a
      key response element within the TF promoter, and increased the expression of Egr
      1 protein. Transient transfections of RAW cells with mutated TF promoter
      constructs showed that the Egr-1 binding region is an important transcriptional
      regulator of C pneumoniae-induced TF expression. Furthermore, C pneumoniae
      stimulated phosphorylation of ERK1/2 and Elk-1 and pharmacological inhibition of
      mitogen-activated protein kinase activity reduced the expression of TF and Egr-1.
      Antibody and polymyxin B blocking of the Toll-like receptor 4 (TLR4) partially
      reduced the C pneumoniae-induced expression of TF and Egr-1. In conclusion, the C
      pneumoniae-induced increase in TF expression in macrophages is mediated in part
      by Egr-1, signaling through TLR4, and activation of the MEK-ERK1/2 pathway.

PMID- 12600890
TI  - Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress
      induced ventricular tachycardia and Ca2+-dependent action potential remodeling.
AB  - The cardiac troponin T (TnT) I79N mutation has been linked to familial
      hypertrophic cardiomyopathy and high incidence of sudden death, despite causing
      little or no cardiac hypertrophy in patients. Transgenic mice expressing mutant
      human TnT (I79N-Tg) have increased cardiac contractility, but no ventricular
      hypertrophy or fibrosis. Enhanced cardiac function has been associated with
      myofilament Ca2+ sensitization, suggesting altered cellular Ca2+ handling. In the
      present study, we compare cellular Ca2+ transients and electrophysiological
      parameters of 64 I79N-Tg and 106 control mice in isolated myocytes, isolated
      perfused hearts, and whole animals. Ventricular action potentials (APs) measured
      in isolated I79N-Tg hearts and myocytes were significantly shortened only at 70%
      repolarization. No significant differences were found either in L-type Ca2+ or
      transient outward K+ currents, but inward rectifier K+ current (IK1) was
      significantly decreased. More critically, Ca2+ transients of field-stimulated
      ventricular I79N-Tg myocytes were reduced and had slow decay kinetics, consistent
      with increased Ca2+ sensitivity of I79N mutant fibers. AP differences were
      abolished when myocytes were dialyzed with Ca2+ buffers or after the Na+-Ca2+
      exchanger was blocked by Li+. At higher pacing rates or in presence of
      isoproterenol, diastolic Ca2+ became significantly elevated in I79N-Tg compared
      with control myocytes. Ventricular ectopy could be induced by isoproterenol
      challenge in isolated I79N-Tg hearts and anesthetized I79N-Tg mice. Freely moving
      I79N-Tg mice had a higher incidence of nonsustained ventricular tachycardia (VT)
      during mental stress (warm air jets). We conclude that the TnT-I79N mutation
      causes stress-induced VT even in absence of hypertrophy and/or fibrosis, arising
      possibly from the combination of AP remodeling related to altered Ca2+ transients
      and suppression of IK1.

PMID- 12600891
TI  - Induction of glutathione synthesis in macrophages by oxidized low-density
      lipoproteins is mediated by consensus antioxidant response elements.
AB  - The uptake of oxidized low-density lipoproteins (oxLDL) by macrophages leading to
      conversion into foam cells is a seminal event in atherogenesis. Excessive
      accumulation of oxLDL can cause oxidative stress in foam cells leading to cell
      death and the progression and destabilization of atherosclerotic lesions.
      Oxidative stress induces a protective compensatory increase in the synthesis of
      the endogenous antioxidant glutathione (GSH). Glutamate-cysteine ligase (GCL) is
      the rate-limiting enzyme in GSH synthesis and is composed of a catalytic subunit
      (GCLC) and a modifier subunit (GCLM), which are products of separate genes.
      Treatment of RAW 264.7 mouse macrophages and mouse peritoneal macrophages with
      oxLDL (30 microg/mL) induces increased expression of both Gclc and Gclm in vitro.
      The increase in mRNA occurs in part via increased transcription as demonstrated
      with luciferase reporter constructs. The promoters for both GCLC and GCLM contain
      consensus antioxidant response elements (AREs). Electrophoretic mobility shift
      assays revealed induction of nuclear factor binding to these AREs after treatment
      of RAW 264.7 cells and mouse peritoneal macrophages with oxLDL. Nuclear factor
      binding to the AREs is diminished by a single base pair substitution in the core
      sequence. Site-directed mutagenesis of the AREs within the Gclc and Gclm
      promoters resulted in a decrease of oxLDL-induced luciferase activity. Supershift
      analyses revealed that oxLDL stimulates binding of the transcription factors
      Nrf1, Nrf2, and c-jun to the AREs. These data suggest that AREs play a direct
      role in mediating the induction of GSH synthesis by oxLDL and in protecting
      macrophages against oxidized lipid-induced oxidative stress.

PMID- 12600892
TI  - Structural adaptation of the nuclear pore complex in stem cell-derived
      cardiomyocytes.
AB  - Macromolecules are transported in and out of the nucleus through nuclear pores.
      It is poorly understood how these megadalton conduits support nucleocytoplasmic
      traffic during genetic reprogramming associated with cell commitment to a
      specific lineage. Murine embryonic stem cells were differentiated into
      cardiomyocytes within embryoid bodies, and contracting cells expressing
      myocardial-specific proteins were isolated from the mesodermal layer. Compared
      with postmitotic cardiac cells from heart muscle, these proliferative and
      differentiating stem cell-derived cardiomyocytes demonstrated a significantly
      lower density of nuclear pores. At nanoscale resolution, the pore channel was
      commonly unoccupied in heart muscle-isolated cardiac cells, yet a dense material,
      presumably the central transporter, protruded toward the cytosolic face of the
      nuclear pore complex in stem cell-derived cardiomyocytes. Stem cell-derived
      cardiac cells distributed the nuclear transport factor Ran in the nucleus,
      decreased the number of spare nuclear pore complexes from the cytosolic annulate
      lamellae reservoir, and expressed a set of nucleoporins, NUP214, NUP358, NUP153,
      and p62, involved in nuclear transport. Stem cell-derived cardiomyocytes secured
      transport of nuclear constitutive proteins, cardiogenic transcription factors,
      and cell cycle regulators, including the prototypic histone H1, myocyte enhancer
      binding factor 2, and p53. Thus, differentiating stem cell-derived cardiomyocytes
      undergo structural adaptation and mobilize nuclear transport regulators in
      support of nucleocytoplasmic communication during commitment to mature cardiac
      lineage.

PMID- 12600893
TI  - Alveolar type 1 cells express the alpha2 Na,K-ATPase, which contributes to lung
      liquid clearance.
AB  - The alveolar epithelium is composed of alveolar type 1 (AT1) and alveolar type 2
      (AT2) cells, which represent approximately 95% and approximately 5% of the
      alveolar surface area, respectively. Lung liquid clearance is driven by the
      osmotic gradient generated by the Na,K-ATPase. AT2 cells have been shown to
      express the alpha1 Na,K-ATPase. We postulated that AT1 cells, because of their
      larger surface area, should be important in the regulation of active Na+
      transport. By immunofluorescence and electron microscopy, we determined that AT1
      cells express both the alpha1 and alpha2 Na,K-ATPase isoforms. In isolated,
      ouabain-perfused rat lungs, the alpha2 Na,K-ATPase in AT1 cells mediated 60% of
      the basal lung liquid clearance. The beta-adrenergic agonist isoproterenol
      increased lung liquid clearance by preferentially upregulating the alpha2 Na,K
      ATPase protein abundance in the plasma membrane and activity in alveolar
      epithelial cells (AECs). Rat AECs and human A549 cells were infected with an
      adenovirus containing the rat Na,K-ATPase alpha2 gene (Adalpha2), which resulted
      in the overexpression of the alpha2 Na,K-ATPase protein and caused a 2-fold
      increase in Na,K-ATPase activity. Spontaneously breathing rats were also infected
      with Adalpha2, which increased alpha2 protein abundance and resulted in a
      approximately 250% increase in lung liquid clearance. These studies provide the
      first evidence that alpha2 Na,K-ATPase in AT1 cells contributes to most of the
      active Na+ transport and lung liquid clearance, which can be further increased by
      stimulation of the beta-adrenergic receptor or by adenovirus-mediated
      overexpression of the alpha2 Na,K-ATPase.

PMID- 12600894
TI  - Coordinate control of proliferation and migration by the p27Kip1/cyclin-dependent
      kinase/retinoblastoma pathway in vascular smooth muscle cells and fibroblasts.
AB  - Previous studies have demonstrated a protective effect of the cyclin-dependent
      kinase (CDK) inhibitor p27Kip1 against atherosclerosis and restenosis, two
      disorders characterized by abundant proliferation and migration of vascular
      smooth muscle cells and adventitial fibroblasts. These therapeutic effects might
      result from p27Kip1-dependent suppression of both cell proliferation and
      migration. However, the interplay between cell growth and locomotion remains
      obscure. We show here that p27Kip1 inhibits cellular changes that normally occur
      during cell locomotion (eg, lamellipodia formation and reorganization of actin
      filaments and focal adhesions). Importantly, a p27Kip1 mutant lacking CDK
      inhibitory activity failed to inhibit vascular smooth muscle cell and fibroblast
      proliferation and migration. Moreover, a constitutively active mutant of the
      retinoblastoma protein (pRb) insensitive to CDK-dependent hyperphosphorylation
      inhibited both cell proliferation and migration. In contrast, inactivation of pRb
      by forced expression of the adenoviral oncogene E1A correlated with high
      proliferative and migratory activity. Collectively, these results suggest that
      cellular proliferation and migration are regulated in a coordinated manner by the
      p27Kip1/CDK/pRb pathway. These findings might have important implications for the
      development of novel therapeutic strategies targeting the
      fibroproliferative/migratory component of vascular occlusive disorders.

PMID- 12600895
TI  - Cx43 and dual-pathway electrophysiology of the atrioventricular node and
      atrioventricular nodal reentry.
AB  - Fluorescent imaging has revealed that posterior nodal extensions provide the
      anatomical substrate for the dual-pathway electrophysiology of the
      atrioventricular (AV) node during normal conduction and reentry. The reentry can
      be intranodal, or as well as the posterior nodal extensions, it can involve an
      endocardial layer of atrial/atrial-nodal (A/AN) cells as part of the AV nodal
      reentry (AVNR) circuit. Using fluorescent imaging with a voltage-sensitive dye
      and immunolabeling of Cx43, we mapped the electrical activity and structural
      substrate in 3 types of AVNR induced by premature atrial stimulation in 8 rabbit
      hearts. In 6 cases, the AVNR pathway involved (1) a fast pathway (FP), (2) the
      A/AN layer, and (3) a slow pathway (SP). In 4 cases, reentry took the path (1)
      SP, (2) A/AN layer, and (3) FP. In 2 cases, reentry was intranodal, propagating
      between the 2 posterior nodal extensions. Immunolabeling revealed that the FP and
      SP are formed by Cx43-expressing bundles surrounded by tissue without Cx43. Cx43
      expressing posterior nodal extensions are the substrate of AVNR during both
      intranodal and extranodal reentry.

PMID- 12600896
TI  - Remodeling of gap junctional channel function in epicardial border zone of
      healing canine infarcts.
AB  - The epicardial border zone (EBZ) of canine infarcts has increased anisotropy
      because of transverse conduction slowing. It remains unknown whether changes in
      gap junctional conductance (Gj) accompany the increased anisotropy. Ventricular
      cell pairs were isolated from EBZ and normal hearts (NZ). Dual patch clamp was
      used to quantify Gj. At a transjunctional voltage (Vj) of +10 mV, side-to-side Gj
      of EBZ pairs (9.2+/-3.4 nS, n=16) was reduced compared with NZ side-to-side Gj
      (109.4+/-23.6 nS, n=14, P<0.001). Gj of end-to-end coupled cells was not reduced
      in EBZ. Steady-state Gj of both NZ and EBZ showed voltage dependence, described
      by a two-way Boltzmann function. Half-maximal activation voltage in EBZ was
      shifted to higher Vj in positive and negative directions. Immunoconfocal
      planimetry and quantification showed no change in connexin43 per unit cell volume
      or surface area in EBZ. Decreased side-to-side coupling occurs in EBZ myocytes,
      independent of reduced connexin43 expression, and is hypothesized to contribute
      to increased anisotropy and reentrant arrhythmias.

PMID- 12600897
TI  - Posttranscriptional control of renin synthesis: identification of proteins
      interacting with renin mRNA 3'-untranslated region.
AB  - Stabilization and correct localization of mRNA are important features of renin
      synthesis. To elucidate the molecular basis of cAMP-mediated posttranscriptional
      control via mRNA stabilization, we analyzed the interaction of human preprorenin
      (hREN) mRNA 3'-untranslated region (3'-UTR) with proteins of renin synthesizing
      Calu-6 cells and investigated their functional impact on messenger integrity. To
      identify hREN mRNA binding proteins, electrophoretic mobility shift assays, UV
      cross-linking and RNA-affinity chromatography with subsequent matrix-assisted
      laser desorption/ionization time-of-flight mass spectrometry were performed. The
      following six proteins were unambiguously identified as hREN mRNA 3'-UTR binding
      proteins: hnRNP E1 (synonyms alpha-CP or PCBP), hnRNP K, dynamin, nucleolin, YB
      1, and MINT-homologous protein. All proteins contain various RNA binding motifs,
      and most have been described in the context of mRNA binding and mRNA
      stabilization. Four proteins for which antibodies were available were verified by
      immunological techniques (dynamin, nucleolin, hnRNP E1, and YB-1). Forskolin, an
      activator of cAMP synthesis, considerably stimulates renin synthesis via
      inhibition of REN mRNA decay. Functionally, this cAMP-based mRNA stabilization is
      accompanied by a 3- to 6-fold upregulation of REN mRNA binding proteins. RNase
      degradation assays confirm that 3'-UTR binding proteins are able to protect and
      stabilize REN mRNA in vitro.

PMID- 12600898
TI  - VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte
      mediated mechanism.
AB  - Two signaling receptors for vascular endothelial growth factor (VEGF) in the
      vasculature are known with not yet well-understood roles in collateral vessel
      growth (arteriogenesis). In this study, we examined the involvement of the two
      VEGF receptors in arteriogenesis. Therefore, we used the VEGF homologue placenta
      growth factor (PlGF), which only binds to VEGFR-1 and VEGF-E, which only
      recognizes VEGFR-2. These peptides were locally infused over 7 days after
      ligation of the femoral artery in the rabbit. Evaluation of collateral growth by
      determining collateral conductance and angiographic scores demonstrated that the
      VEGFR-1-specific PlGF contributed significantly more to arteriogenesis than the
      VEGFR-2 specific VEGF-E. The combination of VEGF-E and PlGF did not exceed the
      effect of PlGF alone, indicating that cooperation of the two VEGF receptors in
      endothelial cell signaling is not required for arteriogenesis. In an in vitro
      model of angiogenesis, VEGF and VEGF-E were comparably active, whereas PlGF
      displayed no activity when given alone and did not further increase the effects
      of VEGF or VEGF-E. However, PlGF was as potent as VEGF when monocyte activation
      was assessed by monitoring integrin surface expression. In addition, accumulation
      of activated monocytes/macrophages in the periphery of collateral vessels in PlGF
      treated animals was observed. Furthermore, in monocyte-depleted animals, the
      ability of PlGF to enhance collateral growth in the rabbit model and to rescue
      impaired arteriogenesis in PlGF gene-deficient mice was abrogated. Together,
      these data indicate that the arteriogenic activity observed with the VEGFR-1
      specific PlGF is caused by its monocyte-activating properties.

PMID- 12600899
TI  - Gene transfer of extracellular superoxide dismutase reduces arterial pressure in
      spontaneously hypertensive rats: role of heparin-binding domain.
AB  - Oxidative stress may contribute to hypertension. The goals of this study were to
      determine whether extracellular superoxide dismutase (ECSOD) reduces arterial
      pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding
      domain (HBD), which is responsible for cellular binding, is necessary for the
      function of ECSOD. Three days after intravenous injection of an adenoviral vector
      expressing human ECSOD (AdECSOD), mean arterial pressure (MAP) decreased from
      165+/-4 mm Hg (mean+/-SE, n=7) to 124+/-3 mm Hg (n=7) in adult anesthetized SHR
      (P<0.01) but was not altered in normotensive Wistar-Kyoto rats. Cardiac output
      was not changed in SHR 3 days after AdECSOD. Gene transfer of ECSOD with deletion
      of the HBD (AdECSODDeltaHBD) had no effect on SHR MAP, even though plasma SOD
      activity was greater after AdECSODDeltaHBD than after AdECSOD.
      Immunohistochemistry revealed intense staining for ECSOD in blood vessels and
      kidneys after AdECSOD but not after AdECSODDeltaHBD. Impaired relaxation of the
      carotid artery to acetylcholine in SHR was significantly improved after AdECSOD.
      Cumulative sodium balance in SHR was reduced by AdECSOD compared with
      AdECSODDeltaHBD. Gene transfer of ECSOD also reduced MAP in conscious SHR,
      although the effect was not as profound as in anesthetized SHR. In summary, gene
      transfer of ECSOD, with a strict requirement for its HBD, reduces systemic
      vascular resistance and arterial pressure in a genetic model of hypertension.
      This reduction in arterial pressure may be mediated by vasomotor and/or renal
      mechanisms.

PMID- 12600900
TI  - Antioxidants and atherosclerosis: don't throw out the baby with the bath water.

PMID- 12600901
TI  - Stem cell therapy in perspective.

PMID- 12600903
TI  - Stem cells: the chameleon fountain of youth.

PMID- 12600902
TI  - Adult stem cell therapy in perspective.

PMID- 12600904
TI  - Changing late prognosis of acute myocardial infarction: impact on management of
      ventricular arrhythmias in the era of reperfusion and the implantable
      cardioverter-defibrillator.

PMID- 12600905
TI  - Six-year effect of combined vitamin C and E supplementation on atherosclerotic
      progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP)
      Study.
AB  - BACKGROUND: Self-selected supplementation of vitamin E has been associated with
      reduced coronary events and atherosclerotic progression, but the evidence from
      clinical trials is controversial. In the first 3 years of the ASAP trial, the
      supplementation with 136 IU of vitamin E plus 250 mg of slow-release vitamin C
      twice daily slowed down the progression of carotid atherosclerosis in men but not
      women. This article examines the 6-year effect of supplementation on common
      carotid artery (CCA) intima-media thickness (IMT). METHODS AND RESULTS: The
      subjects were 520 smoking and nonsmoking men and postmenopausal women aged 45 to
      69 years with serum cholesterol > or =5.0 mmol/L (193 mg/dL), 440 (84.6%) of whom
      completed the study. Atherosclerotic progression was assessed
      ultrasonographically. In covariance analysis in both sexes, supplementation
      reduced the main study outcome, the slope of mean CCA-IMT, by 26% (95% CI, 5 to
      46, P=0.014), in men by 33% (95% CI, 4 to 62, P=0.024) and in women by 14% (not
      significant). In both sexes combined, the average annual increase of the mean CCA
      IMT was 0.014 mm in the unsupplemented and 0.010 mm in the supplemented group
      (25% treatment effect, 95% CI, 2 to 49, P=0.034). In men, this treatment effect
      was 37% (95 CI, 4 to 69, P=0.028). The effect was larger in subjects with either
      low baseline plasma vitamin C levels or CCA plaques. Vitamin E had no effect on
      HDL cholesterol. CONCLUSIONS: These data replicate our 3-year findings confirming
      that the supplementation with combination of vitamin E and slow-release vitamin C
      slows down atherosclerotic progression in hypercholesterolemic persons.

PMID- 12600906
TI  - Protease-activated receptor 2-mediated vasodilatation in humans in vivo: role of
      nitric oxide and prostanoids.
AB  - BACKGROUND: Systemic hypotension as a consequence of vascular dysfunction is a
      well-recognized and important feature of critical illness. Although serine
      protease activation has been implicated as a cause of vascular dysfunction in
      systemic inflammation, the mechanism is unknown. Recently, a class of receptors
      with an entirely novel mechanism of action, protease-activated receptors (PARs),
      has been identified that would explain the link between protease activation and
      systemic hypotension. Our aim was to test the hypothesis that in vivo activation
      of protease-activated receptor 2 (PAR-2) in humans would mediate vasodilatation.
      METHODS AND RESULTS: For these first-in-human studies, an activating peptide for
      the human PAR-2 receptor was synthesized and administered to healthy volunteers.
      Using both the dorsal hand vein technique and forearm plethysmography, we studied
      the effects of PAR-2 activation in human blood vessels and investigated the
      mechanism of vasodilation. Activation of PAR-2 receptors in vivo dilated human
      blood vessels in a dose-dependent manner, and the effects were reduced by
      inhibition of both nitric oxide and prostanoid synthesis CONCLUSIONS: These
      findings demonstrate that serine protease activity can cause human vasodilation
      and provide a possible explanation of why serine protease activation in critical
      illness is associated with vascular dysfunction.

PMID- 12600907
TI  - Cost implications of the use of ramipril in high-risk patients based on the Heart
      Outcomes Prevention Evaluation (HOPE) study.
AB  - BACKGROUND: The HOPE study has demonstrated that ramipril is beneficial (ie,
      prevents cardiovascular death, myocardial infarction, and stroke) for a broad
      range of patients without evidence of left ventricular dysfunction or heart
      failure who are at high risk for cardiovascular event. In this study, we report
      the cost implications, in both the United States and Canada, of the use of
      ramipril after the HOPE study. METHODS AND RESULTS: A third-party perspective was
      chosen (Medicare for the United States and Ministry of Health for Canada). We
      calculated the costs of the management strategies of ramipril and placebo. An
      annual discount rate of 3% was used over the 4.5 years of follow-up. Sensitivity
      analyses were performed. Costs are reported in United States dollars and in
      Canadian dollars, respectively. The total costs per patient (including
      acquisition costs of ramipril) were not different between the groups in both
      countries (United States, $13 520 versus $13 631; Canada, $8702 versus $8588).
      From the distribution of cases in the bootstrap analysis, we found that 90% of
      cases fall either into a cost-neutral or cost-saving situation (64% in United
      States and 27% in Canada) or into a cost-effectiveness situation with an
      incremental cost-effectiveness ratio <$10 000 (in respective currency) per
      primary event saved. CONCLUSIONS: On the basis of these results, we suggest that
      the use of ramipril is likely to represent an efficient use of resources in both
      countries. These findings support the use of ramipril in populations included in
      the HOPE study.

PMID- 12600908
TI  - Early and late effects of clopidogrel in patients with acute coronary syndromes.
AB  - BACKGROUND: The risk of ischemic events is high, both early and late after acute
      coronary syndromes (ACS). We examine the benefits and risks associated with the
      use of adding clopidogrel to aspirin within the first 30 days and later (31 days
      to 12 months) in 12 562 patients with ACS. METHODS AND RESULTS: A total of 12 562
      ACS patients were randomized to receive clopidogrel (300 mg initially followed by
      75 mg/d) or placebo for 3 to 12 months. The proportion of patients experiencing
      cardiovascular death, myocardial infarction, or strokes (primary outcome) at 30
      days was 5.4% in the placebo group and 4.3% in the active group (relative risk
      0.79, 95% CI 0.67 to 0.92). Beyond 30 days, the corresponding rates were 6.3%
      versus 5.2% (relative risk 0.82, 95% CI 0.70 to 0.95). There was no significant
      excess in life-threatening bleeds in each period (0.97% versus 1.28%, relative
      risk 1.32, 95% CI 0.95 to 1.84 for 0 to 30 days; 0.83% versus 0.91%, relative
      risk 1.09, 95% CI 0.75 to 1.59 for 31 days to 12 months). Further subdivision of
      the early data indicates benefits within 24 hours with consistently lower rates
      of the primary outcome in combination with refractory or severe ischemia.
      CONCLUSIONS: Clopidogrel reduces the risk of ischemic vascular events, with the
      benefits emerging within 24 hours of initiation of treatment and continuing
      throughout the 12 months (mean 9 months) of the study.

PMID- 12600909
TI  - Role of risk factors in the modulation of tissue factor activity and blood
      thrombogenicity.
AB  - BACKGROUND: Several studies suggest a role for an increased circulating pool of
      tissue factor (TF) in atherothrombotic diseases. Furthermore, certain
      cardiovascular risk factors, such as diabetes, hyperlipemia, and smoking, are
      associated with a higher incidence of thrombotic complications. We hypothesized
      that the observed increased blood thrombogenicity (BT) observed in patients with
      type 2 diabetes mellitus may be mediated via an increased circulating tissue
      factor activity. We have extended our study to smokers and hyperlipidemic
      subjects. METHODS AND RESULTS: Poorly controlled patients with type 2 diabetes
      mellitus (n=36), smokers (n=10), and untreated hyperlipidemic subjects (n=10)
      were studied. Circulating TF was immunocaptured from plasma, relipidated, and
      quantified by factor Xa (FXa) generation in the presence of factor VIIa. BT was
      assessed as thrombus formation on the Badimon perfusion chamber. Patients with
      improvement in glycemic control showed a reduction in circulating TF (362+/-135
      versus 243+/-74 pmol/L per min FXa, P=0.0001). A similar effect was observed in
      BT (15 445+/-1130 versus 12 072+/-596 microm/mm2, P=0.01). Two hours after
      smoking 2 cigarettes, TF was increased (217+/-72 versus 283+/-106 pmol/L per min
      FXa, P=0.003). Hyperlipidemic subjects showed higher TF (237+/-63 versus 195+/-44
      pmol/L per min FXa, P=0.035) than healthy volunteers. CONCLUSIONS: These findings
      suggest that high levels of circulating TF may be the mechanism of action
      responsible for the increased thrombotic complications associated with the
      presence of these cardiovascular risk factors. These observations strongly
      emphasize the usefulness of the management of the patients based on their global
      risk assessment.

PMID- 12600910
TI  - Diagnostic value of pericardial biopsy: improvement with extensive sampling
      enabled by pericardioscopy.
AB  - BACKGROUND: The clinical significance of pericardial biopsy is controversial. The
      aim of this study was to assess the feasibility and diagnostic value of 3
      approaches to pericardial biopsy: fluoroscopic control and standard sampling,
      pericardioscopy guidance with standard sampling, and pericardioscopy guidance
      with extensive sampling. METHODS AND RESULTS: Forty-nine subsequent patients with
      a large pericardial effusion underwent parietal pericardial biopsy. In group 1
      (12 patients, 66.7% males, age 46.7+/-12.2 years), pericardial biopsy was guided
      by fluoroscopy (3 to 6 samples per patient). Group 2 included 22 patients (50%
      males, age 50.8+/-10.4 years) undergoing 4 to 6 pericardial biopsies per patient
      guided by pericardioscopy (16F flexible endoscope). In group 3, extensive
      pericardial sampling was performed, guided by pericardioscopy (15 patients, 53.3%
      males, age 53.7+/-12.8 years, 18 to 20 samples per patient). Sampling efficiency
      was better with pericardioscopy (group 2, 84.9%; group 3, 84.2%) compared with
      fluoroscopic guidance (group 1, 43.7%; P<0.01). Diagnostic value was defined as a
      new diagnosis uncovered, etiology revealed, clinical diagnosis confirmed, and the
      biopsy false-negative. Pericardial biopsy in group 3 had higher diagnostic value
      than in group 1 in revealing new diagnosis (40% versus 8.3%, P<0.05) and etiology
      (53.3% versus 8.3%, P<0.05). In group 2, pericardial biopsy had a higher yield in
      establishing etiology than in group 1 (40.9% versus 8.3%; P<0.05). Pericardial
      biopsy was false-negative in 58.3% in group 1 in contrast to 6.7% in group 3
      (P<0.01). There were no major complications. CONCLUSIONS: Pericardioscopic
      guidance enhanced pericardial sampling efficiency. The diagnostic value of
      pericardial biopsy was significantly improved by extensive sampling made possible
      by pericardioscopy.

PMID- 12600911
TI  - Progression from compensated hypertrophy to failure in the pressure-overloaded
      human heart: structural deterioration and compensatory mechanisms.
AB  - BACKGROUND: The progression of compensated hypertrophy to heart failure (HF) is
      still debated. We investigated patients with isolated valvular aortic stenosis
      and differing degrees of left ventricular (LV) systolic dysfunction to test the
      hypothesis that structural remodeling, as well as cell death, contributes to the
      transition to HF. METHODS AND RESULTS: Structural alterations were studied in LV
      myectomies from 3 groups of patients (group 1: ejection fraction [EF] >50%, n=12;
      group 2: EF 30% to 50%, n=12; group 3: EF <30%, n=10) undergoing aortic valve
      replacement. Control patients were patients with mitral valve stenosis but normal
      LV (n=6). Myocyte hypertrophy was accompanied by increased nuclear DNA and Sc-35
      (splicing factor) content. ACE and TGF-beta1 were upregulated correlating with
      fibrosis, which increased 2.3-, 2.2-, and 3.2-fold over control in the 3 groups.
      Myocyte degeneration increased 10, 22, and 32 times over control. A significant
      correlation exists between EF and myocyte degeneration or fibrosis. Ubiquitin
      related autophagic cell death was 0.5 per thousand in control and group 1, 1.05
      in group 2, and 6.05 per thousand in group 3. Death by oncosis was 0 per thousand
      in control, 3 per thousand in group 1, and increased to 5 per thousand (groups 2
      and 3). Apoptosis was not detectable in control and group 3, but it was present
      at 0.02 per thousand in group 1 and 0.01 per thousand in group 2. Cardiomyocyte
      mitosis was never observed. CONCLUSIONS: These structure-function correlations
      confirm the hypothesis that transition to HF occurs by fibrosis and myocyte
      degeneration partially compensated by hypertrophy involving DNA synthesis and
      transcription. Cell loss, mainly by autophagy and oncosis, contributes
      significantly to the progression of LV systolic dysfunction.

PMID- 12600912
TI  - The antioxidant acetylcysteine reduces cardiovascular events in patients with end
      stage renal failure: a randomized, controlled trial.
AB  - BACKGROUND: Patients with end-stage renal failure have increased oxidative stress
      and show elevated cardiovascular mortality. Whether increased cardiovascular
      events can be prevented by the administration of antioxidants is unknown. METHODS
      AND RESULTS: We evaluated the effects of acetylcysteine, a thiol-containing
      antioxidant, on cardiovascular events in patients undergoing hemodialysis. A
      prospective, randomized, placebo-controlled trial was conducted between October
      1, 1999, and September 30, 2001, in 134 patients (76 male and 58 female) with a
      mean age of 62+/-16 years (mean+/-SD) who had been undergoing maintenance
      hemodialysis for a minimum of 3 months 3 times weekly in an ambulatory center.
      Median (range) follow-up was 14.5 (1 to 24) months. Patients were randomly
      assigned either to receive acetylcysteine (600 mg BID) or placebo. The primary
      end point was a composite variable consisting of cardiac events including fatal
      and nonfatal myocardial infarction, cardiovascular disease death, need for
      coronary angioplasty or coronary bypass surgery, ischemic stroke, peripheral
      vascular disease with amputation, or need for angioplasty. Secondary end points
      included each of the component outcomes, total mortality, and cardiovascular
      mortality. A total of 18 (28%) of the 64 hemodialysis patients assigned to
      acetylcysteine group and 33 (47%) of the 70 hemodialysis patients assigned to
      control group had a primary end point (relative risk, 0.60 [95% CI, 0.38 to
      0.95], P=0.03). No significant differences in secondary end points or total
      mortality were detected. CONCLUSIONS: In hemodialysis patients, treatment with
      acetylcysteine (600 mg BID) reduces composite cardiovascular end points.

PMID- 12600913
TI  - Efficacy and safety of milrinone in preventing low cardiac output syndrome in
      infants and children after corrective surgery for congenital heart disease.
AB  - BACKGROUND: Low cardiac output syndrome (LCOS), affecting up to 25% of neonates
      and young children after cardiac surgery, contributes to postoperative morbidity
      and mortality. This study evaluated the efficacy and safety of prophylactic
      milrinone in pediatric patients at high risk for developing LCOS. METHODS AND
      RESULTS: The study was a double-blind, placebo-controlled trial with 3 parallel
      groups (low dose, 25- microg/kg bolus over 60 minutes followed by a 0.25-
      microg/kg per min infusion for 35 hours; high dose, 75- microg/kg bolus followed
      by a 0.75- microg/kg per min infusion for 35 hours; or placebo). The composite
      end point of death or the development of LCOS was evaluated at 36 hours and up to
      30 days after randomization. Among 238 treated patients, 25.9%, 17.5%, and 11.7%
      in the placebo, low-dose milrinone, and high-dose milrinone groups, respectively,
      developed LCOS in the first 36 hours after surgery. High-dose milrinone
      significantly reduced the risk the development of LCOS compared with placebo,
      with a relative risk reduction of 55% (P=0.023) in 238 treated patients and 64%
      (P=0.007) in 227 patients without major protocol violations. There were 2 deaths,
      both after infusion of study drug. The use of high-dose milrinone reduced the
      risk of the LCOS through the final visit by 48% (P=0.049). CONCLUSIONS: The use
      of high-dose milrinone after pediatric congenital heart surgery reduces the risk
      of LCOS.

PMID- 12600914
TI  - Factor V Leiden protects against blood loss and transfusion after cardiac
      surgery.
AB  - BACKGROUND: The outcome of cardiac surgery is influenced by several factors, but
      the impact of specific genetic variants has not been systematically explored.
      Because blood conservation is a pressing issue in cardiac surgery, we tested the
      hypothesis that factor V Leiden (FVL), a common coagulation factor polymorphism,
      may protect against blood loss and transfusion in patients undergoing cardiac
      surgery. METHODS AND RESULTS: We enrolled 517 patients undergoing cardiac
      surgery, including 26 heterozygous FVL carriers, and evaluated the impact of FVL
      on chest tube output and transfusion by using univariate and multivariate
      techniques. For patients with FVL, blood loss at 6 (238+/-131 mL) and 24 hours
      (522+/-302 mL) was significantly lower than that for noncarriers (358+/-259 mL
      and 730+/-452 mL; P<0.001 and P=0.001, respectively). In a multivariate
      regression analysis, controlling for ethnicity and factors known to affect blood
      loss, FVL was a significant independent contributor at both time points. Using a
      similar regression approach, FVL did not have a significant effect on the number
      of units transfused. However, logistic regression of the risk of receiving any
      transfusion during hospitalization demonstrated a significant independent
      protective effect of FVL on overall transfusion risk. CONCLUSIONS: FVL represents
      a common genetic trait that may protect against blood loss and transfusion in
      this population. This study demonstrates that genetic variability can affect the
      outcome of cardiac surgery.

PMID- 12600915
TI  - Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double
      knockout mice.
AB  - BACKGROUND: Fractalkine (CX3CL1), a CX3C chemokine, is expressed in the vessel
      wall and mediates the firm adhesion and chemotaxis of leukocytes expressing its
      receptor, CX3CR1. A polymorphism in the CX3CR1 gene is associated with low CX3CR1
      expression and reduced risk of acute coronary disease in humans. METHODS AND
      RESULTS: We generated CX3CR1-deficient mice (CX3CR1(-/-)) by targeted gene
      disruption and crossed them with the proatherogenic apolipoprotein E-deficient
      mice (apoE(-/-)). Here we show that the extent of lipid-stained lesions in the
      thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice compared
      with their CX3CR1(+/+)/apoE(-/-) littermates. The development of atherosclerosis
      in the aortic sinus was also markedly altered in the double knockout mice, with
      50% reduction in macrophage accumulation. Although lesions of CX3CR1(-/-) mice
      were smaller in size, they retained a substantial accumulation of smooth muscle
      cells and collagen, features consistent with a stable plaque phenotype. Finally,
      CX3CR1(+/-)/apoE(-/-) mice showed the same reduction in atherosclerosis as the
      CX3CR1(-/-)/apoE(-/-) mice. CONCLUSIONS: The CX3CR1-CX3CL1 pathway seems to play
      a direct and critical role in monocyte recruitment and atherosclerotic lesion
      development in a mouse model of human atherosclerosis.

PMID- 12600917
TI  - Transdifferentiation of blood-derived human adult endothelial progenitor cells
      into functionally active cardiomyocytes.
AB  - BACKGROUND: Further to promoting angiogenesis, cell therapy may be an approach
      for cardiac regeneration. Recent studies suggest that progenitor cells can
      transdifferentiate into other lineages. However, the transdifferentiation
      potential of endothelial progenitor cells (EPCs) is unknown. METHODS AND RESULTS:
      EPCs were obtained from peripheral blood mononuclear cells of healthy adults or
      coronary artery disease (CAD) patients by cultivating with endothelial cell
      medium and growth factors. After 3 days, >95% of adherent cells were functionally
      and phenotypically EPCs. Diacetylated LDL-labeled EPCs were then cocultivated
      with rat cardiomyocytes for 6 days, resulting in significant increases of EPC
      cell length and size to a cardiomyocyte-like morphology. Biochemically, 9.94+/
      1.39% and 5.04+/-1.09% of EPCs from healthy adults (n=15) or CAD patients (n=14,
      P<0.01 versus healthy adults), respectively, expressed alpha-sarcomeric actinin
      as measured by flow cytometry. Immunocytochemistry showed that human EPCs
      expressed alpha-sarcomeric actinin, cardiac troponin I (both with partial
      sarcomeric organization), atrial natriuretic peptide, and myocyte enhancer factor
      2. Fluo 4 imaging demonstrated calcium transients synchronized with adjacent rat
      cardiomyocytes in transdifferentiated human EPCs. Single-cell microinjection of
      Lucifer yellow and calcein-AM labeling of cardiomyocytes demonstrated gap
      junctional communication between 51+/-7% of EPCs (16 hours after labeling, n=4)
      and cardiomyocytes. EPC transdifferentiation into cardiomyocytes was not observed
      with conditioned medium but in coculture with paraformaldehyde-fixed
      cardiomyocytes. CONCLUSIONS: EPCs from healthy volunteers and CAD patients can
      transdifferentiate in vitro into functionally active cardiomyocytes when
      cocultivated with rat cardiomyocytes. Cell-to-cell contact but not cellular
      fusion mediates EPC transdifferentiation. The therapeutic use of autologous EPCs
      may aid cardiomyocyte regeneration in patients with ischemic heart disease.

PMID- 12600916
TI  - High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid
      profile in human endothelial cells: role of protein kinase C and reactive oxygen
      species.
AB  - BACKGROUND: Prostaglandins generated by cyclooxygenase (COX) have been implicated
      in hyperglycemia-induced endothelial dysfunction. However, the role of individual
      COX isoenzymes as well as the molecular mechanisms linking oxidative stress and
      endothelial dysfunction in diabetes remains to be clarified. METHODS AND RESULTS:
      Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2
      mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX
      2. Its upregulation was associated with an increase of thromboxane A2 and a
      reduction of prostacyclin (PGI2) release. Glucose-induced activation of PKC
      resulted in the formation of peroxynitrite and tyrosine nitration of PGI2
      synthase. NO release was reduced despite 2-fold increase of endothelial NO
      synthase expression. Phorbol ester caused an increase of COX-2 and endothelial NO
      synthase expression similar to that elicited by glucose. These effects were
      prevented by the PKC inhibitor calphostin C. N-acetylcysteine, vitamin C, and
      calphostin C prevented ROS formation, restored NO release, and reduced
      colocalization of nitrotyrosine and PGI2 synthase. Expression of p22(phox), a
      subunit of NAD(P)H oxidase, was increased, and diphenyleneiodonium inhibited ROS
      formation. By contrast, indomethacin did not affect glucose-induced ROS
      generation. CONCLUSIONS: Thus, high glucose, via PKC signaling, induces oxidative
      stress and upregulation of COX-2, resulting in reduced NO availability and
      altered prostanoid profile.

PMID- 12600918
TI  - Reduced connexin43 expression inhibits atherosclerotic lesion formation in low
      density lipoprotein receptor-deficient mice.
AB  - BACKGROUND: Gap junctions allow the direct exchange of ions and small molecules
      between cells in contact, thus coordinating physiological processes such as cell
      growth and differentiation. We have recently demonstrated increased expression of
      the gap junction protein connexin43 (Cx43) in specific subsets of cells in
      atherosclerotic lesions. Because the development of atherosclerosis depends
      critically on paracrine cell-to-cell interactions, we hypothesized that direct
      intercellular communication via gap junctions may be another factor controlling
      atherogenesis. METHODS AND RESULTS: The role of Cx43 in atherogenesis was
      examined by use of both a genetic and a pharmacological approach. First,
      atherosclerosis-susceptible LDL receptor-deficient (LDLR-/-) mice with normal
      (Cx43+/+) or reduced (Cx43+/-) levels of Cx43 were fed a cholesterol-rich diet
      for 14 weeks. The progression of atherosclerosis was reduced by 50% (P<0.01) in
      the thoracoabdominal aorta and in the aortic roots of Cx43+/-LDLR-/- mice
      compared with Cx43+/+LDLR-/- controls. Atheroma in Cx43+/-LDLR-/- mice contained
      fewer inflammatory cells and exhibited thicker fibrous caps with more collagen
      and smooth muscle cells. Next, we observed that HMG-CoA reductase inhibitors, or
      "statins," lipid-lowering drugs well known for their pleiotropic antiatherogenic
      effects, reduced Cx43 expression in primary human vascular cells in vitro.
      Atheroma of LDLR-/- mice treated orally with pravastatin contained fewer
      inflammatory cells and exhibited thicker fibrous caps than controls. This was
      associated with reduced Cx43 expression in lesions of statin-treated mice.
      CONCLUSIONS: These data indicate a critical role for Cx43-mediated gap junctional
      communication in atherosclerotic plaque formation.

PMID- 12600919
TI  - Hydrogen peroxide, an endogenous endothelium-derived hyperpolarizing factor,
      plays an important role in coronary autoregulation in vivo.
AB  - BACKGROUND: Recent studies in vitro have demonstrated that endothelium-derived
      hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF)
      in animals and humans. The aim of this study was to evaluate our hypothesis that
      endothelium-derived H2O2 is an EDHF in vivo and plays an important role in
      coronary autoregulation. METHODS AND RESULTS: To test this hypothesis, we
      evaluated vasodilator responses of canine (n=41) subepicardial small coronary
      arteries (> or =100 microm) and arterioles (<100 microm) with an intravital
      microscope in response to acetylcholine and to a stepwise reduction in coronary
      perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO
      synthesis with N(G)-monomethyl-L-arginine (L-NMMA). After L-NMMA, the coronary
      vasodilator responses were attenuated primarily in small arteries, whereas
      combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates
      H2O2 into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large
      conductance K(Ca) channels) attenuated the vasodilator responses of coronary
      arteries of both sizes. Residual arteriolar dilation after L-NMMA plus catalase
      or TEA was largely attenuated by 8-sulfophenyltheophylline, an adenosine receptor
      inhibitor. CONCLUSIONS: These results suggest that H2O2 is an endogenous EDHF in
      vivo and plays an important role in coronary autoregulation in cooperation with
      NO and adenosine.

PMID- 12600920
TI  - Temporal response and localization of integrins beta1 and beta3 in the heart
      after myocardial infarction: regulation by cytokines.
AB  - BACKGROUND: Integrins are involved in structural remodeling and tissue repair.
      This study aimed to elucidate the role of the beta-integrins in cardiac
      remodeling after myocardial infarction (MI). METHODS AND RESULTS: The MI model
      was created by ligation of the left anterior descending coronary artery in rats.
      We detected cardiac integrins beta1 and beta3 gene expression (quantitative in
      situ hybridization) and protein production (Western blot and
      immunohistochemistry) and potential regulation by tumor necrosis factor (TNF)
      using neonatal ventricular myocytes and TNF-/- knockout mice. Integrins beta1 and
      beta3 gene expression and protein production were low in sham-operated hearts.
      After MI, the beta1 and beta3 mRNA and proteins were significantly increased at
      the site of MI at day 3, reached a peak at day 7, and gradually declined
      thereafter. Integrin beta1A localized primarily in fibroblasts and inflammatory
      cells, beta1D localized in myocytes, and integrin beta3 was associated primarily
      with endothelial and smooth muscle cells in peri-infarct vessels. In cultured
      myocytes, there was isoform transition from the adult beta1D to the fetal beta1A
      on exposure to TNF-alpha. This was confirmed in vivo in the peri-infarct
      myocytes, but the transition was voided in TNF-/--knockout mice. CONCLUSIONS:
      Integrins beta1 and beta3 are significantly activated in the infarcted
      myocardium. Integrin beta1 is active particularly at sites of inflammation and
      fibrosis, whereas integrin beta3 localizes to vessels in the peri-infarct zone in
      a temporally coordinated manner. Integrin beta1D to beta1A isoform transition in
      myocytes is regulated by TNF-alpha.

PMID- 12600921
TI  - Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase
      pathway in low-renin hypertension.
AB  - BACKGROUND: Angiotensin II-induced hypertension is associated with NAD(P)H
      oxidase-dependent superoxide production in the vessel wall. Vascular superoxide
      level is also increased in deoxycorticosterone acetate (DOCA)-salt hypertension,
      which is associated with a markedly depressed plasma renin activity because of
      sodium retention. However, the mechanisms underlying superoxide production in low
      renin hypertension are undefined. METHODS AND RESULTS: This study investigated
      (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt
      hypertensive rats, contributes to arterial superoxide generation and (2) the
      effect of gene transfer of manganese superoxide dismutase and endothelial nitric
      oxide synthase. Both superoxide and ET-1 levels were significantly elevated in
      carotid arteries of DOCA-salt rats compared with that of the sham-operated
      controls. ET-1 concentration-dependently stimulated superoxide production in
      vitro in carotid arteries of normotensive rats. The increase in arterial
      superoxide in both ET-1-treated normotensive and DOCA-salt rats was reversed by a
      selective ET(A) receptor antagonist, ABT-627, the flavoprotein inhibitor
      diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the
      nitric oxide synthase inhibitor N(omega)-L-arginine methyl ester or the xanthine
      oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET(A) receptors
      significantly reduced arterial superoxide levels, with a concomitant decrease of
      systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese
      superoxide dismutase or endothelial nitric oxide synthase also suppressed
      superoxide levels in carotid arteries of DOCA-salt rats. CONCLUSIONS: These
      findings suggest that ET-1 augments vascular superoxide production at least in
      part via an ET(A)/NADPH oxidase pathway in low-renin mineralocorticoid
      hypertension.

PMID- 12600922
TI  - His electrogram alternans reveal dual atrioventricular nodal pathway conduction
      during atrial fibrillation: the role of slow-pathway modification.
AB  - BACKGROUND: Traditional tools to study dual-pathway atrioventricular nodal (AVN)
      electrophysiology are not applicable in subjects with permanent atrial
      fibrillation (AF). The presence of fast-pathway (FP) and slow-pathway (SP)
      wavefronts and their possible modification remain uncertain in this condition. We
      demonstrated previously that His electrogram (HE) alternans can determine whether
      the FP or the SP reaches the His bundle on a beat-by-beat basis. We have now
      applied this novel index to monitor dual-pathway conduction and the effects of SP
      modification during AF. METHODS AND RESULTS: In 12 rabbit AVN preparations, HE
      alternans were confirmed during a standard A(1)A(2) pacing protocol. During AF,
      in 9 of the 12 hearts, HE alternans indicated the presence of dual pathways.
      Successful SP modification guided by the HE alternans eliminated the SP,
      resulting in a predominantly FP conduction during AF in all hearts. This
      increased the average His-His interval (204+/-14 versus 276+/-51 ms, P<0.001).
      Morphological studies revealed that SP modification damaged only the posterior
      extension of the AVN. CONCLUSIONS: We have demonstrated for the first time in
      rabbits that HE alternans permit "visualization" of dual-pathway
      electrophysiology and confirmed the presence of both FP and SP wavefronts during
      AF. This novel index has been used in a selective SP ablation that resulted in a
      significant slowing of the ventricular rate. HE alternans provide a new insight
      into the mechanisms of AVN conduction and could guide AVN modification for
      ventricular rate control in AF clinically.

PMID- 12600923
TI  - Images in cardiovascular medicine. Left ventricular outflow tract obstruction
      secondary to a rhabdomyoma.

PMID- 12600924
TI  - American College of Cardiology/American Heart Association clinical competence
      statement on echocardiography: a report of the American College of
      Cardiology/American Heart Association/American College of Physicians--American
      Society of Internal Medicine Task Force on Clinical Competence.

PMID- 12600925
TI  - Images in cardiovascular medicine. Myocardial fibrosis in glycogen storage
      disease type III.

PMID- 12600926
TI  - Sugars and cardiovascular disease.

PMID- 12600927
TI  - Quantitative assessment of intrinsic regional myocardial deformation by Doppler
      strain rate echocardiography in humans.

PMID- 12600928
TI  - Isolated noncompaction of the myocardium.

PMID- 12600929
TI  - Patent foramen ovale and cryptogenic stroke: the controversy continues.

PMID- 12600930
TI  - Atherosclerosis and inflammatory bowel disease: sharing a common pathogenic
      pathway?

PMID- 12600931
TI  - Time course of sympathetic neural hyperactivity after uncomplicated acute
      myocardial infarction.

PMID- 12600932
TI  - When does serendipity become screening? The deliberate search for noncardiac
      pathology on electron-beam computed tomography.

PMID- 12600935
TI  - Pre-mRNA splicing and human disease.

PMID- 12600936
TI  - siRNAs can function as miRNAs.
AB  - With the discovery of RNA interference (RNAi) and related phenomena, new
      regulatory roles attributed to RNA continue to emerge. Here we show, in mammalian
      tissue culture, that a short interfering RNA (siRNA) can repress expression of a
      target mRNA with partially complementary binding sites in its 3' UTR, much like
      the demonstrated function of endogenously encoded microRNAs (miRNAs). The
      mechanism for this repression is cooperative, distinct from the catalytic
      mechanism of mRNA cleavage by siRNAs. The use of siRNAs to study translational
      repression holds promise for dissecting the sequence and structural determinants
      and general mechanism of gene repression by miRNAs.

PMID- 12600937
TI  - Identification of genes that protect the C. elegans genome against mutations by
      genome-wide RNAi.
AB  - An RNA interference (RNAi)-based genome-wide screen was performed to detect genes
      that contribute to genome stability in somatic cells of Caenorhabditis elegans.
      We identified 61 such genes; these also affect spontaneous mutagenesis in the
      germ line. Their sequence suggests a role in DNA repair and/or replication, in
      chromatin remodeling, or in cell cycle control; there are also many novel genes
      that are highly conserved from yeast to human. Because known mutator genes are
      causally involved in many hereditary and sporadic human cancers, it is likely
      that some of these new mutators are equally relevant in cancer etiology.

PMID- 12600938
TI  - Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor
      suppressor.
AB  - Mutations in the NF1 tumor suppressor underlie the familial tumor predisposition
      syndrome neurofibromatosis type I. Although its encoded protein, neurofibromin,
      functions as a Ras-GTPase activating protein (GAP), nothing is known about how it
      is normally regulated or its precise role in controlling Ras signaling pathways.
      We show here that neurofibromin is dynamically regulated by the ubiquitin
      proteasome pathway. Degradation is rapidly triggered in response to a variety of
      growth factors and requires sequences adjacent to the catalytic GAP-related
      domain of neurofibromin. However, whereas degradation is rapid, neurofibromin
      levels are re-elevated shortly after growth factor treatment. Accordingly, Nf1
      deficient mouse embryonic fibroblasts (MEFs) exhibit an enhanced activation of
      Ras, prolonged Ras and ERK activities, and proliferate in response to
      subthreshold levels of growth factors. Thus, the dynamic proteasomal regulation
      of neurofibromin represents an important mechanism of controlling both the
      amplitude and duration of Ras-mediated signaling. Furthermore, this previously
      unrecognized Ras regulatory mechanism may be exploited therapeutically.

PMID- 12600939
TI  - Protein ISGylation modulates the JAK-STAT signaling pathway.
AB  - ISG15 is one of the most strongly induced genes upon viral infection, type I
      interferon (IFN) stimulation, and lipopolysaccharide (LPS) stimulation. Here we
      report that mice lacking UBP43, a protease that removes ISG15 from ISGylated
      proteins, are hypersensitive to type I IFN. Most importantly, in UBP43-deficient
      cells, IFN-beta induces a prolonged Stat1 tyrosine phosphorylation, DNA binding,
      and IFN-mediated gene activation. Furthermore, restoration of ISG15 conjugation
      in protein ISGylation-defective K562 cells increases IFN-stimulated promoter
      activity. These findings identify UBP43 as a novel negative regulator of IFN
      signaling and suggest the involvement of protein ISGylation in the regulation of
      the JAK-STAT pathway.

PMID- 12600940
TI  - Structure and function of the PWI motif: a novel nucleic acid-binding domain that
      facilitates pre-mRNA processing.
AB  - The PWI motif is a highly conserved domain of unknown function in the SRm160
      splicing and 3'-end cleavage-stimulatory factor, as well as in several other
      known or putative pre-mRNA processing components. We show here that the PWI motif
      is a new type of RNA/DNA-binding domain that has an equal preference for single-
      and double-stranded nucleic acids. Deletion of the motif prevents SRm160 from
      binding RNA and stimulating 3'-end cleavage, and its substitution with a
      heterologous RNA-binding domain restores these functions. The NMR solution
      structure of the SRm160-PWI motif reveals a novel, four-helix bundle and
      represents the first example of an alpha-helical fold that can bind single
      stranded (ss)RNA. Structure-guided mutagenesis indicates that the same surface is
      involved in RNA and DNA binding and requires the cooperative action of a highly
      conserved, adjacent basic region. Thus, the PWI motif is a novel type of nucleic
      acid-binding domain that likely has multiple important functions in pre-mRNA
      processing, including SRm160-dependent stimulation of 3'-end formation.

PMID- 12600941
TI  - p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor
      suppressor encoded on human chromosome 19q13.3.
AB  - p190RhoGAP and Rho are key regulators of oligodendrocyte differentiation. The
      gene encoding p190RhoGAP is located at 19q13.3 of the human chromosome, a locus
      that is deleted in 50%-80% of oligodendrogliomas. Here we provide evidence that
      p190RhoGAP may suppress gliomagenesis by inducing a differentiated glial
      phenotype. Using a cell culture model of autocrine loop PDGF stimulation, we show
      that reduced Rho activity via p190RhoGAP overexpression or Rho kinase inhibition
      induced cellular process extension, a block in proliferation, and reduced
      expression of the neural precursor marker nestin. In vivo infection of mice with
      retrovirus expressing PDGF and the p190 GAP domain caused a decreased incidence
      of oligodendrogliomas compared with that observed with PDGF alone. Independent
      experiments revealed that the retroviral vector insertion site in 3 of 50 PDGF
      induced gliomas was within the p190RhoGAP gene. This evidence strongly suggests
      that p190 regulates critical components of PDGF oncogenesis and can act as a
      tumor suppressor in PDGF-induced gliomas by down-regulating Rho activity.

PMID- 12600942
TI  - Impact of p53 loss on reversal and recurrence of conditional Wnt-induced
      tumorigenesis.
AB  - Aberrant activation of Wnt signaling is oncogenic and has been implicated in a
      variety of human cancers. We have developed a doxycycline-inducible Wnt1
      transgenic mouse model to determine the dependence of established mammary
      adenocarcinomas on continued Wnt signaling. Using this model we show that
      targeted down-regulation of the Wnt pathway results in the rapid disappearance of
      essentially all Wnt-initiated invasive primary tumors as well as pulmonary
      metastases. Tumor regression does not require p53 and occurs even in highly
      aneuploid tumors. However, despite the dependence of primary mammary tumors and
      metastases on continued Wnt signaling and the dispensability of p53 for tumor
      regression, we find that a substantial fraction of tumors progress to a Wnt
      independent state and that p53 suppresses this process. Specifically, loss of one
      p53 allele dramatically facilitates the progression of mammary tumors to a Wnt1
      independent state both by impairing the regression of primary tumors following
      doxycycline withdrawal and by promoting the recurrence of fully regressed tumors
      in the absence of doxycycline. Thus, although p53 itself is dispensable for tumor
      regression, it nevertheless plays a critical role in the suppression of tumor
      recurrence. Our findings demonstrate that although even advanced stages of
      epithelial malignancy remain dependent upon continued Wnt signaling for
      maintenance and growth, loss of p53 facilitates tumor escape and the acquisition
      of oncogene independence.

PMID- 12600943
TI  - SWI/SNF-dependent chromatin remodeling of RNR3 requires TAF(II)s and the general
      transcription machinery.
AB  - Gene expression requires the recruitment of chromatin remodeling activities and
      general transcription factors (GTFs) to promoters. Whereas the role of activators
      in recruiting chromatin remodeling activities has been clearly demonstrated, the
      contributions of the transcription machinery have not been firmly established.
      Here we demonstrate that the remodeling of the RNR3 promoter requires a number of
      GTFs, mediator and RNA polymerase II. We also show that remodeling is dependent
      upon the SWI/SNF complex, and that TFIID and RNA polymerase II are required for
      its recruitment to the promoter. In contrast, Gcn5p-dependent histone acetylation
      occurs independently of TFIID and RNA polymerase II function, and we provide
      evidence that acetylation increases the extent of nucleosome remodeling, but is
      not required for SWI/SNF recruitment. Thus, the general transcription machinery
      can contribute to nucleosome remodeling by mediating the association of SWI/SNF
      with promoters, thereby revealing a novel pathway for the recruitment of
      chromatin remodeling activities.

PMID- 12600944
TI  - Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene
      activation and protection from stress.
AB  - The activation of eukaryotic heat shock protein (Hsp) gene expression occurs in
      response to a wide variety of cellular stresses including heat shock, hydrogen
      peroxide, uncoupled oxidative phosphorylation, infection, and inflammation.
      Biochemical and genetic studies have clearly demonstrated critical roles for
      mammalian heat shock factor 1 (HSF1) in stress-inducible Hsp gene expression,
      resistance to stress-induced programmed cell death, extra-embryonic development,
      and other biological functions. Activation of mammalian Hsp gene expression
      involves the stress-inducible conversion of HSF1 from the inactive monomer to the
      DNA-binding competent homotrimer. Although Hsp activation is a central conserved
      process in biology, the precise mechanisms for stress sensing and signaling to
      activate HSF1, and the mechanisms by which many distinct stresses activate HSF1,
      are poorly understood. In this report we demonstrate that recombinant mammalian
      HSF1 directly senses both heat and hydrogen peroxide to assemble into a
      homotrimer in a reversible and redox-regulated manner. The sensing of both
      stresses requires two cysteine residues within the HSF1 DNA-binding domain that
      are engaged in redox-sensitive disulfide bonds. HSF1 derivatives in which either
      or both cysteines were mutated are defective in stress-inducible trimerization
      and DNA binding, stress-inducible nuclear translocation and Hsp gene trans
      activation, and in the protection of mouse cells from stress-induced apoptosis.
      This redox-dependent activation of HSF1 by heat and hydrogen peroxide establishes
      a common mechanism in the stress activation of Hsp gene expression by mammalian
      HSF1.

PMID- 12600945
TI  - The transcriptional activity of human Chromosome 22.
AB  - A DNA microarray representing nearly all of the unique sequences of human
      Chromosome 22 was constructed and used to measure global-transcriptional activity
      in placental poly(A)(+) RNA. We found that many of the known, related and
      predicted genes are expressed. More importantly, our study reveals twice as many
      transcribed bases as have been reported previously. Many of the newly discovered
      expressed fragments were verified by RNA blot analysis and a novel technique
      called differential hybridization mapping (DHM). Interestingly, a significant
      fraction of these novel fragments are expressed antisense to previously annotated
      introns. The coding potential of these novel expressed regions is supported by
      their sequence conservation in the mouse genome. This study has greatly increased
      our understanding of the biological information encoded on a human chromosome. To
      facilitate the dissemination of these results to the scientific community, we
      have developed a comprehensive Web resource to present the findings of this study
      and other features of human Chromosome 22 at http://array.mbb.yale.edu/chr22.

PMID- 12600946
TI  - Which drug tests in medical emergencies?

PMID- 12600947
TI  - Labeled primers for mutation scanning: making diagnostic use of the nucleobase
      quenching effect.

PMID- 12600948
TI  - National academy of clinical biochemistry laboratory medicine practice
      guidelines: recommendations for the use of laboratory tests to support poisoned
      patients who present to the emergency department.
AB  - BACKGROUND: Exposure to drugs and toxins is a major cause for patients' visits to
      the emergency department (ED). METHODS: Recommendations for the use of clinical
      laboratory tests were prepared by an expert panel of analytical toxicologists and
      ED physicians specializing in clinical toxicology. These recommendations were
      posted on the world wide web and presented in open forum at several clinical
      chemistry and clinical toxicology meetings. RESULTS: A menu of important stat
      serum and urine toxicology tests was prepared for clinical laboratories who
      provide clinical toxicology services. For drugs-of-abuse intoxication, most ED
      physicians do not rely on results of urine drug testing for emergent management
      decisions. This is in part because immunoassays, although rapid, have limitations
      in sensitivity and specificity and chromatographic assays, which are more
      definitive, are more labor-intensive. Ethyl alcohol is widely tested in the ED,
      and breath testing is a convenient procedure. Determinations made within the ED,
      however, require oversight by the clinical laboratory. Testing for toxic alcohols
      is needed, but rapid commercial assays are not available. The laboratory must
      provide stat assays for acetaminophen, salicylates, co-oximetry, cholinesterase,
      iron, and some therapeutic drugs, such as lithium and digoxin. Exposure to other
      heavy metals requires laboratory support for specimen collection but not for
      emergent testing. CONCLUSIONS: Improvements are needed for immunoassays,
      particularly for amphetamines, benzodiazepines, opioids, and tricyclic
      antidepressants. Assays for new drugs of abuse must also be developed to meet
      changing abuse patterns. As no clinical laboratory can provide services to meet
      all needs, the National Academy of Clinical Biochemistry Committee recommends
      establishment of regional centers for specialized toxicology testing.

PMID- 12600949
TI  - Anomalous structure of urinary glycosaminoglycans in patients with pseudoxanthoma
      elasticum.
AB  - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a hereditary connective tissue
      disease in which proteoglycans have altered properties. We investigated whether
      altered proteoglycan metabolism occurs in vivo and may be reflected in the urine
      of PXE individuals by analyzing the excreted polysaccharides. METHODS: We
      measured sulfated glycosaminoglycans in the urine of 10 PXE-affected patients, 12
      healthy carriers, and 20 healthy controls by agarose gel electrophoresis.
      Chondroitin sulfate and heparan sulfate disaccharides were also quantified by
      treatment with specific lyases and separation of products by chromatography.
      RESULTS: Total polysaccharides were 34% lower in the urine of PXE-affected
      patients and 17% lower in healthy carriers than in the control group. Chondroitin
      sulfate was significantly (P <0.01) decreased, and heparan sulfate was
      significantly increased. The ratio of chondroitin sulfate to heparan sulfate was
      2.7 for PXE-affected patients, 2.3 for healthy carriers, and 10.7 for controls.
      In PXE-affected individuals and carriers, chondroitin sulfate contained more 4
      sulfated disaccharide, less 6-sulfated disaccharide, and decreased nonsulfated
      disaccharide. Heparan sulfate from PXE-affected individuals and healthy carriers
      produced significantly less N-sulfated disaccharide and more disaccharide
      sulfated at the C-6 position with no significant abnormality of the nonsulfated
      disaccharide percentage and sulfates:disaccharide ratio. CONCLUSIONS: The urinary
      data support the concept that the inherited defect of the ABCC6/MRP6 transporter
      in PXE alters metabolism of key polysaccharides. Structural analysis of urinary
      sulfated polyanions may be useful in the diagnosis of PXE.

PMID- 12600950
TI  - Endothelial nitric oxide synthase gene polymorphisms and risk of coronary artery
      disease.
AB  - BACKGROUND: Endothelial nitric oxide synthase (eNOS) could be a candidate gene
      for coronary artery disease (CAD). This study investigated the relationship of
      the eNOS Glu(298)-->Asp and T(786)-->C polymorphisms with the presence and
      severity of CAD in the Italian population. METHODS: We enrolled 415 unrelated
      individuals who underwent coronary angiography. The severity of CAD was expressed
      by means of the Duke score. The eNOS Glu(298)-->Asp and T(786)-->C variants were
      analyzed by PCR. RESULTS: There was significant linkage disequilibrium between
      the two eNOS polymorphisms (P <0.0001). Both variants were significantly
      associated with the occurrence and severity of CAD (P = 0.01 and 0.004 for
      Glu(298)-->Asp and T(786)-->C, respectively). The risk of CAD was increased among
      individuals homozygous for the C allele of the T(786)-->C polymorphism compared
      with individuals homozygous for the T allele (odds ratio = 2.5; P <0.01) and was
      independent of the other common risk factors (P = 0.04). Moreover, individuals
      with both the Asp/Asp genotype of the Glu(298)-->Asp polymorphism and at least
      one C allele of the T(786)-->C variant in the promoter region of the eNOS gene
      had an increased risk of CAD (odds ratio = 4.0; P <0.001) and a significantly
      higher mean Duke score (26.2 +/- 2.9 vs 45.2 +/- 3.7; P = 0.002) compared with
      individuals with the TT genotype and the Glu allele. CONCLUSIONS: The present
      study provides evidence that the Glu(298)-->Asp and T(786)-->C polymorphisms of
      the eNOS gene are associated with the presence and severity of angiographically
      defined CAD in the Italian population and that those individuals carrying both
      eNOS variants simultaneously might have a higher risk of developing CAD.

PMID- 12600951
TI  - Amplicon melting analysis with labeled primers: a closed-tube method for
      differentiating homozygotes and heterozygotes.
AB  - BACKGROUND: Common methods for identification of DNA sequence variants use gel
      electrophoresis or column separation after PCR. METHODS: We developed a method
      for sequence variant analysis requiring only PCR and amplicon melting analysis.
      One of the PCR primers was fluorescently labeled. After PCR, the melting
      transition of the amplicon was monitored by high-resolution melting analysis.
      Different homozygotes were distinguished by amplicon melting temperature (T(m)).
      Heterozygotes were identified by low-temperature melting of heteroduplexes, which
      broadened the overall melting transition. In both cases, melting analysis
      required approximately 1 min and no sample processing was needed after PCR.
      RESULTS: Polymorphisms in the HTR2A (T102C), beta-globin [hemoglobin (Hb) S, C,
      and E], and cystic fibrosis (F508del, F508C, I507del, I506V) genes were analyzed.
      Heteroduplexes produced by amplification of heterozygous DNA were best detected
      by rapid cooling (>2 degrees C/s) of denatured products, followed by rapid
      heating during melting analysis (0.2-0.4 degrees C/s). Heterozygotes were
      distinguished from homozygotes by a broader melting transition, and each
      heterozygote had a uniquely shaped fluorescent melting curve. All homozygotes
      tested were distinguished from each other, including Hb AA and Hb SS, which
      differed in T(m) by <0.2 degrees C. The amplicons varied in length from 44 to 304
      bp. In place of one labeled and one unlabeled primer, a generic fluorescent
      oligonucleotide could be used if a 5' tail of identical sequence was added to one
      of the two unlabeled primers. CONCLUSION: High-resolution melting analysis of PCR
      products amplified with labeled primers can identify both heterozygous and
      homozygous sequence variants.

PMID- 12600952
TI  - Exploiting the enzymatic recognition of an unnatural base pair to develop a
      universal genetic analysis system.
AB  - BACKGROUND: With the invention of the DNA chip, genome-wide analysis is now a
      reality. Unfortunately, solid-phase detection systems such as the DNA chip suffer
      from a narrow range in quantification and sensitivity. Today the best methodology
      for sensitive, wide dynamic range quantification and genotyping of nucleic acids
      is real-time PCR. However, multiplexed real-time PCR technologies require
      complicated and costly design and manufacturing of separate detection probes for
      each new target. METHODS: We developed a novel real-time PCR technology that uses
      universal energy transfer probes constructed from An Expanded Genetic Information
      System (AEGIS) for both quantification and genotyping analyses. RESULTS: RNA
      quantification by reverse transcription-PCR was linear over four orders of
      magnitude for the simultaneous analysis of beta-actin messenger RNA and 18S
      ribosomal RNA. A single trial validation study of 176 previously genotyped
      clinical specimens was performed by endpoint analysis for factor V Leiden and
      prothrombin 20210A mutation detection. There was concordance for 173 samples
      between the genotyping results from Invader tests and the AEGIS universal energy
      transfer probe system for both factor V Leiden and prothrombin G20210A. Two
      prothrombin and one factor V sample gave indeterminate results (no calls).
      CONCLUSION: The AEGIS universal probe system allows for rapid development of PCR
      assays for nucleic acid quantification and genotyping.

PMID- 12600953
TI  - Application of optical trapping for cells grown on plates: optimization of PCR
      and fidelity of DNA sequencing of p53 gene from a single cell.
AB  - BACKGROUND: Optical trapping has traditionally been used to visually select and
      isolate nonadherent cells grown in suspension because cells grown in monolayers
      will rapidly reattach to surfaces if suspended in solution. We explored methods
      to slow cell reattachment that are also compatible with high-fidelity PCR.
      METHODS: Using HeLa cells grown on plates and suspended after trypsinization, we
      measured the efficiency of capture by retention and movement of the cell by the
      laser. Success for removing a captured cell by pipette was determined by PCR
      amplification of the 5S rRNA gene. After optimizing PCR amplification of a 2049
      bp region of the p53 gene, we determined PCR fidelity by DNA sequencing. RESULTS:
      Addition of bovine serum albumin to suspended cells slowed reattachment from
      seconds to minutes and allowed efficient trapping. The success rate of removing a
      cell from the trap by pipette to a PCR tube was 91.5%. The 5S PCR assay also
      revealed that DNA and RNA that copurify with polymerases could give false
      positive results. Sequence analysis of four clones derived from a single cell
      showed only three polymerase errors in 7200 bp of sequence read and revealed
      difficulties in reading the correct number in a run of 16 A:T. Comparison of the
      HeLa and wild-type human sequences revealed several previously unreported base
      differences and an (A:T)(n) length polymorphism in p53 introns. CONCLUSIONS:
      These results represent the first use of optical trapping on adherent cells and
      demonstrate the high accuracy of DNA sequencing that can be achieved from a
      single cell.

PMID- 12600954
TI  - PCR-based calibration curves for studies of quantitative gene expression in human
      monocytes: development and evaluation.
AB  - BACKGROUND: Quantitative reverse transcription-PCR (RT-PCR) used to detect small
      changes in specific mRNA concentrations is often associated with poor
      reproducibility. Thus, there is a need for stringent quality control in each step
      of the protocol. METHODS: Real-time PCR-based calibration curves for a target
      gene, tissue factor (TF), and a reference gene, beta-actin, generated from PCR
      amplicons were evaluated by running cDNA controls. In addition, the reverse
      transcription step was evaluated by running mRNA controls. Amplification
      efficiencies of calibrators and targets were determined. Variances within and
      between runs were estimated, and power statistics were applied to determine the
      concentration differences that could reliably be detected. RESULTS: Within- and
      between-run variations (CVs) of cDNA controls (TF and beta-actin), extrapolated
      from reproducible calibration curves (CVs of slopes, 4.3% and 2.7%, respectively)
      were 4-10% (within) and 15-38% (between) using both daily and "grand mean"
      calibration curves. CVs for the beta-actin mRNA controls were 12% (within) and 19
      28% (between). Estimates of each step's contribution to the total variation were
      as follows: CV(RT-PCR), 28%; CV(PCR), 15%; CV(RT), 23% (difference between CV(RT
      PCR) and CV(PCR)). PCR efficiencies were as follows: beta-actin
      calibrator/target, 1.96/1.95; TF calibrator/target, 1.95/1.93. Duplicate
      measurements could detect a twofold concentration difference (power, 0.8).
      CONCLUSIONS: Daily PCR calibration curves generated from PCR amplicons were
      reproducible, allowing the use of a grand mean calibration curve. The reverse
      transcription step contributes the most to the total variation. By determining a
      system's total variance, power analysis may be used to disclose differences that
      can be reliably detected at a specified power.

PMID- 12600955
TI  - Comparison of eight computer programs for receiver-operating characteristic
      analysis.
AB  - BACKGROUND: ROC analysis is widely accepted to assess and compare diagnostic
      validity of laboratory tests. Within the last few years, many new ROC programs
      have become available but have not been systematically evaluated. The aim of this
      study was to assess different ROC programs regarding their ease of use,
      mathematical correctness, final output, and their compatibility with other
      graphics programs. METHODS: Eight available programs running under Windows
      (AccuROC, Analyse-It, CMDT, GraphROC, MedCalc, mROC, ROCKIT, and SPSS) were
      evaluated. ROC analyses of prostate-specific antigen and related values were
      performed from a dataset of 928 men with prostate cancer and benign prostatic
      hyperplasia and corresponding subsets. Criteria such as data input, data output,
      and correctness and completeness of results were used to evaluate the
      practicability of the programs. RESULTS: Although the programs produced
      equivalent results (areas under the curves and their characteristics), we
      observed deficiencies concerning input of data, processing of the output data,
      and completeness of the results. Analyse-It, AccuROC, and MedCalc exhibited good
      performance, but each program had different shortcomings. Only GraphROC could
      compare curves at a certain sensitivity or specificity cutoff. CONCLUSIONS:
      Adequate ROC analysis and ROC plotting cannot be performed with a single program.
      Analyse-It, AccuROC, and MedCalc can be recommended with certain limitations.
      Further improvements of the programs are necessary.

PMID- 12600957
TI  - Validation of the FibroTest biochemical markers score in assessing liver fibrosis
      in hepatitis C patients.
AB  - BACKGROUND: Determining the stage of fibrosis by liver biopsy is important in
      managing patients with hepatitis C virus infection. We investigated the
      predictive value of the proprietary FibroTest score to accurately identify
      significant fibrosis in Australian hepatitis C patients. METHODS: Serum obtained
      from 125 confirmed hepatitis C patients before antiviral therapy was analyzed for
      haptoglobin, alpha(2)-macroglobulin, apolipoprotein A1, bilirubin, and gamma
      glutamyltransferase activity, and the FibroTest score was computed. Liver
      fibrosis pathology was staged according to a defined system on a scale of F0 to
      F4. We used predictive values and a ROC curve to assess the accuracy of FibroTest
      scores. RESULTS: The prevalence of significant fibrosis defined by liver biopsy
      was 0.38. The most useful single test for predicting significant fibrosis was
      serum alpha(2)-macroglobulin (cutoff value, 2.52 g/L; sensitivity, 75%;
      specificity, 67%). The negative predictive value of a FibroTest score <0.1 was
      85%, and the positive predictive value of a score >0.6 was 78%. Although 33 of
      the 125 patients had FibroTest scores <0.1 and were therefore deemed unlikely to
      have fibrosis, 6 (18%) had significant fibrosis. Conversely, of the 24 patients
      with scores >0.6 who were likely to have significant fibrosis, 5 (21%) had mild
      fibrosis. Of the 125 patients in the cohort, 57 (46%) could have avoided liver
      biopsy, but discrepant results were recorded in 11 of those 57 (19%). CONCLUSION:
      The FibroTest score could not accurately predict the presence or absence of
      significant liver fibrosis.

PMID- 12600956
TI  - Use of capillary zone electrophoresis for differentiating excessive from moderate
      alcohol consumption.
AB  - BACKGROUND: The poorly sialylated transferrin isoforms in serum were analyzed by
      capillary zone electrophoresis (CZE) to differentiate moderate from heavy alcohol
      consumption. METHODS: We enrolled 614 volunteers, classified after interviews,
      self-reported drinking habits, and AUDIT scores as alcohol abusers (consuming >50
      g/day ethanol for the previous 3 months or longer; n = 413) or moderate drinkers
      (<30 g/day ethanol; n = 201). Serum transferrin isoforms were separated at 28 kV
      and monitored at 214 nm on a P/ACE 5500 CZE with use of fused-silica capillaries
      and the related CEofix CDT reagent set. Immunosubtraction by anti-human
      transferrin and electrophoretic migration times identified the isoforms. Previous
      markers of alcohol abuse and an assay combining anion-exchange minicolumn
      chromatography with immunoturbidimetry (%CDT) were included in the study.
      Sensitivities and specificities were compared by ROC analysis. RESULTS: The
      asialylated isoform was missing in 95% of moderate drinkers but present in 92% of
      alcohol misusers. Disialotransferrin had a specificity and sensitivity of 0.75 at
      a cutoff of 0.7% of total transferrin, whereas the sum (asialo- +
      disialotransferrin) at a threshold of 1.2% had a sensitivity of 0.73 and a
      specificity of 0.92. Trisialotransferrin values did not distinguish between the
      two populations. Sensitivities and specificities of %CDT averaged 0.77 and 0.74,
      respectively, at a 2.6% cutoff; 0.67 and 0.83 at 2.8%; and 0.63 and 0.90 at 3%.
      CDT data were more sensitive and specific for males. Conventional biomarkers
      appeared less discriminating. CONCLUSIONS: Asialotransferrin detected by CZE in
      sera of alcohol abusers offers the highest discrimination between excessive and
      moderate drinking.

PMID- 12600958
TI  - RIA for serum holo-transcobalamin: method evaluation in the clinical laboratory
      and reference interval.
AB  - BACKGROUND: Decreased serum holo-transcobalamin (holoTC) could be the earliest
      marker of cobalamin (Cbl) deficiency, but there has been no method suitable for
      routine use. We evaluated a new commercial holoTC RIA, determined reference
      values, and assessed holoTC concentrations in relation to other biochemical
      markers of Cbl deficiency. METHODS: The reference population consisted of 303
      individuals 22-88 years of age, without disease or medication affecting Cbl or
      homocysteine metabolism. In elderly individuals (>or=65 years), normal Cbl status
      was further confirmed by total homocysteine (tHcy; <19 micro mol/L) and
      methylmalonic acid (MMA; <0.28 micro mol/L) concentrations within established
      reference intervals. HoloTC in Cbl deficiency was studied in a population of 107
      elderly individuals with normal renal function. The Cbl deficiency was graded as
      potential (total Cbl <or=150 pmol/L or tHcy >or=19 micro mol/L), possible (total
      Cbl <or=150 pmol/L and either tHcy >or=19 micro mol/L or MMA >or=0.45 micro
      mol/L), and probable (tHcy >or=19 micro mol/L and MMA >or=0.45 micro mol/L).
      RESULTS: The intra- and between-assay imprecision (CV) for the holoTC RIA were 4
      7% and 6-8%, respectively. A 95% central reference interval for serum holoTC was
      37-171 pmol/L. All participants (n = 16) with probable Cbl deficiency, 86% of
      those with possible, and 30% of those with potential Cbl deficiency had holoTC
      below the reference limit (<37 pmol/L). The holoTC correlated with total Cbl
      (r(s) = 0.80; P <0.0001) and inversely with MMA (r(s) = -0.52; P <0.0001). HoloTC
      concentrations were significantly (P = 0.01) higher in women than in men.
      CONCLUSIONS: The new holoTC RIA is precise and simple to perform. Low holoTC is
      found in individuals with biochemical signs of Cbl deficiency, but the
      sensitivity and specificity of low holoTC in diagnosis of Cbl deficiency need to
      be further evaluated.

PMID- 12600959
TI  - Certification of standard reference material 970, ascorbic acid in serum, and
      analysis of associated interlaboratory bias in the measurement process.
AB  - BACKGROUND: The accurate and reproducible measurement of ascorbic acid is
      essential in delineating the role of ascorbic acid as a diagnostic tool for human
      disease and for the comparison of data acquired by different laboratories. A
      stabilized pair of standards of ascorbic acid in human serum, which is compatible
      with most analytical methods, have been prepared. METHODS: The certification was
      based on the gravimetric addition of ascorbic acid to metaphosphoric acid
      stabilized, ascorbic acid-depleted serum and NIST liquid chromatography
      electrochemical measurements. The NIST results were analyzed statistically for
      homogeneity, and the expanded uncertainty of each SRM was calculated using all of
      the NIST data. An interlaboratory comparison exercise was also performed.
      RESULTS: These materials, Standard Reference Material (SRM) 970 Ascorbic Acid in
      Serum, Level I and Level II, are homogeneous and are certified to contain (10.07
      +/- 0.21) and (30.57 +/- 0.28) mmol ascorbic acid/L of solution (expanded
      uncertainty), respectively. In the interlaboratory comparison (n = 17), the
      relative SDs for the two materials were 22% and 19%. CONCLUSIONS: Two lots of
      serum, each containing different amounts of ascorbic acid stabilized in
      metaphosphoric acid, have been prepared and characterized. Many laboratories
      provide inaccurate results.

PMID- 12600961
TI  - Low-positive anti-hepatitis C virus enzyme immunoassay results: an important
      predictor of low likelihood of hepatitis C infection.
AB  - BACKGROUND: Tests for hepatitis C antibodies (anti-HCV enzyme immunoassays) are
      usually described as positive or negative. Several studies, mainly in blood
      donors, have found that specimens with low signal/cutoff (S/C) ratios are
      commonly negative when tested with a recombinant immunoblot assay (RIBA) or for
      HCV RNA. METHODS: We retrospectively reviewed 17 418 consecutive anti-HCV results
      from a screening program for high-risk veterans; 2986 (17.1%) samples were anti
      HCV-positive, and 490 (16.4%) had S/C ratios <or=3.7 (low positive). Additional
      tests were performed in 1814 anti-HCV-positive individuals. RESULTS: RIBA was
      performed in 263 patients with low-positive anti-HCV; results were negative in
      86%, indeterminate in 12%, and positive in 2%. Only 16 of 140 individuals (11%)
      with low-positive anti-HCV values were HCV RNA-positive, whereas HCV RNA was
      positive in 90% of 1435 individuals with high-positive anti-HCV values (P
      <0.0001). Compared with those with high-positive anti-HCV, individuals with low
      positive anti-HCV values were older (P <0.0001) and were less likely to have risk
      factors for HCV (P <0.0001 for most), multiple increased alanine aminotransferase
      (ALT) activity values (30% vs 81%; P <0.0001), or positive anti-hepatitis B core
      antigen (19% vs 59%; P <0.0002). Among 634 individuals with high anti-HCV titers
      and multiple increased ALT activity values, 95% were HCV RNA-positive.
      CONCLUSIONS: The S/C ratio is important even in high-risk individuals;
      laboratories should report the S/C ratio along with anti-HCV EIA results and
      perform supplemental RIBA testing in those with low-positive values to avoid
      reporting false-positive results.

PMID- 12600960
TI  - Toxicity of free p-cresol: a prospective and cross-sectional analysis.
AB  - BACKGROUND: Uremic syndrome is the consequence of the retention of solutes
      usually cleared by the healthy kidneys. p-Cresol can be considered a prototypic
      protein-bound uremic toxin. It is conceivable, analogous with drugs, that the non
      protein-bound fraction of p-cresol exerts toxicity. This aspect had never been
      evaluated, nor have the factors influencing the free fraction of p-cresol.
      METHODS: In a transsectional study we evaluated the relationship between
      prehemodialysis free p-cresol and the ratio of free to total p-cresol (F:T) to
      clinical and biological factors in 44 chronic renal failure patients. The
      evolution of free p-cresol was assessed prospectively in 12 patients showing a
      change in serum albumin of at least 5 g/L over time. Hospitalization days
      attributable to infection and the free p-cresol concentrations were noted over a
      1-year period. The impact of free p-cresol in vitro on leukocyte functional
      capacity was evaluated by chemiluminescence. RESULTS: We observed a correlation
      between total and free p-cresol (r = 0.84; P <0.001). In the multivariate
      analyses, free p-cresol and F:T showed a negative correlation with albumin. A
      shift from normal serum albumin to hypoalbumininemia in 12 patients led to an
      increase in free p-cresol from 5.9 +/- 3.2 to 8.2 +/- 4.5 micro mol/L (P <0.05;
      0.64 +/- 0.35 to 0.89 +/- 0.49 mg/L). Free p-cresol (P <0.05) was higher in the
      patients hospitalized for infectious disease. In vitro, free p-cresol was higher
      in a 25 g/L than in a 50 g/L albumin solution (P <0.05). Leukocyte
      chemiluminescence production was more inhibited in the low albumin (high free p
      cresol) solution (28% +/- 6% vs 21% +/- 8%; P <0.05). CONCLUSIONS:
      Hypoalbuminemia and total p-cresol increase the free fraction of p-cresol.
      Patients hospitalized for infections have higher free p-cresol. In vitro, high
      free p-cresol has a negative impact on leukocyte chemiluminescence production.
      These data demonstrate the toxicity of free p-cresol.

PMID- 12600962
TI  - Cerebrospinal fluid lactate and pyruvate concentrations and their ratio in
      children: age-related reference intervals.
AB  - BACKGROUND: Lactate (L) and pyruvate (P) concentrations in cerebrospinal fluid
      (CSF) and the L/P ratio have diagnostic value in numerous primary and acquired
      disorders affecting the central nervous system, but age-related reference values
      are not available for children. METHODS: We analyzed CSF and blood lactate and
      pyruvate concentrations and their ratio in a 4-year retrospective survey of a
      children's hospital laboratory database. Reference intervals (10th-90th
      percentiles) were established from data on 197 hospitalized children. A recent
      regression modeling method was used to normalize and smooth values against age.
      The model equation of best fit was calculated for each variable. RESULTS: Slight
      age-related variations were shown by the model, with an increase in lactate, a
      decrease in pyruvate, and a resulting increase in the L/P ratio with increasing
      age. However, the SD did not vary with age. We defined the upper limit of the
      reference intervals as the 90th percentiles, which from birth to 186 months of
      age varied continuously from 1.78 to 1.88 mmol/L (6%), 148 to 139 micro mol/L
      (6%), and 16.9 to 19.2 (14%) for lactate, pyruvate, and the L/P ratio,
      respectively. At a threshold of 2 (in Z-score units), the sensitivity for a
      subgroup of inborn errors of metabolism (respiratory chain disorders) was 73%,
      42%, and 31% for lactate, pyruvate, and the L/P ratio, respectively. CONCLUSIONS:
      In children, CSF lactate and pyruvate concentrations and their ratio appear to
      vary slightly with age. Average 90th percentile values of 1.8 mmol/L, 147 micro
      mol/L, and 17, respectively, could be used in infants up to 24 months of age. In
      older children, age-adjusted reference intervals should be used, especially when
      values are close to the 90th percentile.

PMID- 12600963
TI  - Origin of plasma cell-free DNA after solid organ transplantation.

PMID- 12600965
TI  - Rapid determination of orotic acid in urine by liquid chromatography-electrospray
      tandem mass spectrometry.

PMID- 12600964
TI  - Efficient strategy for molecular diagnosis of Wilson disease in the sardinian
      population.

PMID- 12600967
TI  - Macroprolactin detection by precipitation with protein A-sepharose: a rapid
      screening method compared with polyethylene glycol precipitation.

PMID- 12600966
TI  - Accuracy of the rapid fetal fibronectin TLi system in predicting preterm
      delivery.

PMID- 12600968
TI  - Release of macromolecular cardiac troponin I complex after successful
      percutaneous transluminal coronary angioplasty in acute myocardial infarction.

PMID- 12600969
TI  - Rapid genotyping of melanocortin-1 receptor with use of fluorescence-labeled
      oligonucleotides.

PMID- 12600971
TI  - Evaluation of a turbidimetric Denka Seiken C-reactive protein assay for
      cardiovascular risk estimation and conventional inflammation diagnosis.

PMID- 12600970
TI  - Rapid and simple assay for the determination of tripeptidyl peptidase and
      palmitoyl protein thioesterase activities in dried blood spots.

PMID- 12600972
TI  - Diagnostic validation of capillary electrophoresis analysis of T-cell receptor
      gamma-chain gene rearrangements: prediction of malignant transformation of
      cutaneous T-cell lymphoproliferative disorders.

PMID- 12600973
TI  - Pyridoxal phosphate decreases in plasma but not erythrocytes during systemic
      inflammatory response.

PMID- 12600974
TI  - Stabilization of homocysteine in unseparated blood over several days: a solution
      for epidemiological studies.

PMID- 12600975
TI  - Absence of ABCA1 mutations in individuals with low serum HDL-cholesterol.

PMID- 12600976
TI  - Gamma-glutamyltransferase and vascular disease.

PMID- 12600977
TI  - Serum concentrations of vascular endothelial growth factor in advanced non-small
      cell lung cancer.

PMID- 12600978
TI  - Effects of blood-processing protocols on cell-free DNA quantification in plasma.

PMID- 12600982
TI  - Characterization of cluster N5 as a fast-relaxing [4Fe-4S] cluster in the Nqo3
      subunit of the proton-translocating NADH-ubiquinone oxidoreductase from
      Paracoccus denitrificans.
AB  - The NADH-quinone oxidoreductase from Paracoccus denitrificans consists of 14
      subunits (Nqo1-14) and contains one FMN and eight iron-sulfur clusters. The Nqo3
      subunit possesses fully conserved 11 Cys and 1 His in its N-terminal region and
      is considered to harbor three iron-sulfur clusters; however, only one binuclear
      (N1b) and one tetranuclear (N4) were previously identified. In this study, the
      Nqo3 subunit containing 1x[2Fe-2S] and 2x[4Fe-4S] clusters was expressed in
      Escherichia coli. The second [4Fe-4S](1+) cluster is detected by EPR spectroscopy
      below 6 K, exhibiting very fast spin relaxation. The resolved EPR spectrum of
      this cluster is broad and nearly axial. The subunit exhibits an absorption-type
      EPR signal around g approximately 5 region below 6 K, most likely arising from an
      S = 3/2 ground state of the fast-relaxing [4Fe-4S](1+) species. The substitution
      of the conserved His(106) with Cys specifically affected the fast-relaxing [4Fe
      4S](1+) cluster, suggesting that this cluster is coordinated by His(106). In the
      cholate-treated NDH-1-enriched P. denitrificans membranes, we observed EPR
      signals arising from a [4Fe-4S] cluster below 6 K, exhibiting properties similar
      to those of cluster N5 detected in other complex I/NDH-1 and of the fast-relaxing
      [4Fe-4S](1+) cluster in the expressed Nqo3 subunit. Hence, we propose that the
      His-coordinated [4Fe-4S] cluster corresponds to cluster N5.

PMID- 12600983
TI  - The transcription factor SREBP-1c is instrumental in the development of beta-cell
      dysfunction.
AB  - Accumulation of lipids in non-adipose tissues is often associated with Type 2
      diabetes and its complications. Elevated expression of the lipogenic
      transcription factor, sterol regulatory element binding protein-1c (SREBP-1c),
      has been demonstrated in islets and liver of diabetic animals. To elucidate the
      molecular mechanisms underlying SREBP-1c-induced beta-cell dysfunction, we
      employed the Tet-On inducible system to achieve tightly controlled and
      conditional expression of the nuclear active form of SREBP-1c (naSREBP-1c) in INS
      1 cells. Controlled expression of naSREBP-1c induced massive accumulation of
      lipid droplets and blunted nutrient-stimulated insulin secretion in INS-1 cells.
      K(+)-evoked insulin exocytosis was unaltered. Quantification of the gene
      expression profile in this INS-1 stable clone revealed that naSREBP-1c induced
      beta-cell dysfunction by targeting multiple genes dedicated to carbohydrate
      metabolism, lipid biosynthesis, cell growth, and apoptosis. naSREBP-1c elicits
      cell growth-arrest and eventually apoptosis. We also found that the SREBP-1c
      processing in beta-cells was irresponsive to acute stimulation of glucose and
      insulin, which was distinct from that in lipogenic tissues. However, 2-day
      exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c
      maturation could be implicated in the pathogenesis of beta-cell
      glucolipotoxicity.

PMID- 12600984
TI  - Interaction between Src and a C-terminal proline-rich motif of Akt is required
      for Akt activation.
AB  - Activation of Akt by growth factors is a multistep process. Here, we provide
      evidence that tyrosine kinase Src is directly associated with Akt through the
      interaction between its SH3 domain and a conserved proline-rich motif (PXXP) in
      the C-terminal regulatory region of Akt. Substitution of the proline residues Pro
      424 and Pro-427 by alanines results in loss of Akt activity and phosphorylation
      induced by the epidermal growth factor (EGF), possibly because these mutations
      disrupt the interaction between Akt and the SH3 domain of Src. This possibility
      is corroborated by our observation that the Akt mutant lacking these two prolines
      fails to bind to Src both in vivo and in vitro. We also showed that
      phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the
      integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this
      proline motif fails to block the transcription activity of Forkhead in 293 cells
      and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken
      together, our data suggest that the interaction between the SH3 domain of Src
      family kinases and the proline-rich motif in the C-terminal regulatory region of
      Akt is required for tyrosine phosphorylation of Akt and its subsequent
      activation. It is noteworthy that this PXXP motif is conserved throughout several
      members of AGC kinase family, implying that association of this motif with the
      SH3 domain of an upstream regulator may represent a general mechanism applicable
      to these kinases as well.

PMID- 12600985
TI  - Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of
      the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes.
AB  - Transcription factors of the interferon regulatory factor (IRF) family have been
      identified as critical mediators of early inflammatory gene transcription in
      infected cells. We have shown previously that IRF-5, like IRF-3 and IRF-7, is a
      direct transducer of virus-mediated signaling and plays a role in the expression
      of multiple cytokines/chemokines. The present study is focused on the molecular
      mechanisms underlying the formation and function of IRF-5/IRF-7 heterodimers in
      infected cells. The interaction between IRF-5 and IRF-7 is not cooperative and
      results in a repression rather than enhancement of IFNA gene transcription. The
      formation of the IRF-5/IRF-7 heterodimer is dependent on IRF-7 phosphorylation,
      as shown by the glutathione S-transferase pull-down and immunoprecipitation
      assays. Mapping of the interaction domain revealed that formation of IRF-5/IRF-7
      heterodimers occurs through the amino terminus resulting in a masking of the DNA
      binding domain, the consequent alteration of the composition of the enhanceosome
      complex binding to IFNA promoters in vivo, and modulation of the expression
      profile of IFNA subtypes. Thus, these results indicate that IRF-5 can act as both
      an activator and a repressor of IFN gene induction dependent on the IRF
      interacting partner, and IRF-5 may be a part of the regulatory network that
      ensures timely expression of the immediate early inflammatory genes.

PMID- 12600986
TI  - Pulmonary surfactant protein-A (SP-A) restores the surface properties of
      surfactant after oxidation by a mechanism that requires the Cys6 interchain
      disulfide bond and the phospholipid binding domain.
AB  - Reactive oxygen species produced by activated leuko-cytes in the alveolar
      epithelial lining fluid have been implicated in the inactivation of pulmonary
      surfactant and the impairment of lung function. Oxidation of bovine lipid extract
      surfactant (BLES), a therapeutic surfactant, with hypochlorous acid (H-BLES) or
      the Fenton reaction (F-BLES) led to temporary increases in conjugated dienes and
      formation of malondialdehyde and 4-hydroxy-2-nonenal. Electrospray ionization
      mass spectrometry revealed the appearance of lipid hydroperoxides, peroxides,
      lysophospholipids, and free fatty acids. Captive bubble tensiometer studies of H
      BLES demonstrated prolonged adsorption times, film instability at low surface
      tensions during film compression, and reduced respreadability during film
      expansion. F-BLES exhibited prolonged adsorption times, a marked effect on
      increasing compressibility during compression, and a lesser effect on reducing
      respreadability on expansion. Addition of native bovine or rat surfactant
      associated protein A (SP-A) reversed the effects of oxidation on surfactant
      biophysical properties. Studies using mutant recombinant rat SP-As indicated that
      an intact carbohydrate recognition domain and disulfide-dependent oligomeric
      assembly are critical for these effects, but the collagen-like region is not
      required. We conclude that SP-A can reverse the detrimental effects of surfactant
      oxidation on the biophysical properties of surfactant, by a mechanism that is
      dependent on interchain disulfide bond formation and the C-terminal domains of
      the protein.

PMID- 12600987
TI  - A conserved structural motif at the N terminus of bacterial translation
      initiation factor IF2.
AB  - The 18-kDa Domain I from the N-terminal region of translation initiation factor
      IF2 from Escherichia coli was expressed, purified, and structurally characterized
      using multidimensional NMR methods. Residues 2-50 were found to form a compact
      subdomain containing three short beta-strands and three alpha-helices, folded to
      form a betaalphaalphabetabetaalpha motif with the three helices packed on the
      same side of a small twisted beta-sheet. The hydrophobic amino acids in the core
      of the subdomain are conserved in a wide range of species, indicating that a
      similarly structured motif is present at the N terminus of IF2 in many of the
      bacteria. External to the compact 50-amino acid subdomain, residues 51-97 are
      less conserved and do not appear to form a regular structure, whereas residues 98
      157 form a helix containing a repetitive sequence of mostly hydrophilic amino
      acids. Nitrogen-15 relaxation rate measurements provide evidence that the first
      50 residues form a well ordered subdomain, whereas other regions of Domain I are
      significantly more mobile. The compact subdomain at the N terminus of IF2 shows
      structural homology to the tRNA anticodon stem contact fold domains of the
      methionyl-tRNA and glutaminyl-tRNA synthetases, and a similar fold is also found
      in the B5 domain of the phenylalanine-tRNA synthetase. The results of the present
      work will provide guidance for the design of future experiments directed toward
      understanding the functional roles of this widely conserved structural domain
      within IF2.

PMID- 12600988
TI  - Independent and cooperative activation of chromosomal c-fos promoter by STAT3.
AB  - The c-fos gene was one of the earliest vertebrate genes shown to be
      transcriptionally induced by growth factors. Intensive study of the promoter of c
      fos (-325 to -80) by transient or permanent transfections of synthetic DNA
      constructs has repeatedly shown the importance of several sequence elements and
      the resident nuclear proteins that bind them (e.g. ternary complex factor/ELK1;
      serum response factor, cAMP response element-binding protein/amino-terminal
      fragment/AP-1). However these studies have left unanswered numerous questions
      about the role of these proteins in the regulation of the native chromosomal
      gene. In particular, the role of a site in this enhancer that binds STATs has
      been controversial. We present evidence here that STAT3 and not STAT1 accumulates
      on the chromosomal c-fos promoter and provides a boost to transcription without
      the activation of resident nuclear proteins through serine kinases. Also, when
      resident nuclear proteins such as ELK1 are activated to varying extents by
      mitogen-activated protein kinase pathways, STAT3 activation provides a 2-fold
      boost regardless of the final level of activated transcription. Thus the several
      proteins that interact with the c-fos enhancer apparently can act either in a
      cooperative or independent manner to achieve very different levels of
      transcription.

PMID- 12600990
TI  - Declusterization of GABAA receptors affects the kinetic properties of GABAergic
      currents in cultured hippocampal neurons.
AB  - Speed and reliability of synaptic transmission are essential for information
      coding in neuronal networks and require the presence of clustered
      neurotransmitter receptors at the plasma membrane in precise apposition to
      presynaptic terminals. Receptor clusterization is the result of highly regulated
      processes involving functional and structural proteins. Among the structural
      elements, microtubules are known to play a crucial role in anchoring of gamma
      aminobutyric acid, type A (GABA(A)) receptors. Here we show that microtubule
      depolymerization with nocodazole induces the declusterization of GABA(A)
      receptors and modifies the kinetic properties of GABAergic currents in cultured
      hippocampal neurons. In particular, this drug, applied either in the bath or via
      the patch pipette, induced the acceleration of the onset kinetics of miniature
      inhibitory postsynaptic currents (mIPSCs) without significantly affecting their
      frequency, thus suggesting a main postsynaptic site of action. After nocodazole
      treatment, current responses to ultrafast applications of GABA exhibited a faster
      rise time and an accelerated onset of desensitization. A quantitative analysis of
      GABA-evoked currents and model simulations suggest that declusterization affects
      the gating properties of GABA(A) receptors. In particular, a faster entry into
      the desensitized state of declustered GABA(A) receptors may account for the
      changes in the kinetic properties of mIPSCs after nocodazole treatment. Hence it
      appears that the clustered condition of GABA(A) receptors contributes in shaping
      GABAergic currents.

PMID- 12600989
TI  - Neuregulin-1 enhances motility and migration of human astrocytic glioma cells.
AB  - Gliomas are the most frequently diagnosed adult primary brain malignancy. These
      tumors have a tendency to invade diffusely into the surrounding healthy brain
      tissue, thereby precluding their successful surgical removal. In this report, we
      examine the potential for the neuregulin-1/erbB receptor signaling network to
      contribute to this process by modulating glioma cell motility. Neuregulin-1 is
      expressed throughout the immature and adult central nervous system and has been
      demonstrated to influence the migration of a variety of cell types in the
      developing brain. In addition, erbB2, an integral member of the heterodimeric
      neuregulin-1 receptor, has been shown to be overexpressed in human glioma
      biopsies. Using antibodies specific for erbB2 and erbB3, we show that these
      receptors localize preferentially in regions of the plasma membrane which are
      involved in facilitating cellular movement. Here, erbB2 colocalizes and
      coimmunoprecipitates with members of the focal complex including beta1-integrin
      and focal adhesion kinase. Further, erbB receptor activation by neuregulin-1
      enhances cell motility in two-dimensional scratch motility assays and stimulates
      cell invasion in three-dimensional Transwell migration assays. These effects of
      neuregulin-1 appear to involve the activation of focal adhesion kinase, which
      occurs downstream from erbB2 receptor stimulation. Taken together these data
      suggest that neuregulin-1 plays an important modulatory role in glioma cell
      invasion.

PMID- 12600991
TI  - Biochemical analysis of the 20 S proteasome of Trypanosoma brucei.
AB  - We describe here biochemical characterization of the 20 S proteasome from the
      parasitic protozoan Trypanosoma brucei. Similar to the mammalian proteasome, the
      T. brucei proteasome is made up of seven alpha- and seven beta-subunits. Of the
      seven beta-type subunits, five contain pro-sequences that are proteolytically
      removed during assembly, and three of them are predicted to be catalytic based on
      primary sequence. Affinity labeling studies revealed that, unlike the mammalian
      proteasome where three beta-subunits were labeled by the affinity reagents, only
      two beta-subunits of the T. brucei proteasome were labeled in the complex. These
      two subunits corresponded to beta2 and beta5 subunits responsible for the trypsin
      like and chymotrypsin-like proteolytic activities, respectively. Screening of a
      library of 137,180 tetrapeptide fluorogenic substrates against the T. brucei 20 S
      proteasome confirmed the nominal beta1-subunit (caspase-like or PGPH) activity
      and identified an overall substrate preference for hydrophobic residues at the P1
      to P4 positions in a substrate. This overall stringency is relaxed in the 11 S
      regulator (PA26)-20 S proteasome complex, which shows both appreciable activities
      for cleavage after acidic amino acids and a broadened activity for cleavage after
      basic amino acids. The 20 S proteasome from T. brucei also shows appreciable
      activity for cleavage after P1-Gln that is minimally observed in the human
      counterpart. These results demonstrate the importance of substrate sequence
      specificity of the T. brucei proteasome and highlight its biochemical divergence
      from the human enzyme.

PMID- 12600992
TI  - A G protein-coupled receptor kinase induces Xenopus oocyte maturation.
AB  - Several recent studies have suggested that resumption of oocyte meiosis,
      indicated by germinal vesicle breakdown or GVBD, involves inhibition of
      endogenous heterotrimeric G proteins in both frogs and mice. These studies imply
      that a heterotrimeric G protein(s), and hence its upstream activator (a G protein
      coupled receptor or GpCR), is activated in prophase oocytes and is responsible
      for maintaining meiosis arrest. To test the existence and function of this
      putative GpCR, we utilized a mammalian G-protein-coupled receptor kinase (GRK3)
      and beta-arrestin-2, which together are known to cause GpCR desensitization.
      Injection of mRNA for rat GRK3 caused hormone-independent GVBD. The kinase
      activity of GRK3 was essential for GVBD induction as its kinase-dead mutant (GRK3
      K220R) was completely ineffective. Another GRK3 mutant (GRK3-DeltaC), which
      lacked the C-terminal G(betagamma)-binding domain and which was not associated
      with oocyte membranes, also failed to induce GVBD. Furthermore, injection of rat
      beta-arrestin-2 mRNA also induced hormone-independent GVBD. Several inhibitors of
      clathrin-mediated receptor endocytosis (the clathrin-binding domain of beta
      arrestin-2, concanavalin A, and monodansyl cadaverine) significantly reduced the
      abilities of GRK3/beta-arrestin-2 to induce GVBD. These results support the
      central role of a yet-unidentified GpCR in maintaining prophase arrest in frog
      oocytes and provide a potential means for its molecular identification.

PMID- 12600993
TI  - Human replication protein A. The C-terminal RPA70 and the central RPA32 domains
      are involved in the interactions with the 3'-end of a primer-template DNA.
AB  - Although the mechanical aspects of the single-stranded DNA (ssDNA) binding
      activity of human replication protein A (RPA) have been extensively studied, only
      limited information is available about its interaction with other physiologically
      relevant DNA structures. RPA interacts with partial DNA duplexes that resemble
      DNA intermediates found in the processes of DNA replication and DNA repair.
      Limited proteolysis of RPA showed that RPA associated with ssDNA is less
      protected against proteases than RPA bound to a partial duplex DNA containing a
      5'-protruding tail that had the same length as the ssDNA. Modification of both
      the 70- and 32-kDa subunits, RPA70 and RPA32, respectively, by photoaffinity
      labeling indicates that RPA can bind the primer-template junction of partial
      duplex DNAs by interacting with the 3'-end of the primer. The identification of
      the protein domains modified by the photoreactive 3'-end of the primer showed
      that domains located in the central part of the RPA32 subunit (amino acids 39
      180) and the C-terminal part of the RPA70 subunit (amino acids 432-616) are
      involved in these interactions.

PMID- 12600994
TI  - Genomic correlates of hyperthermostability, an update.
AB  - It has been shown (Cambillau, C., and Claverie, J. M. (2000) J. Biol. Chem. 275,
      32383-32386) that a large difference between the proportions of charged versus
      polar (non-charged) amino acids (CvP-bias) was an adequate, if empirical,
      signature of the proteome of hyperthermophilic organisms (T(growth) >80 degrees
      C). Since that study, the number of available microbial genomes has more than
      doubled, raising the possibility that the simple CvP-bias rule might no longer
      hold. Taking advantage of the new sequence data, we re-analyzed the genomes of 9
      fully sequenced thermophiles, 9 hyperthermophiles, and 53 mesothermophile
      microorganisms to identify the genomic correlates of hyperthermostability on a
      wider data set. Our new results confirm that the CvP-bias previously identified
      on a much smaller data set still holds. Moreover, we show that it is an optimal
      criterion, in the sense that it corresponds to the most discriminating factor
      between hyperthermophilic and mesothermophilic microorganisms in a principal
      component analysis. In parallel, we evaluated two other recently proposed
      correlates of hyperthermostability, the proteome average pI and the dinucleotide
      statistical index (Kawashima, T., Amano, N., Koike, H., Makino, S., Higuchi, S.,
      Kawashima-Ohya, Y., Watanabe, K., Yamazaki, M., Kanehori, K., Kawamoto, T.,
      Nunoshiba, T., Yamamoto, Y., Aramaki, H., Makino, K., and Suzuki, M. (2000) Proc.
      Natl. Acad. Sci. 97, 14257-14262). We show that the CvP-bias is the sole
      criterion that is able to clearly discriminate hyperthermophile from
      mesothermophile microorganisms on a global genomic basis.

PMID- 12600995
TI  - An inverse correlation between expression of a preprocathepsin B-related protein
      with cysteine-rich sequences and steroid 11beta -hydroxylase in adrenocortical
      cells.
AB  - A cDNA encoding a secretory protein hitherto unknown was cloned from mouse
      adrenocortical cells by subtractive hybridization between the cells without and
      with expressing steroid 11beta-hydroxylase (Cyp11b-1), a marker for the
      functional differentiation of cells in the zonae fasciculata reticularis (zFR).
      The deduced protein consisting of 466 amino acids contained a secretory signal,
      epidermal growth factor-like repeats, and a proteolytically inactive cathepsin B
      related sequence. The amino acid sequence was 89% identical with that of human
      tubulointerstitial nephritis antigen-related protein. Among the mouse organs
      examined, adrenal glands prominently expressed its mRNA. The mRNA and its encoded
      protein were detected in the outer adrenocortical zones that do not express
      Cyp11b-1, i.e. the zona glomerulosa and the undifferentiated cell zone, while
      being undetectable in zFR that express Cyp11b-1. The new protein was designated
      as adrenocortical zonation factor 1 (AZ-1). Clonal lines with different levels of
      AZ-1 expression were established from Y-1 adrenocortical cells that originally
      express Cyp11b-1 but little AZ-1. Analyses of the clonal lines revealed that
      Cyp11b-1 is detected in the clonal lines maintaining little AZ-1 expression and
      becomes undetectable in those expressing AZ-1. On the other hand, irrespective of
      the AZ-1 expression, all clones expressed cholesterol side-chain cleavage enzyme,
      which occurs throughout the cortical zones. These results demonstrated that
      adrenocortical cells expressing AZ-1 do not express Cyp11b-1, whereas those with
      little AZ-1 express this zFR marker in vitro and in vivo, implying a putative
      role of AZ-1 in determining the zonal differentiation of adrenocortical cells.

PMID- 12600996
TI  - High affinity ligand binding by integrins does not involve head separation.
AB  - Conformational change in the integrin extracellular domain is required for high
      affinity ligand binding and is also involved in post-ligand binding cellular
      signaling. Although there is evidence to the contrary, electron microscopic
      studies showing that ligand binding triggers alpha- and beta-subunit dissociation
      in the integrin headpiece have gained popularity and support the hypothesis that
      head separation activates integrins. To test directly the head separation
      hypothesis, we enforced head association by introducing disulfide bonds across
      the interface between the alpha-subunit beta-propeller domain and the beta
      subunit I-like domain. Basal and activation-dependent ligand binding by
      alpha(IIb)beta(3) and alpha(V)beta(3) was unaffected. The covalent linkage
      prevented dissociation of alpha(IIb)beta(3) into its subunits on EDTA-treated
      cells. Whereas EDTA dissociated wild type alpha(IIb)beta(3) on the cell surface,
      a ligand-mimetic Arg-Gly-Asp peptide did not, as judged by binding of complex
      specific antibodies. Finally, a high affinity ligand-mimetic compound stabilized
      noncovalent association between alpha(IIb) and beta(3) headpiece fragments in the
      presence of SDS, indicating that ligand binding actually stabilized subunit
      association at the head, as opposed to the suggested subunit separation. The
      mechanisms of conformational regulation of integrin function should therefore be
      considered in the context of the associated alphabeta headpiece.

PMID- 12600998
TI  - A developmentally regulated two-component signal transduction system in
      Chlamydia.
AB  - Two-component systems allow bacteria to adapt to changing environmental
      conditions and may induce developmental changes necessary for survival. Chlamydia
      trachomatis alternates between two distinct developmental forms, each optimized
      for survival in a separate niche. Transcriptional regulation of development is
      not understood. The C. trachomatis genome sequence revealed a single pair of
      genes (ctcB-ctcC) predicted to encode proteins with sequence conservation to
      bacterial two-component systems. Sequence analysis revealed that the sensor
      kinase, CtcB, possessed an energy-sensing PAS domain and phosphorylation site.
      The response regulator, CtcC, had homology to sigma(54) activators, possessing
      conserved receiver and ATPase domains and phosphorylation site, but lacked the C
      terminal DNA-binding domain. ctcB and ctcC were expressed late in the
      developmental cycle, and both proteins were detected in EB lysates. Recombinant
      CtcB and CtcC were purified from denatured Escherichia coli inclusion bodies and
      refolded. CtcC was found to aggregate as dimers and tetramers in solution. In
      vitro phosphorylation assays showed that CtcB autophosphorylated in the presence
      of Mg(2+), Mn(2+), and Fe(2+) and transferred the phosphoryl group in the
      presence of CtcC. Collectively, these results show that CtcB and CtcC function as
      a two-component system and are likely responsible for transcriptional regulation
      by sigma(54) holoenzyme during late-stage chlamydial development.

PMID- 12600997
TI  - Interactions of the non-coding RNA DsrA and RpoS mRNA with the 30 S ribosomal
      subunit.
AB  - Expression of sigma(s), the gene product of rpoS, is controlled translationally
      in response to many environmental stresses. DsrA, a small 87-nucleotide non
      coding RNA molecule, acts to increase translational efficiency of RpoS mRNA under
      some growth conditions. In this work, we demonstrate that DsrA binds directly to
      the 30 S ribosomal subunit with an observed equilibrium affinity of 2.8 x 10(7)
      m(-1). DsrA does not compete with RpoS mRNA or tRNA(f)(Met) for binding to the 30
      S subunit. The 5' end of DsrA binds to 30 S subunits with an observed equilibrium
      association constant of 2.0 x 10(6) m(-1), indicating that the full affinity of
      the interaction requires the entire DsrA sequence. In order to investigate
      translational efficiency of RpoS mRNA, we examined both ribosome-binding site
      accessibility and the binding of RpoS mRNA to 30 S ribosomal subunits. We find
      that that ribosome-binding site accessibility is modulated as a function of
      divalent cation concentration during mRNA renaturation and by the presence of an
      antisense sequence that binds to nucleotides 1-16 of the RpoS mRNA fragment. The
      ribosome-binding site accessibility correlates with the amount of RpoS mRNA
      participating in 30 S-mRNA "pre-initiation" translational complex formation and
      provides evidence that regulation follows a competitive model of regulation.

PMID- 12600999
TI  - Hypertonicity-induced aquaporin-1 (AQP1) expression is mediated by the activation
      of MAPK pathways and hypertonicity-responsive element in the AQP1 gene.
AB  - Aquaporin-1 (AQP1) is a water channel that is induced by hypertonicity. The
      present study was undertaken to clarify the osmoregulation mechanism of AQP1 in
      renal medullary cells. In cultured mouse medullary (mIMCD-3) cells, AQP1
      expression was significantly induced by hypertonic treatment with impermeable
      solutes, whereas urea had no effect on AQP1 expression. This result indicates the
      requirement of a hypertonic gradient. Hypertonicity activated ERK, p38 kinase,
      and JNK in mIMCD-3 cells. Furthermore, all three MAPKs were phosphorylated by the
      upstream activation of MEK1/2, MKK3/6, and MKK4, respectively. The treatments
      with MEK inhibitor U0126, p38 kinase inhibitor SB203580, and JNK inhibitor
      SP600125 significantly attenuated hypertonicity-induced AQP1 expression in mIMCD
      3 cells. In addition, hypertonicity-induced AQP1 expression was significantly
      reduced by both the dominant-negative mutants of JNK1- and JNK2-expressing mIMCD
      3 cells. NaCl-inducible activity of AQP1 promoter, which contains a hypertonicity
      response element, was attenuated in the presence of U0126, SB203580, and SP600125
      in a dose-dependent manner and was also significantly reduced by the dominant
      negative mutants of JNK1 and JNK2. These data demonstrate that the activation of
      ERK, p38 kinase, and JNK pathways and the hypertonicity response element in the
      AQP1 promoter are involved in hypertonicity-induced AQP1 expression in mIMCD-3
      cells.

PMID- 12601000
TI  - RNA polyadenylation and degradation in cyanobacteria are similar to the
      chloroplast but different from Escherichia coli.
AB  - The mechanism of RNA degradation in Escherichia coli involves endonucleolytic
      cleavage, polyadenylation of the cleavage product by poly(A) polymerase, and
      exonucleolytic degradation by the exoribonucleases, polynucleotide phosphorylase
      (PNPase) and RNase II. The poly(A) tails are homogenous, containing only
      adenosines in most of the growth conditions. In the chloroplast, however, the
      same enzyme, PNPase, polyadenylates and degrades the RNA molecule; there is no
      equivalent for the E. coli poly(A) polymerase enzyme. Because cyanobacteria is a
      prokaryote believed to be related to the evolutionary ancestor of the
      chloroplast, we asked whether the molecular mechanism of RNA polyadenylation in
      the Synechocystis PCC6803 cyanobacteria is similar to that in E. coli or the
      chloroplast. We found that RNA polyadenylation in Synechocystis is similar to
      that in the chloroplast but different from E. coli. No poly(A) polymerase enzyme
      exists, and polyadenylation is performed by PNPase, resulting in heterogeneous
      poly(A)-rich tails. These heterogeneous tails were found in the amino acid coding
      region, the 5' and 3' untranslated regions of mRNAs, as well as in rRNA and the
      single intron located at the tRNA(fmet). Furthermore, unlike E. coli, the
      inactivation of PNPase or RNase II genes caused lethality. Together, our results
      show that the RNA polyadenylation and degradation mechanisms in cyanobacteria and
      chloroplast are very similar to each other but different from E. coli.

PMID- 12601001
TI  - Light and X-ray scattering show decorin to be a dimer in solution.
AB  - Decorin is a widely distributed member of the extracellular matrix small leucine
      rich repeat glycoprotein/proteoglycan family. For investigation of its physical
      properties, decorin from two sources (young steer skin and a recombinant
      adenovirus) was used. The first sample was extracted into 7 m urea and purified,
      while the second was isolated from medium conditioned by 293A cells infected with
      adenovirus and purified without chaotropes. The only chemical differences
      detected between these materials were a slightly shorter glycosaminoglycan chain
      and the retention of the propeptide on the latter. Circular dichroism spectra of
      the two samples were virtually identical, showing a high proportion of beta-sheet
      and beta-turn and little alpha-helix. The protein cores were completely denatured
      in 2.25 m guanidine HCl (GdnHCl) but recovered their secondary structure on
      removal of chaotrope. Light scattering of material eluted from gel-filtration
      columns in Tris-buffered saline, pH 7.0, gave molecular mass values of 165 +/- 1
      kDa and 84.6 +/- 4 kDa for intact decorin and the glycoprotein core produced by
      digestion with chondroitin ABC lyase, respectively. Intact recombinant prodecorin
      had a mass of 148 +/- 18 kDa. These values, which are double those estimated from
      SDS gel electrophoresis or from the known sequences and compositions, were halved
      in 2.5 m GdnHCl. Data from solution x-ray scattering of intact decorin and its
      core in Tris-buffered saline are consistent with a dimeric particle whose protein
      component has a radius of gyration of 31.6 +/- 0.4 A, a maximum diameter of 98 +/
      5 A, and approximates two intertwined C shapes.

PMID- 12601002
TI  - Diurnal pineal 3-O-sulphotransferase 2 expression controlled by beta-adrenergic
      repression.
AB  - The 3-O-sulfotransferases (3OSTs) catalyze the addition of sulfate groups at the
      3-OH site of glucosamine in heparan sulfate proteoglycans, which serve as
      critical mediators of various biological functions. We demonstrate that the 3OST2
      isoform is expressed at high levels in the rat pineal specifically during the
      daylight hours. The dramatic diurnal rhythm of 3OST2 is regulated by central
      clock-controlled activities of the superior cervical ganglion, persists in
      constant darkness, and is inducible by light at nighttime. Importantly, 3OST2
      transcription is blocked by beta-adrenergic agonists that activate the pineal
      melatonin formation and is induced by beta-adrenergic antagonists, which block
      melatonin production in vivo. Because of the inverse expression and regulation
      patterns of 3OST2 with serotonin N-acetyltransferase, the enzyme controlling the
      melatonin rhythm in the pineal, we tested the effects of forced expression of
      3OST2 in the night pineals on N-acetyltransferase gene expression and melatonin
      production and found that, surprisingly, 3OST2 expression at night fails to
      interfere with melatonin synthesis. These data suggest 3OST2 may serve a unique
      function in the pineal that may be independent of melatonin formation.

PMID- 12601003
TI  - Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP
      binding cassette transporters G5 and G8.
AB  - Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in
      orchestrating the trafficking of sterols between tissues. Treatment of mice with
      a potent and specific LXR agonist, T0901317, is associated with increased biliary
      cholesterol secretion, decreased fractional cholesterol absorption, and increased
      fecal neutral sterol excretion. Here we show that expression of two target genes
      of LXRalpha, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is
      required for both the increase in sterol excretion and the decrease in fractional
      cholesterol absorption associated with LXR agonist treatment. Mice expressing no
      ABCG5 and ABCG8 (G5G8(-/-) mice) and their littermate controls were treated for 7
      days with T0901317. In wild type animals, treatment with the LXR agonist resulted
      in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in
      fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol
      excretion. In contrast, the LXR agonist did not significantly affect biliary
      cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol
      excretion in the G5G8(-/-) mice. Thus Abcg5 and Abcg8 are required for LXR
      agonist-associated changes in dietary and biliary sterol trafficking. These
      results establish a central role for ABCG5 and ABCG8 in promoting cholesterol
      excretion in vivo.

PMID- 12601004
TI  - Evidence for a functional interaction between the ClC-2 chloride channel and the
      retrograde motor dynein complex.
AB  - The ClC-2 chloride channel has been implicated in essential physiological
      functions. Analyses of ClC-2 knock-out mice suggest that ClC-2 expression in
      retinal pigment epithelia and Sertoli cells normally supports the viability of
      photoreceptor cells and male germ cells, respectively. Further, other studies
      suggest that ClC-2 expression in neurons may modify inhibitory synaptic
      transmission via the gamma-aminobutyric acid, type A receptor. However, complete
      understanding of the physiological functions of ClC-2 requires elucidation of the
      molecular basis for its regulation. Using cell imaging and biochemical and
      electrophysiological techniques, we show that expression of ClC-2 at the cell
      surface may be regulated via an interaction with the dynein motor complex. Mass
      spectrometry and Western blot analysis of eluate from a ClC-2 affinity matrix
      showed that heavy and intermediate chains of dynein bind ClC-2 in vitro. The
      dynein intermediate chain co-immunoprecipitates with ClC-2 from hippocampal
      membranes suggesting that they also interact in vivo. Disruption of dynein motor
      function perturbs ClC-2 localization and increases the functional expression of
      ClC-2 in the plasma membranes of COS7 cells. Thus, cell surface expression of ClC
      2 may be regulated by dynein motor activity. This work is the first to
      demonstrate an in vivo interaction between an ion channel and the dynein motor
      complex.

PMID- 12601005
TI  - Vectorial acylation in Saccharomyces cerevisiae. Fat1p and fatty acyl-CoA
      synthetase are interacting components of a fatty acid import complex.
AB  - In Saccharomyces cerevisiae Fat1p and fatty acyl-CoA synthetase (FACS) are
      hypothesized to couple import and activation of exogenous fatty acids by a
      process called vectorial acylation. Molecular genetic and biochemical studies
      were used to define further the functional and physical interactions between
      these proteins. Multicopy extragenic suppressors were selected in strains
      carrying deletions in FAA1 and FAA4 or FAA1 and FAT1. Each strain is unable to
      grow under synthetic lethal conditions when exogenous long-chain fatty acids are
      required, and neither strain accumulates the fluorescent long-chain fatty acid
      C(1)-BODIPY-C(12) indicating a fatty acid transport defect. By using these
      phenotypes as selective screens, plasmids were identified encoding FAA1, FAT1,
      and FAA4 in the faa1Delta faa4Delta strain and encoding FAA1 and FAT1 in the
      faa1Delta fat1Delta strain. Multicopy FAA4 could not suppress the growth defect
      in the faa1Delta fat1Delta strain indicating some essential functions of Fat1p
      cannot be performed by Faa4p. Chromosomally encoded FAA1 and FAT1 are not able to
      suppress the growth deficiencies of the fat1Delta faa1Delta and faa1Delta
      faa4Delta strains, respectively, indicating Faa1p and Fat1p play distinct roles
      in the fatty acid import process. When expressed from a 2-mu plasmid, Fat1p
      contributes significant oleoyl-CoA synthetase activity, which indicates vectorial
      esterification and metabolic trapping are the driving forces behind import.
      Evidence of a physical interaction between Fat1p and FACS was provided using
      three independent biochemical approaches. First, a C-terminal peptide of Fat1p
      deficient in fatty acid transport exerted a dominant negative effect against long
      chain acyl-CoA synthetase activity. Second, protein fusions employing Faa1p as
      bait and portions of Fat1p as trap were active when tested using the yeast two
      hybrid system. Third, co-expressed, differentially tagged Fat1p and Faa1p or
      Faa4p were co-immunoprecipitated. Collectively, these data support the hypothesis
      that fatty acid import by vectorial acylation in yeast requires a multiprotein
      complex, which consists of Fat1p and Faa1p or Faa4p.

PMID- 12601006
TI  - The epidermal platelet-activating factor receptor augments chemotherapy-induced
      apoptosis in human carcinoma cell lines.
AB  - Most chemotherapeutic agents exert their cytotoxic effects in part through the
      induction of apoptosis. In addition, many chemotherapeutic agents are potent pro
      oxidative stressors. Although the lipid mediator platelet-activating factor (PAF)
      is synthesized in response to oxidative stress, and many epidermal carcinomas
      express PAF receptors, it is not known whether PAF is involved in
      chemotherapeutic agent-induced apoptosis. These studies examined the role of the
      PAF system in chemotherapy-mediated cytotoxicity using model systems created by
      retroviral mediated transduction of the PAF receptor-negative human epidermal
      carcinoma cell line KB with the human PAF receptor (PAF-R) and ablation of the
      endogenous PAF-R in the carcinoma cell line HaCaT with a retroviral mediated
      inducible antisense PAF-R vector. The presence of the PAF-R in these models
      resulted in an augmentation of apoptosis induced by chemotherapeutic agents
      etoposide and mitomycin C but not by tumor necrosis factor-related apoptosis
      inducing ligand or by C(2) ceramide. Oxidative stress and the transcription
      factor nuclear factor kappaB (NF-kappaB) are found to be involved in this
      augmentative effect because it was blocked by antioxidants and inhibition of the
      NF-kappaB pathway using a super-repressor form of inhibitor B. These studies
      provide evidence for a novel pathway whereby the epidermal PAF-R can augment
      chemotherapy-induced apoptotic effects through an NF-kappaB-dependent process.

PMID- 12601007
TI  - Calcium- and cell cycle-dependent association of annexin 11 with the nuclear
      envelope.
AB  - Annexin 11 is a widely expressed calcium- and phospholipid-binding protein that
      resides in the nucleoplasm in many cultured cell lines. This is in contrast to
      its most extensively characterized in vitro ligand, the small calcium-binding
      protein S100A6 (calcyclin), which is concentrated in the nuclear envelope. Here
      we have examined the significance of the association of annexin 11 and S100A6 by
      asking whether circumstances exist in which the two proteins occupy the same
      subcellular localization. First, we show that in both A431 and vascular smooth
      muscle cells, elevation of intracellular Ca2+ leads to translocation of annexin
      11 from the nucleus to the nuclear envelope where it co-localizes with S100A6. We
      also demonstrate, using fusions of annexin 11 with green fluorescent protein,
      that whereas the C-terminal core domain of annexin 11 is essential for Ca2+
      sensitivity, the N-terminal domain is required for targeting to the nuclear
      envelope. Second, we show that annexin 11 relocalizes to the nuclear envelope as
      A431 cells transit from early to mid-prophase. In late prophase, at the time of
      nuclear envelope breakdown, annexin 11 and S100A6 become intensely localized with
      lamina-associated polypeptide 2 to folds in the nuclear envelope. From metaphase
      to telophase S100A6 is degraded, but in late telophase annexin 11 associates with
      the reforming nuclear envelope before resuming a nucleoplasmic location in
      interphase. These results show that co-localization of annexin 11 and S100A6 at
      the nuclear envelope may be regulated either by elevation of intracellular Ca2+
      or by cell cycle progression and provide the first evidence that these proteins
      may associate in vivo.

PMID- 12601008
TI  - Nevirapine resistance mutation at codon 181 of the HIV-1 reverse transcriptase
      confers stavudine resistance by increasing nucleotide substrate discrimination
      and phosphorolytic activity.
AB  - Recombinant HIV-1 reverse transcriptase (RT) carrying non-nucleoside inhibitors
      (NNRTIs) resistance mutation at codon 181 showed reduced incorporation and high
      efficiency of phosphorolytic removal of stavudine, a nucleoside RT inhibitor.
      These results reveal a new mechanism for cross-resistance between different
      classes of HIV-1 RT inhibitors.

PMID- 12601010
TI  - A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12I
      functions to modulate nuclear factor of activated T cell activation.
AB  - The PXIXIT calcineurin binding motif or highly related sequences are found in a
      variety of calcineurin-binding proteins in yeast, mammalian cells, and viruses.
      The accessory protein p12(I) encoded in the HTLV-1 pX ORF I promotes T cell
      activation during the early stages of HTLV-1 infection by activating nuclear
      factor of activated T cells (NFAT) through calcium release from the endoplasmic
      reticulum. We identified in p12(I), a conserved motif, which is highly homologous
      with the PXIXIT calcineurin-binding motif of NFAT. Both immunoprecipitation and
      calmodulin agarose bead pull-down assays indicated that wild type p12(I) and
      mutants of p12(I) that contained the motif-bound calcineurin. In addition, an
      alanine substitution p12(I) mutant (p12(I) AXAXAA) had greatly reduced binding
      affinity for calcineurin. We then tested whether p12(I) binding to calcineurin
      affected NFAT activity. p12(I) competed with NFAT for calcineurin binding in
      calmodulin bead pull-down experiments. Furthermore, the p12(I) AXAXAA mutant
      enhanced NFAT nuclear translocation compared with wild type p12(I) and increased
      NFAT transcriptional activity 2-fold greater than wild type p12(I). Similar to
      NFAT, endogenous calcineurin phosphatase activity was increased in Jurkat T cells
      expressing p12(I) independent of its calcineurin binding property. Thus, the
      reduced binding of p12(I) to calcineurin allows enhanced nuclear translocation
      and transcription mediated by NFAT. Herein, we are the first to identify a
      retroviral protein that binds calcineurin. Our data suggest that HTLV-1 p12(I)
      modulates NFAT activation to promote early virus infection of T lymphocytes,
      providing a novel mechanism for retrovirus-mediated cell activation.

PMID- 12601009
TI  - Mutations in the immunoglobulin-like domain of gp190, the leukemia inhibitory
      factor (LIF) receptor, increase or decrease its affinity for LIF.
AB  - The leukemia inhibitory factor (LIF) receptor comprises the low affinity binding
      chain gp190 and the high affinity converter gp130. The ectodomain of gp190 is
      among the most complex in the hematopoietin receptor family, because it contains
      two typical cytokine receptor homology domains separated by an immunoglobulin
      like (Ig-like) domain. Human and murine gp190 proteins share 76% homology, but
      murine gp190 binds human LIF with a much higher affinity, a property attributed
      to the Ig-like domain. Using alanine-scanning mutagenesis of the Ig-like domain,
      we mapped a LIF binding site at its carboxyl terminus, mainly involving residue
      Phe-328. Mutation of selected residues into their orthologs in the murine
      receptor (Q251E and N321D) significantly increased the affinity for human LIF.
      Interestingly, these residues, although localized at both the amino and carboxyl
      terminus, make a spatially unique LIF binding site in a structural model of the
      Ig-like module. These results demonstrate definitively the role of the Ig-like
      domain in LIF binding and the potential to modulate receptor affinity in this
      family with very limited amino acid changes.

PMID- 12601011
TI  - Interactions of the cbbII promoter-operator region with CbbR and RegA (PrrA)
      regulators indicate distinct mechanisms to control expression of the two cbb
      operons of Rhodobacter sphaeroides.
AB  - In a previous study (Dubbs, J. M., Bird, T. H., Bauer, C. E., and Tabita, F. R.
      (2000) J. Biol. Chem. 275, 19224-19230), it was demonstrated that the regulators
      CbbR and RegA (PrrA) interacted with both promoter proximal and promoter distal
      regions of the form I (cbb(I)) promoter operon specifying genes of the Calvin
      Benson-Bassham cycle of Rhodobacter sphaeroides. To determine how these
      regulators interact with the form II (cbb(II)) promoter, three cbbF(II)::lacZ
      translational fusion plasmids were constructed containing various lengths of
      sequence 5' to the cbb(II) operon of R. sphaeroides CAC. Expression of beta
      galactosidase was monitored under a variety of growth conditions in both the
      parental strain and knock-out strains that contain mutations that affect
      synthesis of CbbR and RegA. The binding sites for both CbbR and RegA were
      determined by DNase I footprinting. A region of the cbb(II) promoter from +38 to 
      227 bp contained a CbbR binding site and conferred low level regulated cbb(II)
      expression. The region from -227 to -1025 bp contained six RegA binding sites and
      conferred enhanced cbb(II) expression under all growth conditions. Unlike the
      cbb(I) operon, the region between -227 and -545 bp that contains one RegA binding
      site, was responsible for the majority of the observed enhancement. Both RegA and
      CbbR were required for maximal cbb(II) expression. Two potentially novel and
      specific cbb(II) promoter-binding proteins that did not interact with the cbb(I)
      promoter region were detected in crude extracts of R. sphaeroides. These results,
      combined with the observation that chemoautotrophic expression of the cbb(I)
      operon is RegA independent, indicated that the mechanisms controlling cbb(I) and
      cbb(II) operon expression during chemoautotrophic growth are quite different.

PMID- 12601012
TI  - P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential
      negative regulator of eIF2alpha signaling.
AB  - The unfolded protein response, which is activated in response to the loss of
      endoplasmic reticulum (ER) Ca(2+) homeostasis and/or the accumulation of
      misfolded, unassembled, or aggregated proteins in the ER lumen, involves both
      transcriptional and translational regulation. In the current studies we sought to
      identify novel ER stress-induced genes by conducting microarray analysis on
      tunicamycin-treated cells. We identified P58(IPK), an inhibitor of the interferon
      induced double-stranded RNA-activated protein kinase, as induced during ER
      stress. Additional studies suggested that p58(IPK) induction was mediated via
      ATF6 and that P58(IPK) played a role in down-regulating the activity of the
      pancreatic eIF2 kinase/eukaryotic initiation factor 2alpha (eIF2alpha)-like ER
      kinase/activation transcription factor (ATF) 4 pathway. Modulation of P58(IPK)
      levels altered the phosphorylation status of eIF2alpha, and thereby affected
      expression of its downstream targets, ATF4 and Gadd153. Overexpression of
      P58(IPK) inhibited eIF2alpha phosphorylation and reduced ATF4 and Gadd153 protein
      accumulation, whereas silencing of P58(IPK) expression enhanced pancreatic
      eIF2alpha-like ER kinase and eIF2alpha phosphorylation and increased ATF4 and
      Gadd153 accumulation. These findings implicate P58(IPK) as an important component
      of a negative feedback loop used by the cell to inhibit eIF2alpha signaling, and
      thus attenuate the unfolded protein response.

PMID- 12601014
TI  - Ocular growth and refractive error development in premature infants without
      retinopathy of prematurity.
AB  - PURPOSE: This investigation studied the factors involved in the development of
      refractive error (RE) in premature infants unaffected by retinopathy of
      prematurity (ROP). METHODS: Premature infants enrolled in the national ROP
      screening program were recruited and examined at 32, 36, 40, 44, and 52 weeks'
      postmenstrual age. At each examination, axial length (AXL), anterior chamber
      depth (ACD), and lens thickness (LT) were measured on the A-scan biometer.
      Corneal curvature (CC) was recorded with a video-ophthalmophakometer, and
      refractive state was determined with routine cycloplegic refraction. Multilevel
      modeling techniques were used to determine the relationships between all the
      variables throughout the study period, as well as individual growth rates.
      RESULTS: Sixty-eight premature infants were included. AXL and ACD showed linear
      patterns of growth, whereas LT changed little over the study period. CC showed a
      quadratic growth pattern, and unlike the previous variables, correlated well with
      refractive state. Premature infants were myopes at the start of the study, with
      refraction becoming emmetropic as they neared full term and then hypermetropic
      toward the end of the study. CONCLUSIONS: Most of the components of refractive
      status showed linear patterns of growth during this early phase of ocular
      development. CC displayed a more complex pattern of growth, which correlated well
      with refractive state. Compared with full-term infants examined around term, this
      group has shorter AXLs, shallower anterior chambers, and more highly curved
      corneas. In addition, less of the expected hypermetropia developed in the
      premature group, which seems mainly due to the differences in ACD and corneal
      curvature.

PMID- 12601013
TI  - Xanthophyll binding sites of the CP29 (Lhcb4) subunit of higher plant photosystem
      II investigated by domain swapping and mutation analysis.
AB  - The binding sites for xanthophylls in the CP29 antenna protein of higher plant
      Photosystem II have been investigated using recombinant proteins refolded in
      vitro. Despite the presence of three xanthophyll species CP29 binds two
      carotenoids per polypeptide. The localization of neoxanthin was studied producing
      a chimeric protein constructed by swapping the C-helix domain from CP29 to LHCII.
      The resulting holoprotein did not bind neoxanthin, confirming that the N1 site is
      not present in CP29. Neoxanthin in CP29 was, instead, bound to the L2 site, which
      is thus shown to have a wider specificity with respect to the homologous site L2
      in LHCII. Lutein was found in the L1 site of CP29. For each site the selectivity
      for individual xanthophyll species was studied as well as its role in protein
      stabilization, energy transfer, and photoprotection. Putative xanthophyll binding
      sequences, identified by primary structure analysis as a stretch of hydrophobic
      residues including an acidic term, were analyzed by site-directed mutagenesis or,
      in one case, by deleting the entire sequence. The mutant proteins were unaffected
      in their xanthophyll composition, thus suggesting that the target motifs had
      little influence in determining xanthophyll binding, whereas hydrophobic
      sequences in the membrane-spanning helices are important.

PMID- 12601015
TI  - Ultrastructural localization of the HNK-1 carbohydrate epitope to glial and
      neuronal cells of the human retina.
AB  - PURPOSE: To localize the cell adhesion-related HNK-1 carbohydrate epitope in the
      human retina at cellular and subcellular levels. METHODS: Retinas were obtained
      from seven normal human eyes at autopsy (age, 43-78 years). The specimens were
      embedded in medium-grade resin and studied by postembedding immunoelectron
      microscopy using the primary mouse mAb HNK-1 (Leu 7) to the HNK-1 epitope and
      secondary antibodies conjugated to 10-nm colloidal gold particles. RESULTS:
      Prominent immunolabeling with mAb HNK-1 was observed on the outer surface of the
      entire plasma membrane of Muller radial glial cells, including their microvilli
      between the inner segments of rods and cones, on the plasma membranes of
      astrocytes in the ganglion cell layer, in bipolar cells in the inner nuclear
      layer, and in photoreceptor cells in the outer nuclear layer. Fewer gold
      particles were present on plasma membranes of other main types of retinal
      neurons, including ganglion cells. Only the outer segments of rods and cones and
      the endothelial cells of retinal capillaries were never labeled. In the ciliary
      epithelium, gold particles localized to the basement membrane of the nonpigmented
      and pigmented layers and to the cytoplasm of the pigmented epithelium.
      CONCLUSIONS: Unlike in many other species, the HNK-1 epitope in the human retina
      is found on both glial and neuronal cells, including photoreceptors. This epitope
      potentially contributes to neuron-to-neuron and glia-to-neuron adhesion of human
      retinal cells.

PMID- 12601016
TI  - Mosaic regularity of horizontal cells in the mouse retina is independent of cone
      photoreceptor innervation.
AB  - PURPOSE: To determine whether the density and the mosaic regularity of the
      population of horizontal cells is dependent on innervation from the cone
      photoreceptors by comparing these features in wild-type and transgenic mice
      expressing an attenuated diphtheria toxin in the cones. METHODS: Retinal
      wholemounts from coneless transgenic mice and their wild-type littermates were
      immunostained for calbindin or for cone opsins, and labeled cells and outer
      segments were counted to determine horizontal cell and photoreceptor density. The
      x-y positional coordinates of each horizontal cell were also determined, from
      which the geometrical properties of the horizontal cell mosaic were examined
      using nearest-neighbor and Voronoi domain analyses. Autocorrelation and density
      recovery profile analyses were also conducted to identify the presence of
      exclusion zones within the population of horizontal cells. For each sampled
      field, random simulations of matched density, constrained by the physical size of
      the horizontal cells, were generated in parallel and analyzed with the real data.
      RESULTS: Coneless mice were confirmed to contain only 3% of the normal cone
      photoreceptor population. Despite the loss of these afferents, horizontal cell
      density did not differ between the wild-type and coneless retinas. Mosaic
      regularity in wild-type and coneless retinas did not differ, but each differed
      significantly from random simulations of identical density. Horizontal cells in
      both the wild-type and coneless mouse retina exhibited exclusion zones extending
      beyond the physical size of the soma, suggested to reflect intercellular
      interactions during early development that drive tangential dispersion; these
      were slightly larger in the wild-type retina. CONCLUSIONS: Cone innervation is
      not a necessary condition for horizontal cell survival during postnatal
      development. The resiliency of the regularity in the horizontal cell mosaic is
      consistent with the hypothesis that such global patterning is an emergent
      property of these cells as they engage in local interactions that are largely
      independent of their afferent innervation.

PMID- 12601018
TI  - Expression of somatostatin receptors in uveal melanomas.
AB  - PURPOSE: To investigate the distribution of somatostatin receptor (SSR) subtypes
      2, 3, and 5 in uveal melanomas and their diagnostic and possible therapeutic
      value. METHODS: SSRs were investigated in 25 paraffin-embedded eyes with uveal
      melanomas and in 6 normal eyes without any disease, by using polyclonal antiserum
      directed to SSR2A, -2B, -3, and -5. Antigen expression was evaluated by a
      semiquantitative method. The expression pattern of SSR was correlated with the
      patients' ad vitam prognosis by use of the Kaplan-Meier survival curve. Six
      different human melanoma cell lines were incubated with octreotide and
      vapreotide, and a proliferation assay was performed by determining [(3)H]-TdR
      uptake. [111-Indium-DTPA-D-Phe1]-octreotide scintigraphy was performed in the
      eyes of four patients with known uveal melanomas. RESULTS: All uveal melanomas
      were positive for SSR2. SSR2A was expressed in 15 of 25, SSR2B in 23 of 25, SSR3
      in 7 of 25, and SSR5 in 13 of 25 uveal melanomas. A Kaplan-Meier survival curve
      showed a significantly better ad vitam prognosis for patients with tumors
      expressing high levels of SSR2. Cell proliferation was inhibited up to 36% +/- 6%
      in three of six melanoma cell lines at a concentration of 10(-4) M octreotide or
      vapreotide. Eyes of two patients with uveal melanomas showed positive uptake of
      [111-Indium-DTPA-D-Phe1]-octreotide. CONCLUSIONS: SSR2, -3, and -5 are expressed
      in human uveal melanomas and patients with a high amount of SSR2 in the melanoma
      tissue have a better ad vitam prognosis. Because a melanoma cell proliferation
      assay showed an inhibitory effect of up to 36% +/- 6% using octreotide or
      vapreotide, somatostatin analogues may be beneficial in the treatment of patients
      with ocular melanomas.

PMID- 12601017
TI  - COX-2 inhibition and retinal angiogenesis in a mouse model of retinopathy of
      prematurity.
AB  - PURPOSE: The prostaglandin-cyclooxygenase (COX) pathway influences new blood
      vessel growth in a variety of tissues. This study was conducted to determine the
      cellular location of COX-2 in the retina and whether the inhibition of COX-2
      would reduce retinal angiogenesis in a rodent model of retinopathy of prematurity
      (ROP). METHODS: ROP was induced in C57BL/6 mice by exposing 7-day-old mice to 75%
      oxygen (hyperoxia) for 5 days followed by 5 days in room air (relative hypoxia
      and retinal angiogenesis). Normal mice were those with a normally developing
      retinal vasculature exposed to room air from birth until postnatal day (P)17. The
      COX-2 inhibitor, rofecoxib (15 mg/kg body weight intraperitoneally) was
      administered to normal and ROP mice from P12 to P17. Immunohistochemistry for COX
      2 was performed on retinas from all groups by the avidin-biotin method.
      Histologic methods were used to count blood vessel profiles (BVPs) in the inner
      retina (inner limiting membrane, ganglion cell layer, and inner plexiform layer)
      with a masked approach. RESULTS: Intense COX-2 immunolabeling was specifically
      localized to ganglion cells and blood vessels of all mice retinas. In ROP mice,
      COX-2 immunolabeling was detected on blood vessels extending into the vitreous
      cavity. Quantitation of BVPs in the inner retina revealed an increase in
      untreated ROP mice compared with untreated normal mice (P < 0.001). Rofecoxib
      decreased BVPs by approximately 45% in normal mice and 37% in ROP mice.
      CONCLUSIONS: COX-2 is localized to sites associated with retinal blood vessels.
      The finding that the selective COX-2 inhibitor, rofecoxib, attenuated the retinal
      angiogenesis that accompanies ROP, and normal retinal development indicates that
      COX-2 plays an important role in blood vessel formation in the retina.

PMID- 12601019
TI  - Venous anatomy of the orbit.
AB  - PURPOSE: To define the normal and variant venous anatomy in the human orbit.
      METHODS: Orbital dissections, focusing on the venous system, were performed on 17
      formalin-preserved human cadavers (34 orbits) and two fresh orbits. Dissections
      were carefully documented photographically. Results were compared with those in
      previous reports on the venous anatomy of the orbit. RESULTS: The superior
      ophthalmic vein (SOV) is the most consistent vein within the superior orbit. The
      inferior ophthalmic vein (IOV) demonstrated more variation, but important
      variations were noted in both. Smaller veins demonstrated the largest
      variability. Several formerly published observations on the venous anatomy of the
      orbit could not be confirmed in this study. A previously unreported variation in
      the SOV was found in 9 of 36 orbits, with the SOV having a duplicated segment,
      which is likely to be a variant medial ophthalmic vein. CONCLUSIONS: The venous
      anatomy of the orbit demonstrates considerable variability. Some of these
      variations may have implications in surgical management and natural history of
      ophthalmic conditions, such as carotid-cavernous sinus fistula (CCSF).

PMID- 12601020
TI  - Gene expression networks underlying retinoic acid-induced differentiation of
      human retinoblastoma cells.
AB  - PURPOSE: To understand the genetic regulatory pathways underlying the retinoic
      acid (RA) induction of cone arrestin, gene array technology and other molecular
      tools were used to profile global gene expression changes in human retinoblastoma
      cells. METHODS: Weri-Rb-1 retinoblastoma cells were cultured in the absence or
      presence of RA for various periods. DNA microarray analysis profiled gene
      expression followed by real-time PCR and Northern and immunoblot analyses to
      confirm the change in expression of selected retinal genes and their gene
      products. Additional methodology included flow cytometry analysis,
      immunocytochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick
      end labeling (TUNEL) assay. RESULTS: DNA microarray analysis of approximately
      6800 genes revealed RA-induced upregulation of cone-specific genes and
      downregulation of rod-specific genes in Weri-Rb-1 cells. Other significantly
      upregulated mRNAs included chicken ovalbumin upstream promoter-transcription
      factor (COUP-TF1), retinoid X receptor (RXR)-gamma, thyroid hormone receptor (TR)
      beta2, and guanylyl cyclase-activating protein (GCAP)-1. Real-time PCR and/or
      Northern blot analysis confirmed the expression changes of a subset of genes
      including the upregulation of a pineal- and retina-specific transcription factor,
      CRX. RA treatment also led to G(0)/G(1) cell cycle arrest and increased both the
      intensity of human cone arrestin (hCAR)-immunoreactivity and the number of
      apoptotic cells. The cell-cycle-arrest stage correlated with the observed
      microarray results in which the RA treatment downregulated critical genes such as
      cyclins (cyclin E, cyclin D3) and cyclin-dependent kinases (CDK5, CDK10).
      CONCLUSIONS: These data suggest that RA induces a subpopulation of retinoblastoma
      cells to differentiate toward a cone cell lineage while selectively leading other
      cells into apoptosis.

PMID- 12601021
TI  - Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors
      of survival.
AB  - PURPOSE: To correlate monosomy 3 in uveal melanoma with clinical and histologic
      prognostic variables and death caused by metastatic disease. METHODS: Loss of
      heterozygosity (LOH) on chromosome 3 was investigated by PCR-based microsatellite
      analysis in 105 tumors and related to large basal tumor diameter (LBD), ciliary
      body (CB) involvement, tumor cell type, periodic acid-Schiff (PAS)-positive
      loops, and death related to metastatic disease. A model relating monosomy 3 to
      these was created with forward-stepwise logistic regression and used to derive a
      prognostic index. RESULTS: Monosomy 3 occurred in 54 (51%) tumors and regional
      chromosome 3 LOH in another six (6%) tumors. Monosomy 3 was associated with
      epithelioid cells (chi(2) test, P < 0.001), PAS-positive loops (chi(2), P =
      0.001), LBD (Mann-Whitney test, P = 0.002), CB involvement (chi(2) test, P =
      0.008), and metastasis-related death (log rank analysis, P = 0.0003). The
      regression coefficients indicated that epithelioid histology was 15 times as
      influential with each millimeter of increase in LBD. A prognostic score was
      derived: one point for each LBD category (<7.4, 7.5-12.4, 12.5-17.4, and >17.4
      mm) and three points for epithelioid histology. The prevalence of monosomy 3
      increased with score, from 0% in 18 tumors scoring less than 4 to 95% in 21
      tumors scoring 7. CONCLUSIONS: Monosomy 3 correlates with survival but can be
      predicted only in patients with large epithelioid tumors. The absence of monosomy
      3 is predictable only in patients who have small, spindle-cell tumors. In most
      patients, prediction of monosomy 3 according to tumor size and histology is
      unreliable.

PMID- 12601022
TI  - TGFbeta-induced factor: a candidate gene for high myopia.
AB  - PURPOSE: To investigate the coding exons of transforming growth factor (TGF)-beta
      induced factor (TGIF) for mutations in Chinese patients with high myopia.
      METHODS: Seventy-one individuals with high myopia of -6.00 D or less and 105
      control subjects were screened by DNA sequencing for sequence alterations.
      Univariate analysis and logistic regression were performed to identify single
      nucleotide polymorphisms (SNPs) and their interactions in TGIF that may be
      associated with myopia. RESULTS: Six SNPs showed a significant difference (P <
      0.05) between patient and control subject in univariate analysis. Four of them
      cause codon changes: G223R, G231S, P241T, and A262G. Among all the SNPs that
      entered multivariate analysis, only 657(T-->G) showed statistical significance in
      the logistic regression model (odds ratio 0.133; 95% confidence interval 0.037
      0.488; P = 0.002). CONCLUSIONS: TGIF is a probable candidate gene for high
      myopia. Further studies are needed to identify the underlying mechanism.

PMID- 12601023
TI  - Acceleration of key reactions as a strategy to elucidate the rate-limiting
      chemistry underlying phototransduction inactivation.
AB  - PURPOSE: A reconstituted system was used to establish a strategy to determine the
      rate-limiting chemistry responsible for recovery of the dim-flash response in rod
      photoreceptors. METHODS: A general approach for identifying the rate-limiting
      step in a series of reactions is to evaluate the consequences of accelerating
      each step separately, while monitoring the rate of formation of the end product
      of the series. This strategy was applied to the reactions involved in quenching
      phototransduction in bovine rod outer segment (bROS) homogenates. The decay of
      photoactivated rhodopsin (R*) and inactivation of transducin by guanosine
      triphosphate (GTP) hydrolysis are the leading candidates for limiting the rate of
      phototransduction turn-off. These reactions were accelerated separately and
      together by adding hydroxylamine and/or the regulator of G-protein signaling-9
      catalytic domain (RGS9d) while monitoring phosphodiesterase (PDE) activity
      triggered by a pulse of light in bROS homogenates. RESULTS: PDE activity in bROS
      homogenates triggered by a flash of light returned to its dark value with a rate
      constant of 0.087 +/- 0.002 seconds in this system. The rate of PDE recovery
      increased to 0.11 +/- 0.004 seconds when R* decay was accelerated with 10 to 50
      mM hydroxylamine, suggesting that R* inactivation limits the rate of
      phototransduction turn-off under these conditions. Adding both hydroxylamine and
      RGS9d, a factor that accelerates transducin inactivation, increased the rate of
      PDE decay even further. RGS9d had no effect on PDE recovery kinetics unless
      quenching of R* was also accelerated. CONCLUSIONS: Under in vitro conditions in
      bROS homogenates, the quenching of R* normally limits the rate of
      phototransduction shut-off. If R* decay is accelerated, inactivation of
      transducin by GTP hydrolysis becomes rate limiting. This study offers a general
      approach that could be used to investigate the rate-limiting chemistry of
      phototransduction turn-off in vivo.

PMID- 12601024
TI  - Development of refractive error and strabismus in children with Down syndrome.
AB  - PURPOSE: To investigate the development of refractive errors and strabismus in a
      cohort of children with Down syndrome. METHOD: Data for 55 children with Down
      syndrome who are participating in this longitudinal study of visual development,
      first examined by us when aged less than 2 years and on at least two other
      occasions, were analyzed. Mohindra retinoscopy was used to measure refractive
      error. Ocular alignment was assessed using the Hirschberg test and, when
      possible, the cover test. RESULTS: Despite the high prevalence of large
      refractive errors in children with Down syndrome, longitudinal data showed that
      these are not always present in early infancy. Twenty-one (38%) of the children
      were emmetropic throughout the study. Of the 24 children with a significant
      refractive error at the outset, only 6 (25%) showed emmetropization. The others
      retained or increased their refractive errors. The remaining 10 children were
      emmetropic at the outset, but then had a significant refractive error develop.
      There is a high prevalence of strabismus in children with Down syndrome (29% of
      the total group), which cannot be attributed to the presence of hypermetropia or
      anisometropia. CONCLUSIONS: The retention or development of infantile refractive
      errors in many children with Down syndrome indicates a failure of
      emmetropization. All children were at risk of strabismus whatever the refractive
      error. The findings have implications for timing of screening programs.

PMID- 12601026
TI  - Retinotopic accommodation responses in myopia.
AB  - PURPOSE: A reduced sensitivity to retinal image blur has been reported in myopes.
      Diminished blur detection reduces the error signal to the retinotopic (blur
      induced) accommodation system and results in impaired accommodation responses
      under retinotopic conditions. This study was conducted to investigate retinotopic
      accommodation responses in emmetropia and myopia under dynamic conditions.
      METHODS: Static accommodation responses to a blur-only target with vergences of 0
      to 4.5 D were measured with an optometer. Microfluctuations of accommodation were
      recorded with the subject viewing the target at a vergence of 4 D, and dynamic
      step responses were measured for step stimuli from 2.5 to 3.5 D and 2.0 to 4.0 D,
      with the optometer in dynamic recording mode. Measurements were obtained from a
      group of 32 visually normal emmetropes (EMMs) and subjects with progressing
      myopia. RESULTS: Stimulus-response curves were not significantly different
      between the refractive groups. Subjects with late-onset myopia (LOMs)
      demonstrated significantly larger accommodation microfluctuations compared with
      emmetropes and subjects with early-onset myopia (EOMs). Fourier analysis revealed
      that the increase in the magnitude of the fluctuations was mediated by the low
      frequency components. Accommodation step responses revealed longer reaction times
      in LOMs. Further analysis showed that LOMs responded to accommodation step
      stimuli only between 43% and 64% of the time. In contrast, the other groups
      showed a response rate of almost 100%. CONCLUSIONS: The experiments demonstrate a
      reduction in retinotopic processing in LOMs, which results in an increased
      variability in their dynamic accommodation response to stationary near targets
      and reduced performance for dynamic step tasks. The results demonstrate a reduced
      blur appreciation under dynamic conditions in these refractive groups that may
      lead to periods of retinal image blur of varying magnitude during near work.

PMID- 12601025
TI  - Incidence of blindness in southern Germany due to glaucoma and degenerative
      conditions.
AB  - PURPOSE: To estimate population-based incidence rates of registered blindness
      separately, to determine its main causes. METHODS: The files of all newly
      registered blindness-allowance recipients in Wurttemberg-Hohenzollern, Germany
      (population: approximately 5 million), between 1994 and 1998 were reviewed. From
      ophthalmological reports on file the fulfillment of the German criteria for
      blindness (visual acuity of 1/50 or less or equivalent reduction of visual
      function) was ascertained, and the causes of blindness were obtained. Incidence
      rates of blindness due to macular degeneration, glaucoma, cataract, optic
      atrophy, and diabetic retinopathy were estimated. RESULTS: There were 3531 newly
      registered blindness-allowance recipients (67.1% female; mean age, 72.8 +/- 21.0
      years). Standardized incidence rates in the general population (per 100,000
      person-years; 95% confidence interval): All causes 12.27 (11.87-12.68), macular
      degeneration 5.29 (5.02-5.55), cataract 3.32 (3.11-3.52), optic atrophy 2.86
      (2.66-3.05), glaucoma 2.43 (2.25-2.61), diabetic retinopathy 2.13 (1.96-2.30),
      other or unknown causes 5.17 (4.91-5.43). In many cases, blindness was
      attributable to more than one cause. Assuming that incidence rates are the same
      in other parts of the country, 9,939 (9,608-10,270) new cases of blindness were
      estimated to occur in Germany per year. CONCLUSIONS: The most common single cause
      of blindness was macular degeneration. Incidence rates of blindness due to such
      treatable conditions as glaucoma were also high. This finding suggests that the
      taking of measures for secondary prevention (e.g., early detection and optimal
      treatment of patients with glaucoma and diabetic retinopathy) should be
      intensified.

PMID- 12601027
TI  - Outcome of vitreous surgery and the balance between vascular endothelial growth
      factor and endostatin.
AB  - PURPOSE: To predict the results of vitreous surgery in patients with
      proliferative diabetic retinopathy (PDR), the correlation between vitreous fluid
      levels of vascular endothelial growth factor (VEGF) or endostatin and the
      postoperative outcome was investigated. METHODS: VEGF and endostatin levels in
      vitreous fluid specimens obtained during vitreous surgery were measured by enzyme
      linked immunosorbent assay. Expression of VEGF and endostatin in epiretinal
      membranes was assessed immunohistochemically. Patients were prospectively
      followed up for 6 months. RESULTS: No improvement and/or progression of PDR was
      seen in 11 (25%) of 44 eyes (progression group). The vitreous fluid level of VEGF
      was significantly higher in the progression group than in the regression group (P
      = 0.0023). Conversely, the vitreous fluid level of endostatin was significantly
      higher in the regression group than in the progression group (P = 0.0299). Eyes
      with a high vitreous fluid level of VEGF and a low endostatin level had a
      significantly greater risk of progression of PDR after vitreous surgery than did
      eyes with low VEGF and high endostatin levels (odds ratio = 10.00, P = 0.047).
      VEGF and endostatin were detected immunohistochemically in the fibrovascular
      epiretinal membranes resected from the subjects. CONCLUSIONS: In this study both
      VEGF and endostatin were expressed in eyes with PDR. VEGF and endostatin levels
      in the vitreous fluid correlated with the outcome of vitreous surgery for PDR.
      Therefore, the outcome of PDR surgery can probably be predicted by measuring
      cytokines and/or growth factors in the vitreous fluid, with VEGF and endostatin
      being good candidates.

PMID- 12601028
TI  - Human corneal epithelial cells require MMP-1 for HGF-mediated migration on
      collagen I.
AB  - PURPOSE: To investigate the potential regulation of matrix metalloproteinases
      (MMPs) by hepatocyte growth factor (HGF), and to identify individual MMPs
      essential for migration of human corneal epithelial cells. METHODS: Migration of
      human corneal epithelial cells (HCECs) was measured with a colony dispersion
      assay in response to concentrations of HGF (0-50 ng/mL). MMP activity in the
      conditioned media collected from the dispersion assay was assessed by zymography.
      The broad-spectrum MMP inhibitor ilomastat (1-100 microM) or an MMP-9
      neutralizing antibody (1-10 microg/mL) were included in the dispersion assay to
      determine their effects on HCEC migration. Immunocytochemistry and in situ
      hybridization were used to localize MMP-1 in HCECs in the colony dispersion assay
      and in a human ex vivo corneal wound-healing model, respectively. ELISA for MMP-1
      was performed on conditioned medium from migrating HCECs. Neutralizing antibodies
      to MMP-1 and -9 were added to an in vitro scratch-wound model to assess the
      effect on HCEC healing. RESULTS: HCEC migration (P < 0.05) and MMP-2 and -9
      released into the medium increased in response to HGF in a dose-dependent manner
      up to 20 ng/mL. Broad-spectrum MMP inhibition significantly reduced HCEC
      migration (P < 0.05). In contrast, neutralization of MMP-9 increased migration (P
      < 0.05). MMP-1 was found in association with HCECs at the migratory leading edge
      in both the dispersion and the ex vivo wound-healing experiments, and was found
      to be stimulated above basal levels by HGF. Neutralization of MMP-1 significantly
      decreased (P < 0.05), whereas neutralization of MMP-9 significantly increased (P
      < 0.05), scratch-wound closure. CONCLUSIONS: This study provided novel data
      regarding HCEC migration in response to HGF and highlighted the importance of
      MMPs, particularly MMP-1 in migration and possibly reepithelialization in vivo.
      MMP-9 and/or -2 may be released by HCECs to remodel matrix behind the leading
      migratory front. Studies such as this are essential to assist in the safe and
      efficacious design of MMP inhibitors for therapeutic use in the eye.

PMID- 12601029
TI  - Vertical movement of epithelial basal cells toward the corneal surface during use
      of extended-wear contact lenses.
AB  - PURPOSE: To study the effects of extended contact lens wear (EW) on the movement
      of basal epithelial cells toward the corneal surface. METHODS: Rabbits (n = 32)
      were injected with 5-bromo-2-deoxyuridine (BrdU) to label a group of
      proliferating basal epithelial cells, and, 24 hours later, one randomly chosen
      eye was fitted with a low- or medium-oxygen-transmissible (Dk/t) rigid gas
      permeable (RGP) contact lens, while the other eye served as the control (n = 28).
      Four rabbits were not fitted with any contact lens. Rabbits were euthanatized at
      different time points and the corneal epithelium was immunocytochemically stained
      for BrdU and/or Ki-67 and counterstained with propidium iodide or Syto 59.
      Corneal flatmount tissues were examined three dimensionally under a laser
      confocal microscope and the location of each BrdU-labeled cell in the corneal
      epithelium (basal or suprabasal) was determined. RESULTS: Four days after
      injection of BrdU, both low- (P < 0.001) and medium-Dk/t RGP (P < 0.001) lens
      groups showed significantly more BrdU-labeled cells in the basal cell layer than
      in the control eyes. Six days after injection of BrdU, a small percentage of BrdU
      labeled cells (<0.5%) were Ki-67 positive. CONCLUSIONS: Within 6 days, the
      majority (80%) of BrdU-labeled basal cells became terminally differentiated and
      rarely divided secondarily in the central epithelium. Short-term use of low- and
      medium-Dk/t RGP EW contact lenses slows the normal movement of basal epithelial
      cells toward the surface in the central cornea. This is consistent with known EW
      lens-induced decreases in corneal epithelial basal cell proliferation and surface
      cell exfoliation. Overall, the data suggest that EW lenses significantly inhibit
      the normal homeostatic turnover rate of the corneal epithelium.

PMID- 12601030
TI  - Long-term corneal morphology after PRK by in vivo confocal microscopy.
AB  - PURPOSE: To examine human corneal morphology and nerve recovery 5 years after
      photorefractive keratectomy (PRK). METHODS: Fourteen eyes of 14 patients (ages,
      27-53 years) who underwent 6-mm diameter PRK for low to moderate myopia
      (spherical equivalent [SE] -2.5 to -8.0 D) were examined once 5 years after
      surgery. Nine healthy individuals served as control subjects. Standard
      biomicroscopy, manifest refraction, and visual acuity tests were performed. The
      morphology of the corneas was examined by in vivo confocal microscope.
      Thicknesses of the epithelium and stroma, as well as the density of corneal
      opacity (haze) were obtained from digital image analysis of the confocal
      microscopy through-focusing (CMTF) scans. RESULTS: Confocal microscopy revealed
      increased reflectivity in the subepithelial extracellular matrix, keratocyte
      nuclei and processes in all patients. The mean objective haze estimate was 166.7
      U (range, 50-390) in control corneas compared with a mean of 225.9 U (range, 125
      430, P = 0.15) in the post-PRK corneas. The density of the subbasal nerve fiber
      bundles in post-PRK corneas (mean, n = 4.2; range, n = 1-7 per field of view) was
      not significantly lowered from that in control subjects (mean, n = 4.9; range, n
      = 3-6; P = 0.56). Bowman's layer was undetectable in all post-PRK corneas.
      Clinically, slit-lamp-observed trace of haze in four corneas correlated
      positively with the ablation depth (P = 0.016) and the thickness of the haze area
      (P = 0.006) in the confocal microscope. CONCLUSIONS: In vivo confocal microscopy
      demonstrates the presence of morphologic alterations even 5 years after PRK.
      However, these alterations are overcome by cellular and neural recovery and do
      not seem to interfere with visual performance.

PMID- 12601031
TI  - Topographical thickness of the epithelium and total cornea after hydrogel and
      PMMA contact lens wear with eye closure.
AB  - PURPOSE: To determine changes in topographical thickness of the epithelium and
      total cornea after hydrogel (2-hydroxyethyl methacrylate; HEMA or soft lens) and
      PMMA rigid contact lens wear with eyes closed, as measured by optical coherence
      tomography (OCT). METHODS: Epithelial and total corneal thickness in 18 neophyte
      eyes was measured with OCT at intervals of 10 degrees across a 10-mm zone of the
      horizontal meridian of the cornea, before and after 3 hours of soft and rigid
      contact lens wear with the eye closed. These measurements were repeated 20
      minutes after removal of the lenses. RESULTS: Lens type, time, and location were
      found to be significant main influences (P < 0.0001) on corneal swelling in
      patched eyes, by three-way ANOVA, and there was a significant three-way
      interaction among lens type, time, and location (F((16,272)) = 1.78, P = 0.033).
      However, there was no significant main effect and interaction of epithelial
      thickness (F((16, 272)) = 0.33, P = 0.99). Immediately after removal of the
      lenses, total corneal thickness in the horizontal meridian was significantly
      greater with both soft and PMMA lenses (P < 0.001) at each location with each
      lens, compared with the baseline measurements. With both lenses, the increase in
      actual thickness and percentage of corneal swelling at the center was greater
      than at each peripheral point (excluding the first 10 degrees points; P < 0.005).
      HEMA lenses caused greater corneal swelling than the PMMA lenses at each location
      immediately after removal of the lenses (P < 0.005). CONCLUSIONS: This study
      shows that corneal swelling is dependent on lens type and corneal location when
      eyes are closed, but epithelial thickness across the horizontal corneal meridian
      does not change during lens wear with eyes closed. OCT is an efficient method of
      measuring topographical corneal and epithelial thickness in response to contact
      lens wear.

PMID- 12601032
TI  - Signal transduction pathways used by EGF to stimulate protein secretion in rat
      lacrimal gland.
AB  - PURPOSE: To determine the effects of epidermal growth factor (EGF) on lacrimal
      gland secretion of proteins and characterize its signal-transducing components.
      METHODS: Both exorbital lacrimal glands were removed from male Sprague-Dawley
      rats. Dispersed acini were isolated by collagenase digestion in Krebs-Ringer
      bicarbonate (KRB) buffer at 37 degrees C. Acini were incubated with EGF (10(-7)
      M), the cholinergic agonist carbachol (10(-4) M), or the alpha(1)-adrenergic
      agonist phenylephrine (10(-4) M), and peroxidase secretion was measured by a
      fluorescence assay. To measure intracellular calcium ([Ca(2+)](i)), acini were
      incubated in fura-2 tetra-acetoxymethyl ester for 60 minutes at 22 degrees C, and
      fluorescence was measured at 340 and 380 nm with an emission wavelength of 505
      nm. Extracellular Ca(2+) was chelated with KRB-BSA without CaCl(2) and with 2 mM
      EGTA before measurement of peroxidase secretion. Protein kinase C (PKC) was
      downregulated by incubating acini overnight, with or without the phorbol ester,
      phorbol 12-myristate 13-acetate (PMA; 10(-6) M), and peroxidase secretion was
      measured. RESULTS: EGF-stimulated peroxidase secretion in a concentration
      dependent manner with a significant increase at 10(-7) M. EGF-stimulated
      secretion was inhibited by the EGF receptor (EGFR) inhibitor AG1478, but not by
      the phosphoinositide-3 kinase inhibitor LY292004 or the mitogen-activated kinase
      kinase (MEK) inhibitor U0126. EGF increased [Ca(2+)](i), whereas chelation of
      extracellular Ca(2+) inhibited EGF-induced peroxidase secretion by 90%.
      Downregulation of PKC also inhibited EGF-stimulated peroxidase secretion.
      CONCLUSIONS: EGF stimulates lacrimal gland secretion of protein by activating the
      EGFR to increase [Ca(2+)](i) and activate PKC.

PMID- 12601033
TI  - Frequency and metrics of square-wave jerks: influences of task-demand
      characteristics.
AB  - PURPOSE: Square-wave jerks (SWJs) during visual fixation and pursuit tracking of
      targets of varying speed and predictability were investigated in the present
      study. METHODS: SWJs were measured in 91 subjects as they fixated a target or a
      remembered target location and tracked targets that varied in velocity and
      predictability. RESULTS: Percentages of subjects making SWJ and mean SWJ
      frequency per minute in the high- and low-predictability conditions were 99% and
      9.34 and 91% and 2.78, respectively. SWJ rates were significantly lower when
      observers fixated remembered target locations rather than visual targets and
      during tracking of faster-moving and less predictable targets. Differences in
      task conditions cannot be explained by volitional influences to control the first
      saccade in the SWJ. There was also no influence of age on SWJ rate. CONCLUSIONS:
      Reduced SWJ rates after manipulations that increased task demands on visual
      pursuit of targets suggest an inverse relationship between current demands
      imposed by visual tasks and rates of intrusive saccades. These findings suggest
      that signals from cortical attentional systems may suppress inappropriate
      saccades that would divert the eyes from objects of interest during conditions
      imposing high task demands on the visual system.

PMID- 12601034
TI  - Optic neuropathy induced by reductions in mitochondrial superoxide dismutase.
AB  - PURPOSE: Reactive oxygen species (ROS) are suspected to play a pivotal role in
      the pathogenesis of Leber hereditary optic neuropathy (LHON), caused by mutated
      complex I subunit genes. It seems surprising that optic neuropathy has not been
      described in animals with a knockout of genes encoding critical anti-ROS
      defenses. If ROS have a role in the optic nerve injury of LHON, then increasing
      mitochondrial levels of ROS should induce optic neuropathy. METHODS: To develop
      an animal model system for study of oxidative injury to the optic nerve,
      mitochondrial defenses were decreased against ROS by designing hammerhead
      ribozymes to degrade SOD2 mRNA. Several potential ribozymes were analyzed in
      vitro. The one with the best kinetic characteristics was cloned into a
      recombinant adeno-associated virus (rAAV) vector for delivery and testing in
      cells and animals. The effects of the AAV-expressing ribozyme on murine cell
      growth, SOD2 mRNA and protein, cellular ROS levels, and apoptosis were evaluated
      by RNase protection assay, immunoblot analysis, and ROS- and apoptosis-activated
      fluorescent probes. The rAAV-ribozyme was then injected into the eyes of DBA/1J
      mice, and the effect on the optic nerve was evaluated by ocular histopathologic
      examination. RESULTS: The AAV-expressing ribozyme decreased SOD2 mRNA and protein
      levels by as much as 85%, increased cellular superoxide, reduced mitochondrial
      membrane potential, and culminated in the death of infected cell lines by
      apoptosis without significantly altering complex I and III activity, somewhat
      spared in the most common LHON mutation (G11778A), although adenosine
      triphosphate (ATP) synthesis is markedly reduced. When inoculated into the eyes
      of mice, the AAV-expressing ribozyme led to loss of axons and myelin in the optic
      nerve and ganglion cells in the retina, the hallmarks of optic nerves examined at
      autopsy of patients with LHON. CONCLUSIONS: The striking similarity of the optic
      neuropathy to the histopathology of LHON is powerful evidence supporting ROS as a
      key factor in the pathogenesis of LHON.

PMID- 12601036
TI  - Matrix metalloproteinase inhibition modulates fibroblast-mediated matrix
      contraction and collagen production in vitro.
AB  - PURPOSE: To investigate the effect of matrix metalloproteinase (MMP) inhibition
      on fibroblast-mediated matrix contraction and production. METHODS: Free-floating
      fibroblast-populated type I collagen lattices were prepared with human Tenon's
      capsule fibroblasts. Lattice areas were photographed and digitally analyzed to
      indicate the degree of lattice contraction. Quantitative competitive reverse
      transcription-polymerase chain reaction (QCRT-PCR) and enzyme-linked
      immunosorbent assay (ELISA) were used to quantify mRNA and protein respectively
      for MMP-1, -2, and -3 by fibroblasts during lattice contraction. Gelatin
      zymography demonstrated activity of MMPs released into the conditioned medium of
      contracting lattices. Concentrations of the broad-spectrum MMP inhibitors
      ilomastat, CellTech (Slough, UK), and BB-94 were added to the contracting
      fibroblast-populated collagen lattices. Secreted C-terminal propeptide of type I
      collagen was measured in conditioned medium of contracting lattices by ELISA.
      Fibroblast proliferation in the presence of concentrations of ilomastat was
      measured by using the reagent water-soluble tetrazolium-1 (WST-1). RESULTS:
      During contraction of type I collagen lattices, Tenon's capsule fibroblasts
      expressed MMP-1, -2, and -3 mRNA and protein. Zymography demonstrated the release
      of four gelatinolytic species into the conditioned medium of contracting lattices
      (57, 72, 91, and 100 kDa). Inclusion of MMP inhibitors in the zymogram-developing
      buffer reduced the proteolytic activity of the detected bands. MMP inhibition (1
      100 microM) significantly reduced fibroblast-mediated collagen lattice
      contraction (P < 0.05), and this effect was found to be reversible. Ilomastat
      also significantly inhibited production of collagen in a dose-dependent manner (P
      < 0.05). No effect on fibroblast proliferation was found in the presence of
      ilomastat. CONCLUSIONS: MMPs are produced during Tenon's capsule fibroblast
      mediated collagen lattice contraction. Broad-spectrum MMP inhibition
      significantly reduced matrix contraction and production without cell toxicity.
      Future clinical use of MMP inhibitors may be possible, because MMP inhibition
      significantly reduces fibroblast functions associated with contractile scarring.

PMID- 12601035
TI  - Matrix metalloproteinase inhibition modulates postoperative scarring after
      experimental glaucoma filtration surgery.
AB  - PURPOSE: To determine whether postoperative application of a broad-spectrum
      matrix metalloproteinase (MMP) inhibitor, GM6001 (ilomastat), reduces scarring
      after glaucoma filtration surgery. METHODS: In a randomized, prospective, masked
      observer study, 40 New Zealand White rabbits underwent modified glaucoma
      filtration surgery. The animals were randomly allocated to receive postoperative
      subconjunctival injections of either phosphate-buffered saline (PBS) or 100
      microM ilomastat for 10 days. The animals were killed on days 7, 14, 21, and 30.
      Clinical characteristics, which included bleb morphology and intraocular
      pressure, were recorded. Tissue sections were immunohistochemically stained for
      alpha smooth muscle actin (alphaSMA) and extracellular matrix components in the
      two groups. RESULTS: Surgical outcome was significantly prolonged in the
      ilomastat-treated group compared with the vehicle-treated group (P < 0.001). At
      day 30, all the blebs had survived except two in the ilomastat-treated group,
      whereas no blebs survived to day 30 with vehicle treatment (n = 11). The
      intraocular pressure remained significantly lower throughout the course of the
      experiment in the ilomastat group compared with the vehicle group (P < 0.0017).
      Histologically, less scar tissue was observed at the sclerostomy site with
      inhibition of MMP, compared with vehicle treatment. CONCLUSIONS: The data
      presented suggest that the healing response after surgery can be modulated by
      inhibiting the effects of MMPs. Inhibition of MMP significantly improved surgical
      outcome by reducing the amount of scar tissue produced. By targeting the actions
      of these proteolytic enzymes, a more controlled and physiological method of
      modulating scarring may be achieved.

PMID- 12601037
TI  - Appearance of the frequency doubling stimulus in normal subjects and patients
      with glaucoma.
AB  - PURPOSE: To determine whether the spatial structure of the frequency doubling
      technology (FDT) perimetry stimulus is visible at detection-contrast threshold in
      normal observers and those with glaucoma and to assess its perceived spatial
      frequency at threshold and suprathreshold contrast. METHODS: Three subject groups
      were assessed: 10 young normal observers (aged <40 years), 10 older normal
      observers (aged >50 years), and 10 subjects with glaucoma. Detection thresholds
      for centrally and eccentrically presented 10 degrees squares, 0.25-cyc/deg, 25-Hz
      counterphase flicker sine-wave gratings were obtained by using a yes-no staircase
      procedure. Eccentric locations were in areas of loss of FDT sensitivity (< or =21
      degrees ) in subjects with glaucoma, or at 7 degrees or 21 degrees inferonasally
      in normal observers. Resolution-contrast thresholds were determined by a two
      alternative, forced-choice staircase procedure in which subjects selected the
      orientation of the grating stimulus tilted at +/-45 degrees. Perceived spatial
      frequency was determined by having subjects alter the spatial frequency of a
      temporally interleaved stationary sine-wave grating to match the FDT stimulus.
      RESULTS: No significant difference was found between detection- and resolution
      contrast thresholds, implying that spatial structure was visible at detection
      threshold. In general, subjects perceived the spatial structure to have a spatial
      frequency closer to doubled than to veridical, although the young normal subjects
      reported a lower apparent spatial frequency than older individuals. CONCLUSIONS:
      When instructed as for clinical testing, subjects respond to the presence of the
      structure of the grating, and perceive the FDT stimulus to have a spatial
      frequency greater than its true spatial frequency. These findings were consistent
      across both normal observers and those with glaucoma, at both central and
      eccentric test locations.

PMID- 12601038
TI  - Matrix metalloproteinases and their inhibitors in aqueous humor of patients with
      pseudoexfoliation syndrome/glaucoma and primary open-angle glaucoma.
AB  - PURPOSE: To determine the presence, activity, and quantitative differences of
      matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in
      aqueous humor and serum samples of patients with pseudoexfoliation (PEX)
      syndrome, PEX glaucoma (PEXG), primary open-angle glaucoma (POAG), and cataract.
      METHODS: Aqueous humor and serum samples were collected from 100 patients with
      PEX syndrome, PEX glaucoma (PEXG), POAG, and cataract, respectively. Levels of
      MMP-1, -2, -3, -7, -9, and -12 and TIMP-1 and -2 were determined by zymography,
      Western blot analysis, and specific immunoassays. Activity assay kits were used
      to quantitate levels of endogenously activated MMP-2 and -9. RESULTS: MMP-2, -3, 
      7, -9, and -12 and TIMP-1 and -2 were identified in human aqueous humor samples
      from all groups of patients with a six to sevenfold molar excess of TIMPs over
      MMPs. Whereas serum samples showed no significant differences, total MMP-2 and -3
      and TIMP-1 and -2 were detected at significantly higher concentrations in aqueous
      samples from PEX eyes with and without glaucoma compared with cataractous eyes.
      MMP-2 and -3 and TIMP-1 were also detected in higher, but not significantly
      different, amounts in aqueous samples of POAG eyes. However, levels of
      endogenously activated MMP-2 were significantly decreased in both PEX and POAG
      samples. The ratio of MMP-2 to its principal inhibitor TIMP-2 was balanced in
      cataract samples, but was decreased in samples from patients with PEXG, resulting
      in an excess of TIMP-2 over MMP-2. CONCLUSIONS: The findings suggest that complex
      changes in the local MMP-TIMP balance and reduced MMP activity in aqueous humor
      may promote the abnormal matrix accumulation characteristic of PEX syndrome and
      may be causally involved in the pathogenesis of both PEX glaucoma and POAG.

PMID- 12601039
TI  - Reasons for rim area variability in scanning laser tomography.
AB  - PURPOSE: To determine reasons for rim area variability in scanning laser
      tomography. METHODS: Regional rim area variability from testing in same and
      different visits and by same and different observers was characterized in 30
      normal and 42 glaucomatous eyes. Variations in (1) optic nerve head (ONH) surface
      geometry (center of gravity: X, Y, Z), (2) image tilting (horizontally and
      vertically), and (3) position of the reference plane in relation to the ONH (REF)
      were analyzed by multiple regression analysis. Whether and how much these factors
      explain rim area variability was studied in cross-sectional and longitudinal data
      by using two different reference planes. RESULTS: Variability was higher in
      glaucoma and in testing by different observers in separate visits. Across a range
      of eyes, approximately 40% of variability in single-topography images and 60% of
      variability in mean-topography images was explained. In individual image series,
      a median 85% of variability was explained, exceeding 90% in at least 25% of eyes.
      The most frequent contributors to rim area variability were REF (in > or =95%)
      and Z (in > or =80%); they also usually explained more variability than other
      factors. The nature of variability differed between reference planes.
      CONCLUSIONS: A large proportion of rim area variability was explained by
      variation in the topographical features studied, especially REF and Z. Reference
      plane definition also influenced variability. Variation in the position of the
      reference plane in relation to the ONH can affect rim area measurements and
      should be considered when evaluating the progression of glaucoma.

PMID- 12601040
TI  - Reference plane definition and reproducibility in optic nerve head images.
AB  - PURPOSE: To describe and evaluate a new experimental reference plane for
      measuring rim area in scanning laser tomography. METHODS: The experimental
      reference plane was positioned so that (1) it always lay entirely below the
      margin of the optic nerve head (ONH), (2) it remained at a set z-axis distance
      below the ONH in images of each eye, and (3) it was at a level where variability
      in rim area is least. Twenty normal control subjects and 20 patients with
      glaucoma underwent test-retest scanning laser tomographic imaging by same and
      different operators during same and separate visits. Control subjects had image
      series spanning at least 3 years. The effect of the positioning of the reference
      plane on global and regional rim area variability was assessed in intra- and
      intervisit test-retest images and longitudinal image series and compared with the
      standard and 320- microm reference planes. RESULTS: Variability in the
      experimental reference plane was less in test-retest images and longitudinal data
      (P < 0.05) and more uniform around the ONH than with other reference planes.
      Variability in the former was not appreciably affected by testing involving
      different operators and visits, or by the presence of glaucoma. CONCLUSIONS:
      Variability in rim area by the experimental reference plane was significantly
      less, more uniform around the ONH, not affected by different operators and
      visits, and less affected by glaucomatous morphology than other reference planes.
      This difference was pronounced in sequential data and has implications for
      detecting progression of glaucoma.

PMID- 12601041
TI  - Method for the noninvasive measurement of intraocular pressure in mice.
AB  - PURPOSE: To evaluate the applicability of rebound tonometry for measurement of
      IOP in the mouse eye. METHODS: An induction-impact (I/I) tonometer, which
      operates on the rebound principle, was scaled down and adapted to determine IOP
      of the mouse eye. IOP measurement using this concept is based on contacting the
      eye with a probe and detecting the motion as the probe collides with the eye and
      bounces back. The motion parameters of the probe vary according to eye pressure
      and are used to calculate IOP. A prototype instrument was constructed for
      measurement of IOP in mouse eyes, and its ability to accurately and reliably
      measure IOP was tested by comparing the measurements against the manometric
      (true) IOP determined in cannulated mouse eyes ex vivo. The I/I tonometer was
      also used to measure IOP in vivo in anesthetized adult C57BL/6 mice. RESULTS: A
      strong correlation between the true IOP and the I/I measurements (R(2) = 0.95)
      was found for IOPs in the range of 3.7 to 44.1 mm Hg in cannulated mouse eyes.
      Repeat determinations in individual eyes showed a low degree of variability in
      the relationship of the measured IOP with the true IOP. In anesthetized mice,
      mean IOP +/- SD as determined by rebound tonometry was 9.8 +/- 3.9 mm Hg when the
      animals were anesthetized with ketamine alone and 7.6 +/- 1.9 mm Hg when a
      mixture of ketamine, acepromazine, and xylazine was used. Contralateral eyes
      differed by 0.9 +/- 2.5 and 0.1 +/- 2.7 mm Hg, respectively, for the two
      anesthetic regimens. CONCLUSIONS: The I/I tonometer can be used for noninvasive,
      in vivo IOP measurement in mouse eyes. The availability of an easy-to-use,
      reliable tonometer for IOP measurements in mice will allow more extensive use of
      the mouse as a model for glaucoma.

PMID- 12601043
TI  - Ultraviolet radiation-induced cataract: age and maximum acceptable dose.
AB  - PURPOSE: To investigate the effect of age on ultraviolet radiation-B (UVR-B)
      induced cataract and to detect the maximum acceptable dose in rats of different
      age groups. METHODS: Four age groups of 20 rats each, aged 3, 6, 10, and 18
      weeks, were included. Each age group was divided into five UVR-B dose subgroups.
      The rats were unilaterally exposed to UVR-B (lambda(max) = 302.6 nm, lambda(0.5)
      = 4.5 nm). The incident dose on the cornea varied between 0 and 8 kJ/m(2). One
      week after exposure, the rats were killed, both lenses were extracted, the
      intensity of forward light-scattering was measured, and photographs were taken.
      The sensitivity of the lens to UVR-B was estimated as the maximum acceptable
      dose. RESULTS: The maximum acceptable dose for 3-, 6-, 10-, and 18-week-old rats
      was estimated to be 1.4, 2.7, 4.3 and 5.2 kJ/m(2), respectively. CONCLUSIONS:
      Young rats were more sensitive to UVR-B than old ones. Age should be considered
      when estimating the risk for UVR-B-induced cataract.

PMID- 12601042
TI  - Advantages of using mitochondrial 16S rDNA sequences to classify clinical
      isolates of Acanthamoeba.
AB  - PURPOSE: This work was intended to test the classification of Acanthamoeba into
      genotypes based on nuclear ribosomal RNA gene (18S rDNA, Rns) sequences. Nearly
      all Acanthamoeba keratitis (AK) isolates are genotype RnsT4. This marked
      phylogenetic localization is presumably either due to an innate potential for
      pathogenicity or to a peculiarity of the gene sequences used. To differentiate
      between these possibilities, relationships among isolates have been reexamined,
      using a second gene. METHODS: Phylogenetic relationships among isolates of
      Acanthamoeba were studied, using sequences of the mitochondrial small subunit
      ribosomal RNA gene (16S rDNA; rns). Genotypes based on complete sequences of
      approximately 1540 bp were determined for 68 strains, by using multiple
      phylogenetic analyses. RESULTS: Each strain's mitochondria contained a single
      intron-free rns sequence (allele). The 68 strains had 35 different sequences.
      Twenty-eight strains had unique sequences, and 40 strains each shared one of the
      seven remaining sequences. Eleven mitochondrial rns genotypes corresponding to 11
      of 12 previously described nuclear Rns genotypes were identified. Genotype rnsT4
      was subdivided into eight distinct clades, with seven including Acanthamoeba
      keratitis (AK) isolates. CONCLUSIONS: The phylogenetic clustering of AK isolates
      was confirmed and thus is not specific to the nuclear gene. Rns and rns sequences
      are both suitable for genotyping of ACANTHAMOEBA: However, the mitochondrial
      sequences are shorter and more consistent in length, have a higher percentage of
      alignable bases for sequence comparisons, and have none of the complications
      caused by multiple alleles or introns, which are occasionally found in Rns. In
      addition, the more common occurrence of strains with identical rns sequences
      simplifies identification and clustering of isolates.

PMID- 12601044
TI  - Alteration of protein-protein interactions of congenital cataract crystallin
      mutants.
AB  - PURPOSE: A recent study demonstrated the presence of protein-protein interactions
      among lens crystallins in a mammalian cell two-hybrid system assay and speculated
      about the significance of these interactions for protein solubility and lens
      transparency. The current study extends those findings to the following
      crystallin genes involved in some congenital cataracts: CRYAA (R116C), CRYAB
      (R120G), and CRYGC (T5P). METHODS: A mammalian two-hybrid system was used to
      assay the protein-protein interactions. Congenital cataract crystallin genes were
      cloned and fused into the two-hybrid system vectors (target and prey proteins).
      Together, with the third vector containing a reporter gene, chloramphenicol
      acetyltransferase (CAT), they were cotransfected into human HeLa cells. The
      presence of protein-protein interactions and the strength of these interactions
      were assayed by CAT ELISA. RESULTS: The pattern of changes in protein-protein
      interactions of those congenital cataract gene products with the three major
      crystallins, alphaA- or alphaB-, betaB2-, and gammaC-crystallins, differed. For
      the T5P gammaC-crystallin, most of the interactions were decreased; for the R116C
      alphaA-crystallin, the interactions with betaB2- and gammaC-crystallin decreased
      and those with alphaB-crystallin and heat-shock protein (Hsp)27 increased; and
      for the R120G alphaB-crystallin, the interactions with alphaA- and alphaB
      crystallin decreased, but those with betaB2- and gammaC-crystallin increased
      slightly. An attempt was made to interpret the results on the basis of
      conformational change and disruption of dimeric interaction involving beta
      strands. CONCLUSIONS: The results clearly indicate that crystallin mutations
      involved in congenital cataracts altered protein-protein interactions, which may
      contribute to decreased protein solubility and formation of cataract.

PMID- 12601045
TI  - IGF-I-induced phosphorylation of connexin 43 by PKCgamma: regulation of gap
      junctions in rabbit lens epithelial cells.
AB  - PURPOSE: To determine the role of PKCgamma in insulin-like growth factor (IGF)-I
      induced phosphorylation of connexin (Cx)43 and control of gap junctions in lens
      epithelial cells. METHODS: N/N1003A rabbit lens epithelial cells were used in the
      experiments. PKC translocation or in vivo Cx43 phosphorylation on serine was
      determined by Western blot analysis. Gap junction activity was measured by scrape
      loading/dye-transfer assay. The number of cell surface gap junction plaques was
      detected by confocal microscopy. The interaction between PKCgamma and Cx43 was
      determined by coimmunoprecipitation. In vitro Cx43 phosphorylation was assayed by
      PKC assay kit. Endogenous sn-1,2-diacylglycerol (DAG) was measured by detecting
      (32)P-labeled phosphatidic acid. RESULTS: IGF-I stimulated activation and
      translocation of PKCgamma in a dose- and time-dependent manner, acidic FGF (aFGF)
      had no effect on translocation of PKCgamma, and PKCalpha was not translocated by
      IGF-I at 25 ng/mL. PKCgamma translocation resulted in coimmunoprecipitation with
      and phosphorylation of Cx43. IGF-I- or DAG-induced activation of PKCgamma caused
      a decrease in gap junctions. IGF-I increased endogenous DAG. Exogenous CaCl(2)
      and DAG stimulated PKCgamma translocation. TMB-8, an internal calcium
      mobilization inhibitor, blocked CaCl(2)-induced PKCgamma translocation; however,
      it had no effect on IGF-I- or DAG-induced translocation of PKCgamma. CONCLUSIONS:
      PKCgamma mediated IGF-I-induced decreases in gap junctional communication through
      interaction with and phosphorylation of Cx43. IGF-I caused an increase in DAG,
      and this increased translocation of PKCgamma, whereas mobilization of calcium was
      not essential for IGF-I-stimulated translocation of PKCgamma.

PMID- 12601046
TI  - Iganidipine, a new water-soluble Ca2+ antagonist: ocular and periocular
      penetration after instillation.
AB  - PURPOSE: To evaluate the potential of topical iganidipine ophthalmic solution to
      exert Ca(2+)-antagonistic activity in the posterior parts of the eye without
      inducing systemic effects, ocular and periocular penetration of topically
      instilled iganidipine was studied in pigmented rabbits. METHOD: First, (14)C
      iganidipine solution (0.03%, 30 microL) was instilled into one eye, and vehicle
      into the other eye to determine the intraocular penetration of iganidipine and to
      measure the radioactivity of ocular tissues 0.25, 0.5, 1, 2, 4, and 12 hours
      after a single instillation (n = 3, respectively). Second, iganidipine (0.03%) or
      betaxolol (0.5%) was unilaterally instilled twice daily for 20 days to study the
      effects on intravitreously injected various doses of endothelin (ET)-1-induced
      retinal artery constriction to evaluate whether a pharmacologically active level
      of the drug penetrated to the posterior retina and to estimate the drug level in
      the posterior retina (n = 6, respectively). Third, iganidipine (0, 10, or 30
      microg/kg: n = 6, 3, and 6, respectively) was intravenously injected to study the
      effects on intravitreously injected ET-1-induced retinal artery constriction to
      evaluate iganidipine levels in the posterior retina. Fourth, periocular
      penetration of iganidipine was studied by means of whole-head autoradiography
      after a single instillation of (14)C-iganidipine (0.09%, 30 microL; n = 5).
      RESULTS: Penetration of topically applied iganidipine to the cornea or aqueous
      humor was high and estimated to be at least 10 times higher than that reported
      for timolol or carteolol. Concentrations in the iris-ciliary body or retina
      choroid were much higher than in the plasma, both in the treated and control
      eyes, suggesting that iganidipine binds to uveal pigments. Twice-daily 20-day
      instillation of iganidipine (0.03%), but not of betaxolol (0.5%), significantly
      suppressed constriction of the retinal arteries induced by intravitreous
      injection of ET-1 at a dose of 2.5 or 0.5 ng in the ipsilateral eye. Intravenous
      injection of iganidipine at a dose of 30 microg/kg (giving a free plasma
      concentration of approximately 10(-8) M), but not at a dose of 10 microg/kg,
      significantly suppressed intravitreous ET-1-induced (0.5 ng) constriction of the
      retinal artery to a similar degree as twice-daily 20-day instillation of 0.03%
      iganidipine. After a single instillation of 0.09% iganidipine, the equivalent
      concentration of iganidipine in the ipsilateral retrobulbar periocular space
      estimated from autoradiography was approximately 3.9 x 10(-8) M between 15
      minutes and 1 hour after instillation, consistently higher than in the untreated
      contralateral eyes by approximately 3.0 x 10(-8) M (P = 0.043). CONCLUSIONS: In
      rabbits, topically instilled iganidipine, a Ca(2+) antagonist, in a 0.03%
      solution reaches the ipsilateral posterior retina or retrobulbar periocular space
      by local penetration at concentrations sufficient to act as a Ca(2+) antagonist.

PMID- 12601047
TI  - Effects of cloricromene, a coumarin derivative, on endotoxin-induced uveitis in
      Lewis rats.
AB  - PURPOSE: To investigate the effects of cloricromene, a coumarin derivative, in
      rats subjected to endotoxin-induced uveitis (EIU). METHODS: Endotoxin uveitis was
      induced in male Lewis rats by a single footpad injection of 200 microg
      lipopolysaccharide (LPS). Cloricromene was topically applied to the rat eye twice
      at 1 hour before and 7 hours after injection of LPS. A separate group of animals
      was treated with vehicle. Rats were killed 16 hours after injection and the eyes
      enucleated for histologic examination and immunohistochemical analysis. The
      effect of treatment was also evaluated by slit lamp examination, by the number of
      intraocular inflammatory cells on histologic sections, and by measuring the
      protein and TNFalpha levels in the aqueous humor. Nitrite and nitrate production
      was also measured in the aqueous humor. RESULTS: The histopathology of the iris
      ciliary body included inflammatory cell infiltration and nuclear modification of
      vessel endothelial cells. Cloricromene treatment reduced the inflammatory cell
      infiltration and improved histologic status of the ocular tissue.
      Immunohistochemical analysis for P-selectin, intracellular adhesion molecule
      (ICAM)-1, nitrotyrosine, and poly(ADP-ribose) synthetase (PARS) revealed a
      positive staining in inflammatory cell infiltration from LPS-treated rats. The
      degree of staining for P-selectin, ICAM-1, nitrotyrosine, and PARS was markedly
      reduced in tissue sections obtained from LPS-recipient rats that had received
      cloricromene. Cloricromene strongly inhibited cell infiltration, protein
      exudation, TNFalpha production, and nitrite-nitrate formation. CONCLUSIONS: This
      study provides the first evidence that cloricromene, a coumarin derivative,
      attenuates the degree of inflammation and tissue damage associated with EIU in
      rats.

PMID- 12601048
TI  - Effects of ion transport and channel-blocking drugs on aqueous humor formation in
      isolated bovine eye.
AB  - PURPOSE: To investigate the role of active chloride secretion by the ciliary
      epithelium in the formation of aqueous humor (AH), by using the in vitro perfused
      eye. METHODS: Bovine eyes collected from an abattoir were cannulated through the
      ophthalmic artery and perfused with oxygenated Krebs' solution at 37 degrees C.
      Aqueous humor formation (AHF) was measured by the fluorescein-dilution technique.
      Drugs were added to the perfusate and/or to the anterior chamber. RESULTS: NaK
      adenosine triphosphatase (ATPase) inhibitor, ouabain (1.0 mM), produced a
      significant reduction in AHF by 46% and 42% when added to the stromal or aqueous
      side, respectively. When added to both sides (1.0 mM), it produced a reduction of
      61%. Bumetanide (0.1 mM), a specific inhibitor of Na-K-2Cl cotransport, and
      furosemide (0.1 mM), a nonspecific anion transport inhibitor, produced 35% and
      45% reductions when applied to the stromal side. DIDS (0.001-0.1 mM), which is
      believed to inhibit the Cl-HCO(3) exchanger, Na-HCO(3) cotransporter, and
      chloride channel, produced a dose-dependent reduction when added to the stromal
      side. The inhibition was 55% by the highest concentration used. 5-Nitro-2-(3
      phenylpropylamino)-benzoic acid (NPPB; 0.1 mM), a chloride channel blocker in the
      nonpigmented cells, produced a 25% reduction when applied to the aqueous side.
      Acetazolamide (0.1 mM), a carbonic anhydrase inhibitor, applied to the stromal
      side, produced 31% reduction. CONCLUSIONS: At least 60% of the AH is formed by
      active secretion in bovine eyes. Transport of anions through the ciliary
      epithelium (CE), particularly the chloride ion, plays a crucial role in AHF.

PMID- 12601049
TI  - Subconjunctival nano- and microparticles sustain retinal delivery of budesonide,
      a corticosteroid capable of inhibiting VEGF expression.
AB  - PURPOSE: The purpose of this study was to determine whether budesonide inhibits
      expression of vascular endothelial growth factor (VEGF) in a retinal pigment
      epithelial cell line (ARPE-19) and to determine whether subconjunctivally
      administered budesonide nano- and microparticles sustain retinal drug levels.
      METHODS: The effect of budesonide (100 pM to 10 microM) on VEGF secretion,
      expression of VEGF mRNA, and cytotoxicity were determined in ARPE-19 cells by
      ELISA, RT-PCR, and a cell-viability assay, respectively. To determine the
      involvement of glucocorticoid receptor in the observed effects of budesonide,
      secretion and mRNA expression studies were also performed in the presence of a
      glucocorticoid receptor antagonist (RU486). DL-Polylactide (PLA) nano- and
      microparticles containing budesonide were prepared by a solvent evaporation
      technique, and the particles were characterized for size, morphology,
      encapsulation efficiency, and in vitro release. Budesonide-PLA nano- and
      microparticles were administered subconjunctivally to one eye of Sprague-Dawley
      rats and drug levels in the retina, vitreous, lens, and cornea of both eyes were
      determined at the end of 1, 7, and 14 days. RESULTS: At concentrations devoid of
      cytotoxicity, budesonide inhibited VEGF secretion as well as mRNA expression in
      ARPE-19 cells in a dose-dependent manner. RU486 treatment prevented budesonide
      mediated inhibition of VEGF secretion and VEGF mRNA expression. Budesonide-PLA
      nano- (345 nm) and microparticles (3.6 microm), with an encapsulation efficiency
      of 65% and 99%, respectively, sustained budesonide release in vitro. After
      subconjunctival administration, both budesonide-PLA nano- and microparticles
      produced sustained budesonide levels in the retina and other ocular tissues.
      CONCLUSIONS: Budesonide is capable of inhibiting VEGF expression through
      glucocorticoid receptor activity. Subconjunctivally administered budesonide-PLA
      nano- and microparticles sustain retinal drug delivery.

PMID- 12601050
TI  - Regulation of L-cystine transport and intracellular GSH level by a nitric oxide
      donor in primary cultured rabbit conjunctival epithelial cell layers.
AB  - PURPOSE: Metabolism and transport of cysteine are critical for maintenance of the
      intracellular glutathione (GSH) level. In this study, transport mechanisms of L
      cystine and regulation of GSH biosynthesis in the absence or presence of NO
      induced oxidant stress were investigated in primary cultured rabbit conjunctival
      epithelial cells (RCECs). METHODS: RCECs were grown in membrane filters to
      exhibit tight barrier properties. Uptake and transepithelial transport of L
      cystine were determined in the presence or absence of extracellular Na(+). Uptake
      was determined at 10 minutes after (14)C-L-cystine instillation into apical (a)
      or basolateral (b) bathing fluid. The effect of nitric oxide (NO) on L-cystine
      uptake, cellular GSH level, and expression level of two subunits of the rate
      limiting enzyme gamma-glutamylcysteine synthetase (GCS) was examined after a 24
      hour incubation of primary cultured RCECs with an NO donor, S-nitroso-N
      acetylpenicillamine (SNAP; N-acetyl-3-(nitrosothio)-D-valine. RESULTS: Cellular
      uptake of L-cystine by RCECs occurred through both Na(+)-dependent and 
      independent mechanisms. Uptake from apical fluid was higher than that from
      basolateral fluid, except for the highest concentration of L-cystine tested (200
      microM). Transepithelial permeability (P(app)) of L-cystine (at 2.5 microM) was
      three times higher in the a-to-b direction than in the b-to-a direction in the
      presence of Na(+), whereas the reverse was true in the absence of Na(+). Na(+)
      dependent L-cystine uptake from apical fluid was significantly elevated in
      primary cultured RCECs treated for 24 hours with various concentrations (0.1-2.0
      mM) of SNAP, with maximum uptake observed at 1 mM. A similar pattern of SNAP
      induced increase of Na(+)-independent L-cystine uptake from apical fluid was
      observed, whereas no significant difference was observed for basolateral uptake.
      Concomitantly, a significant elevation of intracellular GSH (up to fivefold
      versus the control) was recorded, with the highest increase occurring at 0.1 to
      0.25 mM SNAP. A parallel increase in the expression levels of both catalytic and
      regulatory subunits of GCS was observed by Western blot analysis of lysates from
      RCECs treated with 0.25 mM SNAP for 24 hours. CONCLUSIONS: L-Cystine is
      transported by both Na(+)-dependent and -independent amino acid transport systems
      in RCECs. At low substrate concentrations, L-cystine uptake was higher from
      apical than basolateral fluid. Permeability studies indicated net absorption of L
      cystine across RCECs. SNAP caused significant increases in both L-cystine uptake
      and intracellular GSH level, which occurred concomitantly with elevation of both
      catalytic and regulatory subunits of GCS. Understanding sulfur amino acid
      precursor-dependent cellular mechanisms of GSH homeostasis would be of value in
      devising GSH-based treatment for conjunctival or other ocular disorders.

PMID- 12601051
TI  - P2Y receptor-mediated stimulation of Muller glial cell DNA synthesis: dependence
      on EGF and PDGF receptor transactivation.
AB  - PURPOSE: To determine whether P2Y receptor-evoked proliferation of Muller glial
      cells depends on transactivation of receptor tyrosine kinases. METHODS: Primary
      cultures of Muller cells of the guinea pig were treated with test substances for
      16 hours. The DNA synthesis rate was assessed by a bromodeoxyuridine (BrdU)
      immunoassay, and the phosphorylation states of the extracellular signal-regulated
      kinase (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) were
      determined by Western blot analysis. RESULTS: In Muller cells, the mitogenic
      effect of P2Y receptor activation by extracellular adenosine triphosphate (ATP)
      depended on transactivation of both the platelet-derived growth factor (PDGF) and
      the epidermal growth factor (EGF) receptor tyrosine kinases, as suggested by the
      blocking effects of the tyrphostins AG1296 and AG1478 on the ATP-induced
      proliferation and phosphorylation of ERK1/2. Moreover, the PDGF-induced
      proliferation may depend on transactivation of the EGF receptor kinase.
      Antibodies against heparin-binding EGF (HB-EGF) or PDGF, as well as inhibition of
      matrix metalloproteinases (MMPs) blocked ATP-evoked proliferation. At least one
      metalloproteinase (MMP-9), was implicated in the signal transfer from P2Y to EGF
      receptors. In contrast, the mitogenic effect of fetal calf serum was independent
      of growth factor receptor activity. P2Y receptor activation stimulated Muller
      cell proliferation by activating the ERK1/2 and the phosphatidylinositol 3 (PI3)
      kinase signaling pathways, whereas the p38 MAPK pathway was not involved in
      mitogenic signaling. CONCLUSIONS: The present data suggest that P2Y-receptor
      induced mitogenic signaling in Muller cells is mediated by transactivation of the
      PDGF and EGF receptor tyrosine kinases. The transactivation may be mediated by
      release of PDGF and MMP-dependent shedding of HB-EGF from the Muller cell matrix,
      respectively. The transactivation of the receptor tyrosine kinases may result in
      activation of ERK1/2 and PI3 kinase and an increase in the proliferation rate.

PMID- 12601053
TI  - Glutathione peroxidase induced in rat retinas to counteract photic injury.
AB  - PURPOSE: To examine the hypothesis that glutathione peroxidase (GPX) is induced
      at different time points after retinal exposure to light and localizes in
      different retinal cells. METHODS: The rats were kept in cyclic light for 2 weeks
      before the experiments. The animals were maintained in 12-hour light-dark cycles,
      before and after exposure to intense white fluorescent light, for as long as 24
      hours and then returned to cyclic light. Expression of GPX was measured by
      immunohistocytochemistry and Western and Northern blot analyses. Light-induced
      retinal damage was determined by the thickness of the outer nuclear layer (ONL)
      thickness in relation to total retinal thickness. RESULTS: GPX labeling did not
      appear in the photoreceptor inner segments, and slight labeling was observed in
      the photoreceptor outer segments or the retinal pigment epithelial (RPE) cells in
      the normal retina kept in cyclic light. In retinal specimens maintained in light
      for 12 and 24 hours, GPX labeling was induced in the photoreceptor outer segments
      and RPE cells. High expression of GPX in the RPE was sustained until day 7 after
      challenge. In contrast, GPX expression in the photoreceptor outer segments
      decreased on day 1 and disappeared on days 3 and 7 after exposure. Intense GPX
      labeling was seen from the internal limiting membrane to the ganglion cell layer.
      GPX labeling was constantly localized in both high-intensity white light and
      cyclic conditions, suggesting no induction of GPX in those areas. In addition,
      GPX labeling was apparent at the posterior retinal pole but not at the peripheral
      retina. We observed marked upregulation of GPX mRNA in rats kept in high
      intensity white light. One, 3, and 7 days after exposure to high-intensity white
      light, there was a significant difference (P < 0.0001) between the control and
      experimental groups in the ratio of the outer nuclear layer thickness to the
      entire retina. CONCLUSIONS: GPX was induced at different time points after
      exposure to high-intensity white light and localized in different retinal cells.
      Changes in expression of GPX after exposure to light may be related to the
      difference in susceptibility of the retina to damage by light.

PMID- 12601052
TI  - Female gender, estrogen loss, and Sub-RPE deposit formation in aged mice.
AB  - PURPOSE: Estrogen status influences the incidence and severity of many diseases
      in women. Because women with early menopause appear at risk for worse ARMD,
      estrogen deficiency may also contribute to the onset or severity of ARMD in
      women. It has been observed that aged male C57BL/6 mice fed a high-fat diet and
      briefly exposed to blue-green light exhibit development of significant sub-RPE
      deposits and mild Bruch's membrane (BrM) thickening. This model was used in an
      attempt to delineate the role of gender and estrogen status in this model.
      METHODS: C57BL/6 male and female mice of 9 or 16 months were fed a high-fat diet
      for 4.5 months. Several groups of 9-month-old female mice underwent estrogen
      depletion by ovariectomy, with or without supplementation with exogenous 17beta
      estradiol. After 4 weeks of a high-fat diet, the eyes were exposed to seven 5
      second doses of nonphototoxic levels of blue-green light over 2 weeks. Three and
      a half months after cessation of blue light treatment, transmission electron
      microscopy was performed to assess severity of deposits, BrM changes, and
      choriocapillaris endothelial morphology. In some mice, gelatin zymography and
      Western blot analyses were performed on protein extracts of freshly isolated RPE
      to determine the effect of estrogen on matrix metalloproteinase (MMP)-2 activity
      in the RPE. RESULTS: Both male and female 16-month-old mice showed qualitatively
      similar basal laminar deposit morphology, but the severity of thickness,
      continuity, and content was significantly greater in female mice. Aged female
      mice also demonstrated a trend toward more severe endothelial changes and
      increased BrM thickening compared with age-matched male mice. Ovariectomized
      middle-aged mice showed more severe deposits than sham-surgery control animals.
      However, ovariectomized mice that received high-dose estrogen supplementation
      also showed significant deposits, although they had thinner BrMs than did the
      estrogen-deficient mice. Loss of RPE MMP-2 activity correlated with deposit
      severity, with estrogen-deficient mice expressing less MMP-2 than ovary-intact
      control mice. CONCLUSIONS: Female gender in aged mice and estrogen deficiency in
      middle-aged mice appears to increase the severity of sub-RPE deposit formation.
      Estrogen deficiency may increase susceptibility to formation of sub-RPE deposits
      by dysregulating turnover of BrM, contributing to collagenous thickening and
      endothelial changes. Estrogen supplementation at the dosages used in this study
      does not appear to protect against formation of sub-RPE deposits.

PMID- 12601054
TI  - Mechanism of inhibitory actions of oxidizing agents on calcium-activated
      potassium current in cultured pigment epithelial cells of the human retina.
AB  - PURPOSE: To identify the mechanisms by which oxidative stress with oxidizing
      agents alters the activity of ion channels in human retinal pigment epithelial
      (RPE) cells. METHODS: The effects of oxidizing agents on ion currents were
      investigated in human RPE R-50 cells with the aid of the whole-cell, cell
      attached, and inside-out configurations of the patch-clamp technique. RESULTS: In
      the whole-cell configuration, t-butyl hydroperoxide (t-BHP; 1 mM), thimerosal (30
      microM), and 4,4'-dithiodipyridine (DTDP; 30 microM) suppressed voltage-dependent
      K(+) current (I(K)) that was sensitive to inhibition by iberiotoxin or paxillin,
      yet not by apamin or 5-hydroxydecanoate sodium. Meclofenamic acid or Evans blue,
      but not diazoxide, reversed the decrease in I(K) caused by t-BHP. In cells
      dialyzed with ceramide (30 microM), neither t-BHP (1 mM) nor thimerosal (30
      microM) had any effect on I(K), whereas DTDP (30 microM) slightly suppressed it.
      In cell-attached recordings, t-BHP (1 mM), thimerosal (30 microM), and DTDP (30
      microM) suppressed the activity of large-conductance Ca(2+)-activated K(+)
      (BK(Ca)) channels. Dithiothreitol (10 microM) reversed DTDP-induced decrease in
      channel activity. Under current-clamp conditions, cell exposure to oxidizing
      reagents caused membrane depolarization. In cells dialyzed with ceramide (30
      microM), membrane potential remained unaltered in the presence of t-BHP.
      CONCLUSIONS: The results demonstrate that hydrophilic oxidants (e.g., t-BHP and
      thimerosal) suppress I(K) and suggest that the underlying mechanism of this
      inhibitory action may involve the generation of intracellular ceramide. However,
      the inhibition of BK(Ca) channels by DTDP, a membrane-permeable oxidant, in human
      RPE cells may result from the direct inhibition of BK(Ca) channels and indirectly
      from an increase in the intracellular production of ceramide.

PMID- 12601055
TI  - Stray light-induced multifocal electroretinograms.
AB  - PURPOSE: To evaluate the characteristics of stray light-induced response in
      multifocal ERG (mfERG) elicited by the stimulus falling on the disc. METHODS: A
      patient with an enlarged optic disc (4 x 4 disc diameters of disc of normal
      fellow eye) and four normal volunteers served as subjects. The mfERGs elicited by
      different stimulus intensities (0.67-4.67 cd-sec/m(2)) were recorded from the
      patient, and the mfERGs obtained with stimuli on the enlarged optic disc. For
      comparison, full-field pseudorandom ERGs (ffprERGs) were also recorded in all
      subjects. The first-order kernels (K1) and the second-order kernels (K2.1) were
      analyzed. RESULTS: A small and delayed K1 was recorded on the enlarged disc, but
      K2.1 was flat on the disc at all intensities. The implicit time of K1 at lower
      intensities was longer than at higher intensities. ffprERGs at very low
      intensities in the patient and normal subjects were similar to the mfERG on the
      disc (delayed K1 associated with flat K2.1). CONCLUSIONS: The responses elicited
      by stimulating the disc were delayed in K1 and flat in K2.1. Because similar
      ffprERGs were observed at very low intensities, it is likely that an optic disc
      with high reflectance scattered the stimulus light to create a weak full-field
      stimulus. Thus, care must be taken when focal lesions are investigated with
      mfERGs.

PMID- 12601056
TI  - Accumulation of neurocan, a brain chondroitin sulfate proteoglycan, in
      association with the retinal vasculature in RCS rats.
AB  - PURPOSE: To examine whether and how the retinal distribution of the chondroitin
      sulfate proteoglycan neurocan is affected after photoreceptor cell loss and
      whether it correlates with the multiple secondary cellular changes that accompany
      the photoreceptor degeneration. METHODS: Retinas from normal rats (Sprague
      Dawley; postnatal days [P]0-P70), RCS rats with dystrophic retinas (P0-P300), RCS
      rdy(+) congenic rats with nondystrophic retinas (P0-202), and rhodopsin mutant
      rats, P23H (P0-P257) and S334ter (P0-P220), were processed for
      immunohistochemistry using a polyclonal antibody to rat neurocan. RESULTS: The
      overall distribution of neurocan was similar in all retinas examined. Neurocan
      immunostaining was detected over the nerve fiber layer, the plexiform layers, the
      photoreceptor outer segments region, and the ciliary epithelium. With age,
      labeling throughout the plexiform layers decreased continuously. In RCS rats
      however, conspicuous labeling was also seen in association with retinal vessels,
      from P15 onward. CONCLUSIONS: Accumulation of neurocan in association with the
      retinal vasculature does not correlate with photoreceptor cell loss, because it
      was not observed in the rhodopsin mutant rats. During the earliest stages of the
      disease, accumulation of debris in the subretinal space in RCS rats may be
      sufficient per se to initiate a cascade of metabolic changes that result in
      accumulation of neurocan. With time, the neurocan accumulated perivascularly may,
      by interaction with other matrix molecules, modulate at least some of the
      vascular alterations observed in this animal model.

PMID- 12601057
TI  - Caspase activation in an experimental model of retinal detachment.
AB  - PURPOSE: To test for apoptotic photoreceptor cell death and caspase activation as
      a function of time after induction of an experimental retinal detachment.
      METHODS: Retinal detachments were created in Brown Norway rats by injecting 10%
      hyaluronic acid into the subretinal space using a transvitreous approach. Light
      microscopy and terminal dUTP-biotin nick end-labeling (TUNEL) was performed at 1,
      3, 5, and 7 days after detachment to assess for the morphologic features
      associated with apoptosis. Western blot analysis of retinal protein extracts was
      performed using antibodies against caspase-3, -7, and -9 and poly-ADP ribose
      polymerase (PARP) at 1, 3, and 5 days after detachment. RESULTS: Light
      microscopic analysis of detached retinas showed the presence of pyknotic nuclei
      in the outer nuclear layer and disruption of the normal organization of the
      photoreceptor outer segments. TUNEL-staining was positive in the outer nuclear
      layer only in the detached portions of the retina. Western blot analysis
      confirmed the time-dependent activation of caspase-3, -7, and -9 and PARP in the
      detached retinas. No morphologic stigmata of apoptosis or caspase activation was
      detected in attached retinas. CONCLUSIONS: The apoptotic photoreceptor cell death
      in experimental retinal detachments is associated with caspase activation.

PMID- 12601058
TI  - Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome
      caused by mutations in NR2E3.
AB  - PURPOSE: To determine the relationship between cone deactivation kinetics in
      patients with the enhanced S cone syndrome (ESCS) caused by mutations in NR2E3
      and the immunoreactivity to G-protein-coupled receptor kinase 1 (GRK1) and GRK7.
      METHODS: Electroretinogram (ERG) photoresponses were used to investigate
      activation kinetics of cones with a model of cone phototransduction. Deactivation
      kinetics of cones after bright flashes was quantified with a paired-flash ERG
      paradigm. Immunocytochemistry was performed with antibodies against cone opsins
      and kinases GRK1 and GRK7 in postmortem normal and ESCS retinal tissue. RESULTS:
      Activation kinetics of long/middle-wavelength-sensitive (L/M) cone-mediated
      responses in patients with ESCS were similar to those of normal L/M cones.
      Activation kinetics of ESCS short-wavelength-sensitive (S) cones, when compared
      with normal L/M cone responses evoked by the same stimulus, were slower by an
      amount consistent with the expected differences in spectral sensitivities. After
      bright flashes chosen to evoke identical activation kinetics, ESCS S cones
      deactivated much more slowly than ESCS or normal L/M cones. Normal human retina
      revealed strongly labeled cone outer segments with anti-GRK1 and anti-GRK7. In an
      ESCS retina, outer segments positive for L/M opsin were strongly labeled with
      anti-GRK1, whereas outer segments positive for S opsin showed no detectable GRK1
      reactivity. GRK7 labeling was absent in all photoreceptors of the ESCS retina.
      CONCLUSIONS: The cone-dominant human retina resulting from NR2E3 mutations
      affords greater understanding of the physiological roles of GRK1 and GRK7 in
      human cone photoreceptors. Normal deactivation kinetics in human L/M cones can
      occur without GRK7 when GRK1 is present in ESCS, but does not occur when GRK7 is
      present but GRK1 is deficient in Oguchi disease. Lack of both GRK1 and GRK7 in S
      cones of patients with ESCS results in a more pronounced abnormality in
      deactivation kinetics and suggests the existence of partial compensation by
      either GRK when the other is deficient.

PMID- 12601059
TI  - Diagnosis of autosomal dominant retinitis pigmentosa by linkage-based exclusion
      screening with multiple locus-specific microsatellite markers.
AB  - PURPOSE: To describe a hierarchical approach for efficient genetic diagnosis of
      autosomal dominant retinitis pigmentosa (adRP). METHODS: Forty di-, tri-, or
      tetra-nucleotide repeats tightly linked to 10 genes known to be responsible for
      adRP were identified from the human genome sequence and used as markers in
      multiplex amplification and genotyping, followed by linkage analysis. Discordance
      of cosegregation of markers and the disease excluded the majority of the examined
      genes as candidates, and mutation screening for the remaining genes was
      performed. RESULTS: With this strategy, examination of an adRP-affected family
      indicated that 3 of 10 candidate genes segregated concordantly with the disease.
      Further searches for mutations revealed a novel insertion and deletion in the
      last exon of a splicing factor gene, PRPF8. CONCLUSIONS: This systematic approach
      facilitates the molecular diagnosis of adRP, which is known to have a highly
      heterogeneous genetic background.

PMID- 12601060
TI  - The role of Fas-FasL in the development and treatment of ischemic retinopathy.
AB  - PURPOSE: Define a role for Fas-FasL in oxygen-induced retinopathy and explore the
      mechanism of pigment-epithelium-derived growth factor (PEDF) inhibition in this
      model. METHODS: Seven-day-old mice C57BL/6J (B6), FasL-defective (B6-gld), or Fas
      defective (B6-lpr) mice were exposed to 75% oxygen for 5 days (postnatal day [P]7
      P12) and returned to room air. On day P17, vascular architecture was assessed
      microscopically after perfusion with FITC-dextran, and preretinal nuclei were
      quantified by PAS and hematoxylin staining. In some experiments, mice were
      treated intraperitoneally with PEDF. Vascular architecture and preretinal nuclei
      counts were compared with those in PBS-treated control animals. RESULTS: Oxygen
      induced retinopathy was significantly increased in FasL-defective gld mice
      compared with wild-type B6 animals. This was manifested by an increase in the
      number of microaneurysms, neovascular tufts, and preretinal nuclei. PEDF
      treatment prevented retinopathy in B6, B6-gld, and B6-lpr mice. CONCLUSIONS: Fas
      FasL interactions regulate the extent of oxygen-induced retinal
      neovascularization. The inhibition of neovascularization in B6 gld, and B6-lpr
      mice by PEDF suggests that Fas-FasL interactions are probably not the mechanism
      for inhibition in this model.

PMID- 12601061
TI  - Double cone dystrophy and RPE degeneration in the retina of the zebrafish gnn
      mutant.
AB  - PURPOSE: To characterize morphologic alterations in the retina of the visual
      mutant zebrafish gantenbein (gnn) and to examine whether these alterations
      correlate with those present in human hereditary eye diseases. METHODS: The gnn
      mutant was isolated by behavioral and macroscopic screening. Retinas of gnn
      zebrafish larvae were examined at different developmental stages from 2 to 9 days
      postfertilization (dpf) by standard histologic staining techniques and by
      immunocytochemistry. Ultrastructural alterations were examined by electron
      microscopy. The genetic map position of the induced mutation was identified by
      mapping with two candidate primer pairs on single larvae. RESULTS: The gnn mutant
      exhibited shortened outer photoreceptor segments and altered RPE morphology. In
      the photoreceptor layer of the mutant, the total number of lectin-labeled cones
      was reduced in all developmental stages from 2 to 7 dpf, whereas the amount of
      rhodopsin-positive cells remained at the wild-type (WT) level. Labeling with
      zebrafish opsin antibodies revealed dystrophic red cones at 5 dpf, whereas the
      morphology of all other cone types was largely unaffected. Electron microscopy
      unveiled electron-dense deposits between the discs of the double cone outer
      segments. In addition, the onset of progressive RPE degeneration was observed at
      this stage of development. At later stages, all cone types and the RPE became
      degenerative. The morphology of distinct second-order neurons remained largely
      unaffected by the mutation. The gnn mutation was located approximately 4.3 cM
      from the simple sequence length polymorphism (SSLP) marker Z15453 on linkage
      group 16. CONCLUSIONS: In gnn mutant zebrafish, cones, and especially red cones,
      are dystrophic in early retinal development. Subsequent to this cone dystrophy,
      the RPE becomes dysfunctional and starts to degenerate in later stages of
      development. Thus, the early developmental morphology of gnn exhibits
      similarities to cone dystrophies most commonly seen in age-related macular
      degeneration (AMD) among humans, whereas the later stages of degeneration in gnn
      resemble RPE alterations in retinitis pigmentosa (RP) in humans. The gnn
      zebrafish mutant may therefore be a useful model for examining the possible
      interplay and connection between cone dystrophy and RPE degeneration.

PMID- 12601062
TI  - Retinal preconditioning and the induction of heat-shock protein 27.
AB  - PURPOSE: Brief periods of ischemia have been shown to protect the retina from
      potentially damaging periods of ischemia. This phenomenon has been termed
      ischemic preconditioning or ischemic tolerance. In the present study the cellular
      changes in levels of heat shock protein (Hsp)27, -70, and -90 mRNA and expression
      of Hsp in the rat retina associated with ischemic preconditioning were evaluated.
      METHODS: Unilateral retinal ischemia was created in Long-Evans and Sprague-Dawley
      rats for 5 minutes. Rats were then left for 1 hour to 7 days, to allow the retina
      to reperfuse. Retinas were dissected, the mRNA and protein isolated, and Northern
      and Western blot analyses conducted to detect changes in expression of Hsp27, 
      70, and -90. Immunohistochemical studies were used to identify retinal regions
      where Hsp changes occurred. Selected animals were subjected to a second ischemic
      event, 60 minutes in duration, to correlate the changes in expression of Hsp with
      functional protection of the retina from ischemic injury. RESULTS: In control and
      sham-treated animals retinal Hsp27, -70, and -90 mRNAs were detectable. Five
      hours after retinal preconditioning, levels of Hsp27 mRNA were elevated above
      control levels, and 24 hours later, mRNA levels increased 200% over basal levels.
      Hsp27 expression remained elevated for up to 72 hours and then began to return to
      control levels. Hsp27 protein levels were increased by 200% over basal levels 24
      hours after retinal preconditioning, remained at this level for 72 hours, and
      then returned to control levels. In contrast, no consistent change in Hsp70 or 
      90 mRNA or protein levels was observed during the course of the study.
      Immunohistochemical studies demonstrated that the increase in expression of Hsp27
      was localized to neuronal and non-neuronal cells in the inner layers of the
      retina. Electroretinography studies demonstrated a strong correlation between the
      protection of retinal function from ischemic injury and the expression of Hsp27.
      CONCLUSIONS: These results provide evidence that the induction of Hsp27 is a gene
      specific event associated with ischemic preconditioning in the retina. This
      increase in expression of Hsp27 occurs in both neuronal and non-neuronal retinal
      cells, and appears to be one component of the neuroprotective events induced by
      ischemic preconditioning in the retina.

PMID- 12601064
TI  - Blue light-induced generation of reactive oxygen species in photoreceptor
      ellipsoids requires mitochondrial electron transport.
AB  - PURPOSE: To investigate whether photoreceptor ellipsoids generate reactive oxygen
      species (rOx) after blue light illumination. METHODS: Cultured salamander
      photoreceptors were exposed to blue light (480 +/- 10 nm; 10 mW/cm(2)). The light
      induced catalytic redox activity in the culture was monitored with the use of
      3,3'-diaminobenzidine (DAB). Tetramethylrhodamine ethyl ester (TMRE) and 2',7'
      dichlorodihydro-fluorescein acetate (DHF-DA) were used as probes to measure the
      mitochondrial membrane potential and intracellular rOx, respectively. RESULTS: A
      significant deposit of DAB polymers was found in the culture after exposure to
      blue light. Basal levels of rOx were observed in photoreceptor ellipsoids when
      cells were stained with DHF-DA. This staining colocalized with TMRE. After
      exposure to blue light, a sharp increase of rOx immediately occurred in the
      ellipsoids of most photoreceptors. When the light intensity was reduced, the
      response kinetics of rOx generation were slowed down; however, comparable amounts
      of rOx were generated after a standard time of exposure to light. The production
      of rOx in photoreceptors was markedly decreased when an antioxidant mixture was
      included in the medium during exposure to light. Rotenone or antimycin A, the
      respiratory electron transport blockers at complex I and III, respectively,
      significantly suppressed the light-evoked generation of rOx. CONCLUSIONS: A
      robust amount of rOx is produced in the ellipsoid when photoreceptors are exposed
      to blue light. This light-induced effect is antioxidant sensitive and strongly
      coupled to mitochondrial electron transport. The cumulative effect of light on
      rOx generation over time may implicate a role for mitochondria in light-induced
      oxidative damage of photoreceptors.

PMID- 12601063
TI  - Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and
      neural retina of the 5A11/basigin-null mouse.
AB  - PURPOSE: The neural retina expresses multiple monocarboxylate transporters (MCTs)
      that are likely to play a key role in the metabolism of the outer retina.
      Recently, it was reported that targeting of MCT1 and -4 to the plasma membrane
      requires association with 5A11/basigin (CD147). In the present study, the
      hypothesis that reduced amplitudes in the electroretinograms in the 5A11/basigin
      null mouse (Bsg(-/-)) may be linked to altered expression of MCTs was studied.
      METHODS: The expression and subcellular distribution of MCTs in Bsg(-/-) mice was
      analyzed by immunofluorescence microscopy with isoform-specific antibodies.
      Protein expression was analyzed by Western blot analysis, and mRNA expression was
      examined with RT-PCR. RESULTS: Immunofluorescence labeling of tissue sections
      from the Bsg(-/-) mice revealed a dramatic reduction in labeling with MCT
      antibodies. There was a loss of MCT1 labeling in the apical membrane of the RPE
      and in the neural retina. MCT3, which is expressed in the basolateral membrane of
      the RPE wild-type mouse, was expressed at very low levels in both the apical and
      basolateral membranes of the Bsg(-/-) mouse. There was no change in expression or
      distribution of the glucose transporter (GLUT)-1 in the RPE and retina of the
      Bsg(-/-) mouse. Western blot analysis of detergent-soluble lysates prepared from
      wild-type and Bsg(-/-) eyes confirmed that the levels of MCT1, MCT3, and MCT4
      protein were severely reduced in Bsg(-/-) mice. RT-PCR analyses of mRNA levels
      from wild-type and Bsg(-/-) mice demonstrated that the MCT1 transcript was
      expressed at normal levels in Bsg(-/-) mice. CONCLUSIONS: In Bsg(-/-) mice, there
      is a severe reduction in accumulation of the MCT1 and -3 proteins in the RPE and
      a concomitant reduction in MCT1 and -4 in the neural retina supporting a role for
      5A11/basigin in the targeting of these transporters to the plasma membrane.
      Decreased expression of MCT1 and -4 on the surfaces of Muller and photoreceptor
      cells may compromise energy metabolism in the outer retina, leading to abnormal
      photoreceptor cell function and degeneration.

PMID- 12601065
TI  - Activation and role of MAP kinase-dependent pathways in retinal pigment
      epithelium cells: JNK1, P38 kinase, and cell death.
AB  - PURPOSE: Retinal pigment epithelial (RPE) cell death is an important step in the
      pathogenesis of ocular diseases. JNK1 and P38 kinase, two stress-activated
      kinases, play key roles relaying stress signals leading to cell death through
      cyclin D1 and c-Myc. Recently, stress-activated kinases have been shown to
      regulate cell proliferation. In the current study, the involvement of the JNK1
      and P38 kinase signaling pathways in RPE cell proliferation and death was
      investigated. METHODS: RPE cell proliferation was stimulated with 10% fetal calf
      serum (FCS). Activation of the JNK1 and P38 kinase cascades and their potential
      targets was detected by Western blot analysis. Pharmacologic inhibitors and
      activators, and antisense oligodeoxynucleotides (ODN) directed against the stress
      kinases were used to analyze the signaling involved in RPE cell death. RESULTS:
      P38 and JNK1 and their respective upstream activating kinases, MKK3/6 and -4,
      were all transiently activated in FCS-stimulated RPE cell cultures. Ras
      controlled only the activation of JNK1, whereas Rho transmitted the activation of
      both JNK1 and P38, suggesting parallel signaling pathways and cross talk between
      the two kinases. Pharmacologic inhibition of JNK1 did not affect cell
      proliferation in FCS-stimulated cells. Inactivation of P38 kinase and antisense
      ODN-induced downregulation of P38 kinase also had no affect on cell
      proliferation. Long-term, high-level activation of JNK1 and P38 kinase occurred
      during serum depletion-induced RPE cell death. Overactivation of JNK1 and P38
      kinase was also observed during pharmacologically induced cell death, suggesting
      that this process is common to RPE cell-death-signaling pathways induced by
      various stress stimuli. Cell death mediated by the overactivation of JNK1 and P38
      kinase was cyclin D1- and c-Myc-independent. CONCLUSIONS: The inhibition of JNK1
      or P38 kinase had no effect on FCS-stimulated proliferation of RPE cells, whereas
      the overactivation of these two enzymes was involved in RPE cell death in FCS
      depleted cultures. Parallel upstream signaling pathways and cross talk between
      the two kinases suggest that the regulation of signaling in RPE cell death is
      complex.

PMID- 12601066
TI  - Variable effects of previously untested muscarinic receptor antagonists on
      experimental myopia.
AB  - PURPOSE: Atropine, pirenzepine, and himbacine prevent form-deprivation myopia
      (FDM) when administered intravitreously. The mechanisms and sites of action of
      these drugs against myopia are not clear. To shed further light on whether this
      mechanism is muscarinic, several other muscarinic antagonists were tested.
      METHODS: Various concentrations of atropine, pirenzepine, dexetimide,
      scopolamine, tropicamide, benztropine, dicyclomine, gallamine, mepenzolate,
      oxyphenonium, propantheline, procyclidine, 4-diphenylacetoxy-N-methylpiperidine
      (4-DAMP), hexahydro-sila-difenidol (HHSiD), p-fluorohexahydro-sila-difenidol (pf
      HHSiD), methoctramine, AFDX-116, and quinuclidinyl benzilate (QNB) were injected
      into goggled eyes of Leghorn cockerels three times at 48-hour intervals. Fellow
      control eyes received saline. Control animals received saline in both eyes.
      Twenty-four hours after final injections, refraction, eye weight, and axial
      length were measured, and eyes were prepared for microscopy. RESULTS: Other than
      atropine and pirenzepine, only oxyphenonium caused full rescue from FDM (goggled
      versus control; mean +/- SD; refraction differences: -9.50 +/- 0.22 D vs. 0.83 +/
      0.31 D, P < 0.001; wet weight differences: 75.67 +/- 3.84 mg vs. 2.33 +/- 6.14
      mg, P < 0.001; axial length differences: 0.80 +/- 0.05 mm vs. 0.03 +/- 0.04 mm, P
      < 0.001). Oxyphenonium-treated retinas showed no damage. Of the other compounds,
      several elicited partial rescue and/or damaged the retina, whereas others had no
      effect. CONCLUSIONS: Oxyphenonium prevents FDM in chicks. The ineffectiveness or
      partial effectiveness of other compounds, coupled with the high concentrations of
      effective compounds required to prevent FDM, suggests that muscarinic antagonists
      act to prevent FDM, either at sites distant from the retina, or through a
      nonmuscarinic mechanism, on which only some of these drugs act.

PMID- 12601067
TI  - Effect of mutant IkappaB on cytokine-induced activation of NF-kappaB in cultured
      human RPE cells.
AB  - PURPOSE: The nuclear transcription factor (NF)-kappaB is a central regulator of
      multiple inflammatory cytokines. The current study was conducted to determine
      whether infection of human retinal pigment epithelial (RPE) cells by adenovirus
      carrying a mutant inhibitory (I)-kappaB (IkappaB) transgene inhibits cytokine
      induced activity of NF-kappaB and expression of NF-kappaB-dependent cytokines by
      preventing degradation of IkappaB. The persistence of recombinant protein
      expression and function after the viral infection was also examined. METHODS:
      Cultured human RPE cells were infected with adenovirus encoding either beta
      galactosidase (LacZ) or mutant IkappaB and were treated with interleukin (IL)
      1beta or tumor necrosis factor (TNF)-alpha. IkappaB protein expression was
      determined by Western blot. NF-kappaB nuclear translocation was evaluated by
      immunofluorescence, and functional NF-kappaB activation was determined by
      luciferase reporter assay. NF-kappaB-dependent cytokine gene expression was
      determined by reverse transcription-polymerase chain reaction. IL-1beta-induced
      monocyte chemoattractant protein (MCP)-1 protein secretion was measured by enzyme
      linked immunosorbent assay. RESULTS: Stimulation of RPE cells with IL-1beta or
      TNF-alpha caused rapid degradation of the endogenous, but not mutant, IkappaB
      protein. Expression of the mutant IkappaB isoform inhibited cytokine-stimulated
      NF-kappaB nuclear translocation, NF-kappaB transcriptional activity, NF-kappaB
      dependent gene expression, and secretion of MCP-1. Significant levels of mutant
      IkappaB protein were expressed for at least 7 weeks after infection. CONCLUSIONS:
      Infection of human RPE by an adenoviral vector carrying a mutant IkappaB
      transgene blocks NF-kappaB activation and expression of multiple NF-kappaB
      dependent cytokine genes over an extended period. This technique will be useful
      to determine the role of NF-kappaB in experimental proliferative
      vitreoretinopathy (PVR), and may offer a novel approach to treatment of PVR with
      a gene therapy approach.

PMID- 12601068
TI  - The effect of ischemic preconditioning on light-induced photoreceptor injury.
AB  - PURPOSE: To determine whether ischemic preconditioning (IPC) upregulates certain
      retinal survival factors and to assess the protective effect of retinal IPC
      against light-induced photoreceptor degeneration. METHODS: Albino rats underwent
      IPC induced by raising the intraocular pressure in one eye to 120 mm Hg for 5
      minutes. The fellow eye underwent sham treatment. Basic fibroblast growth factor
      (bFGF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor
      (BDNF), glial fibrillary acidic protein (GFAP), and Bcl-2 were measured after 6
      and 48 hours, by the reverse transcription-polymerase chain reaction and
      immunoblot analysis. Other preconditioned rats received 48 hours of photic injury
      (2000 lux) 24 hours after IPC. The a- and b-wave amplitudes of the flash
      electroretinograms were measured 5 days later, followed by analysis of rhodopsin
      mRNA levels and histology. The influence of adenosine A1 receptor blockade was
      assessed. RESULTS: bFGF, GFAP, and Bcl-2 were upregulated after IPC. BDNF was not
      upregulated. The marked reduction of the a- and b-wave amplitudes and the
      structural injury to the photoreceptors induced by the photic insult were
      significantly reduced by IPC. The protection afforded by IPC was not influenced
      by adenosine A1 antagonism. CONCLUSIONS: IPC upregulates bFGF, GFAP, and Bcl-2
      and protects photoreceptors against light-induced injury. These factors may be
      involved in the protective response.

PMID- 12601069
TI  - Tractional force generation by human muller cells: growth factor responsiveness
      and integrin receptor involvement.
AB  - PURPOSE: To assess the ability of human Muller cells to generate tractional
      forces and to determine the role of growth factors and collagen binding integrins
      in this process. METHODS: Muller cells were isolated from papain-DNase-digested
      human retina. Cell identity and changes in cell phenotype were confirmed by
      immunodetection of glial fibrillary acidic protein (GFAP), cellular retinaldehyde
      binding protein (CRALBP), vimentin, and alpha-smooth muscle actin (alpha-SMA).
      Generation of tractional force was assessed with a tissue culture assay involving
      incubation of cells on three-dimensional collagen gels. The effects of
      contraction-promoting growth factors were examined by adding these directly to
      the culture medium. Muller cell expression and the involvement of specific
      integrin receptors were assessed by immunodetection, RT-PCR, and subunit-specific
      blocking antibodies. RESULTS: During maintenance in culture, human Muller cells
      adopted a fibroblast-like phenotype capable of generating tractional forces.
      Matrix contraction was stimulated in a dose-dependent fashion by insulin-like
      growth factor I and platelet-derived growth factor. Modest responses were
      observed with high concentrations of transforming growth factor (TGF)-beta1 and 
      beta2. Muller cells express all four integrin subunits that comprise the collagen
      binding receptors including alpha1, alpha2, alpha3, and beta1. Blocking
      antibodies against receptor subunits alpha2 and beta1 significantly reduced the
      overall rate of matrix contraction. Antibodies against the alpha1 subunit were
      modestly inhibitory, whereas anti-alpha3 was without effect. CONCLUSIONS: Human
      Muller cells acquire the capacity to generate tractional forces in vitro and the
      contraction-promoting growth factors insulin-like growth factor (IGF)-I and
      platelet-derived growth factor (PDGF) are potent stimuli. Generation of
      tractional force by Muller cells primarily involves integrin receptors containing
      alpha2 and beta1 subunits.

PMID- 12601070
TI  - Conventional pattern-reversal VEPs are not equivalent to summed multifocal VEPs.
AB  - PURPOSE: To compare conventional pattern-reversal visual evoked potentials
      (cVEPs) with multifocal VEPs (mfVEPs). METHODS: mfVEPs and cVEPs were recorded
      during the same session in 12 normal subjects with an active electrode at Oz
      referenced to the inion (Oz-In) or to a midfrontal position, Fz (Oz-Fz). The
      mfVEP stimulus, a 60-sector dartboard, had a mean luminance of 100 cd/m(2) and a
      diameter of 42.2 degrees. The cVEP checkerboard stimulus subtended 21 degrees,
      had a mean luminance of 75 cd/m(2) and a contrast of 90%. Transient responses
      (2.5 Hz) were recorded for check sizes ranging from 12 to 50 minutes of arc
      (minarc). White cardboard masks were used to isolate upper and lower hemifields,
      within various field windows, for comparison with corresponding parts of the
      mfVEP. In a second experiment, VEPs were obtained using slowed m-sequences (8 and
      16 video frames per m-step), as well as square-wave periodic reversals (2.4 Hz),
      for both the scaled dartboard display and an unscaled checkerboard display (check
      size of 50 minarc). RESULTS: The mfVEPs to fast m-sequence stimulation showed a
      strong polarity reversal between waveforms from the upper versus the lower
      hemifield. The cVEPs had larger amplitudes (approximately 3x) and longer implicit
      times (approximately 15-20 ms) and did not show the polarity reversal. Amplitude
      asymmetry between upper and lower hemifields was larger for cVEPs than for
      mfVEPs. As the stimulation rate was slowed, response amplitudes and implicit
      times of the major features increased, the upper versus lower polarity reversal
      was generally lost, and asymmetry of hemifield amplitudes grew. The same pattern
      of results was observed for scaled and unscaled spatial displays and for Oz-Fz
      and Oz-In signal derivations. CONCLUSIONS: Full-field cVEPs cannot be simply
      related to the sum of mfVEPs when each are recorded under their typical
      conditions. The stimulation rate has the largest influence on the differences
      between the two response types. The findings suggest that contributions from
      extrastriate sources are greater with the cVEP paradigm or the slowed mfVEP
      sequence than with the standard mfVEP paradigm.

PMID- 12601071
TI  - Spontaneous synaptic activity in an organotypic culture of the mouse retina.
AB  - PURPOSE: Many strains of mutant mice die at birth, when the retina is still very
      immature. The retinas of such mice can be studied in organotypic cultures. After
      a preceding anatomic study of the synaptic development, the electrical activity
      of the synaptic circuits within such cultures was studied in wild-type and
      gephyrin-deficient mice. METHODS: Organotypic cultures of newborn mouse retinas
      were grown for 14 days in vitro. Spontaneous postsynaptic currents (sPSCs) of
      amacrine cells were measured by using the whole-cell configuration of the patch
      clamp technique. GABAergic and glycinergic currents that were isolated with
      specific antagonists, and retinas from wild-type (geph(+/+)) and gephyrin
      deficient (geph(-/-)) mice were compared. RESULTS: Rapidly decaying sPSCs that
      were blocked by kynurenic acid were mediated by ionotropic glutamate receptors,
      whereas sPSCs with significantly higher peak amplitudes and slow-decay kinetics
      were identified as spontaneous inhibitory postsynaptic currents (sIPSCs) mediated
      by gamma-aminobutyric acid type A receptors (GABA(A)Rs) and glycine receptors
      (GlyRs). In gephyrin-deficient (geph(-/-)) cultures, we found no sIPSCs mediated
      by GlyRs. sIPSCs mediated by GABA(A)Rs expressed in amacrine cells of geph(-/-)
      retinas decayed significantly faster than GABAergic sIPSCs recorded in amacrine
      cells of geph(+/+) retinas. CONCLUSIONS: The different decay kinetics of
      GABA(A)Rs expressed in amacrine cells of geph(+/+) and of geph(-/-) retinas
      suggests that these cells express at least two types of GABA(A)R subtypes. In
      amacrine cells of geph(-/-) mice, a specific GABA(A)R subtype that may contain
      the alpha2 subunit, is impaired by the absence of gephyrin, whereas other
      GABA(A)Rs appear to function normally.

PMID- 12601072
TI  - A new rapid threshold algorithm for short-wavelength automated perimetry.
AB  - PURPOSE: To develop and test a short and reliable visual field threshold program
      for the early detection of glaucomatous visual field loss, by adapting the
      Swedish interactive test algorithm (SITA) to short-wavelength-automated-perimetry
      (SWAP). METHODS: Computer simulations were performed to test the accuracy of
      several versions of SITA SWAP, and to optimize speed versus reliability. The
      selected SITA SWAP version was evaluated and compared with the older Full
      Threshold SWAP and Fastpac SWAP programs in 41 patients with glaucoma and normal
      subjects. RESULTS: Average test time was 3.6 minutes for SITA SWAP, 11.8 minutes
      for Full Threshold SWAP, and 7.7 minutes for Fastpac SWAP, differences were
      significant at P < 0.0001. Mean threshold reproducibility, calculated as absolute
      difference between two tests, did not differ significantly between programs and
      was 2.4 dB for SITA, 2.3 dB for Full Threshold, and 2.4 dB for Fastpac SWAP.
      Simultaneous comparison showed significant differences in threshold sensitivity,
      P = 0.023: SITA SWAP showed highest sensitivity, 21.6 dB on average, compared
      with both Full Threshold SWAP and Fastpac SWAP with a mean sensitivity of 17.3
      and 17.8 dB, respectively. CONCLUSIONS: SITA SWAP was much faster than the older
      SWAP strategies, and reproducibility did not differ. This implies that SITA SWAP
      could become a clinically useful method for the detection of early glaucoma. SWAP
      tests may also be applicable in larger groups of patients because of the
      increased dynamic range.

PMID- 12601073
TI  - Perceived blur in amblyopia.
AB  - PURPOSE: The well-documented fact that visual acuity and contrast sensitivity in
      amblyopia are attenuated at high spatial frequencies predicts that amblyopes
      should perceive objects as blurred, because they do not have the high spatial
      frequency information necessary to represent sharp edges adequately. In the
      current study, the representation of blur in amblyopia with blur-discrimination
      and blur-matching tasks was explored in a series of experiments. METHODS:
      Monocular blur-discrimination thresholds were measured in a spatial two
      alternative forced-choice procedure. Observers were required to discriminate
      which edge (right or left) appeared to be the lesser blurred. Observers also
      interocularly matched edges that were identical with those used in the blur
      discrimination tasks, with the exception that they were viewed dichoptically at
      all times. RESULTS: Blur-discrimination thresholds were elevated in both the
      amblyopic and fellow fixing eyes but were within the normal range for interocular
      matching thresholds. CONCLUSIONS: The results suggest that blur is veridically
      represented in the amblyopic visual system. The surprising result is that all
      amblyopes, even those with the most severe visual loss, veridically matched all
      blurred edges, including the sharpest ones. This implies that amblyopes are able
      to represent levels of blur that are defined by spatial structure beyond their
      resolution limit.

PMID- 12601074
TI  - Warfarin for venous thromboembolism - walking the dosing tightrope.

PMID- 12601075
TI  - Long-term, low-intensity warfarin therapy for the prevention of recurrent venous
      thromboembolism.
AB  - BACKGROUND: Standard therapy to prevent recurrent venous thromboembolism includes
      3 to 12 months of treatment with full-dose warfarin with a target international
      normalized ratio (INR) between 2.0 and 3.0. However, for long-term management, no
      therapeutic agent has shown an acceptable benefit-to-risk ratio. METHODS:
      Patients with idiopathic venous thromboembolism who had received full-dose
      anticoagulation therapy for a median of 6.5 months were randomly assigned to
      placebo or low-intensity warfarin (target INR, 1.5 to 2.0). Participants were
      followed for recurrent venous thromboembolism, major hemorrhage, and death.
      RESULTS: The trial was terminated early after 508 patients had undergone
      randomization and had been followed for up to 4.3 years (mean, 2.1). Of 253
      patients assigned to placebo, 37 had recurrent venous thromboembolism (7.2 per
      100 person-years), as compared with 14 of 255 patients assigned to low-intensity
      warfarin (2.6 per 100 person-years), a risk reduction of 64 percent (hazard
      ratio, 0.36 [95 percent confidence interval, 0.19 to 0.67]; P<0.001). Risk
      reductions were similar for all subgroups, including those with and those without
      inherited thrombophilia. Major hemorrhage occurred in two patients assigned to
      placebo and five assigned to low-intensity warfarin (P=0.25). Eight patients in
      the placebo group and four in the group assigned to low-intensity warfarin died
      (P=0.26). Low-intensity warfarin was thus associated with a 48 percent reduction
      in the composite end point of recurrent venous thromboembolism, major hemorrhage,
      or death. According to per-protocol and as-treated analyses, the reduction in the
      risk of recurrent venous thromboembolism was between 76 and 81 percent.
      CONCLUSIONS: Long-term, low-intensity warfarin therapy is a highly effective
      method of preventing recurrent venous thromboembolism.

PMID- 12601077
TI  - Rice proteomics: a step toward functional analysis of the rice genome.
AB  - The technique of proteome analysis with two-dimensional PAGE has the power to
      monitor global changes that occur in the protein expression of tissues and
      organisms and/or expression that occurs under stresses. In this study, the
      catalogues of the rice proteome were constructed, and a functional
      characterization of some of these proteins was examined. Proteins extracted from
      tissues of rice and proteins extracted from rice under various kinds of stress
      were separated by two-dimensional PAGE. An image analyzer was used to reveal a
      total of 10,589 protein spots on 10 kinds of two-dimensional PAGE gels stained by
      Coomassie Brilliant Blue. The separated proteins were electroblotted onto a
      polyvinylidene difluoride membrane, and the N-terminal amino acid sequences of
      272 of 905 proteins were determined. The internal amino acid sequences of 633
      proteins were determined using a protein sequencer or mass spectrometry after
      enzyme digestion of the proteins. Finally, a data file of rice proteins that
      included information on amino acid sequences and sequence homologies was
      constructed. The major proteins involved in the growth and development of rice
      can be identified using the proteome approach. Some of these proteins, including
      a calcium-binding protein that turned out to be calreticulin and a gibberellin
      binding protein, which is ribulose-1,5-bisphosphate carboxylase/oxygenase
      activase in rice, have functions in the signal transduction pathway. The
      information thus obtained from the rice proteome will be helpful in predicting
      the function of the unknown proteins and will aid in their molecular cloning.

PMID- 12601078
TI  - Sensitivity and specificity of photoaptamer probes.
AB  - The potential of photoaptamers as proteomic probes was investigated.
      Photoaptamers are defined as aptamers that bear photocross-linking functionality,
      in this report, 5-bromo-2'-deoxyuridine. A key question regarding the use of
      photoaptamer probes is the specificity of the cross-linking reaction. The
      specificity of three photoaptamers was explored by comparing their reactions with
      target proteins and non-target proteins. The range of target/non-target
      specificity varies from 100- to >10(6)-fold with most values >10(4)-fold. The
      contributions of the initial binding step and the photocross-linking step were
      evaluated for each reaction. Photocross-linking never degraded specificity and
      significantly increased aptamer specificity in some cases. The application of
      photoaptamer technology to proteomics was investigated in microarray format.
      Immobilized anti-human immunodeficiency virus-gp120 aptamer was able to detect
      subnanomolar concentrations of target protein in 5% human serum. The levels of
      sensitivity and specificity displayed by photoaptamers, combined with other
      advantageous properties of aptamers, should facilitate development of protein
      chip technology.

PMID- 12601079
TI  - Insect resistance to Bacillus thuringiensis: alterations in the indianmeal moth
      larval gut proteome.
AB  - Insect resistance to the Cry toxins of Bacillus thuringiensis (Bt) has been
      examined previously using a number of traditional biochemical and molecular
      techniques. In this study, we utilized a proteomic approach involving two
      dimensional differential gel electrophoresis, mass spectrometry, and function
      based activity profiling to examine changes in the gut proteins from the larvae
      of an Indianmeal moth (IMM, Plodia interpunctella) colony exhibiting resistance
      to Bt. We found a number of changes in the levels of certain specific midgut
      proteins that indicate increased glutathione utilization, elevation in oxidative
      metabolism, and differential maintenance of energy balance within the midgut
      epithelial cells of the Bt-resistant IMM larva. Additionally, the electrophoretic
      migration pattern of a low molecular mass acidic protein, which apparently is an
      ortholog of F(1)F(0)-ATPase, was considerably altered in the Bt-resistant insect
      indicating that variations in amino acid content or modifications of certain
      proteins also are important components of the resistance phenomenon in the IMM.
      Furthermore, there was a dramatic decrease in the level of chymotrypsin-like
      proteinase in the midgut of the Bt-resistant larva, signifying that reduction of
      chymotrypsin activity, and subsequently decreased activation of Cry toxin in the
      insect midgut, is an important factor in the resistant state of the IMM. The
      proteomic analysis of larval gut proteins utilized in this study provides a
      useful approach for consolidating protein changes and physiological events
      associated with insect resistance to Bt. Our results support the hypothesis that
      physiological adaptation of insects and resistance to Bt is multifaceted,
      including protein modification and changes in the synthesis of specific larval
      gut proteins. We believe that increased oxidative metabolism may be an adaptive
      response of insects that undergo survival challenge and that it could mediate
      detoxification as well as higher rates of generalized and localized mutations
      that enhance their resistance and provide survival advantage.

PMID- 12601080
TI  - Signaling initiated by overexpression of the fibroblast growth factor receptor-1
      investigated by mass spectrometry.
AB  - Overexpression of the fibroblast growth factor receptor-1 (FGFR-1), a prototypic
      receptor tyrosine kinase, is a feature of several human tumors. In human 293
      cells overexpression of the FGFR-1 leads to constitutive activation of the
      receptor with concomitant sustained high increase in the cellular level of
      phosphotyrosine-containing proteins. Here we use mass spectrometry to study the
      tyrosine-phosphorylated proteins induced by overexpression of the FGFR-1. Several
      well known components of FGFR-1 signaling were identified along with two novel
      candidates: NS-1-associated protein-1 and target of Myb 1-like protein. We
      subsequently applied mass spectrometry precursor ion scanning to identify 22
      tyrosine phosphorylation sites distributed on six substrate proteins of the FGFR
      1 or downstream tyrosine kinases. Novel in vivo tyrosine phosphorylation sites
      were found in the FGFR-1, phospholipase Cgamma, p90 ribosomal S6 kinase,
      cortactin, and NS-1-associated protein-1 as a result of sustained FGFR-1
      signaling, and we propose these as functional links to downstream molecular and
      cellular processes.

PMID- 12601081
TI  - Protein database, human retinal pigment epithelium.
AB  - The retinal pigment epithelium (RPE) is a single cell layer adjacent to the rod
      and cone photoreceptors that plays key roles in retinal physiology and the
      biochemistry of vision. RPE cells were isolated from normal adult human donor
      eyes, subcellular fractions were prepared, and proteins were fractionated by
      electrophoresis. Following in-gel proteolysis, proteins were identified by
      peptide sequencing using liquid chromatography tandem electrospray mass
      spectrometry and/or by peptide mass mapping using matrix-assisted laser
      desorption ionization time-of-flight mass spectrometry. Preliminary analyses have
      identified 278 proteins and provide a starting point for building a database of
      the human RPE proteome.

PMID- 12601083
TI  - SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B
      cells.
AB  - Measurements of membrane capacitance were applied to dissect the cellular
      mechanisms underlying PKA-dependent and -independent stimulation of insulin
      secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive)
      component correlated with a rapid increase in membrane capacitance of
      approximately 80 fF that plateaued within approximately 200 ms, the PKA-dependent
      component became prominent during depolarizations >450 ms. The PKA-dependent and 
      independent components of cAMP-stimulated exocytosis differed with regard to cAMP
      concentration dependence; the K(d) values were 6 and 29 micro M for the PKA
      dependent and -independent mechanisms, respectively. The ability of cAMP to
      elicit exocytosis independently of PKA activation was mimicked by the selective
      cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense
      oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of
      PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1
      deficient mice (SUR1(-/-) mice) lacked the PKA-independent component of
      exocytosis. Measurements of insulin release in response to GLP-1 stimulation in
      isolated islets from SUR1(-/-) mice confirmed the complete loss of the PKA
      independent component. This was not attributable to a reduced capacity of GLP-1
      to elevate intracellular cAMP but instead associated with the inability of cAMP
      to stimulate influx of Cl(-) into the granules, a step important for granule
      priming. We conclude that the role of SUR1 in the B cell extends beyond being a
      subunit of the plasma membrane K(ATP)-channel and that it also plays an
      unexpected but important role in the cAMP-dependent regulation of Ca(2+)-induced
      exocytosis.

PMID- 12601084
TI  - Common molecular determinants of flecainide and lidocaine block of heart Na+
      channels: evidence from experiments with neutral and quaternary flecainide
      analogues.
AB  - Flecainide (pKa 9.3, 99% charged at pH 7.4) and lidocaine (pKa 7.6-8.0,
      approximately 50% neutral at pH 7.4) have similar structures but markedly
      different effects on Na(+) channel activity. Both drugs cause well-characterized
      use-dependent block (UDB) of Na(+) channels due to stabilization of the
      inactivated state, but flecainide requires that channels first open before block
      develops, whereas lidocaine is believed to bind directly to the inactivated
      state. To test whether the charge on flecainide might determine its state
      specificity of Na(+) channel blockade, we developed two flecainide analogues, NU
      FL (pKa 6.4), that is 90% neutral at pH 7.4, and a quaternary flecainide
      analogue, QX-FL, that is fully charged at physiological pH. We examined the
      effects of flecainide, NU-FL, QX-FL, and lidocaine on human cardiac Na(+)
      channels expressed in human embryonic kidney (HEK) 293 cells. At physiological
      pH, NU-FL, like lidocaine but not flecainide, interacts preferentially with
      inactivated channels without prerequisite channel opening, and causes minimal
      UDB. We find that UDB develops predominantly by the charged form of flecainide as
      evidenced by investigation of QX-FL at physiological pH and NU-FL investigated
      over a more acidic pH range where its charged fraction is increased. QX-FL is a
      potent blocker of channels when applied from inside the cell, but acts very
      weakly with external application. UDB by QX-FL, like flecainide, develops only
      after channels open. Once blocked, channels recover very slowly from QX-FL block,
      apparently without requisite channel opening. Our data strongly suggest that it
      is the difference in degree of ionization (pKa) between lidocaine and flecainide,
      rather than gross structural features, that determines distinction in block of
      cardiac Na(+) channels. The data also suggest that the two drugs share a common
      receptor but, consistent with the modulated receptor hypothesis, reach this
      receptor by distinct routes dictated by the degree of ionization of the drug
      molecules.

PMID- 12601085
TI  - Rapid induction of P/C-type inactivation is the mechanism for acid-induced K+
      current inhibition.
AB  - Extracellular acidification is known to decrease the conductance of many voltage
      gated potassium channels. In the present study, we investigated the mechanism of
      H(+)(o)-induced current inhibition by taking advantage of Na(+) permeation
      through inactivated channels. In hKv1.5, H(+)(o) inhibited open-state Na(+)
      current with a similar potency to K(+) current, but had little effect on the
      amplitude of inactivated-state Na(+) current. In support of inactivation as the
      mechanism for the current reduction, Na(+) current through noninactivating hKv1.5
      R487V channels was not affected by [H(+)(o)]. At pH 6.4, channels were maximally
      inactivated as soon as sufficient time was given to allow activation, which
      suggested two possibilities for the mechanism of action of H(+)(o). These were
      that inactivation of channels in early closed states occurred while
      hyperpolarized during exposure to acid pH (closed-state inactivation) and/or
      inactivation from the open state was greatly accelerated at low pH. The absence
      of outward Na(+) currents but the maintained presence of slow Na(+) tail
      currents, combined with changes in the Na(+) tail current time course at pH 6.4,
      led us to favor the hypothesis that a reduction in the activation energy for the
      inactivation transition from the open state underlies the inhibition of hKv1.5
      Na(+) current at low pH.

PMID- 12601088
TI  - Treat the patient, not the test.

PMID- 12601086
TI  - On the conformation of the COOH-terminal domain of the large mechanosensitive
      channel MscL.
AB  - COOH-terminal (S3) domains are conserved within the MscL family of bacterial
      mechanosensitive channels, but their function remains unclear. The X-ray
      structure of MscL from Mycobacterium tuberculosis (TbMscL) revealed cytoplasmic
      domains forming a pentameric bundle (Chang, G., R.H. Spencer, A.T. Lee, M.T.
      Barclay, and D.C. Rees. 1998. SCIENCE: 282:2220-2226). The helices, however, have
      an unusual orientation in which hydrophobic sidechains face outside while charged
      residues face inside, possibly due to specific crystallization conditions. Based
      on the structure of pentameric cartilage protein, we modeled the COOH-terminal
      region of E. coli MscL to better satisfy the hydrophobicity criteria, with
      sidechains of conserved aliphatic residues all inside the bundle. Molecular
      dynamic simulations predicted higher stability for this conformation compared
      with one modeled after the crystal structure of TbMscL, and suggested distances
      for disulfide trapping experiments. The single cysteine mutants L121C and I125C
      formed dimers under ambient conditions and more so in the presence of an oxidant.
      The double-cysteine mutants, L121C/L122C and L128C/L129C, often cross-link into
      tetrameric and pentameric structures, consistent with the new model. Patch-clamp
      examination of these double mutants under moderately oxidizing or reducing
      conditions indicated that the bundle cross-linking neither prevents the channel
      from opening nor changes thermodynamic parameters of gating. Destabilization of
      the bundle by replacing conservative leucines with small polar residues, or
      complete removal of COOH-terminal domain (Delta110-136 mutation), increased the
      occupancy of subconducting states but did not change gating parameters
      substantially. The Delta110-136 truncation mutant was functional in in vivo
      osmotic shock assays; however, the amount of ATP released into the shock medium
      was considerably larger than in controls. The data strongly suggest that in
      contrast to previous gating models (Sukharev, S., M. Betanzos, C.S. Chiang, and
      H.R. Guy. 2001a. NATURE: 409:720-724.), S3 domains are stably associated in both
      closed and open conformations. The bundle-like assembly of cytoplasmic helices
      provides stability to the open conformation, and may function as a size-exclusion
      filter at the cytoplasmic entrance to the MscL pore, preventing loss of essential
      metabolites.

PMID- 12601087
TI  - Mg2+-dependent gating and strong inward rectification of the cation channel
      TRPV6.
AB  - TRPV6 (CaT1/ECaC2), a highly Ca(2+)-selective member of the TRP superfamily of
      cation channels, becomes permeable to monovalent cations in the absence of
      extracellular divalent cations. The monovalent currents display characteristic
      voltage-dependent gating and almost absolute inward rectification. Here, we show
      that these two features are dependent on the voltage-dependent block/unblock of
      the channel by intracellular Mg(2+). Mg(2+) blocks the channel by binding to a
      site within the transmembrane electrical field where it interacts with permeant
      cations. The block is relieved at positive potentials, indicating that under
      these conditions Mg(2+) is able to permeate the selectivity filter of the
      channel. Although sizeable outward monovalent currents were recorded in the
      absence of intracellular Mg(2+), outward conductance is still approximately 10
      times lower than inward conductance under symmetric, divalent-free ionic
      conditions. This Mg(2+)-independent rectification was preserved in inside-out
      patches and not altered by high intracellular concentrations of spermine,
      indicating that TRPV6 displays intrinsic rectification. Neutralization of a
      single aspartate residue within the putative pore loop abolished the Mg(2+)
      sensitivity of the channel, yielding voltage-independent, moderately inwardly
      rectifying monovalent currents in the presence of intracellular Mg(2+). The
      effects of intracellular Mg(2+) on TRPV6 are partially reminiscent of the gating
      mechanism of inwardly rectifying K(+) channels and may represent a novel
      regulatory mechanism for TRPV6 function in vivo.

PMID- 12601089
TI  - Sporadic hemiplegic migraine: stamp collecting or food for thought?

PMID- 12601090
TI  - Practice parameter: temporal lobe and localized neocortical resections for
      epilepsy: report of the Quality Standards Subcommittee of the American Academy of
      Neurology, in association with the American Epilepsy Society and the American
      Association of Neurological Surgeons.
AB  - OBJECTIVES/METHODS: To examine evidence for effectiveness of anteromesial
      temporal lobe and localized neocortical resections for disabling complex partial
      seizures by systematic review and analysis of the literature since 1990. RESULTS:
      One intention-to-treat Class I randomized, controlled trial of surgery for mesial
      temporal lobe epilepsy found that 58% of patients randomized to be evaluated for
      surgical therapy (64% of those who received surgery) were free of disabling
      seizures and 10 to 15% were unimproved at the end of 1 year, compared with 8%
      free of disabling seizures in the group randomized to continued medical therapy.
      There was a significant improvement in quantitative quality-of-life scores and a
      trend toward better social function at the end of 1 year for patients in the
      surgical group, no surgical mortality, and infrequent morbidity. Twenty-four
      Class IV series of temporal lobe resections yielded essentially identical
      results. There are similar Class IV results for localized neocortical resections;
      no Class I or II studies are available. CONCLUSIONS: A single Class I study and
      24 Class IV studies indicate that the benefits of anteromesial temporal lobe
      resection for disabling complex partial seizures is greater than continued
      treatment with antiepileptic drugs, and the risks are at least comparable. For
      patients who are compromised by such seizures, referral to an epilepsy surgery
      center should be strongly considered. Further studies are needed to determine if
      neocortical seizures benefit from surgery, and whether early surgical
      intervention should be the treatment of choice for certain surgically remediable
      epileptic syndromes.

PMID- 12601091
TI  - Variability of total phenytoin serum concentrations within elderly nursing home
      residents.
AB  - BACKGROUND: Approximately 6% of all elderly nursing home residents receive
      phenytoin. Phenytoin concentrations are often measured to guide therapy.
      OBJECTIVE: To evaluate the intraresident variability among multiple measurements
      of total phenytoin serum concentrations in nursing home residents. METHODS: This
      was an observational study of 56 elderly (>or=65 years) nursing home residents
      from 32 nursing homes who had at least 3 phenytoin concentrations measured while
      on the same dose of phenytoin for at least 4 weeks and who were not taking any
      interfering concomitant medications. These were a subset of 387 elderly nursing
      home residents from 112 nursing homes across the United States who had total
      phenytoin concentration measurements between June 1998 and December 2000.
      RESULTS: The mean age was 80.1 years (range, 65 to 100 years) and 58.9% were
      women. The mean daily dose of phenytoin per resident was 4.9 +/- 1.5 mg/kg. Total
      phenytoin concentrations within an elderly nursing home resident varied as much
      as two- to threefold, even though there was no change in dose. The person with
      the smallest variability had a minimum concentration of 10.0 micro g/mL and a
      maximum of 10.4 micro g/mL. The person with the largest variability had a minimum
      concentration of 9.7 micro g/mL and a maximum of 28.8 micro g/mL. CONCLUSIONS:
      There is considerable variability in the total phenytoin concentrations in the
      elderly nursing home resident and measurement of a single total phenytoin
      concentration should not be used to guide treatment.

PMID- 12601093
TI  - Meta-analysis of EEG test performance shows wide variation among studies.
AB  - BACKGROUND: EEG results are used for counseling patients with seizures about
      prognosis and deciding on medications. Published sensitivities of interictal EEG
      vary widely. OBJECTIVE: To account for variation in test characteristics between
      studies. METHODS: Meta-analysis. Medline search, 1970 to 2000, of English
      language studies. Standard methods for meta-analysis of diagnostic test
      performance were used to determine the ability of EEG results to distinguish
      between patients who will and will not have seizures. Using linear regression,
      the authors assessed the influence of readers' thresholds for classifying the EEG
      as positive, sample probability of seizure, percent of subjects with prior
      neurologic impairment, percent treated, and years followed. RESULTS: Twenty-five
      studies involving 4,912 EEG met inclusion criteria. Specificity (range 0.13 to
      0.99) and sensitivity (range 0.20 to 0.91) of epileptiform EEG interpretations
      varied widely and were heterogeneous by chi(2) analysis (p < 0.001 for each).
      Diagnostic accuracy of EEG and the thresholds for classifying EEG as positive
      varied widely. In the multivariate model, differences in readers' thresholds
      accounted for 37% of the variance in EEG diagnostic accuracy, and no other
      reported factors were significant. CONCLUSION: This analysis suggests that there
      is wide interreader variation in sensitivity and specificity of EEG
      interpretations, and that this variation influences the ability of EEG to
      discriminate between those who will and will not have seizure recurrences. In
      clinical practice, interpreting the degree to which a positive EEG result
      predicts increased seizure risk in an individual patient is difficult.
      Interpreting EEG with higher specificity yields more accurate predictions.

PMID- 12601092
TI  - GABA(B) receptor 1 polymorphism (G1465A) is associated with temporal lobe
      epilepsy.
AB  - BACKGROUND: Dysfunction of gamma-aminobutyric acid (GABA) (B) receptors has been
      implicated in the pathogenesis of temporal lobe epilepsy (TLE). OBJECTIVE: To
      evaluate the genetic contribution of cloned human GABA(B) receptors to TLE.
      METHODS: The authors genotyped 141 patients (78 women and 63 men; mean age = 49.1
      +/- 18.0 years) with nonlesional TLE and 372 age- and sex-matched normal
      individuals for the known polymorphism G1465A in the human GABA(B) receptor 1
      [GABA(B[1])] gene. RESULTS: There was a highly significant overrepresentation of
      the G1465A heterozygote in patients with TLE compared with controls. The A/G
      genotype was found in 17% of the 141 patients with TLE and in only 0.5% of the
      372 controls (p < 0.0001). The authors also found that patients carrying the A
      allele had a significantly higher risk (p = 0.003, OR = 6.47, 95% CI = 2.02 to
      20.76) of developing drug-resistant TLE. Furthermore, the age at onset of
      seizures tended to be lower in patients with A/G genotype, but the difference was
      not significant. CONCLUSIONS: The results of this study indicate that the
      GABA(B[1]) polymorphism (G1465A) confers a highly increased susceptibility to
      TLE. Moreover, it seems to influence the severity of this common epileptic
      disorder.

PMID- 12601094
TI  - Fasting serum insulin and lipid levels in men with epilepsy.
AB  - BACKGROUND: Previous studies suggest that obese women taking valproate (VPA) for
      epilepsy are insulin resistant. OBJECTIVE: To assess the effects of antiepileptic
      drugs on serum insulin and lipid levels in men with epilepsy. METHODS: Body mass
      index (BMI) and fasting serum concentrations of insulin and lipids were measured
      in 102 men with epilepsy who were treated with VPA, carbamazepine (CBZ), or
      oxcarbazepine (OXC) monotherapy. Thirty-two healthy men served as control
      subjects. RESULTS: Obesity was not more common among VPA-treated men than among
      other men with epilepsy or the control subjects. However, the obese VPA-treated
      men had higher serum insulin levels (p < 0.001) than the obese control subjects
      despite similar BMI. CBZ and OXC did not have any significant effect on any of
      the measurements. Fasting serum insulin concentrations above the normal range
      were observed in seven obese VPA-treated patients (35%) but in only one obese
      control subject (5%). Five obese VPA-treated patients (25%) and one obese control
      subject (5%) had serum triglyceride levels above the normal range, and a low high
      density lipoprotein/total cholesterol ratio was observed in two obese VPA-treated
      patients (10%). CONCLUSIONS: Obese valproate-treated men have high serum insulin
      levels, indicating insulin resistance. Moreover, some of the valproate-treated
      men cluster cardiovascular risk factors such as obesity, hyperinsulinemia, and
      elevated serum triglyceride concentrations. CBZ and OXC do not seem to have any
      significant effects on serum insulin or lipid levels in men with epilepsy.

PMID- 12601095
TI  - Major malformations in offspring of women with epilepsy.
AB  - BACKGROUND: The offspring of women with epilepsy are at an increased risk of
      major congenital malformations, but the impact of the various contributing
      factors remains unresolved. METHOD: In 1980 through 1998, the authors
      prospectively followed up 970 pregnancies in women with epilepsy at a single
      maternity clinic. Of their 979 offspring, 740 were exposed to maternal
      antiepileptic drugs (AED) during the first trimester of pregnancy and 239 were
      not exposed. Maternal AED levels and serum folate concentrations were measured at
      the end of the first trimester. Logistic regression analysis was applied to
      identify factors associated with the occurrence of major malformations in the
      fetuses and newborns. RESULTS: Major malformations were detected in 28 fetuses
      (3.8%) exposed to maternal AED and in 2 (0.8%) not exposed (p = 0.02). After
      logistic regression analysis, the occurrence of major malformations was
      independently associated with use of carbamazepine (adjusted OR 2.5; 95% CI 1.0
      to 6.0), use of valproate (4.1; 1.6 to 11), use of oxcarbazepine (10.8; 1.1 to
      106), low serum folate concentration (5.8; 1.3 to 27), and low maternal level of
      education (3.0; 1.3 to 6.8). Major malformations were not associated with
      seizures during the first trimester (0.6; 0.1 to 2.9). CONCLUSIONS: Major
      malformations in the offspring of mothers with epilepsy are associated with use
      of AED during early pregnancy, and also with low serum folate concentrations and
      a low level of education.

PMID- 12601096
TI  - Malformations of cortical development with balloon cells: clinical and radiologic
      correlates.
AB  - BACKGROUND: Balloon cells are a key feature of tuberous sclerosis (TS) but are
      also seen in focal cortical dysplasia (FCD). The authors compare the clinical and
      MRI characteristics in children with medically refractory localization-related
      epilepsy who were found to have balloon cells on histology after cortical
      resections. METHODS: A retrospective review of clinical and MRI data in cases
      ascertained from a search of pathology records from 1990 until 2000 for those
      with a diagnosis of FCD or TS. Seventeen patients were identified with
      malformations of cortical development with balloon cells on histology. Seven had
      clinical diagnosis of TS and the remaining 10, FCD with balloon cells (FCDBC).
      RESULTS: Seventy percent of patients with FCDBC (mean follow-up 3.3 years) and
      33% of patients with TS (mean follow-up 5.1 years) are seizure free after
      surgery. There was agreement between the diagnosis based on preoperative MR
      imaging and on histology in 60% of patients with FCDBC and 71% of patients with
      TS. Myelin depletion and calcification were noted more frequently in patients
      with TS. CONCLUSIONS: No significant differences were noted between patients with
      refractory epilepsy caused by TS or FCDBC. There was a trend toward better
      postoperative seizure control in the FCDBC group. These two conditions are
      difficult to distinguish on the basis of MR and histologic appearances. The
      authors conclude that FCDBC likely represents a phenotypic variation of TS, and
      as such, all patients with balloon cell dysplasias should be carefully screened
      for other features of TS to enable appropriate genetic counseling.

PMID- 12601097
TI  - Postoperative speech disorder after medial frontal surgery: role of the
      supplementary motor area.
AB  - BACKGROUND: Patients undergoing surgical resection of medial frontal lesions may
      present transient postoperative speech disorders that remain largely
      unpredictable. OBJECTIVE: To relate the occurrence of this speech deficit to the
      specific surgical lesion of the supplementary motor area (SMA) involved during
      language tasks using fMRI. METHODS: Twelve patients were studied using a verbal
      fluency task before resection of a low-grade glioma of the medial frontal lobe
      and compared with six healthy subjects. Pre- and postoperative MR variables
      including the hemispheric dominance for language, the extent of SMA removal, and
      the volume of resection were compared to the clinical outcome. RESULTS: Following
      surgery, 6 of 12 patients presented speech disorders. The deficit was similar
      across patients, consisting of a global reduction in spontaneous speech, ranging
      from a complete mutism to a less severe speech reduction, which recovered within
      a few weeks or months. The occurrence of the deficit was related to the resection
      of the activation in the SMA of the dominant hemisphere for language (p < 0.01).
      Increased activation in the SMA of the healthy hemisphere on the preoperative
      fMRI was observed in patients with postoperative speech deficit. CONCLUSIONS:
      fMRI is able to identify the area at risk in the SMA, of which resection is
      related to the occurrence of characteristic transient postoperative speech
      disorders. Increased SMA activation in the healthy hemisphere suggested that a
      plastic change of SMA function occurred in these patients.

PMID- 12601098
TI  - Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine.
AB  - OBJECTIVE: To compare clinical characteristics of patients with sporadic
      hemiplegic migraine (SHM) with those of patients with migraine with typical aura
      (MA) and patients with familial hemiplegic migraine (FHM). METHODS: The authors
      used a computer search of Denmark's National Patient Register to screen the
      population for patients with migraine with aura with motor weakness, and also
      examined case records from headache clinics and private practicing neurologists
      and placed advertisements. The authors screened patients and their relatives with
      a semi-structured validated telephone interview. All recruited patients were then
      interviewed by a physician and given a neurologic examination. RESULTS: A total
      of 105 patients with SHM were identified. Seventy-two percent had four typical
      aura symptoms: visual, sensory, aphasic, and motor. All had at least two symptoms
      present during SHM attacks. A gradual progression and sequential appearance of
      aura symptoms was typical; compared with MA, the duration of each aura symptom
      was usually prolonged and bilateral motor symptoms were more frequent. Of the
      patients with SHM, 72% fulfilled the criteria for basilar migraine during SHM
      attacks. The aura was usually followed by headache, as is common in FHM but not
      MA. CONCLUSIONS: Patients with sporadic hemiplegic migraine had clinical symptoms
      identical to familial hemiplegic migraine and significantly different from
      migraine with typical aura. Sporadic hemiplegic migraine is a separate entity,
      and should be classified with familial hemiplegic migraine.

PMID- 12601099
TI  - Tremor in Parkinson's disease and serotonergic dysfunction: an 11C-WAY 100635 PET
      study.
AB  - BACKGROUND: The pathophysiologic mechanisms underlying parkinsonian tremor remain
      unclear. The response to dopaminergic treatment is variable and nondopaminergic
      mechanisms may play a role in tremor generation. Midbrain raphe 5-HT(1A) binding
      provides a functional measure of serotonergic system integrity. With PET, the aim
      of this study was to examine regional cerebral (11)C-WAY 100635 binding to 5
      HT(1A) receptors in patients with PD and to correlate it with severity of tremor.
      METHODS: (11)C-WAY 100635 PET was performed on 23 patients with PD and eight age
      matched healthy volunteers. Brain 5-HT(1A) receptor binding was computed using
      compartmental modeling with a cerebellar reference tissue input function.
      RESULTS: The authors found mean 27% reduction in the midbrain raphe 5-HT(1A)
      binding potential in patients with PD compared to healthy volunteers (p < 0.001).
      They also showed that Unified Parkinson's Disease Rating Scale composite tremor
      scores, but not rigidity or bradykinesia, correlate with 5-HT(1A) binding in the
      raphe (p < 0.01). CONCLUSIONS: These findings support previous indirect evidence
      that serotonergic neurotransmission is decreased in PD in vivo. The authors
      hypothesize that the reduction in raphe 5-HT(1A) binding represents receptor
      dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both.
      An association between 5-HT(1A) receptor availability in the raphe and severity
      of parkinsonian tremor was also found.

PMID- 12601100
TI  - Tic reduction with pergolide in a randomized controlled trial in children.
AB  - OBJECTIVE: To determine whether pergolide, a mixed D1/D2/D3 dopamine agonist, is
      efficacious and safe in the treatment of children with chronic tic disorders and
      Tourette syndrome. BACKGROUND: Neuroleptics, which block dopamine transmission,
      are currently used to treat children with severe tics, but major side effects and
      limited efficacy reduce clinical utility. Prior open-label and crossover studies
      of pergolide suggest potential benefit. METHODS: The authors enrolled 57 children
      and adolescents, ages 7 to 17 years, randomizing them in a 2:1 ratio to either
      pergolide (0.15 to 0.45 mg per day) or placebo. Tic symptoms had to be >30 on the
      Yale Global Tic Severity Scale (YGTSS). The primary outcome measure was change in
      tic severity assessed by YGTSS. RESULTS: Compared to placebo treatment, pergolide
      treatment was associated with lower tic severity scores (treatment effect 8.8,
      pergolide vs placebo; 95% CI 0.1 to 17.6; p = 0.05) and attention-deficit
      hyperactivity disorder symptoms scores (treatment effect 3.8; 95% CI 0.7 to 6.8;
      p = 0.02). No patient had a serious adverse event and pergolide was well
      tolerated. CONCLUSIONS: In this randomized, placebo-controlled trial, pergolide
      appeared to be an efficacious and safe medication for tic reduction in children,
      and may also improve attention-deficit hyperactivity disorder symptoms.

PMID- 12601101
TI  - Enhancement of brain activation during trial-and-error sequence learning in early
      PD.
AB  - BACKGROUND: Although the pathophysiology remains unknown, most nondemented
      patients with PD have difficulty with frontal tasks, including trial-and-error
      sequence learning. If given time, they can perform cognitive tasks of moderate
      difficulty as well as controls. However, it is not known how brain function is
      altered during this time period to preserve higher cortical function in the face
      of PD pathology. METHOD: To evaluate this phenomenon, the authors matched
      sequence learning between PD and control subjects for the last 30 seconds of a
      PET scan. Learning during the initial 50 seconds of PET was unconstrained.
      RESULTS: Learning indices were equivalent between groups during the last 30
      seconds of the scan, whereas rates of acquisition, correct movements, and
      forgetting differed in the first 30 seconds. In normal controls sequence learning
      was associated with activations in the right prefrontal, premotor, parietal,
      rostral supplementary motor area, and precuneus regions. To achieve equal
      performance, the PD group activated greater volume within these same regions, and
      also their left sided cortical homologs and the lateral cerebellum bilaterally.
      CONCLUSIONS: Mildly affected patients with PD demonstrated only modest impairment
      of learning during the first 30 seconds of the task and performed equivalently
      with controls thereafter. However, the mechanism by which they achieved
      equiperformance involved considerable changes in brain function. The PD group had
      to activate four times as much neural tissue as the controls, including
      recruiting brain from homologous cortical regions and bilateral lateral
      cerebellum.

PMID- 12601102
TI  - The effect of pneumonia on mortality among patients hospitalized for acute
      stroke.
AB  - OBJECTIVE: To determine the effect of pneumonia on 30-day mortality in patients
      hospitalized for acute stroke. METHODS: Subjects in the initial cohort were
      14,293 Medicare patients admitted for stroke to 29 greater Cleveland hospitals
      between 1991 and 1997. The relative risk (RR) of pneumonia for 30-day mortality
      was determined in a final cohort (n = 11,286) that excluded patients dying or
      having a do not resuscitate order within 3 days of admission. Clinical data were
      obtained from chart abstraction and were merged with Medicare Provider Analysis
      and Review files to obtain deaths within 30 days. A predicted-mortality model (c
      statistic = 0.78) and propensity score for pneumonia (c-statistic = 0.83) were
      used for risk adjustment in logistic regression analyses. RESULTS: Pneumonia was
      identified in 6.9% (n = 985) of all patients and in 5.6% (n = 635) of the final
      cohort. The rates of pneumonia were higher in patients with greater stroke
      severity and features indicating general frailty. Unadjusted 30-day mortality
      rates were six times higher for patients with pneumonia than for those without
      (26.9% vs 4.4%, p < 0.001). After adjusting for admission severity and propensity
      for pneumonia, RR of pneumonia for 30-day death was 2.99 (95% CI 2.44 to 3.66),
      and population attributable risk was 10.0%. CONCLUSION: In this large community
      wide study of stroke outcomes, pneumonia conferred a threefold increased risk of
      30-day death, adding impetus to efforts to identify and reduce the risk of
      pneumonia in patients with stroke.

PMID- 12601103
TI  - Does compensatory hyperparathyroidism predispose to ischemic stroke?
AB  - BACKGROUND: Parathyroid hormone (PTH) is vasoactive, and the endothelium is one
      of the target tissues of this hormone. Hyperparathyroidism is frequently
      associated with hypertension. OBJECTIVE: To determine if hyperparathyroidism,
      which develops particularly in elderly women as a compensatory mechanism to
      osteoporosis, may be a risk factor for ischemic stroke. METHODS: Serum PTH levels
      and bone mineral density (BMD) in 107 elderly patients with ischemic stroke
      (>or=65 years old) were assessed on the day of onset. The control group consisted
      of 107 healthy volunteers matched for age and sex. RESULTS: BMD was significantly
      lower and serum PTH higher in female stroke patients than in control subjects;
      there was a negative correlation between these two measurements. One-third of the
      female stroke patients had a serum PTH level higher than the mean + 2 SD of the
      control subjects (high PTH group), and the interval between menopause and the
      stroke was significantly longer in the high PTH group than in the normal PTH
      group. Multiple logistic analyses revealed hypertension and ischemic heart
      disease were more prevalent in the high PTH group. BMD and PTH were normal in
      male stroke patients. CONCLUSION: High serum PTH level may be associated with
      high incidence of ischemic stroke in women, possibly through the increased
      incidence of hypertension.

PMID- 12601104
TI  - Intranasal sumatriptan in cluster headache: randomized placebo-controlled double
      blind study.
AB  - BACKGROUND: Current evidence-based acute treatments of cluster headache are
      limited to oxygen inhalation and subcutaneous sumatriptan. Intranasal sumatriptan
      is a new formulation with better tolerability than the subcutaneous route. Two
      open-label studies suggested efficacy of intranasal sumatriptan in cluster
      headache. METHODS: In a double-blind placebo-controlled randomized trial,
      patients with episodic or chronic cluster headache whose attacks lasted at least
      45 minutes each treated one attack with 20 mg sumatriptan nasal spray and another
      one, at least 24 hours later, with matching placebo. They scored their headache
      on a five-point scale (very severe, severe, moderate, mild, or none) at 5, 10,
      15, 20, and 30 minutes. The primary outcome measure was headache response (a
      decrease in pain from very severe, severe, or moderate to mild or none) at 30
      minutes. Secondary outcome measures included pain-free rates, relief of
      associated symptoms, and rates of adverse events. Multilevel multivariate
      analysis was used for statistical analysis. RESULTS: Five study centers enrolled
      118 patients in whom 154 attacks were treated: 77 with sumatriptan and 77 with
      placebo. The responder rates at 30 minutes were 57% for sumatriptan and 26% for
      placebo (p = 0.002). Pain-free rates at 30 minutes were 47% for sumatriptan and
      18% for placebo (p = 0.003). Sumatriptan was also superior to placebo considering
      initial response, meaningful relief, and relief of associated symptoms. There
      were no serious adverse events. CONCLUSION: Sumatriptan nasal spray is effective
      and well tolerated in the acute treatment of cluster headache attacks of at least
      45 minutes' duration.

PMID- 12601105
TI  - Persistent neutralizing antibodies abolish the interferon beta bioavailability in
      MS patients.
AB  - BACKGROUND: MxA is an antiviral protein exclusively induced by type I interferons
      (IFN) and some viruses, and MxA gene expression is one of the most appropriate
      markers for measuring the biologic activity of exogenous IFNbeta. METHODS: A new
      quantitative-competitive PCR method was used to quantify MxA mRNA in peripheral
      blood mononuclear cells of 99 treatment-naive and 92 IFNbeta-treated patients
      with MS (22 Avonex, 17 Betaferon, and 53 Rebif-22). Every 3 months, IFNbeta
      induced neutralizing antibodies (NAb) were evaluated in sera using a cytopathic
      effect assay. Three categories of patients were identified: NAb negative (NAb-),
      persistent NAb positive (NAb+, >or=2 consecutive positive samples), and isolated
      NAb+ (one positive sample). RESULTS: Treatment-naive patients expressed
      detectable MxA mRNA levels (mean = 36 +/- 32 fg MxA/pg glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH); range 1 to 160) and an upper normal threshold was
      established (mean + 3 SD = 132 fg MxA/pg GAPDH). IFNbeta-treated patients
      exhibited more than 11-fold higher levels (mean = 412 +/- 282 fg MxA/pg GAPDH;
      range 16 to 1,172). However, 17 patients did not exhibit an increase in MxA mRNA
      level; 15 of these 17 patients showed a concurrent Nab+ titer. Moreover, 13 were
      persistent NAb+. Isolated NAb+ patients did not show a decrease in
      bioavailability of IFNbeta (n = 9; mean = 567 +/- 366 fg MxA/pg GAPDH; range 83
      to 1,120). In NAb- patients, bioavailability was comparable among the three
      different IFNbeta preparations 12 hours after injection. CONCLUSION: During
      IFNbeta therapy, the presence of NAb reduced or abolished bioavailability in a
      relevant percentage of patients. These data could be important for the early
      detection of patients with MS who are not responsive to IFNbeta therapy.

PMID- 12601106
TI  - MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly
      intervals.
AB  - BACKGROUND: One of the diagnostic imaging hallmarks of MS is the uptake of IV
      administered contrast material in new lesions in the brain, signaling blood-brain
      barrier breakdown and active inflammation. Many clinical drug trials are designed
      based on the assumption that lesion enhancement on MRI remains visible on average
      for 1 month. For practical reasons, few serial MRI studies of patients with MS
      have been performed at intervals shorter than 4 weeks. METHODS: The authors
      performed a year-long longitudinal study in 26 patients with relapsing-remitting
      MS (RRMS), which comprised an initial phase of MRI follow-up at weekly intervals
      for 8 weeks, followed by imaging every other week for another 16 weeks, and
      monthly thereafter. They present a quantitative analysis (using a supervised
      interactive thresholding procedure) of new enhancing lesions appearing during the
      first 6 weeks in this cohort and evaluated from the time of first detection until
      enhancement was no longer seen. RESULTS: The average duration of Gd-DTPA
      enhancement in individual new lesions was 3.07 weeks (median, 2 weeks).
      Significant correlations were demonstrated between the duration of contrast
      enhancement or initial growth rates and lesion volumes. Different lesions in the
      same patient appeared to develop largely independent of each other and
      demonstrated a large range in the duration of enhancement during the acute phase
      of their evolution. CONCLUSIONS: The average duration of blood-brain barrier
      impairment in RRMS is shorter than earlier estimates. Early lesion growth
      parameters may predict final lesion size. Within-patient heterogeneity of lesion
      evolution suggests that individual lesions develop independently.

PMID- 12601107
TI  - HLA-related subpopulations of MS in Japanese with and without oligoclonal IgG
      bands. Human leukocyte antigen.
AB  - BACKGROUND: Oligoclonal IgG bands (OCB) are present in most patients with MS in
      Western countries; however, in Japanese MS patients, the OCB-positive rate is not
      as high. A relationship between immunogenetic backgrounds, namely, human
      leukocyte antigen (HLA) DR2 and DR4 positivity, and OCB production in MS patients
      from Hokkaido, the northernmost island of Japan, has been previously suggested by
      the authors. OBJECTIVES: To investigate the role of OCB in Japanese MS and to
      verify the interaction between immunogenetic backgrounds and OCB positivity.
      METHODS: OCB, DR2(15), and DR4 positivity were studied in 45 patients with newly
      diagnosed MS. In addition to confirming the authors' previous findings, the
      clinical and demographic features, MRI findings, OCB positivity, and DRB1*15 and
      DRB1*04 polymorphisms of an expanded data set of 99 MS patients were investigated
      by using multivariate analysis. Patients with opticospinal MS (OS-MS) were
      excluded from this study. RESULTS: A relatively low OCB-positive rate (53.3%),
      HLA-DR15 association with OCB-positive MS (p = 0.0044), and DR4 association with
      OCB-negative MS (p = 0.0410) were confirmed. DR15 was not associated with OCB
      negative MS. Demographic features, disease course, and disability were similar in
      the OCB-negative and OCB-positive group, whereas there was a preponderance of
      women in the OCB-positive group. An independent negative association of DRB1*0405
      (p = 0.0021, adjusted odds ratio = 0.21) with OCB positivity was found.
      CONCLUSIONS: MS is heterogeneous in its association with HLA alleles, and based
      on the immunogenetic differences, the MS patients in this population include at
      least two HLA-related subpopulations with and without OCB.

PMID- 12601108
TI  - CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based
      autopsy study.
AB  - OBJECTIVE: To investigate the relationship of amyloid neuropathology to
      postmortem CSF Abeta 42 levels in an autopsy sample of Japanese American men from
      the population-based Honolulu-Asia Aging Study. METHODS: In 1991, participants
      were assessed and diagnosed with dementia (including subtype) based on published
      criteria. At death CSF was obtained from the ventricles. Neuritic plaques (NP)
      and diffuse plaques in areas of the neocortex and hippocampus were examined using
      Bielschowsky silver stains. Cerebral amyloid angiopathy (CAA) was measured by
      immunostaining for beta4 amyloid in cerebral vessels in the neocortex.
      Neuropathologically confirmed AD was diagnosed using Consortium to Establish a
      Registry for Alzheimer's Disease criteria. In 155 autopsy samples, log
      transformed linear regression models were used to examine the association of NP
      and CAA to Abeta 42 levels, controlling for clinical dementia severity, time
      between diagnosis and death, age at death, brain weight, hours between death and
      collection of CSF, education, and APOE genotype. RESULTS: Higher numbers of NP in
      the neocortex (p trend = 0.001) and in the hippocampus (p trend = 0.03) were
      strongly associated with lower levels of Abeta 42. Individuals with CAA had lower
      Abeta 42 levels (beta coefficient = -0.48; 95% CI -0.9, -0.1). Compared to
      participants with a diagnosis of clinical dementia, those with pathologically
      confirmed AD had lower Abeta 42 levels (beta coefficient = -0.74; 95% CI -1.4, 
      0.1). CONCLUSION: The current study suggests that lower Abeta 42 levels reflect
      neuropathologic processes implicated in amyloid-related pathologies, such as NP
      and CAA.

PMID- 12601109
TI  - Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum.
AB  - BACKGROUND: Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic
      myopathy PROMM) are dominantly inherited disorders with unusual multisystemic
      clinical features. The authors have characterized the clinical and molecular
      features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of
      the zinc finger protein 9 (ZNF9) gene. METHODS: Three-hundred and seventy-nine
      individuals from 133 DM2/PROMM families were evaluated genetically, and in 234
      individuals clinical and molecular features were compared. RESULTS: Among
      affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts,
      23% diabetes, and 19% cardiac involvement. Because of the repeat tract's
      unprecedented size (mean approximately 5,000 CCTGs) and somatic instability,
      expansions were detectable by Southern analysis in only 80% of known carriers.
      The authors developed a repeat assay that increased the molecular detection rate
      to 99%. Only 30% of the positive samples had single sizeable expansions by
      Southern analysis, and 70% showed multiple bands or smears. Among the 101
      individuals with single expansions, repeat size did not correlate with age at
      disease onset. Affected offspring had markedly shorter expansions than their
      affected parents, with a mean size difference of -17 kb (-4,250 CCTGs).
      CONCLUSIONS: DM2 is present in a large number of families of northern European
      ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular
      dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and
      cardiac conduction defects. An important distinction is the lack of a congenital
      form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate
      that the multisystemic features common to both diseases are caused by CUG or CCUG
      expansions expressed at the RNA level.

PMID- 12601110
TI  - Clinical course correlates poorly with muscle pathology in nemaline myopathy.
AB  - OBJECTIVE: To report pathologic findings in 124 Australian and North American
      cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from
      124 Australian and North American patients with primary nemaline myopathy were
      reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha
      actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW)
      (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods,
      fiber-type distribution of rods, and presence or absence of intranuclear rods
      were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis
      was possible at all ages. Most biopsies contained nemaline bodies in more than
      50% of fibers, although rods were seen only on electron microscopy in 10
      patients. Rod numbers and localization correlated poorly with clinical severity.
      Frequent findings included internal nuclei and increased fiber size variation,
      type 1 fiber predominance and atrophy, and altered expression of fiber type
      specific proteins. Marked sarcomeric disruption, increased glycogen deposition,
      and intranuclear rods were associated with more severe clinical phenotypes.
      Serial biopsies showed progressive fiber size variation and increasing numbers of
      rods with time. Pathologic findings varied widely in families with multiple
      affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen
      accumulation, and marked sarcomeric disruption were common in nemaline myopathy
      associated with mutations in skeletal alpha-actin. Nemaline myopathy due to
      mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod
      formation in, and atrophy of, type 1 fibers. Light microscopic features of
      nemaline myopathy correlate poorly with disease course. Electron microscopy may
      correlate better with disease severity and genotype.

PMID- 12601112
TI  - The epidemiology of ALS in Modena, Italy.
AB  - OBJECTIVE: To determine the incidence, prevalence, and mortality rates of ALS in
      the province of Modena, Northern Italy, from 1990 through 1999. METHODS: A
      retrospective epidemiologic study was conducted, ascertaining cases from all
      neurologic centers and hospitals of the province, death certificates, and the
      Italian ALS Association, section of Modena. All clinical records were reviewed,
      and only patients fulfilling the El Escorial revised diagnostic criteria were
      included. RESULTS: During the period considered (1990 to 1999), 143 residents (67
      men and 76 women) entered the study. The average annual incidence was 2.16 per
      100,000, with a peak in the age class of 75 to 79 years. Mean prevalence rate was
      4.02 per 100,000, and mean mortality rate was 1.69 per 100,000. The incidence
      rate remained constant over time, whereas the prevalence and mortality rates
      increased owing to a rise in survival time (ALS mean duration was 17.38 months in
      1990, 43.18 months in 1999). In the mountainous areas, where agricultural work is
      more common, the incidence, prevalence, and mortality rates were higher than in
      urban areas and the disease onset occurred 10 years later. Of the risk factors
      examined, only agricultural work and rural residence were significant.
      CONCLUSIONS: The incidence, prevalence, and mortality rates agree with those in
      recent Italian surveys and with most international studies, but the distribution
      of cases varied with higher rates in mountainous areas. Further prospective
      studies are required.

PMID- 12601111
TI  - Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11
      families.
AB  - OBJECTIVE: To report clinical, neuroradiologic, neurophysiologic, and genetic
      findings on 16 patients from 11 unrelated families with a remarkable uniform
      phenotype characterized by infantile ascending hereditary spastic paralysis
      (IAHSP). METHODS: Sixteen patients from 11 families, originating from North
      Africa and Europe, who presented severe spastic paralysis and ascending
      progression were studied. RESULTS: Spastic paraplegia started in the first 2
      years of life in most patients and extended to the upper limbs by the end of the
      first decade. The disease progressed to tetraplegia, anarthria, dysphagia, and
      slow eye movements in the second decade. The clinical course showed a long
      survival and preservation of intellectual skills. Clinical, neuroradiologic, and
      neurophysiologic findings were consistent with a relatively selective early
      involvement of the corticospinal and corticobulbar pathways. No signs of lower
      motor neuron involvement were observed, whereas motor evoked potentials
      demonstrated predominant involvement of the upper motor neurons. MRI was normal
      in young patients but showed brain cortical atrophy in the oldest, predominant in
      the motor areas, and T2-weighted bilateral hyperintense signals in the posterior
      arm of the internal capsule. The ALS2 gene, recently found mutated in
      consanguineous Arabic families with either an ALS2 phenotype or a juvenile-onset
      primary lateral sclerosis, was analyzed. Alsin mutations were found in only 4 of
      the 10 families, whereas haplotype analysis excluded the ALS2 locus in one
      family. CONCLUSIONS: The syndrome of IAHSP is genetically heterogeneous, and no
      clinical sign can help to distinguish patients with and without Alsin mutations.

PMID- 12601113
TI  - Will caloric restriction and folate protect against AD and PD?
AB  - Recent epidemiologic studies of different sample populations have suggested that
      the risk of AD and PD may be increased in individuals with high-calorie diets and
      in those with increased homocysteine levels. Dietary restriction and
      supplementation with folic acid can reduce neuronal damage and improve behavioral
      outcome in mouse models of AD and PD. Animal studies have shown that the
      beneficial effects of dietary restriction result, in part, from increased
      production of neurotrophic factors and cytoprotective protein chaperones in
      neurons. By keeping homocysteine levels low, folic acid can protect cerebral
      vessels and can prevent the accumulation of DNA damage in neurons caused by
      oxidative stress and facilitated by homocysteine. Although further studies are
      required in humans, the emerging data suggest that high-calorie diets and
      elevated homocysteine levels may render the brain vulnerable to neurodegenerative
      disorders.

PMID- 12601114
TI  - CMT with pyramidal features. Charcot-Marie-Tooth.
AB  - To determine whether Charcot-Marie-Tooth (CMT) with pyramidal features is
      genetically distinct from other dominantly inherited axonal neuropathies, the
      authors examined all chromosomal loci and genes for axonal CMT. Two families were
      identified with an axonal CMT phenotype with distal wasting, weakness, pes cavus,
      sensory loss, and mild pyramidal signs (including extensor plantar responses,
      mild increase in tone, and preserved or increased reflexes but no spastic gait).
      Linkage studies excluded CMT2A, 2B, 2D, 2E, and 2F; ALS4; and HMN2. There were no
      mutations in the PMP22, MPZ/Po, or EGR2 genes.

PMID- 12601115
TI  - The phenylalanine loading test in the differential diagnosis of dystonia.
AB  - Early diagnosis of dopa-responsive dystonia (DRD) and its delineation from other
      dystonic syndromes is of great relevance because DRD is an eminently treatable
      condition. The possible relevance of the phenylalanine loading test (Phe-L) in
      differentiating DRD from primary focal and generalized dystonia was investigated.
      A marked difference in the phenylalanine/tyrosine ratio between patients with DRD
      and patients with other types of dystonia was observed. This indicates that Phe-L
      may be helpful in the differential diagnosis of dystonias.

PMID- 12601117
TI  - fMRI of triggerable aurae in musicogenic epilepsy.
AB  - The authors studied a patient with musicogenic epilepsy triggered by one specific
      musical piece using 3D PRESTO fMRI. During epileptic aurae initiated by the
      stimulus, signal increases were found in the left anterior temporal lobe,
      correlating with ictal EEG and SPECT showing a left anterior temporal focus, and
      the right gyrus rectus. Because fMRI indicated a cascade of recruitment of the
      ventral frontal lobes by epileptogenic music, left anterior temporal lobe
      activity could be secondary to a right gyrus rectus focus, possibly triggered by
      emotional processing of music.

PMID- 12601116
TI  - Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin.
AB  - The authors compared the functional activation state and cytokine secretion
      profile of CD8+ T cells in patients with relapsing-remitting and secondary
      progressive (SP) MS to those in normal controls. In addition, they examined
      cytokine secretion in relationship to single nucleotide polymorphism (SNP)
      analysis of cytokine genes. A significant increase in lymphotoxin secretion from
      anti-CD3-stimulated CD8+ T cells was observed in patients with SPMS as compared
      to normal controls. The authors found no significant differences in SNP frequency
      or in secretion of other cytokines.

PMID- 12601118
TI  - Trends in dementia mortality from two National Mortality Followback Surveys.
AB  - The National Center for Health Statistics conducted National Mortality Followback
      Surveys (NMFS) in 1986 and 1993. The next-of-kin's report of a physician's
      diagnosis of AD before death and a listing of AD or other dementia as the
      underlying cause increased significantly among women but remained stable among
      men. Currently, AD is among the top 10 leading causes of death in elderly white
      men and women in the United States.

PMID- 12601119
TI  - Antithyroid antibodies in the CSF: their role in the pathogenesis of Hashimoto's
      encephalopathy.
AB  - Antithyroid antibodies and circulating immune complexes (CIC) were found in the
      CSF of six patients with Hashimoto's encephalopathy (HE) but not in the CSF of 21
      controls. The synthesis of autoantibodies and CIC was intrathecal and their
      titers were independent of the patients' clinical status or therapy. Their
      presence in the CSF of patients with acute or subacute encephalopathy may be
      useful in diagnosing HE.

PMID- 12601121
TI  - Migraine-like disorder segregating with mtDNA 14484 Leber hereditary optic
      neuropathy mutation.
AB  - The authors report neurologic features in a large family harboring the
      mitochondrial DNA (mtDNA) mutation T14484C associated with Leber hereditary optic
      neuropathy (LHON). In the maternal line the mtDNA mutation was associated with
      optic neuropathy or migraine with aura or without aura and transient
      neurologic/visual disturbances. The segregation of familiar cases of migraine and
      LHON mutation broadens the clinical phenotype associated with a primary LHON
      mutation.

PMID- 12601120
TI  - Juvenile-onset glycogen storage disease type II with novel mutations in acid
      alpha-glucosidase gene.
AB  - The authors describe two novel mutations of the acid alpha-glucosidase gene,
      P361L and R437C, which define the juvenile-onset glycogen storage disease type II
      (GSDII) in a 16-year-old Chinese patient. The asymptomatic 13-year-old brother of
      the proband is also a compound heterozygote of the two mutations. These results
      confirm that intrafamilial phenotypic variation of juvenile-onset GSDII is
      ethnically diverse and suggest the contribution of other genes to the phenotypic
      variability of GSDII.

PMID- 12601122
TI  - The cold hands sign in MSA. Multiple system atrophy.

PMID- 12601123
TI  - Collateralization of vertebral arteries.

PMID- 12601124
TI  - Acute hemorrhagic leukoencephalitis vs ADEM: FLAIR MRI and neuropathology
      findings.

PMID- 12601125
TI  - Emotional facial paresis in a patient with a lateral medullary infarction.

PMID- 12601126
TI  - Case report: recurrent temporalis muscle swelling and headache.

PMID- 12601127
TI  - Ptosis in patients with hemispheric strokes.

PMID- 12601128
TI  - Diffusion abnormalities and Wernicke encephalopathy.

PMID- 12601129
TI  - Ipsilateral thalamic MRI abnormality in an epilepsy patient.

PMID- 12601130
TI  - Safety, tolerability, and efficacy of orally administered cannabinoids in MS.

PMID- 12601131
TI  - Oxidative damage and cytogenic analysis in leukocytes of Parkinson's disease
      patients.

PMID- 12601132
TI  - Proposed diagnostic criteria and nosology of acute transverse myelitis.

PMID- 12601133
TI  - Prediction of the disulfide bonding state of cysteines in proteins with hidden
      neural networks.
AB  - A hybrid system (hidden neural network) based on a hidden Markov model (HMM) and
      neural networks (NN) was trained to predict the bonding states of cysteines in
      proteins starting from the residue chains. Training was performed using 4136
      cysteine-containing segments extracted from 969 non-homologous proteins of well
      resolved 3D structure and without chain-breaks. After a 20-fold cross-validation
      procedure, the efficiency of the prediction scores as high as 80% using neural
      networks based on evolutionary information. When the whole protein is taken into
      account by means of an HMM, a hybrid system is generated, whose emission
      probabilities are computed using the NN output (hidden neural networks). In this
      case, the predictor accuracy increases up to 88%. Further, when tested on a
      protein basis, the hybrid system can correctly predict 84% of the chains in the
      data set, with a gain of at least 27% over the NN predictor.

PMID- 12601134
TI  - Closed loops: persistence of the protein chain returns.
AB  - It has recently been discovered that globular proteins are universally built from
      standard loop-n-lock units of about 30 amino acid residues. The hypothesis has
      been put forward on the loop stage in the protein evolution when the units were
      autonomous. Later they joined together making longer chains. One would expect
      that the early individual loop-n-lock elements might still be detected in modern
      protein sequences as remnants of the hypothetical 30-residue sequence prototypes.
      Among several strong sequence motifs, extracted from protein sequences of 23
      complete bacterial proteomes, one 32-residue prototype was studied here in
      detail. Numerous sequence segments related to the prototype are identified in the
      crystal structures of proteins of a PDB_SELECT database. Analysis of the
      respective chain trajectories for the cases with different degrees of sequence
      conservation confirms that the majority of the segments correspond to the closed
      loops. In the evolutionary diversification of the prototypes the secondary
      structure yields first, while the sequence is still moderately conserved. The
      last feature to go is the chain return property. Apparently, the opening of the
      loops would severely destabilize the protein fold, which explains their
      conservation.

PMID- 12601135
TI  - MASKER: improved solvent-excluded molecular surface area estimations using
      Boolean masks.
AB  - A fast algorithm for computing the solvent-accessible molecular surface area
      (SAS) using Boolean masks [Le Grand,S.M. and Merz,K.M.J. (1993). J. Comput.
      Chem., 14, 349-352) has been modified to estimate the solvent-excluded molecular
      surface area (SES), including contact, toroidal and re-entrant surface
      components. Numerical estimates of arc lengths of intersecting atomic SAS are
      used to estimate the toroidal surface and intersections between those arcs are
      used to estimate the re-entrant surface area. The new method is compared with an
      exact analytical method. Boolean molecular surface areas are continuous and
      pairwise differentiable and should be useful for molecular dynamics simulations,
      especially as the basis for an implicit solvent model.

PMID- 12601136
TI  - Identification of conserved residue patterns in small beta-barrel proteins.
AB  - Our abilities to predict three-dimensional conformation of a polypeptide, given
      its amino acid sequence, remain limited despite advances in structure analysis.
      Analysis of structures and sequences of protein families with similar secondary
      structural elements, but varying topologies, might help in addressing this
      problem. We have studied the small beta-barrel class of proteins characterized by
      four strands (n = 4) and a shear number of 8 (S = 8) to understand the principles
      of barrel formation. Multiple alignments of the various protein sequences were
      generated for the analysis. Positional entropy, as a measure of residue
      conservation, indicated conservation of non-polar residues at the core positions.
      The presence of a type II beta-turn among the various barrel proteins considered
      was another strikingly invariant feature. A conserved glycyl-aspartyl dipeptide
      at the beta-turn appeared to be important in guiding the protein sequence into
      the barrel fold. Molecular dynamics simulations of the type II beta-turn peptide
      suggested that aspartate is a key residue in the folding of the protein sequence
      into the barrel. Our study suggests that the conserved type II beta-turn and the
      non-polar residues in the barrel core are crucial for the folding of the
      protein's primary sequence into the beta-barrel conformation.

PMID- 12601138
TI  - Analysis of membrane stereochemistry with homology modeling of sn-glycerol-1
      phosphate dehydrogenase.
AB  - Different enantiomeric isomers, sn-glycerol-1-phosphate and sn-glycerol-3
      phosphate, are used as the glycerophosphate backbones of phospholipids in the
      cellular membranes of Archaea and the remaining two kingdoms, respectively. In
      Archaea, sn-glycerol-1-phosphate dehydrogenase is involved in the generation of
      sn-glycerol-1-phosphate, while sn-glycerol-3-phosphate dehydrogenase synthesizes
      the enantiomer in Eukarya and Bacteria. The coordinates of sn-glycerol-3
      phosphate dehydrogenase are available, although neither the tertiary structure
      nor the reaction mechanism of sn-glycerol-1-phosphate dehydrogenase is known.
      Database searching revealed that the archaeal enzyme shows sequence similarity to
      glycerol dehydrogenase, dehydroquinate synthase and alcohol dehydrogenase IV. The
      glycerol dehydrogenase, with coordinates that are available today, is closely
      related to the archaeal enzyme. Using the structure of glycerol dehydrogenase as
      the template, we built a model structure of the Methanothermobacter
      thermautotrophicus sn-glycerol-1-phosphate dehydrogenase, which could explain the
      chirality of the product. Based on the model structure, we determined the
      following: (1) the enzyme requires a Zn(2+) ion for its activity; (2) the enzyme
      selectively uses the pro-R hydrogen of the NAD(P)H; (3) the putative active site
      and the reaction mechanism were predicted; and (4) the archaeal enzyme does not
      share its evolutionary origin with sn-glycerol-3-phosphate dehydrogenase.

PMID- 12601137
TI  - Binding free energy calculations of galectin-3-ligand interactions.
AB  - Galectins show remarkable binding specificity towards beta-galactosides. A
      recently developed method for calculating binding free energies between a protein
      and its substrates has been used to evaluate the binding specificity of galectin
      3. Five disaccharides and a tetrasaccharide were used as the substrates. The
      calculated binding free energies agree quite well with the experimental data and
      the ranking of binding affinities is well reproduced. For all the six protein
      ligand complexes it was observed that electrostatic interactions oppose binding
      whereas the non-polar contributions drive complex formation. The observed binding
      specificity of galectin-3 for galactosides rather than glucosides is discussed in
      light of our results.

PMID- 12601139
TI  - Domain swapping in ribonuclease T1 allows the acquisition of double-stranded
      activity.
AB  - A mutant of ribonuclease T1 (RNase T1), denoted RNase Talpha, that is designed to
      recognize double-stranded ribonucleic acid was created. RNase Talpha carries the
      structure of RNase T1 except for a part of its loop L3 domain, which has been
      swapped for a corresponding domain from alpha-sarcin. The RNase Talpha maintains
      the pleated beta-sheet structure and retains the guanyl-specific ribonuclease
      activity of the wild-type RNase T1. A steady-state kinetic study on the RNase
      Talpha-catalyzed transesterification of GpU dinucleoside phosphates reveals a
      slightly reduced K(m) value of 6.94 x 10(-7) M. When the stranded specificity is
      examined, RNase Talpha catalyzes the hydrolysis of guanine base not only of
      single-stranded but also, as by design, of double-stranded RNA. The change of
      stranded specificity suggests the feasibility of using domain swapping to make a
      substrate-specific ribonuclease. This study suggests that the loop L3 in RNase T1
      can be used as a 'cassette player' for inserting a functional domain to make
      ribonuclease of various specificities.

PMID- 12601140
TI  - Structural basis of ICF-causing mutations in the methyltransferase domain of
      DNMT3B.
AB  - Mutations in the gene encoding for a de novo methyltransferase, DNMT3B, lead to
      an autosomal recessive Immunodeficiency, Centromeric instability and Facial
      anomalies (ICF) syndrome. To analyse the protein structure and consequences of
      ICF-causing mutations, we modelled the structure of the DNMT3B methyltransferase
      domain based on Haemophilus haemolyticus protein in complex with the cofactor
      AdoMet and the target DNA sequence. The structural model has a two-subdomain fold
      where the DNA-binding region is situated between the subdomains on a surface
      cleft having positive electrostatic potential. The smaller subdomains of the
      methyltransferases differ in length and sequences and therefore only the target
      recognition domain loop was modelled to show the location of an ICF-causing
      mutation. Based on the model, the DNMT3B recognizes the GC sequence and flips the
      cytosine from the double-stranded DNA to the catalytic pocket. The amino acids in
      the cofactor and target cytosine binding sites and also the electrostatic
      properties of the binding pockets are conserved. In addition, a registry of all
      known ICF-causing mutations, DNMT3Bbase, was constructed. The structural
      principles of the pathogenic mutations based on the modelled structure and the
      analysis of chi angle rotation changes of mutated side chains are discussed.

PMID- 12601141
TI  - Exploring the potential of the monobody scaffold: effects of loop elongation on
      the stability of a fibronectin type III domain.
AB  - The tenth fibronectin type III domain of human fibronectin (FNfn10) is a small,
      monomeric beta-sandwich protein, similar to the immunoglobulins. We have
      developed small antibody mimics, 'monobodies', using FNfn10 as a scaffold. We
      initially altered two loops of FNfn10 that are structurally equivalent to two of
      the hypervariable loops of the immunoglobulin domain. In order to assess the
      possibility of utilizing other loops in FNfn10 for target binding, we determined
      the effects of the elongation of each loop on the conformational stability of
      FNfn10. We found that all six loops of FNfn10 allowed the introduction of four
      glycine residues while retaining the global fold. Insertions in the AB and FG
      loops exhibited very small degrees of destabilization, comparable to or less than
      predicted entropic penalties due to the elongation, suggesting the absence of
      stabilizing interactions in these loops in wild-type FNfn10. Insertions in the
      BC, CD and DE loops, respectively, resulted in modest destabilization. In
      contrast, the EF loop elongation was highly destabilizing, consistent with
      previous studies showing the presence of stabilizing interactions in this loop.
      These results suggest that all loops, except for the EF loop, can be used for
      engineering a binding site, thus demonstrating excellent properties of the
      monobody scaffold.

PMID- 12601142
TI  - Novel mutant human fibronectin FIII9-10 domain pair with increased conformational
      stability and biological activity.
AB  - The ninth and tenth type III domains (FIII9-10) in the central cell binding
      domain of human fibronectin contain integrin receptor binding sites, including
      RGD in FIII10 and a synergy site, PHSRN, in FIII9. The specific amino acids that
      contribute to cell binding have been identified by the use of wild-type and
      mutant fragments of human fibronectin containing the FIII9-10 domain pair. At
      high concentrations FIII9-10 mimics, to a large extent, the biological activity
      of the full-length fibronectin molecule. However, FIII9 is conformationally
      unstable, even in the context of the FIII9-10 pair. Here we report the
      construction of a series of hybrid mouse-human FIII9-10 pairs that confer varying
      degrees of conformational stability to FIII9. The conformational stability of the
      human FIII9 module was increased 2-3-fold by substitution of Leu1408 with Pro. We
      demonstrate that the biological activity of this mutant is enhanced. The
      resulting FIII9-10 mutant has good solution properties and will provide a
      template into which further mutations can be incorporated in order to probe the
      structure-function relationship of the cell binding module of fibronectin.

PMID- 12601143
TI  - A universal, vector-based system for nucleic acid reading-frame selection.
AB  - The identification of a nucleic acid sequence's correct reading frame has
      important implications for homology-independent protein engineering techniques
      such as incremental truncation and SCRATCHY. We report the development and
      experimental implementation of a general in-frame selection system, pSALect, a
      plasmid vector that utilizes two marker sequences flanking the DNA of interest.
      This dual selection approach overcomes inconsistencies observed with traditional
      C-terminally fused reporter proteins. In the pSALect vector, sequences of
      interest are positioned between an N-terminal Tat-signal sequence and a C
      terminal beta-lactamase reporter. In-frame selection of the resulting three
      domain protein is performed by growing colonies on ampicillin-containing plates,
      requiring full-length translation in order to link covalently the signal sequence
      to the lactamase for export into the periplasm. This dual selection scheme has
      been validated successfully using defined sequences of glycinamide ribonucleotide
      formyltransferases (GARTs) from Escherichia coli and human and, in contrast to C
      terminal fusion systems, proved effective when applied towards the selection of
      in-frame constructs in an incremental truncation library.

PMID- 12601145
TI  - Investigating antibody-catalyzed ozone generation by human neutrophils.
AB  - Recent studies have suggested that antibodies can catalyze the generation of
      previously unknown oxidants including dihydrogen trioxide (H(2)O(3)) and ozone
      (O(3)) from singlet oxygen ((1)O(2)(*)) and water. Given that neutrophils have
      the potential both to produce (1)O(2)(*) and to bind antibodies, we considered
      that these cells could be a biological source of O(3). We report here further
      analytical evidence that antibody-coated neutrophils, after activation, produce
      an oxidant with the chemical signature of O(3). This process is independent of
      surface antibody concentration down to 50% of the resting concentration,
      suggesting that surface IgG is highly efficient at intercepting the neutrophil
      generated (1)O(2)(*). Vinylbenzoic acid, an orthogonal probe for ozone detection,
      is oxidized by activated neutrophils to 4-carboxybenzaldehyde in a manner
      analogous to that obtained for its oxidation by ozone in solution. This discovery
      of the production of such a powerful oxidant in a biological context raises
      questions about not only the capacity of O(3) to kill invading microorganisms but
      also its role in amplification of the inflammatory response by signaling and gene
      activation.

PMID- 12601144
TI  - Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific
      T cells can induce complete remissions of relapsed leukemia.
AB  - Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or
      multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been
      shown to be a successful treatment approach. The hematopoiesis-restricted minor
      histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of
      the recipient may serve as target antigens for alloreactive donor T cells.
      Recently we treated three mHAg HA-1- and/or HA-2-positive patients with a relapse
      of their disease after alloSCT with DLI from their mHAg HA-1- and/or HA-2
      negative donors. Using HLA-A2HA-1 and HA-2 peptide tetrameric complexes we showed
      the emergence of HA-1- and HA-2-specific CD8(+) T cells in the blood of the
      recipients 5-7 weeks after DLI. The appearance of these tetramer-positive cells
      was followed immediately by a complete remission of the disease and restoration
      of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer
      positive T cells isolated during the clinical response specifically recognized HA
      1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited
      the growth of leukemic precursor cells in vitro. Thus, HA-1- and HA-2-specific
      cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate
      graft-versus-leukemia or myeloma reactivity resulting in a durable remission.
      This finding implies that in vitro generated HA-1- and HA-2-specific cytotoxic T
      lymphocytes could be used as adoptive immunotherapy to treat hematological
      malignancies relapsing after alloSCT.

PMID- 12601147
TI  - Abundance not linked to survival across the end-Cretaceous mass extinction:
      patterns in North American bivalves.
AB  - Ecological studies suggest that rare taxa are more likely to go extinct than
      abundant ones, but the influence of abundance on survivorship in the fossil
      record has received little attention. An analysis of Late Maastrichtian bivalve
      subgenera from the North American Coastal Plain found no evidence that
      survivorship is tied to abundance across the end-Cretaceous mass extinction (65
      million years ago), regardless of abundance metric or spatial scale examined. The
      fact that abundance does not promote survivorship in end-Cretaceous bivalves
      suggests that the factors influencing survivorship during mass extinctions in the
      fossil record may differ from those operating during intervals of background
      extinction.

PMID- 12601146
TI  - Atomic-level observation of macromolecular crowding effects: escape of a protein
      from the GroEL cage.
AB  - Experimental work has demonstrated that the efficient operation of the GroEL
      GroES chaperonin machinery is sensitive to the presence of macromolecular
      crowding agents. Here, I describe atomically detailed computer simulations that
      provide a microscopic view of how crowding effects are exerted. Simulations were
      performed to compute the free energy required to extract the protein rhodanese
      from the central cavity of GroEL into solutions containing a range of crowder
      concentrations. The computed energetics allow the total yield of folded protein
      to be predicted; the calculated yields show a nonlinear dependence on the
      concentration of crowding agent identical to that observed experimentally. The
      close correspondence between simulation and experiment prompts the use of the
      former in a truly predictive setting: simulations are used to suggest that more
      effective crowding agents might be designed by exploiting an "agoraphobic
      effect."

PMID- 12601148
TI  - DNA molecule provides a computing machine with both data and fuel.
AB  - The unique properties of DNA make it a fundamental building block in the fields
      of supramolecular chemistry, nanotechnology, nano-circuits, molecular switches,
      molecular devices, and molecular computing. In our recently introduced autonomous
      molecular automaton, DNA molecules serve as input, output, and software, and the
      hardware consists of DNA restriction and ligation enzymes using ATP as fuel. In
      addition to information, DNA stores energy, available on hybridization of
      complementary strands or hydrolysis of its phosphodiester backbone. Here we show
      that a single DNA molecule can provide both the input data and all of the
      necessary fuel for a molecular automaton. Each computational step of the
      automaton consists of a reversible software molecule input molecule hybridization
      followed by an irreversible software-directed cleavage of the input molecule,
      which drives the computation forward by increasing entropy and releasing heat.
      The cleavage uses a hitherto unknown capability of the restriction enzyme FokI,
      which serves as the hardware, to operate on a noncovalent software input hybrid.
      In the previous automaton, software input ligation consumed one software molecule
      and two ATP molecules per step. As ligation is not performed in this automaton, a
      fixed amount of software and hardware molecules can, in principle, process any
      input molecule of any length without external energy supply. Our experiments
      demonstrate 3 x 10(12) automata per microl performing 6.6 x 10(10) transitions
      per second per microl with transition fidelity of 99.9%, dissipating about 5 x
      10(-9) W microl as heat at ambient temperature.

PMID- 12601150
TI  - Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated
      overexpression of human alpha-synuclein: a new primate model of Parkinson's
      disease.
AB  - We used a high-titer recombinant adeno-associated virus (rAAV) vector to express
      WT or mutant human alpha-synuclein in the substantia nigra of adult marmosets.
      The alpha-synuclein protein was expressed in 90-95% of all nigral dopamine
      neurons and distributed by anterograde transport throughout their axonal and
      dendritic projections. The transduced neurons developed severe neuronal
      pathology, including alpha-synuclein-positive cytoplasmic inclusions and granular
      deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and
      pyknotic, densely alpha-synuclein-positive perikarya. By 16 wk posttransduction,
      30-60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine
      hydroxylase-positive innervation of the caudate nucleus and putamen was reduced
      to a similar extent. The rAAV-alpha-synuclein-treated monkeys developed a type of
      motor impairment, i.e., head position bias, compatible with this magnitude of
      nigrostriatal damage. rAAV vector-mediated alpha-synuclein gene transfer provides
      a transgenic primate model of nigrostriatal alpha-synucleinopathy that is of
      particular interest because it develops slowly over time, like human Parkinson's
      disease (PD), and expresses neuropathological features (alpha-synuclein-positive
      inclusions and dystrophic neurites, in particular) that are similar to those seen
      in idiopathic PD. This model offers new opportunities for the study of
      pathogenetic mechanisms and exploration of new therapeutic targets of particular
      relevance to human PD.

PMID- 12601149
TI  - Identification of the coupling between skeletal muscle store-operated Ca2+ entry
      and the inositol trisphosphate receptor.
AB  - Examination of store-operated Ca(2+) entry (SOC) in single, mechanically skinned
      skeletal muscle cells by confocal microscopy shows that the inositol 1,4,5
      trisphosphate (IP(3)) receptor acts as a sarcoplasmic reticulum [Ca(2+)] sensor
      and mediates SOC by physical coupling without playing a key role in Ca(2+)
      release from internal stores, as is the case with various cell types in which SOC
      was investigated previously. The results have broad implications for
      understanding the mechanism of SOC that is essential for cell function in general
      and muscle function in particular. Moreover, the study ascribes an important role
      to the IP(3) receptors in skeletal muscle, the role of which with respect to
      Ca(2+) homeostasis was ill defined until now.

PMID- 12601151
TI  - Long-term depression of climbing fiber-evoked calcium transients in Purkinje cell
      dendrites.
AB  - In recent years much has been learned about the molecular requirements for
      inducing long-term synaptic depression (LTD) in various brain regions. However,
      very little is known about the consequences of LTD induction for subsequent
      signaling events in postsynaptic neurons. We have addressed this issue by
      examining homosynaptic LTD at the cerebellar climbing fiber (CF)-Purkinje cell
      (PC) synapse. This synapse is built for reliable and massive excitation:
      Activation of a single axon produces an unusually large alpha-amino-3-hydroxy-5
      methyl-4-isoxazole propionic acid receptor-mediated synaptic current, the
      depolarization of which drives a regenerative complex spike producing a large,
      widespread Ca(2+) transient in PC dendrites. Here we test whether CF LTD has an
      impact on dendritic, complex spike-evoked Ca(2+) signals by simultaneously
      performing long-term recordings of complex spikes and microfluorimetric Ca(2+)
      measurements in PC dendrites in rat cerebellar slices. Our data show that LTD of
      the CF excitatory postsynaptic current produces a reduction in both slow
      components of the complex spike waveform and complex spike-evoked dendritic
      Ca(2+) transients. This LTD of dendritic Ca(2+) signals may provide a
      neuroprotective mechanism and/or constitute "heterosynaptic metaplasticity" by
      reducing the probability for subsequent induction of those forms of use-dependent
      plasticity, which require CF-evoked Ca(2+) signals such as parallel fiber-PC LTD
      and interneuron-PC LTP.

PMID- 12601153
TI  - The weighted-volume derivative of a space-filling diagram.
AB  - Computing the volume occupied by individual atoms in macromolecular structures
      has been the subject of research for several decades. This interest has grown in
      the recent years, because weighted volumes are widely used in implicit solvent
      models. Applications of the latter in molecular mechanics simulations require
      that the derivatives of these weighted volumes be known. In this article, we give
      a formula for the volume derivative of a molecule modeled as a space-filling
      diagram made up of balls in motion. The formula is given in terms of the weights,
      radii, and distances between the centers as well as the sizes of the facets of
      the power diagram restricted to the space-filling diagram. Special attention is
      given to the detection and treatment of singularities as well as discontinuities
      of the derivative.

PMID- 12601152
TI  - The ATP hydrolyzing transcription activator phage shock protein F of Escherichia
      coli: identifying a surface that binds sigma 54.
AB  - Members of the protein family called ATPases associated with various cellular
      activities (AAA(+)) play a crucial role in transforming chemical energy into
      biological events. AAA(+) proteins are complex molecular machines and typically
      form ring-shaped oligomeric complexes that are crucial for ATPase activity and
      mechanism of action. The Escherichia coli transcription activator phage shock
      protein F (PspF) is an AAA(+) mechanochemical enzyme that functions to sense and
      relay the energy derived from nucleoside triphosphate hydrolysis to catalyze
      transcription by the sigma(54)-RNA polymerase. Closed promoter complexes formed
      by the sigma(54)-RNA polymerase are substrates for the action of PspF. By using a
      protein fragmentation approach, we identify here at least one sigma(54)-binding
      surface in the PspF AAA(+) domain. Results suggest that ATP hydrolysis by PspF is
      coupled to the exposure of at least one sigma(54)-binding surface. This
      nucleotide hydrolysis-dependent presentation of a substrate binding surface can
      explain why complexes that form between sigma(54) and PspF are transient and
      could be part of a mechanism used generally by other AAA(+) proteins to regulate
      activity.

PMID- 12601154
TI  - Single-cell perforin and granzyme expression reveals the anatomical localization
      of effector CD8+ T cells in influenza virus-infected mice.
AB  - Influenza virus infection activates cytolytic T lymphocytes (CTL) that contribute
      to viral clearance by releasing perforin and granzymes from cytoplasmic granules.
      Virus-specific, perforin-dependent CD8(+) CTL were detected in freshly isolated
      cells from the mouse lung parenchyma but not from the mediastinal lymph nodes
      (MLN), where they are primed, or from the spleen during primary influenza virus
      infection. To determine whether this difference was due to the low frequency or
      incomplete maturation of effector CTL in MLN, we measured expression of perforin,
      granzymes A, B, and C, and IFN-gamma mRNAs in CD8(+) populations and single cells
      immediately after isolation from virus-infected mice. Quantitative PCR revealed
      significant expression of perforin, granzyme A, granzyme B, and IFN-gamma in
      activated CD8(+) cells from MLN, spleen, and lung parenchyma. Granzyme C
      expression was not detected. Individual activated or nucleoprotein peptide/class
      I tetramer-binding CD8(+) cells from the three tissues expressed diverse
      combinations of perforin, granzyme, and IFN-gamma mRNAs. Although cells from lung
      expressed granzymes A and B at higher frequency, each of the tissues contained
      cells that coexpressed perforin with granzymes A and/or B. The main difference
      between MLN and lung was the elevated frequency of activated CD8(+) T cells in
      the lung, rather than their perforin/granzyme expression profile. The data
      suggest that some CTL mature into perforin/granzyme-expressing effector cells in
      MLN but reach detectable frequencies only when they accumulate in the infected
      lung.

PMID- 12601155
TI  - Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion
      neurons by expression of exogenous calcium channels.
AB  - Fast cholinergic neurotransmission between superior cervical ganglion neurons
      (SCGNs) in cell culture is initiated by N-type Ca(2+) currents through Ca(v)2.2
      channels. To test the ability of different Ca(2+)-channel subtypes to initiate
      synaptic transmission in these cells, SCGNs were injected with cDNAs encoding
      Ca(v)1.2 channels, which conduct L-type currents, Ca(v)2.1 channels, which
      conduct P/Q-type Ca(2+) currents, and Ca(v)2.3 channels, which conduct R-type
      Ca(2+) currents. Exogenously expressed Ca(v)2.1 channels were localized in nerve
      terminals, as assessed by immunocytochemistry with subtype-specific antibodies,
      and these channels effectively initiated synaptic transmission. Injection with
      cDNA encoding Ca(v)2.3 channels yielded a lower level of presynaptic labeling and
      synaptic transmission, whereas injection with cDNA encoding Ca(v)1.2 channels
      resulted in no presynaptic labeling and no synaptic transmission. Our results
      show that exogenously expressed Ca(2+) channels can mediate synaptic transmission
      in SCGNs and that the specificity of reconstitution of neurotransmission
      (Ca(v)2.1 > Ca(v)2.3 >> Ca(v)1.2) follows the same order as in neurons in vivo.
      The specificity of reconstitution of neurotransmission parallels the specificity
      of trafficking of these Ca(v) channels to nerve terminals.

PMID- 12601156
TI  - Requirement for the synaptic protein interaction site for reconstitution of
      synaptic transmission by P/Q-type calcium channels.
AB  - Ca(v)2.1 channels, which conduct P/Q-type Ca(2+) currents, were expressed in
      superior cervical ganglion neurons in cell culture, and neurotransmission
      initiated by these exogenously expressed Ca(2+) channels was measured. Deletions
      in the synaptic protein interaction (synprint) site in the intracellular loop
      between domains II and III of Ca(v)2.1 channels reduced their effectiveness in
      synaptic transmission. Surprisingly, this effect was correlated with loss of
      presynaptic localization of the exogenously expressed channels. Ca(v)1.2
      channels, which conduct L-type Ca(2+) currents, are ineffective in supporting
      synaptic transmission, but substitution of the synprint site from Ca(v)2.1
      channels in Ca(v)1.2 was sufficient to establish synaptic transmission initiated
      by L-type Ca(2+) currents through the exogenous Ca(v)1.2 channels. Substitution
      of the synprint site from Ca(v)2.2 channels, which conduct N-type Ca(2+)
      currents, was even more effective than Ca(v)2.1. Our results show that
      localization and function of exogenous Ca(2+) channels in nerve terminals of
      superior cervical ganglion neurons require a functional synprint site and suggest
      that binding of soluble NSF attachment protein receptor (SNARE) proteins to the
      synprint site is a necessary permissive event for nerve terminal localization of
      presynaptic Ca(2+) channels.

PMID- 12601157
TI  - ToxR regulon of Vibrio cholerae and its expression in vibrios shed by cholera
      patients.
AB  - Toxigenic Vibrio cholerae cause cholera, a severe diarrheal disease responsible
      for significant morbidity and mortality worldwide. Two determinants, cholera
      enterotoxin (CT) and toxin coregulated pilus (TCP) are critical factors
      responsible for this organism's virulence. The genes for these virulence
      determinants belong to a network of genes (the ToxR regulon) whose expression is
      modulated by transcriptional regulators encoded by the toxRS, tcpPH, and toxT
      genes. To define the ToxR regulon more fully, mutants defective in these
      regulatory genes were transcriptionally profiled by using V. cholerae genomic
      microarrays. This study identified 13 genes that were transcriptionally repressed
      by the toxT mutation (all involved in CT and TCP biogenesis), and 27 and 60 genes
      that were transcriptionally repressed by the tcpPH and toxRS mutations,
      respectively. During the course of this analysis, we validated the use of a
      genomic DNA-based reference sample as a means to standardize and normalize data
      obtained in different microarray experiments. This method allowed the accurate
      transcriptional profiling of V. cholerae cells present in stools from cholera
      patients and the comparison of these profiles to those of wild-type and mutant
      strains of V. cholerae grown under optimal conditions for CT and TCP expression.
      Our results suggest that vibrios present in cholera stools carry transcripts for
      these two virulence determinants, albeit at relatively low levels compared with
      optimal in vitro conditions. The transcriptional profile of vibrios present in
      cholera stools also suggests that the bacteria experienced conditions of
      anaerobiosis, iron limitation, and nutrient deprivation within the human
      gastrointestinal tract.

PMID- 12601158
TI  - Autonomous T cell trafficking examined in vivo with intravital two-photon
      microscopy.
AB  - The recirculation of T cells between the blood and secondary lymphoid organs
      requires that T cells are motile and sensitive to tissue-specific signals. T cell
      motility has been studied in vitro, but the migratory behavior of individual T
      cells in vivo has remained enigmatic. Here, using intravital two-photon laser
      microscopy, we imaged the locomotion and trafficking of naive CD4(+) T cells in
      the inguinal lymph nodes of anesthetized mice. Intravital recordings deep within
      the lymph node showed T cells flowing rapidly in the microvasculature and
      captured individual homing events. Within the diffuse cortex, T cells displayed
      robust motility with an average velocity of approximately 11 microm x min(-1). T
      cells cycled between states of low and high motility roughly every 2 min,
      achieving peak velocities >25 microm x min(-1). An analysis of T cell migration
      in 3D space revealed a default trafficking program analogous to a random walk.
      Our results show that naive T cells do not migrate collectively, as they might
      under the direction of pervasive chemokine gradients. Instead, they appear to
      migrate as autonomous agents, each cell taking an independent trafficking path.
      Our results call into question the role of chemokine gradients for basal T cell
      trafficking within T cell areas and suggest that antigen detection may result
      from a stochastic process through which a random walk facilitates contact with
      antigen-presenting dendritic cells.

PMID- 12601159
TI  - Modulation of cardiac Ca(V)1.2 channels by dihydropyridine and phosphatase
      inhibitor requires Ser-1142 in the domain III pore loop.
AB  - Dihydropyridine-sensitive, voltage-activated calcium channels respond to membrane
      depolarization with two distinct modes of activity: short bursts of very short
      openings (mode 1) or repetitive openings of much longer duration (mode 2). Here
      we show that both the dihydropyridine, BayK8644 (BayK), and the inhibitor of
      SerThr protein phosphatases, okadaic acid, have identical effects on the gating
      of the recombinant cardiac calcium channel, Ca(V)1.2 (alpha(1)C). Each produced
      identical mode 2 gating in cell-attached patches, and each prevented rundown of
      channel activity when the membrane patch was excised into ATP-free solutions.
      These effects required Ser or Thr at position 1142 in the domain III pore loop
      between transmembrane segments S5 and S6, where dihydropyridines bind to the
      channel. Mutation of Ser-1142 to Ala or Cys produced channels with very low
      activity that could not be modulated by either BayK or okadaic acid. A molecular
      model of Ca(V)1.2 indicates that Ser-1142 is unlikely to be phosphorylated, and
      thus we conclude that BayK binding stabilizes mode 2 gating allosterically by
      either protecting a phospho Ser/Thr on the alpha(1)C subunit or mimicking
      phosphorylation at that site.

PMID- 12601160
TI  - Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in
      a murine model of HIV central nervous system infection.
AB  - HIV-1 infection in the brain induces neuronal apoptosis leading to HIV-associated
      dementia. To explore the underlying mechanism, we developed a murine model by
      using human peripheral blood mononuclear cell (PBMC)-transplanted nonobese
      diabetic (NOD)-severe combined immunodeficiency (SCID) (hu-PBMC-NOD-SCID) mice.
      Administration of lipopolysaccharide (LPS) to HIV-1-infected hu-PBMC-NOD-SCID
      mice induced infiltration of HIV-1-infected human cells into the perivascular
      region of the brain and neuronal apoptosis was found in macrophage (M)-tropic but
      not T cell (T)-tropic HIV-1-infected brains. The apoptotic neurons were
      frequently colocalized with the HIV-1-infected macrophages that expressed tumor
      necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Administration
      of a neutralizing antibody against human TRAIL but not human TNF-alpha or Fas
      ligand (FasL) blocked the neuronal apoptosis in the HIV-1-infected brain. These
      results strongly suggest a critical contribution of TRAIL expressed on HIV-1
      infected macrophages to neuronal apoptosis.

PMID- 12601161
TI  - Estrogen is a critical determinant that specifies the duration of the window of
      uterine receptivity for implantation.
AB  - Many underlying causes of human infertility have been overcome by using in vitro
      fertilization (IVF) and embryo transfer (ET) techniques. Nevertheless,
      implantation rates in IVF programs remain low despite the transfer of apparently
      healthy embryos. This suggests that there are problems with the differentiation
      of the uterus to the receptive state in response to the ovarian hormones estrogen
      and progesterone. The molecular basis of this receptive state when the uterine
      environment is conducive to blastocyst acceptance and implantation remains poorly
      understood. Normally, the "window" of uterine receptivity lasts for a limited
      time. Using ETs and the progesterone-treated delayed-implantation model in mice,
      we demonstrate here that levels of estrogen within a very narrow range determine
      the duration of the window of uterine receptivity. Although estrogen at different
      physiological concentrations can initiate implantation, we find that the window
      of uterine receptivity remains open for an extended period at lower estrogen
      levels but rapidly closes at higher levels. The uterine refractoriness that
      follows the receptive state at high estrogen levels is accompanied by aberrant
      uterine expression of implantation-related genes. These results suggest that
      careful regulation of estrogen levels is one of the important factors for
      improvement of female fertility in IVFET programs.

PMID- 12601162
TI  - Progesterone receptors mediate male aggression toward infants.
AB  - Neuroendocrine mechanisms that mediate male aggression toward infants are poorly
      understood. Although testosterone is known to enhance aggression in other social
      contexts, evidence that it modulates aggression toward infants is equivocal. We
      have found that male progesterone receptor knockout (PRKO) mice exhibit no
      infanticidal behavior and little aggression toward young. Male PRKO mice also
      display significantly enhanced parental behaviors. In wild-type mice, blockade of
      PR induces a behavioral phenotype similar to that of the PRKO males, whereas
      progesterone exacerbates aggressive tendencies toward infants. Aggressive
      behaviors directed toward adult males, by contrast, are unaffected by
      progesterone, PR antagonism, or PR gene deletion. Previously thought to be of
      diminished importance in male animals, PRs play a critical and specific role in
      modulating infant-directed behaviors in male mice.

PMID- 12601163
TI  - Mexican hats and pinwheels in visual cortex.
AB  - Many models of cortical function assume that local lateral connections are
      specific with respect to the preferred features of the interacting cells and that
      they are organized in a Mexican-hat pattern with strong "center" excitation
      flanked by strong "surround" inhibition. However, anatomical data on primary
      visual cortex indicate that the local connections are isotropic and that
      inhibition has a shorter range than excitation. We address this issue in an
      analytical study of a neuronal network model of the local cortical circuit in
      primary visual cortex. In the model, the orientation columns specified by the
      convergent lateral geniculate nucleus inputs are arranged in a pinwheel
      architecture, whereas cortical connections are isotropic. We obtain a trade-off
      between the spatial range of inhibition and its time constant. If inhibition is
      fast, the network can operate in a Mexican-hat pattern with isotropic connections
      even with a spatially narrow inhibition. If inhibition is not fast, Mexican-hat
      operation requires a spatially broad inhibition. The Mexican-hat operation can
      generate a sharp orientation tuning, which is largely independent of the distance
      of the cell from the pinwheel center.

PMID- 12601164
TI  - Pathogen DNA as target for host-generated oxidative stress: role for repair of
      bacterial DNA damage in Helicobacter pylori colonization.
AB  - Helicobacter pylori elicits an oxidative stress during host colonization. This
      oxidative stress is known to cause lesions in the host DNA. Here we addressed the
      question as to whether the pathogen DNA is subject to lethal or mutational damage
      by the host-generated oxidative response. H. pylori Hpnth mutants unable to
      repair oxidized pyrimidines from the bacterial DNA were generated. H. pylori
      strains lacking a functional endonuclease III (HpNth) showed elevated spontaneous
      and induced mutation rates and were more sensitive than the parental strain to
      killing by exposure to oxidative agents or activated macrophages. Although under
      laboratory conditions the Hpnth mutant strain grows as well as the wild-type
      strain, in a mouse infection the stomach bacterial load gradually decreases while
      the population in the wild-type strain remains stable, showing that endonuclease
      III deficiency reduces the colonization capacity of the pathogen. In coinfection
      experiments with a wild-type strain, Hpnth cells are eradicated 15 days
      postinfection (p.i.) even when inoculated in a 1:9 wild-type:mutant strain ratio,
      revealing mutagenic lesions that are counterselected under competition
      conditions. These results show that the host effectively induces lethal and
      premutagenic oxidative DNA adducts on the H. pylori genome. The possible
      consequences of these DNA lesions on the adaptability of H. pylori strains to new
      hosts are discussed.

PMID- 12601165
TI  - Role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during
      activation.
AB  - In the G protein-coupled receptor rhodopsin, the conserved NPxxY(x)(5,6)F motif
      connects the transmembrane helix VII and the cytoplasmic helix 8. The less
      geometrically constrained retinal analogue 9-demethyl-retinal prevents efficient
      transformation of rhodopsin to signaling metarhodopsin (Meta) II after retinal
      photoisomerization. Here, we demonstrate that Ala replacement mutations within
      the NPxxY(x)(5,6)F domain, which eliminate an interaction between aromatic
      residues Y306 and F313, allow formation of Meta II despite the presence of 9
      demethyl-retinal. Also a disulfide bond linking residues 306 and 313 in the 9
      demethyl-retinal-reconstituted mutant Y306C/F313C/C316S prevented Meta II
      formation, whereas the reduced form of the mutant readily transformed to Meta II
      after illumination. These observations suggest that the interaction between
      residues 306 and 313 is disrupted during the Meta I/Meta II transition. However,
      this enhancement in Meta II formation is not reflected in the G protein
      activation, which is dramatically reduced for these mutants, suggesting that
      changes in the Y306-F313 interaction also lead to a proper realigning of helix 8
      after photoisomerization. The E134Q mutation, located in the second conserved
      motif, D(E)RY, rescues activity in 9-demethyl-retinal-reconstituted mutants to
      different degrees, depending on the position of the Ala replacement in the
      NPxxY(x)(5,6)F motif, thus revealing distinct roles for the NP and Y(x)(5,6)F
      portions. Our studies underscore the importance of the NPxxY(x)(5,6)F and D(E)RY
      motifs in providing structural constraints in rhodopsin that rearrange in
      response to photoisomerization during formation of the G protein-activating Meta
      II. The dual control of the structural rearrangements secures reliable
      transformation of quiescent rhodopsin to activating Meta II.

PMID- 12601166
TI  - Quantitative proteomic analysis indicates increased synthesis of a quinolone by
      Pseudomonas aeruginosa isolates from cystic fibrosis airways.
AB  - The opportunistic bacterial pathogen Pseudomonas aeruginosa colonizes airways of
      individuals with cystic fibrosis (CF) with resultant chronic destructive lung
      disease. P. aeruginosa adaptation to the CF airway includes biofilm formation and
      antibiotic resistance. Isolates from asymptomatic individuals in the first 3
      years of life have unique characteristics, suggesting that adaptation occurs
      before clinical symptoms. One defined early adaptation is expression of a
      specific proinflammatory lipopolysaccharide (LPS) that is associated with
      antimicrobial peptide resistance. This CF-specific LPS is induced when P.
      aeruginosa is grown in medium that is limited for magnesium. Therefore,
      qualitative and quantitative proteomic approaches were used to define 1,331 P.
      aeruginosa proteins, of which 145 were differentially expressed on limitation of
      magnesium. Among proteins induced by low magnesium were enzymes essential for
      production of 2-heptyl 3-hydroxy 4-quinolone, the Pseudomonas quinolone signal
      (PQS), which interacts with the homoserine lactone signaling pathway. Measurement
      of PQS in P. aeruginosa isolates from asymptomatic children with CF indicated
      that strains with increased synthesis of PQS are present during early
      colonization of CF patient airways.

PMID- 12601167
TI  - Identification, classification, and partial characterization of genes in humans
      and other vertebrates homologous to a fish membrane progestin receptor.
AB  - Recently we discovered a previously uncharacterized gene with the characteristics
      of a membrane progestin receptor (mPR) in a fish model, spotted seatrout. Here,
      we report the identification, cloning, and characteristics of other members of
      this hitherto unknown family of putative mPRs from several vertebrate species,
      including human, mouse, pig, Xenopus, zebrafish, and Fugu, with highly conserved
      nucleotide and deduced amino acid sequences and similar structures to the spotted
      seatrout mPR. The 13 vertebrate genes identified seem to belong to an unknown
      gene family. Phylogenetic analysis indicates these cDNAs comprise three distinct
      groups (named alpha, beta, and gamma) within this gene family. Structural
      analyses of the translated cDNAs suggest they encode membrane proteins with seven
      transmembrane domains. The transcript sizes of the human alpha, beta, and gamma
      putative mPR mRNAs varied from 2.8 to 5.8 kb and showed distinct distributions in
      reproductive, neural, kidney and intestinal tissues, respectively. Recombinant
      human alpha, gamma, and mouse beta proteins produced in an Escherichia coli
      expression system demonstrated high affinity (K(d) = 20-30 nM) saturable binding
      for progesterone. Further analysis of binding to the gamma-subtype revealed
      binding was specific for progestins and was displaceable, with rapid rates of
      association and dissociation (t(1/2) = 2-8 min). These results suggest this is a
      new family of steroid receptors unrelated to nuclear steroid receptors, but
      instead having characteristics of G protein-coupled receptors.

PMID- 12601168
TI  - Sex- and age-dependent human transcriptome variability: implications for chronic
      heart failure.
AB  - Heart failure (HF) is the end result of progressive and diverse biological
      adaptations within the diseased myocardium. We used cDNA microarrays and
      quantitative PCR to examine the transcriptomes of 38 left ventricles from failing
      and nonfailing human myocardium. After identification of a pool of putative HF
      responsive candidate genes by microarrays on seven nonfailing and eight failing
      hearts, we used quantitative PCR and a general linear statistical model in a
      larger sample set (n = 34) to validate and examine the role of contributing
      biological variables (age and sex). We find that most HF-candidate genes
      (transcription factors, Cebpb, Npat; signaling molecules, Map2k3, Map4k5;
      extracellular matrix proteins, Lum, Cola1; and metabolic enzymes, Mars)
      demonstrated significant changes in gene expression; however, the majority of
      differences among samples depended on variables such as sex and age, and not on
      HF alone. Some HF-responsive gene products also demonstrated highly significant
      changes in expression as a function of age and/or sex, but independent of HF
      (Ngp1, Cd163, and Npat). These results emphasize the need to account for
      biological variables (HF, sex and age interactions) to elucidate genomic
      correlates that trigger molecular pathways responsible for the progression of HF
      syndromes.

PMID- 12601169
TI  - Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele
      occurs after maternal and paternal transmission.
AB  - Phenotypic variation that cannot be explained by genetic or environmental
      heterogeneity has intrigued geneticists for decades. The molecular basis of this
      phenomenon, however, is largely a mystery. Axin-fused (Axin(Fu)), first
      identified in 1937, is a classic example of a mammalian allele displaying
      extremely variable expression states. Here we demonstrate that the presence or
      absence of its characteristic phenotype, a kinked tail, correlates with
      differential DNA methylation at a retrotransposon within Axin(Fu) and identify
      mutant transcripts arising adjacent to the retrotransposon LTR that are likely to
      be causative of the phenotype. Furthermore, the epigenetic state at Axin(Fu) can
      be inherited transgenerationally after both maternal and paternal transmission.
      This is in contrast to epigenetic inheritance at the murine agouti-viable yellow
      (A(vy)) allele, which occurs through the female only. Unlike the egg, the sperm
      contributes very little (if any) cytoplasm to the zygote, and therefore paternal
      inheritance at Axin(Fu) argues against the possibility that the effects are due
      to cytoplasmic or metabolic influences. Consistent with the idea of
      transgenerational inheritance of epigenetic marks, we find that the methylation
      state of Axin(Fu) in mature sperm reflects the methylation state of the allele in
      the somatic tissue of the animal, suggesting that it does not undergo epigenetic
      reprogramming during gametogenesis. Finally, we show that epigenetic inheritance
      is influenced by strain background. These findings enable us to propose a model
      for transgenerational epigenetic inheritance in mammals.

PMID- 12601170
TI  - In vivo identification of human cortical areas using high-resolution MRI: an
      approach to cerebral structure-function correlation.
AB  - Understanding the relationship between the structural and functional organization
      of the human brain is one of the most important goals of neuroscience. Individual
      variability in brain structure means that it is essential to obtain this
      information from the same subject. To date, this has been almost impossible. Even
      though noninvasive functional imaging techniques such as functional MRI (fMRI)
      are now commonplace, there is no complementary noninvasive structural technique.
      We present an in vivo method of examining the detailed neuroanatomy of any
      individual, which can then be correlated with that individual's own functional
      results. This method utilizes high-resolution structural MRI to identify distinct
      cortical regions based on cortical lamination structure. We demonstrate that the
      observed MR lamination patterns relate to myeloarchitecture through a correlation
      of histology with MRI. In vivo high-resolution MRI studies identify striate
      cortex, as well as visual area V5, in four individuals, as defined by using fMRI.
      The anatomical identification of a cortical area (V5MT) outside of striate cortex
      is a significant advance, proving it possible to identify extra-striate cortical
      areas and demonstrating that in vivo structural mapping of the human cerebral
      cortex is possible.

PMID- 12601171
TI  - Comparative analyses of genomic locations and race specificities of loci for
      quantitative resistance to Pyricularia grisea in rice and barley.
AB  - Comparative genomic analyses have revealed extensive colinearity in gene orders
      in distantly related taxa in mammals and grasses, which opened new horizons for
      evolutionary study. The objective of our study was to assess syntenic
      relationships of quantitative trait loci (QTL) for disease resistance in cereals
      by using a model system in which rice and barley were used as the hosts and the
      blast fungus Pyricularia grisea Sacc. as the pathogen. In total, 12 QTL against
      three isolates were identified in rice; two had effects on all three isolates,
      and the other 10 had effects on only one or two of the three isolates. Twelve QTL
      for blast resistance were identified in barley; one had effect on all three
      isolates, and the other 11 had effects on only one or two of the three isolates.
      The observed isolate specificity led to a hypothesis about the durability of
      quantitative resistance commonly observed in many plant host-pathogen systems.
      Four pairs of the QTL showed corresponding map positions between rice and barley,
      two of the four QTL pairs had complete conserved isolate specificity, and another
      two QTL pairs had partial conserved isolate specificity. Such corresponding
      locations and conserved specificity suggested a common origin and conserved
      functionality of the genes underlying the QTL for quantitative resistance and may
      have utility in gene discovery, understanding the function of the genomes, and
      identifying the evolutionary forces that structured the organization of the grass
      genomes.

PMID- 12601173
TI  - Immunomic analysis of human sarcoma.
AB  - The screening of cDNA expression libraries from human tumors with serum antibody
      (SEREX) has proven to be a powerful method for identifying the repertoire of
      tumor antigens recognized by the immune system of cancer patients, referred to as
      the cancer immunome. In this regard, cancer/testis (CT) antigens are of
      particular interest because of their immunogenicity and restricted expression
      patterns. Synoivial sarcomas are striking with regard to CT antigen expression,
      with >80% of specimens homogeneously expressing NY-ESO-1 and MAGE-A3. In the
      present study, 54 sarcoma patients were tested for serum antibodies to NY-ESO-1,
      SSX2, MAGE-A1, MAGE-A3, MAGE-A4, MAGE-A10, CT7, and CT10. Two patients had
      detectable antibodies to CT antigens, and this seroreactivity was restricted to
      NY-ESO-1. Thus, although highly expressed in sarcoma, CT antigens do not induce
      frequent humoral immune responses in sarcoma patients. Sera from these two
      patients were used to immunoscreen cDNA libraries from two synovial sarcoma cell
      lines and normal testis, resulting in the identification of 113 distinct
      antigens. Thirty-nine antigens were previously identified by SEREX analysis of
      other tumor types, and 2339 antigens (59%) had a serological profile that was not
      restricted to cancer patients, indicating that only a proportion of SEREX-defined
      antigens are cancer-related. A novel CT antigen, NY-SAR-35, mapping to chromosome
      Xq28 was identified among the cancer-related antigens, and encodes a putative
      extracellular protein. In addition to testis-restricted expression, NY-SAR-35
      mRNA was expressed in sarcoma, melanoma, esophageal cancer, lung cancer and
      breast cancer. NY-SAR-35 is therefore a potential target for cancer vaccines and
      monoclonal antibody-based immunotherapies.

PMID- 12601174
TI  - Genomewide analysis of Drosophila GAGA factor target genes reveals context
      dependent DNA binding.
AB  - The association of sequence-specific DNA-binding factors with their cognate
      target sequences in vivo depends on the local molecular context, yet this context
      is poorly understood. To address this issue, we have performed genomewide mapping
      of in vivo target genes of Drosophila GAGA factor (GAF). The resulting list of
      approximately 250 target genes indicates that GAF regulates many cellular
      pathways. We applied unbiased motif-based regression analysis to identify the
      sequence context that determines GAF binding. Our results confirm that GAF
      selectively associates with (GA)(n) repeat elements in vivo. GAF binding occurs
      in upstream regulatory regions, but less in downstream regions. Surprisingly, GAF
      binds abundantly to introns but is virtually absent from exons, even though the
      density of (GA)(n) is roughly the same. Intron binding occurs equally frequently
      in last introns compared with first introns, suggesting that GAF may not only
      regulate transcription initiation, but possibly also elongation. We provide
      evidence for cooperative binding of GAF to closely spaced (GA)(n) elements and
      explain the lack of GAF binding to exons by the absence of such closely spaced GA
      repeats. Our approach for revealing determinants of context-dependent DNA binding
      will be applicable to many other transcription factors.

PMID- 12601175
TI  - Interaction of mismatch repair protein PMS2 and the p53-related transcription
      factor p73 in apoptosis response to cisplatin.
AB  - Mismatch repair (MMR) proteins contribute to genome integrity by correcting
      replication errors. In higher eukaryotes, MMR proteins also regulate the cellular
      response to DNA lesions such as oxidized, alkylated, or crosslinked bases.
      Previous studies have linked MMR proteins to the activation of apoptosis through
      p53-dependent and p53-independent mechanisms. MMR-deficient cells exhibit
      variable defects in the induction of p53 and its related p73, which are
      activators of apoptosis. However, the specific role of each MMR protein in the
      regulation of apoptosis has not been determined. Here, we describe an interaction
      between PMS2, an MMR protein, and p73. This interaction causes the stabilization
      of p73 and the redistribution of PMS2 to the nuclear compartment. Exposure to
      cisplatin enhances the association between PMS2 and p73. Moreover, stimulation of
      the p73 proapoptotic function by cisplatin requires PMS2. These results suggest
      that PMS2 contributes to genome integrity not only through DNA repair but also by
      enhancing DNA damage-induced apoptosis.

PMID- 12601176
TI  - The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative
      splicing and calmodulin binding to its N terminus.
AB  - Channels of the C-type transient receptor potential (TRPC) are involved in
      agonist-stimulated and capacitative calcium entry. There are seven TRPCs, all of
      which have a Ca(2+)-dependent calmodulin (CaM)-binding domain in their C termini.
      We now tested binding of CaM to TRPC N termini and show that only that of TRPC2
      binds CaM in a Ca(2+)-dependent manner. Four TRPC2 cDNAs have been reported: a
      (also clone 14), b (also clone 17), alpha, and beta. Sequences responsible for
      CaM binding in TRPC2 a and b are absent from the alpha and beta isoforms. The
      alpha and beta cDNAs of TRPC2 were reported as alternative forms, when recloning
      of TRPC2 a and b proved impossible. Here we analyzed total RNA samples from brain
      and testis for presence of TRPC2 a and b and describe the splicing patterns
      responsible for their formation, as well as those leading to the alpha and beta
      forms of TRPC2. We re-assert existence of RNA encoding the TRPC2 a and b, encoded
      in 21 exons with an initiator ATG in exon 2 for TRPC2a and in exon 4 for TRCP2b.
      The analysis of alpha and beta TRPC2 cDNAs indicates that although the TRPC2 beta
      mRNA may exist, the TRPC2 alpha cDNA is derived from an incompletely processed
      TRPC2a mRNA: It includes in its presumed 5'-untranslated sequence, 713 nt of
      TRPC2a cDNA fused to 291 nt of an incompletely excised intron. While encoding an
      active channel in the mouse, the human TRPC2 appears to be a pseudogene. We
      searched for the human gene in the data bank and located approximately one-half
      of it in a chromosomal region syntenic to that of the mouse, with similar intron
      exon structure. We conclude that the human TRPC2 gene may never have been an
      active gene because of incomplete ancestral duplication or, if it was complete at
      one point, that it became inactive upon loss of chromosomal sequences.

PMID- 12601177
TI  - A plant signal peptide-hepatitis B surface antigen fusion protein with enhanced
      stability and immunogenicity expressed in plant cells.
AB  - The use of transgenic plants to express orally immunogenic protein antigens is an
      emerging strategy for vaccine biomanufacturing and delivery. This concept has
      particular suitability for developing countries. One factor that has limited the
      development of this technology is the relatively modest levels of accumulation of
      some antigenic proteins in plant tissues. We used fusion protein design to
      improve expression of the hepatitis B surface antigen (HBsAg) by attempting to
      mimic the process of HBsAg targeting to the endoplasmic reticulum of human liver
      cells during hepatitis B virus infection. We created a gene encoding a
      recombinant HBsAg modified to contain a plant signal peptide fused to its amino
      terminus. The signal peptide from soybean vegetative storage protein vspA (VSP
      alpha S) directed endoplasmic reticulum targeting of HBsAg in plant cells, but
      was not cleaved and resulted in enhanced VSP alpha S-HBsAg fusion accumulation.
      This product was more stable and presented the protective "a" antigenic
      determinant to significantly higher levels than unmodified native HBsAg expressed
      in plant cells. It also showed a greater extent of intermolecular disulfide bond
      formation and formation of virus-like particles. Moreover, VSP alpha S-HBsAg
      stimulated higher levels of serum IgG than native HBsAg when injected into mice.
      We conclude that HBsAg tolerates a polypeptide fusion at the amino terminus and
      that VSP alpha S-HBsAg is an improved antigen for plant-based expression of a
      subunit vaccine for hepatitis B virus.

PMID- 12601179
TI  - Maternal induction of ventral fate by zebrafish radar.
AB  - In vertebrate embryos, maternal determinants are thought to preestablish the
      dorsoventral axis by locally activating zygotic ventral- and dorsal-specifying
      genes, e.g., genes encoding bone morphogenetic proteins (BMPs) and BMP
      inhibitors, respectively. Whereas the canonical Wntbeta-catenin pathway fulfills
      this role dorsally, the existence of a reciprocal maternal ventralizing signal
      remains hypothetical. Maternal noncanonical WntCa(2+) signaling may promote
      ventral fates by suppressing Wntbeta-catenin dorsalizing signals; however,
      whether any maternal determinant is directly required for the activation of
      zygotic ventral-specifying genes is unknown. Here, we show that such a function
      is achieved, in part, in the zebrafish embryo by the maternally encoded
      transforming growth factor beta (TGF-beta) signaling molecule, Radar. Loss-of
      function experiments, together with epistasis analyses, identify maternal Radar
      as an upstream activator of bmps expression. Maternal induction of bmps by Radar
      is essential for zebrafish development as its removal results in larval-lethal
      dorsalized phenotypes. Double-morphant analyses further suggest that Radar
      functions through the TGF-beta receptor Alk8 to initiate the expression of bmp
      genes. Our results support the existence of a previously uncharacterized maternal
      ventralizing pathway. They might further indicate that maternal TGF-betaRdr and
      WntCa(2+) pathways complementarily specify ventral cell fates, with the former
      triggering bmps expression and the latter indirectly repressing genes encoding
      BMP antagonists.

PMID- 12601178
TI  - Endothelial lipase is a major genetic determinant for high-density lipoprotein
      concentration, structure, and metabolism.
AB  - High-density lipoprotein (HDL) protects against atherosclerosis. Endothelial
      lipase (EL) has been postulated to be involved in lipoprotein, and possibly HDL,
      metabolism, yet the evidence has been scarce and conflicting. We have inactivated
      EL in mice by gene targeting. EL(-/-) mice have elevated plasma and HDL
      cholesterol, and increased apolipoproteins A-I and E. NMR analysis reveals an
      abundance of large HDL particles. There is down-regulation of the transcripts for
      phospholipid transfer protein, but up-regulation of those for hepatic lipase and
      lipoprotein lipase. Plasma lecithin:cholesterol acyltransferase is unchanged
      despite an increase in hepatic mRNA; lecithin:cholesterol acyltransferase
      activity toward endogenous EL(-/-) substrate is, however, reduced by 50%. HDL
      clearance is decreased in EL(-/-) mice; both the structure of HDL and the
      presence of EL are factors that determine the rate of clearance. To determine
      EL's role in humans, we find a significant association between a single
      nucleotide polymorphism 584C/T in the EL (LIPG) gene and HDL cholesterol in a
      well characterized population of 372 individuals. We conclude that EL is a major
      determinant of HDL concentration, structure, and metabolism in mice, and a major
      determinant of HDL concentration in humans.

PMID- 12601181
TI  - Lung cancer screening with CT: Mayo Clinic experience.
AB  - PURPOSE: To evaluate a large cohort of patients at high risk for lung cancer by
      using screening with low-dose spiral computed tomography (CT) of the chest.
      MATERIALS AND METHODS: A prospective cohort study was performed with 1,520
      individuals aged 50 years or older who had smoked 20 pack-years or more.
      Participants underwent three annual low-dose CT examinations of the chest and
      upper abdomen. Characteristics of pulmonary nodules and additional findings were
      tabulated and analyzed. RESULTS: Two years after baseline CT scanning, 2,832
      uncalcified pulmonary nodules were identified in 1,049 participants (69%). Forty
      cases of lung cancer were diagnosed: 26 at baseline (prevalence) CT examinations
      and 10 at subsequent annual (incidence) CT examinations. CT alone depicted 36
      cases; sputum cytologic examination alone, two. There were two interval cancers.
      Cell types were as follows: squamous cell tumor, seven; adenocarcinoma or
      bronchioloalveolar carcinoma, 24; large cell tumor, two; non-small cell tumor,
      three; small cell tumor, four. The mean size of the non-small cell cancers
      detected at CT was 15.0 mm. The stages were as follows: IA, 22; IB, three; IIA,
      four; IIB, one; IIIA, five; IV, one; limited small cell tumor, four. Twenty-one
      (60%) of the 35 non-small cell cancers detected at CT were stage IA at diagnosis.
      Six hundred ninety-six additional findings of clinical importance were
      identified. CONCLUSION: CT can depict early-stage lung cancers. The rate of
      benign nodule detection is high.

PMID- 12601180
TI  - Deep venous thrombosis: diagnosis by using venous enhanced subtracted peak
      arterial MR venography versus conventional venography.
AB  - PURPOSE: To assess diagnostic accuracy and interobserver variability at venous
      enhanced subtracted peak arterial (VESPA) magnetic resonance (MR) venography
      compared with those at conventional venography for the diagnosis of femoral and
      iliac deep venous thrombosis (DVT). MATERIALS AND METHODS: A single
      anteroposterior maximum intensity projection (MIP) venogram of the femoral and
      iliac veins was constructed by using VESPA MR venography in 55 symptomatic
      patients suspected of having lower limb DVT. All patients also underwent
      conventional venography, results of which were used as the standard of reference.
      VESPA MR venograms were interpreted by two independent reviewers (reviewers A and
      B) who were unaware of other results. Sensitivity and specificity of VESPA MR
      venography for the diagnosis of thrombus in the femoral and iliac veins were
      calculated. Interobserver variability was calculated for these observations by
      using weighted kappa with equally spaced weights for positive, nondiagnostic, and
      negative studies. Nondiagnostic studies were reinterpreted separately by reviewer
      A on the basis of source data. RESULTS: Sensitivity of VESPA MR venography for
      the femoral veins (20 of 20) and iliac veins (seven of seven) was 100% for both
      reviewers. Specificity was 100% (39 of 39 for reviewer A, 40 of 40 for reviewer
      B) for the iliac veins and 97% (31 of 32) for the femoral veins for both
      reviewers. Segments in which the VESPA MR venograms were nondiagnostic were
      excluded from this analysis. Interobserver variability as calculated by using
      weighted kappa for positive, negative, and nondiagnostic studies was 0.85 for
      femoral veins and 0.97 for iliac veins. Interpretation of the source data led to
      correct diagnosis in six of six cases in which the VESPA MR venograms were
      nondiagnostic. CONCLUSION: VESPA MR venography yielded MIP venograms that were
      highly accurate for the diagnosis of DVT in femoral and iliac veins.
      Interpretation of the studies was also highly reproducible.

PMID- 12601182
TI  - MR imaging screening of the contralateral breast in patients with newly diagnosed
      breast cancer: preliminary results.
AB  - PURPOSE: To investigate the role of screening magnetic resonance (MR) imaging in
      the detection of synchronous contralateral breast cancer in patients with newly
      diagnosed breast cancer. MATERIALS AND METHODS: Between January 1999 and July
      2001, 182 patients with newly diagnosed breast cancer (after either core or
      excisional biopsy with positive or close margins of resection) underwent
      bilateral contrast material-enhanced MR imaging at 1.5 T with a dedicated
      bilateral breast multicoil array. The contralateral breast was imaged for cancer
      screening. Family history of breast cancer, index cancer histology, breast
      density, and age at diagnosis of first breast cancer were assessed as potential
      risk factors for synchronous contralateral breast cancer. RESULTS: Fifteen
      patients (8.2%) had a suspicious enhancing lesion depicted in the contralateral
      breast. Seven patients (3.8%) had malignant results: ductal carcinoma in situ
      (DCIS) in four, invasive ductal carcinoma with DCIS in two, and invasive ductal
      carcinoma in one. Eight patients (4.4%) had benign results: fibrocystic changes
      in four, atypical ductal hyperplasia in two, atypical lobular hyperplasia and
      focal lobular carcinoma in situ in one, and ductal hyperplasia in one. Six
      patients with negative MR findings underwent prophylactic mastectomy; no
      malignancy was found. No significant differences were noted among patients with
      true-positive (n = 7), false-positive (n = 8), or negative (n = 167) MR findings
      with regard to family history of breast cancer (P <.27), index cancer histology
      (P <.19), breast density (P <.34), or age at diagnosis of first breast cancer (P
      <.10). CONCLUSION: The preliminary results demonstrate the feasibility of using
      MR imaging of the breast in a screening role, specifically to evaluate the
      contralateral breast in patients with newly diagnosed breast cancer to detect
      mammographically and clinically occult synchronous breast cancer.

PMID- 12601183
TI  - Characterization of viable and nonviable myocardium at MR imaging: comparison of
      gadolinium-based extracellular and blood pool contrast materials versus manganese
      based contrast materials in a rat myocardial infarction model.
AB  - PURPOSE: To determine the contrast agent behavior of gadolinium-based
      (extracellular and albumin-binding) and manganese-based contrast media for late
      enhancement imaging of myocardial infarction. MATERIALS AND METHODS: Coronary
      ligation was performed in 30 rats, and they were serially imaged with segmented
      inversion-recovery gradient-echo magnetic resonance (MR) imaging (repetition time
      msec/echo time msec/inversion time msec [fixed], 5.2/2.5/430; flip angle, 15
      degrees ) during 1 hour after administration of contrast media by using a 1.5-T
      MR unit. Serial measurements of the longitudinal relaxation were performed by
      using the Look-Locker approach (repetition time msec/echo time msec, 1,000/3.5;
      flip angle, 10 degrees ). Detection and size of infarction were evaluated at each
      time point and compared with end-point histologic findings. RESULTS: For all
      manganese-based media, the contrast agent cleared from the blood pool rapidly.
      Manganese-based contrast media allowed precise labeling of viable cardiomyocytes
      within 30 minutes, and the labeling persisted for at least 1 hour. Accumulation
      of gadoversetamide in the infarct area was apparent after 5 minutes, and the peak
      contrast-to-noise ratio (CNR) between infarct and myocardium was comparable to
      the peak CNR of manganese-based contrast agents. Extracellular gadopentetate
      dimeglumine provided excellent infarct detection but a small imaging window for
      precise sizing of the infarct if a fixed inversion time of 430 msec was used.
      Albumin-binding gadolinium-based contrast media provided a longer imaging window,
      but infarct size was overestimated because of the nonspecific distribution of the
      unbound gadolinium agent. CONCLUSION: When extracellular gadolinium-based agents
      are used for infarct size measurement, imaging parameters and timing are
      important because the kinetics of both normal and irreversibly injured myocardium
      must be considered. Manganese-based agents are highly specific and less sensitive
      to timing for infarct size determination, but further studies are required to
      determine if they are feasible for human use.

PMID- 12601184
TI  - Pseudomass of the bladder neck after prostatectomy: report of two cases.
AB  - The authors reviewed ultrasonographic (US) images, cystoscopic findings, and
      biopsy results at the vesicourethral anastomosis in two patients suspected of
      having local recurrence after radical prostatectomy. A focal, masslike bulge was
      identified with US at the posterior aspect of the bladder neck, just above the
      anastomosis. This bulge mimicked the appearance of local recurrence of cancer;
      however, diagnostic studies, biopsy results, and clinical follow-up failed to
      demonstrate recurrent cancer. A review of the surgical technique led the authors
      to conclude that a pseudomass at the vesicourethral anastomosis may result from
      focal infolding of normal bladder mucosa.

PMID- 12601185
TI  - The iceman: discovery and imaging.
AB  - The anatomic features of a 5,300-year-old mummy, the iceman, were documented with
      conventional radiographic, portable computed radiographic, and conventional and
      spiral computed tomographic images obtained between September 1991 and June 2001.
      A team of scientists and radiologists from Austria, Italy, and the United States
      supervised the examinations and interpreted the images. The images demonstrated
      excellent preservation of the mineralized skeleton with profound dehydration of
      the soft tissues. The skeleton exhibited several types of trauma, including (a)
      healed rib fractures, (b) hairline skull fractures and a compression deformity of
      the thorax, probably acquired while encased in the glacier, and (c) damage
      acquired during the effort to recover the corpse. Skeletal variants were present,
      as was evidence of degenerative arthritis, frostbite, vascular calcification, and
      adaptation to cultural and geographic influences. In terms of anatomy and
      apparent health-related conditions, the iceman was very similar to modern humans.
      An arrowhead lodged between the rib cage and the left scapula was the probable
      cause of the iceman's death. Study of the images also provided insight regarding
      postmortem processes that led to the iceman's mummification.

PMID- 12601186
TI  - The pearl necklace sign: an imaging sign of adenomyomatosis of the gallbladder at
      MR cholangiopancreatography.
AB  - PURPOSE: To evaluate the demonstration of the pearl necklace sign at magnetic
      resonance (MR) cholangiopancreatography (MRCP) in patients with proven
      adenomyomatosis and carcinoma of the gallbladder. MATERIALS AND METHODS: MRCP
      findings and those of a combination of unenhanced and arterial phase computed
      tomography (CT) and arterial phase MR imaging were retrospectively compared in 29
      patients who were pathologically proven to have adenomyomatosis of the
      gallbladder and in 18 patients with pathologically proven gallbladder carcinoma.
      Receiver operating characteristic (ROC) analysis was used with a five-point
      confidence scale. The relative sensitivity, specificity, and accuracy of each
      imaging modality were also calculated. The pearl necklace sign was defined on
      MRCP images as small round foci, with the same markedly high signal intensity as
      bile, within the thickened wall of the gallbladder. RESULTS: The mean area under
      the ROC curve of MRCP alone and that of the combination of MRCP and arterial
      phase MR imaging was significantly higher than that of combined CT (unenhanced
      and arterial phase) and arterial phase MR imaging alone (P <.01). The relative
      sensitivities in the diagnosis of adenomyomatosis of the gallbladder were 24% for
      the combined CT, 29% for arterial phase MR imaging, 62% for MRCP, and 57% for the
      combination of MRCP and arterial phase MR imaging. The mean relative sensitivity,
      specificity, and accuracy of the pearl necklace sign on MRCP images were 62%,
      92%, and 74%, respectively. In eight (28%) of 29 patients with adenomyomatosis of
      the gallbladder, the pearl necklace sign was not identified by all three readers
      on the MRCP images. CONCLUSION: The pearl necklace sign, which indicates the
      presence of Rokitansky-Aschoff sinuses within the thickened gallbladder wall, was
      specifically detected at MRCP for adenomyomatosis of the gallbladder.

PMID- 12601187
TI  - Obstetric MR pelvimetry: reference values and evaluation of inter- and
      intraobserver error and intraindividual variability.
AB  - PURPOSE: To establish obstetric magnetic resonance (MR) pelvimetric reference
      values in a large study population and stratify them according to delivery
      modality and to determine the intra- and interobserver error and intraindividual
      variability of MR pelvimetric assessment in volunteers. MATERIALS AND METHODS: MR
      pelvimetric data were retrospectively reviewed in 781 women (mean age, 28.9 years
      +/- 5.2 [SD]) clinically referred, and the data were correlated to obstetric
      history to derive normative values. Five observers assessed results of multiple
      MR pelvimetric examinations in 10 female volunteers (mean age, 34.7 years +/-
      6.0; eight nullipara, two primipara) to provide data for measurement error
      analysis. RESULTS: All values were higher in the spontaneous vaginal delivery
      subgroup (n = 100) and lower in the cesarean section or vacuum extraction
      subgroup (n = 130; intersubgroup difference, P <.001, Mann-Whitney U test).
      Pelvimetric parameters in the group undergoing spontaneous vaginal delivery were
      as follows: obstetric conjugate, 121.7 mm +/- 8.6; interspinous distance, 112.3
      mm +/- 7.9; intertuberous distance, 120.6 mm +/- 11.3; transverse diameter, 129.5
      mm +/- 8.7; and sagittal outlet, 115.8 mm +/- 9.9. In the volunteer study,
      intraobserver, interobserver, and intraindividual reliabilities were high for the
      obstetric conjugate (0.94-0.96), interspinous distance (0.92-0.95), and
      transverse diameter (0.95-0.98) but low for intertuberous distance (0.64-0.87)
      and sagittal outlet (0.66-0.85). CONCLUSION: Pelvimetric dimensions are smaller
      in women undergoing cesarean section or vacuum extraction than they are in those
      delivering vaginally. The pelvimetric parameters associated with the largest
      measurement errors are intertuberous distance and sagittal outlet.

PMID- 12601188
TI  - Radiologic phenotypes in lumbar MR imaging for a gene defect in the COL9A3 gene
      of type IX collagen.
AB  - PURPOSE: To evaluate whether the COL9A3 tryptophan allele (Trp3 allele) is
      associated with a specific radiologic phenotype among patients with sciatica.
      MATERIALS AND METHODS: One hundred fifty-three patients with sciatica were
      evaluated for the presence of Trp3 allele, Scheuermann disease, intervertebral
      disk degeneration, Schmorl nodules, dorsal anular tears, hyperintense lesions,
      and endplate degeneration on sagittal T2-weighted lumbar magnetic resonance
      images. The Trp3 genotype was determined by means of sequencing the COL9A3 gene.
      Radiologic phenotypes were evaluated while blinded to the genotype. Scheuermann
      disease was diagnosed if either endplate irregularities or Schmorl nodules and
      two of the other three criteria (disk space narrowing, disk dehydration, and
      wedging of anterior vertebral body margins) were present at three or more
      adjacent disk levels from T10-11 to L3-4. Disk degeneration was evaluated
      separately for each disk (T11-12 to L5-S1) and for all disks combined.
      Frequencies of radiologic phenotypes between individuals with or without Trp3
      allele were compared. RESULTS: Thirty-four patients had at least one Trp3 allele.
      When compared with the matched control subjects, they had an increased likelihood
      of Scheuermann disease (P =.035) and an increased number of degenerated disks
      from T11 to S1 (P =.021). Comparisons at individual disks showed a statistically
      significant increase in disk degeneration at T11-12 (analysis of all grades of
      degeneration [graded], P =.018; analysis of any degeneration vs none
      [dichotomous], P =.039) and L4-5 (graded, P =.011; dichotomous, P =.016).
      Prevalences of anular tears, endplate degeneration, Schmorl nodules, and
      hyperintense lesions were comparable. CONCLUSION: The results of this study
      indicate that the presence of Trp3 allele is associated with Scheuermann disease
      and intervertebral disk degeneration. No associations were found for other
      radiologic phenotypes.

PMID- 12601189
TI  - CT findings in peripheral T-cell lymphoma involving the gastrointestinal tract.
AB  - PURPOSE: To evaluate whether computed tomography (CT) accurately depicted
      gastrointestinal tract involvement in peripheral T-cell lymphoma (PTCL).
      MATERIALS AND METHODS: CT scans were retrospectively reviewed in 14 patients with
      pathologically proved PTCLs of the gastrointestinal tract for the following
      considerations: sites, patterns of involvement (ie, morphologic features, bowel
      wall thickness or mass size, and contrast enhancement pattern), and ancillary
      findings at other sites (ie, lymphadenopathy, bowel perforation, and involvement
      of other organs). RESULTS: PTCL involved the stomach in three patients, the small
      intestine in eight, both the stomach and the small intestine in one, and the
      sigmoid colon in two; multifocal involvement was seen in three (21%) patients. CT
      failed to demonstrate the bowel lesions in three of 14 patients. At CT, 11
      patients had gastric or bowel wall thickening (n = 10) and a polypoid mass (n =
      1). In 10 patients, the gastric or bowel wall thickening was mild (<1 cm) in six,
      moderate (1-2 cm) in three, and severe (>2 cm) in one. Lymphadenopathy was noted
      in nine (64%) patients, with the nonbulky type in eight and the bulky type in
      one. Bowel perforation occurred in four (29%) patients. Other organs were
      involved in eight (57%) patients. CONCLUSION: CT can depict PTCL involving the
      gastrointestinal tract if it is not confined to the mucosa. There is a tendency
      toward preferential jejunal or duodenal involvement, as well as bowel
      perforation.

PMID- 12601190
TI  - Aortoiliac and renal arteries: prospective intraindividual comparison of contrast
      enhanced three-dimensional MR angiography and multi-detector row CT angiography.
AB  - PURPOSE: To compare contrast material-enhanced three-dimensional (3D) magnetic
      resonance (MR) angiography and multi-detector row computed tomographic (CT)
      angiography in the same patients for assessment of the aortoiliac and renal
      arteries, with digital subtraction angiography (DSA) as the standard of
      reference. MATERIALS AND METHODS: DSA, 3D MR angiography, and multi-detector row
      CT angiography were performed in 46 consecutive patients. A total of 769 arterial
      segments were analyzed for arterial stenosis by using a four-point grading
      system. Aneurysmal changes were noted. The time required for performing 3D
      reconstructions and image analysis of both MR and CT data sets was measured.
      Patient acceptance for each modality was assessed with a visual analogue scale.
      Statistical analysis of data was performed. RESULTS: Sensitivity of MR
      angiography for detection of hemodynamically significant arterial stenosis was
      92% for reader 1 and 93% for reader 2, and specificity was 100% and 99%,
      respectively. Sensitivity of CT angiography was 91% for reader 1 and 92% for
      reader 2, and specificity was 99% and 99%, respectively. Differences between the
      two modalities were not significant. Interobserver and intermodality agreement
      was excellent (kappa = 0.88-0.90). The time for performance of 3D reconstruction
      and image analysis of CT data sets was significantly longer than that for MR data
      sets (P <.001). Patient acceptance was best for CT angiography (P =.016).
      CONCLUSION: There is no statistically significant difference between 3D MR
      angiography and multi-detector row CT angiography in the detection of
      hemodynamically significant arterial stenosis of the aortoiliac and renal
      arteries.

PMID- 12601191
TI  - Acute cerebral infarction: effect of JPEG compression on detection at CT.
AB  - PURPOSE: To evaluate the effect of Joint Photographic Experts Group (JPEG)
      compression ratios of 10:1 and 20:1 on detection of acute cerebral infarction at
      computed tomography (CT). MATERIALS AND METHODS: CT images obtained in 25
      patients with acute cerebral infarction and 25 patients with no lesions were
      compressed by means of a JPEG algorithm at ratios of 10:1 and 20:1. Normal and
      abnormal sections (on original and compressed images) were reviewed by using a
      color soft-copy computed monochrome cathode ray tube monitor. Five observers
      rated the presence or absence of a lesion with a 50-point scale (0, definitely
      absent; 25, equivocal; and 50, definitely present). Diagnostic accuracy was
      evaluated with receiver operating characteristic (ROC) curve analysis.
      Significant difference was defined as a P value less than.05 for the area tested
      with a two-tailed paired Student t test. RESULTS: At ROC analysis, no
      statistically significant difference was detected for all cases considered
      together (Az [area under the ROC curve] = 0.887 +/- 0.038 [mean +/- SD] on
      noncompressed images, Az = 0.897 +/- 0.038 on 10:1 compressed images, and Az =
      0.842 +/- 0.073 on 20:1 compressed images; P >.05). CONCLUSION: JPEG compression
      at ratios of 10:1 and 20:1 was tolerated in the detection of acute cerebral
      infarction at CT.

PMID- 12601192
TI  - Cervical degenerative disease at flexion-extension MR imaging: prediction
      criteria.
AB  - PURPOSE: To determine if there are any neutral-position imaging criteria that can
      help predict functional cord impingement at flexion-extension cervical magnetic
      resonance (MR) imaging. MATERIALS AND METHODS: Sixty-two patients with cervical
      degenerative disease were evaluated with regard to the dynamic changes of canal
      stenosis at flexion-extension MR imaging. Functional cord impingement was
      considered if the cord was impinged or more impinged after neck flexion or
      extension. Selection criteria for neutral-position MR imaging, such as cervical
      curvature, canal space, degenerative stage, intramedullary high signal intensity
      on T2-weighted images, and resting instability, were evaluated for their ability
      to predict functional cord impingement at flexion-extension MR imaging (Fisher
      exact test, logistic regression analysis). RESULTS: MR images in 19 (31%) of 62
      patients showed functional cord impingement at extension MR imaging compared with
      images in two (3%) patients at flexion MR imaging. Statistically significant
      differences were found for the criteria cervical degeneration stage (P <.001) and
      spinal canal space (P =.037) for predicting functional cord impingement at
      extension MR imaging. In contrast, no significant differences were found among
      selection criteria for flexion MR imaging. Probabilities of functional cord
      impingement at extension MR imaging were calculated with different combinations
      of degenerative stages and canal spaces. Probability could increase to 79% if the
      patient had both stabilization degeneration (disk protrusion or osteophytic
      formation with hypertrophy of the ligamentum flavum) and C7 canal space of 10 mm
      or less. CONCLUSION: None of the selection criteria evaluated in this study has
      the ability to predict functional cord impingement at flexion MR imaging;
      however, prediction of impingement at extension MR imaging can increase from 31%
      to 79% if proper criteria are selected.

PMID- 12601193
TI  - Coronary artery anomalies: assessment with free-breathing three-dimensional
      coronary MR angiography.
AB  - PURPOSE: To evaluate a simplified protocol by using free-breathing three
      dimensional (3D) coronary magnetic resonance (MR) angiography to determine the
      anatomy of anomalous coronary arteries, in particular the relationship of the
      vessels to the aortic root. MATERIALS AND METHODS: Twenty-six patients (18 men,
      eight women; mean age, 50 years; age range, 18-77 years) who had a history of
      chest pain, palpitations, or syncope and who were suspected of having coronary
      artery anomalies were examined with free-breathing MR angiography. Multiple 3D
      volume slabs were acquired at the level of the sinuses of Valsalva by using
      diaphragmatic navigators for respiratory artifact suppression. The proximal
      anatomy of the coronary arteries was determined. RESULTS: Six anomalous
      circumflex arteries originated from the right sinus of Valsalva and passed behind
      the aortic root. Six right coronary arteries arose from the left sinus of
      Valsalva and coursed between the aortic root and the right ventricular outflow
      tract (RVOT). Nine left coronary arteries arose from the right sinus of Valsalva;
      seven of nine coursed between the aortic root and the RVOT. Five patients had
      minor anomalies. Overall, in eight patients with anomalous arteries that coursed
      between the aortic root and the RVOT, conventional coronary angiography could not
      be used confidently to identify the proximal course. CONCLUSION: Free-breathing
      3D coronary MR angiography can be used to identify the proximal anatomy of
      anomalous coronary arteries.

PMID- 12601194
TI  - Massive hemoptysis: prediction of nonbronchial systemic arterial supply with
      chest CT.
AB  - PURPOSE: To evaluate the diagnostic accuracy of chest computed tomography (CT) in
      the prediction of a nonbronchial systemic arterial supply in patients with
      massive hemoptysis. MATERIALS AND METHODS: Forty consecutive patients with
      massive hemoptysis underwent contrast material-enhanced CT. Massive hemoptysis
      was defined as the expectoration of 300-600 mL of blood per day. Two CT features
      were considered to be suggestive of a nonbronchial systemic arterial supply: (a)
      pleural thickness of more than 3 mm adjacent to the parenchymal lesion and (b)
      enhancing vascular structures within the extrapleural fat layer. Conventional
      angiography was used as the standard of reference. CT scans were evaluated by two
      radiologists in consensus. The CT findings were compared with those of
      conventional angiography. The sensitivity, specificity, predictive values, and
      accuracy of CT for predicting the presence of a nonbronchial systemic arterial
      supply were assessed. RESULTS: In the determination of a nonbronchial systemic
      arterial supply, CT had a sensitivity of 80%, specificity of 84%, positive
      predictive value of 73%, negative predictive value of 91%, and accuracy of 84%.
      Sensitivity was highest for predicting the branches of subclavian and axillary
      arterial supply and was lowest for predicting the internal mammary arterial
      supply. Specificity and accuracy were highest for predicting the intercostal
      arterial supply. CONCLUSION: CT demonstrates acceptable sensitivity, specificity,
      and accuracy in the prediction of a nonbronchial systemic arterial supply in
      patients with massive hemoptysis.

PMID- 12601195
TI  - Ileocecal valve: spectrum of normal findings at double-contrast barium enema
      examination.
AB  - PURPOSE: To characterize the spectrum of normal findings of the ileocecal valve
      at double-contrast barium enema examination to allow differentiation between a
      normal valve and one infiltrated by tumor. MATERIALS AND METHODS: A search of
      radiology and endoscopy files showed 106 patients who underwent double-contrast
      barium enema examination and colonoscopy. The radiographic images were reviewed
      by two authors to determine the morphology of the ileocecal valve and to evaluate
      whether it appeared normal or abnormal. The radiographic data were then
      correlated with endoscopic and pathologic findings. RESULTS: The ileocecal valve
      was visible in 91 (86%) of 106 patients. It was round or ovoid in 71 patients
      (78%) and triangular in 20 (22%). In the 88 patients with a normal valve at
      colonoscopy, mean valve height was 1.7 cm, and mean width was 2.8 cm. The valve
      was smooth in 75 patients (85%) and smoothly lobulated in 13 (15%). The lips of
      the valve were symmetric in 77 patients (88%) and asymmetric in 11 (12%). All 87
      patients with a normal valve at double-contrast barium enema examination had a
      normal valve at colonoscopy, whereas the two patients with a valve suspicious for
      tumor at barium enema examination had neoplasms (one carcinoma and one villous
      adenoma) at colonoscopy. CONCLUSION: The ileocecal valve may show a spectrum of
      normal findings at double-contrast barium enema examination and may appear as a
      round, ovoid, or triangular structure with a maximal height of nearly 4 cm. The
      valve may be large, asymmetric, or smoothly lobulated, even in the absence of
      tumor.

PMID- 12601196
TI  - Ultraviolet protectants: causative agents for screen and image artifacts in
      radiography.
AB  - PURPOSE: To determine the specific causative agent(s) and mechanism of formation
      of opacity artifacts seen on some radiographs acquired at the authors' facility.
      MATERIALS AND METHODS: Various substances likely to come into contact with
      technologists' hands were tested. Initial test results showed that a hand lotion
      with sun protection produced artifacts similar to the ones seen clinically and
      left no visible evidence on the screen after cleaning. Further experimental
      findings showed that substances without sun protection did not produce the
      artifacts, while other products with sun protection did produce artifacts. The
      four most commonly used active ingredients (ultraviolet [UV] filters) in products
      with sun protection were tested to determine if they produced artifacts. The
      temporal dependence and penetration depth of the causative agent(s) were
      determined. A sample of screens commonly used in radiology departments was tested
      to determine if artifacts were produced. RESULTS: Each of the UV filters tested
      caused artifacts when added to a lotion that had no sun protection and did not
      produce artifacts by itself. The UV filters quickly penetrated the protective
      layer of the screens and therefore could not be removed with conventional
      cleaning methods. Artifacts appeared only when using screens with a primary
      emission in the UV portion of the spectrum. CONCLUSION: The UV filters in the
      products with sun protection absorb the UV light emitted by the screens and cause
      artifacts. Screens with UV emissions are susceptible to artifacts from the use of
      UV protectants.

PMID- 12601197
TI  - Detection of atherosclerosis: systemic imaging for systemic disease with whole
      body three-dimensional MR angiography--initial experience.
AB  - In 100 consecutive patients with peripheral vascular disease whole-body three
      dimensional magnetic resonance (MR) angiography was performed by using the
      rolling table platform system with a 1.5-T MR unit and five three-dimensional MR
      angiographic data sets during 72 seconds (0.2 mol per kilogram of body weight of
      gadobenate dimeglumine). Apart from the proved peripheral vascular disease,
      additional clinically relevant disease was found in 33 segments in 25 patients as
      follows: renal arterial narrowing (n = 15), carotid arterial stenosis (n = 12),
      subclavian arterial stenosis (n = 2), and abdominal aortic aneurysms (n = 4).
      Confirmatory studies performed in 11 patients in this study revealed no false
      positive or false-negative findings at examination.

PMID- 12601198
TI  - Percutaneous cecostomy: updates in technique and patient care.
AB  - PURPOSE: To evaluate the authors' 7-year experience with the percutaneous
      cecostomy procedure and the long-term outcome of the procedure. MATERIALS AND
      METHODS: Since 1994, 163 tube cecostomies for fecal incontinence were performed
      in patients aged 2-23 years and who weighed 8-72 kg (mean, 32.2 kg). Underlying
      conditions included spina bifida (n = 106), imperforate anus (n = 53), Klippel
      Feil deformity (n = 1), cerebral palsy (n = 1), Hirschsprung disease (n = 1), and
      paraplegia (n = 1). Ventriculoperitoneal shunts were present in 85 (52%) of the
      163 patients. The authors have followed up 124 (76%) of the 163 cecostomy
      patients. Information regarding enema technique, satisfaction with the procedure,
      postprocedure problems, and long-term outcome of the procedure was obtained by
      interviewing either the patients or the parents. RESULTS: Tube placement was
      successful in all patients. One hundred ten (89%) of the 124 patients experienced
      a substantial decrease in the frequency of soiling accidents. The vast majority
      of patients expressed satisfaction with the procedure; 117 (94%) of the 124
      patients rated the cecostomy procedure as better than the bowel control procedure
      used before. Late complications of the procedure included granulation tissue and
      accidentally dislodged tubes. Four patients elected to have their tubes removed
      for aesthetic and tube management reasons. There was no mortality related to the
      procedure, although one patient died of pneumonia 5 years later. CONCLUSION: The
      percutaneous cecostomy procedure is a safe and effective method for treating
      fecal incontinence.

PMID- 12601199
TI  - Severe liver fibrosis or cirrhosis: accuracy of US for detection--analysis of 300
      cases.
AB  - PURPOSE: To determine the accuracy of various ultrasonographic (US) signs for
      assessment of the degree of liver fibrosis, with histologic results as reference
      standard. MATERIALS AND METHODS: Three hundred consecutive asymptomatic patients
      with at least 6 months of increased levels of aspartate aminotransferase and/or
      alanine aminotransferase underwent liver US and biopsy. The estimated pretest
      probability of severe fibrosis or cirrhosis was 35%. Three US parameters were
      investigated: liver surface nodularity, caudate lobe hypertrophy, and pattern of
      hepatic venous blood flow. US results were compared with histologic results
      obtained after liver biopsy, which constituted the reference standard for
      diagnosis of severe fibrosis or cirrhosis. The degree of fibrosis was graded
      according to METAVIR criteria, with stages 3 and 4 considered together. Data were
      analyzed with kappa and chi2 statistics. Sensitivity, specificity, positive and
      negative likelihood ratios, and posttest probability were calculated for each US
      sign. RESULTS: In 107 (36%) patients with severe fibrosis (n = 34) or cirrhosis
      (n = 73), liver surface nodularity had the highest diagnostic accuracy, with
      specificity of 95% and positive and negative likelihood ratios 11.6 and 0.51,
      respectively. When liver surface nodularity was considered alone, posttest
      probability of severe fibrosis or cirrhosis increased from 35% to 86%. When
      caudate lobe hypertrophy and hepatic venous blood flow were also taken into
      account, posttest probability increased by only 2% (ie, to 88%). CONCLUSION: US
      determination of liver surface nodularity is an accurate method for identifying
      the subset of asymptomatic patients with severe liver fibrosis or cirrhosis,
      which indicates a worse prognosis.

PMID- 12601200
TI  - Suspected pulmonary embolism: enhancement of pulmonary arteries at deep
      inspiration CT angiography--influence of patent foramen ovale and atrial-septal
      defect.
AB  - PURPOSE: To investigate if abnormal early contrast enhancement of the aorta and
      decreased attenuation of pulmonary arteries at deep-inspiration spiral computed
      tomographic (CT) angiography might be caused by a patent foramen ovale (PFO).
      MATERIALS AND METHODS: Two hundred forty-four spiral CT angiographic images of
      the pulmonary arteries obtained during deep inspiration in patients suspected of
      having pulmonary embolism (PE) were reviewed for evidence of abnormal early
      enhancement of the aorta. In 45 patients, enhancement of the ascending aorta was
      equal to or more than that of the pulmonary arteries. Nonenhanced or contrast
      material-enhanced echocardiography was performed in 39 of these cases. All CT
      images with abnormal enhancement patterns were graded for contrast quality with
      respect to sufficient enhancement of pulmonary arteries (four grades) at three
      anatomic levels: right and left main and lobar and segmental branches. In
      addition, all spiral CT angiographic images were evaluated concerning the
      diagnosis of PE and the grouping of central (main pulmonary artery to proximal
      lobar arteries) and peripheral (beyond proximal lobar branches) locations of
      emboli. Mean attenuation values of ascending aortas and main pulmonary arteries
      in group 1 (n = 244) were compared with those in groups 2 and 3 (n = 45) by means
      of the two-tailed Student t test for unpaired data (P <.05). RESULTS: Attenuation
      values for ascending aortas in group 1 were significantly lower than those in
      groups 2 and 3 (P <.001). Attenuation values in main pulmonary arteries were
      significantly higher in group 1 than in groups 2 and 3 (P <.001).
      Echocardiographic images showed an intracardiac right-to-left shunt in all 39
      cases with abnormal contrast dynamics in the CT study (16% of the whole study
      population). Three patients had an atrial-septal defect, and 36 had a PFO. Images
      with a shunt had good (9%), intermediate (37%), fair (33%), and poor (23%)
      contrast of the pulmonary arteries. Sufficient vessel contrast for the diagnosis
      of PE could not be achieved in 27 of 45 patients with a shunt, but severe central
      PE could be ruled out. PE could be diagnosed in 31% of the 244 images, 58% were
      negative, and 11% were indeterminate. CONCLUSION: A PFO may frequently lead to
      insufficient attenuation of the pulmonary arteries, which potentially limits the
      diagnosis of PE if the examination is performed during deep inspiration.

PMID- 12601201
TI  - Comparison of supine and prone scanning separately and in combination at CT
      colonography.
AB  - PURPOSE: To compare colonic distention, adequacy of colonic preparation, and
      colorectal polyp detection as assessed with supine and prone scanning separately
      and in combination at computed tomographic (CT) colonography. MATERIALS AND
      METHODS: CT colonography and colonoscopy were performed in 182 patients.
      Distention and preparation of eight colonic segments were rated separately on a
      scale of 1-4 (1, segment completely distended or no residual material; 4, segment
      collapsed or large amounts of residual material). The distention, preparation,
      and polyp detection data were compared with regard to each position alone and
      then in combination. CT findings were correlated with colonoscopic findings.
      RESULTS: The percentage of colonic segments with grade 1 distention and
      preparation was 93.7% (1,364 of 1,456) and 66.6% (969 of 1,456), respectively,
      with combined scanning; 86.4% (1,258 of 1,456) and 52.1% (759 of 1,456),
      respectively, with supine scanning alone; and 85.6% (1,246 of 1,456) and 57.1%
      (831 of 1,456), respectively, with prone scanning alone. The sensitivity for
      detection of colorectal polyps 10 mm or larger, 5.0-9.9 mm, and smaller than 5 mm
      and polyps of all sizes was 92.7%, 79.8%, 60.3%, and 69.9%, respectively, with
      combined scanning. Sensitivity was 58.5%, 47.2%, 36.3%, and 42.1%, respectively,
      with supine scanning and 51.2%, 41.6%, 30.2%, and 36.3%, respectively, with prone
      scanning. The improved sensitivities for use of combined versus individual
      scanning positions were highly significant (P <.001) for polyps in all size
      categories. CONCLUSION: Colonic distention and preparation at CT colonography
      were significantly improved by using supine and prone scanning in combination,
      and results correlated directly with improved sensitivity of polyp detection.

PMID- 12601202
TI  - Atherosclerotic renal arterial stenosis: clinical outcomes of stent placement for
      hypertension and renal failure.
AB  - PURPOSE: To assess technical success rates and long-term clinical outcomes of
      primary renal arterial stent placement in atherosclerotic renal arterial stenosis
      (RAS). MATERIALS AND METHODS: Primary stent placement was performed in 100
      consecutive patients with atherosclerotic RAS. Indications for treatment were
      resistant hypertension (n = 25), impaired renal function, (n = 50), and both (n =
      25). Immediate technical results were evaluated with angiography. Clinical
      outcomes were assessed with serial systolic and diastolic blood pressure and
      serum creatinine values obtained from retrospective review of case notes. Results
      obtained every 6 months after the procedure were compared with those obtained at
      the time of the procedure with the paired t test. Radiologic reports were
      evaluated for immediate and case notes for delayed complications. RESULTS:
      Technical success was achieved in 120 (95.2%) of 126 RAS in 95 patients. Mean
      follow-up was 25 months (median, 24 months; range, 1-66 months). Resistant
      hypertension was cured in two (4.2%) of 48 patients, had improved in 38 (79.1%),
      and had failed to respond to treatment in eight (16.7%). Mean systolic and
      diastolic blood pressures were significantly lower at 6, 12, 18, 24, and 30
      months (P <.01) than before the procedure. Among 65 patients treated for renal
      impairment, renal function improved in 20 (30.8%), stabilized in 25 (41.7%), and
      continued to deteriorate in 20 (30.8%). The mean serum creatinine level did not
      show significant change with time for this group. In the improved subgroup, it
      was significantly higher at 6, 12, 18, 24, 36, and 42 months (P <.05) than prior
      to the procedure. Procedure-related complications occurred in 18 (18%) cases: Ten
      were minor and self-limiting and eight were major and included two procedure
      related deaths. CONCLUSION: In atherosclerotic RAS, primary stent deployment has
      a high technical success rate, producing clinical benefits in the majority of
      patients when performed for resistant hypertension and recovery of renal
      function.

PMID- 12601204
TI  - Hypothesis testing I: proportions.
AB  - Statistical inference involves two analysis methods: estimation and hypothesis
      testing, the latter of which is the subject of this article. Specifically, Z
      tests of proportion are highlighted and illustrated with imaging data from two
      previously published clinical studies. First, to evaluate the relationship
      between nonenhanced computed tomographic (CT) findings and clinical outcome, the
      authors demonstrate the use of the one-sample Z test in a retrospective study
      performed with patients who had ureteral calculi. Second, the authors use the two
      sample Z test to differentiate between primary and metastatic ovarian neoplasms
      in the diagnosis and staging of ovarian cancer. These data are based on a subset
      of cases from a multiinstitutional ovarian cancer trial conducted by the
      Radiologic Diagnostic Oncology Group, in which the roles of CT, magnetic
      resonance imaging, and ultrasonography (US) were evaluated. The statistical
      formulas used for these analyses are explained and demonstrated. These methods
      may enable systematic analysis of proportions and may be applied to many other
      radiologic investigations.

PMID- 12601203
TI  - MR imaging of reperfused myocardial infarction: comparison of necrosis-specific
      and intravascular contrast agents in a cat model.
AB  - PURPOSE: To compare T2-weighted and Gadomer-17- and bis-gadolinium mesoporphyrins
      enhanced magnetic resonance (MR) images for distinguishing reversibly from
      irreversibly damaged myocardium in a cat model of reperfused myocardial
      infarction. MATERIALS AND METHODS: Twelve cats underwent 90 minutes of occlusion
      and 90 minutes of reperfusion of the left anterior descending coronary artery.
      After baseline T1- and T2-weighted MR images were obtained, Gadomer-17-enhanced
      and bis-gadolinium mesoporphyrins-enhanced T1-weighted images were sequentially
      obtained for 6 hours and 2 hours, respectively. After MR imaging, all cats were
      sacrificed for 2,3,5-triphenyltetrazolium chloride (TTC) histochemical tissue
      staining. Areas of abnormal signal intensity on T2-weighted and Gadomer-17
      enhanced and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images were
      compared with the areas of infarction seen at TTC histochemical staining by using
      repeated-measures two-way analysis of variance, linear regression analysis, and
      Bland-Altman analysis. RESULTS: Mean areas of abnormally high signal intensity on
      T2-weighted and Gadomer-17-enhanced T1-weighted MR images (43.9% of the left
      ventricular surface area +/- 11.9 [SD] and 37.7% +/- 10.1, respectively) were
      significantly larger than the mean area of myocardial infarction at TTC staining
      (25.7% +/- 12.5) (P <.001). However, there was excellent correlation between the
      size of an enhancing area on bis-gadolinium mesoporphyrins-enhanced T1-weighted
      MR images and that of myocardial infarction at TTC staining (r = 0.916, P <.001).
      CONCLUSION: bis-Gadolinium mesoporphyrins-enhanced T1-weighted MR images
      accurately reflect the area of infarction, whereas the size of infarction is
      overestimated on T2-weighted and Gadomer-17-enhanced T1-weighted MR images, which
      seem to depict the periinfarct area as well as the infarct area.

PMID- 12601205
TI  - CT of acute bowel ischemia.
AB  - Bowel ischemia may be caused by many conditions and manifest with typical or
      atypical and specific or nonspecific clinical, laboratory, and radiologic
      findings. It may mimic various intestinal diseases and be confused with certain
      nonischemic conditions clinically and at computed tomography (CT). Bowel ischemia
      severity ranges from mild (generally transient superficial changes of intestinal
      mucosa) to more dangerous and potentially life-threatening transmural bowel wall
      necrosis. Causes of critically reduced blood flow to the bowel are diverse,
      ranging from occlusions of mesenteric arteries or veins to complicated bowel
      obstruction and overdistention. CT can demonstrate changes in ischemic bowel
      segments accurately, is often helpful in determining the primary cause of
      ischemia, and can demonstrate important coexistent findings or complications.
      Unfortunately, common CT findings in bowel ischemia are not specific, and
      specific findings are rather uncommon. Therefore, it often is a combination of
      nonspecific clinical, laboratory, and radiologic findings-especially detailed
      knowledge about the pathogenesis of acute bowel ischemia in different conditions
      that helps most in correct interpretation of CT findings. To improve
      understanding of this complex heterogeneous entity, this article provides an
      overview of the anatomy and physiology of mesenteric perfusion and discussions of
      causes and pathogenesis of acute bowel ischemia, CT findings in various types of
      acute bowel ischemia, and potential pitfalls of CT.

PMID- 12601206
TI  - US-guided core-needle biopsy of the breast: how many specimens are necessary?
AB  - PURPOSE: To analyze the diagnostic yield for each specimen obtained at 14-gauge
      ultrasonography (US)-guided breast biopsy and compare these findings with mass,
      procedural, and specimen characteristics that could affect yield. MATERIALS AND
      METHODS: Seventy-three consecutive biopsies of breast masses were performed by
      using a 14-gauge handheld biopsy device. Each specimen was graded for whether it
      was nonfragmented or fragmented and for whether it sank or floated, and each pass
      was graded for whether or not the needle passed through the lesion. Each specimen
      was mounted on a separate slide. A pathologist who was unaware of the final
      diagnoses reviewed the slides in random order. A diagnosis was determined for
      each specimen whenever possible, and diagnostic yield was calculated as a
      function of number of passes. The Fisher exact test was used to compare yield for
      different specimen characteristics. RESULTS: Fourteen (19%) lesions were
      malignant and 59 (81%) were benign. Cells indicating the final diagnosis were
      contained in 249 (75%) of 334 specimens. Cells indicating the diagnosis were
      contained in the first specimen in 51 (70%) lesions, in the second specimen in 67
      (92%), in the third specimen in 70 (96%), and in the fourth specimen in 73
      (100%). Of the 14 malignancies, 13 (93%) were diagnosed with cells contained in
      the first or second specimen; one cancer (ductal carcinoma in situ) was diagnosed
      with cells contained in the fourth specimen. Specimens that were nonfragmented (P
      <.001) and sank (P <.001) showed correlation with being diagnostic, but needle
      visualization within the lesion did not. CONCLUSION: A minimum of four specimens,
      preferably those that are nonfragmented and that sink, should be obtained with 14
      gauge US-guided breast biopsy.

PMID- 12601207
TI  - Influence of percutaneous transluminal angioplasty on transcutaneous oxygen
      pressure in patients with peripheral arterial occlusive disease.
AB  - PURPOSE: To determine in a prospective controlled trial the effect of
      percutaneous transluminal angioplasty (PTA) on skin oxygen supply and
      microcirculation as measured by means of transcutaneous oxygen pressure in
      patients with disabling lower-limb ischemia compared with that in patients who
      underwent intraarterial angiography for the assessment of disabling lower-limb
      ischemia. MATERIALS AND METHODS: Thirty-four patients (17 men, 17 women; mean
      age, 68.6 years +/- 9.8 [SD]) with peripheral arterial occlusive disease (PAOD)
      (claudication, n = 15; critical ischemia, n = 19) underwent transcutaneous oxygen
      pressure measurement at the dorsum of the foot 1 day before PTA, during PTA, 1
      day after PTA, and 6 weeks after PTA. Measurements were obtained with the patient
      in the supine and erect sitting positions, as well as after exercise. Thirty-one
      patients (21 men, 10 women; mean age, 68.5 years +/- 9.3) with symptomatic PAOD
      who were undergoing intraarterial angiography served as the control group.
      RESULTS: Mean pressure before PTA was 31.6 mm Hg +/- 24 in the supine position,
      50.8 mm Hg +/- 22 in the sitting position, and 22.2 mm Hg +/- 23 after exercise.
      Immediately after PTA, a significant increase to 34 mm Hg +/- 20 in the supine
      position was noted (P <.05). One day after PTA, pressure was 37.3 mm Hg +/- 20
      for the supine position and 52 mm Hg +/- 20 for the sitting position. Six weeks
      after treatment, a further significant increase to 43.9 mm Hg +/- 19 in the
      supine position, 61 mm Hg +/- 15 in the sitting position, and 44.7 mm Hg +/- 24
      after exercise was noted (P <.05). In the control group, a significant pressure
      decrease immediately after and 1 day after angiography was noted (P <.05).
      Measurements returned to baseline at 6 weeks follow-up. CONCLUSION: PTA has a
      positive effect on oxygen supply to the skin in patients with PAOD. Conversely,
      intraarterial angiography in patients with PAOD deteriorates skin
      microcirculation temporarily.

PMID- 12601208
TI  - Coarse nodular US pattern in hepatic cirrhosis: risk for hepatocellular
      carcinoma.
AB  - PURPOSE: To determine the prevalence of the coarse nodular ultrasonographic (US)
      pattern and its prognostic importance in terms of hepatocellular carcinoma (HCC)
      risk in hepatic cirrhosis caused by hepatitis B virus (HBV); HBV with hepatitis D
      virus (HDV), formerly known as hepatitis delta virus; hepatitis C virus (HCV);
      and alcoholic cirrhosis (ALC) or primary biliary disease (primary biliary
      cirrhosis [PBC]). MATERIALS AND METHODS: Four hundred two cases of hepatic
      cirrhosis caused by HBV (94 patients), HDV (100 patients), HCV (100 patients),
      ALC (63 patients), or PBC (45 patients) were retrospectively reviewed to identify
      the US pattern present at diagnosis and its possible association with the cause
      of the disease and subsequent development of HCC during a mean follow-up of 43.9
      months +/- 29.9 (SD). Data were analyzed with the chi2, Fisher exact, and log
      rank tests and with the Kaplan-Meier method (all two-tailed). RESULTS: The coarse
      nodular pattern was found in a significantly higher percentage of patients with
      HDV-related cirrhosis (51%) compared with those with HBV (9%), HCV (9%), ALC
      (11%), or PBC (9%) (P <.001). This pattern was associated with a significantly
      increased risk for HCC in patients with cirrhosis and HBV-, HCV-, and ALC-related
      disease but not in those with HDV-related disease and PBC. CONCLUSION: The coarse
      nodular pattern is more often seen in patients with HDV-related cirrhosis, and,
      in this setting (in contrast to HBV-, HCV-, and ALC-related cirrhosis, as well as
      in PBC), it does not represent an added risk factor for HCC.

PMID- 12601209
TI  - Coronary artery imaging with real-time navigator three-dimensional turbo-field
      echo MR coronary angiography: initial experience.
AB  - PURPOSE: To examine the value of a commercially available three-dimensional (3D)
      real-time navigator magnetic resonance (MR) coronary angiographic examination for
      detection of significant coronary artery stenoses, with conventional coronary
      angiography as the standard of reference. MATERIALS AND METHODS: Twenty-one
      patients underwent 3D navigator MR coronary angiography immediately before
      catheterization. Two observers independently graded image quality on a scale from
      1 (unreadable) to 5 (excellent), quantified coronary artery visualization, and
      evaluated the presence of significant (ie, >50% narrowing) stenoses. kappa
      statistics were used to assess interobserver agreement, and receiver operating
      characteristic (ROC) analysis was used to assess stenosis detection. RESULTS: For
      two of 21 patients, MR coronary angiogram quality was insufficient for analysis
      (mean score < 2). For the remaining 19 patients, the mean image quality scores
      assigned by observers 1 and 2 were 3.3 +/- 1.0 (SD) and 3.2 +/- 0.9,
      respectively. A mean of 71% of all coronary artery segments were visible at MR
      coronary angiography, and there was 91% agreement between the observers (kappa =
      0.78). Observers 1 and 2 detected significant stenoses (n = 29) at MR coronary
      angiography with sensitivities of 44.4% and 55.5%, respectively; specificities of
      95.1% and 83.7%, respectively; and 80% agreement (kappa = 0.35). Areas under the
      ROC curve were 0.817 and 0.795 for observers 1 and 2, respectively. CONCLUSION:
      Large portions of the coronary arteries can be visualized with MR coronary
      angiography. Imaging results are not consistently reliable, however. The
      examination is premature for routine clinical assessment of significant coronary
      artery stenosis owing to low sensitivity and large observer variability.

PMID- 12601210
TI  - Pilonidal sinus disease: MR imaging distinction from fistula in ano.
AB  - PURPOSE: To describe magnetic resonance (MR) imaging features in patients with
      proved pilonidal sinus disease and to compare these features with those in a
      matched group of patients with proved fistula in ano to determine the accuracy
      with which MR imaging can be used to distinguish between the two diseases.
      MATERIALS AND METHODS: Seven patients with pilonidal sinus disease underwent MR
      imaging with a body coil. The site and morphology of sepsis were noted, with
      particular reference to natal cleft sepsis and deep-seated sepsis, including
      intersphincteric anal canal sepsis and any enteric communication. Comparison was
      made with 14 age- and sex-matched patients with fistula in ano. Categoric
      frequencies were compared to calculate differences between the groups and
      sensitivities, specificities, and predictive values. RESULTS: All patients with
      pilonidal sinus had natal cleft sepsis, but five (71%) had sepsis at deep-seated
      sites more characteristic of fistula in ano. Eight patients with fistula in ano
      (57%) had natal cleft sepsis that was thought characteristic of pilonidal sinus.
      No patient with pilonidal sinus had intersphincteric sepsis or an enteric
      communication, in contrast to all patients with fistula in ano having both (P
      <.001). Natal cleft sepsis reached the subcutaneous tissues overlying the coccyx
      and sacrum in only one patient with fistula (7%), in contrast to six (86%) with
      pilonidal sinus (P <.001). MR imaging had a sensitivity of 86% (six of seven),
      specificity of 100% (14 of 14), positive predictive value of 100% (six of six),
      and negative predictive value of 93% (14 of 15) for diagnosis of pilonidal sinus
      disease. CONCLUSION: MR imaging features of perianal and deep-seated sepsis,
      characteristic of fistula in ano, are also found in patients with pilonidal
      sinus, but the absence of intersphincteric sepsis or enteric opening allows
      reliable MR imaging distinction between the two.

PMID- 12601211
TI  - MR imaging of the menisci and cruciate ligaments: a systematic review.
AB  - PURPOSE: To systematically review and synthesize published data on the diagnostic
      performance of magnetic resonance (MR) imaging of the menisci and cruciate
      ligaments and to assess the effect of study design characteristics and magnetic
      field strength on diagnostic performance. MATERIALS AND METHODS: Articles
      published between 1991 and 2000 were included if at least 30 patients were
      studied, arthroscopy was the reference standard, the magnetic field strength was
      reported, positivity criteria were defined, and the absolute numbers of true
      positive, false-negative, true-negative, and false-positive results were
      available or derivable. Pooled weighted and summary receiver operating
      characteristic (ROC) analyses were performed for tears of both menisci and both
      cruciate ligaments separately and for the four lesions combined, by using random
      effects models. Differences were assessed according to lesion type. RESULTS:
      Twenty-nine of 120 retrieved articles were included. Pooled weighted sensitivity
      was higher for medial meniscal tears than that for lateral meniscal tears.
      However, pooled weighted specificity for the medial meniscus was lower than that
      for the lateral meniscus. In summary ROC analyses performed per lesion, various
      study design characteristics were found to influence diagnostic performance.
      Higher magnetic field strength significantly improved discriminatory power only
      for anterior cruciate ligament tears. When all lesions were combined in one
      overall summary ROC analysis, magnetic field strength was a significant but
      modest predictor of diagnostic performance. CONCLUSION: Diagnostic performance of
      MR imaging of the knee is different according to lesion type and is influenced by
      various study design characteristics. Higher magnetic field strength modestly
      improves diagnostic performance, but a significant effect was demonstrated only
      for anterior cruciate ligament tears.

PMID- 12601212
TI  - Combined first-pass perfusion and viability study at MR imaging in patients with
      non-ST segment-elevation acute coronary syndromes: feasibility study.
AB  - PURPOSE: To assess the feasibility of combined perfusion and viability testing by
      using magnetic resonance (MR) imaging in one setting in patients with non-ST
      segment-elevation acute coronary syndromes. MATERIALS AND METHODS: The data of 13
      patients (mean age, 68 years; range, 40-85 years) at high risk for myocardial
      infarction who underwent MR imaging at 1.5 T were reviewed. Risk factors were
      increased troponin T levels in seven, reversible ST depression on an
      electrocardiogram in four, history of myocardial infarction in two, and presence
      of heart failure in four. Cine imaging of the left ventricle was performed with a
      true-fast imaging with steady-state precession (FISP) sequence to assess the
      regional myocardial contraction and ejection fraction. After injection of 0.1
      mmol per kilogram of body weight of gadopentetate dimeglumine, first-pass MR
      images were obtained by using an inversion-recovery true-FISP sequence at rest
      and during infusion of adenosine (140 microg/kg/min). Resting and stress images
      were assessed qualitatively for abnormal regional perfusion (hypoenhancement).
      The myocardium was divided into three radial segments corresponding to the three
      coronary artery territories. Delayed (after 15 minutes) contrast material
      enhanced images were acquired with use of a segmented inversion-recovery fast low
      angle shot sequence. Conventional coronary angiograms were compared with the
      first-pass images. A more than 50% stenosis in diameter in any coronary artery
      was considered substantial. Mann-Whitney test was used to assess any significant
      difference between the left ventricular ejection fraction (LVEF) in patients with
      and those without myocardial infarct. RESULTS: Mean LVEF was 51.5% (range, 30%
      77%). First-pass stress perfusion studies depicted 25 segments of hypoenhancement
      in 11 patients. Comparison of first-pass perfusion defects with findings on
      coronary angiograms indicated an overall sensitivity of 92% (24 of 26) and
      specificity of 92% (12 of 13) in detection of substantial coronary artery
      disease. Infarcts detected from hyperenhancement on delayed contrast-enhanced
      images were present in eight segments (four were transmural) in five patients. No
      significant difference was noted in the LVEF between patients with and those
      without infarct (P =.724). CONCLUSION: Combined stress perfusion and viability MR
      imaging was feasible in patients with acute coronary syndromes. First-pass MR
      perfusion defects compare well with the presence of substantial coronary artery
      stenosis on conventional angiograms.

PMID- 12601213
TI  - Morton neuroma: MR imaging in prone, supine, and upright weight-bearing body
      positions.
AB  - PURPOSE: To assess the effect of prone, supine, and upright weight-bearing body
      positions on visibility, position, shape, and size of Morton neuroma during
      magnetic resonance (MR) imaging. MATERIALS AND METHODS: Eighteen patients with 20
      Morton neuromas underwent MR imaging of the forefoot in prone (plantar flexion of
      the foot), supine (dorsiflexion of the foot), and upright weight-bearing
      positions. Visibility (3 = good, 2 = moderate, 1 = poor), position relative to
      the metatarsal bone, shape, and transverse diameter of Morton neuroma were
      assessed on transverse T1-weighted MR images. Associations between different body
      positions and variables of interest were calculated with Wilcoxon signed rank
      test, chi2 test, and paired Student t test. RESULTS: In the prone position,
      visibility of all 20 Morton neuromas was rated with a score of 3; visibility in
      the supine and weight-bearing positions was inferior (mean score, 2.4). All 20
      (100%) Morton neuromas changed their position relative to the metatarsal bone
      between prone and supine and between prone and weight-bearing positions. When
      compared with the prone position, there was a difference in the shape of all 20
      Morton neuromas in the weight-bearing position (P <.001). Between prone (mean
      transverse diameter of Morton neuroma, 8 mm) and supine (mean transverse diameter
      of Morton neuroma, 6 mm) positions, the transverse diameter of Morton neuroma
      significantly decreased by 2 mm (P =.03); between prone and weight-bearing
      positions, the decrease of the mean transverse diameter was also significant
      (difference, 2 mm; P =.03). CONCLUSION: Morton neuroma appears significantly
      different during MR imaging in prone, supine, or weight-bearing positions. The
      transverse diameter of Morton neuroma is significantly larger on images obtained
      in the prone position than it is on images obtained in the supine and upright
      weight-bearing positions. Visibility of Morton neuroma is best on MR images
      obtained in the prone position.

PMID- 12601214
TI  - Gastrointestinal complications in the neutropenic patient: characterization and
      differentiation with abdominal CT.
AB  - PURPOSE: To characterize the computed tomographic (CT) findings of
      gastrointestinal complications in neutropenic patients and to identify CT
      features that can help differentiate these complications. MATERIALS AND METHODS:
      Abdominal CT scans obtained during a 6-year period were reviewed retrospectively
      to identify 76 neutropenic patients with radiologic bowel abnormalities. Scans
      were analyzed for wall thickening, pneumatosis, wall nodularity, mucosal
      enhancement, bowel dilatation, ascites, and mesenteric stranding. The location
      and extent of abnormalities were noted. Independent chart and pathology report
      reviews were used to determine the patients' final diagnoses: neutropenic
      enterocolitis (n = 53), Clostridium difficile colitis (n = 14), graft-versus-host
      disease (n = 7), cytomegaloviral colitis (n = 1), and ischemic bowel (n = 1).
      Results were assessed with the Student t test for quantitative wall thickness and
      the chi2 test for the number of patients with each diagnosis who demonstrated
      each CT finding. RESULTS: Mean bowel wall thickening was greatest in C difficile
      colitis (12 mm) and least in graft-versus-host disease (5 mm). Pneumatosis was
      limited to neutropenic enterocolitis (21% [11 of 53 patients]) and bowel
      ischemia. Wall nodularity was significantly more common (P <.01) in C difficile
      colitis (36% [five of 14 patients]). In graft-versus-host disease, the rates of
      mucosal enhancement and bowel dilatation were highest (P <.05) (71% [five of
      seven patients] and 86% [six of seven patients], respectively). In C difficile
      colitis, the rates of ascites and mesenteric stranding were highest (57% [eight
      of 14 patients] and 71% [10 of 14 patients], respectively). Although findings in
      neutropenic enterocolitis and graft-versus-host disease could involve any bowel
      segment, C difficile colitis was always limited to the colon. CONCLUSION: Several
      CT findings can help differentiate specific gastrointestinal complications in
      neutropenic patients.

PMID- 12601215
TI  - Brain changes with aging: MR spectroscopy at supraventricular plane shows
      differences between women and men.
AB  - PURPOSE: To assess the effect of aging on the proportions of choline (Cho),
      creatine, and N-acetylaspartate (NAA) in the brains of elderly women and men.
      MATERIALS AND METHODS: A transverse plane above the ventricle of the brain was
      mapped with magnetic resonance spectroscopy. Examinations were performed in 1995
      1996 with 271 healthy subjects (age range, 60-90 years; mean age, 73 years) and
      were repeated 4 years later (1999-2000). Student t tests were used for
      statistical analysis. RESULTS: Difference analysis of the changes in 4 years
      (paired data) reproduced the decrease in Cho in women only (2.9% per year, P
      <.001) that had been indicated with intersubject correlation analyses. Decreases
      in NAA, though significant in both men and women according to age correlation
      analyses (P <.01 for both), did not reach significance. The resulting sex
      difference in the Cho/NAA ratio at a mean age of 77 years, while not yet
      significant at a mean age of 73 years, was especially manifest in the posterior
      half of the plane analyzed. CONCLUSION: Increasing sex differences in Cho/NAA
      ratios in a supraventricular plane indicate that brain metabolite levels differ
      between women and men at advanced age.

PMID- 12601216
TI  - Endovascular treatment of basilar tip aneurysms with Guglielmi detachable coils:
      predictors of immediate and long-term results with multivariate analysis 6-year
      experience.
AB  - PURPOSE: To analyze anatomic and clinical results and factors predictive of
      outcome in treatment of basilar tip aneurysms with Guglielmi detachable coils
      (GDCs). MATERIALS AND METHODS: During 6 years, 55 unselected consecutive saccular
      aneurysms in 53 patients (mean age, 47 years) were treated with GDC occlusion.
      Forty-one (75%) aneurysms were ruptured (Hunt-Hess and Fisher grades were
      assigned in patients); 14 (25%), unruptured. Clinical and angiographic
      evaluations were performed 6 months after treatment and during follow-up (mean
      follow-up, 2 years). Multivariate analysis was used to determine factors
      predictive of outcome. RESULTS: GDC occlusion was a success in 52 (95%)
      aneurysms, a failure in two (4%), and not attempted in one (2%). Occlusion at
      final follow-up, evaluated in 44 aneurysms, was complete in 34 (77%), near
      complete in four (9%), and incomplete in six (14%). At 6-12 months, mean
      aneurysmal occlusion rate significantly worsened because of revascularization (P
      <.001) but improved at final follow-up because of reembolization in 10 aneurysms
      (P =.009); it remained stable (P =.351) between initial and final follow-up.
      Multivariate binary logistic regression indicated that before treatment started,
      aneurysmal neck size was the only independent predictor of initial occlusion rate
      (P =.002) and revascularization (P =.004). After the initial procedure, sac size
      and initial occlusion rate were independent predictors of revascularization (P
      =.004 and.008, respectively), irrespective of neck size. Occlusion rate at 6-12
      month follow-up was the only independent predictor of that at final follow-up (P
      =.021), regardless of shape of aneurysm. Overall morbidity was 2% (one of 51);
      mortality, 6% (three of 51). Mortality correlated significantly with Hunt-Hess
      grade 4 at admission (P =.003) and incidence of vasospasm (P =.058). CONCLUSION:
      GDC occlusion proved to be a safe effective therapeutic alternative to surgery in
      patients with ruptured or unruptured basilar tip aneurysms. Morphologic and
      clinical factors were respectively identified as predictors of the optimal
      anatomic and clinical outcomes.

PMID- 12601217
TI  - Do highly concentrated gadolinium chelates improve MR brain perfusion imaging?
      Intraindividually controlled randomized crossover concentration comparison study
      of 0.5 versus 1.0 mol/L gadobutrol.
AB  - PURPOSE: To assess the potential advantages of using a 1.0 mol/L versus 0.5 mol/L
      gadobutrol formulation for magnetic resonance (MR) brain perfusion imaging.
      MATERIALS AND METHODS: Forty-three healthy volunteers were enrolled in an
      intraindividually controlled, randomized crossover comparison study. Two
      gadobutrol formulations-0.5 and 1.0 mol/L- were randomly injected during two
      separate treatment periods. For intraindividual comparison of effectiveness
      parameters, single-section gradient-echo brain perfusion MR imaging was performed
      under identical conditions for both investigations. Quantitative and qualitative
      evaluations were performed. Differences between the two gadobutrol formulations
      were evaluated at analysis of covariance and tested for statistical significance
      (P <.05) with a t test. RESULTS: Use of 1.0 mol/L gadobutrol resulted in a
      significantly smaller bolus width at half maximum signal intensity decrease, a
      smaller mean peak time, a higher contrast and contrast-to-noise ratio between
      gray and white matter, and significant increases in both maximum change in
      transverse relaxation rate (DeltaR2max) and differences in peak enhancement in
      gray matter among all volunteers (P <.001). In white matter, increases in
      DeltaR2max (P =.262) and in differences in peak enhancement (P =.262) were
      smaller and not significant (P =.292). Parameter map analysis revealed improved
      quality and superior contrast in relative regional cerebral blood flow (P =.034)
      and mean transit time (P <.001). The lack of difference regarding relative
      regional cerebral blood volume maps was consistent with the use of the same dose
      of each gadobutrol formulation. CONCLUSION: Brain perfusion images obtained with
      1.0 mol/L gadobutrol were superior to those obtained with 0.5 mol/L gadobutrol in
      healthy volunteers examined with the described MR imaging protocol.

PMID- 12601218
TI  - CT colonography: digital subtraction bowel cleansing with mucosal reconstruction
      initial observations.
AB  - The authors evaluated a computed tomography (CT) colonographic technique with a
      combination of preexamination orally ingested positive contrast material and
      postacquisition image processing to subtract out the ingested opacified bowel
      contents. With this technique, rigorous physical purging of the bowel was not
      necessary before structural examination of the colon. With images obtained in 20
      patients, two readers were able to correctly identify the majority of polyps
      confirmed at colonoscopy. Their performance for detection of lesions larger than
      1 cm was similar to that with conventional CT colonography.

PMID- 12601219
TI  - US-guided core-needle biopsy of the thyroid gland.
AB  - PURPOSE: To evaluate safety, yield, and accuracy of ultrasonography (US)-guided
      core-needle biopsy of the thyroid gland. MATERIALS AND METHODS: Findings at 209
      consecutive core-needle biopsies of lesions of the thyroid gland in 198 patients
      (median age, 48 years; age range, 14-80 years) were retrospectively reviewed. In
      138 (66%), findings at previous fine-needle aspiration cytologic (FNAC) analysis
      were nondiagnostic on one to five occasions. Biopsy was performed as an
      outpatient procedure with direct US guidance by using nonadvancing 16-18-gauge
      core needles. Hospital records were reviewed 6 months to 5 years following biopsy
      to determine final diagnosis, delayed complications, and influence of biopsy
      findings on subsequent patient treatment. Final diagnoses were determined on the
      basis of findings at excisional histologic analysis, clinical course, or other
      laboratory values. The sensitivity, specificity, and accuracy of US-guided core
      needle biopsy were calculated. RESULTS: One hundred ninety-nine (95%) specimens
      were adequate for histologic diagnosis. The sensitivity, specificity, and
      accuracy of core biopsy in differentiating neoplastic (malignant and benign) from
      nonneoplastic lesions of the thyroid gland were 96% (74 of 77), 89% (109 of 122),
      and 92% (183 of 199), respectively. The sensitivity, specificity, and accuracy of
      core-needle biopsy in the detection of malignant neoplasms were 61% (11 of 18),
      100% (181 of 181), and 96% (192 of 199), respectively. After US-guided core
      needle biopsy, 115 (58%) of 198 patients were treated conservatively, and no
      evidence of missed tumor manifested during the follow-up period. In the 83
      patients who underwent surgical resection, biopsy was performed for therapeutic
      reasons in 76 (92%) and for diagnostic reasons in seven (8%). There were three
      cases of small postbiopsy hematomas and one of minor hemoptysis, but none
      required hospital admission. There were no major complications. CONCLUSION: US
      guided core-needle biopsy of the thyroid gland is a safe outpatient procedure
      with a high diagnostic yield and accuracy, and frequently it obviates surgery in
      patients in whom findings at FNAC analysis are recurrently nondiagnostic.

PMID- 12601220
TI  - Giant gastric folds: differential diagnosis at US.
AB  - PURPOSE: To evaluate ultrasonographic (US) features in the differential diagnosis
      of giant gastric folds. MATERIALS AND METHODS: One hundred sixty-five patients
      with giant gastric folds at transabdominal US examination (five with Menetrier
      disease, 24 with anisakiasis, 61 with acute gastric mucosal lesion [AGML], 13
      with gastric lymphoma, and 62 with scirrhous carcinoma) were examined. With 3-6
      MHz curved and 5-11-MHz linear-array transducers, the authors evaluated gastric
      wall thickness, wall stratification, main thickened layer, echogenicity, and
      compressibility of the lesion in each case. The Fisher protected least
      significant-difference method was used to compare statistically the thickness of
      the gastric wall among diseases. RESULTS: Wall thickness of AGML was
      significantly (P <.001) less than that of anisakiasis, gastric lymphoma, and
      scirrhous carcinoma. US findings revealed regular gastric wall thickening of the
      second or third layer, with preservation of wall stratification in all patients
      with benign conditions. The fourth layer was thickened only in patients with
      malignancy. The echogenicity of gastric lymphoma was markedly lower than that of
      any other condition. Compressibility of scirrhous carcinoma was absent, whereas
      it was well preserved in all benign conditions. CONCLUSION: Transabdominal US can
      depict gastric wall stratification and is a useful noninvasive modality for
      differential diagnosis of giant gastric folds.

PMID- 12601222
TI  - Folate and depression.

PMID- 12601221
TI  - Tourniquet application to facilitate axillary venous access in percutaneous
      central venous catheterization.
AB  - The authors evaluated the location of peripheral venous lines and changes in
      opacification of cephalic and axillary veins at fluoroscopically guided
      venography after tourniquet application. Results suggested that tourniquet
      application effectively reduces the superficial venous flow and consequently
      enhances the opacification of the axillary veins. Tourniquet application is a
      simple and effective way of facilitating axillary venous puncture.

PMID- 12601223
TI  - Getting what you ask for: on the selectivity of depression rating scales.
AB  - A large number of rating scales has been developed to assess depression severity
      and change during antidepressant therapy. When reviewing the literature, the
      choice of the rating scales used in a particular study often seems arbitrary. The
      most frequently used observer rating scales, the Hamilton Depression Rating Scale
      (HDRS) and the Montgomery-Asberg Depression Rating Scale (MADRS), and the most
      frequently used self-rating scale (the Beck Depression Inventory, or BDI) were
      developed more than 20 years ago. Their historical background is too often
      forgotten and they are reflections of their origin: the HDRS and the MADRS
      reflect antidepressant activity while the BDI reflects psychotherapy. Moreover,
      the HDRS is at risk of putting 'all depressions in one basket', while the MADRS
      is at risk of putting 'all antidepressants in one basket'. Therefore, the
      question whether a particular antidepressant could be more effective in a
      particular subtype of depression cannot be answered. Observer rating scales are
      more frequently used than self-rating scales, and when scales are used that do
      exist in an observer rating and a self-rating version, interesting differences
      are found. The present paper does not suggest that one scale is better than
      another, but suggests that a better knowledge of their differential background
      can help the researcher choose the correct scale for his purposes.

PMID- 12601224
TI  - Lines of evidence on the risks of suicide with selective serotonin reuptake
      inhibitors.
AB  - BACKGROUND: There has been a long-standing controversy about the possibility that
      selective serotonin reuptake inhibitor (SSRI) antidepressants might induce
      suicidality in some patients. METHODS: Starting from the clinical studies that
      gave rise to this issue, this paper reviews an unselected cohort of randomized
      clinical trials (RCTs), a series of meta-analyses undertaken to investigate
      aspects of the problem, studies in recurrent brief depressive disorders,
      epidemiological studies and healthy volunteer studies using SSRIs to shed light
      on this issue. RESULTS: The original clinical studies produced evidence of a dose
      dependent link, present on a challenge, dechallenge and rechallenge basis,
      between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted
      around this time indicate that SSRIs may reduce suicidal ideation in some
      patients. These same RCTs, however, yield an excess of suicides and suicide
      attempts on active treatments compared with placebos. This excess also appears in
      the best-controlled epidemiological studies. Finally, healthy volunteer studies
      give indications that SSRIs may induce agitation and suicidality in some
      individuals. CONCLUSIONS: The data reviewed here, which indicate a possible
      doubling of the relative risk of both suicides and suicide attempts on SSRIs
      compared with older antidepressants or non-treatment, make it difficult to
      sustain a null hypothesis, i.e. that SSRIs do not cause problems in some
      individuals to whom they are given. Further studies or further access to data are
      indicated to establish the magnitude of any risk and the characteristics of
      patients who may be most at risk.

PMID- 12601225
TI  - Depression and folate status in the US Population.
AB  - BACKGROUND: Folate deficiency and low folate status have been linked in clinic
      studies to depression, persistent depressive symptoms, and poor antidepressant
      response. These relationships have not been demonstrated in general populations.
      This study examined associations between depression and folate status indicators
      in an ethnically diverse general US population sample aged 15-39 years. METHODS:
      Healthy subjects whose red blood cell (RBC) folate concentrations had been
      measured were determined to have no depression (n = 2,526), major depression (n =
      301), or dysthymia (n = 121) using a diagnostic interview schedule. Serum
      concentrations of folate and total homocysteine (tHcy) were also measured.
      RESULTS: After adjustment for sociodemographic factors, serum vitamin B(12)
      concentration, alcohol consumption over the past year and current status as to
      overweight and use of vitamin/mineral supplements, cigarettes and illegal drugs,
      subjects who met criteria for a lifetime diagnosis of major depression had folate
      concentrations in serum and RBCs that were lower than those of subjects who had
      never been depressed. Subjects who met criteria for dysthymia alone had lower RBC
      folate concentrations than never-depressed subjects, but the serum folate
      concentrations of the two groups were comparable. Serum tHcy concentration was
      not related to lifetime depression diagnoses. Low folate status was found to be
      most characteristic of recently recovered subjects, and a large proportion of
      such subjects were folate deficient. CONCLUSIONS: Low folate status was
      detectable in depressed members of the general US population. Folate
      supplementation may be indicated during the year following a depressive episode.

PMID- 12601226
TI  - Somatoform pain disorder in the general population.
AB  - BACKGROUND: Chronic pain disorder is assumed to represent a frequent and
      disabling condition. However, data on the prevalence of somatoform pain symptoms
      and somatoform pain disorder in the community are limited to date. METHODS:
      German versions of the Composite International Diagnostic Interview were
      administered to a representative national sample of 4,075 people. Somatoform pain
      disorder was diagnosed by standardized diagnostic algorithm based on the DSM-III
      R criteria (absence of adequate physical findings). One subgroup was identified
      as also meeting the DSM-IV criterion B for 'significant distress or psychosocial
      impairment due to the somatoform pain'. RESULTS: A lifetime prevalence rate of
      somatoform pain disorder according to DSM-III-R of 33.7% and a 6-month rate of
      17.3% was found. When applying the DSM-IV B criterion, the prevalence rate
      dropped to 12.3 and 5.4%, respectively. In both groups more than 95% of the
      probands had contacted their doctor because of the pain. In 25% of the probands
      the pain was positively assigned to psychological factors. A female:male ratio of
      2:1 was found. CONCLUSIONS: Somatoform pain disorder (DSM-III-R) is a frequent
      condition. However, only about one third of these subjects is severely distressed
      or impaired by the pain. A clear operationalized concept of the DSM-IV criterion
      C 'psychological factors are judged to have an important role in the onset,
      severity, exacerbation or maintenance of the pain' should be provided in the
      further development of the diagnosis 'pain disorder' in order to make this
      diagnosis suitable for general population surveys.

PMID- 12601227
TI  - A self-controlled, naturalistic study of selective serotonin reuptake inhibitors
      versus tricyclic antidepressants.
AB  - OBJECTIVE: To compare the effectiveness of serotonin reuptake inhibitors (SSRIs)
      and tricyclic antidepressants (TCAs) for anxiety and mood disorders in a
      naturalistic setting. METHODS: 114 of 2,000 outpatients drawn from a private
      facility with a diagnosis of mood or anxiety disorder had two separate episodes
      during which they were treated once with a SSRI and once with a TCA. The drugs
      had to be in monotherapy and appropriate according to the recent guidelines. Key
      outcome measures included several rating scales, the results of which were
      combined into three measures of outcome: full response (no symptom), partial
      response (residual symptoms), poor response. RESULTS: TCAs produced a better
      response in 63 cases and SSRIs in 18 cases (p < 0.00001). When the outcome was
      dichotomized, TCAs were still superior (stricter criterion of full response: p =
      0.0002; lower threshold: p < 0.0001). Considering depressive and anxiety
      disorders separately, TCAs remained superior in terms of efficacy (for
      depression: p < 0.0001; for anxiety: p = 0.026). Moreover, the second episode of
      illness showed a better outcome than the first (p = 0.0008). CONCLUSIONS: In
      those cases where two different antidepressants were prescribed over two
      different episodes of illness, TCAs were significantly more effective than SSRIs,
      regardless of the type of disorder and order of prescription.

PMID- 12601228
TI  - Behavioral and emotional disturbances in the offspring of depressed parents with
      anger attacks.
AB  - BACKGROUND: To examine the emotional and behavioral characteristics of the
      offspring of depressed parents with and without anger attacks. METHODS: Forty
      three parents who met criteria for major depressive disorder (MDD) completed the
      Achenbach Child Behavior Checklist - Parent Report Version (CBCL) for each of
      their birth children (n = 58, age range 6-17 years). Unpaired t tests were used
      to evaluate the CBCL scale score differences between children of parents with and
      children of parents without anger attacks. Baseline demographics and clinical
      differences between the two groups of parents were also evaluated. RESULTS:
      Parents with anger attacks had a significantly younger age of onset of MDD.
      Offspring of depressed parents with anger attacks were found to have
      significantly lower social and school competency scale scores and higher scores
      for delinquency, attention problems, and aggressive behavior. In addition, this
      group was found to have a significantly higher total T score (a global measure of
      psychopathology). CONCLUSIONS: There are some important differences between
      offspring of depressed parents with and without anger attacks. This finding may
      be important in identifying and formulating intervention strategies for childhood
      problems in the offspring of depressed parents.

PMID- 12601229
TI  - How could antidepressants worsen unipolar depression?

PMID- 12601230
TI  - Training psychiatry residents in evidence-based treatments for major depression.

PMID- 12601232
TI  - Attribution of improvement to medication and increased risk of relapse of panic
      disorder with agoraphobia.

PMID- 12601234
TI  - The drive to look for insight.

PMID- 12601235
TI  - Pediatric tumors of the orbit and optic pathway.
AB  - We present an overview of the treatment and clinical outcome of 30 pediatric
      patients with orbital and optic pathway tumors cared for in our center from 1991
      to 2002. Follow-ups were available for 48 months on average. Eight of 14 gliomas
      of the optic nerve or pathway were subtotally resected via a pterional approach.
      Two were totally resected with transection of the optic nerve, 2 were only
      biopsied and 2 were observed. One of 4 optic nerve sheath meningiomas in patients
      with good visual acuity was subtotally resected with decompression of the optic
      canal. Two were totally resected with transection of the prechiasmal optic nerve
      and 1 was only biopsied. Four infectious intra-/extraconal lesions were biopsied
      (transconjunctival approach) and treated with antibiotics. Two vascular intra
      /extraconal tumors (hemangiomas) were removed via a transconjunctival approach
      and a lateral orbitotomy. The following histologies only occurred once: dermoid
      cyst, aneurysmal bone cyst, eosinophilic granuloma, fibrous dysplasia,
      osteopetrosis and rhabdomyosarcoma. The spectrum of pathology in pediatric
      orbital tumors is wide and requires multidisciplinary treatment.

PMID- 12601236
TI  - Transient cerebellar eye closure and mutism after cerebellar tumor surgery: long
      term clinical follow-up of neurologic and behavioral disturbances in a 14-year
      old girl.
AB  - Transient cerebellar eye closure (TCES) is a complication of cerebellar tumor
      surgery in children and is almost exclusively observed in the context of the
      syndrome of mutism and subsequent dysarthria. As knowledge about the course of
      transient cerebellar eye closure is absent, we describe in detail the clinical
      picture in a 14-year-old girl. The process of improvement of TCES is
      characterized by four distinct phases, can last more than 1 month and may be
      associated with severe persistent cerebellar dysfunction.

PMID- 12601237
TI  - Late gestational intrauterine myelomeningocele repair does not improve lower
      extremity function.
AB  - OBJECTIVE: To determine whether intrauterine myelomeningocele repair performed at
      between 20 and 28 weeks gestation improves lower extremity function (LEF).
      METHODS: Thirty-seven consecutive patients who had undergone intrauterine repair
      of their myelomeningocele at Vanderbilt University Medical Center had their lower
      extremity function and radiographic level (first defective vertebral level)
      compared to these same parameters in 40 controls who had undergone traditional
      postgestational repair of their myelomeningocele at the Children's Hospital in
      Birmingham, Ala., USA. RESULTS: Of all 77 patients (controls and study group), 13
      had a LEF that matched their radiographic level, 27 had a LEF that was rostral to
      their radiographic level, and 37 had a LEF that was caudal to their radiographic
      level. Further stratification revealed that for the intrauterine repaired
      myelomeningoceles, 11% had no difference between LEF and radiographic level, 43%
      had a LEF that was rostral to their radiographic level, and 46% had a LEF that
      was caudal to their radiographic level. For those closed in a traditional manner,
      LEF matched their radiographic level, was rostral to their radiographic level,
      and was caudal to their radiographic level in 22.5%, 27.5%, and 50% respectively.
      However, the overall mean differences between institutions produced a p-value of
      0.2026 (paired t-test). CONCLUSIONS: Although the current timing of intrauterine
      myelomeningocele repair has been found to lessen the degree of herniation of the
      rhombencephalon and reduce the incidence of shunt-dependent hydrocephalus, it
      does not statistically improve LEF. Parents should be advised of these findings
      prior to surgical intervention so as to focus their expectations.

PMID- 12601239
TI  - Combined positron emission tomography and magnetic resonance imaging for the
      planning of stereotactic brain biopsies in children: experience in 9 cases.
AB  - Because brain tumors can be histologically heterogeneous, stereotactic brain
      biopsies (SBB) may lead to inaccurate diagnosis or grading. Positron emission
      tomography (PET) has been used in pediatric neuro-oncology to help in the
      understanding and management of brain neoplasms. We combined PET and magnetic
      resonance (MR) imaging in the planning of SBB in 9 children (5 males and 4
      females, aged 2-14 years) with infiltrative, ill-defined brain lesions. Tracers
      used for PET were (18)F-2-fluoro-2-deoxy-D-glucose in 4 cases, (11)C-methionine
      in 2 cases and both tracers in 3 cases. Biopsy targets were selected in
      hypermetabolic areas. PET-guided SBB provided accurate histological diagnosis in
      all patients and allowed a reduction of the number of trajectories in lesions
      located in functional areas. It also helped in better understanding and
      management of complex cases. This preliminary series suggests that combining PET
      and MR imaging in the planning of SBB in children (1) improves the diagnostic
      yield of SBB in infiltrative, ill-defined brain lesions, (2) makes it possible to
      reduce the sampling in high-risk/functional areas and (3) improves the quality of
      therapeutic management of pediatric brain tumors.

PMID- 12601238
TI  - Spinal dysraphism: trends in northern India.
AB  - OBJECTIVE: To evaluate the clinical profiles, image findings and surgical outcome
      of 155 cases of spinal dysraphism. METHODS: 155 patients were studied
      prospectively (143) or retrospectively (12). The male to female ratio was 1.5:1.
      Mean age at presentation was 5.7 years. Out of 155 cases of spinal dysraphism,
      119 had open spina bifida [meningomyelocele (MMC) in 113 (72%), meningocele in 3
      (2%) and myelocystocele in 3 (2%)] and 36 had occult spina bifida [split cord
      malformation (SCM) without overt MMC sac (pure SCM) in 29 (19%) and midline
      dermal sinus in 7 (4.5%)]. Lipomeningomyelocele constituted 73 of the 113 cases
      of MMC (65%). Twenty cases of MMC (18%) had associated SCM (complex spina
      bifida). The total number of cases with SCM was 49 (32%). Twenty-four children
      with MMC presented with an operative scar from previous surgery, performed at the
      periphery. After a detailed clinical evaluation of all patients, craniospinal MRI
      was the preferable mode of investigation. All patients underwent surgery and were
      clinically assessed over a mean follow-up period of 3.6 years. RESULTS: MMC sac
      was the commonest skin manifestation seen in 89/155 cases (57%). Hypertrichosis
      and previous operative scar were noticed in 24 cases each (15%). Cutaneous
      hemangioma, skin tag and multiple neurofibroma were the other common superficial
      skin manifestations. Clinically, 103 patients (66.5%) had variable weakness of
      the lower limbs, and muscle atrophy was noticed in 56 cases (41%). Graded sensory
      loss, sphincteric dysfunction, trophic ulcer and backache were present in 89
      (57%), 64 (36%), 17 (11%) and 9 cases (6%), respectively. Significant scoliosis
      in 56 cases (36%) and congenital talipes equinovarus in 51 cases (33%) were the
      most frequent neuroorthopedic deformities apart from high-arched foot, leg length
      discrepancy and flat foot. Common image findings were low-lying cord in 101
      (65%), neural placode in 76/113 (49%), hydrosyrinx in 42 (27%), hydrocephalus in
      71 (46%) and Chiari malformation in 62 cases (45%). The lumbosacral region in 56
      cases (38%), followed by the lumbar region in 47 (30%), were the most common
      sites of occurrence of spina bifida. Of 71 hydrocephalic patients, 39 (55%)
      needed shunting before definitive surgery and 21 (30%) after the surgery. Eleven
      patients (15%) did not require shunting at all. CSF leak in 51 patients (33%),
      pseudomeningocele in 26 (17%), wound infection in 22 (14%) and meningitis in 13
      (8%) were the most common postoperative complications. Two patients died in the
      postoperative period. During an average follow-up of 3.6 years (range 1.5-8
      years), motor weakness improved in 47 children (45%) and remained static in 53
      (52%), and 3 children showed deterioration in motor power. Sensory dysfunction
      improved in 43 (48%), remained static in 42 (47%) and deteriorated in 4 patients
      (4%). Sphincteric function clinically improved in 26 patients (41%) and was
      static in 38 (59%), and 6 patients (4%) had deterioration. Backache was
      dramatically relieved in all 9 patients with this complaint (100%). In 13
      children with trophic ulcer (76%), it completely healed. CONCLUSION: A
      significant proportion of patients with open spinal dysraphism harbor an
      underlying SCM, an entity coined complex spina bifida (in our previous study).
      The incidence of hydrocephalus in spinal dysraphism is low in India in comparison
      to the Western world. Some patients with mild hydrocephalus on scan may not
      require a shunt operation. Surgical intervention should be early after entire
      neural axis screening by MRI.

PMID- 12601240
TI  - Transient Anton's syndrome: a presenting feature of acute epidural hematoma at
      the confluens sinuum.
AB  - Although unilateral epidural hematomas are well known, bilateral presentation,
      especially at the confluens sinuum, is uncommon, and its diagnosis may be
      delayed, thus causing morbidity. We report a case of acute posttraumatic cortical
      blindness due to epidural hematoma at the confluens sinuum caused by venous sinus
      tearing. The epidural hematoma was evacuated and the dural tear was repaired. The
      patient remained alert throughout the hospitalization. Examination of the visual
      field revealed recovery postoperatively, and the patient was discharged. We
      discuss the pathological mechanisms of transient blindness. The importance of
      anopsia as an early sign of epidural hematoma is emphasized.

PMID- 12601241
TI  - Sphenoid encephalocele without hypothalamic-pituitary and optic nerve
      dysfunction.

PMID- 12601242
TI  - Clear cell meningioma in a 22-month-old male: update after five years.

PMID- 12601243
TI  - Shunt dependency in shunted arachnoid cyst: a reason to avoid shunting.

PMID- 12601244
TI  - Spina bifida, somitic count and carnegie stage twelve.

PMID- 12601245
TI  - Detection of a processed pseudogene of the human MBL-associated serine protease,
      MASP1.
AB  - Southern hybridization analysis of the MASP1 gene using an intron-specific probe
      detected a single band. An exon-specific probe detected several bands. PCR of
      genomic DNA using several exon-specific primer sets of MASP1 produced short and
      long products. Sequence of the shorter products corresponded to the processed
      pseudogene of MASP1. By fluorescence in situ hybridization, this pseudogene
      (MASP1P1) was mapped to 1p34.

PMID- 12601246
TI  - Assignment of the porcine MAM domain containing glycosylphosphatidylinositol
      anchor 1 (MDGA1) gene on chromosome 7q11-->13 by in situ hybridisation and
      somatic hybrid panel mapping.

PMID- 12601247
TI  - Assignment of neuronal pentraxin I (NPTX1) gene to porcine chromosome 12pter by
      somatic cell and radiation hybrid panel mapping.

PMID- 12601256
TI  - Effects of direct hemoperfusion with a beta2-microglobulin adsorption column on
      hypercytokinemia in rats.
AB  - BACKGROUND/AIM: Blood purification therapies have been clinically applied to
      treat the cytokine-induced pathological responses. The effects of direct
      hemoperfusion(DHP) with a beta(2)-microglobulin (BMG) adsorption column on
      hypercytokinemia were investigated. METHODS: A hypercytokinemia model was
      prepared by injecting lipopolysaccharide (LPS) into femoral veins of male Wistar
      rats weighing 250-400 g. The hypercytokinemic rats were connected to the DHP
      system using a small BMG adsorption column, and time course changes in plasma
      levels of inflammatory cytokines were then examined. RESULTS: Plasma levels of
      interleukins (IL) 1beta and 6 and tumor necrosis factor alpha (TNF-alpha) were
      found to be significantly elevated within 3 h after LPS injection in the control
      group that underwent extracorporeal circulation without the BMG adsorption
      column, whereas the increases in plasma levels of IL-6 and TNF-alpha were
      significantly inhibited in the group that was treated with the BMG adsorption
      column. The adsorption rates of cytokines with the BMG adsorption column were 20
      40% for IL-1beta and IL-6 and 10-85% for TNF-alpha during treatment for 3 h.
      CONCLUSIONS: These results suggest that the systemic inflammatory response
      syndrome with hypercytokinemia might be treated with DHP using the BMG adsorption
      column.

PMID- 12601257
TI  - Does continuous venovenous hemodiafiltration concomitant with radiological
      procedures provide a significant and safe removal of the iodinated contrast
      ioversol?
AB  - BACKGROUND: The purpose of our study was to investigate whether continuous
      venovenous hemodiafiltration (CVVHDF) concomitant with radiological procedures
      (RxP) was feasible, well tolerated and could significantly remove iodinated
      contrast media (CM). METHODS: 26 patients with various degrees of renal
      insufficiency who were submitted to RxP were included in the study. The CVVHDF
      session was started immediately before CM administration. All the patients were
      evaluated for feasibility and tolerability; furthermore a pharmacokinetic study
      was done on 12 patients to calculate the amount of CM eliminated. The baseline
      incidence of CM nephropathy was studied in 25 consecutive historical controls.
      RESULTS: The CM administered was 208 +/- 146 g; the fractional removal of CM was
      9.2 +/- 4.9% during RxP and 30.9 +/- 20.7% during the whole CVVHDF session.
      Hemodynamic tolerance was excellent. The incidence of CM nephropathy in the
      experimental and control groups was 37 and 24%, respectively. CONCLUSIONS: CVVHDF
      during RxP is feasible and well tolerated but ioversol removal is modest. This
      fact together with the high incidence of renal function impairment, the
      complexity of the procedure and its intrinsic risks, and the large amount of
      resources needed discourage the routine use of CVVHDF as a prophylactic tool to
      avoid CM nephropathy.

PMID- 12601258
TI  - Patients on chronic hemodialysis have no intrinsic lymphocyte defect upon
      stimulation with interleukin-2, interleukin-15 or tumor necrosis factor-alpha.
AB  - BACKGROUND: Patients on chronic hemodialysis (HD) suffer from general immune
      incompetence, resulting in a high incidence of infectious complications, impaired
      response to vaccinations and a high incidence of malignancy. Although various
      abnormalities in T cell function of HD patients have been described, it remains
      unclear whether this is due to an intrinsic T cell defect. AIM: In the present
      study we tested the capacity of T cells to proliferate upon stimulation with
      antigen-presenting cell and T-cell-derived cytokines. METHODS: The proliferation
      capacity of lymphocytes obtained from patients on HD and healthy controls was
      determined by measuring the proliferation of peripheral blood mononuclear cells
      (PBMC) after stimulation with rhIL-2, rhIL-15, rhTNF-alpha, or combination of
      those cytokines. In all samples the percentage of alpha/beta TCR-positive T cells
      was measured. RESULTS: After isolation of PBMC the percentage of T cells varied
      from 70% (before stimulation) to 80% (after stimulation). IL-2, IL-15 and TNF
      alpha all induced PBMC proliferation, while the combination TNF-alpha plus IL-2
      or TNF-alpha plus IL-15 appeared to be additive. No difference between PBMC from
      HD patients and controls was found. CONCLUSION: We conclude that lymphocytes from
      HD patients have no intrinsic defects in their proliferation capacity after
      stimulation with IL-2, IL-15 or TNF-alpha, in vitro, as the increase in counts
      per minute is predominant.

PMID- 12601259
TI  - Determinants of left ventricular hypertrophy and its progression in high-flux
      haemodialysis.
AB  - AIM: To identify factors contributing to the development and progression of left
      ventricular hypertrophy (LVH) in patients on high-flux haemodialysis. METHOD:
      Fifty patients without clinical cardiac disease underwent baseline
      echocardiography, related measurements and follow-up studies 6-12 months later.
      RESULTS: Residual urea clearance was lower (0.7 +/- 1.1 vs. 2.2 +/- 2.4 ml/min; p
      = 0.034) while systolic blood pressure (162 +/- 21 vs. 147 +/- 11 mm Hg; p =
      0.003), duration of dialysis dependence (38 +/- 37 vs. 17 +/- 13 months; p =
      0.004) and interdialytic weight gain (1.98 + 0.84 vs. 1.32 + 1.08 kg; p = 0.026)
      were higher in those with LVH. Parathyroid hormone changed less in those whose
      LVH regressed (186 +/- 89 vs. 303 +/- 280 pg/ml; p = 0.032). Regression did not
      occur when parathyroid hormone was >300 pg/ml. ACE gene polymorphism did not
      affect LVH development or progression. CONCLUSION: Systolic hypertension,
      duration of dialysis dependence and high interdialytic weight gains promote LVH.
      Hyperparathyroidism retards LVH regression.

PMID- 12601260
TI  - End-stage renal failure patients requiring renal replacement therapy in the
      intensive care unit: incidence, clinical features, and outcome.
AB  - AIMS: To study incidence, clinical features, and outcome of critically ill
      patients with end-stage renal failure (ESRF) requiring renal replacement therapy
      (RRT) in the intensive care unit (ICU) and to test the validity of severity
      scoring systems for these patients. METHODS: Data for ESRF patients treated with
      RRT were collected from 81 Australian adult ICUs providing RRT. They were
      compared with matched controls with acute renal failure. RESULTS: Thirty-eight
      ESRF patients received RRT in the ICU over 3 months. The mean APACHE II score was
      21.8 (predicted mortality: 37%) and the SAPS II score 44.7 (predicted mortality:
      37%). The hospital mortality was 34%. Receiver operating characteristic curves
      showed good discrimination ability for hospital mortality for these two scores
      (AUC: 0.81 for APACHE II and 0.84 for SAPS II). Using admission diagnosis and
      SAPS II scores, 32 ESRF patients treated with continuous RRT (CRRT) were matched
      to 32 acute renal failure patients also treated with CRRT. ICU mortality (22 vs.
      38%) and hospital mortality (38 vs. 38%) were comparable between the two groups.
      CONCLUSIONS: ESRF patients requiring RRT in the ICU were relatively frequent.
      Severity scores could be used to predict the hospital outcome for these patients.
      Their mortality, when treated with CRRT, was similar to that of diagnosis- and
      severity-score-matched patients with acute renal failure.

PMID- 12601261
TI  - Comparison of the effects of cellulose triacetate and polysulfone membrane on
      GPIIb/IIIa and platelet activation.
AB  - BACKGROUND: During hemodialysis session, several adverse reactions can occur on
      platelets, which are attributable to bioincompatibility of the dialysis membrane.
      Glycoprotein IIb/IIIa (GPIIb/IIIa) is the receptor for fibrinogen, which mediates
      platelet aggregation and adhesion. Accordingly, we compared the influence of a
      cellulose triacetate (CTA) and polysulfone (PS) membrane on GPIIb/IIIa and
      platelet activation. METHODS: Blood samples from 5 patients on hemodialysis were
      taken at 0 time, 15 min, 30 min, 60 min and 240 min, during a single hemodialysis
      session, by a crossover design using CTA or PS. Platelet count and plasma
      concentration of GPIIb/IIIa, beta-thromboglobulin (beta-TG) and platelet factor 4
      (PF-4) were measured. GPIIb/IIIa was measured by flow cytometry. beta-TG and PF-4
      were measured by ELISA. RESULTS: There was no significant change in the total
      amount of GPIIb/IIIa during dialysis session between the CTA and PS. However, the
      level of bound GPIIb/IIIa was significantly (p < 0.0002) increased from 1,426 +/-
      435 to 40,446 +/- 2,777 mol/PLT with PS. In contrast, there was no significant
      change with CTA (3,258 +/- 1,469 to 4,301 +/- 1,422 mol/PLT). The platelet counts
      and beta-TG and PF-4 behavior during the dialysis session did not show
      significant change between the PS and CTA. CONCLUSION: The characterization of
      changes in platelet membrane receptor (GPIIb/IIIa) may be a useful marker for
      studying the biocompatibility of dialysis membranes. On platelet aggregation, CTA
      might be more biocompatible membrane than PS.

PMID- 12601263
TI  - "The pieces fall into place": the views of three Swedish habilitation teams on
      conductive education and support of disabled children.
AB  - A survey concerning how Swedish habilitation staff view the support of disabled
      children and their families was conducted in 2001. It focused on what support the
      staff knew about, offered and considered good for the children and parents, and
      on how they viewed conductive education. Interviews were conducted with 25 team
      members in three habilitation teams in the south of Sweden. The results show that
      the support habilitation staff most feel children need is the opportunity to
      investigate their surroundings, play with other children, meet other children in
      the same situation and try out different activities. The support that parents are
      felt to need is mainly aid and housing adaptation, relief, financial help,
      information, medical knowledge, emotional support and to meet others in the same
      situation. The staff gave information pertaining to different methods of
      treatment only if the parents specifically asked for it. What the habilitation
      teams recommended were contracture prophylaxis, motor skills exercises, riding,
      swimming, splints, standing shells, surgery, injections and medicines. The
      habilitation staff were of the opinion that conductive education is focused
      purely on intensive mobility training.

PMID- 12601262
TI  - The Demand-Control-Support model as a predictor of return to work.
AB  - The present study investigated work-related determinants of return to work. Our
      hypothesis was based on the strain hypothesis of the Demand-Control-Support
      model, which postulates a relation between job demands, job control and support
      at work on the one hand, and the aetiology of health complaints on the other
      hand. High demands were hypothesized to obstruct return to work, whereas high
      control and high support were thought to have a positive effect on return to
      work. This hypothesis was tested in a population of employees who were sick
      listed for 6-8 weeks. Return to work, as operationalized by the categories (i)
      not working; (ii) return to work with adjustments; and (iii) full return to work,
      was determined 4 months after the onset of the sick leave. The hypothesis was
      tested by logistic regression analyses. High job demands were the least
      predictive of full return to work. However, the likelihood of employees with high
      job demands returning to work with adjustments was higher than the likelihood of
      them not working. Therefore, job demands might also work as a pressure to return
      to work (compare this with Smulders and Nijhuis, 1999). Furthermore, high skill
      discretion in combination with high job demands predicted working with
      adjustments in comparison with not working. Finally, high supervisor support was
      the most predictive of return to work without adjustments, and the least
      predictive of not working.

PMID- 12601264
TI  - Struggling for inclusive education in the North and the South: educators'
      perceptions on inclusive education in Finland and Zambia.
AB  - A survey assessed the perceptions of 1350 Zambian teachers and parents and 512
      Finnish teachers regarding inclusive education and consequently the best
      placement for children with different disabilities. On the whole, perceptions
      varied but were quite critical. On inclusion in general, the regular (also termed
      "ordinary") Finnish teachers were the most critical group and the Finnish special
      education teachers the most optimistic. Most respondents felt that inclusive
      education enhances social justice. However, the pursuit of inclusion in practice,
      especially the guarantee of good and effective education for all, was seen as
      problematic. Compared with Finnish respondents, the Zambian respondents preferred
      a more segregated educational environment for children with different
      disabilities. Type and severity of disability affected the preferred educational
      setting and there were clear differences in this regard between the respondents
      from the two countries. The findings support the idea that educators' attitudes
      towards inclusion are important in developing inclusive school systems and that
      inclusive education is best understood as a multidimensional concept that, at the
      practical level, is highly context-dependent.

PMID- 12601265
TI  - Beliefs about feeding practices and nutrition for children with disabilities
      among families in Dharavi, Mumbai.
AB  - Attitudes arise from specific experiences and emotions driven by cultural
      beliefs. An understanding of societal constructs regarding disability in a given
      culture contributes to developing strategies to meet the needs of children with
      disabilities by providing culturally competent services. In 1999, a series of
      focus-group discussions were conducted with families in a low-income community in
      Mumbai, India to collect qualitative information on the knowledge, skills and
      attitudes (KSA) regarding disability, feeding and nutrition to facilitate the
      development of an intervention to improve the nutritional well-being of children
      with disabilities. The KSA of this population of poor families has seldom been
      directly examined. The specific objectives of this study were (i) to describe the
      experiences of families with young disabled children in the local community; (ii)
      to identify the nutritional and feeding needs of children with disabilities; and
      (iii) to identify any service, environmental or attitudinal barriers to acquiring
      an adequate nutritional status. Content analysis of concepts in the focus groups
      identified four emerging themes: (i) acceptance of disability; (ii) services and
      needs; (iii) future; and (iv) food and nutrition. The focus-group findings
      enabled a broader understanding of attitudes towards disability within this
      population, which can have an impact on the care of the child. The findings
      provided insights into the content of the intervention to be helpful for local
      families incorporating an understanding of the cultural background of the local
      community that must be included alongside our understanding of the feeding
      impairment.

PMID- 12601266
TI  - Health-related quality of life of stroke patients' families during the patients'
      hospitalization: a pilot study in Japan.

PMID- 12601267
TI  - Eccentric exercise training in patients with chronic obstructive pulmonary
      disease.
AB  - The oxygen cost of eccentric exercise is lower than that of concentric exercise
      at similar work-loads. In this study, the response to eccentric cycle exercise
      training (EET) in addition to general exercise training (GET) on exercise
      performance and quality of life was investigated in 24 patients with severe
      chronic obstructive pulmonary disease (COPD). All patients had a normal resting
      PaO2 and an arterial oxygen saturation (SaO2) below 90% at Wmax, achieved during
      a maximal incremental concentric cycle exercise test. The patients participated
      in a comprehensive inpatient pulmonary rehabilitation programme of 10 weeks. They
      were randomly assigned either to GET (GET group: mean FEV 38% predicted) or to
      GET and additional EET (GET/EET group: FEV1 45% predicted). During EET, the
      patients were able to cycle eccentrically for 15 min continuously at a mean of
      160 (69%) of Wmax whereas the Borg dyspnoea score did not exceed 3.0 and SaO2 did
      not fall below 90%. Parameters of cardiocirculatory fitness and gas exchange
      improved in the GET/EET group but no further improvement in exercise capacity
      occurred compared to GET. It is concluded that eccentric cycle exercise is a safe
      and attractive training modality for patients with severe COPD and can be
      performed at a high intensity without the patient becoming out of breath or
      needing supplemental oxygen.

PMID- 12601268
TI  - Return to work after lower limb amputation.
AB  - This study investigated the proportion of patients who returned to work following
      amputation and the factors that influenced a positive or negative outcome. One
      hundred patients of working age who had sustained unilateral lower limb
      amputation at least 1 year previously and who were established prosthesis users
      participated in the study. A specially designed questionnaire similar to a guided
      interview was administered by the rehabilitation physician at the patients'
      routine follow-ups. The questionnaire yielded a unique score dependent on whether
      return to work (or a different or preferred occupation) had been achieved with
      good or reduced productivity. All patients were eligible for mobility benefit,
      including schemes to purchase suitably adapted vehicles if necessary. However, no
      vocational rehabilitation was available. Sixty-six per cent of patients returned
      to employment and this was related to mobility, time since amputation and
      Handicap Scale scores. Age, socket comfort, level and cause of amputation, type
      of previous work or the presence of other medical problems did not differ between
      those who did and did not return to work. The Employment Questionnaire showed
      good correspondence with the London Handicap Scale, indicating some concurrent
      validity, although future development might include consideration of
      psychological factors, which could explain more of the reasons for continued
      unemployment.

PMID- 12601269
TI  - Use of an Innsbruck sensorimotor activator and regulator (ISMAR) in the treatment
      of oral motor dysfunctions: a single case report.
AB  - Many patients with cerebral palsy have difficulties during the oral preparatory
      phase and also during the food transport phase (swallowing), and oral
      sensorimotor therapy is practised with these individuals. With oral-sensorimotor
      therapies, the functioning of the lips, cheeks, tongue and pharyngeal structures,
      and the interplay between these structures, can be improved. An Innsbruck
      sensorimotor activator and regulator (ISMAR) is one of the appliances used for
      oral-motor therapy. The purpose of this study is to describe the appliance and
      report a patient using ISMAR.

PMID- 12601270
TI  - Parental attitudes towards offspring's return home after psychiatric
      hospitalization.

PMID- 12601271
TI  - Gender difference in self-esteem of Hong Kong Chinese with cardiac diseases.
AB  - Self-esteem is an indicator of a person's subjective quality of life due to its
      close relationship to a person's behavioural competence, positive self
      experience, and sense of self-actualization. The present study aimed to
      investigate the basis of self-esteem in people with cardiac diseases, according
      to gender, after their cardiac surgery. The findings showed that there were
      prominent gender differences in the subjects' self-esteem. Women (aged<60) showed
      statistically significant higher ratings in the importance of 11 life events
      importance and the satisfaction of three life events than men. The study also
      found cultural uniqueness: Hong Kong Chinese (both men and women) with cardiac
      diseases generally indicated that social (interpersonal) self-concept dimensions
      were more important than achievement (personal) self-concept dimensions in their
      life perception. These findings are noteworthy for setting optimum goals of
      rehabilitation apart from return to work.

PMID- 12601272
TI  - Documentation of prestroke ambulation.

PMID- 12601273
TI  - Factors that influence the use of rehabilitation services in an urban Ugandan
      hospital.
AB  - The aim of the present study was to determine factors that motivate or deter
      injured individuals from using outpatient rehabilitation services at an urban
      Ugandan hospital. A qualitative study design was employed to obtain information
      about injured individuals' experiences with rehabilitation therapy services after
      they were discharged from a hospital setting. Key informant interviews were
      conducted with 13 Ugandan individuals who were currently attending an outpatient
      physiotherapy clinic at Mulago Hospital in the city of Kampala. Nine
      rehabilitation therapists from Mulago Hospital were interviewed in a focus-group
      format to identify factors that prevent individuals from attending therapy. Study
      participants identified a number of fears and misconceptions about the
      rehabilitation services being offered. Many individuals reported the cost and
      availability of transport as a major barrier. Interview respondents believed that
      by attending physiotherapy they were rejecting the use of a local healer and were
      benefiting from medically trained experts. Rehabilitation therapists reported
      responses similar to interview respondents. Individuals who are currently
      accessing rehabilitation services at Mulago Hospital are motivated and committed
      to their recovery process. These individuals reported a number of improvements
      since starting therapy. However, more research is required to better understand
      how local methods of healing influence health-seeking behaviours.

PMID- 12601275
TI  - Nonmyeloablative alternative donor transplants.
AB  - The advent of nonmyeloablative preparative regimens and the expected lower
      regimen-related toxicities associated with them hold significant promise for
      extension of the use of allogeneic hematopoietic stem cell transplantation.
      Nonmyeloablative hematopoietic stem cell transplantation using human leukocyte
      antigen matched sibling donor, which carries a relatively low risk of transplant
      related complications and can result in impressive antitumor responses, may
      benefit older patients and patients with preexisting organ impairment. However,
      more than 65% of patients in need of this procedure lack a human leukocyte
      antigen matched sibling donor. Therefore, attention has focused on alternative
      donors such as genotypically matched unrelated donors and partially mismatched
      related donors. Early clinical results suggest that the use of alternative donors
      is feasible, therefore potentially allowing full extension of the benefits of
      allografting to the group of patients in highest need.

PMID- 12601276
TI  - Predictive and prognostic factors in malignant pleural mesothelioma.
AB  - Predictive and prognostic factors are of great importance in patients with
      malignant pleural mesothelioma. In the following article, the recent knowledge
      about these factors is presented in order to determine the patients who may
      benefit most from current experimental therapies.

PMID- 12601277
TI  - The role of new imaging techniques in diagnosis and staging of malignant pleural
      mesothelioma.
AB  - This review highlights the different imaging modalities for the detection of
      malignant pleural mesothelioma. The chest film is the initial diagnostic tool of
      choice because it is easy to perform, inexpensive, and widely available.
      Unfortunately, it demonstrates malignant pleural mesothelioma in later stages of
      disease and is not suitable for an early sensitive and specific diagnosis.
      Computed tomography is capable of distinguishing the different forms of pleural
      abnormalities. The knowledge of computed tomography findings is important for
      differentiation of malignant pleural diseases from benign diseases. Contrast
      enhanced magnetic resonance imaging in three planes can be clinically useful to
      differentiate pleural mesothelioma from other malignancies or from benign pleural
      diseases. Furthermore, magnetic resonance imaging offers the possibility to
      differentiate invasion of the diaphragm from transdiaphragmatic tumor growth,
      and, in patients who are surgical candidates and who have questionable areas of
      local tumor extension on computed tomography, magnetic resonance imaging may
      provide additional information to plan or avoid surgery. Improvements in the
      detection of regional and distant metastases are needed to identify patients most
      likely to benefit from aggressive combined modality treatment regimes. In this
      context, positron emission tomography is a metabolic imaging technique that
      offers the possibility to evaluate active malignant cells. Drawbacks to this
      technique include false-positive findings, which may occur at sides of
      inflammation, and lesser anatomic detail information. A complete and accurate
      staging of malignant pleural mesothelioma is essential to evaluate the efficacy
      of new therapeutic strategies. This implies the need to be familiar with the most
      recently developed staging system from the International Mesothelioma Interest
      Group.

PMID- 12601279
TI  - Indications and limitations of radiotherapy in malignant pleural mesothelioma.
AB  - In patients with malignant pleural mesothelioma, radiotherapy is useful in the
      palliation of symptoms of chest pain and painful masses. Prophylactic chest wall
      irradiation appears to reduce the incidence of chest wall recurrences at incision
      sites. An area of active ongoing research is the role of high-dose hemithorax
      irradiation after extrapleural pneumonectomy for early stage disease. In
      carefully staged patients, this approach has resulted in a marked reduction in
      local tumor recurrences, although nearly one half of patients subsequently
      developed isolated distant metastases. Relevant issues for planning postoperative
      radiotherapy in such patients are highlighted. These multimodality protocols
      await evaluation within prospective randomized clinical trials, and effective
      systemic chemotherapy regimens will also need to be integrated into such
      approaches.

PMID- 12601278
TI  - The role of surgery in diagnosis and treatment of malignant pleural mesothelioma.
AB  - The role of surgery in the management of mesothelioma has largely been confined
      to obtaining a tissue diagnosis or to effect symptom control by pleurodesis.
      Noninvasive, image-guided methods of obtaining pleural tissue are reducing the
      need for surgical biopsy, and increased use of thoracoscopy under sedation by
      pulmonologist is also reducing surgical involvement. However, the increasing
      incidence of the disease together with reports of long-term survivors has
      resulted in a more aggressive surgical approach toward therapy. Surgical
      debulking may have a role in symptom control beyond that of pleurodesis. Radical
      surgery, with the aim of macroscopic clearance of the tumor, may not be of
      prognostic benefit alone but, as part of a multimodality treatment regime, may
      result in long-term survivors. Adjuvant treatments with chemotherapy and
      radiotherapy appear to prolong survival, whereas photodynamic therapy may be
      detrimental. Selection criteria for radical treatment need to be refined and a
      radical multimodality protocol must be subjected to a randomized, controlled
      evaluation.

PMID- 12601280
TI  - Chemotherapy for malignant pleural mesothelioma.
AB  - This paper covers the outcome of previously conducted clinical trials on
      chemotherapy for malignant pleural mesothelioma and presents data from recent
      phase II and phase III trials. In contrast to conventional cytotoxic drugs, which
      have barely produced response rates exceeding 30%, recently introduced
      chemotherapeutic agents and their combinations promise to be more effective.
      Especially pemetrexed has yielded response rates of up to 45% in combination with
      platinum compounds. Furthermore, raltitrexed-oxaliplatin has shown promising
      activity and gemcitabine was found to improve quality of life in patients with
      malignant pleural mesothelioma when applied as a single agent or in combination
      with cisplatin. Based on robust phase III study results, pemetrexed-cisplatin may
      soon be considered with chemotherapy for this aggressive disease.

PMID- 12601281
TI  - Is there a role for genetic testing in patients with melanoma?
AB  - Autosomal dominant inheritance of mutations in the locus or the gene may confer a
      high risk of cutaneous melanoma development. The penetrance of mutations is
      influenced by UV exposure. Inherited variants in the melanocortin-1 receptor also
      confer increased risk of cutaneous melanoma. Features associated with increased
      genetic susceptibility to cutaneous melanoma include the presence of multiple
      affected first-degree relatives on one side of the family, multiple primary
      melanomas in the same individual, earlier age of onset, and the presence of
      multiple atypical nevi, but none of these factors reliably predicts for the
      presence of mutations. It is currently premature to offer predictive DNA testing
      for melanoma outside of defined research protocols. This is because of (1). the
      low likelihood of finding mutations in known melanoma susceptibility genes, even
      in more than 60% of melanoma-prone kindreds; (2). the broad confidence limits on
      current estimates of lifetime penetrance of mutations and the wide variation in
      this penetrance with locality; (3). a high "background" incidence of melanoma in
      non-mutation carriers in melanoma-prone families; (4). current uncertainties
      about the factors determining the functionality and phenotypic expression of the
      trait among carriers of these mutations (penetrance), even if found; and (5). the
      lack of proved efficacy of melanoma prevention and surveillance strategies, even
      for mutation carriers. Rather than singling out those deemed to be at high risk
      because of family history, all patients carrying risk factors for cutaneous
      melanoma should be subject to stringent programs of sun protection and skin
      surveillance.

PMID- 12601282
TI  - Dopamine-induced protection against indomethacin-evoked intestinal lesions in
      rats--role of anti-intestinal motility mediated by D2 receptors.
AB  - BACKGROUND: Although it is known that dopamine prevents various gastrointestinal
      lesions, the underlying mechanism remains unclear. In the present study, we
      examined the protective effect of dopamine on indomethacin-induced small
      intestinal lesions, in relation to intestinal hypermotility. MATERIAL/METHODS:
      Male SD rats received indomethacin (10 mg/kg) subcutaneously (s.c.), and the
      small intestine was examined for lesions 24 hr later. Dopamine (1-10 mg/kg) or
      atropine (3 mg/kg) was administered s.c. twice, 30 min before and 8 hr after
      indomethacin, while sulpiride (3 mg/kg) and domperidone (3 mg/kg), the dopamine
      D2 receptor antagonists, or yohimbine (10 mg/kg), the alpha2-adrenoceptor
      antagonist, were administered s.c. twice, 30 min before each dosing of dopamine.
      Intestinal motility was measured using a balloon under urethane anesthesia.
      RESULTS: Indomethacin caused severe lesions in the small intestine, mainly both
      the jejunum and ileum. The intestinal ulcerogenic response to indomethacin was
      dose-dependently prevented by dopamine as well as atropine. The protective effect
      of dopamine was almost totally antagonized by domperidone and sulpiride but not
      by yohimbine. On the other hand, indomethacin markedly enhanced intestinal
      motility, and the hypermotility response was also prevented by dopamine as well
      as atropine. Both sulpiride and domperidone, but not yohimbine, also antagonized
      the inhibitory effect of dopamine on the indomethacin-induced intestinal
      hypermotility. CONCLUSIONS: These results suggest that dopamine protects the
      small intestine against indomethacin-induced damage, probably by inhibiting the
      intestinal hypermotility mediated by dopamine D2 receptors.

PMID- 12601283
TI  - Adenoviral-mediated skeletal muscle transcriptional targeting using chimeric
      tissue-specific promoters.
AB  - BACKGROUND: Adenoviral vectors are promising tools to achieve skeletal muscle
      gene transfer for the treatment of peripheral ischemia. However, the use of
      ubiquitous viral promoters represents a major safety issue that could limit their
      use. Cellular regulatory sequences that allow strong and tissue-specific
      expression could circumvent this problem. MATERIAL/METHODS: Adenoviral vectors
      encoding the firefly luciferase under the control of the human skeletal a-actin
      promoter, alone or combined with the b-enolase or creatine kinase enhancer, were
      studied in vitro in murine C2C12 cells and in vivo in C57BL/6 mice. The
      expression of the reporter gene was measured in cell lysates and animal tissue
      homogenates. Adenoviral distribution was evaluated by PCR on DNA extracted from
      liver, spleen, heart and lungs. RESULTS: Skeletal a-actin promoter-based
      expression cassettes follow the regulation of the endogenous skeletal a-actin
      gene in vitro as luciferase expression strongly increases with myoblast
      differentiation into myotubes. The addition of the cellular b enolase or the
      creatine kinase enhancer improves the specificity of the skeletal a-actin
      promoter in vitro as well as in vivo. When adenoviral vectors are locally
      injected into skeletal muscles, the chimeric promoters drive a relatively strong
      gene expression, ranging from 16 to 28% of the Rous sarcoma virus promoter
      related expression. CONCLUSIONS: Chimeric regulatory sequences based on the
      skeletal a-actin promoter are highly specific and allow transgene expression in
      vivo at high levels. These results indicate that expression cassettes designed
      for the treatment of peripheral ischemia by gene therapy can efficiently target
      gene expression to skeletal muscle.

PMID- 12601284
TI  - The mechanisms of brush border Na+/H+ exchanger activation by corticosteroids.
AB  - BACKGROUND: Previously we showed that corticosterone and aldosterone increased
      proton fluxes in proximal tubule, by micropuncture and stationary microperfusion.
      Since the Na+/H+ exchanger is responsible for the main proximal proton secretion,
      we have now evaluated the effects aldosterone on Na+/H+ exchange activity in
      brush border vesicles. In order to evaluate the mechanism of action of
      glucocorticoids and mineralocorticoids, we studied the comparative effects of
      corticosterone and aldosterone on the abundance of NHE3 and NHE2 isoforms.
      MATERIAL/METHODS: We isolated renal brush border vesicles from rats by
      differential centrifugation in sham-operated, adrenalectomized, and
      adrenalectomized-aldosterone treated (ADX + aldosterone) animals. We measured the
      kinetics of H+ transport in response to increasing concentrations of Sodium
      Gluconate by fluorimetry using acridine orange. For Na+/H+ exchanger abundance we
      used Western blot analysis of brush border proteins in the above groups and in
      adrenalectomized-corticosterone treated rats. RESULTS: The Vmax in
      adrenalectomized animals was 22,162+/-1828 fluorescence units/min; in sham
      animals, 37,020+/-2722; and in ADX + aldosterone, 42,344+/-3044 (p<0.01
      adrenalectomized vs others). No differences in Km were observed. Adrenalectomy
      decreased NHE3 abundance over Sham by 32% without modifying NHE2. Corticosterone
      replacement enhanced NHE3 abundance by 76% and failed to increase NHE2.
      Aldosterone enhanced NHE2 abundance by 75% and did not increase NHE3.
      CONCLUSIONS: Mineralocorticoids enhance Na+/H+ exchange activity by increasing
      NHE2 abundance; glucocorticoids, by increasing NHE3 abundance.

PMID- 12601285
TI  - Colloid osmotic pressure (COP) can be a good indicator of occurrence of vasospasm
      following subarachnoid hemorrhage (SAH).
AB  - BACKGROUND: The aim of this study was to evaluate the value of measurement of
      colloid osmotic pressure (COP) directly concerned with cerebral vasospasm
      following subarachnoid hemorrhage (SAH). MATERIAL/METHODS: The subjects were 20
      patients who received clipping operation within 48 hours after onset. We
      conducted a two weeks monitoring of COP measured directly by osmometer and
      evaluated serum concentrations of albumin at the same time. We divided the
      patients into Group A (angiographical vasospasm +) and Group B (spasm -)
      according to the angiographical findings. The differences of the data between the
      groups were analyzed by ANOVA test (p<0.05). Furthermore, the correlations
      between the serum concentrations of albumin and COP levels were estimated.
      RESULTS: Vasospasm was angiographically confirmed in 10 of the 20 patients.
      Significant decrease of COP levels was observed from day 7 until day 11 and
      significant decrease of albumin was observed on day 6 and from day 8 until day 11
      in the Group A. We did not observe any significant change of COP and albumin
      levels in the Group B. A liner analysis was performed and a significant
      correlation was determined between the COP levels and albumin in the Group A, but
      we did not observe significant correlation between them in the Group B.
      CONCLUSIONS: These results showed that a significant decrease of COP levels
      indicate the occurrence of cerebral vasospasm. We concluded that COP measurement
      could be a useful monitor of the occurrence of vasospasm following SAH.

PMID- 12601286
TI  - Prediction of native coronary artery disease progression following PTCA or CABG
      in the Emory Angioplasty Versus Surgery Trial.
AB  - BACKGROUND: The natural history of atherosclerosis progression following
      revascularization procedures (PTCA or CABG) limits the long-term benefits of
      these procedures and requires continuation of risk management. MATERIAL/METHODS:
      Of 392 patients with multivessel disease randomized to an initial strategy of
      PTCA or CABG in the Emory Angioplasty Versus Surgery Trial (EAST), 298 patients
      (152 PTCA and 146 CABG) completed 3-year angiographic follow-up. Native coronary
      artery disease progression was defined as lesions with <50% diameter stenosis
      (%S) at baseline, measured by QCA, that increased at least 10%S to become
      >or=50%S during the 3-year follow-up. Major ischemic events (new Q-wave
      myocardial infarction, a large reversible thallium defect or additional
      revascularization procedures) attributed to these new lesions were determined
      based on the ECG ischemic changes and/or the details of the coronary anatomy.
      RESULTS: Of 298 patients, 53 (18%) (15% of PTCA and 21% of CABG) developed at
      least one significant new native coronary artery lesion. Of 136 patients with
      events, 19 (14%) had such events due to progression. In multivariate analysis,
      native coronary disease progression was independently correlated with
      hypertension (OR=2.4, p=0.03), ST segment depression =1mm on baseline ETT
      (OR=2.7, p=0.01), and percent of small LDL particles (LDL IIIa-IVb) (OR=1.2 for
      every 5% increase, p=0.01). CONCLUSIONS: In EAST, the native CAD progression
      accounted for one in seven major ischemic episodes over a 3-year follow-up.
      Patients with metabolic atherogenic risk profiles were more likely to have
      disease progression. These findings indicate the importance of more aggressive
      risk factor modification following revascularization.

PMID- 12601287
TI  - Regression of left ventricular hypertrophy after aortic valve replacement in
      patients over 55 years old with different valve types.
AB  - BACKGROUND: We planned a prospective study to evaluate the regression of left
      ventricular mass one year after surgery in older patients (<or=55 years) who have
      undergone aortic valve replacement with stentless bioprostheses or mechanical
      valve. MATERIAL/METHODS: Between 1998 and 2000, 54 patients had aortic valve
      replacement with stentless bioprostheses (14 CryoLife-O'Brien, 40 Medtronic
      Freestyle), and 62 patients had aortic valve replacement with St. Jude Medical
      mechanical valve. In preoperative echocardiographic evaluation, the St. Jude
      group had the highest left ventricular mass (LVM). The difference between groups
      was significant (O'Brien group: 329+/-75 g, Medtronic group: 382+/-116 g, St.
      Jude group: 445+/-138 g, p=0.006). The same level of statistical significance was
      achieved when LVM indexes were compared (LVMI; 192+/-39 g/m2, 217+/-65 g/m2,
      255+/-78 g/m2, respectively, p=0.008). All the surviving patients were evaluated
      echocardiographically one year after surgery. RESULTS: Regression of LVM occurred
      in all patients after aortic valve replacement: 26% in the O'Brien group, 37% in
      the Medtronic group and 32% in the St. Jude group. The difference between the
      groups was not significant. LVM and LVMI's were significantly lower when compared
      with preoperative values, but the degree of regression was not different between
      groups one year after surgery. CONCLUSIONS: Regression of left ventricular mass
      after aortic valve replacement is directly related to the preoperative
      ventricular mass and independent of the valve type in older patients. The choice
      of prosthesis should be based on patient characteristics.

PMID- 12601288
TI  - Early hemodynamic changes after renal transplantation: determinants of low
      central venous pressure in the recipients and correlation with acute renal
      dysfunction.
AB  - BACKGROUND: Transplantation of organs leads to several physiologic changes in the
      recipients who, during their anephric state on chronic hemodialysis, have
      increased total body water and several electrolyte imbalances. Several abnormal
      parameters are observed in the physiology of the renal recipient. The central
      venous pressure (CVP) in the recipient invariably declines despite vigorous fluid
      resuscitation for reasons that are not clear at the present time.
      MATERIAL/METHODS: We studied 77 kidney transplants retrospectively, in which we
      observed a significant decline in central venous pressure (CVP) in the immediate
      posttransplant period. This phenomenon occurred despite aggressive fluid
      management and positive fluid balances averaging nearly four liters. Our analysis
      included the time course of the phenomenon itself as well as a detailed
      comparison of various parameters in the recipient and the renal graft for
      possible correlation with this consistent decline in CVP. RESULTS: Neither the
      absolute CVP nor the drop in CVP appeared to influence the rate of ATN.
      Interestingly, we found that the kinetics of the decline in CVP were remarkably
      similar in recipients of both cadaveric and living-related kidneys. CONCLUSIONS:
      This finding suggests that the reperfusion injury or a related effect may be
      responsible for the clinical phenomenon presented in this study.

PMID- 12601289
TI  - Impact of Chlamydia pneumoniae infection on survival rate after heart
      transplantation.
AB  - BACKGROUND: As Chlamydia pneumoniae (Cp), a common cause of respiratory
      infection, is of vasotropic character, chronic infection may be associated with
      the development of coronary disease, although there have been few reports on the
      impact of Cp infection on the post-orthotopic heart transplantation (OHT)
      survival rate. MATERIAL/METHODS: A total of 41 patients (4 females) were followed
      up for one year after OHT. Serology investigations for IgM, IgG and IgA
      antibodies against Cp were performed using the enzyme immunoassay (EIA) method.
      Univariate and multivariate analyses were carried out with respect to IgA, IgG,
      gender and type of cardiomyopathy. The IgA-IgG joint effect was also studied.
      RESULTS: The one-year survival rate was reported for patients with IgA < 8 EIU to
      be 72.2%, whereas those with IgA >or= 8 EIU accounted for only 43.5% (Kaplan
      Meier analysis, p = 0.0548). In multivariate analysis IgA /IgG status proved to
      be a highly significant factor in survival. IgA positive outcome combined with
      IgG negative outcome showed that the relative risk of death equaled 12.08 versus
      other combinations of IgA/IgG status. In the Cox multivariate model ischemic
      cardiomyopathy showed a relative risk of 2.79 (p=0.0594), although it was not
      significant in univariate CONCLUSIONS: Chronic Cp infection, as expressed through
      a high IgA level, seems to have adverse impact on the survival rate in one-year
      follow-up after OHT. IgA titers against Cp in heart transplant recipients should
      therefore be assessed, as the high values might be a predictive risk factor
      within the first post-operative year.

PMID- 12601290
TI  - Chondrotympanoplasty: a modified technique of cartilage graft tympanoplasty.
AB  - BACKGROUND: Although the temporalis fascia has been widely used since 1957as a
      graft in tympanoplasty, it can eventually become thin and atrophic. In addition,
      due to the lack of elasticity and resistance to pressure changes in the external
      ear canal, secondary perforations may also develop. Therefore, several authors
      have suggested that temporalis fascia should be strengthened by periosteum or
      replaced by cartilage. MATERIAL/METHODS: In the present paper the term
      chondrotympanoplasty is introduced to describe modified techniques of cartilage
      graft tympanoplasty and intratympanal chondroplasties. These techniques were used
      in 76 patients who were prospectively followed up for two years post-operatively.
      RESULTS: In type I chondrotympanoplasty, the mean pre-operative air-bone gap was
      reduced from 20 dB to 8 dB at 2000 Hz. In 93% of these cases the cartilage graft
      was taken without problems and there was no perforation in the new eardrum. In
      two cases of type I chondrotympanoplasty who experienced acute post-operative
      otitis media, the cartilage graft was found to be relatively resistant to
      infection, as only a pinhole perforation was noted. Type III chondrotympanoplasty
      with endotympanic chondroplasty (intratympanal tubal chondroplasty and
      intratympanal stapes chondroplasty) was found to give good aeration in the
      cavity, an intact new eardrum, and remarkable hearing results, reducing the mean
      pre-operative air-bone gap from 25 dB to 10 dB at 2000 Hz. CONCLUSIONS: Cartilage
      was found to be an excellent graft material and the described
      chondrotympanoplasties gave very promising results. Cartilage should be used more
      widely in tympanoplasty (chondrotympanoplasty).

PMID- 12601291
TI  - Health status and socioeconomic factors as determinants of physical activity
      level in the elderly.
AB  - BACKGROUND: The aim of our study was to assess the health status and Physical
      Activity Level (PAL) of the elderly population and determine the role of health
      status and socioeconomic factors in PAL. MATERIAL/METHODS: A total of 84 subjects
      (65 men and 19 women) participated in this study. These individuals were living
      independently, and attending rehabilitation centers for the elderly in
      Thessaloniki, Greece. The mean age of the subjects was 74.4 years (SD 7.9). Data
      was collected with a special questionnaire regarding health status and PAL,
      during individual interviews. RESULTS: The mean PAL value was 1.519, SD 0.115.
      Significant positive correlation was found between PAL and educational level
      (r=0.286, p<0.05). Regarding the relation of illnesses to PAL, one-way ANOVA
      indicated that individuals under treatment for heart arrhythmia and myocardial
      infarction, as well as those who had undergone a by-pass operation, had higher
      PAL values (1.659+/-0.0649, 1.551+/-0.093 and 1.613+/-0.0978, respectively)
      compared to those not suffering from any of these disorders (1.512+/-0.112,
      1.515+/-0.118 and 1.508+/-0.112 respectively, p<0.05 for each comparison). Cancer
      affected PAL negatively. CONCLUSIONS: In conclusion, the elderly spent most of
      their time carrying out low-intensity activities and did not participate in
      leisure activities of high or moderate intensity. Educational level was the only
      socio-economic factor that was correlated to PAL. The positive effect of certain
      disorders on PAL might be attributed to patients' compliance with physicians'
      instructions. Further research is necessary.

PMID- 12601292
TI  - Glycemic and insulinemic responses to energy bars of differing macronutrient
      composition in healthy adults.
AB  - BACKGROUND: This study investigated how energy bars of differing macronutrient
      composition affect postprandial glycemia and insulinemia in normal subjects
      compared with white bread and chicken breast controls. MATERIAL/METHODS: A total
      of 20 healthy adult subjects were recruited to participate in this randomized
      block protocol. After an overnight fast, subjects were fed 60-g portions of one
      of 5 meals, which were as follows: low carbohydrate bar (Atkins Advantage Bar,
      LC), moderate carbohydrate bar (Balance Bar, MC), high carbohydrate bar (Power
      Bar, HC), white bread (WB), and chicken breast (CHI). Capillary fingerstick and
      venous blood samples were analyzed for glucose and insulin concentrations,
      respectively, at baseline and at 15, 30, 45, 60, 90 and 120 minutes after start
      of the test meal. RESULTS: Compared with WB, plasma glucose area under the curve
      (AUC) for the meals was: 71% (P<0.001) lower for the LC bar, 50% (P<0.001) lower
      for MC bar, 4% (P=0.996) higher for the HC bar, and 83% (P<0.001) lower for the
      CHI. Serum insulin AUC, again compared with WB, was: 26% (P=0.497) lower for the
      LC bar, 35% (P=0.210) higher for the MC bar, 73% (P<0.001) higher for the HC bar,
      and 78% (P<0.001) lower for the CHI. CONCLUSIONS: This study demonstrated that
      substitution of other macronutrients for carbohydrate is effective for reducing
      postprandial glycemia. However, the insulin response may not decrease to the same
      degree and, for some bars, may actually be elevated compared with white bread.

PMID- 12601294
TI  - Prevalence and risk factors for hepatitis B virus infections among STD patients
      in northeast region of Iran.
AB  - BACKGROUND: In many parts of the world, sexual transmission of hepatitis B virus
      plays a major role in acquisition of infections. In Northeast region of Iran the
      prevalence rate and risk factors influencing this type of transmission was not
      investigated. Therefore, the concurrence of hepatitis B virus (HBV) and STDs was
      studied to determine the prevalence and risk factors of sexual transmission of
      hepatitis B virus. MATERIAL/METHODS: This study was carried out among 1500
      attendances to the laboratories for STDs examination between 1998 and 2000. Those
      who were positive for STDs (syphilis & gonorrhea) were examined for HBV infection
      by determination of hepatitis B surface antigen (HBsAg). The data was analyzed
      and compared to the normal population. RESULTS: The prevalence of STD in this
      population was 4.66% for syphilis and 6% for gonorrhea. Among this population the
      seroprevalence of HBsAg was 10% in women and 14.2% in men (mean seroprevalence of
      HBsAg was 13.13%). The concurrence of hepatitis B virus and syphilis was 14.28%
      which was slightly higher than concurrence for gonorrhea (12.22%). CONCLUSIONS:
      The prevalence of HBV in our patient population was high, exceeding the national
      estimates. This population also represents a high-risk group in Northeast of
      Iran. Further, our data indicates that such high prevalence is significantly more
      evident in patients with low socioeconomic status.

PMID- 12601293
TI  - A search for association between hereditary hemochromatosis HFE gene mutations
      and type 2 diabetes mellitus in a Polish population.
AB  - BACKGROUND: Hereditary hemochromatosis (HH) is characterized by excess iron
      deposition. Two mutations in the HFE gene are associated with HH. Heterozygous
      carriers of HFE mutations are at higher risk of developing type 2 diabetes
      mellitus (T2DM). The aims of our project were to identify the frequency of C282Y
      and H63D mutations in a population from the Malopolska region of south-eastern
      Poland, and to search for an association of HFE mutations with T2DM.
      MATERIAL/METHODS: We included 391 individuals in this study: 222 T2DM patients
      and 169 controls. Genotypes were determined by electrophoresis of the DNA
      digestion products from SnaBI and DpnII, respectively. Differences in
      distributions between the groups were then analyzed by the chi-squared test.
      RESULTS: The frequency of wild/C282Y alleles was 98.2%/1.8% in T2DM patients and
      96.7%/3.2% in controls (p=0.19). The frequency of wild/H63D alleles was
      85.6%/14.4% and 88.8%/11.2% (p= 0.19), respectively. The distribution of
      genotypes was not statistically different. However, in stratified analyses based
      on age of T2DM onset and gender, we observed a higher prevalence of wild/H63D and
      H63D/H63D genotypes among T2DM patients diagnosed at > 49 years of age, the mean
      age for the entire group (p=0.018), and among male T2DM individuals (p=0.005)
      than in controls. CONCLUSIONS: The frequency of HH-associated mutations in this
      population from south-eastern Poland is similar to other Caucasians. We found no
      evidence for the association of the C282Y mutation with T2DM. The results do
      suggest, however, that the H63D mutation may play a role in the pathogenesis of
      late onset T2DM and in males in this Polish population.

PMID- 12601295
TI  - Presence of a 88 kDa Eales protein in uveitis, tuberculosis, leprosy and
      rheumatoid arthritis.
AB  - BACKGROUND: Eales disease (ED) is an idiopathic retinal vasculitis affecting
      young adult males. We have earlier reported the identification, purification and
      partial characterization of a novel 88 kDa protein found in the serum of patients
      with ED. The aim of the present study was to look for the 88 kDa protein in serum
      samples obtained from cases of retinal vasculitis mimicking ED and in other
      systemic inflammatory diseases. MATERIAL/METHODS: Serum samples from healthy
      volunteers and from patients with ED, uveitis, parsplanitis ocular sarcoidosis,
      toxoplasmosis, leprosy, diabetic retinopathy, viral hepatitis, and rheumatoid
      arthritis were analyzed for the presence of the 88 kDa protein by polyacralymide
      gel electrophoresis (PAGE). The immunological identity of the 88 kDa protein
      found in ED and in other diseases was investigated by Western blot.
      Immunohistochemistry was performed on epiretinal membranes (ERM) obtained from ED
      patients to localize the 88 kDa protein. RESULTS: 88 kDa protein were detected in
      serum samples obtained from patients with posterior uveitis, tuberculosis,
      leprosy and rheumatoid arthritis. The 88 kDa protein found in serum from patients
      with ED is immunologically identical to that found in other systemic inflammatory
      conditions. 88 kDa protein was localized in inflammatory cells and in nonvascular
      endothelium in ERMs obtained from patients with ED. CONCLUSIONS: We have
      identified a novel acute phase reactant, which is elaborated in ocular and
      systemic inflammatory conditions other than Eales disease. Further work is
      necessary to decipher the precise role of the 88 kDa protein in the
      pathophysiology of these inflammatory diseases.

PMID- 12601296
TI  - Prevalence of iron deficiency anemia in 6 months to 5 years old children in Fars,
      Southern Iran.
AB  - BACKGROUND: Iron-deficiency anemia (IDA) is a common clinical problem throughout
      the world and an enormous public health risk in developing and even in
      industrialized countries. Traditionally, several methods other than serum
      ferritin were used to assess IDA. Our main objective was to obtain the prevalence
      of IDA by serum ferritin in 6 month to 5-year-old children in the province of
      Fars in southern Iran. MATERIAL/METHODS: 5 cc blood of 583 randomly selected, 6
      months to 5 years old children was collected. The serum ferritin, hemoglobin
      (Hb), Hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular
      hemoglobin (MCH), mean corpuscular hemoglobin concentrate (MCHC), RBC counts and
      WBC counts were checked. A questionnaire was filled and the data analyzed.
      RESULTS: The mean value for SF was 23.6+/-14.3 ng/dl. 115 (19.7%) children had
      low serum ferritin (SF<12ng/dl). The low serum Hb showed statistical correlation
      with low serum ferritin (p<0.05). CONCLUSIONS: The prevalence of IDA (19.7%) in
      our study was less than the prevalence reported in other developing countries
      (25+/-35%), (p<0.05). However, the prevalence was higher compared to
      industrialized countries (5+/-8%). This demonstrates that in southern Iran the
      nutritional status has improved, which is probably because of obligatory iron
      supplements given to the pregnant mothers and their under two year old infants,
      by the Health Care Centers, but we are still below the standards of WHO
      recommendations.

PMID- 12601297
TI  - Launois-Bensaude syndrome in a female with type 2 diabetes.
AB  - BACKGROUND: The Launois-Bensaude syndrome (LBS) is a rare disease characterized
      by an accumulation of multiple lipomata with a preponderance at the thorax,
      abdomen, upper arms and the thighs. Frequently, the condition is associated with
      past or present alcohol abuse with no clear temporal coincidence between the
      onset and termination of lipomata growth and onset or termination of alcohol
      consumption. Due to the massive accumulation of adipose tissue, the patients
      frequently have features of the metabolic syndrome as hypertension, impaired
      fasting glucose or diabetes mellitus, hyperuricemia or hyperlipidemia. CASE
      REPORT: A 79-yr-old female observed an increase of fat mass especially at the
      upper arms, the thighs and the thorax in combination with a weight gain of 19 kg
      within 2 years without any changes in the nutrition habits. The unique features
      confirmed the diagnosis of LBS. Interestingly, she had diabetes mellitus,
      hypertension and hyperlipidemia before the manifestation of LBS and without any
      history of heavy alcohol consumption. Furthermore, the condition predominantly
      affects males. In her very case, treatment with sultanol, as successfully
      performed in some cases, could not be recommended due to her cardiac
      insufficiency. A surgical approach is of limited value due to the frequent
      relapses of the lipomata. CONCLUSIONS: Establishing the diagnosis of LBS is an
      important step for patients confronted with an inexplicable physical
      disfigurement that is not related to excessive nutrition. The disease is often
      not diagnosed because of its rareness, but its features are unique and easily to
      be distinguished from 'simple' truncal obesity.

PMID- 12601298
TI  - Radioguided parathyroidectomy for renal hyperparathyroidism.
AB  - BACKGROUND: The usefulness of radioguided parathyroidectomy for primary
      hyperparathyroidism has been demonstrated in recent years, however, its
      applicability to renal hyperparathyroidism is uncertain. We report a case in
      which radioguided parathyroidectomy was used to treat renal hyperparathyroidism
      and was found to be helpful in preventing persistent and recurrent
      hyperparathyroidism. CASE REPORT: The patient was a 55-year-old Japanese woman
      who had received hemodialysis for 67 months. Three enlarged parathyroid glands
      were identified preoperatively by ultrasonography. Two hours before the
      operation, the patient received an intravenous injection of 600 MBq 99mTc
      sestamibi and radioguided parathyroidectomy was performed. The three enlarged
      parathyroid glands were resected easily by the use of radioguided surgery.
      However, the localization of the residual parathyroid gland was uncertain. The
      operative field was analyzed using an intraoperative gamma probe, and the upper
      mediastinum was found to have higher radioactivity than the other regions. The
      upper mediastinum was dissected and the enlarged parathyroid gland was identified
      in the anterosuperior mediastinum in front of the trachea. The target parathyroid
      gland was then removed. The pathological diagnosis was hyperplasia of the
      parathyroid. No complications were observed and a follow-up examination 30 months
      later did not show any recurrence. CONCLUSIONS: An intraoperative gamma probe can
      be used to locate supernumerary and ectopic parathyroid glands. Radioguided
      parathyroidectomy for renal hyperparathyroidism can theoretically decrease the
      risk of persistent and recurrent hyperparathyroidism that is due to remaining
      parathyroid tissue.

PMID- 12601299
TI  - A comparison of the specificity and sensitivity of two Candida antigen assay
      systems for the diagnosis of deep candidiasis in patients with hematologic
      diseases.
AB  - BACKGROUND: Latex agglutination assay for detection of circulating Candida
      antigen (Cand-Tec, Ramco Laboratories), which is now commercially available,
      provides a rapid and simple means for the diagnosis and management of deep-seated
      Candida infections. MATERIAL/METHODS: The Cand-Tec microtiter system (Cand-Tec
      MT, Ramco Japan), new latex agglutination assay for Candida antigen, expresses
      Candida antigen level as the cutoff index (C.I.) value by means of colorimetric
      analysis and is expected to be more objective method. RESULTS: In this study, we
      evaluated the advantages, if any, of Cand-Tec MT compared with the original Cand
      Tec for the diagnosis of deep-seated Candida infections in 25 patients with
      hematologic diseases. A total of 80 serum specimens were taken from the patients
      when they showed febrile neutropenia and were suspected of having infectious
      disease. The C.I. value in Cand-Tec MT well correlated with the Cand-Tec titer.
      The sensitivity and specificity of Cand-Tec MT were 100% and 80%, respectively.
      The change in C.I. value in the sera was followed up during antifungal therapy.
      The C.I. value decreased in 75% of cases that responded to antifungal therapy,
      but did not show any tendency in non-responsive cases. In some cases, the C.I.
      value showed improvement corresponding to the therapeutic effect, while the Cand
      Tec titer did not. CONCLUSIONS: Cand-Tec MT is a useful method for the early
      diagnosis and accurate evaluation of the therapeutic effect of systemic
      candidiasis.

PMID- 12601300
TI  - Thyroid function and incidentalomas in kidney transplant recipients.
AB  - BACKGROUND: Ultrasound (US) is currently the best method for detecting thyroid
      nodules, especially those less than 1 cm in diameter, known as 'incidentaloma'.
      The ultimate diagnosis of non-palpable masses is done by fine-needle aspiration
      biopsy (FNAB), especially sonographically controlled (S-FNAB). Because of the
      increasing prevalence of thyroid nodules in Poland, it is essential to assess the
      nodules for FNAB and S-FNAB, especially in persons at high risk for thyroid
      carcinoma (patients after transplant with immunosuppression, persons with endemic
      goiter). MATERIAL/METHODS: Prospective sonographic, color Doppler and power
      Doppler tests of the thyroid were performed in 44 kidney allograft recipients.
      The TSH level and urine iodide level was assessed in each patient. The control
      group included 35 healthy volunteers. RESULTS: TSH levels were normal. The urine
      iodide concentration was over 30 mg/100 ml in 5 cases. In the rest of the group
      and in the controls it was below 30 mg/100 ml. In each case the thyroid was
      enlarged when compared to volunteers. There were thyroid nodules in 19 cases,
      single in 6 cases and multiple in 13. Of these nodules, 31 were smaller than 1
      cm, 20 nodules were 1-2 cm in diameter, and none was greater than 2 cm. Nodules
      were classified according to whether or not there was flow within the nodule with
      eventual perinodular flow. FNAB revealed malignancies in 5 cases (nodules with
      flow). CONCLUSIONS: Goiter was observed in all patients after thyroid transplant.
      In five of 44 cases malignancies were detected. In patients after transplant the
      US picture and the TSH and iodide levels should be checked.

PMID- 12601302
TI  - Kyo-Green improves sexual dysfunction in men and women.
AB  - BACKGROUND: Serendipitously, we discovered the effects of Kyo-Green, a green
      powdered nutritional supplement, on improving sexual dysfunctions in both men and
      women. In this paper, we presented two case reports and an open-labeled pilot
      study involving 40 subjects for a period of three months to determine the effects
      of Kyo-Green on sexual dysfunctions. MATERIAL/METHODS: Twenty-five men and 15
      women were enrolled into this study. All the male subjects had suffered erectile
      dysfunction (ED). All the female subjects reported lack of libido. Subjects took
      one teaspoonful of Kyo-Green two times a day. Subjects completed a questionnaire
      at the beginning, and at the end of one, two, and three months while taking Kyo
      Green. The analysis of data was based on the four questionnaires completed by the
      subjects. RESULTS: Increase of energy was reported by all the subjects. Sixteen
      males and 12 females reported satisfaction with their sex life after taking Kyo
      Green for three months. Twenty of the 25 male subjects reported significant
      improvement in erectile dysfunction, and ability to initiate and maintain sexual
      activity with satisfaction. CONCLUSIONS: All the subjects experienced an increase
      of energy levels within a few weeks after taking this supplement. Eighty percent
      of the male subjects with ED regained erections while taking this supplement. The
      study suggests that Kyo-Green, particularly when used in conjunction with a
      lifestyle modification approach, may be useful in the management of sexual
      dysfunction in men and women who prefer a non-drug approach.

PMID- 12601301
TI  - Gemcitabine combined with sequential paclitaxel and carboplatin in patients with
      urothelial cancers and other advanced malignancies.
AB  - BACKGROUND: To investigate a novel schedule of gemcitabine (G), paclitaxel (P),
      and carboplatin (C), based on preclinical studies demonstrating greater activity
      and decreased toxicity of administering P prior to C. MATERIAL/METHODS: The
      effect of the P and C drug sequence on tumor cell viability was assessed with a
      tetrazolium assay on T24 bladder and DU145 prostate cancer cells. Patients with
      transitional cell cancer (TCC) and other advanced malignancies were treated with
      G and P on days 1, 8, and 15 of each 28 day cycle. C was administered on day 2 at
      an AUC of 5. Doses of G and P were varied among cohorts of three patients.
      RESULTS: Preclinical studies demonstrated that the sequence of P followed by C
      induced greater cytotoxicity than the reverse sequence. The recommended phase II
      dose (RPTD) was defined as 70 mg/m2 P, 300 mg/m2 G, and C with AUC of 5. Therapy
      was well tolerated; fever and neutropenia occurred in only one patient at the
      RPTD. Grade 3 thrombocytopenia occurred in 5 of 21 patients treated at the RPTD.
      Out of all 37 patients treated on study, 9 achieved a partial tumor response (PR)
      and two patients achieved a complete response (CR). Out of the 15 patients with
      TCC, six had a PR and two had a CR. CONCLUSIONS: Preclinical studies demonstrated
      that the sequence of paclitaxel followed by carboplatin was more effective than
      the opposite sequence. Administration of gemcitabine and paclitaxel followed by
      carboplatin was well tolerated and clinically active. GCP should be compared to
      other combination regimens under investigation for the treatment of TCC.

PMID- 12601303
TI  - The therapeutic use of the relaxation response in stress-related diseases.
AB  - The objective of this work was to investigate a possible (therapeutic) connection
      between the relaxation response (RR) and stress-related diseases. Further, common
      underlying molecular mechanisms and autoregulatory pathways were examined. For
      the question of (patho)physiology and significance of RR techniques in the
      treatment of stress-related diseases, we analyzed peer-reviewed references only.
      The RR has been shown to be an appropriate and relevant therapeutic tool to
      counteract several stress-related disease processes and certain health
      restrictions, particularly in certain immunological, cardiovascular, and
      neurodegenerative diseases/mental disorders. Further, common underlying molecular
      mechanisms may exist that represent a connection between the stress response,
      pathophysiological findings in stress-related diseases, and physiological
      changes/autoregulatory pathways described in the RR. Here, constitutive or low
      output nitric oxide (NO) production may be involved in a protective or
      ameliorating context, whereas inducible, high-output NO release may facilitate
      detrimental disease processes. In mild or early disease states, a high degree of
      biological and physiological flexibility may still be possible (dynamic balance).
      Here, the therapeutic use of RR techniques may be considered particularly
      relevant, and the observable (beneficial) effects may be exerted via activation
      of constitutive NO pathways. RR techniques, regularly part of professional stress
      management or mind/body medical settings, represent an important tool to be added
      to therapeutic strategies dealing with stress-related diseases. Moreover, as part
      of 'healthy' life-style modifications, they may serve primary (or secondary)
      prevention. Further studies are necessary to elucidate the complex physiology
      underlying the RR and its impact upon stress-related disease states.

PMID- 12601304
TI  - Stress induced disturbances of the HPA axis: a pathway to Type 2 diabetes?
AB  - Type 2 diabetes is the most common form of hyperglycemia. The disease exists in
      all populations, but in developed societies, the prevalence has risen as the
      population ages and above all becomes more obese. In the prediabetic state, type
      2 diabetes involves two defects, peripheral insulin resistance and
      hyperinsulinemia, which is followed by the failure of insulin secretion to
      compensate for the insulin resistance. As with nearly any disease, it is likely
      that multiple environmental and genetic factors are involved in the development
      of insulin resistance. An acquired pathogenic factor is obesity, particularly
      visceral obesity. Compelling evidence suggests that progressive dysfunction of
      the hypothalamic-pituitary-adrenal (HPA) axis, with elevated levels of
      circulating cortisol, is implicated in the development of visceral obesity. The
      HPA axis perturbations associated with visceral obesity can be accounted for, in
      part, by increased environmental stress that destabilizes the hypothalamic
      pituitary system in individuals with genetic susceptibility.

PMID- 12601305
TI  - Emerging therapeutic applications of botulinum toxin.
AB  - Botulinum toxin, the most potent known biological neurotoxin, holds great promise
      in the therapy of many diseases. It has been used effectively to treat
      strabismus, dystonias and other movement disorders, and spasticity. However, a
      number of potential new therapeutic indications have emerged and attracted a
      considerable amount of interest from the scientific community. These emerging
      indications included treatment for conditions associated with pain (e.g.
      headaches, myofascial pain, chronic low back pain), hypersecretion of glands
      (e.g. hyperhidrosis, sialorrhea, intrinsic rhinitis), and excessive or
      dyssynergic muscle contraction, and for cosmesis (e.g. myokymia, bruxism, anal
      fissure). There is a need for more controlled clinical trials, dose-ranging
      studies to determine optimal treatment, validated clinical scales and studies
      developed to assess the value of electromyographic guidance and skill of
      investigators on the outcome of treatment for some of these diseases. The long
      term cost effectiveness of treatment and immunoresistance from repeated
      injections are also important clinical issues to address.

PMID- 12601306
TI  - Policy and ethical issues in applying medical biotechnology in developing
      countries.
AB  - A brief review of some of the key issues in policy relating to the ethical issues
      raised by medical biotechnology in developing countries is presented, using India
      as an example. A series of some key issues is discussed, including information
      obtained from interviewing Indian government policy makers. Some of the issues
      discussed include: Economic and social incentives to encourage biotechnology;
      Health policy and ethics review; Patents on drugs; Medical genetics; Relationship
      to traditional medical practices; Positive public attitudes to biotechnology;
      Limited public participation; Infrastructural hurdles; Indian progress in stem
      cell research; and dilemmas of expensive technologies. The results show that
      although the needs of developing countries are different to those of rich
      countries, government policy utilizing guidelines and ethics committees has
      evolved as mechanisms to aid ethical health care delivery in India. In all
      countries there may be some of these concerns that are raised here, however, the
      integration of traditional medicine and advanced medical technology, and access
      to medical services by people in need, are particularly important challenges in
      developing countries. Better public involvement in policy making will require
      education and infrastructural organization as well as mutual willingness on the
      part of policy makers and citizens.

PMID- 12601308
TI  - Evidence-based public health, community medicine, preventive care.
AB  - The use of evidence-based reasoning and decision-making theory and practice is
      becoming increasingly commonplace in most of the health sciences. Public health,
      which encompasses health protection, disease prevention and health promotion, has
      traditionally been more evidence-based than clinical medicine. However, more must
      be done to grade evidence in the absence of classical clinical trials or other
      experimental proof. Decisions in public health also rely on economical, social
      and political considerations, but how can evidence in these fields be graded for
      the best possible decision-making in public health? Moreover, evidence is often
      unequally distributed in relation to different focus groups. For example,
      evidence in the area of women's health should be as extensive as it is in the
      area of men's health. Medicine has traditionally been more ethically inclined
      than many other fields of human endeavour. In light of this, should we require
      all decision makers involved in health policies (i.e. politicians, economists,
      and other stakeholders) to be equally ethically minded? Decisions made without
      using the best evidence in setting the priorities of health programs and health
      policies may be ethically questionable. However, the burden and responsibility no
      longer lie exclusively on the shoulders of physicians and nurses. Evidence-based
      problem solving and decision-making in health sciences are only approximately a
      decade old. As a result, the already impressive, but still incomplete
      accomplishments of the evidence-based medical world require further advancements.

PMID- 12601307
TI  - Adiponectin and resistin--new hormones of white adipose tissue.
AB  - Adiponectin and resistin are recently described secretory products of adipose
      tissue. Adiponectin is secreted by fat cells and circulates in the blood. Plasma
      adiponectin concentration is reduced in obese animals and humans and in patients
      with type 2 diabetes mellitus. Adiponectin stimulates fatty acids oxidation,
      decreases plasma triglycerides, and improves glucose metabolism by increasing
      insulin sensitivity. In addition, adiponectin inhibits the inflammatory process
      and possibly atherogenesis by suppressing the migration of monocytes/macrophages
      and their transformation into foam cells. Plasma adiponectin is lower in patients
      with ischemic heart disease than in body mass index-matched healthy individuals.
      Hypoadiponectinemia may contribute to insulin resistance and accelerated
      atherogenesis associated with obesity. Resistin/FIZZ3 is a member of the newly
      discovered cysteine-reach secretory protein family, referred to as 'resistin-like
      molecules' (RELM) or 'found in inflammatory zone' (FIZZ), together with
      FIZZ1/RELMalpha and FIZZ2/RELMbeta. Each of these has unique tissue distribution.
      Both resistin and FIZZ1/RELMalpha are expressed in adipose tissue. Initial
      studies in rodents suggested that resistin is upregulated in obesity and may be
      involved in the development of insulin resistance. Later studies failed to
      confirm this hypothesis and demonstrated reduced resistin expression in adipose
      tissue of obese animals. In human adipose tissue resistin is detectable at a very
      low level, and there is no relationship between resistin expression and obesity.
      Although the role of resistin in linking human obesity with type 2 diabetes is
      thus questionable, this protein is detected in peripheral blood monocytes,

PMID- 12601309
TI  - A year of major changes for residencies and fellowships.

PMID- 12601310
TI  - Comparison of DNA content parameters in paired, fresh tissue pretreatment
      biopsies and surgical resections from squamous cell carcinoma of the head and
      neck.
AB  - OBJECTIVE: Cellular DNA characteristics derived from pretreatment biopsy (PTB)
      may become important for predicting treatment outcomes in patients with head and
      neck squamous cell cancer (HNSCC). Whether the PTB adequately represents the
      whole specimen is of critical importance. STUDY DESIGN: In a series of >700
      HNSCCs, we identified 59 cases in which the PTB and the surgical resection (SR)
      met the following criteria: PTB and SR were from the same site, and SR was
      obtained within 5 weeks of PTB with no intervening treatments. RESULTS: Twenty
      nine percent of the PTB specimens were DNA diploid. Only 1 of the 11 subsequent
      DNA diploid SR was associated with a DNA aneuploid PTB (91% concordance). Of the
      48 DNA aneuploid tumors, 3 were associated with DNA diploid PTB (94%
      concordance). Three other DNA aneuploid SRs were associated with PTB of poor
      quality. CONCLUSION: With respect to DNA ploidy, PTB are representative of SR
      specimens.

PMID- 12601312
TI  - Nodal yield in neck dissection and the likelihood of metastases.
AB  - OBJECTIVES: The purpose of this study was to begin investigating the relationship
      between nodal yield in neck dissection and the likelihood of finding cervical
      metastases in T1 and T2 head and neck squamous cell carcinoma (HNSCC). No
      clinical implications are drawn from this preliminary work. STUDY DESIGN AND
      SETTING: This study was a retrospective analysis of 564 patients with T1 and T2
      HNSCC of the oral cavity, oropharynx, or hypopharynx from the National Cancer
      Institute Surveillance, Epidemiology, and End Results (SEER) Program registry. A
      multivariate analysis was performed to evaluate the relationship between nodal
      yield in neck dissection and the discovery of cervical metastases. Other
      independent factors included in the analysis were gender, age, race, and primary
      site of tumor. RESULTS: Compared with nodal yield < 13, cervical metastases were
      more likely to be found for nodal yield 21-28 (P < 0.001, odds ratio [OR] =
      3.68), 29-40 (P = 0.021, OR = 1.98), and >40 (P < 0.001, OR = 3.52). Increased
      age, male sex, and oropharynx and hypopharynx primaries were also associated with
      a significantly increased likelihood of finding cervical metastases. CONCLUSION:
      In T1 and T2 cases of HNSCC, nodal yield >20, increased age, male sex, and
      primary site correspond with an increased likelihood of finding cervical
      metastases.

PMID- 12601311
TI  - Combined positron emission tomography/computed tomography imaging of recurrent
      thyroid cancer.
AB  - OBJECTIVE: The study goal was to evaluate the use of combined positron emission
      tomography/computed tomography (PET/CT) imaging for localization of recurrent
      disease in thyroid cancer patients. STUDY DESIGN AND SETTING: Eight patients with
      suspected recurrence of thyroid cancer on the basis of elevated serum
      thyroglobulin or calcitonin levels underwent combined PET/CT imaging on a
      prototype device. All 8 patients had previously undergone total thyroidectomy and
      (131)I ablation for thyroid carcinoma. Patients with papillary carcinoma had
      negative (131)I scans. RESULTS: Eight patients underwent combined PET/CT
      scanning. Four (50%) of 8 patients underwent PET/CT indicating recurrence in the
      head and neck. A total of 11 lesions in these 4 patients were suspicious for
      recurrence on combined PET/CT imaging. Three patients with 8 lesions suspicious
      for recurrence on PET/CT underwent surgical removal of disease. All 3 patients
      had pathologic confirmation of recurrence, with 6 (75.0%) of 8 lesions being
      positive. CONCLUSION: Combined PET/CT imaging is a valuable tool for the
      diagnosis and anatomic localization of recurrent thyroid cancer.

PMID- 12601313
TI  - Management of T3 N0 and T4 N0 glottic carcinomas: results of a national survey.
AB  - OBJECTIVE: A survey was undertaken to document the clinical management of T3 and
      T4 pure glottic primary carcinomas and the management of the N0 neck by
      otolaryngologists and radiation oncologists. STUDY DESIGN AND SETTING: This study
      represents the results of a national survey of 250 otolaryngologists and 250
      radiation oncologists regarding management of T3 N0 M0 and T4 N0 M0 glottic
      carcinomas. RESULTS: Of the surveys sent, 208 completed questionnaires were
      received. Results of this survey suggest that 87% and 90% will treat the neck for
      a T3 N0 M0 and T4 N0 M0 glottic tumor, respectively, with a large number choosing
      to perform a radical neck dissection. CONCLUSIONS: A significant percentage of
      otolaryngologists perform neck dissections in the management of T3 N0 M0 and T4
      N0 M0 glottic carcinomas. Given the relatively low risk of occult metastasis,
      potentially high morbidity associated with overtreatment, and the lack of a well
      designed outcome study investigating treatment alternatives, a prospective
      randomized study is needed to address the issue.

PMID- 12601314
TI  - Amputation neuromas after neck dissection.
AB  - OBJECTIVE: We sought to define the incidence of neuroma formation after neck
      dissection in a large series of patients. METHODS: One hundred fifty-three
      patients who were seen during a 2-year period (followed for 3 months to 10 years;
      mean, 52 months) were evaluated for neuroma formation after neck dissection (185
      procedures). Cut nerve edges were not routinely ligated or cauterized. RESULTS:
      Operative records indicated that except for 4 cases, the stumps of the great
      auricular nerve and cervical branches were left intact after resection. No cases
      of palpable neuromas were found. In one case of a revised neck, a small
      macroscopically indiscernible nodule was histologically defined as neuroma.
      CONCLUSION: No neuromas were discovered in our series of neck dissection cases.
      If found, it is imperative these lesions be differentiated from recurrent cancer.
      Our results do not support any interference with cut nerve edges.

PMID- 12601315
TI  - Partial laryngectomy after irradiation failure.
AB  - INTRODUCTION: Radiation therapy is often the first method of treating patients
      with early cancer of the glottis. There is a substantial failure rate among these
      patients. Total laryngectomy has usually been the means of treating patients with
      failure after radiation. In recent decades, partial laryngectomy has been used
      for salvage in such patients. This article will discuss the use of partial
      laryngectomy for radiation failure both from the oncologic result as well as the
      morbidity. PATIENTS AND METHODS: Between 1984 and 1995, 27 patients with early
      stage laryngeal carcinoma underwent salvage partial laryngectomy after
      irradiation failure. Vertical laryngectomy was performed in 18 patients (13 with
      T1 N0 and 5 with T2 N0) and horizontal-supraglottic laryngectomy in 9 patients (3
      with T1 N0, 1 with T2 N0, and 5 with T2 N1). The mean follow-up was 4.1 years.
      RESULTS: Local control was obtained in 77.7% of patients with glottic lesions
      (T1: 84.6%; T2: 60%, P = NS) and in 55.5% of patients with supraglottic lesions
      (T1: 66.6%; T2: 50%; P = NS). There was no regional recurrence in the vertical
      laryngectomy group, whereas the regional control rate in the horizontal
      supraglottic laryngectomy group was 77.7%. Distant control was achieved in 94.4%
      of patients with glottic disease and in 77.7% of patients with supraglottic
      disease. The overall survival rate for glottic lesions was 88.8% (T1: 92.3%; T2:
      80%; P = NS) versus 66.6% for supraglottic lesions (T1: 100%; T2: 50%; P = NS).
      CONCLUSION AND SIGNIFICANCE: Vertical laryngectomy was not associated with an
      increased complication rate. Morbidity in the horizontal-supraglottic
      laryngectomy group was higher, but a satisfactory functional outcome was obtained
      in all cases. Therefore, in early laryngeal cancer (glottic T1-T2, supraglottic
      T1) partial laryngectomy can be performed with good expectation of cure and
      satisfactory laryngeal function. In T2 supraglottic lesions, the oncologic
      results are less satisfactory; further research is required for developing more
      efficient complimentary or alternative treatments modalities.

PMID- 12601316
TI  - The effect of capillary ultrafiltration probes on skin flap edema.
AB  - OBJECTIVE: Edema clearly has deleterious effects on the microcirculation and,
      consequently, cell viability. Prior work from this laboratory demonstrated that
      hyperosmolar microdialysis can reduce tissue edema, but this method is
      technically challenging. A new, simpler technique of microdialysis using
      capillary ultrafiltration probes (CUPs) has been studied to determine if CUP
      microdialysis is as effective in reducing tissue edema in the same animal model.
      METHODS: Twenty-four Sprague-Dawley rats were studied using a modified McFarlane
      skin flap. Microdialysis was accomplished using a catheter constructed of four 4
      cm hollow fibers that were connected to polyethylene tubing. Catheters on the
      experimental side of the flap were attached to a vacuum manifold for 8 hours. The
      control side was treated in 2 ways. In group 1, catheters were placed but not
      applied to suction. In group 2, no catheters are placed on the control side.
      Tissue water content was determined by a biopsy-drying technique. RESULTS: Tissue
      water content was significantly reduced (by paired t test) in both groups by a
      mean of 3.2 mL/100 g of wet tissue. CONCLUSION: CUP microdialysis reduced tissue
      water content as effectively as did hyperosmolar microdialysis, but in a simpler
      and therefore more cost-effective method. The technique could be easily adapted
      for clinical application.

PMID- 12601317
TI  - Transoral versus extraoral reduction of mandible fractures: a comparison of
      complication rates and other factors.
AB  - OBJECTIVE: This retrospective study evaluates results and complications of the
      transoral and extraoral approaches for open reduction and internal fixation of
      mandibular body, angle, and ramus fractures. Our aim was to describe advantages
      and disadvantages of the techniques and to develop criteria for choosing between
      surgical approaches. STUDY DESIGN AND SETTING: A retrospective chart review was
      performed on patients with mandible fractures occurring between August 1999 and
      October 2001 at a level I trauma center. Only mandibular body, angle, and ramus
      fractures requiring open reduction were selected for this study. Cases were
      evaluated for cause, age, gender, dentition, site and extent of fractures,
      surgical approach, postoperative complications, operative time, and postoperative
      occlusion. RESULTS: Of the 227 patients with mandibular fractures, 78 had body,
      angle, or ramus fractures requiring open reduction. Of these, 36 were treated
      extraorally, and 42 were treated transorally. Criteria for selecting one
      procedure over another often involved training and surgeon experience and those
      factors normally considered important in defining the difficulty of treatment and
      prognosis of the patient. Seven of the 42 patients were converted from a
      transoral to an extraoral approach because of inadequate exposure. Similar
      complication rates occurred for the transoral and extraoral approaches, but
      because of the time required for converting from the transoral to extraoral
      approach, the average operative time was found to be increased in patients
      undergoing the transoral approach. CONCLUSION AND SIGNIFICANCE: Decisions
      regarding treatment approaches for open reduction of mandible fractures often
      relate to surgeon experience and training, modified by factors that can affect
      uncomplicated healing such as fracture locations and displacement, comminution of
      the fracture, infection, dentition, and atrophic changes of the mandible. In some
      cases, the choice is affected by availability of equipment and experience of
      operating room personnel. More difficult cases involving an edentulous, atrophic
      mandible or comminution should be considered for extraoral exposure.

PMID- 12601318
TI  - A comparison of nasal clearance after treatment of perennial allergic rhinitis
      with budesonide and mometasone.
AB  - OBJECTIVE: Evidence in vitro suggests that benzalkonium chloride, a preservative
      in many intranasal preparations, interferes with ciliary function and thus could
      potentially interfere with mucociliary transport, the mechanism for clearing
      secretions from the nasal cavity. STUDY DESIGN: We performed a parallel
      randomized study with 10 subjects in each arm comparing Rhinocort AQUA (an
      intranasal steroid [budesonide] spray without benzalkonium chloride) and Nasonex
      (an intranasal steroid [mometasone furoate] spray with benzalkonium chloride).
      Before and after 2 weeks of treatment, subjects completed a Rhinoconjunctivitis
      Quality of Life Questionnaire (RQLQ) and underwent a measurement of nasal
      clearance of a radioactive colloidal spray into the nose. RESULTS: The groups
      were matched at entry for nasal clearance, even though there was variability
      among subjects. The amount of change after 2 weeks of treatment (Delta before
      versus after treatment) showed a significant difference in nasal clearance
      favoring budesonide. After 2 weeks of treatment, both budesonide and mometasone
      demonstrated overall improvement in quality of life as assessed by the RQLQ. Both
      treatments were well tolerated. CONCLUSION: Our study extends the observation in
      vitro that demonstrates the adverse effect of benzalkonium chloride on cilia to a
      measurement in vivo of clearance. The effects after 2 weeks might not reflect
      changes after longer periods of treatment. SIGNIFICANCE: To determine the
      clinical significance of the small improvement in mucociliary transport will
      require large clinical trials.

PMID- 12601319
TI  - "Balanced" orbital decompression for severe Graves' orbitopathy: technique with
      treatment algorithm.
AB  - BACKGROUND: Graves' orbitopathy can produce proptosis, compressive optic
      neuropathy, and extraocular motility abnormalities; symptoms result from an
      increase in orbital volume due to expansion of intraorbital fat, with or without
      extraocular muscle involvement. STUDY DESIGN: We conducted a chart review of
      patients who underwent orbital decompression to treat Graves' orbitopathy. Twenty
      two orbits (13 patients) underwent orbital bone decompression, of which 17 orbits
      (9 patients) underwent the combined medial and lateral "balanced" decompression.
      RESULTS: All patients had significant improvement with an average decrease in
      proptosis of 5.9 mm in the balanced decompression group. Restoration of normal
      optic nerve function was achieved in all patients with compressive optic
      neuropathy. Diplopia was noted in 4 patients (30.7%) preoperatively. Two patients
      had new postoperative diplopia (15.35%). CONCLUSION: In our experience,
      "balanced" decompression results in a reduction of proptosis and improved optic
      nerve function and has a low incidence of complications.

PMID- 12601320
TI  - Anatomic variations of the arteries of the nasal fossa.
AB  - OBJECTIVE: This study was performed for knowledge about the vascular supply of
      the nasal fossa and a description of the site of division and number of branches
      of the sphenopalatine artery. STUDY DESIGN: This study was performed on 10 fresh
      nonembalmed cadavers. Anatomic variations of nasal fossa arteries were studied.
      METHODS: First, 10 cephalic anatomic preparations were injected with red color
      latex into the right and left carotid arteries. Then, these specimens were
      sagittaly cut to dissect the sphenopalatine artery. Twenty vascularization cases
      were studied for the external branch of the sphenopalatine artery, and 10 cases
      were studied for the internal branch. RESULTS: The principal observations were:
      1. the sphenopalatine artery division is 18 times in the infratemporal fossa and
      twice in the nasal fossa; 2. the nasopalatine artery supplies blood to the lower
      part of the septum and its anterosuperior area; and 3. the vascularization of the
      external wall is via the sphenopalatine artery through the arteries of the meatus
      and conchae. CONCLUSION: This study defines the vascular territories of the nasal
      fossa arteries and includes photographs of dissections.

PMID- 12601321
TI  - Vestibular rehabilitation: useful but not universally so.
AB  - OBJECTIVE: Although vestibular rehabilitation (VR) is gaining popularity, few
      data support its utility in improving locomotor stability, and no good predictors
      exist of whom will benefit most. STUDY DESIGN AND SETTING: A double-blind,
      placebo-controlled randomized trial of vestibular rehabilitation was conducted at
      a large tertiary care hospital on 124 patients (59 +/- 18 years old) with
      unilateral (n = 51) or bilateral (n = 73) vestibular hypofunction, of whom 86
      completed a 12-week intervention. Of these 86, 27 returned for long-term (1-year)
      follow-up testing. The primary outcome measure was locomotor stability. RESULTS:
      Group A (6 weeks of VR) significantly (P < 0.01) increased their gait velocity
      and stability compared with group B (6 weeks of strengthening exercise), but
      there was a smaller difference (P = 0.05) between groups at 12 weeks, when both
      had had VR; there were no group differences at 1 year. Of the 86 who completed
      the intervention, 52 (61%) had clear locomotor gains. CONCLUSION AND
      SIGNIFICANCE: VR is helpful for most patients in providing locomotor stability,
      but further work is needed to determine the factors that prevent VR from being
      effective for all patients with vestibulopathy.

PMID- 12601323
TI  - The use of cortical evoked response audiometry in the assessment of noise-induced
      hearing loss.
AB  - OBJECTIVES: The study aims were to determine the incidence of exaggerated hearing
      thresholds in individuals complaining of noise-induced hearing loss (NIHL) as a
      result of impulse noise using cortical evoked response audiometry (CERA) and to
      identify any associated audiometric features. SETTING: We conducted an office
      based study. STUDY DESIGN: In this prospective case series, 1154 males
      complaining of NIHL were assessed with pure tone audiometry; 673 had CERA. Pure
      tone averages (PTA) and hearing disability were calculated using the Irish and
      American Medical Association systems. A PTA of >10 dB worse than the CERA average
      was considered evidence of exaggerated thresholds. RESULTS: The mean PTA was 33
      dB. Seventy-two percent had a hearing disability of an average of 26% when
      assessed by the Irish system. Fifty-four percent had a hearing disability of an
      average of 30% when assessed by the American Medical Association system. Twenty
      six percent of subjects had exaggerated thresholds based on CERA. A binaural
      hearing threshold of >25 dB at 500 Hz had a sensitivity of 94% and a specificity
      of 59% for the detection of exaggerated thresholds. CONCLUSION: Exaggerated
      hearing thresholds are common. A hearing threshold of >25 dB at 500 Hz should be
      considered an indication for CERA testing.

PMID- 12601322
TI  - A reliable radiologic landmark for the facial nerve in axial temporal bone
      computed tomography scans.
AB  - OBJECTIVE: We sought to test the reliability of a radiologic marker in
      identifying the vertical portion of the facial nerve in axial computed tomography
      (CT) temporal bone scans. STUDY DESIGN AND SETTING: At a tertiary care academic
      center, we used, with a random sample of 25 CT scans, a marker (the "B-line") to
      identify the facial nerve. The variations in distance from this marker to the
      facial nerve were measured. RESULTS: This marker, which consists of a tangent
      line extrapolated from the posterior border of the basal turn of the cochlea,
      fell within 1 mm of the facial nerve on average. The average distance from the
      midpoint of the posterior border of the basal turn of the cochlea to the facial
      nerve was 11 +/- 1 mm. CONCLUSION: This is a very reliable marker for the
      vertical portion of the facial nerve. SIGNIFICANCE: This marker can be used to
      rapidly find the facial nerve, even in diseased or postsurgical temporal bones.

PMID- 12601324
TI  - Efficacy of surgical treatment of chronic otitis media.
AB  - This article presents our results of surgical treatment of chronic otitis media
      (COM) and discusses its efficacy regarding the control of disease and hearing
      results. A retrospective chart review of 84 ears was performed. Forty-one ears
      with noncholesteatomatous COM underwent tympanomastoidectomy, 43 ears with
      cholesteatoma were managed according to the extension of the disease, closed
      mastoidectomy was indicated in 19 cases, and open mastoidectomy was performed in
      24 ears. In the group without cholesteatoma, a stable ear with closed tympanic
      membrane was obtained in 85% of cases after the first procedure. The speech
      response threshold before and after surgery was 38 and 26 dB. In patients with
      cholesteatoma, a dry ear was achieved in 79% of cases on both techniques after
      the first intervention. The recurrence rate of cholesteatoma was 10% for the
      closed technique and 4% for the open technique. The mean preoperative and
      postoperative SRTs for the closed technique were 30 and 29 dB and for the open
      technique were 50 and 54 dB. The surgical treatment for COM can be a rewarding
      procedure if a correct technique is indicated. The surgery should be tailored
      regarding the clinical stage and intraoperative findings in each case.

PMID- 12601325
TI  - Composite chondroperichondrial clip tympanoplasty: the triple "C" technique.
AB  - OBJECTIVES: The study goal was to assess the success rate and efficacy of a
      myringoplasty (tympanoplasty type I) technique using a composite
      chondroperichondrial graft in a combined overlay-underlay fashion. STUDY DESIGN:
      A retrospective analysis of patients subjected to the technique was conducted.
      METHODS: A sample of 15 patients who met the inclusion criteria were reviewed for
      surgical results. All patients were treated by a single surgeon. RESULTS: This
      transcanal technique provides minimal morbidity and excellent results in selected
      patients. CONCLUSIONS: The described technique provides an effective method of
      closing nonmarginal perforations of the tympanic membrane.

PMID- 12601326
TI  - Pain intensity after laseruvulopalatoplasty and tonsillectomy.
AB  - OBJECTIVE: The first objective of this study was to evaluate pain intensity and
      opioid consumption during the first 24 hours after uvulopalatoplasty and
      tonsillectomy in the hospital, and the second was to evaluate pain intensity and
      its progression during the first 2 weeks after surgery at home. STUDY DESIGN AND
      SETTINGS: In a prospective parallel group study, 51 patients with
      uvulopalatoplasty or tonsillectomy were studied. Ketoprofen, a nonsteroidal
      antiinflammatory drug, and fentanyl citrate, an opioid, were used as analgesics.
      RESULTS: Despite ketoprofen infusion and free access to a patient-controlled pump
      with fentanyl citrate for rescue analgesia, inadequate pain relief was common
      both after uvulopalatoplasty (35%) and after tonsillectomy (28%) during the first
      24 hours after surgery. The consumption of fentanyl citrate was similar after
      both operations. At home, pain intensity was highest in the mornings during the
      first 5 days, and 10 patients had some pain still after 2 weeks. Also at home,
      high pain scores were reported commonly in both groups. CONCLUSION: Significant
      pain after uvulopalatoplasty and tonsillectomy lasted for several days.
      Ketoprofen in the commercial capsule form proved to be too short acting for
      overnight pain relief. SIGNIFICANCE: Pain treatment in patients with
      uvulopalatoplasty and tonsillectomy should be improved to allow patients a
      peaceful recovery after surgery.

PMID- 12601327
TI  - Visual loss after intraturbinate steroid injection.

PMID- 12601328
TI  - Middle turbinate osteoma presenting with ipsilateral facial pain, epiphora, and
      nasal obstruction.

PMID- 12601329
TI  - Cavernous sinus thrombophlebitis secondary to petrous apicitis: a case report.

PMID- 12601331
TI  - Thirty-centimeter barbecue skewer hooked on the pharyngoesophageal junction of a
      healthy young adult.

PMID- 12601330
TI  - Marble in the right main-stem bronchus: management.

PMID- 12601332
TI  - Bilateral external laryngoceles in a bagpiper: a case report.

PMID- 12601334
TI  - Cervical emphysema and pneumomediastinum after tonsillectomy: it can happen.

PMID- 12601335
TI  - Parapharyngeal lipoma causing obstructive sleep apnea syndrome.

PMID- 12601333
TI  - Metastasis of retinoblastoma to the parotid gland: diagnosis by fine needle
      aspiration cytology.

PMID- 12601336
TI  - Saccular cyst of the larynx.

PMID- 12601337
TI  - Epidemiology of urinary tract infections: incidence, morbidity, and economic
      costs.
AB  - Urinary tract infections (UTIs) are considered to be the most common bacterial
      infection. According to the 1997 National Ambulatory Medical Care Survey and
      National Hospital Ambulatory Medical Care Survey, UTI accounted for nearly 7
      million office visits and 1 million emergency department visits, resulting in
      100,000 hospitalizations. Nevertheless, it is difficult to accurately assess the
      incidence of UTIs, because they are not reportable diseases in the United States.
      This situation is further complicated by the fact that accurate diagnosis depends
      on both the presence of symptoms and a positive urine culture, although in most
      outpatient settings this diagnosis is made without the benefit of culture. Women
      are significantly more likely to experience UTI than men. Nearly 1 in 3 women
      will have had at least 1 episode of UTI requiring antimicrobial therapy by the
      age of 24 years. Almost half of all women will experience 1 UTI during their
      lifetime. Specific subpopulations at increased risk of UTI include infants,
      pregnant women, the elderly, patients with spinal cord injuries and/or catheters,
      patients with diabetes or multiple sclerosis, patients with acquired
      immunodeficiency disease syndrome/human immunodeficiency virus, and patients with
      underlying urologic abnormalities. Catheter-associated UTI is the most common
      nosocomial infection, accounting for >1 million cases in hospitals and nursing
      homes. The risk of UTI increases with increasing duration of catheterization. In
      noninstitutionalized elderly populations, UTIs are the second most common form of
      infection, accounting for nearly 25% of all infections. There are important
      medical and financial implications associated with UTIs. In the nonobstructed,
      nonpregnant female adult, acute uncomplicated UTI is believed to be a benign
      illness with no long-term medical consequences. However, UTI elevates the risk of
      pyelonephritis, premature delivery, and fetal mortality among pregnant women, and
      is associated with impaired renal function and end-stage renal disease among
      pediatric patients. Financially, the estimated annual cost of community-acquired
      UTI is significant, at approximately $1.6 billion.

PMID- 12601338
TI  - The etiology of urinary tract infection: traditional and emerging pathogens.
AB  - The microbial etiology of urinary infections has been regarded as well
      established and reasonably consistent. Escherichia coli remains the predominant
      uropathogen (80%) isolated in acute community-acquired uncomplicated infections,
      followed by Staphylococcus saprophyticus (10% to 15%). Klebsiella, Enterobacter,
      and Proteus species, and enterococci infrequently cause uncomplicated cystitis
      and pyelonephritis. The pathogens traditionally associated with UTI are changing
      many of their features, particularly because of antimicrobial resistance. The
      etiology of UTI is also affected by underlying host factors that complicate UTI,
      such as age, diabetes, spinal cord injury, or catheterization. Consequently,
      complicated UTI has a more diverse etiology than uncomplicated UTI, and organisms
      that rarely cause disease in healthy patients can cause significant disease in
      hosts with anatomic, metabolic, or immunologic underlying disease. The majority
      of community-acquired symptomatic UTIs in elderly women are caused by E coli.
      However, gram-positive organisms are common, and polymicrobial infections account
      for up to 1 in 3 infections in the elderly. In comparison, the most common
      organisms isolated in children with uncomplicated UTI are Enterobacteriaceae.
      Etiologic pathogens associated with UTI among patients with diabetes include
      Klebsiella spp., Group B streptococci, and Enterococcus spp., as well as E coli.
      Patients with spinal cord injuries commonly have E coli infections. Other common
      uropathogens include Pseudomonas and Proteus mirabilis.Recent advances in
      molecular biology may facilitate the identification of new etiologic agents for
      UTI. The need for accurate and updated population surveillance data is apparent,
      particularly in light of concerns regarding antimicrobial resistance. This
      information will directly affect selection of empiric therapy for UTI.

PMID- 12601339
TI  - The optimal use of diagnostic testing in women with acute uncomplicated cystitis.
AB  - Acute uncomplicated cystitis is a common and costly disorder in women, and there
      is considerable variation in the diagnostic strategies currently used in clinical
      practice. Because the diagnosis of cystitis can be established in most patients
      using the history alone, the clinician's responsibility is to determine which
      patients require additional diagnostic testing. Patients with typical symptoms
      (i.e., dysuria, frequency, urgency, hematuria), without risk factors for
      complicated infection or pyelonephritis, and without a history of vaginal
      discharge, have a very high probability of cystitis and are appropriate
      candidates for empiric treatment. It is more difficult, however, to rule out
      infection in patients with suspected cystitis. Because the prevalence of culture
      proven infection is very high in women who present with >or=1 symptom, and
      because the treatment threshold for this condition is low, a urine culture is
      generally required to rule out infection in patients with atypical symptoms, even
      in the presence of a negative dipstick test. In population-based, before-and
      after studies, use of diagnostic algorithms has been shown to significantly
      decrease the use of urinalysis, urine culture, and office visits while increasing
      the percentage of patients who receive recommended antibiotics. These strategies
      have substantially reduced the cost of managing cystitis without an increase in
      adverse events or a decrease in patient satisfaction. Randomized controlled
      trials are needed to more closely examine the outcomes, costs of care, and
      patient satisfaction from different diagnostic and management strategies.

PMID- 12601340
TI  - Addressing antibiotic resistance.
AB  - Management of uncomplicated urinary tract infections (UTIs) has traditionally
      been based on 2 important principles: the spectrum of organisms causing acute UTI
      is highly predictable (Escherichia coli accounts for 75% to 90% and
      Staphylococcus saprophyticus accounts for 5% to 15% of isolates), and the
      susceptibility patterns of these organisms have also been relatively predictable.
      As a result, empiric therapy with short-course trimethoprim-sulfamethoxazole (TMP
      SMX) has been a standard management approach for uncomplicated cystitis.However,
      antibiotic resistance is now becoming a major factor not only in nosocomial
      complicated UTIs, but also in uncomplicated community-acquired UTIs. Resistance
      to TMP-SMX now approaches 18% to 22% in some regions of the United States, and
      nearly 1 in 3 bacterial strains causing cystitis or pyelonephritis demonstrate
      resistance to amoxicillin. Fortunately, resistance to other agents, such as
      nitrofurantoin and the fluoroquinolones, has remained low, at approximately 2%.
      Preliminary data suggest that the increase in TMP-SMX resistance is associated
      with poorer bacteriologic and clinical outcomes when TMP-SMX is used for therapy.
      As a result, these trends have necessitated a change in the management approach
      to community-acquired UTI. The use of TMP-SMX as a first-line agent for empiric
      therapy of uncomplicated cystitis is only appropriate in areas where TMP-SMX
      resistance prevalence is <10% to 20%. In areas where resistance to TMP-SMX
      exceeds this rate, alternative agents need to be considered.

PMID- 12601341
TI  - Urinary tract infection: traditional pharmacologic therapies.
AB  - Urinary tract infections (UTIs) are common bacterial infections, particularly in
      women. Antimicrobial therapy is seldom indicated for asymptomatic infection, but
      antimicrobial therapy is usually indicated for amelioration of symptoms.
      Management of acute uncomplicated UTI (cystitis) is generally straightforward,
      with a predictable distribution of uropathogens isolated. First-line treatment of
      acute uncomplicated UTI has traditionally involved a 3-day regimen of
      trimethoprim-sulfamethoxazole (TMP-SMX) or TMP alone for patients with sulfa
      allergies. Increasing resistance among community-acquired Escherichia coli to TMP
      SMX worldwide has led to a reassessment of the most appropriate empiric therapy
      for these infections. Alternative first-line agents include the fluoroquinolones,
      nitrofurantoin, and fosfomycin. Factors to be considered in the selection of
      appropriate antimicrobial therapy include pharmacokinetics, spectrum of activity
      of the antimicrobial agent, resistance prevalence for the community, potential
      for adverse effects, and duration of therapy. Ideal antimicrobial agents for UTI
      management have primary excretion routes through the urinary tract to achieve
      high urinary drug levels. In addition, there are special considerations in the
      management of UTI among selected populations, including postmenopausal and
      pregnant women, and for women with frequent recurrent UTIs.

PMID- 12601342
TI  - The expanding role of fluoroquinolones.
AB  - There has been a growing rate of resistance among common urinary tract pathogens,
      such as Escherichia coli, to traditional antimicrobial therapies including the
      "gold standard" trimethoprim-sulfamethoxazole (TMP-SMX). Consequently,
      fluoroquinolone antimicrobial agents have taken on an expanding management role
      for UTIs. In fact, the recent Infectious Diseases Society of America clinical
      management guidelines for UTI recommend fluoroquinolones as first-line therapy
      for uncomplicated UTI in areas where resistance is likely to be of concern.
      Fluoroquinolones have demonstrated high bacteriologic and clinical cure rates, as
      well as low rates of resistance, among most common uropathogens. There are
      currently 7 fluoroquinolones with indications for UTI in the United States.
      However, only 3 are commonly used: levofloxacin, ciprofloxacin, and, to a lesser
      extent, gatifloxacin. Many of the fluoroquinolone agents have once-daily dosing
      regimens, enhancing patient adherence. In addition, levofloxacin and gatifloxacin
      have same-dose bioequivalency between their intravenous and oral formulations,
      allowing for "switch" or step-down therapy from parenteral to oral formulations
      of the same agent at the same dose. Fluoroquinolones are indicated for the
      management of acute uncomplicated UTIs, as well as complicated and severe UTI and
      pyelonephritis, in adults. They are the first-line treatment of acute
      uncomplicated cystitis in patients who cannot tolerate sulfonamides or TMP, who
      live in geographic areas with known resistance >10% to 20% to TMP-SMX, or who
      have risk factors for such resistance. Fluoroquinolone properties include a broad
      spectrum of coverage, low rates of resistance, and good safety profiles.

PMID- 12601344
TI  - National Center for Complementary and Alternative Medicine.

PMID- 12601343
TI  - Genetic polymorphisms and the progression of liver fibrosis: a critical
      appraisal.
AB  - Liver fibrosis is a highly dynamic process in which multiple genes interact with
      environmental factors. Recent human epidemiologic studies have identified
      possible polymorphisms in a number of candidate genes that influence the
      progression of liver fibrosis. These genetic factors could explain the broad
      spectrum of responses to the same etiologic agent found in patients with chronic
      liver diseases. Polymorphisms in genes encoding immunoregulatory proteins,
      proinflammatory cytokines, and fibrogenic factors may influence disease
      progression in patients with alcohol-induced liver disease, primary biliary
      cirrhosis, or chronic hepatitis C. However, some of the studies have yielded
      contradictory results. For example, conflicting results have been obtained in
      studies assessing the role of mutations in the hemochromatosis gene on fibrosis
      progression in patients with chronic hepatitis C. Large-scale, well-designed
      studies are required to clarify the actual role of this factor and other genetic
      variants in liver fibrosis.

PMID- 12601345
TI  - Angiostatin and hepatocellular carcinoma.

PMID- 12601346
TI  - HCC surveillance: who is the target population?

PMID- 12601347
TI  - Arterial and portal circulation and parenchymal changes in Budd-Chiari syndrome:
      a study in 17 explanted livers.
AB  - Hepatic parenchymal changes associated with Budd-Chiari syndrome (BCS) have been
      tentatively explained by combined arterial and portal perfusion disturbances in
      addition to the complete occlusion of hepatic veins. The aim of this study was to
      correlate pretransplant course and vascular imaging with pathologic findings in
      livers explanted for BCS. Seventeen consecutive white patients who underwent
      transplantation for severe classic BCS were retrospectively analyzed.
      Pretransplant course was 1 year or less in 8 patients and more than 1 year in 9
      patients. Thrombophilia was found in 16 patients (94%). Imaging showed decreased
      portal perfusion in 16 patients (94%) and increased arterial perfusion in 9
      patients. Histology showed obstructive portal venopathy and nodular regenerative
      hyperplasia (NRH) aspects in all cases, large regenerative nodules resembling
      focal nodular hyperplasia (FNH) in 9 cases, and cirrhosis in 2 cases. Patients
      with increased arterial inflow had large regenerative nodules and a protracted
      pretransplant course. Patients with acute thrombi in portal veins had parenchymal
      infarcts (2 cases) and a short pretransplant course. In conclusion, patients with
      severe BCS have a constant impaired perfusion inflow unrelated to progression of
      cirrhosis but related to the outcome. An early decrease in portal perfusion is
      observed in the short term and is responsible for NRH or infarcts if complicated
      with large thrombi. An increase in arterial perfusion compensates impaired portal
      flow in chronic BCS. Arterial hyperemia contributes to the development of large
      regenerative nodules that are FNH-like. This pathologic situation offers an
      interesting vascular model to further understand the parenchymal response to
      changes in hepatic blood flow.

PMID- 12601348
TI  - Prospective analysis of risk factors for hepatocellular carcinoma in patients
      with liver cirrhosis.
AB  - Better knowledge of the risk factors associated with the appearance of
      hepatocellular carcinoma (HCC) could improve the efficacy of surveillance
      programs. A total of 463 patients aged 40 to 65 years with liver cirrhosis in
      Child-Pugh class A or B were included in a program of early diagnosis. The
      predictive value of different risk factors was evaluated using the Kaplan-Meier
      method and Cox regression model. Thirty-eight patients developed HCC. In the
      multivariate analysis, 4 variables showed an independent predictive value for the
      development of HCC: age 55 years or older, antibody to hepatitis C virus (anti
      HCV) positivity, prothrombin activity 75% or less, and platelet count less than
      75 x 10(3)/mm(3). According to the contribution of each of these factors to the
      final model, a score ranging between 0 and 4.71 points was constructed to allow
      the division of patients into 2 different risk groups. The low-risk group
      included those with a score of 2.33 points or less (n = 270; 4 with HCC;
      cumulative incidence of HCC at 4 years, 2.3%), and the high-risk group included
      those with a score greater than 2.33 (n = 193; 34 with HCC; cumulative incidence
      of HCC at 4 years, 30.1%) (P =.0001). In conclusion, a simple score made up of 4
      clinical and biological variables allowed us to distinguish 2 groups of cirrhotic
      patients at high and low risk for the development of HCC. We believe this score
      can be useful in establishing a subset of cirrhotic patients in whom a
      surveillance program for early detection of HCC could be unjustified.

PMID- 12601349
TI  - Overexpression of orphan G-protein-coupled receptor, Gpr49, in human
      hepatocellular carcinomas with beta-catenin mutations.
AB  - To identify the genes responsible for carcinogenesis and progression of
      hepatocellular carcinoma (HCC), we screened differentially expressed genes in
      several human HCC cell lines. Among these genes, Gpr49 was up-regulated in
      PLC/PRF/5 and HepG2. Gpr49 is a member of the glycoprotein hormone receptor
      subfamily, which includes the thyroid-stimulating hormone receptor (TSHR).
      However, Gpr49 remains to be an orphan G-protein-coupled receptor. By real-time
      quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis,
      overexpression (>3-fold increase compared with the corresponding noncancerous
      liver tissue) of Gpr49 mRNA was observed in 18 of 38 (47%) HCCs compared with
      corresponding noncancerous livers. Clinicopathologically, overexpression of Gpr49
      was frequently observed in HCC with mutation in beta-catenin exon 3 (14 of 16
      cases, 87.5%). Moreover, introduction of mutant beta-catenin into mouse
      hepatocytes in culture caused up-regulation of the Gpr49 mouse homologue.
      Therefore, Gpr49 is likely to be a target gene activated by Wnt-signaling in HCC.
      In conclusion, although much is still unknown, Gpr49 may be critically involved
      in the development of HCCs with beta-catenin mutations and has the potential to
      be a new therapeutic target in the treatment of HCC.

PMID- 12601350
TI  - Cyclins and cyclin-dependent kinases: comparative study of hepatocellular
      carcinoma versus cirrhosis.
AB  - Increasing evidence has indicated that perturbation of cyclins is one of the
      major factors leading to cancer. The aim of this study was not only to
      investigate various cell cycle-related kinase activities in hepatocellular
      carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase
      activity levels between hepatitis C virus (HCV)-induced HCC and HCV-induced
      cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent
      kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous
      cirrhosis were determined by Western blot. The enzymatic activities of cyclins
      D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase
      assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin
      A, and Wee1 were significantly elevated in HCC compared with surrounding
      cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was
      accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The
      kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and
      surrounding cirrhotic tissues. In addition, the protein levels and kinase
      activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated
      HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E,
      cyclin A, and Wee1 play an important role in the development of HCC from
      cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the
      histopathologic grade and progression of HCC.

PMID- 12601351
TI  - Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic
      steatohepatitis.
AB  - Cytochrome P450 2E1 (CYP2E1) plays an important role in the pathogenesis of
      nonalcoholic steatohepatitis (NASH) in animal models, but its role in the
      pathogenesis of human NASH is unclear. Therefore, we measured hepatic CYP2E1
      activity and its correlates in a cohort of nondiabetic patients with NASH (NDN)
      and controls to explore its role in the pathogenesis of human NASH. Hepatic
      CYP2E1 activity was assessed using the oral clearance (CL(PO)) of chlorzoxazone
      (CHZ) in 20 NDN and 17 age, gender, and body mass index (BMI)-matched controls.
      The relationship between hepatic CYP2E1 activity and demographic and
      anthropometric variables; fasting levels of insulin, glucose, lipids, and beta-OH
      butyrate; insulin resistance; and nocturnal hypoxemia was assessed. Furthermore,
      expression of CYP2E1 in the peripheral lymphocytes was assessed using reverse
      transcription-polymerase chain reaction (RT-PCR). The CL(PO) of CHZ was
      significantly (P =.03) greater in NDN (41 +/- 12 L/h) compared with controls (33
      +/- 16 L/h). Lymphocyte CYP2E1 messenger RNA was significantly higher in NDN
      compared with controls (11.5 x 10(3) +/- 10 x 10(3) vs. 2.6 x 10(3) +/- 1.2 x
      10(3) molecules/microg total RNA, respectively, P <.001). On univariate analysis,
      BMI, respiratory quotient, high-density lipoprotein, triglycerides, insulin,
      insulin resistance, hypoxemia, and beta-OH butyrate significantly correlated with
      hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal
      hypoxemia (r = 0.50, P =.009) and beta-OH butyrate (r = 0.37, P =.04) were
      independent predictors of hepatic CYP2E1 activity. In conclusion, hepatic CYP2E1
      activity and lymphocyte CYP2E1 expression are enhanced in NDN. The significant
      correlations noted between CYP2E1 and hypoxemia and beta-OH butyrate suggest that
      these factors play a role in increased CYP2E1 activity that is seen in patients
      with NASH.

PMID- 12601352
TI  - Oral bile acids reduce bacterial overgrowth, bacterial translocation, and
      endotoxemia in cirrhotic rats.
AB  - Experiments were performed to test whether conjugated bile acid administration
      would decrease bacterial overgrowth, bacterial translocation, and endotoxemia in
      ascitic cirrhotic rats. Cholylsarcosine, a deconjugation-dehydroxylation
      resistant and cholylglycine, a deconjugation-dehydroxylation susceptible bile
      acid were used. Rats with CCl(4)-induced cirrhosis and ascites were fed
      cholylsarcosine, cholylglycine (both at 70 mg/kg/d), or placebo for 2 weeks.
      Healthy rats, as controls, were treated similarly. In cirrhotic rats receiving
      placebo, bile secretion from an acute biliary fistula was lower than in healthy
      rats (27.2 +/- 6.5 vs. 53.0 +/- 3.1 microL/kg/min; mean +/- SE, P<.05). The
      administration of conjugated bile acids to cirrhotic rats normalized bile
      secretion (cholylsarcosine, 51.8 +/- 6.29; cholylglycine, 52.72 +/- 8.9
      microL/kg/min). Total ileal bacterial content was 6-fold higher in ascitic
      cirrhotic rats than in healthy rats. Conjugated bile acid administration reduced
      bacterial content to normal levels. Bacterial translocation was less in cirrhotic
      animals receiving conjugated bile acids (cholylsarcosine, 33%; cholylglycine,
      26%) than in animals receiving placebo (66%). Endotoxemia was decreased in
      cirrhotic rats by conjugated bile acid feeding (cholylsarcosine, 0.098 +/- 0.002;
      cholylglycine 0.101 +/- 0.007 EU/mL) compared with placebo (0.282 +/- 0.124, P
      <.001). Survival was greater in animals receiving conjugated bile acids
      (cholylsarcosine, 10/15; cholylglycine, 11/15; placebo, 5/15). In conclusion, the
      administration of conjugated bile acids to ascitic cirrhotic rats increased bile
      acid secretion, eliminated intestinal bacterial overgrowth, decreased bacterial
      translocation, decreased endotoxemia, and increased survival. Oral conjugated
      bile acids may be useful in preventing bacterial translocation, endotoxemia, and
      spontaneous bacterial perotonitis in cirrhotic patients.

PMID- 12601354
TI  - Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion,
      cirrhosis-related complications, and hepatocellular carcinoma.
AB  - The pathologic role of hepatitis B virus (HBV) genotype in Chinese patients with
      HBV infection is largely unknown. We examined the relationship between HBV
      genotypes, and hepatitis B e antigen (HBeAg) seroconversion, acute exacerbation,
      cirrhosis-related complications, and precore/core promoter mutations. Three
      hundred forty-three HBV patients (288 were asymptomatic, 55 presented with
      cirrhosis-related complications) were recruited. HBV genotypes and precore/core
      promoter mutations were determined by line probe assays. Genotypes B and C were
      the 2 most common genotypes, contributing 28% and 60%, respectively. The median
      age of HBeAg seroconversion for patients with genotype B was 9 years earlier than
      patients with genotype C (P =.011). There were no differences in the liver
      biochemistry, HBV DNA level, and cumulative risk of acute exacerbation (defined
      as increased alanine aminotransferase level > or =1.5 x upper limit of normal)
      between patients with genotypes B and C. There was a trend for patients with
      genotype B to have a higher cumulative rate of HBeAg seroconversion compared with
      patients with genotype C at the initial follow-up of 6 years (P =.053), but this
      difference became insignificant during subsequent follow-up. The prevalence of
      both genotypes was the same in patients with and without cirrhosis-related
      complications and/or hepatocellular carcinoma. Genotype B was associated with
      precore mutations (P <.0001), whereas genotype C was associated with core
      promoter mutations (P <.0001). In conclusion, although patients with genotype B
      had earlier HBeAg seroconversion, there was no significant reduction in the risk
      of development of complications. Genotypes B and C are associated with high
      prevalence of precore and core promoter mutations, respectively.

PMID- 12601353
TI  - Thrombopoietin in acute liver failure.
AB  - Thrombopoietin (TPO) is the primary regulator of platelet production. TPO is
      produced in the liver and levels are low in patients with cirrhosis. Because
      thrombocytopenia is common in patients with acute liver failure (ALF), we
      measured TPO concentrations (normal TPO range, 31 to 136 pg/mL) in 51 patients
      with ALF to determine if low levels were associated with thrombocytopenia. TPO
      levels from hospital day 2 were elevated in 43% of patients, normal in 47%, and
      decreased in 10% of patients. Levels were higher in acetaminophen-induced than in
      non-acetaminophen-induced ALF, 160 (12 to 549) pg/mL versus 73 (18 to 563) pg/mL,
      respectively, P =.031. TPO levels did not correlate with platelet count and were
      not related with survival or infection. We analyzed daily TPO levels for the
      first week of hospitalization in 12 patients with acetaminophen-induced ALF and
      observed a gradual increase from a median admission level of 50 (5 to 339) pg/mL
      to a median peak level of 406 (125 to 1,081) pg/mL occurring on day 5 (3 to 6).
      Platelets were reduced in 11 of the 12 patients with a nadir platelet count of 52
      (19 to 156) x 10(9) cells/L occurring on day 5.5 (1 to 6). The peak TPO level did
      not correlate with the nadir platelet count (P =.43). In conclusion, the normal
      inverse relationship between platelet count and TPO levels was not observed in
      ALF. Despite severe hepatic dysfunction, serum TPO levels were initially normal
      and increased during hospitalization in acetaminophen-induced ALF, but did not
      prevent the development of thrombocytopenia.

PMID- 12601355
TI  - Ribavirin and interferon is effective for hepatitis C virus clearance in
      hepatitis B and C dually infected patients.
AB  - Ribavirin and interferon (IFN) are an effective treatment in 30% to 60% of
      patients with chronic hepatitis C. Whether they are also effective in dually
      infected patients with hepatitis B and C is unknown. Twenty-four patients with
      chronic hepatitis seropositive for both hepatitis B surface antigen and antibody
      to HCV received ribavirin 1,200 mg daily for 6 months, together with 6 million
      units (MU) IFN-alpha 2a thrice weekly for 12 weeks and then 3 MU for another 12
      weeks. Serum HCV RNA was positive in 21 patients (group I, serum HBV DNA positive
      in 17 patients) and negative in 3 patients (group II, all HBV DNA positive) by
      Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ). Serum
      alanine aminotransferase (ALT), HCV RNA, and hepatitis B virus (HBV) DNA were
      monitored regularly for 12 months. Another 30 patients with chronic hepatitis C
      alone receiving the same regimen, served as controls. The serum HCV clearance
      rate in group I patients (43%) was comparable with that in controls (60%, P =.63)
      24 weeks posttreatment. The serum ALT normalization rate in group I and group II
      patients was 43% and 0%, respectively, 24 weeks posttreatment. After treatment,
      resurgence of HBV and HCV was encountered in 4 group I patients and 1 group II
      patient, respectively. In conclusion, in hepatitis B and C dually infected
      patients, combination of IFN with ribavirin can achieve a sustained HCV clearance
      rate comparable with hepatitis C alone. In dually infected patients, the
      treatment may alter the dominant, ruling hepatitis virus.

PMID- 12601356
TI  - Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with
      spontaneously resolved HCV infection.
AB  - Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively
      infrequent event, and these individuals provide a unique opportunity to
      characterize correlates of protective immunity as an important first step in the
      development of vaccine candidates. The aim of this study was to directly and
      comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4(+) and
      CD8(+) T cells ex vivo from HLA diverse individuals who had been successful in
      spontaneously resolving HCV infection. We measured interferon gamma (IFN-gamma)
      production with an ELISPOT assay using magnetic bead-separated CD4(+) or CD8(+) T
      cells in response to autologous DCs that had been pulsed with 15mer per peptides
      overlapping by 11 amino acids and spanning all of the NS3 protein (150 total
      peptides). All subjects with spontaneously recovered HCV infection demonstrated
      vigorous and multispecific CD4(+) T-cell responses to NS3 peptides, and 6 of 10
      subjects demonstrated CD8(+) T-cell responses. More importantly, we identified
      novel, previously unpredicted antigenic regions, which in most cases elicited
      high frequencies within a given individual. In conclusion, subjects who have
      spontaneously eradicated HCV infection up to 35 years earlier demonstrate
      persistent CD4(+) and CD8(+) T-cell responses specific to NS3. By providing a
      comprehensive screening of all potential T-cell epitopes contained in the NS3
      region, our strategy defines the breadth of the T-cell response and identifies
      novel, unpredicted specificities.

PMID- 12601357
TI  - Influence of ethnicity in the outcome of hepatitis C virus infection and cellular
      immune response.
AB  - This study was performed to examine the immunologic basis for the apparent ethnic
      difference in clinical outcome of hepatitis C virus (HCV) infection between
      African Americans (AA) and Caucasian Americans (CA). To this end, we recruited 99
      chronically HCV-infected and 31 spontaneously HCV-cleared subjects for clinical,
      virologic, and immunologic analysis. In particular, CD4-proliferative T-cell
      response to genotype 1-derived HCV antigens (core, NS3-NS5) was examined in 82
      patients chronically infected with genotype 1 (54 AA, 28 CA) and in all HCV
      cleared subjects (14 AA, 17 CA). HCV-specific Th1 response also was examined in
      52 chronic and 13 recovered subjects. Our results showed that HCV clearance was
      associated with a vigorous HCV-specific Th1 response irrespective of ethnic
      origin. Although the HCV-specific CD4 T-cell response clearly was weaker during
      chronic infection, AA ethnicity in this setting was associated with a
      significantly greater CD4-proliferative T-cell response to HCV, particularly to
      the nonstructural antigens (22% AA vs. 0% CA, P =.007) as well as better clinical
      parameters of liver disease. Interestingly, most HCV-specific CD4 T-cell
      proliferative responses in AA patients were unaccompanied by concurrent
      interferon gamma (IFN-gamma) production, suggesting a dysregulated virus
      specific, CD4 T-cell effector function during chronic HCV infection. In
      conclusion, our results suggest that host ethnicity does influence the clinical
      outcome and antiviral T-cell response during HCV infection. AA ethnicity is
      associated with a more robust antiviral CD4 T-cell response than CA ethnicity,
      although these T cells are limited in direct virus or disease control due to
      their dysfunctional nature.

PMID- 12601358
TI  - Prediction of treatment outcome in patients with chronic hepatitis C:
      significance of baseline parameters and viral dynamics during therapy.
AB  - In patients with chronic hepatitis C virus (HCV) infection scheduled for a 48
      week treatment period, premature discontinuation of treatment was previously
      recommended if HCV-RNA levels remained detectable at week 24 of therapy.
      Considering the number of side effects and treatment costs, measurement of
      initial viral decline during therapy may identify virologic nonresponse earlier
      than 24 weeks. We retrospectively analyzed 260 European patients treated with
      standard or pegylated interferon alfa (IFN-alpha) and ribavirin for 24 to 48
      weeks. Early prediction of virologic response by HCV-RNA decline at weeks 4 and
      12 (Versant Quantitative [branched DNA (bDNA) 3.0]; Bayer Diagnostics,
      Emeryville, CA; and Qualitative [transcription-mediated amplification (TMA)] HCV
      RNA assay; Bayer Diagnostics) as well as clinical, biochemical, virologic, and
      histologic baseline parameters were analyzed by logistic regression and receiver
      operating characteristic (ROC) curves. A viral load at treatment week 4 above
      450,000 IU/mL and at week 12 above 30,000 IU/mL was 100% predictive for virologic
      nonresponse in all patients. From multivariate logistic regression analysis of
      all patients, independent predictors for sustained virologic response were:
      genotypes 2 and 3 (P <.0001), a low baseline gamma-glutamyltransferase (GGT)
      level (P <.0001), a high baseline alanine aminotransferase level (P =.002), and a
      low baseline viral load (P =.04). None of the latter 3 factors were predictive
      for sustained virologic response when analysis was restricted to the subgroup of
      genotypes 2- and 3-infected patients. In conclusion, virologic nonresponse can be
      predicted early at week 12 of treatment independent from the applied therapeutic
      regimen based on a cutoff level for HCV RNA of 30,000 IU/mL. This algorithm
      recognizes 53.7% of nonresponders previously identified at week 24 of treatment.

PMID- 12601359
TI  - Interferon alfa regulated gene expression in patients initiating interferon
      treatment for chronic hepatitis C.
AB  - Interferon alfa (IFN-alpha) is an approved therapeutic agent for chronic
      hepatitis C. To directly characterize the effects of IFN-alpha in humans, we used
      microarrays to profile gene expression in peripheral blood mononuclear cells
      (PBMCs) from hepatitis C patients treated with IFN-alpha. Seven patients were
      studied using two strategies: (1) in vivo: PBMCs were collected immediately
      before the first dose of IFN-alpha, and 3 and 6 hours after the dose; (2) ex
      vivo: PBMCs that were collected before the first IFN-alpha dose were incubated
      with IFN-alpha for 3 and 6 hours. The microarray datasets were analyzed with
      significance analysis of microarrays (SAM) to identify genes regulated by IFN
      alpha. We identified 516 named genes up-regulated at least 2-fold, at a false
      discovery rate (FDR) of less than 1%. In vivo and ex vivo studies generated
      similar results. No genes were identified as regulated differently between these
      2 experimental conditions. The up-regulated genes belonged to a broad range of
      functional pathways and included multiple genes thought to be involved in the
      direct antiviral effect of IFN-alpha. Of particular interest, 88 genes directly
      relating to functions of immune cells were up-regulated, including genes involved
      in antigen processing and presentation, T-cell activation, lymphocyte
      trafficking, and effector functions, suggesting that IFN-alpha up-regulates
      multiple genes involving different aspects of immune responses to enhance
      immunity against hepatitis C virus. In conclusion, IFN-alpha-inducible genes can
      be identified in human PBMCs in vivo as well as ex vivo. Signature changes
      associated with different treatment outcomes may be found among these genes.

PMID- 12601360
TI  - Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on
      gene expression.
AB  - Bile acids regulate the expression of genes involved in cholesterol homeostasis.
      They are ligands of the farnesoid X receptor, which induces small heterodimer
      partner (SHP)-1, a transcriptional repressor of bile acid synthetic enzymes. In
      cholestatic liver disease, hepatic bile acid concentrations are elevated and
      expression of the major Na+-independent bile acid uptake system, organic anion
      transporting polypeptide (OATP)-C (solute carrier gene family SLC21A6), is
      markedly decreased. Because the OATP-C gene is transcriptionally dependent on the
      hepatocyte nuclear factor (HNF) 1 alpha, we hypothesized that bile acids decrease
      OATP-C expression through direct repression of HNF1 alpha. To test this
      hypothesis, we studied the regulation of the human HNF1 alpha gene by bile acids.
      HNF1 alpha expression in cultured hepatoma cells was decreased approximately 50%
      after 12 hours' exposure to 100 micromol/L chenodeoxycholic acid (CDCA).
      Characterization of the human HNF1 alpha gene promoter identified a consensus
      bile acid response element that binds and is activated by HNF4 alpha. Mutagenesis
      of the HNF4 alpha site abolished baseline HNF1 alpha promoter activity. The
      central mechanism by which bile acids repress HNF1 alpha is decreased activation
      by HNF4 alpha. SHP directly inhibits HNF4 alpha-mediated transactivation of the
      HNF1 alpha promoter in cotransfection assays. In addition, HNF4 alpha nuclear
      binding activity is decreased by CDCA and the human HNF4 alpha gene promoter is
      repressed by CDCA through an SHP-independent mechanism. In conclusion, we show
      that repression of HNF1 alpha is an important new mechanism by which bile acids
      regulate the expression of HNF1 alpha-dependent genes in man. This explains the
      suppressive effect of bile acids on the OATP-C gene promoter, leading to
      decreased expression in cholestatic liver disease.

PMID- 12601361
TI  - Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell
      markers.
AB  - Hepatic oval cells (HOC) are thought to be a type of facultative stem cell that
      arises as a result of certain forms of hepatic injury. A new and more efficient
      model has been established to activate the oval cell compartment in mice by
      incorporating 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) in a standard chow
      at a concentration of 0.1%. At the present time, very few markers exist for the
      mouse oval cells. One accepted marker is A6, an uncharacterized epitope
      recognized by mouse hepatic oval cells and it is accepted to be an oval cell
      marker. Sca-1 is a cell surface marker used to identify hematopoietic stem cells
      in conjunction with Thy-1+, CD34+, and lineage-specific markers. Both the CD34
      and Sca-1 antigens are not normally expressed in adult liver, but are expressed
      in fetal liver, presumably on the hematopoietic cells. We report herein that
      mouse oval cells express high levels of Sca-1 and CD34, as well as CD45 surface
      proteins. Immunohistochemistry revealed that the cells expressing Sca-1/CD34/CD45
      were indeed oval cells because they co-expressed the oval cell-specific marker A6
      (94.57% +/- 0.033%), as well as alpha-fetoprotein (AFP) (75.92% +/- 0.071%). By
      using Sca-1 antibody in conjunction with magnetic activated cell sorting (MACS),
      followed with a flow cytometric cell sorting (FACS) method for CD34 and CD45, we
      have developed a rapid oval cell isolation protocol with high yields of greater
      than 90%. In conclusion, we have an efficient murine model for the production and
      isolation of large numbers of highly purified oval cells. Our system works with
      most strains of mouse, which will facilitate both in vivo and in vitro studies of
      mouse hepatic oval cells.

PMID- 12601362
TI  - GM-CSF expands dendritic cells and their progenitors in mouse liver.
AB  - Dendritic cells (DCs) are rare but ubiquitous antigen-presenting cells situated
      in lymphoid and nonlymphoid organs throughout the body. The study of DCs located
      in the liver has been restricted by their relative scarcity and the difficulty of
      their isolation. Because granulocyte-macrophage colony-stimulating factor (GM
      CSF) is a critical growth factor for DCs in vitro, we postulated that it would
      expand hepatic DCs in vivo. We found that adenoviral-mediated GM-CSF
      overexpression in normal mice increased the number of liver DCs 400-fold to more
      than 100 million cells. GM-CSF-recruited DCs were CD11c(+)DEC205(-) and had high
      expression of major histocompatibility complex (MHC) class II, CD54, and CD80 but
      low CD40 and CD86 staining. Further maturation occurred after overnight culture.
      In addition to CD11c(+)DEC205(-) DCs, a population of CD11c(-)DEC205(low/-) cells
      resembling DC progenitors described previously in normal mice was expanded as
      serum GM-CSF levels increased. GM-CSF-recruited CD11c(+)DEC205(-) DCs and CD11c(
      )DEC205(low/-) cells had different functional capabilities. CD11c(+)DEC205(-) DCs
      captured far more protein antigen in vivo, produced higher amounts of interleukin
      (IL)-6 and tumor necrosis factor (TNF)-alpha, and induced greater allogeneic and
      antigen-specific T-cell stimulation. A proportion of CD11c(-)DEC205(low/-) cells
      differentiated into CD11c(+) cells and gained T-cell stimulatory ability when
      cultured in the presence of GM-CSF. In conclusion, our findings show that GM-CSF
      can profoundly influence recruitment and development of DCs in murine liver.

PMID- 12601363
TI  - Replicative senescence of activated human hepatic stellate cells is accompanied
      by a pronounced inflammatory but less fibrogenic phenotype.
AB  - Limited proliferative capacity is a characteristic of most normal human cells and
      results in a growth-arrested state, called replicative senescence. Functional
      expression of the telomerase catalytic subunit (human telomerase reverse
      transcriptase; hTERT) in human activated hepatic stellate cells (HSCs) rescues
      them from death with immortalization and maintains an activated HSC phenotype.
      The aim of this study was to evaluate alterations in gene and protein expression
      of in vitro aged human activated HSCs and to define the pathway by which
      senescent-activated HSCs are eliminated in culture. Altered patterns of gene
      expression in senescent human HSCs were assessed using DNA microarray analysis
      and compared with early passage HSCs or hTERT immortalized HSCs. Senescent HSCs
      showed higher expression of inflammation and stress-associated genes as compared
      with early passage HSCs. Senescent HSCs expressed reduced levels of extracellular
      matrix proteins, including collagens, tenascin, and fibronectin. TUNEL staining
      of senescent HSCs showed approximately 21% positive cells, indicating DNA
      fragmentation and apoptosis. Apoptosis involved the mitochondrial pathway with
      decreased levels of Bcl-2 and Bcl-x(L) protein, release of cytochrome c, and
      increased caspase-3 activity. In contrast, 4% to 5% of early activated HSCs or
      telomerase positive HSCs were TUNEL positive. In conclusion, cultured human HSCs
      undergo a switch from a fibrogenic to an inflammatory phenotype, suggesting that
      senescent human HSCs might modulate chronic wound healing processes. Maintenance
      of telomere length represents an important survival factor for activated human
      HSCs.

PMID- 12601365
TI  - Proangiogenic role of tumor-activated hepatic stellate cells in experimental
      melanoma metastasis.
AB  - Myofibroblasts infiltrate malignant liver tumors, although their pathogenic
      implications are unclear. Immunohistochemical detection of alpha-smooth muscle
      actin, glial fibrillary acidic protein (GFAP), and CD31 and CD34 expression was
      used to analyze the contribution of myofibroblasts to angiogenesis in hepatic
      metastasis produced by intrasplenically-injected B16 melanoma (B16M). Because
      activated hepatic stellate cells (HSCs) are oxygen-sensing myofibroblasts
      producing vascular endothelial growth factor (VEGF), the effect of B16M and human
      A375 melanoma supernatants on VEGF production by immortalized rat HSC line T6 and
      primary cultured human HSCs also was studied under an hypoxic atmosphere
      mimicking a tumor microenvironment. Myofibroblast infiltration preceded
      endothelium recruitment in avascular micrometastasis and generated specific
      stroma for sinusoidal-type and portal-type angiogeneses. Thereafter,
      myofibroblasts and endothelial cells colocalized within both angiogenic patterns
      and their numerical densities correlated with metastasis development.
      Myofibroblasts often were GFAP-positive, suggesting an HSC origin. Melanoma
      supernatants stimulated VEGF messenger RNA and protein synthesis by HSCs. These
      effects were potentiated by hypoxia. VEGF up-regulation was accompanied by
      increased expression of cyclooxygenase type 2 (COX-2) and PGE2 synthesis. HSC
      production of VEGF decreased under COX-2 inhibition, whereas it was increased by
      exogenous PGE2. The high VEGF expression in HSCs induced by melanoma factors and
      hypoxia resulted in mitogenic, antiapoptotic, and motogenic stimulation of both
      murine hepatic sinusoidal endothelium and human umbilical vein endothelium. In
      conclusion, temporal and positional relationships evolve between myofibroblast
      and endothelium recruitment during metastasis development. Mechanistically,
      hypoxic induction of VEGF in tumor-activated HSCs may create a proangiogenic
      microenvironment, facilitating endothelial cell recruitment and survival during
      hepatic metastasis transition from an avascular to a vascular stage.

PMID- 12601364
TI  - CYP3A4 inducible model for in vitro analysis of human drug metabolism using a
      bioartificial liver.
AB  - CYP3A is responsible for approximately 50% of the therapeutic drug-metabolizing
      activity in the liver. The present study was undertaken to establish the CYP3A4
      inducible model for analysis of human drug metabolism using a bioartificial liver
      composed of the functional hepatocellular carcinoma cell (HCC) line FLC-5. A
      radial-flow bioreactor (RFB), which is a carrier-filled type bioreactor, was used
      for 3-dimensional perfusion culture of FLC-5 cells. The CYP3A4 messenger RNA
      (mRNA) expression level 48 hours after rifampicin treatment in the RBF was
      approximately 100 times higher than that in a monolayer culture. Western blot
      analysis also demonstrated an increase in expression of the CYP3A protein. When
      testosterone, a substrate for CYP3A4, was added to the rifampicin-treated cell
      culture, 6 beta-hydroxy testosterone as a metabolite was formed. Electrophoretic
      mobility shift assay (EMSA) with a CYP3A4 ER6 probe demonstrated that relatively
      high molecular weight complex containing pregnane X receptor (PXR)/retinoid X
      receptor alpha(RXR alpha), compared with that in the monolayer culture, is
      possibly generated in the RFB culture of FLC-5 treated with rifampicin.
      Similarly, the assay with a probe of HNF-4 alpha-binding motif indicated the
      formation of a large protein complex in the RFB culture. Because it is known that
      PXR transactivates CYP3A4 gene via its response element and expression of PXR is
      regulated by HNF-4 alpha, the large complexes binding to response elements of PXR
      or HNF-4 alpha in the RFB culture may contribute to up-regulation of CYP3A4 mRNA.
      In conclusion, the bioartificial liver composed of human functional HCC cell line
      was useful in studying drug interactions during induction of human CYP3A4.

PMID- 12601366
TI  - Hepatocyte growth factor activates CCAAT enhancer binding protein and cell
      replication via PI3-kinase pathway.
AB  - Hepatocyte growth factor (HGF), a ligand of c-Met receptor, stimulates activation
      of cellular kinases via phosphatidylinositol 3-kinase (PI3-kinase).
      CCAAT/enhancer binding protein (C/EBP) controls cell cycle progression. The
      present study was designed to determine whether HGF activates C/EBP in
      association with the S-phase entrance for cell replication and whether PI3-kinase
      contributes to the activation of C/EBP. Treatment of H4IIE cells, a hepatocyte
      derived cell line, with HGF increased protein binding to the C/EBP binding site
      at an early time. Immunodepletion, subcellular fractionation, and confocal
      microscopic analyses showed that the HGF-induced C/EBP DNA binding activity
      depended on nuclear translocation of C/EBP beta. Whereas stable transfection of
      the p110 catalytic subunit of PI3-kinase enhanced HGF-mediated nuclear
      translocation of C/EBP beta and DNA binding, stable transfection of p85 subunit
      or chemical inhibition of PI3-kinase completely blocked C/EBP activation. HGF
      increased luciferase reporter activity in cells transfected with a mammalian cell
      expression vector containing -1.65 kilobase rGSTA2 promoter comprising C/EBP
      response element (pGL-1651). Whereas transfection with pCMV500, a control vector,
      allowed pGL-1651 to respond to HGF, expression of dominant negative mutant C/EBP
      completely inhibited the ability of HGF to stimulate the reporter gene
      expression. Flow cytometric analysis showed that HGF caused an increase in the
      area of S phase with a reciprocal decrease in that of G(1) phase, suggesting that
      HGF promoted cell cycle progression to S phase. In conclusion, HGF induces
      nuclear translocation of C/EBP beta via the PI3-kinase pathway and stimulates
      C/EBP DNA binding and gene transcription and that the PI3-kinase-mediated C/EBP
      activation by HGF may contribute to cell replication.

PMID- 12601367
TI  - Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene.
AB  - Recent studies have reported that antiangiogenic gene delivery into cancer cells
      inhibits growth of certain tumors in vivo. Hepatocellular carcinoma (HCC) is a
      hypervascular cancer, and antiangiogenic gene therapy might be suitable for HCC.
      In the present study, we investigated the antiangiogenic effects of angiostatin
      gene transduction into HCC both in vitro and in vivo. Angiostatin gene was cloned
      into a pSecTag2B mammalian expression vector to construct pSecTag2B-ANG.
      pSecTag2B or pSecTag2B-ANG were transfected into an HCC cell line, PLC/PRF/5, and
      then stable transfectants were obtained by Zeocin selection. pSecTag2B or
      pSecTag2B-ANG transfection did not alter the expression of vascular endothelial
      growth factor (VEGF), a potent angiogenic stimulator, or pigment epithelium
      derived factor (PEDF), an angiogenic inhibitor, in PLC/PRF/5 cells. However,
      conditioned media (CM) derived from pSecTag2B-ANG-transfected PLC/PRF/5 cells (CM
      ANG) suppressed the proliferation and migration of human umbilical vein
      endothelial cells (HUVEC) by 35% and 50%, respectively, relative to their effects
      on nontransfected cells. In in vivo experiments, pSecTag2B-ANG stable transfected
      (CM-Mock) and nontransfected cells (CM-N) were mixed at various proportions and
      the mixed cells were subcutaneously implanted into athymic mice. Suppression of
      tumor growth was noted in mice implanted with angiostatin gene-transfected cells,
      and such suppression was proportional with the percentage of transfected cells.
      Analysis of the vascular density in these tumors showed that the tumor growth
      suppression effect of angiostatin gene correlated with suppression of tumor
      vascularity. In conclusion, antiangiogenic gene therapy using angiostatin gene is
      potentially suitable for the treatment of patients with HCC.

PMID- 12601368
TI  - The clinical penetrance of hereditary hemochromatosis.

PMID- 12601369
TI  - Serum phosphate as a predictor of outcome in acetaminophen-induced fulminant
      hepatic failure.

PMID- 12601370
TI  - Antiviral therapy in HBe-Ag-positive hepatitis B with normal aminotransferase
      levels.

PMID- 12601371
TI  - Modifier genes and cystic fibrosis liver disease.

PMID- 12601372
TI  - Pearls of pathology.

PMID- 12601374
TI  - The risks of exclusion.

PMID- 12601375
TI  - From neuroimaging to neuroethics.

PMID- 12601376
TI  - Intelligence tests predict brain response to demanding task events.

PMID- 12601378
TI  - Plateau properties in pain pathways.

PMID- 12601377
TI  - A new role for an old kinase: CK2 and the circadian clock.

PMID- 12601379
TI  - A switch for oscillatory bursting.

PMID- 12601381
TI  - Neurotrophin-4 mediated TrkB activation reinforces morphine-induced analgesia.

PMID- 12601382
TI  - Toxic gas protects rodent hearts.

PMID- 12601383
TI  - Website to facilitate public participation in federal rulemaking process.

PMID- 12601384
TI  - Follow the unwritten rules?

PMID- 12601385
TI  - What's your diagnosis? Ranavirus infection.

PMID- 12601386
TI  - An analysis of ISO intracutaneous reactivity test results to justify a reduction
      in animal requirements.
AB  - The ISO intracutaneous reactivity test is the standard protocol for determining a
      medical device's potential for causing irritation. The authors present data
      indicating that the number of animals required per test can be reduced from three
      rabbits to two.

PMID- 12601387
TI  - Response to novel objects and foraging tasks by common marmoset (Callithrix
      jacchus) female pairs.
AB  - The authors analyze the effects of enrichment devices on the behavior of common
      marmoset female pairs, and determine which aspects of these devices are more
      likely to elicit explorative behaviors, and how their presence affects aggressive
      and stress-related behaviors. The results support the use of enrichment devices
      for captive primates and show that in marmosets, their effectiveness strongly
      depends on location within the enclosure and the presence of hidden food.

PMID- 12601388
TI  - Sample Power and ExpDesign: tools for improving design of animal experiments.
AB  - Proper experimental design, involving the correct number of animals, should be a
      basic skill for any scientist working with animals. The authors describe a
      university-developed and freely available tutorial program and an interactive
      computer-assisted learning program, both of which guide students through the
      steps necessary for designing animal experiments and estimating optimal sample
      sizes.

PMID- 12601389
TI  - Inhalation anesthetics in rodents.

PMID- 12601391
TI  - Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes.
AB  - Dendritic cells (DC) are professional antigen-presenting cells playing a central
      role in the induction of antigen-specific cytotoxic T-lymphocytes (CTL). We
      analyzed the efficiency of tumor RNA transfection into DC using different sources
      of RNA as well as delivery strategies including electroporation, lipofection and
      CD71-receptor-based delivery. To evaluate the sensitivity of these approaches, we
      utilized in vitro transcribed enhanced green fluorescence protein (EGFP)-RNA and
      whole tumor RNA from EGFP-transfected renal cell carcinoma cell line N43. We
      demonstrate that electroporation was the most effective way yielding about 30%
      EGFP positive cells while less than 1% of DC expressed EGFP using the transferrin
      receptor transfection system. Delivery of RNA with liposomes resulted in 17.5% of
      EGFP positive cells depending on the RNA amount. However, when these approaches
      were applied to transduce DC with RNA derived from the A498 cell line for T-cell
      priming, tumor-specific CTL could be induced using all delivery strategies
      suggesting that this technology has the potential to induce cytotoxic T-cell
      response even when low level of antigen is delivered. Furthermore, we demonstrate
      that amplification of whole tumor messenger RNA (mRNA) as well as the use of
      total instead of purified mRNA can be utilized for stimulating tumor-specific CTL
      responses.

PMID- 12601392
TI  - Enhancement of thymidine kinase-mediated killing of malignant glioma by BimS, a
      BH3-only cell death activator.
AB  - Herpes simplex virus thymidine kinase (HSV-tk)/gancyclovir (GCV) therapy has the
      ability to inhibit tumor formation in animal models but the results of clinical
      trials have been disappointing. To improve the performance of tk/GCV therapy, we
      tried combination therapy designed to enhance its cytotoxic effects by
      introducing genes that induce apoptosis of the tumor cells through different
      pathways. We concentrated our efforts on the use of Bim, a BH3-only member of
      death activators in the Bcl-2 superfamily, because Bim is not involved in the
      pathways through which HSV-tk/GCV therapy induces apoptosis in malignant glioma
      cells. Among three alternative splicing variants, BimEL, BimL, and BimS, BimS
      lacks the binding domain for the dynein light chain LC8, which negatively
      regulates the proapoptotic function of BimEL and BimL. All four malignant glioma
      cell lines, U251, A172, T-430, and U373 underwent cell death after transfer of
      BimS using an adenovirus vector (AVC2). Intriguingly, combination of AVC2-BimS
      with AVC2-tk markedly increased the sensitivity of U251 cells to GCV both in
      vitro and in vivo. In contrast, AVC2-BimL did not induce significant cell death.
      These results indicated that BimS had the ability to improve the efficiency of
      HSV-tk/GCV therapy in the treatment of malignant glioma and suggested that the
      targeting of different proapoptotic pathways may be a useful strategy for the
      development of an effective gene therapy approach to treatment.

PMID- 12601393
TI  - Recombinant adenovirus shedding after intratumoral gene transfer in lung cancer
      patients.
AB  - We conducted two phase 1 trials of direct intratumoral injection of a recombinant
      E1E3-deleted adenovirus (AdR) encoding either the bacterial enzyme beta
      galactosidase (Ad.RSVbetagal) or interleukin 2 (IL2, AdTG5327) into primary
      nonsmall-cell lung cancers of 21 patients. We report here virus shedding and the
      duration of virus expression in the tumor after intrabronchial injection of
      10(7), 10(8) or 10(9) PFU of adenovirus. The infectious AdR and the viral DNA
      were detected in PBL, plasma, stool and aerodigestive samples in a dose-dependent
      manner, since cell cultures and PCRs were found to be positive mainly for samples
      from patients who received the highest AdR dose (10(9) PFU). We detected beta
      galactosidase activity in the tumor biopsy samples of 66% of the patients,
      seemingly dose related, and only low levels of IL2 mRNA could be detected in
      tumor biopsy samples. E1 sequences were not detected by PCR in any of the PBL and
      bronchial samples collected after virus delivery, except in one patient. In this
      patient, E1 sequences were detected in PBL as well as in tumor biopsy samples
      collected at days 8, 30 and 60 and were correlated with longer beta-galactosidase
      expression in tumor samples. PBL tested before and after virus delivery contained
      both E1 sequences indicating that they did not result from replication-competent
      adenovirus (RCA) E1 sequences present in the inoculum. In addition, only on the
      day of the injection was Ad.RSVbetagal also detected in E1-positive PBL,
      indicating that virus replication in blood was very unlikely.

PMID- 12601394
TI  - Microbubble ultrasound improves the efficiency of gene transduction in skeletal
      muscle in vivo with reduced tissue damage.
AB  - Intramuscular injection of naked plasmid DNA is a safe approach to the systemic
      delivery of therapeutic gene products, but with limited efficiency. We have
      investigated the use of microbubble ultrasound to augment naked plasmid DNA
      delivery by direct injection into mouse skeletal muscle in vivo, in both young (4
      weeks) and older (6 months) mice. We observed that the albumin-coated
      microbubble, Optison (licensed for echocardiography in patients), significantly
      improves the transfection efficiency even in the absence of ultrasound. The
      increase in transgene expression is age related as Optison improves transgene
      expression less efficiently in older mice than in younger mice. More importantly,
      Optison markedly reduces muscle damage associated with naked plasmid DNA and the
      presence of cationic polymer PEI 25000. Ultrasound at moderate power (3 W/cm2 1
      MHz, 60 s exposure, duty cycle 20%), combined with Optison, increases
      transfection efficiency in older, but not in young, mice. The safe clinical use
      of microbubbles and therapeutic ultrasound and, particularly, the protective
      effect of the microbubbles against tissue damage provide a highly promising
      approach for gene delivery in muscle in vivo.

PMID- 12601395
TI  - Long-term normalization in the central nervous system, ocular manifestations, and
      skeletal deformities by a single systemic adenovirus injection into neonatal mice
      with mucopolysaccharidosis VII.
AB  - Systemic injection of an adenovirus vector into adult mice resulted in
      pathological improvements in multiple visceral organs of mice with
      mucopolysaccharidosis VII; however, no therapeutic efficacy was observed for
      mental retardation, skeletal deformities, corneal clouding, and retinal
      degeneration. In this study, an adenovirus vector expressing human beta
      glucuronidase was injected into mice with mucopolysaccharidosis VII within 24 h
      of birth, and therapeutic efficacy was evaluated. In the brains of the mice, more
      than 20% of GUSB activity was maintained for at least 20 weeks after birth, and
      histopathological analysis showed no obvious lysosomal storage. Furthermore, no
      vacuolated cells were detected in corneal stroma and retinal pigment epithelium
      in the eyes of the mice treated in the neonatal period, while pathological
      improvement was not observed in adult MPSVII mice that received similar
      treatments. The treated mice also lacked characteristic facial skeletal
      deformities, and radiographic analysis demonstrated that their facial and cranial
      bones were morphologically normal. These results indicate that a single systemic
      adenovirus injection in the neonatal period could prevent the progression of
      mental retardation, corneal clouding, retinal degeneration, and skeletal
      deformities, all of which are frequently observed clinical manifestations and
      difficult to treat in adulthood.

PMID- 12601396
TI  - Transfection of NFkappaB-decoy oligodeoxynucleotides using efficient ultrasound
      mediated gene transfer into donor kidneys prolonged survival of rat renal
      allografts.
AB  - Nuclear factor kappaB (NFkappaB) plays a pivotal role in the coordinated
      transactivation of a series of genes of cytokines and adhesion molecules that are
      highly involved in the onset of acute rejection in organ transplantation. We
      previously developed decoy cis-elements oligo deoxyribonucleic acid against
      NFkappaB (NFkappaB-decoy) that effectively inhibited the activation of major
      inflammatory mediators in vitro and in vivo. Accordingly, we hypothesized that
      transfection of NFkappaB-decoy into the donor kidney would prevent acute
      rejection and prolong graft survival, and thus provide effective therapy for
      renal acute rejection. To transfect NFkappaB-decoy, we employed a novel approach
      using ultrasound exposure with an echocardiographic contrast agent, Optison, and
      clearly demonstrated successful transfection of NFkappaB-decoy into renal tissue.
      The therapeutic effect of NFkappaB-decoy on renal allografts was then evaluated
      in a rat renal allograft model (Wistar-Lewis). In the control group, graft
      function significantly deteriorated with marked destruction of renal tissue,
      accompanied by increased production of major inflammatory mediators, and all
      animals died of renal failure by 9 days. In contrast, graft function (serum
      creatinine on day 2, NFkappaB-treated: 0.97+/-0.16 versus control: 1.84+/-0.23
      mg/dl, P<0.01) and histological structure were well preserved with significantly
      decreased expression of NFkappaB-regulated cytokines and adhesion molecules,
      including IL-1, iNOS, MCP-1, TNF-alpha, and ICAM-1, in allografts transfected
      with NFkappaB-decoy. As a result, animal survival was significantly prolonged in
      this group as compared to controls (14.2+/-5.2 versus 7.1+/-1.2 days, P<0.01).
      Thus, we established a novel ultrasound-Optison-mediated gene transfection
      approach and demonstrated the significant prolongation of graft survival by the
      successful transfection of NFkappaB-decoy into the donor kidney in a rat renal
      allograft model.

PMID- 12601397
TI  - Adenovirus-mediated overexpression of a gene prevents hearing loss and
      progressive inner hair cell loss after transient cochlear ischemia in gerbils.
AB  - The use of adenoviral vectors has recently provided a novel strategy for direct
      gene transfer into the cochlea. In this study, we assessed the utility of an
      adenoviral vector expressing glial-cell-derived neurotrophic factor (GDNF) in
      ischemia-reperfusion injury of the gerbil cochlea. The vector was injected
      through the round window 4 days before ischemic insult. The distribution of a
      reporter transgene was confirmed throughout the cochlea from the basal to the
      apical turn and Western blot analysis indicated significant upregulation of GDNF
      protein 11 days following virus inoculation. Hearing ability was assessed by
      sequentially recording compound action potentials (CAP), and the degree of hair
      cell loss in the organ of Corti was evaluated in specimens stained with rhodamine
      phalloidin and Hoechst 33342. On the seventh day of ischemia, the CAP threshold
      shift and inner hair cell loss were remarkably suppressed in the Ad-GDNF group
      compared with the control group. These results suggest that adenovirus-mediated
      overexpression of GDNF is useful for protection against hair cell damage, which
      otherwise eventually occurs after transient ischemia of the cochlea.

PMID- 12601398
TI  - Nonviral genetic transfer of Fas ligand induced significant growth suppression
      and apoptotic tumor cell death in prostate cancer in vivo.
AB  - To accomplish efficient nonviral gene therapy against prostate cancer (PC),
      Epstein-Barr virus (EBV)-based plasmid vectors containing EBNA1 gene and oriP
      were employed and combined with a cationic polymer or cationic lipid. When EBV
      plasmid/poly-amidoamine dendrimer complex was injected into PC-3-derived tumors
      established in severe combined immunodeficiency mice, a considerable expression
      of marker gene was obtained in the tumors, and the expression level was more than
      eight-fold higher than that achieved by conventional plasmid vector/dendrimer.
      Since most PC cells express the apoptotic signal molecule Fas (Apo-1/CD95) on
      their surface, Fas ligand (FasL) gene was transferred into PC cells to kill the
      tumor cells. In vitro transfection with pGEG.FasL (an EBV-plasmid with the FasL
      gene) significantly reduced the viability of PC cells, which subsequently
      underwent apoptosis. Intratumoral injections of pGEG.FasL into PC induced
      significant growth suppression of the xenograft tumors, in which typical
      characteristics of apoptosis were demonstrated by TUNEL staining and electron
      microscopic observations. When pGEG.FasL transfer was accompanied by systemic
      administrations of cisplatin, the tumors were inhibited even more remarkably,
      leading to prolonged survival of the animals. FasL gene transfection by means of
      EBV-based plasmid/cationic macromolecule complexes may provide a practical
      therapeutic strategy against PC.

PMID- 12601400
TI  - Implementing integrated care in Counties Manukau.

PMID- 12601399
TI  - A direct mechanical method for accurate and efficient adenoviral vector delivery
      to tissues.
AB  - We describe a mechanical method for delivery of adenoviral vector to the
      adventitial surface of arteries and to other tissues. Our goal was to
      characterize, principally in intact carotid artery, the morphological,
      biochemical, and functional effects of mechanical delivery of a recombinant beta
      galactosidase-expressing adenoviral vector following its direct application using
      a small paintbrush. Our ex vivo and in vivo data demonstrate efficient, accurate,
      and rapid transduction of arteries without compromise of their morphological,
      biochemical, and functional integrity. We also demonstrate the general
      applicability of this technique in vivo via transduction of skeletal muscle,
      fibrotendinous tissue, peritoneum, serosal surface of bowel, and wounded skin. We
      conclude that direct mechanical delivery of an adenoviral vector to tissues using
      a suitable paintbrush represents an intuitive, accurate, and effective means of
      augmenting gene transfer efficiency, and may be a useful adjunct to other
      delivery methods.

PMID- 12601401
TI  - Are we spending enough on healthcare in New Zealand?

PMID- 12601402
TI  - Integrating healthcare: the Counties Manukau experience.
AB  - In 1998, Counties Manukau District Health Board (CMDHB) was experiencing rapidly
      increasing demands on its secondary services. It was finding it increasingly
      difficult to meet the health needs of its relatively deprived population. There
      was widespread evidence of "systems failure", with poor coordination of primary
      and secondary services. A strategic plan was devised to meet identified
      priorities and this was subsequently implemented with extensive community
      involvement. A "disruptive change" model was utilised. Thirty separate projects
      were undertaken to improve coordination and integration of health services. Brief
      summaries of all projects are presented, and full evaluations were performed of
      major projects. Factors critical to project success were: dedicated and effective
      leadership; involvement of clinical staff; early engagement of the Maori and
      Pacific community; careful selection of stakeholders; reassurance for providers
      about privacy issues; close monitoring of project progress; realistic timeframes;
      and adequate initial funding. CMDHB believes that the critical factor to success
      in improving the performance of the health sector will be the ability of our key
      leaders in primary and secondary care, in both management and clinical roles, to
      adopt a systems view to problem analysis and solution building

PMID- 12601404
TI  - The development and implementation of the Chronic Care Management Programme in
      Counties Manukau.
AB  - AIMS: To develop an effective and efficient process for the seamless delivery of
      care for targeted patients with specific chronic diseases. To reduce inexplicable
      variation and maximise use of available resources by implementing evidence-based
      care processes. To develop a programme that is acceptable and applicable to the
      Counties Manukau region. METHODS: A model for the management of people with
      chronic diseases was developed. Model components and potential interventions were
      piloted. For each disease project, a return on investment was calculated and
      external evaluation was undertaken. The initial model was subsequently modified
      and individual disease projects aligned to it. RESULTS: The final Chronic Care
      Management model, agreed in September 2001, described a single common process.
      Key components were the targeting of high risk patients, organisation of cost
      effective interventions into a system of care, and an integrated care server
      acting as a data warehouse with a rules engine, providing flags and reminders.
      Return on investment analysis suggested potential savings for each disease
      component from $277 to $980 per person per annum. CONCLUSIONS: For selected
      chronic diseases, introduction of an integrated chronic care management
      programme, based on internationally accepted best practice processes and
      interventions can make significant savings, reducing morbidity and improving the
      efficiency of health delivery in the Counties Manukau region.

PMID- 12601403
TI  - Primary options for acute care: general practitioners using their skills to
      manage "avoidable admission" patients in the community.
AB  - AIM: To enroll 600 primary care "avoidable admission" patients in a programme
      that utilised general practitioners to manage those patients in the community.
      METHODS: The Primary Options for Acute Care (POAC) programme ran from 26 February
      to 31 December 2001. Using networks already established, primary care teams were
      invited to manage patients using any resources they required, up to a cost of
      approximately $266 per patient. If needed, a Service Coordinator was available to
      arrange investigations, care, or treatment. RESULTS: From 26 February to 31
      December 2001, 707 patients were enrolled in POAC by 100 GPs. 104 patients (15%)
      were eventually admitted to hospital. An average of $200.73 per patient per
      episode was spent (not including administrative costs). A wide variety of
      patients and diseases were managed. Patients and general practitioners reported
      high levels of satisfaction with the programme. CONCLUSION: POAC demonstrated the
      ability and willingness of primary care providers to successfully manage patients
      who traditionally would be sent to hospital, within a defined budget

PMID- 12601405
TI  - Establishing a Maori case management clinic.
AB  - AIMS: The Maori Case Management Clinic Project aims to improve Maori health
      outcomes by establishing low cost, high quality, culturally appropriate primary
      care facilities in targeted areas, with a focus on the management of chronic
      illness. Further, the project aims to evaluate this 'by Maori for Maori' model of
      community healthcare delivery. METHODS: Working in partnership with local Maori
      health providers, we analysed the available health utilisation and demographic
      data to choose the three best sites to establish new primary care facilities. We
      established the facilities with initial start-up funding from Counties Manukau
      District Health Board. Rigorous evaluation processes have been built into the
      project. RESULTS: Enrollments at the first of the three clinics exceeded
      expectations. Client satisfaction as reported by independent evaluators was very
      high, with cost, cultural acceptability and convenience of location being the
      three most common reasons given for high satisfaction. CONCLUSIONS: The model
      adopted has been positively received by the targeted population. Further
      evaluation will reveal whether this resulted in improved health outcomes.

PMID- 12601406
TI  - General practitioners' assessments of the primary care caseload in Middlemore
      Hospital Emergency Department.
AB  - AIM: To estimate the proportion of Middlemore Hospital Emergency Department (ED)
      attendances that GPs thought could be handled in primary care. METHODS: A
      retrospective review of 300 randomly selected discharge summaries of non-admitted
      patients by 12 GPs. RESULTS: Data were available from 278 discharges. Agreement
      between GP reviewers was "fair" (kappa = 0.34, Kendall's W = 0.48). In 50 cases,
      the GPs were unanimous that the case was a primary care case (18%). In two cases,
      there was unanimity that the case was an ED case (<1%). The 12 GPs assessed that
      an average of 56% (range 38-81%) of the cases they reviewed could have been
      handled in their surgeries yesterday with no extra resources. This suggests that
      34% of the total ED caseload (ie, including admitted patients) could be managed
      in primary care. CONCLUSIONS: A significant proportion of ED attendances at
      Middlemore Hospital could be handled in primary care; however, there is
      considerable variation in GP estimates of this proportion.

PMID- 12601407
TI  - Integrated care information technology.
AB  - Counties Manukau District Health Board (CMDHB) uses information technology (IT)
      to drive its Integrated Care strategy. IT enables the sharing of relevant health
      information between care providers. This information sharing is critical to
      closing the gaps between fragmented areas of the health system. The tragic case
      of James Whakaruru demonstrates how people have been falling through those gaps.
      The starting point of the Integrated Care strategic initiative was the
      transmission of electronic discharges and referral status messages from CMDHB's
      secondary provider, South Auckland Health (SAH), to GPs in the district.
      Successful pilots of a Well Child system and a diabetes disease management system
      embracing primary and secondary providers followed this. The improved information
      flowing from hospital to GPs now enables GPs to provide better management for
      their patients. The Well Child system pilot helped improve reported immunization
      rates in a high health need area from 40% to 90%. The diabetes system pilot
      helped reduce the proportion of patients with HbA1c rang:9 from 47% to 16%. IT
      has been implemented as an integral component of an overall Integrated Care
      strategic initiative. Within this context, Integrated Care IT has helped to
      achieve significant improvements in care outcomes, broken down barriers between
      health system silos, and contributed to the establishment of a system of care
      continuum that is better for patients.

PMID- 12601409
TI  - Omeprazole-induced acute interstitial nephritis.

PMID- 12601410
TI  - The case of the two red ladies.

PMID- 12601411
TI  - Ischaemic heart disease, deprivation and smoking: a small area study in Te
      Tairawhiti.

PMID- 12601408
TI  - The acceptability of chronic disease management programmes to patients, general
      practitioners and practice nurses.
AB  - AIM: To evaluate the perceived effectiveness and acceptability of a disease
      management programme for patients with congestive heart failure (CHF) in South
      Auckland. METHODS: Focus groups were held with patients, and practice nurses
      (PNs) and general practitioners (GPs) interviewed to develop the questionnaires.
      Questionnaires were posted to the 150 patients, 14 GPs and 6 PNs involved in the
      programme. RESULTS: The programme was reported as changing patient lifestyle
      behaviours and patient understanding of medications and CHF. GP management was
      also seen as having improved. All aspects of the programme were seen as
      important: clinical review with a GP, educational sessions with a PN, patient
      held care plan and educational material. The main issues were lack of time for
      practice staff to be involved, and payment for their time. CONCLUSIONS: Disease
      management programmes such as this are of value and are acceptable to both
      patients and providers.

PMID- 12601412
TI  - Ashburton once again.

PMID- 12601413
TI  - Storage of liquid nitrogen.

PMID- 12601415
TI  - The relevance of overseas audit data to New Zealand.

PMID- 12601414
TI  - The influence of consumption of A1 beta-casein on heart disease and Type 1
      diabetes.

PMID- 12601416
TI  - Balancing research for new risk factors and action for the prevention of chronic
      diseases.

PMID- 12601417
TI  - Fortification of food with folic acid and the prevention of neural tube defects.

PMID- 12601418
TI  - Continuous reassessment, and hopefully improvement.

PMID- 12601419
TI  - Ischaemic heart disease, Type 1 diabetes, and cow milk A1 beta-casein.
AB  - AIM: To test the correlation of per capita A1 beta-casein (A1/capita) and milk
      protein with: 1) ischaemic heart disease (IHD) mortality; 2) Type 1 (insulin
      dependent) diabetes mellitus (DM-1) incidence. METHODS: A1/capita was estimated
      as the product of per capita cow milk and cream supply and its A1 beta-casein
      content (A1/beta) (calculated from herd tests and breed distribution, or from
      tests of commercial milk), then tested for correlation with: 1) IHD five years
      later in 1980, 1985, 1990 and 1995, in 20 countries which spent at least US $1000
      (purchasing power parities) per capita in 1995 on healthcare; 2) DM-1 at age 0-14
      years in 1990-4 (51 were surveyed by WHO DiaMond Project; 19 had A1 data). For
      comparison, we also correlated 77 food, and 110 nutritive supply FAO (Food and
      Agriculture Organization)-based measures, against IHD and DM-1. RESULTS: For IHD,
      cow milk proteins (A1/capita, r = 0.76, p <0.001; A1/capita including cheese, r =
      0.66; milk protein r = 0.60, p = 0.005) had stronger positive correlations with
      IHD five years later, than fat supply variables, such as the atherogenic index (r
      = 0.50), and myristic, the 14-carbon saturated fat (r = 0.48, p <0.05). The
      Hegsted scores for estimating serum cholesterol (r = 0.42); saturated fat (r =
      0.37); and total dairy fat (r = 0.31) were not significant for IHD in 1995.
      Across the 20 countries, a 1% change in A1/capita in 1990 was associated with a
      0.57% change in IHD in 1995. A1/capita correlations were stronger for male than
      female mortality. On multiple regression of A1/capita and other food supply
      variables in 1990, only A1/capita was significantly correlated with IHD in 1995.
      DM-1 was correlated with supply of: A1/capita in milk and cream (r = 0.92, p
      <0.00001); milk and cream protein excluding cheese (r = 0.68, p <0.0001); and
      with A1/beta in milk and cream (r = 0.47, p <0.05). Correlations were not
      significant for A2, B or C variants of milk beta-casein. DM-1 incidence at 0-4, 5
      9 and 10-14 years was equally correlated (r = 0.80, 0.81, 0.81 respectively) with
      milk protein supply. A 1% change in A1/capita was associated with a 1.3% change
      in DM-1 in the same direction. CONCLUSIONS: Cow A1 beta-casein per capita supply
      in milk and cream (A1/capita) was significantly and positively correlated with
      IHD in 20 affluent countries five years later over a 20-year period--providing an
      alternative hypothesis to explain the high IHD mortality rates in northern
      compared to southern Europe. For DM-1, this study confirms Elliott's 1999
      correlation on 10 countries for A1/capita,1 but not for B beta-casein/capita.
      Surveys of A1 beta-casein consumption in two-year-old Nordic children, and some
      casein animal feeding experiments, confirm the A1/capita and milk protein/capita
      correlations. They raise the possibility that intensive dairy cattle breeding may
      have emphasised a genetic variant in milk with adverse effects in humans. Further
      animal research and clinical trials would be needed to compare disease risks of
      A1-free versus 'ordinary' milk.

PMID- 12601420
TI  - The use of complementary/alternative medicine by cancer patients in a New Zealand
      regional cancer treatment centre.
AB  - AIM: To study the prevalence and patterns of complementary/alternative medicine
      (CAM) use in cancer patients managed by a New Zealand regional cancer treatment
      centre. METHODS: A self-administered anonymous questionnaire was used to survey
      patients attending outpatient clinics of the MidCentral Regional Cancer Treatment
      Service. Questions addressed patient demographics, cancer diagnosis and
      conventional treatments received. CAM users were asked to identify types of
      therapies used, reasons for use, perceived effectiveness, safety and financial
      cost. RESULTS: Questionnaires were distributed to 350 patients, with 200
      assessable replies received. Overall, 49% of patients in this group used CAM,
      with vitamins, antioxidants, alternative diets, and herbal therapies the most
      commonly used agents and usage was more common in younger patients. CAM was used
      by 47% to improve quality of life and by 30% in the hope of a cure of their
      cancer. Of CAM users, 71% believed these therapies had been helpful in the
      management of their cancer, and 89% felt they were safe. Only 41% of users had
      discussed CAM with their oncologist and almost one third had started such
      therapies before being seen at the Cancer Treatment Centre. The median cost of
      CAM was NZ$55/month. CONCLUSIONS: CAM is commonly used by New Zealand cancer
      patients, who often use multiple therapies, not only during conventional
      treatment, but also without consultation with their oncologist. This lack of open
      communication about CAM between patients and medical staff may prevent
      identification not only of potential harmful effects, but also of positive and
      negative drug interactions between CAM and conventional therapies.

PMID- 12601421
TI  - Understanding of pulse oximetry among hospital staff.
AB  - AIM: To assess the level of understanding of pulse oximetry in a hospital setting
      and identify training needs. METHODS: Twenty nine nurses and 34 doctors
      anonymously completed a questionnaire survey previously used by researchers in
      Exeter, UK. Respondents were required to explain the basic principles of pulse
      oximetry and demonstrate an understanding of the physiological factors limiting
      its accuracy. They were asked to apply their knowledge in different clinical
      scenarios. RESULTS: A higher proportion of nurses than doctors demonstrated an
      awareness of the physiological limitations of pulse oximetry. The majority of
      respondents correctly identified normal ranges for adult patients. Twenty nine
      per cent of respondents did not know how a pulse oximeter worked. Respondents
      failed to recognise the clinical implications of low oxygen saturations in many
      of the hypothetical scenarios. Only 16% of respondents had received any formal
      training in the use of pulse oximetry, with 65% identifying a need for more
      training. CONCLUSIONS: Medical and nursing staff at Christchurch Hospital have a
      good understanding of pulse oximetry. A higher proportion of participants were
      aware of checking vital signs when the oximeter reading was unreliable, than in
      the original UK study cohort. A need was identified for further education in this
      core technique. Staff training may increase the clinical value of pulse oximetry.

PMID- 12601422
TI  - Alcohol and injury among attendees at a New Zealand emergency department.
AB  - AIM: This study investigated the role of alcohol in injury cases among patients
      attending an emergency department in Auckland during December 2000. METHODS: A
      random sample of patients was interviewed and breath tested in the emergency
      department. Interviewing took place continuously for a three-week period. Using a
      case-crossover design the causal role of alcohol was assessed. RESULTS Thirty
      five per cent of injured patients reported having consumed alcohol prior to
      sustaining their injury; this is a high proportion compared with overseas
      research. Males and the under 30 years age group were over-represented in both
      alcohol-related and non alcohol-related injury cases. The risk of sustaining an
      injury was 2.8 times greater when alcohol was consumed. The median amount of self
      reported absolute alcohol consumed prior to alcohol-involved injury was 103 ml
      (equivalent to about seven cans of beer), with the lower quartile at 37 ml and
      upper quartile at 246 ml. For injury cases reporting consumption of alcohol prior
      to their injury event, there was a cumulative risk of 1.14 for each 30 ml of
      absolute alcohol (two cans of beer) consumed. There were no differences between
      the quantity of alcohol consumed by males and females or younger and older
      participants. Of those with blood alcohol concentration (BAC) readings obtained
      from breath samples, 51% had BAC reading equal or greater than 0.300 mcg.
      Violence was found to be the cause of 17% of the injury cases and alcohol was
      reported as involved (victim and/or perpetrator) in 79% of these cases. Injury
      involving violence occurred most often in a public place or on a licensed outlet.
      CONCLUSIONS: This is the first study of alcohol involvement in injury presenting
      to an emergency department in New Zealand. Findings indicate that a relatively
      high proportion of injury cases requiring emergency department treatment were
      alcohol-related and that the risk of an injury occurring was significantly
      increased by consumption of alcohol.

PMID- 12601424
TI  - Diaphragmatic herniation of laparoscopic Nissen fundoplication wrap due to
      forceful post-operative retching: three case reports.

PMID- 12601423
TI  - An adult asthma assessment and management protocol for use in the emergency
      department.

PMID- 12601426
TI  - Mandatory fortification of flour? Science, not miracles, should inform the
      decision.

PMID- 12601425
TI  - Provide the citizens of New Zealand the miracle of folic acid fortification.

PMID- 12601427
TI  - Angioplasty for intermittent claudication: has the balloon finally burst?

PMID- 12601428
TI  - The hazards of liquid nitrogen.

PMID- 12601429
TI  - Cytomegalovirus and inflammatory bowel disease.

PMID- 12601430
TI  - General practitioners' views on cancer treatment, home care and oncologists: an
      Italian survey.

PMID- 12601431
TI  - Dissemination of guidelines on medical practice.

PMID- 12601432
TI  - Respiratory illness, deprivation and smoking: a small area study in Te
      Tairawhiti.

PMID- 12601433
TI  - Beyond Ashburton: junior hospital doctor employment in New Zealand.

PMID- 12601434
TI  - Inequities in referred services expenditure.

PMID- 12601435
TI  - Walking the line.

PMID- 12601436
TI  - Vampirism in the twenty-first century.

PMID- 12601437
TI  - Predictors of long term outcome in medically treated patients with unstable
      angina.
AB  - BACKGROUND: The choice of invasive or noninvasive strategy for low risk patients
      with unstable angina is a challenge. OBJECTIVES: To investigate the impact of
      clinical factors on adverse outcomes in patients receiving successful medical
      treatment and referred from the hospital without invasive procedures. METHODS:
      The study group consisted of 166 patients (54% men, age 63+/-11 years) who were
      discharged symptom free after pharmacological treatment of unstable angina. The
      authors analyzed demographic, clinical, electrocardiographic, echocardiographic
      and laboratory parameters. RESULTS: During two years of follow-up, the mortality
      rate was 4.2%. A composite end point (coronary disease hospitalization, recurrent
      unstable angina, necessity for revascularization or death) occurred in 99
      patients (60%). In multivariate logistic regression, the Canadian Cardiovascular
      Society (CCS) class (P=0.015) and the left ventricular ejection fraction (P=0.01)
      were independently predictive for the adverse events. A scoring system was
      proposed for simple risk stratification, with one point assigned to the patient
      for CCS class III or IV and left ventricular ejection fraction below 40%, thus
      yielding a score in the range of 0 to 2. The adverse event rates for total scores
      of 0, 1 and 2 were 37%, 64% and 86%, respectively. CONCLUSIONS: Uncomplicated
      follow-up in medically treated patients with unstable angina is rare. Patients
      with CCS class III and IV or left ventricular ejection fraction below 40% have
      particularly high rates of recurrent ischemia.

PMID- 12601438
TI  - Self-reported functional status as a predictor of coronary artery bypass graft
      surgery outcome in elderly patients.
AB  - BACKGROUND: Surgeons have traditionally relied mainly on clinical intuition in
      the selection of elderly candidates for coronary artery bypass grafting (CABG).
      The overall increasing number of patients undergoing CABG and limited resources
      require that a more rational approach be used to screen out candidates who are
      least likely to benefit from the surgery. HYPOTHESIS: Preoperative functional
      status is a more sensitive predictor of mortality and poor postoperative
      functional status than age. PATIENTS AND METHODS: Retrospective preoperative and
      postoperative geriatric assessment was obtained for 123 patients who had
      undergone CABG at the Montreal General Hospital. Montreal, Quebec. Preoperative
      and postoperative health and functional status were assessed using the Canadian
      version of the Medical Outcomes Study 36-Item Short-Form (SF-36) 1 to 1.5 years
      following surgery. The questionnaires were compiled according to the method
      described by Stewart et al and scores were transformed linearly to a 0 to 100
      scale. In addition to functional status, the presence of comorbidities and other
      risk factors known to influence the outcome of CABG were recorded. RESULTS: There
      was no significant difference in the likelihood of having a poor functional
      status before or after surgery, or death as an outcome of CABG in the young
      elderly group versus the old elderly group. Preoperative functional status was
      found to predict postoperative functional status; however, there was no
      significant association between preoperative functional status and the presence
      of comorbidity. The presence of comorbidity did not affect the postoperative
      functional status, but increased the likelihood of death. CONCLUSION: Functional
      status was demonstrated to be a significant predictor of CABG outcome. When
      compared with age, functional status was also found to be a more reliable
      predictor of CABG outcome, which had not been previously demonstrated. Women were
      found to be more likely to have a poor preoperative functional status than their
      male counterparts. This may account in part for the decreased success rate of
      CABG in elderly women.

PMID- 12601439
TI  - Baroreflex resetting after successful surgical repair of tetralogy of Fallot.
AB  - BACKGROUND: Tetralogy of Fallot (TOF) and its surgical repair are associated with
      alterations in right ventricular systolic and diastolic functions. The
      cardiopulmonary baroreflex describes the peripheral vasoconstriction response to
      the volume-unloading deactivation of left and possibly right ventricular
      receptors. Alterations in cardiac geometry or distensibility and pulmonary
      vasculature of operated TOF may affect the mechanical stimulation of sensitive
      cardiopulmonary receptors leading to an impaired baroreflex function. There has
      to date been no report on the integrity of baroreflex function in postoperative
      TOF. OBJECTIVE: To characterize the combined cardiopulmonary and baroreflex
      response of patients successfully operated for TOF in early childhood to central
      volume unloading using graded lower body negative pressure (LBNP) application.
      METHODS: Fifteen patients operated on for TOF (mean+/-SEM) 15.7+/-1.4 years
      previously and 13 healthy age-matched control subjects were submitted to four
      consecutive 5 min LBNP applications at -10, -20, -30 and -40 mmHg. Forearm blood
      flow and vascular resistance, left ventricle end-diastolic diameter (LVEDD),
      arterial blood pressure and heart rate were obtained. RESULTS: TOF exhibited a
      lower LVEDD (42.7+/-1.5 mm) than control subjects (51.9+/-1.6). The forearm
      vascular resistance to LVEDD relationship was shifted left and upward in TOF
      compared with that of control subjects, but the slope of the relationship was not
      different between groups. LBNP -40 mmHg induced a lesser change in heart rate in
      TOF (+10.6+/-1.5%) than in control subjects (+14.7 +/-2.4%) and an increase
      (P<0.05) in diastolic blood pressure in TOF (-2.4+/-2.5%), which was not seen in
      control subjects (+4.3+/-2.9%). CONCLUSIONS: Young adults successfully operated
      on for TOF in early childhood exhibit a resetting of the cardiopulmonary
      baroreflex to operate at smaller LVEDD and at a higher level of forearm vascular
      resistance. The blunted heart rate response to LBNP -40 mmHg is consistent with
      previous observations pointing to disturbances in the efferent arm of the
      baroreflex.

PMID- 12601440
TI  - Prediction of 24 h, nonfatal complications in patients with acute myocardial
      infarction receiving thrombolytic therapy by calculation of the ST segment
      deviation score.
AB  - OBJECTIVE: To assess whether the sum of ST segment elevation and depression (ST
      segment deviation score [SUMSTdev]) is a better predictor for 24 h, nonfatal
      complications in patients with acute myocardial infarction (MI) than the sum of
      ST segment elevation (SUMSTelev) alone in the admission electrocardiogram.
      METHODS: Patients with acute MI receiving thrombolytic therapy were observed and
      ST scores were evaluated. Nonfatal, 24 h complications were defined as acute
      congestive heart failure or severe rhythm disturbances within 24 h after the
      start of thrombolysis. The outcome measures were the relationship between both
      the SUMSTdev and the SUMSTelev and the occurence of 24 h complications, and the
      identification of a cut-off value with the highest sensitivity and specificity
      for the prediction of complications. RESULTS: Three hundred eighty-two patients
      (288 male patients, mean age 58 years) with acute MI (179 patients with anterior
      MI) were included in the study. The SUMSTdev was significantly higher in patients
      with 24 h complications than in patients without complications (anterior MI 23.9
      mm versus 11.5 mm, respectively, P<0.001; inferior MI 21.6 mm versus 12.0 mm,
      respectively, P<0.001). Using the receiver operating characteristic analysis, the
      SUMSTdev significantly improved the ability to estimate the occurence of 24 h
      complications for anterior and inferior MI compared with the SUMSTelev (anterior
      MI 0.87+/-0.03 versus 0.84+/-0.03, P=0.04; inferior MI 0.79+/-0.03 versus 0.74+/
      0.04, P=0.03). The optimal cut-off for the SUMSTdev was found at 16 mm for
      anterior MI and 13 mm for inferior MI. Multivariate regression analysis showed
      that the SUMSTdev was an independent predictor of the occurrence of early
      complications in patients with anterior MI (odds ratio 28.4, 95% CI 11.0 to 73.6,
      P<0.0001) and inferior MI (odds ratio 9.7, 95% CI 4.7 to 20.2, P<0.001).
      CONCLUSIONS: The SUMSTdev is superior to the SUMSTelev in predicting 24 h,
      nonfatal complications after acute MI. The use of the SUMSTdev is therefore
      recommended for the stratification of patients with acute MI into low and high
      risk patients.

PMID- 12601442
TI  - Rescue therapy with methylene blue in systemic inflammatory response syndrome
      after cardiac surgery.
AB  - Severe unresponsive vasoplegia syndrome following cardiopulmonary bypass is rare.
      The authors report a case of severe vasoplegia, unresponsive to conventional
      treatment three days following cardiopulmonary bypass. A single intravenous bolus
      (2 mg/kg) of methylene blue was administered with normalization of the peripheral
      resistance. The use of methylene blue as rescue therapy in severe vasoplegia
      syndrome is discussed.

PMID- 12601441
TI  - Cost effectiveness in Canada of eptifibatide treatment for acute coronary
      syndrome patients using PURSUIT subgroup analysis.
AB  - OBJECTIVE: To evaluate the cost effectiveness of eptifibatide, a new glycoprotein
      IIb/IIIa receptor inhibitor, for the treatment of acute coronary syndromes (ACS)
      in Canada. DESIGN: A model was created to analyze the cost effectiveness of
      eptifibatide using outcomes and resource utilization data from the Platelet
      Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin
      Therapy (PURSUIT) trial, an international, placebo controlled, randomized
      clinical study evaluating the efficacy of eptifibatide in treating ACS. Cost data
      were derived from Canadian sources. Clinical outcomes were derived from published
      survival analyses based on North American PURSUIT data. SETTING: The present
      analysis is representative of the Canadian health care setting. Data for resource
      use reflected actual resources used by patients in the Canadian arm of the
      PURSUIT study. PATIENTS: Patients included in the PURSUIT study were hospitalized
      for non-ST segment elevation ACS between November 1995 and January 1997.
      INTERVENTIONS: Eptifibatide or placebo treatment was randomly assigned in
      addition to standard treatment with acetylsalicylic acid and heparin. MAIN
      RESULTS: Per patient costs for hospitalization, medical procedures and
      medications associated with standard treatment plus placebo were 10,265 dollars
      compared with 10,691 dollars with eptifibatide, in 1995 Canadian dollars.
      Eptifibatide patients had lower rehospitalization rates in the six months
      following treatment. Discounting future health outcomes by 3%, the cost
      effectiveness of treating ACS patients with eptifibatide in Canada was estimated
      as 5,165 dollars per year of life gained. CONCLUSIONS: Considering both the cost
      of eptifibatide therapy over standard treatment and the health benefits
      associated with it, eptifibatide is a cost effective, economically attractive
      pharmacological option for the treatment of ACS patients in Canada.

PMID- 12601444
TI  - Stentless porcine valves: new mode of failure.

PMID- 12601443
TI  - Access to new cardiovascular therapies in Canadian hospitals: a national survey
      of the formulary process.
AB  - BACKGROUND: Access to new therapies in hospitals depends upon both clinical trial
      evidence and local Pharmacy and Therapeutics (P&T) committee approval. The
      process of formulary evaluation by P&T committees is not well-understood.
      OBJECTIVES: To describe the formulary decision-making process in Canadian
      hospitals for cardiovascular medications recently made available on the Canadian
      market. METHODS: Postal survey of hospital pharmacy directors in all Canadian
      hospitals with more than 50 beds. Target drugs included abciximab, enoxaparin,
      dalteparin, clopidogrel, eptifibatide and tirofiban. RESULTS: Of 428 surveys
      mailed, responses were received from 164 P&T committees representing 350
      hospitals for an effective response rate of 82%. While physicians make up the
      largest proportion of committee membership, pharmacists play an influential role.
      Information most commonly cited as influencing formulary decisions included
      published clinical trials (97%), regional guidelines (90%), pharmacoeconomic data
      (84%), decisions at peer hospitals (73%) and local opinion leaders (60%).
      However, this information was often not required on formulary applications.
      Approval timelines varied widely for target medications but there were no
      regional, hospital or P&T committee characteristics that were independent
      predictors of early formulary application or approval. CONCLUSIONS: There is wide
      variability in the time taken for Canadian institutions to adopt new
      cardiovascular therapies, which is not explained by regional, hospital or P&T
      committee characteristics. Standardization of the formulary application and
      evaluation processes, including sharing of information amongst institutions,
      would lead to broader understanding of the applicable issues, more objectivity
      and improved efficiency.

PMID- 12601445
TI  - The cost of illness.

PMID- 12601446
TI  - [Nuclear medicine in times of recession. Greetings from the the society's new
      president].

PMID- 12601447
TI  - Radioligands for imaging myocardial alpha- and beta-adrenoceptors.
AB  - Alpha- and beta-adrenoceptors play an important role in the control of heart
      function. According to their molecular, biological, and pharmacological
      characteristics, they are subdivided into alpha(1)-, alpha(2)- and beta(1)-,
      beta(2)-, beta(3)-, beta(4)-adrenoceptors. In cardiac disease, there is often a
      selective downregulation of beta(1)-adrenoceptors associated with a relative
      increase in beta(2)- and alpha(1)-adrenoceptors. Functional imaging techniques
      like single-photon emission tomography (SPECT) and positron emission tomography
      (PET) provide the unique capability for non-invasive assessment of cardiac
      adrenoceptors. Radioligands with high specific binding to cardiac alpha- and beta
      adrenoceptors suitable for radiolabelling are required for clinical studies. The
      non-selective beta-adrenoceptor antagonist [(11)C]CGP-12177 was used to quantify
      beta-adrenoceptor density using PET in patients with heart disease. New non
      selective ligands (e. g. [(11)C]CGP-12388, [(18)F]CGP-12388, [(11)C]carazolol and
      [(18)F]fluorocarazolol) are currently evaluated; beta(1)-selective radioligands
      (e. g. [(11)C]CGP-26505, [(11)C]bisoprolol, [(11)C]HX-CH 44) and beta(2)
      selective radioligands (e. g. [(11)C]formoterol, [(11)C]ICI-118551) were assessed
      in animals. None of them turned out as suitable for cardiac PET. Potential
      radioligands for imaging cardiac alpha(1)-adrenoceptors are based on prazosin.
      Whereas [(11)C]prazosin shows low specific binding to myocardium, its derivative
      [(11)C]GB67 looks more promising. The putative alpha(2)-adrenoceptor radioligand
      [(11)C]MK-912 shows high uptake in rodent myocardium but has not yet been
      evaluated in man. A number of radioligands were evaluated for assessing cardiac
      adrenoceptors using PET. New radioligands are needed to provide more insight into
      cardiac pathophysiology which may influence the therapeutic management of
      patients with cardiovascular disease.

PMID- 12601448
TI  - [Stunning effects in radioiodine therapy of thyroid carcinoma: existence,
      clinical effects and ways out].
AB  - In radioiodine therapy for malignant thyroid disease, the pre-therapeutically
      administered iodine-131-dose can reduce the potential of thyroid or thyroid
      carcinoma cells to absorb the following therapeutic iodine-131-dose, possibly
      leading to its failure. This so called stunning effect is controversially
      discussed in the scientific community. Here we summarize and evaluate
      publications with regard to the existence and the effects of stunning as well as
      possible countermeasures.

PMID- 12601449
TI  - Functional activity of human sodium/iodide symporter in tumor cell lines.
AB  - AIM: The sodium/iodide symporter (NIS) actively transports iodide into
      thyrocytes. Thus, NIS represents a key protein for diagnosis and radioiodine
      therapy of differentiated thyroid cancer. Additionally, in the future the NIS
      gene may be used for cancer gene therapy of non-thyroid-derived malignancies. In
      this study we evaluated the functionality of NIS with respect to iodide uptake in
      a panel of tumor cell lines and compared this to gene transfer efficiency.
      METHODS: A human NIS-containing expression vector and reporter-gene vectors
      encoding beta-Galactosidase- or EGFP were used for transient transfection of 13
      tumor cell lines. Following transfection measurements of NIS-mediated radioiodide
      uptake using Na(125)I and of transfection efficiency were performed. The latter
      included beta-Galactosidase activity measurements using a commercial kit and
      observation by fluorescence microscopy for EGFP expression. RESULTS: In contrast
      to respective parental cells, most NIS-transfected cell lines displayed high,
      perchlorate-sensitive radioiodide uptake. Differences in radioiodide uptake
      between cell lines apparently corresponded to transfection efficiencies, as
      judged from reporter-gene assays. CONCLUSION: With respect to iodide uptake we
      provide evidence that NIS is functional in different cellular context. As iodide
      uptake capacity appears to be well correlated to gene transfer efficiency, cell
      type-specific actions on NIS (e. g. post-translational modification such as
      glycosylation) are not inhibitory to NIS function. Our data support the promising
      role of NIS in cancer gene therapy strategies.

PMID- 12601450
TI  - [Hodgkin's lymphoma in nuclear medicine: diagnostic and therapeutic aspects].
AB  - Today, diagnostic and therapeutic strategies of Hodgkin lymphoma (HL) with
      positron emission tomography and radioimmunotherapy include state-of-the-art
      nuclear medicine which require the cooperation between oncology and nuclear
      medicine. The benefit of FDG-PET in HL patients with residual tumor masses
      consists of its high negative predictive value in the therapy control of the
      disease. The concept of waitful watching in patients with PET-negative residual
      masses after BEACOPP-chemotherapy will be evaluated in a large multicenter trial
      of the GHSG (German Hodgkin Study Group). Radioimmunotherapy has been performed
      in patients with CD20-positive Non-Hodgkin lymphoma for 10 years with promising
      results. HL is also an excellent target for immunotherapy due to the expression
      of antigens such as CD25 and CD30. Thus, a new radioimmunoconstruct consisting of
      the murine anti-CD30 antibody Ki-4 labeled with iodine-131 was developed for
      patients with relapsed or refractory HL.

PMID- 12601451
TI  - Intraindividual comparison of [11C]acetate and [11C]choline PET for detection of
      metastases of prostate cancer.
AB  - In a pilot trial we investigated whether significant differences in prostate
      cancer (PCA) imaging would be observed using [(11)C]acetate and [(11)C]choline
      positron emission tomography (PET). METHODS: Twelve patients were studied with
      both radiotracers. Whole body PET without attenuation correction was performed
      after injection of 0.95 +/- 0.15 GBq [(11)C]acetate and 0.84 +/- 0.13 GBq
      [(11)C]choline, respectively, from 5 to 60 min p. i. Focally increased uptake in
      bone, below the urinary bladder or in a lymph node region was considered as
      tumour. Primary tumour, lymph node involvement, bone metastases, local
      recurrence; and no evidence of disease were known in 2, 4, 2, 2; and 2 patients,
      respectively. RESULTS: [(11)C]Acetate uptake was highest in spleen and pancreas
      while [(11)C]choline uptake was predominant in liver and kidney parenchyma.
      However, interindividual variation was high. The potential of both radiotracers
      to detect known bone lesions, lymph node metastases, and imaging of the primary
      tumour was identical. However, both failed to detect a small local recurrence in
      two patients as well as to demonstrate lymph node involvement in one patient,
      which was confirmed by surgery. CONCLUSIONS: In this preliminary study, uptake of
      both radiotracers in prostate cancer or its metastases was nearly identical and
      none of them should be favoured. At present, both radiotracers influence patient
      management by detection of local recurrence, lymph node, or bone metastases of
      PCA.

PMID- 12601452
TI  - [[123I]beta-CIT SPECT imaging of dopamine and serotonin transporters in
      Parkinson's disease and multiple system atrophy.
AB  - AIMS: Definition of the regional pattern of dopamine transporter (DAT)
      dysfunction in advanced Parkinson's disease (PD) and evaluation of a potential
      correlation between DAT binding and symptoms; elucidation of the role of DAT
      imaging in the differential diagnosis of PD and multiple system atrophy (MSA);
      assessment and comparison of serotonin transporter (SERT) binding in PD and MSA.
      METHODS: [(123)I]beta-CIT SPECT was performed in 14 patients with advanced PD, 10
      with moderate MSA and 20 healthy persons. Specific to nonspecific tracer binding
      ratios (V(3)") were calculated via ROI analysis of uptake images at 4 h (SERT
      binding) and 24 h (DAT binding) p. i. RESULTS: In PD bilateral reduction of
      striatal DAT binding (63-70%) was seen. The caudate ipsilateral to the clinically
      predominantly affected side showed relatively the least impairment. Significant
      correlations (r = -0.54 to -0.64) between DAT binding and Hoehn and Yahr stage,
      UPDRS-scores and duration of disease were found. In MSA DAT binding was less
      reduced (40-48%) targeting the putamen contralateral to the side of clinical
      predominance. Significantly lower SERT binding was observed in PD midbrain and
      MSA hypothalamus compared to controls -- and in MSA relative to PD mesial frontal
      cortex. CONCLUSIONS: In advanced PD striatal DAT binding is markedly reduced with
      the least reduction in caudate ipsilateral to the clinically predominantly
      affected side. In moderate MSA with asymmetrical symptoms DAT dysfunction is
      predominant in the contralateral putamen, a pattern seen in early PD. The
      reduction of SERT in the midbrain area of PD patients suggests additional
      tegmental degeneration while in MSA the serotonergic system seems to be more
      generally affected.

PMID- 12601453
TI  - [Appropriate uptake period for myocardial PET imaging with 18F-FDG after oral
      glucose loading].
AB  - AIM: Identification of a rationale for the appropriate uptake period for
      myocardial (18)F-FDG-PET imaging of patients with and without diabetes mellitus.
      METHODS: In a subset of 27 patients, static 2D-PET examination was performed of
      patients with chronic coronary artery disease and known myocardial infarction.
      The patients fasted (at least 4 h) before examination. (18)F-FDG (330 +/- 20 MBq)
      was injected intravenously. The image quality was semiquantitativly determined by
      ROI-analysis and the myocardium-to-blood pool activity ratio (M/B) was
      calculated. I.) Scans 30, 60, and 90 min p. i. of 10 non-diabetic patients (60 g
      oral glucose loading one hour before FDG-injection, low-dose intravenous insulin
      bolus if necessary). II.) Scans 30, 60, and 90 min p. i. of 10 patients with
      known non-insulin dependent diabetes (20 g glucose, insulin bolus). III.) Scans
      90 min p. i. of 7 patients with known non-insulin dependent diabetes and elevated
      fasting serum glucose level (140-200 mg/dl; insulin bolus, no glucose). RESULTS:
      I.) The M/B ratio significantly increases in nondiabetic patients with the uptake
      time (30 min 1.95 +/- 0.20; 60 min 2.96 +/- 0.36; 90 min 3.78 +/- 0.43). II.) In
      patients with non-insulin dependent diabetes the M/B ratio also significantly
      increases with uptake time. Compared to non-diabetic patients group II reached
      smaller M/B values (30 min 1.56 +/- 0.10; 60 min 2.15 +/- 0.14; 90 min 2.71 +/-
      0.19). III.) In the group of patients with elevated fasting serum glucose level
      (who only got insulin but no glucose loading) the M/B activity ratio 90 min p. i.
      was clearly inferior compared with diabetic patients after oral glucose loading
      and insulin administration (M/B 2.71 +/- 0.19 versus 2.16 +/- 0.07). CONCLUSIONS:
      In static myocardial viability PET studies with (18)F-FDG an uptake time of 90
      min yields image quality superior to that obtained after shorter uptake time.

PMID- 12601454
TI  - [Monitoring of 131I incorporation in nuclear medicine personnel by self
      accomplished measurements].
AB  - AIM: The personnel in nuclear medicine therapy wards must be monitored according
      to German guidelines for incorporations of (131)I. A surveillance with the
      employees measuring themselves similarly to the autonomous contamination survey
      using hand-foot-clothing monitors is presented as an alternative to the
      monitoring according to the official guidelines. METHOD: The employees use a
      dedicated device to measure themselves every working day. The automatic
      individual positioning of the device ensures reliable and reproducible results.
      The thyroid dose is determined from the measured time activity curve. The
      individual values of depth and mass of the thyroid are taken into account for
      activity measurement and dose evaluation, respectively. RESULTS: The employees
      measure themselves regularly and utilize the device to check for activities in
      the thyroid at an early stage after suspected incorporation. The almost complete
      surveillance permits a dosimetry with slight uncertainty. The determined thyroid
      doses of all monitored persons average to 0.35 mSv per month. CONCLUSION: The
      incorporation surveillance by autonomous monitoring allows a more reliable and
      more precise dosimetry than the monitoring according to the official guidelines.
      Despite numerous measurements the practice saves time and money as a result of
      the automation.

PMID- 12601455
TI  - [Effectiveness of syringe shieldings using radionuclides in radiation
      synovectomy].
AB  - AIM: The radiation exposure in radiation synovectomy was investigated for
      technician and therapist using Erbium-169, Rhenium-186 and Yttrium-90 with and
      without syringe shieldings. METHODS: Dose rates were measured in relation to the
      distance of the syringe containing the radionuclide. Measurements were repeated
      using syringe shieldings which consist of plastic surrounded by a lead layer.
      RESULTS: The most relevant radiation exposure arises from Yttrium-90. Using
      syringe shieldings radiation exposure can be reduced by a factor of thousand.
      CONCLUSION: This kind of radiological protection is completely sufficient for the
      therapist. Concerning the technician preparing the radiopharmaceutics, the limit
      of the official German dosimetry service (500 mSv) might be exceeded if no
      special radiological protection is established. Thus, special dosimetry is
      recommended.

PMID- 12601456
TI  - The impact of the International Subarachnoid Aneurysm Treatment Trial (ISAT) on
      neurosurgical practice.

PMID- 12601457
TI  - The surgical treatment of intracranial aneurysms based on computer tomographic
      angiography alone--streamlining the acute mananagement of symptomatic aneurysms.
AB  - BACKGROUND: We aimed to prospectively assess the usefulness of computer
      tomographic angiography (CTA) in streamlining the management of symptomatic
      intracranial aneurysms in a tertiary neurosurgical unit, from admission to
      surgery. METHODS: We performed a prospective evaluation over a 2-year period of
      all symptomatic intracranial aneurysms managed according to a standardized
      departmental protocol, to assess how CTA has impacted the decision-making process
      pertaining to the suitability of this investigation to proceed directly to
      surgery. FINDINGS: A total of 90 patients with intracranial aneurysms were
      treated over the 2-year period. 23 (26%) underwent endovascular occlusion while
      67 (74%) patients underwent a surgical clipping procedure. In the surgical group,
      22 (33%) patients had their aneurysms clipped based on CTA alone, while 45 (67%)
      required additional conventional angiography prior to surgery. Thus around one
      quarter of all patients treated for symptomatic intracranial aneurysms in our
      unit had their aneurysm secured surgically based solely on CTA. INTERPRETATION:
      CTA significantly influences the acute management of symptomatic intracranial
      aneurysms by streamlining the decision-making process during the early and acute
      management of these lesions.

PMID- 12601458
TI  - Treatment of failed Adult Chiari Malformation decompression with CSF drainage:
      observations in six patients.
AB  - OBJECTIVE: We report the use of CSF drainage for the management of failed Adult
      Chiari Malformation (ACM) decompression. METHODS: All patients with more than one
      year follow-up after treatment of their failed ACM were included in this study.
      They underwent initial decompression between September 1998 and April 2000.
      Clinical and radiological data were collected initially and at recurrence. Lumbar
      punctures (LP) were done at recurrence for diagnostic and therapeutic purposes.
      Opening pressures and symptomatic relief were recorded. Therapeutic options
      included intermittent LP and ventriculo-peritoneal shunting (VPS). RESULTS: There
      were 6 patients (5 females and one male). Their age ranged from 19 to 43 years.
      Tonsillar descent ranged from 5 to 21 mm. The symptoms recurred 1.5 to 9 months
      postoperatively (average 5.6 months). Postoperative imaging revealed the presence
      of CSF flow behind the tonsils and the formation of a retrotonsillar neocistern
      in all patients. On LP, the opening pressure ranged from 17 to 31 cm of water
      (average 23 cm). All patients improved after CSF drainage, and four patients
      underwent VPS. The other patients were treated with repeat LP+/-Acetazolamide.
      There was significant improvement in all patients, with 18 months follow-up after
      CSF drainage (range 16-21 months). CONCLUSIONS: Our results suggest a role for
      CSF drainage in the treatment of some patients with failed ACM surgery. Possible
      explanations for the failure of ACM surgery in this subgroup include: surgical
      complications leading to neural hydrodynamic alteration, inadequate initial
      surgery, and coexistence with another pathology, possibly a mild form of
      intracranial hypertension. More prospective and hydrodynamic studies are needed
      to further clarify these issues.

PMID- 12601459
TI  - Aplasia of the internal carotid artery.
AB  - BACKGROUND: The majority of previous reports on this rare agenesis of the
      internal carotid artery (ICA) have been limited to reporting upon its association
      with other congenital anomalies case by case. In order to collectively summarize
      this congenital anomaly of ICA, we have reviewed nine cases of ICA aplasia and
      their associated abnormalities. METHODS: Nine cases of ICA aplasia were reviewed.
      The diagnosis of aplasia or agenesis of the ICA was based on angiographic
      findings and the presence of an absent or hypoplastic bony carotid canal by
      temporal bone computed tomography (TBCT). Their presumable embryological
      aetiologies, initial presenting symptoms, unusual collateral circulations, as
      demonstrated by angiographies, and various associated anomalies are reviewed.
      FINDINGS: The initial presentations were; subarachnoid haemorrhage in three
      patients, headache in one patient and ischemic symptoms and signs in three
      patients. The remaining two cases were found incidentally during angiography for
      other diseases. Collateral circulations to the middle cerebral artery ipsilateral
      to the ICA aplasia were via posterior communicating artery (P-com) or anterior
      communicating artery (A-com). On TBCT, all cases but one demonstrated agenesis of
      the bony carotid canal and the remaining case showed a hypoplastic canal.
      Cerebral aneurysms were found in six patients, four with A-com aneurysm, one with
      a basilar bifurcation aneurysm, and one with both a right P-com and a left
      cavernous ICA aneurysm; two incidentally found cases had no aneurysm. Other
      associated abnormalities were found in four cases; one case of hypoplasia of the
      common carotid artery (CCA) with an arachnoid cyst at the temporal pole, one case
      of abnormal origin of the right CCA from the aorta and the right subclavian
      artery from the descending aorta, one case of congenital temporomandibular joint
      (TMJ) ankylosis, and one case of nasopharyngeal angiofibroma with atresia of the
      upper basilar artery. Except for the atresia of the upper basilar artery, all
      such abnormalities were found on the same side as the ICA aplasia.
      INTERPRETATION: Agenesis or aplasia of ICA may be entirely harmless. However,
      associated conditions such as cerebral aneurysm or abnormal collateral channels
      should alert clinicians to the possibility of deterioration to life-threatening
      conditions, such as subarachnoid haemorrhage or irreversible ischemia. Other
      associated anomalies are commonly depicted on the same side as the ICA aplasia
      and may also give rise to issues of clinical importance.

PMID- 12601460
TI  - Usefulness of bone window CT images parallel to the transnasal surgical route for
      pituitary disorders.
AB  - OBJECTIVE: Before operating on 130 patients with pituitary disorders, we
      evaluated their bone window CT images sliced parallel to the transnasal surgical
      route to assess the surgical anatomy of the nasal cavity for transnasal surgery.
      METHODS: High resolution bone window CT was performed in 3- to 5-mm slices
      parallel to the imaginary line connecting the inferior margin of the piriform
      aperture and the top of the sellar floor, parallel to the transnasal surgical
      route. RESULTS: This CT angle was useful in evaluating the width and depth of the
      operative field, the bony components of the nasal conchas, deviation of the nasal
      septum, the bony structure and mucosa in the sphenoid sinus, and the condition of
      the sellar floor. In patients requiring repeat surgery, the location of thin or
      thick nasal mucosa, residual bony septum, and inadequate sellar floor opening
      were easily detected. CONCLUSIONS: Bone window CT images sliced parallel to the
      transnasal surgical route provide direct visualization of the nasal anatomy for
      the transnasal approach. This method is helpful in determining how far to remove
      the sellar floor laterally, especially in cases requiring repeat surgery.

PMID- 12601461
TI  - Assistance of intraoperative microvascular Doppler in the surgical obliteration
      of spinal dural arteriovenous fistula: cases description and technical
      considerations.
AB  - BACKGROUND: Intraoperative microvascular Doppler may be valuable in assisting in
      the surgical obliteration of dural arteriovenous fistula of the spinal cord. It
      enables identification, through flow spectrum analysis, of the anatomic
      components and haemodynamic features of this type of vascular malformation.
      METHODS: In two cases, intraoperative microvascular Doppler was used to assist in
      the surgical obliteration of dural arteriovenous fistula of the spinal cord. The
      fistulas were identified prior to the dura opening, and for this only minimally
      invasive surgery was required. Direct recordings of the arterialised draining
      vein and the nidus of the fistula demonstrated a pathological spectrum caused by
      the arterial supply and the disturbed venous outflow in which a high-resistance
      flow pattern and low diastolic flow resembling an arterial-like flow velocity
      were observed. FINDINGS: The fistulas were obliterated by interruption of the
      draining vein, and Doppler measurements provided information on flow velocity
      changes in the medullary veins from an arterial to a venous pattern. The absence
      of any residual flow in the draining vein confirmed successful haemodynamic
      treatment. INTERPRETATION: Intraoperative microvascular Doppler recording is
      valuable assistance in surgical closure of spinal arteriovenous fistula.

PMID- 12601462
TI  - Choroid plexus papilloma of bilateral lateral ventricle.
AB  - BACKGROUND: Choroid plexus papillomas are rare, accounting for less than 1% of
      all intracranial tumours in adults. However, they are relatively more common in
      childhood and constitute 1.5 to 4% of intracranial tumours. They are most often
      located in the lateral ventricle, followed by the fourth and third ventricles
      and, rarely, in the cerebellopontine angle. Bilateral lateral ventricle choroid
      plexus papilloma is very rare and only a few cases has been reported. CLINICAL
      PRESENTATION: A 3-year-old boy was admitted to our hospital with a history of
      irritability and vomiting. Neurological examination on admission was normal. A
      head computed tomographic scan and magnetic resonance imaging showed tumours in
      both lateral ventricles, hydrocephalus and a left temporal arachnoid cyst. The
      bilateral intraventricular mass enhanced densely and homogeneously. A presumptive
      diagnosis of choroid plexus papillomas was made. INTERPRETATION: The initial
      surgery was performed for removal of the lesion in the right lateral ventricle,
      and 20 days later removal of the left lateral ventricle tumour was carried out.
      Bilateral temporoparietal craniotomy and total removal of tumours was performed.
      Hydrocephalus was controlled by total tumour resection from both sides. The
      histology of these tumours was the same and revealed choroid plexus papilloma.
      Interpretation: Bilateral choroid plexus papilloma is extremely rare and distinct
      from diffuse villous hypertrophy and their surgical approaches are different from
      each other. Differential diagnosis should be made by MRI preoperatively. If
      bilateral choroid plexus papilloma is detected, total surgical resection should
      be performed. Total surgical removal of the neoplasm not only cures the tumour
      but also may lead to complete resolution of the hydrocephalus.

PMID- 12601463
TI  - Extranodal sinus histiocytosis (Rosai-Dorfman disease) of the brain parenchyma.
AB  - Rosai-Dorfman Disease (RDD) is an idiopathic histiocytic proliferation affecting
      lymph nodes. Although extranodal involvement has been reported in diverse sites,
      manifestation in the central nervous system (CNS) is extremely rare, particularly
      in the brain parenchyma. A 39-year-old male presented with an isolated well
      circumscribed brain mass in the right temporal lobe, preoperatively thought to be
      a meningioma. Histology and immunohistochemistry confirmed that the lesion was
      RDD. The intraparenchymal brain location of RDD appears to have a benign course.
      Although the adjuvant therapy is a treatment of choice, surgical resection seems
      to be the appropriate treatment modality. From the clinical point of view RDD
      might be an important intracerebral entity because it may mimic other lesions,
      particularly other histiocytic disorders.

PMID- 12601464
TI  - Nontraumatic spinal subdural haematoma occurring in a postpartum period.
AB  - Spontaneous occurrence of spinal subdural haematoma (SSH) is very rare. While
      many neurological disorders can develop in pregnant patients in relation to
      haemostatic imbalance, there have been no reports in the literature suggesting
      that pregnancy and/or childbirth per se could be a single risk factor for acute
      SSH.A 38-year-old previously healthy woman gave birth to a baby via transvaginal
      normal delivery. The patient had no history of receiving anticoagulants. Eight
      days after delivery, she experienced sudden onset severe interscapular back pain,
      and the next day she developed dysesthesia in the both legs and mild urinary
      retention. Severe meningeal signs were noted. Lumbar puncture revealed bloody
      cerebrospinal fluid. Magnetic resonance images revealed SSH in the ventral
      position spreading from levels Th1 to Th7. The patient underwent conservative
      treatment after which the symptoms gradually improved. Serial MRI study at 17 and
      69 days after onset showed spontaneous regression of the SSH. Spinal angiography
      did not show any vascular malformations, but simultaneous cerebral angiography
      revealed a co-existing cerebral aneurysm on the C2 segment of the left internal
      carotid artery. It is unlikely that the cerebral aneurysm was the origin of the
      SSH, based on the clinical and radiographic findings. Moreover, we confirmed the
      unruptured nature of the aneurysm during the clipping procedure at open surgery.
      We report the unique case of subacute SSH occurring 8 days after childbirth
      without other known risk factors. The possible etiology and magnetic resonance
      imaging (MRI) findings in this case, and the current controversy concerning
      therapy for SSH are discussed.

PMID- 12601465
TI  - Value of 3D CTA in association with accessory anterior cerebral artery with
      ruptured anterior communicating artery aneurysm.

PMID- 12601466
TI  - Early improvement of bilateral abducens nerve palsies following surgery of an
      anterior communicating artery aneurysm.

PMID- 12601469
TI  - Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica.
AB  - We report a comparative genetic characterization of two population isolates with
      parallel demographic histories: the Central Valley of Costa Rica (CVCR) and
      Antioquia (in northwest Colombia). The analysis of mtDNA, Y-chromosome and
      autosomal polymorphisms shows that Antioquia and the CVCR are genetically very
      similar, indicating that closely related parental populations founded these two
      isolates. In both populations, the male ancestry is predominantly European,
      whereas the female ancestry is mostly Amerind. In agreement with their isolation,
      the Amerindian mtDNA diversity of Antioquia and the CVCR is typical of ethnically
      defined native populations and is markedly lower than in other Latin American
      populations. A comparison of linkage disequilibrium (LD) at 18 marker pairs in
      Antioquia and the CVCR shows that markers in LD in both populations are located
      at short genetic distances (<approximately 1 cM), whereas markers separated by
      greater distances are in LD only in the CVCR. This difference probably reflects
      stochastic variation of LD at the limited number of genome regions compared. The
      genetic similarity of the populations from Antioquia and the CVCR together with
      differences in LD between them should be exploitable for the identification and
      fine mapping of shared disease-related gene variants.

PMID- 12601470
TI  - Genome-wide targeted search for human specific and polymorphic L1 integrations.
AB  - Retroelements (REs) occupy up to 40% of the human genome. Newly integrated REs
      can change the pattern of expression of pre-existing host genes and therefore
      might play a significant role in evolution. In particular, human- and primate
      specific REs could affect the divergence of the Hominoidea superfamily. A
      comparative genome-wide analysis of RE sites of integration, neighboring genes,
      and their regulatory interplay in human and ape genomes would be of help in
      understanding the impact of REs on evolution and genome regulation. We have
      developed a technique for the genome-wide comparison of the integrations of
      transposable elements in genomic DNAs of closely related species. The technique
      called targeted genome differences analysis (TGDA) is also useful for the
      detection of deletion/insertion polymorphisms of REs. The technique is based on
      an enhanced version of subtractive hybridization and does not require preliminary
      knowledge of the genome sequences under comparison. In this report, we describe
      its application to the detection and analysis of human specific L1 integrations
      and their polymorphisms. We obtained a library highly enriched in human-specific
      L1 insertions and identified 24 such new insertions. Many of these insertions are
      polymorphic in human populations. The total number of human-specific L1 inserts
      was estimated to be approximately 4000. The results suggest that TGDA is a
      universal method that can be successfully used for the detection of evolutionary
      and polymorphic markers in any closely related genomes.

PMID- 12601471
TI  - Average age-specific cumulative risk of breast cancer according to type and site
      of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast
      cancer families attending Australian family cancer clinics.
AB  - If the risk of disease is not the same for all germline mutations in a given
      gene, or if there are other familial modifiers of risk in carriers, then family
      history-based estimates of average risk for detected mutations in that gene will
      depend on how carriers are sampled. Risk may also depend on the site or type of
      mutation. We studied 51 families with strong histories of breast cancer who
      attended Australian family cancer clinics and in which a germline mutation in
      BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast
      cancer risk in carriers was estimated under maximum likelihood theory, using
      information from all family members including those not tested, with adjustment
      for ascertainment by conditioning on genotype of the proband and family
      phenotype. The average cumulative risk of breast cancer for mutations in either
      BRCA1 or BRCA2 was 27% (95% confidence interval 16-43%) to age 50 and 64% (44
      83%) to age 70. When grouped, the incidence in carriers was on average 17 (10-30)
      times that in non-carriers, independent of gene or mutation type (hazard ratios:
      11 (4-29) for BRCA1, 23 (12-43) for BRCA2 (P for difference = 0.23); 13 (6-29)
      for protein-truncating mutations, 30 (9-104) for missense mutations and 30 (10
      90) for splice-site mutations). For missense mutations, this was equivalent to a
      cumulative risk to age 70 of 83% (40-100%) and was due in part, but not totally,
      to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were
      individually found to be associated with high risk (P<0.001). Mutations in the
      central region of BRCA1 may be associated with a lower risk. The issue of the
      pathogenicity of specific variants may be addressed analytically providing there
      are one or more suitably informative families with that mutation.

PMID- 12601472
TI  - [Rudolf Virchow's influence on medicine after 100 years].
AB  - 100 years after Rudolf Virchow's death, we find it necessary to demonstrate the
      mark his work has left on present day medicine. Curt Froboese wrote 50 years ago:
      "To come to know Rudolf Virchow well, it is sufficient to read him". Therefore
      the present collection of literal quotations from Virchow tries to show how valid
      many statements of Virchow still are. His definition of "health" precedes the
      well-known formulation of the World Health Organization. Virchow had a
      presentiment of molecular pathology, without defining this word, when he ascribed
      molecular forces to the cell and particularly to the cellular nucleus. As a
      terminologist he played a guiding role. His linguistic sense enabled him to
      prematurely find out "barbarisms" in medical terminology. At the same time, he
      also supported an international understanding. In particular the surgeons came to
      know through Virchow that malignant tumors are also primarily local events to be
      surgically treated preferably in the early stage. Therefore he requested a
      population-based statistical survey as developed by the cancer registries today.
      The legend that Virchow fought against bacteriology is not true. He did not stop
      in his efforts to differentiate between etiology, germs and the course of
      infection which presupposes knowledge of the respective cellular phenomena.
      Summing up it can be said that Virchow still plays an important role in our
      medical world.

PMID- 12601473
TI  - [Histopathological diagnosis of Barrett's mucosa and associated neoplasias.
      Results of a consensus conference of the Working Group for "Gastroenterological
      Pathology of the German Society for Pathology" on 22 September 2001].
AB  - There are a number of difficulties regarding the diagnosis of Barrett's mucosa
      and the varying grades of neoplasia that may be associated with it. It was
      therefore the aim of a consensus conference of the "Working Group for
      Gastroenterological Pathology within the German Society of Pathology" to achieve
      standardization regarding the following issues: definition and diagnostic
      criteria for Barrett's mucosa and its discrimination from intestinal metaplasia
      of the cardia, diagnostic criteria for intraepithelial neoplasia, number of
      biopsies necessary to establish the diagnosis, significance of additional
      immunohistochemical and/or molecular biological methods as well as importance of
      a second opinion in the diagnosis of intraepithelial neoplasia.

PMID- 12601474
TI  - [Pathology of intestinal lymphomas].
AB  - Intestinal lymphomas are almost exclusively non-Hodgkin lymphomas (NHL) which
      occur at a slightly lower frequency than those arising in the stomach. Intestinal
      NHLs differ from nodal lymphomas because they retain some properties of the
      mucosa-associated lymphoid tissue (MALT) from which they arise. The recently
      proposed WHO classification of lymphoid neoplasias encompasses and defines all
      the NHLs occurring in the gastrointestinal tract as lymphoma entities. The
      histopathological diagnosis relies on the combination of morphology and
      immunohistochemistry, which represents the gold standard. By this means a correct
      diagnosis can be achieved in the vast majority of cases. If nevertheless
      diagnostic problems arise, they can usually be managed by a re-biopsy, or in
      individual cases by molecular studies. At any rate, the pathologist must classify
      the lymphoma according to the WHO classification and diagnoses such as "low-grade
      B-cell lymphoma" or "small B-cell lymphoma" are not acceptable.

PMID- 12601476
TI  - [Sporadic adenoma and colitis-associated intraepithelial neoplasia: a difficult
      differential diagnosis].
AB  - The differential diagnosis between sporadic adenoma and colitis-associated
      neoplasia is difficult. Clinical, histological and molecular genetic methods are
      available to recognise a difference between these two entities. The aim of the
      present analysis was to check known criteria in a large series of patients and
      352 patients with ulcerative colitis and concomitant intraepithelial neoplastic
      lesions [149 adenomas (A), 123 colitis-associated intraepithelial neoplasias (N),
      80 carcinomas (K)] were investigated. Clinical history helped to identify
      patients with sporadic adenoma since patients with colitis-associated neoplastic
      lesions presented with different data such as age (A: 61.3+/-13 years, N: 48.4+/
      16.4 years, K: 53.9+/-16.9 years), duration of disease (A: 6.9+/-8.1 years, N:
      11.9+/-10 years, K: 13.6+/-9.6 years), frequency of pancolitis (A: 28.6%, N:
      56.3%, K: 48.3%) and frequency of solitary lesions (A: 83.7%, N: 23.1%, K:
      51.9%). The differential diagnosis between adenoma and colitis-associated
      neoplasia in patients with ulcerative colitis appears to be possible but the
      diagnosis should only be made in the remission phase. Furthermore the patients
      need a careful endoscopic and bioptic follow-up. If in doubt one should consider
      colitis-associated neoplasia especially when there are multiple intraepithelial
      neoplastic lesions. Long-term follow-up studies are urgently needed.

PMID- 12601477
TI  - [Morphogenetic aspects of colorectal cancer].
AB  - Patterning is a spatial and temporal process by which ordered arrangements of
      cells and tissue structure are attained. The term is mostly applied to the
      morphogenesis in developmental pathology, but it can also be useful for the
      neomorphogenesis in tumor biology. Despite increasing data on the proliferation
      and differentiation of tumor cells, processes of tumor patterning are rarely
      studied and poorly understood. A fundamental embryonic process of patterning is
      the embryonic gastrulation and a basic patterning is found in the colonic adenoma
      carcinoma sequence. Both processes exhibit distinct nuclear translocation and
      expression of beta-catenin, which is considered to be a decisive transcriptional
      regulator. Our recent studies demonstrated striking analogies of patterning and
      nuclear beta-catenin expression between the colonic adenoma-carcinoma sequence
      and the steps of gastrulation. The shared patterns are dissociation, reassembly,
      tubular reconstruction and branching of neoplastic cells in association with
      nuclear beta-catenin expression. These findings establish patterning as a
      relevant concept for tumor formation and link the neoplastic morphogenesis with
      embryogenesis.

PMID- 12601475
TI  - [Allergy-associated colitis. Characterization of an entity and its differential
      diagnoses].
AB  - There is substantial evidence that allergic reactions exist in the
      gastrointestinal tract (GI). However, patients with food allergy-related
      enteropathy pose a diagnostic challenge to physicians because the clinical
      features are variable, unspecific, occur in other gastrointestinal disorders, and
      specific diagnostic tools are missing. Several recent studies and reviews have
      focused on the function of eosinophilic granulocytes in GI disease. The role of
      eosinophils in the pathophysiology of GI hypersensitivity reactions is poorly
      defined. However, some findings have been reported that imply an involvement of
      eosinophils in allergic reactions of the gut. The presumptive histology of
      allergy-associated colitis in colonic and ileal biopsies is based on prominent
      pure eosinophilic infiltration of a normal lamina propria, submucosa and
      epithelium with variable degrees of degranulation. An immunoperoxidase stain for
      eosinophilic peroxidase is supportive in establishing the diagnosis if suspected.
      Neutrophils or mononuclear infiltrates are not significantly increased and damage
      to the intestinal tissue is not prominent. Despite characteristic histologic
      changes in colonic biopsy specimens, a final diagnosis depends on careful
      clinical examination and exclusion of several differential diagnoses.

PMID- 12601479
TI  - [Regression grading of colorectal carcinoma after preoperative radiochemotherapy.
      An inventory].
AB  - The treatment of patients with colorectal cancer has changed over the last
      decades. More and more patients receive combined modality treatments including
      (preoperative) radiotherapy and chemotherapy. To assess the colorectal cancer
      specimen after neoadjuvant therapy, the pathologist has to be familiar with the
      histological features induced by radiochemotherapy. Performing a standardized
      pathological procedure, different grades of tumour regression can be observed and
      tumour staging should be standardized using valid and reproducible criteria.
      These criteria are recommended in the forthcoming TNM classification (6th
      edition, 2002). In the review, these classification rules will be discussed for
      rectal cancer.

PMID- 12601480
TI  - [Ossification in lung metastases of primary colorectal adenocarcinomas].
AB  - Ossification of lung tissue is a rare phenomenon, which can be found in
      association with carcinoid tumors of the lung or pulmonary blastomas. Very
      rarely, ossifications are observed in lung metastases of extrathoracal epithelial
      tumors. In these cases, the most probable primary focus is a colorectal
      adenocarcinoma. Our question was, whether ossifications in lung metastases are
      pathognomonic for colorectal adenocarcinomas and how they can be pathogenetically
      arranged. A total of 15 lung metastases with ossifications from 5 patients
      suffering from a colorectal adenocarcinoma were examined by means of
      immunohistochemistry. Thereby, we found an increased expression of bone
      morphogenetic protein (BMP) 2/4 and osteonectin in tumor cells, as well as an
      increased stromatogenous expression of collagen type III. We conclude that there
      is strong evidence of a primary colorectal adenocarcinoma when ossifications in
      lung metastases are found. In these cases, a common metastatic spread of tumor
      cells and tumor stroma seems to be probable.

PMID- 12601481
TI  - [Interlaboratory trial 2000 " Immunohistochemistry" of the German Society for
      Pathology and the Professional Association of German Pathologists].
AB  - Early in 2000 an interlaboratory trial on immunohistochemistry was held in
      Germany in which 172 pathologists took part. Each pathologist received one H&E
      stained and five unstained slides of five different tumors to reach a diagnosis
      based on immunohistochemical stains. Additionally, the diagnosis-independent
      staining quality was assessed by using a multi-tissue block. Altogether, 828
      diagnoses were made, among which 57% (468) were correct. The individual steps of
      immunohistochemistry (tentative morphological diagnosis, choice of primary
      antibodies, technical staining quality, conclusions from the diagnosis and
      rendering a final diagnosis) were assessed independently. Although each of these
      steps was correlated to the correct final diagnosis, in the multivariate analysis
      only the tentative diagnosis, choice of primary antibodies and the conclusions
      drawn from individual stains were independent factors to reach the correct final
      diagnosis. In the diagnostic part of the interlaboratory trial, the technical
      quality of the immunostaining was not an independent variable to reach a correct
      diagnosis. In contrast, the results of the multi-tissue block proved that the
      immunohistochemical staining quality has to be standardized to reach reproducible
      results in defining the estrogen receptor expression as a basis for therapeutic
      decisions.

PMID- 12601478
TI  - [Clinical, pathological and molecular prognostic factors in colorectal
      carcinomas].
AB  - Various aspects of the progression and prognosis of colorectal carcinoma have
      been investigated in numerous publications during recent years. An exact
      macroscopic and microscopic examination is still of basic importance but
      different factors of the molecular pathogenesis of colorectal carcinoma could be
      described by immunohistochemistry and molecular biology. Furthermore, they have
      been evaluated regarding their importance for the course of disease and prognosis
      and in particular, the different pathways of carcinogenesis and microsatellite
      instability were included. The detection of micrometastasis was investigated
      applying mostly molecular genetic methods. Numerous oncogenes, tumor suppressor
      genes and regulators of the cell cycle, markers of proliferation and apoptosis,
      cell adhesion antigens and angiogenetic factors were characterized with regard to
      their prognostic potential. In the future, so-called response predictors will
      presumably gain a certain relevance in the context of neoadjuvant (radiotherapy)
      chemotherapy. The present review summarizes these results and discusses the
      future clinical relevance.

PMID- 12601482
TI  - Malignant thymoma: current status of classification and multimodality treatment.
AB  - Classification, understanding of the pathophysiology, and treatment options of
      thymoma have changed during recent years. It is hoped that novel strategies will
      lead to a survival benefit in these patients. It has become clear that patients
      with thymoma are best treated with multimodality therapy. In this review, a
      pathologist, an immunologist, a surgeon, a radiotherapist, a pneumologist, and
      oncologists discuss the current status of classification and strategies for the
      treatment of patients with thymoma.

PMID- 12601483
TI  - Randomized phase III study for the treatment of advanced indolent non-Hodgkin's
      lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus
      rituximab.

PMID- 12601484
TI  - Clinical applicability of the new EORTC/MSG classification for invasive pulmonary
      aspergillosis in patients with hematological malignancies and autopsy-confirmed
      invasive aspergillosis.
AB  - Diagnosis of invasive pulmonary aspergillosis (IPA) is often difficult. Recently,
      the European Organization for Research and Treatment of Cancer/Mycoses Study
      Group (EORTC/MSG) has proposed new criteria for the classification of invasive
      fungal infections. We have studied the clinical applicability of this
      classification in 22 patients with hematological malignancies who had IPA at
      autopsy. While alive, according to the EORTC/MSG criteria, only 2 patients were
      classified as having proven IPA, 6 as probable, 13 as possible, and 1 was
      unclassifiable. Of the patients, 64% had no microbiological or major clinical
      criteria before death. Although the EORTC/MSG criteria are an important step
      forward in the standardization of definitions used for IPA in clinical research
      studies, most patients who die with extensive lung disease only reach a level of
      possible or probable IPA during life, further highlighting that these guidelines
      should not be used for clinical decision-making.

PMID- 12601485
TI  - German multicenter study group for adult ALL (GMALL): recruitment in comparison
      to ALL incidence and its impact on study results.
AB  - Due to eligibility criteria not all patients with the disease under investigation
      can be recruited for therapeutic studies. Thus, the external validity of study
      results cannot per se be taken for granted. The representativity of the admitted
      patients is the most relevant determinant for external validity and has to be
      assessed. As an example we examined the representativity of the patients
      recruited for the German multicenter study group for adult acute lymphoblastic
      leukemia (ALL) (GMALL). Lacking nationwide ALL incidence figures available in
      Germany, a methodology was developed to estimate incidence figures, too. All
      relevant study groups, hospitals, and diagnostic labs were asked to provide data
      about patients with ALL newly diagnosed between 1997 and 1998. A matching
      procedure was developed, as heterogeneous databases had to be pooled and checked
      for duplicates. Age- and sex-specific incidences of ALL were estimated and
      compared with the number of patients recruited for the GMALL in the same time
      period. The purpose was to develop a methodology for estimating incidence figures
      and evaluating the representativity of patients of the GMALL. The combination of
      various data sources allowed estimation of reliable incidence data for ALL in
      Germany. Comparisons with the incidence figures for ALL in other countries and
      crosschecks within Germany confirm our results. Sixty-two percent of all ALL
      patients in Germany were admitted to the GMALL study. The recruitment rate of
      more than 60% of the annual incidence of ALL to the GMALL suggests a high
      external validity as well as an impact of the study on the patterns of treatment
      and referral of ALL in adults in Germany. There is no selection bias of patients
      admitted to the GMALL compared to those patients not included in the study.

PMID- 12601486
TI  - Tc-99m methoxyisobutylisonitrile bone marrow imaging for predicting the levels of
      myeloma cells in bone marrow in multiple myeloma: correlation with CD38/CD138
      expressing myeloma cells.
AB  - The percentage of myeloma cells in bone marrow is subsequently an important index
      of disease in patients with multiple myeloma (MM). Bone marrow myeloma cells can
      be detected by strong CD38/CD138 positivity and light scatter characteristics
      using flow cytometry. The aim of the study was to evaluate the relationship
      between the degree of Tc-99m methoxyisobutylisonitrile (MIBI) uptake and the
      percentage of CD38/CD138 expressing myeloma cells in the bone marrow of patients
      with MM. A total of 15 patients with MM (mean age: 61.7+/-2.4 years; 7 F and 8 M)
      were included in the study. Tc-99m MIBI imaging was obtained 20 min after
      injection of 740 MBq Tc-99m MIBI. Planar spot images of the pelvis and thorax
      were acquired. The uptake of Tc-99m MIBI in the bone marrow was evaluated using a
      qualitative and also a semiquantitative scoring system for the bone marrow in
      areas that included the proximal femurs, anterior iliac crest, and sternum. In
      all patients, flow cytometry was performed for assessing the percentage of
      CD38/CD138 expressing myeloma cells in the bone marrow samples. There was a
      statistically significant positive correlation between the percentage of
      CD38/CD138 expressing plasma cells in bone marrow and both mean qualitative
      (r=0.689, p=0.005) and semiquantitative (r=0.669, p=0.006) results of Tc-99m MIBI
      uptake. In conclusion, our results indicate that increased Tc-99m MIBI uptake of
      bone marrow is related to the percentage of plasma cell infiltration of bone
      marrow. Tc-99m MIBI bone marrow imaging may be a useful tool for predicting the
      levels of myeloma cells in bone marrow of patients with MM.

PMID- 12601488
TI  - Procalcitonin: a useful discriminator between febrile conditions of different
      origin in hemato-oncological patients?
AB  - Plasma concentrations of procalcitonin (PCT) have been shown to be elevated in
      bacterial and fungal infections. In contrast to C-reactive protein (CRP), PCT is
      not elevated in inflammations of noninfectious origin. Febrile inflammatory
      conditions are frequent in patients with hemato-oncological diseases. A reliable
      marker to discriminate infectious inflammations from drug-related and tumor
      associated fever is still lacking. To evaluate the impact of PCT in this setting,
      PCT and CRP were prospectively measured in 95 febrile hemato-oncological
      patients. Infections could be identified in 40 of 95 patients: 38 of 95 had fever
      of unknown origin (FUO), 9 patients were suspected to suffer from drug-related
      fever, and 8 patients from tumor-associated fever. In the noninfection group
      (drug-related and tumor-associated fever), PCT levels were significantly lower
      than in patients with infections (P<0.001) or FUO (P<0.001). Differences were
      still highly significant comparing patients with suspected drug-related or tumor
      associated fever alone with the infection or the FUO cohort. All eight patients
      with tumor-associated fever as well as eight of the nine patients with drug
      related fever had PCT levels within the normal range (<0.5 micro g/l). CRP values
      only partially allowed discrimination between the various subgroups. Differences
      were significant between patients with drug-related fever and the infection
      (P=0.001) or FUO group (P=0.004). However, as CRP levels were far above the
      normal range also in the patients with drug-related fever, the significance of
      individual values was rather limited. In conclusion, PCT may provide useful
      additional information to assess the clinical significance of febrile conditions.
      PCT may facilitate the decision on when to initiate antimicrobial or cytotoxic
      therapy.

PMID- 12601487
TI  - Hepatosplenic fungal infection in patients with acute leukemia in Taiwan:
      incidence, treatment, and prognosis.
AB  - Nosocomial fungal infection increases gradually and has become the leading
      pathogen at National Taiwan University Hospital since 1993. From January 1995
      through May 2002, hepatosplenic fungal infection (HSF) was diagnosed in 37 (7.4%)
      of the 500 adult patients with acute leukemia who received chemotherapy at this
      hospital. There was no significant difference in the incidence of HSF between the
      patients with acute myeloid leukemia and those with acute lymphoblastic leukemia,
      or between the patients treated with high-dose chemotherapy and those with
      conventional or low-dose chemotherapy. Candida tropicalis was the leading
      pathogen, followed by Candida albicans. The computed tomography scan showed
      multiple hypodense lesions in the liver (89%), spleen (70%), and kidney (27%).
      Eighteen patients were initially treated with fluconazole and 19 with
      amphotericin B. Nineteen patients received the planned chemotherapy after the
      diagnosis of HSF. Among them, eight patients underwent hematopoietic stem cell
      transplantation and seven patients survived more than 100 days post
      transplantation; none of these patients had relapse of prior HSF. Twenty-three
      patients (62%) died during a median follow up of 10 months, but only seven died
      due to HSF. In conclusion, a substantial percentage of patients with acute
      leukemia acquired HSF after chemotherapy and carried high mortality. However, HSF
      itself is not a contraindication for subsequent chemotherapy and hematopoietic
      stem cell transplantation.

PMID- 12601489
TI  - Increased inducible nitric oxide synthase expression and nitric oxide
      concentration in patients with aplastic anemia.
AB  - Nitric oxide (NO) is a biological mediator that is synthesized from L-arginine by
      the nitric oxide synthase (NOS) family. We investigated the expression of iNOS in
      bone marrow (BM) mononuclear cells (MNCs) using a reverse transcriptase
      polymerase chain reaction (RT-PCR) assay and the concentration of NO from BM
      serum by measuring the metabolite NO(2)(-) in 13 patients with aplastic anemia
      (AA) compared with 10 normal controls who were donors for allogeneic bone marrow
      transplantation (BMT). All samples of BM MNCs in patients with AA expressed iNOS
      mRNA, but iNOS was not expressed in patients who were treated successfully with
      allogeneic BMT. Normal control samples and samples from leukemia patients who had
      bone marrow aplasia after chemotherapy did not show significant iNOS expression.
      When we measured the density of bands for both iNOS and beta(2)-microglobin
      expressed as the iNOS/beta(2)-microglobin density ratio, there was a significant
      difference in the ratio between AA and normal controls (0.88+/-0.15 vs 0.26+/
      0.05, P<0.001). The BM serum NO(2)(-) concentration in the patients with AA was
      significantly higher than that of normal controls (88.1+/-32.8 microM vs 48.8+/
      8.6 microM, P=0.002). In addition, there was a significant correlation between
      the NO(2)(-) concentration and the calculated iNOS/beta(2)-microglobin density
      ratio (r=0.567, P=0.01). These findings suggest that upregulation of iNOS
      expression for local NO production may contribute in part to the pathogenesis of
      AA.

PMID- 12601491
TI  - Incidence of thrombophilia detected in southern Taiwanese patients with venous
      thrombosis.
AB  - In order to analyze the incidence of thrombophilia in southern Taiwan, we studied
      the prevalence of antithrombin (AT), protein C (PC), and protein S (PS)
      deficiencies, the prevalence of factor V Leiden mutation, and the presence of
      acquired lupus anticoagulant (LA) and anticardiolipin antibody (ACA) in 56
      patients < or =65 years old with deep venous thrombosis (DVT). Of 56 patients, 30
      were male, 26 female, and the mean age of the patients was 43 years (18-65
      years). None had factor V mutation or activated PC resistance; 21 patients
      (37.5%) showed abnormal results: 4 (7.1%) had AT deficiencies, 6 (10.7%) PC
      deficiencies, 6 (10.7%) PS deficiencies, 2 (3.6%) a combined PC and PS
      deficiency, and 3 (5.4%) LA and ACA. Only PC and PS deficiencies were
      significantly associated with increased risk for the development of thrombosis
      with an odds ratio of 4.2 (95% confidence interval: 1.2-15.0, P=0.018) and 8.1
      (95% confidence interval: 1.6-40.6, P=0.003), respectively. We concluded that the
      prevalence of heritable thrombophilia (34.0%) in Taiwan is higher than that in
      Western countries, but that it is lower than previously reported in Hong Kong and
      Taiwan. We attribute this to selection bias.

PMID- 12601490
TI  - Steady-state sVCAM-1 serum levels in adults with sickle cell disease.
AB  - Cytokines and adhesion molecules play an important role in the pathophysiology of
      vaso-occlusion in sickle cell disease (SCD), and their in vivo profiles are
      potential tools for assessing SCD severity. We compared steady-state soluble
      vascular cell adhesion molecule-1 (sVCAM-1) serum levels to clinical (painful
      crisis frequency, occurrence of acute chest syndrome, leg ulcers, and
      cerebrovascular disease) and related hematological parameters of SCD severity
      (such as HbF%, hemoglobin levels, and leukocyte counts) in 29 HbSS adults. Serum
      sVCAM-1 levels were not related to clinical severity, but an inverse correlation
      was demonstrated between sVCAM-1 and hemoglobin levels (r=-0.71, p<0.001) with a
      positive correlation to serum lactate dehydrogenase levels (r=0.59, p=0.008).
      Based upon these results, steady-state serum sVCAM-1 levels do not seem to
      reflect clinical disease severity. However, as VCAM-1 is involved in
      hematopoiesis, sVCAM-1 levels might reflect bone marrow activity in SCD. This
      underlies the pleiotropic nature of adhesion molecules in vivo and the need for
      further research in this area, especially since therapies targeting (cellular)
      adhesive interactions involving the endothelium are emerging for SCD.

PMID- 12601492
TI  - Purpura fulminans in a child with combined heterozygous prothrombin G20210A and
      factor V Leiden mutations.
AB  - Although thrombosis is relatively rare in children, reports of young patients
      with thrombosis are becoming more frequent with time. Activated protein C
      resistance and prothrombin 20210 A mutation are results of point mutations
      described in the last decade. This article highlights a case of a child with
      severe arterial thrombosis who was heterozygous for the factor V Leiden (FVL) and
      prothrombin G20210A mutations. The patient diagnosed with purpura fulminans was
      an 8-year-old boy who was referred to our hospital with purpuric lesions on the
      extremities and necrosis of the penis. We believe that the coexistence of more
      than one thrombophilic mutation contributed to the occurrence of severe
      thrombosis at a young age in this patient.

PMID- 12601493
TI  - Effect of prothrombin complex concentrate on INR and blood coagulation system in
      emergency patients treated with warfarin overdose.
AB  - We investigated the effect of prothrombin complex concentrate (PCC) on the
      international normalized ratio (INR) and blood coagulation system in two emergent
      patients treated with warfarin for secondary prevention of cardioembolic stroke
      due to nonvalvular atrial fibrillation. An 80-year-old woman developed massive
      subcutaneous hemorrhage and swelling on her right upper extremity with weak
      pulsation of the right radial artery and had an INR above 10. An 83-year-old man
      had pleural effusion with an INR value of 6.69 and pleural puncture was
      immediately required. We administered 500 IU of PCC to the two patients (17.2
      IU/kg and 12.5 IU/kg) with 10 mg of vitamin K. The INR decreased to 1.12 and
      1.85, respectively, with an increase of plasma levels of protein C and coagulant
      factors IIa, VIIa, IXa, and Xa 10 min after administration. The plasma levels of
      the thrombin-antithrombin III complex increased (from 4.0 to 12.0 micro g/l and
      from 0.5 to 28.9 micro g/l, respectively, normal value <3.0), but prothrombin
      fragment 1+2 increased minimally 10 min after administration (from 0.4 to 1.1
      nmol/ml and from 0.4 to 0.7 nmol/ml, respectively, normal value 0.4-1.4 nmol/ml).
      Plasma levels of D-dimer remained unchanged. The massive subcutaneous hemorrhage
      in the former patient improved in 14 days. Anticoagulation was restarted in the
      latter patient after 14 days of PCC administration. There were no embolic
      episodes during the month after PCC administration. In conclusion, a small amount
      of PCC may be effective in immediately correcting increased INR levels with
      increased plasma levels of protein C and coagulant factors IIa, VIIa, IXa, and Xa
      and may partially activate the coagulation system without any effects on plasma
      levels of D-dimer.

PMID- 12601494
TI  - Bell's palsy as an early manifestation of acute lymphoblastic leukemia.
AB  - A 20-year-old man with the complaints of malaise, fever, and tooth gum bleeding
      presented at a hospital. He was found to have generalized lymphadenopathy,
      thrombocytopenia, and leukocytosis. Ensuing bone marrow biopsy led to a diagnosis
      of acute lymphoblastic leukemia (ALL). He also had a sense of "facial stretching"
      and difficulty during eating. After clinical examination, he was diagnosed with
      right-sided peripheral type facial nerve paralysis (Bell's palsy). The magnetic
      resonance imaging studies demonstrated bilateral facial nerve involvement,
      predominantly on the right side. The patient received steroid treatment and local
      facial radiotherapy for Bell's palsy. A concurrent facial exercise program was
      ordered. Seemingly a less significant diagnosis in a leukemia patient, we
      considered our case notable since an ALL patient presenting with Bell's palsy,
      especially at the very beginning of the disease, is not that common. The cases of
      relapsing ALL reported in the literature initially presenting with the same
      scenario further strengthen the significance.

PMID- 12601495
TI  - Patients with biochemical iron overload: causes and characteristics of a cohort
      of 150 cases.
AB  - Biochemical iron overload (IO) is a frequent metabolic abnormality. It may be
      caused by several diseases, and data regarding the relative frequency of these
      are scant. A single diagnostic protocol including clinical, biochemical, and
      genetic data was used to diagnose the cause of biochemical IO in a group of 150
      patients referred by general practitioners. Severe alterations of the HFE gene
      (42 patients, 28%), hepatitis C virus infection (33 patients, 22%), and
      dysmetabolic syndrome with iron overload (DSIO) (22 patients, 15%) emerged as the
      main causes, and other single causes were found in 20 patients (13%). In 19
      patients (13%), multiple causes of IO were found, and in 14 patients no cause was
      found, 5 of whom had classical criteria of genetic hemochromatosis (GH) without
      HFE mutations. Transferrin saturation index (TSI) had a very low positive
      predictive value (0.16) for GH among patients with biochemical IO in this
      setting. In conclusion, 90% of patients with biochemical IO were diagnosed with a
      specific disorder. GH, hepatitis C infection, and DSIO were the major causes, and
      a large group of patients had multiple causes of IO. TSI is not a useful
      indicator of GH in patients referred by general practitioners.

PMID- 12601496
TI  - Diffuse large B-cell lymphoma arising from donor lymphoid cells after renal and
      pancreatic transplantation.
AB  - A patient with both a renal and pancreatic transplantation developed a diffuse
      large B-cell lymphoma, Epstein-Barr virus-related, 14 months after the surgical
      procedure. Tumor was confined to the transplanted organs: head of the pancreas
      and hilar lymph node of the transplanted kidney. Chimerism analysis demonstrated
      the tumor origin from donor lymphoid cells. Immunosuppression was discontinued
      and chemotherapy with cyclophosphamide, hydroxydaunomycin, vincristine, and
      prednisone (CHOP) was started. However, no response was observed after three
      courses of this regimen. Finally, a transplantectomy was carried out, followed by
      rituximab (anti-CD20 antibody), with the patient achieving a complete response
      (CR). Two years later the patient remains in CR.

PMID- 12601497
TI  - Acute myocardial infarction after bone marrow transplantation: an unsuspected
      late complication.
AB  - Acute myocardial infarction is a common disease rarely seen as a complication of
      bone marrow transplantation in young patients. We report on a 25-year-old patient
      3.5 years after bone marrow transplantation who suffered an acute anterior wall
      myocardial infarction complicated by cardiogenic shock. The patient was treated
      with thrombolysis and emergent coronary angioplasty but died a few hours
      following admission. We suggest that the combination of low-dose chest
      irradiation and prolonged immunosuppression with graft-versus-host disease
      contributed to the development of the coronary artery disease in this patient.
      Though rarely encountered, physicians caring for young patients after bone marrow
      transplantation should be aware of potential ischemic complications.

PMID- 12601498
TI  - [(18)F]FDG PET monitoring of tumour response to chemotherapy: does [(18)F]FDG
      uptake correlate with the viable tumour cell fraction?
AB  - Because metabolic changes induced by chemotherapy precede the morphological
      changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([(18)F]FDG
      PET) is thought to predict response to therapy earlier and more accurately than
      other modalities. To be a reliable predictor of response, changes in tumour
      [(18)F]FDG uptake should reflect changes in viable cell fraction, but little is
      known about the contribution of apoptotic and necrotic cancer cells and
      inflammatory tissue to the [(18)F]FDG signal. In a tumour mouse model we
      investigated the relation between chemotherapy-induced changes in various tumoral
      components and tumour uptake and size. SCID mice were subcutaneously inoculated
      in the right thigh with 5 x 10(6) Daudi cells. When the tumour measured 15-20 mm,
      Endoxan was given intravenously. At different time points [1-15 days (d1-d15)
      after the injection of Endoxan], ex vivo autoradiography and histopathology were
      performed in two mice and [(18)F]FDG uptake in the tumour and tumour size were
      correlated with the different cell fractions measured with flow cytometry in five
      mice. At d1/d3, similar reductions in [(18)F]FDG uptake and viable tumoral cell
      fraction were observed and these reductions preceded changes in tumour size. By
      d8/d10, [(18)F]FDG uptake had stabilised despite a further reduction in viable
      tumoral cell fraction. At these time points a major inflammatory response was
      observed. At d15, an increase in viable tumour cells was again observed and this
      was accurately predicted by an increase in [(18)F]FDG uptake, while the tumour
      volume remained unchanged. In contrast with variations in tumour volume,
      [(18)F]FDG is a good marker for chemotherapy response monitoring. However,
      optimal timing seems crucial since a transient increase in stromal reaction may
      result in overestimation of the fraction of viable cells.

PMID- 12601499
TI  - Discriminative stimulus and antinociceptive effects of dihydroetorphine in rhesus
      monkeys.
AB  - RATIONALE: Although dihydroetorphine has micro opioid agonist activity there is
      evidence to suggest that it is not identical to that of morphine. OBJECTIVE: This
      study compared dihydroetorphine to other opioids under behavioral conditions that
      are sensitive to micro opioid agonism. METHODS: The acute effects of
      dihydroetorphine, etorphine and morphine were evaluated using two procedures. In
      one procedure, monkeys received 3.2 mg/kg per day of morphine and discriminated
      naltrexone from saline while responding under a fixed-ratio 5 schedule of
      stimulus shock termination. In addition, a warm-water, tail-withdrawal procedure
      was used in untreated monkeys. RESULTS: When acutely deprived of morphine,
      monkeys responded on the naltrexone lever, and this effect was reversed by
      dihydroetorphine, etorphine and morphine. Each agonist produced the maximum (20-s
      latency) antinociceptive effect in 50 degrees C water. Naltrexone antagonized the
      discriminative stimulus and antinociceptive effects of dihydroetorphine and
      etorphine, although Schild analyses yielded large variability in slopes and pA(2)
      values. Naltrexone reversed established effects of dihydroetorphine and morphine
      in both procedures and pretreatment with dihydroetorphine (2, 6 or 24 h) did not
      alter the discriminative stimulus effects of morphine. CONCLUSIONS: Taken
      together, these data support the notion that dihydroetorphine is a micro agonist
      with a short duration of action; however, variability in antagonism of
      dihydroetorphine and morphine might be a manifestation of differences that have
      been reported for these drugs at the cellular level.

PMID- 12601501
TI  - Antidepressant-like effects in various mice strains in the forced swimming test.
AB  - RATIONALE: Strain differences in mice have been reported in response to drugs in
      the mouse forced swimming test (FST), even if few antidepressants were examined.
      OBJECTIVES: The aim of the present study was to investigate the influence of
      genetic factors, using five antidepressants (imipramine, desipramine, citalopram,
      paroxetine and bupropion) in the mouse FST, in outbred strains (Swiss, NMRI) and
      inbred strains (DBA/2, C57BL/6J Rj). Moreover, whole brain levels of dopamine
      (DA), noradrenaline (NA), serotonin (5-HT) in vehicle treated animals, which were
      or were not subjected to the FST, were measured by HPLC analysis in an attempt to
      explain behavioural differences. METHODS: For each antidepressant, a dose range
      (1-16 mg/kg) was tested in the locomotor apparatus and only non-psychostimulant
      doses were then tested in the FST in order to detect antidepressant-like
      activity. RESULTS: No baseline differences among Swiss, NMRI, DBA/2 and C57BL/6J
      Rj strains were observed in our experiments, allowing the comparison of different
      antidepressants in each strain. Imipramine (16 mg/kg), desipramine, citalopram (4
      16 mg/kg) and paroxetine (8 and 16 mg/kg) treatment decreased the immobility time
      in the Swiss strain and the size of the effect reached more than 20% for each of
      these antidepressants. C57BL/6J Rj was the only strain sensitive to bupropion (2
      and 4 mg/kg). In the NMRI strain, only paroxetine treatment decreased the
      immobility time (16 mg/kg). CONCLUSION: Our study showed that drug sensitivity is
      genotype dependent. FST results have shown that Swiss mice are the most sensitive
      strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be
      limited, as an absence of antidepressant-like response was observed in the FST.
      The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due
      to high DA, NA and 5-HT whole brain concentrations.

PMID- 12601503
TI  - Absence of reinforcing, mood and psychomotor performance effects of caffeine in
      habitual non-consumers of caffeine.
AB  - RATIONALE: The extent to which the measured (and felt) psychostimulant effects of
      caffeine represent a real benefit of caffeine consumption or merely withdrawal
      reversal is unclear. Results showing positive psychostimulant effects of acute
      caffeine administration in habitual non-consumers of caffeine would provide
      evidence for a net benefit of caffeine unconfounded by withdrawal. OBJECTIVES: To
      compare the mood, alerting, psychomotor and reinforcing effects of caffeine in
      caffeine non-consumers and acutely (overnight) withdrawn caffeine consumers.
      METHODS: In experiment 1, these participants consumed two differently flavoured
      drinks, one containing 100 mg caffeine and the other containing no caffeine. Each
      drink was consumed on 4 separate days in semi-random order, and self-ratings of
      mood and alertness were completed before and after drink consumption. On day 9,
      both drinks contained 50 mg caffeine and drink preference (choice) and intake
      were assessed. In experiment 2, mood, alertness and performance on a long
      duration simple reaction time task were assessed before and after administration
      of 100 mg or placebo in a single test session. RESULTS: Prior to receiving
      caffeine, the (overnight withdrawn) caffeine consumers were less alert and more
      tense than the non-consumers. Caffeine only had significant reinforcing, mood and
      psychomotor performance effects in the caffeine consumers. The reinforcing effect
      of caffeine was evident from an effect on drink intake, but drink choice was
      unaffected. Caffeine increased self-rated alertness of both caffeine consumers
      and non-consumers; however, for some of the non-consumers this was associated
      with a worsening of performance. CONCLUSIONS: These results support the
      hypothesis that the psychostimulant and related effects of caffeine are due
      largely to withdrawal reversal.

PMID- 12601502
TI  - Efficacy of acute administration of nicotine gum in relief of cue-provoked
      cigarette craving.
AB  - RATIONALE: Acute cravings, often provoked by exposure to smoking cues, appear to
      be important triggers for smoking relapse. Relief of acute craving may therefore
      be an important step in preventing relapse. OBJECTIVES: This study was undertaken
      to assess the effectiveness of nicotine gum in relieving acute craving. METHODS:
      A multi-center, randomized, placebo-controlled study was conducted with smokers (
      n=296) who quit by using either active or inactive gum for 3 days. On their third
      day of abstinence, smokers participated in a laboratory session in which they
      were exposed to a provocative smoking cue, chewed active or inactive gum, and
      then rated their craving at 5-min intervals for 35 min. RESULTS: Craving
      initially decreased in both groups. After 15 min, however, the smokers using
      active nicotine gum experienced significantly greater craving reductions.
      CONCLUSIONS: These results suggest that nicotine gum can effectively reduce acute
      craving following exposure to smoking cues.

PMID- 12601504
TI  - Effects of MDMA exposure on the conditioned place preference produced by other
      drugs of abuse.
AB  - RATIONALE: MDMA is a serotonergic neurotoxin but few pre-clinical studies have
      found long-term behavioural consequences. As human users of MDMA are polydrug
      users, it is important to investigate whether the behavioural effects of other
      drugs are modulated by prior exposure to MDMA. OBJECTIVE: . This study
      investigated whether pretreatment with a multiple high dose regimen of MDMA
      altered the rewarding effects of other drugs of abuse. METHODS: Adult male Lister
      Hooded rats ( n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline
      vehicle IP every 2 h for 6 h. Fourteen days later, conditioned place preference
      (CPP) to d-amphetamine (3 mg/kg), cocaine (20 mg/kg), ethanol (2.0 g/kg), heroin
      (0.5 mg/kg), or MDMA (10 mg/kg) was assessed. RESULTS: In general, MDMA
      pretreatment had no effect on drug reward or habituation to the place
      conditioning apparatus. However, in contrast to saline pretreated rats, those
      animals receiving MDMA failed to show CPP after ethanol. CONCLUSION: MDMA
      pretreatment reduced the rewarding properties of ethanol. This finding may
      represent a functional consequence of MDMA-induced neurotoxicity. By
      extrapolation, human users of MDMA may be exposed to an increase in risks
      associated with alcohol abuse.

PMID- 12601505
TI  - Ameliorative effects of histamine on 7-chlorokynurenic acid-induced spatial
      memory deficits in rats.
AB  - RATIONALE: Histamine plays an important role in modulating acquisition and
      retention in learning and memory process in experimental animals. OBJECTIVES: We
      examined the effects of polyamine and histamine on the N-methyl- d-aspartate
      (NMDA) receptor glycine site antagonist 7-chlorokynurenic acid-induced spatial
      memory deficits in radial maze performance in rats. METHOD: Effects of histamine
      (0.5 or 1 nmol/site intracerebroventricularly), spermidine (1 nmol/site,
      intracerebroventricularly) and spermine (1 nmol/site, intracerebroventricularly)
      on spatial memory deficit in 9-week-old-male Wistar rats were observed. Both
      reference and working memory errors occurred in radial maze performance in rats,
      following intracerebroventricular injection of 7-chlorokynurenic acid (10
      nmol/site). RESULTS: Spermidine (1 nmol/site, intracerebroventricularly) or
      spermine (1 nmol/site, intracerebroventricularly) antagonized 7-chlorokynurenic
      acid-induced deficits on working memory but not on reference memory errors.
      Intracerebroventricular histamine (0.5 or 1 nmol/site) or thioperamide (100
      nmol/site) also ameliorated 7-chlorokynurenic acid-induced working memory
      deficits. To determine whether the effects of histamine involve histamine
      receptors, the effects of some methylhistamines were examined. The effects of R
      alpha-methylhistamine on radial maze performance were mimicked by histamine.
      N(alpha)-methylhistamine had no effect on 7-chlorokynurenic acid-induced memory
      deficits, whereas 1-methylhistamine, but not 3-methylhistamine reversed 7
      chlorokynurenic acid-induced working memory deficits. CONCLUSION: These results
      suggest that the amelioration of 7-chlorokynurenic acid-induced working memory
      deficits by histamine may involve a direct action of histamine at the polyamine
      sites on NMDA receptors.

PMID- 12601509
TI  - Improving the diagnosis of genuine stress incontinence in symptomatic women with
      negative cough stress test: the Distal Urethral Electrical Conductance test
      (DUEC) revisited.
AB  - This retrospective descriptive study was performed to assess the practice of
      using the distal urethral electrical conductance (DUEC) test to objectively
      demonstrate urinary incontinence in symptomatic women with a negative cough
      stress test on examination. One hundred women had stable bladders on cystometry
      (CMG). Genuine stress incontinence (GSI) was diagnosed during CMG in 45 (45%).
      DUEC performed prior to cystometry had revealed stress incontinence in an
      additional 13 with negative CMG, thereby improving the diagnosis of GSI by 13%.
      The test detected urge incontinence in one (1%). The DUEC test improves the
      detection of stress incontinence. However, it should not be considered as an
      alternative to cystometry, but as an additional test when stress incontinence
      cannot be demonstrated clinically.

PMID- 12601506
TI  - Paroxetine as a 5-HT neuroendocrine probe.
AB  - RATIONALE: Acute administration of 40 mg paroxetine (a selective serotonin
      reuptake inhibitor) reportedly increases plasma cortisol in human subjects. This
      suggests that paroxetine may be a useful tool to probe brain serotonin function.
      OBJECTIVE: To investigate a dose-response relationship for paroxetine
      administration, and to determine whether a lower dose of paroxetine is sufficient
      to increase plasma ACTH and cortisol. METHODS: Twenty subjects were tested on
      three occasions in a double-blind, cross-over design receiving: (a) placebo, (b)
      paroxetine 20 mg and (c) paroxetine 40 mg administered orally at 8.00 a.m. In
      addition, five of the 20 subjects received paroxetine 20 mg plus cyproheptadine
      (a 5-HT(2) receptor antagonist) 4 mg and four subjects were given paroxetine 40
      mg plus cyproheptadine 4 mg in an open manner. Plasma ACTH and cortisol levels
      were measured prior to administration and every hour for 6 h thereafter. RESULTS:
      Paroxetine, particularly 20 mg rather than 40 mg, significantly increased plasma
      ACTH and cortisol. Paroxetine 40 mg but not 20 mg caused significantly more
      nausea than the placebo. Cyproheptadine attenuated ACTH and cortisol responses to
      20 mg but not to 40 mg paroxetine. CONCLUSIONS: Low-dose (20 mg) paroxetine has
      greater potential utility than larger doses as a neuroendocrine challenge test.
      The endocrine responses to paroxetine are probably mediated at least partially by
      5-HT(2A/2C) receptors.

PMID- 12601510
TI  - Prevention of genital prolapse following Burch colposuspension: comparison
      between two surgical procedures.
AB  - Our objective was to evaluate the efficacy of cul-de-sac obliteration in
      preventing pelvic floor anatomical defects formation following Burch
      colposuspension. We evaluated 441 patients who had undergone Burch
      colposuspension. The patients were divided into two groups: group A (132
      patients) who underwent Burch colposuspension only, and group B (309 patients)
      who had had a concomitant cul-de-sac obliteration. Cul-de-sac obliteration was
      performed using two different techniques, the Moschocowitz procedure in 131
      patients, and approximation of the sacrouterine ligaments in 178 patients. The
      follow-up period was 8.6 years (range 3-16). In total we found 43/441 (9.7%)
      postoperative anatomical defects. Obliteration of the cul de sac significantly
      (P<0.0001) reduced the formation of anatomical defects compared to Burch
      colposuspension. In a comparison of the two surgical procedures for cul-de-sac
      obliteration, the approximation of the sacrouterine ligaments was significantly
      more effective than either the Moschcowitz procedure (P<0.001) or the Burch
      colposuspension alone (P<0.001). The Moschcowitz procedure reduced the formation
      of anatomical defects to 15/131 (11.4%) compared to Burch colposuspension only
      (25/132; 18.9%), but statistically the difference was insignificant. The time of
      anatomical defect detection was significantly reduced after cul-de-sac
      obliteration: 2 years 6/25 (24%) in group A compared to 1/8 (5.5%) in group B
      (P<0.01). After 5 years the detection rate was 64% (16/25) and 22.2% (4/18)
      respectively (P<0.01). It was concluded that cul-de-sac obliteration using
      approximation of the sacrouterine ligaments significantly reduced the incidence
      of anatomical defect formation following Burch colposuspension. A long follow-up
      period is needed to evaluate the truce incidence.

PMID- 12601508
TI  - Effects of IGF-I gene therapy on the injured rat pudendal nerve.
AB  - Injured nerves and their motor units may undergo enhanced recovery when exposed
      to recombinant human insulin-like growth factor-I (rhIGF-I). The external anal
      sphincter muscle in the female rat was denervated to model incontinence. The
      treatment-group muscle was injected with rhIGF-1 plasmid, whereas in the control
      group the plasmid lacked the cDNA insert and the normal group received neither
      surgery nor treatment. Electromyography data at 56 days post surgery indicated
      more reinnervation without fibrillation potentials in the treatment group (2 of
      6) than in the control group (0 of 6). The histology of the regenerated axons in
      the pudendal nerve distal to the crush site also suggested an improved recovery
      in the treatment group. The number of motor neurons retrogradely labeled with
      horseradish peroxidase was decreased by 50% following pudendal nerve crush in
      both experimental groups compared to the normal group. We conclude from these
      preliminary results that rhIGF-I gene therapy may improve the distal recovery of
      structure and function.

PMID- 12601511
TI  - Randomized trial of porcine dermal sling (Pelvicol implant) vs. tension-free
      vaginal tape (TVT) in the surgical treatment of stress incontinence: a
      questionnaire-based study.
AB  - The objective of this study was to compare porcine dermal sling (Pelvicol
      implant, Bard) with tension-free vaginal tape (TVT) in the surgical treatment of
      stress incontinence. One hundred and forty-two women with genuine stress
      incontinence (GSI) were randomly assigned to either Pelvicol implant pubovaginal
      sling (n=74) or TVT (n=68). They were followed up at a minimum of 6 months (range
      6-24 months), with a median follow-up of 12 months. The majority (n=109) of
      procedures were carried out in a day surgery unit. The median operation time was
      35 minutes (range 15-60) in the TVT group and 30 minutes (range 20-80) in the
      Pelvicol implant group; 81% of the TVT group and 77% of the Pelvicol implant
      group were able to void urine within 24 hours, and had insignificant residual
      bladder volumes. The prevalence of postoperative symptomatic voiding dysfunction
      was 3.4% after TVT and 1.4% after Pelvicol implant. Nine percent of the TVT group
      developed de novo urge incontinence and 6% of the Pelvicol implant group had de
      novo urge incontinence 6 months after the procedure. Postoperative evaluation was
      done at the outpatient department, and a postal questionnaire was also completed
      to determine subjective continence status. The patient-determined cure rate was
      85% in the TVT group and 89% in the Pelvicol implant group. The Pelvicol implant
      sling had a comparable patient- determined success rate with TVT and should be
      considered in the surgical treatment of women with genuine stress incontinence.

PMID- 12601512
TI  - Levator function in nulliparous women.
AB  - Pelvic floor muscle exercises are one of the main conservative options for the
      treatment of female urinary incontinence. Despite this widespread use, there is
      very little information on 'normal' pelvic floor function. In a prospective
      observational study the authors intended to define the spectrum of normality for
      pelvic floor function in women, assessing 206 nulliparous women recruited early
      in their first ongoing pregnancy. Levator function was evaluated using
      translabial ultrasound: cranioventral displacement of the bladder neck was
      utilized to quantify levator activity. The presence of a reflex contraction of
      the external perineal muscles and levator on coughing was registered, as was the
      strongest of at least three contractions. Only 41 of 206 women (20%) had ever
      been taught pelvic floor exercises by a health professional, and this had been
      exclusively verbal. Teaching had no influence on levator strength. Spontaneous
      contractions on request were obtained in 172 women (85%). Advice was necessary in
      96 women (47%) in order to obtain an optimal contraction. Reflex muscle
      activation on coughing was documented in 118 women (57%) and was associated with
      a stronger contraction (P<0.001). Reported use of the levator muscle on
      intercourse was strongly associated with increased levator activity (P<0.001).
      Motivational factors mentioned were boyfriends, mothers, other female relatives
      and, most commonly, articles in popular magazines, e.g. Cosmospolitan and Cleo.

PMID- 12601513
TI  - Treatment-seeking behavior in Hong Kong Chinese women with urinary symptoms.
AB  - A pan-territory telephone survey was conducted in Hong Kong of Chinese women
      concerning urinary symptoms and their treatment preferences; 1500 women replied.
      One hundred and ninety-four (13%) of the 1500 subjects had urinary symptoms. Of
      these 194, 155 (10.3%) had stress incontinence, 64 (4.3%) had urgency, 10 (0.7%)
      had urge incontinence, 63 (4.2%) had frequency of urination, 64 (4.3%) had
      nocturia, 2 (0.1%) had enuresis, and 20 (1.3%) had incomplete emptying. Sixty
      eight (35.1%) of the 194 symptomatic subjects sought medical advice (group 1) and
      126 (64.9%) did not (group 2). In group 1, 28 (41.2%) sought medical advice from
      general practitioners, 26 (38.2%) from private specialists, 2 (2.9%) from Chinese
      herbalists and 12 (17.6%) from public hospitals. In group 2, 4 (3.2%) claimed
      they had no time, 119 (94.4%) did not think their symptoms were serious, and 11
      (8.7%) did not know help was available. None of the subjects felt too embarrassed
      to seek medical advice, or felt that they could not afford medical attention. The
      strongest predictor for treatment-seeking behavior was the symptom of incomplete
      emptying (logistic regression, P=0.004). A substantial proportion of Hong Kong
      Chinese women with urinary symptoms seek medical advice for their symptoms. The
      symptom of incomplete emptying appears to be the strongest reason for them to do
      so.

PMID- 12601514
TI  - The effects of periurethral muscle-derived stem cell injection on leak point
      pressure in a rat model of stress urinary incontinence.
AB  - Our goal was to determine whether periurethral injection of allogenic muscle
      derived stem cells (MDSC) could increase the leak point pressure (LPP) in a
      denervated female rat model of stress urinary incontinence. Cells isolated from
      the gastrocnemius muscle of normal female rats were purified for a myogenic
      population by the preplate technique. Three experimental groups were established:
      a control group (C) had a sham operation without injections; a sciatic nerve
      transection group (D) had periurethral saline injections; and a sciatic nerve
      transsection group had periurethral MDSC injections (M). One week following
      treatment the LPP of groups C, D and M were 25.2+/-1.9 cmH(2)O, 28.6+/-0.8
      cmH(2)O and 36.7+/-2.3 cmH(2)O, respectively. At 4 weeks the LPP of groups C, D
      and M were 25.8+/-2.5 cmH(2)O, 18.6+/-5.2 cmH(2)O and 44.1+/-6.6 cmH(2)O,
      respectively. Allogenic MDSC significantly improved the LPP in sciatic nerve
      transected animals after both 1 and 4 weeks compared to denervated animals
      injected with saline.

PMID- 12601515
TI  - The impact of delivery on anorectal function in women with and women without anal
      incontinence--a prospective study.
AB  - A prospective study was carried out to evaluate the effect of delivery on anal
      physiological parameters in anally incontinent women (n=18) compared with
      continent women (n=42). Perineal plane, anal manometry, anal mucosa
      electrosensitivity and pudendal nerve terminal motor latency (PNTML) were all
      assessed at 26 weeks' gestation and at 3 and 6 months after delivery. No major
      effect on the incremental changes in anal physiological parameters was seen from
      26 weeks of gestation to 3 months after delivery. At 26 weeks of gestation
      perineal plane and maximal squeeze pressure were impaired in incontinent women
      (P=0.02 and P=0.06); PNTML was impaired in incontinent women 6 months after
      delivery (P=0.05). Irrespective of continence status, delivery had an adverse
      effect on maximal squeeze pressure and PNTML. No major incremental changes were
      found between incontinent and continent women after delivery. However, there was
      a tendency to a higher degree of impairment of maximal squeeze pressure among
      incontinent women. Delivery per se had an adverse effect on maximal squeeze
      pressure and PNTML irrespective of continence status.

PMID- 12601516
TI  - The natural history of pelvic organ support in pregnancy.
AB  - Little is known about the anatomic and physiologic changes in the pelvic floor
      that occur during pregnancy. The purpose of this study was to prospectively
      document pelvic organ support throughout pregnancy using the standardized system
      of the International Continence Society, also known as the Pelvic Organ Prolapse
      Quantification (POPQ) Staging System. Pelvic organ support evaluations were
      performed in nulliparous pregnant women presenting for routine obstetric care
      during each trimester. POPQ stage assignments and POPQ component measurements
      were compared for first-, second- and third-trimester examinations. Overall POPQ
      stage was significantly higher in the third trimester than in the first
      (P=0.001). Individual POPQ points which showed significant differences between
      the first and third trimesters include Aa, PB, Ap, Ba, Bp, TVL and GH. These
      findings probably represent normal physiologic changes of the pelvic floor during
      pregnancy, but suggest that significant changes may be objectively demonstrated
      prior to delivery.

PMID- 12601500
TI  - The "two-headed" latent inhibition model of schizophrenia: modeling positive and
      negative symptoms and their treatment.
AB  - RATIONALE: Latent inhibition (LI), namely, poorer performance on a learning task
      involving a previously pre-exposed non-reinforced stimulus, is disrupted in the
      rat by the dopamine (DA) releaser amphetamine which produces and exacerbates
      psychotic (positive) symptoms, and this is reversed by treatment with typical and
      atypical antipsychotic drugs (APDs) which on their own potentiate LI. These
      phenomena are paralleled by disrupted LI in normal amphetamine-treated humans, in
      high schizotypal humans, and in schizophrenia patients in the acute stages of the
      disorder, as well as by potentiated LI in normal humans treated with APDs.
      Consequently, disrupted LI is considered to provide an animal model of positive
      symptoms of schizophrenia with face, construct and predictive validity.
      OBJECTIVES: To review most of the rodent data on the neural substrates of LI as
      well as on the effects of APDs on this phenomenon with an attempt to interpret
      and integrate these data within the framework of the switching model of LI; to
      show that there are two distinct LI models, disrupted and abnormally persistent
      LI; to relate these findings to the clinical condition. RESULTS: The nucleus
      accumbens (NAC) and its DA innervation form a crucial component of the neural
      circuitry of LI, and are involved at the conditioning stage. There is a clear
      functional differentiation between the NAC shell and core subregions whereby
      damage to the shell disrupts LI and damage to the core renders LI abnormally
      persistent under conditions that disrupt LI in normal rats. The effects of shell
      and core lesions parallel those produced by lesions to the major sources of input
      to the NAC: entorhinal cortex lesion, like shell lesion, disrupts LI, whereas
      hippocampal lesion, like core lesion, produces persistent LI with changes in
      context, and basolateral amygdala (BLA) lesion, like core lesion, produces
      persistent LI with extended conditioning. Systemically induced blockade of
      glutamatergic as well as DA transmission produce persistent LI via effects
      exerted at the conditioning stage, whereas enhancement of DA transmission
      disrupts LI via effects at the conditioning stage. Serotonergic manipulations can
      disrupt or potentiate LI via effects at the pre-exposure stage. Both typical and
      atypical APDs potentiate LI via effects at conditioning whereas atypical APDs in
      addition disrupt LI via effects at pre-exposure. Schizophrenia patients can
      exhibit disrupted or normal LI as a function of the state of the disorder (acute
      versus chronic), as well as persistent LI. CONCLUSIONS: Different drug and lesion
      manipulations produce two poles of abnormality in LI, namely, disrupted LI under
      conditions which lead to LI in normal rats, and abnormally persistent LI under
      conditions which disrupt it in normal rats. Disrupted and persistent LI are
      differentially responsive to APDs, with the former reversed by both typical and
      atypical APDs and the latter selectively reversed by atypical APDs. It is
      suggested that this "two-headed LI model" mimics two extremes of deficient
      cognitive switching seen in schizophrenia, excessive and retarded switching
      between associations, mediated by dysfunction of different brain circuitries, and
      can serve to model positive symptoms of schizophrenia and typical antipsychotic
      action, as well as negative symptoms of schizophrenia and atypical antipsychotic
      action.

PMID- 12601519
TI  - Plastic reconstruction of a mega vesicovaginal fistula using broad ligament flaps
      -a new technique.
AB  - Anew technique is described where medially based flaps raised from anterior folds
      of broad ligament were used to close a mega vesicovaginal fistula in a 35-year
      old woman, with a successful outcome.

PMID- 12601517
TI  - A new once-daily formulation of tolterodine provides superior efficacy and is
      well tolerated in women with overactive bladder.
AB  - This study evaluated the efficacy and tolerability of new extended-release (ER)
      tolterodine for the treatment of overactive bladder in women. In this
      subpopulation analysis of a double-blind multicenter trial, 1235 female patients
      were randomized to oral therapy with tolterodine ER 4 mg once daily (n=417),
      tolterodine IR 2 mg twice daily (n=408) or placebo (n=410) for 12 weeks. Both
      formulations reduced the mean number of urge incontinence episodes per week (both
      P=0.001 vs placebo); tolterodine ER was more effective than tolterodine IR
      (P=0.036). Both formulations significantly improved all other micturition chart
      variables compared to placebo. Dry mouth was the most common adverse event. There
      were no safety concerns. Toltrodine ER 4 mg once daily is effective and well
      tolerated in the treatment of women with overactive bladder, and reduces urge
      incontinence episodes more than the existing IR twice-daily formulation.

PMID- 12601518
TI  - Menstrual cycle, female hormone use and urinary incontinence in premenopausal
      women.
AB  - Our aim was to study the association between menstrual cycle characteristics, the
      use of female hormones and urinary incontinence (UI) in an age-stratified random
      population sample of 2158 premenopausal women who answered a questionnaire on
      urinary incontinence. Episodes of UI during 1997 were reported by 18.3% and one
      or more episodes of UI the preceding year by 3.9%. Based on multiple logistic
      regression, self-reported UI the day before answering the questionnaire was found
      to be associated with current hormone use for menstrual disorders (OR 2.7, 95% CI
      1.2-6.6), a recent decrease in bleeding duration (OR 2.2, 95% CI 1.3-3.7), being
      on days 11-15 before the expected end of the menstrual cycle the preceding day
      (OR 2.6, 95% CI 1.3-5.0), and with general UI risk factors, i.e. vaginal
      childbirth, childhood enuresis, BMI >/=530 and exposure to abdominal and/or
      gynecologic surgery. The findings are in accordance with a hypothesis of hormonal
      variation being a risk indicator of UI in premenopausal women.

PMID- 12601520
TI  - Ectopic ureter with urinary incontinence. An unusual presentation of Mayer
      Rokitansky-Kuster-Hauser syndrome.
AB  - Ectopic ureter occurs most commonly in association with ureterocele or
      duplication of the ureter. It is caused by a delay in or failure of separation of
      the ureteric bud from the mesonephric duct during embryologic development.
      Vaginal agenesis is the second most common cause of primary infertility in women
      after gonadal dysgenesis. Agenesis of the vagina in karyotypic females may be
      accompanied by other defects of the urogenital system [1]. We describe a rare
      combination of Mayer-Rokitansky-Kuster-Hauser syndrome and ectopic ureter with
      urinary incontinence.

PMID- 12601521
TI  - The treatment of urinary incontinence in 1814.
AB  - A selection from a little-known medical treatise of the early 19th century is
      presented which describes the condition of urinary stress incontinence and its
      treatment by means of pessaries, mechanical occlusive devices and electrical
      stimulation therapy. The author provides a foreshadowing of therapies that would
      come into more common use 150 years later.

PMID- 12601524
TI  - Polymorphisms of the tumor necrosis factor receptors: no association with
      narcolepsy in German patients.
AB  - Narcolepsy is a debilitating sleep disorder characterized by daytime sleepiness
      and cataplexy. The strong association of narcolepsy with the HLA system suggests
      an autoimmune cause. Tumor necrosis factor is a cytokine involved in both
      regulation of immune mechanisms and sleep. Several studies were undertaken to
      determine a contribution of tumor necrosis factor and its receptors to the
      pathogenesis of narcolepsy. A significant increase in the 196R allele, a
      functionally relevant polymorphism in the TNFR2 gene, has been found in Japanese
      patients, indicating altered transduction of tumor necrosis factor signals. Here
      we explore polymorphisms in both tumor necrosis factor receptor genes as risk
      factors in a German population sample. Neither the polymorphism in the TNFR1 nor
      that in the TNFR2 gene was associated with narcolepsy. Our findings contrast to
      those previously published and thus provide evidence for genetic heterogeneity
      between different narcolepsy populations.

PMID- 12601525
TI  - Cytokine-facilitated priming of CD8+ T cell responses by DNA vaccination.
AB  - Immune responses elicited by plasmid DNA vaccination can be enhanced and
      modulated by codelivery of cytokine-encoding plasmids. We studied whether priming
      of cytotoxic T lymphocyte (CTL) responses against hepatitis B surface antigen
      (HBsAg) by DNA vaccines injected either intramusculary or intradermally with the
      gene gun is enhanced by codelivery of cytokine-encoding plasmids. From a panel of
      tested cytokine plasmids only mouse IFNbeta, IL-15, and GM-CSF encoding plasmids
      showed an effect. Intradermal gene gun vaccination with 1 micro g plasmid DNA
      encoding intracellular HBsAg (large LS) showed enhanced CTL priming when IFNbeta,
      IL15, or GM-CSF encoding plasmids were codelivered; this was not observed when a
      DNA vaccine encoding secreted HBsAg (small S) was injected. Intramuscular
      injection of low (5 micro g) doses of a DNA vaccine encoding large HBsAg did not
      prime CTL when delivered without cytokines, with IFNbeta or IL15-encoding
      plasmids. However, codelivery with GM-CSF encoding plasmid DNA primed potent,
      specific CTL immunity detected either in a cytotoxic assay or by determining the
      frequency of L(d)-restricted CD8(+) T cells specifically inducible to IFNgamma
      production. The codelivery of GM-CSF encoding plasmids with the DNA vaccine
      furthermore enhanced CTL priming to a subdominant, D(d)-restricted epitope of
      HBsAg. The adjuvant effect of cytokine-encoding plasmids on CTL priming by DNA
      vaccines is thus complex and depends on: (a) the type of cytokine (or combination
      of cytokines) codelivered, (b) the type (intracellular vs. secreted) and dose (1
      50 micro g) of the DNA vaccine, (c) the method of DNA vaccine delivery ("naked"
      vs. particle-coated DNA), and (d) the (intramuscular vs. intradermal) route of
      delivery of the DNA vaccine.

PMID- 12601526
TI  - Deficiency of choresteryl ester transfer protein and gene polymorphisms of
      lipoprotein lipase and hepatic lipase are not associated with longevity.
AB  - Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse
      cholesterol transport (RCT). The role of CETP in atherosclerosis remains
      controversial. In this study we investigated the associations between
      polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic
      lipase (C-514T), lipoprotein lipase ( PvuII and HindIII), and ATP-binding
      cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190
      healthy younger controls. Although heterozygous CETP deficiency and the B2 allele
      of the Taq1B polymorphism was consistently associated with higher HDL-C
      concentrations both in centenarians and controls, the allelic frequencies of
      those polymorphisms did not differ between the two groups. The allelic
      frequencies of other gene polymorphisms in RCT were not different between the two
      groups. Centenarians with lipoprotein lipase P(-/-) genotype had significantly
      higher HDL-C concentration than those with P(-/+) or with P(+/+), in contrast,
      there was no such a relationship among controls. In stepwise multiple regression
      analysis, serum albumin, CETP deficiency and lipoprotein lipase PvuII genotype
      were independently associated with HDL-C in centenarians. Sex, CETP deficiency,
      and the Taq1B genotype were also independently associated with HDL-C; however,
      lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in
      controls. In conclusion, we observed that CETP deficiency and other gene
      polymorphisms in RCT have no impact on longevity for Japanese centenarians.

PMID- 12601527
TI  - Nitric oxide in the human hair follicle: constitutive and dihydrotestosterone
      induced nitric oxide synthase expression and NO production in dermal papilla
      cells.
AB  - The free radical nitric oxide, generated by different types of epidermal and
      dermal cells, has been identified as an important mediator in various
      physiological and pathophysiological processes of the skin, such as regulation of
      blood flow, melanogenesis, wound healing, and hyperproliferative skin diseases.
      However, little is known about the role of NO in the human hair follicle and in
      hair cycling processes. Here we demonstrate for the first time that dermal
      papilla cells derived from human hair follicles spontaneously produce NO by
      measuring nitrate and nitrite levels in culture supernatants. This biomolecule is
      apparently formed by the endothelial isoform of nitric oxide synthase, which was
      detected at the mRNA and protein levels. Remarkably, basal NO level was enhanced
      threefold by stimulating dermal papilla cells with 5alpha-dihydrotestosterone
      (DHT) but not with testosterone. Addition of N-[3-(aminomethyl)benzyl]acetamidine
      (1400W), a highly selective inhibitor of inducible nitric oxide synthase,
      restrained the elevation in NO level induced by DHT. Analyses of DHT-stimulated
      cells at the mRNA and protein levels confirmed the expression of inducible nitric
      oxide synthase. These findings suggest NO as a signaling molecule in human dermal
      papilla cells and implicate basal and androgen-mediated NO production to be
      involved in the regulation of hair follicle activity.

PMID- 12601523
TI  - Therapeutic vaccination with tumor cells that engage CD137.
AB  - Therapeutic cancer vaccination is based on the finding that tumors in both humans
      and experimental animals, such as mice, express potential immunological targets,
      some of which have high selectivity for cancer cells. In contrast to the
      successful vaccination against some infectious diseases, where most vaccines
      induce neutralizing antibodies that act prophylactically, the aim of therapeutic
      cancer vaccines is to treat established tumors (primarily micrometastases). Since
      most tumor-destructive immune responses are cell-mediated, therapeutic cancer
      vaccination needs to induce and expand such responses and also to overcome
      "escape" mechanisms that allow tumors to evade immunological destruction. Tumor
      antigens (as with other antigens) are presented by "professional" antigen
      presenting cells, most notably dendritic cells (DC). Therefore DC that have been
      transfected or "pulsed" to present antigen provide a logical source of tumor
      vaccines, and some encouraging results have been obtained clinically as well as
      in preclinical models. An alternative and more physiological approach is to
      develop vaccines that deliver tumor antigen for in vivo uptake and presentation
      by the DC. Vaccines of the latter type include tumor cells that have been
      modified to produce certain lymphokines or express costimulatory molecules, as
      well as cDNAs, recombinant viruses, proteins, peptides and glycolipids which are
      often given together with an adjuvant. Several studies over the past 5 years have
      demonstrated dramatic therapeutic responses against established mouse tumors as a
      result of repeated injections of agonistic monoclonal antibodies (MAbs) to the
      costimulatory molecule CD137 (4-1BB). However, the clinical use of such MAbs may
      be problematic since they depress antibody formation, for example, to infectious
      agents. The alternative approach to transfect tumor cells to express the CD137
      ligand (CD137L) increases their immunogenicity, but vaccination with tumor cells
      expressing CD137L is ineffective in several systems where injection of anti-CD137
      MAb produces tumor regression. Recent findings indicate that a more effective way
      to engage CD137 towards tumor destruction is to transfect tumor cells to express
      a cell-bound form of anti-CD137 single-chain Fv fragments (scFv). Notably, tumors
      from melanoma K1735, growing either subcutaneously or in the lung, could be
      eradicated following vaccination with K1735 cells that expressed anti-CD137 scFv.
      This was in spite of the fact that K1735, as with many human neoplasms, expresses
      very low levels of MHC class I and has low immunogenicity. Similar results were
      subsequently obtained with other tumors of low immunogenicity, including sarcoma
      Ag104. We hypothesize that the concomitant expression of tumor antigen and anti
      CD137 scFv effectively engages NK cells, monocytes and dendritic cells, as well
      as activated CD4(+) and CD8(+) T cells (all of which express CD137) so as to
      induce and expand a tumor-destructive Th1 response. While vaccines in the form of
      transfected tumor cells can be effective, at least in mouse models, the logical
      next step is to construct vaccines that combine genes that encode molecularly
      defined tumor antigens with a gene that encodes anti-CD137 scFv. Before planning
      any clinical trials, vaccines that engage CD137 via scFv need to be compared in
      demanding mouse models for efficacy and side effects with vaccines that are
      already being tested clinically, including transfected DC and tumor cells
      producing granulocyte-macrophage colony-stimulating factor.

PMID- 12601528
TI  - Improvement in muscular performance and decrease in tumor necrosis factor level
      in old age after antioxidant treatment.
AB  - Aging-related loss of muscle function is a predictor of mortality and a surrogate
      parameter of the aging process. Its consequences include a high risk for falls,
      hip fractures, and loss of autonomy. Aging is associated with changes in the
      oxidant/antioxidant balance including a decrease in plasma thiol (cysteine)
      concentration. To assess the importance of cysteine, we determined in a double
      blind study the effects of N-acetylcysteine on the functional capacity of frail
      geriatric patients and their response to physical exercise. The subjects on
      placebo showed only a relatively weak response, and 31% showed even a decrease in
      more than one parameter during the observation period. Low plasma arginine levels
      were correlated with a weak overall performance before exercise and a poor
      response to exercise. N-Acetylcysteine strongly enhanced the increase in knee
      extensor strength and significantly increased the sum of all strength parameters
      if adjusted for baseline arginine level as a confounding parameter. N
      acetylcysteine had no significant effect on growth hormone and IGF-1 levels but
      caused a significant decrease in plasma TNF-alpha. These findings may provide a
      basis for therapeutic intervention and suggest that the loss of function involves
      limitations in cysteine and one or more other amino acids which may compromise
      muscular protein synthesis.

PMID- 12601529
TI  - Association of a polymorphism of the phospholipase D2 gene with the prevalence of
      colorectal cancer.
AB  - Phospholipase D plays an important role in transmembrane signaling in a variety
      of cell types and its activity is increased in certain cancers, suggesting that
      it also contributes to tumorigenesis. A C-->T transition at nucleotide 1814 of
      the human phospholipase D(2) gene, which results in a Thr-->Ile substitution at
      amino acid 577, was noted in the GenBank database. The relationship of this
      polymorphism to the prevalence of cancer of the esophagus, stomach, colon-rectum,
      lung, and breast in Japanese was investigated in a case-control study. The
      genotype of the phospholipase D(2) gene was determined by the polymerase chain
      reaction with confronting two-pair primers. Multivariate logistic regression
      analysis with adjustment for age, gender, and smoking status revealed that the
      frequency of the T allele of the 1814C-->T polymorphism was significantly higher
      in individuals with colorectal cancer than in controls. A significant association
      of the polymorphism with the prevalence of colorectal cancer was found in
      analyses assuming either dominant (TT+CT vs. CC) or additive (CT vs. CC) effects
      of the T allele, but the T allele was not associated with the prevalence of
      esophageal, gastric, lung, or breast cancer. The activities of phospholipase D in
      cell lysates or membrane fractions did not differ between cells transfected with
      cDNAs encoding the Thr-577 or Ile-577 variants of phospholipase D(2). These
      results suggest that the phospholipase D(2) gene is a susceptibility locus for
      colorectal cancer in Japanese individuals, although a functional effect of the
      1814C-->T (Thr577Ile) polymorphism was not detected.

PMID- 12601530
TI  - [Glutamic acid decarboxylase and tyrosine phosphatase-like IA-2 antibodies for
      diabetes classification in unselected diabetic patients].
AB  - BACKGROUND: The determination of glutamic acid decarboxylase and tyrosine
      phosphatase-like antibodies (GAD-AB and IA-2-AB) may be useful for the
      classification of diabetes, and in selected patient groups the measurement of
      these autoantibodies has been shown to be rather sensitive and specific. PATIENTS
      AND METHODS: In this study we examined the use of these antibody determination in
      a clinical setting of 157 diabetic outpatients recruited randomly from our
      diabetes clinic. The prevalence of the different antibodies was set in relation
      to the clinically classified diabetes type and to diabetes duration. RESULTS:
      Among the patients with a clinical diagnosis of type 1 diabetes, the GAD-AB were
      clearly positive in 44% and borderline positive in 10%, whereas the IA-2-AB were
      positive or borderline positive in 36% of these patients. The prevalence of
      positive autoantibodies declined with increasing duration of type 1 diabetes.
      Among the patients with clinically diagnosed type 2 diabetes, the GAD-AB were
      clearly positive in 25.2% and borderline positive in 13.1%, IA-2-AB were only
      found in 4.7%. Patients with a clinical diagnosis of type 2 diabetes but positive
      for GAD-AB could not clearly be identified as having latent autoimmune diabetes
      in adults (LADA), since some of them did not need insulin therapy up to 10 years
      after the diagnosis of diabetes. The prevalence of GAD-AB in type 2 diabetic/LADA
      patients did not depend on diabetes duration. CONCLUSION: We conclude that the
      determination especially of GAD-AB may be useful for the classification of
      diabetes in clinically unclear cases. The additional determination of IA-2-AB
      appears to provide only limited additional information.

PMID- 12601531
TI  - [Calcified plaques of extracranial carotid arteries and left ventricular geometry
      as predictors of coronary artery disease].
AB  - PATIENTS AND METHODS: 113 patients underwent cardiac catheterization with
      selective coronary angiography, ultrasound examination of carotid arteries, and
      echocardiography. Coronary angiograms were analyzed for disease severity and
      extent (number of main vessels with > 50% stenosis) carotid ultrasound for number
      and distribution of calcified plaques among the carotid arteries. Left
      ventricular diameter (LVEDD), interventricular septal thickness (IVS), and
      posterior wall thickness (LVPW) in end-diastole were measured
      echocardiographically. Left ventricular mass divided by body surface area (Q,
      normal < 150 g/m(2)) and left ventricular relative wall thickness (RWT = [IVS +
      LVPW]/LVEDD, normal < 0.44) were calculated. A normal left ventricular mass/body
      surface area with increased relative wall thickness was regarded as left
      ventricular concentric remodeling, while a hypertrophied left ventricle was
      denoted eccentric if the relative wall thickness was normal and concentric if the
      relative wall thickness was increased. Besides the traditional vascular risk
      factors hypertension, diabetes, smoking and hypercholesterolemia as well as body
      mass index, age and sex were analyzed. RESULTS: Calcified plaques of carotid
      arteries were significantly correlated (r = 0.432, p < 0.001) with coronary
      artery stenoses as well as hypercholesterolemia (r = 0.434, p < 0.001),
      increasing age (r = 0.389, p < 0.001), diabetes (r = 0.273, p = 0.002),
      hypertension (r = 0.203, p = 0.015), and left ventricular hypertrophy (r = 0.188,
      p = 0.023) in contrast to smoking status, body mass index, and male sex. The
      number of calcified plaques was also significantly correlated (r = 0.504, p <
      0.001) with severity and extent of coronary artery disease. Multiple stepwise
      regression analysis showed higher predictive values including calcified carotid
      plaques. CONCLUSION: Thus, determination of calcified carotid plaques is useful
      to improve the predictive value of risk factor-based multivariate models.

PMID- 12601532
TI  - [Neuropsychiatric involvement in systemic lupus erythematosus. Part 2: diagnostic
      and therapy].
AB  - BACKGROUND: The diagnosis of neuropsychiatric lupus erythematosus (NPSLE) can be
      difficult and has to be differentiated from neurologic complications that result
      from hypertension, drugs, infection, uremia, and metabolic changes. DIAGNOSTICS:
      There is no single test which is diagnostic. Therefore, the clinical
      presentation, serologic tests and neuroimaging techniques have to be combined to
      support the diagnosis of cerebral lupus. Magnetic resonance imaging (MRI) is
      routinely used with a sensitivity of 50-87%. However, the abnormalities such as
      white matter lesions or brain atrophy are nonspecific and were also found in
      asymptomatic patients (16-52%). A negative MRI result does not exclude a
      diagnosis of cerebral lupus. Antibodies against phospholipids are an important
      immunoserologic marker due to the close association with thromboembolic events.
      Echocardiography and cerebrospinal fluid examination should be added to rule out
      cardiac embolic disease and CNS infection. Functional brain imaging techniques
      such as single-photon emission computed tomography, positron emission tomography,
      magnetization transfer imaging or magnetic resonance spectroscopy may be helpful
      especially in patients with unconspicuous MRI, but the findings are not SLE
      specific. THERAPY: The treatment of cerebral lupus is empiric, due to a lack of
      randomized studies. Inflammatory brain lesions are treated with corticosteroids
      and immunosuppressive drugs (e. g., cyclophosphamide). Anticoagulant therapy with
      coumarins (at a target INR of 3.0-3.5) is recommended in cases of thrombotic
      events associated with antiphospholipid antibodies. However, no studies exist on
      patients with arterial thrombosis, including strokes, supporting this target INR.

PMID- 12601533
TI  - [Anticoagulation in cardioversion of atrial fibrillation. Current status and
      outlook for the future].
AB  - BACKGROUND: Atrial fibrillation is the most common arrhythmias with increasing
      incidence in the elderly. The increased morbidity associated with atrial
      fibrillation is mainly caused by cardiac emboli, mostly from the left atrial
      appendage, that may cause cerebral ischemic infarctions. Although electrical
      cardioversion of atrial fibrillation has been the standard therapy for
      restoration of sinus rhythm for many years, questions regarding the optimal
      anticoagulation for the prevention of thromboembolic complications remain
      unanswered. CURRENT GUIDELINES: Current guidelines advocate the use of oral
      anticoagulation (adjusted to an Internal Standardized Ratio [INR] of 2.0-3.0) for
      at least 3-4 weeks before cardioversion for atrial fibrillation of > 48 h
      duration. Because of the atrial contractice dysfunction following cardioversion,
      the so-called "atrial stunning", anticoagulation for another 3-4 weeks after
      cardioversion is recommended. Alternatively, early cardioversion using high-dose
      intravenous heparin after exclusion of intraatrial thrombi by transesophageal
      echocardiography is possible, also followed by 3-4 weeks of oral anticoagulants.
      Because of the fear of bleeding complications, these anticoagulation schemes are
      frequently underused in the clinical setting, especially in older patients. Thus,
      new therapeutic approaches for anticoagulation in the setting of cardioversion
      are currently being investigated. FUTURE PERSPECTIVES: Low molecular weight
      heparins allow outpatient therapy because no intravenous therapy initiation is
      necessary and the need for anticoagulation monitoring is reduced. Whether oral
      thrombin antagonists may increase the safety of chronic anticoagulation because
      of their higher therapeutic index compared to warfarin has to be determined in
      future studies.

PMID- 12601534
TI  - [Neoadjuvant chemotherapy of primary hepatic non-Hodgkin's lymphoma].
AB  - BACKGROUND: Since primary malignant lymphomas of the liver represent a rare
      entity, no commonly accepted therapeutic strategy has been developed so far. CASE
      STUDY: We report the case of a diffuse large-cell B-cell lymphoma of the liver in
      a 48-year-old female patient. The tumor presented as a solitary mass measuring
      12.5 cm in maximum diameter. After neoadjuvant chemotherapy, the lymphoma was
      completely resected (R0). A massive therapy-induced tumor regression was found
      histologically. No involvement of regional lymph nodes or other organs was
      detected during staging procedures (stage I EA). After six courses of adjuvant
      chemotherapy, the patient has been alive and well for more than 5 years and shows
      no evidence of tumor relapse. CONCLUSION: This case documents the effect of
      systemic chemotherapy on lymphoma cells. In many centers systemic chemotherapy is
      used as the only therapeutic regimen. Neoadjuvant chemotherapy might, however,
      represent an important addition to the therapeutic strategies concerning
      unilocular primary hepatic lymphomas.

PMID- 12601535
TI  - [Kyphoscoliosis as a cause of pulmonary hypertension].
AB  - HISTORY AND CLINICAL FINDINGS: A 61-year-old male patient complained about
      diffuse upper abdominal pain and a progressive dyspnoe on exertion. Of clinical
      relevance were signs of congestive heart failure and a distinct kyphoscoliosis.
      THERAPY AND CLINICAL COURSE: A cardiac catheter examination proved a pulmonary
      hypertension without cardiac genesis. Both, pulmonary function test and computed
      tomography of the thorax rule out obstructive bronchial asthma and embolism of
      the lung. As the sole cause of pulmonary hypertension, kyphoscoliosis was
      diagnosed. Since the patient refused noninvasive positive pressure ventilation, a
      medication with calcium entry blocker and ACE blocker was induced, followed by
      oxygen breathing. This successfully helped to reduce pulmonary resistance (746
      vs. 332 dyn*s*cm(-5)). CONCLUSION: Kyphoscoliosis can create a considerable
      increase of pulmonary resistance. Medical treatment and oxygen breathing have
      proven to be an efficient method to lower that significantly.

PMID- 12601536
TI  - Functional evaluation of cancer surgery in oral and maxillofacial region: speech
      function.

PMID- 12601537
TI  - Current management of ductal carcinoma in situ of the breast.
AB  - Ductal carcinoma in situ (DCIS) accounts for approximately 20% of all screen
      detected breast cancers. Total mastectomy can achieve a 98% cure rate in patients
      with DCIS, but its impact on quality of life should be weighed against the risk
      of local recurrence. Skin-sparing mastectomy with immediate reconstruction using
      autologous tissue can achieve excellent cosmesis and therefore should be
      considered when mastectomy is indicated. Nevertheless, mastectomy is considered
      an over-treatment for localized DCIS, and breast conservation is the goal of
      modern treatment. Three recent randomized controlled trials have demonstrated
      that adjuvant radiotherapy (RT) after adequate local excision of localized DCIS
      significantly reduces the incidence of local recurrence. Non-randomized studies
      suggest that patients with adequately excised small (<15 mm), non-high-grade DCIS
      not associated with necrosis can be safely spared adjuvant RT. However, this
      issue requires further evaluation in randomized controlled trials. The role of
      adjuvant tamoxifen is not well established, especially in relation to the hormone
      receptor status. Formal axillary dissection is not appropriate for DCIS; however,
      the potential role of the sentinel node biopsy (SNB) in selected high-risk cases
      requires further evaluation. The potential role of new selective estrogen
      receptor (ER) modulators and third-generation aromatase inhibitors in
      postmenopausal women with ER-positive DCIS, gene and protein expression
      profiling, and mammary ductoscopy will be the focus of future research.

PMID- 12601539
TI  - Use of complementary and alternative medicine by patients with localized prostate
      carcinoma: study at a single institute in Japan.
AB  - BACKGROUND: The use of complementary/alternative medicine (CAM) has recently
      received considerable attention throughout the world. We evaluated the prevalence
      and predictors of CAM use among Japanese patients with localized prostate cancer.
      METHODS: A total of 177 patients with localized prostate carcinoma underwent
      radical retropubic prostatecotomy or external beam radiation therapy between
      January 1994 and January 2001. Of them, 138 (78%) answered a self-administered
      questionnaire on CAM use and were eligible for this study. The overall
      prevalence, types of CAM used, and costs of CAM were assessed. The effects of
      age, prostate-specific antigen (PSA) level, clinical stage, pretreatment Gleason
      score, patients' income, patients' final educational status, and general health
      related quality of life at baseline and 1 year after treatment, as estimated
      using the European Organization for Research and Treatment of Cancer Prostate
      Cancer Quality of Life Questionnaire on the prevalence of CAM use, were
      evaluated. RESULTS: Twenty-seven patients (20%) had once used or had been using
      some types of CAM. Herbal medicine and vitamins were the most common types of CAM
      used. Preoperative Gleason score was significantly associated with CAM use, as
      determined by the chi(2) test ( P = 0.0198), and PSA level and posttreatment
      physical function domain were marginally associated with CAM use, as determined
      by the Mann-Whitney U-test ( P = 0.0734 and P = 0.0597, respectively). Patient
      age, income, and final educational status had no impact on CAM use. CONCLUSION: A
      relatively small proportion of Japanese patients with localized prostate cancer
      have tried CAM compared with the proportions of patients described in previous
      reports from Western countries.

PMID- 12601538
TI  - Unknown primary carcinoma: a feasibility assessment of combination chemotherapy
      with cisplatin and docetaxel.
AB  - BACKGROUND: Docetaxel (Taxotere) and cisplatin are two of the most active single
      agents used in the treatment of solid tumors. We examined the feasibility of
      using a combination of docetaxel and cisplatin for the treatment of unknown
      primary carcinoma in order to prepare a larger scale prospective study. METHODS:
      Eligible patients were aged 18 to 75 years, with an Eastern Cooperative Oncology
      Group (ECOG) performance status of 2 or less and a life expectancy of 8 weeks or
      more, and had been diagnosed as having unknown primary carcinoma by the required
      examinations. Patients were not permitted to have received prior chemotherapy and
      had to have measurable lesions. Docetaxel (60 mg/m(2)) was given intravenously
      over a 1-h period immediately before cisplatin (80 mg/m(2)), which was given
      intravenously over a 2-h period, every 3 weeks. Premedication included
      dexamethasone, granisetron, and standard hyperhydration. RESULTS: Twenty-six
      treatment courses in five patients were tested according to the protocol and
      feasibility was assessed. Adverse events observed included grade 4 neutropenia,
      leukopenia, grade 3 nausea/vomiting, grade 2 diarrhea, and mucositis. These
      adverse events were well tolerated, reversible, and manageable. Doses were not
      reduced and all injections were given or their due date without any delay in all
      patients. Four patients achieved a partial response and one had stable disease.
      CONCLUSION: Treatment of patients with unknown primary carcinoma with a
      combination of docetaxel and cisplatin is feasible. Conduct of a phase II trial
      of this regimen is warranted.

PMID- 12601540
TI  - Loco-regional failures in head and neck cancer: can they be effectively salvaged
      by nonsurgical therapeutic modalities?
AB  - BACKGROUND: This retrospective study was carried out to ascertain the extent of
      efficacy of nonsurgical salvage modalities, mainly chemotherapy (CT) alone or
      chemoradiotherapy (CTRT), for loco-regional failures in head and neck cancer
      (HNC). METHODS: Between 1991 and 1999, 131 patients with HNC, mostly stages III
      and IV, who had loco-regional residual ( n = 78) or recurrent lesions ( n = 53)
      following curative therapy with either radiotherapy (RT), neoadjuvant CT (NACT)
      followed by RT, or concurrent CTRT were included in this analysis. Of these, 84
      patients (residual, 58; recurrent, 26), did not receive any form of salvage
      therapy, while 47 had either CT alone ( n = 22) or CTRT ( n = 25). Endpoints
      evaluated were: loco-regional response (LRR), post-salvage survival (PS), overall
      survival (OS), and normal tissue acute and late morbidities. RESULTS: Salvage
      therapy enabled a LRR in 46.8% of the patients. Both OS and PS were also
      significantly better for those who received salvage therapy ( P < 0.001). CTRT
      appears to offer significantly better salvage than CT alone for all the evaluated
      endpoints. Multivariate analysis for LRR, PS, and OS consistently showed the
      salvage RT dose to be a significant predictor. Early and late effects of salvage
      therapy were not influenced by either the salvage or total RT doses. CONCLUSION:
      Loco-regional failures in advanced HNC can be effectively salvaged by CTRT to
      significantly prolong OS and PS. However, to achieve an optimum therapeutic
      ratio, the choice of drugs, their schedule, and the RT dose need to be defined
      through randomized trials.

PMID- 12601541
TI  - Prognostic significance of second-look laparotomy for surgically confirmed early
      stage epithelial ovarian cancer: a multicenter retrospective study.
AB  - BACKGROUND: In the present study, we conducted a multicenter retrospective
      analysis to elucidate the prognostic significance of second-look laparotomy (SLL)
      in early-stage epithelial ovarian cancer that was confirmed by complete surgical
      exploration. METHODS: In July 2001, 12 Japanese institutions received
      questionnaires regarding patients with early-stage epithelial ovarian cancer and
      SLL. Eligibility criteria included patients with stage I or II epithelial ovarian
      cancer who were surgically diagnosed between January 1988 and December 1997. Data
      were collected regarding age, performance status, tumor histologic subtype,
      stage, preoperative carbohydrate antigen (CA) 125 level, results of SLL if
      performed, recurrence, disease-free survival, and overall survival. Survival
      analyses and comparisons were performed by univariate methods. RESULTS: There
      were 87 patients who met the eligibility criteria. There were no significant
      differences in the backgrounds of patients who had had SLL ( n = 30) and the non
      SLL group ( n = 57). Of the 30 SLL-group patients, 28 had negative SLL findings
      and 2 had positive findings. Six and 5 patients in the SLL group and the non-SLL
      group, respectively, had recurrence ( P = 0.177), and 4 patients in the SLL group
      had a recurrence after "negative" SLL findings. There was no significant
      difference between the two groups for either overall ( P = 0.73) or disease-free
      survival ( P = 0.273). On univariate analysis, only clear-cell histology was
      associated with a poor prognosis in early-stage epithelial ovarian cancer ( P =
      0.031). CONCLUSION: SLL is not beneficial for early-stage epithelial ovarian
      cancer. More favorable outcomes will be achieved for early-stage patients with
      the improvement of treatment for clear-cell adenocarcinoma.

PMID- 12601542
TI  - Weekly 1-h paclitaxel infusion in patients with recurrent endometrial cancer: a
      preliminary study.
AB  - BACKGROUND: The aim of this study was to evaluate the toxicity and efficacy of
      weekly paclitaxel in patients with recurrent endometrial cancer. METHODS: Nine
      patients with recurrent endometrial cancer who had previously received
      chemotherapy or radiotherapy participated in the study, between May 1999 and
      August 2001. Paclitaxel was given at a dose of 70 mg/m(2) as a 1-h infusion every
      week for at least 20 consecutive weeks unless lesions became progressive.
      Intravenous dexamethasone and cimetidine and oral diphenhydramine were
      administered 30 min before paclitaxel infusion. RESULTS: The nine patients
      received a total of 149 cycles of therapy. No hypersensitivity reactions were
      elicited. Grade 3 leukopenia, neutropenia, and anemia occurred in 22%, 33%, and
      33% of the patients, respectively. Granulocyte colony-stimulating factor was
      required for two patients and no patients experienced febrile neutropenia.
      Neurotoxicity was commonly observed. Grade 1 peripheral neuropathy and myalgias
      were observed in 78% and 11% of the patients, respectively. No grade 3 or higher
      nonhematological toxicities were observed. Partial responses were seen in six of
      the nine patients (67%). The median progression-free interval was 8 months
      (range, 0-12 months) and the median overall survival was 10 months (range, 4-24
      months). CONCLUSION: Weekly 1-h paclitaxel administration is considered safe and
      effective as a salvage therapy for recurrent endometrial cancer, with this
      schedule and delivery making its use more convenient and easier in the outpatient
      setting. The current results support further evaluation.

PMID- 12601544
TI  - Docetaxel and carboplatin combination chemotherapy for recurrent endometrial
      cancer.
AB  - There is no consensus regarding the optimal chemotherapy for endometrial cancer
      patients, and a need for better chemotherapy is evident. Two individuals with
      recurrent metastatic endometrial cancer treated with docetaxel and carboplatin
      combination chemotherapy are presented here. Both cases showed objective response
      to the chemotherapy (one complete response and the other partial response);
      response duration was 7 and 18 months, respectively. One patient who achieved
      complete response is alive without disease for 12 months after recurrence.
      Adverse effects in this regimen were mild and tolerable. Docetaxel in combination
      with carboplatin may be active agents for patients with metastatic endometrial
      cancer.

PMID- 12601543
TI  - Activity and safety of a low dose, fractional administration of irinotecan
      hydrochloride (CPT-11) in combination with cisplatin for relapsed gastric cancer
      patients: a preliminary report.
AB  - BACKGROUND: Irinotecan hydrochloride (CPT-11) in combination with cisplatin has
      emerged as a new therapeutic option for the treatment of advanced gastric cancer.
      So far, very few combination trials have been reported, and a relatively high
      frequency of grade 3/4 toxicities in previous trials has been a major problem.
      The purpose of this study was to elucidate the efficacy and safety of a low dose,
      fractional administration of CPT-11 and cisplatin that is principally based on
      recently acquired knowledge of the synergistic antitumor activities between these
      two agents. METHODS: Five relapsed gastric cancer patients were treated every 2
      weeks with a starting dose of CPT-11 (30 mg/m(2)) and a fixed dose of cisplatin
      (30 mg/m(2)). All patients were of performance status 0 and had received prior
      chemotherapy. Dose escalation of CPT-11 to 40 mg/m(2) or to 50 mg/m(2) was
      performed whenever possible. Responses, toxicities, and at-home ratio during
      chemotherapy were evaluated. RESULTS: The response rate reached 40%. Toxicities
      were grade 1/2, and no grade 3/4 hematological toxicities or diarrhea were
      observed. Repeated subsequent treatments could be performed in an outpatient
      setting without treatment delay or cancellations, which resulted in an 83%-92% at
      home ratio in four patients receiving five or more cycles of treatment. There
      were no treatment-related deaths. CONCLUSION: A low dose, fractional
      administration of CPT-11 and cisplatin seems rational, encouraging, and safe, and
      compares well with other trials of the combination. Outpatient administration
      provides the patients with a better quality of life, suggesting a meaningful
      therapeutic option for relapsed gastric cancer patients in particular.

PMID- 12601545
TI  - Therapy-related erythroleukemia caused by the administration of UFT and mitomycin
      C in a patient with colon cancer.
AB  - A 54-year-old man with colon cancer underwent hemicolectomy. He received
      postoperative adjuvant chemotherapy with UFT (tegafur/uracil at a 1 : 4 molar
      ratio) and mitomycin C (MMC) for 3 years. Three years and 4 months after the
      start of chemotherapy, pancytopenia was noted. Bone marrow aspiration smear
      demonstrated an increased number of immature erythroblasts, including
      megaloblasts and myeloblasts. Chromosomal analysis demonstrated structural and
      numerical abnormalities of 5, 7, 15, and 17. Therapy-related erythroleukemia,
      acute myeloid leukemia (AML), M6, was diagnosed. The disease progressed after 5
      months, and the patient was received chemotherapy with cytosine arabinoside,
      aclacinomycin, and granulocyte colony-stimulating factor (CAG), and showed a
      partial hematological response. Careful monitoring for the generation of therapy
      related leukemia is needed when UFT and MMC are used for postoperative adjuvant
      chemotherapy for colorectal cancer.

PMID- 12601546
TI  - Stage IVB uterine endometrial cancer successfully salvaged by chemoradiotherapy
      and surgery.
AB  - A case of stage IVB adenoacanthoma of the uterine corpus is described. The
      patient was admitted with a large amount of atypical genital bleeding. Computed
      tomography and magnetic resonance imaging revealed a large tumor accompanied by
      lymph node involvement in the left inguinal, multiple pelvic, and paraaortic
      regions. She was diagnosed as having stage IVB endometrial adenoacanthoma.
      Neoadjuvant chemotherapy with carboplatin (CBDCA) and 5-fluorouracil (5-FU) was
      performed, followed by radiotherapy. The tumor responded very well, but still
      remained in Douglas' pouch after treatment. The patient therefore underwent a
      simple hysterectomy, pelvic and paraaortic lymphadenectomy, and partial rectal
      resection. Histopathologically, viable cancer cells were observed only in the
      fundus of the uterus. The patient is alive with no evidence of recurrence 4 years
      after the initiation of chemoradiotherapy.

PMID- 12601547
TI  - Cancer, genes, and catechol estrogen metabolites.

PMID- 12601548
TI  - Molecular genetics of familial hypertrophic cardiomyopathy (FHC).
AB  - Familial hypertrophic cardiomyopathy is an autosomal dominant disease with a wide
      range of clinical features from benign to severe, and is the most common cause of
      sudden death in otherwise healthy individuals. The two prominent clinical
      features are left ventricular hypertrophy and myocyte/myofibrillar disarray. The
      former is responsible for clinical symptoms such as breathlessness and angina,
      whereas the latter may lead to sudden cardiac death. The last decade has seen an
      enormous improvement in our understanding of the molecular genetics of this
      disorder. The clinical heterogeneity has been linked to genetic heterogeneity;
      mutations in nine genes encoding sarcomere proteins have been shown to be the
      molecular basis for the disorder. However, attempts to establish a genotype
      phenotype correlation for each of the more than 100 mutations that have been
      identified have not been highly successful. Additional genetic loci, as well as
      nongenetic factors such as lifestyle, sex, and age, have also been shown to play
      a role in modulating the clinical presentation of the disease. How each mutation
      results in hypertrophy and/or myofibrillar disarray is unclear. The present
      review discusses the current status of the molecular genetic characterization of
      this important disorder.

PMID- 12601550
TI  - Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in
      nine Swedish families with erythropoietic protoporphyria.
AB  - Erythropoietic protoporphyria (EPP) is an inherited disorder, caused by a partial
      deficiency of ferrochelatase (FECH), the last enzyme of the heme biosynthetic
      pathway. The deficiency results in accumulation of protoporphyrin, primarily in
      erythroid cells, and the major clinical feature is cutaneous photosensitivity. In
      addition, some patients may develop liver complications. Several EPP-coupled
      mutations have been identified in the FECH gene, and the less than 50% of FECH
      activity seen in patients with overt EPP was recently shown to be due to the in
      trans inheritance of one deleterious mutation and a IVS3-48T>C transition in
      intron 3 of the FECH gene. This IVS3-48T>C transition modulates the use of a
      constitutive aberrant splice site, which results in a decreased FECH mRNA level
      in the carrier. In the present study, the inheritance of four novel (364C>T,
      393delC, 532G>A, and 1088-89insGG) and two previously reported (343C>T and
      1001C>T) FECH mutations, and the splice site modulator IVS3-48C was investigated
      in nine Swedish families with EPP. The methods used for the FECH gene analysis
      included denaturating gradient gel electrophoresis, sequencing analysis, and
      restriction enzyme cleavage. Haplotype analysis, based on the polymorphic loci
      287(G/A), IVS3-48(T/C), and 921(G/A), revealed that all individuals carrying a
      mutated allele and IVS3-48C in trans to each other were affected by overt EPP.
      Mild clinical and biochemical EPP signs may, however, be present in individuals
      carrying a T at position IVS3-48 in trans to a mutated allele, because this was
      the case in one of the individuals investigated in the present study.

PMID- 12601549
TI  - Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT
      inhibitor, in human hepatoblastomas.
AB  - We recently demonstrated inactivation in hepatocellular carcinomas (HCCs) of the
      gene encoding SOCS1/JAB1/SSI-1, a JAK-binding protein that regulates the JAK/STAT
      signal-transduction pathway. In a follow-up immunochemical investigation of
      expression of SOCS-1 in hepatoblastomas (HBLs), the protein was markedly reduced
      in half of the HBL tumors we examined. CpG-rich regions upstream of the SOCS-1
      gene were hypermehylated in 7 of the 15 HBL cases. The results suggest that
      hypermethylation may play an important role in silencing the SOCS-1 gene, not
      only in adult HCCs, but also in liver tumors arising in childhood.

PMID- 12601551
TI  - Association of the -381T/C promoter variation of the brain natriuretic peptide
      gene with low bone-mineral density and rapid postmenopausal bone loss.
AB  - Osteoporosis is believed to result from interplay among multiple environmental
      and genetic determinants, including factors that regulate bone-mineral density
      (BMD). Recent quantitative trait locus analysis in human suggested a possible
      involvement of chromosomal region 1p36.2-p36.3 for determination of BMD. The
      brain natriuretic peptide (BNP, also named NPPB) gene lies within this candidate
      region for BMD determination. Overexpression of the BNP resulted in skeletal
      overgrowth in transgenic mice. Association analysis between nucleotide variations
      of the BNP gene and radial BMD in 378 Japanese postmenopausal women revealed a
      significant association of the -381T/C variation of the BNP gene with radial BMD
      (r = 0.17, P = 0.01). Homozygous T-allele carriers had the lowest BMD values
      (0.395 +/- 0.056 g/cm(2)), homozygous C-allele carriers had the highest (0.429 +/
      0.051 g/cm(2)), and heterozygous individuals had intermediate radial BMD values
      (0.405 +/- 0.048 g/cm(2)), indicating a dosage effect. Accelerated bone loss also
      correlated with the -381 T allele in a 5-year follow-up study (r = 0.21, P =
      0.017). These results suggest that variation of BNP may be an important
      determinant of postmenopausal osteoporosis, in part through the mechanism of
      accelerated postmenopausal bone loss.

PMID- 12601552
TI  - Haplotype analysis of the human collectin placenta 1 (hCL-P1) gene.
AB  - Collectins are a family of C-type lectins found in vertebrates. These proteins
      have four regions, a relatively short N-terminal region, a collagen-like region,
      an alpha-helical coiled coil, and a carbohydrate recognition domain. Collectins
      are involved in host defense through their ability to bind carbohydrate antigens
      on microorganisms. Type A scavenger receptors are classical-type scavenger
      receptors that also have collagen-like domains. We previously described a new
      scavenger receptor, collectin from placenta [collectin placenta 1 (CL-P1)]. CL-P1
      is a type II membrane protein with all four regions. We found that CL-P1 can bind
      and phagocytize both bacteria and yeast. In addition to that, it reacts with
      oxidized low-density lipoprotein (LDL) but not with acetylated LDL. These results
      suggest that CL-P1 might play important roles in host defenses and/or
      atherosclerosis formation. One rational strategy to study the role of CL-P1 in
      these pathological conditions would be to perform a haplotype association study
      using human samples. As a first step for this strategy, we analyzed the haplotype
      structure of the CL-P1gene. By sequencing the CL-P1 gene in ten Japanese
      volunteers, we identified five single-nucleotide polymorphisms (SNPs) with a
      minor allele frequency of at least 29%. To obtain SNPs in the 5'-upstream region
      of the gene, we screened a total of 20 SNPs described in the database and finally
      picked up one SNP for the present study. Thus, a total of six SNPs, one in the 5'
      upstream region, two in intron 2, one in exon 5, and two in exon 6, were used to
      analyze the haplotype structure of the gene, with DNAs derived from 54
      individuals (108 alleles). The analysis revealed that only two of six SNPs showed
      significant linkage disequilibrium ( r(2) > 0.5) with each other. This haplotype
      information may be useful in disease-association studies in which a contribution
      of the CL-P1 gene has been suspected, especially in immunological disturbance or
      atherosclerosis. Two SNPs in exon 6, both leading to amino acid substitutions,
      could be candidates for influencing disease susceptibility.

PMID- 12601553
TI  - A novel mutation of the insulin-like 3 gene in patients with cryptorchidism.
AB  - Two independent studies demonstrated that transgenic mice with a targeted
      deletion of the insulin-like 3 ( INSL3) gene presented bilateral cryptorchidism.
      Studies in humans have investigated the possibility that mutations in the INSL3
      gene are the cause of cryptorchidism. In the present study, genomic DNA was
      obtained from 150 patients with idiopathic cryptorchidism. DNA was amplified and
      the polymerase chain reaction products of both exons were sequenced. A previously
      unidentified missense mutation was found in only one of the patients studied. In
      exon 2, a heterozygous C/G substitution at nucleotide 2560, which turned
      asparagine into lysine at codon 86, was documented. The familial study revealed
      that the mother was a heterozygous carrier of the mutation and the father was a
      homozygote wild type. We also found three polymorphic changes, previously
      reported in exon 1. The Asn-into-Lys change is likely deleterious because it
      leads to a nonconservative amino acid substitution, changing a highly conserved
      residue. This mutation, located in the A-chain of the INSL3 protein, is the first
      mutation reported in this region. This finding provides new evidence that INSL3
      is involved in testicular descent in humans; however, mutations of this gene are
      not a frequent cause of cryptorchidism.

PMID- 12601554
TI  - Severe congenital muscular dystrophy in a Mexican family with a new nonsense
      mutation (R2578X) in the laminin alpha-2 gene.
AB  - The congenital muscular dystrophies (CMDs) are a heterogeneous group of autosomal
      recessive disorders. Approximately one half of cases diagnosed with classic CMD
      show primary deficiency of the laminin alpha2 chain of merosin. Complete absence
      of this protein is usually associated with a severe phenotype characterized by
      drastic muscle weakness and characteristic changes in white matter in cerebral
      magnetic resonance imaging (MRI). Here we report an 8-month-old Mexican female
      infant, from a consanguineous family, with classical CMD. Serum creatine kinase
      was elevated, muscle biopsy showed dystrophic changes, and there were
      abnormalities in brain MRI. Immunofluorescence analysis demonstrated the complete
      absence of laminin alpha2. In contrast, expression of alpha-, beta-, gamma-, and
      delta-sarcoglycans and dystrophin, all components of the dystrophin-glycoprotein
      complex, appeared normal. A homozygous C long right arrow T substitution at
      position 7781 that generated a stop codon in the G domain of the protein was
      identified by mutation analysis of the laminin alpha2 gene ( LAMA2). Sequence
      analysis on available DNA samples of the family showed that parents and other
      relatives were carriers of the mutation.

PMID- 12601555
TI  - Isolation and characterization of a novel human NM23-H1B gene, a different
      transcript of NM23-H1.
AB  - The NM23 gene is a conspicuous metastasis-suppressor gene. Eight human genes of
      the NM23/nucleoside diphosphate kinase family have been discovered. From our
      large cDNA cloning and sequencing project, we cloned a different transcript (
      NM23-H1B) of human NM23-H1 from 18-week-old human fetal brain. The 987-bp cDNA
      encodes a protein of 177 amino acid residues. Compared with NM23H1, the cDNA
      contained an additional NH(2)-terminal region (25 amino acid residues). It was
      mapped to chromosome 17q21.3 using bioinformatics analysis, which shows that the
      second exon does not exist in NM23-H1. The expression pattern of NM23-H1B showed
      that it was ubiquitously expressed in normal tissues (15 tissues except colon) at
      different levels. Our data also indicated that the expression of the transcript
      in tumors related to tumor differentiation: in poorly differentiated breast
      carcinoma GI-101, pancreatic adenocarcinoma GI-103, and undifferentiated ovarian
      carcinoma GI-102, there was no expression. In poorly differentiated lung
      carcinoma LX-1, lung carcinoma GI-117, the expression level was very low. The
      transcript band in well-differentiated colon adenocarcinoma CX-1 was
      significantly higher than that in poorly differentiated colon adenocarcinoma GI
      112. A high transcription level was also found in grade IV prostatic
      adenocarcinoma PC3.

PMID- 12601556
TI  - Molecular cloning and characterization of the protein 4.1O gene, a novel member
      of the protein 4.1 family with focal expression in ovary.
AB  - Protein 4.1 is an important structural protein that is expressed in erythroid and
      in a variety of nonerythroid tissues. In mammalian erythrocytes, it plays a key
      role in regulating the physical properties of mechanical stability and
      deformability in membranes by stabilizing the spectrin-actin interaction. The
      protein 4.1 family mainly comprises 4.1R, 4.1G (general type), 4.1B (brain type),
      and 4.1N (neuron type). We identified a novel human 4.1 ( 4.1O) gene that is 2312
      bp in length and encodes a protein of 553 amino acid residues. The protein shared
      homology with mouse protein 4.1B (identity 38%, similarity 55%) with a FERM
      domain. The expression pattern of the human 4.1O gene in 16 tissues showed that
      there was a transcript only in ovary, whereas in the remaining 15 tissues,
      specific bands of the transcript could not be detected. In eight human fetal
      tissues, the specific bands of the transcript could be detected in skeletal
      muscle, with lower levels detected in thymus and brain. The 4.1O gene consists of
      14 exons and 13 introns and was mapped to Chromosome 9q21-9q22 by bioinformatics
      analysis.

PMID- 12601557
TI  - Identification of two novel RECQL4exonic SNPs and genomic characterization of the
      IVS12 minisatellite.
AB  - Rothmund-Thomson syndrome is a rare autosomal recessive disorder characterized by
      a widely heterogeneous clinical presentation. Only a subset of clinically
      diagnosed patients carry RECQL4 gene mutations, probably because of their genetic
      heterogeneity and/or the complexity of molecular testing. We here describe the
      polymorphic sites of the RECQL4 gene that detail its genomic structure and may be
      of interest as modulators of the splicing process and gene expression. We
      characterized two novel and one already described single-nucleotide polymorphism
      in the coding region of the RECQL4 gene, which were shown by the exonic splicing
      enhancer (ESE) score matrix to fall into high-score motifs recognized by
      serine/arginine-rich proteins. We also describe the genomic structure of a G-C
      rich minisatellite flanking the 3' splice site of IVS12 in the helicase domain of
      the RECQL4 gene, which may enhance mutations such as those described at the IVS12
      acceptor site. RECQL4 polymorphic sites may be useful for identifying alleles
      associated with missplicing and, more generally, in cancer-susceptibility
      association studies.

PMID- 12601558
TI  - The Strengths and Difficulties Questionnaire (SDQ)--further evidence for its
      reliability and validity in a community sample of Dutch children and adolescents.
AB  - This study was a first attempt to examine the psychometric properties of the
      Strengths and Difficulties Questionnaire (SDQ) in Dutch youths. A large sample of
      normal children and adolescents ( N = 562) and their parents completed the SDQ
      along with a number of other psychopathology measures. Factor analysis of the SDQ
      yielded five factors that were in keeping with the hypothesised subscales of
      hyperactivity-inattention, emotional symptoms, peer problems, conduct problems,
      and prosocial behaviour. Furthermore, internal consistency, test-retest
      stability, and parent-youth agreement of the various SDQ scales were acceptable.
      Finally, the concurrent validity of the SDQ was good: that is, its scores
      correlated in a theoretically meaningful way with other measures of
      psychopathology. It can be concluded that the psychometric properties of the
      parent- and self-report version of the SDQ were satisfactory in this Dutch
      community sample. Moreover, the current data provide further support for the
      utility of the SDQ as an index of psychopathological symptoms in youths.

PMID- 12601559
TI  - The Strengths and Difficulties Questionnaire: a pilot study of a new computer
      version of the self-report scale.
AB  - A computer-based version of the self-report Strengths and Difficulties
      Questionnaire (SDQ) was developed with colourful graphics illustrating each
      question. One hundred and two children referred to child and adolescent mental
      health services were recruited and randomly allocated to complete either the new
      computer-based version or the paper original. A further 112 children from local
      schools were recruited and completed the computer-based version of the scale. All
      children who took part in the study were aged between 8 and 15 years. The paper
      version of the SDQ is recommended for use in children aged 11 and over and, in
      this age group, the computer-based questionnaire was able to discriminate between
      the clinical and community sample (ROC = 0.761, 95 % CI 0.676-0.846). Comparison
      of the paper-based SDQ and computer-based SDQ within the clinic sample found
      trends towards better test-retest reliability, inter-rater reliability and
      significantly better user satisfaction in the computer version compared to the
      paper-based version. The computer-based SDQ has the added advantage of results
      being automatically added to a spreadsheet out of view from the user reducing the
      chance of operator error in coding and entering the data. These preliminary
      results suggest that the computer-based version of the SDQ may represent a
      further improvement on the paper SDQ. All versions of the SDQ, including the
      computer-based version, can be downloaded from the Strengths and Difficulties
      website address www.sdqinfo.com.

PMID- 12601560
TI  - Diagnostic stability in adolescent onset psychotic disorders.
AB  - The purpose was to examine the long-term stability of a diagnosis of psychotic
      disorder in adolescence and to focus on diagnostic change over time. A total of
      88 patients with a first episode of early onset psychosis (before 19 years) were
      followed up an average of 10.5 years (range 5.1-18.2) after admission. This
      report includes the 68 patients who could be traced and interviewed with the
      Positive and Negative Symptom Scale and lifetime Structured Clinical Interview
      for DSM-IV diagnosis. An initial diagnostic split between schizophrenia spectrum
      and affective disorder had a good (> 80 %) Positive Predictive Validity and
      Sensitivity. The main diagnostic shift was an influx to schizophrenia spectrum
      disorder (n = 6). These patients resembled the stable affective group (n = 27) in
      premorbid and prodromal aspects but changed over time to resemble the poor
      outcome of the stable schizophrenia spectrum group (n = 28) albeit with fewer
      negative symptoms and a better social function. Family history of nonaffective
      psychosis in first or second degree relatives was often found in the "change to
      schizophrenia group". A diagnosis in adolescence of schizophrenia spectrum or
      affective psychotic disorder is usually stable over time. A subgroup of non
      schizophrenia patients go on to develop a schizophrenia spectrum disorder.

PMID- 12601561
TI  - Predicting repeat self-harm in children--how accurate can we expect to be?
AB  - The main objective of the study was to find which variables predict repetition of
      deliberate self-harm in children. The study is based on a group of children who
      took part in a randomized control trial investigating the effects of a home-based
      family intervention for children who had deliberately poisoned themselves. These
      children had a range of baseline and outcome measures collected on two occasions
      (two and six months follow-up). Outcome data were collected from 149 (92 %) of
      the initial 162 children over the six months. Twenty-three children made a
      further deliberate self-harm attempt within the follow-up period. A number of
      variables at baseline were found to be significantly associated with repeat self
      harm. Parental mental health and a history of previous attempts were the
      strongest predictors. A model of prediction of further deliberate self-harm
      combining these significant individual variables produced a high positive
      predictive value (86 %) but had low sensitivity (28 %). Predicting repeat self
      harm in children is difficult, even with a comprehensive series of assessments
      over multiple time points, and we need to adapt services with this in mind. We
      propose a model of service provision which takes these findings into account.

PMID- 12601562
TI  - Swedish child and adolescent psychiatric out-patients--a five-year cohort.
AB  - Publications of Swedish child and adolescent psychiatric out-patients have been
      scarce. This study is aimed to give a picture of conditions in a child and
      adolescent psychiatric out-patient setting by reporting five-year data from a
      five-year cohort of first-time visits. All first-visits, 0-18 years of age, where
      screened retrospectively for background factors, symptoms, diagnoses and types of
      treatment. Six hundred and ten patients were registered during the period. The
      estimated accumulated prevalence for 19-year-olds were 19,7 %. Nearly half of
      them were seen 1-3 times. A small group, 2,5 %, accounted for about 20 % of all
      consultations. No or mild psychosocial stress was registered in 37 % of the
      cases. A neuropsychiatric main diagnosis was found for 27 % (2,1:1, boys:girls)
      and depression and anxiety for 20 % [0, 5:1] of the index-cases. These findings
      show that 5,6 % of children applied for child and adolescent psychiatric help
      during a five-year period. Almost one third had a neuropsychiatric disorder. The
      results indicate that ADHD is one of the most common causes both among boys and
      girls to seek help in a child and adolescent out-patient clinic.

PMID- 12601563
TI  - Frontal EEG correlates of externalizing spectrum behaviors.
AB  - An atypical EEG pattern of frontal brain activation, which has been related to
      compromised emotional regulation in children and adults, is hypothesized to be
      also present in children with externalizing behavior problems. Seventy-eight
      children at 11 years of age were examined to answer the following questions: 1)
      do children with externalizing behaviors exhibit an atypical pattern of frontal
      brain activation which can be linked to the severity of their problem behaviors?
      and 2) are there gender differences in these frontal activation patterns?
      Spontaneous EEG activity was subjected to power spectral analysis. In
      externalizing girls, the well-known pattern of a significantly greater right than
      left frontal brain activation emerged that has been found previously in
      emotionally disordered children, whereas healthy girls showed a significantly
      greater left than right frontal activation. In contrast, healthy boys
      demonstrated a significantly greater right than left frontal activation, whereas
      externalizing boys did not display a frontal brain asymmetry. Thus, the pattern
      of frontal brain activation was gender specific. The atypical activation pattern
      in externalizing children is hypothesized to be a biological correlate of
      difficulties in regulating emotion.

PMID- 12601564
TI  - Childhood onset narcolepsy--a case report.
AB  - Narcolepsy is a disorder of the sleep-wake cycle with long-term sequelae.
      Although regarded as rare, it is probably under-diagnosed in both adults and
      children. Clinical heterogeneity, particularly in childhood, and development of
      symptoms over time, contribute to the delay in diagnosis and treatment. We
      present a case of a child with symptoms suggestive of narcolepsy. We discuss the
      merits of early intervention in selected cases, even when full diagnostic
      criteria are lacking.

PMID- 12601565
TI  - A proposed primate animal model of autism.
AB  - Based on the fact that thalidomide, at a certain point in human pregnancy,
      produces autism, we propose administering thalidomide to pregnant monkeys at an
      appropriate point after conception. The infant monkeys born after thalidomide
      treatment of the pregnant mothers should manifest aberrations in social
      vocalization and in socialization behavior. Histological analysis of their brains
      should reveal areas whose damage will lead to autism. This can then be produced
      stereotaxically in infant monkeys to allow the better determination of the
      relation of degree of damage in these areas to the severity of autism.

PMID- 12601568
TI  - Inter- and intracellular signaling in secondary osteoporosis.

PMID- 12601569
TI  - High-intensity pulsed laser irradiation accelerates bone formation in metaphyseal
      trabecular bone in rat femur.
AB  - Low-energy laser irradiation has positive effects on bone fracture healing,
      osteoblast proliferation, bone nodule formation, and alkaline phosphatase
      activity. However, the mechanism by which low-energy laser irradiation affects
      bone is not clearly known. It was recently found that light at a low radiation
      dosage is absorbed by intracellular chromophores. High-intensity pulsed laser
      irradiation can produce acoustic waves in the target surface by rapidly heating
      the tissue. We considered that the acoustic waves induced by high-intensity
      pulsed laser irradiation, in addition to the photochemical effects that are
      induced, accelerate bone formation. To clarify whether high-intensity pulsed
      laser irradiation accelerates bone formation, we investigated bone formation in
      the irradiated femur of rat, using histomorphometric analysis. Rat femurs were
      irradiated with a Q-switched Nd: YAG laser, which has a wavelength of 1064 nm,
      under two conditions: once a day, with the average fluence rate set at 100
      mW/cm(2) (LA1), and twice a day, i.e., every 12 h, with the average fluence rate
      set at 50 mW/cm(2) (LA2). The mean bone volume and mineral apposition rate in the
      LA1 group were significantly higher than those in the nonirradiated group
      (control). These values were highest for the LA2 group, and were about 1.52 and
      1.25-fold those of the control, respectively. These data demonstrated that the
      number of pulses, rather than the intensity of the laser irradiation, affects
      bone formation. Thus, this study indicated that high-intensity pulsed laser
      irradiation accelerates bone formation in the metaphysis. This bone formation
      induced by high-intensity pulsed laser irradiation might be due to laser-induced
      pressure waves.

PMID- 12601570
TI  - Effects of basic fibroblast growth factor on osteoblast-related gene expression
      in the process of medullary bone formation induced in rat femur.
AB  - The effects of basic fibroblast growth factor (bFGF) on osteogenic
      differentiation in-vivo were investigated using a rat bone marrow ablation model.
      bFGF was infused directly into rat femora for 6 days after bone marrow ablation.
      The contralateral femur was infused with vehicle only and used as control. Bone
      formation was induced in the rat femoral cavity, and the gene expression of
      osteoblast markers was examined. Treatment with bFGF at 50 and 100 ng/day
      significantly enhanced the mRNA levels of osteopontin compared with the levels in
      the control leg, with increases of 25% and 24%, respectively. In contrast, bFGF
      infusion at 50 ng/day provoked a significant (nearly 20%) inhibition of
      expression for type I collagen. Infusion of bFGF at a higher dose exhibited an
      inhibitory tendency for bFGF action on gene expression. There were no significant
      changes in alkaline phosphatase and osteocalcin mRNA levels in response to any
      dose of bFGF. The findings presented here suggest that bFGF modulates osteogenic
      differentiation in-vivo and may play an important role in the process of bone
      remodeling.

PMID- 12601571
TI  - A study of mineral phase in immobilized rat femur: structure refinements by
      Rietveld analysis.
AB  - The aim of the present work was to examine whether immobilization of a limb
      influences the structure of bone mineral. The mineral phase in rat femora
      immobilized for 2 weeks during growth was investigated. Bone mineral was
      subjected to powder X-ray diffraction, using a scanning method after ashing the
      bones at 630 degrees C. Occupancy factors of ion positions in bone hydroxyapatite
      (HAP) were analyzed using the Rietveld refinement method. Occupancy factors of
      the positions OH(-), Ca(2+), and P(-) were significantly lower in immobilized
      than in control bones, although the position of ions in the HAP structure did not
      change. Mineralization of tissue in the immobilized bones was lower than in the
      controls, but there was no correlation between mineralization and occupancy
      factors. HAP lattice constants in immobilized bones were slightly but
      significantly different from those in controls. We conclude that the structure of
      HAP synthesized in bone during temporary lack of loading differs from that of HAP
      growing under physiological conditions. The Rietveld refinement method proved to
      be useful in the estimation of the changes in bone mineral.

PMID- 12601572
TI  - Risk factors for osteoporosis in men.
AB  - We evaluated the risk factors for osteoporosis in men. The subjects of this study
      consisted of 686 healthy middle-aged (40-59 years) men who had undergone bone
      mineral density (BMD) measurement and medical examination, including physical
      strength. BMD of L2-4 was measured at the anterior-posterior position, using dual
      X-ray absorptiometry. Physical investigations, such as height, weight, and
      physical strength, were carried out on the examination day. Details of tobacco
      and alcohol consumption, exercise, and food intake were described on a
      questionnaire completed by the subjects. Sixty-five (9.5%) of the 686 subjects
      had a BMD less than 2.5 SD below the peak bone mass (PBM), 182 (26.5%) had a BMD
      between 1 SD and 2.5 SD below the PBM; and 439 (64.0%) had a BMD no less than 1
      SD below the PBM. Body mass index (BMI) and leg strength were significant
      positive determinants of BMD, and smoking was a significant negative determinant
      on multiple regression analysis, with a coefficient of determination of 9.5%.
      Calcium intake, exercise, and alcohol consumption were not significant
      determinants of BMD. These results suggest that poor lifestyle behaviors (i.e.,
      smoking) accelerate the reduction of bone density.

PMID- 12601573
TI  - Various risks of osteoporosis in patients with pituitary adenomas.
AB  - Some pituitary adenomas seem to be related to bone loss. It is unknown what kinds
      of pituitary adenomas affect bone mass. We attempted to determine what kinds of
      pituitary adenomas caused osteoporosis, and whether hormonal disturbance in
      pituitary adenoma patients affected bone mass. This study included 53 surgical
      patients (39 women of premenopausal age and 14 men) aged 21 to 62 years. We
      measured vertebral bone mineral density (BMD); various bone metabolic parameters,
      such as serum calcium, phosphorus, alkaline phosphatase, and blood urea nitrogen,
      parathormone, vitamin D, vitamin K, and hormonal activity in the anterior lobe of
      the pituitary gland. Comparisons were made of the mean Z scores (the ratio to the
      mean BMD of age-matched healthy Japanese women and men) among patient groups and
      controls. Compared with the female controls, the mean Z score was significantly
      higher in the women with acromegalic adenoma and significantly lower in those
      with adrenocorticotrophic hormone (ACTH)-secreting adenoma. In male patients, the
      mean Z scores were significantly decreased in prolactin-secreting adenoma and
      nonfunctioning adenoma, compared with that in normal controls. Acromegalic
      adenoma contributes significantly to vertebral bone mass acquisition, although
      ACTH adenoma may carry a significant risk of osteoporosis in female patients.
      Male patients with prolactin-secreting and nonfunctioning adenoma have a
      significant risk of bone decrease.

PMID- 12601574
TI  - Intra-individual variation in lumbar bone mineral density as a measure of
      spondylotic deformity in the elderly.
AB  - In an attempt at quantitative assessment of spondylotic deformity, the intra
      individual variation in L(1)-L(4) bone mineral density (BMD) was calculated, as
      the standard deviation (SD) and coefficient of variation (CV), obtained by
      dividing the SD by mean L(1)-L(4) BMD, in 463 subjects. The subjects ranged in
      age from their second to tenth decades. Dual-energy X-ray absorptiometry (DXA),
      using the Lunar DPX-L, was employed to assess the BMD. The SD of lumbar (L)BMD
      increased with advancing age in males, but not in females, whereas the CV of LBMD
      increased with age in both males and females, along with the radiographically
      assessed degree of severity of spondylosis deformans. Both the intra-individual
      SD and CV of L(1)-L(4) BMD showed a highly significant correlation with the
      radiological degree of severity of spondylosis deformans, and SD, but not CV,
      showed a strong dependence on the mean L(1)-L(4) BMD on a multiple regression
      test. Multiple regression test revealed no significant correlation between on
      body height, weight, fracture, and intra-individual variation in L(1)-L(4)
      projected area, reflecting compression fracture, one hand and SD or CV of L(1)
      L(4) BMD on the other. Intra-individual variation in lumbar bone mineral density,
      expressed as a coefficient of variation, is suggested as an index of spondylotic
      deformity.

PMID- 12601576
TI  - Vitamin D receptor start codon polymorphism ( FokI) is related to bone mineral
      density in healthy adolescent boys.
AB  - Peak bone mass is considered a major determinant in the emergence of osteoporosis
      and is mainly genetically regulated. Several genes have been investigated, among
      them the vitamin D receptor ( VDR) gene. A single-nucleotide polymorphism
      (defined by the endonuclease FokI) located in the start codon of the VDR creates
      the alleles F and f, resulting in different proteins. A number of previous
      studies have proved the F allele to be more advantageous as concerns bone mineral
      density (BMD). In this longitudinal study of 88 adolescent boys, we have
      investigated whether the different genotypes are associated with BMD, bone
      mineral content (BMC), or bone area. BMD, BMC, and bone area of the right femoral
      neck, lumbar spine, and total body were measured using dual-energy X-ray
      absorptiometry. Differences in phenotypes in relation to the FokI polymorphism
      were calculated by means of an analysis of variance (ANOVA), with Bonferroni's
      correction for multiple comparisons. At the first examination, the FokI genotypes
      were significantly related to lumbar spine BMC and total body bone area in boys
      aged 16.9 +/- 0.3 years (mean +/- SD). There was a strong tendency towards
      significance as regards pubertal stage, total body and femoral neck BMC, weight,
      lean body mass, lumbar spine bone area, and lumbar spine BMD. There were no
      significant differences in height, fat mass, birth height and weight, total body
      and femoral neck BMD, and femoral neck bone area. Regression analysis proved the
      FokI genotypes to be independently related to lumbar spine BMD ( FF > ff; P <
      0.01), and possibly total body BMD ( P = 0.06), but not femoral neck BMD. At the
      second examination, approximately 2 years later, our ANOVA results showed
      significance as regards femoral neck BMC and weight. Using multiple regression,
      the FokI genotypes were independently related to lumbar spine BMD ( FF > ff; P =
      0.03), and total body BMD ( P < 0.05), but not femoral neck BMD. This study
      proves the FokI polymorphism to be an independent predictor of lumbar spine BMD
      are probably total body BMD, but not femoral neck BMD.

PMID- 12601575
TI  - Long-term hospitalization during pregnancy is a risk factor for vitamin D
      deficiency in neonates.
AB  - In order to examine the effects of long-term hospitalization during pregnancy on
      vitamin D metabolism in pregnant women and neonates, we measured the serum 25
      hydroxyvitamin D (25OHD) levels in pregnant women, as well as measuring 25OHD
      levels in cord blood and breast milk. In pregnant women hospitalized for longer
      than 1 month, the serum 25OHD levels were decreased at delivery compared with
      those in control subjects (10.9 +/- 2.6 ng/l vs 19.5 +/- 4.9 ng/l; P < 0.01).
      Although the levels of 25OHD in the cord blood were not significantly different
      between the long-term hospitalized and control pregnant women in this study (9.36
      +/- 1.7 ng/l vs 11.1 +/- 3.0 ng/l), the 25OHD concentrations in the cord blood
      were significantly lower than the maternal levels in both groups; the ratios of
      the levels in cord blood to sera in the long-term hospitalized women and control
      subjects were 82.1% and 60.3%, respectively. Long maternal hospitalization does
      not always cause neonatal vitamin D deficiency, but could be one of its major
      risk factors. Therefore, sufficient sunlight exposure and intake of sufficient
      vitamin D are considered to be important to prevent vitamin D deficiency in long
      term hospitalized pregnant women as well as their babies.

PMID- 12601577
TI  - Assessment of low bone mass in Vietnamese: comparison of QUS calcaneal
      ultrasonometer and data-derived T-scores.
AB  - There is a dearth of data on the prevalence of osteoporosis in Vietnam. This
      study was designed to preliminarily estimate the incidence of osteoporosis in the
      Vietnamese population. The study was designed as a population-based,
      epidemiological investigation. Men and women aged 18 years or above, who were
      residents of the City of Hanoi (Vietnam) and surrounding districts, and free of
      illnesses deemed to affect bone metabolism, were included in the study. Broadband
      ultrasound attenuation (BUA) was taken for each subject. The measurement was
      performed by a QUS-2 ultrasonometer at the calcaneus. The T-score of BUA was
      calculated as the number of standard deviations (SDs) from the value at peak BUA
      of young subjects. The age at peak BUA was estimated by a segmented linear
      regression model. A person was classified as having "low bone mass" if his/her T
      score was less than -2.5. There were no interventions. Six hundred and sixty
      eight men, aged 54.8 +/- 17.2 years (mean +/- SD), and 1390 women, aged 50.1 +/-
      12.9 years, participated in the study. BUA in men (81.3 +/- 20.5 dB/MHz) was
      significantly higher than that in women (78.4 +/- 18.7; P < 0.001). In each sex,
      age, body height, and body mass index were significant determinants of BUA, with
      the three factors collectively accounting for 25% of total variance of BUA. Peak
      BUA in men was 95 +/- 20 and in women, 90 +/- 16 dB/MHz. Age of peak BUA in men
      and women was 27 and 32 years, respectively. According to the instrument-derived
      T-score, 23.9% of men and 56.1% of women aged 60+ years were classified as
      osteoporotic. However, by using the data, 3.2% of men and 20% of women aged 60+
      years were osteoporotic. The kappa statistic (a measure of agreement between the
      instrument T-score and data-derived T-score) was 0.65. It was concluded that the
      prevalence of low bone mass in the Vietnamese population, as estimated by BUA,
      was comparable to that in other Asian and Caucasian populations. The instrument
      derived T-score is not appropriate for the diagnosis of osteoporosis in the
      Vietnamese population.

PMID- 12601580
TI  - One size does not fit all: special topics in stuttering therapy.
AB  - One of the greatest challenges facing clinicians working with school-age children
      who stutter is the fact that there are such vast differences between and among
      children who stutter. These differences are seen not only in the speech behaviors
      children may exhibit, but also in children's experiences with stuttering and in
      their reactions to those experiences. This article introduces the second of two
      issues of Seminars in Speech and Language that focuses on school-age children who
      stutter. The first volume addressed general issues in treatment, and this second
      volume is aimed at helping clinicians face the challenges posed by the
      differences in children who stutter. Specific topics include identifying
      resources designed to meet the needs of different children, tailoring treatment
      programs to children with specific needs (e.g., other cultural backgrounds,
      concomitant disorders), helping children face obstacles to achieving success
      outside the therapy room, and helping clinicians develop partnerships with family
      and teachers.

PMID- 12601578
TI  - Elderly women with oral exostoses had higher bone mineral density.
AB  - We examined the relationship between two opposite phenomena in elderly bone, bone
      loss (osteoporosis) and excessive bone formation (oral exostosis). We recruited,
      randomly, 44 female subjects without any conditions known to affect bone
      metabolism. The subjects were examined for exostosis, and bone mineral density
      (BMD) was measured by dual-energy X-ray absorptiometry. The Z score of the BMD
      was calculated; this is the deviation from the weight-adjusted average BMD of
      each age. Subjects with palatal tori ( n = 15) had a higher femoral BMD than
      controls ( n = 14) (0.580 +/- 0.213 vs -0.271 +/- 0.182; P = 0.0054). The
      subjects with palatal tori ( n = 12) also had a higher BMD than controls ( n =
      12) at the radius (0.417 +/- 0.235 vs -0.533 +/- 0.294; P = 0.0194). In addition,
      subjects with mandibular tori ( n = 13) had a higher femoral BMD than controls (
      n = 14) (0.569 +/- 0.242 vs -0.271 +/- 0.182; P = 0.0097). These results suggest
      that some common mechanisms are involved in the elevation of skeletal BMD and the
      occurrence of oral exostoses.

PMID- 12601581
TI  - Finding good resources for treating school-age children who stutter.
AB  - One of the challenges facing school-based speech-language pathologists is finding
      appropriate resources for use in treating children who stutter. This article
      highlights several excellent resources and provides illustrations of how some of
      these resources may be used. The need to adapt resources for use with specific
      clients to maximize treatment effectiveness is emphasized.

PMID- 12601582
TI  - Developing intervention programs for children with stuttering and concomitant
      impairments.
AB  - School-aged children who stutter often present concomitant impairments in
      articulation and language that can complicate treatment. In this article, a
      framework is offered for designing intervention programs for such children. It is
      stressed that clinicians must first identify clinical priorities by determining
      the severity of the impairments, their impact on daily activities, others'
      reactions to the impairments, and the likelihood of unassisted recovery. Several
      potential treatment models are presented, as are general treatment principles and
      specific treatment strategies for three profiles of children who stutter.
      Suggestions are also provided for including parents and teachers in the
      intervention plan.

PMID- 12601583
TI  - Multicultural issues in school settings.
AB  - As the caseload of ethnically and culturally diverse students who stutter
      increases, speech-language pathologists will need to become more culturally
      sensitive. Many speech-language pathologists, however, indicate that they are not
      comfortable treating clients from diverse backgrounds who stutter. Busy school
      schedules may prevent speech-language pathologists from obtaining information
      about multicultural aspects of stuttering. The purpose of this article,
      therefore, is to provide speech-language pathologists with information that
      addresses multicultural perceptions about stuttering and suggestions for the
      assessment and treatment of stuttering in ethnically and culturally diverse
      groups.

PMID- 12601584
TI  - Self-regulation and the management of stuttering.
AB  - Self-regulation refers to a process by which individuals learn to direct and
      control their own behavior, thoughts, and feelings to manage or eliminate their
      stuttering. As a concept, it has been a vital and enduring component of most
      approaches to managing persistent and chronic stuttering. The theoretical basis
      for self-regulation is briefly reviewed and the main principles of self
      regulation--goal setting, cue management, self-monitoring, and self-evaluation-
      are described and illustrated with clinical examples. Factors related to self
      regulatory failure are also discussed.

PMID- 12601585
TI  - Fostering generalization and maintenance in school settings.
AB  - One of the most challenging aspects of therapy for school-age children who
      stutter is generalizing the skills learned in the therapy room to other settings
      such as the classroom, lunchroom, playground, or home. An additional challenge is
      seen in maintaining gains over the long term. This article reviews common
      roadblocks to generalization and maintenance, including the goals of therapy, the
      nature of the treatment strategies that require generalization, the scheduling
      and implementation of generalization activities within the overall therapy
      process, and the child's understanding of the treatment goals. Specific
      strategies for overcoming these roadblocks include: desensitizing children to
      both stuttering and treatment strategies designed to improve fluency, using
      hierarchies as a way of structuring treatment and moving children toward success
      in their daily activities, integrating the child's real world and clinical
      settings, and using structured practice activities to help children solidify all
      of the lessons they learn in treatment. This article highlights the importance of
      taking a broad-based view of stuttering to help children improve their overall
      communication across a variety of settings and over time.

PMID- 12601586
TI  - Stuttering treatment in schools: developing family and teacher partnerships.
AB  - This article assists school-based clinicians in developing partnerships with the
      families and teachers of youngsters who stutter. Suggestions for initiating this
      relationship are provided, and recommendations for the shared roles that
      families, teachers, and clinicians play are described. School-based clinicians
      face challenges as they attempt to more actively engage families and teachers,
      including securing administrative support, developing creative scheduling and
      service delivery methods, and addressing the feelings of family members and
      teachers about involvement in stuttering treatment. Strategies for meeting these
      challenges are provided.

PMID- 12601587
TI  - The role of stuttering specialists in the school setting.
AB  - The role of the fluency specialist, including how the school-based speech
      language pathologist (SLP) and specialist can coordinate effective service for
      children who stutter is the primary focus of this article. The fluency
      specialist, who is either an employee of the school district or an outside
      consultant, addresses the needs of a particular child and/or clinician. Basic
      challenges of providing fluency intervention in a school setting and locating a
      fluency specialist with whom to work are addressed. The optimal skills that
      fluency specialists need to demonstrate are addressed in relation to their
      ability to assist professionals in their treatment of a stuttering disorder. To
      further clarify the coordination process between the fluency specialist and the
      school-based SLP, three models of collaboration are elaborated, all in pursuit of
      providing the highest quality of service possible for children who stutter in the
      school setting.

PMID- 12601588
TI  - Planning a teacher in-service for stuttering disorders.
AB  - This article addresses the need for teacher in-service presentations about
      stuttering disorders as a means of changing the negative perceptions teachers
      (and others) may have toward people who stutter. Strategies for in-service
      planning include keeping the program simple while one engages, encourages, and
      empathizes with teachers. The agenda for the program includes three key areas:
      content, experience with children who stutter, and classroom adaptations. Ongoing
      follow-up with teachers also helps to shape teacher beliefs about stuttering. The
      article concludes with a discussion about the special challenges faced by the
      speech language pathologist working in the public schools and ideas about how
      clinicians can work to overcome these potential barriers.

PMID- 12601589
TI  - Success in the schools: bringing it all together.
AB  - Children who stutter can successfully be treated in the schools. This has been
      the overriding message of the articles in this two-part series in Seminars in
      Speech and Language, which focuses on school-age children who stutter. This
      summary article reviews several of the key themes presented in the articles in
      this series and highlights the importance of taking a broad-based view of the
      disorder in working with children who stutter. The article ends with a series of
      reminders for clinicians to consider that will help school-age children who
      stutter achieve optimal success in treatment.

PMID- 12601591
TI  - [Assisted suicide in Zurich--questionable suicide assistance offers in
      Switzerland].

PMID- 12601592
TI  - [Caregivers' expectations towards psychiatric hospital].
AB  - OBJECTIVE: Caregivers' expectations regarding optimal psychiatric inpatient care
      should be evaluated using qualitative methodology. METHODS: A content analysis of
      interviews with 32 caregivers was carried out. The statements and categories were
      quantitatively analysed to assess its relative importance. RESULTS: "Much time of
      doctors and psychologists for discussion with the caregivers" was expected most
      frequently. In addition, caregivers assigned high importance to successful
      treatment of patient by competent physicians and psychologists and to information
      provided to caregivers about therapies, medication, side-effects and treatment
      progress. 53 % of all statements were related to the category "treatment and
      contact", 20 % to "information and education", 15 % to "clinical organisation and
      equipment", and 13 % to "admission and discharge". CONCLUSIONS: Taking into
      account these findings, more attention should be paid to caregivers' expectations
      to reduce problems of interaction between clinicians and caregivers. This might
      be helpful to improve the cooperation between caregivers and psychiatric
      hospitals resulting in a higher consumer satisfaction.

PMID- 12601593
TI  - [Discharge reports to the patients as a contribution to a person-centred therapy-
      concept and pilot study in a psychiatric day clinic].
AB  - We present the concept of an extended documentation of psychiatric
      psychotherapeutic treatment with the patients being in the center of information.
      Apart from a short treatment report for the outpatient therapist, we write a
      detailed letter to the patients themselves including informations and backgrounds
      of their psychiatric and medical history, psychopathological findings,
      diagnose(s), course of the current treatment and recommendations for the future.
      This procedure is in agreement with the tradition of psycho-educative approaches
      and self-management concepts. It intends to support patients to be self-conscious
      and responsible partners during and after the treatment process. We performed a
      pilot study for a predominantly descriptive evaluation of the concept in the day
      clinic setting. A standardized questionnaire in 30 previously treated patients
      and three case studies yielded a high acceptance and positive appraisal of the
      received letters with a substantial subjective impact for coping with the
      disorder and a positive option for dealing with family members and friends.

PMID- 12601595
TI  - [What patients think about the living together of smokers and non-smokers on
      psychiatric wards?].
AB  - ISSUE: The results of an inquiry about the difficulties of companionship between
      smokers and non-smokers in psychiatric wards are presented. METHOD: Patients
      stated at the end of their treatment in a routine inquiry, by now focused on the
      issue of smoking, how they felt about the organization of their living together
      within the wards. Smokers have been additionally asked whether they would have
      preferred to be abstinent of tobacco and whether they missed supplementary
      therapy offers. RESULTS: About 70 per cent of the patients were smokers. The
      arrangement, giving permission to smoking in just one room of the ward, was
      agreed more or less by smokers and non-smokers. 30 per cent of the non-smokers
      would apply for a non-smoking ward. About 40 per cent of the smokers would prefer
      to stop smoking and missed suitable therapeutical offers. CONCLUSION: Restriction
      to just one room for smokers in each ward is accepted by smokers and non-smokers.
      A therapeutical offer to withdrawing from tobacco should figure among the routine
      offers of each hospital.

PMID- 12601596
TI  - [Current structural and procedural quality markers of psychiatric day hospitals
      in Germany].
AB  - BACKGROUND: Particularly in the last 10 years the conceptual models of partial
      hospitalization are subjected to major changes, reflecting to the integration of
      day hospitals in regional mental health service systems and especially to the
      provision of an alternative to acute inpatient treatment. Systematic nation-wide
      surveys assessing these changes are missing. METHOD: After developing a
      structured questionnaire integrating differences in European mental health care
      systems, a German national survey of current structural and procedural quality
      markers of psychiatric day hospitals was carried out in 2001. 51.4 % of the
      addressed psychiatric hospitals (N = 191) returned the questionnaire. Analysis is
      based on descriptive and correlational methods, compares the situation in the
      Eastern and Western German Federal States, and uses cluster analysis to
      differentiate the day hospitals according to their main program function.
      RESULTS: In general, establishment of day hospitals in Germany has not yet
      reached the evidence-based capacity level. This statement especially applies to
      the situation in rural areas. 56 % of the day hospitals currently assess
      themselves as an alternative to inpatient treatment simultaneously providing
      differentiated psychotherapeutic treatment. Comparing clinical institutions in
      the Eastern and Western parts of Germany demonstrates the clearer orientation
      towards acute psychiatric treatment in the recently (mostly after 1995)
      established East-German hospitals. This is reflected in the spectrum of main
      clinical diagnoses, in the average length of treatment episodes, in the
      definitions of contraindications, and in the provided diagnostic measures. While
      administrative circumstances are homogeneous for day hospitals, there is a
      considerable variation in staff numbers related to the core professions.
      CONCLUSIONS: Guidelines for professional training and continuous qualification as
      well as staffing have to be modified according to requirements resulting from the
      change of clinical functions. Each day hospital has to clarify and define its
      main program function(s), and has to better communicate the consequences for the
      regional mental health service system.

PMID- 12601594
TI  - [Shame, embarrassment and trouble...relatives of patients with OCD describe
      stigma experiences in every-day life].
AB  - BACKGROUND: There are numerous studies on the stigma of mental illness. However,
      the subjective stigma experiences of patients with obsessive-compulsive disorder
      and their relatives have, so far not been investigated. METHOD: Narrative
      interviews with 22 family members of patients with OCD were carried out as part
      of a study on the burden of mental illness on the family. Experience of stigma
      was analysed as an aspect of subjective burden using a grounded theory approach.
      RESULTS: Different areas of life could be described, in which stigmatization is
      anticipated or experienced by family members of patients with OCD. Concealing is
      a relevant strategy for the members in dealing with the illness. DISCUSSION:
      Stigmatization can be minimized by impartially handling the illness and
      cooperation of patients, their relevant others and professionals.

PMID- 12601597
TI  - [The starting phase of a psychiatric unit--a statistical study].
AB  - OBJECTIVE: The work of a psychiatric department (in Rhede/Westphalia) was
      statistically investigated by compiling the most important patient and therapy
      data in five year periods over its first decade of existence. METHODS: Data of
      1364 admissions were surveyed in the years 1983, 1988 and 1993. These data were
      statistically analysed and showed age, sex, social class, living conditions,
      place of residence, distance to hospital, diagnoses, duration of stay,
      readmission, pre- and aftercare. RESULTS: The number of patients living in the
      catchmentarea increased, the duration of stay decreased, readmissions increased,
      the rate of patients without aftercare decreased, the rate of diagnoses kept
      continuously, patients were more often admitted to hospital directly.
      CONCLUSIONS: These and further results point out an increasing extent of
      community based psychiatry in the region.

PMID- 12601598
TI  - [Organic depressive disorder caused by Cushing's syndrome--case report].
AB  - We report a case of 35-year old female patient with recurrent depressive disorder
      and Cushing's syndrome. MRI of the brain revealed a microadenoma of the pituitary
      gland. After neurosurgery the serum levels of cortisol went back to normal and
      the clinical and mental state of the patient improved rapidly. Depressive
      episodes require additional diagnostics to exclude somatic etiology.

PMID- 12601599
TI  - [Arthrotenolysis of the proximal interphalangeal joint of the fingers. Operative
      technique and results].
AB  - From 1994 to1999, 24 patients were subjected to tenoarthrolysis of the PIP joint
      by a single surgeon for various reasons. All cases were documented by the surgeon
      in photographs and the achieved extent of mobility was followed up to at least
      one year postoperatively. All results were documented in photographs or on video
      films. The patients did not have conventional arthrolysis following injury of the
      capsular ligaments of the PIP joint (with the exception of one case), but complex
      injuries of bone, flexor tendons, diseases, and conditions after infections, some
      of which had occurred up to seven years previously. Four patients had been
      subjected to tenoarthrolysis twice, one had undergone tenoarthrolysis even three
      times. Five joints were fully ankylotic before surgery and had 0 degrees of
      mobility. All cases were referred from external surgeons. It was not possible to
      find common denominators for these cases and to include them in a regular study.
      The sole criterion used for assessment, which has also been used in comparable
      studies, was preoperative mobility and the postoperative mobility achieved after
      one year. Preoperative mobility in the PIP joint was on average 27.5 degrees
      (range, 0 - 60) and could be increased to a mean of 70 degrees (range, 0 to 120)
      after one year. Thus, an improvement of 42.5 degrees was achieved. As the cases
      were very different, this study will probably be no more than a case
      presentation. Nevertheless, based on a careful assessment of video films and
      photographs and the results achieved in individual cases, conclusions may be
      drawn regarding technique, surgical planning and prognosis. The author believes
      that although the data does not suffice to make up a valid study, they still are
      worthy of presentation.

PMID- 12601600
TI  - [Long-term results of the palmar arthrolysis of the proximal interphalangeal
      joint].
AB  - BACKGROUND: Palmar arthrolysis of the proximal interphalangeal joint is seldom
      carried out as an isolated treatment of contractures. The operation is usually
      performed in connection with treatment for a primary illness. Although intra
      operative extension of the interphalangeal joint is normally completely achieved,
      the postoperative results show deficiencies in the extension. METHODS AND
      CLINICAL MATERIAL: The long-term results of 110 arthrolyses of the proximal
      interphalangeal joint of 102 patients are presented. The operations were
      performed on average 4.6 years ago. The analysis was made with standard
      questionnaires and self-made drawings along the side of the patients' maximally
      extended finger. RESULTS: "Successful operations" where performed on 76% of all
      released joints. The angle of the contracture was reduced by at least 10 degrees
      in these joints. The long-term results were compared in conjunction with results
      of injuries or operations of other illnesses: M. Dupuytren (primary), relapses of
      M. Dupuytren, lesions of the flexor tendons, camptodactyly, results of injuries
      due to the consequences of operations or other illnesses. The results in the
      group of lesions of the flexor tendons were on the whole unsuccessful.
      CONCLUSION: Even though thorough postoperative hand therapy(physiotherapy and use
      of splints) and above-average co-operation of the patients are prerequisites for
      a successful arthrolysis, it can be seen that the elimination of the underlying
      illness is of primary importance.

PMID- 12601601
TI  - [Microvascular complications following replantations and revascularisations].
AB  - PURPOSE/BACKGROUND: What are the options for early diagnosis, treatment and
      prevention of the occlusion of microvascular anastomosis after replantations?
      METHOD AND (CLINICAL) MATERIAL: This is a retrospective analysis of 336 cases
      involving primary microvascular repair after an injury between 1984 and 2000. In
      272 cases this was a revascularisation and in 187 a replantation. In 23 cases the
      vascular anastomosis was located proximal to the wrist (macroreplantations) and
      313 times distal to it (microreplantations/-revascularisations). RESULTS:
      Vascular complications developed in seven and 54 cases respectively. 40 % of
      these 61 patients showed a severe soft tissue compromise or/and had sustained an
      injury known to cause widespread intima lesions (15 avulsions, six crush
      injuries, one blast, one gun shoot, one RTA). 37 of the 61 patients had been
      injured by circulating saws. There were 34 arterial and 22 venous occlusions,
      four no-reflow-syndromes and one HIT-syndrome. Almost 90 % of these vascular
      complications occurred within the first four post-operative days, 50 % even
      within the first 36 hours. Treatment was surgical in 39/61 cases and conservative
      22 times. In 55 % (33/61) of all cases this treatment was successful. CONCLUSION:
      With an overall incidence of 1 : 6 vascular crisis is not only the most
      consequential but also the most common post-operative complication after
      replantations. Timely operative and/or non-operative therapeutic measures can
      save more than half of the replants affected.

PMID- 12601602
TI  - [The sympathetic axons of the nerves of the hand].
AB  - PURPOSE: In the hand surgery literature, more and more studies seem to indicate
      that the number of sympathetic fibers in the median and the ulnar nerves varies.
      However, there are no studies that confirm this suspicion. METHOD AND MATERIAL:
      Six hours post mortem samples were taken from the median and ulnar nerves, the
      superficial branch of the radial nerve, and from all digital nerves (each five
      females and males, average age 78 years). 13 samples were taken from one hand. To
      make sympathetic fibers visible, the immunohistochemical staining technique with
      tyrosinhydroxylase (TH) antibodies was used. Quantitative assessment of the
      sympathetic axons was made in whole cross-sections of the nerve. Statistical
      evaluation was performed with Wilcoxon rank-sum tests. RESULTS: The TH-positive
      axons are arranged in groups and are located in the endoneurium. No isolated
      sympathetic fibers were found in the peri- and epineurium. TH-positive axons were
      present on the arterial walls including the smallest arterioles. Proximal to the
      wrist, the median nerve has more sympathetic fibers than the ulnar nerve. The
      number, however, of the fibers was the same in each fascicle. A comparison of the
      digital nerves shows significant differences only between the radial nerve of the
      thumb and the ulnar nerve of the ring finger and between the radial nerve of the
      index finger and the ulnar nerve of the little finger. CONCLUSION: Although the
      median nerve proximal to the wrist has on average 20 fascicles and the ulnar
      nerve only 14, the number of fibres in each fascicle is the same. Therefore,
      based on the present study we conclude that there is no significant difference in
      the sympathetic fiber distribution of the two nerves.

PMID- 12601603
TI  - [Periarterial sympathectomy of the radial and ulnar arteries in Raynaud's
      phenomenon--a preliminary study].
AB  - PURPOSE: Assessment of the post-operative results of peripheral sympathectomy in
      Raynaud's phenomenon. METHODS: Six patients with therapy refractory Raynaud's
      phenomenon underwent a 4 cm long adventitial stripping of the radial and ulnar
      arteries proximal to the wrist. The nerve of Henle was followed up to the surface
      of the palmar arch and resected. The pre- and postoperative examinations were
      performed using the help of a questionnaire, telethermography and infra-red laser
      reflexion rheography. RESULTS: All but two patients (two hands) were free of
      complaints (four patients, six hands), the three ulcers on the finger tips healed
      well. According to the questionnaire there was a dramatic improvement in the
      quality of life of the patients. CONCLUSION: In the follow-up period of two
      years, there was no recurrence. Adventitial stripping of the radial and ulnar
      arteries and resection of the nerve of Henle proximal to the wrist have
      demonstrated favourable results in the treatment of therapy-resistant complaints
      in Raynaud's phenomenon.

PMID- 12601604
TI  - [Scapholunate ligament tears in MR arthrography compared with wrist arthroscopy].
AB  - In a blinded study from January to July 2000, 125 patients suffering from
      specific complaints of the wrist were prospectively examined with direct MR
      arthrography. Within 24 hours an arthroscopy of the wrist was performed. With MR
      arthrography in 21 patients or 17 % of all patients, injury of the scapho-lunate
      ligament was diagnosed. In all patients this could be verified arthroscopically.
      In the remaining 104 patients, no SL-ligament lesions were diagnosed with the MR
      arthrography. However, partial lesions were found via arthroscopy in seven cases
      and complete lesions of the ligament were found in one case, where MRI findings
      expected an intact SL ligament. In the remaining 96 cases, the MRI could
      correctly exclude a lesion of the SL-ligament. The diagnosis of a SL-ligament
      lesion by means of MRI was correct in 100 % of the cases (specificity), the
      exclusion of such lesions in 72 % (sensitivity). Positive or negative predictive
      values of 100 % or 92 % were achieved. Since a sensitivity of 100 % cannot be
      reached at the moment, MR arthrography cannot replace arthroscopy. However, it
      could be a potent additional tool for wrist diagnosis if intraarticular contrast
      is used. It can facilitate the diagnostics and the indication for surgery of the
      wrist and help to reduce arthroscopic interventions for purely diagnostic
      purposes and without any therapeutic consequences. With improvement of the
      technique of magnet resonance tomography we can expect a further increase of
      accuracy in the clinical use of the MR arthrography in the diagnostic workup of
      the wrist.

PMID- 12601605
TI  - [Myosonographic evaluation of rectus abdominis muscle function after DIEP flap
      breast reconstruction].
AB  - Donor-site morbidity following autologous breast reconstruction is a well-known
      disadvantage of free or pedicled TRAM flaps. Bulging and weakness of the
      abdominal wall and sometimes even hernias occur. Due to recent technical advances
      in microsurgery, there are different possibilities for breast reconstruction like
      the deep inferior epigastric perforator (DIEP) flap which is harvested without
      rectus muscle. First studies describe good aesthetic results without the
      complication of hernias and disadvantage of abdominal wall weakness.
      Myosonography is a new method to test the dynamic rectus muscle function and
      evaluate the donor-site morbidity after DIEP flap breast reconstruction. This
      study aims to analyze the value of myosonographic measurements to evaluate the
      donor-site morbidity following perforator flap elevation of the abdominal wall.
      Between November 2000 and August 2001, 34 patients at the Markus Hospital in
      Frankfurt/Main, Germany received breast reconstruction with a DIEP flap.
      Myosonographic examinations pre- and postoperatively were performed. Furthermore,
      clinical testing of rectus muscle function with the Janda score in combination
      with a questionnaire about impairment in daily activities and subjective opinion
      about discomfort took place. Two months postoperatively, myosonography showed
      almost identical rectus muscle function at the side of the vessel preparation
      compared to the contralateral side. Good aesthetic results were also achieved.
      The absolute muscle thickness at maximum contraction and the difference of muscle
      thickness between relaxation and contraction were almost identical on both sides.
      Myosonography is a non-invasive and inexpensive method to test rectus muscle
      function providing exact and reliable data. Results of this study confirm the
      hypothesis of lower donor-site morbidity caused by DIEP flaps compared to free or
      pedicled TRAM flaps. The DIEP flap method for autologous breast reconstruction is
      highly accepted by patients because of good aesthetic results combined with the
      lowest possible donor-site morbidity. After more than 180 DIEP flaps with good
      aesthetic results without abdominal wall hernias this method has become the "gold
      standard" for autologous breast reconstruction in our department.

PMID- 12601606
TI  - [On the existence of nerve compression syndromes by lipomas or other extra- or
      intraneural tumors outside of physiological bottlenecks--remarks to the article
      of P. Gruber, H. Towfigh: Lipoma as a rare cause of nerve compression syndrome in
      the hand and forearm, and the article of J.S. Knabl, L.r. Walzer, A. Hartel, M.
      Frey: Total unar nerve paralysis due to acute traumatic aneurysm at the forearm].

PMID- 12601608
TI  - [Subcutaneous "wash-out" in extravasations].
AB  - Extravasations of chemotherapeutic drugs may lead to large soft-tissue losses in
      the hand and forearm and necessitating surgical excision with secondary flap
      coverage. Unfortunately, a delayed referral to a hand and plastic surgical unit
      with an already established soft-tissue defect is most common. Nevertheless, in
      our unit the method of choice is early emergency subcutaneous "wash-out", which
      facilitates dilution and reduction of concentration of the extravasation and
      therefore reliably avoids the development of soft-tissue defects. The aim of this
      paper is to present the surgical technique.

PMID- 12601609
TI  - [Congenital arterio-venous malformations of the hand (type C)--the only
      therapeutic option].
AB  - We report on a 36-year-old male patient with a congenital arterio-venous
      malformation (type C) of the hand. Symptoms onset was three years ago with an
      ulcer on the tip of the left middle finger, with the fingers and the palm of the
      hand turning increasingly livid. The shunt-volume in the area of an arterio
      venous fistula was 70 ml/min, there was also involvement of the third metacarpal
      bone. Increasing pain from the index to the ring fingers with no tendency of
      healing in the middle finger were indications for surgical intervention. In view
      of the diffuse expansion to all the tissue layers and the danger of peripheral
      circulatory disturbance and associated necrosis if embolisation was performed,
      the entire middle finger along with the third metacarpal bone was resected, and
      the index and the ring fingers were also amputated. Seven months postoperatively,
      the patient had no pain, had good grip function and was able to use his hand
      freely in his job as a labourer.

PMID- 12601610
TI  - Linking cranial kinematics, buccal pressure, and suction feeding performance in
      largemouth bass.
AB  - The rate and magnitude of buccal expansion are thought to determine the pattern
      of water flow and the change in buccal pressure during suction feeding. Feeding
      events that generate higher flow rates should induce stronger suction pressure
      and allow predators to draw prey from further away. We tested these expectations
      by measuring the effects of prey capture kinematics on suction pressure and the
      effects of the latter on the distance from which prey were drawn-termed suction
      distance. We simultaneously, but not synchronously, recorded 500-Hz video and
      buccal pressure from 199 sequences of four largemouth bass, Micropterus
      salmoides, feeding on goldfish. From the video, we quantified several kinematic
      variables associated with the head and jaws of the feeding bass that were
      hypothesized to affect pressure. In a multiple regression, kinematic data
      accounted for 79.7% of the variation among strikes in minimum pressure. Faster
      mouth opening and hyoid depression were correlated with lower pressures, a larger
      area under the pressure curve, and a faster rate of pressure reduction. In
      contrast, buccal pressure variables explained only 16.5% of the variation in
      suction distance, and no single pressure variable had a significant relationship
      with suction distance. Thus, although expected relationships between head
      kinematics and buccal pressure were confirmed, suction distance was only weakly
      related to buccal pressure. Three explanations are considered. First, bass may
      not attempt to maximize the distance from which prey are drawn. Second, the
      response of prey items to suction-induced flow depends on prey behavior and
      orientation and is, therefore, subject to considerable variation. Third, previous
      theoretical work indicates that water velocity decays exponentially with distance
      from the predator's mouth, indicating that variation among strikes in flow at the
      mouth opening is compressed away from the mouth. These findings are consistent
      with other recent data and suggest that suction distance is a poor metric of
      suction feeding performance.

PMID- 12601611
TI  - Cold acclimation strategy is highly variable among the sunfishes (Centrarchidae).
AB  - We tested the hypothesis that the physiological strategy for acclimating to low
      body temperature is similar among closely related fish. Largemouth bass
      (Micropterus salmoides), green sunfish (Lepomis cyanellus), bluegill sunfish
      (Lepomis macrochirus), black crappie (Pomonix nigromaculatus), and white crappie
      (Pomonix annularis), all members of the family Centrarchidae, were acclimated to
      5 degrees and 25 degrees C. Morphometric variables (total mass, total length,
      organ masses) and enzyme activities (hexokinase; lactate dehydrogenase; and
      cytochrome oxidase in heart, liver, and muscle) were measured in 5 degrees C- and
      25 degrees C-acclimated fish at 5 degrees and 25 degrees C assay temperatures.
      Each species displayed a distinct physiological response to cold acclimation that
      differed among tissues. These data suggest that the response to cold acclimation
      is highly variable within families. Our findings are consistent with other
      studies suggesting that acclimation responses are labile and may evolve
      independently even among closely related species.

PMID- 12601612
TI  - Effects of meal size, meal type, body temperature, and body size on the specific
      dynamic action of the marine toad, Bufo marinus.
AB  - Specific dynamic action (SDA), the accumulated energy expended on all
      physiological processes associated with meal digestion, is strongly influenced by
      features of both the meal and the organism. We assessed the effects of meal size,
      meal type, body temperature, and body size on the postprandial metabolic response
      and calculated SDA of the marine toad, Bufo marinus. Peak postprandial rates of
      O(2) consumption (.V(O2)) and CO(2) production (.V(CO2)) and SDA increased with
      meal size (5%-20% of body mass). Postprandial metabolism was impacted by meal
      type; the digestion of hard-bodied superworms (Zophobas larva) and crickets was
      more costly than the digestion of soft-bodied earthworms and juvenile rats. An
      increase in body temperature (from 20 degrees to 35 degrees C) altered the
      postprandial metabolic profile, decreasing its duration and increasing its
      magnitude, but did not effect SDA, with the cost of meal digestion remaining
      constant across body temperatures. Allometric mass exponents were 0.69 for
      standard metabolic rate, 0.85 for peak postprandial .V(O2), and 1.02 for SDA;
      therefore, the factorial scope of peak postprandial .V(O2) increased with body
      mass. The mass of nutritive organs (stomach, liver, intestines, and kidneys)
      accounted for 38% and 20% of the variation in peak postprandial .V(O2) and SDA,
      respectively. Toads forced to exercise experienced 25-fold increases in .V(O2)
      much greater than the 5.5-fold increase experience during digestion. Controlling
      for meal size, meal type, and body temperature, the specific dynamic responses of
      B. marinus are similar to those of the congeneric Bufo alvarius, Bufo boreas,
      Bufo terrestris, and Bufo woodhouseii.

PMID- 12601613
TI  - Rheological properties of digesta suggest little radial or axial mixing in the
      forestomach of the tammar (Macropus eugenii) and the parma (Macropus parma)
      wallaby.
AB  - We examined the physical properties of digesta from the proximal (sacciform) and
      distal (tubiform) regions of the forestomach of tammar and parma wallabies
      maintained on a ryegrass sward. The digesta exhibited high viscosity, which, in
      conjunction with low flow rates calculated from published retention times of
      particulate marker in the stomach, results in a low potential for macrofluid
      mixing during onflow of food by displacement. The pseudoplastic nature of the
      viscosity profile and very low "flow behavior index" also indicate that
      macrofluid mixing around haustrae would be very localized. These findings
      indicate that the uniform mixing of whole digesta required for continuously
      stirred tank reactors (CSTRs) is unlikely. Voidage, the proportion of digesta not
      occupied by solid material, and "consistency index" were greater in the digesta
      from the proximal than in the distal regions of the forestomach. We conclude that
      the mixing conditions in wallaby stomachs are better described as a partially
      emptying batch reactor (PEBR) than a CSTR series and that lower permeabilities in
      conjunction with higher viscosities decrease axial mixing and thus increase
      efficiency in PEBRs.

PMID- 12601614
TI  - Digestion of nectar and insects by Palestine sunbirds.
AB  - In nectarivorous birds, specialization for feeding on nectar has led to a simple
      gut structure with high sugar digestive efficiencies and rapid gut passage rates.
      These features of the digestive system may make digestion of more complex,
      protein-rich food sources, such as pollen or insects, less efficient. In this
      light, we hypothesized that sugar metabolizability in nectarivorous Palestine
      sunbirds (Nectarinia osea) would be high, whereas nitrogen metabolizability would
      be lower than typically found for birds. We measured glucose and fructose
      apparent metabolizabilities (*MCs) and transit times (TTs) in eight Palestine
      sunbirds offered either a 10% or a 50% mixed sugar diet. *MC for glucose (99.9%+/
      0.1%) was significantly greater than for fructose (99.6%+/-0.4%; ANOVA; P<0.001).
      TT for the 10% sugar diet (26.3+/-10.1 min) was significantly shorter than for
      the 50% sugar diet (47.0+/-7.8 min). We measured nitrogen true metabolizability
      (MC) and TT in Palestine sunbirds offered a daily fruit fly intake of either 40
      or 200 flies. Nitrogen MC was not significantly different between diets, and
      average MC for both diets was 58.5%+/-8.5% (n=8). TT was not significantly
      different when birds ate 10 flies (50.1+/-13.6 min) than when they ate 50 flies
      (48.5+/-16.5 min). The high sugar *MC and relatively rapid TT of nectar in
      Palestine sunbirds are similar to those found for other nectarivorous species.
      Transit times of insect material are longer that those found in small
      insectivorous species. However, MCs of insect material are lower. Thus, even
      though sunbirds consume easily digestible soft-bodied insects, they are less
      efficient at extracting protein than nonnectarivores.

PMID- 12601615
TI  - Cutaneous and respiratory water loss in larks from arid and mesic environments.
AB  - Birds from deserts generally have lower total evaporative water loss (TEWL), the
      sum of cutaneous (CWL) and respiratory water loss (RWL), than species from mesic
      areas. We investigated the role of CWL and RWL as a function of air temperature
      (T(a)) in hoopoe larks (Alaemon alaudipes) and Dunn's larks (Eremalauda dunni)
      from the Arabian Desert and skylarks (Alauda arvensis) and woodlarks (Lullula
      arborea) from temperate mesic grasslands. The proportional contribution of CWL to
      TEWL in all larks at moderate T(a) ranged from 50% to 70%. At high T(a) (40
      degrees -45 degrees C), larks enhanced CWL by only 45%-78% and relied on an
      increase in RWL by 676%-2,733% for evaporative cooling. Surface-specific CWL at
      25 degrees C was 29% lower in the arid-zone species than in the mesic larks. When
      acclimated to constant T(a), 15 degrees C-acclimated hoopoe larks increased CWL
      by 22% compared with 35 degrees C-acclimated birds, but the other species did not
      change CWL. This study is consistent with the hypothesis that larks from deserts
      have a reduced CWL at moderate and low T(a) but provided no support for the
      hypothesis that at high T(a) larks from arid regions rely more on CWL than larks
      from mesic environments. Interspecific differences in CWL cannot be attributed to
      acclimation to environmental temperature and are possibly the result of genetic
      differences due to natural selection or of phenotypically plastic responses to
      divergent environments during ontogeny.

PMID- 12601616
TI  - Effects of extracts from the cyanobacterium Microcystis aeruginosa on ion
      regulation and gill Na+,K+-ATPase and K+-dependent phosphatase activities of the
      estuarine crab Chasmagnathus granulata (Decapoda, Grapsidae).
AB  - Recent discoveries indicate that microcystins affect enzymes, such as Na(+),K(+)
      ATPase, involved in ion regulation of aquatic animals, through K(+)-dependent
      phosphatase inhibition. In vitro studies showed the inhibitory effect of
      Microcystis aeruginosa extracts on Na(+),K(+)-ATPase and K(+)-dependent
      phosphatase activities in gills of Chasmagnathus granulata (Decapoda, Grapsidae).
      Extracts of M. aeruginosa were prepared from lyophilized or cultures cells of the
      cyanobacterium. For lyophilized cells, IC(50) values were estimated as 0.46
      microg/L (95% confidence interval [CI]=0.40-0.52 microg/L) and 1.31 microg/L (95%
      CI=1.14-1.51 microg/L) for Na(+),K(+)-ATPase and K(+)-dependent phosphatase,
      respectively. However, extracts prepared from cultured cells presented a much
      lower inhibitory potency against both enzymes. Gas chromatography revealed long
      chain fatty acids in the lyophilized cell extracts, indicating that they are in
      part responsible for the enzyme inhibition. In vivo studies showed that the toxin
      inhibited Na(+),K(+)-ATPase activity in anterior gills, whereas an increased
      augmented activity of glutathione-S-transferase was observed in both kind of
      gills, indicating that the crab has increased its ability to conjugate the toxin.
      No significant differences in hemolymph sodium or chloride concentration were
      detected. This result is in agreement with the lack of effects of microcystin on
      Na(+),K(+)-ATPase activity of posterior (osmoregulating) gills.

PMID- 12601618
TI  - Toad atrial natriuretic peptide: cDNA cloning and functional analysis in isolated
      perfused kidneys.
AB  - A complementary DNA (cDNA) encoding Bufo marinus (toad) preproatrial natriuretic
      peptide (preproANP) was isolated by reverse-transcription polymerase chain
      reaction. Sequence analysis of toad preproANP cDNA revealed an open reading frame
      of 150 amino acid residues, which shared 72% and 66% identity with Rana
      catesbeiana and Xenopus laevis preproANP, respectively. The deduced amino acid
      sequence of toad ANP that corresponded to ANP 1-24 of R. catesbeiana and Rana
      ridibunda was identical, but it differed by four residues from that of X. laevis.
      ANP mRNA transcripts were also shown to be expressed in the toad kidney.
      Subsequently, the effect of frog ANP (1-24) on renal function in toad was
      examined using a perfused kidney preparation. The arterial infusion of frog ANP
      caused a dose-dependent decrease in the arterial perfusion pressure that was
      associated with an increase in the glomerular filtration rate (GFR) and a renal
      natriuresis and diuresis. The renal natriuresis and diuresis resulted
      predominantly from an increased GFR rather than from direct tubular effects. This
      study demonstrates that ANP can regulate renal function, which suggests it may be
      involved in overall fluid volume regulation.

PMID- 12601617
TI  - G proteins immunodetection and adrenergic transduction pathways in the liver of
      Anguilla anguilla.
AB  - G proteins are members of a highly conserved superfamily of GTPases, which
      includes heterotrimeric (alpha, beta, gamma) proteins acting as critical control
      points for transmembrane signaling. In ectothermal vertebrates, knowledge about
      these proteins is scarce, and our work provides the first demonstration that
      G(s), G(q), and G(i) proteins are all present in the liver of a fish. G(q)alpha
      subunits of about 42 kDa have been identified in European eel (Anguilla anguilla)
      liver membranes, supporting previous reports about the existence of hormone
      transduction pathways coupled to inositol 1,4,5-trisphosphate/Ca(2+) enhancement
      in fish hepatocytes. Although two G(s)alpha proteins of about 45 and 52 kDa have
      been reported in mammals, a single isoform of approximately 45 kDa has been
      recognized in eel liver. G(s)alpha and G(q)alpha proteins are involved in the
      epinephrine transduction pathway, leading to cAMP and Ca(2+) intracellular
      increments, respectively. Interestingly, both messengers significantly stimulated
      glucose release from eel hepatocytes but with a different time course. In fact,
      the Ca(2+)-dependent glucose output preceded the cAMP-mediated release by about 7
      min. G(i)alpha subunits of about 40 kDa were also immunodetected, suggesting the
      presence of hormone receptors leading to adenylyl cyclase inhibition in eel
      liver; however, alpha(2)- adrenoreceptor ligands were ineffective on both enzyme
      activity and glucose release.

PMID- 12601619
TI  - Effects of trap retention on body composition of live meadow voles.

PMID- 12601620
TI  - Alcohol intake and glycemia in American Indians: the strong heart study.
AB  - The goal of this study was to explore the relationship between alcohol intake and
      glycemia and type 2 diabetes in American Indians aged 45 to 74 years. Data were
      obtained from participants in the Strong Heart Study, a longitudinal study of 13
      American Indian communities in 3 geographic areas in the United States. Alcohol
      consumption was determined by self-reported alcohol intake history. Participants
      previously diagnosed with diabetes were excluded from the analysis. Analysis of
      covariance (ANCOVA) was used to estimate the adjusted means of blood glucose for
      alcohol intake categories. Logistic regression was used to calculate the odds
      ratios (ORs) and 95% confidence intervals (CIs) to estimate the association
      between alcohol intake and type 2 diabetes in the cross-sectional analysis and
      between alcohol intake and glucose intolerance using longitudinal data. Fasting
      and 2-hour plasma glucose concentrations showed an inverse J-shaped curve across
      categories of alcohol intake. Using never drinkers as the referent group in cross
      sectional analysis, light drinkers had a significantly lower risk of having
      diabetes (OR, 0.66; 95% CI, 0.44 to 0.99); among drinkers, heavy drinkers had a
      higher, although not significant, prevalence of diabetes. Longitudinal analysis
      showed no significant worsening of glucose tolerance across levels of alcohol
      intake. Subanalyses stratified by body mass index (BMI) did not show differences
      between obese and non-obese participants in the relationship between alcohol
      intake and glucose tolerance. Although plasma glucose concentration showed a
      shallow, inverse J-shaped association across levels of increasing alcohol intake
      in American Indians aged 45 to 74 years, alcohol intake did not appear to
      significantly increase the risk for worsening glucose tolerance. Thus, alcohol
      intake does not appear to be a determinant of diabetes risk in this population.

PMID- 12601621
TI  - Effect of weight loss on postprandial lipemia and low-density lipoprotein
      receptor binding in overweight men.
AB  - Obestity is associated with a range of metabolic abnormalities including fasting
      and postprandial dyslipidemia, both of which may contribute to increased
      atherosclerotic risk. Male obese subjects have a decreased level of low-density
      lipoprotein (LDL) receptor binding in mononuclear cells, the level of which
      reflects binding in the liver, compared with lean controls. In this study, we
      investigated whether the implementation of a weight loss regimen in viscerally
      obese subjects improves LDL receptor binding level. We examined apolipoprotein
      B(48) (apo B(48)) and retinyl palmitate (RP) metabolism following an oral fat
      challenge to determine whether weight loss improves postprandial dyslipidemia in
      viscerally obese subjects. Male obese, mildly dyslipidemic, and insulin-resistant
      subjects were randomly assigned to either a weight loss (n = 12) or control
      weight maintenance (n = 10) group. In response to weight loss of 10 kg, insulin
      sensitivity improved as evidenced by decreased fasting insulin and homeostatic
      model assessment (HOMA) score. In addition, LDL receptor binding in mononuclear
      cells increased significantly by 27.5% and LDL-cholesterol was significantly
      reduced. However, despite the increased LDL receptor levels, fasting apo B(48)
      levels did not fall. Postprandially, the area under the curve (AUC) for RP was
      significantly reduced after weight loss, but the incremental and total AUCs for
      apo B(48) were not altered. Apo B(48) is an unequivocal marker of chylomicron
      particle number; hence, the reduction in RP metabolism achieved with weight
      reduction may reflect decreased lipid incorporation into nascent chylomicrons or
      improved hydrolysis of triglyceride-rich chylomicrons resulting from a decreased
      competition with hepatic lipoproteins for lipoprotein lipase. Our findings
      suggest that the improvement in LDL receptor binding following weight reduction
      of 10 kg in insulin-resistant male obese subjects is insufficient to reduce the
      elevated chylomicron remnant levels.

PMID- 12601622
TI  - Porphyromonas gingivalis infection is associated with carotid atherosclerosis in
      non-obese Japanese type 2 diabetic patients.
AB  - The aim of the present study was to investigate whether non-obese Japanese type 2
      diabetic patients with porphyromonas gingivalis infection have atherosclerotic
      vascular diseases. A total of 134 non-obese Japanese type 2 diabetic patients (96
      men and 38 women, aged 36 to 84 years, body mass index [BMI] 20.1 to 26.9
      kg/m(2)) were studied. In conjunction with BMI, glycosylated hemoglobin
      (HbA(1c)), fasting glucose, and serum lipids (triglycerides, total cholesterol,
      high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL]
      cholesterol) were measured. LDL cholesterol was calculated using the Friedewald
      formula. Using high-resolution B-mode ultrasound scan, we measured intimal medial
      thickness (IMT) in plaque-free segments of bilateral common carotid arteries, and
      the mean of IMT in 2 vessels was used for the analysis. Furthermore, we
      calculated the degree of stenosis in plaque segments of bilateral common carotid
      arteries. The degree of carotid atherosclerosis was expressed as a percentage
      ratio between the area of plaque and that of the lumen using the formula (Lumen
      Area Residual - Lumen Area)/Lumem Area x 100. Both the areas were automatically
      measured by the system on a frozen transverse scanning plane at the site of
      maximal narrowing. When 2 or more plaques were present in the vessel, only that
      causing the greatest degree of stenosis was considered for analysis. Values
      represent mean+/-SEM unless otherwise stated. Immunoglobulin G (IgG) titer
      against porphyromonas gingivalis was 245 +/- 65 (mean +/- 2 SD) in nondiabetic
      healthy subjects. In contrast, there was a wide variation in IgG titer against
      porphyromonas gingivalis in type 2 diabetic patients studied (range, 16 to
      26,800). Thus, we classified our type 2 diabetic patients into 2 subpopulations
      according to the value of mean +/- 2 SD (= 310) of nondiabetic healthy subjects:
      one with high IgG titer against porphyromonas gingivalis (>310) (1,422 +/- 408)
      and the other with normal IgG titer against porphyromonas gingivalis (<310) (152
      +/- 10, P =.002). The populations did not differ with respect to age, sex, BMI,
      fasting glucose, HbA(1c), serum triglycerides, total, HDL, and LDL cholesterol
      levels. Although the mean IMT in plaque-free segments was not different between
      the 2 groups (0.73 +/-0.03 v 0.68 +/- 0.02 mm, P =.098), the degree of stenosis
      in plaque segments was significantly higher in the high IgG titer group (12.0% +/
      2.2%) than in normal one (5.5% +/- 1.4%, P =.009). From these results, it can be
      concluded that porphyromonas gingivalis infection, although still a subclinical
      infection, is associated with atherosclerotic vascular disease in non-obese
      Japanese type 2 diabetic patients.

PMID- 12601623
TI  - Effect of homocysteinylation on human high-density lipoproteins: a correlation
      with paraoxonase activity.
AB  - We investigated the effect of homocysteine (Hcy)-thiolactone on the activity of
      the enzyme paraoxonase (PON) associated with human high-density lipoprotein (HDL
      PON). HDL were isolated from plasma of normolipidemic subjects. The increase in
      the levels of sulfhydryl groups (-SH) in HDL incubated with Hcy-thiolactone
      demonstrates that homocysteinylation of HDL occurs. The increase of -SH groups
      correlated with the basal values of HDL-PON activity (r = -0.73, P <.001, and r =
      -0.70, P <.002 using 10 micromol/L and 1 mmol/L Hcy-thiolactone, respectively)
      suggesting a relationship between the susceptibility of HDL to homocysteinylation
      and HDL-PON activity. A decrease in the activity of the enzyme HDL-PON was
      observed in homocysteinylated HDL (Hcy-HDL). The negative correlation established
      between the basal levels of HDL-PON activity and the percentage decrease of HDL
      PON activity (r = -0.76, P <.001, and r = -0.86, P <.001 using 10 micromol/L or 1
      mmol/L Hcy-thiolactone, respectively) suggests that subjects with higher HDL-PON
      activity have a lower decrease in PON activity with respect to subjects with
      lower HDL-PON activity. The positive correlation established between the
      percentage decrease of PON activity and the percentage increase of -SH groups in
      Hcy-HDL (r = 0.80, P <.001, and r = 0.76, P <.001 in HDL incubated in the
      presence of 10 micromol/L and 1 mmol/L Hcy-thiolactone, respectively) suggests
      that the modifications of HDL-PON activity are likely related to the
      compositional changes at the lipoprotein surface of Hcy-HDL. The enzyme PON
      contributes to the protective role of HDL against the oxidative damage and
      against toxicity exerted by Hcy involved in the development of atherosclerosis.
      Therefore the significant decrease of the enzyme activity in HDL incubated with
      Hcy-thiolactone suggests that homocysteinylation could render HDL less protective
      against oxidative damage and against toxicity of Hcy-thiolactone.

PMID- 12601624
TI  - Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene
      expression in untrained but not trained humans.
AB  - In rodents, acute exercise increases skeletal muscle uncoupling protein (UCP)
      gene expression and is associated with elevations in serum nonesterified fatty
      acids (NEFA). To test whether contractions increase UCP mRNA levels in humans,
      vastus lateralis biopsies were obtained 1 hour postexercise from untrained and
      trained subjects and analyzed for UCP-2 and UCP-3 long (UCP-3(L)) and short (UCP
      3(S)) isoforms. The acute exercise bout (graded cycling protocol; 65% to 85%
      relative VO(2)max) induced significant (P <.01) elevations in serum NEFA in both
      untrained and trained subjects, but the increase in untrained subjects was
      significantly (P <.05) greater (60% v 30%). Ribonuclease protection assay
      demonstrated that basal levels of all UCP isoforms measured were similar between
      the 2 groups. However, acute exercise induced a significant increase (P <.02) in
      both UCP-3(L) and UCP-3(S), but not UCP-2 mRNA levels in untrained, but not
      trained subjects. Correlation analysis did not show a significant relationship
      between exercise-induced changes in NEFA and UCP-3 levels. These results
      demonstrate that acute endurance exercise increases UCP-3 gene expression only in
      untrained skeletal muscle, but this effect does not seem to be tightly linked to
      the exercise-induced fluctuations in serum NEFA levels.

PMID- 12601625
TI  - Adrenomedullin concentrations are elevated in plasma of patients with primary
      hyperparathyroidism.
AB  - The aim of the study was to evaluate plasma adrenomedullin (AM) concentration in
      primary hyperparathyroidism (PHP) and its effect on the regulation of blood
      pressure. Forty-one patients with PHP (25 normotensive and 16 hypertensive), and
      31 healthy subjects (HS) were included in the study. As expected the total and
      ionized calcium and i-PTH serum levels were significantly higher in patients with
      PHP than in HS (P <.001). No significant difference was found in calcium
      phosphorus metabolism parameters between normotensive and hypertensive PHP
      patients. Serum i-PTH levels correlated positively with systolic blood pressure
      (SBP) (r = 0.510; P <.02), diastolic blood pressure (DBP) (r = 0.586; P <.01) and
      heart rate (HR) (r = 0.486; P <.043) only in hypertensive PHP patients. Overall,
      mean plasma AM concentrations were significantly higher in PHP patients (16.1 +/-
      7.9 pg/mL) than in HS (11.3 +/- 4.8 pg/mL) (P <.003) and correlated with i-PTH (r
      = 0.430; P <.005). However, in hypertensive PHP patients plasma AM levels (22.5
      +/- 4.7 pg/mL) were higher than in normotensive PHP patients (11.6 +/- 1.8 pg/mL)
      (P <.001) and correlated with DBP (r = 0.902, P <.0029). In HS no correlation was
      found between plasma AM values and biohumoral, hormonal, or hemodynamic
      parameters. In conclusion, we demonstrated that in patients with PHP, plasma AM
      concentrations are increased and correlate with i-PTH and blood pressure values.
      We suggest that increased AM levels could be a compensatory factor in the defence
      mechanism against further blood pressure elevation.

PMID- 12601626
TI  - Increased serum levels of the specific AGE-compound methylglyoxal-derived
      hydroimidazolone in patients with type 2 diabetes.
AB  - A time-delayed fluorescence immunoassay was developed for the determination of
      serum levels of methylglyoxal (MG)-derived hydroimidazolone using a monoclonal
      antiserum raised against Nalpha-acetyl-Ndelta-(5-hydro-5-methyl)-4-imidazolone,
      Europium-labeled anti-mouse IgG antiserum as indicator, and MG modified bovine
      serum albumin (BSA) as standard. Serum levels of hydroimidazolone were measured
      in 45 patients with type 2 diabetes aged 59.4 +/- 6.1 (mean +/- SD) years and
      with duration of diabetes of 7.3 +/- 3.1 years, and in 19 nondiabetic controls
      aged 56.3 +/- 4.3 years. The serum levels of hydroimidazolone were significantly
      higher in patients compared to controls: median, 3.0 (5-95 percentile, 1.6 to
      5.4) U/mg protein versus 1.9 (1.2 to 2.8) U/mg protein (P =.0005). Significant
      positive correlations were observed between the serum levels of hydroimidazolone
      and serum levels of advanced glycation end products (AGEs), measured with a
      polyclonal anti-AGE antibody: r = 0.59 for patients (P <.0001), and r = 0.65 for
      controls (P =.002). Similarly, significant correlations were also found between
      serum levels of hydroimidazolone and N(epsilon)-(carboxymethyl)-lysine (CML): r =
      0.36 in patients and r = 0.55 for controls (both P =.02). Serum hydroimidazolone
      levels did not correlate with fasting plasma glucose or hemoglobin A(1c)
      (HbA(1c)) levels. The observed differences between patients with diabetes and
      nondiabetic controls seem to be comparable to differences measured for other AGE
      compounds.

PMID- 12601627
TI  - Vitamin B12 decreases, but does not normalize, homocysteine and methylmalonic
      acid in end-stage renal disease: a link with glycine metabolism and possible
      explanation of hyperhomocysteinemia in end-stage renal disease.
AB  - The genetic and environmental factors influencing catabolism of homocysteine in
      end-stage renal disease (ESRD) patients remain poorly understood. This study
      investigated how genetic and nutritional influences affect the response to high
      dose vitamin B(12) and folate treatment in ESRD patients with
      hyperhomocysteinemia. We studied 81 hemodialysis patients with
      hyperhomocysteinemia (> 16 micromol/L) on varied doses of a multivitamin
      containing 1 mg of folic acid per day. After screening blood work, all patients
      were switched to daily multivitamin therapy including 1 mg of folic acid for 4
      weeks. Vitamin B(12), 1 mg/d, was added for an additional 4 weeks. Patients were
      then randomized to receive folic acid or placebo. The influence of the 3
      methylenetetrahydrofolate reductase (MTHFR) 677 C-->T genotypes on the efficacy
      of vitamin therapy was assessed. In addition, we investigated how the metabolic
      complications of ESRD, including the relationship between methylmalonic acid
      (MMA) and circulating glycine, may contribute to hyperhomocysteinemia. There was
      no significant difference in total homocysteine (tHcy) levels between the MTHFR
      677 C-->T genotypes during the screening phase of the trial. Treatment with a
      daily multivitamin containing 1 mg folate significantly lowered tHcy levels in
      all patients by 19.2%. Further supplementation with 1 mg vitamin B(12) resulted
      in greater tHcy reduction among subjects with the MTHFR 677 T/T genotype (P<.01,
      T/T v C/C or C/T) while lowering MMA equally in all MTHFR genotypes. There was a
      significant positive correlation between plasma glycine levels and MMA (P <.05).
      High-dose vitamin therapy significantly lowers, but does not normalize, MMA and
      tHcy levels. The MTHFR genotype, while influencing homocysteine levels, was not
      responsible for the majority of the elevation in plasma tHcy.

PMID- 12601628
TI  - The effects of troglitazone, an insulin-sensitizing agent, on the endothelial
      function in early and late type 2 diabetes: a placebo-controlled randomized
      clinical trial.
AB  - Activation of the peroxisome proliferator-activator receptor gamma (PPARgamma)
      improves insulin resistance and glycemic control in patients with diabetes. As
      PPARgamma is expressed in the endothelial cell, we have investigated the effect
      of troglitazone, a PPARgamma activator, on the endothelial function in people
      with type 2 diabetes in a 12-week, prospective, randomized, double-blinded
      clinical trial. We studied 87 type 2 diabetic patients who were divided into 3
      groups. Group A consisted of 27 patients with recently diagnosed diabetes and no
      clinical manifestations of macrovascular disease; group B, 29 patients with long
      term diabetes and no clinically evident macrovascular disease; and group C, 31
      diabetic patients with documented macrovascular disease (cardiovascular,
      cerebrovascular, or peripheral vascular disease). High-resolution ultrasound
      images were used to measure the flow-mediated dilation (FMD, endothelium
      dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) in
      the brachial artery. Laser Doppler perfusion imaging was used to measure
      vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine
      (Ach, endothelium-dependent) and 1% sodium nitroprusside (NaNP, endothelium
      independent). The plasma concentrations of von Willebrand factor (vWF), soluble
      intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion
      molecule (sVCAM) were also measured as indicators of endothelial cell activation.
      The FMD improved in the troglitazone-treated patients in group A (7.72 +/- 3.4 v
      5.27 +/- 2.0, P <.05 [exit visit v baseline, percent of increase in brachial
      artery diameter, mean +/- SD]). The fasting insulin level also improved in this
      group (15.6 +/- 10 v 19.7 +/- 10, P <.05) and was strongly correlated to changes
      in FMD (r = -.73, P <.01). No changes were found in the FMD or the fasting
      insulin levels in the troglitazone-treated patients in groups B or C. The NID was
      not changed by troglitazone treatment in any of the 3 groups. Also, no
      differences were found in the microcirculation reactivity measurements or in the
      biochemical markers of endothelial dysfunction in all 3 groups. A small, but
      significant, improvement of the FMD was found in placebo-treated patients in
      group B, probably related to the low FMD levels at baseline in the patients (5.40
      +/- 3.0 v 4.36 +/- 2.4, P <.05). We concluded that troglitazone treatment for 12
      weeks improved endothelial function in the macrocirculation of patients with
      recently diagnosed type 2 diabetes and no clinical evidence of macrovascular
      disease. This improvement was strongly associated with the improvement of fasting
      plasma insulin concentrations.

PMID- 12601629
TI  - Use of the oral glucose tolerance test to define remission in acromegaly.
AB  - An oral glucose tolerance test (OGTT) was used to assess growth hormone (GH)
      secretion in patients with acromegaly prior to (n = 26) and after (n = 71)
      transsphenoidal adenomectomy as well as in 196 controls. In controls, suppressed
      concentrations of GH showed a negative relationship both with body mass index
      (BMI) and with age. Having calculated the reference intervals for suppressed GH
      concentrations to be expected for any given age and BMI, we compared these
      individually predicted ranges to GH concentrations actually observed in patients
      with acromegaly during OGTT. Preoperatively, concentrations exceeded the normal
      range in all patients. Postoperatively, glucose-suppressed concentrations of GH
      were less than 2.0 ng/mL in 56 (79%) patients and less than 1.0 ng/mL in 44
      (62%). However, only 37 of 71 (52%) patients had glucose-suppressed GH
      concentrations within the calculated reference intervals (defined by the 95th
      percentile of normal). Comparing these data with the patient's concentrations of
      insulin-like growth factor-1 (IGF-1; normal range first established and corrected
      for age and sex in 494 healthy individuals), congruency of both parameters was
      found in 59 (77%) patients with an unexplained discrepancy between GH and IGF-1
      in the remaining in 16 (23%) patients. Our results confirm that concentrations of
      IGF-1 must be corrected for sex and age, whereas glucose-suppressed
      concentrations of GH depend on age and BMI. "Across-the-board" cut-off-values are
      clearly inadequate and should not be used. Rather, serum GH measurements obtained
      during an OGTT must be interpreted individually by comparison to control values
      taking into account both age and BMI.

PMID- 12601630
TI  - Racial differences in subcutaneous and visceral fat distribution in
      postmenopausal black and white women.
AB  - Most studies examining racial disparities in abdominal fat distribution have
      focused on premenopausal women. The purpose of this report was to determine if
      racial differences exist in the abdominal fat distribution in postmenopausal
      white and black women. Fifty-four women (33 white and 21 black) were scanned by
      magnetic resonance imaging (MRI) to determine abdominal fat distribution, were
      measured by hydrostatic weighing for percent body fat, and had their fasting
      blood lipids, glucose, and insulin levels measured. These women were matched for
      age (mean age, 53.5 +/- 0.9 years) and percent body fat (black: 39.6% +/- 2.3%,
      white: 37.3% +/- 1.2%). When adjusted for total body fat mass and hormone
      replacement therapy (HRT), total abdominal fat (white: 10,352.1 +/- 535.2, black:
      11,220.4 +/- 670.1 cm(3)) was not statistically different between groups, but the
      visceral fat content was significantly higher in the white women (white: 2,943.5
      +/- 220.4, black: 2,332.6 +/- 176.1 cm(3)). The percent visceral fat was also
      higher in these women (white: 30.5% +/- 1.3%, black: 22.1% +/- 1.6%, P <.01).
      Subcutaneous adipose tissue (SAT) was significantly higher in the black women
      (white: 7,408.6 +/- 450.2, black: 8,887 +/- 563.1 cm(3), P <.05). No significant
      differences were found in the insulin concentrations or the blood lipid profile
      of these women. Regardless of race, visceral fat was a significant predictor of
      log triglyceride, low-density lipoprotein-cholesterol (LDL-C), cholesterol/LDL-C,
      insulin levels, and insulin resistance. Race was only found to contribute to 8%
      of the variability of LDL-C. HRT use had no effect on abdominal fat distribution
      or the blood lipid profile in this cohort of women. In conclusion, disparities in
      abdominal fat distribution between black and white women continue to exist in the
      early postmenopausal years, and the regression results indicate that the absolute
      amount of visceral fat, and not the relative amounts of visceral fat, is the best
      predictor of the blood lipid profile and insulin sensitivity. HRT use did not
      result in differences in abdominal fat distribution in these women. Factors, such
      as genetics and lifestyle, must play a larger role in explaining the increased
      health risk in black women.

PMID- 12601631
TI  - Effects of the prostaglandin I2 analogue, beraprost sodium, on vascular cell
      adhesion molecule-1 expression in human vascular endothelial cells and
      circulating vascular cell adhesion molecule-1 level in patients with type 2
      diabetes mellitus.
AB  - Beraprost sodium is an orally active prostaglandin (PG)I(2) analogue, which has
      antiplatelet and vasodilating properties. In this study, we investigated the
      effects of beraprost on the expression of vascular cell adhesion molecule-1 (VCAM
      1), one of the key molecules involved in atherosclerosis, in cultured vascular
      endothelial cells. In addition, we examined the effects of beraprost on
      circulating VCAM-1 level and atherosclerosis progression in patients with type 2
      diabetes mellitus. Beraprost significantly decreased tumor necrosis factor-alpha
      (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells.
      Beraprost also repressed human monocytoid U937 cell adhesion to the vascular
      endothelial cells. Twenty-five patients with type 2 diabetes mellitus who had
      atherosclerotic change of carotid arteries were enrolled for an open prospective
      study: 11 patients received beraprost for 3 years, while the other 14 did not.
      The 3-year changes of circulating VCAM-1 level, as well as those of carotid
      arterial intima-media thickness (IMT) were significantly lower in the patients
      receiving the beraprost treatment than that in the patients without the
      treatment. Thus, beraprost had an ability to repress the expression of VCAM-1 in
      human vascular endothelial cells. In addition, beraprost lowered circulating VCAM
      1 level and prevented the increase of carotid IMT in patients with type 2
      diabetes mellitus. Considering that circulating VCAM-1 and IMT are predictive of
      future vascular events, beraprost may have a beneficial effect on progression of
      atherosclerosis in diabetic patients.

PMID- 12601632
TI  - Postprandial leukocyte increase in healthy subjects.
AB  - Atherosclerosis is an inflammatory disorder involving leukocytes and lipids. To
      study the relationship between leukocytes and lipids in vivo, leukocyte changes
      were determined in 14 healthy males (age, 23 +/- 3 years; body mass index [BMI],
      21.9 +/- 1.5 kg/m(2)) after an 8-hour oral fat load (50 g/m(2)) and after water.
      The postprandial triglyceride (TG) increment after fat was paralleled by a
      leukocyte increment, due to an increase in neutrophils in the first 2 hours (142%
      +/- 69% higher than baseline, P =.04). Neutrophil counts did not return to
      baseline at the end of the test. Water ingestion did not induce significant
      neutrophil changes. Blood lymphocytes increased gradually in both tests (142% +/-
      30% higher than baseline, P <.001 after fat, and 128% +/- 36%, P =.02 after
      water). The total leukocyte increment after fat ingestion was related to the
      postprandial TG increase (Spearman's r = 0.73, P =.003). An early postprandial,
      lipid-specific, neutrophil increment is a new characteristic of the postprandial
      phase. Future studies will elucidate the role of postprandial leukocyte changes
      in the pathogenesis of atherosclerosis.

PMID- 12601633
TI  - Brain-derived neurotrophic factor ameliorates hepatic insulin resistance in
      Zucker fatty rats.
AB  - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, has been
      reported to ameliorate hyperglycemia in obese diabetic animal models. To
      elucidate the mechanism of BDNF on glucose metabolism, we determined the glucose
      turnover under basal and euglycemic hyperinsulinemic (insulin infusion rate, 54
      pmol. kg(-1). min(-1)) clamp conditions in obese insulin-resistant rats, male
      Zucker fatty rats, which had been acutely administered a subcutaneous injection
      of BDNF (20 mg/kg) (n = 9, BDNF) or vehicle (n = 8, vehicle). Under the basal
      condition, acute administration of BDNF did not affect the blood glucose level,
      plasma insulin level, rate of glucose disappearance (Rd), and endogenous glucose
      production (EGP). Under the clamp condition, the glucose infusion rate (GIR) was
      significantly higher in BDNF than in vehicle (mean +/- SD, 61.4 +/- 19.1 v 41.4
      +/- 4.9 micromol. kg(-1). min(-1), P <.05). There was no significant difference
      in Rd and EGP between the 2 groups under the clamp condition, but the insulin
      mediated suppression ratio of endogenous glucose production in BDNF was
      significantly greater than in vehicle (48.9 +/- 22.2 v 22.4% +/- 20.6%, P <.05).
      In BDNF, mRNA expressions of hepatic phosphoenolpyruvate carboxykinase (PEPCK)
      and glucose-6-phosphatase (G6Pase) were comparable to those of vehicle, while
      hepatic glucokinase (GK) mRNA expression was significantly higher (1.57 +/- 0.33
      v 1.03 +/- 0.17, P <.05). We conclude that BDNF mainly improves hepatic insulin
      resistance in obese insulin-resistant rats, probably by affecting the hepatic GK
      flux.

PMID- 12601634
TI  - PPARgamma gene polymorphism is associated with exercise-mediated changes of
      insulin resistance in healthy men.
AB  - Exercise training improves insulin sensitivity, but individual responses vary
      greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a
      regulator of adipose cell differentiation and plays an important role in systemic
      insulin action. We investigated whether PPARgamma gene polymorphism affects
      insulin resistance in response to exercise in Japanese healthy men. The exercise
      program at an individual intensity of 50% of the maximal heart rate was performed
      for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical
      activity of 700 kcal/wk. The program was conducted for 3 months without any
      dietary intervention, and the clinical and metabolic characteristics were
      examined before and after the exercise program. Body mass index (BMI) did not
      change significantly after the exercise program, whereas percentage of body fat
      (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased
      significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic
      DNA isolated from human leukocytes and examined with polymerase chain reaction
      (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the
      Ala allele did not correlate with fasting immunoreactive insulin (IRI) and
      homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but
      did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55
      +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R,
      Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests
      that the Ala allele is associated with improvement in insulin resistance after
      exercise. We conclude that PPARgamma gene polymorphism may be a reliable
      indicator of whether exercise will have a beneficial effect as part of the
      treatment of insulin resistance syndrome.

PMID- 12601635
TI  - Association of the PRO12ALA polymorphism of the PPAR-gamma2 gene with oxidized
      low-density lipoprotein and cardiolipin autoantibodies in nondiabetic and type 2
      diabetic subjects.
AB  - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a key component
      in adipocyte differentiation and fat-specific gene expression and may modulate
      macrophage functions, like proinflammatory activities, and stimulate oxidized low
      density lipoprotein (ox-LDL) uptake. We hypothesized that the Pro12Ala
      polymorphism of the PPAR-gamma2 gene may affect the immune response to ox-LDL.
      Therefore, we investigated the association of the Pro12Ala polymorphism of the
      PPAR-gamma2 gene with ox-LDL autoantibodies, as well anticardiolipin antibodies,
      in a 10-year prospective study. The Pro12Ala polymorphism was genotyped in 119
      nondiabetic subjects (age, 45 to 64 years; body mass index [BMI], 19 to 46
      kg/m(2)) and 70 type 2 diabetic patients (age, 45 to 65 years; BMI, 19 to 46
      kg/m(2)) by the polymerase chain reaction-single-strand conformation polymorphism
      (PCR-SSCP) method. Ox-LDL autoantibodies and anticardiolipin antibodies were
      determined at baseline and after 10 years of follow-up. At baseline, the Pro12Ala
      polymorphism was not associated with ox-LDL autoantibodies in nondiabetic
      subjects, whereas type 2 diabetic patients having the Pro12Ala or the Ala12Ala
      genotypes tended to have higher levels of ox-LDL autoantibodies than did type 2
      diabetic patients with the Pro12Pro genotype. At the 10-year follow-up, diabetic
      subjects having the Ala12 allele had higher ox-LDL autoantibody levels than did
      diabetic subjects with the Pro12Pro genotype (P =.043 after adjustment for age,
      gender, BMI, and hemoglobin A(1c) [HbA(1c)] at 5 years). In nondiabetic subjects
      and regarding anticardiolipin antibodies, no such relationship was observed. We
      conclude that the Pro12Ala polymorphism of the PPAR-gamma2 gene was associated
      with increased ox-LDL autoantibodies in type 2 diabetic subjects. Genotype may
      therefore modulate the oxidative modification of LDL in hyperglycemic milieu.

PMID- 12601636
TI  - Reduction of intramyocellular lipid following short-term rosiglitazone treatment
      in Zucker fatty rats: an in vivo nuclear magnetic resonance study.
AB  - The aim of the study was to characterize the effects of rosiglitazone, an oral
      insulin sensitizer, on intramyocellular lipid (IMCL) content in tibialis anterior
      muscle and whole body lipid deposition in Zucker fatty rats using in vivo (1)H
      nuclear magnetic resonance (NMR) spectroscopy. The IMCL/EMCL (extramyocellular)
      ratio was significantly lower in the rosiglitazone (FRSG) group at 7, 14, 21, and
      28 days of treatment at 3 mg/kg/d (0.04 +/- 0.01, 0.09 +/- 0.03, 0.11 +/- 0.02,
      and 0.07 +/- 0.02, respectively) versus baseline (0.43 +/- 0.12, P <.01 v all
      time points), whereas there was no difference in the control (FC) group at these
      time points (0.31 +/- 0.08, 0.36 +/- 0.08, 0.40 +/- 0.14, and 0.49 +/- 0.18,
      respectively) versus baseline (0.37 +/- 0.07). Absolute IMCL content was also
      lower at 28 days in the FRSG (0.41 +/- 0.09 micromol/g) versus FC (2.13 +/- 0.40
      micromol/g, P <.005) group. To further characterize the temporal nature of this
      change, the IMCL/EMCL ratio was examined in the FRSG group on each of the first 4
      days of treatment, and a steady decline was observed (0.38 +/- 0.12, 0.21 +/-
      0.08, 0.12 +/- 0.04, 0.09 +/- 0.04, 0.05 +/- 0.03 at baseline and days 1, 2, 3,
      and 4 respectively, P <.05 baseline v all time points). To examine the
      relationship between IMCL and insulin sensitivity, a euglycemic-hyperinsulinemic
      clamp and IMCL measurement was performed on 7-day treated FRSG and FC groups.
      There was a negative correlation between absolute IMCL content and glucose
      infusion rate (r = -0.47, P <.04). The FRSG and the FC groups had similar whole
      body lipid content (expressed as a percentage of whole body water content) at
      baseline (48% +/- 5% and 44% +/- 2%, respectively), but the value was greater in
      the FRSG group following 28 days of treatment (103% +/- 4 v 84% +/- 6%,
      respectively, P <.02). In summary, there was a rapid (days) and pronounced
      reduction ( downward arrow approximately 70%) in IMCL content in tibialis
      anterior muscle following rosiglitazone treatment. Additionally, the increase in
      whole body lipid in the FRSG group suggests that there was increased adipocyte
      lipid storage following long-term rosiglitazone treatment. These results support
      the hypothesis that rosiglitazone indirectly increases peripheral insulin
      sensitivity by decreasing adipocyte lipolysis, thereby lowering IMCL content.

PMID- 12601637
TI  - Association of plasminogen activator inhibitor-1 with insulin resistance in Japan
      where obesity is rare.
AB  - The association between plasminogen activator inhibitor-1 (PAI-1) and insulin
      resistance is established in western countries. The major component of this
      association is obesity. Accordingly, we examined this association in Japan where
      the prevalence of obesity is low. Data for fasting PAI-1 levels of 404 subjects
      were obtained from a general population in a farming area. We measured body mass
      index (BMI), systolic and diastolic blood pressure, high-density lipoprotein
      (HDL)-cholesterol, triglycerides, fasting plasma glucose (FPG), insulin,
      creatinine, and uric acid. The use of alcohol was ascertained by a questionnaire.
      The formula for the homeostasis model assessment (HOMA) score was used as an
      index of insulin resistance. Uni- and multivariate analyses were applied for the
      determinants of plasma PAI-1. Age and sex did not affect plasma PAI-1. The
      average BMI was 23.0 +/- 3.2 kg/m(2). Thus, most of the subjects were not obese.
      Because, even in this population, BMI (P <.001) was the strongest determinant for
      PAI-1 after univariate analysis, we performed multiple linear regression analyses
      after adjustment for BMI. The significance of triglycerides, FPG, insulin, and
      the HOMA score still remained. PAI-1 levels were linearly related to the HOMA
      score. From the subanalysis of the non-obese subjects (BMI < 25; n = 298), waist
      hip ratio, triglycerides, FPG, and HOMA scores were significant determinants of
      PAI-1. This is the first demonstration that increased PAI-1 levels were
      significantly related to insulin resistance in a Japanese general population. PAI
      1 levels are associated with insulin resistance, irrespective of obesity.

PMID- 12601638
TI  - Reduced production rates of testosterone and dihydrotestosterone in healthy men
      treated with rosiglitazone.
AB  - The effect of the thiazolidinedione, rosiglitazone (8 mg/d for 7 days), on the
      production rates of testosterone (T), dihydrotestosterone (DHT), and cortisol (F)
      was studied in healthy men (n = 10) using the stable isotope dilution technique
      and mass spectrometry. Treatment with rosiglitazone resulted in a decrease in the
      production rates of T from, basal, 318 +/- 62 microg/h to 272 +/- 72 microg/h (P
      <.05). Production rates of DHT fell from, basal, 21 +/- 6 microg/h to 17 +/- 5
      microg/h (P <.05). Hence, the ratio calcuated from the production rates of T and
      DHT was unchanged (basal, 17 +/- 7; rosiglitazone, 17 +/- 3). Production rates of
      cortisol were unchanged (basal, 577 +/- 136 microg/h; rosiglitazone, 627 +/- 141
      microg/h). These results suggest that a clinically relevant dose of at least one
      thiazolidindione, rosiglitazone, impedes the production of testosterone in man.

PMID- 12601640
TI  - In vitro reversal of hyperglycemia normalizes insulin action in fat cells from
      type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity
      in vivo?
AB  - Chronic hyperglycemia promotes the development of insulin resistance. The aim of
      this study was to investigate whether cellular insulin resistance is secondary to
      the diabetic state in human type 2 diabetes. Subcutaneous fat biopsies were taken
      from 3 age-, sex-, and body mass index (BMI)-matched groups with 10 subjects in
      each group: type 2 diabetes patients with either good (hemoglobin A(1c) [HbA(1c)]
      < 7%, G) or poor (HbA(1c) > 7.5%, P) metabolic control and healthy control
      subjects (C). Insulin action in vitro was studied by measurements of glucose
      uptake both directly after cell isolation and following a 24-hour incubation at a
      physiological glucose level (6 mmol/L). The relationship with insulin action in
      vivo was addressed by employing the euglycemic clamp technique. Freshly isolated
      fat cells from type 2 diabetes patients with poor metabolic control had
      approximately 55% lower maximal insulin response (1,000 microU/mL) on glucose
      uptake (P <.05) compared to C. Cells from P were more insulin-resistant (P <.05)
      than cells from G at a low (5 microU/mL) but not at a high (1,000 microU/mL)
      insulin concentration, suggesting insulin insensitivity. However, following 24
      hours of incubation at physiological glucose levels, insulin resistance was
      completely reversed in the diabetes cells and no differences in insulin
      stimulated glucose uptake were found among the 3 groups. Insulin sensitivity in
      vivo assessed with hyperinsulinemic, euglycemic clamp (M-value) was significantly
      associated with insulin action on glucose uptake in fresh adipocytes in vitro (r
      = 0.50, P <.01). Fasting blood glucose at the time of biopsy and HbA(1c), but not
      serum insulin, were negatively correlated to insulin's effect to stimulate
      glucose uptake in vitro (r = -0.36, P =.064 and r = - 0.41, P <.05, respectively)
      in all groups taken together. In the in vivo situation, fasting blood glucose,
      HbA(1c), and serum insulin were all negatively correlated to insulin sensitivity
      (M-value; r = -0.62, P<.001, r= -0.61, P<.001, and r = -0.56, p <.01,
      respectively). Cell size, waist-to-hip ration (WHR), and BMI correlated
      negatively with insulin's effect to stimulate glucose uptake both in vitro (r = 
      0.55, P <.01, r = -0.54, P <.01, and r = -0.43, P <.05, respectively) and in vivo
      (r = -0.43, P <.05, r = -0.50, P <.01, and r = -0.36, P <.05, respectively).
      Multiple regression analyses revealed that adipocyte cell size and WHR
      independently predicted insulin resistance in vitro. Furthermore, insulin
      sensitivity in vivo could be predicted by fasting blood glucose and serum insulin
      levels. We conclude that insulin resistance in fat cells from type 2 diabetes
      patients is fully reversible following incubation at physiological glucose
      concentrations. Thus, cellular insulin resistance may be mainly secondary to the
      hyperglycemic state in vivo.

PMID- 12601639
TI  - Effect of obesity on susceptibility to fatty acid-induced peripheral tissue
      insulin resistance.
AB  - Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown to
      impair the actions of insulin on peripheral glucose uptake and suppression of
      hepatic glucose output (HGO). These studies have been conducted almost
      exclusively in healthy, lean men. We therefore set out to test the hypothesis
      that obese subjects, because they are already insulin-resistant, are less
      susceptible than lean subjects to the inhibitory effects of elevated NEFA on
      insulin-stimulated glucose disposal. We studied 15 lean (11 men, 4 women; age, 45
      +/- 3 years [mean +/- SE]; body mass index [BMI], 22.7 +/- 0.6 kg/m(2)) and 15
      obese normal subjects (11 men, 4 women; 49 +/- 3 years; 31.7 +/- 1.0 kg/m(2)).
      Each subject underwent two 5-hour 80-mU/m(2)/min hyperinsulinemic euglycemic
      clamps with measurement of glucose kinetics (intravenous 3-(3)H-glucose). Plasma
      NEFA levels were elevated in one study for 3 hours before and during the clamp (
      approximately 1 mmol/L in both groups) by infusion of 20% Intralipid (60 mL/h)
      and heparin (900 U/h). The obese subjects had higher fasting insulin levels (9.1
      +/- 1.1 v 4.8 +/- 0.6 mU/L, P <.005) and were insulin-resistant (glucose disposal
      rate [GDR] at the end of the control glucose clamps: obese, 7.96 +/- 0.55, lean,
      10.24 +/- 0.35 mg/kg/min, P <.002). Contrary to our hypothesis, elevation of
      plasma NEFA had a similar effect in the lean and obese subjects, both in terms of
      the absolute reduction of insulin stimulated GDR in the lean (1.82 +/- 0.36
      mg/kg/min decrement) and obese subjects (2.03 +/- 0.37 mg/kg/min decrement) and
      the overall percentage reduction in GDR (lean, 17.1% +/- 3.1%; obese, 24.5% +/-
      4.2%; difference not significant [NS]). Suppression of HGO during the lipid
      clamps was also impaired to a similar extent in the 2 groups. Findings were
      similar for the 9 obese subjects with a BMI of 30 kg/m(2) or more. Combining the
      2 groups, the NEFA induced reduction of insulin stimulated GDR did not correlate
      with BMI (r = 0.08, NS) or with insulin sensitivity (GDR) measured in the control
      study (r = 0.11, NS). In summary, the effect of a short term elevation of plasma
      NEFA levels on insulin stimulated GDR and suppression of HGO is comparable in
      lean and moderately obese subjects.

PMID- 12601641
TI  - Genomic scan of glucose and insulin metabolism phenotypes: the HERITAGE Family
      Study.
AB  - Genetic factors play a role in the regulation of glucose metabolism-related
      traits such as insulin sensitivity (S(I)), insulin secretion, and glucose
      effectiveness (S(G)). Several genomic scans have been performed to localize genes
      involved in glucose metabolism-related traits. However, few of these studies have
      been performed with phenotypes derived from the frequently sampled intravenous
      glucose tolerance test (IVGTT) using the minimal modeling (MINMOD) approach.
      Here, we report on such a scan for glucose metabolism-related traits derived from
      MINMOD analysis of IVGTT data in 322 sibling pairs from 95 sedentary white
      families and 75 sibling pairs from 49 sedentary black families from the HERITAGE
      Family Study. In addition to S(I) and S(G), we also considered acute insulin
      response to a glucose challenge (AIR(Glucose)), which is an index for insulin
      secretion, and disposition index (DI, product of S(I) and AIR(Glucose)), which is
      a measure of the activity of pancreatic beta cells corrected for insulin
      resistance. These traits were adjusted for age, sex, and body mass index (BMI) in
      each of 8 sex-by-generation-by-race groups, and then standardized residuals were
      used as the phenotypes in the linkage analyses. Analyses were with the multipoint
      variance components linkage method, as implemented in the computer program
      SEGPATH, using 509 markers. Several regions with promising linkages (LOD score
      >/= 1.75, P </=.0023) were detected. They include five regions (1q41 and 8p23.2
      for S(I), 4q32.1 and 10p15.3 for AIR(Glucose), and 13q32.1 for DI) in whites and
      2 regions (9p11.2 for S(G) and 10q26.11 for S(I)) in blacks. Three of these
      regions (4q32.1, 9p11.2, 10p15.3) are likely to harbor genes that influence
      interindividual variation in glucose metabolism-related traits as they replicate
      findings from other studies. Fine mapping and association studies of candidate
      genes within these genomic regions are warranted.

PMID- 12601643
TI  - Introduction: the Traumatic Brain Injury Model Systems of Care.
AB  - The Traumatic Brain Injury Model Systems of Care (TBIMS) is a program that has
      been funded by the National Institute on Disability and Rehabilitation Research
      (US Department of Education) since 1987. The program is a collaborative effort of
      rehabilitation centers across the United States to further knowledge about the
      natural history of recovery and outcomes over the life course of individuals with
      traumatic brain injury, as well as to provide comprehensive services across the
      continuum of care and to foster innovative research programs. This introduction
      describes the underlying principles of the TBIMS program and the research
      initiatives carried out in the 1997/1998-2002 funding cycle.

PMID- 12601642
TI  - Garlic extract methylallyl thiosulfinate blocks insulin potentiation of platelet
      derived growth factor-stimulated migration of vascular smooth muscle cells.
AB  - Platelet-derived growth factor (PDGF) is a potent inducer of vascular smooth
      muscle cell (VSMC) migration, whereas insulin, in physiological concentrations,
      helps maintain the nonproliferative phenotype of these cells. However,
      hyperinsulinemia (10 nmol/L) significantly potentiates the PDGF (30 pmol/L)
      induced migration of VSMC. This potentiating effect of hyperinsulinemia appears
      to be mediated by increased availability of geranylgeranylated Rho-A.
      Hyperinsulinemia significantly increased the activity of
      geranylgeranyltransferase I (GGTase I) and the amounts of prenylated Rho-A. This
      action of hyperinsulinemia was inhibited by methylallyl thiosulfinate (MAT), a
      component of garlic extract, which exerted a strong anti-GGTase I activity. MAT
      also completely inhibited the ability of hyperinsulinemia to potentiate the PDGF
      induced VSMC migration. Thus, the purported anti-atherogenic action of garlic may
      be related to its inhibitory influence on GGTase I.

PMID- 12601645
TI  - Predictors of success for state vocational rehabilitation clients with traumatic
      brain injury.
AB  - OBJECTIVES: To determine the characteristics of individuals with traumatic brain
      injury (TBI) who request state vocational rehabilitation services and to
      determine the best predictors of their successful vocational outcomes. DESIGN:
      Observational study. SETTING: Vocational services data from the Missouri Division
      of Vocational Rehabilitation (DVR). PARTICIPANTS: Seventy-eight individuals with
      TBI who requested services from the Missouri DVR. INTERVENTIONS: Not applicable.
      MAIN OUTCOME MEASURES: Demographic, injury severity, neuropsychologic variables,
      vocational services offered, and vocational status at time of case closure
      (successful, unsuccessful, services interrupted, no services provided). RESULTS:
      Individuals requesting DVR services were primarily men (71%), white (82%), single
      (47%), of low average intelligence (Wechsler Adult Intelligence Scales-III full
      scale IQ score, 84.8), and of limited education (11.8 y). The majority
      experienced a significant TBI (ie, 66% were hospitalized after their TBI; 56%
      reported loss of consciousness; 37% reported posttraumatic amnesia; 32% reported
      multiple TBIs; avg time since injury, 9.2 y). At DVR case closure, 17% were rated
      as being successfully employed, with nearly all working in industrial, service,
      or clerical positions (2 in a sheltered workshop, 1 in a professional position).
      Stepwise logistic regressions indicated that delivery of DVR services (ie,
      vocational guidance and counseling, on-the-job training) predicted vocational
      outcome and demographic, injury severity, and neuropsychologic variables did not.
      CONCLUSIONS: DVR clients have multiple impairments that affect them several years
      postinjury; the provision of DVR services may be more important in determining
      vocational outcomes than traditional medical, psychologic, and demographic
      variables.

PMID- 12601644
TI  - Systematic bias in traumatic brain injury outcome studies because of loss to
      follow-up.
AB  - OBJECTIVE: To identify potential sources of selection bias created by subjects
      lost to follow-up in studies of traumatic brain injury (TBI). DESIGN:
      Demographic, premorbid, injury-related, and hospital course characteristics were
      compared for subjects lost and found for 1- and 2-year postinjury follow-ups by
      using bivariate tests and logistic regression analysis. SETTING: Three
      prospective, longitudinal data sets-a single center, a multicenter, and a
      statewide incidence surveillance system and follow-up registry. PARTICIPANTS:
      Adolescents and adults hospitalized with a diagnosis of TBI. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: Subjects were considered lost when no
      information was collected from the person with TBI or only limited information
      could be obtained from a proxy, for any reason, including death, refusal,
      inability to locate, and inability to interview. RESULTS: At year 1 follow-up,
      58.0% to 58.6% of subjects were found; 39.7% to 42.0% of subjects were found by
      year 2. Variables most frequently associated with loss to follow-up were cause of
      injury, blood alcohol level, motor function, hospital payer source, and race and
      ethnicity. CONCLUSIONS: TBI follow-up studies may experience selective attrition
      of subjects who (1) are socioeconomically disadvantaged, (2) have a history of
      substance abuse, and (3) have violent injury etiologies. These phenomena are
      mitigated for those with more severe motor deficits. Loss to follow-up may be a
      problem inherent to this population; however, the high rate and its selective
      nature are problematic for outcome studies.

PMID- 12601646
TI  - Early impaired self-awareness after traumatic brain injury.
AB  - OBJECTIVES: To evaluate predictors of early impaired self-awareness after
      traumatic brain injury (TBI); to examine interrelationships of the perceptions of
      patient, clinician, family, and significant other of how patients are functioning
      after TBI; and to determine how early impaired self-awareness helps to predict
      employability at rehabilitation discharge. DESIGN: Inception cohort. SETTING: Two
      inpatient rehabilitation programs. PARTICIPANTS: A total of 129 patients with TBI
      seen for inpatient rehabilitation at 1 of 2 rehabilitation centers. All subjects
      had emerged from posttraumatic amnesia before being assessed for this study.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Impaired self-awareness as
      measured by the Awareness Questionnaire (patient self-ratings, clinician ratings)
      and employability (rated on the Disability Rating Scale) at discharge from
      inpatient rehabilitation. RESULTS: Regression analysis revealed that early
      impaired self-awareness was predicted by age and functional status (FIM
      instrument total score) at admission to inpatient rehabilitation. Spearman
      correlation coefficients revealed that clinician, family, and significant other
      ratings of patient functioning were related (r(s) =.42, P<.001), but were not
      related to patient self-ratings. Multiple logistic regression analysis revealed
      that early impaired self-awareness was predictive of employability at discharge
      from inpatient rehabilitation. Clinician ratings of patient functioning showed a
      positive relation to employability (P =.05), whereas patient self-ratings showed
      a trend toward a negative relation to employability (P =.09). CONCLUSIONS: Our
      results support the importance of early impaired self-awareness assessment, its
      predictive value for complex functional activities, and the need for further
      research to determine if treatment programs for impaired self-awareness enhance
      functional outcomes.

PMID- 12601647
TI  - Depression after traumatic brain injury: a National Institute on Disability and
      Rehabilitation Research Model Systems multicenter investigation.
AB  - OBJECTIVE: To identify the frequency and manifestations of depression after
      traumatic brain injury (TBI) and the factors that contribute to developing this
      mood disorder. DESIGN: A prospective, nationwide, multicenter study; 17 centers
      supplied data from medical records and patient responses on a standardized
      criterion instrument. SETTING: Traumatic Brain Injury Model Systems programs.
      PARTICIPANTS: A demographically diverse sample of 666 outpatients with TBI was
      evaluated 10 to 126 months after injury. INTERVENTIONS: Not applicable. MAIN
      OUTCOME MEASURES: Depressive symptoms were characterized with the Neurobehavioral
      Functioning Inventory by using the Diagnostic and Statistical Manual of Mental
      Disorders (4th ed; DSM-IV) diagnostic framework. Analysis of variance and Pearson
      correlations were used to identify factors that were significantly related to
      depression. RESULTS: Fatigue (29%), distractibility (28%), anger or irritability
      (28%), and rumination (25%) were the most commonly cited depressive symptoms in
      the sample. Twenty-seven percent of patients with TBI met the prerequisite number
      (>/=5) of criterion A symptoms for a DSM-IV diagnosis of major depressive
      disorder. Feeling hopeless, feeling worthless, and difficulty enjoying activities
      were the 3 symptoms that most differentiated depressed from nondepressed
      patients. Patients who were unemployed at the time of injury and who were
      impoverished were significantly more likely to report DSM-IV criterion A symptoms
      than patients who were employed, were students, or were retired due to age. Time
      after injury, injury severity, and postinjury marital status were not
      significantly related to depression. CONCLUSIONS: Patients with TBI are at great
      risk for developing depressive symptoms. Findings provide empirical support for
      the inclusion of depression evaluation and treatment protocols in brain injury
      programs. Unemployment and poverty may be substantial risk factors for the
      development of depressive symptoms. Future research should develop
      biopsychosocial predictive models to identify high-risk patients and examine the
      efficacy of treatment interventions.

PMID- 12601648
TI  - The natural history of drinking and alcohol-related problems after traumatic
      brain injury.
AB  - OBJECTIVES: To describe changes in drinking from before traumatic brain injury
      (TBI) to 1 year after TBI. DESIGN: Inception cohort with 1-year follow-up.
      SETTING: Level I trauma center. PARTICIPANTS: Adults (N=197) hospitalized with a
      broad range of head injury severity. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Alcohol consumption and alcohol-related problems. RESULTS: Drinking and
      alcohol-related problems decreased substantially from preinjury to 1 year after
      TBI. However, about one quarter of the sample reported heavy drinking,
      significant problems, or both during the first year after TBI. Preinjury alcohol
      use and problems were highly predictive of heavy use and problems after TBI.
      CONCLUSION: Although drinking and alcohol-related problems decreased after TBI,
      there appears to be an ongoing need for prevention and intervention efforts.
      Screening for preinjury alcohol problems can be used to identify the vast
      majority of persons who will develop alcohol-related problems within 1 year after
      injury.

PMID- 12601649
TI  - Supported employment for persons with traumatic brain injury: a preliminary
      investigation of long-term follow-up costs and program efficiency.
AB  - OBJECTIVE: To investigate the long-term follow-up costs of supported employment
      as well as the wage and employment characteristics for individuals with moderate
      to severe traumatic brain injury (TBI) who participated in supported employment
      services over a 14-year time period. DESIGN: Longitudinal design with
      prospectively collected data. SETTING: A university-based supported employment
      program that uses the individual placement model of supported employment.
      PARTICIPANTS: Fifty-nine individuals with moderate to severe TBI who were
      consecutively referred for supported employment services. The sample was
      restricted to individuals who were placed into a least 1 supported employment
      position during the study period. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Data were collected on clients placed into at least 1 competitive
      supported employment position from 1985 to 1999. Analyses were performed to
      examine the costs of supported employment, employment characteristics (eg, wages,
      length of employment), and benefit-cost ratios of supported employment for
      individuals with TBI. RESULTS: The average length of employment for the current
      sample was 42.58 months. Average gross earnings were US dollars 26,129.74 for
      individuals during their entire duration of employment. Billing charges accrued
      for employment services averaged US dollars 10,349.37. Individuals with TBI
      earned an average of US dollars 17,515 more than the costs associated with their
      supported employment. CONCLUSIONS: Our investigation provides additional support
      for the conclusion that supported employment is cost effective for individuals
      with disabilities, including individuals with TBI, and that the costs of
      supported employment decrease over time.

PMID- 12601650
TI  - Preinjury emotional and family functioning in caregivers of persons with
      traumatic brain injury.
AB  - OBJECTIVE: To characterize the preinjury family functioning, emotional distress,
      and social support of caregivers of persons with traumatic brain injury (TBI).
      DESIGN: Inception cohort. SETTING: Three Traumatic Brain Injury Model Systems
      centers' inpatient rehabilitation facilities. PARTICIPANTS: One hundred ninety
      one caregivers, primarily white and female, of persons with TBI. INTERVENTIONS:
      Not applicable. MAIN OUTCOME MEASURES: The Brief Symptom Inventory, Family
      Assessment Device, Multidimensional Scale of Perceived Social Support, and
      history of medical and psychiatric illness. RESULTS: Thirty-seven percent of
      caregivers indicated symptoms of emotional distress consistent with psychiatric
      diagnoses for the month before injury, whereas 27% reported a history of
      psychiatric or psychologic treatment at some point in the past. Between 25% and
      33% of caregivers reported unhealthy family functioning in 1 or more areas for
      the month before injury. Persons with an annual income less than US dollars
      10,000 reported less healthy preinjury family functioning. Caregivers reported
      good satisfaction with preinjury social support, and very few caregivers reported
      a history of substance abuse. CONCLUSION: A substantial proportion of caregivers
      reported emotional distress and/or unhealthy family functioning before injury.
      Such difficulties may make them more vulnerable to the stress associated with
      injury and result in greater coping difficulties.

PMID- 12601651
TI  - Concordance of patient and family report of neurobehavioral symptoms at 1 year
      after traumatic brain injury.
AB  - OBJECTIVE: To determine concordance between patient and family report of
      neurobehavioral symptoms and problems across 6 domains of function and 3 levels
      of injury severity at 1 year after traumatic brain injury (TBI). DESIGN:
      Prospective longitudinal design with follow-up between 10 and 14 months
      postinjury. SETTING: Seventeen Traumatic Brain Injury Model Systems centers.
      PARTICIPANTS: A total of 267 adults with primarily moderate and severe TBI who
      had completed self-ratings and whose neurobehavioral symptoms had also been rated
      by their significant others. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Neurobehavioral Functioning Inventory-Revised, a 70-item scale with
      subscales assessing frequency of symptoms in motor, somatic, memory and
      attention, depression, communication, and aggression domains. RESULTS: Twenty
      three items showed significant differences or trends between the self- and other
      ratings; 18 of these were in the direction of the injured individual reporting
      less frequent problems. Differences were most pronounced on the depression,
      aggression, and memory and attention subscales. On the latter 2 subscales,
      patient-family concordance was higher for those with less severe injuries.
      However, severity effects were not clear cut. Analyses of selected rating
      patterns indicating clinically significant "underreporting" of symptoms revealed
      that these affected the depression, aggression, and memory and attention
      subscales more than the motor or somatic subscales. CONCLUSIONS: At 1 year post
      TBI, concordance between self- and other report of neurobehavioral symptoms was
      moderately high overall, but varied by symptom domain. For persons with moderate
      and severe TBI, reports from significant others may be needed for a full picture
      of the range, severity, and clinical importance of the patient's emotional,
      behavioral, and cognitive difficulties.

PMID- 12601652
TI  - The association of early computed tomography scan findings and ambulation, self
      care, and supervision needs at rehabilitation discharge and at 1 year after
      traumatic brain injury.
AB  - OBJECTIVE: To ascertain the association between early computed tomography (CT)
      scan findings and the need for assistance with ambulation, activities of daily
      living (ADLs), and supervision at rehabilitation discharge and at 1 year after
      traumatic brain injury (TBI). DESIGN: Prospective longitudinal design. SETTING:
      Seventeen Traumatic Brain Injury Model Systems (TBIMS) centers. PARTICIPANTS: A
      total of 1,839 adults with TBI admitted to TBIMS trauma centers with subsequent
      acute rehabilitation; 849 were followed to 1 year after injury. INTERVENTIONS:
      Not applicable. MAIN OUTCOME MEASURES: Accumulated CT scan pathology from the
      first week after injury; FIM instrument and Disability Rating Scale at
      rehabilitation discharge and 1 year after injury; and Supervision Rating Scale at
      1 year. RESULTS: Chi-square analyses showed that individuals with a midline shift
      greater than 5mm (lateral compression) were more likely to require the assistance
      of another person at discharge from acute rehabilitation with ambulation (29% vs
      17%-19%, P=.02), toileting (47% vs 33%-38%, P=.05), lower-body dressing (57% vs
      39%-46%, P=.015), bladder continence (32% vs 19%-23%, P=.03), and overall
      supervision (53% vs 44%, P=.0006) than patients with a midline shift of lesser
      degree. At 1 year, 57% of patients with a midline shift greater than 5mm on acute
      CT scans were being supervised in the home versus 30% to 39% of those with a
      shift of lesser degree (P=.003); there were no significant differences in the
      percentages of those needing assistance for ambulation or ADLs. The association
      of subdural hematoma with ambulation, self-care, and supervision needs was
      related to the degree of midline shift but not to the presence of subdural
      hematoma. Individuals with subcortical contusions were more likely to require
      assistance at rehabilitation discharge for ambulation (32% vs 18%, P<.0001),
      lower-body dressing (61% vs 44%), toileting (52% vs 35%), bladder continence (34%
      vs 22%), and overall supervision (61% vs 44%) than those without subcortical
      contusions (P<.0001). At 1 year, individuals with acute subcortical contusions
      were more likely to need assistance with ambulation (15% vs 8%, P=.004) and stair
      climbing (15% vs 9%, P=.03). Those with bilateral frontal (54% vs 46%, P=.009) or
      bilateral temporal (58% vs 46%, P=.03) contusions were more likely to need
      assistance with overall supervision at rehabilitation discharge, compared with
      those with unilateral or no cortical contusions. CONCLUSIONS: The presence of
      either a midline shift greater than 5mm or a subcortical contusion on acute CT
      scans is associated with a greater need of assistance with ambulation, ADLs, and
      global supervision at rehabilitation discharge. Patients with bilateral cortical
      contusions require more global supervision at rehabilitation discharge but no
      more supervision for ambulation and ADLs. These findings may aid health care
      professionals and potential caregivers in planning for rehabilitation and
      supervision needs after rehabilitation discharge and, to a lesser extent, at 1
      year after TBI.

PMID- 12601654
TI  - Incidence, risk factors, and outcomes of fecal incontinence after acute brain
      injury: findings from the Traumatic Brain Injury Model Systems national database.
AB  - OBJECTIVE: To investigate the incidence, risk factors, and outcome in patients
      with fecal incontinence after acute brain injury. DESIGN: A retrospective study
      of the incidence of and risk factors contributing to fecal incontinence, and
      outcomes at admission to and discharge from inpatient rehabilitation and at 1
      year follow-up. SETTING: Medical centers in the federally sponsored Traumatic
      Brain Injury Model Systems (TBIMS). PARTICIPANTS: A total of 1,013 consecutively
      enrolled rehabilitation inpatients from 17 TBIMS centers who were admitted to
      acute care within 24 hours of traumatic brain injury and seen at 1-year
      postinjury between 1990 and 2000. INTERVENTIONS: Not applicable. MAIN OUTCOME
      MEASURES: Incidence of fecal incontinence, length of coma, length of
      posttraumatic amnesia (PTA), admission Glasgow Coma Scale (GCS) score, length of
      stay (LOS), FIM instrument scores, disposition at discharge and follow-up, and
      incidences of pelvic fracture, frontal contusion, and urinary tract infection
      (UTI). RESULTS: The incidence of fecal incontinence was 68% at admission to
      inpatient rehabilitation, 12.4% at rehabilitation discharge, and 5.2% at 1-year
      follow-up. Analysis of variance and chi-square analyses revealed statistically
      significant associations between the incidence of fecal incontinence at
      rehabilitation admission and admission GCS score, length of coma and PTA, LOS,
      and incidence of UTI and frontal contusion. Fecal incontinence at rehabilitation
      discharge was significantly associated with several variables, including age,
      discharge disposition, admission GCS score, length of coma, PTA, LOS, FIM scores,
      and incidence of pelvic fracture and frontal contusion. Significant associations
      were also found between fecal incontinence at 1-year follow-up and age, discharge
      and current 1-year disposition, admission GCS score, length of coma, LOS, FIM
      scores, and incidence of UTI (P<.05). Although logistic regression analyses were
      significant (P<.001), and predicted continence with 100% accuracy, demographics,
      injury characteristics, medical complications, and functional outcomes did not
      predict incontinence at discharge and at 1-year follow-up. CONCLUSIONS: Fecal
      incontinence is a significant problem after brain injury. Certain factors may
      increase its likelihood. Further studies evaluating mechanisms of fecal
      incontinence and treatment or control interventions would be useful.

PMID- 12601653
TI  - The relationship between neuropsychologic function and level of caregiver
      supervision at 1 year after traumatic brain injury.
AB  - OBJECTIVES: To evaluate distribution of levels of caregiver supervision at 1 year
      after traumatic brain injury, and to determine neuropsychologic predictors of
      supervision level. DESIGN: Prospective longitudinal design, concurrent
      measurement of neuropsychologic function and supervision level. SETTING:
      Seventeen Traumatic Brain Injury Model Systems centers. PARTICIPANTS: A total of
      563 adults tested at 1 year postinjury; and a subgroup of 452 studied for
      neuropsychologic function in the absence of impairment in mobility or basic self
      care, as assessed by high FIM instrument motor scores. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURE: Supervision level measured by scores on
      Supervision Rating Scale (SRS). RESULTS: Two thirds (69%) of the sample was rated
      as independent of supervision. Participants without significant dysfunction on
      motor FIM were grouped into supervision groups differing in intensity of time
      commitment from caregiver (independent, moderate supervision, heavy supervision).
      In univariate analyses, groups differed on demographic variables (education,
      race, productivity prior to injury), duration of altered consciousness, and all
      but 1 neuropsychologic measure. A binomial regression model (complementary log
      log model) revealed that supervision at 1 year was predicted by education and
      scores on the Trail Making Test Part B and digits backward. CONCLUSIONS: Findings
      confirm the importance of preinjury status and measures of working memory and
      cognitive flexibility in predicting functional independence after TBI. The SRS
      appears prone to ceiling effects in persons followed prospectively after moderate
      to severe TBI.

PMID- 12601655
TI  - Financial and vocational outcomes 1 year after traumatic brain injury.
AB  - OBJECTIVE: To characterize financial and vocational outcomes among persons with
      traumatic brain injury (TBI) in terms of employment status, earned and private
      income, and public assistance received at the time of injury and at 1 year after
      injury. DESIGN: Nonexperimental, longitudinal study. SETTING: Inpatient TBI
      rehabilitation unit and participants' community of residence. PARTICIPANTS:
      Thirty-five persons with new TBI from 1 national Traumatic Brain Injury Model
      Systems center. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Employment
      status, earned and private monthly income, and public assistance received monthly
      at the time of injury and at 1-year follow-up. RESULTS: From the time of injury
      until 1-year follow-up, the percentage of persons employed decreased from 69% to
      31%; the percentage unemployed increased from 11% to 49%; the average earned
      monthly income declined 51% (from US dollars 1,491 to US dollars 726); and the
      mean total public assistance received per month increased 275% (from US dollars
      153 to US dollars 421). CONCLUSION: Assuming that this study sample is
      representative of national statistics for TBI, during the first year after
      injury, TBI is associated with an estimated $642 million in lost wages, US
      dollars 96 million in lost income taxes, and US dollars 353 million in increased
      public assistance.

PMID- 12601656
TI  - Characterization and correlates of medical and rehabilitation charges for
      traumatic brain injury during acute rehabilitation hospitalization.
AB  - OBJECTIVE: To identify factors associated with specific categories of charges
      during acute inpatient rehabilitation treatment after traumatic brain injury
      (TBI). DESIGN: Prospective observational study. SETTING: A single Traumatic Brain
      Injury Model Systems (TBIMS) center. PARTICIPANTS: Eighty-four consecutive TBIMS
      patients. One exploratory analysis also included all 350 patients with TBI
      admitted during 1999. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES:
      Average daily charges for specific categories of resource use (eg, room and
      board, rehabilitation therapies, functional labs). RESULTS: Room and board and
      rehabilitation therapy accounted for almost 90% of average daily charges. There
      was no linear component of change in average daily charges, but certain
      categories of charges were significantly higher during the first week than
      thereafter. Functional status at rehabilitation admission correlated with charges
      for respiratory, medical, and surgical supplies and with pharmacy and radiology,
      but not the other categories. Specific medical variables also correlated with
      specific charge categories. Focused chart reviews of patients with low and high
      charges in specific categories led to the formulation of additional predictive
      hypotheses. CONCLUSION: Certain categories of charges correlated with functional
      scores and acute medical variables that are known before admission to acute
      inpatient rehabilitation, allowing for better inpatient admission planning under
      prospective payment. Further research is needed to identify and correlate
      resource use that is bundled within the room and board category.

PMID- 12601657
TI  - Violent traumatic brain injury: occurrence, patient characteristics, and risk
      factors from the Traumatic Brain Injury Model Systems project.
AB  - OBJECTIVES: To examine the occurrence of and characteristics associated with
      violent traumatic brain injury (TBI) in the Traumatic Brain Injury Model Systems
      (TBIMS) project for 4 of the 5 original Model Systems centers and to determine
      the patient characteristics of this group, as well as the risk factors for
      sustaining such an injury. DESIGN: Prospective evaluation of individuals with
      violent TBI over a 10-year period. SETTING: Four TBIMS centers. PARTICIPANTS: A
      total of 1,229 individuals who received acute hospitalization and inpatient
      rehabilitation care for TBI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE:
      The occurrence of a violent TBI. RESULTS: Twenty-six percent of the participants
      in the TBIMS project sustained a violent TBI. This type of injury was more common
      in African-American men who were single and slightly older than the average TBI
      patient, were unemployed before injury, and had had a previous TBI. A higher
      injury rate was noted in the earlier part of the evaluation period. Those who
      sustained a violent TBI had higher levels of caregiver burden and disability, as
      well as decreased productivity and community reintegration at rehabilitation
      discharge and at 1 and 2 years postinjury. CONCLUSIONS: The occurrence of violent
      TBI in the TBIMS project is consistent with national trends of decreasing
      incidence of violent injuries in the 1990s. These results present a profile of
      those who have been injured through violence. The relative risks for sustaining
      such an injury appear to be well defined when considering demographic and
      temporal factors.

PMID- 12601658
TI  - Etiology of traumatic brain injury: characterization of differential outcomes up
      to 1 year postinjury.
AB  - OBJECTIVE: To characterize outcomes after traumatic brain injury (TBI) resulting
      from vehicular crashes, violence, falls, or other causes. DESIGN: Prospective,
      multicenter, longitudinal. SETTING: Seventeen Traumatic Brain Injury Model
      Systems. PARTICIPANTS: A total of 1,170 individuals with moderate to severe TBI
      with data from initial medical and rehabilitation stays and 1-year follow-up.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: At rehabilitation
      discharge, FIM instrument, Disability Rating Scale (DRS), and Rancho Los Amigo
      Levels of Cognitive Functioning Scale. At 1 year postinjury, FIM, DRS, Community
      Integration Questionnaire (CIQ), employment, residence, marital status, and
      seizure occurrence. RESULTS: The 4 etiology groups could be distinguished based
      on premorbid characteristics. Severity of injury indices indicated that
      individuals in vehicular crashes showed a trend toward incurring more severe
      injuries than the other 3 groups. At rehabilitation discharge, there were no
      functional differences between groups. At 1 year postinjury, the groups could be
      differentiated: individuals in violence-related TBI had higher unemployment rates
      and lower CIQ scores; persons in vehicular crashes reported the best functional
      and psychosocial outcomes; and individuals in the falls and other groups had
      outcomes lying between the vehicular and violence groups. CONCLUSION: This study
      elucidated important differences between persons with violence-related TBI and
      those with non-violence-related TBI. Further research is needed to find effective
      interventions to address these differences.

PMID- 12601659
TI  - Ethnographic analysis of traumatic brain injury patients in the national Model
      Systems database.
AB  - OBJECTIVE: To compare demographics, injury characteristics, therapy service and
      intensity, and outcome in minority versus nonminority patients with traumatic
      brain injury (TBI). DESIGN: Retrospective analysis. SETTING: Twenty medical
      centers. PARTICIPANTS: Two thousand twenty patients (men, n=1,518; women, n=502;
      nonminority, n=1,168; minority, n=852) with TBI enrolled in the Traumatic Brain
      Injury Model Systems database. INTERVENTIONS: Not applicable. MAIN OUTCOMES
      MEASURES: Age, gender, marital status, education, employment status, injury
      severity (based on Glasgow Coma Scale [GCS] admission score, length of
      posttraumatic amnesia, duration of unconsciousness), intensity (hours) of therapy
      rendered, rehabilitation length of stay (LOS), rehabilitation charges, discharge
      disposition, postinjury employment status, FIM instrument change scores, and FIM
      efficiency scores. Independent sample t tests were used to analyze continuous
      variables; chi-square analyses were used to evaluate categorical data. RESULTS: 
      DEMOGRAPHICS: overall, minorities were found to be mostly young men who were
      single, unemployed, and less well educated, with a longer work week if employed
      when injured. ETIOLOGY: motor vehicle crashes (MVCs) predominated as the cause of
      injury for both groups; however, minorities were more likely to sustain injury
      from acts of violence and auto-versus-pedestrian crashes. Minorities also had
      higher GCS scores on admission and shorter LOS. Rehabilitation services:
      significant differences were found in the types and intensity of rehabilitation
      services provided; these included physical therapy, occupational therapy, and
      speech-language pathology, but not psychology. CONCLUSION: Minority patients who
      sustain TBI generally tend to be young men with less social responsibility.
      Although MVCs predominate as the primary etiology, acts of violence and auto
      versus-pedestrian incidents are more common in the minority population.
      Minorities tend to have higher GCS scores at admission. Also, the type and
      intensity of rehabilitation services provided differed significantly for the
      various interdisciplinary subspecialties. Rehabilitation charges, discharge
      disposition, and postinjury employment status were similar for the 2 groups, even
      though LOS is typically 3 to 4 days shorter for the minority group. A more
      detailed investigation is warranted to explain these findings.

PMID- 12601660
TI  - The Moss Attention Rating Scale for traumatic brain injury: initial psychometric
      assessment.
AB  - OBJECTIVE: To examine the psychometric properties of the Moss Attention Rating
      Scale (MARS), a new observational rating scale for attention-related behaviors in
      traumatic brain injury (TBI). DESIGN: Prospective observational study. SETTING:
      Eight acute inpatient rehabilitation facilities that are part of the Traumatic
      Brain Injury Model Systems program. PARTICIPANTS: Two hundred twenty-eight
      patients with TBI requiring acute inpatient rehabilitation treatment.
      INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rasch analysis on the 53
      item MARS (45 attention items, 8 control items) as rated separately by the
      treating occupational therapist and physical therapist. RESULTS: The MARS
      appeared to measure a single dimension and demonstrated good person separation
      (5.69) and reliability (.97). In post hoc assessment, misfitting attention items
      may not have required attention and control items that fit the dimension may have
      required at least rudimentary attention. Occupational therapists rated patients
      as slightly less attentive than did physical therapists. Overall, the scale was
      well targeted to an acute inpatient rehabilitation population. CONCLUSION: Our
      results provide preliminary support for the viability of developing an
      observational attention rating scale for use in inpatient TBI rehabilitation.
      Further research will need to explore the existence of subdimensions and provide
      further validation with reference to other neuropsychologic measures of attention
      and knowledge of lesion severity and localization.

PMID- 12601661
TI  - Development of the Key Behaviors Change Inventory: a traumatic brain injury
      behavioral outcome assessment instrument.
AB  - OBJECTIVE: To describe the development and initial validation of a
      neurobehavioral outcome measure, the Key Behaviors Change Inventory (KBCI), for
      individuals with traumatic brain injury (TBI). DESIGN: Scale construction and
      development, and validity study. SETTING: Large state university and postal
      survey. PARTICIPANTS: Seventy-five volunteer undergraduate students and 25
      volunteer collateral informants of individuals with TBI participated in the item
      analysis phase. Thirty members of the Brain Injury Association and 20 members of
      the National Multiple Sclerosis Society rated both an identified patient and an
      age- and gender-equated control in the validation phase. INTERVENTIONS: Not
      applicable. MAIN OUTCOME MEASURES: Content validity was examined through expert
      panel item sorts. Scale internal consistencies were examined with the Cronbach
      alpha. Construct validity was examined by comparing scale elevations between
      controls and 2 neurologic groups. RESULTS: Item-analysis procedures resulted in 8
      scales of 8 items each: inattention, impulsivity, unawareness of problems,
      apathy, interpersonal difficulties, communication problems, somatic difficulties,
      and emotional adjustment. Internal consistency reliability coefficients ranged
      from.82 to.91. Multivariate analysis of variance revealed significant (P</=.001)
      differences in scale elevations among TBI, multiple sclerosis (MS), and control
      groups. The TBI and MS groups scored significantly higher than the control group
      on all scales; a subset of KBCI scales discriminated between the 2 neurologic
      groups. CONCLUSION: The KBCI was both sensitive and specific to typical
      behavioral changes after TBI, thus supporting its usefulness in rehabilitation
      settings. Cross-validation and development of a normative database are future
      steps necessary in its development.

PMID- 12601662
TI  - Screening for venous thromboembolism in traumatic brain injury: limitations of D
      dimer assay.
AB  - OBJECTIVES: To assess whether 2 different D-dimer fibrin degradation assays-a
      second-generation latex immunosorbent agglutination (LIA) and an enzyme-linked
      immunosorbent assay (ELISA)-are predictive for the development of deep venous
      thrombosis (DVT) at the currently accepted level of 500 microg/L of D-dimer assay
      during the first weeks after traumatic brain injury (TBI) and to correlate over 8
      weeks the second-generation LIA assay with the ELISA assay after acute TBI.
      DESIGN: A case series of persons with TBI were screened for DVT at 2 weeks (+/
      3d) using real-time, spectral Doppler ultrasound, as well as D-dimer fibrin split
      products. All persons were rescreened at 4, 6, and 8 weeks (+/-3d) after injury
      using D-dimer LIA and ELISA assays. SETTING: A university hospital with a
      directly connected comprehensive in- and outpatient rehabilitation center that
      are part of the Traumatic Brain Injury Model Systems. PARTICIPANTS: Over 3 years,
      35 TBI subjects with a mean Glasgow Coma Scale score of 6.5 were consecutively
      enrolled into the trial while on acute care. Persons were at least 16 years of
      age with no history of treatment for DVT. INTERVENTIONS: Not applicable. MAIN
      OUTCOME MEASURES: Data were analyzed for the levels of D-dimer and risk as
      established by a predictive value of 500 microg/L. Changes in D-dimer values over
      time and within subjects were assessed by analysis of variance (ANOVA) with
      repeated measures, and the methods were correlated. RESULTS: The mean LIA level
      at 2 weeks was 4.3mg/L and averaged 1.6 mg/L at 8 weeks from injury (P=.012,
      ANOVA), and the ELISA dropped from 4,748 microg/L to 1.695 microg/L (P=.0022,
      ANOVA). Except for 1 ELISA value in 1 patient, D-dimer levels were elevated
      beyond 500 microg/L at 2 weeks. There was a very good correlation between the LIA
      and the ELISA at 2, 4, 6, and 8 weeks after TBI (P<.0001). In individual cases,
      there were only occasional discrepancies between the LIA and ELISA methods. There
      were no positive DVTs at 2 weeks using ultrasound, so prediction of the
      sensitivity and the specificity of D-dimer with DVT was not possible. CONCLUSION:
      Using the currently recommended levels of D-dimer to predict DVT is not
      clinically useful in the acute TBI population.

PMID- 12601663
TI  - The influence of dynamic polyelectromyography in formulating a surgical plan in
      treatment of spastic elbow flexion deformity.
AB  - OBJECTIVE: To determine the influence of motor-control analysis with dynamic
      electromyography on surgical planning in patients with spastic elbow flexion
      deformity. DESIGN: Prospective observational design. SETTING: A Traumatic Brain
      Injury Model Systems-affiliated specialty referral center for the evaluation and
      treatment of mobility problems associated with neurologic injury and disease.
      PARTICIPANTS: Twenty-one patients with spastic elbow flexion deformity.
      INTERVENTIONS: Two surgeons each formulated a detailed surgical plan for each
      individual muscle-tendon unit. Patients then underwent motor-control analysis in
      which kinetic and polyelectromyographic data were collected by using a standard
      protocol. Each surgeon formulated another surgical plan after independently
      reviewing the laboratory study. MAIN OUTCOME MEASURES: The frequency of change
      and degree of agreement in the surgical plans after review of the laboratory data
      were used as measures of the effect of the laboratory studies. RESULTS: Fifty
      seven percent of the surgical plans were changed after the motor-control study.
      The frequency of change did not differ by clinical experience. There was a trend
      toward higher agreement between surgeons after the study than before.
      CONCLUSIONS: Detailed electromyographic motor-control analysis alters surgical
      planning for patients with spastic elbow flexion deformity. Clinical assessment
      alone does not accurately identify the muscles responsible for the deformity or
      dysfunction. More clinical experience does not result in greater accuracy. Motor
      control analysis produces higher agreement between surgeons in planning surgery.

PMID- 12601664
TI  - Splinting the hand in the functional position after brain impairment: a
      randomized, controlled trial.
AB  - OBJECTIVE: To evaluate the effects of 4 weeks of hand splinting on the length of
      finger and wrist flexor muscles, hand function, and pain in people with acquired
      brain impairment. DESIGN: Randomized, assessor-blinded trial. SETTING:
      Rehabilitation center in Australia. PARTICIPANTS: Twenty-eight adults with
      acquired brain impairment, all within 6 months of the first injury. There was 1
      withdrawal. INTERVENTIONS: Subjects in both experimental (n=17) and control
      (n=11) groups participated in routine therapy-motor training for upper-limb use
      and upper-limb stretches-5 days a week. The experimental group also wore an
      immobilizing hand splint in the functional position (10 degrees -30 degrees wrist
      extension) for a maximum of 12 hours each night for the duration of the 4-week
      intervention period. MAIN OUTCOME MEASURES: The length of the wrist and extrinsic
      finger flexor muscles was evaluated by measuring the torque-controlled range of
      wrist extension with the fingers extended. Functional hand use was evaluated with
      the Motor Assessment Scale. Pain was evaluated with a visual analog scale.
      RESULTS: The effects of splinting were statistically nonsignificant and
      clinically unimportant. At follow-up, estimates of treatment effects slightly
      favored the control group: range of motion at the wrist favored controls by 2
      degrees (95% confidence interval [CI], -7.2 degrees to 3.2 degrees ), function
      favored controls by 0.2 points (95% CI, -2.7 to 2.3), and pain favored the
      experimental group by 1cm (95% CI, -4.6 to 2.2). CONCLUSIONS: An overnight splint
      wearing regimen with the affected hand in the functional position does not
      produce clinically beneficial effects in adults with acquired brain impairment.

PMID- 12601665
TI  - Accuracy in the design methodology of abstracts.

PMID- 12601667
TI  - The Law of Laplace and additional applications.

PMID- 12601669
TI  - Garlic as an antioxidant: the good, the bad and the ugly.
AB  - Garlic has played an important dietary and medicinal role throughout the history
      of mankind. In some Western countries, the sale of garlic preparations ranks with
      those of leading prescription drugs. The therapeutic efficacy of garlic
      encompasses a wide variety of ailments, including cardiovascular, cancer, hepatic
      and microbial infections to name but a few. However, the elucidation of its
      mechanism for therapeutic action has proved to be more elusive and a unifying
      theory, which could account for its reported multifarious activities, is yet to
      emerge. Reactive oxygen species (ROS) seem to be at the core of many disease
      processes and it is an attractive and convenient hypothesis that garlic might
      exert its activities through modulatory effects on ROS. A literature search on
      garlic and its antioxidant potential churned up a surprisingly large amount of
      data, some of it good, some bad and some of its definitely ugly. Various
      preparations of garlic, mainly aged garlic extract (AGE), have been shown to have
      promising antioxidant potential. However, the presence of more than one compounds
      in garlic, with apparently opposite biological effects, has added to the
      complexity of the subject. Raw garlic homogenate has been reported to exert
      antioxidant potential but higher doses have been shown to be toxic to the heart,
      liver and kidney. So where do we stand today on this issue of garlic? Is garlic
      always good for health? How safe is it? Is it necessary to isolate the
      antioxidant compounds for its medicinal use in a more effective way? These issues
      are addressed in this review.

PMID- 12601670
TI  - Inhibitory effects of Vietnamese medicinal plants on tube-like formation of human
      umbilical venous cells.
AB  - Seven of 58 plant materials from Vietnamese medicinal plants showed strong to
      moderate inhibitory activity on the tube-like formation induced by human
      umbilical venous endothelial cells in the in vitro angiogenesis assay. These
      plant materials include the herb of Ephedra sinica, leaves and stem of Ceiba
      pentandra, seed of Coix lachryma-jobi, rhizome of Drynaria fortunei, fruits and
      stem of Illicium verum and stem of Bombax ceiba. Of these, the methanol extracts
      of the herb of Ephedra sinica and stem of -Ceiba pentandra exhibited the
      strongest activities with inhibition percentages of 89.3% and 87.5% at 30 and 100
      microgram/mL, respectively.

PMID- 12601671
TI  - Evaluation of a soybean product fujiflavone P40 as an antiosteoporotic agent in
      rats.
AB  - The preventive effects of Fujiflavone P40 (a soybean isoflavone product) against
      both bone loss and periodontal alteration were evaluated using an ovariectomized
      rat model. Rats were divided into five groups: sham-operated (Sham),
      ovariectomized (OVX), OVX given Fujiflavone P40, OVX given 17beta-oestradiol, and
      OVX given the vehicle for 17beta-oestradiol, respectively. Fujiflavone P40
      contains 46.6% isoflavones which consist of 24.1% daidzin, 16.5% glycitin and
      5.9% genistin. Administration of Fujiflavone P40 to OVX rats suppressed the body
      weight gain until 5 weeks. Fujiflavone P40 also decreased total and high-density
      lipoprotein (HDL) cholesterols and triglyceride level of OVX rats, significantly.
      After 7 weeks, Fujiflavone P40 did not recover the coarsened fibre of the
      periodontal ligament. The ovariectomy decreased the uterine weight by 78%. The
      administration of 17beta -oestradiol recovered the weight loss by 99%, while
      Fujiflavone P40 restored it by 33%. The ovariectomy decreased the tibial bone
      mineral density (BMD) by 22%. The administration of 17beta-oestradiol to OVX rats
      recovered the tibial BMD decrease by 100%, while Fujiflavone P40 recovered it by
      78%. The results suggest that Fujiflavone P40 may be useful as a preventive agent
      for osteoporosis.

PMID- 12601672
TI  - Anti-influenza virus activity of crude extract of Ribes nigrum L.
AB  - This experiment was designed to detect the antiviral activities of crude fruit
      extracts of wild Ribes nigrum L. (Kurokarin extract) against influenza virus
      types A and B. Kurokarin extract was prepared as follows: fruits of Ribes nigrum
      L. were heated at 50 degrees C in a heating tank, and then ground under anaerobic
      conditions. The extracts were centrifuged, and the supernatant fluid was filtered
      and sterilized by infrared rays. The crude extract was diluted with Eagle's
      minimum essential medium (MEM) and the solution was adjusted to a pH 7.2 with 0.1
      N or 1 N NaOH. Proven anti-influenza virus effects of the extracts were shown.
      The concentration of extract required to inhibit the plaque formation of both IVA
      and IVB by 50% (IC(50)) was 3.2 microgram/mL. Both IVA and IVB were directly
      inactivated up to 99% by 10 microgram/mL of the extract at pH 2.8, and 95% to 98%
      by this dose at pH 7.2. The growth of IVA in cells treated with 10 and 100
      microgram/mL of the extract for 6 h after infection was completely suppressed.
      Virus titres in culture fluids of the cells treated with 100 microgram/mL of
      Kurokarin extract for 1 h at 8 to 9 h after infection, were completely
      suppressed, indicating that the extract inhibited the virus release from the
      infected cells.

PMID- 12601673
TI  - In vitro antiplasmodial evaluation of medicinal plants from Zimbabwe.
AB  - In this study the in vitro antiplasmodial activities of extracts from Cussonia
      spicata (Araliaceae), Artemisia afra, Vernonia colorata, V. natalensis
      (Asteraceae), Parinari curatellifolia (Chrysobalanaceae), Clutia hirsuta,
      Flueggea virosa, (Euphorbiaceae), Adenia gummifera (Passifloraceae) and
      Hymenodictyon floribundum, (Rubiaceae) were evaluated. The lipophilic extracts
      from the aerial parts of Artemisia afra and Vernonia colorata proved to be the
      most active against the chloroquine-sensitive strain PoW and against the
      chloroquine-resistant clone Dd2 of Plasmodium falciparum. Bioassay-guided
      fractionation of the extract of A. afra yielded seven flavonoids, from which
      acacetin, genkwanin and 7-methoxyacacetin showed in vitro activity; the IC(50)
      values ranged from 4.3 microgram/mL to 12.6 microgram/mL. In addition, several
      sesquiterpene lactones could be obtained from the most active fractions. Whereas
      eudesmaafraglaucolide proved to be inactive, the guaianolides 1-desoxy-1alpha
      peroxy-rupicolin A-8-O-acetate, 1alpha,4alpha-dihydroxybishopsolicepolide and
      rupicolin A-8-O-acetate revealed in vitro antiplasmodial activity. Evaluation of
      V. colorata gained four sesquiterpenes 11beta,13-dihydrovernodalin, vernodalol,
      11beta,13-dihydrovernolide and 11beta,13,17,18-tetrahydrovernolide, from which
      the first two constituents exhibited the strongest antiplasmodial activity
      (IC(50) values: 1.1-4.8 microgram/mL).

PMID- 12601674
TI  - Isolation, characterization and biological activity of betulinic acid and ursolic
      acid from Vitex negundo L.
AB  - Two pentacyclic triterpenoids, betulinic acid (3beta-hydroxylup-20-(29)-en-28-oic
      acid) (3), and ursolic acid (2beta-hydroxyurs-12-en-28-oic acid) (4), were
      isolated for the first time from leaves of Vitex negundo L. along with three
      other compounds; an aliphatic alcohol n-hentriacontanol (1), beta-sitosterol (2)
      and p-hydroxybenzoic acid (5). Their antifeedant activity against the larvae of
      an agricultural pest, the castor semilooper (Achoea janata), in a no-choice
      laboratory assay and their antibacterial activity against Bacillus subtilis and
      Escherichia coli, by the paper disc method, were tested. Ursolic acid (4) showed
      more effective antifeedant activity than the betulinic acid (3). However, both
      these compounds have shown a very mild antibacterial activity. The other three
      compounds; n-hentriacontanol (1), beta-sitosterol (2) and p-hydroxybenzoic acid
      (5) have shown a little antifeedant activity against the larvae and did not show
      any antibacterial activity.

PMID- 12601675
TI  - Effects of intraduodenal application of peppermint oil (WS(R) 1340) and caraway
      oil (WS(R) 1520) on gastroduodenal motility in healthy volunteers.
AB  - Enteric-coated preparations containing a fixed peppermint oil/caraway oil
      combination (e.g. Enteroplant(R)) are widely used in patients with functional
      dyspepsia. The effect of a separate intraduodenal application of the active
      ingredients of Enteroplant(R) (90 mg peppermint oil (WS(R) 1340), 50 mg caraway
      oil (WS(R) 1520) per capsule) and of a hydrophobic phase galenic auxiliary
      material contained in the Enteroplant(R) formulation (dose as contained per
      capsule) on gastroduodenal motility were studied with stationary manometry in
      healthy volunteers. The carrier demanded by the experimental setup also served as
      a control. The results showed that: (1) during phase III of the migrating motor
      complex (MMC) the frequency and duration of contractions showed a significant
      decrease in the duodenum for WS(R) 1340; (2) WS(R) 1520 significantly reduced the
      contraction amplitudes in the duodenum during phase I and II of the MMC; (3)
      trends for decreased values were seen for WS(R) 1340 in the gastric corpus and
      duodenum and for WS(R) 1520 in the gastric antrum; (4) in the gastric corpus the
      duration of contractions was significantly reduced after application of WS(R)
      1340 during phases I and II of the MMC; (5) WS(R) 1520 significantly reduced the
      contraction amplitudes and the duration of contractions in the gastric corpus
      during phase III of the MMC; (6) for the hydrophobic phase a moderate but
      significant decrease of duration of contractions in the duodenum and of frequency
      of contractions in the gastric corpus was seen. No adverse events were observed
      during the study. In conclusion, it could be shown that both WS(R) 1340 and WS(R)
      1520 contribute to the efficacy of Enteroplant(R). They act locally in the
      stomach and duodenum to produce smooth-muscle relaxation. The effects of the
      active ingredients WS(R) 1340 and WS(R) 1520 substantially exceed the effects
      observed with the galenic auxiliary material and the carrier, respectively.

PMID- 12601676
TI  - Effect of oral administration ofHypericum perforatum extract (St. John's Wort) on
      skin erythema and pigmentation induced by UVB, UVA, visible light and solar
      simulated radiation.
AB  - Hypericin from St John's wort (Hypericum perforatum L.) is a photosensitizing
      agent that may cause a severe photodermatitis when higher amounts of St John's
      wort are ingested by animals. Although Hypericum extracts are widely used in the
      treatment of depressive disorders, only a little information on the
      photosensitizing capacity of St John's wort in humans is available. In the
      present prospective randomized study we investigated the effect of the Hypericum
      extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA),
      visible light (VIS) and solar simulated radiation (SIM). Seventy two volunteers
      of skin types II and III were included and were divided into six groups, each
      consisting of 12 volunteers. In the single-dose study the volunteers (n = 48)
      received 6 or 12 coated tablets (5400 or 10 800 microgram hypericin). In the
      steady-state study the volunteers (n = 24) received an initial dose of 6 tablets
      (5400 microgram hypericin), and subsequently 3 x 1 tablets (2700 microgram
      hypericin) per day for 7 days. Phototesting was performed on the volar forearms
      prior to medication and 6 h after the last administration of Hypericum extract.
      The erythema-index and melanin-index were evaluated photometrically using a
      mexameter. After both single-dose and steady-state administration, no significant
      influence on the erythema-index or melanin-index could be detected, with the
      exception of a marginal influence on UVB induced pigmentation (p = 0.0471) in the
      single-dose study. The results do not provide evidence for a phototoxic potential
      of the Hypericum extract LI 160 in humans when administered orally in typical
      clinical doses up to 1800 mg daily. This is in accordance with previous
      pharmacokinetic studies that found hypericin serum and skin levels after oral
      ingestion of Hypericum extract always to be lower than the assumed phototoxic
      hypericin threshold level of 1000 ng/mL.

PMID- 12601677
TI  - Inhibitory effects of Oren-Gedoku-To (Huanglian-Jie-Du-Tang) on free radical
      induced lysis of human red blood cells.
AB  - Oren-gedoku-to (Huanglian-Jie-Du-Tang, OGT) has been used for the treatment of
      cerebrovascular disease, hypertension, gastritis and liver disease in Japan. The
      present study was to test our hypothesis that ingestion of Oren-gedoku-to extract
      (TJ-15) would protect red blood cell (RBC) membrane from free radical-induced
      oxidation if antioxidants in OGT could be absorbed and circulated in blood. When
      incubated with RBC suspension, OGT and its four constituting herbs provided
      strong protection for RBC membrane to hemolysis induced by 2,2-azo-bis (2
      amidinopropane) dihydrochloride (AAPH), an azo free radical initiator. The
      inhibitory effect was in a dose-dependent manner at concentrations of 5
      microgram/ml to 500 microgram/ml. Furthermore, the ingestion of 7.5 g of OGT
      (daily dose) was associated with a significant decrease in susceptibility of RBC
      to hemolysis in humans. The direct protection of RBC membrane from free-radical
      attack as observed in the present study could provide an important
      pathophysiological basis for making use of the favorable hemorheological effect
      of OGT.

PMID- 12601678
TI  - Composition and antimicrobial activity of the essential oil of Hypericum
      rumeliacum subsp. apollinis (Boiss. & Heldr.).
AB  - The composition and the antimicrobial activity of the aerial parts of Hypericum
      rumeliacum are reported. Analysis was carried out by GC/MS. The major
      constituents were alpha-pinene (43.80%), beta-pinene (9.82%), dehydro
      aromadendrene (6.81%) and alpha-copaene (5.41%). The essential oil showed a
      moderate in vitro activity against the six Gram negative and positive bacteria
      and a stronger one against the three-tested pathogenic activity.

PMID- 12601679
TI  - Cytotoxic activity of chalcones isolated from lonchocarpus sericeus (pocr.)
      kunth.
AB  - In the present study, it was demonstrated that the hexanic extract obtained from
      the roots of Lonchocarpus sericeus and one of its major components, derricin, but
      not lonchocarpin, show cytotoxic activity to fertilized sea urchin eggs. Both
      inhibited the first cleavage of sea urchin eggs in a dose-dependent manner with
      an IC(50) of 30.4 (26.2-35.3) microgram/mL for the crude extract and 51.2 (42.1
      62.3) microgram/mL for derricin (n = 6, in both cases). Furthermore, the hexanic
      extract of L. sericeus, and the isolated compounds, derricin and lonchocarpin
      showed cytotoxicity against CEM leukaemic cell line (IC(50) = 17.6 (13.7-22.6),
      13.0 (12.0-14.0) and 10.4 (5.6-19.1) microgram/ml (n = 6), respectively). When
      these substances (6.25 to 125 microgram/25 microL) were examined for
      antimicrobial activity against Escherichia coli, Staphylococcus aureus and
      Candida albicans, none of them were found to be active. Neither the hexanic
      extract, nor the isolated compounds derricin and lonchocarpin (0.5 to 250
      microgram/mL) presented hemolytic activity. These results indicated a possible
      antimitotic activity of L. sericeus crude extract and their major constituents.

PMID- 12601680
TI  - Inhibitory effects of triterpenes isolated from Hoelen on free radical-induced
      lysis of red blood cells.
AB  - Hoelen, sclederma of Poria cocos Wolf, has long been used as a sedative and
      diuretic in traditional medicine. Formerly, we demonstrated that Hoelen in vitro
      protects red blood cells from AAPH-induced hemolysis. In this study, tests were
      carried out to identify the main ingredient of Hoelen that has the scavenging
      effect on free-radicals. Triterpene carboxylic acids isolated from the methanol
      extract of Hoelen, i.e. pachymic acid, polyporenic acid, 3-epidehydrotumulosic
      acid, 3beta-hydroxylanosta-7,9(11), 24-trien-21-oic acid and 3-o-acetyl-16 alpha 
      hydroxytrametenolic acid, were found to have inhibitory activities against AAPH
      induced lysis of red blood cells.

PMID- 12601681
TI  - Effects of the ethyl acetate fraction of Spatholobi caulis on tumour cell
      aggregation and migration.
AB  - The ethyl acetate (EA) fraction obtained from a methanol extract of Spatholobi
      caulis (Leguminosae) has been investigated for anti-metastatic activities in
      vitro. The EA fraction of Spatholobi caulis inhibited platelet aggregation
      induced by B16BL6 melanoma cells with an IC(50) of 50 microgram/mL. The EA
      fraction significantly inhibited HT1080 cancer cell invasion through a matrigel
      coated filter with an IC(50) of 25 microgram/mL. Messenger RNA expression of uPA
      was effectively decreased in HT1080 cells by the EA fraction of Spatholobi caulis
      with an IC(50) of 30 microgram/mL, but the expressions of MMP-2 (matrix
      metalloproteinase) and TIMPs (tissue inhibitors of metalloproteinases) were not
      changed. These findings indicated that the EA fraction suppressed tumour cell
      invasion by downregulation of uPA (urokinase-type plasminogen activator). Taken
      together, these results suggest that the EA fraction of Spatholobi caulis may
      have anti-metastatic activities by blocking tumour cell-induced platelet
      aggregation (TCIPA) and tumour cell invasion.

PMID- 12601682
TI  - Cytotoxic sesquiterpene lactones from Centaurothamnus maximus and Vicoa
      pentanema.
AB  - The aerial parts of Centaurothamnus maximus yielded three cytotoxic guaianolides,
      chlorojanerin (1), cynaropicrin (2) and janerin (3). The structure elucidation of
      1-3 was based on (1)H and (13)C NMR data, mainly 2D-NMR (1)H-(1)H COSY and (1)H
      (13)C HETCOR experiments. Compounds 1-3 showed in vitro cytotoxic activity
      against human cancer cell lines of malignant melanoma (SK-MEL), epidermoid (KB),
      ductal (BT-549) and ovarian (SK-OV-3) carcinomas with IC(50) values of 2-6
      microgram/mL. In addition, 12 sesquiterpene lactones (4-15), isolated previously
      from the aerial parts of Vicoa pentanema, were evaluated for cytotoxic and
      antimicrobial activities. 2alpha- Acetoxy-3beta-hydroxyalantolactone (10) and
      8beta-hydroxyparthenolide (14) were found to be the main cytotoxic agents (IC(50)
      values of 2-6 microgram/mL against SK-MEL, BT-549 and SK-OV-3), while lactones 4,
      5, 11 and 15 selectively inhibited the growth of human malignant melanoma (IC(50)
      value of 3.6-7.3 microgram/mL). Cell aggregation and cell adhesion assays, using
      HL-60 and HeLa cell lines, evaluated the effect of cytotoxic constituents 1-3, 10
      and 14 on immune response and inflammation.

PMID- 12601683
TI  - Panax notoginseng (Burk.) effects on fibrinogen and lipid plasma level in rats
      fed on a high-fat diet.
AB  - Several studies have shown that notoginsenoides improve diastolic function in
      hypertensive subjects, induce the fibrinolytic system in in vitro models and act
      as antiproliferative agents on vessel leiomyocytes. Our aim was to evaluate their
      effect on fibrinogen and lipid plasma levels compared with a well-known HMGCoA
      reductase inhibitor. Seventy Wistar male adult rats on a fat-enriched diet were
      treated orally with P. notoginseng pulverized root (43 mg/kg/day or 86 mg/kg/day;
      20 animals per group), fluvastatin (3 mg/kg/day; 20 animals) or physiological
      saline (5 mL/kg/day; 10 animals). The ten rats on a normocaloric diet were also
      treated with 5 mL/kg/day of physiological saline. After a 28-day treatment, the
      rats were killed and their blood analysed with standard procedures. Treatment
      with 43 mg/kg/day of P. notoginseng or 3 mg/kg/day of fluvastatin showed similar
      activity in decreasing total cholesterol (-23.70%, -19.29%, respectively) and
      triglycerides (-21.59%, -18.55%). The most evident effect of P. notoginseng was
      the reduction of fibrinogenaemia in treated rats compared with the control values
      (-38.10%; p < 0.001), no dose-relationship being shown in this effect. Moreover,
      no significant variation in HDL cholesterol and glucose levels was observed nor
      did relevant behavioural changes occur in association with the root intake.
      Besides a moderate, non dose-related decrease in the plasma lipid levels, P.
      notoginseng appeared to induce a significant reduction in the rat
      fibrinogenaemia.

PMID- 12601684
TI  - A new bioactive steroidal saponin from Sansevieria cylindrica.
AB  - A new steroidal saponin was isolated from the leaves of Sansevieria cylindrica.
      Its structure was established as (3beta,12beta,15alpha,25S)-26-(beta-D
      glucopyranosyloxy)-22-hydroxyfurost-5-en-3-yl 12-O- (6-deoxy-alpha-L
      mannopyranosyl)-15-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside. The
      structural identification was performed using detailed analyses of (1)H and (13)C
      NMR spectra including 2D NMR spectroscopic techniques (COSY, HETCOR, HMBC and
      HMQC) and chemical conversions. The steroidal saponin showed no haemolytic
      effects in the in vitro assays and demonstrated inhibition of the capillary
      permeability activity.

PMID- 12601685
TI  - The in vivo antifungal activity of the aqueous extract from Nigella sativa seeds.
AB  - The effect of an aqueous extract of Nigella sativa seeds was studied on
      candidiasis in mice. An intravenous inoculum of Candida albicans produced
      colonies of the organism in the liver, spleen and kidneys. Treatment of mice with
      the plant extract (6.6 mL/kg equivalent to 5 mg of estimated protein, once daily
      for 3 days) 24 h after the inoculation caused a considerable inhibitory effect on
      the growth of the organism in all organs studied. A 5-fold decrease in Candida in
      kidneys, 8-fold in liver and 11-fold in spleen was observed in the groups of
      animals post-treated with the plant extract. Histopathological examination of the
      respective organs confirmed these findings. These results indicate that the
      aqueous extract of Nigella sativa seeds exhibits inhibitory effect against
      candidiasis and this study validates the traditional use of the plant in fungal
      infections.

PMID- 12601686
TI  - Endothelium-dependent contraction of rat thoracic aorta induced by gallic acid.
AB  - The vascular effect of a component of hydrolysable tannins, gallic acid, was
      examined in isolated rat thoracic aorta. Gallic acid exerted a contractile effect
      on the phenylephrine- or prostaglandin F(2/alpha)-precontracted endothelium
      intact arteries. In endothelium-denuded arteries, the contractile response to
      gallic acid was absent. Pretreatment with N(G)-nitro-L-arginine methyl ester (30
      microM) abolished the gallic acid-induced contraction. Pretreatment with
      indomethacin (10 microM) or BQ610 (100 nM) had no observed effect. Pretreatment
      with gallic acid (1-10 microM) significantly attenuated the relaxation induced by
      acetylcholine, and that with 10 microM gallic acid also reduced the potency of
      sodium nitroprusside in the relaxation, without a reduction in efficacy, in
      endothelium-denuded arteries. These findings indicate that gallic acid induced
      endothelium-dependent contraction and strongly inhibited the endothelium
      dependent relaxation rather than the endothelium-independent relaxation, probably
      through inhibition of endothelial nitric oxide (NO) production. Since NO plays an
      important role in vasodilative regulation and inflammatory disorders, these
      findings may also indicate that gallic acid interferes with the inflammatory
      responses.

PMID- 12601687
TI  - Antifungal, antioxidant and larvicidal activities of compounds isolated from the
      heartwood of Mansonia gagei.
AB  - Eleven compounds isolated from the heartwood of Mansonia gagei were tested for
      their antifungal activities against Cladosporium cucumerinum and Candida
      albicans, as well as for their larvicidal activities against Aedes aegypti and
      radical scavenging properties in a DPPH assay. Mansonone C (4) was found to be
      the most interesting compound with antifungal activities against Cladosporium
      cucumerinum and Candida albicans as well as for its larvicidal properties against
      Aedes aegypti. Mansonone E (5) was active against Cladosporium cucumerinum and
      Candida albicans. Two coumarin derivatives, mansorin A (1) and mansorin B (2)
      were also found to be active against Cladosporium cucumerinum, while mansonone N
      (9) was the only isolated product to show radical scavenging properties.

PMID- 12601688
TI  - Screening of some Greek aromatic plants for antioxidant activity.
AB  - The role of antioxidants in preventing oxygen radical and hydrogen peroxide
      induced cytotoxicity and tissue damage in various human diseases is increasingly
      recognized. In this study the in vitro antioxidant activity of the ethanol
      extracts obtained from 21 aromatic plants belonging to the Lamiaceae family was
      investigated. Of the extracts tested, those of Salvia ringens, Salvia pomifera,
      Stachys spruneri, Origanum dictamnus, Phlomis lanata, Ballota pseudodictamnus,
      Ballota acetabulosa, Teucrium polium, Calamintha glandulosa and Micromeria graeca
      exhibited the same activity as alpha-tocopherol.

PMID- 12601689
TI  - Backbone dynamics of dynein light chains.

PMID- 12601690
TI  - Expression of WASP and Scar1/WAVE1 actin-associated proteins is differentially
      modulated during differentiation of HL-60 cells.
AB  - The Wiskott-Aldrich Syndrome (WAS) is a disease associated with mutations in the
      WAS gene and characterised by developmental defects in haematopoietic cells such
      as myeloid cells. The Wiskott-Aldrich Syndrome protein (WASP)-family includes
      Scar1 and WASP, which are key regulators of actin reorganization in motile cells.
      To understand the roles of Scar1 and WASP in myeloid cells and their cytoskeletal
      control in haematopoietic tissues, we have explored their expression during
      differentiation of the promyeloid cell line HL-60. Undifferentiated HL-60 cells
      expressed Scar1 and WASP, and differentiation to neutrophils, induced by retinoic
      acid or non-retinoid agent treatments, led to a decrease in the level of
      expression of Scar1, whereas WASP expression was unaffected. Differentiation to
      monocytes/macrophages, induced by phorbol ester treatment, resulted in a
      decreased expression of both proteins in the adherent mature cells. Vitamin D(3)
      treatment or cytochalasin D in combination with PMA treatment did not affect WASP
      expression suggesting that adhesion and cytoskeletal integrity were both
      essential to regulate WASP expression. Scar1 expression was regulated by
      differentiation, adhesion, and cytoskeletal integrity. Recently, WASP was found
      to colocalize with actin in the podosomes. In contrast, we show here that Scar1
      did not localize with the podosomes in mature monocytes/macrophages. These
      observations show for the first time that modulation of Scar1 and WASP expression
      is a component of the differentiation program of myeloid precursors and indicate
      that WASP and Scar1 have different roles in mature myeloid cells.

PMID- 12601691
TI  - Calyculin A-induced actin phosphorylation and depolymerization in renal
      epithelial cells.
AB  - This study reports actin phosphorylation and coincident actin cytoskeleton
      alterations in renal epithelial cell line, LLC-PK1. Serine phosphorylation of
      actin was first observed in vitro after the cell lysate was incubated with
      phosphatase inhibitors and ATP. Both the phosphorylated actin and actin kinase
      activities were found in the cytoskeletal fraction. Actin phosphorylation was
      later detected in living LLC-PK1 cells after incubation with the phosphatase
      inhibitor calyculin A. Calyculin A-induced actin phosphorylation was associated
      with reorganization of the actin cytoskeleton, including net actin
      depolymerization, loss of cell-cell junction and stress fiber F-actin filaments,
      and redistribution of F-actin filaments in the periphery of the rounded cells.
      Actin phosphorylation was abolished by 3-h ATP depletion but not by the non
      specific kinase inhibitor staurosporine. These results demonstrate that renal
      epithelial cells contain kinase/phosphatase activities and actin can be
      phosphorylated in LLC-PK1 cells. Actin phosphorylation may play an important role
      in regulating the organization of the actin cytoskeleton in renal epithelium.

PMID- 12601692
TI  - Entropy and information in flagellar axoneme cybernetics: a radial spokes
      integrative function.
AB  - Radial spokes and the consequences of their relationships with the central
      apparatus seem to play a very important role in the regulation of axonemal
      activity. We modeled their behavior and observed that it appears to differ in the
      cilium and the flagellum with respect to the development of bending as a function
      of time. Specifically, our calculation raises the question of the real function
      of the radial spokes in the regulation of the axoneme, because a given curvature
      of the flagellar axoneme may correspond to two opposite of their tilts. The
      stable nil/low amplitude shear points that we had characterized along the
      flagellum allowed us to describe their axoneme as a series of modules [Cibert,
      2002: Cell Motil. Cytoskeleton 51:89-111]. We observed that a nil/low shearing
      point moves along each module during beating when a new bend is created at the
      base of the flagellum [Cibert, 2001: Cell Motil. Cytoskeleton 49:161-175]. We
      propose that the structural gradients of isoforms of tubulin could be basic
      verniers that act as structural references for the axonemal machinery during the
      beating. This allowed us to interpret the axonemal organization as a segmented
      structure, that could be analyzed according to the complexion(1) theory and
      Shannon's information theory, which associate entropy and probability in the
      creation of information. The important consequence of this interpretation is that
      regulation of the axonemal machinery appears to be due to the upstream and
      downstream cross-talk between the axonemal segments that do not involve any
      dedicated integrative structure but depend on the energy level of the entire
      length of each module.

PMID- 12601694
TI  - Treating psychogenic nonepileptic seizures: easier said than done.

PMID- 12601693
TI  - Muscle-specific microtubule-associated protein 4 is expressed early in myogenesis
      and is not sufficient to induce microtubule reorganization.
AB  - The expression of a muscle-specific variant of microtubule-associated protein 4
      (mMAP4) has been analyzed during myogenesis of C(2)C(12) cells using an isoform
      specific antibody. MMAP4 localizes to microtubules (MTs) and is expressed prior
      to a very early morphogenetic event, the formation of mononucleate spindle-shaped
      cells. MMAP4 protein appears at about the same time as titin and coincident with
      Golgi reorganization, but antedates myosin expression. Misexpression of EGFP
      mMAP4 in non-muscle and proliferating C(2)C(12) cells does not induce dramatic
      changes in MT organization or stability, nor in Golgi organization. Expression of
      full-length mMAP4 or of a truncated form lacking the MT-binding domain does not
      disrupt myotube formation or myofibrillogenesis. While previous antisense studies
      indicated that mMAP4 is necessary for normal myotube formation [Mangan and
      Olmsted, 1996: Development 122:771-781], these data indicate mMAP4 is not
      sufficient to induce the reorganization of MTs or the Golgi into patterns typical
      of muscle cells. Thus, with respect to MT organizing properties, this tissue
      specific variant differs from related neuronal MAPs, MAP2, and tau, which induce
      neural-like changes in MT organization.

PMID- 12601695
TI  - Implications of neuroimaging for the treatment of epilepsy.

PMID- 12601696
TI  - Progesterone, neurosteroids, and the hormonal basis of catamenial epilepsy.

PMID- 12601697
TI  - Neurotrophic cross-talk between the nervous and immune systems: implications for
      neurological diseases.
AB  - Inflammatory reactions in the central nervous system usually are considered
      detrimental, but recent evidence suggests that they also can be beneficial and
      even have neuroprotective effects. Intriguingly, immune cells can produce various
      neurotrophic factors of various molecular families. The concept of
      "neuroprotective immunity" will have profound consequences for the pathogenesis
      and treatment of neuroinflammatory diseases such as multiple sclerosis. It also
      will prove important for neurodegenerative disorders, in which inflammatory
      reactions often occur. This review focuses on recent findings that immune cells
      produce brain-derived neurotrophic factor in multiple sclerosis lesions, whereas
      neurons and astrocytes express the appropriate tyrosine kinase receptor TrkB.
      Together with functional evidence for the neuroprotective effects of immune
      cells, these observations support the concept of "neuroprotective immunity." We
      next examine current and future therapeutic strategies for multiple sclerosis and
      experimental autoimmune encephalomyelitis in light of neuroprotective immunity
      and finally address the broader implications of this new concept for other
      neuroinflammatory and neurodegenerative diseases.

PMID- 12601698
TI  - Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164
      patients.
AB  - Our knowledge of longer term outcome in psychogenic nonepileptic seizures (PNESs)
      patients is limited; we know less still about factors predicting prognosis. This
      study was intended to describe outcome in a large cohort and to identify
      predictive clinical and psychological factors to generate new ideas for
      treatment. One hundred sixty-four adult patients with PNESs (66.7%) responded to
      outcome, personality, and psychosymptomatology questionnaires (Dimensional
      Assessment of Personality Pathology-Basic Questionnaire [DAPP-BQ], Dissociative
      Experiences Scale, and Screening Test for Somatoform Symptoms) a mean of 11.9
      years after manifestation and 4.1 years after diagnosis of PNES. Additional
      clinical data were retrieved from hospital records. The responses showed that
      71.2% of patients continued to have seizures and 56.4% were dependent on social
      security. Dependence increased with follow-up. Outcome was better in patients
      with greater educational attainments, younger onset and diagnosis, attacks with
      less dramatic features, fewer additional somatoform complaints, and lower
      dissociation scores. Better outcome was associated with lower scores of the
      higher order personality dimensions "inhibitedness," "emotional dysregulation,"
      and "compulsivity" but not "dissocial behavior" (DAPP-BQ). Outcome in PNESs is
      poor but variable. Clinical and personality factors can be used to provide an
      individualized prognosis. By generating a patient-specific profile, they show
      particular maladaptive traits or tendencies that can identify goals for
      psychological therapy.

PMID- 12601699
TI  - Progressive neocortical damage in epilepsy.
AB  - Our objective was to determine the pattern and extent of generalized and focal
      neocortical atrophy that develops in patients with epilepsy and the factors
      associated with such changes. As part of a prospective, longitudinal follow-up
      study of 122 patients with chronic epilepsy, 68 newly diagnosed patients, and 90
      controls, serial magnetic resonance imaging scans were obtained 3.5 years apart.
      Image subtraction was used to identify diffuse and focal neocortical change that
      was quantified with a regional brain atlas and a fully automated segmentation
      algorithm. New focal or generalized neocortical volume losses were identified in
      54% of patients with chronic epilepsy, 39% of newly diagnosed patients and 24% of
      controls. Patients with chronic epilepsy were significantly more likely to
      develop neocortical atrophy than control subjects. The increased risk of cerebral
      atrophy in epilepsy was not related to a history of documented seizures. Risk
      factors for neocortical atrophy were age and multiple antiepileptic drug
      exposure. Focal and generalized neocortical atrophy commonly develops in chronic
      epilepsy. Neocortical changes seen in a quarter of our control group over 3.5
      years were likely to reflect physiological changes. Our results show that ongoing
      cerebral atrophy may be widespread and remote from the putative epileptic focus,
      possibly reflecting extensive networks and interconnections between cortical
      regions.

PMID- 12601700
TI  - Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.
AB  - Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia
      because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the
      pathophysiological mechanisms underlying their motor coordination deficits remain
      to be elucidated. Here, we show that application of IgG purified from the
      patients' serum to cerebellar slices of mice acutely reduces the basal activity
      of Purkinje cells, whereas application to the flocculus of mice in vivo evokes
      acute disturbances in the performance of their compensatory eye movements. In
      addition, the mGluR1-Abs block induction of long-term depression in cultured
      mouse Purkinje cells, whereas the cerebellar motor learning behavior of the
      patients is affected in that they show impaired adaptation of their saccadic eye
      movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic
      cerebellar ataxia patient showed that the number of Purkinje cells was
      significantly reduced by approximately two thirds compared with three controls.
      We conclude that autoantibodies against mGluR1 can cause cerebellar motor
      coordination deficits caused by a combination of rapid effects on both acute and
      plastic responses of Purkinje cells and chronic degenerative effects.

PMID- 12601701
TI  - Chronic hydrocephalus in rats and humans: white matter loss and behavior changes.
AB  - Chronic hydrocephalus that begins in childhood and progresses only very gradually
      is sometimes called "arrested" hydrocephalus. Data suggest that this state
      eventually can become symptomatic and may be treatable by shunting. However, the
      pathological substrate of the disorder is not entirely understood. We studied
      chronic hydrocephalus in rats, 9 months after induction by kaolin injection into
      the cisterna magna, and in humans. In both circumstances, destruction of
      periventricular white matter structures was worst in those with the largest
      ventricles. Structures damaged include the corpus callosum, corticospinal tract,
      and fimbria/fornix projections from the hippocampus. Myelin turnover was
      increased. These changes were associated with deficits of motor and cognitive
      function. The cerebral cortex was largely spared. There appears to be a threshold
      of ventricle size beyond which functional changes manifest, but this undoubtedly
      is modified by factors such as age of onset and rate of enlargement. These data
      support the need for persistent follow-up of patients with chronic, apparently
      stable hydrocephalus. A slight increase in size of already enlarged ventricles
      might cause significant axonal damage.

PMID- 12601702
TI  - Autoantigen diversity in the opsoclonus-myoclonus syndrome.
AB  - Despite circumstantial evidence that opsoclonus-myoclonus (OM) is often immune
      mediated, no specific autoantigen has been identified. Using sera of 21 patients
      with several types of OM (idiopathic, associated to small cell lung cancer, and
      associated to neuroblastoma), we probed a brainstem cDNA library to isolate
      target neuronal antigens. Thirty-seven clones coding for 25 proteins were
      isolated, with two groups of autoantigens emerging: (1) proteins of the
      postsynaptic density, among them the adenomatous polyposis coli, and 2) proteins
      with expression or function restricted to neurons, including RNA or DNA-binding
      proteins and zinc-finger proteins. Usually, each patient's serum recognized a
      different autoantigen, except for adenomatous polyposis coli that was recognized
      by sera of two patients with idiopathic OM and two control patients with
      nystagmus, diplopia, and paraneoplastic brainstem dysfunction. Overall, in the
      indicated types of OM, (1) we found frequent and heterogeneous immunity to
      neuronal autoantigens without a single specific antibody marker of OM, (2) the
      occasional detection of antibodies to known onconeuronal antigens (ie, Hu
      proteins) probably is related to cancer-induced immunity rather than to OM, and
      (3) the postsynaptic density is a frequent source of novel autoantigens, with
      several proteins of this complex targeted by antibodies of OM patients.

PMID- 12601704
TI  - Mu opioid receptors and analgesia at the site of a peripheral nerve injury.
AB  - Opioid ligands may exert antinociception through receptors expressed on
      peripheral afferent axons. Whether local opioid receptors might attenuate
      neuropathic pain is uncertain. In this work, we examined the function and
      expression of local mu opioid receptors (MORs) associated with the chronic
      constriction injury (CCI) model of sciatic neuropathic pain in rats. Low-dose
      morphine or its carrier were percutaneously superfused over the CCI site with the
      injector blinded to the identity of the injectate. Morphine, but not its carrier,
      and not equimolar systemic doses of morphine reversed thermal hyperalgesia in a
      dose-related, naloxone-sensitive fashion. Moreover, analgesia was conferred at
      both 48 hours and 14 days after CCI, times associated with very different stages
      of nerve repair. Equimolar local DAGO ([D-Ala2, N-Me-Phe4, Gly5-(ol)]
      enkephalin), a selective MOR ligand, provided similar analgesia. Local morphine
      also attenuated mechanical allodynia. MOR protein was expressed in axonal
      endbulbs of Cajal just proximal to the injury site, in aberrantly regenerating
      small axons in the epineurial sheath around the CCI site and in residual small
      axons distal to the CCI lesion. Sensory neurons ipsilateral to CCI had an
      increase in the proportion of neurons expressing MOR. We suggest that local MOR
      expressed in axons may be exploited to modulate some forms of neuropathic pain.

PMID- 12601703
TI  - Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.
AB  - Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the
      major myelin proteins in the CNS, but are also expressed in the PNS. The proteins
      have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific
      domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher
      Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy.
      To identify which mutations cause neuropathy, we have evaluated a cohort of
      patients with PMD and PLP1 mutations for the presence of neuropathy. As shown
      previously, all patients with PLP1 null mutations had peripheral neuropathy. We
      also identified 4 new PLP1 point mutations that cause both PMD and peripheral
      neuropathy, three of which truncate PLP1 expression within the PLP1-specific
      domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1
      and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to
      produce proteins with an intact PLP1-specific domain do not cause peripheral
      neuropathy. Sixty-one individuals with PLP1 duplications also had normal
      peripheral nerve function. These data demonstrate that expression of PLP1 but not
      DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1
      specific domain plays an important role in normal peripheral nerve function.

PMID- 12601705
TI  - Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23.
AB  - Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder
      characterized by episodes of transient hemiparesis followed by headache. Two
      chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on
      chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated
      calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28
      cM, hence hampering the identification of the responsible gene. Here, we report
      the FHM2 locus refining by linkage analysis on two large Italian families
      affected by pure FHM. The new critical region covers a small area of 0.9Mb in
      1q23 and renders feasible a positional candidate approach. By mutation analysis,
      we excluded the calsequestrin and two potassium channel genes mapping within the
      narrowed FHM2 locus.

PMID- 12601706
TI  - Epileptiform ictal discharges are prevented by periodic interictal spiking in the
      olfactory cortex.
AB  - Interictal potentials are commonly observed between seizures in human epilepsies
      and in animal models of epilepsy. It is uncertain whether interictal spiking in
      partial epilepsies is causally related with the onset of an ictal discharge. To
      analyze the reciprocal correlation between interictal and ictal epileptiform
      events, we performed extracellular recordings in the limbic system of the in
      vitro isolated guinea pig brain preparation. Arterial perfusion of bicuculline
      (50 microM) in vitro consistently induced a focal ictal discharge in the
      hippocampal-entorhinal region that in one third of the experiments was associated
      with periodic interictal spikes in the piriform cortex. In the absence of active
      interictal spiking, the piriform cortex was secondarily invaded by the ictal
      discharge initiated in the hippocampal-entorhinal region, whereas no secondary
      ictal entrainment was observed in the presence of periodic piriform cortex spikes
      at circa 0.1 to 0.2 Hz. Similarly, ictal events never occurred when arterial
      perfusion of bicuculline was preceded by a local injection of the same drug in
      the piriform cortex, a procedure that induces a sustained interictal spiking. A
      reduced responsiveness to incoming paroxysmal discharges generated in the
      hippocampus was observed during the interval between two interictal spikes in the
      piriform cortex.

PMID- 12601707
TI  - Seizure exacerbation associated with inhibition of progesterone metabolism.
AB  - The reduced progesterone metabolite tetrahydroprogesterone is a potent positive
      modulator of GABA(A) chloride conductance that exerts powerful neuroinhibitiory
      and anti-seizure effects in animal models. Cyclic natural progesterone use may
      lessen seizure frequency in women with catamenial seizure exacerbation. We report
      a case in which efficacy was eliminated during concomitant treatment with a
      reductase inhibitor. The observation suggests that a reduced metabolite, rather
      than progesterone itself, was responsible for improved seizure control.

PMID- 12601708
TI  - A new mutation of the fukutin gene in a non-Japanese patient.
AB  - Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome, and
      muscle-eye-brain disease are clinically similar autosomal recessive disorders
      characterized by congenital muscular dystrophy, cobblestone lissencephaly, and
      eye anomalies. FCMD is frequent in Japan, but no FCMD patient with confirmed
      fukutin gene mutations has been identified in a non-Japanese population. Here, we
      describe a Turkish CMD patient with severe brain and eye anomalies. Sequence
      analysis of the patient's DNA identified a homozygous 1bp insertion mutation in
      exon 5 of the fukutin gene. To our knowledge, this is the first case worldwide in
      which a fukutin mutation has been found outside the Japanese population. This
      report emphasizes the importance of considering fukutin mutations for diagnostic
      purposes outside of Japan.

PMID- 12601709
TI  - Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function
      mechanism.
AB  - Autosomal dominant partial epilepsy with auditory features (ADPEAF) is a
      genetically heterogeneous disorder. Some patients exhibit mutations in the
      leucine-rich glioma inactivated (LGI1) gene. In an ADPEAF family, a novel
      mutation in the Lgi1 signal peptide is predicted to interfere with the protein
      cell sorting, resulting in altered processing. This finding suggests a loss-of
      function mechanism for LGI1 gene mutations causing ADPEAF even if other
      mechanisms cannot be ruled out.

PMID- 12601711
TI  - Cerebral neurogenesis is induced by intranasal administration of growth factors.
AB  - Neurogenesis persists in the adult brain, where it may contribute to repair and
      recovery after injury, but the lack of methods for noninvasive stimulation of
      cerebral neurogenesis limits its potential for clinical application. We report
      that intranasal administration of either fibroblast growth factor-2 or heparin
      binding epidermal growth factor-like growth factor increases neurogenesis,
      measured by the incorporation of bromodeoxyuridine into cells that express the
      early neuronal marker protein doublecortin in the subventricular zone of mouse
      brain. These findings indicate that intranasal growth factors may have potential
      as neurogenesis-promoting therapeutic agents.

PMID- 12601710
TI  - CMT4A: identification of a Hispanic GDAP1 founder mutation.
AB  - Mutations of the ganglioside-induced differentiation-associated protein 1 gene
      (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report
      four additional families with recessive mutations (487C-->T, Q163X; 359G-->A,
      R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the
      same haplotype suggesting a Spanish founder mutation. Both the Q163X and the
      R120Q mutation cause demyelination and axonal loss. The patients had symptoms
      within the first two years of life and involvement of cranial, sensory, and
      enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb
      formations and focal folding of the outer myelin lamina.

PMID- 12601712
TI  - PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease.
AB  - We analyzed the PRNP M129V polymorphism in a Dutch population-based early-onset
      Alzheimer's disease sample. We observed a significant association between early
      onset Alzheimer's disease and homozygosity of M129V (odds ratio [OR], 1.9; 95%
      confidence interval [CI], 1.1-3.3; p = 0.02) with the highest risk for V
      homozygotes (OR, 3.2; 95% CI, 1.4-7.1; p < 0.01). In patients with a positive
      family history, these risks increased to 2.6 (95% CI, 1.3-5.3; p < 0.01) and 3.5
      (95% CI, 1.3-9.3; p = 0.01), respectively.

PMID- 12601713
TI  - Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI
      study.
AB  - Twelve patients with refractory temporal lobe epilepsy and unilateral hippocampal
      sclerosis had repeat volumetric magnetic resonance imaging scans after a mean of
      3.4 years to determine whether progressive hippocampal volume loss occurred.
      Seizure-free patients showed no change in hippocampal volume. Patients with
      continuing seizures had a decline in ipsilateral hippocampal volume that
      correlated with seizure frequency. Patients with medically refractory temporal
      lobe epilepsy and unilateral hippocampal sclerosis have progressive hippocampal
      atrophy.

PMID- 12601714
TI  - Indifference rather than insensitivity to pain.

PMID- 12601716
TI  - Overlap of optic neuritis and anterior ischemic optic neuropathy.

PMID- 12601718
TI  - Peripheral biomarkers of oxidative damage in Alzheimer's disease.

PMID- 12601720
TI  - Familial dementia with dentate atrophy and failure of neurogenesis.

PMID- 12601724
TI  - Separation of proteins in a multicompartment electrolyzer with chambers defined
      by a bed of gel beads.
AB  - Multicompartment electrolyzers (MEs) with isoelectric membranes were introduced
      in 1989 for purifying proteins in an electric field. At the basis of ME
      technology there are membranes consisting of cross-linked copolymers of
      acrylamide and acrylamido monomers bearing protolytic groups. The technology
      employed for casting the membranes is an extension of the isoelectric focusing in
      immobilized pH gradient technique for which specific acrylamido monomers, known
      with the trade name of Immobiline, have been developed. However, the use of
      continuous membranes presents several disadvantages. Due to the mechanical
      characteristics of polyacrylamide, the gel must physically adhere onto a rigid
      support, which prevents it from collapsing. The support must have a highly porous
      structure in order to be permeable to proteins. The mechanical fragility of the
      membranes is one of the main problems that hinders the industrial scale
      application of ME separators. In order to overcome this problem, we propose to
      substitute the continuous membranes with a bed of gel beads of identical
      comonomer composition, obtained by an inverse emulsion polymerization process.

PMID- 12601725
TI  - Rapid high-resolution electrophoresis of multimeric von Willebrand Factor using a
      thermopiloted gel apparatus.
AB  - Rapid and highly reproducible nonreducing agarose gel electrophoresis (NRAGE) of
      von Willebrand Factor (vWF) multimers was performed using a thermostated minigel
      apparatus that monitors and precisely controls internal gel temperature. The
      substitution of lithium dodecyl sulfate (LiDS) for sodium dodecyl sulfate (SDS)
      allowed electrophoresis to be performed below the 16 degrees C Krafft point of
      SDS and facilitated NRAGE of vWF over the entire range of 0-35 degrees C.
      Internal gel temperature was regulated by a thermocouple probe inserted directly
      into the gel during electrophoresis which interfaced with a thermopilot that
      continually measures and adjusts temperature to within +/- 0.5 degrees C. At 10
      degrees C operative temperature, NRAGE at 1.5% agarose concentration was
      completed in 20 min at 250 V. Electrophoresis could be performed in only 10 min
      at 500 V, but at such high voltages, localized temperature fluctuations as much
      as 6 degrees C resulted in perturbation of banding patterns in those vicinities.
      In the optimized method, both high molecular weight multimers and proteolytic
      fragments of vWF were separable suggesting clinical applicability of this system
      for the diagnosis of von Willebrand Disease and thrombotic thrombocytopenic
      purpura.

PMID- 12601727
TI  - Fluorescence detection and quantitation of recombinant proteins containing
      oligohistidine tag sequences directly in sodium dodecyl sulfate-polyacrylamide
      gels.
AB  - Two fluorophore-nitrilotriacetic acid conjugates, Pro-Q Sapphire 365 and Pro-Q
      Sapphire 488 oligohistidine gel stains, have been developed for the fluorescence
      detection of fusion proteins containing oligohistidine tags directly in sodium
      dodecyl sulfate polyacrylamide gels, without the requirement for electroblotting,
      reporter enzymes or secondary detection reagents. Pro-Q Sapphire 365
      oligohistidine gel stain exhibits bright-blue fluorescence (emission maximum =
      450 nm) when illuminated with UV-A or UV-B light from a standard ultraviolet
      transilluminator. Pro-Q Sapphire 488 oligohistidine gel stain exhibits bright
      green fluorescence (emission maximum = 515 nm) when illuminated with visible
      light from a laser-based gel scanner equipped with a 470 nm second-harmonic
      generation (SHG) or 488 nm argon-ion laser source. Typically, 25-65 ng of
      oligohistidine-tagged fusion protein in whole cell lysates is detectable using
      either stain. After documenting the fluorescence signal from the Pro-Q Sapphire
      dyes, gels may be post-stained with the red-fluorescent SYPRO Ruby protein gel
      stain in order to reveal the total protein pattern.

PMID- 12601726
TI  - Detection of glycoproteins in polyacrylamide gels and on electroblots using Pro-Q
      Emerald 488 dye, a fluorescent periodate Schiff-base stain.
AB  - Pro-Q Emerald 488 glycoprotein stain reacts with periodic acid-oxidized
      carbohydrate groups, generating a bright green-fluorescent signal on
      glycoproteins. The stain permits detection of less than 5-18 ng of glycoprotein
      per band, depending upon the nature and the degree of protein glycosylation,
      making it roughly 8-16-fold more sensitive than the standard colorimetric
      periodic acid-Schiff base method using acidic fuchsin dye (pararosaniline). The
      green-fluorescent signal from Pro-Q Emerald 488 stain may optimally be visualized
      using charge-coupled device/xenon arc lamp-based imaging systems or 470-488 nm
      laser-based gel scanners. Though glycoprotein detection may be performed on
      transfer membranes, direct detection in gels avoids electroblotting and the
      specificity of staining is better in gels. After detecting glycoproteins with Pro
      Q Emerald 488 dye, total protein profiles may subsequently be detected using
      SYPRO Ruby protein gel stain. Using computer-assisted registration techniques,
      images may then be merged to generate differential display maps.

PMID- 12601728
TI  - Microscale analysis of mucin-type O-glycans by a coordinated fluorophore-assisted
      carbohydrate electrophoresis and mass spectrometry approach.
AB  - The total glycan moiety was released in a single step from native glycoproteins
      by a nonreductive beta-elimination procedure. The generated oligosaccharides were
      further derivatized either with the hydrophobic fluorophore 2-aminoacridone
      (AMAC) or the charged 8-aminonaphthalene-1,3,6-trisulfonic acid (ANTS)
      fluorophore, and the resulting fluorescent derivatives were separated according
      to their hydrodynamic size or charge with high-resolution gel electrophoresis.
      Both N- and O-glycans released by this beta-elimination procedure might be
      analyzed simultaneously. AMAC derivatization allows a rapid separation of neutral
      and charged oligosaccharides without prior fractionation. Derivatized
      oligosaccharide species were then eluted from the gel slices and analyzed by mass
      spectrometry. This methodology allowed the rapid structural characterization of
      each glycan in term of monosaccharide composition and sequence. Using this
      technique we were able to screen several heterogeneous O-glycan mixtures isolated
      at the picomolar range from reference glycoproteins or mucins.

PMID- 12601729
TI  - Congruence between starch gel and polyacrylamide gel electrophoresis in detecting
      allozyme variation in pulmonate land slugs.
AB  - The predominantly selfing slug species Arion (Carinarion) fasciatus, A. (C.)
      silvaticus and A. (C.) circumscriptus are native in Europe and have been
      introduced into North America, where each species consists of a single,
      homozygous multilocus genotype (strain), as defined by starch gel electrophoresis
      (SGE) of allozymes. In Europe, the "one strain per species" hypothesis does not
      hold since polyacrylamide gel electrophoresis (PAGE) of allozymes uncovered 46
      strains divided over the three species. However, electrophoretic techniques may
      differ in their ability to detect allozyme variation. Therefore, several
      Carinarion populations from both continents were screened by applying the two
      techniques simultaneously on the same individual slugs and enzyme loci. SGE and
      PAGE yielded exactly the same results, so that the different degree of variation
      in North American and European populations cannot be attributed to differences in
      resolving power between SGE and PAGE. We found four A. (C.) silvaticus strains in
      North America indicating that in this region the "one strain per species"
      hypothesis also cannot be maintained. Hence, the discrepancies between previous
      electrophoretic studies on Carinarion are most likely due to sampling artefacts
      and possible founder effects.

PMID- 12601730
TI  - Sequence-specific and nonspecific mobilities of single-stranded oligonucleotides
      observed by changing the borate buffer concentration.
AB  - The suitability of gel electrophoresis to structural analysis of nucleic acids
      has been examined, using from borate buffer concentrations (in the range from 4.5
      to 450 mM. The gel electrophoretic mobility of single-stranded oligonucleotides
      was shown to be sequence-dependent at higher concentrations than 27 mM of borate
      buffer and nondependent at lower one (less than 9 mM). As a result, each
      dodecamer had a sequence-specific critical concentration of Tris-borate-EDTA
      (TBE) buffer at which each seems to change its structural state. At the lower
      concentration than the critical one, all the dodecamers turned to the state of a
      finite mobility and migrated in a sharp band. This finding is discussed and
      rationalized by the assumption that the difference in conformational dynamics of
      oligonucleotides, due to the difference in their sequence, is mainly responsible
      for the observed difference in their mobility.

PMID- 12601731
TI  - Detection of single-nucleotide polymorphisms coding for three ovine prion protein
      variants by primer extension assay and capillary electrophoresis.
AB  - An alternative method is described for the determination of ovine prion protein
      allelic variants at codon 136, 154, and 171. The four mutations responsible for
      amino acid changes are typed simultaneously. The technique utilizes dideoxy chain
      termination reaction using fluorescently labeled dideoxy nucleotides. The single
      base extended primers are resolved on a capillary electrophoresis instrument.
      Data obtained by our approach are presented according to genotype distribution in
      some breeds as a part of the validation procedure.

PMID- 12601732
TI  - Application of high-resolution capillary array electrophoresis with automated
      fraction collection for GeneCalling trade mark analysis of the yeast genomic DNA.
AB  - Capillary array instrument was applied to transcript profiling of the yeast
      genomic DNA using GeneCalling trade mark chemistry. The instrument integrated a
      12-capillary array for DNA separation with a replaceable sieving matrix, laser
      induced fluorescence detection and an automated microfraction collector. The DNA
      fractions, exiting the separation capillaries, were continuously deposited in a
      1536-well collection plate made of agarose gel. DNA fragments recovered from
      selected fractions were cloned and then sequenced. Over 80% of theoretically
      predicted fragments could be recovered in the collected fractions, cloned and
      sequenced with an average redundancy of threefold. Excellent correlation of the
      experimentally obtained sequences with the theoretically predicted gene fragments
      demonstrated the suitability of capillary array electrophoresis for
      micropreparative recovery of DNA fragments. This approach, useful especially for
      rapid DNA expression profiling of unknown genes for nonsequenced organisms,
      demonstrates the practical capability of the prototype multicapillary fraction
      collector.

PMID- 12601733
TI  - Simplex optimization of electrokinetic injection of DNA in capillary
      electrophoresis using dilute polymer solution.
AB  - In DNA analysis by capillary electrophoresis with polymer solutions there are
      many variables that can be optimized. However, electric field strength, polymer
      solution concentration and temperature of analysis are the most relevant ones.
      These are the variables most responsible for the fragment resolution and analysis
      time. Optimization of such parameters can be obtained simultaneously using
      chemometric techniques, reaching the optimum working conditions with few
      experiments. In this work, we have studied the influence of the sample
      composition and electrokinetic injection conditions in the reproducibility and
      the quality of the DNA separation results. A simplex optimization has been
      carried out and the optimum condition was reached with nine experiments.

PMID- 12601734
TI  - Detection of Escherichia coli O157:H7 bacteria by a combination of
      immunofluorescent staining and capillary electrophoresis.
AB  - As the number of incidents of bacterial infections continues to rise around the
      globe, simpler, faster, and more sensitive diagnostic techniques are required to
      improve the safety of the food supply and to screen for potential bacterial
      infections in humans. We present here direct and indirect approaches for the
      detection of bacteria, which are based upon a combination of immunofluorescent
      staining and capillary electrophoresis. In the direct approach, Escherichia coli
      O157:H7 bacteria stained with fluorescein-tagged specific antibodies are detected
      by CE, while in the indirect approach fluorescein-tagged specific antibodies to
      E. coli are first captured by E. coli O157:H7 bacteria and then released and
      detected by CE. We have identified suitable bacteria staining and CE protocols,
      which involved a 10 mM Tris-borate-EDTA (TBE) buffer, 0.25 micro g antibody/1
      million bacteria, and capillaries dynamically coated with poly-N
      hydroxyethylacrylamide (polyDuramide). We have also successfully detected the
      presence of E. coli O157:H7 in contaminated meat. The total time required for
      analysis was 6-8 h, which is less than that realized in most commercial assays
      presently available.

PMID- 12601735
TI  - Simultaneous separation of fifteen approved protease and reverse transcriptase
      inhibitors for human immunodeficiency virus therapy by capillary electrophoresis.
AB  - In the present investigation, a novel approach towards a complete separation of
      all 15 protease and reverse transcriptase inhibitors which are currently approved
      for use in highly active antiretroviral therapy in a single analytical run is
      presented. The developed method employs an acidic background electrolyte with
      sodium polyanethol sulfonate (SPAS) as polyanionic electroosmotic flow (EOF)
      modifier to establish a strong cathodic EOF, sodium dodecyl sulfate (SDS) as
      pseudostationary selector, and acetonitrile and ethanol as organic modifiers.
      Separation of the analytes is based on two different mechanisms. The more basic
      analytes are protonated at the prevailing pH conditions and thus migrate in front
      of the cathodic EOF, whereas the less basic and neutral analytes interact with
      the SDS and are retained after the EOF. By optimizing electrolyte pH, the amount
      of solvents and SDS concentrations in the background electrolyte it is possible
      to completely separate all compounds of interest.

PMID- 12601736
TI  - Separation of twenty underivatized essential amino acids by capillary zone
      electrophoresis with contactless conductivity detection.
AB  - Twenty underivatized essential amino acids were separated using capillary zone
      electrophoresis and consequently detected with contactless conductivity detection
      (CCD). A simple acidic background electrolyte (BGE) containing 2.3 M acetic acid
      and 0.1% w/w hydroxyethylcellulose (HEC) allowed the electrophoretic separation
      and sensitive detection of all 20 essential amino acids in their underivatized
      cationic form. The addition of HEC to the BGE suppressed both, electroosmotic
      flow and analyte adsorption on the capillary surface resulting in an excellent
      migration time reproducibility and a very good analyte peak symmetry.
      Additionally, the HEC addition significantly reduced the noise and long-term
      fluctuations of the CCD baseline. The optimized electrophoretic separation method
      together with the CCD was proved to be a powerful technique for determination of
      amino acid profiles in various natural samples, like beer, yeast, urine, saliva,
      and herb extracts.

PMID- 12601737
TI  - Differences in capillary electrophoresis profiles of urinary and recombinant
      erythropoietin.
AB  - Different profiles were obtained by capillary zone electrophoresis (CZE) of human
      erythropoietin (EPO) of recombinant and urinary origin. To unambiguously detect
      doping by EPO, direct methods able to determine the presence of the drug itself
      in a physiological fluid are required. Since the host cell line used for EPO
      production influences its glycosylation, the carbohydrate distribution of natural
      human EPO may be different from that of recombinant EPO. The different content in
      sialic acid groups between recombinant and endogenous EPO provide a basis for
      their distinction by CZE.

PMID- 12601738
TI  - Separation of homologues and isomers of linear alkylbenzenesulfonates by
      capillary electrophoresis with sodium dodecyl sulfate, carboxylic acids and bile
      salts.
AB  - The ability of several anionic compounds, including carboxylic and dicarboxylic
      acids, sodium dodecyl sulfate (SDS), and sodium deoxycholate (SDC) and other bile
      salts, to separate the C(10)-C(13) homologues and the corresponding 20 positional
      isomers of linear alkylbenzenesulfonates (LAS) by capillary electrophoresis was
      studied. Up to 19 peaks and a shoulder were observed with a background
      electrolyte (BGE) containing 10 mM phosphate (pH 6.8), 30% acetonitrile and 40 mM
      SDS, and 18 peaks were obtained with a BGE containing 10 mM borate (pH 9), 40%
      ethanol and 40 mM palmitic acid (PA). Resolution increased with the alkyl chain
      length of the carboxylic acid. Dicarboxylic acids with a short alkyl chain, as
      azelaic acid, were useful to separate the homologues without distinguishing
      between the isomers. Up to 16 peaks and a shoulder were distinguished with SDC.
      Resolution decreased with the other bile salts. The 6-C(11)/5-C(11) isomer pair
      was better resolved with SDC than with SDS, and the 2-C(12) isomer was isolated
      using both PA and SDC, but not with SDS. Only the 7-C(13)/6-C(13) pair could not
      be resolved with any of the discriminating agents used.

PMID- 12601739
TI  - Micellar electrokinetic chromatography with on-line Fourier transform infrared
      detection.
AB  - Micellar electrokinetic chromatography (MEKC) was successfully coupled to Fourier
      transform infrared (FTIR) detection, using a micromachined IR-transparent flow
      cell with an optical path length of 15 micro m for the on-line detection of five
      neutral analytes. Tight connections between the flow cell and the capillaries
      were achieved by creating a small O-ring of UV-curing epoxy adhesive on the
      sharply cut capillary ends. The background electrolyte consisted of 15 mM
      phosphate buffer at pH 7 and 40 mM sodium dodecyl sulfate (SDS). Five analytes
      (paracetamol, caffeine, p-nitro benzyl alcohol, m-nitrophenol and p-nitrophenol)
      were successfully separated, yielding detailed IR stack plots that could be used
      for quantification and identification. Linear calibration graphs were obtained
      for each individual analyte present in mixtures at concentrations up to 10 mM.
      The limit of detection (3 S/N) ranged between 1.1 and 1.5 mM (1.2-1.8 ng).
      Analytes were identified by comparing spectra obtained during the MEKC separation
      with those resulting from completely filling the capillary with each individual
      analyte dissolved in the micelle-containing electrolyte. Information on the
      specific functional groups of all analytes could be elucidated from the spectra.
      Since FTIR is a nondestructive detection technique, a conventional on-line UV
      detector was introduced directly after the developed IR flow cell to test the
      system's performance and to demonstrate that tandem FTIR and UV detection is
      feasible.

PMID- 12601740
TI  - Chromatographic behavior of packing materials for capillary electrochromatography
      with a coating of different immobilized polysiloxanes.
AB  - Octadecyl silyl silica (ODS) phase coated with immobilized polysiloxanes (OV1701,
      SE-54, SE-30) were synthesized, their characteristics as capillary
      electrochromatography (CEC) column packing materials were studied. It was found
      that, although the polysiloxane coatings were different in polarity, the
      resulting packing materials showed the highest efficiencies when the respective
      coating ratios (polysiloxane:ODS, w/w) were all 20-30%. As expected, packing
      materials coated with different polysiloxanes resulted in different selectivity
      on solute pairs. Separations on these stationary phases were studied with
      different factors such as pH values and acetonitrile contents of the mobile
      phases. It was found that all these kind of stationary phases could resist basic
      mobile phase with a pH value as high as 11.6. Tests were made to analyze polar,
      basic drugs with CEC using the stationary phases.

PMID- 12601741
TI  - Determination of low-aliphatic aldehydes indoors by micellar electrokinetic
      chromatography using sample dissolution manipulation for signal enhancement.
AB  - This work describes a novel approach for the analysis of selected aldehydes
      (formaldehyde, acetaldehyde, propionaldehyde, and acrolein) and acetone in
      environmental samples using micellar electrokinetic chromatography (MEKC). The
      method is based on the reaction of carbonyl compounds with 3-methyl-2
      benzothiazoline hydrazone (MBTH) that gives an azine intermediate with maximum
      absorbance at 216 nm. A systematic evaluation of sample dissolution medium was
      conducted as a means to enhancing sensitivity. In the best condition, samples
      were dissolved in 0.030 mol.L(-1) tetraborate solution. This condition presented
      enhancement factors in the range of 35-54 for the aldehydes under investigation,
      computed as the improvement of the concentration limits of detection (LODs) with
      reference to the sample dissolved in pure water. The running buffer was 0.020
      mol.L(-1) tetraborate, pH 9.3, containing 0.050 mol.L(-1) sodium dodecyly sulfate
      (SDS). The overall methodology presented several advantages over established
      methods for aldehydes. Worthy mentioning that MBTH is available in high purity
      degree, dispensing laborious reagent purification procedures. A few method
      validation parameters were determined revealing good migration time repeatability
      (< 2.5% coefficient of variation, CV) and area repeatability (< 4% CV), excellent
      linearity (20-120 micro g/L, r > 0.995) and adequate sensitivity for
      environmental applications. The LODs with respect to each single aldehyde were in
      the range of 0.54-4.0 micro g.L(-1) and 11 micro g.L(-1) for acetone. The
      methodology was applied to the determination of aldehydes indoors. Samples were
      collected in an impinger flask containing 0.05% MBTH solution, at a flow rate of
      0.80 L.min(-1), during 2.5 h, at different times during the day. The most
      abundant carbonyls in the samples were acetone, followed by formaldehyde and
      acetaldehyde, with estimate peak concentrations of 452, 5.2 and 2.2 ppbv,
      respectively.

PMID- 12601742
TI  - Mixed micellar electrokinetic capillary chromatography separation of
      depolymerized grape procyanidins.
AB  - Oligomeric procyanidins are potent antioxidant polyphenols of potential interest
      as disease-preventing agents. Their efficiency depends on the size and
      composition of their oligomeric structures. The mean degree of polymerization of
      these compounds is usually estimated by thiolysis with thiol-alpha-toluene
      followed by analysis using high-performance liquid chromatography (HPLC). We show
      the development of a mixed micellar electrokinetic chromatography (MEKC) method
      for the separation of the major components obtained after thiolysis with
      cysteamine (catechins and their cysteamine conjugates). MEKC studies using sodium
      dodecyl sulfate (SDS as pseudostationary phase led to long migration times, e.g.,
      with 100 mM SDS, at pH 7, the solutes were separated in about 40 min), while the
      use of sodium cholate (SC) produced an elution window relatively short. Using a
      mixed micellar SC-SDS system (50 mM phosphate at pH 7 containing 40 mM SC and 10
      mM SDS), it is possible to separate these compounds in less than 15 min. The
      proposed method is useful to separate the major components of the thiolysate in
      effluents from food processing (e.g., skins and seeds from grape and apple)
      considered as potential procyanidin sources.

PMID- 12601743
TI  - Ultrafast analysis of oligosaccharides on microchip with light-emitting diode
      confocal fluorescence detection.
AB  - We have developed a new method for the high-speed separation and high-sensitivity
      detection of complex oligosaccharides based on microchip electrophoresis (nu-CE)
      with light-emitting diode (LED) confocal fluorescence detection. Oligosaccharides
      labeled with 8-aminopyrene-1,3,6-trisulfonate (APTS) were found to strongly
      adsorb to the surface of polymethylmethacrylate (PMMA) microchips. Accordingly,
      three classes of major dynamic coating additives were systematically
      investigated, and cellulose derivatives were found to specifically suppress such
      adsorption and allow high-performance separation on PMMA chips. Additive
      concentration, buffer pH and applied field strength were found to be key factors
      in the high-performance separation& of APTS-labeled oligosaccharides on PMMA
      chips. Under optimal conditions, 15 oligosaccharides in dextrin hydrolysate can
      be separated within 45 s with an electrophoretic separation efficiency of over
      400 000 theoretical plates per meter. The relative standard deviation (RSD)
      values of migration times of fourteen oligosaccharides were less than 0.50%
      between six different channels, and the detection limit for APTS-labeled glucose
      was about 1.98 x 10(-8) mol/L or 8.61 amol with a signal-to-noise ratio (S/N) of
      3. The high speed, high efficiency and high sensitivity of this micro-CE-based
      method indicate that it can be widely applied to analysis of complex
      oligosaccharides.

PMID- 12601744
TI  - Microdevices for manipulation and accumulation of micro- and nanoparticles by
      dielectrophoresis.
AB  - Microfluidic devices with three-dimensional (3-D) arrays of microelectrodes
      embedded in microchannels have been developed to study dielectrophoretic forces
      acting on synthetic micro- and nanoparticles. In particular, so-called deflector
      structures were used to separate particles according to their size and to enable
      accumulation of a fraction of interest into a small sample volume for further
      analysis. Particle velocity within the microchannels was measured by video
      microscopy and the hydrodynamic friction forces exerted on deflected particles
      were determined according to Stokes law. These results lead to an absolute
      measure of the dielectrophoretic forces and allowed for a quantitative test of
      the underlying theory. In summary, the influence of channel height, particle
      size, buffer composition, electric field, strength and frequency on the
      dielectrophoretic force and the effectiveness of dielectrophoretic deflection
      structures were determined. For this purpose, microfluidic devices have been
      developed comprising pairs of electrodes extending into fluid channels on both
      top and bottom side of the microfluidic channels. Electrodes were aligned under
      angles varying from 0 to 75 degrees with respect to the direction of flow.
      Devices with channel height varying between 5 and 50 microm were manufactured.
      Fabrication involved a dedicated bonding technology using a mask aligner and UV
      curing adhesive. Particles with radius ranging from 250 nm to 12 microm were
      injected into the channels using aqueous buffer solutions.

PMID- 12601745
TI  - In-column field-amplified sample stacking of biogenic amines on microfabricated
      electrophoresis devices.
AB  - A novel method for performing in-column field-amplified sample stacking (FASS) in
      chip-based electrophoretic systems is presented. The methodology involves the use
      of a narrow sample channel (NSC) injector. NSC injectors allow sample plugs to be
      introduced directly into the separation channel, and subsequent stacking and
      separation can proceed without any need for leakage control. More importantly,
      stacking and separation occur in a single step negating the requirement for
      complex channel geometries and voltage switching to control sample plugs during
      the stacking procedure. The chip is composed of six paralleled systems. Using the
      NSC injector design, the number of reservoirs in the multiplexed chip is reduced
      to N + 2, where N is the number of paralleled systems. This design feature
      radically reduces the complexity in chip structures and associated chip
      operation. The approach is applied to the analysis of fluorescently labelled
      biogenic amines affording detection at concentrations down to 20 pM.

PMID- 12601746
TI  - Analysis of the quorum-sensing regulon of the opportunistic pathogen Burkholderia
      cepacia H111 by proteomics.
AB  - Burkholderia cepacia H111, an important pathogen for persons suffering from
      cystic fibrosis, employs a quorum-sensing (QS) system, cep, to control expression
      of virulence factors as well as the formation of biofilms. The QS system is
      thought to ensure that pathogenic traits are only expressed when the bacterial
      population density is high enough to overwhelm the host before it is able to
      mount an efficient response. In this study, we compared the protein pattern of
      the intracellular, extracellular, and surface protein fractions of an AHL
      deficient cepI mutant with the one of the parent strain H111 by means of two
      dimensional gel electrophoresis (2-DE). Our analysis showed that 55 proteins out
      of 985 detected spots were differentially expressed; these are expected to
      represent QS-controlled gene products. Addition of the respective signal
      molecules to the growth medium of the cep mutant fully restored the wild-type
      protein expression profile. In total about 5% of the B. cepacia proteome was
      downregulated and 1% upregulated in the cepI mutant, indicating that quorum
      sensing represents a global regulatory system. Nineteen proteins were identified
      with high confidence by N-terminal sequence analysis.

PMID- 12601747
TI  - Sodium dodecyl sulfate versus acid-labile surfactant gel electrophoresis:
      comparative proteomic studies on rat retina and mouse brain.
AB  - A long-chain derivative of 1,3-dioxolane sodium propyloxy sulfate, with similar
      denaturing and electrophoretic properties as SDS, and facilitated protein
      identification following polyacrylamide gel electrophoresis (PAGE) for Coomassie
      stained protein bands, has been tested. Comparative acid-labile surfactant/sodium
      dodecyl sulfate two-dimensional (ALS/SDS 2-D)-PAGE experiments of lower abundant
      proteins from the proteomes of regenerating rat retina and mouse brain show that
      peptide recovery for mass spectrometry (MS) mapping is significantly enhanced
      using ALS leading to more successful database searches. ALS may influence some
      procedures in proteomic analysis such as the determination of protein content and
      methods need to be adjusted to that effect. The promising results of the use of
      ALS in bioanalytics call for detailed physicochemical investigations of
      surfactant properties.

PMID- 12601748
TI  - Multiple polypeptide forms observed in two-dimensional gels of Methylococcus
      capsulatus (Bath) polypeptides are generated during the separation procedure.
AB  - We have examined two-dimensional electrophoresis (2-DE) gel maps of polypeptides
      from the Gram-negative bacterium Methylococcus capsulatus (Bath) and found the
      same widespread trains of spots as often reported in 2-DE gels of polypeptides of
      other Gram-negative bacteria. Some of the trains of polypeptides, both from the
      outer membrane and soluble protein fraction, were shown to be generated during
      the separation procedure of 2-DE, and not by covalent post-translational
      modifications. The trains were found to be regenerated when rerunning individual
      polypeptide spots. The polypeptides analysed giving this type of trains were all
      found to be classified as stable polypeptides according to the instability index
      of Guruprasad et al. (Protein Eng. 1990, 4, 155-161). The phenomenon most likely
      reflects conformational equilibria of polypeptides arising from the experimental
      conditions used, and is a clear drawback of the standard 2-DE procedure, making
      the gel picture unnecessarily complex to analyse.

PMID- 12601751
TI  - Distribution of hepatitis B virus (HBV) genotypes among HBV carriers in the Cote
      d'Ivoire: complete genome sequence and phylogenetic relatedness of HBV genotype
      E.
AB  - The characteristics of hepatitis B virus (HBV) genotype E are not well known
      because only a few studies have been carried out by complete genome analysis. The
      aim of this study was to elucidate the distribution of HBV genotypes in Cote
      d'Ivoire, and to clarify the genotype-related characteristics of genotype E. The
      distribution of HBV genotypes among 48 HBV carriers in Cote d'Ivoire was
      determined using serological and genetic methods. The characteristics of genotype
      E were evaluated by complete genome sequences, and further investigations of
      small S gene, basic core promoter (BCP) mutation, and precore mutation were
      undertaken. HBV genotype distribution among the 48 carriers was 6.3% for genotype
      A, 6.3% for genotype D, and 87.4% for genotype E. Complete genomes of two
      genotype E strains were sequenced, and found to have 98.2% to 99.2% homology at
      the nucleotide level when compared with genotype E strains reported previously.
      In 24 genotype E carriers, the precore mutation was detected in 75% of the
      patients without HBeAg, in contrast to only 25% of the patients with HBeAg (P <
      0.05). All 24 strains have T at nucleotide 1858 in the precore region. In
      contrast, BCP double mutation was detected in 17% of the patients with HBeAg, and
      33% of the patients without HBeAg. These results indicated as the following: (1)
      genotypes A, D, and E of HBV exist in Cote d'Ivoire and genotype E is the most
      prevalent; (2) genotype E spread with low genetic diversity over the complete
      genome in West Africa; (3) HBV precore and/or BCP double variants were common
      among the patients with genotype E infections.

PMID- 12601752
TI  - Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia
      in pregnant women in Taiwan.
AB  - To elucidate the impact of aging of hepatitis B carrier women on their viral
      replicative markers in a hepatitis B endemic area, all the parturients admitted
      to the Hospital were studied from 1985 to 2000. Serum hepatitis B surface (HBsAg)
      and hepatitis B e antigen (HBeAg) were tested by radioimmunoassay. Mann-Whitney U
      and Student's t-tests were used for statistical analysis. The results showed the
      yearly prevalence rate of HBsAg in pregnant women seemed stable with a mean of
      12.0 +/- 1.1% during the period. The yearly positive rate of HBeAg among HBsAg
      positive pregnant women varied between 30.4% and 42.6% from 1985 to 1992 and
      declined from 29.6% in 1993 to 18.1% in 2000. The mean ratio of HBeAg/HBsAg in
      carrier parturients was 24.7% [intraquantile range (IQR) 20.5-28.4] from 1993 to
      2000, which was significantly lower than that of 32.4% (IQR 31.0-39.0) from 1985
      to 1992 (P < 0.0001). The mean age of HBeAg-positive primiparas from 1993 to 2000
      was 29.1 +/- 3.9 years and significantly higher than that of 28.0 +/- 3.7 years
      from 1985 to 1993 (P < 0.001), as well as in secundiparas 31.2 +/- 3.8 years vs.
      30.1 +/- 3.4 years (P < 0.001) and in total parturients 30.3 +/- 4.2 years vs.
      29.3 +/- 3.8 years (P < 0.001). Thus, no significant decrease of HBsAg carriage
      was observed in the past 16 years, whereas a decreased ratio of HBeAg/HBsAg was
      noted in carrier parturients in the past 8 years and the elderly HBeAg-positive
      parturients from 1993 to 2000 may be the cause.

PMID- 12601753
TI  - Decline of hepatitis B carrier rate in vaccinated and unvaccinated subjects:
      sixteen years after newborn vaccination program in Taiwan.
AB  - Taiwan was an endemic area for hepatitis B virus (HBV) infection, and related
      liver diseases cause a significant drain of public resources. To control the
      endemic, a nation-wide newborn vaccination program was started in 1985. We
      reviewed the results of the annual survey for HBV surface antigen (HBsAg)
      performed in freshmen class of two high schools in Hualien, eastern Taiwan, from
      1991 to 2001. A total of 10,194 students, most of them 15 years old, were tested
      for serum HBsAg using enzyme immunoassays. There is a significant trend (P <
      0.0001) of decreasing HBsAg carrier rate from 20.3 to 4.4% in males and 14.3% to
      2.4% in females, respectively, over 11 years. The HBsAg carrier rate was 16.0
      20.3% in students surveyed during 1991-1993 (born more than 6 years before the
      start of the national vaccination program), which decreased to 7.7-11.9% during
      1994-1999 (born 1-6 years before the program). It further declined to 4.7% and
      3.4% in 2000 and 2001 (born after the start of the program). The HBsAg carrier
      rate in male students was significantly higher than that in female students in
      most of the years. The HBV newborn vaccination program not only successfully
      prevented most of the perinatal transmission of HBV but also reduced horizontal
      transmission of HBV to children born up to 6 years before the start of the
      program. Also, the protection persisted for at least 15 years.

PMID- 12601754
TI  - Sequencing of human-viral DNA junctions in hepatocellular carcinoma from patients
      with HCV and occult HBV infection.
AB  - DNA of free hepatitis B viruses (HBV) has been detected in the liver of patients
      infected with hepatitis C virus (HCV). It is unknown whether HBV DNA is
      integrated into such livers; if so, it may affect hepatocarcinogenesis.
      Hepatocellular carcinomas (HCCs) from 34 patients without HBV surface antigen
      (HBsAg) and with anti-HCV, and from 7 patients with HBsAg and without anti-HCV as
      controls, were examined, using the cassette-ligation-mediated polymerase chain
      reaction and primers based on HBV DNA sequence. In the controls, HBV DNA had been
      integrated into human DNA of all HCCs. On the basis of HBV DNA in tumor tissue,
      23 of the 34 patients with anti-HCV had occult infection. Junctions between human
      DNA and HBV DNA were detected in 10 of the 34 patients without HBsAg and with
      anti-HCV. HBV DNA was integrated into chromosome 11q in 4 of the 10 HCCs with
      junctions. The DNA to either side of the human-viral junctions was sequenced.
      Clinically, the mean tumor size of these 10 HCCs was 39 mm; that of the 24 HCCs
      without integrated HBV was 25 mm. The surrounding tissue was cirrhotic in 2 of
      the 10 former HCCs and in 16 of the latter 24 HCCs. In conclusion, integrated HBV
      was detected in some patients with HCV infection; in these patients, the
      integrated DNA was associated with accelerated hepatocarcinogenesis.

PMID- 12601755
TI  - Evolution of hepatitis C virus quasispecies in renal transplant patients with de
      novo glomerulonephritis.
AB  - Long-term renal allograft survival in kidney transplant recipients infected by
      hepatitis C virus (HCV) may be influenced by the occurrence of de novo
      glomerulopathy associated with this virus. Therefore, we studied the evolution of
      HCV quasispecies in kidney transplant recipients infected by HCV with or without
      de novo glomerulopathy. The hypervariable region 1 (HVR-1) of the virus envelope
      was analyzed by cloning and sequencing 20 clones per sample to assess complexity
      and diversity from six kidney transplant patients who developed de novo
      glomerulopathy (group I) matched to six kidney transplant recipients without
      glomerular disease (group II), according to age, time since renal
      transplantation, and HCV genotype. Two sera were analyzed for each patient: one
      at the time of renal transplantation and the other at the time of appearance of
      de novo glomerulopathy, or after a similar duration since transplantation in
      group II. Overall, there was a significant increase of HCV viremia after the
      transplantation. This increase did not differ significantly between group I (+0.5
      log copies/ml) and group II patients (+1 log copies/ml). The intersample
      diversity of HCV was similar in the two groups. Complexity and viral diversity
      were also similar at the time of transplantation. By contrast, complexity,
      diversity, and the proportion of nonsynonymous substitutions per nonsynonymous
      site were significantly higher after transplantation in group I patients. Our
      findings suggest a higher immune response and/or a particular cytokine production
      in patients developing de novo glomerulopathy rather than a direct effect of HCV
      on renal cells.

PMID- 12601756
TI  - Unexpected distribution of hepatitis C virus genotypes in patients on
      hemodialysis and kidney transplant recipients.
AB  - The distribution of hepatitis C virus (HCV) genotypes in patients on hemodialysis
      and in kidney transplant recipients was compared with that observed in a control
      group composed of HCV-infected individuals from the general population. A total
      of 340 patients were included in the study: 46 with end-stage renal disease on
      regular hemodialysis treatment, 22 kidney transplant recipients and 272 controls
      matched for sex and age at a 4:1 ratio (controls to patient). HCV genotype was
      determined by sequencing of the 5' untranslated region of the HCV genome. No
      difference was observed in the distribution of HCV genotypes in hemodialysis
      patients and renal transplant patients (P = 0.47). However, when each of these
      groups was compared with the control group, a significant difference was detected
      in the genotype distribution (P < 0.001). In hemodialysis and renal transplant
      patients the most prevalent subtype was 1a, followed by 1b, 3, and other less
      prevalent genotypes (2, 4, and 5), whereas in the control group the most
      prevalent subtype was 1b, followed by 3, 1a, and others. That observation may
      reflect differences in the epidemiology of HCV infection, viral characteristics
      and host factors in renal patients in comparison to the control group.

PMID- 12601757
TI  - Heparin-interacting sites of bovine lactoferrin are involved in anti-adenovirus
      activity.
AB  - Lactoferrin, a member of the transferrin family of approximately 80 kDa, consists
      of a single polypeptide chain folded in two symmetric, globular lobes (N- and C
      lobes), each able to bind one ferric ion. This glycoprotein, found in
      physiological fluids of mammals, plays an important role in immune regulation and
      in defense mechanisms against bacteria, fungi, parasites, and viruses. Although
      the antiviral activity of lactoferrin is one of the major biological functions of
      such protein, the mechanism of action is still under debate. We have investigated
      both the role of tryptic fragments of bovine lactoferrin and the mechanism of
      lactoferrin antiviral effect toward adenovirus infection in HEp-2 cells. The
      results obtained demonstrated that the anti-adenovirus activity of lactoferrin is
      mediated by the N-terminal half of the protein as the N-lobe was able to inhibit
      adenovirus infection, even if at lower extent than undigested lactoferrin,
      whereas C-lobe was ineffective. The results also showed that the anti-adenovirus
      action of lactoferrin and of its N-terminal peptide lactoferricin took place on
      virus attachment to cell membrane, mainly through competition for common
      glycosaminoglycan receptors. The data provide evidence that the anti-adenovirus
      activity of lactoferrin is mediated mainly by the cluster of positive charges at
      the N-terminus of whole molecule and that the N-terminal peptide lactoferricin
      alone is sufficient to prevent infection.

PMID- 12601758
TI  - Polystyrene derivatives substituted with arginine interact with Babanki
      (Togaviridae) and Kedougou (Flaviviridae) viruses.
AB  - Outbreaks of new or old diseases appear primarily in tropical zones such as
      Africa, south and central America, or Asia. Among these diseases, those induced
      by Arboviruses (the best known of which are being yellow fever, dengue, Ebola,
      and Sindbis) are under intensive observation by the World Health Organization.
      Rapid isolation and identification of the viral species is the first step in the
      diagnosis, study, and control of epidemics. One major problem with the isolation
      of viruses is capturing sufficient numbers of viral particles to test. The work
      presented in this report addresses this question. We have tested the interaction
      between Babanki (Togaviridae), Kedougou (Flaviviridae) viruses, and a range of
      insoluble polystyrene derivatives substituted with arginine groups. Insoluble
      functionalized copolymers were found to develop specific interactions with
      viruses through chemical groups present on their surfaces. The adsorption of
      viruses varied according to the percentage of arginine substituted onto the
      polymer, with a maximum value for both viruses of about 20% of grafting rate. It
      was also found that the Kedougou virus displayed the highest affinity for this
      polymer.

PMID- 12601759
TI  - Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice.
AB  - Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through
      different mechanisms including triggering of autoimmunity. The effect of
      immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the
      non-obese diabetic mice, an animal model for human autoimmune insulin-dependent
      diabetes mellitus. The immunization delayed the onset of diabetes in the mice,
      and the effect was mediated at least partially by virus immunization-activated
      splenocytes as demonstrated by adoptive transfer experiments. Immunization
      resulted in a strong humoral immune response against the immunizing virus,
      formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune response to virus
      antigen was characterised by interferon gamma and interleukin 10 secretion. The
      immunization also resulted in increased antibody levels against several beta-cell
      autoantigens. By using epitope mapping we were able to show that in addition to
      reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA
      2 or heat shock protein 60, responses to some other regions of autoantigens were
      enhanced. In preproinsulin, the response was restricted against an antigenic
      region earlier identified as DR4-dependent epitope. This reactivity can not be
      explained by homologous amino acid sequences and it is possible that enterovirus
      immunization might change the autoantigen specific TH1/TH2 balance in non-obese
      diabetic mice. In conclusion, our results suggest that coxsackievirus
      immunization increased humoral immune response to beta cell autoantigens and this
      was associated with a less destructive pathology for spontaneous diabetes in non
      obese diabetic mice.

PMID- 12601760
TI  - Supernatants from dengue virus type-2 infected macrophages induce permeability
      changes in endothelial cell monolayers.
AB  - The ability of dengue virus-infected human monocyte-derived macrophages to induce
      permeability changes in primary human umbilical vein endothelial cells was
      investigated. Supernatants from dengue virus type 2-infected monocyte-derived
      macrophages increased permeability in human umbilical vein endothelial cell
      monolayers without inducing endothelial cell infection. Production of
      permeabilising activity from monocyte-derived macrophages occurred after the peak
      of progeny virus release. TNF-alpha, a known inducer of endothelial cell
      permeability, was released from dengue virus infected monocyte-derived
      macrophages but its release did not coincide with release of endothelial cell
      permeabilising activity. Permeability induction was enhanced by pre-incubation
      with supernatants from infected monocyte-derived macrophages harvested at the
      time of peak release of TNF-alpha and infectious virus. Thus, supernatants from
      dengue virus-infected monocyte-derived macrophages contain factors that increase
      human umbilical vein endothelial cell permeability, but this is not accompanied
      by endothelial cell infection or directly correlated with release of dengue virus
      or TNF-alpha from monocyte-derived macrophages. This model system can be used for
      further in vitro analysis of mechanisms that may relate to capillary leakage and
      the development of dengue haemorrhagic fever/dengue shock syndrome.

PMID- 12601761
TI  - Molecular and biological analysis of echovirus 9 strain isolated from a diabetic
      child.
AB  - The full-length infectious cDNA clone was constructed and sequenced from the
      strain DM of echovirus 9, which was recently isolated from a 6-week-old child at
      the clinical onset of type 1 diabetes. Parallel with the isolate DM, the full
      length infectious cDNA clone of the prototype strain echovirus 9 Barty (Barty
      INF), was constructed and sequenced. Genetic relationships of the sequenced echo
      9 viruses to the other members of the human enterovirus type B species were
      studied by phylogenetic analyses. Comparison of capsid protein sequences showed
      that the isolate DM was closely related to both prototype strains: Hill and Barty
      INF. The only exception was the inner capsid protein VP4 where serotype
      specificity was not evident and the isolate DM clustered with the strain Hill and
      the strain Barty-INF with echovirus 30 Bastianni. Likewise, the nonstructural
      protein coding region, P2P3, of isolate DM was more similar to strain Hill than
      to strain Barty-INF. However, like echovirus 9 Barty, the isolate DM contained
      the RGD-motif in the carboxy terminus of capsid protein VP1. By blocking
      experiments using an RGD-containing peptide and a polyclonal rabbit antiserum to
      the alpha(v)beta(3)-integrin, it was shown that this molecule works as a cellular
      receptor for isolate DM. By using primary human islets, it was shown that the
      isolate DM is capable of infecting insulin-producing beta-cells like the
      corresponding prototype strains did. However, only isolate DM was clearly
      cytolytic for beta-cells. The infectious clones that were made allow further
      investigations of the molecular features responsible for the diabetogenicity of
      the isolate DM.

PMID- 12601762
TI  - Virus-inhibiting surgical glove to reduce the risk of infection by enveloped
      viruses.
AB  - Needle puncture and other accidents that occur during surgery and other
      procedures may lead to viral infections of medical personnel, notably by
      hepatitis C (HCV) and human immunodeficiency virus (HIV), now that hepatitis B
      can be prevented by vaccination. A new surgical glove called G-VIR, which
      contains a disinfecting agent for enveloped viruses, has been developed. Herpes
      simplex type 1 (HSV) was used as a standard enveloped virus in both in vitro and
      in vivo tests of the virucidal capacity of the glove. Bovine viral diarrhea virus
      (BVDV) and feline immunodeficiency virus (FIV) were used as models for HCV and
      HIV, respectively. For in vitro study, a contaminated needle was passed through a
      glove and residual virus was titrated; for in vivo studies, animals were stuck
      with a contaminated needle through a glove. Despite variation in virus
      enumeration inherent in the puncture technique, statistical evaluation showed
      that infection was reproducibly and substantially reduced by passage through the
      virucidal layer. For BVDV, the amount of virus passing through the virucidal
      glove was reduced in 82% of pairwise comparisons with control gloves that lacked
      the virucidal agent; when plaque counts were adjusted to a common dilution, the
      median count for the virucidal glove was on the average reduced >10-fold. In
      experiments in which the proportion of wells infected with FIV was measured, the
      ratio of TCID(50) values (control glove to G-VIR) was >15, and probably much
      higher. For HSV, the amount of virus passing through the virucidal glove was
      reduced in 81% of comparisons with control gloves; the median of adjusted plaque
      counts was reduced on the average approximately eightfold or ninefold. In vivo
      tests with FIV and HSV in cats and mice, respectively, found smaller percentage
      reductions in infection than the in vitro tests but confirmed the virucidal
      effect of the gloves.

PMID- 12601763
TI  - Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.
AB  - Cervical carcinoma is the leading cause of cancer death in Quechua indians from
      Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants,
      106 HPV-16 positive cervical samples were studied, including 33 low-grade
      squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial
      lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with
      normal colposcopy and cytology. HPV genome variability was examined in the L1 and
      E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also
      analyzed by PCR-sequencing. Most variants belonged to the European branch with
      subtle differences that depended on the viral gene fragment studied. Only about
      10% of the specimens had non-European variants, including eight Asian-American,
      two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the
      samples were identical to HPV-16 prototype, while 57% corresponded to variants.
      Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas
      variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of
      variants, including 69% of European, 19% Asian-American, and 12% Asian. We
      identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus
      two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated
      it in the Asian-American branch. The high proportion of European variants may
      reflect Spanish colonial influence on these native Inca descendants. The
      predominance of HPV-16 variants in pathologic samples when compared to normal
      controls could have implications for the natural history of cervical lesions.

PMID- 12601764
TI  - Pathogenicity and antigenicity of a new influenza A (H5N1) virus isolated from
      duck meat.
AB  - Avian influenza A viruses are the ancestral origin of all human influenza
      viruses. The outbreak of highly pathogenic (HP) avian H5N1 in Hong Kong in 1997
      highlighted the potential of these viruses to infect and cause severe disease in
      humans. Since 1999, HP H5N1 viruses were isolated several times from domestic
      poultry in Asia. In 2001, a HP H5N1 virus, A/Duck/Anyang/AVL-1/2001 (Dk/Anyang),
      was isolated from imported frozen duck meat in Korea. Because of this novel
      source of HP H5N1 virus isolation, concerns were raised about the potential for
      human exposure and infection; we therefore compared the Dk/Anyang virus with HP
      H5N1 viruses isolated from humans in 1997 in terms of antigenicity and
      pathogenicity for mammals. At high doses, Dk/Anyang virus caused up to 50%
      mortality in BALB/c mice, was isolated from the brains and lymphoid organs of
      mice, and caused lymphopenia. Overall Dk/Anyang virus was substantially less
      pathogenic for mice than the H5N1 virus isolated from a fatal human case in 1997.
      Likewise, Dk/Anyang virus was apathogenic for ferrets. Dk/Anyang virus was
      antigenically distinguishable by hemagglutination-inhibition (HI) assay from
      human H5N1 viruses isolated in 1997 and avian H5N1 viruses isolated in 2001 in
      Hong Kong. Nevertheless, prior infection with Dk/Anyang virus protected mice from
      death after secondary infection with HP human H5N1 viruses. These results
      indicate that compared with HP human H5N1 viruses, Dk/Anyang virus is
      substantially less pathogenic for mammalian species. Nevertheless, the novel
      source of isolation of this avian H5N1 virus must be considered when evaluating
      the potential risk to public health.

PMID- 12601765
TI  - Immunogenicity and safety of a novel liposomal influenza subunit vaccine
      (INFLUSOME-VAC) in young adults.
AB  - Influenza and its complications account for substantial morbidity and mortality
      among young adults and especially among the elderly. In young adults,
      immunization provides 70-90% protection, while among the elderly the vaccine may
      be only 30-40% effective; hence the need for new, more immunogenic vaccines. We
      compared the safety and immunogenicity of a novel IL-2-supplemented liposomal
      influenza vaccine (designated INFLUSOME-VAC) with that of a commercial subunit
      vaccine and a commercial split virion vaccine in young adults (mean age 28 years)
      in the winter of 1999-2000. Seventy-three healthy young adults were randomly
      assigned to be vaccinated intramuscularly with the following: a commercial
      subunit vaccine (n = 17, group A), INFLUSOME-VAC (n = 36, group B), and a
      commercial split virion vaccine (n = 20, group C). The three vaccines contained
      equal amounts of hemagglutinin (approximately 15 microg each) from the strains
      A/Sydney (H3N2), A/Beijing (H1N1), and B/Yamanashi. INFLUSOME-VAC induced higher
      geometric mean HI titers and higher-fold increases in HI titers against all three
      strains, compared with the two commercial vaccines. In addition, seroconversion
      rates for the A/Sydney and B/Yamanashi strains were significantly higher (P <
      0.05) compared with the split virion vaccine, and significantly higher for the
      three strains compared with the subunit vaccine (69-97% vs 35-65%, P < or =
      0.02). Moreover, the anti-neuraminidase response was significantly greater (P =
      0.05) in group B vs group A. INFLUSOME-VAC caused mild local pain at the
      injection site in a significantly higher proportion of the vaccinees (83%). Thus,
      INFLUSOME-VAC is an immunogenic and safe vaccine in young adults.

PMID- 12601767
TI  - Antibody response after RSV infection in children younger than 1 year of age
      living in a rural area of Mozambique.
AB  - Serological responses have been studied in respiratory syncytial virus (RSV)
      infected children < 1 year of age attending the outpatient department of the
      Manhica District Hospital (Mozambique). Molecular characterization of viral RNA
      in nasopharyngeal aspirates from the infected children indicated a high level of
      genetic uniformity among the infecting viruses, all of which belonged to a single
      genotype of RSV group A. A representative virus strain, Moz00, was isolated from
      one of the infants and was used, together with the group A strain A2 and the
      group B strain 8/60, as antigens in the quantification of infant antibody
      responses. In this study, 97.5% (39/40) and 96.4% (27/28) of infected children
      produced an antibody response against Moz00 detected by the membrane fluorescent
      antibody test (MFAT) and the neutralization test (NT), respectively.
      Seroconversion rates decreased when the A2 and 8/60 strains were used as antigen
      in MFAT (95.4% and 88.2%, respectively) or NT (81.8% and 54.5%, respectively),
      indicating that antibody responses had both group- and strain-specific
      components. Antibodies in convalescent sera of infected children were compared
      with maternally derived antibodies detected in a group of children also < 1 year
      of age, but with no evidence of RSV infection. The convalescent sera exhibited
      reduced neutralizing capacity when the 8/60 strain was used as antigen (P =
      0.028), suggesting that the infant antibody response lacks neutralizing capacity
      against strains of the heterologous virus group. Restricted cross-reactivity and
      neutralizing capacity of antibodies generated by young children might be expected
      to induce only moderate protection in subsequent epidemics against genetically
      distant strains.

PMID- 12601766
TI  - Incidence and characteristics of endemic Norwalk-like virus-associated
      gastroenteritis.
AB  - Endemic gastroenteritis associated with the Norwalk-like viruses (NLVs) is little
      understood. This study tested for NLV in gastroenteritis cases in 257 households
      in Melbourne, Australia, for the period September 1997 to February 1999 by a
      reverse transcription hemi-nested polymerase chain reaction. Positive samples
      were studied by nucleotide sequencing and phylogenetic analysis. NLV was detected
      in 73 (11.4%) of 638 faecal specimens tested. Twelve (1.9%) were NLV genogroup 1
      (G1) and 61 (9.6%) NLV genogroup 2 (G2). Gastroenteritis symptoms associated with
      NLV G2/no other pathogens were significantly more severe than where no NLV was
      detected. NLV G1 and NLV G2 were detected in adults and children, males and
      females. NLV G2 incidence showed a marked seasonal periodicity with significant
      peaks in the Australian late spring/early summer periods. NLV G1 seasonality was
      significantly different from that of NLV G2. Seven major NLV clusters were
      identified by phylogenetic analysis.

PMID- 12601768
TI  - Epidemiological features of rotavirus infection among hospitalized children with
      gastroenteristis in Ho Chi Minh City, Vietnam.
AB  - An epidemiological study of the G serotype and P genotype distribution of group A
      rotaviruses by using ELISA and/or RT-PCR was conducted in children (aged 1 month
      to 15 years) with diarrhea that were admitted to the General Children's Hospital
      No. 1, Ho Chi Minh City, Vietnam from December 1999 to November 2000. The results
      showed that rotavirus is associated with 65.6% (889/1355) of diarrheal
      admissions. Rotavirus infection mostly affected children under 2 years of age
      with a peak incidence in children 1 to 2 years of age (75.7%) and it occurs year
      round with a slight seasonal pattern; 99.5% of the specimens could be G-typed: G1
      was predominant (68.7%), followed by G4 (15.4%), G2 (12.3%), G3 (0.6%), and G9
      (0.5%). High identities of VP7 nucleotide (96.3 to 96.9%) and deduced amino acid
      (98.1 to 98.4%) were found between two Vietnamese G9 strains and also the recent
      emergence of G9 strains US 1205, Brazilian R143, and Malawian MW69. Mixed
      infections were identified in 17 (2.0%), and 5 strains (0.5%) remained untypable.
      The four most common worldwide strains, G1P[8], G2P[4], G3P[8], and G4P[8],
      constituted 81.1% of all rotaviruses typed with G1P[8] being the most prevalent
      type (58.2%). Unusual G/P combinations (11 strains) were detected in 11.7% of all
      strains, of which, G1P[4] was the most prevalent, accounting for 5.6% of the
      total. Several combinations of G and P types were observed in this study,
      suggesting a complex rotavirus infection pattern in Vietnam. This study has
      provided for the first time clear indication on the circulating G and P genotypes
      among hospitalized children in Ho Chi Minh City, Vietnam. The results suggest
      that these viral infections are prevalent among hospitalized children and that
      the four most common worldwide G types as well as the four most common G-P
      combinations were also infecting children in Ho Chi Minh City, Vietnam. This
      result could have important implications for rotavirus vaccine programs and for
      understanding the epidemiological characteristics of human rotavirus in Ho Chi
      Minh City, Vietnam.

PMID- 12601769
TI  - Fibroblast growth on surface-modified dental implants: an in vitro study.
AB  - A major consideration in designing dental implants is the creation of a surface
      that provides strong attachment between the implant and bone, connective tissue,
      or epithelium. In addition, it is important to inhibit the adherence of oral
      bacteria on titanium surfaces exposed to the oral cavity to maintain plaque-free
      implants. Previous in vitro studies have shown that titanium implant surfaces
      coated with titanium nitride (TiN) reduced bacterial colonization compared to
      other clinically used implant surfaces. The aim of the present study was to
      examine the support of fibroblast growth by a TiN surface that has antimicrobial
      characteristics. Mouse fibroblasts were cultured on smooth titanium discs that
      were either magnetron-sputtered with a thin layer of titanium nitride, thermal
      oxidized, or modified with laser radiation (using a Nd-YAG laser). The resulting
      surface topography was examined by scanning electron microscopy (SEM), and
      surface roughness was estimated using a two-dimensional contact stylus
      profilometer. A protein assay (BCA assay) and a colorimetric assay to examine
      fibroblast metabolism (MTT) were used. Cellular morphology and cell spreading
      were analyzed using SEM and fluorescence microscopy. Fibroblasts on oxidized
      titanium surfaces showed a more spherical shape, whereas cells on laser-treated
      titanium and on TiN appeared intimately adherent to the surface. The MTT activity
      and total protein were significantly increased in fibroblasts cultured on
      titanium surfaces coated with TiN compared to all other surface modifications
      tested. This study suggests that a titanium nitride coating might be suitable to
      support tissue growth on implant surfaces.

PMID- 12601770
TI  - Textured hydroxyapatite interface onto biomedical titanium-based coatings.
AB  - Hydroxyapatite (HAP) bioceramic coatings grown onto titanium-nitride (TiN) buffer
      layers by the aerosol-gel procedure present interfaces with a preferred growth
      orientation. These coatings were crystallized at 800 degrees C and subsequently
      etched to ease the study of the interface by Auger electron spectroscopy depth
      profiling. Ion beam milling was applied to cross-section samples to analyze the
      interface structures using transmission electron microscopy. At the interface,
      the HAP crystals showed a <002> orientation. It was shown by Auger electron
      spectroscopy depth profiling that O atoms diffuse into the nitride interlayer,
      indicating that the formation of O channels in the HAP structure is the driving
      force inducing the textured film. The outstanding biocompatible properties of
      both the materials and properties of their interface suggest that HAP/TiN
      structures are particularly well suited for endoprosthetic applications.

PMID- 12601771
TI  - Behavior of MG-63 cells on nylon/chitosan-blended membranes.
AB  - In this work, the properties of nylon, chitosan, and their blended membranes were
      investigated by scanning electron microscopy (SEM), differential scanning
      calorimetry (DSC), and wide-angle X-ray diffraction analysis. The SEM photographs
      show that the undulating surface of the nylon membrane became less obvious by
      blending with chitosan. The DSC and X-ray diffraction analysis show that
      constitutionally different features in the combination of two polymer chains were
      revealed, suggesting that nylon and chitosan are immiscible at the microscopic
      level in the blended membranes. Furthermore, an attempt was made to understand
      whether the two components contribute independently to the adhesion, growth, and
      activation of MG-63 osteoblastlike cells. The cell adhesion increased with
      increasing chitosan content, indicating that the affinity between the cells and
      the membranes increased with increasing chitosan content. Although the blended
      membranes with higher nylon content exerted an inhibitory effect on cell
      adhesion, cells cultured on the nylon membrane proliferated at higher rates and
      the nylon membrane was the least stimulating of MG-63 cell cytokine production
      over a 4-day period when compared with all the other membranes. Combined with the
      result of cell growth and cell activation, the chitosan content in the blended
      membrane did not proportionally influence the behavior of MG-63 cells. It is
      proposed that cell's size was larger than the scale of nylon or chitosan domain
      in the blended membranes because of the incomplete miscibility between them.
      Therefore, even if the composition of the blended membranes is systematically
      changed, every cell covers a multiphase surface that is considered a totally new
      material for cells. Consequently, cell growth and cell activation on a blended
      membrane are not simply proportional to their composition. In contrast, cell
      adhesion is a simpler process, like a physical adsorption process, which is
      related to the bulk property of a blended membrane.

PMID- 12601772
TI  - The effect of sintered dicalcium pyrophosphate on osteoclast metabolism: an
      ultrastructural study.
AB  - Sintered dicalcium pyrophosphate (SDCP), a synthetic compound, has proved to be
      both bioabsorbable and biocompatible in vivo. Recent work in our institute also
      has demonstrated that the ingestion of SDCP can increase bone mass in the
      ovariectomized rat. In this study, we used an in vitro cell culture model to
      investigate the ultrastructural changes and fate of osteoclasts induced by SDCP.
      Quantitative evaluation of osteoblasts and osteoclasts after administration of
      SDCP was performed. We studied immunohistochemical and ultrastructural features
      of osteoclasts undergoing apoptosis. The results showed that at 10(-4) M SDCP,
      the osteoblast cell count increased significantly, whereas the osteoclast
      population decreased significantly. Apoptosis of the osteoclast population was
      well demonstrated by immunohistochemical study. Ultrastructural study showed that
      the Golgi apparatus was degraded or dispersed in the cytoplasm. Later,
      osteoclasts revealed pyknotic nuclei showing condensation and margination of
      heterochromatins and DNA fragmentation, which are typical features of apoptosis.
      In addition, disruption of nuclear envelopes leading to leakage of nuclear
      contents into the cytoplasm was observed in the late stage of apoptosis. In
      conclusion, SDCP-induced apoptosis of osteoclasts was characterized by
      ultrastructural changes of the nucleus accompanied by degradation of cellular
      organelles.

PMID- 12601773
TI  - Cell adhesion on supported lipid bilayers.
AB  - The cell and protein repellent properties of supported phospholipid bilayer (SPB)
      membranes were investigated. The SPBs were prepared by vesicle adsorption on
      SiO(2) surfaces. The vesicles of phosphatidylcholine fuse and rupture, and form a
      supported bilayer covering the surface. We carried out cell culture experiments
      on several surfaces, including SPBs, using two types of epithelial cells to
      address the cell adhesional properties. The Quartz Crystal Microbalance
      Dissipation (QCM-D) technique was used to monitor the SPB formation and
      subsequent protein adsorption. Neither cell type adhered or proliferated on
      SiO(2) surfaces coated with SPBs, whereas both cell types adhered and
      proliferated on the three control surfaces of SiO(2), tissue culture glass, and
      TiO(2). The QCM-D measurements showed that about two orders of magnitude less
      mass adsorbed on a SPB surface compared to a TiO(2) surface, from serum
      containing media (10% fetal bovine serum). The reduced adsorption on the SPB is a
      likely explanation for the nondetectable epithelial cell adhesion on the SPB
      surface. Biomembranes are therefore attractive candidate systems to achieve
      alternating cell-resistant and cell-interacting regions on surfaces, by including
      specific cell-binding proteins in the latter regions.

PMID- 12601774
TI  - Calcium phosphate coatings obtained by Nd:YAG laser cladding: physicochemical and
      biologic properties.
AB  - The plasma spray (PS) technique is the most popular method commercially in use to
      produce calcium phosphate (CaP) coatings to promote fixation and osteointegration
      of the cementless prosthesis. Nevertheless, PS has some disadvantages, such as
      the poor coating-to-substrate adhesion, low mechanical strength, and brittleness
      of the coating. In order to overcome the drawbacks of plasma spraying, we
      introduce in this work a new method to apply a CaP coating on a Ti alloy using a
      well-known technique in the metallurgical field: laser surface cladding. The
      physicochemical characterization of the coatings has been carried out by means of
      X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy
      dispersive X-ray analysis (EDX). The biologic properties of the coatings have
      been assessed in vitro with human osteoblast-like MG-63 cells. The overall
      results of this study affirm that the Nd:YAG laser cladding technique is a
      promising method in the biomedical field.

PMID- 12601775
TI  - Polymeric matrices based on graft copolymers of PCL onto acrylic backbones for
      releasing antitumoral drugs.
AB  - Graft copolymers of poly(epsilon-caprolactone) (PCL) on poly(dimethylacrylamide)
      (PDMAm), poly(methylmethacrylate) (PMMA), or on copolymers of poly(DMAm-co-MMA)
      have been synthesized and characterized by (1)H NMR spectroscopy, differential
      scanning calorimetry (DSC), and size exclusion chromatography (SEC). These
      partially biodegradable copolymer matrices have been proposed as drug delivery
      systems for the release of low-molecular-weight glycosides. Octyl-N-acetyl-6-O
      [2,2-bis(hydroxymethyl)-3-hydroxypropyl]-alpha-D-glucosamide, a synthetic
      carbohydrate able to inhibit the proliferation of human malignant glioma cells in
      culture and transplanted glioma in rats was selected as drug model. The in vitro
      aqueous behavior of four drug-loaded and unloaded graft copolymers of different
      MMA: DMAm and PCL ratios has been analyzed performing swelling, degradation, and
      drug release experiments. An intimate dependence of the aqueous behavior with the
      composition has been found. The higher was the DMAm content, the higher was the
      hydrophilicity of the synthesized systems as well as the swelling, degradation,
      and drug release rate. In vivo experiments in pigs demonstrated the very good
      tolerance of drug-loaded implanted polymeric discs, and that >95% of the charged
      drug is released after 2 months' implantation.

PMID- 12601776
TI  - Reevaluation of ethylene oxide hemolysis and irritation potential.
AB  - The in vitro hemolytic and in vivo mucosal irritation potential of ethylene oxide
      (EO) was investigated with standard procedures used to determine the
      biocompatibility of medical devices. Test solutions containing EO at
      concentrations of 25, 50, 100, 250, 500, 1,250, 2,500, 5,000, or 10,000 microg/mL
      were prepared in saline to simulate a worst-case aqueous extraction of standard
      medical devices containing 125, 250, 500, 1,250, 2,500, 6,250, 12,500, 25,000, or
      50,000 microg/g of EO, respectively. Concentrations of EO up to 500 microg/mL
      were not hemolytic ( < 5% hemolysis after a 4-h exposure), whereas > or =1250
      microg/mL of EO resulted in significant hemolysis. Hamster cheek pouches exposed
      to cotton pellets saturated with EO at concentrations of up to 2500 microg/mL for
      4 h with a recovery period of 14 days were without effects attributable to EO.
      However, at > or =5000 microg/mL of EO, significant histomorphological
      alterations of the buccal mucosa were observed and attributed to EO exposure. It
      was concluded that solutions of EO of up to 500 microg/mL representing an aqueous
      extract of a general medical device containing at least 2500 microg/g of EO
      residue do not result in significant hemolysis and irritation.

PMID- 12601777
TI  - Electrochemically assisted deposition of thin calcium phosphate coatings at near
      physiological pH and temperature.
AB  - An electrochemical method for the deposition of calcium phosphate phases on
      titanium surfaces using the galvanostatic mode is presented. Deposition was
      performed in a (Ca(2+) / H(x)PO(4) ((3-x)-))-containing electrolyte near
      physiological conditions with regard to pH (6.4) and temperature (36 degrees C).
      Cathodic alkalization leads first to the formation of a thin homogeneous layer
      that shows a nanoscale surface topography of alternating wall-like elevations and
      channels. It is thought that these channels in the calcium phosphate prelayer are
      formed as pathways for hydroxyl ions and hydrogen. Upon this layer, spheres of
      amorphous calcium phosphate (ACP) are formed as indicated by Fourier transform
      infrared spectroscopy (FTIR) and transmission electron microscopy. According to
      transmission electron microscopy images, these spheres consist of small clusters
      of calcium phosphate (approximately 30 nm) and can grow up to 300 nm in diameter.
      Characteristic for this ACP is a high water content as seen by FTIR. As a
      function of current density, the ACP is then transformed into crystalline
      hydroxyapatite (HAP), which was identified using FTIR and X-ray diffraction. The
      morphology of the HAP crystals can be described as needles with dimensions of
      <500-nm length and <60-nm width. By choice of different electrochemical
      parameters, a homogeneous coating of either ACP, HAP, or the intermediate phase
      can be achieved, as shown in a kinetic phase diagram, thus allowing the formation
      of coatings with different properties in solubility and morphology.

PMID- 12601778
TI  - Transmission electron microscopic study on setting mechanism of tetracalcium
      phosphate/dicalcium phosphate anhydrous-based calcium phosphate cement.
AB  - This work studied transmission electron microscopy on the setting mechanism of
      tetracalcium phosphate/dicalcium phosphate anhydrous (TTCP/DCPA)-based calcium
      phosphate cement. The results suggest the process for early-stage apatite
      formation as the follows: when TTCP and DCPA powders are mixed in the phosphate
      containing solution, the TTCP powder is quickly dissolved because of its higher
      solubility in the acidic solution. The dissolved calcium and phosphate ions,
      along with those ions readily in the solution, are then precipitated
      predominantly on the surface of DCPA particles. Few apatite crystals were
      observed on the surface of TTCP powder. During the later stages of reaction, the
      extensive growth of apatite crystals/whiskers, with a calcium/phosphorous ratio
      very close to that of hydroxyapatite, effectively linked DCPA particles together
      and also bridged the larger TTCP particles. It is suggested that, when the large
      TTCP particles are locked in place by the bridging apatite crystals/whiskers, the
      CPC is set and would not dissolve when immersed in Hanks' solution after 20-40
      min of reaction.

PMID- 12601779
TI  - Juniper wood as a possible implant material.
AB  - Natural materials, such as wood and bone, possess structures fulfilling the
      requirements of support and transport of nutrients. Similarity in function and
      properties provides inspiration for investigating the possible use of wood as an
      implant material. Juniperus communis wood is dense, durable, and strong and has
      naturally impregnated essential oils that display antiseptic properties. This
      study investigated the toxicity of the oil, the effect of sterilization on the
      mechanical properties of the wood, and bone attachment with animal studies. The
      possible toxicity of the oil was determined orally and by intravenous injection.
      At low concentrations, the dose that would be released by the wood in the body
      could be tolerated without any detrimental effects. Sterilization of the wood in
      boiling water lowered the elastic modulus and modulus of rupture to a level at
      which the elastic modulus could be better matched to bone. Wood shaped into the
      form of femoral implants were implanted into rabbits and displayed good
      acceptance by the body up to a period of 3 years, indicating bone apposition,
      abutment into pores, and growth into drilled cavities.

PMID- 12601780
TI  - Fibronectin fibrillogenesis on sulfonated polystyrene surfaces.
AB  - Extracellular matrix (ECM) protein adsorption and organization serves as a
      critical first step in the development and organization of tissues. Advances in
      tissue engineering, therefore, will depend on the ability to control the rate and
      pattern of ECM formation. Fibronectin is a prominent component of the ECM, which
      undergoes fibrillogenesis in the presence of cells. Using sulfonated polysyrene
      surfaces, we showed that fibronectin undergoes a transition from monolayer to
      multilayer adsorption at calculated surface charge densities above 0.03 Coulombs
      (C)/m(2). At charge densities above approximately 0.08 C/m(2), distinct
      fibronectin fibrillar networks are observed to form with a fibril morphology
      similar to those observed to form in situ on cell surfaces. This self
      organization process is time dependent, with the fibrils achieving dimensions of
      30-40 microm in length and 1 microm in height after 72 h of incubation. We
      suggest that the polarization of charge domains on the polyampholytic fibronectin
      molecules near high charge density surfaces is sufficient to initiate the
      multilayer adsorption and the organization of these fibrillar structures. These
      results suggest that the nonlinear dependence of adsorption on surface charge
      density may play an important role in the self-organization of many matrix
      components.

PMID- 12601781
TI  - The role of the TH1 and TH2 immune responses in loosening and osteolysis of
      cemented total hip replacements.
AB  - The mechanisms underlying the development of osteolysis and aseptic loosening
      have an impact on the longevity of total hip replacements (THRs). This study
      examines the specific roles of lymphocytes in the TH1 and TH2 subsets in
      osteolysis and aseptic loosening of THR. Tissue from periprosthetic regions from
      patients with loose, cemented acetabular components were used to determine the
      TH1 and TH2 cytokine profile. Twelve tissue specimens from patients with
      radiographic signs of osteolysis, and nine tissue specimens from patients with no
      signs of osteolysis were harvested during revision surgery. Immunohistochemistry
      using primary antibodies against CD3, interferon (IFN)-gamma, interleukin (IL)-2,
      IL-4, and IL-10 was performed on frozen sections to determine the percentage of
      positive cells for each of the sections. No statistically significant differences
      in the percentage of positive cells expressing cytokines characteristic of the
      TH1 pathway (IFN-gamma, IL-2) or TH2 pathway (IL-4, IL-10) were found when
      comparing osteolytic and non-osteolytic tissues. However, significant numbers of
      T cells (averaging about 10% of the total cells) and TH1 and TH2 immune cytokines
      (averaging 3-5% of cells) implicate a possible role for immune processes at the
      prosthetic interface.

PMID- 12601782
TI  - Ultra-high molecular weight polyethylene oxidation reduces metalloproteinase 2
      secretion in human osteoblast-like cells in vitro: a mechanism of modulation of
      extracellular matrix.
AB  - Ultra-high molecular weight polyethylene (UHMWPE) sterilization with gamma rays
      induced high oxidation levels both on the surface and in the bulk that alter its
      structure and mechanical properties. The oxidation process of gamma-radiated
      UHMWPE induces a reduction of molecular weight and, consequently, a less abrasive
      resistance that has been related, among others, to the failure of UHMWPE in vivo.
      To explain the role of cells in such events, human osteoblast-like cells were
      seeded onto UHMWPE and oxidized UHMWPE discs. Cellular viability and morphology
      were evaluated along with matrix metalloproteinases (MMPs) production and
      activity. Oxidized UHMWPE did not induce any significant cytotoxic effects as
      observed by lactate dehydrogenase activity compared to the nonoxidized form; no
      changes in the cell morphology after 4 and 8 days proliferation were observed. In
      growth medium metalloproteinase 2 (gelatinase-A, MMP-2) was produced and released
      by osteoblast-like cells. We observed that cells grown onto oxidized UHMWPE discs
      decreased the release and activity of MMP-2 after 4 and 8 days culture compared
      to cells grown on control and non-oxidized UHMWPE discs; metalloproteinase 9
      (gelatinase-B, MMP-9) release was not significantly influenced. The absence of
      cytotoxic and morphological effects in the presence of a down-regulation of MMP-2
      release and activity suggest that oxidized polyethylene surfaces may modulate
      matrix remodeling and, consequently, bone formation.

PMID- 12601783
TI  - Inhibition of CEM calcification by the sequential pretreatment with ethanol and
      EDTA.
AB  - The major object of the present study is to optimize the anticalcification
      activity of ethanol on bioprosthetic heart valve (BHV) calcification. We
      hypothesize that the chelating agent, in combination with ethanol, will
      synergistically prevent aortic wall calcification. Collagen-elastin matrix (CEM)
      was developed as a calcifiable matrix for simulating the calcification process of
      implantable biomaterials. The efficacy of the combination effects of ethanol and
      EDTA on the calcification process of CEMs was investigated by implanting them
      after pretreatment with various conditions of ethanol and EDTA in the rat
      subdermal model. The relationship between calcium concentrations and pretreatment
      conditions (a series vs. simultaneous, i.e., first ethanol and then EDTA in water
      solution, the reverse, or EDTA in ethanol) was established and the optimal
      condition for prevention of BHV calcification was determined. The mechanistic
      studies on anticalcification effects exerted by particular pretreatment sequences
      were also conducted using FTIR and differential scanning calorimetry (DSC). The
      sequential pretreatment of CEM first with ethanol and then EDTA in water solution
      significantly decreased the calcification rate of CEM compared the control. The
      percentage of prevention of calcification by the serial treatment of ethanol (80%
      v/v) and then EDTA in water solutions decreased, as the concentration of elastin
      in the CEM increased. The percentage of preventing calcification was 42%, 28.6%,
      and 22.9% for CEM containing collagen and elastin ratios of 90:10, 50:50, 20:80,
      respectively. These results indicate that elastin is the major regulatory
      component of BHV calcification, and preventive effects on calcification increased
      only when CEM were pretreated with first ethanol and then EDTA in water solution.
      Moreover, the sequential effect is more apparent in the matrix of less elastin
      content, which is close to the physiological range. The sequential inhibitory
      effects of ethanol and EDTA could occur due to the distinct separate actions of
      each agent, thereby achieving a relatively greater inhibition of calcification.

PMID- 12601789
TI  - Protein decoy assembly using short fragments under geometric constraints.
AB  - A small set of protein fragments can represent adequately all known local protein
      structure. This set of fragments, along with a construction scheme that assembles
      these fragments into structures, defines a discrete (relatively small)
      conformation space, which approximates protein structures accurately. We generate
      protein decoys by sampling geometrically valid structures from this conformation
      space, biased by the secondary structure prediction for the protein. Unlike other
      methods, secondary structure prediction is the only protein-specific information
      used for generating the decoys. Nevertheless, these decoys are qualitatively
      similar to those found by others. The method works well for all-alpha proteins,
      and shows promising results for alpha and beta proteins.

PMID- 12601790
TI  - Computer simulation studies of the fidelity of DNA polymerases.
AB  - Computer simulations can provide in principle quantitative correlation between
      the structures of DNA polymerases and the replication fidelity. This paper
      describes our progress in this direction. Using several theoretical approaches,
      including the free energy perturbation (FEP), linear response approximation
      (LRA), and the empirical valence bond (EVB) methods, we examined the stability of
      several mismatched base pairs in DNA duplex in aqueous solution, the contribution
      of binding energy to the fidelity of DNA polymerases beta and T7, and the
      mechanism and energetics of the polymerization reaction catalyzed by T7 DNA
      polymerase.

PMID- 12601791
TI  - Ab initio structure prediction of two alpha-helical oligomers with a multiple
      chain united-residue force field and global search.
AB  - A hierarchical methodology for ab initio structure prediction is extended to
      treat oligomeric proteins. Modifications are made to a united-residue (UNRES)
      force field and a Conformational Space Annealing (CSA) global search method. The
      computational cost of including additional chains and the increase in speed from
      symmetry optimizations are evaluated. The native structures of two oligomeric
      proteins from the CASP3 exercise, the retro-GCN4 leucine zipper and the synthetic
      domain-swapped dimer, were identified as the lowest-energy families resulting
      from the search of the proteins when rotational symmetry was imposed. Additional
      searches in different symmetries and oligomerization states were carried out, and
      the results indicate some problems in the thoroughness of the search and in the
      search of packing arrangements if symmetry constraints are not imposed.

PMID- 12601792
TI  - Challenges in structure prediction of oligomeric proteins at the united-residue
      level: searching the multiple-chain energy landscape with CSA and CFMC.
AB  - A revised version of the Conformational Space Annealing (CSA) global optimization
      method is developed, with three separate measures of structural similarity, in
      order to overcome the inability of a single distance measure to evaluate multiple
      chain protein structures adequately. A second search method, Conformational
      Family Monte Carlo (CFMC), involving genetic-type moves, Monte Carlo-with
      minimization perturbations, and explicit clustering of the population into
      conformational families, is adapted to treat multiple-chain proteins. These two
      methods are applied to two oligomeric proteins, the retro-GCN4 leucine zipper and
      the synthetic domain-swapped dimer. CFMC proves superior to CSA in its search for
      low-energy representatives of its conformational families, but both methods
      encounter difficulty in finding the native packing arrangements in the absence of
      native-like symmetry constraints, even when native monomers are present in the
      population.

PMID- 12601793
TI  - The physics and bioinformatics of binding and folding-an energy landscape
      perspective.
AB  - It has been recognized in the last few years that unstructured proteins play an
      important role in biological organisms, often participating in signal
      transduction, transcriptional regulation, and a variety of other regulatory
      activities. Various hypotheses have been put forward for the ubiquity of the
      unfolded state; rapid turnover, faster or more specific binding kinetics,
      multifunctionality may all possibly explain apparent ubiquitousness of unfolded
      proteins in eukaryotic cells. In this paper we extend the energy landscape theory
      of protein folding to construct an analytical model of how binding and folding
      are coupled thermodynamically when the energy landscape is partially rugged. To
      deduce the parameters that enter the theory, which is based on Generalized Random
      Energy Model, we have analyzed in a bioinformatic sense a large structural
      database of more than 500 protein complexes. We find that Miyazawa-Jernigan
      contact potential shows similar energy gaps for folding for both hydrophobic and
      hydrophilic proteins, but that for binding contacts hydrophobic interfaces turn
      out to be funneled while hydrophilic ones are antifunneled. This suggests
      evolution has found a mechanism for avoiding frustration between folding and
      binding by making use of indirect water-mediated interactions. By juxtaposing the
      monomeric protein folding free energy profile in the protein complex database
      with another database consisting of only well-folded monomers, we estimate that
      at least 15% of monomers in the former database are unfolded in the absence of
      partner protein interface interactions. When employing the parameters
      characteristic of these unfolded monomers to construct binding/folding phase
      diagrams, we find that these monomers would indeed fold if sufficiently
      stabilizing binding contacts, consistent with that fold, are formed.

PMID- 12601794
TI  - Molecular dynamics of biological macromolecules: a brief history and perspective.
AB  - A description of the origin of my interest in and the development of molecular
      dynamics simulations of biomolecules is presented with a historical overview,
      including the role of my interactions with Shneior Lifson and his group in
      Israel. Some early applications of the methodology by members of my group are
      summarized, followed by a description of examples of recent applications and some
      discussion of possible future directions.

PMID- 12601795
TI  - The dominant interaction between peptide and urea is electrostatic in nature: a
      molecular dynamics simulation study.
AB  - The conformational equilibrium of a blocked valine peptide in water and aqueous
      urea solution is studied using molecular dynamics simulations. Pair correlation
      functions indicate enhanced concentration of urea near the peptide. Stronger
      hydrogen bonding of urea-peptide compared to water-peptide is observed with
      preference for helical conformation. The potential of mean force, computed using
      umbrella sampling, shows only small differences between urea and water solvation
      that are difficult to quantify. The changes in solvent structure around the
      peptide are explained by favorable electrostatic interactions (hydrogen bonds) of
      urea with the peptide backbone. There is no evidence for significant changes in
      hydrophobic interactions in the two conformations of the peptide in urea
      solution. Our simulations suggest that urea denatures proteins by preferentially
      forming hydrogen bonds to the peptide backbone, reducing the barrier for exposing
      protein residues to the solvent, and reaching the unfolded state.

PMID- 12601796
TI  - Vibrational spectroscopy and the development of new force fields for biological
      molecules.
AB  - The role of vibrational spectroscopy in the testing of force fields of biological
      molecules and in the determination of improved force fields is discussed.
      Analysis shows that quantitative testing of potential energy surfaces by
      comparison with spectroscopic data generally requires calculations that include
      anharmonic couplings between different vibrational modes. Applications of the
      vibrational self-consistent field (VSCF) method to calculations of spectroscopy
      of biological molecules are presented, and comparison with experiment is used to
      determine the merits and flaws of various types of force fields. The main
      conclusions include the following: (1) Potential surfaces from ab initio methods
      at the level of MP2 yield very satisfactory agreement with spectroscopic
      experimental data. (2) By the test of spectroscopy, ab initio force fields are
      considerably superior to the standard versions of force fields such as AMBER or
      OPLS. (3) Much of the spectroscopic weakness of AMBER and OPLS is due to
      incorrect description of anharmonic coupling between different vibrational modes.
      (4) Potential surfaces of the QM/MM (Quantum Mechanics/Molecular Mechanics) type,
      and potentials based on improved versions of semi-empirical electronic structure
      theory, which are feasible for large biological molecules, yield encouraging
      results by the test of vibrational spectroscopy.

PMID- 12601797
TI  - Potential energy functions: from consistent force fields to spectroscopically
      determined polarizable force fields.
AB  - We review our methodology for producing physically accurate potential energy
      functions, particularly relevant in the context of Lifson's goal of including
      frequency agreement as one of the criteria of a self-consistent force field. Our
      spectroscopically determined force field (SDFF) procedure guarantees such
      agreement by imposing it as an initial constraint on parameter optimization, and
      accomplishes this by an analytical transformation of ab initio "data" into the
      energy function format. After describing the elements of the SDFF protocol, we
      indicate its implementation to date and then discuss recent advances in our
      representation of the force field, in particular those required to produce an
      SDFF for the peptide group.

PMID- 12601798
TI  - Acetylcholinesterase in motion: visualizing conformational changes in crystal
      structures by a morphing procedure.
AB  - In order to visualize and appreciate conformational changes between homologous
      three-dimensional (3D) protein structures or protein/inhibitor complexes, we have
      developed a user-friendly morphing procedure. It enabled us to detect coordinated
      conformational changes not easily discernible by analytic methods or by
      comparison of static images. This procedure was applied to comparison of native
      Torpedo californica acetylcholinesterase and of complexes with reversible
      inhibitors and conjugates with covalent inhibitors. It was likewise shown to be
      valuable for the visualization of conformational differences between
      acetylcholinesterases from different species. The procedure involves generation,
      in Cartesian space, of 25 interpolated intermediate structures between the
      initial and final 3D structures, which then serve as the individual frames in a
      QuickTime movie.

PMID- 12601799
TI  - Application of the empirical force field to macrocyclic ion carriers,
      siderophores, and biomimetic analogs.
AB  - The empirical force field (EFF), developed by Prof. Lifson, was applied to the
      study of macrocyclic alkali ion carriers and to di- and tripodal and open chain
      siderophores and synthetic biomimetic molecules binding transition metals. The
      highly symmetric nature of these structures facilitated a favorable coordination
      geometry of the ligating groups about the metal, which helped organize the entire
      molecule into a fairly rigid structure. In our combined experimental-theoretical
      approach, EFF calculations were used to help predict likely candidates to
      synthesize, and provided a wealth of structural data to complement what we
      learned from the spectroscopic measurements, while feedback from these
      measurements allowed us to continue improving the EFF itself. The simple, highly
      modular design of the biomimetic analogs allowed rapid synthesis and systematic
      examination of a large number of related structures, as well as facilitating an
      efficient, piecewise conformational scanning for the theoretical calculations. In
      the early years, we focused on macrocyclic polylactones and lactams binding
      monovalent alkali ions, particularly the natural products enniatin and
      valinomycin, including inside a crystal lattice. Later we switched to bi- and
      tridentate siderophores, natural microbial iron carriers, and synthetic
      biomimetic analogs-in particular, of enterobactin, ferrichrome, and ferrioxamine
      B. Over the years a large number of biomimetic siderophores have been prepared,
      some active in a broad range of microorganisms while others are highly species
      specific. The results of this work have broad applications in many areas,
      including the design of novel drugs and antimicrobial agents, helical polymeric
      structures, and polynuclear metal complexes.

PMID- 12601800
TI  - Neuronal assemblies: single cortical neurons are obedient members of a huge
      orchestra.
AB  - Spontaneous cortical activity of single neurons is often either dismissed as
      noise, or is regarded as carrying no functional significance and hence is
      ignored. Our findings suggest that such concepts should be revised. We explored
      the coherent population activity of neuronal assemblies in primary sensory area
      in the absence of a sensory input. Recent advances in real-time optical imaging
      based on voltage-sensitive dyes (VSDI) have facilitated exploration of population
      activity and its intimate relationship to the activity of individual cortical
      neurons. It has been shown by in vivo intracellular recordings that the dye
      signal measures the sum of the membrane potential changes in all the neuronal
      elements in the imaged area, emphasizing subthreshold synaptic potentials and
      dendritic action potentials in neuronal arborizations originating from neurons in
      all cortical layers whose dendrites reach the superficial cortical layers. Thus,
      the VSDI has allowed us to image the rather illusive activity in neuronal
      dendrites that cannot be readily explored by single unit recordings.
      Surprisingly, we found that the amplitude of this type of ongoing subthreshold
      activity is of the same order of magnitude as evoked activity. We also found that
      this ongoing activity exhibited high synchronization over many millimeters of
      cortex. We then investigated the influence of ongoing activity on the evoked
      response, and showed that the two interact strongly. Furthermore, we found that
      cortical states that were previously associated only with evoked activity can
      actually be observed also in the absence of stimulation, for example, the
      cortical representation of a given orientation may appear without any visual
      input. This demonstration suggests that ongoing activity may also play a major
      role in other cortical function by providing a neuronal substrate for the
      dependence of sensory information processing on context, behavior, memory and
      other aspects of cognitive function.

PMID- 12601801
TI  - Structure-function relationship studies of bovine parathyroid hormone [bPTH(1
      34)] analogues containing alpha-amino-iso-butyric acid (Aib) residues.
AB  - The N-terminal 1-34 fragments of the parathyroid hormone (PTH) and parathyroid
      hormone-related protein (PTHrP) elicit the full spectrum of bone-related
      biological activities of the intact native sequences. It has been suggested that
      the structural elements essential for bioactivity are two helical segments
      located at the N-terminal and C-terminal sequences, connected by hinges or
      flexible points around positions 12 and 19. In order to assess the relevance of
      the local conformation around Gly(12) upon biological function, we synthesized
      and characterized the following PTH(1-34) analogues containing Aib residues: (I)
      A-V-S-E-I-Q-F-nL-H-N-Aib-G-K-H-L-S-S-nL-E-R-V-E-Nal-L-R-K-K-L-Q-D-V-H-N-Y-NH(2)
      ([Nle(8,18), Aib(11), Nal(23),Tyr(34)]bPTH(1-34)-NH(2)); (II) A-V-S-E-I-Q-F-nL-H
      N-L-Aib-K-H-L-S-S-nL-E-R-V-E-Nal-L-R-K-K-L-Q-D-V-H-N-Y-NH(2) ([Nle(8,18),
      Aib(12),Nal(23),Tyr(34)]bPTH(1-34)-NH(2)); (III) A-V-S-E-I-Q-F-nL-H-N-L-G-Aib-H-L
      S-S-nL-E-R-V-E-Nal-L-R-K-K-L-Q-D-V-H-N-Y-NH(2) ([Nle(8,18), Aib(13),
      Nal(23),Tyr(34)]bPTH(1-34)-NH(2)); (IV) A-V-S-E-I-Q-F-nL-H-N-Aib-Aib-K-H-L-S-S-nL
      E-R-V-E-Nal-L-R-K-K-L-Q-D-V-H-N-YNH(2) ([Nle(8,18), Aib(11,12),
      Nal(23),Tyr(34)]bPTH(1-34)-NH(2)); (V) A-V-S-E-I-Q-F-nL-H-N-L-Aib-Aib-H-L-S-S-nL
      E-R-V-E-Nal-L-R-K-K-L-Q-D-V-H-N-Y-NH(2) ([Nle(8,18),
      Aib(12,13),Nal(23),Tyr(34)]bPTH(1-34)-NH(2)). (nL= Nle; Nal= L-(2-naphthyl)
      alanine; Aib= alpha-amino-isobutyric acid.) The introduction of Aib residues at
      position 11 in analogue I or at positions 11 and 12 in analogue IV resulted in a
      5-20-fold lower efficacy and a substantial loss of binding affinity compared to
      the parent compound [Nle(8,18), Nal(23),Tyr(34)]bPTH(1-34)-NH(2). Both binding
      affinity and adenylyl cyclase stimulation activity are largely restored when the
      Aib residues are introduced at position 12 in analogue II, 13 in analogue III,
      and 12-13 in analogue V. The conformational properties of the analogues in
      aqueous solution containing dodecylphosphocholine micelles were studied by CD,
      two-dimensional (2D) NMR and computer simulations. The results indicated the
      presence of two helical segments in all analogues, located at the N-terminal and
      C-terminal sequences. Insertion of Aib residues at positions 12 and 13, or of Aib
      dyads at positions 11-12 and 12-13, enhances the stability of the N-terminal
      helix of all analogues. In all analogues the Aib residues are included in the
      helical segments. These results confirmed the importance of the helical structure
      in the N-terminal activation domain, as well as of the presence of the Leu(11)
      hydrophobic side chain in the native sequence, for PTH-like bioactivity.

PMID- 12601803
TI  - Structure-efficiency relationships of zwitterionic detergents as protein
      solubilizers in two-dimensional electrophoresis.
AB  - Several zwitterionic detergents differing in their polar heads, linker parts and
      hydrophobia tail were synthesized and evaluated for their efficiency in protein
      solubilizers for two-dimensional electrophoresis. A model system consisting of
      human red blood cell ghosts was used for this purpose. This study leads to the
      description of several new efficient detergents and allowed us to derive
      structural constraints for the design and synthesis of efficient detergents for
      two-dimensional electrophoresis. These constraints apply to the hydrophilic head
      (sulfobetaine but not carboxybetaine), to the hydrophobic tail (12 to 16 alkyl
      carbons long, linear alkyl or alkylaryl) and to the presence and nature of the
      linker between the hydrophilic head and hydrophobic tail.

PMID- 12601804
TI  - Peptidomics: A new approach to affinity protein microarrays.
AB  - Protein microarrays for diagnostic and proteomic analyses are being developed
      using a number of different techniques for each of the steps required including
      immobilisation methods, assay and detection systems. This is extremely different
      to the development of DNA microarrays which is now a well established technology
      that has demonstrated the capabilities of transcriptomics to deliver validated
      differential transcripts. As mRNA and protein levels do not always correlate,
      protein microarrays would seem to be an obvious successor to DNA arrays. Unlike
      nucleic acids, however, protein targets are typically nonhomogeneous in
      physicochemical properties and affinity capture agents are often poorly
      characterised making the experiments difficult to perfect and reproduce.
      Moreover, running multiple affinity assays in parallel (multiplexing) is
      compromised by the heterogeneity of antibody affinities to their protein targets.
      In the peptidomic approach presented here the assayed mixture of proteins is
      enzymatically digested prior to affinity capture to form a mixture of short
      peptides that are more similar in their physicochemical properties than intact
      proteins. These peptides can be predicted by in silico digestion of individual
      proteins, e.g. from protein databases allowing design of nonhomologous reagents
      for the screening of affinity agent libraries. The use of mass spectrometry (e.g.
      matrix-assisted laser desorption/ionization-time of flight mass spectrometry) for
      a direct confirmation of the identity of the species captured, provides a further
      advantage compared to the more usual method of detection in which fluorescently
      labelled captured species are scanned to give a spatially resolved image of the
      array.

PMID- 12601805
TI  - VIRTUAL2D: A web-accessible predictive database for proteomics analysis.
AB  - The available archive of sequence databases compiled from whole genome projects
      and budding proteomics efforts have enabled us to develop VIRTUAL2D, an
      interactive system for the assembly of virtual protein expression maps computed
      on the basis of theoretical isoelectric focusing point, molecular weight, tissue
      specificity and relative abundance for any set of proteins currently catalogued.
      This tool will assist in the preliminary, albeit putative, prediction of the
      identity and location of unknown and/or low abundance proteins in experimentally
      derived two-dimensional polyacrylamide gel electrophoresis maps.

PMID- 12601806
TI  - Mass spectrometry analysis of CD4-associating proteins using affinity
      chromatography and affinity tag-mediated purification of tryptic peptides.
AB  - The study of protein interactions using mass spectrometry (MS) for identification
      of the components of purified protein complexes is leading to the description of
      increasingly valuable data on protein function. Commonly proteins in a given
      complex are identified via MS analysis of in-gel digests of gel
      electrophoretically separated proteins. In this study, we have evaluated the use
      of an approach employing the digest of the whole protein complex to identify
      directly the proteins present in a purification of the CD4 receptor complex. We
      used a cysteinyl affinity capture method to reduce the complexity of the peptide
      mixture that was obtained from the tryptic digest of the whole protein complex to
      the rather limited mixture of only cysteine-containing peptides. Here we report
      the use of this approach with MS for identification of the CD4 receptor complex
      components CD4 and p56lck, along with several other proteins present in the
      detergent-solubilized fractions from the purification. We have been able to
      identify these proteins using peptide sequence data obtained from cysteine
      containing peptides. With appropriate control experiments, we have demonstrated
      the specific nature of the CD4-p56lck interaction. In contrast, the other
      proteins identified are shown to arise from nonspecific interactions during the
      affinity chromatography purification suggesting a possible loss of specific
      interactions during the chromatography procedure. We found that the complexity of
      the mixture was reduced such that only 10% of the peptides derived from tryptic
      digest of the identified proteins were detected. This represents only one-third
      of the cysteine-containing peptides, however, suggesting that this approach does
      not enable detection of all individual proteins.

PMID- 12601807
TI  - Identification of cellular changes associated with increased production of human
      growth hormone in a recombinant Chinese hamster ovary cell line.
AB  - A proteomics approach was used to identify the proteins potentially implicated in
      the cellular response concomitant with elevated production levels of human growth
      hormone in a recombinant Chinese hamster ovary (CHO) cell line following exposure
      to 0.5 mM butyrate and 80 microM zinc sulphate in the production media. This
      involved incorporation of two-dimensional (2-D) gel electrophoresis and protein
      identification by a combination of N-terminal sequencing, matrix-assisted laser
      desorption/ionisation-time of flight mass spectrometry, amino acid analysis and
      cross species database matching. From these identifications a CHO 2-D reference
      map and annotated database have been established. Metabolic labelling and
      subsequent autoradiography showed the induction of a number of cellular proteins
      in response to the media additives butyrate and zinc sulphate. These were
      identified as GRP75, enolase and thioredoxin. The chaperone proteins GRP78,
      HSP90, GRP94 and HSP70 were not up-regulated under these conditions.

PMID- 12601808
TI  - Progress in the definition of a reference human mitochondrial proteome.
AB  - Owing to the complexity of higher eukaryotic cells, a complete proteome is likely
      to be very difficult to achieve. However, advantage can be taken of the cell
      compartmentalization to build organelle proteomes, which can moreover be viewed
      as specialized tools to study specifically the biology and "physiology" of the
      target organelle. Within this frame, we report here the construction of the human
      mitochondrial proteome, using placenta as the source tissue. Protein
      identification was carried out mainly by peptide mass fingerprinting. The
      optimization steps in two-dimensional electrophoresis needed for proteome
      research are discussed. However, the relative paucity of data concerning
      mitochondrial proteins is still the major limiting factor in building the
      corresponding proteome, which should be a useful tool for researchers working on
      human mitochondria and their deficiencies.

PMID- 12601809
TI  - Diversity of puroindolines as revealed by two-dimensional electrophoresis.
AB  - Puroindolines are endosperm lipid binding proteins, which are separated by
      reversed phase-high-performance liquid chromatography or cation exchange
      chromatography into two isoforms, puroindoline-a (PIN-a) and puroindoline-b (PIN
      b). Being very basic and close in molecular weight, PIN-a and PIN-b have never
      been separated using conventional isoelectric focusing and sodium dodecyl sulfate
      polyacrylamide gel electrophoresis (SDS-PAGE). A two-dimensional electrophoresis
      method, linear immobiline pH gradient (IPGxSDS-PAGE), was developed, using 6-11
      linear immobiline Dry Strips in the first dimension, which allowed the
      puroindolines to be focused between isoelectric point 10.5 and 11. Immunoblotting
      revealed that both PIN-a and PIN-b were each composed of several spots. Two
      dimensional patterns from unrelated wheat varieties revealed that several spots
      can be highlighted among varieties. Matrix-assisted laser desorption/ionization
      time of flight spectrometry allowed the majority of the spots revealed in the
      puroindoline zone to be identified. The two-dimensional IPGxSDS-PAGE of these
      very basic wheat endosperm proteins, puroindolines and related grain softness
      proteins should facilitate the identification of the proteins associated with
      wheat endosperm texture that have a strong effect on milling, dough properties
      and end-uses of wheats.

PMID- 12601810
TI  - Proteomic analysis of the effect of heat stress on hexaploid wheat grain:
      Characterization of heat-responsive proteins from total endosperm.
AB  - High temperatures during grain filling have been reported to be one of the
      factors that can affect the dough properties and quality characteristics of
      wheat. Responses to high temperature have been related to changes in protein
      composition at both quantitative and qualitative levels. The present study was
      conducted to determine the influence of high temperature during grain filling on
      the protein composition of bread wheat evaluated by proteomic tools. Plants were
      grown in the field and transferred to cabinets soon after flowering. They were
      subjected to two thermal regimes 18 degrees C/10 degrees C (day/night) and 34
      degrees C/10 degrees C. Total proteins were extracted from control grains and
      treated plants at three different post-anthesis stages. The proteins were
      separated by two-dimensional gel electrophoresis and analysed by Melanie 3
      software. Of the total number of mature wheat grain proteins, 37 were identified
      as significantly changed by heat treatment. Analysis by matrix-assisted laser
      desorption/ionization mass spectrometry and tandem mass spectrometry coupled with
      database searching allowed the characterization of 25 heat-induced proteins and
      only one heat-decreased protein spot. To learn more about the function of the
      identified proteins, we examined their expression during treatment.

PMID- 12601811
TI  - Protein identification in cerebrospinal fluid using packed capillary liquid
      chromatography Fourier transform ion cyclotron resonance mass spectrometry.
AB  - The identification and characterization of proteins in complex biological samples
      such as body fluids, require powerful and reliable tools. Mass spectrometry is
      today one of the most important methods in such research. This paper reports on
      the results from the first experiment where a tryptic digest of cerebrospinal
      fluid was analyzed applying reversed phase liquid chromatography coupled on-line
      to a 9.4 T Fourier transform ion cyclotron resonance mass spectrometer. In total,
      70 204 peaks were detected, which originated from 16 296 isotopic clusters
      corresponding to 6551 unique peptide masses. From these masses, 39 proteins were
      identified in the sample. The amount of sample required for one experiment
      corresponds to 32 microL of cerebrospinal fluid.

PMID- 12601812
TI  - Protein expression profiling of glutathione S-transferase pi null mice as a
      strategy to identify potential markers of resistance to paracetamol-induced
      toxicity in the liver.
AB  - GST pi (GSTP) is a member of the glutathione S-transferase (EC 2.5.1.18; GST)
      family of enzymes that catalyse the conjugation of electrophilic species with
      reduced glutathione and thus play an important role in the detoxification of
      electrophilic metabolites. Deletion of GSTP in mice has previously been shown to
      lead to enhanced susceptibility to chemical-induced skin carcinoma, consistent
      with its known metabolic functions. A decreased susceptibility to paracetamol
      hepatotoxicity has also been observed, which has not been fully explained. One
      possibility is that deletion of the GSTP gene locus results in compensatory
      changes in other proteins involved in defence against chemical stress. We have
      therefore used complementary protein expression profiling techniques to perform a
      systematic comparison of the protein expression profiles of livers from GSTP null
      and wild-type mice. Analysis of liver proteins by two-dimensional electrophoresis
      confirmed the absence of GSTP in null mice whereas GSTP represented 3-5% of
      soluble protein in livers from wild-type animals. There was a high degree of
      quantitative and qualitative similarity in other liver proteins between GSTP null
      and wild-type mice. There was no evidence that the absence of GSTP in null
      animals resulted in enhanced expression of other GST isoforms in the null mice
      (GST alpha, 1.48%, GST mu, 1.68% of resolved proteins) compared with the wild
      type animals (GST alpha, 1.50%, GST mu, 1.40%). In contrast, some members of the
      thiol specific antioxidant family of proteins, notably antioxidant protein 2 and
      thioredoxin peroxidases, were expressed at a higher level in the GSTP null mouse
      livers. These changes presumably reflect the recently described role of GSTP in
      cell signalling and may underlie the protection against paracetamol toxicity seen
      in these animals.

PMID- 12601813
TI  - Hyperubiquitination of proteins in dilated cardiomyopathy.
AB  - Protein degradation by the ubiquitin-proteasome pathway plays an important role
      in a variety of fundamental cellular processes, including cell cycle regulation,
      transcription, antigen processing and muscle remodelling. Research into disorders
      associated with the ubiquitin-proteasome system has been mainly in the field of
      neurodegenerative diseases. It is however becoming increasingly apparent that
      defects in the system are responsible for a number of non-neurological
      pathologies. Based on initial observations made as part of a proteomic analysis
      of an animal model of dilated cardiomyopathy (DCM) which indicated increased
      activity of the ubiquitin-proteasome system, we sought to determine whether this
      system was perturbed in hearts of human DCM patients. We studied explanted hearts
      from 12 DCM, 9 ischaemic (IHD) and 12 unused donor hearts. Protein expression was
      examined using two-dimensional polyacrylamide gel electrophoresis, Western
      blotting and immunohistochemistry. Expression of mRNA was examined using real
      time quantitative polymerase chain reaction. Ubiquitinated proteins were affinity
      purified using a ubiquitin-binding column and identified using peptide mass
      fingerprinting. All DCM hearts showed significantly higher expression of certain
      key enzymes of the ubiquitin-proteasome pathway. mRNA expression of ubiquitin
      carboxyl-terminal hydrolase (UCH) was significantly higher (5.4-fold) in DCM
      hearts than in control hearts. Myocytes in sections from DCM hearts stained
      positively for UCH, whereas control hearts were negative. Overall protein
      ubiquitination was increased two-fold in DCM relative to IHD hearts and five-fold
      relative to donor hearts. The ubiquitination of a number of distinct proteins was
      greatly enhanced in DCM hearts as revealed by anti-ubiquitin Western blots. A
      number of these proteins were identified using affinity purification and matrix
      assisted laser desorption/ionisation time-of-flight mass spectrometry.

PMID- 12601814
TI  - Novel subunits of the TATA binding protein free TAFII-containing transcription
      complex identified by matrix-assisted laser desorption/ionization-time of flight
      mass spectrometry following one-dimensional gel electrophoresis.
AB  - Initiation of transcription of protein-encoding genes by RNA polymerase II was
      thought to require the transcription factor II D (TF(II)D), a complex comprising
      the TATA binding protein (TBP) and TBP-associated factors. However, another
      multiprotein complex isolated more recently and called TFTC (TBP-free TAF(II
      )containing complex), was shown to mediate initiation of RNA polymerase II (Pol
      II) transcription in the absence of TF(II)D as well as specific acetylation of
      histone H3 in a nucleosomal context. Several subunits of the TFTC complex were
      already identified using classical methods such as Edman based microsequencing
      and Western blot analysis. In this article we present a mass spectrometry based
      proteomic approach to confirm previous results and to identify other possible
      subunits of the TFTC complex. The TFTC complex was separated on one-dimensional
      sodium dodecyl sulfate polyacrylamide electrophoresis and analysed by matrix
      assisted laser desorption/ionization-time of flight mass spectrometry and peptide
      mass fingerprinting. Identifications were realized after databank searches. This
      new characterization of TFTC complex confirmed the presence of already described
      subunits (TRRAP, GCN5, SAP130/KIA0017, TAF(II)150, TAF(II)135, TAF(II)100,
      TAF(II)80, TAF(II)20, SPT3 and PAF65beta). Moreover, a good coverage of these
      sequences was obtained. Interestingly, TAF(II)32 and PAF6alpha were also
      determined as potential novel subunits of TFTC. These results together show the
      suitability and the great potential of this method and offer new perspectives in
      fundamental studies of transcription factor complexes.

PMID- 12601815
TI  - Proteome analysis of the plant pathogen Xylella fastidiosa reveals major cellular
      and extracellular proteins and a peculiar codon bias distribution.
AB  - The bacteria Xylella fastidiosa is the causative agent of a number of
      economically important crop diseases, including citrus variegated chlorosis.
      Although its complete genome is already sequenced, X. fastidiosa is very poorly
      characterized by biochemical approaches at the protein level. In an initial
      effort to characterize protein expression in X. fastidiosa we used one- and two
      dimensional gel electrophoresis and mass spectrometry to identify the products of
      142 genes present in a whole cell extract and in an extracellular fraction of the
      citrus isolated strain 9a5c. Of particular interest for the study of pathogenesis
      are adhesion and secreted proteins. Homologs to proteins from three different
      adhesion systems (type IV fimbriae, mrk pili and hsf surface fibrils) were found
      to be coexpressed, the last two being detected only as multimeric complexes in
      the high molecular weight region of one-dimensional electrophoresis gels. Using a
      procedure to extract secreted proteins as well as proteins weakly attached to the
      cell surface we identified 30 different proteins including toxins, adhesion
      related proteins, antioxidant enzymes, different types of proteases and 16
      hypothetical proteins. These data suggest that the intercellular space of X.
      fastidiosa colonies is a multifunctional microenvironment containing proteins
      related to in vivo bacterial survival and pathogenesis. A codon usage analysis of
      the most expressed proteins from the whole cell extract revealed a low biased
      distribution, which we propose is related to the slow growing nature of X.
      fastidiosa. A database of the X. fastidiosa proteome was developed and can be
      accessed via the internet (URL: www.proteome.ibi.unicamp.br).

PMID- 12601818
TI  - American Society for Laser Medicine and Surgery 23rd Annual Meeting. Anaheim,
      California, USA. April 9-13, 2003. Abstracts.

PMID- 12601827
TI  - Once a Cesarean section, always a Cesarean section: back to the future?

PMID- 12601828
TI  - Ultrasound examination of the cervix to predict preterm delivery: we still know
      too little to use it in clinical practice.

PMID- 12601829
TI  - Three-dimensional ultrasound fetal lung volume measurement: a systematic study
      comparing the multiplanar method with the rotational (VOCAL) technique.
AB  - OBJECTIVES: This study was designed to compare a conventional multiplanar
      technique for three-dimensional (3D) ultrasound measurement of fetal lung volume
      with a rotational method using VOCAL trade mark (Virtual Organ Computer-aided
      AnaLysis). METHODS: Thirty-two fetuses with a variety of conditions at risk for
      pulmonary hypoplasia were studied. 3D volume data sets of the fetal lungs were
      acquired using a commercially available ultrasound system. The right and left
      lung volumes were calculated separately using VOCAL and the multiplanar
      technique. The level of agreement between two independent observers in
      categorizing the 3D volume data set as measurable or non-measurable was
      determined. The interobserver and intermethod variabilities were also evaluated
      for both methods. RESULTS: The intermethod variability was excellent (correlation
      r = 0.93 and r = 0.96 for the left and right lung, respectively), and there was
      substantial agreement between the results of both approaches (limits of agreement
      - 4.4 to 8.9 and - 3.4 to 4.8 mL for the right and left lung, respectively).
      Fetal lung estimation with VOCAL had a significantly higher interobserver
      variability than the multiplanar technique. Interobserver agreement in
      categorizing lung volume data sets as measurable or non-measurable was lower when
      VOCAL was used. CONCLUSION: Fetal lung volume measurements can be undertaken
      interchangeably using the multiplanar technique or the rotational method with
      VOCAL. However, the latter was less reproducible (lower degree of agreement and
      significantly higher interobserver variability) than the former.

PMID- 12601830
TI  - Three-dimensional multiplanar time-motion ultrasound or anatomical M-mode of the
      fetal heart: a new technique in fetal echocardiography.
AB  - OBJECTIVE: To assess the application of a three-dimensional multiplanar rendering
      technique for examination of the fetal heart. MATERIAL AND METHODS: Free-hand
      acquisition of a three-dimensional volume was performed without moving or tilting
      the transducer. While the anatomical plane shows the four cardiac chambers, the
      two other orthogonal planes show vertical and horizontal time-axis planes as M
      mode traces. Because off-line plane positioning is possible on three-dimensional
      multiplanar reconstruction, M-mode traces can be obtained from different stored
      cardiac structures independently of the fetal position. Fifty-two women with
      normal singleton pregnancies at 22-40 weeks underwent transabdominal ultrasound
      examination and five women with singleton fetuses between 13 and 15 weeks were
      assessed transvaginally. Clinical application of the echocardiographic technique
      was tested in a further two fetuses with arrhythmia. RESULTS: Off-line M-mode
      traces from atrioventricular valve excursions and myocardial contractions were
      possible in 45/52 (86.5%) cases examined at 22-40 weeks. Among the 32 fetuses in
      which visualization of the outflow tracts was attempted, M-mode traces of the
      aortic and pulmonary valves were possible in 22 (68.7%) and 20 (62.5%) cases,
      respectively. In three of five cases examined transvaginally, M-mode traces could
      be registered. Both cases with supraventricular extrasystoles (26 and 31 weeks)
      were easily diagnosed using this technique. CONCLUSION: The new technique
      presented here enables the easy acquisition of optimal M-mode traces from
      different fetal heart structures. Based on our promising findings we would
      recommend that, in the future, three-dimensional multiplanar imaging should not
      be limited to automatic volume acquisition but should include the free-hand
      technique.

PMID- 12601831
TI  - The cerebroplacental Doppler ratio revisited.
AB  - OBJECTIVE: To evaluate the distribution of Doppler pulsatility index (PI)
      measurements of the umbilical and middle cerebral arteries in singleton fetuses
      of women with normal uterine artery blood flow and to construct reference ranges
      for the cerebroplacental PI Doppler ratio. METHODS: The PI was determined in the
      mid-portion of the umbilical artery and the mid- or distal segment of the middle
      cerebral artery in 306 normal singleton fetuses. The cerebroplacental Doppler
      ratio (CPR) was determined from paired measurements. After determination of the
      best fit, reference ranges were constructed for each parameter against
      gestational age (GA). RESULTS: The PI for the umbilical artery had a linear
      relationship with GA (umbilical artery PI = - 0.0246 x GA + 1.7791, r(2) =
      0.4025, P < 0.001). The middle cerebral artery PI and the CPR both showed a
      quadratic relationship with GA (middle cerebral artery PI = - 0.0058 x GA(2) +
      0.3335 x GA - 2.7317, r(2) = 0.2365, P < 0.01), (CPR = - 0.0059 x GA(2) + 0.383 x
      GA - 4.0636, r(2) = 0.2788, P < 0.001). CONCLUSION: The CPR is not constant
      throughout gestation. Reference ranges constructed by a standardized Doppler
      technique may be of benefit in the monitoring of high-risk pregnancies.

PMID- 12601832
TI  - Does cervical length at 13-15 weeks' gestation predict preterm delivery in an
      unselected population?
AB  - OBJECTIVE: To assess the role of early mid-trimester cervical length measurement
      as a predictor of spontaneous preterm birth in an unselected population. METHODS:
      In this prospective study, unselected, asymptomatic, Caucasian women with
      singleton pregnancies underwent standardized transvaginal ultrasonographic (TVS)
      cervical length measurement at 13-15 weeks' gestation as a screening test for
      preterm delivery (PTD). Women with multiple gestations, iatrogenic PTD, and
      previous cervical conization were excluded. The primary outcome measures were
      spontaneous PTD at < 37 and < 34 weeks. The correlation between cervical length
      and previous obstetric history was evaluated. RESULTS: A total of 2469 patients
      met the inclusion criteria. The mean gestational age at cervical assessment was
      14 + 2 weeks. The mean gestational age at delivery was 40 + 0 weeks. The rate of
      spontaneous deliveries before 37 weeks' gestation was 1.7%. In 0.2% the delivery
      occurred before 34 weeks' gestation. The mean +/- standard deviation cervical
      length for the entire population was 44.2 +/- 5.4 mm. No difference was observed
      between cervical length in women that delivered at term and those that delivered
      either before 37 or before 34 weeks' gestation. Previous obstetric history (prior
      preterm birth, previous miscarriages and terminations, and parity) did not affect
      cervical length at 14 weeks of gestation. CONCLUSIONS: Performed at 14 weeks'
      gestation, TVS measurement of the cervical canal length to predict spontaneous
      PTD is not a reliable screening procedure.

PMID- 12601833
TI  - Cervical length at 11-14 weeks' and 22-24 weeks' gestation evaluated by
      transvaginal sonography, and gestational age at delivery.
AB  - OBJECTIVE: To compare cervical length measurements obtained at 11 to 14 weeks and
      22 to 24 weeks of gestation in an unselected group of pregnant women and to
      correlate the measurements with time of delivery. METHODS: This was a prospective
      study involving 529 pregnant women attending for routine antenatal care who
      underwent transvaginal scans at 11-14 weeks and 22-24 weeks for evaluation of
      cervical length. The mean cervical length was calculated at both stages of
      gestation and lengths were compared between groups which delivered at term or
      prematurely, this being defined as delivery before 37 completed weeks of
      gestation. RESULTS: The mean cervical lengths at 11-14 and 22-24 weeks were,
      respectively, 42.4 mm and 38.6 mm. Cervical length at 11-14 weeks was not
      significantly different between the groups which delivered at term (42.7 mm) and
      preterm (40.6 mm). However, at the 22-24-week evaluation, cervical length was
      significantly shorter in the group which had a preterm delivery than in that
      which had a term delivery (26.7 mm and 39.3 mm, respectively; P = 0.0001). In the
      group of women with a previous history of one or more preterm deliveries, there
      was a greater shortening in cervical length from the first to the second
      evaluation than there was in the group of women with no previous history of
      preterm delivery. This shortening was also more pronounced in the group which
      delivered prematurely (from 40.6 mm to 26.7 mm) than in that which delivered at
      term (from 42.7 mm to 39.3 mm). CONCLUSION: There is a spontaneous shortening in
      the pregnant cervix from the first to the second trimester of pregnancy. The
      shortening is more rapid in pregnant women who deliver prematurely and who have a
      history of previous preterm delivery.

PMID- 12601834
TI  - Does transvaginal sonographic measurement of cervical length before 14 weeks
      predict preterm delivery in high-risk pregnancies?
AB  - OBJECTIVE: To determine whether high-risk patients manifest cervical length < 25
      mm on transvaginal ultrasound before 14 weeks of gestation, and if this finding
      is predictive of preterm delivery. METHODS: Asymptomatic pregnancies at high risk
      for preterm birth were followed prospectively from 10 + 0 weeks to 13 + 6 weeks
      with transvaginal sonographic measurement of the cervix. A cervical length < 25
      mm was considered a short cervix at this gestational age and at the follow-up
      ultrasound examinations, performed between 14 and 24 weeks. The primary outcome
      was preterm birth at < 35 weeks of gestation. RESULTS: One hundred and eighty
      three pregnancies met the study criteria and were included in the analysis. Only
      10 (5%) patients had a cervix < 25 mm before 14 weeks. The sensitivity,
      specificity and positive and negative predictive values of a short cervix were
      14%, 97%, 50%, and 82%, respectively (relative risk, 2.8; 95% confidence
      interval, 1.4-5.6). The mean transvaginal sonographic cervical length before 14
      weeks of gestation was 33.7 +/- 6.9 mm in pregnancies which delivered preterm (n
      = 36), and 35.0 +/- 6.8 mm in those delivering at term (n = 147) (P = 0.3).
      Follow-up transvaginal ultrasound examination of the cervix to 24 weeks revealed
      that the average gestational age at which a short cervix was detected was 18.7 +/
      2.9 weeks. CONCLUSION: A cervical length < 25 mm on transvaginal sonographic
      assessment rarely occurs before 14 weeks even in high-risk patients destined to
      deliver preterm; in these patients cervical changes predictive of preterm birth
      develop mostly after this gestational age.

PMID- 12601835
TI  - The 'virtual' cervical internal os: diagnosis during the first trimester of
      pregnancy.
AB  - OBJECTIVE: To determine the appropriate time during gestation for assessing the
      cervix for possible incompetence by ascertaining the gestational week at which
      the sac reaches the level of the internal os. METHODS: Three hundred and eighteen
      women with an intact singleton pregnancy at 5 to 15 weeks' gestation underwent
      endovaginal sonographic examination to measure the distance between the
      gestational sac and the cervical internal os. The change in location of the
      gestational sac in the endometrial cavity over time, and the earliest gestational
      week at which the gestational sac reached the level of the internal os, were
      calculated and analyzed with one-way analysis of variance. RESULTS: The distance
      between the gestational sac and the 'virtual' cervical internal os decreased from
      a mean of 4.72 cm at 5 weeks to 1.71 cm at 13 weeks. This distance decreased
      significantly during the early first trimester (weeks 5 to 7) (P = 0.004), but
      remained almost unchanged from 12 to 15 weeks. Only at 12 weeks' gestation could
      the entire cervical length be determined and the configuration of the cervical
      internal os assessed for incompetence. CONCLUSIONS: Transvaginal sonography is a
      good method for evaluating the cervix during pregnancy. The location of the
      'virtual' internal os can be determined in the first trimester using the urinary
      bladder as a reference point.

PMID- 12601836
TI  - Methylcellulose gel is a superior contrast agent for ultrasound examination of
      the cervix in obstetric patients.
AB  - OBJECTIVE: To determine the superior contrast agent for cervical sonography:
      water-soluble methylcellulose gel vs. normal saline. METHODS: Women with an
      indication for cervical sonography underwent placement of 10 mL water-soluble
      methylcellulose gel or normal saline. Assessment of cervical dimensions and
      contour was performed via transperineal sonography prior to and after contrast
      placement. RESULTS: Twenty-five patients with similar demographic characteristics
      and indications for ultrasonography were enrolled into each group. Administration
      of contrast improved the ability to visualize the external os or vaginal fornices
      in 18 women in the gel group vs. six in the saline group (P = 0.002). In the gel
      group, 17 patients had easier identification of the external os and visualization
      of the fornices was enhanced in 13 patients. The assessment of cervical length
      prior to and after contrast administration was not statistically different with
      the use of either of these agents. CONCLUSION: Intravaginal soluble gel is
      superior to normal saline as a cervical contrast agent. Intravaginal contrast may
      allow for easier identification of cervical anatomy during ultrasonographic
      examination in selected patients.

PMID- 12601837
TI  - Nasal bone length throughout gestation: normal ranges based on 3537 fetal
      ultrasound measurements.
AB  - OBJECTIVE: To establish normal ranges for nasal bone length measurements
      throughout gestation and to compare measurements in two subsets of patients of
      different race (African-American vs. Caucasian) to determine whether a different
      normal range should be used in these populations. METHOD: Normal nasal bone
      length reference ranges were generated using prenatal measurements by a
      standardized technique in 3537 fetuses. RESULTS: The nasal bone lengths were
      found to correlate positively with advancing gestation (R(2) = 0.77, second-order
      polynomial). No statistical difference was found between African-American and
      Caucasian subjects. CONCLUSION: These reference ranges may prove to be useful in
      prenatal screening and diagnosis of syndromes known to be associated with nasal
      hypoplasia. Different normal ranges for African-American and Caucasian women are
      not required.

PMID- 12601838
TI  - Fetal nasal bone length: reference range and clinical application in ultrasound
      screening for trisomy 21.
AB  - OBJECTIVES: Fetuses with trisomy 21 typically present with subtle facial
      abnormalities, including a hypoplastic nasal bone. The aim of this study was to
      provide a reference range for the length of the fetal nasal bone and to test its
      value in second-trimester ultrasound screening for trisomy 21. DESIGN: A
      reference range of fetal nasal bone length was established from cross-sectional
      data on 1923 consecutive singleton pregnancies scanned at 16-24 weeks' gestation
      in women older than 35 years. Screening for trisomy 21 was prospectively studied
      using the measurement of fetal nasal bone lengths smaller than the 5(th)
      percentile as a cut-off value. RESULTS: Follow-up was possible in 1631 cases
      (84.8%). Trisomy 21 was found in 22 cases (1.35%). Nasal bone length measurement
      increased as a function of gestational age (P < 0.05) showing a linear
      relationship. Screening for trisomy 21 using the 5(th) percentile as a cut-off
      value resulted in a sensitivity of 59.1% for a 5.1% false-positive rate. The
      likelihood ratio was 11.6. CONCLUSION: Screening for trisomy 21 using fetal nasal
      bone length measurements showed a sensitivity comparable to that of maternal
      biochemistry for a given false-positive rate of 5%. Association of nasal bone
      lengths with other sonographic markers, taking into account the background risk
      for maternal and gestational age, may further improve sensitivity and reduce
      false positives, allowing avoidance of unnecessary invasive diagnostic
      procedures.

PMID- 12601839
TI  - In-utero development of the fetal colon and rectum: sonographic evaluation.
AB  - OBJECTIVE: To construct a normal range for the internal diameter of the fetal
      descending colon and rectum during gestation. SUBJECTS AND METHODS: This was a
      prospective, cross-sectional study including 379 healthy pregnant women with
      normal singleton pregnancies at 19-40 weeks of gestation. Measurements of the
      fetal descending colon (maximum internal diameter) and the fetal rectum (at the
      level of the bladder, measuring the anteroposterior diameter), were performed by
      high-resolution transabdominal sonography. RESULTS: Adequate bowel measurements
      were obtained in all 379 fetuses. The diameter of the descending colon and rectum
      plotted as a function of gestational age had a sigmoid curve; the curve
      estimation was expressed by a cubic regression equation with R(2) of 0.848 and
      0.831, respectively (P < 0.0001). The normal mean and the 95% prediction limits
      were defined. CONCLUSION: The present data provide a normal range of fetal bowel
      (descending colon and rectum) diameters from the early second trimester of
      pregnancy onwards. They may allow intrauterine assessment of the development of
      the fetal colon and may serve as reference values in the detection of anomalies
      of the fetal bowel.

PMID- 12601840
TI  - The addition of activin A and inhibin A measurement to uterine artery Doppler
      velocimetry to improve the early prediction of pre-eclampsia.
AB  - OBJECTIVE: To evaluate whether the measurement of maternal serum activin A and
      inhibin A adds any clinically relevant information for the prediction of pre
      eclampsia in women with altered uterine artery Doppler velocimetry at 24 weeks of
      gestation. METHODS: This was a prospective, controlled, hospital-based study
      involving 58 asymptomatic pregnant women at 24 weeks' gestation in whom a
      diastolic notch of the uterine artery waveform was noted at routine Doppler
      examination. Doppler assessment of the uterine artery waveform and measurement of
      maternal activin A and inhibin A serum levels by specific two-site enzyme
      immunoassays were performed. The cut-off points for defining 'high' serum activin
      A and inhibin A levels for prediction of pre-eclampsia were chosen by receiver
      operating characteristics (ROC) curve analysis. The probability of developing pre
      eclampsia was calculated for several combinations of results of hormone testing.
      RESULTS: Activin A and inhibin A levels were higher in patients who developed pre
      eclampsia (n = 18; mean +/- standard error: 2.69 +/- 0.35 ng/mL and 131.2 +/-
      22.7 pg/mL, respectively) than in those who did not present with pre-eclampsia at
      follow-up (n = 40; activin A: 1.79 +/- 0.18 ng/mL and inhibin A: 91.9 +/- 6.2
      pg/mL; P < 0.05). Activin A at the cut-off value of 1.7 multiples of the median
      (MoM) achieved a sensitivity of 61% and a specificity of 89%, whereas inhibin A
      at the cut-off value of 1.8 MoM combined a sensitivity of 39% with a specificity
      of 92% for prediction of pre-eclampsia. The probability of pre-eclampsia was 31%
      in the whole study population, 86% if both activin A and inhibin A were elevated
      and 17% if both hormone markers were unaltered. CONCLUSION: The measurement of
      serum activin A and inhibin A levels may add significant prognostic information
      for predicting pre-eclampsia in pregnant women showing specific Doppler
      alterations in the late second trimester.

PMID- 12601841
TI  - Comparison of color Doppler uterine artery indices in a population at high risk
      for adverse outcome at 24 weeks' gestation.
AB  - OBJECTIVE: To compare uterine artery Doppler velocity and impedance indices in
      the presence and absence of uterine artery waveform notches, in the prediction of
      adverse pregnancy outcome in high-risk women. METHODS: One hundred and fifty
      seven women identified at Doppler screening as being at 'high risk' underwent a
      further uterine artery Doppler assessment at 24 weeks' gestation. Pulsatility and
      resistance indices and minimum, time averaged and time averaged maximum
      velocities were measured, and the presence of bilateral notches noted. Adverse
      outcomes were pre-eclampsia, birth weight less than the tenth centile, placental
      abruption and intrauterine death. The best cut-off for each parameter was
      assessed by univariate logistic regression, and the comparative performance of
      the screening parameters was assessed using kappa values. RESULTS: The best
      performing index in the presence of bilateral notches was mean resistance index,
      for a cut-off of 0.67, giving a kappa value of 0.65. Mean pulsatility index and
      lowest pulsatility index performed similarly well, both with kappa values of
      0.58. All velocity indices apart from lowest minimum velocity had kappa values of
      < 0.4. When indices were analyzed, irrespective of notch status, mean resistance
      and mean pulsatility indices performed similarly, with kappa values of 0.49 and
      0.46, respectively; mean minimum velocity had a kappa value of 0.4. CONCLUSIONS:
      In a high-risk population, uterine artery Doppler mean resistance indices perform
      better than do velocity indices in the prediction of adverse pregnancy outcome,
      irrespective of notch status.

PMID- 12601842
TI  - Comparison of uterine and spiral artery blood flow in women with unexplained and
      tubal infertility.
AB  - OBJECTIVE: To evaluate the possible difference in uterine and spiral artery
      impedance to blood flow among women with unexplained and tubal infertility during
      spontaneous and gonadotropin-stimulated cycles. METHODS: We prospectively
      compared uterine and spiral artery pulsatility index and peak systolic velocity
      in a longitudinal study in women with either unexplained infertility (n = 20) or
      tubal infertility (n = 18). Measurements of uterine and spiral artery impedance
      were taken on days 11-12, 16-17 and 21-23 of the spontaneous cycle and on days 1,
      5 and 10 during gonadotropin stimulation. In addition, measurements were taken on
      the days of oocyte pick-up and embryo transfer. RESULTS: A clinical pregnancy was
      achieved in 8/20 (40%) women with unexplained and 6/18 (33.3%) women with tubal
      infertility with in-vitro fertilization treatment. There were no differences in
      the uterine artery pulsatility index or peak systolic velocity during the
      spontaneous or the in-vitro fertilization cycle between the two groups. The
      impedance to blood flow in the uterine or spiral artery did not differ between
      women conceiving with in-vitro fertilization-embryo transfer and those who did
      not. However, the spiral artery pulsatility index on the 5th day of gonadotropin
      stimulation was significantly lower among women with unexplained infertility
      (0.96 +/- 0.25) compared to women with tubal infertility (1.24 +/- 0.30; P <
      0.05), but on the other days of gonadotropin stimulation the spiral artery
      pulsatility index and peak systolic velocity were similar. CONCLUSIONS: Impaired
      uterine or spiral artery blood flow is not an important factor in unexplained
      infertility.

PMID- 12601843
TI  - Predictors of success in methotrexate treatment of women with unruptured tubal
      pregnancies.
AB  - OBJECTIVE: The use of methotrexate (MTX) for the treatment of tubal ectopic
      pregnancy (EP) has become common practice, although the factors associated with a
      favorable outcome are not totally clear. The aim of this study was to investigate
      the predictors of successful MTX treatment. METHODS: One hundred and thirty-seven
      women with unruptured tubal EP in whom the hematosalpinx could be directly
      visualized by pelvic ultrasound were studied. Women who met the inclusion
      criteria were treated with MTX either: 50 mg/m(2) intramuscularly (n = 70) or
      with 1 mg/kg injected directly into the hematosalpinx under sonographic guidance
      (n = 67). The associations between the outcome of the treatment and different
      factors studied (human chorionic gonadotropin (hCG) level, progesterone level,
      hematosalpinx diameter, hemoperitoneum volume and mode of MTX administration)
      were analyzed. RESULTS: The overall success rate, defined by a post-treatment
      normal hCG level (< 10 mIU/mL), was 79.6%. The initial hCG level and the route of
      administration of MTX appeared to be two independent factors that predicted
      success. Multivariate analysis demonstrated that the success rate was
      significantly better when MTX was administered locally: the odds ratio (OR) was
      9.7 (95% CI, 3.1-30), and was significantly poorer when the hCG level was >/=
      1000 mIU/mL (P < 0.002): the OR was 0.10 (95% CI, 0.07-0.49). CONCLUSION: Among
      selected women with tubal EPs, the route of administration of MTX and the initial
      level of serum hCG are the most important factors associated with the success of
      medical treatment.

PMID- 12601844
TI  - Invasive intrauterine treatment of pulmonary atresia/intact ventricular septum
      with heart failure.
AB  - The mortality and morbidity of children with pulmonary atresia/intact ventricular
      septum (PA/IVS) are linked to the degree of right ventricular (RV) hypoplasia.
      Opening up the pulmonary valve (PV) in fetal life could result in improved growth
      of the RV making it amenable to biventricular repair postnatally. Successful
      valvulotomy of the PV was performed in a fetus with heart failure at 28 weeks.
      Following the procedure there was significant growth of the tricuspid valve and
      RV. The neonate was delivered at 38 weeks with a RV suitable for biventricular
      repair. In utero pulmonary valvulotomy is feasible and may change the natural
      history of the condition in affected fetuses with PA/IVS.

PMID- 12601845
TI  - Successful outcome in a fetus with an extremely low heart rate due to isolated
      complete congenital heart block.
AB  - Isolated complete congenital heart block (CCHB) in a fetus is usually associated
      with the presence of autoantibodies to SSA (Ro) and SSB (La) antigens in the
      maternal circulation. Although the prognosis for the majority of fetuses is good,
      it is less favorable in fetuses with a ventricular rate < 55 bpm in early
      pregnancy or with a decrease in the ventricular rate by >/= 5 bpm during
      pregnancy. It is not known if the same prognostic criteria apply for the
      occasional fetus with isolated non-autoimmune CCHB. We report a case of a single
      fetus with an isolated non-autoimmune CCHB with an extremely low ventricular rate
      (37 bpm) in which the outcome was favorable. Dilated cardiomyopathy is a rare
      complication in patients with isolated CCHB, despite early institution of cardiac
      pacing, and is usually recognized after several months of relative well-being. It
      is assumed that in the majority of patients it represents a sequel to in utero
      autoimmune or postnatal reactivation myocarditis. However, the possibility of a
      tachycardia-induced cardiomyopathy caused by an excessively high pacing rate
      should also be taken into consideration, as was clearly demonstrated in our
      patient.

PMID- 12601846
TI  - Successful outcome of advanced abdominal pregnancy with exclusive omental
      insertion.
AB  - We report the case of an advanced abdominal pregnancy with exclusive omental
      insertion whose extrauterine location was not established until delivery by
      Cesarean section at 35 weeks' gestation. It is hard to believe that omental
      placentation alone would be sufficient to sustain a pregnancy beyond a gestation
      where the fetus is viable. However, this report challenges such myths and opens
      the debate as to what represents the minimal placental maternal viscus contact
      necessary to achieve fetal viability. The case also demonstrates the continuing
      difficulty in diagnosing this rare but serious condition despite advances in
      obstetric imaging, and advocates methods to avoid missing the diagnosis, which
      could be easily incorporated at booking and mid-trimester scans. Apart from this
      case, few reports describe normal umbilical artery Doppler velocimetry in
      advanced abdominal pregnancy. There is a paucity of research on suitable clinical
      investigations prognostic for abdominal pregnancy, although this case provides
      further evidence for the use of Doppler as a useful surveillance tool in such
      cases. Finally, this case propagates the ethical and clinical controversy that
      exists in managing abdominal pregnancy, particularly when diagnosed late after
      attaining fetal viability. Expectant management may represent a feasible
      alternative to surgical termination provided the woman is fully informed of the
      attendant risks and close surveillance of the pregnancy is undertaken.

PMID- 12601847
TI  - Prenatal ultrasound diagnosis of Nager syndrome.
AB  - Nager syndrome, or acrofacial dysostosis, is a rare malformation complex
      characterized by facial anomalies (external ear abnormalities and micrognathia)
      and limb defects (radial hypoplasia and absence of the thumb and/or other
      digits). Since its first description in 1948, more than 80 cases have been
      reported in the pediatric literature. However, there is only one previous report
      on the prenatal recognition of the syndrome, which was at 30 weeks of gestation.
      We report here a further case of Nager syndrome, prospectively diagnosed at 23
      weeks of gestation.

PMID- 12601848
TI  - Prenatal diagnosis of holoprosencephaly and ectopia cordis in a twin at 12 weeks'
      gestation.

PMID- 12601849
TI  - Osteogenesis imperfecta associated with increased nuchal translucency as a first
      ultrasound sign: report of another case.

PMID- 12601850
TI  - Prenatal diagnosis of de novo mosaic distal 18q deletion associated with
      congenital anomalies.

PMID- 12601851
TI  - Three-dimensional reconstructed fetal lung using VOCAL.

PMID- 12601852
TI  - [Source innovation on drugs and establishment and application of the correlate
      techniques]

PMID- 12601853
TI  - [Laggera pterodonta--a Yunnan Herbal Medicine]
AB  - OBJECTIVE: A systematic study of Laggera pterodonta was performed in order to
      identify its bioactive compounds. METHODS: Solvent partition and column
      chromatography used to isolate and purify Laggera pterodonta compounds. The
      isolated compounds were further elucidated by high field NMR spectroscopy.
      RESULTS: Fifty-two compounds were separated and the structures of 39 compounds
      were elucidated. Twenty-four compounds have not been previously reported. For
      example, the structure of compound 19, a previously undetected compound was
      elucidated as 4gamma, 9alpha,11-triol-enantio-eudesmane using both 1D and 2D NMR
      spectroscopy. Major secondary metabolites of the Laggera pterodonta included
      eudesmane-type sesquiterpenes and flavone derivatives. CONCLUSION: A systematic
      study of a yunnan herbal medicine Laggera pterodonta resvealed several novel
      compounds that may have clinical significance. Further in vivo animal studies
      should be performed to assess their bioactive role.

PMID- 12601854
TI  - [Synthesis of hirsutrin and hyperin]
AB  - OBJECTIVE: To investigate an easier method for preparation of hirsutrin and
      hyperin. METHODS: Rutin was utilized as the starting material. The target
      compounds were produced via benzoylation, hydrolysis, glycosidation and
      deproteination. RESULTS: The yield of key intermediate 5,7,3',4'-tetra-O-benzoyl
      quercetin was improved by reducing the hydrolysis time of 5,7,3',4'-tetra-O
      benzoyl rutin in HCl/EtOH. Hirsutrin and hyperin were synthesized. CONCLSION:
      Hirsutrin can be synthesized and the yield of hyperin improved by this method.

PMID- 12601855
TI  - [Enatiomeric separation of beta-blocking agents and analogs]
AB  - OBJECTIVE: To evaluate enantiomeric separation methods for beta-blocking agents
      and analogs. METHODS: Enantiomeric separation of racemates of 11 beta-blocking
      agents and their analogs was performed using chiral stationary phases and 2,3,4,6
      tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). RESULTS: These beta 
      blocker racemates were separated into enantiomers in one or several
      chormatographic states such as propranolol, bisoprolol, metoprolol, celiprolol,
      carvedilol, sotalol, propafenone, ephedrine, and zomitriptan. Temperature had a
      significant effect on the resolution of the drugs when using chiralcel OD. Lower
      temperatures were associated with higher resolutions. CONCLUSION: When separating
      beta-blocking agents and their analogs, Chiralcel OD, Chiralpak AD, Chiral
      stationary phases and GITC chiral derivative reagents have complementary
      functions.

PMID- 12601856
TI  - [Establishment of BCG combined LPS-induced hepatocyte immunotoxicity model to
      assess liver protective effects]
AB  - OBJECTIVE: To establish a hepatocyte immunotoxicity model for screening of liver
      protective medications. METHODS: Cytotoxicity was induced by coincubating BCG
      pretreated rat hepatocytes in vivo and with 10 mg/L LPS in vitro.
      Biphenyldimethylesterate (DDB), malotilate(MLT), silybin(SB) and glycyrrhizin
      (GRZ) were coincubated along with LPS to prevent the hepatocyte injury and verify
      the applicability and reliability of the model. AST, LDH and nitric oxide (NO)
      were measured in both the serum and supernatant. The liver and spleen index were
      calculated and the liver histopathologic changes were examined microscopically.
      RESULTS: Supernatant AST, LDH and NO in the BCG combined LPS group were increased
      in comparison with the control group (P<0.01). This increase was attenuated by
      the addition of DDB, MLT, SB and GRZ (P<0.05). The serum AST, NO and liver and
      spleen index were also increased significantly compared with the control group
      (P<0.01). Microscopic exam revealed serious histopathologic changes in the BCG
      combined LPS group. Hepatoxicity with associated liver enzyme elevation but
      histopathologic changes were attenuated by DDB, MLT, SB and GRZ. CONCLUSION: BCG
      combined LPS-induced hepatocyte immunotoxicity in an in vitro rat model may be a
      useful technique to assess the effectiveness of liver protective medications.

PMID- 12601857
TI  - [Signal transduction pathways induced by nitric oxide in rat hepatocytes]
AB  - OBJECTIVE: To study signal transduction pathways in cultured rat hepatocytes in
      the high nitric oxide (NO) environment of hepatitis. METHODS: NO levels were
      assessed by measurement of its stable oxidative products nitrite (NO2(-)) and
      nitrate (NO3(-)) using the Griess method with or without thiols (GSH or L-Cys).
      Rat hepatocytes were incubated with Sodium Nitroprusside (SNP) to produce a high
      NO environment and the intracellular cGMP and s-nitrosoglutathione (GSNO) in the
      culture media were measured using radioimmunoassay or with the MTT assay absorbed
      at 334nm respectively. RESULTS: After incubation of 1.543 mmol/L SNP for 30
      minutes 0.63+/-0.06 mmol/L and at 25 minutes 0.98+/-0.11 mmol/L of NO was
      released in containing 25 mmol/L GSH and L-Cys condition. The levels of both cGMP
      and GSNO were significantly increased (compared with control P<0.05) in a dose
      related manner. CONCLUSION: Signal transduction of cultured rat hepatocytes in a
      high NO environment could be a cGMP-dependent as well as a non-cGMP-dependent
      pathway.

PMID- 12601858
TI  - [Augmentation of rat liver microsome glutathione S-transferase preparation]
AB  - OBJECTIVE: To investigate the augmentation of microsomal glutathione S
      transferase (mGST) preparation using simple organic compounds. METHODS: Rat liver
      microsomes were isolated using both the polyethyleneGlyco 6000 (PEG6000) and
      Ca(2+) precipitation methods. Next the mGST activity was measured after
      incubation with the alkylating agent N-ethylmaleimind (NEM). RESULTS: The
      baseline mGST activity of rat microsomes was 0.15 after PEG6000 exposure and
      0.082 after Ca(2+) precipitation. After NEM treatment mGST activity increased to
      1.797 (2.35X) (P<0.01) and 2.375 (4.127X) (P<0.01) respectively followed by
      purified washing. mGST activation was stimulated maximally by 5-10 mmol/L NEM and
      occurred rapidly with 1-2 min of co- incubation. CONCLUSION: For both the PEG6000
      and Ca(2+) precipitation methods the mGST activity of rat microsomes can be
      significantly enhanced after exposure to NEM. This enhancement is more prominent
      with the Ca(2+) precipitation.

PMID- 12601859
TI  - [Preparation of interferon-alpha-containing liposomes by the powder bed grinding
      method]
AB  - OBJECTIVE: To investigate a nwe, simple technique for preparation of interferon
      alpha-liposomes, which may be suitable for industrial use. METHODS The uniform
      design coupled with computerized optimization was utilized to screen the
      formulation and preparation procedure of interferon-alpha-liposomes. Pro
      liposomes were prepared by the powder bed grinding method and combined with
      interferon-alpha-solution to form interferon-alpha-liposomes. Liposome size was
      determined by the particle size analyzer. Free interferon-alpha and interferon
      alpha-liposome were separated by gel filtration. Then the recovered activity of
      interferon-alpha was analyzed by enzyme-linked immunosorbent assay. RESULTS The
      result demonstrated that the best interferon-alpha-liposome formulation was as
      follows: the protectant was sorbitol; weight ratio of protectant to lipid was
      5:1; weight ratio of octadecytamin to lipid was 1:9; weight ratio of sobey
      phosphatidylcholine to cholesterol was 9:1 respectively. Interferon-alpha
      liposome size determined by the particle size analyzer was 80.8+/-36 nm and the
      encapsulation efficiency was 59.0+/-3.3%. CONCLUSION The powder bed grinding
      method can be used to prepare pro-liposomes which can be easily combined with
      interferon-alpha-solution to form interferon-alpha-liposomes.

PMID- 12601860
TI  - [Transdermal delivery of diclofenac sodium gel after iontophoresis]
AB  - OBJECTIVE: To observe the in vivo effect of combined iontophoresis and
      laurocapram pretreatment on transdermal delivery of diclofenac sodium gel.
      METHODS: Diclofenac sodium gel was prepared using polyvinyl alcohol,
      carboxymethylcellulose sodium and hydroxypropylmethyl cellulose. The diclofenac
      blood level in rabbits was measured in four groups: passive diffusion,
      laurocapram pretreatment, iontophoresis (current density controlled at 0.3
      mA/cm(2)) and combined laurocapram pretreatment and iontophoresis. Rabbit stratum
      corneum of each of the four groups was examined using a scanning electron
      microscope. RESULTS: Diclofenac blood concentration in the passive diffusion
      group was undetectable. The diclofenac blood concentration area under the curve
      compared with time was 8.4 &mgr;l ml(-1) h(-1) in the laurocapram pretreatment
      group, 2.7 &mgr;l ml(-1) h(-1) in the iontophoresis group and 15.4 &mgr;l ml(-1)
      h(-1) in the combination group. There was no detectable damage observed by
      scanning electron microscopyto the stratum corneum after iontophoresis or
      laurocapram pretreatment. CONCLUSION: The combination of iontophoresis and
      laurocapram pretreatment appears to enhance transdermal delivery of diclofenac
      sodium gel wi thout significant skin damage.

PMID- 12601861
TI  - [Construction of HBV S gene recombinant and its immunity induced in mice]
AB  - OBJECTIVE: To investigate the feasibility of HBV DNA vaccines. METHODS: HBV S
      gene was obtained by PCR and the PCR product was cloned into pcDNA3. The
      recombinant was screened by antibiotics, identified by digestion and confirmed by
      sequencing. The plasmid was then transfected into mammalian cell COS-7 for
      transient expression. Then the recombinant was injected into mice and the immune
      responses induced in mice were investigated. RESULTS: The sequence of HBV S gene
      was correct and HBsAg could be detected in cells transfected with pcDNA3-S. After
      immunization, the positive rate in mice immunized with pcDNA3-S and pCMV-S was
      70%(7/10) and 80% (8/10). The mean levels of anti-HBs were (32.14+/-13.79)mIU/ml
      and (28.50+/-11.87)mIU/ml respectively. There was no statistically significant
      difference between them P 0.05 . The mean levels of anti HBs in the control group
      and blank groups were both less than 10 mIU/ml. In mice immunized with pcDNA3-S
      and pCMV-S the results were (35.40+/-4.85)% and (38.20+/-7.69)% when E/T was
      20:1, or (23.95+/-3.98)% and (24.55+/-3.59)% when E/T was 10:1, again showing no
      difference statistically (P>0.05). The specific CTL cytotoxicity rate of control
      and blank groups was both less than 5%. CONCLUSION: A specific humoral and
      cellular immune response can be induced in mice by intramuscular injection of
      pcDNA3-S.

PMID- 12601862
TI  - [Histological observation of the interface of oral epithelium and titanium
      implant with titanium dioxide on the surface]
AB  - OBJECTIVE: To investigate the healing process at the interface between oral
      epithelium and a titanium implant with titanium dioxide on the surface and
      whether a good epithelial barrier could be formed. METHODS: Titanium implants
      with titanium dioxide on the surface were placed in the mandibular alveolar area
      of Beagle dogs after their premolars had been removed three months previous. On
      the 15th day, second month and loading second month after implantation specimens
      were taken and examined after HE staining as well as by transmission electron
      microscopy. RESULTS: Fifteen days after implantation the epithelial collar was
      formed, junctional epithelium actively regenerated and attachment to the matrix
      on the surface of the implant occurred by hemidesmosomes. Two months after
      implantation junctional epithelium was increasing, showing three to four layers
      consistent with each other. Junctional epithelium appeared to be generated when
      stimulated by inflammation and shaped into epithelium rete pegs after loading for
      two months. CONCLUSION: Oral junctional epithelium can attach very well to
      titanium implants with titanium dioxide on the surface which also provides a
      biological barrier.

PMID- 12601863
TI  - [Study on the bacterial identification using 16S-23S rRNA gene spacer regions]
AB  - OBJECTIVE: To examine the use of PCR utilizing 16S-23S rRNA gene spacer regions
      in the identification of bacteria. METHODS Primers used in PCR were designed by
      using the target sequences from the genes encoding 16S-23S rRNA spacer regions.
      PCR was used for the detection of different standard and clinical bacterial
      strains. RESULTS Characteristic DNA maps were present after using the PCR to
      identify 27 standard strains from 27 species. The maps could be directly used for
      classification of the tested bacterial strains or further differentiated by RFLP.
      The sensitivity of the PCR may be as high as 2.5 CFU/ml. No non-specific
      amplification products were observed when using DNA from human PBMC funguses or
      viruses as templates. Thirty-two strains of bacteria isolated from clinical
      strains showed DNA maps similar to the DNA maps amplified from standard strains.
      CONCLUSION The PCR detection of bacteria using 16S-23S rRNA gene spacer regions
      is sensitive, rapid, specific and accurate for identification of bacteria and
      provides a new rapid method for determining the clinical diagnosis and the
      etiology of sepsis.

PMID- 12601864
TI  - [Effects of fumaric acid esters on differentiation of dendritic cells in vitro]
AB  - OBJECTIVE: To investigate the effect of anti-psoriatic drug fumaric acid esters
      (FAE) on the differentiation of dendritic cells (DC). METHODS: Dendritic cells
      were obtained by differentiating human monocytes in vitro. Flow cytometry was
      used to analyse the effect of FAE on cell surface expression of CD1a, CD14, CD40,
      CD80, CD86 and HLA-DR by monocyte-derived dendritic cells (MoDC). Mixed
      lymphocyte reaction (MLR) was made to demonstrate the influence of FAE on T cell
      stimulatory activity of MoDC. RESULTS: Dimethylfumarate and
      methylhydrogenfumarate-calcium-salt (0.01 approximate, equals 100 mg/L) inhibited
      MoDC differentiation as well as reducing the capacity of MoDC to stimulate
      lymphocytic proliferation in MLR. CONCLUSION: The mode of action of FAE in pso
      riasis may be mediated by inhibition of DC differentiation.

PMID- 12601865
TI  - [Encoding genes and genotypes of gamma-lactamases produced by a multiple
      resistant Klebsiella pneumoniae]
AB  - OBJECTIVE: To determine the sequence of gene for encoding beta-lactamase produced
      by Klebsiella pneumoniae E3 isolated from Jiaxing Area in Zhejiang Province.
      METHODS The Klebsiella pneumoniae strain E3 was identified as an ESBLs-producing
      bacterium by inhibitor-potentiated broth dilution test. The gene encoding gamma
      lactamase of the strain was amplified by PCR. The purified PCR product was cloned
      and sequenced by Sanger's dideoxy chain termination composition method. RESULTS
      The Klebsiella pneumoniae strain E3 produced both TEM and SHV gamma lactamases.
      The SHV encoding gene had 812 nucleotide residues responsible for encoding SHV-11
      gamma-lactamase and the TEM encoding gene had 973 nucleotide residues responsible
      for encoding TEM-1 gamma-lactamase. CONCLUSION The Klebsiella pneumoniae strain
      E3 isolated from a patient in Jiaxing Area in Zhejiang Province is able to
      produce both TEM-1 and SHV-11 gamma-lactamases.

PMID- 12601866
TI  - [Preliminary observation on the efficiency and safety of Lamivudine used in
      decompensative hepatic cirrhosis (B) accompanied by hypersplenism]
AB  - OBJECTIVE: To study the efficacy and safety in patients with decompensative
      hepatic cirrhosis treated with Lamivudine. METHODS: Eighteen decompensative
      hepatic cirrhosis (B) (active phage) patients accompanied with hypeersplenism
      were treated with Lamivudine 100mg po. per day. The total course of treatment was
      3 months to 6 months when HBVDNA became negative and HBeAg seroconversion
      occurred in these patients after Lamivudine treatment. The efficacy and safety in
      patients were evaluated as follows: HBVDNA were negative, HBeAg seroconversion
      occurred and hepatic cirrhosis child-stageing changed. The efficacy and safety
      between treated group and contrast group were compared during treatment with
      Lamifudine for 1 year and follow-up foe 1 year after completing treatment.
      RESULTS: The total efficacy of treated group was 27.7% and 71.43% respectively
      during the phase II trial and the safety was good in these patients. CONCLUSION:
      The efficacy and safety of Lamivudine are good while it is used in non-registered
      adaptation of decompensative hepatic cirrhosis with hypersplenism.

PMID- 12601867
TI  - [Influence of different DNA extractions on the identification of streptococcus
      sanguis group by arbitrary primed polymerase chain reaction]
AB  - OBJECTIVE: To assess the influence of different DNA extractions on the
      identification of streptococcus sanguis group (SSG) species by arbitrary primed
      polymerase chain reaction (AP-PCR). METHODS: AP-PCR was used to distinguish SSG
      species by designing 25bp arbitrary primer 5'AAG AGA GGA GCT AGC TCT TCT TGG A
      3', and the genomic DNA was extracted by 3 methods. RESULTS: There were great
      differences in the main band of DNA polymorphism among SSG species. The similar
      band could be got from the different DNA extractions in the same species.
      CONCLUSION: Different DNA extractions have no influence on the identification of
      SSG.

PMID- 12601868
TI  - [Observation of the metatarsal nutrient artery]
AB  - OBJECTIVE: To observe the origin, course and diameter of the metatarsal nutrient
      artery. METHODS: The metatarsaL nutrient in 90 feet, ranging in age from newborn
      to 87 years, were studied by perfusion method. The origin, course and diameter of
      these arteries were observed and measured. RESULTS: The diameter of the
      metatarsal nutrient artery was 0.24 approximate, equals 0.30 mm. The nutrient
      arteries of the first metatarsal bone originated from the deep plantar branch and
      the first metatarsal plantar artery in 59.6% of specimens, while the nutrient
      arteries of the other metatarsal bones mainly originate from the plantar
      metatarsal arteries, the plantar arch and its perfora-ting branches. The
      diaphysial nutrient foramina were situated in the middle third of the shaft over
      90% of specimens. CONCLUSION: The metatarsal nutrient artery showes practical
      significance in clinic.

PMID- 12601869
TI  - [Complications of pancreaticoduodenectomy in 298 cases]

PMID- 12601870
TI  - [Expanded excision of sternal tumor with iliac bone grafting for reconstruction
      of the sternum]

PMID- 12601871
TI  - [Modificatory effect of green tea extract on chromatoid breaks induced by
      benzo[a]pyrene diol epoxide]

PMID- 12601873
TI  - [Trend of natural drug development]

PMID- 12601872
TI  - [Surgical treatment of congential heart disease associated with infective
      endocarditis in children]

PMID- 12601875
TI  - [Non-traditional risk factors for atherosclerosis]

PMID- 12601874
TI  - [Advances of chmokines in pathogenesis of psoriasis]

PMID- 12601876
TI  - [Cloning of human vascular endothelial growth factor cDNA and its expression in
      COS-7 cells]
AB  - OBJECTIVE: To clone vascular endothelial growth factor (VEGF) cDNA gene,
      construct its eukaryotic expression vector and to express this recombinant
      plasmid in COS-7 cells. METHODS: Human VEGF165 cDNA was amplified by RT PCR from
      human ovarian carcinoma. After DNA sequenced, the VEGF165 cDNA was inserted into
      eukaryotic expression vector pcDNA3.1(-). The recombinant plasmid pcDNA3.1
      VEGF165 containing VEGF165 cDNA was identified by enzyme digestion and
      transferred into COS-7 cells mediated by liposome. The transient expression of
      VEGF was detected by immunohistochemical staining. RESULTS: The cloned VEGF165
      cDNA was confirmed by enzyme digestion and DNA sequence analysis. The
      immunohistochemical results showed that the VEGF165 protein was expression in COS
      7 cells 72 h after gene transfer. CONCLUSION: VEGF165 cDNA gene successfully
      cloned and expressed in COS-7 cells.

PMID- 12601877
TI  - [Correlation of autoantibodies against oxidized low density lipoprotein and its
      immune complex with coronary artery disease]
AB  - OBJECTIVE: To evaluate the relationship between autoantibodies against oxidized
      low density lipoprotein(ox- LDL), immune complex and coronary artery
      disease(CAD). METHODS: The levels of autoantibodies against ox-LDL and immune
      complex were assayed by ELISA, the content of ox-LDL and lipid levels were also
      measured. The serum samples were taken from 61 patients with CAD, 116 patients
      with essential hypertension(EH) and 123 healthy individuals as control. RESULTS:
      The patients with CAD had significantly higher levels of anti-ox-LDL
      IgG[21.48(17.58 approximate, equals 29.01)U/L], anti-ox-LDL IgM4.71[3.88
      approximate, equals 7.06)U/L] and ox-LDL[0.87(0.44 approximate, equals 1.08)
      mg/L] than EH group[15.93(11.12 approximate, equals 22.26) U/L 2.54(1.17
      approximate, equals 5.05) U/L 0.32(0.16 approximate, equals 0.61) mg/L]and
      healthy control group[11.12(4.70 approximate, equals 16.57)U/L 1.61(0.60
      approximate, equals 3.03)U/L 0.23(0.12 approximate, equals 0.36)mg/L], P<0.001.
      However, the serum ox-LDL immune complex[2.63(1.69 approximate, equals 5.90)U/L]
      was significantly lower in CAD than that in EH group[15.71(6.25 approximate,
      equals 28.74)U/L] and that in healthy control group[12.54(8.28 approximate,
      equals 23.90)U/L], P<0.001. There were discrepancies in the association between
      ox-LDL and autoantibodies against ox-LDL among different groups. CONCLUSION: The
      changes of autoantibodies against ox-LDL and immune complex in patients with CAD
      may be related to the role of ox-LDL and autoantibodies against ox-LDL in the
      process of coronary atherosclerosis.

PMID- 12601878
TI  - [Angiotensin II increases the expression of lectin-like oxidize low-density
      lipoprotein receptor- 1 in cultured human umbilical vein endothlial cells]
AB  - OBJECTIVE: To observe whether angiotensin II (AngII) influences expression of
      lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) in cultured human
      umbilical vein endothlial cells(HUVECs). METHODS: Cultured HUVECs were incubated
      with 10(-5)mol/L approximate, equals 10(-10) mol/L AngII for 24 h or with 10(-6)
      mol/L AngII for various time up to 48 h. Then HUVECs LOX-1 protein expression was
      measured by endothlial cell enzyme linked immunosorbent assay, and mRNA level of
      LOX-1 was detected by quantitative competitive reverse transcription-polymerase
      chain reaction. RESULTS: Incubation of HUVECs with AngII for 24 h significantly
      increased LOX-1 protein expression (P<0.001). The increase was dependent on AngII
      concentration (10(-5)mol/L approximate, equals 10(-9)mol/L). LOX-1mRNA expression
      was also induced by AngII, and after 24 h incubation of AngII(10(-5)mol/L
      approximate, equals 10(-8)mol/L), LOX-1mRNA expression increased 4.43, 4.25,
      2.71, 1.84 times, respectively. After treatment with 10(-6) mol/L AngII for 3 h,
      LOX-1 expression (protein and mRNA) was elevated (P<0.001) in HUVECs, reaching
      its maxium at 24 approximate, equals 36 h. CONCLUSION: AngII upregulates LOX-1
      expression concentration-dependently and time-dependently in HUVECs.

PMID- 12601879
TI  - [Relationship of collagen content, intimal thickening and angiotensin II level of
      iliac arteries after balloon injury in rabbits]
AB  - OBJECTIVE: To investigate the relationship of collagen content intimal thickening
      and angiotensin II level of iliac arteries after balloon injury in rabbits.
      METHODS Fifty male New Zealand white rabbits were randomly devided into 6 groups:
      losartan groups, benazapril groups and control groups for 4 weeks or 8 weeks.
      Every rabbit underwent endothelial debridement of the right iliac artery.
      lorsartan (15 mg/kg/d) and benazapril (5 mg/kg/d) were orally administrated
      respectively in losartan groups and benazepril groups from 5 days before until 4
      weeks or 8 weeks after balloon injury. RESULTS: Collagen content and intimal area
      of rabbit iliac arteries were increased after balloon injury. After intervention
      for 4 weeks with losartan and benazapril, collagen content was decreased in
      losartan and benazapril groups than in control group 23.58+/-6.16 % and 22.67+/
      10.20 % compared with 35.20+/-7.25 % respectively, P<0.05. After intervention for
      8 weeks, collagen content was significantly decreased (20.69+/-11.16)% and
      25.41+/-11.00 % compared with 42.69+/-13.99 % respectively, P<0.05; Intimal area
      and intimal to medial area ratio were also decreased in losartan and benazapril
      groups than in control group; Lumen area was increased in losartan and benazapril
      groups than in control group(0.79+/-0.25)mm2 and (0.76+/-0.28)mm2 compared with
      (0.62+/-0.27)mm2 P<0.05; Tissue angiotensin II level was increased in losartan
      group (516.31+/-70.79)pg/mg.pro compared with (410.72+/-100.11)pg/mg.pro, P<0.05,
      and decreased in benazapril group than in control group (340.62+/-67.69)pg/mg.pro
      compared with (410.72+/-100.11)pg/mg.pro, P<0.05. There were close correlation
      between tissue angiotensin II level and intimal area, or between tissue
      angiotensin II level and intimal to medial area ratio, or and collagen content in
      benazapril group, respectively, P<0.05. Conclusion (1) Collagen protein is a
      dynamic participant in vascular injury. (2) Tissue renin angiotensin system may
      play an important role in collagen accumulation, intimal thickening and vascular
      injury after angioplasty. (3) Losartan and benazapril reduce vascular collagen
      content and inhibit intimal thickening after balloon injury.

PMID- 12601880
TI  - [Serum levels of soluble Fas soluble Fas ligand and soluble IL-2 receptor in
      patients with coronary heart disease]
AB  - OBJECTIVE: To evaluate the relationship between serum levels of soluble
      Fas(sFas), soluble Fas li gand(sFasL), soluble IL-2 receptor(sIL-2R) and coronary
      heart disease (CHD). METHODS: With enzyme-linked immunosorbent assay (ELISA)
      tests, sFas, sFasL and sIL-2R were measured in the sera from 30 patients with CHD
      and 26 subjects without CHD as controls. RESTULTS: Mean level of sFas was
      significantly higher in patients with CHD than in controls [(1 583.41+/
      174.46)ng/L compared with (1 374.55+/-142.42)ng/L, P<0.01]. Compared with the
      controls, the mean level of sIL-2R was significantly higher in patients with CHD
      [(944.50+/-395.59)ng/L compared with (652.45+/-163.36)ng/L P<0.01]. Moreover, in
      patients with CHD sFas and sIL-2R were positively correlated (r=0.418 P<0.05).
      Whereas no such difference was found between both groups in sFasL (P<0.05).
      CONCLUSION: High levels of serum sFas and sIL-2R were associated with CHD, and
      elevation of sFas may inhibit apoptosis in activated T cells, leading to coronary
      events.

PMID- 12601881
TI  - [Effects of carvedilol on circulating levels of endothelin and von Willebrand
      factor in patients with unstable angina pectoris]
AB  - OBJECTIVE: To observe the effect of carvedilol on circulating levels of
      endothelin (ET) and von Willebrand factor (vWF) in patients with unstable angina
      pectoris (UAP). METHODS Forty patients with UAP were randomly divided into two
      groups. On the basis of anti coagulated and vasodilator remedy patients in
      control group(n=21) were given benazeptil(10 mg/d) for three days while patients
      in therapeutic group(n=19) were administered carvedilol(40 mg/d) for three days.
      Before and at the end of treatment,ET was measured by RIA and vWF by ELISA in
      patients with UAP and healthy individuals(n=20), heart rate and blood pressure
      were also recorded. RESTULTS The levels of circulating ET 101.8+/-28.9 versus
      110.6+/-43.5 ng/L and vWF 162.6+/-55.6 versus 172.9+/-37.8 % between control
      group and carvedilol group were not significantly different before treatment, but
      both were higher than those in healthy individual ET 81.2+/-34.0 ng/L, vWF
      142.0+/-49.4 % (P<0.05). After the treatment, the levels of ET 106.3+/-38.2 ng/L
      and vWF 155.4+/-54.2 % in control group did not decrease significantly (P>0.05),
      while those in carvedilol group ET 89.2+/-45.5 ng/L, vWF 129.2+/-48.8 % decreased
      markedly with the reduction of heart rate and blood pressure(P<0.05). CONCLUSION
      Carvedilol can decrease circulating levels of endothelin and von willebrand
      factor in patients with UAP markedly.

PMID- 12601882
TI  - [Clinical significance of plasma homocysteine in the coronary atherosclerosis
      patients]
AB  - OBJECTIVE: To investigate the clinical significance of plasma homocysteine Hcy in
      patients with coronary atherosclerosis. METHODS Plasma Hcy levels of 85 patients
      with coronary atherosclerosis and 68 normal controls were determined by
      fluorescence polarization immunoassay. RESULTS The mean levels of plasma Hcy were
      (9.31+/-3.80)&mgr;mol/L in normal controls and (13.39+/-6.06)&mgr;mol/L in
      patients with coronary atherosclerosis. That was (11.36+/-3.86)&mgr;mol/L in the
      patients with micro-pathological changes of coronary artery, (13.32+/
      6.09)&mgr;mol/L with single-vessel disease,(13.39+/-4.92)&mgr;mol/L with double
      vessel disease, and (18.23+/-8.98)&mgr;mol/L with three-vessel disease by
      coronary angiography. Statistically, the mean plasma Hcy concentrations in male
      and female patients was higher than that in the corresponding control
      subjects(13.77+/-6.68 compared with 10.50+/-4.07, 11.50+/-3.58 compared with
      7.80+/-2.85 &mgr;mol/L,P<0.001 respectively). CONCLUSION The patients with
      coronary atherosclerosis present hyperhomocysteinemia is very important to
      determine plasma homocysteine for diagnosis and therapy in the patients with
      coronary heart disease.

PMID- 12601883
TI  - [Effect of Chrysanthemum morifolium Ramat on apoptosis of bovine aortic smooth
      muscle cells]
AB  - OBJECTIVE: To observe the effect and the mechanism of Chrysanthemum morifolium
      Ramat on apoptosis of bovine aortic smooth muscle cells. METHODS: Vascular smooth
      muscle cells were isolated from thoracic aorta of fetal calf and cultured, then
      incubated with different concentration of Chrysanthemum morifolium Ramat.
      Apoptosis was measured by flow cytometry. SOD and MDA were measured by
      spectrophotometer. RESULTS: We found that: (1) the number of apoptotic cells was
      reduced from (4.425+/-0.624)% to (2.875+/-0.640)% in Chrysanthemum morifolium
      Ramat group, in a concentration dependent manner; (2) the value of SOD was
      increased from (1.683+/-0.149)X10(4) U/L to (2.297+/-0.230)X104 U/L and the value
      of MDA was reduced from(166.454+/-56.805)&mgr;mol/L to (73.068+/
      27.203)&mgr;mol/L in Chrysanthemum morifolium Ramat group, also in a
      concentration dependent manner. CONCLUSION: Chrysanthemum morifolium Ramat can
      inhibit apoptosis of vascular smooth muscle cells in a concentration-dependent
      manner.

PMID- 12601884
TI  - [Assessment of myocardial ischemia and infarction by intravenous myocardial
      contrast echocardiography with perfluorocarbon microbubbles]
AB  - OBJECTIVE: To assess the value of myocardial contrast echocardiography (MCE) with
      intermittent second harmonic technique and perfluorocarbon microbubbles in
      identifying myocardial ischemia and infarction. METHODS: Open-chest dogs were
      performed by intravenous MCE with perfluorocarbon microbubbles after 3 h of left
      anterior descending coronary artery (LAD) occlusion. The parameters of time
      intensity curve were measured and compared between the normal and ischemic
      myocardial area at short-axis view of left ventricule midpapillary muscle level.
      The infarct size assessed by MCE was compared with the gross pathologic specimen
      stained with triphenyltetrazolium chloride (TTC). RESULTS: The peak intensity
      (PI), T1/2, and area under curve (AUC) in the ischemic area were significantly
      different versus the normal area 13.5+/-1.9 compared with 22.5+/-2.4; 16.6+/-0.9
      compared with 9.7+/-0.5; 231.6+/-14.9 compared with 405.6+/-12.3 P<0.02). The
      percents of the no flow area determined by MCE had correlation with those by TTC
      stain(r=0.89, P=0.01). CONCLUSION: Intermittent second harmonic MCE using
      intravenous injection of perfluorocarbon microbubbles could assess myocardial
      perfusion, diagnose ischemia, and define myocardial infarct size.

PMID- 12601885
TI  - [Comparative analysis of metastatic variants from the colorectal tumor cell line
      HT-29]
AB  - OBJECTIVE: To analyze the relationship between metastatic potential and related
      facters of colorectal tumor cell lines. METHODS: The variants HT-29c and HT-29d
      cell lines derived from the selection of HT-29 cells were injected into nude rats
      and the metastatic potential of the two tumor cell variants was analyzed.
      Expression of urokinase-type plasminogen activator (uPA) and plasminogen
      activator inhibitor type 1 (PAI-1) were measured with ELISA in vitro in
      colorectal carcinoma cell lines WiDr, HT-29 and HT-29d. Expression of
      carcinoembryonic antigen (CEA) and phosphoinositide 3-kinase (PI3-Kinase) were
      determined with immunohistochemistry, (IHC) in vitro and in vivo in WiDr, HT-29
      and HT-29d cell lines. In addition, CEA expression was demonstrated with
      fluorescence activated cell sorter (FACS) in vitro. RESULTS: The liver metastasis
      rate of the variant HT-29d (with 4 cycles of selection), increased as compared
      with that of parental HT-29 cells and that of variant HT-29b cells (with 2 cycle
      of selection). The uPA concentration of variant HT-29d cell line was
      significantly higher than that of the non metastatic WiDr and the low metastatic
      HT-29 cells (P<0.05). The variant HT-29d cells produced stronger PI3-kinase
      expression as compared with the non-anetastatic WiDr cells and the low metastatic
      HT-29 cells in vivo. CONCLUSION: The selected variant cell lines can exhibit an
      enhanced metastatic potential. The level of uPA and PAI-1 are positively
      correlated with the metastatic capacity of tumor cells. The expression of PI3
      kinasecorrelates with tumor development and metastasis.

PMID- 12601886
TI  - [Detection of transfusion transmitted virus infection of healthy blood donors in
      Hangzhou region and nucleotide sequence analysis of partial positive samples]
AB  - OBJECTIVE: To investigate the frequency of transfusion transmitted virus (TTV)
      infection in healthy blood donors in Hangzhou area and the mutation of TTV
      genomic fragment. METHODS DNA in serum samples of 203 healthy donors was
      extracted by phenol-chloroform method to detect TTV by semi-nested polymerase
      chain reaction and nucleotide sequences of partial amplification products were
      determined after T-A cloning. RESULTS TTV infection rate in 203 cases of blood
      donors in Hangzhou area was 15.3%. The homology of the amplified products of
      partial TTV positive samples compared with thereported nucleotide and putative
      amino acid sequences of TTV TA278 were 63.51% approximate, equals 67.12% and
      59.46% approximate, equals 66.22% respectively. CONCLUSIONS TTV infection rate in
      the blood donors in Hangzhou is relatively high. The TTV infecting blood donors
      in the area may be a kind of novel genotype.

PMID- 12601887
TI  - [Effect of self-etching primers on microleakage of resin composites in class V
      restorations]
AB  - OBJECTIVE: To evaluate in vitro microleakage of class V restorations using two
      self-etching primers with a flowable resin or hybrid resins. METHODS: Forty human
      molars were divided into 3 groups according to axial surfaces. Each group was
      randomly assigned to 2 subgroups (n=20) with either butt-joint or the beveled
      preparations. Class V preparations were cut in cemento-enamel junction. Groups A,
      B, C were respectively restored with CLB2/Clearfil AP-X, APMB/FHC-Merz or
      APMB/Liquicoat. Half specimens of each subgroup were thermocycled 2 500 times.
      After staining, dye penetration was evaluated in the ordinal scale at
      40Xmagnifications for occlusal and the gingival margins. The wall adaptation of
      the randomly selected specimens was analyzed with a SEM on replicas of the
      sectioned teeth. RESULTS: None of bond systems in this study prevented the
      microleakge. The restorations with the bur-beveled preparations leaked the same
      as those with the butt joint preparations (P>0.05). The thermocycled specimens
      and the non-thermocycled specimens leaked similarly (P>0.05). The flowable resin
      liqucoat leaked significantly more than hybrid resin in dentinal margins
      (P<0.05). CONCLUSION: The self-etching primers can not reduce the microleakge in
      the dentin-restoration interfaces. The flowable resin leak more than the hybrid
      resin in dentin-restoration interfaces. The bur- beveled preparations do not
      significantly reduce the microleakage in class V resin restorations bonded with
      self-etching primers.

PMID- 12601889
TI  - [Virtual colonoscopy in diagnosis of colorectal neoplasia]
AB  - OBJECTIVE: To evaluate the value of virtual colonoscopy in diagnosis of
      colorectal neoplasia. METHODS: Virtual colonoscopy was performed in 29 patients
      with colorectal neoplasia confirmed by colonoscopy. The results were compared
      with colonoscopy for each case. RESULTS: Virtual colonoscopy was successfully
      performed in each patient without any complications. All colorectal carcinomas
      detected by colonoscopy were identified by virtual colonoscopy. Twenty-five
      polyps were detected with colonoscopy, whereas only 16 identified by virtual
      colonoscopy. Compared with the results of colonoscopy, detection rate of polyps
      greater than 1.0 cm between 0.5 approximate, equals 0.9 cm and less than 0.5 cm
      in size was 90.0% 62.5% and 28.6% respectively. CONCLUSION: Virtual colonoscopy
      is fast, minimal invasive and well tolerated. This technique is a valuable
      clinical method in diagnosis of colorectal cancer and polyps larger than 0.5 cm
      in size.

PMID- 12601888
TI  - [Treatment of partial thickness burn wound with herb plaster Tangshangxiaobogao]
AB  - OBJECTIVE: To evaluate the therapeutic effect of the herbal plaster
      Tangshangxiaobagao on partial thickness burn wound. METHODS: A randomized
      controlled trial was conducted with two herbal plasters: Tangshang-xiaobagao and
      Jingwanhong in 57 hospitalized burn patients. Both the effect and safety of two
      herbal plasters were noted in patients with partial thickness burns. RESTULTS: In
      superficial second degree burns, the 7 d healing rate of both groups was (61.35+/
      36.26)%and (51.21+/-37.24)% and the healing time (10.56+/-3.43)d and (11.98+/
      4.13)d P<0.05 respectively. While in deep second degree burns, the 14 d healing
      rate of both groups was (62.9+/-36.0) % and (53.9+/-32.2) % and the healing time
      (19.4+/-4.9)d and (21.5+/-5.5)d, respectively. Study group had lower VAS(visual
      analogue scale)score than control group. No obvious side effects were observed in
      study group. CONCLUSION: Tangshangxiaobagao is safe and may be an effective
      adjunct for treatment of partial thickness burn wounds.

PMID- 12601890
TI  - [Comparison study on child anxiety disorder with different family
      characteristics]
AB  - OBJECTIVE: To investigate the relations between child anxiety disorder with
      different family characte ristics. METHODS Family characteristics were measured
      by family environment scale. 144 mothers of child with anxiety disorder and 100
      mothers of health children were invited to fill out questionnaires. RESULTS There
      were obviously different family characteristics between health children and those
      with anxiety disorder except phobic anxiety disorder. The scores of cohesion,
      independence, achievement orientation and active recreational orientation in
      children with anxiety disorder were significantly lower than those in health
      children P<0.01). In 4 groups of children with anxiety disorder cohesion showed
      correlation with intellectual- cultural orientation r=0.9219, 0.8348, 0.8935,
      0.9550 respectively, P<0.001). CONCLUSION: The importance of family
      characteristics must be emphasized for children with anxiety disorder.

PMID- 12601891
TI  - [Cytogenetic analysis on patients with a history of spontaneous abortion]
AB  - OBJECTIVE: To investigate the incidence and identify the type of chromosome
      abnormalities in couples with spontaneous abortion. Also to observe the effect of
      balanced translocation on pregnancy outcome. METHODS: A total of 9258 cases of
      spontaneous abortion were studied. Lymphocyte culture and harvest were performed
      according to standard methods. Karyotypes were analyzed by G-banding in all cases
      and C- or N-banding in some cases in additions. RESULTS: The overall incidence of
      chromosomal abnormalities was 2.72% (women 3.32%, men 2.12%). In womem with 4 or
      more spontaneous abortions, the incidence of chromosomal abnormalities was
      significantly higher (4.9%, P<0.01). Among the 252 cases the following chromosome
      abnormalities were noted: translocations (81.0%), numerical abnormalities
      (13.1%), inversions (4.0%), deletion (0.4%) and marker chromosomes (0.8%). There
      were 473 pregnancies in 130 carriers of balanced translocations; their
      spontaneous abortions rate was 90.1%. CONCLUSION: Womem with a history of
      spontaneous abortion have a higher rate of chromosomal abnormalities than their
      male partner. Chromosomal abnormalities are significantly more common in women
      with 4 or more spontaneous abortions. Balanced translocations are the major
      abnormal karyotpes associated with spontaneous abortions. In such patients,
      prenatal diagnostic testing is advised for all subsequent pregnancies.

PMID- 12601892
TI  - [Implantation of phakic anterior chamber intraocular lens for high myopia]
AB  - OBJECTIVE: To investigate the efficacy and safety of the implantation of phakic
      anterior chamber intraocular lens for high myopia. METHODS: A consecutive group
      of 29 eyes in 16 patients with (-7.00 to -30.00) D of myopia were implanted.
      RESULTS: All of the 29 eyes were implanted successfully and followed-up 3
      approximate, equals 6 months. The mean best corrected visual acuity was 0.50+/
      0.26 pre-operatively and 0.73+/-0.263 months post-operatively, there was no
      significant difference t=2.043, P=0.051 . The mean refractive diopter was 
      18.03+/-5.54 D pre-operatively and -0.82+/-1.54 D post-operatively t=30.899
      P=0.000 ; The mean intraocular pressure was 2.091+/-0.380 kPa pre-operatively and
      (1.734+/-0.572)kPa post-operatively t=1.98 P=0.07 ; The mean counts of
      endothelial cells was (2704+/-390 /mm2 pre-operatively and (2 519+/-278)/mm2 post
      operatively (t=1.16 P=0.26). CONCLUSION: The implantation of phakic anterior
      chamber intraocular lens for high myopia is predictable, reversible and
      controllable with simple manipulation. Long- time following-up is still required.

PMID- 12601893
TI  - [Application of impression cytology in diagnosis of ocular surface diseases]
AB  - OBJECTIVE: To evaluate the usefulness of impression cytology in diagnosing of
      ocular surface diseases. METHODS: Impression cytology was performed on 18 eyes
      with Sjgren's syndrome (dacryosialo-adenopathia atrophicans), 23 eyes with non
      Sjgren's syndrome, 15 eyes after thermal or chemical burn at the scarred stage
      and 20 normal eyes. Conjunctival goblet cell density, conjunctival epithelial
      squamous metaplasia and corneal cytological features were evaluated respectively.
      RESULTS: In impression cytology, eyes of Sjgren's syndrome demonstrated a
      significantly higher grade of squamous metaplasia and lower goblet cell density
      (P<0.05) as compared with normal eyes and with eyes of non-Sj gren's syndrome in
      the bulbar conjunctiva, whereas no statistically significant difference of
      squamous metaplasia grade or goblet cell density was found in the palpebral
      conjunctiva (P>0.05) in these two groups. In thermal or chemical burned eyes at
      the scarred stage, the inferior, nasal and temporal bulbar conjunctiva showed
      higher conjunctival goblet cell density than in the normal eyes (P<0.01). Before
      surgery of ocular surface reconstruction, conjunctival goblet cells were detected
      on the corneal area in the 8 thermal or chemical burned eyes. However, the goblet
      cells in the corneal area of 7 burned eyes were completely resolved after
      successful ocular surface reconstruction. CONCLUSION The demonstrations of
      impression cytology in Sjgren's syndrome, thermal or chemical burn are
      distinctive. Impression cytology is a noninvasive,quick,easy and inexpensive
      technique, being a useful tool for diagnosis of ocular surface diseases.

PMID- 12601894
TI  - [Peripheral iridoplasty with doubled-frequency Nd:YAG laser as treatment for
      angle-closure glaucoma]
AB  - OBJECTIVE: To examine the effects and safety of doubled-frequency Nd:YAG laser
      peripheral iridoplasty(LPI) for angle-closure glaucoma (ACG) with relieving the
      pupillary block. METHODS: Thirty-seven eyes of 29 patients of ACG with mean
      intraocular pressure (IOP) of (33.5+/-9.3)mmHg, were treated by LPI. In the
      follow-up of 5 approximate, equals 35 months, the IOP, angle and complications
      from LPI were examined. RESULTS: The mean IOP of the patients was reduced to
      (17.2+/-5.3)mmHg (P<0.0001). Thirty-three eyes of 25 patients, who had negative
      of dark room provocative test, maintained the angle opened without adjunctive
      antiglaucoma treatment. Four eyes of 4 patients continued to developed angle
      closure and had a high IOP. CONCLUSION: Peripheral iridoplasty doubled frequency
      Nd:YAG laser is a safe and effective method for treatment of ACG.

PMID- 12601895
TI  - [Character and treatment of diaphragmatic paralysis in infant and toddler]

PMID- 12601896
TI  - [Percutaneous transluminal septal myocardial ablation in hypertrophic obstructive
      cardiomyopathy]

PMID- 12601897
TI  - [Progress and actuatity of cell transplantation as therapy for cardiovascular
      disease]

PMID- 12601898
TI  - [Hot spots of clinical and basic research in oncology]

PMID- 12601899
TI  - [Express of human papillomavirus, P53 and H-ras gene in laryngeal cancer]
AB  - OBJECTIVE: To study the abnormality of p53 and H-ras gene in laryngeal cancer
      cells and their relation to the infection of human papillomavirus(HPV) subtypes.
      METHODS: The HPV subtypes, P53 and H-ras gene were examined in 28 cases of
      laryngeal cancer by polymerase chain reaction (PCR), single strand conformation
      polymorphism(SSCP), restriction fragment length polymorphism (RFLP) and DNA
      sequencing. RESULTS: P53 gene mutation existed in 50%cases of laryngeal cancer
      and DNA sequencing showed base substitution, insertion or deletion in 4 cases;
      The positive rate of the H-ras oncogene mutation was only 3.57% All high risk HPV
      infections (HPV-16 or-18) were distinctly seen in the cancer cases, especially in
      cases with P53 mutation. CONCLUSION: The high risk HPV subtype infection and P53
      gene abnormality may play an important role in laryngeal cancer progression and
      these two factors may be correlated to each other.

PMID- 12601900
TI  - [Cloning of transmembrane domain sequence of EGFR gene]
AB  - OBJECTIVE: To clone the transmembrane (TM) domain sequence of EGFR gene and lay a
      good foundation for constructing the transmembrane expression vector of
      recombinant superantigens and cytokines. METHODS: A pair of primers special to
      the sequence encoding TM domain of EGFR gene were synthesized, TM domain fragment
      was cloned by RT-PCR, and the PCR product of TM domain sequence was ligated with
      the pGEM-T vector and confirmed by DNA sequencing. RESULTS: TM domain sequence
      was successfully cloned and verified by DNA sequencing. CONCLUSION: The
      successful cloning of TM domain sequence provides a basis for the construction of
      transmembrane fusion protein of Superantigen-TM or Cytokines-TM in cancer
      biotherapy.

PMID- 12601901
TI  - [Detection and analysis of bcl-1/IgH rearrangement in mantle cell lymphoma]
AB  - OBJECTIVE: To investigate the specificity and sensitivity of the PCR technique in
      the identification of bcl-1/IgH gene rearrangement in mantle cell lymphoma (MCL)
      and to characterize the bcl-1/IgH junction DNA sequences. METHODS: A semi-nested
      PCR method to amplify bcl-1/IgH gene rearrangement in DNA from fresh frozen
      lymphonode specimen was established. Twenty-eight cases of mantle cell lymphoma
      were analyzed for the presence of bcl-1/IgH gene rearrangement. The rearrangement
      products was cloned and sequenced to recognize the junction sequences, the
      breakpoints in the bcl-1 region, and J(H) gene involved in the rearrangement.
      RESULTS: A bcl-1/IgH gene rearrangement was detected in 17 out of 28 cases of
      MCL, while only 9 cases was detected with single step PCR method (X(2)=4.59,
      P<0.05). The rearrangement product varied in size between 74 to 162 base pairs,
      and the length of the junction sequences ranged from 6 to 24 base pairs. Ten
      different bcl-1 breakpoints were clustered within 65 base-pair spans, among
      which, 5 breakpoints (located at 430, 440, 451, 486 and 492) were never reported
      by other authors. The most common J(H) gene segments utilized in the
      translocation were J(H) 4 (8/18), then J(H)5 (3/18), J(H)6 (2/18), J(H)4/5
      (2/18). J(H)1 2/18, and J(H)3 (1/18). CONCLUSION: These results indicate that the
      semi-nested PCR is a specific and sensitive method for the detection of bcl-1/IgH
      gene rearrangement in mantle cell lymphoma, which has implications for both the
      diagnosis and clinical management of mantle cell lymphoma. The recognization the
      potential mechanism of bcl-1/IgH gene rearrangement will help us to know the
      exact pathogenic machanisms of MCL.

PMID- 12601902
TI  - [Alteration of P73 and P51 genes and its significance in human gastric
      carcinogenesis]
AB  - OBJECTIVE: To evaluate the relatinship between the expression of P51, P73 and the
      oncogenesis and development of human gastric carcinoma. METHODS: The expression
      of P73 mRNA were detected both in 32 human gastric carcinoma tissues and adjacent
      normal gastric tissues by reverse transcriptase polymerase chain reaction (RT
      PCR). RESULTS: Overexpressions of P73 mRNA were found in 17/32 gastric carcinoma
      tissues,in 2/32 adjacent normal gastric tissues.The positive expression rate of
      P73 mRNA in gastric carcinooma tissues was significantly higher than in adjacent
      normal gastric tissues( P<0.01). However, a significant correlation was found
      between the positive expression rate of P73 mRNA in gastric carcinoma tissues and
      the TNM staging(P<0.05). THe low expressions of P51A mRNA and P51B were found in
      all gastric carcinoma tissues and adjacent normal gastric tissues. The expression
      of P51A in gastric carcinoma tissues were much higher than adjacent normal
      gastric tissues (P<0.05). The expression of P51B is no significant correlation
      was observed between gastirc carcinoma tissues and adjacent normal gastric
      tissues. CONCLUSION: The results suggest that there is an overexpression odf P73
      and P51A mRNA in gastric cancer tissues, and their expressions is relationship
      with oncogenesis and developnment of gastric carcinoma.

PMID- 12601903
TI  - [Deletion of P16 gene exon 2 in bronchofibroscopic brush-off cells of human lung
      carcinoma]
AB  - OBJECTIVE: To analyze the relationship between deletion of P16 gene exon 2 and
      lung cancer and to evaluate the possibility of detecting P16 gene exon 2 deletion
      in brush-off cell instead of resected lung cancer mass. METHODS: P16 gene exon 2
      deletion in bronchofibroscopic brush-off cells of lesion side and corresponding
      normal side was detected through PCR-electrophoresis-Image. Image value of P16 Vs
      beta-actin <0.6 was considered as P16 gene exon 2 deletion. RESULTS: The rate of
      P16 gene exon 2 deletion in normal side was 0 (0/19), whereas in lesion side was
      35.5%(11/31), there is a significant statistical difference (P<0.01). In SCLC
      (small -cell lung carcinoma) samples, the rate of P16 gene exon 2 deletion was
      0(0/7). whereas in NSCLC (non-small cell lung carcinoma) samples, that was
      50%(11/12)(P<0.05). CONCLUSION: P16 gene exon 2 deletion might be related to the
      oncogenesis and development of lung carcinoma, especially NSCLC. Brush-off cell
      specimens may replace surgical specimens in Detecting P16 gene exon 2 deletion.

PMID- 12601904
TI  - [Meta-analysis study on risk factors of colorectal cancer]
AB  - OBJECTIVE: To evaluate the risk factors of colorectal cancer in China. METHODS:
      The results of 14 case-control studies from 1988 to 2000 were analyzed by means
      of Meta-analysis. The total numbers of cases and controls were 5034 and 5205
      respectively. Dersimonian and Laird random effective models were applied in
      processing data. RESULTS: Light physical activities and dietary fibers were
      protective factors (pooled OR<0.8); while histories of fecal mucohemorrhage,
      chronic diarrhea and bowel polyps were highly associated with colorecatal cancer
      (pooled OR >4) The stratified results indicated that there were probably some
      differences between OR values of some factors if using different sources of cases
      and controls or using different data from the north and south of China.
      CONCLUSION: Risks of colorectal cancer are significantly associated with the
      histories of intestinal diseases or relative symptoms, fatty food, psychic attack
      and family history of cancers. The light physical activities and dietary fibers
      are probably protective factors.

PMID- 12601905
TI  - [Mechanisms of inhibitory effect of Ubenimex on human leukemic cells]
AB  - OBJECTIVE: To study the mechanism of inhibitory effect of Ubenimex on human
      leukemic cells. METHODS: K562 and HL60 cells were treated with Ubenimex at
      different concentrations, and the growth inhibition was analysed by MTT assay.
      Cell apoptosis was evaluated by light microscopy, agrose gel electrophoresis,
      TUNEL labeling method and flow cytometry (FCM) assay. RESULTS: (1)Treatment with
      Ubenimex remarkably inhibited the growth of HL60 cells, the IC(50) of Ubenimex
      for HL60 cells was 13.03&mgr;g/ml. But K562 cells were less sensitive than HL60.
      Ubenimex inhibited the growth of HL60 and K562 cells in a dose-dependent manner.
      (2)Apoptosis of leukemic cells was induced by Ubenimex, which was shown by the
      changes in morphology, DNA ladder on agrose gel, TUNEL labeling,typical peak
      before G1 phase of cell cycle and the positive of Annexin V(FITC) on the cells
      membrane with FCM. (3)Ubenimex induced apoptosis of K562 and HL60 cells in a dose
      and-time-dependent manner. (4)The cell cycle analysis by FCM showed that the HL60
      cells were blocked in G1 phase after treated by Ubenimex. Conclution Ubenimex can
      efficiently induce apoptosis of HL60 and K562 cells, this may be one of the
      mechanisms for inhibiting effect of Ubenimex on leukemia.

PMID- 12601906
TI  - [Alteration of the content of minor elements in apoptotic cells induced by anti
      cancer drugs with synchronous radiation]
AB  - OBJECTIVE: To explore the change of content of minor elements and its biological
      implication in apoptotic processes. METHODS: The content of minor elements of
      apoptotic cells from breast cancer induced by anti-cancer drugs was
      quantitatively analysed with synchronous radiation X-ray fluorescence. RESULTS:
      Seven kinds of minor elements including Ti, Cr, Fe, Cu, Zn, Ga and Ge as well as
      five major elements P, S, Ca, Cl and K were detected in the apoptotic and control
      cells. The content of elements Zn and P in apoptotic cells after 48 h treatment
      with taxol and colchicine was significantly increased higher than that in the
      control cells P<0.05). The content of element Fe in 48 h treatment with taxol was
      significantly decreased lower than that in the control cells P<0.05). The same
      trend of change of elements was observed during the process of apoptotic cells
      death induced with VP-16 or cycloheximide. CONCLUSION: This results suggest that
      the elements Zn, Fe and P should be involved in apoptosis induced by anti-cancer
      drugs.

PMID- 12601907
TI  - [Relationship of expression of inducible nitric oxide synthase to microvessel
      density in oral squamous cell carcinomas]
AB  - OBJECTIVE: To study expression of inducible nitric oxide synthase (iNOS) in oral
      squamous cell carcinomas (OSCC) and its relations to microvessel density (MVD)
      and lymphatic metastasis. METHODS: With 9 cases of normal oral mucosa as control,
      the expression rate of iNOS in 41 cases of OSCC was evaluated by
      immunohistochemstry SP staining. With CD34 as label, MVDs of these cases were
      also detected. RESULTS: The iNOS expression rate of OSCC cases was 63.41%(26/41),
      while no positive expression was seen in 9 cases of normal oral mucosa. Anymore,
      the expression rate of N+ group was 85.00% while that of N group 42.90%, the rate
      between them was significantly different (P<0.01). There was correlation between
      MVD and lymphatic metastasis (rs=0.51, P<0.01). MVDs in groups of different iNOS
      expression( approximate, equals +++) were 29.667+/-6.945, 34.833+/-4.579,
      46.357+/-6.687, 54.167+/-5.565, respectively, and were significantly different
      with each other (P<0.001). CONCLUSION: There is high expression rate of iNOS in
      OSCC, and it has close relation to lymphatic metastasis; angiogenesis may
      facilitate lymphatic metastasis of OSCC, and expression of iNOS has positive
      relation to MVD in OSCC.

PMID- 12601909
TI  - [Study of neuroendocrine markers in 356 cases of adenocarcinomas]
AB  - OBJECTIVE: To ivestigate the incidence of neuroendocrine (NE) cells and hormone
      products in adenocarcinomas and to explore its clinicopathological significance.
      METHODS: 356 cases of adenocarcinomas were studied by immunocytochemistry with
      antibodies for chromorgranin and polypeptide hormones. RESULTS: The prevalence of
      NE cells and hormone products were detected in 54 of 130(41.5%) and 32 of 54
      (59.3%) colorectal carcinomas, 38 of 96(39.6%) and 14 of 38 (36.8%) gastric
      cancer, 8 of 21(38.1%) and 4 of 8(50.0%) prostatic carcinomas, 17 of 81(21.0%)
      and 3 of 17(17.6%) breast cancer, 5 of 28(17.9%) and 3 of 5 (60.0%) pancreatic
      carcinomas, respectively. Among carcinomas of large intestine, pancreas and
      breast, the incidence of NE cells in well differentiated ones was higher than
      that in the poorly differentiation. By contrast, NE cells were found more
      frequently in the letter than in the former in gastric carcinoma. The cases with
      NE cell (++) or polypeptide positive cells exhibited higher 5-year survival rate
      than those without NE cells in colorectal carcinomas. CONCLUSION: The presence of
      neuroendocrine cells and the hormone products may be close correlated with the
      degree of tumore cell differentiation. For colorectal carcinoms, there is a close
      correlation of the presence of NE cells and the hormone products with the tumor
      staging and prognosis.

PMID- 12601908
TI  - [Antiangiogenesis effect of linomide in treatment of transplanted human oral
      carcinoma in nude mice and its relations to regulation on cytokine secretion of
      macrophage]
AB  - OBJECTIVE: To investigate the antiangiogenesis effect of linomide in treatment of
      transplanted human squamous cell carcinoma of tongue in BALB/C nude mice and to
      study its relations to regulation on cytokine secretion of macrophages. METHODS:
      An animal model was established by inoculating the human squamous cell carcinoma
      cell line Tca8113 into the BALB/c nu/nu nude mice. The mice were randomly divided
      into three groups and received linomide therapy. The microvessel density (MVD) in
      the tumor tissue was investigated by immunohistochemistry The productions of
      TNFalphaand GM-CSF of peritoneal macrophages derived from the tumor -bearing nude
      mice and cultured murine macrophage cell line RAW264.7 after linomide treatment
      were detected by ELISA assay. RESULTS: It showed that the tumor weight of mice
      injected intraperitoneally with 100 mg/kg d-(1), 50 mg/kg d-(1) linomide and mice
      of control group were 0.47+/-0.25g, 0.92+/-0.30g and 1.75+/-0.38g, respectively.
      The microvessel density (MVD) in tumor tissue from mice treated with linomide 100
      mg/kg d-(1), 50 mg/kg d-(1) decreased 38.2%, 57.8% respectively when compared
      with that in mice of control group. After linomide treatment, the function of
      TNFalpha secretion of peritoneal macrophages from tumor-bearing nude mice was
      significantly inhibi ted when compared with macrophages from untreated mice. And
      linomide inhibited the release of TNFalpha of RAW264.7 cells in a dose dependent
      manner. CONCLUSION: It indicats that linomide can effectively inhibit the growth
      of human squamous carcinoma of tongue in nude mice and decrease the microvessel
      density in the tumor tissue. The affection of release of antiangiogenic factor
      TNFalpha of macrophage may be an important mechanism of antitumor activity of
      linomide.

PMID- 12601910
TI  - [Assessment of the estrogenicity of endosulfan and other chemicals with the in
      vitro proliferation of human breast cancer cell]
AB  - OBJECTIVE: To develop a rapid screening method for xenoestrogens and to screen
      the estrogenicity of some environmental chemicals. METHODS: The E-SCREEN test was
      developed based on proliferation of human breast cancer cells (MCF-7), and the
      estrogenicity of diethylstilbestrol, 4-hydrotamoxifen and endosulfan was
      assessed. RESULTS: The E-SCREEN detected estradiol at very low concentration as
      1x10(-13) mol/L. It was found that diethylstilbestrol was a full agonist of
      estrogen receptor, endosulfan was a partial agonist, while 4 hydrotamoxifen
      lacked estrogenic effects at this assay. CONCLUSION: The E-SCREEN test is
      sensitive, rapid, easy to perform and, therefore, suitable for large scale
      screening for estrogenicity of environmental chemicals.

PMID- 12601911
TI  - [Immunomodulatory effects of polysaccharide of Cistanche Deserticola Y C Ma]
AB  - OBJECTIVE: To study the immunomodulatory effects of the polysaccharide Cistanche
      Deserticola Y C Ma (CDPS) and its mechanism. METHODS: The immunomodulatory
      function of CDPS was studied in vitro by observing the proliferation of murine
      thymus lymphocytes, which was measured with MTT method. The effects of CDPS on
      cell cycle and thymus intracellular calcium delivering were studied with FACScan
      flow cytometer. RESULTS: The inhibition function of ISO and DEX and high
      concentration of TNFgamma on lymphocyte proliferation was decreased with CDPS at
      higher concentration. It could stimulate the division of thymus lymphocyte and
      promote thymus intracellular calcium delivering. CONCLUSION: The enhancing effect
      of CDPS on murine thymus lymphocyte proliferation is related to its promotion on
      thymus intracellular calcium delivering.

PMID- 12601912
TI  - [Automated recognition and identification of soft tissue landmarks in
      cephalematric analysis]
AB  - OBJECTIVE: To establish the automatic x-ray cephalometric analysis system to
      provide the convenient and reliable method for clinical cephalometric analysis.
      METHODS The graphics, image processing techniques and artificial intelligence was
      usedand the computer digital image processing and pattern recognition such as
      median filtering, histogram equalization, Laplacian and Canny edge detection were
      introduced. To provide the templates of the variable anatomical structures, which
      could automatically outline the contour lines of the hard and soft tissues.
      Thirty five cases were measured and analysied with the system. RESULTS: The
      computer measurements had the same consistency with hand measurements. The system
      could calculate more precisely and save more time and energy than other systems.
      CONCLUSION: The system can supply a more convenient and precise measurement for
      cephalometry.

PMID- 12601913
TI  - [Applied anatomical studies on the pedicled lateral pedal musculocutaneous flap]
AB  - OBJECTIVE: To provide the anatomical basis for the repair of the soft tissue
      defects on the dorsum of the foot. METHODS: Sixty-eight low extremity specimens
      were taken from fresh cadavers. The arterial distributions of the foot were
      observed by perfusing red latex, barium sulfate, Chinese ink and 10% gelatin,
      also studied by X-ray angiography and microdissection. RESULTS: The blood supply
      of the lateral pedal region was ensured by the lateral tarsal artery and
      perforating branch of the peroneal artery. The external diameter of the lateral
      tarsal artery was 0.9+/-0.2 0.5 approximate, equals 1.8 mm while external
      diameter of the perforating branch of the peroneal artery was 1.2+/-0.3 0.5
      approximate, equals 2.1 mm. CONCLUSION: The lateral pedal musculocutaneous flap
      can be devised according to the different repair regions to restore the defected
      soft tissues of the foot.

PMID- 12601914
TI  - [Comparison between laparoscopic pyloromyotomy and open pyloromyotomy for infants
      with congenital hypertrophic pyloric stenosis]
AB  - OBJECTIVE: To compare the efficacy of laparoscopic pyloromyotomy with open
      pyloromyotomy in treatment of congenital hypertrophic pyloric stenosis(CHPS).
      METHODS: Fifteen patients (age 20%ape;90 days, body weight 2.5 approximate,
      equals 5.0 kg) with CHPS underwent laparoscopic pyloromyotomy (Group I) and 10
      patients (age 26 approximate, equals 90 days, body weight 2.8 approximate, equals
      4.5 kg) with CHPS underwent open pyloromyotomy (Group II). Ambulatory 24 hr
      esophageal pH metry and gastroesophageal mamometry were studied in two groups
      before and after surgery. RESULTS: All patients presented gastroesophageal reflux
      (GER) before operation and all reflux parameters were significantly decreased
      after operation (P<0.01). There was no significant difference between two groups
      in reflux parameters after surgery. Intragastric pressure (GP) significantly
      reduced in two groups after operation(3.83+/-1.45)mmHg compared with (2.38+/
      0.54)mmHg P<0.01 in Group I,(4.52+/-1.96)mmHg compared with (2.38+/-0.72)mmHg
      P<0.05 in Guoup II). There was no significant difference in lower esophageal
      sphincter pressure (LESP), lower esophageal sphincter length (LESL) before and
      after operation in two groups. The mean operative time for Group I was (32+/-19)
      mins, which was close to that of Group II after an initial trail. Oral feeding
      was started 6 h postoperatively in Group I, which was earlier than that in Group
      II. No technical failures and complications in Group I were encountered. One
      wound infection and dehiscense was seen in Group II. CLUSION: Laparoscopic
      pyloromyotomy for infantile hypertrophic pyloric stenosis is safe and feasible,
      which has lesser complication and similar effect of antireflux as open
      pyloromyotomy.

PMID- 12601915
TI  - [Operational indications and management for huge hepatic cavenous hemangioma in
      adults]

PMID- 12601916
TI  - [Clinical and pathological features of male pituitary prolactinoma]

PMID- 12601917
TI  - [Application of modified Blalock-Taussig shunt in neonates]

PMID- 12601918
TI  - [Laparoscopic ureterolithotomy]

PMID- 12601919
TI  - [Methylation of hMLH1 promoter, hMLH1 expression and microsatellite instability]

PMID- 12601920
TI  - New combination vaccine approved.

PMID- 12601921
TI  - [Chemoprevention in gastrointestinal cancer: progress and future directions].

PMID- 12601922
TI  - [Biological therapy to Crohn's disease with anti-tumor necrosis factor alpha].

PMID- 12601923
TI  - [Gain-of-function mutation of c-kit gene and molecular target therapy in GISTs].

PMID- 12601924
TI  - [Clinical significance of faecal calprotectin levels in patients with ulcerative
      colitis].
AB  - AIMS: To assess the clinical significance of faecal calprotectin levels (a
      neutrophil protein) in patients with ulcerative colitis (UC). METHODS: 25
      patients with UC provided stool samples for calprotectin assay and the amount of
      calprotectin was related to UC disease activity index in each patient. Of 25
      patients 4 with prednisolone refractory UC received 10 granulocyte and monocyte
      adsorption apheresis (GMCAP) sessions of 60 minutes duration, flow rate 30 mL per
      minute for 10 consecutive weeks. RESULTS: Calprotectin level in consecutive
      faecal samples from three patients was stable. However, increased calprotectin
      levels were significantly (p < 0.005) associated with Matts's endoscopic index,
      reflecting the level of colorectal inflammation. The 4 patients who received
      GMCAP therapy had a clinical activity index < 2 at week 7, the calprotectin level
      declined with improving Matts' index. CONCLUSIONS: Assay of faecal calprotectin
      holds promise as a sensitive biomarker to identify colorectal inflammation.

PMID- 12601925
TI  - [Gastric cancer with liver metastasis producing alpha-fetoprotein (AFP) and
      protein induced by vitamin K absence or antagonist II (PIVKA-II); a case report].

PMID- 12601926
TI  - [A case of protein-losing enteropathy associated with autoimmune mechanism].

PMID- 12601927
TI  - [Portal venous gas complicated with Crohn's disease. A report of a case].

PMID- 12601928
TI  - [A case of the small intestinal tumor with repeated massive melena].

PMID- 12601929
TI  - [A case of an isolated dissecting aneurysm of the superior mesentric artery].

PMID- 12601930
TI  - [Pure red cell aplasia due to parvovirus B19 occurred in a patient with liver
      cirrhosis C and hepatocellular carcinoma].

PMID- 12601931
TI  - [A case of chronic hepatitis C with interferon-induced retinopathy worsen after
      termination of treatment].

PMID- 12601932
TI  - [A case report of congenital absence of right hepatic lobe associated with
      cholecysto-choledocholithiasis].

PMID- 12601933
TI  - [Gemcitabine treatment of pancreatic cancer peritonitis].

PMID- 12601934
TI  - [A case of rectal carcinoid with characteristic imaging of liver metastasis].

PMID- 12601935
TI  - [Iraqi genocide].

PMID- 12601936
TI  - [Cancer-cryptorchism meta-analysis].
AB  - INTRODUCTION: Testicular cancer in adult and young patients with cryptorchidism
      (operated or not operated on) has been reported previously, but its
      epidemiological impact (as concept to profile cancer and/or therapeutical result
      of cryptorchidism based on quantitative dates) is not defined actually.
      OBJECTIVE: Determination by quantitative meta-analysis of the strength of
      relation (relative risk = RR) cancer and cryptorchidism and by qualitative meta
      analysis of factors of cryptorchidism (anatomical position of teste, age of
      intervention, testicular biopsy) associated to cancer. RESULTS: Case-control and
      cohort studies of medical literature have been included in this report. Relative
      risk of develop cancer in the patient with cryptorchidism is 7.75 more than
      poblational control without cryptorchidism (interval of confiance: 5.2-10.3).
      Qualitative meta-analysis of factors concluded that there is a significative
      relation cancer and abdominal position of teste, and also age of intervention
      after 10 and testicular biopsy. CONCLUSIONS: Significative relation between
      cancer and cryptorchidism with relative risk above control population is
      constated again, although with dates without epidemiological importance. But
      significative relation among cancer with abdominal testes and intervention after
      10 years would recommend prospective studies, with strategy of multivariant
      analysis. Authors recommend not to make testicular biopsy, except if its
      indication is not questionable.

PMID- 12601937
TI  - [Burns in childhood. Social implications in the eve of the year 2000].
AB  - INTRODUCTION: The thermic wounds in childhood are the third cause of morbility at
      hospital in our ambiance. The knowledge about incidence, the causal agents more
      frequent, and the detailed analysis of different variants about the subject are
      the unique manner to try to establish precautions against. The aim of this
      project is to analyse the factors and situations associated with thermic wound,
      through the retrospective study about the patients admitted. MATERIALS AND
      METHODS: During three years, 362 patients were admitted at hospital, between 0
      and 14 years old, following the criterion: barge burn size more than 10%,
      critical location (hands, face, neck), causal agent (electricity, chemical) or
      social situation. Different facts were analyzed about provenance, place, causal
      agent, burned part of the body, degree of lesion and the average stay at
      hospital. RESULTS: There were 59.6% males, and 40.3% females. Children between 1
      and 5 years old, represented the largest group of patients, 205 cases. The 66%
      were from other hospital were they receive the first aid. The 98.7% were burned
      at home, and the place more frequent was kitchen, 51%. The causal agent was
      liquid in 65.4%, specially scald with water about 104 cases. The zones more
      affected were the face (39.2%), and the superior extremities, about 81% second
      degree superficial or deep. The size was 10 to 20% in 19% of patients, and more
      than 40% in 0.2% of children. The average stay was 17.47 days at hospital.

PMID- 12601938
TI  - [Kasai operation in the age of liver transplantation. Healing or merely
      palliative technique?].
AB  - AIM: To assess the results of portoenteroanastomosis (PEA) and liver
      transplantation (OLT) in extrahepatic biliary atresia (EHBA). METHODS: Out of a
      series of 148 EHBA, 92 cases primarily treated by us were selected. Survival with
      the native liver (end point = death or OLT) and its relationship with the age at
      PEA, type of EHBA, ductal size and bile flow restablishment were assessed.
      Patient survival was compared in those patients who had access to OLT when needed
      (Group I, n = 69) and those in whom only PEA was available (Group II, n = 23).
      (OLT program started in january 1986). RESULTS: At the end of follow-up, 32
      children are alive with their native livers, 22 died and 38 had OLT. 40/85
      patients who underwent PEA had complete restablishment of bile flow (47%). The no
      failure rate (survival of the native liver) at 1, 5, 10 and 20 years, was 91%,
      49%, 38% and 21%, respectively. Bile flow restablishment was the only predictor
      significantly associated with good prognosis (survival of native liver at 5, 10
      and 20 years of 89%, 86% and 51%, respectively). Differences in survival were
      significant (p < 0.001) between patients in groups I and II at 1 year (92% vs
      74%), 5 years (78% vs 35%), 10 years (76% vs 30%) and 20 years (76% vs 30%).
      CONCLUSIONS: Bile flow restablishment after PEA can be obtained in experienced
      centers in about 50% of cases of EHBA. The combined and sequential use of PEA and
      OLT allows excellent long-term survival in EHBA.

PMID- 12601939
TI  - [Bile duct atresia: outline for a solution].
AB  - Biliary atresia continues to be a serious and relatively rare disease (1/50,000
      newborns) and whose long-term prognosis has changed drastically since the
      appearance of liver transplant (LT) as a therapeutic weapon. The combination of
      two factors, early diagnosis and correct application of Kasai's surgical
      technique, is essential to obtain acceptable results and sufficient biliary
      drainage allowing the children to overcome the critical 7 kg barrier and place
      them in the lesser morbi-mortality range in relation to a possible LT. But we
      must keep in mind that despite its critics, Kasai's technique can guarantee, both
      in our own experience and in the literature, ten years survival percentages over
      50% with correct hepatic function, as well as clinical normality and a quality of
      life clearly superior to first years post-LT. We present the evolution of a group
      of 20 patients affected with biliary atresia, diagnosed in our center since 1985,
      the year when pediatric LT began to be used as a therapeutic procedure in this
      country. We valued the age of intervention, technique, immediate and long-term
      results and the evolution and necessity of LT. All 20 patients were analyzed
      individually, and they currently have an age range from 2-14 years and were all
      operated by Kasai's technique. We classified the patients as having good, regular
      or poor results with regards to biliary flow, normalization of billirubin levels
      and clinical evolution. Sixteen patients presented biliary flow of such an extent
      that 14 of them, classified as good, completely normalized the billirubin levels.
      Two others, presently aged 14 and 8 years respectively, present average levels of
      2.5-5.5 mg/100 ml and are classified as regular in a situation of advisable
      transplant, although with an acceptable hepatic function. Only one case, the
      first in the poor group, did not initially present biliary elimination and died
      at age six months while on the waiting list. Three other cases in the same group
      presented insufficient biliary elimination and were transplanted with 7, 11 and
      12.5 kg, respectively. The second died in the first year post-transplant.
      CONCLUSIONS: In our opinion, action in biliary atresia must be early and based on
      the correct application of Kasai's technique, seeking to achieve a biliar flow
      that eliminates or distances the patient as far as possible from the necessity of
      a future LT. Three lines come together to obtain this target: an early diagnosis,
      a correct application of Kasai's technique, and an implication in the follow-up
      and treatment of these children by the hepatic transplant groups. All this
      advises us, as is done in other countries, to create reference centers for the
      study of neonatal cholestasis where an accumulated experience of a relatively
      rare pathology can be taken advantage of.

PMID- 12601940
TI  - [Primary liver tumors in children: analysis of 62 consecutive cases].
AB  - Aiming at assessing the impact of the improvements introduced in the treatment of
      primitive liver tumors of children, we reviewed our experience with these tumors
      since 1980. Between January 1980 and June 1999 we treated 62 children with
      primitive liver tumors: 35 hepatoblastomas (HB), 5 hepatocarcinomas (HC), 4
      sarcomas, 2 malignant mesenchymomas, 11 hemangioendotheliomas (HE), 3 mesenchymal
      hamartomas, 1 adenoma and 1 focal nodular hyperplasia. Thirty five were boys and
      27 girls. The age at diagnosis was 34.5 +/- 43.1 months (mean +/- standard
      deviation). Eleven patients had HE and 4 of them (36.3%) died due to haemodynamic
      (n = 3) or other tumor-related causes. All the remaining patients with benign
      tumors survive. Among the HB patients, 3 had stage I, II stage II, 8 stage III
      and 13 stage IV tumors (with lung metastases at diagnosis in 4). For survival
      analysis we divided patients into two groups according to their treatment before
      (Group 1, n = 14) or after 1991 (Group 2, n = 21). Five-year actuarial survival
      was 49% for Group 1 and 78% for Group 2 (p < 0.05). We performed liver
      transplantation in 5 patients with 3 long-term survivals. Three children with
      widespread HC died whereas 2 with localized tumors had liver transplantation and
      survive. In conclusion, the treatment of primitive liver tumors in children
      requires collaborative protocols, concentration of patients in institutions
      capable of offering high-standard liver surgery and transplantation when the
      tumor is localized to the liver and irresectable.

PMID- 12601941
TI  - [Children with intestinal failure as candidates for intestinal transplantation].
AB  - Small bowel is not anymore considered a forbidden organ for transplantation, and
      intestinal transplantation (IT) is currently used as a therapeutic option in
      selected cases of permanent intestinal failure (PIF). Nevertheless, the
      experience is still scarce, and despite recent improvements, IT is nowadays only
      accepted as a life-saving option. However, small children are prone to suffer
      complications related to TPN, particularly end stage liver disease; moreover,
      suitable donor for the small baby who needs an IT is seldom available.
      Subsequently, a high pretransplantation mortality has been reported in the
      pediatric series. In those cases, the indication of IT shouldn't be delayed, and
      these children must be referred early for IT. Since we started our IT program, 17
      children have been assessed, and 3 are currently on the waiting list; two for
      combined liver-small bowel transplantation (LSB), both with short bowel syndrome
      and end stage liver disease, and one patient with microuvillous dysplasia for
      isolated IT (indication loss of venous access). 3 children were referred too late
      and died, so did a fourth patient, candidate for LSB, before he could be
      transplanted.

PMID- 12601942
TI  - [Efficiency of ultrasonography in the diagnosis of acute appendicitis].
AB  - Importance of the problem. Atypical or precocious presentation of acute
      appendicitis in children causes false diagnosis. OBJECTIVES: To determine
      internal and external validity of ultrasonography for confirmation diagnosis of
      acute appendicitis. PATIENTS AND METHODS: Patients with suspicious acute
      appendicitis treated in 1998. They have been classified into two groups. Group 1:
      patients with appendicitis; Group 2: patients with non-specific abdominal pain.
      MATERIAL: Ultrasonography equipment (5 and 7.5 MHz). METHOD: Ultrasonography has
      been considered as positive when 3 or more of the typical signs of appendicitis
      have been detected. Analysis unit: positivity of the test and presence or absence
      of illness confirmed by histologic analysis of the appendix obtained through
      laparotomy. RESULTS: Number of patients selected for the work: 139. Middle age: 8
      years-old (range: 2 to 14 years); 75% were males, 25% females. Patients included
      in group 1: 42; patients included in group 2:97. False positive rate was 12.23%,
      while false negative rate was 7.19%. Sensibility was 76%, specificity was 82%,
      positive predictive value was 65%, negative predictive value was 88% and
      precision was 80%. Odds-ratio pre-test: 0.43; Odds-ratio post-test: 0.64.
      CONCLUSIONS: Probability of accuracy diagnosis is duplicated by ultrasonography.
      Liability of the test is diminished by variability due to observer.

PMID- 12601943
TI  - [Anal fistula treatment with seton].
AB  - The objectives of anal fistula treatment are to drain sepsis, irradicate the
      fistulous tract, and to preserve sphincter integrity and function. These goals
      can be achieved by either fistulotomy or fistulectomy. Alternative techniques
      include chemical setons, drainage setons, cutting setons and two-stage seton
      fistulotomy. We have treated 6 cases of trans-sphincteric fistula Parks type 2.
      The progressive fistulotomy technique was employed with a primary or one-stage
      cutting seton, as an outpatient procedure and without general anaesthetic.
      Complete division of the sphincter muscle took 18-27 days. No child presented
      incontinence or any other complications from the technique employed. No
      recurrences were observed at the 12 month follow-up. We conclude that the use of
      cutting setons is a simple and effective technique for the treatment of anal
      fistula in children, with low complication rates.

PMID- 12601944
TI  - [Necrotizing histiocytic lymphadenitis (Kikuchi-Fujimoto disease) in a 7-year-old
      girl].
AB  - Kikuchi-Fujimoto's disease is a rare self-limited condition of young adults that
      usually involves the cervical lymph nodes and is associated with fever, rash and
      some haematological alterations. Diagnosis is based on characteristic pathologic
      findings that permit differentiation of this disease from lymphoma, systemic
      lupus erythematous and infectious lymphadenopathies. We describe a case of 7 year
      old female presenting with cervical localization of Kikuchi-Fujimoto's disease.
      To our knowledge, this case results the earliest affection of this disease. Our
      proposal with this article is to remind the pediatricians and pediatric surgeons
      of this poorly recognized entity when children ask for cervical masses and fever.

PMID- 12601945
TI  - [Crossed testicular ectopia. Report of a case].
AB  - Crossed testicular ectopia is a rare congenital malformation in which both testis
      are located in the same hemiscrotum, and is related to an anomaly in normal
      testicular descent. This entity was first described by Lenhossek in 1886 and
      posteriorly by Halstead in 1907. Since then, there have been described less than
      a hundred of cases of this rare congenital malformation. Several ethiopathogenic
      theories have been proposed, including testicular adherence to mullerian
      structures, fusion of the wolffian ducts or defective gubemacular development,
      although none of them has been widely accepted. Usually, clinical sign is an
      inguinal hernia with empty contralateral hemiscrotum, and sometimes both testis
      in ipsilateral hemiscrotum. A new case of this pathology is presented.

PMID- 12601946
TI  - [Future perspectives of the S.E.C.P].

PMID- 12601947
TI  - [Pneumopathy in patients surgically treated for type III esophageal atresia].
AB  - Patients following esophageal atresia with tracheoesophageal fistula (EA-TEF)
      treatment have several long-term respiratory complications during infancy. They
      are associated with esophageal dismotility and gastroesophageal reflux (GER) as
      well as lung dysplasia. MATERIAL AND METHODS: Ten patients were evaluated as
      follow: 1. Review of medical record. 2. An annual interview was performed
      concerning respiratory and digestive symptoms. 3. Phmetric score and radiologic
      studies of the digestive tract. 4. Functional respiratory test. 5. Update
      symptoms. RESULTS: Mean follow-up was 7.3 +/- 4.45 years (8 months-15 years).
      Seven cases (70%) had respiratory distress during the first postoperative year.
      Two of them had middle GER, performing a Nissen procedure in another patient with
      severe GER. Spirometry was underwent in 6 cases, showing a restrictive pattern in
      three. CONCLUSION: Respiratory distress were common during the first
      postoperative year (70% of cases in our serie) but only 25% were GER related.
      Pulmonary function test can be performed in long-term evolution of patients
      following operation for EA-TEF in order to have early treatment for respiratory
      complications.

PMID- 12601948
TI  - [Contraindications for the endoscopic treatment of vesicoureteral reflux].
AB  - The endoscopic treatment of vesicoureteral reflux (VUR) has acquired a great
      importance as a therapeutic option during the last years. We present our
      experience with two substances, teflon paste and macroplastic, used in 86
      patients, with 147 refluxing renal units. After first injection, the successful
      rate was 86% for teflon pastes versus 91% for macroplastic in the middle grade
      VUR units. We analyze our complications rates (14.25%) and we conclude that there
      is a close relation with a right technic performance. In our experience we
      consider a major contraindication for this technical option patients less than 1
      year of life. At the same time we presume that an special care must be taken in
      monorenal patients as well.

PMID- 12601949
TI  - [Surgical stress and hypophyseal-adrenal activation in childhood].
AB  - INTRODUCTION: The study on the physiological alterations due to surgical
      aggression (surgical stress), widely investigated in adults, is less known in
      paediatric age. THE OBJECTIVE: Of this work is to quantify surgical stress
      (evaluated by means of Oxford Scale as high or low depending on its value bigger
      or lower than 6), after determining changes of plasmatic concentrations of ACTH,
      beta-endorphin and cortisol in operated children. PATIENTS AND METHODS:
      Observational analytic design of a prospective cohort with internal comparison of
      the groups. SAMPLE SIZE: 33 (age 10 +/- 2.6 years; range 5 to 14 years).
      DEPENDENT VARIABLES: plasmatic concentrations of ACTH, beta-endorphin and
      cortisol determined before and after the intervention (1 and 24 hours after
      surgery), by radio-immune-analysis. RESULTS: Significative increase of the three
      considered hormones one hour after surgery, with decrease of them until
      preoperative levels 24 hours later. Significative correlation between beta
      endorphin (24 hours after surgery), cortisol (1 hour after surgery) and surgical
      stress levels. CONCLUSIONS: Surgery in children provokes the activation of
      hipophysal-suprarrenal system. These levels early came back to normal ones, 24
      hours after surgery. There is a specific change in beta-endorphin, that is why it
      is possible to assure that beta-endorphin is a "stress-hormone", since it is
      affected by surgical aggression. Cortisol seems to be a good index of level of
      surgical stress.

PMID- 12601950
TI  - [Obstetric trauma. A current problem?].
AB  - Advances in obstetric practice have decreased birth traumas in the last years,
      although they are still an important chapter in neonatal age. Between 1993-1998 a
      total of 21,375 stillborns were registered with a total of 309 birth injuries in
      303 neonates (1.44%). The diagnoses were: 2 liver subcapsular hematomas, 105
      cephalohematomas, 16 parietal fractures, 11 subdural hemorrhages, 107 clavicular
      fractures, 10 miscellaneous fractures, 8 soft tissue injuries, 25 facial nerve
      injuries and 25 braquial palsy. About relation between type of labor and birth
      trauma was found that clavicular fracture and cephalic vaginal delivery were
      associated in 50% of the cases, cephalohematoma and forceps in 51%, braquial
      palsy and vaginal delivery in 44% and forceps in 36%. High weight at birth was
      another risk factor for entities such as clavicular fracture and braquial palsy.
      We conclude that birth trauma is a pathology with a relevant incidence and their
      epidemiology factor had to be known.

PMID- 12601951
TI  - [Caudal epidural anesthesia in pyloromyotomy in infants: our experience].
AB  - The aim of this work is to introduce an alternative to ordinary anaesthetic with
      tracheal intubation for the surgery of pyloric stenosis. We argue in favour of
      this alternative that it can be achieved with relative ease if the technique of
      caudal epidural is well known, a better control of peri and post-operative
      analgesia without the need of opiates, and that this technique obviates
      orotracheal intubation and intermittent positive pressure ventilation. Based on
      our experience with 18 patients, we introduce the anaesthetic technique, the
      monitoring systems and the obtained results. Our conclusion is that this
      technique is a good alternative to general anaesthetic for the surgical treatment
      of pyloric stenosis.

PMID- 12601952
TI  - [Congenital fibrosarcoma. Diagnostic-therapeutic implications].
AB  - Most of the soft tissue sarcomas of childhood other than rabdomyosarcoma, have as
      final diagnosis fibrosarcoma, specially in the first months of life. Overlapping
      features between infantile myofibromatosis and congenital fibrosarcoma,
      hemangiopericytoma and fibrohistiocytoma have seen noted. Five patients with
      congenital fibrosarcoma were operated since 1991. Anatomical sites included lower
      limb, hand and forearm, and three of them had previous diagnoses of
      hemangiopericytoma, fibrohistiocytoma and myofibromatosis, with provocated non
      radical surgery and reoperation. The postoperative course was satisfactory and
      all are live one to eight years later. In our experience accurate histological
      diagnosis must be achieved to perform radical surgery on these cases.

PMID- 12601953
TI  - [Ambulatory pediatric surgery: 25 years of experience].
AB  - The objectives of this study are: collect 25 years of experience with ambulatory
      pediatric surgery in The Pediatric Surgery Service of Hospital de Cruces, present
      the results of a parents-patient satisfaction survey and show the estimated money
      savings in the last five years. In the period 1973-1997, 19,934 children (56% of
      the total surgical cases) were operated with ambulatory surgery, and have been
      grouped in five quinquenia, showing a constant increase of the percentage of
      ambulatory surgery. General surgery and ENT are the specialities that more
      frequently uses this type of surgery (72.4% and 68.6% of the surgical cases of
      each speciality, respectively, in the last ten years). In general surgery
      inguinal hernia is the most frequent diagnosis with an increase of orchidopexy in
      the last five years. ENT is doing ambulatory tonsilectomies in the last ten
      years. The prolonged recovery stay and unanticipated admissions are rare, usually
      due to vomiting. The parents satisfaction survey shows great acceptancy, although
      13% preferred an overnight postoperative stay. The estimated money saved in the
      last quinquenia has been important.

PMID- 12601954
TI  - [Advantages of primary rhinoplasty in the treatment of lip fissure].
AB  - Congenital cleft lip is always associated to nasal deformity. The classical
      approach has been not to treat the severe nose defects during childhood, in the
      fear that early surgery would interfere with nasal growth. However, long term
      follow-up in patients with early conservative rhinoplasty has shown the nose to
      hold its new shape and its growth to be normal. During the period between
      november 1996 and november 1998, 22 infants affected with cleft lip underwent
      early rhinoplasty according to McComb's technique. During the follow-up period (6
      months to 30 months) the children had a good nasal growth. The nose tip is in the
      medial position in all cases, and only the inferior view of the nose shows a
      discrete nosetril assimetry in some patients.

PMID- 12601955
TI  - [Progressive bone elongation of the maxillo-facial area: mandibular distraction].
AB  - Thanks to the distraction osteogenesis technique, it is nowadays possible to
      create new bone in the facial area. Between january 1997 and march 1999 we have
      performed 20 such procedures, from which 15 were mandibular. We present our
      experience in 10 patients with this new technique, 5 unilateral and 5 bilateral.
      Those were 7 boys and 3 girls, aged 2 to 14 years, affected with hemifacial
      microsomia, Goldenhar syndrome: 3; retrognatism with severe malocclusion: 4;
      facial assimetry due temporomandibular joint abnormalities: 2; and facial
      assimetry: 1. The proposed elongation was achieved in all cases. There was not
      only a skeletal improvement, but also growth and remodeling of the facial soft
      tissues. Distraction osteogenesis is the early treatment of the mandibulofacial
      deformities and offers a great deal of advantages to the growing patient.

PMID- 12601956
TI  - [Progressive acquired lymphangioma: report of a case and review of the
      literature].
AB  - We present 2-year-old patient with a allopecia lesions in scalp, and clinique
      diagnostic of Cutis Aplasia. The anatomopathologic study have diagnosed the
      lesions as Acquired Progressive Lymphangioma (APL). Is a rare vascular tumour
      that has a tendency to appear in childhood an to progress slowly over the years.
      It could present as a solitary erythematous macule or plaque and a simple
      excision is usually curative. Our patient is the youngest reported in the
      literature.

PMID- 12601957
TI  - [Intestinal atresia and bile duct atresia in a new born infant].
AB  - We report a recent case of small bowel atresia and biliary atresia in a newborn.
      We describe the management of the patient and we make a revision of the
      literature. Only 13 cases have been found, that confirms that this association is
      extraordinary rare.

PMID- 12601958
TI  - [Thoracic deformities in childhood: the reason for our technique].

PMID- 12601960
TI  - [Partial nephrectomy in unilateral Wilms tumor. New draft for a protocol of the
      SIOP].
AB  - Unilateral Wilms' tumor has been treated according to 9301 SIOP protocol, with
      good results. The new pre protocol that SIOP is developing has a high inclusion
      rate. From 1993 to 1999, 11 patients with unilateral Wilms' tumor were treated in
      our center; in 6 cases preop chemotherapy was done, in the other 5 cases pre and
      postoperative chemotherapy were used. Nine of the 11 patients could be included
      in the pre protocol this was due to a thrombosis of the vena cava in one case,
      and in the other the middle renal in area was widely affected. Wilms' tumor has a
      good prognosis with the actual protocol, SIOP. New pre protocol could give a
      better quality of life due to the amount of functional renal parenchyma, without
      decreasing the actual high cure rate.

PMID- 12601959
TI  - [Pre-hepatic portal hypertension as a late complication of liver transplantation
      in children].
AB  - In the long-term after liver transplantation (LT), some children develop
      prehepatic portal hypertension (PPH) and raise problems not very well known yet;
      many of the lessons learned with the management of these patients may be useful
      outside the LT. AIM: 1. To analyze the incidence and risk factors of PPH after
      LT. 2. To evaluate the results with the different treatments used. METHODS:
      Retrospective study over 164 children surviving more than 1 year after LT.
      Univariant analysis of possible risk factors associated and multivariant
      (logistic regression), for those that had significance in the univariant
      analysis. Other factors associated are analyzed as well as the indications and
      results of two types of treatment: percutaneous pneumatic dilatation and surgical
      shunt (splenorenal and Rex shunt). RESULTS: 9 children developed symptomatic PPH
      (hemorrhage in 8, ascites in 1), associated to lymphoproliferative post-LT
      disease in 2, and to anastomotic biliary stricture in 1. The age at first LT
      (children under 1 year old), weight (below 10 kg), and need of retransplantation
      (reLT) were in the univariant analysis the associated variables with increased
      risk of PPH. The diagnosis (biliary atresia) and the emergency status of the LT
      were almost significative. In the multivariant analysis, the need of reLT is the
      only independent variable that increases the risk (relative risk: 4.5, confidence
      interval 95%: 1.29-18.87). At diagnosis 3 cases showed portal estenosis, and 5
      showed absence of permeability with cavernomatous transformation. The PPH was
      caused in one case because of the esplenic vein disconnection (treatment not
      required at the moment); the three cases of portal estenosis were dilated
      percutaneously with success, and 2 of the 5 cases with portal thrombosis have
      been surgically shunted: one by an splenorenal shunt and the other by a Rex shunt
      (first case done in Spain); the other 3 cases are stable waiting for a surgical
      solution. The hepatic function is normal in the 9 cases. CONCLUSIONS: The PPH can
      complicate the prognostic of the pediatric LT in the long term. The treatment
      depends on the permeability of the portal trunk. Whenever possible, percutaneous
      dilatation should be attempted; should surgery be required, the Rex shunt is the
      best option.

PMID- 12601961
TI  - [Pediatric renal transplantation from related living donor].
AB  - Living related donor (LRD) provides significant advantages when compared with
      cadaveric donor (CAD) in term of improved patient and graft survival and shorten
      waiting time. From 1985, 176 kidney transplants were performed at our Center. Of
      these, 156 (89%) were from CAD and 20 (11%) were from LRD, first degree. The
      purpose of this paper is to show our experience at 5 years with use of LRD. All
      donors underwent standardized metabolic workup, angiography assessed and renal
      function test. Twelve children received their first transplant and 8 were
      retransplant (6-second, 1-third and 1-fourth). Immunosuppressive therapy
      consisted of globulin antithymocyte, azathioprine, cyclosporine and prednisolone,
      using FK506 and mycophenolate mofetil in some of them. Four kidneys with multiple
      renal arteries were reconstructed ex vivo with microsurgical technique before
      transplantation. The most significant morbidity was due to FK506-associated
      thrombotic microangiopathy (TMA) with graft lost. All patients (donor and
      recipient) survived. Five years graft survival rate is 95% and mean glomerular
      filtration rate is 81.33 ml/min/1.73 m2.

PMID- 12601962
TI  - [Prognosis assessment of esophageal atresia: our experience of 29 years].
AB  - INTRODUCTION: The major advances in neonatal intensive care have made less useful
      the Waterston's criteria for esophageal atresia (EA) and/or tracheoesophageal
      fistula (TEF), and other prognostic classifications have been reported. The aim
      of this study was to determine the influence of various parameters on the outcome
      of EA-TEF. MATERIAL AND METHODS: We reviewed 97 cases admitted in our hospital
      for 29 years. We divided the cases in two groups in relation to the improvement
      of our neonatal unit care during the years: 1st. 1971-1982 (n = 46); 2nd. 1983
      1999 (n = 51). chi 2 squared test and logistic regression analysis of the
      influence of several parameters before surgical treatment (Waterston's and
      Spitz's birth weight groups, pneumonia, ventilator dependence, severity of
      associated anomalies and cardiac malformations) on mortality was performed.
      RESULTS: The survival rate increased since 1983, reaching 86.2% in the last 10
      years, although the number of neonates with birth weight < 1500 g has increased.
      Association with a major anomaly increased the mortality significantly in the
      2nd. group only (45.5% major vs 7.1% minor and 8.3% none). The cardiac
      malformations were the most common, not only before 1983 (26.8%), but also since
      then (31.3%). When the neonate associated a major cardiac malformation the
      mortality was significantly higher in the 2nd. group (71.4%). The mortality, when
      pneumonia was present, was significantly higher before 1983 only (75% vs 32.4%),
      whereas the mortality was significantly increased by the need of ventilator in
      the 2nd. group only (85.7% vs 9.1%). Before 1983, the best prognostic parameters
      were the pneumonia and the severity of associated anomalies, whereas only the
      ventilator dependence was selected between 1983 and 1999. CONCLUSIONS: The EA-TEF
      mortality has decreased in the last years. The associated cardiac malformation is
      the most common. We think that the ventilator dependence is the most reliable
      prognostic risk factor, showing a poor physiologic status of the neonate.

PMID- 12601963
TI  - [Predictive value of stress leak bladder pressure in urinary incontinence in
      children].
AB  - The stress leak point pressure is the lowest bladder pressure at which leakage
      occurs during increases in intra-abdominal pressure. Our goal was the study of
      the stress leak point pressure in children to determine if it is a useful method
      of evaluation of incontinence and how it can be applied to pediatric clinical
      practice. We prospectively studied 68 consecutive incontinent children: Group 1
      included 50 children neurologically normal. Group 2 included 18 children with
      myelodysplasia. RESULTS: 1) No correlation was found between stress leak point
      pressure and leak point pressure values. 2) The difference between the volumes at
      which the stress and rest leak were obtained was not statistically significant.
      3) Study of stress leak point pressure: Group 1; Leakage during stress only
      occurs in 16%. Stress leak point pressure was greater than 100 cm of H2O in these
      children. Group 2; Leakage during stress occurs in all children (positive test in
      100%). Stress leak point pressure was less than 100 cm of H2O, indicating
      intrinsic sphincter deficiency. These results suggest the stress leak point
      pressure is a diagnostic test that provide information about the function of
      proximal urethra and bladder neck in pediatric population, and an useful tool to
      despite of intrinsic sphincter deficiency.

PMID- 12601964
TI  - [Index finger pollicization for congenitally deficient first finger of the hand
      in children].
AB  - Pollicization is a single-stage neurovascular pedicle transfer of the index digit
      to function as a thumb. The objective of this study is to investigate the results
      of index finger pollicization for correction of congenital deficiency of the
      first ray in pediatric hand. We have done 6 pollicizations of index fingers in 6
      hands (there were 2 right hands, 2 left hands, and 1 bilaterally) in 5 patients
      (4 boys and 1 girl) who had absent or nonfunctioning thumbs (type III-V of
      Blauth's classification). Associated anomalies where numerous and included radial
      club hand, mirror hand and cardiovascular and urologic anomalies. The average
      time of Kirschner wire extraction was 32 days (30 to 36 days) and to beginning
      the hand rehabilitation at 5 degrees to 10 degrees day. The average age at
      pollicization was 5.5 years (range 2 to 8 years), and follow-up averaged 8 years
      (5 to 11 years). The cosmetic and functional results were excellent, with manual
      dexterity of prehension and opposition. Pollicization in children can be
      performed at least 2 years of age, to due of minor risk of neurovascular lesion
      but without delayed the cortical representation of the pollicized finger.

PMID- 12601965
TI  - [Seromuscular colocystoplasty lined by urothelium. Experimental study in rats].
AB  - OBJECTIVE: To determine what technical of vesical extension in rat can offer the
      best functional and histological results. DESIGN: Comparative experimental study
      between pre and postoperative parameters of 60 female Wistar rats. The animals
      were divided in 5 groups using different techniques of vesical augmentation.
      Sham, colocystoplasty (CC), demucosalised colocystoplasty (DCC), demucosalised
      colocystoplasty lined by urothelium (AADCC), autoaugmentation (AA).
      INTERVENTIONS: Preoperative cystometrical study. Microsurgery for vesical
      augmentation. New cystometric study at the month, previous to the sacrifice of
      the animal and extraction of bladder for its histological study. Measurement of
      the volume and pressure of rupture. RESULTS: The technique of seromuscular
      enterocistoplasty presents the high mortality in the rat (63.6%). The increase of
      the vesical volume in both groups that carried seromuscular grafts was little
      (0.22 +/- 0.5 and 0.47 +/- 0.3 ml) in front of the control group (0.11 +/- 0.4
      ml). Only standard colocystoplasty and bladder autoaugmentation produced
      significant increases on vesical volume (0.78 +/- 0.5 and 0.69 +/- 0.6 ml,
      respectively) and rupture volume. There were not observed significant differences
      on vesical rupture pressure.

PMID- 12601966
TI  - [Bilateral distal ureteral obstruction: unusual complication of appendicular
      abscess].
AB  - We describe the case of a 6-year-old boy who presented post-renal anuria and
      renal failure five days after appendectomy and drainage of a periappendicular
      abscess. Only mild dilatation of the urinary tract was observed on ultrasound and
      small calculi were documented at the ureterovesical junction bilaterally.
      Diuresis was restored by the insertion of uretercatheters. Awareness of this
      complication and immediate treatment can avoid permanent impairment of renal
      function.

PMID- 12601967
TI  - [Giant cell reparative granuloma: report of a case and review of the literature].
AB  - We report a case of giant cell reparative granuloma involving proximal phalanx of
      the index finger. Differential diagnosis with other lytic lesions of the
      phalanges is analysed and surgical treatment performed is explained. After 24
      months follow-up there is no recurrence and finger function is normal.

PMID- 12601968
TI  - [The pediatrician surgeons and the communications media].

PMID- 12601969
TI  - [Treatment of tracheobronchomalacia with expandable metallic stents].
AB  - Tracheomalacia is an unfrequent disease that causes tracheal collapse during
      breathing. It is generally associated to esophageal atresia, but cases of primary
      tracheomalacia and others secondary to extrinsic compression, have also been
      described. Spontaneous resolution is generally the rule and only a few cases need
      surgical treatment. When this therapy fails or is not indicated for any reason,
      endoluminal tracheobronchial stents may be used. We have treated two patients
      with four expandable metallic stents: one had severe tracheomalacia associated to
      esophageal atresia and the other tracheobronchomalacia secondary to cardiomegaly.
      Results have been good in both cases.

PMID- 12601970
TI  - [Treatment of vestibular fistulas in older girls].
AB  - The vestibular fistula is the anorectal malformation more frequent in females. In
      this congenital anomaly the anus is located in the vaginal vestibule, having the
      rectum a common wall with the vagina. With the posterior sagittal approach
      described by Alberto Pena it changes the treatment of this anorectal
      malformation, contributing to the possibility of an aesthetic and functional
      improvement. From 1996 we have operated on 6 girls with ages included between 6
      and 22 years (mean of 11 years) that presented a vestibular fistula. Five cases
      had been operated on in the neonatal period of vestibular fistula carrying out
      "cut-back", and a case had been operated on for cloaca syndrome. It was carried
      out in all of them, posterior sagittal approach disecting the rectum, separating
      it from the vagina and placing it in the sphincter. In a case a colostomy was
      carried out and in the other five were carried out intestinal cleaning,
      maintaining absolute diet and postoperative total parenteral nutrition. The
      evolution has been favorable in all the cases. the functionality of the neo-anus
      in terms of continence is absolutely normal, presenting an excellent aesthetic
      aspect. We believe that the posterior sagittal approach is suitable as surgical
      treatment of the vestibular fistula. The aesthetic improvement and the
      satisfaction of our patients motivates us to the realization of this technique
      that also allows us to correct in only one surgical act associated vaginal
      malformations.

PMID- 12601971
TI  - [High flow vascular malformations in children].
AB  - Unlike hemangiomas and low-flow vascular malformations which are very common in
      children, arterial anomalies have small incidence. Differential diagnosis is
      difficult, and needs a physician familiarized with vascular anomalies.
      Appropriate treatment must be planned by multidisciplinary team considering the
      patient's age, and anatomical location. Twenty-eight children with high flow
      vascular malformations have been treated since 1990 at La Paz Children's Hospital
      Vascular Anomalies Program. We excluded of the study group patients with central
      nervous system lesions. 85% of the patients had malformation in stage I or II
      (according the ISSVA accepted Schobinger stating) and most of them were
      erroneously diagnosed as hemangioms with a variety of inappropriate treatments
      previously performed. Doppler Ultrasound and Magnetic Resonance confirmed
      malformation flow and extension. Angiography and selective embolization was only
      considered as therapeutic approach in candidates to surgical resection. 16
      patients underwent complete resection of the malformation including one foot and
      two fingers amputation and five more incomplete resection of the ulcerate area.
      In conclusion, we did not find age at onset, sex and symptoms relationship.
      Laser, radiotherapy, surgical ligation or partial resection must be considered
      inappropriate therapies which may stimulate AVM exacerbation. Only radical
      surgical procedure after selective endovascular embolization will be successful
      but then reconstructive surgery should be performed to achieve good aesthetic and
      functional results.

PMID- 12601972
TI  - [Morphologic study of the intestine in an experimental model of amnioinfusion in
      fetal rabbits with gastroschisis].
AB  - An experimental model of serial amnioinfusion has been developed in fetal rabbits
      with gastroschisis, using an intraamniotic catheter connected to a subcutaneous
      port. Fetuses of 4 groups were compared 7 days after surgery: group A:
      gastroschisis and daily amnioinfusion through an implanted catheter; group C:
      gastroschisis and blind amniotic catheter; group G: gastroschisis without
      catheter; group O: nonoperated fetuses. Survival rate, fetal body weight, lung
      weight, intestinal weight and length were determined. Computer aided morphometric
      analysis was performed, in which intestinal diameter, thickness and villi length
      were measured. Amniotic fluid samples were recovered along the experimental
      period. Intestinal length was significantly shorter and had a significantly
      thicker wall than nonoperated fetuses; we found no other morphometric differences
      between gastroschisis treated with amnioinfusion (group A) and the other
      gastroschisis groups (C and G). Amnioinfusion did not affect fetal survival rate;
      the amniotic catheter alone did not cause pulmonary hypoplasia due to significant
      amniotic leak. The physiological decrease in amniotic volume towards the end of
      gestation has not been modified by this regime of amnioinfusion.

PMID- 12601973
TI  - [Urethrosonocystography with galactose in the diagnosis and follow-up of
      pediatric patients with vesicoureteral reflux].
AB  - INTRODUCTION AND OBJECTIVES: Since early 80's, attempts to detect Vesicoureteric
      Reflux (VUR) with Ultrasound (US) contrast medium have been made to study the
      urinary tract during voiding. The galactose-based agents are comparable in the
      diagnostic range with the standard fluoroscopic cystography, providing high
      values of sensitivity and specificity. The purpose of our work is to show our
      experience during last three years with the urethrosonocystography with echo
      contrast in the diagnosis and follow-up of pediatric patients with urological
      malformations. PATIENTS AND METHODS: 442 patients were included in our study
      (aged 1 day to 13 years; 202 males and 240 females). All cases were referred for
      investigation of VUR based on previous criteria of urinary tract infection, VUR
      follow-up, dilated urinary tract, post endoscopic treatment, surgical treatment
      follow-up and others. After transurethral catheterisation the bladder was filled
      with US galactose-based contrast medium (Levovist). VUR was diagnosed when micro
      bubbles appeared in ureter or pelvicalyceal system and was graded according to
      the International Reflux Study Committee. RESULTS: Of the 442 patients evaluated
      with echo enhanced urethrosonocystography, 227 were screening cases for discard
      VUR. Of these patients, only 58 were diagnosed as having VUR. In 165 cases the
      technique was indicated as follow-up. Two patients with spina bifida developed
      candiduria after the sonographic cystogram. In 6 patients with dilated urinary
      tract without reflux, galactose was detected in renal pelvis 6 months after the
      procedure. CONCLUSIONS: In our experience urethrocystosonography with galactose
      based US medium agents is a more sensitive method than standard Voiding
      Cystourethrography (VCUG) for detecting VUR in pediatric patients. US cystography
      is an attractive technique which involves no ionising radiation and is usually
      well tolerated by the young. This procedure should be considered as a routine
      diagnostic work-up for detecting VUR in pediatrics.

PMID- 12601974
TI  - [Acute appendicitis. Usefulness of a evidence-based critical pathway].
AB  - OBJECTIVE: To determine the effects of an evidence-based clinical pathway for
      acute appendicitis in paediatric patients at a tertiary hospital. METHODS: We
      studied 229 patients with an age range from 3 to 14 years, with a pathological
      diagnosis of acute appendicitis divided in two groups. A prospective,
      experimental clinical pathway group of children (n = 114), (June 1999-January
      2001) was compared with a historical control prepathway group of patients treated
      by conventional means in the previous years, (n = 115), (December 1997-May 1999).
      Age, gender, type of appendicitis (uncomplicated/complicated), length of
      hospitalisation, number of antibiotics doses supplied and rates of complications,
      were compared between pathway and and control patients. RESULTS: There were no
      differences in age (p = 0.61), gender (p = 0.73), either the number of
      complicated/uncomplicated appendicitis (p = 0.91) between the two groups. The
      average duration of hospitalisation was significantly shortened in pathway group
      (4.34 versus 5.33 days) (p = 0.000049) and the number of antibiotics doses were
      reduced from 16.13 to 11.17 doses (p = 0.000000). The number of major
      complications was lower in the pathway group than in the control group (6 and 16
      respectively) but there was no significative difference (p = 0.09). CONCLUSIONS:
      Clinical pathway is an efficient and safe tool for acute appendicitis because
      decrease the length of hospitalisation and the number of antibiotics doses
      supplied, while maintaining quality of care.

PMID- 12601975
TI  - [Beneficial effects of Bifidobacterium lactis in the prevention of bacterial
      translocation in experimental short bowel syndrome].
AB  - BACKGROUND: Probiotics are live organisms that survive passage through the
      gastrointestinal tract and have beneficial effects on the host. Lactobacillus and
      Bifidobacterium have been recommended in cholesterol lowering, acute diarrhea,
      prevention of cancer or inflammatory bowel disease. On the other hand, after
      massive bowel resection bacterial overgrowth is frequent and favours the
      occurrence of bacterial translocation (BT). The possible beneficial effects of
      Bifidobacterium lactis (BL) administration on BT in experimental short bowel
      syndrome (SBS), have not been investigated. AIM: To test the hypothesis that BL
      administration decreases BT in SBS in animals fed orally. METHODS: Thirty-two
      adult Wistar rats fed orally with standard rat chow and tap water "ad libitum"
      were maintained individual metabolic cages for ten days after 80% gut resection
      from the duodeno-jejunal angle to 10 cm above the cecum and divided in two
      groups: -Group A (n = 14): served as control. -Group B (n = 18): daily 7.8 x 109
      CFU Bifidobacterium lactis administration, after orgastric intubation. At the end
      of the experiment they were sacrificed and mesenteric lymph nodes (MLN), and
      peripheral and portal blood specimens were recovered and cultured. Bacterial
      identification in blood was made by conventional methods and MLN culture was
      considered positive with a growth over 100 CFU/g. RESULTS: Bacterial
      translocation was detected in 93% of Group A rats. The incidence of BT in Group B
      was 44%. The relative risk reduction (RRR) was 0.52 (95% confidence interval 0.23
      0.81) and the number needed to treat (NNT) was 2 (95% confidence interval between
      1-5). CONCLUSION: Administration of Bifidobacterium lactis reduces the incidence
      of BT in adult Wister rats, after 80% gut resection.

PMID- 12601976
TI  - [ Pulmonary inflammatory pseudotumor in a child].
AB  - The Inflammatory Pseudotumor is a no neoplastic process characterised by an
      irregular growth of inflammatory cells. A case of 10 years old male is described,
      he was asymptomatic, diagnosed by a casual chest XR, with a spheric mass in the
      inferior lobe of the right lung. An excisional biopsy was done with the result of
      "Inflammatory Pseudotumor". The Inflammatory Pseudotumor is a rare process that
      can be found in different regions of the human body, with most frequent
      localization, in the lung. The image tests are not specific for the diagnosis
      that only can be done by biopsy. The recommended treatment is the complete
      resection.

PMID- 12601978
TI  - [Endoscopic pediatric surgery. A decade of experience].

PMID- 12601977
TI  - [Left paramesocolic hernia with retroperitoneal incarceration of jejunum].
AB  - We present a case left paramesocolic hernia and review the literature. The
      patients was a 14 years old male and had suffered periods of relapses into
      abdominal pain from the age of three. When for years old he was operated on using
      the Nisses technique. Also a laparoscopy had already been performed on this same
      patient when he was 13 years old, without discovering any pathological
      conditions. In a new upper gastrointestinal serie, realized one year later, a
      retroperitoneal incarceration and a paraduodenal loop of jejunum was observed,
      which obstructed, partially the second part of the duodenum. We have not found
      the anatomical characteristics of this case in any previous report. In the ample
      literature pressured, it was confirmed that almost all the clinical cases,
      previously published had suffered a relapse abdominal pain crisis, diagnosed in
      advanced states and in/or emergency situations. This produces a mortality rate
      higher than 20% and or irreparable digestive damage. In cases involving
      paraduodenal hernias, there exists a low rate of diagnostic suspicion. These
      delays and diagnostic errors cause irreparable damage. In those patients who
      suffer relapses into abdominal pain syndrome, one should always include the
      differential diagnosis of PMH, applying a complete gastrointestinal serie or a CT
      Scan with contrast.

PMID- 12601979
TI  - [Early surgery in Poland syndrome].
AB  - Poland's congenital malformation presents a variable grade of complexity,
      depending upon the extent of the muscular and chondro-costal defect. Surgical
      repair for cosmetic reasons only, may be performed during childhood or puberty
      due to the absence of symptoms. However, this does not occur when the costal
      defects has a considerable size, with pulmonary herniation and impairment of
      respiratory function. In this cases, early surgical correction is preferred in
      order to adequately stabilize the chest wall. In this paper we present our
      experience of early surgical treatment in 5 patients affected by a complex
      syndrome, that were treated with autologous costal transplants and the use pof
      polytetrafluoroethylene to cover the chest wall defect. We discuss the surgical
      procedure performed, as well as the advantages of this material with respect to
      others described up to date and the good results obtained in one of the cases
      followed-up for five years.

PMID- 12601980
TI  - [Nine years of experience with laparoscopic appendectomy in children].
AB  - We review the clinical report of 110 patients that were operated on by a
      laparoscopic appendectomy in our hospital since January 1992 until december 2000.
      In 66 patients the reason was an acute appendicitis, and recurrent abdominal pain
      in 44. The age of them was between 4 and 19 year old with a mean of 10.8; there
      were 44 males (39%) and 66 females (61%). The maximum weight was 70 kg and the
      minimum 15, with a mean of 41. In 23% of them vomiting was present in the
      postoperative period. The hospital stay was 2 or 3 days in 73% of the patients.
      In acute appendicitis patients 66.1% were with acute inflammation, in 29%
      complicated and 4.8% negative appendicitis. Of recurrent abdominal pain patients
      in 50% we found pathological alterations. Finally we had complications in 13% of
      cases. As conclusion we achieve a reduction in hospital stay, the patients and
      parents appreciate it, this approach allow a better exploration of abdominal
      cavity and in those patients with recurrent abdominal pain we obtained a clinical
      improve.

PMID- 12601981
TI  - [Integra Artificial dermis in pediatric reconstructive surgery].
AB  - The recent release of artificial dermis for general use, has open wide a new
      field in pediatric reconstructive surgery. The aim of this paper is to analyze
      the results of Integra artificial dermis in our Plastic Surgery Department.
      MATERIALS AND METHODS: The records of the patients treated with Integra between
      february 1999 and january 2001 were analyzed, focusing on the indications, the
      complications and the final results. RESULTS: Fourteen Integra implantation
      procedures in 11 patients aged 16 months to 12 years (mean +/- SD: 80.9 +/- 48.5
      months) were performed. Indications were: acute burns in 5 cases, burns sequelae
      in 5, and partial extirpation of a congenital giant nevus in the last one.
      Integra was used to replace between 2 and 30% of total body surface area. The
      percentage of "take" of skin grafts was 85%. The most frequent early complication
      was the development of infection under the Integra; it occurred in 2 cases and
      artificial dermis had to be partially removed. Hypertrophic scars developed in 2
      patients; both had refused pressure garments. Cosmetic results in the remaining 9
      patients are considered excellent. CONCLUSIONS: The use of artificial dermis has
      settled as a new procedure in plastic pediatric surgery. In spite of possible
      complications, the easy manipulation and the good results make Integra a perfect
      skin substitute in several cutaneous disorders.

PMID- 12601982
TI  - [Creation of a model for myelomeningocele in rabbit embryos].
AB  - Spinal dysraphism causes paraplegia, fecal incontinence, neurogenic bladder,
      sexual dysfunction, hydrocephalus and skeletal abnormalities in newborns. Its
      ethiology and pathogenesis are still not known, and probably multifactorial. AIM:
      To determine whether spinal cord exposition to the amniotic space causes a
      functional (impairment) and anatomic lesion similar to that of human
      myelomeningocele. MATERIAL AND METHODS: Forty-eight fetal rabbits underwent to
      create spina bifida on the 23rd gestational day (term is 31 days). The procedure
      consisted of lumbosacral skin excision and posterior laminectomy. The fetuses are
      allowed to continue their gestation. On the 30th gestational by the operated
      fetuses were harvested, together with a group of nonoperated littermates for
      control. A clinical and neurologic evaluation was done, as well a study of somato
      sensorial evoked potentials in the upper and lower limb and histologic study of
      the affected vertebral and cordial segment. RESULTS: The 26 surviving animals had
      deformity and lack of movement of the lower limbs. Evoked potentials showed
      absent response to stimuli in the lower limbs of animals with spina bifida,
      whereas upper limbs and control animals did respond. Histologically the spinal
      cord of the operated rabbits was uncovered and flattened. CONCLUSION: This model
      of myelomeningocele in fetal rabbit reproduces a variety of features similar to
      human spinal dysraphism, and hence can be used to study the pathophysiology of
      spina bifida.

PMID- 12601983
TI  - [Our experience with the use of Biobrane in the treatment of burns and other
      injuries in children].
AB  - Burns in the pediatric age are accidents which cause a lot of trauma, on the one
      hand because of their immediate consequences and on the other hand because of the
      severity of the pain, the amount of times the dressings need to be change, the
      lengthy hospital stay and the scars that remain for life. Between 1995 and 2000
      we have treated 196 children, (4 months to 14 years old), with Biobrane: 141
      patients affected of first and second degree burn injuries, 45 skin donor sites
      covering, 4 reinforcing of meshed autografts, 3 traumatic dermoabrasions, 2
      extirpation of post-traumatic cutaneous tattoo and 1 Toxic epidermic necrolisis.
      Advantages noticed at the end of the treatment: Excellent skin healing. No pain
      while changing dressings. Reduction the need to use skin grafts. It is very
      useful to cover the skin donor sites and meshed autografts. Shorter Hospital stay
      and less need to be kept in hospital. A higher level of satisfaction is shown by
      children, their parents and sanitary workers. It offers the possibility of
      outpatients treatment in First Aid Health Centers. It reduces hospital costs.

PMID- 12601984
TI  - [The superficial midline cervical cleft].
AB  - Given the anatomy and the histology of the 4 cases of children with a midline
      cervical cleft presented in this work, and after reviewing the specific
      literature, an etiologic relationship between: this congenital malformation and
      the subcutaneous midline cervical bronchogenic cyst can be established. The
      presence of pseudostratified ciliated columnar epithelium in both entities and
      their anatomic relationship are determinant. The anatomic differences with the
      thyroglossal duct cyst indicated that their embryological origins were different,
      in spite of the presence of ciliated epithelium. In a 6 months old infant, the
      extirpation of the lesion without practicing a Z-plasty was carried out due to
      the small size of the malformation with good result after 3 months.

PMID- 12601985
TI  - [Mesenteric-cava shunt's results with autologous jugular vein graft in children
      with pre-sinusoidal portal hypertension].
AB  - Presinusoidal portal hypertension (PPH) in children evaluates without functional
      hepatic damage, and with the time, trends to compensate through the creation of
      spontaneous portosystemic shunts. Nevertheless, some patients suffer episodes of
      gastrointestinal bleeding (GIB) that because of its frequency or severity, force
      to propose the change of surgical treatment. AIM: To evaluate the results of the
      mesocaval shunt (MCS) with autologous jugular vein in children with PPH. MATERIAL
      AND METHODS: Among the 32 children with PPH treated in our Hospital in the last 7
      years, 10 had episodes of GIB that forced to perform a surgical shunt. The types
      of shunt were distal splenorenal in 3 patients and mesocaval in 7. These 7 cases
      are the material of this study. The origin of the PPH was a cavernomatosis
      transformation of the portal vein in 6 cases and a congenital hepatic fibrosis in
      1. Before the surgery the average number of episodes of GIB was 9 (range 2-15);
      all the patients needed transfusion of blood products and variceal sclerosis. In
      2 cases a tamponade with the Sengtaken balloon was required and 5 patients were
      treated with somatostatin and propranolol. The Doppler ultrasounds revealed and
      intense hepatofugal collateral circulation in all the cases. RESULTS: The initial
      flow through the shunt was adequate in all the patients except one who required a
      percutaneous balloon dilatation. Only this patient has suffered an episode of
      GIB. The hyperesplenism signs disappeared or improved in all the seven cases and
      the collateral circulation was significantly reduced. The pressure in the splenic
      territory decreased around 50% in the 4 patients that was measured. There were no
      cases of encephalopasty and only one child with congenital hepatic fibrosis shows
      signs of mild hepatic disfunction. The medium follow up post-shunt is 32 months
      (range 8 m-6 years). CONCLUSIONS: The MCS prevents the GIB in the PPH not
      responsive to the conservative treatment; its effectiveness is related with an
      adequate permeability though the graft and at least in the cases with portal
      cavernomatosis (the most frequent in children) doesn't produce hepatic
      dysfunction. Doppler ultrasounds give a very precise information about the post
      surgical situation and are an excellent method of follow up.

PMID- 12601986
TI  - [Comparative study of differential renal function by DMSA and MAG-3 in congenital
      unilateral uropathies].
AB  - In congenital obstructed hydronephrosis, the assessment of the differential renal
      function (DRF) is essential to provide a prognosis or to determine surgical
      treatment. The most reliable method to measure the differential renal function is
      the isotopic study with DMSA. The MAG-3 is employed to evaluation renal
      elimination, although in the minutes 1-3 it also measures the differential renal
      function. OBJECTIVE: We compared the estimation of differential renal function by
      99Tc-dimercapto-succinic acid (DMSA) and 99Tc-mercaptoacetyltriglycyne (MAG-3)
      methods in congenital unilateral uropathies. MATERIALS AND METHODS: We reviewed
      the results of 138 isotopic studies of children (age range: 0-9 years) with
      congenital unilateral uropathies: 67 cases were obstructed and 71 non-obstructed.
      In all of them were carried out match tests pairs with DMSA and MAG-3. Both
      series were divided into 4 groups: 1) DRF < 40%, 2) DRF 40-45%, 3) DRF 46-50% and
      4) DRF > 50%. The measurement differential renal function correlation by DMSA and
      MAG-3 were analysed. RESULTS: The coefficient of correlation was 0.96 (P < 0.01)
      in obstructed unilateral uropathy and 0.92 (P < 0.01) in non-obstructed serie.
      CONCLUSIONS: The differential renal function measured with DMSA and MAG-3 has a
      close correlation in congenital unilateral uropathies. Therefore in obstructed
      types, differential renal function and half-time elimination can be reliable and
      sure studied with MAG-3, being unnecessary DMSA test, avoiding additional
      radiation to the children.

PMID- 12601988
TI  - [Independent intestinal duplication].
AB  - Some types of intestinal duplication are an infrequent clinical condition in the
      gastroenterology tract that do not meet all classic requisites for their
      definition. We present a case of independent intestinal duplication from small
      intestine that starts with acute abdomen; cystic, perforated and separated tumor
      from wall of normal intestine was founded during surgery. It was totally resected
      with preservation of normal intestine adjacent, because it was an independent
      vascular supply. We review a new vascular classification of intestinal
      duplication and their importance in surgical treatment of this matter.

PMID- 12601987
TI  - [Scientific evidence in the endoscopic treatment of the vesico-ureteral reflux].
AB  - The way used by physicians to obtain information from scientific research may
      have low-quality, with effects on assistance. Evidence-based medicine became
      necessary due to the exponential growing produced in the published research.
      OBJECTIVES: 1. To establish the scientific goodness of published papers on
      endoscopic treatment of vesicoureteral reflux. 2. To quantify the quality level
      of the papers by means of a series of explicit criteria. MATERIAL AND METHODS:
      Work type: Bibliometric revision. Databases: Revision of the electronic bases:
      Medline, ACP Journal Bandolier, Cochrane Collaboration and Pediatric Evidence
      Based Medicine. INCLUSION CRITERIA: Papers on endoscopic treatment of primary
      reflux in children. Evaluation criteria: 1. Scientific level: Evidence
      classification proposed by Goodman, describing 10 levels from 1 (high) to 10
      (low) and the Agency of Evaluation of Technology (AET) describing 9 levels. 2.
      Quality level: Dichotomic characters referred to the presence or absence of:
      experimental design, objectives, result measurement and concordance of methods
      and conclusion with the objectives. RESULTS: 114 papers were found and analyzed
      1. Evidence level: 86.9% of papers showed a low level of evidence by Goodman
      score (level 9) whereas 90.4% presented level 8 of AET. 79.5% of papers were
      consecutive series of clinical cases, 9% were non-critical bibliographic
      revisions, 1.7% were cohorts works, 5.3% non-randomized clinical trials and only
      1 paper was a randomized clinical trial. 2. Quality level: 61.4% did not explicit
      the objectives and 57% did not expose the design. The population was not defined
      in 68.4% of papers and the way to appreciate the results in 73.7%. The
      experimental design, in 57.9% of works, and the conclusions, in 64.9%, did not
      concordate with the objectives. CONCLUSIONS: Endoscopic treatment of
      vesicoureteral reflux is becoming more popular. However, its effectiveness has to
      be proved by means of solid scientific bases, for works referring to it have low
      methodological level and low quality.

PMID- 12601989
TI  - [Subcutaneous nodules in children: subcutaneous granuloma annulare].
AB  - Subcutaneous granuloma annulare is a benign, chronic inflammatory lesion located
      usually at scalp or extremities and typical of childhood. Its etiology is unknown
      and no link with systemic diseases has been found. A thorough clinical history
      and normality at complementary tests are enough for its identification. It tends
      to dissaparition, so no therapy is needed although histologic study will let a
      definitive diagnosis. A case in a three years-old boy is reported. He was
      submitted because of four asymptomatic, long-lasting tough lesions at his scalp,
      without other antecedents. Radiologic and hematologic tests found no alteration.
      Two months later a larger size was appreciated in one of them, so it was removed
      and its histology was diagnostic for granuloma annulare. After a 10 months follow
      up, no change in size has been detected in the remaining ones.

PMID- 12601990
TI  - [Hirschsprung disease: advances and unanswered questions].

PMID- 12601991
TI  - [Reduction of the hospital stay in the surgical treatment of hydronephrosis in
      children].
AB  - A Hydronephrosis operation represents a relatively frequent surgery in childhood.
      There is not agreement about the necessity of using drainage neither on the type
      to use, decisions that rebound in the patient's hospital stay. The objective of
      the study is to show the reduction of the days of stay according to the type of
      drainage used. MATERIAL AND METHODS: We present 14 children diagnosed of
      hydronephrosis operated on by Anderson-Hynes technique with an internal drainage
      double J type no 3 or 4. There were left side predominance (10 kidneys). Age of
      diagnosis varied from 0 to 11 years. We analysed the decrease of the stay with
      regard to the system that we used previously, nephrostomy drainage and stent, as
      well as the presence of complications related with the drainage. A cystoscopy was
      performed fifteen days later, in ambulatory way, to remove the catheter. A
      questionnaire of satisfaction was requested to the parents. RESULTS: Thirteen
      patients abandoned the hospital 2 days postoperatively and 2 three days
      postoperatively. There were 3 complications, being 2 minor and 1 mayor (double J
      ascension removed by ureteroscopy and an additional one day stay hospital). The
      reduction of the stay with regard to the traditional method varied between 7 and
      8 days what represents an important saving of costs. In the questionnaire, the
      methods has appealed to the parents. CONCLUSION: We believe that the placement of
      a double J catheter represents an improvement that saves time and diminishes
      nuisances to patients, although a cystoscopy procedure is necessary for its
      removal. The double J catheters with a straight prolonged end, like a nephrostomy
      tube, recently in the market can avoid this last procedure.

PMID- 12601992
TI  - [Bronchoscopies in neonatal intensive care units: safety and efficiency].
AB  - The aim of our study is to asses the risks and complications in bronchoscopies at
      Neonatal Intensive Care Units (NICU). Between 1991 and 1999, we performed 142
      bronchoscopies at the NICU. The mean age was 1.6 +/- 1.4 months (2 days-6 months)
      and mean weight was 2.5 +/- 1 kg (530 g-4.7 kg). We analysed the complications,
      arterial oxygen saturation and inspired oxygen fraction (FiO2) during
      bronchoscopy and we compared them related to weight, type of anesthesia and type
      of bronchoscope used. Mean basal saturation was 92 +/- 8.9% and end saturation
      was 92.8 +/- 10%. The basal FiO2 was 0.5 +/- 0.3 (0.21-1). There were more
      complications in patients weighting less than 1500 g and in those procedures made
      with rigid bronchoscopy (p < 0.05). There were no differences according to the
      anesthesia. Children who weight fewer than 1500 g and those who underwent rigid
      bronchoscopy suffered a descent in arterial oxygen saturation and needed higher
      FiO2 (p < 0.05). Bronchoscopy is a very useful technique and it is well tolerated
      in neonatal patients. We conclude that flexible fiberoptic bronchoscopy is safer
      than the rigid bronchoscopy, specially in children fewer under 1500 g.

PMID- 12601993
TI  - [Respiratory deadspace and compliance measurements in neonates with congenital
      diaphragmatic hernia].
AB  - The mortality rate of infants with congenital diaphragmatic hernia (CDH) remains
      high, despite clinical improvements. Many attempts have been made to find
      accurate and reliable predictors of outcome. Deadspace (Vd/Vt) and dynamic
      compliance (DC) measured by single breath CO2 analysis may be useful to evaluate
      pulmonary function and perfusion. In the present study we analyse both parameters
      in patients with CDH. Nine patients with CDH were included for Vd/Vt and DC
      study. Measurements of arterial blood gases (pH, PO2, pCO2) were obtained,
      oxygenation index and alveolo-arterial difference calculated at diagnosis,
      preoperatively and postoperatively. Vd/Vt and DC were measured at the same
      moments by analysis of the CO2 espirogram. Statistical analysis was performed
      using Fisher exact test, ANOVA and Mann Whitney and Chi-square. The Vd/Vt was
      significant lower for the group of patients who survived (0.39 +/- 0.07 vs 0.64
      +/- 0.14, p = 0.038). DC was significantly higher in the survivors group (1.39 +/
      0.30 vs 0.5 +/- 0.07, p = 0.011). The analysis of the evolutive Vd/Vt and DC
      (initial and preoperative) showed significant differences within both groups.
      Respiratory deadspace can be easily quantified in neonates with congenital
      diaphragmatic hernia providing an important insight regarding the efficiency of
      the airway-alveolus and its relationship to pulmonary blood flow. Vd/Vt and DC
      measurement constitute a reliable method to predict outcome in patients with CDH.

PMID- 12601995
TI  - [Simple bone cysts in childhood. Retrospective study of 15 cases and review of
      literature].
AB  - We present a review of 15 cases of simple bone cyst treated by curettage and bone
      grafting or intralesional steroids injection. We analysed the localisation, cyst
      activity, the number of cavities and the occupied area, valuing the results
      according to the Neer and Chigira classification. We have noticed a higher rate'
      of cure with curettage and bone grafting than with steroids injection (p: 0.01).
      The activity of the cyst, the uni-multilocutarity and the area related to a
      greater index of recurrence and failure in the cases treated by steroids
      injection, although this is statistically non significant.

PMID- 12601994
TI  - [Satisfaction levels and radiological improvement in patients with chest
      deformity after reconstructive surgery].
AB  - Many methods for surgical correction of anterior chest deformities has been
      described; the modified Ravitch's technique is the most performed. We reviewed
      the clinical reports of 15 patients who had corrected chest deformity from 1991
      to 1999. We compared the photographies, CT images and Haller's pre and
      postsurgery indexes. The modified Ravitch's technique was performed in 14 cases
      and the Nuss's technique in one. A postoperative questionnaire was done to know
      the grade of satisfaction that the patients reported after surgery. Of 15
      patients, 14 were male. The mean age at the moment of surgery was 11 year old
      (range: 4-17). Nine patients (60%) had pectus excavatum and six (40%) pectus
      carinatum. In all cases, the postsurgery photographies and CT images showed
      neither chest depression nor protrussion. The mean of Haller's pre and
      postsurgery indexes changed from 4.75 (range: 2.8-7.7) to 3.12 (range: 2.4-3.7).
      The grade of satisfaction after surgery was high in the 80% of the patients. In
      our limited experience, the most of the patients with anterior chest deformities
      are satisfied with the results of the surgical management.

PMID- 12601996
TI  - [Study of "burnout" syndrome in Spanish pediatric surgeons].
AB  - BACKGROUND: The "burnout syndrome" is characterized by emotional exhaustion,
      despersonalization and decrease of the feeling of personal accomplishment, above
      all, in the field of professional achievement. It appears to be frequent in the
      helping professions and the human services workers, and in its origin labour
      factors seem to intervent. HYPOTHESIS: The "burnout syndrome" can be affecting to
      the collective of spanish pediatric surgeons since the profession presents risk
      factors. OBJECTIVES: The purpose of this study was to evaluate the prevalence of
      "burnout" and level of work satisfaction among spanish pediatric surgeons, and
      related factors. METHODS. DESIGN: [corrected] Crossover descriptive study.
      SUBJECTS: Random sample of members of the Spanish Society of Pediatric Surgery.
      MEASUREMENTS: A survey for self-administration with social and demographic
      variables, a spanish version of the Maslach Bournout Inventory (MBI), and the
      Font Roja questionnaire was used. The MBI consists of 22 items and the Font Roja
      of 24. Respectively, they explore the components of the syndrome and the factors
      of satisfaction with the work. It is considered "burnout" when it is scoring high
      in emotional exhaustion and despersonalization and low in personal achievement.
      RESULTS: 85 people responded (response rate: 45.5%. Male: 81.2%. Mean age: 49.8
      years. Burnout scores were in the average range (43.88 +/- 5.59). The emotional
      exhaustion subscale of the MBI averaged 19.16 +/- 5.35, with 75.3% in the
      moderate range. The despersonalization score averaged 11.79 +/- 3.68, with 45.9%
      of respondents scoring in the high range. The personal achievement subscore
      averaged 12.93 +/- 3.68, with 82.4% scoring in the low range. The overall mean
      satisfaction: 70.46 +/- 11.23. The factors that promote a greater satisfaction
      level are: intrinsic occupational satisfaction, social relationship in the work
      and appropriateness for the task. CONCLUSIONS: It exists a moderate level of
      "burnout syndrome" with a middle level of work satisfaction. Though contradictory
      this circumstance is possible, since it is considered professional satisfied with
      their profession (vocational election) that at the same time lives some difficult
      work conditions that generate a situation of high exhaustion professional.

PMID- 12601998
TI  - [Gynecomastia and testicular tumor in children with Peutz-Jeghers syndrome].
AB  - The rarity of both conditions and the precocity of its onset (4 years old) make
      the case of interest for pediatricians and pediatric surgeons. The finding of a
      testicular tumor poses same differences of criterium about its management.

PMID- 12601997
TI  - [Decrease in bacterial translocation in burned children treated with controlled
      nutritional support].
AB  - INTRODUCTION: Alteration in epithelial enteric cells are the main cause of
      bacteria translocation and local and systemic infections. Our aim is to evaluate
      these infections in burned children treated with enteral nutrition and compare
      the results with our previous observations. Material and methods. We designed a
      prospective study including 50 patients (0-14 years) with TBSA > 10% (total body
      surface area). Bacteriological cultures were performed at their admittance and
      weekly until the discharge. Nutritional necessities were evaluated using
      calorimetry. Nutritional support was supplied by nasoduodenal tube at continuous
      rates. RESULTS: Three (6%) patients with enteral nutrition (Group 1) showed
      positive blood cultures (two of them by enteric bacteriae). 14 patients (28%)
      showed local infections (five by enterococci). We performed a retrospective study
      in a homogenous group of 44 patients (Group 2), previously treated in our
      Department without controlling nutrition. We found five (11.3%) positive blood
      cultures (four by enteric bacteriae) and 22 (50%) local infections (eleven by
      enteric bacteriae). The improvement of systemic and local infection rates and the
      decrease in infections caused by enteric bacteriae were statistically
      significative (p < 0.05). CONCLUSIONS: A controlled nutritional support is a main
      cause of the improvement in infection rates and decrease in bacterial
      translocation in pediatric burned patients.

PMID- 12601999
TI  - [Yuxtapancreatic gastric duplication versus congenital pancreatic cyst].
AB  - We report a clinic case of a child with juxtapancreatic retrogastric cyst tumor
      diagnosed by antenatal ultrasonography, he was operated on with 15 months of age.
      The pathologic diagnosis was of gastric duplication and the liquid inside the
      cyst had 1810 U/L of amylase. We review diagnosis and therapeutic aspects and
      literature overview.

PMID- 12602000
TI  - [Realities].

PMID- 12602001
TI  - [Neuroblastoma: biological markers, surgery, and clinical course].
AB  - INTRODUCTION: The treatment of neuroblastoma is basically chemotherapy, and
      surgery, in spite of advances, this kind of tumor is nowadays a surgical
      challenge. PURPOSE: The aim of this study was to evaluate the impact of our
      therapy in this kind of pediatric tumors. MATERIAL AND METHODS: 32 consecutive
      patients with abdominal neuroblastoma, aged between 1 month and 10 years old,
      median age 3 years old, observed from 1993 through 1997 have been studied.
      Several parameters: age, ferritin, deletion of the chromosome 1p36, chromosomic
      ploidy, LDH, N-myc gene amplification and enolase neuron specific were studied
      and were related with the histology by Joshi and the International Neuroblastoma
      Staging System (INSS) in order to know the prognosis. All the patients were
      treated by means of chemotherapy and surgery, and some cases with radiotherapy
      and bone marrow transplantation. RESULTS: Two patients presented the tumor in
      stage I (INSS) and three in stage II. All the patients had a total resection and
      they live free of disease. In the state III, two patients did not maintain the
      follow-up; five live with disease (two with QT without surgery yet, two local
      recurrences, and one metastasis), and four live free of disease. In the stage IV:
      five died, two live with disease (1 local recurrence and one metastasis), five
      live free of disease, and one did not maintain the follow-up. In the stage IV-S,
      the three patients live free of disease. The method of Kaplan-Meier at 5 years
      shows a mean of 49 months and a median of 60 months. CONCLUSIONS: 1. Of all the
      parameters studied, we consider the ones with biggest prognostic efficacy are,
      the age, the stage INSS, the histology Shimada and the N-myc amplification. 2.
      The total resection of the tumor keeps being essential for a more favourable
      prognostic.

PMID- 12602002
TI  - [New approach in the surgical treatment of the urogenital sinus].
AB  - The urogenital sinus is an embriological anomaly which consists on a common
      channel from the urethra and vagina. The major incidence is produced in the
      congenital adrenal hyperplasia's context. In certain occasions it can be
      associated to an imperforate anus, then the malformation is called a cloacal
      defect. There are multiple surgical techniques to correct this malformation and
      different therapeutical approaches (without surgery, surgery at one or various
      times, early or delayed surgery) being the newest one the total urogenital
      mobilization. The purpose of this work is to reflect our experience with this
      technique. We present seven girls with urogenital sinus (3 with congenital
      adrenal hyperplasia, 2 with a cloacal defect, and the other 2 associated to
      ambiguous genitalia). Five patients were operated in the first year of life. The
      outcome has been favorable, and the cosmetic and functional results have been
      very good. The surgical technique consists on posterior sagittal incision, it can
      be done transanorectal if necessary, the urethrovaginal union is achieved and
      both structures are mobilized together, connecting them to the perineum, as a
      single unit. We believe that the total urogenital mobilization is actually the
      surgical technique to be chosen in every of urogenital sinus, for being easier,
      allowing early realization (girls under 1 year old), correcting simultaneously
      other anomalies, reducing the complications (urethrovaginal fistula, vaginal
      structure, or acquired vaginal atresia); and the result is excellent.

PMID- 12602003
TI  - [External tutor of ePTFE in tracheal stenosis. Clinical application].
AB  - Acquired tracheal stenosis in children can be either to direct cervicothoracic
      trauma or to post-intubation. Resection and end-to-end anastomosis continues to
      be the treatment of choice. The high rate of restenosis is directly related to
      anastomotic tension in resections of more than 2 cm. We report a case of a 7 year
      old child who suffered severe injury caused by car crash and intubation at the
      scene of the accident, with subsequent development of a cervical tracheal
      stenosis which required preoperative iterative laser sessions and balloon
      dilatation on 3 occasions, without result. Resection and primary anastomosis with
      an external stent of ePTFE was performed. The patient was treated successfully
      and was extubated promptly. Post-operative endoscopic studies and magnetic
      resonance imaging showed widely patent tracheal lumina with no stenosis. Three
      years post-operatively, the child is asymptomatic and participates in competitive
      sport activities. We can conclude that the model described above was clinically
      effective in the prevention of post-anastomotic tracheal stenosis in the child.

PMID- 12602004
TI  - [Temporomandibular joint ankylosis (TMA) in children].
AB  - Temporomandibular joint (TMJ) ankylosis is a degenerative disease that produces a
      limitation of mouth opening. In children, TMJ ankylosis usually presents with
      facial asymmetry, difficulty in feeding and rarely upper way obstruction.
      Ankylosis is commonly associated with trauma, infections, systemic and congenital
      diseases. Diagnosis must be clinical, being CT scan and magnetic resonance
      imaging (MRI) the most important methods to evaluate this disease. The treatment
      of TMJ ankylosis requires excision of the involved structures and reconstruction.
      We present our experience in treatment of the temporomandibular joint ankylosis.
      We have analysed the following parameters: age, sex, etiology, surgical
      technique, pre and postoperative oral opening.

PMID- 12602005
TI  - [Demand of emergency pediatric surgery. Study of inappropriate utilization].
AB  - BACKGROUND: Several studies have demonstrated that, between 30-60% of the cases,
      the urgent attention demand is considered inappropriate. This situation causes an
      increase in the sanitary costs and supposes for the patient a partial medical
      care. In the area of the Pediatric Surgery we have not found any work
      accomplished to such effect. OBJECTIVES:  DESIGN: Transverse observational study.
      SETTING: Emergency Service of a University Hospital. PATIENTS: a sample random
      (alpha: 0.05; precision: 0.05) of the patients attended during 1998. MAIN OUTCOME
      MEASURES: Dependent: appropriateness. Independent: age, gender, proximity,
      diagnostic, studies of the parents, previous assistance, if attends by own
      initiative and motives that induce to demand. It was considered hospital
      emergency, continuing the criteria of the WHO, when it is considered vital
      emergency or when there is using of therapeutic or diagnostic means nor available
      in an primary level of health care. The statistic treatment consisted of a
      relative frequencies analysis, test x2 and t Student. RESULTS: Of 2,226 cases
      attended in emergency service, they have 441 reviewed (age: 5.54 years; 63%
      male). The most frequent diagnoses have been: injuries and small traumatisms
      (39.7%), abdominal pain (22.2%), burns (3.6%), appendicitis (3.2%) and hernias
      (3.2%); 86.2% attended by own initiative. The proximity (19.9%), the alarm by the
      symptoms (13.1%) and the ignorance of the existence of other level of health care
      (10%) have been the causes by the parents for attention demand. The 63.9% of the
      visits were considered inappropriate. It has been found relationship between
      inappropriate use and age (p < 0.02), proximity (p < 0.003), to attend by own
      initiative (p < 0.001), and expectation of the parents (p < 0.02). It does not
      exist relationship to the gender or the studies level of the parents.
      CONCLUSIONS: These data suggest that in the Emergency Services exists a high
      appropriateness. The accessibility, the availability of means, the rapidity of
      the attention and who takes the decision of attending are variable associated to
      the appropriateness.

PMID- 12602006
TI  - [Recto-sacral fixation in the treatment of rectal prolapse refractory to
      conservative treatment].
AB  - INTRODUCTION: The clinical cases of 20 patients submitted to Reifferscheid
      intervention (fixation of rectum to promontorium) between 1967 and 1997 are
      presented. PATIENTS AND METHODS: Twenty patients have been treated by means of
      the operation of Reifferscheid. They were divided in two groups: from 1967 to
      1972, ten patients were submitted to this technique (group A). From 1974 to 1997,
      other ten patients (group B). In each case, the following items were registered:
      sex, eventual secondary diagnosis, incision, complications, middle-term
      evolution. RESULTS: Group A: Middle age: 2.15 years old. Sex: 7 girls (5 of them
      presented mielomeningocele) and 3 males; pararectal incision for babies,
      Pfannenstiel incision for children over 1 year-old. FOLLOW-UP: 2 years without
      recidives. Group B: Middle age: 2.5 years-old, 9 males (2 of them were diagnosed
      of mielomeningocele) and 1 girl. No recidives were detected. DISCUSSION: These
      excellent results obtained with Reifferscheid operation contrast with the poor
      results referred by other authors for other therapeutical approaches. That is
      why, in patients affected of serious rectal prolapse, especially when associated
      to other pathologies, rectal fixation to promontorium is an useful and long-term
      sure approach.

PMID- 12602007
TI  - [Fractures of the orbit floor].
AB  - Fractures of the floor are not common during childhood, their main cause being
      trauma. The mechanism is an increased pressure in the orbital cavity, which
      breaks at is weakest point, the floor, where soft tissue may be trapped-
      periorbitary fat, inferior rectus muscle, and inferior oblique muscle. Symptoms
      are diplopia, enoftalmos, eyelid ptosis and soft tissue haematoma. The diagnosis
      is made on the clinical and imaging findings, CT-Scan being the most reliable
      technique. Surgical treatment is necessary when symptoms do not subside and when
      the muscles or the infraorbitary nerve are compromised. We present four cases of
      orbit floor fracture which were completely resolved with conservative management
      (2 cases) or with surgical release of the muscular structures and orbit floor
      reconstruction (2 cases).

PMID- 12602008
TI  - [Scrotal hypospadias. Our experience with free oral mucosa grafts].
AB  - Many surgical techniques, using different tissues, have been performed to repair
      the scrotal hypospadias in this century, but none of them has been completely
      effective. The use of autologous buccal mucosa as a free graft for urethral
      replacement was introduced in 1989. The reported results have been encouraged
      since then. Twenty three patients with scrotal hypospadias, have been treated
      from 1991 to 1998. These patients underwent a 2-stage surgical replacement. The
      first stage of the procedure included correction of the penile curvature and
      advancement of preputial flaps ventrally as described by Byras. The second stage
      of the procedure was the urethroplasty. The neourethra was made of a tubularized
      buccal mucosa graft. The mucosa was harvested from the inner surface of the lower
      lip. The first stage was performed at a mean age of 20 months old, and the second
      stage at a mean age of 32 months old. Micropenis was detected in 26% of patients.
      All of them were treated with topic testosterone before the second stage. The
      follow-up reflected that 7 out of 23 patients (30.4%) had not complications,
      while 16 patients (69.5%) developed urethro-cutaneous fistula. Six of them (26%)
      required only one surgical closure and the other 10 patients required more than
      one surgical procedure to correct several complications. One patient presented
      complications in both the recipient and the donor areas. Nowadays, cosmetic and
      functional results are good in 22 patients.

PMID- 12602009
TI  - [Intraoperative awakening: report of a case in pediatric surgery].
AB  - Intraoperatory awakening or awareness can be defined as recovering of conscience
      during general anesthesia. We report such a case happened in a 11 year-old boy
      during a hypospadias repair. After anesthetic education he related intraoperatory
      conscience without pain, anxiety, displeasing symptoms or long-term
      psychoconductal distress. We remark fisiopathology, diagnostic and preventive
      aspects of this rare event in pediatric surgery.

PMID- 12602010
TI  - [Post-traumatic aneurysm of humeral artery].
AB  - Aneurysms are uncommon in the pediatric age-group. Unlike adults, in which
      aneurysms appear after alteration of the arterial wall due to systemic diseases,
      in children the traumatic etiology has to be considered: blunt trauma may disrupt
      the arterial wall and cause false aneurysm (pseudoaneurysm). Most aneurysms are
      asymptomatic, or they present as a pulsatile mass on an arterial traject.
      Diagnosis is confirmed with Doppler ultrasound and angiography. We present the
      case of a girl who, after blunt trauma of the right upper limb developed a
      pulsatile mass on the traject of the right humeral artery. Doppler ultrasound and
      angiography confirmed aneurysm of the humeral artery. She was successfully
      treated with surgical resection of the aneurysm and reconstruction of the
      arterial wall.

PMID- 12602011
TI  - [Registry of pediatric injuries. Is it sufficient?].

PMID- 12602012
TI  - [Our Society's congresses].

PMID- 12602013
TI  - [Apoptosis of the contralateral testis after unilateral testicular injury.
      Experimental study].
AB  - INTRODUCTION: The results of both clinical and experimental studies suggest that
      some testicular unilateral lesions cause infertility due to disruption of
      spermatogenesis. The cellular mechanism responsible for the degenerative changes
      is still unclear. OBJECTIVE: Study of the cellular viability in the contralateral
      testis after unilateral testis injuries. MATERIAL AND METHOD: Six groups of 10
      prepuberal Wistar rats subjected to unilateral testicular lesion. To identify the
      cellular death by "apoptosis" in situ, analysis of DNA fragmentation was
      performed in cytometric flow. RESULTS: The present study demonstrated an increase
      of the apoptosis in the contralateral testis after unilateral testicular lesion.

PMID- 12602014
TI  - [Surgery of lung metastasis].
AB  - INTRODUCTION: The 30-40% of the oncologic patients have pulmonary metastases.
      Lung can be the only organ affected. In selected patients, exeresis of the
      pulmonary nodules can mean their healing. MATERIAL AND METHODS: Between 1982
      1997, twenty two patients presented metastases, 13 could be operated and 16
      thoracotomies were done. There were 53% boys and 47% girls whose ages ranged from
      3 to 15 years. We have considered: pulmonary tumour location, disease free
      interval, number of metastases, surgical technique and incomplete pulmonary
      tumour resection. RESULTS: Primary tumours were: Wilms tumours 23%, bone tumours
      67% (Ewing and osteosarcoma). Disease free interval was < 2 years in 8 patients
      (61%) and > 2 years in 39%. X-Ray and CT were performed in every case and 66%
      presented a solitary nodule. Surgical techniques were: metastasectomy in two
      cases (12%), wedge resection in 8 (50%) and lobectomy in six cases (38%). We made
      thoracoscopy in two patients. There weren't postoperatory mortality but the
      patients with tumorectomy had an incomplete surgical resection. The overall
      survival is 54 percent and the 5 years survival is 23 percent (3 patients).
      CONCLUSIONS: The patients with a DFI < 2 years have a survival of 25% compared
      with 100% for patients who have a DFI > 2 years. The pulmonary resection in
      selected patients can offer better survival. We can use the thoracoscopy in same
      selected patients.

PMID- 12602015
TI  - [Complex and complicated syndactylia. Review and treatment progress].
AB  - Complex syndactyly is generally defined as abnormal digital interconnection by
      bone, but sometimes simple syndactyly with complicated cutaneous,
      musculotendinous or neurovascular interconnections should be considered complex
      as well. Additionally, complex syndactyly involving anomalous bones (delta
      phalanx, brachiphalangism...) falls in different category called "complicated".
      35 patients with complex or complicated congenital syndactyly are studied and 58
      children with cutaneous syndactyly due to burns and epidermolysis bullosa are
      analyzed as well.

PMID- 12602016
TI  - [Impact of complete resection on survival of patients with large neuroblastoma].
AB  - The aim of our study is to assess the role of complete resection after
      chemotherapy in stage 3 and 4 (INSS) neuroblastoma. MATERIAL AND METHODS: We
      treated in the period 1990-1997 a group of 71 infants and children with neural
      tumors. There were 63 neuroblastomas (median age: 24.8 +/- 25 months, median 18).
      47 were abdominal, 13 thoracic, 2 pelvic and 1 cervical. Survival rate (Kaplan
      Meier) in patients with or without complete resection of the tumor were assessed
      (Mantel Cox). RESULTS: 14 of 17 patients with stage 3 tumors and only 8 of 23
      with stage 4 survive. All patients with stage 3 undergoing complete resection are
      alive, whereas only 4 of 7 with incomplete resection survive (p < 0.01). In
      contrast, the effort and risk of resection do not appear to be worth in stage 4.
      Two kidneys, one spleen and a portion of the pancreas were removed to perform
      complete tumor removal. CONCLUSIONS: Complete resection in stage 3 neuroblastoma
      after chemotherapy improves survival, and radical surgery seems justified even if
      neighboring structures have to be removed. Radical surgery does not seem to be
      useful in stage 4 neuroblastoma.

PMID- 12602017
TI  - [Usefulness of anorectal manometry in the neonatal diagnosis of Hirschsprung
      disease].
AB  - During 1992 through 1998 anorectal manometry studies have been carried out on 32
      newborn, with age between 48 hours and 28 days and weight range of 1,400 and
      4,200 g at the test moment. The test has been prescribed due to a retard in
      meconial evacuation in the 32 patients, moreover, 13 out of them also presented
      an intestinal obstruction or subobstruction. The anorectal manometry is carried
      out with a probe especially designed by us for newborn and a Hellige polygraph.
      Presence or absence or rectoanal inhibitory reflex (RAIR) is assessed. The test
      is repeated after one and three weeks from the first study in the cases of RAIR
      absence. A barium enema was carried out in case of RAIR absence. The RAIR was
      present in 20 out of the 32 newborn, which allowed the exclusion of
      Hirschsprung's disease (HD) in these patients. Of the remaining 12 patients, in
      11 it was shown the absence of RIAR in the first anorectal manometry study,
      making it possible the early diagnosis of HD in 9 patients and transient
      functional obstruction of the colon in 2 newborns. This former diagnosis was
      corroborated by the findings of the enema, which showed a small left colon and by
      the presence of RAIR in a later anorectal manometry control. There was a doubtful
      case in the first study, showing later the absence of RAIR. The first enema in 10
      newborn with HD was considered normal in 3 cases and with transitional zone in 4
      newborns and microcolon in 1 case.

PMID- 12602018
TI  - [Analysis of anti-reflux surgery failure].
AB  - Recurrent gastroesophageal reflux following fundoplication is a challenging
      problem, because it is usually refractory to medical treatment and a second,
      technically difficult, antireflux operation is required. Different factors that
      may contribute to surgery failure have been identified in children. We present 8
      cases who underwent redofundoplication after failed procedures, from a total
      number of 96 patients operated on due to gastroesophageal reflux. Four patient's
      had their initial fundoplication performed at our institution. Six patients were
      neurologically impaired, six had chronic pulmonary disease, and two had
      esophageal atresia. The main presenting symptoms were recurrent vomiting (n = 8)
      and aspiration (n = 4). Gastroesophageal reflux was confirmed by barium swallow
      and endoscopy. Operative findings showed wrap breakdown in two cases, warp
      breakdown associated with hiatal hernia in five, wrap breakdown associated with
      paraesophageal hernia in two cases, and paraesophageal hernia with normal wrap in
      one. A second Nissen procedure were performed in five cases, whereas a Collis
      Nissen gastroplasty was realized in three with a short esophagus. Six patients
      had a successful outcome remaining symptom free, one has severe disphagia, and
      one has recurrent vomiting. In our experience, patients with recurrent
      gastroesophageal reflux disease should undergo an antireflux procedure tailored
      to specific anatomic or functional abnormalities.

PMID- 12602019
TI  - [Auricular alloplastic reconstruction with osteointegrated implants: a new
      therapy option in microtia].
AB  - Microtia has been treated over the years with autogenous tissues, although the
      results continue to improve, it is technically a very demanding procedure, even
      in the hands of a well trained surgeon. Osseointegrated implant-supported ear
      prosthesis, is less demanding, more straightforward, and offers a better cosmetic
      result. Since 1996 we have treated 8 patients with microtia types III and IV,
      with titanium osseointegrated implant-supported ear prosthesis in the bone of the
      mastoid process. The surgical procedure consists in two stages. First stage: when
      the three titanium screws are drill in the mastoid process of the temporal bone,
      with a previous CT scan of the area, that is used to measured the bone thickness.
      Second stage is done 3 to 6 months later. Ear remnants are removed at the
      beginning of the procedure, three titanium couplings are then secured to the
      integrated fixtures, a plastic cap is attached to each of the abutments, until
      healing takes place; three to four weeks later the auricular prosthesis made out
      of silicone over a metallic structure, will we plug in the titanium screws.
      Cosmetic results and patients acceptability have been good in all 8 cases, with
      few postoperative complications. This procedure has become and option for the
      patients with ear malformations.

PMID- 12602020
TI  - [Reduction of anxiety in the anteroom of the operating theater in pediatric
      patients].
AB  - Research indicates that anxiety before surgical intervention in paediatric
      patients negatively affects on post hospital recovery. Numerous investigations
      are, therefore, conducted to alleviate anxiety through different psychological
      techniques at this critical moment that the child is undergoing in surgery. In
      our case, we have considered one of the resources of the Sant Joan de Deu
      Hospital: a voluntary team that works in the anteroom of the operating theatre to
      keep the children company. The aim of our research has been to train these
      volunteers (who previously did not have any specific training for their task) and
      to observe the effect on the children's anxiety. The subjects of our study were
      140 boys and girls between the ages of 0 and 18 years old. Results indicate that
      training not only produces significative changes on volunteers' behaviour, but
      also has resulted in the children's presurgical anxiety behaviour. In this way,
      we recommend that all children be accompanied by a trained volunteer.

PMID- 12602021
TI  - [Use of nitric oxide in a newborn child with pulmonary cystic adenomatoid
      malformation].
AB  - Nitric oxide (NO) inhalation therapy relaxes preconstricted pulmonary blood
      vessels without causing concomitant systemic hypotension and increases oxygen
      uptake into the blood. NO inhalation is a new treatment for various disorders of
      neonates (respiratory distress syndrome, persistent pulmonary hypertension,
      congenital heart disease and congenital diaphragmatic hernia). There is no
      references of its use in congenital cystic adenomatoid malformation (CCAM). We
      report a case of a newborn of 33 week's gestation. The infant underwent resection
      of the CCAM that had occupied the right middle lobe. At the end of the operation,
      arterial blood gases at a fractional inspired oxygen concentration (FiO2) of 1.0
      reveled acidosis and severe hypoxemia probably due to persistent pulmonary
      hypertension. NO therapy was used for 16 hours with decreased oxygen need and
      increase of arterial blood oxygen data. According to the extent of the
      adenomatoid lesion, likely due to the compression of the surrounding tissue,
      these patients at times postoperatively develop difficulty in oxygenation and
      ventilation and the changes are similar to those patients with congenital
      diaphragmatic hernia. The use of NO in these disorders are successfull.

PMID- 12602022
TI  - [Thyroid carcinoma with lung metastasis].
AB  - Thyroid carcinoma is a rare disease in children. Much rare its presentation with
      pulmonary metastases is. We here report a recent case in 12 years-old girl. We
      make a review of recommended treatment and the prognosis.

PMID- 12602023
TI  - [Pulmonary cystic adenomatoid malformation with anomalous vascularization with
      systemic origin].
AB  - We report an infant with the diagnosis of Congenital Cystic Adenomatoid
      Malformation. He was operated and we found an abnormal systemic blood supply
      associated in that lobe. We make a review of the literature, and we make a
      distinction between this rare combination and others like pseudo pulmonary
      sequestration, or Congenital Cystic Adenomatoid Malformation associated to
      pulmonary sequestration.

PMID- 12602024
TI  - [Quo vadis pediatric surgery].

PMID- 12602025
TI  - [Nasal congenital cysts and fistulas: clinical and surgical aspects].
AB  - Eight patients affected with cysts or fistulae on the midline at the nose bridge
      (back of the nose) have been treated at the Pediatric Surgery Service of the
      Hospital Sant Joan de Deu in Barcelona from march 1995 to october 1996. Six
      patients had a cystic mass (four of them having an intranasal prolongation) and
      two had a fistulous orifice (one of them also having intranasal prolongation).
      The test with the highest diagnostic sensibility was the CT-scan, which showed a
      bifid crista galli and intranasal prolongation in 5 of the patients. Pathologic
      exam confirmed the diagnosis of dermoid cyst. At follow-up, all patients were
      doing well. Congenital cysts and fistulae at the nose bridge (back of the nose)
      may appear as a trivial condition; the possibility of them being the only
      clinical feature of an intranasal or intracranial prolongation is the reason for
      a deeper study in order to determine the extension of the lesion. The treatment
      is always surgical removal of the cyst and the fistulous pathway at the time of
      diagnosis, regardless of the patient's age, thus avoiding possible infectious
      complications.

PMID- 12602026
TI  - [Pulmonary complications during parenteral feeding via percutaneous silicon
      catheters].
AB  - Percutaneous fine bore silicone central catheters are frequently used in sick
      full term newborns and in low birth weight premature infants; although their use
      has some risks. We report two cases of pleural effusion in two prematures of 34
      and 33 weeks gestation and birth weight of 1,510 and 1,650 g, respectively; and
      one case neumonitis in a newborn of a 38 weeks gestation and 2,730 g birth
      weight. All of them have in common same initial clinical sign: increase mucus
      secretion of the upper airway a few hours after the beginning of parenteral
      nutrition using the type of catheter mentioned with the tip abnormally located in
      pulmonary artery. These complications are probably related to endothelial injury
      of very slow flow vessels due to the high osmolarity and low pH of the parenteral
      solutions used; which probably, in turn, produce thrombosis and vascular
      perforation, and/or extravasation. We suggest to suspect a pulmonary artery
      abnormally located catheter in patients receiving parenteral nutrition who
      increase upper airway mucus secretion. The rapid correction of the position would
      prevent major complications.

PMID- 12602027
TI  - [Iliac bone for secondary grafting in residual alveolar clefts].
AB  - Iliac cancellous bone has proven efficacy as a bone-graft donor. This study
      analyses the success of iliac bone autografts in secondary alveolar clefts. The
      study group was 30 patients with clefts with complete clinical charts and
      occlusal radiographs with surgery did in Cleft Unit Temuco Regional Hospital
      (Chile) between 1990-1996. The quality of graft "take" was measured
      radiologically and clinically. The results were named "excelent-good-regular-bad"
      and were studied by statistic methods. We did not find complications in donor
      site. We only had two partial dehiscences in recipient site. In 29 grafts, we
      feel "bone consistence" in clinical examination. We had one "nontake" graft. 80%
      of alveolar bone grafts showed similar bone density with respect normal bone. 80%
      of same grafts had similar height of interdental septum. We had 22 cases with
      "good result" and 3 cases with "regular result". All of them statistically
      significant. In our experience, iliac bone graft for alveolar clefts is a good
      technique for this difficult problem.

PMID- 12602028
TI  - [Surgical treatment of pediatric pulmonary metastases].
AB  - OBJECTIVE: We comment and update the surgical treatment for pulmonary metastases
      (PM) within a multidisciplinary approach for paediatric cancer. MATERIAL AND
      METHODS: We analyse patients with PM who have been operated between 1976-1996.
      Scientific literature published in the last 25 years (Cancerlit and Medline) was
      reviewed. RESULTS: PM from 13 patients were removed. Seven were males and 6
      females with a mean age 5 4/12 years (range: 11 months- 12 3/12 years). Diagnoses
      were Wilms' tumour (7), osteosarcoma (3), Ewing sarcoma (1), rabdomiosarcoma (1),
      Yolk sac tumour (1). PM were unilateral in 7 cases and bilateral in six cases. PM
      appeared synchronically in four patients and metacronically in nine cases (3 of
      these after chemotherapy). All patients received chemotherapy and four of them
      local radiotherapy. Surgery consisted on radical segmentectomy and only one
      patient needed lobectomy due to a local relapse. Nowadays five patients (38%) are
      in complete remission with a mean follow-up from surgery of 11 11/12 years
      (range: 6 3/12-20 years). CONCLUSIONS: Metastasectomy is an important surgical
      technique in global treatment of children with PM and for a selected group of
      patients it can offer the only opportunity for curation.

PMID- 12602029
TI  - [Laparoscopic staging in abdominal tumors in children: an alternative to staging
      laparotomy].
AB  - INTRODUCTION: In abdominal tumors in childhood, staging laparotomy is usually an
      essential diagnostic tool to obtain information about the histology and the
      extension of the tumor, when less invasive methods do not reach to clarify the
      process. PATIENTS: In fourteen children between 3 months and 17 years a
      laparoscopical procedure was performed. MATERIAL AND METHOD: Only in patients
      without a clear diagnosis after noninvasive exploration were submitted to an
      explorative laparoscopy in order to define the histology, the extension of the
      illness or to locate it. The laparoscopical instrumentarium used was from Dufner,
      adapted to children. RESULTS: The patients tolerated well this procedure, the
      posoperative period was short (mean 2.07 days), no complications after the
      operation are reported. Only one case of hemorrhage lead to a conversion after
      biopsy of a neuroblastoma. In all cases the diagnosis and staging was achieved.
      CONCLUSIONS: When non invasive diagnostic methods are not conclusive an
      explorative laparoscopy should be performed because it offers a lot of advantages
      over a laparotomy.

PMID- 12602030
TI  - [Cancellations in pediatric surgery].
AB  - Cancellations have an important role in the effectiveness of the surgical
      schedule. OBJECTIVE: Analyze the evolution of the cancellations during the years
      1994-1997, after institution of several corrective measures. MATERIAL AND METHOD:
      We started in 1994 together with the Quality Unit of the Hospital, a program to
      reduce surgical cancellations. It consisted in improvement of parents
      information, surgical schedule centralization, and increasing the awareness of
      the importance of constant improvement. Cancellations have been divided in:
      inevitables and inevitables, and analyzed for the entire Service and for each
      speciality. RESULTS: A significant reduction of cancellations have been obtain
      (from 12.38% in 1992 to 3.35% in 1997). The inevitable causes (no presentation,
      inadequate preparation and lack of time in the surgical room) have shown the most
      improvement. Although the inevitable causes (intercurrent disease) were also
      significantly improved, after obtaining prior information of the health of the
      child, by telephone call or parents advise. ENT is the speciality with greatest
      improvement by significant reduction of the non presentation and intercurrent
      disease. CONCLUSION: After corrective measures conjointly with a realistic
      surgical schedule, prior telephone call and improvement quality concept, have
      permitted a significant reduction of cancellations.

PMID- 12602031
TI  - [Rupture of a gastrostomy button. Importance of choosing the adequate material].
AB  - PEG is a safe, effective and widely used modality for nutritional
      andpharmacological enteral support in children. Rupture of the gastrostomy button
      during replacement is a very infrequent complication that may be avoided by
      choosing the adequate tube.

PMID- 12602032
TI  - [Fibroadenoma of the breast in a 17 month old girl].
AB  - Breast pathology is uncommon in infancy and adolescence. Fibroadenoma is the most
      frequent lesion. The juvenile variant is rare, occurring in only 2-7% of all the
      fibroadenomas. We report a case of juvenile breast fibroadenoma in a patient of
      17 months of age.

PMID- 12602033
TI  - [Congenital sternal cleft. Diagnosis and treatment].
AB  - The first known case of sternal cleft was described by Torres in 1740. Since
      then, many publications have appeared concerning sternal cleft, which have led to
      introduce a classification and some therapeutical procedures. This disease is a
      developmental anomaly of the sternum that usually shows vascular and cardiac
      malformations as well as diaphragmatic, abdominal wall, pericard and middle line
      organs anomalies. Two cases of sternal cleft are presented who have been treated
      in the neonatal period with different associated anomalies. Diagnostic procedures
      and therapeutical aspects are discussed.

PMID- 12602035
TI  - [Bronchial mucoepidermoid carcinoma].
AB  - We submit the case of a child afflicted with a mucoepidermoid bronchial tumor.
      The patient is a boy, aged seven, who after undergoing antibiotic treatment for
      six weeks because of a fever and atelectasia-condensation in the right lower lobe
      showed no signs of clinical improvement and was sent to our department to undergo
      further study and treatment. A bronchoscopy performed shows a polypoid mass that
      partially blocks the main bronchial tube a few milimiters under the access to the
      right upper lobe. A biopsy is carried out and the anatomopathological test shows
      there is a low degree epidermoid carcinoma. We decide to perform a lobectomy
      which for the tumor location and the lung condition has to be medium and lower
      right. We proceed to remove the adenopaty of hilium not affected by the tumor.
      The postoperative period develops without incidents. A check-up bronchoscopy
      performed three months later shows two polypoid masses in the right bronchial
      tube which, once a biopsy is performed, proved to be granulation tissue. Twelve
      months after undergoing surgery, the patient's condition is good, there is no
      evidence of tumor relapse and the breathing capacity is adequate, though there is
      an obstructive restrictive pattern in the espirometry. Even taking into
      consideration that lung tumors are extremely unusual, the epidermoid carcinoma is
      the one which most frequently occurs. The tumor's low malignancy is a sign that
      points to a good prognosis. Performing conservative surgery by means of
      bronchoplasty should be taken into account so as to keep the sequelae on the lung
      condition to a minimum, even though in this case the tumor location made it
      impossible.

PMID- 12602034
TI  - [Congenital lumbar hernia].
AB  - Hernias in the lumbar region are abdominal wall defects that appear in two
      possible locations: the superior lumbar triangle of Grynfelt-Lesshaft and the
      inferior lumbar triangle of Petit. There are 40 cases reported in the pediatric
      literature, and only 16 are considered congenital, associated with the
      lumbocostovertebral syndrome and/or meningomyelocele. A new case is presented. A
      premature newborn with a mass in the left flank that increases when the patient
      cries and reduces easily. The complementary studies confirm the diagnosis of
      lumbar hernia and reveal the presence of lumbocostovertebral syndrome associated.
      At the time of operation a well defined fascial defect at the superior lumbar
      triangle of Grynfelt-Lesshaft is primarily closed. The diagnosis of lumbar hernia
      is not difficult to establish but it is necessary the screening of the
      lumbocostovertebral syndrome. We recommend the surgical treatment before 12
      months of age; the objective is to close the defect primarily or to use
      prosthetic material if necessary.

PMID- 12602036
TI  - Natural products derived from naphthalenoid precursors by oxidative dimerization.

PMID- 12602037
TI  - Prokaryotic glycoproteins.

PMID- 12602038
TI  - Carbazole alkaloids. IV.

PMID- 12602039
TI  - A legal crusader's solution to the malpractice mess. Interview by Wayne J.
      Guglielmo.

PMID- 12602040
TI  - The night I almost played God.

PMID- 12602041
TI  - Medicare audit? You can handle it.

PMID- 12602042
TI  - "What's your e-mail address, doctor?".

PMID- 12602043
TI  - It's not easy to quit medicine.

PMID- 12602044
TI  - Do you really need an officer manager? You bet.

PMID- 12602045
TI  - Do you really need an office manager? No way.

PMID- 12602046
TI  - The right way to close a practice.

PMID- 12602047
TI  - When all else fails....

PMID- 12602048
TI  - Obedience to the unenforceable.

PMID- 12602049
TI  - TMA's 2003 legislative agenda. Nearly everything is new in 2003.

PMID- 12602050
TI  - TMA Legislation Committee considers Capitol Hill agenda for 2003.

PMID- 12602052
TI  - The relationship between health and development: health as an economic engine.

PMID- 12602051
TI  - Negligence or simple oversight?

PMID- 12602053
TI  - Deep brain stimulation: a new treatment for Parkinson's disease.
AB  - Patients suffering from advanced Parkinson's disease (PD) often experience an
      array of symptoms that greatly affect their quality of life. Deep brain
      stimulation (DBS) of the bilateral subthalamic nuclei (STN) has produced
      remarkable improvements in people with advanced PD whose symptoms are not
      adequately controlled with medication. We present a case report on a patient who
      has benefitted immensely from bilateral STN stimulation. Levodopa responsiveness,
      disabling motor fluctuations and dyskinesias, cognition, and concurrent illness
      are major factors in identifying candidates who will receive the greatest
      benefit.

PMID- 12602054
TI  - West Nile virus in Tennessee.
AB  - WNV is a mosquito-borne virus that generally causes asymptomatic or mild illness
      in humans. Less than 1% of infected persons will develop severe disease. Because
      there is no specific treatment for the disease, mildly ill persons seldom require
      testing for WNV. Widespread media coverage may contribute to misperceptions about
      the incidence and severity of the disease, and many patients may benefit from
      reassurance and information which helps them understand the true risk of WNV
      compared with many more common but less sensational public health threats. For
      example, approximately 34,000 Americans die each year from firearms, and 20,000
      die from influenza (a vaccine-preventable disease). Common-sense personal
      protective measures to avoid mosquito bites can substantially reduce an
      individuals' risk of acquiring WNV.

PMID- 12602055
TI  - Electroconvulsive therapy: brief review and present utilization.

PMID- 12602056
TI  - Developing a health care agenda for Michigan.
AB  - Developing a health care agenda for Michigan will require intense dialogue among
      health care providers, policymakers, employers, communities and individuals. What
      follows is an outline of the health problems facing Michigan's residents and
      suggestions for tackling these enormous challenges. We hope that this will
      stimulate discussion among health care stakeholders in Michigan. Only through
      committed partnerships can we begin to improve the health of Michigan residents.

PMID- 12602058
TI  - Learning and creating synergy through dialogue.
AB  - With the complexity and change facing leaders and managers today, continuous
      learning, responsiveness, adaptation and innovation are essential survival
      skills. One constant that human beings seem to want and need more than anything
      else in relationship to another human is to be heard. Often in conversation, we
      spend a lot more time advocating for our position rather than seeking to hear and
      understand another.

PMID- 12602057
TI  - The balance between metrics and mission.
AB  - Culture and change are frequently linked in inquiries into the past, present and
      future of health care. However, an intimate relationship does not necessarily
      mean an easy marriage. Many predicted changes of the past decade (e.g., health
      care reform plans) failed to occur as expected because the culture's ability to
      resist was stronger than politics' power to transform. A force for change can
      also cause a health care entity (e.g., a small or rural hospital) to evolve into
      something very different in order to avoid its demise.

PMID- 12602059
TI  - Spanning the ages: meeting the needs of different generations.
AB  - Never before has the health care profession been challenged like it is today.
      With competitive pressures of increased customer awareness, regulatory compliance
      and staffing concerns, there are also challenges related to various
      generational/diversity issues.

PMID- 12602060
TI  - Back to the future--a recipe for reform.
AB  - The 2002 MHA Health Care Leadership Forum provided an opportunity to review
      health care reform efforts--what we have accomplished, where we are now and what
      we need to do next.

PMID- 12602061
TI  - Creating culture in your organization.
AB  - Every organization has a culture. Simply defined, it is the personality of the
      organization, the way things get done, the values, norms and beliefs that shape
      behaviors. Organizational culture may appear to be beyond our control. But in
      reality, we can choose to either define the culture we want for our organization
      or let it take on a life of its own.

PMID- 12602062
TI  - Staying committed.
AB  - After an intensive and collaborative two-year effort, the Michigan Health and
      Safety Coalition (MH&SC) has publicly released hospital-specific information for
      seven serious medical conditions and for care provided in intensive care units.
      Hospitals' willingness to share this information and to commit to participation
      in ongoing collaborative improvement activities serves as a catalyst to achieving
      a mutual goal--statewide, systemic improvement in the safety and quality of
      health care.

PMID- 12602063
TI  - Hope for the best--plan for the worst: disaster preparedness in a strange new
      world.
AB  - In the last year, local, state and federal governments, as well as not-for-profit
      and private businesses, have had to examine how they would respond to a disaster.
      The responsibility to be well-prepared is especially important for hospitals for
      two reasons.

PMID- 12602064
TI  - Providing care options: traditional medicine and alternative treatments come
      together.
AB  - Bronson Methodist Hospital, Kalamazoo, has expanded its realm of services by
      opening the Bronson Center for Integrated Medicine (BCIM), which features an
      array of complementary therapies that serve to provide alternatives to
      traditional treatments.

PMID- 12602065
TI  - Changing the culture of care.
AB  - Culture: The concepts, habits, skills, arts, and institutions of a given people
      in a given period of civilization, or that which defines who we are.

PMID- 12602066
TI  - Perspectives. CMS and Wall Street report....

PMID- 12602067
TI  - [Adhesions of the labia minora in three young girls].
AB  - Three girls, 2, 5 and 6 years of age, had labial adhesions: one without
      complaints but whose mother was anxious about abnormal anatomy of the external
      genitalia, one with urinary problems because of pooling of the urine in the
      almost completely covered vagina, relapsing after surgical intervention, and one
      with irregular adhesions because of sexual abuse. In all three, after (repeated)
      application of oestrogen cream the adhesions reduced or disappeared. Adhesions of
      the labia minora can often be noticed under the age of 8 years and dissolve after
      that age during the period of progressive natural oestrogen production. Therapy
      consists of application of oestrogen cream on the contact surface of the labia
      minora. Surgical treatment is disputable and causes a high recurrence, probably
      higher than conservative treatment.

PMID- 12602068
TI  - [Nutrition and health--genetically modified food].
AB  - The genetically modified (GM) crops cultivated at present have new properties of
      benefit to agriculture. It is expected that in the future GM crops will also be
      cultivated with more complex genetic modifications that are aimed at improving
      the nutritional and health value to the consumer. The safety assessment of GM
      foods before market approval is based on a comparison of the characteristics of
      the GM food with those of the conventional counterpart. Identified differences
      are thoroughly tested for their toxicological and nutritional consequences.
      Supplementary modern analytical techniques are being developed for the assessment
      of future complex GM foods. No cases of adverse health or nutritional effects in
      consumers have been reported for the existing generation of GM foods. The
      feasibility of post-market surveillance of (GM) foods, in order to identify small
      or chronic effects that have not been noticed in the pre-market phase, is being
      investigated, yet its value should not be overestimated. Surveillance can be
      informative in case of specific questions concerning certain products as long as
      the consumer intake is well documented. To this end traceability and labelling
      systems must be set up.

PMID- 12602069
TI  - [Nutrition and health--sense and nonsense regarding food supplements and
      functional foods].
AB  - A functional food is a proprietary food or beverage with a health-related claim.
      Such functional foods could make it easier to maintain a healthy diet.
      Unfortunately, in many countries regulations allow manufacturers to imply that a
      food promotes health without providing proper scientific evidence. At the same
      time, regulations may forbid claims that a food product prevents disease, even
      when it does (e.g. folic acid, which reduces the risk of neural tube defects).
      Functional foods may have beneficial health effects compared with traditional
      foods in some cases, but current legislation in the Netherlands cannot protect
      consumers from misleading claims.

PMID- 12602070
TI  - [Diagnostic image (121). An artificially ventilated neonate with abdominal
      distension. Pneumoperitonium secondary to intrathoracic air leakage].
AB  - A male neonate was artificially ventilated because of respiratory insufficiency.
      He developed a pneumoperitoneum secondary to pulmonary air leakage.

PMID- 12602071
TI  - [From gene to disease; the nail-patella syndrome and the LMX1B gene].
AB  - Nail-patella syndrome (NPS) is an autosomal dominant hereditary disorder
      characterised by nail dysplasia, patellar apoplasia/hypoplasia, iliac horns,
      elbow dysplasia, and frequently primary open angle glaucoma and progressive
      nephropathy. The gene underlying NPS, LMX1B on chromosome 9q34.1, is a
      transcription factor involved in the normal dorsoventral patterning of the limb
      and normal development of the glomerular basement membrane in the kidney. Recent
      studies suggest a role for LMX1B in the regulation of collagen IV expression and
      in the transcriptional regulation of podocyte specification and differentiation.
      At present, no evidence for a correlation between the presence and severity of
      the clinical anomalies and the LMX1B genotype has been found.

PMID- 12602072
TI  - [Incidence of cervical cancer in women in North-Holland by country of birth from
      1988-1998].
AB  - OBJECTIVE: To describe the incidence of cervical cancer in women in North-Holland
      by country of birth. DESIGN: Descriptive epidemiological study based on data from
      cancer registries. METHOD: The number of cases of cervical cancer in North
      Holland for the period 1988-1998 was determined using data from the regional
      cancer registry of the Comprehensive Cancer Centre, Amsterdam. Based on data from
      the Netherlands Cancer Registry, a comparison was made between the observed (O)
      and the expected (E) number of cases by area of residence (i.e., Amsterdam versus
      the rest of North-Holland) and by the woman's country of birth. RESULTS: In the
      period 1988-1998, the incidence of cervical cancer among women living in North
      Holland was significantly higher than that of the nation as a whole (O/E-ratio:
      1.2; 95% CI: 1.1-1.2). In particular, the incidence of cervical cancer for women
      living in Amsterdam (O/E-ratio: 1.5; 95% CI: 1.4-1.6), and for women born in
      Morocco (O/E-ratio: 2.1; 95% CI: 1.4-3.1) or Surinam (O/E-ratio: 1.5; 95% CI: 1.1
      2.0) was much higher. The country of birth was unknown in 10% of the women. The
      percentage of patients with extension of the disease outside the uterus (TNM
      stages II-IV) did not differ between women born in the Netherlands and those born
      abroad. CONCLUSION: The incidence of cervical cancer during the period 1988-1998
      was significantly higher for women living in Amsterdam and for women born in
      Morocco or Surinam than that for the Netherlands as a whole. No significant
      difference in stage of disease at diagnosis was observed between women born in
      the Netherlands versus those born abroad.

PMID- 12602073
TI  - [A child whose parents denied her psychiatric care].
AB  - A 15-year-old girl was admitted because of an abdominal tumour and inability to
      eat. History revealed that after an accident at 9 years of age she increasingly
      developed medically unexplained signs and symptoms (e.g. tunnel vision with
      blindness, paralysis and loss of sensitivity below the umbilicus, periods of
      diminished consciousness). No somatic explanation could be found; the parents
      rejected psychiatric examination. Upon physical examination the patient's
      weight's was far below the third percentile (32 kg) and the tumour appeared to be
      the lumbar spine, palpable through the abdominal wall. Following tube feeding and
      behavioural therapy the girl gained weight and the tumour disappeared. No cause
      for the underweight was found. Conversion disorder was diagnosed. However, the
      parents strongly refused to accept this diagnosis; they lodged complaints with
      various bodies and made further treatment and counseling impossible. Children
      with psychological problems who were treated as having a somatic disorder by
      their mothers have been described before. The outcome can be lethal. Children
      showing unexplained signs and symptoms whose parents strongly refuse psychiatric
      care will be seriously jeopardised in terms of their somatic and psychological
      development. Physicians should identify this situation at an early stage.

PMID- 12602074
TI  - [Malacoplakia of the female genital tract in a woman with postmenopausal
      bleeding].
AB  - A 74-year-old woman had vaginal bleeding for 6 months with no other complaints. A
      suspected tumour was visible on the cervix and the endometrium was slightly
      thickened. Histological examination revealed Michaelis-Gutmann bodies. Following
      antibiotic treatment, the tumour and the bleeding disappeared. Malacoplakia is a
      chronic inflammation which usually arises in the urinary tract of older women
      and, rarely, in the female genital tract. The abnormality often appears to be a
      malignancy, although histologically it is an inflammatory condition. Histological
      examination is necessary to establish the diagnosis. Treatment usually consists
      of antibiotics and surgical excision.

PMID- 12602075
TI  - [Breast feeding and bottle feeding in the first 4 months of life in 4438
      neonates].

PMID- 12602076
TI  - Bringing the patient back in. Guidelines, practice variations, and the social
      context of medical practice.
AB  - We challenge assumptions that have guided much research and policy aimed at
      understanding and reducing medical practice variation. Paramount is the focus on
      doctors as the cause of variation to the neglect of other possible influences.
      Some research literature suggests that patients, families, and the community
      context of practice may also influence treatment decisions. Failure to question
      present assumptions, despite weak evidence in support of them, may account for
      inability to explain persistent practice variation, develop appropriate
      implementable guidelines, or anticipate the effect on treatment decisions of
      greater patient involvement. In this paper, we discuss the weak response to the
      NIH Consensus Conference on early stage breast cancer because it may have
      reflected these problems. We urge a more complex and more empirical approach in
      explaining treatment choice and guidelines sensitive to the potential for value
      differences.

PMID- 12602077
TI  - Electronic fetal monitoring. Lessons from a formative case of health technology
      assessment.
AB  - OBJECTIVES: The assessment of electronic fetal monitoring (EFM) carried out by
      the authors in the late 1970s provides an early case of a systematic review of
      evidence in health technology assessment. This paper identifies lessons pertinent
      for the present day in this field. METHODS: We reviewed our own files for the
      description of our assessment and reactions to it. We also reviewed recent
      literature to evaluate our observations in relation to recent evidence. RESULTS:
      Our findings of insufficient evidence of efficacy and concerns about safety have
      been confirmed by subsequent research. Still, despite findings and
      recommendations of prominent professional and governmental bodies, EFM continues
      in widespread use in the United States and Europe and is spreading into
      developing countries around the world. Aggressive attacks on our assessment as
      well as our skills and integrity have been mirrored in recent years by criticism
      of other researchers in health technology assessment. CONCLUSIONS: The case of
      EFM points to the limitations of assessment without other actions to assure the
      implementation of results. Health technologies that are accepted by the majority
      of clinicians in a particular field may require extraordinary efforts to assure
      appropriate use of technology assessments.

PMID- 12602078
TI  - Using evidence in the development of local health policies. Some evidence from
      the United Kingdom.
AB  - OBJECTIVES: This paper explores the use of evidence, focusing on economic
      evidence in particular, in the development of local health policies through an in
      depth study of Health Improvement Programmes (HImPs) in England. METHODS: A
      questionnaire was sent to the person responsible for coordinating the development
      of the HImP in each of the 102 English health authorities. In addition, semi
      structured interviews were conducted with 10 HImP leaders, and a random sample of
      26 HImP documents was reviewed using a standard pro forma. RESULTS: Of the 102
      mail questionnaires sent out, 68 (67%) were returned. It was found that those
      developing HImPs had multiple objectives, only some of which (e.g., efficiency in
      healthcare provision) would necessarily require evidence. Where evidence was
      used, this was a mixture of internal (experiential) and external (empirical)
      evidence, with the balance (66%) being in favor of the latter. Government reports
      and guidance from the National Institute for Clinical Excellence (NICE), were the
      main sources of external evidence, rather than published papers. Key barriers to
      the use of economic evidence were lack of time and availability and the
      difficulties in synthesizing information at the local level. CONCLUSIONS: Based
      on responses to our survey, the main ways of increasing the use of evidence in
      the development of local health policies in England are to produce more evidence
      based national guidance and to produce accessible summaries of the available
      literature for local decision makers.

PMID- 12602079
TI  - Incorporation of genuine prior information in cost-effectiveness analysis of
      clinical trial data.
AB  - The Bayesian approach to statistics has been growing rapidly in popularity as an
      alternative to the frequentist approach in the appraisal of healthcare
      technologies in clinical trials. Bayesian methods have significant advantages
      over classical frequentist statistical methods and the presentation of evidence
      to decision makers. A fundamental feature of a Bayesian analysis is the use of
      prior information as well as the clinical trial data in the final analysis.
      However, the incorporation of prior information remains a controversial subject
      that provides a potential barrier to the acceptance of practical uses of Bayesian
      methods. The purpose of this paper is to stimulate a debate on the use of prior
      information in evidence submitted to decision makers. We discuss the advantages
      of incorporating genuine prior information in cost-effectiveness analyses of
      clinical trial data and explore mechanisms to safeguard scientific rigor in the
      use of such prior information.

PMID- 12602080
TI  - The health economics of calcium and vitamin D3 for the prevention of osteoporotic
      hip fractures in Sweden.
AB  - OBJECTIVE: The objective of this study was to examine the economics of
      administering calcium and vitamin D3 to post-menopausal women in Sweden. We focus
      primarily on the cost-effectiveness of treating older women for whom clear
      evidence of efficacy is available. We supplement this information, however, with
      estimates of the cost-effectiveness of treating certain high-risk groups of
      younger women, while acknowledging the greater uncertainty involved. METHODS: We
      developed a Markov model for analyzing the occurrence and timing of hip
      fractures, based almost entirely on peer-reviewed data from Sweden. In a 3-year
      randomized clinical trial, the combination of calcium and vitamin D3 was shown to
      reduce the risk of hip fractures by 27%. Costs for treating hip fractures were
      based on 1,080 women who were hospitalized in Stockholm. RESULTS: Treatment of 70
      year-old women was cost saving at efficacy as low as two-thirds that seen in the
      clinical trials, and upwards. Even at modest rates of efficacy, treatment of the
      high-risk 50- and 60-year-old cohorts was generally cost-effective and in some
      cases even cost saving. Particularly cost-effective was treatment of women with
      identified osteoporosis or a maternal family history of hip fracture. CONCLUSION:
      Simulation results suggest a role for lifetime treatment of older women with
      calcium and vitamin D3 in Sweden. While there is more uncertainty underlying the
      treatment of younger women, our simulation results suggest that treatment may
      also be cost saving or at least cost-effective for many cohorts of high-risk 50-
      and particularly 60-year-old women, in particular those with osteoporosis or a
      maternal family history of hip fracture.

PMID- 12602081
TI  - HTA education and training in Europe.
AB  - OBJECTIVE: To identify training programs and educational resources in health
      technology assessment (HTA) in Europe. METHODS: A postal survey among potential
      informants in European countries and Israel, expanding on surveys among ISTAHC
      and INAHTA members. Informants were identified either using HTA networks or by
      means of Internet sources. RESULTS: The combined results of the three surveys
      show that in the European Union (EU), including Norway and Switzerland, 13 of 17
      countries (76%) provide either university level courses or continuing education
      HTA courses. In the candidate EU countries, 4 of 10 countries (40%) provide HTA
      courses. In the remainder of countries, only Israel provides HTA courses. Ten
      different types of courses were identified, mainly applying traditional teaching
      methods. A substantial number of the courses were first organized in recent
      years. Many countries in central and eastern Europe expressed the wish to become
      more involved in HTA. CONCLUSION: There is a rapid increase in the number and
      diversity of courses in HTA in Europe. In particular, countries in the EU are
      well represented. Education and training in HTA is scarce in EU candidate
      membership countries, and virtually absent in the remainder of countries. In
      general, HTA as a field is in the process of becoming established and
      institutionalized both in individual countries and internationally. To stimulate
      this development in the area of education and training, both bilateral
      cooperation and an EU-wide coordinated effort are recommended.

PMID- 12602082
TI  - The typical Cochrane review. How many trials? How many participants?
AB  - OBJECTIVES: To describe the number of trials and participants in a typical
      systematic review from The Cochrane Database of Systematic Reviews. METHODS: The
      number of trials in 1,000 Cochrane systematic reviews in issue 1, 2001 of The
      Cochrane Database of Systematic Reviews was counted for three categories of
      trial: included trials, ongoing trials, and trials awaiting assessment for
      inclusion. (The term trial is used in this paper, although a small number of
      Cochrane reviews include studies that are not trials.) The total number of
      participants in included trials was extracted from a sample of reviews. RESULTS:
      A total of 9,778 trials were included in the Cochrane reviews. There were a
      further 356 ongoing trials and 1,138 trials awaiting assessment for inclusion. A
      typical review contained six included trials. Forty percent of the reviews listed
      ongoing trials and/or trials awaiting assessment for inclusion. Based on a sample
      of 258 reviews, the median number of participants per review was 945
      (interquartile range, 313 to 2,511) per review and 118 (interquartile range, 60
      to 241) per trial. CONCLUSION: This report is a descriptive study of the number
      of trials and participants in a typical Cochrane review from The Cochrane
      Library, issue 1, 2001.

PMID- 12602084
TI  - Reports from the Swedish council on technology assessment in health care (SBU).
      Treatment of asthma and COPD: an evidence-based review.

PMID- 12602083
TI  - Impact of health technology assessments. Some experiences of SBU.
AB  - OBJECTIVE: A recurring question is whether evidence from systematic reviews has
      any impact on medical practice. We have studied this question in relation to some
      conclusions in seven reports, where relatively simple means to monitor trends
      could be used. RESULTS: As recommended, in the report preoperative routines, the
      number of preoperative examinations diminished at six hospitals, during around
      3,000 operations studied, a savings of SEK 130 million. After the report on
      moderately elevated blood pressure, moderately elevated blood pressure sales of
      the preferred drugs, diuretics and beta-blockers, stopped falling while calcium
      blockers and ACE inhibitors stopped rising. As concluded in the report, general
      prostate cancer screening has not been introduced, but tests as a sign of
      opportunistic screening have increased. Bone density measurements were not
      recommended for screening, and sales of equipment have declined after the report.
      The use of neuroleptics as unspecific calming therapy for old persons was
      discouraged due to the serious side effects. The frequency of patients given this
      medication diminished from 34% to 28% at nursing homes after 1 year. For smoking
      cessation, the use of nicotine substitution medications has increased, which is
      in line with suggestions presented in the report. For stomach pain proton pump
      inhibitors given for functional dyspepsia have diminished in a region of the
      country after special efforts to disseminate the message. CONCLUSIONS: It appears
      to be possible to monitor changes in practice corresponding to selected
      conclusions in systematic reviews. After rather extensive disseminating efforts,
      some results look encouraging.

PMID- 12602085
TI  - Developing hospital efficiency-cost control measures.
AB  - The purpose of this paper is to provide hospital managers with important
      knowledge and skills in developing efficiency measures that hospital can use as
      guidelines in monitoring and controlling operational costs. Efficiency measures
      are judgmental and comparative. Cost and quantity are the variables in the
      computation of efficiency measures but it is very important to integrate these
      variables with quality. A hospital is efficient if it can render quality service
      at the most cost effective manner.

PMID- 12602086
TI  - [Mexico's healthcare in the 20th century].
AB  - The purpose of this article is to present Mexico's healthcare in the 20th
      century. This was a process that was based on illustrated rationalism, positivism
      and neopositivism. Knowledge and science used to veer away from all aspects of
      charity and beneficence. Liberal legacy were favourable to government stocks and
      the state managed to raise a considerable amount of financial and human
      resources.

PMID- 12602087
TI  - [Quality in the healthcare sector: new strategic measures for new challenges].
AB  - This article reviews the experience of the organizations representing the private
      healthcare industry in Argentina in their request to improve the quality of care.
      In it, the author highlights how their collaboration with the PAHO/WHO in the
      nineties led to the drafting of a Quality Accreditation Handbook, as well as its
      circulation in most of the countries in the area. Ten years on, the new
      challenges are analyzed in order to achieve better quality fro all, without
      limits. With these challenges in mind, the study presents the five programmes
      being developed at present, by the private health sector as a way of
      collaborating with society and the government in its progress towards the
      nationalization of resources and achieving a fairer system and better quality in
      healthcare.

PMID- 12602088
TI  - What can be done about the private health sector in low-income countries?
AB  - A very large private health sector exists in low-income countries. It consists of
      a great variety of providers and is used by a wide cross-section of the
      population. There are substantial concerns about the quality of care given,
      especially at the more informal end of the range of providers. This is
      particularly true for diseases of public health importance such as tuberculosis,
      malaria, and sexually transmitted infections. How can the activities of the
      private sector in these countries be influenced so that they help to meet
      national health objectives? Although the evidence base is not good, there is a
      fair amount of information on the types of intervention that are most successful
      in directly influencing the behaviour of providers and on what might be the
      necessary conditions for success. There is much less evidence, however, of
      effective approaches to interventions on the demand side and policies that
      involve strengthening the purchasing and regulatory roles of governments.

PMID- 12602089
TI  - Why the future of architecture doesn't need us.
AB  - The information age has ushered in a well-documented revolution in design and
      production over the past decade. So far these changes mostly have affected our
      ability to envision and illustrate new forms, but soon the entire artificial
      environment may be restructured. Emerging technologies such as nanoscience and
      artificial intelligence may not only restructure the physical world--they may
      also completely alter our understandings of the world and of ourselves.
      Traditional standards of architectural theory may become altogether irrelevant.

PMID- 12602090
TI  - The future of public health.
AB  - The scale of health inequalities in the UK is stark indeed: and their persistence
      has disfigured our society. Can there be any room for complacency when we know
      that a male resident of Manchester can expect to live over seven years less than
      his contemporary in Barnet? Or, that when it comes to healthy life expectancy the
      gap is even greater: The number of years of life in good health that a man can,
      on average, expect to live is almost 11 years better in Surrey than in
      Manchester. For women, the difference is nine years between these local authority
      areas. Death rates from coronary heart disease among first generation South
      Asians aged 20-69 are about 50% higher than the England and Wales average.
      Perinatal mortality among Pakistani born mothers is nearly twice the United
      Kingdom national average. None of this, of course, comes as any surprise to the
      people in this room. But such inequalities are simply unacceptable in Britain
      today and they should be rejected on every level, whether moral, social or
      economic.

PMID- 12602091
TI  - [Romanian pneumology came to Europe].

PMID- 12602093
TI  - [Clinical and epidemiological changes in tuberculosis in children in the last 5
      decades(1950-2000) ].
AB  - This study analyses over a 48 years period (1953-2000) the incidence of various
      clinical forms of TB in children aged 0-8, admitted in several ftizio-pediatric
      institutions. Follow-up included: primary complex, pleuro-pulmonary involvement,
      bronchial adenogenic involvement, extra-respiratory forms and major sequelae of
      primary tuberculosis. The results show a marked decrease of incidence of all TB
      forms in children and disappearance of chronic extensive primary tuberculosis and
      major sequelae of primary tuberculosis. The incidence tappered in steps: a sudden
      decrease in 1964-65, another in 1974, followed by a gradual decline. On contrary,
      the incidence of multiple sequela calcifications seems to be increasing after
      1980. These clinical mutations, especially the one in 1974, may be attributed to
      strictly observed treatment, to reintroduction of national campaign of BCG
      vaccination and to the decrease of TB incidence in adults (diminished bacilli
      offer).

PMID- 12602092
TI  - [Bronchoalveolar lavage findings in the pulmonary impairment related to systemic
      sclerosis].
AB  - The main objective of the study was to evaluate the relationship between the
      findings of the bronchoalveolar lavage (BAL) and the lung function in patients
      with systemic sclerosis and subsequent pulmonary impairment. The study was
      retrospective and included 17 cases with systemic sclerosis and pulmonary
      involvement investigated at "Marius Nasta" Institute. Bucharest, between January
      1999-August 2001. Lung function assessment found the following: VC (% of
      predicted) = 82.5 +/- 14; DLCO (% of predicted) = 67.5 +/- 23.2. Cell count in
      BAL fluid showed: total number of cells x 10(6) = 11.5 +/- 6; lymphocytes (%) =
      22.9 +/- 15.4; neutrophils (%) = 15.2 +/- 13.4; eosinophils (%) = 1.9 +/- 0.9;
      macrophages (%) = 58.1 +/- 19.8. We also compared the cell pattern according to
      DLCO value: the patients with DLCO > 80% had increased levels of eosinophils (5.2
      +/- 4.9 vs 0.9 +/- 0.2, p = 0.007) while the group with DLCO < 80% presented
      significantly higher levels of neutrophils (16.1 +/- 15.5 vs 12.6 +/- 2.8, p =
      0.003) compared to the group with normal lung function. CONCLUSIONS: Patients
      with systemic sclerosis and normal lung function present an increased level of
      eosinophils in BAL fluid, suggesting a transitory alveolitis. In change, those
      with DLCO < 80% have a higher level of neutrophils, usually associated to
      pulmonary fibrosis. The investigation by BAL appears to be a reliable tool for
      the assessment of the pulmonary impairment related to systemic sclerosis.

PMID- 12602094
TI  - [Evolution of annual risk of TB infection in Dolj county in the last 3 decades].
AB  - We determined the Ri (tuberculosis infection risk) of the last three decades in
      Dolj county. For estimating this, we used four calculation methods without
      neglecting the TSRU experts recommendations of evaluation. We estimated the Ri
      regarding the age groups and social environments by four methods using values of
      tuberculosis infection prevalence starting from 340.537 tuberculin tests
      accomplished during 1966-1995. We estimated an unique, medium Ri that has been 1%
      per year from 1970 until nowadays. The annual Ri decline is 1.5% comparing the
      risk from 1995 to the one from 1977 and 1.1% when we consider its value from 1995
      compared to the one from 1980. This evolution of the Ri denotes the concerning
      situation in our county, similar to the national one.

PMID- 12602095
TI  - [Diagnostic and therapeutic clues in idiopathic pulmonary fibrosis].

PMID- 12602096
TI  - [Pulmonary involvement in systemic sclerosis].

PMID- 12602097
TI  - [A rare cause of thoracic shadow].
AB  - The observation of an massive thoracic opacity at a patient with minimum
      symptoms, without considerable medical history makes etiologic diagnosis
      difficult. An uncommon cause is thoracic ectopia of the kidney and a
      supplementary liver lobe, both in a common mass with fatty tissue and an external
      fascis, above the diaphragm, with tumor-like appearance. This malformation of
      kidney and liver is congenital but the diagnosis may be made in adulthood and is
      useful for further monitoring and prognosis.

PMID- 12602099
TI  - [ Effect of smoking on pregnant women and their offspring ].

PMID- 12602098
TI  - [Multiple, paravertebral Pott's abscesses].
AB  - The authors describe a case of vertebral tuberculosis with multiple
      localizations, high thoracical (T2-T6) and of the sacrum (S1-S4) at a young woman
      with nonspecific clinical symptoms and with CT examination suggestive of the
      diagnosis, where the diagnostical certainty was obtained by the bacteriological
      examination for bK of the pus (purulent liquid) extracted by CT guided fine
      needle biopsy performed in the posterior mediastinal tumor.

PMID- 12602101
TI  - [Thoracic macronodular opacity].

PMID- 12602100
TI  - [Indoor pollution a subject always in focus].

PMID- 12602102
TI  - [Atlanta 2002-a Congress where professors become students].

PMID- 12602104
TI  - [Bochum-2002, First German congress].

PMID- 12602103
TI  - [Third European conference" Tobacco or health"- a Romanian success].

PMID- 12602105
TI  - [Current concepts in COPD treatment].

PMID- 12602106
TI  - "Alternative" medicine and science--like fire and water?

PMID- 12602107
TI  - [Suicidal behavior and suicide prevention].

PMID- 12602108
TI  - Perspectives in economic analyses of sepsis.

PMID- 12602109
TI  - Hepatitis E and its emergence in non-endemic areas.
AB  - In areas with a tropical or subtropical climate and poor sanitary conditions,
      hepatitis E is the major cause of enterically transmitted non-A, non-B hepatitis,
      and is responsible for both waterborne outbreaks of variable magnitude and
      sporadic cases of acute hepatitis. The causative agent is the hepatitis E virus
      (HEV), a non-enveloped, single-stranded, positive-sense RNA molecule of
      approximately 7.2 kb in length. Recently, HEV strains have been isolated from
      swine in industrialized countries. In addition, cases of acute hepatitis due to
      novel HEV variants have been reported in humans without recognized risk factors
      for hepatitis E in the US, Japan and Europe. Some of the novel strains were found
      to be closely related to swine HEV isolates from the same area, suggesting that
      hepatitis E is a zoonotic disease. Thus hepatitis E is becoming an issue in
      countries where HEV is not, traditionally, believed to be endemic. This review
      summarizes the current knowledge on the transmission, structure and biology of
      the virus as well as diagnosis of the infection, and describes the present status
      in areas with a low incidence of acute hepatitis E.

PMID- 12602110
TI  - Tubular apoptosis in the pathophysiology of renal disease.
AB  - Apoptosis of renal tubular epithelial cells plays a major role in acute renal
      failure. Several external and internal signals can induce apoptosis, which is
      then effectuated via several pathways. These pathways are either the FAS/FAS-L
      pathway and downstream MAPK (mitogen-activated protein kinases) and JNK (c-Jun N
      terminal kinase) signal transduction, or the RANK/RANK-L (receptor activator of
      NFkB) pathway via activation of the caspase cascade. Other pathways, especially
      for apoptosis induction by toxins, include the mitochondrial permeability
      transition pore activation and Bcl-2 superfamily member differential regulation.
      An important final, irreversible branch of these pathways is the release of
      cytochrome c from the mitochondria, leading to nuclear fragmentation. Therapeutic
      interventions of acute tubular injury focus on the prevention of apoptosis by
      either modulation of the balance of the bcl-2 family or by selectively blocking
      angiotensin receptors. It is not clear yet, which receptor blockade or
      combination of receptor blockers are most effective in apoptosis prevention. In
      chronic renal failure, tubular apoptosis has been found in biopsies from
      polycystic kidneys, but not in a quantitatively meaningful amount in other
      chronic human renal diseases. On the other hand, given the short half-life of
      apoptotic cells of few hours, even low numbers over time might turn out to be
      important modulators of chronic kidney disease, which are characterized by
      tubular cell loss. Potential therapeutic interventions to prevent tubular
      apoptosis in chronic renal disease include angiotensin system inhibition, whereby
      the angiotensin II AT2 receptor blockade seems more promising in apoptosis
      inhibition than the inhibition of other receptor subtypes.

PMID- 12602111
TI  - Pulsed magnetic field therapy for osteoarthritis of the knee--a double-blind sham
      controlled trial.
AB  - BACKGROUND AND METHODS: Pulsed magnetic field therapy is frequently used to treat
      the symptoms of osteoarthritis, although its efficacy has not been proven. We
      conducted a randomized, double-blind comparison of pulsed magnetic field and sham
      therapy in patients with symptomatic osteoarthritis of the knee. Patients were
      assigned to receive 84 sessions, each with a duration of 30 minutes, of either
      pulsed magnetic field or sham treatment. Patients administered the treatment on
      their own at home, twice a day for six weeks. RESULTS: According to a sample size
      estimation, 36 consecutive patients were enrolled. 34 patients completed the
      study, two of whom had to be excluded from the statistical analysis, as they had
      not applied the PMF sufficiently. Thus, 15 verum and 17 sham-treated patients
      were enrolled in the statistical analysis. After six weeks of treatment the WOMAC
      Osteoarthritis Index was reduced in the pulsed magnetic field-group from 84.1 (+/
      45.1) to 49.7 (+/- 31.6), and from 73.7 (+/- 43.3) to 66.9 (+/- 52.9) in the
      sham-treated group (p = 0.03). The following secondary parameters improved in the
      pulsed magnetic field group more than they did in the sham group: gait speed at
      fast walking [+6.0 meters per minute (1.6 to 10.4) vs. -3.2 (-8.5 to 2.2)],
      stride length at fast walking [+6.9 cm (0.2 to 13.7) vs. -2.9 (-8.8 to 2.9)], and
      acceleration time in the isokinetic dynamometry strength tests [-7.0% (-15.2 to
      1.3) vs. 10.1% (-0.3 to 20.6)]. CONCLUSION: In patients with symptomatic
      osteoarthritis of the knee, PMF treatment can reduce impairment in activities of
      daily life and improve knee function.

PMID- 12602112
TI  - Suicide risk-related knowledge and attitudes of general practitioners.
AB  - BACKGROUND: Those attempting or committing suicide very often contact their
      general practitioner (GP) in the weeks before the suicidal act. Therefore, the
      ability of GPs to detect and treat suicidality is of major importance for suicide
      prevention. OBJECTIVES: This study investigated the knowledge, attitudes,
      experiences, and potential problems GPs have in dealing with persons at risk of
      committing suicide in Vienna, a city well known for having a rather high suicide
      rate. METHODS: A 41-item questionnaire was developed and mailed to a random
      sample of 200 Viennese GPs who practice under the health insurance system.
      RESULTS: GPs' knowledge on suicidality and its management is sufficient, as is
      their awareness of risk groups, particularly regarding the suicide risk of
      depressed persons. However, there is a marked underestimation of the suicide risk
      of alcoholics and an overestimation of the risk of physicians. GPs also found it
      difficult to assess suicide risk, and they generally did not receive enough
      training in suicide prevention and were interested in further training.
      CONCLUSIONS: The results indicate a high general knowledge on suicidality, and a
      rather liberal attitude towards the issue, but they also reveal deficits and a
      need for further training.

PMID- 12602113
TI  - [Psychosocial characteristics of victims of suicide in prisons].
AB  - BACKGROUND: Besides some cases reported by the media in recent years about prison
      inmates who committed suicide, hardly anything is known concerning social,
      criminological and psychiatric characteristics of suicide victims in jails and
      prisons in Austria. It therefore seems necessary to evaluate jail and prison
      suicides in order to establish effective means of prevention. METHODS: A study
      was conducted evaluating all suicides in Austrian prisons between 1975 and 1999.
      In addition to nationality, education and working status, other indicators of
      social integration and psychiatric history of suicide victims were studied.
      RESULTS: 220 personal files of 250 suicides were available. During the
      observation period the suicide rate of imprisoned foreigners decreased slightly
      (mean 106.6/100,000), whereas the suicide rate of Austrian citizens increased
      significantly (mean 172.0/100,000). Of all suicide victims, 41% had neither
      finished school nor had they any professional education. 44% were unemployed
      before incarceration, 50% did not work while incarcerated. A high frequency of
      suicidal behavior amongst suicide victims before committing suicide (49% suicide
      attempts, 37% suicide threats), and a high prevalence of mental disorders (37%
      psychopharmacological treatment, 48.6% were assessed by a psychiatrist) could be
      detected. CONCLUSIONS: Screening instruments should be applied which are easy to
      handle for prison officers and indicate the appropriate management of inmates at
      a high suicide risk.

PMID- 12602114
TI  - Economic burden of illness imposed by severe sepsis in Austria.
AB  - INTRODUCTION: Sepsis is a life-threatening disease, requiring instant treatment
      in an intensive care unit (ICU). The aim of this study was to determine the
      direct and indirect costs occurring in Austria due to this disease. PATIENTS AND
      METHODS: Direct costs were calculated based on a retrospective chart analysis in
      four adult Austrian ICUs, evaluating 74 patient records from the years 2000/2001.
      Patients were identified to have suffered from severe sepsis using ACCP
      definitions. Assessed resource use (medication, laboratory analysis, microbiology
      analysis, consumer-goods, diagnostic procedures, staff costs, and basic bed
      costs) was linked with related center specific costs to determine direct costs
      per patient. Indirect costs due to productivity losses were calculated using
      official statistical material. RESULTS: The mean length of ICU stay (LOS ICU) of
      a severely septic patient was 18.1 days. Overall ICU mortality was found to be
      43.2% and showed no gender difference. The mean daily direct ICU costs of care
      for severely septic patients were [symbol: see text] 1,617 and the mean total
      direct ICU costs per septic patient were [symbol: see text] 28,582. In total
      costs, survivors were equally expensive as non-survivors ([symbol: see text]
      28,699 vs. 28,463) although their length of study was considerably longer (21.9
      vs. 13.2 days). Considering a range of patients with severe sepsis in Austria
      from 6,700 to 9,500 per year, total direct costs in Austria range from [symbol:
      see text] 192 million to [symbol: see text] 272 million. Indirect costs
      determined by productivity losses due to unfitness for work (temporary and
      permanent) and premature death amount to [symbol: see text] 484 million to
      [symbol: see text] 686 million in Austria per year (same incidence range). Total
      costs, i.e. burden of illness, combining direct costs with indirect costs, range
      from [symbol: see text] 676 million to [symbol: see text] 958 million.
      CONCLUSION: Patients with severe sepsis have a high mortality rate, spend
      prolonged periods of time in the ICU, and are expensive to treat. Indirect costs
      of severe sepsis due to productivity losses, particularly by premature death, are
      considerable.

PMID- 12602115
TI  - The role of L-alanyl-L-glutamine in the immune response in vitro.
AB  - INTRODUCTION: The amino acid glutamine plays an important role in the immune
      system by providing energy and precursors for biosynthetic processes. For lack of
      stability it could not so far be generally supplied in total parenteral
      nutrition. The development of dipeptides consisting of glutamine and a second
      amino acid offers a solution to this problem. METHODS: In vitro effects of the
      dipeptide L-alanyl-L-glutamine on different cells of the immune system are
      assessed and compared to those of glutamine on its own. RESULTS: T-lymphocyte
      proliferation stimulated with mitogens and alloantigens increased significantly
      and dose-dependently after addition of L-alanyl-L-glutamine or glutamine. Maximal
      effects were observed with a concentration of 2 mmol/l of either substance. The
      stimulatory effects were partly attributed to enhanced cytokine production
      following glutamine or L-alanyl-L-glutamine treatment. In contrast, the activity
      of natural killer and cytotoxic T-cells was not influenced by neither amino acid
      at concentrations of 0.2 and 2 mmol/l, and suppressed at 20 mmol/l. In all
      experiments, early addition of the amino acids to the cultures proved crucial.
      CONCLUSION: In this series of in vitro experiments the dipeptide L-alanyl-L
      glutamine exerted almost identical immunostimulatory activities to glutamine
      alone. Its provision in parenteral nutrition appears commendable.

PMID- 12602116
TI  - [Therapy of diffuse suppurative peritonitis with continuous peritoneal lavage].
AB  - Peritonitis is a severe illness with a high mortality rate and different
      treatment modalities. Over a time period of 12 years 510 patients with
      peritonitis treated with continuous peritoneal lavage (CPL) were retrospectively
      analyzed. 315 of 510 patients with a mean age of 57.4 and a mean APACHE-II-Score
      of 10.2 on admission had a diffuse four quadrant peritonitis. 195 had a local and
      diffuse peritonitis due to perforation of the appendix. 232 of 315 patients with
      diffuse peritonitis (73.7%) had a secondary peritonitis, mostly due to organ
      perforation. The most frequent comorbidities were congestive heart failure
      (36.8%), pulmonary diseases (26%), diabetes mellitus (18.7%), chronic renal
      failure (16.8%), chronic liver diseases (9.5%) and a history of alcohol abuse
      (12.4%). On admission 18.7% had pulmonary insufficiency, 18.4% renal failure,
      14.3% congestive heart failure and 13.3% hepatic insufficiency. 14% had one organ
      , 6.7% two organ-, 2.5% three organ- and 5% four organ failure. The mean duration
      of lavage was 5.1 days with a fluid amount of 8-24 l/day. 81.3% of all patients
      could be treated successfully. 46 patients were reoperated due to persistent
      peritonitis. The mortality rate of the primarily treated patients was 15.6%
      compared to 37.0% of patients who had to be reoperated. The mortality rate of all
      patients was 18.7%. The prognosis of the clinical outcome was significantly
      influenced by preexisting organ failure and by the duration of the peritonitis on
      admission. Our results on CPL for diffuse peritonitis are in accordance with
      results from other treatment modalities; a direct comparison was not possible due
      to the different patient groups.

PMID- 12602117
TI  - Serum osteoprotegerin levels in patients after liver transplantation and
      correlation to bone turnover, bone mineral density and fracture status.
AB  - The aim of this cross sectional study was to evaluate the prevalence of
      osteoporosis, vertebral fracture status and possible risk factors of bone loss
      including serum osteoprotegerin, a novel key regulator of osteoclast
      proliferation and activity in the posttransplantation period. We investigated 15
      patients (10 male, 5 female) 20 +/- 6 (SE) months after orthotopic liver
      transplantation (OLT). All patients received immunosuppressive therapy and non
      were on calcium and/or vitamin D supplements at the time of admission to our
      osteoporosis outpatient clinic. Examinations included a bone densitometry
      measurement at the femoral neck, a standardized spinal X-ray and a morning blood
      sample. According to WHO criteria, osteoporosis at the femoral neck was present
      in 67% (10/15) of the patients with a mean T-score of -2.55 +/- 0.35. Vertebral
      fractures were seen in 33% and the mean number of fractures was 2.4 per patient.
      Secondary hyperparathyroidism (33%), vitamin D deficiency (53%) as well as
      impaired renal function (47%) were frequent findings in the patients. Low serum
      calcium was associated with elevated PTH- (r = -0.75, p = 0.001), serum cross
      laps- (r = -0.61, p = 0.01), osteocalcin levels (r = -0.49, p = 0.05), was an
      independent predictor of femoral neck bone mass (r = 0.57, p = 0.02) and
      accounted for 36% of this variance. Similarly, serum magnesium levels were also
      independently correlated to femoral neck Z-scores (r = -0.68, p = 0.0005). Two
      thirds of the patients had elevated serum cross-laps, osteocalcin and bone
      specific alkaline phosphatase levels reflecting increased bone turnover. Serum
      osteoprotegerin (OPG) in liver transplant recipients was not significantly
      different when compared to healthy, matched controls (84.7 +/- 6.6 vs. 97.3 +/-
      9.4 pg/ml, p = 0.50) and similar when fractured/non-fractured or osteoporotic/non
      osteoporotic patients were compared. Serum OPG was, however, significantly
      correlated to serum cross laps (r = 0.71, p = 0.003), osteocalcin (r = 0.63, p =
      0.01), serum parathyroid hormone (r = 0.61, p = 0.01) and serum creatinine levels
      (r = 0.53, p = 0.04) and showed only a weak and non-significant correlation to
      femoral neck Z-scores (r = -0.38, p = 0.16). Multiple regression analysis
      revealed that serum OPG was correlated independently of PTH, serum calcium and
      creatinine to serum cross-laps concentrations (r = 0.63, p = 0.04). In summary,
      we found a high prevalence of osteoporosis and vertebral fractures in liver
      transplant recipients with many of the patients showing evidence of vitamin D
      deficiency, secondary hyperparathyroidism and accelerated bone turnover. We
      conclude that secondary hyperparathyroidism and possibly serum magnesium seems to
      contribute significantly to the changes in bone mass during the
      posttransplantation period. Serum OPG was not correlated to bone mass or fracture
      status in this cross sectional setting but was elevated together with other bone
      resorption and -formation markers.

PMID- 12602118
TI  - Effects of AT1 and AT2 receptor blockade on angiotensin II induced apoptosis of
      human renal proximal tubular epithelial cells.
AB  - BACKGROUND: Tubular atrophy is a common histological feature of chronic renal
      failure, and epithelial cell death by apoptosis might play an important role in
      its pathogenesis. Angiotensin II contributes to the progressive nature of many
      kidney diseases and treatment with angiotensin converting enzyme inhibitors
      preserves the structure of the tubulointerstitial compartment in human and
      experimental renal diseases. METHODS: Primary cultures of human renal proximal
      tubular epithelial cells were co-incubated with angiotensin II alone or in
      combination with the angiotensin II AT1 receptor antagonist losartan or/and the
      AT2 antagonist PD123319. Apoptosis was determined after 20 hours by TUNEL
      staining and flow cytometry. RESULTS: Angiotensin II at concentrations of 10(-9)
      M induced apoptosis (control vs. angiotensin II 4 +/- 3% vs. 73 +/- 11%; p <
      0.05). This effect was completely offset by co-incubation with the angiotensin II
      AT2 receptor blocker at concentrations 10(-7) M (control vs. PD123319 4 +/- 3%
      vs. 8 +/- 3%; p < 0.05); AT1 blockade was ineffective in apoptosis inhibition.
      When both angiotensin receptors were blocked, no additional effect on apoptosis
      inhibition could be detected. CONCLUSION: We provided evidence, that
      physiological concentrations of angiotensin II can induce apoptosis of human
      renal proximal tubule epithelial cells. This effect is mediated via AT2
      receptors.

PMID- 12602119
TI  - Serum levels of heat shock protein 70 in patients with preeclampsia: a pilot
      study.
AB  - OBJECTIVE: To evaluate the serum levels of heat shock protein (Hsp) 70 in
      patients with severe preeclampsia (PE) in comparison to controls. The
      pathophysiology of PE can be explained, in part, by alterations of endothelial
      function caused by endothelial cell activation and injury. HSP 70 is essential
      for cellular recovery, survival and maintenance of homeostasis. STUDY DESIGN: In
      a matched pair study, serum levels of Hsp 70 were measured in 55 patients with
      late (group A, n = 24) and early (group B, n = 31) onset of severe PE, and in 55
      normotensive controls (group C, n = 24 and group D, n = 31) matched for
      gestational age. Early onset of severe PE was defined as onset of disease at less
      than 34 weeks of gestation (34 + 0). Serum levels were determined using a
      sandwich enzyme-linked immunosorbent assay. RESULTS: The overall median serum
      levels of Hsp 70 were 2.82 ng/mL (SD +/- 8.33) in preeclamptic women, and 1.01
      (SD +/- 1.38) ng/mL in controls (P = 0.08). The median serum levels of Hsp 70
      were 0.52 ng/mL (SD +/- 1.14) in group A and 0.86 (SD +/- 1.29) ng/mL in group C
      (P = 0.15). The median serum levels of Hsp 70 were 4.94 ng/mL (SD +/- 10.46) in
      group B and 1.33 (SD +/- 2.28) ng/mL (P = 0.04) in group D. The difference
      between group A and B was also statistically significant (P = 0.01). CONCLUSION:
      Our study revealed higher serum levels of Hsp 70 in patients with early onset of
      severe PE. Further studies are recommended in order to elucidate the possible
      role of Hsp 70 in the pathophysiology of PE.

PMID- 12602120
TI  - Peritoneal dialysis for continuing renal support after cardiac ECMO and
      hemofiltration.
AB  - Postoperative acute renal insufficiency after cardiac surgery in neonates is
      associated with increased mortality and is usually treated (while using ECMO,
      extracorporeal membrane oxygenation) with hemofiltration. Renal support has to be
      continued after weaning from ECMO when oliguria persists. When using
      hemofiltration, prolonged anticoagulation and a vascular access is needed, which,
      however, carries the risk of hemorrhagic as well as thromboembolic complications.
      Alternatively, peritoneal dialysis (PD) can be performed. We report data from 5
      infants treated with ECMO after corrective cardiac surgery, who experienced
      oliguria after ECMO weaning and were consequently treated with PD. Arterial and
      central venous pressures, inotropic demand, urinary output, blood urea nitrogen,
      creatinine and survival were investigated. All patients survived. Installation of
      PD resulted in stable hemodynamics in all patients, despite continued oliguria.
      Normal renal function was established in four patients. One patient, suffering
      from persistent renal insufficiency, remained on PD. PD effectively supports
      insufficient renal functioning after ECMO weaning without the need for
      anticoagulation or a vascular access. Acute renal insufficiency may be reversible
      even after weeks and, if necessary, PD also enables prolonged treatment until
      renal transplantation.

PMID- 12602121
TI  - Germs make the man.

PMID- 12602122
TI  - The $10 billion pill.

PMID- 12602123
TI  - 100 best companies to work for.

PMID- 12602124
TI  - Congress has its brain on drug benefits.

PMID- 12602125
TI  - The doctor is in.

PMID- 12602127
TI  - The right stuff?

PMID- 12602126
TI  - Nanny boo-boos.

PMID- 12602128
TI  - The DNA revolution. The secret of life.

PMID- 12602129
TI  - The DNA revolution. A twist of fate.

PMID- 12602130
TI  - "You have to be obsessive". Interview by Michael Lemonick.

PMID- 12602131
TI  - The DNA revolution. Future visions.

PMID- 12602132
TI  - Sharing family values.

PMID- 12602133
TI  - [A model of cooperation and harmonization in the field of Public Health in
      Spain].

PMID- 12602134
TI  - [Review of studies on exposure to aluminum and Alzheimer's disease].
AB  - A review has been made of the epidemiological studies published evaluating the
      role of aluminum as a risk factor for developing Alzheimer's disease. A search
      for published studies was conducted in the Medline database by combining the
      terms "Aluminum" and "Alzheimer's disease". In most of the studies reviewed,
      exposure to aluminum in drinking water was examined. These studies suggest that a
      relationship exists between aluminum (Al) and Alzheimer's disease involving
      relative risks of around 2 for populations exposed to Al concentrations in
      drinking water higher than 0.1 mg/l. Types of exposure to this metal by other
      means (food, medications and occupational exposure) have received little
      attention. These epidemiological studies entail certain methodological
      limitations, and their results are not consistent, so the results available to
      date therefore not making it possible to clearly determine that any relationship
      exists between exposure to aluminum and the etiology of Alzheimer's disease.
      Nevertheless, the toxic effect of aluminum on human health cannot be ruled out
      either, and thus exposure to aluminum should be monitored and limited as far as
      possible.

PMID- 12602135
TI  - [Bibliometric study of the original articles published in the Revista Espanola de
      Salud Publica (1991-2000). I. General indicators].
AB  - BACKGROUND: For some time, the most of reports have been being disseminated by
      way of scientific journals, bibliometric studies therefore being fundamental to
      the characterization and evaluation thereof. The purpose of this study is that of
      characterizing the Revista Espanola de Salud Publica based on the original
      articles published therein throughout the 1991-2000 period. METHODS: Original
      articles published in the Revista Espanola de Salud Publica throughout the 1991
      2000 period, all inclusive. A study has been made of the following variables:
      number of original articles, collaboration index or number of signing authors per
      study, productivity index, geographical spread and main subject. RESULTS:
      Throughout the 1991-2000 period, 290 original studies (52.3%) of a total of 555
      studies were published. The number of originals averaged 29 originals/year A 4.5
      degree of collaboration was found to exist for this journal (number signing
      authors/number originals) for the period under study. The annual of originals by
      Autonomous Community reveals in the Autonomous Community of Madrid (20.7%),
      Autonomous Community of Valencia (16.4%), Andalusia (16.1%) and Catalunya (10.0%)
      have published studies every year throughout the ten-year period under study. The
      most prevalent subject of all was that related to "Communicable disease" (86
      originals), Primary Health Care" (34) and "Environmental pollution" (21).
      CONCLUSIONS: Generally speaking, it apparently follows that the Revista Espanola
      de Salud Publica continues to fall within the output-related indicators of other
      Spanish and foreign journals and that it has also evolved in keeping with the
      trend proper of scientific output in the biomedical field. Although "Communicable
      diseases" are not the main cause of mortality, they continue being the main
      subject more frequently studied.

PMID- 12602136
TI  - [Preventive effect of social support on mortality among elderly population: a
      longitudinal study].
AB  - BACKGROUND: The main objective of this study is to analyze the relationship
      between social support and the mortality among a non-institutionalized population
      cohort age 60 or above residing in Barcelona studied throughout the 1996-1999
      monitoring period for the purpose of analyzing the relationship between the
      social support and the mortality of this cohort. METHODS: In 1996, a telephone
      survey was conducted of 755 individuals (316 males and 439 females) who had been
      surveyed in the 1992 Barcelona health survey and who, were age 60 or above that
      year. The questionnaire included socio-demographic, morbility and health
      condition, social support and social network-related variables. The deaths during
      the 1996-1999 period were recorded. Logic regression was used for analyzing the
      social support-mortality relationship. RESULTS: The deaths for the period in
      question totaled 55 individuals (5.9% of the females and 9.2% of the males).
      Among the variables reflecting social support, for the males solely the situation
      of living with someone was found, in the bivariate analysis, to have a
      significant relationship to the mortality, which was higher for those males who
      lived with other family members, but not with their wives or female partner (OR =
      3.7; IC 95% 1.4-9.6). Among the females, the existence of support from neighbors,
      the size of the family network, the number of contacts with the community network
      and the situation of living with someone else were related to the mortality in
      the bivariate analysis, although in the multivariate logic regression, solely the
      support of neighbors (OR = 3.6; IC: 1.1-11.1) was found to have a significant
      relationship. CONCLUSIONS: The results are consistent with prior studies
      revealing a relationship between the social support variables and the mortality.
      The relationship between the different social support variables and the possible
      prevention mechanisms should be taken up in future studies.

PMID- 12602137
TI  - [Factors related to perceived poor health condition or poor quality of life among
      those over 65 years of age].
AB  - BACKGROUND: Nowadays, in the developed countries, a long lifespan is no longer
      the exception to the rule, however there are still many people who even today do
      not manage to age with a good quality of life. The objectives of this study are,
      first of all, to contribute to a better knowledge of the main factors which have
      an impact on the quality of life and the perceived health condition of those over
      age 65 and, secondly, to determine what advantages and disadvantages involved in
      each one of the tools for gauging health and quality of life as compared to the
      other two tools employed. METHODS: Based on 911 home surveys of non
      institutionalized individuals over age 65, a multivariate analysis was made using
      Logistic regression, relating the results obtained in the Nottingham Health
      Profile (NHP), the EuroQol and the Self Perceived Health Status to the socio
      demographic characteristics, the level of economic resources, the degree of
      social-family support, the physical and mental health condition and the
      functional capacity. RESULTS: The main factors related to the perception of a
      poor health condition and a poor quality of life in the EuroQol and the NHP are
      anxiety disorders (Odds Ratio ranging from 1.8(IC:1.2-2.8) for mobility and
      7.9(IC:4.5-13.9) for Profile*11111), depressive disorders (OR:1.8(IC:1.3-2.6) for
      pain/discomfort-3.3(IC:2.1-5.1) for social isolation), lack of exercise (OR:1.4
      (IC:1-2.1) for anxiety/depression -3.9(IC:2.5-6.2) for everyday activities),
      dependence for basic everyday living activities (OR:0.5(IC:0.3-0.9) for emotional
      reaction -4.8(IC:3-7.6) for everyday activities) and dependence for the
      instrumental daily living activities (OR:1.5(IC:1.1-2.1) for Analog Visual Scale
      c < 70-7.1(IC:2.9-17.2) for personal care). CONCLUSIONS: Mental health and
      functioning capacity are the factors which have the greatest bearing on the
      perception of health condition and quality of life of individuals over age 65.
      Given that the three tools used have led to similar results, the EuroQol has
      advantages to offer due to its short length, including an overall evaluation by
      dimensions.

PMID- 12602138
TI  - [Cross-cultural adaptation to Spanish of the Vecu et Sante Percue de l'Adolescent
      (VSP-A):: a generic measure of the quality of life of adolescents].
AB  - BACKGROUND: Different measures of health related quality of life for use
      exclusively in children and adolescents have been developed over the last ten
      years. However, few instruments of this type have been adapted in Spain. The VSP
      A is a generic health related quality of life measure for adolescents aged 11-17
      developed in France. The objective of this study was to adapt the VSP-A into
      Spanish as a first step towards obtaining this questionnaire. METHODS: The
      version of the VSP-A including 39 questions was adapted following the forward
      backward translation methodology, including two translations into Spanish,
      scoring of difficulty (0 min-10 max.) and classification of semantic and
      conceptual equivalence, two panel discussions with adolescents, as well as
      meetings of consensus with the original authors. Finally, a backward translation
      (translation back into the original language) was carried out into French, and
      the final pre-test version was administered in a pilot test. RESULTS: Most of the
      questions were classified as equivalent (24/39). Following the meetings with
      adolescents, changes were made in some questions. After the back-translation into
      French, three questions required some minor changes. CONCLUSIONS: The Spanish
      version of the VSP-A seems to be semantically and culturally equivalent to the
      original version and suitable for adolescents in Spain. The inclusion of easy
      statements in the original version, the comments of the adolescents and the
      involvement in the adaptation process of the original authors has offered the
      possibility of achieving a suitable pre-test version. The next phase of the study
      will involve the questionnaire's reliability and validity testing. The VSP-A is
      expected to be useful for measuring the health-related quality of life in health
      surveys or as a screening tool in schools and primary care centers in Spain.

PMID- 12602140
TI  - [Body fat and fat mass-fat free mass ratio estimated by bioelectric impedance in
      the nutritional evaluation of women 35-55 years of age].
AB  - BACKGROUND: Nutritional evaluation during pre-menopause and menopause plays an
      important role in assessing the changes taking place in a woman's body, a
      comparison being drawn in this study between the parameters body fat and body fat
      muscle ratio (BFMR) estimated by impedancemetry and the body mass index (BMI) for
      defining nutritional status and body composition. METHODS: A cross-sectional
      descriptive study. By random sampling (health card basis), thirty women within
      the 35-55 age range were selected and then evaluated regarding the relationship
      between body fat and fat mass (FM)-fat free mass (FFM) ratio (FM/FFM = BFMR) and
      the BMI, different means of estimating body fat distribution: waist and iliac
      region circumferences, waist-hip and iliac region-hip ratios and iliac region and
      sagittal diameters; systolic (SBP) and diastolic blood pressures (DBP) and serum
      levels of glucose, cholesterol, HDL-cholesterol and triglycerides. RESULTS: The
      percentage of body fat was highly correlated (p < 0.001) with BMI (r = 0.919),
      waist (r = 0.866) and iliac region (r = 0.841) circumferences and sagittal (r =
      0.783) and iliac region (r = 0.772) diameters, and less highly with glycemia (r =
      0.385; p = 0.036) and the SBP (r = 0.497; p = 0.005) and DBP (r = 0.582; p =
      0.001). The BFMR showed similar results, no being significantly related to any
      biochemical parameter. 46.7% of the obese women as per their percentage of body
      fat (> 33%) had a BMI of under 30. CONCLUSIONS: The estimating of the body fat
      and BFMR parameters among women within the 35-55 age range supplements the
      nutritional evaluation made by means of the BMI, although in order to define
      their true figures in this evaluation, the reference values must for the
      population as a whole must be determined.

PMID- 12602139
TI  - [Morbidity perceived and diagnosed among caregivers of immobilized patients in a
      rural health district].
AB  - BACKGROUND: The progressive aging of the population has led to many families
      having to take charge of caring for some disabled family member. This new
      situation involved changes in the family situation, especially in that of the
      main caregiver, whose health may be affected. The objective of this study is to
      ascertain the morbility perceived and diagnosed regarding the main caregivers of
      disabled patients and to detect their health needs. METHODS: A descriptive cross
      sectional study. The group under study was comprised of the caregivers of
      immobilized patients registered in the homecare program of a rural Healthcare
      Center. A sample of 50 caregivers was taken by simple random sampling, with a 95%
      confidence level and a 6% accuracy. The caregivers in question were surveyed
      personally and their Primary Care Clinical Record was reviewed. RESULTS: The
      caregivers in question were predominantly females averaging 60 years of age,
      married, having an elementary school education, the daughters of the patients,
      having lived with the patient for more than 6 months a year. The morbility
      perceived most often were bone and joint problems (67.9%). Twenty-eight percent
      (28%) (IC 95%:--16.2-42.5) showed psychological uneasiness with anxiety, 32% (IC
      95%:--19.5-46.7) related to depression. The number of stress-related problems
      reported by the caregivers totaled 72, a total of 10 being shown in their
      Clinical Record, none of the other problems in their Records being related to
      stress. CONCLUSIONS: The caregiver profile does not differ from other studies.
      Caregivers have multiple disorders (physical and psychological symptoms), go to
      see their physicians little, and their perceived morbility is underdiagnosed.

PMID- 12602142
TI  - [Adolescent's health].

PMID- 12602141
TI  - [Evaluation of a system to feedback information on Public Health: the experience
      of Area 2 of the Community of Madrid].
AB  - BACKGROUND: In January 2000 the Public Health Service of Area 2, in the Region of
      Madrid, began to publish a weekly sheet on epidemiological and public health
      information (HISP) addressed to health professionals working in the Area. The aim
      of the present study was to estimate to how extend the "HISP" was known among
      health professionals of Area 2, and also to estimate the suitability and
      usefulness of its contents, during 2000. METHODS: A postal survey was carried out
      among a random sample of professionals working in Area 2. A descriptive analysis
      of main variables was done, variables associated to the knowledge of the "HISP"
      were investigated. Epi Info 2000 program was used for the analysis. RESULTS: The
      response rate was 79.7%. The best evaluated content was that related to epidemic
      outbreaks. An association between knowing the "HISP" and knowing the regional
      epidemiological bulletin (Boletin Epidemiologico de la Comunidad de Madrid) was
      found (OR = 9.3, IC 95% = 2.9-29.5), and also an association between knowing the
      "HISP" and being a physician (OR = 4.3, IC: 1.5-12.6, p = 0.005). CONCLUSIONS:
      The "HISP" has a good acceptance among health professionals of Area 2. They were
      more interested in contents related to stressful situations. It is necessary to
      improve the diffusion of information on public health among nursing
      professionals.

PMID- 12602143
TI  - [Adolescent's health: a paradigm shift from a focus on dangers to one's health to
      one of healthy lifestyles].

PMID- 12602145
TI  - [Youth sexuality and social changes: the case of Portugal].
AB  - OBJECTIVE: To investigate whether the new generations are creating new social
      values in the current setting of deep social change. MATERIAL AND METHODS: Using
      the generations method (Mannheim), a survey was conducted in 1996, among 2,012
      residents of Portugal, to collect data on values and generations of the
      Portuguese population. The SPAD statistical analysis program was used to perform
      a multiple correspondence factorial analysis, in addition to a cluster-type
      analysis. RESULTS: The main generational gaps were found in sexual attitudes and
      practices. Findings showed that groups and aggregates have overrepresentation
      indices for specific generations, e.g., hedonistic interviewees are characterized
      by a high index of overrepresentation of youngsters, in contrast to the
      moralistic or the inhibited subjects. CONCLUSIONS: Portuguese youngsters are
      depicted as a generation with hedonistic and experimental values regarding love
      and sex life. However, youngsters are at the same time characterized by both
      their vulnerability and risk behaviors.

PMID- 12602144
TI  - [Drugs use among adolescents: results from the National Survey on Addictions,
      1998].
AB  - OBJECTIVE: The aim of this paper is to describe drug and associated factors use
      among adolescents (12 to 17 years of age). MATERIAL AND METHODS: Data come from
      the recent Encuesta Nacional de Adicciones, 1998 (National Survey on Addictions)
      undertaken in urban areas of Mexico. A probabilistic, multi-stage, stratified
      cluster sampling design was used to select the study population. The sampling
      unit was the individual in each household. Statistical analysis consisted of the
      estimation of prevalences of drug use, with 95% confidence intervals.
      Associations were analyzed using logistic regressions models. RESULTS: Excluding
      tobacco and alcohol, 3.57% of males and 0.6% of females have used one or more
      drugs; 2.14% and 0.45% used them in the 12 months previous to the survey, and
      1.4% and 0.3% in the previous 30 days, respectively. Marihuana was the drug more
      often used by males (2.4%) and females (0.45%), followed by inhaled solvents
      (1.08% and 0.20%), and cocaine (0.99% and 0.22%), respectively. The risk of using
      illicit drugs was associated to being male, having dropped out from school,
      perceiving availability, drug use by family and friends, social tolerance among
      friends, and symptoms of depression. CONCLUSIONS: Adolescents between 12 to 17
      years of age are exposed to increasing drug use. The rates of drug use have
      risen, especially in the northern region of Mexico and in the big urban areas
      (Tijuana, Mexico City and Guadalajara). These findings emphasize the need to
      develop campaigns to detect emotional problems. Preventive measures should
      provide appropriate care to prevent drug use as a mechanism to cope with such
      emotional conflicts. Also, more intense preventive interventions should be
      targeted to adolescents with a high probability of developing drug abuse.

PMID- 12602146
TI  - [Masculinity and sexual and reproductive health: a case study among adolescents
      of Mexico City].
AB  - OBJECTIVE: To understand how the social construction and expression of
      masculinity among male adolescents and young adults are related to sexual health
      and reproductive risks. MATERIAL AND METHODS: The study was carried out in an
      underserved and a popular area of Mexico City. Eighteen focal groups and 18
      individual interviews were applied to a sample of males from three age groups: 10
      to 14, 15 to 19, and 20 to 24 years. Data analysis was performed inductively
      through open codification of the verbal transcriptions. These were used to create
      more abstract concepts and search for relationships among them. RESULTS: This
      paper centers on interpretations of masculinity as expressed by the youngsters
      themselves. Our research sheds light on what youngsters do and say to "be men".
      Their ideas and practices produce different forms of masculinity through which
      risk behavior is manifested, as well as specific speech and dressing styles, and
      ways of courting and "going steady". These behaviors and their meanings are
      associated with sexual and reproductive health risk taking. CONCLUSIONS: The
      traditional model of masculinity characteristic of both social settings involves
      poor communication about sexuality in couple relationships, which results in
      infrequent protection and exposure to Sexually Transmitted Infections and
      unwanted pregnancies. On the other hand, their economic living conditions prevent
      them from fully practicing central elements of their own concept of masculinity,
      such as being a hard worker, a provider, and a responsible person. These unmet
      needs may cause frustration, aggression, and domestic violence.

PMID- 12602147
TI  - [The meanings of masculinity, sexuality, power and violence among adolescents].
AB  - OBJECTIVE: To analyze perceived meanings of masculinity and power related to
      sexual violence among adolescents. MATERIAL AND METHODS: A qualitative study was
      carried out between 1998 and 2000 in the metropolitan area of Guadalajara,
      Mexico, among 155 junior high and high school male/female students. Information
      was collected from 12 focal groups in two-hour sessions. Data collection
      instruments included: interviews, observation, and instruction guides. Data were
      recorded using notes and tape recordings. Oral and written information was
      transcribed, categorized, and coded, in order to construct matrixes and interpret
      results. RESULTS: Symbolic explanatory concepts related with rape included:
      constructivism vs. naturalism, heteronomous moral posture, and early exchange
      towards respect and human rights. Females were perceived as the real and
      potential victims. Males were perceived as violent by nature or under challenge,
      and prone to be victimized only if they were children, unmanly, or homosexual.
      Analysis objects included motives, power, female refusal, accusation,
      consequences, management, and prevention. CONCLUSIONS: Sexual violence is
      symbolized within the realm of explanatory and moral controversy. The ideological
      values of masculinity legitimate both legal and judiciary impunity. Social
      meanings and adolescent participation should be considered in research and
      interventions.

PMID- 12602149
TI  - [Objective and subjective knowledge of HIV/AIDS as predictor of condom use in
      adolescents].
AB  - OBJECTIVE: To evaluate the association between objective and subjective knowledge
      on HIV/AIDS and condom use. MATERIAL AND METHODS: Analysis of a database from an
      anonymous, self-applied, randomized survey conducted between 1995 and 1996. Study
      subjects were 1,410 adolescents of four socioeconomic strata from Guadalajara,
      Mexico. Objective knowledge was assessed with 24 questions regarding HIV/AIDS,
      and subjective knowledge with the question "how much do you think you know about
      HIV/AIDS?" The variables associated with condom use were identified using
      logistic regression analysis and by calculating odds ratios with a 95% confidence
      interval. RESULTS: The degree of objective knowledge was "average",
      differentiated by socioeconomic strata (p < 0.001), and was higher in adolescents
      from medium and high socioeconomic strata (p < 0.008). Regarding subjective
      knowledge, adolescents from the low, medium, and high socioeconomic strata
      claimed to know "a little", and the ones from the lowest stratum claimed to know
      "very little". Condom use was higher in males (35.4%), and in adolescents from
      high socioeconomic strata (p < 0.005), than in females (15.3%) (p < 0.001).
      Although there was a correlation between objective and subjective knowledge (r =
      0.37, p < 0.001), a higher degree of subjective knowledge was associated with
      condom use (p < 0.001). CONCLUSIONS: Subjective knowledge, belonging to medium
      and high socioeconomic strata and being male, were predictors of condom use.

PMID- 12602148
TI  - [Validity and reliability of a questionnaire to asses the social, corporal, and
      sexual behaviors among school adolescents].
AB  - OBJECTIVE: To validate a self-administered questionnaire about social and
      corporal sexual behaviors among adolescents, by school level and gender. MATERIAL
      AND METHODS: The data collection instrument was constructed according to DeVellis
      and consisted of 26 items. It was used in a prospective longitudinal study
      conducted in 1994 in Guadalajara, Mexico, among 1243 secondary and high school
      students. The construct validity of the instrument was established using
      exploratory factorial analysis, and its reliability using the Cronbach's alpha
      test. RESULTS: Five factors were obtained in males and an equal number in women,
      using eigenvalues > 1 and by forcing the best solution. The explained variance
      was 59.3-70.6%; the factorial weight average was 0.63-0.75, and 13 different
      factors were selected. The Cronbach's alpha mean was 0.87-0.93 and 16 factors had
      Cronbach's alpha over 0.70. CONCLUSIONS: The instrument has an acceptable
      validity and reliability for studying the sexual, social, and corporal behaviors
      in adolescents similar populations.

PMID- 12602150
TI  - [STD/AIDS-related practices and occupational risk factors in adolescent hotel
      workers in Puerto Vallarta, Mexico].
AB  - OBJECTIVE: To assess STI/AIDS risk behaviors and occupational risk factors among
      adolescent hotel workers in Puerto Vallarta. MATERIAL AND METHODS: Comparative
      cross-sectional study conducted in 1998, among 288 workers adolescents of 38
      hotels in Puerto Vallarta, Mexico. Variables were collected on working
      conditions, environmental conditions, STI/AIDS risk behaviors, and
      sociodemographic characteristics. Statistical analysis consisted of descriptive
      and multivariate techniques: t test, OR, and logistic regression. RESULTS: Study
      subjects had a mean age of 17.7 years; 71.5% were males. Fifty-three percent had
      active sexual relations; 93.6% of them had one or more STI/AIDS risk behaviors.
      Inadequate condom use was found in 77.3%, and 41% drank alcoholic beverages
      before intercourse. Promiscuity was reported by 29.9%, and anal relations by
      9.2%. Associated factors were: perception of a sexually-arousing environment (OR
      2.36), alcohol drinking by peers (OR 2.52) and guests (OR 2.60) before sexual
      intercourse, hotel rules allowing tourist guests in hotel rooms (OR 4.46).
      Confounding variables were: male gender (OR 3.14), being married or in common law
      (OR 21.19), and being 18-19 years of age (OR 3.11). CONCLUSIONS: The high
      frequency of STI/AIDS risk behaviors among adolescent hotel workers is associated
      to specific environmental factors.

PMID- 12602151
TI  - [Unwanted adolescent pregnancy and post-partum utilization of contraceptive
      methods].
AB  - OBJECTIVE: To describe the proportion of unwanted pregnancies among all pregnant
      adolescents, its association with sociodemographic characteristics, and the use
      of post-partum contraceptive methods. MATERIAL AND METHODS: A cross-sectional
      study was conducted among 220 women between 13 and 19 years of age, in two semi
      urban municipalities of the State of Morelos, Mexico, interviewed between 1992
      and 1994. Women were interviewed at home, six to twelve weeks after their
      delivery date. Women were asked whether they had wanted their last pregnancy, and
      about knowledge and use of contraceptive methods after delivery. RESULTS:
      Adolescent pregnancies accounted for 17% of all births registered in these two
      municipalities. Among all adolescent mother 22.73% reported that their pregnancy
      had not been wanted. A positive association was found between the lack of access
      to health services provided by public medical insurance systems (Instituto
      Mexicano del Seguro Social IMSS and Instituto de Seguridad y Servicios Sociales
      para los Trabajadores del Estado ISSSTE) and unwanted pregnancy (adjusted OR =
      3.03, 95% CI (1.31, 7.) An association was also found between living in an urban
      community (adjusted OR = 2.16, 95% CI (1.08, 4.33) and an unwanted pregnancy.
      Among all adolescent mothers, 91.3% were familiar with "the pill" as a
      contraceptive method; 84.72% knew about the IUD, and 63.68% knew about the
      condom. However, only 35% of them were actually using an effective contraceptive
      method six weeks after delivery. No difference in frequency of contraceptive use
      was found among the adolescent mothers, according to whether they wanted their
      last pregnancy. Only 43.39% of mothers who delivered at hospitals or health
      centers were using an effective contraceptive method. CONCLUSIONS: These findings
      suggest that there is a great potential for family planning programs to target
      adolescents, and that the use of contraceptive methods after delivery should be
      promoted among adolescent mothers, especially those lacking access to public
      medical insurance and those living in semi-urban settings. It is also recommended
      to conduct studies on family planning education programs that can be introduced
      earlier in the school system in Mexico.

PMID- 12602152
TI  - [Serum insulin and lipids in high school adolescents in Guadalajara, Mexico].
AB  - OBJECTIVE: To determine the serum concentration of insulin and lipids among high
      school students, according to age, sex, and socioeconomic level. MATERIAL AND
      METHODS: A cross-sectional study was carried out between October 1998 and March
      1999 among 352 high school students aged 14-19 years in Guadalajara, Mexico.
      Insulin, total cholesterol, triglyceride, high-density lipoprotein (HDL), low
      density lipoprotein (LDL), and very low density lipoprotein (VLDL) levels were
      measured. Student's t test, chi-squared tests, and ANOVA, were used to compare
      mean measurements and proportions. RESULTS: Mean values were obtained for insulin
      (54 +/- 30 pmol/l); triglycerides (101 +/- 36 mg/dl); total cholesterol (157 +/-
      27 mg/dl); LDL (95 +/- 26 mg/dl), and HDL (44 +/- 9 mg/dl). CONCLUSIONS: Total
      cholesterol, LDL, and HDL levels were higher among females. Hol levels were lower
      in low socioeconomic level. Insulin levels were higher among younger subjects.

PMID- 12602153
TI  - [Knowledge of HIV/AIDS among urban adolescents: cultural consensus of doubts and
      uncertainties].
AB  - OBJECTIVE: To describe the knowledge of HIV/AIDS among adolescents from different
      socioeconomic strata (SS), using cultural consensus analysis. MATERIAL AND
      METHODS: A cross-sectional descriptive and analytic study was conducted from July
      1995 to March 1996, among 758 adolescents from Guadalajara, Mexico. Data were
      collected using a questionnaire, and analyzed by means of: a) consensus by SS and
      gender using factorial analysis; and b) identification of the cultural pattern of
      correct answers, and concordance of individual/group answers using Pearson's r
      correlation coefficients. RESULTS: There was a high degree of consensus across
      SS. The individual/group knowledge concordance was greater in higher SS. The
      pattern of correct responses showed: a) similar knowledge on casual transmission,
      AIDS characteristics, and higher risk in sex workers; and b) discrepancies
      regarding doubts and uncertainties about condom protection, distinction between
      HIV and AIDS, and HIV transmission in health clinics. CONCLUSIONS: Knowledge was
      homogeneous and mainly medically oriented across all SS. Nevertheless, there were
      elements of doubt and uncertainty that require differentiated informative
      interventions.

PMID- 12602154
TI  - [The epidemiology of Cancer among adolescents].
AB  - OBJECTIVE: To review the international literature on adolescent cancer
      epidemiology. MATERIAL AND METHODS: The Medline database was searched to obtain
      all papers on adolescent cancer epidemiology published during a period of 15
      years (1985-1999). Time, place, and person variables were analyzed, as well as
      their relationships. RESULTS: Few papers on adolescent cancer epidemiology were
      found, likely due to the difficulty in registering cancer cases in the 12 to 18
      year-old group. Either the 10-14 or the 15-19 year-old group has been analyzed in
      different studies; but the latter is more representative of teenagers. A higher
      incidence rate was found in this group (117.3 and 202.2 x 10(6) respectively).
      The main malignancies in the 15-19 year-old group were central nervous system
      tumors (CNST), leukemias, lymphomas, bone tumors, germ-cell tumors, and
      carcinomas. Incidence rates were higher in males and whites; an increasing trend
      was observed. Cancer mortality in this group is decreasing in the United States
      (2.0 or 3.2% per year). Survival is increasing in all groups of neoplasms. No
      data were available on cancer incidence in the 15-19 year-old group in Mexico:
      data were available only for the 10-14 year-old group. The main neoplasms are
      leukemias, lymphomas, bone tumors, and CNST (rates were 41.9, 29.9, 12.0, and
      10.0 x 10(6), respectively). The mortality rate for the 1990-1994 period was 64.1
      and the main neoplasms were leukemias, CNST, and lymphomas. CONCLUSIONS: More
      studies are needed to address the descriptive epidemiology of cancer in
      teenagers.

PMID- 12602155
TI  - [Multisystemic therapy of adolescents with conduct disorders].
AB  - This paper reviews the main features of conduct disorder (CD), as well as the
      principles for diagnosis and multisystemic treatment (MST). MST includes
      biological, psychological and social interventions, and considers the ecological
      environment of conduct manifestations. Some outcomes of MST delivery are
      discussed, along with its advantages and potential applications.

PMID- 12602156
TI  - [Health and development of adolescents and young adults in Latin America and the
      Caribbean: challenges for the next decade].
AB  - Adolescents and young adults make up 30% of the population of the Americas. Their
      health is a key factor in the social, economic, and political development of the
      region. Nevertheless, their needs are frequently excluded from governments'
      public and political agendas. The Pan American Health Organization (PAHO)
      advances a new conceptual framework focusing on human development and health
      promotion within the context of family and community, and of social, political,
      and economic development. The challenge in the near future is to use this
      framework for establishing comprehensive programs, collect disaggregated data,
      improve access to services, adolescents' environs, the ties between schools,
      families and communities, as well as improve and support the transition to
      adulthood through youth participation and interinstitutional and intersectoral
      collaboration.

PMID- 12602157
TI  - [The epidemiologic transition of the adolescents in Mexico].
AB  - OBJECTIVE: To identify the health status of adolescents in Mexico in their
      demographic, social and economic context. MATERIAL AND METHODS: A literature
      search and review of vital statistics, and opinion surveys were performed in
      order to asses the impact of the epidemiologic transition on the availability and
      priority of health services for adolescents. The Omran epidemiologic model was
      used to classify the demographic, social and economic characteristics of Mexican
      adolescents in efforts to define their impact on the epidemiologic transition of
      this age group. RESULTS: Demographic data are presented in the perspective of the
      epidemiologic transition which permit us to make inferences on the social
      conditions, growth patterns and health needs of this age group in Mexico. Data
      are presented regarding the demand and availability of health services, the
      impact of education and employment opportunities and the role of family and the
      economy on their well being. Other important aspects presented include the role
      of education on the sexual and reproductive health of adolescents and the threat
      of the AIDS pandemic in this age group. CONCLUSIONS: These findings reveal a
      sequence of variables that can no longer be addressed in the traditional problem
      oriented approach and strongly suggest a need to profile the health needs of
      adolescents in an integrated, holistic fashion with emphasis in health promotion
      and healthy life styles to favor their integral, just and equitable development,
      and also help focus the societal response in an integrated manner.

PMID- 12602158
TI  - [Statistics of the adolescents' health].

PMID- 12602160
TI  - [Thrombolytic treatment of cerebral infarction].

PMID- 12602159
TI  - [Medical journals specialized in adolescents and youth].

PMID- 12602161
TI  - [Yawn: from ethology to clinical medicine].

PMID- 12602162
TI  - [Diagnostic approach in hyperkinetic children].
AB  - Hyperkinetic syndrome may be either primary, as part of an organic disease, an
      Attention Deficit Hyperactivity Disorder (ADHD) or pervasive developmental
      disorder, either secondary to mood disorders, specific learning disabilities, or
      giftedness. Precise diagnosis requires a decision procedure with clinical,
      anamnestic, behavioral and neuropsychological evaluations.

PMID- 12602163
TI  - [Etio-pathogenic hypothesis of attention deficit disorder in children].
AB  - The aetiological factors of "attention deficit hyperactivity disorder" (ADHD) are
      multiple, and have an importance that vary according to the individual.
      Nevertheless, the current state of knowledge suggests a significant biological
      component to the pathophysiology of this problem, and a genetic influence in
      particular. It thus seems that ADHD is essentially characterised by its dimension
      of impulsivity, linked to a defect of inhibitor control, specifically implying
      certain cerebral structures as well as a dysfunction of the catecholaminergic
      systems, and in particular, the dopaminergic system. Certainly, environmental
      factors influence the symptomotology and expression of the problem, but it is
      noted that ADHD itself influences these factors.

PMID- 12602164
TI  - [Academic difficulties in hyperactive children].
AB  - Hyperactive children frequently display academic difficulties. These may be the
      direct result of their behavioral characteristics (lack of attention,
      impulsiveness, hyperactivity), and/or may reflect specific learning disorders
      which are initially masked by significant behavioral problems. These learning
      disorders need to be diagnosed, so as to include specific therapeutic approaches
      into the overall treatment.

PMID- 12602165
TI  - [Sleep and vigilance in hyperactive children].
AB  - Inattention, impulsiveness and hyperactivity are the main clinical features that
      characterise the attention deficit hyperactivity disorder (ADHD). Children with
      ADHD essentially present with diurnal manifestations but studies have recently
      shown a link between sleep and daytime symptoms. ADHD children could present
      sleep problems such as agitated sleep, sleep-onset difficulties, low arousal
      threshold during the night. Such sleep difficulties have been shown to occur more
      frequently in children with severe diurnal ADHD symptoms. Sleep studies using
      polysomnography have been performed in children with ADHD. Abnormalities during
      sleep such as increased motricity could be responsible for hypovigilance as
      measured using multiple sleep latency tests. Prevalence and physiopathology of
      sleep disorders including awakening mechanisms (micro-arousals, arousal
      threshold) from sleep yet need to be clarified in ADHD children. Understanding
      the mechanisms governing the sleep-wake balance seems essential for the
      comprehension of ADHD. Excessive nocturnal motricity could be the expression of a
      monoaminergic dysfunctioning previously reported in ADHD and could lead to new
      therapeutic gateways as well as hypovigilance.

PMID- 12602166
TI  - [Cognitive aspects of attention deficit hyperactivity disorder in children].
AB  - Inattention, excessive motor activity and impulsivity observed in children with
      attention deficit hyperactivity disorder (ADHD) are presently considered as an
      executive function deficit. Certain authors suggest that children with ADHD,
      combined and inattentive types, present distinct attention disorders. Cognitive
      aspects in ADHD children are measured with an intellectual functioning scale,
      cognitive and executive function tests. Experimental data show mixed results
      concerning these subjects. Similar deficits are found between ADHD children,
      combined and inattentive types, on motor inhibition and different cognitive
      aspects. However, other executive function aspects need to be explored among the
      two ADHD sub-groups.

PMID- 12602167
TI  - [Outcome of hyperactive children].
AB  - Two issues are examined: 1. Does comorbidity in ADHD interfere with the
      longitudinal outcome? 2. Is adult ADHD a clinical reality. It seems that marked
      impairment in ADHD children social functioning (conduct disorders, aggressivity,
      destructive behavior) is a significant predictor of adult social disability
      (substance use disorders, antisocial personality and even criminality). Adult
      ADHD seems to be a reality, but much less frequent than in youths. Impulsivity,
      attention disorder, and emotional status are the main characters of the syndrome.
      We have no data leading to the responsibility of psychostimulant treatment in
      substance use disorders in teenage or adulthood. Implications of early versus
      late onset of ADHD symptoms are not clear. Early onset (before 7) seems to be
      associated with worse clinical outcomes.

PMID- 12602168
TI  - [Psychotherapy in children with attention deficit hyperactivity disorder].
AB  - Alone or used with psychostimulants, psychotherapy is the keystone of the
      treatment in children attention deficit disorder hyperactivity (ADHD). This
      article explains in which matter psychotherapy is essential. To be well done,
      it's necessary before starting the treatment to analyze precisely the disorder
      and how it interferes with the child's environment. It describes how this
      functional analysis must be done in order to be more precise in the choice of the
      treatment objectives. This article explains why in children ADHD treatment, the
      individual therapy must be associated with a family training and describes
      briefly the more studied and recognized psychotherapy techniques in those
      children ADHD and how other partners (teacher, speech or motor therapist) are
      also useful.

PMID- 12602170
TI  - [The Medical College Admission Test (MCAT)].

PMID- 12602171
TI  - [Main pregnancy complications: genital hemorrhage].

PMID- 12602169
TI  - [Role of psychostimulants in hyperactive children].
AB  - The Attention Deficit Hyperactivity Disorder (ADHD) still remains under diagnosed
      and under recognized in France, although this illness affects at least one pupil
      in each classroom. Despite its prevalence, untreated ADHD can lead to school
      failure, relationship break-ups, drug abuse, and a tremendous sense of
      underachievement. The treatment is centred on a combination of psychotherapy,
      psycho-educative skills, and psychostimulant medication. There are concerns about
      the appropriateness of psychostimulant drug prescription to children in France.
      Anyway, a complete review of the literature reveals the efficacy of this
      treatment when compared with placebo in children and adolescents suffering from
      ADHD, and its good tolerability profile. Moreover, pharmacotherapy was associated
      with a reduction in risk for substance use disorders in ADHD youth. We'll try to
      demonstrate that the problem shouldn't be focused on the efficacy of
      psychostimulant drugs but on clinical and diagnostic strategies. Actually, the
      clinical picture of ADHD is not very specific and there could be a risk of
      misdiagnosis of ADHD in children with hyperactive and/or attention behaviours
      from other origins (i.e. social and/or educative problems). As a differential
      diagnosis, the hypothesis of an early-onset bipolar disorder should be
      systematically assessed because of the huge symptomatic overlaps between the two
      illnesses.

PMID- 12602172
TI  - [Rheumatoid arthritis].

PMID- 12602173
TI  - [Evaluation of severity and search for early complications of abdominal trauma].

PMID- 12602174
TI  - [Evaluation and care of full-term neonates].

PMID- 12602175
TI  - [Doctor-patient relations. Announcement of serious illness. Education of patients
      with chronic disease. Personification of medical management].

PMID- 12602176
TI  - [Asthenia and fatigue].

PMID- 12602177
TI  - Supply chain probes point to changing role for GPOs.

PMID- 12602179
TI  - Materials management goes to school.

PMID- 12602178
TI  - Price survey. More options for apparel buys.

PMID- 12602180
TI  - Supply executives predict a better 2003.

PMID- 12602181
TI  - From strategy to action: the strategic action matrix.

PMID- 12602182
TI  - New partnerships in cardiovascular programs.

PMID- 12602183
TI  - The value of staff input in the cardiac design process.

PMID- 12602184
TI  - Improving outcomes and reducing costs in the cath lab: your hemodynamic
      monitoring system database is the key.

PMID- 12602185
TI  - Is health care financing upside down? A commentary on the health care investment
      decision.

PMID- 12602186
TI  - Analysis: 2003 Medicare physician fee schedule.

PMID- 12602187
TI  - Squeezed? Think ancillary services.

PMID- 12602188
TI  - Catch it on the fly. Risks, rewards and realistic expectations of mobile charge
      capture technology.

PMID- 12602190
TI  - Forewarned is forearmed. Avoiding four common financial management mistakes.

PMID- 12602189
TI  - Physician and administrator leadership. Why different is good.

PMID- 12602191
TI  - Keep the lid on. How to avoid opening the administrator's Pandora's box.
AB  - An informal--and enlightening--survey of experienced practice administrators
      asked what mistakes they wouldn't repeat in their careers. Errors in handling
      data, dealing with employees and physicians, financial supervision and personal
      behavior teach lessons in a humbling fashion.

PMID- 12602192
TI  - You get what you pay for. Case example: designing a quality incentive program.
AB  - The author describes her experience in developing a quality incentive program
      with a national health plan. The ultimate goals: To save lives and money, and
      reward providers who do the right thing.

PMID- 12602193
TI  - Reach out to move up. Best practices in A/R outsourcing.
AB  - Outsourcing your practice's accounts receivable can improve efficiency, introduce
      better technology, stabilize your expense structure and increase patient
      satisfaction. It's not for everyone, but if you decide to outsource, first assess
      your needs, find the right vendor and negotiate a smart contract.

PMID- 12602194
TI  - I think I scan. Case study: implementing the computerized patient record--not an
      EMR.
AB  - How a primary care practice moved from paper charts to computerized medical
      records and improved efficiency, saved money and boosted the satisfaction of the
      staff.

PMID- 12602195
TI  - The devil in the doctor. How to cope with problem physicians.
AB  - A primer on spotting a difficult physician before hiring, and coping with an
      individual already entrenched and causing an uproar.

PMID- 12602196
TI  - Rx for compliance. How the new PhRMA code on permissible pharmaceutical marketing
      practices affects your organization.
AB  - The Pharmaceutical Research and Manufacturers of America's recent code on
      interactions with health care professionals has a wide effect on medical
      professionals. A summary of the code's eight primary tenets and their impact on
      health care providers and organizations.

PMID- 12602197
TI  - A 'perfect day' in ambulatory care. Case study: a work redesign method to improve
      access.
AB  - A nationwide network of community-owned health systems and their physicians
      invited several health care practices in New York to participate in a
      collaborative effort to explore advanced-access scheduling to improve same-day
      appointment availability. Roswell Park Cancer Institute, Buffalo, accepted.

PMID- 12602199
TI  - [Frequency and nature of anterior tooth injuries and the use of mouth protectors
      in sports clubs in Bern].
AB  - Tooth injuries are frequently associated with sports injuries. Most of them could
      be minimized or prevented by the use of a mouthguard. The present study
      investigated the occurrence of tooth injuries and the attitude of athletes of
      Bernese sports clubs towards mouthguards, by means of a questionnaire and
      clinical examination. A total of 172 out of 200 athletes from six sports clubs,
      who were contacted directly at the sports fields, returned the questionnaire.
      Fifty of them owned a mouthguard (= 29.1%) and 54 reported having suffered dental
      trauma. The majority of athletes did not wear a mouthguard, despite acknowledging
      its usefulness. Even after a dental injury, the rate of mouthguard-acceptance
      increased just marginally; only 38.9% of all injured athletes were wearing a
      mouthguard after dental trauma. Most of the athletes had not considered wearing a
      mouthguard at all. For many of them, impairment of speech and breathing and
      discomfort were reasons not to wear a mouthguard. Of the 54 reported athletes
      with dental trauma, 48 were examined clinically. The upper central incisors were
      by far the most frequently injured teeth. The clinical examination used an injury
      severity index (NIDR-Index, National Institute of Dental Research) ranging from
      grade 0 (no visible damage), to grade 6 (loss of tooth). The most common finding
      was grade 4 (injuries that were treated by reconstruction). In conclusion there
      is a need to optimize information for athletes concerning mouthguards and sports
      injuries. Providing such information is not only the responsibility of coaches
      and trainers, but also of dentists.

PMID- 12602198
TI  - ["Esthetic plus"-ITI-implants (TPS): a prospective clinical study].
AB  - The purpose of this prospective study was to examine the influence of a 1 mm
      lengthening of the rough surface (TPS) of "esthetic plus"-ITI-implants on the
      periimplant soft and hard tissues. Twenty-one "esthetic plus" ITI-implants were
      inserted into the maxilla in an esthetically critical zone of 12 patients with
      sufficient alveolar bone. Clinical and radiographic examinations were performed
      after ten and 32 months. The mean DIB-score (DIB = distance between implant
      shoulder and first implant-bone contact) was 2.19 mm after 32 month. The average
      DIB-score of implant sites adjacent to natural teeth was 1.90 mm, there only 0.1
      mm of the rough surface did not have bone contact. However, the average DIB
      scores of implant sites adjacent to other implants (2.63 mm) or distal extension
      situations (2.79 mm) were much higher. This means that the coronal part of the
      rough surface had no radiographic bone contact with 0.83 mm (to other implants)
      and with 0.99 mm (to distal extension situations), what should be taken into
      consideration when using an "esthetic plus"-ITI-implant. As a consequence a
      standard ITI-implant with a smooth neck of 2.8 mm would be indicated. The results
      of the present study indicate, that not only the shortening of the smooth implant
      neck to 1.8 mm but also the adjacent structures influence the periimplant soft
      and hard tissues.

PMID- 12602200
TI  - [The effectiveness of therapeutic measures: the post-hoc-ergo-propter-hoc
      fallacy].

PMID- 12602201
TI  - [Dentin hypersensitivity--a review].

PMID- 12602202
TI  - Searching for some answers. Mount Sinai's lawsuit against recruiter Heidrick
      steps into current debate on shortage of qualified replacement executives.
AB  - Heidrick & Struggles, the nation's largest executive recruiting firm and a
      staunch champion of the National Center for Healthcare Leadership, is fighting a
      lawsuit that may test the premise that the healthcare industry lacks future
      leaders. As far as the placement business goes, Michael Doody, left, a senior
      vice president at search firm Witt/Kieffer, is confident a hospital's lawsuit
      alleging Heidrick fell down on the job won't cause irreparable damage.

PMID- 12602203
TI  - A look inside. Settlement requires Kaiser Permanente to publish info on docs's
      decisionmaking.

PMID- 12602204
TI  - Reversal of fortune. CMS reverses policy limiting emergency room visits.

PMID- 12602205
TI  - Executive suite squeeze. Retiring CEOs don't see enough talent to replace them.

PMID- 12602206
TI  - Back on the docket. Justice Department advances appeal challenging Texas system's
      exemption.

PMID- 12602207
TI  - Weathering a 'perfect storm'. Hospitals face plethora of challenges but are
      determined to stay afloat.

PMID- 12602208
TI  - Competing for attention. With tensions building in the Persian Gulf and debate
      heating up over the ailing economy, healthcare interests must fight to be heard.

PMID- 12602209
TI  - Preventive medicine. Disease-tracking software can identify outbreaks, isolate
      trends faster than ever. Its next mission: protect the nation's health.

PMID- 12602210
TI  - Are you ready? Even as crucial HIPAA deadlines loom, there's still plenty of
      unfinished business at many healthcare organizations.

PMID- 12602211
TI  - Straight talk new approaches in healthcare. Performance management: assuring your
      financial and performance goals are met.
AB  - Performance management is a topic thrown around a lot in executive suites, but
      its key tenets are sometimes misunderstood. To be successful, performance
      management involves setting strategy at the board and executive levels and making
      day-to-day decisions at the line-manager level. But the process won't work unless
      those line managers have clearly defined goals to achieve as well as relevant
      reliable and timely information to assist them in monitoring their performance
      and making operational decisions to improve outcomes. Modern Healthcare and
      Pricewaterhouse Coopers present Straight Talk in the tenth installment of
      Straight Talk we discuss the steps necessary to build a successful performance
      management program. The session was held at Modern Healthcare's Chicago head
      quarters on January 7, 2003. Charles S. Lauer, publisher of Modern Healthcare,
      was the moderator.

PMID- 12602212
TI  - Clearing the bureaucracy to promote compassionate care.

PMID- 12602213
TI  - William John Gies Award.

PMID- 12602214
TI  - Striving for excellence.
AB  - The mentored, small-group, patient-based participation study club has been the
      classical means for instilling a sense of excellence and improving the practical
      skills of dentists after they begin practice. This tradition has been especially
      strong in Oregon. The personal experiences and observations of a longtime
      participant and mentor in such study clubs is described.

PMID- 12602215
TI  - My growing involvement in dental study groups.
AB  - The lessons from managing a successful study club are learned over a life-time of
      practice, just a dentistry is. The author, who has taught numerous participation
      continuing education courses using the study club model and mentored many study
      clubs identifies these criteria for success: a respected mentor, open feedback,
      multiple points, of view, a clear mission and structure, and attention to the
      changing needs of the participants over time. A study club that has renewed
      itself effectively over a twenty-year period is described as a possible model.

PMID- 12602217
TI  - The smallest study club.
AB  - A specialist on Guam describes a study club of specialists on the island.
      Although the number of participants is small in absolute terms, the group's
      monthly meetings centered around cases serves the functions of stimulating
      currency and self learning and enhances coordination of complex treatment cases.

PMID- 12602216
TI  - The Carl O. Boucher Prosthodontic Conference spans four decades.
AB  - Dr. Carl O. Boucher was a giant in prosthodontics in the middle of last century.
      To honor his quest for excellence, the Ohio State University School of Dentistry
      established an annual conference bearing his name in 1996. This article describes
      the inaugural conference, the structure of the annual conference, and expanding
      plans to promote continuous improvement in prosthetic dentistry.

PMID- 12602218
TI  - The Jackson Dental Study Group.
AB  - The Jackson (Mississippi) Dental Study Group has grown over twenty-seven years
      into one of the strongest such groups in the state. Over this period the group
      evolved through a rather formal structure with a strong emphasis on education to
      one including more social elements, and eventually into a balanced organization
      serving the professional needs of dentistry in the Jackson area. Throughout its
      history, the JDSG has maintained a healthy inclusive orientation.

PMID- 12602219
TI  - The first honor society for dentists.
AB  - The American Academy of Dental Science was founded in 1986 as a society to
      promote professionalism and high ideals in the emerging discipline of dentistry.
      Throughout its history it has welcomed fellows who have been seminal figures in
      the field and has taken positions on the important issues of the times.

PMID- 12602220
TI  - Thinking about things not thought of: why it is important to volunteer and thank
      those who do.
AB  - The director of the dental ethics program at Columbia University School of Dental
      and Oral Surgery reflects on 9-11. Thinking about the sacrifices of volunteers on
      the Dental ID Team and the ethics program underscores how dependent our society
      is on the quiet efforts of a few who volunteer on numerous fronts to support and
      protect many of the values we hold dear. We, as a society, need to be more
      cognizant of the importance of these efforts and to give thanks, even where none
      is expected.

PMID- 12602221
TI  - Work.
AB  - The very nature of work is changing because of rapid social change, a culture of
      abundance, and the ability to substitute information for equipment, inventory,
      and other material aspects of value creation. In America, we are experiencing an
      erosion of the concept of a "job," a dramatic shift to service and information as
      the basis for value added, market commercialism, and the importance of the self
      managed career. In some of these areas, dentistry has been consistent with the
      patterns of innovation--even being a model in some cases. There are also areas
      where dentistry is moving in contrary directions.

PMID- 12602222
TI  - Key developments in neurology.

PMID- 12602224
TI  - Diagnosis and management of Bell's palsy.

PMID- 12602223
TI  - Drug management of epilepsy.

PMID- 12602225
TI  - Casebook: headache.
AB  - Headache alone rarely indicates a sinister underlying cause.  However, if the red
      flags are flying -- that is, if the patient is over 30 years old when the first
      headache develops, has additional symptoms or signs or has a very acute onset,
      particularly involving vomiting, then suspicion should be raised (see table 4). 
      Although migraine has a high impact on the sufferer and affects a large
      proportion of the population on a monthly basis, the problem of acute muscle
      contraction headache is far greater.  Other forms of headache are actually
      uncommon in comparison to these two.  However, chronic daily headache is the most
      common condition seen by the medical professional because of its impact on the
      patient's quality of life.  The key to the management of this condition is the
      assessment of analgesic dependence including NSAIDs, and particularly the codeine
      containing agents.  These should be avoided while long-term aproached such as
      exercise and certain prophylactic agents are introduced.  It is true to say that
      if a careful initial assessment is made leading to a correct diagnosis, then the
      chance of appropriate management is enormously increased.  Patients undergoing
      the correct management should generally see a massive improvement in their
      quality of life.  Headache can, therefore, be a very satisfying condition for the
      clinician to treat.

PMID- 12602226
TI  - Assessing fitness to drive in the elderly.

PMID- 12602227
TI  - The video: a test of consulting skills.

PMID- 12602228
TI  - [Hepatitis B vaccination and multiple sclerosis: where are we?].

PMID- 12602229
TI  - [History of hepatitis. I. From jaundice to viruses].

PMID- 12602230
TI  - [Epidemiology of tuberculosis].
AB  - Tuberculosis in France is still a topical question. The national incidence rate
      was 11.2 cases per 100,000 population in 2000 and has been stable since 1997. The
      situation is particularly worrying in the Ile-de-France region where the
      incidence is twice the national rate. It reaches 50 cases per 100,000 in Paris.
      The proportion of cases with human immunodeficiency virus infection has
      decreased, but the tuberculosis cases rates are 8 times higher in foreigners,
      especially in young adults. Social deprivation and migration from countries with
      high tuberculosis incidence contribute to this situation. Targeting public health
      initiatives with appropriate fundings should be implemented to combat
      tuberculosis.

PMID- 12602231
TI  - [Mycobacterium tuberculosis and its host].
AB  - Human beings are the only hosts of Mycobacterium tuberculosis. Owing to a
      peculiar architecture and composition of the cell wall, M. tuberculosis presents
      characteristic properties (acid fastness, high hydrophobicity). Molecules,
      proteins and polysaccharides, present on the cell surface play a key role in the
      rapid bacterial phagocytosis by macrophages. M. tuberculosis is able to inhibit
      the intracellular bactericidal mechanisms. Potent thymodependent immune responses
      control bactericial growth through inflammatory reactions.

PMID- 12602232
TI  - [Biological diagnosis of tuberculosis].
AB  - Today, the diagnosis tests for tuberculosis are based on: the observation of acid
      fast-bacilli after Ziehl-Neelsen staining or fluorescent microscopy, the growth
      of a culture, the study of drug sensibility, the observation of granulomatous
      tissue lesions and caseous necrosis. Use of radioactive liquid culture media
      (Bactec) or not, has shortened the time required for obtaining the result, but it
      remains too long and, so far, polymerase chain reaction has not answered the
      challenge. However molecular techniques have been applied with success to the
      identification of mycobacterial strains (DNA fingerprinting) and to rapid
      detection of antimicrobial resistance caused by mutation of the target genes.
      Progress of the molecular tests could lead to desoxyribonucleic microarrays,
      which would be able to revolutionize the microbiological diagnostic tests.

PMID- 12602233
TI  - [Thoracic tuberculosis].
AB  - The diagnosis and treatment of thoracic tuberculosis follow common principles
      whatever the localisation. Tuberculosis is diagnosed on clinical signs: night
      sweats, fever, cough, weight loss, persisting after non-specific treatment, for
      more than 3 weeks. The demonstration of bacilli in sputum is the keystone of
      diagnosis, but in extrapulmonary localisations definitive proof is often drawn
      from a pleural, pericardial or even lymph node biopsy. After diagnosis, or when
      diagnosis is highly suspected, antituberculous treatment is started. Steroid
      could be useful in exsudative forms. The overall cure rate is 95% but side
      effects, poor compliance or bacteriological resistance can yield complex problems
      and lead to failures.

PMID- 12602234
TI  - [Extrathoracic tuberculosis].
AB  - Incidence of extrathoracic tuberculosis has increased these last years. The
      average time to diagnosis is 3 months, owing to the poor specificity of some of
      its clinical signs, but also the failure to evoke these infections. Most common
      localizations are lymph nodes, bones and joints, genitourinary track and more
      rarely neuromeningeal or digestive systems. Diagnosis is based on bacteriological
      data (traditional culture, polymerase chain reaction) and histology. Computed
      tomography and magnetic resonance imaging are effective to detect the lesions at
      an early stage and appreciate their extent. Delayed diagnosis is responsible for
      mortality and sequelae of this affection for which treatment is effective, if it
      is correctly managed and followed.

PMID- 12602235
TI  - [Tuberculosis in children].
AB  - Children tuberculosis accounts for 5.5% of the declared cases of tuberculosis in
      France. Tuberculosis in children is always due to recent contamination from an
      adult. Survey of tuberculosis in children is a good indicator of the Koch's
      bacillus spread. Age is an important risk factor for an infected child to develop
      tuberculous disease. Estimated risk is 43% under 1 year of age, 24% between 1 and
      5 years of age, 16% in teenagers. The risk to develop severe disease (miliary,
      meningitis) is higher in infants. Teenagers may have a rapidly evolutive form.
      Diagnosis of tuberculosis in children is difficult. One has to keep in mind this
      diagnosis which must be assessed by tuberculin skin test, radiologic exams and
      bacteriological sampling. The proof of tuberculosis is rare in children: direct
      examination of gastric fluid is positive only in 20% of cases or less; culture is
      positive only in 50% of cases or less. Infection and disease have to be treated
      in children. The search of the index case is mandatory.

PMID- 12602236
TI  - [Immunodeficiency and tuberculosis].
AB  - A number of medical conditions may alter immune responsiveness, and predispose to
      tuberculosis. Management of immunodeficiency-related tuberculosis treatment is
      complex, and the clinical and public health consequences associated with
      treatment failure are serious. Human immunodeficiency virus infection is a major
      cause of immunodeficiency increasing tuberculosis susceptibility. Whenever
      possible, the care for immunodeficiency-related tuberculosis should be provided
      by experts in the management of both diseases.

PMID- 12602238
TI  - [A report from the World Health Organization].

PMID- 12602237
TI  - [Treatment of tuberculosis and organization of care].
AB  - In case of susceptible organism, treatment of tuberculosis is well defined and
      consists in a combination of 4 drugs during the first 2 months followed by 2
      drugs for a total duration of 6 months. This regimen is effective when treatment
      is taken regularly and completely. The consequences of irregular treatment is the
      emergence of resistant strains which can be transmitted to other persons. The
      quality of treatment adherence is related to a collaboration between health care
      facilities and public health officials.

PMID- 12602239
TI  - [Principles of acute poisoning].

PMID- 12602240
TI  - [Abnormal movements. Diagnostic approach].

PMID- 12602241
TI  - [Mononucleosis. Diagnostic approach].

PMID- 12602242
TI  - [Facial dermatitis. Acne, rosacea, seborrheic dermatitis].

PMID- 12602243
TI  - [Primary and secondary liver neoplasms].

PMID- 12602244
TI  - Cholecystitis: the Ethiopian experience, a report of 712 operated cases from one
      of the referral hospitals.
AB  - This is a prospective study conducted from September 1991 to September 2000.
      Seven-hundred and twelve patients operated for acute and chronic cholecystitis
      were studied. The male to female ratios for elective and emergency admissions
      were 1:5 and 1:2.4, respectively. The mean age was 42.7 years. Acute
      cholecystitis accounted for 10.6% of the 712 cases. There were a total of 666
      (93.5%) calculus and 46 (6.5%) acalculus cases. Empyema was seen in 77 (10.8%)
      patients and hydrops of the gallbladder in 35 (4.9%). Iatrogenic Common Bile Duct
      (CBD) injury was found to be more of a problem of the contracted gallbladder. In
      this study severe complications like gangrenous gallbladder, perforated
      gallbladder, suppurative cholangitis and subhepatic abscess were found more in
      males than in females. Calculus cholecystitis was found to be a common disease in
      Ethiopia, and that its features and prevalence as well as sex predilection
      compare well with reports from other areas. However the findings in this report
      were found to be different from the reports of the rest of the African Continent.

PMID- 12602245
TI  - Elective hysterectomy at Tikur Anbessa Teaching Hospital, Addis Ababa.
AB  - A retrospective analysis of 969 elective hysterectomies performed at Tikur
      Anbessa teaching hospital from February 1992-October 2000 is presented. The
      objectives of the study were to outline the major indications, the frequencies of
      intraoperative and postoperative complications and the variations of these
      frequencies in the various types of hysterectomy, thereby providing data on this
      important gynaecologic operation in an Ethiopian hospital set-up. Elective
      hysterectomies accounted for 79.3% of all hysterectomies performed at the unit.
      There was a preference for the abdominal approach to hysterectomy (77.3%) with
      vaginal hysterectomy being done in only 22.7%. The three major indications for
      hysterectomy were leiomyoma 396/969 (41.1%), uterovaginal prolapse 221/969 (23%)
      and ovarian tumours 188/969 (19.5%). 567/969 (58.5%) of the patients had an
      underlying medical condition; anaemia being the commonest, accounting for 325/969
      (33.5%). In 294/969 (30.2%) of the operations, intraoperative adhesions requiring
      adhesiolysis were encountered. A high proportion of intraoperative complications
      167/969 (17.2%), and postoperative complications, 316/969 (32.6%), were found.
      Intraoperative haemorrhage rate 135/969 (14%) is significantly higher than
      reports from other series of hysterectomy. Postoperative febrile morbidity,
      260/969 (27%), is also significantly higher than rates reported from other
      series. Unexplained fever was however lower, being responsible for only 20% of
      the febrile morbidity. There was a significantly increased risk of urinary tract
      infection in vaginal hysterectomies and unexplained fever in abdominal
      hysterectomy (P < 0.05). There is a need to use the vaginal approach to
      hysterectomy whenever feasible and introduce infection prevention protocols to
      reduce the high incidence of infection at the unit. Analytic studies to assess
      risk factors for haemorrhage and infection are required in order to devise
      preventive strategies.

PMID- 12602247
TI  - Quality of prescription at a tertiary care pharmacy in Addis Ababa.
AB  - The practice of prescribing is one of the critical factors that ensure safety and
      rational use of drugs. The objective of this study was to describe the quality of
      prescription in terms of format, legibility and content. The study was carried
      out in Tikur Anbessa Hospital outpatient pharmacy. All prescriptions that came to
      the hospital pharmacy over one week period were collected and analyzed. A total
      of 2191 prescriptions were received by the hospital pharmacy. Only few of the
      prescriptions had complete information. In about 50% of the prescriptions sex and
      age were not recorded. On average 15% of the prescriptions were not eligible.
      Only 13% of the prescriptions received during weekdays, and 8.5% of those
      received during weekends were scored as good (more than 5 variables out of 8
      assessed were rated good). There was no significant difference in the quality
      between the prescriptions received from Tikur Anbessa hospital and other health
      institutions. Furthermore, weekday prescriptions were better in quality as
      compared to weekend prescriptions without considerable difference between day and
      night shifts. These findings indicate that considerable proportion of
      prescriptions are not properly written. Since Tikur Anbessa is a teaching center,
      immediate action needs to be taken to improve the practice of prescription
      writing.

PMID- 12602246
TI  - Experience in the use of laryngeal mask airway in Tikur Anbessa Hospital.
AB  - The study was designed to make an initial observation in the use of laryngeal
      mask airway with the only existing drug, i.e., ketamine, for induction of
      anaesthesia. Its effective use should be determined to maintain patients airway
      following induction of anaesthesia with the only available drug for induction
      than the drug that is commonly used for its insertion. There were a total of 64
      patients included in the study in a period of seven weeks with a male to a female
      ratio of 1 to 1.33 and age range of 6-70 years. A successful insertion following
      induction of anaesthesia with ketamine was achieved in 40 patients at the 1st
      attempt and in 23 patients at the 2nd attempt. Successful insertion of laryngeal
      mask airway was considered when it was achieved on the first attempt. Deepening
      anaesthesia with halothane/O2 by mask or adding small dose of relaxant
      (Succinylcholine) was necessary in 33 patients. The fact that a second insertion
      attempt was necessary and a large number of cases needed additional anaesthesia
      or relaxation indicated ketamine alone was not a good drug as an induction agent
      for laryngeal mask airway insertion.

PMID- 12602248
TI  - Investigation on the antibacterial properties of garlic (Allium sativum) on
      pneumonia causing bacteria.
AB  - The antibacterial activity of the crude aqueous extract of garlic was
      investigated against some pneumonia causing bacteria by an agar dilution
      technique. The results revealed that Streptococcus pneumoniae standard test
      organism was completely inhibited by 7.8 mg/ml of media and the clinical isolate
      of Klebsiella pneumoniae was completely inhibited by 24.38 mg/ml of media,
      indicating that Streptococcus pneumoniae is the most sensitive and Klebsiella
      pneumoniae the least. Garlic could be used as an effective antibacterial agent
      for these pathogenic microorganisms.

PMID- 12602249
TI  - A community based study of urogenital chlamydia trachomatis in males aged fifteen
      years and above, Dembia District, northwest Ethiopia.
AB  - Chlamydia trachomatis is one of the most common causes of sexually transmitted
      diseases in sexually active males and females. Infertility is one of the serious
      complications of urogenital chlamydial infections. This study was carried out in
      Chuwahit town and the surrounding village, which is located southwest of Gondar
      town. The main objective was to estimate the prevalence of urogenital Chlamydia
      trachomatis among males aged fifteen years and above. The design used was a cross
      sectional survey. First catch urine was collected from males 15 years and above
      and interviews were made using a questionnaire. The urine samples were tested
      with an Enzyme Immuno-Assay (EIA), which is useful in rapid detection of
      chlamydia antigen. Among 199 males included in the study, thirty-three (16.6%)
      had laboratory evidence of urogenital Chlamydia trachomatis. The mean (SD) age of
      the study subjects was 29.3 (+/- 9) years. Students (8 out of 21, 38%) had the
      highest prevalence of urogenital Chlamydia compared to the other groups (OR =
      4.10, 95% CI = 1.12, 14.48). The magnitude of urogenital chlamydia infection in
      males was high in the study area. Health professionals need to consider genital
      Chlamydial infections in the management and control of sexually transmitted
      diseases. Increasing the awareness of students towards urogenital Chlamydial
      trachomatis and teaching them about the benefits of using condoms is recommended.

PMID- 12602250
TI  - Prevalence of onchocercal skin disease and infection among workers of coffee
      plantation farms in Teppi, southwestern Ethiopia.
AB  - In June 1996, a study on the economic impacts of onchocercal skin disease was
      initiated in southwestern Ethiopia. We made parasitological and
      clinicoepidemiological investigations among 1619 workers of a coffee plantation
      firm in Teppi, south-western Ethiopia. Sixty percent of the workers were included
      in the study. The prevalence of onchocercal skin disease (OSD) was 85.3%. Severe
      OSD (SOSD) was found in 17.3% of the study subjects. This was 1/5 of all OSD
      cases. The overall nodule carrier rate was 44.2%, which differed significantly by
      age classes from a rate of 12.3% to 73.0%. This rate varied by sex, 51.7% in
      males and 22.6% in females. Microfilarial carrier rate (MFCR) was 77.6%. This
      rate did not vary neither with severity of disease nor with presence or absence
      of pruritus or onchodermatitis. Mean microfilarial count was determined to be
      38.1 per mg of skin snip or 44.4 per mg of infected skin snips. The geometric
      mean of microfilarial load per infected skin was 23.8. The community
      microfilarial load (CMFL) was estimated to be 14.0 per mg skin snip. The study
      showed that SOSD is prevalent in Teppi and affects a substantial number of the
      working population. An intervention program is called for.

PMID- 12602251
TI  - Leishmaniasis in the middle course of the Ethiopian Rift Valley: II.
      Entomological observations.
AB  - As part of an epidemiological investigation of visceral leishmaniasis,
      entomological surveys were conducted in Ziway-Langano, Dimtu-Bilate and Wadjifo
      Mirab Abaya areas located in the middle course of the Ethiopian Rift Valley
      between November 1994 and June 1996. A total of 4518 sand flies (Diptera:
      Psychodidae) were collected from the study areas using CDC light traps and oiled
      plastic sheets which were identified to nine species of Phlebotomus and 14
      species of Sergentomyia. Most of the Phlebotomus species were from Ziway-Langano
      area and they included P. martini and P. orientalis, which are the principal
      vectors of visceral leishmaniasis in Ethiopia. Among 339 females of nine
      Phlebotomus species dissected, natural infections with flagellates were detected
      in 11 specimens (two P. duboscqi and nine P. rodhami) from Ziway-Langano area,
      but were different from mammalian Leishmania species by their position in the
      insect gut, morphology and behaviour in cultures. However, the reasons for the
      low level of leishmanin skin-test positivity in this portion of the Rift Valley
      are not immediately clear in view of the rich sand fly fauna and the presence of
      potential vectors.

PMID- 12602252
TI  - Hydatid cyst an unusual cause of ovarian enlargement.
AB  - A case of ovarian hydatosis without other evidence of hydatid disease elsewhere
      in the body is reported. This 35 years old para eight abortus two Ethiopian
      mother was admitted to the Gynecology and Obstetrics department of Tikur Anbessa
      teaching hospital with the diagnosis of ovarian tumor. A uniclocular ovarian cyst
      was removed at laparotomy which was diagnosed to be hydatid cyst of the ovary on
      histopathological examination. Epidemiological features, clinical presentation
      and therapeutic options of this rare cause of adnexal enlargement are discussed.

PMID- 12602253
TI  - Renal osteodystrophy presenting with multiple calcified periarticular swellings.
AB  - Renal osteodystrophy denotes skeletal abnormality in patients with renal disease.
      Although radiological and histological evidences of osseous abnormality are
      commonly seen in advanced renal failure, clinical symptoms of bone disease are
      uncommon. In this article a case of chronic renal failure presented with multiple
      calcified periarticular swellings measuring up to 5 cm in diameter is described.
      The patient also had severe osteopenia, subperiosteal erosions, bilateral
      shrunken echogenic kidneys as well as clinical and biochemical evidences of
      chronic renal failure. Renal osteodystrophy is discussed and related literature
      is reviewed.

PMID- 12602254
TI  - [Problems and perspectives of specialized ambulatory surgical care].

PMID- 12602255
TI  - [Medico-legal analysis of violent death in navy servicemen].
AB  - On the model of analysis of violent death in the Armed Forces and the Navy during
      the period of 1975-2000 one of the aspects of military medico-legal laboratory
      (MLL) activity is shown. The authors give the analysis of dynamics of accidents,
      murders and suicides n the Navy compared with the data obtained in the Armed
      Forces. The attention is concentrated on the situation arising in the AF and Navy
      where the crime rate is rather high as the cases of murders and suicides have
      increased and especially during the last years.

PMID- 12602256
TI  - [Medical care rendered to participants involved in accident rescue and clean-up
      work in extreme situations].

PMID- 12602257
TI  - [Clinical course of non-hospital pneumonia in servicemen with "Pneumo-23"].

PMID- 12602258
TI  - [Sanitary and educational aspects of prophylaxis of HIV-infection in servicemen].

PMID- 12602259
TI  - [Current aspects of radiographic diagnosis of pelvis and pelvic organ traumas in
      peace and wartime conditions (review of the literature)].
AB  - The injuries of pelvis and pelvic organs remain one of the difficult problems of
      surgery in military and peace-time. The detection of pathologic changes in the
      cases of pelvic traumas depends on the time, quality and volume of radial
      investigations. The rule that any pelvic injury is considered as the complicated
      one until the opposite will be proved determines the diagnostic algorithm of
      roentgenologic examination, and the contrast methods are of great importance. The
      perspective method of for investigating the casualties with severe combined
      pelvic trauma is the spiral computed tomography. The investigation of casualties
      with pelvis and pelvic organ traumas must be conducted at the shortest periods
      after the trauma using the whole complex of radial investigative methods both the
      conventional roentgenologic and imaging methods.

PMID- 12602260
TI  - [Special features of rendering specialized neurosurgical care during current
      local military conflicts].

PMID- 12602261
TI  - [Clinical and epidemiological aspects and current recommendations on treatment of
      genital herpes].

PMID- 12602262
TI  - [Current approach to the treatment of onychomycosis].

PMID- 12602263
TI  - [Effect of prophylactic vaccination on hepatitis A spreading in the North
      Causcasus district of RF MIA internal troops].

PMID- 12602264
TI  - [Clinical laboratory and morphologic characteristic of mixed hepatitis B + C with
      manifestation of its course].

PMID- 12602265
TI  - [Special features of medical support of service women in the air force].

PMID- 12602266
TI  - [Current mobile medical complexes for rendering qualified medical care].

PMID- 12602267
TI  - [The past, present and future of the blood service of the Armed Forces].
AB  - Creation of the civil blood service permitted to supply the military treatment
      and-prophylactic institutions with blood, to draw up the plan of support in the
      event of hostilities. The blood service of the USSR (Russia) Armed Forces
      originates from 1962 when the blood transfusion stations (BTS) were created in
      the military districts and navy. The departments of blood transfusion (DBT) were
      formed in the central hospitals and Military Medical Academy and the stations of
      blood storage and transfusion not in the regular staff were organized in the
      garrison hospitals. In 2001 the Minister of Defense of Russia approved the
      program "Development of RF MD blood service during the period of 2002-2006". The
      aim of the program is to improve the quality and to raise the effectiveness of
      transfusion therapy for the patients, members of servicemen' families treated in
      the military treatment-and-prophylactic institutions. It is necessary to
      intensify the control of blood and donor service, to improve its material and
      technical basis, to bring the material and normative basis into line with the
      functioning documents of the RF Ministry of Health, to train the transfusion
      specialists.

PMID- 12602268
TI  - [The Central Hospital of Rocket Troops (interview of chief of Central Military
      Clinical Hospital, medical service Colonel V.T. Karpalov)].

PMID- 12602269
TI  - [The Main Hospital of the Baltic Fleet is 60 years].

PMID- 12602271
TI  - Clinical characteristics of hereditary ovarian cancer (HOC) in Poland.
AB  - BACKGROUND: Hereditary ovarian cancer (HOC), as any genetic disease, may display
      clinical characteristics that depends on population. AIM OF THE STUDY: The aim of
      the study was to describe clinical characteristics of HOC in Polish population
      basing on analysis of the following features: age at onset, clinical staging,
      morphological grading and prevalence of serous adenocarcinoma. MATERIAL AND
      METHOD: The cases were selected basing on analysis of pedigree/clinical features
      and molecular studies of founder mutations of BRCA1 gene in Poland. RESULTS: The
      patient's age at diagnosis was ca 49-52 and was similar in all groups. The
      exception was the subgroup without mutations in group II (breast and ovarian
      cancers found in families) with mean age at diagnosis ca 46 years (n = 9). In
      patients with HOC without mutation of BRCA1 gene, lower FIGO stage and lower
      morphological grade were detected more frequently. The majority of HOC showed
      histopathological pattern of serous adenocarcinoma. CONCLUSIONS: Clinical
      features of HOC in Poland and in other countries are similar. 2. Introduction of
      DNA tests to the clinical and pedigree diagnostic criteria allows detection of
      subgroups of HOC with different clinical features.

PMID- 12602272
TI  - [The incidence of human papilloma virus (HPV) DNA in patients with cervical
      carcinoma from Gdansk region].
AB  - OBJECTIVES: We have estimated the incidence of human papilloma virus (HPV) DNA in
      cervical smears of patients with cervical carcinoma, treated in 1997-1998 at the
      II Department of Obstetrics and Gynecology, Medical University of Gdansk, Poland.
      MATERIALS AND METHODS: We have examined 107 patients suffering from cervical
      cancer. The HPV DNA was detected with the polymerase chain reaction (PCR) method
      using two primer pairs located in the E6, E7 open reading frames. HPV typing was
      executed by restriction fragments length polymorphism PCR (RFLP-PCR) method.
      RESULTS: HPV DNA was detected in 75 (70.1%) patients. A group of patients with Ib
      (43%) and IIa (19.6%) clinical degrees made the highest percentage within the
      research group. We found no statistically significant differences between various
      clinical degrees of cervical cancer in the group of patients both HPV positive
      and negative. CONCLUSIONS: The frequency of HPV especially HPV 16 type infection
      incidence in cervical carcinoma is lower in Gdansk region than currently
      published.

PMID- 12602273
TI  - [Biophysical parameters of early puberty in girls].
AB  - OBJECTIVE: The appearance of breast development in girls characterizes an early
      period of puberty. Ultrasonographic examinations of the uterus and ovaries make
      possible the estimation of first pubertal changes in sexual organs. DESIGN: The
      aim of this work was to study the clinical and ultrasonographical features of
      early puberty in girls. MATERIAL AND METHODS: 33 healthy girls were observed
      quarterly in the course of prepuberty. Body mass, height, body mass index (BMI),
      quantity of adipose tissue were investigated. Stage of puberty was established
      according to Tanner. The uterus and ovaries were studied ultrasonographically,
      and the volume of the uterine body, length of the cervix and ovarian volume and
      size of ovarian follicles were scrutinised. RESULTS: Statistical differences were
      observed in weight, height, quantity of adipose tissue and the volume of body and
      that of the uterus, in length of the cervix between prepuberty and early puberty
      periods. Luminastity of mucus in the cervical canal in half of girls in the
      breast stage M1 was obtained. CONCLUSION: Ultrasonographic investigations of
      internal sexual organs with estimation of clinical sexual features are helpful in
      examination of early stage of puberty.

PMID- 12602274
TI  - [Application of color Doppler in diagnosis of malignant breast tumors].
AB  - The object of our research was estimation of blood flow with the application of
      colour Doppler within the scope of changes that occurred in female patients
      suffering from malignant breast tumours. The research covered 30 female patients
      and the results pointed to great usefulness of this method in diagnostics of
      malignant breast tumour.

PMID- 12602275
TI  - [The influence of transdermal nitroglycerin patches on fetal blood flow
      parameters in threatened preterm labor].
AB  - OBJECTIVES: The aim of our study was the assessment of fetal arterial Doppler
      parameters (umbilical artery and middle cerebral artery) in threatened preterm
      labor in the course of transdermal nitroglycerin therapy. MATERIALS AND METHODS:
      16 pregnant women in between 27th and 34th week of gestation with symptoms of
      threatening preterm labor were brought into our study. Patients were treated with
      transdermal nitroglycerin (5 mg) patches. Maternal blood pressure. Manning's test
      score and fetal arterial Doppler blood flow were measured. RESULTS: Whereas
      maternal systolic blood pressure does not vary in the course of therapy,
      significant decrease in diastolic blood pressure was noted. There was no change
      in the mean umbilical and middle cerebral artery blood flow in the course of
      treatment. CONCLUSIONS: Nitroglycerin in the form of transdermal therapeutic
      system releasing nitric oxide doesn't effect fetal artery Doppler parameters.
      Nitroglycerin may be used as a safe therapeutic agent in treatment of preterm
      labor.

PMID- 12602276
TI  - [Reliability of sonographic diagnosis of chorionicity and amnionicity in twin
      pregnancy ].
AB  - OBJECTIVES: The aim of the study was to compare the reliability of chorionicity
      determination in twin pregnancy using different ultrasonographic methods as
      compared with post-partum placental assessment. STUDY DESIGN: The study included
      262 spontaneous twin pregnancies delivered at Kutno Hospital between 1989 and
      1996. All twin gestations were diagnosed by sonography by the 28-th week's
      gestation. The ultrasonographic and pathologic correlation between the chorionic
      and amniotic type was assessed in this group. RESULTS: The ultrasonographic
      evaluation of the 262 spontaneous twin gestations demonstrated 181 (69.1%)
      dichorionic and 81 (30.9%) monochorionic twin pregnancies. Three of monochorionic
      twins were monoamniotic. In all 262 transvaginal and abdominal ultrasonography
      correctly predicted the chorionic and amniotic type as determined by the
      pathologic findings. CONCLUSIONS: Ultrasonography before the 28-th week can
      accurately determine the chorionic and amniotic type in twin pregnancies. The
      determination of chorionicity during the first half of pregnancy should be based
      on the various signs. In the second half of pregnancy, the obstetrician should
      rely on fetal sex in combination with the number of placentas, and
      characteristics of the dividing membrane.

PMID- 12602277
TI  - [Influence of labetalol on the resistance of human fetoplacental vessels in
      perfusion in vitro].
AB  - OBJECTIVES: The main unfavourable effects observed in gestosis include: increased
      vascular peripheral resistance and increased blood pressure with a defective
      uteroplacental flow. The above mentioned changes may result from disorders in
      prostacyclin PGI2/thromboxane A2 balance. DESIGN: The aim of the studies
      presented was to compare the effects of, labetalol on the fetal vascular
      resistance induced by U 46,619--stable analogue of thromboxane A2 an experimental
      bilateral perfusion of the human placental lobule. MATERIALS AND METHODS: The
      researchers used the experimental model described by Schneider. 12 perfusions of
      the human placental lobules were performed. The control and labetalol groups
      consisted in 6 placental lobule perfusions lasting 120 min each. Having obtained
      constant increase in perfusion pressure from the 60th min of the experiment,
      labetalol was administered along with thromboxane A2 analogue into the fetal
      circulation. The perfusion pressure was steadily recorded on the kymograph tape.
      RESULTS: The stable increase of perfusion pressure was observed from the 60th
      minute with the average of 185% of the initial pressure. This value represented
      the reference standard in the second stage of the studies in which the effects of
      labetalol on the experimentally increased perfusion pressure was evaluated.
      CONCLUSIONS: Labetalol did not significantly affect the hemodynamics of
      fetoplacental vessels.

PMID- 12602278
TI  - [Ganglioneurofibroma partim plexiforme of the urinary bladder in a pregnant woman
      -a case report].
AB  - This study describes the case of 29 year old pregnant woman. During the caesarean
      section the tumor of the bladder was detected. The reason for the caesarean
      section was the lack of delivery progress and impending asphyxia. After the
      opening of the abdominal a hard and solid conglomerate of tumors coming out of
      the bladder was certified. The tumor of the urinary bladder was the reason for
      the caesarean section and removing 2/3 of the urinary bladder. The
      histopatological examination showed that it was ganglioneurofibroma partim
      plexiforme. The medical literature knows only very few cases concerning this type
      of cancer of the bladder.

PMID- 12602279
TI  - [Hydronephrosis in course of actinomycosis of female reproductive organs].
AB  - OBJECTIVES: Pelvic actinomycosis is a chronic suppurative granulomatous disease
      caused by an anaerobic Gram positive germ, Actinomyces. The most difficult task
      was to obtain the diagnosis in a patient with an intrauterine device and poor
      general health, signs of infection and a pelvic syndrome. RESULTS: This is a
      report of a case of hydronephrosis in course of actinomycosis of female
      reproductive organs in a patient aged 46 years with the intrauterine
      contraceptive device admitted to The Department of Gynecology & Obstetric in
      Hospital of Slupsk. Symptoms were presented as an acute abdomen associated with
      painful epigastric and mass in right adnexa. A pre-operative diagnosis of the
      right hydronephrosis, on ovarian tumor and uterus myoma were detected which lead
      to an extensive and difficult surgery. The pathologic process infiltrated the
      retroperitoneal space simulated sarcoma or lymphoma. The disease was serious and
      required hysterectomy with salpingo-oophorectomy and intra-abdominal drainage.
      Actinomycosis was confirmed by the postoperative histopathologic examination, and
      the patient was successfully treated with penicillin. The patient was completely
      free of symptoms two months within the operation. CONCLUSIONS: In patients who
      have intrauterine contraceptive devices or who have had them removed recently,
      abdominal pain, recurrent vaginal bleeding or adnexal masses should prompt a
      thorough search for potentially pathogenic actinomyces in the genital tract.

PMID- 12602280
TI  - [Hypertension in pregnancy--risk factors, prevention and treatment].
AB  - The term hypertension in pregnancy stands either for a high blood pressure, which
      has already developed before pregnancy (i.e., chronic hypertension in pregnancy),
      or for a pregnancy-associated disease (i.e., pregnancy-induced hypertension).
      Each form of hypertension may be an isolated phenomenon or constitute a part of
      the syndrome of preeclampsia or eclampsia. This review focuses mainly on the risk
      factor assessment, prevention and treatment of hypertension developing during
      pregnancy. Despite a frequent occurrence of this disease its prevention and
      treatment is still a subject of debates, and only a limited number of studies,
      which fulfill the criteria of "evidence-based medicine" have so far been
      performed in this field. Although the impressive advances in treatment of
      hypertension in the general population have been done, the choice of drugs and
      control of hypertension developing during pregnancy is still far from being
      satisfactory.

PMID- 12602281
TI  - [Genetic bases of human sex determination and differentiation].
AB  - Male and female sex determination depends on Y-linked SRY gene activity. This
      gene initiates the cascade of reactions which lead to the differentiation of
      bipotential, indifferent gonads to testes or ovaries, depending on the presence
      or absence of active from SRY. Since SRY discovery in 1990, several new genes
      playing important role in gonadal and in both internal and external genitalia
      development and differentiation have been identified. Detailed knowledge
      concerning above mentioned genes will enhance our understanding of etiology of
      sexual development abnormalities.

PMID- 12602282
TI  - [Neoadjuvant chemotherapy in the treatment of advanced cervical cancer].
AB  - Neoadjuvant chemotherapy (NAC) has been used for treatment of advanced cervical
      cancer by some institutions for several years. PURPOSE: We investigated the value
      of NAC for patients with IIb cervical cancer. MATERIALS AND METHODS: Eight
      patients treated at the 2nd Department of Obstetrics and Gynecology Medical
      University of Gdansk between 1999 and 2000 for stage IIb cervical cancer were
      enrolled into the study. The drugs infused were: cisplatin 50 mg/m(2) and
      vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days, for three
      cycles. NAC was followed by radical Wertheim-Meigs hysterectomy. All patients
      were evaluated for response and toxicity. RESULTS: In all eight patients partial
      responses were obtained. Despite previous data there was no severe toxicity in
      our study group. Hematological toxicity was mild and there was no need for
      modifying chemotherapy due to side effect of NAC. CONCLUSION: NAC followed by
      radical Wertheim-Meigs hysterectomy is an effective approach to stage IIB
      cervical cancer. Further larger prospective study is necessary. Preoperative
      imaging studies (CT and/or MR) might be consider as selection criteria for future
      study.

PMID- 12602283
TI  - Going 'live' in a hurry.

PMID- 12602284
TI  - Watch dog sniffs out weak links.

PMID- 12602285
TI  - CPOE order from chaos.

PMID- 12602286
TI  - Is there magic in the air?

PMID- 12602287
TI  - When Goliath can't help, David does the job.

PMID- 12602288
TI  - Status report: time is nigh for HIPAA rules.

PMID- 12602289
TI  - Information technology fits nurses like a glove.

PMID- 12602290
TI  - Taking an I.T. leap pays off.

PMID- 12602291
TI  - Electronic records find long-term use.

PMID- 12602292
TI  - MDs ok CPRs, VPN and PDAs.

PMID- 12602293
TI  - Taking the knife to inefficiency.

PMID- 12602294
TI  - Reader's perspectives. Physicians will personally enter information into
      computerized physician order entry systems as more such systems are implemented
      nationwide.

PMID- 12602295
TI  - Few details, big debate. President Bush still needs to fill in the blanks on how
      he wants to reform Medicare, but advocates are already feuding.
AB  - President Bush last week presented his long-awaited plan to overhaul the 38-year
      old Medicare program, but the lack of specifics has led to a heated debate
      between policymakers and advocacy groups on which direction the reforms should
      take. Later in the week, HHS Secretary Tommy Thompson, left, proposed a $12.7
      billion Medicaid expansion that awaits Congress' approval.

PMID- 12602296
TI  - No permission needed. Bush proposes lift of federal Medicaid requirement.

PMID- 12602297
TI  - No gouging allowed. Tenet's new billing, collection practices may signal change
      in industry's strategy regarding the uninsured.

PMID- 12602298
TI  - CMS transfers watchdog role.

PMID- 12602299
TI  - Behind NCFE's (National Century Financial Enterprises) good news. Bondholders
      could be lucky to get back pennies on the dollar.

PMID- 12602300
TI  - Let the safety begin. NQF (National Quality Forum) endorses practices, opens door
      for quality standards.

PMID- 12602301
TI  - Changing the rules. As smaller GPOs customize, the big boys take notice.

PMID- 12602302
TI  - The real road to better coverage. Instead of privatizing Medicare, let's try what
      worked for one state's uninsured.

PMID- 12602303
TI  - Reaching out to the community. ACHE's young executive of the year finds
      innovative ways to serve patients.

PMID- 12602304
TI  - A career of guiding change.

PMID- 12602305
TI  - Familiar themes for ACHE. Labor shortfalls, malpractice insurance reform,
      reimbursement issues top agenda for organization's 46th annual congress next
      month.

PMID- 12602306
TI  - Straight talk--new approaches in healthcare. The performance improvement
      equation: quality care + efficient care = profitable care.
AB  - Healthcare organizations that deliver high quality care as efficiently as
      possible inevitably are profitable. In the eleventh installment of Straight Talk,
      we discuss the performance improvement strategies of three health systems that
      strive to strike a balance between financial and altruistic goals: 15 hospital,
      $1.4-billion St. Vincent Health, Indianapolis, IN., formerly Central Indiana
      Health System and owned by Ascension Health, St. Louis.; 7 hospital, $1.8-billion
      Detroit Medical Center.; 3-hospital, $500-million Bon Secoure Richmond Health
      System, Richmond Va., which is part of Bon Secours Health System Inc.,
      Marriottsville, Md. Modern Healthcare and PricewaterhouseCoopers present Straight
      Talk. The session on performance improvement was held on January 15, 2003 at
      Modern Healthcare's Chicago headquarters Fawn Lopez, associate publisher of
      Modern Healthcare, was the moderator.

PMID- 12602307
TI  - States target health care to solve fiscal crises.

PMID- 12602308
TI  - The doctor takes charge: healthcare prospects brighten under new Senate leader.

PMID- 12602309
TI  - Build quality by investing in technology. An interview with Alan L. Broude.

PMID- 12602310
TI  - Navigating payment pitfalls in managed care.
AB  - Healthcare providers need to identify and address payment problems relating to
      denied or underpaid claims. Before contract renegotiation, providers should
      identify the total dollar amount of claims that are denied or underpaid for each
      payer. Providers should choose managed care contract information systems that can
      grow with the hospital's managed care volume. Providers should identify all
      underpayment problems before negotiating a settlement with a payer.

PMID- 12602311
TI  - The business case for medication safety.
AB  - The decision to invest in a medication-safety system should take into account not
      only implementation costs but also reduced hospital costs for treating
      complications resulting from medication errors and potential liability.
      Medication-safety programs should be analyzed and planned the same as any other
      investment. Providers should base their projected return from a medication-safety
      system on intangible benefits to the organization as well as an ROI calculation.
      Investment in medication-safety systems can be justified in terms of risk
      management and legal liability.

PMID- 12602312
TI  - One CFO's success with transitioning to an automated patient record.

PMID- 12602313
TI  - Structuring a sound securitization of healthcare receivables.
AB  - Securitization of receivables allows healthcare providers to obtain an additional
      funding source by selling their accounts receivables to investors. A double-lock
      box structure allows providers to securitize Medicare and Medicaid receivables
      without violating federal laws. A 2001 revision to the Uniform Commercial Code
      facilitates providers' securitization of private healthcare insurance receivables
      by underscoring rights of a purchaser of those receivables. HIPAA privacy
      standards appear to permit the use and disclosure of protected health information
      in crafting a securitization program. The securitization should be structured to
      shield the value of the receivables to be transferred from the potential
      backruptcies of the originator and the purchaser.

PMID- 12602314
TI  - Clinical technology: are you getting your money's worth?
AB  - Providers investing in a clinical information technology (IT) system should
      consider their organization's specific needs and those of the surrounding
      community. Assessments of clinical IT value should take into account factors
      beyond cost savings. Providers should be aware of related tangible benefits, such
      as reductions in length of stay and enhanced administrative and clinical
      services. The capability of a clinical IT system to help prevent medical errors
      and improve operational efficiency should weight heavily during a provider's
      assessment of whether to invest in the system.

PMID- 12602315
TI  - CMS investigates outlier payments.
AB  - CMS is increasing its scrutiny of hospital billing practices in the wake of
      excessive claims for outlier payments by some healthcare organizations. Hospitals
      should review their billing practices to ensure that they are using a charge
      schedule that complies with Medicare regulations Hospitals also should conduct
      ongoing reviews of their outlier cases to ensure that their charge structures are
      appropriate and their outlier services are medically necessary. Hospitals can
      expect CMS to implement changes to the outlier regulations.

PMID- 12602316
TI  - Judicial review of CMS policies: an evolving doctrine.

PMID- 12602317
TI  - We teach "Irresponsibility 101." What do you teach?

PMID- 12602318
TI  - Taking an IT "go-live" approach to HIPAA readiness.

PMID- 12602319
TI  - A mentor is a key to career success.

PMID- 12602320
TI  - The treasurer as chief liquidity officer: an interview with Adventist Health
      System's Gary Skilton. Interview by Kevin T. Ponton.

PMID- 12602321
TI  - Data trends. U.S. hospital operating efficiency may be improving.

PMID- 12602322
TI  - 2002 Ernest A. Codman Awards presented.

PMID- 12602323
TI  - Existing requirements for telemedicine practitioners explained.

PMID- 12602324
TI  - Jayco to serve as key access point for health care organizations.

PMID- 12602325
TI  - 2003 JCAHO Surveyor Conference.

PMID- 12602326
TI  - Localisation of identical organophosphorus pesticide degrading (opd) genes on
      genetically dissimilar indigenous plasmids of soil bacteria: PCR amplification,
      cloning and sequencing of opd gene from Flavobacterium balustinum.
AB  - Plasmid borne organophosphorus pesticide degrading (opd) gene of Flavobacterium
      balustinum has been amplified using polymerase chain reaction (PCR) and the
      resulting PCR product (1.25 Kb) was cloned in pUC18. Further, a detailed
      restriction map was determined to PCR product and subcloned as overlapping
      restriction fragments. The nucleotide sequence was determined for all subclones
      to obtain complete sequence of PCR amplified fragment. The sequence showed 98%
      similarity to opd genes cloned from other soil bacteria isolated from diversified
      geographical regions. The protein sequence predicted from the nucleotide sequence
      was almost identical to parathion hydrolase, a triesterase involved in hydrolysis
      of triester bond found in variety of op-pesticides. The signal sequence of
      parathion hydrolase contained recently discovered twin arginine transport (tat)
      motif. It appears that tat motif plays a critical role in membrane targeting of
      parathion hydrolase.

PMID- 12602327
TI  - Leadership--creating meaningful vendor relationships.

PMID- 12602328
TI  - [Dyspnea after attempted suicide. Multiple peripheral pulmonary embolisms after
      intravenous injection of paraffin oil].

PMID- 12602329
TI  - [The safety and registration of pharmaceuticals from the point of view of the
      medical practitioner].

PMID- 12602330
TI  - [The secret of the gold sarcophagus from tomb no. 55 in the Valley of the kings].

PMID- 12602331
TI  - [Malignant lymphoma].

PMID- 12602332
TI  - Scheduling of controlled substances in Australia and New Zealand.

PMID- 12602334
TI  - Somatostatin receptor physiology and targets for somatostatin analogue therapy.
      Abstracts of the Young Investigator Meeting. 31 October-2 November 2002,
      Barcelona, Spain.

PMID- 12602333
TI  - [Squamous cell carcinoma of the larynx and hypopharynx--classification,
      investigation and therapy].

PMID- 12602335
TI  - Eleanor Hammerman: a grandmother with a mission.

PMID- 12602336
TI  - Abstracts of the 32nd Critical Care Congress. January 28-February 2, 2003. San
      Antonio, Texas, USA.

PMID- 12602338
TI  - Abstracts of the XIII European Meeting of the French Society of Cardiology. 15-18
      January 2003, Paris, France.

PMID- 12602337
TI  - Abstracts of the 2003 Annual Meeting of the American Society for Clinical
      Pharmacology and Therapeutics. Washington DC, USA, April 2-5, 2003.

PMID- 12602339
TI  - Laboration information systems continue to add features that contribute to
      maximizing personnel and cost containment.

PMID- 12602340
TI  - General adverse reaction to aspirin administered by transdermal iontophoresis.

PMID- 12602341
TI  - Effects of membranotropic agents on mono- and multilayer structures of
      dipalmitoylphosphatidylcholine.
AB  - We have studied the action of some membranotropic agents (MTAs) on the parameters
      of mono- and multilayers of dipalmitoylphosphatidylcholine (DPPC). The MTAs used
      included an antimicrobial drug, decamethoxinum, the model amphiphilic agent
      stearoyl-L-alpha-alanine, and cholesterol as a reference substance. Using
      differential scanning calorimetry and the Langmuir monolayer technique, we
      measured the temperature and enthalpy of the main phase transition of DPPC, the
      mean molecular area, the collapse pressure and the free energy of the mixed
      monolayers of DPPC and MTA. A good correlation has been obtained between the
      structure of the MTA used and changes in the parameters of both mono- and
      multilayers. Thus, for cholesterol, its well-known condensing effect in the L
      alpha phase correlates with its behavior in the mixed monolayers. The disturbing
      action of decamethoxinum (depression of the phase transition in DPPC multilayers
      and relatively high free energy of mixing in monolayers) is presumably connected
      with interaction of its charged ammonium moieties with polar phospholipid heads.
      At the same time, stearoyl-L-alpha- alpha-alanine condensed the lipid layers and
      increased the melting point of DPPC, owing to its interaction with both polar and
      non-polar lipid moieties. One can conclude that the three MTAs used can really be
      considered as representative examples of three different types of behavior in
      mono- and multilayers.

PMID- 12602342
TI  - Severe 5-fluorouracil toxicity associated with a marked alteration of
      pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil:
      a case report.
AB  - OBJECTIVE: To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and
      its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman
      affected by a severe 5-FU toxicity. METHODS: Toxicities were rated according to
      World Health Organization. 5-FU and 5-FDHU plasma concentrations and
      dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear
      cells (PBMC) were measured by HPLC analysis. RESULTS: After a single cycle of 5
      FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3
      vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU
      AUC, elimination half-life, and C(max) were markedly increased (24.75 vs. 9.25 +/
      0.63 h microg/ml, >5 vs. 0.36 +/- 0.05 h, and 58.54 vs. 37.2 +/- 4.03 microg/ml,
      respectively) whereas systemic clearance was decreased (12 vs. 51.29 +/- 2.97
      l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35 +/- 0.7 h microg/ml) and C(max) (3.4 vs.
      4.56 +/- 0.15 microg/ml), which was reached with delay, were reduced.
      Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary
      uracil (68.32 micromol/g urinary creatinine) were within normal range.
      CONCLUSIONS: Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a
      severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and
      suggest the necessity of a pharmacological evaluation of 5-FU treated patients.

PMID- 12602346
TI  - Abstracts of the 28th Annual Scientific Meeting SIR 2003. Salt Lake City, Utah,
      USA. March 27-April 1, 2003.

PMID- 12602347
TI  - Abstracts of the 13th Congress of the European Anthropological Association.
      August 30-September 3, 2002, Zagreb, Croatia.

PMID- 12602343
TI  - Membrane water-penetration profiles from spin labels.
AB  - Spin label hyperfine splittings in mixtures of protic and aprotic solvents are
      used to obtain association constants K(A,h) for hydrogen bonding to oxazolidine
      nitroxides. With the Onsager approach to account for the variation in local
      dielectric constant, these results are used to determine the effective
      penetration profile of water into fluid phospholipid membranes, from recent
      electron paramagnetic resonance (EPR) studies on phospholipids spin-labelled
      systematically down the sn-2 chain. Water penetration is appreciable, depends on
      chain unsaturation, and is strongly affected by cholesterol.

PMID- 12602349
TI  - Abstracts of the 6th International Conference of Nuclear Cardiology. April 27-30,
      2003, Florence, Italy.

PMID- 12602348
TI  - Generation of recombinant virus-like particles of human and non-human
      polyomaviruses in yeast Saccharomyces cerevisiae.
AB  - OBJECTIVES: Non-viral methods of gene transfer have been preferred in gene
      therapy approaches for several reasons, particularly for their safety, simplicity
      and convenience in introducing heterologous DNA into cells. Polyomavirus virus
      like particles (VLPs) represent a promising carrier for encapsidation of foreign
      nucleic acids for gene therapy. For the development of such gene delivery systems
      as well as for providing reagents for improving virus diagnostics, an efficient
      yeast expression system for the generation of different polyomavirus VLPs was
      established. METHODS: A galactose-inducible Saccharomyces cerevisiae yeast
      expression system was used. Formation of empty VLPs was confirmed by cesium
      chloride ultracentrifugation, agarose gel electrophoresis and electron
      microscopy. Cross-reactivity of the major capsid proteins (VP1) of different
      polyomaviruses was analyzed by Western blot using rabbit and mice sera raised
      against the VP1 proteins. RESULTS: VP1 of polyomaviruses from humans (JC
      polyomavirus and serotypes AS and SB of BK polyomavirus), rhesus monkeys (simian
      virus 40), hamsters (hamster polyomavirus), mice (murine polyomavirus) and birds
      (budgerigar fledgling disease virus) were expressed at high levels in yeast.
      Empty VLPs formed by all yeast-expressed VP1 proteins were dissociated into
      pentamers and reassociated into VLPs by defined ion and pH conditions. Different
      patterns of cross-reactivity of the VP1 proteins with heterologous mice and
      rabbit sera were observed. CONCLUSION: The developed heterologous yeast
      expression system is suitable for high-level production of polyomavirus VLPs.
      Yeast-derived VLPs are generally free of toxins, host cell DNA and proteins.
      These VLPs might be useful for the generation of new diagnostical tools, gene
      delivery systems and antiviral vaccines.

PMID- 12602350
TI  - Emerging viruses: the case 'hantavirus'.
AB  - This review briefly summarises the recent knowledge about hantavirus infections
      and raises particular problems in hantavirus research that need further
      investigation. The following questions are addressed: (i) are hantaviruses
      distributed worldwide and what leads to new outbreaks, (ii) what is known about
      hantavirus evolution, (iii) how can hantavirus species be defined, (iv) what are
      the determinants of hantavirus pathogenesis in humans, and (v) what problems are
      associated with the development of new vaccines and antiviral therapeutics.

PMID- 12602352
TI  - Characterization of expression of Puumala virus nucleocapsid protein in
      transgenic plants.
AB  - Transgenic plants expressing a foreign gene are a suitable system for the
      production of relevant immunogens in high amounts that can be used for the
      development of a new generation of vaccines against a variety of infectious
      diseases. In the present study, the expression of the nucleocapsid (N) protein of
      hantavirus serotype Puumala in tobacco and potato plants was investigated.
      Transgenic tobacco and potato plants were generated and established. These
      transgenic plants expressed the N protein of Puumala virus strain CG-1820. No
      major differences were observed when the phenotype and growth rates of transgenic
      plants were compared to those of normal plants. However, it was found that the
      leaves of transgenic tobacco plants were more slender and the tubers of
      transgenic potato plants were smaller than those in normal plants. In order to
      investigate the distribution of the expression of the foreign gene in transgenic
      plants, the proteins of leaves and roots of the individual transgenic tobacco and
      potato plants were examined by Western blot analyses. It was found that all
      transgenic tobacco and potato plants expressed the N protein in the leaves,
      whereas transgenic potato plants are able to significantly express the viral
      proteins also in the tubers and roots. The antigens were expressed at a level of
      1 ng of protein/5 microg of dried leaves. The hantaviral recombinant N proteins
      obtained from transgenic tobacco and potato plants were able to elicit specific
      humoral and mucosal immune responses when administered intraperitoneally or
      orally to rabbits and mice. The expression of viral proteins in plants has two
      major advantages compared to other expression systems: firstly, there is no risk
      of contamination with mammalian viruses or other pathogens, and secondly, the
      production of high amounts of antigens is cheap and therefore of great economic
      interest.

PMID- 12602351
TI  - Review of an inactivated vaccine against hantaviruses.
AB  - OBJECTIVE: Hantaviruses cause haemorrhagic fever with renal syndrome and result
      in severe morbidity and mortality in humans. Safe and effective vaccines are
      needed to reduce the incidence of human illness. In this study, the immune
      response to an inactivated hantavirus vaccine was measured in 64 human volunteers
      for Hantavax and 10 human volunteers for a Hantaan-Puumala virus combination
      vaccine at high risk of infection by virtue of their residence and occupation.
      METHODS: A serum sample was obtained from each volunteer before the initial
      vaccination (day 0), 30 days after each inoculation and 1 year after the initial
      dose. All sera were kept at -20 degrees until tested. IgG-specific antibody
      titres were tested by ELISA and immunofluorescence assay (IFA). Neutralizing
      antibody titres were determined by a plaque reduction neutralizing test. RESULTS:
      Thirty days after vaccination, 79 and 62% of the subjects had developed a
      significant hantavirus antibody titre as measured by IFA and ELISA, respectively.
      Seroconversion rates increased to 97% 1 month after the booster dose.
      Neutralizing antibody titres paralleled this trend, with 13% of vaccine
      recipients producing neutralizing antibody 1 month after the first dose and 75%
      of vaccine recipients responding 1 month after boosting. Antibody titres had
      declined by 1 year, however, with only 37 and 43% of sera found to be positive by
      IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous
      anamnestic response, with 94 and 100% of vaccine recipients yielding positive
      antibody titres. Only 50% of the sampled population, however, produced
      neutralizing antibodies following the booster dose 1 year later. CONCLUSIONS: The
      vaccine was well tolerated and there were no apparent differences in the
      responses in human subjects. However, further improvement of this vaccine is
      necessary in order to induce a longer-lasting humoral immune response.

PMID- 12602353
TI  - Abstracts of the 17th International Congress on Thrombosis. Bologna, Italy,
      October 26-30, 2002.

PMID- 12602354
TI  - Stop codon insertion restores the particle formation ability of hepatitis B virus
      core-hantavirus nucleocapsid protein fusions.
AB  - In recent years, epitopes of various origin have been inserted into the core
      protein of hepatitis B virus (HBc), allowing the formation of chimeric HBc
      particles. Although the C-terminus of a C-terminally truncated HBc (HBc)
      tolerates the insertion of extended foreign sequences, the insertion capacity is
      still a limiting factor for the construction of multivalent vaccines. Previously,
      we described a new system to generate HBc mosaic particles based on a read
      through mechanism in an Escherichia coli suppressor strain [J Gen Virol
      1997;78:2049-2053]. Those mosaic particles allowed the insertion of a 114-amino
      acid (aa)-long segment of a Puumala hantavirus (PUUV) nucleocapsid (N) protein.
      To study the value and the potential limitations of the mosaic approach in more
      detail, we investigated the assembly capacity of 'non-mosaic' HBc fusion proteins
      and the corresponding mosaic constructs carrying 94, 213 and 433 aa of the
      hantaviral N protein. Whereas the fusion proteins carrying 94, 114, 213 or 433 aa
      were not assembled into HBc particles, or only at a low yield, the insertion of a
      stop codon-bearing linker restored the ability to form particles with 94, 114 and
      213 foreign aa. The mosaic particles formed exhibited PUUV-N protein
      antigenicity. Immunization of BALB/c mice with these mosaic particles carrying
      PUUV-N protein aa 1-114, aa 1-213 and aa 340-433, respectively, induced HBc
      specific antibodies, whereas PUUV-N protein-specific antibodies were detected
      only in mice immunized with particles carrying N-terminal aa 1-114 or aa 1-213 of
      the N protein. Both the anti-HBc and anti-PUUV antibody responses were IgG1
      dominated. In conclusion, stop codon suppression allows the formation of mosaic
      core particles carrying large-sized and 'problematic', e.g. hydrophobic,
      hantavirus sequences.

PMID- 12602356
TI  - Abstracts of the 47th Annual Meeting of the Biophysical Society. March 1-5, 2003,
      San Antonio, Texas, USA.

PMID- 12602355
TI  - A malaria vaccine candidate based on a hepatitis B virus core platform.
AB  - OBJECTIVE: The recent success of a Plasmodium falciparum malaria vaccine
      consisting of circumsporozoite (CS) protein (CSP) T and B cell epitopes has
      rekindled interest in the development of a pre-erythrocytic vaccine. Our goal was
      to design an efficient delivery system for known neutralizing epitopes. METHODS:
      Well-characterized CSP-specific neutralizing B cell epitopes and a 'universal' T
      cell epitope were combined with a particulate carrier platform, the hepatitis B
      core antigen (HBcAg), to produce a novel pre-erythrocytic vaccine candidate.
      RESULTS: The vaccine candidate V12.PF3.1 is a potent immunogen in mice, eliciting
      unprecedented levels (greater than 106 titers) of sporozoite-binding antibodies
      after only two doses. The antisporozoite antibodies are long-lasting and
      represent all IgG isotypes, and antibody production is not genetically
      restricted. CSP-specific CD4+ T cells are also primed by V12.PF3.1 immunization
      in a majority of murine strains. Furthermore, the hybrid HBcAg-CS particles can
      be produced inexpensively in bacterial expression systems. CONCLUSION: These
      characteristics suggest that V12.PF3.1 represents an efficient and economical P.
      falciparum vaccine candidate for use separately or in combination with other
      formulations.

PMID- 12602357
TI  - Cowpea mosaic virus: from the presentation of antigenic peptides to the display
      of active biomaterials.
AB  - The potential of cowpea mosaic virus (CPMV), a plant icosahedral virus, for the
      presentation of foreign peptides and proteins is reported. The most prominent
      feature at the virus surface is a region of the smaller of the two coat proteins
      (S) which has been extensively used for the insertion of foreign peptides. Given
      the availability of the three-dimensional structure of the native virus and the
      amenability of foreign peptide-expressing CPMV chimeras to crystallisation,
      immunological data can be correlated with the conformational state of the foreign
      insert. The latter is influenced by proteolysis which occurs within the foreign
      inserts. In an effort to offer an alternative context for peptide expression,
      extensive exploration of a second region of the S protein is reported with
      respect to tolerance to small insertions. Moreover, to make CPMV suitable for a
      wider spectrum of presentation, a technique was developed to allow surface
      coupling of a peptide which can serve as the anchoring point for a range of
      proteins. This new approach is also widely applicable for the direct chemical
      cross-linking of peptides and full-length protein domains to the viral capsid.

PMID- 12602358
TI  - Abstracts of the University of the West Indies' First Faculty Research Day.
      January 23, 2003, Trinidad and Tobago.

PMID- 12602359
TI  - [First Brain Congress. Paris, France, 8-10 January 2003. Abstracts].

PMID- 12602360
TI  - Bibliography. Current world literature. Obstructive, occupational and
      environmental diseases.

PMID- 12602361
TI  - RNA bacteriophage capsid-mediated drug delivery and epitope presentation.
AB  - OBJECTIVE: To use our knowledge of the three-dimensional structure and self
      assembly mechanism of RNA bacteriophage capsids to develop novel virus-like
      particles (VLPs) for drug delivery and epitope presentation. METHODS: Site
      directed mutagenesis of a recombinant MS2 coat protein expression construct has
      been used to generate translational fusions encompassing short epitope sequences.
      These chimeric proteins still self-assemble in vivo into T = 3 shells with the
      foreign epitope in an accessible location. Covalent conjugation has also been
      used to generate RNA stem-loops attached to the toxin, ricin A chain, or to
      nucleotide-based drugs, that are still capable of stimulating self-assembly of
      the capsid in vitro. These packaged drugs can then be directed to specific cells
      in culture by further covalent decoration of the capsids with targeting
      molecules. RESULTS: Chimeric VLPs are strongly immunogenic when carrying either B
      or T cell epitopes, the latter generating cytokine profiles consistent with
      memory responses. Immune responses to the underlying phage epitopes appear to be
      proportional to the area of the phage surface accessible. Phage shells
      effectively protect nucleic acid-based drugs and, for the toxin construct, make
      cell-specific delivery systems with LD50 values in culture sub-nanomolar.
      CONCLUSION: VLP technology has potential for therapeutic and prophylactic
      intervention in disease.

PMID- 12602365
TI  - Pneumoperitoneum secondary to ruptured ovarian abscess.

PMID- 12602364
TI  - Bright leaves, dark leaves.

PMID- 12602366
TI  - Septic thrombophlebitis of the inferior mesenteric vein from sigmoid
      diverticulitis.

PMID- 12602367
TI  - International Academy of Astronautics 5th cosmic study--preparing for a 21st
      century program of integrated, Lunar and Martian exploration and development
      (executive summary).
AB  - This report is an initial review of plans for a extensive program to survey and
      develop the Moon and to explore the planet Mars during the 21st century. It
      presents current typical plans for separate, associated and fully integrated
      programs of Lunar and Martian research, exploration and development, and
      concludes that detailed integrated plans must be prepared and be subject to
      formal criticism. Before responsible politicians approve a new thrust into space
      they will demand attractive, defensible, and detailed proposals that explain the
      WHEN, HOW and WHY of each stage of an expanded program of 21st century space
      research, development and exploration. In particular, the claims of daring,
      innovative, but untried systems must be compared with the known performance of
      existing technologies. The time has come to supersede the present haphazard
      approach to strategic space studies with a formal international structure to plan
      for future advanced space missions under the aegis of the world's national space
      agencies, and supported by governments and the corporate sector.

PMID- 12602368
TI  - 2003 Renal care buyer's guide.

PMID- 12602369
TI  - Proceedings of the Rokuzo Kobayashi Memorial Symposium on Helicobacter Pylori.
      May 11, 2002, Tokyo, Japan.

PMID- 12602370
TI  - Proceedings of the 53rd International Symposium on Crop Protection. Gent,
      Belgium, May 8, 2001.

PMID- 12602371
TI  - Fondaparinux: new preparation. No better than LMWH in preventing pulmonary
      embolism.
AB  - (1) The reference treatment for preventing pulmonary embolism and vein thrombosis
      during surgery for hip fracture and hip or knee replacement is a low-molecular
      weight heparin (LMWH), administered subcutaneously. (2) Fondaparinux, a heparin
      derived anticoagulant, is also licensed for these indications, and administered
      subcutaneously. (3) Four trials versus enoxaparin, an LMWH, showed that
      fondaparinux is no more effective in terms of clinically relevant endpoints
      (mortality, pulmonary embolism, or symptomatic vein thrombosis). (4) The risk of
      haemorrhage is not substantially different from the risk seen with enoxaparin.
      (5) Other adverse effects are also similar. The same close monitoring is required
      for elderly patients, patients with renal failure, and patients with a low body
      weight. (6) An LMWH remains the reference prophylaxis during major orthopaedic
      surgery with high risk of pulmonary embolism.

PMID- 12602372
TI  - Verteporfin: new indication. New indication in complications of high myopia: no
      sustained benefit.
AB  - (1) High myopia can lead to subfoveal choroidal neovascularisation with a marked
      loss of central vision. There is no satisfactory treatment. (2) Marketing
      authorisation has been granted for verteporfin in this indication. Intravenous
      verteporfin injection is followed by cold red laser therapy, in one or several
      sessions. (3) In a multicentre comparative randomised double-blind trial
      involving 120 patients, verteporfin + cold red laser therapy stabilised visual
      acuity in 72% of patients after one year of follow-up, compared to 44% of
      patients who received a placebo + cold red laser therapy. This advantage was lost
      at two years of follow-up. (4) This trial revealed no new side effects of
      verteporfin. (5) In practice, for want of anything better, verteporfin-based
      photodynamic therapy may be helpful, but patients should be told of its
      limitations.

PMID- 12602373
TI  - Telithromycin: new preparation. A needless addition to the other macrolides.
AB  - (1) Macrolides are an alternative to beta-lactam agents for treating
      uncomplicated community-acquired pneumonia, acute exacerbations of chronic
      bronchitis, sinusitis and throat infections. The choice of macrolides is based
      mainly on the risk of interactions, which is lowest with spiramycin. (2)
      Telithromycin is a macrolide antibiotic derived from erythromycin. It was first
      marketed in France in 2002, for the above indications. (3) Telithromycin is no
      more effective than the antibiotics with which it has been compared, namely
      amoxicillin and clarithromycin in non life-threatening pneumonia; amoxicillin
      clavulanate and cefuroxime axetil in acute exacerbations of chronic bronchitis
      and acute sinusitis; and clarithromycin and phenoxymethylpenicillin (penicillin
      V) in pharyngotonsillitis. (4) In clinical trials, telithromycin was not more
      effective than comparator antibiotics on infections thought to be due to
      pneumococcal strains resistant to penicillin and/or erythromycin. Cases of
      erythromycin cross-resistance have been observed. (5) The adverse effects of
      telithromycin are the same as those of other macrolides, mainly gastrointestinal
      disturbances, headache, dizziness, and hepatotoxicity. Telithromycin also carries
      a risk of torsades de pointes, and seems to cause more visual problems than other
      macrolides. (6) Telithromycin inhibits cytochrome P450 isoenzymes, so there is a
      high risk of drug interactions. (7) In practice, spiramycin remains the standard
      option when a macrolide is indicated for the treatment of common ENT and
      pulmonary infections.

PMID- 12602374
TI  - Human protein C: new preparations. Effective replacement therapy for some
      clotting disorders.
AB  - (1) Depending on its severity, congenital protein C deficiency can cause a
      variety of problems, such as increasing the frequency of venous thrombosis in
      high risk situations; recurrent venous thrombosis; skin necrosis at the start of
      treatment with a vitamin K antagonist; and severe thrombotic events in neonates.
      For many years the only available replacement treatment consisted of fresh frozen
      plasma which, among other adverse effects, carries a risk of hypervolemia. (2)
      Two human protein C concentrates prepared from donated blood have been given
      marketing authorisation in Europe for intravenous replacement therapy (Ceprotin
      from Baxter, and Protexel from LFB). (3) Their clinical files contain only
      retrospective case series (22 children with severe deficiency treated with
      Ceprotin; and 10 patients of various ages and with different degrees of severity
      treated with Protexel). The two preparations have not been compared with each
      other. (4) In patients with severe protein C deficiency, including neonates,
      replacement therapy with human protein C is effective, especially for treating
      cutaneous thrombosis and preventing thrombosis in high risk situations. (5) In
      patients with moderate deficiency, a short-course of human protein C prophylaxis
      reduces the frequency of thrombosis in high risk situations. (6) In long-term
      prophylaxis, human protein C replacement therapy, added to ongoing (but
      inadequately effective) vitamin K antagonist therapy, seems to reduce the risk of
      recurrent venous thrombosis even though it has some constraints. (7) The adverse
      effects of the two preparations are poorly documented. Allergic reactions and
      bleeding have been reported. Human protein C is a blood product, and therefore
      carries a risk of infection. (8) Ceprotin offers a small advantage, being
      available in two dose strengths: for a given dose the volume injected is halved.
      (9) In practice, Ceprotin and Protexel are the reference drugs for replacement
      therapy of constitutional protein C deficiency, although their indications and
      adverse effects should be better documented.

PMID- 12602375
TI  - Darbepoetin alfa: new preparation. Just a me-too: no advantage in anaemia of
      chronic renal failure.
AB  - (1) Darbepoetin alfa, an epoetin, is slightly more glycosylated than epoetin alfa
      and beta. (2) The clinical file on anaemic patients with chronic kidney failure
      shows no advantage of darbepoetin alfa over other epoetins in terms of efficacy
      or side effects (subcutaneous injections of darbepoetin alfa are more often
      painful). (3) The dosing schedules of epoetins have not been compared adequately.
      Dosing schedules should be adapted for each patient.

PMID- 12602376
TI  - [Can the prognosis for diabetic arteriopathies be improved? XXXVI Congress of the
      French College of Vascular Pathology. 14 March 2002, Paris, France].

PMID- 12602377
TI  - Neurological disturbances with valaciclovir.

PMID- 12602378
TI  - Chest pain on verteporfin.

PMID- 12602379
TI  - Proceedings of the 6th International Conference on Equine Exercise Physiology. 22
      28 September 2002, Lexington, Kentucky, USA.

PMID- 12602380
TI  - Antidepressants and extrapyramidal effects.

PMID- 12602381
TI  - Perinatal exposure to antiretrovirals.

PMID- 12602382
TI  - Fluoride osteosis with niflumic acid.

PMID- 12602383
TI  - Proceedings from the International Gap Junction Meeting. Honolulu, Hawaii, August
      2001.

PMID- 12602384
TI  - Drug-related hyperprolactinemia.

PMID- 12602385
TI  - Severe colchicine-macrolide interactions.

PMID- 12602386
TI  - Opportunities and risks of xenogeneic thymus transplantation.

PMID- 12602387
TI  - Severe hyperkalaemia.

PMID- 12602388
TI  - Lithium overdose.

PMID- 12602389
TI  - Sideroblastic anaemia and fusidic acid.

PMID- 12602390
TI  - Hepatic adverse effects: another example of undernotification.

PMID- 12602391
TI  - Tendon abnormalities and hypersensitivity of levofloxacin.

PMID- 12602392
TI  - Colonic aphthoid lesions linked to Fleet phospho-soda.

PMID- 12602393
TI  - Do not combine several NSAIDs.

PMID- 12602394
TI  - Preimplantation renal biopsy: structure does predict function.

PMID- 12602395
TI  - Anaphylactic shock with percutalgine.

PMID- 12602396
TI  - Review of coxib adverse effects notified in France.

PMID- 12602397
TI  - Muscular adverse effects of statins.

PMID- 12602398
TI  - Vasoconstrictor: neurological and cardiovascular adverse effects.

PMID- 12602399
TI  - Fatigue damage, remodeling, and the minimization of skeletal weight.
AB  - The skeleton has provided many advantages during the course of vertebrate
      evolution, but it has also contained limitations that have strongly influenced
      bone biology. These limitations have included weight and the potential for
      fatigue failure. Calcified bone tissue is approximately twice as heavy as other
      tissues, so it is important to minimize the size of the skeleton, but this
      implies increasing bone stresses and strains and the potential for fatigue
      fracture. This paper first explores the role of fatigue damage removal by
      remodeling in extending a long bone's fatigue life to match the animal's
      lifetime. Next, an estimate is obtained for the amount that the cross-sectional
      area of a bone would have to be increased in lieu of remodeling to achieve the
      same extension of fatigue life, provided that the associated muscle mass remained
      constant. The result illustrates how remodeling can provide a gracile bone the
      same fatigue life as a substantially more robust bone lacking remodeling.
      Finally, it is shown that if muscle mass increases in linear proportion to bone
      mass, as experimental data suggest, extending a bone's fatigue life by increasing
      its cross-sectional dimensions may not be effective because the inertia of bigger
      bones would result in larger muscles and increased skeletal loads. Thus, bone
      remodeling to remove fatigue damage may be essential for the existence of
      relatively large, long-lived vertebrates.

PMID- 12602400
TI  - Pregnancy exposed to high-dose buprenorphine.

PMID- 12602401
TI  - Drug-induced myopia.
AB  - (1) Acute myopia can be drug-induced. (2) Cholinergic drugs cause accommodative
      spasm responsible for myopia. (3) Many other drugs, such as sulphonamides, and
      diuretics, can cause myopia without accommodative spasm. (4) Early withdrawal of
      the responsible drug leads to rapid recovery.

PMID- 12602402
TI  - Pulmonary adverse effects of nitrofurantoin.

PMID- 12602403
TI  - Treatment of imported uncomplicated malaria: a medical emergency.
AB  - (1) Check for severe malaria (coma, shock, pulmonary oedema), and take account of
      drug resistance in the region. (2) Mefloquine and quinine are first-line options
      for uncomplicated P. falciparum malaria. The atovaquone + proguanil combination
      can be used in patients at high risk of side effects with mefloquine

PMID- 12602404
TI  - Managing trauma and stress caused by terrorism.

PMID- 12602405
TI  - Fluoroquinolones in ambulatory ENT and respiratory tract infections: rarely
      appropriate.
AB  - (1) The risk-benefit ratio of antibiotic therapy in exacerbations of chronic
      bronchitis is uncertain. If an antibiotic is considered, fluoroquinolones are at
      best second-line options, after betalactam agents such as amoxicillin, and
      macrolides. (2) For community-acquired pneumonia the first-line antibiotics are
      betalactam agents such as amoxicillin, and macrolides. Patients with severe
      disease should receive combination therapy with a betalactam and a macrolide or a
      fluoroquinolone. (3) Acute sinusitis generally resolves spontaneously. If an
      antibiotic is prescribed, fluoroquinolones are at best second-line options, after
      betalactam agents such as amoxicillin, and macrolides. The value of systemic
      antibiotic therapy is also controversial in chronic sinusitis and chronic otitis
      media; once again, fluoroquinolones are not agents of first choice. (4)
      Fluoroquinolones share many adverse effects, especially neuropsychiatric,
      cutaneous, tendon, and cardiac involvement. They can also damage cartilage in
      children. They are contraindicated in pregnant women. They potentiate oral
      anticoagulants.

PMID- 12602406
TI  - Treatment of type 2 diabetes: inadequate assessment of oral antidiabetic
      combinations.
AB  - (1) Metformin and glibenclamide are the only oral antidiabetics with a proven
      impact on the complications of type 2 diabetes. (2) Treatment with one of these
      drugs often fails to achieve the recommended target in HbA1c level (below 7%).
      (3) Only one randomised trial has assessed the preventive efficacy of a
      combination of oral antidiabetics when hyperglycaemia persists despite treatment
      with a glucose-lowering sulphonylurea. The trial showed that combining metformin
      and a glucose-lowering sulphonylurea is associated with a higher mortality than
      therapy with a sulphonylurea alone. (4) Despite this result, most clinical
      guidelines recommend the metformin + glucose-lowering sulphonylurea combination
      when oral antidiabetic monotherapy fails. (5) In the absence of convincing data
      supporting any particular strategy, all options should be discussed with patients
      including continuing with oral antidiabetic monotherapy, or starting insulin.

PMID- 12602407
TI  - An introduction to special jurisdiction courts.

PMID- 12602408
TI  - Why study kidney transplant risk factors?

PMID- 12602409
TI  - Changes made to policy, standards for disease-specific care certification.

PMID- 12602410
TI  - Hospitals can accept primary source verification from designated agencies.

PMID- 12602411
TI  - Marriage made in heaven or hell?

PMID- 12602412
TI  - Long-term ventilation in restrictive ventilatory disorders.
AB  - Long-term ventilation (LTV) had its beginning with restrictive ventilatory
      disorders. Today, LTV is predominately represented by noninvasive ventilation
      (NIV). Invasive ventilation was used for a long time but is now usually
      restricted for selected patients in which NIV fails.

PMID- 12602413
TI  - Long-term ventilation in obstructive ventilatory disorders.
AB  - A large randomized, controlled study of NIV plus LTOT versus LTOT in patients
      with COPD is needed that evaluates morbidity, mortality, quality of life, and
      health economic impact. It is to be hoped that funding for this type of study
      will be forthcoming. In the meantime, it reasonably can be concluded from
      existing evidence that domiciliary NIV is unlikely to be effective in most
      patients with stable COPD, particularly if they are normocapnic. A subgroup of
      patients with severe hypercapnia, poor tolerance of LTOT, marked nocturnal
      hypoventilation, or recurrent infective exacerbations may benefit from
      domiciliary NIV. Systematic evaluation is required in patients with CF or
      bronchiectasis.

PMID- 12602414
TI  - Long-term negative pressure ventilation.
AB  - Noninvasive mechanical ventilatory techniques include the use of negative and
      positive pressure ventilators. Negative pressure ventilators support ventilation
      by exposing the surface of the chest wall to subatmospheric pressure during
      inspiration, whereas expiration occurs when the pressure around the chest wall
      increases and becomes equal to or greater than atmospheric pressure. In this
      article, a description of negative pressure ventilators and the physiologic
      effects of negative pressure ventilation (NPV) is given, and the application of
      this technique in the long-term treatment of chronic respiratory failure is
      summarized. Many studies, although uncontrolled, have shown that long-term
      treatment with NPV can improve respiratory muscle function, arterial blood gases,
      and survival in patients with neuromuscular and chest wall disorders. NPV
      devices, however, are more cumbersome and difficult to use than home positive
      pressure ventilators (PPVs) and tend to predispose to obstructive apnoeas during
      sleep. In the last several decades, NPV has been supplanted by mask PPV. In
      experienced hands, NPV remains a second viable option in patients with
      neuromuscular and chest wall disorders who, for technical or other reasons,
      cannot be offered mask PPV. There is no evidence, however, that long-term
      treatment with NPV can improve respiratory muscle function, exercise endurance,
      quality of life, and survival in patients with severe chronic obstructive
      pulmonary disease.

PMID- 12602415
TI  - Outcome of long-term noninvasive positive-pressure ventilation.
AB  - The introduction of NPPV has been one of the most important advances in the
      management of patients at home with chronic respiratory failure. The benefit
      obtained from the therapy depends, however, on the underlying cause of the
      respiratory failure. Patients with chest wall disease and postpolimyelitis show
      the best improvements in survival and quality of life. But even in patients with
      Duchenne muscular dystrophy, useful benefits for survival and quality of life are
      obtained. The longer-term effects of NPPV in hypercapnic COPD are not so clear,
      and further large, well-designed controlled studies are required to evaluate the
      effects of NPPV not only on survival, but also on quality of life and disease
      exacerbation. If the initial experience with NPPV in COPD is confirmed in larger
      trials, then this important therapy will be available to an even larger group of
      patients worldwide.

PMID- 12602416
TI  - Care of the patient requiring invasive mechanical ventilation.
AB  - Patients who require prolonged invasive mechanical ventilation pose a unique set
      of circumstances to the pulmonary and critical care practitioner. This requires a
      delineation of the primary cause for respiratory failure, and, in most cases, a
      comprehensive multidisciplinary approach to the treatment of not only the primary
      disturbance causing respiratory failure, but the consequences that immobility,
      illness, and prolonged ventilation have on swallowing and ambulatory function,
      psychosocial interaction, and the ability to wean from mechanical ventilation.
      The development of multidisciplinary rehabilitative units for patients requiring
      prolonged mechanical ventilation have showed not only a reduction in hospital
      costs and lengths of stay, but also an improvement in patient survival,
      functional status, reduction in ventilator days or need for mechanical
      ventilation at discharge, and, overall, the achievement of a satisfactory quality
      of life.

PMID- 12602417
TI  - Whole-body rehabilitation in long-term ventilation.
AB  - Advances in critical care and mechanical ventilation have improved long-term
      survival of critically ill patients, some of whom develop the need for prolonged
      mechanical ventilator assistance. The rehabilitation of these individuals is
      aimed at restoring function, facilitating independence from mechanical
      ventilation, and in some cases returning them to the community. To accomplish
      these goals, rehabilitation programs require a multidisciplinary approach that
      includes physicians, respiratory therapists, nurses, physical and occupational
      therapists, nutrionists, speech therapists, and social services workers in a
      concerted effort. Chronic mechanical ventilation patients are often complicated
      by multiple comorbidities and by complex physiologic and psychological
      interactions. A careful selection and an individualized assessment are therefore
      paramount in identifying and achieving long-term goals. Special attention has to
      be paid to aggressive respiratory and nonrespiratory muscle rehabilitation, early
      ambulation, nutritional repletion, and psychological support. Careful evaluation
      and treatment by members of a multidisciplinary team may foster the patients'
      independence and ability to tolerate spontaneous ventilation, ultimately
      resulting in an improvement in their quality of life.

PMID- 12602418
TI  - Sleep and long-term ventilation.
AB  - The development of sleep-disordered breathing is common in patients with chronic
      respiratory insufficiency due to neuromuscular and restrictive disorders, as well
      as in those with COPD. Nocturnal hypoventilation and obstructive and central
      apneas result in daytime symptoms of hypersomnolence and fatigue, and contribute
      to abnormalities in awake gas exchange. Long-term mechanical ventilation,
      delivered invasively by tracheostomy or more recently by NPPV, has been shown to
      eliminate sleep-disordered breathing and correct abnormalities in nocturnal gas
      exchange, resulting in an improvement in sleep quality. Improved daytime symptoms
      and gas exchange, with the suggestion of a decrease in morbidity and mortality,
      support the use of long-term mechanical ventilation during sleep in selected
      patients with these disorders.

PMID- 12602419
TI  - Complications of long-term mechanical ventilation.
AB  - Complications of LTMV should be considered in the context of underlying diseases
      and comorbidities, the trigger for ventilator dependency, and site of care. These
      factors have an impact on outcome and on the type and severity of complications.
      In view of the complexity of chronically ill VAIs, complications of mechanical
      ventilation become the major impediment in achieving the ultimate goal of LTMV,
      extending life, and improving psychophysiologic function and quality of life.
      Efforts should not be spared to prevent and aggressively treat these
      complications while continuing plans to wean and rehabilitate the patient.

PMID- 12602420
TI  - Preventing adolescent depression: an evaluation of the problem solving for life
      program.
AB  - This study evaluated the effectiveness of the Problem Solving For Life program as
      a universal approach to the prevention of adolescent depression. Short-term
      results indicated that participants with initially elevated depressions scores
      (high risk) who received the intervention showed a significantly greater decrease
      in depressive symptoms and increase in life problem-solving scores from pre- to
      postintervention compared with a high-risk control group. Low-risk participants
      who received the intervention reported a small but significant decrease in
      depression scores over the intervention period, whereas the low-risk controls
      reported an increase in depression scores. The low-risk group reported a
      significantly greater increase in problem-solving scores over the intervention
      period compared with low-risk controls. These results were not maintained,
      however, at 12-month follow-up.

PMID- 12602421
TI  - Early sudden gains in psychotherapy under routine clinic conditions: practice
      based evidence.
AB  - Sudden gains--large, enduring reductions in symptom intensity from one session to
      the next--were identified by T. Z. Tang and R. J. DeRubeis (1999b) on the basis
      of data from 2 manualized clinical trials of cognitive therapy for depression.
      The authors found similar sudden gains among clients with a variety of disorders
      treated with a variety of approaches in routine clinic settings. Clients (N = 135
      who met inclusion criteria) completed short forms of the Clinical Outcomes in
      Routine Evaluation (CORE-SF) preceding 7 to 74 individual sessions. Those who
      experienced sudden gains within their first 16 sessions (n = 23) had
      significantly lower CORE-SF scores in their final 3 sessions than did the other
      clients.

PMID- 12602422
TI  - Cognitive-behavioral factors in seasonal affective disorder.
AB  - To longitudinally examine cognitive-behavioral correlates of seasonal affective
      disorder (SAD), the authors assessed women with a history of SAD and
      nondepressed, matched controls across fall, winter, and summer. SAD history
      participants reported more automatic negative thoughts throughout the year than
      controls and demonstrated a progression from decreased activity enjoyment during
      fall to reduced activity frequency during winter. Ruminative response style,
      measured in fall, predicted symptom severity during the winter. Across
      assessments, SAD history women endorsed greater depressive affect in response to
      low light intensity stimuli than to bright or ambiguous intensity stimuli, but
      less depressed mood to bright light stimuli than controls. These results suggest
      that the cognitive-behavioral factors related to nonseasonal depression may play
      a role in SAD.

PMID- 12602423
TI  - Treatment of generalized anxiety disorder in older adults.
AB  - Older adults with generalized anxiety disorder (GAD; N = 75; M age = 67.1 years)
      were randomly assigned to cognitive-behavioral therapy (CBT), a discussion group
      (DG) organized around worry-provoking topics, or a waiting period. Participants
      in both active conditions improved relative to the waiting list. Although CBT
      participants improved on more measures than DG participants, the authors found
      only I significant difference immediately after treatment and no differences at 6
      month follow-up. Effect sizes were smaller than in younger samples, but CBT
      showed large effects and DG showed medium-sized effects Overall, results indicate
      that brief treatment of late-life GAD is beneficial, but they provide only
      limited support for the superiority of CBT to a credible comparison intervention.

PMID- 12602424
TI  - The occurrence of partner physical aggression on days of alcohol consumption: a
      longitudinal diary study.
AB  - The likelihood of partner physical aggression on days of male partners' alcohol
      consumption, during a 5-month period, was examined for men entering a domestic
      violence treatment program (n = 137) and domestically violent men entering an
      alcoholism treatment program (n = 135). For men entering the domestic violence
      treatment program (alcoholism treatment program odds in parentheses), the odds of
      any male-to-female physical aggression were more than 8 times (11 times) higher
      on days when men drank than on days of no alcohol consumption. The odds of severe
      male-to-female physical aggression were more than 11 times (11 times) higher on
      days of men's drinking than on days of no drinking. These findings support the
      proximal effect model of alcohol use and partner violence.

PMID- 12602426
TI  - Child, parent, and therapist (dis)agreement on target problems in outpatient
      therapy: the therapist's dilemma and its implications.
AB  - A minimal requirement for success in child psychotherapy is arguably that child,
      parent, and therapist agree about which problems to address. How often is this
      the case? Following clinic intake, the authors asked 315 children, parents, and
      therapists, separately, to identify target problems. More than 3/4 of child
      parent-therapist triads began treatment without consensus on a single problem;
      nearly half failed to agree on even I broad problem domain (e.g., aggression vs.
      anxiety/depression). Therapists agreed more with parents than children for most
      child problems, but for family and environmental problems the reverse was true.
      Findings highlight the therapist's dilemma in identifying treatment foci when
      clients disagree and may help explain the poor effects of clinic-based therapy
      reported in previous research.

PMID- 12602427
TI  - Normative data on cognitive measures of depression.
AB  - The assessment of cognition and cognitive change is important for case
      conceptualization, monitoring the efficacy of specific interventions, and
      evaluating treatment outcome in cognitive-behavioral therapy. Unfortunately, a
      paucity of normative data exists on cognitive measures used for psychotherapy
      outcome research in depression, and little information is available to guide a
      practitioner's understanding of the magnitude and clinical significance of a
      patient's cognitive change. This article presents normative data on 6 self-report
      instruments that assess negative and positive automatic thoughts, hopelessness,
      cognitive biases and errors, and dysfunctional attitudes. Normative data were
      derived from studies published from the date of inception of a given cognitive
      index to the year 2000. Recommendations for the use of these normative data are
      provided.

PMID- 12602425
TI  - Prevalence of mental disorders, psychological distress, and mental health
      services use among lesbian, gay, and bisexual adults in the United States.
AB  - Recent estimates of mental health morbidity among adults reporting same-gender
      sexual partners suggest that lesbians, gay men, and bisexual individuals may
      experience excess risk for some mental disorders as compared with heterosexual
      individuals. However, sexual orientation has not been measured directly. Using
      data from a nationally representative survey of 2,917 midlife adults, the authors
      examined possible sexual orientation-related differences in morbidity, distress,
      and mental health services use. Results indicate that gay-bisexual men evidenced
      higher prevalence of depression, panic attacks, and psychological distress than
      heterosexual men. Lesbian-bisexual women showed greater prevalence of generalized
      anxiety disorder than heterosexual women. Services use was more frequent among
      those of minority sexual orientation. Findings support the existence of sexual
      orientation differences in patterns of morbidity and treatment use.

PMID- 12602428
TI  - Do changes in cognitive factors influence outcome following multidisciplinary
      treatment for chronic pain? A cross-lagged panel analysis.
AB  - Changes in maladaptive cognitions may constitute therapeutic processes of
      multidisciplinary pain programs. A cross-lagged panel design was used to
      determine whether (a) early-treatment cognitive change predicted late-treatment
      outcome index change, but not vice versa; and (b) these effects remained
      significant with depression change controlled. Ninety chronic pain patients, in a
      4-week multidisciplinary program, completed measures of catastrophizing, pain
      helplessness, depression, pain, interference, and activity level at pre-, mid-,
      and posttreatment. With depression changes controlled, early-treatment
      catastrophizing and pain helplessness changes predicted late-treatment outcome
      index changes, but not vice versa; early-treatment depression changes predicted
      late-treatment activity changes, but not vice versa. Findings advance
      understanding of pain treatment process and suggest that negative cognition
      changes may indeed affect improvements in treatment outcome.

PMID- 12602429
TI  - Partner violence before and after individually based alcoholism treatment for
      male alcoholic patients.
AB  - This study examined partner violence in the year before and the year after
      individually based, outpatient alcoholism treatment for 301 married or cohabiting
      male alcoholic patients and used a demographically matched nonalcoholic
      comparison sample. In the year before treatment, 56% of the alcoholic patients
      had been violent toward their female partner, 4 times the rate of 14% in the
      comparison sample. In the year after treatment, violence decreased significantly
      to 25% of the alcoholic sample but remained higher than in the comparison group.
      Among remitted alcoholics after treatment, violence prevalence of 15% was nearly
      identical to the comparison sample and half the rate among relapsed patients
      (32%). Thus, partner violence decreased after alcoholism treatment, and
      clinically significant violence reductions occurred for patients whose alcoholism
      was remitted after treatment.

PMID- 12602430
TI  - Understanding persistence in bulimia nervosa: a 5-year naturalistic study.
AB  - Bulimia nervosa shows a marked tendency to persist, suggesting that powerful
      maintaining mechanisms operate. Using data from a prospective, 5-year, study of
      the natural course of 102 people with bulimia nervosa, the authors sought to
      identify predictors of persistence and to test specific hypotheses derived from
      the cognitive-behavioral theory of the persistence of bulimia nervosa. The
      results of both sets of analyses were consistent with the theory, with the degree
      of overevaluation of shape and weight and a history of childhood obesity
      predicting a persistent course. There was also support for the central prediction
      of the cognitive-behavioral theory. These findings suggest that the mechanisms
      specified by the theory influence its longer term natural course.

PMID- 12602431
TI  - Continuing bonds and adjustment at 5 years after the death of a spouse.
AB  - Thirty-nine bereaved individuals completed the Continuing Bonds Scale (CBS),
      assessing various aspects of the ongoing attachment to the deceased, at 60 months
      postloss in a longitudinal conjugal bereavement study. They also completed
      symptom measures at 6, 14, 25, and 60 months postloss. Higher CBS scores were
      associated with a more elevated grief-specific symptom pattern over the 5-year
      postloss period. Moreover, those who expressed greater helplessness and less
      blame toward the deceased during a monologue role-play involving their deceased
      spouse at 6 months postloss had higher CBS scores. Finally, greater satisfaction
      in the past relationship with the spouse was predictive of higher CBS scores. The
      results were discussed in relation to existing literature on the adaptiveness of
      continuing bonds.

PMID- 12602432
TI  - Coping skills and treatment outcomes in cognitive-behavioral and interactional
      group therapy for alcoholism.
AB  - In the present study 128 alcohol dependent men and women received 26 weeks of
      group treatment in one of two modalities: Cognitive-behavioral treatment (CBT)
      intended specifically to develop coping skills or interactional therapy intended
      to examine interpersonal relationships. Coping skills and drinking were assessed
      prior to and after treatment and up to 18 months after intake. Results indicated
      that both treatments yielded very good drinking outcomes throughout the follow-up
      period. Increased coping skills was a significant predictor of outcome. However,
      neither treatment effected greater increases in coping than the other. Specific
      coping-skills training was not essential for increasing the use of coping skills.
      The results raise questions about the efficacy of specific treatment elements of
      CBT in treatment of alcohol dependence.

PMID- 12602433
TI  - Prospective relations of body image, eating, and affective disturbances to
      smoking onset in adolescent girls: how Virginia slims.
AB  - This study tested whether body image, eating, and affective disturbances
      prospectively predicted onset of cigarette smoking in adolescent girls (N = 496).
      Elevated body dissatisfaction and eating pathology, as well as elevated negative
      affectivity, showed significant univariate relations to subsequent onset of
      smoking. In the multivariate model, the effect for body image and eating
      disturbances remained significant, but the effect for negative affectivity did
      not. Results support the theory that body image and eating disturbances markedly
      increase risk for smoking initiation in adolescent girls and further establish
      the clinical significance of these disturbances. Results also support the theory
      that negative affect is a risk factor for smoking initiation but suggest that the
      self-medication model may have less predictive power than previously concluded.

PMID- 12602434
TI  - The effects of school-based intervention programs on aggressive behavior: a meta
      analysis.
AB  - Research on the effectiveness of school-based programs for preventing or reducing
      aggressive behavior was synthesized with a meta-analysis. Changes in aggressive
      behavior between pretest and posttest were analyzed for developmental patterns
      and characteristics associated with differential effects. Control groups showed
      little change in aggressive behavior, but there were significant reductions among
      intervention groups. Most studies were conducted on demonstration programs; the
      few studies of routine practice programs showed much smaller effects. Among
      demonstration programs, positive outcomes were associated with a variety of
      study, subject, and intervention characteristics. Most notably, higher risk youth
      showed greater reductions in aggressive behavior, poorly implemented programs
      produced smaller effects, and different types of programs were generally similar
      in their effectiveness, other things equal.

PMID- 12602435
TI  - Are all cognitive therapies alike? A comparison of cognitive and noncognitive
      therapy process and implications for the application of empirically supported
      treatments.
AB  - The definition of an empirically supported treatment (EST) arguably embodies 2
      untested assumptions: (a) that different manualized renditions of the same
      therapy are functionally equivalent and (b) that therapies can be reliably
      applied independently of therapist, setting, and format. These assumptions were
      tested as applied to cognitive therapy (CT), using process data from a large
      multisite study (N = 235) that included 3 cognitive and 6 alternative therapies.
      Although the non-CTs were more variable than the CTs on 2 of 4 dimensions studied
      (directiveness and emotional arousal), there was considerable variation among the
      3 CTs, even when implemented in the current context of rigorous training,
      manualization, and adherence checks. Results are discussed as related to the
      assumptions underlying EST criteria.

PMID- 12602437
TI  - Does parental ADHD bias maternal reports of ADHD symptoms in children?
AB  - Within families, co-occurring attention-deficit/hyperactivity disorder (ADHD) in
      parents and children may be common. The authors evaluated the hypothesis that
      parental ADHD may lead to a reporting bias of ADHD symptoms in offspring. They
      combined 2 family case-controlled studies of ADHD using structured interviews.
      They compared rates of maternal reported ADHD symptoms among 3 groups of ADHD
      children: no parental ADHD (n = 231), mother with ADHD (n = 63), and father with
      ADHD (n = 57). With the exception of 1 symptom, the rates of reporting between
      groups did not differ. There was no evidence that the discrepancy between
      maternal reports and self-reports of symptoms differed by parental ADHD. Results
      were similar across child gender or referral status. These results do not support
      the notion that parental ADHD affects maternal reports of offspring ADHD.

PMID- 12602436
TI  - Individual and familial influences on the onset of sexual intercourse among urban
      African American adolescents.
AB  - A sample of 198 African American families, living in urban poverty, participated
      in a longitudinal study of adolescent sexual development beginning when children
      were in the 4th or 5th grade. Self-reports of family conflict and pubertal
      development and videotaped family interaction data were collected at 2 time
      points approximately 2 years apart. Youths reported on sexual debut at each time
      point. More boys than girls reached sexual debut early. Greater levels of family
      conflict predicted early sexual debut. Observational data indicated more
      developed preadolescents with greater family conflict and less positive affect
      were least likely to delay debut. Changes in pubertal development and observed
      family conflict were associated with early debut. Possible mediating mechanisms
      and implications for preventive interventions are discussed.

PMID- 12602438
TI  - Love, marriage, and divorce: newlyweds' stress hormones foreshadow relationship
      changes.
AB  - Neuroendocrine function, assessed in 90 couples during their first year of
      marriage (Time 1), was related to marital dissolution and satisfaction 10 years
      later. Compared to those who remained married, epinephrine levels of divorced
      couples were 34% higher during a Time 1 conflict discussion, 22% higher
      throughout the day, and both epinephrine and norepinephrine were 16% higher at
      night. Among couples who were still married, Time 1 conflict ACTH levels were
      twice as high among women whose marriages were troubled 10 years later than among
      women whose marriages were untroubled. Couples whose marriages were troubled at
      follow-up produced 34% more norepinephrine during conflict, 24% more
      norepinephrine during the daytime, and 17% more during nighttime hours at Time 1
      than the untroubled.

PMID- 12602440
TI  - Review of studies on flight attendant health and comfort in airliner cabins.
AB  - BACKGROUND: A number of studies have examined the effect of the airliner cabin
      environment and other factors on the health and comfort of flight attendants
      (FAs), but no comprehensive review of such studies is available. METHODS: This
      paper reviews studies conducted after 1980 that addressed FA short-term health
      and comfort effects. Relevant literature was identified using the National
      Institute of Health's PUBMED database. RESULTS: Twenty-one studies were
      identified and classified into two types: in-flight surveys and surveys of
      general flight experiences. Most studies used questionnaires to obtain
      perceptions of the cabin environment, comfort, and health-related symptoms, but
      some included objective measurements. Only a few studies used a random sample or
      control groups. Effects of confounding variables generally have not been
      analyzed. DISCUSSION: Most studies shared some weaknesses such as poor response
      rate, significant response bias, exclusive reliance on questionnaires, or limited
      analysis. Taken together, the studies indicate that various complaints and
      symptoms reported by FAs appear to be associated with their job duties and with
      the cabin environment. Most notable are "dryness" symptoms attributable to low
      humidity and "fatigue" symptoms associated with factors such as disruption of
      circadian rhythm. Practically all symptoms are exacerbated by longer flight
      durations. Studies citing problems of "poor aircraft cabin air quality" tend to
      be weak in design and have addressed only general flight experiences of FAs.
      Although certain FA complaints are consistent with possible exposure to air
      pollutants, the relationship has not been proven and such complaints also are
      consistent with causes other than poor air quality.

PMID- 12602439
TI  - Efficacy of cognitive-behavioral therapy for insomnia in women treated for
      nonmetastatic breast cancer.
AB  - This study investigated the efficacy of a multimodal cognitive-behavioral
      intervention for women who had been treated for nonmetastatic breast cancer. Ten
      participants were enrolled in the treatment protocol in a multiple-baseline
      design. Intervention time series analyses of daily sleep diary data revealed
      significant improvements of sleep efficiency and total wake time. These results
      were corroborated by polysomnographic data. In addition, insomnia treatment was
      associated with significant improvements of mood, general and physical fatigue,
      and global and cognitive dimensions of quality of life. These findings suggest
      that cognitive-behavioral therapy, previously found effective for primary
      insomnia, is also of clinical benefit for insomnia secondary to cancer.

PMID- 12602441
TI  - Effects of hypergravity on ovarian-hypophyseal function in antepartum and
      postpartum rats.
AB  - BACKGROUND: Rats exposed to microgravity during the post-implantation phase of
      pregnancy had minimal alterations in ovarian and hypophyseal parameters during
      the antepartum and postpartum periods. In the current study, a similar parallel
      experimental design was employed to ascertain the effects of hypergravity on
      ovarian and hypophyseal function. HYPOTHESIS: We hypothesized that hypergravity
      exposure during the post-implantation stage of pregnancy would not alter
      antepartum and postpartum ovarian and hypophyseal function. METHODS: Pregnant
      rats were assigned to hypergravity (1.5 G, 1.75 G, or 2.0 G), rotational control,
      or stationary control groups (n = 10 each group) beginning on gestation day 11
      and ending on day 20. Hypophyseal and ovarian analyses were conducted on 5 of the
      animals from each group at day 20. The remaining animals in each group were
      allowed to go to term and the same analyses were conducted 3 h postpartum.
      RESULTS: Hypergravity at all levels decreased the percent body mass gain from
      gestation day 11 to 20 (p < 0.05); however, the wet weight of the pituitaries and
      ovaries was not changed. There was no effect of hypergravity on the number of
      healthy or atretic antral follicles of any size at gestation day 20 or
      postpartum. The number of corpora lutea of pregnancy was decreased in all
      hypergravity groups, but the number of live fetuses at gestation day 20 or pups
      at term was not altered. Plasma concentrations of luteinizing hormone (LH),
      follicle stimulating hormone (FSH), prolactin, and progesterone were not changed
      at gestation day 20 or postpartum. Pituitary content of LH, FSH, and prolactin
      was not altered by hypergravity at gestation day 20, but LH content was
      significantly increased (p < 0.05) at 1.5 and 1.75 G postpartum. CONCLUSIONS: We
      conclude that hypergravity, up to and including 2.0 G, is compatible with
      maintenance of pregnancy and has minimal effects on hypophyseal parameters.
      Ovarian follicles are not altered by hypergravity, but corpora lutea may regress
      at a more rapid rate.

PMID- 12602442
TI  - Long-term effects of low-dose proton radiation on immunity in mice: shielded vs.
      unshielded.
AB  - BACKGROUND: Outside the protection of the terrestrial environment, astronauts on
      any long-term missions will unavoidably be exposed to fields of charged particle
      radiation dominated by protons. These fields and their biological risks are
      modified in complex ways by the presence of protective shielding. METHODS: To
      examine the long-term effects of space-like proton exposures on immune status, we
      treated female C57BL/6 mice with 3 or 4 Gy of 250 MeV monoenergetic protons or
      the complex space-like radiation field produced after 250 MeV protons are
      transported through 15 g x cm(-2) aluminum shielding. The animals were euthanized
      122 d post-irradiation and lymphocyte phenotypes, hematological parameters, and
      lymphocyte blastogenesis were characterized. RESULTS: There were significant dose
      dependent decreases in macrophage, CD3+/CD8+ T, NK, platelet, and red blood cell
      populations, as well as low hematocrit and hemoglobin levels. In contrast, dose
      dependent increases in spontaneous, but not mitogen-induced, blastogenesis were
      noted. The differences in dose composition between pristine and shielded proton
      fields did not lead to significant effects in most measures, but did result in
      significant changes in monocyte and macrophage populations and spontaneous
      blastogenesis in the spleen. CONCLUSIONS: The data indicate that whole body
      exposure to proton radiation at doses of the order of large solar particle events
      or clinical treatment fractions may have long-term effects on immune system
      status.

PMID- 12602443
TI  - The effect of posture and positive pressure breathing on the hemodynamics of the
      internal jugular vein.
AB  - BACKGROUND: Mathematical and mechanical models of cerebral circulation indicate
      that the resistance of the collapsed internal jugular veins limits cerebral blood
      flow during high acceleration (+Gz) and that positive pressure breathing (PPB)
      restores cerebral blood flow by elevating blood pressure and preventing collapse
      of the vein. The effect of acceleration and PPB on the jugular resistance and
      flow can be estimated by documenting changes in the lumen area and blood
      velocity. METHODS: The right internal jugular vein was imaged with vascular
      ultrasound in supine and seated human subjects exposed to 0-50 mm Hg of PPB. For
      each of the PPB posture combinations the vein was imaged at four locations along
      the length; resistance and flow were calculated using Poiseuille flow
      approximation. RESULTS: For the supine subjects, the lumen area, just above the
      inferior bulb, was 1.0 +/- 0.49 cm2, the estimated resistance was 0.13 +/- 0.07 x
      10(-3) mm Hg x cm(-3) x min(-1), and the estimated blood flow was 931 +/- 477 cm3
      x min(-1). In the sitting position, the lumen narrowed to 0.11 +/- 0.07 cm2, the
      resistance increased to 6.3 +/- 4.9 x 10(-3) mm Hg x cm(-3) x min(-1), and the
      blood flow dropped to 372 +/- 194 cm3 x min(-1). However, the vessel of a sitting
      subject can be completely reopened with PPB of 30 mm Hg or higher, and the
      resistance can be brought to supine levels. CONCLUSIONS: The results demonstrate
      that the internal jugular vein collapses with transition from supine to sitting
      position. This implies a significant increase in resistance which is inversely
      proportional to the square of the lumen area. However, the collapse can be
      prevented with sufficiently high PPB.

PMID- 12602444
TI  - Cardiovascular baroreceptors mediate susceptibility to hypothermia.
AB  - BACKGROUND: The maintenance of excessively high peripheral blood flow through
      dilated blood vessels during immersion in cold water could explain some
      individuals' predisposition to hypothermia. We hypothesized that interpersonal
      differences in vascular reactivity could account for contrasting susceptibility
      to hypothermia. METHOD: Twenty-two highly fit, volume replete subjects undergoing
      Navy SEAL training were recruited for this study. Vascular reactivity in these
      trainees was determined in a thermal-neutral environment by measuring changes in
      forearm blood flow (FBF) while decreasing their BP with the application of lower
      body negative pressure (LBNP). FBF was also measured during exposure of these
      subjects to ice cold water. BP, heart rate, stroke volume, and skin temperatures
      were also recorded. RESULTS: Changes in FBF induced by a fall in BP correlated
      with an individual's reduction in FBF caused by ice water immersion (n = 17, r =
      0.84, p < 0.001). A subject's decrement in BP induced with LBNP correlated
      inversely with the fall in skin temperature in response to cold water immersion
      (n = 19, r = 0.70, p < 0.001). Finally, we found that sodium excretion also
      correlated with cold-induced decrements in peripheral blood flow (n = 7, r =
      0.83, p < 0.05). CONCLUSIONS: It is suggested that contrasting cardiovascular
      baroreceptor sensitivity and vascular responsiveness contribute to individual
      differences in susceptibility to hypothermia. Furthermore, the trend toward
      dietary salt restrictions may not be salutary in the Navy SEAL who must
      frequently operate in cold ambient environments.

PMID- 12602445
TI  - Air transport of patients with intracranial air: computer model of pressure
      effects.
AB  - INTRODUCTION: Air is commonly trapped within the skull in patients who have been
      treated for trauma or intracranial hemorrhage. In Sweden, when such a patient is
      transported by air ambulance it is standard procedure to maintain sea-level
      pressure in the cabin to prevent increased intracranial pressure (ICP). However,
      this type of flight operation is more difficult and expensive. Maintenance of sea
      level cabin pressure is not common practice all over the world, and the criteria
      supporting the choice of pressurization during transport are inadequate and in
      need of evaluation. The purpose of this study was to develop and evaluate a model
      to simulate the influence of intracranial air on ICP during air transport.
      METHODS: We identified an existing nonlinear model of the cerebral spinal fluid
      and intracranial pressure dynamics, then added intracranial air as a new
      component and evaluated the model through simulations. RESULTS: The model behaved
      as expected, and the simulations indicated that under normal flying conditions
      with decreased cabin pressure the initial intracranial air volume will increase
      by approximately 30% at normal maximum cabin altitude, 8000 ft. The increase in
      ICP depends upon both the initial air volume and the rate of change in cabin
      altitude. For an intracranial air volume of 30 ml the estimated worst-case
      increments of ICP from sea level to maximum altitude would be from 10 mm Hg to
      21.0 mm Hg, or from 20 mm Hg to 31.8 mm Hg. DISCUSSION: Our results support the
      need for maintenance of sea-level pressure during air transport of patients with
      suspected intracranial air, since an ICP increment could potentially impair the
      patient's clinical condition.

PMID- 12602446
TI  - The effects of single-dose fexofenadine, diphenhydramine, and placebo on
      cognitive performance in flight personnel.
AB  - BACKGROUND: Sedation and functional impairments are side effects associated with
      the use of first-generation antihistamines that preclude their use in aviation.
      Selected second-generation antihistamines do not have such side effects and have
      been proposed for use in aircrew. METHODS: Forty-two healthy naval aviation
      personnel served as subjects in this double-blind, randomized, placebo-controlled
      crossover study. Subjective drowsiness, cognitive performance, and vigilance were
      measured under three conditions: 180 mg fexofenadine (F), 50 mg diphenhydramine
      (D) as a positive control, or placebo (P). RESULTS: Subjects receiving F vs. D
      tended to have a faster mean hit reaction time (adjusted mean difference +/- SE, 
      10.5 +/- 6.8 ms, p = 0.127). Subjects performed faster and better with F vs. D on
      measures of omission errors and commission errors (p < 0.05). Variable symbol
      digit coding delayed recall accuracy was better for F vs. D (p = 0.023), and
      approached significance for shifting attention and divided attention tasks (p =
      0.062 and p = 0.057, respectively). Subjects reported significantly more
      drowsiness (p < 0.005) with D than F. CONCLUSIONS: Diphenhydramine administration
      resulted in significant psychomotor decrements compared with fexofenadine, while
      the effects of fexofenadine were similar to placebo. These results provide
      additional support for the safe use of fexofenadine by aviation personnel.

PMID- 12602448
TI  - Acceleration effects on neck muscle strength: pilots vs. non-pilots.
AB  - BACKGROUND: Conditioning of neck muscles, if any, due to repeated exposures to
      +Gz forces has received little research attention. OBJECTIVE: This study was
      conducted to evaluate and compare the neck muscle strength of test volunteers
      representative of the general populations of fighter aircraft pilots and non
      pilots. METHODS: The tests were performed using a special attachment device on a
      computerized dynamometer. Ten pilots and ten non-pilots volunteered as test
      subjects. Each individual's maximal isometric neck muscle strength was evaluated
      in the extension, flexion, and left and right lateral bending directions in a
      single day. Peak values from the measurements were used for data analysis.
      Overall neck strength was calculated as the mean values for the four directions
      in each group. RESULTS: The overall muscular strength of the necks of pilots did
      not differ significantly from that of non-pilots, nor did exposure to +Gz forces
      lead to specific changes in isometric muscle strength across any of the four
      principal directions. Neck muscle strength in the four measured directions pooled
      across the two subgroups were statistically significant. The widespread practice
      of adopting protective head-positioning strategies to minimize neck strains,
      coupled with results from this research study, suggest that the neck muscles are
      subjected to reduced in-flight strengthening workouts during exposures to +Gz
      forces. CONCLUSIONS: To maximize in-flight performance and minimize +Gz-induced
      neck injuries, fighter pilots should be encouraged to perform on-land neck muscle
      strengthening exercise and in-flight head-positioning techniques. More research
      is needed to fine-tune this countermeasure strategy against cervical spine
      injury.

PMID- 12602447
TI  - Improving daytime sleep with temazepam as a countermeasure for shift lag.
AB  - BACKGROUND: Working night shift (reverse cycle) presents problems to personnel
      due to the difficulty in maintaining alertness during the nighttime hours. When
      the shift must be worked several consecutive nights, a cumulative sleep debt is
      created. Appropriate countermeasures are required to help personnel obtain as
      much sleep as possible so they may perform their duties effectively. HYPOTHESIS:
      The objectives were to determine whether a hypnotic taken before daytime sleep
      would improve sleep quality, and to determine whether improved daytime sleep
      would increase alertness, reduce fatigue, and mitigate the usual performance
      decrements which occur on night shift. METHODS: Sixteen UH-60 Army aviators were
      randomly assigned to either a temazepam or a placebo group. Test sessions,
      consisting of vigilance assessments, flight simulation, and mood state
      questionnaires were administered during baseline, three nights of reverse cycle,
      and three days following a return to day shift. Temazepam (30 mg) was
      administered before daytime sleep to one group while another group received a
      lactose-filled capsule. RESULTS: Subjects who received temazepam slept longer and
      with less fragmentation than those who received placebo. Generally, the subjects
      in the temazepam group indicated more subjective alertness and less fatigue than
      those in the placebo group. Flight performance was not unequivocally improved by
      better daytime sleep, but the temazepam group performed better on the Psychomotor
      Vigilance Task than the placebo group. CONCLUSIONS: Temazepam is helpful in
      prolonging daytime sleep, with some attenuation of performance decrements during
      the night shift. However, physicians should be careful when administering this
      substance to ensure the aviator has a minimum of 8 h in which to sleep.

PMID- 12602449
TI  - In-flight hypoxia incidents in military aircraft: causes and implications for
      training.
AB  - BACKGROUND: Hypoxia has long been recognized as a significant physiological
      threat at altitude. Aircrew have traditionally been trained to recognize the
      symptoms of hypoxia using hypobaric chamber training at simulated altitudes of
      25,000 ft or more. The aim of this study was to analyze incidents of hypoxia
      reported to the Directorate of Flying Safety of the Australian Defence Force (DFS
      ADF) for the period 1990-2001, as no previous analysis of these incidents has
      been undertaken. The data will be useful in planning future training strategies
      for aircrew in aviation physiology. METHOD: A search was requested of the DFS-ADF
      database, for all Aircraft Safety Occurrence Reports (ASOR) listing hypoxia as a
      factor. These cases were reviewed and the following data analyzed: aircraft type,
      number of persons on board (POB), number of hypoxic POB, any fatalities, whether
      the victims were trained or untrained as aircrew, if the symptoms were recognized
      as hypoxia, symptoms experienced, the altitude at which the incident occurred,
      and the likely cause. RESULTS: During the period studied. 27 reports of hypoxia
      were filed, involving 29 aircrew. In only two cases was consciousness lost, and
      one of these resulted in a fatality. Most incidents (85.1%) occurred in fighter
      or training aircraft with aircrew who use oxygen equipment routinely. The
      majority of symptoms occurred between 10,000 and 19,000 ft. The most common cause
      of hypoxia (63%) in these aircraft was the failure of the mask or regulator, or a
      mask leak. Rapid accidental decompression did not feature as a cause of hypoxia.
      Symptoms were subtle and often involved cognitive impairment or light-headedness.
      The vast majority (75.8%) of these episodes were recognized by the aircrew
      themselves, reinforcing the importance and benefit of hypoxia training.
      CONCLUSION: This study confirms the importance and effectiveness of hypoxia
      training for aircrew. Hypoxia incidents occur most commonly at altitudes less
      than 19,000 ft. This should be emphasized to aircrew, whose expectation may be
      that it is only a problem of high altitude. Proper fitting of masks, leak checks,
      and equipment checks should be taught to all aircrew and reinforced regularly.
      Current hypobaric chamber training methods should be reviewed for relevance to
      the most at-risk aircrew population. Methods that can simulate subtle
      incapacitation while wearing oxygen equipment should be explored. Hypoxia in
      flight still remains a serious threat to aviators, and can result in fatalities.

PMID- 12602450
TI  - Perception and predictability of travel fatigue after long-haul flights: a
      retrospective study.
AB  - BACKGROUND: The impact of travel fatigue and jet lag varies between individuals
      and may significantly affect the ability of some to perform their occupational
      role following a transmeridian flight. It would be advantageous in an
      occupational setting to be able to predict prior to travel those who may suffer
      most. METHODS: A Traveler Profile Questionnaire was developed to assess the
      perceived severity of travel fatigue in 100 subjects making transmeridian
      flights. RESULTS: The questionnaire provided an internally consistent measure of
      fatigue and confirmed that subjects experienced greater symptoms of travel
      fatigue following east/west flights when compared with north/south. Easterly
      travel was rated marginally worse than travel in a westerly direction. The
      respondents scores as measured by the Circadian Type Inventory (Folkard 1987) and
      Composite Morningness Questionnaire (Smith 1989) were used to identify whether
      such tools could be used as indicators of susceptibility to the effects of travel
      fatigue. After allowing for a gender difference, increased rigidity in sleeping
      habits as shown by a decrease in the Flexibility/Rigidity score on the Circadian
      Type Inventory was associated with an increase in the composite 'severity' score
      for travel fatigue derived from ratings of specific physiological symptoms.
      CONCLUSIONS: The Traveler Profile Questionnaire, while internally consistent was
      nonetheless insufficient to be used in a predictive capacity to identify those
      individuals who would suffer most from the effects of travel fatigue.

PMID- 12602451
TI  - Sinus barotrauma--late diagnosis and treatment with computer-aided endoscopic
      surgery.
AB  - Sinus barotrauma is usually easy to diagnose, and treatment achieves good
      results. We present two severe cases where delayed diagnosis caused significant
      morbidity. The signs and symptoms were atypical and neither the patients
      themselves, nor the initial examiners recognized that the onset of symptoms
      coincided with descent in a commercial airliner. CT and MRI scans of the brain
      were normal, but in both cases showed opafication of the sphenoid sinuses, which
      lead to the correct diagnosis. Subsequent surgical intervention consisting of
      endoscopic computer-aided surgery showed blood and petechia in the affected
      sinuses. This procedure provided immediate relief.

PMID- 12602452
TI  - Multiple sclerosis presenting as neurological decompression sickness in a U.S.
      navy diver.
AB  - A case of clinically definite multiple sclerosis presenting as neurological
      decompression sickness is presented. A 23-yr-old U.S. Navy diver experienced
      onset of hypesthesia of the left upper trunk approximately 19 h after making two
      SCUBA dives. She did not seek medical attention until 3 wk later, at which time
      she was diagnosed with possible neurological decompression sickness. She was
      treated with hyperbaric oxygen, but demonstrated no improvement. Further
      evaluation led to the diagnosis of multiple sclerosis. This case underscores the
      potential similarity in neurological presentation between multiple sclerosis and
      decompression sickness. The differential diagnosis of neurological decompression
      sickness, particularly in atypical cases, should include multiple sclerosis. The
      appropriateness of medically clearing multiple sclerosis patients for diving is
      discussed.

PMID- 12602454
TI  - This month in aerospace medicine history--February 2003.

PMID- 12602453
TI  - Pilots & melanoma.

PMID- 12602455
TI  - Updates on human centered research and development acquisitions.

PMID- 12602456
TI  - Air Force Aerospace Physiology Program.

PMID- 12602457
TI  - Influence of administration vehicles and drug formulations on the pharmacokinetic
      profile of lamotrigine in rats.
AB  - Given that administration vehicles and drug formulations can affect drug
      bioavailability, their influence on the pharmacokinetic profile of lamotrigine
      (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different
      formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1)
      LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50%
      propylene glycol solution, and (3) LTG isethionate dissolved in distilled water.
      Plasma and brain homogenate levels were determined in order to evaluate vehicle
      dependent drug absorption. The results demonstrated rapid absorption of LTG when
      it was administered as an aqueous solution, in contrast to a slower and more
      erratic absorption after the injection of either the lipophilic solution or the
      suspension. A plasma peak was achieved 15 min post-dose with the aqueous
      solution, with a brain peak being achieved 15 min later, while with the other
      formulations both plasma and brain homogenate peaks were reached 2 h after LTG
      administration. This study suggests that LTG isethionate dissolved in distilled
      water is the most suitable formulation for successful LTG pharmacokinetic studies
      in rats.

PMID- 12602458
TI  - Pharmacogenetics and personalised medicine.
AB  - The traditional concern of pharmacogenetics was Mendelian (monogenic) variation,
      which visibly affected some drug responses. Pharmacogenetics was broadened by the
      observation that multifactorial genetic influences, in conjunction with
      environmental factors, usually determine drug responses. Variability of gene
      expression, a new theme of the science of genetics, also affects
      pharmacogenetics; for example, enhanced enzyme activity does not necessarily
      indicate a mutation, but may be the consequence of a drug-induced enhancement of
      gene expression. Methodological advances permit the conversion of
      pharmacogenetics into the broad practice of pharmacogenomics; this improves the
      possibility of identifying genetic causes of common diseases, which means
      establishing new drug targets, thereby stimulating the search for new drugs.
      While the main medical effect of pharmacogenetics was an improvement of drug
      safety, pharmacogenomics is hoped to improve drug efficacy. On the way to
      personalized medicine, we may stepwise improve the chances of choosing the right
      drug for a patient by categorizing patients into genetically definable classes
      that have similar drug effects (as, for example, human races, or any population
      group carrying a particular set of genes). It is wise to expect that, even after
      we have reached the goal to establish personalized medicine, we will not have
      eliminated all uncertainties.

PMID- 12602459
TI  - Relationship between exposure to zidovudine and decrease of P24 antigenemia in
      HIV-infected patients in monotherapy.
AB  - The link between virological response and exposure to zidovudine was studied in
      40 HIV-infected patients of the protocol ANRS 01. During this 45-day trial, the
      patients received only oral zidovudine in six treatment groups. Our objectives
      were: to analyze and model the pharmacokinetics of zidovudine and the decrease of
      P24 antigenemia; to study the links between exposure and efficacy. For the
      pharmacokinetic study, 12 blood samples were collected from 0.16 to 24 h after
      the first dose and a compartmental model was used. For the pharmacodynamic study
      of P24 antigenemia, blood samples were collected before treatment and every 3
      days until day 45; an exponantial decay model was used. The pharmacokinetic and
      pharmacodynamic parameters were estimated for each patient by nonlinear
      regression. The correlations between efficacy parameters and exposure parameters,
      were then studied in the 40 patients. The mean (+/- SD) apparent volume of
      distribution and clearance were 151 L (+/- 94) and 184 L/h (+/- 72),
      respectively. The mean initial antigen level was 472 pg/mL (+/- 409), the
      coefficient of reduction of antigenemia was 0.27 (+/- 0.21) and the rate of
      decrease was 0.27/day (+/- 0.16). The coefficient of P24 reduction was found to
      be significantly correlated to the daily area under the curve (P < 0.0014). This
      relationship was adequately described by an Imax model and the daily area under
      the curve, leading to 50% of antigenemia decrease, was estimated to be 2.32 mg x
      h/L (+/- 0.33). In conclusion, a significant relationship between exposure to
      zidovudine at day 1, and decrease of P24 antigenemia was found. It was estimated
      that the average steady-state concentration, which corresponds to 70% of maximal
      efficacy, was 0.22 mg/L. Together with the large interpatient variability of
      zidovudine pharmacokinetics, these findings confirmed that zidovudine should be
      monitored and a clinical target concentration was defined.

PMID- 12602460
TI  - FOSIDIAL: a randomised placebo controlled trial of the effects of fosinopril on
      cardiovascular morbidity and mortality in haemodialysis patients. Study design
      and patients' baseline characteristics.
AB  - The prevalence of end stage renal disease (ESRD) is growing in western countries.
      Patients with ESRD are more frequently elderly and diabetic and are exposed to
      very high cardiovascular morbidity and mortality. The main aim of the FOSIDIAL
      study is to assess the efficacy and safety of fosinopril, an angiotensin
      converting enzyme (ACE) inhibitor, in reducing the mortality and cardiovascular
      events in haemodialysis patients presenting with left ventricular hypertrophy. A
      total number of 397 patients are included in the study. They are aged 50-80 years
      (average 66.7 years) and have been undergoing haemodialysis for 4.8 years. All
      have left ventricular hypertrophy with cardiac mass index > 100 g/m2 in women and
      > 130 g/m2 in men, measured within 3 months prior to inclusion. Baseline cardiac
      mass index is 174 g/m2. After a 2 week placebo period, the patients are
      randomised into two groups receiving either fosinopril 5-20 mg/day, or a placebo
      for a duration of 24 months. The target dose is reached at the sixth, seventh or
      eighth week of treatment. Depending on tolerance, 300 patients reached the
      maximum recommended dose. Patients are subsequently assessed clinically every 3
      months until the end of the study. The primary outcome is a composite endpoint of
      fatal and nonfatal major cardiovascular events. Secondary endpoints are
      individual cardiovascular events, event-free survival, overall mortality and all
      cause hospitalisations. The trial began in October 1998. All patients were
      included by December 2000 and follow-up is ongoing. The last visit for the last
      patient is scheduled for 30 December 2002. We report here on the study design and
      the baseline characteristics of the study population.

PMID- 12602462
TI  - Blood volume monitoring during acute renal replacement therapy.

PMID- 12602463
TI  - Use of the organ donor with prior hepatitis B infection: a safe option?

PMID- 12602461
TI  - Relationships between the antihypertensive effects of bisoprolol and levels of
      plasma atrial natriuretic peptide in hypertensive patients.
AB  - Previous studies have demonstrated that beta-blockade increases the levels of
      plasma atrial natriuretic peptide (ANP), but relationships between this effect
      and the antihypertensive action of beta-blockade remain unknown. In this study we
      investigated the amplitude and determinants of bisoprolol-induced ANP increase
      and the relationships between this increase and the antihypertensive effect of
      bisoprolol. Nineteen patients with mild to moderate hypertension were included in
      the study. In the first phase of the study (cross-over, placebo controlled,
      randomized phase), the effects of 10 mg bisoprolol on plasma ANP at rest and
      during exercise were compared to placebo. The antihypertensive action of
      bisoprolol was then evaluated after a 2-week period of treatment (10 mg/day)
      using ambulatory blood pressure monitoring. Bisoprolol significantly increased
      plasma ANP level at rest (from 30.6 +/- 20.5 to 42.8 +/- 35.6; P < 0.05) and also
      during exercise (from 54.7 +/- 44.3 to 119.1 +/- 159.9; pg/mL +/- SD; P < 0.05).
      Plasma ANP at rest was not significantly correlated with left ventricular mass.
      After the 15 days of treatment, the bisoprolol-induced daytime diastolic blood
      pressure reduction was significantly correlated to the initial bisoprolol-induced
      plasma ANP increase (r = 0.49, P = 0.035). These results suggest that the
      antihypertensive effect of beta-blocking agents could be partly mediated by an
      increase of ANP release.

PMID- 12602464
TI  - The role of chronic inflammation in cardiovascular mortality of uremic patients.

PMID- 12602465
TI  - Impact of continuous veno-venous hemofiltration on acid-base balance.
AB  - BACKGROUND: Continuous veno-venous hemofiltration (CVVH) appears to have a
      significant and variable impact on acid-base balance. However, the pathogenesis
      of these acid-base effects remains poorly understood. The aim of this study was
      to understand the nature of acid-base changes in critically ill patients with
      acute renal failure during continuous veno-venous hemofiltration by applying
      quantitative methods of biophysical analysis (Stewart-Figge methodology).
      METHODS: We studied forty patients with ARF receiving CVVH in the intensive care
      unit. We retrieved the biochemical data from computerized records and conducted
      quantitative biophysical analysis. We measured serum Na+, K+, Mg2+, Cl-, HCO3-,
      phosphate, ionized Ca2+, albumin, lactate and arterial blood gases and calculated
      the following Stewart-Figge variables: Strong Ion Difference apparent (SIDa),
      Strong Ion Difference Effective (SIDe) and Strong Ion Gap (SIG). RESULTS: Before
      treatment, patients had mild acidemia (pH: 7.31) secondary to metabolic acidosis
      (bicarbonate: 19.8 mmol/L and base excess: -5.9 mEq/L). This acidosis was due to
      increased unmeasured anions (SIG: 12.3 mEq/L), hyperphosphatemia (1.86 mmol/L)
      and hyperlactatemia (2.08 mmol/L). It was attenuated by the alkalinizing effect
      of hypoalbuminemia (22.5 g/L). After commencing CVVH, the acidemia was corrected
      within 24 hours (pH 7.31 vs 7.41, p<0.0001). This correction was associated with
      a decreased strong ion gap (SIG) (12.3 vs. 8.8 mEq/L, p<0.0001), phosphate
      concentration (1.86 vs. 1.49 mmol/L, p<0.0001) and serum chloride concentration
      (102 vs. 98.5 mmol/L, p<0.0001). After 3 days of CVVH, however, patients
      developed alkalemia (pH: 7.46) secondary to metabolic alkalosis (bicarbonate:
      29.8 mmol/L, base excess: 6.7 mEq/L). This alkalemia appeared secondary to a
      further decrease in SIG to 6.7 mEq/L (p<0.0001) and a further decrease in serum
      phosphate to 0.77 mmol/L (p<0.0001) in the setting of persistent hypoalbuminemia
      (21.0 g/L; p=0.56). CONCLUSIONS: CVVH corrects metabolic acidosis in acute renal
      failure patients through its effect on unmeasured anions, phosphate and chloride.
      Such correction coupled with the effect of hypoalbuminemia, results in the
      development of a metabolic alkalosis after 72 hours of treatment.

PMID- 12602466
TI  - Inflammatory response of a new synthetic dialyzer membrane. A randomised cross
      over comparison between polysulfone and helixone.
AB  - Hemodialysis patients suffer from chronic inflammation due to intradialytic
      contact of blood with artificial materials. The FX 60 dialyzer which belongs to
      the new FX-class series of dialyzers is composed of the new membrane Helixone.
      This membrane is derived from the original Fresenius Polysulfone membrane. The FX
      class design is based on modified geometry of fibres and housing and has resulted
      in a new dialyzer with improved efficiency, safety and ease of handling compared
      to the F series (F 60S) dialyzer. The aim of the study was to investigate whether
      the biocompatibility pattern in terms of inflammatory parameters of the new type
      of polysulfone dialyzer has changed compared to the standard. A clinical in vivo
      study was conducted to compare the intradialytic inflammatory response of the two
      dialyzers, FX 60 and F 60S. Eight chronic dialysis patients were selected for the
      study: mean age 65.5 +/- 15.5 years, mean time on dialysis 100 +/- 95 months. The
      randomized cross-over study involved a treatment period of 2 weeks (total 6
      sessions), one week with each dialyzer, starting with one or the other according
      to the randomization scheme. Blood samples were taken at 0 (T0), 15, 60, and 240
      minutes to evaluate white blood cell (WBC) count, complement factor C5a,
      leukocyte elastase, soluble intercellular adhesion molecule 1 (sICAM-1), platelet
      count, C-reactive protein (CRP). At 15 min, WBC count showed a comparably, low
      decrease for both dialyzers: -7.6% for FX 60 versus -6.6% for F 60S, p=not
      significant (ns). At the same time the C5a concentration decreased from 15.0 +/-
      7.5 ng/ml to 13.5 +/- 6.7 ng/ml (p=ns) for FX 60, and from 15.1 +/- 12.5 ng/ml to
      14.9 +/- 25.0 ng/ml for F 60S (p=ns). The elastase concentration progressively
      increased over time with no statistical difference between the two dialyzers. The
      levels of sICAM-1, CRP, and platelet count were similar at each time point for
      both dialyzers, varying around the baseline values (p=ns). No significant
      difference emerged in terms of inflammatory response between the two dialyzers,
      hemo demonstrating that the biocompatibility of the F-series was maintained in
      the FX-class series of dialyzers and is independent of design factors.

PMID- 12602467
TI  - Plasma carnitine profile during chronic renal anemia treatment with recombinant
      human erythropoietin.
AB  - Recombinant human erythropoietin (epoetin) is widely used for correction of
      anaemia in patients with chronic renal disease and its efficacy has been
      confirmed in numerous studies. Disturbances in carnitine metabolism may also
      contribute to the development of renal anaemia. Although increases in erythrocyte
      count (RBC) and changes in RBC metabolism during L-carnitine administration have
      been observed, supplementation with L-carnitine in anaemic hemodialysis patients
      is not routine. The aim of our study was to determine the influence of epoetin on
      hematological parameters and plasma carnitine profile in anaemic hemodialysis
      patients. 36 hemodialysis patients (22 men, 14 female, aged from 17 to 64 years,
      mean 43) and 30 healthy volunteers (12 men, 18 female, aged from 25 to 65 years,
      mean 40) were studied. Epoetin (Eprex, Janssen-Cilag) was administered
      subcutaneously for twelve months with the starting dose 2000 IU three times per
      week (range from 75 to 133, mean 102 +/- 21 IU/kg/week). The target hemoglobin
      (Hb) range at the time of the study was between 10-11 g/dL. Laboratory markers of
      hematological response, carnitine and iron status, were measured before epoetin
      administration and then controlled every three months. During epoetin treatment a
      significant increase in Hb concentration was observed (100% of patients responded
      to epoetin). In the third and six month of epoetin treatment, along with a
      significant increase in mean reticulocyte count and the highest increment of RBC
      count and Hb levels, probably due to increased erythropoiesis, a significant,
      transient decrease of mean total and free plasma carnitine levels was observed.
      This may suggest the utilisation of carnitine by a new RBC population. It also
      indicates that there is a need for L-carnitine in carnitine deficient maintenance
      hemodialysis patients particularily during erythropoiesis induced by epoetin
      treatment.

PMID- 12602468
TI  - Protease removal by means of antiproteases immobilized on supports as a potential
      tool for hemodialysis or extracorporeal blood circulation.
AB  - This work studies protease concentration decrease in aqueous solutions in contact
      with a modified polyethersulphone graft membrane onto which antiproteases were
      immobilized. As a model of protease/antiprotease interaction, elastase and alpha1
      antitrypsin were used. Experiments were carried out either under fixed amounts of
      immobilized antiproteases and variable protease concentration or under fixed
      protease concentration and variable amounts of immobilized antiproteases. In both
      cases, active protease concentrations decreased with increase in contact time
      with the membrane. Experimental conditions under which active elastase
      concentration becomes zero were also found. Occurrence of the same phenomenology
      has also been ascertained with protease solutions obtained from human blood
      neutrophils. The membrane activated with alpha1-antitrypsin showed differential
      inhibitory power on elastase and cathepsin G. This technology could open new
      perspectives in manufacturing new membranes to be used in hemodialysis and
      extracorporeal circulation when elastase is released.

PMID- 12602469
TI  - Successful ex vivo normothermic liver perfusion with purely artificial products
      using artificial blood.
AB  - We tried to make an ex vivo functioning liver with an artificial perfusate that
      consisted of artificial blood in the pig liver. A liver graft from a female pig
      weighing 20 kg was harvested in the usual manner. The perfusion solution
      consisted of artificial blood, L-15 medium, distilled water, bovine serum
      albumin, NaHCO3, NaOH, KCl, human regular insulin, 50% glucose solution, and
      dexamethasone. The isolated liver was perfused with this oxygenated perfusate
      through the portal vein at a rate of 300 ml/min for 9 hours. Seven livers were
      perfused for 9 hours in this system. Five of the livers showed mean oxygen
      consumption of over 8 ml-O2/min during perfusion. Histological findings showed
      that the hepatic architecture was almost completely preserved and numerous
      hepatocytes exhibited PAS-positive cytoplasmic glycogen deposits in these livers.
      These observations indicate that we have succeeded in developing an ex vivo
      functioning liver with an artificial perfusate employing artificial blood.

PMID- 12602470
TI  - A hybrid mock circulatory system: development and testing of an electro-hydraulic
      impedance simulator.
AB  - Mock circulatory systems are used to test mechanical assist devices and for
      training and research purposes; when compared to numerical models, however, they
      are not flexible enough and rather expensive. The concept of merging numerical
      and physical models, resulting in a hybrid one, is applied here to represent the
      input impedance of the systemic arterial tree, by a conventional windkessel model
      built out of an electro-hydraulic (E-H) impedance simulator added to a hydraulic
      section. This model is inserted into an open loop circuit, completed by another
      hybrid model representing the ventricular function. The E-H impedance simulator
      is essentially an electrically controlled flow source (a gear pump). Referring to
      the windkessel model, it is used to simulate the peripheral resistance and the
      hydraulic compliance, creating the desired input impedance. The data reported
      describe the characterisation of the E-H impedance simulator and demonstrate its
      behaviour when it is connected to a hybrid ventricular model. Experiments were
      performed under different hemodynamic conditions, including the presence of a
      left ventricular assist device (LVAD).

PMID- 12602471
TI  - Pathological patient in protocol definition for bench testing of mechanical
      cardiac support system.
AB  - Clinical techniques for the restoration of a failing heart are mainly based on
      the use of mechanical assist devices. In recent years, with the growing need for
      mechanical circulatory support, these devices have been shown to be a useful
      therapeutic tool, thanks to their intrinsic capability to unload the failing
      ventricle, allowing the heart to recover. Mechanical circulatory support systems
      (MCSS) require an accurate biomechanical characterization of the complex
      interaction that occurs between the patient and the mechanical support. A
      protocol for MCSS testing is proposed which takes into account several working
      conditions, in a modified test mock loop apparatus able to mimic various
      pathological conditions. Both physiological and pathological conditions can be
      replicated to show the actual efficacy of a MCSS device in correctly supporting a
      wide spectrum of ventricular conditions. The test bench is able to simulate the
      recovery of the pathological condition quite accurately, showing, at the same
      time, that this set up can be a reliable choice to characterize cardiac support
      devices. Thus the results of this experimentation can be useful to clinicians in
      forecasting the response of the heart affected by a cardiac disease and to set
      appropriate parameters for suitable assistance.

PMID- 12602472
TI  - Exploring the damage limitation possibilities of mineral fibres for future
      integrated solutions: an in vitro study.
AB  - Owing to their possible carcinogenic effect, asbestos and other silica
      derivatives have been identified as priority substances for risk reduction and
      prevention of pollution. Neutralisation procedures have thus become a topical
      research subject in many European and American countries. In the present study,
      silica derivatives (asbestos-containing and asbestos substitutes like slag wool,
      rock wool, cement asbestos) were fully impregnated with an epoxy resin according
      to the procedure used for the in situ impregnation with viscous polymeric media,
      which penetrate and cement the fibres in place and reduce the risk of their
      dispersion in air. Untreated and treated samples were used to investigate their
      in vitro interaction with a human continuous epithelial cell line (NCTC 2544
      keratinocytes) and test the resin's efficiency in passivating the surface
      activity of the fibrous particulate. SEM and morpho-quantitative data evidenced
      that impregnation with the epoxy resin modifies the mineral fibres' bioactivity
      (reduction of cell adhesion and decreased spread/round cell ratio) and
      demonstrated the value of in vitro cell testing after passivation as a risk
      assessment procedure. These tests could be used for the rapid determination of
      the level of passivation of new synthetic mineral fibrous materials subjected to
      resin impregnation.

PMID- 12602473
TI  - Development of a vibratory microinjection method.
AB  - To reduce cellular damage by pronuclear microinjection and nuclear transfer, we
      have recently developed a vibratory microinjection method. A micropipette was
      fixed to a piezoelectric ceramic with a resonance frequency of 70 kHz. When this
      micropipette was vibrated, it easily entered a mouse-fertilized egg without any
      sharp depression of the cell body, whereas a sharp, deep depression at the
      insertion site was observed when the micropipette was not vibrated. A depression
      rate defined as a rate of a depth of depression over an original cell diameter
      was utilized as an index of cellular deformation. The depression rates with and
      without vibration were 11.1 +/- 5.2% (N = 24) and 40.4 +/- 8.8% (N = 16),
      respectively (P < 0.0001, Student's t-test). In conclusion, the vibratory
      microinjection method is a new, useful option for gene transfer because it
      resulted in much less cellular deformation, therefore implicating less cellular
      damage.

PMID- 12602474
TI  - Use of octreotide to treat prolonged sulfonylurea-induced hypoglycemia in a
      patient with chronic renal failure.
AB  - A diabetic patient with chronic renal failure who developed recurrent and
      prolonged episodes of hypoglycemia associated with use of sulfonylurea agent is
      presented here. This patient was hospitalized with neuroglycopenic symptoms of
      hypoglycemia that persisted in spite of large doses of parenteral glucose
      replacement. On administration of somatostatin analogue octreotide, hypoglycemia
      resolved and, blood glucose levels were maintained even after cessation of
      parenteral glucose. The patient received 2 subcutaneous doses of octreotide 12
      hours apart, and made a complete recovery. Our experience suggests that use of
      octerotide to treat refractory or prolonged sulfonylurea-included hypoglycemia in
      renal failure patients is safe and effective; large prospective studies would be
      needed to validate these findings.

PMID- 12602475
TI  - Discrimination between pericardial disease and myocardial disease using tissue
      Doppler imaging in a patient with right-sided heart failure and multiple myeloma.
AB  - We report a case of right-sided heart failure associated with multiple myeloma.
      Amyloidosis was proven by rectal biopsy. In this case we were able to demonstrate
      myocardial disease by using tissue Doppler echocardiography, even in the presence
      of cardiac tamponade.

PMID- 12602476
TI  - A giant aneurysm of the circumflex coronary artery with fistulous connection to
      the coronary sinus: a case report.
AB  - Non-atherosclerotic coronary artery aneurysms are rare and most of them remain
      asymptomatic. We report a case who has a giant circumflex coronary artery
      aneurysm with fistulisation into the coronary sinus. The patient presents with
      dyspnea and palpitation due to atrial fibrillation with rapid ventricular
      response. The diagnostic contributions of echocardiography, coronary angiography
      are discussed. The hemodynamic effects of this anomaly are reviewed.

PMID- 12602477
TI  - Rapid and accurate left ventricular surface generation from three-dimensional
      echocardiography by a catalog based method. Rapid LV surface generation by three
      dimensional echo.
AB  - BACKGROUND: Quantitative analysis from three-dimensional (3D) echocardiography
      requires accurate reconstruction of left ventricular (LV) surfaces. This
      currently requires time-consuming manual image tracing. We describe and validate
      an alternative rapid method of generating LV surfaces. METHODS: A 3D-image set is
      acquired using transthoracic scanning. Images from five standard echo views are
      displayed and border points selected where anatomic landmarks are well defined. A
      LV surface is reconstructed as a convex weighted sum of LVs from a catalog of 80
      LVs. The intersections of the surface with the five views are presented on these
      images. The routine may be rerun until the LV surface matches the images. One LV
      surface is generated in 3 min +/- 27 s. In 41 studies (19 normal, 15 previous
      infarction, seven cardiomyopathy) the volumes of the catalog-fit endocardial and
      epicardial surfaces were compared with volumes from surfaces reconstructed from
      full manual tracing. RESULTS: Over a wide range of LV volumes and ejection
      fraction (EF), the catalog-fit results correlated closely to those from manual
      tracing: end-diastolic volume (194 +/- 99 vs. 204 +/- 110 ml, y = 0.93x, R2 =
      0.99, SEE = 19 ml, p < 0.001), end-systolic volume (122 +/- 95 vs. 131 +/- 106
      ml, y = 0.92x, R2 = 0.99, SEE = 13 ml, p < 0.001), EF (42 +/- 16 vs. 42 +/- 15%,
      y = x, R2 = 0.99, SEE = 4%, p < 0.001) and mass (220 +/- 88 vs. 204 +/- 86 g, y =
      1.1x, R2 = 0.99, SEE = 24 g, p < 0.001). The endocardial catalog surface was
      generated from an average of 20 points and three computational runs for both end
      diastole and end-systole. CONCLUSIONS: The catalog method of LV reconstruction
      from 3D-echo provides accurate measurement of volume, EF and mass. The speed of
      the method is a major advantage.

PMID- 12602478
TI  - Head-to-head comparison of dipyridamole echocardiography and stress perfusion
      scintigraphy for the detection of coronary artery disease: a meta-analysis.
      Comparison between stress echo and scintigraphy.
AB  - OBJECTIVES: This meta-analysis was performed to assess and compare the diagnostic
      accuracy of dipyridamole echocardiography test (DET) vs. stress perfusion
      scintigraphy (SPS) for the diagnosis of coronary artery disease (CAD). METHODS:
      We performed a meta-analysis of peer reviewed articles, published in English
      language reporting head-to-head comparison of DET vs. SPS for the diagnosis of
      CAD. Data of 10 studies comprising 651 patients from 10 different institutions
      were analyzed. DET dose was 0.56 mg/kg (low dose) in two studies, 0.75 mg/kg in
      10 min or 0.84 mg/kg in 10 min (high dose) in six studies, and 0.84 mg/kg in 6
      min (accelerated high dose) in one study and 0.84 mg/kg in 10 min + 1 mg atropine
      co-administration (augmented dose) in one study. SPS was performed with
      dipyridamole in six studies, with exercise in three studies and with dobutamine
      in one study. RESULTS: The overall diagnostic accuracy of the two tests was
      almost similar, 77% (95% CI = 74-81) for DET vs. 81% (95% CI = 78-84) for SPS (p
      = ns). SPS gave higher sensitivity, 88% (95% CI = 85-89) than DET, 70% (95% CI =
      66-75) in cumulative data (p < 0.0001) while DET gave higher specificity, 90%
      (95% CI = 86-94) vs. 67% (95% CI = 60-73) (p < 0.0001). With state of the art
      protocols, i.e. accelerated dose and atropine augmented high dose, sensitivity of
      DET improved and overall accuracy was better than SPS (p < 0.05). CONCLUSION: DET
      and SPS have a similar diagnostic accuracy. DET has a markedly higher specificity
      regardless of the dose employed. SPS shows a superior sensitivity, however this
      sensitivity gap diminishes when more aggressive dipyridamole dosage is used for
      the stress echocardiography.

PMID- 12602479
TI  - Dipyridamole stress echocardiography: to be included in the Guidelines or to be
      abandoned from the clinical arena?

PMID- 12602480
TI  - Comparison of pulmonary venous flow velocities and left ventricular diastolic and
      ejection time in patients with moderate mitral and aortic stenosis. Pulmonary
      venous flow velocities in mitral and aortic stenosis.
AB  - BACKGROUND: Doppler pulmonary venous flow velocities (PVFV) pattern are useful
      parameters in assessing the left ventricular diastolic functions. Both mitral
      stenosis (MS) and aortic stenosis (AS) lead to diastolic dysfunction. We compared
      PVFV and left ventricular diastolic and ejection time (ET) in patients with
      moderate MS and AS. METHODS: Forty-three patients with moderate MS (group 1), 65
      patients with moderate AS (group 2), and 33 healthy subjects as controls (group
      3) were included in this study. After obtaining standard measurements
      echocardiographically, diastolic period (DP), ET, the ratio of the DP to the ET
      (DP/ET), isovolumetric contraction time (ICT), isovolumetric relaxation time
      (IRT), peak systolic flow velocity (PS), peak antegrade diastolic flow velocity
      (PD), peak reversal flow velocity at atrial contraction (PRA), the ratio of the
      peak systolic to the diastolic flow velocity (PS/PD), deceleration time of the
      antegrade diastolic flow (PDDT), and pressure half time of the peak antegrade
      diastolic flow velocity (PDPHT) were measured. Mitral valve area (MVA), aortic
      valve area (AVA), systolic pulmonary artery pressure (PAP), peak and mean
      gradients were calculated with standard formulas. RESULTS: In univariate
      analysis, MVA was correlated with PDPHT and PDDT (r = -0.41; p < 0.01, r = -0.36;
      p < 0.05, respectively), also it was correlated with DP/ET (r = -0.57; p <
      0.001). Mitral peak and mean diastolic gradient were correlated with PS/PD (r = 
      0.43; p < 0.01, r = -0.36; p < 0.05, respectively) and DP/ET (r = 0.51; p < 0.01,
      r = 0.46; p < 0.01, respectively). AVA was only correlated with DP/ET (r = 0.38;
      p < 0.05). Aortic peak and mean systolic gradient were correlated with PS/PD (r =
      -0.29; p < 0.05, r = -0.27; p < 0.05, respectively) and DP/ET (r = -0.38; p <
      0.01, r = -0.40; p < 0.01, respectively). In the same analysis, PAP in patients
      in group 1 and 2 was correlated with PS/PD (r = -0.42; p < 0.01 and r = -0.40; p
      < 0.01, respectively) and also it was correlated with PD (r = 0.37; p < 0.05 and
      r = 0.27; p < 0.05, respectively) in both groups. CONCLUSION: Moderate MS and AS
      similarly affect the PVFV, and PS/PD correlates with hemodynamics similarly both
      in MS and AS. Nevertheless, PDDT and PDPHT correlate with solely MVA. IRT higher
      in AS than MS, though DP/ET and ICT higher in MS than AS, and DP/ET relates with
      the severity of both MS and AS.

PMID- 12602481
TI  - Evaluation of mitral valve prolapse using newly developed real-time three
      dimensional echocardiographic system with real-time volume rendering.
AB  - The development of a real-time three-dimensional (RT3D) image acquisition system
      and direct digital links between ultrasound equipment and the data processing
      computer facilitate improved 3D image reconstruction. However, at present time,
      it is hard to promptly display 3D images and is also ineffective for a practical
      use. The objective of this study was to assess the feasibility of a new
      transthoracic RT3D echocardiographic system for evaluation of mitral valve
      prolapse. Eighteen patients with mitral valve prolapse diagnosed by transthoracic
      two-dimensional (2D) echocardiography and M-mode were examined through this
      technique (11 male, mean age 42 +/- 17 years). Since visualization of mitral
      valve from apical four-chamber view was better than that of the parasternal
      approach, only apical approach was used for mitral valve evaluation. This system
      is capable of acquiring volumetric data from mechanical scanning of the phased
      array transducer (3.5 MHz) as well as displaying the volume rendered images of
      the structure without storing the image data and reconstruction of the object.
      The prolapse of leaflet could be seen in 14/ 18 (77%) of patients with mitral
      valve prolapse based on conventional echocardiography. The newly developed
      transthoracic RT 3D ultrasound system without a reconstruction process seemed to
      be a useful noninvasive tool for diagnosis of mitral valve prolapse and detection
      of prolapsed leaflet or scallop, which is very important for deciding on a
      reliable surgical technique.

PMID- 12602482
TI  - Influence of coronary pulsation on volumetric intravascular ultrasound
      measurements performed without ECG-gating. Validation in vessel segments with
      minimal disease.
AB  - Volumetric analysis of coronary arteries can be performed using intravascular
      ultrasound (IVUS) images selected at 1 mm intervals without ECG gating. However,
      there are few data regarding the influence of coronary pulsation on this
      volumetric analysis. We developed two models of consecutive area measurements
      consisting of duplicated area measurements from short coronary segments and
      virtual measurements based on a sine function. These models allowed the re
      calculation of volumes using different sets of frames from the same simulated
      segments. The variability of the volume determinations was evaluated by its
      percent standard deviation [%SD = (SD/the mean value) x 100]. The relation of the
      variability to the extent of external elastic membrane (EEM) area change during
      the cardiac cycle (amplitude) and heart rates (frequency) were examined. In 58
      short coronary segments of 15 patients, consecutive IVUS images were measured
      [%EEM area change: 12.3 +/- 7.7%, heart rate 78 +/- 21 beats/min (bpm)]. In both
      models, %SD of the volume calculations was directly proportional to the %EEM area
      change and showed two peaks at heart rates of 60 +/- 2 and 90 +/- 2 bpm. In the
      model based on actual coronary measurements, the %SD of volume calculations of a
      segment with 10% EEM area change was 0.7% except for heart rates of 60 +/- 2 and
      90 +/- 2 bpm. The variability of a volumetric analysis based upon measuring IVUS
      images at constant intervals without ECG gating is affected by coronary
      pulsation, extent of cross-sectional area changes, and heart rate. Despite these
      limitations, this method is feasible and provides reproducible volume
      measurements.

PMID- 12602483
TI  - Volumetric intravascular ultrasound measurements in coronary arteries.

PMID- 12602484
TI  - Assessment of myocardial viability in a porcine model of chronic coronary artery
      stenosis with dual dose dobutamine magnetic resonance imaging.
AB  - In a non-surgical porcine coronary stenosis model resulting in chronic left
      ventricle dysfunction, we aimed in this study to evaluate the potential of
      magnetic resonance imaging (MRI) to distinguish dysfunctional but viable from
      necrotic myocardium by using multiple levels of dobutamine inotropic stimulation
      during a cine MRI protocol (F.P. van Rugge et al. Circulation 1994; 90: 127-138).
      We compared our results with histopathology. We were able to demonstrate a
      biphasic effect at increasing doses of dobutamine in a subgroup of animals with a
      high-grade coronary stenosis, while in another subgroup the coronary stenosis
      produced a chronic myocardial infarction, in which no functional recovery could
      be obtained. In this experimental protocol, dual dose dobutamine MRI proved to be
      an accurate and reproducible technique to perform viability studies in chronic
      obstructive coronary artery disease. It permits distinguishing chronic ischemic,
      but viable myocardium from infarcted tissue. The detection of chronically
      underperfused but potentially salvageable myocardium is of significant clinical
      importance since it may aid in determining which patients are eligible for
      revascularization.

PMID- 12602485
TI  - Evaluation of left ventricular dysfunction using multiphasic reconstructions of
      coronary multi-slice computed tomography data in patients with chronic ischemic
      heart disease: validation against cine magnetic resonance imaging.
AB  - PURPOSE: Multi-slice computed tomography (MSCT) is an emerging technique for the
      angiographic assessment of coronary artery disease (CAD). The purpose of this
      work was to determine if multiphasic reconstructions of the same data used for
      the assessment of CAD could also be used for global functional evaluation of the
      left ventricle (LV). MATERIALS AND METHODS: Fifteen patients with chronic
      ischemic heart disease (CIHD) were imaged for CAD using a contrast-enhanced
      retrospective electrocardiographic-gated spiral technique on a MSCT scanner. The
      same data were reconstructed at both end-diastole and end-systole in order to
      measure left ventricular end-diastolic volume (LVEDV), end-systolic volume
      (LVESV), and ejection fraction (LVEF). The results were compared to values
      obtained using a cine true-fast imaging with steady-state precession technique on
      a magnetic resonance imaging (MRI) scanner. Interobserver variability in the
      measurement from MSCT images was also evaluated. RESULTS: For LVEF, there was
      substantial agreement between MSCT and MRI (intraclass correlation coefficient of
      0.825); the intermodality reproducibility for LVEF (5%) was within an acceptable
      clinical range. However, mean values of LVEDV and LVESV with MSCT compared to
      cine MRI (LVEDV: 262.0 +/- 85.6 ml and 297.2 +/- 98.8 ml, LVESV: 196.2 +/- 75.6
      ml and 218.6 +/- 90.99 ml, respectively) were significantly less for both volumes
      (p < 0.015). Intermodality variabilities for these measurements were high (15 and
      13% for LVEDV and LVESV, respectively). Readers' mean measurements of LVESV from
      MSCT images were significantly different (p = 0.003) resulting in differences in
      calculation of LVEF (p < 0.024). Still, interobserver variabilities for all
      values were acceptable (6, 8, and 5% for LVEDV, LVESV, and LVEF, respectively).
      CONCLUSION: Although values for LVEDV and LVESV were less with MSCT than with
      MRI, LVEF values were in agreement. This suggests that combined imaging of CAD
      and the evaluation of global LV dysfunction due to CIHD is feasible with the same
      MSCT acquisition.

PMID- 12602486
TI  - Electron beam computed tomography appearance of endocardial fibroelastosis EBCT
      appearance of endocardial fibroelastosis.
AB  - Recent reports of endocardial fibroelastosis (EFE) have not reported the disease
      to be correctly diagnosed during the patients' life spans. Our purpose in this
      communication is to provide some feasible approaches toward correct diagnosis at
      the primitive stage and possible correlations to the prognosis. We analyzed five
      cases of EFE from 1997 to 2001. Four had pathology proven EFE. Data were sampled
      from the clinical symptoms, eletrocardiography, echocardiography, electron beam
      computed tomography (EBCT), management, and prognosis. A case of anomalous left
      coronary artery originating from main pulmonary artery diagnosed EFE correctly
      before death by utilizing an EBCT. The second case was double outlet of the right
      ventricle with severe calcification and fibrosis shown on EBCT studies, while the
      third case had severe calcification over both apices. Both patients required
      heart transplantation. The fourth case, with a decreasing ejection fraction, was
      idiopathic hypertropic subaortic stenosis with mild calcification and fibrosis on
      the EBCT images. The last stationary case had severe aortic stenosis with trivial
      fibrotic change and calcification. We propose that EBCT may accurately help to
      diagnose EFE before pathology confirmation. The magnitude of calcification and
      fibrotic thickness in the myocardium of the EBCT imaging may predict the outcome
      of EFE.

PMID- 12602488
TI  - Blinding controlled-release tablets for clinical trials.
AB  - The objective of the current study was to develop a method to blind commercially
      available Wellbutrin SR 150 mg sustained-release tablets for a clinical study.
      Overcoating was selected as the most appropriate blinding method. Hydroxypropyl
      methylcellulose (Opadry II) containing red iron oxide and titanium dioxide was
      applied to the Wellbutrin tablets at coating levels ranging from 0.5% to 4%
      weight gain. When compared against the uncoated product, no significant
      differences in drug release were noted over an 8-hr period. Matching placebo
      tablets, prepared using specially designed tablet tooling, were coated with the
      same cellulosic polymer that was used for the active. The coated active and
      placebo tablets were virtually indistinguishable. To test the applicability of
      this overcoating technique for blinding other controlled release products, the
      same procedure was used to coat Glucotrol XL 5 mg tablets and Theo-Dur 200 mg
      tablets. The debossing on the Theo-Dur tablets and the laser-drilled hole on the
      surface of the Glucotrol tablets prevented blinding. The Theo-Dur tablets were
      mechanically weak and not able to withstand the coating process. Dissolution
      testing revealed significantly higher amounts of drug were released from the
      blinded Glucotrol tablets compared to the unblinded product at the 12 hr time
      point. The findings from this study suggest that overcoating with pigmented
      hydroxypropyl methylcellulose may not be useful for blinding all controlled
      release tablets.

PMID- 12602487
TI  - Development and in vitro evaluation of diltiazem hydrochloride transdermal
      patches based on povidone-ethylcellulose matrices.
AB  - To select a suitable formulation for the development of transdermal drug-delivery
      system of diltiazem hydrochloride. Transdermal patches of the drug, employing
      different ratios of polymers, ethylcellulose (EC), and povidone (PVP) were
      developed and evaluated for the potential drug delivery using depilated freshly
      excised abdominal mouse skin. The influence of different film compositions on in
      vitro drug permeation into receptor fluid were studied using a modified Franz
      diffusion cell. The cumulative amount of drug was found to be proportional to the
      square root of time, i.e., Higuchi kinetics. From this study, it was concluded
      that the films composed of povidone:ethylcellulose (1:2) should be selected for
      the development of transdermal drug-delivery system of diltiazem hydrochloride,
      using a suitable adhesive layer and backing membrane, for potential therapeutic
      use.

PMID- 12602490
TI  - Physicochemical properties of amphotericin B liposomes prepared by reverse-phase
      evaporation method.
AB  - The physicochemical properties of phosphatidylcholine-cholesterol liposomes
      containing amphotericin B and prepared by reverse-phase evaporation method were
      studied. Uniformly dispersed liposomal suspensions were obtained by employing 3:1
      ratio (by volume) of diethyl ether to normal saline, 5 min sonication time at 7
      degrees C, and evaporation of diethyl ether at 25 degrees C. Microscopic
      examination showed that the prepared liposomes were spheroids with unilamellar,
      oligolamellar, or multilamellar structure. The liposomes containing amphotericin
      B 2.0 mol% of total lipid led to the highest percentage of drug entrapment.
      Liposomes with maximum entrapment efficiency were obtained from using 250
      micromol of total lipid. The liposomal amphotericin B possessing the highest drug
      entrapment efficiency (approximately 95%) with particle size range of 1307-1451
      nm was the one composed of 1:1 molar ratio of phosphatidylcholine to cholesterol.

PMID- 12602489
TI  - Influence of physiological variables on the in vitro drug-release behavior of a
      polysaccharide matrix controlled-release system.

PMID- 12602491
TI  - HPFP, a model propellant for pMDIs.
AB  - A novel model propellant for the study of the properties of pMDIs (pressurized
      metered-dose inhalers) at atmospheric pressure is proposed and extensively
      characterized. The reasons for the choice of this liquid, with its advantages and
      drawbacks, are explained and justified. Comparison with existing fluorinated
      propellants is also documented.

PMID- 12602492
TI  - Effects of oils and pharmaceutical excipients on the bioavailability of
      ampicillin orally administered, different oily and aqueous suspensions in rabbit.
AB  - The in vivo bioavailability and in vitro drug-release studies of ampicillin
      trihydrate in different oily and aqueous suspensions have been investigated. In
      addition, partition, solubility, and rheological measurements have also been
      carried out. The in vivo experimental design was based on a 6 x 6 latin square
      using the rabbit as the test animal. The bioavailability of ampicillin was
      determined using the plasma levels, which were measured microbiologically.
      Results of the study showed that oily and sucrose-containing aqueous formulations
      enhanced the extent of ampicillin absorption, although not statistically
      significantly, but was close to the borderline of significance. Ampicillin
      appears to be absorbed at essentially the same rate from both aqueous and oily
      formulations. The latter showed plasma-level time curves with biphasic absorption
      and are likely to produce prolonged plasma concentrations of ampicillin because
      of the effects of enterohepatic recycling. Viscosity appears to play an
      insignificant role in the results obtained since the bioavailability parameters
      correlate poorly with the viscosity except Cmax. It is suggested that enhancement
      in the bioavailability of ampicillin is due to the decrease in the gut transit
      rate brought about by the oil which predominates and masks the other effects of
      viscosity and osmotic effects of sucrose. The existence of a correlation between
      the in vitro drug-release rate (t50%) and viscosity and the lack of a correlation
      between in vivo and in vitro parameters support the above suggestion and indicate
      that traditional dissolution rate tests, such as flask-stirrer method, are
      unsatisfactory as bioavailability indicators when applied to dosage forms that
      caused marked changes in physiological factors like GER and biliary excretion.

PMID- 12602493
TI  - Evaluation of the mucoadhesive properties of N-trimethyl chitosan chloride.
AB  - Previous studies have established that N-trimethyl chitosan chloride (TMC) is a
      potent absorption enhancer for peptides and large hydrophilic compounds across
      mucosal surfaces, especially in neutral and basic environments where chitosan is
      ineffective as an absorption enhancer. The degree of quaternization of TMC plays
      an important role on its absorption-enhancing properties. Several TMC polymers
      with different degrees of quaternization were synthesized and the molecular mass
      of the polymers was determined by SEC/MALLS. The mucoadhesive properties of the
      TMC polymers were measured with a modified tensiometer based on the Willhelmy
      plate method. The effect of the TMC polymers on the surface tension of a mixture
      of polymer and mucus was measured with a Du Nouy tensiometer. The degrees of
      quaternization of the synthesized TMC polymers were between 22.1% and 48.8% and
      the molecular mass was above 100,000 g/mole for all the polymers. A decrease in
      mucoadhesivity with an increase in the degree of quaternization of the TMC
      polymers was found. Surface-tension analysis of a mixture of polymer and mucus
      showed the effect of excessive polymer hydration on mucoadhesion. The results
      show that the degree of quaternization of TMC had a pronounced effect on the
      mucoadhesive properties of this polymer. Although the mucoadhesive profiles for
      the TMC polymers were lower than the original chitosan, they still retained
      sufficient mucoadhesive properties for successful inclusion into mucoadhesive
      dosage forms.

PMID- 12602494
TI  - Acrylate-based transdermal therapeutic system of nitrendipine.
AB  - The objective of the present research investigation was to fabricate an acrylate
      based transdermal therapeutic system (TTS) of nitrendipine, which could deliver
      drug at maximum input rate so as to deliver drug in minimum patch size.
      Transdermal patches were fabricated using synthesized acrylate pressure-sensitive
      adhesives (PSAs): PSA1, PSA2, and commercially available PSA3 and PSA4 using d
      limonene as permeation enhancer. Effect of concentration of d-limonene on
      permeation kinetics of nitrendipine in PSAs was studied. Fabricated TTS in
      mentioned PSAs were evaluated for in-vitro release and permeation kinetics
      through guinea-pig skin. Cumulative release of drug in PSA1, PSA2, PSA3, and PSA4
      was observed to be 45%, 40%, 25%, and 25%, respectively, upto 24 hr. Flux of drug
      through guinea-pig skin calculated at 48 hr in PSA1, PSA2, PSA3, and PSA4, with
      and without d-limonene, was observed to be 0.346+/-0.10, 0.435+/-0.17, 0.410+/
      0.17, and 0.162+/-0.06, and 0.625+/-0.19, 1.161+/-0.46, 0.506+/-0.17, and 0.520+/
      0.18 (microg/cm2/hr), respectively. The TTS in PSA2 showed comparatively high
      flux and could deliver drug at high input rate through transdermal route. PSA2
      was found to have good rate-controlling property and could be successfully
      employed in transdermal delivery of nitrendipine.

PMID- 12602496
TI  - Evaluation of mathematical models describing drug release from estradiol
      transdermal systems.
AB  - The in vitro release profiles of 13 patches of estradiol (from five marketed
      products) were determined by the paddle-over-disk method. The transdermal systems
      were membrane-controlled type or matrix diffusion-controlled type. The estradiol
      content of test aliquots of the dissolution medium was determined by HPLC. To
      analyze the release mechanism, several release models were tested such as zero
      order, first order, Higuchi, Weibull, Korsmeyer-Peppas, and Makoid-Banakar. The
      release profiles showed that the drug was released at a constant rate for three
      patches. The drug-release rate from the other 10 patches was not constant, and
      diminished with the square-root of time (Higuchi model).

PMID- 12602495
TI  - Effects of manufacturing process variables on in vitro dissolution
      characteristics of extended-release tablets formulated with hydroxypropyl
      methylcellulose.
AB  - The purpose of this study was to investigate the effect of three process
      variables: distribution of hydroxypropyl methylcellulose (HPMC) within the tablet
      matrix, amount of water for granulation, and tablet hardness on drug release from
      the hydrophilic matrix tablets. Tablets were made both by direct compression as
      well as wet granulation method. Three formulations were made by wet granulation,
      all three having the exact same composition but differing in
      intragranular:intergranular HPMC distribution in the matrix. Further, each
      formulation was made using two different amounts of water for granulation. All
      tablets were then compressed at two hardness levels. Dissolution studies were
      performed on all tablets using USP dissolution apparatus I (basket). The
      dissolution parameters obtained were statistically analyzed using a multilevel
      factorial-design approach to study the influence of the various process variables
      on drug release from the tablets. Results indicated that a change in the
      manufacturing process could yield significantly dissimilar dissolution profiles
      for the same formulation, especially at low-hardness level. Overgranulation could
      lead to tablets showing hardness-dependent drug-release characteristics. Studies
      showed that intergranular addition of a partial amount of HPMC (i.e., HPMC
      addition outside of granules) provided a significant advantage in making the
      formulation more robust over intragranular addition (i.e., that in which the
      entire amount of HPMC was added to the granules). Dissolution profiles obtained
      for these tablets were relatively less dependent on tablet hardness irrespective
      of the amount of water added during granulation.

PMID- 12602497
TI  - Development of a novel soft hydrogel for the transdermal delivery of
      testosterone.
AB  - A soft hydrogel formulation for the transdermal delivery of testosterone (TS) was
      developed, and the effect of various skin-permeation enhancers was studied in
      vitro and in vivo. Testosterone was incorporated into a polyvinyl alcohol (PVA)
      based soft hydrogel with polyisobutylene (PIB) and various skin-permeation
      enhancers (dodecylamine, HPE101, oleic acid, or lauric acid). In vitro rat-skin
      permeation of TS from the soft hydrogel was investigated using Keshary-Chien
      diffusion cells for 24 hr at 37 degrees C. In vivo plasma-concentration profiles
      of TS after applying the soft hydrogel on the dorsal skin of rat were determined
      using a commercial radioimmunoassay kit. The formulated soft hydrogel formed a
      thin film on the skin within 2 to 3 min after application and remained in a dried
      film state for at least 24 hr. Addition of PIB into the hydrogel to increase the
      adhesion resulted in a negligible reduction in the skin-permeation rate of TS.
      However, rat-skin permeation of TS increased with the addition of permeation
      enhancers both in vitro and in vivo. Dodecylamine at the concentration of 3% was
      the most effective among tested. Plasma concentration of TS significantly
      increased for at least 24 hr with the addition of dodecylamine. These results
      suggest the feasibility of the development of a soft hydrogel formulation for the
      transdermal delivery of TS.

PMID- 12602498
TI  - Examination of 19F-NMR as a tool for investigation of drug-cyclodextrin
      complexes.
AB  - Fluorine nuclear magnetic-resonance spectroscopy (19F-NMR) was used to measure
      complexation of three fluorine-containing drugs--dexamthasone, fluoxetine
      hydrochloride, and diflunisal sodium--with 2-hydroxypropyl-beta-cyclodextrin
      (HPbetaCD). Poor aqueous solubility inhibited investigation of dexamethasone
      complexes with this method. Complexation caused separation of the fluorine peaks
      that could be assigned to the two enantiomers of fluoxetine hydrochloride. The
      trifluoromethyl group of the drug was not included, or only partially included,
      in the cyclodextrin cavity and the shift changes resulting from complexation were
      small (0.04 and -0.05 ppm). The NMR method, therefore, could not be used to
      determine complex stoichiometry and complex stability constants, as chemical
      shift changes were influenced by changes in the composition of the solvent
      medium. The difluorophenyl group of diflunisal sodium was fully included in the
      cyclodextrin cavity and the chemical-shift changes were large, 2.0 and 1.4 ppm,
      for C2' and C4' fluorine atoms, respectively. Using the continuous variation
      method, a 1:1 stoichiometry was determined for the complex. The chemical shift
      changes could also be used to determine the stability constant (Kc) for complex
      formation. The value obtained for the fluorine that enters deeper into the cavity
      was 2000 M(-1). The data shows that, given that the drug has sufficient
      solubility, one-dimensional 19F-NMR can be a fast and convenient method to
      investigate drug-cyclodextrin complexes. However, when the results are
      interpreted it must be taken into account that the solvent medium can affect the
      chemical shifts of the fluorine peaks.

PMID- 12602499
TI  - Pathophysiology of hepatic encephalopathy: a new look at ammonia.
AB  - Results of neuropathologic, spectroscopic, and neurochemical studies continue to
      confirm a major role for ammonia in the pathogenesis of the central nervous
      system complications of both acute and chronic liver failure. Damage to
      astrocytes characterized by cell swelling (acute liver failure) or Alzheimer Type
      II astrocytosis (chronic liver failure) can be readily reproduced by acute or
      chronic exposure of these cells in vitro to pathophysiologically relevant
      concentrations of ammonia. Furthermore, exposure of the brain or cultured
      astrocytes to ammonia results in similar alterations in expression of genes
      coding for key astrocytic proteins. Such proteins include the structural glial
      fibrillary acidic protein, glutamate transporters, and peripheral-type
      (mitochondrial) benzodiazepine receptors. Brain-blood ammonia concentration
      ratios (normally of the order of 2) are increased up to fourfold in liver failure
      and arterial blood ammonia concentrations are good predictors of cerebral
      herniation in patients with acute liver failure. Studies using 1H magnetic
      resonance spectroscopy in patients with chronic liver failure reveal a positive
      correlation between the severity of neuropsychiatric symptoms and brain
      concentrations of the brain ammonia-detoxification product glutamine. Increased
      intracellular glutamine may be a contributory cause of brain edema in
      hyperammonemia. Positron emission tomography studies using 13HN3 provide evidence
      of increased blood-brain ammonia transfer and brain ammonia utilization rates in
      patients with chronic liver failure. In addition to the use of nonabsorbable
      disaccharides and antibiotics to reduce gut ammonia production, new approaches to
      the treatment of hepatic encephalopathy by lowering of brain ammonia include the
      use of L-ornithine-L-aspartate and mild hypothermia.

PMID- 12602500
TI  - Cerebral blood flow in hyperammonemia: heterogeneity and starling forces in
      capillaries.
AB  - In the brain hyperammonemia interferes with ion homeostasis, membrane potentials,
      neurotransmission, and neurotransmitter recycling and reduces metabolic rates for
      oxygen and glucose. Because, cerebral blood flow (CBF) is closely coupled to
      metabolism, CBF is most often reduced in diseases associated with hyperammonemia.
      However, in severe cases of hyperammonemia, as in patients with acute liver
      failure, Reye's syndrome, and inherited metabolic disorders of the urea cycle,
      the normal regulation of CBF is also impaired. One of the most prominent findings
      is a failure of CBF autoregulation that uncouples metabolism from CBF. Clinically
      failure of autoregulation may imply that both cerebral hypoxia and hyperaemia may
      develop in the patient depending on the driving pressure of the brain, i.e.,
      cerebral perfusion pressure. In addition a gradual "nonreactive" dilatation of
      the cerebral arterioles often aggravates the mismatch between nutritive demands
      and delivery in the brain. The reason for arteriolar dilation and homogeneous
      capillary blood flow is not settled but seems not to be mediated by excessive
      release of nitro oxide. More likely the arachidonic acid cascade with increased
      synthesis of prostaglandins, cytochrome P450 metabolites, and potassium channel
      activation are implicated in this vasodilatation. The combination of cerebral
      hyperaemia, increased hydrostatic capillary blood pressure, and accumulation of
      organic and nonorganic osmolytes within the brain during hyperammonemia clearly
      will favor cerebral capillary water influx. This imbalance between colloid
      osmotic and hydrostatic pressures in patients with severe hyperammonemia means
      that simple interventions based on physiological principles may help ameliorate
      cerebral hyperaemia and water influx. Thus, it is suggested that not only
      monitoring of intracranial pressure (ICP) and cerebral perfusion are pivotal to
      help prevent high ICP but also basic clinical information, such as Tp, PaCO2, and
      plasma sodium/glucose concentrations, should be closely followed and corrected.

PMID- 12602502
TI  - Increased extracellular brain glutamate in acute liver failure: decreased uptake
      or increased release?
AB  - Glutamatergic dysfunction has been suggested to play an important role in the
      pathogenesis of hepatic encephalopathy (HE) in acute liver failure (ALF).
      Increased extracellular brain glutamate concentrations have consistently been
      described in different experimental animal models of ALF and in patients with
      increased intracranial pressure due to ALF. High brain ammonia levels remain the
      leading candidate in the pathogenesis of HE in ALF and studies have demonstrated
      a correlation between ammonia and increased concentrations of extracellular brain
      glutamate both clinically and in experimental animal models of ALE Inhibition of
      glutamate uptake or increased glutamate release from neurons and/or astrocytes
      could cause an increase in extracellular glutamate. This review analyses the
      effect of ammonia on glutamate release from (and uptake into) both neurons and
      astrocytes and how these pathophysiological mechanisms may be involved in the
      pathogenesis of HE in ALF.

PMID- 12602501
TI  - Effects of hyperammonemia and liver failure on glutamatergic neurotransmission.
AB  - Glutamate is the main excitatory neurotransmitter in mammals. Glutamatergic
      neurotransmission involves several steps, beginning with release of glutamate
      from the presynaptic neuron. Glutamate in the extracellular space activates
      glutamate receptors present in the synaptic membranes, leading to activation of
      signal transduction pathways associated with these receptors. To avoid continuous
      activation of glutamate receptors, glutamate is removed from the synaptic cleft
      by specific glutamate transporters located mainly on astrocytes. All these steps
      are tightly modulated under physiological conditions, and alterations of any of
      the above steps may result in impairment of glutamatergic neurotransmission,
      leading to neurological alterations. There are studies in the literature
      reporting alterations in all these steps in hyperammonemia and/or hepatic
      failure. Glutamatergic neurotransmission modulates important cerebral processes.
      Some of these processes are altered in patients with liver disease and hepatic
      encephalopathy, who show altered sleep-wake patterns, neuromuscular coordination,
      and decreased intellectual capacity. The alterations in glutamatergic
      neurotransmission may be responsible for some of these neurological alterations
      found in hepatic encephalopathy. The effects of hyperammonemia and liver failure
      on different steps of glutamatergic neurotransmission including alterations of
      glutamate concentration in the extracellular fluid in brain, transport and
      transporters of glutamate, the content and function of different types of
      glutamate receptors and signal transduction pathways. Alterations induced by
      hyperammonemia and liver failure on the glutamate-nitric oxide-cGMP pathway in
      brain may result in changes in long-term potetiation and learning ability.

PMID- 12602503
TI  - Reduced expression of astrocytic glycine transporter (Glyt-1) in acute liver
      failure.
AB  - A growing body of evidence suggests that alterations in N-methyl-D-asparate NMDA
      mediated excitatory neurotransmission may be involved in the pathophysiology of
      hepatic encephalopathy (HE) in acute liver failure (ALF). The NMDA receptor
      requires glycine as a positive allosteric modulator. One of the glycine
      transporters Glyt-1 is expressed primarily in astrocytes of the cerebral cortex
      in association with regions of high NMDA receptor expression. As astrocytic
      transporters regulate the amino acid concentrations within excitatory synapses,
      the expression of Glyt-1 was studied in cortical preparations from rats with
      ischemic liver failure induced by portacaval anastomosis followed 24 hr later by
      hepatic artery ligation and from appropriate sham-operated controls. Expression
      of Glyt-1 mRNA, studied by reverse transcriptase-polymerase chain reaction, was
      significantly decreased in the brain at coma stages of encephalopathy (to
      approximately 50% of control) concomitant with a significant threefold increase
      of extracellular glycine, measured by in vivo cerebral microdialysis. These
      findings suggest that loss of expression of the Glyt-1 transporter may cause an
      impairment of regulation of glycine concentration at synaptic level and
      contribute to an overactivation of the NMDA receptor in ALF. The use of NMDA
      receptor antagonists, aimed specifically at the glycine modulatory site, could
      offer novel approaches to the prevention and treatment of HE in ALF.

PMID- 12602504
TI  - Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy.
AB  - There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic
      encephalopathy with a multifactorial pathogenesis. One of the factors considered
      to be important in the pathogenesis of HE is ammonia. However, the mechanisms by
      which ammonia contributes to the manifestations of HE remain poorly defined.
      Ammonia could be more definitively implicated in the pathogenesis of HE if its
      effects can be shown to lead to an enhancement of inhibitory neurotransmission.
      In this context the effects of ammonia on the GABA (gamma-aminobutyric acid)
      neurotransmitter system may be relevant. Ammonia, at the modestly increased
      concentrations that commonly occur in precoma HE (0.15 mM-0.75 mM), has been
      shown to increase GABA-induced chloride current in cultured neurons, probably by
      modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia
      concentrations also enhanced synergistically the binding of a GABA agonist and a
      benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which
      would enhance the neuroinhibitory effects of these ligands. Also, GABA increased
      the potency of ammonia-induced enhancement of the binding of a BZ agonist to the
      GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver
      failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA
      by 30%-50%, an effect which would increase the synaptic availability of GABA at
      GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the
      peripheral-type benzodiazepine receptor in the outer membrane of astroglial
      mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of
      neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and
      tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A)
      receptor complex, on which there are specific binding sites for neurosteroids,
      that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and
      tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model
      of acute liver failure, and, when THP or THDOC was injected into normal mice,
      sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and
      hypothalmus were induced. Each of these direct or indirect effects of ammonia on
      the GABA neurotransmitter system has the potential of increasing inhibitory
      neurotransmission, and, hence, contributing to the manifestations of HE.

PMID- 12602506
TI  - Altered modulation of soluble guanylate cyclase by nitric oxide in patients with
      liver disease.
AB  - The glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in animal
      models of chronic moderate hyperammonemia either with or without liver failure.
      The impairment occurs at the level of activation of soluble guanylate cyclase by
      nitric oxide (NO). It has been suggested that the impairment of this pathway may
      be responsible for some of the neurological alterations found in hyperammonemia
      and hepatic encephalopathy. Soluble guanylate cyclase is also present in
      lymphocytes. Activation of guanylate cyclase by NO is also altered in lymphocytes
      from hyperammonemic rats or from rats with portacaval anastomosis. We assessed
      whether soluble guanylate cyclase activation was also altered in human patients
      with liver disease. We studied activation of soluble guanylate cyclase in
      lymphocytes from 77 patients with liver disease and 17 controls. The basal
      content of cGMP in lymphocytes was decreased both in patients with liver
      cirrhosis and in patients with chronic hepatitis. In contrast, cGMP concentration
      was increased in plasma from patients with liver disease. Activation of guanylate
      cyclase by NO was also altered in liver disease and was higher in lymphocytes
      from patients with cirrhosis or hepatitis than that in lymphocytes from controls.
      Successful treatment with interferon of patients with hepatitis C reversed all
      the above alterations. Altered modulation of soluble guanylate cyclase by NO in
      liver disease may play a role in the neurological and hemodynamic alterations in
      these patients.

PMID- 12602505
TI  - The role of inhibitory amino acidergic neurotransmission in hepatic
      encephalopathy: a critical overview.
AB  - Gamma-Aminobutyric acid (GABA) is the main inhibitory amino acid in the central
      nervous system (CNS). Experiments with animal models of HE, and with brain slices
      or cultured CNS cells treated with ammonia, have documented changes in GABA
      distribution and transport, and modulation of the responses of both the GABA(A)
      benzodiazepine receptor complex and GABA(B) receptors. Although many of the data
      point to an enhancement of GABAergic transmission probably contributing to HE,
      the evidence is not unequivocal. The major weaknesses of the GABA theory are (1)
      in a vast majority of HE models, there were no alterations of GABA content in the
      brain tissue and/or extracellular space, indicating that exposure of neurons to
      GABA may not have been altered, (2) changes in the affinity and capacity of GABA
      receptor binding were either absent or qualitatively different in HE models of
      comparable severity and duration, and (3) no sound changes in the GABAergic
      system parameters were noted in clinical cases of HE. Taurine (Tau) is an amino
      acid that is thought to mimic GABA function because of its agonistic properties
      towards GABA(A) receptors, and to contribute to neuroprotection and
      osmoregulation. These effects require Tau redistribution between the different
      cell compartments and the extracellular space. Acute treatment with ammonia
      evokes massive release of radiolabeled or endogenous Tau from CNS tissues in vivo
      and in vitro, and the underlying mechanism of Tau release differs from the
      release evoked by depolarizing conditions or hypoosmotic treatment. Subacute or
      chronic HE, and also long-term treatment of cultured CNS cells in vitro with
      ammonia, increase spontaneous Tau "leakage" from the tissue. This is accompanied
      by a decreased potassium- or hypoosmolarity-induced release of Tau and often by
      cell swelling, indicating impaired osmoregulation. In in vivo models of HE, Tau
      leakage is manifested by its increased accumulation in the extrasynaptic space,
      which may promote inhibitory neurotransmission and/or cell membrane protection.
      In chronic HE in humans, decreased Tau content in CNS is thought to be one of the
      causes of cerebral edema. However, understanding of the impact of the changes in
      Tau content and transport on the pathogenic mechanisms of HE is hampered by the
      lack of clear-cut evidence regarding the various roles of Tau in the normal CNS.

PMID- 12602507
TI  - Nitric oxide in patients with cirrhosis and bacterial infections.
AB  - Nitric oxide (NO) is a powerful vasodilator agent that has been found to be
      elevated in patients with cirrhosis, and that plays a key role in the
      pathogenesis of the hemodynamic abnormalities found in these patients. The
      reasons for this increased NO synthesis are not entirely known, but at least two
      main mechanisms are involved: shear stress and bacterial-induced NO synthesis.
      This review focuses on bacterial-induced NO synthesis. Induction of NO synthesis
      by different cellular populations occurs when proinflammatory cytokines act
      synergistically, and also by endotoxin. Spontaneous bacterial peritonitis (SBP)
      is the most dangerous infectious complication arising in patients with cirrhosis
      and ascites, and it is associated with high serum and ascitic fluid levels of
      proinflammatory cytokines. A subset of patients in this situation show high
      levels of serum and ascitic fluid NO levels when SBP is diagnosed, and these
      patients seem to be predisposed to the development of renal impairment. The
      increased NO synthesis and associated aggravated vasodilatation may be the reason
      why patients with SBP show high levels of plasma renin activity, in an attempt to
      counterbalance this new situation, and that the administration of albumin during
      the SBP episode significantly reduces the episode-related mortality.

PMID- 12602508
TI  - Nitric oxide and portal hypertension.
AB  - In liver cirrhosis, an increase in hepatic resistance is the initial phenomenon
      leading to portal hypertension. This is primarily due to the structural
      distortion of the intrahepatic microcirculation caused by cirrhosis. However,
      similar to other vascular conditions, architectural changes in the liver are
      associated with a deficient nitric oxide (NO) production, which results in an
      increased vascular tone with a further increase in hepatic resistance and portal
      pressure. New therapeutic strategies are being developed to selectively provide
      the liver with NO, overcoming the deleterious effects of systemic vasodilators.
      On the other hand, a strikingly opposite process occurs in splanchnic arterial
      circulation, where NO production is increased. This results in splanchnic
      vasodilatation and subsequent increase in portal inflow, which contributes to
      portal hypertension. Systemic blockade of NO in portal hypertension attenuates
      the hyperdynamic circulation, but its effects increasing hepatic resistance may
      offset the benefit of reducing portal inflow, thus preventing an effective
      reduction of portal pressure. Moreover, it cannot be ruled out that NO blockade
      may have a deleterious action on cirrhosis progression, which raises caution
      about their use in patients with cirrhosis.

PMID- 12602509
TI  - Nitric oxide in liver inflammation and regeneration.
AB  - Hepatocytes express and release inflammatory mediators after challenge with
      bacterial cell wall molecules and proinflammatory cytokines. Nitric oxide
      synthase-2 (NOS-2) is expressed under these conditions and the high-output NO
      synthesis that follows contributes to the inflammatory response in this tissue
      and participates in the onset of several hepatopathies. However, in the course of
      liver regeneration, for example, after partial hepatectomy, NOS-2 is expressed at
      moderate levels and contributes to inhibit apoptosis and to favor progression in
      the cell cycle until the organ size and function are restored. The mechanisms
      involved in the regulation of NOS-2 expression under these conditions are
      revised.

PMID- 12602510
TI  - Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate
      carrier) deficiency.
AB  - Adult-onset type II citrullinemia (CTLN2), characterized by a liver-specific
      deficiency of urea cycle enzyme, argininosuccinate synthetase, is caused by
      mutations in SLC25A13 that encodes a calcium binding mitochondrial solute carrier
      protein, citrin. Citrin deficiency causes not only CTLN2 but also neonatal
      intrahepatic cholestasis caused by citrin deficiency at neonatal period. Moreover
      citrin and its isoform aralar were found to be aspartate glutamate carrier. From
      the viewpoint of the metabolic functions of citrin as aspartate glutamate carrier
      in urea synthesis and NADH shuttle, symptoms of CTLN2 and neonatal intrahepatic
      cholestasis caused by citrin deficiency are analyzed.

PMID- 12602511
TI  - Central nervous system alterations in liver cirrhosis: the role of portal
      systemic shunt and portal hypoperfusion.
AB  - The role of portal-systemic shunting and portal liver hypoperfusion in the
      pathophysiology of central nervous system dysfunction of cirrhosis is not yet
      well defined. It is well known that one of the most important collateral vessels
      (CV) is a patent paraumbilical vein (PUV) but there is controversy regarding its
      clinical significance. We have evaluated the relationships between
      neuropsychological and EEG alterations, ammonia plasma level (NH4), hepatic
      function, and portal hemodynamics (Doppler Ultrasound) in 95 cirrhotic patients.
      Patency, diameter, or flow of PUV or the presence of other CV were not related to
      an increased prevalence of neuropsychological or EEG abnormalities. Patients with
      effective portal flow (EPF = portal flow - PUV flow) lower than 692 mL/min
      (median) had a significantly higher risk of failing the neuropsychological test,
      or of having an altered EEG. Low EPF and prothrombin time (<50%), and high NH4 (>
      or = 51 micromol/L) were independent predictors of an abnormal EEG. Considering
      both low EPF and the numerosity of CV, only low EPF was found to explain EEG
      alterations. In conclusion, portal liver hypoperfusion and decreased liver
      function were associated with an increased risk of central nervous system
      dysfunction in cirrhotic patients, whereas PUV patency per se was not.

PMID- 12602514
TI  - Manganese neurotoxicity: an update of pathophysiologic mechanisms.
AB  - The central nervous system, and the basal ganglia in particular, is an important
      target in manganese neurotoxicity, a disorder producing neurological symptoms
      similar to that of Parkinson's disease. Increasing evidence suggests that
      astrocytes are a site of early dysfunction and damage; chronic exposure to
      manganese leads to selective dopaminergic dysfunction, neuronal loss, and gliosis
      in basal ganglia structures together with characteristic astrocytic changes known
      as Alzheimer type II astrocytosis. Astrocytes possess a high affinity, high
      capacity, specific transport system for manganese facilitating its uptake, and
      sequestration in mitochondria, leading to a disruption of oxidative
      phosphorylation. In addition, manganese causes a number of other functional
      changes in astrocytes including an impairment of glutamate transport, alterations
      of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, production of
      nitric oxide, and increased densities of binding sites for the "peripheral-type"
      benzodiazepine receptor (a class of receptor predominantly localized to
      mitochondria of astrocytes and involved in oxidative metabolism, mitochondrial
      proliferation, and neurosteroid synthesis). Such effects can lead to compromised
      energy metabolism, resulting in altered cellular morphology, production of
      reactive oxygen species, and increased extracellular glutamate concentration.
      These consequences may result in impaired astrocytic-neuronal interactions and
      play a major role in the pathophysiology of manganese neurotoxicity.

PMID- 12602512
TI  - Hyperammonemia in carnitine-deficient adult JVS mice used by starvation.
AB  - Juvenile visceral steatosis (JVS) mouse is an animal model of human primary
      carnitine deficiency caused by a mutation of the gene encoding carnitine
      transporter, and suffers from various symptoms, such as fatty liver, growth
      retardation, hyperammonemia, hypoglycemia, and cardiac hypertrophy. We have shown
      that hyperammonemia during the weaning period (15-26 days of age) is caused by
      suppression of urea cycle enzyme gene expression. The suppression resulted from
      activation of a transcription factor, AP-1. We have found that a cis-element for
      AP-1 binding is present in the enhancer region of the carbamoylphosphate
      synthetase (CPS) gene, and that the AP-1 binding site is involved in the
      suppression of CPS induction by dexamethasone in cultured hepatocytes and in the
      suppression of CPS expression in the liver of JVS mice. The blood ammonia levels
      in JVS mice increased during the weaning period, and then decreased to almost
      control levels after 30 days of age. In this paper, we report that in adult JVS
      mice, ammonia levels again increased after starvation for at least 24 hr and this
      effect was suppressed by carnitine treatment. Starvation for 48 hr did not
      significantly suppress CPS activity in the liver and did not cause any change in
      hepatic ornithine concentration. The concentration of N-acetylglutamate in the
      liver of starved JVS mice was not significantly different from that of JVS mice
      treated with carnitine. These results indicate that the hyperammonemia in
      carnitine-deficient adult JVS mice during starvation and the suppression by
      carnitine treatment differ from those found during the weaning period, and thus
      the cause of hyperammonemia and the mechanism of suppression remain to be solved.

PMID- 12602513
TI  - Valproate-induced hyperammonemic encephalopathy.
AB  - Valproic acid (VPA) is an effective anticonvulsant useful in many types of
      epilepsy and, although it is usually well tolerated, it has been associated with
      many neurological and systemic side effects. Among these, one of the most
      important is VPA-induced hyperammonemic encephalopathy (VHE): its typical signs
      are acute onset of impaired consciousness, focal neurologic symptoms, and
      increased seizure frequency. The pathogenesis of VHE is still unclear, but it has
      been suggested that hyperammonemia can produce encephalopathy via inhibition of
      glutamate uptake by astrocytes which may lead to potential neuronal injury and
      perhaps cerebral edema. Glutamine production is increased, whereas its release is
      inhibited in astrocytes exposed to ammonia. The elevated glutamine increases
      intracellular osmolarity, promoting an influx of water with resultant astrocytic
      swelling. This swelling could compromise astrocyte energy metabolism and result
      in cerebral edema with increased intracranial pressure. Moreover, VHE seems to be
      more frequently in patients with carnitine deficiency or with congenital urea
      cycle enzymatic defects.

PMID- 12602515
TI  - Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular
      mechanisms.
AB  - Carnitine has beneficial effects in different pathologies and prevents acute
      ammonia toxicity (ammonia-induced death of animals). Acute ammonia toxicity is
      mediated by excessive activation of the NMDA-type of glutamate receptors, which
      mediates glutamate neurotoxicity. We showed that carnitine prevents glutamate
      neurotoxicity in primary cultures of cerebellar neurons. This supports the idea
      that the protective effect of carnitine against ammonia toxicity is due to the
      protective effect against glutamate neurotoxicity. We are studying the mechanism
      by which carnitine protects against glutamate neurotoxicity. Carnitine increases
      the binding affinity of glutamate for metabotropic glutamate receptors. The
      protective effect of carnitine is lost if metabotropic glutamate receptors are
      blocked with specific antagonists. Moreover, activation of metabotropic glutamate
      receptors by specific agonists also prevents glutamate neurotoxicity. This
      indicates that the protective effect of carnitine against glutamate neurotoxicity
      is mediated by activation of metabotropic glutamate receptors. The molecule of
      carnitine has a trimethylamine group. Different compounds containing a
      trimethylamine group (carbachol, betaine, etc.) also prevent ammonia-induced
      animal death and glutamate-induced neuronal death. Moreover, metabotropic
      glutamate receptor antagonists also prevent the protective effect of most of
      these compounds. We summarize here some studies aimed to identify the mechanism
      and the molecular target that are responsible for the protective effect of
      carnitine against ammonia and glutamate neurotoxicity. Finally it is also shown
      that carnitine inhibits the hydrolysis of inositol phospholipids induced by
      activation of different types of metabotropic receptors, but this effect seems
      not responsible for its protective effects.

PMID- 12602518
TI  - Positron emission tomography in the study of hepatic encephalopathy.
AB  - Positron emission tomography (PET) is a powerful and versatile tool for the
      investigation of hepatic encephalopathy (HE). This nuclear medicine imaging
      technique produces quantitative images of the distribution of a
      radiopharmaceutical at one or more times after its administration. Thus, PET
      images can be used as data in mathematical models of physiologically important
      processes, including cerebral blood flow, an index of neural activity, or glucose
      and ammonia metabolism. Using PET, we have demonstrated abnormalities in all of
      these processes in patients, even though many had only minimal HE. In HE patients
      we have found increases in the cerebral ammonia metabolic rate, because of
      hyperammonemia and an increase in the permeability of the blood-brain barrier to
      ammonia and abnormal patterns of blood flow and glucose metabolism. In a recent
      collaborative study, alterations in the resting glucose metabolic rate were found
      to have significant correlations with a variety of neuropsychological tests used
      to detect mild HE including Trailmaking A and B, symbol-digit, and other tests.
      Activation techniques have not yet been applied to map sites affected by HE, but
      recent data using the paced serial auditory addition test and an auditory
      continuous performance task have proven to be sensitive indicators in minimally
      impaired patients. The full potential of PET to evaluate neurotransmitter
      function is as yet unrealized.

PMID- 12602516
TI  - Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in
      cirrhosis and role in the pathogenesis of hepatic encephalopathy.
AB  - In hepatic encephalopathy, a progressive and diffuse impairment in brain function
      is associated with gradual alterations that can be detected by magnetic resonance
      imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS). In some
      patients, a variety of movement disorders suggestive of extrapyramidal impairment
      points toward basal ganglia (BG) alterations. Accordingly, (i) hyperintensities
      at MRI predominant in the pallidum, an important region of BG involved in the
      motor control, (ii) redistribution of cerebral blood flow from cortical areas to
      BG structures observed using positron emission tomography studies, and (iii) the
      preferential pallidal location of Alzheimer astrocytosis, all support this
      hypothesis. In most clinical studies, little if any correlations have been found
      between cerebral hyperintensities and neurological manifestations. The
      application of a test designed to evaluate patients with Parkinson's disease
      (where extrapyramidal signs are typical) showed significant clinical correlations
      both with pallidal hyperintensity and with choline/creatine ratio at 1H MRS in BG
      structures. Because of complex neuronal connections between BG and many cortical
      areas, BG dysfunction may influence the neurocognitive manifestations of hepatic
      encephalopathy. Similarities between chronic Mn intoxication and cirrhosis
      suggest common pathophysiological mechanisms including altered dopaminergic
      neurotransmission, although information in chronic liver failure is limited.
      Clinical observations are presented regarding the evolution of parkinsonian signs
      in various situations.

PMID- 12602517
TI  - 1H magnetic resonance in the study of hepatic encephalopathy in humans.
AB  - 1H magnetic resonance (1H MR) studies of the brain in patients with liver
      diseases have shown several abnormalities that may be relevant for the
      pathogenesis of hepatic encephalopathy. 1H magnetic resonance imaging shows a
      typical pallidal hyperintensity on T1-weighted images. This abnormality appears
      to be secondary to the accumulation of manganese in basal ganglia because of
      portal-systemic shunting. No direct correlation between the magnitude of pallidal
      hyperintensity and the grade of hepatic encephalopathy has been found, but some
      studies have related pallidal hyperintensity to parkinsonism. 1H magnetic
      resonance spectroscopy shows relative to creatine an increase in
      glutamine/glutamate (Glx) signal and a decrease of choline containing compounds
      (Cho) and myo-inositol. Abnormalities in the Glx signal have been interpreted as
      an increase in brain glutamine secondary to the metabolism of ammonia in
      astrocytes. Disturbances of Cho and myo-inositol have been interpreted as a
      compensatory response to the increase in intracellular osmolality caused by the
      accumulation of glutamine in astrocytes. In addition, magnetization transfer
      imaging shows signs compatible with low-grade cerebral edema. Altogether, 1H MR
      studies suggest the accumulation of manganese and the development of osmotic
      abnormalities in the brain of patients with cirrhosis. These abnormalities appear
      to participate in some of the neurological manifestations of hepatic
      encephalopathy.

PMID- 12602519
TI  - Hypothermia for the management of intracranial hypertension in acute liver
      failure.
AB  - Increased intracranial pressure in patients with acute liver failure (ALF)
      remains a major immediate cause of mortality. Several studies in animal models of
      ALF set the stage for the clinical application of moderate hypothermia in man.
      Studies in patients with ALF and increased intracranial hypertension have shown
      that temperatures as low as 32 degrees C are safe and effectively reduce
      increased intracranial pressure unresponsive to other medical therapies, and can
      be used as a successful bridge to liver transplantation. Data from studies in
      patients undergoing liver transplantation for ALF suggest that increases in
      intracranial pressure can be prevented during the dissection and reperfusion
      phases of the operation if the patients are maintained hypothermic during
      surgery. The present review focuses upon the clinical aspects of using
      hypothermia as a treatment of increased intracranial pressure in patients with
      ALF.

PMID- 12602520
TI  - Mild hypothermia in the prevention of brain edema in acute liver failure:
      mechanisms and clinical prospects.
AB  - Mild hypothermia (32 degrees C-35 degrees C) reduces intracranial pressure in
      patients with acute liver failure and may offer an effective adjunct therapy in
      the management of these patients. Studies in experimental animals suggest that
      this beneficial effect of hypothermia is the result of a decrease in blood-brain
      ammonia transfer resulting in improvement in brain energy metabolism and
      normalization of glutamatergic synaptic regulation. Improvement in brain energy
      metabolism by hypothermia may result from a reduction in ammonia-induced decrease
      of brain glucose (pyruvate) oxidation. Restoration of normal glutamatergic
      synaptic regulation by hypothermia may be the consequence of the removal of
      ammonia-induced decreases in expression of astrocytic glutamate transporters
      resulting in normal glutamate neurotransmitter inactivation in brain. Randomized
      controlled clinical trials of hypothermia are required to further evaluate its
      clinical impact.

PMID- 12602521
TI  - Clinical efficacy of L-ornithine-L-aspartate in the management of hepatic
      encephalopathy.
AB  - The clinical efficacy of both oral and parenteral L-ornithine-L-aspartate (OA)
      was confirmed by randomized, placebo-controlled, double-blind studies in patients
      with manifest hepatic encephalopathy and hyperammonemia. The drug was able to
      reduce high blood ammonia levels induced either by ammonium chloride or protein
      ingestion or existing as a clinical complication of cirrhosis per se.
      Furthermore, OA improved performance in Number Connection Test-A as well as
      mental state gradation. In contrast to the positive effects observed in patients
      with more advanced hepatic encephalopathy, oral OA does not seem to affect
      minimal hepatic encephalopathy. In a recent trial, OA decreased protein breakdown
      and stimulated protein synthesis in muscle. The therapy had little side effects,
      increasing with higher intravenously administered dosages, and was well tolerated
      after oral and parenteral administration.

PMID- 12602522
TI  - Improvement in central nervous system functions during treatment of liver failure
      with albumin dialysis MARS--a review of clinical, biochemical, and
      electrophysiological data.
AB  - The Molecular Adsorbent Recirculating System (MARS) is a nonbiological liver
      support method based on the principles of dialysis, filtration, and adsorption.
      It allows the safe and efficient removal of both albumin-bound and water-soluble
      toxic metabolites, including ammonia, aromatic amino acids, tryptophan, and
      related phenolic and indolic products, as well as benzodiazepines. A well
      documented effect of the treatment is the improvement of the hemodynamic
      situation of decompensated chronic patients. Systemic vascular resistance, mean
      arterial pressure, cerebral blood flow, and cerebral oxygen consumption increased
      significantly. The degree of hepatic encephalopathy decreased significantly.
      Increased intracranial pressure could be normalized in both chronic and fulminant
      liver failure. In three randomized clinical trials significant improvement of
      survival could be demonstrated. In a model of murine neuronal networks cultured
      on multi-microelectrode array plates and incubated with plasma from liver failure
      patients, a normalization of the spike and burst pattern could be observed, if
      plasma samples from MARS-treated patients before and after treatment were
      compared. In conclusion, MARS significantly improves central nervous system
      functions. It can serve as a model for the further investigation of the role of
      protein-bound substances in hepatic encephalopathy and cerebral hemodynamics.

PMID- 12602523
TI  - Concept for modular extracorporeal liver support for the treatment of acute
      hepatic failure.
AB  - Acute liver failure has a poor prognosis. The introduction of liver
      transplantation as a therapeutic option reduced mortality to 20-40%.With the
      growing disparity between the number of organ donations and the number of
      patients waiting for liver transplantation, efforts have been made to optimize
      the allocation of organs and to design extracorporeal methods to support the
      failing liver. The modular extracorporeal liver support is a concept for the
      treatment of hepatic failure. The CellModule is a multicompartment bioreactor for
      extracorporeal liver support therapy. The construction provides efficient
      integrated oxygenator functions and decentralized mass transfer is effected by a
      woven array of capillary systems. The bioreactor promotes primary human liver
      cells to spontaneous neo-formation of liver sinusoidal structures in vitro. Small
      capillary subunits, in which interwoven membrane links represent the liver
      lobuli, are simultaneously perfused. The used cell mass of 400-600 g enabled the
      clinical application of a liver lobe equivalent hybrid organ. The DetoxModule
      enables albumin-dialysis for removal of albumin-bound toxins; a DialysisModule
      for continuous veno-venous hemofiltration can be added to the system, in the case
      of hepato-renal failure.

PMID- 12602524
TI  - Bioartificial liver support anno 2001.
AB  - Despite maximal intensive care, mortality of acute fulminant hepatic failure is
      high: 60%-75% in several studies. In addition patients with chronic liver
      insufficiency suffer from a bad quality of life: all patients suffer from
      fatigue; symptoms of hepatic encephalopathy, jaundice, and itching are often
      present. Analogous to artificial kidney treatment in patients with renal failure,
      an artificial liver assist device is needed not only to bridge patients with
      fulminant hepatic failure to liver transplantation or own liver regeneration, but
      also to improve the quality of life of patients with chronic liver insufficiency.
      Several modalities of artificial liver support are under investigation, like
      plasma exchange, haemodialysis, haemadsorption, albumin dialysis, liver cell
      transplantation, and the bioartificial liver. Artificial livers based on only
      supportive detoxification function do not show significant improvement of
      survival in controlled studies. Bioartificial liver support systems have also the
      potential to support hepatic synthetic functions. Bioreactors can be charged with
      freshly isolated or cryopreserved porcine hepatocytes, but also by human hepatoma
      cell lines. Several uncontrolled studies in humans show safety of such a
      treatment, even by using porcine cells. Transmission of porcine endogenous
      retrovirus to recipients has not been found. Furthermore, beneficial effects have
      been reported on symptoms of hepatic encephalopathy, on the height of
      intracranial pressure and on hemodynamic parameters. By using porcine cells
      immunological problems (e.g., serum sickness) can be expected during treatments
      longer than one week. However, "proof of the pudding" in the sense of improvement
      of survival is not yet available. The creation of a "liver dialysis unit" in the
      near future depends mainly on the development of well-differentiated immortalized
      human hepatocytes. Some progress in this field has already been obtained.

PMID- 12602525
TI  - Preliminary observations on the effects of acute infusion of growth hormone on
      coronary vasculature and on myocardial function and energetics of an isolated and
      blood-perfused heart.
AB  - Recent studies have shown that growth hormone (GH) deficiency may deteriorate
      post-ischemic myocardial reperfusion damage. Furthermore, GH has been reported to
      be a promising therapeutic option in the treatment of chronic myocardial
      dysfunction. However, the exact mechanisms of action of GH on the cardiovascular
      system, particularly in the acute setting, are still unclear. The aim of our
      study consisted of monitoring the acute effects of GH infusion on isolated blood
      perfused rabbit heart according to dose-response pattern and during ischemic
      conditions to test its anti-ischemic property. Seven blood-donors perfused
      isolated hearts were used as experimental model. The mechanical and metabolic
      data of the isolated organs were continuously monitored. Under aerobic
      conditions, dose-response curves were initially tested after intracoronary
      infusion of GH at increasing dosages (1, 2, 3 mg/l). After a stabilization
      period, the effects of GH infusion (5 mg/kg) administered 30 minutes prior to
      acute global myocardial ischemia (30 minutes) were also investigated. At the
      doses tested, GH did not induce any changes either in the developed or in the
      diastolic pressures of the isolated organ. However, transient reduction of the
      coronary perfusion pressure was observed at the dosage of 3 mg/l. During the
      ischemia/reperfusion study, at the dosages used in this study, GH did not modify
      either the degree of stunning in the early reperfusion or the recovery of the
      developed pressure at the end of reperfusion. In addition, GH did not prevent
      either the increase of diastolic pressure during ischemia or the release of
      lactate and CPK during reperfusion. Tissue content of high-energy phosphates was
      also not changed by GH infusion. In our experimental model, acute GH infusion did
      not reduce the ischemic/reperfusion damage of the myocardium. However, GH
      transiently induced coronary vasodilation without modifying the myocardial
      contractility. Acute effects of GH appear, therefore, to predominantly relate to
      vascular dilation suggesting that the effects on myocardial contractility may
      require long-lasting intake being likely linked to enhancement of specific
      protein synthesis or gene expression of cardiac myocytes.

PMID- 12602526
TI  - The diagnosis of secondary adrenal insufficiency: low dose vs high dose ACTH
      stimulation test.

PMID- 12602527
TI  - The dilemma of non-palpable thyroid nodules.

PMID- 12602528
TI  - Orbital radiotherapy for Graves' ophthalmopathy: useful or useless? Safe or
      dangerous?
AB  - Treatment of Graves' ophthalmopathy does not always provide favorable results.
      After several decades of efforts, glucocorticoids, orbital radiotherapy (OR) and
      surgery (orbital decompression) remain the milestones in the management of this
      disease. OR produce favorable results in about 55-60% of patients. Its
      effectiveness is increased by the association with systemic glucocorticoids.
      Recent studies have cast some doubts on its real effectiveness and this is
      discussed by participants in this Forum. Selection of patients is particularly
      important to assess treatment outcome, because OR is unlikely to provide
      beneficial effects in patients with longstanding and inactive eye disease. OR is
      a safe procedure, with very limited side-effects. It should be used in patients
      older than 35 years of age. It is recommended that a large, multi-center,
      prospective, randomized and controlled study with well defined inclusion criteria
      be carried out to draw sound conclusions on the role of OR in the management of
      Graves' ophthalmopathy.

PMID- 12602529
TI  - Cortisol, DHEAS and aging: resistance to cortisol suppression in frail
      institutionalized elderly.
AB  - Convincing evidences has linked the hypothalamus-pituitary-adrenal (HPA) axis to
      aging patterns. F excess is implicated in the development of frailty
      characteristics whereas DHEAS is positively correlated to successful aging. We
      compared serum F and DHEAS levels of independent community-living (successful
      group, 19 M and 28 F, 69 to 87 yr) with those of institutionalized elderly (frail
      group, 20 M and 30 F, 65 to 95 yr). Serum F was determined at 1) baseline (08:00
      h, 16:00 h and 23:00 h), 2) after 2 overnight dexamethasone (DEX) suppression
      tests (DST, using 0.25 and 1.0 mg doses), and 3) 60 min after ACTH stimulation
      (250 microg i.v. bolus); serum DHEAS was determined at 08:00 h. Basal serum F at
      08:00 h, 16:00 h and 23:00 h and serum DHEAS levels were similar in both groups;
      however F: DHEAS ratio at 08:00 h was higher in the frail, compared to the
      successful group (mean +/- SD: 0.55 +/- 0.53 and 0.35 +/- 0.41, respectively; p =
      0.04). In response to DST, F suppression was less effective in frail elderly
      after either 0.25 or 1.0 mg doses (9.0 +/- 6.0 and 2.0 +/- 0.9 microg/dl), as
      compared to the successful group (5.8 +/- 4.4 and 1.5 +/- 0.5 microg/dl) (p =
      0.01). In addition, a significant correlation was observed between post-DEX F
      levels (both doses) and parameters of cognitive and physical frailty. Normal and
      similar F levels were observed after ACTH stimulation in both groups. Our data
      suggest a deficient feedback regulation of the HPA axis in frail
      institutionalized elderly, as demonstrated by a higher set point for F
      suppression. This augmented HPA tonus enforces the hypothesis that even milder F
      excess may be related to characteristics of frailty in the elderly.

PMID- 12602530
TI  - Microvascular density and vascular endothelial growth factor expression in normal
      pituitary tissue and pituitary adenomas.
AB  - Microvessel density (MVD) represents a measure of angiogenesis and may be used as
      an indicator of neoplastic aggressiveness. Vascular endothelial growth factor
      (VEGF) plays a pivotal role as angiogenic promoter by stimulating endothelial
      cell proliferation and migration and enhancing vascular permeability. The aim of
      this study was to investigate MVD and VEGF expression in human pituitary adenomas
      and normal pituitary gland tissues by immunohistochemistry, and to correlate data
      with clinical characteristics. Fragments from 46 pituitary adenomas (18 non
      functioning, 12 ACTH-secreting, 12 GH-secreting, 4 PRL-secreting) and 19
      specimens of normal anterior pituitary gland obtained at surgery were evaluated.
      MVD in normal anterior pituitary was significantly higher than in tumors (69.2 +/
      28.5 vs 29.3 +/- 19.7; p < 0.0001). Within adenomas, no difference was found in
      MVD when different histotype, size, sex, age, rate of recurrence or medical pre
      surgical treatment were considered. The degree of vascularity was somewhat
      related only to clinical invasiveness, as evaluated by pre-surgical MRI grading
      (grade 0 p < 0.05 vs grade 1 and vs grade 2). No statistically significant
      difference in VEGF expression was found between normal tissue and adenomas and
      among tumors of different histotype (p = 0.3978). Size, sex, age, rate of
      recurrence and medical pre-surgical treatment did not influence VEGF expression.
      No correlation was found between MVD and VEGF expression. In conclusion, MVD was
      reduced in pituitary adenomas with respect to normal gland. VEGF expression is
      however well preserved in adenomas and this might contribute to adequate tumoral
      vascular supply with complex mechanisms other than endothelial cells
      proliferation.

PMID- 12602531
TI  - Absence of histological malignancy in a patient cohort with follicular lesions on
      fine-needle aspiration.
AB  - Follicular lesions account for 4-6% of all thyroid fine-needle aspiration (FNA)
      cytologies. To date, no cytological criteria exist to distinguish follicular
      adenoma from carcinoma. For this purpose, histological evaluation after surgical
      exeresis is required. From 1993 to 2000 we performed 1,238 US-assisted FNA
      biopsies in patients admitted to our unit for uni- or multi-nodular goiters. In
      the latter goiters, FNA was performed in the dominant nodule. Cytological
      examination revealed a follicular lesion in 71 patients (5.7%). All patients came
      from regions of Northern Italy with moderate iodine deficiency. In 48%, the
      lesion presented as a solitary nodule, while in the other 52% it occurred in the
      context of a multinodular goiter. Surgical exeresis of the neoplasm was
      recommended in all cases. Sixty-three patients (89%) underwent surgery (Group 1)
      while the other 8 patients (11%) opted for follow-up (Group 2). In Group 2, the
      mean nodule volume (3.2 +/- 0.5 ml) at baseline was slightly smaller (p = 0.08)
      than that found in Group 1 (5.4 +/- 0.7 ml). In Group 1, histological examination
      after surgery showed a follicular adenoma in 52 patients (83%) and a colloid
      goiter in the others (17%). No malignancy was detected. Group 2 underwent a
      median follow-up of 46 months (range 24-96 months) on L-thyroxine suppressive
      regimen (dose range 75-125 pg/day), with TSH levels ranging from 0.1 to 0.3
      mlU/l. Throughout the follow-up, no patient developed clinical or
      ultrasonographic features that could be considered worrisome for malignancy;
      thus, no further biopsy was performed. However, an overall slight increase
      (median +5.2%) in nodular volume in respect to baseline was observed. Although
      institutional and cytological bias cannot be ruled out, our data do not confirm
      the reported incidence of malignancy in histological specimens of follicular
      lesions diagnosed on FNA cytology, and prompt us to suggest a less aggressive
      first-step approach (i.e. careful clinical and instrumental evaluation, and
      suppressive L-T4 therapy) for these lesions, unless anamnestic reports or
      clinical and ultrasonographic features of the nodules suggest malignancy.

PMID- 12602532
TI  - Effect of calcium supplementation on blood pressure in patients with secondary
      hyperparathyroidism.
AB  - The aim was to study the effect of calcium supplementation 477 mg twice daily on
      BP in patients with secondary hyperparathyroidism during an intervention study (6
      weeks) and after 954 mg during a short study (3 h). The intervention study was a
      placebo-controlled, double-blind, cross-over, while the short study gave a
      placebo and calcium in random order on separate days. The participants were
      obtained from an epidemiological survey in Tromso 1994-1995 that included more
      than 27.000 subjects. The re-examination was performed in 2000/2001 at the
      University Hospital of North Norway, Norway. There were 18 subjects with
      secondary hyperparathyroidism and 28 control subjects in the intervention study
      while there were 14 cases and 8 control subjects in the short study. The results
      showed that in the subjects with secondary hyperparathyroidism after calcium
      supplementation in the intervention study there was an increase in serum calcium
      from 2.28 +/- 0.09 to 2.36 +/- 0.06 mmol/l (mean +/- SD) and a decrease in serum
      PTH from 8.6+/-1.6 to 6.5+/-2.4 pmol/l. However, there was no significant
      difference in either systolic or diastolic BP between calcium supplementation and
      placebo (138.3 +/- 21.0 vs 135.9 +/- 17.0 mm Hg and 80.9 +/- 11.1 vs 78.9+/-9.5
      mm Hg, respectively). Similar results were seen in the control group. In the
      short study, serum calcium increased and serum PTH decreased after oral calcium,
      but the BP did not differ as compared to when placebo was given. To conclude, in
      the present setting we did not find any effect on BP by calcium supplementation
      in subjects with moderate secondary hyperparathyroidism.

PMID- 12602533
TI  - Insulin resistance is independently related to age in Mexican women.
AB  - Whether the decrease of insulin action is a biological consequence of age or a
      result of lifestyle changes in elderly people is uncertain. Therefore, we
      rigorously controlled potential confounders to evaluate the relationship between
      age and insulin resistance in Mexican women. A total of 100 glucose-tolerant, non
      hypertensive women, 30-65 yr of age, inhabitants of the same neighborhood of
      Durango, a city in the North of Mexico, were randomly enrolled to participate in
      a case-control study. The study was designed to include 50 cases and 50 controls.
      Insulin-resistant women were considered as cases and compared vs a control group
      of non-insulin resistant women, matched by BMI and Waist-to-Hip ratio (WHR). HOMA
      IR index equal or greater than 3.0 defined the presence of insulin resistance.
      Endocrine diseases, pregnancy, smoking, alcohol consumption, and physical
      activity were exclusion criteria. The results showed insulin resistant women were
      significantly older than control women (53.7 +/- 12.2 vs 46.3 +/- 10.4, p =
      0.0004). Women in the case group showed a direct correlation between age and HOMA
      IR index (0.427, p = 0.02), whereas control women did not (0.09, p = 0.626). Step
      wise forward selection logistic regression analysis showed an independent
      relationship between HOMA-IR index and age (OR 1.5, CI95% 1.4-1.8, p = 0.002).
      The results of this study show an independent relationship between age and high
      HOMA-IR index in Mexican women, supporting the hypothesis that age per se could
      be associated with the impairment of insulin action.

PMID- 12602534
TI  - Hypopituitaric patients with corticotropin insufficiency show marked impairment
      of the cortisol response to ACTH (1-24) independently of the duration of the
      disease.
AB  - It is widely accepted that the classical dose of 250.0 microg ACTH (1-24)
      (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 microg have been
      shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F)
      secretion in normal young subjects. Testing with low ACTH dose would better
      evaluate adrenal sensitivity to corticotropin. The aims of the present study
      were: a) to clarify the adrenal sensitivity to ACTH in patients with different
      duration of corticotroph insufficiency by testing with low and very low
      tetracosactin doses; and b) to evaluate diagnostic implication regarding the
      ability of ACTH tests to distinguish patients with corticotroph insufficiency
      from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9
      female, age 22-50 yr, BMI: 22-26 kg/m2) with corticotrophin deficiency we studied
      the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06
      or 0.5 microg iv at 0 min) followed by 250 microg iv (at +60 min). The results in
      HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6
      female, age 22-34 yr, BMI: 20-25 kg/m2). Basal F and DHEA levels in HYPOPIT were
      lower than in NS, while A levels were similar in both groups. The F responses to
      ACTH in HYPOPIT were dose-independent and markedly lower (p < 0.0001) than in NS.
      After the 0.06 and 0.5 microg ACTH dose, 16% of HYPOPIT patients showed AF peak
      within the range of normal response. No HYPOPIT showed AF peak within the normal
      range after 250 microg ACTH. The DHEA responses to ACTH in HYPOPIT were dose
      independent and markedly lower than in NS (p < 0.0001). Overlap between
      individual DHEA responses in HYPOPIT and NS was present after 0.06 microg and 0.5
      microg but not after 250 microg tetracosactin. The A responses in HYPOPIT were
      dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in
      HYPOPIT were not associated with the duration of the disease. In conclusion, the
      present study shows that the mean F and DHEA but not the A responses to ACTH (1
      24) are markedly impaired in hypopituitaric patients with corticotroph
      insufficiency independently of the duration of the disease. The impaired F and
      DHEA response to ACTH is also independent of the dose, suggesting the existence
      of relatively enhanced sensitivity of the fasciculata and reticularis adrenal
      zone to ACTH but meantime remarkable impairment of the adrenal function due to
      corticotrophin deficiency. In the present study, testing with submaximal ACTH
      doses did not distinguish patients with secondary adrenal insufficiency from
      normal subjects.

PMID- 12602535
TI  - Thyroid volumes in schoolchildren of the Emirates.
AB  - Iodine deficiency is a major public health problem, an enlarged goiter being its
      most apparent manifestation. Recent studies have used US as an accurate and
      precise method of measuring thyroid size. The aim of this study was to describe
      thyroid volumes measured by US among school-aged children in the United Arab
      Emirates. Cross-sectional studies were performed in 4,381 school children, aged 6
      17 yr in three locations in the Emirates. Data were collected on age, sex,
      weight, thyroid size by palpation and US, and urinary iodine. Age/sex and body
      surface area (BSA) upper limits of thyroid volume were derived. Median urinary
      iodine in Abu Dhabi, Al Ain and in rural areas of Dubai were 9.9, 12.0 and 9.6
      mg/dl respectively. The goiter prevalence by palpation was 28.1%, 26.4% grade 1
      and 1.7% grade 2. There was significant difference in median and upper limit of
      thyroid volumes between boys and girls (p < 0.001). The thyroid volumes of
      subjects, as assessed by US, progressively increased with age for both sexes (r =
      0.53, p < 0.001). In schoolchildren in the Emirates, the best predictors of
      thyroid volume were BSA, height and weight. The thyroid volumes of the children
      in this study appear comparable with those reported in a European survey in 1997.

PMID- 12602536
TI  - Clinical relevance of non-palpable thyroid nodules as assessed by ultrasound
      guided fine needle aspiration biopsy.
AB  - It is known from autopsy data that thyroid nodules are far more common than can
      be detected by palpation alone. With the wide use of modern non-invasive imaging
      many non-palpable thyroid nodules are discovered but the proper approach to these
      nodules is still debatable. In a retrospective study, we reviewed the data from
      186 US-guided FNA biopsies (US-FNAB) performed between May 1995 and March 1997 at
      the Sapir Medical Center, Israel, a iodine-sufficient urban area. Sixty-one of
      the 186 US-FNAB of the thyroid were performed in non-palpable nodules. The mean
      size of these nodules was 2.4 +/- 1.0 cm (mean +/- SD) ranging from 1.1-5.5 cm.
      Description of the nodule consistency was available in 53 cases; 42/53 were solid
      and 11/53 were solid-cystic. FNAB was diagnostic in 46 patients and non
      diagnostic in 15. Forty-three of the diagnostic cytology reports were benign, one
      revealed papillary carcinoma, one had suspicious findings and the third was
      suspicious for a follicular neoplasm. The last two patients were referred to
      surgery and a follicular adenoma was found in both. Among the 61 non-palpable
      thyroid nodules, only one was papillary carcinoma, a prevalence of 1.6%. The
      other two patients referred to surgery had benign lesions. We found a low
      prevalence of malignancy in relatively large non-palpable thyroid nodules.

PMID- 12602537
TI  - Clinical laboratory findings and results of therapy in 55 patients with Cushing's
      syndrome.
AB  - In this study, 55 patients with Cushing's syndrome (CS) (50 female, 5 male; mean
      age 34 +/- 12.3 yr) who attended our clinics between the years 1983 and 2000 were
      retrospectively evaluated for clinical and laboratory features and modalities and
      results of therapy, due to a few similar studies over the last ten years.
      Cushing's disease was diagnosed in 39 patients (71%), adrenal adenoma in 13
      patients (23.6%) and adrenal carcinoma in 3 patients (5.5%). Centripedal obesity,
      moon face, hypertension, hirsutism and purplish stria were the most frequent
      findings. Loss of normal serum F circadian rhythm was found in all patients with
      CS. The overnight 1 mg oral dexamethasone suppression test and low-dose
      dexamethasone suppression test (LDDST) yielded 100% and 100% diagnostic
      sensitivity for CS, respectively. Sensitivity and specivity of the high-dose
      dexamethasone suppression test (HDDST) in distinguishing Cushing's disease was
      found to be 82% and 100%, respectively. All of the patients with adrenal CS were
      not suppressed with HDDST. Sellar CT and/or MRI accurately identified the tumor
      in 58% of these patients. Recurrence was observed in 3 (11%) of the 28 patients
      with Cushing's disease, treated by transsphenoidal adenomectomy. Recurrence was
      diagnosed 1.5, 3 and 6 yr after the operation in these 3 patients. One patient
      had residue tumor. In our case series, bilateral adrenalectomy plus pituitary
      irradiation achieved the highest remission rate (100%) in Cushing's disease. In 2
      out of 4 patients (50%) treated by left adrenalectomy associated with pituitary
      irradiation, recurrence was observed. Panhypopituitarism due to tumor apoplexy
      was observed in one of the patients with Cushing's disease. All of the patients
      with adrenal CS, the tumor was accurately localized with imaging methods before
      the operation. The appropriate operative procedure resulted in complete remission
      in patients with adrenal adenoma. Consequently, Cushing's disease was the most
      common form of CS. The overnight 1 mg oral DST and 24-h urine free F excretion
      (UFC) as screening tests, 2-day LDDST as diagnostic test and 2-day HDDST as
      differential diagnostic test were good studies. More successful outcomes have
      been achieved in treatment of Cushing's disease with the development of pituitary
      surgery in the recent years, as well as in our case series. Surgery is also
      curative for adrenal adenoma patients. Survival remains poor among carcinoma
      patients.

PMID- 12602538
TI  - Atorvastatin improves metabolic control and endothelial function in type 2
      diabetic patients: a placebo-controlled study.
AB  - Several pieces of evidence support a role of inflammatory processes in the
      pathogenesis of atherosclerosis; it is also known that endothelial dysfunction is
      the initial lesion of the atherosclerotic process. Among other markers of
      endothelial dysfunction, some adhesion molecules seem to play an interesting
      role. The aim of the present study was to evaluate the effect of atorvastatin vs
      placebo on some indexes of leukocytes adhesion in a group of Type 2 diabetic
      patients. Twenty-five Type 2 diabetic patients free from microangiopathic
      complications and with LDL-cholesterol lower than 180 mg/dl were randomized to
      receive either atorvastatin (T2DA) or placebo (T2Dp) for twelve months. BMI,
      fasting plasma glucose, glycated hemoglobin (HbA1c), albumin excretion rate
      (AER), lipid profile, and serum concentrations of vascular cell adhesion molecule
      1 (VCAM1), E-selectin and cadherin-5 were measured at baseline and at the end of
      the follow-up. At T0 E-selectin was 16 +/- 6 ng/ml in T2DA and 17 +/- 13 in T2Dp;
      VCAM1 was 413 +/- 112 ng/ml in T2DA and 411 +/- 112 in T2Dp. At T12 VCAM1 and E
      selectin did not vary in T2Dp, while a significant reduction was observed in T2DA
      (VCAM1 275 +/- 104 ng/ml and E-selectin 8 +/- 3 ng/ml; p < 0.001 and p < 0.01,
      respectively). T2DA also showed a reduction of total and LDL cholesterol and an
      improved glycemic control respect to T2Dp. Hypolipidemic therapy was the
      strongest independent predictor of the cytokines variations along the time. These
      results confirm the role of statins in modulating endothelial function also in
      Type 2 diabetes, outlining a therapeutic role of these molecules probably
      independent from the hypolipidemic effect.

PMID- 12602539
TI  - Moexipril and quinapril inhibition of tissue angiotensin-converting enzyme
      activity in the rat: evidence for direct effects in heart, lung and kidney and
      stimulation of prostacyclin generation.
AB  - The activation of angiotensin converting enzyme (ACE) may contribute to the
      development of vascular and myocardial structural changes. The level of ACE is
      stable in human plasma, and only limited data are available on its regulation at
      the tissue level. The aim of this study was to characterize the effects of two
      ACE inhibitors, moexipril and quinapril on tissue ACE activity. Adult male rats
      were treated intragastrically once daily for 6 days either with 2 mg/kg moexipril
      or quinapril. After single treatment, moexipril and quinapril effectively
      inhibited ACE activity in plasma and slightly in heart and aorta, whereas after 6
      days of treatment they inhibited ACE activity in plasma (87% and 94%,
      respectively), lung (92% and 93%), myocardium (26% and 23%), kidney (21% and
      20%), and aorta (39% and 40%), but not in skeletal muscle. Interestingly, the two
      ACE-inhibitors also induced a significant increase in cardiac homogenates of 6
      keto-PGF1alpha levels, an important index of PGI2 generation. To test whether the
      reduced effects of ACE inhibitors in heart and kidney were caused by a limited
      availability of the drugs, 100 microl of lung, heart and kidney homogenates from
      control rats were incubated in vitro with moexipril and quinapril immediately
      before assay. Both drugs were more effective in lung than heart and kidney
      homogenates, with inhibition values superimposable to those obtained in vivo.
      These results clearly indicate that inhibition of tissue ACE activity does not
      depend primarily on the availability of ACE inhibitors in each organ.

PMID- 12602540
TI  - Bilateral testicular enlargement due to adrenal remnant in a patient with C11
      hydroxylase deficiency congenital adrenal hyperplasia.
AB  - The case of a 15-yr-old boy with C11 hydroxylase deficiency congenital adrenal
      hyperplasia is reported who was diagnosed and treated as true precocious puberty
      at the age of 2 yr because of virilization and bilateral testicular enlargement.
      He later developed hyperpigmentation, hypertension and short stature and because
      of an increase in testes size he underwent testicular biopsy with the assumption
      of Leydig cell tumor. With the intake of glucocorticoids his testes size,
      hypertension and hyperpigmentation improved markedly. We could find only 6 such
      cases in the literature and have reviewed their clinical and laboratory data. All
      patients showed the picture of virilization with hypertension. Leydig cell tumor
      was proposed as the differential diagnosis in all cases except ours.
      Ultrasonography was able to show testicular adrenal-like tissue in all those in
      whom the procedure was undertaken. In the 5 patients of whom we could find enough
      data, 1 responded partially and 4 responded markedly to corticosteroid therapy
      with shrinkage of testicular tumors. We conclude that clinical findings and US
      are very important in the early diagnosis of these patients and with adequate
      treatment most cases show shrinkage in testicular tumors.

PMID- 12602541
TI  - Abnormal bone scintigraphy and acute-onset severe primary hyperparathyroidism.
AB  - Acute-onset primary hyperparathyroidism in a previously asymptomatic individual
      is uncommon. We herein report the case of a 61-yr old woman who underwent bone
      scintigraphy for severe, rapidly worsening, diffuse bone pain, associated with
      weight loss, anxiety and confusion. The patient was asymptomatic until a few days
      before presentation. A marked redistribution of the tracer was observed, with
      poor bone uptake and relevant accumulation in liver, kidneys, lungs and spleen.
      Blood chemistry unequivocally allowed the diagnosis of primary
      hyperparathyroidism due to multiple parathyroid adenomas, as suggested by
      parathyroid scan. Unfortunately, the patient critically worsened and surgery was
      made impossible. She died despite intensive critical care. Autopsy confirmed both
      massive intraparenchymal calcium deposition in the kidneys, lungs, liver and
      spleen, as well as multiple parathyroid adenomas. One may speculate that some
      adaptation of the organism to progressively increasing blood calcium levels and
      to slowly increasing intraparenchymal calcium salt deposition occurred, until
      critically high concentrations were attained.

PMID- 12602543
TI  - Leptin and female reproduction.

PMID- 12602542
TI  - Intranasally and orally active GH secretagogues are useful clinical tools: so why
      are they not on the market?

PMID- 12602544
TI  - PRL-secreting pituitary adenomas in pregnancy.
AB  - Dopamine-agonists have significantly increased the number of pregnancies in women
      with micro- and macro-prolactinomas, as ovulation can be restored in the great
      majority of these patients. Thus, the main questions regard the possible
      consequences of high estrogen levels on tumor volume and the possible effects of
      D2-agonists on fetal development. While the risk of tumor increase is low in
      patients with prolactin secreting micro-adenoma (MIP), in PRL secreting macro
      adenoma (MAP) patients the possibility of tumor growth is enhanced and influenced
      by previous treatment. Moreover, while it is well known that the exposition for
      only the first 4 weeks to bromocriptine (BRC) therapy does not affect the outcome
      of pregnancy, data on the use of BRC during the whole gestation are limited to
      just over 100 cases. Female pregnant patients with MIP, therefore, must be
      reassured and medical therapy suspended, with successive clinical follow-up. In
      the case of pregnant MAP subjects, the best approach from pre-pregnancy
      debulking, dopamine-agonist therapy interruption and BRC therapy continuation
      must be agreed on with the patient, and a careful follow-up instituted.

PMID- 12602545
TI  - Iodine deficiency and goiter prevalence in a population living at sea level in
      Campania (Italy).

PMID- 12602546
TI  - The changing role of radiotherapy in AIDS-related malignancies.
AB  - OBJECTIVE: To review the current literature on the role of radiotherapy in AIDS
      related malignancies published since 1997. METHODS: A comprehensive literature
      review was undertaken to review the recent advances in the role of radiotherapy
      in the management of AIDS-related malignancies. This was combined with the
      clinical experience from our two London treatment centres for AIDS-related
      malignancies. A Medline/Pubmed search was performed for articles published since
      1997, the year of the previous review, which also coincides with the widespread
      usage of highly active antiretroviral treatment (HAART). The MESH search terms
      used were 'HIV or AIDS' and 'radiotherapy'. This search yielded a total of 86
      references. CONCLUSIONS: HAART has had a major impact on the role of radiotherapy
      in AIDS-related malignancy. The use of HAART has led to a decline in the
      incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma and has been
      associated with an improved prognosis in systemic non-Hodgkin's lymphoma in
      people with HIV. In addition HAART alone has been successfully used as therapy
      for early KS lesions. Chemoradiotherapy remains the mainstay of management for
      anal cancer, has a central role in cervical cancer and non-AIDS defining
      malignancies in this population.

PMID- 12602547
TI  - Urgent 2-week referrals for CNS/brain tumours: a retrospective audit.
AB  - OBJECTIVE: To assess the effectiveness of the 2-week referral system for
      CNS/brain tumours and to contrast this with the number of patients with
      neurological cancers identified independently of this system. METHOD:
      Retrospective casenote review of patients referred to emergency neurology clinics
      pre-implementation of the 2-week referral system. Retrospective review of GP
      referral letters via this system and comparison to Department of Health referral
      guidelines. Review of corresponding casenotes to determine the actual
      neurological diagnosis. Identification of patients with CNS/brain tumours
      diagnosed independently of this system from a local CNS cancer register. RESULTS:
      Over a 3-month period pre-implementation of the referral system, of 12 patients
      referred as emergencies, none had CNS/brain cancer. Forty-three patients were
      referred via this system over a 9-month period to neurology departments of a
      teaching hospital and a district general hospital. Thirty per cent of the
      referrals did not follow the Department of Health guidelines. Only 9% actually
      had CNS tumours (two astrocytomas, two cerebral metastases). The remainder were
      diagnosed with chronic daily headache (10), epilepsy (5), migraine (3),
      demyelination (2), essential tremor (2), other (17). During this period at least
      69 neurological cancers were identified independently of the 2-week system.
      CONCLUSION: These guidelines may increase diagnostic precision if adhered to
      rigidly. Inappropriate referrals have extended already lengthy outpatient waiting
      times in other specialities. We suggest early re-consideration of these
      guidelines and further study for earlier identification of CNS cancer.

PMID- 12602548
TI  - Radiotherapy for craniopharyngioma in children: a national audit.
AB  - A survey of current radiotherapy practices in the United Kingdom for treatment of
      craniopharyngioma in children was undertaken in view of the need to optimize
      control and minimize side effects in a patient group who can expect to survive
      for prolonged periods after treatment. Useable replies were received from 16
      practitioners. A high level of conformity was reported in some areas but practice
      varied considerably in others. Thus whereas 15 employed magnetic resonance
      imaging (MRI) alone or with computed tomography (CT) to establish the gross
      tumour volume (GTV), six exclusively used pre-operative and seven exclusively
      used post-operative studies. Twelve added a margin of 1 cm to establish the
      planning target volume (PTV). Nine used CT planning. Fourteen gave radiation
      doses of between 50 and 55 Gy, but eight different dose/fractionation
      combinations were used. The most favoured regime (used by six) was 50 Gy in 30
      fractions. Two centres provided written information on possible side effects of
      treatment. We suggest that it might prove helpful if a national treatment
      protocol was developed.

PMID- 12602549
TI  - Treatment of the internal mammary nodes in early breast cancer: back to the
      future.

PMID- 12602550
TI  - A simple method to test if the internal mammary lymph nodes are covered by the
      wide tangent technique in radiotherapy for high-risk breast cancer.
AB  - AIM: It is often complicated to include the internal mammary lymph nodes in the
      radiation field after breast-conserving therapy. Using the wide tangent technique
      the internal mammary lymph nodes are generally presumed to be included if the
      medial tangential field border is placed 3 cm across the midline. The current
      study was designed to test the validity of this assumption, and if possible, to
      correct the wide tangents without using computed tomography (CT) scanning.
      PATIENTS AND METHODS: Twenty-one consecutive, high-risk, post-lumpectomy patients
      were included. An arrangement of three copper wires was mounted in wax placed
      perpendicular to the skin surface at the ipsilateral border of sternum at
      intercostal spaces 2 to 4. During a standard simulation for wide tangents, it was
      examined if the length of the copper wires projected beneath the skin surface
      (representing the depth of the internal mammary lymph nodes, measured by
      ultrasound) were included in the wide tangent fields. RESULTS: In only one
      patient were the internal mammary lymph nodes covered by the wide tangent
      technique. In 14 of the remaining 20 patients the lateral tangential field border
      was subsequently moved in the posterior direction, and the internal mammary lymph
      nodes could be included without unacceptable normal tissue involvement. In the
      last six patients the irradiated heart and lung volumes exceeded acceptable
      tolerance levels with this correction, and these patients were referred for three
      dimensional CT dose planning. CONCLUSION: The presented simple technique may be
      helpful if CT scanning is not available. In all other cases CT-based dose plan
      should ideally be used as a standard in the planning of radiotherapy after breast
      conserving surgery to assure optimal inclusion of the relevant target, and to
      avoid irradiation of large volumes of critical normal tissue.

PMID- 12602551
TI  - Local recurrence of breast cancer following surgery and radiotherapy: incidence
      and outcome.
AB  - Local recurrence of cancer in the treated breast following breast-conserving
      surgery and radiotherapy occurs in a minority of patients, but can represent a
      significant clinical problem. The impact of local relapse on the subsequent
      course of the disease is disputed. The aim of this retrospective review was to
      identify the rate and prognostic factors for breast recurrence and to determine
      the subsequent outcome. The case notes of 2159 patients treated between 1989 and
      1992 were reviewed. Actuarial local relapse rate was 6.3% at 5 years. Factors
      predictive for recurrence on multivariate analysis were age (P<0.001), status of
      excision margins (P=0.019), and pathological UICC stage (P=0.01). One hundred and
      sixty-one patients developed local recurrence in the treated breast of whom 101
      were treated with further surgery. The 5-year cancer-specific survival of this
      group was comparable with that of the patients who remained free of breast
      relapse (82 vs. 88%) but subsequently fell to 61 vs. 80% at 8 years (P<0.001).
      Sixty patients were unable to have salvage surgery; their cancer-specific
      survival was much worse than that of patients with operable recurrences at 33% at
      5 years and 13% at 8 years. Eighty-three patients (4% of the original 2159
      patients) had uncontrolled local disease at time of death or last follow-up. The
      prognosis of patients who developed recurrence within 2 years of their initial
      treatment was inferior to those who developed recurrences after 4 years (cancer
      specific survival 5 years post-recurrence 23 vs. 57% P=0.008). Systemic therapy
      should be considered for patients with early breast recurrence in view of their
      inferior survival.

PMID- 12602552
TI  - A case of paclitaxel-induced pancreatitis.

PMID- 12602553
TI  - Migration of endoluminal colonic stent following external beam radiotherapy.

PMID- 12602554
TI  - Vascular toxicity associated with cisplatin.

PMID- 12602555
TI  - Arm pain due to subclavian artery stenosis after radiotherapy for recurrent
      breast cancer.

PMID- 12602556
TI  - The name of the centre.

PMID- 12602557
TI  - Report on the U.K. meeting September 2001 to discuss the clinical and scientific
      case for a high-energy proton therapy facility in the U.K.

PMID- 12602558
TI  - What can we expect from dose escalation using proton beams?
AB  - It has been demonstrated without doubt in the literature, including elsewhere in
      this issue, that much better conformal dose distributions in radiation therapy
      can be obtained with proton beams than with photons (X-rays) or electrons. It is
      also clear that this remains entirely true--for the fundamental reason of
      particle range--even after the latest and projected developments in computer
      generated IMRT (intensity-modulated radiation therapy) photon dose escalation are
      fully considered. We consider several examples of tumour dose-response curves
      that illustrate the quite large gains to be obtained when dose escalation can be
      achieved, if normal tissue complications can also be avoided. Two contrasting
      types of tumour are considered in detail, prostate tumours and non-small-cell
      lung carcinomas. There is a considerable way to go yet to achieve really high non
      recurrence rates, especially in the lung tumours. Proton beams would make this
      progress much safer and more effective than any variants with photons.

PMID- 12602559
TI  - The clinical radiobiology of high LET radiotherapy with particular reference to
      proton radiotherapy.

PMID- 12602560
TI  - Particle beams for cancer therapy.
AB  - Particle beams from protons to carbon ions have a number of important advantages
      for radiation therapy. Besides the physical selectivity that makes ions
      especially efficient for deep-seated tumours and tumours close to critical
      organs, carbon ions with their enhanced relative biological effectiveness offer
      an additional biological advantage for slow-growing radioresistant tumours, with
      an additional gain for tumours with hypoxic sections. These advantages can only
      be fully exploited by active beam-shaping and biology-based treatment planning.

PMID- 12602561
TI  - Protons to replace photons in external beam radiation therapy?
AB  - Protons provide the basis for superior distribution of radiation dose due to the
      physical characteristics of protons. Proton beams used in radiation therapy can
      be designed to yield a uniform dose across the target and then virtually zero
      deep to the target and lower dose proximal to the target (for non-superficial
      lesions). Such beams can be employed in comparable number, direction, weighting,
      angulation, intensity modulation as is feasible for photon beams. The result is a
      smaller treatment volume, and hence a lower incidence and frequency of treatment
      related morbidity. Importantly, the reduction in treatment volume permits a
      higher dose to the tumour. This means an improved tumour control probability and
      lower normal tissue complication probability. Clinical gains appear to have been
      realized in the treatment of patient with uveal melanoma, skull-base sarcoma,
      para-nasal sinus carcinomas, selected stages of lung carcinoma and hepatocellular
      carcinoma. There are now three proton therapy centres with gantry systems with
      seven more being built. Further, there are seven additional centres in active
      planning. At present, prospective clinical evaluations are in progress for
      tumours at many anatomical sites.

PMID- 12602562
TI  - Proton radiotherapy for paediatric tumours: potential areas for clinical
      research.
AB  - Radiotherapy plays an important role in the management of children with cancer.
      The aim is to achieve local tumour control while minimizing long-term effects. In
      the treatment of tumours of the central nervous system (CNS) the most important
      long-term effects are neuropsychological. Elsewhere orthopaedic long-term effects
      may compromise function or be cosmetically harmful. Proton therapy has the
      potential for homogeneous irradiation of the target volume while reducing the
      magnitude and/or extent of the low dose area outside the target volume. This may
      be clinically relevant for long-term effects in children. Proton radiotherapy has
      an established role in the treatment of children with chordomas and
      chondrosarcomas of the base of skull. Planning studies have demonstrated the
      potential for improving the therapeutic ratio for radiotherapy for tumours of the
      central nervous system by achieving a uniform dose within the target volume while
      minimizing the severity of neuropsychological sequelae. Clinical experience of
      proton radiotherapy for children remains limited with potential areas for
      clinical research.

PMID- 12602563
TI  - The relative costs of proton and X-ray radiation therapy.
AB  - AIM: To study the costs of intensity-modulated proton therapy and intensity
      modulated X-ray therapy with the particular goal of understanding their relative
      differences. To analyse the ratio of the cost per fraction of proton therapy to
      the cost per fraction of X-ray therapy. MATERIALS AND METHODS: We have used a
      computer spreadsheet tool in which a large number (typically 130) of input
      parameters characterizing a particular therapeutic modality can be stored. From
      these parameters a number of derived variables are computed, and from these
      derived variables the costs of sub-systems, the entire facility, running costs
      and cost per fraction and per treatment can be computed. The sensitivity of any
      given variable (e.g. cost/fraction) to any given parameter (e.g. set-up time) can
      be explored, together with an estimate of the associated confidence interval. The
      costs of facility construction and facility operation are considered separately.
      Key data for the input variables regarding the cost of the therapy equipment (a
      dominant cost for proton beam therapy) were provided by four commercial vendors.
      Other costs, such as costs for building construction and shielding or personnel
      costs, are much more standard and our estimates were primarily based on practical
      experience. We considered two scenarios: (1) both facilities operating under
      current conditions; and (2) future facilities where foreseeable improvements in
      efficiency and a 25% reduction in the cost of the proton equipment were assumed.
      RESULTS: The construction cost of a current two-gantry proton facility, complete
      with the equipment, was estimated at 62,500 kEE and of a two-linac X-ray facility
      at 16,800 kEE. In the case of proton therapy the cost of operation of the
      facility was found to be dominated, by the business cost (42%--primarily the cost
      of repaying the presumed loan for facility construction), personnel costs (28%)
      and the cost of servicing the equipment (21%). For X-ray therapy, the cost of
      operation was seen to be dominated by the personnel cost (51%) and the business
      costs (28%). The costs per fraction were estimated to be 1.025 kEE for protons
      and 0.425 kEE for X-rays--for a ratio of costs of 2.4 +/- 0.35 (85% confidence).
      In a future facility these costs could be reduced to 0.65 kEE and 0.31 kEE
      respectively, leading to a ratio of costs of 2.1. A number of further
      improvements could be imagined which could reduce the ratio of costs by some 20%.
      If, however, the initial capital investment were 'forgiven,' so that the
      operating costs need not repay the investment, both the costs and the ratio of
      costs would be significantly less. We estimate that, under this condition, the
      future costs of proton and X-ray therapies would be 0.37 kEE and 0.23 kEE,
      respectively, for a cost-per-fraction ratio of 1.6. This ratio could also be
      susceptible to a further 20% reduction. CONCLUSIONS: Sophisticated (i.e.,
      intensity-modulated) proton therapy is now, and is likely to continue to be, more
      expensive than sophisticated (i.e., intensity-modulated) X-ray therapy. The ratio
      of costs is about 2.4 at present and could readily come down to 2.1, and even,
      perhaps 1.7 over the next 5 to 10 years. If recovery of the initial investment is
      not required, the ratio of costs would be much lower, in the range of 1.6 to 1.3.
      The question of whether the greater cost of proton beam therapy is clinically
      worthwhile is a cost-effectiveness issue. The goal of this study is to contribute
      to the former arm of this comparison.

PMID- 12602564
TI  - Antihypertensive treatment in the elderly.

PMID- 12602565
TI  - Life expectancy and changing mortality.

PMID- 12602566
TI  - Health and disability.

PMID- 12602567
TI  - Endothelium-dependent and endothelium-independent skin vasoreactivity in the
      elderly.
AB  - BACKGROUND AND AIMS: It was demonstrated that endothelium-dependent
      vasoreactivity, an aspect of endothelial functioning, is impaired in coronary and
      brachial arteries, and in skeletal muscle resistance vessels of elderly people.
      However, little data is available about the influence of aging per se on the
      endothelial function of the skin microcirculation. The aim of the present study
      was to evaluate the endothelial function and intrinsic vasodilatory capacity of
      the skin microcirculation in elderly people with a low atherosclerosis risk
      profile. METHODS: Using laser Doppler flowmetry, we measured the cutaneous
      hyperemic responses following local iontophoresis delivery of an endothelium
      dependent vasodilator, acetylcholine (ACh), and an endothelium-independent
      vasodilator, sodium nitroprusside (SNP), in 15 subjects older than 65 years and
      in 15 subjects younger than 50 years. Exclusion criteria were diabetes,
      hyperlipidemia, smoking, arterial hypertension and cardiovascular diseases.
      RESULTS: Skin maximal hyperemic responses induced both by ACh and by SNP delivery
      did not differ between the younger and the older groups. Cutaneous blood flow
      progressively increased in response to the 8 ACh delivery steps, both in the
      older and younger groups; however, the dose-response curve following ACh delivery
      was significantly lower in the former (p < 0.001). CONCLUSIONS: While these
      results should be viewed as preliminary due to the small sample size, they
      suggest that aging in itself is associated with a mild endothelium dysfunction in
      the skin microcirculation, whereas its overall vasodilatory capacity is
      preserved.

PMID- 12602568
TI  - Enzymatic alterations in single type IIB skeletal muscle fibers with inactivity
      and exercise in 12- and 30-month-old rats.
AB  - The purpose of the present study was to examine the effects of aging, inactivity
      and weight-bearing exercise on fast-twitch single Type IIB skeletal muscle fibers
      from the superficial region of the lateral head of the gastrocnemius (Type IIB
      fibers). Specifically, this study compared the biochemical properties of Type IIB
      fibers after 7 days of hindlimb unweighting (HU), 7 days of HU with intermittent
      weight-bearing (HU-Ex), and cage control (C) from adult and aged Fischer 344
      Brown Norway F1 Hybrid rats (12- and 30-month old). Biochemical measurements
      included total lactate dehydrogenase (LDH) and beta-hydroxy-acyl-coenzyme A
      dehydrogenase activities (BHAD), expressed in nmoles/microg/hr dry weight. Fiber
      typing for myosin heavy chain isoform was determined by SDS-PAGE. With age, LDH
      activity in Type IIB fibers decreased from 52.0 +/- 3.4 nmoles/microg/hr (12
      month old) to 39.5 +/- 2.9 nmoles/microg/hr (30-month old). Following HU, LDH
      activity of single Type IIB fibers increased by 22% (52.0 +/- 3.4 to 66.4 +/- 3.2
      nmoles/microg/hr) in the 12-month-old animals, whereas no difference was observed
      with HU in the Type IIB fibers of the 30-month-old animals. Following HU-Ex, LDH
      activity of Type IIB fibers in the 12-month-old animals was not significantly
      different from that of Type IIB fibers from HU animals, whereas a significant
      increase was observed (38.1 +/- 2.9 to 51.8 +/- 3.1 nmoles/microg/hr) in Type IIB
      fibers of 30-month-old animals, for HU and HU-Ex, respectively. Analysis of
      variance revealed an interaction between age and condition, indicating that Type
      IIB fibers from adult and aged animals have a different biochemical response to
      inactivity. The enzyme activities for BHAD were not different between the
      experimental conditions. The results demonstrate that the total LDH enzyme
      activities of the Type IIB fibers decrease with age, suggesting an age-related
      shift in the biochemical profile. Further, single skeletal muscle fiber
      adaptation is age-dependent.

PMID- 12602570
TI  - Improved health among 70-year olds: comparison of health indicators in three
      different birth cohorts.
AB  - BACKGROUND AND AIMS: Whether or not there has been a "compression of morbidity"
      in older ages has been vividly debated during the last decades. Previous studies
      have found indications of both improved and deteriorated health among elderly
      persons. Few studies have analyzed how changes in health indicators are
      influenced by social background factors. The aim of this study was to analyze the
      differences in morbidity--measured as self-assessed health, number of symptoms,
      number of diseases and physical function--in three different cohorts of 70-year
      olds, with special regard to the impact of social factors. METHODS: We used data
      from random samples of 70-year-old people born in 1901/02 (cohort 1), 1906/07
      (cohort 2), and 1911/12 (cohort 3). In the three cohorts there were 973, 1036 and
      619 participants, respectively. They had a medical examination and were
      interviewed regarding social background, social network, self-assessed health,
      need of care, and number of diseases. RESULTS: There were fewer 70-year olds not
      feeling healthy in the two younger cohorts (OR = 0.68; CI = 0.56-0.83, and OR =
      0.67; CI = 0.53-0.84 respectively) and fewer with many symptoms. There were also
      indications of better physical functioning in the younger cohorts. Women seemed
      to have gained more than men, while the institutionalized persons had a
      deterioration. CONCLUSIONS: There are indications of good years being added, but
      not for the institutionalized persons.

PMID- 12602569
TI  - Relationship of age and psychosocial factors with biological ratings in patients
      with end-stage renal disease undergoing dialysis.
AB  - BACKGROUND AND AIMS: Dialysis is a time-consuming procedure and may cause
      psychological distress. The aim of the present study was to investigate the
      relationship between age, emotional state, life satisfaction, sexual functioning
      and the method of dialysis in patients suffering from end-stage renal failure.
      METHODS: Eighty-two patients of 97 with end-stage chronic renal failure entered
      the study; 56 were under hemodialysis (HD), and 26 were under continuous
      ambulatory peritoneal dialysis (CAPD). Zung Depression Rating Scale (ZDRS), the
      Life Satisfaction Inventory (LSI), the Lasry Sexual Functioning Scale (LSFS), and
      a protocol aiming to register sociodemographic variables and variables
      considering the physical disorders were used. RESULTS: No significant differences
      between groups were found in the ZDRS (HD patients: 40.7 +/- 8.2, CAPD patients:
      41.88 +/- 10.44; p = 0.57), LSI scores (HD patients: 87.9 +/- 14.7, CAPD
      patients: 87.03 +/- 5.25; p = 0.7) and LSFS scores. Multiple linear regression
      analysis showed that LSI scores depended only on gender (females were less
      satisfied) and individual items on level of albumins and the presence of other
      physical disorders; ZDRS individual items depended on leukomatine level, gender,
      diabetes mellitus, albumins, age, creatinine and duration of disease; sexual
      functioning on age, and urea and sleep on albumin level (all with p < 0.001).
      DISCUSSION: No statistically significant differences were detected in depressive
      symptomatology, sexual function and life satisfaction between patients undergoing
      HD or CAPD. Some aspects of depressive symptomatology, sexual functioning and
      life satisfaction may be influenced by age, the kind of treatment and its
      effectiveness. Age was positively related with satisfaction from general quality
      of life, frequency of sexual activity, tiredness and feelings of usefulness.

PMID- 12602571
TI  - Factors of importance to the caregiver burden experienced by family caregivers of
      Parkinson's disease patients.
AB  - BACKGROUND AND AIMS: Caregivers of Parkinson's disease patients are vulnerable to
      detrimental factors related to caregiving because of the progressive course of
      the disease. Studies of caregivers of these patients are scarce. The aim of this
      study was to examine the caregiver burden in Parkinson's disease by analyzing
      caregiver and patient-related factors. METHODS: Every 3rd patient with
      Parkinson's disease registered at the outpatient clinic of the Neurology
      Department was invited to participate. One year after the first investigation, a
      follow-up was performed with a study of caregiver burden. A total of 65
      caregivers took part. In-home interviews with patients and caregivers were
      performed. ASSESSMENTS: a) caregiver burden, 22 items, comprising five indices:
      general strain, isolation, disappointment, emotional involvement, and
      environment; b) sense of coherence, 13 items, with the components
      comprehensibility, manageability and meaningfulness; c) depressive symptoms,
      using the Geriatric Depression Scale, 15 items; d) social contacts, 6 items; e)
      patient subjective health, assessed with the Parkinson's disease questionnaire,
      39 items; and f) patient functional status. RESULTS: Bivariate analyses showed
      significant correlations between caregiver burden and sense of coherence in
      caregivers, patient functional status, depressive symptoms in caregiver and
      patient, patient subjective health and time since diagnosis. Multivariate
      analysis showed depressive symptoms and sense of coherence in caregiver, and
      functional status in patient to be the most important variables for caregiver
      burden. CONCLUSIONS: To ease the caregiver burden, attention should be paid to
      patient functional status and caregivers depressive symptoms. The sense of
      coherence in caregivers is probably more difficult to influence.

PMID- 12602572
TI  - Association of body mass index with joint pain among community-dwelling women in
      Japan.
AB  - BACKGROUND AND AIMS: To investigate the impact of obesity on joint pain, we
      examined the association of body mass index (BMI) with joint pain. METHODS: 351
      community-dwelling Japanese women aged 40-85 years were asked about joint pain at
      specific joints, and height and weight were measured. Logistic regression
      analysis was used to evaluate BMI and other potential predictors of joint pain.
      RESULTS: BMI was positively associated with knee pain, but not with pain at other
      specific joints, after adjusting for age. The association of BMI with knee pain
      remained significant after adjustment for an additional covariate (physical
      activity). We also examined the associations of age, BMI, and regular physical
      activity with joint pain at any site, in the arm, in the leg, or in the back.
      Independently of age and regular physical activity, BMI was positively associated
      with joint pain in the leg, but not with pain at any site, in the arm or in the
      back. No significant association of physical activity with joint pain at any
      site, in the arm, in the leg or in the back was found. CONCLUSIONS: Knee pain was
      associated with greater BMI. This finding supports previous longitudinal studies,
      suggesting that some knee pain could be prevented by avoidance of excess weight,
      if the association is causative. However, the association was not very strong;
      thus, it is likely that many cases of knee pain cannot be avoided by weight
      reduction only, and may require other interventions.

PMID- 12602573
TI  - Dietary calcium intake and serum vitamin D are major determinants of bone mass
      variations in women. A longitudinal study.
AB  - BACKGROUND AND AIMS: Bone mineral density (BMD) is one of the main determinants
      in the pathogenesis of fractures. However, data on factors predicting
      longitudinal variations in BMD are still limited and incomplete. Such data would
      be of great importance in order to better focus prevention strategies in both the
      clinical setting and at the population level. The aim of the study was to
      investigate the predictive value of both serological and questionnaire variables
      for bone mass variations in healthy women participating in a population-based
      longitudinal study carried out in Napoli, Italy. METHODS: High completion rate
      (85.2%) and adequate sample size were obtained: 139 women (45 to 79 years of age)
      were examined at study entry and then again after two years (24 +/- 2 months)
      following the same protocol. They underwent medical examination, questionnaire,
      anthropometric measurements, blood sampling and urine collection. BMD was
      measured by dual energy X-ray absorptiometry (DEXA) at the lumbar spine (L1-L4)
      and femoral neck. Data analysis included calculation of the percent variation in
      BMD in the 2-year period. Longitudinal data underwent stepwise analysis for a
      global evaluation of mutual interactions between independent variables. RESULTS
      AND CONCLUSIONS: Our findings indicate that dietary and serum calcium, and serum
      25(OH)vitamin D are the only independent determinants of BMD variations at the
      lumbar and femoral level, respectively. While the pharmacological significance of
      calcium and vitamin D in the therapy of established osteoporosis is still
      controversial, the present longitudinal data evidence their role as essential
      nutrients in determining the natural history of BMD variations.

PMID- 12602574
TI  - Hip fracture surgery: is the pre-operative American Society of Anesthesiologists
      (ASA) score a predictor of functional outcome?
AB  - BACKGROUND AND AIMS: Many studies have identified specific demographic, social,
      health or life-style pre-operative indicators of long-term outcome among older
      hip fracture patients who underwent surgical treatment. The purpose of this study
      was to determine the predictive value of peri- and intra-operative factors, and
      more specifically of the pre-operative American Society of Anesthesiologists
      (ASA) score on functional outcome in these patients. METHODS: A questionnaire
      designed to assess pre-fracture functional and health status was administered to
      surgically treated hip fracture patients. Post-fracture functional and health
      status was further ascertained by in-home interview one year after the operation.
      Among 140 consecutive eligible patients older than 65 years, 10 either refused
      subsequent interviews or could not be contacted; an additional 16 patients died
      during the year of follow-up, leaving 114 patients available for this study.
      RESULTS: The average age of the patients was 82.4 years. Almost two-thirds of
      them suffered from severe systemic disease, whether or not incapacitating (ASA
      grades III-IV). Subjects classified in these categories presented more frequently
      with cardiovascular disorders, were more frequently disoriented, and already had
      some pre-fracture difficulty with ambulation. The mortality at one year was
      almost nine times higher in severely impaired patients (grades III-IV) than in
      healthy or mildly affected patients (grades I-II). Functional outcome and/or
      ambulatory ability assessed at one year did not reveal any statistically
      significant difference between the ASA I-II and III-IV groups. The most
      pronounced difference was noticed for the functional independence measured by the
      ADL score (p = 0.236). Better prognoses were consistently recorded for patients
      with an intracapsular fracture, for those who were operated within 24 hours, for
      those treated with a prosthesis as opposed to internal fixation, and for those
      whose operating time was less than 1 1/2 hours. CONCLUSIONS: Although the ASA
      classification is a good predictor of long-term mortality, the findings of the
      present investigation do not conclusively associate ASA score with post-operative
      restoration of mobility and functional independence.

PMID- 12602575
TI  - Mild to moderate chronic airways disease does not carry an excess risk of
      cognitive dysfunction.
AB  - BACKGROUND AND AIMS: Whether chronic obstructive pulmonary disease (COPD) carries
      a risk of cognitive dysfunction prior to the onset of arterial hypoxemia is not
      known. Our objective was to assess both the prevalence and main correlates of
      subclinical cognitive dysfunction in older patients with non-hypoxemic COPD.
      METHODS: Home-dwelling non-demented subjects over 64 years of age consecutively
      attending 24 outpatient Departments of Respiratory Medicine or Geriatrics because
      of COPD (N = 233), asthma (N = 203), non-obstructive bronchitis (N = 92) or
      chronic non-respiratory and non-dementing diseases (controls, N = 1080) underwent
      a multidimensional assessment. Cognitive status was assessed by the Mini-Mental
      State Examination (MMSE). Independent correlates of MMSE < 24 were identified by
      logistic regression analysis. In order to limit the confounding effect of
      collinearity between COPD group membership and the 6' walked distance, a properly
      designed multivariate analysis was performed. RESULTS: Prevalence of MMSE < 24
      ranged from 16.7% (controls) to 21.9% (COPD). Education < 9 years (Odds Ratio =
      1.56, Confidence Intervals = 1.22-1.98), a score > 6 on the 15-item Geriatric
      Depression Scale (OR = 1.37, CI = 1.16-1.62). a 6' walked distance < 242 m (OR =
      1.22, CI = 1.02-1.45), a Barthel Index greater than 80 (OR = 1.48, CI = 1.03
      2.14) and a Forced Vital Capacity inferior to 80% of the predicted value (OR =
      1.17, CI = 1.09-1.38) qualified as independent correlates of MMSE < 24. The
      multivariate analysis confirmed that groups had comparable MMSE scores.
      CONCLUSIONS: Non-hypoxemic COPD did not increase the risk of subclinical
      cognitive dysfunction in an older population.

PMID- 12602576
TI  - Development of the 'Patient perspective On Care and Rehabilitation process'
      instrument (POCR).
AB  - BACKGROUND AND AIMS: There is a lack of instruments for assessing patient
      perceived quality of care developed from a process perspective and also from
      theoretical concepts based on a patient perspective. The objective was to develop
      an instrument for following-up the care and rehabilitation process of the elderly
      from the patients' perspective. METHODS: The present instrument, the 'Patient
      perspective On Care and Rehabilitation process" (POCR), is based on a theoretical
      framework for the patients' evaluation of the care process, i.e., an instrument
      construction reflecting that the patients' needs differed during the care
      process. The POCR contains two scales; one measures the fulfilment of needs and
      the other the importance of the fulfilment of needs. Data collection took place
      via telephone interviews. RESULTS: A factor analysis based on 306 cases resulted
      in seven factors reflecting the different phases in the care process and with an
      explained variance of 60.8. Assessed by Cronbach's alpha coefficient, the
      internal consistency was 0.83 for the total importance scale and between 0.55
      0.71 for each factor. CONCLUSIONS: The POCR is a valid, reliable and useful
      multidimensional instrument for measuring patient-perceived outcome of the care
      and rehabilitation process in the elderly.

PMID- 12602577
TI  - Urgency and urge incontinence in an older population: ten-year changes and their
      association with mortality.
AB  - BACKGROUND AND AIMS: Urgency and urge incontinence are common urinary symptoms
      among older people, both men and women. The aim of this population-based
      prospective cohort study was to examine the independent association of urgency
      and urge incontinence with 10-year mortality in older men and women, and to
      describe the changes in these symptoms during those 10 years. METHODS: At
      baseline, 1052 persons (524 men and 528 women) aged 60-89, selected by random
      sampling and stratified by 5-year age group and sex, were interviewed for the
      Tampere Longitudinal Study on Ageing. In 10 years, 541 persons had died, and 435
      persons (175 men and 260 women) were re-interviewed. Cox proportional hazards
      models were used to examine the independent association of urgency and urge
      incontinence in each gender with 10-year mortality, adjusted for age, chronic
      diseases, activities of daily living (ADL) disability, socioeconomic status,
      smoking and alcohol use. RESULTS: In 10 years, 86% of men and 54% of women who
      reported at least urgency at baseline had died. The respective figures for men
      and women without urgency were 57 and 38%. Adjusted for age, both urgency without
      incontinence (Risk Ratio 1.87; 95% Confidence Interval 1.28-2.74) and urge
      incontinence (RR 3.13; 95% CI 2.054.77) significantly predicted mortality in men,
      while only urge incontinence was a statistically significant predictor in women
      (RR 1.63; 95% CI 1.03-2.57). After further adjusting for chronic diseases and ADL
      disability, urge incontinence lost its predictive power (RR 1.44; 95% CI 0.88
      2.23) in women, while the significant predictive power of urgency alone and urge
      incontinence in men persisted even after additional adjustment for socioeconomic
      status, smoking and alcohol use (RR 1.80; 95% CI 1.20-2.71, and RR 1.97; 95% CI
      1.25-3.10, respectively). CONCLUSIONS: Urgency and urge incontinence are
      significant prognostic indicators of mortality especially in older men. This
      emphasizes the importance of evaluation and treatment of urinary symptoms as a
      part of comprehensive geriatric assessment and management.

PMID- 12602578
TI  - Low biochemical nutritional parameters in acutely ill hospitalized elderly
      patients with and without stage III to IV pressure ulcers.
AB  - BACKGROUND AND AIMS: Pressure ulcers are associated with impaired nutritional
      status in acutely ill elderly patients. The objective of this study was to
      establish whether a difference exists between biochemical nutritional parameters
      in acutely ill elderly with stage III to IV pressure ulcers and a group of
      acutely ill elderly with no pressure ulcers. METHODS: In a retrospective study we
      compared 8 biochemical nutritional markers in a group of 22 acutely ill elderly
      patients consecutively admitted to the geriatric ward who had stage III to IV
      pressure ulcers (PU group) in addition to their acute illness with a control
      group of 40 acutely ill elderly patients with no pressure ulcers (NPU group).
      RESULTS: The PU group compared with the NPU group had significantly lower (p <
      0.0001) values of albumin, transferrin, hemoglobin, cholesterol, iron, and zinc
      (p < 0.0059). Total lymphocyte count was slightly, but not significantly lower in
      the PU group. In contrast, C-Reactive Protein levels were significantly higher (p
      < 0.0001) in the PU group compared with the NPU group, indicating a more severe
      illness in the presence of additional pressure ulcers. CONCLUSIONS: In this
      study, serum levels of biochemical nutritional parameters in acutely ill elderly
      patients with stage III to IV pressure ulcers are lower than those of acutely ill
      elderly subjects with no pressure ulcers, indicating a worse nutritional status
      of the PU patients. These findings, while not documenting a causal relationship,
      suggest the need for routine nutritional assessment and support in older
      patients, especially those with pressure ulcers.

PMID- 12602579
TI  - Phototoxic effects of 635-nm light on canine transitional cell carcinoma cells
      incubated with 5-aminolevulinic acid.
AB  - OBJECTIVE: To determine whether transitional cell carcinoma (TCC) cells incubated
      in media containing 5-aminolevulinic acid (ALA) would produce sufficient
      protoporphyrin IX (PpIX) to cause lethal phototoxic effects when exposed to 635
      nm light. SAMPLE POPULATION: Canine TCC cells (K9TCC). PROCEDURE: Cultured K9TCC
      cells were exposed to graded doses of ALA, and PpIX concentrations were
      determined. Cells then were exposed to various doses of 635-nm light from a diode
      laser, and cell viability was assayed. RESULTS: Production of PpIX was dependent
      on time and dose of ALA. The K9TCC cells incubated with ALA produced sufficient
      PpIX to cause lethal phototoxic effects when exposed to 635-nm light. Phototoxic
      effects were dependent on time and dose of ALA. Increasing laser power density
      and energy density decreased cell survival. CONCLUSIONS AND CLINICAL RELEVANCE:
      ALA is an effective photosensitizer for in vitro photodynamic treatment of K9TCC
      cells. Further studies are warranted to assess the safety and efficacy of ALA as
      a photosensitizer for use in treating dogs with TCC. Impact for Human Medicine-On
      the basis of this study, dogs with TCC may be useful in the development of
      protocols for ALA-based photodynamic therapy of humans affected with muscle
      invasive bladder cancer.

PMID- 12602580
TI  - Comparison of electroacupuncture and butorphanol on respiratory and
      cardiovascular effects and rectal pain threshold after controlled rectal
      distention in mares.
AB  - OBJECTIVE: To compare effects of electroacupuncture and butorphanol on
      hemodynamic and respiratory variables and rectal analgesia in mares after
      controlled rectal distention. ANIMALS: 8 healthy mares. PROCEDURE: Each horse
      received saline (0.9% NaCl) solution (0.01 mL/kg, IV; control treatment),
      butorphanol tartrate (0.1 mg/kg, IV), or 2 hours of electroacupuncture (EA) at
      acupoints Bladder 21, 25, and 27 on both sides of the vertebral column, Bai hui,
      and Stomach 36 (right side only). Order of treatments in each mare was
      randomized. At least 7 days elapsed between treatments. A balloon was inserted in
      the rectum of each mare, and controlled distention of the balloon (pressures of <
      or = 220 mm Hg) was used to measure nociceptive rectal pain threshold. Rectal
      temperature and cardiovascular and respiratory variables were measured before
      (baseline) and 5,15, 30, 60, 90, and 120 minutes after onset of each treatment.
      RESULTS: Butorphanol produced greater increases in rectal pain threshold,
      compared with EA (mean +/- SD, 214 +/- 24 vs 174 +/- 35 mm Hg of balloon
      pressure). Electroacupuncture produced minimal cardiovascular and respiratory
      changes. Although clinically not important, butorphanol produced moderate
      significant increases in heart and respiratory rates, arterial blood pressure,
      and rectal temperature and decreases in arterial oxygen tension. Arterial pH,
      carbon dioxide tension, bicarbonate concentrations, base excess, Hct, and
      concentration of total solids were not significantly different from baseline
      values after EA, butorphanol, and control treatments. CONCLUSIONS AND CLINICAL
      RELEVANCE: Electroacupuncture and butorphanol (0.1 mg/kg, IV) may provide useful
      rectal analgesia in horses.

PMID- 12602581
TI  - Spectral analysis of heart rate variability in dogs with mild mitral
      regurgitation.
AB  - OBJECTIVE: To assess autonomic function in dogs with mild mitral regurgitation
      (MR) that did not have clinical signs of the condition. ANIMALS: 6 healthy adult
      Beagles. PROCEDURE: Mild MR was experimentally induced. A 24-hour ambulatory ECG
      was recorded before and after induction of MR. Heart rate variability was
      analyzed in frequency domains by use of the ambulatory ECG. Low-frequency (LF)
      and high-frequency (HF) power were calculated by integrating over their frequency
      intervals, and the ratio of LF to HF was also calculated. Measurements of
      frequency domains were analyzed for 4 time periods (midnight to 6 AM, 6 AM to
      noon, noon to 6 PM, and 6 PM to midnight). RESULTS: Dogs with experimentally
      induced MR were classified as International Small Animal Cardiac Health Council
      class Ia. The HF power of dogs with MR was significantly decreased between 6 AM
      and noon. The ratio of LF to HF in dogs with MR was significantly increased for
      the periods between midnight and 6 AM, 6 AM and noon, and noon and 6 PM.
      CONCLUSIONS AND CLINICAL RELEVANCE: Compensatory response through autonomic
      modulation was observed in dogs with mild MR that did not have abnormalities,
      except for cardiac murmur, during clinical examination. This result suggests that
      treatment during the early stages of mild MR may be beneficial. Additional
      studies are necessary to determine whether such treatment will delay the onset of
      congestive heart failure and prolong survival in dogs affected with mild MR.

PMID- 12602582
TI  - Use of recombinant human thyroid-stimulating hormone for thyrotropin-stimulation
      testing of euthyroid cats.
AB  - OBJECTIVE: To evaluate response of euthyroid cats to administration of
      recombinant human thyroid-stimulating hormone (rhTSH). ANIMALS: 7 healthy cats.
      PROCEDURE: Each cat received each of 5 doses of rhTSH (0, 0.025, 0.050, 0.100,
      and 0.200 mg), IV, at 1-week intervals. Serum concentration of total thyroxine
      (TT4) and free thyroxine (fT4) was measured immediately before each injection
      (time 0) and 2, 4, 6, and 8 hours after administration of each dose. RESULTS:
      Overall TT4 response did not differ significantly among cats when administered
      doses were > or = 0.025 mg. Serum TT4 concentrations peaked 6 to 8 hours after
      administration for all doses > or = 0.025 mg. For all doses > or = 0.025 mg, mean
      +/- SEM TT4 concentration at 0, 6, and 8 hours was 33.9 +/- 1.7, 101.8 +/- 5.9,
      and 101.5 +/- 5.7 nmol/L, respectively. For all doses > or = 0.025 mg, mean fT4
      concentration at 0, 6, and 8 hours was 38.7 +/- 2.9, 104.5 +/- 7.6, and 100.4 +/-
      8.0 pmol/L, respectively. At 8 hours, the fT4 response to 0.025 and 0.050 mg was
      less than the response to 0.100 and 0.200 mg. Adverse reactions after rhTSH
      administration were not detected. CONCLUSIONS AND CLINICAL RELEVANCE: The TSH
      stimulation test can be performed in cats by IV administration of 0.025 to 0.200
      mg of rhTSH and measurement of serum TT4 concentrations at time of injection and
      6 or 8 hours later. Clinical validation of the TSH stimulation test would
      facilitate development of additional tests of thyroid gland function, such as a
      TSH assay.

PMID- 12602583
TI  - Epidemiologic study of results of pulsed-field gel electrophoresis of isolates of
      Rhodococcus equi obtained from horses and horse farms.
AB  - OBJECTIVE: To compare isolates of Rhodococcus equi on the basis of geographic
      source and virulence status by use of pulsed-field gel electrophoresis (PFGE).
      SAMPLE POPULATION: 290 isolates of R equi (218 virulent isolates from foals and
      72 avirulent isolates from feces, soil, and respiratory tract samples) obtained
      between 1985 and 2000 from horses and horse farms from 4 countries. PROCEDURE:
      DNA from isolates was digested with the restriction enzyme Asel and tested by use
      of PFGE. Products were analyzed for similarities in banding patterns by use of
      dendrograms. A similarity matrix was constructed for isolates, and the matrix was
      tested for nonrandom distributions of similarity values with respect to groupings
      of interest. RESULTS: There was little grouping of isolates on the basis of
      country, virulence status, or region within Texas. Isolates of R equi were
      generally < 80% similar, as determined by use of PFGE. Isolates from the same
      farm generally were rarely of the same strain. CONCLUSIONS AND CLINICAL
      RELEVANCE: Considerable chromosomal variability exists among isolates of R
      equiobtained from the same farm, sites withinTexas, or among countries from
      various continents. Only rarely will it be possible to link infections to a given
      site or region on the basis of analysis of isolates by use of PFGE of chromosomal
      DNA.

PMID- 12602584
TI  - Use of an amplified ELISA technique for detection of a house dust mite allergen
      (Der f 1) in skin and coat dust samples from dogs.
AB  - OBJECTIVE: To use an amplified ELISA technique to document the presence and
      quantify the concentration of the house dust mite allergen, Der f 1, in skin and
      coat dust samples collected from dogs. ANIMALS: 29 pet dogs of various breeds.
      PROCEDURE: Dogs were weighed, and body surface area in square meters was
      determined. Skin and coat dust samples were obtained by vacuuming dogs. Collected
      dust was analyzed by use of standard and amplified ELISA techniques. RESULTS: By
      use of the standard ELISA technique, Der f 1 was detected in skin and coat dust
      samples from 6 of 29 (21%) dogs. Mean concentration of Der f 1 in the 6 samples
      with positive assay results was 16.16 ng/mL (range, 5.61 to 31.24 ng/mL). Samples
      with negative assay results were retested for dust mite allergen by use of an
      amplified ELISA technique; an additional 14 dogs had positive assay results. Mean
      concentration of allergen was 0.36 ng/mL (range, 0.19 to 2.20 ng/mL). Combining
      both techniques, 20 of 29 (69%) dogs had positive assay results for Der f 1.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results of our study indicate that house dust
      mite allergens are present on the skin and in the coat of dogs, and this source
      of allergen may act as a reservoir for allergen exposure in hypersensitive dogs.
      Use of an amplified ELISA technique to determine environmental concentrations of
      house dust mite allergens in homes and on dogs will help to identify the
      relationship between immunologic findings and environmental exposures in dogs
      with atopic dermatitis.

PMID- 12602585
TI  - Interactions of morphine and isoflurane in horses.
AB  - OBJECTIVE: To quantitate dose- and time-related magnitudes of interactive effects
      of morphine (MOR) and isoflurane (ISO) in horses and to characterize
      pharmacokinetics of MOR in plasma and the ventilatory response to MOR during
      administration of ISO. ANIMALS: 6 adult horses. PROCEDURE: Horses were
      anesthetized 3 times to determine the minimum alveolar concentration (MAC) of ISO
      in O2 and then to characterize the change in anesthetic requirement as defined by
      the alteration in ISO MAC following IV administration of saline (0.9% NaCl)
      solution and 2 doses of MOR (low dose, 0.25 mg/kg; high dose, 2.0 mg/kg).
      Arterial blood samples were obtained before and after MOR and analyzed. RESULTS:
      Mean +/- SD baseline ISO MAC was 1.43 +/- 0.06%. The ISO MAC did not change with
      time after administration of saline solution. Effects of MOR on ISO MAC varied.
      Maximal change in MAC ranged from -20.2 to +28.3% and -18.9 to +56.2% after low
      and high doses of MOR, respectively. Typical half-life of MOR in plasma was 40 to
      60 minutes and related to dose. Mean PaCO2 increased from 70 mm Hg before MOR to
      88 to 102 mm Hg for 30 to 240 minutes after the high dose of MOR. Recovery from
      anesthesia after administration of the high dose of MOR was considered
      undesirable and dangerous. CONCLUSIONS AND CLINICAL RELEVANCE: Our results do not
      support routine clinical use of MOR administered IV at dosages of 0.25 or 2.0
      mg/kg as an adjuvant to anesthesia in horses administered ISO.

PMID- 12602586
TI  - Detection of biofilm formation and nanobacteria under long-term cell culture
      conditions in serum samples of cattle, goats, cats, and dogs.
AB  - OBJECTIVE: To determine the prevalence of biofilm formation under long-term cell
      culture conditions in serum samples of dairy cattle, goats, cats, and dogs, and
      to determine whether there is an association between nanobacteria and biofilm
      formation. SAMPLE POPULATION: Serum samples of clinically normal animals (313
      dairy cattle, 48 goats, 140 dogs, and 44 cats) and animals with various medical
      conditions (60 dogs and 116 cats). PROCEDURE: Serum was incubated under cell
      culture conditions and observed for biofilm formation by use of light microscopy,
      electron microscopy, and spectroscopy. A polymerase chain reaction assay was
      developed to identify 16S rRNA gene sequences of nanobacteria. RESULTS: Biofilm
      formation developed in serum samples of 304 of 313 (97%) cattle, 44 of 48 (92%)
      goats, 44 of 44 (100%) cats, and 126 of 140 (90%) dogs. Prevalence of serum
      samples with positive results for biofilm formation was not significantly
      different between cats or dogs with and without medical conditions associated
      with pathologic extraskeletal calcification processes. Scanning electron
      microscopy and spectroscopy of biofilm samples revealed small coccoid particles
      consisting mainly of calcium and phosphate. Polymerase chain reaction assay
      failed to amplify sequences of nanobacteria. CONCLUSIONS AND CLINICAL RELEVANCE:
      Under long-term cell culture conditions, biofilm made up of aggregates of calcium
      and phosphate crystals does form in serum samples of clinically normal dairy
      cattle, goats, cats, and dogs. Disease, however, does not predispose to biofilm
      formation in serum samples of dogs and cats. Our findings did not support the
      existence of nanobacteria in serum samples of cattle, goats, cats, and dogs.

PMID- 12602587
TI  - Effects of oral administration of methazolamide on intraocular pressure and
      aqueous humor flow rate in clinically normal dogs.
AB  - OBJECTIVE: To determine magnitude and duration of the effect of oral
      administration of methazolamide at 2 dosages on intraocular pressure (IOP) in
      dogs in single-dose and multiple-dose trials and to determine aqueous humor flow
      rate (AHFR) by use of anterior segment fluorophotometry before and during
      treatment. ANIMALS: 25 healthy adult Beagles. PROCEDURE: Baseline IOPs and AHFRs
      were determined on days 0 and 1, respectively. On day 2, the single-dose trial
      was initiated with oral administration of 25 or 50 mg of methazolamide at 7 AM to
      2 groups of 10 dogs each. Five dogs served as controls. In the multiple-dose
      trial, the same dogs received 25 or 50 mg of methazolamide at 7 AM and at 3 and
      11 PM on days 3 through 9. RESULTS: Intraocular pressures varied diurnally with
      highest IOPs in the morning. In the single-dose trial, IOP decreased
      significantly at 3 to 6 hours after treatment and then increased significantly at
      later time points, compared with baseline values. In the multiple-dose trial,
      dogs in both treatment groups had significantly lower IOPs during the treatment
      period at 10 AM and 1 PM but not at 6 and 9 PM, compared with baseline values. In
      both treatment groups morning IOPs had returned to baseline values by the first
      day after treatment. Evening IOPs were significantly increased by 2 to 3 days
      after treatment, compared with baseline values. The AHFRs in both treatment
      groups were significantly lower than pretreatment AHFRs. CONCLUSIONS AND CLINICAL
      RELEVANCE: Oral administration of methazolamide decreases IOPs and AHFRs in
      clinically normal dogs, with effectiveness diminishing in the evening.

PMID- 12602588
TI  - Use of threshold serum and milk ketone concentrations to identify risk for
      ketosis and endometritis in high-yielding dairy cows.
AB  - OBJECTIVE: To use threshold concentrations of acetone and beta-hydroxybutyrate in
      milk and serum, respectively; identify risk for ketosis and endometritis; and
      assess analyses of blood and milk samples as predictors of risk for ketosis in
      high-yielding dairy cows. ANIMALS: 90 multiparous Holstein cows. PROCEDURE: At
      intervals before and after parturition, blood samples were obtained for
      determination of glucose, nonesterified fatty acids, leptin, insulin, insulin
      like growth factor-1, and beta-hydroxybutyrate concentrations. Samples of milk
      were obtained at similar intervals after parturition for determination of fat
      content and concentrations of acetone, protein, and lactose. Reproductive
      examination of each cow was performed weekly. RESULTS: For each cow, threshold
      concentrations of acetone and beta-hydroxybutyrate were calculated as 75th and
      90th percentiles of maximum postpartum concentrations of acetone in milk (0.40
      and 0.87 mmol/L) and beta-hydroxybutyrate in serum (2.30 and 3.51 mmol/L).
      Significant decrease in milk production (442 to 654 kg of energy-corrected
      milk/305-day period per cow) was associated with acetone or beta-hydroxybutyrate
      in excess of threshold values. Milk acetone concentrations > 0.40 mmol/L were
      associated with 3.2 times higher risk for endometritis. Low plasma glucose, high
      serum beta-hydroxybutyrate, and high milk acetone concentrations during week 1
      after parturition were indicators of increased risk for ketosis later during
      lactation. CONCLUSIONS AND CLINICAL RELEVANCE: Determination of milk acetone
      concentration during the week after parturition may identify cows at risk for
      ketosis and endometritis; with appropriate interventions, development of disease
      and production losses may be reduced.

PMID- 12602589
TI  - Description of an epidemic simulation model for use in evaluating strategies to
      control an outbreak of foot-and-mouth disease.
AB  - OBJECTIVE: To develop a spatial epidemic model to simulate intraherd and
      interherd transmission of foot-and-mouth disease (FMD) virus. SAMPLE POPULATION:
      2,238 herds, representing beef, dairy, swine, goats, and sheep, and 5 sale yards
      located in Fresno, Kings, and Tulare counties of California. PROCEDURE: Using
      Monte-Carlo simulations, a spatial stochastic epidemic simulation model was
      developed to identify new herds that would acquire FMD following random selection
      of an index herd and to assess progression of an epidemic after implementation of
      mandatory control strategies. RESULTS: The model included species-specific
      transition periods for FMD infection, locations of herds, rates of direct and
      indirect contacts among herds, and probability distributions derived from expert
      opinions on probabilities of transmission by direct and indirect contact, as well
      as reduction in contact following implementation of restrictions on movements in
      designated infected areas and surveillance zones. Models of supplemental control
      programs included slaughter of all animals within a specified distance of
      infected herds, slaughter of only high-risk animals identified by use of a model
      simulation, and vaccination of all animals within a 5- to 50-km radius of
      infected herds. CONCLUSIONS AND CLINICAL RELEVANCE: The FMD model represents a
      tool for use in planning biosecurity and emergency-response programs and in
      comparing potential benefits of various strategies for control and eradication of
      FMD appropriate for specific populations.

PMID- 12602590
TI  - Results of epidemic simulation modeling to evaluate strategies to control an
      outbreak of foot-and-mouth disease.
AB  - OBJECTIVE: To assess estimated effectiveness of control and eradication
      procedures for foot-and-mouth disease (FMD) in a region of California. SAMPLE
      POPULATION: 2,238 herds and 5 sale yards in Fresno, Kings, andTulare counties of
      California. PROCEDURE: A spatial stochastic model was used to simulate
      hypothetical epidemics of FMD for specified control scenarios that included a
      baseline eradication strategy mandated by USDA and supplemental control
      strategies of slaughter or vaccination of all animals within a specified distance
      of infected herds, slaughter of only high-risk animals identified by use of a
      model simulation, and expansion of infected and surveillance zones. RESULTS:
      Median number of herds affected varied from 1 to 385 (17% of all herds),
      depending on type of index herd and delay in diagnosis of FMD. Percentage of
      herds infected decreased from that of the baseline eradication strategy by
      expanding the designated infected area from 10 to 20 km (48%), vaccinating within
      a 50-km radius of an infected herd (41%), slaughtering the 10 highest-risk herds
      for each infected herd (39%), and slaughtering all animals within 5 km of an
      infected herd (24%). CONCLUSIONS AND CLINICAL RELEVANCE: Results for the model
      provided a means of assessing the relative merits of potential strategies for
      control and eradication of FMD should it enter the US livestock population. For
      the study region, preemptive slaughter of highest-risk herds and vaccination of
      all animals within a specified distance of an infected herd consistently
      decreased size and duration of an epidemic, compared with the baseline
      eradication strategy.

PMID- 12602591
TI  - Evaluation of the ability of carprofen and flunixin meglumine to inhibit
      activation of nuclear factor kappa B.
AB  - OBJECTIVE: To determine whether the nonsteroidal anti-inflammatory drugs (NSAIDs)
      carprofen, flunixin meglumine, and phenylbutazone have cyclooxygenase (COX)
      independent effects that specifically inhibit activation of the proinflammatory
      transcription factor nuclear factor kappa B (NfkappaB). STUDY POPULATION:
      Purified ovine COX-1 and -2 and cultures of RAW 264.7 murine macrophages.
      PROCEDURE: The COX-1 and -2 inhibitory effects of the NSAIDs were tested in
      assays that used purified ovine COX-1 and -2. Prostaglandin production was
      analyzed by use of a radioimmunoassay. Inhibitory effects of these drugs on
      lipopolysaccharide (LPS)-induction of inducible nitric oxide synthase (iNOS) and
      LPS-stimulated translocation of NficB were determined by use of RAW 264.7 murine
      macrophages. RESULTS: Flunixin meglumine and phenylbutazone were selective
      inhibitors of COX-1. Carprofen and flunixin meglumine, but not phenylbutazone,
      inhibited LPS-induction of iNOS. Carprofen and, to a lesser degree, flunixin
      meglumine had inhibitory effects on NFkappaB activation. CONCLUSIONS AND CLINICAL
      RELEVANCE: The ability of drugs such as carprofen and flunixin meglumine to
      inhibit activation of NfkappaB-dependent genes such as iNOS, in addition to their
      effects on COX, suggests an additional mechanism for their anti-inflammatory
      effects and may explain the ability of flunixin meglumine to be an effective
      inhibitor of the effects of endotoxin in horses with endotoxemia.

PMID- 12602593
TI  - Pharmacokinetics and tissue concentrations of azithromycin in ball pythons
      (Python regius).
AB  - OBJECTIVE: To determine pharmacokinetics and tissue concentrations of
      azithromycin in ball pythons (Python regius) after IV or oral administration of a
      single dose. ANIMALS: 2 male and 5 female ball pythons. PROCEDURES: Using a
      crossover design, each snake was given a single dose of azithromycin (10 mg/kg)
      IV. After a 4-week washout period, each snake was given a single dose of
      azithromycin (10 mg/kg) orally. Blood samples were collected prior to dose
      administration and 1, 3, 6, 12, 24, 48, 72, and 96 hours after azithromycin
      administration. Azithromycin was quantitated by use of liquid chromatography-mass
      spectrometry. RESULTS: After IV administration, azithromycin had an apparent
      volume of distribution of 5.69 L/kg and a plasma clearance of 0.19 L/h/kg.
      Harmonic means for the terminal half-life were 17 hours following IV
      administration and 51 hours following oral administration. Mean residence times
      were 37 and 94 hours following IV and oral administration, respectively.
      Following oral administration, azithromycin had a peak plasma concentration
      (Cmax) of 1.04 microg/mL, a time to Cmax of 8.4 hours, and a prolonged mean
      absorption time of 57 hours. Mean oral bioavailability was 77%. Tissue
      concentrations ranged from 4 to 140 times the corresponding plasma concentration
      at 24 and 72 hours after azithromycin administration. CONCLUSIONS AND CLINICAL
      RELEVANCE: Azithromycin is well absorbed and tolerated by ball pythons. On the
      basis of plasma pharmacokinetics and tissue concentration data, we suggest an
      azithromycin dosage in ball pythons of 10 mg/kg, orally, every 2 to 7 days,
      depending upon the site of infection and susceptibil ity of the infective
      organism.

PMID- 12602592
TI  - Antagonism of adenosine receptors by caffeine and caffeine metabolites in equine
      forebrain tissues.
AB  - OBJECTIVE: To determine the presence of adenosine receptor subtypes A1 and A2a in
      equine forebrain tissues and to characterize the interactions of caffeine and its
      metabolites with adenosine receptors in the CNS of horses. SAMPLE POPULATION:
      Brain tissue specimens obtained during necropsy from 5 adult male research
      horses. PROCEDURE: Membrane-enriched homogenates from cerebral cortex and
      striatum were evaluated by radioligand binding assays with the A1-selective
      ligand [3H]DPCPX and the A2a-selective ligand [3H]ZM241385. Functional responses
      to adenosine receptor agonists and antagonists were determined by a nucleotide
      exchange assay using [35S]-guanosine 5'-(gamma-thio) triphosphate
      ([35S]GTPgammaS). RESULTS: Saturable high affinity [3H]DPCPX binding (A1) sites
      were detected in cerebral cortex and striatum, whereas high-affinity [3H]ZM241385
      binding (A2a) sites were detected only in striatum. Caffeine and related
      methylxanthines had similar binding affinities at A1 and A2a sites with rank
      orders of drug binding affinities (theophylline > paraxanthine > or = caffeine >>
      theobromine) similar to other species. [35S]GTPgammaS exchange revealed that
      caffeine and its metabolites act as pure adenosine receptor antagonists at
      concentrations that correspond to A1 and A2a receptor binding affinities.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results of our study affirm the presence of
      guanine nucleotide binding protein linked adenosine receptors (ie, high-affinity
      A1 and A2a adenosine receptors) in equine forebrain tissues and reveal the
      antagonistic actions by caffeine and several biologically active caffeine
      metabolites. Antagonism of adenosine actions in the equine CNS by these
      stimulants may be responsible for some central actions of methylxanthine drugs,
      including motor stimulation and enhanced racing performance.

PMID- 12602594
TI  - Endotoxn-induced nonthyroidal illness in dogs.
AB  - OBJECTIVE: To determine the effects of endotoxin administration on thyroid
      function test results and serum tumor necrosis factor-alpha (TNF-alpha) activity
      in healthy dogs. ANIMALS: 6 healthy adult male dogs. PROCEDURES: Serum
      concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3'5'
      triiodothyronine (rT3), free T4 (fT4), and endogenous canine thyroid stimulating
      hormone (TSH), and TNF-alpha activity were measured before (day-1; baseline),
      during (days 0 to 3), and after (days 4 to 24) IV administration of endotoxin
      every 12 hours for 84 hours. RESULTS: Compared with baseline values, serum T3
      concentration decreased significantly, whereas rT3 concentration increased
      significantly 8 hours after initial endotoxin administration. Serum T4
      concentration decreased significantly at 8 and 12 hours after initiating
      endotoxin administration. Serum T4 concentration returned to reference range
      limits, then decreased significantly on days 6 to 12 and 16 to 20. Serum fT4
      concentration increased significantly at 12, 24, and 48 hours after cessation of
      endotoxin treatment, compared with baseline values. Serum rT3 concentration
      returned to reference range, then decreased significantly days 5 and 7 after
      stopping endotoxin treatment. Serum TNF-alpha activity was significantly
      increased only 4 hours after initial endotoxin treatment, compared with baseline
      activity. CONCLUSIONS AND CLINICAL RELEVANCE: Endotoxin administration modeled
      alterations in thyroid function test results found in dogs with spontaneous
      nonthyroidal illness syndrome. A decrease in serum T4 andT3 concentrations and
      increase in serum rT3 concentration indicate impaired secretion and metabolism of
      thyroid hormones. The persistent decrease in serum T4 concentration indicates
      that caution should be used in interpreting serum T4 concentrations after
      resolution of an illness in dogs.

PMID- 12602596
TI  - Production of laccase by Coriolus versicolor and its application in
      decolorization of dyestuffs: (II). Decolorization of dyes by laccase containing
      fermentation broth with or without self-immobilized mycelia.
AB  - The capability of decolorization for commercial dyes by Coriolus versicolor
      fermentation broth containing laccase with or without immobilized mycelium was
      evaluated. With cell-free fermentation broth containing laccase, high
      decolorization ratio was achieved foracid orange 7, but not for the other dyes
      concerned. The immobilized mycelium was proved to be more efficient than the cell
      free system. All the four dyestuffs studied were found being decolourized with
      certain extent by immobilized mycelium. The repeated-batch decolorization was
      carried out with satisfactory results. The experimental data showed that the
      continuous decolorization of wastewater from a printing and dyeing industry was
      possible by using the self-immobilized C. versicolor.

PMID- 12602595
TI  - Effect of aerosolized albuterol sulfate on resting energy expenditure determined
      by use of open-flow indirect calorimetry in horses with recurrent airway
      obstruction.
AB  - OBJECTIVE: To evaluate effects of sedation on stability of resistance of the
      respiratory system (RRS) and measures of resting energy expenditure (REE) by use
      of open-flow indirect calorimetry (IC) and treatment with aerosolized albuterol
      on REE in horses with recurrent airway obstruction (RAO). ANIMALS: 9 clinically
      normal horses and 8 horses with RAO. PROCEDURE: In phase 1, RRS was measured by
      using forced oscillometry (FOT) in 5 clinically normal horses before and after
      sedation with xylazine. In phase 2, REE was measured in 4 clinically normal
      horses between 20 and 25 minutes and again 35 to 40 minutes after sedation with
      xylazine. In phase 3, IC was performed between 20 and 25 minutes and FOT was
      performed between 30 and 35 minutes after xylazine administration in 8 horses
      with RAO; after administration of 450 microg of albuterol, IC and FOT were
      repeated. RESULTS: In phase 1, RRS values were significantly lower 5 and 10
      minutes after sedation. In phase 2, diminishing sedation did not significantly
      affect REE. In phase 3, there was a significant decrease in mean RRS (1.15 +/-
      0.25 vs 0.84 +/- 0.14 cm H20/L/s) and REE (30.68 +/- 17.89 vs 27.46 = 16.54
      kcal/kg/d) after albuterol administration. CONCLUSIONS AND CLINICAL RELEVANCE:
      FOT and IC are useful in obtaining repeatable measurements of RRS and REE,
      respectively, in sedated horses. Concurrent bronchodilation and decreased REE
      after albuterol administration suggest that increased work of breathing as a
      result of airway obstruction may contribute to increased energy demands in horses
      with RAO.

PMID- 12602597
TI  - Heavy metals in oysters, mussels and clams collected from coastal sites along the
      Pearl River Delta, South China.
AB  - Concentrations of 8 heavy metals: cadmium (Cd), copper (Cu), zinc (Zn), lead
      (Pb), nickel (Ni), chromium (Cr), antimony (Sb) and tin (Sn) were examined in 3
      species of bivalves ( Perna viridis, Crassostrea rivularis and Ruditapes
      philippinarum) collected from 25 sites along the Pearl River Delta coastal waters
      in the South China Sea from July to August 1996. In general, Cd, Cu, Zn and Sn
      concentrations in the three bivalve species collected from the Estuarine Zone
      were significantly higher than those collected from the Western and Eastern Zones
      of the Pearl River Delta, which are related to the existence of various
      anthropogenic activities in the catchment of the Pearl River Delta. The Western
      Estuarine Zone is mainly impacted hy Cr, Ni and Cu contamination. In Victoria
      Harbor, heavy metal contamination is mainly due to Cu and Pb, Cd, Cu and Zn
      concentrations in oysters were significantly higher than those in mussels and
      clams. This could be explained by the fact that oysters live mainly in the
      Estuarine Zone of the Pearl River Delta which receives most of the polluting
      discharges from the catchment of the Delta. During turbid condition, heavy
      metals( soluble or adsorbed on suspended particulates) discharged from the Delta
      are filtered from the water column and subsequently accumulated into the soft
      body tissues of oysters. Heavy metal concentrations in the three bivalve species
      were compared with the maximum permissible levels of heavy metals in seafood
      regulated by the Public Health and Municipal Services Ordinance, Laws of Hong
      Kong, and it was revealed that Cd and Cr concentrations in the three bivalve
      species exceeded the upper limits. At certain hotspots in the Delta, the maximum
      acceptable daily load for Cd was also exceeded.

PMID- 12602598
TI  - Optimum operation conditions of nitrogen and phosphorus removal by a biofilm
      activated-sludge system.
AB  - In the biofilm and activated sludge combined system, denitrifying bacteria
      attached on the fibrous carriers in the anoxic tank, while the sludge containing
      nitrifying and phosphorus removal bacteria was only recirculated between the
      aerobic and anaerobic tanks. Therefore, the factors affected and restricted
      nitrification, denitrification and phosphorus removal in a traditional A/A/O
      process were resolved. This paper describes the optimum operation conditions for
      nitrogen and phosphorus removal using this system.

PMID- 12602599
TI  - Numerical modeling method on the movement of water flow and suspended solids in
      two-dimensional sedimentation tanks in the wastewater treatment plant.
AB  - Taking the distributing calculation of velocity and concentration as an example,
      the paper established a series of governing equations by the vorticity-stream
      function method, and dispersed the equations by the finite differencing method.
      After figuring out the distribution field of velocity, the paper also calculated
      the concentration distribution in sedimentation tank by using the two-dimensional
      concentration transport equation. The validity and feasibility of the numerical
      method was verified through comparing with experimental data. Furthermore, the
      paper carried out a tentative exploration into the application of numerical
      simulation of sedimentation tanks.

PMID- 12602600
TI  - Micronutrient dynamics in some wetland soils of south-eastern Nigeria.
AB  - The inventory of profile distribution of total iron (Fe), zinc (Zn),
      manganese(Mn) and copper(Cu) were determined in three different soil horizons
      each of the wetland soils selected form Mbiabet(MB), Nkari (NK) and Nkana(NA) in
      Ini Local Government Area of Akwa Ibom State. Total Fe ranged between 3.25 and
      4.15 ppm. The average contents were 3.72, 3.91 and 3.62 ppm in Mbiabet(MB),
      Nkari(NK) and Nkana(NA) soils respectively. The total value of Zn also ranged
      between 2.4 and 4.9 ppm with the average content in each soil being 28.27, 17.73
      and 36.53 ppm respectively. The amount of Fe and Zn in these soil profiles were
      strongly correlated with the clay content and high levels of organic matter of
      3.70%, 2.47% and 2.5% respectively. The content clearly reflected a poor drainage
      conditions. In all the soil profiles Mn and Cu were detected in at least one of
      the soil horizons. However, Mn and Cu were not detected in the soil horizons at
      Nkari. Generally, the relative inventory of these micronutrients appeared to be
      influenced by pH, drainage pattern, organic matter and clay contents of these
      soils. The inventory of total values of the wetland soils considered are assessed
      in the light of establishing a baseline information.

PMID- 12602601
TI  - Prediction of the amount of urban waste solids by applying a gray theoretical
      model.
AB  - Urban waste solids are now becoming one of the most crucial environmental
      problems. There are several different kinds of technologies normally used for
      waste solids disposal, among which landfill is more favorable in China than
      others, especially for urban waste solids. Most of the design works up to now are
      based on a roughly estimation of the amount of urban waste solids without any
      theoretical support, which lead to a series problems. To meet the basic
      information requirements for the design work, the amount of the urban waste
      solids was predicted in this research by applying the gray theoretical model GM
      (1,1) through non-linear differential equation simulation. The model parameters
      were estimated with the least square method (LSM) by running a certain MATALAB
      program, and the hypothesis test results show that the residual between the
      prediction value and the actual value approximately comply with the normal
      distribution N (0, 0.21(2)), and the probability of the residual within the range
      ( -0.17, 0.19) is more than 95%, which indicate obviously that the model can be
      well used for the prediction of the amount of waste solids and those had been
      already testified by the latest two years data about the urban waste solids from
      Loudi City of China. With this model, the predicted amount of the waste solids
      produced in Loudi City in the next 30 years is 8049000 ton in total.

PMID- 12602603
TI  - Reaction mechanism of 3-chlorophenol with OH, H in aqueous solution.
AB  - The reaction mechanism of 3-chlorophenol with OH, H in aqueous solution was
      studied by transient technology. The 3-chlorophenol aqueous solutions have been
      saturated with air or N2 previously. Under alkaline condition, the reaction of OH
      radical with 3-chlorophenol produces 3-chlorinated phenoxyl radical, with the
      absorption peaks at 400 nm and 417 nm. Under neutral condition, the reaction of
      OH radical with 3-chlorophenol produces OH-adduct with the maximal absorption at
      about 340 nm. And in acid solution, the reaction of H with 3-chlorophenol
      produces H-adduct with the maximal absorption at about 320 nm. 3-chlorophenol is
      compared with 4-and 2-chlorophenols from the free radical pathways. The results
      show that the positions of chlorine on the aromatic ring strongly influence the
      dehalogenation and degradation process.

PMID- 12602602
TI  - Response of antioxidase in viscera of Pagrosuma major larvae to water soluble
      fraction of hydrocarbons in No.0 diesel oil.
AB  - Pagrosomus major larvae were exposed to the water-soluble fraction of hydrocarbon
      in No.0 diesel oil (corresponding to No.2 fuel oil) at concentrations of 0, 0.17,
      1.22 and 8.82 mg/L for up to 15 days. Larvae were sampled on days 9 and 15 of the
      experiment. Supernatants of viscera tissue extractions were assayed for
      biochemical response in terms of oxidative stress-superoxide dismutase(SOD),
      activity of selenium-dependant glutathione peroxidase(Se-GPx) and catalase (Ca),
      and the concentration of reduced glutathione (GSH). On day 9 of exposure,
      statistically significant dose-related increases in Se-GPx and SOD activity, and
      GSH concentration were ohserved in all cases except for Se-GPx activity under the
      highest dosage of hydrocarbon. However, on day 15 of exposure, a similar dose
      related response was only observed for Se-GPx activity. GSH concentration
      decreased and SOD activity showed no statistical difference as compared to
      controls. However, a significant decrease in compared to day 9 Se-GPx activity
      and GSH concentration, in contrast to increase SOD activity at day 15 as
      indicates an accelerated accumulation of H2O2 and potential oxidative damage
      under long-term exposure of larvae to hydrocarbons. No statistical changes were
      observed in Ca activity throughout the experiment, possibly owing to the high
      efficiency of Se-GPx. A recovery experiment was performed on indicating that the
      response of antioxidants measured tending to return to their control levels.
      These results prove the function of the antioxidant defense system of the larvae
      to the water-soluble fraction of hydrocarbons in No.0 diesel oil.

PMID- 12602604
TI  - Electrically enhanced photodegradation of an azodye (acid orange II) using a
      Pt/TiO2 film electrode irradiating with an UV lamp.
AB  - A photoelectrochemical process in the degradation of an azodye (Acid Orange II)
      on a Pt/TiO2 film electrode was investigated. By using the glass device and the
      voltage stabilized source of direct current, decolorization ratios higher than
      78% were observed during aperiod of 5 h. Comparing this value with the sum of the
      decolorization ratios obtained by a sole application of electrochemical (lower
      than 3%) and photochemical (about 23%) procedures, a significant synergic effect
      between both processes was observed. The effects of adscititious voltage and pH
      value on the decolorization ratios were obvious while the effect of the amount of
      aeration was minor.

PMID- 12602605
TI  - Comparison of the thermal properties of clay samples as potential walling
      material for naturally cooled building design.
AB  - The thermal properties of different clay samples obtained from locations in Akwa
      Ibom State, Nigeria were investigated and compared, and in order to establish
      their suitability as building material from energy conservation point of view.
      The results showed that stoneware clay has the highest solar radiation
      absorptivity of 22.32 m(-1) while kaolin clay has the lowest radiation
      absoptivity of 14.46 m(-1). A model for the prediction of temperature variation
      with thickness of the samples was developed. Results showed that kaolin would
      make the best choice for the design of a naturally cooled building.

PMID- 12602606
TI  - Electrokinetic characteristic and coagulation behavior flocculant polyaluminum
      silicate chloride (PASiC).
AB  - The electrokinetic characteristics and coagulation behaviors of polyaluminum
      silicate chloride (PASiC) and polyaluminum chloride (PAC) were studied and
      compared by streaming current (SC) measurement and jar test method. The
      experimental results showed that the interaction between polysilicic acid
      characterized negative charge and hydrolyzed aluminum species result in a
      decrease of the charge-neutralizing ability of PASiC, compared to PAC. The
      decrease has a close relationship with the basicity (B) and Al/Si molar ratio in
      PASiC. The less the B value and the Al/Si molar ratio, the lower the charge
      neutralizing ability of PASiC is. In contrast, the preparation technique for
      PASiC affects the charge - neutralization of PASiC to a smaller extent. In
      addition, compared with PAC, PASiC may enhance aggregating efficiency and give
      better coagulating effects.

PMID- 12602607
TI  - Treatment and utilization of septic tank effluent using vertical-flow constructed
      wetlands and vegetable hydroponics.
AB  - Vertical flow constructed wetlands is a typical ecological sanitation system for
      sewage treatment. The removal rates for COD, BOD5, SS, TN, and TP were 60%, 80%,
      74%, 49% and 79%, respectively, when septic tank effluent was treated by vertical
      flow filter. So the concentration of COD and BOD5 in the treated effluent could
      meet the quality standard for irrigation water. After that the treated effluent
      was used for hydroponic cultivation of water spinach and romaine lettuce, the
      removal efficiencies of the whole system for COD, BOD5, SS, TN and TP were 71.4%,
      97.5%, 96.9%, 86.3%, and 87.4%, respectively. And it could meet the integrated
      wastewater discharge standard for secondary biological treatment plant. It was
      found that using treated effluent for hydroponic cultivation of vegetables could
      reduce the nitrate content in vegetables. The removal rates for total bacteria
      and coliform index by using vertical flow bed system with cinder substrate were
      80%-90% and 85%-96%, respectively.

PMID- 12602608
TI  - TiO2/beads as a photocatalyst for the degradation of X3B azo dye.
AB  - The feasibility of photocatalytic degradation of X3B azo dye by TiO2/beads
      photocatalyst was studied. The effects of parameters such as the amount of
      TiO2/beads, airflow, as well as the concentrations of H2O2, Fe3+, Mg2+ and Na+ on
      the photocatalytic degradation of X3B azo dye were also studied. The results
      showed that 25 mg/dm3 X3B azo dye can be photocatalytically degraded completely
      by 30 min illumination with a 375W medium pressure mercury lamp. Adding a small
      amount of H2O2 or Fe3+, the efficiencies of photocatalytic degradation of X3B azo
      dye were increased rapidly. The mechanisms of the reaction and the role of the
      additives were also investigated. After 120 hours TiO2/beads showed no
      significant loss of the photocatalytic activity.

PMID- 12602610
TI  - Desulfurizing absorbent for flue gas and its absorption mechanism.
AB  - A new desulfurizing absorbent for flue gas, i.e., an organic physical solvent of
      DMSO(dimethyl sulfoxide) mixed with a relatively small amount of chemical solvent
      (Mn2+) was studied. Compared with pure physical solvent of DMSO, the purification
      efficiency of the new absorbent was improved. And its absorption and reaction
      mechanism are discussed.

PMID- 12602609
TI  - QSBR study of substituted phenols and benzoic acids.
AB  - The biodegradability of 30 substituted phenols and benzoic acids was determined
      by BOD technique. The molecular weight (Mw), heat of formation (Hf) and the
      energy of the highest occupied molecular orbital (E(Homo)) of the studied
      compounds were calculated by the quantum chemical method MOPAC6.0-AMI. The
      quantitative structure-biodegradability relationships (QSBRs) were developed by
      the linear regression method and neural network approach, respectively. It has
      been shown that the neural network method is able to provide a superior fit to
      the training set data and test set data and produce a lower prediction error than
      the linear regression method.

PMID- 12602611
TI  - Study on an environmental-friendly and high-efficient fuel cell energy conversion
      system.
AB  - The kinds and the distribution of the coal in China are investigated. The results
      indicated that the 80% coal in China is used by the method of the coal
      gasification. The possibility of utilization and development of the fuel cell
      power plant in China is analyzed. A combined cycle generation system is designed.
      Its net electrical efficiency is about 55% (LHV), which is higher than that of
      the fire power plant. So it is environmental-friendly and high-efficient
      generation mode.

PMID- 12602612
TI  - Removal of lead from aqueous solutions by condensed tannin gel adsorbent.
AB  - Lead has caused serious environmental pollution due to its toxicity, accumulation
      in food chains and persistence in nature. In this paper, lead removal from
      aqueous solutions was investigated using condensed tannin gel adsorbent
      synthesized from a natural tannin compound. It is found that the adsorption is
      strongly affected by pH values of aqueous solutions. Within pH range of 3.5-6,
      when initial lead concentration is 100 mg/L, removal efficiency is more than 90%.
      Adsorption equilibrium is reached within 150 minutes. The adsorption isotherm
      fits well with the Langmuir equation, by which the saturated adsorption uptake of
      190 mg Pri2+ /g dry tannin gel adsorbent is obtained. By means of
      thermodynanamics analysis, it is revealed that the process is exothermic and the
      adsorption heat is up to 38.4 kJ/mol. With respect to high efficiency, moderate
      pH requirement and minimized second pollution, the tannin gel adsorbent exhibits
      a promising potential in the removal of lead from wastewater.

PMID- 12602613
TI  - Capacity and degree of iodine absorbed and enriched by vegetable from soil.
AB  - To understand the biogeochemical transfer of iodine, the absorbability and
      bioaccumulation of iodine in tested vegetables (radish, spinach and Chinese
      cabbage) are examined by applying iodic fertilizer composed of kelp and
      diatomaceous earth. The experimental results show that when iodine in soil is not
      excessive, the concentrations of iodine in tested vegetables increase as the
      content of iodine in soil increases. The absorbability and enrichment degree of
      iodine in various vegetables and in various parts of the same vegetable a
      redifferent, which explains that the concentration of iodine in plant is
      determined by the plant type and the physiological action of plant. The patience
      order of tested vegetables to excessive iodine is Chinese cabbage > spinach >
      radish. These results have theoretical and practical significance in opening up a
      new way for ameliorating poor iodine environment with artificial means.

PMID- 12602614
TI  - Relation between some variations of soil and surface vegetatio and desertization
      in agriculture-pasture interlacing zone an example from Kangbao County, North
      Hebei, China.
AB  - The studied agriculture-pasture interlacing zone has its specific natural
      conditions, at which the natural systems are unstable, their self-regulation
      capability is low and the equilibrium is easily broken, and hence the habitat is
      fairly vulnerable. During last 20 years the increasing population and livestock,
      over-reclamation, over-pasturing, over-deforesting, and other intensified
      negative human activities in the zone resulted in coarsening of surface soil,
      decrease of organic mater content in soil, reduction of vegetation coverage,
      variation and degradation of flora structure, and hence in desertization of the
      land, although average of gales and sandstorms some decreased and the climate
      tended to better in the region. However, the frequent sandstorms occurring in the
      springs of last and present years has attracted much attention. Investigations
      confirmed that the main cause for the phenomena is the unreasonable human
      activities rather than the natural factors.

PMID- 12602615
TI  - Heavy metals in surface sediments from Minjiang Estuary-Mazu and Xiamen-Jinmen
      Sea areas.
AB  - The concentrations of Cu, Pb, Zn and Cd in surface sediments from Minjiang
      Estuary-Mazu and Xiamen-Jinmen sea areas of China were investigated during 1995
      1996. The concentration ranges of Cu, Pb, Zn and Cd in the Minjiang Estuary-Mazu
      sea area were 16.4-37.2, 33.4-69.6, 92.1-128, 0.087-0.336 mg/kg(dry wt.),
      respectively; those for Xiamen-Jinmen sea area were 11.0-24.5, 36. 0-80.3, 77.5
      161, 0.135-0.285 mg/kg(dry wt.), respectively. The concentrations and
      distributions of Cu, Pb, Zn and Cd in surface sediments of Minjiang Estuary-Mazu
      and Xiamen-Jinmen sea areas were analyzed and evaluated. The results showed that
      the values of Zn and Pb exceeded those of sediment quality criteria. The average
      concentration of Cu in Minjiang Estuary-Mazu sea area was higher than that in
      Xiamen-Jinmen sea area. The obviously higher concentrations of Cu, Pb, Zn and Cd
      were found at outlets of Minjiang and Jiulong River. From the estuaries to open
      sea, the concentrations of Cu, Pb, Zn and Cd had a decreasing trend, and then
      elevated in the sea areas near Mazu and Jinmen, suggesting that Cu, Pb, Zn and Cd
      in Minjiang Estuary-Mazu and Xiamen-Jinmen sea areas may come from both the
      mainland and Taiwan of China.

PMID- 12602616
TI  - Experimental and mechanism studies on seawater flue gas desulfurization.
AB  - Seawater flue gas desulfurization (Seawater FGD) process has a number of
      advantages, but the study on mechanism of seawater FGD is little. The effects of
      absorbing efficiency of SO2 by the constant component and part of trace
      transition elements in seawater are studied by the experiment. The results
      indicate that the effect factors of absorption of SO% by seawater are alkaline,
      ion intensity, catalysis of Cl- and transition metal ions Fe2+ Mn(2+). The degree
      of effect is alkaline > the catalysis of Cl-, Fe2+ and Mn2+ > ion intensity. The
      mechanisms of catalysis oxidation for S( IV) by Cl -, Fe2+ and Mn2 are discussed.
      According to the results, some measures can be used to improve the capability of
      desulfurization.

PMID- 12602617
TI  - Cleaner production for continuous digester processes based on hybrid Pareto
      genetic algorithm.
AB  - Pulping production process produces a large amount of wastewater and pollutant
      emitted, which has become one of the main pollution sources in pulp and paper
      industry. To solve this problem, it is necessary to implement cleaner production
      by using modeling and optimization technology. This paper studies the modeling
      and multi-objective genetic algorithms for continuous digester process. First,
      model is established, in which environmental pollution and saving energy factors
      are considered. Then hybrid genetic algorithm based on Pareto stratum-nichecount
      is designed for finding near-Pareto or Pareto optimal solutions in the problem
      and a new genetic evaluation and selection mechanism is proposed. Finally using
      the real data from a pulp mill shows the results of computer simulation. Through
      comparing with the practical curve of digester, this method can reduce the
      pollutant effectively and increase the profit while keeping the pulp quality
      unchanged.

PMID- 12602618
TI  - Modeling of residual chlorine in water distribution system.
AB  - Water quality within water distribution system may vary with both location and
      time. Water quality models are used to predict the spatial and temporal variation
      of water quality throughout water system. A model of residual chlorine decay in
      water pipe has been developed, given the consumption of chlorine in reactions
      with chemicals in bulk water, bio-films on pipe wall, in corrosion process, and
      the mass transport of chlorine from bulk water to pipe wall. Analytical methods
      of the flow path from water sources to the observed point and the water age of
      every observed node were proposed. Model is used to predict the decay of residual
      chlorine in an actual distribution system. Good agreement between calculated and
      measured values was obtained.

PMID- 12602619
TI  - Cokriging optimization of monitoring network configuration based on fuzzy and non
      fuzzy variogram evaluation.
AB  - A number of optimization approaches regarding monitoring network design and
      sampling optimization procedures have been reported in the literature. Cokriging
      Estimation Variance (CEV) is a useful optimization tool to determine the
      influence of the spatial configuration of monitoring networks on parameter
      estimations. It was used in order to derive a reduced configuration of a nitrate
      concentration monitoring well network. The reliability of the reduced monitoring
      configuration suffers from the uncertainties caused by the variographer's choices
      and several inherent assumptions. These uncertainties can be described
      considering the variogram parameters as fuzzy numbers and the uncertainties by
      means of membership functions. Fuzzy and non-fuzzy approaches were used to
      evaluate differences among well network configurations. Both approaches permitted
      estimates of acceptable levels of information loss for nitrate concentrations in
      the monitoring network of the aquifer of the Plain of Modena, Northern Italy. The
      fuzzy approach was found to require considerably more computational time and
      numbers of wells at comparable level of information loss.

PMID- 12602620
TI  - Validation of two air quality models for Indian mining conditions.
AB  - All major mining activity particularly opencast mining contributes to the problem
      of suspended particulate matter (SPM) directly or indirectly. Therefore,
      assessment and prediction are required to prevent and minimize the deterioration
      of SPM due to various opencast mining operations. Determination of emission rate
      of SPM for these activities and validation of air quality models are the first
      and foremost concern. In view of the above, the study was taken up for
      determination of emission rate for SPM to calculate emission rate of various
      opencast mining activities and validation of commonly used two air quality models
      for Indian mining conditions. To achieve the objectives, eight coal and three
      iron ore mining sites were selected to generate site specific emission data by
      considering type of mining, method of working, geographical location,
      accessibility and above all resource availability. The study covers various
      mining activities and locations including drilling, overburden loading and
      unloading, coal/mineral loading and unloading, coal handling or screening plant,
      exposed overburden dump, stock yard, workshop, exposed pit surface, transport
      road and haul road. Validation of the study was carried out through Fugitive Dust
      Model (FDM) and Point, Area and Line sources model (PAL2) by assigning the
      measured emission rate for each mining activity, meteorological data and other
      details of the respective mine as an input to the models. Both the models were
      run separately for the same set of input data for each mine to get the predicted
      SPM concentration at three receptor locations for each mine. The receptor
      locations were selected such a way that at the same places the actual filed
      measurement were carried out for SPM concentration. Statistical analysis was
      carried out to assess the performance of the models based on a set measured and
      predicted SPM concentration data. The value of coefficient of correlation for
      PAL2 and FDM was calculated to be 0.990-0.994 and 0.966-0.997, respectively,
      which shows a fairly good agreement between measured and predicted values of SPM
      concentration. The average index of agreement values for PAL2 and FDM was found
      to be 0.665 and 0.752, respectively, which represents that the prediction by PAL2
      and FDM models are accurate by 66.5 and 75.2%, respectively. These indicate that
      FDM model is more suited for Indian mining conditions.

PMID- 12602621
TI  - A regional survey of malformed frogs in Minnesota (USA) (Minnesota malformed
      frogs).
AB  - In late 1995, school children discovered malformed frogs in a south central
      Minnesota pond. Press coverage resulted in numerous citizen reports of frog
      malformation across Minnesota in 1996. After some initial site investigation, 3
      affected frog sites and 4 nearby reference sites were selected for more detailed
      evaluation. Field biologists made 89 visits to study sites beginning spring 1997
      through fall 1999 to examine the number and type of frog malformations. Over
      5,100 Leopard frogs (Rana pipiens) were captured and examined at all study sites.
      Water elevations and associated littoral inundation were recorded from 1997-2000.
      Results indicate that malformation occurred at all study sites above historical
      background levels. Rana pipiens malformation across all sites over three seasons
      averaged 7.9% and ranged from 0 to 7% at reference sites and 4 to 23% at affected
      sites. At one northern Minnesota site, mink frog (Rana septentrionalis)
      malformation was 75% in 1998. A site characteristic common to the most affected
      sites was an elastic zone of littoral inundation. Climate driven hydrologic
      variation likely influenced water depth and associated breeding locations.

PMID- 12602622
TI  - Air quality effects of traffic in a canyon-like street (Falmouth, U.K.).
AB  - It has been suggested that in relation to air quality impacts, roads with low
      (<20000 vpd) traffic flow need not be considered as significant. This study
      examines this suggestion more closely by comparing real-time monitoring of
      traffic related pollutants (NO2, PM10 and PAH) at two sites (including a 'canyon
      street') in Falmouth, Cornwall in relation to traffic flow. For comparison, real
      time monitoring data for NO2 and PM10 is also taken from a well ventilated site
      in Camelford, Cornwall. The data obtained suggest that roads with traffic flow
      considerably lower than 20000 vpd can give rise to pollutant levels which have
      implications for human health. The application of simple linear regression
      techniques to the data suggests that under certain conditions simple estimates
      can be made in relation to likely traffic-related air quality effects in canyon
      like streets.

PMID- 12602623
TI  - Flue gas treatability studies: a tool for techno-economic control of industrial
      air pollution.
AB  - Air pollution problems in developing countries have gained larger fraction in the
      last decade especially due to non functioning and non implementation of effective
      air pollution control devices in industries. In industrial wastewater management,
      adequate treatability studies are conducted to arrive at a techno-economic
      treatment option. However no such studies were done for reducing air pollution or
      emission from industries until now in India. Little information was available
      about such studies in other countries. This article provides information about a
      novel technique known as flue gas treatability studies and to undertake such
      studies, a pilot scale system is installed in Air Pollution Control Division of
      M/s National Environmental Engineering research Institute, NEERI, Nagpur-20,
      India. This study is a tool for techno-economic selection of air pollution
      control systems specially for small/medium scale industrial emissions.

PMID- 12602624
TI  - Ambient toxicity due to chlorpyrifos and diazinon in a central California coastal
      watershed.
AB  - The Salinas River watershed along the central coast of California, U.S.A.,
      supports rapidly growing urban areas and intensive agricultural operations. The
      river drains to an estuarine National Wildlife Refuge and a National Marine
      Sanctuary. The occurrence, spatial patterns, sources and causes of aquatic
      toxicity in the watershed were investigated by sampling four sites in the main
      river and four sites in representative tributaries during 15 surveys between
      September 1998 and January 2000. In 96 hr toxicity tests, significant
      Ceriodaphnia dubia mortality was observed in 11% of the main river samples, 87%
      of the samples from a channel draining an urban/agricultural watershed, 13% of
      the samples from channels conveying agricultural tile drain runoff, and in 100%
      of the samples from a channel conveying agricultural surface furrow runoff. In
      six of nine toxicity identification evaluations (TIEs), the organophosphate
      pesticides diazinon and/or chlorpyrifos were implicated as causes of observed
      toxicity, and these compounds were the most probable causes of toxicity in two of
      the other three TIEs. Every sample collected in the watershed that exhibited
      greater than 50% C. dubia mortality (n = 31) had sufficient diazinon and/or
      chlorpyrifos concentrations to account for the observed effects. Results are
      interpreted with respect to potential effects on other ecologically important
      species.

PMID- 12602625
TI  - Using NOAA AVHRR data to assess flood damage in China.
AB  - The article used two NOAA-14 Advanced Very High Resolution Radiometer (AVHRR)
      datasets to assess flood damage in the middle and lower reaches of China's
      Changjiang River (Yangtze River) in 1998. As the AVHRR is an optical sensor, it
      cannot penetrate the clouds that frequently cover the land during the flood
      season, and this technology is greatly limited in flood monitoring. However the
      widely used normalized difference vegetation index (NDVI) can be used to monitor
      flooding, since water has a much lower NDVI value than other surface features.
      Though many factors other than flooding (e.g. atmospheric conditions, different
      sun-target-satellite angles, and cloud) can change NDVI values, inundated areas
      can be distinguished from other types of ground cover by changes in the NDVI
      value before and after the flood after eliminating the effects of other factors
      on NDVI. AVHRR data from 26 May and 22 August, 1998 were selected to represent
      the ground conditions before and after flooding. After accurate geometric
      correction by collecting GCPs, and atmospheric and angular corrections by using
      the 6S code, NDVI values for both days and their differences were calculated for
      cloud-free pixels. The difference in the NDVI values between these two times,
      together with the NDVI values and a land-use map, were used to identify inundated
      areas and to assess the area lost to the flood. The results show a total of
      358,867 ha, with 207,556 ha of cultivated fields (paddy and non-irrigated field)
      inundated during the flood of 1998 in the middle and lower reaches of the
      Changjiang River Catchment; comparing with the reported total of 321,000 and
      197,000 ha, respectively. The discrimination accuracy of this method was tested
      by comparing the results from two nearly simultaneous sets of remote-sensing data
      (NOAA's AVHRR data from 10 September, 1998, and JERS-1 synthetic aperture radar
      (SAR) data from 11 September, 1998, with a lag of about 18.5 hr) over a
      representative flooded region in the study area. The results showed that 67.26%
      of the total area identified as inundated using the NOAA data was also identified
      as inundated using the SAR data.

PMID- 12602627
TI  - A holistic approach towards assessment of severity of land degradation along the
      Great Wall in northern Shaanxi Province, China.
AB  - The farming and grazing interlocked transitional zone along the Great Wall in
      northern Shaanxi Province is particularly vulnerable to desertification due to
      its fragile ecosystem and intensive human activity. Studies reveal that
      desertification is both a natural and anthropogenic process. Four desertification
      indicators (vegetative cover, proportion of drifting sand area, desertification
      rate, and population pressure) were used to assess the severity of
      desertification in a GIS. The first three factors were derived from multitemporal
      remote sensing and land inventory data. The last factor was calculated from
      census data. It was found that the overall severity of land degradation in the
      study area has worsened during the last two decades with severely, highly and
      moderately degraded land accounting for 84.2% of the total area in 1998. While
      the area affected by desertification has increased, the rate of desertification
      has also accelerated from 0.74 to 0.87%. Risk of land degradation in the study
      area has increased, on an average, by 155% since 1985. Incorporation of both
      natural and anthropogenic factors in the analysis provides realistic assessment
      of risk of desertification.

PMID- 12602626
TI  - Establishing the link between ammonia emission control and measurements of
      reduced nitrogen concentrations and deposition.
AB  - In the context of international efforts to reduce the impacts of atmospheric NH3
      and NH4+ (collectively, NHx). it is important to establish the link between NH3
      emissions and monitoring of NHx concentrations and deposition. This is equally
      relevant to situations where NH3 emissions changes are certain (e.g. due to
      changed source sector activity), as to cases where NH3 abatement technologies
      have been implemented. Correct interpretation of adequate atmospheric
      measurements is essential, since monitoring data provide the only means to
      evaluate trends in regional NH3 emissions. These issues have been reviewed using
      available measurements and modelling from nine countries. In addition to historic
      datasets, the analysis here considers countries where NH3 source sector activity
      changed (both increases and decreases) and countries where NH3 abatement policies
      have been implemented. In The Netherlands an 'ammonia gap' was identified between
      the expected reduction and results of monitoring, and was attributed initially to
      ineffectiveness of the abatement measures. The analysis here for a range of
      countries shows that atmospheric interactions complicate the expected changes,
      particularly since SO2 emissions have decreased at the same time, while at many
      sites the few years of available data show substantial inter-annual variation. It
      is concluded that networks need to be established that speciate between NH3 and
      aerosol NH4+, in addition to providing wet deposition, and sample at sufficient
      sites for robust regional estimates to be established. Such measurements will be
      essential to monitor compliance of the international agreements on NH3 emission
      abatement.

PMID- 12602628
TI  - Potential health risks due to toxic contamination in the ambient environment of
      certain Indian states.
AB  - Toxic or hazardous substances pose two types of risks in the environment, namely
      'short-term or acute risk' and 'long-term or chronic risk'. The short-term risk
      is associated with the one-time acute exposure to potentially hazardous
      substances accidentally released in the environment, whereas the long-term risk
      is resulted from continuous exposure to potentially harmful substances present in
      different environmental media. This article deals with the assessment of
      potential health risks related to certain carcinogens and non-carcinogens (e.g.
      cadmium, chromium and nickel) present in three environmental media, viz. air,
      water and food in different Indian states (regions). Appropriate dose-response
      models have been identified and used for this purpose with the assumptions and
      input data as per the Indian context. Mean values of ambient air concentration
      levels of Cd, Cr and Ni have been used to estimate the individual and societal
      risks of extra cancer in different states of India. The hazard quotients and
      hazard index representing the non-carcinogenic chronic health effects caused by
      chromium and cadmium due to their long-term exposure through water and food have
      also been estimated. The risk results have been compared with the disease
      surveillance data. A definite correlation between the estimated risk results and
      the reported number of lung cancer cases and chronic liver diseases have been
      observed in different regions. As a matter of fact, it is not possible to derive
      precise risk estimates due to various uncertainties included both in available
      data and in the models which are used to calculate potency factors and effective
      concentration. However, average risk levels as estimated and presented in this
      article are quite useful for planning purposes.

PMID- 12602629
TI  - Interpretation of roadside PM10 monitoring data from Sunderland, United Kingdom.
AB  - Roadside PM10 has been monitored by Partisol at three sites in Sunderland between
      August 1997 and February 1998. The sites chosen were an inner city kerbside site;
      a roadside site adjacent to a dual carriageway on the outskirts of Sunderland
      with an open aspect; and a rural site. The results indicate that there is a
      seasonal variation in the relationship between the sites in terms of monitored
      PM10. In the winter there is a poor correlation between the sites whereas in the
      summer significant correlations are obtained. Of the sites monitored PM10 is
      consistently highest at the inner city roadside site. During the summer,
      exceedances of the U.K. 50 microg m(-3) standard (DETR, 2000) are associated with
      conditions suitable for the build-up of photochemical pollution however during
      the winter period exceedances are recorded during a variety of weather
      conditions. At the dual carriageway site PM2.5 has also been recorded and
      contributions to measured PM10 are 77% in summer and 68% in winter. The results
      illustrate a number of inconsistencies between this study utilising the Partisol
      and others reporting results where PM10 has been monitored by TEOM.

PMID- 12602631
TI  - Environmental monitoring of carbaryl applied in urban areas to control the glassy
      winged sharpshooter in California.
AB  - Carbaryl insecticide was applied by ground spray to plants in urban areas to
      control a serious insect pest the glassy-winged sharpshooter, Homalodisca
      coagulata (Say), newly introduced in California. To assure there are no adverse
      impacts to human health and the environment from the carbaryl applications,
      carbaryl was monitored in tank mixtures, air, surface water, foliage and backyard
      fruits and vegetables. Results from the five urban areas - Porterville, Fresno,
      Rancho Cordova, Brentwood and Chico - showed there were no significant human
      exposures or impacts on the environment. Spray tank concentrations ranged from
      0.1-0.32%. Carbaryl concentrations in air ranged from none detected to 1.12
      microg m(-3), well below the interim health screening level in air of 51.7 microg
      m(-3). There were three detections of carbaryl in surface water near application
      sites: 0.125 ppb (parts per billion) from a water treatment basin; 6.94 ppb from
      a gold fish pond; and 1737 ppb in a rain runoff sample collected from a drain
      adjacent to a sprayed site. The foliar dislodgeable residues ranged from 1.54
      7.12 microg cm(-2), comparable to levels reported for safe reentry of 2.4 to 5.6
      microg cm(-2) for citrus. Carbaryl concentrations in fruits and vegetables ranged
      from no detectable amounts to 7.56 ppm, which were below the U.S. EPA tolerance,
      allowable residue of 10 ppm.

PMID- 12602630
TI  - Lichen distribution and bioindicator tobacco plants give discordant response: a
      case study from Italy.
AB  - Epiphytic lichen biodiversity (LB) distribution was evaluated in a 1000 km2 area
      in Tuscany (Central Italy). In the same area, a survey was performed to monitor
      tropospheric ozone (O3) phytotoxic effects using tobacco plants (Nicotiana
      tabacum) cv. Bel-W3 (O3 supersensitive) and cv. Bel-B (O3 resistant) as
      bioindicators. The LB proved to be negatively correlated with ambient levels of
      nitrogen oxides, particulate and carbon monoxide, but not with benzene. LB
      spatial distribution followed a peculiar trend, with highest values in areas with
      low population density. Data from an O3 analyser set in evidence a typical
      circadian profile, confirming the photochemical nature of this pollutant. Quite
      high nocturnal values along the coast were related to the presence of surrounding
      mountains which constrained the back-and-forth flow of the air in sea breezes.
      Long- and short-term phytotoxicity critical levels for O3 were systematically
      trespassed. Bel-W3 tobacco was always affected in every site involved in the
      study; average O3 injury distribution was greater in rural areas; tobacco
      response was positively correlated to several O3 descriptors with second-order
      functions. Correlation analysis failed to demonstrate any association between
      lichen and tobacco data, due to the fact that LB values were higher in inland
      zones, far from the main urban and industrial areas, where instead damage to
      tobacco plants was generally lower. It is concluded that the lichen biodiversity
      is not suitable for monitoring O3 levels, at least in the study area.

PMID- 12602632
TI  - Analysis of macroinvertebrate assemblages in relation to environmental gradients
      among lotic habitats of California's Central Valley.
AB  - We assessed relationships between environmental characteristics and
      macroinvertebrate assemblages in lotic habitats of California's Central Valley
      with community metric and multivariate statistical approaches. Using canonical
      ordination analyses, we contrasted results when assemblage structure was assessed
      with macroinvertebrate metrics, as suggested for use in indices of biotic
      integrity, or with genera abundances. Our objectives were to identify metrics or
      taxa diagnostic of lotic environmental stressors and compare the capacity of
      these approaches to detect stressors in order to suggest how they might be used
      to diagnose stressors. For macroinvertebrate metrics, redundancy analysis (RDA)
      extracted three axes correlated with channel morphology and substrates. For
      genera abundances, canonical correspondence analysis (CCA) extracted two axes
      correlated with soluble salts and with channel morphology and substrates but did
      not separate these gradients onto different axes. Cluster analyses identified
      five RDA and five CCA site groups, which exhibited differences for environmental
      variables, metrics, or genera abundances, and agreement between the analyses in
      partitioning of sites was greater than if sites were partitioned randomly. These
      approaches differ in their ability to detect environmental stressors, because
      they measure different aspects of assemblages and would be complementary in
      design of new metrics diagnostic of stressors.

PMID- 12602634
TI  - Separation anxiety.

PMID- 12602633
TI  - Spatial patterns of nitrate, chloride, sulfate, and fluoride concentrations in
      the Woodbine Aquifer of north-central Texas.
AB  - A geographic information system was used to map and analyze nitrate, chloride,
      sulfate, and fluoride concentrations in 110 wells tapping the Woodbine Aquifer.
      The study area, covering nine counties in north-central Texas, includes large
      percentages of both urban and agricultural land uses. Land use maps were compared
      with solute concentration data, and statistics were applied to detect
      associations between solutes, well depth, and land use. Anthropogenic sources
      such as fertilizer applications and natural sources such as gypsum, lignite, and
      clay deposits controlled nitrate, chloride, and sulfate concentrations, each
      inversely correlated with well depth. However, only one nitrate observation--from
      a shallow well in the aquifer's outcrop zone--surpassed the maximum contaminant
      level (MCL) of 44.3 mg L(-1). By comparison, nearly half of the sulfate and
      several of the chloride observations surpassed the MCL of 250 mg L(-1) for each
      of those ions. Volcanic ash deposits influenced fluoride concentrations, which
      directly correlated with well depth. There were no statistically significant
      associations between solute concentrations and land use. Low recharge rates and
      confining layers have mitigated anthropogenic impacts on solute levels in the
      aquifer.

PMID- 12602635
TI  - Clinical applications of growth factors for articular cartilage repair.
AB  - Articular cartilage injuries and degeneration present a challenge for orthopedic
      surgeons. Chondrocytes have limited regenerative and reparative abilities.
      Healing of a defect results in a fibrocartilaginous repair tissue that lacks the
      structural and biomechanical properties of hyaline cartilage and that degrades
      over time. Polypeptide growth factors have an important role in regulating the
      behavior of all cells, including articular chondrocytes. Our understanding of
      growth factor effects on and interactions with chondrocytes is progressing
      rapidly. The most prominent growth factors identified for articular cartilage
      include insulin-like growth factor, fibroblast growth factor, the transforming
      growth factor-beta superfamily, hepatocyte growth factor, platelet-derived growth
      factor, Indian hedgehog and parathyroid hormone-related peptide, bone
      morphogenetic proteins, and the interleukin-1 receptor antagonist. Orthopedic
      surgeons need to be familiar with the properties of these growth factors, as they
      hold great therapeutic promise. In-progress clinical studies are examining how
      growth factors may have applications in treatments of bone.

PMID- 12602636
TI  - Adult degenerative lumbar scoliosis.
AB  - Degenerative scoliosis of the lumbar spine affects a significant number of
      adults. Although the etiology of this condition is not clear, the most commonly
      implicated causes include osteoporosis and degenerative disc disease. Clinically,
      patients with this condition most commonly complain of axial low back pain, but
      they may also present with radicular complaints. This pain may be generated
      directly by the facet joints or may be due to nerve root impingement or traction.
      Imaging of this spinal deformity should include both plain radiographs and
      computed tomographic myelography. Nonoperative therapy is ideal, but surgery is
      indicated for severe radicular symptoms refractory to conservative management or
      for progression of the curve. Ideally, surgical treatment should consist of
      decompression and fusion with segmental instrumentation.

PMID- 12602637
TI  - Thoracic spinal injuries: operative treatments and neurologic outcomes.
AB  - Between January 1983 and December 1997, 29 patients with either a fracture (11
      patients) or a fracture-dislocation (18 patients) of the thoracic spine were
      treated operatively. All patients underwent posterior decompression and
      stabilization within a mean time of 4 days after injury (range, 0-45 days).
      Patients with complete paraplegia had no postoperative improvement in neurologic
      status, whereas all patients with incomplete spinal cord lesions improved in
      neurologic status after surgery. There was no significant association between
      time from injury to operation and final neurologic outcome. For thoracic
      fractures, the procedure of surgical decompression and stabilization is safe, and
      neurologic recovery may be anticipated in patients with incomplete spinal cord
      lesions.

PMID- 12602638
TI  - Evaluation of registration methods used in frameless stereotactic surgery for the
      lumbar and cervical regions of the spine.
AB  - Computer-assisted pedicle screw insertion is feasible but has proved to be
      problematic. The purpose of this study was to detail the accuracy of registration
      techniques and pedicle screw insertion using a frameless stereotactic system. Two
      registration techniques were evaluated on a model spine. The frameless
      stereotactic system was then used to insert 26 pedicle and 8 lateral mass screws
      in human cadavers. For posterior vertebral elements, trajectory accuracy was 2.5
      +/- 1.0 mm between T12 and L5 and 2.2 +/- 0.9 mm between C2 and T1. Registration
      of the anterior elements, however, was less accurate. Despite this flaw, all
      screws were inserted without penetrating the cortex. Screw trajectory was
      accurate to 2 degrees. The main limitation of frameless stereotactic surgery in
      the spine stems from the fact that only the posterior vertebral elements are used
      during registration. Despite this flaw, the system placed all screws correctly.
      Given these limitations, we believe that this system is most useful for locating
      the screw insertion point and providing a trajectory in the pedicle.

PMID- 12602639
TI  - Bilateral Monteggia fractures.
AB  - The current concepts of anatomic and stable fixation followed by early
      mobilization in Monteggia fractures have clearly resulted in improvements in
      treatment and outcome. Bilateral Monteggia fractures are unusual and to the best
      of our knowledge have not been the subject of any reports in the literature. In
      this case report, we describe the operative technique for treating bilateral
      Monteggia fractures and the common pitfalls associated with this treatment.
      Despite the surgical and rehabilitative challenges posed by our patient's case,
      excellent results were obtained for both elbows.

PMID- 12602640
TI  - Aneurysmal bone cyst in the hamate.
AB  - Aneurysmal bone cysts (ABCs) show a predilection for the metaphysis of the long
      bones and the vertebrae and seldom involve the carpal bones. We present a case of
      an ABC in the left hamate of an 18-year-old man. Curettage and bone grafting were
      performed, and, because destruction of the cortex was extensive, the hamate was
      excised. At 3-year follow-up, the wrist was stable.

PMID- 12602641
TI  - Treatment of type III tibial intercondylar eminence fractures in skeletally
      immature athletes.
AB  - Our retrospective study of 12 skeletally immature athletes with type III
      intercondylar eminence fractures showed that arthroscopic evaluation with mini
      open arthrotomy and repair of the tibial intercondylar eminence fracture with
      absorbable suture can be successful in repairing anterior cruciate ligament
      avulsion fractures and in helping such patients return to their athletic
      endeavors.

PMID- 12602642
TI  - An evaluation of the dose-response relationship in naturalistic treatment
      settings using survival analysis.
AB  - To date, few studies have been published on the dose-response relationship in
      psychotherapy. The current study addresses limitations of previous research by
      using (1) clinical significance methodology to address the meaningfulness of
      patient change, (2) survival analysis to assess change across time, (3)
      assessment of patient change on a session-by-session basis, and (4) a large data
      set representing a variety of treatment settings. A total of 4,761 patients
      representing standard treatment settings in the United States were tracked at
      each session of therapy. A survival analysis of this data reveals that between 15
      and 19 sessions of therapy are required for a 50% recovery rate using clinical
      significance methodology. The results of this study provide a useful overview of
      time-to-change in naturalistic settings that can be used to estimate reliable
      treatment expectations and as a baseline for comparison when modifications are
      made within treatment delivery systems.

PMID- 12602643
TI  - Contexts of social relationship development among assertive community treatment
      clients.
AB  - This exploratory qualitative study examined contexts and processes of social
      relationship development as experienced by adults with schizophrenia
      participating in assertive community treatment (ACT) programs. Semistructured
      interviews with 20 ACT clients diagnosed with schizophrenia-spectrum disorders
      and 2 ACT staff members were analyzed using grounded theory analysis methods.
      Results showed that aside from contacts with family members and providers,
      participants' interactions with fellow mental health clients tended to dominate
      social interactions, and that this pattern appeared to be influenced by both the
      concentration of social opportunities in daily activities of service utilization
      and the ACT program emphasis upon facilitating relationships between clients.
      Participants described their relationships with other mental health clients in
      primarily positive terms, yet several participants expressed dissatisfaction and
      desired greater integration into mainstream social networks. Implications for
      mental health service delivery are discussed.

PMID- 12602644
TI  - Involuntary outpatient commitment and homelessness in persons with severe mental
      illness.
AB  - This study took preliminary steps to explore the relationship between involuntary
      outpatient commitment (OPC) and the risk of homelessness among individuals with
      severe mental disorders. Involuntarily hospitalized patients were randomly
      assigned to be released or maintained under OPC following hospital discharge.
      Multivariate analyses demonstrated that involuntary OPC was associated with a
      significant decrease in the risk of homelessness during the first 4 months
      following hospital discharge for participants with severe functional impairment
      at baseline. OPC did not appear to affect risk of homelessness among participants
      with mild-to-moderate functional impairment. Co-occurring substance abuse,
      treatment nonadherence, and outpatient services intensity were found to be
      strongly associated with episodes of homelessness. This study suggests that
      involuntary OPC may provide a short-term reduction in the risk of homelessness
      among a subgroup of treatment-reluctant individuals with severe mental disorders
      combined with severe functional impairment.

PMID- 12602645
TI  - The effect of Medicaid managed care on mental health care for children: a review
      of the literature.
AB  - Despite its widespread adoption, little is known about the effect of Medicaid
      managed care (MMC) on children using mental health services. To assess the state
      of current research, we reviewed the literature on MMC and synthesized findings
      regarding access to care, expenditures, utilization, cost-shifting, and quality
      of care. A literature search was conducted and updated in November 2001. Studies
      were included if they involved evaluations of MMC, included children with mental
      health or substance abuse disorders, and had a non-MMC comparison group. Eight
      studies were included in the review. Most involved carve-outs and capitation. All
      of the studies that measured cost and service use showed decreases in total
      costs, inpatient care costs, and inpatient service use. These changes were
      frequently accompanied by increases in outpatient care. Some evidence suggests
      that MMC increased access to care for those with less serious conditions. There
      was no convincing evidence of cost-shifting from mental to physical health or
      other public agencies. Finally, no study directly measured health outcomes or
      quality of care. By reducing service use in inpatient settings, MMC has the
      potential to reduce children's mental health expenditures. The available research
      provides virtually no evidence on quality of care.

PMID- 12602646
TI  - Using discrete-time survival analysis to examine patterns of remission from
      substance use disorder among persons with severe mental illness.
AB  - Investigators in mental health research are often interested in examining
      critical events such as onset, relapse, and recovery from illness, including
      substance use disorders. As data on these critical events are often collected at
      discrete-time intervals (e.g., weekly, monthly, or yearly), discrete-time
      survival models are more appropriate than well-known continuous-time methods. In
      this paper, we present discrete-time survival analysis methods at an introductory
      level. Using data collected every 6 months from a 3-year study of assertive
      community treatment in New Hampshire, we show that discrete-time survival models
      can be used to analyze patterns of remission from substance use disorder among
      clients with severe mental illness. The main questions investigated are (1) when
      are remissions more likely to occur? and (2) what variables predict remission?
      The results indicate that remission is more likely to occur in the first 6 months
      and in the 3rd year of the study. Gender, age, baseline use of substances, and
      diagnosis are strong predictors of remission.

PMID- 12602647
TI  - Posttraumatic stress disorder and treatment seeking in a national screening
      sample.
AB  - The behavioral model of service use was employed to identify predictors of mental
      health treatment seeking and treatment readiness among individual with PTSD (N =
      2,713) in data from the 1996 National Anxiety Disorders Screening Day (NADSD).
      This model examines the contribution of predisposing (age, sex, marital status,
      race/ethnicity, education), enabling (employment, geographic location), perceived
      need (interference of symptoms with daily life), and evaluated need (other
      diagnoses) factors to treatment seeking and treatment readiness for individuals
      with PTSD. Results indicate that although need factors (interference by anxiety
      symptoms with daily life, diagnosis of panic disorder) are related to both
      receiving and readiness for treatment, predisposing (age, marital status,
      minority race) factors influence which individuals receive treatment for PTSD.

PMID- 12602649
TI  - Hazardous alcohol use and treatment outcome in male combat veterans with
      posttraumatic stress disorder.
AB  - The relationship between alcohol problems and posttraumatic stress disorder
      (PTSD) remains unclear. Six hundred and eight combat veterans diagnosed with PTSD
      were assessed for PTSD symptoms and alcohol problems prior to group cognitive
      behavioral treatment. They were reassessed 3 and 9 months after treatment.
      Participants were classified into low-risk and hazardous drinkers at each time
      point. Drinking status at intake did not predict PTSD symptoms at intake or
      follow-up. However, drinking status was associated with PTSD symptoms when both
      were assessed at follow-up. PTSD arousal symptoms were the only symptom cluster
      to differentiate drinking groups.

PMID- 12602648
TI  - The prevalence of PTSD following the violent death of a child and predictors of
      change 5 years later.
AB  - In this study, we examined the violent death bereavement trajectories of 173
      parents by following them prospectively for 5 years after their children's deaths
      by accident, suicide, homicide, or undetermined causes. Using latent growth curve
      methodology, we examined how the initial level of PTSD and the rate of change
      over time were influenced by 9 predictors: the deceased children's causes of
      death, parents' gender, self-esteem, 3 coping strategies, perceived social
      support, concurrent levels of mental distress, and an intervention offered in
      early bereavement. Six of the nine factors predicted initial levels of PTSD;
      however, only parents' gender and perceived social support predicted change in
      PTSD over the 5-year time frame. Five years postdeath, 3 times as many study
      mothers (27.7%) met diagnostic criteria for PTSD and twice as many study fathers
      (12.5%) met diagnostic criteria for PTSD compared with the normative samples.

PMID- 12602650
TI  - Psychopathology and sexual trauma in childhood and adulthood.
AB  - This study evaluates the occurrence of psychopathology among 97 women who (1)
      experienced sexual abuse in childhood only, (2) were raped in adulthood only, (3)
      experienced both childhood sexual abuse and rape in adulthood, or (4) experienced
      no sexual trauma. Women were recruited from advertisements and assessed using the
      Structured Clinical Interview for DSM-IV (SCID-I/P) and the Modified PTSD Symptom
      Scale Self-Report. Women who reported sexual trauma were significantly more
      likely to exhibit psychopathology than controls. Being sexually victimized in
      childhood and raped in adulthood was associated with a particular risk for
      substance dependence.

PMID- 12602651
TI  - The Sydney Holocaust study: posttraumatic stress disorder and other psychosocial
      morbidity in an aged community sample.
AB  - We investigated the psychological status and social functioning of Holocaust
      survivors. From 814 responses to a community survey of Jewish elders (aged 60
      years or older), survivors (n = 100), refugees who had not experienced the
      Holocaust (n = 50), and Australian/English-born persons (n = 50), were randomly
      selected for semistructured interview, which included Posttraumatic Stress
      Disorder (PTSD) assessment, ratings on the General Health Questionnaire, Brief
      Psychiatric Rating Scale, Impact of Event Scale, Mini-Mental Status Examination,
      and Instrumental Activities of Daily Living and Social Functioning. On all
      psychological measures, survivors were functioning worse than refugees and
      Australian/English-born persons. The 3 groups were similar in social and
      instrumental functioning. The more severe the trauma the greater the level of
      psychological morbidity. Despite normal social and daily functioning,
      psychological morbidity following massive trauma endures.

PMID- 12602652
TI  - Assessment of psychological functioning in adolescent earthquake victims in
      Colombia using the MMPI-A.
AB  - The earthquake that hit Armenia, Colombia, on January 25, 1999, dramatically
      impacted the lives of thousands of people, including children and adolescents.
      This study used the Hispanic MMPI-A to clinically assess for ongoing
      psychopathology in a group of 59 adolescent earthquake victims. Their scores on
      the basic, content, and supplementary scales of the instrument were compared to
      those of a control group of 62 Colombian adolescents with similar socioeconomic,
      educational, and ethnic backgrounds. The results showed no clinically significant
      elevations for the earthquake victims indicating that the disaster had not
      resulted in diagnosable psychopathology. When compared to controls, earthquake
      victims showed significant elevations on D, Pt, and Sc indicating that they were
      mildly affected (but within the normal range) by the earthquake. The results are
      discussed in the context of cultural factors and the contemporary disaster and
      resiliency literature.

PMID- 12602653
TI  - Is the emotional Stroop paradigm sensitive to malingering? A between-groups study
      with professional actors and actual trauma survivors.
AB  - Six professional actors, trained by psychologists and acting coaches to feign
      PTSD, were covertly enrolled into a treatment outcome study for PTSD with the aim
      of investigating malingering. During pretreatment assessment, individuals
      completed an emotional Stroop task. Vocal response latencies to different classes
      of stimuli were examined for sensitivity to malingering. Actor response latencies
      were compared to those of 6 nonlitigant PTSD patients and 6 nonanxiety controls.
      The actor/dissimulation group was able to feign an overall slowing of response
      latency across stimulus types, similar to the PTSD group. However, they were
      unable to modulate response latency as a function of stimulus content, a pattern
      that characterized the PTSD group. The use of information-processing paradigms to
      detect dissimulation is discussed.

PMID- 12602654
TI  - Emotional experiencing in women with posttraumatic stress disorder: congruence
      between facial expressivity and self-report.
AB  - The congruence between facial expressivity and self-report of emotion was
      examined among 11 women with sexual assault-related PTSD and 8 women without
      PTSD, under both a neutral and a sexual assault prime condition. The PTSD group
      demonstrated some incongruities in emotional responding. Although the PTSD group
      was as facially expressive as the control group, they reported more arousal to
      the emotional stimuli. Further, an inverse relationship between negative facial
      expressivity and self-report to negative stimuli was found for some variables for
      the PTSD group only, such that the less expressions they showed facially, the
      more negative they reported feeling. However, the overall pattern of results
      suggests fewer significant relationships between expression and experience than
      predicted.

PMID- 12602655
TI  - Factor analysis of treatment response in posttraumatic stress disorder.
AB  - Factor analysis is applied to the symptoms of posttraumatic stress disorder
      (PTSD) to reduce the multidimensional symptom space to 2 dimensions; 1 dimension
      strongly correlated with depressive symptoms and 1 independent dimension weakly
      correlated with depressive symptoms. These factors are used to assess whether the
      effectiveness of an antidepressant medication is due to its antidepressant
      effect. The treatment is shown to be effective in both dimensions. The factor
      analysis sheds light on the symptom structure of PTSD, supports PTSD as a
      distinct psychiatric disorder, and supports the current diagnostic criteria.

PMID- 12602656
TI  - Cognitive trauma therapy for battered women with PTSD: preliminary findings.
AB  - This paper describes a treatment-outcome study of Cognitive Trauma Therapy for
      Battered Women (CTT-BW) with PTSD. Derived from psychological learning
      principles, CTT-BW emphasizes the role of irrational beliefs and evaluative
      language in chronic PTSD. CTT-BW includes trauma history exploration, PTSD
      psychoeducation, stress management, psychoeducation about dysfunctional self-talk
      and self-monitoring of self-talk, exposure to abuse reminders, Cognitive Therapy
      for Trauma-Related Guilt (E. S. Kubany & F. P. Manke, 1995), and modules on
      assertiveness, managing contacts with former partners, self-advocacy strategies,
      and avoiding revictimization. Thirty-seven ethnically diverse women were assigned
      to Immediate or Delayed CTT-BW. PTSD remitted in 30 of 32 women who completed CTT
      BW. Gains were maintained at 3-month follow-up. CTT-BW was efficacious across
      ethnic backgrounds. Issues related to disseminability of CTT-BW are discussed.

PMID- 12602657
TI  - A multivariate model of patients' satisfaction with treatment for posttraumatic
      stress disorder.
AB  - Prior studies have concluded that patients' pretreatment characteristics
      contribute more to their satisfaction with mental health treatment than any other
      domain. We expand the representation of treatment characteristics in an
      examination of satisfaction across both inpatient and outpatient settings. Data
      were drawn from an inpatient (n = 831) and an outpatient (n = 554) study of the
      treatment of PTSD. We used structural equation modeling to specify and evaluate a
      model of satisfaction with comparable elements for inpatient and both short and
      long-term outpatient treatment. Results indicate that the quality and quantity of
      patients' participation in treatment were more important to the development of
      their satisfaction with treatment than their pretreatment characteristics. Among
      treatment characteristics, the social climate of the inpatient milieu and the
      focus on war traumas in outpatient therapy had major effects on the quality and
      quantity of patients' participation and their satisfaction.

PMID- 12602658
TI  - Family functioning, coping, and psychological adjustment in victims and their
      families following kidnapping.
AB  - This study examines the psychological aftereffects of economic extortive
      kidnapping on families during captivity, and on kidnapped individuals and family
      members, 2-4, 5-8, and 9-15 months after the release. Fifty-five kidnapped and
      released individuals and 158 family members were evaluated through CAPS-DX, SCL90
      R, FAD, F-COPES, and a family interview. Captivity was the most stressful period
      with the highest CAPS and general distress scores. There were no significant
      differences in psychological distress or in PTSD between the 3 time groups after
      the release or between kidnapped individuals and their relatives. Correlations
      among family functioning, coping, and psychological adjustment, during captivity
      and after the release were analyzed.

PMID- 12602659
TI  - Lamb's quarter, Chenopodium album.

PMID- 12602660
TI  - Evaluation of indoor mold exposure is what allergists do best.

PMID- 12602661
TI  - What factors cause bronchial hyperresponsiveness? Airway inflammation and
      eosinophilia are only part of the puzzle.

PMID- 12602662
TI  - The effects of interventions and glove changes in health care workers with latex
      allergy.

PMID- 12602663
TI  - Membership apathy.

PMID- 12602664
TI  - Pharmacotherapy for allergic rhinitis: a critical review of leukotriene receptor
      antagonists compared with other treatments.
AB  - OBJECTIVE: To review the mechanisms and clinical efficacy of leukotriene receptor
      antagonists, which are investigational therapies for allergic rhinitis, compared
      with intranasal corticosteroids and nonsedating antihistamines, which are the
      most commonly prescribed pharmacotherapies for allergic rhinitis. DATA SOURCES:
      Computer-assisted MEDLINE searches for articles and manual searches of conference
      proceedings on intranasal corticosteroid, antihistamine, leukotriene receptor
      antagonist, leukotriene modifier, zafirlukast, montelukast, allergic rhinitis,
      rhinitis, and asthma. SELECTION: Published articles and pertinent abstracts on
      the topics identified above were selected. Head-to-head comparator trials as well
      as data from placebo-controlled trials were selected. RESULTS AND CONCLUSIONS:
      The studies published to date demonstrate that leukotriene receptor antagonists
      are sometimes more effective than placebo, are no more effective than nonsedating
      antihistamines, and are less effective than intranasal corticosteroids in the
      treatment of allergic rhinitis. The combination of a leukotriene receptor
      antagonist and an antihistamine has not been proven to be more effective than
      either agent alone. This review reveals several inconsistencies that require
      resolution. First, whereas leukotriene receptor antagonists are predicted on the
      basis of their mechanism of action to improve nasal congestion significantly,
      clinical studies reveal leukotriene receptor antagonists to be no better than
      antihistamines at improving congestion. Second, leukotriene receptor antagonists
      would not be expected on the basis of their putative mechanism of action or nasal
      challenge data to improve significantly sneezing, nasal itching, or drainage.
      However, some studies show improvement in these symptoms during treatment with
      leukotriene receptor antagonists. Considered in aggregate, the data available to
      date do not clearly support a unique role of leukotriene receptor antagonists in
      the treatment of allergic rhinitis whether or not it is accompanied by asthma.

PMID- 12602665
TI  - Dose response of inhaled corticosteroids on bronchial hyperresponsiveness: a meta
      analysis.
AB  - BACKGROUND: There is a relatively steep dose-response curve for effects of
      inhaled corticosteroids on conventional airway markers of asthmatic disease
      control. OBJECTIVE: We sought to determine whether a dose-response effect exists
      for bronchial hyperresponsiveness. METHODS: A meta-analysis of placebo-controlled
      trials in asthmatic patients was performed using a computerized systematic review
      of databases. Doubling dose/dilution protection of inhaled corticosteroid was
      compared with placebo. Studies which used direct (methacholine and histamine) and
      indirect (adenosine monophosphate) bronchial challenge stimuli were eligible for
      inclusion. RESULTS: Twenty-five studies fulfilled eligibility criteria (963
      patients). Values for doubling dose/dilution protection categorized by low/medium
      dose (< 1,000 microg) and high dose (> or = 1,000 microg) of inhaled
      corticosteroid amounted to a 1.25 (95% confidence interval 1.08 to 1.42) and 2.16
      (95% confidence interval 1.88 to 2.44) shift, respectively. CONCLUSIONS: High
      doses of inhaled corticosteroids conferred greater improvements in bronchial
      hyperresponsiveness than low doses.

PMID- 12602666
TI  - Unresponsive wheezing to asthma therapy in a 32-year-old female.
AB  - Repeat failure of any patient to respond to asthma therapy, particularly
      corticosteroids, should alert physicians to carry out further pulmonary
      evaluation. This will prevent unnecessary side effects of asthma therapy and
      provide prompt treatment for other diseases that may require urgent attention.

PMID- 12602667
TI  - Fungal contamination of elementary schools: a new environmental hazard.
AB  - BACKGROUND: Sensitivity to fungi is a significant cause of allergic diseases, and
      prolonged indoor exposure to fungi is a growing health concern. OBJECTIVE: This
      study evaluates the health effects of mold-contaminated schools on students and
      teachers. A discussion of the effectiveness of current methods for evaluating
      these schools, with a focus on the importance of using total mold spore counts,
      is also provided. METHODS: Two Connecticut public schools were tested using
      multiple air quality testing methods, with the standard for a healthy indoor
      environment being total mold spore counts lower than 1,000 spores/m3. The health
      impact of the mold exposure at each school was evaluated using the validated
      Rhinitis Outcomes Questionnaire. RESULTS: The testing of the first school found
      indoor mold counts ranging from 6,000 to 50,000 spores/m3. Eighty-five of the
      students and teachers reported significant allergic symptoms to the school nurse.
      This school is currently being demolished. More than 2 years after the exposure
      ended, a number of occupants of the school continue to have elevated symptoms
      compared with before their exposure to the school. The testing of the second
      school revealed total mold spore counts ranging between 2,000 and 9,000
      spores/m3, qualifying it an unhealthy environment in need of immediate
      remediation. Students reported significant allergic symptoms from exposure to
      certain rooms that are currently being remediated. CONCLUSIONS: Because of the
      negative impact on health that indoor mold exposure has, particularly in atopic
      patients, schools should be routinely tested for fungal contamination. Total mold
      spore counts should be performed using volumetric air sampling such as the
      Allergenco MK-3 (Allergenco, San Antonio, TX) because testing air quality via
      semiquantitative culture sampling alone does not give a true reflection of the
      extent of fungal contamination. Finally, the standard for a healthy indoor
      environment should be defined as having <1,000 spores/m3.

PMID- 12602668
TI  - Clinical and occupational outcomes in health care workers with natural rubber
      latex allergy.
AB  - BACKGROUND: There is limited information pertaining to clinical outcomes and
      economic consequences of natural rubber latex (NRL) allergy in health care
      workers (HCWs). OBJECTIVE: To evaluate retrospectively health and economic
      outcomes in HCWs identified with NRL allergy and percutaneous reactivity to NRL.
      METHODS: Sixty-seven HCWs with NRL allergy, confirmed by percutaneous reactivity
      to non-ammoniated latex (NAL) extract, were administered a detailed questionnaire
      to evaluate clinical and economic outcomes of active work and environmental
      interventions subsequent to recognition of work-related symptoms associated with
      NRL gloves. RESULTS: Diagnoses based on predetermined case definitions associated
      with direct or indirect exposure to NRL gloves included contact urticaria in 67
      (100%); work-related rhinitis in 23; work-related asthma symptoms in 25; and work
      related anaphylaxis in 4 workers. Work related symptoms reportedly resolved in 44
      of 49 (90%) of NAL skin test-positive workers who had reported skin, respiratory,
      and/or systematic symptoms and remained in their current work area and who
      switched to non-NRL gloves. Four of 24 (17%) workers with work-related asthma
      symptoms were compelled to change employment to NRL-safe workplaces, resulting in
      a mean 24% reduction in annual income. CONCLUSIONS: Clinical outcomes in this
      group of HCWs with NRL allergy were favorable after institution of interventions
      but incurred deleterious consequences in a minority of workers.

PMID- 12602669
TI  - Randomized controlled trial evaluating the clinical benefit of montelukast for
      treating spring seasonal allergic rhinitis.
AB  - BACKGROUND: Symptoms of allergic rhinitis are mediated in part by cysteinyl
      leukotrienes. OBJECTIVE: To evaluate the clinical benefit of montelukast, a
      cysteinyl leukotriene receptor antagonist, administered once daily for treating
      seasonal allergic rhinitis. METHODS: This multicenter, randomized, double-blind,
      placebo- and active-controlled study enrolled 1,214 healthy, nonsmoking
      outpatients aged 15 to 85 years with spring allergic rhinitis, positive skin test
      to a spring allergen, and predefined daytime nasal symptoms. After a 3- to 5-day
      placebo run-in period, patients were randomly assigned to treatment with
      montelukast 10 mg (n = 522), loratadine 10 mg (n = 171), or placebo (n = 521)
      once daily at bedtime for 2 weeks. During the run-in and treatment periods,
      symptoms were evaluated in a daily diary using a 0 (best) to 3 (worst) scale.
      RESULTS: Baseline characteristics of randomized patients were clinically similar
      in the three treatment groups. Montelukast was significantly more effective than
      placebo (P = 0.003) in improving the daytime nasal symptoms score (difference in
      least square means, -0.09; 95% confidence interval, -0.16, -0.03) averaged over 2
      weeks of therapy. The treatment effect of montelukast was significantly greater
      (P < 0.05), relative to placebo, for all secondary endpoints, including nighttime
      symptoms and daytime eye symptoms, patient and physician global evaluations of
      allergic rhinitis, and rhinoconjunctivitis quality of life. Loratadine, which
      served as a positive control, was significantly more effective than placebo for
      most endpoints, validating the study results. Both montelukast and loratadine
      were well tolerated. CONCLUSION: Therapy with montelukast significantly improves
      assessments of symptom severity as well as quality-of-life parameters for
      patients with seasonal allergic rhinitis.

PMID- 12602670
TI  - Mouse allergy among asthmatic children from rural Appalachia.
AB  - BACKGROUND: Mice are a common finding in the indoor environment of many homes. In
      a recent study, 18% of children with asthma from an inner-city environment were
      reported to be allergic to mouse allergen. OBJECTIVE: To determine the frequency
      of skin test reactivity among asthmatic children in a rural environment. METHODS:
      We consecutively evaluated 209 (82 female, 127 male) children between the ages of
      5 months and 19 years with asthma for mouse allergy. A careful environmental
      history was obtained on all children. Children older than 3 years of age were
      skin tested to mouse allergen and other indoor/outdoor inhalant allergens.
      Children younger than 3 years were skin tested to mouse and indoor allergens.
      RESULTS: Thirty-three percent of parents reported seeing mice in their homes.
      Overall, 25 of 209 (12%) children with asthma were skin test-positive for mouse.
      For children 3 years or younger, 6 of 52 were skin test-positive for mouse (12%).
      There was no correlation among socioeconomic status, skin test reactivity, and
      the presence of mice in the home. Children with multiple skin test reactions were
      more likely to be reactive to mouse (P < 0.01). Mice seen in the home did not
      correlate with positive mouse skin tests. CONCLUSIONS: The frequency of skin test
      reactivity to mouse allergen in asthmatic children from rural areas appears
      slightly less than that in children from inner-city environments. However, a
      frequency of 12% suggests that skin testing for this allergen provides useful
      information for environmental control measures in the home.

PMID- 12602671
TI  - Systemic availability and lung deposition of budesonide via three different
      nebulizers in adults.
AB  - BACKGROUND: Budesonide is an inhaled corticosteroid widely used in the treatment
      of asthma. The local and systemic availability of budesonide has been determined
      in adults via pressurized metered-dose inhaler and dry-powder inhaler. OBJECTIVE:
      To estimate lung deposition and systemic availability of budesonide inhalation
      suspension in healthy adults. METHODS: Twelve adult volunteers entered an open,
      randomized, five-way crossover study and received the following treatments, with
      1-week washout between treatments: separate 2-mg (nominal dose) budesonide doses
      via the Pari Inhalierboy (Inhalierboy; Pari GmbH, Starnberg, Germany), Pari LC
      Jet Plus (Jet Plus, Pari GmbH), and Maxin MA-2 (MA-2; Clinova Medical AB, Malmo,
      Sweden) jet nebulizers, 4 mg budesonide orally, and 0.5 mg budesonide
      intravenously. The plasma concentration of budesonide was measured up to 8 hours
      postadministration. Lung deposition and systemic availability of nebulized
      budesonide were estimated using pharmacokinetic evaluation. RESULTS: In this
      first study of the bioavailability of budesonide inhalation suspension in adults,
      there were no differences between nebulizers in lung deposition (14 to 16%) or
      systemic availability (15 to 17%) relative to the nominal budesonide dose.
      Relative to the actual dose inhaled (dose-to-subject), lung deposition and
      systemic availability were statistically significantly higher for the Jet Plus
      (58 and 63%, respectively) and MA-2 (59 and 64%, respectively) nebulizers than
      the Inhalierboy (36 and 44%, respectively). The Inhalierboy produced larger
      aerosol droplets than Jet Plus or MA-2 nebulizers (7-, 5-, and 3-microm mass
      median diameters, respectively) and delivered a higher dose-to-subject than the
      other two nebulizers. CONCLUSION: Relative to the nominal dose, lung deposition
      and systemic availability of budesonide were similar via the three nebulizers
      tested.

PMID- 12602672
TI  - A large kindred with familial cold autoinflammatory syndrome.
AB  - BACKGROUND: Familial cold autoinflammatory syndrome (FCAS), formerly known as
      familial cold urticaria, is a rare condition characterized by fever, rash, and
      arthralgias elicited by exposure to cold. Recently, mutations responsible for
      FCAS were identified in a novel gene (CIAS1), making it possible to confirm the
      diagnosis in most patients. OBJECTIVE: We present a summary of clinical data from
      a large family with FCAS to further define the characteristics of the disorder
      and to validate previously proposed clinical criteria. METHODS: A total of 73
      participants were evaluated by interview and questionnaire, including 36 affected
      individuals. Responses from the questionnaire were analyzed and comparisons of
      proportions were made using the Z test. DNA was isolated and genotyping was
      performed on all subjects. Affected haplotypes (genotype patterns) were
      identified and used to confirm the diagnosis. Sequencing of the CIAS1 gene was
      performed in selected patients to confirm the mutation. RESULTS: The prevalence
      of rash, fever/chills, joint complaints, nausea, headache, and thirst were not
      significantly different from previously reported proportions. There was
      statistically significant differences in conjunctivitis, sweating, and drowsiness
      with alpha = 0.01. The mean temperature required to produce symptoms was 22
      degrees C, and the average earliest onset of symptoms after exposure was 1.5
      hours. CONCLUSIONS: Applying the proposed clinical criteria, 41% of affected
      subjects met all six criteria, 90% met five criteria, and 100% met four criteria
      for FCAS. None of the unaffected subjects met more than two criteria. Using a
      threshold of 4 of 6 clinical criteria, the data support the diagnostic validity
      of the proposed clinical criteria.

PMID- 12602673
TI  - Immediate allergy to tetanus toxoid vaccine: determination of immunoglobulin E
      and immunoglobulin G antibodies to allergenic proteins.
AB  - BACKGROUND: Adverse reactions to tetanus toxoid (TT) vaccine are mostly mild and
      limited to the injection site. However, immunoglobulin (Ig)E-mediated reactions
      may occur, and the incidence of anaphylactic responses to TT immunization is
      0.001%. When TT induces an allergic reaction, the potential causative agents can
      be TT antigens, thimerosal or aluminum phosphate. OBJECTIVE: We studied four
      children who developed immediate urticaria after TT vaccine, soon after the
      reaction and 5 years later. METHODS: Skin tests were performed separately with TT
      vaccine and two vaccine components, thimerosal and aluminum phosphate, and the
      diagnosis was confirmed by provocation test. IgE and IgG antibodies to TT and
      their specificities were determined. Sodium dodecyl sulfate-polyacrylamide gel
      electrophoresis and immunoblotting were performed to characterize the antigenic
      proteins. RESULTS: All four children were immediate skin test-positive to TT, but
      negative to thimerosal and aluminum phosphate; 3 developed a reaction after
      intramuscular provocation using increasing doses of TT vaccine; and 1 refused to
      be tested. All these tests were negative in five controls, all of whom received
      TT vaccine and developed only local swelling at the site of application 24 hours
      after vaccine administration. After 5 years the IgG antibodies were still high in
      all cases and the IgE antibody values fell by 50%. Patients allergic to TT
      vaccine produced IgE and IgG antibodies, which decreased at different rates but
      remained for at least 5 years. The pattern of antibody decrease was confirmed by
      radioallergosorbent test, enzyme-linked immunoadsorbent assay, or immunoblotting
      assay. IgE and IgG antibodies recognized two proteins derived from TT, of 150 and
      50 kDa, corresponding to the intracellular form and to a chain of the
      extracellular form of the tetanus neurotoxin. CONCLUSIONS: In children with
      immediate allergic reactions to TT vaccine, antibodies may persist for at least 5
      years, requiring evaluation by skin and/or in vitro tests before subsequent
      treatment.

PMID- 12602674
TI  - Antibody response in common variable immunodeficiency.
AB  - BACKGROUND: Common variable immunodeficiency (CVID) describes a heterogeneous
      group of immunologic disorders of unknown etiology. It is characterized by low
      levels of serum immunoglobulin (Ig) and impaired antibody response. OBJECTIVE: To
      describe antibody response and the kinetics of IgG decline in patients identified
      with CVID. METHODS: Clinical and immunologic observations of four patients
      identified with CVID were obtained by chart review. RESULTS: Antibody response to
      polysaccharide antigens in patients identified with CVID is lost earlier than the
      antibody response to protein antigens, which may be preserved even in the face of
      profound hypogammaglobulinemia. In three patients who were followed
      prospectively, the Ig loss was progressive. CONCLUSIONS: Absence of antibody
      response to polysaccharide antigens may be a universal finding in patients with
      CVID, whereas preservation of T cell-dependent protein antibody response may be
      seen.

PMID- 12602675
TI  - The prevalence of IgE antibody reactivity against the alkaline serine protease
      major allergen of Penicillium chrysogenum increases with the age of asthmatic
      patients.
AB  - BACKGROUND: Penicillium species are prevalent airborne fungi. However, the
      prevalence of allergic sensitization to Penicillium antigens and the true impact
      of these ubiquitous fungi on atopic respiratory disorders remain to be
      determined. OBJECTIVE: The purpose of this study was to analyze the prevalence of
      immunoglobulin (Ig)E and IgG antibodies against Penicillium chrysogenum (Pen ch
      13), the alkaline serine protease major allergen of P. chrysogenum, in asthmatic
      patients of different age groups. METHODS: Pen ch 13 was purified from a culture
      medium of P. chrysogenum. The reactivity of IgE and IgG antibodies to Pen ch 13
      in the serum samples of 212 asthmatic patients was analyzed by immunoblotting
      methods. RESULTS: Sixty-nine (33%) of the 212 sera analyzed showed IgE and/or IgG
      immunoblot reactivity to Pen ch 13. Significant differences in the prevalence of
      IgE and/or IgG antibody reactivity to Pen ch 13 were found among eight different
      age groups of 212 asthmatic patients. The frequency of IgE-binding reactivity to
      Pen ch 13 increased significantly with the age of the patients. It was 7% for the
      group less than 10 years old and 42% for the group older than 70 years old. In
      addition, a significant difference between the prevalence of IgE (7%) and IgG
      (33%) antibodies against Pen ch 13 in the group aged 10 or less was also found.
      CONCLUSIONS: Our study demonstrates that IgE and IgG antibodies specific for Pen
      ch 13 were detected in approximately one-third of the 212 asthmatic patients
      analyzed. Our results suggest that allergic sensitization to Pen ch 13, and
      possibly to other airborne Penicillium species, is more common in older asthmatic
      patients.

PMID- 12602676
TI  - An anaphylactic reaction to intra-articular triamcinolone: a case report and
      review of the literature.
AB  - OBJECTIVE: The primary objective was to report a case of triamcinolone-induced
      anaphylaxis and review the proposed mechanisms of corticosteroid-associated
      hypersensitivity reactions. DATA SOURCES: Articles in French and English were
      identified from references in relevant articles and from articles retrieved from
      the PubMed web site. Indexing terms consisted of corticosteroids in conjunction
      with the terms anaphylaxis, hypersensitivity reactions, asthma, urticaria, and
      angioedema. STUDY SELECTION: We reviewed all articles that described a case or
      cases of allergic-type reaction in association with corticosteroid use and for
      which we could obtain the full text of the article (>95%). RESULTS: We report an
      anaphylactic reaction occurring after an intraarticular injection of
      triamcinolone in a 75-year-old man who had positive prick skin tests to
      triamcinolone and negative tests to lidocaine, methylprednisolone, and
      hydrocortisone. CONCLUSIONS: To date, there have been approximately 100 published
      reports of immediate hypersensitivity reactions occurring after oral and
      parenteral administration of corticosteroids. Both immunologic and nonimmunologic
      mechanisms are proposed, but there is no definitive evidence in favor of either
      hypothesis. Our patient demonstrated positive prick skin tests to triamcinolone
      in a dose-response manner, suggesting the likelihood that an immunoglobulin E
      mediated hypersensitivity mechanism may play a role.

PMID- 12602677
TI  - The syndrome of chronic mucocutaneous candidiasis with selective antibody
      deficiency.
AB  - BACKGROUND: Most patients with chronic mucocutaneous candidiasis (CMC) have a
      selective defect of cell-mediated immunity against Candida albicans (as
      demonstrated by cutaneous anergy and decreased lymphoproliferative responses to
      Candida antigen) and intact antibody responses. Many CMC patients also develop
      infections with other organisms, suggesting a more extensive immunologic defect.
      OBJECTIVES: The aim of this study was to describe a patient with CMC and
      selective antibody deficiency and identify eight similar previously reported
      patients. DATA SOURCES: Relevant articles in the English language derived from
      searching the MEDLINE database were used. RESULTS: We describe an 18-year-old
      male patient who was identified with CMC as an infant and later developed
      immunoglobulin (Ig)G2, IgG4, and IgA deficiency at age 12 associated with poor
      antibody responses to vaccine antigens. We have identified eight other previously
      reported CMC patients with selective antibody deficiencies and bacterial
      infections. IgG2 deficiency was present in all nine patients, and was associated
      with IgG4 deficiency in 8 patients and IgA deficiency in 3 patients. Six patients
      had poor or absent antibody responses to pneumococcal polysaccharide vaccine, and
      all nine patients developed severe recurrent lung infections. CONCLUSIONS: We
      suggest that these cases represent a distinct phenotype of CMC and should be
      studied for common histocompatibility leukocyte antigen types and molecular
      defects.

PMID- 12602678
TI  - Hypersensitivity pneumonia-nonspecific interstitial pneumonia/fibrosis
      histopathologic presentation: a study in diagnosis and long-term management.
AB  - BACKGROUND: Nonspecific interstitial pneumonia/fibrosis (NSIP) has been
      classified a form of idiopathic interstitial pneumonia/fibrosis. We have shown
      that cases of NSIP without demonstrable serum precipitins may be caused by
      inhalation of high levels of mold and/or bacteria in closed environments.
      OBJECTIVE: We report a patient with a clinical and histopathologic diagnosis of
      NSIP without serum precipitins caused by a microbial contamination in her home.
      Her case was converted from an acute to an insidious clinical presentation by
      inadequate remediation. A prolonged avoidance-challenge technique demonstrated
      that this case of NSIP was a form of hypersensitivity pneumonia that was
      reversible by effective remediation. METHODS: The patient was identified by
      compatible signs and symptoms, roentgenographic studies, pulmonary function
      tests, and a transbronchial lung biopsy. She was further evaluated with a
      detailed environmental history, serologic tests, and investigation of the home
      environment. An environmental avoidance and challenge technique was performed to
      confirm cause and effect and to determine that remediation had been effective.
      RESULTS: Review of the biopsy showed NSIP and failed to reveal any non-caseating
      granuloma formation. Investigation of the home revealed a Cladosporium species
      contamination of the air conditioning system and Penicillium species beneath an
      entryway carpet. Serum precipitins to commercial antigens of common mold to the
      south Texas area were negative. Avoidance and challenge techniques confirmed the
      home as the causative environment in this case of NSIP. The patient has been free
      of signs and symptoms and has taken no medication for interstitial lung disease
      over the past 30 months. CONCLUSIONS: Some cases of NSIP may be caused by
      inhalation of microbial antigen(s) in a closed environment. An environmental
      challenge technique was an effective method to determine the causative
      environment and confirm that remediation had been effective. Inadequate
      remediation may lead to symptomatic improvement, but may convert a patient from
      an acute to an insidious presenter. The environmental challenge obviates a need
      for specific challenges to determine specific causation. Remediation of or moving
      from an environmental contamination to achieve reversibility or prevent
      progression was the treatment of choice to avoid use of long-term
      immunosuppressive agents.

PMID- 12602679
TI  - Food allergy masquerading as foreign body obstruction.
AB  - BACKGROUND: Allergic reactions to peanut and tree nuts can present as upper
      airway obstruction. OBJECTIVE: To increase awareness that food allergy should be
      considered in the differential diagnosis of upper airway obstruction in children.
      METHODS: We report an allergic reaction to cashew that was initially misdiagnosed
      as foreign body aspiration. RESULTS: When the presenting signs and symptoms of
      food allergy are limited to upper airway obstruction, they can be confused with
      foreign body aspiration. CONCLUSIONS: As peanuts and tree nuts are common causes
      of both food allergy and foreign body aspiration in children, both of these
      diagnoses should be considered in the differential diagnosis of airway
      obstruction.

PMID- 12602680
TI  - Churg-Strauss syndrome in a 7-year-old receiving montelukast and inhaled
      corticosteroids.

PMID- 12602681
TI  - Does Stachybotrys actually cause adverse effects?

PMID- 12602684
TI  - RAPD-PCR and PFGE as tools in the investigation of an outbreak of beta-haemolytic
      Streptococcus group A in a Swedish hospital.
AB  - We evaluated the random amplified polymorphic DNA (RAPD) and pulsed-field gel
      electrophoresis (PFGE) techniques for studying an outbreak of beta-haemolytic
      streptococci group A (GAS) occurred at two maternity wards at Danderyd hospital,
      Stockholm, Sweden. All the isolates were of T-type 8,25. The RAPD technique
      revealed that all RAPD-PCR profiles were identical. PFGE showed that all the
      patterns but one were identical. These patterns were compared with 10 different T
      type GAS from the strain collection of the Swedish Institute for Infectious
      Disease Control (SMI) and T-type 8,25 from different years and locations. The SMI
      strains exhibited patterns different from each other and all different from the
      isolates from Danderyd hospital. Moreover, RAPD could not differentiate among the
      T-type 8,25 isolates from different years and locations but PFGE showed
      differences among the amplicons. Our results indicated that the RAPD and PFGE
      techniques could be efficient tools in epidemiological studies of GAS.

PMID- 12602682
TI  - Natural bovine lentivirus type 1 infection in Holstein dairy cattle. II. Lymphoid
      tissue lesions.
AB  - Bovine immunodeficiency virus (BIV) in Holstein cows was associated with
      morphologic evidence of lymphoid organ deficiency. Cows were subjected to normal
      management practices including parturition and lactation without adverse
      environmental stresses. During the clinical disease process there was marked
      weight loss and wasting with frequent and severe concurrent infections. Lymphoid
      follicular hyperplasia and dysplasia in lymph nodes, and hypertrophy and
      hyperplasia in hemal lymph nodes were characteristics of the lymphoid tissues.
      Atrophy of lymphoid cell compartments with depletion of lymphocytes and a
      lymphocytic lymphoid folliculitis were components of the lymphoid system
      pathology. The nodal tissue lesions resembled those observed in feline, simian,
      and human lentiviral disease. A functional correlation with immune system
      deficiency was the development of multiple bacterial infections which failed to
      resolve after appropriate therapy. The BIV-associated disease syndrome in dairy
      cows may be useful as a model system for investigation of the pathogenesis of the
      lymphoid organ changes that occur in humans and animals with lentiviral
      infection.

PMID- 12602685
TI  - Hsp60 specific antibodies in egg yolks from laying hens naturally infected with
      Salmonella enterica subspecies enterica serovar Enteritidis.
AB  - Heat shock protein (Hsp) 60 of Salmonella appears to be involved in pathogenesis
      of infectious processes and host immune responses. Eggs of laying hens from two
      Salmonella Enteritidis naturally infected flocks (I--acute outbreak of infection;
      II--occasional bacteria excretion) and one control flock (III) were tested for
      the presence of yolk antibodies (IgY) against Hsp60 by applying enzyme-linked
      immunosorbent assay (ELISA). The levels of specific immunoglobulins were related
      to those against lipopolysaccharide (LPS) and flagellin. the antigens of the
      established immunological importance in S. Enteritidis infections. Within flock
      III, the antibody concentrations were consistently low. Elevated levels were
      detected in eggs from two infected flocks. Levels of specific IgY measured for
      flock I were higher than those in flock II; the greatest difference was observed
      for anti-Hsp60. This report indicates a probable important role of Hsp60 as a
      target of the hens' immune response, especially during the acute phase of S.
      Enteritidis infection.

PMID- 12602683
TI  - A serological survey of Rhodococcus equi infection in foals in central Italy:
      comparison of two antigens using an ELISA test.
AB  - A serological survey of Rhodococcus equi infection was carried out on 602 blood
      samples collected from foals in central Italy. The assay was performed with an
      ELISA test using two different antigens prepared with reference strains of R.
      equi, ATCC 33071 and ATCC 6939. A positive reaction was obtained on 81 serum
      samples (13.45%) (OD > or = 0.3) using antigen ATCC 33071, and on 73 serum
      samples (12.12%) using antigen ATCC 6939. Although the frequency of the disease
      was not high, the serological positivity was about 13%. There was no
      statistically significant difference between males and females. The ELISA test
      using either Antigen 33071 or Antigen 6939 is a rapid and reliable tool for
      detecting antibodies against R. equi in foals.

PMID- 12602687
TI  - Serotypes of Escherichia coli isolated from healthy infants in Berlin, Germany
      and Melbourne, Australia.
AB  - The characterization of Escherichia coli strains isolated from healthy infants
      under one year of age with respect to O:H serotype, K1 and K5 antigens in two
      disparate parts of the developed world was the purpose of this investigation. A
      total of 450 strains were examined, 264 from Berlin and 186 from Melbourne. Of
      all the 220 different O:H serotypes found, 179 were only isolated once, 90 in
      Berlin and 89 in Melbourne. However, 30 of the 41 O:H serotypes (73.2%) found
      more than once were isolated in both centers. The most commonly identified
      serotypes were found in both centers and included O1:H-; O1:H7; O2:H2; O2:H4;
      O2:H7; O4:H5; O6:H-; O6:H1; O15:H1; O18:H7; O25:H1; and 075:H-. Potentially
      pathogenic serotypes were found in both cities. Enteropathogenic E. coli (EPEC)
      associated serotypes (O18:H7; O26:H-; O44:H34; O86:H-; O128:H2) were present in
      11 cases and enterohaemorrhagic E. coli (EHEC)-associated types including
      O26:H11; O128:H2) were present in four cases. The distributions of serotypes
      found were similar in the two cities, strongly suggesting the wider applicability
      of these results.

PMID- 12602686
TI  - Differentiation of infectious bursal disease viruses by restriction enzyme
      analysis of RT-PCR amplified VP1 gene sequence.
AB  - In order to differentiate infectious bursal disease virus (IBDV)
      isolates/strains, a quick method of RT-PCR followed by restriction enzyme
      analysis of VP1 gene sequence is being reported for the first time. A 480 bp
      fragment, comprising one of the RNA dependent RNA polymerase motifs of VP1 gene
      sequence of an Indian classical virus, an attenuated vaccine strain, Georgia and
      two Indian field isolates, genetically similar to reported very virulent strains
      of IBDV, was amplified by RT-PCR. Restriction enzyme digestion of PCR products
      with Taq1 enzyme generated distinct profile for field isolates, different from
      the classical and attenuated viruses, whereas restriction profile with BstNI
      restriction enzyme was similar in all the viruses, irrespective of the pathotype.
      Therefore, the present results suggest that Taq1 digestion can be taken up for
      the differentiation of field isolates from the classical and vaccine strains. The
      sequence analysis of VPI gene of reported very virulent IBD viruses from Europe
      and Japan, using 'MapDraw' programme of Lasergene software, revealed similar
      restriction enzyme profile as in Indian field isolates.

PMID- 12602688
TI  - Immunomodulation by dietary vitamin C in healthy and aflatoxin B1-induced
      immunocompromised rohu (Labeo rohita).
AB  - The aim of this study was to examine the immunomodulatory effect of high levels
      of dietary vitamin C in healthy and immunocompromised rohu (Labeo rohita) treated
      with aflatoxin B1 (AFB1). Four groups of rohu were fed experimental diets
      containing either no vitamin C or supplemented with vitamin C at 500 ppm for 60
      days. On the first day of feeding, one group fed the high vitamin C diet and one
      fed the vitamin C deficient diet, were injected intraperitoneally with a single
      doses of AFB1 at 1.25 mg kg(-1) body weight. The effect of AFB1 and high dietary
      vitamin C on specific and non-specific immunity, and disease resistance against
      Aeromonas hydrophila were examined in the rohu. The ability of vitamin C to
      counteract immunosuppression induced by AFB1 was also examined. Specific immunity
      indicated by haemagglutination and haemolysin titres against sheep red blood
      cells (SRBC), and bacterial agglutination appeared to be unaffected by either the
      AFB1 treatment or the vitamin C enriched diet. A significant reduction was
      observed in the non-specific immunity of AFB1-treated fish, however, indicated by
      lowered bactericidal and lysozyme activities. High dietary vitamin C, on the
      other hand, enhanced the non-specific immunity of fish, including an enhanced
      phagocytic ratio and increased serum lysozyme activity. Feeding a high level of
      dietary vitamin C to AFB1-treated fish increased these parameters to levels
      similar to those found in control fish. High dietary vitamin C significantly (p <
      0.05) enhanced protection against Aeromonas hydrophila infection in both healthy
      and immunocompromised fish. Results from this study help to establish the
      beneficial effect of dietary vitamin C on AFB1-induced immunosuppression, as well
      as confirming the immunostimulatory effect of vitamin C in rohu.

PMID- 12602689
TI  - Lessons regarding percutaneous injuries among healthcare providers.

PMID- 12602690
TI  - Occupationally acquired human immunodeficiency virus (HIV) infection: national
      case surveillance data during 20 years of the HIV epidemic in the United States.
AB  - OBJECTIVE: To characterize occupationally acquired human immunodeficiency virus
      (HIV) infection detected through case surveillance efforts in the United States.
      DESIGN: National surveillance systems, based on voluntary case reporting.
      SETTING: Healthcare or laboratory (clinical or research) settings. PATIENTS:
      Healthcare workers, defined as individuals employed in healthcare or laboratory
      settings (including students and trainees), who are infected with HIV. METHODS:
      Review of data reported through December 2001 in the HIV/AIDS Reporting System
      and the National Surveillance for Occupationally Acquired HIV Infection. RESULTS:
      Of 57 healthcare workers with documented occupationally acquired HIV infection,
      most (86%) were exposed to blood, and most (88%) had percutaneous injuries. The
      circumstances varied among 51 percutaneous injuries, with the largest proportion
      (41%) occurring after a procedure, 35% occurring during a procedure, and 20%
      occurring during disposal of sharp objects. Unexpected circumstances difficult to
      anticipate during or after procedures accounted for 20% of all injuries. Of 55
      known source patients, most (69%) had acquired immunodeficiency syndrome (AIDS)
      at the time of occupational exposure, but some (11%) had asymptomatic HIV
      infection. Eight (14%) of the healthcare workers were infected despite receiving
      postexposure prophylaxis (PEP). CONCLUSIONS: Prevention strategies for
      occupationally acquired HIV infection should continue to emphasize avoiding blood
      exposures. Healthcare workers should be educated about both the benefits and the
      limitations of PEP, which does not always prevent HIV infection following an
      exposure. Technologic advances (eg, safety-engineered devices) may further
      enhance safety in the healthcare workplace.

PMID- 12602691
TI  - A comprehensive approach to percutaneous injury prevention during phlebotomy:
      results of a multicenter study, 1993-1995.
AB  - OBJECTIVE: To examine a comprehensive approach for preventing percutaneous
      injuries associated with phlebotomy procedures. DESIGN AND SETTING: From 1993
      through 1995, personnel at 10 university-affiliated hospitals enhanced
      surveillance and assessed underreporting of percutaneous injuries; selected,
      implemented, and evaluated the efficacy of phlebotomy devices with safety
      features (ie, engineered sharps injury prevention devices [ESIPDs]); and assessed
      healthcare worker satisfaction with ESIPDs. Investigators also evaluated the
      preventability of a subset of percutaneous injuries and conducted an audit of
      sharps disposal containers to quantify activation rates for devices with safety
      features. RESULTS: The three selected phlebotomy devices with safety features
      reduced percutaneous injury rates compared with conventional devices. Activation
      rates varied according to ease of use, healthcare worker preference for ESIPDs,
      perceived "patient adverse events," and device-specific training. CONCLUSIONS:
      Device-specific features and healthcare worker training and involvement in the
      selection of ESIPDs affect the activation rates for ESIPDs and therefore their
      efficacy. The implementation of ESIPDs is a useful measure in a comprehensive
      program to reduce percutaneous injuries associated with phlebotomy procedures.

PMID- 12602692
TI  - Evaluation of a safety resheathable winged steel needle for prevention of
      percutaneous injuries associated with intravascular-access procedures among
      healthcare workers.
AB  - OBJECTIVE: To compare the percutaneous injury rate associated with a standard
      versus a safety resheathable winged steel (butterfly) needle. DESIGN: Before
      after trial of winged steel needle injuries during a 33-month period (19-month
      baseline, 3-month training, and 11-month study intervention), followed by a 31
      month poststudy period. SETTING: A 1,190-bed acute care referral hospital with
      inpatient and outpatient services in New York City. PARTICIPANTS: All healthcare
      workers performing intravascular-access procedures with winged steel needles.
      INTERVENTION: Safety resheathable winged steel needle. RESULTS: The injury rate
      associated with winged steel needles declined from 13.41 to 6.41 per 100,000
      (relative risk [RR], 0.48; 95% confidence interval [CI95], 0.31 to 0.73)
      following implementation of the safety device. Injuries occurring during or after
      disposal were reduced most substantially (RR, 0.15; CI95, 0.06 to 0.43). Safety
      winged steel needle injuries occurred most often before activation of the safety
      mechanism was appropriate (39%); 32% were due to the user choosing not to
      activate the device, 21% occurred during activation, and 4% were due to improper
      activation. Preference for the safety winged steel needle over the standard
      device was 63%. The safety feature was activated in 83% of the samples examined
      during audits of disposal containers. Following completion of the study, the
      safety winged steel needle injury rate (7.29 per 100,000) did not differ
      significantly from the winged steel needle injury rate during the study period.
      CONCLUSION: Implementation of a safety resheathable winged steel needle
      substantially reduced injuries among healthcare workers performing vascular
      access procedures. The residual risk of injury associated with this device can be
      reduced further with increased compliance with proper activation procedures.

PMID- 12602693
TI  - Sharps-related injuries in California healthcare facilities: pilot study results
      from the Sharps Injury Surveillance Registry.
AB  - BACKGROUND AND OBJECTIVES: In 1998, the California Department of Health Services
      invited all healthcare facilities in California (n = 2,532) to participate in a
      statewide, voluntary sharps injury surveillance project. The objectives were to
      determine whether a low-cost sharps registry could be established and maintained,
      and to evaluate the circumstances surrounding sharps injuries in California.
      RESULTS: Approximately 450 facilities responded and reported a total of 1,940
      sharps-related injuries from January 1998 through January 2000. Injuries occurred
      in a variety of healthcare workers (80 different job titles). Nurses sustained
      the highest number of injuries (n = 658). In hospital settings (n = 1,780),
      approximately 20% of the injuries were associated with drawing venous blood,
      injections, or assisting with a procedure such as suturing. As expected, injuries
      were caused by tasks conventionally related to specific job classifications. The
      overall results approximate those reported by the Centers for Disease Control and
      Prevention's National Surveillance System for Health Care Workers and the
      University of Virginia's Exposure Prevention Information Network. CONCLUSION:
      These data further support findings from previous studies documenting the complex
      and persistent nature of sharps-related injuries in healthcare workers. In the
      future, mandated reporting using standardized forms and consistent application of
      decision rules would facilitate a more thorough analysis of injury events.

PMID- 12602694
TI  - Nosocomial transmission of hepatitis C virus associated with the use of multidose
      saline vials.
AB  - OBJECTIVE: To identify the source of an outbreak of acute hepatitis C virus (HCV)
      infection among 3 patients occurring within 8 weeks of hospitalization in the
      same ward of a Florida hospital during November 1998. DESIGN: A retrospective
      cohort study was conducted among 41 patients hospitalized between November 11 and
      19, 1998. Patients' blood was tested for antibodies to HCV, and HCV RNA-positive
      samples were genotyped and sequenced. RESULTS: Of the 41 patients, 24 (59%)
      participated in the study. HCV genotype lb infections were found in 5 patients.
      Three of 4 patients who received saline flushes from a multidose saline vial on
      November 16 had acute HCV infection, whereas none of the 9 patients who did not
      receive saline flushes had HCV infection (P = .01). No other significant
      exposures were identified. The HCV sequence was available for 1 case of acute HCV
      and differed by a single nucleotide (0.3%) from that of the indeterminate case.
      CONCLUSION: This outbreak of HCV probably occurred when a multidose saline vial
      was contaminated with blood from an HCV-infected patient Hospitals should
      emphasize adherence to standard procedures to prevent blood-borne infections. In
      addition, the use of single-dose vials or prefilled saline syringes might further
      reduce the risk for nosocomial transmission of blood-borne pathogens.

PMID- 12602695
TI  - Human immunodeficiency virus knowledge and attitudes among hospital-based
      healthcare professionals in Guangxi Zhuang Autonomous Region, People's Republic
      of China.
AB  - BACKGROUND AND OBJECTIVE: Since the discovery of human immunodeficiency virus
      (HIV) on the Chinese mainland in 1985, the virus has spread to all provinces and
      autonomous regions. Although much research emphasis has been placed on studying
      behaviors and transmission knowledge among high-risk populations, especially drug
      abusers and commercial sex workers, little has been done to measure understanding
      within other risk groups. The objective of this study was to investigate
      HIV/acquired immunodeficiency syndrome (AIDS) knowledge and attitudes among
      hospital-based healthcare professionals in Guangxi Zhuang Autonomous Region in
      southern China. METHODS: Data were gathered through a questionnaire completed by
      a convenience sample of individuals from three diverse hospitals. RESULTS:
      Insufficient knowledge of the disease and its transmission resulted in more than
      90% of the respondents expressing apprehension about contracting the virus and
      nearly 24% expressing reservations about caring for infected patients.
      CONCLUSION: Uncorrected, such attitudes and knowledge deficiencies have the
      potential to impact negatively on the quality of care, patient-practitioner
      safety, and proper postexposure prophylaxis.

PMID- 12602697
TI  - Detection of hepatitis C virus antibody and RNA in hemostatic gauze used for
      dentistry.
AB  - We investigated whether the presence of hepatitis C virus (HCV) infection can be
      detected in hemostatic gauze used during oral treatments. We were able to detect
      both antibody to HCV and HCV RNA in samples from patients serologically proven to
      have HCV and also in gauze used for these patients that was left at room
      temperature even for as long as 24 hours. Thus, this method is useful for the
      screening of HCV infection in situations in which blood sampling is not feasible.

PMID- 12602696
TI  - Cost-effectiveness of testing for human immunodeficiency virus and hepatitis C
      virus among blood transfusion recipients.
AB  - OBJECTIVE: To choose the most cost-effective option for detecting human
      immunodeficiency virus (HIV-1) and hepatitis C virus (HCV) among blood
      transfusion recipients. DESIGN: Cost-effectiveness analysis. Effectiveness was
      expressed as the number of HIV-1 or HCV infections detected, regardless of
      whether they were related to transfusion. To estimate costs, we assumed hospital
      insurance would cover costs related to detection and compensation, when granted.
      SETTING: A 2,890-bed acute care teaching hospital in Bordeaux, France. METHODS:
      Eight options were defined, from the simplest, which would be to do nothing, to a
      maximal approach, which would be to keep a serum sample in a serum library for a
      lookback and perform tests for antibody to HIV-1 and to HCV before and 3 months
      after transfusion. Data on probabilities and costs were taken from the literature
      and experiences of French hospitals. RESULTS: The most cost-effective option was
      to perform viral antibody testing before transfusions (option 3), which would
      detect 27 infections per 1,000 patients, for an expenditure of US $1,260 per
      detected patient Option 6, obtaining a serum sample before transfusion and
      performing tests for antibody to HIV-1 and to HCV 3 months after transfusion, had
      a similar cost-effectiveness ratio but detected only 16 infections per 1,000
      patients. Performing tests before and 3 months after transfusion (option 4),
      compared with option 3, would detect 1 additional infection for an additional
      cost of US $8,322. CONCLUSION: The most cost-effective options are not specific
      to blood transfusion recipients and might be more suited to all hospitalized
      patients.

PMID- 12602699
TI  - Infection control practices in clinical laboratories in Pakistan.
AB  - Clinical laboratories in Karachi, Pakistan, were evaluated for adherence to
      standard precautions using an observational checklist. Among 44 laboratories,
      gloves were used in 2, protective gowns in 12, disinfectant in 7, and an
      incinerator in 7. Standard worker safety precautions are not followed at major
      clinical laboratories in Karachi.

PMID- 12602698
TI  - Microbial aerosol contamination of dental healthcare workers' faces and other
      surfaces in dental practice.
AB  - The purpose of this study was to focus attention on the need to adopt infection
      control procedures in dentistry. The quantitative and qualitative bacterial
      contamination of dental healthcare workers' faces and other surfaces in dental
      practice was determined. Oral fluids become aerosolized during dentistry and oral
      microbes have been used as the markers of their spread that may carry blood-borne
      pathogens.

PMID- 12602700
TI  - Monsel's solution: a potential vector for nosocomial infection?
AB  - Monsel's solution is a common topically applied hemostatic agent used in minor
      dermatologic and gynecologic surgery. Clinically, because it is often stored for
      long periods and dispensed from a common source for multiple patients, Monsel's
      solution is a potential vector for transmission of infection. However,
      microbiologic inoculation studies and contamination surveys indicate that
      Monsel's solution has properties that prohibit microbial growth, making it an
      unlikely vector for nosocomial infection.

PMID- 12602701
TI  - Recycling of injection equipment in Pakistan.

PMID- 12602702
TI  - Establishing guidelines for Internet-based prescribing.
AB  - The American Medical Association called for the establishment of guidelines to
      allow electronic prescription of medications "for established patients." Based on
      experience writing more than 10,000 Internet-based prescriptions, we agree that
      guidelines are long overdue. Restricting such prescribing to patients with whom a
      face-to-face relationship has previously been established violates patient
      autonomy and distorts the physician-patient relationship without improving
      patient safety or convenience. A study comparing information obtained and used by
      Internet-based physicians prescribing sildenafil with that obtained by clinic
      based physicians writing similar prescriptions suggests that safety may be
      greater on the Internet. Data regarding the appropriateness of prescriptions for
      other medications suggest that the in-office visit is not the panacea it is often
      assumed to be. Guidelines for electronic prescribing, like guidelines for other
      aspects of medical practice, need to be based on evidence. Such evidence is
      currently lacking, and a serious effort to obtain it should be a top priority.

PMID- 12602703
TI  - The future of medicine.

PMID- 12602704
TI  - Balanitis xerotica obliterans: a form of lichen sclerosus.

PMID- 12602705
TI  - Balanitis xerotica obliterans: epidemiologic distribution in an equal access
      health care system.
AB  - BACKGROUND: We analyzed the incidence of balanitis xerotica obliterans (BXO) by
      both age and ethnicity at an equal-access health care facility. METHODS: We
      retrospectively reviewed discharge records from 1997 to 1999 at Brooke Army
      Medical Center to determine ethnicity and age of patients with BXO. RESULTS: Of
      153,432 male patients, 108 (0.070%) had a diagnosis of BXO. The age distribution
      was similar over a range from 2 to 90 years, with the exception of the third
      decade, when the incidence almost doubled. Black and Hispanic patients had twice
      the incidence found in white patients (10.59, 10.67 and 5.07 per 10,000 patients,
      respectively). CONCLUSION: At our equal-access health care facility, the
      incidence of BXO in black and Hispanic patients was double that in whites. This
      unexpected finding, in concert with the greater incidence in the third decade,
      may result from greater access to medical attention for these patients in the
      military setting. Nevertheless, further research into the origin of the disease
      is warranted.

PMID- 12602706
TI  - Preliminary experience with the use of recombinant factor VIIa to treat
      coagulation disturbances in pediatric patients.
AB  - OBJECTIVE: This study evaluates the efficacy of recombinant factor VII (rVIIa) in
      the treatment of coagulation dysfunction in pediatric patients. METHODS: We
      retrospectively reviewed the records of pediatric patients who received rVIIa in
      the intensive care unit or operating room for treatment of coagulopathy. Case
      series in the literature were also reviewed. RESULTS: Ten patients, ranging in
      age from 3 months to 19 years, received 22 doses of rVIIa. Seven of the 10
      patients had received fresh frozen plasma and cryoprecipitate before the
      administration of rVIIa without effect. All 10 patients had a fibrinogen level
      above 100 mg/dl and platelet count above 100,000/mm3 at the time of rVIla
      administration. After rVIIa administration, there were significant decreases in
      prothrombin time, international normalized ratio, and partial thromboplastin
      time. No adverse effects were noted. CONCLUSION: Recombinant factor VIIa can be
      used to effectively reverse coagulation disturbances in the pediatric patient
      even when treatment with fresh frozen plasma has failed. Given its therapeutic
      potential, prospective, randomized trials are warranted.

PMID- 12602707
TI  - Prevention of thromboembolism after neurosurgery for brain and spinal tumors.
AB  - OBJECTIVE: Deep venous thrombosis (DVT) is a major cause of morbidity and
      mortality after surgery for primary and metastatic brain tumors. METHODS: We
      conducted a confidential survey of American neurosurgeons interested in tumor
      surgery to assess DVT risk awareness and thromboprophylaxis patterns. RESULTS: Of
      the 172 respondents, 108 (63%) underestimated the DVT risk after brain tumor
      surgery. After operating on patients who had brain or spinal tumors, 81.4 and
      78.5% of respondents, respectively, reported using DVT prophylaxis. After
      performing brain tumor surgery, 76.2% of respondents reported using solely
      mechanical methods of prophylaxis "always" or "most of the time." CONCLUSION:
      American neurosurgeons tend to underestimate the risk of DVT associated with
      brain tumor surgery and to use mechanical thromboprophylaxis despite the
      availability of effective pharmacologic antithrombotics. A better appreciation of
      the risk of thrombosis, combined with clinical studies to address safety, may
      enhance the use of prophylaxis and the perceived safety of antithrombotics in
      this setting.

PMID- 12602708
TI  - Cooperative efforts improve compliance with acute stroke guidelines.
AB  - OBJECTIVE: Guidelines for emergency treatment of stroke are not always known or
      followed. Florida Medical Quality Assurance, Inc. collaborated with hospitals to
      determine how closely the current American Heart Association (AHA) and the
      Florida Agency for Health Care Administration (AHCA) guidelines were being
      followed and to improve compliance with these guidelines. METHODS: Medical
      records of patients admitted for acute stroke to 32 hospitals were
      retrospectively reviewed for compliance with six quality indicators (QIs) on the
      basis of AHA and AHCA guidelines. Hospitals were provided feedback on their
      levels of guideline compliance, and they subsequently implemented measures to
      improve compliance. After 6 months, the records of patients admitted after the
      provision of feedback were reviewed for compliance with the same six QIs.
      RESULTS: Compliance improved with regard to all QIs and was statistically
      significant for three of them. CONCLUSION: Feedback on performance, coupled with
      proactive collaboration with emergency department staff, resulted in improved
      compliance with the stroke guidelines.

PMID- 12602709
TI  - Agromedicine focus group: cooperative extension agents and medical school
      instructors plan farm field trips for medical students.
AB  - BACKGROUND: Current medical education policy seeks to address the health care
      needs of underserved populations, among whom are individuals associated with
      agriculture. METHODS: This paper describes a focus group approach to planning
      farm field trips whereby medical students accompany agricultural extension agents
      to study the personal, occupational, and environmental health concerns of
      farmers. RESULTS: The resulting plan joins a state's cooperative extension
      system, medical school, and farm community in partnership to provide an
      experiential approach to agricultural medicine and rural health education.
      CONCLUSION: The planning exercise and the field trips are successful examples of
      agromedicine, a partnership approach to preventive agricultural medicine
      involving professionals in medicine and in agriculture.

PMID- 12602710
TI  - Current controversies in pouch surgery.
AB  - Restorative proctocolectomy with ileal pouch anal anastomosis has become the most
      commonly used procedure for elective treatment of patients with mucosal
      ulcerative colitis and familial adenomatous polyposis. Since its original
      description, the procedure has been modified in an attempt to obtain optimal
      functional results with low morbidity and mortality, and yet provide a cure for
      the disease. These modifications of the technique are discussed in this review,
      limited to the current points of controversy. We reviewed the current literature
      describing restorative proctocolectomy with ileal pouch anal anastomosis. The
      current "hot topics" for debate are transanal mucosectomy with hand-sewn
      anastomosis versus the double-stapled technique, the use of diverting ileostomy,
      indeterminate colitis, the role of laparoscopy, and indications for pouch surgery
      in the elderly. Longer follow-up of patients and increased knowledge and
      experience with pouch surgery, coupled with active prospective evaluation of the
      procedure are required to settle these issues. Patients must be fully informed to
      understand inherent risks of each choice.

PMID- 12602711
TI  - Precordial catch syndrome.
AB  - The precordial catch syndrome is frequently mentioned as part of a long
      differential diagnosis of chest pain in children. It is an extremely common
      complaint but remains underrecognized. This review describes the distinctive
      features of the syndrome and points out that this is not a diagnosis of
      exclusion. Emphasis is placed on the need for taking a careful history to elicit
      the diagnostic features of the syndrome and performing a thorough physical
      examination. Diagnostic testing is usually unnecessary. Familiarity with the
      features of precordial catch syndrome should be helpful to primary care providers
      caring for children.

PMID- 12602712
TI  - Reye's syndrome: down but not out.
AB  - Reye's syndrome presents as acute central nervous system and liver dysfunction in
      children. Its incidence has seen a sharp decline in parallel with the decline in
      the use of aspirin in the pediatric age group. This report describes a patient
      with Reye's syndrome and serves as a reminder for health professionals to
      continue to discourage the use of aspirin for the treatment of viral infections.

PMID- 12602713
TI  - Chronic relapsing thrombotic thrombocytopenic purpura in adult onset Still's
      disease.
AB  - We report the first known case of chronic relapsing thrombotic thrombocytopenic
      purpura associated with adult-onset Still's disease. The patient presented with
      diffuse arthralgias, sore throat, and a maculopapular rash involving the trunk
      and extremities; she was hospitalized with fever and confusion. Thrombocytopenia,
      renal failure, and microangiopathic hemolytic anemia developed within several
      days. After a diagnosis of thrombotic thrombocytopenic purpura was made, she
      responded well to a series of plasma exchanges. Evaluation for infection,
      autoimmune disorders, and malignancy was negative. She was discharged to home in
      good condition, with normal renal function and normal platelet count. Two more
      episodes of TTP developed 7 and 9 months after the first hospitalization. The
      diagnosis of adult-onset Still's disease was then determined on the basis of
      clinical and laboratory criteria. She was successfully treated with plasma
      exchange, prednisone, and azathioprine. She later had splenectomy and has
      subsequently been without recurrence of thrombotic thrombocytopenic purpura for 2
      years.

PMID- 12602714
TI  - Spontaneous pneumopericardium due to exertion.
AB  - We report the unique case of a patient with an idiopathic pneumopericardium due
      to heavy lifting and discuss Valsalva's maneuver as a rare cause in the
      pathogenesis of pneumopericardium. Our patient recovered without treatment and
      had no recurrence of pneumopericardium during follow-up. All physicians should be
      aware of pneumopericardium as a possible cause of chest pain, especially when no
      trauma is visible. Pneumopericardium may also be an occasional complication of
      pneumothorax and pneunomediastinum.

PMID- 12602715
TI  - Early recognition and treatment of calciphylaxis.
AB  - Calciphylaxis is a condition with a high mortality rate that is often found in
      patients with renal failure. It is characterized by soft tissue calcification and
      painful skin ulceration. A serum calcium-phosphorus product of more than 60
      mg2/dl2 indicates great risk for calciphylaxis. The diagnosis is made on the
      basis of an incisional biopsy showing calcification of the small, subcutaneous
      arteries.

PMID- 12602716
TI  - Cystic dysplasia of the testis with terminal ureterectasis and renal absence:
      evidence of involution of a dysplastic kidney?
AB  - Cystic dysplasia of the testis is a rare congenital anomaly, only 29 cases having
      been previously reported. We report a case of cystic dysplasia of the testis and
      absent ipsilateral kidney, but an ipsilateral ectatic terminal ureter, suggesting
      involution of a dysplastic kidney as a reason for the apparent renal agenesis.

PMID- 12602717
TI  - Fatal spontaneous retroperitoneal hematoma secondary to enoxaparin.
AB  - An 83-year-old woman was transferred to our cardiac intensive care unit with an
      acute non-Q-wave myocardial infarction and pulmonary edema. Enoxaparin was one
      component of the treatment regimen used. Her hospital course was complicated by
      episodes of hypotension, as well as by recurrent left hip and left thigh pain.
      The defining event occurred when the patient became acutely hypotensive and
      developed abdominal distention, peritoneal signs, intense left flank pain, and a
      3.3 g/dl hemoglobin decrease. Abdominal computed tomography showed a 9 x 6 x 20
      cm left retroperitoneal hematoma. The hematoma was spontaneous, secondary to
      enoxaparin use. The patient died despite vigorous supportive care. Enoxaparin is
      being increasingly used in patients with acute coronary syndromes. Review of the
      medical literature revealed that this is the first reported case of a patient
      with an acute coronary syndrome who died as a result of an enoxaparin-induced,
      spontaneous retroperitoneal hematoma. This article reviews important clinical
      signs and symptoms, identifies high-risk patient populations, and discusses
      management strategies.

PMID- 12602718
TI  - Internet delusions.
AB  - As the use of computers, the Internet, and Internet technology becomes more
      pervasive in society, psychopathological thought content characterized by the
      incorporation of the Internet into delusions and hallucinations will become
      increasingly common. In the following report, three cases of psychotic inpatients
      are briefly presented to exemplify this trend in pathoplasticity. Interestingly,
      patients with no real familiarity with the Internet may just as readily
      incorporate such computer-associated themes into delusional thought patterns.
      Clinicians should be familiar with the tendency for delusional thoughts to draw
      from ideas important to society in general. Several interesting points about
      these cases include the increasing prevalence of Internet delusions, the complete
      unfamiliarity of two of the patients with the Internet and computers in general,
      and the tendency for such delusions to be of the controlling, broadcasting, and
      persecutory types.

PMID- 12602719
TI  - Rare systemic dermatologic reaction after pneumococcal vaccine administration.
AB  - This case report describes a rare dermatologic reaction in a patient after
      administration of pneumococcal vaccine. A 65-year-old man developed an extensive
      dermatitis with pruritus, urticaria, and petechiae 1 week after receiving an
      intramuscular injection o the vaccine. The reaction resolved with application of
      topical steroids and oral diphenhydramine hydrochloride. This case report and
      others in the literature suggest the importance of recognizing the possibility of
      cutaneous adverse reactions with vaccines, such as the pneumococcal vaccine,
      which in general have a good safety profile.

PMID- 12602720
TI  - Association of pancreatitis with administration of contrast medium and
      intravenous lipid emulsion in a patient with the acquired immunodeficiency
      syndrome.
AB  - Computed tomography is widely used to diagnose acute pancreatitis. Iodinated
      contrast medium lengthens the duration of pancreatitis and may increase the
      incidence of local or systemic complications. Total parenteral nutrition
      including IV lipid emulsion plays an important role in the management of patients
      with pancreatitis. Induction of pancreatitis by IV lipid emulsion is exceedingly
      rare. We report a 30-year-old patient with the acquired immunodeficiency syndrome
      in whom pancreatitis was exacerbated by oral and IV contrast medium and also by
      IV lipid emulsion in the absence of hypertriglyceridemia. Exclusion of the lipid
      emulsion resulted in prompt reduction of lipase levels on three separate
      occasions. This case is the first to implicate IV lipid emulsion in the
      exacerbation of pancreatitis in a patient with acquired immunodeficiency syndrome
      and normal baseline triglyceride levels. Thus, this case report suggests that we
      must exercise caution in the use of contrast medium and IV lipids in the
      diagnosis and management of acute pancreatitis.

PMID- 12602721
TI  - Favorable outcome of long-lasting thoracic spondylodiscitis with spinal epidural
      abscess induced by Staphylococcus aureus.
AB  - A favorable outcome in chronic spondylodiscitis with epidural abscess is rare. A
      65-year-old woman developed recurrent, localized, thoracic back pain over 2.5
      years. Nine months after the onset of the pain, sensory disturbances of the left
      lower leg occurred. Fourteen months before admission, she developed recurrent
      fever, bladder dysfunction, and weakness and numbness of both lower legs. An
      incomplete sensory transverse syndrome with paraparesis was diagnosed. Magnetic
      resonance imaging of the spine suggested destruction of the T11 vertebral body,
      with spondylodiscitis of the adjacent discs and an epidural abscess between
      levels T4 and T9. Laminectomy was immediately performed and the abscess was
      drained. Culture revealed infection with Staphylococcus aureus. After 10 weeks of
      therapy, recovery was almost complete. Spondylodiscitis with epidural abscess may
      have a favorable outcome, even if symptoms start more than 2 years before
      treatment.

PMID- 12602722
TI  - Cryptococcal infection of the larynx simulating laryngeal carcinoma.
AB  - Cryptococcus neoformans is an encapsulated yeast that can cause primary pulmonary
      infections or disseminate and cause infections of the central nervous system,
      meninges, skin, and bone in the immunocompromised host. We present here an
      unusual case of an immunocompetent patient who had laryngitis due to C.
      neoformans that mimicked a laryngeal carcinoma on clinical examination and
      imaging studies.

PMID- 12602723
TI  - Intralobar and extralobar bronchopulmonary sequestration complicated by Nocardia
      asteroides infection.
AB  - Pulmonary sequestration is a rare congenital or acquired pulmonary anomaly.
      Pulmonary sequestration may be classified as intralobar, located within normal
      lung, or extralobar, in which it is separated by pleura. The coexistence of both
      forms is extremely rare. Infection, mainly bacterial, is a major complication of
      sequestration. We report the case of a young man in whom a sequestration with
      both intralobar and extralobar components was complicated by Nocardia asteroides
      infection.

PMID- 12602724
TI  - Pica for foam rubber in patients with sickle cell disease.
AB  - We report three cases of pica for foam rubber among sickle cell disease patients.
      All three were African-American males, and at the times of initial presentation
      for the pica, two of them were 11 years of age and one was 15 years of age. In
      all cases, the pica reportedly had been occurring for at least several years. The
      foam rubber was most often obtained from furniture and mattresses, as well as
      from ironing-board pads, stereo speakers, and padded hair rollers. Reports from
      other researchers also suggest that this is not an uncommon type of pica. We
      discuss this problem from biologic, psychologic, and social perspectives.

PMID- 12602725
TI  - Emphysematous gastritis in a hemodialysis patient.
AB  - Emphysematous gastritis is a condition characterized by gas within the wall of
      the stomach and associated systemic toxicity. We report a case of emphysematous
      gastritis in a 43-year-old diabetic patient receiving hemodialysis and review 41
      cases published since 1889. The most common predisposing factors included
      ingestion of corrosive substances, alcohol abuse, abdominal surgery, diabetes,
      and immunosuppression. Diagnosis is based on clinical presentation of acute
      abdomen with associated features of systemic toxicity. The most commonly involved
      organisms were streptococci (nine cases), Escherichia coli (nine cases),
      Enterobacter species (six cases), Clostridium welchii (four cases), and
      Staphylococcus aureus (four cases). Computed tomography (CT) is the diagnostic
      procedure of choice. The mortality rate was 61% (25 of 41 patients). Gastric
      contractures after recovery were noted in 10% (4 of 41 patients). Antimicrobial
      therapy with antibiotics covering gram-negative organisms and anaerobes, and
      surgery in appropriate cases may enhance survival.

PMID- 12602726
TI  - Extrahepatic bile duct stricture and elevated CA 19-9: malignant or benign?
AB  - Biliary obstruction due to a proximal bile duct stricture is commonly a result of
      cholangiocarcinoma. We describe a patient who began having intermittent episodes
      of jaundice 3 years after cholecystectomy. Despite endoscopic placement of a
      biliary stent and adequate biliary decompression, the serum CA 19-9 level
      remained elevated at 58 U/ml (normal <37 U/ml). Segmental bile duct resection and
      Roux-en-Y hepaticojejunostomy were done. The stricture was caused by a traumatic
      bile duct neuroma. Diagnostic and therapeutic considerations of this entity are
      discussed, with special emphasis on the value of noninvasive biliary imaging by
      magnetic resonance imaging (MRI), the utility and interpretation of the CA 19-9
      level, and the role for resection or surgical biliary decompression.

PMID- 12602727
TI  - Colonic pseudo-obstruction in sickle cell disease.
AB  - A young Arab woman with sickle cell-beta0-thalassemia disease developed acute
      colonic pseudo-obstruction that became chronic but showed some response to
      hydroxyurea. There was no evidence of microvascular or macrovascular occlusion.
      We also report the case of an Arab man with sickle cell anemia who presented with
      acute colonic pseudo-obstruction from which he recovered completely within a few
      days. Although the development of pseudo-obstruction in these two cases seems to
      have been a complication of sickle cell disease, its pathogenesis remains
      unclear. There are several reports of ischemic and inflammatory disorders of the
      colon complicating sickle cell disease; however, these two cases represent the
      first descriptions of large-bowel pseudo-obstruction in this hemoglobinopathy
      [corrected].

PMID- 12602728
TI  - Bullet migration within the inferior vena cava.
AB  - We report the case of a patient who sustained gunshot wounds to the chest. The
      bullet lodged and moved freely within the inferior vena cava and its branches,
      but the patient had no symptoms. The bullet was retrieved from the right common
      femoral vein with a basket. Selective approach to bullet removal can prevent
      serious complications.

PMID- 12602729
TI  - Non-Q-Wave acute anterior myocardial infarction associated with 5-fluorouracil
      and cisplatin chemotherapy.

PMID- 12602730
TI  - Spontaneous pneumothorax as the first manifestation of lymphoma: a rare
      presentation and the importance of diagnostic biopsy.

PMID- 12602731
TI  - Treatment of acute isoniazid toxicity of unknown dose.

PMID- 12602733
TI  - Severe hypermagnesemia as a result of laxative use in renal insufficiency.

PMID- 12602732
TI  - Ascaris lumbricoides?

PMID- 12602734
TI  - Esophageal actinomycosis.

PMID- 12602735
TI  - Magnesium: its proven and potential clinical significance.

PMID- 12602736
TI  - Abdominal wall rhabdomyolysis mimicking peritonitis: a diagnostic pitfall of
      acute abdomen.

PMID- 12602737
TI  - Hyperammonemic encephalopathy precipitated by a bleeding peptic ulcer.

PMID- 12602738
TI  - Acute inflammatory demyelinating polyneuropathy concurrent with Evans syndrome.

PMID- 12602740
TI  - Itching without a rash.

PMID- 12602739
TI  - Hypertension: a turning point.

PMID- 12602741
TI  - Absolute versus relative values.

PMID- 12602742
TI  - Recognition of benign transient hyperphosphatasemia.

PMID- 12602743
TI  - Lumbosacral plexopathy as the harbinger of a silent retroperitoneal hematoma.

PMID- 12602744
TI  - Parasitic chyluria.

PMID- 12602746
TI  - Persistent staphylococcal bacteremia, lest we forget the old catheter site.

PMID- 12602745
TI  - Elective removal of an intramyocardial bullet.

PMID- 12602747
TI  - Society's price for endangered clinical research.

PMID- 12602748
TI  - Is there a role for thiamine in the management of congestive heart failure?

PMID- 12602749
TI  - Refractory pulmonary embolism and right atrial thrombus despite treatment with 3
      thrombolytic regimens.

PMID- 12602750
TI  - Lethal spontaneous retroperitoneal hematoma and multisystem organ failure
      associated with chronic abuse of ibuprofen and alcohol.

PMID- 12602751
TI  - Pineal germinoma followed by hematogenous metastases.

PMID- 12602752
TI  - Abortion incidence and services in the United States in 2000.
AB  - CONTEXT: Nearly half of unintended pregnancies and more than one-fifth of all
      pregnancies in the United States end in abortion. No nationally representative
      statistics on abortion incidence or on the universe of abortion providers have
      been available since 1996. METHODS: In 2001-2002, The Alan Guttmacher Institute
      (AGI) conducted its 13th survey of all known U.S. abortion providers, collecting
      information for 1999, 2000 and the first half of 2001. Trends were calculated by
      comparing the survey results with data from previous AGI surveys. RESULTS: From
      1996 to 2000, the number of abortions fell by 3% to 1.31 million, and the
      abortion rate declined 5% to 21.3 per 1,000 women 15-44. (In comparison, the rate
      declined 12% between 1992 and 1996.) The abortion ratio in 2000 was 24.5 per 100
      pregnancies ending in abortion or live birth, 5% lower than in 1996. The number
      of abortion providers decreased by 11% to 1,819 (46% were clinics, 33% hospitals
      and 21% physicians' offices); clinics provided 93% of all abortions in 2000. In
      that year, 34% of women aged 15-44 lived in the 87% of counties with no provider,
      and 86 of the nations 276 metropolitan areas had no provider. About 600 providers
      performed an estimated 37,000 early medical abortions during the first six months
      of 2001; these procedures represented approximately 6% of all abortions during
      that period. Abortions performed by dilation and extraction were estimated to
      account for 0.17% of all abortions in 2000. CONCLUSIONS: Abortion incidence and
      the number of abortion providers continued to decline during the late 1990s but
      at a slower rate than earlier in the decade. Medical abortion began to play a
      small but significant role in abortion provision.

PMID- 12602753
TI  - The accessibility of abortion services in the United States, 2001.
AB  - CONTEXT: A woman's ability to obtain an abortion is affected both by the
      availability of a provider and by access-related factors such as cost,
      convenience, gestational limits and the provision of early medical abortion
      services. METHODS: In 2001-2002, The Alan Guttmacher Institute surveyed all known
      abortion providers in the United States, collecting information on their delivery
      of abortion services and on the number of abortions performed. RESULTS: A
      minority of abortion providers offer services before five weeks from the last
      menstrual period (37%) or after 20 weeks (24% or fewer), but the proportions have
      increased since 1993. Providers estimate that one-quarter of women having
      abortions in nonhospital facilities travel 50 miles or more for services, and
      that 7% are initially unsure of their abortion decision. The majority of
      providers (59%) say that these clients usually receive abortions during a single
      visit. An average self-paying client was charged $372 for a surgical abortion at
      10 weeks in 2001, up from $319 in 1997; only 26% of clients receive services
      billed directly to public or private insurance. Early medical abortions are
      becoming increasingly available but are more expensive than surgical abortions.
      More than half (56%) of providers experienced antiabortion harassment in 2000,
      but types of harassment other than picketing have declined since 1996.
      CONCLUSIONS: Abortion at very early and late gestations and early medical
      abortion are more available than before, but charges have increased and
      antiabortion picketing remains at high levels. Thus, many women still face
      substantial barriers to obtaining an abortion.

PMID- 12602754
TI  - The public health impact of legal abortion: 30 years later.

PMID- 12602755
TI  - Roe v. Wade at 30: what are the prospects for abortion provision?

PMID- 12602756
TI  - Reflections of a provider before and since Roe: from the voices of choice
      archive.

PMID- 12602757
TI  - Abortion: teaching why as well as how.

PMID- 12602759
TI  - Convincing new providers to offer medical abortion: what will it take?

PMID- 12602758
TI  - Beyond apocalypse and apology: a moral defense of abortion.

PMID- 12602761
TI  - On the classification of research.

PMID- 12602760
TI  - Improving women's sexual assertiveness.

PMID- 12602763
TI  - Mammographic screening: a key factor in the control of breast cancer.

PMID- 12602762
TI  - Current status of selective estrogen receptor modulators (SERMs).

PMID- 12602764
TI  - The power and perils of prediction.

PMID- 12602765
TI  - Residual disease in DCIS: an excision too far?

PMID- 12602766
TI  - Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer
      response to chemotherapy.
AB  - PURPOSE: The relevance of apoptosis to breast cancer response to chemotherapy is
      unclear. We investigated whether changes in tumor cell apoptosis and Bcl-2
      expression immediately after chemotherapy correlated with response to breast
      cancer treatment. PATIENTS AND METHODS: Serial core biopsies of 25 breast cancer
      primary tumors were performed at either two or three time points: before
      treatment (N = 24) and approximately 24 hours (N = 22) and/or 48 hours (N = 19)
      after the initiation of the first cycle of chemotherapy. Apoptosis levels were
      quantified by use of a fluorescent terminal deoxynucleotidyl transferase-mediated
      deoxyuridine triphosphate nick end-labeling (TUNEL) stain, and Bcl-2 and Bax were
      measured by semiquantitative immunohistochemical assays. All calculated P values
      were two sided. RESULTS: The apoptosis level at 48 hours was significantly higher
      in the tumors with pathological complete response or < 1 cm of residual disease
      (median, 22%; range, 6%-51%) than in the tumors with > 1 cm residual disease
      (median, 7%; range, 1%-36%); Mann-Whitney test. This difference was also present
      in the subgroup of 16 tumors treated with docetaxel/doxorubicin chemotherapy (25%
      vs 4%, respectively). A decrease in Bcl2 expression after chemotherapy relative
      to the expression from the pretreatment sample also correlated with disease
      response. Specifically, three of the nine tumors with a decrease in Bcl-2 had a
      pathological complete response, compared with 0 of the 15 tumors with stable
      levels of Bcl-2 (Fisher's exact test). There was no relationship between serial
      measurements of Bax and response. DISCUSSION: These data suggest that apoptosis
      may play an important role in determining breast cancer response to chemotherapy
      and that the level of treatment-induced apoptosis may have some value as a
      predictive marker.

PMID- 12602767
TI  - Factors associated with residual disease on re-excision in patients with ductal
      carcinoma in situ of the breast.
AB  - PURPOSE: This study examines the factors associated with the presence of residual
      disease at re-excision in patients with ductal carcinoma in situ of the breast.
      METHODS: Of 143 consecutive patients undergoing breast conservation treatment
      from 1990 to 1999, 90 patients (63%) underwent re-excision of the tumor bed.
      Grade was recorded in 70% (N = 63), size in 78% (N = 70), margin status in 96% (N
      = 86), volume of excision in 90% (N = 81), and extent of residual disease in 99%
      (N = 89). RESULTS: There was no significant correlation between extent of
      residual disease on re-excision and method of detection, tumor size, histology,
      grade, or first margin status. Of patients undergoing re-excision, 56% (N = 50)
      had no residual disease, 38% (N = 34) had minimal microscopic residual disease,
      and only 6% (N = 5) had either extensive microscopic or gross residual disease.
      For these five patients, the median volume of first excision was similar to that
      of the other patients (26 vs 36 cc), but the median volume of second excision was
      smaller (33 vs 63 cc). The median age for these five patients was 41 years,
      compared with 55 years for the remaining patients. All five patients had comedo
      (N = 4) or solid tumor (N = 1) histology, with grade 3 (N = 3) or unknown grade
      (N = 2). DISCUSSION: Patients with extensive microscopic disease or gross
      residual at the time of re-excision would be at increased risk for local
      recurrence after conventional radiation treatment if re-excision had not been
      performed. Only 6% of patients in this study had such pathology findings. No
      factor predicted for these adverse pathology findings, although these patients
      tended to be younger, with high-grade or comedo histology.

PMID- 12602768
TI  - Locoregional treatment for adult soft tissue sarcomas of the head and neck: an
      institutional review.
AB  - PURPOSE: The purpose of this study was to review treatment results for primary
      soft tissue sarcomas of the head and neck in order to determine prognostic
      factors. PATIENTS AND METHODS: From 1970 to 2000, 44 adult patients were
      diagnosed with a biopsy-proven, nonmetastatic primary soft tissue sarcoma in a
      head and neck subsite; were treated with curative intent; and had adequate follow
      up and records for our review. Patients with extraosseous Ewing's sarcoma,
      Kaposi's sarcoma, rhabdomyosarcoma, dermatofibrosarcoma protuberans, and desmoid
      tumor were excluded. The most common tumor histologies included malignant fibrous
      histiocytoma (15 patients), angiosarcoma (nine patients), fibrosarcoma (six
      patients), and leiomyosarcoma (six patients). RESULTS: The median overall
      survival for all patients was 79 months. The actuarial 5-year local control for
      all patients was 55% and was highly correlated with the extent of surgical
      excision: 25% for subtotal resection/debulking, 65% for wide local excision, and
      100% for radical excision. Local control at 5 years was 60% for patients treated
      with both surgery and radiotherapy, 54% for those treated with surgery alone, and
      43% for those treated with radiotherapy alone. Adjuvant radiotherapy
      significantly improved the local control rates (from 25% to 54%) for patients
      with close (<2 mm) or positive surgical margins. Of 14 patients with locoregional
      failure in whom salvage was attempted, nine (64%) were rendered disease free.
      CONCLUSIONS: Multimodality therapy with both surgery and radiotherapy improves
      local control, particularly in patients with close or positive surgical margins.
      Aggressive attempts at salvage therapy for locoregional failures are warranted
      and frequently produce long-term disease control.

PMID- 12602769
TI  - Phase I study of oral CI-994 in combination with gemcitabine in treatment of
      patients with advanced cancer.
AB  - PURPOSE: The purpose of this study was to determine the maximum tolerated dose,
      pharmacokinetic profile, and evidence of antitumor activity of CI-994 used in
      combination with gemcitabine. METHODS: This was a dose escalation trial in which
      gemcitabine (1,000 mg/m2) was given as a 30-minute infusion on days 1, 8, and 15
      of a 28-day cycle. CI-994 was taken orally on consecutive days 1-21 at escalating
      doses of 2, 4, 6, and 8 mg/m2 per cohort (three patients/cohort). Plasma samples
      were collected on days 1 and 15 of course 1 and analyzed for CI-994
      pharmacokinetic assessment. RESULTS: Twenty patients with advanced cancer
      received a total of 76 courses of treatment. Dose-limitingtoxicity occurred at
      the 8-mg/ m2 dose. Four of seven patients experienced thrombocytopenia during the
      first cycle. Grade 4 thrombocytopenia was observed in three of 10 (30%) courses
      at 8 mg/m2. In contrast, only two of 28 (7%) courses at 6 mg/m2 were associated
      with grade 4 thrombocytopenia. Pharmacokinetic analysis indicated that absorption
      of CI-994 was rapid, with peak plasma concentrations occurring at the first
      sample 2 hours after dosing. Two patients achieved a minor response, 12 had
      stable disease (median duration, 105 days), four had progressive disease, and two
      were not evaluable. CONCLUSIONS: The 6-mg/m2 dose of CI-994 (p.o. x 21 days) was
      defined as the maximum tolerated dose that could safely be administered in
      combination with gemcitabine (1,000 mg/m2 i.v. on days 1, 8, and 15) during a 28
      day cycle.

PMID- 12602770
TI  - The effect of granisetron on in vitro metabolism of paclitaxel and docetaxel.
AB  - PURPOSE: Paclitaxel and docetaxel are effective anticancer agents; however, these
      agents can be associated with the debilitating side effects of nausea and
      vomiting, thereby necessitatingthe administration of concomitant antiemetic
      agents. This increases the potential fordrug-drug interactionsthrough inhibition
      or induction of the cytochrome P450 (CYP) enzymes. The 5-HT3-receptor antagonists
      are currently regarded as the antiemetic 'gold standard' and this study was
      undertaken to investigate the effects of granisetron on the metabolism of
      paclitaxel and docetaxel in human liver microsomal preparations in vitro.
      METHODS: Paclitaxel, 5 nM, and docetaxel, 1.25 nM, were incubated in the presence
      of granisetron, 0, 10, 100, and 1000 pM, in human liver microsomal preparations
      (500 microg). The levels of unchanged paclitaxel and docetaxel in the incubation
      mixture were determined by high-performance liquid chromatography. Ketoconazole,
      10 nM, a potent inhibitor of CYP3A metabolism, served as a positive control.
      RESULTS: In the absence of granisetron, unchanged paclitaxel and docetaxel levels
      measured were 27.2 +/- 2.8% and 44.3 +/- 4.0% of control, respectively.
      Ketoconazole prevented the breakdown of both paclitaxel and docetaxel, to the
      degree that no unchanged paclitaxel or docetaxel was detected in the incubation
      mixture. Granisetron had no effect on the rate of reduction of either paclitaxel
      or docetaxel; unchanged paclitaxel and docetaxel decreased to 25.0 +/- 1.5%, 26.4
      +/- 1.0%, and 27.6 +/- 6.4%, and 44.2 +/- 1.5%, 41.2 +/- 4.1%, and 43.1 +/- 0.5%,
      respectively. DISCUSSION: The results from this study suggest that granisetron
      neither inhibits nor induces the enzymes involved in the metabolism of paclitaxel
      or docetaxel. Thus, granisetron can be used safely as a supportive care agent to
      treat paclitaxel or docetaxel chemotherapy-induced nausea and vomiting with
      minimal risk of drug-drug interactions.

PMID- 12602771
TI  - A simple approach to fitting Bayesian survival models.
AB  - There has been much recent work on Bayesian approaches to survival analysis,
      incorporating features such as flexible baseline hazards, time-dependent
      covariate effects, and random effects. Some of the proposed methods are quite
      complicated to implement, and we argue that as good or better results can be
      obtained via simpler methods. In particular, the normal approximation to the log
      gamma distribution yields easy and efficient computational methods in the face of
      simple multivariate normal priors for baseline log-hazards and time-dependent
      covariate effects. While the basic method applies to piecewise-constant hazards
      and covariate effects, it is easy to apply importance sampling to consider
      smoother functions.

PMID- 12602772
TI  - Rank tests for clustered survival data.
AB  - In a clinical trial, we may randomize subjects (called clusters) to different
      treatments (called groups), and make observations from multiple sites (called
      units) of each subject. In this case, the observations within each subject could
      be dependent, whereas those from different subjects are independent. If the
      outcome of interest is the time to an event, we may use the standard rank tests
      proposed for independent survival data, such as the logrank and Wilcoxon tests,
      to test the equality of marginal survival distributions, but their standard error
      should be modified to accommodate the possible intracluster correlation. In this
      paper we propose a method of calculating the standard error of the rank tests for
      two-sample clustered survival data. The method is naturally extended to that for
      K-sample tests under dependence.

PMID- 12602773
TI  - Maximum likelihood estimation of life-span based on censored and passively
      registered historical data.
AB  - We consider the estimation of life length of people who were born in the
      seventeenth or eighteenth century in England. The data consist of a sequence of
      times of life events that is either ended by a time of death or is right-censored
      by an unobserved time of migration. We propose a semi parametric model for the
      data and use a maximum likelihood method to estimate the unknown parameters in
      this model. We prove the consistency of the maximum likelihood estimators and
      describe an algorithm to obtain the estimates numerically. We have applied the
      algorithm to data and the estimates found are presented.

PMID- 12602774
TI  - Rank estimation of log-linear regression with interval-censored data.
AB  - Interval-censored data arise in a wide variety of research and application fields
      such as cancer and AIDS studies. In this paper, we study a log-linear regression
      model when data are subject to interval censoring. We use a U-statistic based on
      ranks to estimate regression coefficients and establish large sample properties
      of the estimator. We illustrate the performance of the proposed estimate with
      simulations and a numerical example.

PMID- 12602776
TI  - A model of aging and a shape of the observed force of mortality.
AB  - A probabilistic model of aging is considered. It is based on the assumption that
      a random resource, a stochastic process of aging (wear) and the corresponding
      anti-aging process are embedded at birth. A death occurs when the accumulated
      wear exceeds the initial random resource. It is assumed that the anti-aging
      process decreases wear in each increment. The impact of environment (lifestyle)
      is also taken into account. The corresponding relations for the observed and the
      conditional hazard rate (force of mortality) are obtained. Similar to some
      demographic models, the deceleration of mortality phenomenon is explained via the
      concept of frailty. Simple examples are considered.

PMID- 12602775
TI  - Non-parametric hypothesis testing and confidence intervals with doubly censored
      data.
AB  - The non-parametric maximum likelihood estimator (NPMLE) of the distribution
      function with doubly censored data can be computed using the self-consistent
      algorithm (Tumbull, 1974). We extend the self-consistent algorithm to include a
      constraint on the NPMLE. We then show how to construct confidence intervals and
      test hypotheses based on the NPMLE via the empirical likelihood ratio. Finally,
      we present some numerical comparisons of the performance of the above method with
      another method that makes use of the influence functions.

PMID- 12602777
TI  - Understanding myocardial ischemic preconditioning, and the implications for a
      role of adenosine catabolism.

PMID- 12602778
TI  - Clinicopathological study for gastric cancer with liver metastasis.
AB  - Clinicopathological characteristics, stromal volume (Vvf), nuclear DNA content
      and cell protein were retrospectively analyzed in order to scrutinize the risk
      factors of hepatic metastasis from carcinoma of the stomach. We conducted a
      clinicopathological study of 327 patients with gastric cancer, including 34
      patients with liver metastasis (synchronous, 22; metachronous, 12) and 294
      patients without liver metastasis. Univariate analysis revealed significant inter
      group differences in tumor size (p<0.001), depth of invasion (p<0.001), lymph
      node metastasis (p<0.001), vascular involvement (p<0.001), lymphatic involvement
      (p<0.001), peritoneal dissemination (p<0.05), Vvf (p<0.01) and DNA content
      (p<0.01). Vvf and DNA content were estimated in the liver metastasis group (n=20)
      and in the group of patients with stage III-IVa carcinoma but without liver
      metastasis (n=11). In multivariate analysis, only Vvf and DNA content showed
      significant correlations with liver metastasis (p<0.01). A comparison of Vvf and
      expression of the amount of interstitial connective tissue showed that there as a
      significant correlation between them. Our results indicate that gastric cancer
      with low Vvf and high DNA content carries a high risk of hepatic metastasis.
      Therefore, mean DNA content and Vvf are useful indices for predicting liver
      metastasis from gastric carcinoma.

PMID- 12602779
TI  - Theoretical local freezing times of small rodent brains submerged in situ in
      liquid nitrogen.
AB  - In situ freezing is a standard procedure, typically applied in neuroscience, to
      stop post-mortem metabolism and diffusion. However, the concentration of a
      compound under study may well change before the tissue is completely frozen.
      Knowing the approximate local freezing time should make it possible to control
      this problem. A mathematical model of in situ freezing in liquid nitrogen has
      recently been introduced, and freezing times derived from this model are
      presented here. The hope is that this information will be considered useful when
      in situ freezing of small rodent brains is applied.

PMID- 12602780
TI  - Carbonic anhydrase III in liver and muscle of male rats purification and
      properties.
AB  - Cytosolic carbonic anhydrases CAI, CAII, and CAIII from liver, and CAII, and
      CAIII from muscle of adult male Sprague-Dawley rats were purified to homogeneity.
      CAIII from liver and muscle had the same amino acid composition and were
      immunochemically similar. Their kinetic properties at 0 degrees C were also
      similar. Km(CO2) was 4 mM and kcat 3x105 s(-1). Ki was 0.4 and 0.2 M for
      acetazolamide and NaCl, respectively. Both CAIIIs ran as single bands on SDS
      electrophoresis and high-speed centrifugation, with a mol wt of 29.3 kDa. Their
      hydrodynamic properties suggest that CAIII is a compact, nearly spherical
      molecule. It contained 0.9 M zinc per M protein. In both tissues isoelectric
      focusing identified neutral and acidic isoforms with pIs near 7.0 and 6.3,
      respectively. These forms were immunologically identical and had the same amino
      acid composition and mol wts. The acidic forms probably represent subspecies of
      CAIII in different states of oxidation. CAIII is the major soluble protein in rat
      liver and muscle. Its function is probably to protect proteins of these tissues
      from oxidation catalyzed by iron-containing degradation products of haemoglobin
      and myoglobin. Liver CAI and CAII and muscle CAII were identical to CAI and CAII
      of rat erythrocytes.

PMID- 12602781
TI  - Gastric emptying in animal models of human diabetes: correlation to blood glucose
      level and gut neuroendocrine peptide content.
AB  - Gastric emptying was measured in non-obese diabetic (NOD) and in obese diabetic
      mice. The feces were collected and the water content was determined. The
      neuroendocrine peptides known to regulate gastrointestinal motility, namely
      secretin, gastric inhibitory peptide (GIP), motilin, somatostatin, peptide YY
      (PYY), substance P, vasoactive intestinal polypeptide (VIP) and galanin, were
      measured in tissue extracts of different segments of the gut by radioimmunoassay.
      Whereas the gastric emptying of NOD mice was significantly slower than that of
      controls, that of the obese diabetic mice was unaltered. The gastric emptying of
      NOD mice, but not that of obese diabetic mice, correlated with the blood glucose
      level. The feces weight and water content in NOD mice was significantly higher
      than controls. The feces water content in obese diabetic mice was significantly
      lower than that of controls. The concentrations of antral somatostatin, VIP and
      galanin, and duodenal secretin as well as jejunal motilin in NOD mice were higher
      than those of controls. Duodenal GIP and colonic PYY concentration in NOD mice
      was lower than controls. Duodenal GIP and VIP, and colonic somatostatin and VIP
      levels were lower in obese diabetic mice than controls. Secretin and motilin
      levels correlated with gastric emptying in NOD mice. The high duodenal
      concentration of secretin might reflect high synthesis and release of this
      hormone, and may therefore be among the factors that caused slow gastric emptying
      in the NOD mice. The increase in concentration of motilin observed in NOD mice
      may be caused by impaired release of this hormone as a result of hyperglycemia.
      Whereas the high concentrations of antral VIP and galanin and the low level of
      colonic PYY in diabetic NOD mice may contribute to the development of diarrhea in
      NOD mice, the decreased levels of duodenal and colonic VIP and colonic
      somatostatin in obese diabetic mice may account for the constipation encountered
      in these animals.

PMID- 12602782
TI  - Gastrointestinal transit in an animal model of human diabetes type 2:
      relationship to gut neuroendocrine peptide contents.
AB  - Gastrointestinal transit (GIT) was determined in obese diabetic mice (ob/ob,
      Umea/Bom). Blood glucose level, and insulin concentration in the serum and
      pancreas extracts as well as neuroendocrine peptide contents were measured in
      several segments of the gut. GIT was significantly slower in the obese diabetic
      mice, but was not correlated with the blood glucose level, serum insulin, or
      pancreatic insulin content. GIT was correlated with duodenal secretin content and
      colonic vasoactive intestinal peptide (VIP) content, but not with the content of
      other neuroendocrine peptides in different segments investigated. The antral
      gastrin content in obese diabetic mice was significantly higher than in controls.
      The concentration of secretin in obese diabetic mice was higher than in controls.
      Whereas the contents of peptide YY (PYY) and somatostatin were higher in obese
      diabetic mice, the contents of substance P and VIP were lower. The increased
      content of duodenal secretin and decreased content of colonic VIP may be among
      the factors that cause slow GIT in obese diabetic mice. The changes in the
      colonic contents of PYY, VIP and somatostatin may cause low intestinal secretion
      and, together with slow GIT, give rise to constipation, which is a common symptom
      in diabetes.

PMID- 12602783
TI  - Multiple injections of coloured microspheres for islet blood flow measurements in
      anaesthetised rats: influence of microsphere size.
AB  - We investigated if coloured microspheres could be used for repeated measurements
      of pancreatic islet blood flow in rats. An initial injection of 1.0-1.5 x 10(5)
      microspheres (black colour), with a size of 10 or 15 microm, was made into the
      ascending aorta, while an arterial reference sample was collected from the
      femoral artery. Twelve min later, 1 ml of saline or 30% D-glucose was injected
      intravenously. Three min after this injection a second injection of 10- or 15
      microm microspheres (green colour) was given. The animals were then killed, and
      the pancreas and adrenals were removed and samples (150-200 mg) were secured from
      the duodenum, ileum, colon, right kidney and liver. The microsphere contents were
      determined with the aid of a freeze-thawing technique and blood flow values were
      calculated. Our results suggest that 10-microm microspheres, but not 15-microm
      microspheres, provide reproducible islet and total pancreatic blood flow
      measurements when repeatedly injected. Values for the blood flow to the
      intestines, kidney and liver were less sensitive to the size of the microspheres.
      We conclude that repeated administration of 15-microm microspheres induces a high
      risk for erroneous islet and total pancreatic blood flow measurements, whereas
      two such measurements can be performed if 10-microm microspheres are used.

PMID- 12602784
TI  - Safety skills of mental health workers: empirical evidence of a risk management
      strategy.
AB  - To reduce violence in the workplace, health care facilities invest time and
      resources in risk management strategies such as photo identification and
      controlled access and surveillance. Studies of assaultive psychiatric patients
      continue to document that mental health workers (MHWs) are the most frequent
      targets of the patient violence. Unexamined in these findings is the role skilled
      MHWs contribute in restoring safety and order in the aftermath of these assaults.
      This six-year, empirical retrospective study examined the safety skills of MHWs
      in containing violence. Although they were 28% of the workforce, MHWs restored
      order in the majority of single assault incidents and restraint procedures. Their
      skills appear to be a risk management strategy in their own right. The
      implications are discussed.

PMID- 12602785
TI  - Subtypes of psychopathy: proposed differences between narcissistic, borderline,
      sadistic, and antisocial psychopaths.
AB  - Atascadero State Hospital (ASH) is a maximum-security forensic hospital that
      houses male patients with a wide range of psychiatric diagnoses. Psychopaths at
      this institution appear to be a heterogeneous group of individuals who, while
      sharing core personality characteristics, manifest substantial variability in
      their behavior. Identifying subtypes within this clinical classification can have
      implications for patient treatment and management, as well as for the safety of
      the staff who work with them and for the communities to which they will
      eventually return. Several means of identifying subtypes have been proposed in
      the literature, and potential subgroups have been identified. Clinical
      observations at ASH have suggested 4 possible subtypes of psychopathy:
      narcissistic, borderline, sadistic, and antisocial. Issues related to the
      conceptualization of psychopathy are addressed, recognizing that additional data
      are needed to understand the observed variations in cases of psychopathy.

PMID- 12602787
TI  - The management of depression in primary care. Introduction.

PMID- 12602786
TI  - Behavior change and achieving hospital discharge in persons with severe, chronic
      psychiatric disabilities.
AB  - Economic and political pressures have led state governments to shrink and close
      long-term psychiatric inpatient units in favor of community-based treatment.
      These pressures present inpatient clinicians with an opportunity to examine their
      clinical practices and question whether the focus of treatment addresses the
      behaviors most relevant to helping patients achieve discharge and maintain
      community tenure. The social learning approach of Gordon Paul is the empirically
      validated treatment of choice for long-term psychiatric inpatients. In this
      study, we compared changes in daily functioning of sixty-four chronic psychiatric
      inpatients treated in two rehabilitation programs based extensively on Gordon
      Paul's social learning approach. Half of the participants were successfully
      discharged from the hospital. Analysis found both similarities and differences in
      behavioral improvements between the groups. These results provide some clarity to
      the relationship between selfcare skills, participation in programs, maladaptive
      behaviors, and achieving hospital discharge for chronically hospitalized
      individuals.

PMID- 12602788
TI  - Implementing an office system to improve primary care management of depression.
AB  - Studies have shown that many patients treated for depression in primary care
      settings do not achieve the outcomes demonstrated to be possible in randomized
      controlled trials. In general, multifaceted interventions have been more
      successful than single focus interventions in improving care of depression in
      this setting. This article reports on the implementation of such a mulitfaceted
      intervention in primary care practices. Part of the strategy in this case is to
      introduce the intervention through an intermediary organization that has a
      relationship with the practices and has a quality improvement infrastructure to
      support the implementation and help to sustain changes.

PMID- 12602789
TI  - A case report: implementing a nurse telecare program for treating depression in
      primary care.
AB  - The treatment of depression in primary care needs improvement. Previously, we
      reported that a nurse telecare intervention for treating depression in primary
      care clinics significantly improved treatment outcomes. The usefulness of nurse
      telecare, however, depends upon the feasibility of dissemination. In this report
      we describe nurse telecare and the steps required for implementation, and
      describe its dissemination in various settings. In addition to medication, which
      is managed by a primary care physician, the key elements of nurse telecare are
      focused behavioral activation, emotional support, patient education, promotion of
      treatment adherence, and monitoring of progress, delivered in ten brief telephone
      appointments over four months by primary care nurses. Support from key
      administrators and clinical champions is crucial to success. Nurses need
      "dedicated" scheduled time for telecare activities. Nurse telecare has been
      piloted and disseminated in diverse settings. The model required only small
      modifications for dissemination, and was implemented with minimal investment of
      resources and no negative impact on clinic operations.

PMID- 12602790
TI  - Impacting late life depression: integrating a depression intervention into
      primary care.
AB  - groups and semi-structured individual interviews with all Depression Clinical
      Specialists (DCSs) working with Project IMPACT (Improving Mood: Promoting Access
      to Collaborative Treatment), a study testing a collaborative care intervention
      for late life depression, to examine integration of the intervention model into
      primary care. DCSs described key intervention components, including supervision
      from a psychiatrist and a liaison primary care provider, weekly team meetings,
      computerized patient tracking, and outcomes assessment tools as effective in
      supporting patient care. DCSs discussed details of protocols, training,
      environmental set-up, and interpersonal factors that seemed to facilitate
      integration. DCSs also identified research-related factors that may need to be
      preserved in the real world. Basic elements of the IMPACT model seem to support
      integration of late life depression care into primary care. Research-related
      components may need modification for dissemination.

PMID- 12602792
TI  - A simple and rapid liquid chromatographic method for the determination of
      metronidazole and its hydroxymetabolite in plasma and cutaneous microdialysates.
AB  - A rapid, accurate, simple and low-cost method for quantitative determination of
      metronidazole and its hydroxymetabolite, in plasma and microdialysate samples,
      using tinidazole as an internal standard, has been developed. Metronidazole is
      widely used as a valuable agent for antiprotozoal as well as antibiotic therapy
      when anaerobic organisms are involved. Separation of the compounds studied was
      performed on a 120 x 4 mm analytical column, filled with LiChrosorb RP-8, 5
      microm, the mobile phase consisted of 0.05 mol/L aqueous solution of potassium
      dihydrogen phosphate, adjusted to pH = 3.5 with orthophosphoric acid, methanol
      and acetonitrile (40:2:3. v/v/v). Detection was performed at 320 nm. Intra- and
      interserial precision was below 4.6% and 7.9%, respectively, for both the
      compounds studied. The presented method is suitable for pharmacokinetic studies.

PMID- 12602791
TI  - Evidence-based care for depression in Maine: dissemination of the Kaiser
      Permanente Nurse Telecare Program.
AB  - This paper describes the program model, implementation and preliminary results
      from a dissemination of a nurse case management program for treating depression
      in primary care. The program design was modeled after the Kaiser Permanente Nurse
      TeleCare program, which in a randomized clinical trial had previously
      demonstrated significant improvement in depression outcomes and patient
      satisfaction over usual care. As illustrated in this pilot by patient outcomes
      measured using the Hamilton Depression Rating Scale, the SF-12 Mental Health
      Composite Score, and the Work Role, Household and Leisure Time Functioning, the
      authors believe that it is possible to implement successful interventions in
      smaller primary care practices in community-based settings.

PMID- 12602793
TI  - Determination of 2,6-dimethylaniline and o-toluidine impurities in preparations
      for local anaesthesia by the HPLC method with amperometric detection.
AB  - 2,6-Dimethylaniline (2,6-DMA) and o-toluidine (o-TLD) together with their
      decomposition products are potential technological impurities of Pharmaceuticals
      used for local anaesthesia, in which lidocaine and prilocaine appear as active
      substances. Pharmacopoeial analytical methods for the determination of these
      impurities are little sensitive (from about 1 microg ml(-1)) and accurate and
      provide results which are difficult to interpret. Taking the above into account,
      a sensitive and specific amperometric method has been developed, which enables,
      after separation with the use of HPLC, an accurate determination of the content
      of 2,6-DMA and o-TLD in various pharmaceutical preparations. The determinations
      were performed at a glassy carbon electrode at a potential of +0.85 V. The limit
      of detection for both 2,6-DMA and o-TLD was 0.8 ng ml(-1). On the other hand, the
      limit of quantitation, considering a signal to noise ratio, was 1.5 ng ml(-1).
      The developed method allows to determine low concentrations of the impurities in
      question, which are hardly 1/120000 of the main substance. Preparation and
      determination of samples is carried out in a relatively short time, thus the
      method can be applied to routine investigations. Statistical evaluation of the
      obtained results shows that the accuracy and precision of the elaborated HPLC-ED
      method is good.

PMID- 12602794
TI  - Lipophilicity parameter from high-performance liquid chromatography on an
      immobilized artificial membrane column and its relationships to bioactivity of
      the group of 2,4-dihydroxythiobenzanilides.
AB  - Several groups of 2,4-dihydroxythiobenzanilide derivatives are extensively
      studied in our laboratories as potential antifungal or antibacterial agents.
      Previous papers showed that their biological activities are closely correlated
      with the lipophilicity determined in HPLC experiments using on octadecylsilyl
      stationary phase (RP-18). In the present paper we attempted to measure
      chromatographic indices of 2,4-dihydroxythiobenzanilides, using a silica-based
      immobilized artificial membrane (IAM) column especially designed to evaluating
      biological lipophilicity. The theoretical (extrapolated) retention in pure water
      the log k(w)(IAM) parameter for 23 derivatives was determined during poly-cratic
      experiments. Statistical analysis exhibited good correlations between the log
      k(w)(IAM) parameter and the biological data concerning bacteriostatic activity of
      these compounds. Retention on the IAM phase can be used as predictor of
      biological membrane permeability and biological lipophilicity of 2,4
      dihydroxythiobenzanilides in spite of the acidic properties of this group of
      compounds.

PMID- 12602795
TI  - Application of topological indices for prediction of the biological activity of
      selected alkoxyphenols.
AB  - The topological indices based on adjacency and distance matrices, and
      electrotopological states were calculated for selected meta and para
      alkoxyphenols. The toxicities of alkoxyphenols on gram-positive M. pyogenes var.
      aurens and gram-negative S. typhosa bacteria were calculated on the basis of
      linear or parabolic equations with one topological index or hydrophobic
      constants. It was affirmed, that structural descriptors describe better the toxic
      properties of studied alkoxyphenols than the hydrophobic constants.

PMID- 12602796
TI  - Investigation of physical and hypoglycaemic properties of rectal suppositories
      with chosen insulin.
AB  - Rectal suppositories with insulin Humulin M3 (30/70) were prepared. Witepsol H15
      and a polyoxyethyleneglycol mixture, composed of PEG 400, PEG 1000 and PEG 6000,
      were used as bases. Tween 60 and sodium salicylate were used as auxiliary
      substances. Hypoglycaemic properties of the prepared suppositories were tested on
      rabbits. The obtained results were compared with the data acquired after
      intravenous administration of insulin and subcutaneous injection of insulin.

PMID- 12602797
TI  - Photooxidation of papaverine, papaverinol and papaveraldine in their chloroform
      solutions.
AB  - Papaverine hydrochloride, papaverinol, and papaveraldine chloroform solutions
      were exposed to UV light of 254 nm in atmospheric, aerobic and anaerobic (helium)
      conditions. The same degradation products appear (TLC) in the above papaverine
      hydrochloride chloroform solutions. However, the rate of papaverine hydrochloride
      degradation processes is enhanced as a function of oxygen pressure. Papaverinol
      and papaveraldine photooxidation products are essentially not different from
      those observed in the above papaverine hydrochloride solutions. However, the
      amount of an unknown brown degradation product (X) is the greatest in the
      papaverinol chloroform solution degraded. That brown compound was previously
      observed in papaverine either hydrochloride or sulfate injection solutions on
      their storage even when protected from daylight. The preliminary X product
      structure development was undertaken (TLC, molecular weight, elemental analysis,
      UV/VIS, IR and 13C MAS NMR spectroscopy).

PMID- 12602799
TI  - The reactions of cyclization of semicarbazide derivatives of 1,3-diphenyl-1,2,4
      triazolin-5-thione-4-acetic acid.
AB  - In the reaction of hydrazide of 1,3-diphenyl-1,2,4-triazolin-5-thione-4-acetic
      acid with isocyanates. semicarbazide derivatives of 1,3-diphenyl-1,2,4-triazolin
      5-thione-4-acetic acid [I-X] were obtained. Cyclization of these compounds in the
      presence of 2% NaOH led to the formation of derivatives of 1,2,4-triazolin-5-one
      [XI-XX].

PMID- 12602798
TI  - A study on organic nitrates, Part VI. Synthesis and pharmacological activity of 1
      isopropylamino-3-(1-naphthyloxy)-2-propyl nitrate.
AB  - Basing on the studies on the relationship between the structure and activity, we
      have synthesized a nitrate analogue of propranolol as potential donor of nitric
      oxide. The obtained 1-isopropylamino-3-(1-naphthyloxy)-2-propyl nitrate decreases
      blood pressure more than propranolol and slows the heart rate less than
      propranolol. It also affects peripheral vascular resistance less than
      propranolol.

PMID- 12602800
TI  - Search for new non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-1
      RT).
AB  - The derivatives of dibenzoxazocinone, dibenzoxadiazocine, dibenzoxadiazonine, and
      benzodiazepine systems were synthesized as potential lead compounds for
      inhibitors of HIV-1 reverse transcriptase. The suggested structures were derived
      from analysis of the described spatial and physicochemical requirements for HIV-1
      RT inhibitors. All of the evaluated compounds (apart from the oxadiazocine
      derivatives) showed a week inhibitory activity on recombinant HIV-1 RT from
      Escherichia coli.

PMID- 12602801
TI  - Synthesis and pharmacological properties of sulfur derivatives of indane-1,3
      dione.
AB  - Synthesis of sulfur derivatives of indane-1,3-dione, VIIb-c, VIIIa-b, IX and X is
      described. Results of a preliminary pharmacological screening of six compounds
      [VIIb, VIII, VIIIb, IX, X and XI] are presented.

PMID- 12602802
TI  - Estimation of humoral activity of Eleutherococcus senticosus.
AB  - The aim of the present work was an estimation of the influence of two plant
      pharmaceutical preparations containing an extract from the root of
      Eleutherococcus senticosus: Argoeleuter tablets and Immuplant tablets, on the
      humoral response of immunological system. Experiments were performed with female
      Balb/c mice six weeks old. In order to reveal the influence of taking
      preparations, containing an extract from Eleutherococcus senticosus on some
      elements of the immunological system, three ways of their administration have
      been compared: before illness, during illness and a combination of both. The
      obtained results allow formulating the following conclusions: - the
      pharmaceutical preparations, containing the extract from Eleutherococcus
      senticosus administered orally, influence on the increase of the level of
      immunoglobulins comprised in the mice's blood serum, - the pharmaceutical
      preparations act with different power, not fully dependent on the content of
      marker of the active substance - eleutheroside E, - dosage of the preparations
      containing the extract from Eleutherococcus senticosus should not be established
      basing only on the extract content, - best curative results, measured as the
      stimulation of humoral response of the organism were obtained when a given
      preparation was administered therapeutically, even though the combined
      administration - prophylactically with prolonged administration during illness
      also is correct.

PMID- 12602803
TI  - Truxillic and truxinic acids--occurrence in plant kingdom.
AB  - For some years now there has been a systematic increase in the number of reports
      on new secondary metaholites of truxillic and truxinic acid derivatives. The
      paper offers a presentation of existing forms of cyclobutanodicarhoxylic acids in
      plant kingdom. while considering their stereochemical structure and hiosynthesis.
      Also presented are some results of research on the pharmacological activity of
      synthetic and natural derivatives of these compounds. The paper shows
      additionally the results of search in nature for compounds containing fragments
      of truxillic and truxinic acids seen against the occurrence of other compounds of
      cyclobutane derivatives in plant kingdom.

PMID- 12602804
TI  - Integrating qualitative and quantitative methods: comparing HIV-related risk
      behaviors among Puerto Rican drug users in Puerto Rico and New York.
AB  - A dual site project was conducted to assess determinants of injection and sex
      related risk behaviors among Puerto Rican drug users. The project focused on
      injection drug users and crack smokers, and was conducted in East Harlem, NY and
      Bayamon, PR in 1996-2000. Qualitative methods included ethnographic mapping,
      focus groups, in-depth interviews, and observations. A survey component (East
      Harlem, n = 800; Bayamon, n = 400) was also conducted. Procedures to ensure
      integration of methodologies and comparability of data were developed. This paper
      describes the qualitative and survey methods used, and presents the comparative
      HIV risk behaviors. The integration of the two methodologies served multiple
      functions: each component identified issues to be addressed in the other,
      enhanced cross-site comparability of data, and assisted in interpretation of
      findings. The survey data showed high levels of risk behaviors in both
      communities, with significantly higher levels of risk reported in Bayamon.
      Conducting studies of similar ethnic groups in different communities provides
      opportunities to examine diverse sources of influence on risk behaviors. The
      integration of qualitative and quantitative methods can enhance comparability and
      understanding of findings, particularly when there are differences in behaviors
      between communities.

PMID- 12602805
TI  - Motivation in tobacco use cessation research.
AB  - This paper summarizes four major conceptions of motivation that have been applied
      to cigarette smoking cessation. These conceptions are the direction-energy,
      transtheoretical, intrinsic/extrinsic, and self-regulation models. Constituents
      of each of these models are suggested. Implications of these theories of
      motivation for an integrative model of smoking cessation are discussed.

PMID- 12602807
TI  - Measurement of impulsivity in a hierarchical model of personality traits:
      implications for substance use.
AB  - This review describes how measures of a prominent three-dimensional hierarchical
      model of personality traits relate to substance use. H. J. Eysenck proposed a
      biologically based model of personality that gave rise to related models such as
      those of J. A. Gray, C. R. Cloninger, and M. Zuckerman. The varying role of
      impulsivity--a trait related to disinhibition, approach motivation, novelty
      seeking, and sensation seeking--in successive self-report measures of this model,
      including the Eysenck Personality Inventory (EPI) and Eysenck Personality
      Questionnaire (EPQ), is described. It is argued that certain findings in
      experimental, cross-sectional, and longitudinal research using these measures
      point to the importance of impulsivity as a temperamental vulnerability factor
      for substance use.

PMID- 12602806
TI  - Gender differences in the use of alcohol and psychotropics in a Brazilian
      population.
AB  - This cross-sectional, interview-based survey aimed to assess the use of licit
      substances in terms of gender and sociodemographic factors in the city of
      Pelotas, southern Brazil. Subjects aged 15 years and over and living in urban
      areas were eligible and a total of 1277 subjects were interviewed. The prevalence
      of alcohol consumption was 54.2%; 11.9% (21.7% of men and 4.1% of women) reported
      potentially harmful levels of alcohol use ("at-risk alcohol intake"); 4.2% were
      classified as manifesting alcohol dependence by CAGE questionnaire. At-risk
      alcohol intake and subjects with a positive CAGE score were more common among
      males aged 35-54 yrs. Among the youngest age group, the prevalence of CAGE
      positive score was similar for males and females, while subjects with lower
      educational levels showed a higher prevalence. Women were more likely than men to
      report the use of psychotropic drugs (15% vs. 7%). These results highlight the
      importance of substance use in Brazil, and suggest that gender differences must
      to be taken into consideration when planning intervention programs in developing
      countries.

PMID- 12602808
TI  - Chinese fishermen's expectations on medications.
AB  - This study aimed to explore the expectations on medications of Chinese fishermen,
      a group of culturally distinct people, when they consult their family doctors. A
      qualitative method of semistructured focus group interviews was used for data
      collection. Twenty-nine participants took part in eight focus group interviews.
      They were all from the southern district of Hong Kong Island where many of the
      residents have a fishing background. Their expectations of doctors' willingness
      to give them medicines might originate from their previous experiences with
      traditional therapies. Although some would prefer the medicines to be potent
      while others like them not to be too strong, they all wanted the medicines to
      lead them to fast recovery. It is therefore important for their western-trained
      family doctors to be culturally sensitive to their expectations and, hence, make
      more effort in explaining the use and misuse of medicines.

PMID- 12602809
TI  - Structural models of gender, alcohol consumption, and health.
AB  - BACKGROUND: Gender differences exist in patterns of alcohol consumption and in
      the health and social effects of alcohol use, but little is known about gender
      differences in how alcohol use is affected by mental and physical health
      conditions. METHODS: We used structural equation modeling techniques to examine
      gender differences in the relationships among alcohol consumption, physical and
      mental health, functional status, and social and demographic characteristics.
      Data were obtained from a random sample of the adult membership of a health
      maintenance organization in the U.S. Pacific Northwest. Simultaneous models
      evaluated gender differences in predictors of drinking vs. nondrinking status
      and, among drinkers, amount of alcohol consumed. RESULTS: Physical health was
      twice as strong a predictor of drinker/nondrinker status among women compared
      with men, but among drinkers, there were no gender differences in predictors of
      amount of alcohol consumed. Mental health predicted drinking status and alcohol
      consumption among drinkers, but these relationships did not differ by gender.
      Overall, sociodemographic characteristics and physical health were stronger
      predictors of alcohol use among women than among men. CONCLUSIONS: Women may be
      more amenable than men to alcohol-related preventive messages that target
      physical health concerns. Treating mental health conditions may be an important
      method for reducing alcohol consumption.

PMID- 12602810
TI  - Correlates of benzodiazepine use among a sample of arrestees surveyed through the
      Arrestee Drug Abuse Monitoring (ADAM) Program.
AB  - While marijuana and cocaine are the two most prevalent drugs used among arrestee
      populations, benzodiazepine use has surpassed that of opiates in several
      jurisdictions across the United States. Despite this proliferation, few scholarly
      works have focused on benzodiazepine use among individuals under criminal justice
      supervision. In the present study, chi-square statistics and logistic regression
      are utilized to identify significant associations between recent benzodiazepine
      use (as measured by urinalysis), demographic characteristics, and alcohol and
      other drug (AOD) use among a sample of 862 adult Philadelphia arrestees
      interviewed in 1997 through the Arrestee Drug Abuse Monitoring (ADAM) Program.
      Compared to nonusers, benzodiazepine-positive respondents were more likely to be
      White, to have used alcohol and barbiturates in the three days preceding the
      interview, and to have tested positive by urinalysis for marijuana, cocaine,
      opiates, and phencyclidine (PCP). Moreover, logistic regression identified that
      if an arrestee reported three-day barbiturate use, the odds ratio (OR) of recent
      benzodiazepine use was more than nine times higher than an arrestee who reported
      no three-day barbiturate use. Implications for drug surveillance are assessed in
      light of the current findings.

PMID- 12602811
TI  - Juvenile drug offenders who use amphetamine recommitted to a remand center: the
      role of psychiatric morbidity.
AB  - One hundred consecutive juvenile drug offenders with amphetamine use in a remand
      center were assessed for extent of substance use and psychiatric morbidity by a
      psychiatrist from 1998 to 1999. They were monitored for one year after discharge.
      The "risk" of being recommitted to the remand center against use of various drugs
      and psychiatric morbidity was determined. Amphetamine-use disorder was more
      prevalent in those who were recommitted than those who were not, while no
      significant difference was found with licit substances, psychiatric morbidity, or
      the number of substances used between these two groups. In view of the high
      dependency properties of amphetamine, early intervention is suggested to prevent
      reuse.

PMID- 12602812
TI  - Treatment success rate among Iranian opioid dependents.
AB  - AIMS: The goal of this study was to assess the characteristics and treatment
      success rate (outcome) among Iranian opioid addicts. MEASUREMENTS: The data were
      gathered from 437 opioid addicts (using DSM-IV criteria) seeking treatment in
      1998. FINDINGS: Their mean age was 35.6yr., and 72.8% were married. Of these
      subjects 34.1% listed secondary school, 25.9% primary school, and 23.6% listed
      high school as their level of education. Of these addicts 26.1% were unemployed,
      24.5% miscellaneous workers, and 22.4% were drivers. About 49.4% reported opium,
      31.8% heroin, 12.4% cooked dross, and 6.4% reported other opioids as the
      substance currently used. Of the 437 addicts, the majority (54%) did not complete
      detoxification phase, 35% had experienced abstinence at least for three months,
      and 11% relapsed prior to completion of three months of abstinence. The relation
      was statistically significant between outcome and type of used opioid and also
      between dose of used opioid and outcome. CONCLUSIONS: The most commonly used
      opioids were opium, heroin, and cooked dross. During recent years, some
      demographic characteristics of the Iranian addicts have changed. Cultural
      attitudes toward drug use are quite likely to affect types and amount of use and
      also outcome of treatment. These findings can be considered when planning
      preventive and therapeutic programs.

PMID- 12602813
TI  - The intravascular persistence and methemoglobin formation of Hemolink (hemoglobin
      raffimer) in dogs.
AB  - Hemoglobin raffimer (HEMOLINK, Hemosol Inc, Mississauga, Canada) is an o
      raffinose cross-linked, purified human hemoglobin-based oxygen therapeutic that
      is currently being evaluated in late stage clinical trials. It is composed of
      several molecular weight (MW) species, comprising principally of stabilized
      tetramers (34-42%) and oligomers (54-62%). The objective of this study was to
      determine the in vivo circulating half-life (T1/2) of hemoglobin raffimer (Hb
      raffimer) and of its individual MW components in dogs subjected to a topload
      infusion of 25% of the estimated blood volume (18 mL/kg). Sampling was done over
      a 64-hour period that was expected to be equivalent to approximately two-and-half
      to three half-lives. Methemoglobin (MetHb) levels were also measured at intervals
      over the same period. The mean circulating half-life of Hb raffimer was 25.4 +/-
      3.9 hours. The T1/2 for the individual MW components (determined by size
      exclusion chromatography) of Hb raffimer was 11 +/- 2 hours for the cross-linked
      tetramer and 35 +/- 7 hours for the fraction of oligomers. The apparent volume of
      distribution for Hb raffimer was estimated at 78 mL/kg. There was no difference
      in the apparent volumes of distribution of the tetrameric and oligomeric
      components of Hb raffimer. Throughout the course of the experiment (in which
      MetHb could be measured), plasma MetHb concentration, expressed as a percentage
      of the total plasma hemoglobin concentration, remained at 10% or less, and the
      mass concentration of MetHb in plasma remained at about 1 g/L. Thus, in the dog
      subjected to an estimated 25% topload infusion, the T1/2 of the infused Hb
      raffimer is approximately one day with the intravascular retention of the
      individual Hb raffimer components being dependent on the MW. Furthermore,
      oxidation of Hb raffimer to MetHb is limited under these conditions.

PMID- 12602814
TI  - Comparison of chitin and Amberlite IRA-938 for alpha-galactosidase
      immobilization.
AB  - Watermelon alpha-galactosidase (EC 3.2.1.22) was immobilized on a natural
      (chitin) and a synthetic anion-exchange (Amberlite IRA-938) support by covalent
      coupling methods. The procedure entails the activation of supports with 1,1'
      carbonyldiimidazole (CDI), followed by immobilization of the enzyme on to these
      supports without and with a spacer arm; gamma-aminobutyric acid (GABA).
      Optimization of activation was performed by changing the CDI concentrations and
      coupling efficiencies. The comparison of two immobilization techniques for both
      chitin and Amberlite IRA-938 was made by comparing different enzyme
      concentrations against enzyme activity yield. Furthermore, the storage stability
      of the immobilized enzymes was also investigated and chitin immobilized alpha
      galactosidase was found to be better. Although the activity yield of immobilized
      enzymes were the same for both supports, the short storage stability of
      immobilized enzyme on Amberlite IRA-938 is currently a drawback to its
      applications.

PMID- 12602815
TI  - Human osteopenic bone-derived osteoblasts: essential amino acids treatment
      effects.
AB  - The development of in vitro cell culture methods has made it possible to study
      bone cell metabolism and growth and obtain a deeper insight into the
      pathophysiology of common orthopedic diseases such as osteoporosis. After
      analyzing the effect of two essential amino acids, L-arginine (Arg) and L-lysine
      (Lys), in previous in vitro and in vivo studies, the present authors investigated
      the administration of Arg and Lys in osteoblasts derived from human osteopenic
      bone. After isolation, osteoblasts were cultured in DMEM supplemented with either
      Arg (0.625 mg/ml/day, Arg Group) or Lys (0.587 mg/ml/day, Lys Group), or both of
      them (Arg-Lys Group), whereas the Control Group was sham-treated. After 7 days
      the following parameters were tested in all groups: MTT proliferation test,
      Alkaline Phosphatase (ALP), Nitric Oxide (NO), Calcium (Ca), Phosphorus (P),
      Osteocalcin (OC), C-Terminal Procollagen type I (PICP), Interleukin-6 (IL-6),
      Transforming Growth Factor-beta 1 (TGF-beta 1), Platelet Derived Growth Factor
      (PDGF) and Insulin-Like Growth Factor-I (IGF-I). Results were compared with those
      obtained from human healthy bone to verify the effect of the amino acids on
      osteoblasts derived from pathological tissue. In addition, a comparison was also
      made with the results obtained from rat osteopenic bone to assess reliability of
      the in vitro model. The current results support previous findings and indicate
      that Arg and Lys stimulation has a positive effect on osteoblast proliferation,
      activation and differentiation. Therefore, administration of these amino acids
      may be useful in clinical treatment and prevention of osteoporosis.

PMID- 12602816
TI  - Immobilization of glutathione-s-transferase within cross-linked gelatin
      cylindrical molds.
AB  - Rabbit liver cytosolic glutathione-s-transferase (GSTs; EC: 2.5.1.18) was
      immobilized in cross-linked gelatin cylindrical molds which the formaldehyde was
      used as cross linker. Glutathione-s-transferases are the enzymes that catalyze
      the conjugation of wide variety of electrophilic substrates with glutathione.
      This process generally leads to the detoxification of the xenobiotics.
      Characterization of immobilized GST was made by using 1-chloro-2,4
      dinitrobenzene(CDNB) as substrate. Immobilization efficiency of the enzyme was
      calculated in terms of activity yield. Optimal enzyme, gelatin and formaldehyde
      amounts, optimum pH and temperature, Km[CDNB], Km[GSH] and thermal stability was
      searched and compared with the free enzyme. Furthermore, for studying the
      detoxification by conjugation in vitro, immobilized GST was tested using stirred
      batch reactor system and found suitable with a high yield of 2,4-dinitrophenyl
      GSH conjugate formation.

PMID- 12602817
TI  - Collagen as an immobilization vehicle for bone marrow stromal cells enriched with
      osteogenic potential.
AB  - The bone marrow contains mesenchymal cells that can be divided into two
      categories: cells of hemopoietic lineage and stromal cells. The stromal cells are
      adhesive to the surface of culture dish, and could be differentiated into cells
      with bone-forming capability when stimulated with osteogenic supplements. In this
      study, we have employed collagen to immobilize cells with osteogenic potential
      from bone marrow. A more than two-fold increase in cell density was obtained on
      the collagen-coated substratum as compared to the uncoated ones. The selected
      marrow cells exhibited elevated alkaline phosphatase activity in parallel with
      the proliferation of the cells attached to the collagen surface. The osteoblastic
      expression of the selected cells was further confirmed by the histological stains
      of alkaline phosphatase and mineral deposit. This method provides a simple and
      fast screening technique to isolate osteoprogenitor-enriched population from the
      bone marrow stromal cells. It has a great potential for future biological and
      clinical applications.

PMID- 12602819
TI  - The controlled release study of Vincristine Sulfate.
AB  - We prepared microspheres of Vincristine Sulfate (VCR) through drying-from-oil
      method, then mixed the microspheres into 0.7% collagen swelling solution to
      prepare emulsion, spread the emulsion on plate to form film by frozen-dry method.
      The film was cross-linked and sterilized, then planted into the site of tumor and
      expected to release at steady speed. We measured the release of VCR in vivo and
      in vitro by HPLC. The results demonstrated that VCR controlled release films
      release at approximate steady speed in 15 days.

PMID- 12602818
TI  - Plasmaperfusion on triptophan columns can improve the clinical outcome of
      patients affected with myasthenia gravis.
AB  - Myasthenia Gravis (MG) is a neuromuscular disease often associated with thymic
      pathology due to neuromuscular transmission impairment by circulating antibodies
      directed against the cholinergic postsynaptic receptor on the neuromuscular
      junction (Anti-AchR-Ab). The treatment of MG includes cholinesterase inhibitors,
      steroids and thymectomy. Plasmapheresis can remove Anti-AchR-Ab but more recently
      plasma-perfusion (PP), a more specific apheresis for selective removal of noxious
      plasma components, has been developed. AIM OF THE STUDY: To study the effect of
      PP treatment, performed by using specific immunocolumns for Anti-AchR-Ab, on the
      clinical outcome of MG patients non-responder to steroid therapy or thymectomy.
      MATERIALS AND METHODS: We treated 8 patients suffering from severe MG by a cycle
      of 6 sessions of PP. We used columns containing triptophan as a specific ligand
      for Anti-AchR-Ab. In order to evaluate the effectiveness of treatment we used
      functional tests (muscular tests, respiratory function, electromyography) and
      laboratory tests (Anti-AchR-Ab; immunoglobulins, complement fractions,
      immunocomplexes). RESULTS: After one to three PP sessions, early clinical
      improvement in bulbar and respiratory symptoms were found in all patients and EMG
      showed improvement of neuromuscular transmission. Serum concentration of
      immunological markers decreased progressively and significantly during the
      treatment. Clinical improvements were progressive despite the tendency for Anti
      AchR-Ab to reach initial values between one session and another. We observed no
      side effects due to the type of immunocolumns used. CONCLUSIONS: Triptophan
      columns appear to be able to remove large quantities of Anti-AchR-Ab and
      immunological markers from plasma. Our experience shows that PP performed using
      triptophan columns in patients suffering from severe MG provides good clinical
      results, improving patients' outcome, without any risk linked to the procedure.

PMID- 12602821
TI  - Leaching of pesticides through normal-tillage and low-tillage soil--a lysimeter
      study. II. Glyphosate.
AB  - Glyphosate is a widely used non-selective herbicide. Leaching of glyphosate (N
      (phosphonomethyl)glycine) and/or its metabolite AMPA (aminomethylphosphonic acid)
      was studied in four lysimeters, two of them being replicates from a low-tillage
      field (lysimeter 3 and 4), the other two being replicates from a normal tillage
      field (lysimeter 5 and 6). In both cases the soil was a sandy loam soil with 13
      14% clay. The lysimeters had a surface area of 0.5 m2 and a depth of 110 cm.
      Lysimeter 3 and 4 were sprayed with a mixture of 14C-labelled glyphosate and
      unlabelled glyphosate, while lysimeter 5 and 6 were sprayed with unlabelled
      glyphosate. The spraying took place September 18, 1997. The total amount of
      glyphosate sprayed onto each lysimeter was 40 mg, corresponding to 0.8 kg active
      ingredient per ha. The lysimeters were installed in an outdoor system in Research
      Centre Flakkebjerg and were thus exposed to normal climatic conditions of the
      area. A mean of 260 l drainage water were collected from lysimeter 3 and 4 and a
      mean of 375 litres from lysimeter 5 and 6. The mean yearly concentration of
      leached glyphosate and/or AMPA was significantly below 0.1 microg/l from both
      sets of lysimeters, and thus no significant difference between the two lysimeter
      sets was shown. However, in both sets of lysimeters several single findings at
      concentrations above 0.1 microg/l was seen, which might be due to the leaching of
      particle-bound compounds. A significant difference between the soil residual
      concencentrations of AMPA was seen, the higher concentration was found in the set
      of lysimeter where low-tillage had been practiced and where Round Up had been
      used several times in the years before sampling of the lysimeter soil.

PMID- 12602820
TI  - Leaching of pesticides through normal-tillage and low-tillage soil--a lysimeter
      study. I. Isoproturon.
AB  - Isoproturon is a herbicide, which was used in Denmark against grass weeds and
      broad-leaved weeds until 1998. Isoproturon has frequently been detected in ground
      water monitoring studies. Leaching of isoproturon (N,N-dimethyl-N'-(4-(1
      methylethyl)-phenyl)urea) and its metabolites, N'-(4-isopropylphenyl)-N
      methylurea and N'-(4-isopropylphenyl)urea was studied in four lysimetres, two of
      them being replicates from a low-tillage field (lysimeter 3 and 4), the other two
      being replicates from a normal tillage field (lysimeter 5 and 6). In both cases
      the soil was a sandy loam soil with 13-14% clay. The lysimetres had a surface
      area of 0.5 m2 and a depth of 110 cm. Lysimeter 3 and 4 were sprayed with
      unlabelled isoproturon while lysimeter 5 and 6 was sprayed with a mixture of 14C
      labelled and unlabelled isoproturon. The total amount of isoproturon sprayed onto
      each lysimeter was 63 mg, corresponding to 1.25 kg active ingredient per ha. The
      lysimeters were sprayed with isoproturon on October 26, 1997. The lysimetres were
      installed in an outdoor system in Research Centre Flakkebjerg and were thus
      exposed to normal climatic conditions of the area. A mean of 360 l drainage water
      were collected from lysimeter 3 and 4 and a mean of 375 litres from lysimeter 5
      and 6. Only negligible amounts of isoproturon and its primary metabolites were
      found in the drainage water samples, and thus no significant difference between
      the two lysimeter sets was shown. In a total of 82 drainage water samples, evenly
      distributed between the four lysimetres isoproturon was found in detectable
      amounts in two samples and N'-(4-isopropylphenyl)urea was found in detectable
      amounts in two other samples. The detection limit for all the compounds was 0.02
      microg/l. 48% and 54% of the added radioactivity were recovered from the upper 10
      cm soil layer in lysimeter 5 and 6, respectively, and 17 and 14% from 10-20 cm's
      depth. By extraction first with an aquatic CaCl2 solution 0.49% of the added
      radioactivity was extracted from the upper 10 cm layer in lysimeter 5. In the
      subsequent extraction with acetonitril, 1.19% of the added radioactivity was
      extracted. In lysimeter 6, upper 10 cm, 0.2% were extracted with water and 0.56%
      were extracted with acetonitril. Below 10 cm's depth no measurable amounts could
      be extracted.

PMID- 12602822
TI  - Fate of autumn-applied metolachlor in a clay loam in the northern U.S. Corn Belt.
AB  - Application of herbicides in autumn is of interest to land managers who seek to
      reduce the number of field operations during spring in the northern Corn Belt. A
      limited number of herbicides, however, posses the physical characteristics that
      are required to minimize loss from soil over winter. This study examined the fate
      of one of these herbicides, metolachlor, during three consecutive winters (1994
      1995, 1995-1996, and 1996-1997) near Morris, MN. Metolachlor was applied to the
      top 5 cm of a clay loam that was packed into a 1.8-m long plastic pipe. The pipe
      was then set inside a larger diameter 1.8-m long plastic pipe that was buried
      vertically in the field. The gap between the pipes was insulated along the sides
      and sealed at the top; this configuration allowed collection of leachate and
      extraction of the smaller diameter pipe while the field soil was frozen. The
      experimental design was replicated thrice with sample date (date that the smaller
      diameter pipes were extracted from the field) as the main treatment. Pipes were
      extracted from the field at least twice during winter and sectioned into 2 cm or
      larger increments. The soil contained within these sections was then analyzed for
      metolachlor. Downward movement of metolachlor occurred in the soil profile during
      the autumn, but only in 1995. This movement was likely caused by exclusion during
      pore ice formation as the soil froze. At the time of complete soil thaw in
      spring, the majority of metolachlor was still detected in the zone of application
      (0-5 cm depth). Some metolachlor, however, was detected 1 to 3 cm below the zone
      of application in all three years. Downward movement during thaw was due
      primarily to infiltration of snowmelt and rain. Metolachlor was most vulnerable
      to degradation during spring, but some loss occurred in autumn prior to freeze
      up. This study suggests that autumn-applied metolachlor moves little in a
      repacked clay loam profile during winter. Further studies are warranted in
      evaluating movement under a range of soil physical properties and management
      practices.

PMID- 12602823
TI  - Environmental transformation of triadimefon in water and on plant leaf surface.
AB  - Phototransformation of triadimefon was studied in aqueous solution and on plant
      leaf surface under natural and simulated conditions. Photoproducts such as 4
      chlorophenol, 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazole-1-yl)-butan-2-ol
      and 1-phenoxy-3,3-dimethyl-but-2-one were identified on leaf as well as in
      aqueous solution. A new photoproduct product 1-(4-chlorophenoxymethyl)-1,2,4
      triazole was identified only on the leaf surface. The rate of degradation was
      more in tap water as compared to rain and distilled water.

PMID- 12602824
TI  - Biochemical enzyme activity in different tissues of rats exposed to a novel
      phosphorothionate (RPR-V).
AB  - The effects of a novel phosphorothionate (RPR-V) synthesized at Indian Institute
      of Chemical Technology, Hyderabad, was studied using three sub-chronic doses of
      0.033 (low), 0.066 (medium) and 0.099 (high) mg kg(-1) in male and female rats
      for a period of 90 days. This long term and repeated treatment of RPR-V revealed
      that the membrane bound target enzymes Aspartate aminotransferase and Alanine
      aminotransferase increased significantly in serum and kidney, whereas these
      enzymes significantly decreased in liver and lung tissues when measured after 45
      and 90 days of treatment. This compound also caused significant inhibition of RBC
      Acetylcholinesterase, target enzyme of organophosphorus compounds revealing its
      effect on normal synaptic transmission. Two way Anova studies disclosed that the
      alterations were mostly dose and time dependent, sexual dimorphism was not
      observed when the activities of male rats were compared with female rats. Enzyme
      recoveries were recorded after 28 days of post treatment, high degree positive
      correlation was observed with regard to these enzymes between serum versus
      kidney, whereas in case of serum versus liver and lung tissues high degree
      negative correlation was recorded. These enzyme profiles elucidates that they
      increased in serum but they decreased significantly in liver and lung indicating
      necrosis of these tissues. However, in case of kidney the level of these enzymes
      increased significantly with parallel to serum, which is suggestive of an
      increase synthesis of these enzymes, may be an adaptive mechanism due to the
      stress of the toxicant. These biomarker enzymes can be detected rapidly and hence
      may be used for the prediction and diagnosis of pesticide insults.

PMID- 12602825
TI  - Influence of temperature and time on phosphorus removal in swine manure during
      batch aeration.
AB  - This study was conducted to investigate the effects of temperature and time on
      the mechanisms of phosphorus removal in swine manure during aeration. Removal of
      soluble orthophosphates significantly increased with aeration time and
      temperature. Successive significant ortho-P removals were observed between days
      one and nine but no significant additional removals were recorded thereafter.
      Removals were significantly higher at temperatures of 20 and 25 degrees C than at
      temperatures of 5, 10, and 15 degrees C and ranged between 22.9 to 31.0%.
      Insoluble inorganic phosphorus also changed significantly with aeration time and
      temperature and with a similar trend as soluble orthophosphates. The pH of the
      manure explained 92 and 87% of the content of insoluble inorganic phosphorus at
      lower temperatures (5, 10, 15 degrees C) and at higher temperatures (20, and 25
      degrees C), respectively. Organic phosphorus and aerobes growth patterns were
      similar to that of soluble orthophosphates removal. The rapid growth of aerobes
      was most probably the principal factor behind a rapid soluble ortho-P removal
      above 15 degrees C. The contribution of inorganic phosphates to the removal of
      soluble orthophosphates was approximately 61% while that due to organic P was
      approximately 35%. Precipitation was found to be the principal mechanism
      governing removal of soluble ortho-P in swine manure during aeration treatments.

PMID- 12602826
TI  - Bench-scale biofilter for removing ammonia from poultry house exhaust.
AB  - A bench-scale biofilter was evaluated for removing ammonia (NH3) from poultry
      house exhaust. The biofilter system was equipped with a compost filter to remove
      NH3 and calcium oxide (CaO) filter to remove carbon dioxide (CO2). Removal of NH3
      and CO2 from poultry house exhaust could allow treated air with residual heat to
      be recirculated back into the poultry house to conserve energy during winter
      months. Apart from its use as a plant nutrient, NH3 removal from poultry house
      exhaust could lessen the adverse environmental impacts of NH3 emissions. Ammonia
      and CO2 were measured daily with gas detector tubes while temperatures in the
      poultry pen and compost filter were monitored to evaluate the thermal impact of
      the biofilter on treated air. During the first 37 days of the 54-day study,
      exhaust air from 33 birds housed in a pen was treated in the biofilter; for the
      final 17 days, NH3-laden exhaust, obtained by applying urea to the empty pen was
      treated in the biofilter. The biofilter system provided near-complete attenuation
      of a maximum short-term NH3 concentration of 73 ppm. During the last 17 days,
      with a mean influent NH3 concentration of 26 ppm, the biofilter provided 97%
      attenuation. The CaO filter was effective in attenuating CO2. Compared with a
      biofilter sized only for NH3 removal, an oversized biofilter would be required to
      provide supplemental heat to the treated air through exothermic biochemical
      reactions in the compost. The biofilter could conserve energy in poultry
      production and capture NH3 for use as plant nutrient. Based on this study, a
      house for 27,000 broilers would require a compost filter with a volume of
      approximately 34 m3.

PMID- 12602828
TI  - Outcome assessment of the Medicaid managed care program in Harris County
      (Houston).
AB  - Nowadays, managed care has taken over the management of the Medicaid program in
      most states of the nation. The patients treated in the public sector managed care
      system are very vulnerable and at high risk. Thus, we decided to measure the
      impact of managed care in the public-sector population of Texas. To this end, we
      assessed the treatment outcome at the Harris County Psychiatric Center (HCPC).
      Our results showed that after the implementation of the Medicaid managed care
      program in Houston, the bed utilization at HCPC decreased by 32% and the
      readmission rate increased by 21%; concomitantly, the length of stay decreased
      from 15.6 days to 9.3 days. Additionally, African-American and Hispanic-American
      patients were more negatively affected than Caucasian patients. Undoubtedly, the
      implementation of the Medicaid managed care system in Texas has led to untoward
      effects in the quality of care provided to the most disadvantaged population of
      the state.

PMID- 12602827
TI  - Isolation of Salmonella typhimurium Tn5 mutants defective for survival on egg
      shell surface using transposon footprinting.
AB  - The objective of this study was to screen the genome of Salmonella typhimurium
      for genes potentially required for survival on egg shell surfaces using a novel
      transposon footprinting method based on a previously developed Tn5 mutagenesis
      technique. Since the amplified DNA fragment length should usually be unique for
      each mutant, the polymerase chain reaction products separated on an agarose gel
      generate a transposon footprint with each band in the footprint representing the
      corresponding Tn5 mutant. By comparing the footprints from the pools of S.
      typhimurium Tn5 mutants before and after inoculation on egg shell surfaces, Tn5
      mutants not recovered after selection were rapidly identified for potential
      isolation and genetic analysis.

PMID- 12602829
TI  - Creating sanctuary in residential treatment for youth: from the "well-ordered
      asylum" to a "living-learning environment.".
AB  - This paper addresses the need for a coherent conceptual therapeutic approach to
      guide work with disturbed children and adolescents in residential treatment
      centers. The paper identifies changes in the population currently in care;
      examines the two dominant approaches that historically have shaped the standard
      treatment models used by most residential centers; and discusses four
      longstanding debates that have complicated the development of a consistent
      therapeutic approach for residential programs. It concludes with a description of
      The Sanctuary Model. Integrating a variety of treatment approaches, this trauma
      based systems approach to care was first used with adult inpatients traumatized
      as children. It is now being introduced by a major social agency into three of
      its residential centers to provide a systematic treatment model for use in their
      schools, living units, and treatment sessions.

PMID- 12602831
TI  - Sanctuary in a domestic violence shelter: a team approach to healing.
AB  - For survivors of domestic violence, the ongoing effects of trauma are compounded
      by the context of their abusive experience. Injury caused by a person one has
      loved and trusted damages beliefs about oneself, other people, and the world.
      Staff members of various disciplines and educational backgrounds who work in
      domestic violence shelters are dealing with this damage as well as the impact of
      trauma on shelter residents. They face the challenge of observing and responding
      to the effects of recent and past abuse, to traumatic reenactments within the
      setting, and to their own secondary trauma reactions. This paper explores the
      process of implementing the Sanctuary model in a domestic violence shelter as a
      way to address trauma and its impact on clients and staff. The Sanctuary model
      was chosen because of its focus on teamwork, and the guidelines for treatment it
      provides that are accessible to all members of the treatment community.

PMID- 12602830
TI  - Assessing the implementation and effects of a trauma-focused intervention for
      youths in residential treatment.
AB  - This paper describes methods being used to implement and assess the effects of a
      trauma-focused intervention in residential treatment programs for youths with
      emotional and behavioral problems, and histories of maltreatment and exposure to
      family or community violence. Preliminary baseline profiles of the therapeutic
      environments and youths are also presented. The intervention, referred to as the
      Sanctuary Model (Bloom, 1997), is based in social psychiatry, trauma theories,
      therapeutic community philosophy, and cognitive-behavioral approaches. Within the
      context of safe, supportive, stable, and socially responsible therapeutic
      communities, a trauma recovery treatment framework is used to teach youths
      effective adaptation and coping skills to replace nonadaptive cognitive, social,
      and behavioral strategies that may have emerged earlier as means of coping with
      traumatic life experiences.

PMID- 12602832
TI  - Multiple opportunities for creating sanctuary.
AB  - This article describes the experience of five change agents from a diverse group
      of settings: two residential treatment programs for children and adolescents, a
      group home for disturbed adolescents, a residential substance abuse program for
      urban women, and an acute care psychiatric inpatient unit. What all of these
      innovators share is a willingness to engage in the challenging and complex
      process of changing their systems to better address the needs of the traumatized
      children, adolescents, and adults who populate their various programs. Using the
      Sanctuary Model as originally applied to a specialty inpatient psychiatric
      program for adult survivors of childhood abuse as their guide, the leaders of
      each of these organizations discuss the process of change that they are
      directing.

PMID- 12602833
TI  - Using trauma theory and S.A.G.E. in outpatient psychiatric practice.
AB  - In this paper the author reviews case examples of how a thorough understanding of
      trauma and recovery combined with a coherent, nonlinear, phased approach to
      treatment called S.A.G.E., helps to provide a conceptual framework that is easily
      understood by clients and their families and allows the clinician to organize and
      measure treatment success, regardless of the complexity of the cases involved.

PMID- 12602834
TI  - Individualized medicine. What the genetic revolution will bring to health care in
      the 21st century.

PMID- 12602835
TI  - Post Romanow, post Kirby. What's next?

PMID- 12602836
TI  - Getting the facts on physical activity.

PMID- 12602837
TI  - Test result could mean different things.

PMID- 12602838
TI  - Another infectious disease guide for Palms.

PMID- 12602839
TI  - Taking St John's wort during pregnancy.
AB  - QUESTION: A 23-year-old patient of mine has been taking St John's wort for
      postpartum depression for about 2 years. She is now planning her second
      pregnancy. Is she or her fetus at risk if she continues to take the herbal
      therapy? ANSWER: Despite the widespread availability and use of St John's wort
      and extensive research on the herb, there are almost no data on reproductive
      safety. At this stage, therefore, St John's wort cannot be recommended as safe
      therapy during pregnancy.

PMID- 12602840
TI  - Practice Tips: Umbilical cord model. Useful for teaching neonatal resuscitation.

PMID- 12602841
TI  - Hemochromatosis. More common than you think.
AB  - OBJECTIVE: To review current knowledge of the genetics, presentation, diagnosis,
      and management of hereditary hemochromatosis. QUALITY OF EVIDENCE: MEDLINE was
      searched from January 1966 to June 2002, and references of relevant papers were
      reviewed. Most articles were reviews, practice guidelines, or observational
      studies. Several randomized controlled trials were identified but none studied
      primary therapy for hemochromatosis. MAIN MESSAGE: Hemochromatosis, the most
      common genetic disease in white populations, has a prevalence of one in 200, yet
      is still underrecognized. This disease of unregulated iron absorption leads to
      generalized iron overload that can eventually impair organ systems and lead to
      cirrhosis, diabetes, and cardiomyopathy. Symptoms are often nonspecific and
      patients are identified by mild abnormalities in routine laboratory testing.
      Transferrin saturation, ferritin levels, and genotyping can often establish the
      diagnosis. Iron depletion therapy with phlebotomy is helpful if initiated before
      organ damage occurs. CONCLUSION: Family physicians should be aware that
      hemochromatosis can be treated effectively if diagnosed early.

PMID- 12602842
TI  - Genetic susceptibility to cancer. Family physicians' experience.
AB  - OBJECTIVE: To explore family physicians' experiences in dealing with genetic
      susceptibility to cancer. DESIGN: Qualitative study using focus groups. SETTING:
      Four Ontario sites: northern, rural, urban, and inner city. PARTICIPANTS: Forty
      rural and urban FPs participated in four focus groups: 28 were male; average age
      was 41. METHOD: Focus groups using a semistructured interview guide were
      audiotaped and transcribed. The constant comparative method of data analysis was
      used. Key words and concepts were identified. Data were sorted using NUD*IST
      software. MAIN FINDINGS: Participants realized the escalating expectations for
      genetic testing and its effect on family practice. They explored an expanded role
      for themselves in genetic testing. Possible activities included risk assessment,
      gatekeeping, and ordering genetic tests. They were concerned about the complexity
      of genetic testing, the lack of evidence regarding management, and the
      implications for families. CONCLUSION: We must help FPs struggling to integrate
      genetics into their practices, by addressing their concerns, enhancing the way
      they communicate information on genetics, and developing appropriate educational
      tools.

PMID- 12602844
TI  - Canada's family physicians celebrate their heroes and heroines.

PMID- 12602843
TI  - Educating women about breast cancer. An intervention for women with a family
      history of breast cancer.
AB  - OBJECTIVE: To evaluate an "information aid" for women with a family history of
      breast cancer. DESIGN: Before-after descriptive study. SETTING: Family practices
      in Ontario. PARTICIPANTS: Of 405 randomly selected Ontario physician members of
      the College of Family Physician's of Canada's National Research System, 97 agreed
      to participate and to recruit three consecutive female patients with any family
      history of breast cancer. INTERVENTIONS: Patients completed a baseline
      questionnaire and, after reviewing the information aid, a satisfaction
      questionnaire. Four weeks later, they completed a third questionnaire. MAIN
      OUTCOME MEASURES: Patient satisfaction, knowledge, worries related to breast
      cancer, risk perception, and attitudes toward screening. RESULTS: Of 203 patients
      recruited, 160 (79%) completed all three questionnaires. The information aid was
      rated excellent or very good by 91% of the women; 99% would recommend it to other
      women. Knowledge improved significantly; worry about breast cancer did not
      increase. CONCLUSION: The information aid is a useful resource for women and
      primary care physicians and could facilitate appropriate risk assessment and
      management of women with a family history of breast cancer.

PMID- 12602845
TI  - Building on strength.

PMID- 12602846
TI  - Effect of cadmium individually and in combination with other metals on the
      nutritive value of fresh water fish, Channa punctatus.
AB  - Impact of metal cadmium on the nutritive value of Channa punctatus on exposure to
      a sublethal concentration (1.12 mg/l) of cadmium (Cd2+) for 15 and 60 days has
      been studied. Among the various parameters selected, the level of moisture in
      liver and muscle was increased, while decrease was noted in the level of ash,
      total proteins and inorganic constituents like iron, calcium, inorganic
      phosphate, sodium and potassium in both liver and muscle in the two types of
      exposure. The total lipid level of liver increased, while muscle lipid level was
      decreased. On the other hand, calcium, iron, inorganic phosphate, sodium and
      potassium levels showed increase in blood. Zinc and selenium decreased the
      percentage alterations in all the parameters selected for study. In the two types
      of exposure, zinc was most effective to counteract the cadmium toxicity to fish
      as in almost all the parameters insignificant alterations were recorded. In
      combination studies, protection against cadmium toxicity by the two chemicals
      became more marked with increase in the tenure of exposure.

PMID- 12602847
TI  - Host plant resistance to insects: an eco-friendly approach for pest management
      and environment conservation.
AB  - Host plant resistance (HPR) to insects is an effective, economical, and
      environment friendly method of pest control. The most attractive feature of HPR
      is that farmers virtually do not need any skill in application techniques, and
      there is no cash investment by the resource poor farmers. Considerable progress
      has been made in identification and development of crop cultivars with resistance
      to the major pests in different crops. There is a need to transfer resistance
      genes into high-yielding cultivars with adaptation to different agro-ecosystems.
      Resistance to insects should form one of the criteria to release varieties and
      hybrids for cultivation by the farmers. Genes from the wild relatives of crops,
      and novel genes, such as those from Bacillus thuringiensis can also be deployed
      in different crops to make HPR an effective weapon to minimize the losses due to
      insect pests. HPR will not only cause a major reduction in pesticide use and
      slowdown the rate of development of resistance to insecticides in insect
      populations, but also lead to increased activity of beneficial organisms and
      reduction in pesticide residues in food and food products.

PMID- 12602848
TI  - Ovarian changes in response to heavy metal exposure to the fish, Notopterus
      notopterus (Pallas).
AB  - The ovarian and hepatic protein, lipid and cholesterol content were estimated in
      the fish, N. notopterus after exposing it to heavy metals at sublethal
      concentrations. The protein, lipid and cholesterol content of ovary and liver got
      reduced and amongst the three exposures (mercuric chloride, cadmium chloride and
      their combination) it was significantly reduced in the order of
      (HgCl2>HgCl2>+CdCl2>CdCl2>control). The above results indicated that HgCl2 is
      highly toxic and its toxicity gets reduced in combination.

PMID- 12602849
TI  - Fenvalerate-induced macromolecular changes in the catfish, Clarias batrachus.
AB  - The effects of sublethal concentration of fenvalerate on DNA, RNA, RNA/DNA ratio
      and protein contents were estimated in gill and kidney tissues of an air
      breathing fish, Clarias batrachus. Fenvalerate reduced the DNA content in gill,
      whereas it did not produce any significant effect on DNA in kidney. This tissue
      specific change in DNA content may be due to differential effects of fenvalerate
      or its metabolite(s) on synthesis and/degradation of DNA in gill and kidney cells
      of the fish. RNA and protein contents declined substantially in both the tissues
      in response to fenvalerate treatment. However, RNA/DNA ratio remains unchanged.
      It indicates that decrease in protein content in response to fenvalerate
      treatment might have been brought about by reduce rate of translation of
      messenger (mRNA) without a decrease in concentration of ribosomes.

PMID- 12602850
TI  - The toxicity of ammonia, nitrite and nitrate to the fish, Catla catla (Hamilton).
AB  - The acute toxicity of unionized ammonia; nitrite and nitrate to the Indian major
      carp Catla catla (Hamilton) was determined using static and continuous flow
      through systems for 24 hours. The median lethal concentration (LC50) values for
      24 h of ammonia (NH3-N), nitrite (NO2-N) and nitrate (NO3-N) were 0.045 mg/l,
      120.84 mg/l and 1565.43 mg/l in static test respectively and were 0.036 mg/l,
      117.43 mg/l and 1484.08 mg/l in continuous flow through test respectively.

PMID- 12602851
TI  - Study on the gill of field crab, Paratelphusa hydrodromus (Herbst.) exposed to
      nickel.
AB  - Paratelphusa hydrodromus (Herbst.) was exposed to 50 ppm nickel chloride solution
      for a period of 10 days under laboratory conditions. The gills of the treated and
      non-treated animals were sectioned, stained and examined under a compound
      microscope and noticed significant changes such as enlargement of gill lamellae,
      lifting up and rupture of epithelial cells, enlargement of mid rachis,
      hyperplasia and hypertrophy, appearance of pyknotic nuclei and a general necrosis
      in the treated gills. Results suggest that a comparatively low concentration of
      nickel (50 ppm) is enough to elicit pathological changes in Paratelphusa
      hydrodromus.

PMID- 12602852
TI  - Carbaryl-induced alterations in biochemical metabolism of the prawn,
      Macrobrachium malcolmsonii.
AB  - The present study was performed to investigate the toxic impact of carbaryl on
      biochemical metabolism in the hemolymph, brain, hepatopancreas, gills and muscle
      of intermoult juveniles of the economically important prawn, Macrobrachium
      malcolmsonii. The concentration of glutathione S-transferase (GST) was found to
      be higher in test prawns when compared with controls. This suggests that a
      mechanism of detoxification was in operation to neutralise carbaryl toxicity.
      However, the toxic effect of carbaryl was not fully neutralised, and hence,
      alterations were recorded in basic biochemical metabolism of test prawns. The
      concentration of acetylcholinestrase (AchE) was found to be lower in test prawns
      than that of controls. Carbaryl toxicity resulted in utilisation of major
      biochemical constituents, such as total carbohydrate, glycogen, protein and lipid
      to generate required energy as an attempt to withstand the toxic stress.
      Glycogenolysis resulted in elevation of total free sugar level in the hemolymph
      of test prawns. While proteolysis led to elevation of total free amino acid level
      in test prawns. The content of total lipid have also been found lower in test
      prawns than that of controls. This suggests that carbaryl toxicity resulted in
      severe energy crises in test prawns. In the present study, toxic effects of
      carbaryl impair basic metabolic functions and hence pose a threat to the life of
      M. malcolmsonii.

PMID- 12602853
TI  - Role of feeding time and food amount in the reproduction of spotted Munia.
AB  - It was observed that food restriction significantly increase gonadal development
      for about two months indicating that hypothalamo hypophyseal gonadal axis becomes
      more sensitive to feeding stress during the early breeding period than the other
      reproductive phases. Normal testicular development was also not seen in the
      spotted munia in which food was restricted for two times each of 3 hour duration,
      despite the fact that daily food consumption was not significantly less (only by
      6.60%) compared to the control group. This suggests that daily restriction in
      feeding for a longer period (total 6 h or more) may also alter the reproductive
      function in wild birds.

PMID- 12602854
TI  - Researches on Turkoglu Gavur Lake in Kahramanmaras-Turkey and some projections
      from past to future.
AB  - Gavur Lake, takes place on the Saghk Plain in the south of Turkoglu subprovince
      in Kahramanmaras, was one of the most important places, that was available in the
      past time, south of our homeland. Gavur Lake represents the northest point of the
      bird immigration route that extends to Victoria Lake in Africa together with Emen
      and Amik Lakes dried locate on more south. Gavur Lake had been dried because of
      the some reasons those were being the marsh inn time by without oxygen cycle and
      emerging the situation of the microorganisms those were big threat for human
      health and to provide land in 1950's for the people of immigrants in Turkoglu.
      Presently, the big part of the Gavur Lake has dried. Drying activities are
      continuing. Whereas, Gavur Lake have all the conditions of the Ramsar Accord.
      With the improving of the Turkoglu reed bed the local people will earn more money
      by tourism than agricultural. Otherwise, the future of the Gavur Lake is going to
      be like Amik Lake.

PMID- 12602855
TI  - Plant availability of cadmium in presence of organic acids: an interactive
      aspect.
AB  - The present communication reports the effect of various carboxylic and amino
      acids on the uptake and translocation of root-absorbed Cd by maize (Zea mays).
      Statistically significant increases in Cd accumulation in various plant tissues
      with increasing supplementation of organic acids suggested the existence of Cd
      organic acid interaction in soil-rhizosphere environment of the plant. The
      potentiality of phytochelators (organic acids) to form plant available
      organically bound Cd is discussed.

PMID- 12602856
TI  - Copper sulphate (CuSO4) toxicity on tissue phosphatases activity and
      carbohydrates turnover in Achatina fulica.
AB  - A time course study on the sublethal toxicity of CuSO4 on tissue carbohydrate
      metabolites level and their phosphatases activity in Achatina fulica revealed
      differential response. The levels of total carbohydrates and glycogen in the body
      mass muscle, foot muscle and hemolymph revealed their involvement in the
      endogenous derivation of energy during stress. The same metabolites in digestive
      gland revealed its importance to reproduction and development. The lactate
      accumulated in all the tissues implied the mechanism of CuSO4 toxicosis in the
      metabolic acidosis. The decrease of pyruvate in foot muscle, body mass muscle and
      hemolymph inferred the preponderance of glycolysis in energy derivation. In
      contrast, the pyruvate concentration in digestive gland revealed its differential
      response in the stress metabolic sequence of changes, as a unique tissue. The
      lactate/pyruvate ratio and the calcium content in tissues constitute direct
      evidences for the snails adaptation to toxic stress.

PMID- 12602857
TI  - Genital abnormalities in white-tailed deer (Odocoileus virginianus) in west
      central Montana: pesticide exposure as a possible cause.
AB  - From spring, 1996, to early spring, 2000, accident-killed and injured white
      tailed deer, Odocoileus virginianus, in the Bitterroot Valley of west-central,
      Montana, U.S.A., were collected and examined for genital abnormalities at the
      Bitterroot Wildlife Rehabilitation Center. Of the 254 male deer examined, 133
      were fawns aged 3 months to 1 yr, 29 were 1 to 1 1/2 yrs of age, and 92 were 1
      1/2 to 3 yrs of age. Approximately 33% were normal; the remaining 67% showed
      varying degrees of apparent genital developmental anomalies, specifically
      mispositioned and undersized scrota and ectopic testes, and this percentage held
      through all age groups. The sex ratio of fawns and fetuses was skewed towards
      males, significantly so for the 1996 fawn cohort and for the total of all fawns
      and fetuses in the study. Although possible causes of the genital anomalies,
      centering on endocrine disrupting pesticides, are discussed, no conclusions of
      cause and effect can be currently justified.

PMID- 12602858
TI  - Autecology of the common mormon butterfly, Papilio polytes (Lepidoptera :
      Rhopalocera : Papilionidae).
AB  - The adults of the common mormon butterfly Papilio polytes Linn. feed on a variety
      of floral species. The larval food plants in the study area included Citrus limon
      and Murraya koenigii both of the family Rutaceae. The eggs are laid singly, and
      the hatching time is three days. The larvae pass through five instars. The larval
      growth is directly correlated with the quantity of food consumed. The AD
      (approximate digestibility) values decreased from first instar to the last,
      whereas the ECD (efficiency of conversion of digested food) and ECI (efficiency
      of conversion of ingested food) values increased, thus bearing an inverse
      relationship with AD. The development time from egg to adult is 28-30, giving 11
      12 generations in a year, but with better breeding during August-February. Thus
      P. polytes is multivoltine.

PMID- 12602859
TI  - A correlative study on liver glycogen and endosulfan toxicity in Heteropneustes
      fossilis (Bloch.).
AB  - The biochemical tests were conducted to find out the relationship between liver
      glycogen and endosulfan toxicity on a catfish, Heteropneustes fossilis (Bloch.)
      using 0.00075, 0.00050 and 0.000375 ppm concentrations for 15, 30, 45 and 60 days
      of exposure periods. The quantity of liver glycogen showed decreasing trend as
      concentration of toxicant increased. The depletion in glycogen contents is
      greatly affiliated to cellular damage in hepatic cells.

PMID- 12602860
TI  - Impact of cadmium on food utilization of the Indian major carp, Catla catla
      (Ham).
AB  - Catla catla, under the sublethal stress of cadmium exhibited depletion in food
      utilization parameters and it was concentration dependent. Heavy metal
      intoxication was found to exhibit reduction in biomass.

PMID- 12602861
TI  - Effect of linear alkyl benzene sulphonate on erythrocyte sedimentation rate of
      teleost fish, Heteropneustes fossilis.
AB  - ESR increased at all concentrations and exposures to LAS. However, increases were
      more pronounced at LC50 for 24 h and minimum at the end of 96 h.

PMID- 12602862
TI  - Two genes encoding protein phosphatase 2A catalytic subunits are differentially
      expressed in rice.
AB  - Type 2A serine/threonine protein phosphatase (PP2A) plays a variety of regulatory
      roles in metabolism and signal transduction. Two closely related PP2A catalytic
      subunit (PP2Ac) genes, OsPP2A-1 and OsPP2A-3, have been isolated from the monocot
      Oryza sativa. Both genes contain six exons and five introns which intervene at
      identical locations, suggesting they have descended from a recent duplication
      event. Their encoded proteins share 97% sequence identity and are highly similar
      (94-96%) to a PP2Ac subfamily (AtPP2A-1, -2 and -5) identified in Arabidopsis
      thaliana. Both OsPP2A-1 and OsPP2A-3 are ubiquitously expressed, with the
      expression levels high in stems and flowers and low in leaves. OsPP2A-1, but not
      OsPP2A-3, is also highly expressed in roots. Transcript levels of OsPP2A-1 in
      roots and OsPP2A-3 in stems are elevated at the maturation and young stages,
      respectively. Drought and high salinity upregulate both genes in leaves, whereas
      heat stress represses OsPP2A-1 in stems and induces OsPP2A-3 in all organs. These
      findings indicate that the two PP2Ac genes are subjected to developmental and
      stress-related regulation. In situ hybridization results show that both
      transcripts exhibit nearly identical cellular distribution, except in leaves, and
      are abundant in meristematic tissues including the young leaf blade of stems and
      the root tip.

PMID- 12602864
TI  - 4-coumarate:CoA ligase gene family in Rubus idaeus: cDNA structures, evolution,
      and expression.
AB  - The enzyme 4-coumarate:CoA ligase (4CL) activates cinnamic acid and its
      hydroxylated derivatives by forming the corresponding CoA thioesters. These serve
      as substrates for biosynthesis of phenylpropanoid-derived end-products that are
      important determinants of fruit quality in raspberry (Rubus idaeus L.). In higher
      plants, 4CL is typically encoded by a gene family. To investigate the
      participation of distinct 4CL genes in the process of fruit ripening, we have
      characterized this gene family in raspberry. By complementing a PCR-based
      homology search with low-stringency cDNA library screening, we have isolated
      three classes of raspberry 4CL cDNAs (Ri4CL1, Ri4CL2, and Ri4CL3). Phylogenetic
      analysis places the three raspberry 4CL gene family members into two distinct
      groups, a pattern consistent with an ancient divergence from an ancestral
      progenitor. Quantitative RT-PCR assay reveals a differential pattern of
      transcription of each of the three genes in various organs, as well as distinct
      temporal patterns of expression during flower and fruit development. The
      regulatory elements thus appear to have evolved independently of the genes
      themselves. Based on phylogenetic classification, expression patterns and
      recombinant protein activities the different Ri4CL genes are likely to
      participate in different biosynthetic pathways leading to the various
      phenylpropanoid-derived metabolites that help create flavor and color in
      raspberry fruit.

PMID- 12602863
TI  - Evolution and expression of MYB genes in diploid and polyploid cotton.
AB  - R2R3-MYB transcription factors have been implicated in a diversity of plant
      specific processes. Among the functions attributed to myb factors is the
      determination of cell shape, including regulation of trichome length and density.
      Because myb transcription factors are likely to play a role in cotton fiber
      development, the molecular evolutionary properties of six MYB genes previously
      shown to be expressed in cotton fiber initiation were examined. In accordance
      with their presumed central role, each of the genes display conservative
      substitution patterns and limited sequence divergence in diploid members of the
      genus Gossypium, and this pattern is conserved in allotetraploid cottons. In
      contrast to highly reiterated rDNA repeats, GhMYB homologues (duplicated gene
      pairs) exhibit no evidence of concerted evolution, but instead appear to evolve
      independently in the allopolyploid nucleus. Expression patterns for the MYB genes
      were examined in several organs to determine if there have been changes in
      expression patterns between the diploids (G. raimondii and G. arboreum) and the
      tetraploid (G. hirsutum) or between the duplicated copies in the tetraploid.
      Spatial and temporal expression patterns appear to have been evolutionarily
      conserved, both during divergence of the diploid parents of allopolyploid cotton
      and following polyploid formation. However, the duplicated copies of MYB1 in the
      tetraploid are not expressed at equal levels or equivalently in all organs,
      suggesting possible functional differentiation.

PMID- 12602865
TI  - Characterization of the expression of Phaseolus vulgaris OCT1, a dehydration
      regulated gene that encodes a new type of phloem transporter.
AB  - A cDNA coding for a putative organic cation transporter (OCT) was isolated from
      Phaseolus vulgaris roots by differential display RT-PCR and the corresponding
      full-length cDNA (named PvOCT1) was subsequently obtained by RACE-PCR. Hydropathy
      profiles of the deduced amino acid sequence (547 residues) predicted the
      existence of twelve membrane-spanning domains, which are highly conserved in the
      major facilitator superfamily (MFS). Three specific domains, which characterize
      organic ion transporters in animals, can also be observed in the predicted
      protein. In the non-stressed plants, northern analysis showed that PvOCT1 is
      strongly expressed in roots and stems, while in situ hybridization revealed the
      presence of PvOCT1 transcripts in phloem cells. In roots PvOCT1 transcript levels
      transitorily increased after one hour of dehydration and then dramatically
      decreased. This decrease was associated with enhanced abundance of PvNeED1 mRNA
      encoding the enzyme thought to catalyze the limiting step of abscisic acid
      biosynthesis.

PMID- 12602866
TI  - The cryptic enhancer elements of the tCUP promoter.
AB  - Examination of the tCUP cryptic promoter from tobacco demonstrates that cryptic
      gene regulatory elements in the plant genome are functionally equivalent to
      elements responsible for the expression of plant genes. They are also organized
      in a similar fashion. Analysis of the expression pattern of the GUS reporter gene
      in transgenic Arabidopsis plants revealed that all of the information needed for
      strong constitutive expression was located in the truncated, -394tCUP promoter
      fragment. A series of 5' deletion and linker-scan mutagenesis constructs
      identified two separate enhancer elements. A long AT-rich region was identified
      between positions -350 and -161 bp relative to the transcription start site. 5'
      deletions that removed this A/T-rich fragment resulted in a significant decrease
      in promoter activity; whereas, oligomerization enhanced activity. A 21 bp
      sequence (TAGCCCCAATTTCAAATTCAA) spanning nucleotides -150 to -130 relative to
      transcription start site was also identified in a similar fashion and defined a
      novel cryptic constitutive enhancer element (Cce). Electrophoretic mobility-shift
      assays showed that tobacco nuclear proteins that interacted strongly with the
      tCUP promoter bound specifically to the 21-bp Cce element, suggesting that this
      sequence is probably a binding site(s) for transcription factors. The Cce element
      was dependent on the AT-rich element for activity indicating combinatorial
      control. The combined effects of the A/T rich and Cce elements appear to be
      responsible for the constitutive transcriptional activity of the tCUP promoter.

PMID- 12602867
TI  - Light-dependent induction of proline biosynthesis by abscisic acid and salt
      stress is inhibited by brassinosteroid in Arabidopsis.
AB  - Osmotic stress-induced accumulation of proline, an important protective osmolyte
      in higher plants, is dependent on the expression of delta1-pyrroline-5
      carboxylate synthase (P5CS) and proline dehydrogenase (PDH) enzymes that catalyze
      the rate-limiting steps of proline biosynthesis and degradation, respectively.
      Proline metabolism is modulated by differential regulation of organ specific
      expression of PDH and duplicated P5CS genes in Arabidopsis. Stimulation of
      proline synthesis by abscisic acid (ABA) and salt stress correlates with a
      striking activation of P5CS1 expression. By contrast, P5CS2 is only weakly
      induced, whereas PDH is inhibited to different extent by ABA and salt stress in
      shoots and roots of light-grown plants. Proline accumulation and light-dependent
      induction of PSCS1 by ABA and salt stress is inhibited in dark-adapted plants.
      During dark adaptation P5CS2 is also down-regulated, whereas PDH expression is
      significantly enhanced in shoots. The inhibitory effect of dark adaptation on
      PSCS1 is mimicked by the steroid hormone brassinolide. However, brassinolide
      fails to stimulate PDH, and inhibits P5CS2 only in shoots. Proline accumulation
      and induction of P5CS1 transcription are simultaneously enhanced in the ABA
      hypersensitive prl1 and brassinosteroid-deficient det2 mutants, whereas P5CS2
      shows enhanced induction by ABA and salt only in the det2 mutant. In comparison,
      the prl1 mutation reduces the basal level of PDH expression, whereas the det2
      mutation enhances the inhibition of PDH by ABA. Regulation of P5CS1 expression
      thus appears to play a principal role in controlling proline accumulation
      stimulated by ABA and salt stress in Arabidopsis.

PMID- 12602868
TI  - An interaction between an Arabidopsis poly(A) polymerase and a homologue of the
      100 kDa subunit of CPSF.
AB  - The Arabidopsis genome possesses a number of sequences that are predicted to
      encode proteins that are similar to mammalian and yeast polyadenylation factor
      subunits. One of these resides on chromosome V and has the potential to encode a
      polypeptide related to the 100 kDa subunit of the mammalian cleavage and
      polyadenylation specificity factor (CPSF). This gene encodes a ca. 2400
      nucleotide mRNA that in turn can be translated to yield a polypeptide that is 39%
      identical to the mammalian CPSF100 protein. Antibodies raised against the
      Arabidopsis protein recognized distinctive polypeptides in nuclear extracts
      prepared from pea and wheat germ, consistent with the hypothesis that the
      Arabidopsis protein is resident in a nuclear polyadenylation complex.
      Interestingly, the Arabidopsis CPSF100 was found to interact with a portion of a
      nuclear poly(A) polymerase. This interaction was attributable to a 60 amino acid
      domain in the CPSF100 polypeptide and the N-terminal 220 amino acids of the
      poly(A) polymerase. An analogous interaction has yet to be described in other
      eukaryotes. The interaction with PAP thus indicates that the plant CPSF100
      polypeptide is likely part of the 3'-end processing machinery, but suggests that
      this complex may function differently in plants than it does in mammals and
      yeast.

PMID- 12602870
TI  - A maize histone deacetylase and retinoblastoma-related protein physically
      interact and cooperate in repressing gene transcription.
AB  - In mammalian cells the product of the human retinoblastoma tumour suppressor gene
      (pRb) can recruit Rpd3-like histone deacetylases to repress transcription. In
      this study, we investigated whether this mechanism might also be relevant in
      plants and found both conserved and distinct features. The expression profiles of
      the Zea mays Rpd3-type histone deacetylase (ZmRpd3I) and the retinoblastoma
      related (ZmRBR1) homologues were analysed during endosperm development. GST pull
      down and immunoprecipitation experiments showed a physical interaction between
      ZmRBRI and ZmRpd3I. Because ZmRpd3I lacks a LXCXE motif, conserved in several pRb
      interacting proteins, we have mapped the amino acid domains involved in the
      ZmRBR1/ZmRpd3I interaction. Furthermore, we observed that ZmRbAp1, a maize member
      of the MSI/RbAp family, facilitated this protein interaction. Co-transformations
      of tobacco protoplasts with plasmids expressing ZmRBRI and ZmRpd3I showed that
      the two proteins cooperate in repressing gene transcription. Our findings
      represent the first indication that in plants a regulator of important biological
      processes, ZmRBRI, can recruit a histone deacetylase, ZmRpd3I, to control gene
      transcription.

PMID- 12602871
TI  - The Arabidopsis CLV3-like (CLE) genes are expressed in diverse tissues and encode
      secreted proteins.
AB  - Members of the receptor-like kinase gene family play crucial regulatory roles in
      many aspects of plant development, but the ligands to which they bind are largely
      unknown. In Arabidopsis, the receptor kinase CLAVATA1 (CLV1) binds to the small
      secreted polypeptide CLV3, and three proteins act as key elements of a signal
      transduction pathway that regulates shoot apical meristem maintenance. To better
      understand the signal transduction mechanisms involving small polypeptides, we
      are studying 25 Arabidopsis CLV3/ESR (CLE) proteins that share a conserved C
      terminal domain with CLV3 and three maize ESR proteins. Members of the CLE gene
      family were identified in database searches and only a few are known to be
      expressed. We have identified an additional member of the CLE gene family in
      Arabidopsis, which is more similar in gene structure to CLV3 than the other CLE
      genes. Phylogenetic analysis reveals that few of the putative CLE gene products
      are closely related, suggesting there may be little functional overlap between
      them. We show that 24 of the 25 Arabidopsis CLE genes are transcribed in one or
      more tissues during development, indicating that they do encode functional
      products. Many are widely expressed, but others are restricted to one or a few
      tissue types. We have also determined the sub-cellular localization of several
      CLE proteins, and find that they are exported to the plasma membrane or
      extracellular space. Our results suggest that the Arabidopsis CLE proteins, like
      CLV3, may function as secreted signaling molecules that act in diverse pathways
      during growth and development.

PMID- 12602869
TI  - Characterization of Arabidopsis plastid sigma-like transcription factors SIG1,
      SIG2 and SIG3.
AB  - The plastid genome is transcribed by nucleus-encoded (NEP) and plastid-encoded
      (PEP) RNA polymerases. PEP is a prokaryotic-type enzyme whose activity is
      regulated by sigma-like transcription initiation factors that are nucleus
      encoded. cDNAs coding for six different potential a-like factors have been cloned
      and sequenced recently. However, functional analyses of these factors are still
      limited. We have used an anti-sense approach in order to study the function of
      SIG1, SIG2 and SIG3. Only SIG2 anti-sense plants show a visible phenotype
      characterized by chlorophyll deficiency. Surprisingly, this phenotype is
      different from the phenotype of SIG2 knockout plants in that the chlorophyll
      deficiency is limited to cotyledons. In later developmental stages, the SIG2 anti
      sense plants can overcome SIG2 mRNA under-expression by adjusting SIG2 protein
      levels to that of wild-type plants, suggesting that SIG2 expression is also
      regulated at the post-transcriptional level. The efficient recovery of the wild
      type phenotype could also be supported by partial take-over of SIG2 function by
      one of the six other sigma factors. A good candidate for such substitution of
      SIG2 function represents SIG3. SIG3 is constitutively expressed during plant
      development and its specificity in promoter discrimination is less pronounced
      than that of SIG1 and SIG2. Finally, SIG3 protein is enhanced in SIG2 anti-sense
      plants when compared to wild-type plants. SIG2 is present as a soluble factor
      while SIG3 is partly attached to the plastid membranes. We suggest that membrane
      localization is necessary for efficient SIG3 function. Therefore, SIG3 cannot
      substitute for SIG2 function in early chloroplast biogenesis, when plastid
      membranes are not yet made up.

PMID- 12602873
TI  - Transient decreases in methylation at 5'-cCGG-3' sequences in potato (Solanum
      tuberosum L.) meristem DNA during progression of tubers through dormancy precede
      the resumption of sprout growth.
AB  - The 5-methylcytosine (5mC) content in DNA of tuber meristems isolated from field
      grown potatoes (Solanum tuberosum L.) was determined during a 7-month storage
      period at 3 degrees C for three growing/postharvest seasons. No significant
      changes in 5mC levels were noted genome-wide or within 5'-CG-3' dinucleotide
      sequences, 5'-CG-3' islands or 5'-CA(T)G-3' trinucleotide sequences during
      storage. However, a consistent but transient 50-70% decrease in methylation at
      both cytosines within 5'-CCGG-3' sequences was detected that peaked 112-194 days
      after harvest. This result was corroborated by methylation-sensitive amplified
      fragment length polymorphism analysis of meristem DNA. Similar to tuber meristems
      undergoing progression through natural dormancy, premature chemical termination
      of dormancy resulted in rapid, transient 5'-CCGG-3' demethylation in meristem
      DNA. Minimum methylation levels at this sequence preceded initiation of high
      levels of de novo DNA synthesis by two days. Cytosine methylation status was also
      followed in in vitro-generated potato microtubers during 7 months of post-harvest
      storage. As in DNA from tuber bud meristems, no changes in genome-wide 5mC
      content or methylation at 5'-CA(T)G-3' or 5'-CG-3' island sequences were noted in
      microtuber DNA. However, there was a transient 46% drop in methylation at 5'-CG
      3' dinucleotides concomitant with minimum levels of 5'-CCGG-3' methylation (30
      60% below those in dormant microtubers) 57-98 days after harvest. As microtubers
      exited dormancy, there were sustained three- and seven-fold increases in RNA and
      DNA synthesis rates, peaking on or after 98 days of storage, respectively.
      Together, these data demonstrate that demethylation of 5'-CCGG-3' sequences
      occurs independently of tuber age during dormancy progression and precedes
      transcriptional activation of genes leading to cell division and meristem growth
      in potatoes.

PMID- 12602872
TI  - IAA8 expression during vascular cell differentiation.
AB  - We report the characterization of a member of the auxin-induced IAA gene family
      from zinnia, designated zIAA8, which is expressed by mesophyll cells
      differentiating as tracheary elements in vitro. Transcription of zIAA8 is up
      regulated within 3 h after cell isolation in inductive medium, indicating that
      cells perceive and respond to growth factor stimulus early in culture. Transcript
      levels of zIAA8 remain high through 72 h of culture in medium containing auxin
      and cytokinin or auxin alone, but low in medium containing only cytokinin or
      control medium lacking growth factors, demonstrating auxin-specific induction and
      consistent with lack of desensitization to prolonged auxin stimulation. In situ
      localization shows zIAA8 is localized to primary vasculature, root tips, and
      nascent leaves in zinnia seedlings. The observation that zIAA8 is expressed
      during vascular development in planta supports the hypothesis that expression
      early in culture reflects early events during normal vascular differentiation.
      The promoter of Arabidopsis IAA8 drives expression of the GUS reporter in a
      pattern in Arabidopsis similar to that for zIAA8 in zinnia, suggesting
      conservation of cis regulatory elements between the species and confirming the
      results from in situ localization. The vascular expression pattern of the IAA8
      promoter in leaves mirrors the developmentally regulated auxin gradient in
      expanding leaf blades. The expression patterns of zIAA8 and IAA8 yield new
      insight into vascular development in vitro and in planta, and provide much needed
      markers for early vascular differentiation.

PMID- 12602874
TI  - Modulation of berberine bridge enzyme levels in transgenic root cultures of
      California poppy alters the accumulation of benzophenanthridine alkaloids.
AB  - California poppy (Eschscholzia californica Cham.) root cultures produce a variety
      of benzophenanthridine alkaloids, such as sanguinarine, chelirubine and
      macarpine, with potent biological activity. Sense and antisense constructs of
      genes encoding the berberine bridge enzyme (BBE) were introduced into California
      poppy root cultures. Transgenic roots expressing BBE from opium poppy (Papaver
      somniferum L.) displayed higher levels of BBE mRNA, protein and enzyme activity,
      and increased accumulation of benzophenanthridine alkaloids compared to control
      roots transformed with a beta-glucuronidase gene. In contrast, roots transformed
      with an antisense-BBE construct from California poppy had lower levels of BBE
      mRNA and enzyme activity, and reduced benzophenanthridine alkaloid accumulation,
      relative to controls. Pathway intermediates were not detected in any transgenic
      root lines. Suppression of benzophenanthridine alkaloid biosynthesis using
      antisense-BBE also reduced the growth rate of the root cultures. Two-dimensional
      1H-NMR spectroscopy showed no difference in the abundance of carbohydrate
      metabolites in the various transgenic roots lines. However, transformed roots
      with low levels of benzophenanthridine alkaloids contained larger cellular pools
      of certain amino acids compared to controls. In contrast, cellular pools of
      several amino acids were reduced in transgenic roots with elevated
      benzophenanthridine alkaloid levels relative to controls. The relative abundance
      of tyrosine, from which benzophenanthridine alkaloids are derived, was only
      marginally altered in all transgenic root lines; thus, altering metabolic flux
      through benzophenanthridine alkaloid pathways can affect cellular pools of
      specific amino acids. Consideration of such interactions is important for the
      design of metabolic engineering strategies that target benzophenanthridine
      alkaloid biosynthesis.

PMID- 12602875
TI  - A serine carboxypeptidase gene (PsCP), expressed in early steps of reproductive
      and vegetative development in Pisum sativum, is induced by gibberellins.
AB  - A cDNA clone encoding a serine carboxypeptidase (PsCP), isolated from young
      fruits of Pisum sativum L., was used to study the temporal and spatial expression
      and hormonal regulation of serine carboxypeptidase during reproductive and
      vegetative development. In unpollinated pea ovaries PsCP transcript levels
      decreased during senescence. However, during early fruit development, PsCP
      transcript were accumulated in both pericarp and seeds, preferentially in the
      nucellus, with a polar distribution at the chalazal region of the embryo sac,
      suggesting a role in seed development. PsCP transcript levels increased also when
      fruit set was induced in unpollinated ovaries by gibberellins, although the
      distribution was uniform. PsCP expression was also induced by auxins but not
      cytokinins, indicating a selective hormonal regulation of PsCP transcription.
      Localization of PsCP transcript after pollination parallel reported changes in
      gibberellin distribution, suggesting that PsCP transcription in developing fruits
      and seeds is induced by gibberellins. PsCP is also expressed in developing
      seedlings but not in cotyledons, suggesting that it is not involved in the
      mobilization of storage materials. PsCP transcripts were suppressed by treatment
      of seedlings with paclobutrazol and restored by gibberellic acid (GA3) treatment.
      In addition, PsCP transcript levels decreased in etiolated pea seedlings when
      they were exposed to continuous light but not when exposed to light in the
      presence of GA3. These results indicate that PsCP transcript accumulation is
      induced by gibberellins in developing seedlings. This is the first report of a
      serine carboxypeptidase-like gene induced by gibberellins in reproductive and
      vegetative developing tissues in dicotyledoneous plants.

PMID- 12602876
TI  - Two chloroplastic protein translocation components, Tic110 and Toc75, are
      conserved in different plastid types from multiple plant species.
AB  - Most chloroplastic proteins are nuclear-encoded and must be transported into the
      organelle post-translationally. Proteinaceous components in the outer and inner
      envelope membranes of chloroplasts responsible for this import process were
      originally identified from pea seedlings. We sought to determine whether these
      proteins are conserved among different plant species other than pea and among
      different plastid types. We analyzed plant EST databases and found the presence
      of homologues to pea chloroplastic protein translocation components, Tic110 and
      Toc75, in both monocot and dicot species. Because these clones were obtained from
      various tissues, their presence in different types of plastids is proposed.
      Protein extracts were prepared from several plant species and from different
      plant tissues, and then probed with antisera raised against pea Tic110 and Toc75.
      The results support the idea that translocation components originally found in
      pea chloroplasts are conserved among different plant species and are present in
      various plastid types.

PMID- 12602877
TI  - Expression studies of SCA in lily and confirmation of its role in pollen tube
      adhesion.
AB  - During pollination the pollen tube grows into the style and toward the ovary via
      the transmitting tract. In lily the growth of pollen tubes involves tube cell
      adhesion to transmitting tract cells. We reported two molecules involved in this
      adhesion event. One is a pectic polysaccharide and the other, a 9 kDa basic
      protein named SCA for stigma/stylar cysteine-rich adhesin. SCA, which shows some
      identity with LTP (lipid transfer protein), was localized to the transmitting
      tract epidermis of the style where pollen tubes adhere. The present studies on
      the expression of SCA indicate that the protein has a similar expression pattern
      with LTP1 in Arabidopsis and that the protein is abundant in both the stigma and
      the style. For further proof of its role in pollen tube adhesion the activity of
      Escherichia coli-expressed protein has been studied in an in vitro adhesion assay
      system.

PMID- 12602878
TI  - Chlorophyll reduction in the seed of Brassica napus with a glutamate 1
      semialdehyde aminotransferase antisense gene.
AB  - Chlorophyll reduction in the seed of Brassica can be achieved by downregulating
      its synthesis. To reduce chlorophyll synthesis, we have used a cDNA clone of
      Brassica napus encoding glutamate 1-semialdehyde aminotransferase (GSA-AT) to
      make an antisense construct for gene manipulation. Antisense glutamate 1
      semialdehyde aminotransferase gene (Gsa) expression, directed by a Brassica napin
      promoter, was targeted specifically to the embryo of the developing seed.
      Transformants expressing antisense Gsa showed varying degrees of inhibition
      resulting in a range of chlorophyll reduction in the seeds. Seed growth and
      development were not affected by reduction of chlorophyll. Seeds from selfed
      transgenic plants germinated with high efficiency and growth of seedlings was
      vigorous. Seedlings from T2 transgenic lines segregated into three distinctive
      phenotypes: dark green, light green and yellow, indicating the dominant
      inheritance of Gsa antisense gene. These transgenic lines have provided useful
      materials for the development of a low chlorophyll seed variety of B. napus.

PMID- 12602879
TI  - Efficient male germ line transformation for transgenic tobacco production without
      selection.
AB  - Microspores at late uninucleate/early binucleate stages were isolated from flower
      buds of tobacco (Nicotiana tabacum L.) and in vitro culture methods optimised for
      their maturation to fully functional viable pollen which, after application to
      the stigma of emasculated plants in situ, led to the generation of large numbers
      of seed. Efficient protocols were established for the biolistic introduction of a
      construct containing a reporter gene and selectable marker into these microspores
      and hence, after in vitro maturation and in situ fertilisation, for the
      generation of transgenic plants. Stable transformants of low copy number were
      generated by this procedure. The efficiency of transformation achieved allows the
      production of large numbers of transgenic plants without selection, dispensing
      with the requirement for a selectable marker in plant transgenesis.

PMID- 12602880
TI  - Abnormal 'wrinkled' cell walls and retarded development of transgenic Arabidopsis
      thaliana plants expressing endo-1,4-beta-glucanase (cell) antisense.
AB  - Transgenic Arabidopsis thaliana plants expressing cel1 antisense exhibit reduced
      levels of cel1 mRNA and protein compared with wild-type plants. The former
      display significant alterations in their phenotype. cel1 antisense plants have
      shorter stems and roots and are mechanically weaker than their wild-type
      counterparts. In cel1 antisense plants, the cell wall structure is markedly
      disrupted: both fluorescent confocal microscopy and scanning electron microscopy
      revealed 'wrinkled' cell walls, thus indicating that CEL1 plays an important role
      in cell wall relaxation during cell growth and expansion. In cel1 antisense
      plants, the number of xylem elements per bundle is smaller than in the wild-type.
      In addition, both xylem elements and interfascicular fibers are significantly
      less lignified in the former. It is suggested that in A. thaliana, abnormal cell
      wall deposition affected by CEL1 depletion is associated not only with cell
      growth, but also with the differentiation process in the vascular and supporting
      tissues.

PMID- 12602881
TI  - Arrest of chlorophyll synthesis and differential decrease of Photosystems I and
      II in a cyanobacterial mutant lacking light-independent protochlorophyllide
      reductase.
AB  - The chlL gene encodes one subunit of the light-independent protochlorophyllide
      reductase. A chlL-lacking mutant of the cyanobacterium Plectonema boryanum is
      unable to synthesize chlorophyll (Chl) in the dark, causing Chl synthesis to
      become light-dependent as in angiosperms. When the mutant cells were cultivated
      heterotrophically in the dark, Chl synthesis was arrested and the Chl content
      decreased exponentially in reverse profile to cell propagation, indicating that
      most of the pre-existing Chl was recruited for daughter cells. During this
      'etiolating' process the Chl content became less than 0.5% of the original level.
      In parallel to this there was a decrease in the activity of Photosystem I (PSI),
      the amount of its core Chl-binding subunits, PsaA/PsaB, and a peripheral subunit,
      PsaC. Levels of transcripts for these subunits were not significantly changed
      upon the arrest of Chl synthesis. In contrast, Photosystem II (PSII) was
      maintained to a significant extent in terms of activity and protein levels of D1
      and CP47 until a late stage of the etiolation, implying that PSII is newly
      synthesized though Chl synthesis was arrested. Low-temperature (77 K)
      fluorescence spectral analysis supported a selective decrease in Chl associated
      with PSI. Taken together, it is suggested that the pre-existing Chl molecules in
      periphery of PSI could be released and re-distributed for PSII biosynthesis in
      the etiolating cyanobacterial cells.

PMID- 12602882
TI  - Functional characterisation of a cytokinin oxidase gene DSCKX1 in Dendrobium
      orchid.
AB  - Cytokinin oxidase plays an important role in the cytokinin regulatory processes.
      We have cloned a novel putative cytokinin oxidase, DSCKX1 (Dendrobium Sonia
      cytokinin oxidase), by mRNA differential display from shoot apices of Dendrobium
      Sonia cultured in the presence of BA. The DSCKX1 gene appears to have three
      alternative splicing forms and its expression of DSCKX1 was induced in a tissue
      specific manner by cytokinins. In transgenic orchid plants overexpressing DSCKX1,
      the elevated level of cytokinin oxidase activity was accompanied by a reduction
      of cytokinin content. These plants exhibited slow shoot growth with numerous and
      long roots in vitro. Their calli also showed decreased capability of shoot
      formation. Conversly, antisense transgenic plants showed rapid proliferation of
      shoots and inhibition of root growth combined with a higher endogenous cytokinin
      content than wild-type plants. Thus DSCKX1 appears to play an important role on
      cytokinin metabolism and the related developmental programmes in orchid.

PMID- 12602883
TI  - Identification of water-deficit responsive genes in maritime pine (Pinus pinaster
      Ait.) roots.
AB  - Root adaptation to soil environmental factors is very important to maritime pine,
      the main conifer species used for reforestation in France. The range of climates
      in the sites where this species is established varies from flooded in winter to
      drought-prone in summer. No studies have yet focused on the morphological,
      physiological or molecular variability of the root system to adapt its growth to
      such an environment. We developed a strategy to isolate drought-responsive genes
      in the root tissue in order to identify the molecular mechanisms that trees have
      evolved to cope with drought (the main problem affecting wood productivity), and
      to exploit this information to improve drought stress tolerance. In order to
      provide easy access to the root system, seedlings were raised in hydroponic
      solution. Polyethylene glycol was used as an osmoticum to induce water deficit.
      Using the cDNA-AFLP technique, we screened more than 2500 transcript derived
      fragments, of which 33 (1.2%) showed clear variation in presence/absence between
      non stressed and stressed medium. The relative abundance of these transcripts was
      then analysed by reverse northern. Only two out of these 33 genes showed
      significant opposite behaviour between both techniques. The identification and
      characterization of water-deficit responsive genes in roots provide the emergence
      of physiological understanding of the patterns of gene expression and regulation
      involved in the drought stress response of maritime pine.

PMID- 12602884
TI  - Cre recombinase expression can result in phenotypic aberrations in plants.
AB  - The cre recombinase gene was stably introduced and expressed in tomato, petunia
      and Nicotiana tabacum. Some plants expressing the cre gene driven by a CaMV 35S
      promoter displayed growth retardation and a distinct pattern of chlorosis in
      their leaves. Although no direct relation can be proven between the phenotype and
      cre expression, aberrant phenotypes always co-segregate with the transgene, which
      strongly suggests a correlation. The severity of the phenotype does not correlate
      with the level of steady-state mRNA in mature leaves, but with the timing of cre
      expression during organogenesis. The early onset of cre expression in tomato is
      correlated with a more severe phenotype and with higher germinal transmission
      frequencies of site-specific deletions. No aberrant phenotype was observed when a
      tissue-specific phaseolin promoter was used to drive the cre gene. The data
      suggest that for the application of recombinases in plants, expression is best
      limited to specific tissues and a short time frame.

PMID- 12602886
TI  - POR hits the road: import and assembly of a plastid protein.
AB  - The biosynthesis of chlorophyll is a strictly light-dependent multistep process
      in higher plants. The light-dependent step is catalysed by
      NADPH:protochlorophyllide oxidoreductase (POR, EC.1.6.99.1), which reduces
      protochlorophyllide (Pchlide) to chlorophyllide (Chlide). POR is nucleus-encoded
      and post-translationally imported into plastids. It has been proposed that the
      import of a POR protein isozyme (PORA) is totally dependent on Pchlide and uses a
      novel import pathway. This proposal is based on findings that PORA import only
      occurs in the presence of Pchlide and that the presence of overexpressed
      precursor of Rubisco small subunit (pSS), a protein which is known to use the
      general import pathway, does not outcompete PORA import. Another study
      demonstrated that POR precursor protein (pPOR) can be cross-linked to one of the
      components in the translocation machinery, Toc75, in the absence of Pchlide, and
      that its import can be outcompeted by the addition of the pSS. This indicates
      that pSS and pPOR may use the same translocation mechanism. Thus, POR does not
      necessarily need Pchlide for import--which is in contrast to earlier observations
      -and the exact POR import mechanism remains unresolved. Once in the stroma, the
      POR transit peptide is cleaved off and the mature POR protein is associated to
      the plastid inner membranes. Formation of the correct membrane-associated,
      thermolysin-protected assembly is strictly dependent of NADPH. As a final step,
      the formation of the NADPH-Pchlide-POR complex occurs. When POR accumulates in
      the membranes of proplastids, an attraction of monogalactosyl diacylglycerol
      (MGDG) can occur, leading to the formation of prolamellar bodies (PLBs) and the
      development of etioplasts in darkness.

PMID- 12602885
TI  - Transcriptional and biochemical regulation of a novel Arabidopsis thaliana
      bifunctional aspartate kinase-homoserine dehydrogenase gene isolated by
      functional complementation of a yeast hom6 mutant.
AB  - An aspartate kinase-homoserine dehydrogenase (AK-HSDH) cDNA of Arabidopsis
      thaliana has been cloned by functional complementation of a Saccharomyces
      cerevisiae strain mutated in its homoserine dehydrogenase (HSDH) gene (hom6). Two
      of the three isolated clones were also able to complement a mutant yeast
      aspartate kinase (AK) gene (hom3). Sequence analysis showed that the identified
      gene (akthr2), located on chromosome 4, is different from the previously cloned
      A. thaliana AK-HSDH gene (akthr1), and corresponds to a novel bifunctional AK
      HSDH gene. Expression of the isolated akthr2 cDNA in a HSDH-less hom6 yeast
      mutant conferred threonine and methionine prototrophy to the cells. Cell-free
      extracts contained a threonine-sensitive HSDH activity with feedback properties
      of higher plant type. Correspondingly, cDNA expression in an AK-deficient hom3
      yeast mutant resulted in threonine and methionine prototrophy and a threonine
      sensitive AK activity was observed in cell-free extracts. These results confirm
      that akthr2 encodes a threonine-sensitive bifunctional enzyme. Transgenic
      Arabidopsis thaliana plants (containing a construct with the promoter region of
      akthr2 in front of the gus reporter gene) were generated to compare the
      expression pattern of the akthr2 gene with the pattern of akthr1 earlier
      described in tobacco. The two genes are simultaneously expressed in meristematic
      cells, leaves and stamens. The main differences between the two genes concern the
      time-restricted or absent expression of the akthr2 gene in the stem, the
      gynoecium and during seed formation, while akthr1 is less expressed in roots.

PMID- 12602887
TI  - G-box binding coincides with increased Solanum melongena cysteine proteinase
      expression in senescent fruits and circadian-regulated leaves.
AB  - We have previously shown that SmCP, the gene encoding Solanum melongena cysteine
      proteinase, is expressed during developmental events associated with programmed
      cell death (PCD) suggesting its involvement in protein degradation during these
      events (Xu and Chye, Plant Journal 17 (1999) 321-327). Here, we investigated the
      regulation of SmCP expression and showed that it is ethylene-inducible and is
      under circadian control. This circadian rhythm is entrained by light/dark (LD)
      cycling with peak expression in the late light period, as opposed to that in
      early light for rbcS, suggesting that protein degradation and photosynthesis are
      temporally separated by circadian control. Northern blot analysis shows that the
      pattern of ethylene induction of SmCP is consistent with our previous observation
      of its significantly increased expression at leaf senescence and fruit ripening
      when endogenous ethylene is abundant. To further understand SmCP regulation, we
      have cloned the SmCP promoter and identified a G-box (CACGTG) at -85/-80 by DNase
      I footprinting analysis of the -221/+17 region. Its specific interaction with
      nuclear proteins in S. melongena leaves and fruits was confirmed by competitive
      electrophoretic mobility shift assays using oligonucleotides containing the G-box
      and mutant derivatives. G-box binding activity was stronger in senescent than
      young fruits. In circadian-regulated leaves, stronger binding activity coincided
      with peak circadian expression of SmCP. This correlation between binding activity
      and expression suggests that G-box binding factors enhance SmCP transcription and
      that the G-box likely plays a role in circadian regulation of genes affected by
      LD cycling.

PMID- 12602888
TI  - Expression profiles of the Arabidopsis WRKY gene superfamily during plant defense
      response.
AB  - WRKY proteins are a recently identified class of DNA-binding proteins that
      recognize the TTGAC(C/T) W-box elements found in the promoters of a large number
      of plant defense-related genes. With oligo molecules containing the W-box
      sequences as probes, we detected a number of WRKY DNA-binding activities in
      Arabidopsis that were induced by salicylic acid (SA). Search of the Arabidopsis
      genome identifies 72 genes encoding proteins characteristic of WRKY DNA-binding
      transcription factors that can be divided into three groups based on the number
      and structures of their WRKY zinc-finger motifs. Northern blotting analysis
      revealed that 49 of the 72 AtWRKY genes were differentially regulated in the
      plants infected by an avirulent strain of the bacterial pathogen Pseudomonas
      syringae or treated by SA. These pathogen- and/or SA-regulated WRKY genes can be
      further categorized into groups based on their expression patterns in both wild
      type plants and mutants defective in defense signaling pathways. Inspection of
      the 5' sequences upstream of the predicated translation start sites revealed a
      substantial enrichment of W boxes in the promoters of pathogen- and/or SA
      regulated Arabidopsis WRKY genes. These results suggest that defense-regulated
      expression of WRKY genes involves extensive transcriptional activation and
      repression by its own members of the transcription factor superfamily.

PMID- 12602889
TI  - Role of an ABI3 homologue in dormancy maintenance of yellow-cedar seeds and in
      the activation of storage protein and Em gene promoters.
AB  - ABI3/VP1 proteins are members of a large group of transcription factors that act
      as intermediaries in regulating abscisic acid (ABA)-responsive genes during seed
      development, including those involved in reserve deposition, acquisition of
      desiccation tolerance and dormancy induction. CnABI3, an ABI3/VP1 gene homologue
      was recently cloned from yellow cedar, a conifer species that produces seeds that
      are deeply dormant at maturity. Here, we investigated whether the conifer
      ABI3/VP1 gene homologue shares characteristics with its angiosperm counterparts.
      CnABI3 was synthesized exclusively in seeds, with no detectable protein in leaves
      and roots. Stable expression of the CnABI3 gene in two transgenic tobacco lines
      previously transformed with chimeric constructs (vicilin and napin 5' regions
      linked to a beta-glucuronidase (GUS) gene-coding region) showed that the ectopic
      expression of the CnABI3 protein strongly activated both the vicilin and napin
      storage protein gene promoters in leaves and other vegetative tissues. GUS
      activities were up to more than 1000-fold of those in control plants. ABA had a
      synergistic effect, further enhancing GUS activity levels. When expressed
      transiently in yellow-cedar embryos, CnABI3 activated the expression of a
      chimeric Em-GUS gene in the presence of ABA. The role of CnABI3 in dormancy
      maintenance of yellow-cedar seeds was examined by monitoring the expression of
      the CnABI3 gene at the mRNA and protein levels before, during and after dormancy
      termination. CnABI3 protein was present in the megagametophyte and embryo of
      dormant mature and warm stratified seed, but declined during subsequent moist
      chilling, a treatment effective in breaking dormancy. In contrast, the protein
      was preserved (albeit in lower amounts) in seeds subjected to a control treatment
      (12 weeks in warm, moist conditions) that is ineffective in breaking dormancy. A
      decline in CnABI3 gene transcripts was also positively correlated with dormancy
      breakage, but did not occur during moist chilling itself, but rather during
      subsequent germination, indicating potential control at the post-transcriptional
      level.

PMID- 12602890
TI  - Association of decreased expression of a Myb transcription factor with the TPD
      (tapping panel dryness) syndrome in Hevea brasiliensis.
AB  - TPD (tapping panel dryness) is a complex physiological syndrome widely found in
      rubber tree (Hevea brasiliensis) plantations, which causes severe yield and crop
      losses in natural rubber-producing countries. The molecular mechanism underlying
      TPD is not known and there is presently no effective prevention or treatment for
      this serious disease. To investigate the molecular mechanism of TPD, we isolated
      and characterized genes for which the change of expression is associated with
      TPD. We report here the identification and characterization of a Myb
      transcription factor HbMyb1. HbMyb1 is expressed in leaves, barks, and latex of
      rubber trees, but its expression is significantly decreased in barks of TPD
      trees. Our results suggest that the expression of HbMyb1 is likely associated
      with TPD and that the function of HbMyb1 is associated with the integrity of bark
      tissue of rubber trees.

PMID- 12602891
TI  - OsSEND-1: a new RAD2 nuclease family member in higher plants.
AB  - A novel endonuclease, a new member of the RAD2 nuclease family, has been
      identified from the higher plant, rice (Oryza sativa L. cv. Nipponbare), and
      designated as OsSEND-1. The open reading frame of the OsSEND-1 cDNA encoded a
      predicted product of 641 amino acid residues with a molecular weight of 69.9 kDa.
      The encoded protein showed a relatively high degree of sequence homology with the
      RAD2 nuclease family proteins, especially RAD2 nuclease, but it differed markedly
      from FEN-1, XPG or HEX1/EXO1. The N- and I-domains in the family were highly
      conserved in the OsSEND-1 sequence. The protein was much smaller than XPG, but
      larger than HEX1/EXO1 and FEN-1. The genome sequence was composed of 14 exons,
      and was localized at the almost terminal region of the short arm of chromosome 8.
      Northern blotting and in situ hybridization analyses demonstrated preferential
      expression of OsSEND-1 mRNA in proliferating tissues such as meristem. The mRNA
      level of OsSEND-1 was induced by UV and DNA-damaging agent such as MMS or H2O2,
      indicating that OsSEND-1 has some roles in the repair of many types of damaged
      DNA. The recombinant peptide showed endonuclease activity.

PMID- 12602892
TI  - Salinity stress-tolerant and -sensitive rice (Oryza sativa L.) regulate AKT1-type
      potassium channel transcripts differently.
AB  - In the indica rice (Oryza sativa L.) a cDNA was characterized that encoded OsAKT1
      homologous to inward-rectifying potassium channels of the AKT/KAT subfamily.
      Transcript analysis located OsAKT1 predominantly in roots with low abundance in
      leaves. Cell-specificity of OsAKT expression was analyzed by in situ
      hybridizations. In roots, strongest signals were localized to the epidermis and
      the endodermis, whereas lower transcript levels were detected in cells of the
      vasculature and the cortex. In leaves, expression was detected in xylem
      parenchyma, phloem, and mesophyll cells. Transcriptional regulation and cell
      specificity of OsAKT1 during salt stress was compared in rice lines showing
      different salinity tolerance. In the salt-tolerant, sodium-excluding varieties
      Pokkali and BK, OsAKT1 transcripts disappeared from the exodermis in plants
      treated with 150 mM NaCl for 48 h but OsAKT1 transcription was not repressed in
      these cells in the salt-sensitive, sodium-accumulating variety IR29.
      Significantly, all lines were able to maintain potassium levels under sodium
      stress conditions, while sodium concentrations in the leaves of IR29 increased 5
      10-fold relative to the sodium concentration in BK or Pokkali. The divergent,
      line-dependent and salt-dependent, regulation of this channel does not
      significantly affect potassium homeostasis under salinity stress. Rather,
      repression in Pokkali/BK and lack of repression in IR29 correlate with the
      overall tolerance character of these lines.

PMID- 12602893
TI  - Multi-functional T-DNA/Ds tomato lines designed for gene cloning and molecular
      and physical dissection of the tomato genome.
AB  - In order to make the tomato genome more accessible for molecular analysis and
      gene cloning, we have produced 405 individual tomato (Lycopersicon esculentum)
      lines containing a characterized copy of pJasm13, a multifunctional T
      DNA/modified Ds transposon element construct. Both the T-DNA and the Ds element
      in pJasm13 harbor a set of selectable marker genes to monitor excision and
      reintegration of Ds and additionally, target sequences for rare cutting
      restriction enzymes (I-PpoI, SfiI, NotI) and for site-specific recombinases (Cre,
      FLP, R). Blast analysis of flanking genomic sequences of 174 T-DNA inserts
      revealed homology to transcribed genes in 69 (40%), of which about half are known
      or putatively identified as genes and ESTs. The map position of 140 individual
      inserts was determined on the molecular genetic map of tomato. These inserts are
      distributed over the 12 chromosomes of tomato, allowing targeted and non-targeted
      transposon tagging, marking of closely linked genes of interest and induction of
      chromosomal rearrangements including translocations or creation of saturation
      deletions or inversions within defined regions linked to the T-DNA insertion
      site. The different features of pJasm13 were successfully tested in tomato and
      Arabidopsis thaliana, thus providing a new tool for molecular/genetic dissection
      studies, including molecular and physical mapping, mutation analysis and cloning
      strategies in tomato and potentially, in other plants as well.

PMID- 12602894
TI  - Molecular and cellular characterisation of LjAMT2;1, an ammonium transporter from
      the model legume Lotus japonicus.
AB  - Two related families of ammonium transporters have been identified and partially
      characterised in plants in the past; the AMT1 and AMT2 families. Most attention
      has focused on the larger of the two families, the AMT1 family, which contains
      members that are likely to fulfil different, possibly overlapping physiological
      roles in plants, including uptake of ammonium from the soil. The possible
      physiological functions of AMT2 proteins are less clear. Lack of data on cellular
      and tissue location of gene expression, and the intracellular location of
      proteins limit our understanding of the physiological role of all AMT proteins.
      We have cloned the first AMT2 family member from a legume, LjAMT2;1 of Lotus
      japonicus, and demonstrated that it functions as an ammonium transporter by
      complementing a yeast mutant defective in ammonium uptake. However, like AtAMT2
      from Arabidopsis, and unlike AMT1 transporters from several plant species,
      LjAMT2;1 was unable to transport methylammonium. The LjAMT2;1 gene was found to
      be expressed constitutively throughout Lotus plants. In situ RNA hybridisation
      revealed LjAMT2;1 expression in all major tissues of nodules. Transient
      expression of LjAMT2;1-GFP fusion protein in plant cells indicated that the
      transporter is located on the plasma membrane. In view of the fact that nodules
      derive ammonium internally, rather than from the soil, the results implicate
      LjAMT2;1 in the recovery of ammonium lost from nodule cells by efflux. A similar
      role may be fulfilled in other organs, especially leaves, which liberate ammonium
      during normal metabolism.

PMID- 12602895
TI  - Biological and molecular comparison between localized and systemic acquired
      resistance induced in tobacco by a Phytophthora megasperma glycoprotein elicitin.
AB  - We have compared localized (LAR) and systemic (SAR) acquired resistance induced
      in tobacco by a hypersensitive response (HR) inducing Phytophthora megasperma
      glycoprotein elicitin. Three different zones were taken into account: LAR, SAR(T)
      and SAR(S). The LAR zone was 5-10 mm wide and surrounded the HR lesion. SAR(T)
      was the tissue of the elicitor-treated leaf immediately beyond the LAR zone. The
      systemic leaf was called SAR(S). Glycoprotein-treated plants showed enhanced
      resistance to challenge infection by tobacco mosaic virus (TMV). Disease
      resistance was similar in SAR(T) and SAR(S), and higher in LAR. The expression
      pattern, in glycoprotein-treated plants, of acidic and basic PR1, PR2, PR3 and
      PR5 proteins and of O-methyltransferases (OMT), enzymes of the phenylpropanoid
      pathway, was similar to that in TMV-infected plants. OMT was stimulated in LAR
      but not in SAR(T) and SAR(S). The four classes of acidic and basic PR proteins
      accumulated strongly in LAR. Reduced amounts of acidic PR1, PR2, PR3 and only
      minute amounts of basic PR2 and PR3 accumulated in SAR(T) and SAR(S). In
      glycoprotein-treated plants, expression of the acidic and basic PR proteins in
      LAR and SAR of transgenic NahG and ETR tobacco plants and in LAR of plants
      treated with inhibitors of salicylic acid accumulation and of ethylene
      biosynthesis indicated a salicylic acid-dependent signalling pathway for acidic
      isoform activation and an ethylene-dependent signalling pathway for basic isoform
      activation.

PMID- 12602896
TI  - Traumatic resin defense in Norway spruce (Picea abies): methyl jasmonate-induced
      terpene synthase gene expression, and cDNA cloning and functional
      characterization of (+)-3-carene synthase.
AB  - Picea abies (L.) Karst. (Norway spruce) employs constitutive and induced resin
      terpenoids as major chemical and physical defense-shields against insects and
      pathogens. In recent work, we showed that a suite of terpenoids, monoterpenoids
      and diterpenoids was induced in stems of Norway spruce after treatment of trees
      with methyl jasmonate (MeJA) (Martin et al., 2002). Increase of enzyme activities
      of terpenoid biosynthesis and accumulation of terpenoids was associated with MeJA
      induced de novo differentiation of xylem resin ducts. The formation of defense
      related traumatic resin ducts was also found in Norway spruce after attack by
      stem boring insects or after infestation with fungal pathogens. In the present
      study, we analyzed the traumatic resin response in Norway spruce further at the
      molecular genetic level. Treatment of trees with MeJA induced transient
      transcript accumulation of monoterpenoid synthases and diterpenoid synthases in
      stem tissues of Norway spruce. In screening for defense-related terpenoid
      synthase (TPS) genes from Norway spruce, a full-length monoterpenoid synthase
      cDNA, PaJF67, was isolated and the recombinant enzyme expressed in E. coli and
      functionally characterized in vitro. The cloned PaJF67 cDNA represents a new
      monoterpenoid synthase gene and the gene product was identified as 3-carene
      synthase. The enzyme encoded by PaJF67 forms stereospecifically (+)-3-carene (78%
      of total product) together with minor acyclic and cyclic monoterpenes, including
      the mechanistically closely related terpinolene (11% of total product). (+)-3
      Carene is a characteristic monoterpene of constitutive and induced oleoresin
      defense of Norway spruce and other members of the Pinaceae.

PMID- 12602897
TI  - Polygalacturonase: a candidate gene for the soft flesh and deciduous fruit
      mutation in Capsicum.
AB  - The soft flesh and deciduous fruit of pepper (Capsicum spp.) originated from the
      wild C. frutescens BG 2816 accession is a complete dominant trait controlled by
      the S gene. We constructed an F2 population from a cross of BG 2816 (SS) and the
      bell-type C. annuum cultivar Maor (ss) and determined that S cosegregated with
      the tomato fruit-specific endo-polygalacturonase (PG) gene. The soft flesh and
      deciduous fruit phenotypes were observed together in all F2 individuals,
      indicating a pleiotropic effect of PG on the two traits. We mapped S to pepper
      chromosome 10 in the region corresponding to that in which PG was previously
      mapped in tomato. Northern, RT-PCR and western analyses and enzyme activity
      assays, collectively, indicated that PG is not detected in green, breaker or red
      fruits of Maor, nor in green fruits of BG 2816. Accumulation of PG mRNA and
      protein was detected in the fruits of BG 2816, and it increased during ripening
      from breaker to red stages. The sequence analysis of partial PG cDNA isolated
      from BG 2816 revealed high homology (87% identity) with the tomato PG. The
      resemblance of the soft flesh and deciduous fruit phenotypes to PG-associated
      phenotypes in other fruit crops, the complete linkage between S and PG, and the
      greater expression of PG in the fruits of BG 2816 than in those of Maor, all
      strongly indicate that PG is a candidate gene for S.

PMID- 12602898
TI  - Characterization of transgenic rice plants over-expressing the stress-inducible
      beta-glucanase gene Gns1.
AB  - The Gns1 gene of rice (Oryza sativa L. japonica) encodes 1,3;1,4-beta glucanase
      (EC 3.2.1.73), which hydrolyzes 1,3;1,4-beta-glucosidic linkages on 1,3;1,4-beta
      glucan, an important component of cell walls in the Poaceae family. RNA and
      protein gel blot analyses demonstrated that blast disease or dark treatment
      induced the expression of the Gns1 gene. To assess the function of the Gns1 gene
      in disease resistance, we characterized transgenic rice plants constitutively
      expressing the Gns1 gene. The introduced Gns1 gene was driven by the CaMV 35S
      promoter and its products were found in the apoplast and accumulated in up to
      0.1% of total soluble protein in leaves. Although transgenic plants showed
      stunted growth and impaired root formation, fertility, germination, and
      coleoptile elongation appeared unaffected compared to non-transgenic control
      plants, indicating that Gns1 does not play a crucial role in rice germination and
      coleoptile elongation. When transgenic plants were inoculated with virulent blast
      fungus (Magnaporthe grisea), they developed many resistant-type lesions on the
      inoculated leaf accompanying earlier activation of defense-related genes PR-1 and
      PBZ1 than in control plants. Transgenic plants spontaneously produced brown
      specks, similar in appearance to those reported for an initiation type of disease
      lesion-mimic mutants, on the third and fourth leaves and occasionally on older
      leaves without inoculation of pathogens. Expression of the two defense-related
      genes was drastically increased after the emergence of the lesion-mimic
      phenotype.

PMID- 12602900
TI  - Evaluation of lymph node status in male breast cancer patients: a role for
      sentinel lymph node biopsy.
AB  - Sentinel lymph node (SLN) biopsy is rapidly emerging as an alternative to
      axillary lymph node dissection (ALND) for many female breast cancer patients. In
      contrast, ALND remains the standard of care for male breast cancer patients with
      similar tumors. We evaluated the results of SLN biopsy in male breast cancer
      patients with clinically negative axillae. This study included all male breast
      cancer patients who underwent SLN biopsy at our institution between October 1999
      and 2000. All patients had negative axillae on clinical examination and
      sonography. All patients underwent preoperative lymphoscintigraphy followed by
      SLN biopsy performed using a combination of isosulfan blue dye and technetium Tc
      99m sulfur colloid. Tc 99m sulfur colloid was injected at a dose of 2.5 mCi 24 h
      before surgery (four patients) or 0.5 mCi 2-4 h before surgery (three patients).
      Intraoperatively, 5 ml of 1% isosulfan blue was injected adjacent to the breast
      tumor or biopsy cavity prior to SLN biopsy. A gamma probe was used
      intraoperatively in order to localize SLNs. Any node that was blue or associated
      with ex vivo radioactivity counts at least 10 times higher than the axillary
      background counts was defined as a SLN. SLNs were assessed intraoperatively using
      touch preparation cytologic examination. Completion ALND was performed if nodal
      metastases were identified. Seven patients, 44-76 years of age, were included in
      the study. Preoperative lymphoscintigraphy identified SLNs in five patients.
      Intraoperatively, SLNs were identified in all seven patients. SLNs were
      identified in six patients using the gamma probe and in all seven patients using
      blue dye. The mean number of SLNs encountered was 2.9. Findings on touch
      preparation cytology correlated with findings on the final pathological analysis
      examination in all patients. One patient had a positive SLN, this patient had
      three additional positive nodes identified in his completion ALND specimen. Three
      patients with negative SLNs had been elected preoperatively to undergo ALND
      regardless of findings on SLN biopsy, no positive lymph nodes were identified in
      the ALND specimens from these patients. These findings compare favorably with
      findings reported in the literature regarding SLN biopsy in female breast cancer
      patients. Blue dye injection and radioisotope injection were complementary. SLN
      biopsy should be considered for axillary staging in male breast cancer patients
      with clinically negative axillae.

PMID- 12602899
TI  - Sequential doxorubicin and docetaxel as first-line treatment in metastatic breast
      cancer: a GEICAM-9801 phase II study.
AB  - PURPOSE: To evaluate the efficacy and the toxicity profile of the sequential
      administration of doxorubicin and docetaxel as first-line chemotherapy in
      metastatic breast cancer (MBC). PATIENTS AND METHODS: Eighty-one patients
      received a total of 436 cycles of chemotherapy: 236 of doxorubicin (75 mg/m2) and
      200 of docetaxel (100 mg/m2 every 21 days). The first 35 patients received
      doxorubicin every 14 days with G-CSF support, and in the other 46 cases
      doxorubicin was administered every 21 days without G-CSF. RESULTS: After entire
      treatment the overall response rate was 65% (18 complete responses). With a
      median follow-up of 19 months (range, 1-48 months), the median time to
      progression was 11.3 months and the median survival time was 31 months. As
      expected, febrile neutropenia was the most important toxicity and it appeared in
      26 cycles (6%) and 19 patients (23%). In the patients that received doxorubicin
      every 14 days, the febrile neutropenia incidence was higher during docetaxel
      treatment, especially after its first administration. CONCLUSIONS: The dose and
      schedule of doxorubicin and docetaxel used in this trial seems to be active in
      first-line treatment of patients with MBC. The toxicity profile appears to be
      better than observed with concomitant schedules.

PMID- 12602901
TI  - The expression of growth hormone-releasing hormone (GHRH) and its receptor splice
      variants in human breast cancer lines; the evaluation of signaling mechanisms in
      the stimulation of cell proliferation.
AB  - Antagonists of growth hormone-releasing hormone (GHRH) inhibit growth of various
      human cancers including breast cancer, xenografted into nude mice or cultured in
      vitro. Splice variants (SVs) of receptors for GHRH have been found in several
      human cancers and cancer cell lines. The antiproliferative actions of GHRH
      antagonists could be mediated in part through these SVs of GHRH receptors. In
      this study we examined the expression of mRNA for GHRH and SVs of its receptors
      in human breast cancer cell lines MCF-7, MCF-7MIII, MDA-MB-231, MDA-MB-435, MDA
      MB-468, and T47D. mRNA for GHRH was present in all lines tested. mRNA for SV1
      isoform of GHRH receptors was found in MCF-7MIII, MDA-MB-468, and T47D; and for
      SV2 isoform in MCF-7MIII and T47D cell lines. In proliferation studies in vitro,
      the growth of T47D cells was stimulated by GHRH and dose-dependently inhibited by
      GHRH antagonist JV-1-38. H89 (protein kinase A inhibitor), bisindolylmaleimide I
      (protein kinase C [PKC] inhibitor) and verapamil (voltage-dependent calcium
      channel blocker) inhibited the GHRH-stimulated proliferation of T47D cells. The
      GHRH antagonist JV-1-38 suppressed the T47D cell growth in vitro stimulated by
      PKC activator (phorbol-12-myristate-13-acetate). The stimulation of T47D cells by
      GHRH was followed by an increase in cAMP production and GHRH antagonist JV-1-38
      competitively inhibited this effect. Our results suggest that SVs of GHRH
      receptors could mediate the responses to GHRH and GHRH antagonists in breast
      cancer through Ca2+-, cAMP- and PKC-dependent mechanisms. The presence of SV1 of
      GHRH receptors in human cancers provides a rationale for antitumor therapy based
      on the blockade of this receptor by specific GHRH antagonists.

PMID- 12602903
TI  - Cell proliferation, apoptosis, and expression of Bcl-2 and Bax in non-lactating
      human breast epithelium in relation to the menstrual cycle and reproductive
      history.
AB  - Cell proliferation, apoptosis, and the expression of Bcl-2 and Bax were
      investigated in breast tissue of healthy premenopausal women in order to study
      the effect of the menstrual cycle and reproductive history on the cell turnover
      in the non-lactating mammary gland epithelium. Immunohistochemistry was used to
      detect the proliferation-associated antigen Ki-67, as well as Bcl-2 and Bax.
      Apoptotic cells were identified by enzymatic labelling of fragmentized DNA (TUNEL
      technique) and morphologic analysis. Consistent with published data, the
      proliferative activity and the frequency of apoptotic events as detected by
      morphologic analysis was higher in the luteal than in the follicular phase of the
      menstrual cycle. Parity, lactation, and age correlated with lower proliferative
      activity, whereas the frequency of apoptosis was not significantly influenced by
      the reproductive history. Staining patterns for Bax and Bcl-2 showed
      characteristic changes due to the menstrual cycle with a maximum of
      immunoreactivity for Bcl-2 in the follicular phase and for Bax in the luteal
      phase. However, there was no statistically significant association between Bcl
      2/Bax immunoreactivity and menstrual cycle or reproductive parameters. We
      conclude that other molecular pathways than the Bax/Bcl-2 antagonism may
      additionally be involved in the regulation of apoptotic cell death in the breast
      epithelium. Knowledge of the entire complexity of apoptosis regulation is
      necessary to understand the observed effects of parity and lactation on mammary
      epithelial biology, and possibly to be able to influence pathological processes
      caused by an imbalance between cell renewal and elimination.

PMID- 12602902
TI  - Polymorphisms in steroid hormone pathway genes and mammographic density.
AB  - Mammographic density has been linked with exposure to endogenous and exogenous
      steroid hormones, and increased breast cancer risk. Variation in breast density
      may be due, in part, to polymorphisms in steroid hormone biosynthesis, metabolism
      and signaling genes. We conducted cross-sectional analyses within the Nurses'
      Health Study (n = 538), to investigate variation in mammographic breast density,
      by 10 polymorphisms in eight candidate genes (CYP17, CYP19, CYP1A1, CYP1B1, COMT,
      UGT1A1, AR, and AIB1). Breast density was assessed using a computer-assisted
      technique. We evaluated whether associations between variant alleles of these
      genes and breast density differed by menopause and postmenopausal hormone (PMH)
      use. Polymorphisms in CYP17, CYP19, CYP1B1, COMT CYP1A1, or AR were not
      associated consistently with breast density among premenopausal or postmenopausal
      women. Premenopausal women with the 7/7 UGT1A1 genotype had lower breast density
      (difference compared to the 6/6 genotype of: -16.5% density; p = 0.04). In
      contrast, postmenopausal women with the 7/7 UGT1A1 genotype had greater breast
      density compared to those with the 6/6 genotype (+6.2% density; p = 0.05); this
      association was strongest among current PMH users (+13.0% density; p = 0.03). In
      analyses limited to postmenopausal women, breast density was also greater among
      women carrying short AIB1 alleles (< or = 26 glutamine repeats; +4.1% density; p
      = 0.04). Most of the variants in the candidate breast cancer genes evaluated in
      this study are not strong predictors of breast density. However, our findings of
      differences in associations for UGT1A1 and AIB1 genotypes with breast density by
      menopausal status needs additional corroboration.

PMID- 12602904
TI  - Sex hormone-induced mammary carcinogenesis in female Noble rats: detection of
      differentially expressed genes.
AB  - Breast cancer is the most common cancer and the second most frequent cause of
      cancer death in women. Epidemiological data has recognized that an increased
      cumulative exposure to estrogen is the common tie linking most of the established
      risk factors for breast cancer. Sex hormone-induced mammary gland carcinogenesis
      of the Noble rat (using testosterone and 17beta-estradiol) resembles that of the
      human counterpart in its growth pattern as well as the histopathology of the
      tumors induced. This model may provide a paradigm for examination of genetic
      alterations and changes in gene expression between different histological groups
      and to make inferences about the role of known and putative oncogenes and tumor
      suppressor genes. We studied the gene expression profile during sex hormone
      induced mammary carcinogenesis using a cDNA array technique; the results were
      further confirmed by RT-PCR, western blotting and immunohistochemical analyses.
      From the 10 differentially expressed genes identified, we have studied four
      highly overexpressed genes, two cell cycle/growth control regulators, the cyclins
      D1 and D2, a growth factor, IGF-2 and a cytokine TNF-alpha. Cyclins D1 and D2
      were highly expressed in the nuclei of carcinoma cells but at low levels in the
      nuclei of the hyperplastic and normal mammary tissue. IGF-2 was found to
      expressed in the cytoplasm of the carcinoma cells but not in the stromal cells.
      Western blot showed expression of big IGF-2 consistent with the tumor derived
      truncated forms of pro-IGF-2. The matured circulating IGF-2 at 7.5 kDa identified
      in the serum was not expressed in any of the breast tissue samples. TNF-alpha
      expression was found not only in the macrophages but also in the mammary
      carcinoma cells. The result of the present study provides some information on the
      molecular basis of this sex hormone-induced mammary carcinogenesis and the role
      of these proteins in tumor progression.

PMID- 12602906
TI  - The prognostic value of the mitotic activity index in patients with primary
      breast cancer who were not treated with adjuvant systemic therapy.
AB  - BACKGROUND: At the St Gallen meeting of 2001 it was agreed to select high-risk
      patients for adjuvant systemic therapy by lymph node status, tumor size, age,
      hormone receptor status, and histological grade. In The Netherlands it was chosen
      to use either the histological grade or the mitotic activity index (MAI). The aim
      of this study was to retrospectively evaluate the independent prognostic value of
      the MAI in primary breast cancer patients, who were not treated with adjuvant
      systemic therapy, on relapse-free survival (RFS) and overall survival (OS).
      PATIENTS AND METHODS: The data of 137 systemically untreated patients with
      primary breast cancer diagnosed between 1992 and 1996, of whom MAI was assessed,
      were retrospectively collected. The MAI was correlated to classical prognostic
      factors and we determined the prognostic value of the MAI, the histological grade
      and other prognostic factors. RESULTS: The median observation time was 4.2 years.
      The MAI showed a positive correlation to lymph node status (P < 0.001) and a
      negative correlation to age (P = 0.005), menopausal status (P < 0.001) and the ER
      and PgR status (r(s) = -0.390 [ER], r(s) = -0.440 [PgR], both P < 0.001). A high
      MAI (> or = 15) predicted a reduced RFS and OS in the Kaplan-Meier analysis (P =
      0.0070 and P = 0.0017, respectively). Also in the multivariate analysis, the MAI
      showed to be an independent predictor of poor RFS (P = 0.035), in addition to
      lymph node status. However, the MAI did not predict for OS, in contrast to tumor
      size and lymph node status. CONCLUSION: The present study confirms that the MAI
      is an independent prognostic factor for RFS, but not for OS and may be useful for
      daily clinical practice.

PMID- 12602905
TI  - Development and characterization of a progressive series of mammary
      adenocarcinoma cell lines derived from the C3(1)/SV40 Large T-antigen transgenic
      mouse model.
AB  - We have developed four new mammary adenocarcinoma cell lines from the C3(1)/SV40
      Large T-antigen (Tag) transgenic mouse model: M28N2 and M27H4 (weakly
      tumorigenic), M6 (carcinoma), and M6C (metastatic). The C3(1) promoter directs
      Tag expression to the mammary epithelium and 100% of female C3(1)/Tag transgenic
      mice develop mammary adenocarcinoma in a predictable and progressive manner. The
      cell lines we developed from this model are demonstrated to be of epithelial
      origin and display growth rates, both in vitro and following subcutaneous
      inoculation into nude mice, that are consistent with their representative stage
      of tumor progression. The more tumorigenic cell lines, M6 and M6C, both express
      the sodium/iodide symporter, a mammary carcinoma cell marker with potential
      therapeutic and diagnostic applications. All of the cell lines express estrogen
      receptor (ER) alpha and ER beta mRNA, and Western blot analysis demonstrates that
      the ER alpha protein is down-regulated in the M6 and M6C cell lines. M28N2 cells
      also express progesterone receptor (PgR), which is very unusual in a mouse
      mammary carcinoma cell line. In addition, all of the cell lines display growth
      inhibition when plated in media supplemented with charcoal-stripped fetal calf
      serum (CS FBS). When CS FBS is supplemented with beta estradiol or the progestin
      MPA, no significant difference in growth rates is observed relative to growth in
      CS FBS. The development and characterization of a progressive series of new
      mammary carcinoma cell lines will aid in the study of mammary carcinoma
      progression both in vitro and in vivo.

PMID- 12602907
TI  - Matrix metalloproteinase-2 (MMP-2) in T(1-2)N0 breast carcinoma.
AB  - Node-negative breast carcinoma is associated with favorable prognosis in breast
      carcinoma. Despite therapy some early stage breast carcinoma patients still die
      of metastatic disease. Prognostic factors are needed to define patients for new
      treatment modalities. Matrix metalloproteinase-2 (MMP-2) has been shown to be
      associated with tumor invasiveness and MMP-2 negativity has been linked with
      favorable prognosis in node-positive breast carcinoma. Here, the prognostic value
      of MMP-2 in node-negative, T(1-2) breast carcinoma patients was evaluated in 137
      cases. Expression of MMP-2 was studied in paraffin-embedded tissue sections from
      primary tumors using a specific monoclonal antibody for MMP-2 in an avidin-biotin
      peroxidase immunohistochemical staining. Postoperative survival rates were
      analyzed by the Kaplan-Meier method and the differences between the survival were
      compared by means of log-rank test. All MMP-2 negative patients were alive during
      the 10 years' follow-up, compared to the 87% survival in the MMP-2 positive
      group. MMP-2 negativity seemed to improve the prognosis in the estrogen receptor
      negative group. The differences did not achieve statistical significance due to
      few events in the node-negative group. In conclusion, we suggest that MMP-2
      negativity may be linked with a favorable prognosis in node-negative breast
      carcinoma.

PMID- 12602908
TI  - Phase I-II parallel study of docetaxel on a bimonthly schedule in refractory
      metastatic breast carcinoma.
AB  - BACKGROUND: The 3-week schedule with docetaxel (DTC) 75-100 mg/2 is associated
      with severe neutropenia, gastro-intestinal side-effects and fluid retention in a
      significant proportion of patients, which may be of concern in more elderly or
      poor performance status patients. A phase I-II trial was carried out to test the
      feasibility and the activity of a new bimonthly schedule of DCT. PATIENTS AND
      METHODS: The trial included a phase I study which aimed at the identification of
      dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a
      bimonthly schedule. The first group of three patients received DCT 40 mg/m2, and
      in absence of DLT, DCT dosage was escalated by 10 mg/m2/cycle until DLT was
      reached. In the phase II study, patients were randomized to receive: (a) standard
      3-weekly DCT at the dose of 75 mg/m2 (calibration arm); or (b) bimonthly schedule
      with DCT at the dose recommended in the phase I study. All patients were
      pretreated with chemotherapy, mostly anthracycline-based regimens, for
      advanced/metastatic disease. Analysis of response rates, toxicity, and dose
      intensity were the main aims of the study. RESULTS: The DLT was represented by
      severe myelosuppression which was recorded in all patients treated at 70 mg/m2
      dose level. Therefore, the MTD was 60 mg/m2 on a bimonthly schedule. However, the
      dose recommended for the phase II trial was 50 mg/m2, because no difference in
      delivered dose-intesity was seen between the 50 and 60 mg/m2 dose levels, and the
      latter dosage was still associated with grade 3 neutropenia in most patients. The
      parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m2)
      allows to deliver the same dose-intensity of DCT 75 mg/m2 every 3 weeks. Grade 3
      4 side-effects were rather infrequent in patients treated with the bimonthly
      schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m2
      bimonthly and the DCT 75 mg/m2 every 3 weeks, respectively. CONCLUSIONS: Data
      achieved in the phase I part of the study showed that DCT 50 mg/m2 every 15 days
      is the recommended dose for phase II studies, while results achieved in the phase
      II trial suggest that DCT 50 mg/m2 in a bimonthly schedule is active as second
      line chemotherapy for MBC being able to induce an ORR in the range reported for
      DCT 75-100 mg/m2 every 3 weeks. The bimonthly schedule is, however, associated
      with relatively low toxicity. This characteristic may render the bimonthly
      schedule particularly attractive for future phase II trials of DCT in combination
      with other antineoplastic agents.

PMID- 12602909
TI  - Chromosome 17 aneusomy is associated with poor prognostic factors in invasive
      breast carcinoma.
AB  - Aberrations of chromosome 17 are common in breast cancer. Fluorescence in situ
      hybridization (FISH) enables gene or chromosome copy number to be assessed in
      situ in archival tissues and related to morphology and clinical outcome. In this
      study direct labeled DNA probes for the chromosome 17 alpha satellite and the
      HER2/neu gene were applied simultaneously to 5 micron sections of 214 formalin
      fixed paraffin-embedded invasive primary breast carcinomas. A high proportion
      (54%) of invasive breast carcinomas displayed aneusomy of chromosome 17. Polysomy
      17 correlated with multiple copies of HER2/neu (p = < 0.001), but not with
      HER2/neu amplification. Eighty-six patients without HER2/neu amplification had
      aneusomy 17. Fifty-eight of the 86 patients that had aneusomy 17 had high
      HER2/neu copy number. Twelve patients with normal copy number for chromosome 17
      had amplification of HER2/neu and 30 patients had amplification of HER2/neu with
      aneusomy 17. Aneusomy 17 was associated with grade 3 carcinoma (p = 0.008), ER
      negativity (p = 0.0032) and a Nottingham prognostic index of greater than 5.4 (p
      = 0.039) but was not associated with survival by univariate analysis. In
      conclusion, the determination of chromosome 17 copy number should be incorporated
      in assessment of HER2/neu status, as this will give an accurate measure of
      amplification of HER2/neu and may also be helpful in determining suitability for
      breast carcinoma trials.

PMID- 12602910
TI  - A phase II trial of weekly paclitaxel, 5-fluorouracil, and leucovorin as first
      line treatment for metastatic breast cancer.
AB  - PURPOSE: This phase II multicenter trial evaluated the efficacy and toxicity of
      weekly paclitaxel, 5-fluorouracil, and leucovorin administered as first-line
      therapy for metastatic breast cancer. PATIENTS AND METHODS: The study enrolled
      155 women with pathologically confirmed and measurable metastatic adenocarcinoma
      of the breast. Treatment consisted of paclitaxel 80 mg/m2, 5-fluorouracil 425
      mg/m2, and leucovorin 20 mg/m2 administered weekly 4 x per 4-week cycle in the
      first 40 patients enrolled (group 1), and weekly 3 x per 4-week cycle in the
      subsequent 115 patients (group 2) enrolled. Hematologic growth factor support was
      not routinely used. Twenty patients with hepatic dysfunction were enrolled to
      assess the tolerability of the regimen in this population. All therapies were
      delivered in an outpatient setting. RESULTS: The overall response rate was 48%,
      with 12-month estimated survival rates of 53% and 65% for treatment groups 1 and
      2, respectively. Response rates were not statistically different between the two
      treatment schedules. Therapy was well tolerated when delivered on the every 3 of
      4-week schedule, including patients with hepatic involvement and those age > or =
      65. CONCLUSION: Weekly therapy with paclitaxel and 5-fluorouracil with leucovorin
      is active as first-line therapy for metastatic breast cancer. Use of this regimen
      should be given consideration, particularly in patients who are not candidates
      for anthracycline-based therapy.

PMID- 12602911
TI  - Cytotoxic effect of conjugates of doxorubicin and human chorionic gonadotropin
      (hCG) in breast cancer cells.
AB  - Cytotoxic activity of drug conjugates of human chorionic gonadotropin (hCG) and
      doxorubicin alone was investigated compared to doxorubicin in breast cancer cells
      with and without expression of hCG receptors. Expression of hCG receptor was
      determined in MCF-7 and MB231 breast cancer cell line using a multiplex nested rt
      PCR approach. The entire sequence of mRNA encoding for hCG receptor was detected
      in MCF-7 but not in MB231 breast cancer cell line. Cytostatic effect of
      doxorubicin-hCG conjugates was investigated in these cell lines in comparison to
      unconjugated doxorubicin. The number of viable cells was determined after 24, 48,
      72, 96, and 120h. To exclude non-specific uptake of the carrier hCG from the
      culture media, a similar experiment was performed with albumin-doxorubicin
      conjugates. The number of viable cells decreased in a concentration depending
      manner after doxorubicin and hCG-doxorubicin conjugate treatment. However, the
      cytotoxic effect of hCG-doxorubicin conjugate was 10-fold increased compared to
      unconjugated doxorubin in hCG-receptor positive MCF-7 but not in hCG-receptor
      negative MB231 cells. Albumin-doxorubicin conjugates showed no increased toxicity
      compared to doxorubicin. We conclude that the cytotoxic effect of hCG-doxorubicin
      conjugates is mediated specifically via the hCG receptor. By using hCG
      conjugates, the development of more selective cytostatics can be achieved.

PMID- 12602912
TI  - Mutational screening of breast cancer susceptibility gene 1 from early onset, bi
      lateral, and familial breast cancer patients in Taiwan.
AB  - The BRCA1 gene has been shown to be strongly associated with the occurrence of
      familial breast cancer. The spectrum of BRCA1 gene mutations in breast cancer
      patients in various populations has been investigated. In this study, patients in
      Central Taiwan with breast cancer were screened for BRCA1 mutations by sequencing
      PCR products spanning the coding region and partial intronic regions of the BRCA1
      gene. Twelve polymorphisms in four exons and three introns were found. One
      mutation was found in one patient with familial breast cancer. Two patients
      showed LOH at the locus of BRCA1. Also found in the Taiwanese population were two
      common haplotypes and one rare haplotype of BRCA1. These results suggest that the
      mutation of BRCA1 contributes little to the occurrence of breast cancer in the
      Taiwanese population.

PMID- 12602913
TI  - MMP-2 protein in invasive breast cancer and the impact of MMP-2/TIMP-2 phenotype
      on overall survival.
AB  - Crucial event in the metastasis of cancer cells is the secretion of matrix
      metalloproteinases (MMPs), which are responsible for the degradation of
      extracellular matrix (ECM). Among them, matrix metalloproteinase-2 (MMP-2) is a
      gelatinase, which degrades basement membrane type-IV collagen.
      Immunohistochemistry was performed to detect MMP-2 protein in 135 infiltrative
      breast carcinomas. MMP-2 was studied along with clinicopathological parameters
      (tumor size, histological type, nuclear and histological grade, stage, lymph node
      status, ER, and PR), patients' survival and tissue inhibitor metalloproteinase-2
      (TIMP-2), Ki-67, and p53 proteins. MMP-2 immunoreactivity was detected in the
      cytoplasm in cancer cells in 102 (75.6%) and in both tumor and tumor stromal
      cells in 37 (27.4%) of 135 cases respectively. MMP-2 reactivity in cancer cells
      displayed a statistically significant association with tumor size > 2 cm (p =
      0.022). In tumor stromal cells a strong parallel association was observed between
      the expression of MMP-2 and TIMP-2 (p = 0.015), while an inverse correlation was
      found between MMP-2 and both Ki-67 and p53 (p = 0.033 and p = 0.034
      respectively). In the subgroup with negative lymph nodes MMP-2 was also inversely
      associated with p53 in cancer cells (p = 0.045). Finally a statistically
      significant association was revealed using Kaplan-Meier and Cox's proportional
      hazard regression model between the MMP-2/TIMP-2 phenotype and patients' better
      survival (p = 0.021). Our results point out the strong relation between MMP-2 and
      TIMP-2 and the effect of the MMP-2/TIMP-2 phenotype in the patients' overall
      survival. The inverse correlation between MMP-2 and both Ki-67 and p53 can be
      explained by the potential inhibition of MMP-2 by TIMP-2. These results suggest
      the necessity of further investigation.

PMID- 12602914
TI  - Functional expression of sodium iodide symporter (NIS) in human breast cancer
      tissue.
AB  - Sodium iodide symporter (NIS) is a molecule involved in active accumulation of
      iodine in thyroid gland for the biosynthesis of thyroid hormone. Its expression
      has also been demonstrated in extra-thyroidal tissues including lactating mice
      mammary gland and also in human breast cancers. Iodide transport in thyroid cells
      through NIS is the basis for using radioiodine for diagnosis and treatment of
      differentiated thyroid carcinoma. The similar approach may prove beneficial for
      the diagnosis and treatment of breast cancer if iodine uptake, its retention and
      NIS expression can be shown unequivocally in malignant tumors. The aim of the
      present study was to investigate NIS expression, in vivo iodine transport ability
      and fate of iodine in human breast tumors. Women (age 33-58 years) with
      infiltrating duct carcinoma confirmed by FNAC and subsequent histopathology were
      the subject of this study. Expression of NIS RNA and protein was confirmed by
      RNAase protection assay, western blot and immunohistochemistry respectively in
      surgically excised breast tumor tissue. Iodine transport ability and its nature
      was assessed both in vivo and in vitro. We report high NIS expression at both
      transcriptional and translational level and its ability to transport iodine in
      human breast tumors. The in vivo iodine transport ability was confirmed by
      scintigraphy. Unlike thyroid, perchlorate and thiocyanate do not inhibit iodine
      transport in breast tumors. The presence of iodinated proteins suggests the
      longer retention time. The unequivocal demonstration of NIS expression, its
      functionality and retention of iodine by organification further provides
      supportive evidence for use of radioiodine as an additional treatment modality of
      human breast carcinoma.

PMID- 12602915
TI  - Androgen receptor gene alterations in Finnish male breast cancer.
AB  - Mutations in the androgen receptor (AR) gene have been suggested to predispose to
      male breast cancer (MBC). Studies on MBC patients have not been based on the
      mutation screening of the entire coding region of the AR and the number of
      subjects has been small. Therefore, some AR gene alterations may have remained
      undetected. In the present study, we have comprehensively screened the entire
      coding region of the AR gene for mutations and also studied the role of AR CAG
      and GGC repeat lengths as risk factors for MBC in a cohort of 32 Finnish MBC
      patients. To estimate the possible involvement of the prostate cancer
      predisposing AR Arg726Leu germ-line mutation in MBC, this mutation was tested in
      117 MBC patients. No germ-line mutations were found and the CAG and GGC repeat
      lengths were similar among MBC cases as among Scandinavian population. Our data
      indicate that the AR gene does not substantially contribute to MBC
      predisposition.

PMID- 12602916
TI  - Phytoestrogens and breast cancer risk. Review of the epidemiological evidence.
AB  - Phytoestrogens are natural plant substances. The three main classes are
      isoflavones, coumestans, and lignans. Phytoestrogens have anticarcinogenic
      potential, but they have also significant estrogenic properties. For an
      evaluation of the effect of phytoestrogens on breast cancer risk we reviewed the
      analytical epidemiological data. A total of 18 studies were included. Up to now,
      there are 13 studies that have assessed the direct relation between the
      individual dietary intake of soy products and the risk of breast cancer. Overall,
      results do not show protective effects, with the exception maybe for women who
      consume phytoestrogens at adolescence or at very high doses. Only four of these
      13 studies are prospective, and none of them found statistically significant
      breast cancer reductions. Four studies assessed urinary isoflavones excretion in
      relation to breast cancer. Three of these are case control studies, where
      excretion was measured after breast cancer occurrence and thus seriously limiting
      causal interpretation of the results. The only prospective study with urinary
      measurements before breast cancer occurrence was done in a Dutch postmenopausal
      population and showed a non-significant breast cancer risk reduction for high
      excretion. Three studies measured enterolactone (lignan): two case control
      studies reported a preventive effect on breast cancer risk, but the only
      prospective study did not . In conclusion, few prospective studies (n = 5) were
      done to assess the effects of phytoestrogens on breast cancer risk. None of them
      found protective effects. However, these prospective studies did not focus on
      'age at consumption', which seems to be important based on results from dietary
      case control studies done so far.

PMID- 12602917
TI  - Unexpected low efficacy of stealth liposomal doxorubicin (Caelyx) and vinorelbine
      in metastatic breast cancer.
AB  - In this phase II study, 23 patients with metastatic breast cancer were treated
      with a combination of Caelyx (40 mg/m2 on day 1) and vinorelbine (20 mg/m2 on
      days 1 and 8) every 4 weeks. According to the statistical design, enrollment was
      closed after the first stage due to the low response rate observed (four partial
      remissions, 12 stabilizations). Toxicity was acceptable, however, grade 3-4
      neutropenia was not negligible. Our study does not support the development of
      this combination in advanced breast cancer.

PMID- 12602918
TI  - Simple anesthesia for simple mastectomies.
AB  - We describe our technique for simple mastectomy under local anesthesia for
      patients with high anesthetic risk factors, particularly the elderly. Seven
      patients with a mean age of 88 years (range 80-94 years) with American Society of
      Anesthesiologists (ASA) classes of three or four were given a simple mastectomy
      using local anesthesia and an intravenous sedative. Blood loss was minimal (mean
      = 95.7 cm3), as was operating room time (mean = 62 min). Most patients were
      returned to nursing homes on post-operative day 2. There were no complications
      related to the procedure.

PMID- 12602919
TI  - Comparison of topoisomerase-IIalpha gene status between primary breast cancer and
      corresponding distant metastatic sites.
AB  - BACKGROUND: Topoisomerase-IIalpha (topo-IIalpha) is a key enzyme in DNA
      replication and a molecular target for anticancer drugs called topoisomerase-II
      inhibitors, such as anthracyclines. Its value as a predictive marker of
      responsiveness to these cytotoxic drugs is currently being evaluated with
      promising results. However, even in the metastatic setting, the choice of
      treatment is based on the biologic characteristics of the primary tumor. Few data
      are available regarding the expression of biological markers between the primary
      tumor and the corresponding distant metastases. METHODS: Topo-IIalpha gene status
      was evaluated in 29 breast cancer patients in which a primary tumor sample and a
      corresponding metastatic sample were both available. Fluorescent in situ
      hybridization (FISH) with the Vysis triple probe (Vysis multi-color topo-IIalpha
      spectrum orange, Her-2 spectrum green and CEP17 spectrum aqua probe) was used,
      which allowed the concomitant evaluation of HER-2 gene status. RESULTS: As
      previously reported, topo-IIalpha gene aberrations are always associated with HER
      2 gene amplification; indeed no topo-IIalpha gene aberrations have been observed
      in the HER-2 negative tumors. Conversely, 38.5% (five patients) of the HER-2
      positive primary breast tumors (13 patients) were topo-IIalpha amplified, while
      61.5% (eight patients) had a normal topo-IIalpha gene. No topo-IIalpha gene
      deletion was found in our series. Topo-IIalpha gene amplification in the primary
      tumor was always associated with amplification in the corresponding metastases,
      and no metastases with topo-IIalpha gene amplification were seen without
      amplification in the primary tumor. Furthermore, the amplification level of topo
      IIalpha (i.e., ratio topo-IIalpha:CEP17) remained unchanged in primary and
      metastatic sites. CONCLUSION: Despite the low number of patients, our results
      seem to indicate that topo-IIalpha gene status evaluation in the primary breast
      tumor accurately reflects its status in the corresponding distant metastases.

PMID- 12602921
TI  - Breast cancer risk and methylenetetrahydrofolate reductase polymorphism.
AB  - OBJECTIVE: Methylenetetrahydrofolate reductase (MTHFR), a polymorphic enzyme
      involved in folate metabolism, plays a role in DNA biosynthesis, methylation, and
      repair in actively dividing cells. Because breast-cell division occurs in women
      with active ovulatory cycles, polymorphisms in the MTHFR gene could be a risk
      factor for breast cancer. METHODS: We genotyped 352 clinic-based study subjects
      for MTHFR, 105 subjects with breast cancer and 247 with benign breast disease,
      histopathologically classified as high-risk or low-risk for breast cancer.
      Questionnaire data were collected prior to biopsy to blind subjects and
      interviewers to diagnoses. RESULTS: Premenopausal women with the MTHFR
      polymorphism had a threefold increased breast cancer risk (OR = 2.8; 95%CI: 1.02
      7.51) compared to the clinic-based controls with benign breast disease. Results
      were similar using either low- or high-risk controls. However, risk for
      postmenopausal women was not elevated (OR = 0.8; 95%CI 0.4-1.4). No significant
      interaction between genotype and smoking or alcohol was found, but polymorphic
      MTHFR decreased the likelihood of drinking alcohol (OR = 0.5; 95%CI 0.3-0.9).
      CONCLUSION: These data suggest that polymorphic MTHFR increases risk of
      premenopausal, but not postmenopausal, breast cancer. These findings should be
      explored with a larger sample size in order to analyze gene-environment
      interactions between MTHFR and folate. Once the intricate relationship between
      diet and breast cancer has been elucidated, new cancer control initiatives can be
      considered such as folate chemoprevention trials in high-risk individuals.

PMID- 12602920
TI  - Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop
      mammary tumors.
AB  - Elevated body weight is a risk factor for postmenopausal breast cancer and is
      associated with increased incidence of spontaneous and chemically induced mammary
      tumors (MTs) in rodents. In this study, genetically obese Lep(ob)Lep(ob) female
      mice that overexpress human TGF-alpha (transforming growth factor-alpha) were
      used to assess the role of body weight on oncogene-induced MT development in
      comparison to lean counterparts. MMTV (mouse mammary tumor virus)-TGF-alpha and
      Lep strain mice were crossed to produce TGF-alpha/Lep(+)Lep(+) (homozygous lean),
      TGF-alpha/Lep(+)Lep(ob) (heterozygous lean) and TGF-alpha/Lep(ob)Lep(ob)
      (homozygous obese) genotypes. Body weights were determined weekly and mice
      palpated for the presence of MTs until 104 weeks of age. Despite their
      significantly higher body weight, obese TGF-alpha/Lep(ob)Lep(ob) mice failed to
      develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF
      alpha/Lep(+)Lep(ob) mice and for 19/38 TGF-alpha/Lep(+)Lep(+) mice between 67 and
      104 weeks of age. Although MT incidence was not statistically different between
      the lean groups, age of MT detection tended to be younger for TGF
      alpha/Lep(+)Lep(ob) mice (p < 0.09). There were significant effects of both
      genotype and MTs on final body weight, that is, TGF-alpha/Lep(+)Lep(ob) mice
      weighed more than homozygous lean mice, and mice with MTs weighed more than those
      without MTs. TGF-alpha/Lep(ob)Lep(ob) mice are not a good model to evaluate the
      effect of body weight on MT development possibly due to leptin deficiency.
      However, the finding that increased body weight is associated with increased
      oncogene-induced MT development within the normal weight range provides
      experimental support for the role of body weight in breast cancer.

PMID- 12602922
TI  - Altered chemokine receptor sensitivity in FVBN202 rat neu transgenic mice.
AB  - We report here that breast cancer cells from spontaneous tumors that arise in rat
      neu transgenic mice produce several chemokines capable of acting upon cells of
      the immune system. Moreover, mice bearing these spontaneous tumors possess
      splenic T cells as well as CD11c+, CD11b+ and CD19+ cells with an altered
      sensitivity to recombinant chemokines compared to naive mice. A comparison
      between T-cell migration and the level of chemokines produced by the tumor cells
      revealed that the altered chemotactic activity was not a direct consequence of
      tumor-derived chemokines. These data suggest that a growing tumor may indirectly
      alter leukocyte chemotactic activity.

PMID- 12602923
TI  - Concurrent exposure to heat shock and H7 synergizes to trigger breast cancer cell
      apoptosis while sparing normal cells.
AB  - Most cancer therapies, including chemotherapy, kill tumor cells by inducing
      apoptosis. Consequently, the propensity of tumor cells to evade apoptotic signals
      contributes to therapeutic resistance. Here we show that breast cancer cells
      exhibiting a highly resistant phenotype undergo apoptosis when exposed to
      concurrent heat shock and H7, a potent serine/threonine kinase inhibitor. The
      anti-tumor effects of this combination are synergistic as neither treatment alone
      adversely affects breast cancer cell growth/survival. In contrast, non-malignant
      breast epithelial and hematopoietic progenitor cells are resistant to this
      combination therapy, thereby excluding non-specific cytotoxicity as the cause of
      tumor cell apoptosis. Heat or other cell stresses, including chemotherapy,
      preferentially enhance heat shock protein (hsp) synthesis, which serves to
      protect cells from potentially lethal consequences of heat shock stimuli. Ectopic
      overexpression of hsps in breast cancer cells protects against chemotherapy
      induced apoptosis. Furthermore, increased hsps in primary breast cancers
      correlates with resistance to therapy and decreased survival. Stress-induced hsp
      synthesis is mediated by heat shock transcription factor 1 (HSF1). To simulate
      hsp overexpressing primary breast cancers, a number of breast cancer cell lines
      were transfected with HSF1d202-316, a constitutively activated form of HSF1 that
      leads to baseline overexpression of hsps in the absence of stress. Importantly,
      HSF1d202-316 transfected breast cancer cells undergo apoptosis following
      concurrent heat shock and H7. In light of its tumor selective activity against
      breast cancer cells that exhibit a highly resistant phenotype, concurrent H7 and
      heat shock warrants further investigation as a potential cancer therapy.

PMID- 12602924
TI  - Elevated serum periostin levels in patients with bone metastases from breast but
      not lung cancer.
AB  - Periostin is a recently identified gene that is preferentially expressed in
      periosteum, indicating a potential role in bone formation and maintenance of
      structure. We independently identified and isolated periostin from cancer tissue,
      using the palindromic PCR-driven cDNA Differential Display technique. For the
      present work, we developed a novel sandwich chemiluminescence assay to detect
      serum periostin level using newly developed monoclonal and polyclonal antibodies.
      We investigated serum periostin levels in breast cancer and small cell lung
      cancer patients, especially in patients with bone metastasis. The study included
      58 breast cancer and 44 small cell lung cancer patients. Serum periostin levels
      were elevated in breast cancer patients presenting with bone metastases (92.0 +/-
      28.6 ng/ml) compared to similar breast cancer patients without evidence of bone
      metastasis (55.0 +/- 16.6 ng/ml, p = 0.04). No correlation was found between the
      serum periostin level and any other prognostic factors, such as clinical stage
      and lymph node metastasis in breast cancer. Serum periostin levels thus appear to
      serve as a marker of bone metastasis from breast cancer. In contrast, serum
      periostin levels were similar in samples from patients with small cell lung
      cancer who did or did not have bone metastasis. However, increasing T-stage and N
      stage of patients with small cell lung cancer were correlated with higher
      periostin levels (T4, 126.5 +/- 29.7 ng/ml v.s. T2, 64.9 +/- 16.1 ng/ml, p =
      0.03; and T4 v.s. T1, 36.3+/- 7.5 ng/ml, p = 0.01; N3, 108.7 +/- 17.3 ng/ml v.s.
      N2, 49.7+/- 10.9 ng/ml, p = 0.01). Periostin has a substantial homology with the
      insect cell adhesion molecule, fasciclin I. Thus, expression of periostin may
      facilitate tumor cell adhesion to the bone surface. In fact, we found by in situ
      RNA hybridization, that the periostin gene was highly expressed in the stromal
      cells immediately surrounding the tumor, but not within the breast cancer cells
      themselves.

PMID- 12602925
TI  - Cell proliferation, apoptosis, and expression of cyclin D1 and cyclin E as
      potential biomarkers in tamoxifen-treated mammary tumors.
AB  - Tamoxifen has been widely used for treatment, and more recently, for the
      prevention of breast cancer. Since breast carcinomas are composed of
      heterogeneous populations of estrogen receptor-positive (ER+) cells, we
      hypothesized that tamoxifen may suppress tumor growth by differentially affecting
      cell proliferation and apoptosis. ER+ mammary tumors were induced in Sprague
      Dawley rats by N-methyl-N-nitrosourea (MNU) and when they became palpable, the
      animals were treated for 5, 10, or 20 days with tamoxifen, 1.0 mg/kg body weight.
      Tamoxifen induced a time-dependent decrease in proliferating (BrdU-labeled)
      cells, arrested the cells in G1/0 phase, and differentially decreased the cyclin
      E and cyclin D1 expression at mRNA and protein levels. In the same tumors,
      apoptotic cells increased during the first 10 days of treatment, but their number
      remained unchanged with extension of the treatment to 20 days. Thus, we provide
      data that tamoxifen may differentially affect cell proliferation and apoptosis in
      mammary tumors and that the expression levels of cyclin D1 and cyclin E might
      also be considered potential intermediate biomarkers of response of mammary
      tumors to tamoxifen and possibly to other selective estrogen receptor modulators
      (SERMs).

PMID- 12602926
TI  - FosB is highly expressed in normal mammary epithelia, but down-regulated in
      poorly differentiated breast carcinomas.
AB  - FosB is a member of the AP-1 family of transcription factors which represent
      important regulators of cell proliferation and differentiation. Based on prior
      results which indicated a role of FosB in breast cancer, we studied FosB protein
      and mRNA expression by immunohistochemistry and, partly, in situ hybridization in
      68 mammary carcinomas and normal breast tissues. We found strong nuclear FosB
      immunoreactivity in epithelial cells of normal lobules and ducts, whereas
      carcinomas frequently showed loss of FosB expression (n = 8) or weak
      immunostaining (n = 24). Reduced FosB protein expression in tumors correlated
      with high grading (p = 0.005), negative estrogen and progesterone receptor status
      (p < 0.001), and strong HER2/neu expression (p = 0.025). Comparison with
      expression of seven cell-cycle regulators revealed an association of low/absent
      FosB staining with p16MTS1 overexpression (p = 0.005). RT-PCR showed expression
      of full-length FosB and the smaller splice variant FosB2 in most carcinomas and
      cell lines with and without FosB protein expression, indicating that both
      proteins are differentially regulated mainly at a post-transcriptional level. By
      sequence analysis of the coding region in four cell lines and 17 carcinomas we
      detected a mutation in HBL-100 cells. Our results indicate that high FosB
      expression might be necessary for normal proliferation and differentiation of
      mammary epithelial cells, and reduced FosB protein levels might be involved in
      dedifferentiation during breast tumorigenesis.

PMID- 12602927
TI  - hTERT expression in human breast cancer and non-cancerous breast tissue:
      correlation with tumour stage and c-Myc expression.
AB  - Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell
      division and maintains chromosomal length and stability thus leading to cellular
      immortalisation. hTERT (human telomerase reverse transcriptase) gene is the rate
      limiting determinant of telomerase reactivation. The present study aims to
      quantitatively measure the expression of hTERT mRNA in human breast cancer,
      adjacent non-cancerous tissue (ANCT) and benign breast lesions, examine the
      association between hTERT and the clinicopathological characteristics of the
      cancer specimens and to explore the relationship between c-Myc and hTERT
      expressions. RNA was extracted from 49 breast carcinomas, 46 matched ANCT, and
      eight fibroadenomas. hTERT and c-Myc mRNA expressions were estimated by reverse
      transcriptase-PCR (RT-PCR) and Taqman methodology. hTERT mRNA was present in all
      of the cancerous and most of ANCT specimens with levels being much higher in the
      cancerous tissue than in ANCT. The ratio of hTERT mRNA in tumour to that in ANCT
      was 2011 (95% confidence interval 373-10,853, P < 0.0001). There was no
      significant association between tumour hTERT expression and patient's age, tumour
      size, grade, nodal metastasis, estrogen receptor (ER) positivity, lymphovascular
      (LVI) or c-Myc expression. However, there was a weak but significant negative
      correlation between hTERT expression and progesterone receptor (PR) status (p =
      0.04) in tumours. hTERT mRNA expression was also significantly higher in
      carcinomas (median = 2.61 x 10(6)) than in fibroadenomas (median = 424).We
      conclude that hTERT mRNA expression is significantly higher in human breast
      cancer than in non-cancerous breast tissue suggesting that hTERT has a potential
      role in breast cancer diagnosis. The hTERT mRNA levels in tumour do not seem to
      be associated with the patient's age or advanced tumour stage. Furthermore, hTERT
      mRNA expression does not correlate with c-Myc mRNA expression in breast cancer.

PMID- 12602928
TI  - A comparison of risk perception and psychological morbidity in women with ductal
      carcinoma in situ and early invasive breast cancer.
AB  - PURPOSE: To assess how women with ductal carcinoma in situ (DCIS) perceive their
      risks of recurrence, dying from breast cancer, and psychological distress
      compared to women with early stage invasive breast cancer (EIBC). PATIENTS AND
      METHODS: Eligible patients included those with DCIS or EIBC (T1 or T2, N0)
      referred to one cancer center between November 1998 and June 1999. Participants
      completed a self-administered survey regarding their views of their risks of
      developing recurrent cancer, of dying of breast cancer and the presence of
      psychological symptoms of distress. Responses were scored and compared between
      the two groups. RESULTS: In total, 495 patients were screened, 240 found
      ineligible, 228 patients who agreed to participate. No significant difference
      between the two groups was observed in perceptions of risk related to the
      likelihood of developing local recurrence (DCIS: 53%, EIBC 45%, P = 0.14),
      distant recurrence (DCIS: 36%; EIBC: 39%, P = 0.35) or dying of breast cancer
      (DCIS: 27%, EIBC 27%, P = 0.5). Both groups expressed similar levels of
      psychological distress (anxiety, DCIS: 56%, EIBC 54%, P = 0.38; depression, DCIS:
      41%, EIBC, 48%, P = 0.17). CONCLUSIONS: Despite the excellent prognosis, women
      with DCIS express serious concerns and report similar psychological morbidity as
      women with invasive cancer.

PMID- 12602929
TI  - Effect of consumption of finger millet on hyperglycemia in non-insulin dependent
      diabetes mellitus (NIDDM) subjects.
AB  - The effect of consumption of finger millet based diets on hyperglycemia was
      studied in 6 non-insulin dependent diabetes mellitus (NIDDM) subjects. All the
      experimental diets were planned to be isocaloric and also to contain 75 g
      equivalent of carbohydrate load so that glycemic response could be compared with
      a 75 g glucose load. The glycemic response to breakfast items compared to that of
      glucose was determined by comparing the areas under the 2 hr glucose response
      curve. Consumption of finger millet based diets resulted in significantly lower
      plasma glucose levels, mean peak rise, and area under curve which might have been
      due to the higher fiber content of finger millet compared to rice and wheat. The
      lower glycemic response of whole finger millet based diets may also have been due
      to the presence of antinutritional factors in whole finger millet flour which are
      known to reduce starch digestibility and absorption.

PMID- 12602930
TI  - Studies on chemical composition and utilization of the wild edible vegetable
      athalakkai (Momordica tuberosa).
AB  - A wild crop of athalakkai was identified, and the major nutrients of its fruits
      were assessed. South Indian recipes, poriyal, fry, pulikulambu, pickle, and
      vadagam, were prepared using athalakkai. Product acceptabilities were evaluated
      by a panel of 10 trained housewives using a 9-point hedonic scale. It was
      observed that athalakkai contains higher amounts of calcium, potassium, sodium,
      and vitamin C than bitter gourd (Momordica charantia L). It was also observed
      that athalakkai had a high crude fiber (6.42 g/100 g) content. The recipes
      prepared from athalakkai were highly acceptable. This research suggests the need
      to exploit this wild vegetable commercially through its increased use. However
      research should be conducted to identify the antinutritional factors and the
      effect of processing on these factors.

PMID- 12602931
TI  - Effect of heat treatment on the proximate composition, energy values, and levels
      of some toxicants in African yam bean (Sphenostylis stenocarpa) seed varieties.
AB  - The effects of heat treatments on the proximate composition, energy content, and
      levels of some antinutritional factors in brown and marble-colored African yam
      bean (AYB) seed flours were investigated. In raw brown and marble-colored AYB
      seed flours; moisture content, dry matter, crude protein, crude fat, ash, total
      carbohydrate and caloric value did not differ significantly at the 5% level.
      Autoclaving and cooking slightly increased the moisture level. Crude protein,
      crude fat, and ash contents were decreased by autoclaving and were further
      decreased by cooking. The decrease was not, however, considerable for the AYB
      that is not eaten raw and whose full nutritional potential as a legume can be
      derived only when heat treated, as previous reports have indicated for legume
      seeds. The levels of the toxicants were generally higher in the raw brown AYB
      compared to the marble-colored, and were generally reduced by both autoclaving
      and cooking. In the most commonly available and consumed marble-colored AYB,
      autoclaving at 121 degrees C, 15 psi for 20 min decreased cyanogenic glycosides
      by 46%, oxalate by 48.9%, tannin by 15.0%, saponin by 14.8% and trypsin
      inhibitors by 61.3% while cooking for 3.5 hours in tap water decreased these
      toxic factors by 66.5%, 70.3%, 72.2%, 48.7%, and 86.0%, respectively. The results
      indicate that for raw samples, varietal difference did not significantly affect
      nutrient composition though the toxicants were generally higher in the brown AYB
      than the marble-colored. Autoclaving decreased both nutrient value and the level
      of toxicants in the two seed types; values were further reduced by cooking. Of
      the toxicants, trypsin inhibitor was found to be the most heat-labile and of the
      heat treatment methods, cooking to tenderness is recommendable.

PMID- 12602932
TI  - Antiinflammatory screening of the medicinal plant Gynura procumbens.
AB  - Gynura procumbens is used in Thai folk medicine to treat topical inflammation,
      rheumatism, and viral ailments. In the present work, attempts were made to verify
      the folk medicinal claim that the crude ethanolic extract of G. procumbens has
      antiinflammatory action and to relate the activity to particular fractions using
      a croton oil-induced mouse ear inflammation model. The original ethanolic extract
      of G. procumbens was partitioned between water and ethyl acetate. The residues
      were subjected to antiinflammatory evaluation. While the water extract did not
      show any antiinflammatory activity, the administration of the original organic
      extract significantly inhibited the increase in ear thickness in response to
      croton oil (n = 5). The activity of 0.75 mg/ear original organic extract showed
      similar antiinflammatory activity (inhibition 65.2%) to that of 6 mg/ear
      hydrocortisone 21-hemisuccinate sodium salt (inhibition 64.8%). The organic
      extract was then fractionated with a series of solvents in order of increasing
      polarity. Each fraction was dried, dissolved in acetone and monitored using the
      same bioassay. These experiments showed that the hexane and toluene fractions
      showed significant inhibitions of 44.6% and 34.8%, respectively. These two
      fractions had similar activities to 4 mg/ear of hydrocortisone (inhibition
      35.0%). The possible chemical constituents in the extracts and fractions were
      investigated using thin layer chromatography and specific color reagents. These
      tests showed that steroids might be one class of antiinflammatory compounds in
      this plant.

PMID- 12602933
TI  - Pancreatic and intestinal enzyme activities in rats in response to balanced and
      unbalanced plant diets.
AB  - To simulate the effects of nutritionally adequate and inadequate vegetarian
      diets, rats were fed, for 28 days, an isonitrogenous, isocaloric, amino acid
      unbalanced cereal diet (CD) deficient in lysine and tryptophan or a balanced
      cereal-legume diet (CLD). The impact of these diets on enzymes responsible for
      digestion of proteins and carbohydrates were measured. Neither experimental diet
      significantly affected the animal's final weight or feed consumption in
      comparison with controls fed a standard mixed diet from plant and animal sources.
      However, during the first three weeks, the weight gain of rats fed the CD was
      significantly lower (p < 0.01; p < 0.05) than that of the controls. CD fed rats
      also had a higher feed efficiency ratio (p < 0.05), demonstrating increased feed
      consumption per unit of body weight. They also had decreased pancreatic alpha
      amylase activity (p < 0.05), serum phytolytic and zoolytic alpha-amylase activity
      (p < 0.05) and serum protein level (p < 0.05) than the controls. Activity of
      pancreatic trypsin and intestinal enzymes (sucrase, maltase, aminopeptidase N)
      were the same as in the controls. In rats fed CLD, growth, food consumption, and
      enzyme activities did not change, however serum protein and glucose levels were
      higher (p < 0.025; p < 0.005) than in the controls. It is hypothesized that
      decrease in alpha-amylase activity was mostly related to the tryptophan
      deficiency in the CD because this enzyme contains the highest amount of
      tryptophan units among all tested enzymes.

PMID- 12602934
TI  - Fatty acid, amino acid, and trace mineral analyses of five weaning foods from
      Jos, Nigeria.
AB  - Five plant-based weaning foods (WF) (Dietrend, Jot-M, Soy, Ang, and Vic-T)
      locally prepared in Jos, Nigeria were analyzed by gas-liquid chromatography,
      reverse-phase high performance liquid chromatography, and atomic emission
      spectrometry with inductively coupled plasma to determine their fatty acid (FA),
      amino acid, and trace mineral contents, respectively. Results of these direct
      analyses were compared to expected values derived from food composition tables
      prepared by the United States Department of Agriculture (USDA). Additionally,
      results were compared against recommended nutrient values, using breast milk as
      the standard for FA content and recommended dietary allowances (RDA) for amino
      acid and mineral contents. The overall nutritional value of the five WF varied
      considerably and the quantities of particular nutrients determined by direct
      analysis differed markedly from those estimated using USDA food tables.
      Comparison of WF fatty acid composition relative to the RDA recommendations and a
      human milk standard revealed a much higher proportion of both linoleic (35-55
      wt%) and alpha-linolenic acids (1%-7 wt%) relative to human milk lipids (11%-12%
      and 0.8%-0.9% wt, respectively); however, the WF were devoid of arachidonic acid
      and docosahexaenoic acid. Soy contained the highest amounts of linoleic acid
      (59.7 mg/g) and alpha-linolenic acid (7.46 mg/g) compared to the other four WF
      (10.2-41.0 and 0.35-3.18 mg/g, respectively). The linoleic acid/alpha-linolenic
      acid ratio was within the recommended range (5:1 to 10:1) in only Jot-M (10:1)
      and Soy (8:1). Dietrend, Vic-T and Ang, contained linoleic/alpha-linolenic ratios
      of 12:1, 29:1, and 82:1, respectively. The Soy weaning food would provide the
      most protein (24.3 g/day), based on an estimated daily intake of 65 g of weaning
      food by a normal six-month-old infant, compared to Jot-M (11.9 g/day), Dietrend
      (11.7 g/day), Ang (8.07 g/day), and Vic-T (7.26 g/day). The protein RDA for
      children up to 1 year of age is 13-14 g/day. Comparison of the mineral contents
      of the WF to the RDAs for various minerals indicated that all five would provide
      suboptimal amounts of calcium (16 to 250 mg/day) and zinc (1.42 to 3.56 mg/day)
      compared to respective RDAs of 400 mg/day and 5 mg/day. These data show that the
      Soy weaning food is an excellent source of linoleic acid and alpha-linolenic
      acid, as well as being a good source of high quality protein. Jot-M and Dietrend
      provide useful amounts of the essential FA; however, it is advisable to
      reevaluate the composition of Ang and Vic-T to find ways to improve the
      linoleic/alpha-linolenic ratio of each and increase their total protein content.
      These results document the shortcomings of using published food composition
      tables based on foods in America when devising weaning foods based on ingredients
      in another part of the world.

PMID- 12602936
TI  - Alpha-amylase inhibitor changes during processing of sweet potato and taro
      tubers.
AB  - Alpha-amylase inhibitor changes during processing of sweet potatoes (Ipomoea
      batatas) and taro (Colocasia esculenta) indicated that varietal differences
      profoundly influence the thermal inactivation profile. The alpha-amylase
      inhibitors of taro were almost totally inactivated during oven drying of the
      chips at 90 degrees C and 100 degrees C for 24 h, while 0.8-10% activity was
      retained in sweet potato chips under the same conditions. Relatively better
      thermal stability was exhibited by the sweet potato amylase inhibitors at lower
      temperatures (70 and 80 degrees C) as well. Cooking by boiling the tuber pieces
      in water resulted in retention of 29-59% amylase inhibitor in sweet potato and 11
      16% in taro. Microwave baking was a better method for inactivation of amylase
      inhibitors in these tubers. Flour prepared from the tubers retained only trivial
      amounts of the inhibitor.

PMID- 12602935
TI  - Changes in phytates and HCl extractability of calcium, phosphorus, and iron of
      soaked, dehulled, cooked, and sprouted pigeon pea cultivar (UPAS-120).
AB  - UPAS-120, a high yielding and early maturing variety of pigeon peas released by
      the Department of Plant Breeding, CCS Haryana Agricultural University, Hisar
      contained a significant amount of phytic acid, i.e. 886 mg/100 g. When it was
      subjected to various domestic processing and cooking methods viz. soaking (6, 12,
      18 h), dehulling, ordinary as well as pressure cooking and germination (24, 36
      and 48 h), a drastic decrease in level of phytic acid with a remarkable increase
      in the HCl-extractability of mono, divalent, and trivalent ions, like calcium,
      phosphorus, and iron occurred. Germination (48 h) was found to be the best method
      for decreasing the phytic acid content, i.e. 35 to 39 percent less than the
      control and significantly (p < 0.05) increasing the non-phytate phosphorus and
      HCl-extractable phosphorus. Pressure cooking of soaked-dehulled pigeon pea also
      rendered equally good results. The calcium, phosphorus, and iron contents of
      pigeon pea seeds were 197.3, 473.1, and 9.91 mg/100 g, respectively; some losses
      varying from 3 to 9 percent were noticed when the legume was subjected to
      soaking, cooking, and germination but the maximum losses, i.e. 23 percent,
      occurred when the seeds were dehulled. However, HCl-extractability of Ca, P, and
      Fe improved to a significant extent when the pigeon pea seeds were soaked, soaked
      dehulled, cooked and sprouted which may have been due to decrease in the phytate
      content followed by processing and cooking. The significant negative correlations
      between the phytic acid and HCl-extractability of minerals of processed pigeon
      pea strengthens these findings.

PMID- 12602937
TI  - The clinicopathologic significance of enriching grated cassava mash with red palm
      oil in the production of gari.
AB  - The neglect of traditional processing methods in the production of gari (toasted
      cassava granules) has been blamed for reported cases of poisoning following
      consumption of gari. This study investigated the nutritional and
      clinicopathologic effects of not enriching cassava mash with red palm oil (RPO)
      during gari production. Two gari samples were produced with and without RPO.
      Total cyanogen, acetone cyanohydrin, free cyanogen, and crude protein contents
      were not found to be significantly (p > 0.05) different between the two. The
      samples were fed exclusively to two different groups of Sprague-Dawley rats for a
      ten week experimental period during which clinical observations were recorded
      daily. At the end, vital body organs were examined grossly and microscopically.
      There was a significant (p < 0.05) reduction in severity and percentage of
      animals exhibiting clinical abnormalities and lesions of chronic cyanide
      poisoning in the group fed gari produced with RPO. This result implies an
      association between the enrichment of cassava mash with RPO during gari
      production and the reduction of severity and percentage of animals affected by
      chronic cyanide poisoning.

PMID- 12602938
TI  - Effect of domestic processing on zinc bioavailability from ricebean (Vigna
      umbellata) diets.
AB  - The effects of various processing methods viz. pressure cooking with soaking,
      sprouting (48 h), sprouting and pressure cooking, dehulling, and pressure cooking
      of the dehulled legume on the bioavailability of zinc were studied. The total
      zinc content varied from 3.28 to 3.37%; the highest being in raw ricebeans and
      the lowest being in dehulled, soaked and pressure cooked, and sprouted and
      pressure cooked ricebeans, respectively. The soluble zinc content was highest for
      dehulled soaked and pressure cooked ricebeans (28.2%) and lowest for raw
      ricebeans (16.0%). The absorption, retention, and balance of zinc were estimated
      in rats fed experimental and standard ZnSO4 diets using a balance study. The
      maximum retention of zinc was observed in dehulled soaked, and pressure cooked
      diets (63.37%) followed by sprouted (48 h) and pressure cooked (61.38%) diets.
      The gain in body weight, total femur zinc and retention of zinc in liver, kidneys
      and spleen were found to be highest for rats eating the sprouted pressure cooked
      diet followed by the dehulled, soaked and pressure cooked diet. Plasma zinc
      levels were found to range from 3.81 to 6.34 micromol/dl; they were maximum for
      rats fed the dehulled, soaked and pressure cooked diet. It can be concluded that
      dehulling significantly improves the availability of zinc and germination of
      ricebeans is the best method to enhance the zinc availability.

PMID- 12602940
TI  - Quality characteristics of red raspberry fruit spread made with four sweeteners.
AB  - Red raspberry fruit spreads sweetened with sugar (S) or raspberry, red grape, or
      apple juice concentrates were processed by inversion and analyzed for chemical,
      physical, and sensory properties at 1, 12, and 24 weeks. All pH values were
      between 3.0 and 3.5 while all aw were above 0.81. Samples were dark red but
      became duller over time. Viscosities and total solids were lower (p < 0.05) in
      juice sweetened products than in S. Sensory evaluations improved over time for
      all samples, but were always higher (p < 0.05) for S. Mold was detected in all
      samples at 24 weeks. Acceptable products were prepared using fruit juice
      concentrates but inversion processing was not recommended for fruit spread
      preparation.

PMID- 12602941
TI  - Towards the identification of cassava root protein genes.
AB  - The protein population of cassava root layers was characterized by SDS-PAGE and
      bidimensional polyacrylamide gel electrophoresis. SDS-Page revealed the presence
      of a protein population in the molecular weight range between 94 and 20 kDa. The
      expression pattern of these proteins was well-defined within the different
      layers. Partial protein sequence analyses and preliminary results on the layer
      specific expression pattern obtained with Northern analyses are presented.

PMID- 12602942
TI  - A preliminary study on the use of tempe-based formula as a weaning diet in
      Nigeria.
AB  - Tempe, an Indonesian mold fermented food, was prepared from cowpeas and soybeans
      using the traditional oriental process with modifications where appropriate. Four
      complementary foods were developed from whole maize meal or dehydrated fermented
      maize (ogi) flour fortified with either cowpea tempe or soybean tempe.
      Wholesomeness and potentials of the vanilla-flavored foods as weaning diets were
      determined. The nutrient content of all the developed products were within the
      range prescribed by the FAO/WHO pattern for processed weaning foods. The products
      had loose bulk densities between 0.40-0.55 g/ml and packed bulk densities between
      0.68-0.75 g/ml; reconstitution indexes were between 92.30-104.00 g/ml;
      viscosities were 34.2-65.0 CP at 70 degrees C and 45.0-76.9 CP at 30 degrees C.
      Total plate counts ranged from 3.2 x 10(3) - 4.3 x 10(4) cfu/g; coliforms
      staphylococcus, mold, and yeast were absent in some of the products. The results
      on sensory attributes showed that tempe-based weaning diets were comparable with
      Mameal, a commercial product. Maize and maize-fortified diets were slightly
      higher in packed bulk density. Fortification reduced the viscosity of the diets
      and the values reduced with increasing temperature. Tempe-based weaning foods
      reconstituted easily in hot water, while cooking destroyed most of the
      microorganisms present. Maize-based tempe fortified foods were relatively
      inexpensive and have potential as weaning foods.

PMID- 12602939
TI  - Palm oil: biochemical, physiological, nutritional, hematological, and
      toxicological aspects: a review.
AB  - The link between dietary fats and cardiovascular diseases has necessitated a
      growing research interest in palm oil, the second largest consumed vegetable oil
      in the world. Palm oil, obtained from a tropical plant, Elaeis guineensis
      contains 50% saturated fatty acids, yet it does not promote atherosclerosis and
      arterial thrombosis. The saturated fatty acid to unsaturated fatty acid ratio of
      palm oil is close to unity and it contains a high amount of the antioxidants,
      beta-carotene, and vitamin E. Although palm oil-based diets induce a higher blood
      cholesterol level than do corn, soybean, safflower seed, and sunflower oils, the
      consumption of palm oil causes the endogenous cholesterol level to drop. This
      phenomenon seems to arise from the presence of the tocotrienols and the peculiar
      isomeric position of its fatty acids. The benefits of palm oil to health include
      reduction in risk of arterial thrombosis and atherosclerosis, inhibition of
      endogenous cholesterol biosynthesis, platelet aggregation, and reduction in blood
      pressure. Palm oil has been used in the fresh state and/or at various levels of
      oxidation. Oxidation is a result of processing the oil for various culinary
      purposes. However, a considerable amount of the commonly used palm oil is in the
      oxidized state, which poses potential dangers to the biochemical and
      physiological functions of the body. Unlike fresh palm oil, oxidized palm oil
      induces an adverse lipid profile, reproductive toxicity and toxicity of the
      kidney, lung, liver, and heart. This may be as a result of the generation of
      toxicants brought on by oxidation. In contrast to oxidized palm oil, red or
      refined palm oil at moderate levels in the diet of experimental animals promotes
      efficient utilization of nutrients, favorable body weight gains, induction of
      hepatic drug metabolizing enzymes, adequate hemoglobinization of red cells and
      improvement of immune function. Howerer, high palm oil levels in the diet induce
      toxicity to the liver as shown by loss of cellular radial architecture and cell
      size reductions which are corroborated by alanine transaminase to asparate
      transaminase ratios which are higher than unity. The consumtion of moderate
      amounts of palm oil and reduction in the level of oxidation may reduce the health
      risk believed to be associated with the consumption of palm oil. Red palm oil, by
      virtue of its beta-carotene content, may protect against vitamin A deficiency and
      certain forms of cancer.

PMID- 12602943
TI  - Regulation of cell growth and the expression of extracellular matrix proteins in
      colorectal adenocarcinoma: a fibroblast-tumor cell coculture model to study tumor
      host interactions in vitro.
AB  - The production of abundant connective tissue within malignant tumors, the so
      called desmoplastic stromal reaction, is a hallmark of colorectal
      adenocarcinomas. This stroma is produced to a large extent by myofibroblasts and
      contains various amounts of collagens (type I, III, and V), chondroitin sulfate
      proteoglycan, hyaluronic acid, fibronectin, and tenascin-C. In this study we have
      established a monolayer coculture model between two different colorectal
      adenocarcinoma cell lines (HRT-18, and CX-2) and colonic fibroblasts (CCD-18) to
      investigate the mechanisms regulating (i) the production of extracellular matrix
      (ECM) components, (ii) the induction of myofibroblastic differentiation, and
      (iii) cellular proliferation. We found that TGFbeta1 and FGF-2 stimulated ECM
      synthesis of fibroblasts. Myofibroblastic differentiation was stimulated by
      TGFbeta1 but suppressed by FGF-2. There was a mutual stimulation of proliferation
      between fibroblasts and carcinoma cells. The analogies with ECM components
      expressed in cocultures and colorectal adenocarcinoma samples suggest that the
      coculture model used in this study is useful to study tumor cell-fibroblast
      interactions.

PMID- 12602944
TI  - Mycobacteria-containing phagosomes associate less annexins I, VI, VII and XI, but
      not II, concomitantly with a diminished phagolysosomal fusion.
AB  - We have studied the intracellular localization of annexins I,II, VI, VII, and XI
      in cells containing latex beads or Mycobacterium avium at different times after
      ingestion in order to establish whether a correlation existed between the
      association of annexins to phagosomes and phagolysosomal fusion, since the
      intracellular survival of mycobacteria is linked to an impairment of phagosome
      maturation. We demonstrate an important decrease in the levels of association of
      annexins I, VI, VII and XI, but not II to phagosomes containing either live or
      killed mycobacteria compared with phagosomes containing inert latex particles.
      The reduced association of annexins observed was detected only on M. avium
      containing phagosomes and not in other cell membrane nor in cytosolic fractions
      from infected cells, and was apparent from 8 hours through to 4 days after
      phagocytosis. These findings add elements to the present knowledge of the
      phagosomal modifications that accompany the survival of intracellular pathogens,
      suggesting that annexins I, VI, VII, and XI play a secondary role in phagosomal
      fusion events while annexin II does not seem to be related to the mechanism of
      regulation of endolysosomal fusion.

PMID- 12602945
TI  - Serglycin proteoglycan is sorted into zymogen granules of rat pancreatic acinar
      cells.
AB  - Serglycin is known as a secretory granule proteoglyean in hematopoietic cells. In
      this study we identified a high-molecular-weight molecule in aggregated content
      proteins of zymogen granules of pancreatic acinar cells. The amino acid
      composition of the isolated protein showed high similarity to serglycin
      proteoglycan core protein. To confirm the expression of serglycin proteoglycan in
      pancreatic acinar cells we cloned the rat pancreas cDNA of serglycin core protein
      and detected the serglycin mRNA in pancreas tissue and AR4-2J cells by reverse
      transcription-PCR. In AR4-2J cells, transfected with serglycin fused to green
      fluorescent protein (EGFP), serglycin localized within a web-like pattern in the
      perinuclear space as well as with a punctate pattern distributed in the
      cytoplasm. The perinuclear structures colocalized with the Golgi membrane
      associated protein p115 and the punctate structures with the secretory enzyme
      procarboxypeptidase A, indicating that the serglycin-EGFP fusion protein travels
      through compartments of the secretory pathway and is sorted into secretory
      granules. Using an antiserum against serglycin core protein immunofluorescence as
      well as immunogold electron microscopy analysis conrirmed the subcellular
      distribution of serglycin proteoglycan in zymogen granules of pancreatic acinar
      cells. To prevent glycosylation of serglycin core protein we incubated AR4-2J
      cells with 2 mM p-nitrophenyl-beta-D-xylopyranoside (PNP-xyloside), which serves
      as alternate substrate for glycosaminoglycan chain attachment. Furthermore, we
      deleted the serine/glycine repeat region in the serglycin core protein. In both
      approaches the transfected serglycin-EGFP fusion protein could be detected
      predominantly in perinuclear Golgi membrane structures, while in control cells
      the serglycin fusion protein was mostly sorted into the secretory granules.
      Additionally, we show that sorting of secretory enzymes like amylase

PMID- 12602946
TI  - Antiapoptotic effect of interferon-alpha on hepatic stellate cells (HSC): a novel
      pathway of IFN-alpha signal transduction via Janus kinase 2 (JAK2) and caspase-8.
AB  - The hepatic stellate cell (HSC), the pericyte of the liver sinusoids belongs to
      the mesenchymal cells of the liver. Damaging noxae induce a transformation from
      the quiescent (vitamin A-storing cell) to the activated (connective tissue
      producing cell) state. The balance between proapoptotic and surviving factors
      decides about the fate of the activated HSC. Interferon-alpha (IFN-alpha) has
      been shown to elicit antiproliferative and/or antifibrogenic effects in various
      cell types of mesenchymal origin. We therefore investigated the effect of IFN
      alpha on primary cultured rat HSC in their quiescent (day 2) and activated state
      (day 7). IFN-alpha significantly inhibited spontaneous apoptosis in activated HSC
      in vitro and simultaneously inhibited cell cycle progression by inducing a G1
      arrest. The effect of IFN-a is not accompanied by a modulation of CD95, CD95L,
      p53, p21(WAF1), p27, bcl-2, bcl-xL, bax, NFkappaB, or IkappaB gene expression.
      Surprisingly, the IFN-alpha effect could be abolished completely by blocking JAK2
      activity or JAK2 translation. The downregulating effect of IFN-alpha on the
      activity of caspase-8 and caspase-3 could also be neutralized using tyrphostin
      AG490 or JAK-2 antisense. Taken together IFN-alpha inhibits apoptosis of
      activated HSC by activation of JAK2 which inhibits the caspase-8 apoptosis
      pathway.

PMID- 12602947
TI  - Gamma-tubulin distribution during cortical microtubule reorganization at the M/G1
      interface in tobacco BY-2 cells.
AB  - Cortical microtubules are considered to regulate the direction of cellulose
      microfibril deposition. Despite their significant role in determining cell
      morphology, cortical microtubules completely disappear from the cell cortex
      during M phase and become reorganized at G1 phase. The mechanism by which these
      microtubules become properly formed again is, however, still unclear. We have
      proposed that the origin of cortical microtubules is on the daughter nuclear
      surface, but further cortical microtubule reorganization occurs at the cell
      cortex. Hence it is probable that the locations of microtubule organizing centers
      (MTOCs) are actively changing. However, the actual MTOC sites of cortical
      microtubules were not clearly determined. In this paper, we have examined the
      distribution of gamma-tubulin, one of the key molecules of MTOCs in various
      organisms, during cortical microtubule reorganization using both
      immunofluorescence and a GFP reporter system. Using a monoclonal antibody (clone
      G9) that recognizes highly conserved residues in y-tubulin, y-tubulin was found
      to be constitutively expressed and to be clearly localized to microtubule
      structures, such as the preprophase bands, spindles, and phragmoplasts, specific
      to each cell cycle stage. This distribution pattern was confirmed by the GFP
      reporter system. During cortical microtubule reorganization at the M to G1
      transition phase, gamma-tubulin first accumulated at the daughter nuclear
      surfaces, and then seemed to spread onto the cell cortex along with microtubules
      elongating from the daughter nuclei. Based on the results, it was confirmed that
      daughter nuclear surfaces acted as origins of cortical microtubules, and that
      further reorganization occurred on the cell cortex.

PMID- 12602948
TI  - A comparative molecular similarity index analysis (CoMSIA) study identifies an
      HLA-A2 binding supermotif.
AB  - The 3D-QSAR CoMSIA technique was applied to a set of 458 peptides binding to the
      five most widespread HLA-A2-like alleles: A*0201, A*0202, A*0203, A*0206 and
      A*6802. Models comprising the main physicochemical properties (steric bulk,
      electron density, hydrophobicity and hydrogen-bond formation abilities) were
      obtained with acceptable predictivity (q2 ranged from 0.385 to 0.683). The use of
      coefficient contour maps allowed an A2-supermotif to be identified based on
      common favoured and disfavoured areas. The CoMSIA definition for the best HLA-A2
      binder is as follows: hydrophobic aromatic amino acid at position 1; hydrophobic
      bulky side chains at positions 2, 6 and 9; non-hydrogen-bond-forming amino acids
      at position 3; small aliphatic hydrogen-bond donors at position 4; aliphatic
      amino acids at position 5; small aliphatic side chains at position 7; and small
      aliphatic hydrophilic and hydrogen-bond forming amino acids at position 8.

PMID- 12602949
TI  - Predicting anticonvulsant activity of benzamides/benzylamines: computational
      approach using topological descriptors.
AB  - The relationship of Wiener's index (a distance-based topological descriptor),
      Zagreb group parameter (an adjacency-based topological descriptor) and eccentric
      connectivity index (an adjacency-cum-distance-based topological descriptor) with
      the anticonvulsant activity of a series of substituted benazamides/benzylamines
      has been investigated. A training set comprising 41 analogues of substituted
      benazamides/benzylamines was selected for the present investigations. The values
      of the Wiener's index, Zagreb group parameter and eccentric connectivity index
      and of each of 41 analogues comprising the data set were computed and active
      ranges were identified. Subsequently, a biological activity was assigned to each
      analogue involved in the data set which was then compared with the reported
      anticonvulsant activity. An exceptionally high accuracy of predictions ranging
      from a minimum of approximately 88% for the Zagreb group parameter to a maximum
      of approximately 97% for Wiener's index were obtained.

PMID- 12602950
TI  - Genetic algorithm for the design of molecules with desired properties.
AB  - The design of molecules with desired properties is still a challenge because of
      the largely unpredictable end results. Computational methods can be used to
      assist and speed up this process. In particular, genetic algorithms have proved
      to be powerful tools with a wide range of applications, e.g. in the field of drug
      development. Here, we propose a new genetic algorithm that has been tailored to
      meet the demands of de novo drug design, i.e. efficient optimization based on
      small training sets that are analyzed in only a small number of design cycles.
      The efficiency of the design algorithm was demonstrated in the context of several
      different applications. First, RNA molecules were optimized with respect to
      folding energy. Second, a spinglass was optimized as a model system for the
      optimization of multiletter alphabet biopolymers such as peptides. Finally, the
      feasibility of the computer-assisted molecular design approach was demonstrated
      for the de novo construction of peptidic thrombin inhibitors using an iterative
      process of 4 design cycles of computer-guided optimization. Synthesis and
      experimental fitness determination of only 600 different compounds from a virtual
      library of more than 10(17) molecules was necessary to achieve this goal.

PMID- 12602951
TI  - Fast estimation of hydrogen-bonding donor and acceptor propensities: a GMIPp
      study.
AB  - The suitability of the GMIPp energy functional as a fast, efficient method for
      estimating the hydrogen-bond donor and acceptor propensities of a wide variety of
      organic compounds is examined. Comparison of the GMIPp values is made with two
      experimental hydrogen-bond scales: i) the hydrogen-bond basicity scale for N
      heteroaromatics in carbon tetrachloride, and ii) the hydrogen-bond acidities for
      NH/OH donors and hydrogen-bond basicities of N/O acceptors determined in 1,1,1
      trichloroethane. Attention is paid to i) the reliability of semiempirical versus
      ab initio treatments of the quantum mechanical molecule, ii) the role of
      solvation, and iii) the effect of including the polarization energy component in
      the calculation of the GMIPp functional. The statistical analysis of the results
      reveals that the GMIP functional, which combines electrostatic and steric energy
      components, predicts with reasonable accuracy and computational efficiency the
      hydrogen-bond strength for a wide variety of compounds.

PMID- 12602952
TI  - Metal complexes of chiral pentaazacrowns as conformational templates for beta
      turn recognition.
AB  - Examples of reverse turns as recognition motifs in biological systems can be
      found in high-resolution crystal structures of antibody-peptide complexes.
      Development of peptidomimetics is often based on replacing the amide backbone of
      peptides by sugar rings, steroids, benzodiazepines, or other hetero- and
      carbocycles. In this approach, the chemical scaffold of the peptide backbone can
      be replaced while retaining activity as long as the pharmacophoric groups of the
      peptide side chains stay in relatively the same place; in other words, similar
      functional groups must overlap in space for interaction with critical receptor
      sites. This study evaluates the potential of metal complexes of chiral
      pentaazacrowns (PAC) derived by reduction of cyclic pentapeptides as beta-turn
      mimetics. Due to the limited flexibility of the pendant chiral side groups in
      these metal complexes, one can potentially elicit information about the receptor
      bound conformation from their binding affinities. 11 PAC crystal structures with
      different substitution patterns complexed with 3 different metals (Mn, Fe, Cd) as
      a prototypical database of potential side-chain orientations. Complexation with
      different metals induces subtle differences in the conformations of a particular
      azacrown scaffold. The lack of parameterization of transition metals for force
      field calculations precludes a thorough theoretical study. Thus, this study
      utilizes a simple geometrical comparison between the experimental data for
      crystalline PAC complexes and the side-chain orientations seen in classic beta
      turns. The FOUNDATION program was used to overlap the Calpha-Cbeta vectors of the
      corresponding ideal beta-turn side-chains to all possible leaving groups of the
      PAC complexes. When comparing the relative orientations of the chiral side
      chains, a strong overlap of the bonds (between about 0.1 A to about 0.5 A RMS for
      3 residues and up to about 1 A RMS for 4 residues) was observed for many of the
      molecules. Such metal complexes may lack complete peptidomimetic activity due to
      the lack of spatial overlap of all four side-chain residues, however, if only
      three peptide side chains are needed for receptor recognition and/or binding, the
      metal complexes should show biological activity.

PMID- 12602953
TI  - Molecular dynamics simulation of cyclosophoroheptadecaose (Cys-A).
AB  - The conformational preferences of cyclosophoroheptadecaose (Cys-A), which is a
      member of a class of cyclic (1 --> 2)-beta-D-glucan, were characterized by
      molecular dynamics simulations. Simulated annealing and constant temperature
      molecular dynamics simulations were performed on the Cys-A. The simulations
      produced various types of compact and asymmetrical conformations of Cys-A.
      Excellent agreement was found between experimental data and corresponding values
      predicted by molecular modeling. Most glycosidic linkages were concentrated in
      the lowest energy region of phi-psi energy map, and the values of radius of
      gyration (R(G)) and the nuclear Overhauser effect (NOE) distance data derived
      from our simulations were finely consistent with the reported experimental
      values. This result will also give novel insights for the molecular complexation
      mechanism of Cys-A with various guest chemicals.

PMID- 12602954
TI  - QSAR of benzene derivatives: comparison of classical descriptors, quantum
      theoretic parameters and flip regression, exemplified by phenylalkylamine
      hallucinogens.
AB  - A physical model of electronic effects in the QSAR of benzene derivatives,
      together with a regression technique for finding predictive equations, is
      presented. The model is simple, based on the quantum theoretic description of the
      benzene molecule, and accounts for the variance in activity of hallucinogenic
      phenylalkylamines as well as a classical description in terms of electronic
      (atomic charge, orbital energy), hydrophobic (Hansch pi) and steric (substituent
      volume) terms. The new model involves the energies of four pi-like near frontier
      orbitals and the orientations of their nodes. It is less affected by colinearity
      than the classical approach. This model more than any other illustrates the
      essential wave mechanical nature of the interaction of a drug with its receptor,
      as the pi-like orbitals involved are standing waves of probability of finding an
      electron in a given location in the field of the atomic nuclei, and have no
      classical counterpart.

PMID- 12602955
TI  - Parametrization of a force field for metals complexed to biomacromolecules:
      applications to Fe(II), Cu(II) and Pb(II).
AB  - Although techniques for the simulation of biomolecules, such as proteins and
      RNAs, have greatly advanced in the last decade, modeling complexes of
      biomolecules with metal ions remains problematic. Precise calculations can be
      done with quantum mechanical methods but these are prohibitive for systems the
      size of macromolecules. More qualitative modeling can be done with molecular
      mechanical potentials but the parametrization of force fields for metals is often
      difficult, particularly if the bonding between the metal and the groups in its
      coordination shell has significant covalent character. In this paper we present a
      method for deriving bond and bond-angle parameters for metal complexes from
      experimental bond and bond-angle distributions obtained from the Cambridge
      Structural Database. In conjunction with this method, we also introduce a non
      standard energy term of gaussian form that allows us to obtain a stable
      description of the coordination about a metal center during a simulation. The
      method was evaluated on Fe(II)-porphyrin complexes, on simple Cu(II) ion
      complexes and a number of complexes of the Pb(II) ion.

PMID- 12602957
TI  - Fungal infections in immunocompromised patients.

PMID- 12602958
TI  - The many faces of lymphocytoma cutis.

PMID- 12602956
TI  - A comparison of the pharmacophore identification programs: Catalyst, DISCO and
      GASP.
AB  - Three commercially available pharmacophore generation programs, Catalyst/HipHop,
      DISCO and GASP, were compared on their ability to generate known pharmacophores
      deduced from protein-ligand complexes extracted from the Protein Data Bank. Five
      different protein families were included Thrombin, Cyclin Dependent Kinase 2,
      Dihydrofolate Reductase, HIV Reverse Transcriptase and Thermolysin. Target
      pharmacophores were defined through visual analysis of the data sets. The
      pharmacophore models produced were evaluated qualitatively through visual
      inspection and according to their ability to generate the target pharmacophores.
      Our results show that GASP and Catalyst outperformed DISCO at reproducing the
      five target pharmacophores.

PMID- 12602959
TI  - Nitric oxide levels in Behcet's disease.
AB  - Behcet's disease (BD) is a chronic multisystemic disorder which is characterized
      by a relapsing systemic inflammatory process. In certain inflammatory conditions
      such as rheumatoid arthritis, over production of nitric oxide (NO) could damage
      host cells and tissues, either directly and/or following reaction with other free
      radicals, such as superoxide anion to form species including peroxynitrite or
      hydroxyl radicals. Excessive superoxide radical production and impaired
      antioxidant mechanism in both the neutrophils and plasma of patients with BD have
      been reported. Our study was designed to investigate the role of NO in BD. NO is
      an extremely unstable molecule and rapidly converted in vivo and in vitro to
      nitrate (NO3-) and nitrite (NO2-). For this reason serum NO2- and NO3- have been
      used as an index of NO generation. We measured serum nitrate + nitrite levels, by
      using an enzymatic one-step methodology based on the reduction of nitrate to
      nitrite by nitrate reductase from Aspergillus species, in the presence of beta
      NADPH. When compared to healthy controls, serum nitrate + nitrite levels were
      found to be higher in active periods of BD patients (P < 0.01). It was concluded
      that increased NO production in patients with BD might have critical biological
      activities relevant to vasculitic events in the active period of disease.

PMID- 12602960
TI  - Extracorporeal photochemotherapy in the treatment of eosinophilic fasciitis.
AB  - BACKGROUND: Eosinophilic fasciitis (EF) is a rare connective tissue disorder
      characterized clinically by symmetrical swelling, induration and thickening of
      the skin and histologically by thickening of the fascia with chronic inflammatory
      infiltrate containing eosinophils. The disease is classified in the spectrum
      morphea/systemic sclerosis and treated with systemic steroids and other
      immunosuppressant drugs. OBJECTIVE: The purpose of this study was to use
      extracorporeal photochemotherapy (ECP) in patients with EF to evaluate the
      effectiveness of this therapy. SUBJECTS AND METHODS: Three patients affected by
      EF were treated with ECP because they failed to respond or with contraindications
      to immunosuppressant treatment. The patients underwent ECP with a UVAR XTS
      apparatus. Subjects were treated on two consecutive days at 2-week intervals for
      the first 3 months and thereafter every 4 weeks on the basis of clinical
      response. The patients were assessed before therapy and then monthly by means of
      a clinical score. Changes in affected areas were evaluated at predetermined
      points by computerized skin elastometry (Cutometer SEM 474). RESULT: After 1 year
      of therapy we found considerable improvement of clinical parameters in two cases.
      There was less striking improvement in the other case. These clinical results
      were confirmed by the elastometry measurements. All patients reported improved
      quality of life, which enabled a reduction in the dose of immunosuppressants.
      CONCLUSION: ECP emerged as a safe and effective therapy in association with low
      doses of immunosuppressants in our three patients. A randomized comparative
      multicentre study between ECP as single therapy and ECP plus immunosuppressants
      and conventional therapies is required to firmly establish photopheresis as a
      possible basic treatment to combine with conventional therapies for EF.

PMID- 12602961
TI  - Comparative biochemistry of human skin: glycosaminoglycans from different body
      sites in normal subjects and in patients with localized scleroderma.
AB  - OBJECTIVES: The aim of this investigation is to compare the relative proportions
      of disaccharides of chondroitinase-digestible glycosaminoglycans (GAGs) among the
      different body sites in control human skin and in the skin lesions of patients
      with localized scleroderma. METHODS: The disaccharide relative proportions were
      determined using high-performance liquid chromatography (HPLC). RESULTS: DeltaDi
      4S, the main disaccharide unit of dermatan sulphate (DS), was the major skin GAG
      disaccharide (approximately 70% of the total) in control skin among all different
      body sites studied here. In scleroderma there was an increase in the relative
      proportion of both deltaDi-HA, the main disaccharide unit of hyaluronic acid
      (HA), and deltaDi-diS(B) (alpha-deltaUA(2SO4)-1-->3-GalNAc(4SO4)), derived from
      DS, and a decrease in deltaDi-4S, as compared with the uninvolved skin or the
      site-matched control skin. CONCLUSION: DS is the major GAG species in normal skin
      from different body sites. In addition, our results suggest a decrease and also a
      structural change in DS and an increase in the proportion of HA in scleroderma
      skin.

PMID- 12602962
TI  - Merkel cell carcinoma--a retrospective analysis of 17 cases.
AB  - OBJECTIVE: To report clinical experience with the rare neuroendocrine Merkel cell
      carcinoma of the skin. SUBJECTS AND SETTING: Seventeen patients with Merkel cell
      carcinoma of the skin treated at the Departments of Dermatology and ENT,
      Krankenhaus Dresden-Friedrichstadt, Dresden, Germany, during the years 1984-2000
      were evaluated. METHODS: A retrospective analysis was performed. Age and sex
      distribution, clinical data and therapy were collected. Outcome measures
      including overall survival, tumour-free survival and relapse-free survival were
      determined. RESULTS: Six male and 11 female patients with an age range of 68-90
      years (mean age 73.3 years) were identified. The primary tumour localization was
      head and neck region (n = 8), upper limbs (8), lower limbs (1). Twelve patients
      presented in tumour stage I, three in stage II and one in stage III. First line
      therapy was complete surgical excision with wide margins in 16 patients followed
      by loco-regional radiation in 12 of 16 cases. In 16 patients follow up data were
      available. After primary treatment complete response was achieved in 14 of 16
      patients (87.5%), two patients had a partial response. The median of relapse-free
      survival was 44 weeks [mean +/- standard deviation: (44 +/- 118) weeks]. The
      median of overall survival was 102 weeks [mean +/- standard deviation: (137 +/-
      94) weeks]. Three patients with a PR after primary treatment had a median overall
      survival of only 48 weeks [mean +/- standard deviation: (51 +/- 20) weeks].
      CONCLUSIONS: Primary surgical treatment with wide excision combined with
      radiotherapy seems to be a reasonable first-line treatment but prospective
      controlled multicentre trials are necessary for validation.

PMID- 12602963
TI  - Leukoplakia and intraoral malignancies: female cases increase in Greece.
AB  - In the developed world, intraoral malignancies are more frequent in males than
      females. Recent observations from Greece suggest that the number of females is
      increasing. AIM: The present study investigates gender and age statistics among
      subjects with cancers of the mouth or leukoplakia. METHODS: Five hundred and
      twelve subjects of Greek origin participated in this analysis. Chi-square and
      logistic regression statistics were used to compare if there are differences in
      participants' gender and age, stratified by histological type. RESULTS:
      Epithelial cancers and leukoplakia exhibited equal distributions among men and
      women. Men were diagnosed at a much younger age than women. Our data also
      indicates a progression in the process of epithelial cancer development, as
      benign leukoplakia was diagnosed 2-4 years earlier than epithelial dysplasia and
      8 years earlier than squamous cell carcinoma (SSC). The same age difference was
      observed in non-Hodgkin's lymphoma, although the male to female ratio was 3:1. In
      regards to anatomy, 47% of SSC appeared in the tongue. The most prevalent site
      for the development of non-Hodgkin's lymphoma was the gingival (50%), followed by
      the palate (40%). CONCLUSION: Although oral cancer occurs earlier in men than
      women, the risk of females tends to be similar to that of males.

PMID- 12602964
TI  - The 'common mole' from the point of view of digital dermoscopy analysis:
      subjective vs. objective evaluation of easy pigmented skin lesions.
AB  - BACKGROUND: The term 'common mole', often used to describe a subset of benign
      pigmented skin lesions, is traditionally defined on the basis of morpho-chromatic
      features. In recent years, certain research groups have developed equipment and
      methods, such as digital dermoscopy analysis, that enable objective evaluation of
      pigmented skin lesions. OBJECTIVE: In this study we use a digital dermoscopy
      analyser trained for the recognition of pigmented skin lesions to compare the
      subjective definition of 'common' and the mathematical concept of 'close to the
      mean of measurements'. METHODS: A subset (100) of digital images of flat
      pigmented lesions, obtained in daily practice, were classified by trained and non
      expert clinicians as common moles (60) or clear-cut melanoma (40), and processed
      with a DB-Mips analyser. The resulting parameters, validated by a classifier,
      were used to evaluate Hotelling's T2 multivariate distances from the mean.
      RESULTS: 'Common' moles could not be clearly defined in terms of closeness to the
      means of objectively evaluated parameters. Their diagnosis indudes many other
      evaluations and clusters of variables. CONCLUSION: The clinical semantics of the
      term 'common' does not conform to any unambiguous mathematical definition.

PMID- 12602965
TI  - The role of oxidants and antioxidants in psoriasis.
AB  - BACKGROUND: Psoriasis vulgaris is a chronic inflammatory skin disease
      characterized by well-demarcated erythema and scaly plaques. The pathogenesis of
      psoriasis still remains unclear. An increased reactive oxygen species (ROS) and
      insufficient antioxidant activity have been determined in psoriatic lesions. AIM
      OF THE STUDY: To evaluate and compare superoxide dismutase (SOD) and glutathione
      peroxidase (GP) activity in erythrocytes, catalase (CAT) activityand
      malondialdehyde (MDA) levels in serum of subjects with psoriasis and controls as
      well as MDA levels in skin biopsies from both groups. STUDY POPULATION: Twenty
      two psoriatic patients (12 women and ten men) and 22 (12 women and ten men)
      healthy controls were involved in this study. FINDINGS: Statistically significant
      decreased levels of erythrocyte SOD and GP activities were noted in psoriatic
      subjects. Furthermore, a statistically significant increased serum CAT activity
      was found in the psoriasis group. No statistically significant difference was
      found in the serum MDA levels in the two groups, however, statistically
      significant increased tissue levels of MDA were noted in the psoriasis group.
      CONCLUSIONS: Our results support the hypothesis of an imbalance in the oxidant
      antioxidant system in psoriasis.

PMID- 12602966
TI  - New established melanoma cell lines: genetic and biochemical characterization of
      cell division cycle.
AB  - BACKGROUND: Cancer might be envisaged as the result of a genetic process causing
      the unregulated proliferation of a given cell as well as its inability to undergo
      differentiation and/or apoptosis. Alterations of genes regulating cell division
      cycle appear to play a key role in the development of human cancer. OBJECTIVE: On
      the bases of the above considerations, we decided to establish new cell lines
      from human melanoma specimens, in order to analyse the molecular alterations in
      primary preparations of malignant cells. RESULTS: The present paper describes two
      new established cell lines and their genetic and biochemical features. Both the
      melanoma cell lines show inactivation of the cyclin-dependent kinase inhibitor
      gene, CDKN2A/p16INK4A, thus demostrating that this alteration occurs in primary
      human melanomas. No other alterations were observable when we investigated
      several different cell cycle genes including those encoding cyclins, cyclin
      dependent kinases and cyclin-dependent kinase inhibitors. Analyses at protein
      level by means of immunoblotting confirmed the results obtained at the genetic
      level. Moreover, the inducibility of a pivotal cyclin-dependent kinase inhibitor
      gene, namely p21CIP1 gene, was obtained by treating the cells with histone
      deacetylase inhibitors, namely butyrate and phenylbutyrate. CONCLUSIONS: Our
      results suggest a primary role of cyclin-dependent kinase inhibitor genes
      inactivation in the origin of human melanoma and allow the proposal of new
      therapeutic strategies based on the transcriptional activation of p21CIP1 gene.

PMID- 12602967
TI  - Serum levels of interleukin-18 and s-ICAM-1 in patients affected by psoriasis:
      preliminary considerations.
AB  - OBJECTIVE: To find new aspects of the systemic involvement of the Immune System
      in psoriasis, we determined serum levels of interleukin-18 (IL-18) (Th1-inducing
      factor cytokine), CD30 (Th2 marker) and sICAM-1 (adhesion molecule). In addition
      we evaluated the correlation between these molecules and psoriasis area and
      severity index (PASI). BACKGROUND: Psoriasis is associated to an overexpression
      of Th1 cytokines and a relative underexpression of Th2 cytokines. IL-18 plays an
      important role in inducing Th1 response because it is a potent inductor of
      synthesis of IFN-gamma, TNF and other mediators. The two major sources of IL-18
      are monocytes and macrophages but also human keratinocytes constitutively
      synthesized IL-18. SUBJECTS AND METHODS: We selected two groups of subjects: 16
      healthy donors (HD) and 16 patients affected by psoriasis, matched for sex and
      age. Serum IL-18, CD30 and sICAM-1 levels were assayed by immunoenzymatic method
      with commercial kits. RESULTS: IL-18 and sICAM-1 levels in the patients were
      significantly higher than in the HDs (385.94 +/- 193.89 vs. 227.38 +/- 92.76
      pg/mL, P = 0.005 and 445.00 +/- 152.67 vs. 317.88 +/- 107.20 ng/mL, P = 0.02,
      respectively). On the contrary, no significant difference was found between serum
      sCD30 levels of patients in respect to those of HDs. A significant correlation
      was found between serum IL-18 and PASI (Rho = 0.695, P = 0.0071), serum IL-18 and
      sICAM-1 (Rho = 0.543, P = 0.0356) and between sICAM-1 and PASI (Rho = 0.659, P =
      0.0107).

PMID- 12602968
TI  - Cutaneous infection due to Scedosporium apiospermum in an immunosuppressed
      patient.
AB  - Scedosporium apiospermum, the anamorphic form of Pseudallescheria boydii, is a
      filamentous fungus with low inherent virulence. Increasing numbers of cases of
      this infection have been reported probably related to the rising number of
      immunosuppressed persons. Apart from mycetoma, cutaneous and subcutaneous
      infection is rarely encountered in clinical practice. We describe a case of
      cutaneous infection caused by Scedosporium apiospermum in a subject with
      rheumatoid arthritis and diabetes mellitus who was submitted to long-term therapy
      with cyclosporin and corticosteroids. Histopathologic examination of a skin
      biopsy showed a granulomatous infiltrate with hyaline septate hyphae. Culture of
      two skin biopsies taken at two different observations of the woman, 3 weeks
      apart, allowed isolation of Scedosporium apiospermum. Therapy with itraconazole,
      400 mg/day, for 3 months was effective in curing the infection.

PMID- 12602969
TI  - Turner's syndrome associated with psoriasis and alopecia areata.
AB  - Turner's syndrome is a sex chromosomal abnormality characterized by gonadal
      failure, short stature, skeletal and medical anomalies due to structural defects
      or monosomy of the X chromosome. The association between this syndrome and
      autoimmune diseases has been reported in the literature. This case report
      highlights the finding of two immunological skin diseases, alopecia areata and
      psoriasis, in an 18-year-old girl with Turner's syndrome. By the time of her
      referral to the Department of Dermatology, Verona University (Italy) the girl had
      suffered from psoriasis on the scalp for 5 years and alopecia for 6 months; the
      diagnoses were confirmed by histological evaluation. Topical therapy was useful
      for the treatment of the psoriatic lesions but not for the alopecia areata.
      Alopecia areata and psoriasis occurring together in Turner's syndrome may
      indicate some genetic relationship and could support the concept that these
      patients have the tendency to develop autoimmune or immunological diseases.
      Anxiety, depression and unsatisfactory relationships could have been important
      trigger factors in our patient. Multidisciplinary management, including
      psychological, educational and behavioural techniques, in addition to other
      therapies, could be useful in treating these conditions.

PMID- 12602970
TI  - Phakomatosis pigmentovascularis and Lisch nodules. Relationship between Von
      Recklinghausen and phakomatosis pigmentovascularis?
AB  - In 1947, Ota described a malformative syndrome associating a vascular component
      (nevus flammeus) with melanocytic or epidermic nevi, which he named phakomatosis
      pigmentovascularis (PPV). We will discuss the case of a 10-year-old boy
      presenting giant nevus flammeus, nevus spillus, asymmetry in the development of
      both lower limbs, characteristic of PPV, together with interventricular
      communication and Lisch nodules, representative of Von Recklinghausen's disease.
      We believe that this case can be classified as PPV type IIb, associated with
      Lisch nodules and rarely described in Caucasian individuals.

PMID- 12602971
TI  - Three cases of androgen-dependent disease associated with myotonic dystrophy.
AB  - Three cases of androgen-dependent disease in females with myotonic dystrophy are
      described. Serum androgens in individuals affected by myotonic dystrophy are
      known to be lower on average than in normal controls. Despite this these three
      females developed diseases that are androgen dependent, including acne,
      hidradenitis suppurativa, androgenetic alopecia and keratosis pilaris. These
      cases support the hypothesis that the peripheral response to androgens rather
      than absolute circulating levels of androgens is important in androgen-dependent
      conditions.

PMID- 12602972
TI  - A case of sarcomatoid carcinoma of the skin.
AB  - We describe the histological and immunocytochemical findings of an exophytic
      cutaneous tumour with mixed features of atypical fibroxanthoma (AFX) and basal
      cell carcinoma (BCC). A 73-year-old woman presented with a rapidly growing tumour
      measuring 35 mm in diameter and 10 mm in height on the left forearm. The tumour
      was excised and histology revealed a biphasic tumour with a pleomorphic spindle
      cell component and an associated tumour composed of discrete islands of atypical
      basaloid cells with peripheral palisading consistent with BCC. The two tumours
      merged into each other at one point. The spindle cell tumour showed a positive
      immunocytochemical reaction to fibrohistiocytic marker of KP-1 (CD68) and a
      negative immunocytochemical reaction to AE1/AE3, CAM5.2, S-100 and HMB-45,
      features consistent with AFX. Immunocytochemistry of the basaloid tumour showed a
      positive reaction to epithelial markers AE1/AE3 and CAM5.2, and a negative
      reaction to S-100, HMB-45 and KP-1 (CD68). To date, 15 cases of primary cutaneous
      carcinosarcoma have been reported in the literature. It has been postulated that
      these tumours may originate from undifferentiated progenitor cells capable of
      producing multiple cell lines.

PMID- 12602973
TI  - Leg ulcer in Klinefelter's syndrome.
AB  - Hypostatic ulceration of the legs is relatively uncommon in men. Recently, the
      hypothesis that recurrent ulceration in men may be associated with chromosomal
      abnormalities such as Klinefelter's syndrome is gradually being accepted. Herein,
      we describe a patient with Klinefelter's syndrome complicated by recurrent leg
      ulcers, in whom immunological disorders such as positive antinuclear factor,
      antiphospholipid antibodies and cryoglobulins without venous insufficiencies were
      demonstrated. Interestingly, these abnormalities of immune functions were
      normalized after the androgen replacement therapy for Klinefelter's syndrome, and
      his leg ulcers immediately recovered.

PMID- 12602974
TI  - A case of bacillary angiomatosis presenting as leg ulcers.
AB  - We report a 32-year-old immunocompetent man who had multiple leg ulcers caused by
      bacillary angiomatosis without a history of direct contact with cats. Bacillary
      angiomatosis should be kept in mind in the differential diagnosis of leg ulcers
      in cases of unknown aetiology.

PMID- 12602976
TI  - Atrophodermia vermiculata: case report and review of the literature.
AB  - A 21-year-old woman with an 11-year history of symmetric reticular atrophy on
      both cheeks, pre-auricular areas, and forehead is presented. The depressions gave
      a worm-eaten appearance to the skin. Histopathological findings from a biopsy
      specimen of lesional skin revealed an atrophic follicle. The connective tissue
      showed mild inflammation in perifollicular and perivascular distribution. The
      hair follicle was widely dilated and was filled with a keratotic plug. This case
      points out many of the outstanding clinical and histopathological features of
      atrophodermia vermiculata as described previously. Atrophodermia vermiculata
      appears to be one of a group of closely related conditions characterized by
      keratosis pilaris and atrophy of the skin.

PMID- 12602977
TI  - Pachydermoperiostosis and psoriatic onychopathy: an unusual association.
AB  - A 33-year-old man, suffering from cutaneous psoriasis since the age of 16, in the
      last 6 years experienced slow and painless enlargement at his fingertips and
      later at his big toes, which resulted in digital clubbing. Since the age of 31,
      the patient also presented psoriatic nail changes involving all his fingernails,
      without joint pain or inflammation. The patient's family history was negative for
      psoriasis, however, his brother, a 29-year-old healthy man, also presented
      digital clubbing. The diagnosis of pachydermoperiostosis coexistent with ungual
      and cutaneous manifestations of psoriasis vulgaris was made. The differential
      diagnosis with psoriatic onycho-pachydermo-periostitis, as well as other clinical
      conditions that involve the distal interphalangeal joints is discussed.

PMID- 12602975
TI  - An unusual case of palmoplantar keratoderma.
AB  - A 55-year-old woman with palmoplantar keratoderma presented an associated
      hyperhidrosis with distinct odour and maceration. She had had the lesions for
      about 20 years and this seemed to be an isolated case in her family. This case
      appeared very unusual because there were no signs of acanthokeratolysis in the
      biopsies. Two months of treatment with acitretin (Neotigason; 25 mg daily),
      produced a spectacular result: clearance of all the lesions on both hands and a
      strong diminution of the lesions on the soles. The Unna-Thost variant of
      palmoplantar keratoderma usually appears in the first few months of life, and it
      rarely appears in the third decade. The condition is inherited as an autosomal
      dominant with high penetrance and expressivity. Our subject appeared to be an
      exception to these two facts.

PMID- 12602978
TI  - Neutrophilic pustulosis and ulcerative colitis.
AB  - Neutrophilic pustulosis is currently considered as a part of the spectrum of
      Sweet's syndrome, and has been associated with inflammatory bowel disease and
      several other diseases. We report the case of a 34-year-old male who had been
      suffering from ulcerative colitis (UC) for several years and who experienced the
      manifestation of a pustular eruption on both forearms and the abdominal wall
      during an exacerbation of his bowel disease. Both processes were controlled with
      steroids per os. The histological picture showed an inflammatory infiltrate
      composed mainly of neutrophils with scattered neutrophilic epidermal abscesses.
      Certain distinct clinical and histological characteristics have been described as
      diagnostic of the pustular eruption of UC. This picture should be included in the
      spectrum of the neutrophilic dermatosis, in our case associated with an
      ulcerative colitis. This is a well documented clinical and histologic case report
      of a recognized association of inflammatory pustulosis in the course of
      ulcerative colitis.

PMID- 12602979
TI  - Long-term remission of recalcitrant tumour-stage mycosis fungoides following
      chemotherapy with pegylated liposomal doxorubicin.
AB  - Advanced stage mycosis fungoides (MF) generally has a poor prognosis, and
      currently there is no standard treatment available. Here we report the case of a
      young woman with recalcitrant tumour-stage MF (T3, stage IIb) whose disease was
      unresponsive to several therapeutic modalities, but who has showed sustained
      clinical response to pegylated liposomal doxorubucin. No severe infectious
      complications have been observed. The use of this drug in tumour-stage MF should
      be investigated further.

PMID- 12602980
TI  - Hybrid cyst: case reports and review of 15 cases in Japan.
AB  - Hybrid cyst is a rare cystic lesion that includes more than two components of the
      pilosebaceous units. To clarify the clinical and pathological features of hybrid
      cysts, we report two cases and review 15 cases of hybrid cyst in Japan. On the
      whole, the age range was 12-73 years with a 2.95:1 female predominance and
      predilection for the scalp and face (46.7%). Most of the tumours presented as a
      solitary lesion and the size range was 2-45 mm. The most frequent histological
      type was the combination of infundibular and trichilemmal cysts (60.0%). Studying
      the clinicopathological features of hybrid cysts helps us in understanding the
      pathogenesis of diseases arising from pilosebaceous units.

PMID- 12602982
TI  - Bullous eosinophilic cellulitis (Wells' syndrome) associated with Churg-Strauss
      syndrome.
AB  - We report a patient with Churg-Strauss syndrome (CSS) with asthma, eosinophilia,
      nasal polyposis and ANCA-associated multisystem vasculitis, who's skin eruption
      started with erythematous urticarial-plaques followed by haemorrhagic bullae.
      Histology of the plaques revealed 'flame figures' in the dermis with no
      granulomatous or vasculitic process, consistent with the diagnosis of
      eosinophilic cellulitis or Wells' syndrome. The association of CSS and Wells'
      syndrome observed in this patient may have a common pathogenesis. CSS may induce
      Wells' syndrome by an unknown factor.

PMID- 12602981
TI  - Botryomycosis in an HIV-positive subject.
AB  - A 28-year-old male AIDS patient with generalized painful skin ulcers, fever and
      malaise presented to us. The differential diagnosis included varicella zoster
      infection, herpes simplex infection, actinomycosis, sporotrichosis and
      botryomycosis. Histopathology revealed clusters of gram-positive coccoid bacteria
      in the deep dermis, surrounded by a mixed dense inflammatory infiltrate. A
      bacterial culture grew Staphylococcus aureus. Viral cultures remained negative.
      Based on these findings botryomycosis was diagnosed. Large lesions were excised
      surgically and with antimicrobial therapy all skin symptoms disappeared. We
      discuss this case with reference to a short review of the literature on
      botryomycosis in relation to HIV infection.

PMID- 12602983
TI  - Pigmented terminal hair cysts within an intradermal melanocytic naevus.
AB  - The combination of melanocytic naevi and cysts of adnexal or epithelial origin
      has been described previously. Herein we describe a case of intradermal
      melanocytic naevus containing pigmented terminal hair cysts, a rare variant of
      epithelial cysts. Our observation suggests that pigmented follicular cysts and
      combined cystic-melanocytic lesions may be attributed to follicular occlusion.

PMID- 12602984
TI  - Lupus miliaris disseminatus faciei and its debated link to tuberculosis.

PMID- 12602985
TI  - Cutaneous lichen planus and squamous cell carcinoma.

PMID- 12602986
TI  - Tuberous sclerosis with unusual giant ungual fibromas.

PMID- 12602987
TI  - Diagnostic criteria for pityriasis rosea: a prospective case control study for
      assessment of validity.

PMID- 12602988
TI  - Pemphigus vulgaris lesion on a melanocytic naevus.

PMID- 12602989
TI  - Large B-cell lymphoma of the skin arising on a background of polyclonal B-cell
      hyperplasia.

PMID- 12602990
TI  - Safety of cyclosporin A in the treatment of dermatological diseases.

PMID- 12602992
TI  - Gynaecomastia following treatment by fluoxetine.

PMID- 12602991
TI  - Hyalinosis cutis et mucosae: excessively secreted basal lamina by pericytes and
      myofibroblasts and its conversion to hyalin.

PMID- 12602993
TI  - A case of important nodular fasciitis of the leg.

PMID- 12602994
TI  - Homage to Reverdin: pinch grafting.

PMID- 12602996
TI  - Reiter's syndrome-like pattern in AIDS-associated psoriasiform dermatitis.

PMID- 12602995
TI  - Multiple cutaneous squamous carcinoma in a psoriatic associated with ciclosporin,
      alcohol abuse and ultraviolet radiation exposure which were suppressed by
      acitretin.

PMID- 12602997
TI  - A cross-cultural investigation of the communication of suicidal intent in Swedish
      and Turkish adolescents.
AB  - A recent study found that Swedish adolescents were more disapproving of a
      suicidal disclosure by a fictional friend than their Turkish counterparts. Given
      this finding, the present study investigated whether or not more adolescents in
      Turkey than in Sweden disclose their own suicidal thoughts to someone, to whom
      adolescents disclose their suicidal thoughts, what reactions such disclosures
      produce, and reasons for not disclosing suicidal feelings among 966 Swedish and
      956 Turkish high school students. A questionnaire was used to collect information
      about different aspects of suicidal disclosures. More Turkish than Swedish
      adolescent suicide ideators disclosed their thoughts. More Turkish than Swedish
      students believed also that young people thinking about and planning suicide tell
      others of their plans and thereby ask for help. An overwhelming majority of
      adolescents in both groups revealed their thoughts to peers. The social reactions
      to suicidal disclosures in both samples were mainly positive. The two most common
      reasons for not disclosing in both groups involved interpersonal hopelessness.
      Adolescents who disclosed their past suicidal thoughts to someone reported having
      lower current suicidal ideation than those who had not. In line with favorable
      social attitudes towards suicidal disclosures and lower suicidal mortality rates
      in Turkey compared with Sweden, more Turkish than Swedish adolescents reported
      having disclosed their own suicidal thoughts to someone in their social milieu.

PMID- 12602998
TI  - Self-reported assertiveness in Swedish and Turkish adolescents: a cross-cultural
      comparison.
AB  - The present cross-cultural study compared self-reported assertiveness in 652
      Swedish and 654 Turkish high school students by using a multi-dimensional measure
      called the Scale for Interpersonal Behavior (SIB). Four hypotheses were tested in
      the study. First, the hypothesis that Swedish adolescents would be more assertive
      than their Turkish counterparts was supported by the data. Second, the
      expectation that Turkish boys would be more assertive than Turkish girls, while
      there would be no differences between Swedish girls and boys, was not confirmed.
      In general, girls were found to be more skilled than boys in expressing and
      dealing with personal limitations. Third, as expected, more assertive adolescents
      in both Sweden and Turkey reported having more friends and receiving more social
      support than their less assertive peers. Finally, the data supported the
      expectation that older adolescents would be more assertive than younger ones. The
      results are discussed in terms of cultural and gender differences.

PMID- 12602999
TI  - The effects of road traffic noise and meaningful irrelevant speech on different
      memory systems.
AB  - To explore why noise has reliable effects on delayed recall in a certain text
      reading task, this episodic memory task was employed with other memory tests in a
      study of road traffic noise and meaningful but irrelevant speech. Context
      dependent memory was tested and self-reports of affect were taken. Participants
      were 96 high school students. The results showed that both road traffic noise and
      meaningful irrelevant speech impaired recall of the text. Retrieval in noise from
      semantic memory was also impaired. Attention was impaired by both noise sources,
      but attention did not mediate the noise effects on episodic memory. Recognition
      was not affected by noise. Context-dependent memory was not shown. The lack of
      mediation by attention, and road traffic noise being as harmful as meaningful
      irrelevant speech, are discussed in relation to where in the input/storing/output
      sequence noise has its effect and what the distinctive feature of the disturbing
      noise is.

PMID- 12603000
TI  - The assessment of fitness to drive after a stroke: the Nordic Stroke Driver
      Screening Assessment.
AB  - The British Stroke Driver Screening Assessment (SDSA) is a set of four simple
      cognitive tests to evaluate driving fitness in stroke patients. To evaluate its
      usefulness in a Scandinavian context, we adapted the tests and assessed a group
      of 97 stroke patients from Sweden and Norway, using a driving test as the
      criterion. When results were calculated according to the original method, based
      on a discriminant function, less than 70% of the participants were correctly
      classified. To improve the predictive potential, a new discriminant analysis was
      performed, using the scores of a subsample of 49 patients, and validated on the
      remaining 48 participants. In total, 78% of the patients were correctly
      classified, but specificity was superior to sensitivity. We conclude that the
      Nordic version of the SDSA is a useful instrument, provided that test scores are
      interpreted in a balanced manner, taking into account the possibility of
      compensatory traffic behavior.

PMID- 12603001
TI  - Obstructive sleep apnea syndrome: autobiographical memory predicts the course of
      depressive affect after nCPAP therapy.
AB  - Although nCPAP therapy has proven to be efficient at removing symptoms of
      obstructive sleep apnea syndrome (OSAS), recovery from depression frequently
      remains unsatisfactory. Other studies have shown that recall of autobiographical
      memories (AM) is a psychological vulnerability marker for depression, and also
      have shown its predictive power for the course of depression. It is therefore
      hypothesized that AM also predict the course of depressive affect in OSAS
      patients. Fifty-four consecutively admitted OSAS patients received standard nCPAP
      therapy. Specificity of AM assessed at the beginning of treatment was used as a
      predictor in a regression analysis, and the extent of recovery from depression
      over a follow-up period of between six to nine weeks served as the criterion
      variable. The results supported the hypothesis that patients who were able to
      recall more specific AM in response to positively valenced cue words showed a
      more substantial recovery from depression. This has important treatment
      implications.

PMID- 12603002
TI  - Do dispositional attributions regarding peer endorsers influence product
      evaluations?
AB  - The effect of a peer endorsement advertisement on research participants'
      attitudes toward the advertised product was examined. An advertisement for a
      Seiko watch and a questionnaire were administered to participants. The degree of
      dispositional attributions regarding the endorser's motivation and participants'
      subsequent attitudes associated with the Seiko watch were measured. In addition,
      other factors that might affect product evaluation were measured. Whether product
      evaluation could be accounted for by correspondence bias was investigated. The
      results showed that the degree of dispositional attributions correlated with
      product evaluations. There was no correspondence bias. Possible causes for the
      lack of correspondence bias are discussed and a model suggesting factors
      accounting for participants' product evaluations is presented.

PMID- 12603003
TI  - Episodic and semantic memory in bilingual and monolingual children.
AB  - Although bilinguality has been reported to confer advantages upon children with
      respect to various cognitive abilities, much less is known about the relation
      between memory and bilinguality. In this study, 60 (30 girls and 30 boys)
      bilingual and 60 (30 girls and 30 boys) monolingual children in three age groups
      (mean ages 8.5, 10.5 and 12.5 years) were compared on episodic memory and
      semantic memory tasks. Episodic memory was assessed using subject-performed tasks
      (with real or imaginary objects) and verbal tasks, with retrieval by both free
      recall and cued recall. Semantic memory was assessed by word fluency tests.
      Positive effects of bilingualism were found on both episodic memory and semantic
      memory at all age levels. These findings suggest that bilingual children
      integrate and/or organize the information of two languages, and so bilingualism
      creates advantages in terms of cognitive abilities (including memory). Some sex
      differences were also found in episodic memory but not in semantic memory. This
      episodic memory difference was found with younger children.

PMID- 12603004
TI  - Extinction after partial reinforcement: predicted vs. judged persistence.
AB  - The partial reinforcement extinction effect (PREE) (i.e., increased persistence
      following partial reward) is one of the most important generalizations from
      experimental studies of learning. Many theories of PREE assume that it involves
      cognitive and emotional mechanisms, but investigations of PREE have focused
      almost exclusively on behavioral measures. Four experiments with human adults
      investigated whether PREE is also reflected in cognitive measures. Independent
      groups of subjects learned an instrumental response under CRF vs. PRF
      contingencies, and then predicted (Experiments 1, 2, and 3) and/or judged
      (Experiments 3 and 4) their own persistence under extinction conditions.
      Predictions of persistcnce were unrelated to prior continuous or partial
      reinforcement contingencies (Experiments 1, 2, and 3), but subsequent judgments
      of persistence behavior were accurate (Experiments 3 and 4). These results
      indicate that increased persistence due to occasional reward is not well
      represented cognitively prior to its behavioral manifestation, but it is well
      represented after that manifestation. Possible explanations and implications of
      this apparent behavior cognition dissociation are discussed.

PMID- 12603005
TI  - Accuracy in scientific discourse.

PMID- 12603006
TI  - Effects of dietary fish oil on the fatty acid composition of the main lipid
      classes of chick plasma lipoproteins.
AB  - We have studied the effects of diet supplementation with 10% fish oil on fatty
      acid composition of the main lipid classes of chick plasma lipoproteins bearing
      in mind the relationship between platelet aggregation and eicosanoid production
      from arachidonic acid. Fish oil drastically increased the percentages of 20:5 n-3
      and 22:6 n-3 acids in the high density lipoprotein lipids. The 20:5/22:6 ratio
      increased in triacylglycerol fraction whereas in phospholipids and cholesterol
      esters both 20:5 and 22:6 acids increased in a similar proportion. The percentage
      of arachidonic acid was higher in phospholipids than in the other lipid classes
      from this lipoprotein fraction and was significantly reduced by fish oil feeding.
      Linoleic acid, which was the most abundant fatty acid in cholesterol esters,
      strongly decreased after fish oil consumption. Changes induced in low- and very
      low density lipoproteins were similar to that observed in the high density
      lipoproteins. However, in the very low density lipoproteins, the 20:5/22:6 ratio
      was not increased in triacylglycerols, in contrast to that found in the high- and
      low density fractions. Our results suggest that decreases observed by fish oil
      feeding in the percentages of arachidonic acid in phospholipids and linoleic acid
      in cholesterol esters in the three lipoprotein fractions may be of importance to
      explain some pharmacological effects of n-3 PUFA with regard to vascular
      diseases.

PMID- 12603007
TI  - Changes in UCP expression in tissues of Zucker rats fed diets with different
      protein content.
AB  - The effect of dietary protein content on the uncoupling proteins (UCP) 1, 2 and 3
      expression in a number of tissues of Zucker lean and obese rats was studied.
      Thirty-day-old male Zucker lean (Fa/?) and obese (fa/fa) rats were fed on
      hyperproteic (HP, 30% protein), standard (RD, 17% protein) or hypoproteic (LP, 9%
      protein) diets ad libitum for 30 days. Although dietary protein intake affected
      the weights of individual muscles in lean and obese animals, these weights were
      similar. In contrast, huge differences were observed in brown adipose tissue
      (BAT) and liver weights. Lean rats fed on the LP diet generally increased UCP
      expression, whereas the HP group had lower values. Obese animals, HP and LP
      groups showed higher UCP expression in muscles, with slight differences in BAT
      and lower values for UCP3 in subcutaneous adipose tissue. The mean values of UCP
      expression in BAT of obese rats were lower than in their lean counterpart,
      whereas the expression in skeletal muscle was increased. Thus, expression of UCPs
      can be modified by dietary protein content, in lean and obese rats. A possible
      thermogenic function of UCP3 in muscle and WAT in obese rats must be taken into
      account.

PMID- 12603008
TI  - Effect of prenatal stress on the hormonal response to acute and chronic stress
      and on immune parameters in the offspring.
AB  - The effect of prenatal stress on the time course of the corticosterone response
      to acute and chronic stress and on hematological and immunological parameters in
      the offspring were analized in the present study. Pregnant Sprague-Dawley rats
      were stressed daily for 2 hours during the last week of gestation, and female and
      male off-spring were studied during adulthood. Corticosterone response to acute
      immobilization stress was not significantly different in either control or
      prenatally stressed rats. However, after 10 days of immobilization stress the
      corticosterone response completely disappeared in the control animals but not in
      the prenatally stressed group: high levels of corticosterone were found during
      the first hour of stress, although they were lower than those found in acutely
      stressed rats. Adrenal hypertrophy in response to prenatal stress was observed in
      females but not in male offspring, and chronic stress only increased adrenal
      weights in the male control group. Prenatal stress decreased the total peripheral
      leukocyte count, altered its diferential count decreasing lymphocytes and
      increasing neutrophil and eosinhophil counts, and significantly reduced the
      percentage of peripheral lymphocyte T CD8+ subset in male offspring. Chronic
      stress also reduced the percentage of the peripheral T CD8+ lymphocyte subset in
      the control group but not in the prenatally stressed group. These results suggest
      that the exposure to stress during pregnancy alters the adaptative response of
      the hypothalamus-pituitary-adrenocortical axis to chronic stress and presumably
      the immune competence in the offspring.

PMID- 12603009
TI  - Interrelationship between serum lipid profile, serum hormones and other
      components of the metabolic syndrome.
AB  - The aim of the present study was to investigate the association between the serum
      lipid profile and components of the metabolic syndrome, such as central obesity
      (anthropometric, computed tomography and fat cell data), insulin, sex-hormone
      binding-globulin (SHBG) and different hormones influencing this important
      syndrome, e.g. sex steroids, leptin and tumor necrosis factor-alpha (TNF-alpha).
      The sample consisted of 85 obese patients (30 men and 55 women) who had undergone
      abdominal surgery. Fasting serum lipids were analysed, as well as anthropometric
      and computed tomography data, perivisceral and subcutaneous fat cell size and
      serum glucose and hormones. Abdominal fat revealed itself as an important
      correlator of the adverse changes in plasma lipoprotein levels, the waist-to-hip
      ratio and waist-to-thigh-ratio being the best morphological correlators in men
      and women, respectively. Intra-abdominal fat (VA) correlated significantly and
      positively to perivisceral fat cell size in women, while no correlation was found
      between subcutaneous fat accumulation (SA) and adipocyte size in both genders.
      Perivisceral fat cell size showed the greatest number of correlations with the
      adverse plasma lipid profile compared to that in the subcutaneous depot. SHBG and
      sex steroids showed a negative correlation with serum lipids considered a
      cardiovascular risk. In contrast, TNF-alpha and C-peptide were inversely
      correlated with potential protector lipids. In conclusion, abdominal obesity,
      adipocyte hypertrophy from visceral fat, serum TNF-alpha and C-peptide seem to be
      the best correlators of the lipoprotein disturbance characteristic of the
      metabolic syndrome, whereas SHBG and sex steroids could play a protective role
      regarding the lipid profile associated to this syndrome.

PMID- 12603010
TI  - Effects of overexpression of growth hormone on T cell activity in transgenic
      mice.
AB  - Growth hormone plays a key role in the maturation and maintenance of the immune
      response, however, the effects of chronic high circulating concentrations of the
      hormone on the immune system is poorly understood. Transgenic mice overexpressing
      bovine growth hormone (b-GH) gene, fused to the rat phosphoenolpyruvate
      carboxykinase promoter (PEPCK), with very high plasma concentration of
      heterologous b-GH and their littermate normal siblings were used. Spleen
      cellularity, percentages of total T lymphocytes, CD4+ and CD8+ cells, ratio of T
      cell subpopulations, mitogen-induced lymphocyte proliferation and natural killer
      (NK) cell activity were examined in male transgenic mice and normal littermate
      mice at 2 and 6 months of age. The number of splenic lymphocytes was greater in
      transgenic mice than in matched normal littermates at both ages. The NK cell
      activity was lower in transgenic mice than in the matched normal littermates at
      both ages, with the lowest values found in older mice. The b-GH transgenic mice
      had lower percentages of T cells at both ages, however, in young transgenic mice,
      the percentage of CD4+ cells was reduced while percentage of CD8+ cells was
      increased in comparison to normal controls. Both basal and mitogen-induced
      proliferation capacity of splenocytes were reduced in PEPCK-b-GH-25 mice as
      compared to normal littermates of both ages. Proliferative indexes in response to
      concanavalin A and phytohemagglutinin were markedly decreased in 6 month old
      PEPCK-b-GH-25 mice as compared to littermate controls or younger mice. These
      results indicate that overexpression of b-GH in mice is associated with decreased
      T cell function and that these abnormalities are age-dependent.

PMID- 12603011
TI  - IGF1 gene transfer into skeletal muscle using recombinant adeno-associated virus
      in a rat model of liver cirrhosis.
AB  - Systemic administration of recombinant IGF1 at low levels has been shown to
      improve hepatic function, nutritional status and testicular atrophy in rats with
      CCl4-induced cirrhosis. We have developed a recombinant adeno-associated (rAAV)
      viral vector containing the cDNA for rat IGF1 and confirmed the expression of
      IGF1 after intramuscular injection of this vector in a rat model of liver
      cirrhosis. Although weight of injected muscles was significantly increased in
      rats with mild cirrhosis, this was not the case in rats with advanced, de
      compensated cirrhosis. Furthermore, we found no significant amelioration of liver
      damage in treated rats at any stage of liver cirrhosis. Our results suggest that
      IGF1 gene transfer into muscle results in a local effect, at least at the vector
      dose employed here.

PMID- 12603013
TI  - Multiclass cancer classification using gene expression profiling and
      probabilistic neural networks.
AB  - Gene expression profiling by microarray technology has been successfully applied
      to classification and diagnostic prediction of cancers. Various machine learning
      and data mining methods are currently used for classifying gene expression data.
      However, these methods have not been developed to address the specific
      requirements of gene microarray analysis. First, microarray data is characterized
      by a high-dimensional feature space often exceeding the sample space
      dimensionality by a factor of 100 or more. In addition, microarray data exhibit a
      high degree of noise. Most of the discussed methods do not adequately address the
      problem of dimensionality and noise. Furthermore, although machine learning and
      data mining methods are based on statistics, most such techniques do not address
      the biologist's requirement for sound mathematical confidence measures. Finally,
      most machine learning and data mining classification methods fail to incorporate
      misclassification costs, i.e. they are indifferent to the costs associated with
      false positive and false negative classifications. In this paper, we present a
      probabilistic neural network (PNN) model that addresses all these issues. The PNN
      model provides sound statistical confidences for its decisions, and it is able to
      model asymmetrical misclassification costs. Furthermore, we demonstrate the
      performance of the PNN for multiclass gene expression data sets. Here, we compare
      the performance of the PNN with two machine learning methods, a decision tree and
      a neural network. To assess and evaluate the performance of the classifiers, we
      use a lift-based scoring system that allows a fair comparison of different
      models. The PNN clearly outperformed the other models. The results demonstrate
      the successful application of the PNN model for multiclass cancer classification.

PMID- 12603012
TI  - The nitric oxide pathway in the cardiovascular system.
AB  - The present review analyzes the role nitric oxide (NO) plays in the homeostasis
      of the cardiovascular system. By regulating vascular smooth muscle cell and
      myocyte contractility, myocardial oxygen consumption and renal tubular transport,
      this simple molecule plays a central role in the control of vascular tone,
      cardiac contractility and short and long term regulation of arterial pressure.
      Fifteen years ago, all we knew about NO is that it had very similar properties as
      those of endothelium-derived relaxing factor and that its action was probably
      mediated by cGMP. An enormous amount of knowledge has since been amassed on the
      biochemical pathways that NO follows from the moment it is synthesized from L
      arginine until the physiological or pathological actions take place in the
      effector cells. This review intends to organize this knowledge in a fashion that
      is easy to understand. We will dissect the NO pathway in different steps,
      focusing on the physiological and pathophysiological actions of the isoenzymes
      which synthesize NO, the molecules involved in this synthesis such as caveolins,
      protein kinases and cofactors, the situations in which endogenous inhibitors of
      NO synthase are formed from L-arginine instead of NO, the way in which NO exerts
      its physiological actions through cGMP-dependent protein kinases and finally, the
      pathological routes NO may follow when the oxidative status of the cell is high.

PMID- 12603014
TI  - Inferring gene regulatory networks from time-ordered gene expression data of
      Bacillus subtilis using differential equations.
AB  - We describe a new method to infer a gene regulatory network, in terms of a linear
      system of differential equations, from time course gene expression data. As
      biologically the gene regulatory network is known to be sparse, we expect most
      coefficients in such a linear system of differential equations to be zero. In
      previously proposed methods, the number of nonzero coefficients in the system was
      limited based on ad hoc assumptions. Instead, we propose to infer the degree of
      sparseness of the gene regulatory network from the data, where we use Akaike's
      Information Criterion to determine which coefficients are nonzero. We apply our
      method to MMGE time course data of Bacillus subtilis.

PMID- 12603015
TI  - Genome-wide analysis of bacterial promoter regions.
AB  - Identifying prokaryotic promoter sequences is notoriously difficult and for most
      sequenced bacterial genomes the promoter sequences are still unknown. Since
      experimental analysis trails behind sequencing, genome-wide computational
      promoter discovery is often the only realistic way to discover these sequences in
      newly sequenced bacterial genomes. However, genome-wide samples for promoter
      discovery may be very large and corrupted complicating promoter discovery. We
      discuss three aspects of genome-wide promoter discovery: sample generation,
      signal finding algorithms, and scoring signals. We applied our new MITRA
      algorithm to analyze samples of divergent and convergent genes in 20 bacterial
      genomes and found strong putative dyad signals in 17 out of the 20 genomes.
      Moreover, in 12 out of 20 genomes the found signals are identical or similar to
      the known regulatory patterns (Pribnow-Gilbert boxes and CRP binding sites).
      Since many of putative signals correspond to previously known elements of
      bacterial transcriptional regulation, the remaining discovered signals are good
      candidates for unknown regulatory elements.

PMID- 12603016
TI  - MOPAC: motif finding by preprocessing and agglomerative clustering from
      microarrays.
AB  - We propose a novel strategy for discovering motifs from gene expression data. The
      gene expression data in our experiments comes from DNA Microarray analysis of the
      bacterium E. coli in response to recovery from nutrient starvation. We have
      annotated the data and identified the upregulated genes. Our interest is to find
      common regulatory motifs that are responsible for the upregulation of these
      specific genes. We assume that a common motif that a regulatory protein can bind
      to will be present in the upstream region of the upregulated genes and will not
      be present in the upstream regions of genes that showed a constant level of
      expression over time. Our objective is to find the common motifs that are present
      in at least some of the upstream sequences of upregulated genes and not present
      in the control set, which is the set of genes whose expression remained the same.
      Because it is possible that there could be several subsets of co-regulated genes
      under different control mechanisms among the co-expressed genes, we do not want
      to require motifs to be present in all upregulated sequences. Therefore, we
      propose a new algorithm for finding such motifs through stages of pre-processing,
      denoising, agglomerative clustering and consensus checking. Through this process,
      we have found some motifs that are good candidates for further validation.

PMID- 12603017
TI  - Improved gene selection for classification of microarrays.
AB  - In this paper we derive a method for evaluating and improving techniques for
      selecting informative genes from microarray data. Genes of interest are typically
      selected by ranking genes according to a test-statistic and then choosing the top
      k genes. A problem with this approach is that many of these genes are highly
      correlated. For classification purposes it would be ideal to have distinct but
      still highly informative genes. We propose three different pre-filter methods-
      two based on clustering and one based on correlation--to retrieve groups of
      similar genes. For these groups we apply a test-statistic to finally select genes
      of interest. We show that this filtered set of genes can be used to significantly
      improve existing classifiers.

PMID- 12603019
TI  - Extracting conserved gene expression motifs from gene expression data.
AB  - We propose a representation for gene expression data called conserved gene
      expression motifs or XMOTIFs. A gene's expression level is conserved across a set
      of samples if the gene is expressed with the same abundance in all the samples. A
      conserved gene expression motif is a subset of genes that is simultaneously
      conserved across a subset of samples. We present a computational technique to
      discover large conserved gene motifs that cover all the samples and classes in
      the data. When applied to published data sets representing different cancers or
      disease outcomes, our algorithm constructs XMOTIFS that distinguish between the
      various classes.

PMID- 12603018
TI  - Kernel Cox regression models for linking gene expression profiles to censored
      survival data.
AB  - In functional genomics, one important problem is to relate the microarray gene
      expression profiles to various clinical phenotypes from patients. The success has
      been demonstrated in molecular classification of cancer in which gene expression
      data serve as predictors and different types of cancer are the binary or multi
      categorical outcome variable. However, there has been less research in linking
      gene expression profiles to other types of phenotypes, in particular, the
      censored survival data such as patients' overall survival or cancer relapse
      times. In the paper, we develop a kernel Cox regression model for relating gene
      expression profiles to censored phenotypes in the framework the penalization
      method in terms of function estimation in reproducing kernel Hilbert spaces. To
      circumvent the problem of censoring, we use the negative partial likelihood as a
      loss function in the estimation procedure. The functional combinations of the
      original gene expression data identified by the method are highly correlated with
      the patients' survival times and at the same time account for the variability in
      the gene expression levels. We apply our method to data sets from diffuse large B
      cell lymphoma, lung adenocarcinoma and breast carcinoma studies to verify its
      effectiveness. The results from these analyses indicate that the proposed method
      works very well in identifying subgroups of patients with different risks of
      death or relapse and in predicting the risk of relapse or death based on the gene
      expression profiles measured from the tumor samples taken from the patients.

PMID- 12603020
TI  - Decomposing gene expression into cellular processes.
AB  - We propose a probabilistic model for cellular processes, and an algorithm for
      discovering them from gene expression data. A process is associated with a set of
      genes that participate in it; unlike clustering techniques, our model allows
      genes to participate in multiple processes. Each process may be active to a
      different degree in each experiment. The expression measurement for gene g in
      array a is a sum, over all processes in which g participates, of the activity
      levels of these processes in array a. We describe an iterative procedure, based
      on the EM algorithm, for decomposing the expression matrix into a given number of
      processes. We present results on Yeast gene expression data, which indicate that
      our approach identifies real biological processes.

PMID- 12603021
TI  - Suitability and utility of computational analysis tools: characterization of
      erythrocyte parameter variation.
AB  - Systems engineering can provide insights into multivariate regulatory networks
      and pooling in complex biological networks that cannot be fully interpreted
      through experiments alone. Herein, we analyzed the use of phase planes, modal and
      time-lagged correlation (TLC) analyses of the human erythrocyte to explore the
      utility of these techniques for understanding the effect of single parameter
      changes on the behavior of a metabolic network. Specifically, several parameters
      in key regulatory steps in erythrocyte glycolysis, Rapoport-Leubering bypass,
      pentose phosphate pathway, adenosine metabolism, and membrane transport were
      perturbed. The most sensitive parameters were identified based on the steady
      state metabolite concentration changes and were explored further. Modal analysis
      identified relevant time scales for each parameter change. These time scales were
      further explored using phase plane and TLC analyses. Phase plane and TLC both
      inferred pooling changes, while TLC also identified changes in the regulatory
      network structure that resulted from various parameter changes. Each method has
      strengths and weaknesses for exploring and gaining insight into complex
      biological networks.

PMID- 12603022
TI  - Foundations of a query and simulation system for the modeling of biochemical and
      biological processes.
AB  - The analysis of large amounts of data, produced as (numerical) traces of in vivo,
      in vitro and in silico experiments, has become a central activity for many
      biologists and biochemists. Recent advances in the mathematical modeling and
      computation of biochemical systems have moreover increased the prominence of in
      silico experiments; such experiments typically involve the simulation of sets of
      Differential Algebraic Equations (DAE), e.g., Generalized Mass Action systems
      (GMA) and S-systems. In this paper we reason about the necessary theoretical and
      pragmatic foundations for a query and simulation system capable of analyzing
      large amounts of such trace data. To this end, we propose to combine in a novel
      way several well-known tools from numerical analysis (approximation theory),
      temporal logic and verification, and visualization. The result is a preliminary
      prototype system: simpathica/xssys. When dealing with simulation data
      simpathica/xssys exploits the special structure of the underlying DAE, and
      reduces the search space in an efficient way so as to facilitate any queries
      about the traces. The proposed system is designed to give the user possibility to
      systematically analyze and simultaneously query different possible timed
      evolutions of the modeled system.

PMID- 12603023
TI  - Incorporating biological knowledge into evaluation of causal regulatory
      hypotheses.
AB  - Biological data can be scarce and costly to obtain. The small number of samples
      available typically limits statistical power and makes reliable inference of
      causal relations extremely difficult. However, we argue that statistical power
      can be increased substantially by incorporating prior knowledge and data from
      diverse sources. We present a Bayesian framework that combines information from
      different sources and we show empirically that this lets one make correct causal
      inferences with small sample sizes that otherwise would be impossible.

PMID- 12603024
TI  - Assessment of the reliability of protein-protein interactions and protein
      function prediction.
AB  - As more and more high-throughput protein-protein interaction data are collected,
      the task of estimating the reliability of different data sets becomes
      increasingly important. In this paper, we present our study of two groups of
      protein-protein interaction data, the physical interaction data and the protein
      complex data, and estimate the reliability of these data sets using three
      different measurements: (1) the distribution of gene expression correlation
      coefficients, (2) the reliability based on gene expression correlation
      coefficients, and (3) the accuracy of protein function predictions. We develop a
      maximum likelihood method to estimate the reliability of protein interaction data
      sets according to the distribution of correlation coefficients of gene expression
      profiles of putative interacting protein pairs. The results of the three
      measurements are consistent with each other. The MIPS protein complex data have
      the highest mean gene expression correlation coefficients (0.256) and the highest
      accuracy in predicting protein functions (70% sensitivity and specificity), while
      Ito's Yeast two-hybrid data have the lowest mean (0.041) and the lowest accuracy
      (15% sensitivity and specificity). Uetz's data are more reliable than Ito's data
      in all three measurements, and the TAP protein complex data are more reliable
      than the HMS-PCI data in all three measurements as well. The complex data sets
      generally perform better in function predictions than do the physical interaction
      data sets. Proteins in complexes are shown to be more highly correlated in gene
      expression. The results confirm that the components of a protein complex can be
      assigned to functions that the complex carries out within a cell. There are three
      interaction data sets different from the above two groups: the genetic
      interaction data, the in-silico data and the syn-express data. Their capability
      of predicting protein functions generally falls between that of the Y2H data and
      that of the MIPS protein complex data. The supplementary information is available
      at the following Web site: http://www-hto.usc.edu/-msms/AssessInteraction/.

PMID- 12603026
TI  - Influence of network topology and data collection on network inference.
AB  - We recently developed an approach for testing the accuracy of network inference
      algorithms by applying them to biologically realistic simulations with known
      network topology. Here, we seek to determine the degree to which the network
      topology and data sampling regime influence the ability of our Bayesian network
      inference algorithm, NETWORKINFERENCE, to recover gene regulatory networks.
      NETWORKINFERENCE performed well at recovering feedback loops and multiple targets
      of a regulator with small amounts of data, but required more data to recover
      multiple regulators of a gene. When collecting the same number of data samples at
      different intervals from the system, the best recovery was produced by sampling
      intervals long enough such that sampling covered propagation of regulation
      through the network but not so long such that intervals missed internal dynamics.
      These results further elucidate the possibilities and limitations of network
      inference based on biological data.

PMID- 12603025
TI  - Boundary formation by notch signaling in Drosophila multicellular systems:
      experimental observations and gene network modeling by Genomic Object Net.
AB  - The Delta-Notch signaling system plays an essential role in various morphogenetic
      systems of multicellular animal development. Here we analyzed the mechanism of
      Notch-dependent boundary formation in the Drosophila large intestine, by
      experimental manipulation of Delta expression and computational modeling and
      simulation by Genomic Object Net. Boundary formation representing the situation
      in normal large intestine was shown by the simulation. By manipulating Delta
      expression in the large intestine, a few types of disorder in boundary cell
      differentiation were observed, and similar abnormal patterns were generated by
      the simulation. Simulation results suggest that parameter values representing the
      strength of cell-autonomous suppression of Notch signaling by Delta are essential
      for generating two different modes of patterning: lateral inhibition and boundary
      formation, which could explain how a common gene regulatory network results in
      two different patterning modes in vivo. Genomic Object Net proved to be a useful
      and flexible biosimulation system that is suitable for analyzing complex
      biological phenomena such as patternings of multicellular systems as well as
      intracellular changes in cell states including metabolic activities, gene
      regulation, and enzyme reactions.

PMID- 12603027
TI  - Simultaneous sequence alignment and tree construction using hidden Markov models.
AB  - We present a new algorithm (SATCHMO) that simultaneously estimates a tree and
      generates a set of multiple sequence alignments given a set of protein sequences.
      Alignments are constructed for each node in the tree. These alignments predict
      the structurally conserved elements of the sequences in a subtree and are
      therefore of different lengths, and represent different amino acid preferences,
      at different nodes. Hidden Markov Models (HMMs) are also generated for each node
      and are used to determine branching order, to align sequences and to predict
      structurally alignable regions. In experiments on the BAliBASE benchmark
      alignment database, SATCHMO is shown to perform comparably to ClustalW and the
      UCSC SAM HMM software. Results using SATCHMO to identify protein domains are
      demonstrated on potassium channels, with implications for the mechanism by which
      tumor necrosis factor alpha affects potassium current.

PMID- 12603028
TI  - Towards discovering structural signatures of protein folds based on logical
      hidden Markov models.
AB  - With the growing number of determined protein structures and the availability of
      classification schemes, it becomes increasingly important to develop computer
      methods that automatically extract structural signatures for classes of proteins.
      In this paper, we introduce and apply a new Machine Learning technique, Logical
      Hidden Markov Models (LOHMMs), to the task of finding structural signatures of
      folds according to the classification scheme SCOP. Our results indicate that
      LOHMMs are applicable to this task and possess several advantages over other
      approaches.

PMID- 12603029
TI  - Automated construction of structural motifs for predicting functional sites on
      protein structures.
AB  - Structural genomics initiatives are beginning to rapidly generate vast numbers of
      protein structures. For many of the structures, functions are not yet determined
      and high-throughput methods for determining function are necessary. Although
      there has been extensive work in function prediction at the sequence level,
      predicting function at the structure level may provide better sensitivity and
      predictive value. We describe a method to predict functional sites by
      automatically creating three dimensional structural motifs from amino acid
      sequence motifs. These structural motifs perform comparably well with manually
      generated structural motifs and perform better than sequence motifs.
      Automatically generated structural motifs can be used for structural-genomic
      scale function prediction on protein structures.

PMID- 12603030
TI  - Prediction of boundaries between intrinsically ordered and disordered protein
      regions.
AB  - Using proteins with both disordered and ordered regions collected through
      literature searches and database scanning, we assembled a set of 24-residue long
      segments centered on their order/disorder boundaries as well as a larger set of
      non-boundary segments consisting of either order or disorder. We analyzed
      position-specific amino acid compositions around the order/disorder boundaries
      and found more than thirty significant (p < 0.05) compositional differences
      between boundary and non-boundary data. From this analysis, we constructed
      several logistic regression predictors of order/disorder boundaries using
      slightly different data modeling approaches. Exact boundary prediction accuracies
      were estimated to be in the range from 74% to 80% for the different predictors.

PMID- 12603031
TI  - Identifying structural motifs in proteins.
AB  - In biological macromolecules, structural patterns (motifs) are often repeated
      across different molecules. Detection of these common motifs in a new molecule
      can provide useful clues to the functional properties of such a molecule. We
      formulate the problem of identifying a given structural motif (pattern) in a
      target protein (example) and discuss the notion of complete matches vis-a-vis
      partial matches. We describe the precise error criterion that has to be minimized
      and also discuss different metrics for evaluating the quality of partial matches.
      Secondly, we present a new polynomial time algorithm for the problem of matching
      a given motif in a target protein. We also use the sequence and (if available)
      secondary structure information to annotate the different points in motif and the
      target protein, thus reducing the search space size. Our algorithm guarantees the
      detection of a perfect match, if present. Even otherwise, the algorithm computes
      very good matches. Unlike other methods, the error minimized by our algorithm
      directly translates to root mean square deviation (RMSD), the most commonly
      accepted metric for structure matching in biological macromolecules. The
      algorithm does not involve any preprocessing and is suitable for the detection of
      both small and large motifs in the target protein. We also present experiments
      exploring the quality of matches found by the algorithm. We examine its
      performance in matching (both full and partial) active sites in proteins.

PMID- 12603032
TI  - A path planning-based study of protein folding with a case study of hairpin
      formation in protein G and L.
AB  - We investigate a novel approach for studying protein folding that has evolved
      from robotics motion planning techniques called probabilistic roadmap methods
      (PRMS). Our focus is to study issues related to the folding process, such as the
      formation of secondary and tertiary structure, assuming we know the native fold.
      A feature of our PRM-based framework is that the large sets of folding pathways
      in the roadmaps it produces, in a few hours on a desktop PC, provide global
      information about the protein's energy landscape. This is an advantage over other
      simulation methods such as molecular dynamics or Monte Carlo methods which
      require more computation and produce only a single trajectory in each run. In our
      initial studies, we obtained encouraging results for several small proteins. In
      this paper, we investigate more sophisticated techniques for analyzing the
      folding pathways in our roadmaps. In addition to more formally revalidating our
      previous results, we present a case study showing our technique captures known
      folding differences between the structurally similar proteins G and L.

PMID- 12603033
TI  - Profile-profile alignment: a powerful tool for protein structure prediction.
AB  - The problem of computing the tertiary structure of a protein from a given amino
      acid sequence has been a major subject of bioinformatics research during the last
      decade. Many different approaches have been taken to tackle the problem, the most
      successful of which are based on searching databases to identify a similar amino
      acid sequence in the PDB and using the corresponding structure as a template for
      modeling the structure of the query sequence. An important advance for the
      evaluation of sequence similarity in this context has been the use of a frequency
      profile that represents a part of the protein sequence space close to the query
      sequence instead of the query sequence itself. In this paper, we present a
      further extension of this principle by using profiles instead of the template
      sequences, also. We show that, by using our newly developed scoring model, the
      profile-profile alignment approach is able to significantly outperform current
      state of the art methods like PSI-BLAST, HMMs, or threading methods in a fold
      recognition setup. This is especially interesting since we show that it holds for
      closely related sequences as well as for very distantly related ones.

PMID- 12603034
TI  - Protein threading by linear programming.
AB  - Protein three-dimensional structure prediction through threading approach has
      been extensively studied and various models and algorithms have been proposed. In
      order to further explore ways to improve accuracy and efficiency of the threading
      process, this paper investigates the effectiveness of a new method: protein
      threading via linear programming. Based on the contact map model of protein 3D
      structure, we formulate the protein threading problem as a large scale integer
      programming problem, then relax to a linear programming problem, and finally
      solve the integer program by a branch-and-bound method. The final solution is
      optimal with respect to energy functions incorporating pairwise interaction and
      allowing variable gaps. The algorithm has been implemented as software package
      RAPTOR--RApid Protein Threading predictOR. Experimental results for fold
      recognition show that RAPTOR significantly outperforms other programs at the fold
      similarity level. The RAPTOR webserver is at http://www.cs.uwaterloo.ca/
      j3xu/RAPTOR_form.htm.

PMID- 12603035
TI  - Towards identifying lateral gene transfer events.
AB  - This paper is concerned with evaluating the performance of the model and
      algorithm in 5 for detecting lateral gene transfers events. Using a Poisson
      process to describe arrival times of transfer events, a simulation is used to
      generate "synthetic" gene and species trees. An implementation of an efficient
      algorithm in 5 is used to estimate the minimum number of transfers necessary to
      explain disagreements between the generated gene and species trees. Our first
      result suggests that the algorithm can solve realistic size instances of the
      problem. Our second result suggests that the mean error and variance are low when
      saturation does not occur. Additionally, certain plausible evolutionary events
      allowed by our model of evolution used to generate gene and species trees but not
      detectable by the algorithm occur rarely implying the framework should work well
      in practice. Our third, surprising result suggests that the number of optimal
      scenarios is on average low for realistic input sizes.

PMID- 12603036
TI  - Whole genome human/mouse phylogenetic footprinting of potential transcription
      regulatory signals.
AB  - Phylogenetic footprinting is an efficient approach for revealing potential
      transcription factor binding sites in promoter sequences. The idea is based on an
      assumption that functional sites in promoters should evolve much slower then
      other regions that do not bear any conservative function. Therefore, potential
      transcription factor (TF) binding sites that are found in the evolutionally
      conservative regions of promoters have more chances to be considered as "real"
      sites. The most difficult step of the phylogenetic footprinting is alignment of
      promoter sequences between different organisms (fe. human and mouse). The
      conventional alignment methods often can not align promoters due to the high
      level of sequence variability. We have developed a new alignment method that
      takes into account similarity in distribution of potential binding sites (motif
      based alignment). This method has been used effectively for promoter alignment
      and for revealing new potential binding sites for various transcription factors.
      We made a systematic phylogenetic footprinting of human/mouse conserved non
      coding sequences (CNS). 60 thousand potential binding sites were revealed in
      human and mouse genomes. We have developed a database of the predicted potential
      TF binding sites. AVAILABILITY: http://compel.bionet.nsc.ru/FunSite/footprint/;
      www.gene-regulation.com/.

PMID- 12603037
TI  - MAP: searching large genome databases.
AB  - A number of biological applications require comparison of large genome strings.
      Current techniques suffer from both disk I/O and computational cost because of
      extensive memory requirements and large candidate sets. We propose an efficient
      technique for alignment of large genome strings. Our technique precomputes the
      associations between the database strings and the query string. These
      associations are used to prune the database-query substring pairs that do not
      contain similar regions. We use a hash table to compare the unpruned regions of
      the query and database strings. The cost of the ensuing search is determined by
      how the hash table is constructed. We present a dynamic strategy that optimizes
      the random disk I/O needed for accessing the hash table. It also provides the
      user a coarse grain visualization of the similarity pattern quickly before the
      actual search. The experimental results show that our technique aligns genome
      strings up to 97 times faster than BLAST.

PMID- 12603038
TI  - Towards the development of computational tools for evaluating phylogenetic
      network reconstruction methods.
AB  - We report on a suite of algorithms and techniques that together provide a
      simulation flow for studying the topological accuracy of methods for
      reconstructing phylogenetic networks. We implemented those algorithms and
      techniques and used three phylogenetic reconstruction methods for a case study of
      our tools. We present the results of our experimental studies in analyzing the
      relative performance of these methods. Our results indicate that our simulator
      and our proposed measure of accuracy, the latter an extension of the widely used
      Robinson-Foulds measure, offer a robust platform for the evaluation of network
      reconstruction algorithms.

PMID- 12603039
TI  - Identification of regulatory binding sites using minimum spanning trees.
AB  - Recognition of protein-binding sites from the upstream regions of genes is a
      highly important and unsolved problem. In this paper, we present a new approach
      for studying this challenging issue. We formulate the binding-site recognition
      problem as a cluster identification problem, i.e., to identify clusters in a data
      set that exhibit significantly different features (e.g., density) than the
      overall background of the data set. We have developed a general framework for
      solving such a cluster identification problem. The foundation of the framework is
      a rigorous relationship between data clusters and subtrees of a minimum spanning
      tree (MST) representation of a data set. We have proposed a formal and general
      definition of clusters, and have demonstrated that a cluster is always
      represented as a connected component of the MST, and further it corresponds to a
      substring of a linear representation of the MST. Hence a cluster identification
      problem is reduced to a problem of finding substrings with certain features, for
      which algorithms have been developed. We have applied this MST-based cluster
      identification algorithm to a number of binding site identification problems. The
      results are highly encouraging.

PMID- 12603040
TI  - Intrasplicing--analysis of long intron sequences.
AB  - We propose a new model for the splicing of long introns, which we call
      intrasplicing. The basic idea of this model is that the splicing of long introns
      may be facilitated by the splicing of inner parts of the intron prior to the
      splicing of the long intron itself. Since long introns have up to about 100,000
      bases, this model seems to be a likely explanation of their splicing. To
      investigate the possibility of this model, we develop a new computational method
      for the analysis of DNA sequences with respect to splicing. We analyze the
      genomic sequence of four species with our method and derive several results
      indicating that intrasplicing may be an appropriate model for the splicing of at
      least part of the long intron sequences.

PMID- 12603041
TI  - Trajectory clustering: a non-parametric method for grouping gene expression time
      courses, with applications to mammary development.
AB  - Trajectory clustering is a novel and statistically well-founded method for
      clustering time series data from gene expression arrays. Trajectory clustering
      uses non-parametric statistics and is hence not sensitive to the particular
      distributions underlying gene expression data. Each cluster is clearly defined in
      terms of direction of change of expression for successive time points (its
      'trajectory'), and therefore has easily appreciated biological meaning. Applying
      the method to a dataset from mouse mammary gland development, we demonstrate that
      it produces different clusters than Hierarchical, K-means, and Jackknife
      clustering methods, even when those methods are applied to differences between
      successive time points. Compared to all of the other methods, trajectory
      clustering was better able to match a manual clustering by a domain expert, and
      was better able to cluster groups of genes with known related functions.

PMID- 12603042
TI  - Algorithms for multiple genome rearrangement by signed reversals.
AB  - We discuss a multiple genome rearrangement problem by signed reversals: Given a
      collection of genomes, we generate them in the minimum number of signed
      reversals. It is NP-hard and equivalent to finding an optimal Steiner tree to
      connect the genomes by reversal paths. We design two algorithms to find the
      optimal Steiner nodes of the problem: Neighbor-perturbing algorithm and branch
      and-bound algorithm. The first one is a polynomial running time approximation
      algorithm. It searches for the optimal Steiner nodes by perturbing initial
      Steiner nodes nearby their neighborhoods and improving them better and better
      until convergence. The second one is an exact exponential running time algorithm
      for a median problem. It finds the optimal Steiner node by checking all
      candidates that satisfy the necessary conditions for optimal Steiner nodes. We
      implement the algorithms into two programs respectively and show by experimental
      examples that they are more efficient than other similar ones, such as GRAPPA,
      BPAnalysis, and MGR, etc.

PMID- 12603043
TI  - DIGIT: a novel gene finding program by combining gene-finders.
AB  - We have developed a general purpose algorithm which finds genes by combining
      plural existing gene-finders. The algorithm has been implemented into a novel
      gene-finder named DIGIT. An outline of the algorithm is as follows. First,
      existing gene-finders are applied to an uncharacterized genomic sequence (input
      sequence). Next, DIGIT produces all possible exons from the results of gene
      finders, and assigns them their exon types, reading frames and exon scores.
      Finally, DIGIT searches a set of exons whose additive score is maximized under
      their reading frame constraints. Bayesian procedure and a hidden Markov model are
      used to infer exon scores and search the exon set, respectively. We have designed
      DIGIT so as to combine the results of FGENESH, GENSCAN and HMMgene, and have
      assessed its prediction accuracy by using recently compiled benchmark data sets.
      For all data sets, DIGIT successfully discarded many false-positive exons
      predicted by individual gene-finders and yielded remarkable improvements in
      sensitivity and specificity at the gene level compared with the best gene level
      accuracies achieved by any single gene-finder.

PMID- 12603044
TI  - Evaluation of the vector space representation in text-based gene clustering.
AB  - Thanks to its increasing availability, electronic literature can now be a major
      source of information when developing complex statistical models where data is
      scarce or contains much noise. This raises the question of how to deeply
      integrate information from domain literature with experimental data. Evaluating
      what kind of statistical text representations can integrate literature knowledge
      in clustering still remains an unsufficiently explored topic. In this work we
      discuss how the bag-of-words representation can be used successfully to represent
      genetic annotation and free-text information coming from different databases. We
      demonstrate the effect of various weighting schemes and information sources in a
      functional clustering setup. As a quantitative evaluation, we contrast for
      different parameter settings the functional groupings obtained from text with
      those obtained from expert assessments and link each of the results to a
      biological discussion.

PMID- 12603045
TI  - Playing biology's name game: identifying protein names in scientific text.
AB  - A growing body of work is devoted to the extraction of protein or gene
      interaction information from the scientific literature. Yet, the basis for most
      extraction algorithms, i.e. the specific and sensitive recognition of protein and
      gene names and their numerous synonyms, has not been adequately addressed. Here
      we describe the construction of a comprehensive general purpose name dictionary
      and an accompanying automatic curation procedure based on a simple token model of
      protein names. We designed an efficient search algorithm to analyze all abstracts
      in MEDLINE in a reasonable amount of time on standard computers. The parameters
      of our method are optimized using machine learning techniques. Used in
      conjunction, these ingredients lead to good search performance. A supplementary
      web page is available at http://cartan.gmd.de/ProMiner/.

PMID- 12603046
TI  - Mining terminological knowledge in large biomedical corpora.
AB  - Terminological knowledge of the biomedical domain is important for natural
      language processing (NLP) and information retrieval (IR) applications, and a
      number of terminological knowledge sources, such as LocusLink, GeneBank, and the
      UMLS, already exist. However, because of the tremendous amount of research
      activity in the field, new terms and symbols are continually being created, many
      of which are published in the literature, but are not available in any of the
      other resources. Therefore, effective mining of the literature for new
      terminology is critical for furthering NLP and IR applications. Abbreviations are
      widely used in the biomedical domain, and the understanding of abbreviations
      requires a terminological knowledge base that consists of abbreviations with
      their associated senses. In previous work, several methods have been developed
      for automatic construction of abbreviation knowledge bases from parenthetical
      expressions. However, these methods pair abbreviations and their expansions based
      on manually crafted patterns or rules. In this paper, we propose an automatic
      method, which is not based on patterns or rules but is based on the use of
      collocations, to extract a set of related terms from parenthetical expressions
      including abbreviations associated with their expansions and other types of
      related terms such as synonyms, or hyponyms etc. Our method is based on the
      observation that terms associated with parenthetical expressions i) are usually
      related, and ii) are often collocations because they tend to co-occur more often
      than expected by chance. Our method was applied to the collection of MEDLINE
      abstracts. The method and the results were evaluated using two collections:
      Berman's handcrafted abbreviation list and the LocusLink collection.

PMID- 12603047
TI  - A biological named entity recognizer.
AB  - In this paper we describe a new named entity extraction system. Our system is
      based on a manually developed set of rules that rely heavily upon some crucial
      lexical information, linguistic constraints of English, and contextual
      information. This system achieves state of art results in the protein name
      detection task, which is what many of the current name extraction systems do. We
      discuss the need for detection of chemical names and show that we not only obtain
      a high degree of success in recognizing chemicals but that this task can help
      improve the precision of protein name detection as well. We use context and
      surrounding words for categorization of named entities and find the results
      obtained are encouraging.

PMID- 12603048
TI  - Linking biomedical language information and knowledge resources: GO and UMLS.
AB  - Integration of various informatics terminologies will be an essential activity
      towards supporting the advancement of both the biomedical and clinical sciences.
      The GO consortium has developed an impressive collection of biomedical terms
      specific to genes and proteins in a variety of organisms. The UMLS is a composite
      collection of various medical terminologies, pioneered by the National Library of
      Medicine. In the present study, we examine a variety of techniques for mapping
      terms from one terminology (GO) to another (UMLS), and describe their respective
      performances for a small, curated data set attained from the National Cancer
      Institute, which had precision values ranging from 30% (100% recall) to 95% (74%
      recall). Based on each technique's performance, we comment on how each can be
      used to enrich an existing terminology (UMLS) in future studies and how linking
      biological terminologies to UMLS differs from linking medical terminologies.

PMID- 12603049
TI  - A simple algorithm for identifying abbreviation definitions in biomedical text.
AB  - The volume of biomedical text is growing at a fast rate, creating challenges for
      humans and computer systems alike. One of these challenges arises from the
      frequent use of novel abbreviations in these texts, thus requiring that
      biomedical lexical ontologies be continually updated. In this paper we show that
      the problem of identifying abbreviations' definitions can be solved with a much
      simpler algorithm than that proposed by other research efforts. The algorithm
      achieves 96% precision and 82% recall on a standard test collection, which is at
      least as good as existing approaches. It also achieves 95% precision and 82%
      recall on another, larger test set. A notable advantage of the algorithm is that,
      unlike other approaches, it does not require any training data.

PMID- 12603051
TI  - On the power to detect SNP/phenotype association in candidate quantitative trait
      loci genomic regions: a simulation study.
AB  - We use coalescent methods to investigate the ability of linked neutral "markers"
      to reveal in simulated population samples the presence of one or more single
      nucleotide polymorphisms that is contributing to a trait having a complex genetic
      basis (QTN: quantitative trait nucleotide). Realistic mutation and recombination
      rates in our simulations allow us to generate SNP data appropriate for analyzing
      human variation across short chromosomal intervals corresponding to approximately
      100 kilobases. We investigate the performance of both single marker and multiple
      marker (haplotype) data for several ad hoc procedures. Our results with single
      SNP markers indicate that (1) the density of SNP markers need not be much higher
      than 10% in order to achieve near-maximal detection of a QTN; (2) a higher
      density of markers does not improve much on the ability to localize a QTN within
      an interval unless the recombination rate is high. Haplotype-based tests were
      investigated for the case in which more than one QTN is present in the studied
      interval. Larger sample sizes improve both the probability of detecting the
      haplotype with the largest number of QTNs, as well as the ability to infer
      correct haplotypes from genotypic data. Testing a series of short haplotypes
      across a longer interval can also be beneficial. The rate of false positives
      (i.e., when the most significant haplotype does not contain the greatest number
      of QTNs in the sample) can be very high when the contribution of individual QTNs
      to a trait is small. The elimination of low-frequency haplotypes does not
      substantially reduce the probability of detecting the haplotype with the largest
      number of QTNs but it can reduce the rate of false positives.

PMID- 12603050
TI  - Selection of minimum subsets of single nucleotide polymorphisms to capture
      haplotype block diversity.
AB  - We present a simple numerical algorithm to select the minimal subset of SNPs
      required to capture the diversity of haplotype blocks or other genetic loci. This
      algorithm can be used to quickly select the minimum SNP subset with no loss of
      haplotype information. In addition, the method can be used in a more aggressive
      mode to further reduce the original SNP set, with minimal loss of information. We
      demonstrate the algorithm performance with data from over 11,000 SNPs with
      average spacing of 6 to 11 Kb, across all the genes of chromosomes 6, 21, and 22,
      genotyped on DNA samples of 45 unrelated African-Americans and 45 Caucasians from
      the Coriell Human Diversity Collection. With no loss of information, we reduced
      the number of SNPs required to capture the haplotype block diversity by 25% for
      the African-American and 36% for the Caucasian populations. With a maximum loss
      of 10% of haplotype distribution information, the SNP reduction was 38% and 49%
      respectively for the two populations. All computations were performed in less
      than 1 minute for the entire dataset used.

PMID- 12603052
TI  - Errors and linkage disequilibrium interact multiplicatively when computing sample
      sizes for genetic case-control association studies.
AB  - Single nucleotide polymorphisms (SNP) may be used in case-control designs to test
      for association between a SNP marker and a disease. Such designs may assume that
      the genotype data are reported without error. Our goal is quantifying the effects
      that errors have on sample size for case-control studies with haplotypes formed
      by a disease locus and a SNP marker locus in the presence of linkage
      disequilibrium (LD). We consider the effects of a recently published error model
      on 2x3 chi-square analysis. We study the joint relation of LD and errors with
      sample size for three specific genetic disease models and two settings each of
      marker allele frequencies (total of 6 studies). Minimal sample size necessary for
      fixed asymptotic power is estimated as a 4th degree polynomial in the variables S
      (error) and D' (LD measure) via a backward step-wise regression. We find that
      increased error rates lower power. In all studies, we observe that LD and errors
      interact in a non-linear fashion. In particular, regression analyses shows that
      several higher order interaction terms have coefficients significantly different
      from 0 in each study, with fraction of variance explained greater than 0.9999.
      Finally, the increase in sample size necessary to maintain constant asymptotic
      power and level of significance as a function of S is smallest when D' = 1
      (perfect LD). The increase grows monotonically as D' decreases to 0.5 for all
      studies.

PMID- 12603053
TI  - An MDL method for finding haplotype blocks and for estimating the strength of
      haplotype block boundaries.
AB  - We describe a new method for finding haplotype blocks based on the use of the
      minimum description length principle. We give a rigorous definition of the
      quality of a segmentation of a genomic region into blocks, and describe a dynamic
      programming algorithm for finding the optimal segmentation with respect to this
      measure. We also describe a method for finding the probability of a block
      boundary for each pair of adjacent markers: this gives a tool for evaluating the
      significance of each block boundary. We have applied the method to the published
      data of Daly et al. The results are in relatively good agreement with the
      published results, but also show clear differences in the predicted block
      boundaries and their strengths. We also give results on the block structure in
      population isolates.

PMID- 12603054
TI  - PyPop: a software framework for population genomics: analyzing large-scale multi
      locus genotype data.
AB  - Software to analyze multi-locus genotype data for entire populations is useful
      for estimating haplotype frequencies, deviation from Hardy-Weinberg equilibrium
      and patterns of linkage disequilibrium. These statistical results are important
      to both those interested in human genome variation and disease predisposition as
      well as evolutionary genetics. As part of the 13th International
      Histocompatibility and Immunogenetics Working Group (IHWG), we have developed a
      software framework (PyPop). The primary novelty of this package is that it allows
      integration of statistics across large numbers of data-sets by heavily utilizing
      the XML file format and the R statistical package to view graphical output, while
      retaining the ability to inter-operate with existing software. Largely developed
      to address human population data, it can, however, be used for population based
      data for any organism. We tested our software on the data from the 13th IHWG
      which involved data sets from at least 50 laboratories each of up to 1000
      individuals with 9 MHC loci (both class I and class II) and found that it scales
      to large numbers of data sets well.

PMID- 12603055
TI  - Joint Bayesian estimation of mutation location and age using linkage
      disequilibrium.
AB  - Associations between disease and marker alleles on chromosomes in populations can
      arise as a consequence of historical forces such as mutation, selection and
      genetic drift, and is referred to as "linkage disequilibrium" (LD). LD can be
      used to estimate the map position of a disease mutation relative to a set of
      linked markers, as well as to estimate other parameters of interest, such as
      mutation age. Parametric methods for estimating the location of a disease
      mutation using marker linkage disequilibrium in a sample of normal and affected
      individuals require a detailed knowledge of population demography, and in
      particular require users to specify the postulated age of a mutation and past
      population growth rates. A new Bayesian method is presented for jointly
      estimating the position of a disease mutation and its age. The method is
      illustrated using haplotype data for the cystic fibrosis deltaF508 mutation in
      Europe and the DTD mutation in Finland. It is shown that, for these datasets, the
      posterior probability distribution of disease mutation location is insensitive to
      the population growth rate when the model is averaged over possible mutation ages
      using a prior probability distribution for the mutation age based on the
      population frequency of the disease mutation. Fewer assumptions are therefore
      needed for parametric LD mapping.

PMID- 12603057
TI  - Methods for analysis and visualization of SNP genotype data for complex diseases.
AB  - SNP markers are becoming central for studying genetic determinants of complex
      diseases. Large SNP data collected in such studies call for the development of
      specialized analysis tools. We present methods for selecting sets of SNPs that
      can be associated to sample properties in case/control studies. We also describe
      how scoring and selection can be statistically tested. This is done at the single
      locus as well as at the set level.

PMID- 12603056
TI  - SNP analysis and presentation in the Pharmacogenetics of Membrane Transporters
      Project.
AB  - The multidisciplinary UCSF Pharmacogenetics of Membrane Transporters project
      seeks to systematically identify sequence variants in transporters and to
      determine the functional significance of these variants through evaluation of
      relevant cellular and clinical phenotypes. The project is structured around four
      interacting cores: genomics, cellular phenotyping, clinical phenotyping, and
      bioinformatics. The bioinformatics core is responsible for collecting, storing,
      and analyzing the information obtained by the other cores and for presenting the
      results, in particular, for the genomic data. Most of this process is automated
      using locally developed software written in Python, an open source language well
      suited for rapid, modular development that meets requirements that are themselves
      constantly evolving. Here we present the details of transforming ABI trace file
      data into useful information for project investigators and a description of the
      types of data analysis and display that we have developed.

PMID- 12603059
TI  - Towards a broad-coverage biomedical ontology based on description logics.
AB  - We describe an ontology engineering methodology by which conceptual knowledge is
      extracted from an informal medical thesaurus (UMLS) and automatically converted
      into a formal description logics system (LOOM). Our approach consists of four
      steps: concept definitions are automatically generated from the UMLS, integrity
      checking of taxonomic and partonomic hierarchies is performed by LOOM's
      terminological classifier, cycles and inconsistencies are eliminated, as well as
      incremental refinement of the evolving knowledge base is performed by a domain
      expert. We report on experiments with a very large knowledge base composed of
      164,000 concepts and 76,000 relations.

PMID- 12603058
TI  - Functional discrimination of gene expression patterns in terms of the gene
      ontology.
AB  - The ever-growing amount of experimental data in molecular biology and genetics
      requires its automated analysis, by employing sophisticated knowledge discovery
      tools. We use an Inductive Logic Programming (ILP) learner to induce functional
      discrimination rules between genes studied using microarrays and found to be
      differentially expressed in three recently discovered subtypes of adenocarcinoma
      of the lung. The discrimination rules involve functional annotations from the
      Proteome HumanPSD database in terms of the Gene Ontology, whose hierarchical
      structure is essential for this task. While most of the lower levels of gene
      expression data (pre)processing have been automated, our work can be seen as a
      step toward automating the higher level functional analysis of the data. We view
      our application not just as a prototypical example of applying more sophisticated
      machine learning techniques to the functional analysis of genes, but also as an
      incentive for developing increasingly more sophisticated functional annotations
      and ontologies, that can be automatically processed by such learning algorithms.

PMID- 12603060
TI  - Evaluation of ontology merging tools in bioinformatics.
AB  - Ontologies are being used nowadays in many areas, including bioinformatics. One
      of the issues in ontology research is the aligning and merging of ontologies.
      Tools have been developed for ontology merging, but they have not been evaluated
      for their use in bioinformatics. In this paper we evaluate two of the most well
      known ontology merging tools with a bioinformatics perspective. As test
      ontologies we have used Gene Ontology and Signal-Ontology.

PMID- 12603061
TI  - Semantic similarity measures as tools for exploring the gene ontology.
AB  - Many bioinformatics resources hold data in the form of sequences. Often this
      sequence data is associated with a large amount of annotation. In many cases this
      data has been hard to model, and has been represented as scientific natural
      language, which is not readily computationally amenable. The development of the
      Gene Ontology provides us with a more accessible representation of some of this
      data. However it is not clear how this data can best be searched, or queried.
      Recently we have adapted information content based measures for use with the Gene
      Ontology (GO). In this paper we present detailed investigation of the properties
      of these measures, and examine various properties of GO, which may have
      implications for its future design.

PMID- 12603062
TI  - Linking molecular imaging terminology to the gene ontology (GO).
AB  - The rapidly developing domain of molecular imaging represents the merging of
      current advances in the fields of molecular biology and imaging research. Despite
      this merger, an information gap continues to exist between the scientists who
      discover new gene products and the imaging scientists who can exploit this
      information. The Gene Ontology (GO) Consortium seeks to provide a set of
      structured terminologies for the conceptual annotation of gene product function,
      process and location in databases. However, no such structured set of concept
      oriented terminology exists for the molecular imaging domain. Since the purpose
      of GO is to capture the information about the role of gene products, we propose
      that the mapping of GO's established ontological concepts to a molecular imaging
      terminology will provide the necessary bridge to fill the information gap between
      the two fields. We have extracted terms and definitions from an already published
      molecular imaging glossary as well as molecular imaging research articles, and
      developed molecular imaging concepts. We then mapped our molecular imaging
      concepts to the existing gene ontology concepts as a method to comprehensively
      represent molecular imaging.

PMID- 12603063
TI  - A methodology to migrate the gene ontology to a description logic environment
      using DAML+OIL.
AB  - The Gene Ontology Next Generation Project (GONG) is developing a staged
      methodology to evolve the current representation of the Gene Ontology into
      DAML+OIL in order to take advantage of the richer formal expressiveness and the
      reasoning capabilities of the underlying description logic. Each stage provides a
      step level increase in formal explicit semantic content with a view to supporting
      validation, extension and multiple classification of the Gene Ontology. The paper
      introduces DAML+OIL and demonstrates the activity within each stage of the
      methodology and the functionality gained.

PMID- 12603064
TI  - Development under extreme conditions: forensic bioinformatics in the wake of the
      World Trade Center disaster.
AB  - The terrorist attacks of September 11, 2001 resulted in death and devastation in
      three locations, and extraordinary efforts have been exerted to identify the
      remains of all victims. As mass fatalities go, this one has been unusual at a
      policy level because the goal has been not merely to identify remains for every
      decedent, but to identify every bit of remains found so that even small pieces of
      tissue can be returned to families for burial. While the human impact at the
      Pentagon and Shanksville, PA was horrific, the World Trade Center site presented
      a particularly complex challenge for forensic DNA matching and data handling. A
      complete and definitive list of all those killed is still elusive, and human
      remains were crushed and co-mingled by the falling towers. Software tools had
      never been considered for a problem of this scale and scope. New data handling
      systems had to be created under extreme software development conditions
      characterized by incomplete requirements specifications, chaotically changing
      priorities, truly impossible deadlines and rapidly rolling production releases.
      Partly because of the company's experience with mtDNA tools built for the Armed
      Forces DNA Identification Lab starting in 1997, the New York City Office of Chief
      Medical Examiner [OCME] contacted Gene Codes Corporation in late September as
      existing data-handling tools began to fail. We began work on the project in mid
      October, 2001. Our approach to the problem included: Extreme Programming [XP]
      methodology for functional software development, On-site time and motion analysis
      at the OCME for user interface design, Evidentiary references between STR, SNP
      and mtDNA analysis results, and Separate data Quality Control [QC] and software
      Quality Assurance [QA] initiatives. A substantial software suite was developed
      called M-FISys, an acronym for Mass-Fatality Identification System.

PMID- 12603065
TI  - New horizons--a shared vision for the future.

PMID- 12603066
TI  - A decade review: methods to improve adherence to the treatment among
      haemodialysis patients.
AB  - Haemodialysis patients are asked to adhere to a very difficult treatment regimen
      consisting of fluid and diet restrictions, many daily medications, and usually 3
      or 4 hour haemodialysis sessions three times each week. Many haemodialysis
      patients fail to adhere to their prescribed treatment and although this regimen
      is difficult, it is necessary for patients to adhere for optimal health and well
      being. It is important for nephrology nurses to know what interventions help
      patients overcome the barriers that keep them from adhering to prescribed
      treatment The purpose of this paper is to review the literature to examine the
      research that has been published on methods to improve adherence among
      haemodialysis patients. Behavioural approaches, education, and primary nursing
      are interventions that have been researched More research has been reported on
      the demographics of noncompliant haemodialysis patients than on effective methods
      that help patients improve adherence to the treatment regimen. Demographic
      characteristics do not consistently predict compliance for individual patients.
      Each patient is unique. Research supports the idea that the nephrology nurse
      should spend time with the patient on a regular basis in order to understand the
      factors that hinder the individual patient from adhering to the treatment
      regimen. The nurse who knows the patient well is empowered to develop
      individualised interventions aimed at reducing barriers that interfere with the
      patient's ability to adhere to treatment.

PMID- 12603067
TI  - The influence of staff-patient interactions on adherence behaviours.
AB  - The research assessed the influence of staff-patient interactions on adherence to
      a dietary regimen in dialysis patients. A random sample of 147 subjects provided
      data on clinical, psychosocial, and demographic measures. Results indicated that
      staff-patient interactions determine and predict adherence behaviours. However,
      the lack of association between the laboratory data and either individual
      adherence behaviours or staff-patient interactions raised questions about the
      validity of these proxy measures of adherence. To better understand the nature of
      these determinant variables of adherence, more extensive research is suggested.

PMID- 12603068
TI  - Vascular access monitoring evaluated from automated recirculation measurement.
AB  - Vascular access quality monitoring by means of vascular access blood flow (QVA)
      evaluated from automated thermodilutional measurement of recirculation with
      reverse needle position is described. This method provides significant advantages
      over conventional methods based on simple monitoring of pressures in the
      extracorporeal circuit and/or measurement of recirculation with normal needle
      position. AQVA evaluation protocol was developed and introduced into the system
      of primary nursing. The QVA values were found independent of the extracorporeal
      blood flow used during the recirculation measurement. QVA values from below 200
      ml/min to over 2 l/min were seen. In general, lower values were found in
      diabetics compared to non-diabetics and in females compared to males. While blood
      flow below 600 ml/min is considered risky for synthetic vascular grafts, native
      AV-fistulae seem to remain stable and patent at a flow of 400 ml/min or even
      below. The method is able to detect erroneous needle placement in looped grafts,
      stenosis between needles, and is also well suited for effective evaluation of
      success/failure of interventions on access.

PMID- 12603069
TI  - Investigation: basis for nursing practice.
AB  - The term evidence based nursing signifies a systematic process of search,
      assessment and application of the most up-to-date investigation for decision
      taking. In practice the process can be applied in four steps: formulation of the
      question, a search of the bibliography, a critical analysis of the validity of
      the results, and putting the obtained findings into practice. Nursing practise
      must be based on the best available scientific results. Professional nurses are
      more accustomed to acting according to tradition with scarce scientific rigour.
      It is necessary to introduce investigation as an instrument to allow resolution
      of problems with practice and to offer the best possible care alternative. The
      evidence contributed by investigation is evaluated according to criteria of
      validity and utility. There are several scales to assess the methodological
      rigour of investigation studies as well as to recommend a practice or technique
      as appropriate, or not, according to the scientific evidence available.

PMID- 12603071
TI  - Quantity versus quality: ethics and provision of renal replacement therapy.
AB  - 50 years ago if one had renal failure the prognosis was certain death within a
      short timeframe. Now if one receives renal replacement therapy the prognosis has
      dramatically changed. But in this time of economic constraints and ever
      decreasing human resources are we now to be faced with the necessity to make
      choices about who receives replacement therapy? This paper looks at the ethics of
      providing treatment for large numbers but at the risk of 2nd class treatment, or
      selection of a few to receive the best treatment possible. The author asks what
      is the point of choice for the provision of therapy; before treatment has begun
      or having started who has the right to stop treatment and should there be
      criteria for discontinuing this treatment? The paper examines the ethical issues
      facing all the health care team especially those caring for the chronically ill.
      The financial benefits of one kind of therapy over the other are examined and
      again the author puts the question, is it economics that governs the treatment
      prescribed, or a real choice made with knowledge? The author has found that
      "hands on" health care teams are still aiming to treat the ever increasing
      workload but at what cost? How long can we continue to accept patients for
      treatment when we may be putting at risk other patients and the very people who
      are providing the care?

PMID- 12603070
TI  - Internet use by patients--a shift in power?
AB  - Traditionally, the patient has relied on health care professionals for advice and
      knowledge. The unprecedented access to information offered by the Internet may
      challenge this relationship. To investigate this, a questionnaire was sent to 640
      transplant patients. 24 responded positively and were interviewed to see if the
      information they found on the net had been useful, in negotiating a change in
      treatment or as support. Internet use was associated with younger males who had
      access to the net at work. 22 had found useful information although only 1
      patient had negotiated a change in treatment as a result. As the Internet becomes
      universally available, patients will be empowered to have a larger role in
      maintaining their health, and support groups will be better able to help
      patients. To prepare to deal with this avalanche of information we need to
      develop a system of accreditation of Internet sites, to create our own sites and
      to collaborate with patient support groups.

PMID- 12603072
TI  - Haemodialysis and H.I.V. infection--therapeutic management.
AB  - The prevalence of human immunodeficiency virus among haemodialysis patients is of
      interest and this article discusses the management of 25 patients between 1985
      and 1998 in Paris.

PMID- 12603073
TI  - Pre-training assessment tool (JPAT)--a pilot study.
AB  - A tool for assessing the suitability of candidates for home dialysis (Jo-Pre
      training Assessment Tool--JPAT) was developed. JPAT acts as a screening
      instrument to identify suitable candidates for the home dialysis programme, and
      therefore increases a patient's chance of learning to manage the programme. JPAT
      is in the form of an interview questionnaire consisting of 38 assessment items in
      six domains: physical stability, nutritional status, communication, ability to
      maintain self-care, psychological suitability and social support. A pilot study
      was conducted (n = 20, 1996-1997) using a descriptive study design, with subjects
      randomly selected from an existing dialysis programme. Pearson correlation and 2
      tailed tests were employed to explore the relationship between the assessment
      outcome (i.e. the initial JPAT scores) and the follow up data (i.e. data
      collected within the seven days following the initial JPAT assessment). Many of
      the variables attained statistical significance (p < 0.05). The inter-rater
      reliability was calculated at an average Kappa value of 0.909. Overall, results
      suggest that JPAT is sufficiently reliable to be used as a tool for assessing
      patients who suffer from ESRD.

PMID- 12603074
TI  - Restless legs syndrome: a review for the renal care professionals.
AB  - Restless legs syndrome is a common neurological disorder with an estimated
      prevalence between 2 and 10%. It is characterised by an imperative desire to move
      the extremities associated with paraesthesias, motor restlessness, worsening of
      symptoms at rest with at least partial relief by activity, and worsening of
      symptoms in the evening or at night. As a consequence, patients suffer from
      severe sleep disturbances and, less frequently, from daytime sleepiness. The
      cause of restless legs syndrome remains unknown. It has been divided into
      idiopathic and symptomatic (secondary, e.g. uraemic restless legs syndrome)
      forms. Based on pharmacological, neurophysiological and imaging studies it is
      suggested that it is a disease of the subcortical central nervous system with
      involvement of the brainstem and spinal chord. Dopaminergic agents are regarded
      as the first choice of treatment; however, the development of augmentation of
      symptoms especially under levodopa therapy may be a major problem. Alternative
      medications are opioids and benzodiazepines. In secondary restless legs syndrome
      the underlying illness should be treated first, but dopaminergic drugs may also
      be helpful.

PMID- 12603075
TI  - Professional profile of dialysis technicians in Europe.

PMID- 12603076
TI  - Pre-registration nephrology nursing.

PMID- 12603077
TI  - Indomethacin reduces lipid peroxidation in rat brain homogenate by binding Fe2+.
AB  - One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration
      of cholinergic neurons in the cerebral cortex and hippocampus. It is generally
      accepted that this neuronal degeneration is due to free-radical-induced damage.
      These free radicals attack vital structural components of the neurons. This
      implies that agents that reduce free radical generation could potentially delay
      the progression of AD. Free radical generation in the brain is assisted by the
      presence of iron, required by the Fenton reaction. Thus, agents that reduce iron
      availability for this reaction could potentially reduce free radical formation.
      Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce
      the severity of AD, we investigated the possible mechanism by which indomethacin
      could afford neuroprotection. Our results show that indomethacin (1 mM) is able
      to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates.
      In addition, our NMR data indicate that indomethacin binds the Fe(2+)/Fe(3+) ion.
      This was confirmed by a study using UV/Vis spectrophotometry. The results imply
      that indomethacin provides a neuroprotective effect by binding to iron and thus
      making it unavailable for free radical production.

PMID- 12603078
TI  - Toxicity of compound A to C6 rat glioma cells.
AB  - The volatile anesthetic, sevoflurane, undergoes degradation by soda lime to form
      Compound A (2-fluoromethoxy-1,1,3,3,3-pentafluoro-1-propene). Compound A is toxic
      in vivo with the kidney being the primary target. However, peripheral neuropathy
      was recently reported in a group of healthy volunteers who received sevoflurane.
      The present study was undertaken to evaluate the toxicity of Compound A to neural
      cells. Rat glioma C6 cells were grown in T25 flasks in 5 mL of DMEM/F12 were
      exposed to Compound A, and the viability of cells was determined at various time
      points by trypan blue exclusion. Within 1 h after the addition of 10 microL of
      Compound A, the fragmentation of cell processes and rounding of cell bodies
      became apparent. The cellular degeneration progressed over time resulting in the
      loss of all viable cells from the cultures within 6 h. Even brief exposures to
      Compound A ranging from 5 to 30 min resulted in massive cell death observed 24 h
      later, and the toxicity was concentration-dependent. These preliminary
      experiments indicate that Compound A is a potent toxin to glial cells in vitro. A
      plausible mechanism for this toxicity entails the depletion of intracellular
      glutathione resulting in oxidative stress of the cells. However, the relatively
      high doses of Compound A used to observe its effects do not support the toxicity
      of Compound A to glial cells under clinical conditions.

PMID- 12603079
TI  - Effect of leucine administration on creatine kinase activity in rat brain.
AB  - Maple syrup urine disease (MSUD) is a metabolic disorder biochemically
      characterized by the accumulation of branched-chain amino acids (BCAA) and their
      branched-chain keto acids (BCKA) in blood and tissues. Neurological dysfunction
      is usually present in the patients, but the pathophysiology of brain damage is
      still obscure. Considering that brain energy metabolism is possibly altered in
      MSUD, the main objective of this study was to determine creatine kinase activity
      in the brain of rats subjected to acute and chronic administration of leucine.
      Chronic hyperleucinemia was induced by subcutaneous administrations of 4.8
      micromol leucine/g body weight, twice a day, from the 6th to the 21st postnatal
      day. For acute hyperleucinemia, 21-day-old rats received three administrations of
      the amino acid at 3 h interval. Twelve hours after the chronic treatment or 1 h
      after the acute one, rats were killed and creatine kinase activity measured. The
      results indicated that acute or chronic administration of leucine altered
      creatine kinase activity in the brain of leucine-treated rats. Considering the
      crucial role creatine kinase plays in energy homeostasis in brain, if these
      effects also occur in the brain of MSUD patients, it is possible that alteration
      of this enzyme activity may contribute to the brain damage found in this disease.

PMID- 12603080
TI  - Effect of blood ammonia elevation following oral glutamine load on the
      psychometric performance of cirrhotic patients.
AB  - Oral glutamine challenge is a method to increase blood ammonia and may be used to
      study the ammonia lowering effect of drugs potentially useful in hepatic
      encephalopathy (HE). We tested its influence on the psychometric performance of
      18 cirrhotic patients without HE. Twelve nonencephalopatic cirrhotic patients
      were studied before and after glutamine load (20 g in 100 mL tap water) and six
      patients before and after placebo (100 mL tap water) by using the Number
      Connection Test (NCT), the Covert Visual Attention Orienting Test (CVAOT), and
      the Scan Test (SCT). Blood ammonia increased significantly after glutamine (from
      79 +/- 34 to 211 +/- 66 microg/dL) but not after placebo (from 94 +/- 41 to 88 +/
      26). No difference in the NCT was found before and after glutamine load or
      placebo. The CVAOT was similar after glutamine challenge and placebo, nor any
      interaction between Loads (glutamine or placebo) x Cue position was found,
      suggesting that glutamine load did not influence attention-orienting. SCT results
      were also similar after glutamine and placebo, suggesting a lack of influence on
      the working memory. Glutamine challenge is a safe method to induce hyperammonemia
      in nonencephalopatic cirrhotic patients and, therefore, to study the efficacy of
      ammonia lowering treatments.

PMID- 12603081
TI  - Oral amino acid load mimicking hemoglobin results in reduced regional cerebral
      perfusion and deterioration in memory tests in patients with cirrhosis of the
      liver.
AB  - This study tests the hypothesis that administration of an oral amino acid load
      mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration
      in neuropsychological function and a reduction in regional cerebral perfusion.
      Eight overnight fasted, metabolically stable cirrhotic patients with no evidence
      of overt hepatic encephalopathy were studied prior to and 4 h after simulating an
      upper gastrointestinal bleed by oral administration of 75 g of a solution
      mimicking the amino acid composition of hemoglobin. Neuropsychological function
      was measured using a test battery. Peripheral venous blood was collected for the
      measurement of ammonia and amino acid concentrations. Regional cerebral perfusion
      was measured using a head SPECT scanner following intravenous administration of
      technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in
      significant deterioration in the immediate and delayed story recall tests.
      Ammonia concentration increased from a median of 87 (range 67-94) micromol/L to
      105 (98-112) micromol/L at 4 h after the simulated bleed (p < 0.01). The
      concentration of almost all amino acids increased; only isoleucine levels
      decreased following the upper gastrointestinal bleed. SPECT analysis showed a
      significant reduction in cerebral perfusion after the simulated bleed in both
      temporal lobes, left superior frontal gyrus, and right parietal and cingulate
      gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients
      produces hyperammonemia and hypoisoleucinemia and causes a significant
      deterioration in memory tests, probably due to a reduction in regional cerebral
      perfusion. The model of simulating the metabolic effects of an upper
      gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful
      in studying the metabolism of hepatic encephalopathy.

PMID- 12603082
TI  - Central nervous system alterations in liver cirrhosis: the role of portal
      systemic shunt and portal hypoperfusion.
AB  - The role of portal-systemic shunting and portal liver hypoperfusion in the
      pathophysiology of central nervous system dysfunction (CNSD) of cirrhosis is not
      yet well defined. It is well known that one of the most important collateral
      vessels (CVs) is a patent paraumbilical vein (PUV), but there is controversy
      regarding its clinical significance. We have evaluated the relationships between
      neuropsychological and EEG alterations, ammonia plasma level (NH4), hepatic
      function, and portal hemodynamics (Doppler Ultrasound) in 95 cirrhotic patients.
      Patency, diameter, or flow of PUV or the presence of other CVs were not related
      to an increased prevalence of neuropsychological or EEG abnormalities. Patients
      with effective portal flow (EPF = portal flow - PUV flow) lower than 692 mL/min
      (median) had a significantly higher risk of failing the neuropsychological test,
      or of having an altered EEG. Low EPF and prothrombin time (<50%), and high NH4
      (51 micromol/L) were independent predictors of an abnormal EEG. Considering both
      low EPF and the numerosity of CVs, only low EPF was found to explain EEG
      alterations. In conclusion, portal liver hypoperfusion and decreased liver
      function were associated with an increased risk of CNSD in cirrhotic patients,
      whereas PUV patency per se was not.

PMID- 12603083
TI  - Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic
      patients.
AB  - Psychometric performance has been reported to be related to brain atrophy in
      cirrhotics, but the relationship between brain atrophy and EEG findings is still
      unknown. The aim of this study was to ascertain the relationship among brain
      atrophy, EEG, and cognitive performance in cirrhotics. Sixty-eight cirrhotics
      (age = 55 +/- 10 years; males-66%) underwent psychometric evaluation (Symbol
      Digit Test, Trail Making Test-Part A, Scan test), EEG recording and spectral
      analysis (S-EEG), and brain CT scan. Central brain atrophy was ascertained by the
      following indexes of brain atrophy: the Evans' index, the bicaudate index, the
      cella media index, the bifrontal index, and the ventricular index; cortical brain
      atrophy by the sulci index. The severity of liver failure was assessed by the
      Child-Pugh score: 18% of patients were Child-Pugh Class A, 50% Class B, and 32%
      Class C. Central and cortical atrophies were found to be correlated with age, but
      not with the Child-Pugh score. Psychometric performance and the EEG mean dominant
      frequency (MDF) were found to be correlated with brain atrophy. Multivariate
      analysis showed that a poor psychometric performance was independently predicted
      by EEG slowing (MDF: p < 0.01) and by central brain atrophy (cella media index: p
      < 0.01). In conclusion, brain atrophy was associated with a poor psychometric
      performance and EEG alterations in cirrhosis. Both brain atrophy and EEG
      alterations independently predicted cognitive dysfunction in cirrhotic patients.

PMID- 12603084
TI  - Proline reduces acetylcholinesterase activity in cerebral cortex of rats.
AB  - In the present study we investigated the in vivo and in vitro effect of proline
      (Pro) on acetylcholinesterase (AChE) activity in rat cerebral cortex. The action
      of vitamins E and C on the effects produced by Pro was also tested. Twelve-day
      old rats received one s.c. injection of Pro (12.8 micromol/g body weight) or an
      equivalent volume of 0.9% saline solution (control) and were killed 1 h later. In
      another set of experiments, 5-day-old rats were pretreated for 1 week with daily
      i.p. administration of saline (control) or vitamins E (40 mg/kg) and C (100
      mg/kg). Twelve hours after the last injection the rats received one s.c.
      injection of Pro (12.8 micromol/g body weight) or saline (control) and were
      killed 1 h later. For the in vitro studies, cerebral cortex homogenates of 12-day
      old untreated rats were incubated for 1 h with various concentrations of Pro (3.0
      microM-1.0 mM) or with 1.0 mM Pro, 1.0 mM trolox, or 1.0 mM Pro plus 1.0 mM
      trolox. Controls did not contain Pro in the incubation medium. Our results showed
      that the AChE activity significantly decreased (25%) in rat brain subjected to
      Pro administration and that the pretreatment with vitamins E and C prevented this
      effect. Furthermore, Pro (0.5 and 1.0 mM) also inhibits AChE activity in vitro
      and trolox prevented this effect. The data suggest that the inhibitory effect of
      Pro on AChE activity is associated with oxidative stress. Although it is
      difficult to extrapolate our findings to the human condition, our results may be
      relevant to explain, at least in part, the neurologic dysfunction associated with
      hyperprolinemia type II.

PMID- 12603085
TI  - Alanine prevents the in vitro inhibition of glycolysis caused by phenylalanine in
      brain cortex of rats.
AB  - Glycolysis is the main route that provides energy to brain functioning. In this
      study we investigated the in vitro effects of phenylalanine, the main metabolite
      known to accumulate in phenylketonuria, and/or alanine, on pyruvate kinase
      activity, glucose utilization, lactate release, and ADP concentration in brain
      cortex homogenates from 30-day-old Wistar rats. We found that phenylalanine
      decreased PK activity, glucose utilization, and lactate release, and increased
      ADP brain levels. We also verified that alanine per se did not modify these
      parameters, but prevented the effects of phenylalanine. Our data suggest that the
      inhibition of pyruvate kinase by phenylalanine decreases glycolysis and energy
      production, and that alanine, a known competitor of phenylalanine on the enzyme
      activity, prevents the reduction of glycolysis and energy production caused by
      phenylalanine, probably by preventing the enzyme inhibition provoked by the amino
      acid. These results suggest that inhibition of brain PK activity by phenylalanine
      may be related to the diminution of glucose metabolism observed in the brain of
      phenylketonuric patients and may be one of the mechanisms responsible for the
      neurological dysfunction found in these patients.

PMID- 12603087
TI  - The codons 8/9 (+G) mutation found for the first time in the Lebanese population.
AB  - Thalassemia is a common inherited disease in the Mediterranean region. We here
      report a mutation new to the Lebanese population: the insertion of a G nucleotide
      at codons 8/9 [(+G) AAG-TCT (Lys-Ser) --> AAG-G-TCT (beta0)] of the beta-globin
      gene in a thalassemic patient with a mild phenotype. We discuss the possible
      factors that play a role in alleviating the severity of the disease in this case.

PMID- 12603086
TI  - Changes in brain intracellular pH and membrane phospholipids on oxygen therapy in
      hypoxic patients with chronic obstructive pulmonary disease.
AB  - Chronic hypoxia due to chronic obstructive pulmonary disease (COPD) constitutes a
      stress to cerebral metabolic homeostasis. Previous studies using phosphorus-31
      magnetic resonance spectroscopy (31P MRS) have suggested that the brains of such
      patients utilize anaerobic glycolysis, which in neonatal, animal, and in vitro
      studies is associated with a protective intracellular alkalosis. To identify such
      a compensatory intracellular alkalosis in hypoxic COPD patients, in vivo cerebral
      31P MRS was performed in eight patients and eight controls. The mean
      intracellular pH (pHi) in patients with COPD was similar to that of age-matched
      controls, but decreased in the patients with COPD by a mean pHi of 0.02 (p =
      0.04), following supplemental oxygen. There was no change in cerebral pHi in
      normal subjects following oxygen administration. The broadband component of the
      MR spectrum increased in all the patients with COPD (p = 0.01), suggesting
      altered phospholipid membrane fluidity in the brain associated with the change in
      pHi following oxygen administration. The change in the broadband resonance was
      strongly correlated with the change in pHi (r = -0.68, p = 0.014). This study
      suggests that patients with COPD exhibit a compensatory change in pHi and
      abnormalities in cerebral membrane phospholipid conformation in the face of
      chronic hypoxia.

PMID- 12603088
TI  - Hb Lepore in the Indian population.
AB  - A study of the spectrum of beta-thalassemia mutations in 230 patients with
      thalassemia major and 90 patients with thalassemia intermedia revealed mutations
      producing Hb Lepore in four patients. Two were homozygous and two were compound
      heterozygous for Hb Lepore and beta-thalassemia. Among the six delta beta fusion
      genes found in these four patients five were those producing Hb Lepore-Hollandia
      and one producing Hb Lepore-Washington-Boston. We also describe a possible
      misdiagnosis in the heterozygous state of Hb Lepore, as Hb Lepore and Hb A2 are
      not distinctly separated by cation exchange high performance liquid
      chromatography.

PMID- 12603089
TI  - Hb Trento: an elongated C-terminal beta chain due to a new frameshift mutation
      [beta144 (-A)].
AB  - An elongated C-terminal hemoglobin variant, due to the deletion of nucleotide A
      in codon 144 (nucleotide 63600 GenBank entry UO1317) was found in a 31-year-old
      woman from Trento (northeastern Italy). This deletion led to the replacement of
      lysine at beta144 by a serine residue, the disappearance of the stop codon at
      position 147, and the presence of 12 additional residues, identical to those
      observed in Hbs Saveme, Tak and Cranston, which result from a similar mechanism.
      Hb Trento, amounting to 29% of the total hemoglobin, was unstable and had, as the
      other variants of this group, an increased oxygen affinity. It led to a mild
      compensated hemolytic anemia with red cell inclusion bodies. Functional studies
      of the isolated abnormal hemoglobin were difficult to perform because of
      autoxidation, precipitation, and formation of hybrids with Hb A.

PMID- 12603090
TI  - Hb F-M-Osaka [Ggamma63(E7)His --> tyr] in a newborn from southwest France.

PMID- 12603091
TI  - Hb Santander [beta34(B16)Val --> Asp (GTC --> GAC)]: a new unstable variant found
      as a de novo mutation in a Spanish patient.

PMID- 12603092
TI  - Hb Kodaira II [beta146(HC3)His --> Gln] detected in Thailand.

PMID- 12603093
TI  - Association of Hb G-Chinese [alpha30(B11)Glu --> Gln] with alpha-thalassemia-1 of
      the Thai type in a Taiwanese family.

PMID- 12603094
TI  - Hb Prato [alpha31(B12)Arg --> Ser (A2)] and alpha-thalassemia in a Taiwanese.

PMID- 12603095
TI  - The Dutch IVS-I-116 (A --> G) (alpha2) thalassemia mutation induces Hb H
      inclusion bodies when found in combination with the -alpha3.7 deletion defect.

PMID- 12603096
TI  - High prevalence of the -alpha3.7 deletion among thalassemia patients in Iran.

PMID- 12603097
TI  - Hb H disease among Tunisians: molecular characterization of alpha-thalassemia
      determinants and hematological findings.

PMID- 12603098
TI  - Beta-D-galactopyranosyl azide: its one-step quantitative synthesis using E461G
      beta-galactosidase (Escherichia coli) and a demonstration of its potential as a
      reagent for molecular biology.
AB  - A simple one-step synthesis of beta-D-galactopyranosyl azide from o-nitrophenyl
      beta-D-galactopyranoside and azide catalyzed by E461G-beta-galactosidase is
      described. The synthesis is quantitative in the presence of excess azide and only
      the beta anomer is produced. The product was purified (71% yield) from the other
      reaction components by extraction with ethyl acetate, silica gel chromatography,
      and crystallization. The purity was verified by GLC, TLC, and NMR. Thus, E461G
      beta-galactosidase is able to specifically and quantitatively form beta-D
      galactopyranosyl-azide. The purified beta-D-galactopyranosyl azide inhibited the
      growth of Escherichia coli that express beta-galactosidase but not of E. coli
      that do not. Growth is stopped because beta-galactosidase catalyzes the
      hydrolysis of the beta-galactopyranosyl-azide, and the azide that is produced
      inhibits cell growth. This selective inhibition of growth has potential
      application in molecular biology screening.

PMID- 12603099
TI  - Lipase-catalyzed interesterification of soybean oil with an omega-3
      polyunsaturated fatty acid concentrate prepared from sardine oil.
AB  - To reduce the content of linoleoyl moiety in soybean oil, soybean oil that
      contains 53.0% linoleoyl moiety as molar acyl moiety composition was
      interesterified with an omega-3 polyunsaturated fatty acid (PUFA) concentrate
      (24.0 mol% eicosapentaenoic acid [EPA], 40.4 mol% docosahexaenoic acid [DHA])
      prepared from sardine oil, using an immobilized sn-1,3-specific lipase from
      Rhizomucor miehei (Lipozyme IM). The reaction was carried out in a batch reactor
      at 37 degrees C under the following conditions: 500 micromol of soybean oil,
      molar ratio of omega-3 PUFA concentrate to soybean oil = 1.0-6.0,5.0 mL of
      heptane, and 30 batch interesterification units of enzyme. After the reaction
      time of 72 h, modified soybean oil, which contains 34.9% linoleoyl, 10.1%
      eicosapentaenoyl, and 14.2% docosahexaenoyl moieties, was produced at the molar
      reactant ratio of 6.0. In this oil, the total omega-3 acyl moiety composition
      reached 34.1%; the molar ratio of omega-3 to omega-6 acyl moieties was enhanced
      by five times compared with soybean oil. Compared with palmitic acid, DHA was
      kinetically six times less reactive, although the EPA was by 16% more reactive.

PMID- 12603100
TI  - Biosorption of metal ions with Penicillium chrysogenum.
AB  - Biosorption of metal ions with Penicillium chrysogenum mycelium is described in
      this article. Alkaline pretreatment was used to remove proteins and nucleic acids
      from cells, and this treatment increased the adsorption capacities, for Cr3+ from
      18.6 mg g(-1) to 27.2 mg g(-1), for Ni2+ from 13.2 mg g(-1) to 19.2 mg g(-1), for
      Zn2+ from 6.8 mg g(-1) to 24.5 mg g(-1). The adsorption of metal ions was
      strongly pH dependent. The mycelium could be used for large-scale removal of Cr3+
      from tannery wastewater. The results show that this inexpensive mycelium
      adsorbent has potential in industry because of its high adsorption capacity. The
      main chelating sites are amino groups (-NH2) of chitosan in the mycelium. A new
      model is established, which describes the relation of adsorption of metal ions on
      pH according to amino group chelating with metal ions and H+. The relative errors
      of simulation for Cu2+, Ni2+, Zn2+, and Cr3+ are 4.66%, 5.45%,11.55%, and 1.69%,
      respectively.

PMID- 12603101
TI  - Improvements in lipase production and recovery from Acinetobacter radioresistens
      in presence of polypropylene powders filled with carbon sources.
AB  - Polypropylene powders as the adsorbent for organic solution containing n
      hexadecane and olive oil were employed as the carbon source for producing an
      alkaline lipase from Acinetobacter radioresistens. The best volumetric ratio of n
      hexadecane to olive oil around 5 for lipase production was determined from shake
      flask and fermentation cultivations. The existence of a maximum time course
      lipase activity of the aqueous phase was attributed to the compensation effects
      of olive oil on cell growth and lipase production, repression of lipase synthesis
      by oleic acid, and lipase adsorption on the supports. A linear relationship
      between the average cell growth rate in the exponential phase and the ratio of
      surface areas of the supports was found. The benefits of using the present
      fermentation process include less foaming and emulsion of the broth, less organic
      phase used, higher lipase production, and easy recovery of the lipase in the
      centrifugation step.

PMID- 12603102
TI  - Corn-milling pretreatment with anhydrous ammonia.
AB  - Exposure to anhydrous ammonia has been suggested as a pretreatment for corn
      milling. Batches of corn were exposed to ammonia under controlled conditions. The
      amounts of ammonia absorbed and reacted with the corn were measured. The amounts
      were not more than are needed as nutritional supplement for yeast fermentation to
      ethanol. Loosening of the hull was observed qualitatively, and subsequent
      shearing in a disk mill followed by steeping for 2, 4, 6, or 8 h showed that germ
      could be recovered at higher yield and after a shorter steeping time compared to
      untreated control batches. Quality of oil was not affected by treatment with
      ammonia.

PMID- 12603105
TI  - A copper-catalyzed C-N bond formation involving sp-hybridized carbons. A direct
      entry to chiral ynamides via N-alkynylation of amides.
AB  - A copper-catalyzed new C-N bond formation involving a sp-hybridized carbon is
      described here leading to a facile entry for syntheses of chiral ynamides. This
      direct N-alkynylation of amides should have a significant impact on the future
      development of synthetic methodologies employing ynamides.

PMID- 12603103
TI  - Alkaloid production by callous tissue cultures of Cereus peruvianus (Cactaceae).
AB  - The morphologically undifferentiated cells of nonregenerant callous tissue of
      Cereus peruvianus cultured in the original medium and in medium supplemented with
      tyrosine were used as an alkaloid source. Comparison of alkaloid production by C.
      peruvianus plants and by callous tissues indicated that alkaloid levels were
      almost twice as high in callous tissues as in shoots of C. peruvianus plants. The
      ratio of alkaloid concentration between mature plant and morphologically
      undifferentiated cells of callous tissue was 1:1.7. A relationship between
      culture medium containing tyrosine and alkaloid production was also observed in
      the callous tissues of C. peruvianus. Since increased alkaloid production may be
      induced by additional factors such as tyrosine, increasing levels of tyrosine or
      other conditions of the culture medium may be considered factors for inducing
      higher alkaloid production by C. peruvianus callous tissues.

PMID- 12603104
TI  - Electrochemical desorption of self-assembled monolayers noninvasively releases
      patterned cells from geometrical confinements.
AB  - This report describes a method to pattern mammalian cells using self-assembled
      monolayers (SAMs), and then to use electrochemical desorption of these monolayers
      to release cells from their patterns. This method uses an oligo(ethyleneglycol)
      terminated SAM to prevent,-and a methyl-terminated SAM to allow-adsorption of
      proteins and attachment of bovine capillary endothelial cells. Electrochemical
      removal of the oligo(ethyleneglycol)-terminated SAM allowed proteins to adsorb
      onto areas that had been previously inert and enabled cells to migrate into these
      areas. This straightforward technique is useful in bioassays for drug screening
      and for fundamental studies in cell biology.

PMID- 12603106
TI  - Acyclic stereoselective boron alkylation reactions for the asymmetric synthesis
      of beta-substituted alpha-amino acid derivatives.
AB  - Optically active syn- or anti-beta-substituted-alpha-amino acid derivatives are
      prepared in 94 to >/=99% ee and 66-98% ds by reaction of the Schiff base acetate
      of glycine tert-butyl ester with chiral, nonracemic B-alkyl-9-BBN derivatives in
      the presence of the Cinchona alkaloid, cinchonidine (CdOH) or cinchonine (CnOH),
      base, and lithium chloride.

PMID- 12603107
TI  - Hexameric macroring of gable-porphyrins as a light-harvesting antenna mimic.
AB  - Construction of a self-assembled supramolecular macroring that has distances and
      orientations of porphyrin dimer units in close analogy to those of the natural
      light-harvesting complexes was achieved. In natural light-harvesting complexes,
      bacteriochlorophyll-a's are arranged in macroring structures by coordination from
      imidazolyl side chains. A structural determination of a light-harvesting antenna
      complex (LH2) elucidated the arrangement of 18 bacteriochlorophyll-a's in a
      slipped-cofacial way with C9 symmetry in B850 in 1995. To obtain such an elegant
      macroring architecture as an artificial light-harvesting complex, we connected
      slipped-cofacial dimers of imidazolylporphyrins in a gable-porphyrin orientation.
      The introduction of zinc assembled by coordination porphyrins with originally a
      broad molecular weight distribution (MWD). When coordination bonds were cleaved
      and reorganized under high dilution conditions using chloroform/methanol
      solution, the MWD was perfectly converged. This crop gave particle images of a
      uniform height by atomic force microscopy measurements. Further purification was
      successfully achieved by gel permeation chromatography, and the first eluting
      component gave a diameter corresponding to the cyclic hexamer of gable-porphyrins
      from a small-angle X-ray scattering measurement with synchrotron radiation. In
      summary, porphyrin assemblies in a macroring arrangement were constructed using
      the gable-porphyrin motif, and their photophysical properties are highly
      interesting.

PMID- 12603109
TI  - Aluminosilicate nanoparticles for catalytic hydrocarbon cracking.
AB  - Aluminosilicate nanoparticles containing 9.0-20 nm mesopores were prepared
      through the use of protozeolitic nanoclusters as the inorganic precursor and
      starch as a porogen. The calcined, porogen-free composition containing 2 mol %
      aluminum exhibited the porosity, hydrothermal stability, and acidity needed for
      the cracking of very large hydrocarbons. In fact, the hydrothermal stability of
      the nanoparticles to pure steam at 800 degrees C, along with the cumene cracking
      activity, surpassed the analogous performance properties of ultrastable Y
      zeolite, the main catalyst component of commercial cracking catalysts. The
      remarkable hydrothermal stability and catalytic reactivity of the new
      nanoparticles are attributable to a unique combination of two factors, the
      presence of protozeolitic nanoclusters in the pore walls and the unprecedented
      pore wall thickness (7-15 nm). In addition, the excellent catalytic longevity of
      the nanoparticles is most likely facilitated by the small domain size of the
      nanoparticles that greatly improves access to the acid sites on the pore walls
      and minimizes the diffusion length of coke precursors out of the pores.

PMID- 12603108
TI  - Enantioselective total synthesis of (+)-amphidinolide t1.
AB  - An enantioselective first total syntheis of amphidinolide T1 (1) is described.
      Amphidinolide T1 (1), a 19-membered macrolide isolated from Amphidinium sp., has
      shown potent antitumor properties against a variety of NCI tumor cell lines. The
      synthesis is convergent and involves the assembly of C1-C10 segment 2 and C11-C21
      segment 3 by an oxocarbenium ion-mediated alkylation and Yamaguchi
      macrolactonization sequence. The synthesis of fragment 2 involves an efficient
      cross metathesis and hydrogenation sequence between the terminal olefins of 5 and
      6 to form the C4-C5 carbon-carbon bond. Enol ether 4 is designed to be the
      surrogate of fragment 3 where the sensitive C16-exo-methylene and the C13
      hydroxyl group were protected as the bromoether derivative during the Lewis acid
      catalyzed alkylation process. Both stereocenters in fragment 5 as well as the C2
      and C3 stereocenters in fragment 4 are accessed by a highly diastereoselective
      ester-derived titanium enolate-mediated syn-aldol reaction. The bromoether
      derivative 24 was unraveled at the final stage of the synthesis, providing (+)
      amphidinolide T1.

PMID- 12603110
TI  - 19F MAS NMR quantification of accessible hydroxyl sites on fiberglass surfaces.
AB  - Solid-state 19F nuclear magnetic resonance (NMR) spectroscopy is used for the
      quantitative investigation of accessible hydroxyl sites on low surface area glass
      fibers. Samples with surface areas as low as 0.2 m2/g are investigated through
      covalent binding of (3,3,3-trifluoropropyl)dimethylchlorosilane. 19F is an ideal
      nucleus for solid-state NMR, as it has a nuclear spin of 1/2 and a natural
      isotopic abundance of 100%. High-speed MAS techniques (with rotor spinning
      frequencies greater than 15 kHz) sufficiently average the CSA and any strong
      dipolar couplings to allow for superior resolution, especially from terminal -CF3
      groups. Studies of two model silica gels with higher surface area, but different
      pore sizes, provide chemical shift and spin-lattice relaxation rate parameters
      for probe molecules bound within different environments: pores approaching the
      size of the probe molecule and pores much larger than the molecular size where
      intermolecular interactions are assumed to be at a minimum. Resonances assignable
      to both types of binding environments are found in the spectra of similarly
      functionalized low surface area fibers. Accessible hydroxyl coverages in the
      range of 0.8-1.3 OH/nm2 have been measured, and an initial discussion of fiber
      surface roughness and microporosity is advanced.

PMID- 12603111
TI  - A conformationally preorganized universal solid support for efficient
      oligonucleotide synthesis.
AB  - A novel, conformationally preorganized nonnucleosidic universal solid support for
      oligonucleotide synthesis was developed. The solid support featured two
      chemically equivalent hydroxy groups locked in syn-periplanar orientation and
      orthogonally protected with 4,4'-dimethoxytrityl and acetyl groups. The solid
      support was extensively tested in the preparation of oligonucleotides and their
      phosphorothioate analogues containing 2'-deoxy, 2'-O-methyl, and 2'-O
      methoxyethylnucleoside residues at the 3'-terminus. Upon completion of
      oligonucleotide chain assembly, the support-bound oligonucleotide material was
      treated with concentrated ammonium hydroxide, which removed the O-acetyl
      protection. The deprotected hydroxy group then effected the transesterification
      of a phosphate linkage between the solid support and the 3'-terminal nucleoside
      residue to result in a facile release of the oligonucleotide to solution. The
      kinetics of the release process was studied in a continuous flow of concentrated
      aqueous ammonium hydroxide at a temperature of 300.15 K. Optimal conditions for
      the release of oligonucleotides depending on the chemistry of the backbone and 3'
      terminal nucleoside residue were formulated.

PMID- 12603112
TI  - Elimination of 13Calpha splitting in protein NMR spectra by deconvolution with
      maximum entropy reconstruction.
AB  - Homonuclear 13C-13C couplings can significantly reduce the sensitivity and
      resolution of multidimensional NMR experiments. The most important of these
      couplings is the 13Calpha-13Cbeta coupling, and several different methods have
      been developed to eliminate its effect from spectra used for backbone assignment,
      including short or constant-time evolution periods, selectively labeled amino
      acids, and multiple-band decoupling sequences. In this communication we show that
      postacquisition deconvolution of the spectra with a maximum entropy algorithm can
      be superior to experimental decoupling. The method is very robust, does not
      introduce shifts of the resonance positions, and simplifies the measurement of
      the most important NMR experiments for protein backbone assignment.

PMID- 12603113
TI  - Synthesis and characterization of monodispersed core-shell spherical colloids
      with movable cores.
AB  - Gold nanoparticles have been conformally coated with amorphous silica (using a
      sol-gel method) and then an organic polymer (via surface-grafted, atom transfer
      radical polymerization) to form spherical colloids with a core-double-shell
      structure. The thickness of silica and polymer shells could be conveniently
      controlled in the range of tens to several hundred nanometers by changing the
      concentration of the reagent and/or the reaction time. Selective removal of the
      silica layer (through etching in aqueous HF) led to the formation of hollow
      polymer beads containing movable gold cores. This new form of core-shell
      particles provides a unique system for measuring the feature size and transport
      property associated with hollow particles. In one demonstration, we showed that
      the thickness of a closed polymer shell could be obtained by mapping the
      electrons backscattered from the core and shell. In another demonstration, the
      plasmon resonance band of the gold cores was used as an optical probe to follow
      the diffusion kinetics of chemical reagents across the polymer shells.

PMID- 12603114
TI  - Formation of a cyclobutylidene ring: intramolecular [2 + 2] cycloaddition of
      allyl and vinylidene C=C bonds under mild conditions.
AB  - Intramolecular [2 + 2] cycloaddition of two C=C bonds in vinylidene complexes
      [Ru(eta5-C9H7){=C=C(R)H}(PPh3){kappa1-(P)-PPh2(C3H5)][BF4] affords
      cyclobutylidene complexes [Ru(eta5-C9H7){kappa2-(P,C)
      (=CC(R)HCH2CHCH2PPh2)}(PPh3)][BF4], which can be also obtained by reaction of
      terminal alkynes with [Ru(eta5-C9H7)(PPh3){kappa3-(P,C,C)-PPh2(C3H5)}][PF6]. The
      reaction proceeds under mild conditions via vinylidene complexes, and the
      activation parameters were determined by kinetic studies.

PMID- 12603115
TI  - The electrodeposition of high-density, ordered arrays of Bi1-xSbx nanowires.
AB  - Here we report the synthesis of dense arrays of Bi1-xSbx nanowires with >5 x 1010
      nanowires/cm2. The individual wires are crystalline, relatively homogeneous, and
      highly textured in a 110 direction, with diameters of 40 nm and a composition of
      x = 12-15 atom % Sb. By tuning the solution concentrations and controlling the
      growth rate by controlling the potential, the composition, crystallinity, and
      morphology of the nanowires can be varied.

PMID- 12603116
TI  - Restricting the conformational heterogeneity of RNA by specific incorporation of
      8-bromoguanosine.
AB  - In an effort to reduce the conformational heterogeneity of RNA, the modified
      nucleobase 8-bromoguanosine (8BrG) was introduced into oligonucleotides having
      the hairpin tetraloop motif YNMG (Y = U or C and M = C or A). Purine nucleobases
      with bromine at position eight are known to preferentially adopt the syn
      conformation as nucleosides. The hairpin tetraloop motif YNMG was chosen as a
      model system because it has a syn guanosine at position four of the loop that is
      essential for thermodynamic stability. Thermodynamic and structural
      characterization of modified oligonucleotides with the hairpin sequences UUCG,
      CGCG, and CGAG by UV-melting and NMR spectroscopy revealed that 8BrG substitution
      has a small effect upon the hairpin conformation, while the duplex conformation
      is strongly destabilized (DeltaDeltaG degrees 37 approximately +4.7 kcal mol-1),
      thus inhibiting dimerization. These results support a model in which 8BrG
      substitution shifts the hairpin-duplex equilibrium constant toward the hairpin
      conformation by destabilizing the duplex. This methodology should be useful for
      limiting conformational heterogeneity in large RNAs, with potential applications
      in structural biology and enzymology.

PMID- 12603117
TI  - A new structural form of tin in a double O-capped cluster.
AB  - A novel hexameric organooxotin cage [{(n-BuSn)3(PhO)3O}2{HPO3}4] 1 has been
      assembled by the reaction of [n-BuSnO(OH)] with (PhO)2P(O)H. The structure of 1
      consists of two O-capped Sn3 clusters that are attached to each other by four
      bridging tripodal [HPO3]2- ligands.

PMID- 12603118
TI  - New cyanometalate building units: synthesis and characterization of [Re(CN)(7)]3-
      and [Re(CN)(8)]3-.
AB  - Two new cyanorhenate complexes of potential utility in constructing magnetic and
      photomagnetic materials are reported. Reaction of (Bu4N)CN with [ReCl6]2- in
      acetonitrile affords yellow (Bu4N)3[Re(CN)7] (1), featuring the pentagonal
      bipyramidal complex [Re(CN)7]3-. The spectral and magnetic properties of 1
      indicate that the complex has an S = 1/2 ground state with considerable
      anisotropy in the g tensor. In aqueous solution, 1 reacts with Mn2+ ions to
      generate the three-dimensional cyano-bridged solid [fac-Mn(H2O)3][cis
      Mn(H2O)2][Re(CN)7].3H2O (2) containing diamagnetic [Re(CN)7]4-. Addition of KIO4
      to the reaction solution, originally intended to prevent reduction of the rhenium
      during solid formation, instead yields white (Bu4N)3[Re(CN)8] (3). As
      crystallized in K3[Re(CN)8].2MeCN (4.2MeCN), the diamagnetic [Re(CN)8]3- complex
      adopts a nearly perfect square antiprismatic coordination geometry. In solution,
      this species behaves analogously to the isoelectronic [M(CN)8]4- (M = Mo, W)
      complexes, apparently converting to a dodecahedral geometry and photooxidizing
      under UV radiation to give paramagnetic [Re(CN)8]2-.

PMID- 12603119
TI  - Surface polymerization by ion-assisted deposition for polythiophene film growth.
AB  - Cationic polymerization is induced at the gas-solid interface by hyperthermal
      organic cations coincident on a surface with a thermal beam of organic monomers.
      This process, termed surface polymerization by ion-assisted deposition (SPIAD),
      produces films that maintain the chemical structure of the monomer. A
      polythiophene film is produced here by SPIAD with 100 eV thiophene ions and
      terthiophene monomers coincident on Si and indium tin oxide (ITO) substrates held
      under vacuum. X-ray photoelectron spectroscopy observes enhancement in film
      growth for SPIAD compared with either thiophene ion or terthiophene exposure
      alone. Polythiophene films grown by both mass-selected and nonmass-selected ions
      with coincident terthiophene dosing both display similar fluorescence intensities
      at two wavelengths characteristic of emission from films of the terthiophene
      monomer. Raman spectra of films from nonmass-selected ions display several
      vibrations also observed in terthiophene films. Ions therefore play a critical
      role in film growth from nonmass-selected ions, in addition to any radical or
      photochemically driven processes that may also occur.

PMID- 12603120
TI  - Homonuclear correlation experiments of half-integer quadrupolar nuclei using
      multiple-quantum techniques spinning at a P(4) magic angle.
AB  - A new approach for obtaining structural information in half-integer quadrupolar
      nuclei is proposed and demonstrated. In this method, the two-dimensional multiple
      quantum experiment is performed, spinning at one of the angles at which the
      fourth order Legendre polynomial vanishes (P4 magic angle). In such an
      experiment, the dipolar interaction is retained, whereas the second-order
      quadrupolar broadening is refocused by the MQ-1Q correlation scheme. By adding an
      exchange period to this pulse scheme, we performed efficient homonuclear
      correlation experiments in a regular magic angle spinning probe with minor
      modifications. The experiment is demonstrated on a model compound, and the
      results are briefly discussed.

PMID- 12603121
TI  - The total synthesis of the Galbulimima alkaloid GB 13.
AB  - This contribution describes a synthetic approach to alkaloid GB 13, previously
      isolated from the North Australian and Papua New Guinean rain forest tree
      Galbulimima belgraveana. A Birch reductive alkylation of 2,5-dimethoxybenzoic
      acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was
      used to synthesize the [3.3.1]bicyclononane 8. A ring contraction performed on
      the diazo derivative 9 of the [3.3.1]bicyclononane led to [3.2.1]bicyclooctane
      10. This [3.2.1]bicyclooctane was converted into a dienophile and subjected to a
      Diels-Alder reaction to generate a pentacyclic intermediate 13 with a carbon
      skeleton closely resembling the target alkaloid. The surplus substituent,
      required for activation and regioselectivity in the Diels-Alder reaction, was
      removed using Birch reductive conditions to effect a decyanation. It was
      discovered that a Birch reduction of the aromatic ring also present in the
      molecule could be performed at the same time to give the enone 15, which was
      cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in
      the natural product was formed by reductive cyclization of the bis-oxime 18
      derived from the alkynyl ketone 17 and the resulting material further elaborated
      to GB 13 (1) via ketone 20.

PMID- 12603122
TI  - Productive folding of human neutrophil alpha-defensins in vitro without the pro
      peptide.
AB  - Human neutrophil alpha-defensins (HNPs) are small, Cys-rich, cationic
      antimicrobial proteins. Stored in the azurophilic granules of neutrophils, they
      are released during phagocytosis to kill ingested foreign microbes through
      disruption of their cytoplasmic membrane. Recently, the three most abundant forms
      of human alpha-defensins, HNPs 1-3, have been implicated in suppressing HIV-1
      infection in vivo, thereby exhibiting a potential therapeutic value in the
      treatment of AIDS. HNPs are synthesized as inactive precursors in vivo and
      require proteolytic removal of their inhibitory N-terminal pro-peptide for
      activation. Folding of HNPs 1-3 in vitro without the pro-peptide has been
      reported to be extremely difficult, which led to the hypothesis that the 45
      residue anionic pro-peptide may assist proHNPs folding as an intramolecular
      chaperone interacting with the cationic C-terminal domain, a mechanism
      reminiscent of some bacterial serine proteases. Here we show that HNPs without
      the pro-region can fold productively with yields over 80% in the presence of 2 M
      urea and 25% N,N-dimethylformamide (DMF). Our finding demonstrates an efficient
      protocol for the production of large quantities of highly pure human alpha
      defensins and is broadly applicable in folding aggregation-prone, Cys-rich
      proteins of both synthetic and recombinant origin.

PMID- 12603123
TI  - A thermally stable and sterically unprotected terminal electrophilic
      phosphinidene complex of cobalt and its conversion to an eta(1)-phosphirene.
AB  - The terminal chloroaminophosphido complex [Co(CO)3(PPh3){P(Cl)NiPr2}] is formed
      via reaction of K[Co(CO)4] with iPr2NPCl2 in the presence of triphenylphosphine.
      Chloride abstraction by aluminum trichloride leads to the first terminal
      phosphinidene complex of cobalt, [Co(CO)3(PPh3)(PNiPr2)][AlCl4]. The
      electrophilicity of the phosphinidene was demonstrated by its reaction with
      diphenylacetylene to form the phosphirene complex
      [Co(CO)3(PPh3){P(NiPr2)C(Ph)C(Ph)}][AlCl4].

PMID- 12603124
TI  - Tuning reactivity and chemoselectivity in electron transfer initiated cyclization
      reactions: applications to carbon-carbon bond formation.
AB  - In this communication, we demonstrate that the scope of our electron transfer
      initiated cyclization reaction can be significantly broadened by exploiting the
      relationship between the oxidation potentials of homobenzylic ethers and the
      mesolytic benzylic carbon-carbon bond dissociation energies of their radical
      cations. By lowering the oxidation potential of the electrophore and the benzylic
      carbon-carbon bond dissociation energy, we can initiate reactions under mild,
      nonphotochemical conditions. The selectivity of the arene oxidation and the mild
      reaction conditions allow a variety of electron-rich olefins to serve as
      nucleophilic groups to form carbon-carbon bonds with excellent efficiency.

PMID- 12603125
TI  - Solubilization of carbon nanotubes by Nafion toward the preparation of
      amperometric biosensors.
AB  - The ability to solubilize single-wall and multiwall carbon nanotubes (CNT) in the
      presence of the perfluorinated polymer Nafion is described. Such use of Nafion as
      a solubilizing agent for CNT overcomes a major obstacle for creating CNT-based
      biosensing devices. Their association with Nafion does not impair the
      electrocatalytic properties of CNT. The resulting CNT/Nafion modified glassy
      carbon electrodes exhibit a strong and stable electrocatalytic response toward
      hydrogen peroxide. The marked acceleration of the hydrogen peroxide redox process
      is very attractive for the operation of oxidase-based amperometric biosensors, as
      illustrated for the highly selective low-potential (-0.05 V vs Ag/AgCl)
      biosensing of glucose. These findings open the door for using CNT in a wide range
      of chemical sensors and nanoscale electronic devices.

PMID- 12603127
TI  - Remarkable 1,6-acyclic diastereoselection in the coupling of a novel butadienyl
      di-indium compound with aldehydes.
AB  - The reaction between a novel butadienyl di-indium reagent and aldehydes showed
      remarkable 1,6-diastereoselectivity to give acetylenic diol products as a single
      diastereomer. A bicyclic transition state formed through intramolecular chelation
      control was proposed that might account for the high 1,6-diastereoselection
      result.

PMID- 12603126
TI  - Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric
      catalyst.
AB  - A dinuclear asymmetric zinc catalyst generated by mixing a 2:1 ratio of
      diethylzinc and 2,6-bis[5-2-diarylhydroxy methyl-1-pyrrolidinyl]-4-methylphenol
      has been contrasted with enzymes for the desymmetrization of some meso diols. The
      best ligand has a p-biphenylyl group as the aromatic substituent defining the
      chiral space. A series of 2-substituted propanediols were examined. The best acyl
      transfer agent proved to be vinyl benzoate. Diacylation normally did not occur.
      The phenyl substituted substrate gave 91-95% ee which compares favorably with the
      best ee of 92% reported for an enzymatic desymmetrization. The methyl substituted
      substrate gave significantly better results with the dinuclear zinc catalyst (89%
      yield, 82% ee) as compared to the best enzymatic esterification (70% yield, 60%
      ee). One case of a 1,4-diol, cis-1,2-bis(hydroxymethyl) cyclohexane, also gave
      much better results with the dinuclear zinc catalysts (93% yield, 91% ee) as
      compared to the reported enzymatic process (44% yield, 7% ee). A model to
      rationalize the results is presented.

PMID- 12603128
TI  - (Eta2-alkyne)methyl(dioxo)rhenium complexes as aldehyde-olefination catalysts.
AB  - Complexes CH3ReO2L (L = 2-butyne, 3-hexyne, diphenylacetylene) are catalysts for
      the olefination of aldehydes, using 4-nitrobenzaldehyde (4-nba) as the standard
      aldehyde and ethyldiazoacetate (eda) as the diazo compound. Spectroscopic studies
      including in situ 31P, 17O, 13C, and 1H NMR spectroscopy are used to elucidate
      the mechanism and the nature of the active species. One of the key steps of the
      mechanism is the rapid formation of phosphazine at the beginning of the cycle and
      its subsequent reaction with the metal dioxide complex to form the catalytically
      active carbene species.

PMID- 12603129
TI  - A modular cross-linking approach for exploring protein interactions.
AB  - A method is described for the elucidation of protein-protein interactions using
      novel cross-linking reagents and mass spectrometry. The method incorporates (1) a
      modular solid-phase synthetic strategy for generating the cross-linking reagents,
      (2) enrichment and digestion of cross-linked proteins using microconcentrators,
      (3) mass spectrometric analysis of cross-linked peptides, and (4) comprehensive
      computational analysis of the cross-linking data. This integrated approach has
      been applied to the study of cross-linking between the components of the
      heterodimeric protein complex negative cofactor 2.

PMID- 12603130
TI  - Synthesis of lipid A derivatives and their interactions with polymyxin B and
      polymyxin B nonapeptide.
AB  - Lipid A is the causative agent of Gram-negative sepsis, a leading cause of
      mortality among hospitalized patients. Compounds that bind lipid A can limit its
      detrimental effects. Polymyxin B, a cationic peptide antibiotic, is one of the
      simplest molecules capable of selectively binding lipid A and may serve as a
      model for further development of lipid A binding agents. However, association of
      polymyxin B with lipid A is not fully understood, primarily due to the low
      solubility of lipid A in water and inhomogeneity of lipid A preparations. To
      better understand lipid A-polymyxin B interaction, pure lipid A derivatives were
      prepared with incrementally varied lipid chain lengths. These compounds proved to
      be more soluble in water than lipid A, with higher aggregation concentrations.
      Isothermal titration calorimetric studies of these lipid A derivatives with
      polymyxin B and polymyxin B nonapeptide indicate that binding stoichiometries
      (peptide to lipid A derivative) are less than 1 and that affinities of these
      binding partners correlate with the aggregation states of the lipid A
      derivatives. These studies also suggest that cooperative ionic interactions
      dominate association of polymyxin B and polymyxin B nonapeptide with lipid A.

PMID- 12603131
TI  - Rapid ligand exchange in the MCRred1 form of methyl-coenzyme M reductase.
AB  - Methyl-coenzyme M reductase (MCR) from Methanothermobacter marburgensis (Mtm),
      catalyses the final step in methane synthesis in all methanogenic organisms.
      Methane is produced by coenzyme B-dependent two-electron reduction of methyl
      coenzyme M. At the active site of MCR is the corphin cofactor F(430), which
      provides four-coordination through the pyrrole nitrogens to a central Ni ion in
      all states of the enzyme. The important MCRox1 ("ready") and MCRred1 ("active")
      states contain six-coordinate Ni(I) and differ in their upper axial ligands;
      furthermore, red1 appears to be two-electrons more reduced than in ox1 and other
      Ni(II) states that have been studied. On the basis of the reactivity of MCRred1
      and MCRox1 with a substrate analogue and inhibitor (3-bromopropanesulfonate) and
      other small molecules (chloroform, dichloromethane, mercaptoethanol, and nitric
      oxide), we present evidence that the six-coordinate Ni(I) centers in the MCRred1
      and MCRox1 states exhibit markedly different inherent reactivities. MCRred1
      reacts faster with chloroform (2100-fold or 35000-fold when corrected for
      temperature effects), nitric oxide (90-fold), and 3-bromopropanesulfonate (10(6)
      fold) than MCRox1. MCRred1 reacts with chloroform and dichloromethane and, like
      F(430), can catalyze dehalogenation reactions and produce lower halogenated
      products. We conclude that the enhanced reactivity of MCRred1 is due to the
      replacement of a relatively exchange-inert thiol ligand in MCRox1 with a weakly
      coordinating upper axial ligand in red1 that can be easily replaced by incoming
      ligands.

PMID- 12603132
TI  - Deoxyribozymes with 2'-5' RNA ligase activity.
AB  - In vitro selection was used to identify deoxyribozymes that ligate two RNA
      substrates. In the ligation reaction, a 2'-5' RNA phosphodiester linkage is
      created from a 2',3'-cyclic phosphate and a 5'-hydroxyl group. The new Mg(2+)
      dependent deoxyribozymes provide 50-60% yield of ligated RNA in overnight
      incubations at pH 7.5 and 37 degrees C, and they afford 40-50% yield in 1 h at pH
      9.0 and 37 degrees C. Various RNA substrate sequences may be joined by simple
      Watson-Crick covaration of the DNA binding arms that interact with the two RNA
      substrates. The current deoxyribozymes have some RNA substrate sequence
      requirements at the nucleotides immediately surrounding the ligation junction
      (either UAUA GGAA or UAUN GGAA, where the arrow denotes the ligation site and N
      equals any nucleotide). One of the new deoxyribozymes was used to prepare by
      ligation the Tetrahymena group I intron RNA P4-P6 domain, a representative
      structured RNA. Nondenaturing gel electrophoresis revealed that a 2'-5' linkage
      between nucleotides A233 and G234 of P4-P6 does not disrupt its Mg(2+)-dependent
      folding (DeltaDeltaG degrees ' < 0.2 kcal/mol). This demonstrates that a 2'-5'
      linkage does not necessarily interfere with structure in a folded RNA. Therefore,
      these non-native linkages may be acceptable in modified RNAs when
      structure/function relationships are investigated. Deoxyribozymes that ligate RNA
      should be particularly useful for preparing site-specifically modified RNAs for
      studies of RNA structure, folding, and catalysis.

PMID- 12603133
TI  - Sialic acid biosynthesis: stereochemistry and mechanism of the reaction catalyzed
      by the mammalian UDP-N-acetylglucosamine 2-epimerase.
AB  - The bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase,
      catalyzes the first two steps in the biosynthesis of the sialic acids in mammals.
      The epimerase domain converts UDP-GlcNAc into ManNAc and UDP. This paper
      demonstrates that alpha-ManNAc is the first formed anomer and therefore the
      reaction proceeds with a net retention of configuration at C-1. Studies in
      deuterated buffer show that solvent-derived deuterium is quantitatively
      incorporated into the C-2 position of the product during catalysis, but it is not
      incorporated into the remaining pool of substrate. This indicates that the
      inversion of stereochemistry is ultimately brought about by the removal and
      replacement of a proton at C-2 and is consistent with a two-base mechanism.
      Studies with (18)O-labeled UDP-GlcNAc show that the anomeric oxygen of the
      glycosyl phosphate bond departs with the UDP product and therefore the net
      hydrolysis reaction involves C-O bond cleavage. Incubation of the putative
      intermediate, 2-acetamidoglucal, with the enzyme resulted in a slow hydration
      reaction to give the product, ManNAc. Additional kinetic isotope effect and
      positional isotope exchange (PIX) experiments address the nature of the rate
      determining step of the reaction and show that C-H bond cleavage is not rate
      limiting. Overall, these results support a reaction mechanism involving an anti
      elimination of UDP to give 2-acetamidoglucal, followed by a syn-addition of
      water.

PMID- 12603135
TI  - Quantum mechanical predictions of the stereoselectivities of proline-catalyzed
      asymmetric intermolecular aldol reactions.
AB  - Quantum mechanical calculations were employed to predict the ratio of four
      stereoisomeric products expected from two complex reactions involving the aldol
      reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed
      by (S)-proline. Experimental tests of these predictions provide an assessment of
      the state-of-the-art in quantum mechanical prediction of products of complex
      organic reactions in solution.

PMID- 12603136
TI  - Design of an adenosine analogue that selectively improves the affinity of a
      mutant U1A protein for RNA.
AB  - The RNA recognition motif (RRM), one of the most common RNA binding domains,
      contains three highly conserved aromatic amino acids that participate in stacking
      interactions with RNA bases. We have investigated the contribution of these
      highly conserved aromatic amino acids to the affinity of the complex formed
      between the N-terminal RRM of the U1A protein and stem loop 2 of U1 snRNA.
      Previously, we found that substitution of one of these conserved aromatic amino
      acids, Phe56, with Ala resulted in a large destabilization of the complex. Here,
      we have modified A6, the base in stem loop 2 RNA that stacks with Phe56, to
      compensate for a portion of the destabilization caused by the Phe56Ala mutation.
      We have designed two modified adenosines, A-3CPh and A-4CPh, in which a phenyl
      group is linked to the adenosine such that it may replace the phenyl group that
      is eliminated by the Phe56Ala mutation in the complex. We have found that
      incorporation of A-3CPh into stem loop 2 RNA stabilizes the complex formed with
      Phe56Ala by 0.6 kcal/mol, while incorporation of A-4CPh into stem loop 2 RNA
      stabilizes this complex by 1.8 kcal/mol. Either base modification destabilizes
      the wild-type complex by 0.8-0.9 kcal/mol. Experiments with other U1A mutant
      proteins suggest that the stabilization of the complex between the Phe56Ala U1A
      protein and stem loop 2 RNA is due to a specific interaction between the Phe56Ala
      U1A protein and A6-4CPh stem loop 2 RNA.

PMID- 12603134
TI  - Fundamental reaction mechanism for cocaine hydrolysis in human
      butyrylcholinesterase.
AB  - Butyrylcholinesterase (BChE)-cocaine binding and the fundamental pathway for BChE
      catalyzed hydrolysis of cocaine have been studied by molecular modeling,
      molecular dynamics (MD) simulations, and ab initio calculations. Modeling and
      simulations indicate that the structures of the prereactive BChE/substrate
      complexes for (-)-cocaine and (+)-cocaine are all similar to that of the
      corresponding prereactive BChE/butyrylcholine (BCh) complex. The overall binding
      of BChE with (-)-cocaine and (+)-cocaine is also similar to that proposed with
      butyrylthiocholine and succinyldithiocholine, i.e., (-)- or (+)-cocaine first
      slides down the substrate-binding gorge to bind to Trp-82 and stands vertically
      in the gorge between Asp-70 and Trp-82 (nonprereactive complex) and then rotates
      to a position in the catalytic site within a favorable distance for nucleophilic
      attack and hydrolysis by Ser-198 (prereactive complex). In the prereactive
      complex, cocaine lies horizontally at the bottom of the gorge. The fundamental
      catalytic hydrolysis pathway, consisting of acylation and deacylation stages
      similar to those for ester hydrolysis by other serine hydrolases, was proposed on
      the basis of the simulated prereactive complex and confirmed theoretically by ab
      initio reaction coordinate calculations. Both the acylation and deacylation
      follow a double-proton-transfer mechanism. The calculated energetic results show
      that within the chemical reaction process the highest energy barrier and Gibbs
      free energy barrier are all associated with the first step of deacylation. The
      calculated ratio of the rate constant (k(cat)) for the catalytic hydrolysis to
      that (k(0)) for the spontaneous hydrolysis is approximately 9.0 x 10(7). The
      estimated k(cat)/k(0) value of approximately 9.0 x 10(7) is in excellent
      agreement with the experimentally derived k(cat)/k(0) value of approximately 7.2
      x 10(7) for (+)-cocaine, whereas it is approximately 2000 times larger than the
      experimentally derived k(cat)/k(0) value of approximately 4.4 x 10(4) for (-)
      cocaine. All of the results suggest that the rate-determining step of the BChE
      catalyzed hydrolysis of (+)-cocaine is the first step of deacylation, whereas for
      (-)-cocaine the change from the nonprereactive complex to the prereactive complex
      is rate-determining and has a Gibbs free energy barrier higher than that for the
      first step of deacylation by approximately 4 kcal/mol. A further analysis of the
      structural changes from the nonprereactive complex to the prereactive complex
      reveals specific amino acid residues hindering the structural changes, providing
      initial clues for the rational design of BChE mutants with improved catalytic
      activity for (-)-cocaine.

PMID- 12603137
TI  - Experimental determination of the absolute enantioselectivity of an antibody
      catalyzed Diels-Alder reaction and theoretical explorations of the origins of
      stereoselectivity.
AB  - The exo and endo Diels-Alder adducts of p-methoxycarbonylbenzyl trans-1,3
      butadiene-1-carbamate and N,N-dimethylacrylamide have been synthesized, and the
      absolute configurations of resolved enantiomers have been determined. On the
      basis of this information, the absolute enantioselectivities of the Diels-Alder
      reaction catalyzed by antibodies 13G5 and 4D5 as well as other catalytic
      antibodies elicited in the same immunizations have been established. The effects
      of different arrangements of catalytic residues on the structure and energetics
      of the possible Diels-Alder transition states were modeled quantum mechanically
      at the B3LYP/6-311++G**//B3LYP/6-31+G** level of theory. Flexible docking of
      these enantiomeric transition states in the antibody active site followed by
      molecular dynamics on the resulting complexes provided a prediction of the
      transition-state binding modes and an explanation of the origin of the observed
      enantioselectivity of antibody 13G5.

PMID- 12603138
TI  - Catalytic, asymmetric Mannich-type reactions of N-acylimino esters: reactivity,
      diastereo- and enantioselectivity, and application to synthesis of N-acylated
      amino acid derivatives.
AB  - In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N
      acylimino esters reacted with silyl enol ethers to afford the corresponding
      Mannich-type adducts in high yields with high enantioselectivities. A wide
      variety of silyl enol ethers derived from ketones, as well as esters and
      thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol
      ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high
      yields with high diastereo- and enantioselectivities. Several intermediates for
      the synthesis of biologically important compounds were prepared using this novel
      catalytic asymmetric Mannich-type reaction, and at the same time, absolute and
      relative stereochemical assignments were made. In addition, it has been revealed
      that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a
      catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type
      adducts in high yields with high enantioselectivities. This is the first example
      of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The
      reaction mechanism, structure of chiral catalyst-electrophile complexes, and
      transition states of these catalytic asymmetric reactions were assumed based on X
      ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3
      calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1
      hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of
      ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM)
      synthesis, has been synthesized efficiently using the present Mannich-type
      reaction as a key step. The synthesis involved three steps (two-pot), and total
      yield was 82.9%.

PMID- 12603139
TI  - Chiral stimuli-responsive gels: helicity induction in poly(phenylacetylene) gels
      bearing a carboxyl group with chiral amines.
AB  - Poly(phenylacetylene) gels (gel-1-H and gel-2-H) bearing a carboxy pendant were
      synthesized either by the copolymerization of (4-carboxyphenyl)acetylene (gel-1
      H) with a bis(phenylacetylene) derivative as the cross-linking reagent using a
      rhodium complex ([Rh(cod)(2)]BF(4): cod = 1,5-cyclooctadiene) as the catalyst or
      by the cross-linking of poly[(4-carboxyphenyl)acetylene] with diamines (gel-2-H).
      The obtained gels were found to swell in DMSO and exhibited an induced circular
      dichroism (ICD) in the long absorption region of the main chain in the presence
      of optically active amines. These results indicate that a predominantly one
      handed helix can be induced in the polymer network of the gels through chiral
      acid-base interactions. The swelling properties and the Cotton effect intensities
      of the gels depend on the cross-linking ratio and the chiral amines. Gel-1-Na and
      gel-2-Na prepared from gel-1-H and gel-2-H, respectively, also significantly
      swelled in water and showed ICDs characteristic of chiral amino alcohols and free
      amino acids in water.

PMID- 12603140
TI  - Nitro-functionalized oligothiophenes as a novel type of electroactive molecular
      material: spectroscopic, electrochemical, and computational study.
AB  - A novel series of terthiophenes bearing electron-donor and electron-acceptor
      groups at the end alpha-positions has been prepared. The analysis of the UV-vis,
      infrared, and Raman spectra, performed with the aid of density functional theory
      calculations, shows that the asymmetrically substituted nitro compounds
      PhT(3)NO(2) and BrT(3)NO(2) behave as push-pull systems and present an intense
      photoinduced charge transfer in the visible spectrum. The symmetrically
      substituted dinitro compound NO(2)T(3)NO(2) displays a highly delocalized
      structure with a low single-double bond length alternation and also displays a
      low-energy absorption band in the visible region. The novel nitroterthiophenes
      possess attractive electrochemical properties since they generate stable species
      both upon oxidation and reduction. Oxidation mainly involves changes in the
      oligothiophene backbone and leads to the formation of stable cations even for
      NO(2)T(3)NO(2). Reduction is mainly nitro-centered but also affects the
      conjugated structure. Radical anions and dianions are formed for PhT(3)NO(2) and
      BrT(3)NO(2). Dianions, not radical anions, and trianions are obtained for
      NO(2)T(3)NO(2). Nitro-functionalized terthiophenes are shown to be very promising
      as electroactive molecular materials since they behave as push-pull systems,
      present a very intense photoinduced charge transfer in the visible region, and
      could act as both n- and p-channel conductors in organic electronic transistors.

PMID- 12603141
TI  - Protonation of the pyrimidine ring at the C(5) position: formation of a stable
      cationic sigma-complex.
AB  - NMR studies showed that, in addition to the expected N(1) protonation, 2,4,6
      pyrimidinetriamine, N,N,N',N',N",N"-hexamethyl- (1) could also be protonated at
      the C(5) position in water, leading to an equilibrium between the C(5) and N(1)
      protonated forms. Analysis of the NMR titration data gives 6.87 and 6.89 for the
      pK(a) of the C(5) and N(1) protonation equilibria. Moreover, the reaction of 1
      with chloroacetyl chloride leads to a novel 1,1-bis(pyrimidin-5-yl)-2
      chloroethene type derivative (4) that is, peculiarly, fully monoprotonated at the
      C(5) position in either of the pyrimidine rings, forming a stable cationic sigma
      complex.

PMID- 12603142
TI  - Slow diffusion of macromolecular assemblies by a new pulsed field gradient NMR
      method.
AB  - The translational diffusion coefficient of an integral membrane
      protein/surfactant complex has been measured using a novel pulsed field gradient
      NMR method. In this new approach, the information about the localization of the
      molecules is temporarily stored in the form of longitudinal magnetization of
      isotopes with long spin-lattice relaxation times. This allows one to increase the
      duration of the diffusion interval by about 1 order of magnitude. Unlike standard
      proton NMR methods using pulsed field gradients and stimulated echoes, the new
      method can be applied to macromolecular assemblies with diffusion coefficients
      well below 10(-10) m(2) s(-1), corresponding to masses in excess of 25 kDa in
      aqueous solution at room temperature. The method was illustrated by application
      to a water-soluble complex of tOmpA, the hydrophobic transmembrane domain of
      bacterial outer membrane protein A, with the detergent octyl-tetraoxyethylene
      (C(8)E(4); overall mass of complex approximately 45 kDa). The diffusion
      coefficient was found to be D = (4.99 +/- 0.07) x 10(-11) m(2) s(-1), consistent
      with measurements by size exclusion chromatography and by ultracentrifugation.
      The method has also been applied to a solution of recombinant human tRNA(3)(Lys),
      which has a molecular mass of 24 kDa, and the diffusion coefficient D = (1.05 +/-
      0.015) x 10(-10) m(2) s(-1).

PMID- 12603143
TI  - Synthesis and activity of ruthenium alkylidene complexes coordinated with
      phosphine and N-heterocyclic carbene ligands.
AB  - This paper reports the synthesis and characterization of a variety of ruthenium
      complexes coordinated with phosphine and N-heterocyclic carbene (NHC) ligands.
      These complexes include several alkylidene derivatives of the general formula
      (NHC)(PR(3))(Cl)(2)Ru=CHR', which are highly active olefin metathesis catalysts.
      Although these catalysts can be prepared adequately by the reaction of
      bis(phosphine) ruthenium alkylidene precursors with free NHCs, we have developed
      an alternative route that employs NHC-alcohol or -chloroform adducts as
      "protected" forms of the NHC ligands. This route is advantageous because NHC
      adducts are easier to handle than their free carbene counterparts. We also
      demonstrate that sterically bulky bis(NHC) complexes can be made by reaction of
      the pyridine-coordinated precursor (NHC)(py)(2)(Cl)(2)Ru=CHPh with free NHCs or
      NHC adducts. Two crystal structures are presented, one of the mixed bis(NHC)
      derivative (H(2)IMes)(IMes)(Cl)(2)Ru=CHPh, and the other of
      (PCy(3))(Cl)(CO)Ru[eta(2)-(CH(2)-C(6)H(2)Me(2))(N(2)C(3)H(4))(C(6)H(2)Me(3))],
      the product of ortho methyl C-H bond activation. Other side reactions encountered
      during the synthesis of new ruthenium alkylidene complexes include the formation
      of hydrido-carbonyl-chloride derivatives in the presence of primary alcohols and
      the deprotonation of ruthenium vinylcarbene ligands by KOBu(t). We also evaluate
      the olefin metathesis activity of NHC-coordinated complexes in representative RCM
      and ROMP reactions.

PMID- 12603144
TI  - Isolation of the latent precursor complex in electron-transfer dynamics.
      Intermolecular association and self-exchange with acceptor anion radicals.
AB  - Transient [1:1] complexes formed in the bimolecular interactions of electron
      acceptors (A) with their reduced anion radicals (A(-.)) are detected and
      characterized in solution for the first time. The recognition of such metastable
      intermediates as the heretofore elusive precursor complex (A(2)(-.)) in electron
      transfer processes for self-exchange allows the principal parameters lambda
      (Marcus reorganization energy) and H(DA) (electronic coupling element) to be
      experimentally determined from the optical (charge-transfer) transitions inherent
      to these intermolecular complexes. The satisfactory correspondence of the
      theoretically predicted with the experimentally observed rate constants validates
      these ET parameters and the Marcus-Hush-Sutin methodology for strongly coupled
      redox systems lying in the (Robin-Day) Class II category. Most importantly, the
      marked intermolecular electronic interaction (H(DA)) within these precursor
      complexes must be explicitly recognized, since it dramatically affects the
      electron-transfer dynamics by effectively lowering the activation barrier. As
      such, the numerous calculations of the reorganization energy previously obtained
      from various self-exchange kinetics based on lambda = 4DeltaG must be
      reconsidered in the light of such a precursor complex, with the important result
      that ET rates can be substantially faster than otherwise predicted. On the basis
      of these studies, a new mechanistic criterion is proposed for various outer
      sphere/inner-sphere ET processes based on the relative magnitudes of H(DA) and
      lambda.

PMID- 12603145
TI  - Structural studies of ammonia and metallic lithium-ammonia solutions.
AB  - The technique of hydrogen/deuterium isotopic substitution has been used to
      extract detailed information concerning the solvent structure in pure ammonia and
      metallic lithium-ammonia solutions. In pure ammonia we find evidence for
      approximately 2.0 hydrogen bonds around each central nitrogen atom, with an
      average N-H distance of 2.4 A. On addition of alkali metal, we observe directly
      significant disruption of this hydrogen bonding. At 8 mol % metal there remains
      only around 0.7 hydrogen bond per nitrogen atom. This value decreases to 0.0 for
      the saturated solution of 21 mol % metal, as all ammonia molecules have then
      become incorporated into the tetrahedral first solvation spheres of the lithium
      cations. In conjunction with a classical three-dimensional computer modeling
      technique, we are now able to identify a well-defined second cationic solvation
      shell. In this secondary shell the nitrogen atoms tend to reside above the faces
      and edges of the primary tetrahedral shell. Furthermore, the computer-generated
      models reveal that on addition of alkali metal the solvent molecules form voids
      of approximate radius 2.5-3.0 A. Our data therefore provide new insight into the
      structure of the polaronic cavities and tunnels, which have been theoretically
      predicted for lithium-ammonia solutions.

PMID- 12603146
TI  - Direct catalytic asymmetric Michael reaction of hydroxyketones: asymmetric Zn
      catalysis with a Et2Zn/linked-BINOL complex.
AB  - Full details of our direct Michael addition of unmodified ketones using new
      asymmetric zinc catalysis are described. Et(2)Zn/(S,S)-linked-BINOL complexes
      were successfully applied to direct 1,4-addition reactions of hydroxyketones. The
      first generation Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was effective for 1,4
      addition of 2-hydroxy-2'-methoxyacetophenone (3). Using 1 mol % of (S,S)-linked
      BINOL 1 and 2 mol % of Et(2)Zn, we found that a 1,4-addition reaction of beta
      unsubstituted enone proceeded smoothly at 4 degrees C to afford products in high
      yield (up to 90%) and enantiomeric excess (up to 95%). In the case of beta
      substituted enones, however, the first generation Et(2)Zn/(S,S)-linked-BINOL 1 =
      2/1 system was not at all effective. The second generation Et(2)Zn/(S,S)-linked
      BINOL 1 = 4/1 with MS 3A system was developed and was effective for various beta
      substituted enones to afford products in good dr, yield (up to 99%), and high
      enantiomeric excess (up to 99% ee). With the Et(2)Zn/1 = 4/1 systems, catalyst
      loading for beta-unsubstituted enone was reduced to as little as 0.01 mol %
      (substrate/chiral ligand = 10 000). The new system was also effective for 1,4
      addition reactions of 2-hydroxy-2'-methoxypropiophenone (9) to afford chiral tert
      alcohol in high enantiomeric excess (up to 96% ee). Mechanistic investigations as
      well as transformations of the Michael adducts into synthetically versatile
      intermediates are also described.

PMID- 12603148
TI  - Formation and structure of self-assembled monolayers of alkanethiolates on
      palladium.
AB  - The adsorption of n-alkanethiols onto polycrystalline thin films of palladium
      containing a strong (111) texture produces well-organized, self-assembled
      monolayers. The organization of the alkane chains in the monolayer and the nature
      of the bonding between the palladium and the thiol were studied by contact angle
      measurements, optical ellipsometry, reflection absorption infrared spectroscopy
      (RAIRS), and X-ray photoelectron spectroscopy (XPS). The XPS data reveals that a
      compound palladium-sulfide interphase is present at the surface of the palladium
      film. The RAIR spectra, ellipsometry data, and wetting properties show that the
      palladium-sulfide phase is terminated with an organized, methyl-terminated
      monolayer of alkanethiolates. The local molecular environment of the alkane
      chains transitions from a conformationally disordered, liquidlike state to a
      mostly all-trans, crystalline-like structure with increasing chain length (n = 8
      26). The intensities and dichroism of the methylene and methyl stretching modes
      support a model for the average orientation of an ensemble of all-trans-conformer
      chains with a tilt angle of approximately 14-18 degrees with respect to the
      surface normal and a twist angle of the CCC plane relative to the tilt plane of
      approximately 45 degrees. The SAMs are stable in air, although the sulfur present
      at the surface oxidizes in air over a period of 2-5 days at room temperature. The
      differences in chain organization between SAMs formed by microcontact printing
      and by solution deposition are also examined by RAIRS and XPS.

PMID- 12603147
TI  - An enantiomerically pure adamantylimido molybdenum alkylidene complex. An
      effective new catalyst for enantioselective olefin metathesis.
AB  - An enantiomerically pure Mo-based complex that bears an alkylimido ligand is
      prepared and characterized through NMR spectroscopy and X-ray analysis. Mo
      complex 4 is the only reported chiral alkylimido catalyst; all previous chiral
      complexes are arylimido systems. These studies show that the chiral Mo catalyst
      exists exclusively as the syn isomer and that it offers unique reactivity and
      selectivity profiles in asymmetric olefin metathesis.

PMID- 12603149
TI  - Solvent-controlled diastereoselective synthesis of cyclopentane derivatives by a
      [3 + 2] cyclization reaction of alpha,beta-disubstituted
      (alkenyl)(methoxy)carbene complexes with methyl ketone lithium enolates.
AB  - Reaction of alpha,beta-unsaturated methoxycarbene complexes 1 and 11 with methyl
      ketone lithium enolates 2 leads to the corresponding five-membered carbocyclic
      compounds 4 or diast-4 and 12. The influence of the solvent and/or cosolvent
      (PMDTA), which turned out to be crucial to direct the reaction to 4 or diast-4,
      is studied, and a tentative mechanism according to these facts is proposed. In
      addition, the reaction of carbene complex 1a with alkynyl methyl ketone lithium
      enolates can be directed to the formal [3 + 2] or [4 + 1] cyclization products by
      a slight variation of the reaction conditions. Finally, consecutive three
      component coupling reactions with carbene complex 1a, lithium enolates 2, and
      aldehydes 18 to give, in a diastereoselective way, hydroxy carbonyl compounds 19
      and tricyclic polyethers 20 are presented.

PMID- 12603150
TI  - Nanoscopic assemblies between supramolecular redox active metallodendrons and
      gold nanoparticles: synthesis, characterization, and selective recognition of
      H2PO4-, HSO4-, and adenosine-5'-triphosphate (ATP2-) anions.
AB  - Tri- and nonaferrocenyl thiol dendrons have been synthesized and used to assemble
      dendronized gold nanoparticles either by the ligand-substitution method from
      dodecanethiolate-gold nanoparticles (AB(3) units) or Brust-type direct synthesis
      from a 1:1 mixture of dodecanethiol and dendronized thiol (AB(9) units). The
      dendronized colloids are a new type of dendrimers with a gold colloidal core. Two
      colloids containing a nonasilylferrocenyl dendron have been made; they bear
      respectively 180 and 360 ferrocenyl units at the periphery. These colloids
      selectively recognize the anions H(2)PO(4)(-) and adenosine-5'-triphosphate
      (ATP(2)(-)) with a positive dendritic effect and can be used to titrate these
      anions because of the shift of the CV wave even in the presence of other anions
      such as Cl(-) and HSO(4)(-). Recognition is monitored by the appearance of a new
      wave at a less positive potential in cyclic voltammetry (CV). The anion HSO(4)(-)
      is also recognized and titrated by the dendronized colloid containing the tris
      amidoferrocenyl units, because of the progressive shift of the CV wave until the
      equivalence point. These dendronized colloids can form robust modified electrodes
      by dipping the naked Pt electrode into a CH(2)Cl(2) solution containing the
      colloids. The robustness is all the better as the dendron is larger. These
      modified electrodes can recognize H(2)PO(4)(-), ATP(2)(-) and HSO(4)(-), be
      washed with minimal loss of adsorbed colloid, and be reused.

PMID- 12603152
TI  - Structural dependence of thermodynamics of alkene binding to yttrium alkyl
      complexes and of kinetics of alkyl migration to coordinated alkenes.
AB  - Agostic interactions in yttrium alkyls are structure dependent. Primary alkyl
      yttrium complexes have beta-CH(2) agostic interactions at low temperature, but a
      shift toward alpha-agostic interactions occurs on warming. For the more crowded
      beta-disubstituted yttrium alkyls, an alpha-CH(2) agostic interaction is seen.
      The thermodynamics of alkene binding to the primary alkyl yttrium complex
      Cp(2)YCH(2)CH(2)CH(CH(3))(2) (2) depend strongly on the structure of the alkene.
      A single allylic substituent on the alkene has a small effect on alkene binding,
      but a second allylic substituent has a large destabilizing effect. Propene
      binding to yttrium alkyls is largely independent of the nature of the alkyl
      ligand. Equilibrium constants for propene binding to n-, gamma-substituted, beta
      substituted, and secondary alkyl yttrium complexes are similar. The rate of
      migration of an alkyl group to a coordinated alkene depends strongly on the
      structure of the alkyl group: n-alkyl approximately gamma-substituted >> beta
      substituted >> alpha-substituted. The approximately 200-fold slower insertion of
      propene into Cp(2)YCH(2)CH(CH(3))(2) (6) than that into
      Cp(2)YCH(2)CH(2)CH(CH(3))(2) (2) is therefore due to kinetically slow migration
      of the beta-disubstituted alkyl group of 6 and not to differences in the
      equilibrium binding of propene. Processes related to chain transfer and site
      epimerization at the metal center are also reported.

PMID- 12603151
TI  - Electron and hydrogen-atom self-exchange reactions of iron and cobalt
      coordination complexes.
AB  - Reported here are self-exchange reactions between iron 2,2'
      bi(tetrahydro)pyrimidine (H(2)bip) complexes and between cobalt 2,2'
      biimidazoline (H(2)bim) complexes. The (1)H NMR resonances of
      [Fe(II)(H(2)bip)(3)](2+) are broadened upon addition of
      [Fe(III)(H(2)bip)(3)](3+), indicating that electron self-exchange occurs with
      k(Fe,e)(-) = (1.1 +/- 0.2) x 10(5) M(-1) s(-1) at 298 K in CD(3)CN. Similar
      studies of [Fe(II)(H(2)bip)(3)](2+) plus [Fe(III)(Hbip)(H(2)bip)(2)](2+) indicate
      that hydrogen-atom self-exchange (proton-coupled electron transfer) occurs with
      k(Fe,H.) = (1.1 +/- 0.2) x 10(4) M(-1) s(-1) under the same conditions. Both self
      exchange reactions are faster at lower temperatures, showing small negative
      enthalpies of activation: DeltaH++(e(-)) = -2.1 +/- 0.5 kcal mol(-1) (288-320 K)
      and DeltaH++(H.) = -1.5 +/- 0.5 kcal mol(-1) (260-300 K). This behavior is
      concluded to be due to the faster reaction of the low-spin states of the iron
      complexes, which are depopulated as the temperature is raised. Below about 290 K,
      rate constants for electron self-exchange show the more normal decrease with
      temperature. There is a modest kinetic isotope effect on H-atom self-exchange of
      1.6 +/- 0.5 at 298 K that is close to that seen previously for the fully high
      spin iron biimidazoline complexes.(12) The difference in the measured activation
      parameters, E(a)(D) - E(a)(H), is -1.2 +/- 0.8 kcal mol(-1), appears to be
      inconsistent with a semiclassical view of the isotope effect, and suggests
      extensive tunneling. Reactions of [Co(H(2)bim)(3)](2+)-d(24) with
      [Co(H(2)bim)(3)](3+) or [Co(Hbim)(H(2)bim)(2)](2+) occur with scrambling of
      ligands indicating inner-sphere processes. The self-exchange rate constant for
      outer-sphere electron transfer between [Co(H(2)bim)(3)](2+) and
      [Co(H(2)bim)(3)](3+) is estimated to be 10(-)(6) M(-1) s(-1) by application of
      the Marcus cross relation. Similar application of the cross relation to H-atom
      transfer reactions indicates that self-exchange between [Co(H(2)bim)(3)](2+) and
      [Co(Hbim)(H(2)bim)(2)](2+) is also slow, < or =10(-3) M(-1) s(-1). The slow self
      exchange rates for the cobalt complexes are apparently due to their
      interconverting high-spin [Co(II)(H(2)bim)(3)](2+) with low-spin Co(III)
      derivatives.

PMID- 12603153
TI  - Alkylidene and metalacyclic complexes of tungsten that contain a chiral
      biphenoxide ligand. synthesis, asymmetric ring-closing metathesis, and
      mechanistic investigations.
AB  - Two complexes that contain the racemic or enantiomerically pure (S) form of the
      3,3'-di-tert-butyl-5,5',6,6'-tetramethyl-1,1'-biphenyl-2,2'-diolate (Biphen(2-))
      ligand, W(NAr)(CHCMe(2)Ph)(Biphen) (2a) and W(NAr')(CHCMe(2)Ph)(Biphen) (2b) (Ar
      = 2,6-i-Pr(2)C(6)H(3); Ar' = 2,6-Me(2)C(6)H(3)), were prepared and shown to be
      viable catalysts for several representative ring-closing reactions to give
      products in good yields in most cases and high % ee in asymmetric reactions.
      Exploration of the reaction between 2a and a stoichiometric amount of one
      desymmetrization substrate allowed two intermediate tungstacyclobutane complexes
      to be observed, in addition to the final and quite stable tungstacyclobutane
      complex formed in a reaction between the ring-closed product and a tungsten
      methylene complex. Reactions involving (13)C labeled ethylene allowed for the
      observation of an unsubstituted tungstacyclobutane complex, an ethylene complex,
      an unsubstituted tungstacyclopentane complex, and a heterochiral dimeric form of
      a methylene complex. The tungstacyclopentane complex was found to catalyze the
      dimerization of ethylene to 1-butene slowly.

PMID- 12603154
TI  - Structures, bonding, and reaction chemistry of the neutral organogallium(I)
      compounds (GaAr)n(n = 1 or 2) (Ar = terphenyl or related ligand): an experimental
      investigation of Ga-Ga multiple bonding.
AB  - The synthesis, structure, and properties of several new organogallium(I)
      compounds are reported. The monovalent compounds GaAr* (Ar* = C(6)H(3)-2,6
      Trip(2), Trip = C(6)H(2)-2,4,6-Pr(i)()(3), 1), GaAr# (Ar# = C(6)H(3)
      2,6(Bu(t)Dipp)(2), Bu(t)Dipp = C(6)H(2)-2,6-Pr(i)(2)-4-Bu(t)(), 4), and the
      dimeric (GaAr')(2) (Ar' = C(6)H(3)-2,6-Dipp(2), Dipp = C(6)H(3)-2,6-Pr(i)(2), 6)
      were synthesized by the reaction of "GaI" with (Et(2)O)LiAr*, (Et(2)O)LiAr# (3),
      or (LiAr')(2). Compounds 1 and 4 were isolated as green crystals, whereas 6 was
      obtained as a brown-red crystalline solid. All three compounds dissolved in
      hydrocarbon solvents to give green solutions and almost identical UV/visible
      spectra. Cryoscopy of 1 and 6 showed that they were monomeric in cyclohexane.
      Crystals of 1 and 4 were unsuitable for X-ray crystal structure determinations,
      but an X-ray data set for 6 showed that it was weakly dimerized in the solid with
      a long Ga-Ga bond of 2.6268(7) A and a trans-bent CGaGaC core array. The 1,2
      diiodo-1,2-diaryldigallane compounds [Ga(Ar*)I](2) (2), [Ga(Ar#)I](2) (5), and
      [Ga(Ar')I](2) (7) were isolated as byproducts of the synthesis of 1, 4, and 6.
      The crystal structures of 2 and 7 showed that they had planar ICGaGaCI core
      arrays with Ga-Ga distances near 2.49 A, consistent with Ga-Ga single bonding.
      Treatment of 1, 4, and 6 with B(C(6)F(5))(3) immediately afforded the 1:1 donor
      acceptor complexes ArGa[B(C(6)F(5))(3)] (Ar = Ar*, 8; Ar#, 9; Ar', 10) that
      featured almost linear gallium coordination, Ga-B distances near the sum of the
      covalent radii of gallium and boron, as well as some close Ga...F contacts.
      Compound 1 also reacted with Fe(CO)(5) under ambient conditions to give
      Ar*GaFe(CO)(4) (11), which had been previously synthesized by the reaction of
      GaAr*Cl(2) with Na(2)Fe(CO)(4). Reaction of 1 with 2,3-dimethyl-1,3-butadiene
      afforded the compound [Ar*GaCH(2)C(Me)C(Me)CH(2)]2 (12) that had a 10-membered
      1,5-Ga(2)C(8) ring with no Ga-Ga interaction. Stirring 1 or 6 with sodium readily
      gave Na(2)[Ar*GaGaAr*] (13) and Na(2)(Ar'GaGaAr') (14). The former species 13 had
      been synthesized previously by reduction of GaAr*Cl(2) with sodium and was
      described as having a Ga-Ga triple bond because of the short Ga-Ga distance and
      the electronic relationship between [Ar*GaGaAr*](2-) and the corresponding
      neutral group 14 alkyne analogues. Compound 14 has a similar structure featuring
      a trans-bent CGaGaC core, bridged by sodiums which were also coordinated to the
      flanking aryl rings of the Ar' ligands. The Ga-Ga bond length was found to be
      2.347(1) A, which is slightly (ca. 0.02 A) longer than that reported for 13.
      Reaction of Ga[N(Dipp)C(Me)](2)CH, 15 (i.e., GaN(wedge)NDipp(2)), which is
      sterically related to 1, 4, and 6, with Fe(CO)(5) yielded
      Dipp(2)N(wedge)NGaFe(CO)(4) (16), whose Ga-Fe bond is slightly longer than that
      observed in 11. Reaction of the less bulky LiAr"(Ar"= C(6)H(3)-2,6-Mes(2)) with
      "GaI" afforded the new paramagnetic cluster Ga(11)Ar(4)" (17). The ready
      dissociation of 1, 4, and 6 in solution, the long Ga-Ga distance in 6, and the
      chemistry of these compounds showed that the Ga-Ga bonds are significantly weaker
      than single bonds. The reduction of 1 and 6 with sodium to give 13 and 14
      supplies two electrons to the di-gallium unit to generate a single bond (in
      addition to the weak interaction in the neutral precursor) with retention of the
      trans-bent geometry. It was concluded that the stability of 13 and 14 depends on
      the matching size of the sodium ion, and the presence of Na-Ga and Na-Ar
      interactions that stabilize their Na(2)Ga(2) core structures.

PMID- 12603155
TI  - Development of fluorescent film sensors for the detection of divalent copper.
AB  - Monolayers of several peptide lipids at air-water and air-solid interfaces were
      prepared using Langmuir and Langmuir-Blodgett (LB) film techniques, and tested as
      fluorescent sensors for copper ions in aqueous phase. In one method, both the
      ionophore and the fluorophore were in the same molecule (lipid A), so
      intramolecular interaction was responsible for the fluorescence quenching of
      monolayers of this lipid. In the other method, ionophore and fluorophore were
      located on two different molecules (lipids B and C) so the intramolecular
      coupling does not exist; instead the fluorescence quenching was realized by a
      through-space interaction mechanism. Several experimental techniques, including
      pi-A isotherm, epifluorescence microscopy, and absorption and emission
      spectroscopies were used to study the different characteristics of copper ion
      effect on the properties of the lipid monolayers. Additionally, the fluorescence
      quenching properties of the Langmuir monolayers were found to be transferred to
      the one-layer LB films. On LB films, the fluorescence response presented a clear
      selectivity for copper ions in comparison with several other transition metal
      ions. Further, an excellent reversibility was observed: the fluorescence was
      switched OFF by immersing the solid substrate in copper ion solution and ON by
      washing with HCl solution. The intermolecular approach used here seems to be a
      very flexible and general method to design surface-oriented fluorescent sensors
      to meet different analytic purposes.

PMID- 12603156
TI  - Ultrafast singlet excited-state polarization in electronically asymmetric ethyne
      bridged bis[(porphinato)zinc(II)] complexes.
AB  - The excited-state dynamics of two conjugated bis[(porphinato)zinc(II)] (bis[PZn])
      species, bis[(5,5'-10,20-bis[3,5-bis(3,3-dimethyl-1
      butyloxy)phenyl]porphinato)zinc(II)]ethyne (DD) and [(5,-10,20-bis[3,5-bis(3,3
      dimethyl-1-butyloxy)phenyl]porphinato)zinc(II)]-[(5',-15'-ethynyl-10',20'
      bis(heptafluoropropyl)porphinato)zinc(II)]ethyne (DA), were studied by pump-probe
      transient absorption spectroscopy and hole burning techniques. Both of these meso
      to-meso ethyne-bridged bis[PZn] compounds display intense near-infrared (NIR)
      transient S(1)-->S(n) absorptions and fast relaxation of their initially
      prepared, electronically excited Q states. Solvational and conformational
      relaxation play key roles in both DD and DA ground- and excited-state dynamics;
      in addition to these processes that drive spectral diffusion, electronically
      excited DA manifests a 3-fold diminution of S(1)-->S(0) oscillator strength on a
      2-20 ps time scale. Both DD and DA display ground-state and time-dependent
      excited-state conformational heterogeneity; hole burning experiments show that
      this conformational heterogeneity is reflected largely by the extent of porphyrin
      porphyrin conjugation, which varies as a function of the pigment-pigment dihedral
      angle distribution. While spectral diffusion can be seen for both compounds,
      rotational dynamics driving configurational averaging (tau approximately 30 ps),
      along with a small solvational contribution, account for essentially all of the
      spectral changes observed for electronically excited DD. For DA, supplementary
      relaxation processes play key roles in the excited-state dynamics. Two fast
      solvational components (0.27 and 1.7 ps) increase the DA excited-state dipole
      moment and reduce concomitantly the corresponding S(1)-->S(0) transition
      oscillator strength; these data show that these effects derive from a time
      dependent change of the degree of DA S(1)-state polarization, which is stimulated
      by solvation and enhanced excited-state inner-sphere structural relaxation.

PMID- 12603157
TI  - Complex alpha-MoO(3) nanostructures with external bonding capacity for self
      assembly.
AB  - Through manipulating crystal growth directions, we devised a versatile synthetic
      method to fabricate complex alpha-MoO(3) nanostructures with external bonding
      capacity for self-organization. Using four-armed forklike alpha-MoO(3) as
      nanobuilding blocks, we assembled more complex crystal morphologies, such as
      centrally holed nanorods, tridents, and paintbrushes. With prolonged ultrasonic
      treatments, pristine forklike alpha-MoO(3) crystals can be turned into less armed
      nanostructures, giving away the secondary arms (width < 100 nm) at the same time.
      On the other hand, the resultant alpha-MoO(3) itself can act as a template to
      produce shaped TiO(2) and other nanocrystals. Square- and horseshoe-shaped
      nanocrystals of anatase TiO(2) are left undissolved after removing alpha-MoO(3)
      templates in basic medium.

PMID- 12603158
TI  - HSAB principle applied to the time evolution of chemical reactions.
AB  - Time evolution of various reactivity parameters such as electronegativity,
      hardness, and polarizability associated with a collision process between a proton
      and an X- atom/ion (X = He, Li(+), Be(2+), B(3+), C(4+)) in its ground ((1)S) and
      excited((1)P,(1)D,(1)F) electronic states as well as various complexions of a two
      state ensemble is studied using time-dependent and excited-state density
      functional theory. This collision process may be considered to be a model
      mimicking the actual chemical reaction between an X-atom/ion and a proton to give
      rise to an XH(+) molecule. A favorable dynamical process is characterized by
      maximum hardness and minimum polarizability values according to the dynamical
      variants of the principles of maximum hardness and minimum polarizability. An
      electronic excitation or an increase in the excited-state contribution in a two
      state ensemble makes the system softer and more polarizable, and the proton,
      being a hard acid, gradually prefers less to interact with X as has been
      discerned through the drop in maximum hardness value and the increase in the
      minimum polarizability value when the actual chemical process occurs. Among the
      noble gas elements, Xe is the most reactive. During the reaction: H(2) + H(+) -->
      H(3)(+) hardness maximizes and polarizability minimizes and H(2) is more reactive
      in its excited state. Regioselectivity of proton attack in the O-site of CO is
      clearly delineated wherein HOC(+) may eventually rearrange itself to go to the
      thermodynamically more stable HCO(+).

PMID- 12603159
TI  - Characterization of electronic structure and properties of a Bis(histidine) heme
      model complex.
AB  - Ferric and ferrous hemes, such as those present in electron transfer proteins,
      often have low-lying spin states that are very close in energy. To explore the
      relationship between spin state, geometry, and cytochrome electron transfer, we
      investigate, using density functional theory, the relative energies, electronic
      structure, and optimized geometries for a high- and low-spin ferric and ferrous
      heme model complex. Our model consists of an iron-porphyrin axially ligated by
      two imidazoles, which model the interaction of a heme with histidine residues.
      Using the B3LYP hybrid functional, we found that, in the ferric model heme
      complex, the doublet is lower in energy than the sextet by 8.4 kcal/mol and the
      singlet ferrous heme is 6.7 kcal/mol more stable than the quintet. The difference
      between the high-spin ferric and ferrous model heme energies yields an adiabatic
      electron affinity (AEA) of 5.24 eV, and the low-spin AEA is 5.17 eV. Both values
      are large enough to ensure electron trapping, and electronic structure analysis
      indicates that the iron d(pi) orbital is involved in the electron transfer
      between hemes. Mossbauer parameters calculated to verify the B3LYP electronic
      structure correlate very well with experimental values. Isotropic hyperfine
      coupling constants for the ligand nitrogen atoms were also evaluated. The
      optimized geometries of the ferric and ferrous hemes are consistent with
      structures from X-ray crystallography and reveal that the iron-imidazole
      distances are significantly longer in the high-spin hemes, which suggests that
      the protein environment, modeled here by the imidazoles, plays an important role
      in regulating the spin state. Iron-imidazole dissociation energies, force
      constants, and harmonic frequencies were calculated for the ferric and ferrous
      low-spin and high-spin hemes. In both the ferric and the ferrous cases, a single
      imidazole ligand is more easily dissociated from the high-spin hemes.

PMID- 12603160
TI  - Determination of internuclear distances in uniformly labeled molecules by
      rotational-resonance solid-state NMR.
AB  - Rotational-resonance magic-angle spinning NMR experiments are frequently used to
      measure dipolar couplings and to determine internuclear distances. So far most
      measurements were performed on samples containing isolated spin pairs. Thus,
      extensive structure elucidation, for example in biomolecules, requires the
      preparation of a whole set of doubly labeled samples. Here, we describe the
      analysis of the rotational-resonance polarization-exchange curves obtained from a
      single, uniformly labeled sample. It is shown experimentally that, at a magnetic
      field of 14.09 T, the rotational-resonance conditions in uniformly (13)C-labeled
      threonine are sufficiently narrow to permit the measurement of five distances
      between the four carbon spins with an accuracy of better than 10%. The
      polarization-exchange curves are analyzed using a modified two-spin model
      consisting of the two active spins. The modified model includes an additional
      offset in the final polarization, which comes from the coupling to the
      additional, passive, spins. The validity of this approach is experimentally
      verified for uniformly (13)C-labeled threonine. The broader applicability of such
      a model is demonstrated by numerical simulations which quantify the errors as a
      function of the most relevant parameters in the spin system.

PMID- 12603161
TI  - Aspects of enantioselective heterogeneous catalysis: structure and reactivity of
      (S)-(-)-1-(1-naphthyl)ethylamine on Pt[111].
AB  - The molecular orientation, spatial distribution, and thermal behavior of the
      powerful chiral catalyst modifier precursor (S)-naphthylethylamine adsorbed on
      Pt[111] have been studied by NEXAFS, XPS, STM, and temperature programmed
      reaction. At 300 K, both in the presence and in the absence of coadsorbed
      hydrogen, the strongly tilted molecules do not form ordered arrays. These results
      constitute the first direct evidence against the template model and are at least
      consistent with the 1:1 interaction model of chiral induction in the
      enantioselective hydrogenation of alkyl pyruvates. Raising the temperature beyond
      320 K (the temperature of enantioselectivity collapse) leads either to
      irreversible dimerization with hydrogen elimination or to dissociation of the
      ethylamine moiety, depending on whether coadsorbed H(a) is present. Either way,
      the stereogenic center is destroyed. These findings provide the first direct clue
      as to the possible origin of enantioselectivity collapse, by a mechanism not
      previously considered. When NEA and methyl pyruvate are coadsorbed in the
      presence of H(a), STM reveals entities that could correspond to a 1:1 docking
      complex between the prochiral reactant and the chiral modifier.

PMID- 12603162
TI  - Motions of single molecules and proteins in trehalose glass.
AB  - The fluorescence intensity-time records of individual metal-free porphyrin
      cytochrome-c and Zn porphyrin cytochrome-c molecules whose translational motions
      are restricted by encapsulation in trehalose are examined by single-molecule
      spectroscopy by means of a two-channel confocal microscope that records transient
      fluorescence signals in two orthogonal polarization directions. Large angular
      motions often occur on time scales ranging to many seconds. Measurements of the
      photobleaching time distributions indicate that the trehalose glass restricts the
      accessibility of the fluorescent molecules to oxygen.

PMID- 12603163
TI  - Surface chemistry on bimetallic alloy surfaces: adsorption of anions and
      oxidation of CO on Pt3Sn(111).
AB  - The microscopic structure of the Pt(3)Sn(111) surface in an electrochemical
      environment has been studied by a combination of ex situ low-energy electron
      diffraction (LEED), Auger electron spectroscopy (AES), and low-energy ion
      scattering (LEIS) and in situ surface X-ray scattering (SXS) and Fourier
      transform infrared (FTIR) spectroscopy. In ultrahigh vacuum (UHV) the clean
      annealed surface produces a p(2 x 2) LEED pattern consistent with the surface
      composition, determined by LEIS, of 25 at. % Sn. SXS results show that the p(2 x
      2) structure can be "transferred" from UHV into 0.5 M H(2)SO(4) and that the
      surface structure remains stable from 0.05 to 0.8 V. At 0.05 V the expansion of
      Pt surface atoms, ca. +2% from the bulk lattice spacing, is induced by adsorption
      of underpotential-deposited (UPD) hydrogen. At 0.5 V, where Pt atoms are covered
      by (bi)sulfate anions, the topmost layer is contracted relative to 0.05 V,
      although Sn atoms expand significantly, ca. 8.5%. The p(2 x 2) structure is
      stable even in solutions containing CO. In contrast to the Pt(111)-CO system, no
      ordered structures of CO are formed on the Pt(3)Sn(111) surface and the topmost
      layer expands relatively little (ca. 1.5%) from the bulk lattice spacing upon the
      adsorption of CO. The binding site geometry of CO on Pt(3)Sn(111) is determined
      by FTIR. In contrast to the near invariant band shape of a-top CO on Pt(111),
      changes in band morphology (splitting of the band) and vibrational properties
      (increase in the frequency mode) are clearly visible on the Pt(3)Sn(111) surface.
      To explain the line shape of the CO bands, we suggest that in addition to
      alloying effects other factors, such as intermolecular repulsion between
      coadsorbed CO and OH species, are controlling segregation of CO into cluster
      domains where the local CO coverage is different from the coverage expected for
      the CO-CO interaction on an unmodified Pt(111) surface.

PMID- 12603164
TI  - Different surface chemistries of water on Ru[0001]: from monomer adsorption to
      partially dissociated bilayers.
AB  - Density functional theory has been used to perform a comparative theoretical
      study of the adsorption and dissociation of H(2)O monomers and icelike bilayers
      on Ru[0001]. H(2)O monomers bind preferentially at atop sites with an adsorption
      energy of approximately 0.4 eV/H(2)O. The main bonding interaction is through the
      H(2)O 1b(1) molecular orbital which mixes with Ru d(z)2 states. The lower-lying
      set of H(2)O molecules in an intact H(2)O bilayer bond in a similar fashion; the
      high-lying H(2)O molecules, however, do not bond directly with the surface,
      rather they are held in place through H bonding. The H(2)O adsorption energy in
      intact bilayers is approximately 0.6 eV/H(2)O and we estimate that H bonding
      accounts for approximately 70% of this. In agreement with Feibelman (Science
      2002, 295, 99) we find that a partially dissociated OH + H(2)O overlayer is
      energetically favored over pure intact H(2)O bilayers on the surface. The barrier
      for the dissociation of a chemisorbed H(2)O monomer is 0.8 eV, whereas the
      barrier to dissociate a H(2)O incorporated in a bilayer is just 0.5 eV.

PMID- 12603165
TI  - Variety of the molecular conformation in Peptide nanorings and nanotubes.
AB  - Possible molecular conformations in peptide nanorings and nanotubes were
      theoretically investigated by a mathematical conformation analysis as well as ab
      initio Hartree-Fock calculations. The mathematical analysis predicts not only the
      conventional nanorings having an extended-type (E-type) backbone (trans zigzag)
      but also the novel ones having bound-type (B-type) backbones with a smaller
      internal diameter. Ab initio calculations for the amino acid substitution reveal
      that all 20 encoded residues can form both types of the above nanorings as a
      local minimum. However, the energetically stable type is determined in accordance
      with the kind of the replaced side chains. Moreover, the present work
      theoretically reveals that both types of nanorings stack to form nanotubes
      through inter-ring hydrogen bonds, i.e., larger E-type nanotubes and smaller B
      type nanotubes. Electronically, the HOMO and LUMO states of the nanoring and
      nanotube backbones are formed by the in-plane pi state. The replacement by the
      appropriate residues is furthermore predicted to intrude additional levels in the
      energy gap and to form the frontier states localized at the side chains.

PMID- 12603166
TI  - Theoretical conformational analysis for neurotransmitters in the gas phase and in
      aqueous solution. Norepinephrine.
AB  - The natural neurotransmitter (R)-norepinephrine takes the monocationic form in
      93% abundance at the physiological tissue pH of 7.4. Ab initio and DFT/B3LYP
      calculations were performed for 12 protonated conformers of (R)-norepinephrine in
      the gas phase with geometry optimizations up to the MP2/6-311++G level, and with
      single-point calculations up to the QCISD(T) level at the HF/6-31G-optimized
      geometries. Four monohydrates were studied at the MP2/6-31G//HF/6-31G level. In
      the gas phase, the G1 conformer is the most stable with phenyl.NH(3)(+) gauche
      and HO(alc).NH(3)(+) gauche arrangements. A strained intramolecular hydrogen bond
      was found for conformers (G1 and T) with close NH(3)(+) and OH groups. Upon
      rotation of the NH(3)(+) group as a whole unit about the C(beta)-C(alpha) axis, a
      3-fold potential was calculated with free energies for barriers of 3-12 kcal/mol
      at the HF/6-31G level. Only small deviations were found in MP2/6-311++G single
      point calculations. A 2-fold potential was calculated for the phenyl rotation
      with free energies of 11-13 kcal/mol for the barriers at T = 310 K and p = 1 atm.
      A molecular mechanics docking study of (R)-norepinephrine in a model binding
      pocket of the beta-adrenergic receptor shows that the ligand takes a conformation
      close to the T(3) arrangement. The effect of aqueous solvation was considered by
      the free energy perturbation method implemented in Monte Carlo simulations. There
      are 4-5 strongly bound water molecules in hydrogen bonds to the conformers.
      Although hydration stabilizes mostly the G2 form with gauche phenyl.NH(3)(+)
      arrangement and a water-exposed NH(3)(+) group, the conformer population becomes
      T > G1 > G2, in agreement with the PMR spectroscopy measurements by Solmajer et
      al. (Z. Naturforsch. 1983, 38c, 758). Solvent effects reduce the free energies
      for barriers to 3-6 and 9-12 kcal/mol for rotations about the C(beta)-C(alpha)
      and the C(1)(ring)-C(beta) axes, respectively.

PMID- 12603167
TI  - Computational studies of the optical emission of silicon nanocrystals.
AB  - We have computed absorption and emission energies of silicon nanocrystals as a
      function of size and of surface passivants, using both density functional theory
      and quantum Monte Carlo calculations. We have found that the ionic rearrangements
      and electronic relaxations occurring upon absorption and emission are extremely
      sensitive to surface chemistry. In particular, nanoclusters with similar sizes
      and similar absorption gaps can exhibit strikingly different emission energies.
      Our results provide a unifying interpretation of several recent measurements,
      which have observed significantly different emission energies from clusters with
      similar sizes. Our calculations also show that a combination of absorption and
      emission measurements can provide a powerful tool for identifying both the size
      and the surface passivants of semiconductor nanocrystals.

PMID- 12603169
TI  - Origin of the acidity enhancement of formic acid over methanol: resonance versus
      inductive effects.
AB  - Density functional theory calculations were employed to study the relative
      contribution of resonance versus inductive effects toward the 37 kcal/mol
      enhanced gas-phase acidity (DeltaH degrees (acid)) of formic acid (1) over
      methanol (2). The gas-phase acidities of formic acid, methanol, vinyl alcohol
      (5), and their vinylogues (6, 8, and 9) were calculated at the B3LYP/6-31+G level
      of theory. Additionally, acidities were calculated for the formic acid and vinyl
      alcohol vinylogues in which the formyl group and the vinyl group, respectively,
      were perpendicular to the rest of the conjugated system. Comparisons among these
      calculated acidities suggest that inductive effects are the predominant effects
      responsible for the enhanced acidity of formic acid over methanol, accounting for
      between roughly 62% and 65% of the total enhanced acidity; the remaining 38% to
      35% of the acidity enhancement appears to be due to resonance effects. Further
      comparisons suggest that resonance effects are between roughly 58% and 65% of the
      26 kcal/mol calculated acidity enhancement of vinyl alcohol over methanol, and
      the remaining 42% to 35% are due to inductive effects.

PMID- 12603168
TI  - Substituent-control exciton in J-aggregates of protonated water-insoluble
      porphyrins.
AB  - A series of protonated porphyrin J-aggregates of various water-insoluble
      tetraphenylporphyrin derivatives was prepared by aggregation at the liquid-liquid
      or gas-liquid interface. Using atomic force microscopy, we observed
      microcrystalline porphyrin J-aggregates. The J-aggregates have two strong exciton
      bands corresponding to the B (Soret)- and Q-bands of the protonated porphyrin.
      Interestingly, the excitation energy of the lower exciton (denoted by S1)
      markedly depends on the meso-substituents, whereas that of the higher exciton
      (denoted by S2) does not depend on them. These results indicate that the nature
      of the exciton coupling of the S1 transition dipole moment can be systematically
      changed by the substituents.

PMID- 12603170
TI  - Relationship between photoisomerization path and intersection space in a retinal
      chromophore model.
AB  - A low-lying segment of the intersection space (IS) between the excited-state and
      the ground-state energy surfaces of a retinal chromophore model has been mapped
      using ab initio CASSCF computations. Analysis of the structural relationship
      between the computed IS cross-section and the excited state Z --> E isomerization
      path shows that these are remarkably close both in energy and in structure.
      Indeed, the IS segment and the Z --> E path remain roughly parallel and merge
      only when the double bond reaches a 70 degree twisting. This finding supports the
      idea that, in certain chromophores, a more extended segment of IS, and not a
      single conical intersection, contributes to the decay to the ground state.

PMID- 12603171
TI  - Does metal ion complexation make radical clocks run fast?
AB  - Ab initio molecular orbital and density functional calculations at the CBS
      RAD(QCISD,B3-LYP) level for Li+ and at B3LYP for Na+, K+, Cu+,and Ag+ reveal that
      the barrier to ring-closure of the 1-hexen-6-yl ("Delta(5)-hexenyl") radical to
      the cyclopentylmethyl radical, a so-called radical clock reaction, is decreased
      very significantly by complexation of the double bond to metal cations. This
      barrier lowering should occur on complexation with many metal ions, as shown by
      calculations on all of the monovalent ions listed above. Additional density
      functional calculations including explicit solvation of the model system
      complexed to the lithium ion with tetrahydrofuran suggest that the effect found
      is not limited to the gas phase but may also be significant in experimental
      radical clock reactions in solution, even for lithium.

PMID- 12603172
TI  - Origin of asymmetric charge partitioning in the dissociation of gas-phase protein
      homodimers.
AB  - The origin of asymmetric charge and mass partitioning observed for gas-phase
      dissociation of multiply charged macromolecular complexes has been hotly debated.
      These experiments hold the potential to provide detailed information about the
      interactions between the macromolecules within the complex. Here, this unusual
      phenomenon of asymmetric charge partitioning is investigated for several protein
      homodimers. Asymmetric charge partitioning in these ions depends on a number of
      factors, including the internal energy, charge state, and gas-phase conformation
      of the complex, as well as the conformational flexibility of the protein monomer
      in the complex. High charge states of both cytochrome c and disulfide-reduced
      alpha-lactalbumin homodimers dissociate by a symmetrical charge partitioning
      process in which both fragment monomers carry away roughly an equal number of
      charges. In contrast, highly asymmetric charge partitioning dominates for the
      lower charge states. Cytochrome c dimer ions with eleven charges formed by
      electrospray ionization from two solutions in which the solution-phase
      conformation differs dissociate with dramatically different charge partitioning.
      These results demonstrate that these gas-phase complexes retain a clear "memory"
      of the solution from which they are formed, and that information about their
      solution-phase conformation can be obtained from these gas-phase dissociation
      experiments. Cytochrome c dimer ions formed from solutions in which the
      conformation of the protein is native show greater asymmetric charge partitioning
      with increasing ion internal energy. Cytochrome c dimers that are
      conformationally constrained with intramolecular cross-linkers undergo
      predominantly symmetric charge partitioning under conditions where asymmetric
      charge partitioning is observed for cytochrome c dimers without cross-links.
      Similar results are observed for alpha-lactalbumin homodimers. These results
      provide convincing evidence that the origin of asymmetric charge partitioning in
      these homodimers is the result of one of the protein monomers unfolding in the
      dissociation transition state. A mechanism that accounts for these observations
      is proposed.

PMID- 12603173
TI  - Clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its
      metabolites.
AB  - This review discusses the pharmacokinetics and pharmacodynamics of glyceryl
      trinitrate (nitroglycerin; GTN) pertinent to clinical medicine. The
      pharmacokinetics of GTN associated with various dose regimens are characterised
      by prominent intra- and inter-individual variability. It is, nevertheless,
      important to clearly understand the pharmacokinetics and characteristics of GTN
      to optimise its use in clinical practice and, in particular, to obviate the
      development of tolerance. Measurements of plasma concentrations of GTN and of 1,2
      glyceryl dinitrate (1,2-GDN), 1,3-glyceryl dinitrate (1,3-GDN), 1-glyceryl
      mononitrate (1-GMN), and 2-glyceryl mononitrate (2-GMN), its four main
      metabolites, remain difficult and require meticulous techniques to obtain
      reliable results. Since GDNs have an effect on haemodynamic function,
      pharmacokinetic analyses that include the parent drug as well as the metabolites
      are important. Although the precise mechanisms of GTN metabolism have not been
      elucidated, two main pathways have been proposed for its biotransformation. The
      first is a mechanism-based biotransformation pathway that produces nitric oxide
      (NO) and contributes directly to vasodilation. The second is a clearance-based
      biotransformation or detoxification pathway that produces inorganic nitrite
      anions (NO(2) -). NO(2) - has no apparent cardiovascular effect and is not
      converted to NO in pharmacologically relevant concentrations in vivo. In
      addition, several non-enzymatic and enzymatic systems are capable of metabolising
      GTN. This complex metabolism complicates considerably the evaluation of the
      pharmacokinetics and pharmacodynamics of GTN. Regardless of the route of
      administration, concentrations of the metabolites exceed those of the parent
      compound by several orders of magnitude. During continuous steady-state delivery
      of GTN, for instance by a patch, concentrations of 1,2-GDN are consistently 2-7
      times higher than those of 1,3-GDN, and concentrations of 2-GMN are 4-8 times
      higher than those of 1-GMN. Concentrations of GDNs are approximately 10 times
      higher, and of GMNs approximately 100 times higher, than those of GTN during
      sustained administration. The development of tolerance is closely related to the
      metabolism of GTN, and can be broadly categorised as haemodynamic tolerance
      versus vascular tolerance. Efforts are warranted to circumvent the development of
      tolerance and facilitate the use of GTN in clinical practice. Although this
      remains to be accomplished, it is likely that, in the near future, regimens will
      be developed based on a full understanding of the pharmacokinetics and
      pharmacodynamics of GTN and its metabolites.

PMID- 12603175
TI  - Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition
      of diclofenac and celecoxib.
AB  - OBJECTIVE: To analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype
      on the steady-state disposition of the standard NSAID diclofenac and the new COX
      2 selective inhibitor celecoxib, both of which are metabolised by the
      polymorphically expressed CYP2C9. DESIGN: Double-blind randomised crossover study
      under steady-state conditions. SUBJECTS: 12 young (age 32 +/- 5 years, bodyweight
      71 +/- 12kg; mean +/- SD) and 12 elderly (68 +/- 2 years, 82 +/- 15kg) healthy,
      drug-free, nonsmoking Caucasians of both sexes. METHODS: All subjects received
      oral celecoxib (200mg twice daily) and diclofenac (75mg twice daily) for 15 days
      separated by a drug-free interval of at least 3 weeks. Following the last morning
      dose, multiple blood samples were taken for 25 hours. Concentrations of celecoxib
      and diclofenac were measured by specific and sensitive high performance liquid
      chromatography. Identification of CYP2C9 genotype was performed by genomic DNA
      sequencing. Pharmacokinetic parameters for total and unbound drugs were
      individually analysed by noncompartmental techniques. RESULTS: For diclofenac,
      area under the concentration-time curve over the dosage interval (AUC(tau)) was
      larger in young subjects (3.2 +/- 1.0 mg * h/L) than in older individuals (2.4 +/
      0.4 mg * h/L; p < 0.05). As the terminal half-life (t((1/2)Z)) was very similar
      in both groups (3.9 +/- 4.4 vs 3.5 +/- 3.3 hours), either less complete
      absorption in the elderly or their higher bodyweight could account for the
      difference. For celecoxib, AUC(tau) (5.8 +/- 1.7 vs 5.6 +/- 2.3 mg * h/L) and
      t((1/2)z) (11.8 +/- 8.7 vs 11.2 +/- 2.9 hours) were almost identical in young and
      older subjects. Plasma protein binding of both NSAIDs was unaffected by age, and
      apparent oral clearances for unbound drugs were not different between the two
      groups of healthy subjects. When considering the genotype of all individuals
      (CYP2C9*1/*1, n = 10; CYP2C9*1/*2, n = 6; CYP2C9*2/*2, n = 2; CYP2C9*1/*3, n = 4;
      CYP2C9*3/*3, n = 1), no association with any pharmacokinetic parameter of either
      drug was apparent. Moreover, there was no significant correlation between the AUC
      values of celecoxib and diclofenac. CONCLUSIONS: Age and CYP2C9 genotype do not
      significantly affect the steady-state disposition of celecoxib and diclofenac.
      This would indicate that both drugs need no dosage reduction in the elderly (at
      least up to 75 years) and that, besides CYP2C9, additional CYP species contribute
      to the elimination of both agents.

PMID- 12603177
TI  - Good prescribing: where to next?

PMID- 12603174
TI  - Drug interactions between antiretroviral drugs and comedicated agents.
AB  - HIV-infected individuals usually receive a wide variety of drugs in addition to
      their antiretroviral drug regimen. Since both non-nucleoside reverse
      transcriptase inhibitors and protease inhibitors are extensively metabolised by
      the cytochrome P450 system, there is a considerable potential for pharmacokinetic
      drug interactions when they are administered concomitantly with other drugs
      metabolised via the same pathway. In addition, protease inhibitors are substrates
      as well as inhibitors of the drug transporter P-glycoprotein, which also can
      result in pharmacokinetic drug interactions. The nucleoside reverse transcriptase
      inhibitors are predominantly excreted by the renal system and may also give rise
      to interactions. This review will discuss the pharmacokinetics of the different
      classes of antiretroviral drugs and the mechanisms by which drug interactions can
      occur. Furthermore, a literature overview of drug interactions is given,
      including the following items when available: coadministered agent and dosage,
      type of study that is performed to study the drug interaction, the subjects
      involved and, if specified, the type of subjects (healthy volunteers, HIV
      infected individuals, sex), antiretroviral drug(s) and dosage, interaction
      mechanism, the effect and if possible the magnitude of interaction, comments,
      advice on what to do when the interaction occurs or how to avoid it, and
      references. This discussion of the different mechanisms of drug interactions, and
      the accompanying overview of data, will assist in providing optimal care to HIV
      infected patients.

PMID- 12603176
TI  - Investigation of the mutual pharmacokinetic interactions between bosentan, a dual
      endothelin receptor antagonist, and simvastatin.
AB  - BACKGROUND: In vitro, bosentan has been shown to be a mild inducer of cytochrome
      P450 (CYP) 2C9 and 3A4. PURPOSE: To investigate in vivo the mutual
      pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4
      substrate. METHODS: Nine healthy male subjects were treated in a three-period
      randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days;
      (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily
      and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma
      concentration-time profiles of bosentan and its metabolites (treatments A and C)
      and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were
      determined on day 6. RESULTS: Steady-state conditions for bosentan and its
      metabolites were attained on day 4 of treatment. The pharmacokinetic parameters
      of bosentan and its metabolites were not influenced by concomitant treatment with
      simvastatin: areas under the plasma concentration-time curve over one
      administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were
      4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan
      significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by
      34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2)
      and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0
      (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C,
      respectively. CONCLUSIONS: Concomitant treatment with bosentan reduces the
      exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%,
      indicating that in vivo bosentan is also a mild inducer of CYP3A4.

PMID- 12603178
TI  - Injecting drug use in Australia: needle/syringe programs prove their worth, but
      hepatitis C still on the increase.

PMID- 12603179
TI  - Preventing perinatal group B streptococcal infection: the jury is still out.

PMID- 12603180
TI  - Whither pathology in medical education?

PMID- 12603181
TI  - Doctors' perceptions and attitudes to prescribing within the Authority
      Prescribing System.
AB  - OBJECTIVE: To examine doctors' perceptions and attitudes to prescribing within
      the Authority Prescribing System (APS). DESIGN AND SETTING: Questionnaire survey
      of Australian doctors' responses to a number of statements and factorial
      vignettes, conducted between 1 May and 30 June 2001. PARTICIPANTS: A national
      random sample of 1200 doctors, stratified according to specialist/generalist,
      rural/urban and high/low prescriber: 669 (56%) responded. MAIN OUTCOME MEASURES:
      Self-reported perceptions of the APS and attitudes to prescribing within the APS.
      RESULTS: 72% of doctors agreed that the APS makes effective medications available
      to the socioeconomically disadvantaged members of the Australian public and 50%
      agreed that it compromises patient privacy. Fewer agreed that authority
      indicators were based on the highest quality of evidence quality (40%) or
      medication safety (12%). Doctors placed more emphasis on the doctor-patient
      relationship than on the criteria for authority prescribing in their decisions
      about prescribing APS medications. Doctors who used computers to prescribe were
      more likely to agree that computers can improve the authority prescribing
      process. CONCLUSIONS: This study suggests that authority-required prescribing is
      not achieving the stated aims of the National Medicines Policy in reducing
      variability in prescribing. Strategies to improve the quality of prescribing must
      consider the professional and ethical conundrum associated with prescribing
      outside of PBS/APS approved use for clinical and patient-centred reasons.

PMID- 12603182
TI  - A simple intervention to improve hospital antibiotic prescribing.
AB  - OBJECTIVE: To evaluate changes in prescribing behaviour after distribution of
      antibiotic guidelines printed on a 9 x 6 cm laminated card suitable for clipping
      to a hospital identification badge. INTERVENTION: Guidelines for appropriate
      antibiotic prescribing for 20 common and important paediatric infections were
      printed on a laminated 9 x 6 cm card suitable to clip to a hospital
      identification badge and distributed to all medical staff. DESIGN: We collected
      data from medical records for three marker conditions (tonsillitis, pneumonia,
      and orbital/periorbital cellulitis) on samples of patients from the six-month
      periods either side of the month in which the cards were distributed. Prescribers
      were unaware of the study and investigators analysed the prescriptions without
      knowledge of the period in which they were written. Prescriptions were rated for
      appropriate choice of antibiotic and appropriate dose. Data were also collected
      on antibiotic costs. MAIN OUTCOME MEASURES: Proportion of cases in which
      antibiotic choice was appropriate; proportion of cases in which antibiotic dose
      was appropriate; annualised costs of third-generation cephalosporins. RESULTS:
      For tonsillitis there was little change in prescribing practice after the cards
      were introduced. For pneumonia, cases with appropriate choice increased from 77%
      to 92% (P = 0.028) and cases with appropriate dose increased from 48% to 81% (P =
      0.001). For orbital/periorbital cellulitis, cases with appropriate choice
      increased from 19% to 78% (P < 0.001) and cases with appropriate dose increased
      from 30% to 51% (P = 0.11). Annualised costs of third-generation cephalosporins
      were $193 245 pre-cards and $89 814 post-cards. CONCLUSION: The cards appeared to
      have a beneficial effect on prescribing practice for the three marker conditions.
      This simple intervention is likely to be cost-effective and useful in reducing
      inappropriate use of antibiotics.

PMID- 12603183
TI  - Effect of computerised prescribing on use of antibiotics.
AB  - OBJECTIVES: To examine whether the use of current prescribing software systems
      might raise rates of repeat prescribing, with a consequent increase in use of
      antibiotics in the community. DESIGN AND SETTING: A prospective audit of
      consecutive prescriptions for amoxycillin, cefaclor, roxithromycin and
      amoxycillin/clavulanate presented to community pharmacies in the Hunter region of
      New South Wales and a follow-up survey of people who received a repeat
      prescription, October to November 2000. MAIN OUTCOME MEASURES: The frequency of
      repeat prescription ordering on computer-generated and handwritten prescriptions;
      the proportion of people who filled their repeat prescription. RESULTS: Data were
      collected for 1667 prescriptions presented to 35 pharmacies; 126 people who
      received repeat prescriptions completed the survey. The rate of repeat
      prescription ordering on computer-generated prescriptions was 69%, compared with
      40% for handwritten prescriptions (odds ratio, 3.3; 95% CI, 2.6-4.2). Computer
      generated repeat prescriptions were as likely to be filled as hand-written
      prescriptions (61% and 69%, respectively). CONCLUSIONS: The default settings on
      computerised prescribing packages result in a significant increase in the use of
      antibiotics. We estimate these settings result in about 500 000 additional
      prescriptions being filled annually in Australia for the four antibiotics in the
      study.

PMID- 12603184
TI  - Adrenal crises in children treated with high-dose inhaled corticosteroids for
      asthma.
AB  - Three children presented with adrenal crises, manifested by vomiting and
      hypoglycaemia, after protracted courses of high-dose inhaled corticosteroids for
      asthma. Significant dose reduction was possible in all three without loss of
      asthma control, emphasising the importance of back-titration to minimise dose.
      Parents of children taking high doses of inhaled corticosteroids should be
      alerted to the clinical features of adrenal insufficiency. If suspected, prompt
      medical assessment should be arranged, including serum glucose and cortisol
      measurement.

PMID- 12603185
TI  - Computerised reminders and feedback in medication management: a systematic review
      of randomised controlled trials.
AB  - OBJECTIVE: To systematically review randomised controlled trials (RCTs) of
      computer-generated medication reminders or feedback directed to healthcare
      providers or patients. DATA SOURCES: Extensive computerised and manual literature
      searches identified 76 English-language reports of RCTs reported before 1 January
      2002. Searches were conducted between June 1998 and April 2002. STUDY SELECTION:
      26 papers making 29 comparisons (two papers reported on multiple interventions)
      of computer-supported medication management to a control group. DATA EXTRACTION:
      The quality of the RCTs was systematically assessed and scored independently by
      two reviewers. Rates of compliance with (potential) reminders for the control and
      intervention groups were extracted. DATA SYNTHESIS: Heterogeneity of studies
      prevented a meta-analysis. Where possible, rates were calculated using the
      intention-to-treat principle. The comparisons were grouped into five areas.
      Reminders to providers in outpatient settings: six of 12 comparisons demonstrated
      positive effects (relative rates [RRs: intervention rates/control rates], 1.0 to
      42.0). Provider feedback in outpatient settings: five of seven comparisons showed
      improved clinician behaviour (RRs, 1.0 to 2.5). Combined reminders and feedback
      in outpatient settings: the single comparison found no improvement. Reminders to
      providers in inpatient settings: three of five comparisons showed improvements
      (RRs, 1.0 to 2.1). Patient-directed reminders: two of four comparisons showed
      improvements in patient compliance. CONCLUSION: Reminders are more effective than
      feedback in modifying physician behaviour related to medication management.
      Patient-directed reminders can improve medication adherence.

PMID- 12603187
TI  - Management of acute adult sexual assault.
AB  - An estimated 13% of women and 3% of men worldwide report sexual assault in their
      lifetime. Although managing sexual assault may appear daunting, some victims want
      medical care only. After disclosure, discuss forensic assessment. If a complaint
      to the police is possible, give the first dose of emergency contraception if
      required, and refer for forensic assessment. If medical care only is desired,
      determine the timing and type of assault and current contraception, manage
      general and genital injuries and perform relevant tests. After unprotected
      vaginal rape, offer emergency contraception, chlamydia prophylaxis and
      vaccination against hepatitis B virus. Counselling is important for all victims
      of sexual assault, as psychosocial consequences are more common than physical
      injuries. Management by a sympathetic, non-judgmental health practitioner helps
      the victim to regain control.

PMID- 12603186
TI  - Inhaled corticosteroid doses in asthma: an evidence-based approach.
AB  - OBJECTIVE: To define the evidence for doses of inhaled corticosteroids in asthma
      and describe this in clinically meaningful, evidence-based terms. DATA SOURCE:
      Cochrane Database of Systematic Reviews. STUDY SELECTION AND DATA EXTRACTION: We
      identified systematic reviews of randomised controlled trials of dosing of
      inhaled corticosteroids in asthma. Data on efficacy and safety of different doses
      were extracted from meta-analyses and summarised as the number needed to treat
      (NNT) and number needed to harm (NNH). DATA SYNTHESIS: Inhaled corticosteroids
      were highly efficacious, with a relatively flat dose-response curve. Three
      patients needed to be treated with fluticasone 100 microg daily to prevent
      worsening asthma (NNT 3), and for fluticasone 1000 microg the NNT was 2.1
      patients. The dose-response curve for side effects was steep. For a dose of
      fluticasone 100 microg, oral candidiasis developed in one of every 90 subjects
      treated (NNH 90). In contrast, the NNH for fluticasone 1000 microg and 2000
      microg daily were 23 and 6, respectively. CONCLUSION: Level 1 evidence supports
      the use of low-dose inhaled corticosteroids in asthma. Clinicians should review
      doses of inhaled corticosteroids used for treating patients with asthma.

PMID- 12603188
TI  - Behavioural and psychological symptoms of dementia: a seven-tiered model of
      service delivery.
AB  - People with dementia usually experience behavioural and psychological symptoms of
      dementia (BPSD) during the course of their illness. Currently, in Australia,
      there is a lack of comprehensive planning for managing and preventing BPSD, and
      the resources required for optimal care are inadequate and unevenly distributed.
      We propose a seven-tiered model of service delivery based on severity and
      prevalence of BPSD, ranging from no dementia through tiers of increasingly severe
      behavioural disturbance to the propensity for extreme violence in a small number
      of individuals. Each tier is associated with a different model of intervention.
      People with dementia may move up or down between tiers depending on their
      condition, their care and the intervention provided. Lower-level interventions
      may prevent the need for the more intensive interventions needed when disturbance
      becomes more severe.

PMID- 12603189
TI  - Is physiotherapy an effective treatment for lymphoedema secondary to cancer
      treatment?

PMID- 12603190
TI  - 3: Rehabilitation principles for treating chronic musculoskeletal injuries.
AB  - Evaluation of patients for rehabilitation after musculoskeletal injury involves
      identifying, grading and assessing the injury and its impact on the patient's
      normal activities. Management is guided by a multidisciplinary team, comprising
      the patient, doctor and physical therapist, with other health professionals
      recruited as required. Parallel interventions involving the various team members
      are specified in a customised management plan. The key component of the plan is
      active mobilisation utilising strengthening, flexibility and endurance exercise
      programs. Passive physical treatments (heat, ice, and manual therapy), as well as
      drug therapy and psychological interventions, are used as adjunctive therapy.
      Biomechanical devices or techniques (eg, orthotic devices) may also be helpful.
      Coexisting conditions such as depression and drug dependence are treated at the
      same time as the injury. Effective team communication, simulated environmental
      testing and, for those employed, contact with the employer facilitate a staged
      return to normal living, sports and occupational activities.

PMID- 12603191
TI  - Lymphoedema in breast cancer patients.

PMID- 12603192
TI  - Human fasciolosis acquired in an Australian urban setting.

PMID- 12603193
TI  - Community-acquired MRSA bacteraemia: four additional cases including one
      associated with severe pneumonia.

PMID- 12603194
TI  - Ventricular tachycardia following ingestion of a commonly used antihistamine.

PMID- 12603195
TI  - Indigenous health: chronically inadequate responses to damning statistics.

PMID- 12603196
TI  - Inhaled steroids--too much of a good thing?

PMID- 12603197
TI  - Attention-deficit hyperactivity disorder: divergent perspectives.

PMID- 12603198
TI  - Doctor shoppers' rights: privacy or lunacy?

PMID- 12603200
TI  - Topology of the Erwinia chrysanthemi oligogalacturonate porin KdgM.
AB  - The Erwinia chrysanthemi oligogalacturonate-specific monomeric porin, KdgM, does
      not present homology with any porins of known structure. A model of this protein,
      based on sequence similarity and the amphipathy profile, was constructed. The
      model depicts a beta-barrel composed of 14 antiparallel beta-strands. The
      accuracy of this model was tested by the chemical labelling of cysteine residues
      introduced by site-directed mutagenesis. The protein has seven surface-exposed
      loops. They are rather small with the exception of one, loop L6. Deletion of this
      loop allowed the entry of maltopentaose into the bacteria, a molecule too large
      to enter through the wild-type KdgM. Loop L6 could fold back into the lumen of
      the pore and play the role of the constriction loop L3 of general porins. With 14
      transmembrane segments, the KdgM porin family could represent the smallest porin
      characterized to date.

PMID- 12603199
TI  - Transmembrane segments 1, 5, 7 and 8 are required for high-affinity glucose
      transport by Saccharomyces cerevisiae Hxt2 transporter.
AB  - Hxt2 is a high-affinity facilitative glucose transporter of Saccharomyces
      cerevisiae and belongs to the major facilitator superfamily. Hxt1 shares
      approximately 70% amino acid identity with Hxt2 in its transmembrane segments
      (TMs) and inter-TM loops, but transports D-glucose with an affinity about one
      tenth of that of Hxt2. To determine which TMs of Hxt2 are important for high
      affinity glucose transport, we constructed chimaeras of Hxt2 and Hxt1 by randomly
      replacing each of the 12 TMs of Hxt2 with the corresponding segment of Hxt1, for
      a total of 4096 different transporters. Among > 20000 yeast transformants
      screened, 39 different clones were selected by plate assays of high-affinity
      glucose-transport activity and sequenced. With only two exceptions, the selected
      chimaeras contained Hxt2 TMs 1, 5, 7 and 8. We then constructed chimaeras
      corresponding to all 16 possible combinations of Hxt2 TMs 1, 5, 7 and 8. Only one
      chimaera, namely that containing all four Hxt2 TMs, exhibited transport activity
      comparable with that of Hxt2. The K (m) and V (max) values for D-glucose
      transport, and the substrate specificity of this chimaera were almost identical
      with those of Hxt2. These results indicate that TMs 1, 5, 7 and 8 are necessary
      for exhibiting high-affinity glucose-transport activity of Hxt2.

PMID- 12603201
TI  - Differential functional properties of calmodulin-dependent protein kinase IIgamma
      variants isolated from smooth muscle.
AB  - Six variants of calmodulin-dependent protein kinase IIgamma were isolated from a
      ferret-aorta smooth-muscle cDNA library. Variant G-2 is generated by a novel
      alternative polyadenylation, utilizing a site contained in an intron. The last 77
      residues of the association domain are replaced with 99 residues of a unique
      sequence containing Src homology 3-domain-binding motifs, which alter catalytic
      activity. Variant C-2 has an eight-residue deletion in an ATP-binding motif and
      does not autophosphorylate Thr(286), but does phosphorylate exogenous substrate.
      Two variants, B and J, autodephosphorylate. Four variants differing only in the
      variable domain have differing catalytic activities, despite identical sequences
      in the catalytic domains. Thus structural features determined by variable and
      association domains are important for the catalytic activity of calmodulin
      dependent protein kinase II.

PMID- 12603202
TI  - Synthesis of paucimannose N-glycans by Caenorhabditis elegans requires prior
      actions of UDP-N-acetyl-D-glucosamine:alpha-3-D-mannoside beta1,2-N
      acetylglucosaminyltransferase I, alpha3,6-mannosidase II and a specific membrane
      bound beta-N-acetylglucosaminidase.
AB  - We have previously reported three Caenorhabditis elegans genes ( gly-12, gly-13
      and gly-14 ) encoding UDP- N -acetyl-D-glucosamine:alpha-3-D-mannoside beta1,2- N
      -acetylglucosaminyltransferase I (GnT I), an enzyme essential for hybrid and
      complex N-glycan synthesis. GLY-13 was shown to be the major GnT I in worms and
      to be the only GnT I cloned to date which can act on
      [Manalpha1,6(Manalpha1,3)Manalpha1,6](Manalpha1,3)Manbeta1, 4GlcNAcbeta1,4GlcNAc
      R, but not on Manalpha1,6(Manalpha1,3)Manbeta1- O -R substrates. We now report
      the kinetic constants, bivalent-metal-ion requirements, and optimal pH,
      temperature and Mn(2+) concentration for this unusual enzyme. C. elegans
      glycoproteins are rich in oligomannose (Man(6-9)GlcNAc(2)) and 'paucimannose'
      Man(3-5)GlcNAc(2)(+/-Fuc) N-glycans, but contain only small amounts of complex
      and hybrid N-glycans. We show that the synthesis of paucimannose Man(3)GlcNAc(2)
      requires the prior actions of GnT I, alpha3,6-mannosidase II and a membrane-bound
      beta- N -acetylglucosaminidase similar to an enzyme previously reported in
      insects. The beta- N -acetylglucosaminidase removes terminal N -acetyl-D
      glucosamine from the GlcNAcbeta1, 2Manalpha1,3Manbeta- arm of
      Manalpha1,6(GlcNAcbeta1,2Manalpha1,3) Manbeta1,4GlcNAcbeta1,4GlcNAc-R to produce
      paucimannose Man(3)GlcNAc(2) N-glycan. N -acetyl-D-glucosamine removal was
      inhibited by two N -acetylglucosaminidase inhibitors. Terminal GlcNAc was not
      released from [Manalpha1,6(Manalpha1,3)Manalpha 1,6]
      (GlcNAcbeta1,2Manalpha1,3)Manbeta1,4GlcNAcbeta1,4GlcNAc-R nor from the
      GlcNAcbeta1,2Manalpha1,6Manbeta- arm. These findings indicate that GLY-13 plays
      an important role in the synthesis of N-glycans by C. elegans and that therefore
      the worm should prove to be a suitable model for the study of the role of GnT I
      in nematode development.

PMID- 12603204
TI  - Non-classical pathways of cell-mediated allograft rejection: new challenges for
      tolerance induction?
AB  - Allograft rejection results from separate pathways primarily controlled by CD4+ T
      cells. Refinement of transplantation models together with investigations on
      rejection occurring despite co-stimulation blockade revealed unexpected pathways
      involving CD8+ T cells, NK cells and Th2 cytokines. In this minireview, we
      discuss these non-classical pathways of allograft rejection and their relevance
      for the induction of tolerance in the clinics.

PMID- 12603203
TI  - Cobalt activation of Escherichia coli 5'-nucleotidase is due to zinc ion
      displacement at only one of two metal-ion-binding sites.
AB  - Escherichia coli 5'-nucleotidase activity is stimulated 30- to 50-fold in vitro
      by the addition of Co(2+). Seven residues from conserved sequence motifs
      implicated in the catalytic and metal-ion-binding sites of E. coli 5'
      nucleotidase (Asp(41), His(43), Asp(84), His(117), Glu(118), His(217) and
      His(252)) were selected for modification using site-directed mutagenesis of the
      cloned ushA gene. On the basis of comparative studies between the resultant
      mutant proteins and the wild-type enzyme, a model is proposed for E. coli 5'
      nucleotidase in which a Co(2+) ion may displace the Zn(2+) ion at only one of two
      metal-ion-binding sites; the other metal-ion-binding site retains the Zn(2+) ion
      already present. The studies reported herein suggest that displacement occurs at
      the metal-ion-binding site consisting of residues Asp(84), Asn(116), His(217) and
      His(252), leading to the observed increase in 5'-nucleotidase activity.

PMID- 12603205
TI  - Contrasting alloreactive CD4+ and CD8+ T cells: there's more to it than MHC
      restriction.
AB  - Surface expression of CD4 or CD8 is commonly used to identify T-cell subsets that
      recognize antigen presented by class II MHC or class I MHC, respectively. This
      holds true for T cells that respond to allogeneic MHC molecules that are directly
      recognized as foreign, as well as peptides from allogeneic MHC molecules that are
      indirectly presented by self MHC molecules. CD4 or CD8 expression was initially
      believed to define cytokine secreting helper T cells or cytotoxic cells,
      respectively. However, this association of phenotype and function is not
      absolute, in that CD4+ cells may possess lytic activity and CD8+ cells secrete
      cytokines, notably IFNgamma. Recently, additional fundamental differences in the
      immunobiology of these T-cell subsets have been identified. These include
      differences in costimulatory requirements, cytokine responsiveness, cytokine
      production, cell survival, and the maintenance of memory. This review will survey
      these differences, emphasizing alloreactive T-cell responses as well as relevant
      observations that have been made in other systems.

PMID- 12603206
TI  - Parainfluenza virus infection in adult lung transplant recipients: an emergent
      clinical syndrome with implications on allograft function.
AB  - Parainfluenza virus is a common cause of seasonal upper respiratory tract
      infections in children and adults. Studies indicate that parainfluenza virus may
      play an important role in the etiology of respiratory tract infections in lung
      transplant recipients with an estimated incidence of 5.3 per 100 patients.
      Parainfluenza virus type 3 is the most frequent serotype in lung transplant
      patients. The rate of lower respiratory tract infections with parainfluenza virus
      among lung transplant recipients is between 10 and 66% of cases. In addition,
      trans-bronchial biopsy at the time of parainfluenza infection shows signs of
      acute allograft rejection. Subsequently, 32% of patients have been found to have
      active bronchiolitis obliterans at a median time of 6 months (range 1-14)
      postviral infection. These findings indicate that parainfluenza virus infections
      may have long-term implications for lung transplant recipients. Further studies
      are required to identify the mechanisms of immunomodulation of parainfluenza
      virus among these patients. In addition, controlled studies are needed to
      evaluate the efficacy of aerosolized ribavarin in the treatment of parainfluenza
      virus infection and to determine whether vaccines may be effective in these high
      risk patients.

PMID- 12603207
TI  - New frontiers: the 2002 FASEB Summer Research Conference in Transplant
      Immunology.
AB  - The first Federation of American Societies for Experimental Biology (FASEB)
      summer research conference on transplantation immunology was organized by Angus
      Thomson (University of Pittsburgh), Robert Lechler (Imperial College London),
      Laurence Turka (University of Pennsylvania) and Megan Sykes (Massachusetts
      General Hospital). Over the past four decades, patient and graft survival rates
      for solid organ transplant recipients have improved dramatically; however,
      chronic rejection and the untoward effects of potent immunosuppressive drugs
      continue to loom. This symposium is a testament to the importance of bringing
      investigators from diverse biological backgrounds together in a single forum to
      discuss the fundamental issues of immune biology and advance the goal of
      transplant-specific tolerance.

PMID- 12603209
TI  - Impaired NF-kappaB activation in T cells permits tolerance to primary heart
      allografts and to secondary donor skin grafts.
AB  - T-cell activation is essential for acute allograft rejection. However, the
      biochemical signaling pathways used by T cells mediating rejection have not been
      extensively investigated. In vitro, T-cell activation is associated with nuclear
      translocation of specific transcription factors that regulate expression of genes
      critical for T-cell function. Given the central role of NF-kappaB in T-cell
      activation In vitro, we examined its role in the acute rejection of skin and
      cardiac allografts using mice with defective NF-kappaB translocation in T cells
      due to the presence of a super repressor IkappaBalpha transgene. T-cell-intrinsic
      NF-kappaB activation was required for cardiac but not skin allograft rejection,
      suggesting differential T-cell priming by the two tissues. Strikingly, priming
      with heart allografts induced complete acceptance of subsequently transplanted
      donor skin grafts, indicating that impaired NF-kappaB activation in T cells
      facilitates the induction of donor-specific tolerance to highly immunogenic
      tissues. These data suggest the biochemical pathways necessary for allograft
      rejection vary, based on the antigen and the context in which it is presented,
      and that inhibition of T-cell-intrinsic NF-kappaB activation during allogeneic
      priming may represent a novel strategy whereby tolerance to transplanted organs
      can be achieved.

PMID- 12603208
TI  - Stable alpha- and beta-islet cell function after tolerance induction to
      pancreatic islet allografts in diabetic primates.
AB  - Pancreatic islet transplantation (PIT) is an attractive alternative for type 1
      diabetic patients. PIT is not yet an effective clinical reality due in part to
      early loss of functional islet mass. In addition, current immunosuppressive drugs
      have toxic effects on islets and increase the risk of morbidity and mortality.
      Precise and durable alpha- and beta-cell function is essential for the success of
      PIT. Therefore, it is important to establish whether PIT can produce adequate
      long-term metabolic control, especially in the absence of chronic
      immunosuppressive therapy (CIT). In the present study, the stability of
      functional alpha- and beta-cell mass and metabolic function was assessed in
      streptozotocin (STZ)-induced diabetic primates following PIT in the absence of
      CIT. Diabetes was induced in rhesus macaques with STZ, 140 mg/kg. Hyperglycemia
      was reversed rapidly by PIT coupled with a 14-day tolerance induction protocol
      based on F(Ab)2-IT and DSG (n = 7). Two diabetic animals received the tolerance
      induction protocol without PIT. Acute rejection was presented in three animals at
      70, 353 and 353 days post transplant in the tolerance induction protocol, whereas
      the controls [F(Ab)2-IT or DSG alone] showed early 10-day function but all lost
      islet function by days 15-70. One recipient [F(Ab)2-IT or DSG] died euglycemic
      after a surgical procedure on day 187. At 2 years, three animals studied had a
      normal FIM evaluated by oral glucose tolerance test, mixed meal test, acute
      insulin response to glucose, glucose disposal rate, and hyperinsulinemic
      hypoglycemic clamp. PIT in STZ-induced diabetic primates resulted in restoration
      of normal alpha- and beta-cell function. Operational tolerance induction was
      achieved with only peritransplant administration of F(Ab)2-IT and DSG sparing the
      animals from chronic exposure of diabetogenic immunosuppressive drugs. These
      results offer an exciting new potential for treatment of type 1 diabetes
      mellitus.

PMID- 12603210
TI  - Effect of hepatic artery flow on bile secretory function after cold ischemia.
AB  - These studies evaluated the influence of hepatic arterial flow on biliary
      secretion after cold ischemia. Preparation of livers for transplantation or
      hepatic support impairs biliary secretion. The earliest indication of cold
      preservation injury during reperfusion is circulatory function. Arterial flow at
      this time may be critical for bile secretion. Porcine livers were isolated,
      maintained at 4 degrees for 2 h and connected in an extracorporeal circuit to an
      anesthetized normal pig. The extracorporeal livers were perfused either by both
      the hepatic artery and portal vein (dual) or by the portal vein alone (single).
      Incremental doses of sodium taurocholate were infused into the portal vein of
      both the dual and single perfused livers, and the bile secretion was compared.
      Most endogenous bile acids are lost during hepatic isolation. After
      supplementation, the biliary secretion of phosphatidyl choline and cholesterol
      was significantly better in the dual than single vessel-perfused livers; however,
      no difference was seen in bilirubin output. Single perfused livers were
      completely unable to increase biliary cholesterol in response to bile acid. The
      dependence of bile cholesterol secretion on arterial flow indicates the
      importance of this flow to the detoxification of compounds dependent on
      phosphatidyl choline transport during early transplantation.

PMID- 12603211
TI  - Pooled human gammaglobulin modulates surface molecule expression and induces
      apoptosis in human B cells.
AB  - We have previously shown that the pooled human gammaglobulin (IVIG) inhibited
      mixed lymphocyte reaction (MLR). In this study, we examined (1) if IVIG contains
      blocking antibodies reactive with cell surface molecules required for alloantigen
      recognition and (2) if IVIG modulates these surface molecule expressions using
      flow cytometry. IVIG does not contain significant amounts of blocking antibodies
      against CD3, CD4, CD8, CD20, CD14, CD40, MHC class I and class II. It reduces the
      number of intact B cells and monocytes, reduces or modulates CD19, CD20 and CD40
      expression on B cells, and induces morphological changes in B cells. This B-cell
      modulation results primarily because of apoptosis. IVIG also induces apoptosis in
      T cells and monocytes, but to a lesser degree. Induction of apoptosis requires
      the intact IgG molecule. Reduction of intact B cell and monocyte cell numbers,
      modulation of surface molecule expression on B cells, and deletion of B and T
      cells by apoptosis could result in inhibition of optimal T-cell activation. This
      likely represents the primary mechanism responsible for IVIG suppression of the
      MLR, and may account for many of the observed beneficial effects of IVIG seen in
      the treatment of human autoimmune and alloimmune disorders.

PMID- 12603212
TI  - Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of
      kidney recipients trigger apoptosis.
AB  - The vascular endothelium of transplanted organs represents an important target
      for allograft-directed immune responses. Although HLA antigens expressed on graft
      endothelial cells (EC) can become targets of the host immune response, the role
      of other, non-HLA-encoded EC antigens has been proposed but is still unclear. The
      aim of this study was to investigate the presence of and to characterize anti-EC
      antibodies (AECA) in 57 kidney transplant recipients according to their HLA
      immunization status. Flow cytometry in pretransplant sera was used to detect AECA
      reactive with surface antigens on ABO and HLA-typed primary cultures of arterial
      ECs, stimulated or not with tumor necrosis factor-alpha (TNFalpha) or interferon
      gamma (IFNgamma). FACS analysis revealed the presence of AECA in 47% of HLA
      sensitized (PRA = 10%: mostly IgG) vs. 16.0% in nonsensitized patients (PRA <
      10%) (p < 0.02). No significant correlation was found between the presence of
      AECA and acute rejection occurrence and graft outcome. Non-HLA reactive AECA are
      directed against TNFalpha- and IFNgamma-inducible membrane molecule(s), and react
      with two predominant antigens of approximately 35 kDa and approximately 50 kDa
      expressed on ECs but not on B cells. Binding of AECA decreases in vitro EC
      viability by 50-60% by promoting EC apoptosis, as demonstrated by DNA
      fragmentation assays.

PMID- 12603214
TI  - The living anonymous kidney donor: lunatic or saint?
AB  - Studies indicate that 11% to 54% of individuals surveyed would consider donating
      a kidney, while alive, to a stranger. The idea of 'living anonymous donors'
      (LADs) as a donor source, however, has not been embraced by the medical
      community. Reservations focus on the belief that LADs might be psychologically
      unstable and thus unsuitable donors. Our goal was to inform policy development by
      exploring the psycho-social make up and motivations of the LAD. Ninety-three
      unsolicited individuals contacted our center expressing interest in living
      anonymous donation. Of these, 43 participated in our study, completing two
      extensive inventories of psychopathology and personality disorder and taking part
      in the Comprehensive Psycho-Social Interview (CPSI). From the Personality
      Assessment Inventory (PAI), the revised NEO Personality Inventory (NEO PI-R), and
      the CPSI, coders assessed psychological health, psycho-social suitability,
      commitment, and motivations. Twenty-one participants passed the stringent
      criteria to be considered potential LADs. Content analysis of motivations showed
      that potential LADs were more likely than non-LADs (those who did not pass the
      criteria) to have a spiritual belief system and to be altruistic. Non-LADs were
      more likely than potential LADs to use donation to make a statement against their
      families. The authors conclude with a preliminary outline of eight policy
      recommendations.

PMID- 12603215
TI  - Renal complications following heart transplantation in children: a single-center
      study.
AB  - Renal dysfunction is common following heajt transplantation (Tx) in adults, but
      little is known in children. Thus, a retrospective chajt review was performed in
      children who underwent heajt Tx at the Hospital for Sick Children between April
      1994 and April 1999. The inclusion criteria were: age <18 years, survival >1 year
      post-Tx. The Schwajtz formula was used to calculate glomerular filtration rate
      (GFR). Decreased GFR was defined as <80 mL/min/1.73 m2. Changes in GFR were
      analyzed using Repeated Measures Analysis of Variance. Forty-one eligible
      children were included. The mean age at Tx was 7 years (range: 1 month to 16.7
      years). The mean F/UP was 33 +/- 17 months, with 32/41 patients followed for at
      least 24 months. The GFR was decreased in 42% pre-Tx, and in 7.3% at the last
      F/UP (p = 0.0001). GFR did not decline significantly with time after Tx; in fact,
      GFR increased in the first year and remained stable afterwards (p = 0.0002).
      Acute renal dysfunction (ARD) episodes were common (12/41 children). Hypertension
      was diagnosed in 76% of children during the first year post-Tx, but persisted in
      only 11 (27%). GFR improves in the majority of children following heajt Tx. ARD
      episodes are frequent in the post-Tx period. Hypertension is common but does not
      persist.

PMID- 12603213
TI  - Diabetes mellitus after kidney transplantation in the United States.
AB  - New onset diabetes is a major complication after kidney transplantation. However,
      the incidence, risk factors and clinical relevance of post-transplant diabetes
      mellitus (PTDM) vary among reports from single-center observational studies and
      clinical trials. Using data from the United Renal Data System we identified 11
      659 Medicare beneficiaries who received their first kidney transplant in 1996
      2000. The cumulative incidence of PTDM was 9.1% (95% confidence interval = 8.6
      9.7%), 16.0% (15.3-16.7%), and 24.0% (23.1-24.9%) at 3, 12, and 36 months post
      transplant, respectively. Using Cox's proportional hazards analysis, risk factors
      for PTDM included age, African American race (relative risk = 1.68, range: 1.52
      1.85, p < 0.0001), Hispanic ethnicity (1.35, range: 1.19-1.54, p < 0.0001), male
      donor (1.12, range: 1.03-1.21, p = 0.0090), increasing HLA mismatches, hepatitis
      C infection (1.33, range: 1.15-1.55, p < 0.0001), body mass index >or=30 kg/m2
      (1.73, range: 1.57-1.90, p < 0.0001), and the use of tacrolimus as the initial
      maintenance immunosuppressive medication (1.53, range: 1.29-1.81, p < 0.0001).
      Factors that reduced the risk for PTDM included the use of mycophenolate mofetil,
      azathioprine, younger recipient age, glomerulonephritis as a cause of kidney
      failure, and a college education. As a time-dependent covariate in Cox analyses
      that also included multiple other risk factors, PTDM was associated with
      increased graft failure (1.63, 1.46-1.84, p < 0.0001), death-censored graft
      failure (1.46, 1.25-1.70, p < 0.0001), and mortality (1.87, 1.60-2.18, p <
      0.0001). We conclude that high incidences of PTDM are associated with the type of
      initial maintenance immunosuppression, race, ethnicity, obesity and hepatitis C
      infection. It is a strong, independent predictor of graft failure and mortality.
      Efforts should be made to minimize the risk of this important complication.

PMID- 12603216
TI  - Concomitant surgery with laparoscopic live donor nephrectomy.
AB  - Routine live donor evaluations reveal unexpected silent pathologies. Herein, we
      describe our experience treating such pathologies at the time of laparoscopic
      donor nephrectomy. We have not encountered any previous reports of such an
      approach. We prospectively collected data on 321 donors. Concomitant surgeries at
      the time of procurement included two laparoscopic adrenalectomies, one
      colposuspension, one laparoscopic cholecystectomy, and one liver biopsy. Mean
      operative time was 321 min (range 230-380), with a mean blood loss of 280 mL
      (range 150-500). No blood transfusions were required. The left kidney was
      procured in four cases. The right kidney was obtained on one occasion. Mean
      hospital stay was 3 days (median 3, range 2-4). No short- or long-term
      complications have been identified. Mean follow-up time was 2.63 years (median
      2.76, range 2.23-2.99). Four of the five kidney recipients were first-time
      transplants who had not yet started dialysis. Simultaneous surgical interventions
      at the time of laparoscopic live kidney donation are safe and can be undertaken
      in selected cases. This practice is beneficial to both the donor and the
      recipient, and is likely to become more commonplace with changing practice
      patterns involving donor evaluation and management.

PMID- 12603218
TI  - Sirolimus may promote thrombotic microangiopathy.

PMID- 12603217
TI  - Adenovirus infection in pediatric liver and intestinal transplant recipients:
      utility of DNA detection by PCR.
AB  - To evaluate the incidence of adenovirus (AdV) infection in pediatric liver and
      intestinal transplant recipients, the records of patients with possible AdV
      infection were reviewed for demographic data, symptomatology, methods of
      diagnosis, treatment and outcome. To evaluate the impact of polymerase chain
      reaction (PCR) amplification and identification of AdV DNA as a diagnostic test,
      the incidence and outcome of AdV before and after the introduction of PCR were
      compared. Adenovirus infection was identified in 4.1% of liver recipients and
      20.8% of intestinal transplant recipients. The overall incidence of AdV did not
      increase over time, even following the introduction of PCR for virus detection.
      The higher incidence of AdV in the pediatric intestinal transplant recipients may
      be attributed to the frequent application of PCR methodology to intestinal biopsy
      material. Detection of AdV by PCR was associated with reduced mortality compared
      with detection by culture, either because of earlier detection of invasive
      disease or because PCR detects the presence of latent as well as active AdV.

PMID- 12603220
TI  - Use of a pelvic kidney for living transplantation: case report and review of the
      literature.
AB  - Pelvic kidneys have anomalous vascular supplies and collecting systems.
      Therefore, careful radiologic and functional evaluation of these kidneys must be
      performed prior to procurement for transplantation. We report the successful use
      of a pelvic kidney for living-related transplantation.

PMID- 12603219
TI  - Rapamycin as rescue therapy in a patient supported by biventricular assist device
      to heart transplantation with consecutive ongoing rejection.
AB  - Rapamycin is a new immunosuppressive agent that has been shown to be effective in
      acute heart allograft rejection. This case documents a patient suffering from
      cardiac sarcoidosis who was bridged to transplantation for 90 days with ongoing
      rejection after allograft implantation. Rejection did not abate despite treatment
      with antithymocyte globulin (ATG), FK506, a mycophenolate switch and courses of
      multiple apheresis. Initiation of rapamycin treatment resulted in a rapid
      resolution of cardiac rejection and reduction of concomitant immunosuppressive
      agents with few side-effects. Most notably was the reduction of panel reactive
      antibodies within a few weeks after the rapamycin initiation. This case
      illustrates that the utilization of rapamycin ceased ongoing rejection in a
      patient with a clear hyperimmune state despite prior extensive utilization of a
      variety of immunosuppressive strategies after heart transplantation.

PMID- 12603222
TI  - Dutch government backs down on heroin prescription, despite successful trial.

PMID- 12603225
TI  - The Israel Society for the Prevention of Alcoholism.
AB  - This paper describes the profile of the Israel Society for the Prevention of
      Alcoholism (ISPA), which is a nation-wide, public, non-profit association. It
      portrays various aspects of ISPA treatment and rehabilitation facilities-the
      residential treatment center, the rehabilitative hostel and the 'warm home' for
      homeless alcoholics. It depicts ISPA prevention activities, prevention materials
      and its usage of the media, and deals with ISPA involvement in policy issues. The
      paper also addresses the research reality of ISPA and its scientific journal, and
      refers to the society's structure and its future.

PMID- 12603223
TI  - Methadone treatment outcomes appear mainly unaffected by cannabis use.

PMID- 12603221
TI  - Early, rapidly progressive cholestatic hepatitis C reinfection and graft loss
      after adult living donor liver transplantation.

PMID- 12603226
TI  - The history of 'medicinal specifics' as addiction cures in the United States.

PMID- 12603228
TI  - The Finnish press's political position on alcohol between 1993 and 2000.
AB  - AIMS: To examine Finnish commentary on changes in alcohol policy between 1993 and
      2000. Data. A corpus of newspaper editorials on alcohol issues from six daily
      newspapers published between 1993 and 2000. METHOD: The editorials were analysed
      as 'pending narratives' by examining how they used 'morally loaded binary
      discourse', 'utopian discourse' and 'truth discourse'. FINDINGS: Almost half the
      editorials discussed alcohol policy in terms of freedom from the restrictive
      alcohol policy of the state. Encouraging liberalization of alcohol policy peaked
      in 1996 and 1997. However, as problems of public order became more prominent in
      the media at the end of the 1990s, claims for the liberalization of alcohol
      policy died away and between 1998 and 2000 issues of public order dominated those
      of freedom. In addition, concern about the intoxication-orientated drinking
      habits of the young and of children became prominent. CONCLUSIONS: The results
      suggest that, after advocating more liberalized alcohol policy and then seeing
      that there were some groups who responded irresponsibly to this, the middle-class
      concern about freedom turned into concern about the security of public places and
      this was reflected in the media. This analysis highlights the dynamic nature of
      public opinion and media advocacy in response to changes in policy.

PMID- 12603227
TI  - Does cannabis use predict poor outcome for heroin-dependent patients on
      maintenance treatment? Past findings and more evidence against.
AB  - AIMS: To determine whether cannabinoid-positive urine specimens in heroin
      dependent out-patients predict other drug use or impairments in psychosocial
      functioning, and whether such outcomes are better predicted by cannabis-use
      disorders than by cannabis use itself. DESIGN: Retrospective analyses of three
      clinical trials; each included a behavioral intervention (contingency management)
      for cocaine or heroin use during methadone maintenance. Trials lasted 25-29
      weeks; follow-up evaluations occurred 3, 6 and 12 months post-treatment. For the
      present analyses, data were pooled across trials where appropriate. SETTING:
      Urban out-patient methadone clinic. PARTICIPANTS: Four hundred and eight polydrug
      abusers meeting methadone-maintenance criteria. MEASUREMENTS: Participants were
      categorized as non-users, occasional users or frequent users of cannabis based on
      thrice-weekly qualitative urinalyses. Cannabis-use disorders were assessed with
      the Diagnostic Interview Schedule III-R. Outcome measures included proportion of
      cocaine- and opiate-positive urines and the Addiction Severity Index (at intake
      and follow-ups). FINDINGS: Cannabis use was not associated with retention, use of
      cocaine or heroin, or any other outcome measure during or after treatment. Our
      analyses had a power of 0.95 to detect an r2 of 0.11 between cannabis use and
      heroin or cocaine use; the r2 we detected was less than 0.03 and non-significant.
      A previous finding, that cannabis use predicted lapse to heroin use in heroin
      abstinent patients, did not replicate in our sample. However, cannabis-use
      disorders were associated weakly with psychosocial problems at post-treatment
      follow-up. CONCLUSIONS: Cannabinoid-positive urines need not be a major focus of
      clinical attention during treatment for opiate dependence, unless patients report
      symptoms of cannabis-use disorders.

PMID- 12603229
TI  - The National Treatment Outcome Research Study (NTORS): 4-5 year follow-up
      results.
AB  - AIMS: The National Treatment Outcome Research Study (NTORS) is the first
      prospective national study of treatment outcome among drug misusers in the United
      Kingdom. NTORS investigates outcomes for drug misusers treated in existing
      services in residential and community settings. DESIGN, SETTING AND PARTICIPANTS:
      The study used a longitudinal, prospective cohort design. Data were collected by
      structured interviews at intake to treatment, 1 year, 2 years and at 4-5 years.
      The sample comprised 418 patients from 54 agencies and four treatment modalities.
      MEASUREMENTS: Measures were taken of illicit drug use, injecting and sharing
      injecting equipment, alcohol use, psychological health and crime. FINDINGS: Rates
      of abstinence from illicit drugs increased after treatment among patients from
      both residential and community (methadone) programmes. Reductions were found for
      frequency of use of heroin, non-prescribed methadone, benzodiazepines, injecting
      and sharing of injecting equipment. For most variables, reductions were evident
      at 1 year with outcomes remaining at about the 1 year level or with further
      reductions. Crack cocaine and alcohol outcomes at 4-5 years were not
      significantly different from intake. CONCLUSIONS: Substantial reductions across a
      range of problem behaviours were found 4-5 years after patients were admitted to
      national treatment programmes delivered under day-to-day conditions. The less
      satisfactory outcomes for heavy drinking and use of crack cocaine suggest the
      need for services to be modified to tackle these problems more effectively.
      Despite differences between the United Kingdom and the United States in patient
      populations and in treatment programmes, there are many similarities between the
      two countries in outcomes from large-scale, multi-site studies.

PMID- 12603230
TI  - Cumulative adversity and drug dependence in young adults: racial/ethnic
      contrasts.
AB  - AIMS: To study cumulative exposure to stressors as a risk factor for drug
      dependence, and evaluate whether group differences in exposure contribute to
      differences in prevalence. DESIGN: Cross-sectional community survey of life-time
      adverse experiences and substance and psychiatric disorders. SETTING: Data
      collected between 1997 and 2000 in Miami-Dade County, USA. PARTICIPANTS: A total
      of 1803 former Miami-Dade public school students, 93% between ages 19 and 21
      years when interviewed. Males and females of Cuban origin, other Caribbean basin
      Hispanics, African-Americans and non-Hispanic whites are represented equally.
      MEASUREMENTS: Drug dependence disorder assessed by DSM-IV criteria using the
      Composite International Diagnostic Interview, and a 41-item checklist of life
      time exposure to major and potentially traumatic experiences. Both measures
      include age at time of first occurrence. FINDINGS: Life-time rate of drug
      dependence disorder (total 14.3%) did not vary significantly (P > 0.05) by socio
      economic group. Male rate (17.6%) was significantly greater than female rate
      (10.9%). The African-American rate (6.5%) was dramatically lower than non
      Hispanic white (17.0%), Cuban (18.1%) and non-Cuban Hispanic (16.0%) rates
      despite their dramatically higher exposure to adversity. Twenty-eight of 33
      individual adversities were associated with the subsequent onset of drug
      dependence (P < 0.05). Cumulative life-time exposure was greatest for males and
      for African-Americans, and was associated inversely with socio-economic level.
      Multivariate discrete-time event history analysis revealed significant
      independent effects of distal (>1 year earlier) and proximal (previous year)
      exposure to adverse events (P < 0.05), controlling for childhood conduct
      disorder, attention deficit hyperactive disorder and previous psychiatric
      disorder. CONCLUSIONS: Life-time cumulative exposure to distant as well as more
      recent adversity predicts risk of subsequent drug dependence, although it does
      not explain ethnic group differences in risk.

PMID- 12603232
TI  - Long-term influence of duration and intensity of treatment on previously
      untreated individuals with alcohol use disorders.
AB  - AIMS: This study examined the influence of the duration and intensity of the
      first episode of treatment for previously untreated individuals with alcohol use
      disorders on short-term and long-term outcomes, and the effect of additional
      treatment and delayed treatment on outcomes. DESIGN, SETTING, PARTICIPANTS: A
      sample of alcoholic individuals (n = 473) was recruited at alcoholism information
      and referral centers and detoxification units and was surveyed at baseline and 1
      year, 3 years and 8 years later. MEASUREMENTS: At each contact point,
      participants completed an inventory that assessed their treatment utilization
      since the last assessment and their current alcohol-related, psychological and
      social problems. FINDINGS: Compared with individuals who remained untreated,
      individuals who entered treatment relatively quickly and who obtained a longer
      duration of treatment had better short- and long-term alcohol-related outcomes
      and better short-term social functioning. Individuals who obtained a longer
      duration of additional treatment had better alcohol-related outcomes than
      individuals who obtained no additional treatment but, among individuals who
      delayed treatment entry, the duration of treatment was not associated with
      treatment outcomes. In general, the intensity of treatment was not related to
      better outcomes. CONCLUSIONS: Rapid entry into treatment and the duration of
      treatment for alcohol use disorders may be more important than the intensity of
      treatment. Treatment providers should consider structuring their programs to
      emphasize continuity, rather than intensity of care.

PMID- 12603231
TI  - Measuring outcome in cocaine clinical trials: a comparison of sweat patches with
      urine toxicology and participant self-report.
AB  - AIMS: To evaluate the advantages of using a sweat patch (PharmCheck) for
      detecting cocaine abuse in cocaine-dependent patients participating in a clinical
      trial. The utility of the sweat patch was assessed from the following
      perspectives: the reliability and validity of quantitative sweat patch results,
      the possible degradation of cocaine to benzoylecgonine (BE) as a function of the
      length of time that a patch is worn, the completeness of the dataset yielded by
      thrice-weekly urine toxicology compared with thrice-weekly and weekly sweat
      patches, and the relative costs associated with sweat patch versus urine
      measures. DESIGN: Data were collected during a 10-week out-patient clinical trial
      in which participants wore two sweat patches, one applied every visit and one
      applied weekly. Urine samples were collected thrice weekly, as were self-reports
      of substance use. SETTING: A multi-site clinical trial conducted in Boston,
      Cincinnati and New York, USA. PARTICIPANTS: Twenty-seven participants with
      comorbid diagnoses of cocaine dependence and adult attention deficit disorder
      completed the study. MEASUREMENTS: Sweat patch and urine samples were analyzed by
      standard methods for cocaine and cocaine metabolites. FINDINGS: Quantitative
      sweat patch measures had good reliability in that the correlation between the
      weekly and per-visit patches was 0.96 (P < 0.0001). The concurrent validity, as
      judged by the correlation between quantitative urine BE levels and either weekly
      (0.76, P < 0.0001) or per-visit (0.73, P < 0.0001) cocaine sweat patch levels was
      reasonable. The correlation between the self-report of cocaine use and these same
      two patches, however, was lower (0.40, P < 0.05 and 0.30, P < 0.05,
      respectively). The results revealed no significant degradation of cocaine to BE
      associated with wearing the patch for a longer time. Finally, the per-visit patch
      provided cocaine use data on 80.5% of all study days (a total of 70), while urine
      toxicology and the weekly patch provided 77.4% and 76.1%, respectively.
      CONCLUSIONS: The present findings suggest that the PharmCheck patch might be an
      attractive alternative to urine toxicology for use as an outcome measure in
      cocaine clinical trials.

PMID- 12603233
TI  - Prevalence of alcohol dependence in a town in Nepal as assessed by the CAGE
      questionnaire.
AB  - BACKGROUND: In spite of a perception that alcohol use is rampant in Nepal, there
      has been no survey to assess the extent of alcohol dependence in the country.
      AIMS: (i) To assess prevalence of alcohol dependence in the community of Dharan
      and (ii) to correlate this with various socio-demographic characteristics.
      DESIGN: The CAGE questionnaire was administered to all adult individuals in
      houses selected randomly in the township of Dharan. FINDINGS: Among 2344 adults
      assessed, the prevalence of alcohol dependence was found to be 25.8%. The
      prevalence of alcohol dependence increased with age to peak in the age group 45
      54 years and was more than twice as common in men as in women. Also, alcohol
      dependence was more common among those with lower level of education, widowers
      and divorcees and those belonging to the Matwali community. The extent of
      dependence was influenced by socio-cultural sanctions. CONCLUSIONS: The
      prevalence of alcohol dependence is too high for comfort in Dharan, a town in
      eastern Nepal. There is an urgent need to formulate a policy for substance abuse
      in the country taking into account the findings of this study.

PMID- 12603234
TI  - A controlled trial of an expert system and self-help manual intervention based on
      the stages of change versus standard self-help materials in smoking cessation.
AB  - AIM: To examine the population impact and effectiveness of the Pro-Change smoking
      cessation course based on the Transtheoretical Model (TTM) compared to standard
      self-help smoking cessation literature. DESIGN: Randomized controlled trial.
      SETTING: Sixty-five West Midlands general practices. PARTICIPANTS: Randomly
      sampled patients recorded as smokers by their general practitioners received an
      invitation letter and 2471 current smokers agreed. INTERVENTIONS: Responders were
      randomized to one of four interventions. The control group received standard self
      help literature. In the Manual intervention group, participants received the Pro
      Change system, a self-help workbook and three questionnaires at 3-monthly
      intervals, which generated individually tailored feedback. In the Phone
      intervention group, participants received the Manual intervention plus three
      telephone calls. In the Nurse intervention group, participants received the
      Manual intervention plus three visits to the practice nurse. MEASUREMENTS:
      Biochemically confirmed point prevalence of being quit and 6-month sustained
      abstinence, 12 months after study commencement. FINDINGS: A total of 9.1% of
      registered current smokers participated, of whom 83.0% were not ready to quit.
      Less than half of participants returned questionnaires to generate second and
      third individualized feedback. Telephone calls reached 75% of those scheduled,
      but few participants visited the nurse. There were small differences between the
      three Pro-Change arms. The odds ratio (95% confidence intervals) for all Pro
      Change arms combined versus the control arm were 1.50 (0.85-2.67) and 1.53 (0.76
      3.10), for point prevalence and 6-month abstinence, respectively. This
      constitutes 2.1% of the TTM group versus 1.4% of the control group achieving
      confirmed 6-month sustained abstinence. CONCLUSIONS: There was no statistically
      significant benefit of the intervention apparent in this trial and the high
      relapse of quitters means that any population impact is small.

PMID- 12603235
TI  - A prospective study of the association between smoking and later alcohol drinking
      in the general population.
AB  - AIMS: To address the possible prospective association between smoking habits and
      risk of later heavy drinking in the adult population. DESIGN: Pooled population
      based long-term cohort studies with repeated assessments of smoking and alcohol
      habits. SETTING: Copenhagen, Denmark. PARTICIPANTS: A total of 14,130 non- to
      moderate drinkers at baseline, who attended re-examination. MEASUREMENTS: Among
      the non- to moderate drinkers we addressed the relation between smoking habits at
      first examination and the risk of becoming a heavy and excessive drinker at
      follow-up. FINDINGS: Level of tobacco consumption at first examination predicted
      an increased risk of becoming a heavy and excessive drinker in a dose-dependent
      manner. Men who smoked more than 25 g of tobacco per day had adjusted odds ratios
      of 2.12 (95% confidence interval (CI): 1.44-3.11) and 3.95 (95% CI: 1.93-8.95)
      for becoming heavy and excessive drinkers, compared to participants who had never
      smoked. Equivalent estimates among women were 1.76 (95% CI: 1.02-3.04) and 2.21
      (95% CI: 1.00-4.58), respectively. CONCLUSIONS: This study suggests that tobacco
      use is associated quantitatively with later risk of heavier drinking.

PMID- 12603237
TI  - Alcohol consumption level in Russia: a viewpoint on monitoring health conditions
      in the Russian Federation (RLMS).

PMID- 12603236
TI  - Death following ingestion of MDMA (ecstasy) and moclobemide.
AB  - Four deaths following the ingestion of moclobemide and MDMA ('ecstasy') are
      described. The probable cause of death in each case was serotonin syndrome as a
      result of an interaction between the two drugs. As none of the victims had been
      prescribed moclobemide it seems that each had taken the drug to enhance the
      effects of MDMA, with fatal consequences. Warnings are needed against misinformed
      attempts to potentiate the pharmacological effects of illicit drugs.

PMID- 12603238
TI  - Robert F. Borkenstein: an appreciation.

PMID- 12603243
TI  - Preface: mild cognitive impairment.

PMID- 12603244
TI  - Memory function in normal aging.
AB  - Basic findings obtained on memory functions in normal aging are presented and
      discussed with respect to five separate but interacting memory systems. These
      systems are: episodic memory, semantic memory, short-term memory, perceptual
      representation system and procedural memory. All available evidence from cross
      sectional research shows that there is a linear, decreasing memory performance as
      a function of age for episodic memory. Longitudinal studies suggest, however,
      that this age deficit may be an overestimation, by showing a relatively stable
      performance level up to middle age, followed by a sharp decline. Studies on
      semantic memory, short-term memory, perceptual representation system, and
      procedural memory show a relatively constant performance level across the adult
      life span, although some tasks used to assess short-term memory and procedural
      memory have revealed an age deficit. Disregarding the mixed results for these
      latter two memory systems, it can be concluded that episodic memory is unique in
      showing an age deficit. Episodic memory is also unique in the sense that it is
      the only memory system showing gender differences in performance throughout the
      adult life span with a significantly higher performance for women.

PMID- 12603245
TI  - What is mild cognitive impairment? Variations in definitions and evolution of
      nondemented persons with cognitive impairment.
AB  - Numerous studies have endeavoured to explore the nature of cognitive impairment
      in nondemented elderly persons. Comparison of this literature is hampered by huge
      variations in criteria and methodology. Despite these limitations, there are
      repeated reports that nondemented persons with cognitive impairment have a higher
      chance of progressing to dementia. Evidence also indicates higher mortality in
      cognitively impaired persons but there is also a chance of improvement in
      cognition over time. The current paper provides an overview of the various
      concepts and criteria proposed for cognitive impairment in nondemented persons,
      discusses some of the problems with current research in this field, and presents
      some of the findings concerning the evolution of cognitive impairment in relation
      to dementia, mortality and cognitive improvement.

PMID- 12603246
TI  - Mild cognitive impairment: experience from a memory clinic.
AB  - Mild cognitive impairment (MCI) is sometimes a transition between normal aging
      and dementia. We investigated the occurrence of MCI in a population referred to a
      memory clinic. The criteria used to diagnose the state were similar to those used
      by Petersen et al. in many previous publications. A clinical evaluation after
      approximately 3 years was also performed. In a subsample of 43 subjects, we found
      that, during 1 year, 37% (136/402) of all investigated subjects were patients
      with MCI. After a mean follow-up time of 3 years, 11% (5/43) showed cognitive
      improvement, while 53% (23/43) were stable and showed no cognitive decline or
      improvement. Fifteen out of 42 patients (35%) deteriorated and were diagnosed as
      demented during the same time. We conclude that MCI is a heterogeneous concept
      and that the outcome at follow-up is dependent on which population is studied and
      how MCI has been defined.

PMID- 12603248
TI  - Cognitive deficits in preclinical Alzheimer's disease.
AB  - We review the literature on cognitive functioning during the transition from
      normal aging to clinical Alzheimer's disease (AD). There is ample empirical
      evidence that deficits across multiple cognitive domains are apparent years to
      decades before the AD diagnosis, with impairments in episodic memory representing
      a common cognitive manifestation of the preclinical phase of the disease.
      Interestingly, the magnitude of the preclinical cognitive deficits appears to be
      relatively stable until a few years before clinical diagnosis. The behavioural
      deficits associated with preclinical AD are consistent with the neural changes
      that appear many years before eventual diagnosis. In addition to increasing our
      theoretical understanding of AD development, research on cognition in preclinical
      AD contributes to the identification of persons at risk of developing AD for
      purposes of intervention.

PMID- 12603247
TI  - Psychiatric symptoms/syndromes in elderly persons with mild cognitive impairment.
      Data from a cross-sectional study.
AB  - OBJECTIVE: This study examined the prevalence of psychiatric syndromes and
      symptoms in elderly persons with mild cognitive impairment (MCI). METHODS: Data
      from a population-based study (the Kungsholmen Project) were used. All subjects
      with a Mini-Mental State Examination (MMSE) score < or =23 and a comparable
      random of those > or =24 were selected for further examination. Physicians
      carefully examined the included persons and those affected with dementia were
      excluded. The rest were stratified into 14 groups according to age and level of
      education. The mean MMSE score was calculated for each group and those subjects
      with scores 1SD below the age- and education-specific mean were classified as
      MCI. A structured psychiatric interview was performed and diagnoses of
      depression, anxiety and psychosis were made according to DSM-III-R. RESULTS:
      Being suspicious was the only symptom and being affected by an anxiety syndrome
      was the only diagnosis found to be associated with MCI. The association with
      suspiciousness might reflect the feeling of losing control that probably
      accompanies the loss of cognitive function experienced by the person. The
      association with anxiety syndromes might be a result of the fact that physical
      disorders have been reported to be more common in persons with cognitive
      impairment, as well as in persons with anxiety syndromes. CONCLUSION: The results
      of this study suggest that the psychiatric syndromes present in MCI might be
      related to MCI per se. Additionally, it might reflect a developing dementia or a
      concomitant physical disorder.

PMID- 12603249
TI  - Neuropsychological features of mild cognitive impairment and preclinical
      Alzheimer's disease.
AB  - Recent research has identified a transitional state between the cognitive changes
      of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment
      (MCI). MCI patients experience memory loss to a greater extent than one would
      expect for age, yet they do not meet currently accepted criteria for clinically
      probable AD. An issue currently under investigation is whether MCI represents the
      preclinical stages of AD or a distinct and static cognitive aetiology. In an
      attempt to address this issue, the present investigations are adopting a
      convergent approach to the detection of preclinical AD, where multiple risk
      factors are considered when making a diagnosis. Currently, one of the most
      important tools when assessing early cognitive changes is neuropsychological
      evaluation. MCI subjects typically record neuropsychological performance between
      that of healthy older individuals and demented patients. Tests assessing new
      learning, delayed recall and attention/executive function seem to provide
      valuable information for screening and diagnosis of MCI and early AD if
      interpreted properly. Recommendations concerning methodological issues and the
      early management of neuropsychological MCI studies were made.

PMID- 12603250
TI  - Instrumental activities of daily living: a stepping-stone towards Alzheimer's
      disease diagnosis in subjects with mild cognitive impairment?
AB  - This paper challenges the requirements of normal activities of daily
      living/instrumental activities of daily living (ADL/IADL) functioning in mild
      cognitive impairment and stresses the need for further research and assessment
      refinement. Although people who develop dementia seem to experience subtle
      changes in complex IADLs long before the disease onset, studies that compare
      cognitively mildly impaired subjects with demented and nondemented subjects
      present no clear consensus regarding differentiation according to IADL ability.
      The traditional ADL/IADL assessment instruments and techniques seem to present a
      major problem when the purpose is to predict or differentiate between diagnoses.
      It is therefore argued that the diagnosis of MCI should include rather than
      exclude observed or experienced changes in complex everyday life activities.

PMID- 12603251
TI  - Cerebrospinal fluid levels of total-tau, phospho-tau and A beta 42 predicts
      development of Alzheimer's disease in patients with mild cognitive impairment.
AB  - Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help
      in the diagnosis early in the course of Alzheimer's disease (AD), especially in
      the phase before clinically overt dementia, i.e. in patients with mild cognitive
      impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up
      investigation, had progressed to AD with dementia, and 32 controls. Three CSF
      biomarkers related to the central pathogenic processes in AD were analysed,
      including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF
      phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for
      the formation of neurofibrillary tangles), and CSF A beta 42 (as a marker for A
      beta metabolism, and possibly for the formation of senile plaques). At baseline,
      35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P
      tau, while 34/44 (77.3%) had low CSF-A beta 42 levels. The positive likelihood
      ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF A beta 42.
      These findings suggest that these CSF-markers are abnormal before the onset of
      clinical dementia, and that they may help to identify MCI patients that will
      progress to AD. CSF diagnostic markers will be especially important when drugs
      with potential effects on the progression of AD (e.g. gamma-secretase inhibitors)
      will reach the clinical phase.

PMID- 12603252
TI  - A critical discussion of the role of neuroimaging in mild cognitive impairment.
AB  - OBJECTIVE: In this paper, the current neuroimaging literature is reviewed with
      regard to characteristic findings in mild cognitive impairment (MCI). Particular
      attention is drawn to the possible value of neuroimaging modalities in the
      prediction and early diagnosis of Alzheimer's disease (AD). METHODS: First, the
      potential contribution of neuroimaging to an early, preclinical diagnosis of
      degenerative disorders is discussed at the background of our knowledge about the
      pathogenesis of AD. Second, relevant neuroimaging studies focusing on MCI are
      explored and summarized. Neuroimaging studies were found through Medline search
      and by systematically checking through the bibliographies of relevant articles.
      RESULTS: Structural volumetric magnetic resonance imaging (MRI) and positron
      emission tomography (PET)/single photon emission tomography (SPECT) are currently
      the most commonly used neuroimaging modalities in studies focusing on MCI. There
      were considerable variations in demographical and clinical characteristics across
      studies. However, significant hippocampal and entorhinal cortex volume reductions
      were consistently found in subjects with MCI as compared with cognitively
      unimpaired controls. While hippocampal and entorhinal cortex atrophy in subjects
      with MCI are also well-established risk factors for the development of AD, these
      measures cannot be regarded as being of high predictive value in an individual
      case. Evidence for other typical neuroimaging changes in MCI is still scarce. In
      PET and SPECT studies, reduced blood flow and/or glucose metabolism in
      temporoparietal association areas, posterior cingulate and hippocampus were
      associated with a higher risk of progressive cognitive decline in MCI. In
      quantitative electroencephalogram (QEEG), low beta, high theta, low alpha and
      slowed mean frequency were associated with development of dementia. CONCLUSIONS:
      Existing studies suggest that neuroimaging measures have the potential to become
      valuable tools in the early diagnosis of AD. To establish their value in routine
      use, larger studies, preferably with long prospective follow-up are needed.

PMID- 12603253
TI  - Clinical findings in nondemented mutation carriers predisposed to Alzheimer's
      disease: a model of mild cognitive impairment.
AB  - Individuals carrying a mutation associated with Alzheimer's disease (AD) may
      serve as a model of mild cognitive impairment (MCI). Nondemented individuals from
      these families can be subdivided into asymptomatic and symptomatic groups. Four
      families were studied. Two families are associated with APP mutations
      (KN670/671ML, E693G) and two with PS1 mutation (M146V, H163Y). Clinical symptoms,
      level of global cognitive functioning as evaluated by Mini-Mental State
      Examination, neuropsychological test results, neuroradiological examinations
      (magnetic resonance imaging (MRI) and single-photon emission tomography (SPECT)),
      as well as cerebrospinal fluid (CSF) measurements of tau and beta-amyloid are
      reported. Nondemented mutation carriers did not report any symptoms indicating
      cognitive decline. In addition, no clinical signs of dementia or marked cognitive
      impairment in neuropsychological tests were found. A reduction of temporal blood
      flow with SPECT was indicated in 5/13 nondemented mutation carriers. Two of these
      13 individuals had moderate hyperintensities in deep white matter as observed on
      MRI. CSF measurements of A beta 42/43 were inconclusive because of large
      biological variation. A nonsignificant elevation of tau was detected in mutation
      carriers. In conclusion, clinical examinations of relatively young individuals
      carrying an AD mutation did not reveal any marked abnormalities before the
      clinical onset of dementia.

PMID- 12603254
TI  - Treatment of mild cognitive impairment: rationale, present and future strategies.
AB  - Mild cognitive impairment (MCI) is a condition with a high conversion rate to
      Alzheimer's disease (AD), which justifies early diagnostic and therapeutic
      interventions. At the moment, treatment strategies for AD could be extrapolated
      to interventional strategies in MCI. This article reviews currently available
      symptomatic treatments with acetylcholinesterase inhibitors, putative treatments
      such as antiglutamatergic drugs, nootropics, antioxidants, anti-inflammatory
      drugs and still controversial estrogen replacement therapy, and visionary
      treatments targeting neuropathological substrates of the disease, such as amyloid
      production and aggregation, phosphorylation of tau, formation of neurofibrillary
      tangles and apoptosis. Findings from epidemiological studies have expanded our
      knowledge on risk as well as possible neuroprotective factors and given means to
      develop preventive strategies with antihyperlipidaemic drugs such as statins. A
      wide range of suggested treatments and their possible combinations necessitate
      their efficacy assessment in well-designed randomized clinical trials where the
      crucial prerequisites are selection of the treatment population and definitions
      of outcome measures. Prevention and disease-modifying strategies are raising
      ethical questions because interventions are focused on non-diseased elderly at
      risk, which means that emphasis should be not only on efficacy but also on long
      term safety.

PMID- 12603256
TI  - Mild cognitive impairment: unanswered questions and future directions.

PMID- 12603255
TI  - Pharmacoeconomics of mild cognitive impairment.
AB  - There is little written about the pharmacoeconomics of mild cognitive impairment
      (MCI), particularly with regard to intervention. The aim of the paper is to
      highlight methodological issues and to present some results that are of
      importance when drug interventions of MCI are discussed. There is a relationship
      between severity of dementia and costs, but to what extent such results can be
      extrapolated to MCI is not known. Even if it is logical to consider a
      postponement of the shift from MCI to dementia as cost effective, this statement
      must be proven, particularly in light of the insufficient knowledge about the
      effects of anti-dementia drugs on survival. From the Kungsholmen project in
      Sweden, there are indications that the postponement between MCI and manifest
      dementia may result in short-term benefits (a few years) of about SEK50,000 (5300
      US dollars).

PMID- 12603257
TI  - Connecting the dots: trafficking of neurotrophins, lectins and diverse pathogens
      by binding to the neurotrophin receptor p75NTR.
AB  - The common receptor for neurotrophins, p75, has important roles in
      internalization and trafficking of neurotrophins along axons. Recent studies show
      that an astonishing array of proteins, including lectins, pathogens and
      neurotoxins, bind the p75 receptor, suggesting that they can hijack and utilize
      this receptor for trafficking between neuronal populations within the nervous
      system. Such pathogens include the neurologically important rabies viruses, prion
      proteins, beta-amyloid and possibly tetanus toxin. These proteins may hijack
      existing transport machineries designed to traffick neurotrophins, thus allowing
      the infiltration and distribution of pathogens and toxins among vulnerable
      neuronal populations with devastating effects, as seen in rabies, prion
      encephalopathies, Alzheimer's disease and tetanic muscle spasm. The discovery of
      an entry and transport machinery that is potentially shared between pathogens and
      neurotrophins sheds light ono trafficking systems in the nervous system and may
      assist the design of novel therapeutic avenues that prevent or slow the
      progression of diverse chronic and acute neurological disorders.

PMID- 12603258
TI  - Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal
      neurons.
AB  - Dideoxyforskolin, a forskolin analogue unable to stimulate adenylate cyclase, and
      tamoxifen, an antioestrogen widely used against breast cancer, are both known to
      block some Cl- channels. Their effects on Cl- responses to glycine or GABA have
      been tested here by using whole-cell recording from cultured spinal neurons.
      Dideoxyforskolin (4 or 16 microm) and tamoxifen (0.2-5 microm) both potentiate
      responses to low glycine concentrations. They also induce blocking effects,
      predominant at high glycine concentrations. At 5 microm, tamoxifen increased
      responses to 15 microm glycine by a factor >4.5, reaching 20 in some neurons.
      Potentiation by extracellular dideoxyforskolin or tamoxifen persisted after
      intracellular application of the modulator and was not due to Zn2+ contamination.
      Potentiation by tamoxifen also persisted in a Ca2+-free extracellular solution,
      after intracellular Ca2+ buffering and protein kinase C blockade. Thus, the
      critical sites of action are not intracellular. The EC50 for glycine was lowered
      6.6-fold by 5 microm tamoxifen. The kinetics and voltage-dependence of the
      effects of tamoxifen on glycine responses support the idea that this hydrophobic
      drug may act from a site located within the membrane. Tamoxifen (5 micro m) also
      increased responses to 2 micro m GABA by a factor of 3.5, but barely affected
      peak responses to 20 microm GABA. The demonstration that tamoxifen affects some
      of the main inhibitory receptors should be useful for better evaluating its
      neurological effects. Furthermore, the results identify a new class of molecules
      that potentiate glycine receptor function.

PMID- 12603259
TI  - Potentiation of intracellular Ca2+ mobilization by hypoxia-induced NO generation
      in rat brain striatal slices and human astrocytoma U-373 MG cells and its
      involvement in tissue damage.
AB  - The relationship between nitric oxide (NO) and intracellular Ca2+ in hypoxic
      ischemic brain damage is not known in detail. Here we used rat striatal slices
      perfused under low-oxygen and Ca2+-free conditions and cultured human astrocytoma
      cells incubated under similar conditions as models to study the dynamics of
      intracellular NO and Ca2+ in hypoxia-induced tissue damage. Exposure of rat
      striatal slices for 70 min to low oxygen tension elicited a delayed and sustained
      increase in the release of 45Ca2+. This was potentiated by the NO donors sodium
      nitroprusside (SNP) and spermine-NO and inhibited by N-omega-nitro-L-arginine
      methyl ester (L-NAME) or by the NO scavenger 2-phenyl-4,4,5,5
      tetramethylimidazoline-1-oxyl-3-oxide (PTIO). A membrane-permeant form of heparin
      in combination with either ruthenium red (RR) or ryanodine (RY) also inhibited
      45Ca2+ release. In human astrocytoma U-373 MG cells, hypoxia increased
      intracellular Ca2+ concentration ([Ca2+]i) by 67.2 +/- 13.1% compared to normoxic
      controls and this effect was inhibited by L-NAME, PTIO or heparin plus RR. In
      striatal tissue, hypoxia increased NO production and LDH release and both effects
      were antagonized by L-NAME. Although heparin plus RR or RY antagonized hypoxia
      induced increase in LDH release they failed to counteract increased NO
      production. These data therefore indicate that NO contributes to hypoxic damage
      through increased intracellular Ca2+ mobilization from endoplasmic reticulum and
      suggest that the NO-Ca2+ signalling might be a potential therapeutic target in
      hypoxia-induced neuronal degeneration.

PMID- 12603260
TI  - Acute antinociceptive responses in single and combinatorial opioid receptor
      knockout mice: distinct mu, delta and kappa tones.
AB  - We have examined responses of mice lacking mu, delta and kappa opioid receptor
      (MOR, DOR and KOR, respectively) genes, as well as combinatorial mutants, in
      several pain models. This is the first truly comparative study of all three
      opioid receptor-deficient mice, with genotypes and gender analysis using mice on
      the hybrid 50% 129/SV : 50% C57BL/6 genetic background. In the tail-immersion
      test, only KOR-/- females showed decreased withdrawal latencies. This
      modification was also found in MOR/KOR and MOR/DOR/KOR, but not MOR/DOR mutants.
      The hotplate test revealed increased nociceptive sensitivity for MOR-/-, a
      phenotype which was also observed in double mutants involving the MOR deletion,
      and in the triple mutants. The tail-pressure test showed increased response for
      both MOR-/- and DOR-/- mutants, a modification which was enhanced in the triple
      mutant mice. In the formalin test, MOR-/- and DOR-/- mice showed increased
      responses in the early and late phases, respectively, while the triple mutant
      tended to show enhanced nociception in both phases. Finally, the enhanced
      response of KOR-/- mice in the writhing test, which we have demonstrated
      previously, was confirmed in double MOR/KOR- and triple-mutant mice. Together,
      the data support the existence of an antinociceptive opioid tone. Each receptor
      presents a distinct pattern of activities, with mu receptors influencing
      responses to mechanical, chemical and thermal nociception at a supraspinal level,
      kappa receptors involved in spinally mediated thermal nociception and chemical
      visceral pain, and delta receptors modulating mechanical nociception and
      inflammatory pain. Phenotypes of mutant mice were subtle, suggesting a low
      endogenous opioid tone in the regulation of physiological pain.

PMID- 12603261
TI  - The eye of the african mole-rat Cryptomys anselli: to see or not to see?
AB  - In an attempt to clarify its possible physiological role, we studied the eye of
      the Zambian mole rat Cryptomys anselli by light, electron and confocal microscopy
      using conventional staining as well as immunolabelling with rod and cone cell
      markers. The small eyes of Cryptomys are located superficially and display all
      features typical of sighted animals: iris, pupil and well-developed lens,
      separating the anterior chamber and the vitreous. The retina shows a well
      stratified organization and the folds described in blind subterranean or
      nocturnal mammals were not observed. The major population of the photoreceptor
      cells in the Cryptomys retina consists of rod cells, again with a morphology
      quite similar to that found in sighted animals. The relatively short outer
      segments contain numerous well-stacked disks and show a strong rod-opsin as well
      as transducin immunoreaction. Synapses were evident in the spherules, the round
      basal processes of the rod cell, but they lacked the precise organization
      reported for sighted mammals. Cone cells were present as well, as indicated by
      peanut lectin staining, but no immunolabelling with polyclonal M/L-opsin antisera
      was detectable. The presence of cone cells was also suggested by some basal
      processes at the outer plexiform layer which displayed several synaptic active
      sites and irregular contours. While the other retinal layers also showed an
      organization typical of sighted mammals, there were signs of less tightly
      preserved morphology as well. Displaced rods and amacrine and/or ganglion cells
      were observed, and some sparse rod spherules penetrated into the inner nuclear
      layer. A major reduction was observed in the number of ganglion cells, estimated
      from the number of axons in the optic nerve, that was very low (approximately
      1000 per retina on average) relative to sighted mammals. The data we have suggest
      a slow, ongoing loss of cells with ageing. Apoptotic nuclei, mainly corresponding
      to photoreceptor cells and ganglion cells, were detected in young individuals,
      and an overall reduction in the thickness of the retina was observed in older
      animals. The morphological data presented here allow some first speculations on
      the physiological role of the Cryptomys eye and will hopefully trigger detailed
      studies on the chronobiology and the anatomy of the retinal projections and of
      the visual cortex of this remarkable species.

PMID- 12603262
TI  - The small conductance Ca2+-activated K+ channel SK3 is localized in nerve
      terminals of excitatory synapses of cultured mouse hippocampal neurons.
AB  - In the central nervous system small conductance Ca2+-activated K+ (SK) channels
      are important for generating the medium/slow afterhyperpolarization seen after
      single or trains of action potentials. Three SK channel isoforms (SK1,-2,-3) are
      differentially distributed throughout the brain, but little is known about their
      specific expression in particular neuronal compartments. In the hippocampus SK3
      was found in the neuropil, predominantly in the terminal field of the mossy
      fibres and in fine varicose fibres, but excluded from the pyramidal and granule
      cell layers. Because this expression pattern suggested a presynaptic
      localization, we examined the subcellular distribution of SK3 in cultured
      hippocampal neurons using high-resolution immunofluorescence analysis. SK3 was
      localized in a punctate, synaptic pattern. The SK3 clusters were precisely
      colocalized with the presynaptic marker synapsin and at close range (0.4-0.5
      microm) from NMDA-receptors and PSD-95. This arrangement is consistent with a
      localization of SK3 in the presynaptic nerve terminal, but not restricted to the
      synaptic membrane proper. In agreement with the increasing expression of SK3
      during early postnatal development in vivo, the fraction of synapses containing
      SK3 increased from 14% to 57% over a six-week culture period. SK3-containing
      synapses were equally observed on spiny, glutamatergic and smooth GABAergic
      neurons. In contrast to its close association with NMDA-receptors and PSD-95, SK3
      was rarely associated with GABAA-receptor clusters. Thus, SK3 is a presynaptic
      channel in excitatory hippocampal synapses, with no preference for glutamatergic
      or GABAergic postsynaptic neurons, and is probably involved in regulating
      neurotransmitter release.

PMID- 12603263
TI  - Protective effect of HSV-mediated gene transfer of nerve growth factor in
      pyridoxine neuropathy demonstrates functional activity of trkA receptors in large
      sensory neurons of adult animals.
AB  - The distinct distribution of trkA receptors on small neurons and trkC receptors
      on large neurons in the dorsal root ganglion correlates with the dependence of
      these two classes of neurons on nerve growth factor and neurotrophin-3,
      respectively, for survival during development. In adult animals, the distribution
      of high affinity neurotrophin (trk) is complex and overlapping; neurotrophins are
      not required for cell survival, but may influence cell phenotype and the response
      to injury. In order to test the functional activity of trkA receptors in the
      sensory ganglia of adult animals in vivo, we examined the ability of a nerve
      growth factor-expressing recombinant replication-defective herpes simplex virus
      based vector to prevent the selective degeneration of large sensory fibres caused
      by intoxication with pyridoxine. Transduction of dorsal root ganglion neurons in
      vivo by subcutaneous inoculation of the nerve growth factor-expressing vector
      prevented the development of pyridoxine-induced neuropathy measured by
      electrophysiological, morphological and behavioural measures. These results
      demonstrate a functional activity of trkA receptors expressed on large neurons in
      the dorsal root ganglion in mature animals; this observation has important
      implications for the choice of neurotrophic factors for treatment of peripheral
      nerve disease.

PMID- 12603265
TI  - Pedunculopontine tegmental stimulation evokes striatal dopamine efflux by
      activation of acetylcholine and glutamate receptors in the midbrain and pons of
      the rat.
AB  - The pedunculopontine tegmental nucleus appears to influence striatal dopamine
      activity via cholinergic and glutamatergic afferents to dopaminergic cells of the
      substantia nigra pars compacta. We measured changes in striatal dopamine
      oxidation current (dopamine efflux) in response to electrical stimulation of the
      pedunculopontine tegmental nucleus using in vivo electrochemistry in urethane
      anaesthetized rats. Pedunculopontine tegmental nucleus stimulation evoked a three
      component change in striatal dopamine efflux, consisting of: (i) an initial rapid
      increase of 2 min duration; followed by (ii) a decrease below prestimulation
      levels of 9 min duration; then by (iii) a prolonged increase lasting 35 min.
      Intra-nigral infusions of the ionotropic glutamate receptor antagonist kynurenate
      (10 microg/ microL) or the nicotinic cholinergic receptor antagonist mecamylamine
      (5 microg/0.5 microL) selectively attenuated the rapid first component, while
      systemic injections of the muscarinic cholinergic antagonist scopolamine (5
      mg/kg, i.p.) diminished the second and third components. In addition, intra
      pedunculopontine tegmental nucleus infusions of the M2 muscarinic antagonist
      methoctramine (50 microg/ microL) selectively abolished the inhibitory second
      component, while intranigral infusions of scopolamine (200 microg/ microL)
      selectively abolished the prolonged third component. Intra-nigral infusions of
      the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4
      carboxyphenylglycine (2 microg/ microL) had no effect on pedunculopontine
      tegmental nucleus-elicited striatal dopamine efflux. These results suggest that
      the pedunculopontine tegmental nucleus utilizes nicotinic and ionotropic
      glutamate receptors in the substantia nigra to mediate rapid activation, M2-like
      muscarinic autoreceptors in the pedunculopontine tegmental nucleus to mediate
      decreased activation, and muscarinic receptors in the substantia nigra (probably
      of the M5 subtype) to mediate prolonged activation, of the nigrostriatal
      dopaminergic system.

PMID- 12603264
TI  - Group I metabotropic glutamate receptor-mediated calcium signalling and immediate
      early gene expression in cultured rat striatal neurons.
AB  - Group I metabotropic glutamate receptors (mGluRs) are positively coupled to
      phospholipase C (PLC) via Galphaq-proteins and are expressed in the medium-sized
      projection neurons of striatum. To characterize the group I mGluR/PLC-sensitive
      modulation of intracellular Ca2+ ([Ca2+]i) signalling, primary neuronal cultures
      were prepared from the striatum of E19 rat embryos or neonatal day-1 rat pups.
      Cytoplasmic Ca2+ signals were examined with fura-2/AM at a signal cell level.
      After 17-18 days in culture, a profound Ca2+ response consisting of two phases
      was induced in cultured striatal neurons following bath application of the
      selective group I agonist, 3,5-dihydroxyphenylglycine (DHPG). The [Ca2+]i
      elevation was concentration- and time-dependent, and was blocked by coexposure to
      the group I antagonist, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a
      carboxamide (PHCCC), or the PLC inhibitor, U-73122, but not to the group II/III
      antagonist (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE). A
      series of further pharmacological studies demonstrated that the initial spike
      like transient was dependent on intracellular Ca2+ mobilization through 1,4,5
      triphosphate-sensitive stores, and the second long-lasting rise was dependent on
      extracellular Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors and
      especially L-type voltage-operated Ca2+ channels. Lastly, using an immediate
      early gene c-fos as a report of inducible gene expression, the resultant [Ca2+]i
      elevation contributes to DHPG-stimulated c-fos mRNA and Fos protein expression in
      striatal neurons as revealed by quantitative in situ hybridization and
      immunocytochemistry, respectively. These results demonstrate that group I mGluRs
      are able to affect Ca2+ homeostasis at multiple levels and trigger Ca2+-sensitive
      gene transcription in striatal neurons.

PMID- 12603266
TI  - Selective stimulation of striatal dopamine receptors of the D1- or D2-class
      causes opposite changes of fos expression in the rat cerebral cortex.
AB  - It has been suggested that activation of striatal neurons expressing D1 or D2
      dopamine receptors elicits opposite changes in the net output of the basal
      ganglia circuitry and, consequently, in the functional interactions of the
      circuit with the cerebral cortex. In particular, it has been recently reported
      that striatal D1 receptors may regulate cortex function. To further address this
      issue, we mapped cerebral expression of Fos protein following intrastriatal
      stimulation of D1- or D2-class receptors in freely moving animals. Using
      permanent cannulas implanted in the right striatum, Sprague-Dawley rats received
      intrastriatal microinfusions of SKF 38393 (D1 agonist) or quinpirole (D2 agonist)
      or saline (controls), combined with systemic administration of D1 antagonist SCH
      23390 or D2 antagonist eticlopride or saline. Animals treated with SKF 38393
      showed dose-dependent, massive Fos increases in the motor, somatosensory,
      auditory, visual and limbic regions of the cerebral cortex, ipsilaterally to the
      injected striatum. Consistent Fos expression was also found in the injected
      striatum and, bilaterally, in the nucleus accumbens shell. These increases were
      effectively counteracted by systemic SCH 23390. Conversely, quinpirole did not
      induce significant cortical or striatal expression of Fos, which was instead
      observed after the systemic administration of eticlopride. Fos was not detected
      in any of the other basal ganglia nuclei, regardless of the dopamine agonists or
      antagonists used. Our results confirm that striatal D1 dopamine receptors play a
      central role in the modulation of cortical activity, thus providing additional
      information on the functional interaction between basal ganglia circuitry and
      cerebral cortex.

PMID- 12603267
TI  - Conditional involvement of striatal serotonin3 receptors in the control of in
      vivo dopamine outflow in the rat striatum.
AB  - Serotonin3 (5-HT3) receptors can affect motor control through an interaction with
      the nigrostriatal dopamine (DA) neurons, but the neurochemical basis for this
      interaction remains controversial. In this study, using in vivo microdialysis, we
      assessed the hypothesis that 5-HT3 receptor-dependent control of striatal DA
      release is conditioned by the degree of DA and/or 5-HT neuron activity and the
      means of DA release (impulse-dependent vs. impulse-independent). The different DA
      releasing effects of morphine (1 and 10 mg/kg), haloperidol (0.01 mg/kg),
      amphetamine (1 and 2.5 mg/kg), and cocaine (10 and 20 mg/kg) were studied in the
      striatum of freely moving rats administered selective 5-HT3 antagonists
      ondansetron (0.1 mg/kg) or MDL 72222 (0.03 mg/kg). Neither of the 5-HT3
      antagonists modified basal DA release by itself. Pretreatment with ondansetron or
      MDL 72222 reduced the increase in striatal DA release induced by 10 mg/kg
      morphine but not by 1 mg/kg morphine, haloperidol, amphetamine or cocaine. The
      effect of 10 mg/kg morphine was also prevented by intrastriatal ondansetron (1
      microm) administration. Reverse dialysis with ondansetron also reduced the
      increase in DA release induced by the combination of haloperidol and the 5-HT
      reuptake inhibitor citalopram (1 mg/kg). Considering the different DA and 5-HT
      releasing properties of the drugs used, our results demonstrate that striatal 5
      HT3 receptors control selectively the depolarization-dependent exocytosis of DA
      only when central DA and 5-HT tones are increased concomitantly.

PMID- 12603268
TI  - Differentiation and migration of astrocytes in the spinal cord following dorsal
      root injury in the adult rat.
AB  - Nerve fibre degeneration in the spinal cord is accompanied by astroglial
      proliferation. It is not known whether these cells proliferate in situ or are
      recruited from specific regions harbouring astroglial precursors. We found cells
      expressing nestin, characteristic of astroglial precursors, at the dorsal surface
      of the spinal cord on the operated side from 30 h after dorsal root injury.
      Nestin-expressing cells dispersed to deeper areas of the dorsal funiculus and
      dorsal horn on the operated side during the first few days after injury.
      Injection of bromodeoxyuridine (BrdU) 2 h before the end of the experiment, at 30
      h after injury, revealed numerous BrdU-labelled, nestin-positive cells in the
      dorsal superficial region. In animals surviving 20 h after BrdU injection at 28 h
      postlesion, cells double-labelled with BrdU and nestin were also found in deeper
      areas. Labeling with BrdU 2 h before perfusion showed proliferation of microglia
      and radial astrocytes in the ventral and lateral funiculi on both sides of the
      spinal cord 30 h after injury. Nestin-positive cells coexpressed the calcium
      binding protein Mts1, a marker for white matter astrocytes, in the dorsal
      funiculus, and were positive for glial fibrillary acidic protein (GFAP), but
      negative for Mts1 in the dorsal horn. One week after injury the level of nestin
      expression decreased and was undetectable after 3 months. Taken together, our
      data indicate that after dorsal root injury newly formed astrocytes in the
      degenerating white and grey matter first appear at the dorsal surface of the
      spinal cord from where some of them subsequently migrate ventrally, and
      differentiate into white- or grey-matter astrocytes.

PMID- 12603269
TI  - Selective increase of tumour necrosis factor-alpha in injured and spared
      myelinated primary afferents after chronic constrictive injury of rat sciatic
      nerve.
AB  - Chronic constriction of the sciatic nerve, leading to a hyperalgesic state,
      results in a partial lesion wherein some axons are injured and others remain
      intact. Here we sought to characterize reactive changes which occur in DRG cell
      bodies of injured and uninjured axons projecting to skin and muscle. Using
      immunohistochemistry combined with flurorogold and fluororuby retrograde
      labelling to define DRG cell bodies associated with injured and uninjured axons,
      we analysed the DRG immunoreactivity (IR) for tumour necrosis factor-alpha (TNF),
      interleukin-10 (IL-10), the sensory neuron-specific channel vanilloid receptor 1
      (VR1), isolectin B4 (IB4) and calcitonin-gene-related peptide (CGRP) 4 days after
      a unilateral chronic constriction injury (CCI) of the rat sciatic nerve. TNF IR
      was predominantly localized in neuronal DRG cells. In DRG with an intact nerve,
      TNF IR was present in 45%, IL-10 IR in 46%, VR1 IR in 44%, IB4 IR in 51% and CGRP
      IR in 40% of all neuronal profiles. Four days after CCI, TNF IR was increased in
      medium-sized neurons, whereas IR for IL-10, VR1 and IB4, predominantly present in
      small neurons, was reduced. Importantly, not only injured but also adjacent
      spared neurons contributed markedly to increased TNF IR. Neurons projecting to
      both muscle and skin displayed upregulated TNF IR after CCI. TNF in medium-sized
      neurons colocalized with neurofilament and trkB, but not with IB4, trkA or RET,
      suggesting a selective phenotypic switch in presumably low-threshold myelinated
      primary afferents. Spared myelinated fibres with intact sensory functions but
      upregulated TNF expression may contribute to behavioural changes observed after
      nerve injury.

PMID- 12603270
TI  - Repeated, non-habituating stress suppresses inflammatory plasma extravasation by
      a novel, sympathoadrenal dependent mechanism.
AB  - The mechanism by which chronic stress affects the course of inflammatory diseases
      is still not well understood. We have evaluated the effect of two types of
      nonhabituating stress on a major component of the inflammatory response, synovial
      plasma extravasation, induced by perfusion of the potent inflammatory mediator,
      bradykinin and evaluated the underlying neuroendocrine mechanism in the rat.
      Chronic intermittent noise or ether stress induced profound inhibition of
      bradykinin-induced plasma extravasation, which is associated with increased
      adjuvant-arthritis severity. This inhibition, however, took 24 h to fully develop
      after the last exposure to stress and persisted for at least 48 h. The inhibition
      could be reversed by an additional exposure to the stressor, just prior to
      measuring the inflammatory response, suggesting that the delay is due to stress
      induced release of a factor that acutely masks the inhibition of the inflammatory
      response. This novel, unexpected feature of the effect of nonhabituating stress
      on inflammation may help explain variability in effects of stress in patients
      with inflammatory disease. The effect of nonhabituating stress on inflammation
      was dependent on the sympathoadrenal axis with no detectable contribution by the
      hypothalamic-pituitary-adrenal axis.

PMID- 12603271
TI  - Beta-amyloid peptide potentiates inflammatory responses induced by
      lipopolysaccharide, interferon -gamma and 'advanced glycation endproducts' in a
      murine microglia cell line.
AB  - beta-Amyloid (Abeta) plaques are characteristic hallmarks of Alzheimer's disease
      (AD). In AD, it has been suggested that activation of microglial cells might be
      the link between Abeta deposition and neuronal degeneration. Activated microglia
      are associated with senile plaques and produce free radicals and inflammatory
      cytokines. However, it is still not clear whether Abeta needs a prestimulated
      environment to exert its proinflammatory potential. Advanced glycation
      endproducts (AGEs), protein-bound oxidation products of sugars, have been shown
      to accumulate in senile plaques and could induce a silent but chronic
      inflammation in the AD brain. We tested whether Abeta acts as an amplifier of a
      submaximal proinflammatory response initiated by exposure to chicken egg albumin
      AGE, lipopolysaccharide or interferon-gamma. Synthetic Abeta was used to produce
      three different samples (Abeta-fibrilar; Abeta-aggregated; Abeta-AGE), which were
      characterized for beta-sheeted fibrils by the thioflavin-T test and electron
      microscopy. As markers of microglial activation, nitric oxide, interleukin-6,
      macrophage-colony stimulation factor and tumour necrosis factor-alpha production
      was measured. All three Abeta samples alone could not induce a detectable
      microglial response. The combination of Abeta preparations, however, with the
      coinducers provoked a strong microglial response, whereby Abeta-AGE and fibrilar
      Abeta were more potent inflammatory signals than aggregated Abeta. Thus, Abeta in
      senile plaques can amplify microglial activation by a coexisting submaximal
      inflammatory stimulus. Hence, anti-inflammatory therapeutics could either target
      the primary proinflammatory signal (e.g. by limiting AGE-formation by AGE
      inhibitors or cross-link breakers) or the amplifyer Abeta (e.g. by limiting Abeta
      production by beta- or gamma-secretase inhibitors).

PMID- 12603272
TI  - A hVIPR transgene as a novel tool for the analysis of circadian function in the
      mouse suprachiasmatic nucleus.
AB  - A mouse bearing a novel transgene encoding the human VPAC2 receptor (hVIPR; Shen
      et al. (2000) PNAS, 97, 11575-11580) was used to investigate circadian function
      in the hypothalamic suprachiasmatic nuclei (SCN). Neurons expressing hVPAC2R,
      detected by a beta-galactosidase (beta-GAL) tag, have a distinct distribution
      within the SCN, closely matching that of neurophysin (NP) neurons and extending
      into the region of peptide histidine isoleucine (PHI) cells. In common with NP
      and PHI cells, neurons expressing hVPAC2R are circadian in nature, as revealed by
      synchronous rhythmic expression of mPERIOD (mPER) proteins. A population of SCN
      cells not expressing PHI, NP or hVPAC2R exhibited circadian PER expression
      antiphasic with the rest of the SCN. Nocturnal light exposure induced mPER1 in
      the ventral SCN and mPER2 widely across the nucleus. Induction of nuclear mPER2
      in hVPAC2R cells confirmed their photic responsiveness. Having established their
      circadian properties, we tested the utility of SCN neurons expressing the hVIPR
      transgene as functionally and anatomically explicit markers for SCN tissue
      grafts. Prenatal SCN tissue from hVIPR transgenic pups survived transplantation
      into adult CD1 mice, and expressed beta-GAL, PER and PHI. Over a series of
      studies, hVIPR transgenic SCN grafts restored circadian activity rhythms to 17 of
      72 arrhythmic SCN lesioned recipients (23.6%). By using heterozygous hVIPR
      transgenic grafts on a heterozygous Clock mutant background we confirmed that
      restored activity rhythms were conferred by the donor tissue. We conclude that
      the hVIPR transgene is a powerful and flexible tool for examination of circadian
      function in the mouse SCN.

PMID- 12603273
TI  - Analysis of penetrance and expressivity during ontogenesis supports a stochastic
      choice of zebrafish odorant receptors from predetermined groups of receptor
      genes.
AB  - Olfactory receptor neurons select a single odourant receptor gene for expression
      out of a large gene family. The mechanisms of this extreme selectivity are
      largely unknown. We have determined in detail the developmental expression
      dynamics of a representative subset of the zebrafish odourant receptor
      repertoire, using in situ hybridization analysis. We have thus generated a
      dataset, which allows us to test hypotheses of odourant receptor gene regulation.
      The receptors chosen belong to four different groups with respect to ontogenetic
      onset of expression (onset groups). Statistical analysis of the data supports a
      model in which the final choice of an individual odourant receptor gene occurs
      stochastically from within a group of genes sharing a deterministically defined
      onset of expression. Genomic mapping revealed a pronounced correlation of onset
      of expression with genomic neighbourhood. During a protracted juvenile
      developmental period individual regulatory influences seem to modify the
      expression of odourant receptor genes, a notable example being a transient
      decrease in expressivity of two odourant receptor genes.

PMID- 12603274
TI  - Long-term potentiation of glutamatergic synaptic transmission induced by
      activation of presynaptic P2Y receptors in the rat medial habenula nucleus.
AB  - A novel form of long-term potentiation of glutamatergic synaptic transmission is
      described in the rat medial habenula nucleus. It occurs when uridine 5'
      triphosphate is bath applied at low micromolar concentrations and is prevented by
      Reactive Blue 2, suggesting that it is mediated by P2Y4 receptors. Uridine 5'
      diphosphate can also cause such a Reactive Blue 2-sensitive potentiation, but at
      higher concentrations (200 microm), suggesting that this might also be an effect
      on the relatively uridine 5'-diphosphate-insensitive P2Y4 receptor. The
      potentiation is due to an increase in presynaptic release probability. It
      requires neither depolarization nor calcium influx postsynaptically and is thus
      probably non-Hebbian. When potentiation due to low concentrations of uridine 5'
      triphosphate is inhibited in the presence of Reactive Blue 2, uridine 5'
      triphosphate causes instead a significant inhibition of glutamate release. We
      suggest that this inhibition may be mediated by a Reactive Blue 2-insensitive
      P2Y2-like receptor. At higher concentrations of uridine 5'-triphosphate (200
      micro m), the inhibitory effect dominates such that even in the absence of
      Reactive Blue 2 no potentiation is seen.

PMID- 12603275
TI  - Attenuation of sucrose reinforcement in dopamine D1 receptor deficient mice.
AB  - Dopaminergic systems are thought to mediate the rewarding and reinforcing effects
      of palatable food. However, the relative contribution of different dopamine
      receptor subtypes is not clear. We used dopamine D1 receptor deficient mice (D1 
      /-) and their wild-type and heterozygous littermates to study the role of the D1
      receptor in palatable food reinforced behaviour using operant responding and free
      access paradigms. Non-deprived mice were trained to press a lever for sucrose
      pellets under three schedules of reinforcement including fixed ratios (FR-1 and
      FR-4) and a progressive ratio (PR). Responding on one lever was reinforced by the
      delivery of a sucrose pellet or solution while responding on a second lever had
      no programmed consequences. Initially, D1 mutant mice took longer to learn to
      discriminate between the two levers and had significantly lower operant
      responding for sucrose pellets and solution than wild-type and heterozygous mice
      under all schedules of reinforcement. Food deprivation enhanced responding on the
      active lever in all mice although it remained significantly lower in D1 -/- mice
      than in control mice. Following extinction of sucrose reinforcement and reversal
      of the levers, D1 -/- mice showed deficits in extinguishing and reversing
      previously learned responses. Home cage intake and preference of sucrose pellets
      and solutions when given under free-choice access paradigms were similar among
      the groups. These results suggest that the dopamine D1 receptor plays a role in
      the motivation to work for reward (palatable food) but not in reward perception
      and is critical in learning new but relevant information and discontinuing
      previously learned responses.

PMID- 12603276
TI  - Local energy depletion in the basal forebrain increases sleep.
AB  - Sleep saves energy, but can brain energy depletion induce sleep? We used 2,4
      dinitrophenol (DNP), a molecule which prevents the synthesis of ATP, to induce
      local energy depletion in the basal forebrain of rats. Three-hour DNP infusions
      induced elevations in extracellular concentrations of lactate, pyruvate and
      adenosine, as well as increases in non-REM sleep during the following night.
      Sleep was not affected when DNP was administered to adjacent brain areas,
      although the metabolic changes were similar. The amount and the timing of the
      increase in non-REM sleep, as well as in the concentrations of lactate, pyruvate
      and adenosine with 0.5-1.0 mM DNP infusion, were comparable to those induced by 3
      h of sleep deprivation. Here we show that energy depletion in localized brain
      areas can generate sleep. The energy depletion model of sleep induction could be
      applied to in vitro research into the cellular mechanisms of prolonged
      wakefulness.

PMID- 12603277
TI  - Saccadic eye movements evoked by microstimulation of striate cortex.
AB  - Experiments were performed to assess the excitability of neural elements
      activated while inducing saccadic eye movements electrically from different
      cortical layers of striate cortex (area V1) in rhesus monkeys. Excitability was
      assessed by measuring current thresholds, saccadic latencies, chronaxies, and the
      effectiveness of anode-first vs. cathode-first pulses. Minimum current thresholds
      for the evocation of saccades (i.e. less than 5 microA) were observed when the
      deepest layers of V1 were stimulated. The shortest saccadic latencies were also
      observed at these depths. The shortest latency at 10 times the threshold current
      was 49 ms on average. The chronaxies of the elements mediating saccades were less
      in deep V1 (i.e. 0.17 ms) than in superficial V1 (i.e. 0.23 ms). Anode-first
      pulses were more effective at evoking saccades from superficial V1, whereas
      cathode-first pulses were more effective at evoking saccades from deep V1. These
      results indicate that the excitability properties of superficial and deep V1 are
      distinct for the generation of saccades. Moreover, the excitability of elements
      mediating saccades in V1 of monkeys is comparable to that of elements mediating
      phosphenes in human V1.

PMID- 12603278
TI  - Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM
      expression in the adult rat dentate gyrus.
AB  - Chronic restraint stress has been shown to induce structural remodelling
      throughout the interconnected dentate gyrus-CA3 fields. To find out how this
      stressor affects the rate of adult hippocampal neurogenesis, we subjected rats to
      acute or chronic restraint stress and assessed the proliferation, survival and
      differentiation of newly born cells in the dentate gyrus. We also examined
      polysialylated neural cell adhesion molecule expression, a molecule normally
      expressed in immature neurons and important for morphological plasticity. The
      results show that acute restraint stress did not change either the proliferation
      of dentate gyrus precursor cells or the expression of polysialylated neural cell
      adhesion molecule, whereas 3 weeks of chronic restraint stress suppressed
      proliferation by 24% and increased polysialylated neural cell adhesion molecule
      expression by 40%. The study was extended for an additional 3 weeks to trace the
      survival and development of the cells born after the initial 3 weeks of
      restraint. Rats subjected to 6 weeks of daily restraint stress exhibited
      suppressed cell proliferation and attenuated survival of the recently born cells
      after the extended time course, resulting in a 47% reduction of granule cell
      neurogenesis. Furthermore, 6 weeks of chronic stress significantly reduced the
      total number of granule cells by 13% and the granule cell layer volume by 5%.
      Expression of polysialylated neural cell adhesion molecule followed a biphasic
      time course, displaying a significant up-regulation after 3 weeks of daily
      restraint stress that was lost after 6 weeks of stress. These studies may help us
      understand the basis for hippocampal shrinkage and raise questions about the
      ultimate reversibility of the effects of chronic stress.

PMID- 12603279
TI  - Functional NMDA receptor channels generated by NMDAR2B gene transfer in rat
      cerebellar Purkinje cells.
AB  - The adult cerebellar Purkinje cell is an exceptional neuron in the central
      nervous system in that it expresses high levels of NMDAR1 (NR1) mRNA without
      expressing any NMDAR2 (NR2) mRNAs. It has no functional NMDA receptor (NMDAR)
      channels, although it receives enormous numbers of excitatory inputs. Despite the
      high level of NR1 mRNA expression, the presence and localization of NR1 protein
      in mature Purkinje cells are controversial. To examine the presence of NR1
      protein and its ability to form functional NMDARs, we expressed the NR2B subunit
      in rat mature Purkinje neurons by Sindbis viral-mediated gene transfer. The
      recombinant virus encoding both the NR2B and enhanced green fluorescent protein
      (GFP) genes (designated as SIN-EG-NR2B) infected Purkinje cells without infecting
      glial cells. GFP fluorescence was detected in the soma and throughout dendrites
      of Purkinje cells 18-24 h postinfection. In most of GFP-positive cells, the
      expression of NR2B protein was detected by immunostaining with NR2B-specific
      antibodies. In Purkinje cells infected with SIN-EG-NR2B, the iontophoretic
      application of NMDA induced prominent NMDAR-mediated current responses,
      indicating that the exogenous NR2B was assembled with endogenous NR1 to form
      functional NMDARs. Furthermore, NMDAR-mediated synaptic currents were detected at
      both the climbing fibre and parallel fibre synapses in infected Purkinje cells.
      Thus, the mature Purkinje cell produces NR1 protein that is ready to combine with
      NR2 to form functional NMDARs in excitatory synapses.

PMID- 12603280
TI  - Synaptic localization of the glutamate receptor subunit GluR2 in the rat nucleus
      tractus solitarii.
AB  - The GluR2 subunit controls several key features of the alpha amino-3-hydroxy-5
      methyl-4-isoxazole propionate (AMPA)-type glutamate receptor including calcium
      permeability, rectification and gating. In the present study,
      electrophysiological recordings and immunocytochemistry were used to document the
      synaptic localization of GluR2 in the rat nucleus tractus solitarii (NTS).
      Synaptic responses recorded in NTS neurons exhibited linear current-voltage
      relationships suggestive of GluR2-containing AMPA receptor responses.
      Furthermore, after antigen retrieval GluR2 immunolabelling in the NTS mainly
      consisted of small puncta. Double-labelling experiments showed that these GluR2
      puncta were apposed to glutamatergic synaptic terminals identified by type II
      vesicular glutamate transporter immunoreactivity. These results indicate that NTS
      glutamatergic synapses are endowed with AMPA receptors which contain the GluR2
      subunit and are therefore likely to be both calcium-impermeable and slowly
      desensitizing.

PMID- 12603281
TI  - Inhibition of hippocampal Jun N-terminal kinase enhances short-term memory but
      blocks long-term memory formation and retrieval of an inhibitory avoidance task.
AB  - Learning initiates a series of plastic events the occurrence of which are
      required for the storage of information related to the training experience.
      Several lines of evidence indicate that, in the rat hippocampus, different
      members of the family of mitogen-activated protein kinases (MAPK) play a key role
      in the onset of such plastic events. Using SP600125, the newly developed
      inhibitor of the MAPK c-Jun amino-terminal kinase (JNK), we show a direct
      involvement of this protein kinase in mnemonic processes. The intra-CA1 infusion
      of SP600125, at a dose that in naive animals significantly reduced the
      phosphorylation levels of c-Jun without affecting the activity of ERK1/2 or p38
      MAPK, enhanced short-term memory (STM) but blocked long-term memory (LTM)
      formation and retrieval of an inhibitory avoidance learning task. No action of
      this drug on locomotor/exploratory activity or general anxiety state could be
      detected. The significance of these results is discussed in the context of others
      describing the independence of LTM from STM.

PMID- 12603282
TI  - Pairing elevation of [cyclic GMP] with inhibition of PKA produces long-term
      depression of glutamate release from isolated rat hippocampal presynaptic
      terminals.
AB  - Data suggest both presynaptic and postsynaptic changes contribute to activity
      dependent long-term synaptic plasticity. We have shown that pairing elevation of
      intracellular [cyclic GMP], using the type V phosphodiesterase inhibitor
      zaprinast, with inhibition of cyclic AMP-dependent protein kinase (PKA), is
      sufficient to elicit chemical long-term depression (CLTD) of synaptic
      transmission at Schaffer collateral-CA1 and mossy fibre-CA3 synapses in rat
      hippocampus. CLTD does not require synaptic activity, and selective postsynaptic
      drug injections do not affect it, suggesting it is presynaptically induced and
      expressed. To directly evaluate this hypothesis, we tested whether CLTD of
      transmitter release can be expressed in isolated presynaptic nerve terminals.
      Presynaptic nerve terminals (synaptosomes) were isolated from rat hippocampi by
      Percoll density gradient centrifugation. Synaptosomes were loaded with
      [3H]glutamate, and basal and depolarisation-induced release of [3H]glutamate
      measured in control medium versus medium containing zaprinast (20 microm) plus or
      minus the PKA inhibitor H-89 (10 microm). Zaprinast produced a significant
      decrease in basal [3H]glutamate release. However, only combining zaprinast with H
      89 significantly depressed K+-evoked [3H]glutamate release. After a 20-min drug
      washout, basal release returned to normal in all conditions, but K+-evoked
      [3H]glutamate release was persistently reduced only by the combination of
      zaprinast plus H-89. Long-term reduction of [3H]glutamate release from
      synaptosomes was completely prevented by the PKG inhibitor KT5823 (5 microm).
      These data demonstrate the existence of a presynaptic, cyclic GMP-PKG dependent
      cascade capable of expressing LTD of glutamate release from isolated hippocampal
      nerve terminals.

PMID- 12603283
TI  - Vagal modulation of nociception is mediated by adrenomedullary epinephrine in the
      rat.
AB  - Vagal afferent activity modulates mechanical nociceptive threshold and
      inflammatory mediator-induced hyperalgesia, effects that are mediated by the
      adrenal medulla. To evaluate the role of epinephrine, the major hormone released
      from the adrenal medulla, the beta2-adrenergic receptor antagonist ICI 118,551
      was chronically administered to vagotomized rats and epinephrine to normal rats.
      In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated
      vagotomy-induced enhancement of bradykinin hyperalgesia but had no effect on
      nociceptive threshold. In normal rats, chronic epinephrine had the opposite
      effect, enhancing bradykinin hyperalgesia. Like vagotomy-, epinephrine-induced
      enhancement of hyperalgesia developed slowly, taking 14 days to reach its peak.
      Vagotomy induced a chronic elevation in plasma concentrations of epinephrine. We
      suggest that ongoing activity in vagal afferents inhibits the release of
      epinephrine from the adrenal medulla. Chronically elevated levels of epinephrine,
      occurring after vagotomy, desensitize peripheral beta2-adrenergic receptors and
      lead to enhancement of bradykinin hyperalgesia. The ability of prolonged elevated
      plasma levels of epinephrine to sensitize bradykinin receptors could contribute
      to chronic generalized pain syndromes.

PMID- 12603286
TI  - CSF tau protein and beta-amyloid (1-42) in Alzheimer's disease diagnosis:
      discrimination from normal ageing and other dementias in the Greek population.
AB  - Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide
      (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's
      disease (AD). In order to evaluate their diagnostic potential in clinical
      practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15
      patients with non-AD neurodegenerative dementias (NAND), six patients with
      vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek
      origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in
      the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and
      a sensitivity of 82% in differentiating AD from normal ageing, whilst the
      corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67
      and 82%, respectively. Tau was better in differentiating AD, from normal ageing
      (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and
      VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values
      comparable or even better than tau for differentiating AD from normal ageing
      (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and
      definitely better than any of the candidate markers alone, for differentiating AD
      from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau
      and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful
      adjuvant to clinical criteria for dementia diagnosis.

PMID- 12603287
TI  - Transcranial Doppler and risk of recurrence in patients with stroke and patent
      foramen ovale.
AB  - The importance of patent foramen ovale (PFO) in stroke of unknown cause remains
      disputed, as PFO may be present in up to 20% of normal people and in a high
      proportion of patients with non-vascular disorders. Recent evidence suggests that
      the amount of right-to-left shunt (RLS) may be the crucial factor for stroke
      occurrence and relapse. The aim of the study was to assess predictors of
      recurrence in PFO-related stroke patients with particular emphasis on amount of
      shunting. Patients less than 61 years old who had been admitted for a PFO-related
      stroke within the previous 5 years, were re-evaluated on a follow-up visit. The
      clinical syndrome, residual disability, vascular risk factors and number of
      relapses as the index event were assessed. RLS sizing was semi-quantitatively
      performed with saline-enhanced transcranial Doppler (TCD), by assuming a cut-off
      of more or less 10 bubbles recorded in the cerebral vessels as a criterion to
      discriminate large versus small shunt, respectively. Thereafter patients were
      prospectively followed-up for a median time of 23 months. Total follow-up was 61
      months. Fifty-nine patients (M/F = 23/36, mean age 43 +/- 13) were studied.
      Overall there were 23 relapses in 13 patients. The amount of shunting was the
      only significant independent variable associated with relapse: at the end of the
      follow-up period the recurrence rate was 0.66 and 8.2% per patient per year in
      patients with small and large shunt, respectively. This difference was
      statistically significant (chi2 = 10.39, P = 0.0012; OR 17.05, 95% CI 2.10
      755.22). In patients with PFO-related stroke, the amount of RLS as assessed with
      TCD is the only independent predictor of relapse. PFO sizing is mandatory in
      patients with PFO.

PMID- 12603288
TI  - The tolerability and efficacy of entacapone over 3 years in patients with
      Parkinson's disease.
AB  - The long-term safety and efficacy of the catechol-O-methyltransferase (COMT)
      inhibitor entacapone was investigated in a 3-year open-label extension of the 6
      month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out
      following this study, 132 patients with Parkinson's disease (PD) experiencing
      motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor
      received additional therapy with entacapone 200 mg, administered with each dose
      of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness
      (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only
      19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred
      shortly after initiation of entacapone, and these could be managed by levodopa
      down-adjustment. The mean duration of benefit of a single dose of levodopa
      increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained
      prolonged for the whole study. At the end of the study, the mean daily dose of
      levodopa was significantly decreased from baseline (from 737 to 696 mg; P <
      0.05). The patients' global assessment indicated that 69% of patients improved
      when given entacapone and this proportion was maintained until the end of the
      study (64%). There was a significant worsening of disability upon withdrawal of
      entacapone. In conclusion, entacapone given in combination with levodopa, has a
      good long-term safety profile and a sustained beneficial effect in patients with
      PD with motor fluctuations.

PMID- 12603289
TI  - Depression and anxiety disorders associated with headache frequency. The Nord
      Trondelag Health Study.
AB  - The aim of this large cross-sectional population-based study was to examine the
      association between migraine, non-migrainous headache and headache frequency with
      depression, and anxiety disorders. From 1995 to 1997, all 92 566 inhabitants aged
      20 years and above in Nord-Trondelag County in Norway were invited to participate
      in the Nord-Trondelag Health Study ('Helseundersokelsen i Nord-Trondelag' = HUNT
      2). A total of 64 560 participated, whereof 51 383 subjects (80%) completed a
      headache questionnaire that was included. Of these 51 383 individuals, 47 257
      (92%) completed the depression subscale items and 43 478 (85%), the anxiety
      subscale items of the Hospital Anxiety and Depression Scale (HADS). Associations
      were assessed in multivariate analyses, estimating prevalence odds ratios (OR)
      with 95% confidence intervals (CI). Depression and anxiety disorders as measured
      by HADS, were significantly associated with migraine (OR = 2.7, 95% CI 2.3-3.2;
      OR = 3.2, 95% CI 2.8-3.6) and non-migrainous headache (OR = 2.2, 95% CI 2.0-2.5;
      OR = 2.7, 95% CI 2.4-3.0) when compared with headache-free individuals. The
      association was stronger for anxiety disorders than for depression. The ORs for
      depression and anxiety disorders amongst both migraine and non-migrainous
      sufferers increased with increasing headache frequency. Depression and anxiety
      disorders are associated with both migraine and non-migrainous headache, and this
      association seems more dependent on headache frequency than diagnostic category.

PMID- 12603290
TI  - Progressive visual loss due to a muslinoma--report of a case and review of the
      literature.
AB  - Intracranial internal carotid artery (ICA) aneurysms are frequently treated
      either by microsurgical clipping of the aneurysm neck, by endovascular coiling of
      the aneurysm sac or by balloon occlusion of the parent vessel. For some broad
      based aneurysms that may not be suitable for any of these options, microsurgical
      wrapping of the aneurysm wall with muslin or gauze rarely is applied. We report
      the case of a patient who suffered from a minor stroke because of arterio
      arterial embolism from an intracranial ICA aneurysm. The aneurysm was treated by
      wrapping muslin material. After 12 months, he experienced progressive visual
      loss. Cranial magnetic resonance testing magnetic resonance tomography (MRT)
      revealed a granulomatous inflammation surrounding the site of the aneurysm and
      affecting optochiasmatic structures. A muslin-induced optic neuropathy is a rare
      but serious complication of a chronic inflammatory reaction in response to muslin
      or gauze used in intracranial aneurysm wrapping. If the foreign body inflammatory
      reaction to muslin or gauze leads to a mass formation, the term muslinoma or
      gauzoma is applied. Various treatment strategies include surgery, steroids and
      cyclophosphamide, but recovery of the vision is not predictable. As a
      consequence, muslin or cotton gauze should only be applied with great caution in
      neurovascular surgery.

PMID- 12603291
TI  - Familial Parkinson's disease: a community-based study.
AB  - Genetic factors seem to be important in the pathogenesis of Parkinson's disease
      (PD). It is however, still controversial whether these factors also are reflected
      in a familial aggregation of PD. The aim of this study was to investigate the
      frequency of PD patients with a positive PD family history compared with two
      control groups. The included 245 PD patients were examined by neurologists and
      information was obtained through a semi-structured interview. The patients and
      the control groups were examined for the frequency of PD and dementia in their
      families. The 245 patients with PD were included in this study. A positive PD
      family history could be obtained in 53 (21.6%) patients. The frequency was three-
      and four-fold increased as compared with the control groups (P < 0.001). Age at
      onset of disease was not different among patients with and without PD in the
      family. The frequency of dementia did not differ in the family of individuals
      with and without PD (P > 0.1). As a conclusion our study of PD in a community
      based population supports previous reports of a three- to fourfold increased risk
      for PD in the families of patients with the disease. Our results indicate that
      the familial aggregation of the disease is independent of the age of the proband.

PMID- 12603292
TI  - Neurological disorders associated with Mycoplasma pneumoniae infection.
AB  - Neurological syndromes caused by Mycoplasma pneumoniae (MP) infection are
      occasionally reported in adults, usually in the post-infectious period, and three
      computed tomography documented cases have recently appeared in this journal. Here
      we present the cases of three young women with recent respiratory tract infection
      caused by MP some weeks prior to neurological complication documented by magnetic
      resonance imaging. Two cases suffered from demyelinating disorders of the central
      nervous system (CNS). The other case had a middle cerebral artery thrombosis, a
      rare complication of MP infection. Another potential risk factor for stroke in
      the latter case was the use of oral contraceptives. Recent infection with MP is
      discussed as a risk factor for cerebrovascular disorders and CNS demyelinating
      diseases.

PMID- 12603293
TI  - Prolactinomas, dopamine agonists and headache: two case reports.
AB  - Headache is a common problem in patients with pituitary tumours. Small pituitary
      lesions can cause debilitating headache, suggesting that the size of the
      pituitary tumour may not be the only causal factor in pituitary-related headache.
      We present two cases of prolactinoma-associated headache. The first case has a
      clinical diagnosis of short-lasting unilateral headache attacks with conjunctival
      injection and tearing (SUNCT). The second case has a clinical diagnosis of
      hemicrania continua and idiopathic stabbing headache. In each case, the
      administration of dopamine agonists has led to an exacerbation of symptoms. We
      review the relevant literature to understand the pathophysiological implications
      of these cases.

PMID- 12603294
TI  - Early predictors of post-concussion symptoms in patients with mild head injury.
AB  - A small proportion of patients with mild head injury (MHI) develop post
      concussion symptoms (PCSs). We searched simple measures for the early detection
      of patients who are probable to develop PCSs. We recorded signs and symptoms,
      history of previous diseases, medications, and lifestyle factors and measured
      serum protein S-100B on admission in a series of 172 consecutive MHI patients
      admitted into the emergency room of a general hospital. A modified Rivermead Post
      Concussion Symptoms Questionnaire was used to identify the patients with and
      without PCSs 1 month after the injury. We identified 37 patients with MHI who
      developed PCSs (22%). Odds ratios (OR) and 95% confidence intervals (CI) after
      adjustment for possible confounding variables were calculated by logistic
      regression. Independent early risk factors for PCSs in the MHI patients were
      skull fracture (OR 8.0, 95% CI 2.6-24.6), serum protein S-100B >/= 0.50 microg/l
      (OR 5.5, 95% CI 1.6-18.6), dizziness (OR 3.1, 95% CI 1.2-8.0), and headache (OR
      2.6, 95% CI 1.0-6.5). Serum protein S-100B proved to be a specific, but not
      sensitive predictor of PCSs. The presence of skull fracture, elevated serum
      protein S-100B, dizziness, and headache may help the emergency room physician to
      identify patients at risk of PCSs and to refer them for further examination and
      follow-up.

PMID- 12603295
TI  - Motor-axonal polyneuropathy associated with hepatitis C virus.
AB  - The association between hepatitis C virus (HCV) infection, the presence of mixed
      cryoglobulinemia and peripheral neuropathy is well-documented (Apartis et al.,
      1996). HCV is the chief cause of essential mixed cryoglobulinemia (type II
      cryoglobulinemia) with cryoglobulins present in up to half of patients with HCV
      infection (Akriviadis et al., 1997). More recently it has been stated that
      peripheral polyneuropathy may be associated with HCV chronic infection without
      mixed cryoglobulinemia (Lidove et al., 2001). Patients usually present with a
      clinical and electrophysiology--predominantly sensory axonopathies (Apartis et
      al., 1996; Heckmann et al., 1999) or less frequently with fulminating vasculitis
      and mononeuropathy multiplex syndrome (David et al., 1996)--especially when
      associated with cryoglobulinemia. We report, for the first time, the association
      between pure motor-axonal polyneuropathy and HCV infection without
      cryoglobulinemia.

PMID- 12603296
TI  - Isolated peroneal nerve palsy complicating weight loss due to anterior pituitary
      hypofunction.

PMID- 12603297
TI  - Bickerstaff's brainstem encephalitis, Miller Fisher syndrome and Guillain-Barre
      syndrome overlap with negative anti-GQ1b antibodies.

PMID- 12603298
TI  - Tripterugium wilfordii multiglucoside-treated case of sensory perineuritis.

PMID- 12603299
TI  - Multiple sclerosis manifesting as a Brown-Sequard syndrome.

PMID- 12603300
TI  - Is the internet transforming the physician-consumer relationship? Preliminary
      data in a neurological setting.

PMID- 12603311
TI  - Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and
      asparaginyl hydroxylation.
AB  - To sustain life mammals have an absolute and continual requirement for oxygen,
      which is necessary to produce energy for normal cell survival and growth. Hence,
      maintaining oxygen homeostasis is a critical requirement and mammals have evolved
      a wide range of cellular and physiological responses to adapt to changes in
      oxygen availability. In the past few years it has become evident that the
      transcriptional protein complex hypoxia-inducible factor (HIF) is a key regulator
      of these processes. In this review we will focus on the way oxygen availability
      regulates HIF proteins and in particular we will discuss the way oxygen-dependent
      hydroxylation of specific amino acid residues has been demonstrated to regulate
      HIF function at the level of both protein stability and transcriptional potency.

PMID- 12603312
TI  - The subtle side to hypoxia inducible factor (HIFalpha) regulation.
AB  - The transcription factor hypoxia inducible factor alpha-subunit (HIFalpha) is
      pivotal in the cellular response to the stress of hypoxia. Post-translational
      modification of HIFalpha by hydroxylase enzymes has recently been identified as a
      key "oxygen sensing" mechanism within the cell. The absence of the substrate
      oxygen prevents the hydroxylases from modifying HIFalpha during hypoxia and
      allows dramatic up-regulation of both HIFalpha protein stability and
      transcriptional activation capability. In addition to this oxygen-dependent
      response, increased HIFalpha protein levels and/or enhanced transcriptional
      activity during normoxic conditions can be stimulated by various receptor
      mediated factors such as growth-factors and cytokines (insulin, insulin-like
      growth factor 1 or 2, endothelial growth factor, tumour necrosis factor alpha,
      angiotensin-2). Oncogenes are also capable of HIFalpha activation. This induction
      is generally less intense than that stimulated by hypoxia and although not fully
      elucidated, appears to occur via hypoxia-independent, receptor-mediated signal
      pathways involving either phosphatidyl-inositol-3-kinase/Akt or mitogen activated
      protein kinase (MAPK) pathways, depending on the cell-type. Activation of Akt
      increases HIFalpha protein synthesis in the cell and results in increased
      HIFalpha protein and transcriptional activity. MAPK also activates HIFalpha
      protein synthesis and additionally may potentiate HIF1alpha transcriptional
      activity via a separate mechanism that does not necessarily require protein
      stabilization. Here we review the mechanisms and function of receptor-mediated
      signals in the multifaceted regulation of HIFalpha.

PMID- 12603313
TI  - The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily.
AB  - The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) exporter superfamily
      (TC #2.A.66) consists of four previously recognized families: (a) the ubiquitous
      multi-drug and toxin extrusion (MATE) family; (b) the prokaryotic polysaccharide
      transporter (PST) family; (c) the eukaryotic oligosaccharidyl-lipid flippase
      (OLF) family and (d) the bacterial mouse virulence factor family (MVF). Of these
      four families, only members of the MATE family have been shown to function
      mechanistically as secondary carriers, and no member of the MVF family has been
      shown to function as a transporter. Establishment of a common origin for the
      MATE, PST, OLF and MVF families suggests a common mechanism of action as
      secondary carriers catalyzing substrate/cation antiport. Most protein members of
      these four families exhibit 12 putative transmembrane alpha-helical segments
      (TMSs), and several have been shown to have arisen by an internal gene
      duplication event; topological variation is observed for some members of the
      superfamily. The PST family is more closely related to the MATE, OLF and MVF
      families than any of these latter three families are related to each other. This
      fact leads to the suggestion that primordial proteins most closely related to the
      PST family were the evolutionary precursors of all members of the MOP
      superfamily. Here, phylogenetic trees and average hydropathy, similarity and
      amphipathicity plots for members of the four families are derived and provide
      detailed evolutionary and structural information about these proteins. We show
      that each family exhibits unique characteristics. For example, the MATE and PST
      families are characterized by numerous paralogues within a single organism (58
      paralogues of the MATE family are present in Arabidopsis thaliana), while the OLF
      family consists exclusively of orthologues, and the MVF family consists primarily
      of orthologues. Only in the PST family has extensive lateral transfer of the
      encoding genes occurred, and in this family as well as the MVF family,
      topological variation is a characteristic feature. The results serve to define a
      large superfamily of transporters that we predict function to export substrates
      using a monovalent cation antiport mechanism.

PMID- 12603314
TI  - Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing
      with alphavbeta3 integrin for vitronectin binding.
AB  - Functional cooperation between integrins and growth factor receptors has been
      reported for several systems, one of which is the modulation of insulin signaling
      by alphavbeta3 integrin. Plasminogen activator inhibitor type-1 (PAI-1), competes
      with alphavbeta3 integrin for vitronectin (VN) binding. Here we report that PAI
      1, in a VN-dependent manner, prevents the cooperation of alphavbeta3 integrin
      with insulin signaling in NIH3T3 fibroblasts, resulting in a decrease in insulin
      induced protein kinase B (PKB) phosphorylation, vascular endothelial growth
      factor (VEGF) expression and cell migration. Insulin-induced HUVEC migration and
      angiotube formation was also enhanced in the presence of VN and this enhancement
      is inhibited by PAI-1. By using specific PAI-1 mutants with either VN binding or
      plasminogen activator (PA) inhibiting activities ablated, we have shown that the
      PAI-1-mediated interference with insulin signaling occurs through its direct
      interaction with VN, and not through its PA neutralizing activity. Moreover,
      using cells deficient for uPA receptor (uPAR) we have demonstrated that the
      inhibition of PAI-1 on insulin signaling is independent of uPAR-VN binding. These
      results constitute the first demonstration of the interaction of PAI-1 with the
      insulin response.

PMID- 12603315
TI  - Secretion of pigment epithelium-derived factor. Mutagenic study.
AB  - Pigment epithelium-derived factor (PEDF), a neurotrophic and antiangiogenic
      protein, is an extracellular component of the retinal interphotoreceptor matrix
      which has been shown to be secreted by human fetal retinal pigment epithelial
      cells. It belongs to the serpin superfamily and contains the typical exposed
      reactive center loop. The function of this loop is still unknown. In this study
      we used site-directed mutagenesis of the cDNA encoding PEDF to show that (a)
      truncation of the C-terminal tail (Pro415-Pro418) of PEDF, (b) deletion of the
      Pro373-Ala380 segment that resides within the reactive center loop of the
      protein, and (c) alanine substitution of amino-acid residues Asn391-Thr403
      located within its hydrophobic core inhibit PEDF secretion, but not its
      transcription, by cells transfected with the various PEDF cDNAs. On the basis of
      the crystal structure of PEDF, these mutations are presumed to alter the protein
      conformation, suggesting that conservation of the 3D structure of PEDF is
      essential for its secretion. In addition, we show that replacement of Gly376 and
      Leu377 with alanine prevents PEDF secretion. As these two residues are located
      within the highly exposed segment of the reactive center loop, we propose a novel
      function for this loop in PEDF. Our results imply that the reactive center loop,
      specifically Gly376 and Leu377, is involved in the interaction of PEDF with
      components of the quality control system in the endoplasmic reticulum, thus
      ensuring its efficient secretion.

PMID- 12603316
TI  - Calreticulin-melatonin. An unexpected relationship.
AB  - Increasing evidence suggests that melatonin can exert some effect at nuclear
      level. Previous experiments using binding techniques clearly showed the existence
      of specific melatonin binding sites in cell nucleus of rat liver. To further
      identify these sites, nuclear extracts from rat hepatocytes were treated with
      different percentages of ammonium sulfate and purified by affinity
      chromatography. Subsequent ligand blot analysis shows the presence of two
      polypeptides of approximately 60 and approximately 74 kDa that bind specifically
      to melatonin. N-Terminal sequence analysis showed that the 60 kDa protein shares
      a high homology with rat calreticulin, whereas the 74 kDa protein shows no
      homology with any known protein. The binding of melatonin to calreticulin was
      further characterized incubating 2-[125I]melatonin with recombinant calreticulin.
      Binding kinetics show a Kd = 1.08 +/- 0.2 nm and Bmax = 290 +/- 34 fmol.mg
      protein-1, compatible with other binding sites of melatonin in the cell. The
      presence of calreticulin was further identified by Western blot analysis, and the
      lack of endoplasmic reticulum contamination in our material was assessed by
      Western blot and immunostaining with anti-calnexin Ig. The results suggest that
      calreticulin may represent a new class of high-affinity melatonin binding sites
      involved in some functions of the indoleamine including genomic regulation.

PMID- 12603317
TI  - The relationship between thermal stability and pH optimum studied with wild-type
      and mutant Trichoderma reesei cellobiohydrolase Cel7A.
AB  - The major cellulase secreted by the filamentous fungus Trichoderma reesei is
      cellobiohydrolase Cel7A. Its three-dimensional structure has been solved and
      various mutant enzymes produced. In order to study the potential use of T. reesei
      Cel7A in the alkaline pH range, the thermal stability of Cel7A was studied as a
      function of pH with the wild-type and two mutant enzymes using different
      spectroscopic methods. Tryptophan fluorescence and CD measurements of the wild
      type enzyme show an optimal thermostability between pH 3.5-5.6 (Tm, 62 +/- 2
      degrees C), at which the highest enzymatic activity is also observed, and a
      gradual decrease in the stability at more alkaline pH values. A soluble
      substrate, cellotetraose, was shown to stabilize the protein fold both at optimal
      and alkaline pH. In addition, unfolding of the Cel7A enzyme and the release of
      the substrate seem to coincide at both acidic and alkaline pH, demonstrated by a
      change in the fluorescence emission maximum. CD measurements were used to show
      that the five point mutations (E223S/A224H/L225V/T226A/D262G) that together
      result in a more alkaline pH optimum [Becker, D., Braet, C., Brumer, H., III,
      Claeyssens, M., Divne, C., Fagerstrom, R.B., Harris, M., Jones, T.A., Kleywegt,
      G.J., Koivula, A., et al. (2001) Biochem. J.356, 19-30], destabilize the protein
      fold both at acidic and alkaline pH when compared with the wild-type enzyme. In
      addition, an interesting time-dependent fluorescence change, which was not
      observed by CD, was detected for the pH mutant. Our data show that in order to
      engineer more alkaline pH cellulases, a combination of mutations should be found,
      which both shift the pH optimum and at the same time improve the thermal
      stability at alkaline pH range.

PMID- 12603318
TI  - On the molecular basis of the recognition of angiotensin II (AII). NMR structure
      of AII in solution compared with the X-ray structure of AII bound to the mAb
      Fab131.
AB  - The high-resolution 3D structure of the octapeptide hormone angiotensin II (AII)
      in aqueous solution has been obtained by simulated annealing calculations, using
      high-resolution NMR-derived restraints. After final refinement in explicit water,
      a family of 13 structures was obtained with a backbone RMSD of 0.73 +/- 0.23 A.
      AII adopts a fairly compact folded structure, with its C-terminus and N-terminus
      approaching to within approximately 7.2 A of each other. The side chains of Arg2,
      Tyr4, Ile5 and His6 are oriented on one side of a plane defined by the peptide
      backbone, and the Val3 and Pro7 are pointing in opposite directions. The
      stabilization of the folded conformation can be explained by the stacking of the
      Val3 side chain with the Pro7 ring and by a hydrophobic cluster formed by the
      Tyr4, Ile5 and His6 side chains. Comparison between the NMR-derived structure of
      AII in aqueous solution and the refined crystal structure of the complex of AII
      with a high-affinity mAb (Fab131) [Garcia, K.C., Ronco, P.M., Verroust, P.J.,
      Brunger, A.T., Amzel, L.M. (1992) Science257, 502-507] provides important
      quantitative information on two common structural features: (a) a U-shaped
      structure of the Tyr4-Ile5-His6-Pro7 sequence, which is the most immunogenic
      epitope of the peptide, with the Asp1 side chain oriented towards the interior of
      the turn approaching the C-terminus; (b) an Asx-turn-like motif with the side
      chain aspartate carboxyl group hydrogen-bonded to the main chain NH group of
      Arg2. It can be concluded that small rearrangements of the epitope 4-7 in the
      solution structure of AII are required by a mean value of 0.76 +/- 0.03 A for
      structure alignment and approximately 1.27 +/- 0.02 A for sequence alignment with
      the X-ray structure of AII bound to the mAb Fab131. These data are interpreted in
      terms of a biological "nucleus" conformation of the hormone in solution, which
      requires a limited number of structural rearrangements for receptor-antigen
      recognition and binding.

PMID- 12603319
TI  - Site-directed mutagenesis of a loop at the active site of E1 (alpha2beta2) of the
      pyruvate dehydrogenase complex. A possible common sequence motif.
AB  - Limited proteolysis of the pyruvate decarboxylase (E1, alpha2beta2) component of
      the pyruvate dehydrogenase (PDH) multienzyme complex of Bacillus
      stearothermophilus has indicated the importance for catalysis of a site (Tyr281
      Arg282) in the E1alpha subunit (Chauhan, H.J., Domingo, G.J., Jung, H.-I. &
      Perham, R.N. (2000) Eur. J. Biochem. 267, 7158-7169). This site appears to be
      conserved in the alpha-subunit of heterotetrameric E1s and multiple sequence
      alignments suggest that there are additional conserved amino-acid residues in
      this region, part of a common pattern with the consensus sequence -YR-H-D-YR-DE-.
      This region lies about 50 amino acids on the C-terminal side of a 30-residue
      motif previously recognized as involved in binding thiamin diphosphate (ThDP) in
      all ThDP-dependent enzymes. The role of individual residues in this set of
      conserved amino acids in the E1alpha chain was investigated by means of site
      directed mutagenesis. We propose that particular residues are involved in: (a)
      binding the 2-oxo acid substrate, (b) decarboxylation of the 2-oxo acid and
      reductive acetylation of the tethered lipoyl domain in the PDH complex, (c) an
      "open-close" mechanism of the active site, and (d) phosphorylation by the E1
      specific kinase (in eukaryotic PDH and branched chain 2-oxo acid dehydrogenase
      complexes).

PMID- 12603320
TI  - Adaptive changes in the expression of nuclear and mitochondrial encoded subunits
      of cytochrome c oxidase and the catalytic activity during hypoxia.
AB  - The effects of physiologically relevant hypoxia on the catalytic activity of
      cytochrome c oxidase (CytOX), mitochondrial gene expression, and both nuclear and
      mitochondrial encoded CytOX mRNA levels were investigated in murine monocyte
      macrophages, mouse C2C12 skeletal myocytes and rat adrenal pheochromocytoma PC12
      cells. Our results suggest a coordinated down regulation of mitochondrial genome
      coded CytOX I and II and nuclear genome-coded CytOX IV and Vb mRNAs during
      hypoxia. Hypoxia also caused a severe decrease in mitochondrial transcription
      rates, and associated decrease in mitochondrial transcription factor A. The
      enzyme from hypoxia exposed cells exhibited altered subunit content as revealed
      by blue native gel electrophoresis. There was a generalized decline in
      mitochondrial function that led to a decrease in total cellular heme and ATP
      pools. We also observed a decrease in mitochondrial heme aa3 content and
      decreased levels of CytOX subunit I, IV and Vb, though the catalytic efficiency
      of the enzyme (TN for cytochrome c oxidase) remained nearly the same. Increased
      glycolytic flux and alterations in the kinetic characteristics of the CytOX might
      be the two mechanisms by which hypoxic cells maintain adequate ATP levels to
      sustain life processes. Reoxygenation nearly completely reversed hypoxia-mediated
      changes in CytOX mRNA contents, rate of mitochondrial transcription, and the
      catalytic activity of CytOX enzyme. Our results show adaptive changes in CytOX
      structure and activity during physiological hypoxia.

PMID- 12603321
TI  - Metabolic flux profiling of Escherichia coli mutants in central carbon metabolism
      using GC-MS.
AB  - We describe here a novel methodology for rapid diagnosis of metabolic changes,
      which is based on probabilistic equations that relate GC-MS-derived mass
      distributions in proteinogenic amino acids to in vivo enzyme activities. This
      metabolic flux ratio analysis by GC-MS provides a comprehensive perspective on
      central metabolism by quantifying 14 ratios of fluxes through converging pathways
      and reactions from [1-13C] and [U-13C]glucose experiments. Reliability and
      accuracy of this method were experimentally verified by successfully capturing
      expected flux responses of Escherichia coli to environmental modifications and
      seven knockout mutations in all major pathways of central metabolism.
      Furthermore, several mutants exhibited additional, unexpected flux responses that
      provide new insights into the behavior of the metabolic network in its entirety.
      Most prominently, the low in vivo activity of the Entner-Doudoroff pathway in
      wild-type E. coli increased up to a contribution of 30% to glucose catabolism in
      mutants of glycolysis and TCA cycle. Moreover, glucose 6-phosphate dehydrogenase
      mutants catabolized glucose not exclusively via glycolysis, suggesting a yet
      unidentified bypass of this reaction. Although strongly affected by environmental
      conditions, a stable balance between anaplerotic and TCA cycle flux was
      maintained by all mutants in the upper part of metabolism. Overall, our results
      provide quantitative insight into flux changes that bring about the resilience of
      metabolic networks to disruption.

PMID- 12603322
TI  - Interaction of the small heat shock protein with molecular mass 25 kDa (hsp25)
      with actin.
AB  - The interaction of heat shock protein with molecular mass 25 kDa (HSP25) and its
      point mutants S77D + S81D (2D mutant) and S15D + S77D + S81D (3D mutant) with
      intact and thermally denatured actin was analyzed by means of fluorescence
      spectroscopy and ultracentrifugation. Wild type HSP25 did not affect the
      polymerization of intact actin. The HSP25 3D mutant decreased the initial rate
      without affecting the maximal extent of intact actin polymerization. G-actin
      heated at 40-45 degrees C was partially denatured, but retained its ability to
      polymerize. The wild type HSP25 did not affect polymerization of this partially
      denatured actin. The 3D mutant of HSP25 increased the initial rate of
      polymerization of partially denatured actin. Heating at more than 55 degrees C
      induced complete denaturation of G-actin. Completely denatured G-actin cannot
      polymerize, but it aggregates at increased ionic strength. HSP25 and especially
      its 2D and 3D mutants effectively prevent salt-induced aggregation of completely
      denatured actin. It is concluded that the interaction of HSP25 with actin depends
      on the state of both actin and HSP25. HSP25 predominantly acts as a chaperone and
      preferentially interacts with thermally unfolded actin, preventing the formation
      of insoluble aggregates.

PMID- 12603323
TI  - Acryloyl-CoA reductase from Clostridium propionicum. An enzyme complex of
      propionyl-CoA dehydrogenase and electron-transferring flavoprotein.
AB  - Acryloyl-CoA reductase from Clostridium propionicum catalyses the irreversible
      NADH-dependent formation of propionyl-CoA from acryloyl-CoA. Purification yielded
      a heterohexadecameric yellow-greenish enzyme complex [(alpha2betagamma)4;
      molecular mass 600 +/- 50 kDa] composed of a propionyl-CoA dehydrogenase (alpha2,
      2 x 40 kDa) and an electron-transferring flavoprotein (ETF; beta, 38 kDa; gamma,
      29 kDa). A flavin content (90% FAD and 10% FMN) of 2.4 mol per alpha2betagamma
      subcomplex (149 kDa) was determined. A substrate alternative to acryloyl-CoA (Km
      = 2 +/- 1 microm; kcat = 4.5 s-1 at 100 microm NADH) is 3-buten-2-one (methyl
      vinyl ketone; Km = 1800 microm; kcat = 29 s-1 at 300 microm NADH). The enzyme
      complex exhibits acyl-CoA dehydrogenase activity with propionyl-CoA (Km = 50
      microm; kcat = 2.0 s-1) or butyryl-CoA (Km = 100 microm; kcat = 3.5 s-1) as
      electron donor and 200 microm ferricenium hexafluorophosphate as acceptor. The
      enzyme also catalysed the oxidation of NADH by iodonitrosotetrazolium chloride
      (diaphorase activity) or by air, which led to the formation of H2O2 (NADH oxidase
      activity). The N-terminus of the dimeric propionyl-CoA dehydrogenase subunit is
      similar to those of butyryl-CoA dehydrogenases from several clostridia and
      related anaerobes (up to 55% sequence identity). The N-termini of the beta and
      gamma subunits share 40% and 35% sequence identities with those of the A and B
      subunits of the ETF from Megasphaera elsdenii, respectively, and up to 60% with
      those of putative ETFs from other anaerobes. Acryloyl-CoA reductase from C.
      propionicum has been characterized as a soluble enzyme, with kinetic properties
      perfectly adapted to the requirements of the organism. The enzyme appears not to
      be involved in anaerobic respiration with NADH or reduced ferredoxin as electron
      donors. There is no relationship to the trans-2-enoyl-CoA reductases from various
      organisms or the recently described acryloyl-CoA reductase activity of propionyl
      CoA synthase from Chloroflexus aurantiacus.

PMID- 12603325
TI  - Mechanism of the reaction catalyzed by dehydroascorbate reductase from spinach
      chloroplasts.
AB  - Dehydroascorbate reductase (DHAR) reduces dehydroascorbate (DHA) to ascorbate
      with glutathione (GSH) as the electron donor. We analyzed the reaction mechanism
      of spinach chloroplast DHAR, which had a much higher reaction specificity for DHA
      than animal enzymes, using a recombinant enzyme expressed in Escherichia coli.
      Kinetic analysis suggested that the reaction proceeded by a bi-uni-uni-uni-ping
      pong mechanism, in which binding of DHA to the free, reduced form of the enzyme
      was followed by binding of GSH. The Km value for DHA and the summed Km value for
      GSH were determined to be 53 +/- 12 micro m and 2.2 +/- 1.0 mm, respectively,
      with a turnover rate of 490 +/- 40 s-1. Incubation of 10 microm DHAR with 1 mm
      DHA and 10 microm GSH resulted in stable binding of GSH to the enzyme. Bound GSH
      was released upon reduction of the GSH-enzyme adduct by 2-mercaptoethanol,
      suggesting that the adduct is a reaction intermediate. Site-directed mutagenesis
      indicated that C23 in DHAR is indispensable for the reduction of DHA. The
      mechanism of catalysis of spinach chloroplast DHAR is proposed.

PMID- 12603324
TI  - Distinguishing between different pathways of bilayer disruption by the related
      antimicrobial peptides cecropin B, B1 and B3.
AB  - Different pathways of bilayer disruption by the structurally related
      antimicrobial peptides cecropin B, B1 and B3, revealed by surface plasma
      resonance analysis of immobilized liposomes, differential scanning calorimetry of
      peptide-large unilamellar vesicle interactions, and light microscopic analysis of
      peptide-treated giant unilamellar vesicles, have been identified in this study.
      Natural cecropin B (CB) has one amphipathic and one hydrophobic alpha-helix,
      whereas cecropins B1 (CB1) and B3 (CB3), which are custom-designed, chimaeric
      analogues of CB, possess either two amphipathic or two hydrophobic alpha-helices,
      respectively. Surface plasma resonance analysis of unilamellar vesicles
      immobilized through a biotin-avidin interaction showed that both CB and CB1 bind
      to the lipid bilayers at high concentration (>10 microm); in contrast, CB3
      induces disintegration of the vesicles at all concentrations tested. Differential
      scanning calorimetry showed the concentration-dependent effect of bilayer
      disruption, based on the different thermotrophic phase behaviours and the shapes
      of the thermal phase-transition curves obtained. The kinetics of the lysis of
      giant unilamellar vesicles observed by microscopy demonstrated that both CB and
      CB1 effect a continuous process involving loss of integrity followed by
      coalescence and resolution into smaller vesicles, whereas CB3 induces rapid
      formation of irregular-shaped, nonlamellar structures which rapidly disintegrate
      into twisted, microtubule-containing debris before being completely destroyed. On
      the basis of these observations, models by which CB, CB1 and CB3 induce lysis of
      lipid bilayers are discussed.

PMID- 12603326
TI  - Deamidation of labile asparagine residues in the autoregulatory sequence of human
      phenylalanine hydroxylase.
AB  - Two dimensional electrophoresis has revealed a microheterogeneity in the
      recombinant human phenylalanine hydroxylase (hPAH) protomer, that is the result
      of spontaneous nonenzymatic deamidations of labile asparagine (Asn) residues
      [Solstad, T. and Flatmark, T. (2000) Eur. J. Biochem.267, 6302-6310]. Using of a
      computer algorithm, the relative deamidation rates of all Asn residues in hPAH
      have been predicted, and we here verify that Asn32, followed by a glycine
      residue, as well as Asn28 and Asn30 in a loop region of the N-terminal
      autoregulatory sequence (residues 19-33) of wt-hPAH, are among the susceptible
      residues. First, on MALDI-TOF mass spectrometry of the 24 h expressed enzyme, the
      E. coli 28-residue peptide, L15-K42 (containing three Asn residues), was
      recovered with four monoisotopic mass numbers (i.e., m/z of 3106.455, 3107.470,
      3108.474 and 3109.476, of decreasing intensity) that differed by 1 Da. Secondly,
      by reverse-phase chromatography, isoaspartyl (isoAsp) was demonstrated in this 28
      residue peptide by its methylation by protein-l-isoaspartic acid O
      methyltransferase (PIMT; EC 2.1.1.77). Thirdly, on incubation at pH 7.0 and 37
      degrees C of the phosphorylated form (at Ser16) of this 28-residue peptide, a
      time-dependent mobility shift from tR approximately 34 min to approximately 31
      min (i.e., to a more hydrophilic position) was observed on reverse-phase
      chromatography, and the recovery of the tR approximately 34 min species decreased
      with a biphasic time-course with t0.5-values of 1.9 and 6.2 days. The fastest
      rate is compatible with the rate determined for the sequence-controlled
      deamidation of Asn32 (in a pentapeptide without 3D structural interference),
      i.e., a deamidation half-time of approximately 1.5 days in 150 mm Tris/HCl, pH
      7.0 at 37 degrees C. Asn32 is located in a cluster of three Asn residues (Asn28,
      Asn30 and Asn32) of a loop structure stabilized by a hydrogen-bond network.
      Deamidation of Asn32 introduces a negative charge and a partial beta
      isomerization (isoAsp), which is predicted to result in a change in the backbone
      conformation of the loop structure and a repositioning of the autoregulatory
      sequence and thus affect its regulatory properties. The functional implications
      of this deamidation was further studied by site-directed mutagenesis, and the
      mutant form (Asn32-->Asp) revealed a 1.7-fold increase in the catalytic
      efficiency, an increased affinity and positive cooperativity of L-Phe binding as
      well as substrate inhibition.

PMID- 12603327
TI  - Structural and biological effects of a beta2- or beta3-amino acid insertion in a
      peptide.
AB  - Molecular mechanics calculations on conformers of Ac-HGly-NHMe, Ac-beta2-HAla
      NHMe and Ac-beta3-HAla-NHMe indicate that low-energy conformations of the beta
      amino acids backbone, corresponding to gauche rotamers around the Calpha-Cbeta
      bond, may overlap canonical backbone conformers observed for alpha-amino acids.
      Therefore, Substance P (SP) was used as a model peptide to analyse the structural
      and biological consequences of the substitution of Phe7 and Phe8 by (R)-beta2
      HPhe and of Gly9 by HGly (R)-beta2-HAla or (S)-beta3-HAla. [(R)-beta2-HAla9]SP
      has pharmacological potency similar to that of SP while [HGly9]SP and [(S)-beta3
      HAla9]SP show a 30- to 50-fold decrease in biological activities. The three
      analogues modified at position 9 are more resistant to degradation by angiotensin
      converting enzyme than SP and [Ala9]SP. NMR analysis of these SP analogues
      suggest that a beta-amino acid insertion in position 9 does not affect the
      overall backbone conformation. Altogether these data suggest that [HGly9]SP, [(S)
      beta3-HAla9]SP and [(R)-beta2-HAla9]SP could adopt backbone conformations similar
      to that of SP, [Ala9]SP and [Pro9]SP. In contrast, incorporation of beta2-HPhe in
      position 7 and 8 of SP led to peptides that are almost devoid of biological
      activity. Thus, a beta-amino acid could replace an alpha-amino acid within the
      sequence of a bioactive peptide provided that the additional methylene group does
      not cause steric hindrance and does not confine orientations of the side chain to
      regions of space different from those permitted in the alpha-amino acid.

PMID- 12603328
TI  - Identification and functional expression of a second human beta-galactoside
      alpha2,6-sialyltransferase, ST6Gal II.
AB  - BLAST analysis of the human and mouse genome sequence databases using the
      sequence of the human CMP-sialic acid:beta-galactoside alpha-2,6
      sialyltransferase cDNA (hST6Gal I, EC2.4.99.1) as a probe allowed us to identify
      a putative sialyltransferase gene on chromosome 2. The sequence of the
      corresponding cDNA was also found as an expressed sequence tag of human brain.
      This gene contained a 1590 bp open reading frame divided in five exons and the
      deduced amino-acid sequence didn't correspond to any sialyltransferase already
      known in other species. Multiple sequence alignment and subsequent phylogenic
      analysis showed that this new enzyme belonged to the ST6Gal subfamily and shared
      48% identity with hST6Gal-I. Consequently, we named this new sialyltransferase
      ST6Gal II. A construction in pFlag vector transfected in COS-7 cells gave raise
      to a soluble active form of ST6Gal II. Enzymatic assays indicate that the best
      acceptor substrate of ST6Gal II was the free disaccharide Galbeta1-4GlcNAc
      structure whereas ST6Gal I preferred Galbeta1-4GlcNAc-R disaccharide sequence
      linked to a protein. The alpha2,6-linkage was confirmed by the increase of
      Sambucus nigra agglutinin-lectin binding to the cell surface of CHO transfected
      with the cDNA encoding ST6Gal II and by specific sialidases treatment. In
      addition, the ST6Gal II gene showed a very tissue specific pattern of expression
      because it was found essentially in brain whereas ST6Gal I gene is ubiquitously
      expressed.

PMID- 12603329
TI  - Interaction of caspase-3 with the cyclic GMP binding cyclic GMP specific
      phosphodiesterase (PDE5a1).
AB  - Here, we show that recombinant bovine PDE5A1 is proteolysed by recombinant
      caspase-3 in in vitro and transfected Cos-7 cells. In addition, the treatment of
      PDE5A1-transfected Cos-7 and PC12 cells with staurosporine, an apoptotic agent
      that activates endogenous caspase-3, also induced proteolysis and inactivation of
      PDE5A1. These findings suggest that there is specificity in the interaction
      between caspase-3 and PDE5A1 that requires application of an apoptotic stimulus.
      The potential proteolysis of the [778]DQGD[781] site in PDE5A1 by caspase-3 might
      affect cGMP's hydrolyzing activity as this is within the boundary of the active
      site. We therefore created a truncated D781 mutant corresponding exactly to the
      potential cleavage product. This mutant was expressed equally well compared with
      the wild-type enzyme in transfected Cos-7 cells and was inactive. Inactivity of
      the truncated mutant was not due to potential misfolding of the enzyme as it
      eluted from gel filtration chromatography in the same fraction as the wild-type
      enzyme. Homology model comparison with the catalytic domain of PDE4B2 was used to
      probe a functional role for the region in PDE5A1 that might be cleaved by caspase
      3. From this, we can predict that a caspase-3-mediated cleavage of the
      [778]DQGD[781] motif would result in removal of the C-terminal tail containing
      Q807 and F810, which are potentially important amino acids required for substrate
      binding.

PMID- 12603330
TI  - Biochemical characterization of a U6 small nuclear RNA-specific terminal
      uridylyltransferase.
AB  - The HeLa cell terminal uridylyltransferase (TUTase) that specifically modifies
      the 3'-end of mammalian U6 small nuclear RNA (snRNA) was characterized with
      respect to ionic dependence and substrate requirements. Optimal enzyme activity
      was obtained at moderate ionic strength (60 mm KCl) and depended on the presence
      of 5 mm MgCl2. In vitro synthesized U6 snRNA without a 3'-terminal UMP residue
      was not accepted as substrate. In contrast, U6 snRNA molecules containing one,
      two or three 3'-terminal UMP residues were filled up efficiently, generating the
      3'-terminal structure with four UMP residues observed in newly transcribed
      cellular U6 snRNA. In this reaction, the addition of more than one UMP nucleotide
      depended on higher UTP concentrations. The analysis of internally mutated U6
      snRNA revealed that the fill-in reaction by the U6-TUTase was not controlled by
      opposite-strand nucleotides, excluding an RNA-dependent RNA polymerase mechanism.
      Furthermore, electrophoretic mobility-shift analyses showed that the U6-TUTase
      was able to form stable complexes with the U6 snRNA in vitro. On the basis of
      these findings, a protocol was developed for affinity purification of the enzyme.
      In agreement with indirect labeling results, PAGE of a largely purified enzyme
      revealed an apparent molecular mass of 115 kDa for the U6-TUTase.

PMID- 12603331
TI  - Studies on the regulatory properties of the pterin cofactor and dopamine bound at
      the active site of human phenylalanine hydroxylase.
AB  - The catalytic activity of phenylalanine hydroxylase (PAH, phenylalanine 4
      monooxygenase EC 1.14.16.1) is regulated by three main mechanisms, i.e. substrate
      (l-phenylalanine, L-Phe) activation, pterin cofactor inhibition and
      phosphorylation of a single serine (Ser16) residue. To address the molecular
      basis for the inhibition by the natural cofactor (6R)-l-erythro-5,6,7,8
      tetrahydrobiopterin, its effects on the recombinant tetrameric human enzyme (wt
      hPAH) was studied using three different conformational probes, i.e. the limited
      proteolysis by trypsin, the reversible global conformational transition
      (hysteresis) triggered by L-Phe binding, as measured in real time by surface
      plasmon resonance analysis, and the rate of phosphorylation of Ser16 by cAMP
      dependent protein kinase. Comparison of the inhibitory properties of the natural
      cofactor with the available three-dimensional crystal structure information on
      the ligand-free, the binary and the ternary complexes, have provided important
      clues concerning the molecular mechanism for the negative modulatory effects. In
      the binary complex, the binding of the cofactor at the active site results in the
      formation of stabilizing hydrogen bonds between the dihydroxypropyl side-chain
      and the carbonyl oxygen of Ser23 in the autoregulatory sequence. L-Phe binding
      triggers local as well as global conformational changes of the protomer resulting
      in a displacement of the cofactor bound at the active site by 2.6 A (mean
      distance) in the direction of the iron and Glu286 which causes a loss of the
      stabilizing hydrogen bonds present in the binary complex and thereby a complete
      reversal of the pterin cofactor as a negative effector. The negative modulatory
      properties of the inhibitor dopamine, bound by bidentate coordination to the
      active site iron, is explained by a similar molecular mechanism including its
      reversal by substrate binding. Although the pterin cofactor and the substrate
      bind at distinctly different sites, the local conformational changes imposed by
      their binding at the active site have a mutual effect on their respective binding
      affinities.

PMID- 12603332
TI  - Choline increases serum insulin in rat when injected intraperitoneally and
      augments basal and stimulated aceylcholine release from the rat minced pancreas
      in vitro.
AB  - Intraperitoneal injection of choline (30-90 mg.kg-1) produced a dose-dependent
      increase in serum insulin, glucose and choline levels in rats. The increase in
      serum insulin induced by choline (90 mg.kg-1) was blocked by pretreatment with
      the muscarinic acetylcholine receptor antagonists, atropine (2 mg.kg-1),
      pirenzepine (2 mg.kg-1) and 4-diphenylacetoxy-N-methylpiperidine (2 mg.kg-1) or
      the ganglionic nicotinic receptor antagonist, hexamethonium (15 mg.kg-1). The
      effect of choline on serum insulin and glucose was enhanced by oral glucose
      administration (3 g.kg-1). Choline administration was associated with a
      significant (P < 0.001) increase in the acetylcholine content of pancreatic
      tissue. Choline (10-130 microm) increased basal and stimulated acetylcholine
      release but failed to evoke insulin release from the minced pancreas at
      considerably higher concentrations (0.1-10 mm). Hemicholium-3, a choline uptake
      inhibitor, attenuated the increase in acetylcholine release induced by choline
      augmentation. Choline (1-32 mm) inhibited [3H]quinuclidinyl benzilate binding to
      the muscarinic receptors in the pancreatic homogenates. These data show that
      choline, a precursor of the neurotransmitter acetylcholine, increases serum
      insulin by indirectly stimulating peripheral acetylcholine receptors through the
      enhancement of acetylcholine synthesis and release.

PMID- 12603333
TI  - Nucleotide excision repair rates in rat tissues.
AB  - We have determined and compared nucleotide excision repair capability of several
      rat tissues by a method based on restoration of the transformation activity of UV
      irradiated pBlueScript by incubation in repair-competent protein extracts. After
      3 h of incubation, plasmid DNA was isolated and used to transform competent
      Escherichia coli cells. Damaged plasmids showed low transformation efficiency
      prior to incubation in repair-competent extracts. After incubation the
      transformation efficiency was restored to different extents permitting
      calculation of the repair capacity of the extracts. Our results showed that
      rapidly proliferating tissues such as liver, kidney and testis showed higher
      nucleotide excision repair capacity than slowly proliferating tissues such as
      heart, muscle, lung and spleen. When liver and splenocytes were stimulated to
      proliferation by partial hepatectomy and mitogen stimulation, their repair
      capability increased in parallel with the respective proliferative rates.

PMID- 12603334
TI  - The catalytic role of the distal site asparagine-histidine couple in catalase
      peroxidases.
AB  - Catalase-peroxidases (KatGs) are unique in exhibiting an overwhelming catalase
      activity and a peroxidase activity of broad specificity. Similar to other
      peroxidases the distal histidine in KatGs forms a hydrogen bond with an adjacent
      conserved asparagine. To investigate the catalytic role(s) of this potential
      hydrogen bond in the bifunctional activity of KatGs, Asn153 in Synechocystis KatG
      was replaced with either Ala (Asn153-->Ala) or Asp (Asn153-->Asp). Both variants
      exhibit an overall peroxidase activity similar with wild-type KatG. Cyanide
      binding is monophasic, however, the second-order binding rates are reduced to
      5.4% (Asn153-->Ala) and 9.5% (Asn153-->Asp) of the value of native KatG [(4.8 +/-
      0.4) x 105 m-1.s-1 at pH 7 and 15 degrees C]. The turnover number of catalase
      activity of Asn153-->Ala is 6% and that of Asn153-->Asp is 16.5% of wild-type
      activity. Stopped-flow analysis of the reaction of the ferric forms with H2O2
      suggest that exchange of Asn did not shift significantly the ratio of rates of
      H2O2-mediated compound I formation and reduction. Both rates seem to be reduced
      most probably because (a) the lower basicity of His123 hampers its function as
      acid-base catalyst and (b) Asn153 is part of an extended KatG-typical H-bond
      network, the integrity of which seems to be essential to provide optimal
      conditions for binding and oxidation of the second H2O2 molecule necessary in the
      catalase reaction.

PMID- 12603335
TI  - The N-acetylglutamate synthase/N-acetylglutamate kinase metabolon of
      Saccharomyces cerevisiae allows co-ordinated feedback regulation of the first two
      steps in arginine biosynthesis.
AB  - In Saccharomyces cerevisiae, which uses the nonlinear pathway of arginine
      biosynthesis, the first two enzymes, N-acetylglutamate synthase (NAGS) and N
      acetylglutamate kinase (NAGK), are controlled by feedback inhibition. We have
      previously shown that NAGS and NAGK associate in a complex, essential to synthase
      activity and protein level [Abadjieva, A., Pauwels, K., Hilven, P. & Crabeel, M.
      (2001) J. Biol. Chem.276, 42869-42880]. The NAGKs of ascomycetes possess, in
      addition to the catalytic domain that is shared by all other NAGKs and whose
      structure has been determined, a C-terminal domain of unknown function and
      structure. Exploring the role of these two domains in the synthase/kinase
      interaction, we demonstrate that the ascomycete-specific domain is required to
      maintain synthase activity and protein level. Previous results had suggested a
      participation of the third enzyme of the pathway, N-acetylglutamylphosphate
      reductase, in the metabolon. Here, genetic analyses conducted in yeast at
      physiological level, or in a heterologous background, clearly demonstrate that
      the reductase is dispensable for synthase activity and protein level. Most
      importantly, we show that the arginine feedback regulation of the NAGS and NAGK
      enzymes is mutually interdependent. First, the kinase becomes less sensitive to
      arginine feedback inhibition in the absence of the synthase. Second, and as in
      Neurospora crassa, in a yeast kinase mutant resistant to arginine feedback
      inhibition, the synthase becomes feedback resistant concomitantly. We conclude
      that the NAGS/NAGK metabolon promotes the co-ordination of the catalytic
      activities and feedback regulation of the first two, flux controlling, enzymes of
      the arginine pathway.

PMID- 12603338
TI  - The renal medullary interstitium: focus on osmotic hypertonicity.
AB  - 1. There has been continued interest in the functional role of the renal
      medullary interstitium and intense research in this area has furnished new
      information regarding the extent, dynamics and mechanisms determining
      fluctuations in medullary osmotic hypertonicity. 2. Any change in the tonicity
      (interstitial solute concentration) indicates an imbalance of the rate of solute
      delivery to the interstitium (by tubular transport) and solute removal therefrom
      (by the microcirculation). It is often difficult to establish whether alteration
      of the delivery or removal triggered the change in medullary tissue tonicity. 3.
      Newer in vivo studies have confirmed earlier predictions and indirect evidence
      indicating that the rate of NaCl transport in the ascending limb of the loop of
      Henle is the major determinant of medullary ionic hypertonicity. 4. The
      hypothesis of a 'washout' of medullary solutes during increased medullary blood
      flow (MBF) has been re-evaluated. A novel experimental approach has provided
      direct evidence of a modest dissipation of medullary solutes with increasing MBF
      and a modest accumulation of solutes with decreasing MBF. 5. Increasing evidence
      is reviewed indicating that medullary tonicity is not only a regulated variable,
      but also that it may itself modulate the activity of multiple local endocrine and
      paracrine control systems and thereby affect local microcirculation and the
      function of medullary interstitial and tubular cells.

PMID- 12603336
TI  - Biosynthesis of riboflavin in archaea. 6,7-dimethyl-8-ribityllumazine synthase of
      Methanococcus jannaschii.
AB  - Heterologous expression of the putative open reading frame MJ0303 of
      Methanococcus jannaschii provided a recombinant protein catalysing the formation
      of the riboflavin precursor, 6,7-dimethyl-8-ribityllumazine, by condensation of 5
      amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione and 3,4-dihydroxy-2-butanone 4
      phosphate. Steady state kinetic analysis at 37 degrees C and pH 7.0 indicated a
      catalytic rate of 11 nmol.mg-1.min-1; Km values for 5-amino-6-ribitylamino
      2,4(1H,3H)-pyrimidinedione and 3,4-dihydroxybutanone 4-phosphate were 12.5 and 52
      micro m, respectively. The enzyme sediments at an apparent velocity of about 12
      S. Sedimentation equilibrium analysis indicated a molecular mass around 1 MDa but
      was hampered by nonideal solute behaviour. Negative-stained electron micrographs
      showed predominantly spherical particles with a diameter of about 150 A. The data
      suggest that the enzyme from M. jannaschii can form capsids with icosahedral 532
      symmetry consisting of 60 subunits.

PMID- 12603339
TI  - Comparison of the in vitro neuromuscular activity of venom from three Australian
      snakes (Hoplocephalus stephensi, Austrelaps superbus and Notechis scutatus):
      efficacy of tiger snake antivenom.
AB  - 1. Tiger snake antivenom, raised against Notechis scutatus venom, is indicated
      not only for the treatment of envenomation by this snake, but also that of the
      copperhead (Austrelaps superbus) and Stephen's banded snake (Hoplocephalus
      stephensi). The present study compared the neuromuscular pharmacology of venom
      from these snakes and the in vitro efficacy of tiger snake antivenom. 2. In chick
      biventer cervicis muscle and mouse phrenic nerve diaphragm preparations, all
      venoms (3-10 microg/mL) produced inhibition of indirect twitches. In the biventer
      muscle, venoms (10 micro g/mL) inhibited responses to acetylcholine (1 mmol/L)
      and carbachol (20 micromol/L), but not KCl (40 mmol/L). The prior (10 min)
      administration of 1 unit/mL antivenom markedly attenuated the neurotoxic effects
      of A. superbus and N. scutatus venoms (10 microg/mL), but was less effective
      against H. stephensi venom (10 microg/mL); 5 units/mL antivenom attenuated the
      neurotoxic activity of all venoms. 3. Administration of 5 units/mL antivenom at
      t90 partially reversed, over a period of 3 h, the inhibition of twitches produced
      by N. scutatus (10 microg/mL; 41% recovery), A. superbus (10 microg/mL; 25%
      recovery) and H. stephensi (10 microg/mL; 50% recovery) venoms. All venoms (10
      100 microg/mL) also displayed signs of in vitro myotoxicity. 4. The results of
      the present study indicate that all three venoms contain neurotoxic activity that
      is effectively attenuated by tiger snake antivenom.

PMID- 12603340
TI  - Inhibition of nuclear translocation of transcription factor nuclear factor-kappa
      B induces FAS- as well as tumour necrosis factor-alpha-mediated apoptosis through
      downregulation of a conserved family of inhibitor of apoptosis 1.
AB  - 1. In the present study, we examined whether the nuclear transcription factor
      (NF)-kappaB activity plays a role in the determination of sensitivity to tumour
      necrosis factor (TNF)-alpha or agonistic Fas antibody (Ab) in human vascular
      smooth muscle cells (hVSMC). 2. To inhibit agonist-induced NF-kappaB activation
      in hVSMC, a cell-permeable peptide (SN50), which carried the nuclear localization
      sequence of the NF-kappaB p50 subunit, was used. Nuclear factor-kappaB activity
      was examined by both immunoblot analysis of nuclear extracts and by ELISA. The
      hVSMC were treated with TNF-alpha or agonistic Fas Ab (CH11) and then apoptosis
      was determined by cell death ELISA for DNA fragmentation. To investigate the
      mechanisms for protection against apoptosis in hVSMC, we analysed the expression
      of a conserved family of inhibitor of apoptosis 1 (c-IAP1) protein using
      immunoblot analysis. 3. Although both CH11 and TNF-alpha alone failed to induce
      hVSMC death in the presence of SN50, they markedly increased the apoptotic hVSMC
      estimated by cell death ELISA. In addition, these effects could be blocked with
      the pan-caspase inhibitor z-VAD.fmk. Western blotting analysis indicated that TNF
      alpha alone increased c-IAP1 protein levels, whereas CH11 alone had no effect.
      Inhibition of NF-kappaB activation by SN50 suppressed c-IAP1 protein expression
      and enhanced apoptosis induced by either TNF-alpha or CH11. 4. These findings
      suggest that c-IAP1 is an important intracellular modulator of Fas as well as TNF
      alpha death signalling pathways in hVSMC. The expression of c-IAP1 is regulated
      by a NF-kappaB-mediated phenomenon.

PMID- 12603341
TI  - Effects of five commonly used glucocorticoids on haemangioma in vitro.
AB  - 1. High-dose systemic or intralesional steroids are the first-line
      pharmacological treatments for haemangioma. However, the mechanism of action of
      steroids is unknown. Using the in vitro model developed by us, the present study
      examined some of the effects of five commonly used glucocorticoids on haemangioma
      biopsies taken from two patients. 2. At 12 micro mol/L, triamcinolone and
      dexamethasone consistently exhibited capillary growth inhibition, whereas
      methylprednisolone displayed an inhibitory effect during the first 7 days of
      culture. At this concentration, inhibition of capillary growth was observed in
      betamethasone-treated cultures derived from one patient but not in those derived
      from the other. However, hydrocortisone had a negligible effect on capillary
      growth. 3. Transcription of various factors considered important for haemangioma
      development were studied by reverse transcription-polymerase chain reaction.
      Neither vascular endothelial growth factor nor fibroblast growth factor-2 played
      a vital role in steroid-induced inhibition of capillary growth. All
      glucocorticoids induced a marked decrease of interleukin (IL)-6 transcripts. 4.
      Capillary growth inhibition in cultures treated with all glucocorticoids, except
      triamcinolone, was associated with an increased transcription of
      clusterin/apolipoprotein J (clust/apoJ), an apoptotic gene. There was increased
      transcription of mitochondrial cytochrome (cyt) b in the inhibited cultures
      resulting from triamcinolone, dexamethasone or methylprednisolone treatment that
      was associated with capillary growth inhibition, suggesting an important role of
      mitochondria in glucocorticoid-induced regression of haemangioma. 5. Our results
      indicate that glucocorticoids may modulate haemangiogenesis via an upregulation
      of cyt b, clust/apoJ and/or IL-6. The variable effects of different
      glucocorticoids on one or more of these factors may explain the interindividual
      variation in the in vivo response of haemangioma to the steroids.

PMID- 12603343
TI  - Disposition kinetics of ketotifen from liposomal dry powder for inhalation in rat
      lung.
AB  - 1. The aim of the present study was to understand the benefit of liposomal dry
      powder for inhalation (LDPI) of ketotifen fumarate (KF) over plain drug dry
      powder for inhalation as a pulmonary targetted drug-delivery system. 2. The KF
      liposomes, composed of egg phosphatidyl choline and cholesterol, were prepared by
      the lipid film hydration technique. The liposomal dispersion was freeze dried and
      formulated to a dry powder for inhalation. Values of 89.0-65.3% drug entrapment
      of freeze-dried liposomes were estimated in prepared batches. 3. Rehydrated KF
      liposomes formed by the hydration of LDPI or the plain KF solution was delivered
      to rat lungs by intratracheal instillation. Simultaneous monitoring of drug
      levels in the bronchoalveolar lavage and lung tissue enabled assessment of
      pulmonary drug disposition. 4. Cumulative drug levels in lung tissue after
      intratracheal administration revealed that with liposomes targetting factors were
      between 1.36 and 1.54. The maximal drug concentration in lung homogenate for LDPI
      was 42.0 micro g compared with 73.6 micro g for plain drug solution. 5.
      Similarly, the time to reach maximum drug concentration in the lung homogenate
      for liposomal dry powder was 9-12 h compared with 3 h for plain drug. 6. Hence,
      the use of LDPI of KF was found to provide desired drug levels in the lung for a
      long time and thereby increased pulmonary targetting 7. This is expected to
      enhance the therapeutic index of the drug and probably reduce the dose
      administered and the cost of therapy.

PMID- 12603342
TI  - Pyruvate-dependent preconditioning and cardioprotection in murine myocardium.
AB  - 1. Whether pyruvate inhibits or can actually initiate myocardial preconditioning
      is unclear and whether pyruvate provides protection via its action as a
      'cosubstrate' with glucose or via alternative mechanisms also remains
      controversial. We examined effects of a high concentration of pyruvate (10
      mmol/L) alone or with 15 mmol/L glucose in mouse hearts subjected to 20 min
      ischaemia and 30 min reperfusion. 2. Provision of 10 mmol/L pyruvate alone or as
      a cosubstrate markedly reduced ischaemic contracture and enhanced postischaemic
      recovery. Time to contracture was increased from approximately 3 min to over 8
      min, peak contracture was reduced from 90 mmHg to less than 60 mmHg and
      postischaemic pressure development was also improved. Effects on contracture were
      independent of the presence of pyruvate during ischaemia and improved
      postischaemic recovery was evident with pre-ischaemic pyruvate perfusion. 3.
      Cardioprotection did not require the presence of pyruvate during ischaemia or
      reperfusion and effects of pyruvate pretreatment could be mimicked by
      pretreatment with 1 mmol/L dichloroacetate (DCA), an activator of pyruvate
      dehydrogenase. 4. Myocardial adenosine efflux and Ca2+ content were elevated (by
      215 and 65%, respectively) following pretreatment with pyruvate, potentially
      triggering a preconditioned state. A role for adenosine A1 receptors is supported
      by lack of added protection with pyruvate in hearts transgenically overexpressing
      adenosine A1 receptors. 5. Collectively, these observations demonstrate that pre
      ischaemic treatment with pyruvate or DCA provides a beneficial preconditioning
      like effect in ischaemic and postischaemic myocardium. The response appears
      unrelated to glycolytic inhibition, but may be mediated via transient changes in
      adenosine levels and/or cellular Ca2+.

PMID- 12603344
TI  - Modulatory effect of Coccinia indica on aortic collagen in streptozotocin-induced
      diabetic rats.
AB  - 1. The effects of Coccinia indica, an indigenous plant used in Ayurvedic medicine
      in India, on aortic collagen content and its characteristics were assessed in
      streptozotocin (STZ) diabetic rats. 2. Rats were made diabetic with a single
      intraperitoneal injection of STZ (45 mg/kg). Blood glucose, hydroxyproline,
      collagen, extent of glycation, collagen-linked fluorescence, soluble pattern of
      pepsin-soluble collagen, shrinkage temperature, alpha/beta ratio of type I
      collagen and type I/type III collagen ratio were determined in rats treated with
      C. indica leaf extract (CLEt; 200 mg/kg for 45 days using an oral intragastric
      tube). 3. In diabetic rats, the collagen content, as well as the degree of cross
      linking, was increased, as evidenced by increased shrinkage temperature and
      decreased pepsin solubility. The alpha/beta ratio of type I collagen and the type
      I/type III collagen ratio of pepsin-soluble collagen were significantly decreased
      in STZ diabetic rats. 4. In conclusion, administration of CLEt for 45 days to STZ
      diabetic rats significantly reduced the accumulation and cross-linking of
      collagen. The effects of C. indica (collagen content 23.87 +/- 1.52 mg/100 mg
      tissue (t value = 6.80), extent of cross-linking 0.893 +/- 0.072 mg
      hydroxyproline/100 mg tissue (t value = 9.0)) were comparable with those of
      glibenclamide (collagen content 26.18 +/- 1.65 mg/100 mg tissue (t value = 4.58),
      extent of cross-linking 0.787 +/- 0.057 mg hydroxyproline/100 mg tissue (t value
      = 7.1)), a reference drug.

PMID- 12603345
TI  - Synergism between beta 2-adrenoceptor agonists and subtype-selective alpha 1A
      adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro.
AB  - 1. Despite great efforts in recent decades, premature birth is still a leading
      cause of perinatal morbidity and mortality. beta2-Adrenoceptor agonists are
      frequently used as tocolytics, although their use is rather controversial.
      Previous animal studies have revealed that blockade of alpha1A-adrenoceptors
      results in relaxation of the pregnant rat myometrium. 2. The aim of the present
      study was to investigate the uterus relaxant effect of the beta2-adrenoceptor
      agonists (terbutaline, ritodrin) applied together with the subtype-selective
      alpha1A-adrenoceptor antagonists (WB 4101, 5-methylurapidil) in an in vitro rat
      model. The main objective of the experiments was to clarify whether there was an
      additive or a potentiating synergism between the two drug classes. 3. Myometrial
      rings were taken from female, 22-day pregnant (end-term) Sprague-Dawley rats.
      Electrical field stimulation (EFS) was used to elicit rhythmical contractions.
      Non-cumulative concentration-response curves were constructed to the beta2
      adrenoceptor agonists and the alpha1A-adrenoceptor antagonists alone and to beta2
      adrenoceptor agonists co-administered with the alpha1A-adrenoceptor antagonists.
      4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent
      way. Administering the beta2-adrenoceptor agonists in combination with the
      alpha1A-adrenoceptor antagonists resulted in a significant decrease in the EC50
      and an increase in the maximal contraction inhibiting effect. 5. The potentiating
      synergism that has been revealed between beta2-adrenoceptor agonists and alpha1A
      adrenoceptor antagonists in the uterus relaxant effect may be of great clinical
      importance because it could improve the efficacy of therapy of preterm delivery.

PMID- 12603346
TI  - Upregulation of muscarinic receptors by long-term nitric oxide inhibition in the
      rat ileum.
AB  - 1. The aim of the present study was to examine the effects of long-term nitric
      oxide (NO) blockade on contractions of the rat ileum induced by muscarinic
      agonists. 2. Male Wistar rats received the NO synthesis inhibitor NG-nitro-l
      arginine methyl ester (l-NAME; 20 mg/rat per day) in drinking water for 7, 15, 30
      and 60 days. Concentration-responses curves to methacholine and carbachol were
      obtained and pEC50 values were calculated. Saturation binding assays were
      performed in membranes prepared from rat ileum after 60 days of l-NAME treatment
      and the dissociation constant (KD) and maximal number of binding sites (Bmax)
      were determined by Scatchard analysis. 3. The NO synthase activity of the ileum
      was markedly reduced in all l-NAME-treated groups. At 60 days after l-NAME
      treatment, a significant increase in the potency of methacholine (fourfold) and
      carbachol (threefold) was observed. In binding studies, we found a significant
      increase in Bmax for [3H]-quinuclidinyl benzilate of approximately 57% in the l
      NAME treated group without any significant change in KD values. The contractile
      response to methacholine was not modified by the soluble guanylate cyclase
      inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (3 micro mol/L). No
      morphological alterations in the rat ileum were observed in l-NAME-treated rats.
      4. Our findings suggest that treatment with l-NAME for 60 days induces a marked
      increase in the potency of methacholine and carbachol, as well as an increase in
      receptor number in the rat ileum.

PMID- 12603347
TI  - Adenosine inhibits N-type calcium channels at the rat neuromuscular junction.
AB  - 1. In earlier studies, it has been reported that under in vitro conditions
      transmitter release at the rat neuromuscular junction is normally suppressed due
      to the effect of adenosine release from the isolated tissue. In the present study
      we wanted to determine whether this action may involve the inhibition of calcium
      influx through adenosine-sensitive calcium channels. 2. In order to test this
      hypothesis, we examined the role of N-type calcium channels in regulating nerve
      evoked transmitter release by using the N-type calcium channel-specific blocker
      omega-conotoxin GVIA (CTX). In order to control the inhibitory action of
      adenosine, we also used the adenosine A1 receptor antagonist 1,3-dipropyl-8
      cyclopentylxanthine (DPCPX). We tested the effect of blocking N-type calcium
      channels with CTX in the presence and absence of DPCPX. We examined the effects
      of these drugs on quantal transmitter release in the transected preparation of
      the phrenic nerve-hemidiaphragm of the rat using intracellular recording
      techniques. 3. At 10 nmol/L, CTX alone had no effect on nerve-evoked transmitter
      release; however, in the presence of 0.1 micro mol/L DPCPX, CTX significantly
      depressed nerve-evoked transmitter release. 4. These data support the view that
      adenosine inhibits nerve-evoked transmitter release by inhibiting N-type calcium
      channels on nerve terminals.

PMID- 12603348
TI  - Restoration of osmotically inhibited twitch force in rat cardiac trabeculae: role
      of Na+-H+ exchange.
AB  - 1. When rat cardiac muscle is subjected to an increase of osmolality, its peak
      twitch force is immediately inhibited. Subsequently, over a period of several
      minutes, twitch force undergoes restoration, the extent of which is determined by
      the osmolality. The aim of the present study was to determine the factors that
      contribute to this restorative phenomenon. 2. Trabeculae were isolated from the
      right ventricles of rat hearts and mounted in an organ bath at 37 degrees C. The
      osmolality of the bathing solution was increased by 100 mOsmol (to 400 mOsmol) by
      the addition of various proportions of NaCl and sucrose while recording twitch
      force production. The role of Na+-H+ exchange in restoring twitch force was
      examined by use of the specific inhibitor cariporide (HOE 642). The role of Na+
      Ca2+ exchange was examined by reducing [Ca2+]o (from 2 mmol/L to 0.5 mmol/L) or
      by substituting LiCl for NaCl. 3. Cariporide (25 micro mol/L) completely
      abolished twitch force restoration, thereby implicating a central role for the
      Na+-H+ exchanger. At constant [Na+]o, the extent of restoration was [Ca2+]o
      dependent, suggesting an independent contribution by the Na+-Ca2+ exchanger. This
      suggestion was supported by the finding that Li+, which substitutes for Na+ on
      the Na+-H+ exchanger, but not on the Na+-Ca2+ exchanger, also reduced the extent
      of restoration of hyperosmotically inhibited twitch force. 4. We conclude that
      the immediate inhibition of peak twitch force of rat cardiac muscle by
      hyperosmotic solutions reflects, in part, elevation of [H+]i, subsequent to
      reduction of cell volume. Hyperosmotic activation of Na+-H+ exchange then
      progressively relieves the inhibitory effect of protons on force development. The
      accompanying increase in [Na+]i in turn enhances Ca2+ influx on the Na+-Ca2+
      exchanger, with the result that twitch force undergoes further restoration.

PMID- 12603349
TI  - Relationship between anti-oxidant activities and doxorubicin-induced lipid
      peroxidation in P388 tumour cells and heart and liver in mice.
AB  - 1. The present study found that, compared with mouse heart and liver, P388
      ascitic tumour had significantly lower superoxide dismutase (SOD) activity and
      that compared with the mouse liver, the heart had significantly lower SOD and
      catalase activities, as well as a lower glutathione content. 2. At 7.5 mg/kg,
      doxorubicin (DOX), a superoxide radical inducer, induced significant lipid
      peroxidation only in the tumour, whereas 15.0 mg/kg DOX induced lipid
      peroxidation in both the tumour and heart, but not in the liver. 3. Overall, the
      results of the present study suggest that the differential anti-oxidant
      activities in P388 ascitic tumour, heart and liver in mice may explain their
      differential responses and, hence, susceptibility to DOX-induced lipid
      peroxidation.

PMID- 12603350
TI  - Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive
      rats.
AB  - 1. It has been demonstrated that blood pressure variability (BPV) is increased in
      hypertension and related to organ damage. It will be important to lower BPV in
      the treatment of hypertension. The present study was designed to investigate the
      effect of ketanserin, a 5-HT2A receptor antagonist with a weak alpha1
      adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats
      (SHR). 2. It was found that ketanserin decreased blood pressure (BP) and BPV in
      SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV,
      but not the BP level, when administered intracerebroventricularly (50 microg/rat,
      i.c.v.). 3. Prazosin, an alpha1-adrenoceptor antagonist, lowered BP but did not
      affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 microg/rat).
      Ritanserin (0.625 mg/kg, i.v.; 40 microg/rat, i.c.v.), a 5-HT2A receptor
      antagonist, decreased BPV only when administered i.c.v. and did not modify the BP
      level. 4. Ketanserin enhanced arterial baroreflex function in SHR when given
      either i.v. or i.c.v. 5. The stabilizing effect of ketanserin on BP was
      persistent when administered intragastrically. This administration route is
      similar to oral administration clinically. 6. It is concluded that ketanserin is
      an antihypertensive agent with an effect of reducing BPV. This effect is mainly
      mediated by central 5-HT2A receptors and is probably attributable to the
      restoration of arterial baroreflex function.

PMID- 12603352
TI  - Effect of an intrathoracic injection of sodium hyaluronic acid on the prevention
      of pleural thickening in excess fluid of tuberculous thoracic cavity.
AB  - 1. The aim of the present study was to evaluate the effect of a hyaluronate-based
      gel (HAbg) on the prevention of pleural thickening and adhesion in tuberculous
      pleural effusions (TPE). 2. Fifty-two patients who had accumulated a medium or
      large volume of tuberculous thoracic fluid, fluid being bound by fibre tissues
      and a pleura thickened more than 2 mm were divided randomly into two groups. All
      patients were all given standard treatments with antituberculous drugs. The HAbg
      was injected into the thoracic cavity in the treatment group (n = 27 patients),
      whereas normal saline was introduced into the thoracic cavity in the control
      group (n = 25 patients). Before and after HAbg injection, routine thoracic fluid
      examinations (including qualitative protein analysis, cell counts and
      classification of cell types) and protein quantification were performed. A chest
      radiograph and B-ultrasound were performed and pulmonary function was tested
      after 2 weeks and 3 months of thoracic fluid absorption. 3. The results show that
      patients who were treated with the HAbg had a significantly thinner pleura, a
      lower protein concentration and white blood cell count in the thoracic fluid and
      a higher forced expiratory volume in 1 s and forced vital capacity compared with
      patients in the control group. 4. Intrathoracic HAbg can prevent pleural
      thickening and improve lung function in patients who have a large amount of TPE.

PMID- 12603351
TI  - Membrane-bound and releasable nucleotidase activities: differences in canine
      mesenteric artery and vein.
AB  - 1. At least two enzymatic activities are proposed to degrade the extracellular
      ATP: (i) ubiquitously expressed membrane-bound enzymes (ecto-nucleotidases); and
      (ii) soluble (releasable) nucleotidases that are released during stimulation of
      sympathetic nerves and break down neuronal ATP. No quantitative data have placed
      the magnitude of these nucleotidase activities into a physiological perspective
      of neurovascular control. 2. We studied comparatively the membrane-bound and
      releasable nucleotidase activities in canine isolated inferior mesenteric
      arteries and veins using 1,N6-etheno(epsilon)-nucleotides (i.e. epsilon-ATP,
      epsilon-ADP, epsilon-AMP and epsilon-adenosine) as exogenous substrates. The
      enzymatic activities were estimated by measuring the disappearance of the epsilon
      substrate and appearance of epsilon-products by means of HPLC-fluorescence
      detection during either stimulation of sympathetic perivascular nerves
      (releasable activity) or in the absence of nerve stimulation (ecto-nucleotidase
      activity). 3. Incubation of vascular segments with 50 nmol/L epsilon-ATP for 60
      min resulted in a decrease of the epsilon-ATP substrate by 63.5 +/- 4.6 and 91.2
      +/- 6.2% in the artery and vein, respectively. In contrast, the decrease of the
      epsilon-ATP during electrical field stimulation (EFS; 16 Hz, 0.3 msec, 2 min) was
      39.8 +/- 4.2% in the artery and 13.1 +/- 7.3% in the vein. Therefore, the
      mesenteric arteries demonstrate a greater releasable ATPase activity and a weaker
      ecto-ATPase activity than mesenteric veins. 4. The degradation of epsilon-ADP and
      epsilon-AMP was similar in both blood vessels under either experimental protocol.
      The epsilon-adenosine was not significantly degraded in the absence or presence
      of EFS. 5. These data implicate a differential removal of extracellular ATP as a
      potential mechanism of serving resistance and capacitance in the splanchnic
      circulation.

PMID- 12603353
TI  - New dynamics of setting vaccination strategies in developing countries.

PMID- 12603354
TI  - The value of the PedsQLTM in assessing quality of life in survivors of childhood
      cancer.
AB  - AIMS: To determine differences in ratings of quality of life (QOL) depending on
      respondent (mother or child) and implications for the validity of measures of
      QOL, and interpretation of scores. METHOD: Forty-five survivors of acute
      lymphoblastic leukaemia (ALL) and 23 survivors of central nervous system (CNS)
      tumours and their mothers completed a generic measure of QOL: the Pediatric
      Quality of Life Inventory Version 4.0 (PedsQL 4.0; Varni et al., 2001). RESULTS:
      Although correlations between mother and survivor ratings were largely moderate
      to good, further analyses showed that mothers reported QOL to be worse than
      survivors. Both mothers and survivors rated physical health worse than
      psychological health, and survivors of a CNS tumour had poorer QOL than survivors
      of ALL. Although survivors of ALL reported reasonably good physical health, their
      psychosocial health was more adversely affected. CONCLUSIONS: Implications for
      further use of the PedsQL 4.0 in the clinical or research context are discussed.
      Incidental findings highlight some limitations of the PedsQL 4.0 for work with
      this population.

PMID- 12603355
TI  - A 6-year follow-up study of chronic constipation and soiling in a specialist
      paediatric service.
AB  - OBJECTIVE: Constipation and soiling is a relatively common condition in childhood
      and its course is often chronic. This study investigated long-term outcome of
      children with chronic constipation and soiling by following up a cohort of
      children 6 years after their presentation to a specialist paediatric
      gastroenterology clinic with chronic constipation and soiling. DESIGN:
      Retrospective postal survey. SETTING/SAMPLE: All children referred in 1991 to a
      specialist paediatric gastroenterology clinic accepting both secondary and
      tertiary referrals. MEASURES: A semi-structured postal questionnaire was sent to
      all families, and the Strengths and Difficulties Questionnaire (SDQ) was sent to
      a random sample. RESULTS: The response rate (of those who could be traced) was
      89%. Of these, over a third (36%) still had a problem with constipation and
      soiling and 17% were using regular laxatives. Three people still having problems
      with constipation and soiling in the sample were aged over 18 years. No
      significant difference was found with regard to age, sex or age at referral
      between the group that improved and the group that did not. Both groups felt they
      had suffered a high degree of distress because of the problem, with parents
      highlighting their powerlessness to help their child and the child identifying
      the embarrassment caused by the problem. CONCLUSIONS: A significant number of
      children presenting to a specialist paediatric clinic continue to have problems
      for several years. Further research is needed to identify these cases and to
      identify which factors promote resolution of the problem.

PMID- 12603356
TI  - Children's representation of family mealtime in the context of maternal eating
      disorders.
AB  - BACKGROUND: Recent research provides evidence for specific disturbance in feeding
      and growth in children of mothers with eating disorders. AIM: To investigate the
      impact of maternal eating disorders during the post-natal year on the internal
      world of children, as expressed in children's representations of self and their
      mother in pretend mealtime play at 5 years of age. METHODS: Children of mothers
      with eating disorders (n = 33) and a comparison group (n = 24) were videotaped
      enacting a family mealtime in pretend play. Specific classes of children's play
      representations were coded blind to group membership. Univariate analyses
      compared the groups on representations of mother and self. Logistic regression
      explored factors predicting pretend play representations. RESULTS: Positive
      representations of the mother expressed as feeding, eating or body shape themes
      were more frequent in the index group. There were no other significant group
      differences in representations. In a logistic regression analysis, current
      maternal eating psychopathology was the principal predictor of these positive
      maternal representations. Marital criticism was associated with negative
      representations of the mother. CONCLUSIONS: These findings suggest that maternal
      eating disorders may influence the development of a child's internal world, such
      that they are more preoccupied with maternal eating concerns. However, more
      extensive research on larger samples is required to replicate these preliminary
      findings.

PMID- 12603357
TI  - Multimedia versus written information for nocturnal enuresis education: a cluster
      randomized controlled trial.
AB  - OBJECTIVE: This study evaluated the impact of child-focused information provision
      using a multimedia software package 'All About Nocturnal Enuresis' and written
      leaflets containing the same information for bedwetting children. DESIGN: A
      stratified cluster randomized controlled trial with data on 270 children
      collected longitudinally. SETTING: Fifteen school nurse-led community enuresis
      clinics in Leicestershire, UK. MAIN OUTCOME MEASURES: The outcome measures were
      becoming and remaining dry and time to dry, non-attendance and dropout rates. The
      psychological measures completed by children were the impact of bedwetting and
      Coopersmith self-esteem scales. Parents completed the maternal tolerance scale.
      RESULTS: No significant intervention effect was found for any of the outcome
      measures recorded during treatment, at discharge or six-months post discharge.
      CONCLUSIONS: Multimedia educational programs and written leaflets are widely used
      to enable children to learn more about their health-related conditions. However,
      our result suggests that multimedia is no more effective than traditional
      materials at effecting health-related behavioural change.

PMID- 12603358
TI  - Ecology of development in children with brain impairment.
AB  - BACKGROUND: Many children with brain impairments develop well in spite of
      negative risk factors or prognoses. Most follow-up and review studies do not show
      uncontroversial effects of particular physiotherapy or activation programmes.
      Evidence is accumulating of environmental influence on brain plasticity, but it
      is not clear what exactly this means for human beings. This paper reports a
      qualitative study of the life histories of 20 children, with severe developmental
      disturbance of neurological origin, who showed marked functional improvements.
      METHODS: Qualitative analysis of a group of 20 children, heterogeneous in
      aetiology or severity of brain impairments (hydrocephalus, porencephalic brain
      cysts, cerebral palsy, Rubinstein-Taybi, Down's or other genetic syndromes), in
      methods of rehabilitation as well as in outcome. RESULTS: In these particular
      children, gross brain abnormalities apparent on initial imaging and early
      functional testing did not appear highly predictive of final outcome. There was
      no observed association between final functioning and any particular type of
      rehabilitation. The outcome rather seems to be the result of a complex process of
      interaction between the child and his/her human ecology; the way the child, as
      well as significant people in his/her environment, perceive problems and possible
      solutions; and the quality and quantity of activation and mediated learning
      experience. CONCLUSION: Development in children with brain impairment does not
      seem to happen spontaneously. It is not a linear but an unpredictable process.
      Both outer (a stimulating environment with lots of activities) as well inner
      aspects (will and interactive processes) constitute a child's rehabilitative
      ecology. The findings are also suggestive for a brain plasticity influenced by
      the ecology of the child.

PMID- 12603359
TI  - Detecting emotional and behavioural problems in paediatric clinics.
AB  - BACKGROUND: Children with chronic illness have increased rates of mental health
      problems and psychological difficulties often present as physical conditions.
      This prevalence survey aims to determine whether children attending general
      paediatric out-patient clinics are at increased risk of suffering from emotional
      and behavioural disturbance and whether there is an unmet need for psychiatric
      liaison to paediatric clinics. METHODS: Participants were 307 children aged 5-15
      years attending a representative sample of paediatric out-patient clinics in one
      UK hospital. A national community sample of 10,438 children aged 5-15 years was
      used as a comparison group. Parental ratings of child behaviour were obtained
      using the Strengths and Difficulties Questionnaire (SDQ). Doctors rated the
      extent of any emotional difficulties using a modification of the SDQ 'impact
      supplement'. RESULTS: Children attending paediatric out-patient clinics were more
      than twice as likely (OR = 2.3, 95% CI 1.7-3.1) to score in the abnormal range of
      the SDQ. Of the 60 (20%) children with a probable psychiatric disorder only 15
      had received specialist help from Child Mental Health Services. There were no
      gender differences in the profile of difficulties with emotional symptoms being
      particularly evident in both boys (OR = 2.85, 95% CI 1.97-4.11) and girls (OR =
      3.04, 95% CI 1.92-4.70). The risk of psychiatric disorder was highest among those
      children with brain disorders attending neurological clinics (OR = 5.8, 95% CI
      2.5-11.3). Clinicians only identified emotional or behaviour problems in a
      quarter of those children with parent-rated disorder. CONCLUSION: There is an
      increased prevalence of emotional and behavioural disturbance in children
      attending paediatric out-patient clinics. The SDQ could be added to routine
      paediatric assessments to aid appropriate referral of children with a possible
      psychiatric disorder to child mental health services.

PMID- 12603361
TI  - Neuromuscular synapse function in typical migraine.

PMID- 12603362
TI  - Acetazolamide acts on neuromuscular transmission abnormalities found in some
      migraineurs.
AB  - Mild subclinical impairment of neuromuscular transmission can be detected with
      single-fibre electromyography (SFEMG) in subgroups of patients suffering from
      migraine and could be due to dysfunctioning Ca2+-channels on motor axons
      controlling stimulation-induced acetylcholine release. Acetazolamide, which is
      thought to ameliorate ion channel function, was shown effective in familial
      hemiplegic migraine and episodic ataxia type 2, both of which are associated with
      mutations of the neuronal Ca2+-channel gene CACNA1A, as well as in aura status.
      We treated therefore in an open pilot study five non-hemiplegic migraineurs
      showing mild SFEMG abnormalities with acetazolamide for several weeks. This was
      followed by a normalization of SFEMG recordings in all patients and by clinical
      improvement in four. These results support the assumption that the subclinical
      impairment of neuromuscular transmission found in certain migraineurs might be
      due to dysfunctioning Ca2+-channels.

PMID- 12603363
TI  - Symptoms of depression and anxiety, and screening for mental disorders in
      migrainous patients.
AB  - The purpose of this clinic-based study was the assessment of symptoms of
      depression, anxiety, and non-specific psychiatric disorders amongst patients with
      migraine, compared with healthy subjects and with individuals with a non
      neurological chronic disease. A cross-sectional study was carried out in which
      178 individuals (migraine 51; psoriasis 35; healthy 92) were submitted to three
      scales: MADRS (depression), STAI-T (anxiety) and SRQ (screening for mental
      disorders). The subjects with migraine and psoriasis were from the Out-patient
      Clinics of Headache and of Dermatology, and the healthy volunteers were persons
      who were accompanying out-patients in the same hospital. Scores were analysed by
      manova and by association analysis and logistic regression. Scores of all
      instruments were higher in the migrainous group, but the univariate analysis of
      association (using cut-offs) showed significance only for suspicion of mental
      disorders (SRQ). By logistic regression, variables with strongest association to
      migraine were gender, education, and SRQ in decreasing order.

PMID- 12603364
TI  - Sleep apnoea and chronic headache.
AB  - The objective of this study was to estimate prevalence of headache and body pain
      among patients referred for suspected sleep apnoea syndrome compared with the
      occurrence in a large population-based study (the Nord-Trondelag Health Study).
      Between 1995 and 1998, ambulatory polysomnography was successfully performed in
      421 consecutive patients, 324 of whom completed a questionnaire about sleep
      related habits, headache and body pain. Headache and neck pain were more likely
      among patients admitted for polysomnography compared with the general population
      (n = 41 340). In the multivariate analyses, this association was mainly
      restricted to those with frequent complaints (> or =7 days per month). Chronic
      headache (headache > or = 15 days per month) was seven times more common among
      individuals with and without confirmed obstructive sleep apnoea syndrome than in
      the general population. There was no linear dose-response relationship between
      headache and neck pain and severity of apnoea or oxygen desaturation. Thus,
      hypoxia per se is less likely to explain the high headache prevalence among
      patients admitted for polysomnography.

PMID- 12603365
TI  - Cranial and peripheral interictal vascular changes in migraine patients.
AB  - As migraine is associated with an increased risk for ischaemic stroke and
      peripheral vasospastic disorders, it was hypothesized that interictal vascular
      changes may be present in migraine patients. Using ultrasound and applanation
      tonometry, the cardiovascular properties of migraine patients were compared with
      those of matched control subjects. Vascular parameters of the carotid arteries,
      cardiac output and systemic vascular resistance did not differ between both
      groups. Right temporal artery diameter was larger in migraine patients (mean
      difference 101 micro m; 95% confidence interval (CI) 9/194 micro m; P = 0.033).
      At the brachial artery, migraine patients displayed a smaller distension
      (difference -24 micro m; 95% CI -45/-4 micro m; P = 0.021) and a decreased
      compliance (difference -0.025 mm2/kPa; 95% CI -0.047/-0.003 mm2/kPa; P = 0.024).
      Thus, migraine patients display an increased peripheral arterial stiffness. The
      presence of these interictal vascular changes suggests that migraine might be
      part of a more generalized vascular disorder.

PMID- 12603366
TI  - Prevalence of headache in patients with Behcet's disease without overt
      neurological involvement.
AB  - The aims of the present study were to evaluate the prevalence of headache and the
      frequency of different headache syndromes in patients with Behcet's Disease (BD)
      without neurological involvement and to investigate the relationship with other
      clinical, and behavioural variables. Twenty-seven BD patients and 27 control
      subjects underwent a validated semistructured questionnaire based on the
      International Headache Society criteria. Levels of anxiety and depression,
      disease activity, and current medication were collected. Headache occurred in
      88.9% of BD patients. There was no difference in the prevalence of the different
      headache syndromes between BD patients and controls. Only migraine without aura
      (MwA) was significantly more frequent in BD patients than controls (44.4% vs.
      11.1%, respectively, P= 0.013). No relationship was found between MwA and
      clinical, and behavioural variables. Among headache syndromes, MwA showed the
      highest frequency in BD. A vascular or neuronal subclinical dysfunction could
      justify this association. A careful interview for migraine might be included in
      the diagnostic work-up of BD.

PMID- 12603367
TI  - Tender points are not sites of ongoing inflammation -in vivo evidence in patients
      with chronic tension-type headache.
AB  - Increased muscle tenderness is the most prominent finding in patients with
      tension-type headache, and it has recently been shown that muscle blood flow is
      diminished in response to static exercise in tender points in these patients.
      Although tenderness has been ascribed to local inflammation and release of
      inflammatory mediators, the interstitial concentration of inflammatory mediators
      has not previously been studied in tender muscles of patients with tension-type
      headache. The aim of the present study was to investigate in vivo concentrations
      of prostaglandin E2 (PGE2), adenosine 5'-triphosphate (ATP), glutamate,
      bradykinin and other metabolites in a tender point of patients with chronic
      tension-type headache, in the resting state as well as in response to static
      exercise, and to compare findings with measurements in a matched non-tender point
      of healthy controls. We recruited 16 patients with chronic tension-type headache
      and 17 healthy control subjects. Two microdialysis catheters were inserted into
      the trapezius muscle and dialysates were collected at rest, 15 and 30 min after
      start of static exercise (10% of maximal force) and 15 and 30 min after end of
      exercise. All samples were coded and analysed blindly. There was no difference in
      resting concentration of any inflammatory mediators or metabolites between tender
      patients and non-tender controls (P > 0.05). We also found no difference in
      change in interstitial concentration of ATP, PGE2, glutamate, glucose, pyruvate
      and urea from baseline to exercise and post-exercise periods between patients and
      controls (P > 0.05). The present study provides in vivo evidence of normal
      interstitial levels of inflammatory mediators and metabolites in tender trapezius
      muscle in patients with chronic tension-type headache during both rest and static
      exercise. Thus, our data suggest that tender points in these patients are not
      sites of ongoing inflammation.

PMID- 12603368
TI  - Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine
      (mCPP) involves nitric oxide and 5-HT2B receptor activation.
AB  - The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine
      like head pain in some subjects, was evaluated for its ability to induce dural
      plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose
      dependently increased PPE. This effect was inhibited by non-selective 5-HT2
      receptor antagonists (methysergide, LY53857, LY215840), by a peripherally
      restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective
      receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B
      receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME
      and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role
      for nitric oxide (NO) and the trigeminal system, respectively. NO release has
      been linked to activation of the 5-HT2B receptor on the vascular endothelium.
      However, LY202146 did not block PPE induced by electrical stimulation of the
      trigeminal ganglion. These data are consistent with activation of peripheral 5
      HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists
      might be effective prophylactic therapies for migraine.

PMID- 12603369
TI  - Cluster headache as a manifestation of intracranial inflammatory myofibroblastic
      tumour: a case report with pathophysiological considerations.
AB  - We report a patient with a secondary form of chronic cluster headache, caused by
      an intracranial presentation of inflammatory myofibroblastic pseudotumour located
      in the posterior fossa, with total remission of the pain after resection. The
      headaches were resistant to many of the usual treatments for cluster headache.
      The patient had two normal computed tomography scans and one normal magnetic
      resonance imaging of the head before the additional diagnosis of brain tumour was
      made. This is an unusual cause of cluster headache with intracranial mass, with
      an unexpected clinical presentation, a rare triggering manoeuvre, unusual
      pathology and successful treatment. This patient probably had the hypothalamic
      biological predisposition to cluster headache and, when a small mass disturbed
      pain-sensitive structures in the posterior fossa, it excited the
      trigeminovascular system via posterior fossa trigeminal and upper cervical
      afferents, and triggered the pathophysiological processes that resulted in a
      secondary form of chronic cluster headache.

PMID- 12603370
TI  - Epidemiology of headache in an English district.
AB  - Headache prevalence, characteristics and impact in adults were measured using a
      cross-sectional general population survey in North Staffordshire, UK. A postal
      survey was mailed out to 4885 adults (aged > or = 18 years) with an adjusted
      response rate of 56% (n = 2662). Of respondents 93% reported headache ever and
      70% in the last 3 months. Women and younger people reported higher headache
      prevalences. Of those reporting headache in the last 3 months, 23% experienced
      headache at least weekly and 16% experienced severe headache pain. Headaches
      affected work, home or social activities in 43% of sufferers and 20% reported at
      least moderate headache-related disability. Higher levels of disability were
      associated with higher levels of pain, 61% with severe disability reporting
      severe pain compared with 13% who had mild or moderate disability. In the total
      adult population sample headache affected more than two-thirds in the last 3
      months and 14% of all adults reported headache-related disability of at least
      moderate level, which translates to a large burden in the general population.

PMID- 12603371
TI  - The sensitivity and specificity of the case definition criteria in diagnosis of
      headache: a school-based epidemiological study of 5562 children in Mersin.
AB  - The objectives of the present study were to estimate the prevalence of recurrent
      headaches in schoolchildren (ranging from 2nd to 5th degrees) in Mersin city of
      Turkey and to determine the sensitivity, specificity, positive predictive value
      and positive likelihood ratio of the diagnostic headache characteristics in
      children with migraine and Tension Type Headache (TTH) using neurologist's
      diagnosis as the gold standard. The stratified sample of study was composed of
      5562 children. The prevalence of recurrent headache was 49.2% (2739 of 5562) and
      the prevalence of current headache was 31.3% (859 of 2739). TTH was more common
      than migraine (24.7% vs. 10.4%). The most sensitive headache characteristic for
      migraine was 'severity of pain' and the most sensitive definitive symptom is
      'duration of headache' in children with TTH. IHS-based symptom definition
      criteria are highly beneficial in diagnosis of childhood headache, if used
      together with detailed clinical assessment.

PMID- 12603372
TI  - Headache associated with dialysis: the International Headache Society criteria
      revisited.
AB  - The International Headache Society (IHS) criteria for headache related to
      haemodialysis consider that the headaches must begin during haemodialysis and
      terminate within 24 h. Twenty-eight patients whose headaches started by the time
      they entered the dialysis programme were prospectively studied. We were not able
      to classify eight patients that presented the headaches between the sessions.
      Despite the small number of patients in our study being too low to provide a
      basis for change in the IHS classification, it serves as an observational report
      demonstrating possible varieties of headache related to haemodialysis.

PMID- 12603373
TI  - Hypnic headache syndrome: association of the attacks with REM sleep.
AB  - We describe the polysomnographic data of two patients with nocturnal headache
      attacks fulfilling the clinical criteria for hypnic headache syndrome. Two
      overnight polysomnographic studies were performed in each patient. Four nocturnal
      headache attacks were captured, all emerging from the REM phase of sleep. Our
      findings suggest a close relationship between the REM phase of sleep and the
      appearance of hypnic headache attacks.

PMID- 12603374
TI  - A case of carotidynia with response to almotriptan.

PMID- 12603375
TI  - Hemicrania with response to indomethacin and prevalent autonomic symptoms: four
      cases.

PMID- 12603376
TI  - Why most women with breast cancer still undergo mastectomy.

PMID- 12603377
TI  - Breast-conserving therapy in low-literacy patients in a developing country.
AB  - The purpose of this study was to determine the frequency with which low-literacy
      patients in a developing country chose their treatment plan. In this study, data
      for 312 patients admitted to different hospitals in Egypt were reviewed regarding
      their disease stage, optimal management plan, and treatment. It was found that
      the majority of patients were primarily concerned with keeping their breasts,
      regardless of the disease stage.

PMID- 12603378
TI  - Breast-conserving therapy with adjuvant paclitaxel and radiation therapy:
      feasibility of concurrent treatment.
AB  - As commonly used, adjuvant paclitaxel after doxorubicin in high-risk breast
      cancer patients results in a prolonged delay of the onset of radiation therapy
      after breast-conserving surgery. Concurrent delivery of breast irradiation with
      paclitaxel would allow for earlier initiation of radiation. We report on the
      toxicity of concurrent paclitaxel and breast irradiation after doxorubicin and
      cyclophosphamide. Twenty-four patients were treated with concurrent breast
      radiation and paclitaxel. All patients received four cycles of doxorubicin and
      cyclophosphamide followed by four cycles of paclitaxel, 175 mg/m2 every 3 weeks.
      The radiation therapy started after the first cycle in 3 patients, after the
      second cycle in 16, and after the third in 5. The breast received 4680-5040 cGy
      external beam irradiation, followed by a boost of 1000-2000 cGy. Fifteen patients
      received supraclavicular irradiation, and a posterior axillary supplement was
      used in five patients. Median follow-up after completion of irradiation was 11.5
      months (range 2-29 months) with 21 patients followed >or=6 months, 12 followed
      >or=12 months, and 7 followed >or=18 months. Using Radiation Therapy Oncology
      Group (RTOG) acute toxicity scoring criteria, 7 patients experienced grade 1 skin
      and/or soft tissue reactions and 17 patients had grade 2 reactions. The average
      total duration of radiation treatment was 49 days (range 41-57 days). Only eight
      patients had radiation therapy interruptions for a median of 3.5 days (range 2-8
      days): two more than 5 days. None had a chemotherapy dose reduction. One patient
      discontinued paclitaxel after the third cycle due to bilateral upper extremity
      neuropathy. No cases of pneumonitis or brachial plexopathy were seen. Concurrent
      treatment with every 3-week paclitaxel and breast irradiation was well tolerated.
      Additional study is needed to determine optimal timing, long-term toxicity, and
      potential benefits of concurrent radiation therapy and paclitaxel.

PMID- 12603379
TI  - Inflammatory breast cancer: results of antracycline-based neoadjuvant
      chemotherapy.
AB  - Twenty-three patients with inflammatory breast cancer treated with a combined
      modality approach including anthracycline-based induction chemotherapy-surgery
      chemotherapy-radiotherapy were reviewed. Twelve patients (52.2%) received FAC (5
      fluorouracil, adriamycin, cyclophosphamide) and 11 patients (47.8%) were treated
      with FEC (5-fluorouracil, epirubicin, cyclophosphamide) induction chemotherapy
      for three cycles every 3 weeks. Surgery was followed by the initial chemotherapy
      or second-line chemotherapy for an additional six cycles to complete nine cycles
      and radiotherapy, respectively. The median overall survival (OS) time was 27
      months and the median disease-free survival (DFS) was 13 months. Furthermore,
      patients treated with FAC induction chemotherapy have been found to have longer
      median OS and DFS periods compared to patients with FEC induction chemotherapy in
      both univariate and multivariate analysis. In conclusion, the superiority of
      doxorubicin-containing chemotherapy over epirubicin-containing chemotherapy
      should be established in larger randomized studies and more effective
      chemotherapeutic agents such as taxans are required for better survival rates in
      inflammatory breast cancer patients.

PMID- 12603381
TI  - Expression of interleukin-6 and tumor necrosis factor alpha and histopathologic
      findings in painful and nonpainful breast tissue.
AB  - Mastalgia is a common condition that is thought to be hormonally related, but the
      mechanisms of pain causation are unknown. Inflammatory cytokines are implicated
      in pain modulation, but have not been studied with regard to mastalgia. We
      compared the relationship of mastalgia to the expression of the cytokines
      interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha and the
      degree of tissue infiltration with inflammatory cells in breast tissue from 29
      premenopausal women with breast pain and 29 age-matched pain-free controls.
      Paraffin sections from breast biopsy samples were scored for the presence of
      inflammatory infiltrate and were evaluated for the expression of IL-6, IL-1beta,
      and TNF-alpha using standard immunohistochemical procedures. TNF-alpha and IL-6
      expression displayed a trend toward slightly lower values in patients with pain
      (median TNF-alpha score, 3 versus 5; median IL-6 score, 3 versus 4). In the
      luteal phase, patients with mastalgia showed a trend toward lower expression of
      IL-6 (p = 0.4) in comparison to those without pain. A similar trend was also seen
      with TNF-alpha expression (p = 0.4). IL-1beta expression was extremely scant in
      the first 30 samples and was not investigated further. The degree of inflammatory
      infiltrate in the tissue was unrelated to the presence of breast pain. These data
      suggest that the three cytokines tested in this study do not play a significant
      role in the causation of mastalgia and lend weight to the previous finding that
      there are no identifiable histologic correlates of this troubling condition.
      Further investigation of the role of cytokines in breast pain is warranted,
      especially in view of the possible association between mastalgia and breast
      cancer risk.

PMID- 12603380
TI  - Failure to harvest sentinel lymph nodes identified by preoperative
      lymphoscintigraphy in breast cancer patients.
AB  - Selective sentinel lymphadenectomy dissection has been demonstrated to have high
      predictive value for axillary staging in breast cancer patients. Preoperative
      lymphoscintigraphy can localize and facilitate the harvesting of sentinel lymph
      nodes (SNLs) with a high success rate. The failure rate of selective sentinel
      lymphadenectomy ranges between 2% and 8%. Details of the failures were seldom
      addressed. This study analyzes the causes of failure to harvest SLNs in spite of
      positive preoperative lymphoscintigraphy. From November 1997 through November
      2000, 201 female patients with histologically confirmed and operable breast
      carcinoma underwent selective sentinel lymphadenectomy at the University of
      California, San Francisco (UCSF) Carol Franc Buck Breast Care Center. Among these
      patients, 183 (91%) received preoperative lymphoscintigraphy to identify axillary
      lymph nodes. The causes of failure to harvest the SLNs in this group of patients
      despite successful preoperative lymphoscintigraphy were analyzed. In our series,
      the failure rate of SLN identification was 7.0% (14/201). The failure rate for
      our first year was 11.1% (6/54), second year 9.1% (7/77), and third year 1.4%
      (1/70). The incidence of failure in spite of positive preoperative
      lymphoscintigraphy was 3.5% (6/170). The shine-through effect of the primary
      injection site and failure to visualize a blue lymph node were the main reasons
      for technical failure. Most of these cases occurred during our learning curve of
      the procedure. The possibility of failure to get the SLN should be explained to
      patients before surgery. Axillary lymph node dissection (ALND) should be done if
      selective SLN dissection is not successful.

PMID- 12603382
TI  - Variation of the prognostic significance of HER-2 expression in breast cancer
      according to tumor size.
AB  - The prognostic importance of HER-2 status in breast cancer has been investigated
      extensively, but findings have not been uniform across immunohistochemical
      studies using fixed, paraffin-embedded specimens. We speculate that studies with
      an overrepresentation of large tumors might not produce evidence for an
      independent effect of a single marker because breast tumors of larger size tend
      to exhibit multiple adverse attributes as the malignancy advances through the
      metastatic cascade. Further, it has been posited that results from certain
      studies of biologic markers might be generalizable only to larger tumors because
      tumor repositories tend to house a disproportionate number of larger tumors. To
      test our hypothesis that the prognostic effect of HER-2 status might be modified
      by the size of the tumor, we conducted a survival analysis of a nested case-case
      sample of 156 women diagnosed with primary breast cancer from 1983 to 1995.
      Relative risks (RRs) and confidence intervals (CIs) for recurrence in relation to
      HER-2 status were estimated using a multivariate Cox proportional hazards model.
      Immunohistochemistry of archival tissue was used to detect HER-2 expression.
      Positive HER-2 status was associated with recurrence (RR = 4.24, 95% CI 1.30
      13.78) among patients with axillary lymph node-positive involvement. This
      analysis identified an interaction (p < 0.01) between tumor size and
      overexpression. Stratification by tumor size revealed an increased risk of
      recurrence associated with HER-2-positive tumors that were <or=2 cm in size (RR =
      13.68, 95% CI 1.06-175.76), whereas no such association was observed among
      patients with HER-2-positive tumors larger than 2 cm. Eligible patients without
      available tumor tissue tended to have smaller tumors compared to study
      participants. Our results might partly explain the variation in evidence across
      HER-2 prognostic studies using fixed tissue and might apply to other putative
      markers of prognosis in breast cancer.

PMID- 12603383
TI  - Intraoperative radiation therapy for breast cancer: technical notes.
AB  - Interest in intraoperative radiation therapy (IORT) for breast cancer is
      increasing as the possible benefits of this technique for the patient become
      apparent. The rationale for the use of this segmental radiation therapy in place
      of whole-breast irradiation is based on the finding that approximately 85% of
      breast relapses are confined to the same quadrant of the breast as the primary
      tumor. Phase I and II trials have demonstrated no increase in postsurgical
      complication rates following the use of single-dose IORT in localized breast
      cancers. Longer follow-up is needed to assess the cosmetic outcome. Clinical
      trials to evaluate the effectiveness of IORT in the treatment of breast cancer
      are currently under way at the European Institute of Oncology (EIO) at the
      University of Milan, Italy, and at Memorial Sloan-Kettering Cancer Center (MSKCC)
      in New York. Here we report the two different techniques in use in these trials.

PMID- 12603384
TI  - Invasive mucinous (colloid) adenocarcinoma of ectopic breast tissue in the vulva:
      a case report.
AB  - We present the first case of primary vulvar mucinous adenocarcinoma of ectopic
      breast origin. The patient is an 84-year-old woman with a mass on the left side
      of her vulva. A left partial vulvectomy with bilateral inguinal lymph node
      dissections revealed a mucinous adenocarcinoma that involved the dermis and
      subcutaneous tissue. The tumor cells were positive for estrogen receptors (ERs),
      progesterone receptors (PRs), and BRST-1 markers. The clinical and pathologic
      features, differential diagnosis, and treatment are discussed.

PMID- 12603385
TI  - Central nervous system progression during systemic response to trastuzumab,
      humanized anti-HER-2/neu antibody, plus paclitaxel in a woman with refractory
      metastatic breast cancer.
AB  - Treatment of selected patients with anti-HER-2/neu antibodies alone (1) or in
      combination with chemotherapy (2) may be of benefit to patients with refractory
      breast cancer. Approximately 30% of breast cancers overexpress HER-2/neu, a
      member of the epidermal growth factor receptor family. These patients may have a
      poorer overall prognosis (3) due to relative resistance to both hormonal therapy
      and chemotherapy (4-6). We recently observed a patient with refractory breast
      cancer who responded to rhuMAB HER-2 (trastuzumab) plus paclitaxel after
      progressing on paclitaxel alone. While on combination treatment she developed
      cerebellar metastases. Follow-up computed tomography (CT) scan revealed that her
      disease continued to respond in the liver, lungs, and bone. This case suggests
      that failure of trastuzumab to cross the blood-brain barrier may compromise its
      overall effectiveness and raises the possibility that the central nervous system
      (CNS), or other sanctuary sites, may become clinically more significant in
      patients with breast cancer in the era of antibody-based therapies.

PMID- 12603386
TI  - Breast cancer in reduction mammaplasty specimens: case reports and guidelines.
AB  - Increasing numbers of women of all ages are electing to have reduction
      mammaplasty for very large breasts. Breast cancer can be an incidental finding in
      reduction mammaplasty specimens. We report here the discovery of breast cancer in
      specimens from four patients who underwent elective breast reduction, three of
      whom had not had recent mammograms. All four patients underwent modified radical
      mastectomy. The role of mammography, surgical options, specimen evaluation, and
      practical guidelines are discussed.

PMID- 12603387
TI  - Treatment of metastatic breast cancer with liver transplantation.
AB  - Resection of liver metastases is accepted as an appropriate treatment for
      colorectal metastases in suitable patients. Liver transplant is not often used
      for malignant disease as there is a high incidence of undetectable
      micrometastases elsewhere and recurrence is likely. The effects of
      immunosuppression may also enhance the growth of malignant cells at other sites.
      We report a case where a young patient with undiagnosed breast cancer with
      axillary and liver metastases underwent liver transplantation and is effectively
      leading a normal life 33 months after transplant.

PMID- 12603388
TI  - Mammary calcifications of the ossifying type.

PMID- 12603389
TI  - HIV-related gynecomastia.

PMID- 12603390
TI  - Breast changes after reduction mammaplasty: a case report with mammographic and
      ultrasonographic findings and a literature review.

PMID- 12603391
TI  - Diffuse hypersecretory micropapillary invasive carcinoma: an unusual ductal
      carcinoma.

PMID- 12603392
TI  - Management of giant fibroadenomas: a case for small incisions for large tumors.

PMID- 12603393
TI  - False-negative cases of breast cancer deaths in mammography screening
      evaluations.

PMID- 12603394
TI  - The aetiology, pathophysiology and management of chronic orchialgia.

PMID- 12603395
TI  - Neuroendocrine differentiation in human prostate tissue: is it detectable and
      treatable?

PMID- 12603396
TI  - Pharmacological management of erectile dysfunction.
AB  - Erectile dysfunction (ED) is a common medical condition that affects the sexual
      life of millions of men worldwide. Many drugs are now available for treating ED;
      oral pharmacotherapy represents the first-line option for most patients with ED.
      Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the
      most widely prescribed oral agent and has a very satisfactory efficacy-safety
      profile in all patient categories. Apomorphine SL is a dopamine D1- and D2
      receptor agonist which has recently been approved for marketing in Europe. It is
      best selected for treating patients with mild to moderate ED. Vardenafil and
      tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be
      approved this year. Both of them have significant positive efficacy-safety
      profiles. Patients who do not respond to oral pharmacotherapy or who cannot use
      it are good candidates for intracavernosal and intraurethral therapy. Alprostadil
      is the most widely used drug, both for injection therapy and for the
      intraurethral route. The efficacy of second-line treatment is high but the
      attrition rate remains significant.

PMID- 12603397
TI  - The role of antiandrogen monotherapy in the treatment of prostate cancer.
AB  - The mainstay of hormonal therapy in prostate cancer has been medical or surgical
      castration, both of which are associated with loss of libido and impotence, and
      may not always be acceptable to the patient. Antiandrogen monotherapy is an
      alternative treatment option to castration. There are two types of antiandrogen,
      i.e. steroidal (cyproterone acetate, CPA), and nonsteroidal (bicalutamide,
      flutamide and nilutamide). Data comparing survival outcome with CPA and
      castration are limited and conflicting. Furthermore, CPA is associated with loss
      of libido and erectile dysfunction. Large phase III trials have established that
      monotherapy with bicalutamide 150 mg once daily provides a survival outcome that
      is not significantly different to that after castration in men with locally
      advanced, non-metastatic disease, while conferring significant advantages for
      sexual interest and physical capacity. Current data are inadequate to draw
      conclusions on the comparative efficacy of flutamide and castration, while
      nilutamide is not licensed for monotherapy. Recent data reveal that bicalutamide
      150 mg given once daily in addition to standard care (radical prostatectomy,
      radiotherapy or 'watchful waiting') significantly delays the progression of early
      (localized or locally advanced) prostate cancer. Bicalutamide has a more
      favourable side-effect profile than the other antiandrogens and is more likely to
      promote compliance.

PMID- 12603398
TI  - Gene-chip technology and prostate cancer: the identification of new genes
      regulating tumour progression.

PMID- 12603399
TI  - The tomato: an important part of the urologist's diet?

PMID- 12603400
TI  - Early ejaculation.

PMID- 12603401
TI  - The use of bisphosphonates in prostate cancer.

PMID- 12603402
TI  - The andropause: bare facts for urologists.

PMID- 12603405
TI  - Time after surgery, symptoms and well-being in survivors of urinary bladder
      cancer.
AB  - OBJECTIVE: To evaluate how an increasing burden of symptoms influences well
      being, anxiety and depression at different intervals after a radical cystectomy
      with urostomy for bladder cancer, as this therapy can induce long-term
      distressful symptoms. PATIENTS AND METHODS: Patients with bladder cancer
      undergoing radical cystectomy in Stockholm between 1969 and 1995 were matched
      with 434 controls from the normal population; all 404 patients operated on
      between 1985 and 1995 at three other hospitals in Sweden were invited to enter
      the study. The final analysis included 306 patients and 310 controls, all
      assessed for symptoms and well-being. RESULTS: A low or moderate level of well
      being was reported by 35% of the patients having none or one of the symptoms
      studied, by 39% with two symptoms, by 45% with three symptoms and by 66% of those
      with four or more symptoms. The values, irrespective of symptom burden, were 45%
      after 2-5 years of follow-up, 58% after 6-10 years and 38% at>10 years after
      surgery. The total symptom burden also influenced the risk of anxiety and
      depression. Symptom prevalence remained largely unaffected by the duration of
      follow-up, except for defecation urgency. CONCLUSIONS: The number of long-term
      symptoms after radical surgery with a urostomy for urinary bladder cancer affects
      the risk of anxiety, depression and low or moderate well-being.

PMID- 12603403
TI  - Banking of fresh-frozen prostate tissue: methods, validation and use.
AB  - OBJECTIVE: To describe the establishment, methods, validation and use of a bank
      of fresh-frozen human prostate tissue. MATERIALS AND METHODS: On obtaining
      informed patient consent, protocols were followed for banking prostate tissue
      from any type of prostatectomy or cystoprostatectomy. A pseudobanking procedure
      was devised to determine the accuracy of assessing the histopathological status
      of the banked tissue. RNA was extracted, its quality assessed and used for
      quantitative real-time reverse transcription-polymerase chain reaction for the
      serine protease hepsin. RESULTS: To date prostate tissue from 112 patients has
      been banked, with pseudobanking in 58. The histopathological assessment showed
      pseudobanked tissue matched adjacent unbanked tissue in 98% of cases for benign
      vs malignant diagnoses, and in 92% of carcinomas for the Gleason score. Hepsin
      expression was significantly higher in malignant than in benign tissues (P <
      0.0001). CONCLUSION: We established a validated method for banking human fresh
      frozen prostate tissue and applied it successfully. Hepsin expression can be used
      to differentiate malignant and benign prostate tissue, and as an indicator of
      tissue heterogeneity.

PMID- 12603408
TI  - Recent trends in the use of radical prostatectomy in England: the epidemiology of
      diffusion.
AB  - OBJECTIVE: To describe recent trends in the use of radical prostatectomy (RP) in
      England, as there is currently no consensus on the most effective treatment for
      localized prostate cancer, although RP is the treatment of choice among
      urological surgeons for men aged < 70 years. METHODS: Routine data were assessed
      to establish the number of RPs performed in England in 1991-99. Age-standardized
      operation rates were compared by region and socio-economic group, and the
      geographical spread of use mapped. RESULTS: The number of RPs performed annually
      increased nearly 20-fold between 1991 and 1999. Rates of surgery were greatest in
      the London National Health Service (NHS) regions and lowest in the Trent region.
      Outside London, the risk of surgery in a NHS hospital was significantly greater
      for men living in the least deprived areas; in London this trend was reversed.
      CONCLUSION: Rapid increases in the use of RP showed marked regional variations,
      most likely related to access to prostate-specific antigen testing and the
      location of surgeons able to carry out radical surgery. By 1999, a third of
      procedures were still being undertaken in 'low-volume' hospitals, with
      implications for the quality of care and outcomes. Crucially, these developments
      occurred in the absence of robust information about the effectiveness of RP.
      Recent funding of a randomized trial of treatment options in this area is
      welcome, but wider questions remain about the timing of the evaluation of
      surgical technologies.

PMID- 12603410
TI  - Testicular-sparing surgery: a reasonable option in selected patients with
      testicular lesions.
AB  - OBJECTIVE: To describe our experience of inguinal exploration in patients who had
      a reasonable chance of having a benign testicular lesion. PATIENTS AND METHODS:
      From 1995 to 2002, 11 patients (mean age 43 years, range 27-63) with testicular
      masses that were suspected to be benign underwent inguinal exploration. RESULTS:
      In nine of the 11 patients, frozen-section analysis and the final pathological
      results were similar, and two underwent inguinal orchidectomy. In seven patients
      the testicle was spared. Finally, because of an uncertain pathological diagnosis
      and patient age, two patients underwent orchidectomy. CONCLUSIONS: Inguinal
      exploration and testicular-sparing surgery are reasonable options in patients
      with peripheral intratesticular lesions, on the basis of preoperative
      ultrasonographic characteristics, and if there is a possibility of the mass being
      benign because of age, race, physical examination and tumour markers.

PMID- 12603411
TI  - Hand-assisted laparoscopic vs the open (flank incision) approach to radical
      nephrectomy.
AB  - OBJECTIVE: To compare the outcome in contemporaneous groups of patients
      undergoing hand-assisted laparoscopic radical nephrectomy (HALRN) or open (flank)
      radical nephrectomy (ORN), as many series worldwide have confirmed the
      feasibility and advantages of LRN in managing renal cell carcinoma (RCC).
      PATIENTS AND METHODS: We retrospectively evaluated 44 patients who underwent
      radical nephrectomy for RCC from 1999 to 2001, 22 by HALRN and 22 by ORN, through
      an extraperitoneal 11th or 12th rib flank incision. Standard perioperative
      variables were assessed; a validated questionnaire was also sent to each patient
      after surgery, allowing them to report their overall satisfaction and the period
      needed for them to return to both routine and full activities. The outcomes of
      HALRN and ORN were compared using Wilcoxon rank-sum analysis. RESULTS: There was
      a statistically significant difference between HALRN and ORN in operative
      duration, length of hospital stay, total narcotic requirement, pain scores at 1
      week and 1 month after surgery, and the time to resume routine and full activity,
      with all variables (except operative duration) lower in the HALRN group. There
      were no significant differences between the groups in pain at 1-3 days, estimated
      blood loss or overall satisfaction. CONCLUSION: Compared with ORN, HALRN is
      associated with lower narcotic requirement, pain scores, a shorter hospital stay
      and earlier resumption of routine and full activities. However, several obstacles
      remain, including increased operative duration and the increased equipment costs.

PMID- 12603412
TI  - Corticosteroid use after prostate brachytherapy reduces the risk of acute urinary
      retention.
AB  - OBJECTIVES: To evaluate the role of short-term steroids after prostate
      brachytherapy to reduce oedema and thus the risk of urinary retention associated
      with brachytherapy, as this can require surgical intervention and may even result
      in incontinence. PATIENTS AND METHODS: A retrospective review was conducted on
      400 consecutive patients with early-stage prostate cancer who underwent
      ultrasonography-guided transperineal brachytherapy. Androgen deprivation was
      given to 146 patients for 3 months before the implant and 280 received a 2-week
      course of dexamethasone (4 mg twice daily for 1 week then 2 mg twice daily).
      Forty-five patients developed acute urinary retention at a median of 12 days
      after implantation. Univariate and multivariate analyses were used to evaluate
      the potential risk factors for urinary retention. RESULTS: Acute urinary
      retention developed in 11.1% of the patients and the risk was predicted by
      increasing prostate volume at the time of diagnosis. This risk was higher (18.8%)
      for men receiving no dexamethasone and lower (8.2%) for those who did. In the
      multivariate analysis the volume at diagnosis and the use of dexamethasone
      remained significant. The use of steroids counterbalanced the effect of
      increasing prostate volume on the incidence of retention. The risk of retention
      was higher in those men receiving androgen deprivation to shrink their prostates
      than in those whose prostates were of suitable size for implantation at the time
      of diagnosis. CONCLUSION: Reducing prostate volume by androgen deprivation before
      brachytherapy may be less important in preventing brachytherapy-related urinary
      retention than the use of corticosteroids to reduce oedema afterward.

PMID- 12603413
TI  - Clinical management of prostatic intraepithelial neoplasia as diagnosed by
      extended needle biopsies.
AB  - OBJECTIVE: To examine the results of the clinical management of patients with
      high-grade prostatic intraepithelial neoplasia (PIN), as diagnosed by extended
      needle biopsies. PATIENTS AND METHODS: The clinical data were reviewed from a
      cohort of 387 men who underwent > or = 10 core prostate needle biopsies between 1
      January 1996 and 31 December 1997 by one urologist (W.C.D.). Two study groups
      were identified; the first comprised 47 patients with only high-grade PIN and the
      second was a control group of 137 patients with only benign findings on their
      biopsies. Those patients with cancer, atypia or a prostatic biopsy with fewer
      than 10 cores were excluded. The clinical and histological data were evaluated.
      The criteria for re-biopsy were two successive increases in prostate specific
      antigen (PSA) level or any change in the findings on digital rectal examination
      (DRE). All patients were monitored at 6-12 month intervals. RESULTS: Of the 387
      patients, 46% had normal findings, 5.2% had atypia, 12.6% had PIN alone, 15
      (3.9%) had PIN plus atypia, 6.7% had PIN plus cancer and 32.3% had cancer. There
      was no significant difference between the PIN and control groups in age, DRE, PSA
      level, prostate size (by ultrasonography), free testosterone level, number of the
      cores and time of follow-up (median 34.8 and 36.6 months for the PIN and control
      groups, respectively). Of the PIN and control groups, 21 (45%) and 43 (31%)
      respectively had at least one re-biopsy. Five patients (24%) in the PIN and one
      (2.3%) in the control group developed cancer (P = 0.0124). All these patients had
      organ-confined disease and were found to have either Gleason scores 3 + 3 or 3 +
      4 on surgical specimens. There was no correlation between the original location
      of PIN and the location of subsequent malignancy. CONCLUSIONS: Patients with one
      set of extended needle biopsies with high-grade PIN should be followed clinically
      every 6-12 months, and it may be safe to reserve repeat biopsy for those with
      changes in PSA level and/or in the DRE.

PMID- 12603414
TI  - The role of neuromodulation in the management of urinary urge incontinence.
AB  - OBJECTIVE: To examine the benefit-risk profile of neuromodulation in treating
      refractory urinary urge incontinence and other voiding disorders. PATIENTS AND
      METHODS: The outcome measures from all patients in pivotal clinical trials who
      had undergone sacral nerve stimulation were analysed retrospectively. RESULTS:
      Neuromodulation was effective in several clinical studies; the response is
      durable and the benefit-risk profile good. CONCLUSION: Sacral nerve stimulation
      is becoming the standard of care for refractory overactive bladder and retention
      problems. The potential benefit of neuromodulation should be included in female
      urology and gynaecology training programmes.

PMID- 12603415
TI  - A prospective evaluation of detrusor ultrastructural changes in bladder outlet
      obstruction.
AB  - OBJECTIVES: To characterize the ultrastructure of detrusor smooth muscle from the
      bladders of symptomatic men with bladder outlet obstruction (BOO) caused by
      benign prostatic enlargement (BPE) and compare this with a matched control group;
      to determine how detrusor morphology relates to urodynamic findings and to
      develop a better understanding of the natural development of bladder dysfunction
      related to BOO. PATIENTS AND METHODS: Twelve men (mean age 66 years, range 52-77)
      with urodynamically confirmed BOO caused by BPE and 12 age-matched asymptomatic
      normally voiding controls (mean age 67.8 years, undergoing cystoscopy for other
      conditions) had detrusor biopsies taken endoscopically. The biopsies were
      processed for electron microscopy using standard methods. The specimens were
      randomized and examined at medium power (x 4000) by an examiner unaware of the
      urodynamic findings. Any ultrastructural patterns identified subjectively were
      noted. RESULTS: In the BOO group eight of the 12 men had a myohypertrophic
      pattern, half of which were associated with a degenerative pattern of
      hypocontractility. Of the remaining four patients, two had the degenerative
      pattern alone and two were normal. The six men whose biopsies had a degenerative
      pattern had consistent postvoid residual volumes of > 150 mL; the remainder all
      had volumes of < 150 mL. There were no ultrastructural abnormalities in the
      control patients. CONCLUSIONS: There are interesting qualitative ultrastructural
      changes in the obstructed detrusor, but they are not consistent enough to provide
      a reliable diagnostic tool. However, there may be an important relationship
      between the degenerative pattern and postvoid residual volume in BOO.

PMID- 12603416
TI  - High-energy transurethral microwave thermotherapy: symptomatic vs urodynamic
      success.
AB  - OBJECTIVE: To evaluate the subjective and objective treatment results of high
      energy transurethral microwave thermotherapy (TUMT) for symptomatic benign
      prostatic hyperplasia (BPH), and investigate the possible variables for
      predicting symptomatic and/or urodynamic success. PATIENTS AND METHODS: Between
      October 1998 and October 2000, 40 men with BPH underwent high-energy TUMT using
      the Targis device (Urologix, Inc., Minneapolis, MN, USA). Evaluation after
      treatment included a clinical determination of the symptom score, a urodynamic
      assessment by peak flow rate and pressure-flow, magnetic resonance imaging (MRI),
      transrectal ultrasonography and endoscopy. The objective and subjective success
      was correlated with several variables before, during and after treatment.
      RESULTS: All patients completed at least 1 year of follow-up after TUMT as
      monotherapy. The symptom score improved from a median (range) of 20.5 (11-28)
      initially to 9 (0-28) (P < 0.001). Twenty-two patients (55%) had a marked and 11
      (28%) a moderate response, giving an overall subjective success rate of 83%.
      Similarly, there was a significant improvement in peak flow rate, from 9.2 (4.4
      13.4) to 15 (3.3-22.9) mL/s (P < 0.001). Twenty-one patients (53%) had a maximum
      flow rate of > 15 mL/s while in eight (20%) it was 10-15 mL/s. Only 20 patients
      changed from unobstructed on the pressure-flow nomogram, i.e. an overall
      objective success rate of 50%. Gadolinium-enhanced T1-weighted MRI 1 week after
      treatment showed a median (range) perfusion defect of 20.7 (5.5-76.6)% of the
      total gland volume. Despite this persisting in all patients, a well-defined
      cavity was apparent in only in seven (18%) at the final evaluation. Cystoscopy 1
      month after therapy showed evidence of necrotic tissue occupying the prostatic
      fossa in all patients. Younger patients were more likely to be urodynamically
      successful, and a higher grade of obstruction predicted symptomatic success.
      CONCLUSION: High-energy TUMT can induce considerable necrosis of the prostate, as
      shown by MRI and cystoscopy. Although there was an adequate improvement in most
      patients' symptoms, there was a successful urodynamic change to unobstructed in
      only half the patients. Younger patients and those with a higher grade of
      obstruction were more likely to have urodynamic and symptomatic success,
      respectively.

PMID- 12603417
TI  - Correlation of intravesical prostatic protrusion with bladder outlet obstruction.
AB  - OBJECTIVES: To determine the effect of intravesical protrusion of the prostate
      (IPP, graded I to III) on lower urinary tract function, by correlating it with
      the results of a pressure-flow study. PATIENTS AND METHODS: In a prospective
      study men (aged> 50 years) with lower urinary tract symptoms were initially
      evaluated as recommended by the International Consultation on Benign Prostatic
      Hyperplasia, together with the IPP and prostate volume, as measured by
      transabdominal ultrasonography. These variables were then correlated with the
      results from a pressure-flow study. RESULTS: The IPP was a statistically
      significant predictor (P < 0.001) of bladder outlet obstruction (BOO) compared
      with other variables in the initial evaluation. In all, 125 patients had
      significant BOO, defined as a BOO index of> 40. Of these men, 94 had grade III
      and 30 had grade I-II IPP. Seventy-five patients had a BOO index of < 40; 69 had
      grade I-II and six grade III IPP. In patients with BOO confirmed on the pressure
      flow study, grade III IPP was associated with a higher BOO index than was grade I
      II (P < 0.001). CONCLUSION: The IPP assessed by transabdominal ultrasonography is
      a better and more reliable predictor of BOO than the other variables assessed.

PMID- 12603418
TI  - Preoperative urodynamic and symptom evaluation of patients undergoing
      transurethral prostatectomy: analysis of variables relevant for outcome.
AB  - OBJECTIVE: To assess the value of preoperative symptom score assessment and
      pressure-flow measurement in men undergoing transurethral prostatectomy (TURP).
      PATIENTS AND METHODS: In a prospective study, 95 men (mean age 74.3 years)
      scheduled for TURP because of their lower urinary tract symptoms, flow rates and
      urinary residual volumes were assessed using the self-administered International
      Prostate Symptom Score (IPSS) and urodynamic pressure-flow studies. At 3 months
      after TURP the patients were reassessed with a flow rate measurement and the
      IPSS. The baseline IPSS and urodynamic values were analysed with respect to the
      endpoints of the study, flow rate and IPSS after TURP, and the improvements
      thereof, respectively. RESULTS: There were significant improvements in mean IPSS
      (- 10.87 points) and peak flow rate (+ 7.06 mL/s) 3 months after TURP.
      Classifying the patients into subgroups with distinctly different initial values
      for IPSS, flow rate, residual urine volume and degree of obstruction (as
      expressed by Abrams-Griffiths number) showed that the flow rate and degree of
      obstruction influenced the improvement in flow rate but not in symptoms after
      TURP. Symptom improvement was only related to the initial level of symptoms. In a
      multivariate analysis, only age was an independent predictor of the outcome
      variables of flow rate and symptoms. CONCLUSIONS: Clinical decision-making
      remains a valid instrument for selecting patients for TURP. Both the IPSS and
      pressure-flow assessment are useful to exclude patients who are unlikely to
      benefit from TURP. Age is an important predictor of the improvement in symptoms
      and flow rates after TURP for the lower urinary tract symptom complex associated
      with benign prostatic enlargement.

PMID- 12603419
TI  - Use and misuse of the concept of quality of life in evaluating surgical
      treatments for lower urinary tract symptoms.
AB  - OBJECTIVE: To investigate how quality of life (QoL) components measured by given
      instruments direct the QoL perspective in treatment studies of lower urinary
      tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). METHODS: Computer
      searches were conducted in Medline, CINAHL and Psychinfo; MeSH terms covering QoL
      and surgical treatments for BPH and LUTS were combined for the search. The
      analysis was based on a framework linking components of QoL to patient outcome.
      RESULTS: Of the 74 papers meeting the inclusion criteria, 48 were published in
      1997-2001, showing the increase of interest of the topic. Most of the papers
      reported the change in QoL by a one-item scale, whilst only a few reported
      results from several of the components in the QoL concept. Some papers regarded
      the change in general health status or parts of health status as changes in QoL.
      Functional status and symptoms, and the bother of symptoms, were often regarded
      as indicators of a change in QoL. CONCLUSION: These analyses show an increasing
      interest in measuring QoL after surgery for LUTS and BPH. In most of the studies
      analysed, the batteries of instruments selected were too narrow in scope to study
      the complexity of QoL. Most papers are based on instruments sensitive to change,
      but the reports do not distinguish the basic assumptions for understanding
      relationships important in QoL research and as a result, the reason for change is
      open to question.

PMID- 12603420
TI  - Endoluminal ultrasonography before retrograde endopyelotomy: can the results
      match laparoscopic pyeloplasty?
AB  - OBJECTIVE: To present the results of endopyelotomy using endoluminal
      ultrasonography (EUS) to identify crossing vessels, as the success rates of
      endopyelotomy are generally lower than pyeloplasty, especially in patients with
      crossing vessels. PATIENTS AND METHODS: Forty-one consecutive patients who
      underwent EUS before a planned retrograde endopyelotomy were analysed
      retrospectively. EUS was used to direct the endopyelotomy incision for patients
      with crossing vessels. Treatment was considered successful if the patient was
      asymptomatic and unobstructed or improved on renography. The results were
      compared to those from 18 patients treated by laparoscopic pyeloplasty, some of
      whom had undergone EUS. RESULTS: Crossing vessels were identified in 27 of the 41
      patients (66%). Primary treatment consisted of endopyelotomy for 26 patients and
      laparoscopic pyeloplasty for 15. The overall success rate for 24 endopyelotomy
      patients with an adequate follow-up (mean 19 months) was 71%, with more success
      in patients with no crossing vessels (11 of 13 (85%) vs six of 11 (55%)). Of the
      18 patients treated by laparoscopic pyeloplasty (mean follow-up 15.1 months) 17
      were successful. CONCLUSION: The results for endopyelotomy were disappointing in
      patients with crossing vessels, despite using EUS. The results suggest that
      patients with crossing vessels should be treated by laparoscopic pyeloplasty.
      More data are needed to compare endopyelotomy with laparoscopic pyeloplasty in
      patients with no crossing vessels.

PMID- 12603421
TI  - The neuroanatomy of the human scrotum: surgical ramifications.
AB  - OBJECTIVE: To define the scrotal nerve origin and distribution with respect to
      surrounding structures in male human fetuses, by using neuronal-specific markers
      and three-dimensional (3D) imaging techniques, as the developmental neuroanatomy
      of the human scrotum has not been studied in detail and an explicit description
      of nerve derivation and distribution in the human scrotum is germane to genital
      reconstructive surgery. MATERIALS AND METHODS: Sixteen normal human fetal penile
      specimens at 17.5-38 weeks of gestation were studied. Specimens were fixed in
      formalin, embedded in paraffin wax, serially sectioned at 6 micro m and stained
      with the neuronal marker S-100. All of the specimens contained the whole penis
      and scrotum from glans to anal verge. The gestational age of the fetuses was
      determined by fetal heel-to-toe length. 3D-computer reconstruction of serial
      sections allowed a detailed analysis of the neuroanatomy of the fetal penis and
      scrotum. RESULTS: The nerves innervating the ventral side of the proximal penis
      and scrotum originated mainly from the perineal nerves arising from pudendal
      nerves. The nerves travelling along the ventral side of penis coalesced at the
      penoscrotal area to be directed into the interscrotal septum. At the penoscrotal
      junction, nerves on both sides of the ventral penis shifted to the interscrotal
      septum in a triangular fashion. The interscrotal septum was densely occupied by
      nerve fibres. Nerves were distributed horizontally to both hemiscrotal walls
      through this interscrotal septum. Both hemiscrota seem primarily to be innervated
      separately. CONCLUSION: The interscrotal septum has a dense innervation. Both
      hemiscrota were innervated mainly by horizontally distributed nerve fibres
      arising from the interscrotal septum. Any procedure violating the penoscrotal and
      interscrotal septal area may jeopardize scrotal innervation.

PMID- 12603422
TI  - The use of tolterodine in children after oxybutynin failure.
AB  - OBJECTIVE: To assess the safety and efficacy of tolterodine tartrate prescribed
      to children who previously failed to tolerate oxybutynin chloride. PATIENTS AND
      METHODS: We reviewed 34 children, followed for>1 year, who were prospectively
      crossed-over from oxybutynin to tolterodine because of side-effects. The initial
      diagnosis was dysfunctional voiding in 31 patients. All patients were placed on a
      behavioural modification protocol. When their symptoms did not improve after 6
      months, treatment with an anticholinergic agent was considered. Urodynamic
      studies were conducted in 20 patients, confirming uninhibited contractions in 19.
      The remaining 14 patients were empirically started on antimuscarinic or
      anticholinergic agents. The 34 patients were treated with oxybutynin for a median
      (range) of 6 (2-84) months. When significant side-effects were reported, they
      were crossed over to tolterodine. The efficacy of tolterodine was assessed as
      defined by the International Children's Continence Society, with tolerability
      assessed and side-effects documented using a questionnaire. RESULTS: The mean age
      at the first dose of tolterodine was 8.9 years; the dose was 1 mg twice daily for
      12 patients and 2 mg twice daily for 22. The median treatment with tolterodine
      was 11.5 months, with 20 (59%) patients reporting no side-effects; six described
      the same but tolerable side-effects as with oxybutynin. Eight patients
      discontinued tolterodine because of side-effects after a median (range) of 5 (1
      11) months. The efficacy of tolterodine was comparable with that of oxybutynin,
      as reported by the questionnaire and voiding diaries. The reduction in wetting
      episodes at 1 year was> 90% in 23 (68%), more than half in five and less than
      half (or failure) in six patients. CONCLUSION: Tolterodine is tolerated well in
      children. In this subgroup of patients who could not tolerate oxybutynin, 77%
      were able to continue tolterodine treatment with no significant side-effects.

PMID- 12603423
TI  - Posterior urethral injuries and the Mitrofanoff principle in children.
AB  - OBJECTIVE: To report our experience of children with trauma causing posterior
      urethral injury who at some stage underwent a Mitrofanoff intervention, as post
      traumatic urethral injuries can demand long-term treatment which (regardless of
      the surgical intervention) requires a period of dilatation of the reconstructed
      urethra. PATIENTS AND METHODS: From 1992 to 2001, 14 patients with urethral
      injuries underwent a Mitrofanoff procedure. Thirteen had been run over by a motor
      vehicle and had severe hip injuries, and one had a direct non-penetrating
      perineal impact lesion (13 boys and one girl, aged 2-13 years at the time of the
      accident). In all cases the Mitrofanoff procedure involved interposing the
      appendix between the bladder and the umbilicus. Only one of the children (because
      of extremely high bladder filling pressures) also underwent an augmentation
      cystoplasty and closure of the bladder neck because there were bony fragments in
      the urethra. RESULTS: The Mitrofanoff technique was considered useful in most
      cases. All patients during a given period used the Mitrofanoff conduit to empty
      their bladder every 3 h; 10 of the 14 are currently voiding urethrally, with an
      adequate flow, and four are not, but emptying the bladder periodically via the
      appendicovesicostomy. The only girl in the group has a major hip deformity and is
      unlikely to undergo urethroplasty; two patients are expecting definitive
      treatment and the other, although having a patent urethra, has no urinary flow.
      He is currently 19 years old and has no erections. CONCLUSIONS: The treatment of
      posterior urethral injuries represents a challenge to surgical teams. Although
      primary suturing of the separated urethral ends is accepted as the best
      treatment, the construction of a temporary continent urinary diversion may be
      considered in the most severe cases.

PMID- 12603424
TI  - Intermittent testicular pain: fix the testes.
AB  - OBJECTIVE: To analyse the presenting features, signs and operative findings of
      children presenting with intermittent testicular pain, as testicular torsion is a
      relatively common and serious emergency in children that can lead to testicular
      loss in up to 80%, although half of these children have previous episodes of pain
      suggestive of intermittent torsion. PATIENTS AND METHODS: Data were collected
      prospectively for all patients presenting with recurrent pain between December
      2000 and June 2001. Variables assessed included presenting symptoms, age, size,
      lie and position of the testis when supine and erect, the operative findings and
      follow-up. RESULTS: Eight children had at least two previous episodes of
      testicular pain; four of these were admitted on six occasions. Two had undergone
      previous scrotal exploration. On clinical examination, six boys had a transverse
      testicle and two a discrepancy in testicular size. All children had their testes
      fixed. At operation in all patients there was abnormal attachment of the tunica
      vaginalis with a typical 'bell clapper' deformity. On follow-up only one patient
      still complains of pain. CONCLUSION: In view of high incidence of abnormalities
      we consider that to improve the testicular salvage rate and prevent testicular
      atrophy, bilateral testicular fixation is recommended for boys with intermittent
      testicular pain and positive clinical findings.

PMID- 12603425
TI  - Loss of CD38 correlates with simultaneous up-regulation of human leukocyte
      antigen-DR in benign prostatic glands, but not in fetal or androgen-ablated
      glands, and is strongly related to gland atrophy.
AB  - OBJECTIVE: To determine whether CD38 loss in benign and malignant prostatic
      disease is related to human leukocyte antigen (HLA)-DR up-regulation, by
      assessing the histopathology of the prostate and the effect of androgen
      deprivation. MATERIALS AND METHODS: Serial sections of frozen fetal (eight),
      infant (six), normal adult (10), benign hyperplastic (BPH, 24), and primary (10)
      and hormone-treated (11) carcinomatous human prostatic tissues were analysed by
      immunohistology for anti-CD38 and HLA-DR antigens. RESULTS: In BPH samples there
      was a significant correlation between CD38 loss (mean 21% of acini) and HLA-DR up
      regulation (mean 20%; P < 0.001). Moreover, 76% of all CD38-negative acini in BPH
      had HLA-DR up-regulation in the same prostate epithelial cells, predominantly in
      atrophic and cystic glands, and in cells with retained secretions (74%). In
      contrast to the uniform expression in normal adult prostate, CD38 was negative or
      partly expressed in fetal acini (mean 19%) and almost completely negative in
      acini of the early infant period (mean 0.7%). In contrast to BPH, cancer cells
      did not selectively up-regulate HLA-DR when CD38 was lost. In patients with
      cancer treated by androgen deprivation, cancer cells were CD38-negative.
      CONCLUSIONS: The absence of CD38 and presence of HLA-DR expression in prostatic
      epithelium is consistent in BPH and tissue surrounding tumour, and strongly
      related to gland atrophy. This is particularly interesting as HLA-DR triggering
      can induce apoptosis of cells, whereas CD38 prevents it. A permissive role for
      androgens to maintain full CD38 expression in epithelial cells is suggested.

PMID- 12603426
TI  - NF-kappa B nuclear localization and its prognostic significance in prostate
      cancer.
AB  - OBJECTIVE: To detect the subcellular localization of NF-kappa B (p65) in human
      prostate cancer tissues of different histological grades, and to test whether NF
      kappa B localization alone, or combined with the histological grade, can be used
      to predict patient outcome. PATIENTS AND METHODS: Prostate cancer tissues were
      obtained from radical prostatectomy specimens; the histological grade was
      determined using the Gleason grading system. Clinical outcomes were defined as
      good (5-year disease-free survival with undetectable levels of prostate specific
      antigen) or poor (progression to bone metastases). The subcellular localization
      of NF-kappa B was visualized by immunohistochemistry using an anti-p65 antibody.
      RESULTS: The NF-kappa B subcellular localization was initially assessed in 45
      specimens; in these samples a nuclear localization of NF-kappa B was specific to
      cancer tissues, but did not correlate with the Gleason score (P = 0.089). NF
      kappa B was then assessed as a prognostic marker to complement Gleason score in
      predicting cancer progression. Tumour tissues from 30 men with a known clinical
      outcome were included; 10 of 17 patients who had a poor outcome were positive for
      NF-kappa B nuclear staining, whereas only two of 13 with a good outcome were
      positive (P = 0.026). When NF-kappa B subcellular localization and Gleason score
      were combined, two risk categories of progression were defined. Eleven of 13
      specimens from those with a good outcome were in the low-risk category (Gleason 2
      4 or Gleason 5-7 with negative nuclear NF-kappa B) and 12 of 17 in the poor
      outcome group were in the high-risk category (Gleason 8-10 or Gleason 5-7 with
      positive nuclear NF-kappa B; P = 0.004). CONCLUSION: NF-kappa B is detectable in
      the nucleus in prostate cancer tissues and positivity can be used to help predict
      patient outcome. Multivariate analyses using other clinical and molecular
      variables are underway, and will validate the usefulness of NF-kappa B as a
      prognostic factor.

PMID- 12603427
TI  - Gene therapy, urological disease and the pharmaceutical industry.

PMID- 12603428
TI  - A novel technique for ureteric access in ileal conduits.

PMID- 12603430
TI  - Elastosis perforans serpiginosa of the penis.

PMID- 12603429
TI  - A type 2B von Hippel-Lindau family masquerading as a metastatic sporadic renal
      cell carcinoma.

PMID- 12603432
TI  - Circumcision and newborn UTIS: Winberg's solution.

PMID- 12603433
TI  - Intra-ureteric capsaicin in loin pain haematuria syndrome: efficacy and
      complications.

PMID- 12603434
TI  - An audit of urodynamic standardization in the West Midlands, UK.

PMID- 12603439
TI  - Contraceptive practice of women with opiate addiction in a rural centre.
AB  - This study aimed to explore the contraceptive practices of women in methadone
      treatment for opiate use in rural New South Wales and the reasons for those
      practices. Demographic characteristics, including age, marital status, sexual
      activity and contraceptive use, of all 23 women on a rural methadone program were
      documented. A smaller subgroup of seven women was interviewed using a semi
      structured qualitative technique and issues around contraception explored in more
      depth. The study found that women who did not use contraception often had a low
      perceived risk of pregnancy for a variety of reasons including past infertility,
      menstrual irregularities and effect of drugs. The women had concerns about, and
      often felt guilty about, the effect of drug use on their children. They also had
      concerns about the side-effects of contraception. The study has implications for
      education and counselling of women when they enter drug treatment programs.
      Problems associated with opiate use are not just restricted to metropolitan areas
      but are part of rural health.

PMID- 12603440
TI  - Professional and social support networks of rural general practitioners.
AB  - This study explored the nature of rural general practitioners' (GPs) professional
      and personal support networks. A qualitative design was employed, using in-depth
      interviews with a diverse sample of GPs in rural Queensland. The support network
      of the rural GPs in this study incorporated the domains of clinical, workforce
      and social support, with clinical support as the most important domain. There was
      a preference for face-to-face contact wherever possible. Such contact was
      particularly important in the process of developing the network and for personal
      support. Despite this, many network contacts were by telephone out of necessity.
      There were few notable differences between male and female rural GPs on the
      issues explored in the present study. General Practitioners' satisfaction with
      their professional interactions was varied across the sample. The findings
      suggest that level of satisfaction may be associated with intentions to leave or
      stay for this group.

PMID- 12603441
TI  - Ruralising medical curricula: the importance of context in problem design.
AB  - The establishment of a new medical school in northern Australia, with its focus
      on preparing graduates to understand the health care needs of the regional
      population, has raised an interesting issue in problem design for teaching and
      assessing in an integrated curriculum. This issue is the extent to which the
      clinical content of a teaching or assessment problem should consider more subtle
      contextual issues that help to define the different roles played by rural
      practitioners, rather than what might be regarded as appropriate for "generic"
      medical education. This brief paper provides example case studies that highlight
      the challenge facing curriculum designers developing programs for rural clinical
      schools.

PMID- 12603442
TI  - Variation in religious affiliations between different populations: metropolitan,
      rural, agricultural and elderly.
AB  - People with a religious affiliation are more likely to hold beliefs affecting
      health care choices. It is hypothesised that a religious affiliation,
      particularly to a Christian religion, is more common outside metropolitan areas,
      particularly in rural, very elderly and agricultural populations. The study's aim
      was to test this hypothesis. Rural, very elderly and agricultural populations
      within regional Victoria were compared with Melbourne on religious affiliations
      reported in the 1996 census. A religious affiliation was significantly more
      common in the very elderly (83.3%) and agricultural (86.1%) populations than in
      Melbourne (79.1%). A Christian affiliation was significantly more common in the
      rural (78.6%), very elderly (82.9%) and agricultural (85.8%) populations than in
      the metropolitan area (72.5%), while a non-Christian affiliation was
      significantly less common (< 0.8 vs. 6.6%). This study confirms that a Christian
      religious affiliation is more common outside metropolitan areas, particularly in
      rural, very elderly and agricultural populations. Beliefs affecting health-care
      choices are also likely to be more common in very elderly and agricultural
      populations due to their higher level of religious affiliation overall.

PMID- 12603443
TI  - Analysis of ante-partum maternal morbidity in rural Bangladesh.
AB  - This paper presents the results of a prospective study of maternal morbidity
      during the ante-partum period in rural areas of Bangladesh. The data came from a
      survey of Maternal Morbidity in Bangladesh, conducted by the Bangladesh Institute
      of Research for Promotion of Essential and Reproductive Health and Technologies
      (BIRPERHT) during the period from November 1992 to December 1993. Since then no
      such national level survey has been conducted in Bangladesh. This paper employs
      multiple-decrement life table technique, a convenient way of analysing the risks
      of different types of disease conditions that women experience during the
      antenatal period for different age categories. The high-risk complications such
      as ante-partum haemorrhage, excessive vomiting, fits/convulsion and oedema were
      considered in this study. In this study a cause specific model was applied to
      explore the differences in the risks exerted at different ages of reproductive
      life attributable to some selected complications of pregnancy. The results of
      this study indicate that women of age 25-29 years are less susceptible to most of
      the selected life-threatening and high-risk complications during pregnancy such
      as haemorrhage, fits/convulsion and oedema. However, younger women (age < 25
      years) are more likely to have excessive vomiting during pregnancy, and older
      women (age > or = 30 years) are at greater risk of haemorrhage, fits/convulsion
      and oedema.

PMID- 12603444
TI  - Rural community pharmacy: a feasible site for a health promotion and screening
      service for cardiovascular risk factors.
AB  - A pharmacist-delivered health promotion and screening service for cardiovascular
      risk factors in rural community pharmacy was implemented in the Upper Hunter
      Valley, New South Wales (NSW). We describe the development of the service and
      profile 204 participants at their initial screening. A standardised clinical
      protocol guided the pharmacist through delivery of the service. The mean age of
      participants was 44 years (SD +/- 13). Over half (54%) had a Body Mass Index
      (BMI) > 25, 54% had cholesterol > 5.0 mmol L-1 and 18% a systolic BP> or = 140
      mmHg and/or diastolic BP >or = 90 mmHg. Most (80%) received lifestyle information
      (dietary, exercise or smoking cessation). One third required referral to a
      general practitioner. Provision of the service through community pharmacy
      increased the community's access to screening, 28% reported that they had never
      had their cholesterol measured. Since this new service was able to identify,
      educate and refer people at risk of cardiovascular disease in a rural community,
      we recommend a broader adoption through rural pharmacies.

PMID- 12603445
TI  - Starting out in rural New South Wales: the experiences of new graduate
      occupational therapists.
AB  - The current shortage of health personnel in rural Australia is compounded by the
      difficulty in recruiting and retaining new graduate health professionals in rural
      practice. This qualitative study aimed to explore the experiences of five new
      graduate occupational therapists who began their careers in rural New South Wales
      (NSW). Data were collected via semi-structured, individual interviews. Results
      indicated that new graduates were attracted to their rural positions by multiple
      factors, especially their previous rural experience. Participants experienced low
      self-confidence during their transition from student to therapist. Rewarding and
      challenging aspects of rural practice were identified. New graduates valued
      challenging aspects of rural practice as opportunities for skill development.
      Results suggest that increasing the number of occupational therapy graduates with
      rural experience may attract more graduates to rural practice. Furthermore,
      enhancing the support available to new graduates in rural positions may help
      retain graduates in rural practice.

PMID- 12603446
TI  - New South Wales rural general practice from a Yank's perspective.
AB  - The author, a family practice specialist from Minnesota in the United States,
      worked as a locum in rural New South Wales for 6 months. This provided him with
      the opportunity to reflect on the differences between the specialty of family
      practice in his home state of Minnesota and general practice in New South Wales;
      and to recognise that general practice in New South Wales is at a crossroads.
      This paper highlights the need for general practitioners (GPs) to work together
      and support each other, to provide quality care and to lobby both State and
      Commonwealth governments on the importance of broadly trained GP specialists in
      rural communities. To influence the future of their profession, GPs in New South
      Wales need to focus on quality of care and on educating themselves, their
      colleagues and the communities in which they work.

PMID- 12603449
TI  - Meeting the challenge of clinical governance in pain management.

PMID- 12603450
TI  - Adverse airway events during brief nasal inhalations of volatile anaesthetics:
      the effect of humidity and repeated exposure on incidence in volunteers
      preselected by response to desflurane.
AB  - Twelve volunteers known to have airways that responded adversely to 2.0 MAC
      desflurane were recruited. Each volunteer inhaled three single breaths of each of
      0.5, 1.0 and 2.0 MAC of sevoflurane, halothane, isoflurane, desflurane and
      balance air, with breaths of air between, whilst breathing nasally through a face
      mask attached to one of three filters that provided three different levels of
      humidification. The incidence of any adverse airway events was recorded. The
      anaesthetic inhaled significantly affected the incidence of adverse airway events
      (p < 0.001), with the least to most irritant being sevoflurane, halothane,
      isoflurane and desflurane. Increasing the concentration of anaesthetic also
      significantly increased the incidence of adverse airway events (p < 0.001). The
      filter used, and hence the level of humidification, did not affect the incidence
      of adverse airway events (p = 0.09), but repeated exposure caused a significant
      reduction in the incidence of adverse airway events (p < 0.001).

PMID- 12603451
TI  - A comparison of propofol and sevoflurane anaesthesia: effects on aortic blood
      flow velocity and middle cerebral artery blood flow velocity.
AB  - We compared systemic (aortic) blood flow and cerebral blood flow velocity in 30
      patients randomly allocated to receive either propofol or sevoflurane
      anaesthesia. Cerebral blood flow velocity (CBFv) was measured in the middle
      cerebral artery using transcranial Doppler. Systemic blood flow velocity (SBFv)
      was measured in the aorta using transthoracic Doppler sonography at the level of
      the aortic valve. Bispectral index (BIS) was used to measure the depth of
      anaesthesia. Measurements were made in the awake patient and repeated during
      propofol or sevoflurane anaesthesia, with BIS measurements of 40-50. The effects
      of SBFv on CBFv were estimated by calculating the cerebral/systemic blood flow
      velocity-index (CsvI). A CsvI value of 100 indicating a 1 : 1 relationship
      between CBFv and SBFv. The results demonstrated that propofol anaesthesia
      produced a significantly greater reduction in CsvI than did sevoflurane
      anaesthesia [propofol: 60 (19); sevoflurane: 83 (16), p = 0.009, t-test]. This
      suggests a direct reduction in CBFv independent of SBFv during propofol
      anaesthesia. The greater reduction of CBFv occurring during propofol anaesthesia
      may be due to lower cerebral metabolic demand compared with sevoflurane
      anaesthesia at comparable depths of anaesthesia.

PMID- 12603452
TI  - Changes in calcitonin gene-related peptide, atrial natriuretic peptide and brain
      natriuretic peptide in patients undergoing coronary artery bypass grafting.
AB  - The initiation of cardiopulmonary bypass creates significant derangements in
      cardiovascular volume status and both endocrine and autonomic nervous system
      function. To examine whether such derangements might differ in patients with
      different pre-operative physical status scores, we measured the plasma
      concentrations of calcitonin gene-related peptide, atrial natriuretic peptide and
      brain natriuretic peptide, catecholamines and antidiuretic hormone, as well as
      haemodynamic variables, during and after cardiopulmonary bypass in 27 consecutive
      patients undergoing coronary artery bypass grafting. The pre-operative levels of
      atrial natriuretic peptide and brain natriuretic peptide differed significantly
      between ASA II patients and III and IV patients [mean (SD) brain natriuretic
      peptide levels = 14 (8.2) vs. 129 (51) pg.ml-1]. Plasma calcitonin gene-related
      peptide increased significantly in both groups after the initiation of
      cardiopulmonary bypass, and remained increased throughout cardiopulmonary bypass.
      The changes in plasma epinephrine, norepinephrine and antidiuretic hormone were
      similar to those reported previously. The changes in plasma calcitonin gene
      related peptide, atrial natriuretic peptide and brain natriuretic peptide did not
      correlate with any changes in haemodynamic variables before or after
      cardiopulmonary bypass. Measurement of plasma brain natriuretic peptide might
      usefully be included in the pre-operative evaluation of patients with cardiac
      disease.

PMID- 12603453
TI  - Anaesthetists' attitudes to teamwork and safety.
AB  - A questionnaire survey was conducted with 222 anaesthetists from 11 Scottish
      hospitals to measure their attitudes towards human and organisational factors
      that can have an impact on effective team performance and consequently on patient
      safety. A customised version of the Operating Room Management Attitude
      Questionnaire (ORMAQ) was used. This measures attitudes to leadership,
      communication, teamwork, stress and fatigue, work values, human error and
      organisational climate. The respondents generally demonstrated positive attitudes
      towards the interpersonal aspects of their work, such as team behaviours and they
      recognised the importance of communication skills, such as assertiveness.
      However, the results suggest that some anaesthetists do not fully appreciate the
      debilitating effects of stress and fatigue on performance. Their responses were
      comparable with (and slightly more favourable than) those reported in previous
      ORMAQ surveys of anaesthetists and surgeons in other countries.

PMID- 12603454
TI  - Clinical governance and chronic pain: towards a practical solution.
AB  - There have been many studies into the effectiveness of single interventions in
      pain, however, little is known of performance or outcome of pain clinics where
      treatment often consists of multiple, complex interventions. Many pain clinicians
      currently experience considerable difficulty in fulfilling the requirements of
      clinical governance and completing a personal portfolio. There is a clear and
      urgent need for a viable method of monitoring performance. This study describes a
      well-developed computer-based system - Pain Audit Collection System (PACS). PACS
      has been designed by pain clinicians through consensus and its success in uptake
      suggests that it is a viable method for outcome evaluation. An analysis is
      provided of outcome data in typical pain clinics. Further work is needed to
      investigate the utility of this data.

PMID- 12603455
TI  - Nasotracheal intubation for head and neck surgery.
AB  - Nasotracheal intubation offers the head and neck surgeon more scope for surgical
      manoeuvre in operations of the mouth, pharynx, larynx and also the neck. Concern
      over the complications of using this route of intubation and lack of training may
      be limiting its use. A thorough knowledge of the anatomy, benefits of using nasal
      vasoconstrictors and attention to technique are prerequisites to maintaining the
      skill. This article reviews each of these topics and aims to encourage the
      appropriate use of nasotracheal intubation in current practice.

PMID- 12603457
TI  - Flow through disposable alternatives to the laryngeal mask.

PMID- 12603456
TI  - Probable dystonic reaction after a single dose of cyclizine in a patient with a
      history of encephalitis.
AB  - A patient underwent an emergency Caesarean section under general anaesthesia for
      an antepartum haemorrhage. Following delivery of a live infant, cyclizine was
      administered in accordance with departmental anti-emetic protocol. On awakening
      she was confused, slow to articulate and had slurred speech. A computed
      tomography (CT) scan, which was performed to exclude an intracranial event, was
      normal. Her symptoms were suggestive of a lingual-facial-buccal dyskinesia as
      seen with dopamine antagonists. A presumptive diagnosis of a dystonic reaction to
      cyclizine was made. She received two doses of procyclidine before her symptoms
      completely resolved. Cyclizine has had a resurgence in popularity owing to the
      recent withdrawal of droperidol and anaesthetists should be aware that, although
      extremely rare, dystonic reactions may occur with this agent.

PMID- 12603458
TI  - General principles of consent.

PMID- 12603459
TI  - In defence of traditional Chinese herbal medicine.

PMID- 12603461
TI  - Transoesophageal echocardiography during surgery for intra-atrial masses.

PMID- 12603462
TI  - A sore throat in a dialysis patient.

PMID- 12603463
TI  - Cocaine and pulmonary oedema.

PMID- 12603464
TI  - Magnesium sulphate as a first line therapy in the management of tetanus.

PMID- 12603465
TI  - Minor or major?

PMID- 12603467
TI  - A simple leak detection device for TIVA.

PMID- 12603468
TI  - Phenylephrine in obstetric regional anaesthesia.

PMID- 12603469
TI  - Problems performing a sciatic nerve block in an amputee.

PMID- 12603471
TI  - Volume and colour coding for syringes.

PMID- 12603472
TI  - Stylet for reinforced laryngeal mask airway.

PMID- 12603473
TI  - Measurement of oxygen consumption during low-flow anaesthesia.

PMID- 12603474
TI  - Diffusion of nitrous oxide into the cuff of the laryngeal tube.

PMID- 12603475
TI  - Anaesthesia for cardioversion.

PMID- 12603476
TI  - Let there be light.

PMID- 12603477
TI  - Air in the epidural space leading to a neurological deficit.

PMID- 12603478
TI  - Treating ECG changes during Caesarean section: is it worth the headache?

PMID- 12603479
TI  - The use of nitrous oxide in anaesthetic practice: a second questionnaire survey.

PMID- 12603480
TI  - Concealed airway complication during LeFort I osteotomy.

PMID- 12603481
TI  - Not NICE advice.

PMID- 12603482
TI  - Sevoflurane conscious sedation for MRI scanning.

PMID- 12603483
TI  - To premed or not to premed.

PMID- 12603484
TI  - Midwifes putting the pressure on...?

PMID- 12603485
TI  - Why so slow?

PMID- 12603493
TI  - Fever of unknown origin in adults: 40 years on.
AB  - A revision of the criteria of fever of unknown origin (FUO), established in 1961,
      is desirable because of important evolutions in medical practice and the
      emergence of new patient populations. The development of rapid laboratory tests
      and powerful diagnostic tools, such as ultrasonography, computed tomography and
      magnetic resonance imaging often makes hospitalization unnecessary and new
      categories of patients such as those with HIV infection, neutropenia,
      immunosuppression and nosocomial illness require an approach different from
      classical FUO. The more then 200 reported causes of FUO can be classified into
      four diagnostic categories; infections, tumours, noninfectious inflammatory
      diseases (NIID) and miscellaneous. A uniform classification system is highly
      wanted to allow comparison between different series. The reports of the 1990s
      show slight changes in the distribution of causes, namely less infections, less
      tumours, more NIID and more undiagnosed cases. A uniform diagnostic strategy
      cannot be determined. The initial investigation should be directed by potentially
      diagnostic clues revealed by extensive history, meticulous physical examination
      and a standard set of laboratory tests. 18Fluoro-deoxy-glucose-positron-emitted
      tomography is a new valuable total body scintigraphy in the search for the site
      of origin of the fever. In view of the rather good long-term prognosis, a wait
      and-see strategy may be more appropriate than a systematic staged approach.
      Elderly patients and patients with episodic fever represent two specific groups
      of classical FUO that require a distinct approach. HIV-associated, nosocomial and
      neutropenic FUO should be considered as separate clinical entities.

PMID- 12603492
TI  - Exercise stress testing, myocardial perfusion imaging and stress echocardiography
      for detecting restenosis after successful percutaneous transluminal coronary
      angioplasty: a review of performance.
AB  - When chest symptoms recur in a patient who underwent percutaneous transluminal
      coronary angioplasty (PTCA), it is necessary to rule out restenosis (R). Three
      main noninvasive tests suggest the presence of R: exercise stress test (XT),
      myocardial perfusion imaging (MPI) and stress echocardiography (s-echo). The
      objectives of this review were: (1) to estimate the pretest probability of R as a
      function of time after PTCA in symptomatic patients and (2) to obtain an
      approximation of the diagnostic parameters of the XT, MPI and s-echo for
      detecting R. A MEDLINE search (English-language, years: 1980-2001) was conducted
      to identify studies examining post-PTCA functional testing for diagnosing R. Data
      from the studies were pooled. Comparing studies was often difficult due to
      varying methodology in the studies. Pretest probability of R in symptomatic
      patients increases in a nonlinear fashion from 20% or less at 1 month, to nearly
      90% at 1-year postangioplasty. The approximated accuracy of the XT, MPI, and s
      echo for detecting R was 62, 82 and 84%, respectively. During the first month
      after PTCA, none of the noninvasive modalities is able to accurately detect R.
      Late (7-9 months) after PTCA, the pretest probability of R is high and therefore
      the noninvasive measure may be spared. Our analysis suggests that MPI and s-echo
      should be preferred over the XT for diagnosing R.

PMID- 12603494
TI  - Mortality amongst participants in Vasaloppet: a classical long-distance ski race
      in Sweden.
AB  - OBJECTIVE: The aim of this study was to assess mortality amongst participants in
      long-distance ski races during the Vasaloppet week. We considered the 90 km races
      for men and 90 or 30 km for women. The vast majority of the participants in these
      races are not competing on the elite level. It is assumed, however, that they
      have to undergo regular physical training during a long period of time in order
      to successfully finish the race. DESIGN: The cohort study consisted of 49 219 men
      and 24 403 women, who participated in any of the races during 1989-1998. All
      subjects were followed up in the National-Cause-of-Death-Register until 31
      December 1999. We computed the standardized mortality ratios (SMRs) adjusting for
      age and calendar year. RESULTS: Overall, 410 deaths occurred, compared with 850.6
      expected, yielding an SMR of 0.48 [95% confidence interval (CI) 0.44-0.53]. Low
      SMRs were found in all age groups in both men and women and in all groups after
      categorization by finishing time and number of races. The lowest SMRs were found
      amongst older participants and in those who participated in several races. A
      decreased mortality was observed in all major diagnostic groups, namely cancers
      (SMR = 0.61; 95% CI 0.52-0.71), diseases of the circulatory system (SMR = 0.43;
      95% CI 0.35-0.51), and injuries and poisoning (SMR = 0.73; 95% CI 0.60-0.89). For
      lung cancer the SMR was 0.22, but even after exclusion of lung cancer the all
      cancer mortality was low (SMR = 0.72; 95% CI 0.59-0.86). CONCLUSIONS: We conclude
      that participants in long-distance skiing races, which demand prolonged regular
      physical training, have low mortality. The extent to which this is due to
      physical activity, related lifestyle factors, genetics or selection bias is yet
      to be assessed.

PMID- 12603496
TI  - Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes.
AB  - OBJECTIVES: Amongst nondiabetic individuals, a high serum homocysteine
      concentration is an independent but relatively weak risk factor for coronary
      events. However, it is not known whether homocysteine increases risk of coronary
      events in type 2 diabetes. Therefore, we examined the combined effect of
      homocysteine and type 2 diabetes on risk of fatal and nonfatal coronary events.
      SUBJECTS: We assessed the 10-year risk of coronary events associated with
      homocysteine amongst diabetic (n = 140) and nondiabetic (n = 361) individuals.
      DESIGN: We did this in the Hoorn Study, a population-based study of glucose
      tolerance and related complications in Caucasian men and women aged 50-75 years.
      RESULTS: The incidence rate for coronary events was 2.63 (29 of 140) per 100
      person-years amongst diabetic and 1.29 (42 of 361) amongst nondiabetic
      individuals. Amongst diabetic individuals, risk of coronary events increased 28%
      for each 5-micromol L(-1) increment of homocysteine (hazard ratio, 1.28; 95% CI,
      1.02-1.58). This risk was independent of age, sex, hypertension, total
      cholesterol, HDL-cholesterol, cigarette smoking, body mass index and glomerular
      filtration rate. In nondiabetic participants, homocysteine was not associated
      with an increased risk of coronary events (hazard ratio for each 5-micromol L(-1)
      increment of homocysteine, 0.86; 0.52-1.41). CONCLUSIONS: These data suggest that
      homocysteine is significantly associated with coronary events in individuals with
      type 2 diabetes, independent of traditional cardiovascular risk factors.
      Investigation of the effect of treatment with vitamin B on prognosis of
      individuals with type 2 diabetes is warranted.

PMID- 12603495
TI  - Plasma total homocysteine levels and prognosis in patients with previous
      premature myocardial infarction: a 10-year follow-up study.
AB  - OBJECTIVES: To explore plasma total homocysteine (tHcy) as a predictor of long
      term prognosis after premature myocardial infarction (MI). DESIGN: Prospective
      cohort study. SETTINGS: Akershus University Hospital. SUBJECTS: A total of 247
      patients (193 men and 54 women) in stable clinical phase after premature MI
      (males: first MI at age < or =55; females < or =60). MAIN OUTCOME MEASURES: The
      primary end-point was total mortality and the secondary end-point was cardiac
      death. The third end-point was major cardiac events: a combination of cardiac
      death, MI and cardiac arrest. RESULTS: After 10 years, 44 patients had died, 36
      from cardiac causes. Major cardiac event occurred in 70 patients. The relative
      risk for death of all causes increased 1.43 (95% CI, 1.08-1.88) per tHcy quartile
      (P for trend = 0.01), and was only modestly reduced after adjustment for age,
      ejection fraction, total cholesterol, C-reactive protein, fibrinogen, smoking and
      hypertension to 1.37 (95% CI, 1.04-1.80) (P for trend = 0.03). Similar results
      were observed when cardiac death was used as the end-point, but we observed no
      association between tHcy and the end-point major cardiac event. CONCLUSIONS:
      Total homocysteine was an independent predictor of total and cardiac mortality in
      stable patients following premature MI. tHcy had no effect on major cardiac event
      in contrast to most other risk factors in this study. Thus, the mechanism(s)
      underlying the effects of homocysteine on coronary heart disease may differ from
      other risk factors.

PMID- 12603497
TI  - Changing sex ratio in acute coronary heart disease: data from Swedish national
      registers 1984-99.
AB  - OBJECTIVES: To examine trends in sex ratios for different manifestations of
      coronary disease. DESIGN: National Swedish registers on hospital discharges and
      cause-specific deaths were used to calculate age- and sex-specific trends and sex
      ratios for coronary admissions and deaths. SETTING: Nineteen Swedish counties,
      average population 4.8-5.1 million in the investigated age groups. SUBJECTS: All
      patients aged 25-84 years with first hospital admissions or deaths as a result of
      coronary heart disease in 1984-99, in total 432,871 cases. MAIN OUTCOME MEASURES:
      Ratio men/women and rates (per 100,000) of acute myocardial infarction (AMI),
      acute admissions for angina and total of all acute admissions for any coronary
      disease. RESULTS: Below age of 65 years AMI incidence decreased more for men than
      for women and rates of acute admissions for angina increased more in women than
      in men. In men and women above 65 years trends were almost identical. In 1984-87
      the ratio men/women with respect to myocardial infarction was 5.6 at age 25-44
      years, but decreased to 3.7 in 1996-99. Corresponding sex ratios for angina
      decreased from 3.2 to 1.8 and for total coronary heart disease from 4.7 to 2.8.
      Amongst men and women aged 45-54 years, the sex ratio with respect to myocardial
      infarction decreased from 5.6 to 4.1, for angina from 2.4 to 1.7 and for total
      acute coronary disease from 4.2 to 2.7. Ratios men/women decreased less at higher
      ages and remained unchanged throughout the period in the oldest age group.
      CONCLUSIONS: Overall, we found decreasing sex ratios at ages below 65, but above
      age 65 years trends in men and women were similar. These developments could be
      due to changing criteria for admission and diagnosis, but true differences in the
      clinical manifestation of coronary disease, possibly in response to secular
      trends in risk factor levels, cannot be excluded.

PMID- 12603498
TI  - Elevation of biochemical markers for myocardial damage prior to hospital
      admission in patients with acute chest pain or other symptoms raising suspicion
      of acute coronary syndrome.
AB  - OBJECTIVES: To evaluate the occurrence of elevation of serum biochemical markers
      for myocardial damage in the prehospital setting amongst patients who called for
      an ambulance due to a suspected acute coronary syndrome (ACS). DESIGN:
      Prospective observational study. SUBJECTS: All the patients who called for an
      ambulance due to suspected ACS. SETTING: South Hospital's catchment area in
      Stockholm and in the Municipality of Goteborg, Sweden between January and
      November in the year 2000, were included. INTERVENTIONS: On arrival of the
      ambulance crew, a blood sample was drawn for bedside analysis of serum myoglobin,
      creatine kinase MB and troponin I. A 12-lead electrocardiogram (ECG) was
      simultaneously recorded. MAIN OUTCOME MEASURES: Elevation of biochemical markers
      prior to hospital admission. RESULTS: In all, 511 patients participated on 538
      occasions. Elevation of any biochemical marker was observed in 11% of all
      patients. The corresponding figure for patients developing myocardial infarction
      was 21%; for patients with myocardial ischaemia 8%; for patients with a possible
      myocardial ischaemia 4% and for patients with other diagnoses 5%. Amongst those
      who had a final diagnosis of acute myocardial infarction (AMI), 47% had ST
      elevation on initial ECG and 57% had either ST-elevation or elevation of any
      biochemical marker. CONCLUSION: Bedside analysis of biochemical markers in serum
      is already feasible prior to hospital admission amongst patients with a suspected
      ACS. About 20% of patients with AMI have elevated biochemical markers at that
      stage. When found this data might increase the possibility of diagnosing an AMI
      very early in the course. However, false positives were found and whether this
      strategy will improve the triage of these patients in the prehospital setting
      remains to be proven.

PMID- 12603499
TI  - Trends in sudden cardiac death in the northern Sweden MONICA area 1985-99.
AB  - OBJECTIVES: To describe time trends in sudden cardiac death (SCD) occurrences
      between 1985 and 1999. DESIGN: Cohort study with analysis of a database of all
      symptomatic and/or fatal acute myocardial infarctions (AMI) in the two
      northernmost counties in Sweden, partly north of the Arctic Circle. SUBJECTS: A
      total of 1139 cases of SCD amongst men and women aged 35-64 years. MAIN OUTCOME
      MEASURE: Sudden cardiac death. RESULTS: Amongst men the proportion of SCD to all
      AMI deaths (within 28 days of an AMI) was 38% and for women 31%. The mean yearly
      incidence of SCD in this age group was 65 per 100,000 men and 12 per 100,000
      women. Amongst men the mean yearly incidence decreased by 1.8% (95% confidence
      interval -3.2 to -0.3) and amongst women the decrease was 1.0% (95% confidence
      interval -4.4 to 2.4). Diabetes mellitus was more common in women compared with
      men (24% vs. 14%, P = 0.001). Men suffered an SCD more often around noon and on
      Saturdays, whereas women suffered their SCD on Mondays and Fridays. For season,
      men and women behaved similarly with a winter peak, although statistical
      significance was reached only for men. CONCLUSIONS: The SCD decreased amongst men
      between 1985 and 1999. There was also a decrease amongst women during the same
      time period but not to a statistically significant degree, possibly caused by
      lack of statistical power due to small numbers.

PMID- 12603500
TI  - Efficacy of losartan in patients with primary focal segmental glomerulosclerosis
      resistant to immunosuppressive treatment.
AB  - OBJECTIVES: Angiotensin II may play an important role in the progression of renal
      disease. Currently, angiotensin converting enzyme (ACE) inhibitors and
      angiotensin II receptor antagonists are commonly used for renoprotection. To our
      knowledge, there is no study investigating this effect of angiotensin II receptor
      antagonists in patients with primary focal segmental glomerulosclerosis (FSGS) in
      the literature. The aim of this study was to evaluate the effects of losartan on
      proteinuria and renal function in patients with FSGS refractory to
      immunosuppressive treatment. DESIGN: Twenty-three normotensive patients with FSGS
      proven through renal biopsy were included in the study. Thirteen of them, five
      men and eight women, were given losartan in a dose of 50 mg day(-1) during 12
      months, and 10, four men and six women, were in the control group. Mean arterial
      blood pressure (MAP), 24-h urine protein excretion, serum total protein and
      albumin levels were determined just before the start of treatment as well as
      after 1, 6 and 12 months of the study. In addition, serum creatinine, creatinine
      clearance (CrCl), cholesterol and triglyceride levels were determined at the
      beginning and end of the study. RESULTS: Age, gender and baseline levels of
      proteinuria, serum albumin, total protein, creatinine, CrCl and MAPs were similar
      in the two groups. Nephrotic range of proteinuria was present in five of 13
      patients (38.4%) in the losartan group and in four of 10 patients (40%) in the
      control group. In the losartan group, 24-h proteinuria had decreased from 3.6 +/-
      0.5 g to 2.3 +/- 0.5 g after 1 month, to 2.4 +/- 0.7 g after 6 months and to 1.9
      +/- 0.7 g after 12 months. In the control group, a significant increase in
      proteinuria compared with the baseline value was noticed after 12 months.
      Proteinuria levels were significantly higher in the control group than in the
      losartan group after 6 and 12 months. Whilst total protein and albumin levels
      increased in the losartan group, they did not change significantly in the control
      group. The total protein levels after 6 and 12 months, and albumin levels after 6
      months were significantly higher in the losartan group than in the control group.
      No significant change was observed between the baseline and the 12-month
      creatinine and CrCl levels of the groups when intra- and inter-group comparisons
      were made. Furthermore, serum cholesterol levels of the losartan group were
      reduced significantly. The changes in MAP values did not reach significant levels
      in either of the groups. There was no correlation between the percentage changes
      in MAP and in proteinuria of the losartan group after 12 months. CONCLUSIONS:
      Angiotensin II receptor antagonists may be an alternative therapy in FSGS
      patients who are resistant to immunosuppressive therapy.

PMID- 12603501
TI  - Extrapolation of reciprocal creatinine plot is not reliable in predicting the
      onset of dialysis in patients with progressive renal insufficiency.
AB  - BACKGROUND: Reciprocal creatinine plot is often used to monitor patients with
      progressive renal insufficiency and to predict the onset of dialysis, although
      the latter practice has not been validated. OBJECTIVE: We examined whether
      extrapolating the reciprocal creatinine plot can predict the onset of dialysis.
      SETTING: Single centre study in the dialysis unit of a University teaching
      hospital. DESIGN: We studied 170 consecutive patients with progressive renal
      insufficiency referred to a single nephrology unit and subsequently dialysed.
      Reciprocal creatinine plot was constructed by all available serum creatinine
      values before dialysis (the 'definitive plot'). Four 'interim plots' were
      constructed for each patient by using serum creatinine below 400, 500, 600 and
      700 micromol L(-1). Interim plots with at least five points and Pearson's r > 0.9
      were analysed. The date of dialysis was predicted from the least squares linear
      regression formula and a target serum creatinine level cor- responding to
      estimated creatinine clearance of 7 mL min-1, at which dialysis was recommended.
      RESULTS: The median duration of observation was 25 months. After serum creatinine
      500 micromol L(-1), the slope of the interim plot remained stable and
      extrapolation was possible in 117 patients (68.8%). However, the limits of
      agreement for predicting the onset of dialysis were wide (from -11.7 to +9.5
      months). At this creatinine level, the onset of dialysis fell within 1 month of
      the predicted onset in only 41 patients (24.1%). The limits of agreement for
      prediction narrowed when time points of higher serum creatinine were included
      into the plot. However, nine patients (5.3%) required dialysis within 1 month at
      creatinine 600 micromol L(-1) and the dialysis was not predicted by the
      reciprocal creatinine plot. Target serum creatinine did not correlate with acute
      serum creatinine at which dialysis was started (r = 0.051, P = 0.51). A slower
      decline in renal function was associated with a higher prediction error (r =
      0.212, P = 0.014). CONCLUSIONS: The onset of dialysis cannot be predicted by
      extrapolation of the reciprocal creatinine plot because of individual variation
      in the renal function that require dialysis. Dialysis would be almost imminent in
      some patients by the time serum creatinine reaches a level that allows accurate
      construction and extrapolation of a plot.

PMID- 12603502
TI  - Birth weight--a risk factor for progression in diabetic nephropathy?
AB  - OBJECTIVES: Intrauterine growth retardation, as seen in individuals with low
      weight at birth, may give rise to a reduction in nephron number. Oligonephropathy
      has been linked to hypertension and renal disease in adult life. We tested the
      concept that low weight at birth acts as a risk factor for progression of
      diabetic nephropathy. DESIGN AND SUBJECTS: We performed an observational follow
      up study of 161 (97 men) type 1 diabetic patients with diabetic nephropathy [mean
      age (SD): 35 (11) years, mean duration of diabetes: 22 (8) years]. All patients
      had been followed for at least 3 years [median (range): 8 (3-20)] with at least
      three measurements [9 (3-31)] of glomerular filtration rate (GFR) (51Cr-EDTA).
      Information about birth size was obtained from midwife registrations. SETTINGS:
      Steno Diabetes Center, a tertiary referral centre. MAIN OUTCOME MEASURES: Loss of
      kidney function according to birth weight and weight/length ratio at birth.
      RESULTS: There was no correlation in univariate analysis between birth weight or
      weight/length ratio and rate of decline in GFR, neither in men nor in women.
      Furthermore, the 27 patients with birth weights below the 20th centile had a rate
      of decline in GFR [median (range)] similar to the 134 patients above: 2.6 (-4.7;
      9.6) vs. 3.4 (-2.3; 19.3) mL min(-1) year(-1), respectively (NS). A multiple
      regression analysis revealed that albuminuria, arterial blood pressure, and
      haemoglobin A1C during follow-up showed a significant correlation with the
      decline in GFR [R2 (adjusted) = 0.34], whereas birth weight and birth
      weight/length ratio did not. CONCLUSIONS: Our study does not suggest that weight
      at birth is associated with progression of established diabetic nephropathy in
      type 1 diabetic patients, whilst several other potential modifiable risk factors
      were identified.

PMID- 12603503
TI  - Airway hyperresponsiveness in a large group of subjects with alpha1-antitrypsin
      deficiency: a cross-sectional controlled study.
AB  - BACKGROUND: It has been suggested that subjects with alpha-antitrypsin (AAT)
      deficiency, lacking a major antiprotease defence against airway inflammation,
      might be more susceptible of development of airway hyperresponsiveness (AHR).
      Moreover, lower AAT blood levels might also be able to influence the severity of
      AHR. OBJECTIVES: This study was aimed to investigate the prevalence of AHR in a
      large group of subjects with AAT deficiency included in the Italian Registry and
      to evaluate the relationship between AAT blood levels and the severity of AHR in
      this population. DESIGN: Cross-sectional controlled study. SETTING: Regional
      Reference Centre for AAT deficiency in Brescia, Italy. METHODS: A total of 114
      subjects with AAT deficiency underwent pulmonary function tests. Eighty-six were
      eligible to perform a bronchial provocation test with methacholine (MCh)
      (baseline FEV1 > 60% predicted) to assess the provocative dose producing a 20%
      fall of FEV1 (PD20FEV1). Similar measurements were performed in a control group
      of 27 age-matched normal subjects. RESULTS: The prevalence of AHR (PD20FEV1 <
      2000 microg MCh) was not different between AAT deficiency subjects and controls
      (16.3% and 11.1%, respectively; P = 0.66), and also amongst two subgroups of AAT
      deficiency subjects divided according to different protease inhibitor (Pi)
      phenotypes (PiMZ-MS, PiSZ-ZZ). Hyperresponsive subjects with AAT deficiency,
      however, showed a positive correlation between AAT blood levels and PD20FEV1
      values (r = 0.71, P < 0.01). CONCLUSIONS: These findings indicate that AAT
      deficiency subjects did not exhibit a greater prevalence of airway
      hyperresponsiveness as compared with control subjects, but suggest that, in the
      subset of AAT deficiency subjects hyperresponsive to MCh, lower levels of AAT are
      associated with a higher severity of AHR.

PMID- 12603504
TI  - Decreased muscle strength and contents of Mg and Na,K-pumps in chronic alcoholics
      occur independently of liver cirrhosis.
AB  - OBJECTIVES: To evaluate the influence of established liver cirrhosis on muscle
      strength and muscle contents of magnesium (Mg), potassium (K) and sodium,
      potassium pumps (Na,K-pumps) in chronic alcoholic patients. DESIGN: An open cross
      sectional study. SETTING AND SUBJECTS: Forty consecutive chronic alcoholics (18
      with cirrhosis and 22 without cirrhosis) admitted to the Department of
      Hepatology, Aarhus University Hospital, Denmark, or to a collaborating alcoholism
      treatment centre, and 36 healthy control subjects. MAIN OUTCOME MEASURES:
      Evaluation of participant's subjective physical ability and measurement of
      maximum isokinetic muscle strength and muscle mass, as well as measurements of
      Mg, K and Na,K-pumps in skeletal muscle. RESULTS: Maximum isokinetic muscle
      strength and muscle mass were equally reduced in patients with and without
      cirrhosis (P < 0.01 all). In keeping with this, both groups of patients felt
      equally physically restricted. Muscle Mg was reduced to the same extent in the
      two groups of patients (by 12 and 9%, P < 0.001, both), whereas the muscle K
      content was only significantly lower in the cirrhotic patients (10%, P < 0.001).
      The muscle content of Na,K-pumps was reduced by 14%, (P < 0.01) in the cirrhotic
      patients and by 8% (P < 0.05) in the noncirrhotic patients. CONCLUSION: Our
      alcoholic patients complained of physical disability, had reduced skeletal muscle
      mass, isokinetic muscle strength, content of muscle Mg and content of Na,K-pumps.
      There was no difference between patients with and without cirrhosis. It appears
      that it is the heavy alcohol intake, and not the cirrhosis per se, that is
      responsible for the observed defects.

PMID- 12603505
TI  - Association of alcohol consumption with white blood cell count: a study of
      Japanese male office workers.
AB  - OBJECTIVES: To investigate the association of alcohol consumption with white
      blood cell (WBC) count. DESIGN: Cross-sectional study. SETTING: A work site in
      Japan. SUBJECTS: A total of 5218 Japanese male office workers aged 23-59 years
      who participated in annual health examinations. MAIN OUTCOME MEASURES: Subjects
      were classified as nondrinkers, or current drinkers who averaged <12, 12-22, 23
      34, 35-45, 46-68 or > or = 69 g day(-1) of ethanol. The association between
      alcohol consumption and WBC count was examined by smoking status. RESULTS: After
      controlling for age, body mass index, systolic blood pressure, and levels of
      total cholesterol, high-density lipoprotein (HDL) cholesterol and fasting plasma
      glucose, WBC count showed a negative dose-response relation with alcohol
      consumption in each smoking status. The WBC count increment per category of
      alcohol intake (x10(9) cells L(-1)) was -0.07 [95% confidence interval (CI), 
      0.11 to -0.04] for never smokers, -0.11 (95% CI, -0.15 to -0.06) for ex-smokers,
      and -0.04 (-0.08 to -0.00) for current smokers. For current smokers, additional
      adjustment for cigarettes smoked per day heightened the magnitude of these
      associations [the respective WBC count increment (x10(9) cells L(-1)), -0.07 (95%
      CI, -0.11 to -0.03)]. The risk for high WBC count (fifth quintile) also showed a
      negative linear trend related to alcohol intake in each smoking status.
      CONCLUSIONS: The WBC count was inversely associated with alcohol consumption in
      both nonsmokers and smokers. In view of the firm association of WBC count with
      the increased risk of coronary heart disease, alcohol consumption seems to have a
      favourable impact on the link between WBC count and the risk of cardiovascular
      disease.

PMID- 12603506
TI  - Decreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol
      during fasting and caloric restriction.
AB  - OBJECTIVES: To investigate the effects of caloric restriction on the serum
      concentrations of retinoids in man. DESIGN: Samples were drawn before and during
      caloric restriction by fasting or 4-6 weeks after gastric surgery. SUBJECTS: The
      fasting group included 17 healthy subjects (11 women and six men) and 16 obese
      patients (10 women and six men) who underwent bariatric surgery (vertical banded
      gastroplasty). MAIN OUTCOME MEASURES: Serum concentrations of all-trans, 13-cis,
      4-oxo-13-cis retinoic acids and retinol. RESULTS: The serum concentrations of
      retinol, all-trans and 13-cis retinoic acids decreased by about 20% after 5 days
      of fasting. After gastroplasty, the serum concentration of retinol, all-trans, 13
      cis retinoic acids, retinol-binding protein and transthyretin also decreased to a
      similar extent after 1 month. In both groups we found a correlation between the
      delta values of 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic
      acid. In all subjects there were also correlations between the delta values of
      the retinoids. However, these correlations were comparatively weak (e.g. r2 =
      0.36 for retinol--all-trans retinoic acid). The change in retinoid concentrations
      did not correlate to the change of weight or body mass index. CONCLUSION: Our
      results support the hypothesis that serum retinol is one of the determinants of
      serum concentrations of all-trans and 13-cis retinoic acid and that the
      catabolism of 13-cis retinoic acid is not affected by fasting. However, in the
      individual case, S-Retinol is a poor predictor of S-All-trans retinoic acid.

PMID- 12603507
TI  - Intestinal pseudo-obstruction and urinary retention: cardinal features of a
      mitochondrial DNA-related disease.
AB  - The syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and
      stroke-like episodes (MELAS) is a multisystemic disorder associated in most of
      the patients with an A to G transition at nucleotide position 3243 in the
      transfer RNA (tRNA)Leu(UUR) (A3243G) of the mitochondrial DNA. This syndrome is
      characterized by the preponderant involvement of skeletal muscle and central
      nervous system, but urinary or gastrointestinal symptoms are seldom documented.
      Here we report an unusual case of a 52-year-old woman with a clinical phenotype
      characterized by encephalopathy, left hemiparesis, urinary retention and
      gastrointestinal pseudo-obstruction. She had the classical A3243G mitochondrial
      DNA point mutation of MELAS syndrome. We also present a clinically heterogeneous
      multigenerational pedigree with several affected members in the maternal lineage.

PMID- 12603508
TI  - Recurrent myopericarditis in association with Crohn's disease.
AB  - Myopericarditis is a rare extraintestinal complication of inflammatory bowel
      disease (IBD). It has also been described as a side-effect of the treatment of
      IBD. We report a 37-year-old-woman with Crohn's disease who had several mild
      episodes of myopericarditis, two of which were associated with a pleural
      effusion, and two with conduction abnormalities in the atrioventricular node.
      During the last episode, a nodal rhythm was followed by a third-degree
      atrioventricular block and a prolonged pause, resulting in loss of consciousness
      and convulsions. A permanent pacemaker was implanted. Our patient is also human
      lymphocyte antigen (HLA) B27-positive. HLA B27 is known to be associated with
      conduction disturbances in the AV node. Recurrent myopericarditis can be a sign
      of IBD.

PMID- 12603509
TI  - Diagnostic and prognostic role of cardiac troponins--reply.

PMID- 12603510
TI  - Steatohepatitis during methylprednisolone therapy for ulcerative colitis
      exacerbation.

PMID- 12603512
TI  - Including disabled children in Africa.

PMID- 12603513
TI  - Preliminary evaluation of a scale to assess cognitive function in adults with
      Down's syndrome: the Prudhoe Cognitive Function Test.
AB  - BACKGROUND: In the clinical diagnosis of dementia in Down's syndrome (DS), it may
      be difficult to distinguish between cognitive deterioration and the various
      degrees of pre-existing intellectual disability (ID). Serial measurements of both
      cognitive function and behaviour are required. The aim of the present study was
      to evaluate the performance of non-demented adults with DS on a subject-directed
      instrument, the Prudhoe Cognitive Function Test (PCFT), preliminary to its serial
      use in a prospective study. METHODS: From 1985 to 1986, 85 non-demented
      hospitalized adults with DS were interviewed using the PCFT. The Adaptive
      Behavior Scale (ABS) was administered to the carers. The subjects' levels of ID
      (graded from mild through moderate, severe and profound to untestable) were based
      on their scores on the Stanford-Binet Intelligence Scale, as reported in the
      medical records, and the relationship between level of disability and performance
      on the PCFT and ABS, and their respective domains, was examined. RESULTS: Both
      scales produced a wide range of scores and the correlation between them was
      highly significant. Both scales correlated highly significantly with the degree
      of ID, but more subjects with high levels (i.e. profound to untestable) of
      disability obtained very low or zero scores on the PCFT and its domains than on
      the ABS. CONCLUSIONS: The PCFT provides a reliable quantitative measure of
      cognitive function in subjects with DS, and could be a useful adjunct to the
      diagnosis of dementia in prospective studies. However, the almost uniformly low
      scores obtained by those with high levels of ID suggests that its power to detect
      cognitive decline will be limited to those who are less disabled, while the ABS
      may be more useful than the PCFT in detecting deterioration in people with
      profound ID.

PMID- 12603514
TI  - Healthcare needs of people with intellectual disability in institutions in
      Taiwan: outpatient care utilization and implications.
AB  - BACKGROUND: The present study assessed the outpatient care use of people with
      intellectual disability (ID) in order to identify patterns of healthcare needs
      and the factors affecting this utilization. METHODS: The primary method used in
      this study was a cross-sectional survey of 1390 subjects with ID in Taiwan. Data
      were obtained from questionnaires completed at 30 registered institutions caring
      for people with ID. RESULTS: The findings show that people with ID in Taiwan are
      likely to make more outpatient visits per year than members of the general
      population. The prevalence of illness in people with ID was 41%, with epilepsy
      being the most frequently reported disease. A total of 39.5% of individuals with
      ID took medicine regularly, and 38.9% had used alternative forms of medication
      besides Western medicine. In terms of the use of outpatient facilities by people
      with ID, paediatric clinics were the most frequently utilized. The average
      monthly number of outpatient visits per person with ID was 2.18 (around 26 visits
      per year). This study found that the need for outpatient care is determined by a
      variety of factors relating to: the age of people with ID, the type of handicap,
      the place of medical treatment, having a family physician, the accessibility of
      medical care, the time-consuming nature of the medical visits, having an illness,
      ID accompanied with other disabilities, and finally, a need for rehabilitative
      care. CONCLUSIONS: From the examination of the expressed needs of people with ID,
      it was found that these individuals have a heightened need for healthcare and the
      treatment of special diseases/disorders in comparison to members of the general
      population in Taiwan. Within the context of ordinary services, it is particularly
      important to have a precise view of the ways in which the health needs of people
      with ID are different from the general population as a whole. This will enable
      healthcare services to respond to these needs, either through support systems
      within generic care or, in some cases, through the delivery of specific
      healthcare through specialized services which are kept separate from generic
      care.

PMID- 12603515
TI  - A comparative study of mastery motivation in young children with Down's syndrome:
      similar outcomes, different processes?
AB  - BACKGROUND: Findings from previous research into motivation in young children
      with Down's syndrome (DS) have been mixed. Some studies have suggested that
      development is merely delayed, while others have proposed that there are inherent
      differences or deficits. Using the mastery motivation paradigm, studies of young
      children have often found that those with DS are just as persistent and goal
      directed as typically developing children of the same mental age (MA). However,
      research involving children with DS with MAs above 2 years is very limited. The
      major aim of the present study was to extend previous research by focusing on
      children with MAs between 24 and 36 months. A secondary aim was to investigate
      issues which would advance conceptual knowledge about the construct of mastery
      motivation. METHOD: The participants were 25 children with DS and 43 typically
      developing children, matched for MA (24-36 months). The main measures of mastery
      motivation were persistence with structured mastery tasks (i.e. puzzles and shape
      sorters) and maternal reports. RESULTS: With the challenging tasks, children with
      DS were just as persistent as the typically developing children. Correlations of
      persistence measures in the group with DS suggested that persistence for these
      children represented a more generalized approach rather than a task-specific
      response. Maternal ratings of persistence were lower in the group with DS.
      CONCLUSIONS: The main conclusion was that children with DS in the MA range of 24
      36 months do not differ in their persistence with challenging tasks when compared
      with typically developing children of the same MA. The implication is that
      motivational development is delayed for children with DS, rather than deficient.
      However, there were some indications of possible differences in the processes
      underlying mastery behaviour in the two groups. The study addresses a number of
      conceptual and methodological issues associated with mastery motivation research,
      and stresses the important contribution that future longitudinal studies could
      make.

PMID- 12603516
TI  - Psychological treatment of reported sleep disorder in adults with intellectual
      disability using a multiple baseline design.
AB  - BACKGROUND: The literature on sleep disturbance in adults with intellectual
      disability (ID) is sparse. Although prevalence rates for sleep disorders appear
      similar to those of non-disabled populations, previous treatment studies have
      largely been comprised of uncontrolled cases. Therefore, the present study
      adopted a single-case experimental methodology to evaluate behavioural sleep
      intervention. METHODS: A screening questionnaire was posted to 384 adults with ID
      and the sleep pattern of respondents with possible sleep disorders was further
      assessed using a structured diagnostic schedule. From the sleep-disordered
      subgroup, 12 participants were selected for a 4-week behavioural sleep
      intervention that was evaluated using randomly allocated, multiple-baseline,
      across-subjects designs and within-subject interrupted time series analyses
      (ITSAs). RESULTS: A total of 155 adults with ID (83 females and 72 males; mean
      age = 32 years, SD = 16.5 years), or their carers, completed the questionnaire
      (return rate = 40%). The application of sleep diagnostic criteria revealed that
      17% had clinically significant difficulty getting to sleep and 11% had difficulty
      remaining asleep. Nine out of the 12 participants recruited for the intervention
      completed all the experimental phases, thus providing three sets of three
      multiple-baseline designs. Visual inspection of within- and between-subject
      effects suggested beneficial treatment-specific effects across a range of target
      variables. The ITSA confirmed significant effects (P < 0.05) or trends (P < 0.10)
      for six out of the nine participants. CONCLUSIONS: Behavioural sleep management
      may improve sleep pattern or sleep-related functioning in the majority of adults
      with ID who have significant sleep problems. The single-case methodology is
      helpful in addressing the heterogeneity of individual presentation, although
      clinical trial methodology is required to confirm these findings on a larger
      scale.

PMID- 12603517
TI  - Working with sex offenders with intellectual disability: evaluation of an
      introductory workshop for direct care staff.
AB  - BACKGROUND: Sexual aggression by men with intellectual disability (ID) is a
      serious problem requiring attention from the relevant agencies. Training for
      staff working with this problem is often not given sufficient attention and is
      rarely evaluated. In the present study, an introductory workshop for direct care
      staff that aimed to increase knowledge and improve attitudes towards work with
      this client group was evaluated. METHOD: Sixty-six staff working in inpatient and
      community settings completed a 2.5-day workshop. Before training began, the
      participants completed a survey questionnaire concerning their experiences of
      work with this client group. An assessment of their knowledge and attitudes was
      carried out prior to and at the end of training in order to evaluate any changes.
      The participants also rated the effectiveness of the workshop and their level of
      satisfaction with the training at the end of the workshop. RESULTS: The
      participants' knowledge and attitudes improved significantly following the
      workshop. Staff with greater experience over time and those who had worked with
      fewer sex offender clients responded to different aspects of the training. The
      participants' ratings indicated that they were highly satisfied with the training
      and found it to be effective. CONCLUSIONS: Brief workshop training is acceptable
      to and can be effective in improving the knowledge, attitudes and confidence of
      direct care staff working with sex offenders with ID. However, because the
      results are based on participant self-report, caution should be exercised
      concerning their external validity.

PMID- 12603518
TI  - Assessment of change with the Developmental Behaviour Checklist.
AB  - BACKGROUND: The Developmental Behaviour Checklist (DBC) is a 96-item instrument
      designed for assessing behavioural and emotional problems among young people with
      intellectual disability. METHODS: The present study investigated the validity of
      the DBC as a measure of change. Changes in individual's DBC scores were
      correlated with changes in expert clinicians' ratings of the same subjects.
      RESULTS: A high correlation was found between expert clinician ratings of change
      in behaviour and change in the total behaviour problem score of the DBC.
      CONCLUSIONS: The DBC is able to measure changes in behaviour and emotions which
      are recognized by an experienced clinician who is following the progress of a
      child with ID.

PMID- 12603519
TI  - Defining actuarial and clinical prediction: comment on Johnston S.J. Risk
      assessment in offenders with intellectual disability: the evidence base. Journal
      of Intellectual Disability Research, 46 (Suppl.1), 47-56.

PMID- 12603520
TI  - Expanding horizons for the Journal: The role of the Journal of Gastroenterology
      and Hepatology Foundation.

PMID- 12603521
TI  - Dual effect of lafutidine on the gut and liver.

PMID- 12603522
TI  - Asian-Pacific consensus statement on the management of chronic hepatitis B: an
      update.

PMID- 12603523
TI  - Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti
      hepatitis B virus therapy.
AB  - Hepatitis flares or acute exacerbations, defined as an abrupt elevation of serum
      alanine aminotransferase (ALT) over fivefold the upper limit of normal (ULN), of
      chronic hepatitis B virus (HBV) infection are the results of HLA-I restricted,
      cytotoxic T lymphocyte (CTL)-mediated immune response against HBV and its
      downstream mechanisms. Higher ALT levels reflect a more vigorous immune response
      and a more extensive hepatolysis that, in the extreme situation, may lead to
      decompensation and failure. In contrast, higher ALT also reflects a more robust
      immune clearance of HBV and, therefore, a higher chance of HBV-DNA loss and
      hepatitis B e antigen (HBeAg) seroconversion, both in the setting of natural
      course and drug therapy. Alanine aminotransferase of fivefold the ULN appears to
      be a significant cut-off level to categorize the patients in terms of endogenous
      immune response against HBV. Patients with ALT levels less than fivefold the ULN
      or those with a less vigorous immune response require immunomodulation to induce
      robust immune response to enhance HBV clearance. In contrast, those with a more
      vigorous immune response or those with ALT flare over fivefold the ULN should be
      monitored closely for spontaneous HBV clearance/HBeAg seroconversion or to start
      direct antiviral therapy in time to prevent the occurrence or deterioration of
      hepatic decompensation. In conclusion, a better understanding of the pathogenetic
      mechanisms and natural course of hepatitis flares, wiser selection of patients
      and the timing of drug therapy are crucial to achieve better treatment results.

PMID- 12603524
TI  - Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C.
AB  - BACKGROUND AND AIM: Hyaluronic acid (HA) is a glycosaminoglycan synthesized by
      hepatic stellate cells that has been shown to correlate with liver fibrosis in
      chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over
      time has not been established. The aim of the present study was to assess the
      serial relationships between HA and liver fibrosis before and after treatment.
      METHODS: Seventy-six previously untreated chronic HCV patients received
      interferon-based therapy over 48 weeks. Serum HA levels were measured and liver
      biopsies were obtained at baseline, and 24 weeks post-treatment. Histological
      fibrosis was assessed by using the Knodell and METAVIR scoring systems. RESULTS:
      Knodell fibrosis was evaluated in 76 patients; METAVIR fibrosis in 72 patients.
      Following treatment, patients were grouped into those with increased fibrosis
      (Knodell = 17; METAVIR = 16), no change (Knodell = 50; METAVIR = 45), or
      decreased fibrosis (Knodell = 9; METAVIR = 11), relative to baseline. Moderate
      correlations between HA and fibrosis scores were found before treatment (Knodell
      R = 0.45; METAVIR R = 0.40) and post-treatment (Knodell R = 0.45; METAVIR R =
      0.61). However, changes in HA correlated poorly with changes in fibrosis scores
      over the study period (Knodell R = 0.11; METAVIR R = 0.06). There was poor
      qualitative agreement between the direction of HA change and the direction of
      change in fibrosis scores (Knodell kappa = 0.04; METAVIR kappa = 0.08). The
      sustained virological response group (n = 18) had a significantly decreased mean
      HA compared with non-responders (-27.9 vs 21.7 micro g/L; P = 0.009), but
      pretreatment HA did not predict a response. CONCLUSIONS: Serum HA showed a modest
      association with hepatic fibrosis, and remains a useful non-invasive marker.
      However, serum HA alone has limited value in predicting histological changes over
      a treatment period.

PMID- 12603525
TI  - Incidence of Sjogren's syndrome in Japanese patients with hepatitis C virus
      infection.
AB  - BACKGROUND AND AIM: Hepatitis viruses induce not only chronic liver diseases but
      also the impairment of other organs and tissues as extrahepatic manifestations.
      In particular, hepatitis C virus (HCV) is involved in various extrahepatic
      manifestations. The purpose of the present study was to evaluate Sjogren's
      syndrome (SS) and lichen planus (LP) involvement, which are various extrahepatic
      manifestations in patients with liver diseases related to hepatitis B virus (HBV)
      or HCV. METHODS: We examined a total of 110 Japanese patients with chronic liver
      disease: 29 with HBV infections and 81 HCV infections. RESULTS: The prevalence of
      SS according to European and Japanese criteria in patients with chronic HCV
      infection was significantly higher than in patients with chronic HBV infection
      (European criteria: 25.9 vs 3.4%; P < 0.05, Japanese criteria: 21.0 vs 3.4%; P =
      0.05). Lichen planus was observed in one (3.4%) of 29 patients with chronic HBV
      infection, and in 11 (13.6%) of 81 patients with chronic HCV infection.
      Simultaneously combined LP and SS occurred in 8.6% (seven of 81) of patients with
      HCV infection, but in none with HBV infection. CONCLUSIONS: Clinicians should
      routinely follow the HCV-infected patients, paying sufficient attention to the
      presence of SS and LP, and they should also carefully monitor their prognosis.

PMID- 12603526
TI  - Longer survival in female than male with hepatocellular carcinoma.
AB  - AIM: There is a limited amount of data regarding the gender difference in the
      survival in cases of hepatocellular carcinoma (HCC). The aim of the present study
      was to investigate the difference in the survival between males and females with
      HCC and the possible factors affecting the gender difference of survival in HCC.
      METHODS: Analyses were performed based on 704 consecutive patients with HCC
      observed for 12 years between January 1989 and December 2000 at the Internal
      Medicine Department, Saga Prefectural Hospital Koseikan, who were retrospectively
      enrolled in the study. The 1-, 3-, 5- and 7-year survivals and various factors at
      the detection of HCC were compared between 487 male and 217 female patients with
      HCC using the Kaplan-Meier method, Mantel-Cox test, chi squared test and Fisher's
      exact analysis. RESULTS: There was a significant difference in survival between
      male and female patients with a 1-, 3-, 5- and 7-year survival estimate of 67.7,
      40.6, 23.8 and 8.7%versus 73.5, 50.3, 26.3 and 15.4%, respectively (P-value:
      0.0167). Of the clinical variables examined, the significant factors related to
      gender difference were found to be age, tumor size, the number of tumors, the
      presence of portal thrombosis and the type of follow-up. Of the patients with HCC
      lesions measuring 3 cm or less in the greatest dimension or those with solitary
      HCCs, however, there was no significant difference in survival between both
      sexes. The patients were divided into three categories: closely followed-up group
      (regular periodic follow-up with monthly alpha-fetoprotein measurements plus
      ultrasonography at least every 4 months); a non-closely followed-up group; and an
      incidental group (incidentally discovered due to related symptoms). The detection
      rates of HCC through the closely followed-up, non-closely followed-up and
      incidental groups were 19.3%, 46.2% and 34.5% in men and 28.1%, 46.5% and 25.4%
      in women, respectively, which reached a significant difference between both sexes
      (P-value: 0.0097). CONCLUSION: The survival of female cases of HCC was longer
      than that of male cases. Disparities in the type of follow-up for women in
      comparison to men exist and may contribute to gender disparities in survival.
      Women with a high risk for HCC tended to be better cared for during the follow
      up. To reduce gender disparities in survival, efforts should be directed at the
      earlier identification of HCC.

PMID- 12603527
TI  - Assessment of cancer cell differentiation in small hepatocellular carcinoma by
      computed tomography and magnetic resonance imaging.
AB  - AIM: To study whether cancer cell differentiation in small hepatocellular
      carcinoma (HCC) can be assessed by computed tomography (CT) and magnetic
      resonance (MR) imaging. METHODS: We retrospectively evaluated the relationship
      between cancer cell differentiation in 127 HCC 3 cm or less in diameter (113
      patients) and CT and MR images. Images were reviewed in a consensus conference by
      three authors (SA, TY, and ME). Histopathological diagnosis of HCC was made from
      liver specimens obtained by sonographically guided biopsy. RESULTS: The degree of
      histological differentiation of cancer cells was significantly different between
      HCC that were isodense with liver parenchyma in both artery-dominant and
      equilibrium phases in contrast-enhanced CT and tumors that were hyperdense in the
      artery-dominant phase and iso- or hypodense in the equilibrium phase (P =
      0.0054), as well as tumors that were iso- or hypodense artery-dominant and
      hypodense equilibrium (P = 0.0002). Histological differentiation of lesions that
      were hyperintense in T1-weighted images and hypointense in T2-weighted images
      differed significantly from those with the opposite MR characteristics (P =
      0.0122). In T1-weighted fat-suppression images and T2-weighted images,
      respectively, the degree of histological differentiation was significant between
      the hypointense/hyperintense and the hyperintense/hypointense patterns (P <
      0.0001), as well as the hyperintense/isointense (P = 0.0296), the
      hyperintense/hyperintense (P = 0.0434), and the isointense/hyperintense (P =
      0.0171). Using these differences an equation was developed that could determine
      with 76% accuracy whether the tumors were well or less-well differentiated.
      CONCLUSION: CT and MR imaging patterns were useful in predicting the degree of
      histological differentiation of cancer cells in HCC.

PMID- 12603528
TI  - Wnt signaling in hepatocellular carcinoma: analysis of mutation and expression of
      beta-catenin, T-cell factor-4 and glycogen synthase kinase 3-beta genes.
AB  - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a common killer cancer in
      the world. Recently, abnormal activation of the Wnt pathway has been found to be
      involved in the carcinogenesis of several human cancers including HCC. The goal
      of the present study was to investigate the mechanism of inappropriate activation
      of the Wnt pathway in hepatocarcinogenesis. METHODS: We analyzed the alterations
      of three key components of the Wnt pathway: beta-catenin, glycogen synthase
      kinase (GSK)-3beta and T-cell factor (Tcf)-4 in 34 HCC and paracancerous normal
      liver by immunohistochemistry, polymerase chain reaction (PCR)-single-strand
      conformation polymorphism (SSCP), direct sequencing, and quantitative real-time
      reverse transcription (RT)-PCR. RESULTS: We found that 61.8% (21/34) of all HCC
      examined showed an abnormal beta-catenin protein accumulation in the cytoplasm or
      nuclei. The RT-PCR-SSCP and direct sequencing showed that beta-catenin exon 3
      mutations existed in 44.1% (15/34) of the HCC. No mutations of GSK-3beta or Tcf-4
      were detected in HCC. Moreover, messenger RNA of beta-catenin and Tcf-4, but not
      GSK-3beta, was found to be overexpressed in HCC. On analyzing the relationship
      between alterations of beta-catenin or Tcf-4 and C-myc or Cyclin D1 expression,
      we found that mutations of beta-catenin, as well as overexpression of beta
      catenin or the Tcf-4 gene were independently correlated with C-myc gene
      overexpression in HCC. CONCLUSION: Our present findings strongly suggest that
      mutations of beta-catenin, as well as overexpression of beta-catenin and the Tcf
      4 gene, independently activate the Wnt pathway in HCC, with the target gene most
      likely to be C-myc.

PMID- 12603529
TI  - Evaluation of the albumin-gamma-glutamyltransferase isoenzyme as a diagnostic
      marker of hepatocellular carcinoma-complicating liver cirrhosis.
AB  - AIM: The present study aimed to evaluate the usefulness of albumin-gamma
      glutamyltransferase isoenzyme in the diagnosis of hepatocellular carcinoma.
      METHODS: Electrophoretic assays of gamma-glutamyltransferase isoenzymes were
      performed on sera from 190 cirrhotics with (n = 131) or without (n = 59)
      hepatocellular carcinoma, 36 patients with chronic active hepatitis, 17 patients
      with liver metastases, and 16 control subjects. In the group of cirrhotic
      patients, the serum level of alpha-fetoprotein was also assessed. RESULTS:
      Albumin-gamma-glutamyltransferase was found in 88 of 131 cirrhotics with
      hepatocellular carcinoma, 14 of 59 cirrhotics without hepatocellular carcinoma,
      nine of 17 patients with liver metastases, and in none of the chronic active
      hepatitis or control patients. Within the cirrhotic subgroup, albumin-gamma
      glutamyltransferase was effective in detecting hepatocellular carcinoma in
      general (sensitivity: 67%; specificity: 76%; diagnostic accuracy: 70%), and small
      hepatocellular carcinoma (< 3 cm; corresponding figures: 58, 76, and 69%). The
      best alpha-fetoprotein value discriminating between hepatocellular carcinoma and
      non-hepatocellular carcinoma cirrhotics was 20 ng/mL (sensitivity: 54%;
      specificity 85%; accuracy: 64%). The combined use of albumin-gamma
      glutamyltransferase and alpha-fetoprotein, > 20 ng/mL, was associated with
      greater sensitivity and accuracy (84 and 74%, respectively) than those observed
      with either of the two markers considered alone. CONCLUSIONS: Albumin-gamma
      glutamyltransferase appears to be a sensitive diagnostic marker of both advanced
      and small hepatocellular carcinoma-complicating liver cirrhosis.

PMID- 12603530
TI  - Effects of insulin-like growth factors-IR and -IIR antisense gene transfection on
      the biological behaviors of SMMC-7721 human hepatoma cells.
AB  - BACKGROUND AND AIMS: Insulin-like growth factors (IGFs) are closely related to
      hepatocellular carcinoma growth. The study aim was to investigate the effects of
      IGF-IR and IGF-IIR antisense gene transfection on the biological behaviors of
      SMMC-7721 human hepatoma cells. METHODS: 7721-IGF-IR-AS cells (human hepatoma
      SMMC-7721 cells transfected with IGF-IR antisense gene in our previous study)
      were transfected with a plasmid vector expressing IGF-IIR cDNA in the antisense
      orientation by DOTAP liposome.7721-IGF-R-AS cells were obtained by selection with
      G418 and hygromycin. Morphological changes of the cells were observed with optic
      and electron microscopes. In vitro growth of the 7721-IGF-R-AS cells was observed
      with a soft agar test, MTT test and with naked mice inoculation test in vivo.
      RESULTS: The following changes were found in the SMMC-7721 cells after being
      transfected with the IGF-IR and IGF-IIR antisense genes: (i) the degree of
      malignancy of the tumor cells as revealed by cell morphology was ameliorated;
      (ii) the growth capability of the tumor cells in soft agar and their
      tumorigenicity in naked mice were significantly depressed. However, in the
      control groups, the SMMC-7721 cells transfected both with IGF-IR and IGF-IIR
      sense cDNA and SMMC-7721 cells transfected without any external genes, had no
      such changes. However, the cell growth curves had no significant differences
      among these three groups. CONCLUSION: IGF-IR and IGF-IIR antisense genes could
      significantly restrain the malignant behavior of human hepatoma cells and might
      be useful in investigating a potential route for hepatocellular carcinoma gene
      therapy.

PMID- 12603531
TI  - Colonic mucosa in patients with portal hypertension.
AB  - BACKGROUND AND AIMS: To do a histomorphometric study of vascular changes in
      colonic mucosa of patients with portal hypertension (PHT) and to find their
      association with clinical and upper and lower gastrointestinal endoscopic
      observations. METHODS: Full length colonoscopy was carried out in 55 patients
      with portal hypertension and 25 controls. Hemorrhoids, anorectal varices and
      colopathy were carefully looked for and recorded. Two biopsies each were taken
      from the caecum, ascending colon, transverse colon, descending colon and rectum.
      Sections from all the five sites were examined for histopathological changes with
      special reference to changes in mucosal capillaries. Morphometric assessment of
      the diameter of the capillary and thickness of the capillary wall was performed.
      These histomorphometric changes were correlated with clinical parameters and
      findings of upper and lower gastrointestinal endoscopic findings. RESULTS:
      Dilated and congested capillaries as well as capillaries with irregular
      thickening of the wall were seen in a significantly higher number of sections
      from patients than controls in biopsies from all the five sites from caecum to
      rectum. On morphometry, the diameter of the capillaries and the thickness of the
      capillary wall in biopsies from all the five sites in patients was significantly
      higher than that in the control group. Apart from vascular changes, edema and
      inflammatory infiltrate in lamina propria were the other significant histological
      features noted. No significant association between clinical and endoscopic
      features and histomorphometric assessment was found. CONCLUSION: Dilated tortuous
      mucosal capillaries with irregular thickening of wall, edema of lamina propria
      and mild chronic inflammatory infiltrate are the major histopathological changes
      seen in colonic biopsies of patients with PHT, showing that PHT produces changes
      in the colonic mucosa similar to those seen in the mucosa of upper GI tract.
      However, the histological changes had no correlation with the clinical or
      endoscopic findings except that the thickness of the capillary wall was higher in
      patients who had undergone endoscopic sclerotherapy as opposed to those who had
      not received sclerotherapy.

PMID- 12603532
TI  - Role of para-esophageal collateral veins in patients with portal hypertension
      based on the results of endoscopic ultrasonography and liver scintigraphy
      analysis.
AB  - BACKGROUND AND AIMS: Para-esophageal collateral veins (para-ECV) are observed by
      endoscopic ultrasonography (EUS) in patients with portal hypertension. However,
      the role of para-ECV in the portal venous system is not clear. To verify the role
      of para-ECV in the portal venous system, we investigated the relationship between
      the development of para-ECV as determined by EUS, and the portal blood flow ratio
      (PBFR) as determined by liver scintigraphy using 99mTc-phytate. METHODS: Eighteen
      patients who did not have fundal gastric varices were studied before the start of
      and after the completion of all endoscopic sclerotherapy sessions for esophageal
      varices. EUS was performed to observe veins around the esophagus, para-ECV and
      perforating veins. To quantify the degree of development of para-ECV, the cross
      sectional area of each para-ECV observed by EUS was measured. The sum total of
      these areas was used as an index of development of para-ECV. The PBFR was
      calculated by liver scintigraphy using 99mTc-phytate. The correlation between the
      sum total cross-sectional area of para-ECV and PBFR was examined. RESULTS: After
      all endoscopic injection sclerotherapy sessions, the total cross-sectional area
      of para-ECV was 29.32 (26.72) mm2 (mean (SD)) and the PBFR was 48.47 (17.87)%
      (mean (SD)). A significant correlation between them was noted after treatment (r
      = - 0.70, P < 0.01). Variceal recurrence was observed in three of the patients
      who had perforating veins connected with para-ECV, regardless of degree of the
      para-ECV. CONCLUSION: The para-ECV are collaterals, which reflect the portal
      blood flow after endoscopic sclerotherapy. para-ECV without perforating veins
      were considered to be important collaterals after treatment.

PMID- 12603533
TI  - Lower esophagus in dyspeptic Iranian patients: a prospective study.
AB  - BACKGROUND: Gastroesophageal junction cancer has increased over time in Western
      countries. Gastroesophageal reflux disease (GERD) is considered to be a major
      risk factor. We prospectively studied the prevalence of clinical, histological
      and endoscopic GERD, and premalignant changes among dyspeptic Iranian patients
      referred for upper gastrointestinal endoscopy (UGIE). METHODS: Consenting
      patients referred for UGIE to our clinic were enrolled. Their symptoms were
      recorded, UGIE was conducted, and biopsies from all suspicious lesions and across
      the Z-line were taken. RESULTS: Of the 344 enrolled patients, 269 (135 women, 134
      men; mean age: 41.6 years) were evaluated. One major GERD symptom (heart burn,
      acid regurgitation, dysphagia and chest pain) was seen in 209 (77.6%) patients,
      and 207 patients (76.1%) had endoscopic esophagitis. Thirteen patients (5%) had
      specialized intestinal metaplasia at the gastrointestinal junction (SIM-GEJ), and
      three had glandular dysplasia (two low-grade, one high-grade). No symptom could
      predict the presence of histological or endoscopic findings. Patients with
      dysplasia had more advanced degrees of endoscopic esophagitis. CONCLUSION:
      Gastroesophageal reflux disease is common among Iranian patients referred for
      diagnostic endoscopy. The prevalence of SIM-GEJ among this population was
      comparable to that reported in Western countries.

PMID- 12603534
TI  - Cost of community gastroenteritis.
AB  - BACKGROUND AND AIM: Gastroenteritis is a common illness that causes considerable
      morbidity in developed countries. Endemic gastroenteritis that is not associated
      with outbreaks causes the greatest number of cases, but information is limited
      about the burden of this disease, and the resources required to manage its impact
      on society. In the present study, we estimated the rate of endemic
      gastroenteritis, the number of visits to the local doctor, use of medication, and
      the cost of gastroenteritis in Australia. METHODS: Data from a community-based
      study of gastroenteritis, a general practice surveillance network, the Australian
      Bureau of Statistics and the Health Insurance Commission were used to measure
      endemic gastroenteritis and other study outcomes. The results were then
      extrapolated to the Australian Community. RESULTS: There were an estimated 0.8
      cases of gastroenteritis per person per year in Australia. This equated to
      15,173,430 cases of gastroenteritis in Australia annually. The age-standardized
      estimate of the total number of visits to the general practitioner (GP) for
      gastroenteritis was 1024,214 at a cost of 26,722,691 Australian dollars. The
      average cost of prescribed medication per visit was 6.83 Australia dollars; the
      estimated total cost of prescribed medication was 6995,381 Australian dollars.
      The estimated cost of over-the-counter medication was 14,587,477 Australia
      dollars. It was estimated that people working full or part-time had 0.13 days-off
      per person per year because of gastroenteritis, at a cost of 137,924,170
      Australian dollars. The estimated total cost of endemic gastroenteritis in
      Australia was 342,855,616 Australian dollars of which 75,908,274 Australian
      dollars was direct medical costs and 266,947,342 Australian dollars was time
      costs and the costs for time off work to care for a sick family member.
      CONCLUSIONS: Endemic gastroenteritis is an important illness in both developed
      and developing countries. Although in developed countries, the majority of
      individual cases are mild to moderate in their severity; the overall costs are
      significant. The results highlight the need for ongoing research to identify the
      main causes of endemic gastroenteritis.

PMID- 12603535
TI  - Increasing incidence of Crohn's disease in Victorian children.
AB  - BACKGROUND: The incidence of Crohn's disease has been increasing in Western
      communities, but there are no published studies which have examined this change
      in children in Australia. The centralization of pediatric gastroenterology
      services in Victoria provides an opportunity to examine these changes within one
      state. METHODS: We undertook a retrospective study over a 31-year period of all
      children aged 16 years or less initially diagnosed with Crohn's disease at either
      the Royal Children's Hospital, or Monash Medical Center, Melbourne, Victoria.
      RESULTS: We identified 351 patients who met the diagnostic criteria between 1971
      and 2001. The incidence of Crohn's disease in children aged 16 years or less rose
      from 0.128 to 2.0 per 100,000 per year over the three decades (r = 0.964, P <
      0.01). There was a disproportionate over-representation of children from an urban
      background (incidence rate ratio 1.66, 95% CI 1.28-2.16). Children currently
      being diagnosed had on average a lower erythrocyte sedimentation rate (ESR) and
      higher albumin than in previous decades. The use of flexible endoscopy has
      increased markedly (1970s: 60%; 1990s: 96%, P < 0.05) and the proportion of
      children recognized at diagnosis with upper gastrointestinal and colonic
      involvement has increased significantly. CONCLUSION: There has been a significant
      increase in the incidence of Crohn's disease in Victorian children. The pattern
      of disease has also changed with colonic disease now more frequent, and
      inflammatory indices less abnormal. The increased use of endoscopy has
      established the frequent involvement of the upper gastrointestinal tract.

PMID- 12603536
TI  - Microbiology of choledochal bile in patients with choledocholithiasis admitted to
      a tertiary hospital.
AB  - AIM: The present study was designed to investigate the microbiology of
      choledochal bile of patients with cholangitis and choledocholithiasis. METHODS:
      We identified and determined the antimicrobial susceptibility of bacteria
      isolated in the bile of patients with cholangitis and choledocholithiasis
      diagnosed by endoscopic retrograde cholangiopancreatography (ERCP). RESULTS:
      Nineteen (82.6%) of 23 patients with choledocholithiasis had positive bile
      cultures. A single agent was detected in 11 patients (57.9%), while a mixed
      growth, with pathogens ranging from two to three species, were seen in eight
      patients (42.1%). Patients with clinical manifestations of cholangitis had
      significantly higher counts of colonies per mL of bile (> 105 cfu/mL). The
      predominant Gram-negative aerobic bacteria isolated were Escherichia coli (9,
      31.0%), Klebsiella pneumoniae (5, 17.2%), Enterobacter cloacae (2, 6.9%), Pantoea
      agglomerans (1, 3.4%), and Pseudomonas aeruginosa (1, 3.4%). The predominant Gram
      positive bacteria were Enterococcus faecalis (5, 17.2%) and Streptococcus sp. (5,
      17.2%). Bacteroides fragilis was isolated in one patient with mixed growth. All
      Gram-positive bacteria isolated in bile were sensitive to ampicillin, and all
      Gram-negative bacteria isolated were sensitive to gentamicin with a minimum
      inhibitory concentration (CIM90) ranging from 0.5 to 1.0- micro g/mL. Gram
      negative bacteria were also sensitive to imipenem, fluorquinolones, second and
      third generation cephalosporins. Although all five isolates of E. faecalis were
      sensitive to ampicillin, two of five (40%) E. faecalis isolates demonstrated high
      levels of resistance to gentamicin. CONCLUSION: E. coli, K. pneumoniae, E.
      faecalis and Streptoccocus sp. were the most common bacteria isolated in the bile
      of patients with cholangitis and choledocholithiasis, which were sensitive to a
      simple therapeutic regimen, such as the combination of ampicilin and gentamicin.

PMID- 12603538
TI  - Gastrointestinal: gastric metastases.

PMID- 12603537
TI  - Cholangiocarcinoma in liver cirrhosis.
AB  - BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is usually associated with
      chronic liver diseases and liver cirrhosis, while conversely, cholangiocarcinoma
      (CC) usually occurs in a non-cirrhotic liver. The purpose of the present study
      was to evaluate CC in liver cirrhosis. METHODS: Between January 1998 and December
      1999, 26 patients with CC were retrospectively reviewed. The occurrence of CC in
      chronic hepatitis B infection-related liver cirrhosis, portal vein thrombosis
      (PVT) and survival were analyzed. RESULTS: Twenty-six patients with CC (19 with a
      non-cirrhotic liver and seven with chronic hepatitis B infection-related liver
      cirrhosis) were included in the present study. All cases of CC in the cirrhotic
      group were incidentally discovered during routine screening for HCC. The mean age
      (+/- SD) was 58.8 +/- 14 years in the cirrhotic group and 73.2 +/- 15.9 years (P
      = 0.001) in the non-cirrhotic group. When compared to the cirrhotic group, the
      non-cirrhotic group had a higher median level of albumin (42 compared to 30 g/L,
      P = 0.005), bilirubin (117.5 compared to 18 micro mol/L, P = 0.01), alkaline
      phosphatase (291.5 compared to 100 U/L, P = 0.001) and gamma glutamyl
      transpeptidases (215.5 compared to 31 U/L, P = 0.001). In contrast, the cirrhotic
      group had a higher median prothrombin time (PT) compared to the non-cirrhotic
      group (18.2 compared to 12 s, P = 0.05). In the non-cirrhotic group, only one
      patient (5.3%) showed evidence of PVT on a computerized tomography and Doppler
      ultrasound, while in the cirrhotic group six patients (85.7%) had PVT (P <
      0.001). The median survival period in the cirrhotic group was six months (range 2
      24 months) compared to 16 months (range 6-41 months) in the non-cirrhotic group
      (P = 0.036). CONCLUSION: CC in cirrhotic liver presented at a younger age and
      patients who developed CC were prone to PVT. The survival period was also shorter
      in comparison to that of non-cirrhotic liver patients.

PMID- 12603539
TI  - Hepatobiliary and pancreatic: a diabetic woman with chronic liver disease
      unrelated to a virus or alcohol.

PMID- 12603540
TI  - Skip lymph node metastases from a small hepatocellular carcinoma with difficulty
      in preoperative diagnosis.
AB  - Recent autopsy studies have clarified the frequency of lymph node (LN) metastases
      from hepatocellular carcinoma (HCC). However, LN metastases commonly occur in
      advanced and poorly differentiated HCC and are very rare in small HCC. We
      encountered a patient with skip LN metastases from a small HCC, 10 mm in
      diameter. An intra-abdominal tumor adjoining the duodenum was detected by follow
      up ultrasonography for viral hepatitis C. Computed tomography showed, in addition
      to the tumor bordering the duodenum, a small low-density area of the liver (S6),
      2 cm in diameter, and a swelling of LN adjacent to the common hepatic artery.
      Upper gastrointestinal rentogenography revealed a compression of the duodenal
      second portion without irregularity of the mucosa. Our pre-operative diagnosis
      was duodenal gastrointestinal stromal tumor with LN metastasis and HCC or liver
      metastasis. However, laparotomy proved them to be LN metastases from a small HCC
      and partial hepatectomy and LN dissection were performed. The patient is doing
      well 22 months after surgery with no signs of recurrence. In the cases of HCC
      with LN metastases, the prognosis is generally very poor. However, in small HCC,
      the clinical characteristics are not fully evaluated. In treatment, we have to
      keep LN metastases, particularly skip LN metastases, in mind, even in cases of
      small HCC.

PMID- 12603542
TI  - Extra-hepatic bile duct adenoma in a patient with a choledochal cyst.

PMID- 12603544
TI  - Severe hepatotoxicity associated with Chinese diet product 'Onshidou-Genbi
      Kounou'.

PMID- 12603543
TI  - Superior diaphragmatic adenopathy from primary hepatocellular carcinoma.

PMID- 12603546
TI  - Square pegs in round holes: reviewing qualitative research proposals.

PMID- 12603547
TI  - Nursing roles and levels of practice: a framework for differentiating between
      elementary, specialist and advancing nursing practice.
AB  - The recent profusion of new nursing roles in the UK has led to much confusion in
      the minds of health care consumers, employers, nursing practitioners and
      educationalists regarding the meaning, scope of practice, preparation for, and
      expectations of such roles. Titles such as Clinical Nurse Specialist (CNS), Nurse
      Practitioner (NP), Advanced Nurse Practitioner (ANP), Higher Level Practitioner
      (HLP) and more recently Nurse Consultant (NC) are being adopted in a variety of
      care settings with little understanding or consensus as to the nature of or
      differences between such roles. Further, the former United Kingdom Central
      Council for Nursing, Midwifery and Health Visiting (1992) initiative for
      extending the scope of professional practice allows for the prospect that nurses
      can adopt additional clinical tasks or alter the nature of service provision
      provided that they acquire the appropriate education or training, levels of
      competence and are prepared to be accountable for their new practices.
      Consequently, nursing practice is becoming more diverse than ever before and the
      boundaries of inter- and intraprofessional practices are becoming increasingly
      blurred. The UKCC (1999a) has recently contributed to an understanding of the
      levels of clinical practice undertaken at the specialist level but the situation
      at advanced or consultant levels remains unclear.

PMID- 12603548
TI  - Views of job satisfaction and dissatisfaction in Australian long-term care.
AB  - The existing job satisfaction literature has tended towards an overemphasis on
      job satisfaction instruments. In the study reported here the views of 27 nurses
      and assistants-in-nursing, collected through focus group interviews, were
      examined to determine the factors that contribute to workplace satisfaction and
      dissatisfaction in long-term care of older people. Content analysis of focus
      group interview data revealed that job satisfaction was related to workplace
      flexibility, residents, working within a team environment and dedication to the
      service of optimal resident care. Dissatisfaction was linked to working with
      unskilled or inappropriately trained staff, laborious tasks such as
      documentation, staffing levels, tensions within role expectations and the
      increasing need to be available for overtime. In spite of different role
      expectations, long-term nursing home care is reported to be a very satisfying
      area in which to work. However, care managers need to put in place strategies for
      building improved job satisfaction and workplace incentives to encourage
      graduates to consider long-term care opportunities. Limitations of the study
      include the small number of participants, bias towards one organization and lack
      of generalizability of the results. However, the findings confirm many earlier
      job satisfaction studies and further support the need to consider these issues in
      relation to recruitment and retention in long-term care.

PMID- 12603549
TI  - Nurses' personalities, nursing-related qualities and work satisfaction: a 10-year
      perspective.
AB  - The personalities and qualities of nursing personnel are considered to be of
      great importance for their interactions and nursing relationships with patients
      and may also influence work satisfaction. The aim of the study was to explore the
      extent to which different personal qualities and personality factors, with a
      possible effect on motivation, professional conduct and coping with stress and
      anxiety, are represented in a group of assistant nurses (second level nurses),
      and how these qualities are related to nursing competence and long-range work
      satisfaction. A group of 51 female nursing students (mean age 31.8 years)
      participated in the study. The nursing-related qualities were empathy,
      sensitivity to non-verbal communication, feelings of discomfort in different
      nursing situations and work satisfaction. The personality factors were
      psychogenic needs and defence mechanisms. At a follow-up 2 years later, 43 nurses
      were interviewed, work satisfaction was assessed and nursing competence was
      appraised. At a follow-up 10 years after completion of nursing school, 33 of the
      nurses took part in a telephone interview. Work satisfaction was assessed in 23
      of those who were still working as nurses. Cluster analysis performed on baseline
      data resulted in four groups: empathic, discomfort prone, service-minded and
      dominant. At the first follow-up, the service-minded had the greatest work
      satisfaction, with many considered to be 'real jewels'. At the second follow-up 8
      years later, there appeared to be an overrepresentation of injuries and long-term
      sick leave in this group, whose members had apparent difficulties in being
      dominant and asserting own interests. Work satisfaction diminished in all the
      groups over time. Long-term work satisfaction was found, however, to be related
      to degree of empathy and a low degree of sensitivity to aggressiveness.

PMID- 12603550
TI  - Team supervision in multiprofessional teams: team members' descriptions of the
      effects as highlighted by group interviews.
AB  - The aim of the study was to describe the effects of team supervision in
      multiprofessional teams as perceived by team members. The literature describes
      team supervision as a way to develop collaboration in multiprofessional teams.
      However, little empirical research into the effects of team supervision is
      available. A research project was undertaken on five units of a university
      hospital between 1995 and 1998. Data were collected using group interviews with
      62 interviewees and were analysed using qualitative content analysis. Team
      members' perceptions of the feeling of togetherness varied. Communication had
      become more open in the teams, but the frankness of expression varied:
      communication had generally become more tactful, whereas in one of the teams
      frankness offended some members. Team members had learned to know each other.
      This had improved mutual understanding, but also increased tension. Teams'
      working methods had changed. Joint decision making had developed, but conflicts
      had also emerged. Motivation for work had improved as a result of the awareness
      of shared problems. However, motivation had been lessened by frustration caused
      by slow progress in the team. Perceptions of the effects of team supervision in
      the multiprofessional teams varied by units and teams. The study showed that team
      supervision is a challenge to supervisors.

PMID- 12603551
TI  - Evaluation of patient records as part of developing a nursing care
      classification.
AB  - The aim of the study was to evaluate the content of nursing care records and the
      usefulness of the instrument used for their evaluation. The evaluation involved
      70 patient records from seven acute special care inpatient units. The evaluation
      instrument used was based on Phaneuf's Nursing Audit as further developed by
      Lukander. The nursing records in all the care units evaluated was very good or
      good. However, some deficiencies were found, for instance, regarding patient
      teaching and recording patients' own opinions. The method proved adequate for
      evaluating the content of patient records.

PMID- 12603552
TI  - Prerequisites and consequences of nursing documentation in patient records as
      perceived by a group of Registered Nurses.
AB  - The issue of nursing documentation and care planning has been discussed in
      numerous articles, revealing barriers and few facilitators in nursing practice.
      Few of these articles are scientifically researched and they are often based on
      small samples. This study aimed to illuminate the factors that Registered Nurses
      (RNs) in acute care perceived as prerequisites and consequences relevant to their
      documentation of nursing care when using the VIPS model (VIPS is an acronym
      formed from the Swedish words for Well-being, Integrity, Prevention and
      Security). In total 377 RNs divided into two groups (Groups A and B) completed a
      questionnaire concerning opinions about nursing documentation. Both groups had
      received a 3-day course on nursing documentation based on the VIPS model. Group A
      had also participated in a 2-year comprehensive intervention programme. The
      findings showed that most participants, regardless of group, perceived nursing
      documentation to be beneficial to them in their daily practice and to increase
      patient safety, and that use of the VIPS model facilitated documentation of
      nursing care. The inhibitors, facilitators and consequences of nursing
      documentation identified here should help both RNs in practice and their leaders
      to be more attentive to the prerequisites needed to achieve satisfactory nursing
      documentation in patient records.

PMID- 12603553
TI  - Observations, confirmations and strategies - useful tools in decision-making
      process for nurses in practice?
AB  - The aim of the study was to describe how nurses make decisions on measures in
      clinical practice. The data-collection method consisted of audio-taped interviews
      with six nurses. The interviews were then transcribed verbatim. The questions in
      the interviews were based on nursing situations observed earlier when the nurses
      initiated and implemented patient-related measures and the focus was on the
      nurses' experience of decision making. A content analysis was performed. The
      results show that the nurses' decisions on measures were based on three themes:
      observation of cues related to the patient's situation, confirmation of
      information gathered and implementation of action strategies. The results are
      discussed in relation to earlier empirical research on decision-making activities
      in the nurse's clinical practice and the nurse's utilization of knowledge during
      the decision-making process. It is concluded that the nurse's awareness of the
      patient's situation, together with a well-founded basis for decisions, can have
      positive effects on the nursing care provided by the nurse.

PMID- 12603554
TI  - Congestive heart failure, spouses' support and the couple's sleep situation: a
      critical incident technique analysis.
AB  - Sleep related breathing disorders are common as well as a poor prognostic sign
      associated with higher mortality in patients with congestive heart failure (CHF).
      These patients often have a shorter total duration of sleep, disturbed sleep
      structure and increased daytime sleepiness, which can negatively affect all
      dimensions of the life situation. The spouse has an important role in supporting
      the patient in relation to sleep disorders, but this role may be adversely
      affected by the sleep situation of the couple. The aim of this study was to
      describe decisive situations that influence spouses' support to patients with CHF
      in relation to the couple's sleep situation. A qualitative descriptive design
      using critical incident technique was employed. Incidents were collected by means
      of interviews with 25 spouses of patients with CHF, strategically selected from
      two hospital-based specialist clinics in southern Sweden. Two main areas emerged
      in the analysis: support stimulating situations and support inhibiting
      situations. Support stimulating situations described how spouses' support was
      positively affected by their own adaptation in psychosocial or practical
      situations, and receiving help from others. Support inhibiting situations
      described how the spouses' support was negatively affected by sleep disturbances
      as a result of the patient's symptoms, anxiety in relation to the disease,
      limitations as a result of the sleeping habits, dissatisfaction with care related
      to the sleep situation, and being left to cope alone with the problems. An
      increased understanding of the stimulating and inhibiting situations influencing
      spouses' support for patients with CHF can guide health care personnel in
      deciding if an intervention is needed to improve the sleep situation for patient
      and spouse.

PMID- 12603556
TI  - Living in the shadow of fibromyalgic pain: the meaning of female partners'
      experiences.
AB  - The aim of this study was to elucidate the meaning of being a female partner
      living with a man with fibromyalgic pain. Fourteen partners were interviewed
      about the meaning of their experiences, using a narrative approach. A
      phenomenological hermeneutic method, inspired by the French philosopher Ricoeur,
      was used to interpret the interview text. The structural analysis is presented in
      three major themes: struggling to give support and comfort, struggling to keep
      going on, and experiencing lack of understanding and support. The findings
      elucidate that the meaning of living with a man with fibromyalgic pain meant
      living a life strongly influenced by the man's illness and in the shadow of the
      man's pain. Taking daily life for granted was interrupted and restricted family
      and social life. Prominent in this study was the frustration partners felt as a
      result of men's reluctance to communicate. This led to feelings of being excluded
      from men's emotions. The responsibility day in and day out meant that women's own
      caring and tenderness were replaced, which brought about an almost constant sense
      of fatigue. Women became drained by the long duration of men's illness. This gave
      them a feeling of being alone, although they were a couple. Gaining comfort
      outside the family helped partners to reach a new insight and appreciation for
      life, which was viewed from a renewed perspective. This involved feelings of both
      togetherness and separateness in the relationship. The findings also consider the
      lack of support from the health care system for female partners living with men
      with fibromyalgic pain.

PMID- 12603557
TI  - The experience of fatigue for people living with hepatitis C.
AB  - Hepatitis C affects approximately 3% of the world population, with fatigue being
      acknowledged as the cardinal symptom. Despite growing recognition that hepatitis
      C fatigue impacts in a negative manner on quality of life, at the time of this
      study no empirical information existed regarding the nature of this fatigue or
      the way in which it affects a person's life. Such information is needed to enable
      nurses to engage in appropriate sensitive symptom management which is the core
      nursing activity with this population, as to date there is no vaccine or widely
      effective pharmacological therapy. The aim of the study was to ascertain the
      nature of hepatitis C fatigue. A qualitative approach using a grounded theory
      approach was employed. Theoretical sampling generated 28 participants for in
      depth interview. Data analysis consisted of three coding processes, each type of
      coding having its own purpose and method. Ethical approval was obtained, both
      from the principal author's academic institution and the participating health
      care institution. Hepatitis C fatigue emerged as being multidimensional in
      nature, with both acute and chronic versions existing. The hepatology community
      is beginning to acknowledge the significant prevalence of hepatitis C fatigue.
      This study provides a valuable insight into its nature. This information can
      serve as resource for practitioners in their development of interventions to
      enable the hepatitis C virus population live with fatigue in a proactive manner.

PMID- 12603558
TI  - Patients' experiences of laparoscopic cholecystectomy in day surgery.
AB  - Previous research has concentrated mainly on surgical aspects and postoperative
      complication rates after day surgery laparoscopic cholecystectomy (LC), and less
      on patients' experiences and nursing care aspects. A qualitative study was
      conducted aimed at investigating patients' experiences of LC in day surgery. Ten
      women and two men were interviewed. The material was coded, categorized and
      analysed using qualitative analysis. The findings demonstrate that individuals
      with gallstone disease experience limitations in their daily life and feelings of
      socially handicapped. Prior to surgery, the patients felt anxious and expressed a
      wish for tranquilizers, and to meet the surgeon responsible. At discharge after
      day surgery, amnesia was experienced and the respondents did not remember
      important information about the operation given by the surgeon. Experience of
      postoperative pain varied greatly. Several respondents had a relapse of pain on
      the third day lasting up to 1 week. The need for additional pain medication and a
      bloated feeling were reported. Some respondents reported nausea and vomiting, and
      most had questions about wound care. The need for additional telephone follow-up
      was mentioned, as was the fact that it was difficult to come home to small
      children. However, the great majority felt that returning home on the same day as
      the operation, was positive.

PMID- 12603559
TI  - First-time mothers - identifying their needs, perceptions and experiences.
AB  - The aim of this research was to identify needs, perceptions and experiences of
      first-time mothers in the postnatal period. Data were collected through focus
      groups and in-depth interviews from a sample of 13 women, 61% were aged 20 years
      or less, from an urban city area in Southern Ireland. Through content analysis,
      key themes were identified relating to birth and hospitalization, support,
      motherhood and psychological issues. Attendance at antenatal classes was variable
      and perceptions of being unprepared for birth and motherhood prevailed.
      Participants appeared shocked at the amount of pain experienced during birth and
      had little rest during hospitalization. They received physical and emotional
      support and preparation for childcare from midwives. Breastfeeding, while
      promoted, by midwives was not acceptable. The 'maternal mother' was key in
      providing direct childcare, advice and emotional help, support for attendance at
      school and 'time out' to socialize. Support was reciprocal if the maternal mother
      had young children. Professional support by public health nurses was well
      established. However, emphasis was perceived to be on 'baby's development'.
      Maternal depression, loneliness, living in homes with limited space and
      difficulty in 'letting go' of baby care to return to school or work were
      reported. Implications for antenatal preparation, national policies, motherhood,
      and the need for further research are discussed.

PMID- 12603560
TI  - Unsatisfied basic needs of older patients in emergency care environments -
      obstacles to an active role in decision making.
AB  - Little attention is paid in Emergency Care Units (ECUs) in Sweden to the special
      needs of older people. The aim of this study was thus to analyse older people's
      basic needs in the emergency care environment. The study was carried out with a
      life-world interpretative approach, and the theoretical framework for
      interpretation was Abraham Maslow's theory of motivation and personality. Seven
      informants aged between 65 and 88 years, with various experiences of being
      patients with urgent as well as non-urgent health-related problems, were
      interviewed about their experiences of ECU care. Their basic needs at the lower
      levels of Maslow's hierarchy were well-represented in the data. Higher needs,
      such as desire to know and understand, appeared to be totally neglected. Safety
      needs dominated the whole situation. Our conclusion is that standards of care
      must be developed in Sweden to make older patients feel safer and more secure in
      ECUs. Furthermore, the principles of nursing care for older patients need to be
      defined in order to encourage them to take an active part in their own health
      process.

PMID- 12603561
TI  - Literacy, readability and cultural barriers: critical factors to consider when
      educating older African Americans about anticoagulation therapy.
AB  - The number of patients on anticoagulation therapy has increased dramatically over
      the past two decades. Yet, few studies have examined the psychosocial barriers of
      low literacy, culture and inappropriate patient education materials used to teach
      older African Americans about their anticoagulation therapy. The aims of this
      study were to investigate literacy levels among older patients, and evaluate the
      readability and determine the cultural sensitivity of written information used in
      an anticoagulation management clinic. A descriptive, correlational design was
      used. Patients' (n = 62) knowledge levels and the readability and cultural
      sensitivity of written materials were examined. The Rapid Estimate of Adult
      Literacy in Medicine (REALM) was used to measure reading skills of patients,
      while the SMOG formula (a formula for assessing readability) was used to test the
      readability of written educational materials used in an Anticoagulation
      Management Clinic. A Knowledge Information Profile, developed for this study by
      one of the authors (Wilson), was used to measure patient knowledge about
      warfarin, medication side-effects and food sources of vitamin K. A modified,
      culturally sensitive and easy-to-read pamphlet was used as an alternative
      teaching tool in the study. The results of the study revealed the average self
      reported for highest grade completed in school was twelfth grade; however, the
      actual mean reading skills were between seventh and eighth grade. The readability
      of the written information was three to four grades higher than patients' reading
      abilities. None of the patient education materials were culturally sensitive.
      This study underscores the importance of having information that is
      understandable and culturally relevant to prevent the outcome of internal
      bleeding. Nurses have a vital role in educating patients and ensuring that
      teaching materials are appropriate for the target population.

PMID- 12603562
TI  - Older South Asian patient and carer perceptions of culturally sensitive care in a
      community hospital setting.
AB  - This study describes the application of grounded theory to establish older, south
      Asian patient and carer views of service delivery in the UK. The purpose of the
      study was to inform the development of culturally sensitive services by defining
      the concept of cultural sensitivity from a user/carer perspective. The study took
      place in two community hospitals providing nurse-led intermediate care to a
      culturally diverse inner city population. Fifty-five per cent of the inner city
      population is of south Asian origin. Admissions to intermediate care, however, do
      not reflect the demography. Recent reports commissioned by the Department of
      Health highlight the failure of the National Health Service in England to provide
      culturally sensitive services to black and Asian patients. The Department of
      Health is trying to redress this inequality providing policy guidance for
      improving access and cultural sensitivity in the British health care system.
      There is little existing empirical evidence, however, to clarify the concept of
      culturally sensitive care. Patients and carers in this study described culturally
      appropriate care as that which respects individuality, creates mutual
      understanding, caters for spiritual need and maintains dignity. Older south Asian
      patients and their carers identified respect, understanding, spirituality and
      dignity as central to their conceptualization of cultural sensitivity. Their
      focus was on the nature of human relationships and their ability to interact in a
      positive way with staff. The findings of this small piece of empirical research
      are limited by the sample size (four patients and three carers), but illustrate
      that cultural sensitivity, although complex, can be defined. This then provides a
      basis for developing appropriate care strategies. One universal principle
      explicit in this research was that to be sensitive to culture staff must
      challenge their own assumptions and develop an understanding of the many layers
      of culture and subculture with which they are dealing. The starting point for any
      service is to understand the expectations of its users and to seek out and manage
      areas of conflict between organizational values and individuals' cultural
      requirements.

PMID- 12603563
TI  - Teaching and learning about skills in minor surgery.
AB  - The aim of this study was to assess the feasibility of a scenario-based approach
      to learning minor surgery skills. After learning component technical skills for
      ellipse excision and wound closure, nurses were provided with an opportunity to
      integrate these skills with communication skills and contextual factors in a
      quasi-clinical environment. Feasibility was assessed using observation of
      procedures and a group interview with participants, simulated patients and
      tutors. The scenario-based approach to teaching and learning about technical and
      communication skills proved feasible and was valued by participants in this
      course on minor surgery. Although all participants expressed anxiety about
      integrating skills in the quasi-clinical setting, they valued the opportunity to
      undergo a formative assessment prior to working in supervised settings with real
      patients. Learners valued highly the opportunity to reflect on their performance
      and to receive feedback on technical and communication skills. Future courses
      should include focused teaching on communication skills prior to the scenario
      based exercise. Limitations of the study centre on the small numbers of
      participants and the novelty of the course. Repeating the evaluations on a
      subsequent course will provide insight into the ways in which nurses acquire and
      integrate new skills.

PMID- 12603564
TI  - Do they practise what we teach? A survey of manual handling practice amongst
      student nurses.
AB  - Experience of training students of nursing in manual handling suggested that they
      did not practise the techniques they had been taught. A search of the literature
      revealed that there was indeed a theory-practice gap. The aim of the project was
      to answer three questions: do students know what they should be doing, do they do
      what they should be doing, and if not, why not. A survey design was used, with
      questionnaires designed specifically for the study. Self report questionnaires
      were distributed to students of nursing (n = 148) on the adult branch in one
      higher education institution in England. One hundred and thirty-nine completed
      questionnaires were returned. Results showed that students' knowledge of whether
      particular techniques were 'recommended' was fair. They indicated however, that
      they were frequently unable to use recommended techniques in practice. The most
      frequent explanation given was the influence of other nurses. Results of this
      small study indicated that male students and younger students were more
      susceptible to socialization into poor ward practice than others. Other reasons
      for not using recommended techniques were unavailability of manual handling aids,
      lack of time and patient needs. The complexity of relationships within the
      nursing team emerged, with students ever aware of the impression they were making
      with regard to their assessment of practice, and their need to be accepted as a
      member of the team. Changes to training are suggested, to help reduce the theory
      practice gap.

PMID- 12603565
TI  - Evaluation of qualitative research.
AB  - It is necessary to subject published research to critical scrutiny, in order to
      evaluate the robustness of the findings. The criteria used in evaluation require
      to be appropriate for the research paradigm, i.e. quantitative or qualitative.
      Quantitative conceptualizations of reliability and validity are unsuitable for
      evaluation of qualitative research as they were not devised for this purpose. The
      use of quantitative criteria to evaluate qualitative research may create the
      impression that the latter is not academically rigorous. Evaluation criteria
      which are specific to qualitative research require identification and
      application, in order to provide a formalized and rigorous approach to critical
      appraisal. A formalized framework for evaluation will help to ensure that the
      contribution of qualitative studies, with specific reference to health services
      research, receives optimum recognition. The work of a number of writers is used
      in this paper to examine the features which distinguish qualitative research and
      the following are discussed: the need for researcher reflexivity; the use of the
      'first person' in academic work; the context in which research takes place; the
      selection of research participants; the interpretation of participants' accounts;
      the active acknowledgement of 'lay' knowledge; researcher flexibility within the
      research process; the generalizability of findings. It is concluded that
      academically rigorous criteria, which are appropriate for evaluation of
      qualitative research, exist and are available for use by practitioners and
      researchers.

PMID- 12603567
TI  - Preparing nurses to face the pandemic of diabetes mellitus: a literature review.
AB  - BACKGROUND: Diabetes constitutes a global public health problem. Today about 135
      million people are affected and it is estimated that the number in 2025 will be
      300 million. AIMS: By reviewing existing literature the aim is to raise awareness
      among nurses, nurse educators and nursing students of the global epidemic of
      diabetes mellitus, its multiple underlying causes, especially social ones, and
      how to fight it. A further aim is to discuss the implications for future
      curriculum content in nurse education programmes. FINDINGS: The main underlying
      causes of the disease are genetic and environmental factors, such as urbanization
      and industrialization, as well as increased longevity and changes in lifestyle
      from a traditional healthy and active life to a modern, sedentary, stressful life
      and over-consumption of energy-dense foods. This process, labelled 'coca
      colonization', is evident all over the world, although more so in developing
      countries. The prevalence of diabetes mellitus varies among populations due to
      differences in genetic susceptibility and social risk factors such as change in
      diet, obesity, physical inactivity and, possibly, factors relating to
      intrauterine development. Migrants are especially affected. Diabetes mellitus
      needs to be treated by a holistic approach through dietary adjustment, exercise,
      medication (if needed), education and self-care measures. Type 2 diabetes
      mellitus is a preventable disease. The main implication for nurses and nursing
      curricula is to change the focus from the individual with diabetes mellitus and
      management to prevent deterioration of health (secondary prevention), to
      population-based community-intervention programmes. These need to focus on health
      promoting activities to raise awareness among healthy people of the risk factors
      for diabetes mellitus. CONCLUSION: Nurses all over the world have an important
      role in fighting the diabetic pandemic by health promotion aimed to keep people
      healthy as long as possible.

PMID- 12603569
TI  - The adaptation of written self-management plans for children with asthma.
AB  - BACKGROUND: Self-management plans are an important element of asthma care.
      Although asthma is common in children, there is limited guidance for adaptation
      of self-management plans for children. AIMS: . A study was conducted in order to
      develop a set of criteria for adaptation of asthma self-management plans for
      school aged children; and to use these criteria to review self-management plans
      used in United Kingdom (UK) centres. METHODS: Self-management plans were obtained
      by telephone survey (response rate: 81%) of 47 selected UK paediatric,
      respiratory and community centres during the period between March and October
      2001. The content of self-management plans was analysed according to criteria
      developed from a review of the literature, including objectives, opportunities
      for individualization, and the implied roles of parent and child in asthma
      management. Agreement was achieved between the authors and a third independent
      rater. RESULTS: The majority of centres (31 of 47) used or planned to use adapted
      self-management plans while the remainder used the standard National Asthma
      Campaign self-management plan. There were wide variations in self-management
      plans, including variation in the person to whom plans were addressed, criteria
      for treatment and the objectives stated for self-management. Few opportunities
      were provided for individualization of self-management. LIMITATIONS: The study
      was limited to the documents used in self-management in selected centres.
      CONCLUSION: The results suggest that many practitioners believe that self
      management education requires adaptation for children. There is little
      consistency in the adaptation of self-management plans for children. Principles
      for devising adapted self-management plans are proposed.

PMID- 12603568
TI  - The changing division of labour between nurses and nursing assistants in New
      Brunswick.
AB  - BACKGROUND: In 1989, the professional nursing organization that represents nurses
      in New Brunswick adopted baccalaureate entry to practice in nursing. This
      decision coincided with a major restructuring of provincial health care.
      Consequently, there has been a reorganization of health care worker roles which
      affects nurses and nursing assistants. AIM: This paper explores the changing
      division of labour between nurses and nursing assistants in the province of New
      Brunswick, Canada. METHODS: The study used archival material, from the period
      1978-1990, of three nursing organizations that played a significant role in
      initiating baccalaureate entry to practice. Interviews with 19 key people
      involved in the decision to upgrade nurse education were conducted. Data from the
      archival material and interviews were analysed jointly. FINDINGS: There are
      ongoing tensions between nurses and nursing assistants. Although nurses would
      like a support worker, they remain ambiguous about the role of nursing assistants
      in health care and which tasks should be delegated to this group. Nursing leaders
      are concerned about the ease with which some patient-related tasks are moved to
      nursing assistants. In the past, these concerns have led nursing leaders to
      attempt to limit nursing assistant responsibilities through both legislative
      means and ways of organizing nursing labour (primary nursing). As a result of
      health care reforms and baccalaureate entry to practice for nurses, nursing
      assistant responsibilities are currently expanding. CONCLUSION: Upgrading nurse
      education, which came into effect in 1996 with the closure of diploma schools in
      New Brunswick, is likely to entrench the role of nursing assistants in health
      care because of the economic value of their work during a period of restructuring
      and rationalization of health care.

PMID- 12603570
TI  - Nursing staff and nursing students' attitudes towards HIV-infected and homosexual
      HIV-infected patients in Sweden and the wish to refrain from nursing.
AB  - BACKGROUND: Two decades after the emergence of human immunodeficiency virus
      (HIV)/acquired immune deficiency syndrome (AIDS), the infection remains enigmatic
      and shameful. In Sweden, many HIV-infected persons still encounter attitudes of
      avoidance. AIMS: The aims were to investigate differences between attitudes of
      nurses, assistant nurses, nursing students and assistant nursing students towards
      HIV-infected and homosexual HIV-infected patients; to measure their fear of
      contracting HIV; and to investigate whether nurses, assistant nurses, nursing
      students and assistant nursing students wanted to refrain from caring for HIV
      infected patients. ETHICAL ISSUES: The participants were informed of the study
      orally and in writing. Completing and returning the anonymous questionnaires
      indicated the participants' tacit consent. RESEARCH METHOD: The study had a
      descriptive, comparative quantitative design. The AIDS Attitude Scale was used,
      along with a questionnaire specially designed for the study. The participants
      were nurses and assistant nurses from one infectious disease clinic in central
      Sweden [response rate was 67% (n = 57)]. Students enrolled in a university
      nursing programme and students of upper secondary assistant nurses' training
      [response rate was 62% (n = 165)] were also included. FINDINGS: In general, both
      the nursing staff and the nursing students expressed empathic attitudes towards
      HIV-infected and homosexual HIV-infected patients, as well as a low degree of
      fear of HIV contagion. The findings also showed, in the professional groups, that
      36% would refrain from caring for HIV-infected patients if that possibility
      existed. The corresponding figure for the student groups was 26%. LIMITATIONS:
      The chosen sample was small and not randomly selected therefore precludes a
      generalization in a wider context. Furthermore, the questionnaire was untested
      for reliability and validity, and may have influenced the findings with respect
      to the wish to refrain from nursing HIV-infected patients. CONCLUSION: Suggested
      guidelines for nursing, mentor-ship by AIDS-dedicated nurses, and educational
      interventions, are given in 'Implications for nursing and nursing education'.

PMID- 12603571
TI  - Theory-driven guidelines for practical care of older people, based on the theory
      of gerotranscendence.
AB  - INTRODUCTION: The theory of gerotranscendence states that human development is a
      process extending into old age. When optimized, this process ends in a new
      perspective. The developmental process towards gerotranscendence can be
      obstructed or accelerated by life crises and grief, but elements in the culture
      can also facilitate or impede the process. Similarly, the caring climate can
      obstruct or accelerate the process toward gerotranscendence. The view introduced
      by the theory may have several consequences for staff treatment of and actions
      towards older people, as it offers a new understanding of living into old age.
      AIM: The aim of the present study was to derive guidelines for practical use in
      the care of older people. The guidelines should be used to promote a development
      toward gerotranscendence and should also be of value for people who already have
      attained a state of gerotranscendence. METHODS: The method of deriving guidelines
      from the theory was focus group interviews. The theory of gerotranscendence was
      used as a foundation for stimulating the discussions in the focus groups as well
      as for organizing the proposals that emerged. FINDINGS: Concrete guidelines at
      three levels, focusing on the individual, activity and organization, were
      derived. The guidelines describe different ways to support older people in their
      process towards gerotranscendence. CONCLUSION: These guidelines could support
      staff in their practical care of older people and could be used as a supplement
      to enrich the present care.

PMID- 12603572
TI  - Models of mental health nurse-general practitioner liaison: promoting continuity
      of care.
AB  - AIM AND RATIONALE: Community mental health nurses and general practitioners share
      a pivotal role in the provision of mental health care in the community. The focus
      of this study was to identify models of general practitioner collaboration used
      by these nurses, and analyse the implications of these models for promoting
      continuity of care. The study was derived from a larger study of how community
      mental health nurses promote wellness with clients who are experiencing an early
      episode of psychotic illness. METHODS: This qualitative study used interviews and
      observation to collect data. The study took place in 1999 in regional and rural
      New South Wales, Australia and involved community mental health nurses. FINDINGS:
      The findings show that two models of nurse and general practitioner (GP)
      collaboration emerged from the data: Shared Care and Specialist Liaison. In the
      Shared Care model, nurses maintain close contact with GPs throughout the episode
      of acute care. In the Specialist Liaison model, the community mental health team
      assumes overall responsibility for care and treatment throughout the acute
      episode of illness. Contact with GPs throughout the episode of care by the
      community mental health team is, at best, intermittent. CONCLUSION: The findings
      suggest that the Shared Care model is more consistent with supporting personal
      and organizational continuity of care, whereas the Specialist Liaison model is
      limited to encouraging personal continuity of care but further study is needed.

PMID- 12603573
TI  - Helping health and social care professionals to develop an 'inequalities
      imagination': a model for use in education and practice.
AB  - BACKGROUND: The 'inequalities imagination model' originated from our own
      research, and led to findings and recommendations regarding clinical and
      education issues. This article focuses on the creation of the model which, we
      suggest, could be used to facilitate the development of an 'inequalities
      imagination' in health and social care professionals. AIM: To describe and
      critically analyse the thinking that led to the concept of an 'inequalities
      imagination' and provide the framework for the theoretical model. METHODOLOGICAL
      APPROACH: Influencing concepts from the fields of social work, sociology, nursing
      and midwifery, and debates around antidiscriminatory and antioppressive practice,
      cultural safety, cultural competence and individualized care are analysed.
      INEQUALITIES IMAGINATION MODEL: Ideas generated from an analysis of the concepts
      of antidiscriminatory/anti-oppressive practice and from the research data led us
      to conceptualize a flexible model that incorporated issues of individual and
      structural agency and a broad definition of disadvantage. The literature review
      underpinning the theoretical framework means that the model has the potential to
      be truly interdisciplinary. CONCLUSIONS: Professional educators face a difficult
      task in preparing practitioners to work with clients in ways that take account of
      differences in background and lifestyle and which respect human rights and
      dignity. The model makes explicit a process that enables practitioners to think
      about their current practice and move towards a greater understanding and
      awareness of the way they work with disadvantaged clients, and ways in which they
      prepare others to do so. We suggest that professionals develop an 'inequalities
      imagination' in order to enhance equality of care. The development of an
      'inequalities imagination' helps practitioners to bridge the gap between the
      challenges they face in day-to-day practice and what they need to achieve to
      aspire to provide equality of care to all.

PMID- 12603574
TI  - Evaluating health promotion: a model for nursing practice.
AB  - AIMS: To investigate the place and validity of effective process in evaluating
      health promotion practice in nursing and, in doing so, develop a specific model
      for this purpose. BACKGROUND/RATIONALE: The failure of many nurses to provide
      successful health promotional programmes is underpinned by a distinct lack of
      evaluation research activity. Without this type of activity, health-related
      nursing practice remains limited in its scope and nature. This article seeks to
      redress this situation by proposing a specific evaluation model that assists the
      nurse in their attempts to include evaluative research activity in future health
      promotion practice. METHOD: This article draws on existing literature to develop
      an evolving theoretical perspective for health promotion practice in nursing. The
      proposed model was developed from this perspective. CONCLUSION: Evaluation is an
      essential activity for any health promotion programme. Failure to include it in
      practice ensures that attempts to conduct health promotion are usually rendered
      ineffective and unsuccessful. Evaluation models are valuable tools that nurses
      can incorporate routinely into existing frameworks of practice, alongside other
      models of health education/health promotion, such as planning models. The
      development of this model is intended to enable nurses to review their current
      practice and offer a further framework for those who wish to extend their current
      health promotion repertoire.

PMID- 12603575
TI  - Relationships with undergraduate nursing exchange students--a tutor perspective.
AB  - BACKGROUND: Student exchange has been used increasingly in nursing education
      throughout Europe as a method of learning intercultural sensitivity. In the host
      country, each foreign student is assigned a personal tutor to enhance learning.
      AIM: The aim of this study was to describe tutor-student relationships between
      Finnish nurse teachers and British exchange students from the tutors'
      perspective. ETHICAL ISSUES: The researcher's close relationship with the study
      context and participants caused some ethical concerns, which will be discussed.
      METHODS: The data consisted of tutorial session observations, research diary
      notes, group interviews and background questionnaires. They were analysed using
      Spradley's developmental research sequence method for ethnographic data.
      FINDINGS: The tutoring relationship was pastoral and clinical rather than
      academic. The pastoral aspect of the relationship was essential in assisting the
      students to adjust to the stress of studying in a foreign country. On the other
      hand, tutors were unable to support all the students to overcome their culture
      shock. Tutors were uncertain about their role and did not integrate Finnish
      culture or practice into theory, but found their role pleasant. CONCLUSIONS: A
      dialogic tutor-student relationship is important for learning intercultural
      sensitivity. Tutoring strategies should be developed to assist students'
      adjustment to the differences in the host culture and to encourage their
      reflection on personal, experiential and scientific cultural knowledge during
      their study abroad.

PMID- 12603576
TI  - Sustainability in changing clinical practice promotes evidence-based nursing
      care.
AB  - AIM: To examine the relationship between sustained work with quality improvement
      (QI) and factors related to research utilization in a group of nurses. DESIGN:
      The study was designed as a comparative survey that included 220 nurses from
      various health care organizations in Sweden. These nurses had participated in
      uniformly designed 4-day basic training courses to manage a method for QI.
      METHODS: A validated questionnaire covering different aspects of research
      utilization was employed. The response rate was 70% (154 of 220). Nurses in
      managerial positions at the departmental level were excluded. Therefore, the
      final sample consisted of 119 respondents. Four years after the training courses,
      39% were still involved in audit-related activities, while 61% reported that they
      had discontinued the QI work (missing = 1). RESULTS: Most nurses (80-90%) had a
      positive attitude to research. Those who had continued the QI work over a 4-year
      period reported more activity in searching research literature compared with
      those who had discontinued the QI work (P = 0.005). The QI-sustainable nurses
      also reported more frequent participation in research-related activities,
      particularly in implementing specific research findings in practice (P = 0.001).
      Some contextual differences were reported: the QI-sustainable nurses were more
      likely to obtain support from their chief executive (P = 0.001), consultation
      from a skilled researcher (P = 0.005) and statistical support (P = 0.001). Within
      the broader health care organization, the existence of a research committee and a
      research and development strategy, as well as access to research assistant staff,
      had a tendency to be more common for nurses who had continued the QI work.
      CONCLUSION: Sustainability in QI work was significantly related to supportive
      leadership, facilitative human resources, increased activity in seeking new
      research and enhanced implementation of research findings in clinical practice.
      It appears that these factors constitute a necessary prerequisite for
      professional development and the establishment of evidence-based practice.

PMID- 12603577
TI  - Bali: a wake-up call.

PMID- 12603578
TI  - Use of computed tomography pulmonary angiography in the diagnosis of pulmonary
      embolismin patients with an intermediate probability ventilation/perfusion scan.
AB  - BACKGROUND: Computed tomography pulmonary -angiography (CTPA) plays an
      increasingly important role in the diagnosis of pulmonary embolism (PE). Although
      accurate in the detection of large PE, its accuracy in other patient groups is
      yet to be defined. AIM: To compare CTPA with pulmonary angiography as a second
      line investigation in patients with a ventilation/perfusion (VQ) scan indicating
      an intermediate probability of PE. METHODS: We recruited 25 patients over a 17
      month period. Subjects were eligible if they: (i). had clinically suspected PE,
      (ii). had a VQ scan indicating an intermediate probability of PE and (iii). were
      referred for pulmonary angiography. Subjects underwent CTPA within 36 h of the VQ
      scan. CTPA was interpreted without knowledge of the results of the pulmonary
      angiogram by two of the authors. RESULTS: PE was prevalent (i.e. embolus detected
      at pulmonary angiography) in seven of 25 subjects (28%). The sensitivity of CTPA
      was 57% and the specificity was 94%. CONCLUSIONS: In the setting of intermediate
      probability VQ scanning, CTPA may be used to clarify the diagnosis of PE.
      However, a negative CTPA cannot -definitely exclude PE. Conventional pulmonary
      angiography may be necessary to determine the presence of PE if CTPA is negative.

PMID- 12603579
TI  - Multiple sclerosis is more prevalent in northern New Zealand than previously
      reported.
AB  - BACKGROUND: There have been no studies of multiple sclerosis (MS) prevalence from
      New Zealand (NZ) in the past two decades, and only one in a northern NZ district.
      Our impression was that the local prevalence of MS was higher than previously
      published data would suggest. There is limited access to new treatments for MS in
      NZ. AIMS: The present paper aims to: (i). measure the prevalence of definite and
      probable MS in the Bay of Plenty (BOP), a North Island province, (ii). compare
      this with previous NZ studies, (iii). study the profile of disability in this
      population-based group and (iv). determine the proportion of MS patients who
      receive government funding for modern drug treatment (beta-interferons). METHODS:
      Patients were identified from a geographically and demographically defined area
      of the North Island of NZ, using multiple sources of case ascertainment and
      modern diagnostic criteria. All clinical records were reviewed and data were
      supported by a telephone interview. All patients' eligibility for -government
      funded treatment with beta-interferon was considered. RESULTS: Eighty-six
      patients were identified as residents in BOP, NZ, on 15 January 2001. Excluding
      'possible' cases, this represented a prevalence of 50/105 (95% confidence
      interval 40-62/105). Half of the population-based cohort had a disability defined
      as 'moderate to severe' (i.e. aids needed to walk, unable to take more than a few
      steps, or worse). Eleven patients (13%) had a primarily progressive form of MS.
      Eleven patients (13%) had the relapsing--remitting form of the disease and
      qualified for -government-funded treatment with beta-interferon. CONCLUSION: The
      prevalence of MS in the defined region was twice as high as that reported from an
      adjacent area, the Waikato, 20 years previous. Our data will help to update NZ
      prevalence statistics and are of direct relevance to current funding issues for
      modern treatments which, in NZ, are presently limited to a proportion of patients
      with relapsing- remitting disease.

PMID- 12603580
TI  - Is magnetic resonance angiography useful in renovascular disease?
AB  - BACKGROUND: Magnetic resonance angiography (MRA) of renal vessels correlates well
      with conventional angiography (CA) and enables non-invasive assessment of renal
      vessels without nephrotoxic contrast. AIMS: We aimed to identify the referral
      source and nature of the patient group undergoing renal MRA, and the impact of
      this test on their management. METHODS: All renal MRA scans performed at the
      Royal Adelaide Hospital from 1 November 1997 to 31 December 2000 were reviewed (n
      = 121). Clinical data were obtained by case-note review or from treating
      physicians. MRA scans were with gadolinium enhancement, using a Siemens Vision
      1.5 Tesla machine (Siemens, New York), with Visual Basic 33 software and 3D
      reconstruction. RESULTS: Nephrologists ordered the majority of renal MRA studies
      (64.5%). Indications for MRA included: (i). hypertension (91.3%), (ii). abnormal
      renal function (78.3%), (iii). other imaging suggesting renovascular disease
      (64.3%) and (iv) renal impairment with angiotensin-converting enzyme inhibition
      (18.3%). Eighty-seven MRA studies revealed renovascular abnormalities
      ('positive'). Over 50% of patients had three or more risk factors associated with
      vascular disease, with MRA positive in 76%. Localized renal artery stenosis was
      identified in 65 cases. In 40 of these, CA and further intervention was not
      undertaken, mainly due to presence of features of irreversible renal damage, low
      grade stenosis or stable clinical parameters. CA was performed in 25 patients,
      all of whom had moderate- to high-grade (>60%)-stenosis on MRA. Revascularization
      was attempted in 21 of the 25 patients, with technical success in 17. In 22
      patients, MRA identified non-localized abnormalities, most commonly diffuse
      arterial disease. None went on to angiography. CONCLUSIONS: Selective use of
      renal MRA in high-risk patients (identified by vascular risk factors or with
      standard renal imaging) can assist in avoidance of invasive, potentially
      nephrotoxic conventional angiography in up to 80% of cases. Those with lesions
      warranting treatment can then be selected for further intervention.

PMID- 12603581
TI  - Thyrotoxic, hypokalaemic periodic paralysis in Australasian men.
AB  - Abstract The present study describes the clinical and laboratory features of 11
      patients with thyrotoxic, hypokalaemic periodic paralysis, presenting to five
      Melbourne teaching hospitals between 1991 and 2000. All 11 patients were Asian or
      Polynesian men aged 18-41 years, and most had experienced previous episodes of
      acute, unexplained paralysis. All cases resolved without significant morbidity.
      Thyrotoxic, hypokalaemic periodic paralysis is a potentially life-threatening and
      terrifying condition, which is often under-recognized and will present with
      increasing frequency in the community. The diagnosis should be considered in any
      Asian-Australian male presenting with sudden onset paralysis.

PMID- 12603582
TI  - Recent trends in lipid management: raising the bar and shifting the goalposts?
AB  - The National Heart Foundation of Australia, in conjunction with the Cardiac
      Society of Australia and New Zealand, updated its Lipid Guidelines at the end of
      2001, but on-going modification is anticipated to stay abreast of the rapid
      progress in this field. Research at all levels re-affirms the fundamental
      importance of lipid metabolism in many physiological and pathological processes.
      In addition, clinical trials such as the recent Heart Protection Study broaden
      the indications for intervention. The present review summarizes recent advances
      and analyzes emerging attitudes towards diagnosis and management that will
      influence future recommendations and practice.

PMID- 12603584
TI  - Outcomes research: what is it and why does it matter?
AB  - Outcomes research is a broad umbrella term without a consistent definition.
      However it tends to describe research that is concerned with the effectiveness of
      public-health interventions and health services; that is, the outcomes of these
      services. Attention is frequently focused on the affected individual - with
      measures such as quality of life and preferences - but outcomes research may also
      refer to effectiveness of health-care delivery, with measures such as cost
      effectiveness, health status and disease burden. The present review details the
      historical background of outcomes research to reveal the origins of its
      diversity. The value and relevance of outcomes research, commonly employed
      research techniques and examples of recent publications in the area are also
      discussed.

PMID- 12603583
TI  - Rapamycin in cardiovascular medicine.
AB  - The cellular action of rapamycin (sirolimus), a natural fermentation product
      produced by Streptomyces hygroscopicus, is mediated by binding to the FK506
      binding protein. By inhibiting a kinase known as the target of rapamycin, it
      restricts the proliferation of smooth-muscle cells by blocking cell-cycle
      progression at the G1/S transition. The finding that rapamycin possesses both
      anti-proliferative and antimigratory activity suggests that it could contribute
      to the control of arterial re-narrowing after percutaneous intervention and
      control the vascular manifestations of chronic rejection in transplanted hearts.
      The first clinical trials of implantation of rapamycin- coated stents in
      obstructive coronary artery lesions have been reported and, in selected patient
      groups, it appears that the restenosis process has been abolished. Studies are
      underway to establish the benefits of rapamycin-coated stents in day-to-day
      interventional practice, including small vessels, long lesions and patients with
      multivessel disease. With the addition of novel antiplatelet agents and delivery
      systems, it is possible that the two major limitations of percutaneous coronary
      intervention - restenosis and stent thrombosis - will be overcome. Cardiac graft
      loss due to intimal hyperplasia and accelerated atherosclerosis remains the major
      limitation to long-term survival following cardiac transplantation. Animal
      studies of rapamycin have suggested that this process can be reduced or
      abolished. Human studies of the efficacy of rapamycin in preventing both acute
      rejection and allograft arterial disease are in progress. Concerns regarding
      toxicity, carcinogenicity, delayed healing and endothelialization remain. As with
      any new agent or technology, we must remain vigilant to late adverse side
      effects.

PMID- 12603586
TI  - The Bali bombings of 12 October, 2002: lessons in disaster management for
      physicians.

PMID- 12603585
TI  - Adjuvant chemotherapy in colon cancer: what is the evidence?
AB  - Over the last 12 years, numerous randomized trials have addressed the role of
      adjuvant chemotherapy in resected colon cancer. Together, these studies give
      conclusive evidence of the benefit of adjuvant 5-fluorouracil combined with
      folinic acid in stage III (node positive) disease and this is now considered the
      standard of care. The chemotherapy appears to be equally effective whether it is
      given daily for 5 days per month or on a weekly schedule. The overall effect is a
      relative reduction in tumour -recurrence of 25% or an absolute improvement in
      survival of 10%. However, doubt remains as to the role of adjuvant chemotherapy
      in stage II colon cancer. To date, most of the randomized trials have
      demonstrated a relative reduction in tumour recurrence but have not shown any
      significant impact on survival. It seems likely that this inability to
      demonstrate a survival benefit from adjuvant chemotherapy in stage II disease
      relates to the fact that the trials have been underpowered to do so.
      Nevertheless, the absolute survival advantage is only about 2% and clinicians
      need to weigh this against the costs and toxicities of the treatment when
      managing these patients.

PMID- 12603587
TI  - Resource allocation and bioethics: the Patti Hearst dilemma.
AB  - Abstract Medicine has entered an era of high technology, accompanied by expensive
      investigation and management. Simultaneously, there is increasing recognition of
      the gap between the costs of medical technology and society's willingness to pay.
      It is debatable whether medicine recognizes that it is a hostage in thrall to the
      medical-industrial complex or whether it has wittingly entered the compact to
      pursue the high-cost, high-technology course. The situation is reminiscent of the
      events surrounding the kidnap of Patti Hearst - a wealthy heiress who was much
      later arrested with the gang of robbers. Whether she was hostage or willing
      accomplice still remains obscure. It is necessary that a body, such as the
      Cochrane Collaboration, pursues these issues in medicine.

PMID- 12603588
TI  - Acute thyroiditis following parathyroidectomy for secondary hyperparathyroidism
      in a chronic renal failure patient.

PMID- 12603589
TI  - Helicobacter pylori hiccup.

PMID- 12603590
TI  - Extreme hypereosinophilia in sclerosing cholangitis.

PMID- 12603591
TI  - General internal medicine in Australasia.

PMID- 12603593
TI  - Complete analysis of the B-cell response to a protein antigen, from in vivo
      germinal centre formation to 3-D modelling of affinity maturation.
AB  - Somatic hypermutation of immunoglobulin variable region genes occurs within
      germinal centres (GCs) and is the process responsible for affinity maturation of
      antibodies during an immune response. Previous studies have focused almost
      exclusively on the immune response to haptens, which may be unrepresentative of
      epitopes on protein antigens. In this study, we have exploited a model system
      that uses transgenic B and CD4+ T cells specific for hen egg lysozyme (HEL) and a
      chicken ovalbumin peptide, respectively, to investigate a tightly synchronized
      immune response to protein antigens of widely differing affinities, thus allowing
      us to track many facets of the development of an antibody response at the antigen
      specific B cell level in an integrated system in vivo. Somatic hypermutation of
      immunoglobulin variable genes was analysed in clones of transgenic B cells
      proliferating in individual GCs in response to HEL or the cross-reactive low
      affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody
      antigen interface demonstrates that recurring mutations in the antigen-binding
      site, selected in GCs, enhance interactions of the antibody with DEL. The effects
      of these mutations on affinity maturation are demonstrated by a shift of
      transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized
      mice. The results show that B cells with high affinity antigen receptors can
      revise their specificity by somatic hypermutation and antigen selection in
      response to a low-affinity, cross-reactive antigen. These observations shed
      further light on the nature of the immune response to pathogens and autoimmunity
      and demonstrate the utility of this novel model for studies of the mechanisms of
      somatic hypermutation.

PMID- 12603592
TI  - B cell inhibitory receptors and autoimmunity.

PMID- 12603595
TI  - Memory T-cell competition for bone marrow seeding.
AB  - The presence in the bone marrow of memory CD8 T cells is well recognized.
      However, it is still largely unclear how T-cell migration from the lymphoid
      periphery to the bone marrow is regulated. In the present report, we show that
      antigen-specific CD4 T cells, as well as antigen-specific CD8 T cells, localize
      to the bone marrow of immunized mice, and are sustained there over long periods
      of time. To investigate the rules governing T-cell migration to the bone marrow,
      we generated chimeric mice in which the lymphoid periphery contained two
      genetically or phenotypically distinct groups of T cells, one of which was
      identical to the host. We then examined whether a distinct type of T cell had an
      advantage over the others in the colonization of bone marrow. Our results show
      that whereas ICAM1 and CD18 molecules are both involved in homing to lymph nodes,
      neither is crucial for T-cell bone marrow colonization. We also observed that
      memory-phenotype CD44high T cells, but not virgin-type CD44-/low T cells,
      preferentially home to the bone marrow upon adoptive transfer to normal young
      mice, but not to thymectomized old recipients where an existing memory T-cell
      pool precludes their free access. Thus, T-cell colonization of the bone marrow
      uses distinct molecules from those implicated in lymph node homing, and is
      regulated both by the properties of the T cell and by the competitive efficacy of
      other T cells inhabiting the same, saturable niche. This implies that the homing
      potential of an individual lymphocyte is not merely an intrinsic property of the
      cell, but rather a property of the lymphoid system taken as a whole.

PMID- 12603594
TI  - Cloning of the complete rat immunoglobulin delta gene: evolutionary implications.
AB  - The recent discovery of a Cdelta encoding gene in artiodactyls has raised
      questions regarding the evolution of the gene. In the present study, we have
      analysed the complete rat Cdelta gene both at the cDNA and genomic levels,
      showing that the rat Cdelta gene is structurally similar to the corresponding
      mouse gene. Analysis of the rat immunoglobulin D heavy chain cDNA tail sequences,
      revealed two transcripts for the secreted form with varying sizes of their 3'
      untranslated region (UTR), resulting from usage of two different poly(A) addition
      signals. Furthermore, a membrane-bound form encoding transcript, possessing a
      long 3' UTR, was also observed. Phylogenetic analysis supports that the Cdelta
      gene appeared early in the evolution of vertebrates, and it was probably
      duplicated from the C micro gene more than 400 million years ago.

PMID- 12603596
TI  - Human CD8 T cells of the peripheral blood contain a low CD8 expressing
      cytotoxic/effector subpopulation.
AB  - Heterogeneity of lymphocyte populations demonstrates the diversity of cellular
      immune responses and provide a better understanding of the immune system. CD3+
      CD8+ T cells exhibit a low CD8 expressing (CD8low) population in flow cytometric
      analysis of peripheral blood T cells. In healthy donors, this population consists
      of 0.2-7.0% of all CD8 T cells. The majority of the CD8low T cell population
      showed an elevated expression of CD25, CD45RA, and CD95L, and low levels of CD28,
      CD62L and CD45RO. Circulating CD8low T cells resemble cytotoxic effector cells
      because they express cytolytic mediators and are able to execute cytotoxicity. A
      restricted T cell receptor profile with increased Vbeta9, Vbeta14 and Vbeta23
      expression was observed and the CD8low T cell population contain Epstein-Barr
      virus-specific T cells. Therefore, the CD8low population represent a subset of
      activated CD8 effector T cells, resulting most probably from a continuous and/or
      balanced immune response to intracellular pathogens.

PMID- 12603597
TI  - Ethanol promotes T cell apoptosis through the mitochondrial pathway.
AB  - Clinical reports suggest that acute ethanol intoxication is often associated with
      lymphopenia. Previously, ethanol was reported to invoke thymocyte apoptosis. We
      studied the effect of ethanol on T cell apoptosis. In addition, we evaluated the
      molecular mechanism of ethanol-induced T cell apoptosis. Human T cells harvested
      from healthy subjects after an alcohol drinking binge showed enhanced T cell
      apoptosis (before, 0.4 +/- 0.2% versus after, 19.6 +/- 2.5% apoptotic
      lymphocytes/field; P < 0.001). In in vitro studies, ethanol in a concentration of
      50 mm and higher enhanced the apoptosis of Jurkat cells. DNA isolated from
      ethanol-treated Jurkat cells displayed integer multiples of 180 base pairs.
      Ethanol decreased Jurkat cell expression of Bcl-2, whereas ethanol increased
      Jurkat cell expression of Bax. Jurkat cells treated with ethanol also showed
      translocation of cytochrome C into cytosol. Moreover, a caspase-9 inhibitor
      partially inhibited ethanol-induced Jurkat cell apoptosis. In in vivo studies,
      after binge drinking, T cell expression of Bcl-2 also decreased. In addition,
      binge drinking induced the cleavage of caspase-3, suggesting activation of
      caspase-3 in T cells. These results suggest that ethanol promotes T cell
      apoptosis through the activation of intrinsic or mitochondrial pathway.

PMID- 12603598
TI  - Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic
      cell subsets.
AB  - Cyclosporin A (CsA) is a potent immuno-suppressant and is approved for the
      treatment of various disease conditions. The molecular biological mechanism of
      CsA has been investigated intensively in T cells and has been shown to involve
      the intracellular calcineurin pathway. Recently, it was reported that CsA has
      capacities to affect not only T cells but also antigen-presenting cells such as B
      cells and dendritic cells (DCs). DCs are a master regulator of immune responses
      that have an integral capacity to prime naive T cells. In the present study, we
      investigated the biological effects of CsA on human peripheral blood DC subsets:
      CD11c+ myeloid and CD11c- lymphoid subsets. CsA inhibited the up-regulation of co
      stimulatory molecules induced with or without microbial stimuli and CD40L on both
      CD11c+ and CD11c- subsets. In addition, CsA negatively regulated the endocytic
      activity of CD11c+ DC during the immature state. CsA inhibited the interleukin-12
      (IL-12) production, but augmented the IL-10 production from the LPS-stimulated
      CD11c+ subset, whereas CsA reduced the interferon-alpha (IFN-alpha) production
      from the CD11c- subset infected with Sendai virus (SV). Both the LPS-stimulated
      CD11c+ subset and SV-infected CD11c- subset preferentially induced the
      development of IFN-gamma-producing T helper-type 1 (Th1) cells. Pretreatment of
      these DC subsets with CsA inhibited the Th1 skewing. These findings suggested a
      DC-mediated mechanism of immunosuppression by CsA.

PMID- 12603599
TI  - Detection of cytoplasmic CD antigens within normal human peripheral blood
      leucocytes.
AB  - Polymorphonuclear neutrophils (PMNs) are capable of synthesizing various pro
      inflammatory cytokines which may indirectly influence specific immune responses.
      PMNs may also have the capacity to present foreign peptides to helper T cells (Th
      cells). In support of this hypothesis, recent studies have shown that
      neutrophils, when activated by the correct combination of cytokines, can be
      induced to express cell surface major histocompatibility complex (MHC) Class II
      (DR) antigen, CD80 (B7.1) and CD86 (B7.2): molecules required for antigen
      presentation and subsequent T-cell activation. In this study we have used normal
      "resting" human peripheral blood neutrophils and demonstrated, using a mild
      fixation and permeabilization protocol, significant cytoplasmic "stores" of these
      molecules known to be important in antigen presentation. Cytoplasmic MHC Class II
      antigen was found with two out of 20 normal donors tested whereas cytoplasmic
      CD80 and CD86 were found to a variable extent within all normal donors.
      Surprisingly, we also found several other neutrophil cytoplasmic CD antigens more
      commonly associated with B cells, i.e. CD20, CD21 (CR2/EBV-R) and CD22 (BL-CAM).
      All of these antigens were confined to the "resting" cell cytoplasm and were
      never found to be expressed on the cell surface. To exclude the possibility that
      these antigens were absorbed from plasma and to provide evidence for active
      synthesis, we used a novel whole blood in situ hybridization flow cytometry assay
      method to detect mRNA specific for these antigens within normal PMNs. We also
      conducted real-time polymerase chain reactions to confirm these findings using
      CD22 as a good example of an "inappropriately expressed" CD antigen. These
      observations therefore provide support for the hypothesis that human PMNs have
      the potential to express molecules required for antigen presentation and cell
      signalling.

PMID- 12603600
TI  - Neither lymphotoxin alpha nor lymphotoxin beta receptor expression is required
      for biogenesis of lymphoid aggregates or differentiation of natural killer cells
      in the pregnant mouse uterus.
AB  - Gene ablation studies in mice indicate that lymphotoxin (LT)alpha, LTbeta and
      LTbetaR are essential for the genesis of lymph nodes (LN), normal structural
      development of peripheral lymphoid tissues and the differentiation of natural
      killer (NK) cells. LTbetaR binds to the heterotrimeric cytokines LTalpha1beta2
      and LIGHT. LTs also regulate stromal cell expression of lymphocyte homing
      chemokines. Uterine decidualization in normal (+/+) mice is accompanied by the
      appearance and maturation of large numbers of uterine NK (uNK) cells that
      differentiate from precursors mobilized to the uterus from secondary lymphoid
      tissues. uNK cells accumulate in a transient, lymphocyte-rich region known as the
      metrial gland or, more recently, the mesometrial lymphoid aggregrate of pregnancy
      (MLAp). To determine if LTs contribute to development of the MLAp, and to the
      differentiation and/or localization of uNK cells, a histological study was
      undertaken of implantation sites from LTalpha null, LTbetaR null and gestation
      day-matched, normal mice. Implantation sites from the gene-ablated mice contained
      abundant numbers of uNK cells that localized appropriately. This indicates that
      the stromally derived molecules supporting NK cell differentiation in the uterus
      differ from those used in secondary lymphoid organs.

PMID- 12603601
TI  - Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis
      and immunoglobulin production in male mice.
AB  - Oestrogen treatment down-regulates B lymphopoiesis in the bone marrow of mice.
      Meanwhile it up-regulates immunoglobulin production. To understand better the
      oestrogen action on bone marrow male mice lacking oestrogen receptor alpha
      (ERalpha; ERKO mice), lacking ERbeta (BERKO mice), lacking both receptors (DERKO
      mice) or wild-type (wt) littermates were castrated and treated for 2.5 weeks with
      30 microg/kg 17beta-oestradiol (E2) or vehicle oil as controls. The B
      lymphopoiesis in the bone marrow was examined by flow cytometry and mature B-cell
      function was studied using an ELISPOT assay enumerating the B cells in bone
      marrow and spleen that were actively producing immunoglobulins. In wt mice the
      frequency of B-lymphopoietic (B220+) cells in the bone marrow decreased from 15%
      to 5% upon E2 treatment. In ERKO and BERKO mice significant reduction was seen
      but not of the same magnitude. In DERKO mice no reduction of B lymphopoiesis was
      seen. In addition, our results show that E2 mediated reduction of different steps
      in B lymphopoiesis require only ERalpha or both receptors. In wt and BERKO mice
      E2 treatment resulted in significantly increased levels of B cells actively
      producing immunoglobulin, while in ERKO and DERKO mice no such change was seen.
      Similar results were found in both bone marrow and spleen. In conclusion our
      results clearly show that both ERalpha and ERbeta are required for complete down
      regulation of B lymphopoiesis while only ERalpha is needed to up-regulate
      immunoglobulin production in both bone marrow and spleen.

PMID- 12603602
TI  - Dendritic cells recruited to the lung shortly after intranasal delivery of
      Mycobacterium bovis BCG drive the primary immune response towards a type 1
      cytokine production.
AB  - We showed in a previous study that the intranasal (i.n) delivery of bacille
      Calmette-Guerin (BCG) to BP2 mice (H-2q) inhibits eosinophilia and bronchial
      hyperreactivity in a mouse model of asthma. The present work has been performed
      to characterize the leucocyte lineages recruited to the lungs of mice after i.n.
      delivery of BCG and potentially involved in the polarization of T lymphocytes.
      The different antigen-presenting cells (APC) recruited to bronchoalveolar lavage
      (BAL) and to lung tissue of mice shortly after the delivery of BCG were analysed
      in parallel as well as their capacity to drive the immune response towards a T
      helper type 1 cytokine production. Alveolar macrophages (AM) from the BAL were
      CD11c+, F4/80+ and CD11b-, and in the lung tissue two major populations of
      potential APC were detected: one CD11c-, F4/80+, CD11b+ and I-Aq- was identified
      as interstitial macrophages (IM) and a second expressing CD11c+ and I-Aq+
      antigens, negative for CD11b and F4/80 markers as leucocytic dendritic cells
      (DC). Freshly isolated DC up-regulated CD11b and CD40 antigens after overnight
      culture, but remained negative for CD8alpha antigen, suggesting a myeloid origin.
      Lung DC which produced high amount of interleukin (IL)-12 were potent inducers of
      naive CD4+ T lymphocyte priming, as assessed by interferon-gamma (IFN-gamma)
      production by these naive CD4+ T cells. Lung explants recovered long term after
      BCG delivery produced sustained levels of IFN-gamma. Our results suggest that AM
      and particularly DC by secreting IL-12 shortly after BCG delivery induce the long
      term persistence of IFN-gamma-secreting T cells percolating in BCG-loaded lung
      tissue.

PMID- 12603603
TI  - Macrophages exposed to Mycobacterium tuberculosis release chemokines able to
      recruit selected leucocyte subpopulations: focus on gammadelta cells.
AB  - Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of
      selected human leucocyte subsets induced by macrophages incubated with
      Mycobacterium tuberculosis (MT)-derived products in vitro. The release of
      monocyte chemotactic protein 1 (MCP-1) and interleukin-8 (IL-8) correlated with
      the specific induction of strong chemotaxis towards monocytes and
      polymorphonuclear leucocytes (PMNs). gammadelta and T helper type 1 (Th1)
      alphabeta lymphocytes were chemoattracted, while T-resting, IL-2-activated and
      Th2 lymphocytes were unaffected. Activation with mycobacterium-derived, phosphate
      containing components, modulated the chemokine receptor profile of gammadelta T
      lymphocytes as well as their pattern of cyto-chemokine production, disclosing a
      potential for their active participation in granuloma formation. In particular,
      CXCR3 and IP-10, which we found to be released by MT-pulsed alveolar macrophages,
      seem to represent the receptor-counter-receptor pair implicated in the chemotaxis
      of gammadelta lymphocytes. Immunohistochemical analysis and in situ hybridization
      revealed the in vivo presence of IL-8, MCP-1 and IL-10 in lymph node and lung
      tuberculous granulomas. Our results underscore the role of MT extracts in the
      induction of macrophage-derived chemokines responsible for the orchestrated
      recruitment of PMNs, monocytes, and Th1 and gammadelta T cells, as well as in the
      regulation of gammadelta function.

PMID- 12603604
TI  - Interleukin-1beta converting enzyme subfamily inhibitors prevent induction of
      CD86 molecules by butyrate through a CREB-dependent mechanism in HL60 cells.
AB  - To investigate the underlying mechanism for induction of CD86 molecules, we
      analysed the ability of the histone deacetylase (HDAC) inhibitor, sodium butyrate
      (NaB), to induce CD86 at the transcriptional level in HL60 cells. Our studies
      showed that the expression of CD86 on the cell surface was increased by 24 hr of
      NaB treatment, and the enhancement of CD86 mRNA expression was observed by real
      time polymerase chain reaction. When we measured NF-kappaB binding activity,
      significant activity was induced upon NaB stimulation, which was suppressed by
      the addition of pyrrolidine dithiocarbamate. Butyrate also induced phosphorylated
      cAMP response element-binding protein (CREB), which bound to cAMP-responsive
      elements. Dibutyryl (db) -cAMP induced active CREB and increased the levels of
      CD86 by 24 hr. These observations indicated that NF-kappaB and/or CREB are
      crucial for butyrate-dependent activation of CD86 gene expression. We examined
      the inhibitory effects of various caspase inhibitors on the expression of CD86 in
      cells treated with NaB, because NaB also induced apoptosis with slow kinetics.
      Intriguingly, our results demonstrated that inhibitors of the interleukin-1beta
      converting enzyme subfamily (caspase-1, -4, -5 and -13) blocked the butyrate
      induced increase in level of CD86. These inhibitors interfered with CD86 gene
      transcription in the presence of activated NF-kappaB, whereas phosphorylated CREB
      was down-regulated in the reactions where these inhibitors were added to inhibit
      CD86 gene expression. These results suggested that butyrate not only acetylates
      histones on the CD86 promoter through the suppression of HDAC activity, but that
      butyrate also regulates CREB-mediated transcription, possibly through the caspase
      activities triggered by NaB.

PMID- 12603605
TI  - An abnormal but functionally active complement component C9 protein found in an
      Irish family with subtotal C9 deficiency.
AB  - Two independently segregating C9 genetic defects have previously been reported in
      two siblings in an Irish family with subtotal C9 deficiency. One defect would
      lead to an abnormal C9 protein, with replacement of a cysteine by a glycine
      (C98G). The second defect is a premature stop codon at amino acid 406 which would
      lead to a truncated C9. However, at least one of two abnormal proteins was
      present in the circulation of the proband at 0.2% of normal C9 concentration. In
      this study, the abnormal protein was shown to have a molecular weight
      approximately equal to that of normal C9, and to carry the binding site for
      monoclonal antibody (mAb) Mc42 which is known to react with an epitope at amino
      acid positions 412-426, distal to 406. Therefore, the subtotal C9 protein carries
      the C98G defect. The protein was incorporated into the terminal complement
      complex, and was active in haemolytic, bactericidal and lipopolysaccharide
      release assays. A quantitative haemolytic assay indicated even slightly greater
      haemolytic efficiency than normal C9. Epitope mapping with six antihuman C9 mAbs
      showed the abnormal protein to react to these antibodies in the same way as
      normal C9. However, none of these mAbs have epitopes within the lipoprotein
      receptor A module, where the C98G defect is located. The role of this region in
      C9 functionality is still unclear. In conclusion, we have shown that the lack of
      a cysteine led to the production of a protein present in the circulation at very
      much reduced levels, but which was fully functionally active.

PMID- 12603606
TI  - Fibroblasts inhibit the production of interleukin-12p70 by murine dendritic
      cells.
AB  - Interleukin-12 p70 (IL-12p70) is a key cytokine produced by dendritic cells (DC)
      able to drive the development of T helper type 1 (Th1) lymphocytes. We showed
      that thymic and other fibroblasts strongly inhibit IL-12p70 production by splenic
      DC stimulated by lipopolysaccharide plus either anti-CD40 or interferon-gamma
      (IFN-gamma) and by purified splenic DC stimulated by Pansorbin plus IFN-gamma.
      This IL-12p70 inhibitory activity is secreted in the conditioned medium of
      primary fibroblasts and fibroblast cell lines but not by haematopoietic cell
      lines. As IL-10 was the unique factor able to inhibit IL-12p70 produced by
      cultured splenic DC, we showed that a neutralizing antibody to IL-10 did not
      suppress the IL-12p70 inhibitory activity of thymic fibroblast-conditioned medium
      (FCM). This FCM potently inhibits the maturation and expression of major
      histocompatibility complex class II and co-stimulatory molecules induced by
      stimulation of spleen-derived DC. While thymic FCM suppressed the IL-12p70
      expression by stimulated spleen-derived DC, tumour necrosis factor-alpha
      production is not affected. This inhibitory activity is able to down-regulate the
      IL-12p35 subunit transcription and expression, resulting in the impaired assembly
      of IL-12p70 heterodimer. As fibroblasts are present in the tissue
      microenvironment and are active players in the establishment of an immune
      response, the nature and role of the fibroblastic inhibitory activity remain to
      be established.

PMID- 12603607
TI  - Histopathological outcome of Leishmania major-infected BALB/c mice is improved by
      oral treatment with N-acetyl-l-cysteine.
AB  - Leishmania major infected BALB/c mice were treated with N-acetyl-l-cysteine
      (NAC), a glutathione precursor, to evaluate the role of in vivo glutathione on
      lesion pathology and cytokine profiles following infection. Mice were maintained
      on NAC-containing water 2 days before infection for a total of 14 weeks. The
      BALB/c response to L. major infection was improved by oral administration of NAC,
      at the level of histopathological outcome, lesion progression and cytokine
      profile. A significantly improved histopathological outcome of the footpad
      lesion, characterized by a mixed inflammatory infiltrate organized in a focal
      pattern with little tissue destruction and a reduced parasite load, was observed
      in NAC-treated BALB/c mice. Histopathological modulation was accompanied by a
      modified cytokine pattern from popliteal lymph node cells, demonstrated by a
      sustained higher frequency of interferon-gamma (IFN-gamma) and tumour necrosis
      factor-alpha (TNF-alpha)-producing cells. This work points to an important role
      for glutathione in the modulation of effector responses in BALB/c mice.

PMID- 12603608
TI  - Tumour-induced polarization of tumour vaccine-draining lymph node T cells to a
      type 1 cytokine profile predicts inherent strong immunogenicity of the tumour and
      correlates with therapeutic efficacy in adoptive transfer studies.
AB  - Previously we have shown that vaccination with the poorly immunogenic B16BL6-D5
      melanoma (D5) elicits a dominant type 2 (T2) cytokine response that fails to
      protect the host from a subsequent tumour challenge. Here we investigated whether
      the inherent immunogenicity of a tumour can be correlated with its ability to
      bias the anti-tumour cytokine response towards either a type 1 (T1) or a T2
      profile. The immune response to six tumours of different inherent immunogenicity
      was assayed. By isolating l-selectinlow T cells from tumour vaccine draining
      lymph nodes (TVDLN), it was possible to detect tumour-specific cytokine responses
      from both immunogenic, poorly immunogenic and non-immunogenic tumours.
      Immunogenic tumours (MCA-304, MCA-309, MPR-4) induced a predominant tumour
      specific T1 cytokine response. In contrast, weakly (MCA-310, MPR-3) and
      poorly/non-immunogenic tumours (MPR-5, D5) sensitized T cells with a predominant
      tumour-specific T2 cytokine response. A significant correlation (P < 0.025)
      between immunogenicity and the ratio of tumour-specific interferon-gamma :
      interleukin-4 (IL-4) secretion by TVDLN T cells was identified. We then
      documented that non-therapeutic T cells primed by the poorly immunogenic D5,
      recognized "tumour-rejection" antigens and that reprogramming their cytokine
      response, by in vitro culture with IL-12 and anti-IL-4, to a T1 profile uncovered
      therapeutic efficacy. In contrast, TVDLN T cells primed by a therapeutic vaccine
      lose therapeutic efficacy when cultured with IL-4. These results provide insights
      into the development of a protective anti-tumour immune response and strengthen
      the hypothesis that a T1 cytokine response is critical for T-cell-mediated tumour
      regression.

PMID- 12603612
TI  - Intrafamilial spread of Helicobacter pylori: a genetic analysis.
AB  - BACKGROUND: A high incidence of Helicobacter pylori among family members of
      children with H. pylori gastritis has previously been documented on biopsy
      material. The main objective of this study was the genetic clarification of H.
      pylori strains involved in intrafamilial dispersion. MATERIALS AND METHODS:
      Formalin-fixed, paraffin-embedded material of antral mucosa from 32 members of 11
      families was studied for the presence of genetic homogeneity. To achieve this
      goal, the entire genome of H. pylori was studied by the polymerase chain reaction
      (PCR)-based random amplified polymorphic DNA (RAPD) fingerprinting method.
      Furthermore, the Urease A gene was analyzed using a multiplex PCR-assay and an
      alternative mutation detection method based on the Hydrolink trade mark analysis.
      RESULTS: RAPD fingerprinting confirmed that closely related H. pylori strains
      were involved in the intrafamilial dispersion. Mutations and small deletions in
      Urease A gene were found in 22 out of 32 individuals. CONCLUSIONS: The homology
      of the H. pylori genome in members of the same family strongly supports the
      hypothesis of transmission of H. pylori from person-to-person or from a common
      source.

PMID- 12603611
TI  - Helicobacter pylori CagA containing ITAM-like sequences localized to lipid rafts
      negatively regulates VacA-induced signaling in vivo.
AB  - BACKGROUND: Helicobacter pylori CagA is injected into the host cell and tyrosine
      phosphorylated. We examined tyrosine-phosphorylation sites of CagA, as well as
      the function of CagA proteins in vivo and in vitro. METHODS: After proteolytic
      digestion of CagA with lysyl endopeptidase, CagA tyrosine-phosphorylation sites
      were determined using quadropolar time-of-flight (Q-TOF) mass spectrometry
      analysis. Specific anti-pY CagA polyclonal and anti-CagA monoclonal antibodies
      were used to examine gastric mucosal biopsy specimens from H. pylori infected
      patients. RESULTS: Mass spectrometry identified five crucial tyrosine
      phosphorylation sites of CagA at Tyr893, Tyr912, Tyr965, Tyr999, and Tyr1033
      within the five repeated EPIYA sequences of H. pylori (NCTC11637)-infected AGS
      cells. CagA protein also had an immuno-receptor tyrosine-based activation motif
      (ITAM)-like amino acid sequences in the 3' region of the cagA, EPIYATIx27EIYATI,
      which closely resembled the ITAM. CagA proteins: (i) were localized to the 1%
      TritonX-100 resistant membrane fraction (lipid rafts); (ii) formed a cluster of
      phosphorylated CagA protein complexes; (iii) associated with tyrosine
      phosphorylated GIT1/Cat1 (G protein-coupled receptor kinase-interactor 1/Cool
      associated tyrosine-phosphorylated 1), substrate molecules of receptor type
      protein-tyrosine phosphatase (RPTPzeta/beta), which is the receptor of VacA; and
      (iv) were involved in a delay and negative regulation of VacA-induced signal.
      Furthermore, immunohistochemical staining of gastric mucosal biopsy specimens
      provided strong evidence that tyrosine-phosphorylated CagA is found together with
      CagA at the luminal surface of gastric foveola in vivo. CONCLUSION: These
      findings suggest an important role for CagA containing ITAM-like sequences in the
      pathogenesis of H. pylori-related disease.

PMID- 12603613
TI  - Helicobacter pylori infection in children and adults: a single pathogen but a
      different pathology.
AB  - BACKGROUND: The aims of this retrospective study were to ascertain in large
      series of children and adults: the relationship of the infecting strain to
      gastric mucosal lesions; and the relationship of the infecting strain to its
      duodenal localization. MATERIALS AND METHODS: We studied 307 and 604 consecutive
      children and adults. In gastric mucosal samples H. pylori was cultured, genotyped
      and histologically assessed, while inflammation, activity and intestinal
      metaplasia were graded. In a subset of 171 patients H. pylori ureaseA (ureA) and
      cagA genes were amplified (PCR) using mucosal biopsies from the duodenum.
      RESULTS: H. pylori infection was diagnosed in 40 children and 308 adults. cagA
      was identified in 50% and 65.5% of infected children and adults. Antral activity
      was associated with the density of infecting bacteria (p <.001) and with cagA (p
      <.01). Intestinal metaplasia was correlated with cagA (p <.001). The ureA gene
      was found in 56 duodenal samples from 82 H. pylori positive patients. Duodenal H.
      pylori ureA was significantly more frequent in patients with duodenal diseases
      than in those without (p <.01), cagA positive strains being mainly involved in
      the infection of this anatomical area (p <.01). CONCLUSIONS: A severe H. pylori
      associated gastritis is more prevalent when the density of infecting bacteria is
      high and when cagA positive strains cause the infection. The most virulent cagA
      positive H. pylori colonizes not only the gastric, but also the duodenal mucosa,
      which can be directly damaged by the bacteria itself or by its products.

PMID- 12603614
TI  - Helicobacter pylori infection, mucosal atrophy and intestinal metaplasia in Asian
      populations: a comparative study in age-, gender- and endoscopic diagnosis
      matched subjects.
AB  - BACKGROUND: It is known that the incidence and mortality rate of gastric cancer
      is high among Japanese and Chinese populations, but extremely low in Thai and
      Vietnamese populations. The aim of this study was to investigate the prevalence
      of Helicobacter pylori infection and the differences in the glandular atrophy and
      intestinal metaplasia scores in stomach specimens of Asian adult subjects of
      different races. MATERIALS AND METHODS: Chinese, Thai, Vietnamese and Japanese
      patients were matched by age, gender and endoscopic diagnosis, in order to
      compare the differences in incidence of H. pylori-related peptic ulcer disease
      and the prevalence of H. pylori infection among four Asian populations (n = 700).
      Glandular atrophy scores and intestinal metaplasia scores were also compared
      among four Asian populations divided into H. pylori-positive cases (n = 120, 109,
      145, 80, respectively) and H. pylori-negative cases (n = 55, 66, 30, 95,
      respectively). RESULTS: Among peptic ulcers, gastric ulcer was more frequently
      seen in Japanese subjects than in the other Asian populations examined. On the
      other hand, duodenal ulcer was more frequently seen in other Asian populations
      than in Japanese subjects. The prevalence of H. pylori infection was similar in
      the Japanese (Tokyo) and Chinese (Beijing and Fuzhou) populations. It was higher
      in Thai (Chiang Mai) subjects compared with Japanese subjects. On the other hand,
      Vietnamese (Ho Chi Minh) subjects had significantly lower rates of H. pylori
      infection than Japanese subjects. The glandular atrophy and intestinal metaplasia
      scores in the stomach were significantly higher in the H. pylori-positive
      Japanese subjects than in H. pylori-positive subjects belonging to other Asian
      populations, except for the higher glandular atrophy scores in Chinese rather
      than Japanese subjects. On the other hand, there were no significant differences
      in the glandular atrophy and intestinal metaplasia scores in the angulus of the
      stomach among H. pylori-negative subjects belonging to the different Asian
      populations examined. CONCLUSIONS: Gastric ulcer was more common among Japanese
      subjects, while duodenal ulcer was more common among the other Asian populations
      examined. Japanese subjects with H. pylori infection showed more severe atrophic
      and metaplastic gastritis compared with that in other Asian subjects with H.
      pylori infection. These results may be related to the higher incidence of gastric
      cancer noted in Japanese subjects and the lower incidence of the cancer seen in
      Thai and Vietnamese patients.

PMID- 12603615
TI  - Clinical application of 20 MHz endosonography and anti-Helicobacter pylori
      immunoblots to predict regression of low-grade gastric MALToma by H. pylori
      eradication.
AB  - AIM: We tested whether serial 20 MHz endosonography (EUS) and anti-Helicobacter
      pylori immunoblots can predict the complete regression of gastric MALToma by H.
      pylori eradication. METHODS: The serums of 17 MALToma patients, including 15 with
      low grade and two with high grade, were collected before therapy. Fifteen
      patients with low-grade MALToma and 18 nonMALToma patients, all infected with H.
      pylori, have been followed with serum sampling, endoscopy, and EUS on enrollment,
      on the 2nd, 6th, and 12th months after anti-H. pylori therapy. All sera were
      tested for anti-H. pylori immunoblots, including 19.5, 26.5, 30, 35, 89, 116 KDa
      (CagA), FldA. The DNAs were extracted serially from the biopsy of MALToma
      patients before and after therapy to perform polymerase chain reaction (PCR) for
      the immunoglobulin heavy-chain gene monoclonality. RESULTS: MALToma patients had
      higher prevalence rates of anti-FldA protein, 19.5 and 30 KDa antibodies of H.
      pylori (p < 0.01). After H. pylori eradication, MALToma patients had negative
      seroconversion of 19.5, 26.5, 30, and 35 KDa antibodies (p < 0.05), but not in
      CagA and FldA. The PCR monoclonality occurred in 80% (12/15) of the MALToma
      patients before therapy, but did not correlate with any seroconversion of anti-H.
      pylori immunoblots after therapy (p > 0.05). Complete regression of MALToma was
      observed in 73.3% (11/15) of patients. Evaluation with 20 MHz EUS, for the
      initial tumor depth and its normalization on the 6th month had 90.9% sensitivity
      and 100% specificity to predict the complete regression. DISCUSSION: The negative
      seroconversions of the smaller-molecular-weight proteins, but not CagA and FldA,
      correlate with regression of MALToma by H. pylori eradication. 20 MHz EUS can
      effectively predict the therapeutic response of MALToma.

PMID- 12603616
TI  - Acid inhibitory potency of twice a day omeprazole is not affected by eradication
      of Helicobacter pylori in healthy volunteers.
AB  - BACKGROUND AND AIMS: The acid inhibitory effect of proton pump inhibitors is
      reported to be greater in the presence than in the absence of an H. pylori
      infection. This study was undertaken to test the hypothesis that the acid
      inhibitory effect of omeprazole given twice a day is greater in H. pylori
      infected healthy volunteers than in the same individuals following eradication
      because of differences in the pharmacodynamics of omeprazole, greater
      duodenogastric reflux, the effects of ammonia produced by the H. pylori, or lower
      gastric juice concentrations of selected cytokines, which may inhibit gastric
      acid secretion. MATERIALS AND METHODS: We undertook 24-hour pH-metry in 12 H.
      pylori-positive healthy volunteers: (1) when on no omeprazole; (2) when on
      omeprazole 20 mg bid for 8 days; (3) 2 months after eradication of H. pylori and
      when on no omeprazole; and (4) after eradication of H. pylori and when on
      omeprazole 20 mg twice a day. RESULTS: In subjects given omeprazole, eradication
      of H. pylori reduced pH and percentage pH >or= 3, as well as increasing the area
      under the H+ concentration-time curve. These differences were not due to
      alterations in (1) gastric juice concentrations of IL-1alpha, IL-8, IL-13,
      epidermal growth factor, or bile acids; (2) serum gastrin concentrations; or (3)
      the pharmacokinetics of omeprazole. There was no change in the difference in the
      H+ concentration-time curve 'without omeprazole' minus 'with omeprazole', when
      comparing 'after' versus 'before' eradication of H. pylori. CONCLUSIONS:
      Eradication of H. pylori was not associated with an alteration in the acid
      inhibitory potency when comparing the difference in gastric acidity 'with' versus
      'without' omeprazole. When the results were expressed by simply taking into
      account the acid measurements while on omeprazole before versus after eradication
      of H. pylori, the acid inhibition with omeprazole was greater in the presence
      than in the absence of a H. pylori infection. The clinical significance of the
      small difference is not clear.

PMID- 12603617
TI  - Preventive effects of Cladosiphon fucoidan against Helicobacter pylori infection
      in Mongolian gerbils.
AB  - BACKGROUND: Recently, the acquisition by Helicobacter pylori of resistance to
      antibiotics has become a serious problem. Therefore, nonantibiotic substances are
      required to diminish H. pylori-induced gastric lesions. In the present study, the
      effects of Cladosiphon fucoidan were examined in terms of H. pylori attachment to
      porcine gastric mucin in vitro and Helicobacter pylori-induced gastritis in vivo.
      METHODS: The inhibitory effect of Cladosiphon fucoidan and other polysaccharides
      on H. pylori attachment to porcine gastric mucin was assayed in vitro with mucin
      coated microtiter plates. The effect of Cladosiphon fucoidan on H. pylori-induced
      gastritis was examined in vivo using Mongolian gerbils. H. pylori-inoculated
      gerbils were given fucoidan in drinking water. Six weeks after H. pylori
      inoculation, gerbils were sacrificed for macroscopic and microscopic examination
      of gastric lesions and counting of viable H. pylori in the gastric mucosa.
      RESULTS: Cladosiphon fucoidan inhibited the H. pylori attachment to porcine
      gastric mucin at pH 2.0 and 4.0. Two other sulfated polysaccharides, Fucus
      fucoidan and dextran sulfate sodium, also inhibited the attachment but only at pH
      2.0. Inhibitory effects of these three sulfated polysaccharides were not observed
      at pH 7.2 and nonsulfated polysaccharides, such as mannan and dextran, exerted no
      influence at any pH. In the in vivo experiment, the H. pylori-induced gastritis
      and the prevalence of H. pylori infected animals were markedly reduced by
      fucoidan in a dose-dependent manner, at doses of 0.05 and 0.5% in the drinking
      water. CONCLUSION: Cladosiphon fucoidan may deserve particular attention as a
      safe agent that can prevent H. pylori infection and reduce the risk of associated
      gastric cancer.

PMID- 12603618
TI  - p16Ink4a is overexpressed in H. pylori-associated gastritis and is correlated
      with increased epithelial apoptosis.
AB  - BACKGROUND: Cell cycle regulatory proteins may be critical targets during
      carcinogenesis. We have previously shown that chronic H. pylori infection is
      associated with decreased expression of the cyclin dependent kinase inhibitor
      (CDI) p27kip1. Loss of p27kip1 and p16Ink4a (p16) expression, another CDI, has
      been reported during the progression of gastric tubular adenomas to advanced
      gastric cancer. The aim of the current study was to examine whether H. pylori
      infection also affects the expression of p16 in the gastric mucosa of H. pylori
      infected patients. METHODS: p16 expression was evaluated in gastric antral
      biopsies by immunohistochemistry in 50 patients with nonulcer dyspepsia (n = 18
      uninfected, n = 32 H. pylori infected, 24 by cagA+ strains). Adjacent sections
      were stained for proliferating epithelial cells (by Ki67) and for apoptotic cells
      (by TUNEL assay). RESULTS: Both in H. pylori infected and uninfected patients the
      expression of p16 was higher in the neck and base of the gland than in the
      foveolar region. Epithelial staining for p16 was increased with H. pylori
      infection (31.3% vs. 11.1% in the foveolar region, 68.8% vs. 27.8% in the neck
      and 75% vs. 50% in the glandular base). There was no correlation between the
      expression of 16 and proliferation but there was a significant positive
      correlation between apoptosis and 16 immunostaining. CONCLUSIONS: The tumor
      suppressor gene 16 is over expressed in gastric epithelial cells of H. pylori
      infected patients and this is associated with an increase in apoptosis. These
      findings suggest a possible role for this cell cycle regulator in the increase in
      gastric cell turnover that is associated with H. pylori infection.

PMID- 12603619
TI  - Statistical model of the interactions between Helicobacter pylori infection and
      gastric cancer development.
AB  - BACKGROUND: The bacterium Helicobacter pylori is associated with a number of
      gastrointestinal diseases, such as gastric ulcer, duodenal ulcer and gastric
      cancer. Several histological changes may be observed during the course of
      infection; some may influence the progression towards cancer. The aim of this
      study was to build a statistical model to discover direct interactions between H.
      pylori and different precancerous changes of the gastric mucosa, and in what
      order and to what degree those may influence the development of the intestinal
      type of gastric cancer. METHODS: To find direct and indirect interactions between
      H. pylori and different histological variables, log-linear analyses were used on
      a case-control study. To generate mathematically and biologically relevant
      statistical models, a designed algorithm and observed frequency tables were used.
      RESULTS: The results show that patients with H. pylori infection need to present
      with proliferation and intestinal metaplasia to develop gastric cancer of the
      intestinal type. Proliferation and intestinal metaplasia interacted with the
      variables atrophy and foveolar hyperplasia. Intestinal metaplasia was the only
      variable with direct interaction with gastric cancer. Gender had no effect on the
      variables examined. CONCLUSION: The direct interactions observed in the final
      statistical model between H. pylori, changes of the mucosa and gastric cancer
      strengthens and supports previous theories about the progression towards gastric
      cancer. The results suggest that gastric cancer of the intestinal type may
      develop from H. pylori infection, proliferation and intestinal metaplasia, while
      atrophy and foveolar hyperplasia interplay with the other histological variables
      in the disease process.

PMID- 12603620
TI  - Mucolytics and Helicobacter pylori eradication.

PMID- 12603622
TI  - Clarithromycin resistance in Iranian H. pylori strains before introduction of
      clarithromycin.

PMID- 12603623
TI  - Citizen involvement in priority-setting.

PMID- 12603624
TI  - Development and evaluation of a breast cancer prevention decision aid for higher
      risk women.
AB  - OBJECTIVE: To develop and evaluate the effectiveness of a breast cancer
      prevention decision aid for women aged 50 and older at higher risk of breast
      cancer. DESIGN: Pre-test-post-test study using decision aid alone and in
      combination with counselling. SETTING: Breast Cancer Risk Assessment Clinic.
      PARTICIPANTS: Twenty-seven women aged 50-69 with 1.66% or higher 5-year risk of
      breast cancer. INTERVENTION: Self-administered breast cancer prevention decision
      aid. MAIN OUTCOME MEASURES: Acceptability; decisional conflict; knowledge;
      realistic expectations; choice predisposition; intention to improve life-style
      practices; psychological distress; and satisfaction with preparation for
      consultation. RESULTS: The decision aid alone, or in combination with
      counselling, decreased some dimensions of decisional conflict, increased
      knowledge (P < 0.01), and created more realistic expectations (P < 0.01). The aid
      in combination with counselling, significantly reduced decisional conflict (P <
      0.01) and psychological distress (P < 0.02), helped the uncertain become certain
      (P < 0.02), and increased intentions to adopt healthier life-style practices (P <
      0.03). Women rated the aid as acceptable, and both women and practitioners were
      satisfied with the effect it had on the counselling session. CONCLUSION: The
      decision aid shows promise as a useful decision support tool. Further research
      should compare the effect of the decision aid in combination with counselling to
      counselling alone.

PMID- 12603625
TI  - Barriers to patient information provision in primary care: patients' and general
      practitioners' experiences and expectations of information for low back pain.
AB  - BACKGROUND: As patient involvement in health-care increases, the role of
      information is crucial, especially in conditions where self-management is
      considered an integral part of care. However, the suitability and applicability
      of much patient information has not been appraised in terms of how far it meets
      patients' information needs. AIMS: To ascertain patients' and clinicians'
      experiences and expectations of information in low back pain in order to suggest
      a suitable 'patient-centred' content for a patient information pack to be used in
      a primary care setting. METHODS: A qualitative study using semi-structured
      interviews with General Practitioners (GPs) (n = 15) and focus groups comprising
      patients with low back pain (n = 37). RESULTS: Barriers to information-giving for
      low back pain in primary care exist. Patients are dissatisfied with the
      information they receive from their GPs, especially regarding diagnosis and
      treatment. Patients tend to access information from a variety of other sources,
      which is often contradictory, conflicts with research evidence and leads to
      unreasonable expectations. GPs have varying views regarding the value of patient
      information and are equivocal about their roles as information providers.
      Although The Back Book is generally acceptable as a patient information leaflet
      for low back pain, attention to the tone of the text is required. CONCLUSIONS:
      Barriers exist to patient information provision, both generally and for low back
      pain, which need to be addressed in order to close the gap between strategy and
      implementation. Improving clinician communication skills and involving patients
      in developing information materials which meet their needs are crucial to this
      process.

PMID- 12603626
TI  - Putting partnership into practice: participatory wellbeing assessment on a south
      London housing estate.
AB  - PURPOSE: Bridging the gap between professionals and communities and establishing
      new forms of partnership is essential if service provision is to be made more
      responsive and accountable. This article describes an innovative approach to
      creating the basis for partnerships to address community wellbeing on an estate
      in south London. METHODS: Drawing on participatory appraisal and action planning
      methods, and drawing together residents and professionals within and beyond the
      health service, a participatory wellbeing assessment exercise was carried out on
      a housing estate with a population of around 6,000 people, involving just under
      10% of residents. RESULTS: The participatory wellbeing assessment exercise served
      as a means of seeking to bridge different perceptions, priorities and
      perspectives on wellbeing and forge new relationships, alliances and partnerships
      for change. Creating this vehicle for change also created opportunities for local
      people to participate in community wellbeing issues. This, in turn, strengthened
      connections between health policy, provision and grassroots community health
      development, broadening opportunities for service responsiveness and citizen
      involvement. CONCLUSION: Broadening involvement in assessing and determining
      priorities for improving wellbeing can serve to do more than enable citizens to
      engage more directly in making and shaping the policies that affect their lives.
      It can also serve as a way of establishing new kinds of partnerships across and
      within the statutory and non-statutory services, opening up space for new, more
      'joined up' forms of work that help to bridge the gap between citizens and
      services.

PMID- 12603627
TI  - Using nominal group technique to assess chronic pain, patients' perceived
      challenges and needs in a community health region.
AB  - PURPOSE: The purpose of this study was to better understand the experiences of
      people suffering from chronic pain in order to plan client-centred educational
      interventions. METHODS: People in the community with chronic pain were invited
      via newspapers, newsletters and e-mail discussion lists to participate in a needs
      assessment process and to attend an educational session at a local community
      college. Using the nominal group technique, which is a qualitative method of data
      gathering, 53 participants reported their perceived challenges and needs in
      dealing with chronic pain. Participants were randomly assigned to one of 10
      groups ranging from three to seven people. Responses were pooled to develop an
      overall list of their major concerns and needs. RESULTS: Issues were classified
      into six priority areas: medical and treatments, problems with daily living,
      emotional distress, social issues, sleep disturbances and financial issues.
      Participants indicated they had difficulty finding accessible, effective and
      acceptable care. Many participants perceived their family physician or other
      health-care providers were not adequately meeting their health-care needs.
      Specifically, sleep disorders; feeling of depression, irritability, worry and
      anxiety were perceived as medical and treatment areas requiring improvement. In
      addition, participants sought greater validation of their lived experience of
      chronic pain. CONCLUSION: Participants perceived that their needs were not being
      met adequately. There is a need for further study on physician-patient
      communication and its impact on patient health status and disability.

PMID- 12603628
TI  - A note on the relative importance that people attach to different factors when
      setting priorities in health care.
AB  - OBJECTIVE: To explore whether and to what extent people wish to give differential
      priority when asked to choose between providing health care treatment for
      different individuals or groups, on the basis of a range of factors, ranging from
      health gain to the number of dependants a person has. DESIGN: A sample of people
      resident in York self-completed a questionnaire. SETTING: The City of York.
      PARTICIPANTS: Twenty-three members of the general public and 29 undergraduate
      students. MAIN OUTCOME MEASURES: The relative importance of factors that people
      think should be taken into account when choosing between providing health care
      treatment for individuals or groups. RESULTS: The results suggest that health
      gain and the consequences for health without treatment are two of the most
      important considerations. CONCLUSIONS: A sample of the general public and
      undergraduate students wish to take account of a number of personal
      characteristics when setting priorities in health care.

PMID- 12603629
TI  - Redesigning mental health services: lessons on user involvement from the Mental
      Health Collaborative.
AB  - OBJECTIVES: To explore the involvement of mental health service users in the
      redesign of in-patient mental health services in six Trusts participating in a
      multi-regional NHS modernization programme. DESIGN: Semi-structured interviews
      and observation of team meetings undertaken as part of an action research study.
      PARTICIPANTS AND SETTING: Users, clinical, medical and managerial staff from six
      mental health trusts which participated in the Northern & Yorkshire and Trent
      regions' Mental Health Collaborative (MHC). RESULTS AND CONCLUSIONS: Whilst there
      were some problems, user involvement was undoubtedly a strength of the MHC in
      comparison to other modernization programmes within the NHS we have studied.
      However, the particular challenges posed by the specific context of acute mental
      health services should not be overlooked. The initial approach taken in each of
      the sites was to simply invite a user or user representative to join the local
      project team. In the course of events, various changes were made to this initial
      mechanism for involving users in the ongoing work of the teams. These changes-
      and setbacks in some sites--make drawing firm conclusions as to the effectiveness
      of the various strategies employed problematic. However, our qualitative data
      suggest a number of broad lessons that will assist both those leading and
      participating in other redesign initiatives to maximize the benefits to be gained
      from service user involvement.

PMID- 12603630
TI  - Are patients' decision-making preferences being met?
AB  - OBJECTIVE: To investigate the information and decision-making expectations of
      general practice patients during real life consultations. DESIGN: Post
      consultation, quantitative patient preference and enablement questionnaire.
      SETTING AND PARTICIPANTS: Patients attending for routine appointments in general
      practice surgeries in Oxfordshire, UK. RESULTS: Thirteen Oxfordshire general
      practitioners (GPs) volunteered to take part and a total of 171 patients
      completed and returned the questionnaire. Between a quarter and one-third of
      patients reported receiving less information than they desired, particularly in
      relation to the risks and benefits of medical treatments. Patients who preferred
      the doctor to make decisions for them (35%), were more likely to have their
      preferences met (64%) compared with patients wishing to share decisions (47%) or
      make their own (18%) who were less likely to achieve this role (52 and 41%,
      respectively). However, it could not be demonstrated unequivocally that these
      differences were statistically significant. In total, 61% of patients perceived
      that they achieved their preferred decision-making role. No significant
      differences were found in post-consultation enablement scores between any of the
      decision preference groups. Patients' assessments indicated that some doctors
      were more successful at achieving congruence than others. CONCLUSION: The
      decision-making preferences of general practice patients tend to vary. However,
      there was a substantial mismatch between the stated preferences of patients for
      the role they wanted to have in decision-making and what they felt actually took
      place in their consultation. Therefore, it remains a challenge for doctors to
      match their consultation style to the decision-making preferences of individual
      patients.

PMID- 12603631
TI  - Overcoming the challenges to consumer involvement in cancer research.
AB  - INTRODUCTION: Within the last decade, there have been many government initiatives
      to promote consumer involvement in research, especially in cancer. At the same
      time, the number and influence of consumer groups themselves have expanded.
      However, the organizational infrastructure necessary to facilitate consumer
      involvement has not been developed. Consequently, consumer involvement has tended
      to remain essentially localized and project driven, with no strategic or regional
      lead. OPPORTUNITIES FOR INVOLVEMENT AND IDENTIFICATION OF CONSUMERS: The
      opportunities for consumers to influence the research process at each stage of
      the research process are identified. The different types of consumer involvement
      are also examined. Novel ways of identifying and recruiting consumers that have
      been adopted by one cancer network are discussed. THE STRATEGIES USED IN ONE
      CANCER NETWORK: An organizational model designed by one cancer network for
      involving consumers in research is illustrated. Three innovations are examined in
      detail. First, how three open consumer conferences have increased awareness of
      research among service users. Second, the recruitment of consumers to sit on
      project steering groups and a committee that provides a strategic overview of
      current research. Third, the establishment of a Consumer Panel for Research where
      reimbursed, trained consumers are able to provide a considered consumer
      perspective in a range of settings. CONCLUSIONS: Cancer networks need to take the
      lead in the development of an organizational infrastructure to facilitate
      consumer involvement. The model developed in Sheffield could be generalizable to
      other diseases and other health-care settings.

PMID- 12603635
TI  - Migraine preventive medication reduces resource utilization.
AB  - OBJECTIVE: To determine if long-term resource utilization is reduced by adding a
      preventive medication to a migraine management regimen that already includes
      acute medication. BACKGROUND: In 2000, new evidence-based guidelines for the
      treatment of migraine were released by the US Headache Consortium and the
      American Academy of Neurology. Although these guidelines emphasize the role of
      preventive medication in achieving significant clinical improvement, little yet
      is known concerning the impact of such management on medical and pharmaceutical
      resources. Methods.-Resource utilization information in a large claims database
      was analyzed retrospectively. RESULTS: Adding a preventive medication to migraine
      management reduced the use of other migraine medications, as well as visits to
      physician offices and emergency departments. In addition, both acute and
      preventive medications were associated with lower utilization of computed
      tomography and magnetic resonance imaging scans. CONCLUSION: Migraine preventive
      drug therapy is effective in reducing resource consumption when added to therapy
      consisting only of an acute medication.

PMID- 12603636
TI  - Does chronic daily headache arise de novo in association with regular use of
      analgesics?
AB  - BACKGROUND: The prevalence of chronic daily headache in association with regular
      use of analgesics is about 2%. Whether regular use of analgesics has a causal or
      consequential relationship to daily headache has not been established. A causal
      relationship has been suggested consequent to the observation of improvement or
      resolution of headache following analgesic withdrawal in patients attending
      headache clinics, but this observation has not been validated by controlled
      trials. PURPOSE: The aim of our investigation was to determine whether regular
      use of analgesics is associated with the development of chronic daily headache de
      novo and to characterize the clinical phenotype of those headaches by carefully
      studying chronic daily headache in patients with regular use of analgesics for a
      nonheadache indication. METHODS: Patients attending a rheumatology-monitoring
      clinic of second-line agents were interviewed by a training neurologist with
      regard to their analgesic and headache history. Headache classification was
      according to the criteria of the International Headache Society. Daily headache
      characteristics were surveyed via a standardized questionnaire, and headache
      features were further explored by a trained medical interviewer. RESULTS: Of 110
      patients presenting to a rheumatology-monitoring clinic, 73% had a diagnosis of
      rheumatoid arthritis, 23% had seronegative arthritis, and 4% comprised a
      miscellaneous group. One hundred three were using one or more analgesics
      regularly for their arthritis. Of this group, 8 (7.6%) reported a history of
      chronic daily headache, each of whom reported a history of migraine. The onset of
      migraine occurred before the onset of chronic daily headache in 7 patients and at
      about the same time as the chronic daily headache in 1 patient. In those with
      onset of migraine prior to chronic daily headache, the mean interval before the
      onset of headache was 30 years (range, 10 to 50 years). Regular use of analgesics
      preceded the onset of daily headache in 5 patients by a mean of 5.4 years (range,
      2 to 10 years). In 1 patient, analgesic use and the development of daily headache
      occurred at about the same time. In 1 patient, the onset of daily headache
      preceded regular use of analgesics by almost 30 years. Five of those with regular
      use of analgesics had been taking an opiate-based preparation in combination with
      a nonsteroidal anti-inflammatory agent in 4. Two had been on a combination of
      acetaminophen (paracetamol) and a nonsteroidal anti-inflammatory drug. The
      minimum number of tablets per week was 7, and the mean was 48 (range, 7 to 87).
      Of those patients who did not have daily headache, 41% had a history of migraine
      and 27% reported a history of tension-type headache. CONCLUSION: These findings
      suggest that individuals with primary headache, specifically migraine, are
      predisposed to developing chronic daily headache in association with regular use
      of analgesics.

PMID- 12603637
TI  - The impact of an over-the-counter migraine medication program on quality of life.
AB  - OBJECTIVE: This study was conducted to assess the health-related quality of life
      of patients treated with samples of an over-the-counter migraine medication.
      BACKGROUND: Population-based epidemiologic studies have reported that over 90% of
      an estimated 28 million migraine sufferers in the United States use both
      prescription and nonprescription medications for their migraine headaches, with
      60% taking over-the-counter medications exclusively. Despite the widespread use
      of nonprescription drugs, no published literature to date has assessed
      migraineurs' health-related quality of life associated with use of over-the
      counter headache medication. METHODS: This prospective and observational study
      evaluated the impact on health-related quality of life of patients from a managed
      care organization who were diagnosed with migraine and prescribed migraine
      medications. Patients were enrolled from four different medical groups and were
      requested to complete health-related quality-of-life questionnaires 2 and 4
      months after they were provided with educational materials on migraine and
      samples of an over-the-counter migraine medication containing a combination of
      acetaminophen, aspirin, and caffeine. RESULTS: A total of 99 patients who chose
      an over-the-counter medication as their initial treatment for acute migraine
      occurring over the ensuing 4 months completed a baseline Short-Form 36, a
      validated and reliable general health status questionnaire. They then were
      retested at months 2 and 4. Results demonstrated significant improvements at
      months 2 and months 4 in one to four of the health-related quality-of-life
      dimensions measured relative to scores recorded before the patients were given
      access to the over-the-counter medication (P <.05). In addition, patients who
      initially took an over-the-counter medication to treat their migraine headaches
      reported increased frequency of relief. CONCLUSION: In the 4 months following
      availability of an over-the-counter migraine medication and educational migraine
      materials, health-related quality of life and frequency of relief improved for
      the managed care migraine sufferers who participated in this study.

PMID- 12603638
TI  - Efficacy, safety, and tolerability of oral eletriptan for treatment of acute
      migraine: a multicenter, double-blind, placebo-controlled study conducted in the
      United States.
AB  - OBJECTIVE: To investigate the efficacy, consistency, safety, and tolerability of
      oral eletriptan in the acute treatment of three migraine attacks. BACKGROUND:
      Eletriptan is a selective 5-HT1B/1D agonist member of a class of agents known to
      be effective in the acute treatment of migraine. METHODS: Thirteen hundred thirty
      four patients were randomized to 20 mg, 40 mg, or 80 mg of eletriptan, or placebo
      and could treat up to three attacks. The primary efficacy endpoint was 2-hour
      headache response for the first attack. Secondary endpoints included associated
      symptom relief, and pain-free, sustained pain-free, and consistency of response.
      RESULTS: Eletriptan 20 mg, 40 mg, and 80 mg achieved significantly (P <.0001)
      better headache response rates than placebo at 2 hours (47%, 62%, and 59%,
      respectively, versus 22%) and 4 hours (64%, 76%, and 79%, respectively, versus
      25%). Headache response was observed to be rapid, showing improvement at 0.5 hour
      and 1 hour. Two-hour pain-free response rates for eletriptan 20 mg, 40 mg, and 80
      mg were 14%, 27%, and 27%, respectively, compared with 4% for placebo. Sustained
      pain-free response rates were significantly (P <.001) better for eletriptan 20 mg
      (10%), 40 mg (20%), and 80 mg (18%) compared with placebo (3%). Eletriptan had a
      higher consistency of intrapatient response than placebo in two of three (68% to
      82%) and three of three attacks (32% to 60%) versus 16% and 8%, respectively. All
      eletriptan doses yielded significant functional improvement at 2 hours. Adverse
      events were generally mild or moderate and transient, with eletriptan 20 mg
      having an adverse event profile comparable to placebo. CONCLUSIONS: Eletriptan is
      efficacious, displaying high consistency of response over multiple attacks, and
      is well tolerated for the acute treatment of migraine.

PMID- 12603639
TI  - Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg.
AB  - OBJECTIVE: To confirm the efficacy advantage of eletriptan 40 mg over sumatriptan
      100 mg. Background.-Eletriptan 80 mg has demonstrated significantly greater
      efficacy when compared to both sumatriptan 50 mg and 100 mg in two studies.
      Eletriptan 40 mg demonstrated significantly greater efficacy than sumatriptan 100
      mg in one previous trial. METHODS: Two thousand one hundred thirteen patients
      with a diagnosis of migraine according to International Headache Society criteria
      were randomized using a double-blind, double-dummy, parallel-group design, and
      treated for a single migraine attack with either eletriptan 40 mg, sumatriptan
      100 mg, or placebo. The primary endpoint was 2-hour headache response. Secondary
      endpoints included headache response rates at 1 hour, pain-free rates, absence of
      associated symptoms, functional response at 1 and 2 hours, and sustained headache
      response. RESULTS: Headache response rates at 2 hours postdose were significantly
      higher for eletriptan 40 mg (67%) than for sumatriptan 100 mg (59%; P <.001) and
      placebo (26%; P <.0001). Eletriptan 40 mg consistently showed significant (P
      <.01) efficacy over sumatriptan 100 mg across secondary clinical outcomes,
      including 1-hour headache response; 2-hour pain-free response; absence of nausea,
      photophobia, and phonophobia; functional improvement; use of rescue medication;
      treatment acceptability; and sustained headache response (P <.05). Overall,
      treatment-related adverse events were low, nausea being the only adverse event
      with an incidence of 2% or higher (4.9% with eletriptan, 4.2% sumatriptan, 2.8%
      placebo). CONCLUSION: This trial confirmed that eletriptan 40 mg offers superior
      efficacy in treating migraine pain and associated symptoms and in restoring
      patient functioning when compared with sumatriptan 100 mg.

PMID- 12603640
TI  - Real-world experiences in migraine therapy with rizatriptan.
AB  - OBJECTIVE: To evaluate the effectiveness of rizatriptan for acute migraine
      treatment and patient satisfaction with the drug in usual clinical practice
      settings. BACKGROUND: Although rizatriptan has been shown to effectively relieve
      migraine symptoms in clinical trials, we wished to assess its utility in typical
      patient care settings. Design.-Multicenter, open-label design involving the
      patients of practicing clinicians. METHODS: Adult migraineurs treated two
      migraine attacks with either rizatriptan 10-mg standard tablets or rizatriptan 10
      mg orally disintegrating tablets in a crossover manner. Participants had not
      taken rizatriptan previously and chose which formulation to take first. Patients
      reported their treatment experiences via an interactive voice response system
      approximately 24 hours after treatment. Prior migraine treatment experiences were
      reported by patients on a baseline questionnaire completed at participating
      clinics. We used conditional logistic regression analysis adjusted for treatment
      sequences to test the statistical significance of comparisons with results
      recorded on the baseline questionnaire. RESULTS: Of the 5388 patients enrolled,
      3953 (73%) completed at least one follow-up and 3183 (59%) completed two follow
      up reports. Patients reported the following outcomes for attacks treated with the
      rizatriptan tablet and orally disintegrating tablet formulations, respectively,
      compared with their prior responses to oral usual care medications (P <.05 in all
      comparisons with baseline data): onset of pain relief within 30 minutes postdose:
      18% and 23% versus 16%; no or mild headache 2 hours postdose: 66% and 67% versus
      37%; largely symptom-free within 2 hours postdose: 52% and 54% versus 35%; return
      to usual activities within 2 hours postdose: 50% and 51% versus 31%; and very or
      somewhat satisfied with treatment: 72% and 74% versus 53%. CONCLUSIONS: In this
      "real-world" setting involving a patient population selected by clinicians,
      rizatriptan appeared to offer better treatment outcomes than those from prior
      treatments with other oral migraine medications.

PMID- 12603641
TI  - Familial occurrence of migraine with aura in a population-based study.
AB  - OBJECTIVE: To better define a possible genetic basis for migraine with aura
      (MWA). METHODS: We investigated the familial occurrence of migraine with aura in
      a sample of (MWA) subjects recruited from an epidemiologic study of migraine with
      aura involving the general population. The sample with migraine with aura (n =
      26) was selected out of a total of 1392 subjects (842 women and 550 men)
      representative of the general population aged 18 to 65 years in the southern
      Italian town of San Severo. A family history of migraine with aura was determined
      via direct interviews with all living first-degree relatives of the 26 subjects
      who could be reached by investigators, 119 people: 71 women and 48 men. The
      diagnosis of migraine with aura was made according to the 1988 International
      Headache Society (IHS) criteria. RESULTS: Of the 26 subjects with migraine with
      aura, 7 (6 women and 1 man) had a positive family history, with a total of 7
      first-degree relatives affected by the disease (1 mother, 2 fathers, 1 brother, 1
      sister, and 2 children). Based on the lifetime prevalence rate of migraine with
      aura (1.6%) in the San Severo general population, the relative risk of migraine
      with aura in the first-degree relatives of the subjects was 3.68 (4.16 for women
      and 2.77 for men). CONCLUSION: Our subjects' relative risk rate for familial
      occurrence of migraine with aura was similar to that reported by one
      investigator, but markedly lower than that reported by another group.

PMID- 12603642
TI  - Shared rearing environment in migraine: results from twins reared apart and twins
      reared together.
AB  - BACKGROUND: Studies of twins who are separated from each other early in life and
      are reared in different environments offer the opportunity to resolve variation
      in liability to disease. OBJECTIVE: To evaluate the importance of genetic and
      environmental influences in migraine; in particular, addressing the role of the
      shared rearing environment. METHODS: A population-based cohort of twins,
      including a subsample of 314 pairs reared apart and 364 matched control pairs
      reared together, was drawn from the Swedish Twin Registry. Data on lifetime
      migraine was collected via self-administered questionnaires mailed to twins aged
      42 to 81 years. Quantitative genetic models and regression models were used to
      analyze sources of twin similarity. RESULTS: We found nonsignificant shared
      rearing environmental influences on migraine for men (17%) and no rearing effects
      at all for women. The heritability of migraine was estimated at 38% (95%
      confidence interval, 0 to 73) for men and 48% (95% confidence interval, 27 to 65)
      for women. Among monozygotic twins reared apart, those separated at 3 years of
      age or earlier were more similar for lifetime migraine than those separated
      later, and this was especially true for women. CONCLUSION: In agreement with
      previous twin data, family resistance in migraine is mainly due to genetic
      factors, whereas environmental influences make family members different, not
      similar.

PMID- 12603643
TI  - Biofeedback-assisted relaxation in migraine headache: relationship to cerebral
      blood flow velocity in the middle cerebral artery.
AB  - OBJECTIVE: To determine if migraineurs with aura respond differently to
      biofeedback/relaxation than those without aura and, if so, whether the
      variability in outcome can be explained by blood flow velocity. Background.-The
      relationship between cerebral blood flow velocity and treatment response to
      biofeedback/relaxation in migraine with and without aura is uncertain. METHOD:
      Twenty migraineurs underwent 12 sessions of biofeedback/relaxation therapy, while
      20 controls simply were told to relax on their own. Cerebral blood flow velocity
      was measured bilaterally in the middle cerebral artery with transcranial Doppler.
      RESULTS: The biofeedback group showed significant (P <.05) reductions in pain,
      depression, and anxiety compared to the control group. Patients with and without
      aura did equally well. There were significant (P <.05) left to right blood flow
      velocity differences only in the migraine with aura group. Maximum blood flow
      velocities were significantly higher (P <.05) in the migraine with aura group
      than in the cohort without aura. There was an inverse correlation between
      indicators of anxiety and blood flow velocity, perhaps related to
      hyperventilation-induced constriction in the small vessels distal to the middle
      cerebral artery. CONCLUSION: The positive treatment response to
      biofeedback/relaxation in migraine headache is not related to presence of aura,
      nor to changes in blood flow velocity, but may be associated with reduction in
      anxiety and depression.

PMID- 12603645
TI  - Migraine disability assessment (MIDAS) score: relation to headache frequency,
      pain intensity, and headache symptoms.
AB  - OBJECTIVE: To determine the extent to which variation in the Migraine Disability
      Assessment (MIDAS) score is associated with headache frequency, pain intensity,
      headache symptoms, gender, and employment status. BACKGROUND: The MIDAS
      questionnaire is a 7-item questionnaire (with 5 scored items) designed to measure
      headache-related disability, to improve physician-patient communication, and to
      identify patients with high treatment needs. METHODS: Data from 3 population
      based studies (total sample, n = 397) conducted in the United States and the
      United Kingdom were used to evaluate the relationship between headache features
      (attack frequency, pain intensity, pain quality, and associated symptoms) and
      MIDAS score. Data on headache features were collected by telephone using a
      standardized interview. The MIDAS questionnaire was completed shortly after the
      telephone interview. General linear models were used to determine the extent to
      which population variation in the MIDAS score was explained by headache features.
      RESULTS: Using linear regression, variables for all headache features (ie,
      headache frequency, pain intensity, pain quality, and associated symptoms) and
      demographic characteristics explained only 22% of the variation in MIDAS scores.
      Almost all (19.9%) the explained variance was accounted for by average pain
      intensity (12.0%), number of headache days (6.1%), and exacerbation of pain with
      movement (1.8%). When pain intensity and headache frequency were included in the
      model, no statistically significant differences in MIDAS scores were observed by
      gender or employment status. Although explaining only 2.1% of the variance, age
      was significantly associated with MIDAS scores, with those under 25 years
      demonstrating higher MIDAS scores than other age groups. No other variables (ie,
      frequency of occurrence of associated symptoms and other measures of quality of
      pain) were associated with MIDAS scores. CONCLUSIONS: Challenges to the utility
      of the MIDAS as a measure include whether headache-related disability is largely
      a function of other routine headache features and whether MIDAS is inherently
      biased based on work status and gender. While the MIDAS score was associated with
      headache frequency and average pain score, these two headache features explain
      only a modest proportion of the variation in MIDAS scores. Additionally, gender
      and work status were not related to MIDAS scores. These findings suggest that the
      MIDAS score captures information about disability that is not inherent to other
      headache features and is independent of gender and work status.

PMID- 12603646
TI  - Academic headache medicine in America: report of academic membership survey of
      the American Headache Society special interest section on academic affairs.
AB  - BACKGROUND: What constitutes the typical clinical experience of an academic
      headache specialist in America is unknown. PURPOSE: To clarify this issue, we
      undertook a survey of academic headache specialists who are members of the
      American Headache Society. METHODS: In June 2000, 181 surveys including questions
      regarding academic rank, departmental and institutional affiliation, and time
      distribution were sent to members drawn from the 1999-2000 Membership Directory
      of the American Headache Society whose primary addresses were recognized academic
      institutions or who, by reputation, had extensive academic affiliation.
      Additional questions about headache teaching, research, and practice were
      included. RESULTS: Seventy-two (39.7%) of the surveys were returned. Forty-nine
      (40%) of the 122 American medical schools were represented. The most prevalent
      academic rank was professor (38%). Included were 2 departmental chairs, 1
      division chief, 1 vice dean, and 1 residency training director. The majority
      (70.8%) were neurologists. Seventy-two percent of respondents spent at least 50%
      of their time in a clinic, 79% spent 25% or less of their time on research, and
      78% spent 25% or less time in teaching. The average number of new patients seen
      per week was 9.0 +/- 7.6, with each visit lasting 62.4 +/- 20.8 minutes.
      Clinicians saw 22.7 +/- 14.6 patients for follow-up per week, with the average
      visit lasting 24.7 +/- 6.8 minutes. Although it appears that at least informal
      instruction in headache is provided to medical students, interns, and residents,
      19.7% (12 of 61) of respondents reported that no formal medical school lecture on
      the topic of headache was offered at their institutions. CONCLUSION: This
      preliminary survey offers some insight into the clinical experience of academic
      headache specialists in the American medical system. Suggestions for future
      studies are discussed.

PMID- 12603644
TI  - Effect of autogenic training on drug consumption in patients with primary
      headache: an 8-month follow-up study.
AB  - OBJECTIVE: To examine the effects of Schultz-type autogenic training on headache
      related drug consumption and headache frequency in patients with migraine,
      tension-type, or mixed (migraine plus tension-type) headache over an 8-month
      period. BACKGROUND: Behavioral treatments often are used alone or adjunctively
      for different types of headache. There are, however, only a few studies that have
      compared the efficacy and durability of the same treatment in different types of
      primary headache, and the effects of treatment on headache-related drug
      consumption rarely have been assessed even in these studies. METHODS: Twenty-five
      women with primary headache (11 with mixed headache, 8 with migraine, and 6 with
      tension-type headache) were evaluated via an open-label, self-controlled, 8
      month, follow-up study design. After an initial 4 months of observation, patients
      began learning Schultz-type autogenic training as modified for patients with
      headache. They practiced autogenic training on a regular basis for 4 months.
      Based on data from headache diaries and daily medication records, headache
      frequencies and the amounts of analgesics, "migraine-specific" drugs (ergots and
      triptans), and anxiolytics taken by the patients were compared in the three
      subgroups over the 8-month period. Results.-From the first month of
      implementation of autogenic training, headache frequencies were significantly
      reduced in patients with tension-type and mixed headache. Significant reduction
      in frequency was achieved in patients with migraine only from the third month of
      autogenic training. Decreases in headache frequencies were accompanied by
      decreases in consumption of migraine drugs and analgesics resulting in
      significant correlations among these parameters. Reduction in consumption of
      anxiolytic drugs was more rapid and robust in patients with tension-type headache
      compared to patients with migraine, and this outcome failed to show any
      correlation with change in headache frequency. CONCLUSION: Schultz-type autogenic
      training is an effective therapeutic approach that may lead to a reduction in
      both headache frequency and the use of headache medication.

PMID- 12603647
TI  - Platelet aggregation profiles in cluster headache.
AB  - BACKGROUND: Platelets are activated in patients with cluster headache, during
      both the remission period and the active cycles. OBJECTIVE: To delineate more
      clearly the origin of platelet activation in cluster headache. Methods.-Platelet
      aggregation induced by collagen (0.5 micro g/mL and 2 micro g/mL), adenosine
      diphosphate (10-5 M and 10-6 M), and platelet-activating factor (10-6 M and 10-7
      M) was determined by the Born's method in 26 patients with cluster headache and
      24 sex- and age-matched controls. RESULTS: The platelets of patients with cluster
      headache aggregated significantly less to collagen at a concentration of 0.5
      micro g/mL compared to those of controls (P =.04). The extent of platelet
      aggregation obtained with a higher dose of collagen (2 micro g/mL) was in the
      same range in both groups. Platelet aggregation obtained via adenosine
      diphosphate at a concentration of 10-6 M was significantly reduced in patients
      with cluster headache in comparison to controls (P =.002), but no differences
      were found at a concentration of 10-5 M. In contrast, the platelets of patients
      with cluster headache aggregated significantly more to platelet-activating factor
      at both the concentrations of 10-6 M (P =.001) and 10-7 M (P =.00001) compared to
      those of controls. CONCLUSIONS: This study suggests that platelet aggregation is
      impaired in patients with cluster headache during the active phase of the
      disease. We found hypoaggregation in response to low doses of collagen and
      adenosine diphosphate, and hyperaggregation when platelets were stimulated with
      platelet-activating factor. Any interpretation of these results can only be
      speculative. It may be that impairment of platelet aggregation with collagen and
      adenosine diphosphate may indicate a derangement of nitric oxide function, while
      the hypersensitivity to platelet-activating factor may be due to fluctuations in
      its plasma levels.

PMID- 12603648
TI  - Postcraniotomy headache.
AB  - BACKGROUND: Persistent headache following craniotomy has been reported in the
      past, but the clinical features of this condition have not been well described.
      OBJECTIVE: This study was undertaken to evaluate the incidence and clinical
      features of postcraniotomy headache. METHODS: The medical records of 107 patients
      who had undergone surgery for brain tumor or intractable epilepsy were reviewed.
      The clinical features of preoperative and postoperative headache and any headache
      therapy initiated were obtained from the medical records. The surgical site and
      the underlying pathology were documented. The subsequent course of the headache
      also was recorded. RESULTS: We evaluated 102 patients who underwent surgery: 76
      for an underlying brain tumor, 21 for intractable epilepsy, and 5 for
      intracranial hemorrhage. Five patients were disqualified because of inadequate
      documentation. Fifty-eight patients did not complain of headache preoperatively.
      Eleven patients who did not have preoperative headache experienced headache
      postoperatively. Eight had undergone surgery for intractable epilepsy and 3 for
      brain tumor. Eighty-two percent of these patients experienced gradual resolution
      of their headaches over time, and most did not require major medical intervention
      for controlling their headache. No cases of debilitating headaches were
      identified. The majority of the headaches were located over the surgical site.
      CONCLUSIONS: The pathogenesis of postoperative headache remains unclear. The
      clinical characteristics of the headache following craniotomy suggest a
      combination of tension-type and "site-of-injury headache" overlying the surgical
      site. These headaches are similar to the headaches described following head
      trauma.

PMID- 12603649
TI  - Refractory episodic cluster headache responsive to percutaneous cervical
      zygapophyseal radiofrequency ablation: a case report.

PMID- 12603650
TI  - Clinical, anatomical, and physiologic relationship between sleep and headache.
AB  - The intimate relationship between sleep and headache has been recognized for
      centuries, yet the relationship remains clinically and nosologically complex.
      Headaches associated with nocturnal sleep have often been perceived as either the
      cause or result of disrupted sleep. An understanding of the anatomy and
      physiology of both conditions allows for a clearer understanding of this complex
      relationship and a more rational clinical and therapeutic approach. Recent
      biochemical and functional imaging studies in patients with primary headache
      disorders has lead to the identification of potential central generators which
      are also important for the regulation of normal sleep architecture. Medical
      conditions (e.g. obstructive sleep apnea, depression) that may disrupt sleep and
      lead to nocturnal or morning headache can often be identified on clinical
      evaluation or by polysomnography. In contrast, primary headache disorders which
      often occur during nocturnal sleep or upon awakening, such as migraine, cluster
      headache, chronic paroxysmal hemicrania, and hypnic headache, can readily be
      diagnosed through clinical evaluation and managed with appropriate medication.
      These disorders, when not associated with co-morbid mood disorders or
      medications/analgesics overuse, seldom lead to significant sleep disruption.
      Identifying and classifying the specific headache disorder in patients with both
      headache and sleep disturbances can facilitate an appropriate diagnostic
      evaluation. Patients with poorly defined nocturnal or awakening headaches should
      undergo polysomnography to exclude a treatable sleep disturbance, especially in
      the absence of an underlying psychological disorder or analgesic overuse
      syndrome. In patients with a well defined primary headache disorder, unless there
      are compelling historical or examination findings suggestive of a primary sleep
      disturbance, a formal sleep evaluation is seldom necessary.

PMID- 12603651
TI  - The late-life migraine "accompaniment" that wasn't.

PMID- 12603652
TI  - Is cardiac evaluation for a possible right-to-left shunt indicated in a scuba
      diver with migraine with aura?

PMID- 12603653
TI  - Tizanidine is not a cure for chronic daily headache.

PMID- 12603655
TI  - Headache associated with refractive errors: overestimated or overlooked?

PMID- 12603680
TI  - Cyclosporin: applications in small animal dermatology.
AB  - Cyclosporin has been increasingly used for the treatment of skin diseases in
      small animals. Reported uses include the treatment of atopy, cutaneous lupus
      erythematosus, feline acquired alopecia resembling pseudopelade of humans,
      pemphigus erythematosus, pemphigus foliaceus, perianal fistulae and sebaceous
      adenitis. In addition, cyclosporin has been used anecdotally for several other
      skin diseases. Few side effects have been noted at doses therapeutic for
      dermatologic diseases. Current suggestions for monitoring, and the value of
      trough cyclosporin serum concentrations for prediction of toxicity and efficacy
      are discussed.

PMID- 12603681
TI  - Comparison of cyclosporine A with methylprednisolone for treatment of canine
      atopic dermatitis: a parallel, blinded, randomized controlled trial.
AB  - The objective of this multicentre, parallel, blinded, randomized controlled study
      was to evaluate the efficacy and the safety of cyclosporine (CsA group, 117 dogs)
      in comparison with methylprednisolone (MP group, 59 dogs) in the treatment of
      atopic dermatitis for 4 months. Mean induction dose of both drugs (5 mg/kg CsA,
      0.75 mg/kg MP) was tapered over time according to the clinical response. At the
      end of the study, the mean estimated percentage reduction from baseline
      (confidence interval) of lesion scores was 52% (44-59) and 45% (35-56), and the
      reduction in pruritus score was 36% (27-43) and 33% (23-43) in dogs in the CsA
      and MP groups, respectively. These percentages were not significantly different
      between groups. A significantly better overall assessment of efficacy was
      obtained in the CsA-treated dogs (76 vs. 63% responses excellent or good in the
      CsA compared with MP group). CsA-treated dogs presented a higher frequency of
      gastrointestinal disorders, mainly vomiting, but MP dogs tended to be more
      susceptible to infections. There was no remarkable change over baseline of the
      haematological and biochemical parameters in the two groups.

PMID- 12603682
TI  - Isotype determination of circulating autoantibodies in canine autoimmune
      subepidermal blistering dermatoses.
AB  - The three most common canine autoimmune blistering skin diseases (AISBD), bullous
      pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa
      acquisita (EBA) have recently been separated based on clinical, histological and
      immunological grounds. The objectives of this study were to determine the isotype
      profiles of circulating autoantibodies in these dermatoses. Serum was collected
      from 5 dogs with BP, 15 with MMP and 11 with EBA. All sera were tested using an
      indirect immunofluorescence method using salt-split canine gingiva as substrate.
      Anti-basement membrane IgG autoantibodies were detected in all patients. Among
      the IgG autoantibodies, IgG1 and IgG4 were encountered most frequently, while
      IgG2 and IgG3 were uncovered in some dogs. IgE autoantibodies were detected more
      often than IgA or IgM autoantibodies in any of the three entities. The
      predominance of IgG1, IgG4 and IgE autoantibody isotypes in dogs with AISBD is
      very similar to the situation found in humans with the homologous diseases.

PMID- 12603683
TI  - Determination of 'irritant' threshold concentrations for intradermal testing with
      allergenic insect extracts in normal horses.
AB  - Sixteen healthy horses with no history of skin or respiratory disease were used
      for an intradermal testing (IDT) threshold study, in order to determine the
      concentrations of 13 commercial allergenic insect extracts most appropriate for
      IDT. Five dilutions of each extract were used, which included the manufacturer's
      recommended concentrations for equine IDT, plus one dilution higher and three
      lower than these standard concentrations. Allergens tested included caddisfly
      (Trichoptera spp.), mayfly (Ephemeroptera spp.), horsefly (Tabanus spp.), deerfly
      (Chrysops spp.), fire ant (Solenopsis invicta), black ant (Camponotus
      pennsylvanicus), cockroach mix (Periplaneta americana and Blattella germanica),
      mosquito (Aedes aegypti), house fly (Musca domestica), moth (Heterocera spp.),
      flea (Ctenocephalides canis/C. felis), Culicoides variipennis and Culicoides
      nubeculosis. Two separate methods were used to calculate the allergen
      concentration for each insect extract where the normal horses, as a group, ceased
      to show false-positive ('irritant') reactions. 'Irritant' threshold
      concentrations were determined for 9/13 of these allergens, whereas the other 4
      were undetermined due to either insufficient reactivity (flea, C. variipennis) or
      excessive reactivity (black ant, moth) to the concentrations tested. Recommended
      concentrations for future use in equine patients with suspected insect
      hypersensitivity include: 125 pnu mL(-1) (mayfly); 250 pnu mL(-1) (caddisfly,
      horsefly, deerfly, fire ant, house fly); 500 pnu mL(-1) (cockroach); 1000 pnu mL(
      1) (mosquito); and 1:10 000 w/v (C. nubeculosis).

PMID- 12603684
TI  - A randomized controlled trial of misoprostol monotherapy for canine atopic
      dermatitis: effects on dermal cellularity and cutaneous tumour necrosis factor
      alpha.
AB  - In this blinded randomized placebo-controlled trial, 20 dogs with atopic
      dermatitis (AD) were given placebo (8 dogs) or misoprostol (12 dogs) at 5 micro g
      kg-1, orally, three times daily for 3 weeks. Administration of the active drug,
      but not of placebo, led to a significant decrease in lesional and pruritus
      scores. The median reduction from baseline of both scores was approximately 30%.
      Misoprostol therapy did not lead to decreases of dermal cell counts or skin
      tumour necrosis factor (TNF)alpha mRNA copy numbers that were significantly
      different from those of placebo. Skin TNFalpha protein production, assessed using
      indirect immunofluorescence, decreased or remained unchanged in dogs receiving
      misoprostol. In contrast, post treatment TNFalpha fluorescence scores were higher
      in all but two dogs given placebo. The changes from baseline of TNFalpha
      fluorescence scores did not correlate significantly with those of lesional or
      pruritus indices. These observations confirm the modest efficacy of misoprostol
      for treatment of canine AD and suggest that its mild anti-allergic effects are
      not associated with either inhibition of inflammatory cell emigration or TNFalpha
      production.

PMID- 12603686
TI  - Marrow Transplantation in Children: Current Results and Controversies, meeting
      #6, proceedings. St Augustine, Florida, USA. 8-10 November 2001.

PMID- 12603685
TI  - Detection of papillomavirus-DNA in mesenchymal tumour cells and not in the
      hyperplastic epithelium of feline sarcoids.
AB  - We examined 12 formalin-fixed paraffin-embedded feline skin tumours which had the
      histopathological features of fibropapillomas for the presence of papillomavirus
      (PV) DNA using touchdown polymerase chain reaction (PCR), DNA sequencing and
      nonradioactive in situ hybridization. Nine of the tumours contained a 102-bp PCR
      product demonstrated using consensus PV primers that amplify a portion of the L1
      gene. The nucleotide sequences are closely related, but not identical to that of
      ovine PV type 2, rabbit oral PV and reindeer PV. The deduced amino acid sequences
      had strong homologies with the major capsid protein L1 of deer PV, bovine
      papillomavirus (BPV) 1 and BPV 2, and European elk PV. Although PV antigens were
      not detected in any of the tumours by immunohistochemistry, PV DNA was
      demonstrated in individual mesenchymal cells or cell nests of 4/12 tumours by in
      situ hybridization. A nonproductive infection of mesenchymal fibroblast-like
      tumour cells with a papillomavirus would explain the lack of PV antigen
      expression and the absence of PV DNA in the hyperplastic epithelium. Because
      these tumours and their pathogenesis are similar to equine sarcoids, we suggest
      that they should be reclassified as 'feline sarcoids' instead of fibropapillomas.

PMID- 12603687
TI  - Costs and consequences of stem cell transplantation in children.
AB  - Economic evaluation is a comparison of the costs and consequences of alternative
      healthcare interventions. Consequences are best assessed as utilities; quality
      adjusted measures of effectiveness. Although few substantive data are available,
      it appears that hematopoietic stem cell transplantation is even more cost
      effective in children than in adults.

PMID- 12603688
TI  - Plasma pharmacokinetics of high-dose oral busulfan in children and adults
      undergoing bone marrow transplantation.
AB  - We have analyzed the plasma pharmacokinetics of busulfan in 272 patients
      receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction
      with allogeneic or autologous bone marrow transplantation. The patients ranged in
      age from 2 months to 59 yr (mean 10, median 12 yr) and had the following
      diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia
      (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45).
      Plasma specimens were collected following the first dose for each patient which
      ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, median 1.15). Busulfan was
      quantitated using ultraviolet absorbance detection after derivatization and HPLC
      separation. Pharmacokinetic parameters were derived by modeling the raw data to
      fit first-order single compartment kinetics. The kinetic parameters showed wide
      interpatient variability independent of age and diagnosis. There was a
      statistically significant correlation of age with the following parameters: area
      under the curve (AUC); maximal concentration; minimum concentration; clearance;
      volume of distribution and absorption half-time. The coefficients of
      determination (i.e. correlation coefficient squared) were low ranging from 0.04
      to 0.12 implying only a small part (i.e. 4-12%) of the variance was explained by
      age. Although busulfan pharmacokinetics are age-related most of the variability
      is not explained by age or diagnosis.

PMID- 12603689
TI  - Steroid-refractory graft-vs.-host disease: past, present and future.
AB  - Despite current standard preventive strategies that include optimizing donor
      selection and the combination of methorexate and a calcineurine inhibitor, acute
      and chronic GVHD remains a major barrier to successful hematopoietic cell
      transplantation for a sizeable proportion of patients. When acute and chronic
      GVHD become manifest a standard primary therapy approach has been the addition of
      glucocorticoid therapy to a background of calcineurine inhibition. When this
      approach fails patients with GVHD require secondary therapy. Ideally, second-line
      agents should promote transplantation tolerance so that the morbidity associated
      with prolonged use of glucocorticoids and other immunosuppressive agents can be
      minimized. Promising new agents or strategies which warrant further controlled
      clinical trials include: mycophenolate mofetil, sirolimus, humanized or chimeric
      monoclonal antibodies such as visilizumab, daclizumab and infliximab, and
      extracorporeal photopheresis. Co-operative studies are necessary to hasten the
      process of evaluating novel treatment strategies for acute and chronic GVHD.

PMID- 12603690
TI  - Genetic variation and hematopoietic stem cell transplantation: expansion of the
      paradigm.
AB  - Genetic variation has been the mainstay of hematopoietic stem cell
      transplantation since the first transplants were attempted. A significant
      expansion of genetic knowledge is under way, as the draft sequence of the human
      genome is annotated. Hematopoietic stem cell transplantation is a field that will
      greatly benefit from this new knowledge, but the manner in which it is applied is
      daunting. Variation within key molecules related to hematopoietic stem cell
      transplant in combination with the current knowledge of human leukocyte antigen
      variation will serve to improve donor-recipient matches and clinical outcome.

PMID- 12603691
TI  - End-of-life issues of children.
AB  - When working with children who have cancer or other life-threatening illnesses,
      providers frequently deal with end-of-life concerns. Children deserve the best of
      care at all times, and the end-of-life is no exception. Controversy surrounds the
      debate between use of hospice care or palliation with children. Laws and
      guidelines dictate how we can treat symptoms and expect reimbursement. This
      article will review some of the main issues and give ideas for caring for
      children who deal with life-threatening illness.

PMID- 12603692
TI  - Epstein-Barr virus associated disease following blood or marrow transplant.
AB  - EBV associated disease continues to be a problem in the post-BHT population. The
      pathogenesis, risk factors, and diagnosis of PTLD, as well as the rationale,
      efficacy and advantages/disadvantages of various prophylactic, pre-emptive and
      treatment strategies are discussed.

PMID- 12603694
TI  - Bone marrow transplantation: it's not just about blood anymore!
AB  - Bone marrow transplantation is established as effective cell therapy for
      hematopoietic disorders. With the recognition that bone marrow also contains
      mesenchymal stem cells, with the potential to differentiate to a wide variety of
      mesenchymal tissues, bone marrow transplantation, in theory, may be used to treat
      many nonhematopoietic disorders as well. Here, we present an overview of the
      developments of clinically oriented marrow mesenchymal stem cell biology and it's
      early applications as adjunct cell therapy in conventional stem cell
      transplantation, and most importantly as stem cell therapy for nonhematopoietic
      disorders.

PMID- 12603693
TI  - Megadose transplantation of highly purified haploidentical stem cells: current
      results and future prospects.
AB  - The transplantation of megadoses of haploidentical hematopoietic stem cells is
      for a number of children with malignant or nonmalignant diseases the only
      curative approach. In order to prevent severe GvHD, the removal of T lymphocytes
      from the stem cell graft either by positive selection of CD34+ stem cells or by
      negative depletion of CD3+ T lymphocytes is necessary. We present the results
      obtained so far by CD34+ positive selection and discuss new techniques of graft
      engineering which might hopefully further improve the outcome of haploidentical
      stem cell transplantation.

PMID- 12603695
TI  - Unrelated donor stem cell transplant: donor selection and search process.
AB  - The article describes the unrelated donor and cord blood search process through
      the National Marrow Donor Program (NMDP) for practising hematologist-oncologists
      and stem cell transplant physicians. The recent changes in the diseases, type of
      transplants and stem cell sources are discussed. Important data showing the
      effects of HLA loci and non-HLA factors on the transplant outcome, including new
      services offered by NMDP were reviewed.

PMID- 12603696
TI  - Peripheral blood as a stem cell source for hematopoietic cell transplantation in
      children: is the effort in vein?
AB  - Since 1968 HSCT utilizing bone marrow as a stem cell source has become an
      accepted treatment modality for a variety of immunologic, hematologic and
      malignant disorders. However, with widespread use it became apparent that BM
      donation is inconvenient, uncomfortable and not without risk. These observations
      led to a search for a more easily and safely acquired hematopoietic stem cell
      source. Recent experience suggests that peripheral blood may serve as an
      alternative to marrow. Indeed if the current trend continues PBSC will soon
      replace BM in adults as the preferred stem cell source for both HLA-matched and
      unrelated HSCT. Furthermore adults who have experienced both seem to prefer PBSC
      to BM donation. Recently a number of small trials support the feasibility of PBSC
      harvest from HLA-matched minor sibling donors. With regard to the recipient, data
      indicate more rapid engraftment, an acceptable incidence of acute and chronic
      GVHD, decreased infection and an increased survival for patients with
      malignancies (suggesting an increased GVT/L effect) when PBSC are utilized. These
      observations based almost entirely on the adult experience are far from
      definitive when children are considered. The relatively lower risk and severity
      of acute and chronic GVHD, the more frequent use of HSCT for non-malignant
      disorders and the diminished role of GVT/L in the treatment of typical
      malignancies are factors particular to pediatric HSCT. In addition the sense that
      mobilization and harvest of PBSC may pose unique and significant risk for the
      young donor suggest to some that PBSC may not posses sufficient advantage to
      warrant their use in the pediatric transplant setting. Thus both the available
      adult-derived data and experience suggest clinical equipoise with regard to the
      choice of stem cell product, under certain circumstances, when children are
      considered. This circumstance strongly supports the need for a comprehensive
      study evaluating the safety and efficacy of PBSC vs. BM HSCT in children.

PMID- 12603697
TI  - The skeletal remains: porosis and necrosis of bone in the marrow transplantation
      setting.

PMID- 12603698
TI  - Recommendations for immunizations in stem cell transplantation.
AB  - Investigations over the past decade have documented that there is a decline in
      immunity to vaccine preventable diseases in many SCT recipients. The majority of
      immunization studies conducted in SCT recipients to date support the use of multi
      dose regimens for most protein and polysaccharide-conjugate vaccine antigens. The
      consensus immunization schedule recommended by ACIP/IDSA/ASBMT provides guidance
      for centers to utilize available vaccines in their SCT populations. With the
      exception of pneumococcal disease, a schedule beginning at 12 months after SCT is
      reasonable given the low incidence of disease in HSCT recipients for most of the
      recommended vaccines and improved immune reconstitution in most recipients by one
      year post transplant. SCT recipients respond poorly to unconjugated pneumococcal
      polysaccharide vaccine and the development of polysaccharide-protein conjugate
      vaccines against S. pneumoniae holds promise to impact potentially on clinical
      disease in this population. In addition, the strategy of donor immunization may
      also be effective in eliciting early protective immune responses to vaccine
      antigens. Future challenges will be the development of safe and effective
      vaccines against the viral pathogens responsible for considerable morbidity and
      mortality after SCT.

PMID- 12603699
TI  - Bone marrow stem cells regenerate infarcted myocardium.
AB  - Heart disease is the leading cause of death in the United States for both men and
      women. Nearly 50% of all cardiovascular deaths result from coronary artery
      disease. Occlusion of the left coronary artery leads to ischemia, infarction,
      necrosis of the affected myocardial tissue followed by scar formation and loss of
      function. Although myocytes in the surviving myocardium undergo hypertrophy and
      cell division occurs in the border area of the dead tissue, myocardial infarcts
      do not regenerate and eventually result in the death of the individual. Numerous
      attempts have been made to repair damaged myocardium in animal models and in
      humans. Bone marrow stem cells (BMSC) retain the ability throughout adult life to
      self-renew and differentiate into cells of all blood lineages. These adult BMSC
      have recently been shown to have the capacity to differentiate into multiple
      specific cell types in tissues other than bone marrow. Our research is focused on
      the capacity of BMSC to form new cardiac myocytes and coronary vessels following
      an induced myocardial infarct in adult mice. In this paper we will review the
      data we have previously published from studies on the regenerative capacity of
      BMSC in acute ischemic myocardial injury. In one experiment donor BMSC were
      injected directly into the healthy myocardium adjacent to the injured area of the
      left ventricle. In the second experiment, mice were treated with cytokines to
      mobilize their BMSC into the circulation on the theory that the stem cells would
      traffic to the myocardial infarct. In both experimental protocols, the BMSC gave
      rise to new cardiac myocytes and coronary blood vessels. This BMSC-derived
      myocardial regeneration resulted in improved cardiac function and survival.

PMID- 12603700
TI  - Use of radiolabeled antibodies in the treatment of childhood acute leukemia.
AB  - Despite advances in therapy for acute leukemia, relapse continues to be the major
      cause of treatment failure. Hematopoietic stem cell transplant can rescue some
      patients after relapse, but the ability to escalate the intensity of preparative
      regimens is limited by toxicity to normal organs. Radiolabeled monoclonal
      antibodies against hematopoietic antigens have emerged as an alternative to
      deliver targeted supplemental radiation to sites of leukemic involvement while
      relatively sparing normal organs. This paper will review the rationale for using
      this approach, our current experience with radiolabeled anti-CD45 antibody, and
      the potential challenges encountered in treating children with radiolabeled
      antibodies.

PMID- 12603702
TI  - Hematopoietic stem and progenitor cell transplants: regulation and accreditation.

PMID- 12603701
TI  - The expanding applications of non-myeloablative stem cell transplantation.
AB  - Non-myeloablative preparative strategies for allogeneic stem cell transplantation
      (SCT) have been increasingly utilized for a variety of hematological
      malignancies, solid tumours, and for tolerance induction. These regimens are
      associated with less transplant-related morbidity and mortality than conventional
      transplant conditioning regimens. It is not yet clear whether graft-vs.-host
      disease (GVHD) protection is afforded. Potent antitumour responses have been
      described in a variety of advanced malignancies. We have utilized a
      cyclophosphamide/anti-T-cell antibody therapy approach, which has resulted in the
      uniform induction of mixed chimerism. In many cases, this has served as an
      immunological platform for adoptive cellular immunotherapy (via donor leukocyte
      infusions). The results of this experience, as well as the outcomes of non
      myeloablative stem cell transplantation (NST) for other malignant and
      nonmalignant conditions are described.

PMID- 12603703
TI  - Teething problems with electronic publishing.

PMID- 12603705
TI  - A review of once-daily delivery of anti-asthmatic drugs in children.
AB  - Determining which drug is suitable for, and which patient can benefit from, a
      once-daily dose of prophylactic treatment is important for practitioners who want
      to improve therapeutic compliance in children with asthma. According to the
      literature, once-daily delivery of cromolyn sodium, nedocromil or beclomethasone
      dipropionate must be avoided. On the other hand, switching from a twice-daily to
      a once-daily regimen is efficient and safe only in children with well-controlled
      asthma using nebulized or dry-powder budesonide, dry-powder fluticasone
      propionate, flunisolide, or sustained-release theophylline. Such information is
      not available for long-acting beta2-agonists, except for oral bambuterol.
      Initiating a once-daily treatment in previously untreated children can only be
      based on low doses of inhaled budesonide or on an oral drug, montelukast. Further
      studies in children with severe asthma or treated with metered-dose inhalers and
      spacer devices are required before recommending a once-daily drug delivery in
      such situations.

PMID- 12603707
TI  - The costs of atopy and asthma in children: assessment of direct costs and their
      determinants in a birth cohort.
AB  - The aim of this study was to estimate costs accrued by the health care of
      children with asthma in comparison to children with atopic eczema and seasonal
      rhinitis and to investigate cost determinants. From the multicenter cohort study
      (MAS-90), we selected children with an asthma, atopic eczema and/or seasonal
      rhinitis diagnosis during the first 8 years of life, and overall 8-year health
      care utilization was estimated retrospectively by reviewing medical records.
      Asthma treatment (n = 76) incurs an average cost of 627 US dollars per year, 44%
      due to hospital stays. Atopic eczema treatment (n = 91) cost on average 219 US
      dollars and seasonal rhinitis (n = 69) 57 US dollars per year. In asthma and
      atopic eczema, costs increase significantly with disease severity. Allergy
      diagnostics use accounts for only 1% of total costs. Costs for asthma and atopic
      eczema treatment are highest in those years when topical steroids are used for
      the first time, but decrease with every further year of steroid use. A remarkable
      25% of asthmatic children with severe symptoms were not treated according to
      national guidelines, so that most steroid treatment was initiated during the
      first hospital stay. In the case of asthma, total direct costs increased until
      the 3rd year of the disease, and then decreased with further years of diagnosis,
      while steroid use continued to increase. These results indicate a 'learning
      effect' in the treatment of asthma and atopic eczema for each patient as well as
      considerable cost-saving potential by preventing severe asthma. Moreover, the
      importance of considering cost-driving factors and using cohort or longitudinal
      designs in cost-of-illness approaches is emphasized.

PMID- 12603706
TI  - Study on the Prevention of Allergy in Children in Europe (SPACE): allergic
      sensitization at 1 year of age in a controlled trial of allergen avoidance from
      birth.
AB  - Several studies have demonstrated that early intervention may modulate the
      natural course of atopic disease. The objective of this study was to prevent
      sensitization to house dust mite and food allergens, as well as development of
      atopic symptoms, during infancy. To achieve this we employed the combination of
      an educational package with the use of mite allergen-impermeable mattress
      encasings. A multi-center European, population-based, randomized controlled study
      of children at increased atopic risk [study on the prevention of Allergy in
      Children in Europe (SPACE)] was performed in five countries (Austria, Germany,
      Greece, Great Britain, Lithuania) and included three cohorts of schoolchildren,
      toddlers and newborns. We report on the newborn cohort. A total of 696 newborns
      were included in Austria, Great Britain and Germany. Inclusion criteria were a
      positive history of parental allergy and a positive skin-prick test or specific
      immunoglobulin E (IgE) of >or= 1.43 kU/l against at least one out of a panel of
      common aeroallergens in one or both parents. At 1 year of age the overall
      sensitization rate against the tested allergens [dust mite allergens:
      Dermatophagoides pteronyssinus and D. farinae (Der p and Der f, respectively)]
      and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in
      the control group. The prevalence of sensitization against Der p was 1.86% in the
      prophylactic group vs. 5% in the control group. In conclusion, we demonstrated,
      in a group of newborns at risk for atopic diseases, that the sensitization rate
      to a panel of aero- and food allergens could be effectively decreased through the
      use of impermeable mattress encasings and the implementation of preventive
      measures that were easy to perform.

PMID- 12603708
TI  - Effects of breast milk from allergic and non-allergic mothers on mitogen- and
      allergen-induced cytokine production.
AB  - Breast milk contains several components that provide specific immunity and affect
      the maturation of the infant's immune system. The aim of this study was to
      analyze the effects of breast milk, on mitogen- and allergen-induced cytokine
      production from cord blood mononuclear cells (CBMC), and if those effects differ
      between allergic and non-allergic mothers. The cells were incubated for 96 h with
      phytohemagglutinin (PHA), ovalbumin or cat dander in the presence of various
      dilutions of colostrum. Colostrum inhibited both mitogen- and cat-induced IFN
      gamma and mitogen-induced interleukin-4 (IL-4) production. The inhibition on IFN
      gamma production was to some extent caused by TGF-beta, as the effect was
      modified when an anti-TGF-beta antibody was added to the cultures. In contrast,
      colostrum enhanced allergen-induced production of the Th2-like cytokines IL-5 and
      IL-13, and this was accompanied with increased production of IL-10. No
      differences were found between allergic and non-allergic mothers. The inhibitory
      effect of breast milk on IFN-gamma production, which was partly due to the high
      levels of TGF-beta, together with the enhancing effect on IL-10 secretion,
      confirm that breast milk is anti-inflammatory. Although the production of IL-5
      and IL-13 was enhanced by colostrum, this was accompanied with an increased
      production of IL-10. Together with the high levels of TGF-beta in breast milk and
      inhibitory effect of colostrum on IL-4 production, this suggests a possible
      mechanism whereby breast-feeding may protect against the development of allergy.
      Despite differences in the composition of breast milk between allergic and non
      allergic mothers, the effects of breast milk on cytokine production from CBMC
      were independent of the atopic status of the mothers.

PMID- 12603710
TI  - Reduced frequency of wheezing respiratory illness in infants with perinatal human
      immunodeficiency virus-type 1 infection: a model for immunologic and inflammatory
      mechanisms of airway obstruction?
AB  - A multivariate analysis using a logistic regression model evaluated odds ratio
      (OR) and 95% confidence limits (95% CL) of pediatrician-diagnosed wheezing
      respiratory illness in 75 infants with perinatal human immunodeficiency virus
      type 1 (HIV-1) infection, 205 uninfected infants of HIV-1 infected mothers, and
      1780 infants of HIV-1 uninfected mothers. Infants were prospectively followed-up
      for the first 2 years of life. Covariates were risk factors for wheezing
      respiratory illness (preterm delivery, low birth weight, maternal smoking,
      formula feeding, and neonatal respiratory disorders). Maternal use of illicit
      drugs in pregnancy, antiretroviral treatment in pregnancy, maternal HIV-1-related
      clinical condition at the time of delivery were also included in the models when
      infants of HIV-1 infected mothers were taken into account. Although the frequency
      of risk factors for wheezing respiratory illness was higher in infants of HIV-1
      infected than in those of uninfected mothers, HIV-1 infection emerged as a
      protective factor [OR: 0.001 (95% CL: 0.0001-0.01); p < 0.001]. The frequency of
      risk factors was similarly high among infants of infected mothers, but OR was
      lower in HIV-1 infected than in uninfected infants of infected mothers (0.005;
      95% CL: 0.0004-0.06; p < 0.001). Finally, OR was higher in uninfected infants of
      HIV-1 infected mothers (who evidenced a higher frequency of risk factors) than in
      infants of HIV-1 uninfected mothers (9.97; 95% CL: 4.87-20.40; p < 0.001).
      Understanding the reason why HIV-1 protects against wheezing respiratory illness
      could shed light on the immunologic and inflammatory mechanisms of airway
      obstruction.

PMID- 12603709
TI  - Cytokine, chemokine and secretory IgA levels in human milk in relation to atopic
      disease and IgA production in infants.
AB  - The relationship between breast-feeding, IgA production and development of atopic
      disease in children is a matter of controversy. Some of this controversy might be
      due to individual differences in the composition of breast milk. The aim of this
      study was to relate the levels of cytokines, chemokines and secretory (S)-IgA
      antibodies in breast milk to the development of atopic manifestation and salivary
      IgA production in infants. Cytokine, chemokine and SIgA levels, as measured with
      enzyme-linked immunosorbent assay (ELISA), in colostrum and mature milk were
      analyzed in relation to the development of positive skin-prick tests (SPT),
      allergic symptoms and salivary IgA antibody production during the first 2 years
      of life in 53 infants. There was no association between levels of IL-4, -5, -6, 
      8, -10, -13, -16, IFN-gamma, TGF-beta1, -beta2, RANTES, eotaxin or SIgA levels in
      the breast milk with either SPT-positivity, development of allergic symptoms or
      salivary IgA levels during the first 2 years of life in the infants. Thus,
      differences in the composition of cytokines, chemokines and SIgA in breast milk
      did not, to any major degree, affect the development of a positive SPT, atopic
      symptoms, nor salivary IgA antibody production during the first 2 years of life.

PMID- 12603711
TI  - Relationship between group A beta-hemolytic streptococcal tonsillopharyngitis and
      asthma.
AB  - Increasing morbidity due to asthma in children and antimicrobial resistance among
      human pathogens are both major public-health concerns. Frequent use of
      antibiotics during childhood might be a factor underlying the rising severity and
      prevalence of asthma and other allergic disorders. The objective of the study was
      to determine if pediatric patients with asthma or allergic rhinitis have an
      altered rate of group A beta hemolytic streptococcal (GABHS) tonsillopharyngeal
      infection which might support any change in guidelines for antibiotic
      prescription. A prospective analysis of all patients presenting a clinical
      feature of GABHS pharyngitis with a sore throat in two pediatric clinics located
      in Detroit, MI, USA and San Antonio de Areco, Buenos Aires, Argentina. Eligible
      patients aged between 2 and 18 years were screened for the presence of asthma
      and/or allergic rhinitis and administered a test (rapid strep test) and throat
      culture to determine GABHS infection. At the Redford Medical Center, Detroit, 500
      patients met the eligibility criteria, with 168 (33.6%) having a positive strep
      test. At the San Antonio de Areco's Hospital, in a rural area 100 km away from
      Buenos Aires, 188 patients met the eligibility criteria, with 41 (21.8%) having a
      positive strep test or GABHS throat cultures. In both the Detroit [odds ratio
      (OR) = 1.36; 95% confidence interval (CI) 0.72-2.57] and Buenos Aires clinics (OR
      = 0.50; 95% CI 0.23-1.07), patients with asthma or allergic rhinitis were not at
      an increased risk for true GABHS tonsillopharyngeal infections when compared with
      the general pediatric population. These results suggest that children with asthma
      do not differ from the normal population in their risk of developing GABHS
      tonsillopharyngeal infection and should not be liberally prescribed antibiotics.

PMID- 12603712
TI  - Effect of oral cyclosporin A in children with Staphylococcus aureus-colonized vs
      S aureus-infected severe atopic dermatitis.
AB  - Atopic dermatitis (AD) is frequently associated with skin colonization or
      infection with Staphylococcus aureus strains producing exotoxins. The aim of this
      investigation was to evaluate the effect of oral cyclosporin A (CsA) on disease
      severity and bacterial counts in colonized and infected patients. Eleven children
      with severe AD (SCORAD index >50, mean objective SCORAD score >40) were treated
      for 8 weeks with 2.5-5 mg/kg CsA. In five patients, the skin was only colonized
      with S. aureus whereas the remaining six patients presented clinically relevant
      suppurative S. aureus skin infections characterized by small pustules, crustings,
      pus and increased pruritus in the presence of S. aureus as determined by contact
      sampling and culture which regularly resulted in the indication for antibiotic
      treatment. Clinical and microbiological investigations were performed before and
      after CsA therapy. Clinical signs and symptoms of AD improved in all patients
      with a reduction in mean SCORAD index from 74 to 29 (p < 0.001). However, disease
      severity and bacterial counts were more reduced by CsA in the colonized patients
      compared with the patients with clinical overt infections. In conclusion,
      treatment with CsA resulted in an improvement of clinical symptoms in children
      suffering from severe AD. However, anti-infective treatment administered before
      immunomodulatory therapy is likely to be decisive for the long-term therapeutic
      effect.

PMID- 12603713
TI  - Steroid-sensitive indices of airway inflammation in children with seasonal
      allergic rhinitis.
AB  - Previous studies involving adults have demonstrated that airway
      glucocorticosteroids inhibit plasma exudation and eosinophil activity in allergic
      rhinitis. This study explores the possibility that plasma exudation, exudative
      responsiveness, and the occurrence of eosinophil activity-related proteins are
      glucocorticosteroid-sensitive nasal mucosal indices in allergic children. Using a
      placebo-controlled, parallel-group design effects of nasal budesonide (64 microg
      per nasal cavity b.i.d) were determined in children with seasonal allergic
      rhinitis. Nasal lavage fluid levels of eotaxin, eosinophil cationic protein
      (ECP), and alpha2-macroglobulin, indicating plasma exudation, were determined,
      the latter with and without challenge with topical histamine. Nasal lavage fluid
      levels of alpha2-macroglobulin and ECP increased significantly during the pollen
      season, and the acute plasma exudation response to histamine was significantly
      greater during than outside the season. There was a trend towards a seasonal
      increase in nasal lavage fluid levels of eotaxin. Budesonide significantly
      inhibited the seasonal increase in alpha2-macroglobulin as well as the exudative
      hyperresponsiveness to histamine. Any tendency of increases in mucosal output of
      eotaxin and ECP was abolished by the glucocorticosteroid treatment. We conclude
      that mucosal exudation of plasma, as a global sign of active inflammatory
      processes, is a glucocorticosteroid-sensitive facet of allergic rhinitis in
      children. Exudative hyperresponsiveness, potentially caused by several weeks of
      mucosal inflammation, emerges as a significant feature of allergic rhinitis in
      children, and its development is prevented by local treatment with a
      glucocorticosteroid drug. The seasonal increase in ECP and the trend for an
      increase in eotaxin were absent in the glucocorticosteroid-treated subjects.

PMID- 12603715
TI  - Basic tips about writing a scholarly manuscript.

PMID- 12603714
TI  - Treatment of allergic alveolitis with methylprednisolone pulse therapy.
AB  - We report on a 13-year-old-boy who had been admitted to our hospital for dyspnea,
      hypoxia, and pulmonary infiltrates. The diagnosis of allergic alveolitis was
      based on history (provocation by exposure), lung function tests, bronchoalveolar
      lavage, and transbronchial lung biopsy. No specific allergen could be identified.
      Five courses of methylprednisolone pulse therapy (15 mg/kg on three consecutive
      days) stabilized the patient with normalization of lung function and blood gas
      analysis. Between pulses the boy returned to his home on a farm without relapse.
      It is estimated that the effect of a single pulse lasted for at least 2-4 weeks.
      We conclude that pulse therapy can be used instead of continuous therapy in this
      rare disease in childhood.

PMID- 12603716
TI  - Defining characteristics of expertise in Japanese clinical nursing using the
      Delphi technique.
AB  - A four-round Delphi technique was conducted on 127 experienced Japanese nurses to
      develop a consensus of opinion on the defining characteristics underlying
      expertise, and the prime requirements for the development of expertise in
      clinical nursing. Sixteen statements identified as the prime defining
      characteristics underlying expertise indicated that experienced Japanese nurses'
      picture of expertise is general, comprehensive and focused on task expertise.
      Four prime requirements for the development of expertise identified indicated
      that neither experience nor accumulation of theoretical knowledge alone is
      sufficient to develop expertise; but that motivation and attitude do play an
      essential role in the development of expertise.

PMID- 12603717
TI  - Postoperative pain management: study of patients' level of pain and satisfaction
      with health care providers' responsiveness to their reports of pain.
AB  - The present prospective survey was conducted in a 1200-bed hospital to examine
      postoperative patients' current pain intensity, most intense pain experienced,
      satisfaction with postoperative pain management, and differences regarding pain
      and satisfaction levels. All adult patients admitted to a hospital in Hong Kong
      for surgery, except those receiving local anesthesia, were eligible to enter this
      study. The patient outcome questionnaire developed by the American Pain Society
      was used to solicit data about patients' pain and satisfaction with pain relief.
      The subjects were 294 postoperative patients. Approximately 85% complained about
      varying degrees of pain during the 24 h prior to the assessment of their pain.
      When interviewed, most patients complained of mild to moderate pain (median = 2
      on a 10-point scale), while the median for 'worst pain intensity' was 5.
      Approximately 80% of the subjects indicated that both the nurses and physicians
      reminded them to report pain when it occurred. Only 143 (48.6%) agreed that the
      nurses and physicians sufficiently emphasized the importance of pain relief.
      Those who received acute pain services, provided by anesthetists, reported lower
      levels of current pain intensity. Over 65% of the subjects were satisfied with
      all levels of health care providers, regarding their postoperative pain
      management.

PMID- 12603718
TI  - Development of the chronic obstructive pulmonary disease activity rating scale:
      reliability, validity and factorial structure.
AB  - The purpose of the present study was to develop the Chronic Obstructive Pulmonary
      Disease (COPD) Activity Rating Scale (CARS) to measure life-related activity in
      patients with COPD, and to confirm its reliability and constructive validity in a
      factorial structure model. The subjects consisted of 114 patients with COPD. An
      88-item life-related activity list, generated previously from a literature
      review, was administered. The secondary structural model consisted of four
      factors with 12 items. The results of the confirmatory factor analysis by
      structural equation modeling showed the fit criteria to be statistically
      significant. The internal consistency of the 12 items was highly reliable
      (Cronbach's alpha = 0.924). The CARS score was correlated with pulmonary function
      tests, breathlessness, and the health-related quality of life (QOL) scales in
      Pearson correlation coefficient. The results suggest that the COPD Activity
      Rating Scale is a valid scale for the assessment of life-related activity in
      patients with COPD.

PMID- 12603719
TI  - Work sampling: valuable methodology to define nursing practice patterns.
AB  - The volatile clinical and managerial environment of today's health care system
      demands that the nursing sector regularly evaluates how staff deliver care.
      Management's central purpose is to support clinical core activities, striving for
      a reasonable balance between cost effectiveness and quality care. Various
      methodologies, such as work sampling and time-and-motion studies, have been used
      to explore work-related activities. As a cost-effective and useful methodology,
      work sampling warrants more in-depth exploration of the various techniques
      involved to ensure nurse managers, clinicians and researchers appreciate the
      complexities of the approach and its potential to contribute to an understanding
      of nursing work. The present paper describes work sampling as a method, reviews
      its use through the literature and outlines some of its advantages and
      disadvantages in comparison to the time-and-motion methodology, a method similar
      in many ways. It is intended to enhance readers' appreciation of work sampling's
      potential value to nurses and other health professionals, and to enhance the
      understanding of the difference between work sampling and time-and-motion
      studies.

PMID- 12603720
TI  - Role of knowledge and ability in student nurses' clinical decision-making.
AB  - Little is known about the acquisition of decision-making skills in nursing
      students as a function of experience and academic ability. Knowing how experience
      and academic skills interact may help inform clinical education programs and
      formulate ways of assessing students' progress. The aims of the present study
      were to develop a problem-solving task capable of measuring clinical decision
      making skills in novice nurses at different levels of domain-specific knowledge;
      and to establish the relative impact on decision-making of domain-specific
      knowledge and general ability as determinants of the acquisition of decision
      making skills. Three types of clinical problems of increasing complexity were
      developed. Sixty second-year and third-year student nurses with high and low
      academic scores were studied in terms of their ability to generate hypotheses for
      a hypothetical case, recognize disconfirming information and the need to access
      additional information, and diagnostic accuracy. The results showed that general
      academic ability and knowledge function partly independently in the acquisition
      of expertise in nursing. Academic ability affects decision-making in low
      complexity tasks, but as case complexity increases, domain-specific knowledge and
      experience determines decision-making skills. There are important differences in
      the way novices with different levels of knowledge and ability make clinical
      decisions and these can be studied by systematically increasing the complexity of
      the decision task. These results have implications for the way in which clinical
      education is structured and evaluated.

PMID- 12603721
TI  - Lessons learned as a research assistant studying ambulatory blood pressure in
      elderly Japanese stroke patients.
AB  - The research assistant plays a critical part in research projects, yet there is
      little structured information about the role. The present paper describes the
      research assistant"s role and provides an example of the research assistant"s
      activities in nursing research. In this pilot study, 24 h ambulatory blood
      pressure monitoring was conducted on 15 elderly Japanese stroke patients in a
      hospital rehabilitation unit. The research assistant's involvement is described
      along the course of the study: pre-data collection; data collection and data
      processing. A research assistant needs to have good communication skills, a
      detail-oriented focus and an inquisitive nature.

PMID- 12603722
TI  - Moral stress and burnout: qualitative content analysis.
AB  - The aim of the present study was to describe and interpret the narrative of an
      Australian nurse's experience of burnout. A qualitative content analysis was used
      for the text of the interview. The main findings of this study concern moral
      stress and burnout. Three themes were identified: shortcomings and health
      problems; hovering between suffering and desire; and responsibility for oneself.
      All themes are related to the nurse's identity, the nurse's personal experience
      of, and reflections on, ethical problems and the existential issues of suffering,
      and the responsibilities and difficulties nurses face. The findings are explained
      and discussed in light of several theories. In conclusion, nurses' needs have to
      be recognized. They need both emotional support and the right to receive
      systematic clinical supervision to help them reflect on their practical work and
      interpret the needs of patients.

PMID- 12603724
TI  - Cross-cultural menopausal experience: comparison of Australian and Taiwanese
      women.
AB  - A more universal approach to the understanding of menopause can offer health
      professionals a broader view of the phenomenon. The present study's objectives
      were to describe and explain the menopausal experiences of Asian and Occidental
      women, and to examine the relationship between social/cultural factors and
      women's menopausal symptoms. Questionnaires were used to investigate psychosocial
      and cultural factors and menopausal symptoms in 45-55 years old Taiwanese (n =
      105) and Australian (n = 450) women. The variables investigated included: social
      demography; menopause status; attitudes toward menopause; mental health;
      vitality; social functioning; and menopausal symptoms. Significant differences
      were found between Taiwanese and Australian women in their attitude towards
      menopause, menopausal symptoms and vitality scores. No significant differences
      were seen in the areas of social functioning, mental health and menopause status.
      The results suggest that cultural factors may influence the experience of
      menopause for women. These findings may improve health professionals'
      understanding of cultural beliefs relating to menopause so that culturally
      appropriate care can be provided.

PMID- 12603723
TI  - Knowledge level and coping strategies according to coagulation levels in older
      persons with atrial fibrillation.
AB  - The present study examined the knowledge level and the coping strategies of older
      persons with atrial fibrillation, who were on oral anticoagulant therapy. The
      relationship among knowledge level, problem and affective-oriented coping
      strategies, and the level of anticoagulant effectiveness were examined. We also
      compared differences between subjects who were within a therapeutic range for
      International Normalized Ratio levels with those who were not. The research
      design was descriptive and correlational. One hundred older persons completed the
      Jaloweic Coping Scale (a knowledge questionnaire) and socio-demographic,
      contextual and clinical characteristic questions. The findings suggested that the
      knowledge levels were low (53%), and problem-oriented coping strategies were most
      often used (32.62%) compared to affective-oriented coping strategies (18.96%).
      Other than praying and putting one's trust in God (P = 0.05), it appeared that no
      other significant coping strategies differentiated the subjects regarding their
      level of anticoagulant effectiveness. It is recommended that further examination
      of the reasons for older persons' low knowledge level, in regard to their oral
      anticoagulant therapy, occurs and that use of problem-oriented coping strategies,
      to improve self-care measures, be encouraged.

PMID- 12603725
TI  - Medication trends and documentation of pain management following surgery.
AB  - The purpose of the present study was to examine prescribing and administering
      activities for sedative and analgesic medication in postoperative patients, and
      to describe nurses' documentation practices for pain management in nursing notes.
      A prospective audit was undertaken of medication order charts and nursing notes
      of 100 patients on the operation day and over the first four days following
      surgery. Almost all patients received some form of infusion, while the use of 'as
      required' analgesics varied from one-third to over two-thirds of patients during
      the postoperative period. Few patients were prescribed fixed-order analgesics or
      sedative medications. An audit of nursing entries found that nurses had
      documented inadequately in four major areas: pain assessment, use of non
      pharmacological interventions, use of pharmacological interventions, and outcome
      of interventions. The findings contribute to improving our understanding of
      nurses' pain management and identify the need to use clinical judgement that is
      individualized to patients' needs.

PMID- 12603727
TI  - Molecular mechanisms of iron uptake in fungi.
AB  - Fungi, like all free-living organisms, are in competition for limiting nutrients.
      In accumulating iron, fungi are faced also with a trace metal whose aqueous and
      redox chemistry make it both relatively bio-unavailable and strongly cytotoxic.
      Successful adaptation to this environmental context has provided fungi with an
      iron uptake strategy that has three features: it relies on redox cycling to
      enhance iron bio-availability and reduce iron cytotoxicity; it includes both high
      and low-affinity pathways that are mechanistically distinct; and it is
      autoregulating so as to maintain intracellular iron homeostasis. Using
      Saccharomyces cerevisiae as a paradigm, this review summarizes current knowledge
      about the four pathways by which this yeast accumulates iron. These four pathways
      include: siderophore iron accumulation; high affinity iron uptake via an iron
      permease; and two lower affinity uptake pathways through relatively non-specific
      divalent metal ion transporters. All of these four pathways are directly or
      indirectly dependent on the activity of metalloreductase activity expressed
      extracellularly on the plasma membrane. A variety of experimental and genomics
      data indicate that this resourcefulness is shared by many, if not most, fungi. On
      the other hand, while the autoregulation of iron metabolism in Baker's yeast is
      well-understood, little is known about the apparent homeostatic mechanisms in
      these other yeasts and fungi. The integration of these multiple uptake mechanisms
      and their regulation into over-all iron homeostasis in yeast concludes this brief
      review.

PMID- 12603728
TI  - Tn5 as a model for understanding DNA transposition.
AB  - Tn5 is an excellent model system for understanding the molecular basis of DNA
      mediated transposition. Mechanistic information has come from genetic and
      biochemical investigations of the transposase and its interactions with the
      recognition DNA sequences at the ends of the transposon. More recently, molecular
      structure analyses of catalytically active transposase; transposon DNA complexes
      have provided us with unprecedented insights into this transposition system.
      Transposase initiates transposition by forming a dimeric transposase, transposon
      DNA complex. In the context of this complex, the transposase then catalyses four
      phosphoryl transfer reactions (DNA nicking, DNA hairpin formation, hairpin
      resolution and strand transfer into target DNA) resulting in the integration of
      the transposon into its new DNA site. The studies that elucidated these steps
      also provided important insights into the integration of retroviral genomes into
      host DNA and the immune system V(D)J joining process. This review will describe
      the structures and steps involved in Tn5 transposition and point out a
      biologically important although surprising characteristic of the wild-type Tn5
      transposase. Transposase is a very inactive protein. An inactive transposase
      protein ensures the survival of the host and thus the survival of Tn5.

PMID- 12603730
TI  - Productive interaction between the chromosome partitioning proteins, ParA and
      ParB, is required for the progression of the cell cycle in Caulobacter
      crescentus.
AB  - In Caulobacter crescentus the partitioning proteins ParA and ParB operate a
      molecular switch that couples chromosome partitioning to cytokinesis. Homologues
      of these proteins have been shown to be important for the stable inheritance of F
      plasmids and the prophage form of bacteriophage P1. In C. crescentus, ParB binds
      to sequences adjacent to the origin of replication and is required for the
      initiation of cell division. Additionally, ParB influences the nucleotide-bound
      state of ParA by acting as a nucleotide exchange factor. Here we have performed a
      genetic analysis of the chromosome partitioning protein ParB. We show that C.
      crescentus ParB, like its plasmid homologues, is composed of three domains: a
      carboxyl-terminal dimerization domain; a central DNA-binding, helix-turn-helix
      domain; and an amino-terminal domain required for the interaction with ParA. In
      vivo expression of amino-terminally deleted parB alleles has a dominant lethal
      effect resulting in the inhibition of cell division. Fluorescent in situ
      hybridization experiments indicate that this phenotype is not caused by a
      chromosome partitioning defect, but by the reversal of the amounts of ATP- versus
      ADP- bound ParA inside the cell. We present evidence suggesting that amino
      terminally truncated and full-length, wild-type ParB form heterodimers which fail
      to interact with ParA, thereby reversing the intracellular ParA-ATP to ParA-ADP
      ratio. We hypothesize that the amino-terminus of ParB is required to regulate the
      nucleotide exchange of ParA which, in turn, regulates the initiation of cell
      division.

PMID- 12603731
TI  - Cytochrome c oxidase genes required for nitrogenase activity and diazotrophic
      growth in Anabaena sp. PCC 7120.
AB  - N2 fixation is an O2-sensitive process and some filamentous diazotrophic
      cyanobacteria that grow performing oxygenic photosynthesis confine their N2
      fixation machinery to heterocysts, specialized cells that maintain a reducing
      environment adequate for N2 fixation. Respiration is thought to contribute to the
      diazotrophic metabolism of heterocysts and the genome of the heterocyst-forming
      cyanobacterium Anabaena sp. PCC 7120 bears three gene clusters putatively
      encoding cytochrome c oxidases. Transcript analysis of these cox gene clusters
      through RNA/DNA hybridization identified two cox operons, cox2 and cox3, that are
      induced after nitrogen step-down in an NtcA- and HetR-dependent manner and appear
      to be expressed specifically in heterocysts. In contrast, cox1 was expressed only
      in vegetative cells. Expression of cox2 and cox3 occurred at an intermediate
      stage (about 9 h) during the process of heterocyst development following nitrogen
      step-down. Inactivation of genes in the two inducible cox operons, but not
      separately in either of them, strongly reduced nitrogenase activity and prevented
      diazotrophic growth in aerobic conditions. These results show that the nitrogen
      regulated cytochrome c oxidase-type respiratory terminal oxidases Cox2 and Cox3
      are essential for heterocyst function in Anabaena sp. PCC 7120.

PMID- 12603729
TI  - Iron and contact with host cells induce expression of adhesins on surface of
      Trichomonas vaginalis.
AB  - The proteins AP65, AP51, AP33 and AP23 synthesized by Trichomonas vaginalis
      organisms in high iron play a role in adherence. Multigene families encode
      enzymes of the hydrogenosome organelles, which have identity to adhesins. This
      fact raises questions regarding the compartmentalization of the proteins outside
      the organelle and about the interactions of adhesins with host cells. Data here
      demonstrate the presence of the proteins outside the organelle under high-iron
      conditions. Fluorescence and immuno-cytochemical experiments show that high-iron
      grown organisms coexpressed adhesins on the surface and intracellularly in
      contrast with low-iron parasites. Furthermore, the AP65 epitopes seen by rabbit
      anti-AP65 serum that blocks adherence and detects surface proteins were
      identified, and a mAb reacting to those epitopes recognized the trichomonal
      surface. Two-dimensional electrophoresis and immunoblot of adhesins from surface
      labelled parasites provided evidence that all members of the multigene family
      were co-ordinately expressed and placed on the trichomonal surface. Similar two
      dimensional analysis of proteins from purified hydrogenosomes obtained from
      iodinated trichomonads confirmed the specific surface labelling of proteins.
      Contact of trichomonads with vaginal epithelial cells increased the amount of
      surface-expressed adhesins. Moreover, we found a direct relationship between the
      levels of adherence and amount of adhesins bound to immortalized vaginal and
      ureter epithelial cells, further reinforcing specific associations. Finally,
      trichomonads of MR100, a drug-resistant isolate absent in hydrogenosome proteins
      and adhesins, were non-adherent. Overall, the results confirm an important role
      for iron and contact in the surface expression of adhesins of T. vaginalis
      organisms.

PMID- 12603732
TI  - Characterization of a novel inhibitory feedback of the anti-anti-sigma SpoIIAA on
      Spo0A activation during development in Bacillus subtilis.
AB  - Compartmentalized gene expression during sporulation is initiated after
      asymmetric division by cell-specific activation of the transcription factors
      sigmaF and sigmaE. Synthesis of these sigma factors, and their regulatory
      proteins, requires the activation (phosphorylation) of Spo0A by the phosphorelay
      signalling system. We report here a novel regulatory function of the anti-anti
      sigmaF SpoIIAA as inhibitor of Spo0A activation. This effect did not require
      sigmaF activity, and it was abolished by expression of the phosphorelay
      independent form Spo0A-Sad67 indicating that SpoIIAA directly interfered with
      Spo0A approximately P generation. IPTG-directed synthesis of the SpoIIE
      phosphatase in a strain carrying a multicopy plasmid coding for SpoIIAA and its
      specific inhibitory kinase SpoIIAB blocked Spo0A activation suggesting that the
      active form of the inhibitor was SpoIIAA and not SpoIIAA-P. Furthermore,
      expression of the non-phosphorylatable mutant SpoIIAAS58A (SpoIIAA-like), but not
      SpoIIAAS58D (SpoIIAA-P-like), completely blocked Spo0A-dependent gene expression.
      Importantly, SpoIIAA expressed from the chromosome under the control of its
      normal spoIIA promoter showed the same negative effect regulated not only by
      SpoIIAB and SpoIIE but also by septum morphogenesis. These findings are discussed
      in relation to the potential contribution of this novel inhibitory feedback with
      the proper activation of sigmaF and sigmaE during development.

PMID- 12603733
TI  - Widespread functional specialization of Plasmodium falciparum erythrocyte
      membrane protein 1 family members to bind CD36 analysed across a parasite genome.
AB  - Plasmodium falciparum-infected erythrocytes sequester from blood circulation by
      binding host endothelium. A large family of variant proteins mediates
      cytoadherence and their binding specificity determines parasite sequestration
      patterns and potential for disease. The aim of the present study was to
      understand how binding properties are encoded into family members and to develop
      sequence algorithms for predicting binding. To accomplish these goals
      computational approaches and a binding assay were used to characterize adhesion
      across Plasmodium falciparum erythrocyte membrane 1 (PfEMP1) proteins in the 3D7
      parasite genome. We report that most family members encode the capacity to bind
      CD36 in the protein's semi-conserved head structure and describe the sequence
      characteristics of a group of PfEMP1 proteins that do not. Structural and
      functional grouping of PfEMP1 proteins based upon head structure and additional
      domain architectural properties provide new insights into the protein family.
      These can be used to investigate the role of proteins in malaria pathogenesis and
      potentially tailor vaccines to recognize particular binding variants.

PMID- 12603734
TI  - Functions of the CckA histidine kinase in Caulobacter cell cycle control.
AB  - The CtrA master transcriptional regulator is a central control element in
      Caulobacter cell cycle progression and polar morphogenesis. Because of its
      critical role, CtrA activity is temporally regulated by multiple mechanisms
      including phosphorylation and ClpXP-dependent degradation of CtrA. The CckA
      histidine kinase is known to contribute to CtrA phosphorylation. We show here
      that genes differentially expressed in a ctrA temperature-sensitive (ts) mutant
      are similarly affected in a cckA ts mutant, that the phosphorylation of CckA
      coincides temporally with CtrA phosphorylation during the cell cycle, and that
      CckA is essential for viability because it is required for CtrA phosphorylation.
      Thus, it is the signal transduction pathway mediated by CckA that culminates in
      CtrA activation, which is temporally regulated and essential for cell cycle
      progression. CckA also positively regulates CtrA activity by a mechanism that is
      independent of CtrA phosphorylation. CtrA is more stable in the presence of CckA
      than it is absence, suggesting that CckA may also be involved, directly or
      indirectly, in the regulation of CtrA proteolysis.

PMID- 12603735
TI  - Genome plasticity in Acinetobacter: new degradative capabilities acquired by the
      spontaneous amplification of large chromosomal segments.
AB  - In Acinetobacter sp. ADP1, growth on benzoate requires regulation of the cat
      genes by two transcriptional activators. Here, mutants were obtained from a
      strain lacking both activators by selecting for growth on benzoate medium. The
      mutants, which arose within 3 weeks at a frequency of approximately 10-8, carried
      amplified chromosomal regions (amplicons) encompassing the cat genes. Multiple
      occurrences of low-level expression of catA and the catBCIJFD operon provided
      sufficient transcription for growth. The amplicons of four independently isolated
      mutants varied in size from approximately 30-100 kbp of the normally 3.8 Mbp
      chromosome. Mutants had approximately 10-20 copies of an amplicon in adjacent
      head-to-tail orientations. At the amplicon's chromosomal endpoint, an atypical
      junction juxtaposed normally distant DNA regions from opposite sides of the cat
      genes. The sequences of these junctions revealed the precise recombination sites
      underlying amplification. Additionally, amplicon stability was evaluated in the
      absence of selective pressure. The natural competence of Acinetobacter for
      transformation by linear DNA has allowed the development of a powerful new model
      system for investigating chromosomal rearrangements and for engineering DNA
      amplifications for wide-ranging applications. The frequent spontaneous
      amplification of these large chromosomal segments demonstrated the importance of
      supra-operonic gene clustering in the evolution of catabolic pathways.

PMID- 12603736
TI  - Proinflammatory signalling stimulated by the type III translocation factor YopB
      is counteracted by multiple effectors in epithelial cells infected with Yersinia
      pseudotuberculosis.
AB  - Type III secretion systems are used by several pathogens to translocate effector
      proteins into host cells. Yersinia pseudotuberculosis delivers several Yop
      effectors (e.g. YopH, YopE and YopJ) to counteract signalling responses during
      infection. YopB, YopD and LcrV are components of the translocation machinery.
      Here, we demonstrate that a type III translocation protein stimulates
      proinflammatory signalling in host cells, and that multiple effector Yops
      counteract this response. To examine proinflammatory signalling by the type III
      translocation machinery, HeLa cells infected with wild-type or Yop-Y.
      pseudotuberculosis strains were assayed for interleukin (IL)-8 production. HeLa
      cells infected with a YopEHJ- triple mutant released significantly more IL-8 than
      HeLa cells infected with isogenic wild-type, YopE-, YopH- or YopJ- bacteria.
      Complementation analysis demonstrated that YopE, YopH or YopJ are sufficient to
      counteract IL-8 production. IL-8 production required YopB, but did not require
      YopD, pore formation or invasin-mediated adhesion. In addition, YopB was required
      for activation of nuclear factor kappa B, the mitogen-activated protein kinases
      ERK and JNK and the small GTPase Ras in HeLa cells infected with the YopEHJ-
      mutant. We conclude that interaction of the Yersinia type III translocator factor
      YopB with the host cell triggers a proinflammatory signalling response that is
      counteracted by multiple effectors in host cells.

PMID- 12603737
TI  - Trigger Factor and DnaK possess overlapping substrate pools and binding
      specificities.
AB  - Ribosome-associated Trigger Factor (TF) and the DnaK chaperone system assist the
      folding of newly synthesized proteins in Escherichia coli. Here, we show that
      DnaK and TF share a common substrate pool in vivo. In TF-deficient cells,
      deltatig, depleted for DnaK and DnaJ the amount of aggregated proteins increases
      with increasing temperature, amounting to 10% of total soluble protein
      (approximately 340 protein species) at 37 degrees C. A similar population of
      proteins aggregated in DnaK depleted tig+ cells, albeit to a much lower extent.
      Ninety-four aggregated proteins isolated from DnaK- and DnaJ-depleted deltatig
      cells were identified by mass spectrometry and found to include essential
      cytosolic proteins. Four potential in vivo substrates were screened for chaperone
      binding sites using peptide libraries. Although TF and DnaK recognize different
      binding motifs, 77% of TF binding peptides also associated with DnaK. In the case
      of the nascent polypeptides TF and DnaK competed for binding, however, with
      competitive advantage for TF. In vivo, the loss of TF is compensated by the
      induction of the heat shock response and thus enhanced levels of DnaK. In
      summary, our results demonstrate that the co-operation of the two mechanistically
      distinct chaperones in protein folding is based on their overlap in substrate
      specificities.

PMID- 12603738
TI  - F1-catalysed ATP hydrolysis is required for mitochondrial biogenesis in
      Saccharomyces cerevisiae growing under conditions where it cannot respire.
AB  - Mutant strains of yeast Saccharomyces cerevisiae lacking a functional F1-ATPase
      were found to grow very poorly under anaerobic conditions. A single amino acid
      replacement (K222 > E222) that locally disrupts the adenine nucleotide catalytic
      site in the beta-F1 subunit was sufficient to compromise anaerobic growth. This
      mutation also affected growth in aerated conditions when ethidium bromide (an
      intercalating agent impairing mtDNA propagation) or antimycin (an inhibitor of
      respiration) was included in the medium. F1-deficient cells forced to grow in
      oxygen-limited conditions were shown to lose their mtDNA completely and to
      accumulate Hsp60p mainly under its precursor form. Fluorescence microscopy
      analyses with a modified GFP containing a mitochondrial targeting presequence
      revealed that aerobically growing F1-deficient cells stopped importing the GFP
      when antimycin was added to the medium. Finally, after total inactivation of the
      catalytic alpha3beta3 subcomplex of F1, mitochondria could no longer be energized
      by externally added ATP because of either a block in assembly or local disruption
      of the adenine nucleotide processing site. Altogether these data strengthen the
      notion that in the absence of respiration, and whether the proton translocating
      domain (F0) of complex V is present or not, F1-catalysed hydrolysis of ATP is
      essential for the occurrence of vital cellular processes depending on the
      maintenance of an electrochemical potential across the mitochondrial inner
      membrane.

PMID- 12603739
TI  - SseA acts as the chaperone for the SseB component of the Salmonella Pathogenicity
      Island 2 translocon.
AB  - The Salmonella Pathogenicity Island 2 (SPI2) encodes a type III secretion system
      (TTSS) shown to be critical for adaptation to the intracellular environment
      within both phagocytic and epithelial cell types. Within SPI2, the Effector
      region encodes several exported proteins that comprise the SPI2 translocon (SseB,
      C, D). SseA is the first protein encoded within the Effector region but remains
      an unclassified factor that is essential for SPI2 function. In the present study,
      we determined that SseA shares several features with TTSS chaperones: it is small
      (12.5 kDa), located directly upstream of a TTSS export target (SseB), and
      contains an amphipathic, C-terminal alpha-helix. Construction and analysis of a
      DeltasseA mutant demonstrated that the total amount of SseB is significantly
      reduced and SPI2 export of SseB to the bacterial surface is prevented. SseB
      accumulation and export were restored when SseA was provided in trans. Loss of
      SseA does not cause a generalized defect in SPI2 secretory function as export of
      SseC, encoded downstream of SseB, still occurs in the DeltasseA strain.
      Quantitative PCR indicates that the loss of SseB in DeltasseA does not occur at
      the transcriptional level. Co-purification studies demonstrate that SseA directly
      binds to SseB. Collectively, these results demonstrate that SseA functions as a
      TTSS chaperone for the SPI2 translocon component, SseB.

PMID- 12603740
TI  - The conserved cytoplasmic module of the transmembrane chemoreceptor McpC mediates
      carbohydrate chemotaxis in Bacillus subtilis.
AB  - Escherichia coli cells use two distinct sensory circuits during chemotaxis
      towards carbohydrates. One circuit requires the phosphoenolpyruvate-dependent
      phosphotransferase system (PTS) and is independent of any specific chemoreceptor,
      whereas the other uses a chemoreceptor-dependent sensory mechanism analogous to
      that used during chemotaxis towards amino acids. Work on the carbohydrate
      chemotaxis sensory circuit of Bacillus subtilis reported in this article
      indicates that the B. subtilis circuit is different from either of those used by
      E. coli. Our chemotactic analysis of B. subtilis strains expressing various
      chimeric chemoreceptors indicates that the cytoplasmic, C-terminal module of the
      chemoreceptor McpC acts as a sensory-input element during carbohydrate
      chemotaxis. Our results also indicate that PTS-mediated carbohydrate transport,
      but not carbohydrate metabolism, is required for production of a chemotactic
      signal. We propose a model in which PTS-transport-induced chemotactic signals are
      transmitted to the C-terminal module of McpC for control of chemotaxis towards
      PTS carbohydrates.

PMID- 12603741
TI  - A conserved region within the Bordetella pertussis autotransporter BrkA is
      necessary for folding of its passenger domain.
AB  - Autotransporter secretion represents a unique mechanism that Gram-negative
      bacteria employ to deliver proteins to their cell surface. BrkA is a Bordetella
      pertussis autotransporter protein that mediates serum resistance and contributes
      to adherence of the bacterium to host cells. BrkA is a 103 kDa protein that is
      cleaved to form a 73 kDa alpha-domain and a 30 kDa beta domain. The alpha domain,
      also referred to as the passenger domain, is responsible for the effector
      functions of the protein, whereas the beta domain serves as a transporter. In an
      effort to characterize BrkA secretion, we have shown that BrkA has a 42 amino
      acid signal peptide for transit across the cytoplasmic membrane, and a
      translocation unit made up of a short linker region fused to the beta-domain to
      ferry the passenger domain to the bacterial surface through a channel formed by
      the beta-domain. In this report, we provide genetic, biochemical and structural
      evidence demonstrating that a region within the BrkA passenger (Glu601-Ala692) is
      necessary for folding the passenger. This region is not required for surface
      display in the outer membrane protease OmpT-deficient Escherichia coli strain
      UT5600. However, a BrkA mutant protein bearing a deletion in this region is
      susceptible to digestion when expressed in E. coli strains expressing OmpT
      suggesting that the region is required to maintain a stable structure. The
      instability of the deletion mutant can be rescued by surface expressing Glu601
      Ala692in trans suggesting that this region is acting as an intramolecular
      chaperone to effect folding of the passenger concurrent with or following
      translocation across the outer membrane.

PMID- 12603742
TI  - Conjugal immunity of Streptomyces strains carrying the integrative element pSAM2
      is due to the pif gene (pSAM2 immunity factor).
AB  - Mechanisms of conjugal immunity preventing redundant exchange between two cells
      harbouring the same conjugative element have been reported in diverse bacteria.
      Such a system does exist for pSAM2, a conjugative and integrative element of
      Streptomyces. The apparition of the conjugative free form of pSAM2 in the donor
      strain during mating can be considered as the initial step of transfer. We
      analysed the genes involved in transfer inhibition by mating donors harbouring
      pSAM2 with recipient strains containing different regions of pSAM2. The conjugal
      immunity was previously thought to be mediated by the transcriptional repressor
      KorSA. Although the transfer efficiency is reduced by its presence in the
      recipient, the initiation of the transfer process is not affected. In contrast,
      the presence in the recipient strain of a single pSAM2 gene, pif (pSAM2 immunity
      factor), was sufficient to abolish both transfer and initiation of transfer.
      Thus, the clustered genes korSA and pif act complementarily to maintain pSAM2 in
      a 'prophage' state under non-conjugal conditions. KorSA is involved in
      intracellular signalling, whereas Pif participates in intercellular signalling.
      The Pif nudix motif is essential for its activity. This is the first protein of
      the nudix family shown to be involved in bacterial conjugation.

PMID- 12603743
TI  - Regulation of Salmonella typhimurium lipopolysaccharide O antigen chain length is
      required for virulence; identification of FepE as a second Wzz.
AB  - Wzz proteins regulate the degree of polymerization of the O antigen (Oag)
      subunits in lipopolysaccharide (LPS) biosynthesis. Although the pathogenic
      relevance of Oag is well recognized, the significance of Oag chain length
      regulation is not well defined. In this report, Salmonella typhimurium was shown
      to possess two functional wzz genes resulting in a bimodal Oag length
      distribution. In addition to the previously described wzzST that results in long
      (L) modal length LPS with 16-35 Oag repeat units (RUs), we now report that
      wzzfepE, a homologue of Escherichia coli fepE, is responsible for the production
      of very long (VL) modal length LPS Oag, estimated to contain> 100 Oag RUs.
      Analysis of a series of isogenic S. typhimurium C5 mutants found that the
      presence of either wzz gene (and hence either modal length) was sufficient for
      complement resistance and virulence in the mouse model of infection, suggesting a
      degree of redundancy in the role of these two wzz genes and their respective Oag
      modal lengths. In contrast, the wzzST/wzzfepE double mutant, with relatively
      short, random-length Oag, displayed enhanced susceptibility to complement and was
      highly attenuated in the mouse. This clearly demonstrates the molecular genetic
      basis for the longer LPS Oag chains previously identified as the basis of
      complement resistance in Salmonella. The presence of wzzfepE homologues in the
      genomic sequences of strains of Escherichia coli, Shigella flexneri and multiple
      serovars of Salmonella suggests that bimodality of LPS Oag is a common phenomenon
      in the Enterobacteriaceae.

PMID- 12603744
TI  - Characterization of the vls antigenic variation loci of the Lyme disease
      spirochaetes Borrelia garinii Ip90 and Borrelia afzelii ACAI.
AB  - The vls locus of Borrelia burgdorferi B31 consists of 15 silent cassettes and one
      expression site (vlsE), and the presence of the encoding plasmid lp28-1
      correlates with high infectivity. Recombination between the expression cassette
      and silent cassettes occurs in vivo, and this process may enable B. burgdorferi
      to evade the immune response. To determine the characteristics of the vls loci in
      other Borrelia strains, we have cloned and characterized the vls silent cassette
      loci of Borrelia garinii Ip90 and Borrelia afzelii ACAI, consisting of 11 vls
      silent cassettes and 14 vls silent cassettes respectively. The silent cassettes
      share 90-97% nucleotide sequence identity with one another within the Ip90 vls
      locus and 84-91% within the ACAI vls locus. In both organisms, the silent
      cassettes resemble the B31 Vls sequences in overall amino acid similarity (50
      65%) and in the presence of six variable regions interspersed between six
      relatively invariant regions. The vlsE expression sites of these two strains have
      not been isolated, but transcripts of vlsE were detected by reverse transcriptase
      polymerase chain reaction for both Ip90 and ACAI. In addition, the occurrence of
      sequence variation within the vlsE cassette region of these transcripts was
      verified. This study indicates that the vls loci present in B. garinii Ip90 and
      B. afzelii ACAI have characteristics similar to those found in B. burgdorferi
      B31.

PMID- 12603745
TI  - Axe-Txe, a broad-spectrum proteic toxin-antitoxin system specified by a multidrug
      resistant, clinical isolate of Enterococcus faecium.
AB  - Enterococcal species of bacteria are now acknowledged as leading causes of
      bacteraemia and other serious nosocomial infections. However, surprisingly little
      is known about the molecular mechanisms that promote the segregational stability
      of antibiotic resistance and other plasmids in these bacteria. Plasmid pRUM (24
      873 bp) is a multidrug resistance plasmid identified in a clinical isolate of
      Enterococcus faecium. A novel proteic-based toxin-antitoxin cassette identified
      on pRUM was demonstrated to be a functional segregational stability module in
      both its native host and evolutionarily diverse bacterial species. Induced
      expression of the toxin protein (Txe) of this system resulted in growth
      inhibition in Escherichia coli. The toxic effect of Txe was alleviated by co
      expression of the antitoxin protein, Axe. Homologues of the axe and txe genes are
      present in the genomes of a diversity of Eubacteria. These homologues (yefM-yoeB)
      present in the E. coli chromosome function as a toxin-antitoxin mechanism,
      although the Axe and YefM antitoxin components demonstrate specificity for their
      cognate toxin proteins in vivo. Axe-Txe is one of the first functional proteic
      toxin-antitoxin systems to be accurately described for Gram-positive bacteria.

PMID- 12603746
TI  - Adaptation of the Lyme disease spirochaete to the mammalian host environment
      results in enhanced glycosaminoglycan and host cell binding.
AB  - The Lyme disease spirochaete, Borrelia burgdorferi, is transmitted to mammals by
      Ixodes ticks and can infect multiple tissues. Host cell attachment may be
      critical for tissue colonization, and B. burgdorferi cultivated in vitro
      recognizes heparin- and dermatan sulphate-related glycosaminoglycans (GAGs) on
      the surface of mammalian cells. To determine whether growth of the spirochaete in
      the mammalian host alters GAG binding, we assessed the cell attachment activities
      of B. burgdorferi grown in vitro or in dialysis membrane chambers implanted
      intraperitoneally in rats. Host-adapted B. burgdorferi exhibited approximately
      threefold better binding to purified heparin and dermatan sulphate and to GAGs
      expressed on the surface of cultured endothelial cells. Three B. burgdorferi
      surface proteins, Bgp, DbpA and DbpB, have been demonstrated previously to bind
      to GAGs or to GAG-containing molecules, and we show here that recombinant
      derivatives of each of these proteins were able to bind to purified heparin and
      dermatan sulphate. Immunofluorescent staining of in vitro-cultivated or host
      adapted spirochaetes revealed that DbpA and DbpB were present on the bacterial
      surface at higher levels after host adaptation. Recombinant Bgp, DbpA and DbpB
      each partially inhibited attachment of host-adapted B. burgdorferi to cultured
      mammalian cells, consistent with the hypothesis that these proteins may promote
      attachment of B. burgdorferi during growth in the mammalian host. Nevertheless,
      the partial nature of this inhibition suggests that multiple pathways promote
      mammalian cell attachment by B. burgdorferi in vivo. Given the observed increase
      in cell attachment activity upon growth in the mammalian host, analysis of host
      adapted bacteria will facilitate identification of the cell binding pathways used
      in vivo.

PMID- 12603747
TI  - A hexA homologue from Photorhabdus regulates pathogenicity, symbiosis and
      phenotypic variation.
AB  - Photorhabdus is a genus of entomopathogenic Gram-negative bacteria that belong to
      the family Enterobactericeae. Remarkably, at the same time as being pathogenic to
      insect larvae, Photorhabdus also have a mutualistic relationship with
      entomophagous nematodes of the family Heterorhabditiae. Photorhabdus can be
      isolated in two phenotypically distinct forms, termed the primary and secondary
      variant. Both variants grow equally well and are equally virulent when injected
      into insect larvae. However, only the primary variant can colonize the intestinal
      tract of the IJ stage of the nematode and support nematode growth and
      development. The primary variant expresses several phenotypes that are absent
      from the secondary variant, including the production of extracellular enzymes,
      pigments, antibiotics and light. In this study, we use Photorhabdus temperata
      strain K122 to show that these primary-specific products are symbiosis factors,
      i.e. factors that are required for nematode growth and development. We also show
      that, in P. temperata K122, the production of these symbiosis factors is
      repressed in the secondary variant by the protein encoded by a gene with homology
      to hexA from Erwinia. Moreover, the derepression of the symbiosis factors in the
      secondary variant results in a significant attenuation of virulence to larvae of
      the greater wax moth, Galleria mellonella. This suggests that, during a normal
      infection, pathogenicity and symbiosis must be temporally separated and that HexA
      is involved in the regulation of this pathogen-symbiont transition.

PMID- 12603748
TI  - Membrane localization of the ToxR winged-helix domain is required for TcpP
      mediated virulence gene activation in Vibrio cholerae.
AB  - ToxR is a bitopic membrane protein that controls virulence gene expression in
      Vibrio cholerae. Its cytoplasmic domain is homologous to the winged helix-turn
      helix ('winged helix') DNA-binding/transcription activation domain found in a
      variety of prokaryotic and eukaryotic regulators, whereas its periplasmic domain
      is of ill-defined function. Several genes in V. cholerae are regulated by ToxR,
      but by apparently different mechanisms. Whereas ToxR directly controls the
      transcription of genes encoding two outer membrane proteins, OmpU and OmpT, it co
      operates with a second membrane-localized transcription factor called TcpP to
      activate transcription of the gene encoding ToxT, which regulates transcription
      of cholera toxin (ctxAB) and the toxin-co-regulated pilus (tcp). To determine the
      requirements for gene activation by ToxR, different domains of the protein were
      analysed for their ability to control expression of toxT, ompU and ompT. Soluble
      forms of the cytoplasmic winged-helix domain regulated ompU and ompT gene
      expression properly but did not activate toxT transcription. Membrane
      localization of the winged helix was sufficient for both omp gene regulation and
      TcpP-dependent toxT transcription, irrespective of the type of periplasmic domain
      or even the presence of a periplasmic domain. These results suggest that (i) the
      major function for membrane localization of ToxR is for its winged-helix domain
      to co-operate with TcpP to activate transcription; (ii) the periplasmic domain of
      ToxR is not required for TcpP-dependent activation of toxT transcription; and
      (iii) membrane localization is not a strict requirement for DNA binding and
      transcription activation by ToxR.

PMID- 12603749
TI  - Cell shape, division and development: the 2002 American Society for Microbiology
      (ASM) conference on prokaryotic development.
AB  - In the last decade, the use of cytological techniques, together with the analysis
      of complete genomes, has dramatically advanced our understanding of bacterial
      development. Work on several well-developed model systems such as Bacillus
      subtilis, Caulobacter crescentus, Myxococcus xanthus and Streptomyces spp., has
      provided us with an in-depth understanding of processes such as sporulation,
      multicellular behaviour and the bacterial cell cycle. At the same time, these
      studies have revolutionized our view of the bacterial cell and shown it to be a
      highly complex entity with spatial and temporal organization. The recent American
      Society for Microbiology (ASM) conference on prokaryotic development demonstrated
      that several laboratories have now started to connect data obtained through
      functional genomic analysis with subcellular organization, thereby generating
      three-dimensional regulatory networks. This meeting report highlights new
      findings in the field, such as regulation of protein localization during
      sporulation and the cell cycle, control of cell-cell interaction and the
      initiation of cell division.

PMID- 12603751
TI  - The clinical teaching context: a cause for concern.

PMID- 12603752
TI  - 'Nothing is but what is not'. William Shakespeare; Macbeth act 1, scene iii.

PMID- 12603753
TI  - Turning practice into theory.

PMID- 12603754
TI  - 'Good' and 'Poor' communication in an OSCE: education or training?

PMID- 12603755
TI  - Promoting 'teaching excellence' through fellowship schemes: three important
      issues to consider.

PMID- 12603756
TI  - Dignity and impudence: how should medical students acquire and practise clinical
      skills for use with older people?

PMID- 12603757
TI  - A discourse analysis study of 'good' and 'poor' communication in an OSCE: a
      proposed new framework for teaching students.
AB  - BACKGROUND: There is still a great deal to be learnt about teaching and assessing
      undergraduate communication skills, particularly as formal teaching in this area
      expands. One approach is to use the summative assessments of these skills in
      formative ways. Discourse analysis of data collected from final year examinations
      sheds light on the grounds for assessing students as 'good' or 'poor'
      communicators. This approach can feed into the teaching/learning of communication
      skills in the undergraduate curriculum. SETTING: A final year UK medical school
      objective structured clinical examination (OSCE). METHODS: Four scenarios,
      designed to assess communication skills in challenging contexts, were included in
      the OSCE. Video recordings of all interactions at these stations were screened. A
      sample covering a range of good, average and poor performances were transcribed
      and analysed. Discourse analysis methods were used to identify 'key components of
      communicative style'. FINDINGS: Analysis revealed important differences in
      communicative styles between candidates who scored highly and those who did
      poorly. These related to: empathetic versus 'retractive' styles of communicating;
      the importance of thematically staging a consultation, and the impact of values
      and assumptions on the outcome of a consultation. CONCLUSION: Detailed discourse
      analysis sheds light on patterns of communicative style and provides an analytic
      language for students to raise awareness of their own communication. This
      challenges standard approaches to teaching communication and shows the value of
      using summative assessments in formative ways.

PMID- 12603758
TI  - The effects of testing in shifts on a clinical in-course computerized exam.
AB  - PROBLEM: Testing a large medical class over two days with a single-form computer
      based test has generated questions related to test security and the influence of
      unequal test preparation times afforded by the testing method. METHODS: An
      analysis of variance (anova) design was used to compare the scores for the two
      days for each of the three tests. In addition, a within-student match-paired t
      test of standard score differences was used to examine the relative standing of
      students across tests administered on different days. RESULTS: Both the anova and
      the match-paired t-test failed to detect a difference between first and second
      day testing. CONCLUSION: This research suggests that using a single test form
      with shift-based computerised assessments, spread over as many as two days, does
      not seriously compromise the integrity of the results. Since creating multiple
      unique-item forms is often not possible, shift-based testing with a single test
      form appears to be a fair method of accommodating a large number of students.

PMID- 12603759
TI  - Reliability and validity of the direct observation clinical encounter examination
      (DOCEE).
AB  - CONTEXT: The College of Medicine and Medical Sciences at the Arabian Gulf
      University, Bahrain, replaced the traditional long case/short case clinical
      examination on the final MD examination with a direct observation clinical
      encounter examination (DOCEE). Each student encountered four real patients. Two
      pairs of examiners from different disciplines observed the students taking
      history and conducting physical examinations and jointly assessed their clinical
      competence. OBJECTIVES: To determine the reliability and validity of the DOCEE by
      investigating whether examiners agree when scoring, ranking and classifying
      students; to determine the number of cases and examiners necessary to produce a
      reliable examination, and to establish whether the examination has content and
      concurrent validity. SUBJECTS: Fifty-six final year medical students and 22
      examiners (in pairs) participated in the DOCEE in 2001. METHODS: Generalisability
      theory, intraclass correlation, Pearson correlation and kappa were used to study
      reliability and agreement between the examiners. Case content and Pearson
      correlation between DOCEE and other examination components were used to study
      validity. RESULTS: Cronbach's alpha for DOCEE was 0.85. The intraclass and
      Pearson correlation of scores given by specialists and non-specialists ranged
      from 0.82 to 0.93. Kappa scores ranged from 0.56 to 1.00. The overall intraclass
      correlation of students' scores was 0.86. The generalisability coefficient with
      four cases and two raters was 0.84. Decision studies showed that increasing the
      cases from one to four improved reliability to above 0.8. However, increasing the
      number of raters had little impact on reliability. The use of a pre-examination
      blueprint for selecting the cases improved the content validity. The
      disattenuated Pearson correlations between DOCEE and other performance measures
      as a measure of concurrent validity ranged from 0.67 to 0.79. CONCLUSIONS: The
      DOCEE was shown to have good reliability and interrater agreement between two
      independent specialist and non-specialist examiners on the scoring, ranking and
      pass/fail classification of student performance. It has adequate content and
      concurrent validity and provides unique information about students' clinical
      competence.

PMID- 12603760
TI  - Medical teachers' concerns about the clinical teaching context.
AB  - INTRODUCTION: Despite several unique aspects of the medical teacher's role
      compared to other teachers in higher education, there has been little research in
      this area. In particular there have been few studies which have explored
      teachers' perspectives on their role. This study aimed to elicit teachers'
      perceptions of the teaching environment in a single medical school at a time of
      curriculum change. METHODS: As part of an ethnographic study to explore the
      culture of the school, 22 teachers took part in in-depth, semi-structured
      interviews to ascertain their views and experiences of teaching. Additional data
      were collected through participant observation of curriculum meetings, and
      informal data collection. The data were analysed using a grounded approach, which
      resulted in over 200 analytic codes being assigned, which were later grouped into
      six main themes. RESULTS: The strongest themes to emerge were teachers' concerns
      about the students, the infrastructure for teaching and their relationship with
      the medical school. These included concerns about the lack of student clerking
      activity, insufficient monitoring of students, poor support or recognition of
      teaching and a perceived lack of inclusion in the medical school. DISCUSSION: The
      structure and culture within the medical school and associated hospital trust
      appeared to offer little support for doctors in their teaching role. This
      suggested that teaching was not highly valued. Teachers were preoccupied with the
      practical issues of teaching, leaving little time to consider more fundamental
      educational issues. These findings have implications for the quality of teaching
      and implementation of curricular change.

PMID- 12603761
TI  - What impact will the 'conversion' of two district general hospitals into teaching
      hospitals have? Views from the field.
AB  - AIM: To gather opinions from a variety of healthcare professionals in Birmingham
      and the Black Country as to the potential impact of 'converting' 2 district
      general hospitals into teaching hospitals. METHODS: Thirty-three semi-structured
      interviews were conducted with healthcare professionals including Directors of
      Public Health, Community Health Council Chief Officers, Trust Chief Executives,
      medical directors, trust managerial and consultant staff, junior doctors and
      nurses. Interviewees were asked to outline what they felt the major impacts of
      the 'conversion' to teaching status were likely to be. RESULTS: Five main
      thematic areas were identified from the interviews. Three of these related to the
      medical students receiving their clinical training in the new teaching hospitals,
      the teachers undertaking new or additional teaching duties and the patients being
      treated in the new teaching settings. Interviewees also identified several
      organisational effects relating to the new, established and non-teaching
      hospitals in the locality and discussed potential impacts outside of health care
      settings. CONCLUSIONS: The majority of views expressed by participants were
      positive citing potential benefits from developments in teaching provision. Areas
      of concern generally related to the need for successful implementation of the
      changes within clinically focused environments rather than to the effects of
      teaching per se. The impacts consequent to the reconfiguration of district
      general hospitals to teaching hospitals should be evaluated by appropriately
      designed longitudinal studies.

PMID- 12603762
TI  - Assessing performance in final year medical students. Can a postgraduate measure
      be used in an undergraduate setting?
AB  - BACKGROUND: The transition between medical school and graduate performance should
      be a continuum. This study aimed to evaluate an assessment tool developed for
      practising doctors when applied to undergraduates. METHODS: A 12-item rating form
      was developed from that used for practising doctors by the Royal Australasian
      College of Physicians. Over a 2-year period, senior doctors, junior doctors and
      nurses completed the rating form on final year medical students. Some students
      completed self-assessments. We performed factor analysis and correlated scores
      between raters and attachments. Correlating ratings with concurrent traditional
      assessment results across the year tested construct validity. RESULTS: Ten forms
      per student were distributed for all 123 students and 856 were returned (70%).
      Internal consistency was very high. In all, 71.1% of the variance was accounted
      for by two factors (clinical skills and humanistic). This factor structure is
      unchanged when restricted to different raters and is the same as that noted
      previously when rating practising doctors. There were good correlations between
      raters (including self) and between attachments. Nurse ratings were reliable but
      nurses rated students significantly lower on humanistic qualities. Correlations
      with traditional assessments were high when all traditional assessments were
      combined. Women scored more favourably than men on humanistic qualities.
      CONCLUSION: A rating instrument for doctors in practice retains the same factor
      structure and a high degree of reliability and validity for senior medical
      students. Reliable ratings by nurses have implications for measures of
      collegiality and teamwork. We believe the instrument could be a useful outcome
      measure for medical programmes and employers.

PMID- 12603763
TI  - The perceptions of attending doctors of the role of residents as teachers of
      undergraduate clinical students.
AB  - INTRODUCTION: Much of undergraduate clinical teaching is provided by residents.
      An earlier study showed the attitude of residents towards teaching to be
      generally positive. Little is known, however, about attending doctors' views on
      their own and residents' roles as teachers of medical students. OBJECTIVES: To
      examine attending doctors' perceptions of the (dis)advantages of resident
      teaching, their own teaching abilities and the need for a teacher training
      programme for residents. METHOD: A questionnaire survey of 76 attending doctors
      was carried out in the Departments of Obstetrics & Gynaecology and Paediatrics at
      the teaching hospitals of the Universities of Maastricht and Amsterdam, the
      Netherlands. RESULTS: Attending doctors perceive teaching by residents to be
      beneficial for students and residents alike. Although they consider themselves to
      be better suited than residents to teach medical students, they see teaching as
      an integral part of residency training and feel it should be recognised as such
      by departments and medical schools. Attending doctors are in favour of a teacher
      training programme for residents, which should include communication, clinical
      and teaching skills as well as skills such as time management and (self-)
      assessment. DISCUSSION: Despite the uneven distribution of participants between
      the departments, no significant differences were found between departments. It is
      interesting that attending doctors perceive teacher training as beneficial to
      residents' teaching skills, but provide more feedback on residents' attitudes
      than on their teaching. The results show that, in general, attending doctors
      share residents' views that teaching is an important component of residency and
      that a teacher training programme for residents is to be recommended.

PMID- 12603764
TI  - Early introduction to interprofessional learning: a simulated ward environment.
AB  - OBJECTIVES: To develop an interprofessional simulated ward environment for junior
      medical and nursing students and to identify themes for future evaluations and
      modify criteria for formative assessment of the exercise. SUBJECTS: Second year
      medical and nursing students. SETTING: The multiprofessional Clinical Skills
      Centre at the Faculty of Medicine, and Nursing, University of Dundee, Scotland.
      METHOD: A simulated ward environment was created in the Clinical Skills Centre
      around patients with common medical conditions. Students were allocated to
      interprofessional teams and, after a briefing given in the form of a ward report,
      were asked to take responsibility for the ward for 'a shift'. Observers from the
      Schools of Medicine and Nursing charted their progress in relation to evidence of
      collaborative team working, effective leadership, the ability to prioritise
      workload and competence in clinical performance. Evaluations of the exercise were
      taken from all participants. The criteria for formative assessment were reviewed
      by the observers after the exercise and a focus group was used to generate
      additional criteria and modify those piloted. RESULTS: The exercise was perceived
      positively by all participating groups. Themes for evaluation of future exercises
      and modified criteria for future assessment were identified. CONCLUSIONS: The
      exercise gave students their first experience of participating independently in a
      realistic and safe operational ward setting. It proved to be a powerful learning
      experience for the students.

PMID- 12603765
TI  - Application of a responsive evaluation approach in medical education.
AB  - INTRODUCTION: This paper reports on the usefulness of a responsive evaluation
      model in evaluating the clinical skills assessment and training (CSAT) programme
      at the Faculty of Medicine, Memorial University of Newfoundland, Canada. The
      purpose of this paper is to introduce the responsive evaluation approach,
      ascertain its utility, feasibility, propriety and accuracy in a medical education
      context, and discuss its applicability as a model for medical education programme
      evaluation. METHODS: Robert Stake's original 12-step responsive evaluation model
      was modified and reduced to five steps, including: (1) stakeholder audience
      identification, consultation and issues exploration; (2) stakeholder concerns and
      issues analysis; (3) identification of evaluative standards and criteria; (4)
      design and implementation of evaluation methodology; and (5) data analysis and
      reporting. This modified responsive evaluation process was applied to the CSAT
      programme and a meta-evaluation was conducted to evaluate the effectiveness of
      the approach. RESULTS: The responsive evaluation approach was useful in
      identifying the concerns and issues of programme stakeholders, solidifying the
      standards and criteria for measuring the success of the CSAT programme, and
      gathering rich and descriptive evaluative information about educational
      processes. The evaluation was perceived to be human resource dependent in nature,
      yet was deemed to have been practical, efficient and effective in uncovering
      meaningful and useful information for stakeholder decision-making. CONCLUSIONS:
      Responsive evaluation is derived from the naturalistic paradigm and concentrates
      on examining the educational process rather than predefined outcomes of the
      process. Responsive evaluation results are perceived as having more relevance to
      stakeholder concerns and issues, and therefore more likely to be acted upon.
      Conducting an evaluation that is responsive to the needs of these groups will
      ensure that evaluative information is meaningful and more likely to be used for
      programme enhancement and improvement.

PMID- 12603766
TI  - Simulation in surgical training: educational issues and practical implications.
AB  - BACKGROUND: Surgical skills are required by a wide range of health care
      professionals. Tasks range from simple wound closure to highly complex diagnostic
      and therapeutic procedures. Technical expertise, although essential, is only one
      component of a complex picture. By emphasising the importance of knowledge and
      attitudes, this article aims to locate the acquisition of surgical skills within
      a wider educational framework. SIMULATORS: Simulators can provide safe, realistic
      learning environments for repeated practice, underpinned by feedback and
      objective metrics of performance. Using a simple classification of simulators
      into model-based, computer-based or hybrid, this paper summarises the current
      state of the art and describes recent technological developments. Advances in
      computing have led to the establishment of precision placement and simple
      manipulation simulators within health care education, while complex manipulation
      and integrated procedure simulators are still in the development phase.
      EVALUATION: Tension often exists between the design and evaluation of surgical
      simulations. A lack of high quality published data is compounded by the
      difficulties of conducting longitudinal studies in such a fast-moving field. The
      implications of this tension are discussed. THE WIDER CONTEXT: The emphasis is
      now shifting from the technology of simulation towards partnership with education
      and clinical practice. This highlights the need for an integrated learning
      framework, where knowledge can be acquired alongside technical skills and not in
      isolation from them. Recent work on situated learning underlines the potential
      for simulation to feed into and enrich everyday clinical practice.

PMID- 12603767
TI  - Students' evaluation of research during medical studies: medical dissertation in
      Germany.

PMID- 12603768
TI  - Measuring self-directed learning.

PMID- 12603772
TI  - JVPT 25 years on.

PMID- 12603774
TI  - Antifungal agents of use in animal health--chemical, biochemical and
      pharmacological aspects.
AB  - A limited number of antifungal agents is licensed for use in animals, however,
      many of those available for the treatment of mycoses in humans are used by
      veterinary practitioners. This review includes chemical aspects, spectra of
      activity, mechanisms of action and resistance, adverse reactions and drug
      interactions of the antifungals in current use.

PMID- 12603775
TI  - Antifungal agents of use in animal health--practical applications.
AB  - The purpose of this paper is to provide an overview of antifungal agents
      currently in use in veterinary medicine. The practical applications and the
      therapeutic regimens that have proved successful in the treatment and prevention
      of fungal infections in dogs and cats, cattle and sheep, horse, pig, poultry and
      other birds, rodents, rabbits and fur animals are summarized.

PMID- 12603776
TI  - A physiologically based pharmacokinetic model for oxytetracycline residues in
      sheep.
AB  - A physiologically based pharmacokinetic model (PBPK) for oxytetracycline (OTC)
      residues in sheep was developed using previously published data from a combined
      serum pharmacokinetic and tissue residue study [Craigmill et al. (2000) J. Vet.
      Pharmacol. Ther.23, 345]. Physiological parameters for organ weights and tissue
      blood flows were obtained from the literature. The tissue/serum partition
      coefficients for OTC were estimated from the serum and tissue residue data
      obtained at slaughter. The model was developed to include all of the tissues for
      which residue data were available (serum, kidney, liver, fat, muscle and
      injection site), and all of the remaining tissues were combined into a slowly
      perfused compartment with low permeability. Total body clearance of OTC
      calculated in the previous study was used as the starting value for clearance in
      the PBPK model, with the kidney being the only eliminating organ. The model was
      built using ACSL (Advanced Continuous Simulation Language) Graphic Modeler, and
      the model was fit to the serum and tissue data using the ACSL Math/Optimizer
      software (AEgis Technologies Group, Inc., Huntsville, AL, USA). A sensitivity
      analysis was also performed to determine which parameters had the greatest effect
      on the goodness of fit. Numerous strategies were tested to model the injection
      site, and a model providing a biexponential absorption of the drug from the
      injection bolus gave the best fit to the experimental data. The model was
      validated using the clearance parameters calculated from the traditional
      pharmacokinetic model for each individual animal in the PBPK model. This simple
      PBPK model well predicted OTC residues in sheep tissues after intramuscular
      dosing with a long-acting preparation and may find use for other species and
      other veterinary drugs.

PMID- 12603777
TI  - Influence of Escherichia coli endotoxin-induced fever on the pharmacokinetic
      behavior of marbofloxacin after intravenous administration in goats.
AB  - The pharmacokinetic behavior of marbofloxacin was studied in seven healthy goats
      and in the same goats with induced fever after single-dose intravenous (i.v.)
      administration of 2 mg/kg b.w. Fever was induced by the administration of
      Escherichia coli endotoxin. Drug concentration in plasma was determined by high
      performance liquid chromatography (HPLC). Drug distribution was somehow altered
      by fever as febrile goats showed a volume of distribution at steady-state (Vss =
      0.72 +/- 0.15 L/kg) lower than normal goats (Vss = 1.19 +/- 0.33 L/kg). The
      elimination of the drug was also modified. Total plasma clearance (Cl) decreased
      from 0.24 +/- 0.12 L/kg/h in healthy animals to 0.13 +/- 0.05 L/kg/h in animals
      with endotoxin-induced fever, which is related to an increase in the area under
      the plasma concentration-time curve (AUC). Consequently, mean residence time
      (MRT) was also slightly increased in sick animals (MRT = 5.28 +/- 00.99 and 6.09
      +/- 01.45 h, in healthy and febrile animals, respectively).

PMID- 12603778
TI  - Postoperative analgesia in dogs receiving epidural morphine plus medetomidine.
AB  - This investigation was carried out to compare the postoperative analgesia and
      plasma morphine concentrations in dogs given epidural morphine or epidural
      morphine combined with medetomidine prior to surgery. Twelve dogs (seven males
      and five females) with ruptured cranial cruciate ligaments presented to the
      Washington State University Veterinary Teaching Hospital. Six dogs received an
      epidural injection of morphine (0.1 mg/kg) and six dogs received epidural
      morphine (0.1 mg/kg) combined with medetomidine (0.005 mg/kg). Numeric rating
      scale (NRS) pain scores and cumulative pain scores (CPS) were assigned to 10-min
      segments of video. Video segments, heart rates and respiratory rates were
      recorded prior to premedication and at 4, 8, 12, 18 and 24 h after epidural
      injection. Blood was sampled from the cephalic vein at each of these times and
      during anesthesia at 0.5, 1, 2 and 3 h after epidural injection. Data were
      analyzed using either Friedman's test or one-way anova for repeated measures. In
      the morphine group, significant increases compared with premedication values were
      detected at 4, 8 and 12 h after epidural injection for NRS and at 4 and 12 h
      after epidural injection for CPS. In the morphine plus medetomidine group, NRS
      was significantly higher at 4 and 8 h whereas there were no differences from
      baseline values for CPS. Plasma morphine concentrations were not significantly
      different between treatment groups, but were significantly increased compared
      with preinjection values at 0.5, 1, 12, 18, and 24 h in the morphine plus
      medetomidine group. Epidurally administered morphine combined with medetomidine
      was associated with only minor benefits based on subjective pain scoring when
      compared with morphine alone in these dogs undergoing repair of a ruptured
      cranial cruciate ligament.

PMID- 12603781
TI  - Patterns of performance degradation and restoration during sleep restriction and
      subsequent recovery: a sleep dose-response study.
AB  - Daytime performance changes were examined during chronic sleep restriction or
      augmentation and following subsequent recovery sleep. Sixty-six normal volunteers
      spent either 3 (n = 18), 5 (n= 16), 7 (n = 16), or 9 h (n = 16) daily time in bed
      (TIB) for 7 days (restriction/augmentation) followed by 3 days with 8 h daily TIB
      (recovery). In the 3-h group, speed (mean and fastest 10% of responses) on the
      psychomotor vigilance task (PVT) declined, and PVT lapses (reaction times greater
      than 500 ms) increased steadily across the 7 days of sleep restriction. In the 7-
      and 5-h groups speed initially declined, then appeared to stabilize at a reduced
      level; lapses were increased only in the 5-h group. In the 9-h group, speed and
      lapses remained at baseline levels. During recovery, PVT speed in the 7- and 5-h
      groups (and lapses in the 5-h group) remained at the stable, but reduced levels
      seen during the last days of the experimental phase, with no evidence of
      recovery. Speed and lapses in the 3-h group recovered rapidly following the first
      night of recovery sleep; however, recovery was incomplete with speed and lapses
      stabilizing at a level comparable with the 7- and 5-h groups. Performance in the
      9-h group remained at baseline levels during the recovery phase. These results
      suggest that the brain adapts to chronic sleep restriction. In mild to moderate
      sleep restriction this adaptation is sufficient to stabilize performance,
      although at a reduced level. These adaptive changes are hypothesized to restrict
      brain operational capacity and to persist for several days after normal sleep
      duration is restored, delaying recovery.

PMID- 12603782
TI  - Rapid tryptophan depletion reverses phenelzine-induced suppression of REM sleep.
AB  - Treatment with the monoamine oxidase inhibitor phenelzine completely suppressed
      rapid eye movement (REM) sleep in five depressed patients. Hypothesizing that
      increased serotonergic neurotransmission eliminated REM sleep, we administered a
      tryptophan-free amino acid drink (TFD) known to reduce plasma tryptophan and
      brain levels of serotonin. The TFD reversed the REM sleep suppression, while the
      control drink (TFD plus tryptophan) had virtually no effect on sleep. Neither TFD
      nor control drink affected mood, total sleep time, sleep efficiency or the all
      night electroencephalogram power spectra in non-rapid eye movement (NREM) sleep.
      We report the first non-disruptive, double-blind method for studying human
      subjects overnight with and without REM sleep. It opens up a novel strategy for
      investigating the functions of REM sleep, and the roles of serotonin and REM
      sleep in the regulation of NREM sleep and mood.

PMID- 12603783
TI  - Effect of infant sleeping position on sleep spindles.
AB  - Sleep spindles play an active role in inducing and maintaining sleep and may
      affect arousal by blocking the transmission of external stimuli through the
      thalamus to the cortex. Previously we have demonstrated that sleeping in the
      prone position impairs arousal in infants at 2-3 months of age, but not at 5-6
      months. We aimed to examine if sleeping position and postnatal age affected
      duration and/or density of sleep spindles. Twenty-one healthy term infants were
      studied using daytime polysomnography at 2-3 months and 16 were again studied at
      5-6 months. Infants slept both prone and supine at each study. The mean duration
      of non-rapid eye movement (NREM) sleep was not different between the two studies
      in either position. At 2-3 months both spindle density (P < 0.001) and proportion
      of NREM sleep (P < 0.025) with spindles were significantly greater in the supine
      than in the prone position. At 5-6 months spindle duration was longer in the
      supine than in the prone position (P < 0.03). Spindle density in the supine
      position was not different between the two studies, however, when infants slept
      prone, it was significantly increased at 5-6 months compared with 2-3 months (P <
      0.001). Arousal threshold was not correlated with either spindle density or
      percentage of NREM sleep with spindles in either position at either study. In
      this study spindle density and the percentage time spent with spindles were not
      well correlated with infant arousability, and hence may not be able to be used as
      markers of depressed arousal responses in infants.

PMID- 12603784
TI  - The ontogeny of mammalian sleep: a reappraisal of alternative hypotheses.
AB  - Newborn mammals spend as much as 90% or more of their time in a sleep state
      characterized by frequent twitches, rapid eye movements (REMs), and irregular
      respiratory cycles. These motor and respiratory patterns resemble the phasic
      motor/respiratory components of adult REM sleep, and as a consequence, this sleep
      state is traditionally viewed as an immature form of REM sleep. An alternative
      view is that a significant portion of what has been called REM sleep in these
      species is a form of spontaneous activity typical of the immature nervous system.
      In this review, we compare and contrast these two opposing views about the
      ontogenetic origins of REM sleep, and review the evidence most often cited to
      support the idea that REM sleep is present in newborn altricial mammals. Critical
      review of this evidence indicates that REM sleep may not be present at birth in
      these species; rather, it appears that all mammals early in development exhibit
      spontaneous, dissociated activity that progressively becomes organized into the
      distinct states of REM and non-rapid eye movement sleep.

PMID- 12603785
TI  - Sleep complaints are not corroborated by objective sleep measures in post
      traumatic stress disorder: a 1-year prospective study in survivors of motor
      vehicle crashes.
AB  - Disturbed sleep is a common complaint among patients with post-traumatic stress
      disorder (PTSD). However, laboratory studies of sleep in PTSD have provided
      inconsistent evidence of objective sleep disturbances. A major shortcoming of
      most previous studies is the fact that they were performed retrospectively in
      patients with chronic PTSD, often complicated by comorbid psychiatric disorders
      and drug abuse. Thus, little is known about the development of sleep disturbances
      in recently traumatized subjects. In this study, 102 motor vehicle collision
      (MVC) survivors were followed from the time of collision throughout 1 year.
      Nineteen subjects hospitalized for elective surgery served as a comparison group.
      Subjective quality of sleep was assessed using the mini-Sleep Questionnaire and
      the Sleep Habit Questionnaire. In addition, a 48-h actigraphic recording was
      obtained 1 week, 3 and 12 months after the collision. At 12 months, a structured
      clinical interview (SCID) was administered to reach a formal diagnosis of PTSD.
      Twenty-six of the MVC survivors, but none of the comparison subjects, met the
      diagnostic criteria for PTSD. While MVC survivors with PTSD reported markedly
      poorer sleep as reflected by significantly higher scores on the mini-Sleep
      Questionnaire, there were no significant differences between the three groups on
      the actigraphic measures that were largely normal. These results, which were
      obtained in subjects with no evidence of active psychiatric symptoms at the time
      of trauma and free of psychotropic or hypnotic medications, further support
      previous polysomnographic (PSG) studies suggesting that altered sleep perception,
      rather than sleep disturbance per se, may be the key problem in PTSD.

PMID- 12603786
TI  - Daytime testing after laboratory or home-based polysomnography: comparisons of
      middle-aged insomnia sufferers and normal sleepers.
AB  - Many studies have shown only modest differences between insomnia sufferers and
      matched, non-complaining normal controls in regard to their levels of daytime
      sleepiness and diurnal performances. The current study was conducted to determine
      whether such daytime comparisons might be affected by the setting (home vs. sleep
      lab) in which study participants sleep on the nights before such testing. The
      study used a counter-balanced, matched-group design in which participants
      underwent three consecutive nocturnal polysomnographs (PSG) conducted either in
      the sleep lab or in their homes prior to undergoing daytime multiple sleep
      latency test (MSLT) and computer-administered performance testing. The study
      participants were 35 (18 women and 17 men) middle-aged (40-59 years) non
      complaining normal sleepers and 33 middle-aged insomnia sufferers (17 women and
      16 men) who met structured interview criteria for persistent primary insomnia.
      Use of a hierarchical linear statistical model showed only insomnia sufferers who
      underwent nocturnal home PSG were more alert on the MSLT than were normal
      sleepers who underwent lab PSG. However, these insomnia sufferers showed a
      greater propensity toward attention lapses on selected reaction time tests than
      did either of the two normal control groups (i.e. either those who slept in the
      lab or those who slept at home). The results suggest the nocturnal sleep setting
      (home vs. lab) may affect subsequent MSLT and performance test comparisons of
      insomnia sufferers and normal sleepers.

PMID- 12603787
TI  - Combined index of heart rate variability and oximetry in screening for the sleep
      apnoea/hypopnoea syndrome.
AB  - Many sleep centres employ a preliminary screening test in order to reduce the
      number of polysomnographies required in the routine diagnosis of the sleep
      apnoea/hypopnoea syndrome (SAHS). We investigated the combination of heart rate
      and oximetry information as a means of performing this test. A retrospective
      study of 100 patients with suspected SAHS was made. All patients had in-hospital
      polysomnography on one night. We estimated the number of respiratory event
      related arousals by counting the number of autonomic arousals (assessed on the
      basis of changes in the heart interbeat interval) that were coincident with a
      rise in oximetry. The hourly index of such events was denoted the "cardiac
      oximetry disturbance index" (CODI). The median apnoea/hypopnoea index (AHI) was
      16.5 (range 1.0-93.6) h-1. The CODI correlated significantly with the AHI
      (Spearman correlation coefficient rs = 0.88, P < 0.01), and the area (+/-
      standard error) under the receiver operating characteristic (ROC) was 0.94 +/-
      0.05. Oximetry alone (based on 4% dips) was a less effective screening test (rs =
      0.80, P < 0.01; area under ROC 0.83 +/- 0.06). Using 2% dips in oximetry offered
      comparable performance with the CODI (rs = 0.91, P < 0.01; area under ROC 0.93 +/
      0.04). The CODI was better correlated with the electroencephalograph arousal
      index (rs = 0.84, P < 0.01) than was oximetry (2% dips, rs = 0.57, P < 0.01). The
      CODI algorithm also offers an informal measure of self-validation: a large
      discrepancy between the number of autonomic arousals and the number of rises in
      oximetry indicates the presence of autonomic arousals without changes in oximetry
      (or vice versa). This self-validation mechanism identified several patients in
      this study, and may be useful in identifying sleep disruption due to chronic pain
      or other causes.

PMID- 12603788
TI  - Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal
      subjects.
AB  - To investigate the pathophysiology of narcoleptic patients' sleep in detail, we
      analysed and compared the whole-night polysomnograms of narcoleptic patients and
      normal human subjects. Eight drug-naive narcoleptic patients and eight age
      matched normal volunteers underwent polysomnography (PSG) on two consecutive
      nights. In addition to conventional visual scoring of the polysomnograms, rapid
      eye movement (REM)-density and electroencephalograph (EEG) power spectra analyses
      were also performed. Sleep onset REM periods and fragmented nocturnal sleep were
      observed as expected in our narcoleptic patients. In the narcoleptic patients,
      REM period duration across the night did not show the significant increasing
      trend that is usually observed in normal subjects. In all narcoleptic patient REM
      periods, eye movement densities were significantly increased. The power spectra
      of narcoleptic REM sleep significantly increased between 0.3 and 0.9 Hz and
      decreased between 1.0 and 5.4 Hz. Further analysis revealed that non-rapid eye
      movement (NREM) period duration and the declining trend of delta power density in
      the narcoleptic patients were not significantly different from the normal
      subjects. Compared with normal subjects, the power spectra of narcoleptic NREM
      sleep increased in the 1.0-1.4 Hz and 11.0-11.9 Hz frequency bands, and decreased
      in a 24.0-26.9 Hz frequency band. Thus, increased EEG delta and decreased beta
      power densities were commonly observed in both the NREM and REM sleep of the
      narcoleptic patients, although the decrease in beta power during REM sleep was
      not statistically significant. Our visual analysis revealed fragmented nocturnal
      sleep and increased phasic REM components in the narcoleptic patients, which
      suggest the disturbance of sleep maintenance mechanism(s) and excessive effects
      of the mechanism(s) underlying eye movement activities during REM sleep in
      narcolepsy. Spectral analysis revealed significant increases in delta components
      and decreases in beta components, which suggest decreased activity in central
      arousal mechanisms. These characteristics lead us to hypothesize that two
      countervailing mechanisms underlie narcoleptic sleep pathology.

PMID- 12603789
TI  - Periodic limb movement disorder of sleep in children.
AB  - To characterize periodic limb movement disorder (PLMD) in a cohort of prepubertal
      children we examined sleep-related identifiable differences between children with
      PLMD and attention-deficit/hyperactivity disorder (ADHD), PLMD alone, and age
      matched controls. Children were selected from a chart review of all children
      referred to a pediatric sleep medicine center and from a community survey of 5-7
      year-old-children. Polysomnography (PSG) and parental report data from all
      children identified as having periodic limb movement index (PLMI) >5 were
      reviewed and compared with a cohort of age-matched controls. A total of 8.4% of
      children in the clinic-referred sample, and 11.9% of the children recruited from
      the community had PLMI >5. Of those, 44.4% were identified as having ADHD.
      Children with PLMD had significantly lower percentage of rapid eye movement (REM)
      than control children (P < 0.001). Children in the PLMD/ADHD group had a
      significantly greater number of arousals associated with PLM (PLMa) than children
      with PLMD only (P < 0.05). While a relationship between ADHD and PLMD was
      observed, it was weaker than previous reports (Chervin, R. D. et al. Sleep, 2002;
      25: 213; Chervin, R. D. and Archbold, K. H. Sleep, 2001; 24: 313; Picchietti et
      al. J. Child Neurol., 1999; 13: 588; Picchietti et al. Mov. Disord., 1999; 14:
      1000; Picchietti and Walters Sleep, 1999; 22: 297). Children in the PLMD/ADHD
      group were more likely to have PLMas than were children with PLMD only. We
      postulate that rather than a direct relationship between ADHD and PLMD, this link
      may be mediated by the presence of reduced REM sleep and more importantly by the
      sleep fragmentation associated with PLM-induced arousals.

PMID- 12603790
TI  - CSF hypocretin (Orexin) in neurological and psychiatric conditions.

PMID- 12603792
TI  - Is there an increase in the prevalence of autism spectrum disorders?
AB  - This report summarizes recent prevalence estimates for autism spectrum disorders
      and outlines possible reasons for an apparent increase in the numbers of children
      diagnosed with autism and Asperger syndrome.

PMID- 12603793
TI  - Hepatitis A vaccination options for Australia.
AB  - The epidemiology of hepatitis A is changing, with an increasing proportion of the
      population becoming susceptible to infection. The burden of hepatitis A is
      comparable to that of other vaccine-preventable diseases for which new vaccines
      are available. Options for vaccination include selective programmes for high-risk
      groups, which could involve screening prior to vaccination, or universal
      programmes for infants and/or adolescents. Selective programmes have been shown
      to be highly cost-effective if well implemented, but there is evidence that they
      might be poorly implemented. If a universal vaccination programme were considered
      for Australia, an infant programme, with doses at 18 months and 2 years, possibly
      with an additional adolescent programme, would be the recommended option.
      Universal hepatitis A vaccination for infants and/or adolescents is of comparable
      cost-effectiveness compared with other preventive strategies, but needs to be
      considered in the context of competing vaccination options.

PMID- 12603794
TI  - Use of bisphosphonate therapy for osteoporosis in childhood and adolescence.
AB  - Congenital and acquired forms of osteoporosis in childhood and adolescence can
      result in morbidity from fracture and pain in childhood, and place an individual
      at significant risk for problems in adult life. A range of therapies exist for
      the prevention and treatment of osteoporosis, including optimization of daily
      calcium intake, adequate vitamin D status, weight-bearing exercise, treatment
      with sex steroids where delayed puberty is a problem and, more recently, use of
      bisphosphonate therapy. Intravenous pamidronate therapy (a bisphosphonate) has
      been shown to reduce fractures and improve bone density in children with
      osteogenesis imperfecta, and might prove to be of benefit in other osteoporotic
      conditions in childhood. However, a number of issues regarding the optimal use of
      bisphosphonate therapy in children and adolescents remain to be resolved,
      including total annual dose and frequency and duration of administration.
      Bisphosphonate therapy should, therefore, be used only in the context of a well
      run clinical programme with specialist knowledge in the management of osteopenic
      disorders in childhood.

PMID- 12603795
TI  - Community based services and the needs of families: is there a mismatch?

PMID- 12603796
TI  - Maternal and Infant Services: examination of access in a culturally diverse
      community.
AB  - OBJECTIVES: The aim of this study was to evaluate access of resident immigrant
      families from a non-English speaking background to Maternal and Infant Services
      operated by Community Health Services in south-western Sydney. METHODS: An
      ecological study compared the demographic characteristics of mothers with an
      infant aged less than 12 months in three separate data collections. These were a
      3-month Community-based Health Services Census, the 1996 Midwives Data Collection
      and the ABS 1996 Census of Population and Housing. RESULTS: Information was
      collected from 2048 infants and their families who were newly registered with
      Maternal and Infant Services. Approximately 75% of newborn infants were
      registered with services. Women who were born in a non-English-speaking country
      were over-represented in the data. For both overseas and Australian-born women
      those who left school aged less than 17 years were under-represented compared
      with analysis of the related data systems. CONCLUSIONS: The data suggest that
      migrant women from non-English-speaking backgrounds are accessing Maternal and
      Infant Services. However, innovative approaches for service delivery are
      indicated for women who may be considered socially disadvantaged, irrespective of
      their ethnic or cultural backgrounds.

PMID- 12603797
TI  - Risk factors for iron deficiency in a hospitalized urban New Zealand population.
AB  - OBJECTIVE: To determine which dietary practices and sociodemographic factors are
      associated with iron deficiency anaemia (IDA) and iron deficiency (ID) in
      hospitalized New Zealand children. METHODOLOGY: A prospective study of children 8
      23 months of age hospitalized with an acute illness from 1997 to 1999. Iron
      deficiency was defined as abnormal values for two out of three of serum ferritin
      (< 10 micro g/L), serum iron saturation (< 10%) and red cell distribution width
      (> 14.5%). Iron deficiency anaemia (IDA) was defined as ID + serum haemoglobin
      concentration <110 g/L. Those with IDA or ID were compared separately with those
      who were not iron deficient. RESULTS: Three hundred and ninety-one children were
      enrolled. Two hundred and twenty had IDA, 73 had ID and 98 were not iron
      deficient. In a multivariate analysis, those children who had a diagnosis of
      pneumonia (odds ratio 4.43, 95% CI 1.49, 13.13) were Pacific (odds ratio 6.31,
      95% CI 2.14, 18.63), were currently drinking breast milk (odds ratio 10.22, 95%
      CI 2.95, 35.42), had a mother who restricted her meat intake during pregnancy
      (odds ratio 4.40, 95% CI 1.53, 12.64) or lived in a household with more than
      three children (odds ratio 7.42, 95% CI 1.88, 29.34) were at increased risk of
      IDA. Those children who were Pacific (odds ratio 5.44, 95% CI 1.37, 21.65) or who
      drank tea (odds ratio 7.88, 95% CI 1.10, 56.33) were at increased risk of ID.
      Those with a diagnosis of gastroenteritis (odds ratio 0.16, 95% CI 0.03, 0.75)
      were at decreased risk of ID. CONCLUSIONS: Both dietary and non-dietary factors
      are associated with an increased risk of IDA and ID in New Zealand children. In
      this hospitalized sample, more non-dietary than dietary factors were associated
      with poor iron status.

PMID- 12603798
TI  - Acute liver failure in children: A regional experience.
AB  - OBJECTIVE: To review the outcome of acute liver failure (ALF) and the effect of
      liver transplantation in children in Australia. METHODOLOGY: A retrospective
      review was conducted of all paediatric patients referred with acute liver failure
      between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric
      liver transplant centre based at the Royal Children's Hospital, Brisbane, that is
      one of three paediatric transplant centres in Australia. RESULTS: Twenty-six
      patients were referred with ALF. Four patients did not require transplantation
      and recovered with medical therapy while two were excluded because of
      irreversible neurological changes and died. Of the 20 patients considered for
      transplant, three refused for social and/or religious reasons, with 17 patients
      listed for transplantation. One patient recovered spontaneously and one died
      before receiving a transplant. There were 15 transplants of which 40% (6/15) were
      < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after
      transplantation. Forty per cent (6/15) survived more than 6 months after
      transplant. There were only four long-term survivors after transplant for ALF
      (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16
      patients that died, 44% (7/16) were from neurological causes. Most of these were
      from cerebral oedema but two patients transplanted for valproate hepatotoxicity
      died from neurological disease despite good graft function. CONCLUSIONS:
      Irreversible neurological disease remains a major cause of death in children with
      ALF. We recommend better patient selection and early referral and transfer to a
      transplant centre before onset of irreversible neurological disease to optimize
      outcome of children transplanted for ALF.

PMID- 12603799
TI  - Paediatric bronchiectasis in the twenty-first century: experience of a tertiary
      children's hospital in New Zealand.
AB  - OBJECTIVE: Despite its decline in developed countries, bronchiectasis appeared to
      be a common diagnosis in Auckland, New Zealand children. The aims of this study
      were: to document the number of children in Auckland with bronchiectasis, their
      severity, clinical characteristics and possible aetiologies; to assess whether
      there was a relationship between ethnicity and poverty; and to estimate a crude
      bronchiectasis prevalence rate for New Zealand. METHODS: A retrospective review
      of the case histories of all children attending a tertiary children's hospital in
      Auckland with bronchiectasis diagnosed by high-resolution chest computed
      tomography (CT) scan, during the period 1998-2000 was undertaken. Data collected
      included patient demographics, number of hospitalizations pre- and post
      diagnosis, lung function tests, radiology and investigations. The New Zealand
      deprivation 1996 index was applied to the data to obtain a measure of socio
      economic status. RESULTS: Bronchiectasis was found to be common, with an
      estimated prevalence of approximately one in 6000 in the Auckland paediatric
      population. It was disproportionately more common in the Pacific Island and Maori
      children. In Pacific Island children, bronchiectasis not caused by cystic
      fibrosis was nearly twice as common in the general population than cystic
      fibrosis. Socio-economic deprivation and low immunization rates may be
      significant contributing factors. The bronchiectasis seen was extensive. Ninety
      three percent had bilateral disease and 64% had involvement of four or more lobes
      on chest CT scan. A wide range of comorbidities and underlying aetiologies were
      evident. CONCLUSIONS: Paediatric bronchiectasis in Auckland, New Zealand, is
      common but underresourced. Only the most severe cases are being recognized,
      providing a significant challenge for paediatric health professionals.

PMID- 12603800
TI  - Epidemiology of childhood nocturnal enuresis in Malaysia.
AB  - OBJECTIVES: To estimate the prevalence of nocturnal enuresis in primary school
      children in Malaysia and to determine the factors associated with primary
      nocturnal enuresis. METHODS: This was a cross-sectional survey. A total of 3371
      self-administered questionnaires were distributed to parents of children aged 7,
      9 and 12 years attending four primary schools in the city. The ICD-10 definition
      of enuresis was used. RESULTS: From an overall response rate of 73.8%, nocturnal
      enuresis was reported in 200 children (8%), primary nocturnal enuresis in 156
      children (6.2%) and secondary nocturnal enuresis in 44 children (1.8%). Fifty
      three percent of those with primary enuresis had a positive family history, and
      54% had two or more wet nights per week. Eighty-seven percent had not sought any
      form of treatment despite 74% admitting to being embarrassed. Using logistic
      regression analysis, only three factors were significant predictors of primary
      nocturnal enuresis. These were: (i) younger age (P < 0.001); (ii) male sex (P <
      0.033); and (iii) Indian ethnic group (P < 0.044) compared to Chinese.
      CONCLUSION: The prevalence of nocturnal enuresis in urban-dwelling Malaysian
      children is similar to that reported from Korea and Taiwan but appears to be
      lower than that reported from developed countries. Predictive factors associated
      with primary nocturnal enuresis included lower age group, male sex and Indian
      ethnicity.

PMID- 12603801
TI  - Emergency department attendances associated with drug-related problems in
      paediatrics.
AB  - OBJECTIVES: To determine the frequency and characteristics of paediatric
      emergency department attendances associated with drug-related problems (DRP) at
      three Victorian hospitals. METHODS: All paediatric medical patients attending the
      emergency department of the Royal Children's Hospital, Geelong Hospital or Box
      Hill Hospital were considered for inclusion. The investigator and attending
      medical practitioners screened eligible patients. A multidisciplinary panel
      reviewed collated data. Causality, preventability and clinical significance
      classifications were established by the panel. RESULTS: Combining data from the
      three hospitals, over 18 weeks of data collection, a total of 8601 patients met
      the eligibility criteria. Of these, 280 (3.3%, 95% CI 2.9-3.7%) were determined
      to have emergency department attendances associated with DRP. Of the 187 cases
      assessed for preventability, 51.3% were judged to be preventable. CONCLUSIONS:
      Emergency department attendances are associated with DRP in paediatrics. Given
      that the need to prevent DRP in adults is recognized, it is now time to act to
      reduce the consequences of DRP in paediatrics.

PMID- 12603802
TI  - Television, computer use and body mass index in Australian primary school
      children.
AB  - OBJECTIVE: To investigate relationships between children's body mass index (BMI)
      and parent reports of children's television and video game/computer habits,
      controlling for other potential risk factors for paediatric obesity. METHODS:
      Child BMI was calculated from measured height and weight collected in 1997 as
      part of a large, representative, cross-sectional study of children in Victoria,
      Australia. Parents reported the amount of time children watched television and
      used video games/computers, children's eating and activity habits, parental BMI
      and sociodemographic details. RESULTS: A total of 2862 children aged 5-13 years
      participated. Child mean BMI z-score was significantly related to television (F =
      10.23, P < 0.001) but not video game/computer time (F = 2.23, P = 0.09), but
      accounted for only 1 and 0.2% of total BMI variance, respectively. When parental
      BMI, parental education, number of siblings, food intake, organized exercise and
      general activity level were included, television ceased to be independently
      significantly related to child BMI. Using adjusted logistic regression, the odds
      of being overweight and obese generally increased with increasing television
      viewing. No relationship was found for video game/computer use. CONCLUSIONS: A
      small proportion of variance in child BMI was related to television, but not
      video game/computer time. This was far outweighed by the influence of other
      variables. Causal pathways are likely to be complex and interrelated.

PMID- 12603803
TI  - To kill or to let die?

PMID- 12603804
TI  - Evidence-based paediatric practice and its relation to the Cochrane
      Collaboration.

PMID- 12603805
TI  - Using an evidence-based approach to a paediatric problem.

PMID- 12603807
TI  - Intermittent intussusception.

PMID- 12603806
TI  - Evidence-based medicine and clinical practice.

PMID- 12603808
TI  - Intrathoracic gastric volvulus mimicking pyloric stenosis.
AB  - A 5-week-old-infant presented to hospital following the acute onset of non
      bilious vomiting with clinical and acid-base features suggestive of pyloric
      stenosis. A chest radiograph obtained because of intercurrent infection
      unexpectedly revealed a left-sided congenital diaphragmatic hernia. A barium meal
      demonstrated the presence of an intrathoracic gastric volvulus, requiring urgent
      surgical management. We discuss the presentation and management of this rare
      surgical cause of non-bilious vomiting in infancy.

PMID- 12603809
TI  - Coeliac disease and alopecia areata in childhood.
AB  - Coeliac disease is a genetic, immunologically mediated small bowel enteropathy
      that causes malabsorption. The immune inflammatory response to gluten frequently
      causes damage to many other tissues of the body. We report the association of
      coeliac disease and alopecia areata in two children, a 13-year-old girl and a 29
      month-old girl. Both of our patients had immunoglobulin A (IgA) class endomysial
      antibodies, IgA and immunoglobulin G (IgG) antigliadin antibodies and subtotal
      villous atrophy on jejunal biopsy. Administration of a gluten-free diet to our
      patients resulted in complete hair growth and improved the gastrointestinal
      symptoms.

PMID- 12603810
TI  - Clinical management of nipple discharge in neonates and children.
AB  - Bloody nipple discharge is a rare but distressing finding in neonates and
      infants. We report an 8-month-old boy who showed bilateral bloody nipple
      discharge for 5 months without signs of infection. Ultrasound examination
      revealed dilated mammary ducts. This benign phenomenon is most likely caused by
      mammary duct ectasia. On the background of the reviewed literature, intensive
      investigations should only be performed in neonates and infants if bloody nipple
      discharge is unilateral, continues, expands in size or shows signs of
      inflammation. We discuss the clinical management of nipple discharge during
      infancy and childhood.

PMID- 12603811
TI  - Transient hyperphosphatasaemia of infancy and early childhood--clinical and
      laboratory data of 52 patients.

PMID- 12603815
TI  - Molecular changes in fetal Down syndrome brain.
AB  - Trisomy of human chromosome 21 is a major cause of mental retardation and other
      phenotypic abnormalities collectively known as Down syndrome. Down syndrome is
      associated with developmental failure followed by processes of neurodegeneration
      that are known to supervene later in life. Despite a widespread interest in Down
      syndrome, the cause of developmental failure is unclear. The brain of a child
      with Down syndrome develops differently from that of a normal one, although
      characteristic morphological differences have not been noted in prenatal life. On
      the other hand, a review of the existing literature indicates that there are a
      series of biochemical alterations occurring in fetal Down syndrome brain that
      could serve as substrate for morphological changes. We propose that these
      biochemical alterations represent and/or precede morphological changes. This
      review attempts to dissect these molecular changes and to explain how they may
      lead to mental retardation.

PMID- 12603816
TI  - Receptor tyrosine kinase and G-protein coupled receptor signaling and sorting
      within endosomes.

PMID- 12603817
TI  - Effect of S 17092, a novel prolyl endopeptidase inhibitor, on substance P and
      alpha-melanocyte-stimulating hormone breakdown in the rat brain.
AB  - In the present study, we have investigated the effects of a novel prolyl
      endopeptidase (EC 3.4.21.26, PEP) inhibitor, compound S 17092, on substance P
      (SP) and alpha-melanocyte-stimulating hormone (alpha-MSH) metabolism in the rat
      brain. In vitro experiments revealed that S 17092 inhibits in a dose-dependent
      manner PEP activity in rat cortical extracts (IC50 = 8.3 nm). In addition, S
      17092 totally abolished the degradation of SP and alpha-MSH induced by bacterial
      PEP. In vivo, a significant decrease in PEP activity was observed in the medulla
      oblongata after a single oral administration of S 17092 at doses of 10 and 30
      mg/kg (-78% and -82%, respectively) and after chronic oral treatment with S 17092
      at doses of 10 and 30 mg/kg per day (-75% and -88%, respectively). Concurrently,
      a single administration of S 17092 (30 mg/kg) caused a significant increase in SP
      and alpha-MSH-like immunoreactivity (LI) in the frontal cortex (+41% and +122%,
      respectively) and hypothalamus (+84% and +49%, respectively). In contrast,
      chronic treatment with S 17092 did not significantly modify SP- and alpha-MSH-LI
      in the frontal cortex and hypothalamus. Collectively, the present results show
      that S 17092 elevates SP and alpha-MSH concentrations in the rat brain by
      inhibiting PEP activity. These data suggest that the effect of S 17092 on memory
      impairment can be accounted for, at least in part, by inhibition of catabolism of
      promnesic neuropeptides such as SP and alpha-MSH.

PMID- 12603820
TI  - Developmental regulation of nicotinic acetylcholine receptor-mediated
      [3H]norepinephrine release from rat cerebellum.
AB  - Presynaptic modulation of synaptic transmission is the primary function of
      central nicotinic acetylcholine receptors (nAChRs) in developing and adult brain.
      nAChR activation regulates release of various neurotransmitters, including
      norepinephrine (NA). Given evidence that NA may serve a critical functional role
      in cerebellar development, we have undertaken studies to determine whether nAChRs
      modulate NA release in developing cerebellum. In vitro experiments using
      cerebellar slices examined the effects of nAChR stimulation on release of
      radiolabeled NA ([3H]NA). Our data indicate the presence of functional nAChRs on
      NA terminals in immature cerebellum and subsequent developmental regulation of
      receptor properties. During postnatal week one, the maximally effective dose of
      nicotine released 35.0 +/- 1.2% of cerebellar [3H]NA stores. There was a
      subsequent decline in maximal nicotine-stimulated NA release until postnatal day
      30, when Emax values were statistically indistinguishable from adult. Although
      the efficacy of nicotine changed substantially throughout development, EC50
      values did not differ significantly (EC50 = 4.4-12.0 micro m). Pharmacological
      analysis indicated that this developmental shift in maximum nicotine effect
      reflects a change in the properties of the nAChRs. These data support recent
      findings of a possible functional role of nAChRs in regulating cerebellar
      ontogeny, and provides further support for the role of NA as a neurotrophic
      factor during development.

PMID- 12603819
TI  - In developing Drosophila neurones the production of gamma-amino butyric acid is
      tightly regulated downstream of glutamate decarboxylase translation and can be
      influenced by calcium.
AB  - The presented work pioneers the embryonic Drosophila CNS for studies of the
      developmental regulation and function of gamma-amino butyric acid (GABA). We
      describe for the first time the developmental pattern of GABA in Drosophila and
      address underlying regulatory mechanisms. Surprisingly, and in contrast to
      vertebrates, detectable levels of GABA occur late during Drosophila neurogenesis,
      after essential neuronal proliferation and growth have taken place and
      synaptogenesis has been initiated. This timeline is almost unchanged when the
      GABA synthetase glutamate decarboxylase (GAD) is strongly misexpressed throughout
      the nervous system suggesting a tight post-translational regulation of GABA
      expression. We confirmed such GABA control mechanisms in an independent model
      system, i.e. primary Drosophila cell cultures raised in elevated [K+]. The data
      suggest that, in both systems, GABA suppression occurs via control of GAD
      activity. Using developing embryos and cell cultures as parallel assay systems
      for pharmacological and genetic studies we show that the negative regulation of
      GAD can be overridden by drugs known to elevate intracellular free [Ca2+]. Our
      results provide the basis for investigations of genetic mechanisms underlying the
      observed phenomenon, and we discuss the potential implications of this work for
      Drosophila neurogenesis but also for a general understanding of GAD regulation.

PMID- 12603818
TI  - Effect of experimenter-delivered and self-administered cocaine on extracellular
      beta-endorphin levels in the nucleus accumbens.
AB  - Beta-endorphin is an endogenous opioid peptide that has been hypothesized to be
      involved in the behavioral effects of drugs of abuse including psychostimulants.
      Using microdialysis, we studied the effect of cocaine on extracellular levels of
      beta-endorphin in the nucleus accumbens, a brain region involved in the
      reinforcing effects of psychostimulant drugs. Experimenter-delivered cocaine (2
      mg/kg, i.v.) increased extracellular beta-endorphin immunoreactive levels in the
      nucleus accumbens, an effect attenuated by 6-hydroxy-dopamine lesions or systemic
      administration of the D1-like receptor antagonist, SCH-23390 (0.25 mg/kg, i.p.).
      The effect of cocaine on beta-endorphin release in the nucleus accumbens was
      mimicked by a local perfusion of dopamine (5 microm) and was blocked by
      coadministration of SCH-23390 (10 microm). Self-administered cocaine (1
      mg/kg/infusion, i.v.) also increased extracellular beta-endorphin levels in the
      nucleus accumbens. In addition, using functional magnetic resonance imaging, we
      found that cocaine (1 mg/kg, i.v.) increases regional brain activity in the
      nucleus accumbens and arcuate nucleus. We demonstrate an increase in beta
      endorphin release in the nucleus accumbens following experimenter-delivered and
      self-administered cocaine mediated by the local dopaminergic system. These
      findings suggest that activation of the beta-endorphin neurons within the arcuate
      nucleus-nucleus accumbens pathway may be important in the neurobiological
      mechanisms underlying the behavioral effects of cocaine.

PMID- 12603821
TI  - The apoptosis/necrosis transition in cerebellar granule cells depends on the
      mutual relationship of the antioxidant and the proteolytic systems which regulate
      ROS production and cytochrome c release en route to death.
AB  - We investigate the death route induced by potassium depletion in cerebellar
      granule cells in 0-15 h time range and study whether and how mutual relationship
      occurs between the cell antioxidant and proteolytic system. To achieve this, we
      incubated cells in the absence or presence of inhibitors of the antioxidant
      system, including superoxide dismutase and catalase, and of the proteolytic
      system, consisting of proteasomes and caspases, and investigated whether and how
      (i) cell survival, (ii) reactive oxygen species (ROS) production and (iii)
      antioxidant enzyme and caspase-3 activity change as a function of time after the
      apoptotic stimulus. The involvement of both antioxidant and proteolytic system on
      cytochrome c release was also investigated. Cell survival was found to increase
      in the presence of either proteasome or caspase inhibitors. On the contrary, as a
      result of the antioxidant system impairment, shift from apoptosis to necrosis
      occurs. We show that the antioxidant system, which exhibits a huge activity
      increase up to 3 h after apoptosis induction, is subjected to the proteasome
      dependent proteolysis and that the increase in the antioxidant system found in
      the absence of proteasome activity is accompanied by ROS production decrease.
      Consistently, the early ROS-dependent release of cytochrome c was found to be
      prevented when the activity of the antioxidant system increased. Finally, caspase
      3 activation was prevented by the inhibitors of both antioxidant system and
      proteasome.

PMID- 12603822
TI  - Differentiation of human retinal pigment epithelial cells into neuronal phenotype
      by N-(4-hydroxyphenyl)retinamide.
AB  - ARPE-19, a human retinal pigment epithelial (RPE) cell line, has been widely used
      in studies of RPE function as well as gene expression. Here, we report the novel
      finding that N-(4-hydroxyphenyl)retinamide (fenretinide), a synthetic retinoic
      acid derivative and a potential chemopreventive agent against cancer, induced the
      differentiation of ARPE-19 cells into a neuronal phenotype. The treated cells
      lost their epithelial phenotype and exhibited a typical neuronal shape with long
      processes (four to five times longer than the cell body). The onset of
      fenretinide-induced neuronal differentiation was dose and time dependent, started
      within 1-2 days, and lasted at least 4 weeks. Immunohistochemical studies
      indicated that the expression of neurofilament proteins (NF160 and NF200),
      calretinin and neural cell adhesion molecule was increased in these
      differentiated cells. Western blot analysis indicated that cellular retinaldehyde
      binding protein, which is normally expressed in RPE cells, was decreased in
      treated cells. Protein analysis on a two-dimensional gel followed by matrix
      assisted laser desorption ionization-time of flight mass spectrometric analysis
      demonstrated that heat-shock protein 70 was increased after fenretinide
      treatment. Thus, fenretinide, a synthetic retinoid, is able to induce neuronal
      differentiation of human RPE cells in culture.

PMID- 12603823
TI  - Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal
      neurons.
AB  - Generation of oxidative stress/reactive oxygen species (ROS) is one of the causes
      of neuronal apoptosis. We have examined the effects of ROS at the transcriptional
      level in an immortalized hippocampal neuronal cell line (H19-7) and in rat
      primary hippocampal neurons. Treatment of H19-7 cells with hydrogen peroxide (150
      micro m) resulted in a 40% decrease in Bcl-2 protein and a parallel decrease in
      bcl-2 mRNA levels. H19-7 cells overexpressing bcl-2 were found to be resistant to
      ROS-induced apoptosis. We had previously shown that bcl-2 promoter activity is
      positively regulated by the transcription factor cyclic AMP response element
      binding protein (CREB) in neurons. In the present study, we demonstrate that ROS
      decreases the activity of luciferase reporter gene driven by a cyclic AMP
      response element site containing bcl-2 promoter. Exposure of neurons to ROS for 6
      h resulted in basal and fibroblast growth factor-2-stimulated
      phosphorylation/activation of CREB. Chronic 24 h treatment with ROS led to a
      significant (p < 0.01) decrease in CREB protein and CREB mRNA levels. Adenoviral
      overexpression of wild type CREB in H19-7 cells resulted in significant (p <
      0.01) protection against ROS-induced apoptosis through up-regulation of Bcl-2
      expression whereas dominant negative CREB exaggerated the injury. These findings
      demonstrate that loss of CREB function contributes to oxidative stress-induced
      neuronal dysfunction.

PMID- 12603825
TI  - Employing a superior BACE1 cleavage sequence to probe cellular APP processing.
AB  - The involvement of beta-secretase (BACE1; beta-site APP-cleaving enzyme) in
      producing the beta-amyloid component of plaques found in the brains of
      Alzheimer's patients, has fueled a major research effort to characterize this
      protease. Here, we describe work toward understanding the substrate specificity
      of BACE1 that began by considering the natural APP substrate and its Swedish
      mutant, APPSw, and proceeded on to include oxidized insulin B chain and ubiquitin
      substrates. From these findings, and the study of additional synthetic peptides,
      we determined that a decapeptide derived from APP in which the P3-P2' sequence,
      ...VKM--DA..., was replaced by ...ISY--EV... (-- = beta site of cleavage),
      yielded a substrate that was cleaved by BACE1 seven times faster than the
      corresponding APPSw peptide, SEVNL--DAEFR. The expanded peptide, GLTNIKTEEISEISY-
      EVEFRWKK, was cleaved an additional seven times faster than its decapeptide
      counterpart (boldface), and provides a substrate allowing assay of BACE1 at
      picomolar concentrations. Several APP mutants reflecting these beta-site amino
      acid changes were prepared as the basis for cellular assays. The APPISYEV mutant
      proved to be a cellular substrate that was superior to APPSw. The assay based on
      APPISYEV is highly specific for measuring BACE1 activity in cells; its homolog,
      BACE2, barely cleaved APPISYEV at the beta-site. Insertion of the optimized ISY-
      EV motif at either the beta-site (Asp1) or beta'-site (Glu11) directs the rate of
      cellular processing of APP at these two accessible sites. Thus, we have
      identified optimal BACE1 substrates that will be useful to elucidate the cellular
      enzymatic actions of BACE1, and for design of inhibitors that might be of
      therapeutic benefit in Alzheimer's disease.

PMID- 12603824
TI  - Interleukin-1beta stimulates macrophage inflammatory protein-1alpha and -1beta
      expression in human neuronal cells (NT2-N).
AB  - Chemokines are important mediators in immune responses and inflammatory processes
      of neuroimmunologic and infectious diseases. Although chemokines are expressed
      predominantly by cells of the immune system, neurons also express chemokines and
      chemokine receptors. We report herein that human neuronal cells (NT2-N) produce
      macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha and MIP-1beta),
      which could be enhanced by interleukin (IL)-1beta at both mRNA and protein
      levels. The addition of supernatants from human peripheral blood monocyte-derived
      macrophage (MDM) cultures induced MIP-1beta mRNA expression in NT2-N cells. Anti
      IL-1beta antibody removed most, but not all, of the MDM culture supernatant
      induced MIP-1beta mRNA expression in NT2-N cells, suggesting that IL-1beta in the
      MDM culture supernatants is a major factor in the induction of MIP-1beta
      expression. Investigation of the mechanism(s) responsible for IL-1beta-induced
      MIP-1alpha and -1beta expression demonstrated that IL-1beta activated nuclear
      factor kappa B (NF-kappaB) promoter-directed luciferase activity in NT2-N cells.
      Caffeic acid phenethyl ester, a potent and specific inhibitor of activation of NF
      kappaB, not only blocked IL-1beta-induced activation of the NF-kappaB promoter
      but also decreased IL-1beta-induced MIP-1alpha and -1beta expression in NT2-N
      cells. These data suggest that NF-kappaB is at least partially involved in the IL
      1beta-mediated action on MIP-1alpha and -1beta in NT2-N cells. IL-1beta-mediated
      up-regulation of beta-chemokine expression may have important implications in the
      immunopathogenesis of inflammatory diseases in the CNS.

PMID- 12603826
TI  - Acidosis has opposite effects on neuronal survival during hypoxia and
      reoxygenation.
AB  - To study the effect of extracellular acidosis on apoptosis and necrosis during
      ischemia and reoxygenation, we exposed human post-mitotic NT2-N neurones to
      oxygen and glucose deprivation (OGD) followed by reoxygenation. In some
      experiments, pH of the cell medium was lowered to 5.9 during either OGD or
      reoxygenation or both. Staurosporine, used as a positive control for apoptosis,
      caused Poly(ADP-ribose)-polymerase (PARP) cleavage and nuclear fragmentation, but
      no PARP cleavage and little fragmentation were seen after OGD. Low molecular
      weight DNA fragments were found after staurosporine treatment, but not after OGD.
      No protective effect of caspase inhibitors was seen after 3 h of OGD and 21 h of
      reoxygenation, but after 45 h of reoxygenation caspase inhibition induced a
      modest improvement in 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide
      (MTT) cleavage. While acidosis during OGD accompanied by neutral medium during
      reoxygenation protected the neurones (MTT: 228 +/- 117% of neutral medium, p <
      0.001), acidosis during reoxygenation only was detrimental (MTT: 38 +/- 25%, p <
      0.01). We conclude that apoptotic mechanisms play a minor role after OGD in NT2-N
      neurones. The effect of acidosis on neuronal survival depends on the timing of
      acidosis, as acidosis was protective during OGD and detrimental during
      reoxygenation.

PMID- 12603827
TI  - Role of NAD(P)H:quinone oxidoreductase in the progression of neuronal cell death
      in vitro and following cerebral ischaemia in vivo.
AB  - A direct involvement of the antioxidant enzyme NAD(P)H:quinone oxidoreductase
      (NQO1) in neuroprotection has not yet been shown. The aim of this study was to
      examine changes, localization and role of NQO1 after different neuronal injury
      paradigms. In primary cultures of rat cortex the activity of NQO1 was measured
      after treatment with ethylcholine aziridinium (AF64A; 40 micro m), inducing
      mainly apoptotic cell death, or oxygen-glucose deprivation (OGD; 120 min), which
      combines features of apoptotic and necrotic cell death. After treatment with
      AF64A a significant NQO1 activation started after 24 h. Sixty minutes after OGD a
      significant early induction of the enzyme was observed, followed by a second
      increase 24 h later. Enzyme activity was preferentially localized in glial cells
      in control and injured cultures, however, expression also occurred in injured
      neuronal cells. Inhibition of the NQO1 activity by dicoumarol, cibacron blue or
      chrysin (1-100 nM) protected the cells both after exposure to AF64A or OGD as
      assessed by the decreased release of lactate dehydrogenase. Comparable results
      were obtained in vivo using a mouse model of focal cerebral ischaemia. Dicoumarol
      treatment (30 nmol intracerebroventricular) reduced the infarct volume by 29% (p
      = 0.005) 48 h after the insult. After chemical induction of NQO1 activity by t
      butylhydroquinone in vitro neuronal damage was exaggerated. Our data suggest that
      the activity of NQO1 is a deteriorating rather than a protective factor in
      neuronal cell death.

PMID- 12603828
TI  - The interaction with the cytoplasmic loops of rhodopsin plays a crucial role in
      arrestin activation and binding.
AB  - The binding of arrestin to rhodopsin is initiated by the interaction of arrestin
      with the phosphorylated rhodopsin C-terminus and/or the cytoplasmic loops,
      followed by conformational changes that expose an additional high-affinity site
      on arrestin. Here we use an arrestin mutant (R175E) that binds similarly to
      phosphorylated and unphosphorylated, wild-type rhodopsin to identify rhodopsin
      elements other than C-terminus important for arrestin interaction. R175E-arrestin
      demonstrated greatly reduced binding to unphosphorylated cytoplasmic loop mutants
      L72A, N73A, P142A and M143A, suggesting that these residues are crucial for high
      affinity binding. Interestingly, when these rhodopsin mutants are phosphorylated,
      R175E-arrestin binding is less severely affected. This effect of phosphorylation
      on R175E-arrestin binding highlights the co-operative nature of the multi-site
      interaction between arrestin and the cytoplasmic loops and C-terminus of
      rhodopsin. However, a combination of any two mutations disrupts the ability of
      phosphorylation to enhance binding of R175E-arrestin. N73A, P142A and M143A
      exhibited accelerated rates of dissociation from wild-type arrestin. Using
      sensitivity to calpain II as an assay, these cytoplasmic loop mutants also
      demonstrated reduced ability to induce conformational changes in arrestin that
      correlated with their reduced ability to bind arrestin. These results suggest
      that arrestin bound to rhodopsin is in a distinct conformation that is co
      ordinately regulated by association with the cytoplasmic loops and the C-terminus
      of rhodopsin.

PMID- 12603829
TI  - Analysis of phospholipid molecular species in brains from patients with infantile
      and juvenile neuronal-ceroid lipofuscinosis using liquid chromatography
      electrospray ionization mass spectrometry.
AB  - Phospholipids (PL) in cerebral cortex from patients with infantile (INCL or CLN1)
      and juvenile (JNCL or CLN3) forms of neuronal ceroid-lipofuscinosis (NCL) and
      controls were analysed by normal phase HPLC and on-line electrospray ionization
      ion-trap mass spectrometric detection (LC-ESI-MS). The method provided
      quantitative data on numerous molecular species of different PL classes, which
      are not achieved by using the conventional chromatographic methods. Compared with
      the controls, the INCL brains contained proportionally more phosphatidylcholine
      (PC), and less phosphatidylethanolamine (PE) and phosphatidylserine (PS).
      Different molecular species of PC, PE, PS, phosphatidylinositol and sphingomyelin
      were quantified using multiple internal PL standards that differed in fatty acyl
      chain length and thus allowed correction for chain length dependency of
      instrument response. In INCL cortex, which had lost 65% of the normal PL content,
      the proportions of polyunsaturated molecular species, especially the PS and PE
      that contained docosahexaenoic acid (22:6n-3), were dramatically decreased. The
      membranes may have adapted to this alteration by increasing the proportions of PL
      molecules substituted with monounsaturated and short-chain fatty acids.
      Lysobisphosphatidic acid was highly elevated in the INCL brain and consisted
      mostly of polyunsaturated species. It is possible that changes in the composition
      of PL membranes accelerate progression of INCL by altering signalling and
      membrane trafficking in neurons.

PMID- 12603831
TI  - Corticotropin-releasing factor (CRF) rapidly suppresses apoptosis by acting
      upstream of the activation of caspases.
AB  - The physiological role of the corticotropin-releasing factor (CRF) family of
      peptides has recently been extended by emerging evidence of their cytoprotective
      effects. To determine whether CRF-mediated cytoprotection is linked to caspase
      dependent apoptosis, the effect of CRF on the activation of caspases was
      investigated in detail in Y79 human retinoblastoma cells. The results presented
      here demonstrate that the cytoprotective effect of CRF against the actions of
      camptothecin (CT) was mediated by CRF receptor subtype 1, but not subtype 2. The
      observed CRF-mediated cytoprotection involved rapid and pronounced suppression of
      proteolytic processing and activation of procaspase-3, exerted even when CRF was
      added hours after the application of the cytotoxic agent. Surprisingly,
      activation of procaspase-3 preceded activation of the initiator procaspases 2, 8,
      9 and 10 during CT-induced apoptosis of Y79 cells. The mechanism of the effect of
      CRF was examined using inhibitors of signalling pathways such as Wortmannin
      (Akt), cyclic AMP-dependent protein kinase (PKA), extracellular signal-regulated
      kinase (ERK), protein kinase c (PKC), p38 mitogen-activated protein kinase (p38
      MAPK), phospholipase c (PLC), nuclear factor-kappaB (NF-kappaBeta) and c-jun N
      terminal kinase (JNK). The involvement of PKA in the mediation of the anti
      apoptotic effect of CRF has been established. Taken together, these results
      demonstrate for the first time that the cytoprotective effect of CRF involved
      suppression of pro-apoptotic pathways at a site upstream of activation of
      procaspase-3.

PMID- 12603830
TI  - Chromaffin cell death induced by 6-hydroxydopamine is independent of
      mitochondrial swelling and caspase activation.
AB  - Our results provide evidence that 6-hydroxydopamine induced, after auto
      oxidation, toxic levels of hydrogen peroxide (H2O2) that caused bovine chromaffin
      cell toxicity and death. 6-Hydroxydopamine (6-OHDA) treatment markedly reduced,
      in a dose-response fashion, chromaffin cell viability. Cell death was accompanied
      by cell shrinkage, nuclear condensation and DNA degradation. Under our
      experimental conditions, 6-OHDA auto-oxidation formed quinones and reactive
      oxygen species (ROS) that mainly contributed to 6-OHDA-induced cytotoxicity in
      bovine chromaffin cells. Accordingly, different antioxidants, including catalase,
      vitamin E, Mn(IIItetrakis(4-benzoic acid)porphyrin chloride (MnTBAP) or ascorbic
      acid, provided protection against 6-OHDA-induced toxicity. Further evidence that
      6-OHDA induces oxidative stress is provided by the fact that this compound
      decreased total mitochondrial reduced NAD(P)H levels. Our results also suggest
      that mitochondrial swelling and caspase activation do not play a direct role in 6
      OHDA-induced death in bovine chromaffin cells.

PMID- 12603832
TI  - Promotion of tau phosphorylation by MAP kinase Erk1/2 is accompanied by reduced
      cholesterol level in detergent-insoluble membrane fraction in Niemann-Pick C1
      deficient cells.
AB  - Niemann-Pick type C (NPC) disease is a cholesterol-storage disease accompanied by
      neurodegeneration with the formation of neurofibrillary tangles, the major
      component of which is the hyperphosphorylated tau. Here, we examined the
      mechanism underlying hyperphosphorylation of tau using mutant Chinese hamster
      ovary (CHO) cell line defective in NPC1 (CT43) as a tool. Immunoblot analysis
      revealed that tau was hyperphosphorylated at multiple sites in CT43 cells, but
      not in their parental cells (25RA) or the wild-type CHO cells. In CT43 cells,
      mitogen-activated protein (MAP) kinase Erk1/2 was activated and the specific MAPK
      inhibitor, PD98059, attenuated the hyperphosphorylation of tau. The amount of
      protein phosphatase 2A not bound to microtubules was decreased in CT43 cells.
      CT43 cells but not 25RA cells were amphotericin B-resistant, indicating that
      cholesterol level in the plasma membrane of CT43 is decreased. In addition, the
      level of cholesterol in the detergent-insoluble, low-density membrane (LDM)
      fraction of CT43 cells was markedly reduced compared with the other two types of
      CHO cells. As LDM domain plays critical role in signaling pathways, these results
      suggest that the reduced cholesterol level in LDM domain due to the lack of NPC1
      may activate MAPK, which subsequently promotes tau phosphorylation in NPC1
      deficient cells.

PMID- 12603833
TI  - Compounds acting at the endocannabinoid and/or endovanilloid systems reduce
      hyperkinesia in a rat model of Huntington's disease.
AB  - We have recently reported that the administration of AM404, an inhibitor of the
      endocannabinoid re-uptake process, which also has affinity for the vanilloid VR1
      receptors, is able to reduce hyperkinesia, and causes recovery from neurochemical
      deficits, in a rat model of Huntington's disease (HD) generated by bilateral
      intrastriatal injections of 3-nitropropionic acid (3NP). In the present study, we
      wanted to explore the mechanism(s) by which AM404 produces its antihyperkinetic
      effect in 3NP-lesioned rats by employing several experimental approaches. First,
      we tried to block the effects of AM404 with selective antagonists for the CB1 or
      VR1 receptors, i.e. SR141716A and capsazepine, respectively. We found that the
      reduction caused by AM404 of the increased ambulation exhibited by 3NP-lesioned
      rats in the open-field test was reversed when the animals had been pre-treated
      with capsazepine but not with SR141716A, thus suggesting a major role of VR1
      receptors in the antihyperkinetic effects of AM404. However, despite the lack of
      behavioral effects of the CB1 receptor antagonist, the pretreatment with this
      compound abolished the recovery of neurochemical [gamma-aminobutyric acid (GABA)
      and dopamine] deficits in the caudate- putamen caused by AM404, as also did
      capsazepine. In a second group of studies, we wanted to explore the potential
      antihyperkinetic effects of various compounds which, compared to AM404, exhibit
      more selectivity for either the endovanilloid or the endocannabinoid systems.
      First, we tested VDM11 or AM374, two selective inhibitors or the endocannabinoid
      re-uptake or hydrolysis, respectively. Both compounds were mostly unable to
      reduce hyperkinesia in 3NP-lesioned rats, although VDM11 produced a certain motor
      depression, and AM374 exhibited a trend to stimulate ambulation, in control rats.
      We also tested the effects of selective direct agonists for VR1 (capsaicin) or
      CB1 (CP55,940) receptors. Capsaicin exhibited a strong antihyperkinetic activity
      and, moreover, was able to attenuate the reductions in dopamine and GABA
      transmission provoked by the 3NP lesion, whereas CP55,940 had also
      antihyperkinetic activity but was unable to cause recovery of either dopamine or
      GABA deficits in the basal ganglia. In summary, our data indicate a major role
      for VR1 receptors, as compared to CB1 receptors, in the antihyperkinetic effects
      and the recovery of neurochemical deficits caused in 3NP-lesioned rats by
      compounds that activate both CB1 and VR1 receptors, either directly or via
      manipulation of the levels of endogenous agonists.

PMID- 12603834
TI  - Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to
      oxidative stress in PC12 cells.
AB  - Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde
      detoxification. The alcohol sensitivity is associated with a genetic deficiency
      of ALDH2. We have previously reported that this deficiency influences the risk
      for late-onset Alzheimer's disease. However, the biological effects of the
      deficiency on neuronal cells are poorly understood. Thus, we obtained ALDH2
      deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. The
      mutant ALDH2 repressed mitochondrial ALDH activity in a dominant negative
      fashion, but not cytosolic activity. The resultant ALDH2-deficient transfectants
      were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative
      generated by the reaction of superoxide with unsaturated fatty acid. In addition,
      the ALDH2-deficient transfectants were sensitive to oxidative insult induced by
      antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2
      nonenal. Thus, these findings suggest that mitochondrial ALDH2 functions as a
      protector against oxidative stress.

PMID- 12603835
TI  - Striatal gene expression of RGS2 and RGS4 is specifically mediated by dopamine D1
      and D2 receptors: clues for RGS2 and RGS4 functions.
AB  - Of all partners involved in G-protein coupled receptor (GPCR) signalling, the
      regulator of G-protein signalling (RGS) proteins are the only ones showing fast
      gene expression changes after various stimuli. These expression changes can offer
      feedback regulation to GPCR signalling as RGS accelerate the return of G-proteins
      to their inactive form and exert regulatory functions on intracellular effectors.
      However, it is not yet known which RGS regulate which receptor transduction
      pathways in the brain. To start to answer this question, we studied the influence
      of specific agonists and antagonists of the dopamine D1 and D2 receptors on the
      gene expression of the five most abundant RGS in the striatum: RGS2, RGS4, RGS8,
      RGS9 and RGS10. Only changes in RGS2 and RGS4 mRNA levels were observed. The D1
      agonist SKF82958 and D2 antagonist haloperidol caused an up-regulation of RGS2 (+
      38.0% and + 41.6%, respectively). The D1 antagonist SCH23390 and D2 agonist
      quinpirole caused a down-regulation of RGS2 (- 25.0% and - 35.0%) and an up
      regulation of RGS4 (+ 57.2% and + 52.5%). D1 and D2 receptors exert opposite
      effects on RGS2 expression, as they do on cAMP levels, suggesting a cAMP-mediated
      transcription of RGS2. This was confirmed by the unique induction of RGS2 (+
      111.1%) observed in the periventricular zone of the striatum after
      intracerebroventricular injection of forskolin. RGS4 was up-regulated only when
      RGS2 was down-regulated. This suggests that both RGS exert distinct functions.
      Considering the coupling of D1 and D2 receptors to the intracellular effector
      adenylate cyclase 5 (AC5) through their respective Galpha subunits in the
      striatum, our data allow us to suggest that RGS2 regulates the D1/Galphaolf/AC5
      pathway and RGS4 the D2/Galphao/AC5 pathway.

PMID- 12603836
TI  - Lipid interaction of alpha-synuclein during the metal-catalyzed oxidation in the
      presence of Cu2+ and H2O2.
AB  - Alpha-synuclein co-exists with lipids in the Lewy bodies, a pathological hallmark
      of Parkinson's disease. Molecular interaction between alpha-synuclein and lipids
      has been examined by observing lipid-induced protein self-oligomerization in the
      presence of a chemical coupling reagent of N-(ethoxycarbonyl)-2-ethoxy-1,2
      dihydroquinoline. Lipids such as phosphatidic acid, phosphatidylinositol,
      phosphatidylserine, phosphatidylethanolamine, and even arachidonic acid induced
      the self-oligomerization whereas phosphatidylcholine did not affect the protein.
      Because the oligomerizations occurred from critical micelle concentrations of the
      lipids, the self interaction of alpha-synuclein was shown to be a lipid-surface
      dependent phenomenon with head group specificity. By employing beta-synuclein and
      a C-terminally truncated alpha-synuclein (alpha-syn97), the head-group dependent
      self-oligomerization was demonstrated to occur preferentially at the N-terminal
      region while the fatty acid interaction leading to the protein self-association
      required the presence of the acidic C-terminus of alpha-synuclein. In the
      presence of Cu2+ and H2O2, phosphatidylinositol (PI), along with other acidic
      lipids, actually enhanced the metal-catalyzed oxidative self-oligomerization of
      alpha-synuclein. The dityrosine crosslink formation responsible for the PI
      enhanced covalent self-oligomerization was more sensitive to variation of copper
      concentrations than that of H2O2 during the metal-catalyzed oxidation. The
      enhancement by PI was shown to be due to facilitation of copper localization to
      the protein because actual binding affinity between copper and alpha-synuclein
      increased from Kd of 44.7 microm to 5.9 microm in the presence of the lipid.
      Taken together, PI not only affects alpha-synuclein to be more self-interactive
      by providing the lipid surface, but also enhances the metal-catalyzed oxidative
      protein self-oligomerization by facilitating copper localization to the protein
      when the metal and H2O2 are provided. This observation therefore could be
      implicated in the formation of Lewy bodies as lipids and metal-catalyzed
      oxidative stress have been considered to be a part of pathological causes leading
      to the neurodegeneration.

PMID- 12603837
TI  - Localization of presenilin-nicastrin complexes and gamma-secretase activity to
      the trans-Golgi network.
AB  - Abundant biochemical and genetic evidence suggests that presenilins are catalytic
      components of gamma-secretase, the protease responsible for generating the
      Alzheimer amyloid beta-protein. However, the differential localization of
      presenilins to early secretory compartments and gamma-secretase substrates to
      late secretory compartments and the plasma membrane (the "spatial paradox")
      argues against this view. We investigated this issue by studying the localization
      of nicastrin, another putative gamma-secretase component, and its association
      with presenilin-1 into proteolytically active complexes. Glycosidase digests
      revealed that nicastrin exists in multiple glycoforms and is terminally
      sialylated, a modification often associated with the trans-Golgi network.
      Trafficking of nicastrin to the trans-Golgi network was confirmed by density
      gradient fractionation and immunofluorescence microscopy. In presenilin-deficient
      cells, however, nicastrin trafficking and maturation were abnormal, as the
      protein was restricted to early secretory compartments and failed to be
      sialylated. Mature sialylated nicastrin in trans-Golgi network fractions was
      complexed quantitatively with N- and C-terminal fragments of presenilin-1,
      whereas immature nicastrin present in early secretory compartments was not.
      Additionally, trans-Golgi network fractions contained the gamma-secretase
      substrate beta-amyloid precursor protein C83 and were enriched in presenilin
      dependent gamma-secretase proteolytic activity. The results resolve the apparent
      spatial paradox by demonstrating that presenilin-nicastrin complexes and
      presenilin-dependent gamma-secretase activity are co-localized to a late
      secretory compartment. The findings provide further evidence that presenilin
      containing complexes are the gamma-secretase, and indicate that presenilins also
      regulate gamma-secretase assembly.

PMID- 12603838
TI  - Blood-brain barrier transport of a novel micro 1-specific opioid peptide, H-Tyr-D
      Arg-Phe-beta-Ala-OH (TAPA).
AB  - The purpose of this study was to clarify the mechanism of the blood-brain barrier
      (BBB) transport of H-Tyr-D-Arg-Phe-beta-Ala-OH (TAPA), which is a novel
      dermorphin analog with high affinity for the micro 1-opioid receptor. The in vivo
      BBB permeation influx rate of [125I]TAPA after an i.v. bolus injection (7.3
      pmol/g body weight) into mice was estimated to be 0.265 +/- 0.025 microL/(min.g
      of brain). The influx rate of [125I]TAPA was reduced 70% by the coadministration
      of unlabeled TAPA (33 nmol/g of brain), suggesting the existence of a specific
      transport system for TAPA at the BBB. In order to elucidate the BBB transport
      mechanism of TAPA, a conditionally immortalized mouse brain capillary endothelial
      cell line (TM-BBB4) was used as an in vitro model of the BBB. The acid-resistant
      binding of [125I]TAPA, which represents the internalization of the peptide into
      cells, was temperature- and concentration-dependent with a half-saturation
      constant of 10.0 +/- 1.7 microm. The acid-resistant binding of TAPA was
      significantly inhibited by 2,4-dinitrophenol, dansylcadaverine (an endocytosis
      inhibitor) and poly-l-lysine and protamine (polycations). These results suggest
      that TAPA is transported through the BBB by adsorptive-mediated endocytosis,
      which is triggered by binding of the peptide to negatively charged sites on the
      surface of brain capillary endothelial cells. Blood-brain barrier transport via
      adsorptive-mediated endocytosis plays a key role in the expression of the potent
      opioid activity of TAPA in the CNS.

PMID- 12603840
TI  - The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment
      and brain oxidative stress in aged SAMP8 mice.
AB  - Oxidative stress may play a crucial role in age-related neurodegenerative
      disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid
      (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the
      SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta
      and severe deficits in learning and memory. We found that 12-month-old SAMP8
      mice, in comparison with 4-month-old mice, had increased levels of protein
      carbonyls (an index of protein oxidation), increased TBARS (an index of lipid
      peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S)
      ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced
      conformational changes in synaptosomal membrane proteins). Chronic administration
      of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T
      maze footshock avoidance paradigm and the lever press appetitive task without
      inducing non-specific effects on motor activity, motivation to avoid shock, or
      body weight. These effects probably occurred directly within the brain, as NAC
      crossed the blood-brain barrier and accumulated in the brain. Furthermore,
      treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of
      oxidative stress. These results support the hypothesis that oxidative stress can
      lead to cognitive dysfunction and provide evidence for a therapeutic role for
      antioxidants.

PMID- 12603841
TI  - Characterization of the functional role of the N-glycans in the AMPA receptor
      ligand-binding domain.
AB  - The ligand-binding domains of AMPA receptor subunits carry two conserved N
      glycosylation sites. In order to gain insight into the functional role of the
      corresponding N-glycans, we examined how the elimination of glycosylation at
      these sites (N407 and N414) affects the ligand-binding characteristics,
      structural stability, cell-surface expression, and channel properties of
      homomeric GluR-D (GluR4) receptor and its soluble ligand-binding domain (S1S2).
      GluR-D S1S2 protein expressed as a secreted protein in insect cells was found to
      be glycosylated at N407 and N414. No major differences in the ligand-binding
      properties were observed between the 'wild-type' S1S2 and non-glycosylated
      N407D/N414Q double mutant, or between S1S2 proteins expressed in the presence or
      absence of tunicamycin, an inhibitor of N-glycosylation. Purified glycosylated
      and non-glycosylated S1S2 proteins also showed similar thermostabilities as
      determined by CD spectroscopy. Full-length homomeric GluR-D receptor with
      N407D/N414Q mutation was expressed on the surface of HEK293 cells like the wild
      type GluR-D. In outside-out patches, GluR-D and the N407D/N414Q mutant produced
      similar rapidly desensitizing current responses to glutamate and AMPA. We
      therefore report that the two conserved ligand-binding domain glycans do not play
      any major role in receptor-ligand interactions, do not impart a stabilizing
      effect on the ligand-binding domain, and are not critical for the formation and
      surface localization of homomeric GluR-D AMPA receptors in HEK293 cells.

PMID- 12603839
TI  - Pharmacological and immunohistochemical characterization of the APJ receptor and
      its endogenous ligand apelin.
AB  - Apelin peptides have recently been identified to be the endogenous ligands for
      the G protein-coupled receptor APJ. However, little is known about the
      physiological roles of this ligand-receptor pairing. In the present study we
      investigated the pharmacology of several apelin analogues at the human
      recombinant APJ receptor using radioligand binding and functional assays. This
      has led to the identification of key residues in the apelin peptide required for
      functional potency and binding affinity through structure-activity studies. In
      particular, we have identified that replacement of leucine in position 5, or
      arginine in position 2 and 4 of the C-terminal apelin peptide, apelin-13,
      resulted in significant changes in pharmacology. We also investigated the
      detailed localization of pre-proapelin and APJ receptor mRNA in a wide range of
      human, rat and mouse tissues using quantitative RT-PCR, and carried out a
      detailed immunohistochemical study of the distribution of the APJ receptor in rat
      brain and spinal cord. Interestingly, the APJ receptor was not only co-localized
      in white matter with GFAP in the spinal cord, but was also clearly localized on
      neurones in the brain, suggesting that this receptor and its peptide may be
      involved in a wide range of biological process yet to be determined.

PMID- 12603842
TI  - Activation of mitochondrial ATP-sensitive potassium channels increases cell
      viability against rotenone-induced cell death.
AB  - We recently showed that activation of ATP-sensitive potassium (KATP) channels in
      PC12 cells induces protection against the neurotoxic effect of rotenone, a
      mitochondrial complex I inhibitor. In this study, we sought to determine the
      locus of the KATP channels that mediate this protection in PC12 cells. We found
      that pretreatment of PC12 cells with diazoxide, a mitochondrial KATP channel
      selective opener, dose-dependently increases cell viability against rotenone
      induced cell death as indicated in trypan blue exclusion assays. The protective
      effect of this preconditioning is attenuated by 5-hydroxydecanoic acid (5-HD), a
      selective mitochondrial KATP channel antagonist but not in the presence of HMR
      1098, a selective plasma membrane KATP potassium channel antagonist. In contrast,
      P-1075, a selective plasma membrane KATP channel opener, does not induce
      protection. Using specific antibodies against SUR1 and Kir6.1, we detected
      immunoreactive proteins of apparent molecular masses 155 and 50 kDa,
      corresponding to those previously reported for SUR1 and Kir6.1, respectively, in
      the mitochondria-enriched fraction of PC12 cells. In addition, whole cell patch
      clamp studies revealed that inward currents in PC12 cells are insensitive to P
      1075, HMR-1098, glibenclamide and diazoxide, indicating that functional plasma
      membrane KATP channels are negligible. Taken together, our results demonstrate
      for the first time that activation of mitochondrial KATP channels elicits
      protection against rotenone-induced cell death.

PMID- 12603843
TI  - Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with
      the activation of microglia.
AB  - Seven days after the injection of different concentrations of thrombin into the
      nigrostriatal pathway, a strong macrophage/microglial reaction was observed in
      the substantia nigra (SN), indicated by immunostaining, using OX-42 and OX-6
      antibodies, and by the induction of iNOS, IL-1alpha, Il-1beta and TNF-alpha.
      Moreover, selective damage to dopaminergic neurones was produced after thrombin
      injection, evidenced by loss of tyrosine hydroxylase immunostaining and tyrosine
      hydroxylase mRNA-expressing cell bodies, and the unaltered transcription of
      glutamic acid decarboxylase mRNA in the SN and striatum. These thrombin effects
      could be produced by its ability to induce the activation of microglia described
      in in vitro studies, and are in agreement with the effects described for other
      proinflammatory compounds. Thrombin effects are produced by its biological
      activity since they almost disappeared when thrombin was heat-inactivated or
      injected along with its inhibitor alpha-NAPAP. Thrombin is a multi-functional
      serine protease rapidly produced from prothrombin at the sites of tissue injury,
      and also upon breakdown of the blood-brain barrier, which strongly suggests it
      could easily enter into the CNS. These results could have special importance in
      some degenerative processes of the nigrostriatal dopaminergic system.

PMID- 12603844
TI  - Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and
      genotype-phenotype correlation.
AB  - The autosomal recessive disorder lipoid proteinosis results from mutations in
      extracellular matrix protein 1 (ECM1), a glycoprotein expressed in several
      tissues (including skin) and composed of two alternatively spliced isoforms,
      ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date,
      mutations that either affect ECM1a alone or perturb both ECM1 transcripts have
      been demonstrated in six cases. However, lipoid proteinosis is clinically
      heterogeneous with affected individuals displaying differing degrees of skin
      scarring and infiltration, variable signs of hoarseness and respiratory distress,
      and in some cases neurological abnormalities such as temporal lobe epilepsy. In
      this study, we sequenced ECM1 in 10 further unrelated patients with lipoid
      proteinosis to extend genotype-phenotype correlation and to add to the mutation
      database. We identified seven new homozygous nonsense or frameshift mutations:
      R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA
      (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound
      heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none
      of which were found in controls. The mutation 507delT occurred in two unrelated
      subjects on different ECM1 haplotypes and may therefore represent a recurrent
      mutation in lipoid proteinosis. Taken with the previously documented mutations in
      ECM1, this study supports the view that exons 6 and 7 are the most common sites
      for ECM1 mutations in lipoid proteinosis. Clinically, it appears that mutations
      outside exon 7 are usually associated with a slightly more severe mucocutaneous
      lipoid proteinosis phenotype, but neurological features do not show any specific
      genotype-phenotype correlation.

PMID- 12603846
TI  - Laboratory acquired infection with recombinant vaccinia virus containing an
      immunomodulating construct.
AB  - Handling of Vaccinia virus represents a risk for laboratory-acquired infections,
      especially in individuals without completed vaccination. We report the case of a
      Vaccinia infection in a previously vaccinated researcher working with various
      genetically modified strains. We could confirm the infection by electron
      microscopy, positive cell culture, virus-specific PCR, sequence analysis, and
      viral neutralization test. The isolated virus carried a functionally inactivated
      cytohesin-1 gene of human origin, which had been shown to impair leukocyte
      adhesion by interacting with the LFA/ICAM-1 axis. The immunomodulating nature of
      the inserted construct might thus have added to the infectivity of the virus. We
      emphasize on the necessity of Vaccinia vaccination in laboratory staff working in
      the field.

PMID- 12603845
TI  - Novel mutations in the gene encoding secreted lymphocyte antigen-6/urokinase-type
      plasminogen activator receptor-related protein-1 (SLURP-1) and description of
      five ancestral haplotypes in patients with Mal de Meleda.
AB  - Mal de Meleda is a recessive, transgressive palmoplantar keratoderma for which we
      previously identified mutations in the gene encoding secreted lymphocyte antigen
      6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1). In
      this report we describe two new mutations: (i) a founder mutation, which changes
      a conserved cysteine residue to tyrosine (C99Y) in a large inbred Tunisian
      pedigree, and (ii) a signal sequence mutation (W15R), which was homozygous in a
      German family and heterozygous in a Scottish patient. Four ancestral haplotypes
      were observed in 69 patients from countries around the Mediterranean basin, and
      an additional haplotype was found in the German and Scottish patients.

PMID- 12603847
TI  - Identification of a commonly used CDR3 region of infiltrating T cells expressing
      Vbeta13 and Vbeta15 derived from psoriasis patients.
AB  - Psoriasis is a common inflammatory skin disease that is thought to be mediated by
      activated T cells. In this study, the complementarity-determining region 3 (CDR3)
      in T cell receptors was examined for a common sequence motif among the T cells
      infiltrated in psoriatic lesional skin. A common specific CDR3 motif (Vbeta13
      DWTSGV-Jbeta2.7) in lesions from psoriasis patients was identified by polymerase
      chain-reaction-based spectratyping analysis and DNA sequencing. In addition, VDJ
      rearrangement with highly homologous amino acid composition in the CDR3 was
      observed in Vbeta15 of T cell receptors in lesions derived from psoriatic
      patients. Remarkably, T cell receptors containing the Vbeta13-DWTSGV-Jbeta2.7
      were also found in the clinically normal skin from the psoriasis patients, which
      might seem to be responsible for the artificial production of psoriatic lesions.
      The identified CDR3 motif was highly expressed in cutaneous lymphocyte antigen
      (CLA+) cells of peripheral blood mononuclear cells from psoriasis patients
      compared with the expression in healthy individuals. This result showed that the
      infiltrated CLA+ T cells with the Vbeta13-DWTSGV-Jbeta2.7 motif in peripheral
      blood mononuclear cells from psoriasis patients might be involved in the
      development of psoriatic lesions. In addition, the results in this study suggest
      that the infiltrated T cells with the Vbeta13-DWTSGV-Jbeta2.7 motif in psoriatic
      lesions may be involved in the pathogenesis of psoriasis.

PMID- 12603848
TI  - RasGAP-like protein IQGAP1 is expressed by human keratinocytes and recognized by
      autoantibodies in association with bullous skin disease.
AB  - Autoantibodies in patients with autoimmune bullous skin diseases, such as
      pemphigus or bullous pemphigoid are of diagnostic value and might play a part in
      the pathogenic scenario. In this study we present five patients with erythematous
      plaques, subepidermal blister formation of the skin, and the presence of
      circulating autoantibodies directed against a so far unrecognized 190 kDa antigen
      in human keratinocytes. Amino acid sequence analysis identified the protein as
      IQGAP1, a recently described human Ras GTPase-activating-like protein suspected
      to act as an effector molecule for Cdc42 and Rac1, members of the Rho small
      GTPase family and to play a key part in regulating E-cadherin-mediated cell
      adhesion. The protein is selectively recognized by a monoclonal anti-IQGAP1
      antibody on western blots and immunoprecipitates from keratinocyte extracts.
      Indirect immunofluorescence locates IQGAP1 within individual keratinocytes in a
      cytoplasmic pattern and along the cell periphery at adhesive sites. Our results
      demonstrate IQGAP1, a newly described multifunctional protein, to be
      constitutively expressed in human keratinocytes where it may contribute to the
      integrity of the epidermal layer. Furthermore, we found autoantibodies reacting
      with IQGAP1 in patients with bullous skin eruptions most apparently belonging to
      the spectrum of bullous pemphigoid.

PMID- 12603849
TI  - Memory B cells specific for the NC16A domain of the 180 kDa bullous pemphigoid
      autoantigen can be detected in peripheral blood of bullous pemphigoid patients
      and induced in vitro to synthesize autoantibodies.
AB  - Bullous pemphigoid is a subepidermal blistering disease characterized by the
      synthesis of autoantibodies against the 180 kDa and the 230 kDa bullous
      pemphigoid antigens. Whether autoimmunity is also reflected by the presence of
      circulating autoantigen-specific memory B cells is still a matter of debate. We
      used a new assay combining two-step immunomagnetic enrichment with multiparameter
      flow cytometry to detect and characterize bullous pemphigoid 180 kDa-specific
      IgG+ B cells in blood of bullous pemphigoid patients. In a first magnetic
      separation, B cells were isolated from peripheral blood mononuclear cells using
      releasable microbeads conjugated to a CD19 antibody. From pre-enriched B cells,
      bullous pemphigoid 180 kDa-specific cells were then positively selected using
      microbeads directly conjugated with a recombinant N-terminal fragment of the
      bullous pemphigoid 180 kDa ectodomain, containing the noncollagenous 16A domain,
      which was recently shown to harbor major epitopes of autoantibodies in bullous
      pemphigoid sera. Noncollagenous 16A domain-specific IgG+ B cells were detectable
      in blood of most, if not all patients with serum autoantibodies against the
      noncollagenous 16A domain. The specificity of the cells was confirmed by in vitro
      differentiation into antibody-forming cells and analysis of the culture
      supernatant for the presence of noncollagenous 16A domain-specific IgG
      antibodies. All noncollagenous 16A domain-specific IgG+ B cells showed a clear
      memory immunophenotype. Noncollagenous 16A domain-specific IgG+ memory B cells
      may be crucial for continuous noncollagenous 16A domain-specific autoantibody
      production and/or play a part as antigen-presenting cells for priming and
      restimulation of bullous pemphigoid 180 kDa-specific T helper cells.

PMID- 12603850
TI  - The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization
      of human skin wounds and is lacking in chronic ulcer epithelium.
AB  - The human cathelicidin anti-microbial protein, hCAP18 is a component of the
      innate immune system and has broad anti-microbial activity conferred by its C
      terminal fragment LL-37. hCAP18 is constitutively produced in leukocytes and is
      induced in barrier organs upon inflammation and infection. We demonstrate here a
      novel role for this peptide in re-epithelialization of skin wounds. We show that
      high levels of hCAP18 are produced in skin in vivo upon wounding. The highest
      hCAP18 levels are attained at 48 h post-injury, declining to pre-injury levels
      upon wound closure. hCAP18 is detected in the inflammatory infiltrate and in the
      epithelium migrating over the wound bed. In chronic ulcers, however, hCAP18
      levels are low and immunoreactivity for hCAP18/LL-37 is absent in ulcer edge
      epithelium. Using a noninflammatory ex vivo wound healing model, composed of
      organ-cultured human skin, we show that hCAP18 is strongly expressed in healing
      skin epithelium, and that treatment with antibodies raised and affinity purified
      against LL-37, inhibits re-epithelialization in a concentration-dependent manner.
      Immunoreactivity for the proliferation marker Ki67 is absent in the epithelium of
      such inhibited wounds, suggesting that LL-37 may play a part in epithelial cell
      proliferation. Thus, we suggest that, in addition to being an anti-microbial
      peptide, LL-37 also plays a part in wound closure and that its reduction in
      chronic wounds impairs re-epithelialization and may contribute to their failure
      to heal.

PMID- 12603851
TI  - p38 Mitogen-activated protein kinase and extracellular signal-regulated kinases
      play distinct roles in the activation of dendritic cells by two representative
      haptens, NiCl2 and 2,4-dinitrochlorobenzene.
AB  - Previous studies have demonstrated that haptens induce several phenotypic and
      functional changes of dendritic cells in vivo as well as in vitro. Although
      recently, the crucial role of p38 mitogen-activated protein kinase has been
      reported in the activation of dendritic cells by haptens, the signal transduction
      elements involved in each phenotypic and functional changes that occur in the
      activation of dendritic cells by haptens remain unknown. Therefore, we examined
      the role of mitogen-activated protein kinases and nuclear factor-kappaB in the
      signal transduction of dendritic cells stimulated with two representative
      haptens, i.e., NiCl2 and 2,4-dinitrochlorobenzene. Human monocyte-derived
      dendritic cells stimulated with 2,4-dinitrochlorobenzene induced the
      phosphorylation of p38 and stress-activated protein kinase/c-jun N-terminal
      kinases, whereas NiCl2 induced that of p44/42 extracellular signal-regulated
      kinases, p38, and stress-activated protein kinase/c-jun N-terminal kinases. In
      addition, NiCl2 phosphorylated inhibitor kappaB and activated nuclear factor
      kappaB. In contrast, primary irritants, e.g., benzalkonium chloride, or sodium
      lauryl sulfate, did not activate these signal transduction pathways. By using
      specific inhibitors for extracellular signal-regulated kinases and p38 pathways,
      PD98059 and SB203580, respectively, we demonstrated that the augmentation of
      CD86, HLA-DR, and CD83, and the production of interleukin-8 along with its
      increased mRNA expression by monocyte-derived dendritic cells stimulated with 2,4
      dinitrochlorobenzene, and the augmentation of CD83 and the interleukin-12 p40
      production by monocyte-derived dendritic cells stimulated with NiCl2, were
      suppressed by SB203580, whereas PD98059 suppressed the production of interleukin
      1beta and tumor necrosis factor-alpha, together with their increased mRNA
      expression by monocyte-derived dendritic cells treated with NiCl2. On the other
      hand, in spite of the activation of nuclear factor-kappaB by monocyte-derived
      dendritic cells stimulated with NiCl2, nuclear factor-kappaB inhibitor did not
      significantly affect the phenotypic and functional changes in the activation of
      monocyte-derived dendritic cells. These data indicate that NiCl2 and 2,4
      dinitrochlorobenzene stimulate different signal transduction pathways in monocyte
      derived dendritic cells, and subsequently induce different phenotypic and
      functional changes in them.

PMID- 12603853
TI  - Cored tubules are present in human epidermal Langerhans cells.
AB  - Cored tubules are ultrastructural organelles described to date only in murine
      cells belonging to the Langerhans cell family and located in the dermis and its
      draining lymph nodes. These organelles, the function of which is unknown, differ
      from Birbeck granules and are interestingly not found in murine epidermal
      Langerhans cells. In this work we demonstrate that cored tubules are present in
      freshly isolated human epidermal Langerhans cells. The tubules were found to be
      interconnected with structures known to belong to the early endosomal pathway and
      could be immunolabeled with gold-conjugated anti-CD1a and anti-Langerin
      monoclonal antibodies, but only at 37 degrees C. At this temperature such
      antibodies are able to progress from the early sorting endosomes to the early
      recycling endosomes, which in human Langerhans cells include the Birbeck
      granules. These findings strongly suggest that cored tubules form part of the
      early recycling compartment.

PMID- 12603852
TI  - Topical mechlorethamine restores autoimmune-arrested follicular activity in mice
      with an alopecia areata-like disease by targeting infiltrated lymphocytes.
AB  - Alopecia areata is an autoimmune disease targeted at hair follicles with
      infiltrated T lymphocytes probably playing an important role in the pathogenesis.
      It was reported in 1985 that mechlorethamine was effective on alopecia areata
      patients. This has never been confirmed since. The aims of the study were to
      investigate the effects of mechlorethamine on balding C3H/HeJ mice affected with
      an alopecia-areata-like disease and to study the underlying mechanisms. Mice were
      treated on half of the dorsal skin with mechlorethamine and the contralateral
      side was treated with the vehicle ointment. After 10 wk of mechlorethamine
      therapy, a full pelage of hair covered the treated side in all the mice and was
      maintained during the study, whereas the vehicle-treated sides showed either no
      change or continued hair loss. Immunohistochemistry revealed that infiltrated
      CD4+ and CD8+ lymphocytes were eliminated from the treated side. In vitro cell
      viability assay showed that lymphocytes were much more sensitive to the cytotoxic
      effects of mechlorethamine than skin and hair follicular cells. RNase protection
      assay and real-time reverse transcription polymerase chain reaction showed that
      tumor necrosis factor alpha/beta, interleukin-12, and interferon-gamma were
      inhibited by mechlorethamine upon successful treatment. Our findings support that
      mechlorethamine restores follicular activity by selectively targeting infiltrated
      lymphocytes in vivo in alopecia-areata-affected mice.

PMID- 12603854
TI  - 17beta-estradiol inhibits the production of interferon-induced protein of 10 kDa
      by human keratinocytes.
AB  - The natural course of psoriasis is often modulated during pregnancy, indicating
      the regulatory effect of estrogen or progesterone on psoriasis. Interferon
      induced protein of 10 kDa chemoattracts T helper 1 cells, and interferon-induced
      protein of 10 kDa production by keratinocytes is enhanced in psoriatic skin
      lesions. We examined in vitro effects of sex hormones on the interferon-induced
      protein of 10 kDa production by human keratinocytes. 17beta-estradiol inhibited
      interferon-gamma-induced interferon-induced protein of 10 kDa secretion, mRNA
      expression, and promoter activity. Interferon-stimulated response element on the
      promoter was responsible for the inhibition by 17beta-estradiol. Interferon-gamma
      induced protein of 10 kDa production was also inhibited by anti-estrogens, ICI
      182 780 and tamoxifen, and membrane-impermeable bovine serum albumin-conjugated
      17beta-estradiol, suggesting the effects via membrane estrogen receptor, whereas
      17alpha-estradiol, progesterone, and dihydrotestosterone had no effects. 17beta
      estradiol and bovine serum albumin-conjugated 17beta-estradiol suppressed
      interferon-gamma-induced transcription through the interferon-stimulated response
      element and signal transducer and activator of transcription 1alpha binding to
      interferon-stimulated response element. 17beta-estradiol and bovine serum albumin
      conjugated 17beta-estradiol suppressed interferon-gamma-induced tyrosine
      phosphorylation of signal transducer and activator of transcription 1alpha, and
      Janus tyrosine kinase 1 and 2. 17beta-estradiol-mediated suppression on the
      interferon-gamma-induced signal transducer and activator of transcription 1alpha
      activation and interferon-induced protein of 10 kDa synthesis was counteracted by
      adenylate cyclase inhibitor SQ22536. 17beta-estradiol, bovine serum albumin
      conjugated 17beta-estradiol, ICI 182 780, and tamoxifen increased intracellular
      3',5'-adenosine cyclic monophosphate level by activating adenylate cyclase in
      keratinocytes. Fluorescein isothiocyanate-labeled bovine serum albumin-conjugated
      17beta-estradiol bound to the surface of keratinocytes, and mRNA for estrogen
      receptor beta but not for estrogen receptor alpha was detected in keratinocytes.
      These results suggest that 17beta-estradiol may interact with the membrane
      receptor on keratinocytes and generate 3',5'-adenosine cyclic monophosphate by
      activating adenylate cyclase, which may lead to the inhibition of interferon
      gamma-induced signal transducer and activator of transcription 1alpha activation
      and interferon-induced protein of 10 kDa synthesis.

PMID- 12603856
TI  - Transport of biotin in human keratinocytes.
AB  - Biotin is an essential micronutrient for normal cellular function, growth, and
      development. Biotin deficiency leads to pathologic, dermatologic, and
      neurocutaneous manifestations in skin and its appendages. Previous studies
      described the presence of specific biotin transport systems in the epithelia of
      the intestine, liver, kidney, and placenta, and in blood mononuclear cells. The
      aim of this study was to examine biotin transport into human keratinocytes.
      Uptake of [3H]biotin was measured both in the HaCaT cell line and in native
      keratinocytes in primary culture. Uptake of [3H]biotin (6 nM) in HaCaT cells was
      linear for up to 5 min of incubation. In the presence of an Na+ gradient total
      biotin uptake was 4- to 5-fold higher than in the absence of sodium ions. Biotin
      uptake was not altered by H+ and Cl- gradients. This transport system exhibited a
      Michaelis-Menten constant for biotin of 22.7+/-1.0 microM and a maximal velocity
      of 163.6+/-3.5 pmol per 5 min per mg protein. [3H]Biotin uptake (6 nM) was
      strongly inhibited by lipoic acid (oxidized form, Ki=4.6 microM; reduced form,
      Ki=11.4 microM), pantothenic acid (Ki=1.2 microM), and desthiobiotin (Ki=15.2
      microM), but not by biocytin or biotin methyl ester. Measured at [3H]biotin
      concentrations of 0.1-10 nM we obtained kinetic evidence for the presence of a
      second transport component that is saturable at very low biotin concentrations
      (Kt=2.6+/-0.1 nM). Unlabeled lipoic acid and pantothenic acid (20 nM) did not
      inhibit the [3H]biotin uptake (1 nM). We conclude that human keratinocytes
      express the Na+-dependent multivitamin transporter with preference for
      pantothenate and a very high affinity transport component with specificity for
      biotin.

PMID- 12603855
TI  - 17beta-estradiol inhibits the production of RANTES in human keratinocytes.
AB  - A chemokine, regulated upon activation, normal T cell expressed and secreted
      (RANTES) attracts T helper-1 cells and macrophages. The production of RANTES is
      enhanced in keratinocytes of psoriatic skin lesions, which may contribute to the
      inflammatory infiltrate. It is known that estrogen regulates the natural course
      of psoriasis. We examined the in vitro effects of 17beta-estradiol on RANTES
      production by human keratinocytes. 17beta-estradiol inhibited tumor necrosis
      factor-alpha or interleukin-1beta-induced RANTES secretion, mRNA expression, and
      promoter activity in keratinocytes, and these effects of 17beta-estradiol were
      counteracted by estrogen receptor antagonist ICI 182 780. Two nuclear factor
      kappaB elements on RANTES promoter were required for tumor necrosis factor-alpha
      or interleukin-1beta-induced transcription and involved in the inhibition by
      17beta-estradiol. 17beta-estradiol inhibited nuclear factor kappaB
      transcriptional activity, whereas it did not inhibit DNA binding of nuclear
      factor kappaB or phosphorylation or degradation of the inhibitor of nuclear
      factor kappaB alpha in tumor necrosis factor-alpha or interleukin-1beta
      stimulated keratinocytes. 17beta-estradiol-induced inhibition of nuclear factor
      kappaB transcriptional activity and RANTES promoter activity was rescued by
      overexpression of a coactivator cyclic AMP response element-binding protein
      (CREB) or nuclear factor kappaB p65 but not by steroid receptor coactivator-1 or
      nuclear factor kappaB p50. The overexpression of CREB-binding protein rescued
      17beta-estradiol-induced inhibition of transcription mediated by a chimeric
      protein, GAL4-p65286-551, which contained GAL4 DNA binding domain fused to C
      terminal transactivating domain of p65 (amino acids 286-551). The transfection of
      estrogen receptor alpha or estrogen receptor beta into estrogen receptor-negative
      SKBR3 cells resulted in 17beta-estradiol-mediated inhibition of transcription via
      GAL4-p65286-551. These results suggest that 17beta-estradiol-bound estrogen
      receptor may inhibit nuclear factor kappaB-dependent transcription of RANTES gene
      by competing with p65 for limiting amounts of CREB-binding protein.

PMID- 12603857
TI  - Antioxidant enzyme activity in human stratum corneum shows seasonal variation
      with an age-dependent recovery.
AB  - The stratum corneum, as the body's principal barrier to the environment, is
      continuously exposed to environmental sources of reactive oxygen species like
      ultraviolet light, ozone, and pollution. Reactive oxygen species are believed to
      be involved in cancer, aging, and inflammatory skin disorders. We have developed
      a method to measure catalase and superoxide dismutase activity on tape strippings
      from the human stratum corneum and demonstrated a gradient of antioxidant enzyme
      activity across the stratum corneum with decreasing levels towards the skin
      surface. Sun exposure resulted in a seasonal variation of the catalase activity
      in stratum corneum, with low activities in summer and higher activities in winter
      for the same person, whereas superoxide dismutase activity in stratum corneum did
      not seem to vary in those conditions. Exposure of human skin to broadband
      ultraviolet-A resulted in a dose-dependent deactivation of the catalase activity
      in stratum corneum within 24 h, whereas exposure to ultraviolet-B had no effect.
      Superoxide dismutase activity in stratum corneum was not affected by ultraviolet
      A or ultraviolet-B irradiation within 24 h. After exposure to a dose of 15 J per
      cm2 broadband ultraviolet-A, full recovery of the catalase activity occurred in 3
      4 wk at an age-dependent rate. We conclude that sun exposure results in a
      disturbed catalase to superoxide dismutase ratio in the stratum corneum. This may
      lead to an increased vulnerability to oxidative damage in stratum corneum barrier
      components. These results therefore stress the importance of providing efficient
      protection for this internal defense mechanism in sun-exposed areas of the skin.

PMID- 12603858
TI  - Human keratinocytes express multiple P2Y-receptors: evidence for functional P2Y1,
      P2Y2, and P2Y4 receptors.
AB  - Extracellular nucleotides are agonists at the family of receptors known as the P2
      receptors, and in keratinocytes the P2Y2 subtype is known to elevate the
      intracellular free calcium concentration (Cai) and stimulate proliferation. In
      this study, we have investigated the presence of other functional members of the
      P2Y subgroup in both normal human keratinocytes and the HaCaT cell line. Using
      reverse transcription polymerase chain reaction, the expression of mRNA for P2Y1,
      P2Y2, P2Y4, and P2Y6 receptors was demonstrated in HaCaT cells and differentiated
      and undifferentiated normal human keratinocytes. Cai was monitored in response to
      a panel of P2Y receptor agonists. To couple mobilized Cai to a downstream
      cellular response, cell proliferation was also addressed. In both cell types,
      adenosine 5'-triphosphate and uridine 5'-triphosphate induced Cai transients of
      approximately equal duration, magnitude, and shape, confirming the presence of
      functional P2Y2 receptors. In HaCaT cells, additional characteristic responses
      were observed in a subpopulation of cells; adenosine 5'-triphosphate failed to
      elevate Cai in some cells responding to uridine 5'-triphosphate, indicating the
      presence of P2Y4 receptors, whereas the P2Y1-specific agonist 2-methylthio-5'
      adenosine diphosphate was, again, only effective in a small subpopulation.
      Uridine 5'-diphosphate was ineffective, indicating the absence of functional P2Y6
      receptors. Adenosine 5'-triphosphate and uridine 5'-triphosphate equally promoted
      cell growth in normal human keratinocytes in comparison with the control. In
      HaCaT cells, adenosine 5'-triphosphate, uridine 5'-triphosphate, and adenosine 5'
      diphosphate significantly increased proliferation in comparison to the controls,
      with a 30% higher response to uridine 5'-triphosphate than with adenosine 5'
      triphosphate. These data demonstrate that multiple P2Y receptors (P2Y1, P2Y2, and
      P2Y4 subtypes) are differentially involved in the regulation of proliferation in
      human keratinocytes and therefore may be important in wound healing.

PMID- 12603859
TI  - Visualization of oleic acid-induced transdermal diffusion pathways using two
      photon fluorescence microscopy.
AB  - In a novel application of dual-channel high-speed two-photon fluorescence
      microscopy, the skin autofluores-cence and the transdermal fluorescent model drug
      spatial distributions were imaged simultaneously over precisely the same spatial
      coordinates. The dual channels enable the detection of the fluorescence emission
      wavelengths characteristic of the endogenous (intrinsic) skin fluorophores, as
      well as of the rhodamine-based model drug intensity emission at a different
      wavelength range of the fluorescence emission spectrum. These fluorescent model
      drugs delineate the oleic acid induced changes in permeant diffusion with respect
      to the skin structural features over the 0.3 mm by 0.3 mm skin area imaged per
      skin sample. The dual-channel high-speed two-photon fluorescence microscopy
      studies presented here provide evidence for the existence of intracorneocyte
      diffusion in addition to the commonly cited lipid multilamellar transdermal
      pathway. The image quantification analysis methodology introduced in this paper
      reveals that intracorneocyte diffusion exists for the hydrophobic (rhodamine B
      hexyl ester) and for the hydrophilic (sulforhodamine B) model drugs, in the
      absence of oleic acid chemical enhancer action. The mechanism of oleic acid
      chemical enhancer action, however, depends on the model drug physicochemical
      properties, where the oleic acid induces hydrophobic model drug localization to
      the lipid multilamellar region, while increasing the hydrophilic model drug lipid
      to corneocyte partitioning.

PMID- 12603860
TI  - Short-term glucocorticoid treatment compromises both permeability barrier
      homeostasis and stratum corneum integrity: inhibition of epidermal lipid
      synthesis accounts for functional abnormalities.
AB  - Prolonged exposure of human epidermis to excess endogenous or exogenous
      glucocorticoids can result in well-recognized cutaneous abnormalities. Here, we
      determined whether short-term glucocorticoid treatment would also display adverse
      effects, specifically on two key epidermal functions, permeability barrier
      homeostasis and stratum corneum integrity and cohesion, and the basis for such
      changes. In humans 3 d of treatment with a potent, commonly employed topical
      glucocorticoid (clobetasol), applied topically, produced a deterioration in
      barrier homeostasis, characterized by delayed barrier recovery and abnormal
      stratum corneum integrity (rate of barrier disruption with tape strippings) and
      stratum corneum cohesion (microg protein removed per stripping). Short-term
      systemic and topical glucocorticoid produced similar functional defects in mice,
      where the basis for these abnormalities was explored further. Both the production
      and secretion of lamellar bodies were profoundly decreased in topical
      glucocorticoid-treated mice resulting in decreased extracellular lamellar
      bilayers. These structural changes, in turn, were attributable to a profound
      global inhibition of lipid synthesis, demonstrated both in epidermis and in
      cultured human keratinocytes. The basis for the abnormality in stratum corneum
      integrity and cohesion was a diminution in the density of corneodesmosomes in the
      lower stratum corneum. We next performed topical replacement studies to determine
      whether lipid deficiency accounts for the glucocorticoid-induced functional
      abnormalities. The abnormalities in both permeability barrier homeostasis and
      stratum corneum integrity were corrected by topical applications of an equimolar
      distribution of free fatty acids, cholesterol, and ceramides, indicating that
      glucocorticoid-induced inhibition of epidermal lipid synthesis accounts for the
      derangements in both cutaneous barrier function and stratum corneum
      integrity/cohesion. These studies indicate that even short-term exposure to
      potent glucocorticosteroids can exert profound negative effects on cutaneous
      structure and function. Finally, topical replenishment with epidermal physiologic
      lipids could represent a potential method to reduce the adverse cutaneous effects
      of both topical glucocorticoid treatment and Cushing's syndrome.

PMID- 12603861
TI  - Interactions of human Myosin Va isoforms, endogenously expressed in human
      melanocytes, are tightly regulated by the tail domain.
AB  - Primary human epidermal melanocytes express six endogenous isoforms of the human
      actin-associated myosin Va motor protein, involved in organelle transport. As
      isoforms containing exon F are most abundant in melanocytes, we hypothesized that
      these isoforms probably have a melanocyte-specific function. To uncover the
      biologic role of the six isoforms we introduced enhanced green fluorescent
      protein (eGFP)-myosin Va tail constructs in human melanocytes. We found that the
      medial tail, undergoing alternative splicing, has to be expressed in combination
      with the globular tail in order to obtain clear colocalization with organelles.
      Our data show that isoforms lacking exon F but containing exon D are associated
      with vesicles near the Golgi area. Myosin Va isoforms containing exon F are able
      to colocalize with and influence melanosome distribution by indirect interaction
      with rab27a and direct interaction with melanophilin. These results indicate that
      the myosin Va medial tail domain provides the globular tail domain with organelle
      interacting specificity.

PMID- 12603862
TI  - Paclitaxel encapsulated in cationic liposomes diminishes tumor angiogenesis and
      melanoma growth in a "humanized" SCID mouse model.
AB  - Paclitaxel is an alkaloid that inhibits endothelial cell proliferation, motility,
      and tube formation at nanomolar concentrations. Cationic liposome preparations
      have been shown to target blood vessels. We wished to explore the possibility
      that paclitaxel encapsulated in cationic liposomes carries paclitaxel to blood
      vessels and thereby provides an antiangiogenic effect. We used a humanized SCID
      mouse melanoma model, which allowed us to analyze tumor growth and tumor
      angiogenesis in an orthotopic tumor model. Here, human melanoma cells grow on
      human dermis and are in part nourished by human vessels. We show that paclitaxel
      encapsulated in liposomes prevents melanoma growth and invasiveness and improves
      survival of mice. Moreover, liposome-encapsulated paclitaxel reduces vessel
      density at the interface between the tumor and the human dermis and reduces
      endothelial cell mitosis to background levels. In contrast, equimolar
      concentrations of paclitaxel solubilized in Cremophor EL(R) had only
      insignificant effects on tumor growth and did not reduce the mitotic index of
      endothelium in vivo, although the antiproliferative effect of solubilized
      paclitaxel in Cremophor EL(R)in vitro was identical to that seen with liposome
      coupled paclitaxel. In conclusion, we present a model of how to exploit cytotoxic
      effects of compounds to prevent tumor growth by using cationic liposomes for
      targeting an antiproliferative drug to blood vessels.

PMID- 12603863
TI  - Inhibition of erbB receptor family members protects HaCaT keratinocytes from
      ultraviolet-B-induced apoptosis.
AB  - In the human epidermis, the cells most at risk for the development of cancer due
      to sunlight exposure are the keratinocytes. In animal models, ultraviolet-B is a
      complete carcinogen, capable of inducing and promoting the development of
      malignant cells. A key element of ultraviolet-B-induced carcinogenesis is the
      ability of ultraviolet-B to induce the expression of a number of cellular
      proteins and activate growth factor receptor tyrosine kinases, including the erbB
      receptor family. Keratinocytes express the erbB1 (also called EGF-R, HER1), the
      erbB2 (also known as neu or HER2), and the erbB3 (HER3) subtypes. In general,
      activation of the erbB receptor family leads to a cellular proliferative
      response. In certain instances, however, activation of an erbB receptor can
      induce differentiation, cell cycle arrest, and even apoptosis. The inhibition of
      tyrosine kinase activity in rodent models and human skin has been shown to
      inhibit some ultraviolet-B response pathways. We have shown that the inhibition
      of erbB receptors, by both pharmaceutical and immunologic means, will inhibit
      ultraviolet-B-induced apoptosis in the HaCaT human keratinocyte cell line. This
      inhibition was specific for the erbB receptor family and specific for ultraviolet
      B-induced apoptosis. These results suggest that, in certain instances,
      ultraviolet-B-induced apoptotic signaling requires erbB family receptor activity.

PMID- 12603864
TI  - Regulation of tissue factor in microvascular dermal endothelial cells.
AB  - Inflammation is accompanied by activation of the coagulation cascade, manifested
      by thrombosis and fibrin generation. Whereas endothelial cells normally provide a
      nonthrombogenic surface, inflammatory mediators may induce the expression of
      tissue factor, rendering their surface thrombogenic. In order to define the
      mechanisms regulating the expression of tissue factor in the skin
      microvasculature, we examined tissue factor expression in human dermal
      microvascular endothelial cells. Quiescent human dermal microvascular endothelial
      cells did not constitutively express tissue factor protein, but were induced to
      express tissue factor by treatment with tumor necrosis factor-alpha in a time-
      and concentration-dependent fashion. Increased expression of tissue factor
      protein was accompanied by increases in steady-state mRNA levels. Tumor necrosis
      factor-alpha treatment resulted in increased expression of tissue factor
      heterogeneous nuclear RNA without changes in mRNA stability, suggesting that
      increased mRNA was mediated primarily via increased tissue factor gene
      transcription. In order to define the pathways regulating tissue factor
      induction, we examined the effects of MG-132, an inhibitor of nuclear factor
      kappaB activation, PD98059, an inhibitor of MEK1 action, and SB203580, an
      inhibitor of activated p38 activity. MG132 only partially blocked tumor necrosis
      factor-alpha-induced tissue factor protein expression, despite an almost complete
      inhibition of tumor necrosis factor-alpha-induced E-selectin expression. In
      contrast, SB203580, almost completely inhibited tumor necrosis factor-alpha
      induced tissue factor expression but inhibition of MEK1 by PD98059 had a minimal
      effect on tumor necrosis factor-alpha-mediated tissue factor induction in human
      dermal microvascular endothelial cells. Both SB203580 and MG132 treatment
      inhibited tumor necrosis factor-alpha-mediated increases in tissue factor mRNA
      and tissue factor gene transcription as measured by expression of tissue factor
      heterogeneous nuclear RNA. These data support a transcriptional role for both
      nuclear factor-kappaB and p38 mitogen-activated protein kinase, but not MEK1 in
      tissue factor gene expression in human dermal microvascular endothelial cells.

PMID- 12603865
TI  - Long-range polymerase chain reaction for specific full-length amplification of
      the human keratin 14 gene and novel keratin 14 mutations in epidermolysis bullosa
      simplex patients.

PMID- 12603867
TI  - Similarities and differences: signaling mechanisms induced by contact
      sensitizers.

PMID- 12603866
TI  - In vivo studies of mutant keratin 1 in ichthyosis hystrix Curth-Macklin.

PMID- 12603870
TI  - The risks of vaccinia in laboratory workers.

PMID- 12603871
TI  - Keratinocytes join forces with immune cells in the prosecution of SMVT as a
      "false" biotin transporter.

PMID- 12603872
TI  - Cardiovascular disorders. Changing behaviour.

PMID- 12603873
TI  - Heart failure.

PMID- 12603874
TI  - Cardiovascular disorders. Primary prevention.

PMID- 12603875
TI  - Secondary prevention of ischaemic cardiac events.

PMID- 12603876
TI  - Stroke management.

PMID- 12603877
TI  - Stroke prevention.

PMID- 12603878
TI  - Thromboembolism.

PMID- 12603880
TI  - Absence seizures in children.

PMID- 12603879
TI  - Unstable angina.

PMID- 12603881
TI  - Acute gastroenteritis in children.

PMID- 12603882
TI  - Acute otitis media.

PMID- 12603883
TI  - Attention deficit hyperactivity disorder in children.

PMID- 12603884
TI  - Bronchiolitis.

PMID- 12603885
TI  - Constipation.

PMID- 12603886
TI  - Croup.

PMID- 12603887
TI  - Depression in children and adolescents.

PMID- 12603888
TI  - Gastro-oesophageal reflux in children.

PMID- 12603889
TI  - Infantile colic.

PMID- 12603891
TI  - Anal fissure.

PMID- 12603890
TI  - Urinary tract infection.

PMID- 12603892
TI  - Colonic diverticular disease.

PMID- 12603893
TI  - Colorectal cancer.

PMID- 12603894
TI  - Helicobacter pylori infection.

PMID- 12603895
TI  - Stomach cancer.

PMID- 12603896
TI  - Meniere's disease.

PMID- 12603898
TI  - Tinnitus.

PMID- 12603897
TI  - Otitis media with effusion.

PMID- 12603900
TI  - Foot ulcers and amputations in diabetes.

PMID- 12603899
TI  - Cardiovascular disease in diabetes.

PMID- 12603901
TI  - Obesity.

PMID- 12603902
TI  - Age related macular degeneration.

PMID- 12603903
TI  - Ocular herpes simplex.

PMID- 12603905
TI  - Congenital toxoplasmosis.

PMID- 12603904
TI  - Chickenpox.

PMID- 12603906
TI  - Diarrhoea.

PMID- 12603907
TI  - HIV infection.

PMID- 12603908
TI  - Influenza.

PMID- 12603909
TI  - Leprosy.

PMID- 12603910
TI  - Lyme disease.

PMID- 12603911
TI  - Malaria: prevention in travellers.

PMID- 12603912
TI  - Meningococcal disease.

PMID- 12603913
TI  - Mother to child transmission of HIV.

PMID- 12603914
TI  - Tuberculosis.

PMID- 12603915
TI  - Acute renal failure.

PMID- 12603916
TI  - Benign prostatic hyperplasia.

PMID- 12603917
TI  - Chronic prostatitis.

PMID- 12603918
TI  - Prostate cancer: metastatic.

PMID- 12603919
TI  - Anorexia nervosa.

PMID- 12603920
TI  - Bulimia nervosa.

PMID- 12603921
TI  - Dementia.

PMID- 12603922
TI  - Depressive disorders.

PMID- 12603923
TI  - Generalised anxiety disorder.

PMID- 12603924
TI  - Obsessive compulsive disorder.

PMID- 12603925
TI  - Panic disorder.

PMID- 12603926
TI  - Post-traumatic stress disorder.

PMID- 12603927
TI  - Schizophrenia.

PMID- 12603928
TI  - Ankle sprain.

PMID- 12603929
TI  - Carpal tunnel syndrome.

PMID- 12603930
TI  - Chronic fatigue syndrome.

PMID- 12603931
TI  - Fracture prevention in postmenopausal women.

PMID- 12603932
TI  - Hallux valgus (bunions).

PMID- 12603933
TI  - Herniated lumbar disc.

PMID- 12603934
TI  - Hip fracture.

PMID- 12603935
TI  - Leg cramps.

PMID- 12603936
TI  - Non-steroidal anti-inflammatory drugs.

PMID- 12603937
TI  - Osteoarthritis.

PMID- 12603938
TI  - Plantar heel pain (including plantar fasciitis).

PMID- 12603939
TI  - Shoulder pain.

PMID- 12603940
TI  - Tennis elbow (lateral epicondylitis).

PMID- 12603941
TI  - Bell's palsy.

PMID- 12603942
TI  - Migraine headache.

PMID- 12603943
TI  - Parkinson's disease.

PMID- 12603944
TI  - Aphthous ulcers: recurrent.

PMID- 12603945
TI  - Impacted wisdom teeth.

PMID- 12603946
TI  - Postoperative pulmonary infections.

PMID- 12603947
TI  - Acute organophosphorus poisoning.

PMID- 12603948
TI  - Paracetamol (acetaminophen) poisoning.

PMID- 12603949
TI  - Perineal care.

PMID- 12603950
TI  - Preterm birth.

PMID- 12603951
TI  - Asthma.

PMID- 12603952
TI  - Chronic obstructive pulmonary disease.

PMID- 12603953
TI  - Community acquired pneumonia.

PMID- 12603954
TI  - Lung cancer.

PMID- 12603955
TI  - Spontaneous pneumothorax.

PMID- 12603956
TI  - Bacterial vaginosis.

PMID- 12603957
TI  - Genital chlamydial infection.

PMID- 12603958
TI  - Genital herpes.

PMID- 12603959
TI  - Genital warts.

PMID- 12603960
TI  - Gonorrhoea.

PMID- 12603961
TI  - Partner notification.

PMID- 12603962
TI  - Pelvic inflammatory disease.

PMID- 12603963
TI  - Atopic eczema.

PMID- 12603964
TI  - Chronic plaque psoriasis.

PMID- 12603965
TI  - Head lice.

PMID- 12603966
TI  - Herpes labialis.

PMID- 12603967
TI  - Non-genital warts.

PMID- 12603968
TI  - Scabies.

PMID- 12603969
TI  - Wrinkles.

PMID- 12603970
TI  - Breast cancer: metastatic.

PMID- 12603971
TI  - Breast cancer: non-metastatic.

PMID- 12603972
TI  - Breast pain.

PMID- 12603973
TI  - Endometriosis.

PMID- 12603974
TI  - Essential vulvodynia (vulval pain).

PMID- 12603975
TI  - Infertility and subfertility.

PMID- 12603976
TI  - Menopausal symptoms.

PMID- 12603977
TI  - Menorrhagia.

PMID- 12603978
TI  - Ovarian cancer.

PMID- 12603979
TI  - Premalignant vulval disorders.

PMID- 12603980
TI  - Pyelonephritis in non-pregnant women.

PMID- 12603981
TI  - Pressure sores.

PMID- 12603982
TI  - Venous leg ulcers.

PMID- 12603983
TI  - Emerging pattern of rabies deaths and increased viral infectivity.
AB  - Most human rabies deaths in the United States can be attributed to unrecognized
      exposures to rabies viruses associated with bats, particularly those associated
      with two infrequently encountered bat species (Lasionycteris noctivagans and
      Pipistrellus subflavus). These human rabies cases tend to cluster in the
      southeastern and northwestern United States. In these regions, most rabies deaths
      associated with bats in nonhuman terrestrial mammals are also associated with
      virus variants specific to these two bat species rather than more common bat
      species; outside of these regions, more common bat rabies viruses contribute to
      most transmissions. The preponderance of rabies deaths connected with the two
      uncommon L. noctivagans and P. subflavus bat rabies viruses is best explained by
      their evolution of increased viral infectivity.

PMID- 12603984
TI  - Aracatuba virus: a vaccinialike virus associated with infection in humans and
      cattle.
AB  - We describe a vaccinialike virus, Aracatuba virus, associated with a cowpoxlike
      outbreak in a dairy herd and a related case of human infection. Diagnosis was
      based on virus growth characteristics, electron microscopy, and molecular biology
      techniques. Molecular characterization of the virus was done by using polymerase
      chain reaction amplification, cloning, and DNA sequencing of conserved
      orthopoxvirus genes such as the vaccinia growth factor (VGF), thymidine kinase
      (TK), and hemagglutinin. We used VGF-homologous and TK gene nucleotide sequences
      to construct a phylogenetic tree for comparison with other poxviruses. Gene
      sequences showed 99% homology with vaccinia virus genes and were clustered
      together with the isolated virus in the phylogenetic tree. Aracatuba virus is
      very similar to Cantagalo virus, showing the same signature deletion in the gene.
      Aracatuba virus could be a novel vaccinialike virus or could represent the spread
      of Cantagalo virus.

PMID- 12603986
TI  - Elimination of epidemic methicillin-resistant Staphylococcus aureus from a
      university hospital and district institutions, Finland.
AB  - From August 1991 to October 1992, two successive outbreaks of methicillin
      resistant Staphylococcus aureus (MRSA) occurred at a hospital in Finland. During
      and after these outbreaks, MRSA was diagnosed in 202 persons in our medical
      district; >100 cases involved epidemic MRSA. When control policies failed to stop
      the epidemic, more aggressive measures were taken, including continuous staff
      education, contact isolation for MRSA-positive patients, systematic screening for
      persons exposed to MRSA, cohort nursing of MRSA-positive and MRSA-exposed
      patients in epidemic situations, and perception of the 30 medical institutions in
      that district as one epidemiologic entity brought under surveillance and control
      of the infection control team of Turku University Hospital. Two major epidemic
      strains, as well as eight additional strains, were eliminated; we were also able
      to prevent nosocomial spread of other MRSA strains. Our data show that
      controlling MRSA is possible if strict measures are taken before the organism
      becomes endemic. Similar control policies may be successful for dealing with new
      strains of multiresistant bacteria, such as vancomycin-resistant strains of S.
      aureus.

PMID- 12603985
TI  - Equine amplification and virulence of subtype IE Venezuelan equine encephalitis
      viruses isolated during the 1993 and 1996 Mexican epizootics.
AB  - To assess the role of horses as amplification hosts during the 1993 and 1996
      Mexican Venezuelan equine encephalitis (VEE) epizootics, we subcutaneously
      infected 10 horses by using four different equine isolates. Most horses showed
      little or no disease and low or nonexistent viremia. Neurologic disease developed
      in only 1 horse, and brain histopathologic examination showed meningeal
      lymphocytic infiltration, perivascular cuffing, and focal encephalitis. Three
      animals showed mild meningoencephalitis without clinical disease. Viral RNA was
      detected in the brain of several animals 12-14 days after infection. These data
      suggest that the duration and scope of the recent Mexican epizootics were limited
      by lack of equine amplification characteristic of previous, more extensive VEE
      outbreaks. The Mexican epizootics may have resulted from the circulation of a
      more equine-neurotropic, subtype IE virus strain or from increased transmission
      to horses due to amplification by other vertebrate hosts or transmission by more
      competent mosquito vectors.

PMID- 12603987
TI  - Annual Mycobacterium tuberculosis infection risk and interpretation of clustering
      statistics.
AB  - Several recent studies have used proportions of tuberculosis cases sharing
      identical DNA fingerprint patterns (i.e., isolate clustering) to estimate the
      extent of disease attributable to recent transmission. Using a model of
      introduction and transmission of strains with different DNA fingerprint patterns,
      we show that the properties and interpretation of clustering statistics may
      differ substantially between settings. For some unindustrialized countries, where
      the annual risk for infection has changed little over time, 70% to 80% of all age
      groups may be clustered during a 3-year period, which underestimates the
      proportion of disease attributable to recent transmission. In contrast, for a
      typical industrialized setting (the Netherlands), clustering declines with
      increasing age (from 75% to 15% among young and old patients, respectively) and
      underestimates the extent of recent transmission only for young patients. We
      conclude that, in some settings, clustering is an unreliable indicator of the
      extent of recent transmission.

PMID- 12603988
TI  - Endemic babesiosis in another eastern state: New Jersey.
AB  - In the United States, most reported cases of babesiosis have been caused by
      Babesia microti and acquired in the northeast. Although three cases of babesiosis
      acquired in New Jersey were recently described by others, babesiosis has not been
      widely known to be endemic in New Jersey. We describe a case of babesiosis
      acquired in New Jersey in 1999 in an otherwise healthy 53-year-old woman who
      developed life-threatening disease. We also provide composite data on 40 cases of
      babesiosis acquired from 1993 through 2001 in New Jersey. The 40 cases include
      the one we describe, the three cases previously described, and 36 other cases
      reported to public health agencies. The 40 cases were acquired in eight (38.1%)
      of the 21 counties in the state. Babesiosis, a potentially serious zoonosis, is
      endemic in New Jersey and should be considered in the differential diagnosis of
      patients with fever and hemolytic anemia, particularly in the spring, summer, and
      early fall.

PMID- 12603989
TI  - Molecular typing of IberoAmerican Cryptococcus neoformans isolates.
AB  - A network was established to acquire basic knowledge of Cryptococcus neoformans
      in IberoAmerican countries. To this effect, 340 clinical, veterinary, and
      environmental isolates from Argentina, Brazil, Chile, Colombia, Mexico, Peru,
      Venezuela, Guatemala, and Spain were typed by using M13 polymerase chain reaction
      fingerprinting and orotidine monophosphate pyrophosphorylase (URA5) gene
      restriction fragment length polymorphism analysis with HhaI and Sau96I in a
      double digest. Both techniques grouped all isolates into eight previously
      established molecular types. The majority of the isolates, 68.2% (n=232), were
      VNI (var. grubii, serotype A), which accords with the fact that this variety
      causes most human cryptococcal infections worldwide. A smaller proportion, 5.6%
      (n=19), were VNII (var. grubii, serotype A); 4.1% (n=14), VNIII (AD hybrid), with
      9 isolates having a polymorphism in the URA5 gene; 1.8% (n=6), VNIV (var.
      neoformans, serotype D); 3.5% (n=12), VGI; 6.2% (n=21), VGII; 9.1% (n=31), VGIII,
      and 1.5% (n=5) VGIV, with all four VG types containing var. gatii serotypes B and
      C isolates.

PMID- 12603990
TI  - Health and economic impact of surgical site infections diagnosed after hospital
      discharge.
AB  - Although surgical site infections (SSIs) are known to cause substantial illness
      and costs during the index hospitalization, little information exists about the
      impact of infections diagnosed after discharge, which constitute the majority of
      SSIs. In this study, using patient questionnaire and administrative databases, we
      assessed the clinical outcomes and resource utilization in the 8-week
      postoperative period associated with SSIs recognized after discharge. SSI
      recognized after discharge was confirmed in 89 (1.9%) of 4,571 procedures from
      May 1997 to October 1998. Patients with SSI, but not controls, had a significant
      decline in SF-12 (Medical Outcomes Study 12-Item Short-Form Health Survey) mental
      health component scores after surgery (p=0.004). Patients required significantly
      more outpatient visits, emergency room visits, radiology services, readmissions,
      and home health aide services than did controls. Average total costs during the 8
      weeks after discharge were US dollars 5,155 for patients with SSI and US dollars
      1,773 for controls (p<0.001).

PMID- 12603991
TI  - Applying network theory to epidemics: control measures for Mycoplasma pneumoniae
      outbreaks.
AB  - We introduce a novel mathematical approach to investigating the spread and
      control of communicable infections in closed communities. Mycoplasma pneumoniae
      is a major cause of bacterial pneumonia in the United States. Outbreaks of
      illness attributable to mycoplasma commonly occur in closed or semi-closed
      communities. These outbreaks are difficult to contain because of delays in
      outbreak detection, the long incubation period of the bacterium, and an
      incomplete understanding of the effectiveness of infection control strategies.
      Our model explicitly captures the patterns of interactions among patients and
      caregivers in an institution with multiple wards. Analysis of this contact
      network predicts that, despite the relatively low prevalence of mycoplasma
      pneumonia found among caregivers, the patterns of caregiver activity and the
      extent to which they are protected against infection may be fundamental to the
      control and prevention of mycoplasma outbreaks. In particular, the most effective
      interventions are those that reduce the diversity of interactions between
      caregivers and patients.

PMID- 12603992
TI  - Using hospital antibiogram data to assess regional pneumococcal resistance to
      antibiotics.
AB  - Antimicrobial resistance to penicillin and macrolides in Streptococcus pneumoniae
      has increased in the United States over the past decade. Considerable geographic
      variation in susceptibility necessitates regional resistance tracking.
      Traditional active surveillance is labor intensive and costly. We collected
      antibiogram reports from North Carolina hospitals and assessed pneumococcal
      susceptibility to multiple agents from 1996 through 2000. Susceptibility in North
      Carolina was consistently lower than the national average. Aggregating
      antibiogram data is a feasible and timely method of monitoring regional
      susceptibility patterns and may also prove beneficial in measuring the effects of
      interventions to decrease antimicrobial resistance.

PMID- 12603993
TI  - Influence of role models and hospital design on hand hygiene of healthcare
      workers.
AB  - We assessed the effect of medical staff role models and the number of health-care
      worker sinks on hand-hygiene compliance before and after construction of a new
      hospital designed for increased access to handwashing sinks. We observed health
      care worker hand hygiene in four nursing units that provided similar patient care
      in both the old and new hospitals: medical and surgical intensive care,
      hematology/oncology, and solid organ transplant units. Of 721 hand-hygiene
      opportunities, 304 (42%) were observed in the old hospital and 417 (58%) in the
      new hospital. Hand-hygiene compliance was significantly better in the old
      hospital (161/304; 53%) compared to the new hospital (97/417; 23.3%) (p<0.001).
      Health-care workers in a room with a senior (e.g., higher ranking) medical staff
      person or peer who did not wash hands were significantly less likely to wash
      their own hands (odds ratio 0.2; confidence interval 0.1 to 0.5); p<0.001). Our
      results suggest that health-care worker hand-hygiene compliance is influenced
      significantly by the behavior of other health-care workers. An increased number
      of hand-washing sinks, as a sole measure, did not increase hand-hygiene
      compliance.

PMID- 12603995
TI  - Risk factors for sporadic giardiasis: a case-control study in southwestern
      England.
AB  - To investigate risk factors for sporadic infection with Giardia lamblia acquired
      in the United Kingdom, we conducted a matched case-control study in southwest
      England in 1998 and 1999. Response rates to a postal questionnaire were 84%
      (232/276) for cases and 69% (574/828) for controls. In multivariable analysis,
      swallowing water while swimming (p<0.0001, odds ratio [OR] 6.2, 95% confidence
      intervals [CI] 2.3 to 16.6), recreational fresh water contact (p=0.001, OR 5.5,
      95% CI 1.9 to 15.9), drinking treated tap water (p<0.0001, OR 1.3, 95% CI 1.1 to
      1.5 for each additional glass per day), and eating lettuce (pc=0.01, OR 2.2, 95%
      CI 1.2 to 4.3) had positive and independent associations with infection. Although
      case-control studies are prone to bias and the risk of Giardia infection is
      minimized by water treatment processes, the possibility that treated tap water is
      a source of sporadic giardiasis warrants further investigation.

PMID- 12603994
TI  - Aeromonas isolates from human diarrheic stool and groundwater compared by pulsed
      field gel electrophoresis.
AB  - Gastrointestinal infections of Aeromonas species are generally considered
      waterborne; for this reason, Aeromonas hydrophila has been placed on the United
      States Environmental Protection Agency Contaminant Candidate List of emerging
      pathogens in drinking water. In this study, we compared pulsed-field gel
      electrophoresis patterns of Aeromonas isolates from stool specimens of patients
      with diarrhea with Aeromonas isolates from patients' drinking water. Among 2,565
      diarrheic stool specimens submitted to a Wisconsin clinical reference laboratory,
      17 (0.66%) tested positive for Aeromonas. Groundwater isolates of Aeromonas were
      obtained from private wells throughout Wisconsin and the drinking water of
      Aeromonas-positive patients. The analysis showed that the stool and drinking
      water isolates were genetically unrelated, suggesting that in this population
      Aeromonas gastrointestinal infections were not linked with groundwater exposures.

PMID- 12603996
TI  - Viral encephalitis in England, 1989-1998: what did we miss?
AB  - We analyzed hospitalizations in England from April 1, 1989, to March 31, 1998,
      and identified approximately 700 cases, 46 fatal, from viral encephalitis that
      occurred during each year; most (60%) were of unknown etiology. Of cases with a
      diagnosis, the largest proportion was herpes simplex encephalitis. Using normal
      and Poisson regression, we identified six possible clusters of unknown etiology.
      Over 75% of hospitalizations are not reported through the routine laboratory and
      clinical notification systems, resulting in underdiagnosis of viral encephalitis
      in England. Current surveillance greatly underascertains incidence of the disease
      and existence of clusters; in general, outbreaks are undetected. Surveillance
      systems must be adapted to detect major changes in epidemiology so that timely
      control measures can be implemented.

PMID- 12603997
TI  - Preparing for a bioterrorist attack: legal and administrative strategies.
AB  - This article proposes and discusses legal and administrative preparations for a
      bioterrorist attack. To perform the duties expected of public health agencies
      during a disease outbreak caused by bioterrorism, an agency must have a
      sufficient number of employees and providers at work and a good communications
      system between staff in the central offices of the public health agency and those
      in outlying or neighboring agencies and hospitals. The article proposes
      strategies for achieving these objectives as well as for removing legal barriers
      that discourage agencies, institutions, and persons from working together for the
      overall good of the community. Issues related to disease surveillance and special
      considerations regarding public health restrictive orders are discussed.

PMID- 12603998
TI  - B-virus (Cercopithecine herpesvirus 1) infection in humans and macaques:
      potential for zoonotic disease.
AB  - Nonhuman primates are widely used in biomedical research because of their
      genetic, anatomic, and physiologic similarities to humans. In this setting, human
      contact directly with macaques or with their tissues and fluids sometimes occurs.
      Cercopithecine herpesvirus 1 (B virus), an alphaherpesvirus endemic in Asian
      macaques, is closely related to herpes simplex virus (HSV). Most macaques carry B
      virus without overt signs of disease. However, zoonotic infection with B virus in
      humans usually results in fatal encephalomyelitis or severe neurologic
      impairment. Although the incidence of human infection with B virus is low, a
      death rate of >70% before the availability of antiviral therapy makes this virus
      a serious zoonotic threat. Knowledge of the clinical signs and risk factors for
      human B-virus disease allows early initiation of antiviral therapy and prevents
      severe disease or death.

PMID- 12603999
TI  - Photorhabdus species: bioluminescent bacteria as emerging human pathogens?
AB  - We report two Australian patients with soft tissue infections due to Photorhabdus
      species. Recognized as important insect pathogens, Photorhabdus spp. are
      bioluminescent gram-negative bacilli. Bacteria belonging to the genus are
      emerging as a cause of both localized soft tissue and disseminated infections in
      humans in the United States and Australia. The source of infection in humans
      remains unknown.

PMID- 12604000
TI  - Life-threatening infantile diarrhea from fluoroquinolone-resistant Salmonella
      enterica typhimurium with mutations in both gyrA and parC.
AB  - Salmonella Typhimurium DT12, isolated from a 35-day-old infant with diarrhea, was
      highly resistant to ampicillin, tetracycline, chloramphenicol, streptomycin,
      gentamycin, sulfamethoxazole/trimethoprim, nalidixic acid, and fluoroquinolones.
      The patient responded to antibiotic therapy with fosfomycin. Multidrug-resistance
      may become prevalent in Salmonella infections in Japan, as shown in this first
      case of a patient infected with fluoroquinolone-resistant Salmonella.

PMID- 12604001
TI  - Invasive type e Haemophilus influenzae disease in Italy.
AB  - We describe the first reported cases of invasive type e Haemophilus influenzae
      disease in Italy. All five cases occurred in adults. The isolates were
      susceptible to ampicillin and eight other antimicrobial agents. Molecular
      analysis showed two distinct type e strains circulating in Italy, both containing
      a single copy of the capsulation locus.

PMID- 12604002
TI  - Public health surveillance for Australian bat lyssavirus in Queensland,
      Australia, 2000-2001.
AB  - From February 1, 2000, to December 4, 2001, a total of 119 bats (85
      Megachiroptera and 34 Microchiroptera) were tested for Australian bat lyssavirus
      (ABLV) infection. Eight Megachiroptera were positive by immunofluorescence assay
      that used cross-reactive ntibodies to rabies nucleocapsid protein. A case study
      of cross-species transmission of ABLV supports the conclusion that a bat
      reservoir exists for ABLV in which the virus circulates across Megachiroptera
      species within mixed communities.

PMID- 12604003
TI  - Infection of cultured human and monkey cell lines with extract of penaeid shrimp
      infected with Taura syndrome virus.
AB  - Taura syndrome virus (TSV) affects shrimp cultured for human consumption.
      Although TSV is related to the Cricket Paralysis virus, it belongs to the
      "picornavirus superfamily," the most common cause of viral illnesses. Here we
      demonstrate that TSV also infects human cell lines, which may suggest that
      Penaeus is a potential reservoir of this virus.

PMID- 12604005
TI  - Dual infection by dengue virus and Shigella sonnei in patient returning from
      India.

PMID- 12604004
TI  - Fluoroquinolone resistance in Campylobacter jejuni isolates in travelers
      returning to Finland: association of ciprofloxacin resistance to travel
      destination.
AB  - Ciprofloxacin resistance was analyzed in 354 Campylobacter jejuni isolates
      collected during two study periods (1995-1997 and 1998-2000) from travelers
      returning to Finland. The increase in resistance between the two periods was
      significant among all isolates (40% vs. 60%; p<0.01), as well as among those from
      Asia alone (45% vs. 72%; p<0.01).

PMID- 12604006
TI  - St. Louis encephalitis in Argentina: the first case reported in the last
      seventeen years.

PMID- 12604007
TI  - Streptomyces bikiniensis bacteremia.

PMID- 12604009
TI  - Pneumocystis carinii vs. Pneumocystis jiroveci: another misnomer (response to
      Stringer et al.).

PMID- 12604008
TI  - Drug-resistant Mycobacterium tuberculosis among new tuberculosis patients,
      Yangon, Myanmar.

PMID- 12604012
TI  - Morphine stimulates iNOS expression via a rebound from inhibition in human
      macrophages: nitric oxide involvement.
AB  - We have previously demonstrated that exposure of human macrophages to morphine
      results in transient inhibition of cell migratory behavior and adoption of an
      inactive conformation followed by a return from inhibition resulting in a
      significant increase in migration velocity and number of activated cells. In the
      current report, we demonstrate that the return to activation is nitric oxide
      dependent and inhibited by prior exposure to the opiate antagonist, naloxone.
      Exposure of macrophages to morphine for 6 hours resulted in a marked inhibition
      of cell activity and shift of the cell confirmation from amoeboid to round. The
      inactivation period lasted approximately 2 hrs and was followed by a period of
      hyperactivity. Incubation of macrophages with naloxone, prior to addition of
      morphine, inhibited both inactivation and hyper activation phases whereas,
      naloxone administration just prior to the hyper activation phase did not affect
      subsequent hyper activation. Morphine acutely stimulates the transient release of
      nitric oxide (NO) resulting in subsequent macrophage rounding and inactivation.
      Prolonged observation of the cells revealed another phase of NO release 12 hours
      following initial morphine exposure that was characterized by prolonged NO
      production. These data are consistent with acute constitutive NO synthase
      activation and inducible NO synthase activation following prolonged morphine
      exposure. Release of NO and changes in cellular activation mediated by morphine
      was abrogated by NOS, or morphine inhibitors, added prior to morphine exposure.
      In contrast, NOS, or morphine inhibitors, added during the inhibitory phase had
      no impact on the subsequent hyper activation phase. It did, however, have an
      impact on the hyper activation phase when added prior to morphine. These data
      demonstrate that morphine is capable of induction of both cNOS and iNOS coupled
      NO release that regulates the macrophage activation state. This may provide
      insight into the functioning of morphine following periods of trauma or stress
      when the levels of the opiate increase and, subsequently, inflammatory function
      is markedly altered.

PMID- 12604011
TI  - Anti-inflammatory actions of flavonoids and structural requirements for new
      design.
AB  - Flavonoids are low molecular weight compounds rich in seeds, citrus fruits, olive
      oil, tea and red wine, with potent antioxidant, cytoprotective and
      antiinflammatory activities. Flavonoids are composed of a three-ring structure
      (A,B and C) with various substitutions; they can be subdivided according to the
      presence of an oxy group at position 4, a double bond between carbon atoms 2 and
      3 or a hydroxyl group in position 3 of the C (middle) ring. Particular
      hydroxylation patterns of the B ring of the flavones permit them to inhibit
      histamine, tryptase, interleukin-6 and interleukin-8 release from human umbilical
      cord derived cultured mast cells, as well as from macrophages. The catechol (o
      dihydroxy) group in the B ring as in quercetin confers potent inhibitory ability,
      while a pyrogallol (trihydroxy) group, as in myricetin, produces even higher
      activity. However, addition of one hydroxyl group on position 2&#x2032; of the B
      ring, as in the flavonol morin, renders this compound inactive. The C2-C3 double
      bond of the C ring appears to increase scavenger activity because it confers
      stability to the phenoxy-radicals produced, while the 4-oxo (keto double bond at
      position 4 of the C ring) increases free radical scavenger activity by
      delocalizing electrons from the B ring. The 3-OH group on the C ring appears tobe
      critical for anti-inflammatory activity. Inhibition of mast cell secretion was
      shown to be mediated by a 78-kD phosphoprotein which has been cloned and serves
      as a bridge between the cell surface and the cytoskeleton. Phosphorylation at
      particular sites in the C-terminus unfolds the three dimensional structure of
      this protein making actin binding sites accessible; crosslinking with actin in
      the cytoskeleton prevents secretion of inflammatory mediators. These properties
      present unique opportunities for the synthesis of new compounds for the treatment
      of inflammatory and possibly proliferative disorders.

PMID- 12604013
TI  - Effect of anticoagulants on activation of polymorphonuclear leukocytes induced by
      shear stress.
AB  - We analyzed how actin polymerization, CD11b expression and homotypic aggregation
      could be used as markers to study leukocyte activation. Leukocytes were obtained
      from blood anticoagulated with: citrate, unfractioned heparin (UH) and low
      molecular weight heparin (LMWH). Flow cytometry was used to study actin
      polymerization and expression of CD11b after leukocyte exposure to shear stress.
      Leukocyte aggregation was microscopically assessed. Shear increased both actin
      polymerization and expression of CD11b in citrated blood (100.1&#x00B1;7.1 vs.
      85.8&#x00B1;8.5 p&#x003C; 0.05 and 53.5&#x00B1;3.5 vs. 20.7&#x00B1;5.1; p&#x003C;
      0.005 respectively). These parameters remained unmodified in UH samples. Using
      both anticoagulants together, we observed increase in CD11b expression induced by
      shear stress (59.3&#x00B1;2.1 vs. 25.1&#x00B1;11.0; p&#x003C; 0,05). LMWH samples
      showed higher basal levels of actin polymerization and CD11b expression than
      citrated samples (237&#x00B1;40.8, vs. 85.8&#x00B1;8.5 p&#x003C; 0.05 and
      47.8&#x00B1;2.6, vs. 20.7&#x00B1;5.1; p&#x003C; 0.005) but no changes induced by
      shear were observed. When LMWH was used in combination with citrate we observed a
      decrease in basal activation and significant modifications in CD11b expression
      induced by shear stress (80.0&#x00B1;4.1 vs. 50.4&#x00B1;2.7). Leukocyte
      aggregation was modified by UH at basal levels and by LMWH after shear stress.
      These results indicate that exposure to shear stress results in leukocyte
      activation. The choice of anticoagulant is a crucial factor in studies of
      leukocyte function.

PMID- 12604014
TI  - Occupational asthma due to metoclopramide hydrochloride (MCPH).
AB  - Metoclopramide hydrochloride (MCPH) is dopamine antagonist antiemetic drug that
      binds D2 receptor at the central nervous system and peripheral levels, which
      stimulates the upper gastrointestinal tract motility. It is often used in the
      management of some forms of nausea and vomiting (1-3). Occupational allergy to
      drugs is seldom reported. No case of occupational allergy to MCPH have been
      reported, to date. We present a case of airborne allergic asthma in a worker
      employed in the synthesis of Metoclopramide hydrochloride.

PMID- 12604015
TI  - Serum tryptase in allergic rhinitis: effect of cetirizine treatment.
AB  - Activated mast cells release a large range of potent mediators of allergic
      inflammation, including proteases. The tryptase serum levels were evaluated in 13
      subjects suffering from allergic perennial rhinitis. Moreover the effects of
      cetirizine treatment on serum tryptase were studied using the UniCap&#x2122;
      tryptase fluoroenzymeimmunoassay. In allergic patients the serum tryptase values
      (M&#x00B1;SD: 6.1 &#x00B1; 2.4 &#x03BC;g/L) were significantly (p &#x003C; 0.02)
      higher than the values detected in controls (3.0 &#x00B1; 1.2 &#x03BC;g/L). In
      allergic rhinitis, after antihistamine treatment, tryptase values (4.4 &#x00B1;
      1.8 &#x03BC;g/L) decreased significantly (p &#x003C; 0.001). After two weeks from
      the cetirizine stop, the tryptase levels increased again (5.5 &#x00B1; 2.6
      &#x03BC;g/l). The results demonstrate that mast cells are constantly activated in
      perennial allergic rhinitis. The antihistamine treatment is effective in reducing
      the tryptase release from mast cells, but the mechanism of action of cetirizine
      is still to understand.

PMID- 12604016
TI  - Cytokine and nitric oxide levels in a rat model of immunologic protection from
      adjuvant-induced arthritis.
AB  - In the present study we investigated the correlation between the progression of
      adjuvant arthritis induced by Mycobacterium butyricum and the production of
      nitric oxide and some pro- and anti-inflammatory cytokines in arthritic rats and
      in rats treated with low intra-peritoneal doses of Mycobacterium 3 and 10 days
      after arthritis induction. The intra-peritoneal administration of Mycobacterium
      antigen significantly inhibited disease development. Compared to healthy rats, a
      rise in serum and peritoneal pro-inflammatory cytokines was observed in all
      arthritic rats already from the 14 day. The treatment with intra-peritoneal
      Mycobacterium was associated with a significant reduction in IL-6 serum
      concentrations and a slight decrease of IFN-gamma production by peritoneal
      macrophages. Nitrite/nitrate plasma and peritoneal levels were significantly
      higher in all arthritic rats. Intra-peritoneal administration of Mycobacterium
      caused a further increase in nitrite/nitrate plasma concentrations, while no
      differences were evident in nitric oxide production by peritoneal macrophages.
      From our data it is evident that among the variables here investigated, IL-6
      seems to be the more representative marker of the disease and of the treatment
      effect. A possible role of nitric oxide as a modulator rather than a direct
      mediator in this model of inflammation is discussed.

PMID- 12604017
TI  - CD23 and CD69 expression on human neutrophils of healthy subjects and patients
      with peripheral arterial occlusive disease.
AB  - In this work we studied, on human neutrophils from healthy donors and patients
      with peripheral arterial occlusive disease, the expression of CD23 and CD69 and
      the modulatory effects of IFN-gamma, GM-CSF and IL-4. Neutrophils were isolated
      from 9 patients and 9 healthy subjects and cultured for 24 h in absence or
      presence of IFN-gamma (1000 U/ml), GM-CSF (10 U/ml) and IL-4 (10 ng/ml).
      Expression of CD23 and CD69 was analyzed by FACScan cytofluorimeter. Neutrophils
      of both patients and healthy donors resulted negative for CD23 and CD69
      expression immediately after isolation. After 24 h without stimuli, neutrophils
      from some patients and healthy donors expressed CD23 and CD69. IFN-gamma and GM
      CSF had opposite effects on these two antigens, down-regulating CD23 and up
      regulating CD69. IFN-gamma, GM-CSF and IL-4 were not able to induce CD23
      expression, while CD69 expression was induced in some negative healthy donors and
      patients by IFN-gamma, GM-CSF and IL-4 respectively. From our data, we identified
      two subpopulations of neutrophils that, independently from the vascular
      pathology, showed a different behaviour towards temperature and some cytokines.

PMID- 12604019
TI  - Leishmania antibodies in children?s serum samples in correlation with the disease
      in dogs.
AB  - Sera of 489 children from Northern Greece aged between 6 months and 15 years of
      age and aflicted with different clinical entities, were tested for anti ?
      Leishmania infantum specific IgG and IgM antibodies, using an ELISA (enzyme
      linked immunosorbent assay) technique. In this survey, a remarkably high
      percentage (8.5&#x0025;) of hospitalized children reacted positively to this
      method. Twenty three out of 489 children (4.7&#x0025;) had IgG antibodies,
      seventeen (3.5&#x0025;) IgM, while two (0.4&#x0025;) had both IgG and IgM
      antibodies against soluble antigen of L. infantum promastigotes. Females had a
      higher seropositivity than males. The highest prevalence was observed in males
      aged between 6 months and 5 years old (10 out of 19), while the lowest was
      observed also in males aged between 11 and 15 years old (5 out of 11).
      Seropositivity rate was higher in children below 5 years of age. Some
      epidemiologic, as well as clinical data of canine Leishmaniosis from Northern
      Greece are discussed.

PMID- 12604018
TI  - Effects of 50 Hz sinusoidal electromagnetic fields on MCP-1 and RANTES generated
      from activated human macrophages.
AB  - Extremely low frequency electromagnetic fields (ELF-EMF) induce cellular changes
      and modulate signal transduction pathways, and may be beneficial in the treatment
      of inflammatory diseases. In this paper we studied two inflammatory chemokines,
      MCP-1 and RANTES produced by human cultured isolated monocytes from peripheral
      blood, with or without PHA and in the absence or presence of 50 Hz magnetic field
      of 1.0 mT for 24 h. The production of MCP-1 and RANTES was determined by ELISA
      method. Here, we found that ELF-EMF strongly inhibited the production of these
      chemokines stimulated by PHA, while the control was not affected. Since MCP-1 and
      RANTES exert chemoattraction for several populations inflammatory leukocytes, the
      inhibitory effect of these chemokines could be one of the mechanisms by which ELF
      EMF is therapeutic in inflammatory diseases.

PMID- 12604020
TI  - Preliminary evidence of modulating Th1 cytokine after allergen challenge.
AB  - We wanted to determine whether a paradigm switch in Th1/Th2 phenotypes in splenic
      lymphocytes could be induced in BALB/c mice after ultraviolet-B (UVB) irradiation
      and exposure to pollen. Results showed that UVB irradiation increased IL-1 but
      decreased IL-12 in vivo, and caused significant cell destruction of macrophages
      in vitro. We then gave mice cedar pollen intranasally, UVB irradiation
      (6kJ/cm<sup>2</sup>), and then splenic lymphocyte functions were examined.
      Results revealed that: 1) the level of IFN-gamma of splenic lymphocytes from UVB
      irradiated mice was significantly decreased, especially in pollen-exposed mice;
      2) UVB irradiation did not augment IL-4 levels; 3) IgE levels from UVB-irradiated
      mice did not increase. UVB irradiation (6kJ/cm<sup>2</sup>) did not induce Th2
      response but suppressed Th1 cytokine, suggesting that Th1 could be more
      susceptible to UVB irradiation than Th2.

PMID- 12604021
TI  - Involvement of bovine lactoferrin moieties in the inhibition of herpes simplex
      virus type 1 infection.
AB  - Bovine lactoferrin (BLf) is an iron binding protein folded in two lobes, N- and C
      lobes. In this study we have reported the inhibitory activity towards herpes
      simplex virus type 1 (HSV-1) in vitro infection of BLf tryptic digested N- and C
      lobes in comparison with the whole protein. The N-lobe and C-lobe exerted an anti
      herpesvirus activity 50- and 10-fold lower than native BLf, respectively. In
      order to assess the phase of viral replication affected, lactoferrin-derived
      lobes were added to the cells at different non cytotoxic concentrations, during
      the whole cycle of viral infection or during viral attachment step, demonstrating
      that both lobes interfered with the early phases of infection. Among the BLf
      tryptic digested fragments, two negatively-charged small peptides deriving from N
      lobe, previously shown effective towards HSV-1, have been further studied. We
      assessed that the net negative charge of these peptides was not responsible for
      the antiviral activity since their activity was not modified when the aspartic
      and glutamic acidic residues of these peptides were replaced with asparagine and
      glutamine, respectively. The experiments here reported confirm a pivotal role of
      N-lobe in inhibiting viral infection. However, the residual inhibiting activity
      of C-lobe and the similar efficacy shown by negatively or positively charged
      peptides strongly support the idea that the antiviral activity of bovine
      lactoferrin cannot be fully explained simply on the basis of competition between
      the protein and viral recognition sites for binding to glycosaminoglycans.

PMID- 12604022
TI  - High incidence of Helicobacter pylori infection in patients with systemic
      sclerosis: association with Sicca Syndrome.
AB  - To test the incidence of Helicobacter pylori (HP) infection in patients affected
      by Systemic Sclerosis (SSc) a swift urease test, followed by histologic
      confirmation for the presence of HP was verified in 35 SSc patients. Serum
      samples from 46 patients were tested for HP IgG antibodies by an enzyme-linked
      immunosorbent assay. Urease test demonstrated the presence of HP in 23 patients
      out of 35 (66&#x0025;); 12 of them were negative to colonization. A Sicca
      syndrome, with abnormal Schirmer?s test and dry mouth was detected in 66&#x0025;
      of the patients. 78&#x0025; of the patients with Sicca syndrome had a concomitant
      HP infection, compared to 42&#x0025; of those without the syndrome (p=0,029).
      Altered peristalsis and reduced salivary clearance usually encourage HP
      infection. In patients with Systemic Sclerosis we found an enhanced frequency of
      HP infection.

PMID- 12604023
TI  - Zafirlukast versus budesonide on bronchial reactivity in subjects with mild
      persistent asthma.
AB  - Asthma is one of the most common chronic diseases in children and adults. Recent
      studies have shown that in asthmatic patients treated with inhaled
      corticosteroids there is a better disease?s control when adding a second drug,
      than increasing the corticosteroid?s dose. The aim of this study has been to
      evaluate the effectiveness and tolerance of zafirlukast, a leukotriene receptor
      antagonist, versus budesonide in clinically steady patients with mild persistent
      bronchial asthma. We have enrolled 36 subjects non smokers, with mild persistent
      bronchial asthma and 12 healthy subjects as control group. At the beginning of
      this study and at the end of the treatment (8 weeks), all patients underwent
      complete clinical work-up, pulmonary function testing (FEV1, PEF and FVC) and
      methacholine challenge test. The patients were divided into 3 groups: group A) 20
      mg of zafirlukast twice a day; group B) 400 mg of budesonide twice a day; group
      C) 20 mg of zafirlukast twice a day and 400 mg of budesonide twice a day. Basal
      FEV1 and PEF presented no significant statistical differences between control
      subjects and patients of group A, B and C. After eight weeks there were no
      significant changes for FEV1 and PEF among the three groups. After therapy a
      strong significant increase of PD20 was documented in group A (p&#x003C;0.005),
      group B (p&#x003C;0.001) and group C (p&#x003C;0.005), respect to baseline
      values. The antileukotriene drugs could be taken as an alternative drug, or in
      association with low-dose inhaled corticosteroids, in patients with mild
      persistent asthma, both for their clinical effectiveness and their easy
      ingestion, which is confirmed in compliance studies on inhaled steroids.

PMID- 12604024
TI  - Clinical practice improvement program for immunotherapy of respiratory allergic
      diseases.
AB  - The aim of this study was to develop a clinical practice improvement (CPI)
      program for the allergen immunotherapy of allergic respiratory diseases. The
      study was conducted between 1994 and 1999, using an observational methodology in
      line with normal clinical practice, in a Hospital allergy center. The program
      comprised four basic steps: setting up a decisional tree, standardizing the main
      diagnostic-therapeutic aspects, recording of the data and statistical evaluation
      of the main clinical endpoints in a long period (36 months). A total of 256
      patients were admitted, all with dust mite allergy; if pharmacological therapy
      failed after 12 months, they were assigned to immunotherapy (95 patients), either
      by subcutaneous injection or by the intranasal or sublingual route, depending on
      the main clinical-prognostic features taken into consideration. For each group of
      patients a control group was set up, given proper pharmacological therapy (40
      patients). Allergen-specific immunotherapy was effective and well tolerated.
      Bronchial hyper-reactivity (BHR) tests indicated that subcutaneous or sublingual
      immunotherapy seemed to give some protection against asthma or BHR worsening. In
      the group only given pharmacological therapy, an increasing percentage of
      patients gradually became non-responders, hence potential candidates for allergen
      immunotherapy. The present findings, even though obtained by a non-randomized
      approach, are based on a large, selected case list and show that setting up a CPI
      program can render possible a better overall efficacy of immunotherapy, through
      appropriate selection and continuous follow-up of patients.

PMID- 12604025
TI  - Hepatic and peripheral T-lymphocyte patterns in patients with chronic hepatitis C
      infection: what correlation with histological activity?
AB  - The immunopathological processes involved in hepatic damage during chronic
      hepatitis C infection are not fully understood. Several works suggest the role of
      T helper 1 (Th1) immune response in both injury and fibrinogenesis. in this
      study, we have analyzed peripheral and intrahepatic T-lymphocyte subsets in liver
      biopsy specimens of 13 patients with definite chronic hepatitis C (CHC) to
      explore the possible direct role of these patterns in the evolution of necrotic
      inflammation and fibrogenesis scored according to the Knodell histological
      activity index. in particular, we have studied CD4+/CD7+ T-lymphocytes, as
      phenotypic marker of Th1 immune response, CD4+/CD7- as Th2 marker, and CD8+/CD38
      as activated CD8+ lymphocytes. on statistical analyses we found a significant
      negative correlation in liver CD8+/CD38+ T-cells grading (r= -0.607;
      p&#x003C;0.05) and staging index (r= -0.650; p&#x003C;0.05) and between CD4+/CD7+
      and grading (r= -0.626; p&#x003C;0.05) index. in addition, we found a positive
      strong correlation between CD38+/CD8+ and CD4+/CD7+ T cells (r= 0.783;
      p&#x003C;0.05) in liver tissue and between peripheral and liver resident
      CD8+/CD38+ (r= 683; p&#x003C;0.05). moreover, the hepatic CD4+/CD7+ T-cells
      showed a positive correlation with peripheral CD 8+/CD38+ T-cells (r= 0.676;
      p&#x003C;0.05). A strong positive correlation was also observed between grading
      and staging index (r= 0.921; p&#x003C;0.01). we found no statistical correlation
      between the above variables and CD4+/CD7- T cells. our data could suggest that a
      preferential hepatic CD4+/CD7+ OR CD8+/CD38+ T cell subset was not directly
      associated with hepatic damage but, on the contrary, it could have been able to
      block liver injury. Concerning the peripheral subsets, the only CD8+/CD 38+ T
      cells result reflect the CTL activity in the liver tissue. further studies are
      required to better understand the possible correlation between peripheral and
      liver resident T-helper, subset and other hepatic resident immunocompetent cells.

PMID- 12604026
TI  - Anti-endothelial cell reactivity, the unresolved enigma.
AB  - Not only are some anti-endothelial cell antibodies (AECA) directed to thus far
      unidentified cell membrane structures, but some ot them recognize "planted"
      antigens and possibly ligand-receptor complexes. The functional heterogeneity of
      AECA is widely acknowledged: part of them activate the complement, mediate
      antibody-dependent cell cytotoxicity of trigger the production of tissue
      procoagulant factor. It has also recently been established that a proportion of
      AECA have the capacity to induce apoptosis of their target cells. In fact, the
      most direct demonstration of the pathogenicity of AECA is the autoantibody
      induced murine model of vasculitis.

PMID- 12604027
TI  - Size distribution of spontaneously formed liposomes by the alcohol injection
      method.
AB  - A dynamic light scattering study of the size distribution of POPC (1-palmitoyl-2
      oleoyl-sn-glycero-3-phosphocholine) liposomes formed by the injection method is
      presented. By this method, an aliquot of methanol stock solution containing the
      surfactant is injected into water. The main aim of the present work was to
      determine under which conditions a monomodal and narrow size distribution could
      be obtained. The influence of several parameters on the size distribution was
      investigated. Firstly, we examined the influence of the POPC concentration in the
      initial stock methanol solution, when the POPC concentration in the final aqueous
      solution remains constant; secondly, the influence of POPC concentration in the
      aqueous phase, while the lipid concentration in the stock methanol remains
      constant. In both cases narrow monomodal size distributions of liposomes,
      centered between 40 and 70 nm, are obtained at low concentrations of POPC, in the
      stock methanol solution (<or=25 mM) as well as in the final aqueous solution.
      However, at a higher lipid concentration range a more complex size distribution
      is observed, and an additional component larger than 500 nm is detected. The
      effect of dilution was also studied. It can be shown that dilution of the more
      concentrated POPC solutions determines the disappearance of the larger component,
      which is then ascribed to aggregates or clusters of smaller liposomes.
      Interestingly, by concentrating the diluted, monomodal liposomal suspensions, the
      monomodal distribution is maintained. Concentrated liposome preparations can
      therefore be obtained having only one population of liposomes centered around 40
      70 nm radii. Finally, the effect of aging was studied. It appears that the larger
      components in the light scattering results are not time-stable, whereas the
      smaller liposome species are. It is shown that these features are also present
      when alcohols different from methanol are used.

PMID- 12604028
TI  - Characterization of the main phase transition in 1,2-dipalmitoyl
      phosphatidylcholine luvs by 1H NMR.
AB  - The main phase transition (Tm) of 100 nm large unilamellar vesicles (LUVs) of 1,2
      dipalmitoylphosphatidylcholine (DPPC) was investigated using 1H NMR (proton
      magnetic resonance) in deuterium oxide, and both DSC (differential scanning
      calorimetry) and IR (infrared) spectroscopy in water and deuterium oxide. The
      ability of 1H NMR to determine Tm was demonstrated and the values obtained were
      in general agreement with those observed with DSC and IR. However, the
      temperature range of the transition observed by NMR was significantly broader
      than that observed with either DSC or IR. The effect of deuterium oxide on Tm was
      studied by comparing results obtained in water and deuterium oxide with DSC and
      IR. The results showed no significant difference in Tm or temperature range of
      transition determined in these solvents.

PMID- 12604029
TI  - Effects of Cl2MDP-encapsulating liposomes in a murine model of Pseudomonas
      aeruginosa-induced sepsis.
AB  - Pseudomonas aeruginosa is a pathogen that frequently causes acute lung injury,
      bacteremia and sepsis in critically ill patients. As tissue macrophages are a
      major producer of inflammatory mediators that contribute to septic physiology,
      and are essential for eliminating bacteria from the circulation, we investigated
      the role of tissue macrophages in the generation of both inflammatory and anti
      inflammatory cytokines in septic shock by using our mouse model of P. aeruginosa
      pneumonia. To see the effects of tissue macrophage depletion, we intravenously
      injected dichloromethylene-diphosphonate (Cl2MDP)-encapsulating liposomes in
      mice. Two days after the liposome injection, we instilled cytotoxic P. aeruginosa
      (PA103) into the lung that disseminates and causes septic shock. After the
      infection, we collected blood and bronchoalveolar lavage fluids. The samples were
      then analyzed for TNF-alpha, MIP-2, and IL-10 concentration. We compared these
      results to control mice that received either liposomes without Cl2MDP or
      phosphate buffered saline alone. Plasma TNF-alpha, MIP-2, and IL-10 levels were
      significantly decreased in the tissue macrophage-depleted mice compared to the
      control groups of mice. Although depletion of tissue macrophages by Cl2MDP
      liposome administration did not affect the severity of bacteremia or the survival
      of infected mice, these results imply that tissue macrophages have a major role
      in the production of both proinflammatory and anti-inflammatory cytokines in the
      circulation and in the causing septic physiology associated with P. aeruginosa
      pneumonia.

PMID- 12604030
TI  - The crossflow injection technique: an improvement of the ethanol injection
      method.
AB  - A novel scalable liposome preparation technique for pharmaceutical application is
      presented. Previous experiments have shown that the concept of continuous
      crossflow injection is a promising approach. For the characterization of the
      process, we focus on the influencing parameters like the lipid concentration, the
      injection hole diameter, the injection pressure, the buffer flow rate, and system
      performance. These experiments demonstrate that the injection hole diameter and
      the system performance do not influence the vesicle forming process and that a
      minimum of buffer flow rate is required to affect batch homogeneity. In contrast,
      strongly influencing parameters are lipid concentration in combination with
      increasing injection pressures. After exceeding the upper pressure limit of the
      linear range, where injection velocities remain constant, the vesicle batches are
      narrowly distributed, also when injecting higher lipid concentrations.
      Reproducibility and scalability data show similar results with respect to vesicle
      size and size distribution and demonstrate the stability and robustness of the
      novel continuous liposome preparation technique.

PMID- 12604031
TI  - Enhanced protein loading into liposomes by the multiple crossflow injection
      technique.
AB  - Methods for encapsulation of a drug into liposomes should preferably result in a
      high encapsulation efficiency and a high encapsulation capacity. Our studies were
      focussed on the establishment of an efficient encapsulation procedure of the
      radical scavenging protein, rh-Cu/Zn-SOD, into liposomes with the cross flow
      injection method. Limitations to increase the encapsulation efficiency are caused
      by the enclosed aqueous volume, by the lipid concentration, the aspired vesicle
      size and the final ethanol concentration. Our research was performed to maximize
      the encapsulation following several strategies of injecting higher lipid
      concentrations into the aqueous phase. The one way triple technique, a
      sophisticated preparation procedure is presented, which enables three times
      higher encapsulation rates in comparison to standard procedures. Additionally,
      scalability studies demonstrate reproducibility independent of the preparation
      volume. Vesicle size distribution and encapsulation efficiency remain constant.
      Furthermore, special attention is paid on reproducibility of prepared liposomes,
      scale-up and on long term stability of the lipid vesicles.

PMID- 12604032
TI  - The next generation of liposome delivery systems: recent experience with tumor
      targeted, sterically-stabilized immunoliposomes and active-loading gradients.
AB  - Three topics are discussed. Enhanced anti-tumor efficacy of targeted doxorubicin
      containing sterically-stabilized liposomes using an anti-beta1 integrin Fab'
      ligand. Use of tumor targeting with an internalizing ligand to improve the
      efficacy of a non-leaky cisplatin-containing sterically-stabilized liposome
      formulation. Formulation variables (remote-loading with dextran ammonium sulfate,
      rigid lipid bilayer) used to optimize in vivo performance of a liposomal
      camptothecin analog.

PMID- 12604033
TI  - Adventures in targeting.
AB  - An overview of our experiences in the field of immunoliposomal anticancer drugs
      is provided with respect to choice of ligand, and choice of model system, in
      order to provide some guidance as to the rational use of this new technology.
      Liposomes targeted by either peptide or monoclonal antibodies showed
      significantly higher binding to their respective target cells in vitro compared
      to non-targeted liposomes in all model systems examined. This higher binding led
      to higher cytotoxicities relative to non-targeted liposomes. For the
      immunoliposomes to deliver their entrapped drug to target cell in vivo, long
      circulations half-lives are required. We have evaluated the pharmacokinetics of
      liposomes prepared by several different coupling techniques, and have found
      significant differences in the clearance of these immunoliposomes from the
      circulation. Immunoliposomes prepared with whole anti-CD19 IgG coupled by the Mal
      PEG-DSPE method demonstrated a short plasma half-life, which may reflect the
      random orientation of the MAb on the liposome surface. Coupling methods that mask
      or eliminate the Fc region result in immunoliposomes that have clearance rates
      more similar to untargeted liposomes. Insertion of peptides or antibodies into
      pre-formed liposomes through incubation with ligand-coupled PEG micelles resulted
      in immunoliposomes, termed post-insertion liposomes, that demonstrated comparable
      in vitro binding, pharmacokinetic profiles and in vivo therapeutic efficacy to
      liposomes made by conventional coupling methods. The therapeutic efficacy of
      liposomes, prepared by various coupling methods and targeted by different
      ligands, was compared in several different animal models of either haematological
      malignancies, pseudometastatic disease or solid tumours. In our hands, successful
      in vivo targeting has been obtained when the target is either small or readily
      accessible from the vasculature, where the liposomes have longer circulating half
      lives and/or where a ligand against an internalizing epitope has been chosen.
      These results should aid in the rational design of applications for
      immunoliposomal drugs in the future.

PMID- 12604034
TI  - Study of in vitro stability of liposomes and in vivo antibody response to antigen
      associated with liposomes containing GM1 after oral and subcutaneous
      immunization.
AB  - In order to evaluate the usefulness of liposomes as possible vaccine vehicles
      (oral and subcutaneous), the stability of liposomes in buffer, plasma and saliva
      at 25 and 37 degrees C was analyzed via fluorescence and enzymatic methodology.
      The tested mixtures included [EggPC/Chol] 1 : 1 (mixture I), [EggPC/Chol/SM] 1 :
      1 : 1 (mixture II), [EggPC/Chol/SM/GM typeIII] 1 : 1 : 1 : 0.14 (mixture III),
      [EggPC/Chol/SM/GM1] 1 : 1 : 1 : 0.14 (mixture IV) and [DIAPC/DMPC] 1 : 1 non
      polymerized (mixture V) and polymerized (mixture VI); all mole ratio. Liposome
      mixtures I and II were more stable in buffer at 25 degrees C. On the other hand,
      mixtures III and IV were more stable in plasma at 37 degrees C; mixture VI was
      more stable in plasma at 37 degrees C than in buffer or saliva. Mixtures IV and V
      liposomes were both stable in saliva for at least one hour. Blood and feces anti
      GM1 response to antigen associated liposomes after subcutaneous and oral
      administration was also examined. After mixture IV mice immunization, no
      detectable anti-ganglioside GM1 antibody response was detected. Negative stain
      transmission electron microscopy, shows that liposomes containing SM, GM1, GM
      typeIII and DIAPC : DMPC were twice the size of those made with EggPC/Chol. The
      hydrophobicity factor expressed as A(570/500) was obtained using the probe
      merocynine 540 (MC540). The order of fluidity increased from: mixture II <
      mixture I < mixture III < mixture IV < mixtureV < mixture VI. Although the high
      hydrophobicity factor for polymerizable lipids there are other factors like
      stability must be taken into account according to the administration via
      selected. Also, the hydrophilicity of the groups protruding from the membrane
      interphase into the solution in the case of subcutaneous inoculation is very
      relevant and for oral administration stability is the property to take into
      account, as long as they have to last through the different fluids of the
      gastrointestinal tract. The results obtained suggest that liposomes that showed
      stability in saliva and plasma at 37 degrees C containing GM1, GM typeIII or
      DIAPC/DMPC would serve effectively as a delivery vehicle for oral and
      subcutaneous non-viral vaccines.

PMID- 12604035
TI  - Heat shock protein micro-encapsulation as a double tool for the improvement of
      new generation vaccines.
AB  - The modern vaccinology encompasses the recombinant DNA technology, protein and
      carbohydrate chemistry to obtain safe molecularly defined vaccines. Nevertheless
      most of the vaccines are poorly immunogenic because a large number of antigens
      are membrane proteins and consequently they are not present in their active
      conformation in the vaccine. Others are not as potent because they contain only B
      epitopes and therefore, cannot stimulate cellular memory. We have been studying
      the characteristics of the recombinant heat shock protein 18kDa-hsp from
      Mycobacterium leprae as an alternative carrier protein with a T epitope source to
      enhance the activity of these second generation vaccines. Here we proved that the
      18kDa-hsp acted as carrier, without masking the activity of the carried antigen,
      with similar immune stimulatory effect when compared with ODN1668. Supramolecular
      aggregates of 18kDa-hsp and Mice serum albumin (MSA) were obtained using
      glutaraldehyde as cross linker. The Neisseria meningitides serogroup C
      polysaccharide (PSC, a B epitope) and the carrier protein 18kDa-hsp were co
      encapsulated within Soybean phosphatidylcholine liposomes (SPC: Cho : alpha-Toc,
      22 : 5 : 0.18 molar ratio, respectively). These liposomes were prepared in MPB
      buffer (20 mM phosphate, 295 mM mannitol pH 7.2) in the presence or absence of
      the ODN1668, TCCATGACGTTCCTGATGCT. When mice were injected with 18kDa-hsp-MSA no
      antibody against the MSA was observed. This means that the 18kDa-hsp acted as
      carrier, without masking the carried protein immune activity. Stable liposomes of
      150 nm were obtained using mannitol as a cryoprotector. Genetically selected mice
      when injected with liposomes containing PSC and 18kDa-hsp displayed an antibody
      titer of 12. In contrast, in those mice injected with free PSC there was no
      response. The 18kDa-hsp adjuvant effect on the PSC liposomal formulation was
      comparable to that observed when ODN1668 was co-encapsulated with PSC. Confirming
      our expectations we observed that the formulation containing 18kDa-hsp conferred
      a memory response to the carried antigen--the Neisseria meningitidis serogroup C
      polysaccharide.

PMID- 12604036
TI  - A new colloidal lipidic system for gene therapy.
AB  - A novel type of liposomal vector for gene therapy is described (Artificial Virus
      Particles; AVPs). This vector is based on the composition of retroviral
      envelopes, serum-resistant and non-toxic and smaller than 200 nm in size. The DNA
      is condensed using low molecular weight branched PEI. Equipment of these
      particles with a cyclic RGD peptide ligand as targeting device renders them
      selective for tumor endothelial and melanoma cells expressing high levels of
      alphavbeta3-integrins, and allows for an efficient delivery of the enclosed
      genetic material. The specificity of the vector system for melanoma cells could
      be further improved by using a melanocyte-specific tyrosinase promoter to drive
      transgene expression.

PMID- 12604037
TI  - The transfection of Jurkat T-leukemic cells by use of pH-sensitive
      immunoliposomes.
AB  - An effective pH-sensitive gene transfer vector has been developed utilising
      anionic liposomes with various formulations as a carrier of plasmid DNA (pEGlacZ,
      7.6 kb) to transfect CD3 T+ lymphocytes (Jurkat cells). The plasmid DNA was
      condensed using poly-l-lysines with a range of molecular masses to form
      polyplexes that were interacted with several anionic liposome formulations to
      form lipopolyplexes. For targeting to the Jurkat cells,
      distearoylphosphatidylethanolamine (DSPE) linked to poly (ethylene glycol)
      molecular mass 2000 and coupled to anti-CD3 antibody was incorporated in the
      liposomes. The polyplexes and lipopolyplexes were characterised in terms of size,
      zeta potential, gel electrophoresis and electron microscopy. The gene transfer
      activity of the lipopolyplexes, assessed from beta-galactosidase expression,
      depended on the charge ratio (NH(3)+/PO(4)-) of the component polyplex and the
      lipid/DNA weight ratio of the lipopolyplex.

PMID- 12604038
TI  - Isothermic titration calorimetry to study CMCs of neutral surfactants and of the
      liposome-forming bolaamphiphile dequalinium.
AB  - Isothermic titration calorimetry was used to measure the heat of micelle
      formation (molar enthalpy of transfer of surfactants monomers from water into
      micellar aggregates. The problems associated with the estimation of the CMC and
      the whole therodynamic profile of micellization of surfactants via Gibbs
      Helmholtz-Equation are discussed. CMC's of octylthioglucoside and the peculiar
      bolaamphilphile dequalinium which concentrates in mitochondria are measured. In
      contrast to earlier reports, no CMC of dequalinium could be found inspite of
      extensive systematic measurements.

PMID- 12604039
TI  - Targeted liposomes for delivery of protein-based drugs into the cytoplasm of
      tumor cells.
AB  - Our goal was to deliver therapeutically active macromolecules into the cytosol of
      target cells. First, attempts were made to prepare virosomes that specifically
      interact with OVCAR-3 cells (human ovarian cancer cells). Detergent solubilized
      influenza virus envelopes were reconstituted forming virosomes. Cell specificity
      was introduced by incorporating PEG-derivatized lipids with mAB 323/A3 (Fab'
      fragments) connected to their distal PEG end. These cell-specific, modified
      virosomes maintained their fusogenic activity when lowering the pH. Most
      importantly, antibody-mediated binding was a prerequisite for low-pH induced
      membrane fusion. However, basically, there are two problems with this approach:
      (1) these virosomes are quite leaky and (2) virosomes can be expected to be
      immunogenic. A solution to tackle leakage and potential immunogenicity of these
      site-specific liposomal structures is to use immuno-PEG-liposomes with a pH
      dependent fusogen inside the liposome. The system that we designed to test this
      concept consisted of (1) the fusogenic di-peptide dINF-7, (2) the monoclonal
      antibody 425 connected to the distal end of PEG-PE (for site specific binding and
      endosomal uptake), (3) diphtheria toxin chain A (DTA, as carrier-dependent active
      compound) and phosphatidylcholine/cholesterol as 'bilayer backbone'. A series of
      tests were performed to show that selective binding and pH-dependent
      destabilization of (endosomal) membranes indeed occurred. To test the cytotoxic
      activity of these DTA loaded liposomes, OVCAR-3 cells were used for testing.
      OVCAR-3 cells express the epidermal growth factor receptor, which is the ligand
      for antibody 425. In vitro, these site specific and fusogenic liposomes showed a
      remarkable, cell specific cytotoxic effect.

PMID- 12604040
TI  - Liposome recognition by resident and newly recruited murine liver macrophages.
AB  - The evidence in this communication indicate that, unlike resident Kupffer cells,
      newly recruited liver macrophages (following monocyte migration from the blood to
      the liver) use complement receptors to recognize and internalize stearylamine
      incorporated liposomes. Within two weeks of hepatic residency complement
      receptors no longer participate in liposome recognition and uptake.

PMID- 12604041
TI  - Assessment of liposome delivery using scintigraphic imaging.
AB  - Scintigraphic imaging is a valuable tool for the development of liposome-based
      therapeutic agents. It provides the ability to non-invasively track and
      quantitate the distribution of liposomes in the body. Liposomes labeled with
      technetium-99 m (99mTc) are particularly advantageous for imaging studies because
      of their favorable physical characteristics. Examples of how scintigraphic
      imaging studies have contributed to the evaluation and development of a variety
      of liposome formulations will be presented. These include liposomes for targeting
      processes with inflammation associated increased vascular permeability such as
      healing bone fractures and viral infections; liposomes for intraarticular
      delivery; and liposomes for delivery of agents to lymph nodes located in the
      extremities, the mediastinum and the peritoneum. Scintigraphic studies of
      liposome distribution are very informational and often suggest new drug delivery
      applications for liposomes.

PMID- 12604042
TI  - Clodronate liposomes: perspectives in research and therapeutics.
AB  - Liposomes encapsulating the bisphosphonate clodronate can be used for the
      transient suppression of macrophage functions. Given the important role of
      macrophages in various disorders, the application of clodronate liposomes has
      been studied in several models of rheumatoid arthritis, neurological disorders
      such as experimental allergic encephalomyelitis and spinal cord injury,
      autoantibody mediated disorders such as immune thrombocytopenic purpura (ITP) and
      for the improvement of the efficacy of gene transfer and drug targeting.

PMID- 12604043
TI  - Optimization of cationic lipid mediated gene transfer: structure-function,
      physico-chemical, and cellular studies.
AB  - The rationale design aimed at the enhancement of cationic lipid mediated gene
      transfer is discussed. These improvements are based on the straight evaluation of
      the structure-activity relationship and on the introduction of new structures.
      Much attention have been given to the supramolecular structures of the lipid/DNA
      complexes, to the effect of serum on gene transfer and to the intracellular
      trafficking of the lipoplexes. Finally new avenue using reducible cationic lipids
      has been discussed.

PMID- 12604044
TI  - Interference of macrophages with immunotargeting of liposomes.
AB  - We investigated the binding, uptake and intracellular degradation of
      immunoliposomes by isolated rat liver macrophages in vitro. Immunoliposomes were
      prepared either by coupling a randomly thiolated anti-CC531 rat colon
      adenocarcinoma monoclonal antibody to bilayer-incorporated MPB-PE by means of a
      thioether linkage or by attaching it through its Fc moiety to the distal terminus
      of hydrazide-modified PEG-DSPE. The two immunoliposome preparations clearly
      differ in their interaction with the tumor target cells, as well as with the
      macrophages. At comparable antibody densities both cell types show 1.5-2-fold
      higher levels of association for the Hz-PEG-immunoliposomes than for the MPB-PEG
      immunoliposomes. We provide evidence that immunoliposome macrophage-interaction
      is both Fc-receptor and scavenger receptor mediated to about equal extents. At
      low antibody density the hydrazide immunoliposomes favor interaction with the
      tumor cells to that with macrophages. At higher antibody densities, on the other
      hand, interaction of these liposomes with the macrophages is increasingly
      favored, mostly due to enhanced scavenger receptor mediated uptake. The rate of
      intracellular degradation of (immuno)liposomes internalized by liver macrophages
      is barely influenced by the presence of either PEG or immunoglobulins on the
      liposomal surface.

PMID- 12604045
TI  - Liposome-enabled synergistic interaction of antimicrobial agents.
AB  - Antimicrobial agents may interact synergistically when both drugs are present at
      the infected site for an adequate period of time at sufficient concentrations.
      Generally speaking, the agents in the combination show different tissue
      distributions and pharmacokinetics. By co-encapsulation of the drugs in a drug
      carrier, like liposomes, parallel tissue distributions of both drugs may be
      ensured and drug concentrations at the site of infection may be increased. In
      this presentation therapeutic efficacy of liposome-co-encapsulated gentamicin
      (GN) and ceftazidime (CZ) will be shown in a GN-CZ-susceptible and GN-CZ
      resistant Klebsiella pneumoniae-pneumonia in rats.

PMID- 12604046
TI  - Ligand-targeted liposomes directed against pathological vasculature.
AB  - The development of liposomes targeted to angiogenic endothelial cells offers
      exciting prospects for intervention in cancer and inflammation. Several proteins
      are (strongly) over-expressed on angiogenic endothelial cells as compared to the
      quiescent endothelium, and could potentially serve as targets for site-specific
      drug delivery. In this contribution particular attention is given to the design
      of targeted long-circulating liposomes directed against the alpha v beta 3
      integrin protein.

PMID- 12604047
TI  - Next generation DNA vaccines for HIV-1.
AB  - We studied the effects of first generation HIV-1 plasmid vaccines in 167
      individuals. The vaccines were very well tolerated and induced helper T cell
      responses in most vaccine recipients. However, the CTL responses were below a 20%
      response rate. Improvement in vaccine potency is an important goal of this
      technology and a central focus of our laboratory. To improve on these response
      rates, we used RNA optimized constructs pGag and pEnv). These vaccines express 20
      100 fold better than first generation vectors. However, our studies support that
      additional enhancements are needed to further boost the immune response. We
      report that we can significantly enhance the induced CD8 effector cell response
      by including engineered B7 costimulatory molecules. We observed that B7.2 was
      more effective at driving cellular immune responses than B7.1 as a plasmid
      vaccine. We developed gene swaps and deletions between these two molecules. This
      manipulation resulted in a dramatically enhanced cellular immune response as
      measured by CTL, or ICC or Elispot. We have also explored the use of cytokines as
      plasmid vaccine adjuvants. We observed that IL-12 and IL-15 were effective as
      plasmid vaccine adjuvants. Interestingly, IL-15 appeared to allow T cell
      expansion in the absence of significant T cell help. Improvement of the immune
      response induced by plasmid vaccines can be engineered in multiple ways. Our
      studies show that both costimulation as well as cytokine signals can be harnessed
      for more potent vaccine development. These results have important implications
      for the design of vaccines for prophylaxis and therapy.

PMID- 12604048
TI  - Follicular liposomal delivery systems.
AB  - Traditionally, the prime pathway for the topical delivery of active agents across
      the skin was thought to be through intercellular routes and transcellular routes
      of the stratum corneum. However, alternative means such as via appenageal
      transport, i.e., follicular transport, is gaining more acceptances in the
      scientific community. Targeting specific sites of the hair follicle may represent
      a feasible therapeutic approach to skin diseases such as hair loss. It is
      therefore an object of this research to develop novel liposomal formulations for
      enabling the topical delivery of difficult-to-absorb agents for localized action,
      specifically to the hair follicles and sebaceous glands. We examined small and
      large molecules. The small molecule chosen was minoxidil, a known hair growth
      stimulator. The large molecular weight molecule was plasmid DNA encoded with
      interleukin-1 receptor antagonist protein (IL-1ra).

PMID- 12604049
TI  - Manipulation of the tumour-associated vasculature to improve tumour therapy.
AB  - Inhibition of tumour vascular growth, destruction of the tumour associated
      vasculature (TAV), and manipulation of the endothelial lining of the TAV provide
      powerful tools for anti-tumour therapy. We previously demonstrated that addition
      of TNF to chemotherapy improved tumour response. The major effect of TNF is an
      increased permeability of the tumour vascular bed resulting in augmented
      accumulation of co-administered drug in the tumour. As the TAV is recognised as a
      major candidate in tumour therapy it is becoming important to understand anti
      vascular effects better. In our laboratory we examine the effect of immunotherapy
      on the TAV, and the effect of anti tumour-vascular therapy on tumours. This is
      studied in animal models, which exhibit similarities with the clinical setting,
      such as tumour perfusion treatment.

PMID- 12604050
TI  - Virosomes in vaccine development: induction of cytotoxic T lymphocyte activity
      with virosome-encapsulated protein antigens.
AB  - Virosomes are reconstituted viral envelopes which lack the genetic material but
      retain the cell entry and membrane fusion characteristics of the virus they are
      derived from. Thus, influenza virosomes are taken up by cells via receptor
      mediated endocytosis, which directs the particles to the endosomal cell
      compartment. Subsequently, the virosomal membrane fuses with the endosomal
      membrane induced by the mildly acidic pH within the endosomes. This fusion
      process establishes continuity between the lumen of the virosome and the cell
      cytosol. Upon interaction of virosomes with antigen-presenting cells (APCs),
      protein antigens encapsulated within virosomes will be delivered to the cell
      cytosol, and thus, into the MHC class I presentation pathway. Indeed, virosome
      mediated delivery of antigens in vivo results in efficient priming of a class I
      MHC-restricted cytotoxic T lymphocyte (CTL) response.

PMID- 12604052
TI  - Induction of a cytotoxic T lymphocyte (CTL) response to plasmid DNA delivered via
      Lipodine liposomes.
AB  - We have previously shown that liposome-mediated plasmid DNA immunisation may be a
      preferred alternative to the use of naked DNA. Lipodine DNA formulations consist
      of liposomes containing entrapped DNA plasmid by the dehydration-rehydration
      (DRV) method. Such liposome formulations are distinct from liposomes with
      externally complexed DNA in that the majority of the DNA is "internal" to the
      liposome structure and hence protected from DNAase degradation. Previous studies
      on the immune response induced by DNA vaccines entrapped in Lipodine have focused
      on the humoural response. In the present study, we have expanded the analysis
      profile in order to include the cytotoxic T lymphocyte (CTL) component of the
      immune response. We have analysed the immune response induced by DNA entrapped in
      Lipodine compared to that induced by DNA alone when delivered subcutaneously, a
      route of administration not normally inducing significant plasmid DNA mediated
      immune activation. Our results indicate that delivery of a small dose of plasmid
      DNA in Lipodine results in an improved antibody response to the plasmid encoded
      antigen and a strong antigen specific CTL response compared to that induced by
      DNA delivered alone.

PMID- 12604051
TI  - Role of complement activation in hypersensitivity reactions to doxil and hynic
      PEG liposomes: experimental and clinical studies.
AB  - Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were
      reported earlier to cause hypersensitivity reactions (HSRs) in a substantial
      percentage of patients treated i.v. with these formulations. Here we report that
      (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty
      liposomes matched with Doxil and HPL in size and lipid composition, and
      phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C
      activators in human serum in vitro, whereas small neutral liposomes caused no C
      activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing
      liposomes also caused massive cardiopulmonary distress with anaphylactoid shock
      in pigs via C activation, whereas equivalent neutral liposomes caused no
      hemodynamic changes. (3) A clinical study showed more frequent and greater C
      activation in patients displaying HSR than in non-reactive patients. These data
      suggest that liposome-induced HSRs in susceptible individuals may be due to C
      activation, which, in turn, is due to the presence of negatively charged PEG-PE
      in these vesicles.

PMID- 12604053
TI  - Liposome (Lipodine)-mediated DNA vaccination by the oral route.
AB  - Plasmid DNA pRc/CMV HBS encoding the S (small) region of hepatitis B surface
      antigen (HBsAg) was incorporated by the dehydration-rehydration method into
      Lipodine liposomes composed of 16 micro moles phosphatidylcholine (PC) or
      distearoyl phosphatidylcholine (DSPC), 8 micro moles of (dioleoyl
      phosphatidylethanolamine (DOPE) or cholesterol and 4 micro moles of the cationic
      lipid 1,2-dioleoyl-3-(trimethylammonium propane (DOTAP) (molar ratios 1 : 0.5 :
      0.25). Incorporation efficiency was high (89-93% of the amount of DNA used) in
      all four formulations tested and incorporated DNA was shown to be resistant to
      displacement in the presence of the competing anionic sodium dodecyl sulphate
      molecules. This is consistent with the notion that most of the DNA is
      incorporated within the multilamellar vesicles structure rather than being
      vesicle surface-complexed. Stability studies performed in simulated intestinal
      media also demonstrated that dehydration-rehydration vesicles (DRV) incorporating
      DNA (DRV(DNA)) were able to retain significantly more of their DNA content
      compared to DNA complexed with preformed small unilamellar vesicles (SUV-DNA) of
      the same composition. Moreover, after 4h incubation in the media, DNA loss for
      DSPC DRV(DNA) was only minimal, suggesting this to be the most stable
      formulation. Oral (intragastric) liposome-mediated DNA immunisation studies
      employing a variety of DRV(DNA) formulations as well as naked DNA revealed that
      secreted IgA responses against the encoded HBsAg were (as early as three weeks
      after the first dose) substantially higher after dosing with 100 micro g liposome
      entrapped DNA compared to naked DNA. Throughout the fourteen week investigation,
      IgA responses in mice were consistently higher with the DSPC DRV(DNA) liposomes
      compared to naked DNA and correlated well with their improved DNA retention when
      exposed to model intestinal fluids. To investigate gene expression after oral
      (intragastric) administration, mice were given 100 micro g of naked or DSPC DRV
      liposome-entrapped plasmid DNA expressing the enhanced green fluorescent protein
      (pCMV.EGFP). Expression of the gene, in terms of fluorescence intensity in the
      draining mesenteric lymph nodes, was much greater in mice dosed with liposomal
      DNA than in animals dosed with the naked DNA. These results suggest that DSPC DRV
      liposomes containing DNA (Lipodine) may be a useful system for the oral delivery
      of DNA vaccines.

PMID- 12604054
TI  - Avoiding untoward immune responses to novel gene products.
AB  - For successful therapeutic transfection of a missing (or corrective) gene, by the
      use of liposomes or other delivery systems, it is essential that the patient be
      immunosuppressed to the corresponding immunogenic, transgenic protein prior to
      its transfection. We have developed a method for antigen-specific, long-term
      suppression of de novo induction of both antibodies and cytotoxic T lymphocytes-
      in spite of repeated administration of the antigen in question over extended
      periods. The method consists of converting the antigen to its tolerogenic
      derivative by coupling it to an appropriate number of molecules of
      monomethoxypolyethylene glycol (mPEG).

PMID- 12604055
TI  - Cell-matrix and cell-cell interactions during corneal epithelial wound healing.
AB  - The corneal epithelium serves as a barrier and contributes to the maintenance of
      corneal transparency and rigidity. In most instances, corneal epithelial defects
      caused by simple injury are resurfaced promptly. However, in individuals with
      certain clinical conditions, such as herpes simplex virus infection, neurotrophic
      keratopathy or diabetic keratopathy, corneal epithelial defects persist and do
      not respond to conventional treatment regimens because of delayed epithelial
      wound healing. After the corneal epithelium is removed by injury, the remaining
      epithelial cells migrate over the denuded surface of the cornea in a manner that
      is dependent both on the interaction of the cells with the underlying substrate
      and on cell-cell adhesion. In this review, we describe the specific roles of cell
      matrix and cell-cell interactions during the course of corneal epithelial wound
      healing. The clinical implications of the basic research findings are also
      discussed.

PMID- 12604056
TI  - Isolated preparations of ocular vasculature and their applications in ophthalmic
      research.
AB  - The purpose of this review is to outline the techniques and applications for
      isolated ocular vascular preparations and their significance to ophthalmic
      research. Various isolated ocular vascular preparations have been utilized in
      studies of ocular vascular biology, physiology and pharmacology, including work
      in both normal and diseased conditions. However, there is still significant
      potential for further studies to improve our understanding of the ocular
      circulation and its regulation. Experience has shown that there is no single
      preparation capable of addressing all of the questions that must be answered if a
      complete understanding of mechanisms of vascular regulation in the eye is to be
      achieved. Rather, it is necessary to select the appropriate preparation and
      techniques to address each individual question in the most appropriate manner. In
      this review, particular emphasis is placed on the applications for isolated
      ocular preparations and the relevance of such studies to our understanding of the
      pathogenesis of eye diseases involving the vasculature. Examples are given where
      therapeutic approaches in diabetes and glaucoma are assessed in terms of their
      impact on the vasoactive properties of the ocular vasculature.A significant
      heterogeneity is present in the different parts of the ocular vasculature, not
      only in the structural and functional properties of vessel itself, but also in
      terms of the tissue environment and innervation. A single vasoactive agent may
      also have different effects when applied to the inside or the outside of the same
      region of a vessel. The vasoactive response of the vascular system as a whole is
      what determines the rate of blood flow through the system, but this is regulated
      by a multitude of factors in different regions of the vascular network. Isolating
      individual components of the ocular vasculature is readily achievable for the
      extraocular vessels such as the ophthalmic or ophthalmocilliary arteries, which
      can be studied in myograph type systems measuring the mechanical vasoactive force
      generated by the vessel. Retinal vessels from very large animals can also be
      studied in this way, but the small diameter of the retinal vessels in most
      species requires a perfusion rather than myograph based technique. Perfusion
      based studies of vessel diameter in response to vasoactive stimuli can be applied
      to individual retinal arteries and their branches. Perfusion of more complex
      elements of the ocular vasculature such as isolated segments of the retina or
      ciliary body, or whole isolated perfused eyes may use the perfusate pressure as
      the determinant of vasoactive state. However, when several components of the
      ocular vasculature are being perfused simultaneously it may be difficult to
      separate out the contribution from the different vascular elements. The advantage
      of isolated preparations is that systemic influences can be eliminated, and
      vascular components can be studied that are inaccessible in vivo. The
      disadvantage is that no matter how well controlled the in vitro environment may
      be, it will always be a relatively poor mimic of the in vivo conditions. However,
      such in vitro work has certainly improved our understanding of the vasoactive
      properties of different regions of the ocular vasculature in both health and
      disease.

PMID- 12604057
TI  - Fundus reflectance--historical and present ideas.
AB  - In 1851 Helmholtz introduced the ophthalmoscope. The instrument allowed the
      observation of light reflected at the fundus. The development of this device was
      one of the major advancements in ophthalmology. Yet ophthalmoscopy allows only
      qualitative observation of the eye. Since 1950 attempts were made to address the
      challenging, quantitative assessment of the amount of light reflected by the
      fundus. At first, only comparative measurements were possible, applied in the
      study of macular and visual pigments. With improvements in light detecting
      techniques, and with the advent of microprocessors, the measurement of spectral
      and spatial distribution of the reflectance became feasible. This led to the
      development of models that explained the observed wavelength dependence and the
      directional behavior of light reflected from the fovea. The models allowed a
      quantitative assessment of many parameters on absorption and reflection by
      structures in the human eye. This paper provides a review of both the
      experimental and theoretical progress, and summarizes the results of fundamental
      and clinical research using fundus reflectometry.

PMID- 12604058
TI  - Multifocal VEP and ganglion cell damage: applications and limitations for the
      study of glaucoma.
AB  - With the multifocal technique, visual evoked potentials (VEPs) can be recorded
      simultaneously from many regions of the visual field in a matter of minutes.
      Recently, the multifocal visual evoked potential technique (mfVEP) has generated
      considerable interest, especially among those seeking objective measures of
      glaucomatous damage. It is well accepted that significant ganglion cell damage
      can occur before functional deficits are detected with static automated
      achromatic perimetry, the "gold standard" for detecting and monitoring
      glaucomatous damage. In this article, we ask the following questions: What are
      the potential applications of the mfVEP technique? What are its limitations? To
      what extent will it replace or augment static automated achromatic perimetry? To
      answer these questions requires an understanding of the mfVEP technique, as well
      as techniques needed to relate its results to those of automated perimetry.
      describes how the mfVEP is elicited, recorded, derived and displayed. If both
      eyes of an individual are normal, then mfVEPs recorded for monocular stimulation
      of each eye are essentially identical. However, the amplitude and waveform of the
      mfVEP responses vary across individuals, as well as across the visual field
      within an individual. These variations in the normal mfVEPs are described in
      Section 3. In, these variations are related to cortical anatomy, and to the
      cortical sources contributing to the mfVEP. The mfVEP is predominantly generated
      in V1. Although there are undoubtedly extrastriate contributions, these
      contributions are probably smaller for the mfVEP than for the conventional VEP.
      The mfVEP is not a small version of the conventional VEP. To detect ganglion cell
      damage with the mfVEP requires methods for analyzing the responses and for
      displaying the results. In, a method for detecting ganglion cell damage is
      described. This method compares the monocular responses from the two eyes of an
      individual and produces a map of the defects. This map is in the form of a
      probability plot similar to the one used to display visual field defects measured
      with automated perimetry. Procedures are described for directly comparing these
      mfVEP probability plots to the probability plots for Humphrey visual fields
      (HVFs). The interocular mfVEP test described in will not be sensitive to
      bilateral damage. describes a test based upon monocular mfVEPs. The statistical
      basis of the monocular mfVEP test is relatively complex (see ). In any case,
      under many conditions the interocular test will be more sensitive and this is
      discussed in. summarizes a number of clinical applications of the mfVEP and
      concludes that the mfVEP has a place in the clinical management of glaucoma. To
      understand the limitations of the mfVEP, a signal-to-noise ratio (SNR) approach
      is described in. Using the techniques described in, the relationship between the
      amplitude of the mfVEP and the sensitivity loss of the HVF is discussed in. The
      evidence supports a simple model in which the amplitude of the signal portion,
      but not the noise portion, of the mfVEP response is proportional to HVF loss
      where HVF loss is expressed in linear, not dB, units. It is hypothesized that
      both the signal in the mfVEP, and the sensitivity of the HVF, are linearly
      related to ganglion cell loss. A theoretical approach, developed in, allows a
      direct comparison of the efficacy of the mfVEP and HVF in detecting glaucomatous
      damage. In short, when the mfVEP has a large SNR it will often be superior to the
      HVF in detecting damage. On the other hand, when the mfVEP has a small SNR, the
      HVF will probably be superior. summarizes the relative advantages of the HVF and
      the mfVEP. In summary, the mfVEP does have a place in the clinical management of
      glaucoma, although it is not likely to replace static automated achromatic
      perimetry in the near future. However, this is an evolving technology and the
      future will undoubtedly see major improvements in the mfVEP technique.

PMID- 12604060
TI  - Biological pollutants and biological pollution--an increasing cause for concern.
AB  - There are increasing concerns regarding the delivery, movement and presence of
      non-indigenous or invasive species into marine and estuarine areas. Such
      introductions can be on a large scale such as the movement to higher latitudes of
      species as the result of global warming. Alternatively, such species can be
      introduced into a marine or estuarine area as the result of small-scale events,
      such as the liberation from waste-water discharges, aquaculture or ballast-water
      discharge. However, if such introductions lead to a successful colonisation then
      they can become a wide-scale problem. This paper considers the introduction of
      such non-indigenous and invasive species as biological pollution and biological
      pollutants and it discusses the definitions and concepts used in assessing and
      managing marine pollution in relation to these terms.

PMID- 12604061
TI  - Asia-Pacific mussel watch: monitoring contamination of persistent organochlorine
      compounds in coastal waters of Asian countries.
AB  - Contamination of persistent organochlorines (OCs) such as PCBs (polychlorinated
      biphenyls), DDT and its metabolites (DDTs), HCH (hexachlorocyclohexane) isomers
      (HCHs), chlordane compounds (CHLs), and HCB (hexachlorobenzene) were examined in
      mussels collected from coastal waters of Asian countries such as Cambodia, China,
      Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, Far East
      Russia, Singapore, and Vietnam in 1994, 1997, 1998, 1999, and 2001 to elucidate
      the contamination status, distribution and possible pollution sources and to
      assess the risks on aquatic organisms and human. OCs were detected in all mussels
      collected from all the sampling sites investigated. Considerable residue levels
      of p,p(')-DDT and alpha-HCH were found in mussels and the concentrations of DDTs
      and HCHs found in mussels from Asian developing countries were higher than those
      in developed nations suggesting present usage of DDTs and HCHs along the coastal
      waters of Asian developing countries. On the other hand, lower concentrations of
      PCBs detected in mussels from Asian developing countries than those in developed
      countries indicate that PCBs contamination in mussels is strongly related to
      industrial and activities. To our knowledge, this is a first comprehensive report
      on monitoring OCs pollution in the Asia-Pacific region.

PMID- 12604062
TI  - Viruses and marine pollution.
AB  - This short review summarises the present knowledge on pollutant impacts on marine
      viruses, virus-host systems and their potential ecological implications. Excess
      nutrients from sewage and river effluents are a primary cause of marine
      eutrophication and mucilage formation, often related to the development of large
      viral assemblages. At the same time, hydrocarbons, polychlorinated biphenyl and
      pesticides alter ecosystem functioning and can determinate changes in the virus
      host interactions, thus increasing the potential of viral infection. All these
      pollutants might have synergistic effects on the virus-host system and are able
      to induce prophage, thus increasing the impact of viruses on marine ecosystems.

PMID- 12604063
TI  - Rocky shore intertidal zonation as a means of monitoring and assessing shoreline
      biodiversity recovery.

PMID- 12604064
TI  - Flow cytometry and conventional enumeration of microorganisms in ships' ballast
      water and marine samples.
AB  - Conventional methods for bacteriological testing of water quality take long
      periods of time to complete. This makes them inappropriate for a shipping
      industry that is attempting to comply with the International Maritime
      Organization's anticipated regulations for ballast water discharge. Flow
      cytometry for the analysis of marine and ship's ballast water is a comparatively
      fast and accurate method. Compared to a 5% standard error for flow cytometry
      analysis the standard methods of culturing and epifluorescence analysis have
      errors of 2-58% and 10-30%, respectively. Also, unlike culturing methods, flow
      cytometry is capable of detecting both non-viable and viable but non-culturable
      microorganisms which can still pose health risks. The great variability in both
      cell concentrations and microbial content for the samples tested is an indication
      of the difficulties facing microbial monitoring programmes. The concentration of
      microorganisms in the ballast tank was generally lower than in local seawater.
      The proportion of aerobic, microaerophilic, and facultative anaerobic
      microorganisms present appeared to be influenced by conditions in the ballast
      tank. The gradual creation of anaerobic conditions in a ballast tank could lead
      to the accumulation of facultative anaerobic microorganisms, which might
      represent a potential source of pathogenic species.

PMID- 12604065
TI  - Partial mortality in massive reef corals as an indicator of sediment stress on
      coral reefs.
AB  - Partial mortality and fission on colonies of four common massive coral species
      were examined at sites differing in their exposure to river sediments in St.
      Lucia, West Indies. Rates of partial mortality were higher close to the river
      mouths, where more sediments were deposited, than away from the rivers in two
      coral species. Frequency of fission showed no significant trend. The percent
      change in coral cover on reefs from 1995 to 1998 was negatively related to the
      rate of partial mortality estimated in 1998 in all species. This suggests that
      partial mortality rates could reflect longer-term temporal changes in coral
      communities. Similar conclusions could also be reached using a less precise
      measure and simply recording partial mortality on colonies as <50% and >/=50%
      dead tissue. We conclude that partial mortality in some species of massive reef
      corals, expressed as the amount of dead tissue per colony, could provide a rapid
      and effective means of detecting sediment stress on coral reefs.

PMID- 12604066
TI  - Integrated use of biomarkers (acetylcholinesterase and antioxidant enzymes
      activities) in Mytilus galloprovincialis and Mullus barbatus in an Italian
      coastal marine area.
AB  - The use of biomarkers to evaluate the biological effects of chemical pollutants
      in marine organisms represents a recent tool in the monitoring field responding
      to the need to detect and assess the effects of chemical contaminants on the
      biota. The aim of the present work was the field application of the integrated
      use of acetylcholinesterase (AChE) and antioxidant enzymes (catalase--CAT,
      glutathione peroxidase--GSH-Px), for detecting the possible exposure/effect
      induced by chemical pollutants in native marine organisms from a coastal marine
      area, represented by Salento Peninsula (Italy), that shows a coastline of high
      environmental value, but under constant urban pressure, including agriculture
      activities, widely diffused in the whole hinterland. Eight sampling stations were
      chosen: four not urbanized areas considered "uncontaminated" controls and four
      clearly exposed to anthropogenic impact. The bioindicator species studied were a
      sessile invertebrate, Mytilus galloprovincialis, and a benthic teleost fish,
      Mullus barbatus.AChE activity in M. galloprovincialis revealed significant
      differences among places; the minimum values observed (3.9+/-1.8 nmolmin(-1)mg(
      1)) was about 50% reduced with respect to the maximum found (11.4+/-0.9 nmolmin(
      1)mg(-1)). The reduction in AChE activity observed in two control stations could
      be explained by the leaching of pesticides into the sea from the agricultural
      lands. Moreover, the inhibition of AChE activity by heavy metals besides
      pesticides, can also explain the reduction of the enzymatic activity observed in
      an industrialized and harbour area. In M. galloprovincialis AChE activity showed
      a significant inverse correlation with catalase activity but not with glutathione
      peroxidase that did not significantly change in animals sampled from the eight
      stations. Also in M. barbatus AChE activity showed significant differences among
      places; it was inversely correlated with liver GSH-Px activity, but not with
      catalase activity, that did not show any significantly variation in animals
      sampled in the different stations. In conclusion, the integrated use of AChE and
      antioxidant enzymes (catalase or glutathione peroxidase) in M. galloprovincialis
      and M. barbatus, two species living in different compartment of marine coastal
      ecosystem, can find a useful application within the framework of marine coastal
      environment monitoring programs for detecting the possible exposure/effect
      induced by chemical pollutants, including pesticides, on living marine organisms.

PMID- 12604067
TI  - Mercury pollution sources in sediments of Patos Lagoon Estuary, Southern Brazil.
AB  - Present study has continued the investigation on distribution of mercury in
      estuarine sediments of Patos Lagoon which began whilst assessing the after-effect
      of enormous accidental discharge of sulfuric acid into the estuary. An attempt to
      evaluate the contribution of anthropogenic effluents on mercury pollution in
      sediments was undertaken. The effluents from Rio Grande City sewages were
      categorized into four groups based on their sources. Comparison of mercury
      concentrations from those, indicated that domestic effluent was prevalent.
      Apparent geographic controls of effluent locations enriched in mercury on zones
      of polluted estuarine sediments were also revealed. Insufficient control on waste
      collecting and absence of sewage treatment are considered the principal causes of
      mercury pollution in estuarine sediments.

PMID- 12604068
TI  - Assessment of urban and industrial contamination levels in the bay of Cadiz, SW
      Spain.
AB  - Measuring the amount of pollution is of particular importance in assessing the
      quality and general condition of an ecosystem. In this paper, some of the results
      obtained as a consequence of the specific agreement between the Environmental
      Agency (Consejeria de Medio Ambiente, Junta de Andalucia) and the University of
      Cadiz to assess the environmental condition of the marine bottom and waters are
      showed. Physical and chemical analyses in water and sediments were undertaken at
      various sampling sites close to urban and industrial locations. Later on, these
      results were studied under statistical analysis to reveal any possible
      relationships between the parameters employed, and to identify any analogous
      behaviour between the sampling sites. Physical-chemical data revealed that
      sediments and waters analysed were moderately contaminated and, in addition, no
      great differences were found between in rising and ebbing tide conditions.
      Finally, considering only the pollution level, from the cluster analysis of
      sediments two major groups appear, one of which corresponded to those sites
      located in the outer bay, and the other to those situated in the inner bay.
      However, number 6 and 14 sampling sites cannot be associated to those groups due
      to be related to points with important local discharges.

PMID- 12604069
TI  - Seasonal changes in zooplanktonic alkaline phosphatase activity in Toulon Bay
      (France): the role of Cypris larvae.
AB  - We studied zooplankton contribution to the total particulate phosphatase
      activity, the kinetics of this activity, the relation to the different taxonomic
      groups and the role of particle-bound bacteria. The activity of total particulate
      material collected from a liter of seawater was more elevated in May, June and
      August than during the rest of the year. These high activities resulted from a
      high contribution of the >90 microm fraction which account then for more than 60%
      of the total particulate activity. Two Michaelian processes with high and low
      V(max) were disclosed on this fraction. The high V(max) component was responsible
      for the high summer activities. During these periods, high densities of cirriped
      Cypris were found which were statistically correlated with this high V(max)
      component as with its specific activity. Moreover, the contribution of attached
      bacteria to these high activities was low. In return, this contribution was
      predominant during the periods of low activity. A simple method was developed to
      characterise this bacterial activity.

PMID- 12604070
TI  - A simple method to reduce discharge of sewage microorganisms from an Antarctic
      research station.
AB  - The majority of coastal Antarctic stations release untreated sewage into the near
      shore marine environment. This study examined bacterial reproduction within the
      temporary sewage-holding tanks of Rothera Research Station (Adelaide Island,
      Antarctic Peninsula) and monitored sewage pollution in the local marine
      environment. By continuously flushing the sewage-holding tanks with cold seawater
      we inhibited microbial reproduction and decreased the numbers of bacteria
      subsequently released into the sea by >90%. The widespread use of this simple
      method could significantly reduce the numbers of faecal coliform and other non
      native microorganisms introduced into the Antarctic marine environment.

PMID- 12604072
TI  - Organohalogens and metals in marine fish and mussels and some relationships to
      biological variables at reference localities in Norway.
AB  - The main goals of this study were to define, for the Norwegian coast, "high
      background" levels of micropollutants routinely monitored within the the Oslo and
      Paris Commission Joint Assessment and Monitoring Programme, and to reassess the
      present Norwegian reference levels used as the basis for a classification of
      environmental quality. The indicator organisms analysed as bulked/individual
      samples were cod (Gadus morhua, n approximately 1170; n approximately 240 for
      organochlorines), dab (Limanda limanda, n approximately 75), plaice (Pleuronectes
      platessa, n approximately 55) lemon sole (Microstomus kitt, n approximately 13).
      and blue mussels (Mytilus edulis, n approximately 200) collected between 1991
      2000. Based on the 90-95 percentiles of measurements at localities far from point
      sources, we propose for liver of cod a reference level for SigmaPCB(7) (CBs 28,
      52, 101, 118, 138, 153 and 180) of 500 microg kg(-1) w.w. and further for DDE 200
      microg kg(-1), SigmaHCHs 30 microg kg(-1), HCB 20 and OCS 5 microgkg(-1) w.w. In
      the same order the proposed reference levels for liver of dab are: 150, 60, 15,
      5, and 2 microgkg(-1) w.w.; and for the soft body of mussels: 3, 1, 1, 0.1 and
      0.1 microg kg(-1) wet weight. Reference levels of metals are 0.1 mgHg kg(-1) w.w.
      in fish fillet, and for Hg, Cd, Pb, Zn, Cu in mussels 0.2, 2, 3, 200 and 10 mg
      kg(-1) d.w., respectively. Hg in fillet of cod and dab were positively correlated
      with length and weight. PCB levels in liver of cod and dab showed a positive but
      weak correlation with length, whereas no co-variation was found between PCBs and
      liver fat. The results of introductory recordings of polychlorinated dibenzo-p
      dioxins/dibenzofurans, polychlorinated naphtalenes, Toxaphene and brominated
      flame retardants in liver of cod from reference sites are also presented.

PMID- 12604071
TI  - Evidence of a high percentage of intersex in the Mediterranean swordfish (Xiphias
      gladius L.).
AB  - The first evidence of the presence of intersexuality in a wild population of
      Mediterranean swordfish (Xiphias gladius L.) is reported. Forty of 162 specimens
      (25%) macroscopically classified as males, showed the presence of female germ
      cells within the testes. In two specimens grouped previtellogenic oocytes were
      present; all the other specimens possessed single scattered previtellogenic
      oocytes. The presence of vitellogenin was demonstrated immunohistochemically in
      the liver of both intersex and normal males. These findings could be due to the
      exposure to oestrogen-mimicking substances.

PMID- 12604073
TI  - Aliphatic hydrocarbons in biota from the Gulf of Naples (Italy).

PMID- 12604074
TI  - Electrochemical degradation of chlorophenoxy and chlorobenzoic herbicides in
      acidic aqueous medium by the peroxi-coagulation method.
AB  - The degradation of 4-chlorophenoxyacetic acid (4-CPA), 4-chloro-2
      methylphenoxyacetic acid (MCPA), 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5
      trichlorophenoxyacetic acid (2,4,5-T) as chlorophenoxy herbicides, as well as of
      3,6-dichloro-2-methoxybenzoic acid (dicamba) as chlorobenzoic herbicide, has been
      studied by peroxi-coagulation. This electrochemical method yields a very
      effective depollution of all compounds in acidic aqueous medium of pH 3.0 working
      under pH regulation, since they are oxidized with hydroxyl radicals produced from
      Fenton's reaction between Fe(2+) and H(2)O(2) generated by the corresponding Fe
      anode and O(2)-diffusion cathode. Their products can then be removed by
      mineralization or coagulation with the Fe(OH)(3) precipitate formed. Both
      degradative paths compete at low currents, but coagulation predominates at high
      currents. The peroxi-coagulation process of dicamba at I>or=300 mA leads to more
      than 90% of coagulation, being much more efficient than its comparative electro
      Fenton treatment with a Pt anode and 1 mM Fe(2+), where only mineralization takes
      place. For the chlorophenoxy compounds, electro-Fenton gives a slightly lower
      depollution than peroxi-coagulation, because more easily oxidable products are
      produced. Oxidation of chlorinated products during peroxi-coagulation is
      accompanied by the release of chloride ion to the solution. The efficiency of
      this method decreases with increasing electrolysis time and current. The decay of
      all herbicides follows a pseudo-first-order reaction, with a similar constant
      rate for 4-CPA, MCPA, 2,4-D and 2,4,5-T, and a higher value for dicamba.

PMID- 12604075
TI  - Observations of 2,4,6-trichlorophenol degradation by ozone.
AB  - The aqueous reactivity of 2,4,6-trichlorophenol (TCP) with ozone has been studied
      at laboratory-scale using a simple gas bubble/liquid contacting system.
      Degradation rate constants were measured directly and found to be 7.6 and 77.2 M(
      1)s(-1) at pH 2 and 7.5, respectively. At pH 7.5, 10 min of ozonation ( identical
      with 15 mM ozone consumption) achieved a 90% degradation of TCP, which
      corresponded to the release of approximately 2 mol Cl(-) per mol TCP. The
      presence of hydrogen peroxide in solution did not significantly increase the TCP
      degradation but increased the overall dechlorination to 2.7 mol Cl(-) per mol
      TCP. The presence of humic acid (HA) in solution was found to enhance the
      degradation rate of TCP at low relative HA concentrations (<0.6 g/g HA:TCP), but
      to reduce the rate at higher HA concentrations.

PMID- 12604076
TI  - A study of volatile organic sulfur emissions causing urban odors.
AB  - Levels of hydrogen sulfide and sulfur containing organic compounds were studied
      in the air at the deltas of the polluted creeks in the city of Izmir, Turkey in
      summer 2001. High concentrations of these malodorous compounds were measured in
      the air samples. Presence of these compounds in the air was connected with the
      dark appearance and rising gas bubbles in the studied segments of the creeks.
      These creeks were like open sewers carrying wastewaters from the industry and
      residential areas into the inner Izmir Bay until September 2001. Within the scope
      of this study organic sulfur compounds such as methane thiol, ethane thiol, 2
      propane thiol, 2-butane thiol, dimethylsulfide, dimethyldisulfide, thiophene,
      diphenylsulfide and hydrogen sulfide were studied in the air at selected urban
      sites where odor nuisance was recognized. Flux measurements from polluted
      surfaces were preferred rather than direct ambient air measurements. Organic
      sulfur emission fluxes from the creek surfaces were found above the values
      reported in the literature. Their concentrations and fluxes were higher in June
      field program. A limited number of measurements of reduced sulfur compound
      emission concentrations from the wastewater treatment plant equalization tank and
      the sludge drying beds as well as the landfill soil surface were also included in
      the study. Concentrations of total organic sulfur compounds and certain
      individual components such as dimethylsulfide and hydrogen sulfide in emitted
      gases from river surfaces were correlated with ambient SO(2) concentrations.

PMID- 12604077
TI  - Occurrence of THMs and HAAs in experimental chlorinated waters of the Quebec City
      area (Canada).
AB  - Haloacetic acids (HAAs) and trihalomethanes (THMs) were generated in bench-scale
      chlorination experiments using treated waters (prior to final chlorination) of
      the three major drinking water utilities of the Quebec City area. The purpose was
      to investigate the formation and occurrence of these chlorination by-products
      (CBPs) on a seasonal basis. Data for HAAs, THMs and other physico-chemical
      parameters were produced through a six-month sampling program with variable
      conditions of water quality, water temperature, applied chlorine dose and
      reaction time. In waters from the three utilities, chloroform (THM specie),
      dichloroacetic and trichloroacetic acid (HAA species) were the most prevalent
      compounds due to the low concentrations of bromide in the utilities' raw waters.
      Significant differences in CBP occurrence were noted between the three utilities'
      chlorinated waters, mainly due to the type of disinfectant applied to raw water.
      The use of pre-ozonation, as opposed to pre-chlorination (or direct chlorination)
      in one of the utilities appears to be the major factor contributing to that
      utility's potential for compliance with current THM and future HAA standards.
      Seasonal variations in THMs and HAAs were mainly associated with variations in
      organic precursors and to changes in water temperature (two parameters which vary
      widely on a seasonal basis in surface waters of southern Quebec), with CBP
      occurrence at its highest in spring. Statistical correlations between HAAs and
      THMs were moderate and only temperature appeared to affect the preponderance of
      one CBP or the other. Finally, a regression analysis was carried out aimed at
      associating each CBP to water quality and the experimental parameters. Thanks to
      their predictive ability, multivariate models seem to be the tools with the best
      potential for decision-making purposes.

PMID- 12604078
TI  - Removal of nitrogen and phosphate from wastewater by addition of bittern.
AB  - Removal of nitrogen and phosphate through crystallization of struvite
      (MgNH(4)PO(4).6H(2)O) has gained increasing interest. Since wastewaters tend to
      be low in magnesium relative to ammonia and phosphates, addition of this mineral
      is usually required to effect the struvite crystallization process. The present
      study evaluated the feasibility of using bittern, a byproduct of salt
      manufacture, as a low-cost source of magnesium ions. High reaction rates were
      observed; the extent of nitrogen and phosphorus removals did not change beyond 10
      min. Phosphorus removals from pure solutions with bittern added were equivalent
      to those obtained with MgCl(2) or seawater. Nitrogen removals with bittern were
      somewhat lower than with the alternate Mg(2+) sources, however. Application of
      bittern to biologically treated wastewater from a swine farm achieved high
      phosphate removal, but ammonia removals were limited by imbalance in the
      nitrogen:phosphorus ratio.

PMID- 12604079
TI  - Effect of pH control at the anode for the electrokinetic removal of phenanthrene
      from kaolin soil.
AB  - Polycyclic aromatic hydrocarbon (PAH)-contaminated soils exist at numerous sites,
      and these sites may threaten public health and the environment because many PAH
      compounds are toxic, mutagenic, and/or carcinogenic. PAHs are also hydrophobic
      and persistent, so conventional remediation methods are often costly or
      inefficient, especially when the contaminants are present in low permeability
      and/or organic soils. An innovative technique, electrokinetically enhanced in
      situ flushing, has the potential to increase soil-solution-contaminant
      interaction and PAH removal efficiency for low permeability soils; however, the
      electrolysis reaction at the anode may adversely affect the remediation of low
      acid buffering capacity soils, such as kaolin. Therefore, the objective of this
      study was to improve the remediation of low acid buffering soils by controlling
      the pH at the anode to counteract the electrolysis reaction. Six bench-scale
      electrokinetic experiments were conducted, where each test employed one of three
      different flushing solutions, deionized water, a surfactant, or a cosolvent. For
      each of these solutions, tests were performed with and without a 0.01 M NaOH
      solution at the anode to control the pH. The test using deionized water with pH
      control generated a higher electroosmotic flow than the equivalent test performed
      without pH control, but the electroosmotic flow difference between the surfactant
      and cosolvent tests with and without pH control was minor compared to that
      observed with the deionized water tests. Controlling the pH was beneficial for
      increasing contaminant solubilization and migration from the soil region adjacent
      to the anode, but the high contaminant concentrations that resulted in the middle
      or cathode soil regions indicates that subsequent changes in the soil and/or
      solution chemistry caused contaminant deposition and low overall contaminant
      removal efficiency.

PMID- 12604080
TI  - A disappearance model for the prediction of trichlorophenol ozonation.
AB  - The disappearance and modeling of the ozonation of 2,4,6-trichlorophenol (TCP)
      was studied under different initial TCP concentrations and initial pH levels. The
      ozonation of TCP was found to follow a pseudo-first-order reaction. The
      degradation rates increased with the initial pH, and decreased with initial TCP
      concentration. 2,6-Dichlorohydroquinone was identified as the major intermediate,
      indicating that dechlorination and hydroxylation co-occurred during TCP
      ozonation. A model was proposed to quantitatively predict the pseudo-first-order
      rate constants under different initial TCP concentration and different initial pH
      levels. The proposed model can successfully describe the reaction; therefore
      another practical equation was proposed to predict the TCP removal rate at any
      detention time, which has high potential for practical applications and reactor
      design.

PMID- 12604081
TI  - Study of the degradation of dyes by MnP of Phanerochaete chrysosporium produced
      in a fixed-bed bioreactor.
AB  - The production of ligninolytic enzymes by the fungus Phanerochaete chrysosporium
      in a fixed-bed tubular bioreactor, filled with cubes of nylon sponge, operating
      in semi-solid-state conditions, was studied. Maximum individual manganese
      dependent peroxidase (MnP) and lignin peroxidase (LiP) activities of 1293 and 225
      U/l were detected. The in vitro decolourisation of two structurally different
      dyes (Poly R-478, crystal violet) by the extracellular liquid obtained in the
      above-mentioned bioreactor was monitored in order to determine its degrading
      capability. The concentration of some compounds (sodium malonate, manganese
      sulphate) from the reaction mixture was optimised in order to maximise the
      decolourisation levels. A percentage of Poly R-478 decolourisation of 24% after
      15 min of dye incubation was achieved. On the other hand, a methodology for a
      long treatment of these dyes based on the continuous addition of MnP enzyme and
      H(2)O(2) was developed. Moreover, this enzymatic treatment was compared with a
      photochemical decolourisation process. The former allowed to maintain the
      degradation rate almost constant for a long time, resulting in a decolourisation
      percentage of 70% and 30% for crystal violet and Poly R-478, respectively, after
      2 h of treatment. As for the latter, it was not able to degrade Poly R-478,
      whereas crystal violet reached a degradation of 40% in 2 h.

PMID- 12604082
TI  - Modeling the reaction kinetics of Fenton's process on the removal of atrazine.
AB  - The degradation of pesticide, atrazine (ATZ), 2-chloro-4-(ethylamino)-6
      (isopropylamino)-s-triazine, by Fenton's reagent (FR) was investigated as a
      function of reagents' concentrations and ratios in a batch reactor. The
      degradation of ATZ was effectively achieved by hydroxyl radicals, which were
      generated in the FR process. The decay rates of ATZ and the oxidation capacities
      of FR were found to depend on the concentrations of hydrogen peroxide and ferrous
      ion. The removal kinetics of ATZ are initiated by a rapid decay and then followed
      by a much slower one. After an extended reaction time (5-10 min), the reactions
      ceased because the Fe(II) and H(2)O(2) were consumed and would be deactivated in
      the process. A mathematical model was successfully developed to describe the two
      stage reaction kinetics by using two simple but critical parameters: the initial
      ATZ decay rate and the final oxidation capacity of Fenton's process. In general,
      higher [Fe(II)] or H(2)O(2) concentrations result in faster initial decay rate
      and higher oxidation capacity. However, the oxidation capacity is more sensitive
      to the initial [Fe(II)] due to the presence of side reactions as discussed in the
      paper.

PMID- 12604083
TI  - Fate of polycyclic aromatic hydrocarbons during vitrification of incinerator ash
      in a coke bed furnace.
AB  - Fate of polycyclic aromatic hydrocarbons (PAHs) during the vitrification of fly
      ash and bottom ash from the municipal waste incinerator in a coke bed furnace was
      investigated. In this system, both coke and lime were added to enhance the
      melting reaction. The major PAH sources in this system were ash and coke, which
      respectively contributed 97% and 3% of PAHs in the input-mass. During
      vitrification process, low molecular PAHs (LM-PAH, 2-3-ring), median molecular
      PAHs (MM-PAH, 4-ring) and high molecular PAHs (HM-PAH, 5-7-ring) mass
      respectively accounted for >99%, >99% and 84% of the output-mass emitted as the
      stack flue gas; while those discharged from the slag were <1%, <1% and 16%,
      respectively. The O/I (output-mass/input-mass) ratio of LM-, MM- and HM-PAHs were
      0.063, 0.002 and <0.001, respectively. The high distribution in flue gas and O/I
      ratio of LM-PAHs is reasonable since they are more easily evaporated, hence
      difficult to be removed by air pollution control devices. On the contrary, the HM
      PAHs, having lower vapor pressure, primarily stays mainly in slag. Based on the
      21 total PAH content in feeding ash and slag, the reduction efficiency of the
      coke bed furnace was >99.9%. To minimize the risk of secondary pollution, the
      efficiency of coke bed furnace should be improved to reduce the PAH emission into
      ambient air.

PMID- 12604084
TI  - Adsorption of phosphate from aqueous solution onto alunite.
AB  - The phosphate removal potential of alunite, a low cost and abundantly available
      material, has been investigated. The effects of calcination temperature and time
      of alunite, adsorbent particle size, pH and initial phosphate concentration on
      the phosphate adsorption by the calcined alunite have been studied. Phosphate
      removal was seen to increase with increasing calcination temperature, decreasing
      adsorbent particle size and pH. Adsorption of phosphate followed first-order rate
      kinetics. Langmuir and Freundlich adsorption isotherm constants and correlation
      coefficients were calculated and compared. It was concluded that the adsorption
      data of phosphate onto calcined alunite fitted to the Langmuir model more than
      Freundlich model. Specific surface areas of the calcined alunite were calculated
      at different calcination temperatures and particle sizes.

PMID- 12604085
TI  - Removal of chromium and reduction of toxicity to Microtox system from tannery
      effluent by the use of calcium alginate beads containing humic acid.
AB  - Removal of chromium (Cr) from tannery effluents by recovery of metal also reduces
      the ecotoxicological impact. To develop such a process, columns packed with
      calcium alginate (CA) beads with or without humic acid (HA) have been used as an
      adsorbent and tannery effluent was passed through it. Concentration of Cr in
      beads and in different fractions collected after adsorption was measured. Change
      in total organic carbon content during the process was also noticed. The
      fractions were also tested for toxicity towards Microtox assay. EC(50) values
      were determined with the help of Microtox analyser 500. Data showed that the CA
      beads along with HA could be effectively utilised in removal of 54% Cr and also
      in reducing the toxicity (EC(50) (%) in 5 min=>100 in fractions collected after
      72 h).

PMID- 12604087
TI  - Expression level dependent changes in the properties of P2X2 receptors.
AB  - The currents of P2X(2) receptors expressed in Xenopus oocytes or HEK293 cells
      show significant cell-to-cell variation in many properties including the rate of
      desensitization and the magnitude of potentiation by zinc or acidic pH. In this
      study, we examined whether differences in expression levels underlie this
      variability. We injected Xenopus oocytes with different concentrations of RNA
      encoding rat P2X(2) to give a wide range of maximum current amplitudes, and then
      measured the potentiation of responses to 10 micro M adenosine 5'-triphosphate
      (ATP) by zinc or acidic pH. Individual oocytes showed potentiation ratios that
      ranged from 1.4- to 25-fold. Oocytes with small amplitude responses to a
      saturating concentration of ATP tended to have larger potentiation ratios than
      oocytes with large amplitude responses. This phenomenon was explained by an
      inverse correlation between the EC(50) for ATP and the maximum current amplitude,
      with the EC(50) decreasing from about 37 to 7 micro M as expression level
      increased. In contrast, the Hill coefficient was not correlated with the maximum
      current amplitude. Truncated receptors lacking the last 76 amino acids also
      showed an inverse correlation between the EC(50) and the maximum current
      amplitude. Thus, the interactions that cause expression-dependent changes in
      P2X(2) receptor properties must involve domains proximal to position H397.

PMID- 12604086
TI  - Biphasic role of dopamine on female sexual behaviour via D2 receptors in the
      mediobasal hypothalamus.
AB  - Dopamine has been implicated in the control of sexual behaviour, but its role
      seems quite complex and controversial. The aim of the present experiments was to
      investigate the effects of dopamine (DA) acting on D2 receptors in the mediobasal
      hypothalamus (MBH) on sexual behaviour in female sheep. To achieve this, the D2
      agonist, quinpirole, was administered bilaterally via microdialysis probes into
      the MBH of ovariectomized ewes either before or after oestradiol (E2)
      administration. Quinpirole (100 ng/ml) infused for 6 h just before E2 hastened
      the onset of oestrus behaviour and the luteinizing hormone surge, whereas the
      same treatment given 6-12 h or 18-21 h after E2 decreased the intensity of sexual
      receptivity without affecting LH or prolactin secretion. We then tested the
      hypothesis that E2 stimulates the onset of oestrus partly by decreasing DA
      activation of D2 receptors. In this case the D2 antagonists pimozide or spiperone
      (100 ng/ml) were infused into the MBH via microdialysis probes for 11 h in the
      absence of E2 administration. A significant number of ewes showed induction of
      receptivity with both antagonists, although its intensity was significantly lower
      than that induced by E2. These treatments generally did not significantly alter
      extracellular concentrations of monoamines or aminoacids although quinpirole
      modulated the ability of sexual interactions to increase noradrenaline release.
      These experiments show that DA acts via D2 receptors in the MBH to control female
      sexual behaviour in a biphasic manner: the onset of sexual motivation and
      receptivity requiring an initial increase in activation followed by a decrease.
      This dual action could explain some of the controversies concerning DA action on
      sexual behaviour.

PMID- 12604089
TI  - Activation of Ih is necessary for patterning of mGluR and mAChR induced network
      activity in the hippocampal CA3 region.
AB  - Neuronal networks of the hippocampal CA3 region generate stereotyped patterns of
      electrical activity in response to activation of metabotropic glutamate receptors
      (mGluRs) or muscarinic acetylcholine receptors (mAChRs) that consist of
      intermittent episodes of prolonged oscillatory activity. In light of the slow
      kinetics of such network responses, we investigated the possible contribution of
      the hyperpolarisation-activated inward current (I(h)) in the generation and
      maintenance of hippocampal oscillatory states. Hippocampal 'mini-slice'
      experiments in which the main subfields of the hippocampus were isolated by
      transection of the connecting afferents revealed that the CA3 region was the
      primary generator of both mGluR and mAChR-mediated network responses. Subsequent
      patch-clamp experiments confirmed the presence of a prominent hyperpolarisation
      activated inward current in the principal cells of the CA3 region that was
      sensitive to caesium chloride and the selective I(h) blocker ZD-7288.Furthermore,
      in the presence of mAChR or mGluR agonists these cells exhibited a slow membrane
      potential oscillation that was independent of AMPA receptor-mediated synaptic
      transmission. Blockade of I(h) suppressed this oscillation as well as mGluR and
      mAChR-induced theta based intermittent network oscillatory behaviour. These data
      support the idea that the I(h) pacemaker current is important in the generation
      of patterned neuronal activities in the hippocampus.

PMID- 12604088
TI  - Differential interactions of lamotrigine and related drugs with transmembrane
      segment IVS6 of voltage-gated sodium channels.
AB  - Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant
      drugs. A receptor site for local anesthetics has been defined in transmembrane
      segment S6 in domain IV (IVS6) of the alpha subunit, but the anticonvulsant
      lamotrigine and related compounds have more complex structures than local
      anesthetics and may interact with additional amino acid residues. Apparent K(D)
      values for inactivated-state block of rat brain type IIA sodium channels
      expressed in Xenopus oocytes were 31.9 micro M, 17.3 micro M, 3.7 micro M and
      10.3 micro M for lamotrigine and compounds 227c89, 4030w92 and 619c89,
      respectively. Compound 619c89 was the strongest frequency-dependent blocker,
      which correlated with higher affinity and a five-fold slower recovery from drug
      block compared to lamotrigine. Examination of lamotrigine block of mutant sodium
      channel alpha subunits, in which alanine had been substituted for each individual
      amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the
      largest reductions in affinity (six-, seven- and 12-fold, respectively). The
      ratios of effects of these three mutations differed for compounds 227c89,
      4030w92, and 619c89. The amino acid residues interacting with these pore-blocking
      drugs define a surface of IVS6 that is exposed to the pore and may rotate during
      gating.

PMID- 12604090
TI  - Serotonin-GABA interactions in the modulation of mu- and kappa-opioid analgesia.
AB  - In the present study, we studied the interaction between serotonergic (5-HTergic)
      and gamma-aminobutyric acid (GABA)-ergic systems in the modulation of analgesia
      from morphine, a mu-opioid agonist, and U50,488, a kappa-opioid agonist. All
      experiments were performed in mice using the 49 degrees C tail-withdrawal assay.
      The benzodiazepine receptor agonist, diazepam, the serotonin synthesis inhibitor,
      para-chlorophenylalanine (p-CPA), and the 5-HT(1A) receptor agonist, 8-OH-DPAT,
      were all found to attenuate morphine and U50,488 analgesia. In each case, the
      attenuation was itself blocked by treatment with L-5-HTP, a serotonin precursor,
      bicuculline, a GABA(A) receptor antagonist or picrotoxin, a GABA(A)-gated
      chloride channel blocker. Neither L-5-HTP nor the GABA(A) receptor antagonists
      were found to affect morphine or U50,488 analgesia per se. Thus, these findings
      indicate that a benzodiazepine-GABAergic agent (diazepam) attenuates opioid
      analgesia through the serotonergic system, and antiserotonergic agents (8-OH
      DPAT, p-CPA) attenuate opioid analgesia through the GABAergic system. The
      intimate interactions between GABA and serotonin in the present study further
      suggest that these neurotransmitters work in complex ways together rather than
      alone in the modulation of opioid analgesia.

PMID- 12604091
TI  - GABAB receptor-mediated presynaptic potentiation of ATP ionotropic receptors in
      rat midbrain synaptosomes.
AB  - Nucleotides can activate ionotropic P2X receptors that induce calcium-responses
      in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+)
      responses producing a monophasic dose-response curve with an EC(50) value of
      24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP
      dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and
      59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is
      52.1% higher than the control. This effect is mimicked or blocked by the specific
      GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively.
      Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in
      62% of the total synaptosomal population. Adenylate cyclase and protein kinase A
      cascades are involved in the potentiatory effects mediated by baclofen and their
      activation or inhibition modifies calcium signalling and synaptosomal cAMP
      levels. The potentiatory action of baclofen was confirmed by microfluorimetry
      performed on single synaptic terminals. In its presence, 86% of the terminals
      responding to 100 micro M ATP, are also able to respond to nanomolar
      concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced
      to 32% in the presence of pertussis toxin. Our data suggest that the activity of
      P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.

PMID- 12604092
TI  - Evaluation of the NR2B-selective NMDA receptor antagonist Ro 63-1908 on rodent
      behaviour: evidence for an involvement of NR2B NMDA receptors in response
      inhibition.
AB  - We have characterised the effects of the recently described NMDA NR2B subtype
      selective antagonist, Ro 63-1908, on spontaneous behaviour and in tasks sensitive
      to non-selective NMDA antagonists. In both rats and wild type mice, Ro 63-1908 (1
      30mg/kg sc) produced a mild increase in motor activity of lesser magnitude than
      that elicited by dizocilpine. No signs of overt PCP-like stereotypy were seen in
      either species at equivalent doses. PPI was also unaffected. However, in mice
      lacking the NR2A subunit, Ro 63-1908 (3-30mg/kg) produced a profound
      hyperactivity of similar magnitude to dizocilpine but few other 'PCP-like'
      behaviours. In rats, Ro 63-1908 (1-10mg/kg) did not affect Morris water maze or
      delayed matching performance. In a 5-choice serial reaction time task, requiring
      rats to respond to a visual stimulus presented after a fixed time interval, Ro 63
      1908 (0.3-3mg/kg) produced a dramatic increase in premature responses - accuracy
      was relatively unaffected. Finally in a DRL24 task, Ro 63-1908 (0.3-3mg/kg)
      reduced inter-response time, increased response rate, and consequently reduced
      efficiency. We conclude that the improved profile of Ro 63-1908 compared to NMDA
      channel blockers is due to both its selectivity for the NR2B vs. NR2A subunit
      containing receptors and its activity-dependent mechanism of action. However, in
      the 5-CSRT and DRL24 tasks, Ro 63-1908 produced behaviours suggestive of impaired
      response inhibition, implicating a critical role of NMDA NR2B transmission in
      this process.

PMID- 12604093
TI  - Selective serotonin reuptake inhibitors enhance cocaine-induced locomotor
      activity and dopamine release in the nucleus accumbens.
AB  - The role for serotonin (5-HT) in mediating the behavioral effects of cocaine may
      be related in part to the ability of 5-HT to modulate the function of the
      dopamine (DA) mesoaccumbens pathways. In the present study, the ability of the
      selective serotonin reuptake inhibitors (SSRIs) fluoxetine (10 mg/kg, IP) and
      fluvoxamine (10 and 20 mg/kg, IP) to alter cocaine (10 mg/kg, IP)-induced
      hyperactivity and DA release in the nucleus accumbens (NAc) was analyzed in male
      Sprague-Dawley rats. Systemic administration of either fluoxetine or fluvoxamine
      enhanced cocaine-induced locomotor activity in a dose-dependent manner;
      fluoxetine (10 mg/kg, IP) also enhanced cocaine (10 mg/kg, IP)-induced DA efflux
      in the NAc. To test the hypothesis that the NAc serves as the locus of action
      underlying these effects following systemic cocaine administration, fluoxetine (1
      and 3 micro g/0.2 micro l/side) or fluvoxamine (1 and 3 micro g/0.2 micro l/side)
      was microinfused into the NAc shell prior to systemic administration of cocaine
      (10 mg/kg, IP). Intra-NAc shell infusion of 3 micro g of fluoxetine or
      fluvoxamine enhanced cocaine-induced hyperactivity, while infusion of fluoxetine
      (1 micro M) through the microdialysis probe implanted into the NAc shell enhanced
      cocaine (10 mg/kg, IP)-induced DA efflux in the NAc. Thus, the ability of
      systemic injection of SSRIs to enhance cocaine-evoked hyperactivity and DA efflux
      in the NAc is mediated in part by local actions of the SSRIs in the NAc.

PMID- 12604094
TI  - Methyllycaconitine (MLA) blocks the nicotine evoked anxiogenic effect and 5-HT
      release in the dorsal hippocampus: possible role of alpha7 receptors.
AB  - Nicotine has bimodal effects on anxiety, with low doses having an anxiolytic
      effect and high doses having an anxiogenic effect. The dorsal hippocampus is one
      of the brain areas that mediate the anxiogenic effect of nicotine through
      enhanced 5-HT release, but the nAChR subtype(s) that mediate these effects are
      not known. Intrahippocampal administration of a high dose of nicotine (1 micro g,
      4.3 mM) had an anxiogenic effect in the social interaction test that was reversed
      by co-administration of a behaviourally inactive dose (1.9 ng, 4.3 micro M) of
      methyllycaconitine (MLA), which is an antagonist at alpha7 and alpha3 nAChR
      subunits. At a dose (0.8 ng, 4.3 micro ;M) at which its actions would be specific
      to alpha4beta2 and alpha3beta2 nAChRs dihydro-beta-erythroidine (DHbetaE) was
      unable to reverse nicotine's anxiogenic effect. Reversal was obtained with a 10
      fold higher, but receptor non-specific concentration of DHbetaE (7.8ng, 43 micro
      M), suggesting that the DHbetaE reversal might have been due to action at alpha7
      nAChRs. Exposure of hippocampal slices to MLA (0.25, 05, 1 and 10 micro M)
      significantly reduced the increase in [(3)H]5-HT release evoked by nicotine (100
      micro M). DHbetaE (0.1-0.5 micro M) failed to reverse this effect of nicotine on
      [(3)H]5-HT release, although higher concentrations (1 and 10 micro M), at which
      alpha7 subunits would also be affected, were able to do so. Because of the lack
      of effects of low, receptor specific concentrations of DHbetaE, it is more likely
      that the MLA reversal of both nicotine's anxiogenic effect and its stimulation of
      [(3)H]5-HT release is due to action at alpha7 than at alpha3 units. This is
      perhaps also more likely because the alpha7 receptors are highly expressed in the
      dorsal hippocampus, whereas the alpha3 subunits are much less abundant. However,
      what is most important is that, in the dorsal hippocampus, nicotine's anxiogenic
      effect and induced release of [(3)H]5-HT are mediated by non alpha4beta2 nAChRs,
      which contrasts with the previously reported anxiolytic effect of a low dose of
      nicotine which is mediated by alpha4beta2 nAChRs within the dorsal raphe nucleus.
      Thus the anxiolytic and anxiogenic effects of nicotine can be distinguished both
      by brain region and by nicotinic receptor subtype.

PMID- 12604096
TI  - Sex dimorphisms in the cognitive-enhancing action of the Alzheimer's drug
      donepezil in aged Rhesus monkeys.
AB  - Brain acetylcholinesterase has been targeted for the development of novel
      treatments for memory deficits associated with Alzheimer's disease (AD) and other
      neurodegenerative disorders. The long-acting AChE inhibitor donepezil (Aricept)
      is used to improve memory and other aspects of cognition in AD patients. Because
      donepezil and other cholinesterase inhibitors are effective in a restricted
      population of AD patients, this study was to designed to determine whether aged
      females monkeys receive the same level of benefit to the mnemonic action of
      donepezil as do males. In this study, six male and six female rhesus monkeys (>20
      years) who were proficient in the performance of a delayed matching-to-sample
      task each received an ascending series of four doses of donepezil (0.01-0.1
      mg/kg) over 5 weeks. As a group, male subjects exhibited improvement in task
      accuracy across the three highest doses, with the maximum effect occurring after
      the 0.025 mg/kg dose. However, the females exhibited increased task accuracy only
      after the highest dose. When data were combined for sessions run 10 min after
      drug administration and for sessions run 24 h later (in the absence of drug),
      improvements in task accuracy were greater on average for males. Most of this
      difference was attributed to the fact that task accuracy by females actually
      declined during sessions run after the two lowest doses of donepezil. When task
      performance after donepezil was determined as the individualized Best Dose, as a
      group, males responded maximally to less than half the dose that was maximal for
      females. These findings support the concept that aged males and females respond
      differently to this class of agents, perhaps representing fundamental sex-related
      differences in memory processing, or in the manner that age affects these
      processes.

PMID- 12604095
TI  - A role for COX-2 and p38 mitogen activated protein kinase in long-term depression
      in the rat dentate gyrus in vitro.
AB  - Long-term potentiation (LTP) and long-term depression (LTD) are two forms of
      activity-dependent synaptic plasticity that are thought to be involved in
      learning and memory. Evidence has shown that cyclooxygenase-2 (COX-2), an enzyme
      that converts arachidonic acid to prostaglandins, is expressed in postsynaptic
      dendritic spines and is regulated by synaptic activity. COX-2 inhibition has been
      shown to directly attenuate LTP in the dentate gyrus of the hippocampus. Also
      recently the p38 MAP kinase cascade, a pathway utilised by cells for COX-2
      expression, has been implicated in LTD induction in the CA1 region of the
      hippocampus. Here we demonstrate for the first time a direct role for COX-2 and
      p38 MAP kinase in LTD and confirm the inhibitory role of COX-2 in LTP in the rat
      dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 micro M) 60 min before
      tetanic stimulation resulted in an attenuation of LTD (84+/-5%, n=5 compared to
      controls of 57+/-7%, n=6, P<0.05). Prolonged exposure (2 h) to NS-398 (1 micro M)
      resulted in a significant reduction in LTP (71+/-8%, n=5, P<0.01 compared to
      controls of 170+/-11%, n=5 at 60 min post HFS). The p38 MAPK inhibitor, SB220025
      (250 nM) significantly attenuated LTD (88+/-5%, n=7; P<0.01 compared to vehicle
      controls at 60 min, 56+/-5%, n=6) but had no significant effect on LTP. Both NS
      398 and SB220025 had no significant effect on the isolated NMDA-mediated EPSP.
      These data demonstrate a role for COX-2 and p38 MAPK in LTD in the dentate gyrus
      in vitro that is independent of NMDA receptor activation.

PMID- 12604097
TI  - Participation of the GABAergic system in the action of 2-amino-4
      phosphonobutyrate on the OFF responses of frog retinal ganglion cells.
AB  - Perfusion of dark adapted frog eyecups with the ON pathway blocker 2-amino-4
      phosphonobutyrate (APB) not only abolished the ganglion cells (GCs)' ON responses
      and the ERG b-wave, but it markedly potentiated the OFF responses of all ON-OFF
      and phasic OFF GCs and the d-wave amplitude of a simultaneously recorded ERG as
      well. The blockade of GABA(A) and GABA(C) receptors by picrotoxin eliminated this
      potentiating effect in 24 out of 41 GCs, although in the rest of the cells it did
      not produce any change in the APB effect. On the other hand, the d-wave
      potentiation was preserved during the GABAergic blockade in all experiments. Our
      results indicate that GABAergic transmission is involved in the inhibition
      exerted by the ON upon the OFF channel in part of the ON-OFF and phasic OFF GCs
      in the frog retina. The tonic OFF GCs probably do not receive an inhibitory input
      from the ON channel, because their light responses were not altered either by APB
      alone or by APB during blockade of GABA(A) and GABA(C) receptors.

PMID- 12604098
TI  - Senescence of the temporal impulse response to a luminous pulse.
AB  - An impulse response function (IRF) to a luminous pulse was derived for 70 normal
      observers ranging in age from 16 to 86 years. Thresholds were measured for two
      pulses separated by interstimulus intervals from 6.7 to 180 ms. The pulses had a
      spatial Gaussian shape (+/-1SD=2.3 degrees diam) and were presented as increments
      on a 10 cd/m(2) background, having the same chromaticity as the pulse. A spatial
      4-alternative forced-choice method was combined with a staircase procedure.
      Retinal illuminance was equated individually by heterochromatic flicker
      photometry and control of pupil area. Each IRF was measured four times, in
      separate sessions, for each observer. IRFs calculated from the threshold data
      revealed significant age-related changes in the response amplitude of both
      excitatory and inhibitory phases. In general, there were no significant changes
      in the time to the first peak or in the first zero crossing. For 12 of 20
      observers over 60 years of age, however, the amplitude of the second (inhibitory)
      phase was reduced relative to the excitatory phase so their IRFs were quite slow
      and long. Control conditions with three pseudophakic observers and two normal
      observers with induced blur demonstrated that age-related changes in the IRF
      under these conditions cannot be ascribed to optical factors. The data suggest
      that the human visual system generally maintains a stable speed of response to a
      flash until at least about 80 years of age, even while there are senescent
      reductions in response signal amplitude.

PMID- 12604099
TI  - Global feature-based attention for motion and color.
AB  - We used a divided attention psychophysical task to test the hypothesis that
      visual attention to a stimulus feature(1) facilitates the processing of other
      stimuli sharing the same feature. Performance on a dual-task was significantly
      better when human observers divided attention across two spatially separate
      stimuli sharing a common feature (same direction of motion or same color)
      compared to opposing features. This attentional effect was dependent upon the
      presence of competing stimuli. These results are consistent with a spatially
      global feature-based mechanism of attention that increases the response of
      cortical neurons tuned to an attended feature throughout the visual field.

PMID- 12604100
TI  - Gaze modulation of visual aftereffects.
AB  - Physiological studies of non-human primates have suggested that the direction of
      gaze can modulate the gain of neuronal responses to visual stimuli in many
      cortical areas including V1. The neural gaze modulation is suggested to subserve
      the conversion from gaze-independent (eye-centered) to dependent (e.g., head
      centered) representations. However, it has not been established whether the gaze
      modulation has significant influences on human visual perception. Here we show
      that gaze direction modestly but significantly modulates the magnitudes of the
      motion aftereffect, the tilt aftereffect and the size aftereffect. These
      aftereffects were stronger when the adaptation and test patterns were presented
      in the same gaze direction, than when they were presented in different gaze
      directions, even though the patterns always stimulated the same retinal location.
      The gaze modulation effect was not statistically significant for the post
      adaptation elevation of contrast detection thresholds. The gaze modulation of
      visual aftereffects provides a useful psychophysical tool to analyze human
      cortical processes for coordinate transformations of visual space.

PMID- 12604101
TI  - Longer VEP latencies and slower reaction times to the onset of second-order
      motion than to the onset of first-order motion.
AB  - We compared visual evoked potentials and psychophysical reaction times to the
      onset of first- and second-order motion. The stimuli consisted of luminance
      modulated (first-order) and contrast-modulated (second-order) 1 cpd vertical sine
      wave gratings drifting rightward for 140 ms at a velocity of 6 degrees /s. For
      each condition, we analysed the latencies and peak-to-baseline amplitudes of the
      P1 and N2 peaks recorded at Oz. For first-order motion, both P1 and N2 peaks were
      present at low (3%) contrast (i.e., depth modulations) whereas for second-order
      motion they appeared only at higher (25%) contrasts. When the two types of motion
      were equated for visibility, responses were slower for second-order motion than
      for first-order motion: about 44 ms slower for P1 latencies, 53 ms slower for N2
      latencies, and 76 ms slower for reaction times. The longer VEP latencies for
      second-order motion support models that postulate additional processing steps for
      the extraction of second-order motion. The slower reaction time to the onset of
      second-order motion suggests that the longer neurophysiological analysis
      translates into slower detection.

PMID- 12604102
TI  - The influence of the Stiles-Crawford peak location on visual performance.
AB  - We investigated the influence of the Stiles-Crawford peak location on visual
      acuity, contrast sensitivity and phase transfer with 6 mm diameter pupils in two
      subjects. Apodising filters were used to move the peak. One subject (SM) had her
      natural peak 0.9 mm below pupil centre, and visual performance was measured for
      both this peak position and when the peak was moved to the same distance above
      pupil centre. The other subject (DAA) had a more centred peak and visual
      performance was measured for this peak position and when the peak was moved both
      2.3 mm temporally and 2.6 mm nasally. Measurements of contrast sensitivity and
      phase transfer were compared with predictions based on aberration measurements.
      The peak position had definite influence on performance, but this was mainly
      noticeable when subjects were defocused e.g. SM's visual acuity was reduced by
      0.13 log units under the peak-shifted condition at -2D (hypermetropic) defocus.

PMID- 12604103
TI  - Velocity dependence of Vernier and letter acuity for band-pass filtered moving
      stimuli.
AB  - The ability to see fine detail diminishes when the target of interest moves at a
      speed greater than a few deg/s. The purpose of this study was to identify
      fundamental limitations on spatial acuity that result from image motion.
      Discrimination of Vernier offset was measured for a pair of vertical abutting
      lines and letter resolution was measured using a four-orientation letter 'T'.
      These stimuli were digitally filtered using one of five band-pass (bandwidth=1.5
      octaves) filters with a center frequency between 0.83 and 13.2 c/deg, and
      presented at velocities that ranged from 0 to 12 deg/s. Filtered and unfiltered
      stimuli were presented for 150 ms at a constant multiple (4x or 2x) of the
      contrast-detection threshold at each velocity. For stimuli of low to middle
      spatial frequency (up to 3.3 c/deg), Vernier and letter acuity for equally
      detectable targets are essentially unaffected by velocity up to 12 deg/s, i.e.,
      for temporal frequencies of motion (velocity x spatial frequency) up to
      approximately 50 Hz. For stimuli of higher spatial frequency, acuity remains
      essentially constant until the velocity corresponds to a temporal frequency of
      about 30 Hz, and increases thereafter. Both Vernier and letter acuities worsen by
      approximately a factor of two for each one-octave decrease in filter spatial
      frequency. Both types of acuities worsen also as the contrast of the stimulus is
      reduced, but Vernier discrimination exhibits a stronger contrast-dependence than
      letter resolution. Our results support previous suggestions that a shift in the
      spatial scale used by the visual system to analyze spatial stimuli is principally
      responsible for the degradation of acuity in the presence of image motion. The
      results are consistent with a spatio-temporal-frequency limitation on spatial
      thresholds for moving stimuli, and not with a temporal-frequency limitation per
      se.

PMID- 12604104
TI  - Independence of mechanisms tuned along cardinal and non-cardinal axes of color
      space: evidence from factor analysis.
AB  - Many previous studies employing paradigms such as adaptation, masking and
      summation-near-threshold have demonstrated the existence of separate mechanisms
      underlying the detection of the three cardinal axes of color space: L+M, L-M and
      S-(L+M). In addition, some studies have demonstrated the existence of higher
      order mechanisms tuned to non-cardinal axes (which are made up of combinations of
      the cardinal axes). In order to address the issue of separate and independent
      color mechanisms further, here we applied factor analysis to contrast threshold
      data obtained from 41 subjects for nine different axes in color space (the three
      cardinal axes and the six non-cardinal axes midway between). In line with
      previous studies, the results of a three-factor analysis performed on contrast
      thresholds for the cardinal axes revealed independence across the three. However,
      in some of our factor analyses (for example, when a two-factor analysis was
      performed on the cardinal axes), intercorrelation was observed between L-M and S
      (L+M) stimuli. With regard to higher-order mechanisms, our factor analyses
      revealed mechanisms selective for non-cardinal axes within the (L-M)/(L+M) and (S
      (L+M))/(L+M) color planes, but not the (L-M)/(S-(L+M)) color plane. To ensure
      that the intercorrelation observed between L-M and S-(L+M) cardinal axes was not
      due to the particular stimulus parameters or testing measures employed, in three
      of our subjects we performed a "summation-near-threshold" experiment using
      experimental conditions nearly identical to those in the factor analysis
      experiments. In accordance with previous findings [Vision Research 39 (1999)
      733], L-M and S-(L+M) stimuli were found to be separable in this analysis. This
      seeming discrepancy between the results of our factor analysis and those obtained
      from paradigms such as summation-near-threshold can be resolved by proposing that
      the mechanisms underlying detection of L-M and S-(L+M) stimuli are separable (as
      defined by the ability to isolate activity within each mechanism using select
      stimuli), yet nonetheless intercorrelated. Such intercorrelation could arise if
      these two mechanisms are limited by the same source of variability and/or subject
      to the same gain control.

PMID- 12604105
TI  - Chromatic induction in neon colour spreading.
AB  - Neon colour spreading occurs when sections of a lattice are replaced by segments
      of a different colour. This colour appears to diffuse out of the segments, and
      produce a slightly tinted transparent surface floating above the lattice. In two
      of the four experiments reported here, observers varied the colour of an area in
      a test display, until it matched the neon colour perceived in a corresponding
      (illusory) area in a comparison display. We found that the neon colour is an
      additive mixture of the colour of the segments and the colour complementary to
      the lattice, as suggested by Bressan (Vision Research 35 (1995) 375). In the
      other two experiments, we separately manipulated the presence and alignment of
      lattice and segments, to test whether the neon effect is fully predicted by a
      combination of colour diffusion and simultaneous colour contrast. We found that
      the colour induced in a neon figure is more saturated than the colour induced in
      a comparable non-neon figure. We discuss the implications of these results on our
      current understanding of the mechanisms of neon colour spreading.

PMID- 12604106
TI  - Effects of contrast and length on vernier acuity explained with noisy templates.
AB  - Vernier acuity depends on the integration of information from multiple
      photoreceptors. For this reason, vernier acuity thresholds ought to exhibit
      effects of stimulus size and contrast analogous to those that occur in area
      summation experiments. In this paper, we consider some area and contrast effects
      found in vernier acuity experiments, and explain them with a model of detection
      and discrimination which we call the Noisy Template model. The Noisy Template
      model assumes that psychophysical tasks are performed (or can be approximated) by
      cross-correlation of the stimulus with a decision template which is optimal for
      the task at hand. The Noisy Template model crucially adds the assumption that the
      template contains noise. This yields inefficiency in the decision process which
      increases with stimulus size and contrast. Predictions of the Noisy Template
      model are derived for the case of vernier acuity, and compared with existing
      experiments.

PMID- 12604107
TI  - Opposing views on orthogonal adaptation: a reply to Westheimer and Gee (2002).

PMID- 12604108
TI  - Opposing views on orthogonal adaptation: a response to Clifford, Arnold, Smith,
      and Pianta (2003).

PMID- 12604109
TI  - In vivo pachymetry in normal eyes of rats, mice and rabbits with the optical low
      coherence reflectometer.
AB  - The aim of this study was to determine the central corneal thickness (CCT) in
      living rats, mice and rabbits using a non-contact, high-speed optical low
      coherence reflectometer (OLCR) mounted on a regular slit lamp. Both eyes of eight
      male Wistar rats, eight male balb-c mice and eight male Japanese rabbits were
      measured. Each eye was measured twice (one measurement consists of 20 scans), the
      average calculated. Additionally, CCT was measured in rabbits using an ultrasound
      pachymeter. The mean CCT was: RATS: 159.08 microm (SD+/-14.99 microm), MICE:
      106.0 microm (SD+/-3.45 microm) and RABBITS: 356.11 microm (SD+/-14.34 microm).
      With the use of OLCR we were able to accurately measure the CCT of rats, mice and
      rabbits in vivo. This technique may prove useful in further refractive,
      pharmacological and glaucoma studies.

PMID- 12604110
TI  - Deficits to global motion processing in human amblyopia.
AB  - We investigated global motion processing in a group of adult amblyopes using a
      method that allows us to factor out any influence of the known contrast
      sensitivity deficit. We show that there are independent global motion processing
      deficits in human amblyopia that are unrelated to the contrast sensitivity
      deficit, and that are more extensive for contrast-defined than for luminance
      defined stimuli. We speculate that the site of these deficits must include the
      extra-striate cortex and in particular the dorsal pathway.

PMID- 12604111
TI  - Ultrasound in space.
AB  - Physiology of the human body in space has been a major concern for space-faring
      nations since the beginning of the space era. Ultrasound (US) is one of the most
      cost effective and versatile forms of medical imaging. As such, its use in
      characterizing microgravity-induced changes in physiology is being realized. In
      addition to the use of US in related ground-based studies, equipment has also
      been modified to fly in space. This involves alteration to handle the stresses of
      launch and different power and cooling requirements. Study protocols also have
      been altered to accommodate the microgravity environment. Ultrasound studies to
      date have shown a pattern of adaptation to microgravity that includes changes in
      cardiac chamber sizes and vertebral spacing. Ultrasound has been and will
      continue to be an important component in the investigation of physiological and,
      possibly, pathologic changes occurring in space or as a result of spaceflight.

PMID- 12604112
TI  - Hemodynamic response of the left gastric vein to glucagon in patients with portal
      hypertension and esophageal varices.
AB  - Flow direction and flow velocity of the left gastric vein (LGV) and the portal
      vein (PV) were examined by a Doppler sonographic machine in 33 patients with
      esophageal varices, before and after venous injection of glucagon (1 mg). In two
      patients with hepatopetal blood flow in the LGV, the flow direction changed to
      hepatofugal after injection of glucagon. In 31 patients with hepatofugal blood
      flow in the LGV, a significant increase of flow velocity was observed in the LGV
      in 18 patients (58.1%) and the changes (26.4 +/- 24.6%) were significantly larger
      than those in the PV (7.9 +/- 16.0%). The changes in flow velocity decreased in
      the LGV as the diameter of the LGV and the size of varices increased. In
      conclusion, glucagon increased collateral blood flow in the LGV in portal
      hypertension. However, the grade of the response decreased as the grade of portal
      hypertension increased.

PMID- 12604113
TI  - Assessment of placental fractional moving blood volume using quantitative three
      dimensional power doppler ultrasound.
AB  - To test the hypothesis that the placental fractional moving blood volume is
      different with advancing gestational age (GA), we assessed the vascularization
      index (VI), flow index (FI), and vascularization-flow index (VFI) of the placenta
      in normal pregnancy by using three-dimensional (3-D) power Doppler ultrasound
      (US). We enrolled 100 healthy pregnant women with gestational age between 20 to
      40 weeks for this study. Three-dimensional power Doppler ultrasonography was used
      to assess the VI, FI and VFI in each case. Our results showed that the linear
      regression equations for VI, FI and VFI, by using GA as the independent variable,
      were VI = 0.27107 x GA -4.02748 (r = 0.84, p < 0.0001), FI = 0.56115 x GA +
      34.28945 (r = 0.49, p < 0.001), and VFI = 0.15663 x GA -2.53810 (r = 0.82, p <
      0.0001), respectively. In addition, the VI, FI and VFI values of the placental
      flow were also positively correlated with the fetal growth indices, namely,
      biparietal diameter, occipitofrontal diameter, head circumference, abdominal
      circumference and estimated fetal weight (all p values < 0.001). In conclusion,
      our study illustrates that the fractional moving blood volume of the placenta is
      positively correlated with the increment of gestational age and the fetal growth
      indices. Our data may be used as a reference in the assessment of the placental
      fractional moving blood volume using the quantitative 3-D power Doppler US.

PMID- 12604114
TI  - Partial cut-off of the left ventricle: determinants and effects on volume
      parameters assessed by real-time 3-D echocardiography.
AB  - A total of 44 patients with coronary artery disease underwent real-time three
      dimensional (3-D) echocardiography for end systolic (ES) and end diastolic (ED)
      left ventricular (LV) volumetric analysis to assess the effect of partial cut-off
      of the left ventricular (LV) apex on volumetric analysis by apical transthoracic
      echocardiography. Patients with LV cut-off were assigned to either group 1
      (ejection fraction, (EF) < 49%) or group 2 (EF > or = 49%). Patients were
      additionally classified as group A if they had anterior or apical wall motion
      abnormalities (WMA) or group B if they had only inferoposterior or lateral WMA.
      Partial LV cut-offs were found in 22 subjects (50%). The estimated end diastolic
      cut-off volumes were as follows: 8.6 +/- 3.2 mL (group 1), 4.3 +/- 2.4 mL (group
      2), 9.1 +/- 3.3 mL (group A) and 1.4 +/- 0.8 mL (group B). In group 1, more
      patients with LV volume cut-off were found than in group 2: chi(2) = 4.52, p <
      0.05; and in group A more than in group B: chi(2) = 8.08, p < 0.01. In all,
      partial LV cut-off led to underestimation of LV volumes: 5.9 +/- 4.7 ml (ED) vs.
      2.1 +/- 1.3 ml (ES), p <0.02. In conclusion, LV cut-offs can potentially alter
      the accuracy of echocardiographic volumetric analysis, particularly in anterior
      or apical WMA.

PMID- 12604115
TI  - Short-term variability of cerebral blood flow velocity responses to arterial
      blood pressure transients.
AB  - The time course of mean beat-to-beat changes in cerebral blood flow velocity
      changes induced by spontaneous transients in mean arterial blood pressure was
      studied in a group of 39 healthy subjects, ages 40 +/- 15 (SD) years. Continuous
      10-min noninvasive recordings of cerebral blood flow velocity (CBFV) from both
      middle cerebral arteries (MCA) with Doppler ultrasound (US) and simultaneous beat
      to-beat arterial blood pressure (ABP) were made. A total of 522 spontaneous
      positive transients of ABP and CBFV were extracted with a maximum of 15
      transients for each subject. The CBFV transient amplitude was normalized by the
      corresponding ABP change and the area-under-the-curve (AUC) of the falling phase
      was used to classify the CBFV regulatory response as either weak, moderate or
      strong. The coherent average of ABP and CBFV of each category confirmed the
      consistency of this classification, reinforced by the agreement of separate
      averages for recordings from the right and left MCA. All 39 subjects showed at
      least two categories of transients, with all three categories present in 33
      subjects (right MCA) and 29 subjects (left MCA), respectively. These results
      indicate a significant short-term variability of CBFV responses in healthy
      subjects whose origin remains unexplained.

PMID- 12604116
TI  - High-frequency 3-D color-flow imaging of the microcirculation.
AB  - High-frequency (> 20 MHz) ultrasound (US) flow imaging has the potential to be an
      important tool for assessing microvascular blood flow in superficial tissues
      noninvasively. In this paper, we describe the development and evaluation of a 3-D
      US flow imaging system capable of operating at center frequencies in the 20- to
      50-MHz range. Flow images are made for tissue volumes of sizes up to 10 mm
      laterally and 5 mm in depth, permitting a range of scientific and clinical
      applications. To acquire data sets in a reasonable time, the 2-D sections were
      derived from data collected with a transducer that was scanning continuously in a
      direction perpendicular to the beam axis. Due to spectral broadening effects
      induced by scanning tissue, significant tradeoffs must be made between frame
      rate, lateral resolution and the minimum detectable blood velocity. 3-D flow
      images were reconstructed with flow data acquired from a series of adjacent
      planes. The system was evaluated at a center frequency of 50 MHz, using two PVDF
      transducers with lateral resolutions of 43 microm and 65 microm and axial
      resolutions of 66 microm to 72 microm, respectively. Velocity ranges were from
      below 1 mm/s to 25 mm/s. In vivo validation experiments using the mouse ear
      demonstrated the ability to follow branching patterns of closely spaced
      microvessels from 30 microm to 100 microm in diameter. Experiments conducted on
      mouse tumors successfully imaged microvessel morphology in the tumor
      microcirculation.

PMID- 12604117
TI  - Doppler colour flow imaging and flow quantification with a novel forward-viewing
      intravascular ultrasound system.
AB  - The aim of this work was to investigate the potential of a novel forward-viewing
      intravascular ultrasound (IVUS) system for flow quantification and colour flow
      imaging combined with B-mode imaging. A stiff 3.8-mm diameter catheter was used
      to scan a 72 degrees sector ahead of its tip. Operating at 30 MHz, the catheter
      was integrated with an IVUS scanner and a radiofrequency (RF) data-acquisition
      system. RF data were software processed for producing B-mode images and deriving
      velocity estimates. Steady flow in the range of 45 to 146 mL/min toward the
      catheter, was used in wall-less tissue-mimicking phantoms simulating healthy
      lumen (8-mm diameter), 30% diameter symmetrical stenosis and 37% diameter
      eccentric stenosis. The system provided colour flow images and good estimation of
      peak velocity and volumetric flows (within 1% to 9% and 16% to 48%, respectively,
      of calculated values) at 5 to 7 mm distal to the catheter. A sector forward
      viewing IVUS imaging/Doppler system is suitable for combined anatomical and
      functional assessment of stenosed vessels.

PMID- 12604118
TI  - MP3 compression of Doppler ultrasound signals.
AB  - The effect of lossy, MP3 compression on spectral parameters derived from Doppler
      ultrasound (US) signals was investigated. Compression was tested on signals
      acquired from two sources: 1. phase quadrature and 2. stereo audio directional
      output. A total of 11, 10-s acquisitions of Doppler US signal were collected from
      each source at three sites in a flow phantom. Doppler signals were digitized at
      44.1 kHz and compressed using four grades of MP3 compression (in kilobits per
      second, kbps; compression ratios in brackets): 1400 kbps (uncompressed), 128 kbps
      (11:1), 64 kbps (22:1) and 32 kbps (44:1). Doppler spectra were characterized by
      peak velocity, mean velocity, spectral width, integrated power and ratio of
      spectral power between negative and positive velocities. The results suggest that
      MP3 compression on digital Doppler US signals is feasible at 128 kbps, with a
      resulting 11:1 compression ratio, without compromising clinically relevant
      information. Higher compression ratios led to significant differences for both
      signal sources when compared with the uncompressed signals.

PMID- 12604119
TI  - Biological and environmental factors affecting ultrasound-induced hemolysis in
      vitro: 1. HIV macrocytosis (cell size).
AB  - This paper reports the results of a further test of the hypothesis that the
      extent of ultrasound (US)-induced cell lysis in the presence of a US contrast
      agent to enhance cavitational effects is a function of cell size. The present
      data support the hypothesis. Human adult erythrocytes in vitro derived from
      patients with HIV (n = 15) and apparently healthy individuals (n = 15) were
      compared for US-induced hemolysis in vitro. The anticoagulated whole blood from
      patients with HIV and macrocytic erythrocytes had significantly greater (p
      <0.0001) mean corpuscular volume (MCV) and a significantly greater (p <0.03)
      extent of US-induced hemolysis in vitro relative to blood from apparently normal,
      healthy individuals. As a control to determine if disease state (i.e., HIV
      infection per se) might be a contributing factor in US-induced hemolysis in
      vitro, the blood from patients with HIV and apparently normal MCVs (n = 15) was
      also tested against an additional population of apparently normal, healthy
      individuals (n = 15); there were no statistically significant differences in MCVs
      or US-induced hemolysis between the two groups (p >> 0.05). There were also no
      statistically significant differences in viscosities or hematocrits of the whole
      blood or plasma in vitro from HIV-macrocytic or apparently healthy individuals
      but, for all blood types, a pooled correlation existed between hematocrit and
      whole blood viscosity.

PMID- 12604120
TI  - Biological and environmental factors affecting ultrasound-induced hemolysis in
      vitro: 2. Medium dissolved gas (pO2) content.
AB  - The data collected in this project supported the a priori hypothesis that the
      concentration of dissolved oxygen in whole human blood in vitro affected the
      extent of ultrasound (US)-induced hemolysis under conditions conducive to the
      occurrence of inertial cavitation. Aliquots of whole human blood in vitro with a
      relatively high O(2) level had statistically significantly more 1-MHz US-induced
      hemolysis than aliquots with a relatively low O(2) level in the presence of
      controlled gas nucleation (Albunex or ALX, supplementation), with US-induced
      hemolytic yields being substantially less at 2.2- and 3.5-MHz exposures or in the
      absence of ALX-supplementation at otherwise comparable acoustic pressures, pulse
      lengths and duty factors. Passive cavitation detection (pcd) measures indicated a
      linear relationship for hemolysis up to about 70% and pcd values (R(2) = 0.99).

PMID- 12604122
TI  - The variation of heating depth with therapeutic ultrasound frequency in
      physiotherapy.
AB  - In patient treatment, different ultrasound (US) frequencies are attributed to
      differences in penetration and, as an effect of that, to different heating depths
      in tissues. A set of 13 experiments was carried out with US frequencies of 0.86,
      2 and 3 MHz. A dynamic treatment protocol and a stationary treatment protocol
      were used. The temperature increase patterns were thermally imaged with a 1-min
      interval during an insonation of 5 min. At every data point, the temperature in
      the reference image was subtracted from the thermal image after 1, 2, 3, 4 and 5
      min. In every difference thermal image, the distance between the US applicator
      and the deepest point of heat increase was measured. Results show that US
      frequencies do not affect the depth limit for the different temperature ranges,
      in either the static treatment protocol or the dynamic treatment protocol.

PMID- 12604121
TI  - Biological and environmental factors affecting ultrasound-induced hemolysis in
      vitro: 3. Antioxidant (Trolox) inclusion.
AB  - This project tested the hypothesis that human erythrocytes pretreated with Trolox
      (a water-soluble analog of vitamin E) would be more susceptible to ultrasound
      (US)-induced hemolysis by a cavitational mechanism because of an increased
      fragility of the erythrocyte membrane over that without Trolox supplementation.
      Samples of whole human blood from apparently healthy donors (hematocrit
      approximately 40%) in vitro were supplemented or not supplemented with Trolox at
      various concentrations, ranging from 1.8 to 0.0018 mg/mL plasma. Mechanical
      fragility tests indicated the Trolox-treated blood in vitro exhibited greater
      hemolysis than untreated blood in vitro (p < 0.001). US exposures at comparable
      acoustic amplitude, pulse length and duty factor in the presence of the US
      contrast agent Albunex yielded differing results; at 1 MHz, the Trolox
      supplemented blood had significantly greater hemolysis in vitro than non-Trolox
      supplemented blood; at 3 MHz, there was a substantial reduction in hemolysis
      relative to that obtained at 1 MHz, and no statistically significant difference
      between the Trolox-supplemented and -unsupplemented blood. There was also
      essentially no support for an alternative hypothesis that the Trolox was
      functioning primarily as a pro-oxidant. These collective experimental results
      support the hypothesis and suggest duality in the functionality of membranous
      antioxidant inclusions or associations; they may foster protection against
      oxidative damage, yet render the cell less capable of withstanding mechanical
      stress.

PMID- 12604123
TI  - High-frequency sound transmissions under water and risk of decompression
      sickness.
AB  - We tested the possible occurrence of a neurological insult secondary to high
      frequency sound exposure. Immersed, anesthetized rats were subjected to a
      simulated diving profile designed to induce decompression sickness, while exposed
      to the transmission of an acoustic beacon. Intermittent sound at a pressure level
      of 184.5 dB re 1 microPa at 1 m (1.7 kPa), a frequency of 37 kHz, and with a
      duration of 4 ms, was transmitted in a duty cycle of 0.26%. Four groups, each
      containing nine animals, were included in the study as follows: group 1,
      immersion only, no sound exposure; group 2, immersion with sound exposure; group
      3, diving simulation when immersed, no sound exposure; group 4, diving simulation
      when immersed, with sound exposure. Somatosensory evoked potentials (SSEPs) were
      recorded the day before the study, and a second recording was made 30 min after
      immersion. Some of the SSEP components disappeared after the dive in 3 rats from
      group 3 and 2 rats from group 4. SSEP components could not be identified in a
      significantly larger number of animals from groups 3 and 4, compared with groups
      1 and 2. No differences were found in wave latency, amplitude or conduction time.
      Our data show that the high-frequency sound exposure employed did not contribute
      to the development of the neurological insult.

PMID- 12604124
TI  - The changes in acoustic attenuation due to in vitro heating.
AB  - The effects of heat-generated changes on the attenuation of ultrasound (US) by
      porcine liver tissue have been studied over a frequency range of 2.0 to 5.0 MHz.
      Samples of fresh tissue, 4- to 5-mm thick, were pressurized and cooled before
      measurement. The insertion loss was measured at room temperature, using a
      broadband 3.5-MHz transducer of focal length 10 cm, employing a pulse-reflection
      technique. Fourier analysis of the results gave the frequency-dependence of the
      insertion loss. Samples were then heated in a water bath to a temperature in the
      range of 40 to 80 degrees C, for between 30 and 500 s. The insertion loss was
      then re-measured at room temperature. The frequency-dependence of the change in
      insertion loss, expressed as a coefficient, in dB/cm, was fitted by linear
      regression, from which the attenuation change at 3.5 MHz was determined. This
      change was attributed to protein coagulation. Increases of up to 2.4 dB/cm, (80
      degrees C, 300 s) were found. The averaged data were fitted to a single step
      exponential model, resulting in a time constant on the order of 118 +/- 5 s, and
      an asymptotic limit to the increase of attenuation coefficient of 2.67 +/- 0.5
      dB/cm.

PMID- 12604125
TI  - Use of growth factors in the elderly patient with cancer: a report from the
      Second International Society for Geriatric Oncology (SIOG) 2001 meeting.
AB  - Over 70% of the total incidence of cancer recorded in Europe in 1996 was in the
      elderly population (> or =60 years). Despite such high statistics, elderly cancer
      patients have often been denied the treatment that younger patients routinely
      receive. The response of elderly cancer patients to full-dose chemotherapy
      treatment in several neoplasms is similar to that of younger patients,
      demonstrating that age should not be a barrier to the administration of
      potentially curative or palliative chemotherapy. In order to provide optimal
      treatment to elderly cancer patients, management guidelines are recommended which
      take into account various factors, such as the physical well-being of the
      patient, the type of malignancy and any conditions that may hamper compliance
      with chemotherapy. The evidence-based guidelines of the National Comprehensive
      Cancer Network (NCCN) in the US recommend that the safest and most effective
      treatment of cancer in older individuals may be achieved by proper patient
      selection based on comprehensive geriatric assessment, dose adjustment of renally
      excreted drugs, prophylactic use of haematopoietic growth factors in patients
      treated with chemotherapy of dose-intensity comparable to
      cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) and maintenance of
      haemoglobin levels > or =12 g/l. The objective of this article is to report the
      conclusions of the meeting of the International Society of Geriatric Oncology
      (SIOG) in September 2001, including the need for geriatric assessment to tailor
      the management of patients to their personal circumstances and general health and
      the importance of evidence-based guidelines for the management of elderly cancer
      patients cannot be over-estimated.

PMID- 12604126
TI  - The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and
      its clinical implications.
AB  - A Runt domain transcription factor AML1/RUNX1 is essential for generation and
      differentiation of definitive hematopoietic stem cells. AML1 is the most frequent
      target of chromosomal translocations in acute leukemias. Several chimeric
      proteins such as AML1-MTG8 and TEL-AML1 have transdominant properties for wild
      type AML1 and acts as transcriptional repressors. The transcriptional repression
      in AML1 fusion proteins is mediated by recruitment of nuclear corepressor complex
      that maintains local histone deacetylation. Inhibition of the expression of AML1
      responsive genes leads to a block in hematopoietic cell differentiation and
      consequent leukemic transformation. On the other hand, mutations in the Runt
      domain of the AML1 are identified in both sporadic acute myeloblastic leukemia
      (AML) without AML1 translocation and familial platelet disorder with
      predisposition to AML. These observations indicate that a decrease in AML1 dosage
      resulting from chromosomal translocations or mutations contributes to
      leukemogenesis. Furthermore, dysregulated chromatin remodeling and
      transcriptional control appears to be a common pathway in AML1-associated
      leukemias that could be an important target for the development of new
      therapeutic agents.

PMID- 12604127
TI  - Matrix metalloproteinase inhibitors--an emphasis on gastrointestinal
      malignancies.
AB  - Gastrointestinal malignancies are the commonest sites of human cancer
      collectively. Improved understanding of tumour biology in the last few decades
      has allowed the identification of cellular pathways responsible for the
      autonomous growth and replication in cancer cells. There is considerable
      preclinical evidence implicating matrix metalloproteinases (MMPs) in cancer
      dissemination and tumour angiogenesis. Effective MMP inhibitors (MMPIs) may,
      therefore, hold an important key in the treatment of gastrointestinal cancers.
      MMPIs are cytostatic agents and traditional values of tumour regression may not
      be the best measures of treatment efficacy. Biological correlation studies are
      increasingly being incorporated into the early development of these agents, but
      many of these studies lack preclinical validation and are often chosen on
      availability rather than biological plausibility. Disappointing results with many
      MMPIs that have entered phase III testing so far would prompt for identification
      of reliable surrogate biomarkers and incorporation of functional imaging in the
      clinical development of matrix metalloproteinase inhibitors in gastrointestinal
      malignancies. In this review, the integral part in which MMPs are involved in
      cancer growth and metastases will be presented. This is then followed by a
      discussion of the challenges that clinicians are facing in assessing the efficacy
      of MMPIs and finally a review of the clinical studies of the synthetic MMPIs in
      development.

PMID- 12604128
TI  - Renal cell carcinoma: current status and future directions.
AB  - Although renal cell carcinoma accounts for only 3% of adult malignancies, it has
      been increasing in incidence by 2-4% per year since the 1970's. Cigarette
      smoking, obesity and end-stage renal disease are important risk factors. Genetic
      syndromes such as von Hippel-Lindau disease are also associated with an increased
      incidence of renal cell carcinoma. Localized disease should be treated with
      surgical resection. However, approximately 30% of patients present with
      metastatic disease. Complete resection of metastases can result in long-term
      survival in some individuals. Removal of the primary renal tumor in patients with
      unresectable disseminated disease has also been shown to improve survival in
      selected good performance status patients receiving systemic immunotherapy. While
      chemotherapy has been relatively ineffective in the treatment of renal cell
      carcinoma, biologic therapy with interleukin-2 or interferon does lead to
      responses in a minority of patients, with occasional long-term survivors.
      Recently, promising results have been reported with allogeneic stem cell
      transplantation using a non-myeloablative conditioning regimen. However, therapy
      for metastatic renal cell carcinoma remains inadequate. Ongoing trials with novel
      approaches such as anti-angiogenesis agents, cyclin-dependent kinase inhibitors,
      and tumor vaccines will hopefully lead to improved outcomes in this disease.

PMID- 12604129
TI  - Overview of gemcitabine triplets in metastatic bladder cancer.
AB  - For more than a decade the MVAC regimen has been gold standard chemotherapy in
      bladder cancer, albeit that the toxicity associated with this therapy hampered
      its use in many of the typical elderly patients with metastatic disease. New
      active agents have been identified, combinations of these new agents with
      platinum compounds (doublets) followed, and results have become available of a
      phase III randomized trial of the gemcitabine and cisplatin doublet versus MVAC,
      that has revealed an efficacy-toxicity profile in favor of the gemcitabine
      cisplatin regimen. During the conduct of this study, investigators in Spain and
      in the United States have incorporated both gemcitabine and paclitaxel in either
      cisplatin- or carboplatin based triplet regimens that, albeit thus far only in
      phase II studies, have indicated notable activity and favorable median survival
      figures, particularly in patients with visceral disease. A randomized study of
      the paclitaxel-cisplatin-gemcitabine triplet versus gemcitabine-cisplatin is
      ongoing.

PMID- 12604130
TI  - Cancer of the nasopharynx.
AB  - Nasopharyngeal cancer (NPC) is quite rare throughout Europe, accounting for an
      annual incidence rate below 1 per 100.000, whereas the highest risk area is South
      East Asia. A predominant occurrence in males is to be noted. NPC is an
      etiologically multifactorial disease, most probably involving viral, genetic and
      environmental factors. Carcinomas of the nasopharynx can be divided into two
      major histotypes: keratinizing squamous cell carcinomas (WHO-type 1) and non
      keratinizing carcinomas (WHO-type 2). The histological type is a prognostic
      factor and it has a clear impact on the outcome of treatment. Standard
      therapeutic option for early stages of NPC is radiation, while an integration of
      radiation therapy and chemotherapy is indicated in more advanced stages.

PMID- 12604131
TI  - Major and minor salivary glands tumours.
AB  - Malignant salivary gland tumours are rare. The most common tumour site is the
      parotid. Aetiologic factors are not clear. Nutrition may be a risk factor, as
      well as irradiation or an histologically benign tumour occurred at a young age.
      Painless swelling of a salivary gland should always be considered as suspicious,
      especially if no sign of inflammation is present. Signs and symptoms related to
      major salivary gland tumours differ from those concerning minor salivary gland
      tumours, as they depend on the different location of the salivary gland. Surgical
      excision represents the standard option in the treatment of resectable tumours of
      both major and minor salivary glands. Neutron radiation may be a treatment option
      for inoperable locoregional disease. Surgery, irradiation or re-irradiation are
      treatment options for local relapse, whereas radical neck dissection is indicated
      for regional relapses. Metastastic disease may be either treated with
      radiotherapy or palliative chemotherapy, depending on the site of metastases.

PMID- 12604132
TI  - Structural identifiability for a class of non-linear compartmental systems using
      linear/non-linear splitting and symbolic computation.
AB  - Under certain controllability and observability restrictions, two different
      parameterisations for a non-linear compartmental model can only have the same
      input-output behaviour if they differ by a locally diffeomorphic change of basis
      for the state space. With further restrictions, it is possible to gain valuable
      information with respect to identifiability via a linear analysis. Examples are
      presented where non-linear identifiability analyses are substantially simplified
      by means of an initial linear analysis. For complex models, with four or more
      compartments, this linear analysis can prove lengthy to perform by hand and so
      symbolic computation has been employed to aid this procedure.

PMID- 12604133
TI  - Analytical methods for predicting the behaviour of population models with general
      spatial interactions.
AB  - Many biologists use population models that are spatial, stochastic and individual
      based. Analytical methods that describe the behaviour of these models
      approximately are attracting increasing interest as an alternative to expensive
      computer simulation. The methods can be employed for both prediction and fitting
      models to data. Recent work has extended existing (mean field) methods with the
      aim of accounting for the development of spatial correlations. A common feature
      is the use of closure approximations for truncating the set of evolution
      equations for summary statistics. We investigate an analytical approach for
      spatial and stochastic models where individuals interact according to a generic
      function of their distance; this extends previous methods for lattice models with
      interactions between close neighbours, such as the pair approximation. Our study
      also complements work by Bolker and Pacala (BP) [Theor. Pop. Biol. 52 (1997) 179;
      Am. Naturalist 153 (1999) 575]: it treats individuals as being spatially discrete
      (defined on a lattice) rather than as a continuous mass distribution; it tests
      the accuracy of different closure approximations over parameter space, including
      the additive moment closure (MC) used by BP and the Kirkwood approximation. The
      study is done in the context of an susceptible-infected-susceptible epidemic
      model with primary infection and with secondary infection represented by power
      law interactions. MC is numerically unstable or inaccurate in parameter regions
      with low primary infection (or density-independent birth rates). A modified
      Kirkwood approximation gives stable and generally accurate transient and long
      term solutions; we argue it can be applied to lattice and to continuous-space
      models as a substitute for MC. We derive a generalisation of the basic
      reproduction ratio, R(0), for spatial models.

PMID- 12604134
TI  - Modeling hybridization kinetics.
AB  - Formation of complementary base pairs between nucleic acids over a short region
      (<or=15 nucleotides) is described by a kinetic model in which the intermediate
      state is assumed to be locally single stranded. The model enables calculation of
      a rate factor that is proportional to the rate constant for hybridization under
      steady-state reaction conditions. Rate factors calculated for various sites in
      acetylcholinesterase mRNA correlated with sites found previously to be
      experimentally accessible for hybridization to antisense oligonucleotides.
      Hybridization rate of longer antisense oligodeoxynucleotides was modeled by
      calculation of a maximal rate factor for all possible 15-nucleotide segments of a
      given antisense molecule. Maximal rate factor calculated for a set of antisense
      oligonucleotides correlated (r=0.95) with initial rate of hybridization reported
      previously. Two other models proposed for identifying accessible sites for
      hybridization were less predictive than the rate factor calculation.

PMID- 12604135
TI  - Coding DNA sequences: statistical distributions.
AB  - The base distributions in coding DNA sequences (CDS) are investigated. We explore
      the scaling properties of the 4-dimensional directed random walk and compare them
      with that for the DNA sequences. Inference from these observation are, however,
      contradicted by alternate analysis using factorial moments. To resolve this
      conflict we look directly at the nucleotide base distributions. In all the cases
      the base distributions change from gaussian to non-gaussian as the scale size is
      increased. The CDS, therefore, have nucleotide distributions different from the
      random.

PMID- 12604136
TI  - Incorporation of variability into the modeling of viral delays in HIV infection
      dynamics.
AB  - We consider classes of functional differential equation models which arise in
      attempts to describe temporal delays in HIV pathogenesis. In particular, we
      develop methods for incorporating arbitrary variability (i.e., general
      probability distributions) for these delays into systems that cannot readily be
      reduced to a finite number of coupled ordinary differential equations (as is done
      in the method of stages). We discuss modeling from first principles, introduce
      several classes of non-linear models (including discrete and distributed delays)
      and present a discussion of theoretical and computational approaches. We then use
      the resulting methodology to carry out simulations and perform parameter
      estimation calculations, fitting the models to a set of experimental data.
      Results obtained confirm the statistical significance of the presence of delays
      and the importance of including delays in validating mathematical models with
      experimental data. We also show that the models are quite sensitive to the mean
      of the distribution which describes the delay in viral production, whereas the
      variance of this distribution has relatively little impact.

PMID- 12604139
TI  - The medical evaluation of sexually abused children.

PMID- 12604137
TI  - Modelling biological invasions: species traits, species interactions, and habitat
      heterogeneity.
AB  - In this paper we explore the integration of different factors to understand,
      predict and control ecological invasions, through a general cellular automaton
      model especially developed. The model includes life history traits of several
      species in a modular structure interacting multiple cellular automata. We
      performed simulations using field values corresponding to the exotic Gleditsia
      triacanthos and native co-dominant trees in a montane area. Presence of G.
      triacanthos juvenile bank was a determinant condition for invasion success. Main
      parameters influencing invasion velocity were mean seed dispersal distance and
      minimum reproductive age. Seed production had a small influence on the invasion
      velocity. Velocities predicted by the model agreed well with estimations from
      field data. Values of population density predicted matched field values closely.
      The modular structure of the model, the explicit interaction between the invader
      and the native species, and the simplicity of parameters and transition rules are
      novel features of the model.

PMID- 12604140
TI  - Characteristics of a group of adolescents undergoing loop electrical excision
      procedure (LEEP).
AB  - STUDY OBJECTIVE: To describe the sociodemographic characteristics of a cohort of
      adolescents undergoing loop electrosurgical excision procedure (LEEP) of the
      cervix, and to determine if LEEP is a safe and effective procedure for evaluation
      and treatment of high-grade squamous intraepithelial lesions (HSIL) of the cervix
      in adolescents. SETTING: Case series of all adolescents who underwent LEEP
      between 1995 and 1997 at Children's Hospital, Boston, MA. DESIGN: Medical and
      laboratory records were reviewed to assess baseline characteristics and the
      following outcomes: (1) LEEP pathology results, (2) postoperative complications,
      (3) pregnancy outcomes, (4) compliance with follow-up appointments, and (5)
      recurrence of disease over a 12- to 37-month period. PARTICIPANTS: Thirty-five
      adolescents underwent LEEP. The mean age of the adolescents at the time of LEEP
      was 17.9 +/- 1.5 yrs. RESULTS: The mean interval between coitarche and LEEP was
      3.69 +/- 2.09 yrs. On preoperative colposcopy, 28 (80%) had HSIL on biopsy, 3
      (8.6%) had HSIL on Pap smear with a discordant biopsy demonstrating low-grade
      squamous intraepithelial lesion (LSIL), 1 (2.9%) had a persistent LSIL, 2 (5.6%)
      had diffuse LSIL with an unsatisfactory colposcopy, and 1 (2.9%) had a HSIL Pap
      smear with a normal biopsy. LEEP specimen histopathology results were: HSIL in 19
      (54%), LSIL in 10 (29%), SIL difficult to grade in 3 (9%), and no residual
      disease in 3 (9.0%). Postoperative complications were bleeding in 2 (5.7%), pain
      in 1 (2.9%), vaginal discharge in 1 (2.9%), cervicitis in 3 (8.6%), and
      endometritis in 2 (5.7%). Fourteen pregnancies were diagnosed after LEEP; no
      spontaneous abortions occurred. Mean follow-up period was 21.1 +/- 9.4 months.
      Compliance with follow-up appointments was 51% in the first 12 months post-LEEP
      and 26% in the second 12 months post-LEEP. Of the 28 patients followed for 12
      months or more, there was one recurrence of HSIL confirmed by colposcopy and
      biopsy. CONCLUSIONS: Outcome and complications of LEEP in adolescent females are
      similar to those reported in larger series of adult women. LEEP appears to be a
      safe and effective procedure for the evaluation and treatment of HSIL of the
      cervix in adolescents, but additional long-term data are needed.

PMID- 12604141
TI  - The surgical treatment of labial adhesions in pre-pubertal girls.
AB  - STUDY OBJECTIVE: A review of our experience with the surgical treatment of labial
      adhesions refractory to medical treatment. DESIGN: Retrospective review. SETTING:
      University tertiary care hospital same-day surgery center. PARTICIPANTS: Nine
      prepubertal females, age 3-6 yrs, presenting with thick, symptomatic labial
      adhesions refractory to medical management. INTERVENTION: All patients underwent
      surgical lysis of labial adhesions under general anesthesia. Adhesions were
      incised sharply and the cut edges were reapproximated with 7-0 chromic suture by
      a pediatric urologist (JGB). MAIN OUTCOME MEASURES: Duration of recurrence-free
      follow-up. RESULTS: No patient had recurrence in an average of 8.6 months of
      follow-up. Surgery was well tolerated in all cases. CONCLUSION: This technique
      effectively treats and prevents the recurrence of moderate to severe labial
      adhesions that are unresponsive to medical therapy.

PMID- 12604142
TI  - Identification of symptoms that indicate a pelvic examination is necessary to
      exclude PID in adolescent women.
AB  - BACKGROUND: Diagnosis of chlamydia, gonorrhea, and vaginitis is now possible in
      adolescents using urine testing and vaginal swabs obtained by care provider or
      patient. However, a complete pelvic examination is necessary to diagnose pelvic
      inflammatory disease (PID). It is thus important to identify patients who might
      have pelvic inflammatory disease to assure complete gynecologic assessment of
      genitourinary symptoms. PURPOSE: To determine whether adolescent patients with
      pelvic inflammatory disease report predictable symptoms during the medical
      interview and to determine what proportion of patients diagnosed with PID report
      at least one predictor symptom. METHODS:  DESIGN: Observational study. SETTINGS:
      Hospital-based adolescent clinic and Job Corps health service. PATIENTS: A
      convenience sample (n = 193) of adolescent and young adult women who had a pelvic
      examination performed to evaluate a wide range of genitourinary symptoms. MAIN
      OUTCOME MEASURE: Clinical diagnosis of pelvic inflammatory disease. ANALYSIS:
      Sensitivity, specificity, and positive and negative predictive value of predictor
      symptoms for identifying patients given a diagnosis of pelvic inflammatory
      disease. RESULTS: Twenty (10.4%) patients received a clinical diagnosis of PID.
      Lower abdominal pain was the most common symptom (90.0%) reported by these
      patients. All of the patients with PID reported either lower abdominal pain or
      dyspareunia in the medical history compared with 97 (56.1%) of those without PID.
      The presence of lower abdominal pain and/or dyspareunia in the clinical history
      yielded a sensitivity of 100%, specificity of 44%, and positive and negative
      predictive value of 17% and 100%, respectively, for identifying patients given a
      diagnosis of PID. CONCLUSION: This study identified two symptoms reported in the
      medical history (lower abdominal pain and dyspareunia) that were associated with
      a clinical diagnosis of pelvic inflammatory disease. If lack of these two
      symptoms was used as a criterion for omitting a pelvic examination, more than one
      third of the patients in this study could have been evaluated for cervical and
      vaginal infections with urine and directly obtained vaginal swabs. Although some
      of these patients might have required a pelvic examination to exclude other
      causes of abnormal vaginal bleeding, at least 30% of the total sample could have
      been evaluated without a speculum and bimanual examination. If further studies
      support these findings, patients with symptoms suggestive of uncomplicated
      genitourinary infection (e.g., vaginal discharge, vaginal pruritus, or dysuria)
      who deny lower abdominal pain and dyspareunia can be evaluated with urine and
      vaginal samples in place of a speculum and bimanual examination.

PMID- 12604143
TI  - Labial adhesions in a girl with isolated premature thelarche: the importance of
      estrogenization.
AB  - BACKGROUND: Premature thelarche, a benign condition that affects young girls, has
      been associated with elevated estrogen levels. On the contrary, labial fusion, a
      common pediatric gynecological problem, has been associated with low estrogen
      status. These two conditions are not known to coexist in the same patient. CASE:
      We report the case of a 2-yr-old girl with premature thelarche and labial fusion
      occurring contemporaneously. She presented with a 7-month history of perivaginal
      itchiness and a palpable painless breast bud. Examination revealed unilateral
      breast enlargement (Tanner stage 2) and partially fused labia minora. Pelvic
      ultrasound findings and gonadotrophin responses to intravenous LHRH were
      consistent with a diagnosis of isolated premature thelarche. Furthermore,
      elevated serum estradiol levels were found. COMMENT: The combination of isolated
      premature thelarche and labial adhesions in our patient suggests the existence of
      other factors as well as estrogen insufficiency in the etiology of the latter.

PMID- 12604144
TI  - Fertility concerns and sexual behavior in adolescent girls with polycystic ovary
      syndrome: implications for quality of life.
AB  - OBJECTIVE: To examine the fertility concerns and sexual behavior of adolescent
      girls with polycystic ovary syndrome (PCOS) as compared to healthy adolescent
      girls and the effect of these concerns on health-related quality of life. DESIGN
      AND SETTING: A cross-sectional study of adolescent girls with PCOS (n = 97) and
      healthy comparisons (n = 186) was conducted at an urban, hospital-based
      adolescent medicine practice. Participants completed the Child Health
      Questionnaire Version CF-87 as a measure of health-related quality of life and a
      general health history questionnaire that included items regarding sexual
      activity, contraception, fertility concerns, and severity of illness. Findings
      were evaluated using multivariate logistic and linear regression models. RESULTS:
      Healthy subjects were 2.8 times more likely to have had sexual intercourse than
      PCOS participants, though the mean age at initiation of sexual intercourse among
      sexually active girls was not significantly different between the two groups.
      Severity of illness and the worry about fertility were not associated with odds
      of being sexually active. Girls with PCOS were 3.4 times more likely to be
      worried about their ability to become pregnant than comparisons and concern about
      future fertility was associated with significant reductions in quality of life.
      CONCLUSION: Adolescents with PCOS are more concerned about fertility than their
      healthy peers and this concern may affect their overall quality of life. The
      finding that more than a third of the adolescents with PCOS in this study were
      sexually active underscores the importance of providing ongoing counseling on
      fertility issues, contraception, and STD prevention in the care of adolescent
      girls with PCOS.

PMID- 12604145
TI  - Testing for HSV-2 infection among pregnant teens: implications for clinical
      practice.
AB  - OBJECTIVES: To pilot test the feasibility of screening pregnant teens for HSV-2
      infection during their first prenatal visit. STUDY DESIGN: A cross-sectional
      study of 127 African-American adolescent females recruited during their first
      attendance to a prenatal clinic in a large urban hospital. A rapid serologic test
      (POCkit, manufactured by Diagnology Inc.) was used to assess HSV-2. The test uses
      a membrane-based immunoassay to detect circulating IgG antibodies to a specific
      antigen obtained from HSV-2 (semi-purified glycoprotein G2). RESULTS: More than
      one-fifth (21.3%) of the adolescents tested positive for HSV-2; only 1 adolescent
      was previously aware of her infection. Older adolescents and those reporting a
      history of other STDs were significantly more likely to test positive for HSV-2.
      CONCLUSIONS: Testing for HSV-2 in early pregnancy may be an efficient strategy
      for (1) initiating patient education designed to promote adoption of protective
      behaviors among adolescents at risk of HSV-2 acquisition during the remainder of
      their pregnancy and (2) teaching those who test positive how to recognize
      symptoms of HSV-2 outbreaks; patients reporting recurrent outbreaks during
      pregnancy may benefit from predelivery assessment.

PMID- 12604147
TI  - Retroareolar cysts in the adolescent.
AB  - BACKGROUND: Retroareolar cysts present in female adolescents with palpable
      subareolar masses that can have concomitant inflammatory changes. The purpose of
      this study was to report our cases of retroareolar cysts and thus to contribute
      to a better knowledge and understanding of this entity. METHODS: Forty-six girls
      were diagnosed with retroareolar cysts between December 2000 and July 2002. A
      retrospective chart review is presented with the clinical and ultrasonographic
      findings. RESULTS: Age at presentation was 10 to 20 years. The reason for
      consultation was acute mastalgia and inflammation in 31 cases and palpable nodule
      in 15 cases. Two patients had areolar discharge. Ultrasonographic imaging in the
      46 girls showed retroareolar simple cysts, either multiple or bilateral. The
      cysts had thin walls and were round, oval, or elongated with a variable diameter
      always less than 20 mm. They had liquid content with an echogenic or calcific
      sediment. When retroareolar cysts presented with inflammatory changes,
      antibiotics and nonsteroidal anti-inflammatory drugs were used. Inflammatory
      changes disappeared in approximately seven days. All patients experienced
      favorable outcomes. CONCLUSIONS: Retroareolar cysts are a benign form of breast
      disease in the adolescent. Further investigation is needed to completely
      understand the pathophysiology, epidemiology, and natural history of this
      diagnosis.

PMID- 12604146
TI  - Triplets after cloacal malformation repair.
AB  - BACKGROUND: Patients with cloacal malformations at birth usually require multiple
      surgical procedures to correct their anatomic defects. In addition, many also
      have associated Mullerian anomalies. Those who conceive after repairs invariably
      are considered "high-risk" pregnancies and are considered poor candidates for
      maintaining multiple gestations. Further, because of the nature of their defects
      and their repairs, following such patients with multiple gestation presents
      unique challenges. CASE: A 29-year-old multipara conceived triplets and delivered
      at 30 weeks with a good maternal and neonatal outcome. CONCLUSIONS: Patients with
      repaired cloacal abnormalities present unique challenges and risks compared to
      the general population with regard to the risks of multiple pregnancies.

PMID- 12604149
TI  - The role of surgical techniques in the treatment of menstrual problems and as
      contraception in adolescents with disabilities.

PMID- 12604150
TI  - The conservative management of abnormal bleeding in teenagers with developmental
      disabilities.

PMID- 12604151
TI  - What's new in the new CDC HIV and STD guidelines.

PMID- 12604152
TI  - Management quandary. Labial agglutination in a teenager.

PMID- 12604153
TI  - Advances in rheumatology: coxibs and beyond.
AB  - Arthritis is a growing health concern in the US with approximately 70 million
      Americans currently affected. This figure will inevitably rise as the population
      ages. The pain and decreased mobility associated with arthritis have a
      significant impact on quality of life and because patients with arthritis are
      less active than the general population, they are at risk of additional
      conditions such as obesity, heart disease, diabetes, and hypertension. There are
      currently no disease modifying osteoarthritis (OA) drugs available; therefore
      anti-inflammatory, and/or analgesic medications such as acetaminophen and NSAIDs
      and simple analgesics form the mainstay of treatment. Coxibs may be preferred to
      traditional NSAIDs because of their improved gastrointestinal (GI ) safety and
      tolerability profile. The use of topical agents may also be beneficial in some
      patients. In rheumatoid arthritis (RA) where disease modifying drugs (DMARDs) are
      available, anti-inflammatory agents such as NSAIDs and coxibs are used as
      adjuncts to disease modifying therapy. However, patients with RA are at increased
      risk of NSAID-related GI injury, particularly if they are also on corticosteroid
      medication. Pharmacological treatment of both RA and OA should be combined with
      appropriate nonpharmacological modalities such as patient education, exercise
      programs, and joint motion and strengthening exercises. Such activities may delay
      joint degradation and help maintain physical function.

PMID- 12604154
TI  - Strategies in pain management: new and potential indications for COX-2 specific
      inhibitors.
AB  - The role of the coxibs in the management of osteoarthritis and rheumatoid
      arthritis has been widely discussed, but there are other potential applications
      for the coxibs that have received less attention. Here we consider the use of the
      coxibs in acute pain syndromes such as primary dysmenorrhea and the pain
      associated with dental extraction, as well as considering their application in
      chronic low back pain and cancer pain. Another area where the coxibs may prove
      particularly beneficial is in the management of post-surgical pain. Traditional
      post-surgical analgesia has involved the use of non-selective NSAIDs and opioids,
      but these agents can be associated with side effects such as post-operative
      bleeding, gastrointestinal problems, nausea, and constipation. Because the coxibs
      do not inhibit COX-1 dependent platelet aggregation like traditional NSAIDs, the
      risk of post-surgical bleeding is reduced. The careful application of coxibs as
      part of a multi-modal approach to pain management in the perioperative period can
      reduce the requirement for opioid medications and thus reduce the risk of post
      operative complications such as ileus. In the future, coxibs are likely to play
      an important role in multi-modal perioperative analgesic regimens with the aim of
      reducing post-operative periods of convalescence.

PMID- 12604155
TI  - Gastrointestinal effects of NSAIDs and coxibs.
AB  - Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used
      drugs in the world, but their use is limited because of their propensity to cause
      gastrointestinal (GI) injury. All patients are at risk of GI injury but certain
      risk factors increase the likelihood of adverse GI effects. The most important
      include a history of ulcer or GI complications, increasing age, concomitant
      anticoagulation, concomitant corticosteroid use, and high-dose NSAIDs or multiple
      NSAIDs (including an NSAID plus low-dose aspirin). Concurrent illness (e.g.,
      severe rheumatoid arthritis, heart disease) has also been reported to increase
      the risk of GI events. NSAID-associated GI side effects markedly increase health
      care costs, with up to 31% of cost of managing arthritis patients accounted for
      through the management of GI side effects. The COX-2 specific inhibitors (coxibs)
      were developed with the aim of maintaining anti-inflammatory efficacy but
      improving gastrointestinal safety in comparison to non-selective NSAIDs. The use
      of COX-2 specific inhibitors significantly decreases the rate of endoscopic
      ulcers as compared to traditional NSAIDs. Prospective GI outcomes studies also
      indicate that these agents decrease clinical GI events as compared to non
      selective NSAIDs. The number of patients needed to treat to avert one clinical
      event in one year is approximately 40-100. The cost-effectiveness of coxibs
      increases (the cost per GI event averted decreases) in patients with high-risk
      clinical features because they have higher rates of GI hospitalizations and
      greater use of expensive prophylactic co-therapy.

PMID- 12604156
TI  - Coxibs--beyond the GI tract: renal and cardiovascular issues.
AB  - Although the coxibs have demonstrated superior gastrointestinal safety compared
      to traditional non-selective NSAIDs, questions remain regarding their effects on
      the renal and cardiovascular systems. In terms of renal function, both Type 1 and
      Type 2 cyclooxygenase (COX-1 and COX-2) are expressed constitutively in the
      kidney. Prostaglandins do not play a major role in the maintenance of renal
      function in healthy individuals but they become profoundly important in certain
      clinical situations such as renal stress, or volume depletion. In such situations
      the effects of the coxibs and non-selective NSAIDs are likely to be similar. The
      incidence of renal side effects is low (1-5%) and the patients at risk of renal
      complications are well defined and can usually be identified prospectively and
      followed up as appropriate. From the cardiovascular point of view, questions have
      been raised as to whether the coxibs have a prothrombotic effect. Here we review
      the available evidence and consider various hypotheses for an apparent increase
      in cardiovascular events reported in one coxib study (the VIGOR trial). Because
      of a lack of anti-platelet activity, coxibs are not suited for the provision of
      cardiovascular prophylaxis, and in patients at risk of myocardial infarction the
      prophylactic use of aspirin should always be considered. Although evidence
      suggests that use of coxibs with low-dose aspirin is safer than the combination
      of traditional NSAIDs with aspirin, further studies are required to confirm that
      this is the case.

PMID- 12604157
TI  - Persistent organochlorine compounds and birth weight.
AB  - PURPOSE: To determine whether weight at birth is related to prenatal exposure to
      persistent organochlorine compounds. METHODS: Birth weight was obtained for 197
      singleton infants drawn from the general population born in two cities in Ukraine
      in 1993 to 1994. Concentrations of seven organochlorine pesticides (p,p'-DDT,
      p,p'-DDE, beta-hexachlorocyclohexane, hexachlorobenzene, trans-nonachlor,
      oxychlordane, heptachlor epoxide) and 11 polychlorinated biphenyl congeners
      measured in maternal milk taken at four or five days after birth were used as an
      index of prenatal exposure. RESULTS: The greatest differences were seen for beta
      hexachlorocyclohexane, with a pattern not suggestive of dose-response; infants in
      the lowest tertile were small, those in the central tertile were large, and those
      in the upper tertile were average. Adjustment for gestational age and other
      potential confounders had little effect on these patterns. Infants in the two
      upper tertiles for p,p'-DDE were larger than those in the lower tertile, with the
      effect being more striking after adjustment for gestational age. Adjustment for
      potential confounders made the pattern disappear. Other chemicals showed no
      convincing evidence of effects. CONCLUSIONS: Prenatal exposure to the chemicals
      studied, at concentrations currently seen in this population, does not impact
      weight at birth.

PMID- 12604158
TI  - Preterm birth in relation to maternal organochlorine serum levels.
AB  - PURPOSE: To evaluate the associations of serum levels of p,pacute;-DDE and two
      other persistent organochlorine pesticides, beta-HCH and HCB, in relation to
      preterm birth. METHODS: During 1995 we performed a case-cohort study and 233
      mothers were recruited at three large maternity hospitals in Mexico City. Serum
      levels were obtained shortly after delivery. RESULTS: A non-significant increased
      risk of preterm birth in relation to serum p,p'-DDE levels was observed. There
      was also a suggestion of an increased risk of preterm birth among women in the
      highest tertile of beta-HCH (adjusted odds ratio 1.85, 95% CI = 0.94-3.66, p
      value for test of trend p = 0.08) compared with the lowest tertile. No
      association was found between HCB serum levels and preterm births. CONCLUSIONS:
      These findings suggest that p,pacute;-DDE and other organochlorine pesticides may
      pose a risk to preterm birth in countries that continue to use such insecticides
      for malaria control.

PMID- 12604159
TI  - Conventional coronary artery disease risk factors and coronary artery calcium
      detected by electron beam tomography in 30,908 healthy individuals.
AB  - PURPOSE: Electron beam tomography (EBT) is a noninvasive measure of coronary
      artery calcium (CAC), a marker for atherosclerosis. In this study we examined the
      association between conventional risk factors for coronary artery disease (CAD)
      and CAC. METHODS: EBT CAC screening was performed on 30,908 asymptomatic
      individuals aged 30 to 90 years. Prior to EBT screening, individuals provided
      demographic and CAD risk factor information. EBT utilized a C-100 EBT scanner,
      and the amount of CAC was determined using the Agatston scoring method. RESULTS:
      The results of this study demonstrate that for both men and women, all
      conventional risk factors were significantly associated with the presence of any
      detectable CAC, and the mean CAC score increased in proportion to the number of
      CAD risk factors. In age-adjusted (multivariable) logistic regression analysis,
      cigarette use, histories of hypercholesterolemia, diabetes, and hypertension were
      each significantly associated with mild to extensive CAC scores (> or =10.0).
      CONCLUSION: CAD risk factors are associated with higher atherosclerotic plaque
      burden in both men and women. The odds ratios associated with each risk factor
      relative to the extent of CAC are similar to those reported for the development
      of clinical CAD, suggesting the existence of an association between CAC
      (subclinical disease) and CAD (clinical disease).

PMID- 12604160
TI  - C-reactive protein, Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus
      and risk for myocardial infarction.
AB  - PURPOSE: C-reactive protein (CRP), Chlamydia pneumonia, Helicobacter pylori, and
      cytomegalovirus (CMV) have each been associated with atherosclerosis. We assessed
      how infection and CRP related to risk for subsequent myocardial infarction (MI).
      METHODS: Using a nested case-control design, we assessed how these factors
      independently and jointly affected risk for myocardial infarction (MI). Cases of
      first MI (N = 121) were identified from among participants in a multiphasic
      health check-up cohort. Controls without MI (N = 204) were matched to cases by
      gender, age, race, and date of serum collection. Sera collected at enrollment
      were tested for antibodies to infection and for CRP. RESULTS: In multivariate
      analysis (mean follow-up of 5.1 years), CRP was associated with MI only in
      subjects older than 51 years (p = 0.004). Although H. pylori infection increased
      risk for MI, this association was modest (OR = 1.90, 95% CI = 0.97-3.71) and was
      not evident in non-smokers or when adjusted for education. No association between
      C. pneumoniae or cytomegalovirus and MI was observed, nor was the association
      between CRP and MI explained by these infections. CONCLUSIONS: Elevated CRP is a
      risk factor for subsequent MI in older individuals. The relationship between Hp
      and MI may be due to confounding or co-linearity with socioeconomic status.

PMID- 12604161
TI  - An unexpected distribution of sodium concentration in serum specimens stored for
      more than 30 years.
AB  - PURPOSE: Sera from over 50,000 pregnant women in the Collaborative Perinatal
      Project have been frozen at -20 degrees C since 1959 to 1966, and with the health
      data on their offspring constitute a resource that is still actively used. In two
      studies using these specimens, we measured sodium concentration to assess
      desiccation. METHODS: Sodium was measured in over 5,000 specimens by two
      different methods. For 10 specimens with unusually low sodium values, a substudy
      was done to investigate the cause. RESULTS: High sodium levels (>140 mmol/L) were
      present in more than 20% of specimens, and levels were unusually low (<130
      mmol/L) in more than 40% of specimens. The substudy showed that filtering the
      specimens increased sodium levels and that about 14% of the sodium was trapped in
      particulate matter. CONCLUSIONS: High sodium levels in these specimens were
      probably due to desiccation and possibly to leaching of sodium from the glass
      containers. Low sodium levels were probably caused by the particulate matter,
      which clogged the analytical sampling devices and also trapped sodium. In serum
      specimens that have been stored for long periods, use of routine laboratory
      procedures for analysis can yield erroneous results. Furthermore, measured
      analyte levels can be affected by more than just degradation and desiccation.

PMID- 12604162
TI  - Effects of isolated post-challenge hyperglycemia on mortality in American
      Indians: the Strong Heart Study.
AB  - PURPOSE: To assess the effects of isolated post-challenge hyperglycemia (IPH) on
      risk of cardiovascular disease (CVD), cancer, and all-cause mortality in American
      Indians using longitudinal data from the Strong Heart Study. METHODS: Of 4549
      American Indian women and men aged 45 to 74 years participating in the Strong
      Heart Study, 4304 had fasting blood measurements or oral glucose tolerance test
      (OGTT) data to ascertain diabetes status. At baseline and follow-up, a personal
      interview was conducted, and physical examinations and laboratory tests were
      performed. Fasting blood samples were drawn for measurement of glucose,
      fibrinogen, insulin, lipids, lipoproteins, creatinine, and hemoglobin A1c
      (HbA1c). A 75-g OGTT was performed. Five diabetes categories were defined: (i)
      known diabetes, (ii) newly diagnosed diabetes (fasting glucose > or =126 mg/dL
      and no history of diabetes or diabetes medication; ADA-new diabetes), (iii) IPH,
      (iv) impaired fasting glucose (> or =110 - <126 mg/dL; IFG), and (v) normal
      fasting glucose (<110 mg/dL; NFG). Surveillance was initiated to determine CVD,
      cancer, and all-cause mortality over 9 years. RESULTS: IPH had a worse CVD risk
      factor profile than NFG, but IPH was associated with a better CVD risk factor
      profile than known diabetes or ADA-new diabetes. At follow-up, individuals with
      IFG had no increased risk for CVD or all-cause mortality, whereas those with ADA
      new or known diabetes had significantly increased risk (RR = 1.70 and 1.40 for
      ADA-new diabetes, and RR = 2.87 and 2.19 for known diabetes, respectively). Those
      with IPH had nonsignificant elevations in risk for CVD (RR = 1.54) and all-cause
      (RR = 1.27) mortality. Cancer mortality was not increased in those with IFG, IPH,
      ADA-new diabetes, or known diabetes compared to those with NFG. CONCLUSIONS:
      Among American Indians 45 to 74 years of age, IPH is associated with
      nonsignificant elevations in total and CVD mortality. The magnitude of mortality
      risk associated with IPH is intermediate between diabetes and IFG. Because those
      with IPH are at high risk for diabetes, American Indians with IPH should be
      targeted for diabetes prevention.

PMID- 12604163
TI  - Anti-oxidized LDL antibodies and wine consumption: a population-based
      epidemiological study in Dicomano, Italy.
AB  - PURPOSE: In previous studies, higher levels of oxidized low-density lipoprotein
      (ox-LDL) have been reported to increase the risk of cardiovascular disease.
      Furthermore, the anti-oxidative properties of red wine have been invoked to
      explain the paradox of low cardiovascular mortality, in spite of high-fat intake,
      in the French population. However, the distribution of ox-LDL-antibodies (ox-LDL
      Ab) in the unselected population and its relationship with red wine consumption
      are unknown. This study was carried out to identify factors associated with ox
      LDL-Ab, with particular emphasis on the association with wine consumption.
      METHODS: We performed a cross-sectional study of 551 unselected, community
      dwelling older adults (aged 65 to 94 years) living in Dicomano (Italy). Ox-LDL-Ab
      titre was measured with an ELISA method. RESULTS: In the whole study sample, ox
      LDL-Ab increased with age and was unrelated to blood lipids, HbA(1c), and smoking
      habit. A significant inverse relationship was found between ox-LDL-Ab titre and
      daily wine intake, which persisted after adjusting for possible confounders or in
      subgroup analyses of participants who reported to drink wine or were free from
      significant morbidity. CONCLUSIONS: These results suggest that wine affects ox
      LDL-Ab titre in older populations, possibly because of its antioxidant
      properties.

PMID- 12604164
TI  - "Probable" versus "confirmed" leptospirosis: an epidemiologic and clinical
      comparison utilizing a surveillance case classification.
AB  - PURPOSE: For surveillance purposes, the Centers for Disease Control and
      Prevention and Council of State and Territorial Epidemiologists (CDC/CSTE) have
      defined two case classifications for leptospirosis: "confirmed" and "probable."
      The objective of this study was to provide data to refine the current
      surveillance case classifications. METHODS: All reported leptospirosis infections
      from exposures within the State of Hawaii, 1974 to 1998 meeting CDC/CSTE
      "confirmed" and "probable" case classifications were compared on a number of
      clinical and epidemiologic parameters. RESULTS: Confirmed cases (n = 276) had
      more severe clinical manifestations than probable cases (n = 180); however,
      probable cases with higher peak microscopic agglutination test (MAT) titers (> or
      =1:800) were clinically and epidemiologically comparable to confirmed cases. In
      addition, 77 cases demonstrating fourfold or greater MAT titer increases in
      paired serum collected less than two weeks apart (currently excluded from the
      "confirmed" case classification) were also comparable to confirmed cases.
      CONCLUSIONS: Our findings support amending the current CDC/CSTE surveillance
      confirmed case classification to include demonstration of a fourfold or greater
      MAT titer increase in paired serum, irrespective of the interval between specimen
      collection. Consideration should also be given to including single MAT titer > or
      =1:800 as a criterion for "confirmation." These changes would both simplify and
      expedite the surveillance confirmation of leptospirosis.

PMID- 12604165
TI  - Sample size for biomarker studies: more subjects or more measurements per
      subject?
AB  - PURPOSE: In molecular epidemiologic studies, optimizing the use of available
      biological specimens while minimizing the cost is always a challenge. This is
      particularly true in pilot studies, which often have limited funding and involve
      small numbers of biological samples too small for assessment of recently
      developed biomarkers. METHODS: In this study we examined several statistical
      approaches for determining how many experimental subjects to use in a biomarker
      study and how many repeated measurements to make on each sample, given specific
      funding considerations and the correlated nature of the repeated measurements.
      RESULTS: A molecular epidemiology study of DNA repair and aging in basal cell
      carcinoma was used to illustrate the application of the statistical methods
      proposed. CONCLUSIONS: Our methods extend traditional designs on biomarker
      studies with repeated measurements to including funding constraints.

PMID- 12604166
TI  - Damage to the liver, kidney, and testis with reference to burden of heavy metals
      in yellow-necked mice from areas around steelworks and zinc smelters in Poland.
AB  - The influence of the steelworks in Warsaw and Krakow as well as the zinc smelters
      in Bukowno and Miasteczko Slaskie on lead, cadmium, zinc and iron concentrations
      and the structure of selected tissues of yellow-necked mice were analysed. The
      Borecka Forest was chosen as a control area. The highest concentrations of lead,
      172.36 g/g dry weight, and cadmium, 23.58 g/g, were detected in the femurs and
      kidneys, respectively, of rodents caught in Bukowno. Zinc and iron concentrations
      ranged over physiological values. No histopathological changes were observed in
      analysed tissues of all rodents in the control area. Damage occurred in the liver
      and kidneys of animals from all other sites and in the testes of rodents from
      Bukowno. Decreased glycogen content, interstitial fibrosis, and increased number
      of pyknotic nuclei as well as necrosis were seen in hepatocytes. In the kidneys
      hyperplasia of the tubules, atrophy of glomeruli, interstitial fibrosis and
      necrosis were observed. Degenerate cells were present in the lumen of
      seminiferous tubules of animals from the Bukowno area. Even relatively low
      concentrations of lead and cadmium, like those found in the liver and kidneys of
      rodents from the neighbourhood of the steelworks, caused histopathological
      changes.

PMID- 12604167
TI  - Effect of low dose mono-ortho 2,3',4,4',5 pentachlorobiphenyl on thyroid hormone
      status and EROD activity in rat offspring: consequences for risk assessment.
AB  - Toxic equivalency factor (TEF) has been proposed to estimate the risk of
      polychlorinated biphenyl (PCB) congeners. However, ortho chlorine substitution in
      the two phenyl rings gives each PCB its own pattern of toxicity which is
      different from the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
      The present study evaluated the effect of prenatal and postnatal exposure to a
      low dose of the mono-ortho pentachlorobiphenyl PCB 118 on thyroid hormone
      concentrations and EROD activity in rats. Moreover, the tissue distribution of
      PCB 118 following one oral dose was evaluated. Sprague-Dawley rats were treated
      by gavage on GD 6 with 375 microg of PCB 118/kg b.w. Decreases in thyroxine and
      TSH levels were observed in dams at the end of lactation. Perinatal exposure to a
      low dose of PCB 118 permanently disrupted the hypothalamo-pituitary-thyroid (HPT)
      axis leading to a significant increase in thyroxine levels in offspring, as a
      'thyroid resistance syndrome'. It is noteworthy that no changes in hepatic EROD
      activity were detected in dams at the end of lactation, even in the presence of
      high amounts of PCB in liver. Based on hepatic EROD activity (as a biomarker for
      aryl hydrocarbon receptor (AhR) induction), the mechanism of thyroid homeostasis
      disruption seems to be AhR-independent. Additionally, the 'thyroid resistance
      syndrome' observed in our study indicates the need for further detailed
      investigations on the HPT axis. We conclude that not only TEF, but also AhR
      independent responses should be taken into account for risk assessment of mono
      ortho PCB congeners.

PMID- 12604168
TI  - The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on chorionic
      gonadotrophin activity in pregnant macaques.
AB  - As many as 62% of all human conceptions are lost prior to 12 weeks of pregnancy
      and it is unknown how many of these losses result from environmental hazards.
      Previous studies have shown that single doses of 1, 2, and 4 microg/kg 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) administrated orally to cynomolgus macaques
      during the peri-implantation period leads to early fetal loss (EFL) within 10-20
      days. TCDD induced EFL is associated with a reduction in the biological activity
      of monkey chorionic gonadotrophin (mCG) but no change in the immunoreactive mCG
      profile. These studies are consistent with either a direct effect of TCDD on
      differentiation of the trophoblast and an indirect effect on mCG synthesis, or a
      direct effect on mCG synthesis and secretion independent of trophoblast
      development. The present study was designed to test the hypothesis that the
      action of TCDD is directly on mCG synthesis rather than on the differentiation of
      the trophoblast. Female macaques (Macaca fascicularis) were treated with a single
      dose of TCDD (4 microg/kg b.wt.) on Gestational Day 20, a stage of pregnancy
      following initial trophoblast differentiation and invasion. Circulating mCG
      concentrations were monitored for the next 6 days. Compared to the controls, the
      peak level of serum bioactive mCG was lower in the treated group (P<0.05), with a
      decrease observed on the day following exposure. The bioactive/immunoreactive mCG
      ratio was also lower in the treated group compared to the controls (P<0.05).
      There was no difference in serum immunoreactive mCG levels between the groups.
      Histological evaluation of the embryo-placental unit showed increased apoptosis
      and vascular congestion after treatment but was otherwise grossly normal. Because
      exposure of the conceptus to TCDD following differentiation of the trophoblast
      decreased the bioactivity of circulating mCG, we conclude that the action of TCDD
      in the placenta is directly on mCG synthesis.

PMID- 12604169
TI  - Effect of selenite on the disposition of arsenate and arsenite in rats.
AB  - Selenite (SeIV) and inorganic arsenicals counter the toxicity of each other. SeIV
      inhibits arsenic methylation in hepatocytes, however, it is unknown whether it
      decreases the formation of the highly toxic monomethylarsonous acid (MMAsIII).
      Therefore, we examined, in comparison with the methylation inhibitor periodate
      oxidised adenosine (PAD), the effect of SeIV (10 micromol/kg, i.v.) on the
      appearance of arsenic metabolites in blood, bile and urine as well as the
      distribution of arsenic metabolites in the liver and kidneys in rats injected
      i.v. with 50 micromol/kg arsenite (AsIII) or arsenate (AsV). Arsenic metabolites
      were analysed by HPLC-hydride generation-atomic fluorescence spectrometry (HPLC
      HG-AFS). In rats given either arsenical, PAD decreased the excretion and tissue
      concentrations of methylated arsenic metabolites (MMAsIII, monomethylarsonic acid
      [MMAsV], and dimethylarsinic acid [DMAsV]), while increasing the tissue retention
      of AsV and AsIII. The effect of SeIV on arsenic disposition differed
      significantly from that of PAD. For example, both in AsIII- and AsV-injected
      animals, SeIV lowered the tissue levels of MMAsIII and MMAsV, but increased the
      levels of DMAsV. SeIV almost abolished the biliary excretion of MMAsIII in AsV
      exposed rats, but barely influenced it in AsIII-dosed rats. The SeIV-induced
      changes in arsenic disposition may largely be ascribable to formation of the
      known complex containing trivalent arsenic and selenide (SeII), which not only
      depends on but also influences the availability and effects of these metalloid
      species in tissues. By such complexation SeII compromises monomethylation of
      arsenic when trivalent arsenic availability is limited (e.g. in AsV-exposed
      rats), but affects it less when the presence of AsIII is overwhelming (e.g. in
      AsIII-dosed rats). As an auxiliary finding, it is shown that DMAsV occurs in the
      blood of rats not injected with arsenic and that DMAsV formation in rats can be
      followed by measuring the build-up of blood-borne DMAsV.

PMID- 12604170
TI  - Up-regulation of macrophage inflammatory protein-2 and complement 3A receptor by
      the trichothecenes deoxynivalenol and satratoxin G.
AB  - The trichothecenes are a group of mycotoxins that target leukocytes and have a
      wide range of immunomodulatory effects. Differential display analysis was applied
      to assess the effects of the trichothecenes deoxynivalenol (vomitoxin, DON) and
      satratoxin G (SG), on mRNA in the RAW 264.7 macrophage cell line. Cells were
      incubated with DON (1 microg/ml) or SG (5 ng/ml) for 2 h and total RNA then
      subjected to RT-PCR with a set of oligo(dT) primers. Resultant cDNA was amplified
      using an oligo (dT) downstream primer and an arbitrary decanucleotide upstream
      primer to make 35S-labeled PCR products. After separation of the products in
      denaturing polyacrylamide gel, 23 differentially expressed cDNA fragments were
      isolated and sequenced. Two of these were identified as known genes, namely,
      macrophage inflammatory protein-2 (MIP-2), a potent neutrophil chemoattractant
      involved in tissue injury and inflammation, and complement 3a receptor (C3aR), a
      proinflammatory mediator. Both MIP-2 and C3aR mRNAs were up-regulated by DON
      while only MIP-2 mRNA was induced by SG. Using commercially available antibodies,
      MIP-2 protein was also found to be induced by both DON and SG in RAW 264.7 cell
      cultures. When mice were treated with DON (12.5 mg/kg), splenic MIP-2 mRNA and
      serum MIP-2 levels were increased. MIP-2 mRNA and serum MIP-2 levels were
      synergistically increased when mice were co-treated with DON and LPS. Up
      regulation of MIP-2 and C3aR are consistent with previous reports of
      trichothecene-induced inflammatory gene up-regulation and suggest that the
      specific genes affected may depend on trichothecene structures.

PMID- 12604171
TI  - Effect of naturally occurring plant phenolics on the induction of drug
      metabolizing enzymes by o-toluidine.
AB  - Plant phenolics modify the metabolic activation of several carcinogens, including
      aromatic amines. In this study, we have evaluated the effects of three
      structurally diversified plant phenolics, protocatechuic acid (PCA), tannic acid
      (TA) and ellagic acid (EA) on cytochrome p450-dependent enzymes and glutathione S
      transferase (GST) activities after oral administration alone or in combination
      with o-toluidine in rat liver and kidney. Protocatechuic and ellagic acids
      significantly decreased the activities of ethoxy- (EROD), methoxy- (MROD) and
      penthoxyresorufin (PROD) dealkylases in liver. In kidney, all phenolics inhibited
      only the activity of PROD. Enzyme modulation in liver correlated with CA
      metabolism measured in plasma. Treatment of rats with ellagic acid 1 h before o
      toluidine administration diminished the activities of all hepatic
      alkoxyresorufine dealkylases induced by o-toluidine but increased renal EROD. In
      contrast to EA, protocatechuic and tannic acids increased the activities of p450
      dependent enzymes in liver. All phenolics administered in combination with o
      toluidine increased the activity of GST, which was reduced after the treatment
      with o-toluidine alone. In addition, CA metabolism in plasma resulting from oral
      treatment with CA was measured. The formation of CA metabolites was reduced by
      PCA and EA, and the metabolism of CA induced by o-toluidine was depressed by
      administration of all three phenolics. Our results indicate that plant phenolics,
      especially EA, may modulate the genotoxic effects of o-toluidine by modifying
      pathways leading to the formation of its reactive metabolite. Moreover, as the
      result of CYP1A modification these compounds may affect the metabolism of CA.

PMID- 12604173
TI  - Polycyclic aromatic hydrocarbons disrupt axial development in sea urchin embryos
      through a beta-catenin dependent pathway.
AB  - Sea urchin (Lytechinus anemesis) embryos were used as an experimental system to
      investigate the mechanisms of the developmental toxicity of creosote, one of the
      most widely used wood preserving chemicals, as well as some of its polycyclic
      aromatic hydrocarbon (PAH) constituents (phenanthrene, fluoranthene, fluorene,
      pyrene and quinoline). Data suggest that creosote and PAHs affect axial
      development and patterning in sea urchin embryos by disrupting the regulation of
      beta-catenin, a crucial transcriptional co-activator of specific target genes in
      the Wnt/wg signaling pathway. When ciliated blastula stage embryos were exposed
      to these compounds, they developed into exogastrulae with completely evaginated
      archentera, demonstrating that these chemicals disrupt axial development and
      patterning. This response occurred in a dose-dependent fashion, with the EC(50)
      of creosote for complete exogastrulation being 1.57 ppm, while the EC(50)s of the
      PAHs ranged from 0.41 ppm (2.0 microM) to 4.33 ppm (33.5 microM).
      Morphologically, the exogastrulae that developed from embryos exposed to creosote
      and PAHs appeared to be identical to those that resulted from exposure to lithium
      chloride, a classical agent known to induce vegetalization and exogastrulation in
      sea urchin embryos. Immunological studies using antibodies against beta-catenin,
      a multi-functional protein known to be involved in cell-cell adhesion and cell
      fate specification during embryonic development, revealed high levels of nuclear
      accumulation of beta-catenin by cells of creosote- and PAH-exposed embryos,
      irrespective of their positions in the developing embryo. Dissociated embryonic
      cells cultured in the presence of these agents rapidly responded in a similar
      fashion. Since beta-catenin accumulation occurs in nuclei of several types of
      cancer cells, it is possible this may be a general mechanism by which PAHs affect
      a variety of different cell types.

PMID- 12604172
TI  - Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione-
      and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide
      (NDPS) in Fischer 344 rats.
AB  - Nephrotoxicity of the agricultural fungicide N-(3,5-dichlorophenyl)succinimide
      (NDPS) in rats is believed to involve metabolism on the succinimide ring. To
      further investigate this hypothesis, we synthesized and tested the following NDPS
      analogues, which contain other cyclic imide rings and may therefore be
      metabolized differently than NDPS: 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione
      (DCPO), 3-(3,5-dichlorophenyl)-2,4-imidazolidinedione (DCPI), 3-(3,5
      dichlorophenyl)-1-methyl-2,4-imidazolidinedione (DCPM) and 3-(3,5-dichlorophenyl)
      2,4-thiazolidinedione (DCPT). Male Fischer 344 rats were administered DCPO, DCPI,
      DCPM, DCPT (0.6 or 1.0 mmol/kg, i.p. in corn oil), NDPS (0.6 mmol/kg, i.p. in
      corn oil) or corn oil (4 ml/kg). As evidenced by diuresis, proteinuria, elevated
      blood urea nitrogen levels, increased kidney weights and proximal tubular damage,
      NDPS produced severe nephrotoxicity in the rats. In contrast, DCPO, DCPI, DCPM
      and DCPT were mild nephrotoxicants. None of the compounds elevated serum alanine
      transferase activity or liver weights in the rats, however DCPT produced
      centrilobular necrosis. These experiments confirm that NDPS-induced
      nephrotoxicity is critically dependent on the presence of the succinimide ring.
      Furthermore, replacement of the succinimide ring with a thiazolidinedione ring
      produced a more pronounced effect on the liver than on the kidney. Liver damage
      has been reported in type II diabetic patients taking troglitazone, rosiglitazone
      and pioglitazone. Since these compounds also contain a thiazolidinedione ring,
      DCPT may be useful for investigating the role of this structural feature in
      hepatotoxicity.

PMID- 12604174
TI  - Changes of serum sex hormone levels and MT mRNA expression in rats orally exposed
      to cadmium.
AB  - It has been demonstrated that cadmium (Cd) is carcinogenic to rodent prostate.
      However, the mechanism of its toxicity is far from fully understood. In the
      present study, the effects of oral Cd exposure (0, 50, 100, 200 ppm in drinking
      water) on serum sex hormone levels, the expression of MT-I and MT-II mRNA, and
      the zinc content of rat prostate were assessed. With Cd administration, serum
      testosterone (T) levels significantly increased in all Cd groups after 3 months
      and in the 200 ppm Cd group after 6 months. A significant depression in the serum
      luteinizing hormone (LH) level was seen in the Cd group (200 ppm) after 6 months.
      It was noted that Cd administration resulted in a significant down-regulation in
      the expression of MT-I and MT-II mRNA in the rat ventral prostate. However, no Cd
      induced changes in the mRNA expression of Metallothioneins (MTs) were detected in
      the dorsolateral prostate. After Cd administration, the content of Cd in both the
      ventral and dorsolateral lobes of the prostate significantly increased with
      increasing dose and duration of Cd administration. In contrast, the Zn content
      decreased with Cd administration in both the ventral and dorsolateral lobes of
      the rat prostate. Taken together, these results suggest that oral Cd exposure may
      disrupt endocrine homeostasis, changing the distribution of Zn and the mRNA
      expression of MTs in rat prostate, and that such Cd-induced changes may
      contribute to the susceptibility of prostate to the carcinogenicity of this heavy
      metal.

PMID- 12604175
TI  - A simplified method to evaluate the acute toxicity of ricin and ricinus
      agglutinin.
AB  - A brief method is described for the assessment of lethal toxicity of ricin and
      ricinus agglutinin using a modified LD(50) assay. With this test, it is possible
      to obtain an LD(50) using only 10 experimental animals. The equation for
      calculating the confidence limit of LD(50) is derived in this article. The LD(50)
      values obtained with the method were compared with data reported in the
      literature using classical methods. The results indicate that the simplified
      method for evaluating the acute toxicity of ricin and ricinus agglutinin gives
      reliable results. For scientific, economic and ethical reason the method is
      suggested to replace the traditional LD(50) assay for plant toxins.

PMID- 12604176
TI  - Perinatal exposure to lead and cadmium affects anxiety-like behaviour.
AB  - The present study examines the effects of early simultaneous exposure to low
      level of lead and cadmium on anxiety-like behaviour in the rat, and on monoamine
      levels in the hypothalamus and hippocampus at weaning and adult animals. Rats
      were intoxicated with cadmium acetate (10 mg/l) and lead acetate (300 mg/l) in
      drinking water from the beginning of pregnancy until weaning. Maternal co
      exposure to lead and cadmium produced mainly alterations in dopaminergic and
      serotoninergic systems of hippocampus in both age studied, while noradrenaline
      content in hypothalamus and hippocampus remained unchanged at 75 days of age. The
      intoxicated rats showed an increased on indices of anxiety on the elevated plus
      maze. These long-term changes in anxiety-like behaviour can be related to
      dopaminergic and serotoninergic alterations detected in hippocampus.

PMID- 12604177
TI  - Individual sensitivity to DNA damage induced by styrene in vitro: influence of
      cytochrome p450, epoxide hydrolase and glutathione S-transferase genotypes.
AB  - Styrene is a monomer of great commercial interest; its polymers and copolymers
      are used in a wide range of applications. In humans, styrene metabolism involves
      oxidation by cytochrome p450 monooxygenases (CYPs) to styrene-7,8-oxide, an
      epoxide thought to be responsible for the genotoxic effects of styrene exposure
      and detoxification by means of epoxide hydrolase (EH) and glutathione S
      transferases (GSTs). The objective of this study was to investigate if genetic
      polymorphisms of metabolic enzymes modulate styrene-induced DNA damage in human
      leukocytes. CYP2E1, CYP1A1, EH, GSTP1, GSTM1 and GSTT1 polymorphisms were
      determined in 30 healthy donors and alkaline comet assay was carried out in
      isolated leukocytes exposed to 5 and 10 mM styrene, using 1% acetone as solvent
      control. The results obtained suggest that CYP1A1 m1, m2 and m4, CYP2E1 Dra I and
      GSTP1 (exons 5 and 6) polymorphisms may affect styrene induction of DNA damage in
      human leukocytes.

PMID- 12604178
TI  - A lignocaine infusion worsens the leukoencephalopathy due to a carbon monoxide
      exposure in sheep.
AB  - Poisoning by carbon monoxide (CO) is common and conventional treatment of
      affected people is frequently unsuccessful. Lignocaine was identified as a
      potential therapy in this context because of the benefit shown for it in other
      brain injuries for which the received toxic mechanisms are similar. Twelve Romney
      ewes were exposed to 1% CO for 120 min were then infused intravenously with
      either lignocaine (N=6) or saline for 72 h, and were killed 5 days after the
      exposure for histological and immunohistochemical examination. This dose of CO
      was narcotic and caused white matter brain infarcts, with associated glial cell
      activation, axonal dysfunction and induction of both neuronal and glial haeme
      oxygenase and nitric oxide synthetase. The frequency of the white matter infarcts
      was significantly greater in the lignocaine-treated group. The mechanism of this
      adverse interaction is neither established here nor is it deducible from other
      published data; alternative antidotes to CO clearly need to be tested.

PMID- 12604179
TI  - Accumulation of silver from drinking water into cerebellum and musculus soleus in
      mice.
AB  - In spite of the general toxicity, ecotoxicity and sparsely known metabolism of
      silver, WHO allows silver ions (Ag) up to 0.1 mg/l in drinking water
      disinfection. In order to determine the accumulation and distribution of silver
      in a mammalian body, mice were given for 1 and 2 weeks drinking water containing
      a 3-fold lower concentration, namely 0.03 mg/l silver ions as silver nitrate
      labelled with 110mAg. The silver concentrations in different tissues were
      analysed by gamma radioactivity. The saturation of tissues with silver seems to
      occur quickly, as there were no statistical differences between silver contents
      of mice tissues in spite of the study design that mice were administered silver
      for 1 or 2 weeks. The highest concentrations were found in musculus soleus (m.
      soleus), cerebellum, spleen, duodenum, and myocardial muscle in the rank order.
      Concentrations of silver in musculus gastrocnemius (m. gastrocnemius) were found
      to correlate negatively with cerebrum and positively with blood and kidneys. The
      accumulation of silver into organs and tissues important in motor functions may
      be of relevance especially in emergency and catastrophe situations in which
      accurate motor functions may be critical. A re-evaluation of the present
      recommendations on the use of silver salts for disinfection of drinking water
      might be necessary.

PMID- 12604180
TI  - Immunobiological effects of AFB1 and AFB1-FB1 mixture in experimental subchronic
      mycotoxicoses in rats.
AB  - Maize co-contamination with aflatoxin B1 (AFB1) and fumonisin B1 (FB1) is
      frequently found in several countries. Although the alterations on nutritional
      and immunologic parameters induced by these mycotoxins, when administered
      individually, are partially characterised, little is known about the effects
      induced in animals by a subchronic administration of both toxins mixtures. We
      have studied the nutritional and immunological alterations induced in rats fed
      during 90 days with a diet without mycotoxins, containing 40 ppb AFB1, and with a
      diet containing a mixture of 40 ppb AFB1 and 100 ppm FB1. Animals fed with the
      mixture of toxins obtained lower body weight than the control ones. The mitogenic
      response of spleen mononuclear cells (SMC) in vivo was higher in animals fed with
      AFB1. In in vitro studies, lower proliferations of SMC pre-exposed to AFB1 and to
      the mixture of toxins were detected. The SMC of animals fed with AFB1 produced
      lower levels of IL-2, higher of IL-4 and equal levels of IL-10. The SMC of
      animals fed with both toxins produced higher levels of IL-4, lower of IL-10 and
      equal levels of IL-2. The SMC preincubated with an AFB1-FB1 mixture produced
      higher concentrations of IL-4, lower of IL-10 and equal levels of IL-2. The
      peritoneal macrophages of animals that consumed AFB1 released less H(2)O(2),
      while animals fed with the mixture of toxins produced higher levels. In in vitro
      studies, macrophages pre-exposed to the mixture of toxins released less H(2)O(2).
      These results show different immunobiological effects produced by a mixture of
      mycotoxins in comparison to the individual action of the same toxins.

PMID- 12604181
TI  - Chromium compounds: cytotoxicity and carcinogenesis.

PMID- 12604184
TI  - Aldehyde dehydrogenase gene superfamily: the 2002 update.
AB  - The aldehyde dehydrogenase (ALDH) superfamily represents a divergently related
      group of enzymes that metabolize a wide variety of endogenous and exogenous
      aldehydes. With the advent of megabase genome sequencing, the ALDH superfamily is
      continuously expanding on many fronts. The presence of ALDH encoding genes in the
      vast majority of archaeal, eubacterial and eukaryotic genomes supports the notion
      that these enzymes are important components of metabolic processes in living
      organisms and that the ALDH superfamily is ancient in origin. As of July 2002,
      the ALDH superfamily consists of 555 distinct genes: 32 in archaea, 351 in
      eubacteria, and 172 in eukaryota. Complete sequencing of individual genomes
      reveals the number of ALDH genes found per organism ranges from 1 to 5 in
      archaeal species, 1-26 genes in eubacterial species, and 8-17 genes in eukaryotic
      species. In the human genome, 17 functional genes and 3 pseudogenes have been
      identified to date. A standardized ALDH gene nomenclature system has been
      developed based on multiple alignment analysis of eukaryotic ALDH amino acid
      sequences. Both Human and Mouse Genome Projects have accepted this nomenclature
      system. In this report, we present a complete listing of all ALDH sequences known
      to date, along with the evolutionary analysis of the eukaryotic ALDHs. Thus far,
      the eukaryotic ALDHs comprise 20 gene families. Detailed information on ALDH gene
      superfamily is also available at
      http://www.uchsc.edu/sp/sp/alcdbase/aldhcov.html.

PMID- 12604185
TI  - An algorithm for identification and ranking of family-specific residues, applied
      to the ALDH3 family.
AB  - An algorithm for detecting amino acid residues characteristic of individual
      protein families from within aligned collections of paralogous sequences, and its
      application to the ALDH3 family versus the rest of the ALDH extended family is
      described. Residues illuminated by this analysis include a key intramolecular
      tether, a lysine that makes an intersubunit contact at the dimer interface, three
      residues in close association with the substrate-binding funnel, and a pair of
      residues suggested to participate in proton relay during the catalytic cycle.

PMID- 12604186
TI  - Aldehyde dehydrogenase 3 expression is decreased by clofibrate via PPAR gamma
      induction in JM2 rat hepatoma cell line.
AB  - In normal liver aldehyde dehydrogenase 3 (ALDH3) is poorly expressed. In hepatoma
      cells, its expression increases in direct correlation with the degree of
      deviation and increased ALDH3 activity is one cause of resistance to the toxicity
      of drugs and lipid peroxidation aldehydes. Hepatoma cells with high ALDH3 content
      are more resistant to the cytotoxic effect of aldehydes than those with low
      ALDH3, and inhibition of the enzyme with aldehydes, specific inhibitors or
      antisense oligonucleotides (AS-ODN), decreases cell growth. It remains open how
      ALDH3 influences cell growth or cell phenotype. Recently, we have shown that
      enrichment of a highly deviated rat hepatoma cell line, JM2, with arachidonic
      acid, a natural ligand of peroxisome proliferator activated receptors (PPARs),
      inhibits growth, partially restores ALDH2 and ALDH3 to their normal levels and
      induces PPAR expression. In the present study we address the effect of
      clofibrate, a hypolipidemic drug and synthetic PPAR ligand on ALDH gene
      expression. We show that treatment of JM2 cells with clofibrate inhibits cell
      growth, induces PPARgamma and decreases ALDH3 expression. To determine the
      relationship between PPARgamma and ALDH3 expression, we exposed JM2 cells to AS
      ODN against PPARgamma. AS-ODN reduced PPARgamma content and prevented the
      inhibitory effect of clofibrate on cell proliferation and ALDH3 expression. Since
      these results indicate that ALDH3 expression is under PPAR control, we examined
      the 5' flanking sequence of the ALDH3 gene, but were unable to find any sequence
      similar to any known peroxisome proliferator response element. We thus believe
      that the effect of PPARgamma on ALDH3 occurs via other transcription factors,
      whose identity remain to be determined. The results indicate that PPARgamma plays
      a key role in regulation of growth and differentiation of hepatoma cells, and
      that ALDH3 collaborates in modulating cell proliferation and in determining some
      aspects of the hepatoma phenotype, i.e. resistance to drugs and to lipid
      peroxidation products.

PMID- 12604187
TI  - Antisense oligonucleotides against aldehyde dehydrogenase 3 inhibit hepatoma cell
      proliferation by affecting MAP kinases.
AB  - The increased activity of enzymes that eliminate anti-tumour drugs or their
      metabolites is one of the important limiting factors in therapeutic protocols.
      Among these enzymes, aldehyde dehydrogenase 3 (ALDH3) is considered a mechanism
      by which tumour cells evade the cytotoxic effects exerted by cyclophosphamide and
      drugs acting by free radical generation. It is also important in metabolising
      cytostatic aldehydes derived from lipid peroxidation. Therefore, ALDH3 may play a
      role in regulating cell proliferation in tumour cells with high activity of this
      enzyme. We previously reported that antisense oligonucleotides (AS-ODN) against
      ALDH3 strongly inhibit hepatoma cell growth, suggesting that this effect could be
      due to the accumulation of cytostatic aldehydes in the cells. In this research we
      demonstrate that AS-ODN against ALDH3 increase the quantity of malondialdehyde in
      the cells, and inhibit cell proliferation by affecting the MAPK pathway: a
      reduction of pRaf-1 and pERK1,2 was observed. These results confirm the
      importance of aldehydes derived from lipid peroxidation and of ALDH3 in
      regulating hepatoma proliferation. Moreover, the results indicate the use of AS
      ODN against ALDH3 as a possible strategy to reduce growth in tumours
      overexpressing this enzyme.

PMID- 12604188
TI  - Ultraviolet radiation decreases expression and induces aggregation of corneal
      ALDH3A1.
AB  - Substantial reduction in corneal ALDH3A1 enzymatic activity associated with eye
      pathology was previously reported in C57BL/6J mice subjected to ultraviolet
      radiation (UVR). The aim of this study was to examine whether UVR diminishes
      corneal ALDH3A1 expression through modifications at the transcriptional,
      translational, or post-translational level. Adult C57BL/6J mice were subjected to
      UVR exposure (302 nm peak wavelength) for various periods of time, and corneal
      ALDH3A1 mRNA and protein levels were monitored by Northern and Western blot
      analysis, respectively. In addition, ALDH3A1 enzymatic activity was determined as
      a measure of post-translational modification. Mice exposed to 0.2 J/cm(2) UVB
      radiation demonstrated an extensive decrease, approximately 80%, in mRNA and
      protein levels, as well as enzymatic activity of corneal ALDH3A1. Significant
      reductions in corneal ALDH3A1 enzymatic activity were detected in mice 96 h after
      exposure to 0.05 and 0.1 J/cm(2) UVB radiation; no significant changes were
      observed in mRNA and protein levels. These data suggest that UVB down-regulates
      corneal ALDH3A1 expression at the transcriptional and/or post-translational level
      depending on the dose of UVB. Reduction in gene transcription requires UVB doses
      greater than or equal to 0.2 J/cm(2). In vitro experiments with human corneal
      epithelial cell lines stably transfected with human ALDH3A1 cDNA, and with
      purified recombinant human ALDH3A1 protein, indicated that ALDH3A1 undergoes post
      translational modifications after UVR exposure. These modifications result in
      both covalent and non-covalent aggregation of the protein with no detectable
      precipitation. Such conformational changes may be associated with the function of
      ALDH3A1 as a chaperone-like molecule in the cornea.

PMID- 12604189
TI  - Acute-phase response to benzo[a]pyrene and induction of rat ALDH3A1.
AB  - The aldehyde dehydrogenase-3A1 (ALDH3A1) enzyme, encoded by a member of the [Ah]
      gene family, is dramatically increased (more than 100-fold) by benzo[a]pyrene
      (BaP) and other polycyclic hydrocarbons. Although much is known regarding the
      mechanism for the drug-metabolizing enzymes up-regulated by the Ah receptor, the
      physiological role of that tremendously increased ALDH3A1 enzyme activity is not
      yet fully clarified. The aim of this study was to identify a possible acute-phase
      response to different classes of xenobiotics affecting the metabolic capacity of
      the hepatocyte, by studying possible changes of serum acute-phase proteins (APPs)
      of hepatic origin, before and after BaP administration. Male Wistar rats were
      used in different series of experiments. The effects of BaP were estimated in
      terms of dose-response and time-response, with regard to the serum level of
      several APPs such as alpha-1-acid-glycoprotein (AAG), alpha-1-antitrypsin (AAT),
      C-reactive protein (CRP), and haptoglobin (HPT). In parallel experiments, levels
      of the same proteins have been determined after a time-dependent treatment with
      lipopolysaccharide (LPS). The changes in serum proteins were compared with the
      results of BaP or LPS administration on both hepatic ALDH3A1 and total ALDH
      enzyme activities. The results showed that BaP induced CRP and HPT in a time
      dependent way, proportional to that caused by LPS. Additionally, ALDH3A1, CRP,
      and HPT were induced by BaP subacute treatment, whereas another type of ALDH
      inducer, phenobarbital, did not affect the levels of APPs or ALDH3A1, but did
      increase ALDH1A3 activity. Former studies of our group have shown that the
      inhibitory effects of different non-steroidal anti-inflammatory drugs (NSAIDs) on
      the ALDH3A1 induction were most possibly due to a decreased formation of
      arachidonic products like prostaglandins. Considering the changes of APPs caused
      by BaP, this study further supports the suggestion that the induction of ALDH3A1
      is related to an atypical hepatocyte inflammation produced by xenobiotics.

PMID- 12604190
TI  - Transient induction of increased aldehyde dehydrogenase 3A1 levels in cultured
      human breast (adeno)carcinoma cell lines via 5'-upstream xenobiotic, and
      electrophile, responsive elements is, respectively, estrogen receptor-dependent
      and -independent.
AB  - Transient up-regulation of ALDH3A1, CYP1A1 and CYP1B1 transcription by transient
      exposure to aryl hydrocarbon receptor (AhR) ligands, e.g. 3-methylcholanthrene,
      is via transient transactivation of xenobiotic responsive elements (XRE) present
      in the 5'-upstream regions of these genes. Others have shown that AhR ligand
      mediated induction of increased CYP1A1 levels in cultured human breast
      (adeno)carcinoma cell lines is apparently estrogen receptor (ER)-dependent, i.e.
      it was observed in ER(+) cell lines but not in ER(-) cell lines, whereas AhR
      ligand-mediated induction of increased CYP1B1 levels is ER-independent, i.e. it
      was observed in both ER(+) and ER(-) cell lines. The present investigation
      established that transient, AhR ligand/XRE-mediated induction of increased
      ALDH3A1 levels in human breast (adeno)carcinoma cell lines was, like that of
      CYP1A1 and unlike that of CYP1B1, apparently ER-dependent. Thus, transient
      exposure to 3-methylcholanthrene induced increased levels of ALDH3A1 in five
      cultured human breast (adeno)carcinoma cell lines that were documented as being
      ER(+), viz., MCF-7/0, MCF-7/OAP, T-47D, ZR-75-1 and MDA-MB-468, but failed to
      induce increased levels of this enzyme in four cultured human breast
      (adeno)carcinoma cell lines that have been historically viewed as being ER(-),
      viz., MDA-MB-231, SK-BR-3, HS-578-T and MDA-MB-435. Somewhat at odds with the
      foregoing, transient exposure to 3-methylcholanthrene also induced increased
      levels of ALDH3A1 and CYP1A1 in cultured, essentially ER(-), human breast
      epithelial MCF-10A cells. These cells, like cultured human breast
      (adeno)carcinoma cells, are immortal, but unlike the latter, are not tumorigenic.
      Transient induction of increased ALDH3A1 levels can also be effected by agents
      that are not AhR ligands, viz., electrophiles such as catechol, and thus, cannot
      up-regulate ALDH3A1 transcription via transactivation of a 5'-upsteam region XRE.
      Rather, they are thought to up-regulate ALDH3A1 transcription via transient
      transactivation of an electrophile responsive element (EpRE) that is putatively
      also present in the 5'-upstream region of this gene. Electrophile-initiated/EpRE
      mediated induction of increased ALDH3A1 levels was found to be ER-independent.
      Thus, catechol transiently induced increased levels of ALDH3A1 in the five ER(+)
      human breast (adeno)carcinoma cell lines, the four ER(-) human breast
      (adeno)carcinoma cell lines, and the ER(-), immortal but not tumorigenic, human
      breast epithelial cell line.

PMID- 12604191
TI  - Initial catalytic events in class 3 aldehyde dehydrogenase: MM and QM/MM
      simulations.
AB  - A novel enzyme mechanism has been predicted by computer simulations for formation
      of the thiohemiacetal intermediate in the rat ALDH3A1 enzyme. We used molecular
      mechanics simulations to study the atomic details of substrate binding and
      quantum mechanical/molecular mechanical methods to study the Cys-243 thiolate
      attack on benzaldehyde (BA) substrate. BA was found to produce more reactive
      conformers when aligned for formation of the tetrahedral thiohemiacetal in the R
      configuration. In addition, the sulfhydryl proton was seen to be important for
      initial binding of the substrate. Finally, the free energy differences between
      forming a thiohemiacetal oxyanion intermediate versus forming a neutral
      thiohemiacetal intermediate where a proton is donated to the intermediate from
      the surroundings strongly favor the latter. Our results suggest that the proton
      donor is the amide proton from the Cys-243 backbone supported by interactions
      with Lys-235.

PMID- 12604192
TI  - Chemical modifications to study mutations that affect the ability of the general
      base (E268) to function in human liver mitochondrial aldehyde dehydrogenase.
AB  - The action of a general base is needed in two possible steps during the aldehyde
      dehydrogenase catalyzed oxidation of an aldehyde to an acid. The base is
      glutamate at position 268 in the cytosolic and mitochondrial class 1 and 2
      enzyme. A chemical modification approach was undertaken to determine if the base
      were necessary in the initial attack of the nucleophilic cysteine (302) on the
      aldehyde as well as the attack by water on the acyl intermediate formed after the
      aldehyde is oxidized. A metabolite of disulfiram, S-methyl-N,N
      diethylthiocarbamoyl sulfoxide (MeDTC-SO), was used as the modifying agent. Three
      recombinantly expressed mutant forms of the human mitochondrial enzyme along with
      the native one were used. These were the E268Q mutant that was lacking the
      general base; the E487K Oriental variant of the enzyme and R475Q, a mutant
      possessing the residue that binds to E487. As expected, the E268Q mutant was
      inactivated very slowly compared with the native or other mutants that were
      inactivated more slowly than the native enzyme. The presence of NAD did not
      increase the rate of inactivation except with the R475Q mutant. It is concluded
      that it is necessary to activate the cysteine at the active site to make it a
      good nucleophile as well to activate water during the hydrolysis of the thio-acyl
      intermediate. Further, it is surmised that the reason some mutants have a lowered
      specific activity is that in those the general base is not capable of functioning
      as it does in the native enzyme.

PMID- 12604193
TI  - Covalent adduction of nucleophilic amino acids by 4-hydroxynonenal and 4
      oxononenal.
AB  - Peroxidation of polyunsaturated fatty acids yields the lipid aldehydes 4
      hydroxynonenal (4HNE) and 4-oxononenal (4ONE). Adduction of proteins by 4HNE is
      thought to be involved in the pathogenesis of several diseases. At the present
      time, the reactivity of 4ONE toward proteins is unknown. The purpose of this
      study was to identify amino acids that react with 4HNE and 4ONE, characterize the
      chemical structure of the adduct, and determine the preference for amino acid
      modification. Model peptides containing one or more nucleophilic residues (i.e.
      Arg, Cys, His, Met and Lys) were reacted with 4HNE and 4ONE at pH 7.4, 37 degrees
      C and analyzed using matrix-assisted laser desorption/ionization mass
      spectrometry (MALDI-TOF-MS). Post-source decay (PSD) analysis was used to confirm
      peptide modification. The bimolecular rate constant for adduction of amino acids
      and peptides by 4HNE and 4ONE was measured. Results of this work indicate that
      Cys, His and Lys are modified by 4HNE. In contrast, 4ONE was found to react with
      Arg, Cys, His and Lys. The predominant adduct resulting from modification of
      peptides by 4HNE or 4ONE had a mass of 156 or 154 Da (respectively), indicating
      that both lipid aldehydes react primarily via Michael addition with peptide
      nucleophiles to yield a covalent adduct. Reactivity of amino acids toward 4HNE
      was found to have the following order of potency: Cys>>His>Lys. Preference for
      the reaction of amino acid nucleophiles with 4ONE was determined to have the
      following order: Cys>>His>Lys>Arg. The presence of an Arg on a Cys-containing
      peptide increased the reaction rate with 4HNE and 4ONE by a factor of
      approximately 5-6 compared to the Cys nucleophile alone. Rate constants for the
      modification of Cys by 4HNE and 4ONE were determined to be 1.21 and 186 M(-1) s(
      1) (respectively), indicating a >150-fold difference in reactivity between the
      lipid aldehydes toward Cys. Spontaneous conjugation of glutathione (GSH) with the
      lipid aldehydes was found to occur with rate constants of 1.33 and 145 M(-1) s(
      1) for 4HNE and 4ONE (respectively), demonstrating a 110-fold difference in the
      rate of GSH modification between the two compounds. Results of the present study
      indicate that both 4HNE and 4ONE react with amino acid nucleophiles via Michael
      addition with the following order of potency: Cys>>His>Lys. However, the
      reactivity of these lipid aldehydes toward amino acid nucleophiles differs
      qualitatively with Arg being a target for 4ONE but not 4HNE and quantitatively by
      a remarkable >100-fold difference in the rate of Cys modification between 4HNE
      and 4ONE.

PMID- 12604194
TI  - Oxidation of 4-hydroxynonenal in rat brain slices.
AB  - 4-Hydroxy-2-nonenal (HNE) is implicated as a neurotoxic 'second messenger' of
      oxidative damage in Alzheimer's disease (AD). The mechanism of HNE toxicity is
      due to alkylation of cellular nucleophilic groups. The C1 aldehyde is key to the
      alkylation ability of HNE. Oxidation of the C1 aldehyde to 4-hydroxy-2-nonenoic
      acid is catalyzed by aldehyde dehydrogenases. In this work, we tested the
      hypothesis that HNE oxidation to HNEAcid occurs in rat cerebral cortex utilizing
      rat cerebral cortical slices exposed extracellularly to HNE. HNEAcid formation
      occurs in a dose dependent manner with approximately 18-25% of the HNE consumed
      accounted for by HNEAcid formation. HNEAcid was found exclusively in the
      incubation media, suggesting that HNEAcid is exported from the cells of the
      slice. These data demonstrate that HNE detoxification through the oxidation
      pathway occur in the cerebral cortex.

PMID- 12604195
TI  - Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl
      metabolizing enzymes. I. Aliphatic alkenals.
AB  - The cytotoxicity of alkenals towards hepatocytes was related to their
      electrophilicity not their hydrophobicity as cytotoxicity decreased as the chain
      length increased from acrolein to hexenal and then cytotoxicity increased from
      hexenal to nonenal. The sequence of events found was rapid glutathione depletion,
      lipid peroxidation, and inhibition of respiration before cell lysis occurred.
      Cytotoxicity markedly increased if glutathione was depleted beforehand. Although
      acrolein-induced cytotoxicity was only delayed by antioxidants or glycolytic
      substrates (e.g. fructose), it was prevented by NADH generators (e.g. xylitol and
      sorbitol) due to increased metabolism by ADH1. Cytotoxicity induced by
      trans,trans-2,4-decadienal (decadienal), on the other hand, was prevented by
      antioxidants and/or glycolytic substrates but was not prevented by NADH
      generators. Decadienal-induced cytotoxicity was also more increased by
      mitochondrial ALDH2 inhibitors than acrolein and was more increased by decreasing
      mitochondrial NAD+ with rotenone or decreased by increasing mitochondrial NAD+
      with oxaloacetate. This suggests that the high electrophilicity of acrolein makes
      acrolein a more promiscuous inhibitor than decadienal. This results in the
      inactivation of more enzymes required for cell viability including the cytosolic
      and mitochondrial ALDHs as well as other enzymes (e.g. mitochondrial) making the
      reductive detoxication of acrolein by ADH1 more important than the oxidative
      detoxification by ALDHs. Decadienal is detoxified by all cytosolic and
      mitochondrial ALDHs and is less dependent on ADH1 for detoxication. There was
      also marked cytotoxic synergism between acrolein and decadienal presumably
      because of ALDH inactivation by acrolein.

PMID- 12604197
TI  - Ligand-induced conformational changes of betaine aldehyde dehydrogenase from
      Pseudomonas aeruginosa and Amaranthus hypochondriacus L. leaves affecting the
      reactivity of the catalytic thiol.
AB  - The reaction catalyzed by betaine aldehyde dehydrogenase (BADH) involves the
      nucleophilic attack of a catalytic cysteinyl residue on the aldehyde substrate.
      As a possible mechanism of regulation, we have studied the modulation by ligands
      of the reactivity and/or accessibility of the essential thiol of the enzyme from
      the human pathogen Pseudomonas aeruginosa and the leaves of the plant Amaranthus
      hypochondriacus (amaranth). In the absence of ligands, the kinetics of
      inactivation by thiol modifying reagents of both enzymes were biphasic,
      suggesting the existence of two enzyme conformers differing in the reactivity of
      their catalytic thiolate. Preincubation of P. aeruginosa BADH with the coenzymes
      or the aldehyde prior to the chemical modification brought about active site
      rearrangements that resulted in an important decrease in the inactivation rate.
      Amaranth BADH responded similarly to the preincubation with NADH or betaine
      aldehyde but NAD(+) elicited opposite changes, increasing the rate of
      inactivation after prolonged preincubation. In amaranth BADH, the different
      behavior of both coenzymes, and the observed biphasic inactivation kinetics are
      consistent with the previously proposed iso kinetic mechanism, characterized by
      the existence of two interconvertible apoenzyme forms, one able to bind NAD(+)
      and the other NADH. Taken together, our results suggest that ligand-induced
      conformational changes in BADH from the two sources studied might be important
      for both proper enzyme function and protection against oxidation.

PMID- 12604196
TI  - Modulating carbonyl cytotoxicity in intact rat hepatocytes by inhibiting carbonyl
      metabolizing enzymes. II. Aromatic aldehydes.
AB  - The molecular cytotoxic mechanisms of dietary benzaldehydes towards hepatocytes
      and its modulation by metabolizing enzymes were compared. Salicylaldehyde was
      found to be the most cytotoxic followed by cinnamaldehyde and both rapidly
      depleted some glutathione before an inhibition of respiration occurred, which
      preceded cell lysis. Reactive oxygen species were formed, but lipid peroxidation
      was induced with cinnamaldehyde, but not salicylaldehyde. Glutathione depleted
      hepatocytes were more susceptible to cytotoxicity. Mitochondrial toxicity and
      cytotoxicity were prevented by glycolytic substrates (e.g. fructose), citric acid
      cycle substrates (e.g. glutamine) or cyclosporin, the mitochondrial permeability
      transition inhibitor. Inhibition of mitochondrial ALDH with chloral hydrate,
      crotonaldehyde or citral or decreasing mitochondrial NAD+ with rotenone increased
      cinnamaldehyde induced cytotoxicity with a much smaller effect on salicylaldehyde
      induced cytotoxicity. Cyanamide was the most effective ALDH inhibitor for
      increasing cinnamaldehyde induced cytotoxicity, presumably because cyanamide also
      inhibits microsomal ALDH. Although cinnamaldehyde was a better substrate than
      salicylaldehyde for ADH1, cytosolic NADH generators (e.g. xylitol) prevented
      salicylaldehyde and cinnamaldehyde cytotoxicity similarly. This could be
      explained as salicylaldehyde was not a substrate for the ALDHs and would then be
      more dependent on ADH for detoxification.

PMID- 12604198
TI  - Monovalent cations requirements for the stability of betaine aldehyde
      dehydrogenase from Pseudomonas aeruginosa, porcine kidney and amaranth leaves.
AB  - Betaine aldehyde dehydrogenase from the human pathogen Pseudomonas aeruginosa
      requires K(+) ions for maintenance of its active conformation. In order to
      explore if this property is shared by other BADHs of different origins and to
      further understand the mechanism underlying the effects of these ions, we carried
      out a comparative study on the stability and quaternary structure of P.
      aeruginosa, porcine kidney and amaranth leaves BADHs in the absence of K(+) ions.
      At low enzyme concentrations, the bacterial and porcine enzymes were totally
      inactivated upon removal of K(+) following biphasic and monophasic kinetics,
      respectively, whereas the amaranth enzyme retained its activity. Inactivation of
      P. aeruginosa BADH was much faster than that of the porcine enzyme. The oxidized
      coenzyme protected both enzymes against inactivation by the absence of K(+),
      whereas betaine aldehyde afforded partial protection to the bacterial BADH and
      increased the inactivation rate of the porcine. Reactivation of the inactive
      enzymes, by adding back to the incubation medium K(+) ions, was dependent on
      enzyme concentration, suggesting that enzyme dissociation takes place in the
      absence of K(+). In the bacterial enzyme, NH(4)(+) but not Na(+) ions could mimic
      the effects of K(+), whereas the three cations tested reactivated porcine BADH,
      indicating a requirement of this enzyme for high ionic strength rather than for a
      specific monovalent cation. Size exclusion chromatography of the inactivated
      enzymes confirmed that K(+) ions or other monovalent cations are required for the
      maintenance of the quaternary structure of these two BADHs. At pH 7.0, in the
      absence of K(+) in a buffer of low ionic strength, the active tetrameric form of
      P. aeruginosa BADH dissociated into inactive monomers and that of porcine kidney
      BADH into inactive dimers. Once reactivated, both enzymes reassociated into
      active tetramers.

PMID- 12604199
TI  - Inactivation of betaine aldehyde dehydrogenase from Pseudomonas aeruginosa and
      Amaranthus hypochondriacus L. leaves by disulfiram.
AB  - Betaine aldehyde dehydrogenase (BADH) activity might be crucial for the growth of
      the human pathogen Pseudomonas aeruginosa under conditions of infection and
      therefore appears to be a suitable target for antimicrobial agents. As a first
      step in the search for BADH inhibitors, we have tested the effects of the known
      aldehyde dehydrogenase inhibitor disulfiram (DSF) on the activity of P.
      aeruginosa and Amaranthus hypochondriacus (amaranth) leaf BADHs. DSF totally
      inactivated both enzymes in a time- and dose-dependent manner. In the case of the
      Pseudomonas enzyme, inactivation kinetics were monophasic with a second-order
      inactivation rate constant at pH 6.9 of 4.9+/-0.4 M(-1) s(-1), whereas the plant
      enzyme was inactivated in a biphasic process with second-order inactivation rate
      constants at pH 7.5 of 6.8+/-0.6 and 0.33+/-0.04 M(-1) s(-1). At pH 8.8, the
      second-order rate constants for inactivation of the bacterial enzyme was 1 x
      10(3) M(-1) s(-1), which compare well with that reported for human liver
      mitochondrial aldehyde dehydrogenase (ALDH2), the target of DSF inhibition in the
      aversion therapy of alcoholism. Both BADHs were inactivated faster in the
      presence of NAD(P)(+) than in its absence, whereas NAD(P)H and betaine aldehyde
      protected the bacterial, but increased the inactivation rate of the plant enzyme.
      The inactivated enzymes were reactivated by dithiothreitol, but not by a high
      concentration of the physiological reductant glutathione. The high in vitro
      sensitivity of the Pseudomonas BADH to DSF, particularly in the presence of
      NAD(P)(+), together with the lack of reversibility of DSF modification by
      glutathione, makes this inhibitor a potential antimicrobial agent and suggests
      that it might be worth testing its effects and those of its metabolites in vivo,
      under culture conditions in which the activity of BADH is required for growth of
      the bacteria.

PMID- 12604200
TI  - Purification and characterization of two distinct aldehyde-oxidizing enzymes from
      the liver of black seabream.
AB  - Two aldehyde dehydrogenases (ALDH) were purified from the liver of black seabream
      (Acanthopagrus schlegeli). Chromatography of the liver homogenate on an alpha
      cyanocinnamate-Sepharose affinity column results in two activity peaks using
      acetaldehyde as the substrate. The eluate was subjected to another affinity
      chromatography on p-hydroxyacetophenone-Sepharose. The final preparation showed a
      single band on SDS-PAGE with a subunit M.W. of 56,000. N-terminal amino acid
      sequencing of the first 29 residues followed by blastp analysis on the NCBI
      database revealed this protein as ALDH-2, as it exhibited 69% identity with human
      mitochondrial ALDH-2. Chromatography of the alpha-cyanocinnamate-Sepharose column
      flow-through fractions on Affi-gel Blue agarose yielded another ALDH. The
      purified protein, with a subunit M.W. of 57,500, was identified as antiquitin
      (turgor ALDH) by its first 18 N-terminal amino acid residues, which showed 83%
      identity with the deduced amino acid sequence of human antiquitin. Kinetically,
      both ALDHs showed maximal activity at pH around 8.5-9.0. They differed, however,
      in their catalytic efficiency towards the oxidation of acetaldehyde. Antiquitin
      had much lower affinity towards acetaldehyde; the Km value being approximately
      220-fold higher than that of ALDH-2. The Vmax of antiquitin was only
      approximately 12% of ALDH-2. Antiquitin is believed to be involved in the
      regulation of cellular turgor pressure. However, all previous studies on
      antiquitin have been confined to the nucleotide level and the protein has never
      been isolated from any source. The development of an effective purification
      procedure and the demonstration that this protein is an enzyme with aldehyde
      oxidizing activity would be highly valuable for further investigations on the
      physiological significance of this evolutionarily conserved protein.

PMID- 12604201
TI  - Conformational changes and activation of yeast aldehyde dehydrogenase by various
      agents.
AB  - Activity assays are characterised by a slow activation phase lasting 1-2 min
      which arises from the conversion of the low activity/inactive form of the
      isolated yeast aldehyde dehydrogenase into a high activity form upon binding
      NADP(+). When Mg(2+) is present as an activator, the binding of coenzyme is
      relatively strong and activation is effectively complete when the steady-state
      rates are measured. Lineweaver-Burk plots with 1/[NADP(+)] as variable are
      linear. In the absence of Mg(2+), coenzyme binding is relatively weak and the
      conversion of inactive to active enzyme is not complete when steady-state rates
      are measured. The balance of equilibrium is now finely balanced and the degree of
      activation depends on the NADP(+) concentration. Under these conditions, rate
      versus [NADP(+)] plots are sigmoid, characterised by a Hill coefficient of 1.8
      because the active (as opposed to the total) enzyme concentration is different in
      assays with different [NADP(+)]. Kinetic studies indicate that the activation
      process involves two steps, but the data do not allow discrimination between
      alternative mechanisms. Gel filtration and sedimentation equilibrium
      centrifugation indicate that the activation process does not involve enzyme
      association-dissociation. Activation of the enzyme can also be achieved by
      replacing Mg(2+) by small amounts of protamine sulphate, poly-L-lysine or poly-L
      arginine. The mechanism for these activations is unknown, but presumably involves
      the binding of the enzyme to these positively charged molecules.

PMID- 12604202
TI  - The mammalian alcohol dehydrogenases interact in several metabolic pathways.
AB  - Mammalian alcohol dehydrogenases (ADHs), including ADH1-ADH5/6, interact
      extensively in the oxidation and reduction of alcohols and aldehydes. ADH1 and
      ADH2 are involved in several metabolic pathways besides the oxidation of ethanol
      and have also been shown to be involved in drug transformations. The ADH2 enzymes
      show further complexity among the species, e.g. in enzymatic characteristics
      where the rodent forms essentially lack ethanol-oxidizing capacity. ADH3
      (glutathione-dependent formaldehyde dehydrogenase) has been shown to catalyze the
      reductive breakdown of S-nitrosoglutathione, indicating involvement in nitric
      oxide metabolism. Mass spectrometry identified the major enzymatic product as
      glutathione sulfinamide. This reductive breakdown directly interferes with the
      formaldehyde scavenging that has been proposed to be the physiological action of
      ADH3. The human ADH5 and rodent ADH6 seem to be the corresponding enzymes due to
      their similar behavior. None of these latter ADHs have so far been assigned to
      any function. They can be expressed as recombinant proteins but no enzymatic
      activity has been detected.

PMID- 12604203
TI  - Specificity of human alcohol dehydrogenase 1C*2 (gamma2gamma2) for steroids and
      simulation of the uncompetitive inhibition of ethanol metabolism.
AB  - The steady-state kinetics of the recombinant human alcohol dehydrogenase (ADH)
      1C*2 with steroids were studied in order to determine substrate and inhibitor
      specificity. The assays were carried out under conditions of pH and temperature
      that are similar to those found in vivo. The enzyme has measurable activity on
      5beta-androstan-17beta-ol-3-one, 5beta-androstan-3beta-ol-17-one, 5beta-pregnan
      3beta-ol-20-one and 5beta-pregnan-3,20-dione, but much less activity with 5beta
      cholanic acid-3-one or 5alpha-pregnan-3beta-ol-20-one. The determinants of
      specificity appear to include a 5beta configuration (cis A/B ring fusion) and a
      3beta-hydroxy or 3-keto group. None of the reactive steroids has a known function
      in vivo. The activities with the human ADH1C*2 are <10% of those found with the
      recombinant horse ADH1S, but higher than the activities with recombinant horse
      ADH1E, which has an active site very similar to human ADH1C. 5alpha
      Dihydrotestosterone is a ketone and a competitive inhibitor against varied
      concentrations of the substrate cyclohexanone, whereas it is an uncompetitive
      inhibitor against ethanol or NAD(+). Such patterns are expected for the binding
      of the steroid as a dead-end inhibitor to the enzyme-NADH complex. Thus, it does
      not appear that 5alpha-dihydrotestosterone is an allosteric inhibitor of the
      enzyme. Another dead-end inhibitor that gives uncompetitive inhibition of alcohol
      oxidation, 3-butylthiolane 1-oxide, is a potent inhibitor of alcohol metabolism
      in rats and mice. Simulation of the kinetics of ethanol elimination in rats with
      varied concentrations of the inhibitor is shown to yield the in vivo inhibition
      constant and an estimate of the rate of elimination of the inhibitor.

PMID- 12604204
TI  - Structure-function relationships in human Class III alcohol dehydrogenase
      (formaldehyde dehydrogenase).
AB  - Human Class III alcohol dehydrogenase (ADH), also known as glutathione-dependent
      formaldehyde dehydrogenase plays an important role in the formaldehyde
      detoxification and reduction of the nitric oxide metabolite s-nitrosoglutathione
      (GSNO). It follows a random bi bi kinetic mechanism and prefers bulkier
      substrates like long chain primary alcohols and glutathione adducts like s
      hydroxymethylglutathione and GSNO over smaller alcohols like ethanol. The
      structure of the FDH.NAD(H) binary complex reported here, in conjunction with the
      other complexes of FDH, provide the structural basis of the kinetic observations.
      These structures show that the apoenzyme has a semi-open domain conformation that
      permits random random addition of alcohol or NAD(H). Moreover, there is no
      significant domain movement upon binding of the coenzyme or the substrate, 12
      hydroxydodecanoic acid. Interestingly, two active site zinc coordination
      environments are observed in FDH. In the apoenzyme, the active site zinc is
      coordinated to Cys44, His66, Cys173 and a water molecule. In the FDH.NAD(H)
      binary complex reported here, Glu67 is added to the coordination environment of
      the active site zinc and the distance between the water molecule and zinc is
      increased. This change in the zinc coordination, brought about by the
      displacement of zinc of about 2 A towards Glu67 could promote substrate exchange
      at the active site metal during catalysis.

PMID- 12604205
TI  - Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to
      retinaldehyde followed by tissue-specific metabolism to retinoic acid.
AB  - The ability of vitamin A (retinol) to control growth and development depends upon
      tissue-specific metabolism of retinol to retinoic acid (RA). RA then functions as
      a ligand for retinoid receptor signaling. Mouse genetic studies support a role
      for cytosolic alcohol dehydrogenases (ADH) in the first step (oxidation of
      retinol to retinaldehyde) and a role for cytosolic retinaldehyde dehydrogenases
      (RALDH) in the second step (oxidation of retinaldehyde to RA). Mice lacking ADH3
      have reduced survival and a growth defect that can be rescued by dietary retinol
      supplementation, whereas the effect of a loss of ADH1 or ADH4 is noticed only in
      mice subjected to vitamin A excess or deficiency, respectively. Also, genetic
      deficiency of both ADH1 and ADH4 does not have additive effects, verifying
      separate roles for these enzymes in retinoid metabolism. As for the second step
      of RA synthesis, a null mutation of RALDH2 is embryonic lethal, eliminating most
      mesodermal RA synthesis, whereas loss of RALDH1 eliminates RA synthesis only in
      the embryonic dorsal retina with no obvious effect on development. Analysis of RA
      rescued RALDH2 mutants has also revealed that RALDH3 and at least one additional
      enzyme produce RA tissue-specifically in embryos. Collectively, these genetic
      findings indicate that metabolism of retinol to retinaldehyde is not tissue
      restricted as it is catalyzed by ubiquitously-expressed ADH3 (a low activity
      form) as well as by tissue-specifically expressed ADH1 and ADH4 (high activity
      forms). In contrast, further metabolism of retinaldehyde to RA is tissue
      restricted as all enzymes identified are tissue-specific. An important concept to
      emerge is that selective expression of enzymes catalyzing the second step is what
      limits the tissues that can completely metabolize retinol to RA to initiate
      retinoid signaling.

PMID- 12604206
TI  - Crystal structure of glutathione-independent formaldehyde dehydrogenase.
AB  - Formaldehyde dehydrogenase from Pseudomonas putida (PFDH) is a member of the zinc
      containing medium-chain alcohol dehydrogenase (ADH) family. The pyridine
      nucleotide NAD(H) in PFDH, which is distinct from the coenzyme (as co-substrate)
      in typical ADHs, is tightly but not covalently bound to the protein and acts as a
      cofactor. Such enzymes with tightly bound NAD(P)(H) acting as a cofactor are
      called nicotinoproteins. The structural basis of the tightly bound cofactor of
      PFDH is unknown. The crystal structure of PFDH has been solved by the
      multiwavelength anomalous diffraction method using intrinsic zinc ions and has
      been refined at a 1.65 A resolution. The 170-kDa-homotetrameric PFDH molecule
      shows 222-point group symmetry. Although the secondary structure arrangement and
      the binding mode of catalytic and structural zinc ions in PFDH are similar to
      those of typical ADHs, a number of loop structures that differ between PFDH and
      ADHs in their lengths and conformations are observed.

PMID- 12604207
TI  - Human class IV alcohol dehydrogenase: kinetic mechanism, functional roles and
      medical relevance.
AB  - Human alcohol dehydrogenase (ADH) constitutes a complex family. Class IV ADH
      (ADH4) is characteristic in its epithelial expression in the aerodigestive tract
      and high V(max) and K(m) for oxidation of ethanol. ADH4 exhibits the highest
      catalytic efficiency for retinol oxidation in human ADH family. Initial velocity,
      product inhibition, and dead-end inhibition studies indicate that ADH4, when
      functioning as ethanol dehydrogenase, conforms to an ordered sequential mechanism
      with coenzyme binding first and releasing last in catalytic cycle. When
      functioning as retinol dehydrogenase, the mechanism of ADH4 deduced from steady
      state kinetic and equilibrium-binding studies is best described as a rapid
      equilibrium random mechanism with two dead-end ternary complex for retinol
      oxidation and a rapid equilibrium ordered mechanism with one dead-end ternary
      complex for retinal reduction, a unique mechanistic form for zinc-containing ADHs
      in the medium chain dehydrogenase/reductase superfamily. Kinetic and genetic
      studies support the proposal that ADH4 may play two important physiological
      roles, i.e., as a major contributor to first-pass metabolism of ethanol in
      stomach as well as involvement in the synthesis of retinoic acid, a hormonal
      ligand controlling a nuclear receptor signaling pathway that regulates growth,
      development, and epithelial maintenance. Quantitative simulation studies indicate
      that retinol metabolism through ADH pathway can be inhibited to a significant
      extent during alcohol consumption. The perturbation of retinoic acid synthesis by
      ethanol may underlie the pathogenesis of fetal alcohol syndrome and alcohol
      related upper digestive tract cancer.

PMID- 12604208
TI  - Properties and functional significance of Saccharomyces cerevisiae ADHVI.
AB  - The completion of the Saccharomyces cerevisiae genome project has provided the
      opportunity to explore for new genes of the medium-chain dehydrogenase/reductase
      enzyme superfamily. Our group has recently identified a new gene, the YMR318C
      open reading frame, which coded for a Zn-containing NADP(H)-dependent alcohol
      dehydrogenase (ADHVI). ADHVI has been purified to homogeneity from over
      expressing yeast cells, and found to be a homodimer of 40 kDa subunits. The
      enzyme showed a strict specificity for NADP(H) and high activity with a variety
      of long chain aliphatic and bulky substrates. Aldehydes exhibited 50-12000 times
      higher catalytic efficiency than the corresponding alcohols. Substrates with high
      k(cat)/K(m) were: pentanal, veratraldehyde and cinnamaldehyde. The ADHVI
      expression was strongly induced when galactose was the sole carbon source in the
      culture medium. Phylogenetic trees include ADHVI in the cinnamyl alcohol
      dehydrogenase (CADH) family. In contrast to the plant CADH, involved in lignin
      biosynthesis, this is not the function for ADHVI, since yeast does not synthesize
      lignin. ADHVI may be physiologically involved in several steps of the lignin
      degradation pathway, initiated by other microorganisms, in the synthesis of fusel
      alcohols, products derived from the aminoacidic metabolism, and in the
      homeostasis of NADP(H). Disruption of ADH6 was not lethal for the yeast, under
      laboratory conditions.

PMID- 12604209
TI  - Tetrameric NAD-dependent alcohol dehydrogenase.
AB  - Three-dimensional structures of the ethanol-induced, tetrameric alcohol
      dehydrogenase from Escherichia coli have recently been determined in the absence
      and presence of NAD. The structure of the E. coli enzyme is similar to those of
      the dimeric mammalian alcohol dehydrogenases, but it has a deletion of 21
      residues located at the surface of the catalytic domain. The catalytic zinc ions
      have two different types of coordination, which are also observed in the class
      III dimeric mammalian alcohol dehydrogenase. Comparison of the structures provide
      new insights into the relationship between tetrameric and dimeric alcohol
      dehydrogenases and provide a link to the structure of the tetrameric yeast
      alcohol dehydrogenase.

PMID- 12604210
TI  - Short-chain dehydrogenases/reductases (SDR): the 2002 update.
AB  - Short-chain dehydrogenases/reductases (SDR) form a large, functionally
      heterogeneous protein family presently with about 3000 primary and about 30 3D
      structures deposited in databases. Despite low sequence identities between
      different forms (about 15-30%), the 3D structures display highly similar
      alpha/beta folding patterns with a central beta-sheet, typical of the Rossmann
      fold. Based on distinct sequence motifs functional assignments and
      classifications are possible, making it possible to build a general nomenclature
      system. Recent mutagenetic and structural studies considerably extend the
      knowledge on the general reaction mechanism, thereby establishing a catalytic
      tetrad of Asn-Ser-Tyr-Lys residues, which presumably form the framework for a
      proton relay system including the 2'-OH of the nicotinamide ribose, similar to
      the mechanism found in horse liver ADH. Based on their cellular functions,
      several SDR enzymes appear as possible and promising pharmacological targets with
      application areas spanning hormone-dependent cancer forms or metabolic diseases
      such as obesity and diabetes, and infectious diseases.

PMID- 12604211
TI  - Multiplicity of eukaryotic ADH and other MDR forms.
AB  - Eukaryotic genomes code for at least eight medium-chain dehydrogenases/reductases
      (MDR) enzyme families of two types, with and without Zn(2+) at the active site.
      Four families have Zn(2+): 'Dimeric alcohol dehydrogenases (ADHs)' (including
      liver ADHs), 'Tetrameric ADHs' (including the yeast ADHs), 'Cinnamyl ADHs' and
      'Polyol DHs'. In the human genome, there are minimally 23 MDR genes, but the list
      is still growing from further interpretations. Of these, seven genes on
      chromosome 4 (and three pseudogenes) represent the ADH classes in the gene order
      IV, Igamma, Ibeta, Ialpha, V, II and III. The lineages leading to human ADH
      establish five levels of divergence, with nodes at the MDR/short-chain
      dehydrogenases/reductases (SDR), dimer/tetramer, class III/non-III, further
      class, and intraclass levels of divergence. These multiplicities allow
      conclusions on pathways of function for ADHs and suggest this activity to have
      two roles in addition to its function in metabolism, one of a basic defence
      nature, the other of regulatory value in higher eukaryotes.

PMID- 12604212
TI  - Substrate specificity of mouse aldo-keto reductase AKR7A5.
AB  - We have determined the substrate specificity of a mouse aldo-keto reductase (AKR)
      AKR7A5, an enzyme that is similar to rat aflatoxin aldehyde reductase (AKR7A1)
      and to human brain succinic semialdehyde reductase (AKR7A2). Previously, we have
      shown that the mouse enzyme is present in a range of tissues including liver,
      kidney, testis and brain, and is able to reduce several carbonyl compounds,
      including succinic semialdehyde, 2-carboxybenzaldehyde, 4-nitrobenzaldehyde and
      9,10-phenanthrenequinone [FEBS Lett. 523 (2002) 213]. It has been suggested that
      it may represent the mouse equivalent of human succinic semialdehyde reductase
      which is responsible for the biosynthesis of gamma-hydroxybutyrate. In this
      study, we show that the enzyme is also able to reduce other aromatic aldehydes
      such as 4-chloro-3-nitrobenzaldehyde, and 3-nitrobenzaldehyde, and has particular
      high specific activity towards dicarbonyls such as acenapthenequinone, 2,3
      bornanedione (camphorquinone), and phenylglyoxal. It has low specific activity
      towards ketones, and alpha,beta-unsaturated carbonyls such as acrolein and 4
      hydroxynonal. The enzyme is inhibited by several compounds including quercitin,
      ethacrynic acid, indomethacin and sodium valproate. Developing selective
      inhibitors may lead to a means of modifying the activity of the enzyme in vivo.

PMID- 12604213
TI  - Coenzyme-based functional assignments of short-chain dehydrogenases/reductases
      (SDRs).
AB  - Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional
      diversity. In spite of a residue identity of only 15-30%, the folds are conserved
      to a large extent, with specific sequence motifs detectable. We have developed an
      assignment scheme based on these motifs and detect five families. Only two of
      these were known before, called 'Classical' and 'Extended', but are now
      distinguished at a further level based on patterns of charged residues in the
      coenzyme-binding region, giving seven subfamilies of classical SDRs and three
      subfamilies of extended SDRs. Three further families are novel entities, denoted
      'Intermediate', 'Divergent' and 'Complex', encompassing short-chain alcohol
      dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The
      assignment scheme was applied to the genomes of human, mouse, D. melanogaster, C.
      elegans, A. thaliana and S. cerevisiae. In the animal genomes, genes
      corresponding to the extended SDRs amount to around one quarter or less of the
      total number of SDR genes, while in those of A. thaliana and S. cerevisiae, the
      extended members constitute about 40% of the SDR forms. The NAD(H)-dependent SDRs
      are about equally many as the NADP(H)-dependent ones in human, mouse and plant,
      while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly,
      worm and yeast. We also find that NADP(H) is the preferred coenzyme among most
      classical SDRs, while NAD(H) is that preferred among most extended SDRs.

PMID- 12604214
TI  - Characterization of truncated mutants of human microsomal short-chain
      dehydrogenase/reductase RoDH-4.
AB  - Human NAD(+)-dependent microsomal short-chain dehydrogenase/reductase RoDH-4
      oxidizes all-trans-retinol, 13-cis-retinol and 3alpha-hydroxysteroids to
      corresponding retinaldehydes and 3-ketones. RoDH-4 behaves as an integral
      membrane protein, but its topology in the membrane is not known. Analysis of RoDH
      4 polypeptide using algorithms for secondary structure predictions suggests that
      RoDH-4 contains four potential membrane-spanning domains: the N-terminal, the C
      terminal, and the two central hydrophobic segments. To determine the role of each
      segment in association of RoDH-4 with the membrane, we prepared several
      expression constructs coding for truncated RoDH-4 polypeptides that lacked the
      putative membrane-spanning domains and expressed them in insect Sf9 cells using
      the Baculovirus system. Association of truncated RoDH-4 constructs with the
      microsomal membranes was analyzed by alkaline extraction and floatation in
      sucrose gradient. Catalytic activity of truncated RoDH-4 constructs was assayed
      using the 3alpha-hydroxysteroid androsterone as substrate. Truncated RoDH-4 that
      lacked the first thirteen amino acids of the N-terminal segment was partially
      active and exhibited the apparent K(m) value for androsterone similar to that of
      the wild-type enzyme. Removal of 23 N-terminal hydrophobic amino acids resulted
      in significant loss of activity and a 14-fold increase in the apparent K(m)
      value. Removal of the C-terminal 27 amino acid segment resulted in a
      approximately 600-fold increase in the apparent K(m) value. Each truncated mutant
      behaved as an integral membrane protein. Furthermore, protein that lacked all
      four hydrophobic segments remained associated with the membrane. Thus, the N
      terminal and the C-terminal ends are both important for RoDH-4 activity and the
      removal of the putative transmembrane segments does not convert RoDH-4 into a
      soluble protein, suggesting additional sites of membrane interaction.

PMID- 12604215
TI  - The high resolution crystal structure of rat liver AKR7A1: understanding the
      substrate specificites of the AKR7 family.
AB  - The structure of the rat liver aflatoxin dialdehyde reductase (AKR7A1) has been
      solved to 1.38 A resolution. The crystal structure reveals details of the ternary
      complex as one subunit of the dimer contains NADP+ and the inhibitor citrate. The
      underlying catalytic mechanism appears similar to other aldo-keto reductases
      (AKR), whilst the substrate-binding pocket contains several positively charged
      amino acids (Arg-231 and Arg-327) which distinguishes it from the well
      characterised AKR1 family of enzymes. These differences account for the substrate
      specificity for 4-carbon acid-aldehydes such as succinic semialdehyde (SSA) and 2
      carboxybenzaldehyde, as well as for the idiosyncratic substrate aflatoxin B1
      dialdehyde of this subfamily of enzymes. The AKR7 enzymes seem to be subdivided
      into two subgroups based on their sequence and kinetic properties. Modelling of
      the rat AKR7A4 highlights important structural differences localised within the
      active site of the two isoenzymes.

PMID- 12604216
TI  - Human testis specific protein: a new member of aldo-keto reductase superfamily.
AB  - Human testis specific protein, HTSP, was identified initially by the search of
      the Expressed Sequence Tag database, followed by the screening of human testis
      cDNA library. Among various organs examined, the HTSP transcripts were detected
      only in the testis, not in other reproductive organs such as vas deferens and
      prostate. No cross-hybridizing signal was detected in the testis of mouse or rat,
      indicating that this gene is specifically expressed in the human testis. We
      isolated four isoforms, HTSP1, 2, 3 and 4. Screening of the high throughput
      genomic sequence database indicated the localization of the HTSP gene in
      chromosome 10. Thus, HTSP isoforms were generated by alternative splicing of a
      single gene. HTSP4, the longest gene product, was composed of 307 amino acids and
      shared 56% identity to mouse vas deferens protein as well as human aldose
      reductase in amino acid levels. Bacterially expressed recombinant HTSP protein
      showed small but significant activity towards 9,10-phenanthrenequinone among the
      putative substrates so far tested. Accordingly, HTSP is a new member of the aldo
      keto reductase superfamily with as yet unidentified function.

PMID- 12604217
TI  - Hydrogen bonding interactions between aldose reductase complexed with NADP(H) and
      inhibitor tolrestat studied by molecular dynamics simulations and binding assay.
AB  - Molecular dynamics simulations and binding affinity studies have been carried out
      in order to probe the effect of the charge state of His110 and cofactor NADPH on
      the binding affinity of the potent inhibitor tolrestat to aldose reductase (ALR2)
      complexed with either NADPH or NADP(+). Molecular dynamics simulations of ALR2
      NADP(+)-tolrestat indicate that the carboxylate group of tolrestat forms a
      hydrogen bond with Tyr48 and His110 of ALR2 regardless of the charge state of
      His110. In the case of ALR2-NADPH-tolrestat, the H-bonding pattern is
      significantly different from that of ALR2-NADP(+)-tolrestat, in that Tyr48 does
      not H-bond to tolrestat. The binding affinity of tolrestat to ALR2 complexed with
      either NADPH or NADP(+) is comparable and pH-dependent. Based on the H-bonding
      interactions seen in computer simulations, it is proposed that the cationic
      moiety at the active site of ALR2-NADP(+) and ALR2-NADPH that interacts with the
      carboxylate of tolrestat is NADP(+) and His110, respectively. The residue that
      gives rise to the pH-dependent binding of tolrestat to ALR2-NADP(+) and ALR2
      NADPH has been identified as Tyr48 and His110, respectively.

PMID- 12604218
TI  - Up-regulation of aldose reductase by the substrate, methylglyoxal.
AB  - Methylglyoxal (MG), a reactive dicarbonyl produced during glucose metabolism, is
      known as a preferred substrate of aldose reductase (AR; AKR1B1) that
      concomitantly catalyzes the reduction of glucose in the polyol pathway. MG
      modifies cellular proteins to form cross-links of amino groups, generating so
      called advanced glycation end products. Increased rates of MG formation under
      hyperglycemic conditions and ensuing high serum levels of MG are reported in
      diabetic patients. As involvement of AR in the pathogenesis of diabetic
      complications has been suggested, we investigated the effects of MG on AR
      activity using cultured vascular smooth muscle cells (SMC) isolated from rat
      aorta. MG-induced a dose- and time-dependent increase in AR mRNA levels to a
      maximum of 4.5-fold. This increase in mRNA was accompanied by elevated enzyme
      activity and protein levels. Pretreatment of SMC with N-acetyl-L-cysteine
      significantly suppressed the MG-induced AR expression, while DL-buthionine-(S,R)
      sulfoximine further augmented the MG-induced increase in AR mRNA level.
      Intracellular levels of reactive oxygen species determined using 2',7'
      dichlorofluorescein diacetate were significantly elevated in SMC treated with MG,
      suggesting the involvement of oxidative stress in this process. Under oxidative
      stress generated by hydrogen peroxide, the major signaling pathway mediating the
      up-regulation of AR expression was demonstrated to be the epidermal growth factor
      receptor-ERK pathway. In contrast, the p38 kinase pathway appears to mediate MG
      induced AR expression. The cytotoxic effect of MG was significantly enhanced in
      the presence of the AR inhibitor ponalrestat, indicating a protective role of AR
      against MG-induced cell damage.

PMID- 12604219
TI  - Aldo-keto reductases as modulators of stress response.
AB  - Human aldose reductase (AKR1B1) has been implicated as a factor in the
      pathogenesis of diabetic complications. However, little is known about the
      physiological role of this enzyme or of related aldo-keto reductases in human
      tissues. In mammalian systems, a gene knock out approach is often employed as an
      experimental strategy to probe for gene function. However, in the murine system,
      phenotypic characterization of an aldose reductase (AKR1B3) knock out is likely
      to be complicated due to functional compensation by redundant AKRs including AKRs
      1A (aldehyde reductase), 1B7 (FR-1) and 1B8 (MVDP). As an alternate strategy, we
      are examining the budding yeast Saccharomyces cerevisiae as a model system for a
      functional genomics study of AKRs. A distinct advantage of this system centers on
      the ability to readily ablate multiple targeted genes in a single strain. In
      addition to providing insights into functional redundancy, this system allows us
      to use a genetic approach to study possible effector pathways associated with one
      or more individual genes. Yeast open reading frames (ORFs) encoding AKRs with
      functional similarity to human aldose reductase (AKR1B1) were identified by BLAST
      analysis and were functionally validated by studies of recombinant proteins. By
      ablating three of the yeast AKR genes most functionally similar to AKR1B1, we
      have created a unique strain of S. cerevisiae that shows enhanced sensitivity to
      stress. Ongoing studies with oligonucleotide arrays show that the triple null
      strain has an altered transcription profile consistent with an enhanced stress
      response in comparison with the parental strain. These data indicate that AKR
      null strains may provide new insights into signaling mechanisms involving this
      family of proteins.

PMID- 12604220
TI  - Regulation of aldose reductase and the polyol pathway activity by nitric oxide.
AB  - Increased flux of glucose through the polyol pathway has been implicated in the
      pathophysiology of secondary diabetic complications. The first step of this
      pathway, which generates sorbitol from glucose, is catalyzed by aldose reductase
      (AR) (AKR1B). In vitro, the binding of substrates and inhibitors to AR is highly
      sensitive to the oxidation state of the enzyme due to the presence of a hyper
      reactive cysteine residue at the active site of the enzyme. This residue (Cys
      298) can be readily modified in air or, by thiol-modifying reagents, nitric oxide
      (NO) donors and nitrosothiols. We show that exposure of rat erythrocytes to NO
      donors inhibits AR activity and AR mediated accumulation of sorbitol, possibly by
      S-glutathiolation of Cys-298. Both glutathiolation and inhibition of AR are
      reversible upon subsequent incubation of the cells with fresh media without NO
      donors. These observations suggest that NO regulates the cellular activity of AR
      and in turn the flux of glucose via the polyol pathway. The inhibition of AR by
      exogenous or endogenous NO appears to be related to reversible S-glutathiolation
      of the AR protein. Because hyperglycemic states are associated with a decrease in
      NO generation, the loss of NO-mediated repression of AR may be a significant
      factor in the activation of the polyol pathway and the development of secondary
      diabetic complications.

PMID- 12604221
TI  - Methylglyoxal metabolism and diabetic complications: roles of aldose reductase,
      glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase.
AB  - The 2-oxoaldehyde methylglyoxal (MeG) is the precursor to a number of the known
      advanced glycation endproducts (AGE) implicated in the development of diabetic
      complications. Other 2-oxoaldehydes that are important in AGE formation, such as
      glyoxal, glucosone, deoxyglucosone, xylosone and deoxyxylosone, are produced by
      nonenzymatic reactions. By contrast, MeG is produced by both enzymatic and
      nonenzymatic processes, most of which appear to be enhanced in diabetes. MeG may
      be a major precursor to formation of AGE, and rates of production of MeG depend
      upon physiological conditions such as hyperglycemia and ketoacidosis. MeG is also
      unique compared to the other 2-oxoaldehydes in its complex metabolism. At least
      four pathways contribute to detoxification of MeG: (1) aldose reductase, a member
      of the aldo-keto reductase superfamily, catalyzes the NADPH-dependent reduction
      of a wide range of aldehydes. MeG is the best of the known physiological aldehyde
      substrates of aldose reductase. The distribution of aldose reductase in human
      tissue is restricted; there is little expression in liver; (2) the ubiquitous and
      highly active glyoxalase system converts MeG into D-lactate. However, this system
      depends upon the availability of glutathione; activity is severely limited by
      conditions of oxidative stress that impact levels of glutathione; (3) betaine
      aldehyde dehydrogenase, also known as ALDH9, is able to catalyze the oxidation of
      MeG to pyruvate, although less efficiently than with its substrate betaine
      aldehyde; (4) the long-known but not widely studied 2-oxoaldehyde dehydrogenases
      (2-ODHs) catalyze the oxidation of MeG to pyruvate, primarily in liver. There are
      two NADP-dependent 2-ODHs in human liver. Both of these require an activating
      amine. The physiological activator is unknown.

PMID- 12604222
TI  - Cloning, expression and tissue distribution of a tetrameric form of pig carbonyl
      reductase.
AB  - In this study, we isolated a cDNA for tetrameric carbonyl reductase (CR) from pig
      heart. The pig CR showed high amino acid sequence identity (81%) with rabbit
      NADP(+)-dependent retinol dehydrogenase (NDRD). The purified recombinant pig CR
      and NDRD were about 100-kDa homotetramers and exhibited high reductase activity
      towards alkyl phenyl ketones, alpha-dicarbonyl compounds and all-trans-retinal.
      The identity of NDRD with the tetrameric CR was verified by protein sequencing of
      CR purified from rabbit heart. Both tetrameric CR and its mRNA were ubiquitously
      expressed in pig and rabbit tissues. The pig and rabbit enzymes belonged to the
      short-chain dehydrogenase/reductase family, and their sequences comprise a C
      terminal SRL tripeptide, which is a variant of the type 1 peroxisomal targeting
      signal, SKL. Transfection of HeLa cells with vectors expressing pig CR
      demonstrated that the enzyme is localized in the peroxisomes. Thus, the
      tetrameric form of CR represents the first mammalian peroxisomal enzyme that
      reduces all-trans-retinal as the endogenous substrate.

PMID- 12604223
TI  - NADPH-dependent reductases and polyol formation in human leukemia cell lines.
AB  - Because of the limited availability of human tissues, leukemia cell lines are
      often utilized as the models for human leukocytes. In this study, we investigated
      the NADPH-dependent reductases and polyol pathway in commonly utilized human
      leukemia cell lines. The relative amounts of aldose and aldehyde reductases were
      estimated by separating two enzymes with chromatofocusing. The flux of glucose
      through the polyol pathway was examined by 19F-NMR using 3-fluoro-3-deoxy-D
      glucose (3FG) as substrate. Sugar alcohol analysis was conducted by gas
      chromatography. In myelocytic leukemia cells, the major reductase was aldehyde
      reductase, and levels of aldose reductase were extremely low. Although
      lymphocytic cells also contained both aldose and aldehyde reductases, the levels
      of aldose reductase appeared to be higher in lymphocytic cells than myeolcytic
      cells. In two lymphocytic cells MOLT-4 and SKW6.4, aldose reductase is clearly
      dominant. When incubated in medium containing D-galactose, all cell lines quickly
      accumulated galactitol. There was correlation between galactitol levels and
      aldose reductase levels. The aldose reductase inhibitor FK 366 significantly
      reduced the formation of galactitol. 19F-NMR of the cells cultured with 3FG as
      substrate demonstrated the formation of 3-fluoro-3-dexoy-sorbitol in all the cell
      lines examined in this study. The relative amounts of sorbitol and fructose
      varied significantly among the cells. The data confirm that the polyol pathway is
      present in both myelocytic and lymphocytic leukemia cell lines. However, there is
      a large variation among the cell lines in the levels of enzymes and flux of
      glucose through the polyol pathway.

PMID- 12604224
TI  - Further characterization of Chinese hamster carbonyl reductases (CHCRs).
AB  - Three cDNAs encoding carbonyl reductases (CHC1-3) have been isolated and
      expressed in bacterial cells. The recombinant enzymes were further characterized
      with respect to substrate specificity, inhibitor sensitivity and response to
      pyruvate. In addition, the expression of the mRNAs of CHCRs encoding in brain,
      liver and kidney was analyzed by RT-PCR. Searches of EST files revealed that
      orthologues of both CHCR3 and human CBR3 are expressed in variety of human cells
      and tissues.

PMID- 12604225
TI  - Examination of the differences in structure-function of human and rat 3alpha
      hydroxysteroid dehydrogenase.
AB  - Human 3alpha-hydroxysteroid dehydrogenases (HSDs) are potential drug targets
      since they regulate the occupancy and trans-activation of steroid hormone
      receptors by interconverting potent hormones with their cognate inactive
      metabolites. The human isoforms (AKR1C1-4) are all members of the aldo-keto
      reductase superfamily and display distinctive differences in steroid specificity
      and catalytic efficiency when compared with the closely related and more
      extensively studied rat 3alpha-HSD (AKR1C9). Specifically, AKR1C1-4 display
      3alpha-, 17beta- and 20alpha-HSD activities to varying degrees whereas AKR1C9 is
      positional- and stereo-specific for the 3alpha-HSD reaction. In addition, AKR1C1
      4 isoforms have significantly lower catalytic efficiencies (k(cat)/K(m)) than
      AKR1C9 and this is largely due to a lower k(cat). To understand these functional
      differences, human type 3 3alpha-HSD (AKR1C2) was studied as a representative
      human 3alpha-HSD. Comparison of the crystal structure of AKR1C2-NADP(+)
      ursodeoxycholate ternary complex (3.0 A) with that of the AKR1C9-NADP(+)
      testosterone ternary complex (2.8 A) demonstrates the expected conservancy in
      overall structure and active site topology. More interestingly, it reveals
      striking differences in the structure of the steroid binding pockets of the two
      enzymes and shows how ursodeoxycholate binds 'backwards' and 'upside-down' with
      respect to testosterone. This difference in steroid binding provides a structural
      basis for the broad positional specificity of AKR1C2 and the exquisite
      stereospecificity of AKR1C9. To determine why AKR1C2 has a much lower k(cat) than
      AKR1C9, the events associated with the binding of cofactor to both enzymes were
      studied by steady state fluorescence titration and stopped-flow experiments.
      Comparable K(d) values for E-NADP(H) and k(obs) values for the fluorescence
      transients were obtained for the two enzymes. These data are consistent with both
      enzymes binding NADP(H) in a conserved manner which is supported by the available
      crystal structures. The results suggest that cofactor binding or release for the
      human and rat 3alpha-HSDs are similar and do not account for the observed
      differences in k(cat).

PMID- 12604226
TI  - Steroid-binding site residues dictate optimal substrate positioning in rat 3alpha
      hydroxysteroid dehydrogenase (3alpha-HSD or AKR1C9).
AB  - Rat liver 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD or AKR1C9), a member of
      the aldo-keto reductase (AKR) superfamily, plays a pivotal role in the
      inactivation of circulating steroid hormones. It is the most thoroughly
      characterized HSD of the AKR superfamily and can be used as a template for
      structure-function studies in other AKR members such as rodent and human 3alpha-,
      17beta- and 20alpha-HSDs. Based on the crystal structure of the E.NADP(+)
      testosterone ternary complex, there are ten residues that line the testosterone
      binding cavity: T24, L54, Y55, H117, F118, F129, T226, W227, N306 and Y310. Each
      residue in the cavity, except for the catalytic residues Y55 and H117, was
      systematically mutated to alanine to determine the role of the individual
      residues in steroid recognition. Binding data and kinetic parameters (K(d),
      k(cat), K(m) and k(cat)/K(m)) of the homogeneous mutants were compared with that
      of the wild type (WT) enzyme. Titration of the intrinsic tryptophan fluorescence
      with NADPH demonstrated that cofactor binding was unaltered. However, binding of
      the steroid hormones testosterone and progesterone to the E.NADPH binary complex
      was affected to varying degrees. The largest effects on K(d) were an 8-fold
      decrease in affinity for testosterone and a 50-fold decrease in affinity for
      progesterone. The mutants bound both hormones in the same rank-order except for
      W227A, where the binding of progesterone was more adversely affected. A series of
      3alpha-hydroxysteroid substrates (A/B trans- and cis-ring fused C(19) and C(21)
      steroids) were used to determine the ability of each mutant to catalyze steroid
      turnover. The alanine mutants that retained k(cat)/K(m) values similar to WT were
      those in which alanine substituted short polar residues such as T24A and T226A.
      The mutants with the lowest catalytic efficiencies were those in which alanine
      substituted aromatic residues such as W227A and F129A. The loss in catalytic
      efficiency was due to large changes in k(cat) (up to 1000-fold), but not K(m).
      Molecular modeling of the alanine mutants showed that changes in the reaction
      trajectory defined by the angles and distances by groups that participate in
      catalysis correlate with changes in k(cat). These results highlight the
      importance of steroid binding site residues in dictating the proper orientation
      of substrates to achieve high catalytic turnover while having minimal effects on
      hormone affinity.

PMID- 12604227
TI  - Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen
      metabolism of prostate cancer cells.
AB  - Four human aldo-keto reductases (AKRs) that belong to the AKR1C subfamily
      function in vitro as 3-keto-, 17-keto- and 20-ketosteroid reductases or as 3alpha
      , 17beta- and 20alpha- hydroxysteroid oxidases to varying degrees. By acting as
      ketosteroid reductases or hydroxysteroid oxidases these AKRs can either convert
      potent sex hormones (androgens, estrogens and progestins) into their inactive
      metabolites or they can form potent hormones by catalyzing the reverse reaction.
      In this manner they may regulate occupancy and trans-activation of steroid
      hormone receptors. Tissue distribution studies previously indicated that AKR1C2
      (type 3 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD)) and AKR1C3 (type 2
      3alpha-HSD) are highly expressed in human prostate. An assessment of the
      directionality of these AKR1C isozymes in a cellular environment would help
      identify which isozymes are responsible for 5alpha-dihydrotestosterone (5alpha
      DHT) formation or its elimination in the prostate. An imbalance in 5alpha-DHT
      levels has been implicated in development of prostate carcinoma and benign
      prostatic hyperplasia. We focused our attention on AKR1C2 since this is the
      isoform that will oxidize 3alpha-androstanediol (3alpha-diol) to 5alpha-DHT in
      vitro, suggesting it could elevate 5alpha-DHT levels. To determine whether AKR1C2
      preferentially functions as a reductase or an oxidase in a cellular context, we
      transiently transfected AKR1C2 (pcDNA3-AKR1C2) into COS-1 cells and stably
      transfected pcDNA3-AKR1C2 and pLNCX-AKR1C2 constructs into PC-3 and LNCaP cells,
      respectively. COS-1 is a monkey kidney cell line, while PC-3 and LNCaP cells are
      androgen receptor (-) and (+) prostate adenocarcinoma cell lines, respectively.
      In transient COS-1-AKR1C2 and in stable PC3-AKR1C2 transfectants, AKR1C2
      functioned as a 3-ketosteroid reductase inactivating 5alpha-DHT. In androgen
      dependent human prostate cancer cells LNCaP, it was not possible to ascertain the
      preferred direction of AKR1C2 by stable transfection due to the high rate of
      5alpha-DHT and 3alpha-diol glucuronidation. Based on these findings AKR1C2 may
      diminish 5alpha-DHT and prevent this ligand from activating the androgen receptor
      in situ.

PMID- 12604228
TI  - Regulation of 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase in Comamonas
      testosteroni: function and relationship of two operators.
AB  - Comamonas testosteroni 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase
      (3alpha-HSD/CR) is a key enzyme in the degradation of steroid compounds in soil,
      and may therefore play a significant role in the bioremediation of hormonally
      active substances in the environment. We previously reported the isolation of the
      3alpha-HSD/CR gene (hsdA) from C. testosteroni and two repressor genes, repA and
      repB, for hsdA transcriptional and translational regulation, respectively. In
      this work, we found that the expression of 3alpha-HSD/CR is closely connected to
      the distance between two 10 bp operator elements (OP1 and OP2) to which the RepA
      protein binds and therefore blocks the transcription of hsdA. The two 10 bp
      palindromic operator sequences are located upstream of hsdA (at 0.935 kb and at
      2.568 kb on an EcoRI fragment) and are separated by 1.644 kb. In order to
      elucidate how the distance between OP1 and OP2 influences the repression of hsdA
      expression, we used E. coli cells transformed with plasmids carrying a set of
      deletions between OP1 and OP2. Our theory that a 'loop-structure' between the two
      operators is formed, which strongly influences hsdA transcriptional regulation,
      was proved by the increasing amounts of 3alpha-HSD/CR expression when the
      distance between the operators was too small to form the 'loop' structure.
      Moreover, additional -3, -5 and -7 nt deletions in each construct, known to
      result in DNA rotations and leading to altered orientations between the two
      operator sequences, reveal strong influences on hsdA expression the shorter the
      distance between the operators was. Our results demonstrate that a cis-regulating
      'stem-loop' operator system is an important determinant in the regulation of the
      3alpha-HSD/CR gene in Comamonas testosteroni.

PMID- 12604229
TI  - Characterization and recombinant expression of the translational repressor RepB
      of 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase in Comamonas
      testosteroni.
AB  - 3alpha-Hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) from
      Comamonas testosteroni is a key enzyme involved in the degradation of steroids
      and xenobiotic carbonyl compounds. The gene of 3alpha-HSD/CR (hsdA) was cloned
      and characterized by our group. We have also reported that two repressor proteins
      (RepA and RepB) have been identified which regulate hsdA expression. To further
      characterize RepB, the protein was expressed in Escherichia coli and purified in
      an active state. Gel shift experiments showed that RepB binds to a 16 nucleotide
      sequence downstream of AUG of the hsdA mRNA, providing evidence that RepB acts on
      the translational level. The addition of testosterone to the culture medium led
      to a derepression. Furthermore, a plasmid was prepared containing a point
      mutation that inactivates only repA, but has no effect on hsdA, with which it
      happens to partly overlap. The result of coexpression experiments with this
      construct and a plasmid containing the genetic information for RepB showed that
      RepB is still active and is therefore not dependent on a functional RepA. In
      conclusion, RepB is a novel regulatory protein that inhibits the translation of
      hsdA mRNA, thereby leading to a decreased expression of 3alpha-HSD/CR.

PMID- 12604230
TI  - Purification, characterization and NNK carbonyl reductase activities of 11beta
      hydroxysteroid dehydrogenase type 1 from human liver: enzyme cooperativity and
      significance in the detoxification of a tobacco-derived carcinogen.
AB  - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) physiologically
      catalyzes the interconversion of receptor-active 11-hydroxy glucocorticoids
      (cortisol) to their receptor-inactive 11-oxo metabolites (cortisone), thereby
      acting as important pre-receptor control device in regulating access of
      glucocorticoid hormones to the glucocorticoid receptor. Evidence is emerging that
      11beta-HSD 1 fulfills an additional role in the detoxification of non-steroidal
      carbonyl compounds, by catalyzing their reduction to the corresponding hydroxy
      derivatives that are easier to conjugate and eliminate. Whereas a number of
      methods were ineffective in purifying 11beta-HSD 1 from human liver, this
      membrane-bound enzyme was successfully obtained in an active state by a
      purification procedure that took advantage of a gentle solubilization method as
      well as providing a favourable detergent surrounding during the various
      chromatographic steps. We could demonstrate that 11beta-HSD 1 is active as a
      dimeric enzyme which exhibits cooperativity with cortisone and
      dehydrocorticosterone (11-oxoreducing activity) as substrates. Accordingly, this
      enzyme dynamically adapts to low (nanomolar) as well as to high (micromolar)
      substrate concentrations, thereby providing the fine tuning required as a
      consequence of great variations in circadian plasma glucocorticoid levels. Due to
      this kinetic peculiarity, 11beta-HSD 1 is also able to even metabolize nanomolar
      concentrations of the tobacco-specific nitrosamine 4-methylnitrosamino-1-(3
      pyridyl)-1-butanone (NNK), a fact which is important in view of the relatively
      low levels of this carcinogen observed in smokers. Finally, 11beta-HSD 1 is
      potently (in nM concentrations) inhibited by glycyrrhetinic acid, the main
      constituent of licorice. Licorice, however, in addition to being a confectionary,
      serves as a major cigarette additive, which is used in cigarette manufacturing as
      a taste and flavour intensifier. Hence, licorice exposure may affect NNK
      detoxification by inhibition of 11beta-HSD 1, a condition which may advance lung
      cancer incidence, especially in smokers expressing low levels of this enzyme.
      Collectively, our data expand insights into the multifunctional nature of
      hydroxysteroid dehydrogenases/carbonyl reductases and emphasize the importance of
      11beta-HSD 1 in the detoxification of a tobacco-derived carcinogen, in addition
      to its endocrinological functions.

PMID- 12604231
TI  - 11beta-Hydroxysteroid dehydrogenase type 1: tissue-specific expression and
      reductive metabolism of some anti-insect agent azole analogues of metyrapone.
AB  - The azole analogues of metyrapone are novel candidates for selective anti-insect
      agents that inhibit the synthesis of 20-hydroxyecdysone (20E), the moulting
      hormone of insects. Metyrapone, which is a model substrate for studying the
      reductive properties of oxidoreductases, is itself effectively reduced to the
      corresponding alcohol by the enzyme 11beta-hydroxysteroid dehydrogenase type 1
      (11beta-HSD 1). For this reason, the ability of 11beta-HSD 1 to metabolize the
      metyrapone analogues as well was studied. In addition, the expression (by Western
      blots) and activity (reduction/oxidation of dehydrocorticosterone/corticosterone)
      of 11beta-HSD 1 in different male and female mouse tissues were investigated.
      Xenobiotic carbonyl reductase activities in these tissues were assessed with
      metyrapone as a model substrate. The kinetic parameters of 11beta-HSD 1 with
      metyrapone analogues as substrates were calculated after high-pressure liquid
      chromatography (HPLC) determination of the product alcohols. Our results indicate
      that the novel insecticides are extensively metabolized by mouse 11beta-HSD 1.
      Moreover, the resulting alcohols are not only less toxic than the parent ketones
      but also have the potential, owing to the newly formed hydroxyl group, to be
      eliminated from the body by consecutive phase II reactions. Thus, the new
      metyrapone analogues may be potential anti-insect agents, safer for humans due to
      their reductive detoxification, mainly by the hepatic 11beta-HSD 1, and
      selectively affecting insect development by inhibiting ecdysone 20-monooxygenase
      (E-20-M).

PMID- 12604232
TI  - Stereochemical aspects of carbonyl reduction of the original anticancer drug
      oracin by mouse liver microsomes and purified 11beta-hydroxysteroid dehydrogenase
      type 1.
AB  - Oracin, 6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2-c]
      isoquinoline, is a potential cytostatic drug for oral use and presently in phase
      II of clinical trials. Major advantages of this novel chemotherapeutic are the
      possibility of oral administration, its negative results in the Ames test on
      mutagenicity, and the lack of cardiotoxicity. Metabolic studies on oracin have
      revealed that the principal metabolite in all laboratory animals is 11
      dihydrooracin (DHO), which is produced by carbonyl reduction of the parent
      compound. Since the carbonyl moiety of oracin is a pro-chiral centre, reduction
      may lead to the two stereoisomer forms (+)-DHO and (-)-DHO. The aim of the
      present study was to infer if 11beta-hydroxysteroid dehydrogenase type 1 (11beta
      HSD 1) is responsible for carbonyl reduction of oracin in mouse liver and if this
      enzyme exhibits stereospecificity in DHO formation. 11beta-HSD 1 was purified
      from mouse liver microsomes, and the kinetics and stereospecificity regarding DHO
      formation were determined and compared to values obtained from the whole
      microsomal fraction. We could show that purified mouse liver 11beta-HSD 1
      catalyzes the stereospecific carbonyl reduction of oracin, thereby following a
      sigmoidal dose-response kinetics. Due to a different ratio of (+)-DHO and (-)-DHO
      (93:7) formed by purified 11beta-HSD 1 compared to that produced in whole
      microsomes (70:30), the existence of at least one other oracin carbonyl reducing
      enzyme can be expected in mouse liver microsomes. This suggestion is further
      supported by the fact that the Hill coefficient of 2 for purified 11beta-HSD 1
      (which is supporting earlier data on the cooperativity of this dimeric enzyme)
      changes to a Hill coefficient of 3 in whole microsomes (which is indicative for
      another enzyme participating in oracin carbonyl reduction).

PMID- 12604233
TI  - The critical role of the N-terminus of 11beta-hydroxysteroid dehydrogenase type
      1, as being encoded by exon 1, for enzyme stabilization and activity.
AB  - 11beta-Hydroxysteroid dehydrogenase type 1 catalyzes the conversion of cortisone
      to hormonally active cortisol and has been implicated in the pathogenesis of a
      number of disorders, including insulin resistance and obesity. Because 11beta-HSD
      1 is a membrane protein with a very hydrophobic character, it is difficult to
      purify it in an active state. Not much is known about the topological and
      structural determinants of 11beta-HSD 1, although the elucidation of the
      structure of 11beta-HSD 1 would be a great advantage in identifying specific
      11beta-HSD 1 inhibitors. Bacterial expression of full-length or truncated 11beta
      HSD 1 forms only led to insoluble proteins or to low amounts of enzyme, not
      sufficient for crystallization. Recently, we reported that the solubility of
      11beta-HSD 1 could be increased by substitution of hydrophobic amino acid
      residues with arginine without affecting activity. Unfortunately, these truncated
      and soluble forms of 11beta-HSD 1 exhibited an unstable activity that declined
      very rapidly. So far, the proteins obtained were not suitable for
      crystallization. To obtain 11beta-HSD 1 in an active and soluble state, in the
      present investigation we focused on the amino acid sequence encoded by the first
      exon. Using bacterial and yeast expression systems, we found that this N-terminal
      peptide could be divided into two parts that have functions other than to anchor
      11beta-HSD 1 into the ER membrane. The first hydrophobic part, consisting of
      amino acid residues 1-15, represents the membrane spanning domain and anchors
      11beta-HSD 1 in the ER membrane. The second hydrophilic part of the peptide,
      consisting of amino acid residues 16-30, plays a crucial role in stabilizing the
      catalytic domain of 11beta-HSD 1 and in addition, acts as a spacer to keep the
      catalytic domain of 11beta-HSD 1 into the lumen of the ER. Evidently, we found
      that the hydrophilic amino acids 24-30 determine 11beta-HSD 1 enzyme activity.
      Combined, all information obtained should help to design an optimal 11beta-HSD 1
      enzyme in the near future with all desired attributes: soluble, active and easy
      to obtain and purify in sufficient amounts. This soluble and active 11beta-HSD 1
      form should be the basis for our ongoing project, which is the determination of
      the three dimensional structure of 11beta-HSD 1.

PMID- 12604234
TI  - 17-beta-Hydroxysteroid dehydrogenase type 1: computational design of active site
      inhibitors targeted to the Rossmann fold.
AB  - 17-beta-Hydroxysteroid dehydrogenase type 1 (17betaHSD1), also called estradiol
      dehydrogenase, catalyzes the NADPH-dependent reduction of the weak estrogen,
      estrone, into the more potent estrogen, 17-beta-estradiol. 17betaHSD1 is an
      attractive drug target in hormone-sensitive breast cancer. Past efforts to
      develop selective inhibitors of 17betaHSD1 have focused on design of substrate
      analogs. It is challenging to develop steroid analogs that are devoid of any
      undesired biological activity. 17betaHSD1 is a member of the short-chain
      dehydrogenase/reductase (SDR) superfamily that includes many hydroxysteroid
      dehydrogenases. Members of the SDR family bind NAD(P)(H) in a motif that is a
      modified Rossmann fold. We demonstrated previously that the Rossmann folds of
      classical dehydrogenases can be selectively inhibited by derivatives and analogs
      of the natural product gossypol. In this study, we have addressed the question
      whether the modified Rossmann fold in 17betaHSD1 is a target for identification
      of lead compounds for structure-based drug design. 17betaHSD1 was purified from
      human placenta. 17betaHSD1 is inhibited by derivatives of gossypol with
      dissociation constants as low as 2 microM. Inhibition is competitive with the
      binding of cofactor. Molecular modeling studies using the published coordinates
      of human 17betaHSD1 suggest that these inhibitors occupy the modified Rossmann
      fold at the nicotinamide end of the dinucleotide-binding site, extending towards
      the substrate site. A computational approach was used to design potential new
      inhibitors of 17betaHSD1. The results suggest not only that derivatives of
      gossypol represent attractive lead compounds for structure-based drug design but
      also suggest that appropriate incorporation of a substrate analog into the design
      of these Rossmann fold inhibitors may provide pan-active site inhibitors that
      span the cofactor and substrate site, potentially offering specificity and
      increased potency.

PMID- 12604235
TI  - Significance of individual amino acid residues for coenzyme and substrate
      specificity of 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus
      lunatus.
AB  - 17beta-Hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta
      HSDcl) is a NADPH dependent member of the short-chain dehydrogenase reductase
      (SDR) superfamily. Recently, we prepared a homology-built structural model of
      17beta-HSDcl using the known three-dimensional structure of homologous 1,3,8
      trihydroxynaphthalene reductase from the fungus Magnaporthe grisea. This model
      structure directed our studies of structure-function relationship of the fungal
      17beta-HSD, as one of the model enzymes of the SDR superfamily. In this work, we
      investigated the significance of individual amino acid residues for coenzyme and
      substrate specificity. We performed site directed mutagenesis of R28, a basic
      residue conserved in most NADPH dependent SDR structures; T200, found only in
      Streptomyces hydrogenans 3alpha,20beta-HSD and Drosophila alcohol dehydrogenases;
      and H230, a residue corresponding to the substrate specificity important H221 in
      human 17beta-HSD type 1. All recombinant proteins were expressed in Escherichia
      coli and purified to homogeneity. Kinetic evaluation of individual mutations was
      performed by analysis of progress curves of interconversions between 4-estrene
      3,17-dione and 4-estrene-17beta-ol-3-one, in the presence of NADPH and NADP(+);
      according to the Theorell-Chance reaction mechanism. The results demonstrate the
      role of the selected amino acid residues; R28 seems to interact with the NADPH 2'
      phosphate group; T200 may be involved in binding and dissociation of
      NADPH/NADP(+); while H230 and the neighboring A231 appears not to be responsible
      for substrate specificity of 17beta-HSDcl.

PMID- 12604236
TI  - Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase
      (AKR1C1) that metabolizes neurosteroids derived from progesterone.
AB  - Neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha
      THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone have been shown to be
      synthesized from progesterone in animal brains. Comparison of kinetic constants
      for the neuroactive steroids and their precursors among four human 3(20)alpha
      hydroxysteroid dehydrogenases (AKR1C1-AKR1C4) suggests that AKR1C1 and AKR1C2 are
      involved in the catabolism and synthesis, respectively, of the neuroactive
      steroids in the human brain. In our efforts to identify agents that would
      specifically inhibit the two enzymes, benzbromarone and 3',3",5',5"
      tetrabromophenolphthalein were found to be relatively selective and potent
      inhibitors of AKR1C1. Kinetic analyses in the oxidoreduction catalyzed by AKR1C1
      in the presence of the inhibitors suggest that the inhibitors bind to the enzyme
      NADP(H) complex (K(i)=0.7 nM) in the ordered bi-bi pathway, including an
      isomerization step. The inhibitors effectively also decreased the reduction of
      3alpha,5alpha-THP to its 20alpha-hydroxy metabolite in HepG2 cells treated with
      ethacrynic acid.

PMID- 12604237
TI  - The xylose reductase (AKR2B5) structure: homology and divergence from other aldo
      keto reductases and opportunities for protein engineering.
AB  - The structure of xylose reductase from Candida tenuis (AKR2B5) has been
      determined and refined to 2.2 A resolution, both in holo and apo forms. These
      structures allow the recognition of numerous hydrophilic residues responsible for
      dimerization, a novel feature for the superfamily of enzymes. The residues
      allowing for dual NADH/NADPH cosubstrate specificity are also identified. Since
      xylose reductase functions in conjunction with an NAD(+)-specific xylitol
      dehydrogenase in the xylose assimilation pathway, this is a key step in
      engineering an enzyme specific for only NADH which will permit cosubstrate
      recycling between the two enzymes in a high-flux pathway. The structure of xylose
      reductase, combined with others in the superfamily provides an opportunity to
      examine and compare structural divergence as a function of sequence homology. It
      also suggests that the dimeric aldo-keto reductases (AKRs) from families 2 and 7
      evolved from a common dimeric ancestor.

PMID- 12604238
TI  - Altering dimer contacts in xylose reductase from Candida tenuis by site-directed
      mutagenesis: structural and functional properties of R180A mutant.
AB  - Xylose reductase (XR) from Candida tenuis (CtXR) is a structurally characterized
      member of family 2 of the aldo-keto reductase (AKR) superfamily of proteins, its
      family designation being AKR2B5. The enzyme is composed of two identical subunits
      that contact each other in a largely hydrated, predominantly polar interface. An
      important question not clearly answered by CtXR structure pertains to the
      relationship of oligomerization and enzyme activity. In an effort to destabilize
      the wild-type dimer, the most important secondary structural element of the CtXR
      interface, the alpha5 helix, was altered by site-directed mutagenesis. Ala-173
      and Leu-174 were replaced individually by arginine, and Arg-180 was changed into
      alanine. A173R and L174R mutants did not fold properly during recombinant protein
      production in Escherichia coli and could not be isolated. Like the wild type, the
      R180A mutant is a dimer in solution which does not dissociate into subunits under
      mild urea conditions (</=2 M). Catalytic efficiency (k(cat)/K(xylose)) and
      turnover number (k(cat)) of the R180A mutant for NADH-dependent reduction of D
      xylose are both approximately 2.5-fold decreased compared to corresponding
      kinetic parameters of the wild type. Differences in kinetic isotope effects for
      the mutant (Dk(cat)=1.0; Dk(cat)/K(xylose)=1.9) and the wild type (Dk(cat)=1.5;
      Dk(cat)/K(xylose)=2.8) suggest subtle changes in catalytic function as result of
      the mutation. Therefore, altering interactions at the dimer interface may have
      long range effects that were not predictable from the X-ray structure.

PMID- 12604239
TI  - Characterization of recombinant xylitol dehydrogenase from Galactocandida
      mastotermitis expressed in Escherichia coli.
AB  - The plasmid-encoded gene of xylitol dehydrogenase from the yeast Galactocandida
      mastotermitis was expressed in Escherichia coli at 25 degrees C. Recombinant
      enzyme was isolated in 70% yield using two steps of biomimetic affinity
      chromatography with the dye ligand Procion Red HE3B immobilized onto Sepharose 4B
      CL. Similar to natural enzyme, recombinant xylitol dehydrogenase is a functional
      homotetramer with a stoichiometric content of catalytic zinc in each 37-kDa
      subunit. Though lacking bound Mg(2+) found in xylitol dehydrogenase isolated from
      yeast cell extracts, the recombinant enzyme is as active and stable as the native
      enzyme. Stereospecificity of enzymic hydrogen transfer from NADH has been
      determined by 1H-NMR and is 4-pro-R. A detailed steady-state kinetic analysis has
      been carried out for the enzymic reaction, polyol+NAD(+)<-->ketose+NADH+H(+), at
      pH 7.5 and 25 degrees C using xylitol and D-xylulose, the physiological polyol
      ketose pair, as well as D-sorbitol and D-fructose. Primary deuterium kinetic
      isotope effects on steady-state kinetic parameters for oxidation of D-sorbitol
      and reduction of D-fructose have been measured at pH 7.5. Combined results of
      initial-rate analysis and isotope effect studies suggest that the enzyme utilizes
      a preferentially ordered kinetic mechanism in which NAD(+) binds before D
      sorbitol and D-fructose is released before NADH. Dissociation of NADH appears to
      be the main rate-limiting step for D-sorbitol oxidation under substrate-saturated
      reaction conditions.

PMID- 12604240
TI  - Identification of amino acid residues involved in substrate recognition of L
      xylulose reductase by site-directed mutagenesis.
AB  - L-Xylulose reductase (XR) catalyzes the oxidoreduction between xylitol and L
      xylulose in the uronate cycle. The enzyme has been shown to be identical to
      diacetyl reductase, an enzyme that reduces alpha-dicarbonyl compounds. XR belongs
      to the short-chain dehydrogenase/reductase family, and shows high sequence
      identity with mouse lung carbonyl reductase (MLCR), an enzyme that reduces 3
      ketosteroids but not sugars. In this study, we have confirmed the roles of
      Ser136, Tyr149 and Lys153 of XR as the catalytic triad by drastic loss of
      activity resulting from the mutagenesis of S136A, Y149F and K153M in rat XR. We
      have also constructed several mutant XRs, in which putative substrate binding
      residues from rat XR were substituted with those found in the corresponding
      positions of MLCR, in order to identify amino acids responsible for the different
      substrate recognition of the enzymes. While single mutants at positions 137, 143,
      146, 190 and 191 caused little or moderate change in substrate specificity, a
      double mutant (N190V and W191S) and triple mutant (Q137M, L143F and H146L)
      resulted in almost loss of activity for only the sugars. In addition, the triple
      mutant exhibited 3-ketosteroid reductase activity, which was further enhanced by
      quintuple mutagenesis of the above five residues. These results suggest the
      importance of the size and hydrophobicity of the five residues for substrate
      recognition by XR and MLCR. Furthermore, the mutant enzymes containing a Q137M
      mutation were stable against cooling, which provides a structural mechanism of
      the cold inactivation that is a characteristic of the rodent XR.

PMID- 12604241
TI  - Crystal structure of Pseudomonas fluorescens mannitol 2-dehydrogenase: evidence
      for a very divergent long-chain dehydrogenase family.
AB  - Mannitol 2-dehydrogenase from Pseudomonas fluorescens (pfMDH) is a secondary
      alcohol dehydrogenase that catalyzes the reversible NAD(P)-dependent oxidation of
      D-mannitol to D-fructose, D-arabinitol to D-xylulose, and D-sorbitol to L
      sorbose. It is a member of the mostly prokaryotic family of long-chain mannitol
      dehydrogenases that so far includes 66 members. Unlike other alcohol and polyol
      dehydrogenases that utilize metal cofactors or a conserved active-site tyrosine
      for catalysis, an invariant lysine is the general base. The crystal structure of
      pfMDH in a binary complex with NAD(H) and a ternary complex with NAD(H) and D
      mannitol have been determined to 1.7 and 1.8 A resolution respectively.
      Comparison of secondary structure assignment to sequence alignments suggest the
      shortest members of this family, mannitol-1-phosphate 5-dehydrogenases, retain
      core elements but lack secondary structural components found on the surface of
      pfMDH. The elements predicted to be absent are distributed throughout the primary
      sequence, implying that a simple truncation or fusion did not occur. The closest
      structural neighbors are 6-phosphogluconate dehydrogenase, UDP-glucose
      dehydrogenase, N-(1-D-carboxyethyl)-L-norvaline dehydrogenase, and glycerol-3
      phosphate dehydrogenase. Although sequence identity is only a barely recognizable
      7-10%, conservation of secondary structural elements as well as homologous
      residues that are contributed to the active site indicates they may be related by
      divergent evolution.

PMID- 12604242
TI  - Pseudomonas fluorescens mannitol 2-dehydrogenase and the family of polyol
      specific long-chain dehydrogenases/reductases: sequence-based classification and
      analysis of structure-function relationships.
AB  - Multiple sequence alignment and analysis of evolutionary relationships have been
      used to characterize a family of polyol-specific long-chain
      dehydrogenases/reductases (PSLDRs). At the present time, 66 known and putative
      NAD(P)H-dependent oxidoreductases of mainly prokaryotic origin and between 357
      and 544 amino acids in length constitute this family. The family is shown to
      include D-mannitol 2-dehydrogenase, D-mannonate 5-oxidoreductase, D-altronate 5
      oxidoreductase, D-arabinitol 4-dehydrogenase, and D-mannitol-1-phosphate 5
      dehydrogenase which form individual sub-families (defined by internal sequence
      identity of >/=30%) having distant origin and divergent substrate specificity but
      clearly displaying entire-chain relationship. When all forms are aligned, only
      three residues, Gly-33, Asp-230, and Lys-295 (in the numbering of Pseudomonas
      fluorescens D-mannitol 2-dehydrogenase (PsM2DH)) are strictly conserved. By
      combining sequence alignment with the known structure of PsM2DH and results from
      site-directed mutagenesis, we have developed a structure/function analysis for
      the family. Gly-33 is in the N-terminal coenzyme-binding domain and part of a
      nucleotide fingerprint region for the family, and Asp-230 and Lys-295 are at an
      interdomain segment contributing to the active site in which the lysine likely
      functions as the catalytic general acid/base. PSLDRs do not require a metal
      cofactor for activity and are specific for transferring the 4-pro-S hydrogen from
      NAD(P)H. Comparisons reveal that the core part of the two-domain fold has been
      conserved throughout all family members, perhaps reflecting the recruitment of a
      stable oxidoreductase structure and extensive trimming thereof to acquire
      functional properties specific to each sub-family. They also identify
      interactions that define the chemical mechanism of oxidoreduction and likely
      contribute to substrate and co-substrate specificities and are thus relevant for
      protein engineering.

PMID- 12604243
TI  - Effect of antisense oligodeoxynucleotide for sepiapterin reductase on the
      viability of PC12 cells in the presence of exogenous carbonyl compounds.
AB  - Sepiapterin reductase (SPR) is known as an essential enzyme for the biosynthesis
      of tetrahydrobiopterin. SPR belongs to the short-chain dehydrogenase/reductase
      (SDR) family and also reduces various exogenous carbonyl compounds including
      phenylpropanedione. We found in the present study that phenylpropanedione
      decreased the rate of proliferation of PC12 cells and that this rate was further
      diminished by the transfection of the cells with antisense oligodeoxynucleotide
      for SPR mRNA. When the cells were treated with N-acetylserotonin, a specific
      inhibitor of SPR, in the presence of phenylpropanedione, the cell number
      decreased to almost the same level as when the cells were transfected with the
      antisense oligodeoxynucleotide. Thus, the SDR activity of SPR in PC12 cells may
      serve for detoxification of exogenous carbonyl compounds besides functioning as a
      specific enzyme for the formation of tetrahydrobiopterin.

PMID- 12604245
TI  - Protein kinase C-dependent phosphorylation of the beta-subunit of the voltage
      sensitive potassium channels (Kvbeta2).
AB  - The K(v)beta proteins are members of the aldo-keto reductase (AKR) superfamily
      that interact with the cytoplasmic face of the pore-forming alpha-subunits of the
      voltage-sensitive K(+) channels. The physiological functions of K(v)beta are
      unclear, although some members of the K(v)beta family impart rapid inactivation
      to non-inactivating K(+) channels. Structural analyses reveal that the NADPH
      binding site as well as the active site architecture and residues of other AKR
      proteins are conserved in the K(v)beta proteins. The K(v)beta2 displays high
      affinity NADPH binding, although no catalytic activity for this protein has been
      reported. Recent studies show that K(v)beta2 is constitutively associated with
      protein kinase C (PKC) zeta via the zeta-interacting protein (ZIP). The primary
      structure of K(v)beta displays 25 PKC consensus phosphorylation sites. We report
      that incubation of recombinant K(v)beta2 with PKCalpha in vitro leads to rapid
      phosphorylation of the protein. Stimulation of PKC by phorbol-12-myristate-13
      acetate (PMA) also induced the phosphorylation of K(v)beta2 expressed in COS-7
      cells. Deletion of the first 35 amino acids of the variable N-terminus led to a
      substantial decrease in the overall extent of phosphorylation in vitro,
      indicating that the N-terminus peptide is the preferred site of PKC
      phosphorylation. Analysis of the phosphorylated protein by HPLC coupled with an
      ion-trap electrospray mass spectrometer revealed phosphorylation of Ser-266
      located near the NADPH-binding site of the protein. We propose that
      phosphorylation could affect the N-terminus-mediated beta-alpha interactions or
      the binding of NADP(H) to the conserved AKR domain of the K(v)beta proteins.

PMID- 12604244
TI  - Aldose reductase mediates the mitogenic signals of cytokines.
AB  - Chronic hyperglycemia is associated with the activation of aldose reductase (AR),
      an increase in cytokines such as TNF-alpha and IL-8 and oxidative stress.
      Alterations in this interdependent cascade of signals may be responsible for the
      diabetes-induced increase in the incidence and severity of cardiovascular
      diseases such as atherosclerosis and hypertension. We have previously shown that
      inhibition of AR prevents cultured vascular smooth muscle cell (VSMC) growth and
      restenosis of balloon-injured carotid arteries. To identify the mechanisms by
      which inhibition of AR prevents cell growth, we examined the effects of AR
      inhibition on mitogenic signaling by cytokines. Stimulation with TNF-alpha led to
      the activation of the transcription factor NF-kappaB and enhanced VSMC growth.
      Treatment with the AR inhibitors sorbinil or tolrestat, attenuated mitogen
      induced activation of NF-kappaB and VSMC proliferation. In cultured VSMC, AR
      inhibitors prevented signaling events upstream of NF-kappaB activation, i.e.
      IkappaB-alpha phosphorylation and IkappaB-alpha degradation. Inhibition of AR
      also prevented protein kinase C (PKC) activation by TNF-alpha, but did not affect
      PKC activation by phorbol esters, indicating that inhibition of AR interrupts
      mitogenic signaling upstream of PKC. Together, these results indicate a pivotal
      role of AR or its reaction product(s) in the mitogenic signals initiated by
      cytokines that are elevated in diabetes and its cardiovascular complications such
      as atherosclerosis. These observations suggest a possible therapeutic use of AR
      inhibitors in these pathological conditions.

PMID- 12604247
TI  - Differential pyridine nucleotide coenzyme binding to the beta-subunit of the
      voltage-sensitive K+ channel: a mechanism for redox regulation of excitability?
AB  - The pore-forming subunits of the voltage-sensitive K(+) channel (K(v)) associate
      with ancillary beta-subunits that regulate inactivation and voltage-dependence of
      the channel. The beta-subunits are members of the aldo-keto reductase (AKR)
      superfamily. We have previously demonstrated that recombinant K(v)beta2.1
      displays tight binding to NADP(H). The protein also binds NAD(H), but with less
      affinity. To assess the physiological significance of this binding, we examined
      how pyridine nucleotides regulate the K(v)beta-mediated inactivation of K(+)
      channels. Transient transfection of COS-7 cells with an pIRES-hrGFP vector
      containing the Kvalpha1.5 cDNA led to the appearance of the K(v)1.5 protein in
      the membrane fraction and large non-inactivating potassium currents were recorded
      from the transfected cells. No such currents were observed in cells transfected
      with the empty vector alone or with K(v)beta1.3 (AKR6A3), which was localized to
      the cytoplasm. In contrast, K(v)beta1.3 co-transfected with Kvalpha1.5 was
      localized to the membrane, suggesting high affinity binding of the two proteins.
      Moreover, the K currents recorded from cells transfected with both K(v)alpha1.5
      and K(v)beta1.3 displayed pronounced inactivation. Inclusion of 1 mM NAD(+) in
      the internal solution of the patch pipette abolished K(v)beta-induced
      inactivation of K(v)1.5 currents, but did not affect the non-inactivating
      currents recorded from cells transfected with K(v)1.5 alone, indicating that in
      the absence of K(v)beta, NAD(+) does not affect the activity of K(v)alpha. The
      inactivating currents recorded from cells expressing both K(v)alpha1.5 and
      K(v)beta1.3 were unaffected by the inclusion of 0.1 mM NADPH in the pipette
      solution. Together, these data suggest that NADPH and NAD(+) impart different
      conformational states to the K(v)beta protein and that only the NADPH bound
      K(v)beta imparts inactivation to non-inactivating K(+) currents. Thus,
      differential binding of pyridine nucleotide coenzymes to K(v)beta could regulate
      membrane potential and excitability as a function of the cellular redox state.
      Because NAD(+)/NADPH ratio is sensitive to oxygen concentration, the differential
      changes in K(v)beta-mediated inactivation of K currents by NAD(+) and NADPH could
      represent an oxygen-sensing mechanism.

PMID- 12604246
TI  - Role of aldose reductase in TNF-alpha-induced apoptosis of vascular endothelial
      cells.
AB  - Apoptosis of vascular endothelial cells (VECs) and concomitant proliferation of
      the underlying vascular smooth muscle cells (VSMCs) in large arteries are the key
      features of atherosclerosis and restenosis. However, the mechanisms underlying
      endothelial cell death and abnormal smooth muscle cell proliferation during the
      development of vascular lesions remain unclear. We have previously demonstrated
      that treatment with inhibitors of the aldehyde-metabolizing enzyme and aldose
      reductase (AR) attenuates restenosis of balloon-injured rat carotid arteries. The
      inhibition of AR also prevents the apoptosis of VECs induced by the tumor
      necrosis factor-alpha (TNF-alpha). Apoptosis of the VECs was determined by the
      incorporation of [3H]-thymidine and the activation of caspase-3. Stimulation of
      the VECs with TNF-alpha led to an increase in the DNA-binding activity of the
      transcription factor, nuclear factor-kappa binding protein (NF-kappaB) and the
      induction of the adhesion molecule (ICAM)-1. Treatment of VECs with the AR
      inhibitor, tolrestat, prevented the activation of NF-kappaB and diminished ICAM-1
      induction stimulated by TNF-alpha. These results indicate an obligatory
      requirement of AR activity in the transduction of intracellular signaling
      initiated by the ligation of the TNF-alpha receptors leading to the activation of
      NF-kappaB. Although the specific signaling events interrupted by AR inhibition
      remain unknown, our results suggest that product(s) of AR catalysis may be
      essential for NF-kappaB activation. These observations could form the basis of
      future investigations into the therapeutic utility of AR inhibitors in preserving
      endothelial function and integrity during atherosclerosis and diabetes.

PMID- 12604248
TI  - The aldo-keto reductase superfamily homepage.
AB  - The aldo-keto reductases (AKRs) are one of the three enzyme superfamilies that
      perform oxidoreduction on a wide variety of natural and foreign substrates. A
      systematic nomenclature for the AKR superfamily was adopted in 1996 and was
      updated in September 2000 (visit www.med.upenn.edu/akr). Investigators have been
      diligent in submitting sequences of functional proteins to the Web site. With the
      new additions, the superfamily contains 114 proteins expressed in prokaryotes and
      eukaryotes that are distributed over 14 families (AKR1-AKR14). The AKR1 family
      contains the aldose reductases, the aldehyde reductases, the hydroxysteroid
      dehydrogenases and steroid 5beta-reductases, and is the largest. Other families
      of interest include AKR6, which includes potassium channel beta-subunits, and
      AKR7 the aflatoxin aldehyde reductases. Two new families include AKR13 (yeast
      aldose reductase) and AKR14 (Escherichia coli aldehyde reductase). Crystal
      structures of many AKRs and their complexes with ligands are available in the PDB
      and accessible through the Web site. Each structure has the characteristic
      (alpha/beta)(8)-barrel motif of the superfamily, a conserved cofactor binding
      site and a catalytic tetrad, and variable loop structures that define substrate
      specificity. Although the majority of AKRs are monomeric proteins of about 320
      amino acids in length, the AKR2, AKR6 and AKR7 family may form multimers. To
      expand the nomenclature to accommodate multimers, we recommend that the
      composition and stoichiometry be listed. For example, AKR7A1:AKR7A4 (1:3) would
      designate a tetramer of the composition indicated. The current nomenclature is
      recognized by the Human Genome Project (HUGO) and the Web site provides a link to
      genomic information including chromosomal localization, gene boundaries, human
      ESTs and SNPs and much more.

PMID- 12604249
TI  - Operational parameters affecting the performannce of a mediator-less microbial
      fuel cell.
AB  - A mediator-less microbial fuel cell was optimized in terms of various operating
      conditions. Current generation was dependent on several factors such as pH,
      resistance, electrolyte used, and dissolved oxygen concentration in the cathode
      compartment. The highest current was generated at pH 7. Under the operating
      conditions, the resistance was the rate-determining factor at over 500 omega.
      With resistance lower than 500 omega, proton transfer and dissolved oxygen (DO)
      supply limited the cathode reaction. A high strength buffer reduced the proton
      limitation to some extent. The DO concentration was around 6 mg l(-1) at the DO
      limited condition. The fact that oxygen limitation was observed at high DO
      concentration is believed to be due to the poor oxygen reducing activity of the
      electrode used, graphite. The current showed linear relationship with the fuel
      added at low concentration, and the electronic charge was well correlated with
      substrate concentration from up to 400 mg l(-1) of COD(cr). The microbial fuel
      cell might be used as a biochemical oxygen demand (BOD) sensor.

PMID- 12604250
TI  - Amperometric hydrogen peroxide biosensor with sol-gel/chitosan network-like film
      as immobilization matrix.
AB  - A new type of sol-gel/organic hybrid composite material based on the cross
      linking of natural polymer chitosan with (3-aoryloxypropyl) dimethoxymethylsilane
      was developed for the fabrication of an amperometric H(2)O(2) biosensor. The
      composite film was used to immobilize horseradish peroxidase (HRP) on a gold disk
      electrode. The properties of sol-gel/chitosan and sol-gel/chitosan-HRP films have
      been carefully characterized by atomic force microscopy and Fourier transform
      infrared. By using fluorescent label, a protein density on sol-gel/chitosan has
      been calculated to be 3.14 x 10(12) moleculescm(-2). With the aid of catechol
      mediator, the biosensor had a fast response of less than 2 s with linear range of
      5.0 x 10(-9)-1.0 x 10(-7) mol l(-1) and a detection limit of 2 x 10(-9) mol l(
      1). Its current response shows a typical Michaelis-Menten mechanism. The apparent
      Michaelis-Menten constant K(M)(app) is found to be 1.30 micromol l(-1). The
      activation energy for enzymatic reaction is calculated to be 8.22 kJ mol(-1). The
      biosensor retained approximately 75% of its original activity after about 60 days
      of storage in a phosphate buffer at 4 degrees C.

PMID- 12604251
TI  - Use of competitive inhibition for driving sensitivity and dynamic range of urea
      ENFETs.
AB  - An urea biosensor based on urease-BSA (bovine serum albumin) membrane immobilised
      on the surface of an ion-sensitive field effect transistor (ISFET) has been
      studied in a mix buffer solution composed of potassium phosphate, Tris, citric
      acid and sodium tetraborate. In this mix buffer, the biosensor showed a dynamic
      larger than the one observed in a phosphate or Tris buffer. Investigation of the
      individual effect of each component of the buffer solution on the biosensor
      response has shown that tetraborate anion acts as a strong competitive inhibitor
      for the hydrolysis reaction of urea catalysed by urease. The biosensor response
      was investigated in a phosphate buffer with different concentrations of
      tetraborate anion. The results showed that the apparent constant of Michaelis
      Menten, K(m(app)), increases from 4.3 to 79.3 mM, for experiments realised
      without and with 0.5 mM sodium tetraborate, respectively. The mean value,
      determined graphically, for the inhibition constant, K(i), was 29 microM. The
      graphical representation of biosensor calibration curves in semilogarithmic co
      ordinates showed that the linear range of the biosensor can be extended up to
      three orders of magnitude, allowing an urea detection in a concentration range 0
      100 mM.

PMID- 12604253
TI  - Surface functionalization of polypyrrole film with glucose oxidase and viologen.
AB  - A surface modification technique was developed for the functionalization of
      polypyrrole (PPY) film with glucose oxidase (GOD) and viologen moieties. The PPY
      film was first graft copolymerized with acrylic acid (AAc) and GOD was then
      covalently immobilized through the amide linkage formation between the amino
      groups of the GOD and the carboxyl groups of the grafted AAc polymer chains in
      the presence of a water-soluble carbodiimide. Viologen moieties could also be
      attached to the PPY film via graft-copolymerization of vinyl benzyl chloride with
      the PPY film surface followed by reaction with 4,4'-bipyridine and alpha,alpha'
      dichloro-p-xylene. X-ray photoelectron spectroscopy (XPS) was used to
      characterize the PPY films after each surface modification step. Increasing the
      AAc graft concentration would allow a greater amount of GOD to be immobilized but
      this would decrease the electrical conductivity of the PPY film. The activity of
      the immobilized GOD was compared with that of free GOD and the kinetic effects
      were also studied. The immobilized GOD was found to be less sensitive to
      temperature deactivation as compared to the free GOD. The results showed that the
      covalent immobilization technique offers advantages over the technique involving
      the entrapment of GOD in PPY films during electropolymerization. The presence of
      viologen in the vicinity of the immobilized GOD also enabled the GOD-catalyzed
      oxidation of glucose to proceed under UV irradiation in the absence of O(2).

PMID- 12604252
TI  - Voltammetric sensor for vanillylmandelic acid based on molecularly imprinted
      polymer-modified electrodes.
AB  - Despite the increasing number of applications of molecularly imprinted polymers
      (MIPs) in analytical chemistry, the construction of a biomimetic voltammetric
      sensor remains still challenging. This work investigates the development of a
      voltammetric sensor for vanillylmandelic acid (VMA) based on acrylic MIP-modified
      electrodes. Thin layers of MIPs for VMA have been prepared by spin coating the
      surface of a glassy carbon electrode with the monomers mixture (template,
      methacrylic acid, a cross-linking agent and solvent), followed by in situ
      photopolymerisation. After extraction of the template molecule, the peak current
      recorded with the imprinted sensor after rebinding was linear with VMA
      concentration in the range 19-350 microg ml(-1), whereas the response of the
      control electrode is independent of incubation concentration, and was about one
      tenth of the value recorded with the imprinted sensor at the maximum
      concentration tested. Under the conditions used, the sensor is able to
      differentiate between VMA and other closely structural-related compounds, such as
      3-methoxy-4-hydroxyphenylethylene glycol (not detected), or 3,4- and 2,5
      dihydroxyphenilacetic acids, which are adsorbed on the bare electrode surface but
      not at the polymer layer. Homovanillic acid was detected with the imprinted
      sensors after incubation, indicating that the presence of both methoxy and
      carboxylic groups in the same position as in VMA is necessary for effective
      binding in the imprinted sites. Nevertheless, both species can be differentiated
      by the oxidation potential. It can be concluded that MIP-based voltammetric
      electrodes are very promising analytical tool for the development of highly
      selective analytical sensors.

PMID- 12604254
TI  - Detection of progesterone in whole blood samples.
AB  - The progesterone concentration in blood samples can be utilised as a marker for
      the diagnosis of early pregnancy, endocrinopathy and virilism. Here, we describe
      a method for progesterone detection and measurement in whole blood samples by a
      surface sensitive biosensor used in conjunction with an integrated optical
      grating coupler. This device determines refractive index changes near the
      biosensor's surface. Hence, biological species bound to a surface layer can be
      measured in real-time without any label. For the measurements, we have modified
      the indirect competitive immunoassay principle. The concentration of the
      progesterone antibody was kept at 1 microg/ml. Progesterone concentration was
      determined in buffer solution and whole blood in a range between 0.005 and 10
      ng/ml. The detection limit was determined to be 3 pM. The relative standard
      deviation was calculated to be 3.5%.

PMID- 12604255
TI  - A study of piezoelectric and mechanical anisotropies of the human cornea.
AB  - The piezoelectric and dynamic mechanical properties of human cornea have been
      investigated as a function of drying time. As expected, the piezoelectric
      coefficient, d(31), and the Young's modulus, Y, were found to be extremely
      sensitive to water content. d(31) decreased with dehydration of the corneal
      tissue and Y increased with dehydration. While these results are significant, the
      discovery of the unprecedented mechanical and electromechanical anisotropy
      exhibited by the cornea are the major findings of this study and indicate that
      the collagen fibrils comprising the cornea are highly oriented. The piezoelectric
      responses of corneas observed in this study are: diagonally cut samples starting
      at an average piezoelectric coefficient value of 2250 pC/N, followed by the
      vertically cut samples, with an average starting value of about 600 pC/N and
      finally the horizontally cut samples with an average starting value of about 200
      pC/N.

PMID- 12604256
TI  - A tethered bilayer sensor containing alamethicin channels and its detection of
      amiloride based inhibitors.
AB  - Alamethicin, a small transmembrane peptide, inserts into a tethered bilayer
      membrane (tBLM) to form ion channels, which we have investigated using electrical
      impedance spectroscopy. The number of channels formed is dependent on the
      incubation time, concentration of the alamethicin and the application of DC
      voltage. The properties of the ion channels when formed in tethered bilayers are
      similar to those for such channels assembled into black lipid membranes (BLMs).
      Furthermore, amiloride and certain analogs can inhibit the channel pores, formed
      in the tBLMs. The potency and concentration of the inhibitors can be determined
      by measuring the change of impedance. Our work illustrates the possibility of
      using a synthetic tBLM for the study of small peptide voltage dependent ion
      channels. A potential application of such a device is as a screening tool in drug
      discovery processes.

PMID- 12604257
TI  - Use of surface plasmon resonance biosensor technology as a possible alternative
      to detect differences in binding of enantiomeric drug compounds to immobilized
      albumins.
AB  - The use of biosensors for monitoring real time interactions between biomolecules
      and drug compounds has a lot of advantages over presently existing detection
      methods, the major ones being the elimination of radio labels and rapid
      screening. We can also obtain information about the kinetic parameters and these
      values may serve as useful indicators towards subtle differences in the binding
      strength and characteristics of closely related drug compounds and enantiomers.
      The Biacore 3000 biosensor based on the Surface Plasmon Resonance (SPR)
      technology was used to assess the albumin protein binding differences between two
      enantiomers of a drug compound. Normalized responses (NRU) and affinity constants
      (K(D)) were readily calculated. Statistical parameters like mean normalized
      responses, %CV values were determined to make the technique robust. The %CV
      values obtained were within the preset limits of < or = 25% (FDA limits for drug
      development and method validation protocols) for the binding interactions for
      majority of the concentrations studied. For example, the %CV values for the
      normalized responses for the binding of the control drug warfarin to human
      albumin ranged from 7.9 to 24.3%. The method gave reproducible results, and the
      results indicated slight differences in binding patterns of the enantiomers to
      human and rat albumin.

PMID- 12604259
TI  - Application of the optical waveguide lightmode spectroscopy to monitor lipid
      bilayer phase transition.
AB  - An instrument for optical waveguide lightmode spectroscopy (OWLS) was designed
      and developed for measurements at different and controlled temperatures in a
      range of 15 degrees C around room temperature. The instrument allows to scan the
      waveguide modes at different wavelengths on the same optical chip using different
      lasers. This instrument was used to monitor DMPC lipid bilayer main phase
      transition around the critical temperature. The main problem in these experiments
      is that the OWLS measurements do not give enough information about an optically
      anisotropic system like a lipid bilayer. Experimental OWLS data at two different
      wavelengths can however approximately solve the problem. The temperature
      dependence of the thickness and the refractive indices (ordinary and
      extraordinary) for the lipid bilayer around the phase transition is presented. (A
      theoretical derivation of the extraordinary refractive index is given in.)

PMID- 12604258
TI  - RNA biosensor for the rapid detection of viable Escherichia coli in drinking
      water.
AB  - A highly sensitive and specific RNA biosensor was developed for the rapid
      detection of viable Escherichia coli as an indicator organism in water. The
      biosensor is coupled with protocols developed earlier for the extraction and
      amplification of mRNA molecules from E. coli [Anal. Biochem. 303 (2002) 186].
      However, in contrast to earlier detection methods, the biosensor allows the rapid
      detection and quantification of E. coli mRNA in only 15-20 min. In addition, the
      biosensor is portable, inexpensive and very easy to use, which makes it an ideal
      detection system for field applications. Viable E. coli are identified and
      quantified via a 200 nt-long target sequence from mRNA (clpB) coding for a heat
      shock protein. For sample preparation, a heat shock is applied to the cells prior
      to disruption. Then, mRNA is extracted, purified and finally amplified using the
      isothermal amplification technique Nucleic acid sequence-based amplification
      (NASBA). The amplified RNA is then quantified with the biosensor. The biosensor
      is a membrane-based DNA/RNA hybridization system using liposome amplification.
      The various biosensor components such as DNA probe sequences and concentration,
      buffers, incubation times have been optimized, and using a synthetic target
      sequence, a detection limit of 5 fmol per sample was determined. An excellent
      correlation to a much more elaborate and expensive laboratory based detection
      system was demonstrated, which can detect as few as 40 E. coli cfu/ml. Finally,
      the assay was tested regarding its specificity; no false positive signals were
      obtained from other microorganisms or from nonviable E. coli cells.

PMID- 12604260
TI  - Backside contacted field effect transistor array for extracellular signal
      recording.
AB  - A new approach to the design of field-effect transistor (FET) sensors and the use
      of these FETs in detecting extracellular electrophysiological recordings is
      reported. Backside contacts were engineered by deep reactive ion etching and a
      gas phase boron doping process of the holes using planar diffusion sources. The
      metal contacts were designed to fit on top of the bonding pads of a standard
      industrial 22-pin DIL (dual inline) chip carrier. To minimise contact resistance,
      the metal backside contacts of the chips were electroless plated with gold. The
      chips were mounted on top of the bonding pads using a standard flip-chip process
      and a fineplacer unit previously described. Rat embryonic myocytes were cultured
      on these new devices (effective growth area 6 x 6 mm(2)) in order to confirm
      their validity in electrophysiological recording.

PMID- 12604261
TI  - Protein patterning on silicon-based surface using background hydrophobic thin
      film.
AB  - A new and convenient protein patterning method on silicon-based surface was
      developed for protein array by spin coating of hydrophobic thin film (CYTOP).
      Photolithographic lift-off process was used to display two-dimensional patterns
      of spatially hydrophilic region. The background hydrophobic thin film was used to
      suppress nonspecific protein binding, and the hydrophilic target protein binding
      region was chemically modified to introduce aldehyde group after removal of the
      photoresist layer. The difference in surface energy between the hydrophilic
      pattern and background hydrophobic film would induce easier covalent binding of
      proteins onto defined hydrophilic areas having physical and chemical constraints.
      Below 1 microg/ml of total protein concentration, the CYTOP hydrophobic film
      effectively suppressed nonspecific binding of the protein. During the process of
      protein patterning, inherent property of the hydrophobic thin film was not
      changed judging from static and dynamic contact angle survey. Quantitative
      analysis of the protein binding was demonstrated by streptavidin-biotin system.

PMID- 12604263
TI  - Optical whole-cell biosensor using Chlorella vulgaris designed for monitoring
      herbicides.
AB  - An optical biosensor was designed for determination of herbicides as aquatic
      contaminants. Detection was obtained with immobilised Chlorella vulgaris
      microalgae entrapped on a quartz microfibre filter and placed in a five-membrane
      home-made-flow cell. The algal chlorophyll fluorescence modified by the presence
      of herbicides was collected at the tip of an optical fibre bundle and sent to a
      fluorimeter. A continuous culture was set up to produce algal cells in
      reproducible conditions for measurement optimisation. Effects of flow rate, algal
      density, temperature, and pH on the biosensor response to atrazine were studied.
      Reversibility and detection limits were determined for DNOC and atrazine,
      simazine, isoproturon, diuron. Detection of photosystem II (PSII) herbicides was
      achieved at sub-ppb concentration level.

PMID- 12604264
TI  - Substituted 4-[4-(dimethylamino)styryl]pyridinium salt as a fluorescent probe for
      cell microviscosity.
AB  - In aqueous solution, 4-[4-(dimethylamino)styryl]pyridine (DMASP) derivatives
      displayed dual fluorescence, in which excitation at either 469 or 360 nm produced
      an emission band near 600 nm. Increasing the viscosity of the environment
      intensified the fluorescence emission obtained at the longer wavelength of
      excitation, whereas the emission at the lower wavelength of excitation showed
      little change in intensity. Thus, using the ratio of the 600 nm emission obtained
      by exciting at 469 nm to that obtained with 360 nm excitation, it is possible to
      obtain a value related to the local viscosity that does not depend on the system
      parameters. The fluorescence emission of the dye in aqueous solution, as well as
      in living cells, is well suited for use with visible fluorescence spectroscopy.
      The N-carboxymethyl butyl ester DMASP derivative (1) was found to be irreversibly
      loaded into living smooth muscle cells, presumably because it is hydrolyzed by
      cellular esterases, transforming it into a membrane-impermeable fluorescent
      carboxylate DMASP derivative. (2) After calibrating 2 against glycerol/water and
      sucrose/water mixtures of known viscosity, the fluorescence ratio generated from
      cultured smooth muscle cells in dual-excitation mode gave an average
      intracellular viscosity of 4.5 cP. This value corresponds to those reported in
      the literature.

PMID- 12604262
TI  - Stable adhesion of phospholipid vesicles to modified gold surfaces.
AB  - Phospholipid vesicles are well-studied biomembrane mimics that are of increasing
      interest in drug delivery, immunoassays, and sensor chips. In a number of
      biosensor applications it is desirable to be able to adhere vesicles to a surface
      in a manner which does not result in their rupture or fusion. Such behavior
      should, in principle, be achievable by controlling the vesicle-surface and
      vesicle-vesicle interactions. We have varied vesicle composition and charge
      (phosphatidylcholine, phosphatidylcholine-phosphatidic acid 18 mol%) and solution
      ionic strength, to study the adhesion of fluorescent vesicles to glass, gold, and
      gold modified with chemisorbed acetyl-cysteine. The extent of chemisorption was
      characterized with angle-resolved X-ray photoelectron spectroscopy (ARXPS), and
      vesicle integrity and behavior was studied using entrapped and lipophilic
      fluorescent markers, together and in separate measurements. Vesicle fusion (by
      energy transfer), adhesion of intact vesicles (with entrapped calcein) and
      diffusion coefficients (by photobleaching recovery) were monitored using confocal
      fluorescence microscopy. Acetyl-cysteine modified gold surfaces were shown to be
      appropriate substrates for adhesion of intact vesicles. Finally, as a 'proof of
      principle' for fluorescence amplification, release of a self-quenching entrapped
      reporter dye (calcein) by the detergent Triton X-100 was followed in real time.

PMID- 12604265
TI  - An amperometric immunosensor based on an electrochemically pretreated carbon
      paraffin electrode for complement III (C3) assay.
AB  - An electrochemical immunosensor based on the adsorption of anti-complement III
      antibody onto an electrochemical pretreated carbon-paraffin electrode has been
      proposed for the detection of complement III (C(3)). The competitive immunoassay
      format was adopted with horseradish peroxide-C(3) (HRP-C(3)) as a tracer,
      3,3'5,5'-tetramethylbenzidine (TMB) and hydrogen peroxide as the enzyme
      substrates. In order to measure the amount of HRP-C(3) binding onto the electrode
      surface, the product of the enzyme catalytic reaction was detected at 100 mV (vs.
      Ag/AgCl reference electrode). The system was optimized to realize a reliable
      determination of C(3) in the range of 0.06-10 microg/ml. It exhibits some
      advantages, such as simplicity of fabrication, rapidity of measurement, and
      satisfactory sensitivity and reproducibility.

PMID- 12604266
TI  - High sensitivity detection of molecular recognition using magnetically labelled
      biomolecules and magnetoresistive sensors.
AB  - Small magnetoresistive spin valve sensors (2 x 6 microm(2)) were used to detect
      the binding of single streptavidin functionalized 2 microm magnetic microspheres
      to a biotinylated sensor surface. The sensor signals, using 8 mA sense current,
      were in the order of 150-400 microV for a single microsphere depending on sensor
      sensitivity and the thickness of the passivation layer over the sensor surface.
      Sensor saturation signals were 1-2 mV representing an estimated 6-20
      microspheres, with a noise level of approximately 10 microV. The detection of
      biomolecular recognition for the streptavidin-biotin model was shown using both
      single and differential sensor architectures. The signal data compares favourably
      with previously reported signals for high numbers of magnetic microspheres
      detected using larger multilayered giant magnetoresistance sensors. A wide range
      of applications is foreseen for this system in the development of biochips, high
      sensitivity biosensors and the detection of single molecules and single molecule
      interactions.

PMID- 12604267
TI  - Evanescent resonator chips: a universal platform with superior sensitivity for
      fluorescence-based microarrays.
AB  - In the present paper, we introduce for the first time a novel generation of a
      universal fluorescence transducer, the so-called evanescent resonator (ER)
      platform. The device comprises a transparent substrate and a thin dielectric
      surface layer containing sub-micron corrugated structures. The ER chip exhibits
      an inherent physical signal amplification due to confinement of excitation energy
      in the thin surface layer. Energy confinement is based on interference effects
      created by the abnormal reflection geometry and leads to efficient excitation of
      surface-bound fluorophores in the evanescent field of the chip. The evanescent
      resonator platform has the potential to increase the fluorescence yield of
      labelled biomolecules to more than 100-fold when compared with conventional
      microarray chips. The new ER device has been developed for analysis of nucleic
      acids from different species. However, it can be used with all kinds of
      biomolecular affinity systems. The platform combines superior sensitivity with
      exceptional reproducibility and ease of use. The chips are compatible with
      commercially available laser scanners, confocal microscopes, and portable or
      miniaturised CCD read-out equipment.

PMID- 12604268
TI  - Current concepts in central nervous system regeneration.
AB  - A dictum long-held has stated that the adult mammalian brain and spinal cord are
      not capable of regeneration after injury. Recent discoveries have, however,
      challenged this dogma. In particular, a more complete understanding of
      developmental neurobiology has provided an insight into possible ways in which
      neuronal regeneration in the central nervous system may be encouraged. Knowledge
      of the role of neurotrophic factors has provided one set of strategies which may
      be useful in enhancing CNS regeneration. These factors can now even be delivered
      to injury sites by transplantation of genetically modified cells. Another
      strategy showing great promise is the discovery and isolation of neural stem
      cells from adult CNS tissue. It may become possible to grow such cells in the
      laboratory and use these to replace injured or dead neurons. The biological and
      cellular basis of neural injury is of special importance to neurosurgery,
      particularly as therapeutic options to treat a variety of CNS diseases becomes
      greater.

PMID- 12604269
TI  - The influence of diabetes mellitus and hyperglycaemia on stroke incidence and
      outcome.
AB  - Diabetes mellitus is a complex metabolic syndrome with significant effects on the
      systemic and cerebral vasculature. The incidence and severity of ischaemic stroke
      are increased by the presence of diabetes, and outcome from stroke is poorer.
      More than one third of patients admitted with acute stroke are hyperglycaemic at
      presentation. Reasons for the altered prognosis in diabetes associated stroke are
      multifactorial. A direct influence of hyperglycaemia at the time of ischaemia is
      likely to be important. The use of novel methods to delineate stroke topography
      and pathophysiology such as MR spectroscopy, diffusion and perfusion weighted MRI
      appear helpful in delineating the effects of hyperglycaemia on stroke
      pathophysiology. Randomised clinical trials to determine optimal management for
      patients with hyperglycaemia following stroke are ongoing. Such trials will
      determine if aggressive control of acute hyperglycaemia following stroke has
      similar benefits to that observed following acute myocardial infarction.
      Clinicians responsible for stroke patients should be aware of the importance of
      adequate glycaemic control in both primary and secondary prevention of stroke.

PMID- 12604270
TI  - Low-dose tacrolimus for intractable myasthenia gravis.
AB  - We treated two patients suffering from intractable myasthenia gravis (MG) with
      low-dose tacrolimus plus prednisolone. Both patients showed significant
      improvement of myasthenic signs, accompanied by suppressed serum anti
      acetylcholine receptor antibody, waning in compound muscle action potential by
      repetitive nerve stimulation and IL-2 production by peripheral blood mononuclear
      cells. Low-dose tacrolimus plus prednisolone is a promising therapeutic regimen
      for intractable MG.

PMID- 12604271
TI  - Screening for early cognitive impairment in multiple sclerosis patients using the
      clock drawing test.
AB  - The clock drawing test (CDT) is a complex task assessing integrative functions,
      abstract thinking and visuospatial organization. In the present study we
      evaluated the CDT as a possible screening instrument for early cognitive
      impairment in multiple sclerosis (MS) patients. In total, 107 MS patients
      completed the CDT as well as a battery assessing five cognitive domains. There
      were 73 female and 34 male participants (mean age 45.4+/-11.6 years, range 19
      69). The majority (76/107) were diagnosed with a relapsing-remitting disease
      course. Mean expanded disability status scale (EDSS) score was 4.3+/-2.4 (range 0
      8). The CDT was scored on a 1-6 point scale with "1" being a perfect score and
      "6" reflecting severe disorganization. Mean CDT score was 2.6+/-1.4. In 53% of
      patients the CDT was normal while in 11.2% dementia was apparent. The CDT score
      did not correlate with the total EDSS. Significant correlations were obtained
      with the mental functional system score of the EDSS (r = 0.78; p = 0.0001),
      visual learning and recall, sustained attention and concentration. Our findings
      demonstrate the sensitivity of the CDT to several cognitive domains. The absence
      of correlation with total EDSS score coupled with significant correlation with
      the mental functional system suggests that the CDT may be useful for screening MS
      patients.

PMID- 12604272
TI  - Pain resolution after lumbar disc surgery is influenced by macrophage tissue
      infiltration. A prospective consecutive study on 177 patients.
AB  - The aim of this study was to assess the influence of inflammatory reactions in
      herniated lumbar disc specimens on pain resolution after lumbar disc surgery.
      Disc specimens of 200 patients who underwent surgery for lumbar disc herniation
      were studied immunohistologically. Preoperatively each patient received a verbal
      rating scale (VRS) for classification of the pain level and general clinical data
      were recorded prospectively. Varying amounts of macrophages could be
      demonstrated. Eighty-nine percent of patients could be followed up for a mean
      period of 7 months. A statistically significant correlation between the
      histologically observed macrophage infiltration and postoperative pain grading
      according to the VRS was found. Patients with evidence of inflammatory reactions
      rated their postoperative complaints lower than patients with no evidence of
      inflammatory reactions on the VRS (P = 0.04). In our study, a statistically
      significant correlation between inflammatory changes in the herniated lumbar disc
      specimen and outcome after lumbar disc surgery could be demonstrated.

PMID- 12604274
TI  - Talked and deteriorated head injury patients: how many poor outcomes can be
      avoided?
AB  - The objective of this study was to assess the effectiveness of head injury
      management on the incidence and outcome of talked and deteriorated patients. Of
      337 severe head injury patients admitted to Songklanagarind Hospital during 1994
      to 1997, 30 were identified as 'talked and deteriorated'. Most deterioration was
      due to intracranial haematomas. The incidence (8.9%) and poor outcome (40%) were
      lower than those from a previous study in 1990 (incidence 15.8% and poor outcome
      50%). The poor outcome in this group should not be more than 10%, which may be
      achieved by appropriate practice guidelines combined with a multidisciplinary
      team approach in caring for head injury patients, and the collaboration of
      hospitals within a regional trauma system.

PMID- 12604273
TI  - Intracranial tumoural haemorrhage--a report of 58 cases.
AB  - In order to study the computerized tomographic (CT) appearances and clinical
      characteristics of intracranial tumoural haemorrhage (ITH), we analyzed
      retrospectively fifty-eight patients with ITH and reviewed the literature. As a
      result, 91% patients had acute or subacute onset and 26% manifested haemorrhage
      as their first symptoms. CT scanning indicated that intratumoural bleeding
      occurred in 23 cases, bleeding into parenchyma 18 cases, subarachnoid space 6
      cases, ventricle 3 cases and subdural space 8 cases. Thirty-eight patients had
      emergency operations and the others had selective operations. Both tumours and
      haematomas were removed all together in all patients. Fifty-five patients were
      cured or improved and three died during the perioperative stage in our series.
      Among the patients with ITH, there were 21 metastatic tumours, 19 gliomas, 10
      meningiomas, 6 pituitary adenomas, 1 melanoma and 1 acoustic neurilemoma. The
      onset of most ITH resembled that of cerebrovascular diseases. The location of ITH
      and the CT appearances of ITH varied in different cerebral tumours. Radical
      removal of brain tumours with haemorrhage is an effective treatment for ITH,
      which can greatly decrease the perioperative mortality rate and improve the
      prognoses of patients.

PMID- 12604275
TI  - Effects of indirect bypass surgery for occlusive cerebrovascular diseases in
      adults.
AB  - The efficacy of indirect bypass surgery on hemodynamics in elderly adults with
      occlusive/stenotic cerebrovascular disease was retrospectively investigated in
      five elderly patients. Three cases were diagnosed as quasi-moyamoya disease. One
      patient was diagnosed with moyamoya disease. Of these four patients, three
      patients showed marked transdural leptomeningeal anastomosis. All patients showed
      certain areas of hypoperfusion with impairment of the perfusion reserve in the
      affected areas. All patients underwent encephalo-duro-arterio-synangiosis (EDAS)
      unilaterally and were followed up for 1-5 years. Three patients showed
      improvement of hemodynamic status, all of whom showed spontaneously developed
      leptomeningeal anastomosis in the preoperative angiographies. In two of these
      three patients, well-developed collateral formation from the graft was observed
      angiographically. We speculated that in addition to impaired cerebral perfusion
      reserve, spontaneously developed leptomeningeal anastomosis might be the key
      factor for the efficacy of indirect bypass in elderly patients with
      occlusive/stenotic cerebrovascular disease.

PMID- 12604276
TI  - Impact of early endovascular aneurysmal occlusion on outcome of patients in poor
      grade after subarachnoid haemorrhage: a prospective, consecutive study.
AB  - Patients in poor grade (WFNS IV and V) after aneurysmal subarachnoid hemorrhage
      (SAH) often have a bad outcome. To evaluate early GDC embolisation on such
      patients a prospective observational study, with comparison to a historical
      cohort was performed. From January 1996 to December 1998 113 patients were
      admitted to the Department of Clinical Neurosciences in poor grade after SAH (45
      WFNS IV and 68 WFNS V). Eighty-one patients were managed actively with
      endovascular occlusion of the aneurysm (n = 42) where possible and delayed
      clipping (n = 16) where not. On an intention to treat basis, 46% had a favourable
      outcome (Glasgow Outcome Score IV or V) and 48% had died by 3 months. Compared to
      an historical cohort managed in the same unit between 1992 and 1995 (n = 62, 52%
      favourable outcome) these results suggest that early GDC aneurysmal occlusion has
      had a minimal impact on overall outcome.

PMID- 12604278
TI  - Clinical implications of dynamic MRI for pituitary adenomas: clinical and
      histologic analysis.
AB  - To determine the clinical significance of dynamic magnetic resonance imaging
      (MRI) for pituitary adenomas, we analyzed sequential enhancement patterns of
      pituitary adenomas and factors contributing to these sequential patterns. Dynamic
      MRI was performed in 67 patients with pituitary adenomas and compared to
      conventional imaging. Subjects were classified into four categories according to
      the sequential enhancement patterns of the adenomas. Factors supposed to
      correlate with enhancement pattern, such as secreting hormone, tumor size,
      microscopically examined vascularity and arterial involvement, and
      intraoperatively observed texture of the adenomas, were examined among the
      groups. Adenomas inclined to have late enhancement patterns were relatively small
      compared to those with early patterns. Tumors with very early enhancement
      patterns were significantly more fibrous than those with the other three
      patterns. The factors that contribute to sequential enhancement patterns remain
      unclear. None the less, scrutinizing the dynamic sequential pattern may provide
      useful information about the probable texture of the tumor.

PMID- 12604277
TI  - Comparison of thallium-201 uptake and retention indices for evaluation of brain
      lesions with SPECT.
AB  - Thallium-201 chloride single photon emission computed tomography ((201)TlCl
      SPECT) has been applied extensively for studies of human tumors. To assess which
      indices for (201)TlCl SPECT are most useful for diagnosing brain lesions, a total
      of 82 patients (98 images) with intracranial abnormalities were investigated.
      Seventy-six cases with abnormal (201)Tl uptake were evaluated in terms of six
      different (201)Tl uptake and retention indices: (1) average early (201)Tl uptake
      = Av.Le/Av.Be; (2) maximum early (201)Tl uptake = Mx.Le/Av.Be; (3)(201) Tl
      retention A = Av.Ld/Av.Le; (4) (201)Tl retention B = Mx.Ld/Mx.Le; (5) (201)Tl
      retention C = (Av.Ld/Av.Bd)/(Av.Le/Av.Be); (6) (201)Tl retention D =
      (Mx.Ld/Av.Bd)/(Mx.Le/Av.Be), where Av.Le and Mx.Le are average and maximum early
      counts for lesions, Av.Be and Av.Bd are average early and delayed counts for
      contralateral normal brains, and Av.Ld and Mx.Ld are average and maximum delayed
      counts for lesions. Comparison of patients with benign and malignant lesions did
      not demonstrate significant differences with any of the indices. However, low (I
      II) and high (III-IV) grade astrocytomas varied in their average and maximum
      early (201)Tl uptake indices (both P = 0.0026). For patients with and without
      meningiomas, P values for indices of maximum early(201) Tl uptake and (201)Tl
      retention A and B were 0.0338, 0.0005, 0.0002, respectively. While comparison of
      patients with metastatic brain tumors and gliomas again showed no significant
      differences between the groups, the presence or absence of calcification was
      associated with significant variation in all the indices. With (201)TlCl-SPECT
      imaging, the average and maximum early (201)Tl uptake indices are appropriate for
      the assessment of tumor viability or malignancy, while (201)Tl retention indices
      (A,B) are useful for tumor differentiation, especially with meningiomas. Choice
      of suitable indices should enhance the utility of (201)TlCl-SPECT imaging in pre-
      and postoperative evaluation of intracranial lesions.

PMID- 12604279
TI  - An unusual reduction technique prior to surgical treatment for traumatic
      spondylolisthesis in the lower cervical spine.
AB  - Traumatic spondylolisthesis in the lower cervical spine is rare and only a few
      cases have been reported. We present a 56-year-old man who had severe C6-C7
      spondylolisthesis without major neurological complications, caused by a traffic
      accident. Plain CT images showed a pedicular fracture on the right side and a
      laminar fracture on the left side at C6, but magnetic resonance images revealed
      no spinal cord compression. Application of a halo brace and maintaining the neck
      in slight flexion without traction resulted in reduction of the spondylolisthesis
      to nearly normal alignment. Anterior fusion using an autogeneous bone graft and a
      plate was easily performed without loss of correction. We suggest that
      preoperative reduction using a halo brace in slight flexion without longitudinal
      skull traction is useful and effective for severe traumatic spondylolisthesis in
      the lower cervical spine.

PMID- 12604281
TI  - Experiment and observation on invasion of brain glioma in vivo.
AB  - Research on invasion and metastasis of glioma in vivo was performed by implanting
      C6 glioma cells transfected with enhanced green fluorescent protein (EGFP) gene
      into the brain of SD rats. Firstly, C6 glioma cells were transfected with a
      plasmid vector (pEGFP-N3) containing the EGFP gene. Stable EGFP-expressing clones
      were isolated and examination for these cells by flow cytometry and electron
      microscope was done. Secondly, EGFP-expressing cells were stereotactically
      injected into the brain parenchyma of SD rats to establish xenotransplanted
      tumor. Four weeks later rats were killed and continuous brain sections were
      examined using fluorescence microscopy after adjacent sections were examined by
      immunohistochemistry or routine hematoxylin and eosin staining for the
      visualization and detection of tumor cell invasion. Xenotransplanted tumor was
      primarily cultured to determine the storage of EGFP gene in vivo. The results
      showed that EGFP-transfected C6 glioma cells maintained stable high-level EGFP
      expression in the central nervous system during their growth in vivo. EGFP
      fluorescence clearly demarcated the primary tumor margin and readily allowed for
      the visualization of distant micrometastasis and invasion on the single-cell
      level. Small locally invasive foci, including those immediately adjacent to the
      leading invasive edge of the tumor, were virtually undetectable by routine
      hematoxylin and eosin staining and immunohistochemistry. These results suggested
      that EGFP-transfected C6 cells can be visualized by fluorescence microscopy after
      intracranial implantation. This model is an excellent experimental animal model
      in research on invasion and metastasis of brain glioma in vivo.

PMID- 12604282
TI  - Therapeutic effect of caspase inhibitors in the prevention of apoptosis and
      reversal of chronic cerebral vasospasm.
AB  - One of the important histological changes in cerebral vasospasm after
      subarachnoid hemorrhage (SAH) is endothelial cell damage, which involves
      apoptosis. The current study was undertaken to determine whether anti-apoptosis
      therapy prevents apoptosis and reverses vasospasm in a dog SAH model. Twenty
      three mongrel dogs of either sex, weighing 17-25 kg, were subjected to autologous
      arterial blood injection into the cisterna magna on day 0 and day 2, and
      sacrificed on day 7. Angiography was performed on day 0 before blood injection
      and on day 7 before sacrifice. Caspase-2 (Z-VDVAD-FMK, 10 microM) inhibitor,
      caspase-3 (Z-DEVD-FMK, 10 microM) inhibitor, or vehicle (DMSO) were injected
      intrathecally from day 2 to day 6. The effects of caspase inhibitors on apoptosis
      and vasospasm were evaluated by angiography and transmission electron microscopy.
      The residual diameter of the basilar artery on day 7 in SAH dogs without
      treatment was 53.4+/-5.5% of the day 0 diameter. Marked damage to the endothelial
      cells, including apoptotic like changes, was observed in these arteries. Both
      caspase inhibitors prevented apoptosis in the endothelial cells. Only caspase-3
      inhibitor, however, had a near-significant effect on reducing 13.3% of
      angiographic vasospasm. Higher doses and early treatment, as well as other more
      potent apoptosis inhibitors, are recommended for future studies.

PMID- 12604283
TI  - The effect of changing pressures on dural puncture and leak with various spinal
      needles on an in vitro model.
AB  - Postdural puncture headache is one of the most serious complications of spinal
      anesthesia. In this study, spinal needles of various types and shapes were used
      to investigate the amount of fluid leakage in dural puncture under various levels
      of pressures. Dura samples received from 10 cadavers were fixed in an in vitro
      model. The dural punctures were inflicted with 22 G, 25 G, and 27 G Quincke; 25 G
      Withacre; 25 G, 27 G Pencan, and 26 G Atraucan spinal needles. The fluid, which
      leaked during the process, was collected under the pressures of 0, 25, 50, 100,
      and 150 cm H(2)O in one-hour period for each level. The holes in the dura were
      studied under light microscope. While 22 G and 25 G Quincke needles were used,
      the fluid leakage directly correlated the amount of liquid, the diameter of the
      needle, and the pressure used. The puncture of 25 G Withacre and 25 G Pencan
      presented a leakage which did not significantly vary with the liquid pressure and
      was of lesser amount. In 26 G Atraucan, 27 G Pencan, and 27 G Quincke inflicted
      punctures, little liquid was collected and it did not vary with differing
      pressures. Thus, no significant correlation was established between the needle
      diameter and the puncture. It was concluded that the sharp-ended needles could
      not endure changes in the pressure. However, those needles with a very thin
      diameter and a pencil tip were considered as safe tools for anesthetical
      practices.

PMID- 12604284
TI  - Learned movements in a left-handed pianist: an f-MRI evaluation.
AB  - The spatial arrangement of neuronal sources for digit movement is non
      somatotopic, and is structured as extensively arranged through different regional
      cortex. We have functionally examined the cerebro-cortical activation during
      simple and complex motor sequences, before and after learning sessions, in
      healthy volunteers, both considering left- and right-dominant hand use, and left
      non dominant hand use, skillfulness and educational level. We discuss the results
      with a review on the topic.

PMID- 12604285
TI  - Decreased thalamic metabolism without thalamic magnetic resonance imaging
      abnormalities following shearing injury to the substantia nigra.
AB  - A 36-year-old man had fallen about 8 metres. Radiographs showed a mandibular
      fracture, indicating rotatory force applied to the head. Fluid-attenuated
      inversion recovery (FLAIR) imaging showed hyperintensity in both medial temporal
      lobes, left medial midbrain, right midbrain including cerebral peduncle, left
      pulvinar, left external capsule, fornix, splenium of corpus callosum, and deep
      white matter of both frontal lobes. Quantitative [(18)F]fluorodeoxyglucose (FDG)
      positron emission tomography (PET) indicated markedly suppressed glucose
      metabolism in the left thalamus but not markedly in the striatum. At that time
      the neurologic examination demonstrated complete left hemiparesis, severe
      rigidity of the right upper extremity, and inability to move the right hand and
      fingers. Levodopa at 300-600 mg/day improved movement of the fingers, decreased
      the rigidity in the extremity, and lessened the metabolic abnormality. Diminished
      metabolism in the left thalamus may have contributed to symptoms. The case
      illustrates the usefulness of PET in disclosing symptom causing abnormalities not
      detected by magnetic resonance imaging.

PMID- 12604286
TI  - A case of neurosyphilis with a florid Jarisch-Herxheimer reaction.
AB  - A 37 year old man with a 2 year history of progressive cognitive decline,
      unilateral tinnitus and deafness presented with complex partial seizures and a
      fever. On examination there was a sluggish right pupillary response but no other
      abnormal findings. Serum and CSF syphilis serology were both strongly positive.
      High dose intravenous penicillin therapy was complicated by a severe Jarisch
      Herxheimer reaction (JHR) characterised by fever, obtundation, fluctuating upper
      motor neuron signs and complex visual and auditory hallucinations. These symptoms
      resolved over three days and the course of penicillin was completed. At discharge
      the patient's cognitive functioning was unchanged from the pretreatment state. He
      made gradual improvement over the following months but remains unable to live
      alone or work. Clinical, pathologic and radiologic findings of neurosyphilis are
      reviewed, as is the JHR, a self-limiting, systemic febrile response related to
      massive cytokine release that can occur in response to treatment of a number of
      bacterial infections. The similarities in pathophysiology of the JHR and the
      Septic Shock Syndrome are discussed, with particular reference to use of the JHR
      as a potential model for therapeutic agents in the treatment of septic shock.

PMID- 12604287
TI  - Isolated fascicular oculomotor nerve palsy as the initial presentation of the
      antiphospholipid syndrome.
AB  - This case report describes a 24-year-old female who presented with sudden onset
      of painless diplopia and ptosis in her left eye. Examination identified an
      isolated incomplete pupil-sparing left oculomotor nerve palsy. Magnetic resonance
      imaging demonstrated focal hyperintensity in the left midbrain with infarction
      suggested by diffusion-weighted imaging. A diagnosis of primary antiphospholipid
      syndrome was made with the demonstration of a positive lupus anticoagulant. Other
      autoimmune markers were present on initial assessment, but did not fulfil
      diagnostic criteria for systemic lupus erythematosus. Anticoagulation with
      warfarin was commenced, with gradual resolution of neurological deficits. This
      case illustrates an unusual initial manifestation of primary antiphospholipid
      syndrome causing midbrain stroke in a young woman.

PMID- 12604288
TI  - Effectiveness of a transforaminal surgical procedure for spinal extradural
      arachnoid cyst in the upper lumbar spine.
AB  - Spinal extradural arachnoid cysts are relatively rare, and the pathogenesis is
      still unclear. Here, we report a 24-year-old woman with a Type I lesion by
      Nabors' classification (extradural arachnoid cyst without spinal nerve root fiber
      involvements), who complained of low back pain and right thigh pain, treated
      surgically using a transforaminal approach. Magnetic resonance imaging (MRI) and
      myelography showed a large extradural cystic lesion close to the L1 nerve root
      sleeve, accompanied by moderate L1 nerve root compression and a communication
      between the extradural cyst and the subarachnoid space. Resection of the cyst
      wall and closure of the ostium were easily performed by this approach. This
      procedure resulted in the relief of both low back pain and right thigh pain.
      Histological examination showed clusters of meningothelial cells, which was a
      typical feature of arachnoid cysts. Postoperative MRI demonstrated that both the
      cystic lesion and nerve root compression had disappeared. This transforaminal
      procedure proved useful for the treatment of a lesion located around a lumbar
      spinal nerve root.

PMID- 12604289
TI  - Growth of basilar artery aneurysm after ventriculo-peritoneal shunt.
AB  - We report upon two cases of obstructive hydrocephalus produced by giant basilar
      artery aneurysms. They initially presented with symptoms of increased
      intracranial pressure, and were managed by a ventriculo-peritoneal (VP) shunt
      with good symptomatic improvement. With time, however, both showed a gradual
      deterioration of clinical symptoms due to increased aneurysm size. One, with a
      basilar tip aneurysm was treated by direct neck-clipping of the aneurysm, and was
      able to return to work. In the other patient, with a basilar trunk aneurysm,
      endovascular occlusion of one vertebral artery was attempted in an effort to
      decrease the aneurysm size, but the aneurysm enlarged precipitating brain stem
      failure. In conclusion, these cases reveal the risk of the VP shunt, which may
      induce aneurysmal growth, leading to clinical devastation, and emphasize the
      importance of definitive treatment for giant cerebral aneurysms whenever
      possible.

PMID- 12604290
TI  - Suprasellar cystic meningioma: unusual presentation and review of the literature.
AB  - We report on a case of suprasellar cystic meningioma. The magnetic resonance
      imaging of this tumor resembled that of a craniopharyngioma. The definitive
      diagnosis of meningioma was made only after histopathological confirmation. We
      conclude that preoperative studies are often equivocal. The possibility of
      meningioma should be considered in the diagnosis of any intracranial neoplasms
      with radiological and surgical evidence of a cystic lesion.

PMID- 12604292
TI  - Recurrent intracranial germinoma with dissemination along the ventricular
      catheter: a case report.
AB  - Most recurrences of intracranial pure germinoma occur at the primary site,
      ventricular wall or subarachnoid space. We report a rare case of intracranial
      germinoma that recurred along the shunt tube 17 years after prior
      ventriculoperitoneal shunt and radiotherapy. The recurrent tumor, verified
      histologically as a pure germinoma, involved the right frontal lobe along the
      ventricular catheter. In spite of subsequent surgery, radiation and chemotherapy,
      the tumor recurred repeatedly. Recurrence after such a long period highlights the
      necessity of long-term follow up for patients with germinoma. We also discuss
      possible causes of tumor dissemination along the ventricular catheter.

PMID- 12604291
TI  - Malignant fibrous histiocytoma originating at the site of a previous fronto
      temporal craniotomy.
AB  - Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in
      adults. MFH occurrence in the bones of the skull is extremely rare, and, to our
      knowledge, it has not been reported in a patient with a history of craniotomy. A
      69 year old woman presented with a large mass in the left fronto-temporal bone.
      The patient's medical history included a left fronto-temporal craniotomy 8 years
      prior to the present admission for neck clipping of an aneurysm of the left
      middle cerebral artery. Following preoperative work up, the skull tumor was
      resected, and pathology showed that the mass was composed of spindle-shaped
      fibroblastic cells arranged in a storiform pattern, and of numerous
      multinucleated giant cells. A diagnosis of MFH was established. The patient died
      of intracranial hemorrhage from a subsequent tumor 22 months after resection of
      the first tumor.

PMID- 12604293
TI  - Transient aphasia and persistent amnesia after surgery for internal carotid
      artery--posterior communicating artery aneurysm.
AB  - We report a case of transient aphasia and persistent amnesia after clipping of a
      ruptured cerebral aneurysm to treat a subarachnoid hemorrhage. Postoperatively,
      aphasia was identified and magnetic resonance imaging (MRI) showed an abnormal
      intensity area in the left anterior thalamus. Single photon emission computed
      tomography (SPECT) revealed a wider area of low perfusion surrounding the left
      thalamus and left frontotemporal lobe than that shown by the MRI. His aphasia
      resolved over the subsequent 12-week period. He was left with an isolated
      disturbance of memory; in the absence of any dementia, aphasia or disturbance of
      consciousness, his condition was classified as one of amnesia. SPECT 14 weeks
      after admission revealed an area of low perfusion limited to the left thalamus.
      These findings suggest that the persistence of amnesia in this case was caused by
      the infarction of the mammillothalamic tract, and the recovery from aphasia may
      have resulted from the disappearance of surrounding edema.

PMID- 12604294
TI  - Intratumoral hemorrhage due to hemangioblastoma arising from a cervical nerve
      root--a case report.
AB  - We describe a case of a 70 year old man suffering from sudden weakness of the
      left foot. Preoperative neuroimaging examinations showed an oval mass 2 cm in
      maximal diameter with intratumoral hemorrhage at the seventh cervical vertebra.
      The mass was supplied by the right lateral thoracocervical artery and was drained
      to the anterior spinal vein. The intraoperative findings showed the hard reddish
      tumor was not attached to the pia and the posterior root of the fifth cervical
      nerve was totally encased by the tumor. A histopathological examination revealed
      that hemangioblastoma encasing the posterior nerve root totally, so that the
      tumor was thought to arise from it. Unusual presentation of the neuroimaging
      examinations is described.

PMID- 12604295
TI  - Hypoglossal neurinoma presenting with intratumoral hemorrhage.
AB  - Focal or microscopic hemorrhage in a neurinoma is common, but tumor origin from
      the hypoglossal nerve and extensive symptomatic intratumoral hemorrhage are both
      rare. A 59-year-old male presented with severe neck pain, nausea and vomiting of
      1-day duration, accompanied by right hypoglossal nerve palsy. Neuroimaging
      disclosed a tumor located in the right cerebellomedullary fissure and containing
      a hematoma. The right hypoglossal canal was slightly dilated. The intracranial
      tumor was resected via a suboccipital approach. Histological examination
      demonstrated spindle-shaped tumor cells with nuclear palisading and also relative
      hypervascularity with hyaline degeneration of the vessels. Extensive hemorrhage
      was present, as was necrosis. Thickening and hyalinization of arterial walls, a
      common occurrence in neurinomas, may have contributed to symptomatic intratumoral
      hemorrhage.

PMID- 12604296
TI  - Camel racing: a new cause of extradural haemorrhage in Australia.
AB  - Camel racing is a relatively new sport in Australia. A 52 year old woman fell
      from her camel during a country race. Although she was wearing an approved
      equestrian helmet, she suffered a skull fracture and a life-threatening
      extradural haematoma. Her treatment highlights the key issues of management of
      head injuries in remote places. A paramount requirement is close collaboration
      between country medical practitioner, neurosurgeon and retrieval specialist.

PMID- 12604297
TI  - Extramedullary haemopoiesis in thalassemia intermedia presenting as paraplegia.
AB  - Extramedullary haemopoiesis causing spinal cord compression is a rare
      manifestation of thalassemia. We describe a 17 year old male with thalassemia
      intermedia who presented with progressive paraplegia and sphincter disturbance.
      Magnetic resonance imaging revealed an epidural lesion extending from T5 to T8
      compressing the spinal cord. The patient recovered completely after surgical
      decompression with postoperative radiation therapy. Histological examination of
      the lesion confirmed the diagnosis of extramedullary haemopoiesis. Clinical
      awareness of this phenomenon with early treatment is essential for optimizing the
      neurological outcome.

PMID- 12604298
TI  - Spinal leptomeningeal metastases following glioblastoma multiforme treated with
      radiotherapy.
AB  - A case of glioblastoma with leptomeningeal spread after control of the primary
      lesion by radiation therapy. A discussion is made regarding leptomeningeal
      metastatic disease with reference to the literature.

PMID- 12604300
TI  - The evolution of the cortico-cerebellar complex in primates: anatomical
      connections predict patterns of correlated evolution.
AB  - Investigations into the evolution of the primate brain have tended to neglect the
      role of connectivity in determining which brain structures have changed in size,
      focusing instead on changes in the size of the whole brain or of individual brain
      structures, such as the neocortex, in isolation. We show that the primate
      cerebellum, neocortex, vestibular nuclei and relays between them exhibit
      correlated volumetric evolution, even after removing the effects of change in
      other structures. The patterns of correlated evolution among individual nuclei
      correspond to their known patterns of connectivity. These results support the
      idea that the brain evolved by mosaic size change in arrays of functionally
      connected structures. Furthermore, they suggest that the much discussed expansion
      of the primate neocortex should be re-evaluated in the light of conjoint
      cerebellar expansion.

PMID- 12604301
TI  - Individual variation in the rate of use of tree-hole tools among wild orang
      utans: implications for hominin evolution.
AB  - Primate tool use varies among species, populations, and individuals. Individual
      variation is especially poorly understood. Orang-utans in the Sumatran swamp
      forest of Suaq Balimbing varied widely in rates of tool use to extract honey,
      ants or termites from tree holes and in the degree to which they specialized on
      this tree-hole tool use. We tested whether individual variation was best
      explained by effects of social dominance, habitat differences, or by
      opportunities for socially learning the skills during ontogeny. There was no
      evidence for the first two hypotheses. However, we found a strong relationship
      between tool use specialization and mean female party size, which was used as a
      proxy for the opportunities for socially mediated learning in a foraging context
      during their development. This use was justified because females are rather
      philopatric and their mean party size remained stable over time, thus reflecting
      long-term tendencies. The correlation was not an artifact of a direct effect of
      party size on tool use tendencies, and did not hold for males, the dispersing
      sex. Thus, variation in the number of opportunities for social learning explains
      tool use variation within populations, corroborating hypotheses for between
      population variation. The emergence of human culture was accompanied by vastly
      improved mechanisms of social learning. In order for these improvements to be
      favored by natural selection, the cultural potential must have actually been
      expressed. Thus, a combination of strong sociability and a reliance on tool-using
      or other technical skills acquired through social learning must have
      characterized early hominins.

PMID- 12604302
TI  - Historical contingency in the evolution of primate color vision.
AB  - Primates are unique among eutherian mammals for possessing three types of retinal
      cone. Curiously, catarrhines, platyrrhines, and strepsirhines share this anatomy
      to different extents, and no hypothesis has hitherto accounted for this
      variability. Here we propose that the historical biogeography of figs and
      arborescent palms accounts for the global variation in primate color vision.
      Specifically, we suggest that primates invaded Paleogene forests characterized by
      figs and palms, the fruits of which played a keystone function. Primates not only
      relied on such resources, but also provided high-quality seed dispersal. In turn,
      figs and palms lost or simply did not evolve conspicuous coloration, as this
      conferred little advantage for attracting mammals. We suggest that the abundance
      and coloration of figs and palms offered a selective advantage to foraging groups
      with mixed capabilities for chromatic distinction. Climatic cooling at the end of
      the Eocene and into the Neogene resulted in widespread regional extinction or
      decimation of palms and (probably) figs. In regions where figs and palms became
      scarce, we suggest primates evolved routine trichromatic vision in order to
      exploit proteinaceous young leaves as a replacement resource. A survey of the hue
      and biogeography of extant figs and palms provides some empirical support. Where
      these resources are infrequent, primates are routinely trichromatic and consume
      young leaves during seasonal periods of fruit dearth. These results imply a link
      between the differential evolution of primate color vision and climatic changes
      during the Eocene-Oligocene transition.

PMID- 12604303
TI  - Mediolateral reaction forces and forelimb anatomy in quadrupedal primates:
      implications for interpreting locomotor behavior in fossil primates.
AB  - The forelimb joints of terrestrial primate quadrupeds appear better able to
      resist mediolateral (ML) shear forces than those of arboreal quadrupedal monkeys.
      These differences in forelimb morphology have been used extensively to infer
      locomotor behavior in extinct primate quadrupeds. However, the nature of ML
      substrate reaction forces (SRF) during arboreal and terrestrial quadrupedalism in
      primates is not known. This study documents ML-SRF magnitude and orientation and
      forelimb joint angles in six quadrupedal anthropoid species walking across a
      force platform attached to terrestrial (wooden runway) and arboreal supports
      (raised horizontal poles). On the ground all subjects applied a lateral force in
      more than 50% of the steps collected. On horizontal poles, in contrast, all
      subjects applied a medially directed force to the substrate in more than 75% of
      the steps collected. In addition, all subjects on arboreal supports combined a
      lower magnitude peak ML-SRF with a change in the timing of the ML-SRF peak force.
      As a result, during quadrupedalism on the poles the overall SRF resultant was
      relatively lower than it was on the runway. Most subjects in this study adduct
      their humerus while on the poles. The kinetic and kinematic variables combine to
      minimize the tendency to collapse or translate forelimbs joints in an ML plane in
      primarily arboreal quadrupedal primates compared to primarily terrestrial
      quadrupedal ones. These data allow for a more complete understanding of the
      anatomy of the forelimb in terrestrial vs. arboreal quadrupedal primates. A
      better understanding of the mechanical basis of morphological differences allows
      greater confidence in inferences concerning the locomotion of extinct primate
      quadrupeds.

PMID- 12604304
TI  - 'Gatherings' of social grooming among wild chimpanzees: implications for
      evolution of sociality.
AB  - Chimpanzees (Pan troglodytes) often groom in gatherings that cannot simply be
      divided into unilateral dyadic grooming interactions. This feature of grooming is
      studied at two different levels: grooming cliques and grooming clusters. Grooming
      cliques are defined as directly connected configurations of grooming interactions
      at any given moment, and when any member of a clique successively grooms any
      member of another clique within 5min and within a distance of 3m, all the members
      of both cliques are defined as being in the same grooming cluster. Twenty-seven
      types of cliques are observed, with the largest one consisting of seven
      individuals. Mutual and/or polyadic cliques account for more than 25% of all
      cliques. The size of grooming clusters varies from two to 23 individuals, and
      almost 70% of the grooming time is spent in polyadic clusters. Although adult
      males groom the longest in relatively smaller clusters (size=2-4), adult females
      groomed the longest in clusters of five or more individuals. A review of the
      literature implies that mutual and polyadic cliques occur less often in other
      primate species than in chimpanzees. The importance of overlapping interactions
      for these kinds of gatherings and its possible significance in the evolution of
      sociality is discussed in this article.

PMID- 12604305
TI  - New discoveries on the middle ear anatomy of Ignacius graybullianus
      (Paromomyidae, Primates) from ultra high resolution X-ray computed tomography.
AB  - A skull of Ignacius graybullianus (USNM 421608) was studied using ultra high
      resolution X-ray computed tomography (uhrCT). The anatomy of the middle ear in
      this specimen was previously studied through partial removal of the auditory
      bulla on one side. The data now available allow for examination of the others
      unprepared ear, which is more completely preserved, as well as adding to the
      information available about the previously studied ear. Analysis of the
      relationships between the bones making up the auditory bulla confirms previous
      assertions that it is formed from the entotympanic, and not from the petrosal,
      basioccipital, or basisphenoid. Contrary to previous reconstructions of the
      middle ear anatomy in all known plesiadapiforms, this specimen exhibits a bony
      canal for the promontorial artery and/or internal carotid nerves running across
      the lateral extreme of the promontorium. The identification of this structure is
      confirmed by the clear presence of a lumen, and its origination at a posterior
      carotid foramen (pcf) in a position that corresponds to that identified in
      previous studies of the paromomyid basicranium (Am. J. Phys. Anthropol., 36
      (1972) 59, Am. J. Phys. Anthropol., 89 (1992) 477). Remnants of this canal are
      present bilaterally in USNM 421608, which additionally supports its
      identification. The presence of bony canals for branches of the internal carotid
      artery and the internal carotid nerves is a feature seen in scandentians and
      euprimates that is missing in dermopterans. The unusual lateral route followed by
      the internal carotid nerves is a primitive euprimate feature missing in all other
      archontans. As such, this evidence is consistent with a close euprimate
      paromomyid relationship, and the inclusion of the latter in the order Primates.
      The discovery of this feature in paromomyids after almost 30 years of study of
      the ear region of this family acts as a cautionary note to the interpretation of
      the middle ear in damaged specimens.

PMID- 12604306
TI  - Taphonomic aspects of crowned hawk-eagle predation on monkeys.
AB  - This study provides a taphonomic analysis of prey accumulations of crowned hawk
      eagles (Stephanoaetus coronatus) from Ngogo, Kibale National Park, Uganda,
      collected over 37 months from below nests of two eagle pairs. Crowned hawk-eagles
      are powerful predators capable of killing animals much larger than themselves,
      and are significant predators of cercopithecoid monkeys in forest habitats
      throughout sub-Saharan Africa. At Ngogo, 81% of the individuals in the kill
      sample are monkeys. Redtail monkeys (Cercopithecus ascanius) are particularly
      well represented in the sample, making up 66% of monkeys identified to species.
      Despite an impressive killing apparatus, crowned hawk-eagles are fastidious
      eaters that inflict far less damage to bone than mammalian predators. Examination
      of skeletal material from the Ngogo kill sample reveals that crania, hindlimb
      elements, and scapulae survive predation better than do other bones. Crania of
      adults are typically complete and accompanied by mandibles, while crania of young
      individuals are usually dissociated from mandibles and lack basicrania and faces.
      Long bones are often whole or show minimal damage. Thin bones, such as crania and
      innominates, are marked by numerous nicks, punctures, and "can-opener"
      perforations. Scapular blades are heavily raked and shattered. Along with the
      strong preference for cercopithecoids, these distinct patterns of bone survival
      and damage indicate the feasibility of recognizing specific taphonomic signatures
      of large raptors in fossil assemblages. Berger and Clarke (1995) hypothesized
      that crowned hawk-eagles or similar large raptors were principally responsible
      for the accumulation of the late Pliocene fossil fauna from Taung, South Africa,
      including the type infant skull of Australopithecus africanus. The results of our
      study suggest that the faunal composition and type of damage to the hominid skull
      and other bone from Taung are consistent with the predatory activities of large
      raptors. More rigorous assessment of their hypothesis will require sorting the
      Taung fauna by locality and further detailed analysis of species composition and
      bone damage and survivability patterns.

PMID- 12604307
TI  - The Neanderthal taxonomic position: models of intra- and inter-specific
      craniofacial variation.
AB  - The Neanderthal taxonomic position is a matter of wide disagreement among
      paleoanthropologists. Some workers consider this fossil human group to represent
      a different species, Homo neanderthalensis, while others see it as a subspecies
      of Homo sapiens. This study developed two models of morphological variation to be
      applied to a comparison between Neanderthals and modern humans: modern human
      populations provided a measure of intra-specific variation, while the species and
      subspecies of Pan provided measures of both intra- and inter-specific
      morphological differences. Although such an approach has been advocated strongly,
      it has not been systematically undertaken until recently. The techniques of
      geometric morphometrics were used to collect data in the form of three
      dimensional coordinates of craniofacial landmarks. The data were processed using
      generalized procrustes analysis, and analyzed by an array of multivariate
      statistical methods, including principal components analysis, canonical variates
      analysis and Mahalanobis D(2). The morphological distances between Neanderthals
      and modern humans, and between Neanderthals and Late Paleolithic/early
      anatomically modern specimens, are consistently greater than the distances among
      recent human populations, and greater than the distances between the two
      chimpanzee species. Furthermore, no strong morphological similarities were found
      between Neanderthals and Late Paleolithic Europeans. This study does not find
      evidence for Neanderthal contribution to the evolution of modern Europeans.
      Results are consistent with the recognition of Neanderthals as a distinct
      species.

PMID- 12604308
TI  - Beta cell-specific CD80 (B7-1) expression disrupts tissue protection from
      autoantigen-specific CTL-mediated diabetes.
AB  - T cell responses toward pancreatic beta cell autoantigens arise spontaneously or
      on immunization in many mouse strains, yet sustained islet infiltration and
      progressive diabetes rarely ensues. Most mouse diabetes models overcome the
      innocuous coexistence of anti-islet specific T cells and endogenous islets via
      incompletely understood mechanisms (e.g. the spontaneous disease onset of the non
      obese diabetic mouse) or depend on overwhelming numbers of peripheral islet
      specific T cells. We report that insulin promoter murine CD80 (RIP-CD80)
      transgenic mice are extraordinarily susceptible to autoantigen-induced diabetes,
      while spontaneous disease is rare. Autoimmunity to the pancreatic beta cell
      expressed glycoprotein (GP) of the lymphocytic choriomeningitis virus (LCMV) was
      elicited by a single injection of syngeneic fibroblastoid cell lines (FCL) loaded
      with the immunodominant LCMV-GP peptide, gp33. While both RIP-GP(+)and RIP
      CD80(+)GP(+)mice mounted moderate CD4-independent CTL responses, only
      CD80(+)GP(+)mice developed severe insulitis and diabetes due to islet
      infiltration of activated, gp33-specific, CD8(+)T cells. Strikingly, DNA
      immunization using plasmids encoding LCMV-GP or murine preproinsulin also
      efficiently induced Ag-specific RIP-CD80-dependent diabetes. We conclude that
      aberrant CD80-expression in a peripheral tissue disrupts that tissue's natural
      resistance to CD8 T cell-mediated autoimmune destruction. This rodent model thus
      represents a novel approach to identify beta cell-derived autoantigenic
      determinants involved in the pathogenesis of autoimmune diabetes, and may also
      serve as a prototype approach to uncover relevant autoantigens leading to a
      variety of organ-specific autoimmune disorders.

PMID- 12604309
TI  - Type I Interferon controls the onset and severity of autoimmune manifestations in
      lpr mice.
AB  - Type I Interferons (IFN-I) are immunoregulatory cytokines that enhance activation
      and survival of many cellular components of the immune system. In the present
      work, we evaluated the effect of IFN-I on the development of the
      lymphoproliferative disorder in Fas-defective lpr mice. We report that sustained
      injection of polyinosinic:polycytidylic acid, a potent inducer of IFN-I, in B6
      lpr mice resulted in a dramatic aggravation of the renal disease, higher titers
      of autoantibodies, a 10-fold increase in serum Ig and accumulation of activated
      lymphocytes. Moreover, introducing a null mutation for the IFN-I-Receptor gene
      into the lpr background resulted in dramatic decrease of immune complexes
      deposition in the kidney and reduced lymphadenopathy. While several recent
      reports correlated serum levels of IFN-alpha with disease activity in systemic
      Lupus erythematosus patients, our findings establish a causal link from IFN-I
      production to the onset and severity of another related autoimmune syndrome.

PMID- 12604310
TI  - Type 1 cytokines polarize thymocytes during T cell development in adult thymus
      organ cultures.
AB  - Peripheral T cells can be polarized towards type 1 or type 2 cytokine immune
      responses during TCR engagement. Because T cell selection by peptide plus self
      MHC in the thymus requires TCR engagement, we hypothesized that type 1 cytokines
      may polarize developing T cells. We cultured thymi from BBDR rats in adult thymus
      organ cultures (ATOC) under type 1 cytokine conditions in the absence of
      exogenous antigen. Type 1 cytokine-conditioned ATOC generated cells that
      spontaneously secreted high levels of IFNgamma, but not IL-4. A second exposure
      to type 1 cytokines further increased IFNgamma secretion by these cells, most of
      which were blasts that expressed the activation markers CD25, CD71, CD86, and
      CD134. Studies using blocking antibodies and pharmacological inhibitors suggested
      that both IL-18 and cognate TCR-MHC/ligand interactions were important for
      activation. Blocking anti-MHC class I plus anti-MHC class II antibodies,
      neutralizing anti-IL-18 antibody, and the p38 MAP-kinase inhibitor SB203580 each
      reduced IFNgamma production by approximately 75-80%. Cyclosporin A, which
      prevents TCR signaling, inhibited IFNgamma production by approximately 50%. These
      data demonstrate that exposure to type 1 cytokines during intrathymic development
      can polarize differentiating T cells, and suggest a mechanism by which
      intrathymic exposure to type 1 cytokines may modulate T cell development.

PMID- 12604311
TI  - Functional alteration of peripheral CD25(+)CD4(+)immunoregulatory T cells in a
      transgenic rat model of autoimmune diseases.
AB  - Transgenic rats carrying the env-pX gene of human T cell leukemia virus type-I
      (env-pX rats) develop various collagen vascular diseases. Since autoantibodies
      are present in their sera, env-pX rats are considered to be a prototype model for
      autoimmune diseases. Adoptive transfers of spleen cells from syngenic non
      transgenic rats decreased the incidence of diseases in env-pX rats, thus
      suggesting that normal spleen contains cells, which suppress autoimmune diseases.
      Murine peripheral CD25(+)CD4(+)T cells play roles in maintaining immunological
      self-tolerance. To examine if alterations of immunoregulatory cells may be
      evident in env-pX rats, quantitative and qualitative analyses of splenic
      CD25(+)CD4(+)T cells were done before these rats developed autoimmune diseases.
      Env-pX and non-transgenic rats had equivalent number of CD25(+)CD4(+)T cells.
      However, CD25(+)CD4(+)T cells from env-pX rats did not suppress proliferation of
      T cells stimulated by anti-CD3 antibodies (Ab) in vitro, whereas those from non
      transgenic rats did. Additionally, env-pX CD25(+)CD4(+)T cells showed autologous
      and anti-CD3 Ab-mediated proliferation, in contrast to the anergic features in
      non-transgenic rats. These findings appear to be the first evidence that
      CD25(+)CD4(+)immunoregulatory T cells are altered in animal models, which
      naturally develop autoimmune diseases.

PMID- 12604312
TI  - Optimization of an animal model of experimental autoimmune encephalomyelitis
      achieved with a multiple MOG(35-55)peptide in C57BL6/J strain of mice.
AB  - The severity of the experimental autoimmune encephalomyelitis (EAE) induced by
      peptide myelin oligodendrocyte glycoprotein(35-55)(pMOG(35-55)) is thought to be
      predominantly influenced by the major histocompatibility complex (MHC), so that
      C57BL6/J mice, on H2(b) strain, were only mildly sick. However, it remains
      unclear as to how non-MHC gene regions affect EAE. To determine whether the
      immunization protocol could have an influence on clinical signs, C57BL6/J mice
      were immunized with a multiple antigen peptide (MAP) containing eight pMOG(35
      55)branches synthesized directly onto a lysine core, myelin oligodendrocyte
      glycoprotein (35-55)-multiple antigen peptide (MOG(35-55)-MAP), in complete
      Freund's adjuvant (CFA). In most of the mice, clinical onset (marked weakness)
      occurred approximately at day 15. All mice injected with MOG(35-55)-MAP had more
      severe symptoms than those injected with pMOG(35-55), which developed no leg
      paralysis. All MOG(35-55)-MAP-immunized mice developed EAE symptoms, but 50% had
      primary-progressive EAE, while the other 50% had relapsing-remitting disease.
      Leukocyte infiltrations, associated with increased glial fibrillary acidic
      protein (GFAP) expression by reactive astrocytes, were observed around the
      lateral ventricles and blood vessels in the brain. Significant positive
      correlations were established between anti-MOG(35-55)antibody levels and clinical
      scores or GFAP positivity in the spinal cord. The heterogeneity of EAE
      progression, observed in these genetically identical individuals, suggests that
      the environment rather than the genetics plays a role. This observation is highly
      pertinent as it corresponds to what is seen in clinical MS.

PMID- 12604313
TI  - Small-molecular compounds enhance the loading of APC with encephalitogenic MBP
      protein.
AB  - Small-molecular compounds with hydrogen bond (H-bond) donor function are able to
      trigger exchange reactions of MHC class II ligands. Here, we show that their
      effect is not limited to short peptides. Also encephalitogenic myelin basic
      protein (MBP) is transferred with great efficiency onto HLA-DR molecules when H
      bond donor molecules such as parachlorphenol (pCP) are present. The effect was
      observed not only with soluble MHC class II but also with HLA-DR1 and HLA-DR2
      molecules on the cell surface. The improved loading of APC translates directly
      into improved T cell activation. In the presence of pCP T cells reacted at
      significantly lower antigen concentrations, an effect observed with purified MBP
      protein as well as with crude spinal cord homogenate. The 'accidental' transfer
      of autoantigens such as MBP onto activated APC might trigger fatal autoimmune
      reactions and small molecules as catalysts of this process could represent risk
      factors, which had not been accounted for as yet.

PMID- 12604314
TI  - CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells
      may distinguish patients with multiple sclerosis from healthy controls.
AB  - Multiple sclerosis (MS) is an inflammatory disease of the central nervous system,
      thought to be mediated in part by an autoimmune response of T cells to protein
      components of the myelin sheath. The reaction of naive T cells against these
      antigens requires co-stimulation through CD28. However, the proliferative
      response of peripheral blood mononuclear cells isolated from patients with MS and
      stimulated with myelin basic protein (MBP) has been shown to be relatively
      independent of B7-CD28 co-stimulation, suggesting that dysregulation of co
      stimulatory pathways may be involved in the pathogenesis of MS. Here, the role of
      CTLA-4 engagement was investigated. As expected, blocking CTLA-4-mediated
      signaling during stimulation of MBP-reactive T cells from healthy controls
      enhanced the proliferative and cytokine responses. In contrast, CTLA-4 blockade
      had less effect in patients with MS, suggesting that at least two regulatory
      mechanisms may be impaired in these individuals. Understanding how co-stimulatory
      signals may be dysregulated in patients with MS is important at a time when
      targeting of these pathways is being developed.

PMID- 12604315
TI  - T-cell function in anti-GAD65(+)diabetes with residual beta-cell function.
AB  - We have recently reported that in patients with anti-glutamic acid decarboxylase
      (GAD) 65(+)diabetes with residual beta-cell function, most with a 'high-titer'
      (>10U/ml) required insulin within 5 years, whereas most with a 'low-titer' (1.3
      9.9U/ml) did not need insulin for over 15-20 years after the onset. We therefore
      examined T-cell function to evaluate the difference between the high-titer and
      low-titer groups. Interleukin (IL)-10 production upon polyclonal activation was
      significantly lower in the high-titer group than in the low-titer group. The
      serum level of interferon-inducible protein-10 (IP-10) was higher in the high
      titer than the low-titer group. Although GAD65-reactive CD4(+)cells in the
      periphery were detected in both groups, a significant positive correlation
      between serum IP-10 level and the number of GAD65-reactive CD4(+)cells was
      observed only in the high-titer group. Therefore, it has been speculated that the
      co-existence of GAD65-reactive IFN-gamma-producing CD4(+)cells and a high serum
      IP-10 level may be important for rapid disease progression as seen in the high
      titer group. Based upon these results, T-cell function is considered to be
      different between the high-titer and low-titer groups in anti-GAD65(+)diabetes
      with residual beta-cell function, supporting our previous findings regarding the
      clinical outcome of insulin-dependence in the two groups.

PMID- 12604316
TI  - Paraneoplastic pemphigus is associated with the DRB1*03 allele.
AB  - Pemphigus is a group of autoimmune blistering diseases caused by autoantibodies
      directed against keratinocyte adhesion molecules. Pemphigus vulgaris (PV) and
      pemphigus foliaceus (PF), in which autoantibodies bind, respectively, to
      desmoglein 3 and desmoglein 1, are strongly associated with HLA-class II DR4 and
      DR14 alleles. In paraneoplastic pemphigus (PNP), a rare variant associated with
      neoplasia, autoantibodies target proteins of the plakin family in addition to
      desmogleins 1 and 3. The presence of anti-desmoglein antibodies in all types of
      pemphigus raises the question of common molecular mechanisms of susceptibility,
      particularly similar MHC-class II allele associations, in the different forms of
      the disease. HLA-DRB1 typing was performed in 13 PNP patients and results were
      compared to those obtained from 84 healthy controls, 37 PV and 31 PF patients.
      Our data demonstrate a significant association of PNP with HLA-DRB1*03 allele
      which was found in 61.5% of the patients, whereas DRB1*04 and DRB1*14 appear not
      to be involved in PNP susceptibility. Therefore, the HLA-genetic background of
      PNP differs from that of other types of pemphigus, which suggests that distinct
      mechanism(s) initiate(s) the immunological response in this form of pemphigus.

PMID- 12604317
TI  - Integrative care--product and process: considering the three T's of timing, type
      and tuning.
AB  - In the biomedical model of care, practitioners are familiar with the focus of
      service being the product or outcome. Integrative care is an ongoing creative
      process where patients and health practitioners work together to bring about
      healing for the patient by carefully choosing and using biomedical and
      complementary therapies. How complementary and biomedical therapies are united to
      meet the special needs of the patient is an important part of the process and is
      often overlooked. The three T's, timing, type, and tuning are parts of the
      integrative process. Integrative care as a spiritual process must demonstrate not
      only the masculine qualities of health care such as producing the name of the
      condition and the remedy. It must also demonstrate the feminine qualities of the
      process, the "how" of healing.

PMID- 12604318
TI  - Homeopathy in multiple sclerosis.
AB  - Multiple sclerosis (MS) is the most common disease of the central nervous system
      affecting people between the ages of 20 and 40 years in the UK, Northern Europe
      and the USA. No definitive treatment yet exists to halt the almost inevitable
      decline in function and accumulation of disability over the years in sufferers.
      Management is largely directly of symptoms which arise variably in the course of
      the condition. Such problems as urinary incontinence, sexual dysfunction, cramps
      and spasms, tremor and trigeminal neuralgia can often be helped to some extent
      using conventional therapies. These treatments though are not effective in
      everyone, or cause unacceptable side-effects and there are some commonly reported
      symptoms, such as fatigue or emotional lability for which there are no generally
      accepted treatments. Here, a knowledge of complementary and alternative medicine
      (CAM) can bring benefits to the person with MS. CAM is widely used by people with
      MS and some studies in this area are briefly summarised. It is interesting to
      reflect what lies behind all this CAM use and what that might tell conventional
      medicine about just what it is the MS sufferer really wants from their carers.
      Homeopathy is a form of CAM unique in the UK in having been available in the NHS
      since the foundation in 1948. Medical homeopaths in the UK have always been
      concerned with the integration of the best of conventional and complementary
      treatments for the benefit of their patients. Glasgow Homeopathic Hospital has
      around 100 admissions each year of people with MS at different stages of the
      condition and aims at an integrated response to their distress. Different
      therapeutic modalities are employed, but a homeopathic approach in particular is
      of benefit in MS. By its nature, it is a whole-person approach and allows for
      complete individualisation of treatment, taking account of the minutiae of
      someone's life. This is discussed and some examples of homeopathic treatments,
      which seem to be more generalisable for commonly encountered MS symptoms, are
      given.

PMID- 12604319
TI  - Implementing complementary therapies into midwifery practice.
AB  - This paper discusses ways in which midwives can incorporate complementary
      therapies into their practice and describes some of the innovative services
      established by midwives in the UK to date.

PMID- 12604320
TI  - Provision of acupuncture in a university health centre--a clinical audit.
AB  - A retrospective audit was carried out between May 1999 and April 2000 at a
      university-based acupuncture clinic. Two acupuncturists saw a total of 69 clients
      of whom three-quarters were female; just over a third were less than 29 years of
      age; two-thirds were below the age of 40; 67% of clients were Caucasians; a third
      smoked; three-quarters currently consumed some alcohol. Most had no experience of
      using complementary and alternative medicine (CAM), therefore the service
      provided the first access to CAM. Of those attending a follow-up appointment, 43
      (80%) reported feeling better, 10 the same and one worse. No side-effects were
      reported by 50 (73%) clients, but four reported minor side-effects (one bruising
      and three drowsiness). The process of carrying out the audit provided the
      opportunity for the practitioners to reflect on their clinical practice and
      improve service delivery.

PMID- 12604321
TI  - Education for integration--a view from the bridge!!

PMID- 12604322
TI  - Reintegrating masculinity: developing a sustainable, holistic perspective.

PMID- 12604323
TI  - Theory and exemplars of advanced practice spiritual intervention.
AB  - Spirituality, defined consistently with the work of Martha E Rogers, is explored
      and application of spiritual interventions is described and discussed using two
      case studies that exemplify working with clients in a manner that blends
      environmental resources with personal needs. This paper illustrates how nurses
      can perform non-denominational spiritual interventions without compromising
      belief systems of client or nurse and without a great deal of material resources
      or time. Simple, time-limited interventions that respond to clients' minimal
      needs are well within the abilities of all nurses to perform, do not require
      excessive material or personnel resources and may reduce clients' anxieties,
      leading to reduced dissatisfactions with care and facilitating client recovery
      and rehabilitation.

PMID- 12604325
TI  - Re: The article in Vol. 8 No. 2 (pp. 77-80): "Herbal medicine in pregnancy" by
      Pinn and Pallett.

PMID- 12604328
TI  - Rice MAPKs.
AB  - Mitogen-activated protein kinase (MAPK) cascades are evolutionary conserved from
      unicellular to complex eukaryotic organisms, and constitute one of the major
      signalling pathways involved in regulating a wide range of cellular activities
      from growth and development to cell death. MAPKs of rice (Oryza sativa L.), the
      most important of all food crops and an established monocot plant research model,
      have seen considerable progress mainly on their identification and
      characterization during the past one year alone. These studies have provided new
      information on the response and regulation of rice MAPKs, in particular on their
      possible role/function in the rice self-defense pathways. It is believed that
      further work on MAPK cascades in rice will widen our understanding of the MAPK
      signalling pathways, and may lead to the establishment of a biological model on
      this critical early signalling event in monocots. In this review, we bring
      together all the recent developments in rice MAPKs and discuss their significance
      and future direction in light of the present data and the progress made in dicot
      model plants.

PMID- 12604329
TI  - Differential effects of trichostatin A on gelatinase A expression in 3T3
      fibroblasts and HT-1080 fibrosarcoma cells: implications for use of TSA in cancer
      therapy.
AB  - Trichostatin A (TSA) is a histone deacetylase (HDAC) inhibitor with potential in
      cancer therapeutics. In a recent communication, we demonstrated that TSA is a
      selective, potent inhibitor of gelatinase A in 3T3 fibroblasts. In the present
      study, we extend these observations and examine the effects of TSA in 3T3
      fibroblasts compared to HT-1080 fibrosarcoma cells with respect to gelatinase A
      expression, cell viability, and apoptosis. We find that while expression of
      gelatinase A in 3T3 fibroblasts is exquisitely sensitive to inhibition by TSA,
      expression of this enzyme in HT-1080 cells is minimally affected by this
      compound. Moreover, we show that TSA is pro-apoptotic in HT-1080 cells, but is
      anti-apoptotic in 3T3 cells. We propose a two-pronged model for the therapeutic
      action of TSA. On the one hand TSA selectively decreases cancer cell viability,
      while enhancing the viability of stromal cells. On the other hand, by selectively
      decreasing gelatinase A expression in stromal but not cancer cells, TSA acts to
      control metastatic potential by reducing the ability of metastatic cells to
      recruit stromal cells to secrete gelatinase A.

PMID- 12604330
TI  - Novel in vitro and in vivo phosphorylation sites on protein phosphatase 1
      inhibitor CPI-17.
AB  - CPI-17 is a protein phosphatase 1 (PP1) inhibitor that has been shown to act on
      the myosin light chain phosphatase. CPI-17 is phosphorylated on Thr-38 in vivo,
      thus enhancing its ability to inhibit PP1. Thr-38 has been shown to be the target
      of several protein kinases in vitro. Originally, the expression of CPI-17 was
      proposed to be smooth muscle specific. However, it has recently been found in
      platelets and we show in this report that it is endogenously phosphorylated in
      brain on Ser-128 in a domain unique to CPI-17. Ser-128 is within a consensus
      phosphorylation site for protein kinase A (PKA) and calcium calmodulin kinase II.
      However, these two kinases do not phosphorylate Ser-128 in vitro but
      phosphorylate Ser-130 and Thr-38, respectively. The kinase responsible for Ser
      128 phosphorylation remains to be identified. CPI-17 has strong sequence
      similarity with PHI-1 (which is also a phosphatase inhibitor) and LimK-2 kinase.
      The novel in vivo and in vitro phosphorylation sites (serines 128 and 130) are in
      a region/domain unique to CPI-17, suggesting a specific interaction domain that
      is regulated by phosphorylation.

PMID- 12604331
TI  - Structural and functional analysis of BmjMIP, a phospholipase A2 myotoxin
      inhibitor protein from Bothrops moojeni snake plasma.
AB  - A protein, which neutralizes the enzymatic, toxic, and pharmacological activities
      of various basic and acidic phospholipases A(2) from the venoms of Bothrops
      moojeni, Bothrops pirajai, and Bothrops jararacussu, was isolated from B. moojeni
      snake plasma by affinity chromatography using immobilized myotoxins on Sepharose
      gel. Biochemical characterization of this myotoxin inhibitor protein (BmjMIP)
      showed it to be an oligomeric glycoprotein with a M(r) of 23,000-25,000 for the
      monomeric subunit. BmjMIP was stable in the pH range from 4.0 to 12.0, between 4
      and 80 degrees C, even after deglycosylation. The role of the carbohydrate moiety
      was investigated and found not to affect the in vitro function of the inhibitor.
      The corresponding 500bp cDNA obtained by RT-PCR from the liver of the snake
      encodes a mature protein of 166 amino acid residues including a 19 amino acid
      signal peptide. The primary structure of BmjMIP showed a high similarity with
      other snake phospholipase A(2) inhibitors (PLIs) in which the carbohydrate
      recognition domain (CRD) and the glycosylation site (Asn103) are conserved.
      Circular dichroism spectroscopy indicated that no significant alterations in the
      secondary structure of either the BmjMIP or the target protein occur upon their
      interaction. BmjMIP has a wide range of inhibitory properties against basic and
      acidic PLA(2)s from Bothrops venoms (anti-enzymatic, anti-myotoxic, anti-edema
      inducing, anti-cytotoxic, anti-bactericidal, and anti-lethal). However, the
      inhibitor showed a reduced ability to neutralize the biological activities of
      crotoxin B (CB), the PLA(2) homologue associated with crotapotin in Crotalus
      durissus terrificus snake venom. Finally, the purified PLA(2) inhibitor was shown
      to protect in vivo against the toxic and pharmacological effects of a homologous
      PLA(2) enzyme, suggesting that PLIs or a corresponding derived peptide may prove
      useful in the treatment of snakebite victims or, more importantly, in the
      treatment of the many human diseases in which these enzymes have been implicated.

PMID- 12604333
TI  - Hemocytes of Ciona intestinalis express multiple genes involved in innate immune
      host defense.
AB  - Ascidians, which are classified as urochordata, appear to employ a primitive
      system of host defense that is considered to be a prototype of vertebrate innate
      immunity. We performed a cDNA/EST study to identify the genes expressed in the
      hemocytes of Ciona intestinalis. We obtained 3357 one-path reads that were then
      grouped into 1889 independent clusters. Although two thirds of the clusters could
      not be assigned to any particular gene, the remaining 530 clusters had
      significant homology to genes with known function. Of these, 62 clusters appeared
      to be related to host defense mechanisms. These include transcripts whose
      products are probably involved in cytotoxicity, detoxification, inflammation, and
      apoptosis. As expected, elements of acquired immunity were not detected. Thus,
      Ciona hemocytes appear to express a number of host defense-related genes involved
      in innate immune mechanisms.

PMID- 12604334
TI  - A new inhibitor of the transcription-termination factor Rho.
AB  - In this study we describe BI-K0058, a new inhibitor of the transcription
      termination factor Rho belonging to a different chemical class from bicyclomycin,
      the only known antibiotic acting on Rho. BI-K0058 inhibits the poly(C)-dependent
      ATPase activity of Rho with an IC(50) of 25 microM as well as in vitro
      transcription-termination of two natural substrates, the Salmonella enterica hisG
      cistron and the f1 phage intergenic region. BI-K0058 does not affect
      photolabeling of Rho by ATP. The results of gel mobility shift experiments with a
      natural RNA substrate demonstrate that BI-K0058 inhibits the formation of the ATP
      independent high affinity Rho-RNA complex.

PMID- 12604332
TI  - Comparative effects of basophil-directed growth factors.
AB  - IL-3, IL-5, and GM-CSF exert various overlapping functions in basophils. We
      investigated the receptor expression profiles and concentration-dependent effects
      of IL-3, IL-5, and GM-CSF on several basophil functions in comparison with their
      effects on eosinophils. The order of the receptor expression levels was IL
      3Ralpha>IL-5Ralpha>GM-CSFRalpha in basophils and IL-5Ralpha>or=GM-CSFRalpha>IL
      3Ralpha in eosinophils. Compared with eosinophils, basophils expressed a much
      higher level of IL-3Ralpha and similar levels of IL-5Ralpha and GM-CSFRalpha. The
      order of potency was IL-3>IL-5=GM-CSF for degranulation, survival, and CD11b
      expression in basophils, and IL-5=GM-CSF>or=IL-3 for survival and CD11b
      expression in eosinophils. However, IL-3 induced CD69 expression preferentially
      in basophils. Our results indicate that IL-3 is the most potent activator of
      human basophils, and that the rank order of potency of hemopoietic growth factors
      virtually corresponded to their receptor expression levels in both cell types.

PMID- 12604336
TI  - Pre- and postsynaptic inhibition mediated by GABA(B) receptors in rat
      ventrolateral periaqueductal gray neurons.
AB  - The present study examined the actions of a GABA(B)-receptor agonist, baclofen,
      on synaptic transmission in rat ventrolateral periaqueductal gray (PAG) neurons
      of brainstem slices by using whole-cell voltage-clamp recordings. Baclofen (10
      microM) induced a slow outward current (peak amplitude: 30.1+/-3.1pA, n=13) at 
      70mV, which persisted in the presence of tetrodotoxin (0.5 microM) and was
      diminished in the presence of postsynaptic intracellular K(+)-channel blockers
      (Cs(+) and TEA) and GDP-beta-S, indicating a direct postsynaptic depression
      mediated by K(+) channels and G proteins. Baclofen (10 microM) also decreased the
      frequency of both glutamatergic spontaneous EPSC (by 36+/-7%, n=11) and GABAergic
      spontaneous IPSC (by 37+/-12%, n=6) without changes in their amplitudes,
      indicating its presynaptic inhibitions. Taken together, the activation of
      postsynaptic GABA(B) receptors inhibits ventrolateral PAG neurons directly. At
      the same time, activating presynaptic GABA(B) receptors on glutamatergic and
      GABAergic nerve terminals inhibits glutamate and GABA release, respectively. The
      overall effects might influence an output of ventrolateral PAG neurons that build
      up the descending pain control system to the spinal dorsal horn.

PMID- 12604335
TI  - Neuroprotective effects of interleukin-6 on NMDA-induced rat retinal damage.
AB  - This study shows that interleukin-6 (IL-6) combined with soluble interleukin-6
      receptors (sIL-6R) modulates N-methyl-D-aspartate (NMDA)-induced retinal damage.
      Eyes pretreated with a combined injection of IL-6 and sIL-6R had NMDA
      administered into the vitreous cavity. Morphometric analysis and retrograde
      labeling analysis found that pretreatment with either IL-6 or sIL-6R alone did
      not bring about any neuroprotective effect. However, pretreatment with a combined
      administration of IL-6 and sIL-6R induced a significant neuroprotective effect
      against NMDA-induced retinal damage. Apoptotic changes in the retina were
      assessed by the TUNEL method. The results indicated that pretreatment with IL-6
      combined with sIL-6R prevents NMDA-induced apoptosis. Western blotting studies
      demonstrated upregulation of gp130 expression in the NMDA-injected retina.
      Present studies suggest that IL-6 combined with sIL-6R provides a neuroprotective
      effect on NMDA-induced retinal damage.

PMID- 12604337
TI  - Merlin suppresses the SRE-dependent transcription by inhibiting the activation of
      Ras-ERK pathway.
AB  - The neurofibromatosis type 2 (NF2) gene encodes an intracellular membrane
      associated protein called merlin or schwannomin, which is known to be a tumor
      suppressor. Numerous studies have suggested that merlin is involved in the
      regulation of cell growth and proliferation. Previously, merlin/schwannomin was
      reported to block Ras-induced cell proliferation and anchorage-independent cell
      growth. Also, the N-terminus of merlin was found to suppress cell proliferation,
      although it appears to be less effective than full-length merlin. However, the
      inhibitory mechanism of merlin is unknown. In this report, merlin is shown to be
      effective at suppressing serum/Ras-induced and Elk-mediated SRE dependent
      transactivation, and serum-induced ERK phosphorylation in NIH3T3 cells. In
      addition, merlin inhibited serum-induced Elk phosphorylation, a downstream
      effector of ERKs. Also, the N-terminal deficient merlin mutant could not block
      serum-induced and Elk-mediated SRE dependent transactivation, although the C
      terminal deficient merlin mutant could. These results suggest that merlin
      inhibits SRE dependent transactivation by repressing serum-induced ERK
      phosphorylation and its downstream effector, Elk phosphorylation. Also, the N
      terminus of merlin may be important for its inhibitory effect. Our results show
      that merlin acts as a negative regulator of the SRE signaling pathway via the Ras
      ERKs pathway.

PMID- 12604338
TI  - Insertion mutagenesis of Escherichiacoli GroEL.
AB  - To gain insights into the in vivo folding and assembly of bacterial chaperonins,
      groEL was subjected to insertion mutagenesis using transposon ISlacZ/in. Four
      GroEL-LacZ fusions and the corresponding insertion mutants were obtained after
      residues 34, 90, 291, and 367. Apical domain insertion mutants GroEL291 and
      GroEL367 were degraded into monomeric 30- and 40-kDa fragments, respectively.
      Only the latter was fully soluble, suggesting that proper isomerization of an
      essentially complete apical domain is required for efficient protomer folding.
      Truncated variants were inactive as minichaperones as they failed to restore the
      growth of groEL140 cells at 43 degrees C whether or not GroES was co-expressed. A
      31-residue insertion in equatorial helix D led to complete degradation of
      GroEL90. By contrast, extraneous amino acids were tolerated at equatorial
      position 34, indicating that this region is highly flexible. Nevertheless,
      GroEL34 did not fold as efficiently as authentic GroEL and reached only a
      heptameric conformation.

PMID- 12604339
TI  - Potent dual anti-HIV and spermicidal activities of novel oxovanadium(V) complexes
      with thiourea non-nucleoside inhibitors of HIV-1 reverse transcriptase.
AB  - We have previously demonstrated that tetrahedral
      bis(cyclopentadienyl)vanadium(IV) complexes and square pyramidal oxovanadium(IV)
      complexes of vanadium are rapid and selective spermicidal agents at low
      micromolar concentrations. This study investigated the potential utility of
      oxovanadium in combination with thiourea non-nucleoside inhibitors (NNIs) of HIV
      1 reverse transcriptase (RT) for the development of an effective dual-function
      anti-HIV spermicide. Two rationally designed substituted phenyl-ring containing
      pyridyl thiourea NNIs, N-[2-(2-chlorophenethyl)]-N(')-[2-(5-bromopyridyl)
      thiourea) [1] and N-[2-(2-methoxyphenethyl)]-N(')-[2-(pyridyl)-thiourea [2] that
      exhibited subnanomolar IC(50) values against the drug-sensitive, drug-resistant,
      and multidrug-resistant strains of HIV-1, were complexed with oxovanadium. The
      oxovanadium-thiourea [OVT] NNIs, C(29)H(27)Br(2)Cl(2)N(6)O(2)S(2)V [3], and
      C(31)H(35)N(6)O(4)S(2)V [4], were synthesized by reacting VOSO(4), a V(IV)
      compound, with the corresponding deprotonated thiourea NNI compounds as ligands.
      Elemental analysis showed that each OVT-NNI used two thiourea molecules as
      ligands. The existence of the Vz.dbnd6;O bond (968cm(-1)) was confirmed by IR
      spectroscopy. No d-d bands were observed in the visible spectra of OVT-NNIs and
      their EPR spectra were featureless, indicating that the vanadium centers were
      oxidized to V(V). The new OVT-NNIs as well as their thiourea NNI ligands were
      evaluated for (i) anti-HIV activity using the cell-free recombinant RT inhibition
      assays, (ii) cellular HIV replication assays, (iii) spermicidal activity against
      human sperm by computer-assisted sperm analysis (CASA), and (iv) cytotoxicity
      against normal human female genital tract epithelial cell using MTT (3-(4,5
      dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assays.
      Similar to thiourea NNIs 1 and 2, the OVT-NNIs 3 and 4, exhibited potent anti-HIV
      activity with submicromolar IC(50[p24]) values (0.08 and 0.128 microM,
      respectively) and submicromolar IC(50[RT]) values (2.1 and 0.87 microM,
      respectively). Notably, OVT-NNIs were spermicidal against human sperm at low
      micromolar concentrations (IC(50)=34 and 55 microM, respectively) and induced
      rapid sperm immobilization (T(1/2)=12 and 240s) when compared with their
      respective thiourea NNI ligands (EC(50)=>400 microM and T(1/2)=>180min).
      Moreover, OVT-NNIs displayed high selectivity indices against normal female
      genital tract epithelial cells (IC(50) values >250 microM) when compared to the
      detergent-type spermicide, nonoxynol-9, which was cytotoxic at spermicidal
      concentrations (IC(50) values 32-64 microM). This is the first report on the dual
      anti-HIV and spermicidal activities of a vanadium/oxovanadium complex. Our
      discovery of potent anti-HIV and rapid spermicidal activities of OVT-NNIs may be
      useful for the development of an effective and safe vaginal anti-HIV spermicide
      for women who are at high risk for acquiring HIV/AIDS by heterosexual
      transmission.

PMID- 12604340
TI  - Ethanolamine plasmalogen and cholesterol reduce the total membrane oxidizability
      measured by the oxygen uptake method.
AB  - To investigate the effects of ethanolamine plasmalogen, phosphatidylethanolamine,
      cholesterol, and alpha-tocopherol on the oxidizability of membranes, various
      large unilamellar vesicles (LUVs) including these lipids and antioxidant were
      examined for their total membrane oxidizabilities, evaluated as R(p)/R(i)(1/2)
      value (where R(p) is rate of oxygen consumption and R(i)(1/2) is the square root
      of rate of chain initiation) by the oxygen uptake method with water-soluble
      radical initiator and inhibitor. Incorporation of bovine brain ethanolamine
      plasmalogen (BBEP) into vesicles as well as cholesterol led to lower the total
      membrane oxidizability dose-dependently. The effect of BBEP was more efficient in
      the presence of cholesterol in vesicles. On the other hand, diacyl counterpart,
      egg yolk phosphatidylethanolamine, and a typical radical scavenger, alpha
      tocopherol, had no effect on the membrane oxidizability. Alpha-tocopherol only
      prolonged an induction period dose-dependently in the present oxidizing system,
      suggesting a novel antioxidant mechanism of ethanolamine plasmalogens besides the
      action of scavenging radicals.

PMID- 12604341
TI  - Effects of soy protein isolate on LEC rats, a model of Wilson disease: mechanisms
      underlying enhancement of liver cell damage.
AB  - Soy-protein isolate (SPI) enhances liver cell damage in Long-Evans rats with a
      cinnamon-like coat color (LEC rats), which have a defect in Atp7b, the Wilson
      disease gene. Animals administered an SPI-diet from an age of six weeks died
      significantly earlier than those administered a control-diet, AIN-93G, from
      severe liver cell damage associated with jaundice. Since the liver copper level
      was higher with the SPI-diet than the control-diet, one of the reasons for SPI
      toxicity to LEC rats might be due to the higher uptake of copper into liver
      cells. In the present study, liver levels of glutathione, and liver and
      intestinal mRNA and protein levels were determined for metallothionein, MT-1 and
      MT-2. Furthermore, liver and intestinal mRNA expression for the high affinity
      copper transporter, Ctr1, was determined. None of the parameters showed any
      significant differences between the SPI-diet and control-diet groups, except for
      Ctr1 mRNA levels in the liver. It is thus suggested that SPI enhances liver cell
      copper uptake through induction of Ctr1 expression and this might be the
      mechanism underlying increased liver damage in LEC rats.

PMID- 12604342
TI  - Vasoactive intestinal peptide inhibits IL-8 production in human monocytes by
      downregulating nuclear factor kappaB-dependent transcriptional activity.
AB  - Although interleukin-8 (IL-8) is a chemokine that plays a beneficial and central
      role in the inflammatory response, hematopoiesis, and angiogenesis, excessive IL
      8 production can be deleterious to the host, and its selective inhibition
      represents an important therapeutic goal. Vasoactive intestinal peptide (VIP) is
      a neuropeptide that acts as a potent anti-inflammatory agent inhibiting the
      function of activated macrophages/monocytes. The present study reports the effect
      of VIP on IL-8 production by stimulated human THP1 monocytes. VIP inhibits IL-8
      production in a dose- and time-dependent manner at the mRNA level. VIP seems to
      act by inhibiting the NF-kappaB-dependent IL-8 gene activation. The specific
      VPAC1 receptor mediates the inhibitory effect of VIP. Two transduction pathways
      appear to be involved, a major cAMP-independent pathway that preferentially
      blocks nuclear translocation of NF-kappaB and its binding to the kappaB site of
      the IL-8 promoter, and a cAMP-dependent pathway that inhibits the activation and
      binding to the IL-8 promoter of both CREB-binding protein (CBP) and TATA box
      binding protein (TBP), two transcriptional cofactors strictly required for the
      transactivating activity of NF-kappaB. These findings support the proposed role
      of VIP as a key endogenous anti-inflammatory agent and describe a novel
      mechanism, i.e., the inhibition of the production of monocyte-derived IL-8, and
      are of obvious physiological significance, because VIP, through the inhibition of
      IL-8 production, could reduce the monocyte-induced neutrophil
      chemotaxis/infiltration, an important event in the pathogenesis of several
      inflammatory and autoimmune disorders.

PMID- 12604343
TI  - New membrane-associated and soluble peptide methionine sulfoxide reductases in
      Escherichia coli.
AB  - It is known that reactive oxygen species can oxidize methionine residues in
      proteins in a non-stereospecific manner, and cells have mechanisms to reverse
      this damage. MsrA and MsrB are members of the methionine sulfoxide family of
      enzymes that specifically reduce the S and R forms, respectively, of methionine
      sulfoxide in proteins. However, in Escherichia coli the level of MsrB activity is
      very low which suggested that there may be other enzymes capable of reducing the
      R epimer of methionine sulfoxide in proteins. Employing a msrA/B double mutant, a
      new peptide methionine sulfoxide reductase activity has been found associated
      with membrane vesicles from E. coli. Both the R and S forms of N-acetylmethionine
      sulfoxide, D-ala-met(o)-enkephalin and methionine sulfoxide, are reduced by this
      membrane associated activity. The reaction requires NADPH and may explain, in
      part, how the R form of methionine sulfoxide in proteins is reduced in E. coli.
      In addition, a new soluble Msr activity was also detected in the soluble extracts
      of the double mutant that specifically reduces the S epimer of met(o) in
      proteins.

PMID- 12604344
TI  - Ultraviolet irradiation increases FADD protein in apoptotic human keratinocytes.
AB  - Ultraviolet irradiation (UV) can induce keratinocyte apoptosis by activating
      death receptors that recruit the intracellular adaptor molecule FADD/MORT1 (Fas
      associating death domain protein/mediator of receptor-induced toxicity). We
      hypothesized that UV could alter FADD expression levels to augment UV-induced
      keratinocyte apoptosis. In a dose-dependent manner UV B irradiation increased the
      expression of FADD protein in a human keratinocyte cell line (CCD-1106) with a
      corresponding increase in caspase-8 cleavage and cellular apoptosis. FADD
      overexpression induced cell death in 80% of cells compared with 10% spontaneous
      cell death in controls. Inhibition of FADD protein by adenoviral expression of
      anti-sense FADD reduced keratinocyte apoptosis. Regulation of FADD expression by
      UV may serve to enhance death receptor-mediated keratinocyte death.

PMID- 12604345
TI  - Non-randomness in Shine-Dalgarno regions: links to gene characteristics.
AB  - A probabilistic approach to the study of the Shine-Dalgarno region was used to
      identify the most non-random positions based on parsing of genomes in four
      species: Escherichia coli, Bacillus subtilis, the AT-rich Clostridium
      perfringens, and the GC-rich Streptomyces coelicolor. The compositional non
      randomness shows a clear peak centered around 9-11 nucleotides upstream of the
      start codon. This peak was in all species associated with guanine as the most
      abundant nucleotide, flanked by guanine in the closest proximity and adenines
      farther away (cytosine in case of S. coelicolor). Using contingency tables, the
      nucleotides in the Shine-Dalgarno region were shown to have a strong association
      to the choice of start codons. We also show that gene characteristics such as
      length, aromaticity, and lipophilicity are related to the nucleotide at this peak
      position upstream of the start codon.

PMID- 12604346
TI  - The CRG1 gene required for resistance to the singlet oxygen-generating
      cercosporin toxin in Cercospora nicotianae encodes a putative fungal
      transcription factor.
AB  - The Cercospora nicotianae CRG1 gene is involved in cellular resistance to the
      perylenequinone toxin, cercosporin, that generates highly toxic singlet oxygen
      upon exposure to light. The entire open reading frame (ORF) of CRG1 was isolated
      and sequenced. The gene contains an ORF of 1950bp including a 65-bp intron. The
      predicted 650 amino acid CRG1 protein contains a Cys(6)Zn(2) binuclear cluster
      DNA-binding motif with homology to various fungal regulatory proteins, indicating
      that CRG1 may act functionally as a transcription activator. Targeted gene
      disruption of CRG1 resulted in mutants that are partially sensitive to
      cercosporin and reduced in cercosporin production. Genetic complementation
      revealed that CRG1 fully restored cercosporin resistance, but only slightly
      restored cercosporin production in a UV-derived mutant (CS10) containing a single
      nucleotide substitution in crg1. Complementation of a crg1-null mutant, however,
      yielded strains that are similar to the wild-type in both phenotypes. These
      results indicate that the transcription regulator CRG1 is involved in the
      activation of genes associated with cercosporin resistance and production in the
      fungus Cercospora nicotianae.

PMID- 12604347
TI  - Protein minimization: characterization of the synthetic cyclic dodecapeptide
      corresponding to the reactive site region of the oil rape trypsin inhibitor type
      III.
AB  - The design of minimal units required for enzyme inhibition is a major field of
      interest in structural biology and biotechnology. The successful design of the
      cyclic dodecapeptide corresponding to the Phe17-Val28 reactive site amino acid
      sequence of the low-molecular-mass trypsin inhibitor RTI-III from Brassica napus
      (micro-RTI-III) and of the recombinant murine dihydrofolate reductase-(DHFR
      )micro-RTI-III fusion protein (DHFR-micro-RTI-III) is reported here. Micro-RTI
      III was synthesized using a stepwise solid-phase approach based on the standard
      Fmoc chemistry, purified by RP-HPLC, and oxidatively refolded. DHFR-micro-RTI-III
      was expressed in Escherichia coli, purified by metal-chelate affinity
      chromatography, and oxidatively refolded. The affinity of micro-RTI-III for
      bovine trypsin (K(d)=1.6x10(-9)M) is similar to that determined for DHFR-micro
      RTI-III (K(d)=6.3x10(-10)M) and native RTI-III (K(d)=2.9x10(-10)M), at pH 8.2 and
      22.0 degrees C. Remarkably, micro-RTI-III protects the DHFR domain of DHFR-micro
      RTI-III from trypsin digestion. Micro-RTI-III is a new minimal trypsin inhibitor
      and may be regarded as a tool in protein structure-function studies and for
      developing multifunctional and multidomain proteinase inhibitors.

PMID- 12604348
TI  - Double-stranded RNA can mediate the suppression of uracil
      phosphoribosyltransferase expression in Toxoplasma gondii.
AB  - Double-stranded RNA (dsRNA) homologous to the Toxoplasma gondii uracil
      phosphoribosyltransferase (TgUPRT) gene is able to modulate the UPRT gene
      expression in T. gondii. The dsRNA, which was produced either from a constructed
      plasmid or from an in vitro transcription reaction, was capable of down
      regulating the expression of TgUPRT. Stably transformed T. gondii expressing the
      dsRNA, which was capable of growing in the presence of the prodrug 5-fluoro-2(')
      deoxyuridine (FDUR), appeared to maintain the engineered plasmid as an extra
      chromosomal DNA. When cultured in the absence of the selection pressure, the FDUR
      resistant parasites slowly reverted to the FDUR sensitive phenotype. The level of
      the dsRNA necessary to confer FDUR resistance was estimated at 2-8 copies per
      parasite. More importantly the introduction of the in vitro synthesized dsRNA
      homologous to the TgUPRT gene into T. gondii can also induce the specific mRNA
      degradation, resulting in a lowered UPRT activity.

PMID- 12604349
TI  - Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2,
      and ZO-3.
AB  - Occludin, the transmembrane integral protein of the tight junction, plays a
      crucial role in the molecular organization and function of tight junction. While
      the homotypic interaction of extracellular loops of occludin appears to determine
      the barrier function of tight junction, the intracellular C-terminal tail, C
      occludin, interacts with other tight junction proteins such as ZO-1, ZO-2, and ZO
      3 and with the actin filaments of cytoskeleton. In the present study we
      phosphorylated GST-fused C-occludin on tyrosine residues, in TKX1 Epicurian coli
      or by active c-Src in vitro. c-Src binds to occludin and phosphorylates it on
      tyrosine residues. The effect of tyrosine phosphorylation of C-occludin on its
      ability to bind ZO-1, ZO-2, ZO-3, and F-actin was evaluated. Results show that
      the amounts of ZO-1, ZO-2, and ZO-3 bound to tyrosine phosphorylated C-occludin
      were several fold less than the amounts bound to non-phosphorylated C-occludin.
      However, the amount of tyrosine phosphorylated C-occludin bound to F-actin was
      not significantly different from the amount of non-phosphorylated C-occludin
      bound to F-actin. These results demonstrate that tyrosine phosphorylation of
      occludin reduces its ability to bind ZO-1, ZO-2, and ZO-3, but not F-actin.
      Results also suggest that c-Src-mediated disruption of tight junction may involve
      tyrosine phosphorylation of occludin.

PMID- 12604350
TI  - Regulation of leukotriene-dependent induction of cyclooxygenase-2 and Bcl-2.
AB  - Leukotrienes play an important pathophysiological role in chronic inflammatory
      states and, as previously shown, cause increased levels of cyclooxygenase-2 (COX
      2) in intestinal epithelial cells. The anti-apoptotic protein Bcl-2 is also
      elevated by LTD(4) stimulation, and in colon cancer, so we studied the mechanisms
      of COX-2 and Bcl-2 regulation. We found that LTD(4) induced a 3-fold elevation of
      COX-2 transcription in Int 407 cells and a 2-fold equivalent in colon cancer
      cells, Caco-2. This was mediated through a pertussis toxin (PTX) sensitive G
      protein and the MAP kinase Erk-1/2 pathway, and this was also shown to be the
      route to up-regulation of Bcl-2 by LTD(4). In good agreement with this, we
      detected a strong activation of Erk-1/2 that was further increased by COX-2
      inhibition, pointing towards the existence of negative feedback regulation.
      Furthermore, COX-2 activity is responsible for the effects on Bcl-2, but this is
      not conveyed through the production of PGE(2).

PMID- 12604351
TI  - A constitutively active aryl hydrocarbon receptor causes loss of peritoneal B1
      cells.
AB  - The dioxin/aryl hydrocarbon (Ah) receptor functions as a ligand-activated
      transcription factor that mediates toxicity of dioxins and related environmental
      pollutants. We have developed a transgenic mouse model that expresses a
      constitutively active Ah receptor. The immune system is one of the most sensitive
      target organs for dioxin toxicity and we have therefore investigated alterations
      of different lymphocyte populations in these mice. The population of mature bone
      marrow derived B cells was enlarged, consistent with previous findings in dioxin
      exposed mice. In contrast, the peritoneal population of CD5-expressing B cells
      (B1 cells) was significantly diminished. This is the first study that
      demonstrates the effect of an activated Ah receptor on B1 cells. Since these
      cells are important mediators of innate immunity against pathogens such as
      Influenza virus, these results may explain the decreased resistance against
      infections that has been documented after dioxin exposure.

PMID- 12604352
TI  - PAX4 mutation (R121W) as a prodiabetic variant in Okinawans.
AB  - We previously reported that a missense mutation at codon 121 (CGG(Arg) to
      TGG(Trp), R121W) of PAX4 may be associated with the onset of type 2 diabetes in
      Japanese. In this study, we determined the frequency of the R121W mutation of
      PAX4 and characterized the prodiabetic phenotype in a population-based study.
      Healthy 372 residents participated in annual health check-ups in Nishihara
      (Okinawa, Japan) and unrelated 193 type 2 diabetic patients from the outpatient
      clinic of Ryukyu University Hospital were enrolled. Diagnosis of diabetes was
      based on the 1997 American Diabetes Association criteria. The R121W mutation in
      PAX4 was genotyped by PCR-RFLP analysis. In healthy residents, R121W mutation was
      detected in 12 of 372 residents (3.1%). The prevalence of newly diagnosed type 3
      diabetes (25% vs. 5%, p=0.004) and HbA(1c) (5.6+/-1.9 vs. 5.1+/-0.7, p=0.026) was
      higher in the variants than in the wild-types. The odds ratio of diabetes in the
      R121W variants was 5.98 with 95% confidence interval from 1.50 to 23.9. The R121W
      mutation was observed in 12 of the 193 type 2 diabetic patients (6.2%). Onset
      ages of diabetes were earlier (37+/-10 vs. 47+/-13 years, p=0.010) and the rate
      of insulin user was two times higher (83% vs. 41%, p=0.005) in the variants. The
      R121W mutation in PAX4 is a predisposing factor for the development of type 2
      diabetes in Okinawans.

PMID- 12604354
TI  - Efficient adenovirus transduction of 3T3-L1 adipocytes stably expressing
      coxsackie-adenovirus receptor.
AB  - 3T3-L1 adipocytes have proven difficult to transfect with plasmid-encoded cDNAs
      or even infect with virally-derived cDNAs. We have developed and characterized a
      3T3-L1 adipocyte cell line stably expressing the truncated receptor for
      coxsackievirus and adenovirus receptor (CAR) for its ability to be infected with
      adenoviruses at a low multiplicity of infection (m.o.i.). Using green fluorescent
      protein driven by the cytomegalovirus promoter in adenovirus fiber type 5 we
      compared infection efficiencies of CAR adipocytes versus the parental 3T3-L1
      adipocytes. As assessed by immunofluorescence, CAR adipocytes were infected at
      approximately 100-fold greater efficiency than regular 3T3-L1 adipocytes. The
      efficiency of transduction for the CAR adipocytes was >90% at multiplicities of
      infection of 50 whereas standard adipocytes were poorly transduced even at an
      m.o.i. of 2000. Since many investigators studying insulin action use 3T3-L1
      adipocytes, we compared CAR adipocytes versus regular adipocytes and showed that
      the two cell lines were similar with respect to insulin stimulation of insulin
      receptor, MAPK, and Akt phosphorylation and basal- and insulin-stimulated glucose
      transport. In addition, CAR adipocytes accumulated GLUT4 and SCD1 proteins during
      the adipogenesis program with the same time course as regular 3T3-L1 adipocytes.
      Lastly, CAR adipocytes produced and secreted the adipose-specific hormone Acrp30.
      These data suggest 3T3-L1CARDelta1 adipocytes are virtually indistinguishable
      from their parental cells, but demonstrate a significant advantage with improved
      efficiency of adenoviral transduction for gain or deletion of function studies.

PMID- 12604353
TI  - Characterization of transcripts generated from mouse hepatocyte growth factor
      activator inhibitor type 2 (HAI-2) and HAI-2-related small peptide (H2RSP) genes:
      chimeric mRNA transcribed from both HAI-2 and H2RSP genes is detected in human
      but not in mouse.
AB  - We previously reported a novel small gene, designated hepatocyte growth factor
      activator inhibitor type 2 (HAI-2) related small peptide (H2RSP), in the process
      of the search for splicing variant forms of HAI-2 by 3(')-rapid amplification of
      cDNA ends method [Biochem. Biophys. Res. Commun. 288 (2001) 390]. Human H2RSP
      gene consisted of four exons spanning approximately 1kbp and was located in 11kbp
      downstream of HAI-2 gene. In this study, we cloned and characterized the mouse
      counterpart of H2RSP gene, which was located in 6.6kbp downstream of mouse HAI-2
      gene, and analyzed the transcripts generated from both genes. Similar to human,
      mouse H2RSP mRNA (0.5kb) was detected abundantly in various tissues including the
      gastrointestinal tract, and has nuclear localization signal (NLS) in the lysine
      rich region (exon 4), which was well-conserved between human and mouse genes.
      However, chimeric mRNA transcribed from both HAI-2 (exons 1-7) and H2RSP (exons 2
      4) genes, which was found in the kidney, prostate, and placenta of human by
      Northern blot analysis, was not detected in mouse tissue even by a reverse
      transcription-polymerase chain reaction (RT-PCR). Instead of the chimeric mRNA, a
      novel splicing variant lacking putative transmembrane domain of HAI-2 was found
      in mouse but not in human as a putative secrete form of HAI-2. These results
      suggest that the organization of H2RSP and HAI-2 gene complex is well-conserved,
      but the usage of these genes was quite different between human and mouse.

PMID- 12604356
TI  - Chromosomal organization and transcription analysis of genes in the vicinity of
      Pseudomonas aeruginosa glmM gene encoding phosphoglucosamine mutase.
AB  - A computer-aided analysis of the Pseudomonas aeruginosa PAO1 genome surrounding
      the glmM gene was carried out and the organization of this chromosomal region was
      compared with the equivalent regions in other gamma-proteobacteria species with
      the genome sequence available. glmM encodes the enzyme phosphoglucosamine mutase
      which catalyses the interconversion of glucosamine-6-phosphate into glucosamine-1
      phosphate in the biosynthetic pathway leading to the synthesis of UDP-N
      acetylglucosamine which is simultaneously a precursor for the biosynthesis of
      cell-wall peptidoglycan and outer membrane lipopolysaccharide. Northern blot
      analysis suggests that glmM may be a part of the five-cistron operonic structure
      composed by the Escherichia coli homologues ftsJ, ftsH, folP, glmM, and tpiA. The
      secG gene, downstream tpiA, does not make part of this polygenic organization,
      being actively transcribed as a monocistronic mRNA during transition to the
      stationary phase of growth. Differently, transcription of genes in the glmM
      operon is more active in the early exponential phase, decreasing with the
      increase of cell density during exponential growth and reaching negligible values
      in stationary phase cells.

PMID- 12604355
TI  - Growth hormone, but not insulin, activates STAT5 proteins in adipocytes in vitro
      and in vivo.
AB  - STAT 5 proteins are latent transcription factors which have been shown to be
      activated by growth hormone (GH) in many cell types. However, some recent studies
      also suggest that STAT 5B is a physiological substrate of the insulin receptor.
      In our studies, we have shown that physiological levels of insulin do not induce
      STAT 5 tyrosine phosphorylation or affect the nuclear distribution of STATs 5A or
      5B in 3T3-L1 adipocytes. Moreover, we did not observe the activation of STAT 5 in
      the adipose tissue or skeletal muscle of mice following an acute intraperitoneal
      injection of insulin. However, acute GH administration, both in vitro and in
      vivo, resulted in the activation of STAT 5 proteins. In summary, our results
      indicate that STAT 5 proteins are not activated by physiological levels of
      insulin in adipose tissue.

PMID- 12604357
TI  - Coordinate induction of AMP deaminase in human atrium with mitochondrial DNA
      deletion.
AB  - Despite the heteroplasmic lower population of mitochondrial (mt) DNA deletion,
      mtDNA deletion is significantly related to the loss of atrial adenine
      nucleotides. To elucidate its mechanism, we examined the frequency of a 7.4-kb
      mtDNA deletion, the concentration of adenine nucleotides, and the activity of AMP
      catabolic enzymes in 10 human right atria obtained from cardiac surgery, using
      quantitative PCR, HPLC, and immunoprecipitations. The atrial concentrations of
      ATP, ADP, AMP, and the total adenine nucleotides were significantly lower in
      patients with deletion than those in patients without deletion, despite the lower
      frequency of their deletion. The activities of total AMP deaminase (AMPD), liver
      type (AMPD 2), and heart-type isoform (AMPD 3) were significantly higher in
      patients with deletion than in patients without deletion, although there was no
      significant difference in the cytosolic 5(')-nucleotidase among them. In
      conclusion, mtDNA deletion coordinately induces AMP deaminase to contribute to
      the loss of atrial adenine nucleotides through degrading AMP excessively.

PMID- 12604358
TI  - Comparison of nucleic acid-based detection of avian influenza H5N1 with virus
      isolation.
AB  - Nucleic acid sequence-based amplification with electrochemiluminescent detection
      (NASBA/ECL) of avian influenza virus was compared with viral culture in
      embryonated chicken eggs. Virus was isolated from blood or anal swabs of chickens
      artificially infected with highly pathogenic avian influenza A/Chicken/Hong
      Kong/1000/97 (H5N1). Viral nucleic acid was detected in blood samples by
      NASBA/ECL immediately prior to death, whilst nucleic acid extracted from anal
      swabs was detected from the day following artificial infection until death. Thus,
      blood and/or anal swabs are a suitable source of material for the detection of
      avian influenza in dead birds, but anal swabs are more suitable for detection of
      viral genetic material in live birds. Dilution of a known viral standard was used
      to determine the limit of sensitivity for both NASBA/ECL and egg culture
      detection methods. The NASBA/ECL method was equivalent in sensitivity to egg
      culture. The NASBA/ECL results agreed with egg culture data in 71/94 (75.5%)
      tissue samples obtained from artificially infected birds.

PMID- 12604359
TI  - Deregulation of Cdc2 kinase induces caspase-3 activation and apoptosis.
AB  - Progression of the cell cycle and control of apoptosis are tightly linked
      processes. It has been reported that manifestation of apoptosis requires cdc2
      kinase activity yet the mechanism(s) of which is largely unclear. In an attempt
      to study the role of human MDM2 (HDM2) in interphase and mitosis, we employed the
      Xenopus cell-free system to study HDM2 protein stability. Interestingly, HDM2 is
      specifically cleaved in Xenopus mitotic extracts but not in the interphase
      extracts. We demonstrate that HDM2 cleavage is dependent on caspase-3 and that
      activation of cdc2 kinase results in caspase-3 activation in the Xenopus cell
      free system. Furthermore, expression of cdc2 kinase in mammalian cells leads to
      activation of caspase-3 and apoptosis. Taken together, these data indicate that
      deregulation of cdc2 kinase activity can trigger apoptotic machinery that leads
      to caspase-3 activation and apoptosis.

PMID- 12604360
TI  - Carbon monoxide exposure in rat heart: glutathione depletion is prevented by
      antioxidants.
AB  - Rat hearts were perfused for 15min with buffer equilibrated with 0.01% or 0.05%
      CO. The buffer was equilibrated with 21% O(2) throughout. The ventricular
      glutathione content decreased by 76% and 84%, 90min post-exposure to 0.01% and
      0.05% CO, respectively, compared with 0% CO controls (0.45+/-0.01 micromol/g wet
      tissue; +/-SEM, n=3). Both reduced and oxidised glutathione contributed to this
      decline. When ascorbate and Trolox C were included during exposure to 0.05% CO
      the glutathione pool was partly protected; here the glutathione decrease was 46%.
      In most hearts additional creatine kinase activity in the perfusate indicated
      minor tissue injury occurring immediately after the start and/or about 10min
      after the end of exposure to 0.01% CO or 0.05% CO. Ventricle lactate levels were
      unaffected by exposure to 0.01% CO. This evidence supports a role for oxidative
      stress in CO cardiotoxicity.

PMID- 12604361
TI  - Inhibition of peroxynitrite-mediated cellular toxicity, tyrosine nitration, and
      alpha1-antiproteinase inactivation by 3-mercapto-2-methylpentan-1-ol, a novel
      compound isolated from Allium cepa.
AB  - Peroxynitrite formation in vivo is implicated in numerous human diseases and
      there is considerable interest in the use of antioxidants and natural products
      such as thiols as "peroxynitrite scavengers". We therefore investigated the
      effects of a recently identified constituent of onions, 3-mercapto-2-methylpentan
      1-ol (3-MP), for its ability to inhibit peroxynitrite-mediated processes in vitro
      and using cultured human cells and compared its effectiveness against
      glutathione. 3-MP significantly inhibited peroxynitrite-mediated tyrosine
      nitration and inactivation of alpha(1)-antiproteinase to a greater extent than
      glutathione at each concentration tested (15-500 microM). 3-MP also inhibited
      peroxynitrite-induced cytotoxicity, intracellular tyrosine nitration, and
      intracellular reactive oxygen species generation in human HepG2 cells in culture
      to a greater extent than glutathione. These data suggest that 3-MP has the
      potential to act as an inhibitor of ONOO(-)-mediated processes in vivo and that
      the antioxidant action of 3-MP deserves further study.

PMID- 12604362
TI  - Unusual function of the activation loop in the protein kinase DYRK1A.
AB  - Protein kinases of the DYRK (dual-specificity tyrosine phosphorylation-regulated
      kinase) family require phosphorylation of a conserved tyrosine residue in the
      activation loop for full activity. Here we have characterized the role of
      conserved amino acids that are located in the vicinity of the phosphorylated
      tyrosine in DYRK1A (Tyr-321). Mutation of Gln-323, but not Asn-365 or Glu-366, to
      either alanine, glutamate, or asparagine reduced the in vitro-kinase activity of
      DYRK1A towards the peptide substrate, DYRKtide, to a similar degree (15-37% of
      wild type) as the mutation of the phosphorylation site itself (Y321F). Similarly,
      the in vivo-kinase activity of DYRK1A-Q323N and of DYRK1A-Y321F, as assessed by
      Ser-727 phosphorylation of signal transducer and activator of transcription 3
      (STAT3) in COS-7 cells, was markedly reduced in comparison with wild type DYRK1A.
      These data show that the contribution of Gln-323 and Tyr-321 to the full
      catalytic activity of DYRK1A is a specific functional characteristic of the DYRK
      family.

PMID- 12604363
TI  - (-)-Epigallocatechin-3-gallate prevents oxidative damage in both the aqueous and
      lipid compartments of human plasma.
AB  - When human plasma was exposed to the hydrophilic radical initiator, AAPH, (-)
      epigallocatechin-(3)-gallate (EGCG) dose-dependently inhibited the aqueous
      compartment oxidation (IC(50)=0.72 microM) (monitored by DCFH oxidation) and
      spared the lipophilic antioxidants, alpha-tocopherol, and carotenoids, but not
      ascorbic acid. When radicals were selectively induced in the lipid compartment by
      the lipophilic radical initiator, MeO-AMVN, EGCG spared alpha-tocopherol, but not
      carotenoids and inhibited the lipid compartment oxidation (monitored by BODIPY
      581/591) with a potency lower than that found in the aqueous compartment
      (IC(50)=4.37 microM). Our results indicate that EGCG, mainly localized in the
      aqueous compartment, effectively quenches aqueous radical species, thus limiting
      their diffusion into the lipid compartment and preventing lipid-soluble
      antioxidant depletion. Further, ESR experiments confirmed that EGCG recycled
      alpha-tocopherol through a H-transfer mechanism at the aqueous/lipid interface
      affording an additional protective mechanism to the lipid compartment of plasma.

PMID- 12604364
TI  - 15-Deoxy-Delta(12,14)-prostaglandin J2 inhibits the expression of proinflammatory
      genes in human blood monocytes via a PPAR-gamma-independent mechanism.
AB  - The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been
      implicated in inhibition of the expression of proinflammatory cytokines and
      inducible enzymes such as cyclooxygenase-2 (COX-2). Using real-time RT-PCR the
      present study investigates the impact of two PPAR-gamma agonists, 15-deoxy
      Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and ciglitazone, on the expression
      of several proinflammatory genes in lipopolysaccharide (LPS)-stimulated human
      blood monocytes. Stimulation of cells with LPS resulted in a profound induction
      of the expression of COX-2, interleukin (IL)-1, IL-6, tumor necrosis factor
      (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Treatment
      of cells with 15d-PGJ(2) (10 microM) was associated with a nearly complete
      inhibition of the expression of all genes that remained unaltered in the presence
      of the PPAR-gamma antagonist bisphenol A diglycidyl ether (BADGE; 100 microM). By
      contrast, treatment of cells with another potent PPAR-gamma agonist, ciglitazone
      (50 microM), and the PPAR-alpha agonist WY-14,643 (100 microM) did not suppress
      LPS-induced expression of the investigated genes. Stimulation of monocytes with
      LPS resulted in an 88% inhibition of PPAR-gamma mRNA expression that was fully
      restored by 15d-PGJ(2) but only to a partial extent by ciglitazone and WY-14,643.
      Again, BADGE did not alter the effect of 15d-PGJ(2). Collectively, our results
      show that alterations of gene expression by 15d-PGJ(2) in LPS-stimulated human
      blood monocytes are mediated by PPAR-gamma-independent mechanisms. Moreover, it
      is concluded that both inhibition of proinflammatory gene expression and
      restoration of LPS-induced decrease of PPAR-gamma expression may contribute to
      the biological action of 15d-PGJ(2).

PMID- 12604365
TI  - HMGB1 interacts differentially with members of the Rel family of transcription
      factors.
AB  - HMGB1 is an architectural factor that enhances the DNA binding affinity of
      several proteins. We have investigated the influence of HMGB1 on DNA binding by
      members of the Rel family. HMGB1 enhances DNA binding by p65/p50 and p50/p50, but
      reduces binding by p65/p65, c-Rel/c-Rel, p65/c-Rel, and p50/c-Rel. In pull-down
      assays, HMGB1 interacts directly with the p50 subunit via its HMG boxes and this
      interaction is weakened by the presence of the acidic tail. Functionally, HMGB1
      is required for the NF-kappaB-dependent expression of the adhesion molecule VCAM
      1.

PMID- 12604366
TI  - Low-frequency electromagnetic fields induce a stress effect upon higher plants,
      as evident by the universal stress signal, alanine.
AB  - 15N NMR analysis reveals alanine production in Duckweed plants exposed to low
      intensity sinusoidally varying magnetic fields (SVMF) at 60 and 100Hz, and fed by
      15N-labeled ammonium chloride. Alanine does not accumulate in the absence of
      SVMF. Addition of vitamin C, a radical scavenger, reduced alanine production by
      82%, indicating the roll of free radicals in the process. Alanine accumulation in
      plants and animals in response to exposure to a variety of stress conditions,
      including SVMF, is a general phenomenon. It is proposed that alanine is a
      universal first stress signal expressed by cells.

PMID- 12604367
TI  - The two pathways of apoptosis: one led to Stockholm, the other led home.

PMID- 12604368
TI  - A glance into somatic stem cell biology: basic principles, new concepts, and
      clinical relevance.
AB  - Somatic stem cells are undifferentiated cells with a high capacity for self
      renewal that can give rise to one or more specialized cell types with specific
      functions in the body. Profound characterization of these cells has been
      difficult due to the fact that their frequency in different tissues of the body
      is extremely low; furthermore, their identification is not based on their
      morphology but on immunophenotypic and functional assays. Nevertheless,
      significant advances in the study of these cells at both cellular and molecular
      levels have been achieved during the last decade. The majority of what we know
      concerning somatic stem cell biology has come from work on hematopoietic stem
      cells. More recently, however, there has been a great amount of information on
      neural and epithelial stem cells. The importance of stem cell research has gone
      beyond basic biology and is currently contributing to the development of new
      medical approaches for treatment of hematologic, neurologic, autoimmune, and
      metabolic disorders (cellular therapy).

PMID- 12604369
TI  - Comparison of single- and dual-platform approaches to enumerate CD34(+) cells in
      bone marrow and mobilized peripheral blood stem cells.
AB  - BACKGROUND: Different flow cytometric methods have been developed to derive
      absolute CD34(+) cells in predicting transplant outcome. Two techniques for
      preparing cells for quantification of CD34(+) cells were compared. METHODS:
      Enumeration of CD34(+) cells in 16 samples of bone marrow (BM) and in 29 samples
      of mobilized peripheral blood stem cells (PBSC) obtained by leukapheresis was
      assessed simultaneously by single-platform (ProCOUNT kit) and dual-platform
      (Milan protocol) approaches within the first 3 h of collection. RESULTS: Absolute
      number of CD34(+) cells obtained in PBSC and BM using single- and dual-platform
      methods showed high determination coefficients as follows: for PBSC, slope =
      1.0515 +/- 0.048, y-intercept = 88.638 +/- 52.45, and r(2) = 0.941, and for BM,
      slope = 1.0203 +/- 0.093, y-intercept = 122.25 +/- 20.65, and r(2) = 0.878. There
      were no statistically significant differences in absolute number of CD34(+) cells
      from PBSC between single-platform (mean 575/microL, range 70-3683/microL) and
      dual-platform (786/microL, range 51-3804/microL) assays. In contrast, absolute
      number of CD34(+) cells from BM was significantly lower (p = 0.0002) when
      enumerated by ProCount kit (135/microL, 14-758/microL) than with dual-platform
      method (260/microL, 74-889/microL). CONCLUSIONS: Both approaches can be used
      indistinctly to estimate absolute number of CD34(+) cells in PBSC but not in BM.

PMID- 12604370
TI  - Transforming growth factor-beta decreases survival of Mycobacterium bovis
      activated T cells.
AB  - BACKGROUND: A comprehensive understanding of the immune response induced by
      Mycobacterium bovis Bacille Calmette-Guerin in activation of protective T cells
      against tuberculosis is important to develop effective therapies to combat this
      disease. In this study, our experiments were designed to determine effects of
      transforming growth factor (TGF)-beta on M. bovis-induced T-cell activation and
      survival. METHODS: Fluorescence-activated cell sorter (FACS) analysis was used
      for detection of apo-ptotic cells by three different methods: 1). scattered light
      change during early phase of apoptosis; 2). detection of hypodiploid DNA, or 3).
      terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) technique.
      Quantification of positively stained population was based on samples stained with
      isotype control antibodies analyzed on a FACScan. RESULTS: TGF-beta added at
      initiation of culture did not alter percentage of viable cells. By contrast, TGF
      beta added 72 h post-activation decreased percentage of viable cells. This effect
      was statistically significant (p <0.05). Furthermore, addition of anti-TGF-beta
      MoAb together with TGF-beta abolished the ability of this cytokine to decrease
      survival in post-activated human T cells. Role of TGF-beta on post-activated
      human T cells was further confirmed by staining apoptotic nuclei with propidium
      iodide, which detects late events of apoptosis, and by DNA fragmentation
      determined using TUNEL assay. Interestingly, TGF-beta did not promote Fas
      mediated killing. Finally, TGF-beta increased apoptosis of CD4(+) T cells after
      mycobacterial stimulation. CONCLUSIONS: This study indicated an important role
      for TGF-beta in suppression of protective immune response against M. bovis by
      promoting elimination of post-activated T cells. Furthermore, results showed that
      TGF-beta had no direct effect on M. bovis-induced up-regulation of Fas (CD95).

PMID- 12604371
TI  - Differential diagnostic problems of decompression sickness--examples from
      specialist physicians' practices in diving medicine.
AB  - It can be expected that the differential diagnosis problem of decompression
      sickness will increase in the future due to the increasing number of divers.
      During the last 30 years, 232 divers were treated for decompression sickness
      (DCS) at the Naval Medical Institute (NMI) in Split, Croatia. In 66 cases (28%),
      physicians at various diving sites reached diagnosis with difficulty, and 86
      divers (37%) came directly to the NMI without seeing a physician first.
      Physicians at remote diving locations frequently have only basic knowledge of
      diving medicine and are often inexperienced. The language barrier was a major
      obstacle in obtaining a medical history and examination of foreign divers.
      Consultations at the NMI proved a major contribution to correct diagnosis and
      treatment. We present six illustrative cases from NMI Archives that demonstrate
      how prejudices, panic, and inexperience could create problems in establishing DCS
      diagnosis.

PMID- 12604372
TI  - High doses of dexamethasone in adult patients with idiopathic thrombocytopenic
      purpura.
AB  - BACKGROUND: High-dose dexamethasone (DXM) has been used in treatment of patients
      with idiopathic thrombocytopenic purpura (ITP) who are refractory to other
      treatments such as prednisone and splenectomy; nevertheless, different studies
      show variable success rates, this postulated as possibly being due to racial
      differences. The objective of this study was to determine DXM effectiveness at
      high doses in Mexican mestizo adult patients diagnosed with ITP with and without
      splenectomy. METHODS: Nonhospitalized adult patients with ITP were included,
      eight patients previously splenectomized (group 1) and 11 who had not undergone
      splenectomy (group 2). Patients received DXM 40 mg/day intravenously (i.v.)
      during 4 consecutive days every 4 weeks until six cycles were completed. RESULTS:
      There were no differences between the two groups regarding age (mean 39 vs. 33
      years of age) and initial platelet count (M 17 vs. 24 x 10(9)/L). Median
      evolution time was 84 months for group 1 and 7 months for group 2 (p = 0.002). Of
      19 patients, nine achieved a favorable response (FR), six belonged to group 1,
      and three to group 2 (Fisher p = 0.07). Nevertheless, after 6 months only two
      group 1 patients and two group 2 patients maintained FR (Fisher exact test p =
      1). Patients achieving FR to initiation of second cycle maintained FR at the end
      of six cycles. CONCLUSIONS: Thus, the previously mentioned high-dose DXM therapy
      appears to be useful for both patients with ITP with and without splenectomy and
      high-dose DXM appears to be a good alternative therapy for postsplenectomy and
      relapse patients. However, duration of FR to treatment was brief; therefore,
      other treatment plans might be required to achieve longer remission duration.
      Response was similar to that observed in other studies carried out in different
      populations; thus, apparently no genetic or racial variations exist. In addition,
      whether patients not responding after second cycle should continue until
      completing the 6-month plan or should try a different therapeutic approach must
      be considered in the treatment plan.

PMID- 12604373
TI  - Systolic pulmonary artery pressure and serum uric acid levels in patients with
      hyperthyroidism.
AB  - BACKGROUND: The aim of this study was to investigate systolic pulmonary artery
      pressure (SPAP) and serum uric acid (SUA) levels in patients with hyperthyroidism
      and after euthyroid state was reached. METHODS: Twenty five (10 male, 15 female,
      mean age 49.8 +/- 11.6 years) consecutive patients with hyperthyroidism (18 due
      to toxic nodular goiter, seven to Graves' disease) and 25 (eight male, 17 female,
      mean age 48.7 +/- 8.7 years) healthy controls were included in the study. Thyroid
      hormones, SUA, glucose, urea, creatinine, and transthoracic echocardiography were
      performed in all patients. All tests were repeated after treatment of
      hyperthyroidism. RESULTS: Mean SPAP and SUA levels in patients with
      hyperthyroidism were significantly higher than in controls (30.4 +/- 8.5 vs. 22
      +/- 3.7 mmHg, p <0.0001, and 5.1 +/- 1.1 vs. 4.3 +/- 0.5 mg/dL, p = 0.004,
      respectively). Elevated SPAP and SUA levels in patients with hyperthyroidism
      decreased significantly after treatment to levels comparable with controls (24.4
      +/- 5.4 mmHg, p = 0.001 and 4.6 +/- 0.9 mg/dL, p = 0.002, respectively).
      Correlation between SPAP and SUA levels, however, was not significant in
      hyperthyroid population and after euthyroid stage was reached (r = 0.34, p =
      0.097, and r = 0.256, p = 0.216, respectively), possibly due to relatively low
      number of patients (overall correlation of SPAPs and SUAs was r = 0.4, p
      <0.0001). CONCLUSIONS: Hyperthyroidism should be included in differential
      diagnosis of pulmonary arterial hypertension. However, further investigations are
      needed to determine the exact mechanism between hyperthyroidism and pulmonary
      hypertension.

PMID- 12604374
TI  - RET oncogene mutations in medullary thyroid carcinoma in Mexican families.
AB  - BACKGROUND: Different RET oncogene mutations have been found to be associated
      with inherited medullary thyroid carcinoma (MTC) in the context of three
      different syndromes including multiple endocrine neoplasia types 2A (MEN 2A) and
      2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). These mutations have
      been recorded in different populations, but to date there is no corresponding
      study in Mexican families. Our purpose was identification of RET mutations in
      Mexican families with inherited or sporadic MTC (SMTC) and search for RET protein
      expression as prognostic marker in MTC tumors. METHODS: Nine unrelated families
      with MTC corresponding either to two MEN 2A, three MEN 2B, or four SMTC were
      studied. Screening of exons 10, 11, and 13-16 of RET oncogene in DNA from
      circulating lymphocytes and tumor samples were analyzed. Immuno- staining for RET
      was performed in the corresponding tumor. RESULTS: Germline 918 ATG-->ACG RET
      mutation was present in three unrelated MEN 2B individuals and corresponding
      somatic mutation in one individual with SMTC; 634 TGC-->TTC RET mutation was
      detected in two related patients in an MEN 2A family and the 634 TGC-->TAC RET
      mutation was detected in 12 related individuals from a second MEN 2A family. RET
      protein expression was detected in all MTC tumors showing different staining
      intensity. CONCLUSIONS: RET mutations found in Mexican patients with MTC are
      similar to those previously reported in several MTC families worldwide. This
      indicates that RET mutations are highly conserved and that MTC etiology does not
      depend to a great extent on environmental factors or ethnic differences.
      Detection of RET protein in MTC tissue sections is not useful as prognostic
      marker.

PMID- 12604375
TI  - Nephrotoxic effects of mercury exposure and smoking among Egyptian workers in a
      fluorescent lamp factory.
AB  - BACKGROUND: It is known that mercury (Hg) has a nephrotoxic effect in exposed
      workers. This effect is evident when there is advanced damage of kidney tissue.
      METHODS: A random morning urine sample was collected from each participant for
      measuring urinary concentrations of total protein (UTP), retinol-binding protein
      (URBP), creatinine (UCr), Hg (UHg), and the activities of leucine-aminopeptidase
      (ULAP) and glutathione S-transferase (UGST) as well as N-acetyl-beta-D
      glucosaminidase (UNAG). RESULTS: Urinary excretion of the measured parameters was
      significantly increased among Hg-exposed workers who were smokers and among Hg
      exposed workers with work duration >or=11 years than those with <or=10 years work
      duration. CONCLUSIONS: Results of this investigation demonstrated that these
      urinary parameters of kidney integrity could be used as indicators of nephrotoxic
      effect of Hg exposure and that cigarette smoking has toxic and synergistic
      effects with Hg exposure on kidney. Present results additionally suggest
      reduction in recommended biological threshold limit (50 microg Hg/g Ucr) or
      biological exposure index (35 microg Hg/g Ucr) of urinary mercury levels because
      elevated levels of measured parameters were observed at urinary Hg levels of 17.3
      28.2 microg Hg/g Ucr.

PMID- 12604376
TI  - Incidence of rheumatoid nodule in Dalmatia: similarities and differences among
      populations.
AB  - BACKGROUND: The specific aim of our study was neither prognosis nor long-term
      evaluation but focus on determining incidence of rheumatoid nodules (RN) in a
      large population of patients with rheumatoid arthritis (RA) on the coastline of
      Croatia (Dalmatia) within a certain range. We compared our data with those
      published previously in the literature. METHODS: Our study was focused on
      determining incidence of RN occurrence in patients with rheumatoid arthritis in
      Dalmatia, Croatia by comparing these figures with data reported elsewhere and
      evaluating its importance in the process of diagnosing RA. The duration of the
      study was 10 years (1991-2001). There were 421 patients (344 women and 77 men)
      with confirmed RA diagnosis. Median follow-up time was 2 years (range: 1.4-3.5
      years). RESULTS: Existence of RN was established by clinical examination in 109
      of 421 patients; incidence density was 17.3%. RN occurred somewhat more
      frequently in men (32%) as compared to women (24%) without statistically
      significant difference. In 38% of patients, RN occurred simultaneously in several
      sites, more frequently in men (64%) than in women (30%) (odds ratio [OR] 2.13, p
      <0.05). Correlation of seropositivity and RN appearance was very high: positive
      in 84% of patients with nodules as compared to 58% of patients without nodules
      (OR 1.45, p <0.05) with no statistically significant differences between sexes.
      CONCLUSIONS: Results obtained warrant the conclusion that RN incidence in our
      patients from Dalmatia is comparable with results of earlier Croatian studies as
      well as with Western European figures and Caucasian population data reported on
      other continents. RN incidence differs significantly for Asian and Arabian
      populations, i.e., is less frequent, and for the U.S. population, where it is
      more frequent.

PMID- 12604377
TI  - Comparison of Helicobacter pylori prevalence in symptomatic patients in
      northeastern Mexico with the rest of the country: its association with
      gastrointestinal disease.
AB  - BACKGROUND: Prevalence of Helicobacter pylori varies among different geographic
      regions. The aim of this study was to assess H. pylori prevalence in symptomatic
      patients in northeastern Mexico and its possible association of H. pylori with
      disease. METHODS: We studied 261 symptomatic patients (female/male 1.44, mean age
      53 years) who underwent gastrointestinal endoscopy at Hospital Universitario Dr.
      Jose Eleuterio Gonzalez in Monterrey, Nuevo Leon, Mexico. Among patients included
      in this study, 209 (80.1%) had nonulcer dyspepsia (NUD), 30 (11.5%) peptic ulcer
      disease (PUD), and 22 (8.4%) high-grade dysplasia or gastric cancer. H. pylori
      status was determined by histology, positive rapid urease test, culture, or IgG
      whole-cell anti-H. pylori. Specific IgG antibodies for CagA status were
      determined by ELISA as previously described. Patients were defined as infected
      with H. pylori by positive results of two or more diagnostic tests used. RESULTS:
      Overall prevalence of H. pylori was 67.8%. According to clinical presentation,
      gender (male) was related with gastric cancer (p <0.01) and with PUD (p <0.05).
      Of 177 patients infected with H. pylori, 90 (50.8%) were seropositive for CagA
      antigen; in addition, H. pylori CagA+ was more common in patients with PUD
      (77.8%) than with NUD (43.2%) (p <0.05). However, no association was found
      between gastric cancer patients and presence of CagA+ H. pylori strains.
      CONCLUSIONS: H. pylori prevalence in symptomatic patients in northeastern Mexico
      is as high as the prevalence reported for the entire country. We confirmed that
      patients with gastric cancer and PUD are more likely to be male. CagA+ strains
      were associated with patients who presented PUD but not gastric cancer.

PMID- 12604378
TI  - Metabolic acidosis and hepatic steatosis in two HIV-infected patients on
      stavudine (d4T) treatment.
AB  - Nucleoside analog reverse transcriptase inhibitors (NRTI) have been used to treat
      HIV-infected patients for >10 years. Some severe adverse events have been
      attributed to mitochondrial dysfunction. Since 1991, cases of severe lactic
      acidosis have been reported in association with nucleoside therapy. Our objective
      was to report two cases of metabolic acidosis and hepatic steatosis in patients
      receiving stavudine (d4T) and to review the literature. A male and a female, 47
      and 45 years of age, respectively, presented with abdominal pain, nausea,
      vomiting, and weakness after 9 and 6 months, respectively, of treatment with
      stavudine. At presentation, both patients had severe metabolic acidosis and liver
      failure. Ultrasonography showed hepatic steatosis (confirmed by biopsy in one
      case). All antiretroviral drugs were withdrawn and patients were treated with
      bicarbonate. Both patients developed fulminant liver dysfunction and multiple
      organ failure. We reviewed the literature and found 75 cases of lactic acidosis
      and hepatic steatosis associated with use of NRTI; 57 of these patients received
      d4T (76%). Of all cases reported in association with nucleoside therapy, 63% were
      females and mortality was 47%. General weakness, hepatic enzyme elevation, and
      liver steatosis are data that should alert physicians to this serious adverse
      event and to respond with prompt interruption of antiretroviral drugs and
      measurement of lactic acid in plasma. It is important to report serious adverse
      events in commercially released drugs to know prevalence in an exposed
      population. Physicians should be aware of risk and early signs of this serious
      adverse event.

PMID- 12604380
TI  - [60th anniversary of the French society of clinical biology].

PMID- 12604381
TI  - [Biochemical and pharmacological check-up in emergency orientation].
AB  - Biochemical and pharmacological tests usually prescribed in casualty department
      were reviewed taking into account their physiological significance and predictive
      value : ions, total proteins, carbohydrate and nitrogenous metabolites, enzymes,
      tissue markers, pharmacological drugs. Few blood components were kept with the
      first intention, ideally with a turn around time below one hour: sodium,
      potassium, chloride, bicarbonate, total proteins, pCO2 and pO2, creatinine,
      glucose, ketone compounds, calcium, bilirubin, transaminases, lipase, C-reactive
      protein, myoglobin, troponin, chorionic gonadotropin hormone. Those tests do not
      have to be systematically performed but prescribed only after the evaluation of
      pre-test probabilities by the clinician.

PMID- 12604379
TI  - Familial hypercholesterolemia due to ligand-defective apolipoprotein B100: first
      case report in a Mexican family.
AB  - BACKGROUND: Familial defective apolipoprotein B100 (FDB) is one of the known
      causes of familial hypercholesterolemia (FH). Its frequency among subjects with
      FH varies among ethnic groups; information on FH is insufficient for populations
      from Latin America. We proposed to describe prevalence of FDB in a cohort of
      Mexican FH probands (n = 30). METHODS: We searched for the known FDB mutations
      using polymerase chain reaction assays. In this set of patients, mean lipid
      values were representative of FH (cholesterol 351 mg/dL, LDL cholesterol 274
      mg/dL, HDL cholesterol 51 mg/dL, and triglycerides 132 mg/dL). RESULTS: One
      subject with Arg3500Gln mutation was found: a 44-year-old male with a history of
      coronary heart disease (CHD) among paternal relatives. His lipid profile was
      cholesterol 370 mg/dL, LDL-cholesterol 300 mg/dL, HDL-cholesterol 32 mg/dL, and
      triglycerides 189 mg/dL. Tendinous xanthomata were detected. Three of four
      siblings, one of three sons, and one of nine nieces and nephews carried the
      mutation. The mutation was confirmed by automated sequencing. Tendinous
      xanthomata were absent in affected subjects younger than age 20 years;
      additionally, the subjects had borderline cholesterol levels. CONCLUSIONS: Our
      data suggest that FDB explains the small number of FH cases in Mexico. Inclusion
      of molecular biology assays to the clinical laboratory makes it possible to
      diagnose affected individuals with borderline cholesterol levels or without
      tendinous xanthomata.

PMID- 12604382
TI  - [Human pasteurellosis: diagnosis, treatment and precautions].
AB  - The circumstances of diagnosis of human pasteurellosis are reviewed. The
      diagnosis is usually suspected for animal bite or scratch wounds. Conversely, in
      other infections the diagnosis is only based on bacteriological data. Phenotypic
      misidentification of Pasteurellaceae from clinical material is common. The
      phenotypic criteria of identification of the six species of human pathogen
      Pasteurella are presented. We emphasise that bite wound specimens have to be
      cultured for aerobic and anaerobic bacteria and yield an average of 5 bacterial
      isolates per culture. Antibiotic therapy relies upon amino-penicillins or
      cephalosporins, although b-lactamase producing strains are scarce.
      Fluoroquinolones can be an alternative for systemic infections. Molecular typing
      unequivocally points out the risk of transmission from pets to humans.
      Immunocompromised persons have to be made aware of precautions.

PMID- 12604383
TI  - [Thrombin: a multifunctional enzyme].
AB  - Thrombin is the final enzyme of blood coagulation cascade. It belongs to the
      trypsin family of serine proteases. Its two primary actions are to cleave
      fibrinogen to release fibrin and to activate platelets through a limited
      proteolysis of a specific receptor. In addition, thrombin is the major regulator
      of blood coagulation. It is both a procoagulant enzyme in the activation of
      factors V and VIII, and an anticoagulant enzyme through the activation of protein
      C and TAFI. This multi-functionality of thrombin depends upon the conformation of
      its active site: depth for high specificity and shape for a finely tuned
      selection of substrates. Since new anticoagulant molecules, some with anti
      thrombin activity, are emerging, it is important to understand the mechanisms
      allowing thrombin to be so specifically multifunctional.

PMID- 12604384
TI  - [Contribution of the laboratory in case of resistance to acyclovir of herpes
      simplex and varicella zoster virus].
AB  - Herpes simplex virus (HSV) and varicella zoster virus (VZV) are susceptible to
      acyclovir which inhibits viral replication through two viral enzymes, thymidine
      kinase (TK) and DNA polymerase. Resistance may occur, it is a rare phenomenon
      among immunocompetent patients but resistance is more frequent and may be
      associated with serious complications among immunocompromised patients.
      Virological survey of these at risk patients is needed to detect resistant virus
      as soon as possible through phenotypic tests performed on virus isolated on cell
      cultures. Resistant virus may also be genetically characterised by detection of
      mutations within TK and DNA polymerase genes. Pharmacological parameters also
      have to be taken into consideration and a determination of acyclovir blood
      concentration should be performed in case of unexplained therapeutic failure.
      Improvement of immune system, when possible, may resolve these infections.
      Alternative treatments using drugs such as foscarnet or cidofovir which have a
      different mechanism of action compared to acyclovir, are recommended but these
      molecules are often more toxic than acyclovir.

PMID- 12604385
TI  - [Growth hormone and doping].
AB  - Growth hormone is widely used as a doping agent, particularly because of his
      anabolic and lipolytic properties. The potential benefit of large doses of growth
      hormone on acute exercise is not clearly demonstrated, but the associated side
      effects are well known. The detection of growth hormone abuse is not yet possible
      with the techniques available. This article describes the GH axis physiology,
      especially during acute exercise, the use of GH as a doping agent, as well as the
      difficulties and perspectives in GH doping detection.

PMID- 12604386
TI  - [Update on the susceptibility of streptococci to antibiotics (enterococci and
      Streptococcus pneumoniae excluded)].
AB  - Over the last years, the emergence of resistance to antibiotics has complicated
      the management of streptococcal infections. The resistance of streptococci to
      antibiotics is increasing and seems to be linked to the consumption of
      antibiotics. Resistances to antibiotics have been noted in all species of
      streptococci and no family of antibiotics is unaffected by resistances. The
      incidence of resistance to antibiotics varies from one species to another and
      according to countries. Presently, even though no Streptococcus pyogenes has
      shown diminished susceptibility to betalactams, this phenomenon has been reported
      for some strains in the B, C, and G groups, and for up to 56 % of oral
      streptococci. As for the resistance to macrolides, it reaches as many as 41 % of
      Streptococcus pyogenes, 46 % of group B streptococci, and 63 % of oral
      streptococci responsible for severe infections. This evolution is worrying for
      all streptococci but particularly for oral streptococci which represent a
      potential reservoir of virulence genes, notably towards Streptococcus pneumoniae.
      New families of antibiotics as the ketolides or the oxazolidinones appear to be
      effective in the treatment of streptococcal infections, but it seems that only a
      policy of control of the consumption of antibiotics could globally decrease the
      occurrence of resistance.

PMID- 12604387
TI  - [Apolipoprotein E and bleomycin hydrolase. Polymorphisms: association with
      neurodegenerative diseases].
AB  - Several studies indicate a possible association between different genes and
      chronic neurodegenerative diseases including Alzheimer's disease (DTA). To
      further investigate, we have analyzed association between the apolipoprotein E
      (apo E) and bleomycin hydrolase (BH) polymorphisms and three groups of elderly
      patients: control subjects (T) (n = 68), late-onset sporadic DTA patients (DTAst)
      (n = 65) and other non vascular neurodegerative diseases (MNDA) (n = 52). Apo E
      epsilon4 and BH-G alleles frequencies (%) are: 8.2 (T), 31.5 (DTAst), 16.4 (MNDA)
      and 41.4 (T), 35.6 (DTAst). No association has been observed between carrying the
      G allele and DTA in epsilon4 negative subjects but, our data have confirmed the
      earlier reports: carrying the epsilon4 allele is a dose-dependent risk factor for
      the DTAst (OR: 6.0, IC 95 %: 2.6-13.7) and decrease the age of symptom onset (p <
      0.005). They have also suggested that apo E genotyping may be of interest to
      perform differential diagnosis of neurodegenerative diseases in elderly subjects.

PMID- 12604388
TI  - [Usual values for 5-hydroxy-indol acetic acid and homovanillic acid in
      cerebrospinal fluid].
AB  - The aim of this work was to reinvestiagte usual values of neurotransmitter
      catabolites (5-HIAA and HVA) in CSF, their determination being a current method
      for studying pathological processes and/or drug induced changes on CNS
      metabolism. 5-HIAA and HVA have been measured by reverse phase HPLC and
      electrochemical detection. Since many confounding factors have been identified to
      modify the concentration of both analytes in CSF, data from 1.480 patients have
      been revisited with strict exclusion and 323 have been selected. Age dependent
      variation and asymetric distributions were observed. Age-related usual values
      ranges were established after identification of outliers by non-parametric
      analysis. In a group of patients for which repeated CSF collection have been
      performed for the follow up of acute leukemia, wide and unpredictible individual
      variations (up to 400 %) of CSF 5-HIAA and HVA concentrations have been observed.
      These large interindividual and individual variations may explain the numerous
      discrepancies found in studies investigating the CNS monoamine metabolism,
      especially when small groups of patients are used. Such observation limits the
      interpretation of monoamine metabolic for diagnostic purposes without a strict
      selection of indication.

PMID- 12604389
TI  - [False-positive results of troponin assay with increased IgM antibodies].

PMID- 12604390
TI  - [Reactive hemophagocytic syndrome: about one case].

PMID- 12604391
TI  - [Coma in type 2 diabete mellitus on metformin treatment].
AB  - Non traumatic coma in diabete mellitus has two origins : hypo- or hyperglycemia.
      Coma with hyperglycemia can be due to ketoacidosis, hyperosmolar state or lactic
      acidosis. The present observation reports on a type 2 diabete mellitus patient
      presenting with a coma while the patient was on metformin and glibenclamide
      treatment. On admission, biologicals tests showed major acidosis, hyperglycemia
      and hyperosmolarity. No metformine accumulation was demonstrated by analytical
      measure. In this case, the association of hyperosmolar state and metabolic
      acidosis prove the difficulty of the differential diagnosis.

PMID- 12604392
TI  - [A laboratory artefact to detect: the EDTA-dependent pseudothrombocytopenia].

PMID- 12604393
TI  - [Simultaneous occurrence of Sezary syndrome and B-cell chronic lymphocytic
      leukaemia].

PMID- 12604394
TI  - [Waldenstrom macroglobulinemia and involvement of the central nervous system. A
      case report].

PMID- 12604395
TI  - [Use of formulas for calculating serum osmolality].
AB  - Osmolality can be measured or calculated. More than ten formulas have been
      proposed for calculating serum osmolality from chemical concentrations. The aim
      of this work was to compare results obtained whith some of these formulas, those
      calculated in the laboratory using a multiple regression model and measurements
      with an osmometer. Scattered results for natremia and chloremia, depending on the
      automate, led us to define formulas adapted for each measurement system in order
      to reduce the risk of error in the evaluation of the " osmolar gap ".

PMID- 12604396
TI  - [Rapid identification of pneumococcal antigenes in urines by the Now
      Streptococcus pneumoniae Binax  test].
AB  - Streptococcus pneumoniae is responsible for many infectious conditions but
      probably with an underestimated incidence especially because of the fragility of
      the bacteria. The present study has evaluated a new test which detects a
      pneumococcal antigen in urine (Now S.p Binax). Urine samples from 181 children
      and 40 adults have been tested. All the patients presented with typical clinical
      signs of pneumococcal infection. Sensitivity = 91.7 %; specificity = 54.2 %;
      positive predictive value = 50 %; and negative predictive value = 92.9 % have
      been observed. Although the sensitivity and specificity were lower than those
      announced by the manufacturer, the test is easy to handle and provides a rapid
      argument for the diagnosis of pneumococcal infection, especially in the case of
      invasive infections like meningitis and bacteraemia.

PMID- 12604397
TI  - [For a clear expression of laboratory results: about two examples].

PMID- 12604398
TI  - Differences and similarities among phenotypes of mesenchymal and neural stem
      cells.

PMID- 12604400
TI  - Stem cell transplantation for patients with solid tumors.

PMID- 12604399
TI  - Bone marrow angiogenesis in multiple myeloma: closing in on the loop.

PMID- 12604402
TI  - Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural
      progenitor cells.
AB  - BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSC) and neural progenitor
      cells (NPC) are pluripotent cells. The former can give rise to myocytes,
      chondrocytes, adipocytes, and osteogenic cells, while the latter can give rise to
      astrocytes, neurons, and oligodendrocytes. The aim of this study was to analyze
      and compare the antigen expression patterns of MSC and NPC. DESIGN AND METHODS:
      Human bone marrow-derived MSC and NPC were analyzed by flow cytometry and
      immunocytochemistry using a variety of unique monoclonal antibodies (57D2, W4A5,
      W8B2) generated in our laboratory. In addition, the expression profile of CD
      antigens and intracellular differentiation markers was analyzed. RESULTS: We show
      for the first time that CD10+, CD13+, CD61+, CD90+, CD105 (endoglin)+, CD45-,
      CD34-, and CD133- MSC also expressed CD109, CD140b (PDGF-RB), CD164, and CD172a
      (SIRPa). In addition, we found heterogeneity of MSC as demonstrated by the
      preferential expression of nestin and W8B2 antigen on distinct MSC
      subpopulations. Morphologically, these populations comprised small single cells
      and larger cells with polygonal appearance. NPC expressed high levels of CD56,
      CD90 and nestin and moderate levels of CD15, W4A5, and 57D2 antigens. In
      contrast, CD133 and CD172 were found only on NPC subpopulations. INTERPRETATION
      AND CONCLUSIONS: Our data demonstrate nestin expression in most NPC as well as in
      immature MSC subpopulations. MSC and NPC subpopulations can now be distinguished
      using our novel antibodies W8B2, 57D2, and W4A5.

PMID- 12604403
TI  - Function of the ABC transporters, P-glycoprotein, multidrug resistance protein
      and breast cancer resistance protein, in minimal residual disease in acute
      myeloid leukemia.
AB  - BACKGROUND AND OBJECTIVES: Relapse is common in acute myeloid leukemia (AML)
      because of persistence of minimal residual disease (MRD). ABC-transporters P
      glycoprotein (Pgp) and multidrug resistance protein (MRP), are thought to
      contribute to treatment failure, while it is unknown whether breast cancer
      resistance protein (BCRP) does so. However, whether up-regulation of pump
      activity or selection of subpopulations with higher pump activity occurs during
      chemotherapy is unclear. The aim of this study was to elucidate whether ABC
      transporter function changes during the course of disease. DESIGN AND METHODS:
      MRD cells were identified using leukemia-associated phenotypes combined with a
      fluorescent probe assay with substrate/modulator: Syto16/ PSC833 (Pgp), calcein
      AM/probenecid (MRP) and BODIPY-prazosin/Ko143 (BCRP); efflux profiles were
      directly compared with blasts at diagnosis and relapse from the same patient.
      RESULTS: At diagnosis BCRP activity was undetectable in AML blasts from 23/26
      cases, while Pgp activity was present in 36/45 and MRP activity in 26/44 of the
      cases. Furthermore, no subpopulations of blasts with considerably higher drug
      efflux capacities were found. Overall, no consistent changes were observed at
      follow-up [during chemotherapy (n=20), MRD (n=37), relapse (n=26))] in forty-five
      patients, the mean activities (as percentages of values at diagnosis) were 97%
      (Pgp), 103% (MRP) and 102% (BCRP). INTERPRETATION AND CONCLUSIONS: Emergence of
      MRD is thus not accompanied by either upregulation of ABC-transporter function
      during or after chemotherapy or by selection of pre-existing highly resistant
      subpopulations. The prognostic value of Pgp and MRP is, therefore, likely related
      to drug efflux capacity homogeneously distributed in the whole blast population,
      while BCRP probably has a limited function in drug efflux-related resistance in
      AML.

PMID- 12604405
TI  - Associations between polymorphisms in the thymidylate synthase and serine
      hydroxymethyltransferase genes and susceptibility to malignant lymphoma.
AB  - BACKGROUND AND OBJECTIVES: Polymorphisms in thymidylate synthase (TS) 28-bp
      tandem repeats in the promoter region and in cytosolic serine
      hydroxymethyltransferase (SHMT1 C1420T) have been reported to modulate the risk
      of adult acute lymphocytic leukemia (ALL). We examined the associations between
      susceptibility to malignant lymphoma and these polymorphisms. DESIGN AND METHODS:
      A hospital-based prevalent case-control study was conducted in Aichi Cancer
      Center. One hundred and eight patients with histologically confirmed lymphoma and
      494 control subjects without cancer were evaluated. RESULTS: In a risk estimation
      of each genotype, those who harbored at least one TS 2 repeat (2R) allele had a
      1.6-fold increase in the risk of malignant lymphoma (OR=1.63; 95%CI, 1.05-2.53,
      p=0.030) when using those without the TS 2R allele as a reference. For the SHMT1
      C1420T polymorphism, those harboring at least one T allele showed a 2.2-fold
      decrease in risk (OR =0.46; 95% CI, 0.23-0.93, p=0.031). Moreover, combined
      analysis of TS and SHMT1 polymorphisms revealed that the OR for lymphoma in
      patients with SHMT1 1420 CC and the TS 2R allele, which might be expected to
      provide the basis for the highest susceptibility, was 2.88 (95% CI, 1.26-6.58,
      p=0.013). INTERPRETATIONS AND CONCLUSIONS: This study suggests that genetic
      traits involving low penetrance polymorphisms in folate-metabolizing genes may
      modulate the risk of malignant lymphoma.

PMID- 12604404
TI  - CD40 triggering enhances fludarabine-induced apoptosis of chronic lymphocytic
      leukemia B-cells through autocrine release of tumor necrosis factor-alpha and
      interferon-gama and tumor necrosis factor receptor-I-II upregulation.
AB  - BACKGROUND AND OBJECTIVES: In chronic lymphocytic leukemia (CLL) B-cells are
      refractory to activation signals and to apoptosis. CD40 triggering, however,
      rescues CLL B-cells from their anergic state and upregulates the FAS receptor. We
      therefore studied whether CD40 triggering enhances CLL B-cell sensitivity to
      fludarabine, and receptors or cytokines potentially involved in apoptosis. DESIGN
      AND METHODS: CD40-activation of CLL B-cells was carried out by co-culture with
      CD40L-transfected cells. After fludarabine treatment, apoptosis was evaluated by
      propidium iodide (PI), annexin-V/PI or DiOC6 staining and flow cytometry
      analysis. Modulation of Bcl-2, of tumor necrosis factor receptor (TNFRI/II) and
      release of tumor necrosis factor (TNF)alpha/interferon (IFN)gamma was also
      analyzed. Furthermore, addition of caspase-inhibitors or anti-TNFalpha/-IFNgamma
      monoclonal antibodies to fludarabine-treated cells allowed us to determine the
      mediators of apoptosis. Student's t tests or ANOVA variance statistical analysis
      were performed to evaluate whether any differences observed might be considered
      significant. RESULTS: CD40 triggering enhanced fludarabine sensitivity of CLL B
      cells, downmodulated Bcl-2 and upregulated TNFRI/II. Caspases 1 and 6 were the
      major caspases involved in fludarabine apoptosis induction in resting B cells,
      while only anti-TNFalpha/-IFNgamma monoclonal antibodies reduced apoptosis in
      activated cells. In agreement with this observation, autocrine production of
      TNFalpha and IFNgamma by CD40-activated CLL B cells was found. INTERPRETATION AND
      CONCLUSIONS: B-cells from a considerable proportion of CLL cases studied (11/20)
      are more prone to fludarabine-induced apoptosis after CD40 triggering;
      accordingly Bcl-2 expression was lower in activated cells. Moreover, upregulation
      of TNFRI/II, release of TNFalpha and IFNgamma, and inhibition of apoptosis by
      anti-TNFalpha/-IFNgamma monoclonal antibodies in CD40-activated cells strongly
      suggest that these cytokines may play a role in sensitizing B-cells to
      fludarabine treatment.

PMID- 12604406
TI  - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas apoptosis
      in Burkitt's lymphomas with loss of multiple pro-apoptotic proteins.
AB  - BACKGROUND AND OBJECTIVES: Normal B-cells in the germinal center (GC) may be
      exposed to both tumor necrosis factor-related apoptosis inducing ligand (TRAIL)
      and Fas-L. Whether abrogation of TRAIL apoptosis is a feature in the genesis of B
      cell lymphomas of GC-phenotype is not known. We assessed the integrity of the
      TRAIL pathway in Fas-resistant and Fas-sensitive Burkitt s lymphomas (BLs).
      DESIGN AND METHODS: Expression of TRAIL receptors was determined by flow
      cytometry and Western blots. The extent of apoptosis following exposure to TRAIL
      was measured by annexin-V/propidium iodide dual staining. The integrity of the
      Fas and TRAIL apoptotic pathways was determined by Western blotting to assess
      cleavage of downstream caspases. Western blot analyses were used to determine the
      expression of pro- and anti-apoptotic proteins and the profile of expression was
      correlated with response to TRAIL and CH11. RESULTS: Our results demonstrate that
      BL expresses both functional and decoy TRAIL receptors. BLs with a functional Fas
      pathway retained sensitivity to TRAIL: Frequent and compound loss of expression
      of pro-apoptotic proteins can be identified in BLs resistant to Fas. However,
      loss of Bax, Bak and Bcl-Xs did not compromise sensitivity to TRAIL:
      INTERPRETATION AND CONCLUSIONS: Our results indicate that BLs frequently retain
      sensitivity to the TRAIL pathway. These results underscore the utility of TRAIL
      based therapeutic strategies in the treatment of those B-cell lymphomas that may
      have compromised expression of several pro-apoptotic proteins.

PMID- 12604407
TI  - A paracrine loop in the vascular endothelial growth factor pathway triggers tumor
      angiogenesis and growth in multiple myeloma.
AB  - BACKGROUND AND OBJECTIVES: In tumors, vascular endothelial growth factor-A (VEGF
      A) stimulates angiogenesis and vascular permeability by activating the tyrosine
      kinase receptor-2 (VEGFR-2 or KDR/Flk-1) and-1 (VEGFR-1 or Flt-1). DESIGN AND
      METHODS: The distribution and function of VEGF homologs and their receptors on
      bone marrow plasma cells, endothelial cells, and other stromal cells (residual
      stromal cells) were examined in patients with multiple myeloma (MM). RESULTS:
      Plasma cells secrete VEGF-A (and VEGF-B, VEGF-C and VEGF-D, albeit marginally)
      into their conditioned medium (CM). CM VEGF-A stimulates proliferation and
      chemotaxis in endothelial cells (both being mandatory for angiogenesis) via VEGF
      receptor-2 (VEGFR-2), and in residual stromal cells via the VEGFR-1. Residual
      stromal cells secrete VEGF-C and VEGF-D, but little of the other homologs. Their
      CM VEGF-C and VEGF-D increase in response to plasma cell CM and trigger plasma
      cell proliferation via VEGFR-3. Proliferation in all cell types parallels VEGFR
      and extracellular signal-regulated protein kinase-2 (ERK-2) phosphorylation. The
      homologs and receptors are weakly or inconstantly expressed in patients with
      monoclonal gammopathies of undetermined significance or vitamin B12/iron
      deficiency anemias. INTERPRETATION AND CONCLUSIONS: This study shows that the
      VEGF pathway is directly involved in tumor angiogenesis and growth in MM. A
      paracrine VEGF loop for MM progression is suggested. This, in turn, provides a
      further indication that the VEGF pathway and its signaling proteins may be
      appropriate targets in the management of MM.

PMID- 12604408
TI  - Hyperhomocysteinemia: could the post-methionine oral loading test sometimes be
      avoided?
AB  - BACKGROUND AND OBJECTIVES: Measurement of homocysteinemia, a risk factor for
      venous and arterial thrombosis, is carried out in patients fasting for 12 hours
      and after an oral methionine load (PML). The procedure is time-consuming and
      several of the patients suffer from nausea and malaise. We wondered whether
      methionine loading could sometimes be avoided by considering fasting
      homocysteinemia (tHcy) levels. DESIGN AND METHODS: We evaluated whether fasting
      tHcy levels were useful to predict PML and deltaPML tHcy with acceptable
      sensitivity and specificity in 381 patients with venous and arterial thrombosis
      through the generation of receiver operating characteristic curves. RESULTS: Both
      PML and deltaPML tHcy correlated with fasting tHcy values. The cut-off of fasting
      tHcy value yielding a 100% sensitivity in predicting normal PML and deltaPML tHcy
      was 6.5 and 5.0 micromol/L in females, and 7.1 and 7.2 micromol/L in males.
      Fasting tHcy values yielding a 95% specificity in predicting a positive PML and
      tHcy result ranged from 12.5 to 13.1 micromol/L in males and from 10.4 to 10.5
      micromol/L in females. A 95% specificity in predicting a positive deltaPML tHcy
      result ranged from 10.8 to 11.6 micromol/L in females and from 15.9 to 17.0
      micromol/L in men. Considering PML tHcy, 186 out of 381 patients could have
      avoided methionine loading while using deltaPML tHcy 123 out of 381 could have
      done so. INTERPRETATION AND CONCLUSIONS: Nearly 50% of our patients considering
      PML tHcy, and about 30% considering deltaPML tHcy could have been spared the
      methionine loading test. We propose this model for those who wish to carry out
      this analysis on their own.

PMID- 12604409
TI  - Glutamine-enriched parenteral nutrition after autologous peripheral blood stem
      cell transplantation: effects on immune reconstitution and mucositis.
AB  - BACKGROUND AND OBJECTIVES: Glutamine (gln), a non-essential amino acid, has
      recently received increasing attention because it becomes essential during stress
      and catabolic states: glutamine seems to modulate immune function and to promote
      faster intestinal healing after chemotherapy. We designed two consecutive
      randomized clinical trials to evaluate the role of glutamine-enriched parenteral
      nutrition (GEPN) in patients with hematologic malignancies submitted to high dose
      chemotherapy and autologous peripheral blood stem cell transplantation (aPBSCT)
      or immunoselected CD34+ aPBSCT. DESIGN AND METHODS: In study1, the Gln group (12
      patients) received total parenteral nutrition (TPN) enriched with glutamine 20 g
      from day +1 after aPBSCT, while the placebo group (15 patients) received TPN
      lacking in glutamine (placebo). In study2, the Gln group (10 patients) received
      TPN enriched with glutamine 13.46 g from day +1, while the placebo group (11
      patients) received a placebo. RESULTS: In the first study, a lymphocyte count
      >0.5 109/L was achieved on day 16.5 in the Gln group and on day 29 in the placebo
      group (p=0.005); in the second study, the lymphocyte count >0.5 109/L was
      achieved on day 18 in the Gln group and on day 29 in the placebo group (p=0.009).
      Lymphocyte subset analysis showed an increase of CD3+ and CD4+ and normalization
      of the CD16+CD56+ subset. Furthermore patients receiving GEPN showed a decrease
      in the mucositis severity peak calculated by the DMS (daily mucositis score: sum
      of the daily score of signs and symptoms) (p=0.047). INTERPRETATION AND
      CONCLUSIONS: GEPN is safe and effective and improves lymphocyte recovery after
      aPBSCT; further studies are needed to assess the clinical benefits of such an
      approach in order to justify its economic impact.

PMID- 12604410
TI  - The verdict is not in yet. Analysis of the randomized trials of high-dose
      chemotherapy for breast cancer.
AB  - BACKGROUND: The relative efficacy of high-dose chemotherapy (HDC) compared to
      standard treatment for high-risk primary (HRPBC) or metastatic breast cancer
      (MBC) constitutes an area of intense controversy among the medical oncology
      community. A number of randomized trials have been conducted to address this
      issue. In most cases, the results of these trials are premature and
      contradictory. Furthermore, they have often been interpreted, incorrectly in this
      author's judgment, as proof of lack of benefit of HDC. EVIDENCE AND INFORMATION
      SOURCES: The results of studies published in peer-reviewed medical journals or
      presented in scientific meetings are discussed. In some cases, the status of the
      studies was determined through direct communication with the trial's principal
      investigator. RESULTS: The encouraging results of phase II trials suggested a
      benefit for HDC in important categories of patients with breast cancer. It has
      been argued that selection of patients might have been a critical factor in those
      studies. The results, in most cases preliminary, of numerous randomized trials in
      metastatic and high-risk primary disease cannot offer a definitive answer to this
      crucial question as of yet. Important concepts in the interpretation of these
      studies, such as size and statistical power, length of follow-up, magnitude of
      clinical benefit, and broad applicability of the results, are discussed in this
      review. CONCLUSIONS: The role of HDC for HRPBC or MBC patients remains undefined.
      Longer follow-up and mature analyses of the randomized trials are necessary
      before definitive conclusions are drawn. In the meantime, it is imperative that
      research continues, to enhance the efficacy of the procedure through innovative
      strategies.

PMID- 12604411
TI  - Messengers of cell death: apoptotic signaling in health and disease.
AB  - BACKGROUND AND OBJECTIVES: Apoptosis is a genetically controlled mechanism of
      cell death involved in the regulation of tissue homeostasis. Understanding the
      molecular basis of apoptosis signaling may reveal novel clues for
      lymphomagenesis. EVIDENCE AND INFORMATION SOURCES: Pro-apoptotic signaling is
      mediated by specific ligands and surface death receptors (extrinsic pathway of
      apoptosis regulation), which are capable of delivering a death signal from the
      microenvironment and can activate the execution of apoptosis in the cell
      cytoplasm and organelles. Death receptors include tumor necrosis factor-receptor
      1, Fas, death receptor (DR) 3, DR4, DR5 and DR6, whereas death ligands include
      tumor necrosis factor-a, lymphotoxin, Fas-Ligand, Apo3-Ligand and TRAIL (TNF
      Related Apoptosis-Inducing Ligand). Once activated, death receptors recruit
      adaptor proteins, which in turn recruit initiator caspases, giving rise to a pro
      apoptotic complex termed the death-inducing signaling complex (DISC). Besides
      being triggered from microenvironmental signals, apoptosis can also be activated
      from inside the cell through specific cell sensors residing in the cell nucleus
      and cytoplasm (intrinsic pathway of apoptosis regulation). The intrinsic pathway
      of apoptosis leads to the formation of a pro-apoptotic complex termed an
      apoptosome. Both the extrinsic and the intrinsic pathways of apoptosis signaling
      converge into a common pathway causing the activation of the effector enzymes
      caspases. Consistent with the role of apoptosis as a main regulator of B-cell
      homeostasis in the germinal center, the pathogenesis of several germinal-center
      derived lymphomas is characterized by deregulation of one or more steps of the
      apoptosis signaling pathways. PERSPECTIVES: Tumor-specific alterations in the
      apoptotic machinery may represent new potential targets for molecular therapy of
      lymphoma.

PMID- 12604412
TI  - Prevalence of hereditary hyperferritinemia-cataract syndrome in blood donors and
      patients with cataract.

PMID- 12604413
TI  - Risk factors for hyperbilirubinemia and gallstones in Chinese patients with b
      thalassemia syndrome.

PMID- 12604414
TI  - Partial splenectomy in children with sickle cell disease.

PMID- 12604415
TI  - Rituximab chimeric anti-CD20 monoclonal antibody treatment for refractory
      hemolytic anemia in patients with lymphoproliferative disorders.

PMID- 12604416
TI  - Immunophenotypic analysis in 119 patients with acute myeloid leukemia following a
      previous malignancy: a comparison with the immunophenotype of 231 de novo AML.

PMID- 12604418
TI  - Oral induction and consolidation chemotherapy with idarubicin and etoposide in
      elderly patients with acute myeloid leukemia.

PMID- 12604419
TI  - Aberrant promoter methylation in gastric lymphoma.

PMID- 12604417
TI  - Granulocyte colony-stimulating factor reverses cytopenia and may permit
      cytogenetic responses in patients with chronic myeloid leukemia treated with
      imatinib mesylate.

PMID- 12604420
TI  - Rapid genotyping of XbaI and MspI DNA polymorphisms of the human factor VIII
      gene: estimation of their combined heterozygosity in the Argentinean population.

PMID- 12604421
TI  - Molecular analyses in hemophilia B families: identification of six new mutations
      in the factor IX gene.

PMID- 12604422
TI  - Evaluation of the factor V HR2 haplotype as a risk factor for ischemic
      cerebrovascular disease.

PMID- 12604423
TI  - Safety and effectiveness of low dose oral vitamin K1 administration in
      asymptomatic out-patients on warfarin or acenocoumarol with excessive
      anticoagulation.

PMID- 12604424
TI  - Dysfunction of the Fas apoptotic signaling pathway in persistent polyclonal B
      cell lymphocytosis.

PMID- 12604425
TI  - Autoimmune hemolityc anemia after treatment of severe systemic lupus
      erythematosus with high-dose chemotherapy and autotransplantation of selected
      peripheral hematopoietic progenitors.

PMID- 12604426
TI  - Multidrug resistance and myelomonocytic leukaemia in gaucher's disease.

PMID- 12604427
TI  - Pre-emptive treatment of early unstable mixed chimerism in a Chinese thalassaemia
      major patient by graded peripheral blood stem cell infusions.

PMID- 12604428
TI  - Mediastinal follicular dendritic cell sarcoma.

PMID- 12604429
TI  - Leg ulcers associated with hydroxyurea therapy.

PMID- 12604430
TI  - Fatal skin rashes and myalgia in a leukaemic patient.

PMID- 12604431
TI  - MLL intrachromosomal amplification in a pre-B acute lymphoblastic leukemia.

PMID- 12604432
TI  - Intravenous itraconazole for treating invasive pulmonary aspergillosis in
      neutropenic patients with acute lymphoblastic leukemia.

PMID- 12604433
TI  - Immune thrombocytopenia induced by fludarabine successfully treated with
      rituximab.

PMID- 12604434
TI  - Chromosomal abnormalities in Philadelphia (Ph)-negative cells of patients with
      chronic myeloide leukemia treated with Imatinib (ST1571).

PMID- 12604435
TI  - Simplified capillary electrophoresis detection of the Flt-3 internal tandem
      duplications and D835 point mutations in acute myeloid leukemia.

PMID- 12604437
TI  - Most alternative therapies not so hot for hot flashes.

PMID- 12604436
TI  - Your heart attack risk: inflammation counts. A woman with normal cholesterol
      levels can still be at high risk for a heart attack. Should she have a test to
      find out?

PMID- 12604439
TI  - Nutrition update. Food pyramid in need of renovation.

PMID- 12604440
TI  - By the way, doctor. After stopping Prempro last year, I developed really
      uncomfortable vaginal dryness. My doctor has recommended the vaginal estrogen
      ring. Is it safe?

PMID- 12604438
TI  - Mohs surgery for basal cell carcinoma on the face.

PMID- 12604441
TI  - By the way, doctor. I recently read that Tylenol and anti-inflammatory drugs can
      cause high blood pressure. This doesn't leave me with many pain relief options.
      What do you suggest?

PMID- 12604443
TI  - The statin drugs: new proof, more hope, and a disappointment.

PMID- 12604442
TI  - Antioxidant supplements: bad news and good news.

PMID- 12604444
TI  - Prostate cancer surgery: busier is better.

PMID- 12604445
TI  - On call. I'm bothered by cold sores two or three times a year. What are they, and
      what can I do about them?

PMID- 12604446
TI  - Anorexia nervosa--Part I. How the mind starves the body, and what can be done to
      prevent it.

PMID- 12604447
TI  - Diet and Alzheimer's disease.

PMID- 12604449
TI  - Bossed to death?

PMID- 12604448
TI  - Disturbing news: journalistic trauma.

PMID- 12604450
TI  - The defiant one. Hard to detect and quick to spread, pancreatic cancer is among
      the deadliest of cancers. Researchers hope that genetic research will make it
      more like other cancers--a treatable disease.

PMID- 12604451
TI  - Why do we need another test? The predictive powers of a cholesterol test only go
      so far. If your LDL is low, your C-reactive protein may be a better sign of
      impending heart trouble.

PMID- 12604452
TI  - A new wave of treatment. After other treatments have failed, shock-wave therapy
      may help some people with heel pain and tennis elbow.

PMID- 12604453
TI  - Heartfelt injections.

PMID- 12604454
TI  - Strong reactions to nutty kisses.

PMID- 12604455
TI  - Preventing a Niagara of viagra.

PMID- 12604456
TI  - By the way, doctor. I'm 84 and had a small heart attack last year. My kids tell
      me I should be taking a statin. But at my age, I don't see how any medication is
      going to clean out my arteries and get rid of my atherosclerosis. What do you
      think?

PMID- 12604457
TI  - By the way, doctor. I recently had an ultrasound to look for gallstones. No
      gallstones. But they found an abdominal aortic aneurysm instead. The doctors said
      it's pretty small--only 3.8 centimeters. But I'm worried that it might get larger
      and break open. Is there anything I can do to prevent it from getting bigger?

PMID- 12604458
TI  - 9 preemptive strikes against stroke. Take steps now to prevent a brain attack
      later.

PMID- 12604459
TI  - Beyond statins. New drugs can work with, or in place of, cholesterol-lowering
      statins.

PMID- 12604460
TI  - When big-hearted is bad. An overgrown heart muscle can kill. In most cases,
      though, it's just a reason for extra care.

PMID- 12604461
TI  - A big lift for your heart.

PMID- 12604463
TI  - A specialist or generalist for your heart?

PMID- 12604464
TI  - Heart profiler.

PMID- 12604462
TI  - Aortic stenosis.

PMID- 12604465
TI  - Ask the doctor. What's the right treatment if I have a high value on a "heart
      scan" but no other symptoms?

PMID- 12604466
TI  - Role of glycosylation in the renal electrogenic Na+-HCO3- cotransporter (NBCe1).
AB  - The electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1 is important for the
      regulation of intracellular pH (pH(i)) and for epithelial HCO(3)(-) transport in
      many tissues, including kidney, pancreas, and brain. In the present study, we
      investigate glycosylation sites in NBCe1. Treatment of rat kidney membrane
      extracts with peptide N-glycosidase F (PNGase F) shifted the apparent molecular
      weight (MW) of NBCe1 from 130 to 116, the MW predicted from the deduced amino
      acid sequence. Treatment with endoglycosidase F(2) or H or O-glycosidase did not
      affect the MW of NBCe1. Lectin-binding studies, together with the enzyme data,
      suggest that the N-linked carbohydrates are of tri- or tetra-antennary type. To
      localize glycosylation sites, we individually mutated the seven consensus N
      glycosylation sites by replacing asparagine (N) with glutamine (Q) and assessing
      mutant transporters in Xenopus laevis oocytes. Immunoblotting of oocyte membrane
      extracts treated with PNGase F indicates that NBCe1 is normally glycosylated at
      N597 and N617 (both on the third extracellular loop). However, N592 (on the same
      loop) is glycosylated when the other two sites are mutated. The triple mutant
      (N592Q/N597Q/N617Q) is completely unglycosylated but, based on microelectrode
      measurements of membrane potential and pH(i) in oocytes, preserves the Na(+) and
      HCO(3)(-) dependence and electrogenicity of wild-type NBCe1.

PMID- 12604467
TI  - cAMP-dependent activation of the renal-specific Na+-K+-2Cl- cotransporter is
      mediated by regulation of cotransporter trafficking.
AB  - The murine apical bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter gene
      (mBSC1) exhibits two spliced isoform products that differ at the COOH-terminal
      domain. A long COOH-terminal isoform (L-mBSC1) encodes the Na(+)-K(+)-2Cl(-)
      cotransporter, and a short isoform (S-mBSC1) exerts a dominant-negative effect on
      L-mBSC1 cotransporter activity that is abrogated by cAMP. However, the mechanism
      of this dominant-negative effect was not clear. In this study, we used confocal
      microscopic analysis of an enhanced green fluorescent protein (EGFP) fusion
      construct (L-mBSC1-EGFP) expressed to characterize the surface expression of the
      L-BSC1 isoform in Xenopus laevis oocytes. Functional expression was also assessed
      in L-mBSC1-injected oocytes by measuring the bumetanide-sensitive (86)Rb(+)
      uptake. Oocytes injected with L-mBSC1-EGFP cRNA developed a distinct plasma
      membrane-associated fluorescence that colocalized with the fluorescent membrane
      dye FM 4-64. The fluorescence intensity in L-mBSC1-EGFP oocytes did not change
      after cAMP was added to the extracellular medium. In contrast, L-mBSC1-EGFP
      fluorescence intensity was reduced in a dose-dependent manner, with coexpression
      of S-mBSC1. The inhibitory effect of S-mBSC1 was abrogated by cAMP. Finally, the
      exocytosis inhibitor colchicine blocked the effect of cAMP on the L-mBSC1-EGFP/S
      mBSC1-coinjected oocytes. All changes in L-mBSC1 surface expression correlated
      with modification of bumetanide-sensitive (86)Rb(+) uptake. Our data suggest that
      the dominant-negative effect of S-mBSC1 on L-mBSC1 transport function is due to
      the effects of the cotransporter on trafficking.

PMID- 12604468
TI  - Update on lead poisoning in a Nicaraguan community.

PMID- 12604469
TI  - Navajo uranium miners in Utah, 1951.

PMID- 12604471
TI  - Science and spirituality.

PMID- 12604473
TI  - Models of population health: their value for US public health practice, policy,
      and research.

PMID- 12604474
TI  - Is child-centered tobacco prevention a trap?

PMID- 12604475
TI  - Consuming research, producing policy?
AB  - The authors' 1990 article "Producing Health, Consuming Health Care" presented a
      conceptual framework for synthesizing a rapidly growing body of findings on the
      nonmedical determinants of health. The article received a very positive response,
      and here the authors reflect on what lessons might be learned from that response
      about the style or content of effective interdisciplinary communication. Much
      substantive knowledge has been accumulated since 1990, and a number of different
      frameworks have been developed before and since. The authors situate theirs
      within this literature and consider how they might have modified it if they "knew
      then what they know now." They ask what impact this article, and the much broader
      stream of research on the determinants of health, has had on public policy?

PMID- 12604476
TI  - What is population health?
AB  - Population health is a relatively new term that has not yet been precisely
      defined. Is it a concept of health or a field of study of health determinants? We
      propose that the definition be "the health outcomes of a group of individuals,
      including the distribution of such outcomes within the group," and we argue that
      the field of population health includes health outcomes, patterns of health
      determinants, and policies and interventions that link these two. We present a
      rationale for this definition and note its differentiation from public health,
      health promotion, and social epidemiology. We invite critiques and discussion
      that may lead to some consensus on this emerging concept.

PMID- 12604477
TI  - The contribution of the World Health Organization to a new public health and
      health promotion.
AB  - The author traces the development of the concept of health promotion from 1980s
      policies of the World Health Organization. Two approaches that signify the
      modernization of public health are outlined in detail: the European Health for
      All targets and the settings approach. Both aim to reorient health policy
      priorities from a risk factor approach to strategies that address the
      determinants of health and empower people to participate in improving the health
      of their communities. These approaches combine classic public health dictums with
      "new" strategies, some setting explicit goals to integrate public health with
      general welfare policy. Health for All, health promotion, and population health
      have contributed to this reorientation in thinking and strategy, but the focus of
      health policy remains expenditure rather than investment.

PMID- 12604478
TI  - Evolution of the determinants of health, health policy, and health information
      systems in Canada.
AB  - The history of health determinants in Canada influenced both the direction of
      data gathering about population health and government policies designed to
      improve health. Two competing movements marked these changes. The idea of health
      promotion grew out of the 1974 Lalonde report, which recognized that determinants
      of health went beyond traditional public health and medical care, and argued for
      the importance of socioeconomic factors. Research on health inequalities was led
      by the Canadian Institute for Advanced Research in the 1980s, which produced
      evidence of health inequalities along socioeconomic lines and argued for policy
      efforts in early child development. Both movements have shaped current
      information gathering and the policies that have come to be labeled "population
      health."

PMID- 12604479
TI  - Population health in Canada: a brief critique.
AB  - An internationally influential model of population health was developed in Canada
      in the 1990s, shifting the research agenda beyond health care to the social and
      economic determinants of health. While agreeing that health has important social
      determinants, the authors believe that this model has serious shortcomings; they
      critique the model by focusing on its hidden assumptions. Assumptions about how
      knowledge is produced and an implicit interest group perspective exclude the
      sociopolitical and class contexts that shape interest group power and citizen
      health. Overly rationalist assumptions about change understate the role of
      agency. The authors review the policy and practice implications of the Canadian
      population health model and point to alternative ways of viewing the determinants
      of health.

PMID- 12604480
TI  - The politics of emergency health powers and the isolation of public health.
AB  - The Model State Emergency Health Powers Act became a contentious document in more
      than 30 states in 2001 and 2002. Controversy has focused on recommendations by
      the authors of the Model Act that seemed to accord higher priority to collective
      action in emergencies than to protecting privacy and property. This situation has
      several causes that derive from the characteristics of public health emergencies
      during the past half century and the relative isolation of public health
      officials from both their colleagues in government and many members of the
      public.

PMID- 12604481
TI  - Implications of the World Trade Center attack for the public health and health
      care infrastructures.
AB  - The September 11, 2001, attack on the World Trade Center had profound effects on
      the well-being of New York City. The authors describe and assess the strengths
      and weaknesses of the city's response to the public health, environmental/
      occupational health, and mental health dimensions of the attack in the first 6
      months after the event. They also examine the impact on the city's health care
      and social service system. The authors suggest lessons that can inform the
      development of a post-September 11th agenda for strengthening urban health
      infrastructures.

PMID- 12604482
TI  - Aligning quality for populations and patients: do we know which way to go?
AB  - Both the medical care and public health systems have invested considerable
      resources to define, measure, and improve quality and health outcomes. A movement
      toward accountability has generated performance indicators from the medical arena
      and "leading health indicators" from the public health arena. The focus on
      specific conditions by the medical care system has been at odds with public
      health's emphasis on improving population health and has perpetuated a bifurcated
      system. Aligning the goals of medical care with those of public health will
      require reformulation of performance measurement and accountability into a common
      language that is valued by both systems. Such a creation would amount to a whole
      that is stronger than the sum of the component parts.

PMID- 12604485
TI  - African American women and smoking: starting later.
AB  - It is commonly accepted that adolescence is the period for initiation into
      smoking and other tobacco use behaviors. However, evidence is increasing that the
      set of presumptions about adolescent onset of tobacco use may not be true for all
      cultural or subpopulation groups. Secondary analysis of data from the 2000
      National Health Interview Survey (NHIS) was used to examine ethnic differences in
      smoking patterns among African American and White women. Results showed a
      striking racial/ethnic difference in age of onset; African American women
      initiate smoking later than White women at each age group. Prevention
      interventions need to continue beyond adolescence well into the adult years,
      especially for African American women. Late onset for these women represents an
      often missed window of opportunity for prevention.

PMID- 12604484
TI  - A balanced tobacco control policy.
AB  - By raising the price of cigarettes through tobacco taxes, policymakers might only
      be delaying some smokers' initiation of smoking rather than permanently
      preventing them from smoking. This is one of several reasons for adopting a
      balanced tobacco control policy that relies only in part on cigarette taxation.

PMID- 12604483
TI  - Is smoking delayed smoking averted?
AB  - Antismoking efforts often target teenagers in the hope of producing a new
      generation of never smokers. Teenagers are more responsive to tobacco taxes than
      are adults. The author summarizes recent evidence suggesting that delaying
      smoking initiation among teenagers through higher taxes does not generate
      proportionate reductions in prevalence rates through adulthood. In consequence,
      the impact of taxes on smoking among youths overstates the potential long-term
      public health effects of this tobacco control strategy.

PMID- 12604487
TI  - Early modern childbirth.

PMID- 12604486
TI  - The population health approach in historical perspective.
AB  - The origin of the population health approach is an historic debate over the
      relationship between economic growth and human health. In Britain and France, the
      Industrial Revolution disrupted population health and stimulated pioneering
      epidemiological studies, informing the early preventive public health movement. A
      century-long process of political adjustment between the forces of liberal
      democracy and propertied interests ensued. The 20th-century welfare states
      resulted as complex political mechanisms for converting economic growth into
      enhanced population health. However, the rise of a "neoliberal" agenda,
      denigrating the role of government, has once again brought to the fore the
      importance of prevention and a population health approach to map and publicize
      the health impacts of this new phase of "global" economic growth.

PMID- 12604488
TI  - Prevalence of and risk factors for exertional chest pain in older Mexican
      Americans.

PMID- 12604489
TI  - Immigrant South Asian women at greater risk for injury from intimate partner
      violence.

PMID- 12604490
TI  - A prospective study of exposure to rap music videos and African American female
      adolescents' health.

PMID- 12604491
TI  - Food messages on African American television shows.

PMID- 12604492
TI  - Socioeconomic status and health among Californians: an examination of multiple
      pathways.

PMID- 12604493
TI  - Decreased congenital syphilis incidence in Haiti's rural Artibonite region
      following decentralized prenatal screening.

PMID- 12604494
TI  - Disparities in trends of hospitalization for potentially preventable chronic
      conditions among African Americans during the 1990s: implications and benchmarks.
AB  - OBJECTIVES: We compared trends in prevalence rates of preventable cardiovascular-
      and diabetes-related hospitalizations between African Americans and members of
      other major US racial/ethnic groups. METHODS: Standardized rates for 1991 to 1998
      were derived from hospital and US census data for California. RESULTS: African
      Americans had significantly higher hospitalization rates in 1991, and
      discrepancies in rates continued to widen through 1998. Overall male and female
      rates were approximately 3 times higher for angina, 7 times higher for
      hypertension, between 7 and 8 times higher for congestive heart failure, and 10
      times higher for diabetes. CONCLUSIONS: Widening disparities in cardiovascular-
      and diabetes-related health conditions were observed in this study, possibly
      owing to racial inequalities in provision of effective primary care.

PMID- 12604495
TI  - Adolescent health in the Caribbean: risk and protective factors.
AB  - OBJECTIVES: This study sought to identify, among youths, factors associated with
      characteristics such as poor health status, substance use, and suicide risk and
      to explore the extent to which the risk and protective factors identified cut
      across health-compromising behaviors. METHODS: A survey was administered to
      representative samples of young people from 9 Caribbean countries. RESULTS:
      Physical/sexual abuse and having a friend or relative who had attempted suicide
      were associated with an increased prevalence of health-compromising behaviors.
      Connectedness with parents and school and attendance at religious services were
      associated with fewer health risk behaviors. CONCLUSIONS: When the identified
      risk and protective factors were compared with those seen among young people in
      the United States, similarities as well as important differences were found.

PMID- 12604496
TI  - A population-based analysis of socioeconomic status and insurance status and
      their relationship with pediatric trauma hospitalization and mortality rates.
AB  - OBJECTIVES: We investigated socioeconomic disparities in injury hospitalization
      rates and severity-adjusted mortality for pediatric trauma. METHODS: We used 10
      years of pediatric trauma data from Sacramento County, Calif, to compare trauma
      hospitalization rates, trauma mechanism and severity, and standardized hospital
      mortality across socioeconomic strata (median household income, proportion of
      households in poverty, insurance). RESULTS: Children from lower-socioeconomic
      status (SES) communities had higher injury hospitalization and mortality rates,
      and presented more frequently with more lethal mechanisms of injury (pedestrian,
      firearm), but did not have higher severity-adjusted mortality. CONCLUSIONS:
      Higher injury mortality rates among children of lower SES in Sacramento County
      are explained by a higher incidence of trauma and more fatal mechanisms of
      injury, not by greater injury severity or poorer inpatient care.

PMID- 12604497
TI  - Neighborhood physical conditions and health.
AB  - OBJECTIVES: We explored the relationship between boarded-up housing and rates of
      gonorrhea and premature mortality. METHODS: In this ecological study of 107 US
      cities, we developed several models predicting rates of gonorrhea and premature
      death before age 65 from all causes and from specific causes. We controlled for
      race, poverty, education, population change, and health insurance coverage.
      RESULTS: Boarded-up housing remained a predictor of gonorrhea rates, all-cause
      premature mortality, and premature mortality due to malignant neoplasms,
      diabetes, homicide, and suicide after control for sociodemographic factors.
      CONCLUSIONS: Boarded-up housing may be related to mortality risk because of its
      potential adverse impact on social relationships and opportunities to engage in
      healthful behaviors. Neighborhood physical conditions deserve further
      consideration as a potential global factor influencing health and well-being.

PMID- 12604498
TI  - Assessing the capacity of health departments to engage in community-based
      participatory public health.
AB  - OBJECTIVES: We created indicators of local public health agency capacity to
      engage in community-based participatory public health. METHODS: We sent a survey
      of 27 items reflecting aspects of community-based participatory public health to
      429 employees in 4 local health departments. Two thirds (n = 282) responded. We
      performed a factor analysis to identify components of community-based
      participatory practice. RESULTS: We identified 4 factors: (1) the agency's and
      (2) the individual employee's skills in working with community groups and
      minority populations, (3) the extent and frequency of agency networking, and (4)
      community participation in health department planning. CONCLUSIONS: Our findings
      suggest that it is possible to measure the competencies needed by health
      department staff to engage in community-based participatory public health.

PMID- 12604499
TI  - Why do WIC participants fail to pick up their checks? An urban study in the wake
      of welfare reform.
AB  - OBJECTIVES: This study explored whether work or immigration concerns affect
      women's participation in the Special Supplemental Nutrition Program for Women,
      Infants, and Children (WIC). METHODS: The sample included women who had withdrawn
      from the WIC program and current WIC clients from 1 center in New York City.
      Logistic regression analyses were used to predict noncollection of checks;
      demographic characteristics, program participation, and problems with the WIC
      program were independent variables. RESULTS: Strong predictors of noncollection
      of checks were job conflicts, transportation or illness problems, and WIC receipt
      by the woman herself (rather than by her children). CONCLUSIONS: Employment
      conflicts were related to failure to pick up WIC checks; immigration concerns
      were not. As a means of enhancing WIC participation, flexibility is recommended
      in terms of center hours, locations, and staffing and program check distribution
      policies.

PMID- 12604500
TI  - Parental smoking and infant respiratory infection: how important is not smoking
      in the same room with the baby?
AB  - OBJECTIVES: We sought to quantify the effect of good smoking hygiene on infant
      risk of respiratory tract infection in the first 12 months of life. METHODS: A
      cohort of 4486 infants in Tasmania, Australia, was followed from birth to 12
      months of age for hospitalization with respiratory infection. Case ascertainment
      was 98.2%. RESULTS: Relative to the infants of mothers who smoked postpartum but
      never in the same room with their infants, risk of hospitalization was 56% (95%
      confidence interval [CI] = 13%, 119%) higher if the mother smoked in the same
      room with the infant, 73% (95% CI = 18%, 157%) higher if the mother smoked when
      holding the infant, and 95% (95% CI = 28%, 298%) higher if the mother smoked
      while feeding the infant. CONCLUSIONS: Parents who smoke should not smoke with
      their infants present in the same room.

PMID- 12604501
TI  - Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with
      mebendazole and metronidazole use among Filipino laborers in Taiwan.
AB  - OBJECTIVES: This study sought to identify the risk factors associated with an
      outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among
      Filipino laborers in Taiwan. METHODS: Forty-six SJS/TEN patients were matched to
      92 controls according to month of arrival in Taiwan, sex, and age. RESULTS: The
      odds ratio for development of SJS/TEN was 9.5 (95% confidence interval [CI] =
      3.9, 23.9) among workers who had used both metronidazole and mebendazole sometime
      in the preceding 6 weeks. In addition, a gradient increase in the occurrence of
      SJS/TEN was found with an increasing level of exposure to metronidazole.
      CONCLUSIONS: This outbreak highlights the risk of SJS/TEN resulting from the use
      of both metronidazole and mebendazole and the need for control measures.

PMID- 12604503
TI  - Body composition assessment in extreme obesity and after massive weight loss
      induced by gastric bypass surgery.
AB  - Body composition methods were examined in 20 women [body mass index (BMI) 48.7 +/
      8.8 kg/m(2)] before and after weight loss [-44.8 +/- 14.6 (SD) kg] after gastric
      bypass (GBP) surgery. The reference method, a three-compartment (3C) model using
      body density by air displacement plethysmography and total body water (TBW) by
      H(2)18O dilution (3C-H(2)18O), showed a decrease in percent body fat (%BF) from
      51.4 to 34.6%. Fat-free mass hydration was significantly higher than the
      reference value (0.738) in extreme obesity (0.756; P < 0.001) but not after
      weight reduction (0.747; P = 0.16). %BF by H(2)18O dilution and air displacement
      plethysmography differed significantly from %BF by 3C-H(2)18O in extreme obesity
      (P < 0.05) and 3C models using (2)H(2)O or bioelectrical impedance analysis (BIA)
      to determine TBW improved mean %BF estimates over most other methods at both time
      points. BIA results varied with the equation used, but BIA better predicted %BF
      than did BMI at both time points. All methods except BIA using the Segal equation
      were comparable to the reference method for determining changes over time. A
      simple 3C model utilizing air displacement plethysmography and BIA is useful for
      clinical evaluation in this population.

PMID- 12604504
TI  - A highly sensitive and specific assay for determination of IGF-I bioactivity in
      human serum.
AB  - At present, the circulating bioactivity of insulin-like growth factor I (IGF-I)
      is estimated by immunological measurements of IGF-I levels. However, immunoassays
      ignore the modifying effects of the IGF-binding proteins (IGFBPs) on the
      interaction between IGF-I and the IGF-I receptor (IGF-IR). Therefore, we
      developed an IGF-I kinase receptor activation assay (KIRA) based on cells
      transfected with the human IGF-IR gene. The bioassay was sensitive (detection
      limit 0.08 microg/l), specific (cross-reactivity of insulin, insulin analogs, and
      proinsulin was <1%; IGF-II cross-reactivity was 12%), and accurate (within- and
      between-assay coefficients of variation <7 and <15%). The operational range of
      the assay (0.25-10.0 microg/l) allowed for determination of IGF-I bioactivity in
      serum from patients with, for example, growth hormone deficiency, type 1
      diabetes, and acromegaly. Addition of IGFBPs dose dependently reduced the KIRA
      signal, whereas addition of IGF-II to preformed complexes (1:1 molar ratio) of
      IGF-I and IGFBP dose dependently increased IGF-I bioactivity by displacement of
      bound IGF-I. In conclusion, the KIRA will enable us to compare IGF-I bioactivity
      with existing immunological measurements of IGF-I in serum and, hopefully, to
      elucidate the factors that determine IGF-I bioactivity in vivo.

PMID- 12604505
TI  - Gluconeogenesis in humans with induced hyperlactatemia during low-intensity
      exercise.
AB  - We studied the role of lactate in gluconeogenesis (GNG) during exercise in
      untrained fasting humans. During the final hour of a 4-h cycle exercise at 33-34%
      maximal O(2) uptake, seven subjects received, in random order, either a sodium
      lactate infusion (60 micromol x kg(-1) x min(-1)) or an isomolar sodium
      bicarbonate infusion. The contribution of lactate to gluconeogenic glucose was
      quantified by measuring (2)H incorporation into glucose after body water was
      labeled with deuterium oxide, and glucose rate of appearance (R(a)) was measured
      by [6,6-(2)H(2)]glucose dilution. Infusion of lactate increased lactate
      concentration to 4.4 +/- 0.6 mM (mean +/- SE). Exercise induced a decrease in
      blood glucose concentration from 5.0 +/- 0.2 to 4.2 +/- 0.3 mM (P < 0.05);
      lactate infusion abolished this decrease (5.0 +/- 0.3 mM; P < 0.001) and
      increased glucose R(a) compared with bicarbonate infusion (P < 0.05). Lactate
      infusion increased both GNG from lactate (29 +/- 4 to 46 +/- 4% of glucose R(a),
      P < 0.001) and total GNG. We conclude that lactate infusion during low-intensity
      exercise in fasting humans 1). increased GNG from lactate and 2). increased
      glucose production, thus increasing the blood glucose concentration. These
      results indicate that GNG capacity is available in humans after an overnight fast
      and can be used to sustain blood glucose levels during low-intensity exercise
      when lactate, a known precursor of GNG, is available at elevated plasma levels.

PMID- 12604506
TI  - Dual effects on HDL metabolism by cholesteryl ester transfer protein inhibition
      in HepG2 cells.
AB  - Cholesteryl ester transfer protein (CETP) promotes reverse cholesterol transport
      via exchange of cholesteryl ester and triglyceride among lipoproteins. Here, we
      focused on HDL metabolism during inhibition of CETP expression by using CETP
      antisense oligodeoxynucleotides (ODNs) in HepG2 cells. CETP secretion was
      decreased by 70% in mRNA levels and by 52% in mass 20 h after ODNs against CETP
      were delivered to HepG2 cells. Furthermore, as a consequence of the
      downregulation of CETP, the expression of scavenger receptor class B type I (SR
      BI), an HDL receptor, was also reduced by approximately 50% in mRNA and protein
      levels, whereas the apolipoprotein A-I (apoA-I) expression and secretion were
      increased by 30 and 92%, respectively. In a functional study, the selective
      uptake of (125)I-[(14)C]cholesteryl oleate-labeled HDL(3) was decreased.
      Cholesterol efflux to apoA-I and HDL(3) was significantly increased by 88 and
      37%, respectively. Moreover, the CE levels in cells after antisense treatment
      were elevated by 20%, which was related to the about twofold increase of
      cholesterol esterification and increased acyl-CoA:cholesterol acyltransferase 1
      mRNA levels. Taken together, these findings suggest that although acute
      suppression of CETP expression leads to an elevation in cellular cholesterol
      stores, apoA-I secretion, and cellular cholesterol efflux to apoA-I, the return
      of HDL-CE to hepatocytes via an SR-BI pathway was inhibited in vitro. Thus
      antisense inhibition of hepatic CETP expression manifests dual effects: namely,
      increased formation of HDL and suppression of catabolism of HDL-CE, probably via
      the SR-BI pathway.

PMID- 12604507
TI  - Measurement of protein metabolism in epidermis and dermis.
AB  - We found that, in the rabbit ear, the dermal protein contains 75.5% of cutaneous
      phenylalanine and 97.9% of cutaneous proline; the remaining 24.5% of
      phenylalanine and 2.1% of proline are in the epidermal protein. This finding led
      us to develop two novel models that use phenylalanine and proline tracers and the
      rabbit ear to quantify protein kinetics in the epidermis and dermis. The four
      pool model calculates the absolute rates of protein kinetics and amino acid
      transport, and the two-pool model calculates the apparent rates of protein
      kinetics that are reflected in the blood. The results showed that both epidermis
      and dermis maintained their protein mass in the postabsorptive state. The rate of
      epidermal protein synthesis was 93.4 +/- 37.6 mg x 100 g(-1) x h(-1), which was
      10-fold greater than that of the dermal protein (9.3 +/- 5.8 mg x 100 g(-1) x h(
      1)). These synthetic rates were in agreement with those measured simultaneously
      by the tracer incorporation method. Comparison of the four-pool and two-pool
      models indicated that intracellular cycling of amino acids accounted for 75 and
      90% of protein kinetics in the dermis and epidermis, respectively. We conclude
      that, in the skin, efficient reutilization of amino acids from proteolysis for
      synthesis enables the maintenance of protein mass in the postabsorptive state.

PMID- 12604508
TI  - Acute cold exposure, leptin, and somatostatin analog (octreotide) modulate
      thyroid 5'-deiodinase activity.
AB  - We investigated the effect of acute cold exposure, leptin, and the somatostatin
      analog octreotide (OCT) on thyroid type I (D1) and II (D2) deiodinase activities.
      Microsomal D1 and D2 activities were measured by the release of (125)I from
      (125)I-reverse triiodothyronine (rT(3)) under different assay conditions. Rats
      exposed to 4 degrees C (15, 30, 60, and 120 min) showed progressive reduction in
      thyroidal D1 and D2, reaching approximately 40% at 2 h (P < 0.05) despite
      increased circulating TSH (P < 0,05) associated with the higher thyroid D1 and D2
      in hypothyroid rats. A single injection of leptin (8 microg/100 g body wt sc)
      induced increased thyroid and liver D1 (P < 0.05), but not thyroid D2, activities
      at 30 and 120 min, independently of the serum TSH rise shown only at 2 h. OCT (1
      microg/kg body wt sc) increased D1 and D2 activity significantly 24 h after a
      single injection, with no changes in serum TSH. Therefore, leptin and
      somatostatin are potential physiological upregulators of thyroid deiodinases, and
      their low secretion during acute cold exposure may be a potential mechanism
      contributing to cold-induced reduction in thyroid deiodinase activity.

PMID- 12604509
TI  - Mycobacterium tuberculosis in the extracellular compartment: an underestimated
      adversary.

PMID- 12604511
TI  - Relationships between respiration and susceptibility to azole antifungals in
      Candida glabrata.
AB  - Over the past two decades, the incidence of infections due to Candida glabrata, a
      yeast with intrinsic low susceptibility to azole antifungals, has increased
      markedly. Respiratory deficiency due to mutations in mitochondrial DNA (mtDNA)
      associated with resistance to azoles frequently occurs in vitro in this species.
      In order to specify the relationships between respiration and azole
      susceptibility, the effects of respiratory chain inhibitors on a wild-type
      isolate of C. glabrata were evaluated. Respiration of blastoconidia was
      immediately blocked after extemporaneous addition of potassium cyanide, whereas a
      4-h preincubation was required for sodium azide. Antifungal susceptibility
      determined by a disk diffusion method on Casitone agar containing sodium azide
      showed a significant decrease in the susceptibility to azoles. Biweekly
      subculturing on Casitone agar supplemented with sodium azide was therefore
      performed. This resulted after 40 passages in the isolation of a respiration
      deficient mutant, as suggested by its lack of growth on glycerol-containing agar.
      This respiratory deficiency was confirmed by flow cytometric analysis of
      blastoconidia stained with rhodamine 123 and by oxygraphy. Moreover, transmission
      electron microscopy and restriction endonuclease analysis of the mtDNA of mutant
      cells demonstrated the mitochondrial origin of the respiratory deficiency.
      Finally, this mutant exhibited cross-resistance to all the azoles tested. In
      conclusion, blockage of respiration in C. glabrata induces decreased
      susceptibility to azoles, culminating in azole resistance due to the deletion of
      mtDNA. This mechanism could explain the induction of petite mutations by azole
      antifungals which have been demonstrated to act directly on the mitochondrial
      respiratory chain.

PMID- 12604510
TI  - FemABX peptidyl transferases: a link between branched-chain cell wall peptide
      formation and beta-lactam resistance in gram-positive cocci.

PMID- 12604513
TI  - Low-level resistance to rifampin in Streptococcus pneumoniae.
AB  - Rifampin is recommended for combination therapy of meningitis due to beta-lactam
      resistant Streptococcus pneumoniae. High-level rifampin resistance (MIC, > or =4
      mg/liter) has been mapped to point mutations in clusters I and III of rpoB of the
      pneumococcus. The molecular basis of low-level resistance (MICs, > or =0.5 and <4
      mg/liter) was analyzed. Spontaneous mutants of clinical pneumococcal isolates
      were selected on Columbia sheep blood agar plates containing rifampin at 0.5, 4,
      10, or 50 mg/liter. Low-level resistance could be assigned to mutations in
      cluster II (I(545)N, I(545)L). Sensitive (MIC, <0.048 mg/liter) wild-type strains
      acquired low-level resistance at a rate approximately 10 times higher than that
      at which they acquired high-level resistance (average mutation frequencies, 2.4 x
      10(-7) for low-level resistance versus 2.9 x 10(-8) for high-level resistance [P
      < 0.0001]). In second-step experiments, the frequencies of mutations from low- to
      high-level resistance were over 10 times higher than the frequencies of mutations
      from susceptibility to high-level resistance (average mutation frequencies, 7.2 x
      10(-7) versus 5.0 x 10(-8) [P < 0.001]). Mutants with low-level resistance were
      stable upon passage. Sequencing of a clinical isolate with low-level resistance
      (MIC, 0.5 mg/liter) revealed a Q(150)R mutation upstream of cluster I. The
      frequencies of mutations to high-level resistance for this strain were even
      higher than the rates observed for the in vitro mutants. Therefore, a resistance
      mediating mutation located outside clusters I, II, and III has been described for
      the first time in the pneumococcus. In vitro low-level rifampin resistance in S.
      pneumoniae could be mapped to cluster II of rpoB. Mutants of pneumococcus with
      low-level resistance may be selected in vivo during therapy in tissue
      compartments with low antibiotic concentrations and play a role in the
      development of resistance.

PMID- 12604512
TI  - Quinolone-DNA interaction: sequence-dependent binding to single-stranded DNA
      reflects the interaction within the gyrase-DNA complex.
AB  - We have investigated the interaction of quinolones with DNA by a number of
      methods to establish whether a particular binding mode correlates with quinolone
      potency. The specificities of the quinolone-mediated DNA cleavage reaction of DNA
      gyrase were compared for a number of quinolones. Two patterns that depended on
      the potency of the quinolone were identified. Binding to plasmid DNA was examined
      by measuring the unwinding of pBR322 by quinolones; no correlation with quinolone
      potency was observed. Quinolone binding to short DNA oligonucleotides was
      measured by surface plasmon resonance. The quinolones bound to both single- and
      double-stranded oligonucleotides in an Mg(2+)-dependent manner. Quinolones bound
      to single-stranded DNA with a higher affinity, and the binding exhibited sequence
      dependence; binding to double-stranded DNA was sequence independent. The
      variations in binding in the presence of metal ions showed that Mg(2+) promoted
      tighter, more specific binding to single-stranded DNA than softer metal ions
      (Mn(2+) and Cd(2+)). Single-stranded DNA binding by quinolones correlated with
      the in vitro quinolone potency, indicating that this mode of interaction may
      reflect the interaction of the quinolone with DNA in the context of the gyrase
      DNA complex.

PMID- 12604514
TI  - Resistance genes of aminocoumarin producers: two type II topoisomerase genes
      confer resistance against coumermycin A1 and clorobiocin.
AB  - The aminocoumarin resistance genes of the biosynthetic gene clusters of
      novobiocin, coumermycin A(1), and clorobiocin were investigated. All three
      clusters contained a gyrB(R) resistance gene, coding for a gyrase B subunit.
      Unexpectedly, the clorobiocin and the coumermycin A(1) clusters were found to
      contain an additional, similar gene, named parY(R). Its predicted gene product
      showed sequence similarity with the B subunit of type II topoisomerases.
      Expression of gyrB(R) and likewise of parY(R) in Streptomyces lividans TK24
      resulted in resistance against novobiocin and coumermycin A(1), suggesting that
      both gene products are able to function as aminocoumarin-resistant B subunits of
      gyrase. Southern hybridization experiments showed that the genome of all three
      antibiotic producers and of Streptomyces coelicolor contained two additional
      genes which hybridized with either gyrB(R) or parY(R) and which may code for
      aminocoumarin-sensitive GyrB and ParY proteins. Two putative transporter genes,
      novA and couR5, were found in the novobiocin and the coumermycin A(1) cluster,
      respectively. Expression of these genes in S. lividans TK24 resulted in moderate
      levels of resistance against novobiocin and coumermycin A(1), suggesting that
      these genes may be involved in antibiotic transport.

PMID- 12604515
TI  - Prevalence of tetracycline resistance genes in oral bacteria.
AB  - Tetracycline is a broad-spectrum antibiotic used in humans, animals, and
      aquaculture; therefore, many bacteria from different ecosystems are exposed to
      this antibiotic. In order to determine the genetic basis for resistance to
      tetracycline in bacteria from the oral cavity, saliva and dental plaque samples
      were obtained from 20 healthy adults who had not taken antibiotics during the
      previous 3 months. The samples were screened for the presence of bacteria
      resistant to tetracycline, and the tetracycline resistance genes in these
      isolates were identified by multiplex PCR and DNA sequencing. Tetracycline
      resistant bacteria constituted an average of 11% of the total cultivable oral
      microflora. A representative 105 tetracycline-resistant isolates from the 20
      samples were investigated; most of the isolates carried tetracycline resistance
      genes encoding a ribosomal protection protein. The most common tet gene
      identified was tet(M), which was found in 79% of all the isolates. The second
      most common gene identified was tet(W), which was found in 21% of all the
      isolates, followed by tet(O) and tet(Q) (10.5 and 9.5% of the isolates,
      respectively) and then tet(S) (2.8% of the isolates). Tetracycline resistance
      genes encoding an efflux protein were detected in 4.8% of all the tetracycline
      resistant isolates; 2.8% of the isolates had tet(L) and 1% carried tet(A) and
      tet(K) each. The results have shown that a variety of tetracycline resistance
      genes are present in the oral microflora of healthy adults. This is the first
      report of tet(W) in oral bacteria and the first report to show that tet(O),
      tet(Q), tet(A), and tet(S) can be found in some oral species.

PMID- 12604516
TI  - Diversity of tetracycline resistance genes in bacteria from Chilean salmon farms.
AB  - Twenty-five distinct tetracycline-resistant gram-negative bacteria recovered from
      four Chilean fish farms with no history of recent antibiotic use were examined
      for the presence of tetracycline resistance (tet) genes. Sixty percent of the
      isolates carried 1 of the 22 known tet genes examined. The distribution was as
      follows. The tet(A) gene was found in six isolates. The tet(B) gene was found in
      two isolates, including the first description in the genus Brevundimonas: Two
      isolates carried the tet(34) and tet(B) genes, including the first description of
      the tet(34) gene in Pseudomonas and Serratia and the first description of the
      tet(B) gene in Pseudomonas: The tet(H) gene was found in two isolates, which
      includes the first description in the genera Moraxella and Acinetobacter: One
      isolate carried tet(E), and one isolate carried tet(35), the first description of
      the gene in the genus Stenotrophomonas: Finally, one isolate carried tet(L),
      found for the first time in the genus Morganella: By DNA sequence analysis, the
      two tet(H) genes were indistinguishable from the previously sequenced tet(H) gene
      from Tn5706 found in Pasteurella multocida. The Acinetobacter radioresistens
      isolate also harbored the Tn5706-associated 1,063-bp IS element IS1597, while the
      Moraxella isolate carried a 1,026-bp IS-like element whose 293-amino-acid
      transposase protein exhibited 69% identity and 84% similarity to the transposase
      protein of IS1597, suggesting the presence of a novel IS element. The
      distribution of tet genes from the Chilean freshwater ponds was different than
      those that have previously been described from other geographical locations, with
      40% of the isolates carrying unidentified tetracycline resistance genes.

PMID- 12604517
TI  - New anti-human immunodeficiency virus type 1 6-aminoquinolones: mechanism of
      action.
AB  - A 6-aminoquinolone derivative, WM5, which bears a methyl substituent at the N-1
      position and a 4-(2-pyridyl)-1-piperazine moiety at position 7 of the bicyclic
      quinolone ring system, was previously shown to exhibit potent activity against
      replication of human immunodeficiency virus type 1 (HIV-1) in de novo-infected
      human lymphoblastoid cells (V. Cecchetti et al., J. Med. Chem. 43:3799-3802,
      2000). In this report, we further investigated WM5's mechanism of antiviral
      activity. WM5 inhibited HIV-1 replication in acutely infected cells as well as in
      chronically infected cells. The 50% inhibitory concentrations were 0.60 +/- 0.06
      and 0.85 +/- 0.05 micro M, respectively. When the effects of WM5 on different
      steps of the virus life cycle were analyzed, the reverse transcriptase activity
      and the integrase and protease activities were not impaired. By using a transient
      trans-complementation assay to examine the activity of WM5 on the replicative
      potential of HIV-1 in a single round of infection, a sustained inhibition of Tat
      mediated long terminal repeat (LTR)-driven transcription (>80% of controls) was
      obtained in the presence of 5 micro M WM5. Interestingly, the aminoquinolone was
      found to efficiently complex TAR RNA, with a dissociation constant in the
      nanomolar range (19 +/- 0.6 nM). These data indicate that WM5 is a promising lead
      compound for the development of a new class of HIV-1 transcription inhibitors
      characterized by recognition of viral RNA target(s).

PMID- 12604518
TI  - Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy
      of uncomplicated acute cystitis in women.
AB  - One hundred sixty-three women with uncomplicated acute lower urinary tract
      infections were included in a multicenter randomized study comparing cefpodoxime
      proxetil (one 100-mg tablet twice daily) with trimethoprim-sulfamethoxazole (one
      double-strength tablet [160/800 mg] twice daily) for 3 days. A total of 30 women
      in both arms were excluded from the study for various reasons. At 4 to 7 days
      after the discontinuation of therapy, 62 of 63 (98.4%) cefpodoxime-proxetil
      recipients and 70 of 70 (100%) trimethoprim-sulfamethoxazole patients were
      clinically cured and demonstrated bacteriological eradication, respectively. At
      28 days after treatment, 48 of 55 (87.3%) and 43 of 50 (86%) cefpodoxime-proxetil
      recipients as well as 51 of 60 (85%) and 42 of 50 (84%) trimethoprim
      sulfamethoxazole recipients were clinically cured and demonstrated
      bacteriological eradication, respectively. Independently of the prescribed
      regimen, a significant difference (P < 0.001) in failure rates was observed only
      for patients with a previous history of three or more episodes of acute cystitis
      per year. With the exception of one patient in the trimethoprim-sulfamethoxazole
      arm who discontinued therapy because of gastrointestinal pain, both
      antimicrobials were well tolerated. In conclusion, cefpodoxime-proxetil treatment
      for 3 days was as safe and effective as trimethoprim-sulfamethoxazole for 3 days
      for the treatment of uncomplicated acute cystitis in women.

PMID- 12604520
TI  - Synergistic activity of colistin and ceftazidime against multiantibiotic
      resistant Pseudomonas aeruginosa in an in vitro pharmacodynamic model.
AB  - Despite the marketing of a series of new antibiotics for antibiotic-resistant
      gram-positive bacteria, no new agents for multiple-antibiotic-resistant gram
      negative infections will be available for quite some time. Clinicians will need
      to find more effective ways to utilize available agents. Colistin is an older but
      novel antibiotic that fell into disfavor with clinicians some time ago yet still
      retains a very favorable antibacterial spectrum, especially for Pseudomonas and
      Acinetobacter spp. Time-kill curves for two strains of multiantibiotic-resistant
      Pseudomonas aeruginosa were generated after exposure to colistin alone or in
      combination with ceftazidime or ciprofloxacin in an in vitro pharmacodynamic
      model. MICs of colistin, ceftazidime, ciprofloxacin, piperacillin-tazobactam,
      imipenem, and tobramycin were 0.125, > or =32, >4, >128/4, 16, and >16 mg/liter,
      respectively. Colistin showed rapid, apparently concentration-dependent
      bactericidal activity at concentrations between 3 and 200 mg/liter. We were
      unable to detect increased colistin activity at concentrations above 18 mg/liter
      due to extremely rapid killing. The combination of colistin and ceftazidime was
      synergistic (defined as at least a 2-log(10) drop in CFU per milliliter from the
      count obtained with the more active agent) at 24 h. Adding ciprofloxacin to
      colistin did not enhance antibiotic activity. These data suggest that the
      antibacterial effect of colistin combined with ceftazidime can be maximized at a
      peak concentration of < or =18 mg/liter.

PMID- 12604519
TI  - Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria
      in Gabon.
AB  - Artesunate is one of the most important antimalarial agents available, since it
      is effective against parasites that have developed resistance to conventional
      antimalarials in sub-Saharan Africa. Antimalarial combination chemotherapies with
      artesunate (4 mg/kg of body weight once daily for 3 days) as one partner have
      been proposed. However, the efficacy of a 3-day course of artesunate alone has
      never been evaluated in individuals in Africa (which has 90% of the worldwide
      malaria burden) living in regions of hyperendemicity, where a considerable degree
      of immunity might substantially enhance the efficacy of short courses of
      artesunate compared to those in regions where the levels of endemicity are low.
      This lack of information does not permit a systematic assessment of the value of
      artesunate-based combination chemotherapies in Africa. Therefore, we studied the
      efficacy and safety of a 3-day course of artesunate (4 mg/kg of body weight,
      orally, once daily) for the treatment of uncomplicated Plasmodium falciparum
      malaria in Gabonese patients aged 4 to 15 years (n = 50). Artesunate was well
      tolerated, and no severe adverse event was reported. Parasite elimination was
      rapid and was achieved in all patients within < or =72 h (geometric mean time to
      elimination, 34 h). The PCR-corrected cure rate by day 14 was 92% (46 of 50
      patients), but it dropped to 72% (36 of 50 patients) by day 28. We conclude that
      a 3-day course of artesunate fails to achieve sufficiently high cure rates for
      uncomplicated falciparum malaria in Gabonese children.

PMID- 12604521
TI  - Activities of garenoxacin (BMS-284756) and other agents against anaerobic
      clinical isolates.
AB  - A total of 590 clinical isolates consisting of 33 species of both gram-positive
      and gram-negative anaerobes were collected from nine centers in the Chicago area
      in 1998-1999. The largest number of isolates (330 isolates, 56%) belonged to the
      Bacteroides group. Isolates were tested by agar dilution against garenoxacin (BMS
      284756, T-3811 ME), trovafloxacin, moxifloxacin, clindamycin, imipenem,
      piperacillin-tazobactam, and cefoxitin. All but one species (2% of Bacteroides
      vulgatus isolates) were fully susceptible to piperacillin-tazobactam and
      imipenem. A number of species were resistant to clindamycin. Among the
      fluoroquinolones, garenoxacin and trovafloxacin had an MIC at which 90% of the
      isolates tested were inhibited of <4 micro g/ml for all but two species
      (Fusobacterium mortiferum/varium and Peptostreptococcus anaerobius).

PMID- 12604522
TI  - Clinical concentrations of thioridazine kill intracellular multidrug-resistant
      Mycobacterium tuberculosis.
AB  - The phenothiazines chlorpromazine (CPZ) and thioridazine (TZ) have equal in vitro
      activities against antibiotic-sensitive and -resistant Mycobacterium
      tuberculosis. These compounds have not been used as anti-M. tuberculosis agents
      because their in vitro activities take place at concentrations which are beyond
      those that are clinically achievable. In addition, chronic administration of CPZ
      produces frequent severe side effects. Because CPZ has been shown to enhance the
      killing of intracellular M. tuberculosis at concentrations in the medium that are
      clinically relevant, we have investigated whether TZ, a phenothiazine whose
      negative side effects are less frequent and serious than those associated with
      CPZ, kills M. tuberculosis organisms that have been phagocytosed by human
      macrophages, which have nominal killing activities against these bacteria. Both
      CPZ and TZ killed intracellular antibiotic-sensitive and -resistant M.
      tuberculosis organisms when they were used at concentrations in the medium well
      below those present in the plasma of patients treated with these agents. These
      concentrations in vitro were not toxic to the macrophage, nor did they affect in
      vitro cellular immune processes. TZ thus appears to be a serious candidate for
      the management of a freshly diagnosed infection of pulmonary tuberculosis or as
      an adjunct to conventional antituberculosis therapy if the patient originates
      from an area known to have a high prevalence of multidrug-resistant M.
      tuberculosis isolates. Nevertheless, we must await the outcomes of clinical
      trials to determine whether TZ itself may be safely and effectively used as an
      antituberculosis agent.

PMID- 12604523
TI  - In vitro activity of S-3578, a new broad-spectrum cephalosporin active against
      methicillin-resistant staphylococci.
AB  - The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin,
      against clinical isolates was evaluated. The MICs of the drug at which 90% of the
      isolates were inhibited were 4 micro g/ml for methicillin-resistant
      Staphylococcus aureus (MRSA) and 2 micro g/ml for methicillin-resistant
      Staphylococcus epidermidis, which were fourfold higher than and equal to those of
      vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be
      due to its high affinity for penicillin-binding protein 2a (50% inhibitory
      concentration, 4.5 micro g/ml). In time-kill studies with 10 strains each of MRSA
      and methicillin-susceptible S. aureus, S-3578 caused more than a 4-log(10)
      decrease of viable cells on the average at twice the MIC after 24 h of exposure,
      indicating that it had potent bactericidal activity. Furthermore, in population
      analysis of MRSA strains with heterogeneous or homogeneous resistance to
      imipenem, no colonies emerged from about 10(9) cells on agar plates containing
      twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578
      resistant strains from MRSA. S-3578 was also highly active against penicillin
      resistant Streptococcus pneumoniae (PRSP), with a MIC(90) of 1 micro g/ml, which
      was comparable to that of ceftriaxone. S-3578 also had antibacterial activity
      against a variety of gram-negative bacteria including Pseudomonas aeruginosa,
      though its activity was not superior to that of cefepime. In conclusion, S-3578
      exhibited a broad antibacterial spectrum and, particularly, had excellent
      activity against gram-positive bacteria including methicillin-resistant
      staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further
      evaluation.

PMID- 12604524
TI  - In vivo killing of Porphyromonas gingivalis by toluidine blue-mediated
      photosensitization in an animal model.
AB  - Porphyromonas gingivalis is one of the major causative organisms of periodontitis
      and has been shown to be susceptible to toluidine blue-mediated
      photosensitization in vitro. The aims of the present study were to determine
      whether this technique could be used to kill the organism in the oral cavities of
      rats and whether this would result in a reduction in the alveolar bone loss
      characteristic of periodontitis. The maxillary molars of rats were inoculated
      with P. gingivalis and exposed to up to 48 J of 630-nm laser light in the
      presence of toluidine blue. The number of surviving bacteria was then determined,
      and the periodontal structures were examined for evidence of any damage. When
      toluidine blue was used together with laser light there was a significant
      reduction in the number of viable P. gingivalis organisms. No viable bacteria
      could be detected when 1 mg of toluidine blue per ml was used in conjunction with
      all light doses used. On histological examination, no adverse effect of
      photosensitization on the adjacent tissues was observed. In a further group of
      animals, after time was allowed for the disease to develop in controls, the rats
      were killed and the level of maxillary molar alveolar bone was assessed. The bone
      loss in the animals treated with light and toluidine blue was found to be
      significantly less than that in the control groups. The results of this study
      show that toluidine blue-mediated lethal photosensitization of P. gingivalis is
      possible in vivo and that this results in decreased bone loss. These findings
      suggest that photodynamic therapy may be useful as an alternative approach for
      the antimicrobial treatment of periodontitis.

PMID- 12604525
TI  - Alteration of Escherichia coli topoisomerase IV to novobiocin resistance.
AB  - DNA gyrase and topoisomerase IV (topo IV) are the two essential type II
      topoisomerases of Escherichia coli. Gyrase is responsible for maintaining
      negative supercoiling of the bacterial chromosome, whereas topo IV's primary role
      is in disentangling daughter chromosomes following DNA replication. Coumarins,
      such as novobiocin, are wide-spectrum antimicrobial agents that primarily
      interfere with DNA gyrase. In this work we designed an alteration in the ParE
      subunit of topo IV at a site homologous to that which confers coumarin resistance
      in gyrase. This parE mutation renders the encoded topo IV approximately 40-fold
      resistant to inhibition by novobiocin in vitro and imparts a similar resistance
      to inhibition of topo IV-mediated relaxation of supercoiled DNA in vivo. We
      conclude that topo IV is a secondary target of novobiocin and that it is very
      likely to be inhibited by the same mechanism as DNA gyrase.

PMID- 12604526
TI  - Proteomic approach to understanding antibiotic action.
AB  - We have used proteomic technology to elucidate the complex cellular responses of
      Bacillus subtilis to antimicrobial compounds belonging to classical and emerging
      antibiotic classes. We established on two-dimensional gels a comprehensive
      database of cytoplasmic proteins with pIs covering a range of 4 to 7 that were
      synthesized during treatment with antibiotics or agents known to cause
      generalized cell damage. Although each antibiotic showed an individual protein
      expression profile, overlaps in the expression of marker proteins reflected
      similarities in molecular drug mechanisms, suggesting that novel compounds with
      unknown mechanisms of action may be classified. Indeed, one such substance, a
      structurally novel protein synthesis inhibitor (BAY 50-2369), could be classified
      as a peptidyltransferase inhibitor. These results suggest that this technique
      gives new insights into the bacterial response toward classical antibiotics and
      hints at modes of action of novel compounds. Such a method should prove useful in
      the process of antibiotic drug discovery.

PMID- 12604527
TI  - Ergosterol biosynthesis inhibitors become fungicidal when combined with
      calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida
      krusei.
AB  - Azoles target the ergosterol biosynthetic enzyme lanosterol 14alpha-demethylase
      and are a widely applied class of antifungal agents because of their broad
      therapeutic window, wide spectrum of activity, and low toxicity. Unfortunately,
      azoles are generally fungistatic and resistance to fluconazole is emerging in
      several fungal pathogens. We recently established that the protein phosphatase
      calcineurin allows survival of Candida albicans during the membrane stress
      exerted by azoles. The calcineurin inhibitors cyclosporine A (CsA) and tacrolimus
      (FK506) are dramatically synergistic with azoles, resulting in potent fungicidal
      activity, and mutant strains lacking calcineurin are markedly hypersensitive to
      azoles. Here we establish that drugs targeting other enzymes in the ergosterol
      biosynthetic pathway (terbinafine and fenpropimorph) also exhibit dramatic
      synergistic antifungal activity against wild-type C. albicans when used in
      conjunction with CsA and FK506. Similarly, C. albicans mutant strains lacking
      calcineurin B are markedly hypersensitive to terbinafine and fenpropimorph. The
      FK506 binding protein FKBP12 is required for FK506 synergism with ergosterol
      biosynthesis inhibitors, and a calcineurin mutation that confers FK506 resistance
      abolishes drug synergism. Additionally, we provide evidence of drug synergy
      between the nonimmunosuppressive FK506 analog L-685,818 and fenpropimorph or
      terbinafine against wild-type C. albicans. These drug combinations also exert
      synergistic effects against two other Candida species, C. glabrata and C. krusei,
      which are known for intrinsic or rapidly acquired resistance to azoles. These
      studies demonstrate that the activity of non-azole antifungal agents that target
      ergosterol biosynthesis can be enhanced by inhibition of the calcineurin
      signaling pathway, extending their spectrum of action and providing an
      alternative approach by which to overcome antifungal drug resistance.

PMID- 12604529
TI  - Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa
      PAO1.
AB  - Pseudomonas aeruginosa strains are less susceptible to tigecycline (previously
      GAR-936; MIC, 8 micro g/ml) than many other bacteria (P. J. Petersen, N. V.
      Jacobus, W. J. Weiss, P. E. Sum, and R. T. Testa, Antimicrob. Agents Chemother.
      43:738-744, 1999). To elucidate the mechanism of resistance to tigecycline, P.
      aeruginosa PAO1 strains defective in the MexAB-OprM and/or MexXY (OprM) efflux
      pumps were tested for susceptibility to tigecycline. Increased susceptibility to
      tigecycline (MIC, 0.5 to 1 micro g/ml) was specifically associated with loss of
      MexXY. Transcription of mexX and mexY was also responsive to exposure of cells to
      tigecycline. To test for the emergence of compensatory efflux pumps in the
      absence of MexXY-OprM, mutants lacking MexXY-OprM were plated on medium
      containing tigecycline at 4 or 6 micro g/ml. Resistant mutants were readily
      recovered, and these also had decreased susceptibility to several other
      antibiotics, suggesting efflux pump recruitment. One representative carbenicillin
      resistant strain overexpressed OprM, the outer membrane channel component of the
      MexAB-OprM efflux pump. The mexAB-oprM repressor gene, mexR, from this strain
      contained a 15-bp in-frame deletion. Two representative chloramphenicol-resistant
      strains showed expression of an outer membrane protein slightly larger than OprM.
      The mexCD-OprJ repressor gene, nfxB, from these mutants contained a 327-bp in
      frame deletion and an IS element insertion, respectively. Together, these data
      indicated drug efflux mediated by MexCD-OprJ. The MICs of the narrower-spectrum
      semisynthetic tetracyclines doxycycline and minocycline increased more
      substantially than did those of tigecycline and other glycylcyclines against the
      MexAB-OprM- and MexCD-OprJ-overexpressing mutant strains. This suggests that
      glycylcyclines, although they are subject to efflux from P. aeruginosa, are
      generally inferior substrates for P. aeruginosa efflux pumps than are narrower
      spectrum tetracyclines.

PMID- 12604528
TI  - Modulation of the activity of secretory phospholipase A2 by antimicrobial
      peptides.
AB  - The antimicrobial peptides magainin 2, indolicidin, and temporins B and L were
      found to modulate the hydrolytic activity of secretory phospholipase A(2)
      (sPLA(2)) from bee venom and in human lacrimal fluid. More specifically,
      hydrolysis of phosphatidylcholine (PC) liposomes by bee venom sPLA(2) at 10 micro
      M Ca(2+) was attenuated by these peptides while augmented product formation was
      observed in the presence of 5 mM Ca(2+). The activity of sPLA(2) towards anionic
      liposomes was significantly enhanced by the antimicrobial peptides at low
      [Ca(2+)] and was further enhanced in the presence of 5 mM Ca(2+). Similarly, with
      5 mM Ca(2+) the hydrolysis of anionic liposomes was enhanced significantly by
      human lacrimal fluid sPLA(2), while that of PC liposomes was attenuated. These
      results indicate that concerted action of antimicrobial peptides and sPLA(2)
      could improve the efficiency of the innate response to infections. Interestingly,
      inclusion of a cationic gemini surfactant in the vesicles showed an essentially
      similar pattern on sPLA(2) activity, suggesting that the modulation of the enzyme
      activity by the antimicrobial peptides may involve also charge properties of the
      substrate surface.

PMID- 12604530
TI  - New insertion sequence elements in the upstream region of cfiA in imipenem
      resistant Bacteroides fragilis strains.
AB  - The 747-bp cfiA gene, which encodes a metallo-beta-lactamase, and the regions
      flanking cfiA in six imipenem-resistant and four imipenem-susceptible Bacteroides
      fragilis strains isolated in Japan were analyzed by PCR and DNA sequencing. The
      nucleotide sequences of the cfiA genes (designated cfiA(1) to cfiA(10)) of all 10
      strains tested varied from that of the standard cfiA gene from B. fragilis
      TAL2480. However, putative proteins encoded by the cfiA variants contained
      conserved amino acid residues important for zinc binding and hairpin loop
      formation, suggesting that cfiA variants have the capability of producing metallo
      beta-lactamases with full catalytic activities. PCR assay indicated that six
      metallo-beta-lactamase-producing, imipenem-resistant strains had an insertion
      mutation in the region immediately upstream of cfiA. Nucleotide sequencing of the
      PCR-amplified fragments along with the upstream region of cfiA revealed that
      there were five new kinds of insertion sequence (IS) elements (designated IS612,
      IS613, IS614, IS615, and IS616, with a size range of 1,594 to 1,691 bp), of which
      only IS616 was found to be almost identical to IS1188, one of the IS elements
      previously identified in the upstream region of cfiA. These elements had target
      site duplications of 4 or 5 bp in length, terminal inverted repeats (14, 15, or
      17 bp in size), and a large open reading frame encoding a putative transposase
      which is required for the transcription of IS elements. Each element was inserted
      such that the transcriptional direction of the transposase was opposite to that
      of cfiA. A computer-aided homology search revealed that, based on the homology of
      their putative transposases, the sizes of their terminal inverted repeat
      sequences, and their target site duplications, IS612, IS613, IS614, and IS615
      belong to the IS4 family, which includes IS942, previously found in some drug
      resistant B. fragilis strains, but that IS616 belongs to the IS1380 family. All
      the IS elements appear to have putative promoter motif sequences (the -7 region's
      TAnnTTTG motif and the -33 region's TTG or TG) in their end regions, suggesting
      that the IS elements provide a promoter for the transcription of cfiA upon
      insertion. These data provide additional proof that various IS elements may exist
      to provide a promoter to express the cfiA gene.

PMID- 12604531
TI  - High variability of plasma drug concentrations in dual protease inhibitor
      regimens.
AB  - Ritonavir (RTV) strongly increases the concentrations of protease inhibitors
      (PIs) in plasma in patients given a combination of RTV and another PI. This
      pharmacological interaction is complex and poorly characterized and shows marked
      inter- and intraindividual variations. In addition, RTV interacts differently
      with saquinavir (SQV), indinavir (IDV), amprenavir (APV), and lopinavir (LPV). In
      this retrospective study on 542 human immunodeficiency virus-infected patients,
      we compared inter- and intraindividual variability of plasma PI concentrations
      and correlations between the C(min) (minimum concentration of drug in plasma)
      values for RTV and the coadministered PI C(min) values. Mean RTV C(min)s are
      significantly lower in patients receiving combinations containing APV or LPV than
      in combinations with SQV or IDV. With the most common PI dose regimens (600 mg of
      IDV twice a day [BID], 800 mg of SQV BID, and 400 mg of LPV BID), the
      interindividual C(min) variability of patients treated with a PI and RTV seemed
      to be lower with APV and LPV than with IDV and SQV. As regards intraindividual
      variability, APV also differed from the other PIs, exhibiting lower C(min)
      variability than with the other combinations. Significant positive correlations
      between RTV C(min) and boosted PI C(min) were observed with IDV, SQV, and LPV,
      but not with APV. Individual dose adjustments must take into account the
      specificity the pharmacological interaction of each RTV/PI combination and the
      large inter- and intraindividual variability of plasma PI levels to avoid
      suboptimal plasma drug concentrations which may lead to treatment failure and too
      high concentrations which may induce toxicity and therefore reduce patient
      compliance.

PMID- 12604532
TI  - Pharmacokinetics of intravenous acyclovir, zidovudine, and acyclovir-zidovudine
      in pregnant rats.
AB  - The pharmacokinetics and placental transfer of acyclovir and zidovudine
      monotherapies and acyclovir-zidovudine combination therapy were compared in the
      pregnant rat. Timed-pregnancy Sprague-Dawley rats were used for the study. Doses
      of 60 mg of each drug/kg of body weight in monotherapy and in combination therapy
      were given by intravenous bolus, and samples of maternal plasma, amniotic fluid,
      fetal tissue, and placental tissue were collected over a period of 8 h postdose.
      Concentrations of each drug in the various matrices were measured by high
      performance liquid chromatography. All data were analyzed by using WinNonlin. A
      one-compartment model with first-order elimination was used to fit the AZT plasma
      data from the combination therapy rats, but the plasma data from the other groups
      were fit to a two-compartment model. Tissue data were analyzed by
      noncompartmental analysis to generate area-under-the-concentration-time-curve
      values. Implementation of the combination therapy altered the pharmacokinetics of
      each drug compared to its monotherapy pharmacokinetics. The combination of these
      two drugs may potentiate fetal and amniotic fluid exposures to each drug.

PMID- 12604533
TI  - Comparing pharmacokinetics of amoxicillin given twice or three times per day to
      children older than 3 months with pneumonia.
AB  - For children with ambulatory pneumonia, the World Health Organization (WHO)
      recommends oral amoxicillin (15 mg/kg of body weight/dose) thrice daily (t.i.d.)
      or oral cotrimoxazole (4 mg of trimethoprim/kg/dose) twice daily (b.i.d.). The
      more frequent amoxicillin dosing may lead to compliance problems. To compare the
      pharmacokinetics and levels of amoxicillin in plasma in the current WHO acute
      respiratory infection recommendations with the 25-mg/kg/dose b.i.d. regimen, we
      performed a two-group parallel study of 66 children ages 3 to 59 months with
      pneumonia. Amoxicillin was given orally at 25 mg/kg/dose b.i.d. or 15 mg/kg/dose
      t.i.d. Amoxicillin concentrations were determined by high-performance liquid
      chromatography after the first dose on days 1 and 3. After the first dose on day
      1, the mean area under the concentration-time curve (AUC) for amoxicillin after
      the 25-mg/kg dose was 54.7 versus 24.9 micro g. h/ml after the 15-mg/kg dose.
      After the first dose on day 3, the mean AUC was 44.1 versus 28.5 micro g. h/ml.
      All but two children had plasma amoxicillin concentrations above 0.5 micro g/ml
      for >50% of the dose interval on both days. Six children on day 1 and five
      children on day 3 had concentrations above 1.0 micro g/ml for <50% of the dose
      interval. On day 1, 16 of 27 children in the b.i.d. group and 11 of 26 children
      in the t.i.d. group had concentrations that were above 2.0 micro g/ml for <50% of
      the dose interval, and on day 3, 18 of 31 children in the b.i.d. group and 8 of
      31 children in the t.i.d. group had concentrations that were above 2.0 micro g/ml
      for <50% of the dose interval. Amoxicillin b.i.d. is a feasible alternative for
      t.i.d. dosing. To lengthen the time above the MIC at higher concentration levels,
      a 30- to 40-mg/kg/dose b.i.d. should be considered instead of the 25 mg/kg/dose
      used in this study.

PMID- 12604534
TI  - Effects of sulfamethizole and amdinocillin against Escherichia coli strains (with
      various susceptibilities) in an ascending urinary tract infection mouse model.
AB  - Resistance to antibiotics used for the treatment of urinary tract infections
      (UTIs) is increasing worldwide. The impact of in vitro resistance on clinical
      outcome in UTIs requires further study, since most studies of both humans and
      animals have evaluated only the efficacy of antibiotics toward bacteria
      susceptible in vitro. We were interested in evaluating the relationship between
      the in vitro antibacterial effect and the in vivo efficacy after antibiotic
      treatment. We simulated a natural ascending UTI by use of the ascending UTI mouse
      model and used Escherichia coli strains with various susceptibilities to
      amdinocillin (mecillinam) and sulfamethizole. Mice were treated for 3 days with
      antibiotic doses approximating human urinary tract concentrations after a
      standard oral dose. For a susceptible strain (MIC, 0.5 micro g/ml) and a
      resistant strain (MIC, 128 micro g/ml), respectively, there were significant
      reductions in bacterial counts in the urine, bladder, and kidneys after treatment
      with amdinocillin, whereas for a strain for which the MIC was 16 micro g/ml,
      there was a significant reduction in bacterial counts in the kidneys only (P <
      0.05). Treatment with sulfamethizole resulted in a significant reduction in
      bacterial counts in all samples from a susceptible strain (MIC, 128 micro g/ml)
      and a resistant strain (MIC, 512 micro g/ml). Infection with a sulII gene
      positive strain (MIC, >2,048 micro g/ml) could not be treated with
      sulfamethizole, as no effect could be demonstrated in the urine, bladder, or
      kidneys. For amdinocillin, there was no clear-cut relationship between the in
      vitro susceptibility and the in vivo outcome, while for sulfamethizole, we found
      a relationship between the MIC for the strain and the effect in the urinary
      tract.

PMID- 12604535
TI  - Aminoglycoside nephrotoxicity: modeling, simulation, and control.
AB  - The main constraints on the administration of aminoglycosides are the risks of
      nephrotoxicity and ototoxicity, which can lead to acute, renal, vestibular, and
      auditory toxicities. In the present study we focused on nephrotoxicity. No
      reliable predictor of nephrotoxicity has been found to date. We have developed a
      deterministic model which describes the pharmacokinetic behavior of
      aminoglycosides (with a two-compartment model), the kinetics of aminoglycoside
      accumulation in the renal cortex, the effects of aminoglycosides on renal cells,
      the resulting effects on renal function by tubuloglomerular feedback, and the
      resulting effects on serum creatinine concentrations. The pharmacokinetic
      parameter values were estimated by use of the NPEM program. The estimated
      pharmacodynamic parameter values were obtained after minimization of the least
      squares objective function between the measured and the calculated serum
      creatinine concentrations. A simulation program assessed the influences of the
      dosage regimens on the occurrence of nephrotoxicity. We have also demonstrated
      the relevancy of modeling of the circadian rhythm of the renal function. We have
      shown the ability of the model to fit with 49 observed serum creatinine
      concentrations for a group of eight patients treated for endocarditis by
      comparison with 49 calculated serum creatinine concentrations (r(2) = 0.988; P <
      0.001). We have found that for the same daily dose, the nephrotoxicity observed
      with a thrice-daily administration schedule appears more rapidly, induces a
      greater decrease in renal function, and is more prolonged than those that occur
      with less frequent administration schedules (for example, once-daily
      administration). Moreover, for once-daily administration, we have demonstrated
      that the time of day of administration can influence the incidence of
      aminoglycoside nephrotoxicity. The lowest level of nephrotoxicity was observed
      when aminoglycosides were administered at 1:30 p.m. Clinical application of this
      model might make it possible to adjust aminoglycoside dosage regimens by taking
      into account both the efficacies and toxicities of the drugs.

PMID- 12604536
TI  - Effects of an efflux mechanism and ribosomal mutations on macrolide
      susceptibility of Haemophilus influenzae clinical isolates.
AB  - This study investigated macrolide resistance mechanisms in clinical Haemophilus
      influenzae strains with different levels of susceptibility to macrolides. A total
      of 6,382 isolates were collected during the Alexander Project from 1997 to 2000.
      For 96.9% of these isolates, the azithromycin MICs were 0.25 to 4 micro g/ml, and
      these were defined as baseline strains. For 1.8% of the isolates, the
      azithromycin MICs were lower (<0.25 micro g/ml), and for 1.3% of the isolates,
      the MICs were higher (>4 micro g/ml). These isolates were defined as
      hypersusceptible and high-level macrolide-resistant strains, respectively. To
      identify the mechanisms associated with these three susceptibility patterns,
      representative strains were studied for the presence of macrolide efflux pumps
      and for ribosomal alterations. Macrolide efflux was studied by measuring the
      accumulation of radioactive azithromycin and clarithromycin in the presence or
      absence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophore.
      Treatment with CCCP increased the accumulation of macrolides in baseline as well
      as high-level resistant strains, demonstrating the presence of an efflux
      mechanism, but not in the 20 hypersusceptible strains tested. Among the 31
      strains studied that showed high-level resistance to both azithromycin and
      clarithromycin, 28 had ribosomal alterations, 7 had mutations in ribosomal
      protein L4, 11 had mutations in L22, 2 had mutations in 23S rRNA, 8 had multiple
      mutations, and 3 had no mutations. From these results, we conclude that the vast
      majority (>98%) of H. influenzae strains have a macrolide efflux mechanism, with
      a few of these being hyperresistant (1.3%) due to one or several ribosomal
      mutations. Occasional hypersusceptible strains (1.8%) were found and had no
      macrolide resistance mechanisms and appeared to be the only truly macrolide
      susceptible variants of H. influenzae.

PMID- 12604537
TI  - Mutant prevention concentration of garenoxacin (BMS-284756) for ciprofloxacin
      susceptible or -resistant Staphylococcus aureus.
AB  - The new quinolone garenoxacin (BMS-284756), which lacks a C-6 fluorine, was
      examined for its ability to block the growth of Staphylococcus aureus.
      Measurement of the MIC and the mutant prevention concentration (MPC) revealed
      that garenoxacin was 20-fold more potent than ciprofloxacin for a variety of
      ciprofloxacin-susceptible isolates, some of which were resistant to methicillin.
      The MPC for 90% of the isolates (MPC(90)) was below published serum drug
      concentrations achieved with recommended doses of garenoxacin. These in vitro
      observations suggest that garenoxacin has a low propensity for selective
      enrichment of fluoroquinolone-resistant mutants among ciprofloxacin-susceptible
      isolates of S. aureus. For ciprofloxacin-resistant isolates, the MIC at which 90%
      of the isolates tested were inhibited was below serum drug concentrations while
      the MPC(90) was not. Thus, for these strains, garenoxacin concentrations are
      expected to fall inside the mutant selection window (between the MIC and the MPC)
      for much of the treatment time. As a result, garenoxacin is expected to
      selectively enrich mutants with even lower susceptibility.

PMID- 12604538
TI  - Transcriptional induction of the penicillin-binding protein 2 gene in
      Staphylococcus aureus by cell wall-active antibiotics oxacillin and vancomycin.
AB  - We found an increased abundance of pbpB-specific transcripts in vancomycin
      intermediate-resistant Staphylococcus aureus (VISA) isolates compared with that
      found in paired, genetically identical, susceptible isolates. This difference in
      expression cannot be explained by differences in the pbpB promoter sequence.
      Since the factors controlling pbpB gene expression have remained largely
      unexplored, various conditions that might affect pbpB transcript abundance were
      examined. In both vancomycin-susceptible and VISA strains, pbpB expression varied
      with the growth phase, with the highest abundance of pbpB-specific transcripts
      detected during mid-log phase. Interestingly, both vancomycin and oxacillin were
      able to induce pbpB transcription above a constitutive level. When vancomycin was
      absent, one of the three pbpB-specific transcripts that were usually faintly
      detected in non-VISA strains was more readily detected in VISA strains during mid
      log but not stationary phase. This transcript was enhanced in non-VISA strains by
      vancomycin induction. Gel shift assays indicated that an increased amount of the
      putative transcription factor that binds to both P1 and P1' promoter regions is
      present in the cytosol of vancomycin-induced cells. Neither the SigB sigma factor
      nor the quorum-sensing agr locus was required for growth phase-variable pbpB
      expression or transcriptional induction of pbpB by vancomycin or oxacillin. Also,
      MecI, MecR1, BlaI, and BlaR1, regulatory proteins that mediate beta-lactam
      inducible expression of mecA and beta-lactamase, were not required for antibiotic
      induction of pbpB transcription. These data support the idea that pbpB expression
      is modulated by a trans-acting factor in response to the presence of the cell
      wall-active antibiotics vancomycin and oxacillin.

PMID- 12604540
TI  - Influence of P-glycoprotein inhibitors on accumulation of macrolides in J774
      murine macrophages.
AB  - The influence of inhibitors of P-glycoprotein (verapamil [VE], cyclosporine [CY],
      and GF120918 [GF]) on the cell handling of macrolides (erythromycin [ERY],
      clarithromycin [CLR], roxithromycin [ROX], azithromycin [AZM], and telithromycin
      [TEL]) was examined in J774 murine macrophages. The net influx rates of AZM and
      TEL were increased from 2- to 3.5-fold in the presence of these inhibitors, but
      their efflux was slowed only marginally. At 3 h, the inhibitors increased the
      levels of AZM, ERY, and TEL accumulation approximately three- to fourfold (the
      effect of VE, however, was lower) but did not influence CLR accumulation (the
      inhibitors had an intermediate behavior on ROX accumulation). The effect was
      concentration dependent (half-maximal increases in the level of accumulation of
      AZM were obtained with GF, CY, and VE at 0.5, 5, and 10 micro M, respectively).
      ATP depletion also caused an approximately threefold increase in the level of
      accumulation of AZM. Two inhibitors of MRP (probenecid [2.5 mM] and gemfibrozil
      [0.25 mM]) had no effect. Monensin (a proton ionophore) completely suppressed the
      accumulation of AZM in control cells as well as in cells incubated in the
      presence of VE, demonstrating that transmembrane proton gradients are the driving
      force causing the accumulation of AZM in both cases. Yet, VE did not alter the pH
      of the lysosomes (approximately 5) or of the cytosol (approximately 7.1). P
      glycoprotein was detected by immunostaining at the cell surface as well as in
      intracellular vacuoles (endosomes and lysosomes). The data suggest that the
      influx of AZM, ERY, TEL, and ROX is adversely influenced by the activity of P
      glycoprotein in J774 macrophages, resulting in suboptimal drug accumulation.

PMID- 12604539
TI  - Active-site residues of Escherichia coli DNA gyrase required in coupling ATP
      hydrolysis to DNA supercoiling and amino acid substitutions leading to novobiocin
      resistance.
AB  - DNA gyrase is a bacterial type II topoisomerase which couples the free energy of
      ATP hydrolysis to the introduction of negative supercoils into DNA. Amino acids
      in proximity to bound nonhydrolyzable ATP analog (AMP. PNP) or novobiocin in the
      gyrase B (GyrB) subunit crystal structures were examined for their roles in
      enzyme function and novobiocin resistance by site-directed mutagenesis. Purified
      Escherichia coli GyrB mutant proteins were complexed with the gyrase A subunit to
      form the functional A(2)B(2) gyrase enzyme. Mutant proteins with alanine
      substitutions at residues E42, N46, E50, D73, R76, G77, and I78 had reduced or no
      detectable ATPase activity, indicating a role for these residues in ATP
      hydrolysis. Interestingly, GyrB proteins with P79A and K103A substitutions
      retained significant levels of ATPase activity yet demonstrated no DNA
      supercoiling activity, even with 40-fold more enzyme than the wild-type enzyme,
      suggesting that these amino acid side chains have a role in the coupling of the
      two activities. All enzymes relaxed supercoiled DNA to the same extent as the
      wild-type enzyme did, implying that only ATP-dependent reactions were affected.
      Mutant genes were examined in vivo for their abilities to complement a
      temperature-sensitive E. coli gyrB mutant, and the activities correlated well
      with the in vitro activities. We show that the known R136 novobiocin resistance
      mutations bestow a significant loss of inhibitor potency in the ATPase assay.
      Four new residues (D73, G77, I78, and T165) that, when changed to the appropriate
      amino acid, result in both significant levels of novobiocin resistance and
      maintain in vivo function were identified in E. coli.

PMID- 12604541
TI  - Structure-based design and engineering of a nontoxic recombinant pokeweed
      antiviral protein with potent anti-human immunodeficiency virus activity.
AB  - A molecular model of pokeweed antiviral protein (PAP)-RNA interactions was used
      to rationally engineer FLP-102((151)AA(152)) and FLP-105((191)AA(192)) as
      nontoxic PAPs with potent anti-human immunodeficiency virus (anti-HIV)
      activities. FLP-102 and FLP-105 have been produced in Escherichia coli and tested
      both in vitro and in vivo. These proteins depurinate HIV type 1 (HIV-1) RNA much
      better than rRNA and are more potent anti-HIV agents than native PAP or
      recombinant wild-type PAP. They are substantially less toxic than native PAP in
      BALB/c mice and exhibit potent in vivo activities against genotypically and
      phenotypically nucleoside reverse transcriptase inhibitor-resistant HIV-1 in a
      surrogate human peripheral blood lymphocyte (Hu-PBL) SCID mouse model of human
      AIDS. Rationally engineered nontoxic recombinant PAPs such as FLP-102 and FLP-105
      may provide the basis for effective salvage therapies for patients harboring
      highly drug-resistant strains of HIV-1. The documented in vitro potencies of FLP
      102 and FLP-105, their in vivo antiretroviral activities in the HIV-infected Hu
      PBL SCID mouse model, and their favorable toxicity profiles in BALB/c mice
      warrant the further development of these promising new biotherapeutic agents.

PMID- 12604542
TI  - Amino acid sequence requirements at residues 69 and 238 for the SME-1 beta
      lactamase to confer resistance to beta-lactam antibiotics.
AB  - Carbapenem antibiotics have been used to counteract resistant strains of bacteria
      harboring beta-lactamases and extended-spectrum beta-lactamases. Four enzymes
      from the class A group of beta-lactamases, NMC-A, IMI-1, SME-1, and KPC-1,
      efficiently hydrolyze carbapenem antibiotics. Sequence comparisons and structural
      information indicate that cysteines at amino acid residues 69 and 238, which are
      conserved in all four of these enzymes, form a disulfide bond that is unique to
      these beta-lactamases. To test whether this disulfide bond is required for
      catalytic activity, the codons for residues Cys69 and Cys238 were randomized
      individually and simultaneously by PCR-based mutagenesis to create random
      replacement libraries for these positions. Mutants that were able to confer
      resistance to ampicillin, imipenem, or cefotaxime were selected from these
      libraries. The results indicate that positions Cys69 and Cys238 are critical for
      hydrolysis of all of the antibiotics tested, suggesting that the disulfide bond
      is generally required for this enzyme to catalyze the hydrolysis of beta-lactam
      antibiotics.

PMID- 12604543
TI  - In vitro activities of caspofungin compared with those of fluconazole and
      itraconazole against 3,959 clinical isolates of Candida spp., including 157
      fluconazole-resistant isolates.
AB  - Caspofungin is an echinocandin antifungal agent with broad-spectrum activity
      against Candida and Aspergillus spp. The in vitro activities of caspofungin
      against 3,959 isolates of Candida spp. obtained from over 95 different medical
      centers worldwide were compared with those of fluconazole and itraconazole. The
      MICs of the antifungal drugs were determined by broth microdilution tests
      performed according to the NCCLS method using RPMI 1640 as the test medium.
      Caspofungin was very active against Candida spp. (MIC at which 90% of the
      isolates were inhibited [MIC(90)], 1 micro g/ml; 96% of MICs were < or =2 micro
      g/ml). Candida albicans, C. dubliniensis, C. tropicalis, and C. glabrata were the
      most susceptible species of Candida (MIC(90), 0.25 to 0.5 micro g/ml), and C.
      guilliermondii was the least susceptible (MIC(90), >8 micro g/ml). Caspofungin
      was very active against Candida spp., exhibiting high-level resistance to
      fluconazole and itraconazole (99% of MICs were < or =1 micro g/ml). These results
      provide further evidence for the spectrum and potency of caspofungin activity
      against a large and geographically diverse collection of clinically important
      isolates of Candida spp.

PMID- 12604544
TI  - High-dose, short-duration, early valacyclovir therapy for episodic treatment of
      cold sores: results of two randomized, placebo-controlled, multicenter studies.
AB  - Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir
      bioavailability three- to fivefold. This provides the opportunity to explore
      whether high systemic acyclovir concentrations are effective in the treatment of
      cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled
      studies were conducted. Subjects were provided with 2 g of valacyclovir twice
      daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and
      then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching
      placebo and instructed to initiate treatment upon the first symptoms of a cold
      sore. In study 1, the median duration of the episode (primary endpoint) was
      reduced by 1.0 day (P = 0.001) with 1-day treatment and 0.5 days (P = 0.009) with
      2-day treatment compared to placebo. Similarly, the mean duration of the episode
      was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7
      days with 2-day treatment compared to placebo. The proportion of subjects in whom
      cold sore lesion development was prevented and/or blocked was increased by 6.4%
      (P = 0.096) with 1-day treatment and 8.5% (P = 0.061) with 2-day treatment
      compared to placebo. The time to lesion healing and time to cessation of pain
      and/or discomfort were statistically significantly reduced with valacyclovir
      compared to placebo. In study 2, results similar to those in study 1 were
      obtained. AEs were similar across treatment groups. These studies provide
      evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores
      that is safe and effective. The 1-day valacyclovir regimen offers patients a
      unique and convenient dosing alternative compared to available topical therapies.

PMID- 12604546
TI  - Activities of moxifloxacin against, and emergence of resistance in, Streptococcus
      pneumoniae and Pseudomonas aeruginosa in an in vitro pharmacokinetic model.
AB  - The pharmacodynamics of moxifloxacin against Streptococcus pneumoniae and
      Pseudomonas aeruginosa were investigated in a pharmacokinetic infection model.
      Three strains of S. pneumoniae, moxifloxacin, and two strains of P. aeruginosa
      were used. Antibacterial effect and emergence of resistance were measured for
      both species over a 72-h period using an initial inoculum of about 10(8) CFU/ml.
      At equivalent area under the curve (AUC)/MIC ratios, S. pneumoniae was cleared
      from the model while P. aeruginosa was not. For S. pneumoniae, the area under the
      bacterial kill curve up to 72 h could be related to AUC/MIC ratio using an
      inhibitory maximum effect (E(max)) model (concentration required for 50% E(max)
      [EC(50)], 45 +/- 22; r(2), 0.97). For P. aeruginosa even at the highest AUC/MIC
      ratio (427), bacterial clearance was insufficient for the EC(50) to be
      calculated. Emergence of resistance occurred with P. aeruginosa but not to any
      significant extent with S. pneumoniae. Emergence of resistance in P. aeruginosa
      as measured by population analysis profile (PAP-AUC) was dependent on drug
      exposure and time of exposure. In weighted least-squares regression analysis
      AUC/MIC ratio was predictive of PAP-AUC. When emergence of resistance was
      measured by the time for the colony counts on media containing antibiotic to
      increase by 2 logs, again AUC/MIC was the best predictor of emergence of
      resistance. However, for both experiments using S. pneumoniae and P. aeruginosa
      the correlation between all the pharmacodynamic parameters was high. These data
      indicate that for a given fluoroquinolone the magnitude of the AUC/MIC ratio for
      antibacterial effect is dependent on the bacterial species. Emergence of
      resistance is dependent on (i) species, (ii) duration of drug exposure, and (iii)
      drug exposure. A single AUC/MIC ratio magnitude is not adequate to predict
      antibacterial effect or emergence of resistance for all bacterial species.

PMID- 12604545
TI  - Use of the microbial growth curve in postantibiotic effect studies of Legionella
      pneumophila.
AB  - Using the standard Craig and Gudmundsson method (W. A. Craig and S. Gudmundsson,
      p. 296-329, in V. Lorian, ed., Antibiotics in Laboratory Medicine, 1996) as a
      guideline for determination of postantibiotic effects (PAE), we studied a large
      series of growth curves for two strains of Legionella pneumophila. We found that
      the intensity of the PAE was best determined by using a statistically fitted line
      over hours 3 to 9 following antibiotic removal. We further determined the PAE
      duration by using a series of observations of the assay interval from hours 3 to
      24. We determined that inoculum reduction was not necessarily the only predictor
      of the PAE but that the PAE was subject to the type and dose of the drug used in
      the study. In addition, there was a variation between strains. Only levofloxacin
      at five and ten times the minimum inhibitory concentration (MIC) resulted in a
      PAE duration of 4 to 10 h for both strains of L. pneumophila tested.
      Ciprofloxacin at five and ten times the MIC and azithromycin at ten times the MIC
      caused a PAE for one strain only. No PAE could be demonstrated for either strain
      with erythromycin or doxycycline. Using the presently described method of
      measuring PAE for L. pneumophila, we were able to detect differences in PAE which
      were dependent upon the L. pneumophila strain, the antibiotic tested, and the
      antibiotic concentration. We suggest the use of mathematically fitted curves for
      comparison of bacterial growth in order to measure PAE for L. pneumophila.

PMID- 12604547
TI  - Mechanism of fluoroquinolone resistance is an important factor in determining the
      antimicrobial effect of gemifloxacin against Streptococcus pneumoniae in an in
      vitro pharmacokinetic model.
AB  - Antibacterial effect and emergence of resistance to gemifloxacin and levofloxacin
      were studied in an in vitro pharmacokinetic model of infection. A panel of
      Streptococcus pneumoniae strains with known mechanisms of resistance were used;
      two strains had no known resistance mechanism, two had efflux pumps, three had
      gyrA plus parC mutations, and one had only a parC mutation. Gemifloxacin MICs
      were in the range of 0.016 to 0.25 mg/liter, and levofloxacin MICs ranged from 1
      to 16 mg/liter. Antimicrobial effect was measured by area under the bacterial
      kill curve up to 72 h, and emergence of resistance was determined by population
      analysis profile before and during drug exposure. The area under the curve
      (AUC)/MIC ratios for gemifloxacin and levofloxacin were 35 to 544 and 3 to 48,
      respectively. As expected on the basis of these AUC/MIC ratio differences,
      antibacterial effect was much greater for gemifloxacin than levofloxacin. In the
      gemifloxacin simulations, mechanism of resistance as well as MIC determined the
      antibacterial effect, as indicated by gemifloxacin's greater effect against
      efflux strains compared to those with gyrA or parC mutations despite similar
      MICs. This was not true of levofloxacin. Emergence of resistance was not easily
      demonstrated with either agent, and mechanism of resistance did not have any
      impact on it.

PMID- 12604548
TI  - Aminoglycoside efflux in Pseudomonas aeruginosa: involvement of novel outer
      membrane proteins.
AB  - The expression of tripartite multidrug efflux pumps such as MexA-MexB-OprM in
      Pseudomonas aeruginosa contributes to intrinsic resistance to a wide variety of
      antimicrobials, including beta-lactams, chloramphenicol, macrolides, quinolones,
      and tetracycline. The MexX-MexY linker-pump combination has been shown to be
      involved in intrinsic resistance to aminoglycosides, but the identity of the
      cognate outer membrane channel component remains under debate. Fourteen
      uncharacterized OprM homologs identified in the genome of P. aeruginosa were
      examined as candidates for this role by assessing the minimum inhibitory
      concentrations (MICs) of aminoglycosides in P. aeruginosa strain PAK knockout
      mutants lacking the corresponding genes. Insertional inactivation of OpmG, OpmI,
      and OpmH resulted in decreases of various degrees in the MICs of streptomycin,
      kanamycin, and gentamicin. When reintroduced into P. aeruginosa on multicopy
      plasmids, OpmG was able to complement the susceptibility of an opmG::miniTn5
      mutant; however, cloned opmH, the proposed ortholog of Escherichia coli tolC
      according to our phylogenetic analysis, was able to only partially complement the
      opmH::miniTn5 mutant. Mini-microarray hybridization analysis demonstrated that
      opmG disruption does not affect expression of OpmI or OpmH (ruling out such
      indirect effects on aminoglycoside resistance); however, opmH disruption did have
      possible effects on expression of OpmG and OpmI. Based on the data, we propose
      that OpmG is a major outer membrane efflux channel involved in aminoglycoside
      efflux in P. aeruginosa PAK and that OpmI, its most related paralog, may share an
      overlapping function.

PMID- 12604549
TI  - Erythromycin and clindamycin resistance and telithromycin susceptibility in
      Streptococcus agalactiae.
AB  - The rates of resistance to erythromycin and clindamycin among Streptococcus
      agalactiae strains isolated in our hospital increased from 4.2 and 0.8% in 1993
      to 17.4 and 12.1%, respectively, in 2001. Erythromycin resistance was mainly due
      to the presence of an Erm(B) methylase, while the M phenotype was detected in
      3.8% of the strains. Telithromycin was very active against erythromycin-resistant
      strains, irrespective of their mechanisms of macrolide resistance.

PMID- 12604550
TI  - Mercury resistance determinants related to Tn21, Tn1696, and Tn5053 in
      enterobacteria from the preantibiotic era.
AB  - Three mer transposons from the Murray collection of preantibiotic enterobacteria
      show >99% sequence identity to current isolates. Tn5073 is most closely related
      to Tn5036 and Tn1696, and Tn5074 is most closely related to Tn5053. Tn5075 is
      most closely related to Tn21 but lacks integron In2 and is flanked by insertion
      elements.

PMID- 12604551
TI  - A point mutation in the 14alpha-sterol demethylase gene cyp51A contributes to
      itraconazole resistance in Aspergillus fumigatus.
AB  - The genes encoding 14alpha-sterol demethylases (cyp51A and cyp51B) were analyzed
      in 12 itraconazole (ITC)-resistant and three ITC-susceptible clinical isolates of
      Aspergillus fumigatus. Six ITC-resistant strains exhibited a substitution of
      another amino acid for glycine at position 54, which is located at a very
      conserved region of the Cyp51A protein. The cyp51A gene from the A. fumigatus
      wild-type strain (CM-237) was replaced with the mutated cyp51A gene copy of an
      ITC-resistant strain (AF-72). Two transformants exhibited resistance to ITC, both
      of which had incorporated the mutated copy of the cyp51A gene.

PMID- 12604552
TI  - PCR-restriction fragment length polymorphism analysis for detection of point
      mutations associated with macrolide resistance in Campylobacter spp.
AB  - A 23S rRNA gene fragment in domain V was sequenced from 30 clinical isolates of
      Campylobacter spp., including 22 resistant to macrolides. Two point mutations
      associated with erythromycin resistance were identified at positions 2074 and
      2075 on the 23S rRNA gene (homologous to A2142C and A2143G mutations in
      Helicobacter pylori) in which an adenine residue is also replaced with a cytosine
      and a guanine residue, respectively. A combined PCR-restriction fragment length
      polymorphism technique was developed to detect these mutations by using the BsaI
      and BceAI enzymes.

PMID- 12604553
TI  - ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate.
AB  - We assessed the pharmacokinetics and interaction of ABT-773 in 12 volunteers
      receiving ABT-773 alone or concomitantly with ranitidine or sucralfate. Data for
      150 mg of ABT-773 were as follows: the maximum concentration of the drug in
      plasma (C(max)) was 318 ng/ml, its half-life was 5.66 h, and its area under the
      plasma concentration-time curve from 0 h to infinity (AUC(0- infinity )) was
      1,662 ng. h/ml. Coadministration of ranitidine, reduced the C(max) (-25.7%) and
      AUC(0- infinity ) (-15.8%) significantly. Sucralfate had no impact on the
      bioavailability of ABT-773.

PMID- 12604554
TI  - In vitro bactericidal activities of ABT-773 against ermB strains of Streptococcus
      pneumoniae.
AB  - The bactericidal activities of ABT-773, a new ketolide, were compared to those of
      cefuroxime and amoxicillin-clavulanate against 10 strains of Streptococcus
      pneumoniae containing the ermB gene. MICs and time-kill curves were determined in
      duplicate per NCCLS guidelines with cation-adjusted Mueller-Hinton broth with 3%
      lysed horse blood. Viable counts were done at 0, 2, 6, and 24 h. Antibiotic
      concentrations tested were two and eight times the MIC. ABT-773 MICs ranged from
      0.008 to 1.0 micro g/ml. Bactericidal activity was observed with ABT-773 at eight
      times the MIC against 4 of 10 strains at 24 h compared to 10 of 10 strains with
      the beta-lactam antibiotics.

PMID- 12604555
TI  - In vitro activities of rifamycin derivatives ABI-1648 (Rifalazil, KRM-1648), ABI
      1657, and ABI-1131 against Chlamydia trachomatis and recent clinical isolates of
      Chlamydia pneumoniae.
AB  - ABI-1648 (rifalazil) is a semisynthetic rifamycin with potent bactericidal
      activity against intracellular respiratory bacteria, including Mycobacterium
      tuberculosis, and a long half-life (approximately 60 h) and thus can be
      administered once weekly. We therefore tested the in vitro activities of ABI
      1648, its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin
      against 10 strains of Chlamydia trachomatis and 10 recent clinical isolates of
      Chlamydia pneumoniae. The MICs at which 90% of the isolates were inhibited and
      the minimal bactericidal concentration at which 90% of the isolates were killed
      for ABI-1648, ABI-1657, and ABI-1131 were 0.0025 micro g/ml for C. trachomatis
      and 0.00125 to 0.0025 micro g/ml for C. pneumoniae. ABI-1648, ABI-1657, and ABI
      1131 were 10- to 1,000-fold more active than azithromycin and levofloxacin.

PMID- 12604556
TI  - In vitro susceptibilities of Shigella flexneri and Streptococcus pyogenes to
      inner gel of Aloe barbadensis Miller.
AB  - Aloe barbadensis Miller (or Aloe vera) has widespread use in health products, and
      despite numerous reports on the whole plant, little work has been performed on
      the inner gel, which has been used extensively in these products. This report
      describes the in vitro susceptibilities of two bacteria to this component.

PMID- 12604557
TI  - Postantibiotic effects of garenoxacin (BMS-284756) against 12 gram-positive or 
      negative organisms.
AB  - Conventional in vitro methods were used to determine the postantibiotic effects
      (PAEs), sub-MIC effects (SMEs), and postantibiotic sub-MIC effects (PA-SMEs) of
      garenoxacin for a range of organisms. The mean PAEs of garenoxacin for
      pneumococci, staphylococci, and enterococci were 0.3 to 2.2 h. For Escherichia
      coli and Pseudomonas aeruginosa, the PAEs were 0.9 to 1.6 h. The mean PA-SMEs
      (0.4 times the MIC) for pneumococci, staphylococci, and enterococci were 3.0 to
      >10 h, 1.8 to >10.7 h, and 5.8 h, respectively, while those for E. coli and P.
      aeruginosa were 7.6 and 4.4 h, respectively.

PMID- 12604558
TI  - Antianaerobe activity of RBX 7644 (ranbezolid), a new oxazolidinone, compared
      with those of eight other agents.
AB  - The activity of ranbezolid (RBX 7644), a new oxazolidinone, against 306 anaerobes
      was compared with those of 11 other agents. The MICs at which 50% of the isolates
      tested are inhibited and those at which 90% of the isolates tested are inhibited
      (in micrograms per milliliter) were as follows: ranbezolid, 0.03 and 0.5;
      linezolid, 2 and 4; vancomycin, >16 and >16; teicoplanin, 1 and >16; quinupristin
      dalfopristin, 1 and >8; amoxicillin-clavulanate, 0.5 and 2; imipenem, 0.125 and
      1; clindamycin, 0.25 and 8; metronidazole, 1 and 4; gatifloxacin, 0.5 and 4; and
      moxifloxacin, 0.5 and 2, respectively. Ranbezolid had very good in vitro activity
      against both gram-negative and -positive anaerobes.

PMID- 12604559
TI  - Antipneumococcal and antistaphylococcal activities of ranbezolid (RBX 7644), a
      new oxazolidinone, compared to those of other agents.
AB  - For 260 pneumococcal and 266 staphylococcal strains, ranbezolid MICs ranged from
      < or =0.06 to 4 micro g/ml. The MICs for pneumococci were similar irrespective of
      the strains' beta-lactam, macrolide, or quinolone susceptibilities, and
      ranbezolid MICs for coagulase-negative staphylococci were lower than those for
      Staphylococcus aureus. Ranbezolid was bacteriostatic against pneumococci.
      Ranbezolid MICs were similar to or lower than those of linezolid. Vancomycin and
      quinupristin-dalfopristin were also very active.

PMID- 12604560
TI  - Lack of synergy of erythromycin combined with penicillin or cefotaxime against
      Streptococcus pneumoniae in vitro.
AB  - We investigated a possible synergistic effect of a macrolide and beta-lactams
      against Streptococcus pneumoniae strains with different resistance profiles.
      Checkerboard and time-kill assays of erythromycin combined with penicillin or
      cefotaxime essentially showed indifference, suggesting that these antibiotics in
      combinations in vitro act substantially as individuals in their activity against
      S. pneumoniae.

PMID- 12604561
TI  - Vancomycin resistance is maintained in enterococci in the viable but
      nonculturable state and after division is resumed.
AB  - Stressed vancomycin-resistant enterococci (VRE) can activate a survival strategy
      known as the viable but nonculturable (VBNC) state and are able to maintain
      vancomycin resistance. During restoration of division they continue to express
      the vancomycin resistance trait. We suggest that VBNC enterococci may constitute
      further reservoirs of VRE and therefore represent an additional risk for human
      health.

PMID- 12604562
TI  - Activities of temporin family peptides against the chytrid fungus
      (Batrachochytrium dendrobatidis) associated with global amphibian declines.
AB  - Temporin A and structurally related peptides produced in amphibian dermal
      granular glands and in wasp venom were tested for growth inhibition of
      Batrachochytrium dendrobatidis, a pathogen associated with global amphibian
      declines. Two natural amphibian temporins, a wasp temporin, and six synthetic
      analogs effectively inhibited growth. Differences in potency due to amino acid
      substitution suggest that ability to penetrate membranes and form an alpha
      helical structure is important for their effectiveness against this pathogen.

PMID- 12604564
TI  - Imipenem resistance in Salmonella enterica serovar Wien related to porin loss and
      CMY-4 beta-lactamase production.
AB  - Two multidrug-resistant Salmonella enterica serovar Wien strains (SW468 and
      SW1107) were isolated in 2001 in Tunis. Both strains produced the beta-lactamases
      TEM-1, SHV-2a, and CMY-4, whereas strain SW1107 also produced the beta-lactamase
      CTX-M-3. The imipenem-resistant strain (SW468) was totally devoid of the OmpF
      immunorelated porin. Imipenem resistance was shown as being related to porin loss
      and CMY-4 beta-lactamase production.

PMID- 12604563
TI  - In vitro effects of ciprofloxacin and roxithromycin on apoptosis of jurkat T
      lymphocytes.
AB  - Ciprofloxacin (CPFX) and roxithromycin (RXM) induced apoptosis of activated
      Jurkat T cells in vitro. CPFX showed concentration-dependent acceleration of
      apoptosis of activated Jurkat T cells by enhancing the expression of FasL and
      activities of caspase-3 and -8. RXM accelerated cell death, enhanced expression
      of FasL and caspase-3 but not caspase-8, and did not show the concentration
      dependency.

PMID- 12604566
TI  - Three-day quinine-clindamycin treatment of uncomplicated falciparum malaria
      imported from the tropics.

PMID- 12604565
TI  - A new sulfonamide resistance gene (sul3) in Escherichia coli is widespread in the
      pig population of Switzerland.
AB  - A new gene, sul3, which specifies a 263-amino-acid protein similar to a
      dihydropteroate synthase encoded by the 54-kb conjugative plasmid pVP440 from
      Escherichia coli was characterized. Expression of the cloned sul3 gene conferred
      resistance to sulfamethoxazole on E. coli. Two copies of the insertion element
      IS15Delta/26 flanked the region containing sul3. The sul3 gene was detected in
      one-third of the sulfonamide-resistant pathogenic E. coli isolates from pigs in
      Switzerland.

PMID- 12604567
TI  - Enhanced in vitro activity of dihydrofolate reductase and dihydropteroase
      synthase inhibitors in combination against Nocardia spp.

PMID- 12604568
TI  - Artemisinin antimalarials do not inhibit hemozoin formation.

PMID- 12604569
TI  - Stavudine protective function and emergence of Lamivudine resistance.

PMID- 12604570
TI  - Mitogen-activated protein kinases: new signaling pathways functioning in cellular
      responses to environmental stress.
AB  - The mitogen-activated protein kinase (MAPK) superfamily consists of three main
      protein kinase families: the extracellular signal-regulated protein kinases
      (ERKs), the c-Jun N-terminal kinases (JNKs) and the p38 family of kinases. Each
      is proving to have major roles in the regulation of intracellular metabolism and
      gene expression and integral actions in many areas including growth and
      development, disease, apoptosis and cellular responses to external stresses. To
      date, this cellular signal transduction network has received relatively little
      attention from comparative biochemists, despite the high probability that MAPKs
      have critical roles in the adaptive responses to thermal, osmotic and oxygen
      stresses. The present article reviews the current understanding of the roles and
      regulation of ERKs, JNKs and p38, summarizes what is known to date about MAPK
      roles in animal models of anoxia tolerance, freeze tolerance and osmoregulation,
      and highlights the potential that studies of MAPK pathways have for advancing our
      understanding of the mechanisms of biochemical adaptation.

PMID- 12604571
TI  - Steady swimming muscle dynamics in the leopard shark Triakis semifasciata.
AB  - Patterns of red muscle strain and activation were examined at three positions
      along the body (0.42, 0.61 and 0.72 L, where L is total body length) and
      correlated with simultaneous measurements of midline kinematics during steady
      swimming (approx. 1.0 L s(-1)) in the leopard shark Triakis semifasciata.
      Analysis of lateral displacement along the body indicates that the leopard shark
      is a subcarangiform swimmer. Longitudinal variation in red muscle strain was
      observed with strain amplitudes ranging from +/-3.9% in the anterior, +/-6.6% in
      the mid, to +/-4.8% in the posterior body position. Strain was in-phase with
      local midline curvature. In addition, strain amplitude calculated from a bending
      beam model closely matched strain measured using sonomicrometry at all three body
      positions. There is a high degree of similarity in red muscle activation patterns
      along the body between the leopard shark and many fish species, in that the onset
      of activation occurs during muscle lengthening while offset occurs during muscle
      shortening. However, we found no significant longitudinal variation in the
      EMG/strain phase relationship and duty cycles, with onset of muscle activation
      occurring at 51.4-61.8 degrees and offset at 159.7-165.2 degrees (90 degrees is
      peak length). This consistent pattern of activation suggests that red muscle
      along the entire length of the body contributes to positive power production.
      Thus, sharks such as Triakis may have no regional specialization in red muscle
      function like that seen in many teleosts, which may indicate that the evolution
      of differential muscle function along the body occurred after the divergence of
      cartilaginous and bony fishes.

PMID- 12604572
TI  - Predicting the metabolic energy costs of bipedalism using evolutionary robotics.
AB  - To understand the evolution of bipedalism among the hominoids in an ecological
      context we need to be able to estimate the energetic cost of locomotion in fossil
      forms. Ideally such an estimate would be based entirely on morphology since,
      except for the rare instances where footprints are preserved, this is the only
      primary source of evidence available. In this paper we use evolutionary robotics
      techniques (genetic algorithms, pattern generators and mechanical modeling) to
      produce a biomimetic simulation of bipedalism based on human body dimensions. The
      mechanical simulation is a seven-segment, two-dimensional model with motive force
      provided by tension generators representing the major muscle groups acting around
      the lower-limb joints. Metabolic energy costs are calculated from the muscle
      model, and bipedal gait is generated using a finite-state pattern generator whose
      parameters are produced using a genetic algorithm with locomotor economy (maximum
      distance for a fixed energy cost) as the fitness criterion. The model is
      validated by comparing the values it generates with those for modern humans. The
      result (maximum efficiency of 200 J m(-1)) is within 15% of the experimentally
      derived value, which is very encouraging and suggests that this is a useful
      analytic technique for investigating the locomotor behaviour of fossil forms.
      Initial work suggests that in the future this technique could be used to estimate
      other locomotor parameters such as top speed. In addition, the animations
      produced by this technique are qualitatively very convincing, which suggests that
      this may also be a useful technique for visualizing bipedal locomotion.

PMID- 12604574
TI  - The effect of heat transfer mode on heart rate responses and hysteresis during
      heating and cooling in the estuarine crocodile Crocodylus porosus.
AB  - The effect of heating and cooling on heart rate in the estuarine crocodile
      Crocodylus porosus was studied in response to different heat transfer mechanisms
      and heat loads. Three heating treatments were investigated. C. porosus were: (1)
      exposed to a radiant heat source under dry conditions; (2) heated via radiant
      energy while half-submerged in flowing water at 23 degrees C and (3) heated via
      convective transfer by increasing water temperature from 23 degrees C to 35
      degrees C. Cooling was achieved in all treatments by removing the heat source and
      with C. porosus half-submerged in flowing water at 23 degrees C. In all
      treatments, the heart rate of C. porosus increased markedly in response to
      heating and decreased rapidly with the removal of the heat source. Heart rate
      during heating was significantly faster than during cooling at any given body
      temperature, i.e. there was a significant heart rate hysteresis. There were two
      identifiable responses to heating and cooling. During the initial stages of
      applying or removing the heat source, there was a dramatic increase or decrease
      in heart rate ('rapid response'), respectively, indicating a possible cardiac
      reflex. This rapid change in heart rate with only a small change or no change in
      body temperature (<0.5 degrees C) resulted in Q(10) values greater than 4000,
      calling into question the usefulness of this measure on heart rate during the
      initial stages of heating and cooling. In the later phases of heating and
      cooling, heart rate changed with body temperature, with Q(10) values of 2-3. The
      magnitude of the heart rate response differed between treatments, with radiant
      heating during submergence eliciting the smallest response. The heart rate of C.
      porosus outside of the 'rapid response' periods was found to be a function of the
      heat load experienced at the animal surface, as well as on the mode of heat
      transfer. Heart rate increased or decreased rapidly when C. porosus experienced
      large positive (above 25 W) or negative (below -15 W) heat loads, respectively,
      in all treatments. For heat loads between -15 W and 20 W, the increase in heart
      rate was smaller for the 'unnatural' heating by convection in water compared with
      either treatment using radiant heating. Our data indicate that changes in heart
      rate constitute a thermoregulatory mechanism that is modulated in response to the
      thermal environment occupied by the animal, but that heart rate during heating
      and cooling is, in part, controlled independently of body temperature.

PMID- 12604573
TI  - Growth hormone is a weaker candidate than prolactin for the hormone responsible
      for the development of a larval-type feature in cultured bullfrog skin.
AB  - Prolactin (PRL) has, for some years, been considered to be the 'juvenile hormone'
      in amphibians. Recently, growth hormone (GH) has been proposed as another
      candidate, because in the larval stages the expression of the mRNA GH is high but
      it is downregulated in the climax stages of metamorphosis or following treatment
      with thyroid hormone. In the present study, we investigated whether GH promotes
      the development of one particular larval-type feature of bullfrog tadpole skin in
      vitro. The amiloride-, acetylcholine- and ATP-stimulated short-circuit current
      (SCC) is a physiological marker of larval-type bullfrog skin. These types of
      ligand-stimulated SCC (1) developed when EDTA-treated tadpole skin was cultured
      with corticoids supplemented with PRL or GH and (2) were not significantly
      different between skin cultured with PRL and intact tadpole skin. However, the
      amiloride-induced SCC response in skin cultured with GH differed in its kinetics
      from that of the intact (control) tadpole. On this basis, PRL seems a better
      candidate than GH for the juvenile hormone, at least with regard to the
      development of amiloride-stimulated non-selective cation channels.

PMID- 12604575
TI  - Diving experience and the aerobic dive capacity of muskrats: does training
      produce a better diver?
AB  - We tested the hypothesis that the body oxygen stores, aerobic dive limit (ADL)
      and dive performance of muskrats can be enhanced by dive-conditioning in a
      laboratory setting. We compared several key variables in 12 muskrats trained to
      swim a 16 m underwater course to a feeding station ('divers') with those of 12
      animals precluded from diving but required to travel identical distances in water
      to feed ('surface swimmers'). Acclimated muskrats assigned to each group were
      trained concurrently over a 9-11 week period. We observed significant gains in
      the haematocrit (P=0.0005) and blood haemoglobin concentration (P=0.015) of
      'divers', but not 'surface swimmers'. The post-training blood O(2) store
      calculated for 'divers' (22.9 ml O(2) kg(-1)) was nearly 26% higher than that
      (18.2 ml O(2) kg(-1)) derived for 'surface swimmers' (P=0.03). Dive-conditioning
      had no apparent effect on lung volume, whole blood and plasma volumes, nor on the
      glycogen level and buffering capacity of skeletal muscles. Cardiac and skeletal
      muscle myoglobin levels were also similar in both test groups following training.
      The mean total body oxygen store of 'divers' (37.8ml O(2) STPD kg(-1)) was 13.5%
      higher (P=0.037) than for 'surface swimmers' (33.3 ml O(2) STPD kg(-1)), an
      increase attributed entirely to the gain in blood O(2) storage capacity of the
      former group. However, owing to a slightly higher estimate of diving metabolic
      rate in dive-conditioned animals, the calculated ADL for this group (61.3 s) was
      indistinguishable from that of 'surface swimmers' (61.8 s). Few differences were
      observed in the post-training dive behaviour of 'surface swimmers' and 'divers',
      a finding consistent with the strong similarity in their calculated aerobic dive
      capacities.

PMID- 12604576
TI  - Photolysis of caged calcium in cilia induces ciliary reversal in Paramecium
      caudatum.
AB  - Intracellular Ca(2+) concentration controls both the pattern and frequency of
      ciliary and flagellar beating in eukaryotes. In Paramecium, it is widely accepted
      that the reversal of the direction of ciliary beating (ciliary reversal) is
      induced by an increase in intra-ciliary Ca(2+) levels. Despite this, the Ca(2+)
      sensitive region of the cilium that initiates ciliary reversal has not been
      clearly identified. We injected caged calcium into living P. caudatum cells and
      applied ultraviolet (UV) light to portions of the injected cells to raise
      artificially the intracellular Ca(2+) level ([Ca(2+)](i)). UV application to the
      upper ciliary region above the basal body induced ciliary reversal in injected
      cells. Furthermore, UV application to the tips of cilia induced weak ciliary
      reversal. Larger areas of photolysis in the cilium gave rise to greater angles of
      ciliary reversal. These results strongly suggest that the Ca(2+)-sensitive region
      for ciliary reversal is distributed all over the cilium, above the basal body.

PMID- 12604578
TI  - Evolution of water conservation mechanisms in Drosophila.
AB  - Flies of the genus Drosophila inhabit a wide range of habitats, from the tropics
      to deserts to boreal forests. The primary physiological mechanism allowing
      Drosophila and other insects to survive in arid habitats is a reduction in rates
      of water loss. To understand mechanisms of water retention in greater detail, we
      investigated the three main routes by which Drosophila lose water: excretion,
      cuticular transpiration and respiratory loss through the spiracles. Excretory
      losses comprised <6% of total water flux and did not differ between xeric
      (cactophilic) and mesic species. No consistent relationship was observed between
      water-loss rates and the composition, physical properties or amounts of cuticular
      hydrocarbons, suggesting that cuticular transpiration did not differ among
      species from different habitats. Metabolic rates and water-loss rates were highly
      correlated. Cactophilic Drosophila were less active, and female cactophiles had
      lower metabolic rates than female mesic species of the same size. They were also
      more likely to exhibit a pattern of cyclic CO(2) release that may help to
      conserve water. We conclude that lower overall rates of water loss are achieved
      primarily by reduction of respiratory losses.

PMID- 12604577
TI  - Variability in brain and arterial blood temperatures in free-ranging ostriches in
      their natural habitat.
AB  - We used implanted miniature data loggers to measure brain (in or near the
      hypothalamus) and carotid arterial blood temperatures at 5 min intervals in six
      free-ranging ostriches Struthio camelus in their natural habitat, for a period of
      up to 14 days. Carotid blood temperature exhibited a large amplitude (3.0-4.6
      degrees C) circadian rhythm, and was positively correlated with air temperature.
      During the day, brain temperature exceeded carotid blood temperature by approx.
      0.4 degrees C, but there were episodes when brain temperature was lowered below
      blood temperature. Selective brain cooling, however, was not present in all
      ostriches, and was not tightly coupled to the prevailing body temperature. Brain
      temperature was maintained within narrow daily limits of approx. 2 degrees C, and
      varied significantly less than blood temperature at short time scales of 5 to 20
      min. At night, brain temperature exceeded blood temperature by as much as 3
      degrees C. We attribute the elevated brain temperatures to warming of cerebral
      arterial blood, by reduced heat exchange in the ophthalmic rete or possibly heat
      gain from cranial structures, before supplying the hypothalamus. Further studies
      are necessary to elucidate the significance of such variations in brain
      temperature and the importance of selective brain cooling in free-living birds.

PMID- 12604580
TI  - High mechanical efficiency of the cross-bridge powerstroke in skeletal muscle.
AB  - We were interested to estimate the maximum mechanical efficiency with which
      chemical energy derived from ATP hydrolysis is converted into mechanical work by
      individual cross-bridges when they perform their powerstroke synchronously.
      Glycerinated rabbit psoas muscle fibres, containing ATP molecules almost equal in
      number to the cross-bridges within the fibre, were activated to shorten under
      various afterloads by laser-flash photolysis of caged Ca(2+). In these
      conditions, almost all the cross-bridges are in the state where the ATP is
      hydrolyzed but the products have not yet been released from the cross-bridge (M
      ADP-P(i)) immediately before activation, and can hydrolyze only one ATP molecule
      during the flash-induced mechanical response. Power output records of the fibres
      following activation indicated that the cross-bridges actually started their
      powerstroke almost synchronously. The amount of ATP utilized at 1 s after
      activation was estimated from the amount of isometric force developed after
      interruption of fibre shortening, while the amount of work done was calculated by
      multiplying the amount of afterload by the distance of fibre shortening. A
      conservative estimation of the maximum mechanical efficiency at a load of 0.5-0.6
      P(o) was 0.7, suggesting that the actual maximum mechanical efficiency of cross
      bridge powerstrokes may be close to unity.

PMID- 12604581
TI  - Modulation of foregut synaptic activity controls resorption of molting fluid
      during larval molts of the moth Manduca sexta.
AB  - We examined the role of the foregut in the resorption of molting fluid (MF) from
      the exuvial space during the last larval-larval molt of the moth Manduca sexta.
      In intermolt larvae, the activity of the foregut is characterized by robust
      peristaltic contractions. With the onset of the molt, MF is secreted into the
      exuvial space where it digests and weakens the old cuticle. The appearance of MF
      in the exuvial space is accompanied by a dramatic reduction in the amplitude of
      the foregut contractions. Foregut peristalsis returned about halfway through the
      molt, followed shortly by the appearance of MF in the gut. These observations
      suggested that larvae use their foreguts to remove MF from the exuvial space.
      Animals whose foreguts were surgically inactivated did not resorb their MF and
      most failed to successfully shed their old cuticles. The reduction in foregut
      motility at the onset of the molt was correlated with a sharp decline in the
      amplitude of the excitatory junctional potentials. With the onset of the molt
      there was also a decline in the number of presynaptic terminals on the foregut
      that loaded with the activity-dependent dye FM1-43. In the second half of the
      molt, the appearance of MF in the foregut and the return of foregut motility was
      correlated with an increase in FM1-43 loading. These data reveal that during a
      larval-larval molt, vesicle release and/or recycling of the presynaptic endings
      on the foregut muscles is modulated to assure the proper timing of MF resorption.

PMID- 12604579
TI  - Seasonal acclimatisation of muscle metabolic enzymes in a reptile (Alligator
      mississippiensis).
AB  - Reptiles living in heterogeneous thermal environments are often thought to show
      behavioural thermoregulation or to become inactive when environmental conditions
      prevent the achievement of preferred body temperatures. By contrast, thermally
      homogeneous environments preclude behavioural thermoregulation, and ectotherms
      inhabiting these environments (particularly fish in which branchial respiration
      requires body temperature to follow water temperature) modify their biochemical
      capacities in response to long-term seasonal temperature fluctuations. Reptiles
      may also be active at seasonally varying body temperatures and could, therefore,
      gain selective advantages from regulating biochemical capacities. Hence, we
      tested the hypothesis that a reptile (the American alligator Alligator
      mississippiensis) that experiences pronounced seasonal fluctuations in body
      temperature will show seasonal acclimatisation in the activity of its metabolic
      enzymes. We measured body temperatures of alligators in the wild in winter and
      summer (N=7 alligators in each season), and we collected muscle samples from wild
      alligators (N=31 in each season) for analysis of metabolic enzyme activity
      (lactate dehydrogenase, citrate synthase and cytochrome c oxidase). There were
      significant differences in mean daily body temperatures between winter (15.66+/
      0.43 degrees C; mean +/- S.E.M.) and summer (29.34+/-0.21 degrees C), and daily
      body temperatures fluctuated significantly more in winter compared with summer.
      Alligators compensated for lower winter temperatures by increasing enzyme
      activities, and the activities of cytochrome c oxidase and lactate dehydrogenase
      were significantly greater in winter compared with summer at all assay
      temperatures. The activity of citrate synthase was significantly greater in the
      winter samples at the winter body temperature (15 degrees C) but not at the
      summer body temperature (30 degrees C). The thermal sensitivity (Q(10)) of
      mitochondrial enzymes decreased significantly in winter compared with in summer.
      The activity of mitochondrial enzymes was significantly greater in males than in
      females, but there were no differences between sexes for lactate dehydrogenase
      activity. The differences between sexes could be the result of the sex-specific
      seasonal demands for locomotor performance. Our data indicate that biochemical
      acclimatisation is important in thermoregulation of reptiles and that it is not
      sufficient to base conclusions about their thermoregulatory ability entirely on
      behavioural patterns.

PMID- 12604582
TI  - Age and aerobic performance in deer mice.
AB  - Age impacts the phenotype of all multicellular animals, but lifetime changes in
      physiological traits are poorly understood for all but a few species. Here, we
      describe a cross-sectional study of age effects on body composition, aerobic
      performance and ventilation in deer mice Peromyscus maniculatus. This species
      lives considerably longer in captivity (in excess of 5 years) than most
      laboratory rodents, and the adaptational biology of its aerobic physiology is
      well studied. Our deer mice grew throughout life, and, as is typical for mammals,
      their basal metabolic rate (BMR) and maximal oxygen consumption in exercise
      ((VO(2)max)) and thermogenesis ((VO(2)sum)) increased as power functions of mass.
      Age did not affect BMR, but we found abrupt decreases in growth rate, (VO(2)max)
      and (VO(2)sum) at approximately 485 days of age, and the mass-adjusted maximal
      aerobic performance of old mice (5 years of age) was 20% ((VO(2)max)) to 35%
      ((VO(2)sum)) less than that of young animals. Breathing frequency (f) and oxygen
      extraction (E(O(2))) also declined with age but did not change abruptly. However,
      there were no consistent age-related changes in tidal volume (V(T)) or minute
      volume ((Vmin)) after accounting for the effects of mass and (VO(2)sum). Age
      influenced several aspects of body composition (lean and fat mass). However,
      these changes were insufficient to explain the age-related declines in aerobic
      performance, suggesting that mass-specific oxidative capacity of lean tissue
      decreased with age. The performance changes we found could engender substantial
      reductions in the mobility and thermal tolerances of old deer mice. However, very
      few wild mice are likely to survive to ages where substantial performance
      decreases occur, so these declines are probably not subjected to strong selection
      in natural populations.

PMID- 12604583
TI  - The toxic and lethal effects of the trehalase inhibitor trehazolin in locusts are
      caused by hypoglycaemia.
AB  - The main blood sugar of locusts is trehalose, which is hydrolysed to two glucose
      units by trehalase. Homogenates of locust flight muscles are rich in trehalase
      activity, which is bound to membranes. A minor fraction of trehalase is in an
      overt form while the remainder is latent, i.e. active only after impairing
      membrane integrity. Trehazolin, an antibiotic pseudosaccharide, inhibits locust
      flight muscle trehalase with apparent K(i)- and EC(50) values of 10(-8) mol l(-1)
      and 10(-7) mol l(-1), respectively. Trehazolin is insecticidal: 50 micro g
      injected into locusts completely and selectively blocked the overt form of muscle
      trehalase (with little effect on latent activity) and killed 50% of the insects
      within 24 h. Here, it is demonstrated for the first time that trehazolin causes
      dramatic hypoglycaemia. Injection of 10 micro g trehazolin caused glucose levels
      to fall by over 90% in 24 h, from 2.8 mmol l(-1) to 0.23 mmol l(-1), while
      trehalose increased from 61 mmol l(-1) to 111 mmol l(-1). Feeding glucose to the
      locusts fully neutralized the effects of a potentially lethal dose of trehazolin.
      This indicates that hypertrehalosaemia is not acutely toxic, whereas lack of
      glucose causes organ failure (presumably of the nervous system), and that
      sufficient haemolymph glucose can only be generated from trehalose by trehalase.
      The results also suggest that overt flight muscle trehalase is located in the
      plasma membrane with the active site accessible to the haemolymph. Trehalase
      inhibitors are valuable tools for studying the molecular physiology of trehalase
      function and sugar metabolism in insects.

PMID- 12604584
TI  - Metabolic enzyme activities across an altitudinal gradient: an examination of
      pikas (genus Ochotona).
AB  - Changes in metabolic enzyme activities were examined in three species of pikas
      that occur over a range of altitudes. Because these closely related mammals live
      in comparable ecosystems and face similar environmental factors regardless of
      altitude, modifications of metabolic machinery are probably due to differences in
      oxygen availability. Citrate synthase (CS), beta-hydroxyacyl CoA dehydrogenase
      (HOAD) and lactate dehydrogenase (LDH) activities were measured in heart,
      diaphragm, vastus lateralis, gastrocnemius and soleus muscles. Additionally, the
      activity levels of both M-LDH (skeletal muscle type) and H-LDH (heart type)
      isozymes were quantified in tissue samples. Pikas from high altitude had greater
      CS and HOAD activities in heart and diaphragm when compared with pikas from low
      altitude, while activity levels did not differ in skeletal muscles. The increase
      in oxidative enzyme activities in tissues with high metabolic demand is thought
      to enhance oxygen utilization when oxygen availability is low and may reflect
      greater metabolic demand on heart and diaphragm tissue. Pikas from high altitude
      were also found to have greater total LDH activities in all tissues examined.
      High altitude animals had dramatically higher H-LDH activity (2.3-3.8 times
      greater) while M-LDH activity was more comparable (1.8 times lower to 1.7 times
      greater) when compared with low altitude animals. High total LDH activity enables
      pikas to perform short bouts of anaerobic activity, while high levels of H-LDH
      isozymes may serve to enhance lactate removal and decrease recovery time in
      animals living at high altitude.

PMID- 12604585
TI  - N-methyl-D-aspartate receptors mediate chemoreflexes in the shorthorn sculpin
      Myoxocephalus scorpius.
AB  - Glutamate microinjected into the vagal sensory area in the medulla produces
      cardiorespiratory responses mimicking oxygen chemoreflexes in fish. Here we
      directly investigate whether these reflexes are dependent on the ionotropic N
      methyl-D-aspartate (NMDA) glutamate receptor. Fish were equipped with opercular,
      branchial and snout cannulae for measurements of cardiorespiratory parameters and
      drug injections. Oxygen chemoreceptor reflexes were evoked by rapid hypoxia, NaCN
      added into the blood (internal, 0.3 ml, 50 microg ml(-1)) and the mouth
      (external, 0.5 ml, 1 mg ml(-1)), before and after systemic administration of the
      NMDA receptor antagonist MK801 (3 mg kg(-1)). Hypoxia produced an MK801-sensitive
      increase in blood pressure and ventilation frequency, whereas the marked
      bradycardia and the increased ventilation amplitude were NMDA receptor
      independent. The fish appeared more responsive to externally applied cyanide, but
      the injections and MK801 treatment did not distinguish whether external or
      internal oxygen receptors were differently involved in the hypoxic responses. In
      addition, using single-labelling immunohistochemistry on sections from the
      medulla and ganglion nodosum, the presence of glutamate and NMDA receptors in the
      vagal oxygen chemoreceptor pathway was established. In conclusion, these results
      suggest that NMDA receptors are putative central control mechanisms that process
      oxygen chemoreceptor information in fish.

PMID- 12604586
TI  - AP-1 binding to sorting signals and release from clathrin-coated vesicles is
      regulated by phosphorylation.
AB  - The adaptor protein complex-1 (AP-1) sorts and packages membrane proteins into
      clathrin-coated vesicles (CCVs) at the TGN and endosomes. Here we show that this
      process is highly regulated by phosphorylation of AP-1 subunits. Cell
      fractionation studies revealed that membrane-associated AP-1 differs from
      cytosolic AP-1 in the phosphorylation status of its beta1 and mu1 subunits. AP-1
      recruitment onto the membrane is associated with protein phosphatase 2A (PP2A)
      mediated dephosphorylation of its beta1 subunit, which enables clathrin assembly.
      This Golgi-associated isoform of PP2A exhibits specificity for phosphorylated
      beta1 compared with phosphorylated mu1. Once on the membrane, the mu1 subunit
      undergoes phosphorylation, which results in a conformation change, as revealed by
      increased sensitivity to trypsin. This conformational change is associated with
      increased binding to sorting signals on the cytoplasmic tails of cargo molecules.
      Dephosphorylation of mu1 (and mu2) by another PP2A-like phosphatase reversed the
      effect and resulted in adaptor release from CCVs. Immunodepletion and okadaic
      acid inhibition studies demonstrate that PP2A is the cytosolic cofactor for Hsc
      70-mediated adaptor uncoating. A model is proposed where cyclical
      phosphorylation/dephosphorylation of the subunits of AP-1 regulate its function
      from membrane recruitment until its release into cytosol.

PMID- 12604587
TI  - Identification of a tight junction-associated guanine nucleotide exchange factor
      that activates Rho and regulates paracellular permeability.
AB  - Rho family GTPases are important regulators of epithelial tight junctions (TJs);
      however, little is known about how the GTPases themselves are controlled during
      TJ assembly and function. We have identified and cloned a canine guanine
      nucleotide exchange factor (GEF) of the Dbl family of proto-oncogenes that
      activates Rho and associates with TJs. Based on sequence similarity searches and
      immunological and functional data, this protein is the canine homologue of human
      GEF-H1 and mouse Lfc, two previously identified Rho-specific exchange factors
      known to associate with microtubules in nonpolarized cells. In agreement with
      these observations, immunofluorescence of proliferating MDCK cells revealed that
      the endogenous canine GEF-H1/Lfc associates with mitotic spindles. Functional
      analysis based on overexpression and RNA interference in polarized MDCK cells
      revealed that this exchange factor for Rho regulates paracellular permeability of
      small hydrophilic tracers. Although overexpression resulted in increased size
      selective paracellular permeability, such cell lines exhibited a normal overall
      morphology and formed fully assembled TJs as determined by measuring
      transepithelial resistance and by immunofluorescence and freeze-fracture
      analysis. These data indicate that GEF-H1/Lfc is a component of TJs and functions
      in the regulation of epithelial permeability.

PMID- 12604588
TI  - Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling.
AB  - In platelets, the nitric oxide (NO)-induced cGMP response is indicative of a
      highly regulated interplay of cGMP formation and cGMP degradation. Recently, we
      showed that within the NO-induced cGMP response in human platelets, activation
      and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we
      identify cyclic GMP-dependent protein kinase I as the kinase responsible for the
      NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly
      activate PDE5 without phosphorylation in platelet cytosol, most likely via
      binding to the regulatory GAF domains. The reversal of activation was slow, and
      was not completed after 60 min. Phosphorylation enhanced the cGMP-induced
      activation, allowing it to occur at lower cGMP concentrations. Also, in intact
      platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was
      detected. Finally, the long-term desensitization of the cGMP response induced by
      a low NO concentration reveals the physiological relevance of the PDE5 activation
      within NO/cGMP signaling. In sum, we suggest NO-induced activation and
      phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback
      loop shaping the cGMP response in human platelets in order to adapt to the amount
      of NO available.

PMID- 12604589
TI  - Tyrosine-phosphorylated and nonphosphorylated isoforms of alpha-dystrobrevin:
      roles in skeletal muscle and its neuromuscular and myotendinous junctions.
AB  - alpha-Dystrobrevin (DB), a cytoplasmic component of the dystrophin-glycoprotein
      complex, is found throughout the sarcolemma of muscle cells. Mice lacking alphaDB
      exhibit muscular dystrophy, defects in maturation of neuromuscular junctions
      (NMJs) and, as shown here, abnormal myotendinous junctions (MTJs). In normal
      muscle, alternative splicing produces two main alphaDB isoforms, alphaDB1 and
      alphaDB2, with common NH2-terminal but distinct COOH-terminal domains. alphaDB1,
      whose COOH-terminal extension can be tyrosine phosphorylated, is concentrated at
      the NMJs and MTJs. alphaDB2, which is not tyrosine phosphorylated, is the
      predominant isoform in extrajunctional regions, and is also present at NMJs and
      MTJs. Transgenic expression of either isoform in alphaDB-/- mice prevented muscle
      fiber degeneration; however, only alphaDB1 completely corrected defects at the
      NMJs (abnormal acetylcholine receptor patterning, rapid turnover, and low
      density) and MTJs (shortened junctional folds). Site-directed mutagenesis
      revealed that the effectiveness of alphaDB1 in stabilizing the NMJ depends in
      part on its ability to serve as a tyrosine kinase substrate. Thus, alphaDB1
      phosphorylation may be a key regulatory point for synaptic remodeling. More
      generally, alphaDB may play multiple roles in muscle by means of differential
      distribution of isoforms with distinct signaling or structural properties.

PMID- 12604590
TI  - A role of topoisomerase II in linking DNA replication to chromosome condensation.
AB  - The condensin complex and topoisomerase II (topo II) have different biochemical
      activities in vitro, and both are required for mitotic chromosome condensation.
      We have used Xenopus egg extracts to investigate the functional interplay between
      condensin and topo II in chromosome condensation. When unreplicated chromatin is
      directly converted into chromosomes with single chromatids, the two proteins must
      function together, although they are independently targeted to chromosomes. In
      contrast, the requirement for topo II is temporarily separable from that of
      condensin when chromosome assembly is induced after DNA replication. This
      experimental setting allows us to find that, in the absence of condensin, topo II
      becomes enriched in an axial structure within uncondensed chromatin. Subsequent
      addition of condensin converts this structure into mitotic chromosomes in an ATP
      hydrolysis-dependent manner. Strikingly, preventing DNA replication by the
      addition of geminin or aphidicolin disturbs the formation of topo II-containing
      axes and alters the binding property of topo II with chromatin. Our results
      suggest that topo II plays an important role in an early stage of chromosome
      condensation, and that this function of topo II is tightly coupled with prior DNA
      replication.

PMID- 12604591
TI  - Minus-end capture of preformed kinetochore fibers contributes to spindle
      morphogenesis.
AB  - Near-simultaneous three-dimensional fluorescence/differential interference
      contrast microscopy was used to follow the behavior of microtubules and
      chromosomes in living alpha-tubulin/GFP-expressing cells after inhibition of the
      mitotic kinesin Eg5 with monastrol. Kinetochore fibers (K-fibers) were frequently
      observed forming in association with chromosomes both during monastrol treatment
      and after monastrol removal. Surprisingly, these K-fibers were oriented away
      from, and not directly connected to, centrosomes and incorporated into the
      spindle by the sliding of their distal ends toward centrosomes via a NuMA
      dependent mechanism. Similar preformed K-fibers were also observed during spindle
      formation in untreated cells. In addition, upon monastrol removal, centrosomes
      established a transient chromosome-free bipolar array whose orientation specified
      the axis along which chromosomes segregated. We propose that the capture and
      incorporation of preformed K-fibers complements the microtubule plus-end capture
      mechanism and contributes to spindle formation in vertebrates.

PMID- 12604592
TI  - A mechanism of coupling RCC1 mobility to RanGTP production on the chromatin in
      vivo.
AB  - The RanGTP gradient across the interphase nuclear envelope and on the condensed
      mitotic chromosomes is essential for many cellular processes, including
      nucleocytoplasmic transport and spindle assembly. Although the chromosome
      associated enzyme RCC1 is responsible for RanGTP production, the mechanism of
      generating and maintaining the RanGTP gradient in vivo remains unknown. Here, we
      report that regulator of chromosome condensation (RCC1) rapidly associates and
      dissociates with both interphase and mitotic chromosomes in living cells, and
      that this mobility is regulated during the cell cycle. Our kinetic modeling
      suggests that RCC1 couples its catalytic activity to chromosome binding to
      generate a RanGTP gradient. Indeed, we have demonstrated experimentally that the
      interaction of RCC1 with the chromatin is coupled to the nucleotide exchange on
      Ran in vivo. The coupling is due to the stable binding of the binary complex of
      RCC1-Ran to chromatin. Successful nucleotide exchange dissociates the binary
      complex, permitting the release of RCC1 and RanGTP from the chromatin and the
      production of RanGTP on the chromatin surface.

PMID- 12604594
TI  - Dynamic regulation of histone H3 methylated at lysine 79 within a tissue-specific
      chromatin domain.
AB  - Post-translational modifications of individual lysine residues of core histones
      can exert unique functional consequences. For example, methylation of histone H3
      at lysine 79 (H3-meK79) has been implicated recently in gene silencing in
      Saccharomyces cerevisiae. However, the distribution and function of H3-meK79 in
      mammalian chromatin are not known. We found that H3-meK79 has a variable
      distribution within the murine beta-globin locus in adult erythroid cells, being
      preferentially enriched at the active betamajor gene. By contrast, acetylated H3
      and H4 and H3 methylated at lysine 4 were enriched both at betamajor and at the
      upstream locus control region. H3-meK79 was also enriched at the active cad gene,
      whereas the transcriptionally inactive loci necdin and MyoD1 contained very
      little H3-meK79. As the pattern of H3-meK79 at the beta-globin locus differed
      between adult and embryonic erythroid cells, establishment and/or maintenance of
      H3-meK79 was developmentally dynamic. Genetic complementation analysis in null
      cells lacking the erythroid and megakaryocyte-specific transcription factor
      p45/NF-E2 showed that p45/NF-E2 preferentially establishes H3-meK79 at the
      betamajor promoter. These results support a model in which H3-meK79 is strongly
      enriched in mammalian chromatin at active genes but not uniformly throughout
      active chromatin domains. As H3-meK79 is highly regulated at the beta-globin
      locus, we propose that the murine ortholog of Disruptor of Telomeric Silencing-1
      like (mDOT1L) methyltransferase, which synthesizes H3-meK79, regulates beta
      globin transcription.

PMID- 12604595
TI  - Induction of flexibility through protein-protein interactions.
AB  - The dimerization/docking (D/D) domain of the cyclic AMP-dependent protein kinase
      (PKA) holoenzyme mediates important protein-protein interactions that direct the
      subcellular localization of the enzyme. A kinase anchoring proteins (AKAPs)
      provide the molecular scaffold for the localization of PKA. The recent solution
      structures of two D/D AKAP complexes revealed that the AKAP binds to a surface
      exposed, hydrophobic groove on the D/D. In the present study, we present an
      analysis of the changes in hydrogen/deuterium exchange protection and internal
      motions of the backbone of the D/D when free and bound to the prototype anchoring
      protein, Ht31(pep). We observe that formation of the complex results in
      significant, but small, increases in H/D exchange protection factors as well as
      increases in backbone flexibility, throughout the D/D, and in particular, in the
      hydrophobic binding groove. This unusual observation of increased backbone
      flexibility and marginal H/D exchange protection, despite high affinity protein
      ligand interactions, may be a general effect observed for the stabilization of
      hydrophobic ligand/hydrophobic pocket interactions.

PMID- 12604593
TI  - Chromosome order in HeLa cells changes during mitosis and early G1, but is stably
      maintained during subsequent interphase stages.
AB  - Whether chromosomes maintain their nuclear positions during interphase and from
      one cell cycle to the next has been controversially discussed. To address this
      question, we performed long-term live-cell studies using a HeLa cell line with
      GFP-tagged chromatin. Positional changes of the intensity gravity centers of
      fluorescently labeled chromosome territories (CTs) on the order of several microm
      were observed in early G1, suggesting a role of CT mobility in establishing
      interphase nuclear architecture. Thereafter, the positions were highly
      constrained within a range of approximately 1 microm until the end of G2. To
      analyze possible changes of chromosome arrangements from one cell cycle to the
      next, nuclei were photobleached in G2 maintaining a contiguous zone of unbleached
      chromatin at one nuclear pole. This zone was stably preserved until the onset of
      prophase, whereas the contiguity of unbleached chromosome segments was lost to a
      variable extent, when the metaphase plate was formed. Accordingly, chromatin
      patterns observed in daughter nuclei differed significantly from the mother cell
      nucleus. We conclude that CT arrangements were stably maintained from mid G1 to
      late G2/early prophase, whereas major changes of CT neighborhoods occurred from
      one cell cycle to the next. The variability of CT neighborhoods during clonal
      growth was further confirmed by chromosome painting experiments.

PMID- 12604596
TI  - Tumor necrosis factor receptor-associated death domain protein is involved in the
      neurotrophin receptor-mediated antiapoptotic activity of nerve growth factor in
      breast cancer cells.
AB  - The common neurotrophin receptor p75(NTR) has been shown to initiate
      intracellular signaling that leads either to cell survival or to apoptosis
      depending on the cell type examined; however, the mechanism by which p75(NTR)
      initiates its intracellular transduction remains unclear. We show here that the
      tumor necrosis factor receptor-associated death domain protein (TRADD) interacts
      with p75(NTR) upon nerve growth factor (NGF) stimulation. TRADD could be
      immunodetected after p75(NTR) immunoprecipitation from MCF-7 breast cancer cells
      stimulated by nerve growth factor. In addition, confocal microscopy indicated
      that NGF stimulation induced the plasma membrane localization of TRADD. Using a
      dominant negative form of TRADD, we also show that interactions between p75(NTR)
      and TRADD are dependent on the death domain of TRADD, thus demonstrating its
      requirement for binding. Furthermore, the p75(NTR)-mediated activation of NF
      kappaB was inhibited by transfection with a dominant negative TRADD, resulting in
      an inhibition of NGF antiapoptotic activity. These results thus demonstrate that
      TRADD is involved in the p75(NTR)-mediated antiapoptotic activity of NGF in
      breast cancer cells.

PMID- 12604597
TI  - Activation of the Ras-ERK pathway inhibits retinoic acid-induced stimulation of
      tissue transglutaminase expression in NIH3T3 cells.
AB  - Retinoic acid (RA) is a potent activator of tissue transglutaminase (TGase)
      expression, and it was recently shown that phosphoinositide 3-kinase (PI3K)
      activity was required for RA to increase TGase protein levels. To better
      understand how RA-mediated TGase expression is regulated, we considered whether
      co-stimulation of NIH3T3 cells with RA and epidermal growth factor (EGF), a known
      activator of PI3K, would facilitate the induction or increase the levels of TGase
      expression. Instead of enhancing these parameters, EGF inhibited RA-induced TGase
      expression. Activation of the Ras-ERK pathway by EGF was sufficient to elicit
      this effect, since continuous Ras signaling mimicked the actions of EGF and
      inhibited RA-induced TGase expression, whereas blocking ERK activity in these
      same cells restored the ability of RA to up-regulate TGase expression. However,
      TGase activity is not antagonistic to EGF signaling. The mitogenic and anti
      apoptotic effects of EGF were not compromised by TGase overexpression, and in
      fact, exogenous TGase expression promoted basal cell growth and resistance to
      serum deprivation-induced apoptosis. Moreover, analysis of TGase expression and
      GTP binding activity in a number of cell lines revealed high basal TGase GTP
      binding activity in tumor cell lines U87 and MDAMB231, indicating that
      constitutively active TGase may be a characteristic of certain cancer cells.
      These findings demonstrate that TGase may serve as a survival factor and RA
      induced TGase expression requires the activation of PI3K but is antagonized by
      the Ras-ERK pathway.

PMID- 12604598
TI  - Distinct gene expression programs function in progenitor and mature islet cells.
AB  - Homeodomain transcription factor Nkx2.2 is required for the final differentiation
      of the beta-cells in the pancreas and for the production of insulin. Nkx2.2 is
      expressed in islet cell precursors during pancreatic development and persists in
      a subset of mature islet cells including all beta-cells. To understand the
      mechanisms regulating the expression of Nkx2.2 in these different cell
      populations, we outlined the structure of the mouse nkx2.2 gene and identified
      regions that direct cell type-specific expression. The nkx2.2 gene has two
      noncoding alternative first exons (exons 1a and 1b). In transgenic mice,
      sequences upstream from exon 1a directed expression predominantly in mature islet
      cells. Within this exon 1a promoter, cooperative interactions between HNF3 and
      basic helix-loop-helix factors neurogenin-3 or NeuroD1 binding to adjacent sites
      played key roles in its islet cell-specific expression. In contrast, sequences
      upstream from exon 1b restricted expression specifically to islet cell
      precursors. These studies reveal distinct mechanisms for directing the expression
      of a key differentiation factor in precursors versus mature islet cells.

PMID- 12604599
TI  - Interferon regulatory factor-7 synergizes with other transcription factors
      through multiple interactions with p300/CBP coactivators.
AB  - Interferon regulatory factor (IRF)-7 is activated in response to virus infection
      and stimulates the transcription of a set of cellular genes involved in host
      antiviral defense. The mechanism by which IRF-7 is activated and cooperates with
      other transcription factors is not fully elucidated. Activation of IRF-7 results
      from a conformational change triggered by the virus-dependent phosphorylation of
      its C terminus. This conformational change leads to dimerization, nuclear
      accumulation, DNA-binding, and transcriptional transactivation. Here we show that
      activation of IRF-7, like that of IRF-3, is dependent on modifications of two
      distinct sets of Ser/Thr residues. Moreover, we show that different virus
      inducible cis-acting elements display requirements for specific IRFs. In
      particular, the virus-responsive element of the ISG15 gene promoter can be
      activated by either IRF-3 or IRF-7 alone, whereas the P31 element of the
      interferon-beta gene is robustly activated only when IRF-3, IRF-7, and the
      p300/CBP coactivators are all present. Furthermore, we find that IRF-7 interacts
      with four distinct regions of p300/CBP. These interactions not only stimulate the
      intrinsic transcriptional activity of IRF-7, but they are also indispensable for
      its ability to strongly synergize with other transcription factors, including c
      Jun and IRF-3.

PMID- 12604600
TI  - Mitochondrial regulation of synaptic plasticity in the hippocampus.
AB  - Synaptic mechanisms of plasticity are calcium-dependent processes that are
      affected by dysfunction of mitochondrial calcium buffering. Recently, we observed
      that mice deficient in mitochondrial voltage-dependent anion channels, the outer
      component of the mitochondrial permeability transition pore, have impairments in
      learning and hippocampal synaptic plasticity, suggesting that the mitochondrial
      permeability transition pore is involved in hippocampal synaptic plasticity. In
      this study, we examined the effect on synaptic transmission and plasticity of
      blocking the permeability transition pore with low doses of cyclosporin A and
      found a deficit in synaptic plasticity and an increase in base-line synaptic
      transmission. Calcium imaging of presynaptic terminals revealed a transient
      increase in the resting calcium concentration immediately upon incubation with
      cyclosporin A that correlated with the changes in synaptic transmission and
      plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when
      mitochondria were depolarized prior to cyclosporin A exposure, and the effects of
      cyclosporin A and mitochondrial depolarization on presynaptic resting calcium
      were similar, suggesting a mitochondrial locus of action of cyclosporin A. To
      further characterize the calcium dynamics of the mitochondrial permeability
      transition pore, we used an in vitro assay of calcium handling by isolated brain
      mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly
      and subsequently triggered a more rapid mitochondrial depolarization. Similarly,
      mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized
      more readily than littermate controls. The data suggest a role for the
      mitochondrial permeability transition pore and voltage-dependent anion channels
      in mitochondrial synaptic calcium buffering and in hippocampal synaptic
      plasticity.

PMID- 12604601
TI  - The vesicular monoamine content regulates VMAT2 activity through Galphaq in mouse
      platelets. Evidence for autoregulation of vesicular transmitter uptake.
AB  - Variations in the neurotransmitter content of secretory vesicles enable neurons
      to adapt to network changes. Vesicular content may be modulated by vesicle
      associated Go(2), which down-regulates the activity of the vesicular monoamine
      transmitter transporters VMAT1 in neuroendocrine cells and VMAT2 in neurons.
      Blood platelets resemble serotonergic neurons with respect to transmitter storage
      and release. In streptolysin O-permeabilized platelets, VMAT2 activity is also
      down-regulated by the G protein activator guanosine 5'-(beta(i)gamma
      imido)triphosphate (GMppNp). Using serotonin-depleted platelets from peripheral
      tryptophan hydroxylase knockout (Tph1-/-) mice, we show here that the vesicular
      filling initiates the G protein-mediated down-regulation of VMAT2 activity.
      GMppNp did not influence VMAT2 activity in naive platelets from Tph1-/- mice.
      GMppNp-mediated inhibition could be reconstituted, however, when preloading Tph1
      /- platelets with serotonin or noradrenaline. Galpha(q) mediates the down
      regulation of VMAT2 activity as revealed from uptake studies performed with
      platelets from Galpha(q) deletion mutants. Serotonergic, noradrenergic, as well
      as thromboxane A(2) receptors are not directly involved in the down-regulation of
      VMAT2 activity. It is concluded that in platelets the vesicle itself regulates
      transmitter transporter activity via its content and vesicle-associated
      Galpha(q).

PMID- 12604602
TI  - The involvement of heparan sulfate (HS) in FGF1/HS/FGFR1 signaling complex.
AB  - Fibroblast growth factor (FGF) signaling begins with the formation of a ternary
      complex of FGF, FGF receptor (FGFR), and heparan sulfate (HS). Multiple models
      have been proposed for the ternary complex. However, major discrepancies exist
      among those models, and none of these models have evaluated the functional
      importance of the interacting regions on the HS chains. To resolve the
      discrepancies, we measured the size and molar ratio of HS in the complex and
      showed that both FGF1 and FGFR1 simultaneously interact with HS; therefore, a
      model of 2:2:2 FGF1.HS.FGFR1 was shown to fit the data. Using genetic and
      biochemical methods, we generated HSs that were defective in FGF1 and/or FGFR1
      binding but could form the signaling ternary complex. Both genetically and
      chemically modified HSs were subsequently assessed in a BaF3 cell mitogenic
      activity assay. The ability of HS to support the ternary complex formation was
      found to be required for FGF1-stimulated cell proliferation. Our data also proved
      that specific critical groups and sites on HS support complex formation.
      Furthermore, the molar ratio of HS, FGF1, and FGFR1 in the ternary complex was
      found to be independent of the size of HS, which indicates that the selected
      model can take place on the cell surface proteoglycans. Finally, a mechanism for
      the FGF.FGFR signaling complex formation on cell membrane was proposed, where FGF
      and FGFR have their own binding sites on HS and a distinct ternary complex
      formation site is directly responsible for mitogenic activity.

PMID- 12604603
TI  - Complete spectra of the far-red chemiluminescence of the oxygenase reaction of
      Mn2+-activated ribulose-bisphosphate carboxylase/oxygenase establish excited Mn2+
      as the source.
AB  - Chemiluminescence emitted by Mn(2+)-activated ribulose-1,5-bisphosphate
      carboxylase/oxygenase (rubisco) while catalyzing oxygenation was analyzed to
      clarify the source of the emission. Using dual detectors capturing radiation over
      a wide range of visible and infrared wavelengths, we tested for radiation from
      singlet O(2) decay and found it to be essentially absent (less than 0.1% of the
      total luminescence intensity). Spectra were determined between 647 and 885 nm
      with a very sensitive, charge-coupled detector-based spectrograph to detect
      differences in the emission spectra between rubiscos from bacterial and higher
      plant sources. All Mn(2+)-activated rubiscos emitted a broad, smooth spectrum of
      chemiluminescence, unchanging as the reaction progressed. The spectra from higher
      plant rubiscos (spinach and both the wild type and an L335V mutant from tobacco),
      all exhibited maxima at about 800 nm. However, Mn(2+)-activated rubisco from the
      bacterium, Rhodospirillum rubrum, emitted at shorter wavelengths (760 nm peak),
      demonstrating host ligand-field influences arising from aminoacyl residue
      differences and/or conformational changes caused by the absence of small
      subunits. The findings provide strong evidence that the chemiluminescence arises
      from an excited state of the active-site Mn(2+) that is produced during
      oxygenation. We propose that the Mn(2+) becomes excited by a one-electron
      exchange mechanism of oxygenation that is not available to Mg(2+)-activated
      rubisco.

PMID- 12604604
TI  - Identification of RGS2 and type V adenylyl cyclase interaction sites.
AB  - The production of cAMP is controlled on many levels, notably at the level of cAMP
      synthesis by the enzyme adenylyl cyclase. We have recently identified a new
      regulator of adenylyl cyclase activity, RGS2, which decreases cAMP accumulation
      when overexpressed in HEK293 cells and inhibits the in vitro activity of types
      III, V, and VI adenylyl cyclase. In addition, RGS2 blocking antibodies lead to
      elevated cAMP levels in olfactory neurons. Here we examine the nature of the
      interaction between RGS2 and type V adenylyl cyclase. In HEK293 cells expressing
      type V adenylyl cyclase, RGS2 inhibited Galpha(s)-Q227L- or beta(2)-adrenergic
      receptor-stimulated cAMP accumulation. Deletion of the N-terminal 19 amino acids
      of RGS2 abolished its ability to inhibit cAMP accumulation and to bind adenylyl
      cyclase. Further mutational analysis indicated that neither the C terminus, RGS
      GAP activity, nor the RGS box domain is required for inhibition of adenylyl
      cyclase. Alanine scanning of the N-terminal amino acids of RGS2 identified three
      residues responsible for the inhibitory function of RGS2. Furthermore, we show
      that RGS2 interacts directly with the C(1) but not the C(2) domain of type V
      adenylyl cyclase and that the inhibition by RGS2 is independent of inhibition by
      Galpha(i). These results provide clear evidence for functional effects of RGS2 on
      adenylyl cyclase activity that adds a new dimension to an intricate signaling
      network.

PMID- 12604605
TI  - Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a
      glycoprotein involved in bone formation and angiogenesis.
AB  - The goal of this study was to discover novel partners for perlecan, a major
      heparan sulfate proteoglycan of basement membranes, and to examine new
      interactions through which perlecan may influence cell behavior. We employed the
      yeast two-hybrid system and used perlecan domain V as bait to screen a human
      keratinocyte cDNA library. Among the strongest interacting clones, we isolated a
      approximately 1.6-kb cDNA insert that encoded extracellular matrix protein 1
      (ECM1), a secreted glycoprotein involved in bone formation and angiogenesis. The
      sequencing of the clone revealed the existence of a novel splice variant that we
      name ECM1c. The interaction was validated by co-immunoprecipitation studies,
      using both cell-free systems and mammalian cells, and the specific binding site
      within each molecule was identified employing various deletion mutants. The C
      terminus of ECM1 interacted specifically with the epidermal growth factor-like
      modules flanking the LG2 subdomain of perlecan domain V. Perlecan and ECM1 were
      also co-expressed by a variety of normal and transformed cells, and
      immunohistochemical studies showed a partial expression overlap, particularly
      around dermal blood vessels and adnexal epithelia. ECM1 has been shown to
      regulate endochondral bone formation, stimulate the proliferation of endothelial
      cells, and induce angiogenesis. Similarly, perlecan plays an important role in
      chondrogenesis and skeletal development, as well as harboring pro- and anti
      angiogenic activities. Thus, a physiological interaction could also occur in vivo
      during development and in pathological events, including tissue remodeling and
      tumor progression.

PMID- 12604606
TI  - The low viral production in trophoblastic cells is due to a high endocytic
      internalization of the human immunodeficiency virus type 1 and can be overcome by
      the pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
AB  - Maternal-infant transmission of human immunodeficiency virus type-1 (HIV-1) is
      the primary cause of this retrovirus infection in neonates. Trophoblasts have
      been proposed to play a critical role in modulating virus spread to the fetus.
      This paper addresses the mechanism of HIV-1 biology in trophoblastic cells. The
      trophoblastic cell lines BeWo, JAR, and JEG-3 were infected with reporter HIV-1
      particles pseudotyped with envelope glycoproteins from the vesicular stomatitis
      virus or various strains of HIV-1. We demonstrate that despite a high
      internalization process of HIV-1 and no block in viral production, HIV-1
      established a limited infection of trophoblasts with the production of very few
      progeny viruses. The factor responsible for this restriction to virus replication
      in such a cellular microenvironment is that the intracellular p24 is concentrated
      predominantly in endosomal vesicles following HIV-1 entry. HIV-1 transcription
      and virus production of infectious particles were both augmented upon treatment
      of trophoblasts with tumor necrosis factor-alpha and interleukin-1. However, the
      amount of progeny virions released by trophoblasts infected with native HIV-1
      virions was so low even in the presence of pro-inflammatory cytokines that a co
      culture step with indicator cells was necessary to detect virus production.
      Collectively these data illustrate for the first time that the natural low
      permissiveness of trophoblasts to productive HIV-1 infection is because of a
      restriction in the mode of entry, and such a limitation can be overcome with
      physiologic doses of tumor necrosis factor-alpha and interleukin-1, which are
      both expressed by the placenta, in conjunction with cell-cell contact.
      Considering that there is a linear correlation between viral load and HIV-1
      vertical transmission, the environment may thus contribute to the propagation of
      HIV-1 across the placenta.

PMID- 12604607
TI  - An intronic splicing enhancer element in survival motor neuron (SMN) pre-mRNA.
AB  - Spinal muscular atrophy is caused by the homozygous loss of survival motor neuron
      1 (SMN1). SMN2, a nearly identical copy gene, differs from SMN1 only by a single
      nonpolymorphic C to T transition in exon 7, which leads to alteration of exon 7
      splicing; SMN2 leads to exon 7 skipping and expression of a nonfunctional gene
      product and fails to compensate for the loss of SMN1. The exclusion of SMN exon 7
      is critical for the onset of this disease. Regulation of SMN exon 7 splicing was
      determined by analyzing the roles of the cis-acting element in intron 7 (element
      2), which we previously identified as a splicing enhancer element of SMN exon 7
      containing the C to T transition. The minimum sequence essential for activation
      of the splicing was determined to be 24 nucleotides, and RNA structural analyses
      showed a stem-loop structure. Deletion of this element or disruption of the stem
      loop structure resulted in a decrease in exon 7 inclusion. A gel shift assay
      using element 2 revealed formation of RNA-protein complexes, suggesting that the
      binding of the trans-acting proteins to element 2 plays a crucial role in the
      splicing of SMN exon 7 containing the C to T transition.

PMID- 12604608
TI  - Expression of galectin-3 in skeletal tissues is controlled by Runx2.
AB  - The beta-galatoside-specific lectin galectin-3 is expressed in vivo in
      osteoblasts as well as in epiphyseal cartilage. Here we show that in vitro,
      galectin-3 expression is up-regulated in the preosteoblastic cell line MC3T3-E1
      during the matrix maturation stage of the osteoblast developmental sequence.
      Expression persists into late differentiation stages when the mature osteoblastic
      phenotype is established. The skeletal expression pattern of galectin-3 overlaps
      at many sites with that of the transcription factor Runx2. Runx2 is a key
      regulator of osteoblast development and necessary for chondrocyte differentiation
      in the growth plate. Both human and mouse galectin-3 promoters contain putative
      Runx-binding sites. The constitutive or inducible forced expression of Runx2 is
      sufficient for the onset of galectin-3 transcription in the mesenchymal precursor
      cell line C3H10T1/2. Moreover, Runx2 is able to bind to at least two sites in the
      galectin-3 promoter region. The crucial role of Runx2 was confirmed in Runx2
      deficient mice, which are devoid of galectin-3 expression in skeletal cells. The
      overlapping expression pattern of galectin-3 with the other two members of the
      Runt family of transcription factors (Runx1 and Runx3) points to a potential
      regulation of the galectin-3 gene (LGALS3) by these factors in hematopoietic,
      skin, and dorsal root ganglial cells.

PMID- 12604609
TI  - Mammalian elongin A is not essential for cell viability but is required for
      proper cell cycle progression with limited alteration of gene expression.
AB  - Elongin A is a transcription elongation factor that increases the overall rate of
      mRNA chain elongation by RNA polymerase II. To investigate the function of
      Elongin A in vivo, the two alleles of the Elongin A gene have been disrupted by
      homologous recombination in murine embryonic stem (ES) cells. The Elongin A
      deficient ES cells are viable, but show a slow growth phenotype because they
      undergo a delayed mitosis. The cDNA microarray and RNase protection assay using
      the wild-type and Elongin A-deficient ES cells indicate that the expression of
      only a small subset of genes is affected in the mutant cells. Taken together, our
      results suggest that Elongin A regulates transcription of a subset but not all of
      genes and reveal a linkage between Elongin A function and cell cycle progression.

PMID- 12604610
TI  - The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR
      substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif.
AB  - The mammalian target of rapamycin (mTOR) controls multiple cellular functions in
      response to amino acids and growth factors, in part by regulating the
      phosphorylation of p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E
      binding protein 1 (4E-BP1). Raptor (regulatory associated protein of mTOR) is a
      recently identified mTOR binding partner that also binds p70S6k and 4E-BP1 and is
      essential for TOR signaling in vivo. Herein we demonstrate that raptor binds to
      p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs
      to be required for amino acid- and mTOR-dependent regulation of these mTOR
      substrates in vivo. A point mutation of the TOS motif also eliminates all in
      vitro mTOR-catalyzed 4E-BP1 phosphorylation and abolishes the raptor-dependent
      component of mTOR-catalyzed p70S6k phosphorylation in vitro. Raptor appears to
      serve as an mTOR scaffold protein, the binding of which to the TOS motif of mTOR
      substrates is necessary for effective mTOR-catalyzed phosphorylation in vivo and
      perhaps for conferring their sensitivity to rapamycin and amino acid sufficiency.

PMID- 12604612
TI  - N-cadherin-catenin complexes form prior to cleavage of the proregion and
      transport to the plasma membrane.
AB  - Cadherins are calcium-dependent glycoproteins that function as cell-cell adhesion
      molecules and are linked to the actin cytoskeleton via catenins. Newly
      synthesized cadherins contain a prosequence that must be proteolytically removed
      to generate a functional adhesion molecule. The goal of this study was to examine
      the proteolytic processing of N-cadherin and the assembly of the cadherin-catenin
      complex in cells that express endogenous N-cadherin. A monoclonal antibody
      specific for the proregion of human N-cadherin was generated and used to examine
      N-cadherin processing. Our data show that newly synthesized proN-cadherin is
      phosphorylated and proteolytically processed prior to transport to the plasma
      membrane. In addition, we show that beta-catenin and plakoglobin associate only
      with phosphorylated proN-cadherin, whereas p120(ctn) can associate with both
      phosphorylated and non-phosphorylated proN-cadherin. Immunoprecipitations using
      anti-proN-cadherin showed that cadherin-catenin complexes are assembled prior to
      localization at the plasma membrane. These data suggest that a core N-cadherin
      catenin complex assembles in the endoplasmic reticulum or Golgi compartment and
      is transported to the plasma membrane where linkage to the actin cytoskeleton can
      be established.

PMID- 12604611
TI  - Splicing factor SRp30c interaction with Y-box protein-1 confers nuclear YB-1
      shuttling and alternative splice site selection.
AB  - The multifunctional DNA- and RNA-associated Y-box protein 1 (YB-1) specifically
      binds to splicing recognition motifs and regulates alternative splice site
      selection. Here, we identify the arginine/serine-rich SRp30c protein as an
      interacting protein of YB-1 by performing a two-hybrid screen against a human
      mesangial cell cDNA library. Co-immunoprecipitation studies confirm a direct
      interaction of tagged proteins YB-1 and SRp30c in the absence of RNA via two
      independent protein domains of YB-1. A high affinity interaction is conferred
      through the N-terminal region. We show that the subcellular YB-1 localization is
      dependent on the cellular SRp30c content. In proliferating cells, YB-1 localizes
      to the cytoplasm, whereas FLAG-SRp30c protein is detected in the nucleus. After
      overexpression of YB-1 and FLAG-SRp30c, both proteins are co-localized in the
      nucleus, and this requires the N-terminal region of YB-1. Heat shock treatment of
      cells, a condition under which SRp30c accumulates in stress-induced Sam68 nuclear
      bodies, abrogates the co-localization and YB-1 shuttles back to the cytoplasm.
      Finally, the functional relevance of the YB-1/SRp30c interaction for in vivo
      splicing is demonstrated in the E1A minigene model system. Here, changes in
      splice site selection are detected, that is, overexpression of YB-1 is
      accompanied by preferential 5' splicing site selection and formation of the 12 S
      isoform.

PMID- 12604613
TI  - Functional identification of galactosyltransferases (SCGs) required for species
      specific modifications of the lipophosphoglycan adhesin controlling Leishmania
      major-sand fly interactions.
AB  - Lipophosphoglycan (LPG) is an abundant surface molecule that plays key roles in
      the infectious cycle of Leishmania major. The dominant feature of LPG is a
      polymer of phosphoglycan (PG) (6Galbeta1,4Manalpha1-PO(4)) repeating units. In L.
      major these are extensively substituted with Gal(beta1,3) side chains, which are
      required for binding to midgut lectins and survival. We utilized evolutionary
      polymorphisms in LPG structure and cross-species transfections to recover genes
      encoding the LPG side chain beta1,3-galactosyltransferases (betaGalTs). A
      dispersed family of six SCG genes was recovered, whose predicted proteins
      exhibited characteristics of eukaryotic GalTs. At least four of these proteins
      showed significant LPG side chain betaGalT activity; SCG3 exhibited initiating
      GalT activity whereas SCG2 showed both initiating and elongating GalT activity.
      However, the activity of SCG2 was context-dependent, being largely silent in its
      normal genomic milieu, and different strains show considerable variation in the
      extent of LPG galactosylation. Thus the L. major genome encodes a family of SCGs
      with varying specificity and activity, and we propose that strain-specific LPG
      galactosylation patterns reflect differences in their expression.

PMID- 12604614
TI  - The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth
      factor receptor (IGF1R) is influenced by secondary structure in the IGF1R
      transcript.
AB  - The type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by
      tumors and mediates growth and apoptosis protection. We previously showed that
      antisense reagents complementary to the IGF1R translation start site enhance
      radio- and chemosensitivity and impair Atm function. However these agents induce
      relatively modest IGF1R down-regulation and affect insulin receptor levels. To
      identify alternative sites for molecular targeting, we utilized scanning
      oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This
      strategy enabled selection of antisense oligonucleotides that generated high
      heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense
      oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down
      regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides
      were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to
      block IGF1R expression correlated with the accessibility of the target sequence
      within the transcript. Thus, siRNAs corresponding to weakly hybridizing
      oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to
      accessible targets induced profound sequence-specific IGF1R gene silencing,
      blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates
      that secondary structure in the target transcript has a major effect on siRNA
      efficacy. These findings have implications for siRNA design and suggest that
      IGF1R-targeting agents incorporating this mode of action have potential as
      anticancer therapy.

PMID- 12604615
TI  - Aha1 binds to the middle domain of Hsp90, contributes to client protein
      activation, and stimulates the ATPase activity of the molecular chaperone.
AB  - The ATP-dependent molecular chaperone Hsp90 is an essential and abundant stress
      protein in the eukaryotic cytosol that cooperates with a cohort of
      cofactors/cochaperones to fulfill its cellular tasks. We have identified Aha1
      (activator of Hsp90 ATPase) and its relative Hch1 (high copy Hsp90 suppressor) as
      binding partners of Hsp90 in Saccharomyces cerevisiae. By using genetic and
      biochemical approaches, the middle domain of Hsp90 (amino acids 272-617) was
      found to mediate the interaction with Aha1 and Hch1. Data base searches revealed
      that homologues of Aha1 are conserved from yeast to man, whereas Hch1 was found
      to be restricted to lower eukaryotes like S. cerevisiae and Candida albicans. In
      experiments with purified proteins, Aha1 but not Hch1 stimulated the intrinsic
      ATPase activity of Hsp90 5-fold. To establish their cellular role further, we
      deleted the genes encoding Aha1 and Hch1 in S. cerevisiae. In vivo experiments
      demonstrated that Aha1 and Hch1 contributed to efficient activation of the
      heterologous Hsp90 client protein v-Src. Moreover, Aha1 and Hch1 became crucial
      for cell viability under non-optimal growth conditions when Hsp90 levels are
      limiting. Thus, our results identify a novel type of cofactor involved in the
      regulation of the molecular chaperone Hsp90.

PMID- 12604617
TI  - Purification and characterization of plasma membrane-associated human sperm alpha
      L-fucosidase.
AB  - Detergent and salt extraction studies, as well as cytochemical localization with
      fluorescein isothiocyanate-bovine serum albumin-L-fucose, have provided further
      evidence for the plasma membrane association of a novel human sperm, alpha-L
      fucosidase. This alpha-L-fucosidase has been solubilized and purified 8600-fold
      to high specific activity (35 000 U/mg protein) by affinity chromatography on
      agarose-C(24)-fucosylamine. To our knowledge, this is the first report concerning
      the purification and characterization of a mammalian plasma membrane-associated
      alpha-L-fucosidase. Both SDS-PAGE and Western blot analysis indicated the alpha-L
      fucosidase is highly purified and contains a single subunit with a molecular mass
      of 51 kDa. N-glycanase studies indicated the subunit contains N-glycans, and
      lectin blot analysis detected the presence of mannose, but no terminal galactose
      or sialic acid residues. Isoelectric focusing indicated the presence of two major
      alpha-L-fucosidase isoforms (pIs 6.5 and 6.7) and a possible minor isoform (pI
      6.3). Treatment of alpha-L-fucosidase with neuraminidase did not change its
      isoform profile, providing further evidence for the enzyme's lack of sialic acid
      residues. Kinetic analysis with 4-methylumbelliferyl alpha-L-fucopyranoside
      indicated that sperm alpha-L-fucosidase has a pH optimum near 7, an apparent K(m)
      of 0.08 mM, and a V(max) of 6.8 micro mol/min/mg protein. The unusual properties
      of human sperm alpha-L-fucosidase argue in support of a potentially important,
      but presently unknown, role for this enzyme in human reproduction.

PMID- 12604616
TI  - Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine
      phosphorylation and subsequent ERK activation.
AB  - Signaling through fibroblast growth factor receptors (FGFRs) is essential for
      many cellular processes including proliferation and migration as well as
      differentiation events such as angiogenesis, osteogenesis, and chondrogenesis.
      Recently, genetic screens in Drosophila and gene expression screens in zebrafish
      have resulted in the identification of several feedback inhibitors of FGF
      signaling. One of these, Sef (similar expression to fgf genes), encodes a
      transmembrane protein that belongs to the FGF synexpression group. Here we show
      that like zebrafish Sef (zSef), mouse Sef (mSef) interacts with FGFR1 and that
      the cytoplasmic domain of mSef mediates this interaction. Overexpression of mSef
      in NIH3T3 cells results in a decrease in FGF-induced cell proliferation
      associated with a decrease in Tyr phosphorylation of FGFR1 and FRS2. As a
      consequence, there is a reduction in the phosphorylation of Raf-1 at Ser(338),
      MEK1/2 at Ser(217) and Ser(221), and ERK1/2 at Thr(202) and Tyr(204).
      Furthermore, mSef inhibits ERK activation mediated by a constitutively activated
      FGFR1 but not by a constitutively active Ras and decreases FGF but not PDGF
      mediated activation of Akt. These results indicate that Sef exerts its inhibitory
      effects at the level of FGFR and upstream of Ras providing an additional level of
      negative regulation of FGF signaling.

PMID- 12604618
TI  - Function of DNA-protein kinase catalytic subunit during the early meiotic
      prophase without Ku70 and Ku86.
AB  - All components of the double-stranded DNA break (DSB) repair complex DNA
      dependent protein kinase (DNA-PK), including Ku70, Ku86, and DNA-PK catalytic
      subunit (DNA-PKcs), were found in the radiosensitive spermatogonia. Although p53
      induction was unaffected, spermatogonial apoptosis occurred faster in the
      irradiated DNA-PKcs-deficient scid testis. This finding suggests that
      spermatogonial DNA-PK functions in DNA damage repair rather than p53 induction.
      Despite the fact that early spermatocytes lack the Ku proteins, spontaneous
      apoptosis of these cells occurred in the scid testis. The majority of these
      apoptotic spermatocytes were found at stage IV of the cycle of the seminiferous
      epithelium where a meiotic checkpoint has been suggested to exist. Meiotic
      synapsis and recombination during the early meiotic prophase induce DSBs, which
      are apparently less accurately repaired in scid spermatocytes that then fail to
      pass the meiotic checkpoint. The role for DNA-PKcs during the meiotic prophase
      differs from that in mitotic cells; it is not influenced by ionizing radiation
      and is independent of the Ku heterodimer.

PMID- 12604619
TI  - Relationship of the hormone-sensitive lipase-mediated modulation of cholesterol
      metabolism in individual compartments of the testis to serum pituitary hormone
      and testosterone concentrations in a seasonal breeder, the mink (Mustela vison).
AB  - The role of cholesterol differs in the two compartments of the testis. In the
      interstitial tissue, cholesterol is necessary for the synthesis of testosterone,
      whereas in the seminiferous tubules, membrane cholesterol content in developing
      germ cells will influence the gametes' fertility. Here we evaluate the hormone
      sensitive lipase (HSL) modulation of the cholesterol metabolism in each
      compartment of the testis. Two HSL immunoreactive bands of 104- and 108-kDa were
      detected in Western blots performed with polyclonal anti-human HSL antibodies in
      the interstitial tissue (ITf)- and seminiferous tubule (STf)-enriched fractions
      generated from testes harvested at 30-day intervals during puberty and, in the
      adult mink, during the annual seasonal reproductive cycle. Epididymal spermatozoa
      expressed a 104-kDa HSL isoform, and HSL was active in these cells.
      Immunolabeling localized HSL to interstitial macrophages; Sertoli cells, where
      its distribution was stage specific; spermatids; and the equatorial segment of
      spermatozoa. Total HSL protein levels, specific enzymatic activity, and free
      cholesterol (FC):esterified cholesterol (EC) ratios varied concomitantly in STf
      and ITf and reached maximal values in the adult during the period of maximal
      spermatogenic activity. In STf, HSL-specific activity correlated with FC:EC
      ratios but not with triglyceride levels. In STf, high HSL-specific activity
      occurred concomitantly with high FSH serum levels. In ITf, HSL-specific activity
      was high during periods of low serum prolactin levels and high serum testosterone
      levels. The results suggest that 1) modulation of cholesterol metabolism in
      individual testicular compartments may be regulated by HSL isoforms expressed by
      distinct cells; 2) interstitial macrophages may be part of a system involved in
      the synthesis of steroid hormones and in the recycling of sterols in the
      interstitium, whereas in the tubules, recycling could be ensured by Sertoli
      cells; 3) there is distinctive substrate preference for testicular HSL; and 4)
      HSL may be the only cholesterol esterase in this location.

PMID- 12604620
TI  - Molecular characterization and expression of porcine bone morphogenetic protein
      receptor-IB in the uterus of cyclic and pregnant gilts.
AB  - Previous gene mapping analyses revealed a quantitative trait locus for uterine
      capacity on chromosome 8. Comparison of porcine and human genetic maps suggests
      that the bone morphogenetic protein receptor IB (BMPR-IB) gene may be located
      near this region. The objectives of this study were to 1) clone the full coding
      region for BMPR-IB, 2) examine BMPR-IB gene expression by the endometrium and its
      cellular localization in cyclic and pregnant gilts, and 3) map the BMPR-IB gene.
      By iterative screening of an expressed sequence tag library, we obtained a 3559
      base pair cDNA clone including the full coding region of BMPR-IB. Endometrial
      BMPR-IB mRNA expression of White composite gilts was determined by Northern
      blotting in Days 10, 13, and 15 cyclic and Days 10, 13, 15, 20, 30, and 40
      pregnant gilts. In cyclic gilts, endometrial BMPR-IB mRNA expression was elevated
      on Days 13 and 15 (P < 0.01) compared with Day 10. Expression of BMPR-IB mRNA was
      localized in both luminal and glandular epithelium on Day 15. However, in
      pregnant gilts, BMPR-IB mRNA expression was not significantly different in the
      endometrium from Day 10 to Day 20, and it was significantly decreased on Days 30
      and 40 (P = 0.011). The BMPR-IB gene was mapped to 108 cM on chromosome 8. These
      findings show that BMPR-IB mRNA expression is regulated differently in cyclic and
      pregnant gilts; this pattern of gene expression may be important for endometrial
      function during the luteal phase of the estrous cycle as compared with early
      pregnancy.

PMID- 12604621
TI  - Expression and regulation of cytosolic prostaglandin E synthase in mouse uterus
      during the peri-implantation period.
AB  - Prostaglandin E(2) (PGE(2)) is considered important for blastocyst spacing,
      implantation, and decidualization in rodent uteri. PGE synthase (PGES) catalyzes
      the isomerization of PGH(2) to PGE(2). Two isoforms of PGES exist: microsomal
      PGES (mPGES) and cytosolic PGES (cPGES); however, the expression and regulation
      of cPGES in the mammalian uterus during early pregnancy are still unknown. The
      aim of this study was to investigate the differential expression of cPGES in
      mouse uterus during early pregnancy and its regulation under different conditions
      using in situ hybridization and immunohistochemistry. A strong level of cPGES
      mRNA signal was exhibited in the stromal cells at the implantation site on Day 5
      of pregnancy, whereas cPGES immunostaining was strongly detected in the luminal
      epithelium. The signals for both cPGES mRNA and immunostaining were strongly
      detected in the decidualized cells from Days 6-8 of pregnancy. A basal level of
      cPGES mRNA signal and immunostaining was exhibited in the uterus in delayed
      implantation. After delayed implantation was terminated by estrogen treatment and
      embryo implantation was initiated, cPGES mRNA signal was strongly detected in the
      stroma underlying the luminal epithelium at the implantation site, and cPGES
      immunostaining was strongly observed in the luminal epithelium surrounding the
      implanting blastocyst. A strong cPGES mRNA signal and immunostaining were
      detected in decidualized cells under artificial decidualization, whereas only a
      basal level of cPGES mRNA signal and immunostaining were observed in the control
      horn. Our data suggest that cPGES may play an important role during implantation
      and decidualization.

PMID- 12604622
TI  - Tumor necrosis factor alpha stimulates adenylyl cyclase activity in human
      myometrial cells.
AB  - Cytokines such as tumor necrosis factor alpha (TNFalpha) have been implicated in
      amniotic fluid infections and preterm and term labor. The underlying mechanisms
      are incompletely understood. In some smooth muscle cells, TNFalpha affects
      function of the beta-adrenergic/adenylyl cyclase pathway. The present study was
      performed to examine the effects of chronic TNFalpha exposure on adenylyl cyclase
      activity in cell cultures of human myometrium. Chronic TNFalpha exposure led to a
      dose- and time-dependent increase in basal-, GTP-, NaF-, and forskolin-stimulated
      adenylyl cyclase (AC) activity. The increase in AC activity was not mediated by
      changes in the expression of the heterotrimeric G proteins G(s)alpha or G(i)alpha
      as determined by immunoblotting. In addition, increases in AC activity occurred
      in the presence of indomethacin, indicating that these changes were not provoked
      by TNFalpha-induced changes in prostaglandin production. The present results
      suggest that TNFalpha-induced increases in AC activity in human myometrial cells
      obtained from the lower uterine segment occur at the level of G-protein/AC
      interaction or at the level of the AC enzyme itself.

PMID- 12604624
TI  - A role for alphavbeta3 integrin during implantation in the rabbit model.
AB  - The study of implantation has been facilitated by the identification of specific
      biomarkers that are associated with uterine receptivity. The alpha(v)beta(3)
      integrin is a cell surface adhesion receptor, whose expression has been shown to
      be elevated in the endometrium at the time of implantation in both humans and
      other mammalian species; however, the distribution of alpha(v)beta(3) in the
      rabbit model is unknown. The rabbit has been shown to be an excellent model for
      the study of implantation. As an obligate ovulator, the timing of pregnancy can
      be precisely established, and embryonic attachment occurs through specialized
      trophoblast-endometrial structures known as trophoblastic knobs. In the present
      study, the expression of alpha(v)beta(3) integrin subunit in the rabbit uterus
      was examined by reverse transcription-polymerase chain reaction (RT-PCR),
      immunohistochemistry, and in situ hybridization. Expression of the
      alpha(v)beta(3) integrin was examined in Day 6.5 embryos, flushed from pregnant
      does. Immunofluorescence demonstrated strong immunostaining on the rabbit
      blastocyst (Day 6.5). RT-PCR analyses showed higher levels of mRNA for beta(3)
      subunit at the implantation site, with reduced expression in nonimplantation
      sites and in nonpregnant adult and immature endometrium. Immunohistochemistry
      demonstrated little, if any, beta(3) immunoreactivity on the endometrial
      epithelium. In contrast, in situ hybridization showed expression of the beta(3)
      integrin subunit mRNA in the uterine myometrium and on the trophoblast. To
      further determine the functional significance of alpha(v)beta(3) integrin
      expression during implantation, pregnant female rabbits that underwent ventral
      laparotomy on the morning of Day 6 received intrauterine injection of the
      following into the right uterine horn: 1) the monoclonal alpha(v)beta(3)
      neutralizing antibody (LM609), 2) arg-gly-asp (RGD) hexapeptides (GRGDSP), 3) non
      RGD hexapeptides (GRGESP), and 4) IgG isotype matched control antibody. The left
      horn served as a control and received only saline injections. A significant
      reduction in the number of implantation sites was observed in the horns receiving
      anti-alpha(v)beta(3) antibody (P < 0.001) and the RGD peptides (P = 0.03). In the
      rabbit, the alpha(v)beta(3) integrin is present on the embryo and trophoblast and
      appears to be involved in early embryo-maternal interaction.

PMID- 12604623
TI  - Oocyte-mediated suppression of follicle-stimulating hormone- and insulin-like
      growth factor-induced secretion of steroids and inhibin-related proteins by
      bovine granulosa cells in vitro: possible role of transforming growth factor
      alpha.
AB  - The objective was to investigate the potential role of the oocyte in modulating
      proliferation and basal, FSH-induced and insulin-like growth factor (IGF)-induced
      secretion of inhibin A (inh A), activin A (act A), follistatin (FS), estradiol
      (E(2)), and progesterone (P(4)) by mural bovine granulosa cells. Cells from 4- to
      6-mm follicles were cultured in serum-free medium containing insulin and
      androstenedione, and the effects of ovine FSH and IGF analogue (LR3-IGF-1) were
      tested alone and in the presence of denuded bovine oocytes (2, 8, or 20 per
      well). Medium was changed every 48 h, cultures were terminated after 144 h, and
      viable cell number was determined. Results are based on combined data from four
      independent cultures and are presented for the last time period only when
      responses were maximal. Both FSH and IGF increased (P < 0.001) secretion of inh
      A, act A, FS, E(2), and P(4) and raised cell number. In the absence of FSH or
      IGF, coculture with oocytes had no effect on any of the measured hormones,
      although cell number was increased up to 1.8-fold (P < 0.0001). Addition of
      oocytes to FSH-stimulated cells dose-dependently suppressed (P < 0.0001) inh A (6
      fold maximum suppression), act A (5.5-fold), FS (3.6-fold), E(2) (4.6-fold), and
      P(4) (2.4-fold), with suppression increasing with FSH dose. Likewise, oocytes
      suppressed (P < 0.001) IGF-induced secretion of inh A, act A, FS, and E(2) (P <
      0.05) but enhanced IGF-induced P(4) secretion (1.7-fold; P < 0.05). Given the
      similarity of these oocyte-mediated actions to those we observed previously
      following epidermal growth factor (EGF) treatment, we used immunocytochemistry to
      determine whether bovine oocytes express EGF or transforming growth factor (TGF)
      alpha. Intense staining with TGFalpha antibody (but not with EGF antibody) was
      detected in oocytes both before and after coculture. Experiments involving
      addition of TGFalpha to granulosa cells confirmed that the peptide mimicked the
      effects of oocytes on cell proliferation and on FSH- and IGF-induced hormone
      secretion. These experiments indicate that bovine oocytes secrete a factor(s)
      capable of modulating granulosa cell proliferation and responsiveness to FSH and
      IGF in terms of steroidogenesis and production of inhibin-related peptides,
      bovine oocytes express TGFalpha but not EGF, and TGFalpha is a prime candidate
      for mediating the actions of oocytes on bovine granulosa cells.

PMID- 12604626
TI  - Effect of vasectomy on gene expression in the epididymis of cynomolgus monkey.
AB  - Vasectomy has been shown to affect the pattern of mRNA expression of P34H, a
      human sperm protein added to the acrosomal cap during epididymal transit. It has
      been reported that vasectomy alters the histology of the reproductive tract in
      various species as a result of the increased pressure in the epididymis. The aim
      of this study was to evaluate if other epididymis-specific mRNAs, which are
      expressed in different patterns along the duct, are altered by vasectomy as well.
      We analyzed the expression of P31m (a monkey homologue of human P34H) and three
      different HE-like (HE-l) mRNAs along the epididymis in the cynomolgus monkey
      (Macaca fascicularis). Sexually mature cynomolgus monkeys were vasectomized
      unilaterally; then the epididymides were surgically removed at different time
      points. The ipsilateral normal epididymis was used as a control.
      Histomorphometric measurements showed that the height of the epididymal
      epithelial cells started to be affected only at 14 wk postsurgery. However,
      Northern blot and in situ hybridization analysis showed that the expression
      pattern of P31m, HE1, and HE5-like mRNA along the epididymis was not affected by
      vasectomy. Only the HE2-like mRNA predominantly expressed in the normal corpus
      epididymidis was significantly lowered 14 wk after vasectomy. Thus, ductal
      obstruction differentially alters mRNA expression along the epididymis of the
      cynomolgus monkey.

PMID- 12604625
TI  - Ovine placental lactogen specifically binds to endometrial glands of the ovine
      uterus.
AB  - A hormonal servomechanism has been proposed to regulate differentiation and
      function of the endometrial glandular epithelium (GE) in the ovine uterus during
      pregnancy. This mechanism involves sequential actions of estrogen, progesterone,
      ovine interferon tau (IFNtau), placental lactogen (oPL), and placental growth
      hormone (oGH). The biological actions of oPL in vitro are mediated by
      homodimerization of the prolactin receptor (oPRLR) and heterodimerization of the
      oPRLR and oGH receptor. The objectives of the study were to determine the effects
      of intrauterine oPL, oGH, and their combination on endometrial histoarchitecture
      and gene expression and to localize and characterize binding sites for oPL in the
      ovine uterus in vivo using an in situ ligand binding assay. Intrauterine infusion
      of oPL and/or oGH following IFNtau into ovariectomized ewes treated with
      progesterone daily differentially affected endometrial gland number and
      expression of uterine milk proteins and osteopontin. However, neither hormone
      affected PRLR, insulin-like growth factor (IGF)-I, or IGF-II mRNA levels in the
      endometrium. A chimeric protein of placental secretory alkaline phosphatase
      (SEAP) and oPL was used to identify and characterize binding sites for oPL in
      frozen sections of interplacentomal endometrium from pregnant ewes. Specific
      binding of SEAP-oPL was detected in the endometrial GE on Days 30, 60, 90, and
      120 of pregnancy. In Day 90 endometrium, SEAP-oPL binding to the endometrial GE
      was displaced completely by oPL and prolactin (oPRL) but only partially by oGH.
      Binding experiments using the extracellular domain of the oPRLR also showed that
      iodinated oPL binding sites could be competed for by oPRL and oPL but not by oGH.
      Collectively, results indicate that oPL binds to receptors in the endometrial
      glands and that oPRL is more effective than oGH in competing for these binding
      sites. Thus, effects of oPL on the endometrial glands may be mediated by
      receptors for oPRL and oGH.

PMID- 12604627
TI  - Biphasic effects of leptin in porcine granulosa cells.
AB  - The direct effects of recombinant porcine leptin on porcine granulosa cells were
      studied to test the hypothesis that leptin, acting through the nuclear
      transcription factor signal transducer and activator of transcription 3 (STAT-3),
      modulates sterol regulatory element-binding protein 1 (SREBP1) thereby increasing
      steroidogenesis. In porcine granulosa cells in culture over 48 h, leptin at 10
      ng/ml increased progesterone accumulation 3-fold while it was reduced by leptin
      at 1000 ng/ml. Leptin had no effect on progression of granulosa cells through the
      cell cycle nor on the frequency of cell death. Leptin treatment at 24 or 48 h of
      culture resulted in dose-dependent 2- to 4-fold increases in tyrosine
      phosphorylation of STAT-3. Leptin had a biphasic effect on the abundance of
      membrane-bound and transcriptionally active forms of SREBP1. In transient
      transfection of primary porcine granulosa cells, the plasmid expressing the
      transcriptionally active form of SREPB-1 induced transcription of the key
      regulator of steroidogenesis, the steroidogenic acute regulatory protein (StAR).
      StAR transcription was also increased by the low dose of leptin and was further
      upregulated in the presence of the SREBP plasmid. Leptin at 1000 ng/ml inhibited
      SREBP1-induced StAR expression. Thus, leptin, acting through STAT-3, modulates
      steroidogenesis in a biphasic and dose-dependent manner, and SREBP1 induction of
      StAR expression may be in the cascade of regulatory events.

PMID- 12604628
TI  - Epidermal growth factor-receptor tyrosine kinase activity regulates expansion of
      porcine oocyte-cumulus cell complexes in vitro.
AB  - We have recently shown that epidermal growth factor (EGF) strongly stimulates
      expansion of porcine oocyte-cumulus complexes (OCCs) isolated from large
      follicles (>6 mm) and does not promote expansion of OCCs from small (3-4-mm)
      follicles. In order to elucidate the role of EGF in OCCs expansion, in the
      present study, we first examined the presence of EGF receptors (EGFRs) in cumulus
      cells isolated from follicles of different sizes. Surprisingly, immunoblotting
      showed that cumulus cells obtained from all follicular size categories contained
      similar amounts of EGFR protein. On the other hand, we found a dramatic
      difference in the pattern of protein tyrosine phosphorylation in a comparison of
      cumulus cells isolated from small and large follicles treated by EGF.
      Furthermore, tyrosine-phosphorylated EGFR was specifically immunoprecipitated
      with antiphosphotyrosine antibodies from EGF-treated cumulus cells isolated from
      the large follicles. This result strongly indicates that only OCCs from the large
      follicles contain mature EGFRs that are capable of becoming activated by EGF.
      Remarkably, preincubation of cumulus cells from small follicles (3-4 mm) with FSH
      strongly increased EGF-stimulated tyrosine phosphorylation to levels comparable
      with OCCs from large follicles. The FSH-dependent activation of EGFRs was
      beneficial for expansion of OCCs isolated from the small follicles since OCCs
      treated sequentially by FSH (3 h) and EGF (1 h) underwent expansion significantly
      better then OCCs cultured in FSH or EGF alone. We conclude that a FSH-dependent
      pathway has an important role in the maturation of the EGFR in cumulus cells and
      that activation of EGFR-dependent signaling is sufficient to induce expansion.

PMID- 12604630
TI  - Assessment of oocyte quality following repeated gonadotropin stimulation in the
      mouse.
AB  - The present study assessed the effects of repeated ovarian stimulation on oocyte
      quality. Female mice were stimulated with eCG and hCG at 1-wk intervals for 4 wk.
      Germinal vesicle (GV)-stage oocytes were evaluated in relation to size, somatic
      cell association, and chromatin organization after each week of stimulation. In
      addition, ATP content and expression of meiotic competence were monitored in GV
      and in vivo (IVO) or in vitro (IVM)-matured oocytes. The developmental competence
      of ovulated oocytes was determined after in vitro fertilization and embryo
      culture, and reproductive outcome was evaluated after mating following repeated
      cycles of stimulation. In GV oocytes, the degree of somatic cell association,
      size, and timing of transcriptional repression were altered when comparing
      repeated with single cycle(s) of stimulation. Meiotic competence expression was
      unaffected for IVO oocytes while IVM oocytes exhibited a progressive decrease in
      meiotic competence with repeated stimulation. The ATP content of immature and IVO
      oocytes decreased with repeated stimulation. Although after one cycle of
      stimulation ATP content was lower in IVM than IVO oocytes, IVM oocytes exhibited
      stable levels of ATP across cycles of stimulation. Last, the in vitro
      developmental competence of IVO oocytes retrieved after repeated stimulation was
      not significantly different, and in vivo, similar implantation and resorption
      rates were observed following mating of animals subjected to repeated
      stimulation. Therefore, despite measurable consequences of repeated stimulation
      on specific parameters of follicular oocyte quality, compensatory mechanisms may
      exist in vivo to optimize the developmental competence of ovulated oocytes in the
      mouse.

PMID- 12604629
TI  - Expression of messenger RNA for prostaglandin E receptor subtypes EP4/EP2 and
      cyclooxygenase isozymes in mouse periovulatory follicles and oviducts during
      superovulation.
AB  - Prostaglandin (PG) E(2) is synthesized from arachidonic acid by cyclooxygenase
      (COX) and acts as a regulator in ovulation and fertilization reactions. We
      present the temporal and regional expression patterns of mRNAs for the two Gs
      coupled PGE receptors, EP2 and EP4, and for COX-1 and COX-2 in mouse
      periovulatory follicles and oviducts during superovulation. Analysis using
      reverse transcription polymerase chain reaction revealed that the mouse ovaries
      express a significant amount of EP4 mRNA in addition to EP2 mRNA during
      superovulation. In situ hybridization results revealed that the signals for EP4
      mRNA were localized mostly to oocytes in the preantral follicles. Three hours
      after hCG injection, the signals for EP4 and EP2 mRNA were present in both
      granulosa and cumulus cells. However, 9 h after hCG injection, just before
      ovulation, the signals for EP4 mRNA were still detectable in both cell types,
      whereas those for EP2 mRNA were found only in cumulus cells. COX-2 mRNA
      expression was present in both granulosa and cumulus cells at 3 h but was present
      only in cumulus cells at 9 h. COX-1 mRNA expression was not found in granulosa
      cells at 3 h but was found in these cells at 9 h. In the oviduct, the expression
      of EP4 and COX-1 mRNA was localized to epithelial cells, whereas expression of
      EP2 mRNA was localized to the smooth muscle layer. The tightly regulated
      expression of both EP2 and EP4 in the preovulatory follicles may reflect the
      essential role of PGE(2) in the ovulation process.

PMID- 12604631
TI  - Plasma concentrations of inhibin a and follicle-stimulating hormone differ
      between cows with two or three waves of ovarian follicular development in a
      single estrous cycle.
AB  - Patterns of ovarian follicle development were monitored daily in Holstein
      Friesian cows that had two (n = 4) or three (n = 4) waves of ovarian follicle
      development during a single estrous cycle. The plasma from daily blood samples
      was used in assays for inhibin A, FSH, progesterone, and estradiol-17beta. Mean
      cycle lengths for cows with two and three waves were 21.8 and 25.3 days,
      respectively (P < 0.02). Although the average number of follicles >3-mm diameter
      on each pair of ovaries was similar for two- and three-wave cows on Days 2, 3,
      and 4 (Day 0 = day of ovulation; 8.6 vs. 9.6 follicles), there were more
      follicles >6-mm diameter on the ovaries of cows with two waves on Days 3 and 4.
      This difference was associated with a shorter interval from wave emergence to
      peak concentrations of inhibin A during the first wave in two-wave cows (2.0 vs.
      3.8 days; P = 0.03) and with higher peak concentrations (474 vs. 332 pg/ml; P =
      0.03). Differences in peak FSH concentrations were not significant (1.7 vs. 1.3
      ng/ml; P = 0.10) and were inversely related to inhibin A concentrations. The peak
      concentrations of inhibin A and FSH in the second nonovulatory wave in the three
      wave cows were similar to the low concentrations measured in the first wave (292
      vs. 332 pg/ml of inhibin A, 1.3 vs. 1.3 ng/ml of FSH; P > 0.20). Average peak
      concentrations of inhibin A and FSH were similar during the ovulatory wave for
      cows with either two or three waves in a cycle (432 vs. 464 pg/ml of inhibin A,
      2.3 vs. 2.1 ng/ml of FSH; P > 0.3). The lower concentrations of FSH during the
      emergence of the first follicular wave in cows with three-wave cycles may have
      reduced the rate of development of some of the follicles and reduced the
      concentrations of inhibin A. This pattern of lower concentrations of FSH and
      inhibin A was repeated in the second nonovulatory wave but not in the ovulatory
      wave. Subtle differences in the concentrations of these two hormones may underlie
      the mechanism that influences the number of waves of ovarian follicle development
      that occur during the bovine estrous cycle.

PMID- 12604632
TI  - Development of parthenogenetic rat embryos.
AB  - In an effort to establish cloning technology for the rat, we tested several
      methods (electric stimulation, treatment with ethanol or strontium) for the
      parthenogenetic activation of rat oocytes. We observed marked individual
      differences among rats of the outbred Wistar strain in their ability to yield
      activatable oocytes. These differences were independent of the activation
      protocol and may be due to a genetic predisposition that is crucial for the
      parthenogenetic activation of oocytes. The activation of oocytes was dependent
      upon the time between superovulation of the donor animal and the collection of
      the embryos. Aged oocytes (derived about 24 h after superovulation) were more
      prone to activation by each method than were younger oocytes, and some even
      underwent spontaneous activation without treatment and exhibited pronuclear
      formation and blastocyst development. All activation methods were effective in
      generating parthenogenetic rat embryos, and rat parthenotes developed until
      implantation. However, in general, short-term (15 min) and long-term (2 h)
      strontium treatment was superior to stimulation by ethanol or electric pulse for
      parthenogenetic activation. These results will be helpful in achieving successful
      cloning in the rat.

PMID- 12604633
TI  - Remodeling of the actin cytoskeleton during mammalian sperm capacitation and
      acrosome reaction.
AB  - The sperm acrosome reaction and penetration of the egg follow zona pellucida
      binding only if the sperm has previously undergone the poorly understood
      maturation process known as capacitation. We demonstrate here that in vitro
      capacitation of bull, ram, mouse, and human sperm was accompanied by a time
      dependent increase in actin polymerization. Induction of the acrosome reaction in
      capacitated cells initiated fast F-actin breakdown. Incubation of sperm in media
      lacking BSA or methyl-beta-cyclodextrin, Ca(2+), or NaHCO(3), components that are
      all required for capacitation, prevented actin polymerization as well as
      capacitation, as assessed by the ability of the cells to undergo the acrosome
      reaction. Inhibition of F-actin formation by cytochalasin D blocked sperm
      capacitation and reduced the in vitro fertilization rate of metaphase II-arrested
      mouse eggs. It has been suggested that protein tyrosine phosphorylation may
      represent an important regulatory pathway that is associated with sperm
      capacitation. We show here that factors known to stimulate sperm protein tyrosine
      phosphorylation (i.e., NaHCO(3), cAMP, epidermal growth factor, H(2)O(2), and
      sodium vanadate) were able to enhance actin polymerization, whereas inhibition of
      tyrosine kinases prevented F-actin formation. These data suggest that actin
      polymerization may represent an important regulatory pathway in with sperm
      capacitation, whereas F-actin breakdown occurs before the acrosome reaction.

PMID- 12604634
TI  - Evidence that estrogen receptor alpha, but not beta, mediates seasonal changes in
      the response of the ovine retrochiasmatic area to estradiol.
AB  - In ewes, anestrus results from a reduction in LH pulsatility due to an increased
      sensitivity of the hypothalamic estradiol negative feedback system. Considerable
      evidence has implicated the A15 group of dopaminergic neurons in the
      retrochiasmatic area in this seasonally dependent estradiol effect. Moreover,
      estradiol administered to the retrochiasmatic area in ovariectomized anestrous
      ewes inhibits LH secretion. However, A15 neurons do not appear to contain the
      classical estrogen receptors (ERalpha). Therefore, we tested the hypothesis that
      beta-estrogen receptors mediate the action of estradiol in the retrochiasmatic
      area by comparing the effects of estradiol and genistein, a selective ERbeta
      agonist. We also examined whether there are seasonal changes in response of the
      retrochiasmatic area to these agonists and if these effects are mediated by
      dopamine. To test these hypotheses, ovariectomized ewes were implanted with
      bilateral guide cannulae targeting the retrochiasmatic area. Crystalline agonists
      were administered via microimplants inserted down the cannulae. Blood samples
      taken before and 4 days after microimplant insertion were analyzed for LH
      concentrations, pulse frequency, and amplitude. Genistein treatment produced no
      significant change in LH levels in either season. Estradiol treatment decreased
      both mean LH concentrations and pulse frequency in anestrous but not breeding
      season ewes. Administration of the dopamine antagonist sulpiride to
      ovariectomized ewes with estradiol microimplants in the retrochiasmatic area
      returned LH pulse frequency to levels indistinguishable from controls. From these
      data, we hypothesize that estradiol acts on local ERalpha-containing neurons in
      this area to stimulate a dopaminergic pathway that inhibits LH secretion during
      anestrus.

PMID- 12604635
TI  - Mouse testis brain RNA-binding protein/translin selectively binds to the
      messenger RNA of the fibrous sheath protein glyceraldehyde 3-phosphate
      dehydrogenase-S and suppresses its translation in vitro.
AB  - The testis brain RNA-binding protein (TB-RBP/translin) is a DNA- and RNA-binding
      protein with multiple functions. As an RNA-binding protein, TB-RBP binds to
      conserved sequence elements often present in the 3' untranslated regions (UTRs)
      of specific mRNAs modulating their translation and transport. To identify
      additional mRNA targets of TB-RBP, immunoprecipitation and reverse transcription
      polymerase chain reaction (RT-PCR) assays were carried out using an affinity
      purified antibody to TB-RBP with testicular extracts. Gapds mRNA was found to be
      selectively precipitated in a TB-RBP-mRNA complex. Consistent with the delayed
      translation of GAPDS and the subcellular ribonucleoprotein location of TB-RBP,
      polysomal gradient analysis showed that most of the Gapds mRNA in adult testis
      extracts was present in the nonpolysomal fractions. In vitro translation assays
      revealed that Gapds mRNA translation was inhibited by recombinant TB-RBP or by a
      TB-RBP mutant protein, Nb, capable of binding RNA. No inhibition was seen with
      mutant forms of TB-RBP lacking domains required for RNA binding, including the TB
      RBP Cb mutant and the C-terminal-truncated form of TB-RBP that disrupts the
      leucine zipper. As an additional indicator of the specificity of TB-RBP
      inhibition of Gapds mRNA translation, a putative TB-RBP binding H-element was
      deleted from the 5' UTR of the Gapds mRNA. No translational inhibition by
      recombinant TB-RBP was seen with Gapds mRNA lacking the H element. These data
      suggest that TB-RBP is involved in the posttranscriptional regulation of Gapds
      gene expression during spermiogenesis. Moreover, the Gapds mRNA is the first mRNA
      shown to have a functional TB-RBP binding site in its 5' UTR.

PMID- 12604636
TI  - Determinants of retroviral-mediated gene delivery to mouse spermatogonia.
AB  - Spermatogonia represent a new route to transgenesis in mice and potentially in
      some commercially important domesticated animals. In addition, these cells are
      also a potential target for viral integration in patients receiving somatic cell
      gene therapy. But the factors influencing retroviral transduction into
      spermatogonia are not well understood. Because retroviral transduction is
      affected in part by the proliferative status of the host cell, we developed an
      improved cell culture system in which spermatogonia survive and proliferate for
      several days. We used this system to test the ability of a variety of murine and
      avian retroviruses to infect spermatogonia. We investigated the factors
      influencing retroviral transduction of spermatogonia, including the proliferative
      status of the infected cell, the type of viral envelope, the type of retroviral
      long terminal repeat, and the method of viral delivery. Here we show that many of
      the widely used retroviral vector systems can be used to successfully transduce
      spermatogonia at high efficiency. Moreover, we show that retroviral delivery of
      MDM2, the major downregulator of p53, promotes spermatogonial survival in
      culture, suggesting that p53 plays a role in regulating spermatogonial apoptosis
      induced by growth factor deprivation. These results further demonstrate the
      usefulness of this novel system of targeting substances of interest to the
      testis. These data have important implications for improving animal transgenesis
      and for understanding the risks associated with somatic cell gene therapy.

PMID- 12604637
TI  - Prenatal exposure to estrogenic compounds alters the expression pattern of
      platelet-derived growth factor receptors alpha and beta in neonatal rat testis:
      identification of gonocytes as targets of estrogen exposure.
AB  - We examined the effects of maternal exposure to estrogens on platelet-derived
      growth factor (PDGF) receptor (PDGFR) expression in newborn rat testis. Pregnant
      rats were treated from gestation Day 14 to birth with corn oil containing
      diethylstilbestrol, bisphenol A, genistein, or coumestrol by gavage or
      subcutaneous injection. These treatments induced a dose-dependent increase in the
      expression of PDGFR alpha and beta mRNAs, determined by semiquantitative reverse
      transcription polymerase chain reaction, though diethylstilbestrol had a biphasic
      effect on both mRNAs. In situ hybridization analysis showed that PDGFRalpha mRNA
      increased mostly in the interstitium, while PDGFRbeta mRNA increased both in the
      interstitium and seminiferous cords. Immunohistochemical studies of PDGFRalpha
      and beta proteins revealed that both receptors were present in testis before and
      after birth and that they were upregulated upon treatment with estrogens in 3-day
      old rats, with PDGFRbeta increasing dramatically in gonocytes. PDGFRalpha and
      beta mRNAs and proteins were also found in purified gonocytes. Our previous
      finding that PDGF and 17beta-estradiol induce gonocyte proliferation in vitro,
      together with the present finding that in vivo exposure to estrogens upregulates
      PDGF receptors in testis, suggest that PDGF pathway is a target of estrogens in
      testis. In addition, these data identify PDGFRbeta in gonocytes as a major target
      of gestational estrogen exposure, suggesting that estrogen may have a
      physiological interaction with PDGF during gonocyte development. These results,
      however, do not exclude the possibility that the effects of the compounds
      examined in this study might be due to estrogen receptor-independent action(s).

PMID- 12604638
TI  - Successful cryopreservation of mouse ovaries by vitrification.
AB  - We developed a new method of cryopreservation of whole ovaries by vitrification
      using DAP213 (2 M dimethyl sulfoxide, 1 M acetamide, and M propylene glycol) as a
      cryoprotectant. Four-week-old C57BL/6 mice that underwent partial ovariectomy
      were orthotopically transplanted with cryopreserved or fresh ovaries
      (experimental or control group) isolated from 10-day-old green fluorescent
      protein (GFP)-transgenic mice (+/+). GFP-positive pups were similarly obtained
      from both groups by natural mating or in vitro fertilization (IVF) followed by
      embryo transfer, indicating that the cryopreserved ovaries by vitrification
      retain their fecundity. However, a statistically significant difference (P <
      0.05) was found between both groups with respect to the following parameters: the
      number of GFP-positive pups born by natural mating/grafted ovary (0.8 +/- 0.3 for
      the experimental group versus 2.0 +/- 0.7 for the control group, mean +/- SEM),
      the number of collected oocytes by superovulation per mouse (7.0 +/- 1.7 for the
      experimental group versus 22.7 +/- 3.2 for the control group), the percentage of
      two-cell embryos obtained from GFP-positive oocytes by IVF (38.5% for the
      experimental group versus 90.0% for the control group). Histologically, normal
      development of follicles and formation of corpora lutea were observed in frozen
      thawed grafts. However, estimated number of follicles decreased in frozen-thawed
      ovaries compared with fresh ovaries. Taken together, cryopreservation of the
      ovary by vitrification seems a promising method to preserve ovarian function, but
      further studies are required to overcome the possible inhibitory effects of this
      method on the growth of the ovarian graft.

PMID- 12604639
TI  - Epididymal phenotype in luteinizing hormone receptor knockout animals and its
      response to testosterone replacement therapy.
AB  - Previous studies reported that epididymis contains functional LH receptors. The
      LH receptor knockout mice, which have epididymal phenotypes, gave us an
      opportunity to test the hypothesis that testosterone replacement alone may not be
      sufficient to reverse phenotypes to wild-type epididymis. The morphological
      phenotype in knockout animals includes a decrease in luminal diameter of the
      proximal and distal caput and cauda epididymis, the absence of clear and halo
      cells in the epithelial lining, a decrease in the height of principal cells and
      the number of cells containing cilia, a decrease in cilia length, and a change
      from basal to central location of nuclei in the principal cells. The biochemical
      phenotype includes a decrease in periodic acid-Schiff reaction product,
      reflecting the glycogen and glycoprotein synthesis and secretion, a decrease in
      androgen receptor (AR) and estrogen receptor (ER)beta, and an increase in ERalpha
      levels. Twenty-one-day testosterone replacement therapy in 30-day-old knockout
      animals reversed some, but not all, morphological and biochemical phenotypes.
      Those that did not reverse include luminal diameters of proximal and distal caput
      and cauda epididymis, the percentage of ciliated principal cells in caput
      epididymis, and nuclear AR localization. In summary, while our results reaffirm
      that androgens are important for normal epididymal morphology and function, they
      indicate that LH could be required for certain facets of epididymal morphology
      and/or function.

PMID- 12604640
TI  - Copper-deficient rat embryos are characterized by low superoxide dismutase
      activity and elevated superoxide anions.
AB  - The teratogenicity of copper (Cu) deficiency may result from increased oxidative
      stress and oxidative damage. Dams were fed either control (8.0 microg Cu/g) or Cu
      deficient (0.5 microg Cu/g) diets. Embryos were collected on Gestational Day 12
      for in vivo studies or on Gestational Day 10 and cultured for 48 h in Cu
      deficient or Cu-adequate media for in vitro studies. Superoxide dismutase (SOD),
      glutathione peroxidase (GPX), and glutathione reductase (GR) activities were
      measured in control and Cu-deficient embryos as markers of the oxidant defense
      system. Superoxide anions were measured as an index of exposure to reactive
      oxygen species (ROS). No differences were found in GPX or GR activities among
      treatment groups. However, SOD activity was lower and superoxide anion
      concentrations higher in Cu-deficient embryos cultured in Cu-deficient serum
      compared to control embryos cultured in control serum. Even so, Cu-deficient
      embryos had similar CuZnSOD protein levels as controls. In the in vitro system,
      Cu-deficient embryos had a higher frequency of malformations and increased
      staining for superoxide anions in the forebrain, heart, forelimb, and somites
      compared to controls. When assessed for lipid and DNA oxidative damage,
      conjugated diene concentrations were similar among the groups, but a tendency was
      observed for Cu-deficient embryos to have higher 8-hydroxy-2'-deoxyguanosine
      concentrations than controls. Thus, Cu deficiency resulted in embryos with
      malformations and reduced SOD enzyme activity. Increased ROS concentrations in
      the Cu-deficient embryo may cause oxidative damage and contribute to the
      occurrence of developmental defects.

PMID- 12604641
TI  - Zona pellucida induces activation of phospholipase A2 during acrosomal exocytosis
      in guinea pig spermatozoa.
AB  - Phospholipase A(2) (PLA(2)) is activated in spermatozoa in response to
      progesterone and Ca(2+) ionophores, but to our knowledge, no study has yet
      reported zona pellucida (ZP)-induced activation of PLA(2). We investigated
      whether PLA(2) is involved in ZP-stimulated acrosomal exocytosis, if Ca(2+) is
      required for activation of PLA(2), and signal transduction pathways modulating
      PLA(2) using guinea pig sperm as a model. Spermatozoa were capacitated and
      labeled in low-Ca(2+) medium with [(14)C]choline chloride or [(14)C]arachidonic
      acid and were then exposed to millimolar Ca(2+) and various reagents and
      stimulated with ZP. Precapacitated spermatozoa exposed to millimolar Ca(2+) and
      stimulated with ZP experienced increases in arachidonic acid (AA) and
      lysophosphatidylcholine (lysoPC) levels and a parallel decrease in
      phosphatidylcholine level; these changes are indicative of PLA(2) activation.
      Simulation with ZP also led to acrosomal exocytosis in a high proportion of
      spermatozoa. Lipid changes and exocytosis were prevented if spermatozoa were
      exposed to aristolochic acid, a PLA(2) inhibitor, before treatment with ZP.
      Stimulation with ZP in medium without added Ca(2+) or in medium with millimolar
      Ca(2+) and EGTA or La(3+) resulted in no lipid changes or exocytosis.
      Pretreatment with pertussis toxin, a G(i) protein inhibitor, before stimulation
      with ZP blocked the release of AA and lysoPC as well as acrosomal exocytosis.
      Exposure of spermatozoa to the diacylglycerol (DAG) kinase inhibitor R59022
      before ZP stimulation led to a significant increase in generation of lysoPC and
      exocytosis. Taken together, these results indicate very strongly that PLA(2)
      plays an essential role in ZP-induced exocytosis in spermatozoa, that PLA(2)
      activation requires Ca(2+) internalization, and that PLA(2) activation is
      regulated by signal transduction pathways involving G proteins and DAG.

PMID- 12604643
TI  - Numerical chromosome errors in day 7 somatic nuclear transfer bovine blastocysts.
AB  - Day 7 bovine somatic nuclear transfer (NT) embryos reconstructed from granulosa
      cells were examined for numerical chromosome aberrations as a potential cause of
      the high embryonic and fetal loss observed in such embryos after transfer. The NT
      embryos were reconstructed using a zona-free manipulation method: half-cytoplasts
      were made from zona-free oocytes by bisection, after which two half-oocytes and
      one granulosa cell (serum-starved primary culture) were fused together and
      activated. The NT embryos were cultured in modified synthetic oviductal fluid
      containing essential and nonessential amino acids, myoinositol, sodium citrate,
      and 5% cattle serum in microwells for 7 days, at which time nuclei from all
      blastocysts were extracted and chromosome aberrations were evaluated using dual
      color fluorescent in situ hybridization with bovine chromosome 6- and 7-specific
      probes. Five embryo clone families, consisting of 112 blastocysts reconstructed
      from five different primary granulosa cell cultures, were examined. Overall, the
      mean chromosome complement within embryos was 86.9 +/- 3.7% (mean +/- SEM)
      diploid, 2.6 +/- 0.5% triploid, 10.0 +/- 3.1% tetraploid, and 0.5 +/- 0.2%
      pentaploid or greater; the vast majority (>75%) of the abnormal nuclei were
      tetraploid. Completely diploid and mixoploid embryos represented 22.1 +/- 4.5%
      and 73.7 +/- 5.5%, respectively, of all clones. Six totally polyploid
      blastocysts, containing <or=91 nuclei, were recorded. The ploidy distributions
      (classified as 2N, 3N, 4N, and >or=5N chromosome complements, respectively)
      between two clone families were different (P < 0.01), as were blastocyst yields
      between other clone families (P < 0.01). Blastocyst yield was not correlated to %
      total ploidy error between clone families, but an inverse relationship (P < 0.01)
      between blastocyst total cell number and total % chromosome abnormality was
      observed within embryos. Categorization of the blastocysts into three quality
      grades (good, medium, and poor) and comparison of the distribution of ploidies
      when classified into 0%, 0.1-5.0%, 5.1-10.0%, 10.1-15.0%, and 15.1-100% errors
      within embryos indicated that medium- and poor-grade embryos were different (P <
      0.05) from good-quality, in vitro-produced embryos. In a separate study, 11
      different granulosa cell cultures (that did not correspond to those used for NT)
      were evaluated and found to possess only 0.23 +/- 0.12% ploidy errors. These
      results demonstrate that 1) the percentage of ploidy errors in bovine NT
      blastocysts is inversely related to total blastocyst cell number, 2) the
      mixoploid condition is representative of the majority of embryos, 3) 100%
      polyploid NT blastocysts can exist, and 4) the ploidy errors seem not to be
      derived from the donor cells.

PMID- 12604642
TI  - Expression of progesterone receptor (PR) A and B isoforms in mouse granulosa
      cells: stage-dependent PR-mediated regulation of apoptosis and cell
      proliferation.
AB  - The intracellular progesterone receptor (PR) in the mammalian ovary is a part of
      the physiological pathway that facilitates ovulation. Two PR isoforms (A and B)
      exist, with different molecular and biological functions. Previous studies have
      revealed that the cellular ratio of the PR isoforms is important for progesterone
      responsive tissues and is under developmental control in different species.
      However, the relative expression of PR isoforms in the ovary is unknown. In this
      study we have demonstrated first that the expression of both PR isoforms in mouse
      granulosa cells was rapidly up-regulated by hCG treatment and dramatically down
      regulated when the granulosa cells were undergoing luteinization. The relative
      level of protein expression of the A and B forms was 2:1 and the highest total PR
      protein expression was found after hCG stimulation. Second, we demonstrated that
      the expression of PR protein was specific to granulosa cells of periovulatory
      follicles and was absent in undifferentiated granulosa cells of growing
      follicles. It was not detected in other cell types (i.e., corpora lutea or any
      stage of follicles with features of apoptosis). Third, we demonstrated that
      treatment with the PR antagonist RU 486 in vivo resulted in down-regulation of
      both isoforms in parallel with increased activation of caspase-3, a decreased
      level of proliferating cell nuclear antigen, and a reduced rate of ovulation.
      Fourth, we demonstrated, in vitro, that the PR antagonists RU 486 and Org 31710
      increased internucleosomal DNA fragmentation parallel with a decrease in DNA
      synthesis in granulosa cells, which express PR. These results indicate that PR
      and its isoforms participate in regulation of ovulation, along with suppression
      of granulosa cell apoptosis and promotion of cell survival in the mouse ovary.

PMID- 12604644
TI  - Maternal regulation of milk composition, milk production, and pouch young
      development during lactation in the tammar wallaby (Macropus eugenii ).
AB  - Specific changes in milk composition during lactation in the tammar wallaby
      (Macropus eugenii) were correlated with the ages of the developing pouch young
      (PY). The present experiment was designed to test the hypothesis that the sucking
      pattern of the PY determines the course of mammary development in the tammar
      wallaby. To test this hypothesis, groups of 60-day-old PY were fostered
      repeatedly onto one group of host mothers so that a constant sucking stimulus on
      the mammary gland was maintained for 56 days to allow the lactational stage to
      progress 42 days ahead of the age of the young. Analysis of the milk in fostered
      and control groups showed the timing of changes in the concentration of protein
      and carbohydrate were essentially unaffected by altering the sucking regime. The
      only change in milk protein secretion was a small delay in the timing of down
      regulation of the secretion of whey acidic protein and early lactation protein in
      the host tammars. In addition, the rates of growth and development of the foster
      PY were significantly increased relative to those of the control PY because of
      ingesting more milk with a higher energy content and different composition than
      normal for their age. The present study demonstrates that the lactating tammar
      wallaby regulates both milk composition and the rate of milk production and that
      these determine the rates of PY growth and development, irrespective of the age
      of the PY.

PMID- 12604645
TI  - Contraction of cultured human uterine smooth muscle cells after stimulation with
      endothelin-1.
AB  - To our knowledge, the problem of how to maintain isolated smooth cells in a
      "contractile" phenotypic state without deviation after subculturing has yet to be
      resolved. The present study characterized the in vitro contractile response of
      human uterine smooth muscle cell to endothelin-1, which induces contractions in
      isolated uterine strips. Contractile effects were qualitatively investigated
      using silicone rubber substrata. Endothelin-1 was able to distort and reduce the
      wrinkles in the silicone surface. Contractions were also quantified by measuring
      the resulting change in the collagen lattice area. Endothelin-1 significantly
      increased the contractile response in a dose-dependent manner by selectively
      activating endothelin A receptors. When myometrial cells were cultured within
      collagen lattices, a microfilament-disrupting agent, cytochalasin B, abolished
      contractions, and no change was observed in smooth muscle alpha-actin
      immunostaining. Taken together, these observations show that the uterine smooth
      muscle cells are contractile and respond appropriately to a potent uterotonic
      agent. Based on these findings, a cultured uterine smooth muscle cell model,
      which could be used to elucidate the mechanisms controlling uterine activity, is
      proposed.

PMID- 12604646
TI  - Rotation of meiotic spindle is controlled by microfilaments in mouse oocytes.
AB  - The completion of meiosis requires the spatial and temporal coordination of
      cytokinesis and karyokinesis. During meiotic maturation, many events, such as
      formation, location, and rotation of the meiotic spindle as well as chromosomal
      movement, polar body extrusion, and pronuclear migration, are dependent on
      regulation of the cytoskeleton system. To study functions of microfilaments in
      meiosis, we induced metaphase II (MII) mouse oocytes to resume meiosis by in
      vitro fertilization or parthenogenetic activation, and we treated such oocytes
      with cytochalasin B (CB). The changes of the meiotic spindle, as visualized in
      preparations stained for beta-tubulin and chromatin, were observed by fluorescent
      confocal microscopy. The meiotic spindle of MII oocytes was observed to be
      parallel to the plasmalemma. After meiosis had resumed, the spindle rotated to
      the vertical position so that the second polar body could be extruded into the
      perivitelline space. When meiosis resumed and oocytes were treated with 10 micro
      g/ml of CB, the spindle rotation was inhibited. Consequently, the oocyte formed
      an extra pronucleus instead of extruding a second polar body. These results
      indicate that spindle rotation is essential for polar body extrusion; it is the
      microfilaments that play a crucial role in regulating rotation of the meiotic
      spindle.

PMID- 12604647
TI  - Amino acid-permeable anion channels in early mouse embryos and their possible
      effects on cleavage.
AB  - Effects of several Cl(-) channel blockers on ionic currents in mouse embryos were
      studied using whole-cell patch-clamp and microelectrode methods. Microelectrode
      measurements showed that the resting membrane potential of early embryonic cells
      (1-cell stage) was -23 mV and that reduction of extracellular Cl(-) concentration
      depolarized the membrane, suggesting that Cl(-) conductance is a major
      contributor for establishing the resting membrane potential. Membrane currents
      recorded by whole-cell voltage clamp showed outward rectification and confirmed
      that a major component of these embryonic currents are carried by Cl(-) ions. A
      Cl(-) channel blocker, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS),
      suppressed the outward rectifier current in a voltage- and concentration
      dependent manner. Other Cl(-) channel blockers (5-nitro-2-[3-phenylpropyl-amino]
      benzoic acid and 2-[3-(trifluoromethyl)-anilino] nicotinic acid [niflumic acid])
      similarly inhibited this current. Simultaneous application of niflumic acid with
      DIDS further suppressed the outward rectifier current. Under high osmotic
      condition, niflumic acid, but not DIDS, inhibited the Cl(-)current, suggesting
      the presence of two types of Cl(-) channels: a DIDS-sensitive (swelling
      activated) channel, and a DIDS-insensitive (niflumic acid-sensitive) Cl(-)
      channel. Anion permeability of the DIDS-insensitive Cl(-) current differed from
      that of the compound Cl(-) current: Rank order of anion permeability of the DIDS
      sensitive Cl(-) channels was I(-) = Br(-) > Cl(-) > gluconate(-), whereas that of
      the DIDS-insensitive Cl(-) channel was I(-) = Br(-) > Cl(-) >> gluconate(-).
      These results indicate that early mouse embryos have a Cl(-) channel that is
      highly permeable to amino acids, which may regulate intracellular amino acid
      concentration.

PMID- 12604649
TI  - Successful intra- and interspecific male germ cell transplantation in the rat.
AB  - The lumen of the seminiferous tubules has hitherto been regarded as an
      immunologically privileged site. We report here the birth of young following
      transplantation of stem spermatogonia from Long-Evans rats to the seminiferous
      tubules of Sprague-Dawley rats after treatment with the immunosuppressive agent
      cyclosporin. Follicle-stimulating hormone was also given to stimulate Sertoli
      cell proliferation, and testosterone to stimulate the recovery of
      spermatogenesis. Donor germ cells underwent normal spermatogenesis, and progeny
      were repeatedly produced from the donor germ cells as demonstrated by
      microsatellite paternity analysis. In addition, donor germ cells from the
      cryptorchid testes of LacZ mice were also able to colonize the seminiferous
      tubules of Sprague-Dawley rats using this protocol. Morphologically normal rat
      and mouse spermatozoa were present in the epididymis and vas deferens of the
      recipient rats. This highlights the potential for transplantation of male germ
      cells between different species.

PMID- 12604648
TI  - Cytoplasmic versus nuclear localization of Fos-related proteins in the frog, Rana
      esculenta, testis: in vivo and direct in vitro effect of a gonadotropin-releasing
      hormone agonist.
AB  - Evidence has been accumulated indicating that GnRH-like peptides are present in a
      variety of extrabrain areas of mammalian and nonmammalian vertebrates. A pioneer
      study carried out in the frog, Rana esculenta, demonstrated that testicular GnRH
      induced spermatogonial proliferation. Recently, we have shown that in
      proliferating spermatogonia (SPG) of frogs, a change of localization of the
      oncoprotein Fos, from the cytoplasm to the nucleus, occurs. This leads to the
      hypothesis that one or more testicular GnRH peptides may regulate SPG
      proliferation through Fos family proteins. Therefore, in vivo experiments in
      intact R. esculenta and in vitro incubations of testis fragments have been
      carried out using GnRH agonist (GnRHa; buserelin) and GnRH antagonist (D
      pGlu(1),D-Phe(2),D-Trp(3,6)-GnRH). Cytoplasmic and nuclear Fos-like protein
      localization has been found by Western blot analysis in testicular extracts.
      Immunocytochemistry confirmed that cytoplasmic immunostaining was restricted to
      SPG; change of localization into the nuclear compartment was observed after GnRHa
      treatment. Northern blot analysis showed that treatments of testis fragments with
      GnRHa did not modify testicular c-fos mRNA expression. On the contrary, a Fos
      like protein of 52 kDa, while not affected in vivo, disappeared from testicular
      cytosolic extracts after in vitro treatment with GnRHa. Contemporaneously, a 55
      kDa Fos-related signal appeared in nuclear extracts. The GnRH antagonist
      counteracted the effects of GnRHa. Furthermore, in vivo treatments showed that
      GnRHa acted negatively on a 43-kDa nuclear Fos-related signal and that
      gonadotropins caused the decrease of 52-kDa cytoplasmic signal. In conclusion, we
      show, to our knowledge for the first time, that Fos is regulated by GnRHa
      directly (not through the pituitary) at the testicular level. The main effect
      appears to be related to Fos translocation from cytoplasmic to nuclear
      compartments of SPG.

PMID- 12604651
TI  - Three different promoters control expression of the aromatase cytochrome p450
      gene (cyp19) in mouse gonads and brain.
AB  - Aromatase cytochrome P450, the key enzyme of estrogen biosynthesis, is encoded by
      Cyp19. To elucidate the complex regulation of this gene in mouse gonads (ovary
      and testis) and brain (thalamic/hypothalamic areas), Cyp19 transcripts were
      isolated using rapid amplification of cDNA 5' ends and transcript concentrations
      were estimated in juveniles at different postnatal days (P0, P7, and P14) and in
      adult animals by real time polymerase chain reaction (PCR). In addition, the
      murine Cyp19 locus including all known exons and promoters was reconstructed from
      a recently published sequence of a mouse bacterial artificial chromosome. From
      each of the tissues investigated, Cyp19 transcripts with a specific 5'
      untranslated region (5' UTR) were isolated: T(ov) from ovary, T(br) from brain,
      and T(tes) from testis. T(tes) included a novel 5' UTR that did not show sequence
      similarities to other Cyp19 transcripts. Real time PCR experiments revealed
      similar levels of Cyp19 transcript concentrations in neonatal gonads of both
      sexes. The majority of transcripts were T(ov) in ovaries and T(tes) in testes.
      During further postnatal development, testicular Cyp19 transcript concentrations
      transiently decreased, but the contributions of different transcript variants
      basically remained unchanged. However, ovarian Cyp19 transcript concentrations
      increased by about 100 times, and almost 100% of all Cyp19 transcripts were
      identified as T(ov) in adult ovaries. Brains of both sexes showed highest
      transcript concentrations at P0. However, concentrations in female brains were
      reduced to adult levels earlier than in male brains. In brains of both sexes,
      T(br) was found to predominate throughout postnatal life. The results suggest
      that the mouse Cyp19 gene includes three different promoters that specifically
      direct expression in ovary, testis, and brain.

PMID- 12604650
TI  - Characterization of ribosomal S6 protein kinase p90rsk during meiotic maturation
      and fertilization in pig oocytes: mitogen-activated protein kinase-associated
      activation and localization.
AB  - Mitogen-activated protein kinase (MAPK) becomes activated during the meiotic
      maturation of pig oocytes, but its physiological substrate is unknown. The 90-kDa
      ribosome S6 protein kinase (p90rsk) is the best known MAPK substrate in Xenopus
      and mouse oocytes. The present study was designed to investigate the expression,
      phosphorylation, subcellular localization, and possible roles of p90rsk in
      porcine oocytes during meiotic maturation, fertilization, and parthenogenetic
      activation. This kinase was partially phosphorylated in oocytes at germinal
      vesicle (GV) stage through a MAPK-independent mechanism, but its full
      phosphorylation is dependent on MAPK activity. After fertilization or electrical
      activation, p90rsk was dephosphorylated shortly before pronucleus formation,
      which coincided with the inactivation of MAPK. A protein phosphatase inhibitor,
      okadaic acid, accelerated the phosphorylation of p90rsk during meiotic maturation
      and induced its rephosphorylation in activated eggs. MAPK kinase (MAPKK or MEK)
      inhibitor U0126 inhibited the activation of MAPK and p90rsk in both cumulus
      enclosed and denuded pig oocytes, but prevented GV breakdown (GVBD) only in
      cumulus-enclosed oocytes. Active MAPK and p90rsk were detected in pig cumulus
      cells, and U0126 induced their dephosphorylation. In meiosis II arrested eggs,
      U0126 led to the inactivation of MAPK and p90rsk, as well as the interphase
      transition of the eggs. P90rsk was distributed evenly in GV oocytes, but it
      accumulated in the nucleus before GVBD. It was localized to the meiotic spindle
      after GVBD and concentrated in the spindle mid zone during emission of the polar
      bodies. All these results suggest that p90rsk is downstream of MAPK and plays
      functional roles in the regulation of nuclear status and microtubule
      organization. Although MAPK and p90rsk activity are not essential for the
      spontaneous meiotic resumption in denuded oocytes, activation of this cascade in
      cumulus cells is indispensable for the gonadotropin-induced meiotic resumption of
      pig oocytes.

PMID- 12604652
TI  - Expression profiles and chromosomal localization of genes controlling meiosis and
      follicular development in the sheep ovary.
AB  - In female sheep fetuses, two of the most crucial stages of ovarian development
      are prophase of meiosis I and follicle formation. In the present study, sheep
      ovaries collected on Days 25, 38, 49, 56, 67, 75, 94, and 120 of gestation, at
      birth, and in adulthood were tested by reverse transcription-polymerase chain
      reaction (RT-PCR) for the expression of 14 genes known to be involved in the
      ovarian differentiation in diverse organisms. The aim of this study was to
      determine 1) the expression pattern of six genes involved in germ cell
      development or meiosis (DMC1, SPO11, MSH4, MSH5, DAZL, and Boule) and five ovary
      derived factors (OVOL1, SIAH2, DIAPH2, FOXL2, and FGF9), 2) the onset of gene
      expression for several members of the bone morphogenetic protein (BMP) pathway
      involved in follicular development (GDF9, BMP15, BMPR-IB), and 3) the chromosomal
      localization of seven of these genes in the sheep genome. The RT-PCR analysis
      revealed that the two germline-specific genes, DAZL and Boule, were expressed
      between 49 and 94 days postcoitum (dpc) with a similar pattern to typical meiosis
      genes (DMC1, MSH4, and MSH5), suggesting their possible participation in prophase
      of meiosis I. GDF9 and OVOL1 gene transcription started at 56 dpc and extended
      until birth, while BMP15 presented a more restricted window of expression between
      94 dpc and birth, corresponding to the formation of first growing follicles. The
      homologous ovine genes for SPO11, DMC1, MSH5, DAZL, FGF9, DIAPH2, and SIAH2 were
      located on OAR 13q21-22, 3q35, 20q22, 19q13, 10q15, Xq44, and 1q41-42,
      respectively. In sheep, quantitative trait loci affecting female reproductive
      capacities are currently being detected. The ontology and precise mapping of
      ovarian genes will be useful to identify potential candidate genes that might
      underlie these effects.

PMID- 12604653
TI  - Isolation of sertoli cells from adult rat testes: an approach to ex vivo studies
      of Sertoli cell function.
AB  - Much of what is known about the molecular regulation and function of adult
      Sertoli cells has been inferred from in vitro studies of immature Sertoli cells.
      However, adult and immature cells differ in significant ways and, moreover, many
      Sertoli cell functions are regulated by conditions that are difficult to
      replicate in vitro. Our objective was to develop a procedure to isolate Sertoli
      cells rapidly and in sufficient number and purity to make it possible to assess
      Sertoli cell function immediately after the isolation of the cells. The isolation
      procedure described herein takes less than 4 h and does not require culturing the
      cells. From a single 4-mo-old adult rat, we routinely obtain 7.0 +/- 0.4 x 10(6)
      Sertoli cells per testis, and from a 21-mo-old rat, 7.2 +/- 0.4 x 10(6) Sertoli
      cells per testis. The purity, determined by morphologic analyses of plastic
      embedded cells or after staining for tyrosine-tubulin or vimentin, averaged 80%.
      The contaminants typically included germ cells (10%) and myoid cells (10%). The
      germ cell-expressed genes protamine-2 and hemiferrin were not detected in the
      Sertoli cell preparations by Northern blot analyses, but the Sertoli cell
      expressed genes clusterin, cathepsin L, and transferrin were highly expressed.
      Transferrin mRNA levels were greater in Sertoli cells isolated from aged than
      from young adult rats, consistent with previous analyses of whole testes; and
      cathepsin L mRNA levels were far more highly expressed in Sertoli cells isolated
      from stages VI-VII than from other stages of the cycle of the seminiferous
      epithelium, also consistent with previous analyses of whole testes and isolated
      tubules. These studies indicate that the freshly isolated cells retain
      differentiated function, and thus it should be possible to assess the in vivo
      function of adult Sertoli cells by isolating the Sertoli cells and immediately
      assessing their function.

PMID- 12604654
TI  - Viable piglets generated from porcine oocytes matured in vitro and fertilized by
      intracytoplasmic sperm head injection.
AB  - Intracytoplasmic sperm injection (ICSI) of a nonmotile cell into the ooplasm for
      assisted fertilization is a highly specialized procedure for producing the next
      generation. The production of piglets by ICSI has succeeded when in vivo-matured
      oocytes have been used as recipients. Our objective was to generate viable
      piglets by using porcine oocytes matured in vitro and fertilized by ICSI after
      evaluating the efficacy of using donor spermatozoa in which the acrosome had been
      artificially removed by treatment with calcium ionophore A23187 (Ca-I). The rate
      of acrosomal loss in spermatozoa was increased significantly as the duration of
      treatment with 10 micro M Ca-I was prolonged for 30-120 min (Ca-I treated; 55.6
      78.6%), whereas the rate was not different as the duration of incubation without
      Ca-I was prolonged for 30-120 min (control; 45.3-58.4%). On the sixth day of in
      vitro culture after injection of the sperm head and subsequent stimulation with
      an electrical pulse, the rates of blastocyst formation were not significantly
      different between the two groups: the rates for oocytes injected with Ca-I
      treated sperm heads (incubated for 120 min) and for those injected with control
      sperm heads were 8.6% and 4.0%, respectively. The mean cell numbers of the
      blastocysts were not significantly different between the two groups (25.6 and
      22.7, respectively). Within 2 h after the stimulation, the injected oocytes were
      transferred to estrous-synchronized recipients. The three recipients that
      received oocytes injected with Ca-I-treated sperm heads (77-150 oocytes per
      recipient) were not pregnant, whereas two of the four recipients given oocytes
      injected with control sperm heads (55-100 oocytes per recipient) were pregnant.
      One of these farrowed three (a male and two female) healthy piglets. The results
      demonstrate clearly that in vitro-matured oocytes injected with sperm heads are
      developmentally competent and can produce viable piglets. They also suggest that
      removal of the acrosome from the spermatozoon before injection does not affect
      the development of the blastocyst in vitro. This might not also improve the
      production of piglets in vivo.

PMID- 12604655
TI  - Genome-wide epigenetic alterations in cloned bovine fetuses.
AB  - To gain a better understanding of global methylation differences associated with
      development of nuclear transfer (NT)-generated cattle, we analyzed the genome
      wide methylation status of spontaneously aborted cloned fetuses, cloned fetuses,
      and adult clones that were derived from transgenic and nontransgenic cumulus,
      genital ridge, and body cell lines. Cloned fetuses were recovered from ongoing
      normal pregnancies and were morphologically normal. Fetuses generated by
      artificial insemination (AI) were used as controls. In vitro fertilization (IVF)
      fetuses were compared with AI controls to assess effects of in vitro culture on
      the 5-methylcytosine content of fetal genomes. All of the fetuses were female.
      Skin biopsies were obtained from cloned and AI-generated adult cows. All of the
      adult clones were phenotypically normal and lactating and had no history of
      health or reproductive disorders. Genome-wide cytosine methylation levels were
      monitored by reverse-phase HPLC, and results indicated reduced levels of
      methylated cytosine in NT-generated fetuses. In contrast, no differences were
      observed between adult, lactating clones and similarly aged lactating cows
      produced by AI. These data imply that survivability of cloned cattle may be
      closely related to the global DNA methylation status. This is the first report to
      indicate that global methylation losses may contribute to the developmental
      failure of cloned bovine fetuses.

PMID- 12604656
TI  - Transcriptional regulation of the bovine oxytocin receptor gene.
AB  - The oxytocin receptor (OTR) is expressed in the cow uterus at high levels at
      estrus and at term of pregnancy. This expression appears to be controlled mostly
      at the transcriptional level and correlates with increasing estrogen
      concentration and progesterone withdrawal. Approximately 3200 base pairs of the
      upstream region of the bovine OTR gene were cloned and analyzed using a
      combination of bioinformatic, electrophoretic mobility shift (EMSA), and
      transfection analyses. Using nuclear proteins from high- and low-expressing
      tissues, EMSA indicated no significant quantitative or qualitative changes in
      specific DNA-protein binding, suggesting that transcription is probably
      controlled by signalling systems targeting constitutive factors. Using various
      cell types, including primary and immortalized ruminant endometrial epithelial
      cells, as hosts for transfection of promoter-reporter constructs showed that
      endogenous activity resided only in the longest, i.e., 3.2-kb, construct but not
      in those shorter than 1.0 kb. While estrogen appears to be important in vivo, no
      effect of estradiol was found on any construct directly; only when the longest
      3.2-kb construct was used in combination with some cotransfected steroid receptor
      cofactors, e.g., SRC1e, was an estradiol-dependent effect observed. A putative
      interferon-responsive element (IRE) was found at approximately -2,400 from the
      transcription start site. This element was shown to bind mouse IRF1 and IRF2 as
      well as similar proteins from bovine endometrial and myometrial nuclear extracts.
      This element also responded to these factors when cotransfected into various cell
      types. The bovine equivalents to IRF1 and IRF2 were molecularly cloned from
      endometrial tissue and shown to be expressed in a temporal fashion, supporting
      the role of interferon-tau in maternal recognition of pregnancy. Of many factors
      tested or analyzed, these components of the IFN system are the only ones found to
      significantly influence the transcription of the bovine OTR gene.

PMID- 12604657
TI  - Adenosine stimulates anion secretion across cultured and native adult human vas
      deferens epithelia.
AB  - Experiments were conducted to determine the responsiveness of human vas deferens
      epithelial cell monolayers to adenosine and related agonists. Human abdominal vas
      deferens epithelial cells have been isolated from adult tissues and grown to
      confluence on permeable supports. All cells exhibit intense ZO-1 and cytokeratin
      immunoreactivity. Cultured cell monolayers exhibit high electrical resistance
      with a lumen-negative potential difference and short circuit current (I(sc))
      indicative of anion secretion and/or cation absorption. A portion of the basal
      I(sc) is inhibited by amiloride. Amiloride-sensitive I(sc) is enhanced by
      exposure to glucocorticoids and is Na(+) dependent, indicating the presence of
      epithelial sodium channel-mediated Na(+) absorption. Epithelial anion secretion
      and intracellular generation of cAMP are acutely stimulated by adenosine and the
      adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine (NECA), with these
      effects being fully blocked by 8-phenyltheophylline. Adenosine receptors are
      localized to the apical membrane of the epithelial cells, as basolateral
      adenosine is without effect. Freshly excised human vas deferens recapitulate
      observations made on cultured epithelia when evaluated with the self-referencing
      vibrating probe: amiloride inhibition of basal ion transport, stimulation by
      adenosine, and inhibition by 8-phenyltheophyline. These results demonstrate that
      adult human vas deferens epithelium actively transports ions to generate the
      luminal environment of the deferent duct. Thus, vas deferens epithelium likely
      plays an active role in male fertility, and interventions that modulate
      epithelial function might be exploited to treat male-factor infertility or in
      contraception.

PMID- 12604658
TI  - Influence of different isoforms of recombinant trophoblastic interferons on
      prostaglandin production in cultured bovine endometrial cells.
AB  - In ruminants, interferon produced by the trophectoderm (IFN-tau) is recognized as
      the embryonic signal responsible for maternal recognition of pregnancy. IFN-tau
      is believed to act by down-regulating estrogen receptors, thus preventing
      appearance of oxytocin receptors responsible for the release of prostaglandin
      F(2alpha) (PGF(2alpha)) by the endometrium. The present study was undertaken to
      determine in vitro the biological activities of different IFN-tau isoforms and
      document putative alternate luteotrophic mechanisms. Endometrial cells in primary
      cultures were treated with five different rIFN-tau isoforms: two ovine isoforms
      (ro-4 and ro-11) and three bovine isoforms (rb-1a, rb-2b and rb-3b). Their effect
      was quantified by measurement of PGE(2) and PGF(2alpha) production by ELISA and
      induction of cyclooxygenase (COX-2) by Western and Northern analysis and
      correlated with antiviral activity previously reported. The overall pattern of
      response to the IFNs tested suggests that low concentrations (<1 microg/ml)
      reduced the production of both PGs and higher concentrations (>1 microg/ml)
      stimulated preferentially PGE(2); however, exceptions were noted. Isoform rb-2b
      with high antiviral activity inhibited PG production in both cell types at all
      concentrations tested. IFNs rb-1a and ro-11 had similar antiviral activities,
      inhibiting PG at low concentrations and stimulating them at high concentrations.
      Isoform rb-3b stands out relative to the other IFNs tested because it induced a
      variable non-dose-dependent effect on PG production and low antiviral activity.
      An increase in COX-2 protein expression and messenger was correlated with
      increased PG production. The results showing two distinct responses to IFN-tau
      depending on its concentration and/or isoform and the absence of correlation with
      antiviral activity suggest that complex transduction mechanisms are involved.

PMID- 12604659
TI  - Phtf1 is an integral membrane protein localized in an endoplasmic reticulum
      domain in maturing male germ cells.
AB  - Phtf1 is a gene evolutionarily conserved from Drosophila to human that is
      abundantly expressed in testis. In adult rat, transcripts were abundant in
      germinal meiotic and postmeiotic cells. Phtf1-specific antibodies revealed weak
      activity in a juxtanuclear region of early pachytene spermatocytes. Labeling
      progressively extended to the entire cytoplasm of step 2-3 spermatids, became
      intense from step 4, and persisted until the end of spermiogenesis, when it was
      eliminated in the residual bodies. Phtf1 displayed the properties of an integral
      membrane protein. In transfected cells and haploid cells of rat seminiferous
      epithelium, it colocalized with ER markers (calnexin and calmegin, respectively).
      By using both ER and Golgi markers (TGN-38, p58), we were able to show that, in
      pachytene spermatocytes and in Golgi phase spermatids, phtf1 labeled a region
      neighboring the cis-Golgi that probably corresponded to the peripheral Golgi
      region. Phtf1 staining was not related to beta-COP, AP1, or AP2 aptamers,
      indicating that it was not transported between Golgi saccules or between the
      Golgi complex and plasma membrane. However, aptamer labeling showed that chlatrin
      vesicles could be engaged in a new traffic route, raising the possibility of a
      meiotic proacrosomal vesicle origin. Colocalization between phtf1 and calmegin
      decreased during the acrosomal phase. During the maturation phase, phtf1 was able
      to identify different ER domains, as described previously for the peripheral
      Golgi region. Phtf1 provides a potential new marker for Golgi modifications as
      well as for many of the obscure transformations undergone by the endoplasmic
      reticulum. It could help to elucidate the morphogenic events connected with the
      transformation of spermatogenic cells.

PMID- 12604661
TI  - Restoration of spermatogenesis in infertile mice by Sertoli cell transplantation.
AB  - The niche is considered to play an important role in stem cell biology. Sertoli
      cells are the only somatic cells in the seminiferous tubule that closely interact
      with germ cells to create a favorable environment for spermatogenesis. However,
      little is known about how Sertoli cells develop to form the male germ line niche.
      We report here that Sertoli cells recovered and dissociated from testes of donor
      male mice can be microinjected into recipient testes, form mature seminiferous
      tubule structures, and support spermatogenesis. Sertoli cells from perinatal
      donors had a dramatically greater capacity for generating seminiferous tubules
      than those from adult donors. Furthermore, transplantation of wild-type Sertoli
      cells into infertile Steel/Steel(dickie) testes created a permissive testicular
      microenvironment for generating spermatogenesis and spermatozoa. Thus, our
      results demonstrate that the male germ line stem cell niche can be transferred
      between animals. In addition, the technique provides a novel tool with which to
      analyze spermatogenesis and might provide a mechanism for correcting fertility in
      males suffering from supporting cell defects.

PMID- 12604660
TI  - Stimulatory effect of progesterone on the expression of steroidogenic acute
      regulatory protein in MA-10 Leydig cells.
AB  - The steroidogenic acute regulatory protein (StAR), by virtue of its ability to
      facilitate the intramitochondrial transport of cholesterol, plays an important
      role in regulating steroid hormone biosynthesis in steroidogenic cells. In
      agreement with published data, both StAR expression and progesterone production
      in MA-10 mouse Leydig tumor cells could be stimulated with hCG and 8Br-cAMP.
      Addition of aminoglutethimide, an inhibitor of cholesterol side chain cleavage
      (P450(scc)) enzyme, not only resulted in a drastic inhibition of progesterone
      production but also in an attenuation of StAR expression in response to either
      hCG or 8-Br-cAMP. Therefore, we addressed the question of whether progesterone,
      the end product of the steroidogenic cascade in these cells, could be in a
      position to regulate the StAR gene expression. In MA-10 cells, we report here
      that progesterone in microgram amounts can induce StAR gene expression in a time-
      and dose-dependent manner. StAR expression in response to a maximally effective
      concentration of progesterone of 10 microg/ml was highest at 6 h and started
      decreasing thereafter. The effect of progesterone on StAR protein and StAR mRNA
      induction was mimicked by its synthetic analog, progestin R5020, but not by other
      steroids, including dexamethasone, estradiol, testosterone, and
      dihydrotestosterone. Dexamethasone, in contrast, was able to inhibit StAR
      expression in MA-10 cells. Surprisingly, RU486, a potent antagonist of
      progesterone and glucocorticoid action, had a stimulatory effect on StAR mRNA
      levels. Reverse transcription-polymerase chain reaction analysis demonstrated the
      absence of the classical form of progesterone receptor in MA-10 cells. Thus, for
      the first time, a direct stimulatory effect of a steroid on StAR gene expression
      has been demonstrated. Furthermore, these results provide a new insight,
      indicating that progesterone mediates the activation of StAR expression exerted
      presumably through a novel, nonclassical progesterone receptor in mouse Leydig
      cells.

PMID- 12604662
TI  - Pregnancy-induced alterations of vascular function in mouse mesenteric and
      uterine arteries.
AB  - Normal pregnancy involves dramatic changes to maternal vascular function, while
      abnormal vascular adaptations may contribute to pregnancy-associated diseases
      such as preeclampsia. Many genetic mouse models have recently emerged to study
      vascular pathologies of pregnancy. However, vascular adaptations to pregnancy in
      normal mice are not fully understood. Thus, we studied changes in vascular
      reactivity during normal mouse pregnancy. We hypothesized that pregnant mice will
      have enhanced endothelial-dependent vasodilation compared with nonpregnant mice,
      via an enhancement of the nitric oxide synthase (NOS) prostaglandin H synthase
      (PGHS), and other endothelial-derived hyperpolarizing pathways. Late pregnant
      (Day 17-18) C57BL/6J mice (n = 10) were compared with nonpregnant mice (n = 7).
      Uterine and mesenteric arteries were mounted on a wire myograph system and
      assessed for endothelium-dependent (methacholine) and -independent (sodium
      nitroprusside; SNP) relaxation responses. Endothelial-dependent relaxation was
      enhanced in pregnant uterine and mesenteric arteries, which was blunted after the
      addition of inhibitors of the PGHS or NOS pathways. In nonpregnant mice, these
      pathways had no effect in modulating relaxation in uterine arteries, whereas
      vasodilation in mesenteric arteries was reduced only by NOS inhibition. Both
      uterine and mesenteric vessels had nonnitric oxide- and nonprostaglandin-mediated
      relaxation, but this relaxation was not enhanced during pregnancy. Endothelial
      independent relaxation was also enhanced in pregnant uterine but not mesenteric
      arteries. Our data indicate that uterine and mesenteric arteries from pregnant
      mice have enhanced vasodilation. Understanding vascular adaptations to normal
      mouse pregnancy is crucial for interpreting changes that may occur in genetic
      mouse models.

PMID- 12604663
TI  - Drugs targeting Alzheimer's disease: some things old and some things new.
AB  - Enormous effort is now being devoted to developing drugs that slow
      neurodegeneration in Alzheimer's disease (AD), although insights into AD genetics
      and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase
      inhibitors that temporarily slow loss of cognitive function remain the only
      approved AD drugs. Discovery of mutations in three genes leading to severe early
      onset AD was critical in focusing attention on the role of amyloid peptides
      (Abeta) in neuronal cell death, and enhanced understanding of the biology of
      these peptides has led to an array of mechanism-based drug discovery strategies.
      These include inhibitors for Abeta-generating proteases, agents that prevent or
      reverse Abeta oligomerization, immunotherapies to reduce Abeta in brain and
      plasma, and drugs to modulate cholesterol-mediated effects on Abeta transport.
      Strategies are also underway to minimize toxic effects of Abeta fibrils on
      neurons, and these include antioxidants, blockers of glutamate-mediated
      excitotoxicity, and modulators of inflammatory responses within the brain.
      Although several approaches involve new agents for recently discovered targets,
      many are based on new applications of existing drugs such as statins and
      nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated tau
      protein in neurofibrillary tangles in AD brain has led to strategies for
      identifying selective inhibitors of tau kinases and central nervous system/brain
      permeable drugs that help maintain microtubule integrity. Clearly, a large gap
      exists between our understanding of the cellular cascades targeted in drug
      discovery and widespread failure of the nervous system that AD represents.
      Nevertheless, the pace of recent research clearly supports optimism that slowing
      progression of AD will soon be possible.

PMID- 12604664
TI  - Mechanisms of renal cell repair and regeneration after acute renal failure.
AB  - In many cases, acute renal failure (ARF) is the result of proximal tubular cell
      injury and death and can arise in a variety of clinical situations, especially
      following renal ischemia and drug or toxicant exposure. Although much research
      has focused on the cellular events leading to ARF, less emphasis has been placed
      on the mechanisms of renal cell repair and regeneration, although ARF is reversed
      in over half of those who acquire it. Studies using in vivo and in vitro models
      have demonstrated the importance of proliferation, migration, and repair of
      physiological functions of injured renal proximal tubular cells (RPTC) in the
      reversal of ARF. Growth factors have been shown to produce migration and
      proliferation of injured RPTC, although the specific mechanisms through which
      growth factors promote renal regeneration in vivo are unclear. Recently,
      interactions between integrins and extracellular matrix proteins such as collagen
      IV were shown to promote the repair of physiological functions in injured RPTC.
      Specifically, collagen IV synthesis and deposition following cellular injury
      restored integrin polarity and promoted repair of mitochondrial function and
      active Na(+) transport. Furthermore, exogenous collagen IV, but not collagen I,
      fibronectin, or laminin, promoted the repair of physiological functions without
      stimulating proliferation. These findings suggest the importance of establishing
      and/or maintaining collagen IV-integrin interactions in the stimulation of repair
      of physiological functions following sublethal cellular injury. Furthermore, the
      pathway that stimulates repair is distinct from that of proliferation and
      migration and may be a viable target for pharmacological intervention.

PMID- 12604665
TI  - 5-hydroxytryptamine 1A receptor activation protects against N-methyl-D-aspartate
      induced apoptotic cell death in striatal and mesencephalic cultures.
AB  - Apoptosis and glutamate-mediated excitotoxicity may play a role in the
      pathogenesis of many neurodegenerative disorders, including Parkinson's disease
      (PD). In the present study, we investigated whether stimulation of the 5
      hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate- (NMDA)
      and 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptotic cell death in cell
      culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and
      glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation
      in a dose- and time-dependent manner. NMDA-induced caspase-3 activity and DNA
      fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2
      (di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2
      (dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH
      DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were
      reversed by pretreatment with the 5-HT1A antagonists N-[2-[4-(2-methoxyphenyl)-1
      piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) and S-UH
      301, respectively. Similarly, dose- and time-dependent increases in caspase-3
      activity and DNA fragmentation were observed in rat primary mesencephalic neurons
      after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA
      fragmentation in primary mesencephalic neurons were almost completely inhibited
      by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY
      100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell
      death after NMDA exposure and also almost completely attenuated the NMDA-induced
      Ca(2+) influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH
      301 blocked apoptotic cell death in the primary mesencephalic neurons that were
      exposed to the Parkinsonian toxin MPP(+). Together, these results suggest that 5
      HT1A receptor stimulation may be a promising pharmacological approach in the
      development of neuroprotective agents for PD.

PMID- 12604666
TI  - Serine 329 of the mu-opioid receptor interacts differently with agonists.
AB  - To investigate the effect of the hydrophilic Ser amino acid in position 329 of
      the human mu-opioid receptor (hMORwt) on the potency of various agonists, we
      mutated this residue to Ala (hMORS329A). Taking advantage of the functional
      coupling of the opioid receptor with the heteromultimeric G-protein-coupled
      inwardly rectifying potassium channel (GIRK1/GIRK2), either the wild-type hMOR or
      the mutated receptor (hMORS329A) was functionally coexpressed with GIRK1 and
      GIRK2 channels together with a regulator of G-protein signaling (RGS4) in Xenopus
      laevis oocytes. The two-microelectrode voltage-clamp technique was used to
      measure the opioid receptor activated GIRK1/GIRK2 channel responses. The potency
      of the peptide agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO)
      decreased as measured via hMORS329A, whereas the potency of nonpeptide agonists
      like morphine, fentanyl, and beta-hydroxyfentanyl (R004333) increased via the
      mutated receptor. Our results are indicative for the existence of hydrophilic
      interactions between Ser(329) and DAMGO, thereby decreasing the potency of DAMGO
      via the mutated receptor, whereas hydrophobic interactions between the mutated
      receptor and the N-phenylethyl of morphine and fentanyl can explain the increased
      potency. We conclude that the hydroxyl group of Ser(329) is not involved in the
      formation of a hydrogen bond with the beta-hydroxy group of fentanyl and that
      mutation of this residue to alanine caused dual effects depending on the nature
      of the ligand.

PMID- 12604667
TI  - Short-term exposure to melatonin differentially affects the functional
      sensitivity and trafficking of the hMT1 and hMT2 melatonin receptors.
AB  - The hormone melatonin mediates a variety of physiological functions in mammals
      through activation of pharmacologically distinct MT(1) and MT(2) G protein
      coupled melatonin receptors. We therefore sought to investigate how the receptors
      were regulated in response to short melatonin exposure. Using 2
      [(125)I]iodomelatonin binding, cAMP functional assays, and confocal microscopy,
      we demonstrated robust differences in specific 2-[(125)I]iodomelatonin binding,
      receptor desensitization, and cellular trafficking of hMT(1) and hMT(2) melatonin
      receptors expressed in Chinese hamster ovary (CHO) cells after short (10-min)
      exposure to melatonin. Exposure to melatonin decreased specific 2
      [(125)I]iodomelatonin binding to CHO-MT(2) cells (70.3 +/- 7.6%, n = 3) compared
      with vehicle controls. The robust decreases in specific binding to the hMT(2)
      melatonin receptors correlated both with the observed functional desensitization
      of melatonin to inhibit forskolin-stimulated cAMP formation in CHO-MT(2) cells
      pretreated with 10 nM melatonin (EC(50) of 159.8 +/- 17.8 nM, n = 3, p < 0.05)
      versus vehicle (EC(50) of 6.0 +/- 1.2 nM, n = 3), and with the arrestin-dependent
      internalization of the receptor. In contrast, short exposure of CHO-MT(1) cells
      to melatonin induced a small decrease in specific 2-[(125)I]iodomelatonin binding
      (34.2 +/- 13.0%, n = 5) without either desensitization or receptor
      internalization. We conclude that differential regulation of the hMT(1) and
      hMT(2) melatonin receptors by the hormone melatonin could underlie temporally
      regulated signal transduction events mediated by the hormone in vivo.

PMID- 12604668
TI  - Novel expression of vanilloid receptor 1 on capsaicin-insensitive fibers accounts
      for the analgesic effect of capsaicin cream in neuropathic pain.
AB  - Here, we investigated the mechanism of the antihyperalgesic effect of capsaicin
      cream in the nerve injury-induced neuropathic pain model in mice. In naive mice,
      application of capsaicin cream onto footpad caused no significant changes in the
      thermal latency in contrast to the severe thermal hyperalgesia induced by a
      capsaicin ointment. On the other hand, application of the cream 3 h before test
      concentration dependently reversed both thermal and mechanical hyperalgesia
      observed after partial sciatic nerve injury in mice. In algogenic-induced
      nociceptive flexion (ANF) test, application of 0.1% capsaicin cream in naive mice
      blocked intraplantar (i.pl.) nociceptin- and ATP-induced flexion responses,
      whereas prostaglandin I(2) (PGI(2)) agonist-induced responses were unaffected.
      After nerve injury PGI(2) agonist-induced flexion responses were hypersensitized,
      and capsaicin cream concentration dependently blocked these hyperalgesic
      responses. Intraplantar injection of capsaicin solution in ANF test also produced
      potent flexion responses in naive mice that were lost after neonatal capsaicin
      treatment. Partial sciatic nerve injury in neonatal capsaicin-treated mice caused
      reappearance of i.pl. capsaicin-induced flexion responses, suggesting novel
      expression of capsaicin receptors due to injury. The PGI(2) agonist-induced
      responses were also hypersensitized in such injured mice. Capsaicin cream
      completely reversed both i.pl. capsaicin- or i.pl. PGI(2) agonist-induced
      hyperalgesia in neonatal capsaicin-treated injured mice. Finally, novel
      expression of VR1 receptors on neonatal capsaicin-insensitive neurons after nerve
      injury was confirmed by immunohistochemistry. The newly expressed VR1 receptors
      after nerve injury were mainly confined to A-fibers. Together, our results
      suggest that novel expression of capsaicin receptors in neuropathic condition
      contributes to the analgesic effects of the capsaicin cream.

PMID- 12604669
TI  - Evidence for interactions between intracellular calcium stores during
      methylmercury-induced intracellular calcium dysregulation in rat cerebellar
      granule neurons.
AB  - Acute exposure to methylmercury (MeHg) causes severe disruption of intracellular
      Ca(2+) ([Ca(2+)](i)) regulation, which apparently contributes to neuronal death.
      Activation of the mitochondrial permeability transition pore (MTP) evidently
      contributes to this effect. We examined in more detail the contribution of
      mitochondrial Ca(2+) ([Ca(2+)](m)) to elevations of [Ca(2+)](i) caused by acute
      exposure to a low concentration of MeHg in primary cultures of rat cerebellar
      granule neurons. In particular, we sought to determine whether interactions
      occurred between Ca(2+)(i) pools in response to MeHg. Prior depletion of
      Ca(2+)(m) using carbonyl cyanide m-chlorophenylhydrazone (CCCP) and oligomycin
      significantly decreased the amplitude of [Ca(2+)](i) release from intracellular
      stores, and delayed the onset of whole-cell [Ca(2+)](i) elevations, caused by 0.5
      microM MeHg. CCCP alone hastened the MeHg-induced release of Ca(2+) within the
      cell, whereas oligomycin alone delayed the MeHg-induced influx of extracellular
      Ca(2+). In granule cells loaded with rhod-2 acetoxymethylester to measure changes
      in [Ca(2+)](m), MeHg exposure caused a biphasic increase in fluorescence. The
      initial increase in fluorescence occurred in the absence of extracellular Ca(2+)
      and was abolished by mitochondrial depolarization. The secondary increase was
      associated with spreading of the dye from punctate staining to whole-cell
      distribution, and was delayed significantly by the MTP inhibitor cyclosporin A
      and the smooth endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin. We
      conclude that MeHg causes release of Ca(2+) from the mitochondria through opening
      of the MTP, which contributes the bulk of the elevated [Ca(2+)](i) observed
      during MeHg neurotoxicity. Additionally, the Ca(2+) that enters the mitochondria
      seems to originate in the smooth endoplasmic reticulum, providing a mechanism for
      the observed mitochondrial Ca(2+) overload.

PMID- 12604670
TI  - Selective cyclooxygenase-2 inhibition does not alter keratinocyte wound responses
      in the mouse epidermis after abrasion.
AB  - The cyclooxygenase isoforms, COX-1 and COX-2, are the rate limiting enzymes in
      the biosynthesis of prostaglandin E(2), a major prostaglandin involved in
      epidermal homeostasis and repair. Epidermal injury results in transient
      hyperplasia and induction of COX-2 expression. The role of COX-2 in this
      hyperplasia is unknown, however. In this study, we characterized the epidermal
      expression of COX isozymes following wounding by abrasion in SKH-1 mice using
      immunohistochemistry, in situ hybridization, and Western analysis. In addition,
      we evaluated pivotal keratinocyte functions necessary for the reparative
      hyperplasia, including proliferation by 5-bromo-2'deoxy-uridine labeling and
      differentiation by the expression of involucrin, keratin 1, and keratin 6.
      Although COX-1 expression in keratinocytes remained unchanged during wound
      healing, COX-2 expression was induced coincidentally with keratinocyte
      proliferation and keratin 6 expression, suggesting a role for COX-2 in epidermal
      repair. The role of COX-2 was also evaluated using the selective COX-2 inhibitor
      SC-791 and the traditional COX inhibitors indomethacin and diclofenac. Neither
      inhibitor altered keratinocyte proliferation or differentiation following
      abrasion, in contrast to dexamethasone, which delayed these responses. Our
      results indicated that, although COX-2 expression was coincident with transient
      epidermal hyperplasia and keratinocyte proliferation/differentiation during the
      healing of epidermal injury, it does not play a pivotal role in this repair
      process.

PMID- 12604672
TI  - Fluoxetine increases GABA(A) receptor activity through a novel modulatory site.
AB  - Fluoxetine is a selective serotonin reuptake inhibitor used widely in the
      treatment of depression. In contrast to the proconvulsant effect of many
      antidepressants, fluoxetine has anticonvulsant activity. This property may be due
      in part to positive modulation of the GABA(A) receptors (GABARs), which mediate
      most fast inhibitory neurotransmission in the mammalian brain. We examined the
      effect of fluoxetine on the activity of recombinant GABARs transiently expressed
      in mammalian cells. Fluoxetine increased the response of the receptor to
      submaximal GABA concentrations but did not alter the maximum current amplitude.
      Sensitivity did not depend upon the beta- or gamma-subtype composition of the
      receptor when coexpressed with the alpha(1) subunit. Among the six alpha
      subtypes, only the alpha(5) subunit conferred reduced sensitivity to fluoxetine.
      The metabolite norfluoxetine was even more potent than fluoxetine. Mutations at
      residues in the alpha(5) subunit that alter its sensitivity to zinc or selective
      benzodiazepine derivatives did not affect potentiation by fluoxetine. This
      suggests that fluoxetine acts through a novel modulatory site on the GABAR. The
      direct positive modulation of GABARs by fluoxetine may be a factor in its
      anticonvulsant activity.

PMID- 12604671
TI  - Bradykinin B2 receptor activates extracellular signal-regulated protein kinase in
      mIMCD-3 cells via epidermal growth factor receptor transactivation.
AB  - Bradykinin (BK) has been implicated in the regulation of renal function.
      Activation of extracellular signal-regulated protein kinase (ERK1/2) has been
      demonstrated in several models of toxic or proliferative renal injury. We studied
      activation of ERK1/2 by BK in a cell model of the most distal part of the
      nephron, inner medullary collecting duct (mIMCD-3) cells. Exposure of mIMCD-3
      cells to BK (10(-10)-10(-5) M) resulted in a concentration-dependent increase in
      tyrosine phosphorylation of ERK1/2, with maximal effect at 10(-8) M BK. ERK1/2
      activation by BK was observed as early as 1 min, peaked at 5 min, and was
      sustained at least for 1 h. The effect of BK was mediated by the B(2) receptor
      and was pertussis toxin-independent. Inhibition of phospholipase C, protein
      kinase C, or phosphatidylinositol 3-kinase did not alter ERK1/2 activation by BK.
      BK-induced ERK1/2 activation was Ca(2+)-calmodulin-independent but was sensitive
      to genistein, an inhibitor of tyrosine kinase(s). AG1478, a specific inhibitor of
      epidermal growth factor receptor (EGFR) kinase, completely blocked the effect of
      BK, suggesting an essential role of EGFR in ERK1/2 activation by BK.
      Immunoprecipitation/Western blot studies revealed that BK stimulated tyrosine
      phosphorylation of EGFR, its association with an adapter molecule Grb2, and
      complex formation between Grb2 and the adapter protein Shc. Activation studies of
      monomeric G protein Ras showed that BK-induced stimulation of Ras was dependent
      on EGFR tyrosine kinase activity. These studies demonstrate that BK stimulates
      Ras-dependent activation of ERK1/2 in mIMCD-3 cells via transactivation of EGFR
      through a novel mechanism.

PMID- 12604673
TI  - Soy-derived isoflavones exert opposing actions on Guinea pig ventricular
      myocytes.
AB  - Soy-derived isoflavones appear to possess cardioprotective properties, although
      the precise nature of this protection and the particular isoflavones responsible
      remain unclear. We hypothesized that isoflavones may differ in their cardiac
      actions in view of their varying affinities for the estrogen receptor and
      differences in ability to inhibit tyrosine kinase. We investigated the direct
      effects of three closely related isoflavones, genistein, daidzein, and equol (a
      metabolite of daidzein formed by gut microflora), on the contractile function of
      isolated guinea pig ventricular myocytes. Genistein (10 and 40 microM)
      significantly increased cell shortening and the Ca(2+) transient (measured using
      indo-1). In contrast, equivalent concentrations of equol produced the opposite
      effect, decreasing cell shortening and the Ca(2+) transient, whereas daidzein was
      without effect. The opposing actions of genistein and equol were still observed
      in the presence of the specific estrogen receptor antagonist ICI 182,780 (10
      microM). However, the stimulatory actions of genistein were markedly reduced in
      the presence of the potent phosphotyrosine phosphatase inhibitor, bpV(phen). Both
      genistein and equol significantly inhibited the peak L-type Ca(2+) current. We
      conclude that genistein and equol affect the contractile function of ventricular
      myocytes in opposing ways despite a common initial action of Ca(2+) current
      antagonism. These differences occur independently of the estrogen receptor but
      may be partly related to the unique actions of genistein as a tyrosine kinase
      inhibitor. Furthermore, isoflavone metabolites, such as equol, may be more
      biologically active than their precursors and have a greater role in
      cardioprotection than previously realized.

PMID- 12604674
TI  - Distinct effects of ketone bodies on down-regulation of cell surface insulin
      receptor and insulin receptor substrate-1 phosphorylation in adrenal chromaffin
      cells.
AB  - Treatment (>/=24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis
      related concentrations (>/=3 mM) of acetoacetate (but not beta-hydroxybutyrate,
      acetone, and acidic medium) caused a time- and concentration-dependent reduction
      of cell surface (125)I-insulin binding by ~38%, with no change in the K(d) value.
      The reduction of (125)I-insulin binding returned to control nontreated level at
      24 h after the washout of acetoacetate-treated cells. Acetoacetate did not
      increase the internalization rate of cell surface insulin receptor (IR), as
      measured in the presence of brefeldin A, an inhibitor of cell surface vesicular
      exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular
      levels of the immunoreactive IR precursor molecule (approximately 190 kDa) and IR
      by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by
      approximately 23% as early as 6 h, producing their maximum plateau reduction at
      12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to
      9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin
      induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor
      substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no
      change in IRS-1 level. These results suggest that chronic treatment with
      acetoacetate selectively down-regulated the density of cell surface functional IR
      via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced
      activation of IRS-1.

PMID- 12604675
TI  - Prevention of heart failure in rats by trimetazidine treatment: a consequence of
      accelerated phospholipid turnover?
AB  - Heart failure is known for alteration of cardiac catecholamine responsiveness
      involving adrenergic receptor (AR) down-regulation. Trimetazidine, a
      metabolically active anti-ischemic drug, accelerates the turnover of
      phospholipids. The present study evaluated the consequences of trimetazidine
      treatment (supposed to increase phospholipid synthesis) on AR in heart failure in
      rats. In control rats, trimetazidine (7.5 mg/day supplied in the diet) induced
      after 8 weeks a significant increase in both beta- (+54%) and alpha-AR (+30%)
      density, although after 12 weeks, the receptor density was normalized. Heart
      failure was obtained by ascending aortic banding. These heart failure rats
      developed a severe cardiac hypertrophy, mainly affecting the left ventricle,
      which was significantly reduced in the trimetazidine-treated group. The plasma
      level of brain natriuretic peptide (BNP), a marker of heart failure severity, was
      significantly increased in the heart failure group as compared with the sham
      group (900 and 1200% after 8 and 12 weeks, respectively). In the trimetazidine
      treated group, the plasma BNP increase was significantly lower. The development
      of heart failure was associated with a decrease in beta- and alpha-AR sites (-23
      and -36% versus sham, respectively) after 8 weeks and continued to decrease after
      12 weeks (-37 and -48% versus sham, respectively). This down-regulation was
      prevented by trimetazidine without alteration in affinity. These results suggest
      that trimetazidine prevents AR desensitization and cardiac hypertrophy, in a
      pressure-overload model of heart failure. This cytoprotection suggests that
      membrane homeostasis preservation may be considered as a therapeutic target in
      the treatment of heart failure.

PMID- 12604676
TI  - Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after
      oral administration.
AB  - The analgesic effects of opioids, such as morphine and codeine, in mice are
      enhanced by oral administration of the cannabinoid delta(9)-tetrahydrocannabinol
      (delta(9)-THC). However, isobolographic analysis has never been done to confirm a
      synergy between delta(9)-THC and morphine or codeine via oral routes of
      administration. To determine the nature of the interaction between these drugs
      for pain relief and extend previous experimental results, we performed an
      isobolographic analysis to evaluate for additivity or synergy in the tail-flick
      test. Fixed-ratio combinations of delta(9)-THC with either morphine or codeine
      were tested for antinociceptive effects. The experimentally derived ED(50) for
      each combination was compared with the theoretical additive ED(50), using an
      isobolographic analysis. All of the fixed-ratio combinations tested produced
      greater antinociception (synergy) than predicted from simple additivity. These
      findings suggest that the use of a low-dose combination of analgesics is a valid
      and effective approach for the treatment of pain and necessitates further study.

PMID- 12604677
TI  - Small molecule antagonists of complement receptor type 3 block adhesion and
      adhesion-dependent oxidative burst in human polymorphonuclear leukocytes.
AB  - The leukocyte integrin complement receptor type 3 (CR3, Mac-1, CD11b/CD18) is the
      predominant beta(2) integrin receptor of polymorphonuclear leukocytes (PMNs).
      This cell surface receptor plays a central role in innate immunity against
      pathogens as well as being a major cellular effector of inflammation and tissue
      injury. Two small molecules, compounds 1 and 2, have been identified, that
      interact with CR3 and prevent CR3 from binding to its natural ligand, C3bi.
      Compounds 1 and 2 have IC(50) values of 0.14 and 0.33 microM, respectively, for
      the inhibition of binding of monomeric C3bi-alkaline phosphatase to immobilized
      CR3. Both compounds also inhibit binding of CR3 to biotinylated sheep red blood
      cells opsonized with C3bi, with IC(50) values in the micromolar range. Inhibition
      of ligand binding by the compounds is not easily reversed and requires light,
      suggesting the formation of a covalent adduct through photoactivation. Compounds
      1 and 2 also inhibit adhesion of human PMNs to fibrinogen in response to tumor
      necrosis factor (TNF) or PMA, with IC(50) values of 2.5 to >10 microM. They block
      the adhesion-dependent production of H(2)O(2) stimulated by TNF or phorbol 12
      myristate 13-acetate (PMA) with IC(50) values of 0.2 to 0.8 microM and 1 to 3
      microM, respectively. Limited structure-activity relationship studies based on
      compound 2 indicate the importance of the two benzothiazole rings, an ethyl side
      chain, and the length of the carbon chain linking the rings. Further modification
      of these groups may help in making compounds appropriate for in vivo studies.

PMID- 12604678
TI  - Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or
      benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP)
      channels.
AB  - A novel antidiabetic agent, nateglinide, is a D-phenylalanine derivative lacking
      either a sulfonylurea or benzamido moiety. We examined with the patch-clamp
      method the effect of nateglinide on recombinant ATP-sensitive K(+) (K(ATP))
      channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2
      subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In
      inside-out patches, nateglinide reversibly inhibited the spontaneous openings of
      all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2
      channels with high and low affinities (K(i) = 75 nM and 114 microM) but
      SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111
      microM, respectively). Nateglinide inhibited the K(ATP) current mediated by
      Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290
      microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to
      tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of
      SUR1/Kir6.2 channels by nateglinide. MgADP or MgUDP (100 microM) augmented the
      inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or
      SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the
      SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the
      SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results
      indicate that therapeutic concentrations of nateglinide (approximately 10 microM)
      may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1,
      especially when the channel is activated by intracellular MgADP, even though the
      agent does not contain either a sulfonylurea or benzamido moiety.

PMID- 12604679
TI  - Discrimination of a single dose of morphine followed by naltrexone: substitution
      of other agonists for morphine and other antagonists for naltrexone in a rat
      model of acute dependence.
AB  - Rats were trained to discriminate 4-h pretreatment with 10 mg/kg morphine and 15
      min pretreatment with 0.3 mg/kg naltrexone (morphine-->naltrexone) from
      pretreatment with saline and 0.3 mg/kg naltrexone (saline-->naltrexone). The
      discrimination seems to derive from interoceptive stimuli from antagonist
      precipitated withdrawal from acute morphine dependence. The purpose of this study
      was to extend pharmacological characterization of the discrimination by testing
      opioid agonists other than morphine and antagonists other than naltrexone. Of
      seven mu-opioid agonists tested in place of morphine, only two (heroin and
      levorphanol) substituted completely for it; trials completed on the morphine-
      >naltrexone-appropriate lever increased as a function of agonist and naltrexone
      dose. Agonists with intrinsic efficacy higher (etorphine, fentanyl, and
      methadone) or lower (buprenorphine and meperidine) than that of morphine
      substituted only partially. However, when naltrexone was administered during
      continuous infusion of fentanyl or methadone via s.c. osmotic pump, rats
      responded as if they had received morphine-->naltrexone; discriminative
      responding correlated with global withdrawal scores. Rats responded primarily on
      the saline-->naltrexone-appropriate lever when naltrexone was administered after
      pretreatment with dextrorphan, the dextrorotatory isomer of levorphanol, or kappa
      opioid agonists (5-alpha,7-alpha,8-beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1
      oxaspiro(4,5)dec-8-yl]-benzeneacetamide (U69,593) and spiradoline. Antagonists
      with no intrinsic efficacy at mu-opioid receptors (naloxone and diprenorphine)
      substituted completely for naltrexone, whereas those with some efficacy
      (nalorphine and levallorphan) substituted partially. Thus, morphine-->naltrexone
      like stimulus control of behavior by drugs administered acutely requires
      pretreatment with certain mu-opioid agonists and a pure antagonist, is
      independent of agonist efficacy, and is stereoselective. Interoceptive stimuli
      from naltrexone-precipitated opioid withdrawal are more similar across morphine
      like agonists during chronic dependence than they are during acute dependence.

PMID- 12604680
TI  - 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4
      imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel
      calmodulin antagonist, reduces brain edema through the inhibition of enhanced
      blood-brain barrier permeability after transient focal ischemia.
AB  - An alteration of the blood-brain barrier (BBB) permeability contributes to the
      development of brain edema after stroke. In this study, we evaluated the effects
      of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4
      imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel
      calmodulin antagonist, on brain edema formation and BBB integrity in rats
      subjected to transient focal ischemia. DY-9760e (1 mg/kg/h) was intravenously
      infused for 6 h, starting immediately after reperfusion of a 1-h middle cerebral
      artery occlusion. Treatment with DY-9760e significantly suppressed the increase
      in water content and the extravasation of Evans blue dye after transient focal
      ischemia. Analysis of a magnetic resonance imaging method revealed that DY-9760e
      significantly prevented the development of brain edema in the cortical region of
      the ipsilateral hemisphere. Trifluoperazine, a calmodulin antagonist that is
      structurally different from DY-9760e, also attenuated brain edema elicited by
      transient focal ischemia. Furthermore, DY-9760e and trifluoperazine reduced tumor
      necrosis factor-alpha-induced hyperpermeability of inulin through a cultured
      brain microvascular endothelial cell monolayer, suggesting an involvement of
      calmodulin in the regulation of brain microvascular barrier function. The present
      results demonstrate that DY-9760e ameliorates brain edema formation and suggest
      that this effect may be mediated in part by the inhibition of enhanced BBB
      permeability after ischemic insults. Thus, DY-9760e is expected to be a
      therapeutic drug for treatment of acute stroke patients.

PMID- 12604681
TI  - Mechanisms of down-regulation of CYP2E1 expression by inflammatory cytokines in
      rat hepatoma cells.
AB  - CYP2E1 is one of the major cytochrome P450 forms whose expression is strongly
      inhibited by inflammatory cytokines in humans and rodents. In the present study,
      we have used the Fao rat hepatoma cell line that constitutively expresses CYP2E1
      enzyme to investigate mechanisms of cytokine action. The cells were treated with
      interleukin (IL)-1beta, tumor necrosis factor-alpha (TNFalpha), or IL-6 for 24 or
      72 h, and the expression of CYP2E1 was monitored at the transcriptional, mRNA,
      and protein levels. All three cytokines decreased the CYP2E1 mRNA levels after 24
      h, and the effect was even stronger after 72 h. In contrast, significant
      inhibition of CYP2E1 protein was seen only after 72 h. In transfection assays
      using a CYP2E1 5' -3685 to +29-luciferase construct, it was found that IL-6
      inhibited gene transcription after 24 h, but a similar effect by IL-1beta and
      TNFalpha was registered only after 72 h. Using 5' deletions of the CYP2E1 5'
      reporter construct a responsive region for the IL-6 effect was located to -669 to
      -507 base pairs in the CYP2E1 5'-flanking region. Interestingly, IL-1beta, but
      not TNFalpha, was found to reduce hepatocyte nuclear factor (HNF)-1alpha binding
      to the CYP2E1 promotor. However, the transactivation function of HNF-1alpha was
      found to be impaired in Fao cells. In mouse primary hepatocytes, IL-1beta
      decreased HNF-1alpha-mediated transactivation. In conclusion, our data indicate
      that inflammatory cytokines inhibit CYP2E1 expression by multiple mechanisms,
      including control of HNF-1alpha function and regulation of other transcriptional
      factors acting on the CYP2E1 5'-upstream regulatory region. In addition,
      regulation of factors of importance for the CYP2E1 mRNA stability may be
      involved.

PMID- 12604682
TI  - Facilitation by endogenous prostaglandins of capsaicin-induced gastric protection
      in rodents through EP2 and IP receptors.
AB  - We investigated the role that prostaglandins (PGs) and EP receptors play in
      facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats
      and mice. Male Sprague-Dawley rats and C57BL/6 mice were used after 18 h of
      fasting. The animals were given HCl/ethanol (60% in 150 mM HCl) p.o. and killed 1
      h later. Capsaicin or various EP agonists were given p.o. 30 min or i.v. 10 min
      before HCl/ethanol. In some cases, indomethacin or various EP agonists were given
      s.c. 30 min or i.v 10 min before capsaicin, respectively. Gastric lesions induced
      by HCl/ethanol were significantly inhibited by PGE(2) as well as capsaicin. The
      effect of PGE(2) was antagonized by ONO-AE-829 (EP1 antagonist), whereas the
      capsaicin action was mitigated by indomethacin as well as sensory deafferentation
      but not by ONO-AE-829. The generation of mucosal PGE(2) was not affected by
      either capsaicin or sensory deafferentation, but was significantly inhibited by
      indomethacin. Although neither butaprost (EP2), ONO-NT-012 (EP3), nor 11-deoxy
      PGE1 (EP4) alone had any effect on HCl/ethanol-induced gastric lesions, only
      butaprost restored the protective action of capsaicin in the presence of
      indomethacin. Capsaicin provided a protective action against HCl/ethanol-induced
      gastric lesions in wild-type (+/+) mice in an indomethacin-sensitive manner, and
      this action was similarly observed in EP1 (-/-) and EP3 (-/-) mice but not in the
      animals lacking IP receptors. These results suggest that capsaicin exhibits
      gastric cytoprotection, essentially by stimulating sensory neurons, and this
      action is facilitated by endogenous PGs through EP2/IP receptors, probably
      sensitizing the sensory neurons to capsaicin.

PMID- 12604683
TI  - Modification of noradrenaline release in pithed spontaneously hypertensive rats
      by I1-binding sites in addition to alpha2-adrenoceptors.
AB  - It is known that moxonidine acts as an agonist at presynaptic alpha(2)
      adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a
      reduction in noradrenaline release. In addition, it is conceivable that I(1)
      binding sites located in other regions of the pre- and postganglionic sympathetic
      neurons are involved in this effect. Our aim was to investigate whether and to
      what extent activation of the I(1)-binding sites contributes to the moxonidine
      induced inhibition of noradrenaline release. Noradrenaline release was induced in
      pithed spontaneously hypertensive rats (pretreated with
      phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic
      overflow from the spinal cord. Noradrenaline overflow was reduced using
      moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even
      when all alpha(1)-/alpha(2)-adrenoceptors were blocked effectively by
      phenoxybenzamine. In contrast, the I(1)-antagonist efaroxan (0.1, 1, and 3 mg/kg)
      increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml,
      suggesting an autoreceptor-like function of I(1)-binding sites. In consequence,
      moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline
      overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%,
      respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I(1)-binding
      sites, reduced noradrenaline overflow (-36 or 53%), even under alpha(2)
      adrenoceptor blockade. When 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane
      (AGN192403) (10 mg/kg) was injected, a selective blocker of I(1)-binding sites,
      noradrenaline overflow was not influenced by agmatine. It is concluded that
      moxonidine reduces noradrenaline overflow by acting at I(1)-binding sites in
      addition to its agonistic property at alpha(2)-adrenoceptors. The exact location
      of the I(1)-binding sites on the pre- or postsynaptic sympathetic neurons is
      unknown, but the location in the pre- or postsynaptic membrane of the sympathetic
      ganglion is the most plausible explanation.

PMID- 12604684
TI  - Behavioral pharmacology of AR-A000002, a novel, selective 5-hydroxytryptamine(1B)
      antagonist.
AB  - The present review summarizes the behavioral pharmacology conducted to profile
      the anxiolytic and antidepressant potential of the selective 5-hydroxytryptamine
      (HT)(1B) antagonist (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro
      2-naphthyl]-4-morpholinobenzamide (AR-A000002). AR-A000002 functions as a 5
      HT(1B) antagonist in vivo, which was shown by the antagonism of the
      discriminative stimulus effects in the guinea pig of the 5-HT(1B) agonist 3-(N
      methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-lH-indole (CP135,807).
      Anxiolytic activity of AR-A000002 was demonstrated in the separation-induced
      vocalization paradigm in guinea pig pups, and in a suppressed responding
      procedure in pigeons and guinea pigs, but only a weak trend was noted in a
      suppressed responding procedure in squirrel monkeys. Antidepressant efficacy was
      shown in a number of paradigms. In pigeons and guinea pigs responding under a
      differential reinforcement of low rates schedule of reinforcement (DRL), AR
      A000002 increased the number of reinforcers earned without altering the number of
      responses made. In guinea pigs trained under a response duration differentiation
      paradigm, AR-A000002 increased mean lever-press duration. Finally, AR-A000002 was
      shown to block escape failures in guinea pigs submitted to a learned helplessness
      paradigm. Taken together, these data suggest utility for 5-HT(1B) antagonists in
      the treatment of both anxiety and affective disorders.

PMID- 12604685
TI  - Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated
      efflux.
AB  - The adequate distribution of STI-571 (Gleevec) to the central nervous system
      (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated
      efflux in the blood-brain barrier may play a role in the CNS delivery of this
      drug. Whether STI-571 is a substrate of P-glycoprotein was determined by
      examining the directional flux of [(14)C]STI-571 in parental and MDR1-transfected
      Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral
      to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux
      in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers.
      This difference in directional flux was significantly reduced by a specific P
      glycoprotein inhibitor (2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5
      yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride (LY335979). The
      role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo,
      using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25
      mg/kg [(14)C]STI-571. In the wild-type mice, the brain-to-plasma STI-571
      concentration ratio at all time points was low (1-3%); however, there was an 11
      fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-)
      mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given
      intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was
      approximately 7-fold greater than that of wild-type mice up to 120 min postdose.
      These data indicate that STI-571 is a substrate of P-glycoprotein, and that the
      inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII
      monolayers. Moreover, P-glycoprotein plays an important role in limiting the
      distribution of STI-571 to the CNS.

PMID- 12604686
TI  - Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed
      endotoxin antagonist.
AB  - Alpha-D-glucopyranose,3-O-decyl-2-deoxy-6-O-[2-deoxy-3-O-[(3R)-3-methoxydecyl]-6
      O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-4-O-phosphono-beta-D
      glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-1-(dihydrogen phosphate),
      tetrasodium salt (E5564) is a second-generation synthetic lipodisaccharide
      designed to antagonize the toxic effects of endotoxin, a major immunostimulatory
      component of the outer cell membrane of Gram negative bacteria. In vitro, E5564
      dose dependently (nanomolar concentrations) inhibited lipopolysaccharide (LPS)
      mediated activation of primary cultures of human myeloid cells and mouse tissue
      culture macrophage cell lines as well as human or animal whole blood as measured
      by production of tumor necrosis factor-alpha and other cytokines. E5564 also
      blocked the ability of Gram negative bacteria to stimulate human cytokine
      production in whole blood. In vivo, E5564 blocked induction of LPS-induced
      cytokines and LPS or bacterial-induced lethality in primed mice. E5564 was devoid
      of agonistic activity when tested both in vitro and in vivo and has no
      antagonistic activity against Gram positive-mediated cellular activation at
      concentrations up to 1 microM. E5564 blocked LPS-mediated activation of nuclear
      factor-kappaB in toll-like receptor 4/MD-2-transfected cells. In a mouse
      macrophage cell line, activity of E5564 was independent of serum, suggesting that
      E5564 exerts its activity through the cell surface receptor(s) for LPS, without
      the need for serum LPS transfer proteins. Similar to (6-O-[2-deoxy-6-O-methyl-4-O
      phosphono-3-O-[(R)-3-Z-dodec-5-endoyloxydecl]-2-[3-oxo-tetradecanoylamino]-beta-O
      phosphono-alpha-D-glucopyranose tetrasodium salt (E5531), another lipid A-like
      antagonist, E5564 associates with plasma lipoproteins, causing low concentrations
      of E5564 to be quantitatively inactivated in a dose- and time-dependent manner.
      However, compared with E5531, E5564 is a more potent inhibitor of cytokine
      generation, and higher doses retain activity for durations likely sufficient to
      permit clinical application. These results indicate that E5564 is a potent
      antagonist of LPS and lacks agonistic activity in human and animal model systems,
      making it a potentially effective therapeutic agent for treatment of disease
      states caused by endotoxin.

PMID- 12604687
TI  - Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis,
      induces cell cycle arrest and apoptosis in human colon cancer cells.
AB  - Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in
      the leaves of Strychnos usambarensis, a well known African shrub or little tree.
      The roots contain quaternary alkaloids, which are used to make a curare-like
      arrow poison. However, tertiary alkaloids isolated from the same plant possess
      cytotoxic activities against mammalian cells and protozoa. The effect of ISP has
      been investigated on the growth and viability of HCT-116 colon cancer cells
      during their exponentially growing phase. ISP induced apoptotic cell death as
      shown by the translocation of phosphatidylserine from the inner layer to the
      outer layer of the plasma membrane, chromatin condensation, DNA fragmentation,
      and caspase-3 and -9 activation. ISP provoked also cell cycle arrest in the G(2)
      M phase. We also showed that the expression of p53 was not modified in ISP
      treated cells, but that p21 was induced in a p53-independent manner. Finally, we
      demonstrated that ISP did not affect the catalytic activity of human
      topoisomerases I and II. In conclusion, ISP, which promotes cell death by a p53
      independent apoptotic pathway, could be an interesting lead for cancer
      chemotherapy.

PMID- 12604688
TI  - Delayed neurologic and behavioral effects of subtoxic doses of cholinesterase
      inhibitors.
AB  - We tested the hypothesis that pyridostigmine bromide (PB) intake and/or low-level
      sarin exposure, suggested by some as causes of the symptoms experienced by
      Persian Gulf War veterans, induce neurobehavioral dysfunction that outlasts their
      effects on cholinesterase. Adult male Sprague-Dawley rats were treated during 3
      weeks with s.c. saline, PB in drinking water (80 mg/l), sarin (62.5 microg/kg;
      0.5x LD(50), three times/week s.c.), or PB in drinking water + sarin. Animals
      were tested for passive avoidance, nociceptive threshold, acoustic startle, and
      open field activity 2, 4, or 16 weeks after treatment. Two weeks after sarin,
      acoustic startle was enhanced, whereas distance explored in the open field
      decreased. These effects were absent with PB + sarin or PB by itself. No effect
      on any variable was found at 4 weeks, whereas at 16 weeks sarin induced a
      decrease and PB + sarin induced an increase in habituation in the open field
      test. Nociceptive threshold was elevated in the PB + sarin group at 16 weeks. No
      effect of treatment on passive avoidance was noted in any group. Brain regional
      acetylcholinesterase and cholineacetyltransferase activities were not affected at
      any time after treatment, but muscarinic receptors were down-regulated in
      hippocampus, caudate putamen, and mesencephalon in the sarin group at 2 weeks. In
      conclusion, this study gives further support to the use of PB against nerve agent
      poisoning and does not support the hypothesis that delayed symptoms experienced
      by Persian Gulf War veterans could be due to PB, alone or in association with low
      level sarin exposure.

PMID- 12604689
TI  - Selective tryptic cleavage at the tethered ligand site of the amino terminal
      domain of proteinase-activated receptor-2 in intact cells.
AB  - In intact cells, trypsin activates proteinase-activated receptor-2 (PAR(2)) by
      hydrolysis at residues R(36)/S(37) (amino acids are abbreviated by their one
      letter code), revealing an active tethered ligand sequence. We sought to
      determine whether in intact cells, the tryptic cleavage/activation of PAR(2)
      might also be accompanied by hydrolysis at other potential N-terminal cleavage
      sites, like residues K(34), R(41), K(51), and K(72), as implied by the tryptic
      cleavage in vitro at these residues of Escherichia coli-expressed human N
      terminal PAR(2)R(31)-P(79). To this end, four PAR(2) mutants with altered tryptic
      cleavage sites were prepared (PAR(2)R(36)A, PAR(2)S(37)P, PAR(2)R(41)A, and
      PAR(2)R(36)AR(41)A), expressed in Kirsten virus-transformed rat kidney cells and
      were evaluated together with the wild-type PAR(2)-expressing cells for 1)
      activation (Ca(2+) signaling) by trypsin and the receptor-activating peptide
      SLIGRL-NH(2) (SL-NH(2)) and 2) the tryptic release of two antigenic receptor
      determinants, one N-terminal to the R(36)/S(37) cleavage/activation site detected
      by SLAW-A antibody and the second (detected by antibody, B5), N-terminal to
      residues K(51), K(72). None of the mutants resistant to cleavage at R(36) were
      activated by trypsin, yet all retained reactivity to B5 and all were activated by
      SL-NH(2). In contrast, trypsin activated both wild-type and PAR(2)R(41)A, leading
      to a disappearance of SLAW-A but not B5 reactivity. We conclude that, as opposed
      to the E. coli-expressed PAR(2) N-terminal polypeptide, PAR(2) expressed in
      intact cells displays selective tryptic cleavage at the R(36)/S(37) activation
      site, without cleaving downstream. Thus, in intact cells, trypsin activation does
      not concurrently "disarm" rat PAR(2), but leaves the "tethered ligand"
      persistently attached to the body of the receptor.

PMID- 12604690
TI  - Enhancement effect under high-glucose conditions on U46619-induced spontaneous
      phasic contraction in mouse portal vein.
AB  - The effect of the thromboxane A(2) analog 9,11-dideoxy-11alpha, 9alpha
      epoxymethanoprostaglandin F(2alpha) (U46619) on spontaneous phasic contractions
      in the mouse portal vein was studied. U46619 induced concentration-dependent (1
      100 nM) increases in amplitude, frequency, and contractile period (ON-time) of
      the contraction. Both amplitude and ON-time were enhanced significantly under
      high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation
      may be associated with portal vein dysfunction in diabetes. However, the
      mechanisms remain unclear. HG enhanced the U46619-induced accumulation of
      endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed
      accumulation under normal conditions; however, this suppression was not observed
      under HG conditions. The HG-induced enhancement of U46619-induced contraction was
      inhibited by protein kinase C (PKC) inhibition. This finding indicated that
      accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase
      activation as a feedback mechanism. DG kinase inhibition also suppressed the HG
      induced enhancement of contraction. Increased myo-inositol incorporation was
      detected under HG conditions, indicating an acceleration of phosphatidylinositol
      (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors.
      These findings indicated that HG treatments increased DG synthesis derived from
      incorporated glucose, PKC, and DG kinase activation. These responses induce
      hyperactivation of the amplitude and contractile period of contraction mediated
      by acceleration of PI turnover. This series of responses may be involved in the
      dysfunction of the portal vein under the HG conditions occurring with diabetes.

PMID- 12604691
TI  - Dual action of n-butanol on neuronal nicotinic alpha4beta2 acetylcholine
      receptors.
AB  - N-alcohols exert a dual action on neuronal nicotinic acetylcholine (ACh)
      receptors with short-chain alcohols exhibiting potentiating action and long-chain
      alcohols exhibiting inhibitory action. n-Butanol lies at the transition point
      from potentiation to inhibition. To elucidate the mechanism of dual action of
      alcohols, the effects of n-butanol on the human alpha4beta2 ACh receptors
      expressed in the HEK293 cell line were analyzed in detail by the whole-cell patch
      clamp technique. Prolonged applications of n-butanol evoked small currents with
      an EC(50) value of 230 +/- 90 mM and a Hill coefficient of 1.8 +/- 0.4. This
      current was blocked by either the ACh channel blocker mecamylamine or the
      receptor blocker dihydro-beta-erythroidine, indicating that butanol activated
      receptors as a partial agonist. As expected from its partial agonist action, n
      butanol also modulated ACh-induced currents in a concentration-dependent manner.
      Butanol at 300 mM potentiated currents induced by low concentrations of ACh
      (</=30 microM), while inhibiting the currents induced by high concentrations of
      ACh (100-3,000 microM). In addition, butanol at a low concentration (10 mM)
      suppressed the currents evoked by 10 to 3,000 microM ACh, a result consistent
      with a channel-blocking action. Most features of n-butanol effects were
      satisfactorily simulated by a model in which butanol acts as a partial agonist
      and as a channel blocker.

PMID- 12604692
TI  - Opposite effects of rofecoxib on nuclear factor-kappaB and activating protein-1
      activation.
AB  - Rofecoxib is a selective cyclooxygenase (COX)-2 inhibitor approved for the
      treatment of pain and inflammation in rheumatoid and osteoarthritis. Daily doses
      between 12.5 and 50 mg were found to reduce pain and inflammation, however,
      without a clear dose-effect relationship. Interestingly, rofecoxib treatment is
      associated with an unexpected incidence of renal adverse events compared with
      other COX inhibitors. Here, the effects of rofecoxib on the transcription factors
      nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) were analyzed
      to find out whether transcriptional changes might explain the lack of clear dose
      dependency and the occurrence of renal side effects. In vitro, rofecoxib dose
      dependently inhibited DNA binding capacity of NF-kappaB at doses of 10 to 100
      microM, whereas the binding activity of AP-1 was considerably increased at 100
      microM. In vivo, the anti-inflammatory effect of rofecoxib was equal at 1 and 10
      mg/kg, whereas 50 mg/kg caused a significant further reduction of a zymosan
      induced paw edema. This was associated with a clear decrease of inducible nitric
      oxide synthase (iNOS) protein expression in the spinal cord at this dose. At 1
      and 10 mg/kg, however, iNOS was increased but COX-2 was decreased. Thus, the
      expression of proinflammatory proteins was similarly inconsistent as
      transcription factor regulation. In conclusion, the opposite effects of rofecoxib
      on AP-1 and NF-kappaB may explain the lack of clear dose dependency with
      rofecoxib in clinical studies or animal experiments. The effects on AP-1 may
      possibly affect renal sodium transport because certain renal sodium channels are
      regulated through AP-1. Transcription factor regulation might therefore influence
      both wanted and unwanted effects of rofecoxib.

PMID- 12604694
TI  - Modulatory effect of bolinaquinone, a marine sesquiterpenoid, on acute and
      chronic inflammatory processes.
AB  - The marine metabolite bolinaquinone is a novel inhibitor of secretory
      phospholipase A(2) (sPLA(2)), with a potency on the human synovial enzyme (group
      II) higher than that of manoalide. This activity on the sPLA(2) was confirmed in
      vivo in the 8-h zymosan rat air pouch on the secretory enzyme accumulation in the
      pouch exudate. Additionally, bolinaquinone decreased potently the synthesis and
      release of leukotriene B(4) (LTB(4)) in calcimycin (A23187)-stimulated human
      neutrophils as a consequence of the inhibition of 5-lipoxygenase activity, as
      well as PGE(2) and NO production on zymosan-stimulated mouse peritoneal
      macrophages. This compound exerted anti-inflammatory effects by topical and oral
      routes on the mouse ear edema induced by 12-O-tetradecanoylphorbolacetate, with
      ID(50) values of 76.7 microg/ear and 5.6 mg/kg, respectively, with a significant
      decrease in PGE(2), LTB(4), and tumor necrosis factor-alpha (TNF-alpha) levels
      being more effective than indomethacin. This effect was confirmed in the mouse
      paw carrageenan edema after oral administration. Moreover, bolinaquinone was able
      to reduce the inflammatory response of adjuvant arthritis by inhibiting PGE(2),
      NO, and TNF-alpha production in paw homogenates without affecting PGE(2) levels
      in the stomach. Additionally, bolinaquinone inhibited inducible nitric oxide
      synthase expression and reduced the degree of bone resorption, soft tissue
      swelling, and osteophyte formation.

PMID- 12604693
TI  - Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5
      (CCR5) with ritonavir in rats and monkeys: role of CYP3A and P-glycoprotein.
AB  - The mechanisms of pharmacokinetic interactions of a novel anti-human
      immunodeficiency virus (anti-HIV-1) antagonist of chemokine receptor 5 (CCR5) [2
      (R)-[N-methyl-N-(1-(R)-3-(S)-((4-(3-benzyl-1-ethyl-(1H)-pyrazol-5-yl)piperidin-1
      yl)methyl)-4-(S)-(3-fluorophenyl)cyclopent-1-yl)amino]-3-methylbutanoic acid (MRK
      1)] with ritonavir were evaluated in rats and monkeys. MRK-1 was a good substrate
      for the human (MDR1) and mouse (Mdr1a) multidrug resistance protein transporters
      and was metabolized by CYP3A isozymes in rat, monkey, and human liver microsomes.
      Both the in vitro MDR1-mediated transport and oxidative metabolism of MRK-1 were
      inhibited by ritonavir. Although the systemic pharmacokinetics of MRK-1 in rats
      and monkeys were linear, the oral bioavailability increased with an increase in
      dose from 2 to 10 mg/kg. The area under the plasma concentration-time curve (AUC)
      of MRK-1 was increased 4- to 6-fold when a 2 or 10 mg/kg dose was orally
      coadministered with 10 mg/kg ritonavir. Further pharmacokinetic studies in rats
      indicated that P-glycoprotein (P-gp) inhibition by ritonavir increased the
      intestinal absorption of 2 mg/kg MRK-1 maximally by approximately 30 to 40%, and
      a major component of the interaction likely resulted from its reduced systemic
      clearance via the inhibition of CYP3A isozymes. Oral coadministration of
      quinidine (10 and 30 mg/kg) increased both the extent and the first-order rate of
      absorption of MRK-1 (2 mg/kg) by approximately 40 to 50% and approximately 100 to
      300%, respectively, in rats, thus further substantiating the role of P-gp in
      modulating the intestinal absorption of MRK-1 in this species. At the 10 mg/kg
      MRK-1 dose, however, the entire increase in its AUC upon coadministration with
      ritonavir or quinidine could be attributed to a reduced systemic clearance, and
      no effects on intestinal absorption were apparent. In contrast to rats, the
      effects of P-gp in determining the intestinal absorption of MRK-1 appeared less
      significant in rhesus monkeys at either dose.

PMID- 12604695
TI  - Methylphenidate alters vesicular monoamine transport and prevents methamphetamine
      induced dopaminergic deficits.
AB  - It has been hypothesized that high-dose methamphetamine treatment rapidly
      redistributes cytoplasmic dopamine within nerve terminals, leading to
      intraneuronal reactive oxygen species formation and well characterized persistent
      dopamine deficits. We and others have reported that in addition to this
      persistent damage, methamphetamine treatment rapidly decreases vesicular dopamine
      uptake, as assessed in purified vesicles prepared from treated rats; a phenomenon
      that may contribute to aberrant intraneuronal dopamine redistribution proposedly
      caused by the stimulant. Interestingly, post-treatment with dopamine transporter
      inhibitors protect against the persistent dopamine deficits caused by
      methamphetamine; however, mechanisms underlying this phenomenon have not been
      elucidated. Also of interest are findings that dopamine transporter inhibitors,
      including methylphenidate, rapidly increase 1) vesicular dopamine uptake, 2)
      vesicular monoamine transporter-2 (VMAT-2) ligand binding, and 3) VMAT-2
      immunoreactivity in a vesicular subcellular fraction prepared from treated rats.
      Therefore, we hypothesized that methylphenidate post-treatment might protect
      against the persistent striatal dopamine deficits caused by methamphetamine by
      rapidly affecting VMAT-2 and vesicular dopamine content. Results reveal that
      methylphenidate post-treatment both prevents the persistent dopamine deficits and
      reverses the acute decreases in vesicular dopamine uptake and VMAT-2 ligand
      binding caused by methamphetamine treatment. In addition, methylphenidate post
      treatment reverses the acute decreases in vesicular dopamine content caused by
      methamphetamine treatment. Taken together, these findings suggest that
      methylphenidate prevents persistent methamphetamine-induced dopamine deficits by
      redistributing vesicles and the associated VMAT-2 protein and presumably
      affecting dopamine sequestration. These findings not only provide insight into
      the neurotoxic effects of methamphetamine but also mechanisms underlying dopamine
      neurodegenerative disorders, including Parkinson's disease.

PMID- 12604696
TI  - Selective depression by general anesthetics of glutamate versus GABA release from
      isolated cortical nerve terminals.
AB  - The role of presynaptic mechanisms in general anesthetic depression of excitatory
      glutamatergic neurotransmission and facilitation of GABA-mediated inhibitory
      neurotransmission is unclear. A dual isotope method allowed simultaneous
      comparisons of the effects of a representative volatile (isoflurane) and
      intravenous (propofol) anesthetic on the release of glutamate and GABA from
      isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were
      prelabeled with L-[(3)H]glutamate and [(14)C]GABA, and release was determined by
      superfusion with pulses of 30 mM K(+) or 1 mM 4-aminopyridine (4AP) in the
      absence or presence of 1.9 mM free Ca(2+). Isoflurane maximally inhibited Ca(2+)
      dependent 4AP-evoked L-[(3)H]glutamate release (99 +/- 8% inhibition) to a
      greater extent than [(14)C]GABA release (74 +/- 6% inhibition; P = 0.023).
      Greater inhibition of L-[(3)H]glutamate versus [(14)C]GABA release was also
      observed for the Na(+) channel antagonists tetrodotoxin (99 +/- 4 versus 63 +/-
      5% inhibition; P < 0.001) and riluzole (84 +/- 5 versus 52 +/- 12% inhibition; P
      = 0.041). Propofol did not differ in its maximum inhibition of Ca(2+)-dependent
      4AP-evoked L-[(3)H]glutamate release (76 +/- 12% inhibition) compared with
      [(14)C]GABA (84 +/- 31% inhibition; P = 0.99) release. Neither isoflurane (1 mM)
      nor propofol (15 microM) affected K(+)-evoked release, consistent with a
      molecular target upstream of the synaptic vesicle exocytotic machinery or voltage
      gated Ca(2+) channels coupled to transmitter release. These findings support
      selective presynaptic depression of excitatory versus inhibitory
      neurotransmission by clinical concentrations of isoflurane, probably as a result
      of Na(+) channel blockade.

PMID- 12604697
TI  - Regulation of semicarbazide-sensitive amine oxidase expression by tumor necrosis
      factor-alpha in adipocytes: functional consequences on glucose transport.
AB  - Membrane-associated semicarbazide-sensitive amine oxidase (SSAO) is mainly
      present in the media of aorta and in adipose tissue. Recent works have reported
      that SSAO activation can stimulate glucose transport of fat cells and promote
      adipose conversion. In this study, the murine 3T3-L1 preadipose cell line was
      used to investigate SSAO regulation by tumor necrosis factor-alpha (TNF-alpha), a
      cytokine that is synthesized in fat cells and known to be involved in obesity
      linked insulin resistance. SSAO mRNA and protein levels, and enzyme activity were
      decreased by TNF-alpha in a dose- and time-dependent manner, without any change
      of SSAO affinity for substrates or inhibitors. SSAO inhibition caused by TNF
      alpha was spontaneously reversed along the time after TNF-alpha removal. The
      decrease in SSAO expression also occurred in white adipose tissue of C57BL/6 mice
      treated with mTNF-alpha. Overall, we demonstrated that reduction in SSAO
      expression induced by the cytokine had marked repercussions on amine-stimulated
      glucose transport, in a dose- and time-dependent manner. This effect was more
      pronounced than the inhibiting effect of TNF-alpha on insulin-stimulated glucose
      transport. Moreover, the peroxisome proliferator-activated receptor gamma
      agonists thiazolidinediones did not reverse either TNF-alpha effect on amine
      sensitive glucose transport or the inhibition of SSAO activity, whereas they
      antagonized TNF-alpha effects on insulin-sensitive glucose transport. These
      results demonstrate that TNF-alpha can strongly down-regulate SSAO expression and
      activity, and through this mechanism can dramatically reduce amine-stimulated
      glucose transport. This suggests a potential role of this regulatory process in
      the pathogenesis of glucose homeostasis dysregulations observed during diseases
      accompanied by TNF-alpha overproduction, such as cachexia or obesity.

PMID- 12604698
TI  - Neuroendocrine evidence that (S)-2-(chloro-5-fluoro-indol- l-yl)-1
      methylethylamine fumarate (Ro 60-0175) is not a selective 5-hydroxytryptamine(2C)
      receptor agonist.
AB  - The 5-hydroxytryptamine(2A) and (2C) (5-HT(2A) and 5-HT(2C)) receptors are so
      closely related that selective agonists have not been developed until recently
      with the advent of (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate
      (Ro 60-0175), a putatively selective 5-HT(2C) receptor agonist. In the present
      study, Ro 60-0175 was used to analyze the importance of 5-HT(2C) receptors in
      hormone secretion. Injection of Ro 60-0175 (5 mg/kg s.c.) produced a maximum
      increase in plasma levels of adrenocorticotrophic hormone, oxytocin, and
      prolactin at 15 min postinjection and a maximum increase in plasma corticosterone
      levels at 60 min postinjection. Ro 60-0175-mediated increases in plasma hormone
      levels were dose-dependent (corticosterone ED(50) = 2.43 mg/kg; oxytocin ED(50) =
      4.19 mg/kg; and prolactin ED(50) = 4.03 mg/kg). To assess the role of 5-HT(2C)
      and 5-HT(2A) receptors in mediating the hormone responses to Ro 60-0175, rats
      were pretreated with the 5-HT(2C) antagonist 6-chloro-5-methyl-1-[2-(2
      methylpyridyl-3-oxy)-pyrid-5-yl carbonyl] indoline (SB 242084) or 5-HT(2A)
      antagonists (+/-)-2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] (MDL 100,907)
      before injection of Ro 60-0175 (5 mg/kg s.c.). Neither SB 242084 (0.1, 0.5, 1,
      and 5 mg/kg i.p.) nor MDL 100,907 (1, 5, and 10 microg/kg s.c.) significantly
      inhibited the Ro 60-0175-induced increases in plasma hormone levels. The data
      suggest that Ro 60-0175 increases hormone secretion by mechanisms independent of
      the activation of 5-HT(2C) and/or 5-HT(2A) receptors and suggest that Ro 60-0175
      is not a highly selective 5-HT(2C) receptor agonist.

PMID- 12604700
TI  - Metabolism of flavonoids via enteric recycling: role of intestinal disposition.
AB  - The purpose of this study was to determine the importance of intestinal
      disposition in the first-pass metabolism of flavonoids. A four-site perfused rat
      intestinal model, rat liver and intestinal microsomes, Caco-2 cell microsomes,
      and the Caco-2 cell culture model were used. In the four-site model,
      approximately 28% of perfused aglycones are absorbed (approximately 450 nmol/30
      min). Both absorption and subsequent excretion of metabolites were rapid and site
      dependent (p < 0.05). Maximal amounts of intestinal conjugates excreted per 30
      min were 61 and 150 nmol for genistein and apigenin, respectively. Maximal
      amounts of biliary conjugates excreted per 30 min were 50 and 30 nmol for
      genistein and apigenin, respectively. Microsomes, prepared from Caco-2 cells, rat
      intestine, and rat liver, always glucuronidated apigenin faster than genistein (p
      < 0.05). In addition, rat jejunal microsomes glucuronidated both flavonoids
      faster (p < 0.05) than rat intestinal microsomes prepared from other regions.
      When comparing glucuronidation in different organs, jejunal microsomes often but
      not always glucuronidated both flavonoids faster than liver microsomes. In the
      Caco-2 model, both flavonoids were rapidly absorbed and rapidly conjugated, and
      the conjugates were excreted apically and basolaterally. Similar to the four-site
      perfusion model, apigenin conjugates were excreted much faster than genistein
      conjugates (>2.5 times for glucuronic acid, >4.5 times for sulfate; p < 0.05). In
      conclusion, intestinal disposition may be more important than hepatic disposition
      in the first-pass metabolism of flavonoids such as apigenin. In conjunction with
      enterohepatic recycling, enteric recycling may be used to explain why flavonoids
      have poor systemic bioavailabilities.

PMID- 12604699
TI  - Molecular determinants of melanocortin 4 receptor ligand binding and MC4/MC3
      receptor selectivity.
AB  - The molecular basis of ligand recognition by the melanocortin 4 receptor (MC4R)
      has not been fully defined. In this study, we investigated the molecular
      determinants of MC4R ligand binding, employing a large array of ligands, using
      three approaches. First, molecular modeling of the receptor was used to identify
      Phe284, in transmembrane (TM) 7, as a potential site of ligand interaction.
      Mutation of Phe284 to alanine reduced binding affinity and potency of peptides
      containing L-Phe by up to 71-fold but did not appreciably affect binding of
      linear peptides containing D-Phe, consistent with a hydrophobic interaction
      between the Phe7 of alpha-melanocyte-stimulating hormone and Phe284. Second, we
      examined the effect of a naturally occurring mutation in TM3 (I137T) that is
      linked to obesity. This mutation decreased affinity and potency of cyclic, rigid
      peptides but not more flexible peptides, consistent with an indirect effect of
      the mutation on the tertiary structure of the receptor. Third, we examined the
      residues that support ligand selectivity for the MC4R over the MC3R. Mutation of
      Ile125 (TM3) of the MC4R to the equivalent residue of the MC3R (phenylalanine)
      selectively decreased affinity and potency of MC4R-selective ligands. This effect
      was mirrored by the reciprocal MC3R mutation F157I. The magnitude of this effect
      indicates that this locus is not of major importance. However, it is considered
      that an isoleucine/phenylalanine mutation may affect the orientation of Asp122,
      which has been identified as a major determinant of ligand binding affinity.
      Thus, this study provides further characterization of the MC4R binding pocket.

PMID- 12604702
TI  - Effects of large clostridial cytotoxins on activation of RBL 2H3-hm1 mast cells
      indicate common and different roles of Rac in FcepsilonRI and M1-receptor
      signaling.
AB  - Using Rho GTPases-inhibiting clostridial cytotoxins, we showed recently in RBL
      cells that the GTPase Rac is involved in FcepsilonRI (high-affinity receptor for
      IgE) signaling and receptor-mediated calcium mobilization, including influx via
      calcium release-activated calcium channels. Here, we studied the role of Rho
      GTPases in muscarinic M1 receptor signaling in RBL 2H3-hm1 cells. Clostridium
      difficile toxin B, which inactivates Rho, Rac, and Cdc42, and Clostridium
      sordellii lethal toxin, which inhibits Rac but not Rho, blocked M1-mediated
      exocytosis, indicating that Rac but not Rho is involved in the regulation of
      receptor-mediated exocytosis. Although antigen-induced FcepsilonRI stimulation
      caused tyrosine phosphorylation of the Rac guanine nucleotide exchange factor
      Vav, M1 stimulation by carbachol activated Rac independently of Vav. The Rac
      inactivating toxins blocked M1 receptor-induced membrane translocation of the
      pleckstrin homology domain of protein kinase B, which is a phosphoinositide 3
      kinase effector. The M1-induced calcium release from internal stores was not
      affected by toxin B; however, the subsequent calcium influx from the
      extracellular space was inhibited. The data suggest that besides capacitative
      calcium entry, the M1 signaling pathway activates further calcium entry channels
      with mechanisms that are not affected by the inhibition of Rac.

PMID- 12604701
TI  - Minalrestat, an aldose reductase inhibitor, corrects the impaired microvascular
      reactivity in diabetes.
AB  - We demonstrated that aldose reductase inhibition corrects the impaired
      microvascular responses to inflammatory mediators in diabetic rats. To study the
      mechanism involved in the restoring effect of aldose reductase inhibition, we
      examined the effects of minalrestat, another aldose reductase inhibitor, on the
      responses of mesenteric microvessels studied in vivo to permeability-increasing
      agents in diabetic and galactosemic rats. The diabetic group was treated from 3
      days after the alloxan injection with minalrestat (10 mg/kg/day) for 30 days and
      the minalrestat treatment (10 mg/kg/day/7 days) of galactosemic rats started
      concomitantly with the induction of galactosemia. The mesenteric microvessel
      reactivity was studied using intravital microscopy and changes in vessel
      diameters were estimated after the topical application of vasoactive agents. The
      impaired responses to bradykinin, histamine, and platelet-activating factor of
      arterioles and venules observed in diabetic and galactosemic rats were completely
      prevented by minalrestat. Neither diabetes nor galactosemia affected responses to
      acetylcholine and sodium nitroprusside. Responses to these agents were not
      modified by aldose reductase inhibition. The restoring effect of minalrestat was
      reversed by inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L
      arginine methyl ester, by blocking K(+) channel with tetraethylammonium but not
      by cyclooxygenase inhibition with diclofenac. Therefore, we concluded that NO,
      membrane hyperpolarization, but not cyclooxygenase products are involved in the
      beneficial effect of minalrestat on the microvascular reactivity in diabetes.
      Together, these findings led us to suggest that aldose reductase inhibition might
      ameliorate diabetic complications through the correction of the altered
      microvascular reactivity by a mechanism that involves NO and membrane
      hyperpolarization.

PMID- 12604703
TI  - Dose-dependent EEG effects of zolpidem provide evidence for GABA(A) receptor
      subtype selectivity in vivo.
AB  - Zolpidem is a nonbenzodiazepine GABA(A) receptor modulator that binds in vitro
      with high affinity to GABA(A) receptors expressing alpha(1) subunits but with
      relatively low affinity to receptors expressing alpha(2), alpha(3), and alpha(5)
      subunits. In the present study, it was investigated whether this subtype
      selectivity could be detected and quantified in vivo. Three doses (1.25, 5, and
      25 mg) of zolpidem were administered to rats in an intravenous infusion over 5
      min. The time course of the plasma concentrations was determined in conjunction
      with the change in the beta-frequency range of the EEG as pharmacodynamic
      endpoint. The concentration-effect relationship of the three doses showed a dose
      dependent maximum effect and a dose-dependent potency. The data were analyzed for
      one- or two-site binding using two pharmacodynamic models based on 1) the
      descriptive model and 2) a novel mechanism-based pharmacokinetic/pharmacodynamic
      (PK/PD) model for GABA(A) receptor modulators that aims to separates drug- and
      system-specific properties, thereby allowing the estimation of in vivo affinity
      and efficacy. The application of two-site models significantly improved the fits
      compared with one-site models. Furthermore, in contrast to the descriptive model,
      the mechanism-based PK/PD model yielded dose-independent estimates for affinity
      (97 +/- 40 and 33,100 +/- 14,800 ng x ml(-1)). In conclusion, the mechanism-based
      PK/PD model is able to describe and explain the observed dose-dependent EEG
      effects of zolpidem and suggests the subtype selectivity of zolpidem in vivo.

PMID- 12604704
TI  - Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P
      glycoprotein-mediated transport.
AB  - Flavonoids are constituents of fruits, vegetables, and plant-derived beverages,
      as well as components in herbal-containing dietary supplements. The objective of
      this investigation was to characterize the effect of flavonoids on P-glycoprotein
      (P-gp)-mediated cellular efflux and to determine the molecular mechanism(s) of
      the flavonoid-drug interaction. Studies were conducted in the sensitive and
      multidrug resistant human breast cancer cell lines MCF-7 and MDA435/LCC6 and
      examined the effects of the flavonoids biochanin A, morin, phloretin, and
      silymarin on daunomycin (DNM) accumulation and doxorubicin cytotoxicity. The
      potential mechanism(s) involved in the interaction was evaluated by determining
      flavonoid effects on 1) P-gp ATPase activity, 2) [(3)H]azidopine photoaffinity
      labeling of P-gp, and 3) cellular P-gp levels. The flavonoids increased [(3)H]DNM
      accumulation in P-gp positive cells, but not P-gp negative cells, and these
      effects were both flavonoid concentration- and P-gp expression level-dependent.
      Biochanin A and silymarin potentiated doxorubicin cytotoxicity in P-gp positive
      cells. Biochanin A and phloretin stimulated, whereas morin and silymarin
      inhibited P-gp ATPase activity, confirming that these flavonoids interact with P
      gp. Morin and silymarin significantly inhibited [(3)H]azidopine photoaffinity
      labeling of P-gp, suggesting a direct interaction with P-gp substrate binding. A
      24-h preincubation with all flavonoids, followed by flavonoid removal, did not
      alter cellular P-gp level in P-gp positive cells. In conclusion, biochanin A,
      morin, phloretin, and silymarin all inhibited P-gp-mediated cellular efflux and
      the mechanism of the interaction involved, at least in part, a direct
      interaction. The findings of this study indicate a potential for significant
      flavonoid-drug interactions with P-gp substrates.

PMID- 12604706
TI  - A role for TRPV1 in bradykinin-induced excitation of vagal airway afferent nerve
      terminals.
AB  - Using single-unit extracellular recording techniques, we have examined the role
      of the vanilloid receptor-1 (VR1 aka TRPV1) in bradykinin-induced activation of
      vagal afferent C-fiber receptive fields in guinea pig isolated airways. Of 17
      airway C-fibers tested, 14 responded to bradykinin and capsaicin, 2 fibers
      responded to neither capsaicin nor bradykinin, and 1 fiber responded to capsaicin
      but not bradykinin. Thus, every bradykinin-responsive C-fiber was also responsive
      to capsaicin. Bradykinin (200 microl of 0.3 microM solution) evoked a burst of
      approximately 130 action potentials in C-fibers. In the presence of the TRPV1
      antagonist capsazepine (10 microM), bradykinin evoked 83 +/- 9% (n = 6; P < 0.01)
      fewer action potentials. Similarly, the TRPV1 blocker, ruthenium red (10 microM),
      inhibited the number of bradykinin-evoked action potentials by 75 +/- 10% (n = 4;
      P < 0.05). In the presence of 5,8,11,14-eicosatetraynoic acid (10 microM), an
      inhibitor of lipoxygenase and cyclooxygenase enzymes, the number of bradykinin
      induced action potentials was reduced by 76 +/- 10% (n = 6; P < 0.05). Similarly,
      a combination of the 12-lipoxygenase inhibitor, baicalein (10 microM) and the 5
      lipoxygenase inhibitor ZD2138 [6-[3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H
      pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone] (10 microM) caused significant
      inhibition of bradykinin-induced responses. Our data suggest a role for
      lipoxygenase products in bradykinin B(2) receptor-induced activation of TRPV1 in
      the peripheral terminals of afferent C-fibers within guinea pig trachea.

PMID- 12604705
TI  - Active transport of high-affinity choline and nicotine analogs into the central
      nervous system by the blood-brain barrier choline transporter.
AB  - Cigarette smoking is strongly implicated in the development of cardiovascular
      disorders. Recently identified nicotinium analogs may have therapeutic benefit as
      smoking cessation therapies but may have restricted entry into the central
      nervous system by the blood-brain barrier (BBB) due to their physicochemical
      properties. Using the in situ perfusion technique, lobeline, choline, and
      nicotinium analogs were evaluated for binding to the BBB choline transporter.
      Calculated apparent K(i) values for the choline transporter were 1.7 microM N-n
      octyl choline, 2.2 microM N-n-hexyl choline, 27 microM N-n-decylnicotinium
      iodide, 31.9 microM N-n-octylpyridinium iodide, 49 microM N-n-octylnicotinium
      iodide (NONI), 393 microM lobeline, and >/=1000 microM N-methylnicotinium iodide.
      Nicotine and N-methylpyridinium iodide, however, do not apparently interact with
      the BBB choline transporter. Given NONI's apparent K(i) value determined in this
      study and its ability to inhibit nicotine-evoked dopamine release from superfused
      rat brain slices, potential brain entry of NONI via the BBB choline transporter
      was evaluated. [(3)H]NONI exhibited a BBB transfer coefficient value of
      approximately 1.6 x 10(-3) ml/s/g and a K(m) of approximately 250 microM.
      Unlabeled choline addition to the perfusion fluid reduced [(3)H]NONI brain
      uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI
      facilitates brain entry via the BBB choline transporter. Thus, NONI may have
      utility as a smoking cessation agent, given its ability to inhibit nAChRs
      mediating nicotine-evoked dopamine release centrally, and to be distributed to
      brain via the BBB choline transporter.

PMID- 12604707
TI  - A long-acting suicide gene toxin, 6-methylpurine, inhibits slow growing tumors
      after a single administration.
AB  - We have demonstrated antitumor activity against refractory human glioma and
      pancreatic tumors with 6-methylpurine (MeP) using either a suicide gene therapy
      strategy to selectively release 6-methylpurine in tumor cells or direct
      intratumoral injection of 6-methylpurine itself. A single i.p. injection in mice
      of the prodrug 9-beta-D-[2-deoxyribofuranosyl]-6-methylpurine (MeP-dR; 134 mg/kg)
      caused sustained regression lasting over 70 days of D54 (human glioma) tumors
      transduced with the Escherichia coli purine nucleoside phosphorylase (PNP), and a
      single intratumoral injection of 6-methylpurine (5-10 mg/kg) elicited prolonged
      delays of the growth of D54 tumors and CFPAC human pancreatic carcinoma. Because
      the D54 tumor doubling time is >15 days, the experiments indicate that prodrug
      activation by E. coli PNP engenders destruction of both dividing and nondividing
      tumor compartments in vivo and, therefore, address a fundamental barrier that has
      limited the development of suicide gene strategies in the past. A prolonged
      retention time of 6-methylpurine metabolites in tumors was noted in vivo (T(1/2)
      >24 h compared with a serum half-life of <1 h). By high-pressure liquid
      chromatography, metabolites of [(3)H]MeP-dR were 5- to 6-fold higher in tumors
      expressing E. coli PNP. These experiments point to new endpoints for monitoring
      E. coli PNP suicide gene therapy, including intratumoral enzymatic activity, in
      situ (intratumoral) prodrug conversion, and tumor regressions after direct
      injection of a suicide gene toxin. The findings also help explain the strong in
      vivo bystander killing mechanism ascribed by several laboratories to E. coli PNP
      in the past.

PMID- 12604708
TI  - Pharmacological assessment of the nitric-oxide synthase isoform involved in
      eosinophilic inflammation in a rat model of sephadex-induced airway inflammation.
AB  - Excessive local production of nitric oxide (NO) has been suggested to play a role
      in rodent models of airway inflammation and in pulmonary diseases such as asthma.
      However, even given the plethora of data available including gene expression
      data, pharmacological data, and gene deletion studies in animal models, it is
      still not clear which nitric-oxide synthase (NOS) isoform is involved in
      eosinophilic airway inflammation. In this rat study, the nonselective NOS
      inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester), but not a selective
      inducible NOS (iNOS) inhibitor 1400W (N-3-(aminomethyl)benzyl)acetamidine),
      impacted on Sephadex-induced inflammation by significantly inhibiting lung edema,
      eosinophil infiltration, tumor necrosis factor alpha, interleukin-13, and eotaxin
      levels in the lung tissue. Furthermore, iNOS gene expression was not induced
      following Sephadex administration, which confirms that iNOS does not play a role
      in this model. To demonstrate that this phenomenon was not restricted to this
      model of asthma, L-NAME, but not 1400W, was shown to reduce eosinophilia in an
      antigen-induced model. However, in contrast to the Sephadex model, there was an
      induction of iNOS gene expression after antigen challenge. In a model of
      aerosolized lipopolysaccharide-induced inflammation, where iNOS gene expression
      is increased, 1400W inhibited the increased neutrophilia. These data suggest that
      the compound has been administered using an appropriate dosing regimen for iNOS
      inhibition in the rat lung. In conclusion, it appears that constitutive, not
      inducible, NOS isoforms are important in NO production in models of allergic
      inflammation, which questions whether there is a role for iNOS inhibitors as
      therapy for the treatment of asthma.

PMID- 12604709
TI  - The nitric oxide- and prostaglandin-independent component of the renal
      vasodilator effect of thimerosal is mediated by epoxyeicosatrienoic acids.
AB  - Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of
      arachidonic acid that elicit vasodilation via activation of K(+) channels. They
      have been implicated as endothelium-derived hyperpolarizing factors (EDHFs),
      mediating the effect of some endothelium-dependent vasodilator agents such as
      bradykinin in some vascular tissues. We reasoned that an agent that increases the
      availability of free arachidonic acid should also elicit cytochrome P450
      dependent vasodilation that is associated with increased release of EETs and
      attenuated by agents that inhibit the synthesis or action of EETs. Thus, we used
      thimerosal as an inhibitor of reacylation of arachidonic acid and determined the
      contribution of prostaglandins, nitric oxide, and EETs to the vasodilator effect
      in the isolated, perfused, preconstricted kidney of the rat. Thimerosal elicited
      vasodilator responses that were unaffected by inhibition of cyclooxygenase with
      indomethacin but were reduced by the further inhibition of nitric oxide
      synthesis. The vasodilator activity that remained after inhibition of
      cyclooxygenase and nitric oxide synthase was reduced by inhibition of K(+)
      channels with tetraethylammonium and was associated with increased release of
      EETs measured by gas chromatography-mass spectroscopy following hydrolysis to the
      corresponding diols. Inhibition of cytochrome P450 with miconazole or epoxygenase
      with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexamide reduced the nitric oxide-
      and prostaglandin-independent vasodilator effect of thimerosal and attenuated the
      increase in the release of EETs. We conclude that thimerosal causes vasodilation
      of the isolated perfused kidney via nitric oxide-dependent and -independent
      mechanisms. The nitric oxide-independent component of the response involves
      activation of K(+) channels and is likely mediated by EETs, possibly acting as
      EDHFs.

PMID- 12604710
TI  - Up-regulation of regulator of G protein signaling 4 expression in a model of
      neuropathic pain and insensitivity to morphine.
AB  - We hypothesized that the up-regulated expression of one or more members of the
      regulator of G protein signaling (RGS) family can cause an attenuation of
      signaling via Gi/Go-coupled opioid receptors, and thereby play a role in the
      development of hyperalgesia and accompanying insensitivity to morphine observed
      in animal models of neuropathic pain. Accordingly, we examined the mRNA
      expression of several RGS genes in a rat model of chronic neuropathic pain
      induced by partial ligation of the sciatic nerve. During the development of
      hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased
      significantly (up to 230%) in the lumbar spinal cord. In situ hybridization
      studies confirmed that RGS4 is present in the dorsal horn of the spinal cord
      where mu-opioid receptors (MORs) are also expressed. Overexpression of RGS4 in
      human embryonic kidney 293 cells stably expressing mu-opioid receptors
      predictably attenuated opioid agonist-induced inhibition of adenylyl cyclase.
      This inhibitory effect was overcome partially at high agonist concentrations,
      supporting the view that morphine insensitivity is promoted by RGS4
      overexpression. These studies provide evidence that the up-regulation of RGS4
      expression may contribute to changes in pain signal processing that lead to the
      development of hyperalgesia, and further affect its modulation by morphine.

PMID- 12604712
TI  - Phosphorylation of 4'-thio-beta-D-arabinofuranosylcytosine and its analogs by
      human deoxycytidine kinase.
AB  - 4'-thio-beta-D-arabinofuranosylcytosine (T-araC) exhibits excellent in vivo
      antitumor activity against a variety of solid tumors despite its structural
      similarity to beta-D-arabinofuranosylcytosine (araC), an agent which is poorly
      active against solid tumors in vivo. It is of great interest to elucidate why
      these compounds show a profound difference in antitumor activity. Because
      deoxycytidine kinase (dCK) is the critical enzyme in the activation of both
      compounds, here we report the differences in the substrate characteristics with
      human dCK between these compounds. The catalytic efficiency (V(max)/K(m)) of araC
      was 100-fold higher than that of T-araC using either ATP or UTP as the phosphate
      donor. However, V(max) values of araC and T-araC were similar when UTP was the
      phosphate donor. Since UTP is believed to be the true phosphate donor for dCK in
      intact cells, these data indicated that the rates of phosphorylation of these two
      compounds at high pharmacologically relevant concentrations would be similar.
      This prediction was confirmed in intact cell experiments, which supported the
      hypothesis that UTP is the physiological phosphate donor for dCK phosphorylation
      in cells. The relative lack of importance of phosphate donor to the
      phosphorylation of T-araC by dCK revealed important insights into the activation
      of this compound in human cells at pharmacological doses. These studies indicated
      that replacement of the 4'-oxygen with sulfur significantly reduced the substrate
      activity of nucleoside analogs with dCK and that the superior activity of T-araC
      with respect to araC against solid tumors was not due to superior activity with
      dCK.

PMID- 12604711
TI  - Adenosine A1 receptor agonist N6-cyclopentyladenosine affects the inactivation of
      acetylcholinesterase in blood and brain by sarin.
AB  - The objective of the present study was to develop a kinetics of pharmacodynamics
      model to properly describe and investigate the in vivo interaction between the
      selective adenosine A(1) agonist N(6)-cyclopentyladenosine (CPA),
      acetylcholinesterase (AChE) in blood and brain, and the AChE-inhibitor sarin
      (isopropylmethylphosphonofluoridate). The direct interaction of CPA (2 microM) on
      the inhibition of AChE by sarin was studied in vitro in heparinized rat blood and
      in 10% (w/v) brain homogenate. CPA did not directly influence the sarin-mediated
      inactivation of AChE in either system. In sarin-poisoned (144 microg/kg s.c.)
      rats not treated with CPA, AChE was completely inactivated in blood and brain
      within 7 min. CPA (2 mg/kg i.m.) treatment, 1 min after sarin administration,
      caused a small delay in the inhibition of AChE in blood. Treatment with CPA, 2
      min before sarin, protected the neuronal AChE partially from being inhibited, but
      not the enzyme localized in blood. With a dose-response-time model the proportion
      of the dose of sarin reaching the site of action was estimated to be 48 +/- 12 or
      13 +/- 3% after CPA post- or pretreatment, respectively. A correlation between
      the residual AChE activity in the brain and the incidence of cholinergic symptoms
      could be established with logistic regression analysis: lower inhibition of AChE
      in the brain precluded the onset of critical symptoms. In conclusion, CPA affects
      the concentration of sarin reaching the site of action, which contributes to the
      protection previously observed in sarin-poisoned rats.

PMID- 12604713
TI  - Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel
      nonsteroidal agonist for the androgen receptor.
AB  - The present study characterized the in vitro androgen receptor (AR) binding
      affinity, in vitro and in vivo pharmacological activity, and in vivo
      pharmacokinetics and metabolism of acetothiolutamide, a nonsteroidal AR ligand.
      AR binding was determined by a competitive binding assay. In vitro AR agonist
      activity was examined by a cotransfection assay. Acetothiolutamide displayed high
      AR binding affinity (K(i) = 4.9 +/- 0.2 nM) and full agonist activity in the in
      vitro studies. Next, the androgenic, anabolic, and antiandrogenic activity of
      acetothiolutamide was evaluated in a castrated immature rat model. In this animal
      model, acetothiolutamide exhibited an overall negligible androgenic effect, but a
      statistically significant anabolic effect at high subcutaneous doses. Also,
      acetothiolutamide demonstrated a noticeable antiandrogenic effect in castrated
      rats supplemented with testosterone propionate. To understand the causes for the
      observed disparity between in vitro and in vivo activities, pharmacokinetics and
      metabolism of acetothiolutamide were studied in male Sprague-Dawley rats.
      Acetothiolutamide was rapidly cleared from rat plasma (clearance of about 45
      ml/min/kg) in a concentration-independent manner after i.v. dosing.
      Acetothiolutamide was completely absorbed after subcutaneous administration, but
      not bioavailable after oral dose. In the metabolism study, the unchanged molecule
      and its metabolites in urine and fecal samples were detected by high-performance
      liquid chromatography-mass spectrometry. The structures of major metabolites were
      elucidated with liquid chromatography-tandem mass spectrometry. After i.v.
      administration, acetothiolutamide was excreted in urine and feces as unchanged
      drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation
      of phase I metabolites were the major metabolic pathways of acetothiolutamide in
      rats. Overall, the high plasma clearance of acetothiolutamide, due to its
      extensive hepatic metabolism, likely contributed to its lack of androgenic
      activity in vivo.

PMID- 12604714
TI  - Pharmacodynamics of selective androgen receptor modulators.
AB  - The present study aimed to identify selective androgen receptor modulators
      (SARMs) with in vivo pharmacological activity. We examined the in vitro and in
      vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in
      our laboratories. In the in vitro assays, these compounds demonstrated moderate
      to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4
      to 37 nM, and three of the compounds efficaciously stimulated AR-mediated
      reporter gene expression. The compounds were then administered subcutaneously to
      castrated rats to appraise their in vivo pharmacological activity. Androgenic
      activity was evaluated by the ability of these compounds to maintain the weights
      of prostate and seminal vesicle, whereas levator ani muscle weight was used as a
      measure of anabolic activity. The maximal response (E(max)) and dose for half
      maximal effect (ED(50)) were determined for each compound and compared with that
      observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in
      vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The
      activities of S-1 and S-4 were tissue-selective in that both compounds stimulated
      the anabolic organs more than the androgenic organs. These two compounds were
      less potent and efficacious than TP in androgenic activity, but their anabolic
      activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused
      significant luteinizing hormone or follicle stimulating hormone suppression at
      doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs
      with potent and tissue-selective in vivo pharmacological activity, and represent
      the first members of a new class of SARMs with selective anabolic effects.

PMID- 12604715
TI  - Watchful waiting as a treatment option for localized prostate cancer in the PSA
      era.
AB  - The incidence rate of early-stage prostate cancer has dramatically increased
      since the introduction of the widespread use of PSA testing in developed
      countries, including Japan. With the downward stage migration there has been much
      interest in the concept of watchful waiting not only for elderly patients with a
      life expectancy of less than 10 years but also in younger patients with good
      social and sexual activity. The results of a recent randomized comparison between
      radical prostatectomy and watchful waiting for localized disease indicated
      comparable overall survival but superiority of surgery in disease-specific
      survival. The predictive value of clinico-pathological parameters including
      biopsy features and serum PSA seems insufficient to predict tumor growth
      potential. Our ongoing prospective study is aimed at clarifying whether PSA
      doubling time assessment for 6 months in patients with favorable biopsy features
      can be a good indicator for further watchful waiting or immediate aggressive
      treatment without any survival disadvantage.

PMID- 12604716
TI  - Decreased expression of catalase mRNA in thyroid anaplastic carcinoma.
AB  - BACKGROUND: A decreased expression of glutathione peroxidase mRNA, an antioxidant
      enzyme, was previously observed in thyroid anaplastic carcinomas. METHODS: To
      clarify the expression of antioxidant-related enzymes in thyroid anaplastic
      carcinomas, the expression levels of catalase, copper and zinc superoxide
      dismutase and manganese superoxide dismutase mRNA in 85 benign and malignant
      thyroid tissues were measured by means of real-time quantitative reverse
      transcription-polymerase chain reaction. RESULTS: Decreased expression levels of
      catalase and copper and zinc superoxide dismutase mRNAs, but not manganese mRNA,
      were observed in five anaplastic carcinomas compared with normal thyroid tissues
      and differentiated tumors. CONCLUSION: These results suggest the possibility that
      anaplastic carcinoma cells are more likely to suffer damage by oxygen free
      radicals than normal thyroid cells or differentiated tumor cells.

PMID- 12604718
TI  - Correlation among intratumoral blood flow in breast cancer, clinicopathological
      findings and Nottingham Prognostic Index.
AB  - BACKGROUND: The purpose of this study was to evaluate the correlation among
      intratumoral blood flow as assessed by color Doppler ultrasonography,
      clinicopathological findings and the Nottingham Prognostic Index (NPI). METHODS:
      Twenty-seven patients with breast cancer were examined. All patients received
      surgical treatment. Color Doppler ultrasonography was performed prior to surgery
      to detect arterial blood flow signals within the tumors. The lowest resistance
      index (RI) was recorded. Formalin-fixed, paraffin-embedded slides were reviewed
      by senior pathologists to evaluate the size of tumor, histological size, lymph
      node status and histological grade. Estrogen and progesterone receptor levels
      were measured by enzyme immunoassay. The Nottingham Prognostic Index was
      calculated using the equation NPI = 0.2 x tumor size (cm) + grade (I-III) + lymph
      node score (1-3). RESULTS: The lowest RI correlated well with NPI and
      histological grade (grade II:III = RI 1.037:0.816, P = 0.0035). Regression
      analysis revealed a linear relationship between the lowest RI and NPI
      (correlation coefficient = 0.475; P = 0.0153). CONCLUSIONS: Intratumoral blood
      flow analysis assessed by color Doppler ultrasonography correlates well with
      histological grade and NPI. Preoperative assessment using color Doppler
      ultrasonography provides useful information and may contribute to the
      determination of prognosis.

PMID- 12604717
TI  - Calcification in large cell neuroendocrine carcinoma of the lung.
AB  - BACKGROUND: The aim was to investigate the prevalence of intratumoral
      calcification in large cell neuroendocrine carcinoma (LCNEC) and to review
      computed tomography (CT) and histological findings. PATIENTS AND METHODS: From
      August 1992 through March 2000, 35 out of 1183 surgically resected lung cancer
      patients were histologically diagnosed as having LCNEC at our institute. We
      reviewed the plain radiographs and CT scans of these 35 LCNEC patients. In LCNEC
      cases with intratumoral calcification, we examined the size, number, distribution
      and pattern of intratumoral calcifications visible on the CT scans and the
      histological features. RESULTS: Three cases (9%) exhibited calcification. The
      calcifications were recognized by CT scans alone. The CT scans showed punctate or
      eccentric intratumoral calcifications, which are considered to be a malignant
      feature, in all three cases. In two cases, the calcifications were histologically
      confirmed to be located within the necrotic areas of a tumor nest. CONCLUSION: We
      found three LCNEC cases with intratumoral calcification. The prevalence of LCNEC
      calcification was similar to that in previous reports on lung cancer. The
      mechanism of the intratumoral calcification in our LCNEC cases is speculated to
      be dystrophic calcification.

PMID- 12604719
TI  - Ile-Leu substitution (I415L) in germline E-cadherin gene (CDH1) in Japanese
      familial gastric cancer.
AB  - BACKGROUND: Germline mutation in the cell adhesion molecule E-cadherin is known
      to be associated with the development of undifferentiated or diffuse-type
      familial gastric cancers, but the prevalence of this contribution seems to be low
      in Japanese familial cases, so far. METHODS: We screened all exons of the E
      cadherin gene for mutations in 101 Japanese patients having an intense family
      history of gastric cancers. RESULTS: An abnormal band pattern was found in exon 9
      in three patients (Y6, B21, B37) from two families by PCR-SSCP. DNA sequencing
      analysis of these three patients revealed isoleucine-leucine substitution at
      codon 415 in exon 9. B21 and B37 are siblings and the other three brothers died
      of gastric cancer and another brother (B36) has not been affected by gastric
      cancer to date. This case (B36) did not have this alteration in the exon 9 of E
      cadherin. CONCLUSION: Although the mechanistic basis is not clear, our findings
      may provide a possibility that this additional missense mutation in germline E
      cadherin gene may contribute to gastric cancer predisposition.

PMID- 12604720
TI  - Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an
      important risk factor for lymphatic metastasis in undifferentiated early gastric
      carcinoma.
AB  - BACKGROUND: Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are
      considered to be potentially lymphangiogenic and can selectively induce
      hyperplasia of the lymphatic vasculature. In this study, we aimed to clarify the
      relation between expression of VEGF-C and -D and lymphatic metastasis in early
      gastric cancers. METHODS: Using the specific antibodies, we classified 105 cases
      which were treated as gastrectomy with standard lymphadenectomy at the First
      Department of Surgery, Tokyo University Hospital, between 1994 and 2001, into
      three groups (diffuse type, focal type and negative type) for VEGF-C and two
      groups (positive and negative) for VEGF-D. RESULTS: There was a significant
      correlation between the expression of VEGF-C and -D and lymphatic invasion but
      not with venous invasion. All of the 22 cases that were negative for VEGF-C and 
      D were histologically classified as adenocarcinoma of undifferentiated type and
      showed negative lymph node metastasis and also negative lymphatic invasion. VEGF
      C was positive in all tumors of differentiated type, while its expression varied
      in tumors of undifferentiated type. The VEGF-D positive rate is much lower than
      that of VEGF-C. In undifferentiated tumors in particular, VEGF-D was positive
      only in 4/64 (6%) and three of these four had nodal metastasis. Therefore, in
      tumors of differentiated type, expression of VEGF-C and -D had no clinical
      relevance. In tumors of undifferentiated type, the negative expression of VEGF-C
      suggests lack of nodal metastasis, while the positive expression of VEGF-D
      suggests nodal metastasis. The lymph node metastasis was significantly related to
      the expression of VEGF-C and -D in adenocarcinomas of undifferentiated type but
      not in those of differentiated tumors. CONCLUSIONS: In early gastric cancers of
      histologically undifferentiated type with negative expression of VEGF-C and -D,
      limited surgery might be safely applied because the possibility of nodal
      metastasis is very low. These observations are based only on retrospective
      analysis of a small case series and further evaluation with a larger number of
      cases is necessary.

PMID- 12604721
TI  - A Phase II study of irinotecan in combination with 120-h infusion of 5
      fluorouracil in patients with metastatic colorectal carcinoma: Japan Clinical
      Oncology Group Study (JCOG9703).
AB  - PURPOSE: To evaluate the antitumor effect and feasibility of a combination of
      irinotecan (CPT-11) and 5-day infusional 5-fluorouracil (5-FU) in a sequential
      schedule based on our previous combination phase I studies in patients with
      metastatic colorectal cancer. PATIENTS AND METHODS: Forty chemotherapy-naive
      patients with metastatic colorectal cancer received 90-min infusion of CPT-11 at
      a dose of 150 mg/m(2) on days 1 and 15 and 120-h protracted infusion of 5-FU at
      600 mg/m(2)/day on days 3-7, which were repeated every 4 weeks. RESULTS: The
      median number of actually administered courses was five, ranging from one to 14.
      There were 16 (40%) patients who developed grade 3 or 4 neutropenia. Grade 3 or 4
      nausea/vomiting and diarrhea were seen in three (8%) and seven (18%) patients,
      respectively. Only one early death not related to treatment occurred during the
      study. There was one complete response and 17 partial responses with a response
      rate of 45% (95% confidence interval: 29.3-61.5%). With a median follow-up period
      of 22.5 months for survivors, the median survival and median progression-free
      survival times were 15.9 and 7.0 months, respectively. CONCLUSIONS: Although the
      toxicities were modest, this sequentially combined regimen is active and feasible
      in patients with metastatic colorectal cancer.

PMID- 12604722
TI  - Long-term prognostic value of conventional peritoneal cytology after curative
      resection for colorectal carcinoma.
AB  - BACKGROUND: This study was undertaken to evaluate the long-term prognostic
      significance of conventional peritoneal cytology in patients with advanced
      colorectal carcinoma after curative resection. METHODS: A review was performed of
      189 patients who underwent curative resection for pT3/T4 carcinoma of the colon
      and upper/middle rectum between March 1987 and December 1991. Patient outcomes
      were reviewed retrospectively. Peritoneal cytology was performed before
      manipulation of the tumor. Intraoperatively, 50 ml of saline were instilled and
      20 ml were reaspirated for cytology. In all patients, Papanicolaou and Giemsa
      stainings were performed to detect intraperitoneal free tumor cells. RESULTS: The
      median follow-up was 103 months. Malignant cells were identified in peritoneal
      washings from 11 patients (5.8%). Of the 11 patients with positive cytology, six
      (54.5%) developed recurrence and peritoneal recurrence was observed in four
      (36.4%). In contrast, of the 178 patients with negative cytology, 46 (25.8%)
      developed recurrence and peritoneal recurrence was observed in four (2.2%). The
      peritoneal recurrence rate was significantly increased (P = 0.0004) in the
      patients with positive cytology. The cancer-specific 10-year survival rates for
      the patients with positive and negative cytology were 45.5 and 80.3%,
      respectively (P = 0.0051). Multivariate analysis (Cox proportional hazard model)
      revealed that peritoneal cytology (positive: P = 0.0256) and lymph node
      metastasis (pN2: P = 0.0004) were independent predictors of cancer-specific
      survival. CONCLUSION: Conventional peritoneal cytology serves as a new prognostic
      marker after curative resection in patients with advanced colorectal carcinoma.
      It appears to be a useful diagnostic procedure for predicting recurrence,
      especially peritoneal recurrence.

PMID- 12604723
TI  - Synchronous colorectal carcinoma: clinico-pathological features and prognosis.
AB  - OBJECTIVE: The present study was undertaken to clarify the clinical and
      pathological features of synchronous colorectal carcinomas, to compare prognosis
      between cases with synchronous carcinomas and those with single carcinomas and to
      explore prognostic factors of synchronous carcinomas. PATIENTS AND METHODS: Among
      876 surgically resected primary colorectal carcinomas, 42 cases (4.8%) with
      synchronous carcinomas were identified. Clinical characteristics, routine
      pathological findings according to the TNM classification and postoperative
      survival were compared between synchronous cases and single cases. Prognostic
      factors of synchronous cases were explored using the proportional hazard model.
      RESULTS: The index lesions of synchronous cases did not differ from single
      lesions in age, size, differentiation, location, pT value, pN value, pathological
      stage, morphology or lymphatic invasion. However, the male:female ratio was
      higher and distant metastasis was more frequent in synchronous cases than in
      single cases. Although postoperative survival of synchronous cases was shorter
      than that of single cases, they were similar in the multivariate proportional
      hazard model including pathological stage and curability as co-factors. Only
      pathological stage and curability of the index lesion were significant co-factors
      of postoperative survival of synchronous cases. CONCLUSION: Synchronous
      carcinomas and single carcinomas were similar in clinical characteristics and
      routine pathological findings. The prognosis of synchronous cases and that of
      single cases did not differ if the pathological stages were identical and the
      resections were curative.

PMID- 12604724
TI  - Neovasculature of benign thrombus of the inferior vena cava demonstrated by
      computed tomography during hepatic arteriography, mimicking a small
      hepatocellular carcinoma.
AB  - A 64-year-old man who underwent hepatectomy for hepatocellular carcinoma (HCC) 4
      years ago followed by transarterial chemoembolization for recurrent foci 1 year
      later had a thrombus in the inferior vena cava (IVC). Tumor thrombus derived from
      HCC was suspected owing to the increase in size and hepatic arteriography was
      performed. Common hepatic arteriography demonstrated a small stain suggesting a
      recurrent HCC in the remnant liver. However, CT during hepatic arteriography
      revealed that the stain localized not in the liver but within the thrombus in the
      IVC; there was no recurrent HCC in the liver. The dense stain associated with
      thin neovasculature developed through the thrombus was recognized. The thrombus
      spontaneously regressed 8 months later. It was speculated that the neovasculature
      played an important role in a process of absorption of the thrombus. One should
      note that the stain shown on angiography does not always suggest that the lesion
      is localized in the liver and is malignant.

PMID- 12604725
TI  - A new germline mutation of the PTCH gene in a Japanese patient with nevoid basal
      cell carcinoma syndrome associated with meningioma.
AB  - We employed polymerase chain reaction and DNA sequencing analysis to characterize
      the PTCH gene in a Japanese nevoid basal cell carcinoma syndrome (NBCCS) patient
      suffering from meningioma, multiple basal cell carcinoma and epidermal cysts.
      Direct sequence analyses revealed a novel single base deletion at nucleotide 2613
      in exon 16 (2613delC) in one PTCH allele, resulting in the frame shift and the
      introduction of a premature termination codon in this mutated allele.

PMID- 12604727
TI  - Counting the true cost and value of medicines.

PMID- 12604728
TI  - Growth factor receptors in breast cancer: potential for therapeutic intervention.
AB  - Increased expression and activation of receptor tyrosine kinases occurs
      frequently in human breast carcinomas. Several therapies targeting these
      receptors are currently in clinical trials. Therapeutic strategies include
      blockade of individual receptors with monoclonal antibodies and inhibition of
      tyrosine kinase function. Trastuzumab is the first of these biologic therapies to
      be approved for patients with human epidermal growth factor receptor 2 (HER2)
      overexpressing metastatic breast cancer. Novel trastuzumab-based combinations are
      being investigated in patients with advanced breast cancer. Large clinical trials
      have also been launched in the adjuvant setting. Small molecules that inhibit
      specific tyrosine kinases (e.g., epidermal growth factor receptor, HER2) are in
      phase I and phase II clinical trials. Other growth-factor-targeted drugs that
      have reached clinical development include STI571 and antibodies directed at the
      insulin-like growth factor pathway. Biologic therapies directed against these
      important receptors are promising. In this review we discuss challenges and
      opportunities for the development of growth-factor-targeted approaches for the
      treatment of breast cancer.

PMID- 12604729
TI  - Metastatic pancreatic cancer: emerging strategies in chemotherapy and palliative
      care.
AB  - This update is devoted to discussion of optimal supportive and palliative care of
      patients with pancreatic cancer. Approximately 33,000 new cases of pancreatic
      cancer are predicted for the U.S. in 2002. Because diagnosis and intervention
      occur late in the course of this disease, the vast majority of patients already
      have metastatic disease at the time of diagnosis. These tumors are relatively
      resistant to systemic chemotherapy, making pancreatic cancer the fourth leading
      cause of cancer-related death in the U.S. and the Western world. For these
      reasons, efforts at identifying and treating disease-related symptomatology are
      priorities. This update overviews symptom management, supportive care strategies,
      and both standard and emerging palliative chemotherapy options. The incorporation
      of molecularly targeted therapies into treatment of metastatic pancreatic cancer
      is reviewed as well. These strategies are of relevance to internists,
      gastroenterologists, oncologists, and other specialists who care for patients
      with pancreatic cancer.

PMID- 12604730
TI  - Docetaxel, cisplatin, 5-fluorouracil (TPF)-based induction chemotherapy for head
      and neck cancer and the case for sequential, combined-modality treatment.
AB  - Since the publication of the Veterans Affairs study in the early 1990s, much has
      been learned regarding the role of chemotherapy, radiation therapy, and more
      importantly, the role of combined-modality treatment with chemoradiation in the
      therapy of locally advanced head and neck cancer. There continues to be
      widespread variation and controversy in the timing, schedule, and intensity of
      chemotherapy and chemoradiation. Herein, we present the various approaches
      currently used in the year 2003 with a specific emphasis on the role of
      sequential combined-modality therapy combining chemotherapy, chemoradiotherapy,
      and surgery in the treatment of these malignancies.

PMID- 12604731
TI  - Molecular cytogenetics in solid tumors: laboratorial tool for diagnosis,
      prognosis, and therapy.
AB  - The remarkable progress in the understanding of leukemogenesis was soundly
      sustained by methodological developments in the cytogenetic field. Nonrandom
      chromosomal abnormalities frequently associated with specific types of
      hematological disease play a major role in their diagnosis and have been
      demonstrated as independent prognostic indicators. Molecular pathways altered by
      chimeric or deregulated proteins as a consequence of chromosomal abnormalities
      have also significantly contributed to the development of targeted therapies, and
      cytogenetic assays are valuable for selecting patients for treatment and
      monitoring outcome. In solid tumors, significantly high levels of chromosome
      abnormalities have been detected, but distinction between critical and irrelevant
      events has been a major challenge. Consequently, the application of cytogenetic
      technology as diagnostic, prognostic, or therapeutic tools for these malignancies
      remains largely under appreciated. The emergence of molecular-based techniques
      such as fluorescence in situ hybridization was particularly useful for solid
      malignancies, and the spectrum of their application is rapidly expanding to
      improve efficiency and sensitivity in cancer prevention, diagnosis, prognosis,
      and therapy selection, alone or in combination with other diagnostic methods.
      This overview illustrates current uses and outlines potential applications for
      molecular cytogenetics in clinical oncology.

PMID- 12604732
TI  - Current status of sentinel lymph node mapping and biopsy: facts and
      controversies.
AB  - Lymphatic mapping and sentinel lymph node biopsy were first reported in 1977 by
      Cabanas for penile cancer. Since that time, the technique has become rapidly
      assimilated into clinical practice. Morton first described the application of
      lymphatic mapping for melanoma only a decade ago, and this technique is now
      accepted as the standard of care. The application for lymphatic mapping and
      sentinel lymph node biopsy in breast cancer remains approximately 5 years behind
      its utilization in melanoma. This technique has the potential to be utilized in
      all solid tumors. The rapid assent of this technique in clinical practice is the
      result of multiple factors, including accuracy, decreased morbidity, and
      supplying the pathologist with only a few nodes to allow a more focused and
      sensitive pathologic evaluation. Despite the success and acceptance of lymphatic
      mapping, many controversies remain. We have attempted to clearly highlight these
      controversies in this review.

PMID- 12604734
TI  - Phase I study of paclitaxel and topotecan for the first-line treatment of
      extensive-stage small cell lung cancer.
AB  - Extensive-stage small cell lung cancer (SCLC) is an aggressive disease with a
      median survival of approximately 8 months. Although current combination
      chemotherapy regimens provide high initial tumor response rates, they have not
      translated into large gains in survival. Topotecan and paclitaxel have
      nonoverlapping mechanisms of action and are active agents in SCLC. Additionally,
      these two agents demonstrate in vitro synergy in animal and human tumor models.
      We investigated the maximum tolerated dose of 3-day topotecan in combination with
      paclitaxel in previously untreated patients with extensive SCLC. Seventeen
      patients were enrolled in an open-label, phase I, dose-escalation study and were
      treated with intravenous paclitaxel 135-175 mg/m(2) over 1 hour on day 1,
      followed by intravenous topotecan 1.25-1.5 mg/m(2) over 30 minutes on days 1-3 of
      a 21-day course. Sixty-nine courses of therapy were administered with no delays
      due to hematologic toxicity. Prophylactic hematologic support was required for
      24% of patients. The topotecan/paclitaxel combination was well tolerated, with
      24%, 12%, and 6% of patients experiencing grade 3/4 neutropenia, anemia, or
      thrombocytopenia, respectively. Dose-limiting neutropenia was seen in three of
      five patients treated with topotecan 1.5 mg/m(2) and paclitaxel 175 mg/m(2).
      Therefore, topotecan 1.5 mg/m(2) with paclitaxel 135 mg/m(2) was determined to be
      the maximum tolerated dose. Of the 17 evaluable patients, 53% achieved a partial
      response and 18% achieved stable disease. In summary, we have identified a
      regimen of topotecan 1.5 mg/m(2) and paclitaxel 135 mg/m(2) that was well
      tolerated and active in this patient group. Additional studies of topotecan and
      paclitaxel at these dose levels are needed to fully elucidate the efficacy of
      this combination in extensive SCLC.

PMID- 12604733
TI  - Use of temozolomide with other cytotoxic chemotherapy in the treatment of
      patients with recurrent brain metastases from lung cancer.
AB  - The use of chemotherapy for the treatment of brain metastases arising from lung
      cancer has been limited by poor efficacy and high toxicity. Temozolomide, an
      orally bioavailable alkylating agent that crosses the blood-brain barrier, has
      activity against brain metastases from both small cell lung cancer (SCLC) and non
      small cell lung cancer (NSCLC) when used as a single agent, but response rates
      are low. Preclinical experiments and early clinical studies in other malignancies
      indicate that temozolomide may have additive or synergistic effects when used
      with other chemotherapeutic agents. We report a case of a patient with SCLC with
      recurrent brain metastases after treatment with multiple chemotherapeutic
      regimens and whole-brain radiation therapy (WBRT) who was treated with
      temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and oral etoposide (50
      mg/m(2) for 10 days in a 28-day cycle). A second patient with NSCLC and brain
      metastases who progressed after treatment with chemotherapy and WBRT was treated
      with temozolomide (150 mg/m(2) for 5 days in a 28-day cycle) and gemcitabine
      (1,000 mg/m(2) weekly for 2 weeks in a 3- week cycle). In both patients, the
      temozolomide regimens were extremely well tolerated and resulted in dramatic and
      durable responses. The combination of temozolomide with other chemotherapeutic
      agents represents a promising strategy for treating patients with lung cancer and
      recurrent brain metastases and merits further study.

PMID- 12604736
TI  - Baseline and early treatment factors are not clinically useful for predicting
      individual response to erythropoietin in anemic cancer patients.
AB  - Recombinant human erythropoietin (rHuEPO) is an effective treatment for anemia in
      patients with cancer, and recent studies show that over two-thirds of patients
      can be expected to respond with a large increase (>2 g/dl) in hemoglobin
      concentration. However, it would be helpful to identify likely responders and
      nonresponders before initiating treatment. Previous studies have suggested that
      high pretreatment endogenous erythropoietin levels are associated with a lower
      response to erythropoietin, especially in certain patient groups, such as
      patients with hematological malignancies, non-chemotherapy patients, or patients
      with myelodysplastic syndrome. Various algorithms have therefore been developed
      to predict patient response to rHuEPO using baseline serum erythropoietin levels
      and other baseline factors. We performed an analysis of data pooled from four
      randomized clinical trials of 604 patients with non-myeloid malignancies,
      examining the clinical usefulness of pretreatment and early treatment factors for
      predicting response to erythropoietin. The analysis confirms several other
      reports that the most predictive models combined pretreatment and early treatment
      factors, including change in hemoglobin at 4 weeks, but even these models did not
      increase sensitivity above 85% (total response in unselected patients was 68.1%),
      while specificity remained poor. We conclude that clinically useful prediction of
      response to erythropoietin is not possible using baseline or early response
      variables because of poor sensitivity and specificity of prediction compared with
      generally accepted clinical tests.

PMID- 12604735
TI  - Immunotherapy for Epstein-Barr virus-associated cancers in children.
AB  - Latent Epstein-Barr virus (EBV) infection is associated with several
      malignancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal
      carcinoma, and post-transplant lymphoproliferative disease (LPD). The presence of
      EBV antigens in these tumors provides a target for immunotherapy approaches, and
      immunotherapy with EBV-specific cytotoxic T cells (CTLs) has proved effective in
      post-transplant LPDs, which are highly immunogenic tumors expressing type III
      latency. The malignant cells in Hodgkin's disease and nasopharyngeal carcinoma
      express type II latency and hence a more restricted pattern of EBV antigens.
      Trials with autologous EBV-specific CTL responses are under way in both of these
      diseases, and while some activity has been seen, no patient has yet been cured.
      This reduced CTL efficacy may reflect either downregulation of immunodominant EBV
      proteins, which are major CTL targets, or the ability of these tumors to evade
      the immune response by secreting inhibitory cytokines. Further improvement of EBV
      specific CTL therapy for these type II latency tumors will require improved
      methods to activate and expand CTLs specific for the subdominant EBV genes
      expressed and to genetically modify the expanded CTLs to render them resistant to
      inhibitory cytokines. If these strategies to improve the therapeutic potential of
      immunotherapy for EBV-associated tumors prove successful, this type of treatment
      may be adapted to other tumors expressing known (viral) antigens.

PMID- 12604740
TI  - The war on "anti-aging medicine".
AB  - Leading members of the gerontological community have recently launched a war on
      anti-aging medicine, seeking to discredit what they judge to be fraudulent and
      harmful products and therapies, and to distinguish their research from what they
      regard as the pseudoscience of the anti-aging movement. This article interprets
      the contemporary war on anti-aging medicine as largely an attempt by established
      gerontological researchers to preserve their hard-won scientific and political
      legitimacy, as well as to maintain and enhance funding for research on the basic
      biological mechanisms of aging. First, it recounts the difficult struggle of U.S.
      biogerontologists to join the scientific mainstream in terms of legitimization
      and public funding. Second, it examines how elements of a contemporary anti-aging
      movement seem to threaten the hard-won public legitimacy of established
      gerontological researchers and practitioners. Third, it looks at the "boundary
      work" responses of the gerontological community to the anti-aging movement.
      Finally, it assesses the consequences of the war on anti-aging medicine to date.

PMID- 12604737
TI  - Living as a cancer surpriser: a doctor tells his story.
AB  - Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at
      Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The
      Schwartz Center is a non-profit organization dedicated to supporting and
      advancing compassionate health care delivery, which provides hope to the patient,
      support to the caregivers, and sustenance to the healing process. The center
      sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where
      caregivers reflect on important psychosocial issues faced by patients, their
      families, and their caregivers and gain insight and support from fellow staff
      members. We tell the story of one physician with incurable non-small cell lung
      cancer (NSCLC) who had an unexpectedly favorable response to an experimental
      treatment while receiving it as a part of his palliative care. His unique insight
      provides an opportunity to elucidate some of the issues that arise from living
      both as a patient-caregiver and as a cancer "surpriser." When caregivers face
      their own cancer, their reflections as patient-caregivers offer an internal
      perspective on the illness experience and help us as fellow caregivers to better
      understand and support all patients who face serious illnesses, both those who
      are colleagues and those who are not. Just like any patient with cancer, patient
      caregivers experience the dramatic changes in health, daily life, and perspective
      that come with serious illness. Within the context of a life-threatening illness,
      caregiver-patients and their families search for new meaning as they face an
      uncertain future and address the issues of life and death. In addition to such
      processes, patient-caregivers with cancer also find that their own medical
      knowledge and their colleagues' reactions shape their experiences and to an
      extent separate them from those of other patients.

PMID- 12604741
TI  - The science of including older ethnic and racial group participants in health
      related research.

PMID- 12604742
TI  - Lessons learned about minority recruitment and retention from the Centers on
      Minority Aging and Health Promotion.
AB  - PURPOSE: This article presents a summary of an earlier monograph on the
      recruitment and retention of older ethnic minority individuals. DESIGN AND
      METHODS: The authors provide an overview of recruitment and retention efforts
      made by six National Institutes of Health Office of Minority Research/National
      Institute on Aging-funded Centers on Minority Aging and Health Promotion. We rely
      on a model that focuses on barriers and enablers to recruitment that stem from
      the minority community as well as the research community. RESULTS: The summary of
      findings suggests that recruitment and retention success occurs when there is a
      match between the goals of the ethnic minority communities and the research
      community. IMPLICATIONS: Recognizing and understanding the culture of each ethnic
      minority community as well the research perspectives is essential to successful
      recruitment and retention of ethnic minority elderly individuals.

PMID- 12604743
TI  - Recruiting older African American men to a cancer screening trial (the AAMEN
      Project).
AB  - PURPOSE: This article describes the demographic characteristics of participants
      in a randomized trial (the AAMEN Project) designed to recruit older (aged 55+
      years) African American men to a cancer screening trial. DESIGN AND METHODS: The
      AAMEN Project is a recruitment trial developed for African American men aged 55+
      years living in southeastern Michigan. RESULTS: Of the 34,376 African American
      men in the study, 37.6% had low incomes and 62.4% had moderate-to-high incomes.
      The average age of the men was 63.3 years (SD = 5.9 years). Among men who were
      eligible and interested in participating, the proportion of men with low incomes
      was significantly greater than the proportion of men with moderate-to-high
      incomes (p <.001). IMPLICATIONS: The AAMEN Project demonstrated success in
      recruiting a substantial proportion of men with low incomes as well as men with
      moderate-to-high incomes. These findings may facilitate the development of future
      recruitment efforts involving older African American men.

PMID- 12604744
TI  - Recruitment and retention of older minorities in mental health services research.
AB  - PURPOSE: This article reviews the problems associated with recruiting older
      minorities into mental health research studies and proposes a consumer-centered
      model of research methodology that addresses the barriers to recruitment and
      retention in this population. DESIGN AND METHODS: The authors discuss and compare
      the results of recruitment and retention interventions for two geriatric mental
      health studies, one that used traditional methods of recruitment and retention
      and another that used consumer-centered methods. RESULTS: Although the consumer
      centered methods result in better recruitment of older minorities in general
      (chi(2) = 54.90, p <.001), it was not superior to the traditional method in
      recruiting older minorities (chi(2) = 0.82, ns). However, the consumer-centered
      approach yielded better retention of older minorities (chi(2) = 6.20, p <.05)
      than did the traditional method. Within both methods, recruitment through
      provider referral and face-to-face contact were the superior recruitment methods
      (chi(2) = 6.78, p <.05). Having an experienced recruiter or a community recruiter
      resulted in greater agreement to participate than simply having an ethnically
      matched recruiter (chi(2) = 36.00, p <.001). IMPLICATIONS: Although these data
      are observational, and rigorous research on the best methods for recruiting and
      retaining older minorities is still necessary, the results suggest that a
      consumer-centered model of research yields greater overall recruitment and
      retention rates than do traditional research methods.

PMID- 12604745
TI  - Recruitment and retention of latino dementia family caregivers in intervention
      research: issues to face, lessons to learn.
AB  - PURPOSE: This article reviews and critiques several issues of importance to those
      whose goal is to make intervention research with Latino caregivers more "user
      friendly." Issues range from current demographic trends showing the ever
      increasing number of Latino caregivers to discussion of cultural values that
      influence their help-seeking behavior. DESIGN AND METHODS: This article presents
      a review of current published information on this topic. The gerontological
      literature was searched for the past decade for relevant material; in addition,
      the authors' own experience in this area is described. RESULTS: Although limited
      information was found that derived from actual empirical studies, a number of
      articles describe potential barriers to research involvement and provide
      suggestions for making participation more attractive and culturally appropriate
      for Latinos. IMPLICATIONS: Clinical researchers need to increase their
      sensitivity to such issues as cultural values and language preference and develop
      effective collaborations with the Latino community so that intervention research
      programs can be designed and implemented successfully with Latinos caring for
      cognitively impaired elderly family members at home.

PMID- 12604746
TI  - Recruitment of older African Americans for survey research: a process evaluation
      of the community and church-based strategy in The Durham Elders Project.
AB  - PURPOSE: The disproportionately high burden of morbidity and mortality among
      older African Americans is due, in part, to a lack of understanding of the
      factors contributing to these outcomes. In order to more fully understand the
      factors that contribute to African American morbidity and mortality, researchers
      must identify strategies for increasing the inclusion of older African Americans
      in research on social and health phenomena. DESIGN AND METHODS: This article is a
      process evaluation describing the successes and challenges associated with
      recruitment of older African Americans into research. It considers an effort to
      nurture collaboration between university and community institutions to both
      facilitate research endeavors and offer meaningful and culturally-appropriate
      contributions to the community. RESULTS: The primary challenges discovered in
      this observational process evaluation of a church-based recruitment strategy
      include the effective coordination of a community research advisory board,
      ensuring participant autonomy, and reducing concerns of exploitation among
      potential participants. IMPLICATIONS: A strategy of coordinating a community
      research advisory board to incorporate the views of community members and to
      drive a church-based recruitment procedure provides a starting point for tapping
      into an immensely important segment of society historically ignored by the
      research community.

PMID- 12604747
TI  - Willingness to participate in clinical treatment research among older African
      Americans and Whites.
AB  - PURPOSE: Using a health services utilization conceptual framework, the purpose of
      this analysis was to examine race differences in factors predictive of the
      behavioral intention of older persons to participate in a clinical treatment
      trial should they have a diagnosis of cancer. In addition, the analysis sought to
      determine if older African Americans were less likely than Whites to express
      willingness to participate, given knowledge of the Tuskegee syphilis study and
      greater fatalistic cancer beliefs. DESIGN AND METHODS: Data were drawn from a
      community-based telephone survey of 216 African Americans and 222 Whites, 50
      years of age and older. RESULTS: Findings show that willingness to participate
      was significantly higher among males, persons of younger age, higher incomes, and
      with nonfatalistic cancer beliefs. Race differences were only apparent for the
      two significant interactions of race with age and high income. Neither knowledge
      of the Tuskegee study nor fatalistic cancer beliefs were more important for
      African Americans than for Whites. IMPLICATIONS: Study findings suggest that
      recruitment strategies need to be tailored to racial differences in factors
      affecting willingness to participate, particularly those related to age and
      income level.

PMID- 12604748
TI  - The Cleveland Alzheimer's managed care demonstration: outcomes after 12 months of
      implementation.
AB  - PURPOSE: This demonstration evaluates the effects of integrating Alzheimer's
      Association care consultation service with health care services offered by a
      large managed care system. The primary hypothesis is that Association care
      consultation will decrease service utilization, increase satisfaction with
      managed care, and decrease caregiver depression and care-related strain.
      Secondary modifying-effects hypotheses posit that the effects of the intervention
      will be intensified when patients have not received a firm dementia diagnosis,
      patients have more severe memory problems, caregivers use other Association
      services in tandem with care consultation, and caregivers are not patients'
      spouses. DESIGN AND METHODS: The demonstration is a randomized trial that
      examines outcomes after a 12-month study period. Interview data from 157 primary
      family caregivers are combined with data abstracted from medical/administrative
      records. RESULTS: Support for the primary hypothesis is found for selected, but
      not all, service utilization outcomes and for caregiver depression. Support for
      secondary modifying-effects hypotheses is found for satisfaction outcomes and
      care-related strain outcomes. IMPLICATIONS: Care consultation delivered within a
      partnership between a managed care health system and an Alzheimer's Association
      is a promising strategy for improving selected outcomes for patients with
      dementia and their caregivers.

PMID- 12604749
TI  - Health care utilization in dementia patients with psychiatric comorbidity.
AB  - PURPOSE: The purpose of this research was to determine if differences in service
      use exist between dementia patients with and without psychiatric comorbidity.
      DESIGN AND METHODS: A retrospective cohort study was conducted on all Veterans
      Affairs (VA) beneficiaries seen at the Houston Veterans Affairs Medical Center
      with a VA Outpatient Clinic File diagnosis of dementia in 1997. The primary
      dependent measure was amount of Houston VA health service use from study entry
      until the end of fiscal year 1999 or until death. RESULTS: Of the 864 dementia
      patients in the identified cohort, two thirds had a comorbid psychiatric
      diagnosis. Examination of 2-year health service use revealed that, after
      adjusting for demographic and medical comorbidity differences, dementia patients
      with psychiatric comorbidity had increased medical and psychiatric inpatient days
      of care and more psychiatric outpatient visits compared with patients without
      psychiatric comorbidity. IMPLICATIONS: Further understanding of the current
      health service use of dementia patients with psychiatric comorbidity may help to
      establish a framework for considering change in the current system of care. A
      coordinated system of care with interdisciplinary teamwork may provide both cost
      effective and optimal treatment for dementia patients.

PMID- 12604751
TI  - The living conditions of elderly Americans.
AB  - PURPOSE: This article profiles the housing settings of frail elderly individuals,
      whether their homes are facilitating or impeding their ability to live in the
      community, and the change in disability and housing status before and after
      passage of the 1990 Americans with Disabilities Act. DESIGN AND METHODS: The
      analysis relies primarily on statistical analysis of the 1995 national American
      Housing Survey (AHS), with supplementary analysis of the 1978 AHS. RESULTS: In
      1995, roughly 14% of elderly individuals had a "housing-related disability," 49%
      had at least one dwelling modification, and 23% had an unmet need for
      modifications. Because half those with dwelling modification also reported unmet
      need, the match between disabling condition and modification, not the presence of
      modifications, is key. Multivariate results indicate that although unmet need is
      greater among the poor, lack of modifications is not. Prevalence of modifications
      nearly doubled between 1978 and 1995. Overall unmet need declined, but some needs
      were less likely to be met in 1995 than 1978. IMPLICATIONS: The analysis
      highlights the importance of information about housing for understanding the care
      and service needs of elderly individuals and provides a compelling argument for a
      minimum dataset on their housing and neighborhood environments.

PMID- 12604750
TI  - Housing issues and realities facing grandparent caregivers who are renters.
AB  - PURPOSE: This study determined the prevalence of grandparents raising
      grandchildren who are living in rental housing and explored the sociodemographic
      characteristics and challenges faced by such renters. DESIGN AND METHODS: Data
      were obtained from the Census 2000 Supplementary Survey, a nationally
      representative survey of 700,000 households with a response rate of 96.8%.
      Frequencies and bivariate analyses were focused on the 2,639 respondents who were
      grandparent caregiver renters. RESULTS: Of the 2,350,000 grandparent caregivers
      in the United States in 2000, 26% were renters, almost one third of whom were
      spending 30% or more of their income on rent. For the quarter of a million
      grandparent caregiver renters living below the poverty line, 60% were spending at
      least 30% of their household income on rent and 3 of 10 were living in
      overcrowded conditions. IMPLICATIONS: Grandparent caregivers who are renters
      represent a particularly vulnerable population. The need for further research,
      policy, and programs for this group is discussed.

PMID- 12604752
TI  - Validity of self-report screening scale for elder abuse: Women's Health Australia
      Study.
AB  - PURPOSE: Early identification of elder abuse requires a valid, easily
      administered screening instrument. This study examined the reliability and
      validity of the Vulnerability to Abuse Screening Scale (VASS), a 12-item self
      report measure with four factors (Vulnerability, Dependence, Dejection, and
      Coercion). DESIGN AND METHODS: The sample consisted of 10,421 nationally
      representative Women's Health Australia study participants, aged 73-78, who
      completed the Time 2 postal survey in 1999. We tested validity of the VASS factor
      structure and whether baseline risk status independently predicted Time 2
      attrition. RESULTS: Findings confirmed the VASS factor structure and construct
      validity. Four factors explained 51% of variance, and these factors were
      internally consistent. The Vulnerability and Coercion factors held the strongest
      face and construct validity for physical and psychological abuse. The Dependence
      and Dejection factors were valid and reliable and significantly predicted 3-year
      attrition after controlling for confounders. IMPLICATIONS: Further work is needed
      to determine sensitivity and specificity of VASS as a screening instrument for
      elder abuse. Qualitative research could examine specific experiences and contexts
      of vulnerable women.

PMID- 12604753
TI  - Psychometric properties of an abridged version of The Zarit Burden Interview
      within a representative Canadian caregiver sample.
AB  - PURPOSE: Given the exponential increase in dementia prevalence anticipated in the
      coming years, measurement of caregiver burden has become common in gerontological
      research and clinical practice. The Zarit Burden Interview (BI) has emerged as
      the most widely utilized burden measure. The current study examines the
      psychometric properties of responses to an abridged, 12-item version of this
      scale. DESIGN AND METHODS: Data were derived from a national epidemiological
      study of dementia incidence and patterns of care (N = 1,095). Informal caregivers
      of surviving institutionalized and community-dwelling index subjects were
      interviewed 5 years subsequent to initial recruitment (n = 770). RESULTS: Results
      of both the exploratory and confirmatory factor analyses support a two-factor
      structure of responses to this abridged scale. Subsequent to control for
      demographic variables, dementia illness features, and baseline depressive
      symptoms at baseline, responses to this brief BI provide a significant increase
      to prediction of depressive symptoms at Time 2 (R(2) =.24, p <.01) with no
      additional variance provided by the 10 remaining items from the complete BI
      (deltaR(2) = 0, ns). IMPLICATIONS: The results of this study are discussed
      relative to theory and the operational definition of caregiver burden. Findings
      can be generalized with greater confidence given the representative and national
      composition of caregivers recruited for this study.

PMID- 12604759
TI  - Is anybody out there? Integrating HIV services in rural regions.
AB  - As the HIV epidemic has changed nationally, the parallel change in the Southern
      states has been a disproportionate increase in HIV infection among people of
      color and among women. Due to the limited and disjointed health care and social
      service resources in rural Southern regions, already marginalized groups have
      difficulty in accessing appropriate care and services to address their HIV
      infection seamlessly and with continuity. To ameliorate the limitations in the
      health care infrastructure, the North Carolina Services Integration Project
      collaborated with North Carolina medical and social service providers and state
      agencies to create a sustainable and replicable model of integrated care for HIV
      positive, geographically dispersed residents.

PMID- 12604760
TI  - Costs of medically treated craniofacial conditions.
AB  - OBJECTIVES: Determining the magnitude of the burden of diseases and health
      disorders on the U.S. population is a high priority for health policy makers.
      Conditions such as malignant neoplasms and injuries from craniofacial trauma
      contribute to adverse oral health. This study estimates the number of cases of
      diseases and disorders relevant to oral health that are treated annually in the
      medical care, as opposed to the dental care, system and associated costs. Policy
      makers can use this cost model to compare the impact of different conditions, to
      target areas for reducing costs, and to allocate appropriate health resources.
      METHODS: Data from four national and two state data systems were used to estimate
      the number of cases of selected dental, oral, and craniofacial diseases and
      conditions treated in the medical system annually and associated medical and
      wage/household work loss costs. RESULTS: Per case, the most costly conditions
      were estimated to be malignant neoplasms at 83,080 US dollars annually (in 1999
      dollars), diabetes-related oral conditions at 51,030 US dollars, endocarditis at
      48,610 US dollars, and chlamydiae at 41,100 US dollars. Total estimated costs for
      oral conditions treated in the medical care system in 1996 were approximately
      95.9 billion US dollars, including 21.4 billion US dollars in medical costs and
      74.4 US dollars billion in wage/household work loss costs. CONCLUSIONS:
      Conditions treated outside the dental care system are major contributors to oral
      health costs. They should be an important focus for the National Institute of
      Dental and Craniofacial Research.

PMID- 12604761
TI  - A prospective study of the validity of self-reported use of specific types of
      dental services.
AB  - OBJECTIVE: The purpose of this study was to quantify the validity of self
      reported receipt of dental services in 10 categories, using information from
      dental charts as the "gold standard." METHODS: The Florida Dental Care Study was
      a prospective cohort study of a diverse sample of adults. In-person interviews
      were conducted at baseline and at 24 and 48 months following baseline, with
      telephone interviews at six-month intervals in between. Participants reported new
      dental visits, reason(s) for the visit(s), and specific service(s) received. For
      the present study, self-reported data were compared with data from patients'
      dental charts. RESULTS: Percent concordance between self-report and dental charts
      ranged from 82% to 100%, while Kappa values ranged from 0.33 to 0.91. Bivariate
      multiple logistic regressions were performed for each of the service categories,
      with two outcomes: self-reported service receipt and service receipt determined
      from the dental chart. Parameter estimate intervals overlapped for each of the
      four hypothesized predictors of service receipt (age group, sex, "race" defined
      as non-Hispanic African American vs. non-Hispanic white, and annual household
      income < 20,000 US dollars vs. > or = 20,000 US dollars), although for five of
      the 10 service categories, there were differences in conclusions about
      statistical significance for certain predictors. CONCLUSIONS: The validity of
      self-reported use of dental services ranged from poor to excellent, depending
      upon the service type. Regression estimates using either the self-reported or
      chart-validated measure yielded similar results overall, but conclusions about
      key predictors of service use differed in some instances. Self-reported dental
      service use is valid for some, but not all, service types.

PMID- 12604762
TI  - Rural/urban differences in access to and utilization of services among people in
      Alabama with sickle cell disease.
AB  - OBJECTIVE: This study examined relationships between socioeconomic factors and
      the geographic distribution of 662 cases of sickle cell disease in Alabama in
      1999-2001. METHODS: Measures of community distress, physical functioning, and
      medical problems were used in analyzing utilization differences between
      individuals with sickle cell disease living in urban and rural areas. RESULTS:
      Utilization of comprehensive sickle cells disease services was lower for
      individuals with sickle cell disease living in rural areas than for those living
      in urban areas. Rural clients reported significantly more limitations than urban
      clients on several measures of physical functioning. The results also suggest
      that utilization of services was higher for those with more medical problems and
      those who lived in high distress areas, although these findings did not meet the
      criterion for statistical significance. CONCLUSIONS: Conclusions based on
      statistical evidence that geographic location and socioeconomic factors relate to
      significantly different health care service experience bear important
      implications for medical and health care support systems, especially on the
      community level.

PMID- 12604763
TI  - On-site HIV testing in residential drug treatment units: results of a nationwide
      survey.
AB  - OBJECTIVE: Residential drug treatment units are uniquely situated to provide HIV
      testing and counseling to their patients. This article examines the extent to
      which residential drug treatment units in the United States provide HIV testing
      on-site, and identifies organizational and institutional characteristics that
      differentiate units in which on-site HIV testing is available from those in which
      it is not. METHODS: The analyses use data collected in telephone interviews with
      unit managers from a random nationwide sample (N = 138) of residential drug
      treatment units in 2001. RESULTS: About half (48.6%) of the residential drug
      treatment units made HIV testing available to their patients on-site. Residential
      units were significantly more likely to make on-site testing available if they
      were larger (i.e., had a greater number of patients treated each month or had a
      greater number of staff that provided direct patient services) and if they were
      publicly rather than privately owned. Provision of on-site HIV testing was
      significantly correlated with having a medical orientation, i.e., with being
      operated by a hospital, with the unit viewing itself as patients' primary medical
      provider, or with providing medical care to the patients either on-site or at
      another part of the same treatment agency. CONCLUSION: In view of the critical
      importance of HIV testing for individuals who use illicit drugs and the existence
      of a simplified testing protocol involving saliva samples (eliminating the need
      for phlebotomy), units that do not have a medical orientation should be
      encouraged to make HIV testing available on-site.

PMID- 12604764
TI  - Neighborhood environment, racial position, and risk of police-reported domestic
      violence: a contextual analysis.
AB  - OBJECTIVES: The purpose of this study was to examine the contribution of
      neighborhood socioeconomic conditions to risk of police-reported domestic
      violence in relation to victim's race. Data on race came from police forms
      legally mandated for the reporting of domestic violence and sexual assault.
      METHODS: Using 1990 U.S. census block group data and data for the years 1996-1998
      from Rhode Island's domestic violence surveillance system, the authors generated
      annual and relative risk of police-reported domestic violence and estimates of
      trends stratified by age, race (black, Hispanic, or white), and neighborhood
      measures of socioeconomic conditions. Race-specific linear regression models were
      constructed with average annual risk of police-reported domestic violence as the
      dependent variable. RESULTS: Across all levels of neighborhood poverty (< 5% to
      100% of residents living below the federal poverty level), the risk of police
      reported domestic violence was higher for Hispanic and black women than for white
      women. Results from the linear regression models varied by race. For black women,
      living in a census block group in which fewer than 10% of adults ages > or = 25
      years were college-educated contributed independently to risk of police-reported
      domestic violence. Block group measures of relative poverty (> or = 20% of
      residents living below 200% of the poverty line) and unemployment (> or = 10% of
      adults ages > or = 16 years in the labor force but unemployed) did not add to
      this excess. For Hispanic women, three neighborhood-level measures were
      significant: percentage of residents living in relative poverty, percentage of
      residents without college degrees, and percentage of households monolingual in
      Spanish. A higher degree of linguistic isolation, as defined by the percentage of
      monolingual Spanish households, decreased risk among the most isolated block
      groups for Hispanic women. For white women, neighborhood-level measures of
      poverty, unemployment, and education were significant determinants of police
      reported domestic violence. CONCLUSION: When data on neighborhood conditions at
      the block group level and their interaction with individual racial position are
      linked to population-based surveillance systems, domestic violence intervention
      and prevention efforts can be improved.

PMID- 12604765
TI  - Outbreak of beriberi among illegal mainland Chinese immigrants at a detention
      center in Taiwan.
AB  - OBJECTIVE: The authors describe an outbreak of beriberi in a detention center in
      Taiwan and examine risk factors for illness. METHODS: A survey was conducted
      among a sample of 176 randomly selected detainees. A menu-assisted dietary recall
      method was used to obtain diet information from nine hospitalized detainees. A
      probable case patient was defined as an individual who had at least two of the
      following characteristics: leg edema, weakness of the extremities, poor appetite,
      and dyspnea. Possible case patients were those who had only one of these
      characteristics. RESULTS: Of the 176 survey respondents, 19% were classified as
      probable case patients and 40% as possible case patients. The mortality rate
      based on probable cases was 1.1%. Body Mass Index (BMI) was negatively associated
      with illness (p < 0.0001), and length of stay in the detention center was
      independently positively associated with illness (p < 0.05). The average intake
      of dietary thiamine among the nine hospitalized case patients who completed three
      day dietary recall surveys was 0.49 +/- 0.1 mg/day. After thiamine
      administration, all symptoms and signs of beriberi resolved. CONCLUSION: This
      outbreak is a reminder of the importance of ensuring adequate diets for poor,
      institutionalized, or refugee populations who are unable to supplement their
      diets.

PMID- 12604768
TI  - IOM: overhaul of public health education needed.

PMID- 12604766
TI  - Climatic variables and transmission of malaria: a 12-year data analysis in
      Shuchen County, China.
AB  - OBJECTIVE: The objective of this study was to explore the impact of climate
      variability on the transmission of malaria, a vector-borne disease, in a county
      of China and provide suggestions to similar regions for disease prevention.
      METHODS: A time-series analysis was conducted using data on monthly climatic
      variables and monthly incidence of malaria in Shuchen County, China, for the
      period 1980-1991. RESULTS: Spearman's correlation analysis showed that monthly
      mean maximum and minimum temperatures, two measures of monthly mean relative
      humidity, and monthly amount of precipitation were positively correlated with the
      monthly incidence of malaria in the county. Regression analysis suggested that
      monthly mean minimum temperature and total monthly rainfall, with a one-month
      lagged effect, were significant climatic variables in the transmission of malaria
      in Shuchen County. Seasonality was also significant in the regression model and
      there was a declining secular trend in the incidence of malaria. CONCLUSION: The
      results indicate that climatic variables should be considered as possible
      predictors for regions with similar geographic, climatic, and socioeconomic
      conditions to those of Shuchen County.

PMID- 12604769
TI  - IOM: overhaul of government public health infrastructure, new partners needed.

PMID- 12604770
TI  - Mutual exchanges support academic and community collaboration.

PMID- 12604771
TI  - Single-locus heterotic effects and dominance by dominance interactions can
      adequately explain the genetic basis of heterosis in an elite rice hybrid.
AB  - The genetic basis of heterosis of an elite rice hybrid was investigated by using
      an "immortalized F(2)" population produced by randomly permutated intermating of
      240 recombinant inbred lines from a cross between the parents of Shanyou 63, the
      most widely cultivated hybrid in China. Measurements of heterosis for crosses in
      the immortalized F(2) population were obtained from replicated field trials over
      2 years by inter-planting the hybrids with the parental recombinant inbred lines.
      The analyses were conducted making use of a linkage map comprising 231
      segregating molecular marker loci covering the entire rice genome. Heterotic
      effects were detected at 33 loci for the four traits with modified composite
      interval mapping. The heterotic loci showed little overlap with quantitative
      trait loci for trait performance, suggesting that heterosis and trait performance
      may be conditioned by different sets of loci. Large numbers of digenic
      interactions were resolved by using two-way ANOVA and confirmed by randomization
      tests. All kinds of genetic effects, including partial-, full-, and overdominance
      at single-locus level and all three forms of digenic interactions (additive by
      additive, additive by dominance, and dominance by dominance), contributed to
      heterosis in the immortalized F(2) population, indicating that these genetic
      components were not mutually exclusive in the genetic basis of heterosis.
      Heterotic effects at the single-locus level, in combination with the marginal
      advantages of double heterozygotes caused by dominance by dominance interaction
      at the two-locus level could adequately explain the genetic basis of heterosis in
      Shanyou 63. These results may help reconcile the century-long debate concerning
      the genetic basis of heterosis.

PMID- 12604772
TI  - Community disassembly by an invasive species.
AB  - Invasive species pose serious threats to community structure and ecosystem
      function worldwide. The impacts of invasive species can be more pervasive than
      simple reduction of species numbers. By using 7 years of data in a biological
      preserve in northern California, we documented the disassembly of native ant
      communities during an invasion by the Argentine ant. In sites without the
      Argentine ant, native ant communities exhibit significant species segregation,
      consistent with competitive dynamics. In sites with the Argentine ant, native ant
      communities appear random or weakly aggregated in species co-occurrence.
      Comparisons of the same sites before and after invasion indicate that the shift
      from a structured to a random community is rapid and occurs within a year of
      invasion. Our results show that invasive species not only reduce biodiversity but
      rapidly disassemble communities and, as a result, alter community organization
      among the species that persist.

PMID- 12604773
TI  - The pair of bacteriophytochromes from Agrobacterium tumefaciens are histidine
      kinases with opposing photobiological properties.
AB  - Bacteriophytochrome photoreceptors (BphPs) are a family of phytochrome-like
      sensor kinases that help a wide variety of bacteria respond to their light
      environment. In Agrobacterium tumefaciens, a unique pair of BphPs with
      potentially opposing roles in light sensing are present. Both AtBphPs contain an
      N-terminal chromophore-binding domain that covalently attaches a biliverdin
      chromophore. Whereas AtBphP1 assumes a Pr ground state, AtBphP2 is unusual in
      that it assumes a Pfr ground state that is produced nonphotochemically after
      biliverdin binding through a transient Pr-like intermediate. Photoconversion of
      AtBphP2 with far-red light then generates Pr but this Pr is also unstable and
      rapidly reverts nonphotochemically to Pfr. AtBphP1 contains a typical two
      component histidine kinase domain at its C terminus whose activity is repressed
      after photoconversion to Pfr. AtBphP2 also functions as a histidine kinase but
      instead uses a distinct two-component kinase motif that is repressed after
      photoconversion to Pr. We identified sequences related to this domain in numerous
      predicted sensing proteins in A. tumefaciens and other bacteria, indicating that
      AtBphP2 might represent the founding member of a family of histidine phosphorelay
      proteins that is widely used in environmental signaling. By using these mutually
      opposing BphPs, A. tumefaciens presumably has the capacity to simultaneously
      sense red light-rich and far-red light-rich environments through deactivation of
      their associated kinase cascades.

PMID- 12604774
TI  - Evidence for defective retinoid transport and function in late onset Alzheimer's
      disease.
AB  - The hypothesis of this article is that late onset Alzheimer's disease (AD) is
      influenced by the availability in brain of retinoic acid (RA), the final product
      of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and
      environmental/dietary evidence is cited supporting this hypothesis. Significant
      genetic linkages to AD are demonstrated for markers close to four of the six RA
      receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X
      receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding
      proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23
      and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid
      hypofunction and impaired transport as contributing factors. These findings
      suggest testable experiments to determine whether increasing the availability of
      retinoid in brain, possibly through pharmacologic targeting of the RA receptors
      and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid
      plaque formation.

PMID- 12604775
TI  - T cell receptor (TCR) alpha/delta locus enhancer identity and position are
      critical for the assembly of TCR delta and alpha variable region genes.
AB  - T cell receptor (TCR) delta and alpha variable region genes are assembled from
      germ-line gene segments located in a single chromosomal locus in which TCR delta
      segments are situated between TCR alpha segments. The TCR alpha enhancer (E
      alpha) located at the 3' end of the TCR alpha/delta locus functions over a long
      chromosomal distance to promote TCR alpha rearrangement and maximal TCR delta
      expression; whereas the TCR delta enhancer (E delta) is located among the TCR
      delta segments and functions with additional element(s) to mediate TCR delta
      rearrangement. We used gene-targeted mutation to evaluate whether the identity of
      E alpha and the position of E delta are critical for the developmental stage
      specific assembly of TCR delta and alpha variable region genes. Specific
      replacement of E alpha with E delta, the core E alpha element (E alpha C), or the
      Ig heavy chain intronic enhancer (iE mu), all of which promote accessibility in
      the context of transgenic V(D)J recombination substrates, did not promote a
      significant level of TCR alpha rearrangement beyond that observed in the absence
      of E alpha. Therefore, the identity and full complement of E alpha-binding sites
      are critical for promoting accessibility within the TCR alpha locus. In the
      absence of the endogenous E delta element, specific replacement of E alpha with E
      delta also did not promote TCR delta rearrangement. However, deletion of
      intervening TCR alpha/delta locus sequences to restore the inserted E delta to
      its normal chromosomal position relative to 5' sequences rescued TCR delta
      rearrangement. Therefore, unlike E alpha, E delta lacks ability to function over
      the large intervening TCR alpha locus and or E delta function requires proximity
      to additional upstream element(s) to promote TCR delta accessibility.

PMID- 12604776
TI  - Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src
      and growth factor receptors.
AB  - Cellular Src and epidermal growth factor receptor (EGFR) collaborate in the
      progression of certain human malignancies, and their cooverexpression
      characterizes relatively aggressive animal tumors. Our study addressed the mode
      of oncogenic cooperation and reports that overexpression of c-Src in model
      cellular systems results in the accumulation of EGFR at the cell surface. The
      underlying mechanism involves inhibition of the normal, c-Cbl-regulated process
      of ligand-induced receptor down-regulation. In response to activation of c-Src, c
      Cbl proteins undergo tyrosine phosphorylation that promotes their ubiquitylation
      and proteasomal destruction. Consequently, ubiquitylation of EGFR by c-Cbl is
      restrained in Src-transformed cells, and receptor sorting to endocytosis is
      impaired. In conclusion, by promoting destruction of c-Cbl, c-Src enables EGFR to
      evade desensitization, which explains Src-EGFR collaboration in oncogenesis.

PMID- 12604777
TI  - Nonhomologous end joining and V(D)J recombination require an additional factor.
AB  - DNA nonhomologous end-joining (NHEJ) is the major pathway for repairing DNA
      double-strand breaks in mammalian cells. It also functions to carry out
      rearrangements at the specialized breaks introduced during V(D)J recombination.
      Here, we describe a patient with T(-)B(-) severe combined immunodeficiency, whose
      cells have defects closely resembling those of NHEJ-defective rodent cells. Cells
      derived from this patient show dramatic radiosensitivity, decreased double-strand
      break rejoining, and reduced fidelity in signal and coding joint formation during
      V(D)J recombination. Detailed examination indicates that the patient is defective
      neither in the known factors involved in NHEJ in mammals (Ku70, Ku80, DNA
      dependent protein kinase catalytic subunit, Xrcc4, DNA ligase IV, or Artemis) nor
      in the Mre11/Rad50/Nbs1 complex, whose homologue in Saccharomyces cerevisiae
      functions in NHEJ. These results provide strong evidence that additional
      activities are crucial for NHEJ and V(D)J recombination in mammals.

PMID- 12604779
TI  - Transcriptional analysis of the B cell germinal center reaction.
AB  - The germinal center (GC) reaction is crucial for T cell-dependent immune
      responses and is targeted by B cell lymphomagenesis. Here we analyzed the
      transcriptional changes that occur in B cells during GC transit (naive B cells -
      > centroblasts --> centrocytes --> memory B cells) by gene expression profiling.
      Naive B cells, characterized by the expression of cell cycle-inhibitory and
      antiapoptotic genes, become centroblasts by inducing an atypical proliferation
      program lacking c-Myc expression, switching to a proapoptotic program, and down
      regulating cytokine, chemokine, and adhesion receptors. The transition from GC to
      memory cells is characterized by a return to a phenotype similar to that of naive
      cells except for an apoptotic program primed for both death and survival and for
      changes in the expression of cell surface receptors including IL-2 receptor beta.
      These results provide insights into the dynamics of the GC reaction and represent
      the basis for the analysis of B cell malignancies.

PMID- 12604778
TI  - Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological
      evidence for a role in Huntington's disease.
AB  - Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine
      (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to
      involve the formation of neuronal intranuclear inclusions and the abnormal
      regulation of transcription and signal transduction. To identify previously
      uncharacterized htt-interacting proteins in a simple model system, we used a
      yeast two-hybrid screen with a Caenorhabditis elegans activation domain library.
      We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal
      htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting
      protein 4 (CIP4), a protein involved in Cdc42 and Wiskott-Aldrich syndrome
      protein-dependent signal transduction. CIP4 interacted in vitro with full-length
      htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with
      neuropathological severity in the neostriatum of HD patients and partially
      colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was
      observed in Western blot from human HD brain striatum. The overexpression of CIP4
      induced the death of striatal neurons. Our data suggest that CIP4 accumulation
      and cellular toxicity may have a role in HD pathogenesis.

PMID- 12604780
TI  - The FKBP-associated protein FAP48 is an antiproliferative molecule and a player
      in T cell activation that increases IL2 synthesis.
AB  - FAP48 was identified and cloned thanks to its interaction with FK506-binding
      proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of
      immunophilins that bind the macrolide immunosuppressant drugs FK506 and
      rapamycin. We have previously shown that FAP48-FKBP complexes are dissociated by
      FK506 and rapamycin, suggesting that FAP48 is an endogenous ligand of FKBP. The
      present work describes the biochemical consequences of FAP48 overexpression,
      induced by the tetracycline analogue doxycycline, in an established cell line
      derived from Jurkat T cells. We report that overexpression of FAP48 results in
      the inhibition of cellular proliferation as does the exposure of Jurkat T cells
      to FK506. We also show that the expression levels of argininosuccinate synthetase
      and the Myc antagonist Mxi1 are modified by overexpression of FAP48, suggesting
      that these proteins could be good candidates to mediate the antiproliferative
      effect of FAP48. FAP48 affects neither the calcineurin-dependent nuclear factor
      of activated T cells (NFAT)1 nor JNKp38-dependent pathways that mediate
      immunosuppression by FK506. However, contrary to FK506, which blocks IL2
      synthesis, we observed that FAP48-FKBP complexes increase IL2 production, thus
      revealing a previously uncharacterized aspect of the immunosuppressive mechanism
      of FK506.

PMID- 12604781
TI  - Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial
      calcium and Bcl-2 expression.
AB  - Estrogens are neuroprotective against glutamate excitotoxicity caused by an
      excessive rise in intracellular calcium ([Ca(2+)](i)). In this study, we
      demonstrate that 17 beta-estradiol (E(2)) treatment of hippocampal neurons
      attenuated the excitotoxic glutamate-induced rise in bulk-free [Ca(2+)](i)
      despite potentiating the influx of Ca(2+) induced by glutamate. E(2)-induced
      attenuation of bulk-free [Ca(2+)](i) depends on mitochondrial sequestration of
      Ca(2+), which is blocked in the presence of the combination of rotenone and
      oligomycin or in the presence of antimycin, which collapse the mitochondrial
      membrane potential, thereby preventing mitochondrial Ca(2+) transport. Release of
      mitochondrial Ca(2+) by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)
      after excitotoxic glutamate treatment resulted in a greater [Ca(2+)](i) in E(2)
      treated cells, indicating an E(2)-induced increase in the mitochondrial calcium
      ([Ca(2+)](m)) load. The increased [Ca(2+)](m) load was accompanied by increased
      expression of Bcl-2, which can promote mitochondrial Ca(2+) load tolerance. These
      findings provide a mechanism of E(2)-induced neuronal survival by attenuation of
      excitotoxic glutamate [Ca(2+)](i) rise via increased mitochondrial sequestration
      of cytosolic Ca(2+) coupled with an increase in Bcl-2 expression to sustain
      mitochondrial Ca(2+) load tolerance and function.

PMID- 12604782
TI  - Colocalization and nonrandom distribution of Kv1.3 potassium channels and CD3
      molecules in the plasma membrane of human T lymphocytes.
AB  - Distribution and lateral organization of Kv1.3 potassium channels and CD3
      molecules were studied by using electron microscopy, confocal laser scanning
      microscopy, and fluorescence resonance energy transfer. Immunogold labeling and
      electron microscopy showed that the distribution of FLAG epitope-tagged Kv1.3
      channels (Kv1.3/FLAG) significantly differs from the stochastic Poisson
      distribution in the plasma membrane of human T lymphoma cells. Confocal laser
      scanning microscopy images showed that Kv1.3/FLAG channels and CD3 molecules
      accumulated in largely overlapping membrane areas. The numerical analysis of
      crosscorrelation of the spatial intensity distributions yielded a high
      correlation coefficient (C = 0.64). A different hierarchical level of molecular
      proximity between Kv1.3/FLAG and CD3 proteins was reported by a high fluorescence
      resonance energy transfer efficiency (E = 51%). These findings implicate that
      reciprocal regulation of ion-channel activity, membrane potential, and the
      function of receptor complexes may contribute to the proper functioning of the
      immunological synapse.

PMID- 12604783
TI  - Stabilizing the open conformation of the integrin headpiece with a glycan wedge
      increases affinity for ligand.
AB  - The affinity of the extracellular domain of integrins for ligand is regulated by
      conformational changes signaled from the cytoplasm. Alternative types of
      conformational movement in the ligand-binding headpiece have been proposed. In
      one study, electron micrograph image averages of the headpiece of integrin aV
      beta 3 show two different conformations. The open conformation of the headpiece
      is present when a ligand mimetic peptide is bound and differs from the closed
      conformation in the presence of an obtuse angle between the beta 3 subunit hybrid
      and I-like domains. We tested the hypothesis that opening of the hybrid-I-like
      domain interface increases ligand-binding affinity by mutationally introducing an
      N-glycosylation site into it. Both beta 3 and beta1 integrin glycan wedge mutants
      exhibit constitutively high affinity for physiological ligands. The data uniquely
      support one model of integrin activation and suggest that movement at the
      interface with the hybrid domain pulls down the C-terminal helix of the I-like
      domain and activates its metal ion-dependent adhesion site, analogously to
      activation of the integrin I domain.

PMID- 12604784
TI  - Domestication quantitative trait loci in Triticum dicoccoides, the progenitor of
      wheat.
AB  - Wild emmer wheat, Triticum dicoccoides, is the progenitor of modern tetraploid
      and hexaploid cultivated wheats. Our objective was to map domestication-related
      quantitative trait loci (QTL) in T. dicoccoides. The studied traits include
      brittle rachis, heading date, plant height, grain size, yield, and yield
      components. Our mapping population was derived from a cross between T.
      dicoccoides and Triticum durum. Approximately 70 domestication QTL effects were
      detected, nonrandomly distributed among and along chromosomes. Seven
      domestication syndrome factors were proposed, each affecting 5-11 traits. We
      showed: (i) clustering and strong effects of some QTLs; (ii) remarkable genomic
      association of strong domestication-related QTLs with gene-rich regions; and
      (iii) unexpected predominance of QTL effects in the A genome. The A genome of
      wheat may have played a more important role than the B genome during
      domestication evolution. The cryptic beneficial alleles at specific QTLs derived
      from T. dicoccoides may contribute to wheat and cereal improvement.

PMID- 12604785
TI  - Disorder in the nuclear pore complex: the FG repeat regions of nucleoporins are
      natively unfolded.
AB  - Nuclear transport proceeds through nuclear pore complexes (NPCs) that are
      embedded in the nuclear envelope of eukaryotic cells. The Saccharomyces
      cerevisiae NPC is comprised of 30 nucleoporins (Nups), 13 of which contain
      phenylalanine-glycine repeats (FG Nups) that bind karyopherins and facilitate the
      transport of karyopherin-cargo complexes. Here, we characterize the structural
      properties of S. cerevisiae FG Nups by using biophysical methods and predictive
      amino acid sequence analyses. We find that FG Nups, particularly the large FG
      repeat regions, exhibit structural characteristics typical of "natively unfolded"
      proteins (highly flexible proteins that lack ordered secondary structure).
      Furthermore, we use protease sensitivity assays to demonstrate that most FG Nups
      are disordered in situ within the NPCs of purified yeast nuclei. The conclusion
      that FG Nups constitute a family of natively unfolded proteins supports the
      hypothesis that the FG repeat regions of Nups form a meshwork of random coils at
      the NPC through which nuclear transport proceeds.

PMID- 12604786
TI  - Neural deficits in children with dyslexia ameliorated by behavioral remediation:
      evidence from functional MRI.
AB  - Developmental dyslexia, characterized by unexplained difficulty in reading, is
      associated with behavioral deficits in phonological processing. Functional
      neuroimaging studies have shown a deficit in the neural mechanisms underlying
      phonological processing in children and adults with dyslexia. The present study
      examined whether behavioral remediation ameliorates these dysfunctional neural
      mechanisms in children with dyslexia. Functional MRI was performed on 20 children
      with dyslexia (8-12 years old) during phonological processing before and after a
      remediation program focused on auditory processing and oral language training.
      Behaviorally, training improved oral language and reading performance.
      Physiologically, children with dyslexia showed increased activity in multiple
      brain areas. Increases occurred in left temporo-parietal cortex and left inferior
      frontal gyrus, bringing brain activation in these regions closer to that seen in
      normal-reading children. Increased activity was observed also in right-hemisphere
      frontal and temporal regions and in the anterior cingulate gyrus. Children with
      dyslexia showed a correlation between the magnitude of increased activation in
      left temporo-parietal cortex and improvement in oral language ability. These
      results suggest that a partial remediation of language-processing deficits,
      resulting in improved reading, ameliorates disrupted function in brain regions
      associated with phonological processing and produces additional compensatory
      activation in other brain regions.

PMID- 12604787
TI  - Origin and evolution of circadian clock genes in prokaryotes.
AB  - Regulation of physiological functions with approximate daily periodicity, or
      circadian rhythms, is a characteristic feature of eukaryotes. Until recently,
      cyanobacteria were the only prokaryotes reported to possess circadian
      rhythmicity. It is controlled by a cluster of three genes: kaiA, kaiB, and kaiC.
      Using sequence data of approximately 70 complete prokaryotic genomes from the
      various public depositories, we show here that the kai genes and their homologs
      have quite a different evolutionary history and occur in Archaea and
      Proteobacteria as well. Among the three genes, kaiC is evolutionarily the oldest,
      and kaiA is the youngest and likely evolved only in cyanobacteria. Our data
      suggest that the prokaryotic circadian pacemakers have evolved in parallel with
      the geological history of the earth, and that natural selection, multiple lateral
      transfers, and gene duplications and losses have been the major factors shaping
      their evolution.

PMID- 12604788
TI  - Dopamine controls the firing pattern of dopamine neurons via a network feedback
      mechanism.
AB  - Changes in the firing pattern of midbrain dopamine neurons are thought to encode
      information for certain types of reward-related learning. In particular, the
      burst pattern of firing is predicted to result in more efficient dopamine release
      at target loci, which could underlie changes in synaptic plasticity. In this
      study, the effects of dopamine on the firing patterns of dopaminergic neurons in
      vivo and their electrophysiological characteristics in vitro were examined by
      using a genetic dopamine-deficient (DD) mouse model. Extracellular recordings in
      vivo showed that, although the firing pattern of dopamine neurons in normal mice
      included bursting activity, DD mice recordings showed only a single-spike pattern
      of activity with no bursts. Bursting was restored in DD mice after systemic
      administration of the dopamine precursor, L-3,4-dihydroxyphenylalanine (L-dopa).
      Whole-cell recordings in vitro demonstrated that the basic electrophysiology and
      pharmacology of dopamine neurons were identical between DD and control mice,
      except that amphetamine did not elicit a hyperpolarizing current in slices from
      DD mice. These data suggest that endogenously released dopamine plays a critical
      role in the afferent control of dopamine neuron bursting activity and that this
      control is exerted via a network feedback mechanism.

PMID- 12604789
TI  - The role of E2F4 in adipogenesis is independent of its cell cycle regulatory
      activity.
AB  - The E2F and pocket protein families are known to play an important role in the
      regulation of both cellular proliferation and terminal differentiation. In this
      study, we have used compound E2F and pocket protein mutant mouse embryonic
      fibroblasts to dissect the role of these proteins in adipogenesis. This analysis
      shows that loss of E2F4 allows cells to undergo spontaneous differentiation. The
      ability of E2F4 to prevent adipogenesis seems to be quite distinct from the known
      properties of E2F. First, it can be separated from any change in either E2F
      responsive gene expression or cell cycle regulation. Second, it is a specific
      property of E2F4, and not other E2Fs, and it occurs independently of E2F4's
      ability to interact with pocket proteins. In addition, E2F4 loss does not
      override the differentiation defect resulting from pRB loss even though it
      completely suppresses the proliferation defect of Rb(-/-) mouse embryonic
      fibroblasts. This finding definitively separates the known, positive role of pRB
      in adipogenesis from its cell cycle function and shows that this pocket protein
      is required to act downstream of E2F4 in the differentiation process.

PMID- 12604790
TI  - The Cdc23 (Mcm10) protein is required for the phosphorylation of minichromosome
      maintenance complex by the Dfp1-Hsk1 kinase.
AB  - Previous studies in Saccharomyces cerevisiae have defined an essential role for
      the Dbf4-Cdc7 kinase complex in the initiation of DNA replication presumably by
      phosphorylation of target proteins, such as the minichromosome maintenance (Mcm)
      complex. We have examined the phosphorylation of the Mcm complex by the Dfp1-Hsk1
      kinase, the Schizosaccharomyces pombe homologue of Dbf4-Cdc7. In vitro, the
      purified Dfp1-Hsk1 kinase efficiently phosphorylated Mcm2p. In contrast, Mcm2p,
      present in the six-subunit Mcm complex, was a poor substrate of this kinase and
      required Cdc23p (homologue of Mcm10p) for efficient phosphorylation. In the
      presence of Cdc23p, Dfp1-Hsk1 phosphorylated the Mcm2p and Mcm4p subunits of the
      Mcm complex. Cdc23p interacted with both the Mcm complex and Dfp1-Hsk1 by
      selectively binding to the Mcm467 subunits and Dfp1p, respectively. The N
      terminus of Cdc23p was found to interact directly with Dfp1-Hsk1 and was
      essential for phosphorylation of the Mcm complex. Truncated derivatives of Cdc23p
      that complemented the temperature-sensitive phenotype of cdc23 mutant cells also
      stimulated the phosphorylation of Mcm complex, implying that this activity might
      be a critical role of Cdc23p in vivo. These results suggest that Cdc23p
      participates in the activation of prereplicative complex by recruiting the Dfp1
      Hsk1 kinase and stimulating the phosphorylation of the Mcm complex.

PMID- 12604791
TI  - Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q.
AB  - Substantial evidence supports that there is a genetic component to panic disorder
      (PD). Until recently, attempts at localizing genes for PD by using standard
      phenotypic data have not proven successful. Previous work suggests that a
      potential subtype of PD called the panic syndrome exists, and it is characterized
      by a number of medical conditions, most notably bladder/renal disorders. In the
      current study, a genome scan with 384 microsatellite markers was performed on 587
      individuals in 60 multiplex pedigrees segregating PD and bladder/kidney
      conditions. Using both single-locus and multipoint analytic methods, we found
      significant linkage on chromosome 22 (maximum heterogeneity logarithm of odds
      score = 4.11 at D22S445) and on chromosome 13q (heterogeneity logarithm of odds
      score = 3.57 at D13S793) under a dominant-genetic model and a broad phenotypic
      definition. Multipoint analyses did not support the observation on chromosome 22.
      The chromosome 13 findings were corroborated by multipoint findings, and extend
      our previous findings from 19 of the 60 families. Several other regions showed
      elevated scores by using when one analytic method was used, but not the other.
      These results suggest that there are genes on chromosome 13q, and possibly on
      chromosome 22 as well, that influence the susceptibility toward a pleiotropic
      syndrome that includes PD, bladder problems, severe headaches, mitral valve
      prolapse, and thyroid conditions.

PMID- 12604793
TI  - Interferon-inducible gene expression signature in peripheral blood cells of
      patients with severe lupus.
AB  - Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease
      that affects multiple organ systems. We used global gene expression profiling of
      peripheral blood mononuclear cells to identify distinct patterns of gene
      expression that distinguish most SLE patients from healthy controls. Strikingly,
      about half of the patients studied showed dysregulated expression of genes in the
      IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker
      for more severe disease involving the kidneys, hematopoetic cells, and/or the
      central nervous system. These results provide insights into the genetic pathways
      underlying SLE, and identify a subgroup of patients who may benefit from
      therapies targeting the IFN pathway.

PMID- 12604792
TI  - The endocrine-gland-derived VEGF homologue Bv8 promotes angiogenesis in the
      testis: Localization of Bv8 receptors to endothelial cells.
AB  - We recently identified an angiogenic mitogen, endocrine-gland-derived vascular
      endothelial growth factor (EG-VEGF), with selective activity for endothelial
      cells of endocrine tissues. Here we describe the characterization of a highly
      related molecule, Bv8, also known as prokineticin-2. Human Bv8 shares 60%
      identity and 75% similarity with EG-VEGF. The human and mouse Bv8 genes share a
      common structure. Like EG-VEGF, Bv8 is able to induce proliferation, survival and
      migration of adrenal cortical capillary endothelial cells. Bv8 gene expression is
      induced by hypoxic stress. Bv8 expression occurs predominantly in the testis and
      is largely restricted to primary spermatocytes. Adenoviral delivery of Bv8 or EG
      VEGF to the mouse testis resulted in a potent angiogenic response. We have
      localized the expression of the Bv8EG-VEGF receptors within the testis to
      vascular endothelial cells. The testis exhibits relatively high turnover of
      endothelial cells. Therefore, Bv8 and EG-VEGF, along with other factors such as
      VEGF-A, may maintain the integrity and also regulate proliferation of the blood
      vessels in the testis.

PMID- 12604794
TI  - von Hippel-Lindau protein binds hyperphosphorylated large subunit of RNA
      polymerase II through a proline hydroxylation motif and targets it for
      ubiquitination.
AB  - The transition from transcription initiation to elongation involves
      phosphorylation of the large subunit (Rpb1) of RNA polymerase II on the
      repetitive carboxyl-terminal domain. The elongating hyperphosphorylated Rpb1 is
      subject to ubiquitination, particularly in response to UV radiation and DNA
      damaging agents. By using computer modeling, we identified regions of Rpb1 and
      the adjacent subunit 6 of RNA polymerase II (Rpb6) that share sequence and
      structural similarity with the domain of hypoxia-inducible transcription factor 1
      alpha (HIF-1 alpha) that binds von Hippel-Lindau tumor suppressor protein (pVHL).
      pVHL confers substrate specificity to the E3 ligase complex, which ubiquitinates
      HIF-alpha and targets it for proteasomal degradation. In agreement with the
      computational model, we show biochemical evidence that pVHL specifically binds
      the hyperphosphorylated Rpb1 in a proline-hydroxylation-dependent manner,
      targeting it for ubiquitination. This interaction is regulated by UV radiation.

PMID- 12604795
TI  - Structural basis for recognition by an in vitro evolved affibody.
AB  - The broad binding repertoire of antibodies has permitted their use in a wide
      range of applications. However, some uses of antibodies are precluded due to
      limitations in the efficiency of antibody generation. In vitro evolved binding
      proteins, selected from combinatorial libraries generated around various
      alternative structural scaffolds, are promising alternatives to antibodies. We
      have solved the crystal structure of a complex of an all alpha-helical in vitro
      selected binding protein (affibody) bound to protein Z, an IgG Fc-binding domain
      derived from staphylococcal protein A. The structure of the complex reveals an
      extended and complementary binding surface with similar properties to protein
      antibody interactions. The surface region of protein Z recognized by the affibody
      is strikingly similar to the one used for IgG(1) Fc binding, suggesting that this
      surface contains potential hot-spots for binding. The implications of the
      selected affibody binding-mode for its application as a universal binding protein
      are discussed.

PMID- 12604796
TI  - The Tre2 (USP6) oncogene is a hominoid-specific gene.
AB  - Gene duplication and domain accretion are thought to be the major mechanisms for
      the emergence of novel genes during evolution. Such events are thought to have
      occurred at early stages in the vertebrate lineage, but genomic sequencing has
      recently revealed extensive amplification events during the evolution of higher
      primates. We report here that the Tre2 (USP6) oncogene is derived from the
      chimeric fusion of two genes, USP32 (NY-REN-60), and TBC1D3. USP32 is an ancient,
      highly conserved gene, whereas TBC1D3 is derived from a recent segmental
      duplication, which is absent in most other mammals and shows rapid amplification
      and dispersal through the primate lineage. Remarkably, the chimeric gene Tre2
      exists only in the hominoid lineage of primates. This hominoid-specific oncogene
      arose as recently as 21-33 million years ago, after proliferation of the TBC1D3
      segmental duplication in the primate lineage. In contrast to the broad expression
      pattern of USP32 and TBC1D3, expression of Tre2 is testis-specific, a pattern
      proposed for novel genes implicated in the emergence of reproductive barriers.
      The sudden emergence of chimeric proteins, such as that encoded by Tre2, may have
      contributed to hominoid speciation.

PMID- 12604797
TI  - Yeast Rad17/Mec3/Ddc1: a sliding clamp for the DNA damage checkpoint.
AB  - The Saccharomyces cerevisiae Rad24 and Rad17 checkpoint proteins are part of an
      early response to DNA damage in a signal transduction pathway leading to cell
      cycle arrest. Rad24 interacts with the four small subunits of replication factor
      C (RFC) to form the RFC-Rad24 complex. Rad17 forms a complex with Mec3 and Ddc1
      (Rad1731) and shows structural similarities with the replication clamp PCNA. This
      parallelism with a clamp-clamp loader system that functions in DNA replication
      has led to the hypothesis that a similar clamp-clamp loader relationship exists
      for the DNA damage response system. We have purified the putative checkpoint
      clamp loader RFC-Rad24 and the putative clamp Rad1731 from a yeast overexpression
      system. Here, we provide experimental evidence that, indeed, the RFC-Rad24 clamp
      loader loads the Rad1731 clamp around partial duplex DNA in an ATP-dependent
      process. Furthermore, upon ATP hydrolysis, the Rad1731 clamp is released from the
      clamp loader and can slide across more than 1 kb of duplex DNA, a process which
      may be well suited for a search for damage. Rad1731 showed no detectable
      exonuclease activity.

PMID- 12604798
TI  - Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by
      high-throughput crystallization.
AB  - Pharmaceutical compounds are molecular solids that frequently exhibit
      polymorphism of crystal form. One high profile case of polymorphism was
      ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in
      1996. In 1998, a lower energy, more stable polymorph (form II) appeared, causing
      slowed dissolution of the marketed dosage form and compromising the oral
      bioavailability of the drug. This event forced the removal of the oral capsule
      formulation from the market. We have carried out high-throughput crystallization
      experiments to comprehensively explore ritonavir form diversity. A total of five
      forms were found: both known forms and three previously unknown forms. The novel
      forms include a metastable polymorph, a hydrate phase, and a formamide solvate.
      The solvate was converted to form I via the hydrate phase by using a simple
      washing procedure, providing an unusual route to prepare the form I "disappearing
      polymorph" [Dunitz, J. D. & Bernstein, J. (1995) Acc. Chem. Res. 28, 193-200].
      Crystals of form I prepared by using this method retained the small needle
      morphology of the solvate and thus offer a potential strategy for particle size
      and morphology control.

PMID- 12604799
TI  - Structural specificity of heparin binding in the fibroblast growth factor family
      of proteins.
AB  - Heparin and heparan sulfate glycosaminoglycans (HSGAGs) mediate a wide variety of
      complex biological processes by specifically binding proteins and modulating
      their biological activity. One of the best studied model systems for protein
      HSGAG interactions is the fibroblast growth factor (FGF) family of molecules, and
      recent observations have demonstrated that the specificity of a given FGF ligand
      binding to its cognate receptor (FGFR) is mediated by distinct tissue-specific
      HSGAG sequences. Although it has been known that sulfate and carboxylate groups
      in the HSGAG chain play a key role by interacting with basic residues on the
      proteins, there is little understanding of how these ionic interactions provide
      the necessary specificity for protein binding. In this study, using all of the
      available crystal structures of different FGFs and FGF-HSGAG complexes, we show
      that in addition to the ionic interactions, optimal van der Waals contact between
      the HSGAG oligosaccharide and the protein is also very important in influencing
      the specificity of FGF-HSGAG interactions. Although the overall helical structure
      is maintained in the FGF-bound HSGAG compared with unbound HSGAG, we observe
      distinct changes in the backbone torsion angles of the oligosaccharide chain
      induced upon protein binding. These changes result in local deviations in the
      helical axis that provide optimal ionic and van der Waals contact with the
      protein. A specific conformation and topological arrangement of the HSGAG-binding
      loops of FGF, on the other hand, impose structural constraints that induce the
      local deviations in the HSGAG structure, thereby enabling maximum contact between
      HSGAG and the protein.

PMID- 12604801
TI  - Reverse genetics studies on the filamentous morphology of influenza A virus.
AB  - We have investigated the genetic determinants responsible for the filamentous
      morphology of influenza A viruses, a property characteristic of primary virus
      isolates. A plasmid-based reverse genetics system was used to transfer the M
      segment of influenza A/Udorn/72 (H3N2) virus into influenza A/WSN/33 (H1N1)
      virus. While WSN virions display spherical morphology, recombinant WSN-Mud virus
      acquired the ability of the parental Udorn strain to form filamentous virus
      particles. This was determined by immunofluorescence studies in infected MDCK
      cells and by electron microscopy of purified virus particles. To determine the
      gene product within the M segment responsible for filamentous virus morphology,
      we generated four recombinant viruses carrying different sets of M1 and M2 genes
      from WSN or Udorn strains in a WSN background. These studies revealed that the M1
      gene of Udorn, independently of the origin of the M2 gene, conferred filamentous
      budding properties and filamentous virus morphology to the recombinant viruses.
      We also constructed two WSN viruses encoding chimeric M1 proteins containing the
      amino-terminal 1-162 amino acids or the carboxy-terminal 163-252 amino acids of
      the Udorn M1 protein. Neither of these two viruses acquired filamentous
      phenotypes, indicating that both amino- and carboxy-terminal domains of the M1
      protein contribute to filamentous virus morphology. We next rescued seven mutant
      WSN-M1ud viruses containing Udorn M1 proteins carrying single amino acid
      substitutions corresponding to the seven amino acid differences with the M1
      protein of WSN virus. Characterization of these recombinant viruses revealed that
      amino acid residues 95 and 204 are critical in determining filamentous virus
      particle formation.

PMID- 12604800
TI  - Alternative base pairs attenuate influenza A virus when introduced into the
      duplex region of the conserved viral RNA promoter of either the NS or the PA
      gene.
AB  - The development of plasmid-based rescue systems for influenza virus has allowed
      previous studies of the neuraminidase (NA) virion RNA (vRNA) promoter to be
      extended, in order to test the hypothesis that alternative base pairs in the
      conserved influenza virus vRNA promoter cause attenuation when introduced into
      other gene segments. Influenza A/WSN/33 viruses with alternative base pairs in
      the duplex region of the vRNA promoter of either the polymerase acidic (PA) or
      the NS (non-structural 1, NS1, and nuclear export, NEP, -encoding) gene have been
      rescued. Virus growth in MDBK cells demonstrated that one of the mutations, the
      D2 mutation (U-A replacing G-C at nucleotide positions 12'-11), caused
      significant virus attenuation when introduced into either the PA or the NS gene.
      The D2 mutation resulted in the reduction of PA- or NS-specific vRNA and mRNA
      levels in PA- or NS-recombinant viruses, respectively. Since the D2 mutation
      attenuates influenza virus when introduced into either the PA or the NS gene
      segments, or the NA gene segment, as demonstrated previously, this suggests that
      this mutation will lead to virus attenuation when introduced into any of the
      eight gene segments. Such a mutation may be useful in the production of live
      attenuated viruses.

PMID- 12604802
TI  - Genetic diversity and phylogenetic analysis of glycoprotein 5 of European-type
      porcine reproductive and respiratory virus strains in Spain.
AB  - The gene encoding glycoprotein 5 (ORF5) of 21 porcine reproductive and
      respiratory syndrome virus (PRRSV) isolates from Spain and two European-type
      vaccines currently available in that country were analysed using RT-PCR and
      sequencing. Sequences were then compared with other European-type sequences
      available through GenBank. Results showed percentages of similarity to Lelystad
      virus (LV), which, in most cases, were below 90 %. In contrast, two strains were
      very similar (>99 %) to a PRRSV variant from the Czech Republic. Evolutionary
      trees showed three types of strains: one grouped old Spanish sequences; a second
      grouped isolates from this study together with two Czech variant strains; and the
      third comprised other GenBank sequences. Regarding the predicted protein
      sequences, some isolates from this study showed a low degree of similarity to LV
      (below 50 %) and most of the strains examined had additional N-linked
      glycosylation sites compared to LV. These results provide evidence of the
      existence of variant PRRSV strains in Spain with characteristics that may be
      advantageous for immune evasion.

PMID- 12604804
TI  - Characterization of secreted and intracellular forms of a truncated hepatitis C
      virus E2 protein expressed by a recombinant herpes simplex virus.
AB  - A replication-defective herpes simplex virus type 1 (HSV-1) recombinant lacking
      the glycoprotein H (gH)-encoding gene and expressing a truncated form of the
      hepatitis C (HCV) E2 glycoprotein (E2-661) was constructed and characterized. We
      show here that cells infected with the HSV/HCV recombinant virus efficiently
      express the HCV E2-661 protein. Most importantly, cellular and secreted E2-661
      protein were both readily detected by the E2-conformational mAb H53 and despite
      the high expression levels, only limited amounts of misfolded aggregates were
      detected in either the cellular or secreted fractions. Furthermore, cell
      associated and secreted E2-661 protein bound to the major extracellular loop
      (MEL) of CD81 in a concentration-dependent manner and both were highly reactive
      with sera from HCV-infected patients. Finally, BALB/c mice immunized
      intraperitoneally with the recombinant HSV/HCV virus induced high levels of anti
      E2 antibodies. Analysis of the induced immunoglobulin G (IgG) isotypes showed
      high levels of IgG2a while the levels of the IgG1 isotype were significantly
      lower, suggesting a Th1-type of response. We conclude that the HSV-1 recombinant
      virus represents a promising tool for production of non-aggregated,
      immunologically active forms of the E2-661 protein and might have potential
      applications in vaccine development.

PMID- 12604803
TI  - The regulation of hepatitis C virus (HCV) internal ribosome-entry site-mediated
      translation by HCV replicons and nonstructural proteins.
AB  - Hepatitis C virus (HCV), the global leading cause of chronic liver disease, has a
      positive-sense, ssRNA genome that encodes a large polyprotein. HCV polyprotein
      translation is initiated by an internal ribosome-entry site (IRES) located at the
      5' end of the viral genome, in a cap-independent manner, but the regulatory
      mechanism of this process remains poorly understood. In this study, we
      characterized the effect of HCV nonstructural proteins on HCV IRES-directed
      translation in both HCV replicon cells and transiently transfected human liver
      cells expressing HCV nonstructural proteins. Using bicistronic reporter gene
      constructs carrying either HCV or other viral IRES sequences, we found that the
      HCV IRES-mediated translation was specifically upregulated in HCV replicon cells.
      This enhancement of HCV IRES-mediated translation by the replicon cells was
      inhibited by treatment with either type I interferon or ribavirin, drugs that
      perturb HCV genome replication, suggesting that the enhancement is probably due
      to HCV-encoded protein function(s). Reduced phosphorylation levels of both
      eIF2alpha and eIF4E were observed in the replicon cells, which is consistent with
      our previous findings and indicates that the NS5A nonstructural protein may be
      involved in the regulatory mechanism(s). Indeed, transient expression of NS5A or
      NS4B in human liver cells stimulated HCV IRES activity. Interestingly, mutation
      in the ISDR of NS5A perturbed this stimulation of HCV IRES activity. All these
      results suggest, for the first time, that HCV nonstructural proteins
      preferentially stimulate the viral cap-independent, IRES-mediated translation.

PMID- 12604806
TI  - Analysis of the subcellular localization of hepatitis C virus E2 glycoprotein in
      live cells using EGFP fusion proteins.
AB  - Hepatitis C virus (HCV) E1 and E2 glycoproteins assemble intracellularly to form
      a non-covalently linked heterodimer, which is retained in the endoplasmic
      reticulum (ER). To study the subcellular localization of E2 in live cells, the
      enhanced green fluorescent protein (EGFP) was fused to the N terminus of E2.
      Using fluorescence and confocal microscopy, we have confirmed that E2 is located
      in the ER, where budding of HCV virions is thought to occur. Immunoprecipitation
      experiments using a conformation-sensitive antibody and a GST pull-down assay
      showed that fusion of EGFP to E2 interferes neither with its heterodimeric
      assembly with E1, nor with proper folding of the ectodomain, nor with the
      capacity of E2 to interact with human CD81, indicating that the EGFP-E2 fusion
      protein is functional. As a tool to study binding of E2 to target cells, we also
      described the expression of an EGFP-E2 fusion protein at the cell surface.

PMID- 12604805
TI  - Identification and characterization of amphiphysin II as a novel cellular
      interaction partner of the hepatitis C virus NS5A protein.
AB  - The hepatitis C virus (HCV) NS5A protein is highly phosphorylated by cellular
      protein kinases. To study how NS5A might be integrated in cellular kinase
      signalling, we isolated phosphoproteins from HuH-7 hepatoma cells that
      specifically interacted with recombinant NS5A protein. Subsequent mass
      spectrometry identified the adaptor protein amphiphysin II as a novel interaction
      partner of NS5A. Mutational analysis revealed that complex formation is primarily
      mediated by a proline-rich region in the C-terminal part of NS5A, which interacts
      with the amphiphysin II Src homology 3 domain. Importantly, we could further
      demonstrate specific co-precipitation and cellular co-localization of endogenous
      amphiphysin II with NS5A in HuH-7 cells carrying a persistently replicating
      subgenomic HCV replicon. Although the NS5A-amphiphysin II interaction appeared to
      be dispensable for replication of these HCV RNAs in cell culture, our results
      indicate that NS5A-amphiphysin II complex formation might be of physiological
      relevance for the HCV life cycle.

PMID- 12604807
TI  - Role of type I and type II interferon responses in recovery from infection with
      an encephalitic flavivirus.
AB  - We have investigated the contribution of the interferon (IFN)-alpha/beta system,
      IFN-gamma and nitric oxide to recovery from infection with Murray Valley
      encephalitis virus, using a mouse model for flaviviral encephalitis where a small
      dose of virus was administered to 6-week-old wild-type and gene knockout animals
      by the intravenous route. We show that a defect in the IFN-alpha/beta responses
      results in uncontrolled extraneural virus growth, rapid virus entry into the
      brain and 100 % mortality. In contrast, mice deficient in IFN-gamma or nitric
      oxide production display an only marginally increased susceptibility to infection
      with the neurotropic virus.

PMID- 12604808
TI  - Characterization of a recombinant type 3/type 2 poliovirus isolated from a
      healthy vaccinee and containing a chimeric capsid protein VP1.
AB  - A Sabin 3/Sabin 2/Sabin 3 (S3/2/3) intertypic recombinant poliovirus was isolated
      from a faecal specimen from a 2-year-old healthy boy approximately 12 weeks after
      administration of oral poliovirus vaccine. The first recombination junction was
      in the genomic region encoding the VP1 capsid protein between nucleotide
      positions 3274 and 3285 (numbering according to Sabin 3) and the second was in
      the RNA polymerase region (nucleotide positions 6824 and 6825). The recombination
      had introduced six Sabin 2-derived amino acids into the Sabin 3 capsid
      environment in the carboxyl terminus of VP1. The complete genome of the
      recombinant virus differed from corresponding parental Sabin strains at 33
      nucleotide positions, nine of them resulting in an amino acid substitution. Four
      substitutions were in the capsid proteins and five were in the region encoding
      the non-structural proteins. One amino acid was changed in the antigenic site 2B
      and two in site 3B. In addition, the whole antigenic site 3A was replaced by
      Sabin 2-specific amino acids, but the antigenic characteristics of the S3/2/3 did
      not show type 2-specific features. Neutralizing antibody titres in sera from
      Finnish children immunized with the inactivated poliovirus vaccine were not lower
      against the recombinant virus than against Sabin 3. Our results suggest that the
      chimeric virus was most likely generated by recombination events in the vaccinee,
      rather than representing progeny of circulating vaccine-derived virus.

PMID- 12604809
TI  - Variation in the NS3 gene and protein in South African isolates of bluetongue and
      equine encephalosis viruses.
AB  - Bluetongue virus (BTV) and equine encephalosis virus (EEV) are agriculturally
      important orbiviruses transmitted by biting midges of the genus Culicoides. The
      smallest viral genome segment, S10, encodes two small nonstructural proteins, NS3
      and NS3A, which mediate the release of virus particles from infected cells and
      may subsequently influence the natural dispersion of these viruses. The NS3 gene
      and protein sequences of South African isolates of these viruses were determined,
      analysed and compared with cognate orbivirus genes from around the world. The
      South African BTV NS3 genes were found to have the highest level of sequence
      variation for BTV (20 %), while the highest level of protein variation of BTV NS3
      (10 %) was found between South African and Asian BTV isolates. The inferred NS3
      gene phylogeny of the South African BTV isolates grouped them with BTV isolates
      from the United States, while the Asian BTV isolates grouped into a separate
      lineage. The level of variation found in the NS3 gene and protein of EEV was
      higher than that found for BTV and reached 25 and 17 % on the nucleotide and
      amino acid levels, respectively. The EEV isolates formed a lineage independent
      from that of the other orbiviruses. This lineage segregated further into two
      clusters that corresponded to the northern and southern regions of South Africa.
      The geographical distribution of these isolates may be related to the
      distribution of the Culicoides subspecies that transmit them.

PMID- 12604810
TI  - A region of the C-terminal tail of the gp41 envelope glycoprotein of human
      immunodeficiency virus type 1 contains a neutralizing epitope: evidence for its
      exposure on the surface of the virion.
AB  - The approximately 150 amino acid C-terminal tail of the gp41 transmembrane
      glycoprotein of human immunodeficiency virus type 1 (HIV-1) is generally thought
      to be located inside the virion. However, we show here that both monoclonal IgG
      and polyclonal epitope-purified IgG specific for the (746)ERDRD(750) epitope that
      lies within the C-terminal tail neutralized infectious virus. IgG was mapped to
      the C-terminal tail by its failure to neutralize tail-deleted virus, and by
      sequencing of antibody-escape mutants. The fact that antibody does not cross
      lipid membranes, and infectious virus is by definition intact, suggested that
      ERDRD was exposed on the surface of the virion. This was confirmed by reacting
      virus and IgG, separating virus and unbound IgG by centrifugation, and showing
      that virus was neutralized to essentially the same extent as virus that had been
      in constant contact with antibody. Epitope exposure on virions was independent of
      temperature and therefore constitutive. Monoclonal antibodies specific to
      epitopes PDRPEG and IEEE, upstream of ERDRD, also bound to virions, suggesting
      that they too were located externally. Protease digestion destroyed the ERDRD and
      PDRPEG epitopes, consistent with their proposed external location. Altogether
      these data are consistent with part of the C-terminal tail of gp41 being exposed
      on the outside of the virion. Possible models of the structure of the gp41 tail,
      taking these observations into account, are discussed.

PMID- 12604811
TI  - A functional genetic approach suggests a novel interaction between the human
      immunodeficiency virus type 1 (HIV-1) Tat protein and HIV-1 TAR RNA in vivo.
AB  - Human immunodeficiency virus type 1 (HIV-1) Tat and human Cyclin T1 form a
      complex and together recognize the viral TAR RNA element with specificity. Using
      HIV-1/equine infectious anaemia virus TAR chimeras, we show that in addition to
      the well-characterized interaction with the bulge, Tat recognizes the distal stem
      and the loop of TAR. These data support previously proposed, but unproven,
      molecular models.

PMID- 12604812
TI  - Influence of human immunodeficiency virus type 1 subtype on mother-to-child
      transmission.
AB  - The present study was designed to assess whether the subtype of human
      immunodeficiency virus type 1 (HIV-1) could affect the rate of HIV-1 mother-to
      child transmission in a cohort of 31 HIV-1-seropositive pregnant Tanzanian women.
      In order to assign a subtype to the samples analysed, nucleotide sequencing of
      the HIV-1 long terminal repeat U3 and C2V3C3 envelope regions was performed from
      the sera of these 31 pregnant women. Except in three cases, amplification of both
      regions was achieved in all samples. Subtypes A (n=13, 46 %), C (n=6, 21 %) and D
      (n=2, 7 %), as well as a number (25 %) of A/C, C/A, D/A and C/D recombinant forms
      (n=3, 2, 1 and 1, respectively), were identified. Of the 31 HIV-1 seropositive
      pregnant women analysed, eight (26 %) transmitted HIV-1 to their infants. Among
      the eight transmitter mothers, four (4 of 13, 31 %) were infected with HIV-1
      subtype A, one (1 of 6, 17 %) with HIV-1 subtype C, none (0 of 2, 0 %) with HIV-1
      subtype D and three (3 of 7, 43 %) with HIV-1 subtype recombinant A/C. These
      findings show no significant differences in the mother-to-child transmissibility
      of HIV-1 subtypes A, C and D and detected recombinants forms.

PMID- 12604813
TI  - Reduced transmission and prevalence of simian T-cell lymphotropic virus in a
      closed breeding colony of chimpanzees (Pan troglodytes verus).
AB  - A retrospective study spanning 20 years was undertaken to investigate the
      prevalence and modes of transmission of a simian T-cell lymphotropic virus (STLV)
      in a closed breeding colony of chimpanzees. Of the 197 animals tested, 22 had
      antibodies that were cross-reactive with human T-cell lymphotropic virus type-1
      (HTLV-I) antigens. The specificity of the antibody response was confirmed by
      Western blot analysis and the presence of a persistent virus infection was
      established by PCR analysis of DNA from peripheral blood mononuclear cells.
      Sequence analysis revealed that the virus infecting these chimpanzees was not
      HTLV-I but STLV(cpz), a virus that naturally infects chimpanzees. The limited
      number of transmission events suggested that management practices of social
      housing of family units away from troops of mature males might have prevented the
      majority of cases of transmission. Evidence for transmission by blood-to-blood
      contact was documented clearly in at least one instance. In contrast,
      transmission from infected mother to child was not observed, suggesting that this
      is not a common route of transmission for STLV in this species, which is in
      contrast to HTLV-1 in humans.

PMID- 12604814
TI  - Delineation of sequences important for efficient packaging of feline
      immunodeficiency virus RNA.
AB  - We have used systematic deletion analysis of the 5' untranslated region (UTR) of
      the feline immunodeficiency virus (FIV) genome, both in the presence and absence
      of various amounts of gag, to define the cis-acting sequences responsible for
      efficient RNA packaging. Our analyses revealed that the primary FIV packaging
      signal consists of two essential core elements located within the first 90-120 bp
      of the 5'UTR and the first 90 bp of the gag gene. Interestingly, the region
      between the major splice donor (SD) and gag, including approximately 130-160 bp
      upstream of the SD, is dispensable for encapsidation. Finally, other determinants
      of packaging were found to be present in the viral LTR and/or within the 3' end
      of the viral genome. Taken together, our results suggest that the primary
      packaging determinants of FIV are multipartite and discontinuous, composed of two
      elements within the 5'UTR and gag gene.

PMID- 12604815
TI  - Transmission of pseudorabies virus from immune-masked blood monocytes to
      endothelial cells.
AB  - Pseudorabies virus (PRV) may cause abortion, even in the presence of vaccination
      induced immunity. Blood monocytes are essential to transport the virus in these
      immune animals, including transport to the pregnant uterus. Infected monocytes
      express viral proteins on their cell surface. Specific antibodies recognize these
      proteins and should activate antibody-dependent cell lysis. Previous work showed
      that addition of PRV-specific polyclonal antibodies to PRV-infected monocytes
      induced internalization of viral cell surface proteins, protecting the cells from
      efficient antibody-dependent lysis in vitro (immune-masked monocytes). As a first
      step to reach the pregnant uterus, PRV has to cross the endothelial cell barrier
      of the maternal blood vessels. The current aim was to investigate in vitro
      whether immune-masked PRV-infected monocytes can transmit PRV in the presence of
      virus-neutralizing antibodies via adhesion and fusion of these monocytes with
      endothelial cells. Porcine blood monocytes, infected with a lacZ-carrying PRV
      strain, were incubated with PRV-specific antibodies to induce internalization.
      Then, cells were co-cultivated with endothelial cells for different periods of
      time. Only PRV-infected monocytes with internalized viral cell surface proteins
      adhered efficiently to endothelial cells. LacZ transmission to endothelial cells,
      as a measure for monocyte-endothelial cell fusion, could be detected after co
      cultivation from 30 min onwards. Virus transmission was confirmed by the
      appearance of plaques. Adhesion of immune-masked PRV-infected monocytes to
      endothelial cells was mediated by cellular adhesion complex CD11b-CD18 and
      subsequent fusion was mediated by the virus. In conclusion, immune-masked PRV
      infected monocytes can adhere and subsequently transmit virus to endothelial
      cells in the presence of PRV-neutralizing antibodies.

PMID- 12604816
TI  - Detection of human cytomegalovirus DNA replication in non-permissive Vero and 293
      cells.
AB  - Human cytomegalovirus (HCMV) displays an exceptionally restricted host range in
      tissue culture with human fibroblasts being the principal fully permissive
      system. Nevertheless, immediate early (IE) proteins are expressed following
      infection of many non-permissive cell types of human, simian and murine origin,
      and viral origin-dependent DNA synthesis has been reconstituted by transfection
      of plasmids into Vero cells, a non-permissive line from African green monkey. We
      have examined the accumulation of HCMV strain AD169 DNA, and the replication of
      transfected HCMV origin-containing plasmids, in infected Vero and human embryonic
      kidney 293 cells, which were previously reported to express the major IE protein
      in a small proportion of infected cells but to be non-permissive for viral DNA
      synthesis. In Vero cells accumulation of origin-containing plasmid but not viral
      DNA occurred, whilst in 293 cells both DNAs accumulated. Immunofluorescence
      experiments indicated that following infection with 3 p.f.u. per cell, a small
      fraction of both cell types expressed the UL44 DNA replication protein. Neither
      cell line, however, supported the generation of infectious progeny virus. These
      results suggest that IE proteins expressed in Vero and 293 cells can induce the
      synthesis of early proteins capable of functioning in viral DNA replication, but
      there is a failure in later events on the pathway to infectious virus production.
      This provides further support for transfected Vero cells being a valid system in
      which to study HCMV DNA synthesis, and suggests that 293 cells may also prove
      useful in similar experiments.

PMID- 12604818
TI  - Homology between the human cytomegalovirus RL11 gene family and human adenovirus
      E3 genes.
AB  - A significant proportion of the human cytomegalovirus (HCMV) genome comprises 12
      multigene families that probably arose by gene duplication. One, the RL11 family,
      contains 12 members, most of which are predicted to encode membrane
      glycoproteins. Comparisons of sequences near the left end of the genome in
      several HCMV strains revealed two adjacent open reading frames that potentially
      encode related proteins: RL6, which is hypervariable, and RL5A, which has not
      been recognized previously. These genes potentially encode a domain that is the
      hallmark of proteins encoded by the RL11 family, and thus constitute two new
      members. A homologous domain is also present in a subset of human adenovirus E3
      membrane glycoproteins. Evolution of genes specifying the shared domain in
      cytomegaloviruses and adenoviruses is characterized by extensive divergence, gene
      duplication and selective sequence loss. These features prompt speculation about
      the roles of these genes in the two virus families.

PMID- 12604817
TI  - Human cytomegalovirus glycoprotein N (gpUL73-gN) genomic variants: identification
      of a novel subgroup, geographical distribution and evidence of positive selective
      pressure.
AB  - Human cytomegalvirus (HCMV) ORF UL73 is a polymorphic locus, encoding the viral
      glycoprotein gpUL73-gN, a component of the gC-II envelope complex. The previously
      identified gN genomic variants, denoted gN-1, gN-2, gN-3 and gN-4, were further
      investigated in this work by analysing a large panel of HCMV clinical isolates
      collected from all over the world (223 samples). Sequencing and phylogenetic
      analysis confirmed the existence of the four gN genotypes, but also allowed the
      identification of a novel subgroup belonging to the gN-3 genotype, which was
      designated gN-3b. The number of non-synonymous (d(N)) and synonymous (d(S))
      nucleotide substitutions and their ratio (d(N)/d(S)) were estimated among the gN
      genotypes to evaluate the possibility of positive selection. Results showed that
      the four variants evolved by neutral (random) selection, but that the gN-3 and gN
      4 genotypes are maintained by positive selective pressure. The 223 HCMV clinical
      isolates were subdivided according to their geographical origin, and four main
      regions of gN prevalence were identified: Europe, China, Australia and Northern
      America. The gN variants were found to be widespread and represented within the
      regions analysed without any significant difference, and no new genotype was
      detected. Finally, for clinical and epidemiological purposes, a rapid and low
      cost method for genetic grouping of the HCMV clinical isolates was developed
      based on the RFLP revealed by SacI, ScaI and SalI digestion of the PCR-amplified
      UL73 sequence. This technique enabled us to distinguish all four gN genomic
      variants and also their subtypes.

PMID- 12604819
TI  - Kaposi's sarcoma-associated herpesvirus K8 protein interacts with hSNF5.
AB  - Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus
      related to Epstein-Barr virus (EBV) and herpesvirus saimiri. KSHV open reading
      frame K8 encodes a basic region-leucine zipper protein of 237 aa that
      homodimerizes. K8 shows significant similarity to the EBV immediate-early protein
      Zta, a key regulator of EBV reactivation and replication. In this study, a
      carboxyl-terminal deletion mutant of K8, K8(1-115), that had strong
      transactivating properties was found. Screening using transcriptionally inactive
      K8(1-75) showed that K8 interacts and co-localizes with hSNF5, a cellular
      chromatin-remodelling factor, both in vivo and in vitro. This interaction
      requires aa 48-183 of hSNF5 and 1-75 of K8. In a yeast expression system, the
      ability of K8 and K8(1-115) to activate transcription requires the presence of
      SNF5, the yeast homologue of hSNF5. These data suggest a mechanism by which the
      SWI-SNF complex is recruited to specific genes. They also suggest that K8
      functions as a transcriptional activator under specific conditions and that its
      transactivation activity requires its interaction with the cellular chromatin
      remodelling factor hSNF5.

PMID- 12604820
TI  - Site-directed mutagenesis in a conserved motif of Epstein-Barr virus DNase that
      is homologous to the catalytic centre of type II restriction endonucleases.
AB  - Sequence alignment of human herpesvirus DNases revealed that they share several
      conserved regions. One of these, the conserved motif D203...E225XK227 (D.EXK) in
      the sequence of Epstein-Barr virus (EBV) DNase, has a striking similarity to the
      catalytic sites of some other nucleases, including type II restriction
      endonucleases, lambda exonuclease and MutH. The predicted secondary structures of
      these three residues were shown to resemble the three catalytic residues of type
      II restriction endonucleases. Site-directed mutagenesis was carried out to
      replace each of the acidic residues near the motif by residues with different
      properties. All substitutions of D203, E225 and K227 were shown to cause
      significant reductions in nuclease activity. Six other acidic residues, within
      the conserved regions, were also replaced by Asn or Gln. Five of these six
      variants retained nuclease activity and mutant D195N alone lost nuclease
      activity. The four charged residues, D195, D203, E225 and K227, of EBV DNase were
      found to be important for nuclease activity. Biochemical analysis indicated that
      the preference for divalent cations was altered from Mg2+ to Mn2+ for mutant
      E225D. The DNA-binding abilities of D203E, E225D and E225Q were shown to be
      similar to that of wild-type. However, K227 mutants were found to have variable
      DNA-binding abilities: K227G and K227N mutants retained, K227E and K227D had
      reduced and K227R lost DNA-binding ability. Comparison of the biochemical
      properties of the corresponding substitutions among EBV DNase and type II
      restriction enzymes indicated that the D...EXK motif is most likely the putative
      catalytic centre of EBV DNase.

PMID- 12604822
TI  - Effective transduction of osteogenic sarcoma cells by a baculovirus vector.
AB  - Efficient gene delivery of a baculovirus-derived vector (BV-p53-lacZ) to a human
      osteogenic sarcoma cell line, Saos-2, was serendipitously found while evaluating
      the vector for gene delivery to human p53-null tumour cells in a previous study.
      Therefore, we investigated other human, rat and mouse osteogenic sarcoma and
      other types of tumour cell lines for transduction efficiency via baculovirus
      vectors containing a lacZ reporter gene under the control of either a
      cytomegalovirus or Rous sarcoma virus promoter. The expression of beta
      galactosidase protein, assessed by X-Gal staining and beta-galactosidase ELISA,
      demonstrated an extremely high level of transduction efficiency in some
      osteogenic sarcoma cell lines, such as U-2OS, Saos-2 and Saos-LM2. These human
      osteogenic sarcoma cell lines showed levels of beta-galactosidase expression 5-40
      times greater than HepG2 cells, which were previously thought to be the mammalian
      cells most susceptible to baculovirus-mediated gene delivery. The level of
      acetylated histone proteins in these tumour lines did not correlate well with the
      high level of reporter gene expression. These results strongly suggest that some
      osteogenic sarcoma cells are highly susceptible to baculovirus-mediated gene
      delivery and that a baculovirus-derived vector is an efficient gene delivery
      vehicle into human osteogenic sarcoma cells.

PMID- 12604821
TI  - Human adenovirus serotypes 4 and 11 show higher binding affinity and infectivity
      for endothelial and carcinoma cell lines than serotype 5.
AB  - Adenoviruses are promising vectors for human cancer gene therapy. However, the
      extensively used adenoviruses serotypes 2 and 5 (Ad2 and Ad5) from species C have
      a major disadvantage in being highly prevalent; thus, most adults have an
      immunity against the two viruses. Furthermore, the expression of coxsackievirus
      and adenovirus receptors for Ad2 and Ad5 varies in different cells. This study
      aims to identify adenovirus serotypes with specific tropism for endothelial cells
      and epithelial tumour cells. Comparison of the binding affinities of Ad31, Ad11,
      Ad5, Ad37, Ad4 and Ad41, belonging to species A-F, respectively, to established
      cell lines of hepatoma (HepG2), breast cancer (CAMA and MG7), prostatic cancer
      (DU145 and LNCaP) and laryngeal cancer (Hep2), as well as to endothelial cells
      (HMEC), was carried out by flow cytometric analysis. Ad11 from species B showed
      markedly higher binding affinity than Ad5 for the endothelial cell line and all
      carcinoma cell lines studied. Ad4 showed a specific binding affinity for hepatoma
      cells and laryneal carcinoma cells. The ability of Ad11, Ad4 and Ad5 to be
      expressed in hepatoma, breast cancer and endothelial cell lines was studied by
      immunostaining and (35)S-labelling of viral proteins in infected cells. Ad11 and
      Ad4 manifested a higher proportion of infected cells and a higher degree of hexon
      expression than Ad5.

PMID- 12604823
TI  - Induction of apoptosis in an insect cell line, IPLB-Ld652Y, infected with
      nucleopolyhedroviruses.
AB  - Ld652Y cells derived from the gypsy moth, Lymantria dispar, were infected with
      seven different nucleopolyhedroviruses (NPVs) including those from Autographa
      californica, Bombyx mori (BmNPV), Hyphantria cunea (HycuNPV), Spodoptera exigua
      (SeMNPV), L. dispar, Orgyia pseudotsugata (OpMNPV) and Spodoptera litura
      (SpltMNPV). The results showed that Ld652Y cells infected with BmNPV, HycuNPV,
      SeMNPV, OpMNPV and SpltMNPV underwent apoptosis, displaying apoptotic bodies,
      characteristic DNA fragmentation and increased caspase-3-like protease activity;
      HycuNPV induced the most severe apoptosis. In HycuNPV-infected Ld652Y cells, a
      considerable amount of viral DNA was synthesized although there was no detectable
      yield of budded virions and polyhedrin. Northern blot and immunoblot analyses
      revealed that HycuNPV inhibitor of apoptosis 3 (IAP3), which has been shown to
      function in Sf9 cells, was expressed in HycuNPV-infected Ld652Y cells at a level
      higher than or comparable with that in HycuNPV-infected SpIm cells, which
      produced a high titre of progeny virions without any apoptotic response. These
      results imply that the relative ease of apoptosis induction in NPV-infected
      Ld652Y cells is largely dependent on inherent cellular properties rather than
      functions of the respective NPVs, and indicate that the defect in progeny virion
      production is not merely due to the virus-induced apoptosis in HycuNPV-infected
      Ld652Y cells.

PMID- 12604824
TI  - A naturally occurring recombinant DNA-A of a typical bipartite begomovirus does
      not require the cognate DNA-B to infect Nicotiana benthamiana systemically.
AB  - Species of the genus Begomovirus (family Geminiviridae) found in the western
      hemisphere typically have a bipartite genome that consists of two 2.6 kb DNA
      genomic components, DNA-A and DNA-B. We have identified and cloned genomic
      components of a new tomato-infecting begomovirus from Brazil, for which the name
      Tomato crinkle leaf yellows virus (TCrLYV) is proposed, and a DNA-A variant of
      Tomato chlorotic mottle virus (ToCMV-[MG-Bt1]). Sequence analysis revealed that
      TCrLYV was most closely related to ToCMV, although it was sufficiently divergent
      to be considered a distinct virus species. Furthermore, these closely related
      viruses induce distinguishable symptoms in tomato plants. With respect to ToCMV
      [MG-Bt1] DNA-A, evidence is presented that suggests a recombinant origin. It
      possesses a hybrid genome on which the replication compatible module (AC1 and
      replication origin) was probably donated by ToCMV-[BA-Se1] and the remaining
      sequences appear to have originated from Tomato rugose mosaic virus (ToRMV).
      Despite the high degree of sequence conservation with its predecessors, ToCMV-[MG
      Bt1] differs significantly in its biological properties. Although ToCMV-[MG-Bt1]
      DNA-A did not infect tomato plants, it systemically infected Nicotiana
      benthamiana, induced symptoms of mottling and accumulated viral DNA in the apical
      leaves in the absence of a cognate DNA-B. The modular rearrangement that resulted
      in ToCMV-[MG-Bt1] DNA-A may have provided this virus with a more aggressive
      nature. Our results further support the notion that interspecies recombination
      may play a significant role in geminivirus diversity and their emergence as
      agriculturally important pathogens.

PMID- 12604826
TI  - Phylogeography of Rice yellow mottle virus in Africa.
AB  - The sequences of the coat protein gene of a representative sample of 40 isolates
      of Rice yellow mottle virus (RYMV) from 11 African countries were analysed. The
      overall level of nucleotide diversity was high (approximately 14%). Great
      geographical distances between the sites where isolates were collected were
      consistently associated with high genetic distances. In contrast, a wide range of
      genetic distances occurred among isolates spread over short geographical
      distances. There was no evidence of long-range dispersal. RYMV diversity in
      relation to land area was eight times greater in East Africa than in West/Central
      Africa. West/Central African isolates with up to 9 % divergence belonged to a
      monophyletic group, whereas the East African isolates with up to 13 % divergence
      fell into distantly related groups. In East Africa, each Tanzanian strain had a
      specific and restricted geographical range, whereas West/Central African strains
      had large and partially overlapping geographical distributions. Overall, our
      results suggest an earlier RYMV diversification in East Africa and a later
      radiation in West/Central Africa. The West African situation was consistent with
      virus adaptation to savanna, forest and other ecological conditions. In contrast
      East Africa, as exemplified by the Tanzanian situation, with numerous physical
      barriers (mountain chains, sea channel, lakes), suggested that RYMV strains
      resulted from divergence under isolated conditions. For RYMV and for two other
      viruses, phylogenetic relationships were established between isolates from
      Madagascar and isolates from the Lake Victoria region.

PMID- 12604825
TI  - Dysfunctionality of a tobacco mosaic virus movement protein mutant mimicking
      threonine 104 phosphorylation.
AB  - Replication of tobacco mosaic virus (TMV) is connected with endoplasmic reticulum
      (ER)-associated membranes at early stages of infection. This study reports that
      TMV movement protein (MP)-specific protein kinases (PKs) associated with the ER
      of tobacco were capable of phosphorylating Thr(104) in TMV MP. The MP-specific
      PKs with apparent molecular masses of about 45-50 kDa and 38 kDa were revealed by
      gel PK assays. Two types of mutations were introduced in TMV MP gene of wild-type
      TMV U1 genome to substitute Thr(104) by neutral Ala or by negatively charged Asp.
      Mutation of Thr(104) to Ala did not affect the size of necrotic lesions induced
      by the mutant virus in Nicotiana tabacum Xanthi nc. plants. Conversely, mutation
      of Thr to Asp mimicking Thr(104) phosphorylation strongly inhibited cell-to-cell
      movement. The possible role of Thr(104) phosphorylation in TMV MP function is
      discussed.

PMID- 12604827
TI  - Spatio-temporal analysis of the RNAs, coat and movement (p7) proteins of
      Carnation mottle virus in Chenopodium quinoa plants.
AB  - Time-course and in situ hybridization analyses were used to study the spatio
      temporal distribution of Carnation mottle virus (CarMV) in Chenopodium quinoa
      plants. Genomic and subgenomic RNAs of plus polarity accumulated linearly with
      time, whereas the corresponding minus strands reached a peak during infection in
      inoculated leaves. Analyses of serial tissue sections showed that plus polarity
      strands were localized throughout the infection area, whereas minus strands were
      localized at the borders of the chlorotic lesions. The accumulation kinetics of
      the coat protein (CP) and the p7 movement protein (MP) as well as their
      subcellular localization were also studied. Unlike most MPs, CarMV p7 showed a
      non-transient expression and a mainly cytosolic location. However, as infection
      progressed the presence of p7 in the cell wall fraction increased significantly.
      These results are discussed on the basis of a recent model proposed for the
      mechanism of cell-to-cell movement operating in the genus Carmovirus.

PMID- 12604828
TI  - Identification of neutral mutants surrounding two naturally occurring variants of
      Potato spindle tuber viroid.
AB  - Single point mutations in the pathogenicity domain of Potato spindle tuber viroid
      (PSTVd) can have a dramatic effect on disease expression, and only three
      substitutions are required for the spontaneous conversion of the type strain
      PSTVd-Intermediate to the rapidly replicating, highly pathogenic variant RG1
      (Gruner et al., Virology 209, 60-69, 1995). To identify available evolutionary
      pathways linking these two variants, we mutagenized five positions in an
      infectious cDNA copy of PSTVd-Intermediate and screened the resulting mixture of
      768 sequences for neutral or near-neutral mutants. Numerical simulations based on
      the bioassay data indicate that the 23 variants recovered represent >80 % of all
      such sequences. RG1 was the only naturally occurring variant recovered, and the
      overall pattern of sequence changes observed indicates that PSTVd-Int occupies a
      comparatively steep peak within the fitness landscape.

PMID- 12604829
TI  - PBPK modeling advances understanding of D4 pharmacokinetics.

PMID- 12604830
TI  - Physiological modeling of inhalation kinetics of octamethylcyclotetrasiloxane in
      humans during rest and exercise.
AB  - In a recent pharmacokinetic study, six human volunteers were exposed by
      inhalation to 10 ppm (14)C-D(4) for 1 h during alternating periods of rest and
      exercise. Octamethylcyclotetrasiloxane (D(4)) concentrations were determined in
      exhaled breath and blood. Total metabolite concentrations were estimated in
      blood, while the amounts of individual metabolites were measured in urine. Here,
      we use these data to develop a physiologically based pharmacokinetic (PBPK) model
      for D(4) in humans. Consistent with PBPK modeling efforts for D(4) in the rat, a
      conventional inhalation PBPK model assuming flow-limited tissue uptake failed to
      adequately describe these data. A refined model with sequestered D(4) in blood,
      diffusion-limited tissue uptake, and an explicit pathway for D(4) metabolism to
      short-chain linear siloxanes successfully described all data. Hepatic extraction
      in these volunteers, calculated from model parameters, was 0.65 to 0.8, i.e.,
      hepatic clearance was nearly flow-limited. The decreased retention of inhaled
      D(4) seen in humans during periods of exercise was explained by altered
      ventilation/perfusion characteristics during exercise and a rapid approach to
      steady-state conditions. The urinary time course excretion of metabolites was
      consistent with a metabolic scheme in which sequential hydrolysis of linear
      siloxanes followed oxidative demethylation and ring opening. The unusual
      properties of D(4) (high lipophilicity coupled with high hepatic and exhalation
      clearance) lead to rapid decreases in free D(4) in blood. The success of D(4)
      PBPK models with a similar physiological structure in both humans and rats
      increases confidence in the utility of the model for predicting human tissue
      concentrations of D(4) and metabolites during inhalation exposures.

PMID- 12604831
TI  - Cadmium uptake kinetics in rat hepatocytes: correction for albumin binding.
AB  - The relationship between cytotoxicity and kinetics of cadmium uptake was
      investigated in primary rat hepatocyte cultures. Primary rat hepatocytes were
      exposed to cadmium concentrations ranging from 1.0 to 80 micro M in albumin-free
      buffer or 32 to 8,000 microM in buffer containing physiological concentrations of
      bovine serum albumin (600 micro M) for 1 h, and cellular toxicity was observed at
      23 h postexposure. Hepatocytes exposed to cadmium in the presence of albumin
      appeared less sensitive to cadmium toxicity when compared to cells exposed in the
      absence of albumin. The experimentally derived 23-h postexposure EC(50)s for
      hepatocytes exposed to cadmium in both presence and absence of albumin was 65.5
      +/- 2.4 and 14.3 +/- 3.9 microM, respectively. A Scatchard plot of cadmium
      binding to albumin suggested two high-affinity binding sites. The observed uptake
      of cadmium by hepatocytes in the absence and presence of albumin consisted of a
      composite fast uptake rate and cell membrane association (Component I), and a
      slow, sustained uptake rate (Component II). Cadmium uptake rates in hepatocytes,
      based on total medium cadmium concentrations, indicated that Component II uptake
      rates were four times faster under albumin-free exposure conditions. However,
      when uptake rates were evaluated, based on the calculated equilibrium
      concentration of free cadmium in the exposure buffer, uptake rates in hepatocytes
      exposed in the presence of albumin were two times as fast. This faster cadmium
      uptake in the presence of albumin may result from diffusion-limited,
      nonequilibrium conditions occurring at the cell surface.

PMID- 12604832
TI  - Subchronic studies in Sprague-Dawley rats to investigate mechanisms of MTBE
      induced Leydig cell cancer.
AB  - High MTBE exposures caused rat Leydig cell (LC) tumors in inhalation and gavage
      cancer bioassays. Investigating early endocrine changes consistent with known
      mechanisms of LC carcinogenesis, we gavaged adult male Sprague-Dawley rats with
      MTBE in five different subchronic experiments and studied testosterone
      biosynthesis in isolated rat LCs exposed in vitro to MTBE or a major metabolite,
      t-butanol. In vitro LC testosterone production declined 29-50% following 3-h
      exposures to 50-100 mM MTBE or t-butanol. Within hours after gavaging with 1,000
      or 1,500 mg/kg MTBE, circulating testosterone declined to 38-49% of control (p <
      0.05). If sampled longer after treatment or with lower doses, testosterone
      reductions were less dramatic or nondetectable even after 28 days of treatment.
      Accessory organ:brain weight ratios decreased only slightly although showing dose
      response with 40-800 mg/kg/day after 28 days. High MTBE doses caused slight liver
      weight and total P450 increases. Reduced aromatase activity in liver and testis
      microsomes predicted low serum estradiol, but estradiol was 19% higher than corn
      oil controls concurrent with testosterone reduction 1 h after the last of 14
      daily 1,200-mg/kg doses (p < 0.05). Pituitary luteinizing hormone (LH) and
      prolactin measured in both intact and orchiectomized rats, with testosterone
      implants in some castrated rats providing stable levels of testosterone, revealed
      no consistent direct effect on hypothalamic-pituitary function. MTBE-treated rat
      livers showed no evidence of peroxisome proliferation, a characteristic of some
      LC carcinogens. Considering recognized mechanisms of Leydig cell cancer in rats,
      collectively these results suggested reduced LC steroidogenesis enzyme activity
      as a possible mechanism underlying MTBE LC carcinogenesis.

PMID- 12604834
TI  - Acetaminophen exhibits weak antiestrogenic activity in human endometrial
      adenocarcinoma (Ishikawa) cells.
AB  - The purpose of this study was to test the hypothesis that acetaminophen would
      alter an estrogen-regulated process in human cells that express endogenous
      estrogen receptor alpha and beta (ERalpha and ERbeta). Specifically, the extent
      to which acetaminophen altered the expression of estrogen-inducible alkaline
      phosphatase in endometrial adenocarcinoma (Ishikawa) cells and directly
      interacted with ERbeta and ERalpha was determined. Ishikawa cells were exposed to
      estradiol and/or to a range of concentrations of acetaminophen for four days, and
      alkaline phosphatase activity was measured spectrophotometrically. Acetaminophen
      inhibited both basal and estradiol-induced alkaline phosphatase activity in
      Ishikawa cells in a concentration-dependent manner. The reduction of Ishikawa
      cell alkaline phosphatase was not due to direct inhibition of enzyme activity by
      acetaminophen. Toxic effects of acetaminophen on Ishikawa cells were determined
      by measuring loss of cellular lactate dehydrogenase to culture medium. High
      concentrations of acetaminophen (>/=0.5 mM) induced lactate dehydrogenase release
      from cells and reduced the amount of cellular protein in culture dishes,
      indicating some acetaminophen-induced reduction of alkaline phosphatase activity
      might be attributed to toxic effects. However, lower concentrations of
      acetaminophen significantly reduced alkaline phosphatase activity in the absence
      of detectable toxicity. Acetaminophen also augmented 4-hydroxy-tamoxifen
      reduction of alkaline phosphatase activity. Competition binding assays with human
      ERalpha and ERbeta demonstrated 10(6)-fold molar excess acetaminophen did not
      directly interact significantly with the ligand-binding domain of either
      receptor. These studies indicate acetaminophen exerts weak antiestrogenic
      activity in Ishikawa cells without directly binding ERalpha or ERbeta.

PMID- 12604833
TI  - Role of neutrophils in the synergistic liver injury from monocrotaline and
      bacterial lipopolysaccharide exposure.
AB  - Synergistic liver injury develops in Sprague-Dawley rats from administration of a
      small, noninjurious dose (7.4 x 10(6) EU/kg) of bacterial lipopolysaccharide
      (LPS) given 4 h after a nontoxic dose (100 mg/kg) of the pyrrolizidine alkaloid,
      monocrotaline (MCT). Previous studies demonstrated that liver injury is mediated
      through inflammatory factors, such as Kupffer cells and tumor necrosis factor
      alpha (TNF-alpha), rather than through simple interaction between MCT and LPS. In
      the present study, the hypothesis that neutrophils (polymorphonuclear leukocytes
      or PMNs) are causally involved in this injury model is tested, and the
      interdependence between PMNs and other inflammatory components is explored.
      Hepatic PMN accumulation and the appearance of cytokine-induced neutrophil
      chemoattractant-1 in plasma preceded the onset of liver injury, suggesting that
      PMNs contribute to toxicity. Hepatic PMN accumulation was partially dependent on
      TNF-alpha. Prior depletion of PMNs in MCT/LPS-cotreated animals resulted in
      attenuation of both hepatic parenchymal cell (HPC) and sinusoidal endothelial
      cell (SEC) injury at 18 h. PMN depletion did not, however, protect against early
      SEC injury that occurred before the onset of HPC injury at 6 h. This observation
      suggests that SEC injury is not entirely dependent on PMNs in this model. In
      vitro, MCT caused PMNs to degranulate in a concentration-dependent manner. These
      results provide evidence that PMNs are critical to the HPC injury caused by
      MCT/LPS cotreatment and contribute to the progression of SEC injury.

PMID- 12604835
TI  - Discriminating redox cycling and arylation pathways of reactive chemical toxicity
      in trout hepatocytes.
AB  - The toxicity of four quinones, 2,3-dimethoxy-1,4-naphthoquinone (DMONQ), 2-methyl
      1,4-naphthoquinone (MNQ), 1,4-naphthoquinone (NQ), and 1,4-benzoquinone (BQ),
      which redox cycle or arlyate in mammalian cells, was determined in isolated trout
      (Oncorhynchus mykiss) hepatocytes. More than 70% of cells died in 3 h when
      exposed to BQ or NQ; 50% died in 7 h when exposed to MNQ, with no mortality
      compared to controls after 7 h DMONQ exposure. A suite of biochemical parameters
      was assessed for ability to discriminate these reactivity pathways in fish. Rapid
      depletion of glutathione (GSH) with appearance of glutathione disulfide (GSSG)
      and increased dichlorofluoroscein fluorescence were used as indicators of redox
      cycling, noted with DMONQ, MNQ, and NQ. Depletion of GSH with no GSSG
      accumulation, and loss of free protein thiol (PrSH) groups (nonreducible)
      indicated direct arylation by BQ. All toxicants rapidly oxidized NADH, with
      changes in NADPH noted later (BQ, NQ, MNQ) or not at all (DMONQ). Biochemical
      measures including cellular energy status, cytotoxicity, and measures of reactive
      oxygen species, along with the key parameters of GSH and PrSH redox status,
      allowed differentiation of responses associated with lethality. Chemicals that
      arylate were more potent than redox cyclers. Toxic pathway discrimination is
      needed to group chemicals for potency predictions and identification of
      structural parameters associated with distinct types of reactive toxicity, a
      necessary step for development of mechanistically based quantitative structure
      activity relationships (QSARs) to predict chemical toxic potential. The
      commonality of reactivity mechanisms between rodents and fish was also
      demonstrated, a step essential for species extrapolations.

PMID- 12604836
TI  - Comparison of in vitro and in vivo bioassays for estrogenicity in effluent from
      North American municipal wastewater facilities.
AB  - Attempts to better understand causal factors affecting estrogenicity in municipal
      wastewater have primarily focused on analytical evaluation of specific chemical
      estrogens and the use of estrogen receptor (ER) based in vitro assays. To compare
      analytical,in vitro, and in vivo assays for estrogenicity, wastewater from four
      New York and one Texas municipal wastewater facilities was evaluated for
      estrogenic activity using the yeast estrogen screen assay (YES) and an in vivo
      fish vitellogenin (VTG) assay. Estrogenic activity, as measured by the YES assay,
      was observed in methanol and/or methylene chloride eluents from C18 extracts in
      two of the New York treatment facilities and the Texas facility. Estradiol
      equivalents for the YES assay data ranged from </=1 to 15 ng/l. Male Japanese
      medaka (Oryzias latipes) were then exposed for 7 days to solvent extracts from
      the New York-Red Hook facility and the Texas facility. Hepatic and plasma
      vitellogenin were induced in medaka after exposure to the methanol eluent from
      the New York facility, even though the YES assay indicated that both the methanol
      and methylene chloride eluents were estrogenic. Whereas an estrogenic response in
      the YES assay was only observed in the methanol eluent from the Texas facility,
      plasma VTG induction was observed in both the methanol and methylene chloride
      eluents. In vivo estrogenic activity was nearly 10-fold greater than YES activity
      indicating the presence of nonestrogen receptor ligands that elicit estrogenic
      effects in fish through indirect mechanisms. The sole use of in vitro assays to
      screen for estrogenicity may underestimate estrogenic potential of wastewater.

PMID- 12604837
TI  - TCDD treatment eliminates the long-term reconstitution activity of hematopoietic
      stem cells.
AB  - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disrupting chemical
      (EDC), can cause carcinogenesis, immunosuppression, and teratogenesis, through a
      ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR).
      Despite remarkable recent advances in stem cell biology, the influence of TCDD on
      hematopoietic stem cells (HSCs), which possess the ability to reconstitute long
      term multilineage hematopoiesis, has not been well investigated. In this study we
      examined the influence of TCDD on HSCs enriched for CD34(-), c-kit(+), Sca-1(+),
      lineage negative (CD34-KSL) cells. The number of the CD34-KSL cells was found to
      be increased about four-fold upon a single oral administration of TCDD (40 micro
      g/kg body weight). Surprisingly, we found that these TCDD-treated cells almost
      lost long-term reconstitution activity. This defect was not present in AhR(-/-)
      mice. These findings suggest that modulation of AhR/ARNT system activity may have
      an effect on HSC function or survival.

PMID- 12604838
TI  - Role of residual additives in the cytotoxicity and cytokine release caused by
      polyvinyl chloride particles in pulmonary cell cultures.
AB  - Occupational exposure to polyvinyl chloride (PVC) dust has been linked to
      pulmonary disease. The aim of the present study was to investigate, in vitro, the
      role of additives in the cytotoxicity and the release of inflammatory mediators
      caused by PVC particles in different cells. We compared two types of emulsion PVC
      particles (E3 and E8) with their washed (hence, "additive-free") counterparts (W3
      and W8). A positive control (crystalline SiO2, Min-U-Sil) and the pure additives,
      sodium lauryl sulfate (A3) and sodium alkylbenzenesulfonate (A8), were tested
      concurrently. Cytotoxicity (MTT assay) was assessed in primary cultures of rat
      alveolar macrophages, rat type II pneumocytes, and human alveolar macrophages (h
      AM), and cultures of the A549 cell line (type II cell-derived) and the
      differentiated THP-1 cell line (macrophage-like). Hemolytic potential was
      assessed after a 2-h incubation with human erythrocytes. Cytokine release (IL-8,
      IL-6, and TNF-alpha) by A549 cells, THP-1 cells, and h-AM, was measured by ELISA
      after 4, 16, 24 and/or 48 h of exposure. Cytotoxicity and hemolytic activity of
      the washed particles were abolished or markedly decreased compared with their
      nonwashed forms. In A549 cells, E3 and E8 (2.5 mg/ml) caused a 3-fold increase in
      IL-8 release and a more than 10-fold increase in IL-6 release, whereas W3 and W8
      did not elicit any significant response at similar concentrations. Compared with
      Min-U-Sil (0.1, 0.5, and 2.5 mg/ml), the response to E3 and E8 occurred later and
      was slightly lower (IL-8) or much more pronounced (IL-6). A3 and A8 exhibited
      similar responses to E3 and E8, at concentrations corresponding to those present
      in the particles. In conclusion, the in vitro cytotoxicity and inflammatory
      potential of some PVC particles appear to be mostly due to their residual
      additives.

PMID- 12604840
TI  - Systemic administration of Bordetella pertussis enhances pulmonary sensitization
      to house dust mite in juvenile rats.
AB  - The incidence of allergies and asthma has increased significantly in the past few
      decades. The objectives of this study were to establish an allergy model in
      weanling rats to more closely reflect the developing immune system of children,
      and to determine whether systemic administration of inactivated Bordetella
      pertussis could enhance pulmonary and systemic immune responses to locally
      administered house dust mite antigen (HDM). Three-week old female Brown Norway
      rats were sensitized with 10 micro g HDM intratracheally or intraperitoneally,
      with or without a simultaneous injection of 10(8) whole killed B. pertussis
      organisms. Ten days later, all the rats were challenged with 5 micro g HDM via
      the trachea. Bronchial lymph nodes and bronchoalveolar lavage fluid (BAL) were
      collected 0, 2, and 4 days post-challenge. Coadministration of pertussis and
      intratracheal instillation of HDM enhanced HDM-specific lymphoproliferative
      responses and increased BAL levels of total protein, lactate dehydrogenase, HDM
      specific IgE and IgG antibodies, and the number of eosinophils in BAL to the same
      extent as had occurred in the systemically immunized animals. The data show that
      intratracheal instillation of HDM induces a mild allergic sensitization in
      juvenile rats, and that ip injection with B. pertussis enhances this
      sensitization process to levels seen in animals injected with antigen and B
      pertussis together. These results suggest that simultaneous exposure to Th2
      inducing vaccine components and allergenic proteins may be a risk factor for
      allergic sensitization and the development of asthma in susceptible individuals.

PMID- 12604839
TI  - Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the antigen-presenting
      activity of dendritic cells.
AB  - We have previously shown that exposure of mice to 2,3,7, 8-tetrachlorodibenzo-p
      dioxin (TCDD) induces activation-like changes in splenic dendritic cells (DC) in
      the absence of antigen challenge. Since activation of DC reduces their ability to
      phagocytize antigen, we examined the effects of TCDD on the ability of DC to
      process and present antigen to antigen-specific T cells and to internalize latex
      beads. Additionally, the expression of costimulatory and adhesion molecules was
      examined on DC from TCDD-treated mice injected with allogeneic tumor cells. The
      ability of DC from C57Bl/6 mice to induce proliferation of keyhole limpet
      hemocyanin (KLH)-specific 10.5.17 T cells and production of IL-4 was not
      significantly altered by TCDD exposure, either when KLH was added in vitro or
      when the mice were injected with KLH prior to DC isolation. In contrast,
      ovalbumin (OVA) presentation by DC from TCDD-treated Balb/c mice induced enhanced
      proliferation of OVA-specific D011.10 T cells, although the production of IL-2
      and IFN-gamma was not affected. Enhanced in vivo proliferation of adoptively
      transferred, CFSE-labeled DO11.10 T cells was also observed in TCDD-treated
      Balb/c mice that were challenged with OVA. TCDD treatment modulated the
      expression of major histocompatibility complex (MHC) class II, CD24, ICAM-1,
      CD40, and LFA-1 on splenic DC from C57Bl/6 mice injected with allogeneic tumor
      cells; however, the effects of TCDD were identical to changes seen previously in
      nonimmune mice, suggesting that these effects were not antigen-dependent.
      Finally, TCDD treatment did not affect the ability of splenic DC to internalize
      latex beads administered in vivo. Taken together, these results suggest that the
      activation-like changes induced in DC by TCDD do not suppress the ability of DC
      to process and present antigen, but may enhance their ability to provide
      activation signals to T cells. This, in turn, may alter the survival of the T
      cells, the DC, or both, and might lead to dysregulation of the immune response.

PMID- 12604841
TI  - Resazurin metabolism assay is a new sensitive alternative test in isolated pig
      cornea.
AB  - The main object of our study was to investigate whether the resazurin metabolism
      assay is a sensitive surfactant and alcohol toxicity test in isolated pig cornea
      and to compare this recently developed fluorometric assay with the data collected
      in the eye irritation reference chemical data bank. Resazurin is a substrate that
      changes color in response to metabolic activity. Isolated pig corneas were
      immersed for 10 min in surfactants and alcohol irritant solutions. After
      incubation, resorufin fluorescence was read and corneal viability was assessed.
      This corneal viability was compared with the maximal modified average score
      published in the report of ECETOC. This assay highlighted different concentration
      dependent irritation potentials of the three surfactants tested, and the same
      results were obtained with corneas treated with the alcohols. We observed that
      the degree of surfactant- and alcohol-induced decrease in corneal viability,
      using the resazurin reduction test, was correlated with the in vivo irritancy
      measurements as determined by the Draize test and scored with the Modified
      Maximum Average Score (MMAS). This assay allowed us to classify the ocular
      irritancy of the tested surfactants and alcohols in the same ranking order as the
      Draize classification. Corneal viability measurement can be used as a potential
      alternative for the toxicological assessment of surfactants and alcohols. The
      nontoxic, nonradioactive resazurin metabolism assay allows rapid assessment of
      many samples with simple equipment and at reduced cost for continuous monitoring
      of corneal viability. This assay seems to be suitable as a toxicological
      screening test for eye irritation determination.

PMID- 12604842
TI  - Rapid, sequential activation of mitogen-activated protein kinases and
      transcription factors precedes proinflammatory cytokine mRNA expression in
      spleens of mice exposed to the trichothecene vomitoxin.
AB  - Since proinflammatory cytokine mRNA expression is induced within lymphoid tissue
      in vivo by the trichothecene vomitoxin (VT) in a rapid (1-2 h) and transient (4-8
      h) fashion, it was hypothesized that mitogen-activated protein kinases (MAPKs)
      and transcription factors associated upstream with gene transcription of these
      cytokines are activated prior to or within these time windows. To test this
      hypothesis, mice were first treated with a single oral dose of VT and then
      analyzed for MAPK phosphorylation in the spleen. As little as 1 mg/kg of VT
      induced JNK 1/2, ERK 1/2, and p38 phosphorylation with maximal effects being
      observed at 5 to 100 mg/kg of VT. VT transiently induced JNK and p38
      phosphorylation over a 60-min time period with peak effects being observed at 15
      and 30 min, respectively. In contrast, ERK remained phosphorylated from 15 to 120
      min. Next, the binding of activating protein 1 (AP-1), CCAAT enhancer-binding
      protein (C/EBP), CRE-binding protein (CREB), and nuclear factor-kappaB (NF
      kappaB) was measured by electrophoretic mobility shift assay (EMSA) using four
      different consensus transcriptional control motifs at 0, 0.5, 1.5, 4, and 8 h
      after oral exposure to 25 mg/kg of VT. AP-1 binding activity was differentially
      elevated from 0.5 h to 8 h, whereas C/EBP binding was elevated only at 0.5 h.
      CREB binding decreased slightly at 0.5 h but gradually increased, reaching a
      maximum at 4 h. NF-kappaB binding was increased only slightly at 4 and 8 h. The
      specificities of AP-1, C/EBP, CREB, and NF-kappaB for relevant DNA motifs were
      verified by competition assays, using an excess of unlabeled consensus and mutant
      oligonucleotides. Supershift EMSAs and Western blot analysis identified specific
      VT-inducible DNA binding proteins for AP-1 (cJun, phospho c-jun, JunB, and JunD),
      C/EBP (C/EBPbeta), CREB (CREB-1 and ATF-2), and NF-kappaB (p50 and cRel).
      Finally, when the effects of oral VT exposure on proinflammatory gene expression
      were assessed at 3, 6, and 9 h, splenic TNF-alpha, IL-1beta, and IL-6 mRNA were
      found to peak at 3 h and were still significantly elevated at 6 h but not at 9 h.
      Taken together, VT first activated MAPKs in vivo and either concurrently (AP-1,
      C/EBP) or subsequently (AP-1, CREB, NF-kappaB) modulated binding activities of
      transcription factors specific for potential regulatory motifs in cytokine
      promoters. The timing of these events was highly consistent with the kinetics of
      proinflammatory gene expression in the spleens of mice exposed to VT. This study
      provides a novel model for studying the interrelationship of MAPK
      phosphorylation, transcription factor activation, and cytokine gene expression in
      an intact animal exposed to a toxic compound.

PMID- 12604843
TI  - Homologous recombination initiated by benzene metabolites: a potential role of
      oxidative stress.
AB  - Benzene is a ubiquitous pollutant and known human leukemogen. Benzene can be
      enzymatically bioactivated to reactive intermediates that can lead to increased
      formation of reactive oxygen species (ROS). ROS formation can directly induce DNA
      double-strand breaks, and also oxidize nucleotides that are subsequently
      converted to double-strand breaks during DNA replication that can be repaired
      through homologous recombination, which is not error-free. Therefore increased
      DNA double-strand-break levels may induce hyper-recombination, which can lead to
      deleterious genetic changes. To test the hypothesis that benzene and its
      metabolites can initiate hyper-recombination and to investigate the potential
      role of ROS, a Chinese hamster ovary (CHO) cell line containing a neo direct
      repeat recombination substrate (CHO 3-6), was used to determine whether benzene
      or its metabolites phenol, hydroquinone, catechol, or benzoquinone initiated
      increased homologous recombination and whether this increase could be diminished
      by the coincubation of cells with the antioxidative enzyme catalase. Results
      demonstrated that cells exposed to benzene (1, 10, 30, or 100 micro M) for 24 h
      did not exhibit increased homologous recombination. Increased recombination
      occurred with exposure to phenol (1.8-, 2.6-, or 2.9-fold), catechol (1.9-, 2-, 5
      , or 3.2-fold), or benzoquinone (2.7-, 5.5-, or 6.9-fold) at 1, 10, and 30- micro
      M concentrations, respectively, and with exposure to hydroquinone at 10 and 30
      micro M concentrations (1.5-1.9-fold; p < 0.05). Studies investigating the
      effects of catalase demonstrated that increased homologous recombination due to
      exposure to phenol, hydroquinone, catechol, or benzoquinone (10 micro M) could be
      completely abolished by the addition of catalase. These data support the
      hypothesis that increased homologous recombination mediates benzene-initiated
      toxicity and supports a role for oxidative stress in this mechanism.

PMID- 12604845
TI  - Thresholds of carcinogenicity in the ED01 study.
AB  - The results of the articles on the carcinogenicity of 2-acetylaminofluorene (J.
      H. Farmer et al., 1980, J. Environ. Pathol. Toxicol. 3, 55-68; N. A. Littlefield
      et al., 1980, J. Environ. Pathol. Toxicol. 3, 17-34) in approximately 25,000
      female mice were reanalyzed by the procedure proposed earlier (W. J. Waddell,
      2002, TOXICOL: Sci. 68, 275-279) using the Rozman scale (K. K. Rozman et al.,
      1996, Drug Metab. Rev. 28, 29-52). In contrast to some conclusions of the lack of
      a threshold for carcinogenesis that have been made in the past from this study,
      this reanalysis showed a clear and consistent threshold for bladder neoplasms at
      about 10 19.5 molecules/kg/day and for liver neoplasms at about 10 19.1
      molecules/kg/day. The slopes of the dose-response curves for bladder neoplasms
      from 17 months through 33 months were consistently very steep, while those for
      liver neoplasms increased from a shallow slope at 18 months to a steep slope at
      33 months. This is interpreted to indicate that the mechanism of carcinogenesis
      may be different in the two organs. A linear response for percentage tumors
      plotted against dose on a logarithmic scale is confirmed by this analysis, which
      is based on the fundamental principle that chemical potential effects a linear
      response. Furthermore, this application continues to show a sharp threshold for
      carcinogenesis. The implications of these observations should be important in the
      extrapolation of results from animal experiments to human risk assessment.

PMID- 12604846
TI  - Effect of nefiracetam, a neurotransmission enhancer, on primary uroepithelial
      cells of the canine urinary bladder.
AB  - Repeated oral treatment of dogs with a high dose of nefiracetam is reported to
      induce hemorrhagic lesions in the urinary bladder. To delineate its pathogenesis,
      we established the primary culture of uroepithelial cells of the canine urinary
      bladder, and then explored the effect of nefiracetam on the cultured cells.
      Uroepithelial cells scraped from the connective tissues of the urinary bladder of
      naive dogs were suspended in the minimum essential medium containing dispase, and
      then resuspended in the keratinocyte medium to be 6.0-7.0 x 10(5) cells/ml.
      Afterward, they were added to an apical chamber with a 12-mm transwell filter,
      cultured for three days, and recultured in the keratinocyte medium containing 1
      mM CaCl(2) for 20 days. Microscopically, these cultured cells consisted of three
      cell layers with high transepithelial electric resistance (TER; > 10,000 ohm
      cm(2)). Immunofluorescence observations revealed ZO-1 and E-cadherin bands, and
      electron microscopic examinations displayed the superficial cells with the
      assembly of tight junctions. When the effect of nefiracetam and its five main
      metabolites (M-3, M-10, M-11, M-18, and M-20) on TER and the ZO-1 band was
      assessed using cultured cells, only M-18 significantly reduced TER in the
      coculture for 48 h or more. Both M-10 and M-18 exhibited a deformation of
      uroepithelial cells and a slight reduction of the ZO-1 band from 120 h later. In
      conclusion, this culture system possesses both functional and morphological
      features of the uroepithelium reflected in vivo, and M-18 may play a pivotal role
      in the impairment of uroepithelial cells, leading to the onset of the urinary
      bladder lesion in dogs due to nefiracetam.

PMID- 12604844
TI  - Induction of chemokines by low-dose intratracheal silica is reduced in TNFR I
      (p55) null mice.
AB  - Previous studies suggest that tumor necrosis factor alpha (TNF-alpha) and the
      TNFRI (p55) and TNFRRII (p75) receptors mediate the pulmonary fibrotic response
      to silica. In order to further define the role of the TNFRI (p55) receptor in
      induction of profibrotic chemokines by low-dose silica/crystalline silica (50
      micro g/50 micro l/mouse) or control diluent saline was instilled into the
      trachea of TNFRI gene ablated ((-/-)) and C57BL/6 (WT) control mice. Lung tissue
      was harvested and bronchoalveolar lavage (BAL) performed 24 h and 28 days
      following silica administration. Selected profibrotic chemokine mRNAs were
      quantified by ribonuclease protection assay, normalized to ribosomal protein L32
      mRNA content and expressed relative to saline control treated lungs. Induction of
      MIP-1beta, MIP-1alpha, MIP-2, IP-10, and MCP-1 mRNAs was attenuated in the TNFRI(
      /-) mice, in comparison to WT mice, particularly at 28 days after exposure. ELISA
      assays for MIP-1alpha and MIP-2 in homogenized lung tissue similarly demonstrated
      marked induction of both chemokines 24 h after silica treatment, which was
      persistent at 28 days in WT but not in TNFRI(-/-) mice. The percentage of BAL
      cells that was neutrophils was comparably increased in WT and RI(-/-) lungs at 24
      h (49 +/- 12% vs. 46 +/- 10%) and 28 days (6.2 +/- 1.5% vs. 4.5 +/- 1%). The
      increase in total lavagable cells and BAL protein was also independent of strain.
      Histology revealed mild alveolitis without granuloma formation in both strains,
      slightly decreased in TNFRI(-/-). This study demonstrates an increase in pro
      fibrotic chemokines in response to a single intratracheal exposure to crystalline
      silica that was sustained at 28 days after treatment in WT but not in TNFRI(-/-)
      mice. Silica dependent recruitment of neutrophils to the alveolar space and
      alveolar protein leak were, however, not altered by the absence of the TNF
      receptor.

PMID- 12604847
TI  - Augmentation of aflatoxin B1 hepatotoxicity by endotoxin: involvement of
      endothelium and the coagulation system.
AB  - Aflatoxin B(1) (AFB(1)) is a fungal toxin that causes both acute hepatotoxicity
      and liver carcinoma in exposed humans and animals. Previous studies have shown
      that exposure of rats to nontoxic doses of bacterial lipopolysaccharide (LPS)
      augments AFB(1) acute hepatotoxicity, resulting in enhanced injury to hepatic
      parenchymal cells and bile ducts. At larger doses, LPS causes damage to
      sinusoidal endothelial cells (SECs) and activation of the coagulation system.
      Accordingly, we tested the hypothesis that treatment of rats with AFB(1) and LPS
      damages SECs and activates the coagulation system, which is critical for
      potentiation of AFB(1) hepatotoxicity by LPS. Male, Sprague-Dawley rats were
      given 1 mg/kg AFB(1) (ip), then 4 hours later 7.4 x 10(6) EU/kg LPS was
      administered (iv). A time-dependent injury to SECs and parenchymal cells was
      observed in AFB(1)/LPS-cotreated animals that became significant by 12 h, as
      estimated by increases in plasma hyaluronic acid (HA) and alanine
      aminotransferase (ALT) activities, respectively. Immunohistochemical analysis
      revealed that endothelial cell immunostaining was decreased in both centrilobular
      and periportal regions after AFB(1)/LPS treatment. Immunohistochemical evidence
      of fibrin deposition was found in both centrilobular and periportal regions by 12
      h, but these deposits persisted only in periportal regions by 24 h.
      Administration of the anticoagulant heparin to AFB(1)/LPS-cotreated animals
      markedly attenuated increases in markers of hepatic parenchymal cell injury but
      provided only minimal amelioration of bile duct injury. These results suggest
      that AFB(1)/LPS coexposure results in SEC injury and activation of the
      coagulation system, and that the coagulation system is required for the
      development of hepatic parenchymal cell injury but not bile duct injury in this
      model.

PMID- 12604848
TI  - X-ray fluorescence holography: a novel treatment for crystal structure
      determination.
AB  - It is shown that it is possible to use a linear regression algorithm direct
      method to solve crystal structures from X-ray fluorescence holography (XFH) data.
      It is found that, in contrast to conventional X-ray structure determination
      methods, which do not always work unambiguously, the sustainable method utilizing
      the XFH data generally provides the unique phase-retrieval structure solution and
      is able, in many cases, to replace the above for determining both the absolute
      values (moduli) and phases of structure factors. The XFH (theta, varphi) scan
      with a fluorescing Cu atom from a spherical cluster of a Cu(3)Au single crystal,
      at an energy of 10 keV for the incident unpolarized plane-wave X-radiation, is
      numerically simulated to test the performance of the method in finding a unique
      solution for the structure factors involved in the restoration procedure using
      the linear regression algorithm.

PMID- 12604849
TI  - Structure of Ti2P solved by three-dimensional electron diffraction data collected
      with the precession technique and high-resolution electron microscopy.
AB  - The crystal structure of Ti(2)P has been analysed using electron diffraction and
      high-resolution electron-microscopy techniques. A new unit cell was found, the
      compound is hexagonal with a = 19.969 (1) and c = 3.4589 (1) A. The structure was
      first solved in space group P-62m in projection using direct methods on electron
      diffraction data from the [001] zone axis. A three-dimensional solution was
      obtained using again direct methods but on a three-dimensional set of electron
      diffraction data recorded with the precession technique. Ti(2)P is a distorted
      Fe(2)P structure and, based on high-resolution images, it is possible to explain
      that the tripling of the unit cell is due to the ordering of P vacancies that
      reduces the symmetry to P-6.

PMID- 12604850
TI  - On the choice of d-orbital coordinate system in charge-density studies of low
      symmetry transition-metal complexes.
AB  - The distribution of the d electrons over the corresponding orbitals in transition
      metal complexes is a central concept in the theory of metal-ligand bonding. The
      description requires the assignment of an axis of quantization, which is
      unambiguous in symmetric environments but not clear-cut in the now commonly
      encountered case of a low-symmetry coordination environment. As the d-electron
      population can be derived from accurate diffraction data using the methods of
      charge-density analysis [HollaDay et al. (1983). Acta Cryst. A39, 377-387], the
      need for an appropriate procedure is relevant in this area of crystallography.
      Several criteria for the choice of coordinate system based on the resulting
      orbital populations are discussed. They are tested on a cobalt atom in a trigonal
      bipyramidal site and applied to transition-metal sites in Cu(II)-alanyl-valine,
      and an open zirconocene. The population of the d-orbital cross terms for the
      different coordinate-system orientations is used to judge the results. In the
      cases examined, the intuitively most reasonable coordinate system corresponds to
      the one with smaller value of the sum of the populations of the d-orbital cross
      terms.

PMID- 12604851
TI  - A one-dimensional model for small-angle X-ray scattering from crystalline block
      copolymers.
AB  - Small-angle X-ray scattering patterns (SAXS) are widely used to study polymers.
      Quantitative treatment of the intensity curves is often realized to obtain the
      long period and the linear crystallinity of semicrystalline homopolymers
      presenting a lamellar morphology, mainly using the correlation function. But even
      in the one-dimensional case, block copolymer systems exhibit more complicated
      morphologies that cannot be fully interpreted by this standard method. In this
      work, a model has been developed based on a previous treatment applicable to
      systems characterized by two different densities. Two additional densities have
      been considered to model four phase systems that can occur with block copolymers
      (e.g. two different crystalline domains and amorphous parts). The scattering
      intensity function was derived as a function of various parameters like the
      number of stacked lamellar units, the mean values and distributions of widths,
      and the electron densities.

PMID- 12604852
TI  - A holographic approach to point defect structure determination in inorganic
      crystals: Er-doped Sc2O3.
AB  - A holographic approach to the analysis of a Bragg scattering pattern has been
      described by Szoke [Acta Cryst. (1993), A49, 853-866]. The combination of
      crystallographic procedures and holographic interpretation allows reconstruction
      of an unknown part of the crystalline structure model-free if the other part of
      the structure is known. By introducing the concept of an average crystal, this
      approach is extended to point defect structures in inorganic crystals. In this
      case, the host lattice is well known while the defect structure is regarded as
      the unknown part. To demonstrate the feasibility of this approach, an Sc(2)O(3)
      sample doped with Er at low concentration has been studied. An additional
      electron density has been observed, which can be interpreted as an interstitial
      Er position.

PMID- 12604853
TI  - Experimental lensless soft-X-ray imaging using iterative algorithms: phasing
      diffuse scattering.
AB  - Images of randomly placed two-dimensional arrays of gold balls have been
      reconstructed from their soft-X-ray transmission diffraction patterns. An
      iterative hybrid input-output (HiO) algorithm was used to solve the phase problem
      for the continuous distribution of diffuse X-ray scattering. Knowledge of the
      approximate size of the clusters was required. The images compare well with
      scanning electron microscope (SEM) images of the same sample. The use of
      micrometre-sized silicon nitride window supports is suggested, and absorption
      filters have been used to allow collection of low spatial frequencies often
      obscured by a beam stop. This method of phasing diffuse scattering may have
      application to scattering from individual inorganic nanostructures or single
      macromolecules.

PMID- 12604854
TI  - Theory of diffraction from D019 ordered c.p.h structures containing complex
      stacking faults on basal planes.
AB  - Antiphase boundaries and stacking faults affect the deformation behaviour of
      intermetallics. In an ordered c.p.h. (close-packed hexagonal) structure of D0(19)
      type (e.g. Mg(3)Cd, Ti(3)Al-based alloys), stable planar faults of two types are
      possible on the basal plane. These are antiphase boundaries (APBs) and complex
      stacking faults (CSFs), which are a combination of an APB and a stacking fault.
      The latter can be either of shear or of climb type. If the bounding partial
      dislocations of a CSF lie in its plane, then it is designated as a shear CSF,
      otherwise it is called a climb CSF. A mathematical formulation of the theory of
      diffraction from a D0(19) structure having a shear or climb type of CSF has been
      carried out. The diffraction effects owing to the presence of these CSFs have
      been found. Integrated intensities and widths of the reflections are affected.
      These have been evaluated in terms of the probability of the occurrence of these
      faults.

PMID- 12604855
TI  - A universal computation method for two-beam dynamical X-ray diffraction.
AB  - A general-purpose method that includes nearly all possible two-beam diffraction
      mechanisms is presented for calculating diffracted and specularly reflected X-ray
      intensities from single crystals. Based on this method, it is demonstrated that a
      small universal computational routine can be developed to accurately treat two
      beam diffraction for any scattering geometry.

PMID- 12604856
TI  - Structures of a hollow filamentary conical helix.
AB  - A hollow conical helix (HCH) of graphitic materials broadens the conical
      configuration by introduction of wrapping about 120 degrees symmetry positions in
      addition to the traditional rotation about 60 degrees symmetry sites. Complete
      structural models are established for a HCH and examined taking into account the
      rotation mode, coincidence site lattice (CSL), disclination angle and packing
      pattern. Combined with experimental observations, it is revealed that the size of
      the CSL, hence the density of the coincidence lattice sites, dominates the
      overlap configuration of a conical helix.

PMID- 12604857
TI  - The crystallographic fast Fourier transform. II. One-step symmetry reduction.
AB  - An algorithm for evaluation of the crystallographic FFT for 67 crystallographic
      space groups is presented. The symmetry is reduced in such a way that it is
      enough to calculate P1 FFT in the asymmetric unit only and then, in a
      computationally simpler step, recover the final result. The algorithm yields the
      maximal symmetry reduction for every space group considered. For the central step
      in the calculation consisting of general P1 FFTs, any generic fast Fourier
      subroutine can be used. The approach developed in this paper is an extension of
      the scheme derived for p3-symmetric data [Rowicka, Kudlicki & Otwinowski (2002).
      Acta Cryst. A58, 574-579]. Algorithms described here will also be used in our
      forthcoming papers [Rowicka, Kudlicki & Otwinowski (2003). Acta Cryst A59, 183
      192; Rowicka, Kudlicki & Otwinowski (2003), in preparation], where more
      complicated groups will be considered.

PMID- 12604858
TI  - The crystallographic fast Fourier transform. III. Centred lattices.
AB  - Algorithms for evaluation of the crystallographic FFT for centred lattices are
      presented. These algorithms can be applied to 80 space groups containing centring
      operators. For 44 of them, combining these algorithms with those described by
      Rowicka, Kudlicki & Otwinowski [Acta Cryst A59, 172-182] yields the maximal
      symmetry reduction. For other groups, new algorithms, to be presented in our
      forthcoming paper [Rowicka, Kudlicki & Otwinowski (2003), in preparation], are
      needed. The requirements on the grid size and how they interact with the choice
      of algorithms are also discussed in detail.

PMID- 12604859
TI  - A formula to estimate the size of a fullerene.
AB  - A formula to estimate the radius of an equiareal sphere for any C(n) fullerene as
      a function of n is suggested. It asymptotically characterizes the series of C(n)
      fullerenes with increasing n and is mostly adapted to the symmetric shapes. The
      estimated radius may also be a reasonable approximation if the shape is not too
      elliptic.

PMID- 12604860
TI  - On the symmetry of 11-hedra.
AB  - The symmetry point-group statistics for all combinatorially non-isomorphic 11
      hedra (440564 in total) are contributed in the paper for the first time. The most
      symmetrical shapes with 3 to 36 automorphism group orders (305 in total) are
      drawn in Schlegel projection and characterized by facet symbols and symmetry
      point groups.

PMID- 12604862
TI  - Noninvasive ultrasound techniques for the assessment of atherosclerosis in
      coronary artery disease.

PMID- 12604863
TI  - Stent implantation and subsequent dilatation for pulmonary vein stenosis in
      pediatric patients: maximizing effectiveness.
AB  - The outcome of stent implantation and redilatation was investigated in 4
      pediatric patients with 7 stenotic lesions of the pulmonary vein (PV), paying
      particular attention to late neointimal proliferation. The minimal diameter of
      the lesions increased from 0.8-3.6 (2.3+/-1.1) mm to 3.6-8.4 (5.1+/-1.6) mm
      immediately after stent implantation. Although the pressure gradient across the
      lesion was not measured in patient 4, in patients 1-3, it decreased from 4-34
      (18+/-13) mmHg to 3-15 (7+/-4) mmHg. Except for case 4, who achieved a lesion
      diameter of 8.4 mm after initial stent dilatation, the other 6 lesions all
      restenosed within a few months, with an increasing pressure gradient. One patient
      with multiple PV stenoses associated with persistent severe pulmonary
      hypertension died suddenly. However, repeat dilatations were effective in all
      other lesions. Furthermore, in one lesion in patient 1, no serious restenosis
      developed for 20 months after the lesion was dilated up to 5.6 mm. Although
      further follow-up is mandatory, the final stent diameter within a vessel may
      determine long-term patency, and aggressive redilatation may be crucial for
      successful therapy of such a difficult disease.

PMID- 12604864
TI  - Failure to raise blood pressure during exercise is a poor prognostic sign in
      patients with hypertrophic non-obstructive cardiomyopathy.
AB  - Sudden cardiac death is a well-documented complication of hypertrophic
      cardiomyopathy and additionally, failure to raise blood pressure (BP) during
      exercise has been associated with a poor outcome. The present study group
      comprised 58 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) who
      were receiving beta-blocker therapy. All patients underwent submaximal exercise
      radionuclide ventriculography (RNVG) to evaluate left ventricular (LV) function
      at both rest and peak exercise. Patients were divided into 2 groups based on the
      increase in systolic BP during exercise (ie, group A <30% or group N >/=30% of
      resting systolic BP) and were involved in long-term follow-up (10.4+/-4.0 years).
      Group A comprised 29% of the subjects. Age and workload at peak exercise were
      similar in the 2 groups. LV end-diastolic dimension was smaller and the
      interventricular septum was thicker in group A. LV ejection fraction on RNVG was
      similar in the 2 groups at rest and at peak exercise. During the follow-up
      period, more patients in group A than group N suffered syncopal attack (29% vs
      5%, p<0.05) and cardiac sudden death (24% vs 2%, p<0.05). Patients with HNCM
      whose BP fails to rise during exercise have a poor prognosis.

PMID- 12604865
TI  - Therapeutic monitoring of class I antiarrhythmic agents using high-resolution
      electrocardiography instead of blood samples.
AB  - Antiarrhythmic therapy requires monitoring of serum drug concentrations to
      determine a patient's optimal oral dose of medication. Repeated examination of
      blood samples, however, is costly and time-consuming, so the present study
      evaluated whether changes in serum concentrations could be estimated from changes
      in electrocardiographic (ECG) parameters. Of 36 patients receiving antiarrhythmic
      drugs for supraventricular or ventricular arrhythmias, 12 were treated with
      flecainide, 12 with pilsicainide, and 12 with pirmenol. Signal-averaged ECG
      (SAECG) were recorded before starting drug administration, 1 month later, and
      twice during ongoing therapy. At the time of the 2nd to the 4th recordings, serum
      concentrations of the drugs were also measured. As previously reported, all
      agents, but especially flecainide and pilsicainide, prolonged the filtered QRS (f
      QRS) and the duration of low-amplitude signals at the terminal portion of the QRS
      complex. The SAECG parameters varied between the recordings made during therapy.
      Differences in the duration of the f-QRS between 2 recordings correlated
      significantly with differences in serum drug concentrations (r=0.91 for
      flecainide, r=0.70 for pilsicainide, and r=0.61 for pirmenol). No significant
      correlation between drug concentration and other SAECG parameters was found.
      Changes in the serum concentration of flecainide, pilsicainide and pirmenol can
      be estimated from changes in the duration of the f-QRS on the SAECG and periodic
      monitoring of such could help reduce the number of repeat measurements of drug
      concentrations in blood samples.

PMID- 12604866
TI  - Management of asymptomatic aortic stenosis in patients undergoing coronary artery
      bypass grafting.
AB  - This study compared the outcomes of combined coronary artery bypass grafting
      (CABG)/aortic valve replacement (AVR) and CABG alone in patients with moderate
      aortic stenosis and determined the possible indications for AVR at the time of
      CABG. Between December 1988 and January 2001, in Tenri Hospital, 41 patients with
      aortic stenosis underwent CABG: 26 patients underwent the combined procedure and
      15 patients underwent CABG alone. The patients who underwent CABG alone were
      separated them into 2 groups on the basis of the results of annual
      echocardiography: the rapid progression group, defined by an increase of deltaP
      by >/=10 mmHg/year, and the slow progression group. Of the 15 patients who
      underwent CABG alone, the probability of survival at the end of the study in 2001
      was 92% at 5 years and 74% at 10 years, and the respective event-free rates were
      65% and 50%. Patients less than 70 years old and who were in the rapid
      progression group had a greater risk for re-operation. The study suggests that
      patients younger than 70 years old with risk factors for rapid progression should
      undergo CABG/AVR, and conversely, those older than 70 years old without the risk
      factors can undergo CABG only.

PMID- 12604867
TI  - Embolic attack in patients with atrial fibrillation and atrial thrombus depends
      on the character of the thrombus.
AB  - It is very important to prevent embolisms from left atrial thrombi (LAT). The
      present study was a trial for the management of patients with AT using 122
      patients with atrial fibrillation and LAT who were followed for 1 year after
      transesophageal echocardiography. LAT were classified by their shape and mobility
      into the mobile ball type (MB, n=28), fixed ball type (FB, n=32) and mountain
      type (MO, n=42). The patients were given warfarin (INR: 1.5-2.0, n=43), aspirin
      81 mg (n=74) and/or ticlopidine 200 mg/day (n=31). The embolic rate (ER) in the
      MB group was significantly higher than in the other groups [ie, MB 39.3% vs FB
      15.6% (p<0.05), vs MO 2.4% (p<0.05)]. The ER in the FB group was significantly
      higher than in the MO group (p<0.05). Therapy with a combination of ticlopidine
      and aspirin reduced the ER in the patients with ball thrombi. The ER of the ball
      thrombus type group, especially the MB group, was very high in spite of therapy
      with anti-coagulants and/or anti-platelet agents, and such patients should be
      treated by early surgical intervention. However, the combination of ticlopidine
      and aspirin may be useful for preventing embolism.

PMID- 12604868
TI  - Comparison of the efficacy of reperfusion therapies for early mortality from
      acute myocardial infarction in Japan: registry of Miyagi Study Group for AMI
      (MsAMI).
AB  - The current reperfusion strategy in Japan for acute myocardial infarction (AMI)
      is that the majority of early arrival patients are treated with primary
      percutaneous coronary intervention (PCI). However, the efficacy of primary PCI,
      intravenous thrombolysis (IV-T), intracoronary thrombolysis (IC-T) and rescue PCI
      has not been compared in the clinical situation. In the present study, 3,258
      cases of AMI in 1992-2000 from the data base of the Miyagi Study Group for AMI
      were analyzed. These patients were hospitalized within 6 h of the onset of
      symptoms. IV-T and IC-T were initially performed in 120 and 441 patients,
      respectively, and 41 and 199 rescue PCI procedures, respectively, were needed.
      Primary PCI was performed in 1,822 cases, and no reperfusion therapy was done in
      875 patients. The crude 30-day in-hospital mortality was 12.7% for IV-T, 3.7% for
      IC-T, 4.8% for primary PCI, 7.9% for rescue PCI, and 14.1% in patients who did
      not undergo reperfusion therapy. The covariate-adjusted odds ratio (95%
      confidence interval) was 0.38 (0.28-0.52) for primary PCI, 0.30 (0.15-0.60) for
      IC-T, 1.04 (0.51-2.10) for IV-T and 0.77 (0.46-1.30) for rescue PCI. The present
      data verify that primary PCI is superior to other reperfusion strategies in the
      real clinical situation and justifies the current unique strategy of reperfusion
      therapy for AMI used in Japan.

PMID- 12604869
TI  - Health-related quality of life of Japanese patients with chronic heart failure:
      assessment using the Medical Outcome Study Short Form 36.
AB  - Chronic heart failure is characterized by impaired cardiac function, but the
      relationship between clinical indices and subjective perception is not clear.
      This study was undertaken to investigate the relationship between cardiac
      function, exercise capacity and clinical classification, and the health-related
      quality of life (HRQOL) in 91 outpatients with an left ventricular ejection
      fraction (LVEF) less than 40%. Exercise capacity was evaluated by the Specific
      Activity Scale, and HRQOL by the Medical Outcome Study Short Form 36. Exercise
      capacity and the cardiothoracic ratio were correlated with the HRQOL related to
      physical functioning, although the correlation between exercise capacity and
      mental health was not significant. LVEF was not related to HRQOL. Factor analysis
      revealed (1) LVEF was independent of physical functioning; (2) physical function
      and exercise capacity comprise a factor reflecting physical HRQOL; and (3) socio
      emotional functioning is the third factor independent of LVEF and physical
      function. Physical and socio-mental HRQOL measurement included information
      independent of the widely used clinical indices such as LVEF and New York Heart
      Association classification. The evaluation of HRQOL should be included in the
      assessment of patient status.

PMID- 12604870
TI  - Effect of regular exercise on coronary endothelial function in patients with
      recent myocardial infarction.
AB  - Exercise training improves the endothelial function of arteries in skeletal
      muscle, but few studies have examined its clinical effect on human coronary
      endothelial function. Non-infarct-related coronary arteries in 41 patients with a
      recent myocardial infarction who underwent successful percutaneous transluminal
      coronary angioplasty were studied. Patients were divided into 2 groups: regular
      exercisers (n=24, 17 males, mean age: 58 years), and non-exercisers (n=17, 12
      males, mean age: 58 years). Acetylcholine (ACh) was infused into the non-infarct
      related coronary artery and its diameter was measured by quantitative angiography
      at baseline and at 6 months after angioplasty. ACh, given in doses of 1, 3, 10,
      30 microg/min, increased the coronary artery diameter in a dose-dependent manner
      in both groups. The mean percent change in the diameter at the site of stenosis
      change (%DS) was less in the regular exercisers than in the non-exercisers (11%+/
      12 vs 41%+/-36, p<0.05). Multivariate analysis showed that regular exercise was
      the only significant determinant of improvement in endothelial function (p=0.01).
      These findings suggest that regular exercise improves endothelial function in the
      coronary arteries following myocardial infarction.

PMID- 12604871
TI  - Relationship between heart rate variability and left ventricular remodeling after
      reperfused first anterior wall acute myocardial infarction.
AB  - The aim of the present study was to test the hypothesis that inadequate
      improvement in heart rate variability (HRV) in the healing stage of acute
      myocardial infarction (AMI) is associated with left ventricular (LV) remodeling.
      The study group comprised 20 patients (14 men, 6 women; mean age, 61+/-12 years)
      with a reperfused first anterior AMI (</=24 h). The standard deviation of normal
      RR intervals (SDNN) was calculated from the 24-h ambulatory electrocardiogram
      recorded on day 3 of admission and at predischarge from the hospital. Left
      ventriculography was performed immediately after primary angioplasty and at
      predischarge. The change in SDNN (deltaSDNN) was compared with the change in the
      LV end-systolic volume index (deltaLVESVI), a parameter of LV remodeling. SDNN
      increased from 73+/-19 ms on day 3 to 109+/-35 ms at predischarge (p=0.0003).
      SDNN at predicharge and deltaSDNN correlated negatively with deltaLVESVI (r=
      0.52, p=0.02, and r=-0.61, p=0.004, respectively), whereas SDNN on day 3 did not
      correlate with deltaLVESVI. Multiple regression analysis selected deltaLVESVI
      (p=0.02) as an independent factor of deltaSDNN. This study indicates that
      deltaSDNN and SDNN at predicharge are associated with deltaLVESVI in patients
      with a reperfused first anterior wall AMI, indicating that persistently reduced
      HRV is associated with postinfarction LV remodeling.

PMID- 12604872
TI  - Relationship between ECG findings and pulmonary artery pressure in patients with
      acute massive pulmonary thromboembolism.
AB  - Pulmonary thromboembolism (PTE) is associated with various electrocardiogram
      (ECG) abnormalities, but the utility of evaluating the severity of PTE based on
      ECG abnormalities alone has not been investigated in Japanese patients
      previously. The purpose of this study was to examine the relationship between ECG
      abnormalities and the mean pulmonary artery pressure (MPAP) in patients with
      acute massive PTE (AMPTE). ECG examination of 21 patients, who were diagnosed
      with AMPTE by pulmonary arteriography, found that S(1)Q(3)T (3) was the most
      frequently observed abnormality (in 67% of the patients), followed by negative T
      (62%), clockwise rotation (57%), and ST elevation (48%). When these patients were
      divided into 2 groups based on the level of MPAP, 8 of the 11 ECG findings, which
      were associated with PTE in a previous report, were more frequently observed in
      Group H (MPAP >/=40 mmHg) than in Group L (MPAP <40 mmHg). MPAP correlated
      significantly with the total number of ECG abnormalities (r=0.82, p<0.001). In
      particular, at least 5 ECG abnormalities were noted in patients with MPAP >/=45
      mmHg. These results suggested that the total number of ECG abnormalities in
      patients with AMPTE can be used to evaluate the severity of APTE, including PAP
      level.

PMID- 12604873
TI  - Improvement of left ventricular dysfunction during exercise by walking in
      patients with successful percutaneous coronary intervention for acute myocardial
      infarction.
AB  - A growing body of evidence suggests that walking reduces the incidence of
      coronary events, so the present study investigated whether walking influences
      left ventricular function in 30 patients with acute myocardial infarction (AMI)
      who had undergone successful percutaneous coronary intervention (PCI). The
      patients were randomly assigned to either a 3-month exercise training program of
      walking (group W, n=15) or a control group (group C, n=15). At both the beginning
      and end of the study, patients underwent exercise stress echocardiography to
      determine left ventricular ejection fraction (LVEF) at rest and during exercise.
      At baseline, there was no difference in LVEF at rest or during exercise between
      the two groups. After 3 months, LVEF during exercise was significantly improved
      compared with at rest in group W (61+/-3% during exercise vs 57+/-5% at rest,
      p<0.01), whereas no difference was observed between the LVEF at rest and that
      during exercise in group C (54+/-5% at rest vs 52+/-7% during exercise, NS).
      Walking may be beneficial for improving left ventricular function during exercise
      in patients with AMI.

PMID- 12604874
TI  - Significance of thrombolysis in myocardial infarction (TIMI) grade 2 flow early
      after thrombolysis followed by immediate percutaneous coronary intervention in
      patients with acute myocardial infarction.
AB  - Although pre-interventional thrombolysis has recently been shown to restore early
      patency and preserve left ventricular function in patients with acute myocardial
      infarction, the significance of Thrombolysis in Myocardial Infarction (TIMI)
      grade flow early after thrombolysis remains unclear. Patients were classified
      into 3 groups according to TIMI grade flow 45 min after thrombolysis; 38 patients
      with TIMI grade 0 or 1 flow (group T0) and 46 with TIMI grade 2 flow (group T2)
      additionally received immediate percutaneous coronary intervention (PCI) and 50
      patients with TIMI grade 3 flow (group T3) were treated conservatively after
      thrombolysis. Although the door-to-balloon times did not differ in groups T0 and
      T2, group T2 had lower peak creatine kinase, a higher rate of complete (>/=70%)
      ST resolution and better regional wall motion at discharge as compared with group
      T0, similar to group T3 (group T2, group T3 vs group T0; 2,857+/-1,756, 2,314+/
      1,948 vs 3,779 +/-2,214 mU/ml; 57, 72 vs 34%; -1.5+/-1.6, -1.2+/-1.6 vs -2.2+/
      1.6; all p<0.01, respectively). These results suggest TIMI grade 2 flow at 45 min
      after thrombolysis followed by immediate PCI, as well as TIMI grade 3 flow, is
      associated with greater myocardial salvage than TIMI grade 0 or 1 flow.

PMID- 12604875
TI  - New index for grading the severity of aortic regurgitation based on the cross
      sectional area of vena contracta measured by color Doppler flow mapping.
AB  - This study was designed to examine whether the cross-sectional area of vena
      contracta measured by color Doppler flow mapping (CFM) could be used for
      assessing aortic regurgitation (AR) and developing an index for grading AR. The
      75 study patients with AR were classified into quadrant grades according to New
      York Heart Association functional class, regurgitant fraction, left ventricular
      (LV) end-diastolic dimension and LV end-systolic dimension. Using CFM, the cross
      sectional area of the vena contracta was measured and it could distinguish all
      grades without significant overlap. An area of less than 0.10 cm(2) corresponded
      to Grade 1, 0.10-0.19 cm(2) corresponded to Grade 2, 0.20-0.29 cm(2) corresponded
      to Grade 3 and an area of more than 0.30 cm(2) corresponded to Grade 4. An area
      of vena contracta of more than 0.30 cm(2) identified high-scoring AR (Grade 4) in
      11 of 11 (sensitivity 100%) and correctly predicted the absence of high-scoring
      AR in 60 of 64 (specificity 94%). Conversely, there was considerable overlap
      between the jet distances with the clinical grades. The cross-sectional area of
      the vena contracta measured by CFM can provide a simple quantitative assessment
      of AR that correlates well with the clinical grade of AR.

PMID- 12604876
TI  - Participation of caspase-3-like protease in necrotic cell death of myocardium
      during ischemia-reperfusion injury in rat hearts.
AB  - This experimental study was designed to determine if caspase-3-like protease is
      activated during a short period of ischemia - reperfusion (I-R) that did not
      induce apoptosis, and whether protease-3-protease inhibitor could prevent
      myocardial I-R injury, especially necrotic cell death. The subjects were 20
      isolated rat hearts; 10 were pretreated for 20 min with 100 micromol/L of the
      protease-3-protease inhibitor, peptide antagonist Asp-Glu-Val-Asp-CHO (DEVD)
      (Group D), and compared with the 10 no-pretreated hearts (Group C). The hearts
      were then subjected to 20, 30, 45, and 60 min of normothermic global ischemia
      followed by 30 min of reperfusion. Caspase-3-like protease was significantly
      elevated after 45 min and 60 min in ischemic hearts. Group D had reduced levels
      of caspase-3-like protease activity after 45 min and 60 min (302+/-58%, 378+/-69%
      of pre-ischemic control, respectively), as compared with Group C (542+/-74%,
      689+/-85%, respectively) (p<0.05, p<0.05, respectively). Histological analysis
      also demonstrated a decrease in cellular damage in Group D, as the count ratio of
      necrotic cells with total cardiomyocytes was 38%, as compared with 78% in the
      control group (p<0.05). Caspase-3-like protease participated in I-R injury in rat
      hearts and inhibition of this protease resulted in a reduction of necrotic cell
      death.

PMID- 12604877
TI  - Protective effects of hydrogen peroxide against ischemia/reperfusion injury in
      perfused rat hearts.
AB  - Among the several mechanisms proposed for ischemic preconditioning (IPC),
      generation of reactive oxygen species (ROS) is reported to be involved in the
      cardioprotective effects of IPC. The present study was designed to investigate
      whether repetitive exposure to hydrogen peroxide (H(2)O(2)) can protect the
      myocardium against subsequent ischemia/reperfusion injury, and whether the
      H(2)O(2)-induced cardioprotection is related to the preservation of energy
      metabolism. Langendorff-perfused rat hearts were exposed to two, 5 min episodes
      of IPC or to various concentrations of H(2)O(2) twice and then to 35 min global
      ischemia and 40 min reperfusion. Using (31)P nuclear magnetic resonance ((31)P
      NMR) spectroscopy, cardiac phosphocreatine (PCr) and ATP and intracellular pH
      (pH(i)) were monitored. IPC and the treatment with 2 micromol/L H(2)O(2)
      significantly improved the post-ischemic recovery of left ventricular developed
      pressure (LVDP) and the PCr and ATP compared with those of the control
      ischemia/reperfusion (LVDP: 36.9 +/-7.4% of baseline in control hearts, 84.0+/
      3.5% in IPC, 65.4+/-3.8% in H(2)O(2); PCr: 51.1+/-5.3% in control hearts, 81.4+/
      5.5% in IPC, 81.7+/-5.2% in H(2)O(2); ATP: 12.3+/-1.6% in control hearts; 30.0+/
      2.8% in IPC, 28.6+/-2.3% in H(2)O(2), mean +/- SE, p<0.05). However, lower (0.5
      micromol/L) or higher (10 micromol/L) concentration of H(2)O (2) had no effect.
      There were significant linear correlations between mean LVDP and high-energy
      metabolites after 40 min reperfusion in H(2)O(2)-treated hearts. In IPC-treated
      hearts, the mean LVDP was greater than that in the 2 micromol/L H(2)O(2)-treated
      hearts under similar levels of high-energy metabolites. IPC also ameliorated
      intracellular acidification (6.38+/-0.03 in control hearts, 6.65+/-0.04 in IPC,
      p<0.05), but treatment with H(2)O(2) did not affect pH(i) during ischemia (6.40+/
      0.05 in H(2)O(2)). In conclusion, H(2)O(2) had protective effects against
      ischemia/reperfusion injury and the effects were related to the preservation of
      energy metabolism. IPC could have additional protective mechanisms that are
      associated with the amelioration of intracellular acidosis during ischemia.

PMID- 12604878
TI  - Existence of alpha-adrenoceptor subtypes in isolated human gastroepiploic and
      omental arteries.
AB  - Establishing the existence of alpha-adrenoceptor subtypes in isolated human
      gastroepiploic and omental arteries was the goal of the present study. Functional
      vascular reactivity of selective alpha(1)- and alpha(2)-adrenoceptor agonists and
      antagonists was studied, using a cannula inserting technique. Intraluminal
      administration of norepinephrine (NE), phenylephrine (PE) or BHT-933 caused a
      vasoconstrictive response in a dose-related manner. The relative potencies of the
      3 agonists were almost the same in both arteries. NE-induced vasoconstrictions
      were significantly antagonized by either prazosin or rauwolscine. PE-induced
      responses were strongly inhibited by prazosin. BHT-933-induced constrictions were
      inhibited by rauwolscine. These results indicate that both alpha(1)- and alpha(2)
      adrenoceptors exist in the human gastroepiploic and omental arteries.

PMID- 12604880
TI  - Marked improvement of left ventricular function after parathyroidectomy in a
      hemodialysis patient with secondary hyperparathyroidism and left ventricular
      dysfunction.
AB  - A 52-year-old woman, a hemodialysis patient, was admitted because of exertional
      dyspnea. Echocardiography showed left ventricular (LV) dilatation and reduced
      contraction. Coronary angiography showed no fixed stenosis. She had elevated
      levels of parathyroid hormone (PTH) as a result of secondary hyperparathyroidism
      with advanced renal failure. After parathyroidectomy, marked improvement of LV
      function following immediate decrease of blood levels of PTH was observed. It is
      suggested that PTH might have a significant role in the pathogenesis of LV
      dysfunction and that parathyroidectomy might be effective as a therapy for heart
      failure in some patients with secondary hyperparathyroidism and LV dysfunction.

PMID- 12604881
TI  - Acetylcholine-induced coronary spasm with a history of Kawasaki disease: case
      report.
AB  - A 21-year-old woman without any known coronary risk factors was found at coronary
      catheterization to have normal coronary angiograms, but demonstrated
      acethylcholine (ACh)-induced coronary spasm. She had a history of Kawasaki
      disease (KD) at 19 months of age and, although coronary angiography was not
      performed at that time, no coronary aneurysms were detected by echocardiography.
      To the best of our knowledge, this is the first case report of ACh-induced
      coronary spasm associated with normal coronary angiograms in a young person with
      a history of KD. The findings suggest that subclinical, persistent coronary
      endothelial dysfunction may exist in this patient; furthermore, the dysfunction
      appears diffuse and might be unrelated to coronary aneurysm formation. The long
      term significance of coronary endothelial dysfunction in patients with KD, as
      suspected by coronary spasm, remains unknown but may be an important risk factor
      for future atherosclerosis.

PMID- 12604879
TI  - Ventricular tachyarrhythmias in a canine model of LQT3: arrhythmogenic effects of
      sympathetic activity and therapeutic effects of mexiletine.
AB  - The ventricular tachyarrhythmias associated with the LQT3 syndrome are typically
      bradycardia-dependent. However, some episodes can be associated with exercise or
      emotional stress, suggesting a different arrhythmogenic mechanism when
      sympathetic activity predominates. This study examined the potential
      arrhythmogenic mechanisms during periods of autonomically mediated transient
      heart rate acceleration in a canine anthopleurin-A model of LQT3 syndrome. Using
      plunge needle electrodes, transmural unipolar electrograms of the left ventricle
      were recorded from endocardial (Endo), mid-myocardial (Mid) and epicardial (Epi)
      sites. The activation-recovery interval (ARI) was measured to estimate local
      refractoriness. The cardiac cycle length was gradually shortened by cessation of
      vagal stimulation (vagal stimulation protocol (VSP)), and intramural electrograms
      and onset mode of ventricular tachyarrhythmias were analyzed in 7 experiments.
      The VSP was performed 8 times before and 5 times after administration of
      mexiletine in each experiment. Before mexiletine, vagal stimulation slowed the
      heart rate and created large transmural ARI dispersion because of a greater ARI
      prolongation at Mid rather than Epi/Endo sites. After cessation of vagal
      stimulation, unipolar electrograms started to show ARI alternans and ventricular
      premature beats developed sporadically. Sustained ventricular tachyarrhythmias
      were induced in 12 of the 56 trials of the VSP. Initiation of ventricular
      tachyarrhythmias was associated with delayed conduction at Mid/Endo sites.
      Mexiletine attenuated transmural ARI dispersion, and neither ARI alternans nor
      ventricular tachyarrhythmias was observed during all 35 trials of the VSP after
      mexiletine administration. Heart rate acceleration induced by an abrupt shift to
      a state of predominant sympathetic activity enhances arrhythmias in this LQT3
      model. Mexiletine homogenizes ventricular repolarization, suppresses premature
      complexes and was antiarrhythmic during ventricular tachyarrhythmias induced by
      the VSP.

PMID- 12604882
TI  - Complete heart block resulting from quadricuspid aortic valve penicillin
      resistant pneumococcal endocarditis: a case report.
AB  - A 62-year-old woman was referred to hospital to be treated for complete heart
      block with syncope. A quadricuspid aortic valve without vegetation and aortic
      valve regurgitation (AR) were observed by transesophageal echocardiography. Blood
      culture showed penicillin-resistant Streptococcus pneumoniae. The patient
      received a permanent pacemaker implantation (VDD type) and was given antibiotics.
      Although infection improved, heart failure was not improved because AR
      hemodynamic changes became worse. An aortic valve replacement was performed using
      a prosthesis on the 26th day of hospitalization. The patient recovered and was
      discharged.

PMID- 12604883
TI  - Decreased left atrial appendage flow velocity with atrial fibrillation caused by
      negative inotropic agents: report of two cases.
AB  - Although pharmacological agents are frequently used to control ventricular rate
      or restore sinus rhythm of patients with atrial fibrillation (AF), there are no
      reports of the relationship between those agents and left atrial appendage (LAA)
      function. Two cases of a decrease in LAA blood flow velocity caused by negative
      inotropic agents are presented as an indication that negative inotropic agents
      are a risk factor for systemic thromboembolism with AF.

PMID- 12604884
TI  - The distinction between primary and metastatic mucinous carcinomas of the ovary:
      gross and histologic findings in 50 cases.
AB  - The gross and routine microscopic features of 25 stage I primary mucinous ovarian
      carcinomas without clinical evidence of recurrence and 25 mucinous carcinomas
      metastatic to the ovaries were compared. Findings that were frequent in the
      latter and strongly favored a metastasis were: 1) bilaterality, 2) microscopic
      surface involvement by epithelial cells (surface implants), and 3) an
      infiltrative pattern of stromal invasion. Findings that were less frequent but
      present exclusively or almost exclusively in metastatic carcinomas were: 1) a
      nodular invasive pattern, 2) ovarian hilar involvement, 3) single cell invasion,
      4) signet-ring cells, 5) vascular invasion, and 6) microscopic surface mucin.
      Findings that were frequent in, and strongly favored, primary ovarian carcinoma
      were: 1) an "expansile" pattern of invasion and 2) a complex papillary pattern.
      Findings that were less frequent but also favored a primary tumor were: 1) size
      >10 cm, 2) a smooth external surface, 3) benign-appearing and borderline
      appearing areas, 4) microscopic cystic glands, and 5) necrotic luminal debris.
      Findings that did not distinguish the tumors were: 1) a cystic gross appearance,
      2) gross solid, papillary, necrotic, or hemorrhagic areas, 3) nature of cyst
      contents (mucinous vs nonmucinous), 4) stromal mucin (pseudomyxoma ovarii), 5)
      cribriform, villous, or solid growth patterns, 6) focal area resembling typical
      colonic carcinoma, 7) goblet cells, or 8) tumor grade. Primary and metastatic
      mucinous ovarian carcinomas can be distinguished from each other in the great
      majority of cases based solely on their conventional histopathologic findings.
      Careful gross evaluation is also important with special attention paid to the
      external surface of the ovarian tumor(s) to detect abnormalities that have the
      features of surface implants on microscopic evaluation.

PMID- 12604885
TI  - Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative
      disorders.
AB  - The majority of AIDS-related non-Hodgkin's lymphomas are clinically aggressive
      monoclonal B-cell Burkitt's lymphomas, large cell lymphomas, or immunoblastic
      lymphomas. In contrast, the lymphoid proliferations arising in solid organ
      transplant recipients, collectively referred to as posttransplantation
      lymphoproliferative disorders (PT-LPDs), represent a clinically and
      histopathologically heterogeneous group of Epstein-Barr virus (EBV)-driven B-cell
      proliferations of variable clonal composition. During a retrospective
      histopathologic review of lymphoid proliferations associated with human
      immunodeficiency virus (HIV) infection we identified 10 cases that
      morphologically resemble the polymorphic PT-LPDs. They arose in lymph nodes
      (five), lungs (two), and the parotid gland, perineum, and skin (one each). They
      exhibit a diffuse growth pattern and are composed of a polymorphic lymphoid cell
      population exhibiting a variable degree of plasmacytic differentiation, cytologic
      atypia, and numbers of atypical immunoblasts. A clonal B-cell population was
      detected by immunoglobulin heavy and light chain gene rearrangement and/or EBV
      terminal repeat analysis in 8 of the 10 (80%) cases by Southern blotting. The
      nongermline hybridizing bands were usually faint, however, suggesting that the
      clonal B-cell population represented only a subpopulation within the polymorphic
      lesion. Strong clonal rearrangement bands were present in one case in which there
      was clear morphologic evidence of transformation to diffuse large cell lymphoma.
      This case exhibited C-MYC, BCL-6, and p53 gene mutations. One other case
      exhibited a p53 gene mutation. The remaining eight cases lacked C-MYC, BCL-6,
      RAS, and p53 gene alterations. Clonal EBV infection was detected in 4 of the 10
      (40%) lesions. Like EBV-containing PT-LPDs, all four EBV-positive HIV-associated
      polymorphic lesions were associated with type A EBV. The Kaposi's sarcoma
      associated herpesvirus was detectable in two cases by polymerase chain reaction
      analysis, but not by Southern blotting. In situ hybridization demonstrated
      Kaposi's sarcoma-associated herpesvirus in some of the cytologically malignant
      appearing cells. In conclusion, polymorphic B-cell lymphoproliferative disorders
      comparable morphologically and molecularly to those arising after solid organ
      transplantation also occur in association with HIV infection. As in the case of
      their polymorphic PT-LPD counterparts, their malignant status, biologic
      significance, and relationship to monomorphic B-cell lymphomas remain to be
      elucidated.

PMID- 12604886
TI  - CDX2, a highly sensitive and specific marker of adenocarcinomas of intestinal
      origin: an immunohistochemical survey of 476 primary and metastatic carcinomas.
AB  - CDX2 is a recently cloned homeobox gene that encodes an intestine-specific
      transcription factor, expressed in the nuclei of epithelial cells throughout the
      intestine, from duodenum to rectum. While expression of CDX2 protein in primary
      and metastatic colorectal carcinomas has been previously documented, neither the
      sensitivity nor the specificity of CDX2 expression, as determined by
      immunohistochemistry, for colorectal adenocarcinoma has been determined. We
      performed an immunohistochemical survey of 476 tumors with a monoclonal antibody,
      CDX2-88, including 89 tumors from the colon and duodenum and 95 tumors from other
      gastrointestinal sites, including the esophagus, stomach, pancreatobiliary
      system, gastrointestinal carcinoids, and liver. CDX2 was expressed uniformly
      (that is, in 76-100% of tumor cells) in all but one of the evaluated colorectal
      and duodenal tumors. High-level expression of CDX2 was also found, however, in
      mucinous ovarian carcinomas and adenocarcinomas primary to the urinary bladder of
      which 64% and 100% were positive, respectively. Gastric, gastroesophageal, and
      pancreatic adenocarcinomas and cholangiocarcinomas all showed similar,
      heterogeneous patterns of CDX2 expression. Most tumors in each group showed CDX2
      expression by a minority of cells, whereas a substantial minority of cases in
      each group was completely negative and a smaller minority was uniformly positive.
      Gastrointestinal carcinoids gave similarly varied results, but the majority (58%)
      was negative. Hepatocellular carcinomas showed no expression of CDX2. Only very
      rare examples of carcinomas of the genitourinary and gynecologic tracts, breast,
      lung, and head and neck showed significant levels of CDX2 expression. In this
      study of primary and metastatic epithelial tumors, uniform CDX2 expression is
      demonstrated to be an exquisitely sensitive and highly, but incompletely,
      specific marker of intestinal adenocarcinomas. Compared with villin, a previously
      described marker of GI adenocarcinomas, CDX2 demonstrated superior sensitivity
      and comparable specificity. CDX2 expression can be seen, however, in selected non
      GI adenocarcinomas such as mucinous ovarian carcinomas and adenocarcinomas of the
      urinary bladder.

PMID- 12604887
TI  - Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a
      clinicopathologic and immunohistochemical study of 75 cases.
AB  - We collected 75 primary pulmonary carcinomas with pleomorphic, sarcomatoid, or
      sarcomatous elements to better define their clinical, histologic, and
      immunohistochemical profile. The patient's age ranged from 42 to 81 years (mean
      65 years), and the male-to-female ratio was 9.7:1. Sixty-nine patients (92%) were
      smokers. Cough and hemoptysis were the most frequent presenting symptoms. Fifty
      nine patients (65%) died of disease: only stage significantly predicts overall
      survival (p = 0.0273). Microscopically, based on the WHO criteria, 58 cases were
      classified as pleomorphic carcinoma (51 with an epithelial component, 7 composed
      exclusively of spindle and giant cells), 10 as spindle cell carcinoma, 3 as giant
      cell carcinoma, 3 as carcinosarcoma, and 1 as pulmonary blastoma.
      Immunohistochemically, in the tumors composed exclusively of spindle and/or giant
      cells, thyroid transcription factor-1 (TTF-1) and cytokeratin 7 were positive in
      55% and 70% of the cases, respectively, whereas surfactant protein-A was always
      negative. In pleomorphic carcinomas with an epithelial component, cytokeratin 7,
      TTF-1, and surfactant protein-A were positive in the sarcomatoid component in
      62.7%, 43.1%, and 5.9% of the cases, respectively, whereas they were always
      negative in the sarcomatous part of carcinosarcomas and blastoma. In the
      epithelial component of pleomorphic carcinomas, cytokeratin 7, TTF-1, and
      surfactant protein-A were positive in 76.4%, 58.8%, and 39.2% of the cases,
      respectively, whereas the same antibodies did not react with the epithelial
      component of carcinosarcomas; in the case of blastoma, the epithelial part of the
      tumor was positive for cytokeratin 7 and TTF-1, whereas it was negative for
      surfactant protein-A. Cytokeratin 20 was always negative. In our opinion, this
      study: 1) supports the metaplastic histogenetic theory for this group of tumors;
      2) shows that cytokeratin 7 and TTF-1, but not surfactant protein-A, are useful
      immunohistochemical markers in this setting; 3) confirms that stage is at the
      moment the only significant prognostic parameter, as in conventional non-small
      cell lung carcinomas; and 4) shows that this group of tumors has a worse
      prognosis than conventional non-small cell lung carcinoma at surgically curable
      stages I, justifying their segregation as an independent histologic type in the
      WHO classification.

PMID- 12604888
TI  - Invasive mammary carcinoma after immediate and short-term follow-up for lobular
      neoplasia on core biopsy.
AB  - Lobular neoplasia (LN), including atypical lobular hyperplasia (ALH) and lobular
      carcinoma in situ, may be encountered in breast core biopsies performed for
      mammographic abnormalities even though LN is often not, in itself, responsible
      for the abnormal mammogram. The need for surgical excision following a diagnosis
      of LN on core biopsy is not well defined. We examined pathologic and mammographic
      findings in a consecutive series of cases diagnosed as LN to address this issue.
      Radiology/pathology records were reviewed for cases with a pathology diagnosis of
      pure LN during the period 1998-2001. Specifically excluded were cases with
      associated atypical ductal hyperplasia, ductal carcinoma in situ, invasive
      mammary carcinoma, or any history of breast malignancy. Thirty-five women 39-76
      years of age (mean 52 years) were identified. Specimens were obtained as
      stereotactic core (31) or limited wire-guided biopsy (four). The diagnoses were
      lobular carcinoma in situ (12), lobular carcinoma in situ/ALH (10), and ALH (13).
      Fourteen patients did not undergo excisional biopsy and had no subsequent
      clinical follow-up to warrant additional biopsy (follow-up 6 months to 3 years).
      Five patients had no immediate excision, but eventually during clinical follow-up
      for LN (1 month to 3 years), two developed mammographic lesions in the
      ipsilateral (one patient) or contralateral breast (one patient) that led to
      diagnoses of invasive mammary carcinoma (lobular and composite ductal-lobular
      types, 10 and 8 mm, respectively); three patients had subsequent mammographic
      findings in the ipsilateral or contralateral breast leading to biopsies showing
      only LN (two patients) or no neoplastic pathology (one patient). The remaining 16
      patients (all core biopsied) underwent immediate wire-guided excisions. Thirteen
      (81%) showed additional foci of LN, one (6.3%) with atypical ductal hyperplasia,
      and two (12.5%) with invasive lobular carcinoma (3 mm and <1 mm). Three (19%) had
      no residual disease; however, additional clinical follow-up in one of these
      patients revealed an invasive mammary carcinoma in the contralateral breast
      (false-negative mammography). Radiographic findings were calcifications and
      density/mass lesions in 27 and 8 cases, respectively. Of 27 cases presenting with
      Ca, 10 showed colocalization of LN and Ca. In the eight cases presenting with
      density/mass, incidental microscopic microcalcifications colocalized to LN were
      found in two cases. When present, histologic Ca was associated with LN in 12 of
      29 cases studied (41%). Of the 21 patients with immediate or subsequent excision,
      five (24%) were found to have an associated invasive mammary carcinoma (two on
      immediate excision and three after short-term follow-up of up to 3 years). The
      bilaterality of cancer risk was expected; however, the number of invasive
      carcinomas was not. That the invasive carcinomas detected at follow-up were small
      implies that they might have been present (but occult) at initial presentation.
      We conclude that lobular carcinoma in situ detected on core biopsy is potentially
      a significant marker for concurrent and near-term breast pathology requiring
      complete intensive multidisciplinary clinical follow-up with specific
      individualization of patient care.

PMID- 12604889
TI  - Eosinophilic pancreatitis and increased eosinophils in the pancreas.
AB  - Prominent eosinophilic infiltrates are an unusual finding in the pancreas.
      Eosinophilic pancreatitis is one rare etiology of pancreatic eosinophilia, but
      other described causes of eosinophilic infiltrates have also included pancreatic
      allograft rejection, pancreatic pseudocyst, lymphoplasmacytic sclerosing
      pancreatitis (LPSP), inflammatory myofibroblastic tumor, and histiocytosis X. In
      this study we describe the clinicopathologic features of three new cases of
      eosinophilic pancreatitis and conduct a retrospective 18-year institutional
      review of the myriad disease processes associated with pancreatic eosinophilia.
      In the files of the Johns Hopkins Hospital, <1% of all pancreatic specimens had
      been noted to show increased numbers of eosinophils. Eosinophilic pancreatitis
      itself was a rare etiology for pancreatic eosinophilia, with only one in-house
      case over the 18-year study period and two additional referral cases. Other
      disease processes associated with prominent eosinophilic infiltrates were more
      common and included pancreatic allograft rejection (14 cases), LPSP (5 of 24
      total LPSP cases evaluated), inflammatory myofibroblastic tumor (4 cases), and
      systemic mastocytosis (1 case). Patients with eosinophilic pancreatitis showed
      two distinct histologic patterns: 1) a diffuse periductal, acinar, and septal
      eosinophilic infiltrate with eosinophilic phlebitis and arteritis; and 2)
      localized intense eosinophilic infiltrates associated with pseudocyst formation.
      All three patients with eosinophilic pancreatitis had peripheral eosinophilia,
      and all had multiorgan involvement. One patient with LPSP also had marked
      peripheral eosinophilia, and 5 of 24 LPSP cases demonstrated prominent
      eosinophilic infiltrates in the gallbladder, biliary tree, and/or duodenum.
      Notably, not all of these patients with LPSP with prominent eosinophils in other
      organs had increased eosinophils in the pancreas itself. These results emphasize
      the infrequent nature of pancreatic eosinophilia and its multiple potential
      disease associations. True eosinophilic pancreatitis, although a fascinating
      clinicopathologic entity, is one of the rarest causes of pancreatic eosinophilia.

PMID- 12604890
TI  - Periductal stromal tumor: a rare lesion with low-grade sarcomatous behavior.
AB  - Biphasic breast tumors with benign ductal elements and a sarcomatous stroma
      lacking a phyllodes architecture are a source of diagnostic problems,
      particularly because of the lack of an appropriate designation. At the Armed
      Forces Institute of Pathology, we have used the term "periductal stromal sarcoma"
      to distinguish these from phyllodes tumors. All cases coded as periductal stromal
      sarcoma or PDSH were retrieved from the files of the Armed Forces Institute of
      Pathology. Cases that fulfilled the following criteria were included in this
      study. The histologic features of periductal stromal sarcoma were defined as 1) a
      predominantly spindle cell stromal proliferation of variable cellularity and
      atypia around open tubules and ducts devoid of a phyllodes pattern, 2) one or
      more often multiple nodules separated by adipose tissue, 3) stromal mitotic
      activity of >/=3/10 high power fields, and 4) stromal infiltration into
      surrounding breast tissue. Criteria for periductal stromal hyperplasia included
      1) nodular, bland stroma growing as cuffs around normal or altered ducts, 2) no
      to minimal atypia, and 3) at most 0-2 stromal mitotic figures per 10 high power
      fields. Immunohistochemistry was used to further characterize these neoplasms. Of
      the cases retrieved, 20 qualified as periductal stromal sarcoma and seven as
      periductal stromal hyperplasia. Patients with periductal stromal sarcoma ranged
      in age from 37 to 89 years (mean 55.3 years). The tumors measured 0.2-6.0 cm
      (mean 2.97 cm). Eighteen patients had excisional biopsies and two had partial
      mastectomies. Overall follow-up time ranged from 1 to 72 months (mean 25.3
      months) with two patients (10%) showing recurrence or probable metastasis. The
      neoplastic cells of periductal stromal sarcoma were at least focally
      immunoreactive for CD34 (13 of 15), CD117 (6 of 15), less reactive for actin
      (HHF35, 2 of 15), and negative for estrogen and progesterone receptors.
      Periductal stromal sarcoma is a useful descriptive designation for generally low
      grade biphasic tumors with sarcomatous stroma that do not have features of a
      phyllodes tumor. The development of focal phyllodes pattern in the recurrent
      tumor as well as development of a specific soft tissue sarcoma in one of the
      above cases suggest that some and possibly all periductal stromal sarcoma may
      evolve into a phyllodes tumor with time. Given the presence of infiltrative
      margins, excision with a rim of uninvolved tissue is required.

PMID- 12604891
TI  - The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis.
AB  - We examined histologically the bile duct lesions from 53 patients with end-stage
      primary sclerosing cholangitis (PSC) and compared them with similar lesions found
      in 25 surgically excised carcinomas of the extrahepatic bile ducts not associated
      with PSC. Of the 53 cases of PSC, 50 bile ducts were obtained at liver
      transplantation, two common bile ducts were segmentally resected for almost
      complete obstruction, and the entire extrahepatic biliary tract of another case
      was obtained at autopsy. Twenty bile ducts from patients who died without
      evidence of biliary tract disease served as controls. A modest increase in the
      number of intramural glands (mild hyperplasia) was noted in 13 cases (24.5%) of
      PSC. A marked increase in the number of intramural glands (florid hyperplasia)
      was found in 14 cases (26.4%) of PSC. In one case of florid hyperplasia, there
      was perineural and intraneural invasion of benign hyperplastic glands, which
      still maintained their lobular pattern. All cases of florid hyperplasia of
      intramural glands were accompanied by extensive fibrosis and marked nerve
      proliferation. Three of 24 (12.5%) invasive adenocarcinomas of the extrahepatic
      bile ducts showed mild hyperplasia of intramural glands without excessive nerve
      proliferation. Four invasive adenocarcinomas and one in situ carcinoma of the
      extrahepatic bile ducts showed florid hyperplasia of intramural glands (16%). The
      hyperplastic intramural glands were p53 negative and had low proliferative
      activity as measured by the low MIB-1 labeling index. In contrast, both in situ
      and invasive carcinoma expressed p53 protein and had a high MIB-1 labeling index.
      Focal high-grade dysplasia was found in one case of PSC (1.8%) and a small
      invasive adenocarcinoma in another (1.8%). Hyperplasia of intramural glands of
      the extrahepatic bile ducts is a reactive process that lacks specificity and is
      part of the morphologic spectrum of end-stage PSC. The incidence of dysplasia in
      PSC is low. Small invasive adenocarcinomas may be incidentally found in end-stage
      PSC, and detecting their presence before liver transplantation may be impossible.

PMID- 12604892
TI  - Primary and secondary cutaneous diffuse large B-cell lymphomas: a multiparameter
      analysis of 25 cases including fluorescence in situ hybridization for t(14;18)
      translocation.
AB  - Although primary cutaneous diffuse large B-cell lymphomas (DLBCLs) except for
      those of the leg are grouped together with primary cutaneous follicle center cell
      lymphoma in the European Organization for Research and Treatment of Cancer
      classification of primary cutaneous lymphomas, they typically lack the usual
      phenotypic profile of follicular lymphoma. Whether they are truly of follicular
      center cell origin, have a molecular pathogenesis similar to nodal follicular
      lymphoma, or have any biologic features that distinguish them from secondary
      DLBCL involving skin remains uncertain. To address these issues, a retrospective
      multiparameter study of 25 patients including clinical, histologic,
      immunophenotypic, and cytogenetic analyses was performed. A classic CD10+, bcl-6+
      follicular center cell profile was found in 10 (40%) cutaneous DLBCL (2 of 11
      primary, 5 of 8 secondary, 3 of 6 unclassified) with bcl-2 expression seen only
      in the nonprimary cases. Of the remaining cases, 14 cases (56%) were CD10-, bcl
      6+, bcl-2+/- (9 primary) and one case (4%) was CD10-, bcl-6-, bcl-2+ (0 primary).
      Fluorescence in situ hybridization analysis showed a t(14;18) in 0 of 9 primary
      and 3 of 5 secondary cases. Primary cases were frequently found in the head/neck
      region, whereas secondary cases were more common on the trunk and extremities.
      Patients with primary disease were all alive, usually having received only local
      therapy, at a median follow-up of 19 months. Most secondary cases were treated
      with chemotherapy with only one untreated patient dead of disease at a median
      follow-up of 5 months. Primary cutaneous DLBCLs therefore appear to be
      distinctive as they have fewer features of follicular lymphoma than do secondary
      cases. Nevertheless, some appear to be of follicular center cell origin, even
      though they probably have a different molecular pathogenesis than most nodal
      follicular lymphomas.

PMID- 12604893
TI  - Basal cell cocktail (34betaE12 + p63) improves the detection of prostate basal
      cells.
AB  - Antibodies against high molecular weight cytokeratin (34betaE12) and p63 are
      frequently used basal cell markers to aid in the diagnosis of prostate cancer
      (Pca). Absence of a basal cell marker in an atypical lesion histologically
      suspicious for cancer supports a diagnosis of Pca. However, absence of basal
      cells demonstrable by basal cell immunohistochemistry (IHC) is not always
      conclusive for PCa. Some benign prostatic lesions may have inconspicuous or even
      lack basal cell lining focally. Technical factors such as tissue fixation and
      antigen retrieval techniques may also make the detection of basal cells
      difficult. Improving the sensitivity of current basal cell markers is critical if
      these tests are being used to help make diagnostic decisions in conjunction with
      standard histology. In this study, we test the hypothesis that that inclusion of
      both 34betaE12 and p63 in the same IHC reaction (basal cell cocktail) is
      advantageous over either marker used alone. One thousand three hundred fifty
      glands from 9 trans-urethral resectioned of prostate specimens with benign
      prostatic hypertrophy were used to study the immunostaining intensity and pattern
      for 34betaE12, p63, and the basal cell cocktail. Basal cell marker expression was
      scored as strong, moderate, weak, or negative. Basal cell staining was considered
      complete if 75% of the gland's circumference was positive for the basal cell
      marker and partial if <25% of the circumference was stained. The mean staining
      intensity and variance were calculated for 34betaE12, p63, and the basal cell
      cocktail. A paired test was used to evaluate whether the overall basal cell
      staining was significantly different between 34betaE12, p63, and the basal cell
      cocktail. F-test was used to assess the variances for 34betaE12, p63, and the
      basal cell cocktail. A high-density tissue microarray (TMA) comprising prostate
      tissue from 103 tumors from men with clinically localized Pca and a separate TMA
      comprising metastatic hormone-refractory Pca samples from 23 rapid autopsy cases
      were used to study the aberrant expression of 34betaE12 and p63 in clinically
      localized and poorly differentiated Pca. The prostate glands in transition zone
      have variable basal cell staining intensity and pattern with 34betaE12, p63, or
      the cocktail. Histologically, benign glands lack basal cell lining in 2%, 6%, and
      2% of glands with cocktail, 34betaE12, and p63 staining, respectively. The
      staining variance for the cocktail is significantly smaller than that for
      34betaE12 (0.0100 vs 0.1559, p = 0.0008). It is also smaller than that for p63,
      although a statistical significance has not been reached (0.0100 vs 0.0345, p =
      0.099). The basal cell cocktail stains the basal cell layers more intensely than
      either 34betaE12 or p63 alone, with complete and partial strong basal cell
      staining in 93% and 1% of benign glands, compared with 55% and 4% with 34betaE12
      and 81% and 1% with p63. Complete and partial weak staining is seen in 0% and 0%
      of benign glands with basal cell cocktail, compared with 8% and 7% with 34betaE12
      and 4% and 1% with p63 (p = 0.007 and 0.014 for cocktail vs 34betaE12 and
      cocktail vs p63, respectively). A total of 2.8% clinically localized Pca had
      positive 34betaE12 staining and 0.3% had positive p63 staining. Five (22%) of the
      metastatic Pca is positive for 34betaE12. However, none had p63 expression. The
      basal cell cocktail had a staining pattern identical to that of 34betaE12. IHC of
      the prostatic glands from the transition zone is subjected to staining
      variability that results in frequent variable and occasional negative basal cell
      staining in histologically benign glands; 34betaE12 is most susceptible, and
      basal cell cocktail is least susceptible to such variability. Basal cell cocktail
      not only increases the sensitivity of the basal cell detection, but also reduces
      the staining variability and therefore renders the basal cell immunostaining more
      consistent. We recommend this basal cell cocktail for routine Pca diagnostic work
      up.

PMID- 12604894
TI  - Clinicopathologic spectrum of the so-called calcifying odontogenic cysts: a study
      of 21 intraosseous cases with reconsideration of the terminology and
      classification.
AB  - The so-called calcifying odontogenic cyst (COC) represents a heterogeneous group
      of lesions that exhibit a variety of clinicopathologic and behavioral features.
      Because of this diversity, there has been confusion and disagreement on the
      terminology and classification of these lesions. We reviewed the
      clinicopathologic features of 21 intraosseous cases that were previously
      diagnosed as COC or under related diagnostic terms. Based on the biologic
      behavior, the lesions of the present series were divided into three subgroups:
      cyst, benign tumor, and malignant tumor. Sixteen cases (nine men and seven women)
      proved to be unicystic lesions with (five cases) or without associated odontoma.
      The lining epithelium of the cystic lesions fulfilled the histologic criteria for
      COC proposed by the World Health Organization, and their overall
      clinicopathologic features were consistent with that of developmental odontogenic
      cysts. The age of patients from the cyst group peaked at the second decade. The
      maxilla was affected more often (69%) than the mandible, with a predilection for
      the canine-premolar region (62.5%). Thirteen patients with follow-up information
      revealed no recurrence following enucleation. The four cases in the benign tumor
      group had variable clinicopathologic features. Two cases were solid tumors
      consisting of ameloblastoma-like sheets of odontogenic epithelium that contained
      ghost cells/calcification foci and juxtaepithelial dentinoid. Both patients
      experienced multiple recurrences following conservative surgeries. The other two
      lesions contained typical areas of COC and other types of odontogenic tumors (one
      ameloblastoma and one odontogenic myxofibroma). All four lesions occurred in the
      mandible and were relatively large. In the present series one case identified as
      malignant tumor arose from a previously benign COC. The tumor shared some
      features of COC (ghost cell foci and dystrophic calcification) but also had
      prominent mitotic activity, nuclear and cytoplasmic pleomorphism, areas of tumor
      necrosis, and infiltrative/destructive growth. Recognizing the extreme diversity
      in clinicopathologic features and biologic behavior among the so-called COCs, we
      suggest that the term COC should be used to specifically designate the unicystic
      lesions with or without an associated odontoma, i.e., lesions of the cyst group,
      and other related lesions identified as benign tumor and malignant tumor should
      be termed and classified separately. A tentative scheme with respect to the
      terminology and classification for this group of disparately behaving lesions was
      herein proposed to reflect the likely difference of their nature.

PMID- 12604895
TI  - Histologic localization of sentinel lymph node metastases in breast cancer.
AB  - Data from a recent study support the hypothesis that axillary lymph node
      metastases frequently localize near the inflow junction of the afferent lymphatic
      vessel. Our goal was to evaluate the microscopic location of axillary sentinel
      lymph node metastases in a prospective study of breast cancer patients. A total
      of 305 axillary sentinel lymph nodes from 213 breast cancer patients undergoing
      surgery at our institution were evaluated. Preoperative lymphoscintigraphy using
      technetium-labeled sulfur colloid and intraoperative isosulfan blue dye injection
      were used for identifying the sentinel lymph node. Intraoperatively, the surgeon
      placed a suture either at the point of entry of isosulfan blue dye or at the area
      with the highest radioactive counts, and this area was inked at the grossing
      bench before processing. Metastases were identified in 55 of the 305 lymph nodes
      examined. Thirty-four nodes contained metastases in both the inked half and the
      opposite half. Metastatic tumor was identified in the inked half alone in 18
      lymph nodes. Only three nodes contained metastatic tumor in the opposite half
      with no tumor in the inked half (p <0.001). Similar results were found when nodes
      tagged at the point of blue dye entry and nodes tagged at the area with the
      highest radioactive counts were analyzed separately. Our findings suggest that
      metastatic tumor has a higher probability of being present in the region of the
      inflow junction of the afferent lymphatic vessel. This information may be useful
      in determining the optimal method for evaluating axillary sentinel lymph node
      specimens from breast cancer patients.

PMID- 12604896
TI  - 2002 Fred Waldorf Stewart Award recipient: Elaine S. Jaffe, MD.

PMID- 12604897
TI  - Ethical issues in anatomic pathology: are we going the way of the financial
      sector?

PMID- 12604898
TI  - Giant vertebral notochordal rest: a lesion distinct from chordoma: discussion of
      an evolving concept.
AB  - A 14-year-old boy with severe back pain for several years is described.
      Roentgenograms, bone scans, and computed tomographic scans of the spine were
      normal, but magnetic resonance imaging studies showed a lumbar vertebral body
      lesion, confined to the bone, with low T1- and high T2-weighted signal
      intensities. Histologically, the lesion consisted of sheet-like notochordal-type
      tissue, containing physaliphorous cells but lacking the usual features of
      chordoma. A diagnosis of giant notochordal rest was made. A review of prior
      possible examples of this recently described and controversial entity is made
      with a discussion of its embryologic foundations and distinction from chordoma.

PMID- 12604899
TI  - Renal-type clear cell carcinoma occurring in the prostate.
AB  - Clear cell lesions of the urinary tract often present diagnostic challenges. We
      report a previously undescribed lesion in the prostate, occurring in a 73-year
      old man who presented with hematuria and subsequently underwent transurethral
      resection of the prostate. A total of 24 g of tissue was removed, and in 4 of 17
      blocks submitted a lesion morphologically and immunohistochemically similar to
      clear cell carcinoma of the kidney was noted. A thorough cystoscopic and full
      body, radiologic workup was performed, but no renal tumor was discovered. Random
      cystoscopic biopsies of the bladder and prostatic urethra as well as bladder
      washings were benign. Subsequent needle biopsies of the prostate were also
      benign. The patient underwent a pelvic lymph node dissection with radical
      cystoprostatectomy and orthotopic Studer pouch diversion. There was organ
      confined, ordinary-type prostatic adenocarcinoma (Gleason's 3 + 3) present
      bilaterally in the peripheral zone; no residual clear cell carcinoma was
      identified. All lymph nodes were negative, and the urinary bladder showed no
      dysplasia or neoplasia. We think this tumor represents a primary renal type of
      clear cell carcinoma arising in the prostate. To our knowledge, this type of
      tumor has not been previously reported to arise in an extrarenal location.

PMID- 12604900
TI  - Melanocytic nevi of palms and soles.

PMID- 12604901
TI  - Familial adenomatous polyposis associated with sporadic MEN 1 and thyroid
      carcinoma related to APC mutation.

PMID- 12604902
TI  - Reactivity of granular cell tumors for inhibin and other markers of sex cord and
      steroid cell differentiation.

PMID- 12604903
TI  - Translocation-based molecular diagnosis of sarcomas.

PMID- 12604904
TI  - Atlanta redux.

PMID- 12604905
TI  - Prevalence and predictors of severity as defined by atlanta criteria among
      patients presenting with acute pancreatitis.
AB  - INTRODUCTION: Effective triage of patients with acute pancreatitis is dependent
      on the ability to accurately predict a severe course. Predictors (e.g., APACHE II
      score of >8) have been tested against wide-ranging definitions of severity
      (prevalence, 15%-40%). To ensure uniformity in defining a severe course of acute
      pancreatitis, the Atlanta symposium of 1992 adopted all-encompassing criteria
      (local complications, systemic complications, need for surgery, or death). AIMS:
      To assess the prevalence of each Atlanta criteria for severe acute pancreatitis
      and to determine the sensitivity, specificity, and positive and negative
      predictive values of the APACHE II score as a predictor of these criteria for
      severe acute pancreatitis. METHODOLOGY: We reviewed records of patients admitted
      to the University of Cincinnati Medical Center (Cincinnati, OH, U.S.A.) between
      1994 and 1998 with acute pancreatitis. Exclusion criteria included referral from
      an outside hospital, immunocompromised state, and chronic pancreatitis. RESULTS:
      Seventy-four consecutive patients met our inclusion criteria. Ten patients
      (13.5%) had a severe course. Seven patients developed only local complications.
      Three patients had systemic complications. Pancreatic surgical intervention was
      required in four patients. No deaths occurred. An APACHE II score of >8 exhibited
      50% sensitivity and 69% specificity (positive predictive value, 20%; negative
      predictive value, 89%). All patients with systemic complications and two of seven
      patients with only local complications had an APACHE II score of >8. CONCLUSIONS:
      The prevalence of severity among our nonreferred patients with acute pancreatitis
      was less than previously reported. The APACHE II scoring system exhibited
      reasonable sensitivity in predicting systemic complications and/or the need for
      surgery, with a low positive predictive value. This most certainly is a function
      of the low pretest probability of severe pancreatitis. Future studies attempting
      to identify predictive systems that triage patients in a more cost-effective
      manner should restrict their analysis to Atlanta criteria other than local
      complications.

PMID- 12604906
TI  - Coagulative disorders in human acute pancreatitis: role for the D-dimer.
AB  - INTRODUCTION AND AIMS: We investigated coagulative disorders, particularly the
      role of the D-dimer, in acute pancreatitis where coagulation abnormalities
      related to disease severity are known to occur. METHODOLOGY: D-dimer levels in 30
      patients with acute pancreatitis were evaluated; pancreatitis was mild and
      uncomplicated in 11 patients, accompanied by complications in 15, and severe in
      4. We attempted to find a relationship between the D-dimer level and the
      antithrombin III level, prothrombin time, partial thromboplastin time, the C
      reactive protein level, and results of routine laboratory tests. RESULTS: In the
      11 patients with uncomplicated pancreatitis, the D-dimer level increased about
      1.5 times over the limit, while in the 15 patients with complications and the
      four patients with severe pancreatitis, the D-dimer level increased about seven
      times above the normal limit; this difference was highly significant (p <
      0.0001). The rise in the D-dimer level was inversely related to albumin and
      calcium levels (p = 0.0001) and directly related to the C-reactive protein level,
      fibrinogen level and leukocyte count (p = 0.0001), prothrombin time (p = 0.006),
      partial thromboplastin time (p = 0.03), and acute abdominal collections and lung
      involvement (p = 0.0001). The increase appeared early on, lasting for the entire
      study and peaking on days 3-6. CONCLUSIONS: The D-dimer is the expression of
      pancreatitis and the extension of systemic involvement; it may be considered a
      prominent link in the chain of events leading to severe disease.

PMID- 12604907
TI  - Cefepime tissue penetration in experimental acute pancreatitis.
AB  - INTRODUCTION: Antibiotic treatment represents a cornerstone in the management of
      severe acute pancreatitis. However, different antibiotic substances are currently
      used. In this study, we analyzed penetration of cefepime into pancreatic tissue
      in two models of acute pancreatitis. AIMS AND METHODOLOGY: Following induction of
      acute pancreatitis, animals were treated with a single intravenous dose of
      cefepime (0.1 mg/g of body weight). At two different time points, blood and
      tissue samples were obtained for determination of cefepime concentration and
      microbiologic analysis. RESULTS: Mean pancreatic tissue concentrations +/- SEM 30
      minutes after drug administration were significantly higher in animals with
      either mild acute pancreatitis (113 +/- 22 mg/kg) or severe acute pancreatitis
      (75 +/- 22 mg/kg) than in control animals (30 +/- 6 mg/kg) (p < 0.005). The
      minimal inhibitory concentrations (MIC90) for organisms usually isolated from
      infected pancreatic necrosis vary between 0.05 and 8 mg/L, which is between nine
      and 1,500 times lower than the mean peak concentration found in necrotic
      pancreatic tissue. Seven hours 30 minutes after antibiotic administration,
      pancreatic cefepime concentrations were still above the MIC90 in 100% and 83% of
      animals with mild and severe disease, respectively. The infection rate of
      pancreatic tissue was significantly lower after antibiotic treatment and was
      similar after imipenem/cilastatin or cefepime treatment. CONCLUSION: Because of
      its antibacterial coverage and proven tissue penetration in acute pancreatitis,
      cefepime should be studied in patients with severe acute pancreatitis.

PMID- 12604908
TI  - Role of the gut in the course of severe acute pancreatitis.
AB  - INTRODUCTION: The pathogenesis of acute pancreatitis remains elusive. Sepsis and
      multiple organ failure continue to cause death (overall mortality rate,
      approximately 10%) despite immense improvements in supportive, radiologic, and
      surgical therapy. The gut appears to play a key role in the development of these
      complications. AIM: To critically review the evidence implicating the gut in the
      pathogenesis of acute pancreatitis. METHODS: Relevant English-language literature
      or abstracts cited in the MEDLINE database were reviewed. RESULTS AND CONCLUSION:
      Gram-negative enteric organisms account for most infections of pancreatic
      necrosis and subsequent sepsis, which suggests the gut as a source. Intestinal
      permeability is increased early in patients with severe acute pancreatitis and
      correlates with endotoxemia, which suggests translocation as a possible
      mechanism. The pathogenesis of the deranged function of the gut mucosal barrier
      and the possible sites of increase in intestinal permeability are discussed. The
      gut also plays a role in priming neutrophils and the release of inflammatory
      cytokines, which initiate and propagate nearly all the detrimental consequences
      of severe inflammation and sepsis. Future research avenues and potential
      therapeutic measures that may restore and preserve gut barrier function are
      explored.

PMID- 12604909
TI  - Bile acid malabsorption or disturbed intestinal permeability in patients treated
      with enzyme substitution for exocrine pancreatic insufficiency is not caused by
      bacterial overgrowth.
AB  - INTRODUCTION: In some patients with severe exocrine pancreatic insufficiency,
      enzyme replacement therapy will not lead to clinical improvement or reduction of
      steatorrhea. Therefore, other mechanisms separately or in interplay with reduced
      enzyme secretion might be responsible for malabsorption in these patients. AIMS:
      To evaluate the prevalence of bacterial overgrowth, bile acid absorption
      capacity, and intestinal permeability in a group of patients with well
      characterized exocrine pancreatic insufficiency. METHODOLOGY: Eleven men with
      severe exocrine pancreatic insufficiency, of whom 10 were receiving enzyme
      replacement therapy, were studied. The prevalence of bacterial overgrowth was
      evaluated by means of a hydrogen and methane breath test with glucose. Gamma
      camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was
      used to evaluate bile acid absorption capacity. Intestinal permeability was
      assessed from urine excretion of ingested 14C-mannitol and 99mTc
      diethylenetriaminepentaacetic acid (99mTc-DTPA), and these data were compared
      with results for 10 age-matched healthy men. RESULTS: No patients had abnormal
      breath hydrogen or methane concentrations after glucose intake. Abdominal
      retention of 75Se-HCAT was reduced in three of the patients. The patients had
      lower urine excretion of 14C-mannitol than the control subjects, whereas no
      difference was revealed in urine excretion of 99mTc-DTPA. CONCLUSION: Bile acid
      absorption and small intestinal permeability might be affected in patients with
      exocrine pancreatic insufficiency who receive treatment with enzyme
      supplementation. The prevalence of bacterial overgrowth seems to be low among
      these patients and does not explain the findings.

PMID- 12604910
TI  - Matrix metalloproteinase-1 and cytokines in patients with acute pancreatitis.
AB  - INTRODUCTION: Hypercytokinemia is known to occur in severe acute pancreatitis,
      suggesting that the production, deposition, and degradation of the extracellular
      matrix (ECM) occur actively as a result of the actions of the complicated
      cytokine network. AIMS AND METHODOLOGY: To examine the influence of cytokines and
      growth factors on the ECM in acute pancreatitis from the points of view of the
      severity of the disease, the complication of multiple organ dysfunction syndrome
      (MODS), and the prognosis, 25 patients with acute pancreatitis were divided into
      three groups according to the severity of the condition as assessed by the Ranson
      score. The serum levels of matrix metalloproteinase (MMP)-1, tissue inhibitor of
      metalloproteinases (TIMP)-1, the MMP-1.TIMP-1 complex, tumor necrosis factor
      (TNF)-alpha, and transfer growth factor (TGF)-beta1 were determined by enzyme
      linked immunosorbent assay. RESULTS: Comparison of the three groups divided
      according to the severity of the disease revealed significant differences in the
      levels of MMP-1 and TNF-alpha among the three groups, with the levels being
      higher in patients with more severe disease. The TIMP-1/MMP-1 ratio and the TGF
      beta1 levels were found to be significantly lower in patients with more severe
      disease. Comparison between the group with the complication of MODS and the group
      without the complication showed that the levels of MMP-1, the MMP-1.TIMP-1
      complex, and TNF-alpha were significantly higher in the former group than in the
      latter group. The TIMP-1/MMP-1 ratio and the TGF-beta1 levels were significantly
      lower in the group with the complication of MODS than in the group without the
      complication. Comparison between the nonsurvivor group and the survivor group
      revealed significantly higher levels of MMP-1, TIMP-1, and TNF-alpha in the
      nonsurvivors than in the survivors. The TIMP-1/MMP-1 ratio and the TGF-beta1
      levels were significantly higher in the survivors than in the nonsurvivors. A
      significant correlation was observed between MMP-1 levels and TNF-alpha levels.
      On the other hand, a significant negative correlation was noted between MMP-1
      levels and TGF-beta1 levels. CONCLUSION: The results of our study suggest that
      the activity of the ECM catabolic enzyme MMP-1 and cytokines are related to the
      development of acute pancreatitis.

PMID- 12604911
TI  - Noninvasive in vivo assessment of the pancreatic microcirculation: orthogonal
      polarization spectral imaging.
AB  - INTRODUCTION: Capillary perfusion failure of the pancreatic microcirculation is
      characteristic in the pathogenesis of acute pancreatitis and ischemia-reperfusion
      damage after pancreas transplantation. Up to now, no logistic suitable method for
      analyzing pancreatic capillary perfusion during operations in humans has been
      established without the use of fluorescent dyes. AIM: To compare the well
      established technique of intravital epifluorescence microscopy with the novel
      noninvasive method of orthogonal polarization spectral (OPS) imaging for
      measurement of the pancreatic functional capillary density. METHODOLOGY: In eight
      anesthetized rats, six identical capillary regions of interest per animal were
      measured by both methods, and the results were compared. RESULTS: Absolute values
      from the capillary perfusion data were not significantly different between the
      two methods (fluorescence microscopy: 394 +/- 44 cm/cm2; OPS imaging: 385 +/- 45
      cm/cm2). Correlation parameters were significant, and Bland-Altman analyses
      showed good agreement with a mean difference (bias) between the two methods of
      6.9 cm/cm2, indicating that slightly smaller values are measured with OPS
      imaging. CONCLUSION: OPS imaging is a valid noninvasive method that analyzes the
      pancreatic microcirculation as accurately as the established intravital
      microscopy technique and therefore could be useful for clinical research and
      diagnosis during transplantation and operations.

PMID- 12604913
TI  - Ultrastructural study of the pancreas in AIDS.
AB  - INTRODUCTION: Frequent histologic changes (90%) in the pancreas suggesting
      protein-energy malnutrition were found in a previous necropsy study of pancreas
      morphology in patients with AIDS. However, additional studies were required to
      clarify subcellular changes. AIM: To ultrastructurally analyze pancreas changes
      in AIDS patients through transmission electron microscopy. METHODOLOGY AND
      RESULTS: Pancreas specimens for necropsy were obtained from nine consecutive AIDS
      patients and four normal controls. A semiquantitative histologic and
      ultrastructural analysis of exocrine pancreas was carried out with the following
      findings: preserved pancreas structure with little autolysis, marked decrease in
      zymogen granules (100%), increased lipofuscin pigment (80%), augmented and
      dilated rough endoplasmic reticulum (100%), and increased number and size of
      mitochondria. The Golgi complex could be identified only in two cases. In all
      cases, acinar nuclei were decreased in size, with peripherally condensed
      chromatin and undulated membrane suggesting early apoptosis. In addition,
      immunohistochemical evaluation of the pancreas was carried out to detect
      opportunistic agents. CONCLUSION: Decreased zymogen granules, acinar atrophy,
      increased lipofuscin pigment, and rarefying Golgi complex represent the
      morphologic substrate of protein-energy malnutrition in AIDS patients. The
      combination of rough endoplasmic reticulum and mitochondria changes could be due
      to the need for supplying vital plasma proteins rather than exportation protein
      synthesis associated, or not, with the deleterious effects of inflammatory
      cytokines and/or therapy for disease.

PMID- 12604912
TI  - Serum profiles of E-selectin, interleukin-10, and interleukin-6 and oxidative
      stress parameters in patients with acute pancreatitis and nonpancreatic acute
      abdominal pain.
AB  - INTRODUCTION: Excessive inflammatory response is one of the major causes of early
      mortality in acute pancreatitis (AP). AIM: To evaluate the serum profiles of E
      selectin, interleukin (IL)-6, and IL-10 along with their correlation to the
      markers of oxidative stress and neutrophil activation in patients with AP and
      patients with nonpancreatic acute abdominal pain (NPAAP). METHODOLOGY: This
      prospective clinical study included 56 patients with AP (28 with mild AP and 28
      with severe AP) as well as 15 patients with NPAAP. RESULTS: Serum concentrations
      of E-selectin, IL-10, and IL-6 and plasma concentrations of polymorphonuclear
      leukocyte elastase (determined on days 1-3, 5, and 10 after admission) were the
      highest in severe AP during the first 3 days and then declined. At day 10, the E
      selectin level in severe AP was still higher than that in mild AP, and the IL-10
      concentration increased again. There was no elevation in the E-selectin
      concentration in NPAAP patients, and IL-10 levels remained unchanged in mild AP.
      Oxidative stress, measured by serum malondialdehyde and 4-hydroxyalkenals levels,
      was the most pronounced in severe AP. CONCLUSIONS: The serum E-selectin
      concentration is markedly elevated in severe AP and is less in mild AP but not in
      NPAAP. It may result from stimulation with different inflammatory mediators or
      indicate vascular endothelium injury mediated by oxidative stress, especially in
      the severe form of AP.

PMID- 12604914
TI  - Expression of survivin after acute necrohemorrhagic pancreatitis in rats.
AB  - INTRODUCTION: Survivin is one of the inhibitors of the apoptosis family and has
      dual effects: antiapoptotic effect and regulation of the cell cycle. AIM: To show
      involvement of survivin in acute pancreatitis. METHODOLOGY: Acute
      necrohemorrhagic pancreatitis was induced in male Wistar rats by intraductal
      infusion of 4% sodium taurocholate. RESULTS: By northern blotting, the survivin
      mRNA level was significantly increased at 36 hours and peaked at 48 hours after
      induction of acute pancreatitis. Survivin protein was found in cytoplasm of
      ductal cells by immunohistochemical analysis at 48-72 hours. It was also observed
      in nuclei of both acinar and ductal cells as well as infiltrating cells.
      Apoptotic cells were observed in pancreatic acinar cells. Survivin protein
      partially colocalized with 5-bromo-2'-deoxyuridine in some nuclei of ductal
      cells. CONCLUSIONS: We showed involvement of survivin in acute pancreatitis in
      rats. Survivin may have some roles in the regulation of pancreatic regeneration
      and proliferation as well as an antiapoptotic effect after acute pancreatitis.

PMID- 12604915
TI  - Angiogenesis inhibition with TNP-470, 2-methoxyestradiol, and paclitaxel in
      experimental pancreatic carcinoma.
AB  - INTRODUCTION: Inhibition of tumor angiogenesis is a novel therapeutic modality
      for various malignancies. AIM: To investigate the effect of different
      antiangiogenic agents (TNP-470, 2-methoxyestradiol, and paclitaxel) on growth and
      neovascularization of experimental pancreatic cancer. METHODOLOGY: In 25 male
      Lewis rats, tumor induction was achieved by orthotopic and subcutaneous tumor
      fragment implantation of ductlike pancreatic cancer DSL6A. Four weeks after tumor
      implantation, the animals were randomly treated with TNP-470, 2-methoxyestradiol,
      or paclitaxel. After 2 weeks of antiangiogenic therapy, total tumor volume, vital
      tumor surface, vascular density, and apoptosis were measured. RESULTS: Total
      tumor volume and vital tumor surface were not significantly different in any of
      the treatment groups. Similarly, vascular density and apoptosis were not altered
      by treatment with the various angiogenesis inhibitors at the specific doses used.
      CONCLUSION: We conclude that in contrast to many earlier studies, angiogenesis
      inhibition by a single-drug application and by the doses used in the present
      model did not reveal a favorable therapeutic effect on pancreatic cancer DSL6A.
      The combination of different angiogenesis inhibitors or higher doses might be
      more effective.

PMID- 12604916
TI  - Impaired insulin action on phosphatidylinositol 3-kinase activity and glucose
      transport in skeletal muscle of pancreatic cancer patients.
AB  - INTRODUCTION: Glucose intolerance or overt diabetes occurs in 80% of patients
      with pancreatic cancer (PC). This associated metabolic disorder includes
      peripheral insulin resistance, which may be caused by factors produced by the PC.
      The mechanism underlying PC-associated insulin resistance has not been clearly
      defined. AIM: To characterize basal and insulin-stimulated glucose transport,
      phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in
      skeletal muscles of PC patients. METHODOLOGY: Skeletal muscle samples were
      obtained from the abdominal wall of 17 PC patients during surgery. Control
      muscles were sampled in the same way from 11 donors undergoing abdominal surgery
      for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were
      assessed in vitro in these muscles. RESULTS: In the presence of physiologic
      concentrations of insulin, glucose transport and PI 3-kinase activity were
      significantly decreased in the PC group compared with controls. At
      supraphysiologic insulin concentrations, glucose transport was significantly
      decreased but PI 3-kinase activity was normalized. In the absence of insulin,
      these parameters were not significantly different between PC and control groups.
      Muscle GLUT4 contents were similar between PC and control groups. CONCLUSION:
      Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute
      to the insulin resistance in patients with PC.

PMID- 12604917
TI  - Expression and function of the calcium-sensing receptor in pancreatic islets and
      insulinoma cells.
AB  - INTRODUCTION: We previously demonstrated that human insulinoma cells express the
      calcium-sensing receptor (CaR). AIM: To investigate the expression of CaR in the
      human pancreas and to evaluate the differences in responses of human insulinoma
      cells and normal rat islets to extracellular calcium2+ [Ca2+]o. METHODOLOGY: To
      evaluate CaR expression in the normal human pancreas, immunohistochemical and
      reverse transcription polymerase chain reaction studies were performed. To
      evaluate the response of normal islets and insulinoma cells to changes in the
      [Ca2+]o concentration, cytosolic free calcium levels were measured by
      microfluorometry. Because it is difficult to obtain viable normal human islets,
      we used normal rat islets instead. RESULTS: CaR is expressed in both human
      pancreatic islets and human insulinoma cells. Microfluorometry showed an increase
      in the [Ca2+]i level in response to changes in the [Ca2+]o concentration, with a
      more sensitive response in human insulinoma cells than in normal islets. When 1
      micromol/L wortmannin (a selective phosphatidylinositol 3-kinase inhibitor) was
      added to the perfusion medium, the response disappeared in insulinoma cells but
      not in islets. CONCLUSION: Both insulinoma cells and islets expressed CaR;
      however, the reactivity to changes in the [Ca2+]o concentration was different
      between them. These findings suggest that the signaling pathways controlling the
      changes in [Ca2+]i differ between normal rat islets and human insulinoma cells.

PMID- 12604918
TI  - Comparative study of adult porcine pancreatic endocrine cell preparation using a
      technique of multiple injections and pancreatic duct cannulation without a
      proteolytic enzyme.
AB  - INTRODUCTION: A method for isolation and primary monolayer culture of pancreatic
      endocrine (PE) cells from the porcine pancreas has already been established. It
      is very important for the PE cell preparation to expand the pancreas to separate
      PE cells from acinar cells. For this purpose, we developed a pancreatic injection
      system. AIM: To compare two pancreatic injection methods: perfusion from an
      accessory pancreatic duct (cannulation method) and the traditional pancreatic
      tissue injection method (multiple injection method). RESULTS: A comparison of the
      results of the two methods revealed that the PE cell yield was significantly
      higher with the cannulation method (2.97 +/- 0.59 x 10(7) cells per pancreas)
      than with the multiple injection method (0.89 +/- 0.15 x 10(7) cells per
      pancreas) (p < 0.0001). The number of dithizone-positive cells was significantly
      higher with the cannulation method (1.64 +/- 0.36 x 10(7) cells per pancreas)
      than with the multiple injection method (0.36 +/- 0.09 x 10(7) cells per
      pancreas) (p < 0.0001). The number of adhesion cells after 7 days of culture
      following isolation was higher with the cannulation method (1.07 +/- 0.26 x 10(7)
      cells per pancreas) than with the multiple injection method (0.36 +/- 0.03 x
      10(7) cells per pancreas) (p < 0.0001). The glucose stimulation index of insulin
      secretion was higher with the cannulation method than with the multiple injection
      method (p < 0.01). CONCLUSION: These results indicate that pancreatic duct
      perfusion is useful for obtaining a high yield of PE cells from porcine
      pancreases.

PMID- 12604919
TI  - Trace element changes in the pancreas during viral infection in mice.
AB  - INTRODUCTION: The trigger for some cases of juvenile diabetes has been suggested
      to be an interaction between a virus and various trace elements. Infection with
      human coxsackievirus B3 (CB3) in the murine model results in viral replication
      and inflammation in the pancreas. AIM: To determine how infection affects the
      trace element balance in the pancreas. METHODOLOGY: Concentrations of the
      following trace elements were measured in the serum and pancreas during the early
      phase (days 1 and 3) of CB3 infection in female Balb/c mice: aluminium, arsenic,
      cadmium (Cd), calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), lead (Pb),
      magnesium (Mg), manganese (Mn), mercury (Hg), selenium, silver, vanadium (V), and
      zinc (Zn). The trace element concentrations were measured through inductively
      coupled plasma mass spectrometry. The histopathology was established by
      hematoxylin-eosin techniques and immunohistochemical staining of both CD4 and CD8
      cells of the pancreas. RESULTS: Infected mice developed expected clinical signs
      of disease. The only changes at day 1 occurred in the serum, with a pronounced
      decrease in the Zn concentration and a small increase in the V concentration. At
      day 3, concentrations of several trace elements, including Cu, Zn, Fe, Ca, V, and
      Mn, showed pronounced changes in both the serum and the pancreas. Ca, Cu, Mg, Mn,
      and V, but none of the potentially toxic elements, accumulated in the pancreas.
      Cu and V concentrations increased in the serum as well. CONCLUSION: Several trace
      element changes, preceding the development of pancreatitis, occurred in the
      pancreas in this viral infection, the exact pathogenic interpretation of which
      warrants further studies.

PMID- 12604921
TI  - Traumatic transection of the pancreas head: report of a case with santorini duct
      injury treated by damage-control surgery.

PMID- 12604920
TI  - Oleic acid-induced pancreatitis alters expression of transforming growth factor
      beta1 and extracellular matrix components in rats.
AB  - INTRODUCTION AND AIMS: Extracellular matrix (ECM) components participate in the
      process of tissue repair and development of fibrosis in the pancreas. We studied
      the production kinetics of ECM components and transforming growth factor (TGF)
      beta1 and identified their production sites in the pancreas following
      pancreatitis. METHODOLOGY: Pancreatitis was induced in rats by a single
      intraductal infusion of oleic acid. Gene expression of TGF-betas and ECM
      components was studied by northern blotting. Pancreatic stellate cell activation
      was assessed by immunostaining for alpha-smooth muscle actin (alphaSMA) and
      desmin. RESULTS: Gene expression of TGF-betas and ECM components was increased in
      association with pancreatic fibrosis after 1-2 weeks and remained higher than the
      control levels for the ensuing 12 weeks. Both alphaSMA and desmin were strongly
      immunostained around small vessels and faintly stained in mesenchymal cells and
      tubular complexes at 1 week. The combination of staining for alphaSMA plus in
      situ hybridization for procollagen type III mRNA revealed that procollagen type
      III mRNA was expressed in both alphaSMA-positive and alphaSMA-negative cells in
      the mesenchyma. CONCLUSIONS: Our findings demonstrate that expression of genes
      for both TGF-betas and ECM components was increased and that both alphaSMA
      positive myofibroblasts and mesenchymal cells are the major sources of ECM
      components after pancreatitis.

PMID- 12604923
TI  - Mirtazapine: another drug responsible for drug-induced acute pancreatitis? A
      letter of warning.

PMID- 12604922
TI  - Tumor-forming pancreatitis diagnosed preoperatively as intraductal papillary
      mucinous tumor: report of a case.

PMID- 12604924
TI  - Spirits and gastrectomy increase risk for chronic pancreatitis in Japanese male
      alcoholics.
AB  - INTRODUCTION: Most cases of chronic pancreatitis are alcohol-related, but not all
      alcoholics develop pancreatitis. AIM: To elucidate historical and biologic risk
      factors for this disease. METHODOLOGY: Alcoholic Japanese men (n = 132)
      consecutively admitted to the National Alcoholism Center over 24 months,
      including 54 with chronic pancreatitis (diagnosed by endoscopic retrograde
      cholangiopancreatography) and 78 without, were surveyed about drinking history,
      smoking, education, and marital status, and tested for amylase, glycosylated
      hemoglobin, body mass, alcohol and aldehyde dehydrogenase genotypes, and K-ras
      gene mutations in pancreatic juice. RESULTS: Higher risk for chronic pancreatitis
      was associated with drinking spirits rather than lower-alcohol beverages (odds
      ratio [OR], 2.58; p= 0.01). Daily ethanol consumption by those who drank spirits
      was greater than that among those who drank lower-alcohol beverages; however, no
      differences in either daily ethanol consumption or duration of drinking were
      observed between alcoholics with and without chronic pancreatitis.
      Postgastrectomy patients were at higher risk for chronic pancreatitis than
      unoperated comparison subjects (OR, 4.35, P< 0.05). Elevated glycosylated
      hemoglobin (OR, 4.62, p< 0.01), decreased amylase (OR 4.20, P<0.02), and low body
      mass (OR 1.89, P<0.1) were more frequent in alcoholics with chronic pancreatitis.
      K- gene mutations existed in 18.8% of alcoholics with chronic pancreatitis but in
      only 11.4% of those without the disorder. The frequencies of alcohol and aldehyde
      dehydrogenase genotypes in alcoholics with and without pancreatitis did not
      differ significantly. CONCLUSION: Our study strongly suggested that spirits and
      partial gastrectomy increase the risk for chronic pancreatitis in male
      alcoholics.

PMID- 12604925
TI  - The biochemical detection of biliary etiology of acute pancreatitis on admission:
      a revisit in the modern era of biliary imaging.
AB  - INTRODUCTION: Compared with traditional radiologic methods for the detection of
      cholelithiasis, early transient hypertransaminasemia had provided a useful
      prediction of biliary etiology in patients with acute pancreatitis. AIM: To
      investigate whether this application remains valid in the modern era of imaging
      for microlithiasis. METHODOLOGY: The biochemical detection (LFT) of
      cholelithiasis was based on an increase in serum alanine transaminase of >or=80
      IU/L (normal range, 0-45 IU/L) within 24 hours of admission. We have taken the
      collective findings of abdominal ultrasound (USS), endoscopic ultrasound (EUS),
      and postmortem examination to represent the denominator for the diagnosis of
      cholelithiasis against which comparison with LFT was made. RESULTS: Of 68
      patients with acute pancreatitis who were treated between October 2000 and
      December 2001, cholelithiasis was the etiological factor in 44 patients (65%).
      EUS detected microlithiasis in 5 of 10 patients examined. The etiology remained
      idiopathic in 3 patients (4.4%). The sensitivity, specificity, and positive and
      negative predictive values for USS were 86%, 100%, 100%, and 80% respectively;
      for LFT, they were 91%, 100%, 100%, and 86%; and for USS and LFT combined, they
      were 98%, 100%, 100%, and 96%, respectively. CONCLUSIONS: In patients with acute
      pancreatitis, the biochemical analysis within 24 hours of admission provided a
      simple, rapid, and more accurate prediction of cholelithiasis than USS. The
      combination of LFT and USS detected or excluded a biliary etiology in almost all
      patients.

PMID- 12604927
TI  - Studies on hypertrophic effect of 90% partial pancreatectomy on the stomach in
      rats.
AB  - INTRODUCTION: Stomach changes after major pancreatectomy (Px) are unclear. We
      previously reported that 90% Px increased stomach weight in rats similarly to
      endogenous hypergastrinemia by lansoprazole, a proton-pump inhibitor. AIM: To
      investigate the role of endogenous gastrin in gastric hypertrophy after Px.
      METHODOLOGY: In male Wistar rats, we compared the wet weight of the stomach and
      serum gastrin levels between normal (n = 10) or sham-operated controls (n = 10)
      and 90% partially pancreatectomized rats (n = 7). Then, using Northern blot
      analysis, we compared gene expression of gastrin, cholecystokinin-B (CCK-B)
      receptor, and somatostatin in the stomach among normal controls (n = 7), sham
      operated rats (n = 7), and 90% partially pancreatectomized rats (n = 8). The
      samples were obtained on the third and seventh postoperative days (POD). RESULTS:
      Wet weight of the stomach was significantly heavier in the Px rats than in the
      sham-operated controls (3.90 +/- 0.12 mg/g vs 2.63 +/- 0.07mg/g; p< 0.0001) on
      the 14th POD. Serum gastrin levels were also higher in the Px rats than in
      controls (161.4 +/- 13.35 pg/mL vs 110.6 +/- 5.67 pg/mL; p< 0.005) on the 14th
      POD. Gene expression of gastrin in the stomach on the 7th POD was significantly
      higher in the Px rats than in the sham-operated rats (p < 0.05), and gene
      expression of CCK-B receptor clearly increased in the Px rats on the 7th POD,
      when compared with that of controls (p < 0.05). Gastric somatostatin gene
      expression in both operated groups increased approximately twice as much as in
      normal controls after operation (p < 0.005). However, on the 7th POD, it returned
      to control levels only in Px rats and not in sham-operate rats (p < 0.05).
      CONCLUSION: Increased gene expression of gastrin and CCK-B receptor suggests that
      gastrin may act as a trophic factor on the stomach after partial Px. Moreover,
      the relative decrease in gastric somatostatin gene expression may also influence
      gastric hypertrophy after Px.

PMID- 12604926
TI  - Effect of long-term high-fat feeding on the expression of pancreatic lipases and
      adipose tissue uncoupling proteins in mice.
AB  - INTRODUCTION: A diet containing a high amount of fat has been shown, in short
      term studies, to increase the expression of pancreatic lipase and colipase. AIM:
      To investigate the effects of long-term high-fat-feeding (113 days) on the mRNA
      expression of pancreatic lipase, colipase, pancreatic lipase-related proteins (1
      and 2), and uncoupling proteins during the development of obesity and glucose
      intolerance. METHODOLOGY: Mice were fed either a high-fat or standard diet and
      killed after 3, 13, 57, and 113 days. Brown and white adipose tissue and pancreas
      were collected for mRNA extraction [corrected]. RESULTS: The high-fat-fed mice
      became obese and glucose-intolerant by 113 days. The high-fat diet increased
      lipase (p < 0.05) expression initially. At the end of the experiment, the lipase
      levels had decreased to the level of the control. Colipase levels did not change
      during the first 57 days of high-fat feeding but decreased below control levels
      by 113 days (p < 0.05). The high-fat diet increased brown adipose tissue
      uncoupling protein 1 (UCP1)(p < 0.005) expression but not the expression of
      uncoupling protein 2. CONCLUSION: Long-term high-fat feeding, leading to glucose
      intolerance, occurs with a simultaneous decrease in the mRNA expression of
      pancreatic lipase and colipase and an increase in UCP1 expression.

PMID- 12604928
TI  - Determinants of left atrial size in patients with newly diagnosed untreated
      hypertension.
AB  - The present study determined the relationships between ambulatory blood pressure,
      left ventricular mass, body mass index, and other clinical and demographic
      variables to left atrial size in previously untreated hypertensive and
      normotensive subjects. Left atrial size was measured uni-dimensionally using M
      mode echocardiography in 58 newly diagnosed never-treated hypertensive patients
      (office blood pressure 149/96 +/- 15/7 mmHg) and 28 normotensive control subjects
      (office blood pressure, 122/78 +/- 8/8 mmHg). Left ventricular mass, septal and
      posterior wall thickness were significantly increased in hypertensive compared to
      normotensive subjects (230 +/- 63 g versus 181 +/- 45 g, 1.1 +/- 0.2 cm versus
      0.94 +/- 0.2 cm, and 1.04 +/- 0.2 cm versus 0.92 +/- 0.2 cm respectively; all p <
      0.001). Left ventricular internal diameter (4.9 +/- 0.6 versus 4.8 +/- 0.4 cm, =
      0.54) and left atrial size (3.74 +/- 0.48 versus 3.70 +/- 0.34 cm, p = 0.86) were
      not different between the two groups respectively. Body mass index, weight, left
      ventricular mass, wall thickness, and 24-h pulse pressure were significant
      correlates of left atrial size in the entire group and in the hypertensive
      subgroup. In the normotensive subgroup, body weight, body mass index, 24-h
      systolic and pulse pressure, and left ventricular mass were significant
      correlates. Multiple regression analyses in the entire group and the hypertensive
      subgroup alone showed that body mass index and left ventricular mass were the two
      best predictors of left atrial dimension. These data demonstrate that body mass
      index and left ventricular mass were the main correlates of left atrial size in
      patients with previously untreated stage I-II hypertension.

PMID- 12604929
TI  - Relation of coronary artery calcium to left ventricular mass and geometry in
      patients with essential hypertension.
AB  - BACKGROUND: There is a close relationship between left ventricular hypertrophy
      and cardiovascular diseases that are observed in hypertension. In this study, the
      amount of coronary artery calcium, which is an indicator of atherosclerosis, has
      been measured and its relationship with left ventricular hypertrophy and geometry
      and other traditional risk factors has been investigated. DESIGN: A total of 249
      (104 females, 145 males) hypertensive asymptomatic patients, without diabetes
      with an average age of 55.09 +/- 11.32 years were included in the study. Left
      ventricular mass of the patients was measured with M-mode echocardiography and
      coronary artery calcium with electron beam tomography. The average age of the
      patients who had calcium in their coronary arteries (CAC+) was 59.99 +/- 9.85
      years, and the average age of the ones without calcium (CAC-) was 49.29 +/- 10.19
      years. RESULTS: Mean left ventricular mass index (LVMI) was measured as 130.18 +/
      43.24 g/m2 in CAC+ patients and as 108.47 +/- 29.09 g/m2 in CAC- patients. These
      two groups did not differ in terms of the parameters such as total cholesterol,
      high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol
      (LDL-C), triglyceride and uric acid levels, the presence of early coronary
      disease in the family and smoking. Patients who had calcium in their coronary
      arteries (CAC+) were more obese (P < 0.004). In the logistic regression analysis,
      we demonstrated that body mass index and age were the factors affecting the
      presence and amount of calcification seen in coronary arteries in left
      ventricular hypertrophy. In the analysis performed by taking left ventricular
      hypertrophy into consideration, mean calcium scores of the patients with normal
      remodeling, concentric remodeling, eccentric hypertrophy and concentric
      hypertrophy were 50.9 +/- 187.4, 68.6 +/- 159.3, 92.2 +/- 160.2 and 315.4 +/-
      760.6, respectively. In the patients with concentric left ventricular hypertrophy
      (LVH), the mean calcium scores of the coronary arteries and the rate of being
      CAC+ were significantly high, although these patients were also older. After
      linear regression, the relationship between concentric LVH and coronary artery
      calcium (CAC) was still significant. CONCLUSION: In conclusion, left ventricular
      hypertrophy that is observed in hypertension is an important risk factor for sub
      clinical atherosclerosis. Concentric left ventricular hypertrophy is a more
      important risk factor than other geometric patterns.

PMID- 12604930
TI  - The Working Group on Blood Pressure Monitoring of the European Society of
      Hypertension.

PMID- 12604931
TI  - Demise of the mercury sphygmomanometer and the dawning of a new era in blood
      pressure measurement.
AB  - After a little more than a century of use, the conventional Riva-Rocci/Korotkoff
      technique of measuring blood pressure with a mercury sphygmomanometer and
      stethoscope, is now being relegated to the museum shelves. Affectionately
      attached though we may be to this clinical measurement, we must acknowledge that
      the technique is fraught with inaccuracy and that the age of technology has
      brought more accurate alternative methodologies. However, we must ensure that the
      automated devices that are replacing the conventional technique are validated
      independently for accuracy. The Working Group on Blood Pressure Monitoring of the
      European Society of Hypertension has recently published an International Protocol
      to facilitate the validation of more automated devices than was possible with the
      earlier more complicated protocols.

PMID- 12604932
TI  - What will replace the mercury sphygmomanometer?
AB  - Mercury sphygmomanometers are gradually being phased out, not because of any
      technological advances but because of environmental concerns. While mercury is
      still accepted as the 'gold standard' for routine clinical measurement, it
      suffers from two deficiencies: poor observer technique, and problems due to poor
      maintenance of the devices. At the same time, there is no generally accepted
      alternative; the most widely advocated candidates are aneroid or oscillometric
      devices. Oscillometric devices have the advantages of eliminating observer error
      and mechanical drift, but it is suggested that the inherent limitations of the
      oscillometric method mean that it cannot become the gold standard for clinical
      measurement in individual patients. Aneroid monitors have been found in practice
      to be frequently deficient, and are subject to the same deficiencies in observer
      technique as mercury devices. Two possible but so far untested techniques are a
      'hybrid' sphygmomanometer, whereby the mercury column is replaced by an
      electronic transducer and display, and the wideband recording technique, which
      has the potential of using the same basic principle as the auscultatory
      technique, while eliminating the human observer.

PMID- 12604933
TI  - Finometer, finger pressure measurements with the possibility to reconstruct
      brachial pressure.
AB  - OBJECTIVE: To evaluate three methods aimed at the reconstruction of brachial
      pressure from non-invasive finger arterial pressure measurements as implemented
      in the Finometer trade mark, (FMS, Finapres Measurement Systems, Arnhem,
      Netherlands), the successor to the Finapres trade mark (TNO Biomedical
      Instrumentation, Amsterdam, Netherlands). METHODS: Finger arterial pressure
      (FinAP) may differ from intra-brachial pressure (BAP). Pulse shape differences
      are removed by applying a generalized waveform filter. Pressure level differences
      are corrected by a generalized level correction equation using filtered systolic
      and diastolic levels and by level calibration, which uses an additional return-to
      flow (RTF) systolic pressure measurement on the ipsilateral upper arm for an
      individual calibration of the reconstructed brachial pressure. VALIDATION: These
      methods were validated in 37 subjects, aged 41 to 83 years after a cardiac
      catheterization procedure. Intra-brachial and Finometer pressures were recorded
      simultaneously. Finometer pressures were compared after application of waveform
      filtering and level correction (flcAP), and after an additional RTF calibration
      (reBAP). RESULTS: Finger arterial systolic, diastolic and mean pressures for the
      group differed from BAP by -9.7 +/- 13.0, -11.6 +/- 8.0 and -16.3 +/- 7.9 mmHg
      (mean +/- SD) respectively. Similarly flcAP differed by -1.1 +/- 10.7, -0.2 +/-
      6.8 and -1.5 +/- 6.6 mmHg and reBAP differed by 3.1 +/- 7.6, 4.0 +/- 5.6 and 2.7
      +/- 4.7 mmHg. CONCLUSION: Reconstruction of BAP from FinAP as implemented in the
      Finometer reduces the pressure differences, with an individual RTF calibration to
      well within AAMI requirements.

PMID- 12604934
TI  - Non-invasive beat-to-beat blood pressure monitoring: new developments.
AB  - Continuous blood pressure monitoring is an essential prerequisite for any study
      on blood pressure variability. Invasive procedures are no longer acceptable for
      research projects in a clinical setting, and recently developed devices able to
      record blood pressure on a beat-by-beat basis in a non-invasive fashion may
      represent valuable alternative tools. This article will briefly review the
      available information on the most recent advances in this field. It will focus on
      further developments of the original technology for finger blood pressure
      monitoring introduced by Penaz, as well as on newer devices that have been
      proposed over the last few years for non-invasive cardiovascular monitoring both
      in research and in clinical studies.

PMID- 12604936
TI  - Simultaneous recording of blood pressure and ST-segment with combined, triggered
      ambulatory 24-h devices.
AB  - Silent myocardial ischemia is defined as an ischemic episode without chest pain
      but with transient ST abnormalities during stress testing or Holter monitoring.
      With Holter monitoring the prevalence of silent myocardial ischemia in
      hypertensive patients without coronary artery disease is between 25% and 73%.
      Simultaneous recording of ambulatory 24-h ECG and 24-h ambulatory blood pressure
      measurements (ABPM) with the option of additional ST-triggered blood pressure
      measurement is useful to detect silent ischemia and triggers of silent ischaemia.
      It is surprising that only a few combined 24-h Holter/ABPM devices are on the
      market, and in turn only three devices allow additional triggered blood pressure
      measurements. The paper provides an overview of studies investigating
      hypertensive patients with Holter monitoring for the detection of ST segment
      depression indicating myocardial ischaemia. Furthermore, requirements for
      combined devices allowing simultaneous ambulatory 24-h ECG and ABPM are defined.

PMID- 12604935
TI  - Determinants of white-coat syndrome assessed by ambulatory blood pressure or self
      measured home blood pressure.
AB  - BACKGROUND: Gender, age, smoking, race, and body mass index have been reported to
      determine the ambulatory white-coat effect (WCE) and white-coat hypertension
      (WCH). METHODS: Baseline conventional, day-time ambulatory and self-measured home
      blood pressure measurements from the THOP trial were used to study the effect of
      gender, age, body mass index, smoking habits and treatment status on the white
      coat syndrome as assessed by ambulatory monitoring or self-measurement. RESULTS:
      The mean systolic/diastolic WCE was 9.1/6.7 mmHg if based on ambulatory blood
      pressure and 12.2/8.7 mmHg if based on self-measured blood pressure. The
      ambulatory WCE was significantly higher in women, in older subjects (65+), in
      obese subjects, in non-smokers and in patients on antihypertensive drug
      treatment. The self-measured WCE was significantly higher in women and in non
      smokers. Ambulatory WCH was present in 6.6% of the untreated patients and 14.2%
      had self-measured WCH. The proportion of ambulatory WCH was significantly higher
      in obese subjects; the proportion of self-measured WCH did not differ by gender,
      age, body mass index, or smoking habits. CONCLUSIONS: The ambulatory white-coat
      syndrome was determined by gender, age, body mass index, smoking habits, and
      treatment status. The self-measured white-coat syndrome was greater than the
      ambulatory white-coat syndrome but depended less on the determinants under study.

PMID- 12604937
TI  - Silent myocardial ischaemia in treated hypertensives with and without left
      ventricular hypertrophy.
AB  - BACKGROUND: Silent ischaemia has been reported to be associated with an increased
      risk of myocardial infarction and sudden death in a wide range of patient groups.
      The aim of this study was to examine the prevalence of silent ischaemia in
      hypertensive patients with and without left ventricular hypertrophy (LVH).
      METHODS: Twenty hypertensive patients participating in the Anglo-Scandinavian
      Cardiac Outcomes Trial with echocardiographic LVH (11 males, nine females), and
      20 age, sex, blood pressure, and drug treatment-matched hypertensive patients
      without LVH underwent 24-h combined ambulatory blood pressure and
      electrocardiographic (ECG) monitoring. Ischaemic events were defined by the 'rule
      of 3 x 1'-asymptomatic ST-depression >/= 1 mm (0.1 mV), lasting at least 1 min,
      and with a duration of at least 1 min between two events. RESULTS: Thirteen
      patients with LVH had ischaemic events, whilst only four without LVH demonstrated
      ischaemia. Median numbers of events (seven versus zero; P < 0.01) and median
      total ischaemic area (0.25 versus 0 mV*min/day; P < 0.01) were significantly
      increased amongst hypertensive patients with LVH by comparison to those without
      LVH. CONCLUSION: Despite similar levels of established risk factors for
      atherosclerotic coronary artery disease, the prevalence of silent ischaemia was
      markedly increased amongst hypertensive patients with LVH by comparison to those
      with normal left ventricular dimensions. Ambulatory ECG monitoring may have a use
      in the identification of those at greatest risk of cardiovascular complications
      and sudden death, amongst hypertensive patients with persistent cardiac
      hypertrophy despite anti-hypertensive therapy.

PMID- 12604938
TI  - Heart rate measurement and outcome.
AB  - Previous studies on the predictive value of heart rate and heart rate variability
      for the risk of cardiovascular disease remains controversial. Since heart rate is
      known to be variable with several physical and mental stresses, the inconclusive
      nature of previous studies might reflect the difference in accuracy and
      reproducibility of the heart rate measurement. In the Ohasama study, which has
      been conducted since 1985 in the northern part of Japan, home measurements and
      ambulatory monitoring of heart rate as well as blood pressure were examined with
      special reference to cardiovascular mortality. Heart rate measured at home and
      averaged for 21 days was shown to be linearly associated with cardiovascular
      mortality, while heart rate variability (standard deviation of daytime ambulatory
      heart rate measured every 30 min) inversely correlated with cardiovascular
      mortality. In conclusion, heart rate and heart rate variability must not be
      overlooked when evaluating hypertension.

PMID- 12604939
TI  - More than who and when.

PMID- 12604940
TI  - Longitudinal parental perceptions of spinal fusion for neuromuscular spine
      deformity in patients with totally involved cerebral palsy.
AB  - Retrospective surveys of caregivers of patients with totally involved cerebral
      palsy who are undergoing arthrodesis for spine deformity have demonstrated
      satisfaction with results but are subject to retrospective bias. The Pediatric
      Orthopaedic Society of North America outcomes questionnaire was prospectively
      administered to parents of patients with consecutively presenting, totally
      involved cerebral palsy before spinal fusion, 6 months after spinal fusion, and 1
      year after spinal fusion. Review of medical records determined complication
      rates. Parents of 20 consecutive patients completed preoperative questionnaires.
      Ten of these completed questionnaires 6 months and 1 year postoperatively, and
      seven more completed only 1-year postoperative questionnaires. There were no
      significant changes between preoperative and postoperative assessments of
      physical function, school absence, comorbidities, and parental health. Patient
      pain, happiness, frequency of feeling sick and tired, and parental satisfaction
      improved significantly by 1 year postoperatively. All but pain and happiness were
      significantly improved by 6 months postoperatively, also. The presence of
      complications did not significantly affect questionnaire results. This
      prospective study substantiates the subjective gains noted in previous
      retrospective studies of spinal fusion for neuromuscular spine deformity in
      cerebral palsy.

PMID- 12604941
TI  - Comparison of proximal and distal rotational femoral osteotomy in children with
      cerebral palsy.
AB  - This study compares the complication rates and results of 27 proximal
      (intertrochanteric) and 51 distal femoral rotational osteotomies in 48 patients
      with static encephalopathy. There was no significant difference between the 14%
      rate of orthopaedic complications in the intertrochanteric osteotomy (ITO) group
      and the 10% rate in the distal osteotomy (DO) group. Loss of fixation occurred in
      three of 51 limbs (6%) in the DO group and in none of 27 limbs in the ITO group.
      If the results of one surgeon are excluded, fixation loss occurred in one of the
      49 remaining DO cases (2%). There was one delayed union in the study population
      (1/27 limbs [4%] in the ITO group). Of the 33 limbs studied with postoperative
      gait analysis, overcorrection was present in two limbs (6%): one of 10 limbs
      (10%) in the ITO group and one of 23 (4%) in the DO group. Static and dynamic
      measures of femoral rotation improved in both groups, and no statistically
      significant differences were present between the two groups. Though variable, the
      mean change in dynamic and static measurements postoperatively was approximately
      40% less than the amount of derotation reported at surgery.

PMID- 12604942
TI  - Radial head dislocation in children with cerebral palsy.
AB  - Dislocation of the radial head in children with cerebral palsy (CP) is rarely
      reported, and the incidence of the condition is unknown. The authors present the
      treatment and outcome of 10 painful radial head dislocations in eight children
      with spastic quadriplegic-pattern CP treated over a 21-year period. Four patients
      were managed by open reduction of the radial head and reconstruction of the
      annular ligament, and four were managed by radial head excision followed by early
      motion. All of the patients who underwent reconstructive surgery suffered
      redislocation within 16 weeks of the procedure, with a return of pain and
      contracture of the elbow at subsequent follow-up. All four patients who underwent
      excision of the radial head remained pain-free, with improved elbow motion, at a
      follow-up of 4 years 4 months. The authors believe that once symptomatic radial
      head dislocation is established in CP patients, excision of the radial head gives
      a better final outcome than reconstructive procedures.

PMID- 12604943
TI  - Spinal arthrodesis for scoliosis in Down syndrome.
AB  - The results of operative treatment of scoliosis in Down syndrome at one
      institution are reviewed. Seven patients with progressive scoliosis who had
      undergone arthrodesis of the thoracolumbar spine were identified. Clinical and
      radiographic results were noted, as were any complications. Mean patient follow
      up was 9 years (range 2-25). All patients eventually showed radiographic evidence
      of solid fusion with no curve progression. One patient had undergone a revision
      procedure for pseudoarthrosis and failure of Dwyer instrumentation. Other
      complications included a lateral subluxation under the fusion area, pneumonia,
      and one asymptomatic hook dislodgment. Progressive deformities of the
      thoracolumbar spine in Down syndrome patients can be treated with fusion and
      instrumentation with cessation of progression. As is the case for upper cervical
      fusion in these patients, the complication rate is notable.

PMID- 12604944
TI  - Septic arthritis of the hip in infancy: long-term follow-up.
AB  - At a mean 15-year follow-up, the authors evaluated five hips in five patients who
      had complete destruction of the femoral head and neck from septic arthritis when
      they were 3 months old. All patients were treated with a trochanteric
      arthroplasty in combination with a proximal femoral varus osteotomy at a mean age
      of 30 months in an attempt to salvage a femoral-pelvic articulation. Results
      suggest this treatment can provide a stable, painless, and functional hip, with
      an improved gait and less leg-length discrepancy than predicted if no
      reconstructive effort were attempted.

PMID- 12604945
TI  - Outcome of slipped capital femoral epiphysis in renal osteodystrophy.
AB  - The cases of renal osteodystrophy-associated slipped capital femoral epiphysis in
      11 consecutive patients were reviewed. Nine patients had bilateral involvement,
      totaling 20 hips. The mean age at presentation was 10.6 years. Slip location was
      physeal in 13 and metaphyseal in seven hips. All patients had prompt medical
      treatment of their bone disease, and nine patients underwent surgical
      stabilization. Fixation consisted of multiple custom-machined Steinmann pins that
      were smoothed distally but threaded proximally, allowing continued proximal
      femoral growth. The mean radiographic and clinical follow-up was 5.7 years and
      9.1 years, respectively. Slips stabilized in 14 of 16 operated hips (88%),
      whereas one patient with inadequate renal disease control had slip progression
      requiring subsequent subtotal parathyroidectomy and repeat fixation. Combined
      medical management and surgery with custom-machined pins prevented slip
      progression while allowing continued physeal growth.

PMID- 12604946
TI  - Use of an abduction brace for developmental dysplasia of the hip after failure of
      Pavlik harness use.
AB  - The authors reviewed the records of 15 infants who were treated with an abduction
      brace after Pavlik harness use for developmental dysplasia of the hip (DDH)
      failed. Failure was defined as persistent dislocation or instability of the hip.
      Thirteen of these 15 patients had resolution of DDH with the use of an abduction
      brace. The median time spent in the brace before stabilization of examination
      findings was 24 days; the median time in the brace before normalization of
      ultrasound parameters was 46 days. There were no complications with regard to use
      of the abduction orthosis. At final follow-up of an average of 3 years and 7
      months, no patient had undergone surgery and no patient had residual dysplasia or
      avascular necrosis of the hip. The two patients in whom both the Pavlik harness
      and abduction brace failed went on to successful closed reduction and spica cast
      application.

PMID- 12604947
TI  - Habitual dislocation of the hip in children: report of eight additional cases and
      literature review.
AB  - The purpose of this study was to report eight additional cases of habitual
      dislocation of the hip (HDH) and to combine the authors' data with a compilation
      of the cases from the literature. The authors attempted to investigate the
      various causative factors, outcomes, and indications for conservative and
      operative treatments. The results suggest that an unusual ability to dislocate
      the hip voluntarily at a young age constitutes a specific pediatric entity, and
      no single factor can be determined to be the definite cause of HDH. Multiple
      triggering factors (generalized ligamentous laxity, excessive anteversion of the
      femur and acetabulum, osteocartilaginous defect of acetabulum, coxa valga,
      psychiatric immaturity) appear to be associated with HDH. Treatment should be
      conservative in the first instance; it includes simple observation with or
      without psychiatric counseling and immobilization with cast or brace. Hip
      stabilization by surgical means is selectively indicated when the episodes of hip
      dislocation do not fade away in due time despite conservative treatment and when
      primary or secondary capsular laxity or osteocartilaginous deformation or defect
      of the hip is severe enough to cause repeated dislocation or residual
      subluxation, which may cause persistent pain or discomfort.

PMID- 12604948
TI  - Biological internal fixation of comminuted femur shaft fractures by bridge
      plating in children.
AB  - Fourteen children (mean age 11.3 y) with a closed comminuted femur shaft fracture
      were surgically treated by biologic internal fixation using a bridging plate. The
      fractured area was not opened. After indirect reduction, internal fixation was
      made by a bridging plate through two small incisions, exposing the lateral
      aspects of proximal and distal fragments. The mean complete radiographic healing
      time was 12.4 weeks. After a mean follow-up period of 4 years, all patients were
      satisfied with the clinical outcome. The mean radiographic torsional deformity of
      the injured limb with respect to the uninjured limb was 4.5 degrees. A residual
      radiographic frontal or sagittal plane angulation of more than 10 degrees was
      seen only in one patient. It was concluded that biologic internal fixation by
      bridge plating was an effective surgical treatment method for the closed
      comminuted fractures of the proximal and distal thirds of the femur shaft in
      children.

PMID- 12604949
TI  - Open reduction and plate fixation of femoral shaft fractures in children aged 4
      to 10.
AB  - A retrospective review of 40 children aged 4 to 10 years with 46 femur fractures
      treated with open reduction and plate fixation is presented. Follow-up time was
      6.3 years (range 2.5-17.5). There were no nonunions. One case of osteomyelitis
      and one refracture occurred. Leg-length discrepancy averaging 1.2 cm (range 0.4
      1.8), with lengthening on the operated side, was observed in 15 patients.
      Although there is some risk for complications, and although good early results
      have been reported with elastic intramedullary nails, plate fixation continues to
      be a viable alternative in the surgical treatment of femoral shaft fractures in
      children aged 4 to 10.

PMID- 12604951
TI  - Acute traumatic knee effusions in children and adolescents.
AB  - A prospective analysis was completed during a 6-month period to identify all
      patients, age 18 years or younger, who presented for evaluation of their knee
      effusion. There were 44 injured knees in 44 patients. There were a total of 55
      diagnoses: 16 (29%) anterior cruciate ligament (ACL) injuries, 16 (29%) meniscal
      tears, 14 (25%) patellofemoral subluxations or dislocations, 3 (5%) medial
      collateral ligament sprains, 2 (4%) patellar osteochondral fractures, 2 (4%)
      retinacular injuries, 1 (2%) posterior cruciate ligament rupture, and 1 (2%)
      tibial eminence fracture. Girls had 11 of the 14 patellofemoral injuries; 58% of
      the girls had effusions secondary to patellofemoral pathology compared with 12%
      of the boys. Boys had 10 of the 16 meniscal tears and 13 of the 16 ACL tears.
      Fifty-two percent of boys had an injury to the ACL and 44% had an injury to a
      meniscus. In contrast, 16% of girls had an ACL injury and 32% had meniscal tears.
      ACL injuries, meniscal tears, and patellofemoral pathology accounted for 87%
      (48/55) of the diagnoses. Girls were more likely to have patellofemoral
      pathology; boys were more likely to have ACL and meniscal tears.

PMID- 12604950
TI  - Versatility of the distally based superficial sural flap for reconstruction of
      lower leg and foot in children.
AB  - Twenty children are presented after undergoing a distally based superficial sural
      flap for coverage of defects at the lower leg and foot. The age of the patients
      was between 1 and 12 years. Fifteen patients had trauma to the lower leg, with
      eight of them having associated injuries. Three had postburn contracture and two
      had pressure sore. In 14 cases, the flap was used as a fasciocutaneous flap,
      whereas in six cases it was used as a fascial flap covered with a skin graft. The
      flaps were used to cover the defects from the dorsum of the foot distally up to
      the mid third of tibia proximally. The mean follow-up was for a period of 2
      years. Even though free tissue transfer is reliable and safe for the
      reconstruction of major leg injuries in children, the distally based superficial
      sural flap has the advantage of being easy to perform, with short operating time,
      minimal donor side morbidity, and preservation of major arteries of the leg.

PMID- 12604953
TI  - Severely displaced proximal humeral epiphyseal fractures.
AB  - The purpose of this study was to document the late outcome of a group of patients
      with Neer grade III/IV proximal humeral physeal fractures who were treated with
      reduction of the fracture and maintenance of reduction until fracture
      consolidation. A total of 28 patients treated between 1984 and 1999 at a large
      children's hospital were included in this study. Nineteen of the 28 patients were
      15 years or older (range 5-16 y). All patients were treated in the operating room
      with closed reduction followed by immobilization (n = 3), closed reduction and
      pin fixation (n = 20), open reduction and screw fixation (n = 3), or open
      reduction and pin fixation (n = 2). Postoperatively, all had Neer grade I or II
      displacement, which was maintained until fracture union. No operative or
      postoperative complications occurred. At an average follow-up of 4 years, all
      patients had near-normal glenohumeral motion and excellent strength and uniformly
      reported regaining full preinjury functional use of the involved extremity.
      Achieving and maintaining reduction in Neer grade III/IV proximal humeral
      epiphyseal fractures can be safely performed and results in excellent long-term
      shoulder function. This is of particular significance in the older adolescent who
      has minimal remodeling potential.

PMID- 12604952
TI  - Longitudinal growth after nonphyseal forearm fractures.
AB  - The overgrowth phenomenon after fracture has been considered rare in the upper
      extremity. This study analyzes 119 patients with forearm fractures treated
      conservatively. All patients had scanograms of both forearms 5 years later. A
      difference in length more than 2 mm was considered a discrepancy. Positive values
      of discrepancy were called overgrowth. A radial length discrepancy was observed
      in 80 patients (67.2%) and overgrowth in 38 (26.8%); ulnar values were 65 (54.6%)
      and 29 (24.3%), respectively. Radial overgrowth and ulnar overgrowth were related
      to the location of the radial fracture and handedness but not to the type of
      fracture, age or sex of the patient, or the presence or absence of an associated
      ulnar fracture. Discrepancy did not show a significant relationship to any of
      these variables. Surprisingly, fractures in the proximal and middle thirds often
      presented with overgrowth, whereas those closer to the distal physis did not.

PMID- 12604954
TI  - Scaphoid fractures in children: problems and treatment.
AB  - From 1984 to 1999, the authors treated 64 cases of fracture of the scaphoid in
      children. Causes of injury were sports (n = 27), punching game machines or
      fighting (n = 22), and traffic accident or other trauma (n = 15). Most (46 cases)
      were nonunion cases. Eighteen cases were acute. Cast immobilization was performed
      in 10 acute cases and two nonunion cases. Screw fixation was performed in 52
      cases, including 35 cases of bone graft. In 10 of these operated cases, freehand
      screw insertion was used. Ultimately, good bony fusion was achieved in all cases,
      but in two nonunion cases a secondary bone graft was necessary. Functional
      results in all cases were acceptable. A major problem is that children are not
      brought to clinics immediately after injury, so the percentage of nonunion is
      high.

PMID- 12604955
TI  - Epiphyseal involvement of simple bone cysts.
AB  - Epiphyseal involvement of a simple bone cyst (SBC) is uncommon. Eight patients
      are reported in whom an SBC was found to cross the growth plate, involving the
      epiphysis in seven patients and the apophysis in one. All patients had more than
      two pathologic fractures. In seven patients growth disturbance was found.
      Functional impairment did not develop in any patient. Radiographically, all
      lesions presented a characteristic involvement of the epiphysis and metaphysis in
      various proportions. Only one of four cysts treated with methylprednisolone
      acetate injections showed incomplete healing; the others failed to respond. After
      percutaneous grafting of autologous bone marrow, three of seven cysts healed and
      the others attained incomplete healing. Epiphyseal involvement of SBC should be
      considered a more aggressive form of an active lesion.

PMID- 12604956
TI  - Extensible endoprostheses for bone tumors of the proximal femur in children.
AB  - Between 1983 and 1996, nine children were treated with extensible endoprosthetic
      replacements of the proximal femur after resection of primary bone tumors. Four
      patients died of their disease. The remaining five patients were observed for an
      average follow-up period of 7.6 years. In these five patients, the authors
      performed an average of 10.2 operations per patient, including five lengthenings
      and a mean total extension of 69.7 mm per patient. Acetabular loosening and hip
      dislocations were the most frequent complications. Only two patients have not had
      a revision or a major complication. Despite this, four children are alive with a
      functioning lower limb and a mean Musculoskeletal Tumor Society functional score
      of 77.6%. Extensible endoprosthesis of the proximal femur is a viable alternative
      to hip disarticulation and in selected children offers an opportunity for near
      normal development of the lower limb by allowing equalization of limb length and
      the ability to walk without the use of mobility aids.

PMID- 12604957
TI  - Treatment of longitudinal deficiency affecting the femur: comparing patient
      mobility and satisfaction outcomes of Syme amputation against extension
      prosthesis.
AB  - Patients with proximal focal femoral deficiency or longitudinal deficiency
      affecting the femur were selected from a large regional center. Twenty-eight such
      patients were identified and were divided into two groups depending on how their
      condition was managed. Group 1 had opted for the surgical approach of ankle
      disarticulation (Syme amputation) and the fitting of an above-the-knee
      prosthesis. The patients in group 2 had been managed in a nonsurgical fashion
      using an extension prosthesis. They were asked about their level of mobility
      using the recognized Locomotor Index and their overall satisfaction using self
      designed questions. The two groups' scores were similar for mobility whether
      using their prosthesis or not, but group 1 had lower satisfaction scores than
      group 2. Current opinion advocates the use of surgery in the management of
      proximal focal femoral deficiency because it is believed to have better cosmetic
      and functional results, but in the authors' comparison similar scores for
      mobility were shown. The nonsurgical extension prosthesis was associated with
      fewer musculoskeletal and residual limb problems, fewer problems with public
      transport, and greater satisfaction than Syme amputation. Overall, this small
      study suggests that the nonsurgical approach is preferable.

PMID- 12604958
TI  - Ultrasound of the navicular during the simulated Ponseti maneuver.
AB  - Nonoperative treatment of the equinovarus foot has had a recent resurgence
      because of popularization of the Ponseti casting method. This method is based in
      part on reducing the talonavicular joint by moving the navicular laterally and
      the head of the talus medially. This study dynamically demonstrates the effect of
      a simulated Ponseti manipulation on the navicular.

PMID- 12604959
TI  - Leg-length discrepancy and bone age in unilateral idiopathic talipes equinovarus.
AB  - The goals of this retrospective review were to evaluate leg-length discrepancy in
      patients with a unilateral clubfoot and to determine the relationship between
      bone age and chronologic age in the same population. Thirty-two of 47 patients
      referred for scanograms had a discrepancy more than 0.5 cm. Shortening was
      predominantly in the tibia, and four patients had radiographic evidence of growth
      disturbance. Five had been treated surgically at the time of review. If
      clinically indicated, a scanogram and standing radiographs of the ankle are
      necessary to determine the location and magnitude of discrepancy. Although the
      literature supports a neurologic etiology in some patients, and bone age may be
      delayed in certain neuromuscular conditions associated with limb shortening
      (hemiplegia), the authors' results suggest that bone age is statistically
      equivalent to chronologic age in the unilateral clubfoot population. These
      findings do not provide indirect support for a neurologic etiology.

PMID- 12604960
TI  - Prenatal ultrasound: detection and diagnosis of limb abnormalities.
AB  - Many cases of congenital limb abnormalities referred for orthopaedic treatment
      are not diagnosed prenatally, despite routine ultrasound scanning. The authors
      aimed to study the detection rate and diagnostic accuracy of prenatal scans. Data
      concerning two groups of patients were collected. First, the authors followed-up
      26,203 babies that had been scanned prenatally. Sixty had limb abnormalities; 15
      of the abnormalities were detected prenatally (sensitivity 25%, 95% confidence
      interval 14%-36%). Second, the authors studied 67 cases from the Wessex
      Antenatally Detected Anomalies Register that had been identified prenatally. The
      diagnosis was confirmed postnatally in 56 cases (positive predictive value 84%,
      95% confidence interval 75%-93%).

PMID- 12604961
TI  - Shoulder deformities in obstetric brachial plexus paralysis: a computed
      tomography study.
AB  - Obstetric brachial plexus palsy invariably involves the upper roots. If left
      untreated, characteristic deformities of the shoulder are common sequelae. The
      most objective way to investigate these shoulder deformities is computed
      tomographic (CT) scanning of bilateral upper limbs. In this study, specific
      measurements on CT scans of bilateral upper extremities were performed in a
      population of patients with obstetric brachial plexus palsy before and after
      reconstruction (nerve repairs and secondary procedures). The measurements showed
      that the restoration of external rotation and the scapula stabilization procedure
      correct the inclination of the humeral head, improve the joint congruency
      significantly, and decrease the winging of the scapula, thus improving the
      kinetics of the shoulder. Periodic CT measurement is an objective method of
      measuring the changes at the shoulder joint that occur over time during the
      natural evolution of the obstetric brachial plexus palsy lesion and of
      documenting the benefits of microsurgical intervention.

PMID- 12604962
TI  - Increased postoperative febrile response in children with osteogenesis
      imperfecta.
AB  - Children with osteogenesis imperfecta (OI) often require operative management to
      correct limb and spinal deformities. The authors reviewed the postoperative
      courses of 22 children with OI and compared the febrile responses of these
      children with those of matched subgroups within a published historical control (
      8). The subgroups were matched for perioperative conditions including the
      magnitude of surgery, estimated intraoperative blood loss, transfusion status,
      age, and gender. In all subgroups examined, the patients with OI exhibited a
      significant increase in total febrile response (TFR) compared with those in the
      historical control group. Within the OI group, TFR correlated with estimated
      blood loss and magnitude of surgery. There were three fever workups in the OI
      group with no evidence of infection found. In children with OI, fever workups and
      delays in hospital discharge should be avoided if physical signs of infection are
      absent.

PMID- 12604963
TI  - Genetics and epidemiology of idiopathic congenital talipes equinovarus.

PMID- 12604964
TI  - The use of epidural analgesia after posterior spinal fusion and instrumentation.

PMID- 12604965
TI  - Re: Klemme WR, et al. Hemivertebral excision for congenital scoliosis in very
      young children. J Pediatr Orthop 2001;21:761-764.

PMID- 12604966
TI  - Improving infant milk formulas: near the end of the trail for the holy grail?

PMID- 12604967
TI  - Helicobacter pylori and antimicrobial susceptibility in children.

PMID- 12604968
TI  - Fecal elastase-1 concentration: an indirect test of exocrine pancreatic function
      and a marker of an enteropathy regardless of cause.

PMID- 12604969
TI  - Complementary food supplements to achieve micronutrient adequacy for infants and
      young children.
AB  - Many children in developing countries survive on a nutritionally inadequate diet.
      Dietary inadequacies during the complementary feeding period can be prevented by
      using complementary food supplements (CFSs) such as water dispersible or
      crushable micronutrient tablets, micronutrient sprinkles added to food just
      before feeding, or fortified spreads added to food just before feeding or fed as
      a snacks. A meeting was convened to discuss technical and operational issues
      related to the development of these new approaches and to identify knowledge
      gaps. The technical issues covered: what micronutrients to include, tolerable
      upper intake limits, bioavailability, micronutrient and macronutrient stability,
      package systems and amounts, encapsulation technologies, methods to limit or
      eliminate allergens, bacterial and chemical contamination, interactions between
      CFSs and complementary foods, and flavoring agents. Operational issues included:
      identifying the market positioning of CFSs, cost positioning of CFSs, regulatory
      requirements, CFS production and technology transfer, quality assurance, and
      public-private sector partnership and coordination. Intervention trials are
      needed to determine the efficacy of CFSs in preventing micronutrient
      deficiencies. Other important knowledge gaps relate to technical and operational
      issues. Sprinkles and tablets are produced using well-known technologies, but
      further research is needed to modify them for use as CFSs. Spread development is
      not as advanced as sprinkle and tablet development, and further research is
      needed to improve the technology. Although none of the products is ready for
      widespread use, enough information is available to set research priorities and
      accelerate product development and implementation.

PMID- 12604970
TI  - Nondigestible carbohydrates in the diets of infants and young children: a
      commentary by the ESPGHAN Committee on Nutrition.
AB  - The consumption of nondigestible carbohydrates is perceived as beneficial by
      health professionals and the general public, but the translation of this
      information into dietary practice, public health recommendations, and regulatory
      policy has proved difficult. Nondigestible carbohydrates are a heterogeneous
      entity, and their definition is problematic. Without a means to characterize the
      dietary components associated with particular health benefits, specific
      attributions of these cannot be made. Food labeling for "fiber" constituents can
      be given only in a general context, and the development of health policy, dietary
      advice, and education, and informed public understanding of nondigestible
      carbohydrates are limited. There have, however, been several important
      developments in our thinking about nondigestible carbohydrates during the past
      few years. The concept of fiber has expanded to include a range of nondigestible
      carbohydrates. Their fermentation, fate, and effects in the colon have become a
      defining characteristic; human milk, hitherto regarded as devoid of nondigestible
      carbohydrates, is now recognized as a source for infants, and the inclusion of
      nondigestible carbohydrates in the diet has been promoted for their "prebiotic"
      effects. Therefore, a review of the importance of nondigestible carbohydrates in
      the diets of infants and young children is timely. The aims of this commentary
      are to clarify the current definitions of nondigestible carbohydrates, to review
      published evidence for their biochemical, physiologic, nutritional, and clinical
      effects, and to discuss issues involved in defining dietary guidelines for
      infants and young children.

PMID- 12604971
TI  - Core data for nutrition trials in infants: a discussion document--a commentary by
      the ESPGHAN Committee on Nutrition.

PMID- 12604972
TI  - Randomized double-blind study of the nutritional efficacy and bifidogenicity of a
      new infant formula containing partially hydrolyzed protein, a high beta-palmitic
      acid level, and nondigestible oligosaccharides.
AB  - OBJECTIVES: The aim of this study was to evaluate the nutritional efficacy and
      bifidogenic characteristics of a new infant formula containing partially
      hydrolyzed whey protein, modified vegetable oil with a high beta-palmitic acid
      content, prebiotic oligosaccharides, and starch. METHODS: In a double-blind
      study, healthy formula-fed term infants aged younger than 2 weeks were randomized
      to receive either the new infant formula (NF) or a standard formula (SF) until
      the age of 12 weeks. Anthropometric measurements were taken at enrollment, 6
      weeks, and 12 weeks. In a subsample of infants, blood samples were taken at 6
      weeks and stool samples were taken at enrollment and 6 weeks. Blood samples were
      analyzed for biochemical measures of protein status and amino acids, and stools
      were analyzed for total bacteria and bifidobacteria. Mothers completed a feeding
      diary and questionnaire at 6 and 10 weeks. RESULTS: One hundred fifty-four
      infants were enrolled in the study; 102 completed the trial. The growth of
      infants in both formula groups was in line with published growth curves. During
      the first 6 weeks, NF girls gained more weight and head circumference than the SF
      girls. These velocity differences were not maintained throughout the 12-week
      study period. The NF stools had a higher proportion of bifidobacteria at 6 weeks
      compared with the SF stools, and they were softer. There were no clinically
      significant differences in the blood biochemical and amino acid values between
      groups. Both formulas were well tolerated by the infants. CONCLUSIONS: When
      compared with a standard infant formula, the new formula supported satisfactory
      growth, led to higher counts of bifidobacteria in the feces, produced blood bio
      chemical values typical of formula-fed infants, and was well tolerated.

PMID- 12604973
TI  - Hepatic dysfunction following the Fontan procedure.
AB  - OBJECTIVES: The Fontan procedure offers a palliation for the hemodynamic
      derangements associated with congenital heart lesions characterized by a single
      functional ventricle, but it causes a chronically elevated systemic venous
      pressure that may result in hepatic congestion. The objective of this study was
      to characterize hepatic function and its relationship to cardiac function in
      children who had undergone the Fontan procedure. METHODS: In a cross-sectional
      study of 11 children aged 38 months to 216 months (mean, 149 months), the authors
      evaluated indices of cardiac and hepatic function, including galactose clearance,
      Doppler hepatic ultrasonography, synthetic function, and markers of liver injury,
      at 9 months to 176 months (mean, 100 months) after children had undergone the
      Fontan procedure. RESULTS: The most common biochemical abnormality of hepatic
      function was a prolongation of the prothrombin time and a low factor V level.
      There was a trend toward progressive abnormality in prothrombin time with
      increasing interval since the Fontan procedure. Galactose elimination half-life
      and galactose elimination capacity were inversely correlated with the time after
      Fontan (R2= 0.65, P = 0.004). There was no relationship between cardiac
      functional measurements and liver function. CONCLUSIONS: Prothrombin time and
      galactose elimination half-life are abnormal in children who have undergone the
      Fontan procedure and may be useful markers of hepatic function in the
      longitudinal assessment of these patients.

PMID- 12604974
TI  - Body composition and components of energy expenditure in children with end-stage
      liver disease.
AB  - BACKGROUND: Better understanding of body composition and energy metabolism in
      pediatric liver disease may provide a scientific basis for improved medical
      therapy aimed at achieving optimal nutrition, slowing progression to end-stage
      liver disease (ESLD), and improving the outcome of liver transplantation.
      METHODS: Twenty-one children less than 2 years of age with ESLD awaiting liver
      transplantation and 15 healthy, aged-matched controls had body compartment
      analysis using a four compartment model (body cell mass, fat mass, extracellular
      water, and extracellular solids). Subjects also had measurements of resting
      energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry.
      Nine patients and 15 control subjects also had measurements of total energy
      expenditure (TEE) using doubly labelled water. RESULTS: Mean weights and heights
      were similar in the two groups. Compared with control subjects, children with
      ESLD had higher relative mean body cell mass (33 +/- 2% vs 29 +/- 1% of body
      weight, P < 0.05), but had similar fat mass, extracellular water, and
      extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body
      weight respectively). Compared with control subjects, children with ESLD had 27%
      higher mean REE/body weight (0.285 +/- 0.013 vs 0.218. +/- 0.013 mJ/kg/24h, P <
      0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05).
      Mean TEE of patients was 4.70 +/- 0.49 mJ/24h vs 3.19 +/- 0.76 in controls, (P <
      0.01). CONCLUSIONS: In children, ESLD is a hypermetabolic state adversely
      affecting the relationship between metabolic and nonmetabolic body compartments.
      There is increased metabolic activity within the body cell mass with excess lipid
      oxidation during fasting and at rest. These findings have implications for the
      design of appropriate nutritional therapy.

PMID- 12604975
TI  - The utility of ultrasound site selection for pediatric percutaneous liver biopsy.
AB  - BACKGROUND: The site for percutaneous liver biopsy is determined by physical
      examination and anatomic landmarks. The authors compared physical examination
      with ultrasound examination to determine liver location, size, and an optimal
      biopsy site. METHODS: A pediatric gastroenterology fellow or attending
      gastroenterologist initially selected a biopsy site by physical examination. An
      ultrasonographer performed a limited ultrasound examination to evaluate this
      site. RESULTS: Sixty biopsy sites from 58 patients were evaluated. Forty-six
      patients had no previous liver surgery. Two patients had had a Kasai procedure.
      Ten patients had had orthotopic liver transplantation. The mean age of the
      patients was 11.1 +/- 7.6 years. Ultrasonography detected the following potential
      complications of percutaneous biopsy at the site determined by physical
      examination: insufficient liver (7 of 15, 47.0%), diaphragm injury (4 of 15,
      27.0%), bowel perforation (2 of 15, 13.0%), kidney laceration (1 of 15, 7.0%),
      and large blood vessel laceration (1 of 15, 7.0%). These ultrasound findings
      directed a change in biopsy site for 15 (25.0%) physical examination sites. Major
      biopsy complications were rare (1.7%). CONCLUSION: Ultrasound examination
      resulted in a location change to a more optimal site in 25.0% of the sites
      determined by physical examination. Ultrasound determination of the biopsy site
      should be considered before pediatric percutaneous liver biopsy.

PMID- 12604976
TI  - Helicobacter pylori in children and adolescents: increase of primary
      clarithromycin resistance, 1997-2000.
AB  - BACKGROUND: The authors evaluate the prevalence of Helicobacter pylori resistance
      in 117 children and demonstrate the changes over a 4-year period. METHODS: In 117
      children and adolescents, H. pylori-positive gastritis was revealed by diagnostic
      upper endoscopy. Biopsies from the antrum and body of the stomach were tested by
      histology, urease test, and culture. H. pylori was isolated using standard
      culture techniques, and susceptibility to amoxicillin, clarithromycin, and
      metronidazole was tested using the E-test (AB-Biodisk, Sweden). RESULTS:
      Endoscopy revealed gastric ulcers in 2 of 117 subjects, duodenal ulcers in 6 of
      117, and erosive gastritis or duodenitis in 23 of 117. Almost all patients showed
      antral nodularity. Histology always showed chronic gastritis with different
      degrees of activity. During the 4-year study period, the authors noticed an
      increase of primary clarithromycin-resistant H. pylori strains, from 14.3% to
      27.6% (mean, 20.3%). Metronidazole resistance varied between 5% and 25%. No
      resistance to amoxicillin was found. CONCLUSION: Eradication of H. pylori should
      take place only after testing of susceptibility. The general use of
      clarithromycin in children should be restricted to better-defined indications.
      Resistance to clarithromycin of H. pylori may also become a future problem for
      the treatment of adults.

PMID- 12604977
TI  - Urinary NOx:creatinine ratios during gluten challenge in children with celiac
      disease.
AB  - OBJECTIVES: Celiac disease is a gluten-induced small bowel enteropathy.
      Inflammation is known to be associated with enhanced nitric oxide (NO)
      production. An increase in urinary nitrate and nitrite (NOx) reflects increased
      NO production. The urinary NOx:creatinine ratio can be used as an indicator of
      the endogenous NO production. The aim of the study was to determine whether the
      urinary NOx:creatinine ratio of celiac disease patients increases during gluten
      challenge. METHODS: The authors studied 20 patients with unconfirmed celiac
      disease who had been following a gluten-free diet for at least 1 year. These
      patients underwent an 80-day gluten challenge. Urinary samples were obtained
      before and 10, 20, 40, and 80 days after starting the gluten challenge. The
      Griess reagent method was used for measuring urinary NOx. RESULTS: Gluten
      challenge confirmed the diagnosis of celiac disease in 15 of 20 patients. The
      NOx:creatinine ratios (mmol:mmol) of the biopsy-confirmed celiac disease patients
      were significantly higher than those of the unconfirmed celiac disease patients
      (0.67 vs. 0.17 on day 10; 0.78 vs. 0.15 on day 20; 0.85 vs. 0.25 on day 40; and
      0.85 vs. 0.17 on day 80). CONCLUSIONS: Gluten challenge resulted in an increased
      urinary NOx:creatinine ratio in patients with biopsy-confirmed celiac disease.
      The NOx:creatinine ratio could be useful for the serial evaluation of disease
      activity.

PMID- 12604978
TI  - Helicobacter pylori antigens in stool specimens of gastritis children before and
      after treatment.
AB  - BACKGROUND: Various testing methods are successfully applied to the diagnosis of
      Helicobacter pylori infection, but noninvasive techniques are still needed for
      therapeutic monitoring, especially in children. In the search for new noninvasive
      techniques for the diagnosis of H. pylori infection, the authors evaluated an
      enzyme immunoassay for the detection of H. pylori antigen in stool (HpSA).
      METHODS: The authors studied 62 H. pylori-positive children with chronic
      gastritis and 45 control subjects. H. pylori infection was diagnosed using
      cultures and histology of gastric biopsy specimens and a stool antigen test
      before treatment (clarithromycin, amoxicillin, omeprazole for 7 days) and 4 weeks
      to 6 weeks after treatment. RESULTS: Before therapy, antigen in stool was
      detected in 55 of 62 H. pylori-positive patients, which indicates that the
      sensitivity of the HpSA test was 88.7%. Of the 45 control subjects (with negative
      culture and histology results), 43 had negative results for H. pylori in the
      stool test (specificity, 95.5%). After completion of therapy, eradication was
      obtained (and confirmed by culture and histology) in 53 of the 62 H. pylori
      positive children (85.5%). Four weeks to 6 weeks after eradication therapy, the
      sensitivity, specificity, positive predictive value, and negative predictive
      value of the stool antigen (HpSA) test were 88.9%, 96.2%, 80%, and 98%,
      respectively. CONCLUSIONS: The accuracy of the HpSA test for the detection of H.
      pylori in human stool 4 weeks to 6 weeks after treatment is comparable with the
      accuracy of the culture results. The stool antigen (HpSA) test was found to be a
      useful method for posttreatment eradication testing of infection in children.

PMID- 12604979
TI  - Detection of small bolus volumes using multiple intraluminal impedance in preterm
      infants.
AB  - BACKGROUND: Multiple intraluminal impedance (MII) is a new technique that allows
      detection of reflux and swallows via changes in impedance caused by a liquid
      bolus inside the esophagus. The method is independent of pH. The authors studied
      the ability of this technique to detect the small bolus volumes potentially
      occurring in young infants. METHODS: Ten preterm infants (median gestational age
      at birth, 33 weeks; range, 25-36 weeks; age at study, 9 days; range, 2-39 days)
      underwent 10 instillations each of 0.1 mL to 0.5 mL saline while MII was recorded
      via a 2.4-mm nasogastric catheter. MII signals were analyzed for swallows,
      defined as a decrease in impedance starting within 1 minute. From the liquid
      instillation in the most proximal channel and extending downward, impedance
      changes during these induced swallows were compared with those occurring during
      spontaneous swallows. RESULTS: All 100 liquid instillations resulted in a typical
      impedance pattern, occurring after a median interval of 4.4 seconds (range, 1.8
      8.9 seconds). The decrease in impedance was more pronounced than after
      spontaneous swallows (30% vs. 24%, P < 0.03) and extended downward more rapidly
      (12.3 cm/s vs. 5.8 cm/s, P < 0.01). CONCLUSION: Bolus transport of small liquid
      volumes can be detected via MII.

PMID- 12604980
TI  - Lactobacillus plantarum inhibits the intestinal epithelial migration of
      neutrophils induced by enteropathogenic Escherichia coli.
AB  - BACKGROUND: Lactobacillus plantarum is a Gram-positive bacillus known for its
      effect as a probiotic agent. The goal of the study was to determine whether L.
      plantarum is capable of inhibiting the transepithelial neutrophil migration
      induced by enteropathogenic Escherichia coli (EPEC). METHODS: Cultured intestinal
      epithelial T-84 cell monolayers were rapidly infected with EPEC. L. plantarum or
      culture supernatants were added to the monolayers before and after the infection.
      Indium-labeled neutrophils were added to the basolateral side of inverted
      monolayers. After 150-minute incubation, radioactivity of the neutrophils that
      migrated in the physiologic direction was assayed, and the number of migrating
      neutrophils was calculated. L. plantarum was also added to the monolayers before
      and after EPEC infection, and the number of adherent EPEC was determined by plate
      counting. RESULTS: EPEC-induced neutrophil migration and EPEC binding to
      monolayers were inhibited by viable L. plantarum but only when added to the
      monolayers before EPEC. Culture supernatants failed to inhibit the neutrophil
      migration. CONCLUSIONS: These results suggest that L. plantarum is beneficial in
      inhibiting neutrophil migration induced by EPEC, but only when preincubated with
      host epithelia. Rather than an indirect effect through a secreted substance
      produced by the probiotic agent, its effect is direct and requires the presence
      of the bacterium.

PMID- 12604981
TI  - Low fecal elastase: potentially related to transient small bowel damage resulting
      from enteric pathogens.
AB  - Fecal elastase is considered to be a highly sensitive and specific non-invasive
      exocrine pancreatic function test. However, enteropathy may theoretically cause
      decreased exocrine pancreatic enzyme secretion through alteration of enteric
      hormone release. OBJECTIVE: The aim of this study was to evaluate the possible
      influence of transient small bowel damage on pancreatic elastase secretion.
      METHODS: We studied 166 children (aged 4 months to 14 years, mean 2 years); 114
      of these children had acute enteritis and 52 children were control subjects (with
      gastro-intestinal symptoms or extra-intestinal diseases). Feces were collected
      from each patient 3 days after the onset of diarrhea and then tested for fecal
      elastase, bacterial pathogens, Rotavirus, and Adenovirus. Liquid fecal samples
      were not considered eligible for elastase measurement. Pancreatic elastase was
      measured using an ELISA method (Sche.Bo.Tech, Germany). We classified the
      results, expressed in microg/g stool, as: severe pancreatic insufficiency (<100
      microg/g), moderate pancreatic insufficiency (100 to 200 microg/g), and normal
      (>200 microg/g). RESULTS: In the acute enteritis group we found severe levels in
      14 (12%) children, moderate levels in 18 children (16%), and normal levels in 82
      children (72%). In contrast, 52 of 52 (100%) control subjects demonstrated normal
      results. Statistical analysis (Wilcoxon rank test) demonstrated a significant
      difference between the enteritis and control groups (P < 0.01). Serial
      measurement of fecal elastase performed in 10 patients with enteritis showed a
      progressive increase of levels in 6 patients and an early decline with subsequent
      increases in the other 4 patients. CONCLUSIONS: Transient exocrine pancreatic
      insufficiency may be present in transient small bowel disease, caused by both
      bacterial and viral infections, possibly related to reduced enteric CCK
      secretion.

PMID- 12604982
TI  - Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight
      neonates.
AB  - BACKGROUND: Colonization patterns, especially by anaerobic flora, may play an
      important role in neonatal gut function. Probiotics could affect disease risk
      either directly through colonization or indirectly by promoting changes in gut
      microbial ecology. METHODS: To study the ability of Lactobacillus GG(LGG) to
      colonize the neonatal gut and modify its microbial ecology, a prospective,
      randomized study was performed in 71 preterm infants of less than 2000 g birth
      weight. Infants less than 1500 g (24 treated, 15 control) received 10(9) LGG
      orally twice daily for 21 days. Those infants weighing 1500 to 1999 g (23
      treated, 9 control) were treated for 8 days. Stools were collected before
      treatment and on day 7 to 8 (and day 14 and 21, in the infants weighing less than
      1500 g) for quantitative aerobic and anaerobic cultures. RESULTS: Colonization
      with LGG occurred in 5 of 24 (21%) infants who weighed less than 1500 g versus 11
      of 23 (47%) in larger infants. Colonization was limited to infants who were not
      on antibiotics within 7 days of treatment with LGG. There was a paucity of
      bacterial species at baseline, although larger infants had more bacterial species
      (1.59 +/- 0.13 (SEM) vs 1.11 +/- 0.12; P < 0.03) and higher mean log colony
      forming units (CFU) (8.79 +/- 0.43 vs 7.22 +/- 0.63; P < 0.05) compared with
      infants weighing less than 1500 g LGG. Treatment in infants weighing less than
      1500 g resulted in a significant increase in species number by day 7, with
      further increases by day 21. This increase was mainly the result of increased
      Gram (+) and anaerobic species. No difference in species number was noted in
      controls. Mean log CFU of Gram (-) bacteria did not change in treated infants
      weighing less than 1500 g. However, Gram (+) mean log CFU showed a significant
      increase on day 21 (6.1 +/- 0.9) compared with day 0 (3.5 +/- 0.9) (P < 0.05). No
      significant changes in species number or quantitative counts were noted after LGG
      treatment in the infants weighing 1500 to 1999 g LGG was well tolerated in all
      infants. CONCLUSION: The neonatal response to a probiotic preparation is
      dependent on gestational and post-natal age and prior antibiotic exposure.
      Although LGG is a relatively poor colonizer in infants, especially those infants
      weighing less than 1500 g at birth, it does appear to affect neonatal intestinal
      colonization patterns.

PMID- 12604983
TI  - Anorectal strictures and genital Crohn disease: an unusual clinical association.

PMID- 12604984
TI  - Helicobacter heilmannii gastritis caused by cat to child transmission.

PMID- 12604985
TI  - Helicobacter heilmannii related gastric ulcer in childhood.

PMID- 12604987
TI  - Antireflux or antiregurgitation milk products.

PMID- 12604986
TI  - The unique occurrence of hepatic failure from type 1 autoimmune hepatitis with
      concurrent brain abscess.

PMID- 12604988
TI  - Maternal viral load and hepatitis C virus vertical transmission.

PMID- 12604989
TI  - Endogenous ethanol production in a child with short gut syndrome.

PMID- 12604990
TI  - A comparison of respiratory symptoms and inflammation in sudden infant death
      syndrome and in accidental or inflicted infant death.
AB  - Upper respiratory infection and pulmonary inflammation are common in sudden
      infant death syndrome, but their role in the cause of death remains
      controversial. Controlled studies comparing clinical upper respiratory infection
      and inflammation in sudden infant death syndrome with sudden infant deaths caused
      by accidents and inflicted injuries (controls) are unavailable. Our aim was to
      compare respiratory inflammation and upper respiratory infection within 48 hours
      of death and postmortem culture results in these two groups. A retrospective
      analysis of upper respiratory infection and pathologic variables in the trachea
      and lung of 155 infants dying of sudden infant death syndrome and 33 control
      infants was undertaken. Upper respiratory infection was present in 39% of sudden
      infant death syndrome cases and 40% of control cases. Upper respiratory infection
      was more likely to have occurred in association with more severe lymphocytic
      interstitial pneumonitis when sudden infant death syndrome cases and control
      cases were combined ( P=.04). Proximal and distal tracheal lymphocytic
      infiltration was more severe in control cases than in sudden infant death
      syndrome cases ( P=.01 and.01, respectively). Lymphocytic infiltrations of the
      bronchi, bronchioles, and pulmonary interstitium were similar between groups.
      Bronchial associated lymphoid tissue was more prominent in control cases (
      P=.04). Cultures were positive in 80% of sudden infant death syndrome cases, 78%
      of which were polymicrobial. Among control cases, 89% were positive, with 94%
      being polymicrobial. This study confirms that microscopic inflammatory
      infiltrates in sudden infant death syndrome are not lethal.

PMID- 12604991
TI  - Pathology of sudden death during recreational sports activity: an autopsy study
      of 31 cases.
AB  - A growing number of people are involved in recreational physical activity. It is
      therefore not uncommon for a medical examiner to encounter sports-related sudden
      deaths and to be faced with the legal implications. The authors examined the
      clinical and cardiac pathologic patterns in 31 persons who died suddenly during
      sports activities and underwent autopsy at the Institute of Forensic Medicine of
      Paris between 1991 and 2001. Twenty-nine male subjects, ranging in age from 7 to
      57 years (mean 30 years) and two female subjects, 8 and 60 years old, died
      suddenly during sports activities. The sports involved were various, with running
      the most frequent: 13 cases. Cardiomyopathies (10 cases) and coronary artery
      disease (9 cases) were the most frequent causes of deaths. Despite the severity
      of lesions, only 4 subjects had a known cardiovascular disease. In conclusion,
      with regard to prevention, efforts should be continued to improve the sensitivity
      and specificity of diagnostic tools and screening strategies. In this regard,
      medicolegal autopsies should be systematically performed in cases of sudden death
      during sports activities, because they provide accurate and useful information
      for a better knowledge of sports-related mortality.

PMID- 12604993
TI  - New horizons in forensic radiology: the 60-second digital autopsy-full-body
      examination of a gunshot victim by multislice computed tomography.
AB  - The goal of this study was the full-body documentation of a gunshot wound victim
      with multislice helical computed tomography for subsequent comparison with the
      findings of the standard forensic autopsy. Complete volume data of the head,
      neck, and trunk were acquired by use of two acquisitions of less than 1 minute of
      total scanning time. Subsequent two-dimensional multiplanar reformations and
      three-dimensional shaded surface display reconstructions helped document the
      gunshot-created skull fractures and brain injuries, including the wound track,
      and the intracerebral bone fragments. Computed tomography also demonstrated
      intracardiac air embolism and pulmonary aspiration of blood resulting from bullet
      wound-related trauma. The "digital autopsy," even when postprocessing time was
      added, was more rapid than the classic forensic autopsy and, based on the
      nondestructive approach, offered certain advantages in comparison with the
      forensic autopsy.

PMID- 12604992
TI  - Death by obstruction: sudden death resulting from impromptu ingestion of drugs.
AB  - Over an 18-month period, the department of Forensic Medicine and Science at the
      University of Glasgow investigated four rather unusual drug-related deaths. In
      all cases, death was due to the obstruction of the airway by a foreign body after
      an attempt to evade arrest. In all cases, the obstruction was drug packages of
      various shapes and sizes. Results of toxicology revealed levels of drugs that may
      have had a significant respiratory effect on the deceased in three of the cases.
      Rupturing of the packages and hence leakage of drugs being conducive to death was
      obvious in only one case.

PMID- 12604994
TI  - Diagnosis of sudden unexplained death in epilepsy by immunohistochemical staining
      for prolactin in cerebral vessels.
AB  - Sudden unexplained death in epilepsy occurs when epilepsy patients die suddenly
      and unexpectedly in the absence of recent tonic-clonic seizure activity. There is
      currently no known reliable indicator of acutely lethal seizure activity.
      Clinical studies record a relationship between recent (within 10-40 minutes)
      seizure activity and elevated serum prolactin levels, and postictal elevation of
      prolactin within peripheral vessels has proved clinically useful in determining
      recent seizure activity. The authors hypothesized that elevated prolactin could
      be detected in cerebral vessels by immunohistochemical stains, serving as a
      marker for sudden unexplained death in epilepsy. They conducted a retrospective
      study of individuals who died in their jurisdiction during the 14 years from 1986
      through 1999. The study contained one group of individuals who died of sudden
      unexplained death in epilepsy, a group with epilepsy who died of some other
      cause, and a control group whose members died rapidly of a gunshot wound of the
      torso. Sections of hippocampus and neocortex were obtained and stained with a
      polyclonal prolactin antibody. No significant difference in the level of
      immunostaining for prolactin in cerebral vessels was found between the
      experimental and control groups. A review of the protocols used indicates that
      revision of certain aspects may provide better immunostaining and more conclusive
      results.

PMID- 12604995
TI  - Rapidly growing internal carotid artery aneurysm after amphetamine abuse: case
      report.
AB  - Amphetamine is one of the most common illicitly abused drugs in certain
      countries. It is a potent sympathomimetic that may lead to vascular events,
      including stroke and myocardial infarction. Most reports of stroke after
      amphetamine abuse are of intracerebral hemorrhage. In this report, the authors
      describe a ruptured aneurysm of the right internal carotid artery in a young man
      with amphetamine abuse. It grew rapidly within 2 weeks. Surgery revealed fibrosis
      and fibrinoid necrosis around the aneurysm. The aneurysm was successfully
      embolized with Guglielmi detachable coil. A rapidly growing aneurysm in the major
      intracranial vessels resulting from amphetamine abuse is very rare.

PMID- 12604997
TI  - Fatal Waterhouse-Friderichsen syndrome due to Ewingella americana infection.
AB  - A fatal case of Waterhouse-Friderichsen syndrome resulting from infection in a
      previously healthy 74-year-old woman is reported. The patient died suddenly
      within 14 hours after presentation. The diagnosis of Waterhouse-Friderichsen
      syndrome as the cause of death was established post mortem based on autopsy
      findings, microscopic examination, measurement of serum procalcitonin
      concentration (113 ng/ml), and outcome of postmortem bacteriologic cultures that
      grew in heart and spleen blood samples. Since the introduction of as a new group
      in the family in 1983, more recent case studies have established its clinical
      significance and pathogenic potential to cause severe, life-threatening
      bacteremia and sepsis. is a rare pathogen that should be added to the list of
      unusual bacteria causing Waterhouse-Friderichsen syndrome.

PMID- 12604996
TI  - A method for exposing the intraosseous portion of the carotid arteries and its
      application to forensic case work.
AB  - A method that allows extraction of the intraosseous portion of the carotid
      arteries is presented, along with four cases to illustrate its application to
      forensic case work. The method described permits a cosmetically acceptable
      reconstruction.

PMID- 12604998
TI  - Kawasaki disease: a review of pathologic features of stage IV disease and two
      cases of sudden death among asymptotic young adults.
AB  - Kawasaki disease (KD) primarily affects infants and is rarely fatal in young
      adults. The sequelae of KD can result in death months to years after the exposure
      to the causative agent. Such deaths are defined as Stage IV KD, which is
      characterized by the formation of multiple aneurysms in the coronary arteries,
      calcification and recanalization of the obstructed portions of the coronary
      arteries, and myocardial infarction and ischemia. A 10-year retrospective review
      of sudden deaths in Allegheny County, Pennsylvania, identified two fatal cases of
      Stage IV KD involving young adults. These two young adults were healthy and
      completely asymptomatic; they had no identifiable risk factors for cardiovascular
      disease before the fatal event. One adult was involved in vigorous exercise, and
      the other was recumbent in bed at the time of death.

PMID- 12604999
TI  - A variant of incaprettamento (ritual ligature strangulation) in East Timor.
AB  - Incaprettamento is a ritualized form of ligature strangulation often associated
      with the Italian Mafia. The hallmarks include ligature strangulation and binding
      of the body in a highly stereotyped fashion. The bindings include tying the
      wrists and ankles together, with the body in the prone position (similar to
      "hogtying"), and an additional ligature encircling the neck and attached to the
      bindings of the extremities. The binding of the body may be performed after death
      is inflicted by ligature strangulation, or it may be associated with self
      strangulation, as shown by the arrangement of ligatures and the position of the
      body. A case with great similarities to incaprettamento, in which the body was
      exhumed from a grave in East Timor, is described in detail. However, in addition
      to prone-position binding and a hyoid fracture, chopping wounds of a knee and
      blunt trauma to the posterior torso were found. The implication of these wounds
      is discussed in relation to incaprettamento.

PMID- 12605000
TI  - Pathologic features of suicidal deaths caused by explosives.
AB  - Suicidal explosions that lack a terrorist background are only rarely encountered
      in the field of forensic pathology. The investigation of explosion-related
      fatalities can be a substantial challenge in medicolegal casework. Determining
      whether the manner of death is suicide, homicide, or accident in such cases can
      present an especially difficult task to the forensic pathologist. This study
      considers the pathologic features of suicidal deaths caused by explosives without
      a terrorist background. The modus operandi of the decedents reflected familiarity
      and proficiency, or at least a degree of specialized knowledge, with the
      construction and use of explosive devices. All explosions were set off in
      confined spaces. The injury patterns consisted of a combination of primary blast
      injuries (e.g. decapitation, traumatic amputation of limbs, gross lacerations of
      the body surface, blast injuries of gas-containing and hollow organs), secondary
      blast injuries (e.g. splinter-induced penetrating trauma), tertiary blast
      injuries (e.g. abrasions and contusions), and burn injuries (mostly of the flash
      type). The previously described symmetric distribution pattern of injuries in
      suicidal explosions was apparent only to a certain degree in the present series.
      Our observation of superficially sharp-edged wound margins with bridging in the
      depths of the lesion in blast-induced lacerations of the skin should deserve
      further attention in forthcoming cases of explosion-related fatalities because
      this finding is a diagnostic possibility that may support the theory of an
      explosion-related fatality under special circumstances, e.g. when the body has
      been dumped away from the place of death. Because a terrorist attack may be
      initially suspected in each case of suicide involving explosives, the importance
      of a joint inquiry based on expertise from police investigators, bomb experts,
      and forensic pathologists is evident.

PMID- 12605001
TI  - Infanticide in Malaysia: two case reports and a review of literature.
AB  - In a strict and conservative society like Malaysia, the number of cases of
      infanticide has continued to occur. The authors present two typical cases of
      infanticide in Malaysia. Case 1 concerned a body of a fully mature newborn fetus
      disposed in a rubbish bin. The head was traumatically amputated by the rubbish
      truck's compactor. The umbilical cord was still attached to the body, with no
      reddening around the insertion. The severed neck showed features consistent with
      post-mortem amputation. The significant finding was expanded crepitant lungs,
      which floated in water. The histology of the lungs showed expanded alveoli. It
      was concluded that the baby had been born alive, but no cause of death could be
      elicited. Case 2 concerned a decomposed mature newborn found in a scrub forest.
      The internal organs showed advanced putrefaction, the lungs being collapsed,
      congested, and hemorrhagic, typical of decomposed lungs. No conclusion could be
      made about the state of birth or the cause of death because of the putrefied
      state of the body. The two cases illustrate the typical cases and problems faced
      by pathologists locally and probably elsewhere in the world. Most of the bodies
      are found in a putrefied state. Pathologists have to ascertain not only maturity
      and live birth but also the cause of death, which may be very subtle or masked by
      putrefaction. The problems of diagnosis of live birth are discussed.

PMID- 12605003
TI  - Medical aspects of malpractice crisis in Greece: medical responsibility: a
      doctor's view.
AB  - Malpractice and medical liability have been introduced into Greek reality over
      the last decade. Forensic sciences hold a key role in the investigation of
      medical liability cases. Along these lines, the medical examiner stands between
      colleagues and lawyers, who have divergent intentions in the investigation of
      such cases. This article offers an overview of the rapidly changing reality in
      Greece and approaches medical liability from the doctor's viewpoint. The role of
      forensic science and the medical examiner is portrayed, along with the emerging
      difficulties in the investigation of medical liability cases. Also attempted is
      an interpretation of the crisis phenomena that are very often seen between
      doctors and lawyers. However, the intent of this article is to search for ways to
      turn competition and tension between medical and law professionals into
      cooperation and understanding for the best interest for both professions and,
      more importantly, for the community.

PMID- 12605002
TI  - DNA typing revealing high HLA-Cw polymorphism completes availability of major
      histocompatibility complex loci in forensic medicine.
AB  - Studies of human population genetics in Hungary have revealed relevant
      heterogeneity in the major histocompatibility complex. In the present studies,
      two isolated ethnic groups were chosen: people living in the Kali Basin westward
      from the Danube River, and those living in Opusztaszer, a village eastward from
      Danube, who are known as native ancient Hungarians. Blood samples were collected
      from 70 people in the Kali Basin and from 45 people in Opusztaszer. The frequency
      of HLA-Cw alleles was determined by serology as well as by DNA typing in 46 and
      32 samples of the two populations, respectively, and in 44 randomly selected
      subjects of Hungarian origin. Compared with a random population of cadaver donors
      (the deaths having resulted mostly from accidents or, in a smaller number,
      strokes or heart infarcts) and voluntary bone marrow donors (typed in the last 10
      years) recruited from all parts of Hungary and representing the mixed Hungarian
      population, remarkable differences were found in haplotype and allele
      frequencies. HLA-A, -B, -Cw typing was performed by serology and, in the case of
      the HLA-Cw locus, by polymerase chain reaction (PCR)-SSP and/or PCR-SSOP
      techniques, as well. The PCR-SSO oligotyping procedure allowed the identification
      of 32 Cw alleles in contrast with the 9 serologically detectable types. Because
      of the combination of low antigen expression and the lack of specific serologic
      reagents of good quality, no HLA-Cw antigens were detectable in 41%, and only one
      was detected in 48%, of the investigated individuals by standard serologic
      typing. With PCR-SSO typing, however, 97% of the investigated individuals proved
      to be heterozygous for HLA-Cw alleles. The two isolated populations differed from
      each other, from mixed Hungarian and other Caucasian populations in HLA-Cw*
      allele frequencies, as well as in haplotype distribution. This newly recognized
      polymorphism at the HLA-Cw locus completes the availability of major
      histocompatibility complex typing in forensic science and practice.

PMID- 12605005
TI  - Sudden death in a 35-year-old man with occult malformation of the brain and
      aseptic meningitis.
AB  - A 35-year-old man was found dead by his wife. He was reported to have had
      symptoms of a common cold the week preceding his death. The medicolegal autopsy
      yielded signs of central dysregulation (ectasia of the urinary bladder and
      rectum, dystelectasis of the lungs) together with marked brain edema and fresh
      bite marks on the tongue. The cause of death was presumed to be lethal epileptic
      seizure. Neuropathologic examination revealed neuronal nodular heterotopia as
      well as discrete lymphocytic meningitis (aseptic meningitis). The death was most
      probably caused by the combination of the meningitis with the occult
      malformation, leading to a lowered seizure threshold and subsequent lethal
      seizure. The morphologic findings of this case are presented, and the probable
      mechanisms of death are discussed.

PMID- 12605004
TI  - Fatal aortic injury during laparoscopy: report of two cases.
AB  - The authors report the cases of two young women who died of massive hemorrhage
      resulting from trocar aortic injuries during abdominal laparoscopy. In the first
      case, wherein the patient underwent laparoscopy for cecopexy, the forensic
      autopsy showed a through-and-through perforation of the abdominal aorta and of
      the ileum. The other woman, who had morbid obesity, underwent a laparoscopy for
      gastroplasty. In this second case, the main postmortem findings were stab wounds
      of the thoracic aorta and of the diaphragm.

PMID- 12605007
TI  - Accidental electrocution during autoeroticism: a shocking case.
AB  - A case of atypical autoerotic death is described. An 18-year-old white man clad
      in two brassieres was found dead in his bedroom by his brother. Two wet green
      terry cloths were under the brassiere cups, connected to the house current via
      two metal washers and a bifid electrical cord. Literature depicting nude women
      was found near the victim. Autopsy revealed second-degree and third-degree burns
      of the mammary regions. Death was attributed to accidental self-electrocution.
      The authors will discuss typical and atypical forms of autoerotic death.

PMID- 12605006
TI  - The use of pulmonary interstitial emphysema as an indicator of live birth.
AB  - Making the determination of live birth versus stillbirth in a discarded newborn
      infant based on gross and microscopic autopsy findings can be a challenging task
      for the forensic pathologist. The traditional criteria for live birth
      determination are frequently challenged in court, and indisputable evidence of
      live birth remains elusive. The histologic finding of pulmonary interstitial
      emphysema has not been considered as a useful determinant of live birth. The
      authors report two cases of discarded newborn infants in which the finding of
      pulmonary interstitial emphysema was used as an indicator of live birth.

PMID- 12605008
TI  - Age estimation using radiographic analysis of laryngeal cartilage.
AB  - The laryngeal cartilages undergo age changes, including mineralization and
      ossification. Keen and Wainwright defined, in male and female subjects,
      recognizable stages of radiopacity of the thyroid, cricoid, and arytenoid
      cartilages. The present study analyzed quantitatively the degree of laryngeal
      radiopacity to determine whether radiography of the larynx can be used routinely
      in forensic pathology to estimate age at death. In each of 82 subjects, the
      larynx was removed during forensic autopsy and subjected to radiography in an
      anteroposterior orientation. Each radiograph was independently scored by two
      observers. For each case, the degree of laryngeal radiopacity was evaluated
      according to the classification of Keen and Wainwright. There was a positive
      correlation between the total score of laryngeal radiopacity and age (correlation
      coefficient = 0.74). It was concluded that this method is simple, fast, and
      nondestructive and has a good reproducibility between observers. Because there
      was a wide interindividual variability in the same age class, this method must be
      associated with more accurate methods.

PMID- 12605009
TI  - Medical advances in transsexualism and the legal implications.
AB  - Transsexualism is a condition wherein an individual's psychological gender is the
      opposite of his or her anatomic sex. The general belief now among behavioral
      scientists and physicians is that it is an identifiable and incapacitating
      disease, which can be diagnosed and successfully treated by reassignment surgery
      in carefully selected patients. Although many advances have been made in the
      reassignment surgery techniques, phalloplasty still remains a major challenge; to
      date, no ideal technique has been developed. The new gender created by the
      reassignment surgery has, in turn, led to many legal complications for
      postoperative transsexuals because states and the judiciary have not recognized
      the new gender. However, with wider acceptance of transsexuals by society, this
      outlook has changed for the better, with many states amending their laws in
      accordance with the advances in medical sciences. But in many developed and the
      developing countries, transsexuals are not given a legal identity, thereby adding
      to their agonies and miseries.

PMID- 12605010
TI  - Sudden infant death due to pulmonary embolism.

PMID- 12605011
TI  - Cardiac beta-adrenoceptor changes in monocrotaline-treated rats: differences
      between membrane preparations from whole ventricles and isolated ventricular
      cardiomyocytes.
AB  - In monocrotaline (MCT)-treated rats the beta-adrenoceptor-G-protein-adenylyl
      cyclase system-determined in crude membrane preparations from whole ventricular
      tissue-was desensitized not only in right (RV) but also in left ventricles (LV).
      This study aimed to assess the specific contribution of cardiomyocytes to these
      beta-adrenoceptor changes. Six-week-old male Wistar rats were treated with 60
      mg/kg body weight MCT intraperitoneally; within 4-6 weeks, rats developed marked
      RV hypertrophy. Cardiomyocytes were isolated from RVs and LVs. In RV
      cardiomyocytes of MCT-treated rats, beta-adrenoceptor density was significantly
      reduced whereas it was unaltered in LV cardiomyocytes. Reduction of RV
      cardiomyocyte beta-adrenoceptors was due to a selective beta(1)-adrenoceptor
      reduction. Isoprenaline (100 microM)-induced cAMP increase was significantly
      reduced in RV but not in LV cardiomyocytes of MCT-treated rats. G protein-coupled
      receptor kinase activity was increased in RV but not in LV cardiomyocytes.
      alpha(1)-Adrenoceptor density and noradrenaline-induced increase in inositol
      phosphate formation were significantly reduced only in RV but not in LV
      cardiomyocytes from MCT-treated rats. It is concluded that in cardiomyocytes of
      MCT-treated rats, cardiac beta-adrenoceptors and alpha -adrenoceptors are chamber
      specifically desensitized only in the RV. Thus, changes in cardiac beta
      adrenoceptors determined in membrane preparations from whole tissue homogenates
      do not correctly reflect changes occurring in cardiomyocytes.

PMID- 12605012
TI  - Neurokinins induce relaxation of human pulmonary vessels through stimulation of
      endothelial NK1 receptors.
AB  - The effects of neurokinins and neurokinin receptor selective agonists have been
      investigated on human intralobar pulmonary vessels. Substance P (SP) and [Sar(9)
      Met(O(2)) ]SP(11), a selective NK(1) receptor agonist, induced concentration
      dependent relaxation of pulmonary vessels precontracted with phenylephrine. The
      mean negative log (M) EC (50) values for SP and [Sar (9) Met(O2))]SP(11) were 8.6
      and 8.9, respectively, on arterial preparations and 8.9 and 8.6, respectively, on
      venous preparations. Relaxations to [Sar(9) Met(O(2) ) ]SP were abolished by the
      NK receptor antagonist SR140333. The relaxations to a second application of
      [Sar(9) Met(O (2)) ]SP were markedly reduced, suggesting a rapid desensitization
      of the NK(1) receptor. Such desensitization was not observed with acetylcholine.
      The selective NK receptor agonist, [Nle(10)]NKA, and the selective NK (3)
      receptor agonist, [MePhe(7)]NKB, caused neither contractions nor relaxations of
      pulmonary vessels. The NK(1) receptor-mediated relaxations were abolished by
      removing the endothelium or by a combination of -nitro-L-arginine and
      indomethacin, whereas each compound exerted a partial inhibitory effect. Similar
      results were observed with acetylcholine. Positive immunostaining for NK(1)
      receptors was only found in the endothelium. Reverse transcription-polymerase
      chain reaction detected messenger RNA for NK(1) receptors without any detection
      of messenger RNA for NK(2) or NK(3) receptors. In conclusion, human pulmonary
      arteries and veins express endothelial NK(1) receptors that mediate relaxation
      through a combination of cyclooxygenase and nitric oxide activities and are
      subjected to rapid tachyphylaxis.

PMID- 12605013
TI  - Decreased facilitation by angiotensin II of noradrenergic neurotransmission in
      isolated mesenteric artery of rabbits with chronic heart failure.
AB  - Both in human and in experimental heart failure (HF), the renin-angiotensin
      system and the sympathetic nervous system are activated. In a previous study a
      facilitatory action of angiotensin II (Ang II) was shown in the rabbit mesenteric
      artery, which was mediated via prejunctionally located Ang II type 1 (AT )
      receptors. Very little is known about the effects of Ang II on sympathetic
      neurotransmission at the peripheral level in congestive heart failure (CFH).
      Accordingly, in the isolated mesenteric arteries obtained from rabbits with
      experimentally induced CHF, as well as in age-matched control rabbits, the effect
      of Ang II on contractions provoked by electrical field stimulation was
      investigated in the presence and absence of the AT receptor antagonist
      eprosartan. Additionally, to investigate a possible postjunctional facilitation,
      the effects of Ang II on alpha-adrenoceptor-mediated responses were studied using
      noradrenaline (NA). Lastly, the vasoconstrictor effects of Ang II were compared
      between HF rabbits and controls, by constructing concentration-response curves to
      Ang II. In control rabbits, Ang II 0.5 n caused an enhancement of stimulation
      induced responses by a factor 3.2 +/- 0.5, 2.4 +/- 0.3, and 1.5 +/- 0.08, at 1,
      2, and 4 Hz, respectively ( < 0.05 at all frequencies compared with vehicle). In
      rabbits with HF, the enhancement by Ang II (0.5 n ) amounted to a factor 2.1 +/-
      0.2, 1.7 +/- 0.1, and 1.2 +/- 0.04, at 1, 2, and 4 Hz, respectively ( < 0.05
      compared with vehicle at all frequencies). Accordingly, the enhancing effect of
      Ang II was more pronounced in the control group compared with rabbits with HF ( <
      0.05 at each frequency). Eprosartan (1 nM -0.1 microM) could inhibit the
      facilitatory effects of Ang II in arteries from HF as well as from control
      rabbits. Contractile responses to exogenous NA (3 n -0.1 m ) were the same in HF
      rabbits and controls, and they were unaltered in the presence of Ang II 0.5 n Ang
      II (0.1 nM -1 microM) caused a concentration-dependent increase in contractile
      force, which was the same in HF rabbits and controls. From these findings it can
      be concluded that in rabbits with CHF as well as in control animals, Ang II
      facilitates the stimulation-induced vasoconstrictor responses via prejunctionally
      located AT receptors. The facilitating effect was decreased in vessels obtained
      from rabbits with CHF, whereas responses to exogenous Ang II were unchanged.
      These findings may be explained by downregulation or uncoupling of the
      prejunctional AT receptor.

PMID- 12605014
TI  - Comparison of shear stress-induced platelet microparticle formation and
      phosphatidylserine expression in presence of alphaIIbbeta3 antagonists.
AB  - The use of platelet glycoprotein IIb-IIIa (alphaIIbbeta3) antagonists is an
      accepted practice in the treatment of acute coronary syndromes. Recent studies
      have demonstrated that alpha beta receptor antagonists are effective in
      inhibiting the procoagulant activity of platelets under static conditions. No
      investigation, however, has compared the ability of these platelet antagonists to
      inhibit platelet procoagulant activity, defined as an increase in
      phosphatidylserine (PS) expression, under conditions of shear stress. Thus, the
      goal of this study was to quantify the amount of microparticle formation and PS
      expression of platelets exposed to physiologic and pathophysiologic levels of
      shear stress in the absence and presence of three clinically approved parenteral
      alpha beta antagonists (abciximab, eptifibatide, and tirofiban). Flow cytometric
      results demonstrated that although microparticle formation was significantly
      inhibited by all three antagonists, PS expression by sheared platelets was
      affected differently depending on the antagonist present. Specifically, abciximab
      suppressed PS expression compared with the saline control; both abciximab and
      eptifibatide significantly reduced PS expression compared with tirofiban; and
      tirofiban potentiated PS expression relative to the saline control at the highest
      shear stress. This is the first demonstration of differential regulation of
      platelet PS expression and, by inference, procoagulant activity in the presence
      of alpha receptor antagonists under shear stress. The current results may have
      future importance in improving the design of platelet antagonists as well as
      defining the general role of fluid shear stress in platelet thrombus formation.

PMID- 12605015
TI  - Propagermanium suppresses macrophage-mediated formation of coronary
      arteriosclerotic lesions in pigs in vivo.
AB  - Although the importance of monocytes/macrophages in the pathogenesis of
      arteriosclerosis is widely accepted, effective and safe treatment to inhibit
      those inflammatory cells remains to be developed. It was recently found that
      propagermanium, which is clinically used for the treatment of chronic hepatitis
      type B in Japan, markedly suppresses monocyte chemotaxis in response to
      macrophage chemoattractant protein-1 (MCP-1) through inhibition of its receptor,
      C-C chemokine receptor 2, in vitro. This prompted examination of whether
      propagermanium suppresses the macrophage-mediated formation of coronary
      arteriosclerotic lesions in our porcine model in vivo. It was first confirmed
      that propagermanium inhibited the migration of porcine monocytes in response to
      MCP-1 at therapeutic concentrations in vitro. Pigs were randomly divided into two
      groups; one group was orally treated with propagermanium (1 mg/kg, three
      times/day) and another group served as a control (n = 6 each). Porcine coronary
      segment was treated from the adventitia with MCP-1 and oxidized low-density
      lipoprotein for 2 weeks. In the control group, this treatment resulted in the
      development of stenotic coronary lesions with hyperconstrictive responses to
      serotonin where arteriosclerotic lesions (neointimal formation and constrictive
      remodeling) were developed. Immunohistochemical analysis demonstrated the
      macrophage accumulation in the adventitia and the media. By contrast, in the
      propagermanium group, angiographic coronary stenosis, hyperconstrictive
      responses, histologic changes, and macrophage accumulation were all significantly
      suppressed. These results indicate that propagermanium suppresses macrophage
      mediated formation of coronary arteriosclerotic lesions in vivo, suggesting its
      potential usefulness for the treatment of arteriosclerotic vascular diseases.

PMID- 12605016
TI  - Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth
      muscle cells.
AB  - In order to investigate the signal transduction mechanisms of lysophosphatidic
      acid (LPA)-induced vascular smooth muscle (VSM) DNA synthesis, rat aortic A10
      cells were used as an experimental model and [ H]-thymidine incorporation was
      used as an index of DNA synthesis. LPA caused dose- and time-dependent increase
      in DNA synthesis in A10 VSM cells. LPA (10 microM) also stimulated the activity
      of casein kinase II (CKII) in a time-dependent manner. The inhibitors of CKII,
      daidzein and 5,6-dichlorobenzimidazole riboside, diminished the LPA-induced
      increase in CKII activity and DNA synthesis. The LPA-stimulated activities of
      extracellularly regulated kinases (ERK) and p38 kinases as well as the
      stimulatory effects of LPA on DNA synthesis were blocked by ERK inhibitor,
      PD98059, and p38 kinase inhibitor, SB203580. The LPA-induced increase in
      intracellular free Ca and the LPA-induced DNA synthesis were not affected by Ca
      channel blockers, verapamil and diltiazem, as well as a Ca -dependent protein
      phosphatase (calcineurin) inhibitor, cyclosporine A. These data suggest that the
      LPA-induced DNA synthesis in VSM cells may be mediated by a signal transduction
      mechanism involving CKII, ERK, and p38 K.

PMID- 12605017
TI  - Relationship between eicosanoids and endothelin-1 in the pathogenesis of
      erythropoietin-induced hypertension in uremic rats.
AB  - Recent studies suggest a possible link between recombinant human erythropoietin
      (rhEPO)-induced hypertension and endothelium-derived vasoconstrictor autocoids.
      The current study was designed to evaluate the role of eicosanoids such as
      thromboxane (TX) A and prostacyclin (PGI ) and of endothelin-1 (ET-1) and the
      relationship between these vasoactive substances in rhEPO-induced hypertension in
      uremic rats. Renal failure was induced by a two-stage 5/6 nephrectomy followed by
      a 6-week stabilization period. In protocol A, rats were divided into four groups:
      vehicle, rhEPO (100 u/kg, subcutaneously, three times per week), a selective ET
      receptor antagonist (ABT-627, 10 mg/kg/d), and rhEPO + ABT-627 for 5 weeks. In
      protocol B, uremic animals were divided into two groups: rhEPO and rhEPO + a TX
      receptor antagonist and synthesis inhibitor, ridogrel (25 mg/kg/d), for 5 weeks.
      At the end of the study, immunoreactive eicosanoid metabolites (TXB and 6-keto
      PGF, stable metabolites of TXA and PGI ), and ET-1 were measured in either the
      thoracic aorta or in the mesenteric arterial bed. After 5/6 nephrectomy, the
      animals developed uremia, anemia, and hypertension. rhEPO corrected the anemia
      but aggravated the hypertension. Both drugs were effective in preventing the
      progression of hypertension in rhEPO-treated rats although ABT-627 was more
      potent than ridogrel. rhEPO increased the concentration of ET-1 and TXB in blood
      vessels and ABT-627 decreased tissue levels of both vasopressors. The
      concentration of 6-keto-PGF was not significantly changed. Ridogrel significantly
      decreased tissue TXB concentrations but had no effect on ET-1 levels. These
      results suggest that endothelium-derived vasoconstrictor autacoids (TXA and ET-1)
      are involved in the pathogenesis of rhEPO-induced hypertension in uremic rats.
      TXA probably serves as a mediator of the vascular effect of ET-1.

PMID- 12605018
TI  - Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against
      myocardial dysfunction after ischemia and reperfusion.
AB  - Using an isolated nonworking rat heart model, this study investigated the role of
      beta-adrenergic preconditioning (beta-PC) to attenuate myocardial dysfunction
      after an ischemia/reperfusion injury. After a 20-min stabilization period, the
      noradrenaline depleted hearts were perfused for 5 min with isoproterenol (ISO)
      before 40-min global ischemia (I) followed by 30-min reperfusion (R). ISO 0.02
      microM provided significant protection versus unconditioned in vivo reserpinized
      IR control, causing a decrease of creatine kinase (CK) release (mIU/min/g wet
      weight) on reperfusion in coronary effluent, a preservation of the mean coronary
      flow (MCF) and preservation of left ventricular function assessed by the rate
      pressure product (RPP). These beneficial effects were similar to those of
      ischemic preconditioning (I-PC) in both nonreserpinized and reserpinized rats.
      Propranolol (1 microM) and atenolol (10 microM) completely suppressed the ISO
      preconditioning. In contrast, ICI 118551 (2 microM) a highly selective beta 
      blocker, did not blunt the salutary effects of ISO on CK release and MCF
      preservation. These results indicate that ISO pretreatment provides a significant
      cardioprotection against prolonged ischemic myocardial injury. Although
      endogenous catecholamines are not necessary for I-PC in isolated rat hearts,
      cardioprotection provided by beta-adrenergic stimulation is quite similar to I
      PC. This significant cardioprotection is mediated less by beta -adrenoceptor than
      by beta -adrenoceptor activation, which seems to play a crucial role in the beta
      PC mechanism.

PMID- 12605019
TI  - Desbutylhalofantrine: evaluation of QT prolongation and other cardiovascular
      effects after intravenous administration in vivo.
AB  - Desbutylhalofantrine (Hfm) is an active and equipotent metabolite of halofantrine
      (Hf). Both compounds are effective in the treatment of sensitive and multidrug
      resistant and In vitro data and interpretation of some clinical studies of Hf
      have suggested that, unlike Hf, Hfm may be devoid of adverse cardiac effects. The
      aim of these investigations was to provide the first in vivo examination of the
      intrinsic capacity of Hfm to affect repolarization in the heart, using an
      anesthetized rabbit model. Using a dose-rising regimen, Hfm was administered IV
      at doses of 1, 1, 2, 4, and 8 mg/kg and the baseline rate-corrected QT interval
      (QTc) value of 377 +/- 13 ms rose to 394 +/- 16, 396 +/- 12, 429 +/- 18, 433 +/-
      16, and 489 +/- 15 ms, respectively. There were no significant changes in blood
      pressure, heart rate, or PR or QRS intervals. The Hfm plasma concentrations were
      quantitated after high-performance liquid chromatographic analysis, the results
      indicating a significant correlation between Hfm plasma concentration and QT(c)
      prolongation. The study also identified a concentration-dependent hemolysis of
      erythrocytes after administration of Hfm. The conclusions from this study are
      that IV administration of Hfm does cause a significant prolongation of the QT(c)
      interval in a rabbit model.

PMID- 12605020
TI  - Electrophysiologic effects of SB-237376: a new antiarrhythmic compound with dual
      potassium and calcium channel blocking action.
AB  - Combined potassium and calcium channel blocking activities are suggested to be
      the basis for antiarrhythmic efficacy with low proarrhythmic risk. The
      electrophysiologic effects of SB-237376 were investigated in single myocytes and
      arterially perfused wedge preparations of canine or rabbit left ventricles. The
      concentration-dependent prolongation of action potential duration (APD) and QT
      interval by SB-237376 was bell-shaped and the maximum response occurred at 1-3
      microM SB-237376 inhibited rapidly activating delayed rectifier K current (I(Kr)
      ) with an IC50 of 0.42 microM and use-dependently blocked L-type Ca current (I
      (Ca,L) ) at high concentrations. The SB-237376 (3 microM) induced phase-2 early
      afterdepolarizations (EADs) in five of six rabbit wedge preparations but none of
      six canine wedge preparations. This is probably due to larger increases of APD,
      QT interval, and transmural dispersion of repolarization (TDR) in rabbits than
      dogs. Based on the drug effects on QT interval, TDR, and EAD in rabbit
      ventricular wedge preparations, a scoring system predicted lower proarrhythmic
      risk for SB-237376 than for dl-sotalol, a specific I blocker. In conclusion, SB
      237376 increases APD, QT interval, and TDR mainly by I (Kr) inhibition. These
      effects are self-limited due to SB-237376-induced I(Ca,L) blockade at high
      concentrations, which may explain its lower proarrhythmic risk than dl-sotalol.

PMID- 12605021
TI  - Effects of cerivastatin on human arterial smooth muscle cell growth and
      extracellular matrix expression at varying glucose and low-density lipoprotein
      levels.
AB  - Statins exert pleiotropic effects on several other cellular functions besides
      lipid-lowering. Previously, it was found that cerivastatin is a very potent
      inhibitor of human arterial smooth muscle cell (haSMC) growth. However, because
      increased extracellular matrix (ECM) synthesis also accounts mainly for intimal
      plaque formation, the effects of cerivastatin on ECM expression was examined in
      this study. Furthermore, the influence of varying glucose and low-density
      lipoprotein (LDL) levels on cerivastatin-treated haSMCs was analyzed to mimic the
      conditions in patients with diabetes or hypercholesterolemia. The haSMCs were
      treated with 0.001-5.0 microM cerivastatin in the presence of 5.5-18.9 m glucose
      and 10-1000 microg/ml LDL. After 3 days, the messenger RNA (mRNA) expression of
      eight ECM proteins was analyzed and, after 7 days, mitotic and mitochondrial
      activities and thrombospondin (TSP)-1 protein expression were analyzed. TSP-1 and
      TSP-2 mRNA expression was inhibited highly significantly at cerivastatin doses
      >or=0.01 microM with maximums of 72% and 35%, respectively, at high glucose
      levels. The mRNA signals of the third glycoprotein fibronectin were not
      influenced. Furthermore, collagen-1 mRNA was inhibited highly significantly up to
      71% and biglycan mRNA was similarly inhibited up to 45%. The mRNA expression of
      the matrix-stimulating transforming growth factor (TGF)-beta1 and matrix
      metalloproteinase (MMP)-2 was not altered significantly, whereas mRNA expression
      of the tissue inhibitor of metalloproteinase (TIMP)-2 was stimulated clearly up
      to 150%. Mevalonate, but not LDL replacement, reversed the effects.
      Immunofluorescence staining showed an unaltered TSP-1 pattern with cerivastatin
      doses up to 0.1 microM whereas higher doses impaired TSP-1 excretion. The effects
      of cerivastatin on haSMC growth and mRNA expression of the eight ECM components
      were not diminished by the increase in LDL and glucose levels. Since accelerated
      SMC growth and ECM formation contribute mainly to intimal thickening,
      cerivastatin may be protective against the development of atherosclerotic and
      restenotic lesions by its direct cellular effects. Increased LDL and glucose
      levels, as in diabetes, do not mitigate the beneficial effects of cerivastatin on
      cell growth and ECM formation in vitro.

PMID- 12605022
TI  - Vasorelaxations induced by calcitonin gene-related peptide, vasoactive intestinal
      peptide, and acetylcholine in aortic rings of endothelial and inducible nitric
      oxide synthase-knockout mice.
AB  - The objective of this study was to determine if vasorelaxant responses to
      calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and
      acetylcholine are altered in aortic rings of mice lacking genetic expression of
      endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase
      (iNOS) genes (i.e., eNOS- and iNOS-knockout mice) as compared with control (wild
      type) mice. Aortic rings from eNOS-knockout (eNOS (-/-)) mice did not relax in
      response to acetylcholine, thereby confirming previous reports. Aortic rings from
      iNOS-knockout (iNOS (-/-)) mice relaxed in response to acetylcholine in an
      endothelium-dependent manner. However, maximum relaxations in endothelium-intact
      rings were significantly (p < 0.05) larger than in control mice (85.3 +/- 3.1% in
      iNOS (-/-) mice vs. 67.9 +/- 5.6% in controls). CGRP caused concentration
      dependent relaxations in aortas of all three types of mice: control mice, iNOS (
      /-) mice, and eNOS (-/-) mice. Vasorelaxant responses to CGRP in control and iNOS
      (-/-) mice had identical relationships; both were partially dependent on
      endothelium. In eNOS (-/-) mice, dose-response curves of CGRP in endothelium
      intact and endothelium-denuded rings were not significantly different, indicating
      loss of the partial dependence on endothelium. The vasorelaxant responses to VIP
      were completely dependent on endothelium in control and iNOS (-/-) mice. Maximum
      relaxations to VIP in iNOS (-/-) mice (77.4 +/- 2.7%) were significantly greater
      than in control mice (64.0 +/- 5.5%). Vasorelaxant responses to VIP in eNOS (-/-)
      aortic rings were also endothelium-dependent, but responses were greatly
      attenuated compared with wild-type mice. Relaxations induced by VIP (1 x 10 ) in
      endothelium-intact aortic rings of eNOS (-/-) mice and control mice were 18.3 +/-
      5.4% and 64.0 +/- 5.5%, respectively. These findings demonstrated that, in eNOS (
      /-) mice, aortic vasorelaxant responses to CGRP were fully present but no longer
      dependent on the endothelium, and responses to VIP were greatly attenuated
      compared with control and responses to acetylcholine were abolished. In iNOS (-/
      ) mice, aortic vasorelaxant responses to VIP and acetylcholine were significantly
      greater than wild-type control, suggesting that induction of iNOS may have
      attenuated vascular responses to VIP and acetylcholine in wild-type controls.

PMID- 12605023
TI  - cGMP-dependent and not cAMP-dependent kinase is required for adenosine-induced
      dilation of intracerebral arterioles.
AB  - Adenosine (ADO) is a potent cerebral vasodilator and has been proposed as a
      metabolic regulator of cerebral blood flow. However, the signal transduction
      pathway by which ADO causes vasodilation in cerebral microvessels is currently
      unknown. The current study was designed to investigate the role of cyclic
      nucleotides and cyclic nucleotide-dependent protein kinases in ADO-induced
      dilation of resistance-sized rat cerebral arterioles that develop spontaneous
      tone. Arterioles were cannulated and perfused intraluminally at constant flow (2
      microl/min) and pressure (60 mm Hg). ADO (29.7 +/- 2.0%; 1 microM), CGS-21680 (16
      +/- 4%, 1 microM), 8-bromo-cyclic guanosine monophosphate (8 Br-cGMP; 29.9 +/-
      3.9%; 100 microM), sodium nitroprusside (SNP; 30.6 +/- 3.3%, 1 microM), cyclic
      guanine monophosphate-dependent protein kinase activator (Sp-8-pCPT-cGMPS, 25.9
      +/- 4.2%; 10 microM), forskolin (30.5 +/- 5.9%; 0.1 microM), and pH 6.8 all
      produced large dilations. The selective cGMP-dependent protein kinase inhibitor,
      Rp-8-pCPT-cGMPS (10 microM), had no effect on resting diameter or reactivity to
      acidic pH, but significantly ( < 0.05) attenuated arteriolar dilations to ADO
      (59%, n = 8), CGS-21680 (60%, n = 4), SNP (62%, n = 3), 8 Br-cGMP (88%, n = 3),
      and Sp-8-pCPT-cGMPS (98%, n = 3). H8, the less-selective cyclic nucleotide
      dependent protein kinase inhibitor, had similar effects as Rp-8-pCPT-cGMPS.
      Additionally, the inhibitor of the soluble guanylate cyclase, 1H-[1,24]oxadiazolo
      [4,3-a]quinoxalin-1-one (ODQ), blocked the response to SNP (70% inhibition) and
      significantly inhibited the ADO response (43% inhibition). In contrast,
      inhibition of the cyclic ADO monophosphate (cAMP)-dependent protein kinase Rp-8
      CPT-cAMPS had no effect on the ADO, SNP, or pH responses, but significantly
      blocked forskolin-induced vasodilation (53%). It is concluded that ADO-induced
      vasodilation in cerebral microvessels, at least in part, involves cGMP and cGMP
      dependent protein kinase, but not cAMP or cAMP-dependent kinase. Our data
      therefore provides a new insight into mechanisms by which ADO invokes
      vasodilation in cerebral microvascular arterioles.

PMID- 12605024
TI  - Effect of extracellular volume expansion and surgical stress on splanchnic blood
      flow and cardiac output in anesthetized rats: role of nitric oxide.
AB  - In a normal volume state, surgical stress decreases rather than increases nitric
      oxide (NO) production in the vascular system. In our studies, the effect of minor
      and major surgical stress and three different degrees of volume expansion on
      systemic and splanchnic circulatory parameters and on the NO dependence of the
      circulation have been investigated. When the degree of volume expansion was
      increased, cardiac output and organ blood flow increased without significant
      change in vascular resistances. Major surgical stress reduced the increase in
      cardiac output and organ blood flow elicited by the volume expansion. NO synthase
      (NOS) inhibition significantly increased blood pressure and total peripheral
      resistance (TPR) and decreased cardiac output in all groups of animals. As the
      degree of volume expansion was increased, the NO dependence of the circulation in
      the surgically less- and more-stressed animals was inversely influenced in some
      cases. With the three degrees of volume expansion (20, 40, and 60 ml/kg), the NOS
      inhibition increased the TPR from 30.7 R/kg +/- 1.90 to 73.6 R/kg +/- 5.00, from
      20.7 R/kg +/- 1.43 to 66.7 R/kg +/- 3.88, and from 19.9 R/kg +/- 1.25 to 49.1
      R/kg +/- 3.84 in the surgically less-stressed animals and from 38.6 R/kg +/- 2.14
      to 59.8 R/kg +/- 5.62, from 31.9 R/kg +/- 2.70 to 81.7 R/kg +/- 9.89, and from
      29.1 R/kg +/- 2.49 to 91.1 R/kg +/- 6.36 in the surgically more-stressed animals.
      Volume expansion increases the NO dependence of the vascular resistance in the
      surgically more-stressed animals but decreases it in the surgically less-stressed
      animals.

PMID- 12605025
TI  - Vasoconstrictor effect and mechanism of action of endothelin-1 in human radial
      artery and vein: implication of skin flap vasospasm.
AB  - Vasospasm in the vascular pedicle is a major cause of ischemic necrosis in
      autogenous skin transplantation (i.e., skin free flap surgery), and the
      pathophysiology is unclear. The clinical impression is that veins are more
      susceptible to vasospasm than arteries in the vascular pedicle of skin free
      flaps. The purpose of this study was to compare the vasoconstrictor response of
      the human radial artery (RA) and radial vein (RV) to endothelin (ET)-1 and to
      investigate the mechanism mediating ET-1-induced vasoconstriction. The isometric
      tension of RA and RV rings (4 mm) obtained from the vascular pedicle of human
      radial forearm skin free flaps were studied in organ chambers containing Krebs
      bicarbonate buffer. It was observed that ET-1 elicited concentration-dependent (5
      x 10 (-11)to 2 x 10 (-8) ) contractions in RA and RV rings with similar
      contractile potency. However, the concentration-dependent contractile response to
      ET-1 was significantly (P < 0.05) higher in RV rings than in RA rings, with the
      maximum contractile response twice as high in RV rings than in RA rings. The
      contractile response to ET-1 in RA and RV rings was blocked by the ET receptor
      antagonist BQ 123 (10 (-5M)), but not by the ET receptor antagonist BQ 788 (5 x
      10 (-6)). The ET(B) receptor agonist BQ 3020 (10 (-10) to 2 x 10(-8) ) had no
      significant contractile effect in RA and RV rings. Furthermore, the L-type Ca
      channel antagonist nifedipine (5 x 10 (-6)), the protein kinase C (PKC) inhibitor
      chelerythrine (10(-5M)), and the intracellular Ca chelator BAPTA-AM (10(-5M))
      significantly reduced the contractile potency of ET-1 in RA rings and the maximum
      contractile response to ET-1 in RA and RV rings. It was concluded that the human
      RV is more responsive than RA to the contractile effect of ET-1. The contractile
      response to ET-1 in RA and RV is predominantly mediated by ET(A) receptors and
      the postreceptor mechanism involves L-type Ca (2+) channels, PKC, and
      intracellular Ca(2+).

PMID- 12605026
TI  - Cariporide (HOE642) limits S-100B release during cardiac surgery.
AB  - Cardiac surgery with cardiopulmonary bypass (CPB) results in transient cerebral
      swelling in most patients. Cognitive decline occurs in 24-57% of patients and 2
      5% experience stroke. Serum levels of S-100B, a potential marker of increased
      blood-brain barrier permeability, increase during and early after surgery. The
      authors studied the effects of the novel Na /H exchange inhibitor cariporide
      (HOE642) on postoperative serum levels of S-100B and neuron-specific enolase
      (NSE) in 53 patients at high risk undergoing coronary artery bypass grafting.
      Patients were randomly assigned to one of four groups: I, placebo; II, 20 mg
      cariporide; III, 80 mg cariporide; IV, 120 mg cariporide). In addition, the
      leukocyte activation marker myeloperoxidase (MPO) and malondialdehyde (MDA), a
      marker for lipid peroxidation, were evaluated by enzyme-linked immunoassay.
      Postoperatively, five patients experienced transient ischemic attack or stroke. S
      100B levels increased from 0.43 microg/l +/- 0.33 before operation to 2.27
      microg/l +/- 0.69 1 hour after surgery in the placebo group. Preoperative S-100B
      levels in the HOE642 groups did not differ from the placebo group whereas, 1 hour
      after surgery, levels were significantly lower in groups II, III, and IV (1.63
      microg/l +/- 0.2, 1.27 microg/l +/- 0.27, and 0.90 microg/l +/- 0.21,
      respectively). NSE, MPO, and MDA serum levels did not differ among groups. These
      findings may stimulate larger clinical studies to examine the effects of HOE642
      on cerebral swelling and neurologic/cognitive outcome of cardiac surgery with
      CPB.

PMID- 12605027
TI  - Acute reduction of myocardial infarct size by a hydroxymethyl glutaryl coenzyme A
      reductase inhibitor is mediated by endothelial nitric oxide synthase.
AB  - In addition to their lipid-lowering properties, statins improve endothelial
      function by increasing the activity of endothelial nitric oxide synthase (eNOS).
      It was hypothesized that, by this mechanism, statins protect the myocardium from
      ischemia/reperfusion injury in normocholesterolemic animals. Rats were pretreated
      for 1 week with either cerivastatin (0.3 mg/kg/d) or placebo. Anesthetized
      animals underwent 30 minutes of coronary artery occlusion (CAO) followed by 180
      minutes of reperfusion. In a separate set of experiments, the NOS inhibitor l
      NAME (15 mg/kg; N -nitro-l-arginine methyl ester) was administered 15 minutes
      before CAO. Cerivastatin decreased infarct size by 49% (P < 0.05) without
      reducing plasma cholesterol levels. Cerivastatin increased myocardial eNOS mRNA
      and NOS activity and by 52% and 58% (P < 0.05), respectively. Cardioprotection
      and upregulation of eNOS activity evoked by cerivastatin were not observed in
      rats cotreated with l-NAME. These results show that statins reduce the extent of
      myocardial necrosis in normocholesterolemic rats after acute ischemia/reperfusion
      injury by increasing myocardial eNOS activity. Therefore, statins may protect the
      heart not only by reducing the incidence of ischemic events, but also by limiting
      cell damage during acute myocardial infarction.

PMID- 12605029
TI  - T-cell receptor V beta 8.1 peptide reduces coxsackievirus-induced cardiopathology
      during murine acquired immunodeficiency syndrome.
AB  - Infection of people with human immunodeficiency virus (HIV) as well as LP-BM5
      infection in mice results in progressive deterioration of the immune system in
      the majority of untreated hosts. Peptide immunotherapy has been shown to be
      effective in the stimulation or immunoregulation of T-helper 1 (T(H)1) and T
      helper 2 (T(H) 2) response subsets. In murine acquired immunodeficiency syndrome
      (AIDS), T(H)1 deficiency enables the host to be susceptible to coxsackievirus
      infection, inducing cardiopathology in a short period. T-cell receptor (TCR)
      Vbeta8.1 peptide, a 16-mer peptide containing the entire CDR1 segment and part of
      the FR2 region of human Vbeta8, showed both an immunoregulating and
      immunostimulating effect in murine AIDS. TCR Vbeta8.1 peptide acts on T cells
      promoting interleukin-2 production and therefore enhancing a cell-mediated immune
      response. It retarded development of cardiopathology due to coxsackievirus
      infection. Retrovirus-infected mice treated with the peptide showed a longer life
      span than the nontreated, retrovirus-infected animals.

PMID- 12605028
TI  - Comparison of cardioprotective efficacy of two thromboxane A2 receptor
      antagonists.
AB  - The purpose of the current study was to compare the efficacy of two structurally
      unrelated thromboxane A (TXA ) receptor antagonists, KT2-962 and daltroban (BM
      13.505), in a dog model of myocardial ischemia/reperfusion injury. Pentobarbital
      anesthetized dogs were subjected to left circumflex coronary artery occlusion for
      90 minutes followed by 5 hours of reperfusion. Vehicle, KT2-962 (10 mg/kg), or
      daltroban (10 mg/kg) were administered as intravenous boluses 10 minutes before
      coronary occlusion. Systemic hemodynamics were measured throughout the
      experiments and regional myocardial blood flow was measured by the radioactive
      microsphere technique. At the end of the reperfusion period, myocardial infarct
      size was quantified by staining with triphenyltetrazolium chloride. Neither KT2
      962 nor daltroban significantly altered heart rate, mean arterial blood pressure,
      or regional myocardial blood flow. The content of myeloperoxidase activity in the
      ischemic/reperfused tissue, an index of neutrophil infiltration, was not
      significantly different among the three treatment groups. However, administration
      of KT2-962, but not daltroban, significantly reduced the incidence of ventricular
      fibrillation during the ischemic period and significantly reduced myocardial
      infarct size expressed as a percentage of the risk region (approximately 40%).
      Subsequent in-vitro assays using electron spin resonance spectroscopy
      demonstrated that KT2-962 inhibited the formation of hydroxyl radicals, whereas
      daltroban had no effect. These results suggest that the beneficial effects of KT2
      962 may be due to its direct free radical scavenging properties rather than its
      ability to block TXA receptors.(2) (2) (2)

PMID- 12605030
TI  - Recent developments in signal amplification methods for in situ hybridization.
AB  - In situ hybridization (ISH) allows for the histologic and cytologic localization
      of DNA and RNA targets. However, the application of ISH techniques can be limited
      by their inability to detect targets with low copies of DNA and RNA. During the
      last few years, several strategies have been developed to improve the sensitivity
      of ISH by amplification of either target nucleic acid sequences prior to ISH or
      signal detection after the hybridization is completed. Current approaches
      involving target amplification (in situ PCR, primed labeling, self-sustained
      sequence replication), signal amplification (tyramide signal amplification,
      branched DNA amplification), and probe amplification (padlock probes and rolling
      circle amplification) are reviewed with emphasis on their applications to bright
      field microscopy. More recent developments such as molecular beacons and in situ
      strand displacement amplification continue to increase the sensitivity of in situ
      hybridization methods. Application of some of these techniques has extended the
      utility of ISH in diagnostic pathology and in research because of the ability to
      detect targets with low copy numbers of DNA and RNA.

PMID- 12605031
TI  - Automated colorimetric in situ hybridization (CISH) detection of immunoglobulin
      (Ig) light chain mRNA expression in plasma cell (PC) dyscrasias and non-Hodgkin
      lymphoma.
AB  - Immunohistochemistry (IHC) is frequently used to detect plasma cell (PC) or B
      cell monoclonality in histologic sections, but its interpretation is often
      confounded by background staining. We evaluated a new automated method for
      colorimetric in situ hybridization (CISH) detection of clonality in PC dyscrasias
      and small B cell lymphomas. Cases of PC dyscrasia included multiple myeloma (MM;
      31 cases), plasmacytoma (seven cases), or amyloidosis (one case), while cases of
      lymphoma included small lymphocytic (three cases), marginal zone (four cases),
      lymphoplasmacytic (three cases), and mantle cell lymphomas (three cases). Tissue
      sections were stained for kappa and lambda light chains by IHC and for light
      chain mRNA by automated CISH using haptenated probes. Twenty-eight of 31 MM cases
      had detectable light chain restriction by IHC. Thirty of 31 MM cases demonstrated
      light chain restriction by CISH, including 2 cases with uninterpretable IHC and
      one case of nonsecretory myeloma, which was negative for light chains by IHC.
      Seven of 7 plasmacytoma cases had detectable light chain restriction by CISH,
      including one case of nonsecretory plasmacytoma in which IHC was noninformative.
      Automated CISH demonstrated monoclonality in 9 of 13 cases of B cell non-Hodgkin
      lymphoma and had a slightly higher sensitivity than IHC (6 of 13 cases),
      especially in cases of lymphoplasmacytic and marginal zone lymphoma. Overall,
      there were no discrepancies in light chain restriction results between IHC, CISH,
      or serum paraprotein analysis. Automated CISH is useful in detecting light chain
      expression in paraffin sections and appeared superior to IHC for light chain
      detection in PC dyscrasias and B cell non-Hodgkin lymphomas, predominantly due to
      lack of background staining.

PMID- 12605032
TI  - In situ hybridization for the differentiation of Aspergillus, Fusarium, and
      Pseudallescheria species in tissue section.
AB  - Identification of fungi in tissue sections can be difficult. In particular,
      species of Aspergillus, Fusarium, and Pseudallescheria all appear as septate,
      branched hyphae. However, their differentiation can have significant clinical
      implications, as the latter two groups are often resistant to commonly used
      antifungal agents. In situ hybridization may assist in rapidly distinguishing
      these organisms in the absence of available culture. Oligonucleotide DNA probes
      were directed against the 5S, 18S, or 28S rRNA sequences of three groups of fungi
      with a high degree of specificity for each. Probes were tested on 26 formalin
      fixed, paraffin-embedded tissue specimens, each with culture-proven involvement
      by one of these organisms: Fusarium species, n = 12; Pseudallescheria boydii, n =
      5; Aspergillus species, n = 9 ( probe set validated in an earlier study).
      Accuracy of both ISH and morphology was compared with culture. Morphologic
      examination (GMS and PAS) showed a greater sensitivity in detecting fungi (100%)
      as compared with in situ hybridization (84.6%). When detected, however, DNA
      probes allowed definitive identification of organisms. While there was no ability
      to distinguish between the three groups of organisms by morphologic features, ISH
      probes showed 100% positive predictive value (PPV, 19/19 organisms identified
      correctly). No cross-reactivity was observed when the probes were tested against
      other genera (100% specificity). Furthermore, the use of ISH allowed the
      detection of mixed fungal infections involving multiple organism types in two
      cases, demonstrating another advantage over morphology. In situ hybridization,
      directed against rRNA sequences, provides a rapid and accurate technique for
      distinguishing commonly encountered, nonpigmented filamentous fungi in histologic
      sections. While less sensitive than morphology, ISH is highly accurate and may
      help to distinguish between organisms that have similar or identical morphologic
      features by light microscopy.

PMID- 12605033
TI  - Molecular classification of breast carcinomas using tissue microarrays.
AB  - The histopathologic classification of breast cancer stratifies tumors based on
      tumor grade, stage, and type. Despite an overall correlation with survival, this
      classification is poorly predictive and tumors with identical grade and stage can
      have markedly contrasting outcomes. Recently, breast carcinomas have been
      classified by their gene expression profiles on frozen material. The validation
      of such a classification on formalin-fixed paraffin-embedded tumor archives
      linked to clinical information in a high-throughput fashion would have a major
      impact on clinical practice. The authors tested the ability of tumor tissue
      microarrays (TMAs) to sub-classify breast cancers using a TMA containing 107
      breast cancers. The pattern of expression of 13 different protein biomarkers was
      assessed by immunohistochemistry and the multidimensional data was analyzed using
      an unsupervised two-dimensional clustering algorithm. This revealed distinct
      tumor clusters which divided into two main groups correlating with tumor grade
      (P<0.001) and nodal status (P = 0.04). None of the protein biomarkers tested
      could individually identify these groups. The biological significance of this
      classification is supported by its similarity with one derived from gene
      expression microarray analysis. Thus, molecular profiling of breast cancer using
      a limited number of protein biomarkers in TMAs can sub-classify tumors into
      clinically and biologically relevant subgroups.

PMID- 12605034
TI  - Cell cycle alterations in the blastoid variant of mantle cell lymphoma (MCL-BV)
      as detected by gene expression profiling of mantle cell lymphoma (MCL) and MCL
      BV.
AB  - Overexpression of cyclin D1 is necessary but by itself insufficient for the
      development of mantle cell lymphoma (MCL). To identify pathways in the
      pathogenesis of MCL and the blastoid variant (MLC-BV), we compared the gene
      expression profiles of microdissected normal mantle cells, MCL, and MCL-BV by
      oligonucleotide microarrays and quantitative reverse transcriptase PCR (QRT-PCR).
      We identified and confirmed the overexpression of several genes in MCL-BV that
      are involved in the cell cycle control at the G1/S and G2/M checkpoints or
      inhibit apoptotic cell death. The highly expressed cyclin dependent kinase 4
      (CDK4) is a cell cycle kinase that associates with cyclin D1 for the progression
      through the G1/S checkpoint, whereas overexpression of cdc28 protein kinase 1
      (CKS1) blocks the inhibition of the cyclin D1/CDK4 complex by the CDK inhibitor
      p27/Kip1. Other highly expressed genes in MCL-BV that promote the cells through
      the G1/S-checkpoint include the oncogenes B-Myb, PIM1, and PIM2, and passage
      through the G2/M-checkpoint is enhanced by high levels of cdc25B. Furthermore,
      two highly expressed genes that inhibit apoptosis are defender against cell death
      (DAD1) and RSK1. In summary, our microarray and QRT-PCR analyses identified
      several candidate genes whose expression increased when comparing normal
      follicular mantles with MCL and MCLBV, suggesting a potential pathogenic role in
      the evolution of MCL-BV.

PMID- 12605036
TI  - Promoter hypermethylation and inactivation of hMLH1, a DNA mismatch repair gene,
      in head and neck squamous cell carcinoma.
AB  - Head and neck squamous cell carcinoma (HNSCC) is a multistage process during
      which adverse genetic alterations accumulate resulting in loss of cell cycle
      control, selective cell overgrowth, and ultimately formation of malignancy. Among
      various genetic alterations in HNSCC is increased microsatellite instability
      (MSI). hMLH1 is one of the major mismatch DNA repair genes, the inactivation of
      which caused increased MSI in a variety of human cancers including HNSCC. While
      somatic mutation is a major mechanism of the hMLH1 gene inactivation in
      hereditary form of human cancer, promoter hypermethylation appears to be
      primarily involved in the inactivation of the hMLH1 gene in sporadic form of
      human cancers. In the current study, we analyzed 78 cases of HNSCC for hMLH1
      protein expression and promoter hypermethylation by IHC and methylation-specific
      PCR (MSP). Twenty-four of 78 cases (31%) of HNSCC contained markedly reduced
      levels of the hMLH1 protein. Based on the IHC results, 8 cases without and 8 with
      hMLH1 protein expression (total of 16) were further analyzed by MSP. Seven of 8
      cases (88%) that were negative for the hMLH1 protein displayed promoter
      hypermethylation, whereas 7 of 7 cases (100%) strongly positive for the protein
      were free of promoter methylation. This study confirms our previous conclusion
      that promoter hypermethylation represents a major mechanism of the hMLH1 gene
      inactivation in HNSCC.

PMID- 12605035
TI  - Real-time analysis of beta- and gamma-catenin mRNA expression in ret/PTC-1
      activated and nonactivated thyroid tissues.
AB  - Our group has previously demonstrated an association between ret/PTC-1 activation
      and decreased E-cadherin mRNA levels in papillary thyroid carcinoma. We also
      observed similarities in the E-cadherin expression profiles of Hashimoto
      thyroiditis and ret/PTC-1-positive papillary thyroid carcinomas and have
      hypothesized that ret/PTC-1 activation might cause not only the structural and
      nuclear peculiarities of PTC but also an immune reaction to thyroid epithelium.
      The objective of this study was to examine the expression of E-cadherin's
      ligands, beta- and gamma-catenin, in various thyroid tissue types in the context
      of ret/PTC-1 positivity using laser capture microdissection and TaqMan (Applied
      Biosystems, Foster City, CA). One-Step RT-PCR. Beta-catenin mRNA levels were
      found to be consistently decreased in both papillary and anaplastic carcinomas
      when compared with a normal/follicular adenoma group. A significant difference in
      expression levels was observed between papillary and follicular thyroid
      carcinomas with the latter having elevated mRNA levels of beta-catenin. Gamma
      catenin mRNA was decreased in anaplastic carcinomas compared with
      normal/follicular adenoma groups. A similar expression profile of gamma-catenin
      as beta-catenin was observed in papillary and follicular carcinomas with the
      latter once again having higher mRNA levels. These results therefore suggest that
      although beta- and gamma-catenin may play a role in the progression of thyroid
      cancer in general, they do not appear to be associated with ret/PTC-1-modulated
      pathways.

PMID- 12605037
TI  - Relaxation of imprinting of IGFII gene in juvenile nasopharyngeal angiofibromas.
AB  - IGFII and H19 genes are expressed only from one allele due to genomic imprinting,
      biallelic expression (loss of imprinting) being associated with the tumorigenic
      process of different types of tumors. The mechanism responsible for genomic
      imprinting is not yet determined, although DNA methylation has been considered
      the main genetic event for an imprinted mark. In the current study, the authors
      analyzed the imprinting status and expression levels of the IGFII and H19 genes
      in 27 cases of Juvenile Nasopharyngeal Angiofibroma (JNA) using RFLPs, RT-PCR,
      and Southern and Northern Blots. The authors found that four out of eight
      informative cases (50%) for ApaI/IFGII polymorphism showed biallelic expression
      of IFGII whereas none of the nine informative cases for the polymorphism showed
      biallelic expression of the H19 gene. Overexpression of IFGII was observed in 8
      out of 22 cases (36.4%), and 7 out of 19 cases (36.8%) showed H19 overexpression.
      Hypomethylation was found only in the H19 gene in six out of eight cases
      analyzed. Therefore, our results demonstrate that alterations in the IFGII/H19
      imprinted region occur in JNA.

PMID- 12605038
TI  - New corneal infections: preventing a crisis of identity.

PMID- 12605039
TI  - Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an
      inflammatory component.
AB  - PURPOSE: To evaluate the efficacy and anti-inflammatory activity of systemic
      linoleic (LA) and gamma-linolenic acid (GLA), which decrease chronic inflammation
      in rheumatoid arthritis, on the ocular surface of patients with
      keratoconjunctivitis sicca. METHODS: In a randomized clinical trial, 26 patients
      with aqueous-deficient keratoconjunctivitis sicca were consecutively selected
      from patients presenting to Department of Neurosciences, Ophthalmology and
      Genetics, University of Genoa. The diagnosis was based on dry eye symptom survey
      score, Schirmer-1 test values, positive vital staining with lissamine green, and
      fluorescein break-up time (FBUT). All patients had ocular surface inflammation
      based on HLA-DR expression, a major histocompatibility class II antigen, on
      epithelial bulbar conjunctiva samples. The subjects were randomly divided into
      two groups of 13 patients each. The study group received tablets containing LA
      (28.5 mg) and GLA (15 mg) twice daily for 45 days and used tears; the control
      group received a tear substitute and a placebo tablet for 45 days. RESULTS:
      Statistically significant changes in symptoms (p < 0.005), lissamine green
      staining (p < 0.005), and ocular surface inflammation (p < 0.05) occurred in the
      study group compared with controls. HLA-DR expression varied from 58.5 +/- 14.1%
      positive conjunctival cells to 41.3 +/- 18.9% in the treated group and from 61.4
      +/- 21.9% to 58.0 +/- 13.3% in the controls. No statistically significant
      difference between groups was found for FBUT and the Schirmer-1 test.
      CONCLUSIONS: Therapy with LA and GLA and tear substitutes reduces ocular surface
      inflammation and improves dry eye symptoms. Long-term studies are needed to
      confirm the role of this new therapy for keratoconjunctivitis sicca.

PMID- 12605041
TI  - The influence of keratoplasty on visual prognosis in aniridia: a historical
      review of one large family.
AB  - PURPOSE: To evaluate the visual prognosis in aniridia and the influence of
      keratoplasty in one large family. METHODS: The medical charts of 30 affected
      members of this family were studied retrospectively. Their eyes were divided in
      keratoplasty and nonkeratoplasty groups. In the keratoplasty group, 42
      keratoplasties (26 lamellar and 16 penetrating) were performed (20 eyes), with a
      median follow-up of 18.5 years. In the nonkeratoplasty group, 18 eyes with
      sufficient follow-up were included. Best corrected visual acuity ever measured
      (BCVA-ever), BCVA at the last visit (end-BCVA), and the difference between BCVA
      ever and end-BCVA (long-term Delta-BCVA) were compared in those two groups. Best
      postoperative VA (post-BCVA), the difference between pre- and post-BCVA (short
      term Delta-BCVA), and its duration and outcomes of the grafts were evaluated in
      the keratoplasty group. Possible side effects of other procedures and incidents
      related to aniridia were compared. RESULTS: The median BCVA-ever was 1/10 in both
      groups. The median end-BCVA was 2/300 in the keratoplasty group and 1.5/300 in
      the nonkeratoplasty group; the long-term Delta-BCVA was comparable in the two
      groups. There was a temporary improvement of BCVA in 36 of 42 eyes after corneal
      transplantation, with a median of 8 logMAR and duration of 12 months. Most grafts
      failed because of recurrence of aniridic keratopathy. In the keratoplasty group,
      there were more corneal infections and more retinal detachments. The occurrence
      of glaucoma was comparable in both groups. In the nonkeratoplasty group, more
      eyes (five versus three) lost light perception. CONCLUSION: Corneal
      transplantation in aniridia provided only a temporary improvement in VA in this
      family. The long-term visual outcome was not affected by keratoplasty.

PMID- 12605040
TI  - Intraoperative mitomycin C 0.02% for pterygium: effect of duration of application
      on recurrence rate.
AB  - PURPOSE: To compare the effect of a 3- and 5-minute intraoperative application of
      topical mitomycin C 0.02% on the recurrence of pterygium. METHODS: A comparative,
      prospective clinical design was used. The study population consisted of 134
      consecutive patients with unilateral primary advanced pterygium (growth of 3 mm
      or more horizontally from the limbus). All underwent excision of the lesion,
      leaving the sclera bare. At completion of surgery, topical mitomycin C 0.02% was
      applied for 3 minutes in the first 60 patients (group A) and for 5 minutes in the
      remaining 74 patients (group B). The patients were followed for 26 months by slit
      lamp biomicroscopic examination of the anterior segment. Recurrent pterygium was
      defined as the postoperative appearance of a fibrovascular tissue crossing the
      limbus. RESULTS: After 12 months of follow-up, pterygium recurred in 20 patients
      (33.3%) in group A and in two patients (2.7%) in group B. After 15 months, the
      recurrence rates were 36.6% and 5.4%, respectively, and remained unchanged at 26
      months. There were no cases of drug toxicity in either group. CONCLUSIONS: Five
      minute intraoperative application of a single dose of 0.02% mitomycin C is safe
      and more effective than a 3-minute application in recurrence of pterygium.

PMID- 12605042
TI  - Indications and outcome of optical partial thickness lamellar keratoplasty.
AB  - PURPOSE: To review the indications and outcome of optical partial thickness
      lamellar keratoplasty (LKP) over a 22-year period. METHODS: The study is a
      retrospective review of 138 eyes of 126 patients. Snellen visual acuity,
      preoperative clinical condition, and postoperative clinical status were assessed.
      RESULTS: Postoperative follow-up ranged from 1 month to 174 months (average,
      34.5). In descending order of frequency, climatic droplet keratopathy, infectious
      keratitis scar, and band-shaped keratopathy were the most common indications for
      surgery. Follow-up records were available for 130 eyes; 93% of grafts remained
      transparent. One hundred eyes (80%) preoperative measured Snellen acuity of 6/60
      or less. Postoperatively, only 20 eyes (13.4%) were assessed as worse than 6/60.
      Mean best-corrected visual acuity postoperative was 0.58 +/- 0.24. Twenty-two
      eyes (16.9%) demonstrated postoperative visual acuity of better than 6/12.
      Complications included presumed rejection in two eyes, nonhealing epithelial
      defect in two eyes, and graft infection in seven eyes. CONCLUSION: Vision gain
      following LKP is generally moderate (visual acuity, 6/18-6/12) in the majority of
      eyes (61.5%). Vision-threatening complications are low (6.9%). There is scope for
      reducing complications like postoperative infections and improving visual gain
      through deep lamellar keratoplasty.

PMID- 12605043
TI  - Topical mitomycin C in the treatment of pigmented conjunctival lesions.
AB  - PURPOSE: To assess the clinical efficacy of topical mitomycin C (MMC) 0.04% for
      the treatment of patients with pigmented conjunctival lesions. Clinical efficacy
      was evaluated on the basis of reduction in lesion size and degree of pigmentation
      and histologic study. METHODS: Two patients, one with primary acquired
      conjunctival melanosis with atypia and another with conjunctival melanoma, were
      treated with topical MMC 0.04%. Before treatment, a biopsy was performed that
      confirmed the diagnosis and the absence of atypical melanocytes beyond the basal
      layer. In both patients, MMC was administered with sponges, while one patient
      additionally received MMC 0.04% drops. Each treatment cycle lasted 14 days, with
      repetition after 3 months when necessary. Follow-up was weekly, then monthly, and
      then every 6 months up to 3 years. RESULTS: Treatment with topical MMC 0.04% not
      only reduced the size and degree of pigmentation clinical lesions in both
      patients but also eradicated atypical conjunctival melanocytes as observed in
      histologic studies. In the patient with primary acquired conjunctival melanosis,
      adjunct cryotherapy was required, along with various cycles of MMC, to reduce the
      pigmented areas of skin of the internal canthus and caruncle. In the second case,
      only MMC was used. No severe adverse reactions to the treatment were observed.
      After 3 years of follow-up, no clinical relapse has been detected. CONCLUSION:
      Topical MMC 0.04% is an option worth considering for the treatment of pigmented
      conjunctival lesions, particularly as an adjunct to other forms of treatment.

PMID- 12605044
TI  - Orbscan corneal topography system in evaluating the anterior structures of the
      human eye.
AB  - PURPOSE: To investigate the relationship among horizontal corneal diameter,
      corneal thickness, anterior chamber depth, pupil size, and spherical equivalent
      and to evaluate the variation in these parameters attributable to age, sex, iris
      color, and refractive state of the eye. METHODS: One thousand three hundred forty
      one eyes of 688 consecutive patients who had a LASIK evaluation at World Eye
      Hospital were involved in the study. The information that was reviewed included
      age and sex of the patient, horizontal corneal diameter, corneal thickness,
      anterior chamber depth, iris color, pupil size (scotopic and photopic), and
      spherical equivalent. RESULTS: The mean corneal thickness was 537.6 +/- 37.5
      microm (range, 334-702). The mean anterior chamber depth was 3.5 +/- 0.38 mm
      (range, 1.99-4.75). The iris color was dark in 829 (61.8%) eyes and light in 512
      (38.2%). The mean scotopic pupil size was 6.1 +/- 0.9 mm (range, 3.5-9.0) and the
      mean photopic pupil size was 4.0 +/- 0.7 mm (range, 2.1-7.4). The mean spherical
      equivalent was -3.4 +/- 3.7 D (range, -16.00-+7.50 D). Age was correlated with
      corneal thickness (r = 0.069, p = 0.012), spherical equivalent (r = 0.080, p =
      0.003), and inversely correlated with corneal diameter (r = -0.367, p< 0.001),
      anterior chamber depth (r = -0.335, p< 0.001), scotopic pupil size (r = -0.309,
      p< 0.001), and photopic pupil size (r = -0.367, p< 0.001). Males had larger
      corneas (p< 0.001) and deeper anterior chambers (p< 0.001) than females. The eyes
      with a dark iris color had thicker corneas (p< 0.001), deeper anterior chambers
      (p< 0.001), and more minus spherical equivalents (p = 0.017) than the eyes with a
      light iris color. CONCLUSIONS: There is a substantial range of dimensions of
      anterior structures of the human eye. These dimensions are related to each other
      and are influenced by age, sex, iris color, and refractive state of the eye.

PMID- 12605045
TI  - A profile of keratoconus in New Zealand.
AB  - PURPOSE: To examine the characteristics and risk factors for keratoconus in a New
      Zealand population. METHODS: A one-page questionnaire was designed and sent to
      optometrists and ophthalmologists in New Zealand. Eye care practitioners then
      issued questionnaires to their keratoconic patients over a 6-month period.
      RESULTS: A total of 673 completed questionnaires were received from patients with
      keratoconus. A male bias (59%) was apparent in the sample. In line with previous
      work, a high proportion of the keratoconic cohort rubbed their eyes and suffered
      from atopy. A familial rate of 23.5% was evident, with several families reporting
      multiple keratoconus cases. Eleven pairs of twins were identified with at least
      one keratoconic sibling. Multivariate statistical analysis revealed significant
      independent correlations between the early development of keratoconus and gender,
      allergy, asthma, and latitude of childhood domicile. CONCLUSION: Results from the
      survey concur with a previous local report that keratoconus affects males more
      frequently and earlier in life than females in New Zealand. The concurrence of
      atopic disease and eye rubbing with keratoconus was as expected, and an
      association between the early development of the disease and latitude of the
      childhood domicile emerged. A strong familial component, exceeding previously
      reported figures, was evident in the cohort.

PMID- 12605046
TI  - Evaluation of bone reduction in osteo-odontokeratoprosthesis (OOKP) by three
      dimensional computed tomography.
AB  - PURPOSE: To study the stability and preservation of the osteodental lamina in
      osteo-odontokeratoprosthesis (OOKP) according to Strampelli with spiral computed
      tomography (CT). METHODS: Computed tomography of the orbit was performed in nine
      patients after successful OOKP surgery. Indications for surgery included ocular
      pemphigoid (three patients), Lyell's syndrome (two patients), graft versus host
      disease (one patient), and severe chemical burns (three patients). In four eyes,
      the osteodental lamina was covered with a buccal mucosa graft; in five eyes, a
      "transpalpebral" approach with the placement of the optical cylinder through the
      patient's own lid skin was used. The mean time from surgery to examination was 4
      years. The age of the patients ranged from 32 to 75 years (mean, 52). Spiral CT
      in the transaxial plane was performed, followed by three-dimensional (3D) surface
      reconstruction of the OOKP. The dimensions of the osteodental lamina were
      measured and compared with measurements taken at the time of surgery. RESULTS: A
      minor reduction of the lamina, mainly in the anterior and inferior part, could be
      found in all the patients without loss of stability and integrity of the lamina
      cylinder complex in seven patients. One patient showed complete resorption of the
      inferior half of the osteodental lamina, and another patient demonstrated "moth
      eaten" dissolution of dentine and bone tissue. No correlation between the degree
      of reduction in the dimensions and patient age, diagnosis, or length of follow-up
      could be found. CONCLUSION: Osteo-odontokeratoprosthesis shows good results in
      patients with corneal blindness not amenable to keratoplasty. Nevertheless, the
      surgeon must be aware of eventual signs of dissolution of the osteodental lamina,
      making close follow-up mandatory. Because ultrasound biomicroscopy cannot be used
      in these cases, spiral CT with 3D reconstruction seems to be a good diagnostic
      alternative.

PMID- 12605047
TI  - Phenotype of Pseudomonas aeruginosa isolates causing corneal infection between
      1997 and 2000.
AB  - PURPOSE: To investigate the relationship between functional phenotype of and the
      associated human corneal infection. METHODS: This was an experimental pilot study
      of patients presenting with corneal infections at the Jules Stein Eye Institute
      with presumed infection during the period from 12/30/97 to 9/1/00. Thirteen
      patients were admitted to the study based on positive identification of the
      causative pathogen as and patient consent. Data were collected (including
      bacterial cultures, lens wear schedule and care, gender and age, completed
      history questionnaire, clinical photographs). Statistical analysis of possible
      correlations was performed. Phenotypes of were determined, and clinical factors
      associated with infection were explored. RESULTS: Both invasive and cytotoxic
      phenotypes of were isolated in equal proportion. Cytotoxic strains and invasive
      strains were found to be associated with patients younger than 50 years of age
      and older than 50 years of age, respectively. CONCLUSIONS: remains a significant
      pathogen in corneal infection, especially during contact lens wear. The age of
      the patient may influence the phenotype of causing infection. Since invasive and
      cytotoxic strains have different effects on corneal cells, treatment of the
      infection might require different approaches depending on this phenotype of the
      causative bacteria.

PMID- 12605048
TI  - Squamous cell carcinoma of the conjunctiva in patients with atopic eczema.
AB  - PURPOSE: To report squamous cell carcinoma (SCC) of the conjunctiva in patients
      with atopic eczema. METHODS: A retrospective study of six patients with
      conjunctival SCC associated with atopic eczema. Clinical and pathologic records
      were reviewed. RESULTS: Ten patients with conjunctival SCC were seen from October
      1999 to May 2002 at the Department of Ophthalmology at the University of Essen.
      Six of 10 patients had also atopic eczema. These six patients were treated either
      with local excision and ocular surface reconstruction or proton beam
      radiotherapy. None of the patients had local recurrences or metastases.
      CONCLUSION: Atopic eczema is a common dermatological disease. An association with
      conjunctival SCC has not been reported so far. Squamous cell carcinoma has also
      been found in patients with AIDS and other immunosuppressed individuals. The
      dysfunction of T lymphocytes found in these disorders might play a crucial role
      in the malignant transformation of conjunctival tissue. Because of the reported
      frequency of SCC, patients with atopic eczema should be monitored for
      abnormalities.

PMID- 12605050
TI  - Laser in situ keratomileusis flap stability during simulated aircraft ejection in
      a rabbit model.
AB  - PURPOSE: To determine the stability of the laser in situ keratomileusis (LASIK)
      flap in a rabbit model when subjected to vertical acceleration at nine times the
      force of gravity (+9 Gz) in an aircraft cockpit ejection simulator. METHODS:
      Thirty-six eyes from 25 New Zealand white rabbits underwent LASIK flap creation
      without laser photoablation. One month after surgery, the rabbits were sedated
      and harnessed in a cockpit ejection seat simulator used to train United States
      Air Force pilots. They then underwent a controlled rapid-sequence ejection at +9
      Gz. Subsequently, the rabbits were euthanized and the corneas harvested for
      microscopic examination. Refractive measurements and corneal examination were
      made before LASIK flap creation and prior to and after the +9 Gz ejections.
      Determination of LASIK flap dislocation was based on clinical observation of flap
      slippage or a significant shift in pre-ejection to postejection cylinder axis.
      RESULTS: The average preoperative refraction of the rabbit eye was +1.83 D + 3.25
      D x 086 degrees. The average change from pre-ejection to postejection was 0.04 D
      sphere, 0.02 D cylinder, 6.8 axis degrees, and 0.04 D spherical equivalent. The
      pre-ejection to postejection measurements were not statistically significantly
      different by a paired test. Laser in situ keratomileusis flap dislocation or
      ejection-induced corneal folds or striae were not clinically observed. Histologic
      examination revealed well-healed LASIK flaps but no reactive keratocytes at the
      central stromal-stromal interface. CONCLUSIONS: Healed LASIK flaps as created in
      this rabbit model without laser ablation are stable when subjected to a rapid
      vertical ejection at nine times the force of gravity.

PMID- 12605049
TI  - Role of 0.02% polyhexamethylene biguanide and 1% povidone iodine in experimental
      Aspergillus keratitis.
AB  - PURPOSE: To determine the efficacy of 0.02% polyhexamethylene biguanide and 1%
      povidone iodine in experimental keratitis. METHODS: Aspergillus fumigatus
      keratitis was induced by corneal intrastromal injection of spores in 24 healthy
      rabbits that were randomly divided into four groups of six rabbits each. Drugs
      used were 5% natamycin (standard antifungal), 0.02% polyhexamethylene biguanide
      (PHMB) (test drug), 1% povidone iodine (test drug), and 0.5% hydroxypropylmethyl
      cellulose (HPMC) (control). RESULTS: The average healing times of the ulcer were
      21.5 +/- 3.08 days with 5% natamycin, 27.8 +/- 2.28 days with 0.02% PHMB, 36.4 +/
      2.57 days with 1% povidone iodine, and 38.2 +/- 4.74 days with 0.5% HPMC. While
      no corneal perforations occurred with natamycin treatment, one perforation was
      noted with PHMB, three perforations were noted with povidone iodine, and five
      perforations were noted with controls. CONCLUSION: Polyhexamethylene biguanide
      (0.02%) is a moderately effective drug for experimental Aspergillus keratitis,
      but 1% povidone iodine is not effective.

PMID- 12605051
TI  - Histologic evaluation of corneal stroma in rabbits after intrastromal corneal
      ring implantation.
AB  - PURPOSE: Previous refractive corneal implants have produced histologic changes
      characteristic of nonspecific lipid keratopathy. Intacs intrastromal corneal ring
      segments are polymethylmethacrylate (PMMA) corneal inserts approved for the
      correction of low myopia by the U.S. Food and Drug Administration. The purpose of
      this study was to describe histologic changes associated with these corneal
      implants in rabbit eyes. METHODS: Two 150-degree PMMA arc segments, 0.30 mm
      thick, were surgically implanted through a single radial incision at two-thirds
      stromal depth in the mid-peripheral cornea of five New Zealand white rabbits. We
      collected corneas 6 months after implantation that were prepared for light and
      electron microscopy. We analyzed tissue with oil red O, filipin, and periodic
      acid-Schiff (PAS) staining. Additional studies with energy-dispersive x-ray
      analysis and autofluorescent microscopy were conducted. RESULTS: In all samples,
      we observed new collagen formation with lamellar organization adjacent to the
      implant and increased keratocyte density. Intracellular accumulations of
      osmophilic and saturated lipid material corresponded to stromal opacification
      visible by slit-lamp microscopy. These same regions were autofluorescent and
      stained positively with oil red O, and filipin but negatively with PAS. Granular
      lipid inclusions characteristic of lipofuscinosis were absent on transmission
      electron microscopy. Energy-dispersive x-ray analysis demonstrated elevated
      levels of calcium compared with adjacent tissue. CONCLUSION: Tissue response to
      these corneal inserts includes keratocyte activation, intracellular lipid
      accumulation, and new collagen formation. Our histologic findings suggest that
      these deposit formations are not lipofuscin accumulations.

PMID- 12605052
TI  - Smad7 suppresses the inhibitory effect of TGF-beta2 on corneal endothelial cell
      proliferation and accelerates corneal endothelial wound closure in vitro.
AB  - PURPOSE: The inhibitory activity of transforming growth factor-beta2 (TGF-beta2)
      on corneal endothelial cell proliferation is thought to be a cause of the limited
      regenerative capacity of corneal endothelial cells that may be related to
      impaired corneal transparency when many corneal endothelial cells are lost due to
      various stresses. We determined whether Smad7, an intracellular antagonist of TGF
      beta signaling, regulated the inhibitory activity of TGF-beta2 or aqueous humor
      on corneal endothelial cell proliferation. METHODS: The effect of Smad7 on TGF
      beta2- or aqueous humor-mediated inhibition of corneal endothelial cell
      proliferation was evaluated using thymidine uptake assay with cultured rabbit
      corneal endothelial cells infected with adenovirus carrying Smad7. Expression of
      Smad or cell cycle-related proteins was detected by immunoblotting. In addition,
      a small scrape wound was made across a monolayer of Smad7-expressing cultured
      rabbit corneal endothelial cells to examine the effect of Smad7 on the wound
      healing process in vitro. RESULTS: Overexpression of Smad7 abolished the
      inhibitory effect of TGF-beta2 or aqueous humor on the proliferation of cultured
      rabbit corneal endothelial cells associated with the inhibition of
      phosphorylation of Smad2 and downregulation of p27kip1. Smad7-overexpressing
      cultured rabbit corneal endothelial cells exhibited shorter wound closure time in
      the presence of aqueous humor than LacZ-expressing cells. CONCLUSION:
      Overexpression of Smad7 suppressed the inhibitory effect of TGF-beta2 or aqueous
      humor on corneal endothelial cell proliferation and accelerated corneal
      endothelial wound closure in vitro. Modification of Smad7 expression in corneal
      endothelial cells may thus have applicability in the treatment of wounded corneal
      endothelium.

PMID- 12605053
TI  - In vivo confocal microscopy of Fleck dystrophy and pre-Descemet's membrane
      corneal dystrophy.
AB  - PURPOSE: To assess the value of in vivo confocal microscopy (CM) in the diagnosis
      of Fleck dystrophy and pre-Descemet's membrane corneal dystrophy. METHODS: Case
      report of two patients. Standard slit-lamp and ophthalmic examination and in vivo
      CM were performed on both patients. The thickness of the cornea and the
      morphology of the corneal epithelium, stroma, endothelium, and subbasal nerves
      were evaluated by confocal microscopy. RESULTS: Biomicroscopy revealed bilateral,
      fine, dust-, and flour-like opacities in the corneal stroma for the Fleck
      dystrophy patient. In the pre-Descemet's membrane corneal dystrophy patient,
      biomicroscopy showed opacities larger than those in the first patient. Both
      patients were then examined by in vivo CM. Confocal microscopy of the Fleck
      dystrophy showed intracellular deposits throughout the stroma. In pre-Descemet's
      membrane corneal dystrophy, however, these and the extracellular deposits were
      observed immediately anterior to Descemet's membrane. The thicknesses of the
      corneas were 560 and 650 microm for Fleck and pre-Descemet's membrane corneal
      dystrophy, respectively. The surface epithelium, subbasal nerves, and endothelium
      showed normal morphology in both patients. CONCLUSION: In vivo CM is a valuable
      tool in diagnosing rare corneal dystrophies when the final diagnosis is difficult
      to obtain with conventional methods.

PMID- 12605054
TI  - Penetrating keratoplasty as a globe-saving procedure in fragile cornea.
AB  - PURPOSE: To report a case of fragile cornea associated with osteogenesis
      imperfecta type I in which primary penetrating keratoplasty was done as a
      tectonic procedure. METHODS: A 6-year-old boy with osteogenesis imperfecta type I
      presented with a corneal laceration in his right eye following minor trauma.
      Since wound repair was not possible due to tissue loss, he underwent a primary
      penetrating keratoplasty. RESULTS: Postoperatively, the eye healed well without
      any wound leak. The boy had uneventful suture removal 10 weeks following surgery.
      CONCLUSION: Primary penetrating keratoplasty is a viable option to restore ocular
      integrity in fragile corneas following trauma when tissue loss precludes simple
      repair.

PMID- 12605055
TI  - Keratitis caused by an unusual fungus, Phoma species.
AB  - PURPOSE: To describe the histopathologic profile of a case of keratitis caused by
      Phoma species and to evaluate the role of polymerase chain reaction in the
      diagnosis of this unusual fungal infection. METHODS: Clinical information was
      extracted after a review of the medical records of a 72-year-old man developing a
      nonhealing corneal ulcer with brownish pigmentation. Microbiologic cultures and
      histopathologic examination were performed on the keratectomy specimen.
      Polymerase chain reaction was performed on DNA extracted from five (10-microm
      thick) paraffin-embedded sections using panfungal primers. RESULTS:
      Histopathologic examination revealed round spherules of variable diameter (5-30
      microm) admixed with septate hyphae at the edges of the perforated cornea.
      Microbiologic cultures grew a fungus identified as Phoma species. Polymerase
      chain reaction from the specimen yielded a single product with an approximate
      size of 360 bp. CONCLUSION: Phoma species, though rarely pathogenic to humans,
      may cause keratitis in some patients. To our knowledge, this is the first well
      documented case of Phoma keratitis.

PMID- 12605057
TI  - Oligosymptomatic cornea verticillata in a heterozygote for Fabry disease: a novel
      mutation in the alpha-galactosidase gene.
AB  - BACKGROUND: Fabry disease is an X-linked genetic disorder involving sphingolipid
      catabolism, which is caused by lysosomal alpha-galactosidase A deficiency.
      Ophthalmological findings such as corneal and lens opacities and conjunctival and
      retinal vessel abnormalities can be the only and/or the first recognizable
      symptoms, especially in heterozygous females. METHODS: We report on a 34-year-old
      German woman with cornea verticillata. The alpha-galactosidase A activity was
      determined in leukocytes using a fluorescence substrate, and the sequence
      analysis of the alpha galactosidase A gene was performed with genomic DNA.
      RESULTS: The alpha-galactosidase A activity in leukocytes was significantly low
      (0.24 nmol/min/mg protein; normal range, 0.4-1.2), which is compatible with a
      heterozygote for Fabry disease. The following sequence analysis revealed a
      heterozygous transition in position IVS5 + 2 T > C. Transition of thymine (T) to
      cytosine (C) affects the donor splice motive of exon 5 and most probably leads to
      an aberrant splicing procedure of the alpha-galactosidase A gene. CONCLUSION: Our
      case emphasizes the importance of ophthalmological findings in Fabry disease. The
      subsequent biochemical and molecular analysis provides a secure diagnosis of
      female carriers of Fabry disease.

PMID- 12605056
TI  - Spontaneous corneal hydrops and perforation in keratoconus and pellucid marginal
      degeneration.
AB  - PURPOSE: To report two cases of pellucid marginal degeneration and one case of
      keratoconus associated with spontaneous corneal hydrops leading either to
      perforation or imminent perforation, requiring urgent keratoplasty. METHOD:
      Retrospective interventional case series of three patients with noninflammatory
      peripheral corneal degenerations. A retrospective review was done of the clinical
      courses, surgical interventions, and pathologic specimens, development of
      spontaneous hydrops, perforation, need for surgical intervention, and final
      visual outcome. RESULTS: Two patients with pellucid marginal degeneration and one
      with keratoconus developed spontaneous hydrops followed by aqueous leakage
      through markedly thinned anterior stroma. In one case, the leak site was
      successfully sealed after three separate applications of tissue adhesive,
      although the remaining two cases required penetrating keratoplasty. CONCLUSIONS:
      These cases document the very unusual occurrence of corneal hydrops leading to
      spontaneous corneal perforation in patients with keratoconus and pellucid
      marginal degeneration.

PMID- 12605058
TI  - Aniridia and Brachmann-de Lange syndrome: a review of ocular surface and anterior
      segment findings.
AB  - PURPOSE: To review the ocular surface and anterior segment findings in Brachmann
      de Lange syndrome and describe a new case involving aniridia and congenital
      glaucoma. METHODS: A newborn presented 2 days after birth with bilateral cloudy
      corneas, photophobia, and epiphora. We provide a 5-year descriptive history and
      clinical course with review of the literature on Brachmann-de Lange syndrome.
      RESULTS: Multiple ocular surgeries were performed for ocular sequelae from
      aniridia and congenital glaucoma including Ahmed valve placement and penetrating
      keratoplasties in both eyes. At 5.5 years of age, the child had a clear graft OD
      and amblyopia from graft failure OS following recurrent graft infections. A
      review of Brachmann-de Lange syndrome found 43 patients with ocular surface and
      anterior segment findings. The most common findings included conjunctivitis,
      blepharitis, microcornea, and corectopia. Aniridia and congenital glaucoma were
      not previously reported with Brachmann-de Lange syndrome. CONCLUSIONS: Ocular
      surface and anterior segment abnormalities must be considered when examining
      patients with Brachmann-de Lange syndrome. Ocular findings may include vision
      threatening anomalies, as in our case with aniridia and congenital glaucoma. To
      our knowledge, these findings are previously unreported in Brachmann-de Lange
      syndrome.

PMID- 12605059
TI  - Visual rehabilitation after severe alkali injury with piggyback hyper O2 contact
      lenses.
AB  - PURPOSE: To report successful visual rehabilitation following severe bilateral
      alkali injury using piggyback hyperoxygen-transmissible (hyper O2) contact
      lenses. METHODS: Case report and literature review. RESULTS: More than 15 years
      after a severe bilateral alkali injury, multiple surgical procedures including
      repeat bilateral penetrating keratoplasty, severe tear deficiency, and chronic
      ocular surface disruption, the patient achieved 20/30 best-corrected vision
      through the simultaneous use of a hyper O2 rigid gas permeable contact lens over
      a hyper O2 soft contact lens in his right eye. The patient has tolerated this
      piggyback combination without any adverse reactions or complications, and his
      corneal graft remains clear and healthy. CONCLUSION: Visual rehabilitation for
      conditions that compromise the ocular surface can be accomplished by utilizing
      newer soft and rigid contact lens materials that facilitate oxygen transmission,
      thereby promoting epithelial healing and improving safety in extended wear
      situations. These newer materials may potentially reduce complications previously
      associated with extended wear therapeutic lenses.

PMID- 12605060
TI  - Epithelial ingrowth in a phakic corneal transplant patient after traumatic wound
      dehiscence.
AB  - PURPOSE: To report a case of epithelial ingrowth (downgrowth) occurring in a
      phakic corneal transplant patient after traumatic wound dehiscence with iris
      prolapse that was successfully eradicated with early surgical intervention.
      METHODS: Interventional case report of a 70-year-old monocular, phakic patient
      who developed epithelial ingrowth within 1 week of repair of a traumatic
      penetrating keratoplasty wound dehiscence, with reposition of the iris that had
      been prolapsed for 36 hours. A gradually expanding membrane developed from the
      surface of the reposited iris, across the anterior lens capsule. Argon laser
      photocoagulation applied to the surface of the iris confirmed the diagnosis and
      outlined the extent of the epithelial tissue on the iris. RESULTS: Intraoperative
      peeling of the epithelial membrane from the surface of the lens and excision of
      the involved iris were performed combined with extracapsular cataract extraction
      and insertion of a posterior chamber intraocular lens via an open-sky technique
      through a repeat penetrating keratoplasty opening in the cornea. This resulted in
      complete resolution of the intraocular epithelialization. Histopathologic
      examination of the excised tissue confirmed the diagnosis of epithelial ingrowth.
      CONCLUSIONS: Reposition of traumatically prolapsed iris tissue can result in
      epithelial ingrowth. Early aggressive surgical intervention can successfully
      remove all the epithelial tissue from within the anterior segment.

PMID- 12605061
TI  - Response to symptomatic management of postoperative bullous keratopathy with
      nonpreserved human amniotic membrane.

PMID- 12605062
TI  - Infectious post-LASIK crystalline keratopathy caused by nontuberculous
      mycobacteria.

PMID- 12605063
TI  - Response to efficacy and safety of recurrent pterygium surgery using human
      processed pericardium.

PMID- 12605064
TI  - Neuropeptide y and alcoholism: genetic, molecular, and pharmacological evidence.
AB  - This article presents the proceedings of a symposium presented at the combined
      meeting of the Research Society on Alcoholism and the International Society for
      Biomedical Research on Alcoholism, held in San Francisco, CA, in June 2002. The
      organizers and chairpersons were Subhash C. Pandey and Todd E. Thiele. The
      presentations were (1) Altered ethanol-induced sedation and ethanol drinking in
      mutant mice lacking specific NPY receptor, by Todd E. Thiele; (2) NPY in P and NP
      rats: polymorphism and mRNA expression, by Lucinda G. Carr; (3) The cAMP
      dependent PKA in the central amygdala regulates alcohol intake through NPY gene,
      by Subhash C. Pandey; (4) Involvement of NPY in alcohol dependence: from animal
      models to human genetics, by Markus Heilig; and (5) Association of neuropeptide Y
      polymorphism with the occurrence of type 1 and type 2 alcoholism, by Erkki
      Ilveskoski.

PMID- 12605065
TI  - Gene expression in brain: a window on ethanol dependence, neuroadaptation, and
      preference.
AB  - This article represents the proceedings of a symposium at the 2002 joint
      RSA/ISBRA Conference in San Francisco, California. The organizer was Paula L.
      Hoffman and the co-chairs were Paula L. Hoffman and Michael Miles. The
      presentations were (1) Introduction and overview of the use of DNA microarrays,
      by Michael Miles; (2) DNA microarray analysis of gene expression in brains of P
      and NP rats, by Howard J. Edenberg; (3) Gene expression patterns in brain regions
      of AA and ANA rats, by Wolfgang Sommer; (4) Patterns of gene expression in brains
      of selected lines of mice that differ in ethanol tolerance, by Boris Tabakoff;
      (5) Gene expression profiling related to initial sensitivity and tolerance in
      gamma-protein kinase C mutants, by Jeanne Wehner; and (6) Gene expression
      patterns in human alcoholic brain: from microarrays to protein profiles, by
      Joanne Lewohl.

PMID- 12605066
TI  - Genetics of alcoholism using intermediate phenotypes.
AB  - This article represents the proceedings of a symposium at the 2002 meeting of the
      Research Society on Alcoholism in San Francisco, CA. It was organized by Mary
      Anne Enoch and David Goldman and chaired by David Goldman. The presentations were
      (1) Two functional polymorphisms and their intermediate phenotypes in complex
      behaviors: COMT/executive cognition and anxiety and HTT/anxiety, by David
      Goldman; (2) Role of the EEG in determining genetic risk for alcoholism and
      anxiety disorders, by Mary-Anne Enoch; (3) The response to alcohol as an
      intermediate phenotype for alcoholism, by Marc A. Schuckit; and (4)
      Pharmacogenomic approaches to alcoholism treatment: toward a hypothesis, by
      Bankole A. Johnson.

PMID- 12605067
TI  - Herbal remedies for alcoholism: promises and possible pitfalls.
AB  - This review summarizes the findings of the effects on alcohol intake in alcohol
      preferring rats of extracts or purified compounds from two of the most promising
      herbs: kudzu (Pueraria lobata) and St. John's Wort (Hypericum perforatum). It is
      a summary of a symposium presented at the 2002 RSA meeting in San Francisco. The
      meeting organizers/co-chairs were David Overstreet and Wing-Ming Keung. The
      presentations were (1) Introduction to the symposium, by David Y. W. Lee and
      David H. Overstreet; (2) Effects of daidzin on alcohol intake-search for
      mechanisms of action, by Wing-Ming Keung; (3) Long-term suppressive effects of
      puerarin on alcohol drinking in rats, by David Overstreet and David Y. W. Lee;
      (4) St. John's Wort extract reduces alcohol intake in FH and P rats, by Amir
      Rezvani and David Overstreet; and (5) extracts reduce alcohol intake in
      Marchigian Sardinian alcohol-preferring rats, by Maurizio Massi.

PMID- 12605068
TI  - Changing expectancies: cognitive mechanisms and context effects.
AB  - This article presents the proceedings of a symposium at the 2002 RSA Meeting in
      San Francisco, organized by Reinout W. Wiers and Mark D. Wood. The symposium
      combined two topics of recent interest in studies of alcohol expectancies:
      cognitive mechanisms in expectancy challenge studies, and context-related changes
      of expectancies. With increasing recognition of the substantial role played by
      alcohol expectancies in drinking, investigators have begun to develop and
      evaluate expectancy challenge procedures as a potentially promising new
      prevention strategy. The two major issues addressed in the symposium were whether
      expectancy challenges result in changes in expectancies that mediate intervention
      (outcome relations), and the influence of simulated bar environments ("bar labs,"
      in which challenges are usually done) on expectancies. The presentations were (1)
      An introduction, by Jack Darkes; (2) Investigating the utility of alcohol
      expectancy challenge with heavy drinking college students, by Mark D. Wood; (3)
      Effects of an expectancy challenge on implicit and explicit expectancies and
      drinking, by Reinout W. Wiers; (4) Effects of graphic feedback and simulated bar
      assessments on alcohol expectancies and consumption, by William R. Corbin; (5)
      Implicit alcohol associations and context, by Barry T Jones; and (6) A discussion
      by Kenneth J. Sher, who pointed out that it is important not only to study
      changes of expectancies in the paradigm of an expectancy challenge but also to
      consider the role of changing expectancies in natural development and in
      treatments not explicitly aimed at changing expectancies.

PMID- 12605069
TI  - Diverse research on alcohol and aggression in humans: in memory of John A.
      Carpenter.
AB  - This article summarizes the proceedings of a symposium, chaired and co-organized
      by Helene Raskin White and co-organized by Peter R. Giancola, that was presented
      at the 2002 RSA Meeting in San Francisco. The goal of this symposium was to
      integrate findings from methodologically divergent studies on the topic of
      alcohol-related aggression in humans. The investigators focused on isolating
      mediators and moderators of the alcohol-aggression relationship. Peter R.
      Giancola presented laboratory data demonstrating how alcohol's acute effects on
      aggression are moderated by individual difference and contextual factors.
      Mitchell E. Berman presented laboratory data on alcohol's acute effects on self
      induced aggression. Helene Raskin White reviewed prospective data on how alcohol
      affects the intergenerational transmission of family violence. Stephen Chermack
      reviewed data on the impact of a family history of alcoholism and a family
      history of violence on the development of childhood behavioral problems and adult
      problems with drugs, alcohol, and violence. Finally, Kenneth E. Leonard presented
      data on personal and contextual factors influencing alcohol-related barroom
      violence.

PMID- 12605070
TI  - New neuronal networks involved in ethanol reinforcement.
AB  - This article represents the proceedings of a symposium at the 2002 ISBRA/RSA
      meeting in San Francisco. The organizers were Kalervo Kiianmaa and Andrey E.
      Ryabinin. The chairs were Kalervo Kiianmaa and Jorgen A. Engel. The presentations
      were (1) The role of opioidergic and dopaminergic networks in ethanol-seeking
      behavior, by Kalervo Kiianmaa and Petri Hyytia; (2) Interaction between the
      dopamine systems in the prefrontal cortex and nucleus accumbens during ethanol
      self-administration, by Herman H. Samson; (3) Neurochemical and behavioral
      studies on ethanol and nicotine interactions, by Jorgen A. Engel, Lennart
      Svensson, Bo Soderpalm, and Anna Larsson; (4) Involvement of the GABA receptor in
      alcohol reinforcement in sP rats, by Giancarlo Colombo and Giovanni Vacca; (5)
      Neuroactive steroids and ethanol reinforcement, by Deborah A. Finn, and (6)
      Potential contribution of the urocortin system to regulation of alcohol self
      administration, by Andrey E. Ryabinin and Ryan K. Bachtell.(B)

PMID- 12605072
TI  - Alcoholism: allostasis and beyond.
AB  - Alcoholism is a chronic relapsing disorder characterized by compulsive drinking,
      loss of control over intake, and impaired social and occupational function.
      Animal models have been developed for various stages of the alcohol addiction
      cycle with a focus on the motivational effects of withdrawal, craving, and
      protracted abstinence. A conceptual framework focused on allostatic changes in
      reward function that lead to excessive drinking provides a heuristic framework
      with which to identify the neurobiologic mechanisms involved in the development
      of alcoholism. Neuropharmacologic studies in animal models have provided evidence
      for specific neurochemical mechanisms in specific brain reward and stress
      circuits that become dysregulated during the development of alcohol dependence.
      The brain reward system implicated in the development of alcoholism comprises key
      elements of a basal forebrain macrostructure termed the extended amygdala that
      includes the central nucleus of the amygdala, the bed nucleus of the stria
      terminalis, and a transition zone in the medial (shell) part of the nucleus
      accumbens. There are multiple neurotransmitter systems that converge on the
      extended amygdala that become dysregulated during the development of alcohol
      dependence, including gamma-aminobutyric acid, opioid peptides, glutamate,
      serotonin, and dopamine. In addition, the brain stress systems may contribute
      significantly to the allostatic state. During the development of alcohol
      dependence, corticotropin-releasing factor may be recruited, and the neuropeptide
      Y brain antistress system may be compromised. These changes in the reward and
      stress systems are hypothesized to maintain hedonic stability in an allostatic
      state, as opposed to a homeostatic state, and as such convey the vulnerability
      for relapse in recovering alcoholics. The allostatic model not only integrates
      molecular, cellular, and circuitry neuroadaptations in brain motivational systems
      produced by chronic alcohol ingestion with genetic vulnerability but also
      provides a key to translate advances in animal studies to the human condition.

PMID- 12605073
TI  - The validity of DSM-IV alcohol dependence: what do we know and what do we need to
      know?
AB  - This article presents the proceedings of a symposium at the 2002 RSA Meeting in
      San Francisco, California. Deborah S. Hasin organized the symposium and co
      chaired it with Marc Schuckit. The purpose of the symposium was to provide an
      overview of what is known about the validity of DSM-IV and ICD-10 alcohol
      dependence and abuse, with a focus on work done since 1994. Presentations
      included: (1) Validity of DSM-III-R alcohol dependence in adolescents, by
      Christopher S. Martin; (2) Reliability and validity of DSM and ICD formulations
      of alcohol use disorders: findings from epidemiology, by Bridget F. Grant; (3)
      Validity and reliability of the alcohol-dependence phenotype in the context of
      genetic studies, by Kathleen K. Bucholz; and (4) DSM-IV and beyond: uniting the
      clinical utility of categories with the precision of dimensions, by John E.
      Helzer. The findings supported the validity of DSM-IV alcohol dependence across
      numerous study designs and samples, suggested some value in a dimensional
      dependence measure, and raised questions about the validity of the diagnosis of
      alcohol abuse as currently defined. Marc Schuckit, as discussant for the
      symposium, placed the issues in perspective for the upcoming DSM-V.

PMID- 12605071
TI  - Chemosensory factors influencing alcohol perception, preferences, and
      consumption.
AB  - This article presents the proceedings of a symposium at the 2002 RSA/ISBRA
      Meeting in San Francisco, California, co-organized by Julie A. Mennella and
      Alexander A. Bachmanov of the Monell Chemical Senses Center. The goal of this
      symposium was to review the role that chemosensory factors (taste, smell, and
      chemical irritation) play in the perception, preference, and consumption of
      alcohol. The presented research focused on both humans and laboratory animals and
      used a variety of approaches including genetic, developmental, pharmacological,
      behavioral, and psychophysical studies. The presentations were as follows: (1)
      Introduction and overview of the chemical senses (Julie A. Mennella and Alexander
      A. Bachmanov); (2) Taste reactivity as a measure of alcohol palatability and its
      relation to alcohol consumption in rats (Stephen W. Kiefer); (3) Early learning
      about the sensory properties of alcohol in laboratory animals (Juan Carlos
      Molina); (4) Early learning about the sensory properties of alcohol in humans
      (Julie A. Mennella); (5) Genetic dissection of the ethanol-sweet taste
      relationship in mice (Alexander A. Bachmanov and Michael Tordoff); and (6) Human
      genetic variation in taste: connections with alcohol sensation and intake
      (Valerie B. Duffy and Linda M. Bartoshuk). The symposium concluded with a general
      discussion.

PMID- 12605074
TI  - Course of alcohol problems in treated adolescents.
AB  - Knowledge of the clinical course in treated adolescents is fundamental to
      determining the influence of treatment on long-term functioning and the factors
      associated with change in the severity of alcohol problems over time. This
      symposium, held at the 2002 annual Research Society on Alcoholism meeting and
      organized by Tammy Chung and Christopher S. Martin, presented research on the
      course of alcohol-related problems in treated adolescents who were followed
      prospectively for 1 to 8 years. Presentations included (1) Alcohol use outcomes
      at 1 year among adolescents in the drug abuse treatment outcomes studies (DATOS
      A), by Christine E. Grella; (2) Pathways and predictors of the course of
      adolescent alcohol problems across 1- and 3-year follow-ups, by Tammy Chung; (3)
      Young adult outcomes of an adolescent clinical sample at 5-year follow-up, by Ken
      C. Winters; and (4) Trajectories of alcohol involvement following addiction
      treatment through 8-year follow-up in adolescents, by Ana M. Abrantes, Denis M.
      McCarthy, Gregory A. Aarons, and Sandra A. Brown. Sandra A. Brown, discussant,
      commented on the presentations. Results from these studies indicate multiple
      pathways of change, distinguished by fluctuations in the chronicity and severity
      of alcohol problems. Across studies, most adolescents showed reductions in
      alcohol use and problems after treatment, with concurrent improvements in
      psychosocial functioning. Findings highlight the influence of other drug use on
      posttreatment patterns of alcohol involvement and the need to consider the effect
      of normative developmental transitions on the course of adolescent-onset
      substance use disorders.

PMID- 12605075
TI  - Identification and brief treatment of alcohol problems with medical patients: an
      international perspective.
AB  - This article summarizes the proceedings of a symposium at the 2002 RSA meeting in
      San Francisco, California. The chair was Peter Monti and co-chair was Nancy
      Barnett. The aim of the symposium was to bring together researchers from the
      United States, Sweden, and Mexico to present current findings on the development
      and implementation of screening and intervention research in Emergency
      Departments (ED). Cheryl Cherpitel presented findings on the performance of the
      Rapid Alcohol Problems Screen (RAPS4), a 4-item instrument used for screening for
      alcohol dependence and harmful drinking in the ED. Dr. Cherpitel also presented
      for her collaborator, Guilherme Borges, their research on the performance of a
      number of screening measures including the RAPS among Mexicans and Mexican
      Americans with alcohol-related disorders in the ED. Preben Bendtsen described the
      implementation of an alcohol screening and intervention procedure delivered by
      ordinary ED staff in Sweden. Nancy Barnett presented data on characteristics
      related to readiness to change alcohol use in a sample of young adults who were
      treated in an ED for injury or intoxication.

PMID- 12605076
TI  - Services integration and cost-effectiveness.
AB  - Alcohol treatment services are increasingly combined with other health and social
      services to address the needs of multiple-problem clients. Hence, it has been of
      growing policy interest to find the most effective and the most cost-effective
      ways of linking these services. This symposium presents some recent studies in
      this area. The small but growing body of studies in this area has great potential
      to inform public policy debates.

PMID- 12605077
TI  - Ego depletion and self-regulation failure: a resource model of self-control.
AB  - Effective self-regulation is an important key to successful functioning in many
      spheres, and failed self-regulation may be centrally conducive to substance abuse
      and addiction. The program of research summarized here indicates that self
      regulation operates as a limited resource, akin to strength or energy, especially
      insofar as it becomes depleted after use-leaving the depleted self subsequently
      vulnerable to impulsive and undercontrolled behaviors (including increased
      consumption of alcohol). The self's resources, which are also used for decision
      making and active responding, can be replenished by rest and positive emotions.

PMID- 12605078
TI  - Recent research on the comorbidity of alcoholism and pathological gambling.
AB  - This article summarizes a symposium held at the 2002 Annual Meeting of the
      Research Society on Alcoholism in San Francisco, CA, and was prepared on behalf
      of the symposium participants by the symposium co-organizers/co-chairs. Prior
      research with both clinical and nonclinical populations indicates a high
      comorbidity between alcohol-use disorders and pathological gambling. This
      symposium involved a set of papers in which exciting new research on this form of
      comorbidity was presented. The studies spanned populations of problem-gambling
      helpline callers, problem gamblers attempting to recover, and community-recruited
      gambler research volunteers. The studies used methodologies ranging from
      questionnaire and interview to laboratory-based paradigms (i.e., cognitive and
      alcohol challenge). Study designs ranged from cross-sectional to longitudinal and
      from correlation to experiment. The symposium highlighted novel approaches that
      researchers are using to enhance understanding of functional relations that may
      underlie this common comorbidity.

PMID- 12605079
TI  - Intimate partner violence and drinking: new research on methodological issues,
      stability and change, and treatment.
AB  - This article represents the proceedings of a symposium at the 2002 RSA meeting in
      San Francisco, California. The presentations were (1) Assessing couples'
      agreement about alcohol involvement in intimate partner violence, by John
      Schafer; (2) The occurrence of partner physical aggression on days of alcohol
      consumption: a longitudinal diary study, by Williams Fals-Stewart; (3) The 5-year
      stability of intimate partner violence and drinking among White, Black, and
      Hispanic couples, by Raul Caetano; (4) Partner violence before and after
      individually-based alcoholism treatment for male alcoholic patients, by Timothy
      O'Farrell. The discussant was Brenda Miller.

PMID- 12605080
TI  - Disruption of frontocerebellar circuitry and function in alcoholism.
AB  - This article represents a symposium of the 2002 joint meeting of RSA and ISBRA
      held in San Francisco. Presentations were Neuropathology of alcohol-related
      cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of
      cerebellar damage in an animal model of alcoholism, by Roberta Pentney and
      Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging
      study of chronic alcoholics, by Peter R. Martin and Mitchell H. Parks; and
      Functional reorganization of the brain in alcoholism: neuroimaging evidence, by
      John E. Desmond, S.H. Annabel Chen, Michelle R. Pryor, Eve De Rosa, Adolf
      Pfefferbaum, and Edith V. Sullivan.

PMID- 12605081
TI  - How important are brain banks for alcohol research?
AB  - This article contains the proceedings of a symposium at the 2002 RSA/ISBRA
      Meeting in San Francisco, organized and chaired by Clive Harper and co-chaired by
      Izuru Matsumoto. The presentations were (1) Introduction, by Clive Harper; (2)
      The quality of tissue-a critical issue, by Therese Garrick; (3) The first
      systematic brain tissue donor program in Japan, by Izuru Matsumoto; (4) Brain
      scans after death-really! by Adolf Pfefferbaum, Elfar Adalsteinsson, and Edith
      Sullivan; (5) Capture that (genial) expression, by Joanne Lewohl and Peter Dodd;
      and (6) Neurochemical/pharmacological studies: experimental design and
      limitations, by Roger Butterworth.

PMID- 12605082
TI  - Neural stem cells and alcohol.
AB  - This article summarizes the proceedings of a symposium held at the 2002 Research
      Society on Alcoholism Meeting in San Francisco, California. The aim of this
      symposium was to review research on the effects of ethanol on neural stems cells
      and neurogenesis. Ethanol is known to alter neurogenesis during development;
      however, recent studies indicate that the brain forms new neurons from stem cells
      throughout life. Furthermore, stem cells can be transplanted into the brain,
      creating exciting new possibilities to study brain function. The symposium
      covered these research areas. Dr. Michael W. Miller reviewed knowledge on the
      effects of ethanol on stem cell proliferation and differentiation during
      development. Dr. Wu Ma described studies in culture indicating that (1) neural
      stem cells express functional muscarinic acetylcholine receptors (mAchR), (2)
      mAchR-mediated proliferation involves Ca signaling and mitogen-activated protein
      kinase phosphorylation, and (3) phosphoinositol-3 kinase is a downstream effector
      for mAchR-mediated cell proliferation via activation of Akt. Drs. Kim Nixon and
      Fulton T. Crews followed with in vivo studies on ethanol's effects on adult
      neural stem cell proliferation and differentiation. Dr. W. Michael Zawada
      described studies directed at dopamine neuron cell transplants into mammalian
      central nervous system. These studies clearly establish that ethanol has
      significant effects on stem cells.

PMID- 12605083
TI  - Alcohol metabolism: role in toxicity and carcinogenesis.
AB  - This article contains the proceedings of a symposium at the 2002 RSA Meeting in
      San Francisco, organized and co-chaired by Thomas M. Badger, Paul Shih-Jiun Yin,
      and Helmut Seitz. The presentations were (1) First-pass metabolism of ethanol:
      Basic and clinical aspects, by Charles Lieber; (2) Intracellular CYP2E1
      transport, oxidative stress, cytokine release, and ALD, by Magnus Ingelman
      Sundberg; (3) Pulsatile ethanol metabolism in intragastric infusion models:
      Potential role in toxic outcomes, by Thomas M. Badger and Martin J.J. Ronis; (4)
      Free radicals, adducts, and autoantibodies resulting from ethanol metabolism:
      Role in ethanol-associated toxicity, by Emanuele Albano; and (5) Gastrointestinal
      metabolism of ethanol and its possible role in carcinogenesis, by Helmut Seitz.

PMID- 12605084
TI  - Emerging techniques in biomedical research and their application to alcohol
      toxicity.
AB  - This article represents the proceedings of a symposium at the 2002 RSA-ISBRA
      Meeting in San Francisco. The chairs were Vinood B. Patel and Victor R. Preedy.
      The presentations were (1) Macromolecular structural analysis, by Vinood B.
      Patel; (2) Profiling and imaging of proteins in tissue sections using mass
      spectrometry as a discovery tool in biological research, by Pierre Chaurand and
      Richard M. Caprioli; (3) The use of SELDI ProteinChip trade mark arrays, by Brian
      M. Austen, Emma R. Frears, Francesca Manca, and Huw Davies; (4) DNA hybridization
      array technologies, by Kent E. Vrana; and (5) Adeno- and adeno-associated viral
      mediated gene transfer approaches for alcoholic liver disease, by Michael
      Wheeler. Concluding remarks were by Victor R. Preedy.

PMID- 12605085
TI  - Enduring effects of chronic ethanol in the CNS: basis for alcoholism.
AB  - This symposium focused on functional alterations in the mesolimbic dopamine
      system during the abstinence phase after chronic alcohol intake. Mark Brodie
      first described his recordings from midbrain slices prepared after chronic
      alcohol treatment in vivo by daily injection in C57BL/6J mice. No changes were
      found in the baseline firing frequency of dopaminergic neurones in the VTA
      (ventral tegmental area), but the excitation produced in these neurones by an
      acute ethanol challenge was significantly increased in neurons from ethanol
      treated mice compared with those from the saline-treated controls. There was also
      a significant decrease in the inhibitory response to GABA by the dopamine
      neurones following the chronic ethanol treatment. These data suggest that the
      timing pattern and mode of ethanol administration may determine the types of
      changes observed in dopaminergic reward area neurons. Annalisa Muntoni lectured
      on the relationship between electrophysiological and biochemical in vivo evidence
      supporting a reduction in tonic activity of dopamine neurons projecting to the
      nucleus accumbens at various times after suspension of chronic ethanol treatment
      and morphological changes affecting dopamine neurons in rat VTA. Hilary J. Little
      then described changes in dopaminergic neurone function in the VTA during the
      abstinence phase. Decreases in baseline firing were seen at 6 days after
      withdrawal of mice from chronic ethanol treatment but were not apparent after 2
      months abstinence. Increases in the affinity of D1 receptors in the striatum, but
      not in the cerebral cortex, were seen however up to 2 months after withdrawal.
      Scott Steffensen then described his studies recording in vivo from GABA
      containing neurones in the VTA in freely moving rats. Chronic ethanol
      administration enhanced the baseline activity of these neurones and resulted in
      tolerance to the inhibition by ethanol of these neurones. His results
      demonstrated selective adaptive circuit responses within the VTA or in
      extrategmental structures that regulate VTA-GABA neurone activity.

PMID- 12605087
TI  - 2002 RSA journalism award acceptance speech.

PMID- 12605086
TI  - Neurobehavioral consequences of prenatal alcohol exposure: an international
      perspective.
AB  - This article represents the proceedings of a symposium at the 2002 Research
      Society on Alcoholism/International Society for Biomedical Research on Alcoholism
      meeting in San Francisco, CA. The organizers were Edward P. Riley and Sarah N.
      Mattson, and the chairperson was Edward P. Riley. The presentations were (1)
      Neurobehavioral deficits in alcohol-exposed South African infants: preliminary
      findings, by Sandra W. Jacobson, Christopher D. Molteno, Denis Viljoen, and
      Joseph L. Jacobson; (2) A pilot study of classroom intervention for learners with
      fetal alcohol syndrome in South Africa, by Colleen Adnams, M. W. Rossouw, M. D.
      Perold, P. W. Kodituwakku, and W. Kalberg; (3) Differential effects of prenatal
      alcohol exposure on fluid versus crystallized intelligence, by P. W. Kodituwakku,
      W. Kalberg, L. Robinson, and P. A. May; (4) Neurobehavioral outcomes of prenatal
      alcohol exposure: early identification of alcohol effects, by Claire D. Coles;
      (5) Fetal alcohol syndrome in Moscow, Russia: neuropsychology test performance,
      by Sarah N. Mattson, E. P. Riley, A. Matveeva, and G. Marintcheva; and (6) Long
      term follow-up of Finnish children exposed to alcohol in utero in various
      durations, by Marit I. Korkman and I. Autti-Ramo. The discussant was Ting-Kai Li.

PMID- 12605088
TI  - Biomarkers in diagnostic obstetric and gynecologic pathology: a review.
AB  - Until recently, the histologic diagnosis of obstetrical and gynecologic neoplasia
      was based principally on morphologic criteria. However, interobserver
      reproducibility for entities such as squamous intraepithelial, endometrial, and
      trophoblastic disease varies widely between observers. This inherent variability
      in interpretation between individuals has led to wide ranges in diagnostic
      precision between practices, and in many cases, between recognized experts. The
      advent of immunohistochemistry, and the more recent accelerated discovery of new
      genes and their functions has resulted in the discovery of cellular proteins or
      nucleic acids that are differentially expressed in tumors. When applied in
      conjunction with existing histologic criteria, these "biomarkers" have the
      potential to enhance diagnostic consistency and reproducibility. The gains
      expected are to practicing diagnostic pathologists (who will enjoy greater
      diagnostic consistency) and to academics (for whom biomarkers may uncover new
      pathways unappreciated by histologic diagnosis alone). However, fundamental to
      the success in both arenas will be critical analysis of the potential pitfalls in
      immunohistochemistry, strict validation of new markers as they arrive in the
      field, and a realistic view of their value in the laboratory management of
      obstetrical and gynecologic diseases.

PMID- 12605089
TI  - Endothelial lesions of soft tissues: a review of reactive and neoplastic entities
      with emphasis on low-grade malignant ("borderline") vascular tumors.
AB  - Soft tissue proliferations composed of endothelial cells are a heterogeneous
      group of lesions that can cause diagnostic difficulty. Further complicating the
      issue is the constantly changing nomenclature of some entities, as well as
      reclassification of some vascular tumors from the high-grade malignant category
      to the low-grade malignant or borderline category. Modern ancillary techniques
      such as immunohistochemistry and cytogenetics have done little to advance our
      knowledge of these lesions. This review article outlines the most recent
      classification of endothelial lesions of the skin and soft tissues, with emphasis
      on the low-grade malignant (borderline) category. In addition, many tumor-like
      lesions containing an endothelial component are also discussed.

PMID- 12605090
TI  - Digital imaging applications in anatomic pathology.
AB  - Digital imaging has progressed at a rapid rate and is likely to eventually
      replace chemical photography in most areas of professional and amateur digital
      image acquisition. In pathology, digital microscopy has implications beyond that
      of taking a photograph. The arguments for adopting this new medium are
      compelling, and given similar developments in other areas of pathology and
      radiologic imaging, acceptance of the digital medium should be viewed as a
      component of the technological evolution of the laboratory. A digital image may
      be stored, replicated, catalogued, employed for educational purposes, transmitted
      for further interpretation (telepathology), analyzed for salient features
      (medical vision/image analysis), or form part of a wider digital healthcare
      strategy. Despite advances in digital camera technology, good image acquisition
      still requires good microscope optics and the correct calibration of all system
      components, something which many neglect. The future of digital imaging in
      pathology is very promising and new applications in the fields of automated
      quantification and interpretation are likely to have profound long-term influence
      on the practice of anatomic pathology. This paper discusses the state of the art
      of digital imaging in anatomic pathology.

PMID- 12605091
TI  - Digital imaging guidelines for pathology: a proposal for general and academic
      use.
AB  - Digital imaging is an inexpensive and widely available tool that is used by most
      pathologists in patient reports, education, publication, diagnosis, and data
      archival. Its popularity is due, in part, to the ease of modifying, storing,
      enhancing, and annotating images. Since digital manipulation is essentially
      undetectable in the final product, it poses the potential risk for fraudulent
      manipulation and heightens the possibility of unintentional misrepresentation. In
      an attempt to ensure a high degree of uniformity and quality, and to create a
      professional standardization amongst pathologists, digital imaging guidelines are
      proposed for use in general and academic practice.

PMID- 12605092
TI  - Diagnostic value of microtubule-associated protein-2 (MAP-2) for neuroendocrine
      neoplasms.
AB  - Microtubule associated proteins (MAPs) are major components of cytoskeleton
      proteins associated with microtubule assembly. Microtubule associated protein-2
      (MAP-2), a component of the MAP family, has been shown to be specifically
      expressed in neuronally differentiated cells, and has been previously used as a
      sensitive and specific marker for neurons. Immunoreactivity of MAP-2 has been
      demonstrated in most neuroendocrine and neuroectodermal related neoplasms such as
      small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumor of the
      lung, Merkel cell carcinoma of the skin, medulloblastoma, neurocytoma of the
      central nervous system, extrapulmonary small cell carcinoma and carcinoid tumor,
      and malignant melanomas. This report details the diagnostic value of MAP-2 on
      tumors with neuroendocrine differentiation and neoplasms derived from the neural
      crest.

PMID- 12605093
TI  - Pathology and the internet.

PMID- 12605094
TI  - Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study
      and meta-analysis.
AB  - OBJECTIVE: To further evaluate the controversial putative association between a
      Ser9Gly variant in the first exon of the dopamine D3 receptor gene (DRD3) and
      schizophrenia. METHODS: Swedish patients with schizophrenia ( n=156) and control
      subjects ( n=463) were assessed for the DRD3 Ser9Gly variant. Meta-analyses
      including previous and the present Swedish case-control results were performed.
      RESULTS: No significant difference between the Swedish patients and controls were
      found, but there was an association between DRD3 Ser9Gly Ser/Ser and homozygous
      genotypes and response to anti-psychotic drugs. This finding was supported by an
      incomplete meta-analysis. In a meta-analysis of all case-control studies
      comprising 8761 subjects the association between DRD3 Ser9Gly homozygosity and
      schizophrenia ( =4.96, degree of freedom=1, p <0.05, odds ratio=1.10, 95%
      confidence interval=1.01-1.20) persisted. However, the previously proposed
      association between the Ser/Ser genotype and schizophrenia was not significant
      (chi2 =2.71, degree of freedom=1, p>0.05, odds ratio=1.08, 95% confidence
      interval=0.99-1.17). CONCLUSIONS: Whereas the present Swedish case-control
      analysis did not yield any evidence for association with the diagnosis, the
      present meta-analysis suggests that the DRD3 gene confer susceptibility to
      schizophrenia. Reasons for the discrepancies between prior studies are discussed.

PMID- 12605095
TI  - Associations among the NEO Personality Inventory, Revised and the serotonin
      transporter gene-linked polymorphic region in elders: effects of depression and
      gender.
AB  - OBJECTIVE: The short variant of the serotonin transporter gene-linked functional
      polymorphic region (5-HTTLPR) has been associated with personality traits related
      to anxiety, hostility, and depression. We attempted to replicate findings
      suggesting a positive relation between the short allele variant of 5-HTTLPR and
      Neuroticism, and a negative association between the short allele variant and
      Agreeableness. METHODS: Participants in the present study were 103 geriatric
      depressed patients and 99 non-depressed age matched controls. Depression status
      and gender were examined as potential modifiers of the association between 5
      HTTLPR and personality. RESULTS: Neuroticism was associated with allele frequency
      such that individuals with the short variant of the allele (ss or sl, group S)
      were significantly lower on Neuroticism ( P<0.04) compared with individuals with
      the long allele variant (group L), a pattern opposite to that of previous
      reports. The association did not vary by clinical group (depressed or controls)
      but was conditional on gender ( P<0.01): the mean Neuroticism for males in group
      S was 48.2, whereas the mean Neuroticism for males in group L was 55.9; and the
      mean Neuroticism for females did not differ by allele group. In the total sample,
      Agreeableness was not associated with allele frequency; however, there was a
      significant allele groupxclinical groupxgender interaction ( P<0.01).
      CONCLUSIONS: The present findings failed to replicate prior work suggesting that
      the short variant of the 5-HTTLPR allele is associated with higher Neuroticism
      and lower Agreeableness.

PMID- 12605096
TI  - Association study of oestrogen receptor alpha gene polymorphism and suicidal
      behaviours in major depressive disorder.
AB  - OBJECTIVE: Gender comparison in epidemiological studies has consistently
      demonstrated a greater prevalence for major depressive disorders (MDD) in
      females. Several lines of evidence have implicated oestrogen pathways in this
      gender difference. Furthermore, there is evidence that attempted suicides are
      more frequent in women. A population-based association study was used to test the
      hypothesis that the genetic variants ( II and I polymorphisms) of the oestrogen
      receptor alpha gene (ER-alpha) confer susceptibility to MDD. METHODS: The ER
      alpha was genotyped for 154 patients with MDD and 226 controls in a Chinese
      population. RESULTS: Statistical analysis showed a significant difference in the
      II genotype and allele frequencies between the female MDD patients and the female
      controls ( P=0.010 and P=0.004, respectively). However, no significant
      differences in ER-alpha genotype or allele frequencies were found between male
      MDD patients and male controls. Furthermore, the ER-alpha genotypes were not
      associated with suicide-attempt history for MDD cases. CONCLUSIONS: Our results
      suggest that the ER-alpha may play a role in the susceptibility of MDD in
      females.

PMID- 12605097
TI  - Two NOTCH4 polymorphisms and their relation to schizophrenia susceptibility and
      different personality traits.
AB  - BACKGROUND: Recently, linkage disequilibrium mapping of the major
      histocompatibility complex region on the short arm of human chromosome 6
      suggested that the NOTCH4 locus is highly associated with schizophrenia.
      OBJECTIVES AND METHODS: We analysed two polymorphisms in this gene in Swedish
      schizophrenic patients ( =74) and control subjects ( =135). The NOTCH4 variants
      were also analysed in schizophrenic patients with regard to subdiagnosis, age at
      first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous
      suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs,
      and response to anti-psychotic drug treatment. Control subjects were scrutinized
      with regard to personality, another partially heritable trait suggested being of
      importance in schizophrenia. In addition, two intermediate endophenotypes
      suggested being of importance in schizophrenia, dopamine D(2) receptor density in
      striatum and monoamine metabolites in cerebrospinal fluid, respectively, were
      investigated with regard to the two NOTCH4 variants. RESULTS: There was no
      significant association between the patients and the controls for the two
      investigated polymorphisms neither for the parameters analysed in the
      schizophrenia material. The NOTCH4 SNP2 variant, an A-->G substitution, was
      associated with the Karolinska Scales of Personality Irritability scale. The
      NOTCH4 (CTG)(n) variant was associated with the revised NEO personality inventory
      Extraversion and Activity (E4) scales. However, after correction for multiple
      testing, no difference remained significant. The results for the endophenotypes
      and the polymorphisms were non-significant. CONCLUSIONS: The present study does
      not support that the investigated NOTCH4 variants have a major influence on
      susceptibility to schizophrenia or related neurobiological traits.

PMID- 12605098
TI  - The WFS1 (Wolfram syndrome 1) is not a major susceptibility gene for the
      development of psychiatric disorders.
AB  - BACKGROUND: Wolfram syndrome is a neurodegenerative disorder that is inherited in
      an autosomal recessive mode and characterized by the presence of diabetes
      mellitus and optic atrophy. Patients and heterozygote carriers are at an
      increased risk of suffering psychiatric disorders. Mutations in the Wolfram gene
      (WFS1 ) (4p16.1) are responsible for the development of the disease, and mRNA and
      protein expression of WFS1 have recently been found in areas of the rat brain
      that can be related to the psychiatric symptoms. OBJECTIVE: To test the
      hypothesis that WFS1 mutations in heterozygote carriers or other variants of WFS1
      can predispose to mental illness. METHODS: Stage 1: Exons 2, 4 and 8 of that
      harbour mutations in Spanish Wolfram syndrome families were examined by Single
      Strand Conformation Polymorphism and sequencing analysis in 43 patients with
      affective disorder to identify variants and mutations. Stage 2: two variants
      identified in stage 1 were analysed in 152 psychiatric patients (118
      schizophrenia and 34 affective disorder) and 177 control subjects. RESULTS: Six
      variants (I333V Ile-->Val, F341, N500, R708, K774, K811) and a WFS1 mutation
      (R818C, Arg-->Cys) were found in the 43 patients analysed in stage 1 of the
      study. In stage 2, the R818C mutation was not found in the group of psychiatric
      patients but it was present in one control subject. The association study
      conducted with the I333V variant did not find significant differences in allele
      or genotype frequencies between patients and control subjects. CONCLUSIONS: Our
      results suggest that WFS1 is not a major susceptibility gene for the development
      of psychiatric disorders in our population.

PMID- 12605099
TI  - Genetic origins of anxiety in women: a role for a functional catechol-O
      methyltransferase polymorphism.
AB  - OBJECTIVE: Women are more prone to anxiety than men. The catechol- 
      methyltransferase functional polymorphism, Val158Met, is likely to be implicated
      in anxiety vulnerability. We hypothesized that, particularly in women, the low
      activity Met158 allele would be associated with higher anxiety scores and a
      biological trait, low-voltage alpha resting electroencephalogram (EEG),
      previously associated with alcoholism and anxiety disorders. METHODS: DNA was
      obtained from two independent groups of participants ascertained as community
      samples: 149 predominantly Caucasian individuals (92 women, 57 men), and 252
      Plains American Indians (149 women, 103 men). Dimensional measures of anxiety
      (Tridimensional Personality Questionnaire harm avoidance subscales HA1 and HA2)
      were obtained and DSM-III-R lifetime psychiatric diagnoses were determined. EEGs
      were recorded and EEG phenotypes assigned. RESULT: In both populations, women
      showed significant associations between catechol- -methyltransferase genotype and
      elevated harm avoidance scores, and the Met158/Met158 genotype was most strongly
      associated: predominantly Caucasian participants: HA1, P=0.03, HA2, P =0.03; and
      Plains American Indians: HA2, P=0.01. This was also the case with low-voltage
      alpha resting EEG: predominantly Caucasian participants: P=0.01, odds ratio=5.0
      (95% confidence interval, 1.3-18.7); Plains American Indians: P=0.03, odds
      ratio=3.7 (95% confidence interval, 1.1-12.7). CONCLUSIONS: The results of the
      present study suggest that an inherited difference in catecholamine metabolism is
      important in the pathogenesis of anxiety in women.

PMID- 12605100
TI  - Clinical, cytogenetic, and molecular description of a FRAXE French family.
AB  - BACKGROUND: FRAXE is a second locus associated with X chromosome fragility.
      Similar to FRAXA, the common mutation is a GCC expansion located in the 5'
      untranslated region, leading to the hypermethylation of the region and to the
      subsequent inactivation of specific genes (FMR1 and FMR2, respectively). Unlike
      FRAXA, FRAXE has a rare occurrence and is less currently studied in routine
      analyses. The phenotype associated with FRAXE is usually considered as mild or
      moderate mental retardation, with incomplete penetrance. However,
      phenotype/genotype relations have been less characterized. OBJECTIVE: We report a
      French family with three members affected with mental retardation, including a
      female suffering from West syndrome, and two mentally retarded males. METHODS:
      After exclusion of the FRAXA expansion by Southern blot analysis, we performed a
      karyotype using folate-thymidine-deficient medium and a southern blot to search
      for FRAXE expansion. RESULTS: All three mentally retarded patients had a number
      of repeats over 800 GCC and expressed more than 20% of fragile sites in their
      leukocytes. Another carrier female with a full expansion had a subnormal mental
      impairment. CONCLUSIONS: Clinical features and both the cytogenetic and molecular
      findings seem to correlate in this family. We discuss the bias encountered when
      studying such families and some of the mechanisms that may explain part of the
      clinical variability.

PMID- 12605101
TI  - Variation in the DCP1 gene, encoding the angiotensin converting enzyme ACE, is
      not associated with increased susceptibility to Alzheimer's disease.
AB  - OBJECTIVES: To attempt to replicate previous reports that polymorphic variation
      in the DCP1 gene causes increased susceptibility to the development of
      Alzheimer's disease, either on its own or in interaction with the effects of the
      gene for apolipoprotein E (APOE). METHOD: Subjects older than 65 years of age
      consisting of 81 dementia patients diagnosed as having possible or probable
      Alzheimer's disease and 68 controls were obtained from Camden, Islington and
      Harlow psychiatric services. Subjects were genotyped for APOE alleles e2, e3 and
      e4, and the common insertion/deletion polymorphisms for DCP1* I/D were genotyped.
      RESULTS: There was no statistically significant difference in the frequency of
      the DCP1* insertion/deletion alleles between the cases and controls (X2 =0.04, 1
      degree of freedom, not significant). When subjects were subdivided according to
      whether they possessed at least one copy of the APOE e4 allele, there were still
      no differences in DCP1 allele frequencies between cases and controls.
      CONCLUSIONS: Further research is needed to elucidate any role that the DCP1
      polymorphism may play in relation to Alzheimer's disease. Previous studies may be
      false positive, or inconsistency in replication may be due to heterogeneity.

PMID- 12605102
TI  - Association analysis for dopamine D3 receptor, dopamine D4 receptor and dopamine
      transporter genetic polymorphisms and P300 event-related potentials for normal
      young females.
AB  - OBJECTIVE: It has been demonstrated that the P300 components, a positive event
      related potential, are heritable and are influenced by dopaminergic activity. We
      tested the genetic effects of the dopaminergic system in P300 components by
      association study. METHODS: In a sample population consisting of 120 normal young
      Han-Chinese females, we explored the association between the P300 components,
      and, the genetic polymorphisms including the dopamine D3 receptor (serine-to
      glycine polymorphism in exon I), the dopamine D4 receptor (variable number tandem
      repeat polymorphism in exon III), and the dopamine transporter (variable number
      tandem repeat polymorphism in promoter region). RESULTS: No associations were
      demonstrated between the polymorphisms of these three genes and the P300
      components. CONCLUSIONS: Our negative findings suggest that these genetic
      polymorphisms do not play a major role in the modulation of P300 event-related
      potentials.

PMID- 12605103
TI  - Lack of association in Japanese patients between neuroleptic malignant syndrome
      and the TaqI A polymorphism of the dopamine D2 receptor gene.
AB  - OBJECTIVE: The molecular basis of neuroleptic malignant syndrome (NMS) is
      unclear, but clinical studies have noted a genetic predisposition. A recent
      genetic study suggested an association between NMS and the I A polymorphism in
      the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a
      larger number of subjects. METHODS: We studied 49 Japanese patients previously
      diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics
      without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A
      polymorphism. RESULTS: The I A1 allele frequency was 0.408 in NMS patients and
      0.415 in patients without NMS. No significant differences in allelic or genotypic
      frequencies were observed between the two groups. CONCLUSIONS: We cannot conclude
      that the I A polymorphism is associated with development of NMS.

PMID- 12605104
TI  - Review of solid-organ transplantation in HIV-infected patients.

PMID- 12605105
TI  - Pig cells that lack the gene for alpha1-3 galactosyltransferase express low
      levels of the gal antigen.
AB  - BACKGROUND: The major antigen recognized on pig tissue by primate antibodies is a
      terminal galalpha1-3gal carbohydrate structure (gal antigen) present on
      glycolipids and glycoproteins. The production of animals from somatic cells
      allows for the inactivation of specific genes. It is anticipated that the
      complete inactivation of the gene encoding alpha1-3 galactosyltransferase, the
      enzyme that synthesizes the galalpha1-3gal linkage, will result in loss of that
      antigen from pig organs and tissue and will provide a survival benefit in pig-to
      primate xenotransplants. METHODS: Positive-negative selection was used to produce
      fetal-pig fibroblasts that were a heterozygous knockout (+/-) of the alpha1-3
      galactosyltransferase gene. Nuclear transfer of these cells generated pig embryos
      and live born pigs with the appropriate genotype. Using a novel selection method
      with cells from (+/-) embryos, we produced homozygous (-/-) fetal-pig fibroblast
      cells. RESULTS: Southern blot analysis of the alpha1-3 galactosyltransferase gene
      showed that we had produced (+/-) pig embryos, (+/-) live born pigs, and (-/-)
      pig-fetal fibroblast cells. Fluorescence-activated cell sorter (FACS) analysis
      with some, but not all, mouse anti-gal monoclonal antibodies and sensitized human
      serum showed that (-/-) cells still synthesized the gal antigen at 1 to 2% of the
      level of control heterozygous cells. CONCLUSIONS: Fetal-pig fibroblasts
      homozygous for the knockout of the alpha1-3 galactosyltransferase gene appear to
      express low but detectable levels of the gal antigen.

PMID- 12605106
TI  - Pulmonary preservation studies: effects on endothelial function and pulmonary
      adenine nucleotides.
AB  - BACKGROUND: Lung transplantation is an effective therapy plagued by a high
      incidence of early graft dysfunction, in part because of reperfusion injury. The
      optimal preservation solution for lung transplantation is unknown. We performed
      experiments using an isolated perfused rat lung model to test the effect of lung
      preservation with three solutions commonly used in clinical practice. METHODS:
      Lungs were retrieved from Sprague-Dawley rats and flushed with one of three
      solutions: modified Euro-Collins (MEC), University of Wisconsin (UW), or low
      potassium dextran and glucose (LPDG), then stored cold for varying periods before
      reperfusion with Earle's balanced salt solution using the isolated perfused rat
      lung model. Outcome measures were capillary filtration coefficient (Kfc), wet-to
      dry weight ratio, and lung tissue levels of adenine nucleotides and cyclic AMP.
      RESULTS: All lungs functioned well after 4 hr of storage. By 6 hr, UW-flushed
      lungs had a lower Kfc than LPDG-flushed lungs. After 8 hr of storage, only UW
      flushed lungs had a measurable Kfc. Adenine nucleotide levels were higher in UW
      flushed lungs after prolonged storage. Cyclic AMP levels correlated with Kfc in
      all groups. CONCLUSIONS: Early changes in endothelial permeability seemed to be
      better attenuated in lungs flushed with UW compared with LPDG or MEC; this was
      associated with higher amounts of adenine nucleotides. MEC-flushed lungs failed
      earlier than LPDG-flushed or UW-flushed lungs. The content of the solution may be
      more important for lung preservation than whether the ionic composition is
      intracellular or extracellular.

PMID- 12605107
TI  - Changes in intracellular sodium, potassium, and calcium concentrations in
      transplanted mouse pancreatic islets.
AB  - BACKGROUND: Our previous studies have suggested a chronically low oxygen tension
      in transplanted pancreatic islets. The present study tested the hypothesis that
      this may be coupled to changes in intracellular concentrations of crucial ions
      within the transplanted islet cells and, thus, their function. METHODS: X-ray
      microanalysis was used for studies of native islet cells and islet grafts
      residing for 1 day or 1 month in nondiabetic or diabetic recipients. RESULTS:
      Markedly increased sodium concentrations and decreased potassium concentrations
      were recorded in all transplanted islet cells, irrespective of whether the grafts
      had been implanted into nondiabetic or diabetic recipients or whether they were
      investigated 1 day or 1 month after transplantation. The calcium concentration in
      1-day-old islet grafts was similar to that in native islet cells, but it
      decreased markedly between 1 day and 1 month after transplantation. Again this
      was seen in both nondiabetic and diabetic recipients. CONCLUSIONS: Most probably,
      the disturbances in graft sodium and potassium concentrations reflect ATP
      depletion and inhibition of the Na/K-ATPase in the plasma membrane as a result of
      impeded oxygen supply. The decreased calcium concentrations developing over time
      in the transplanted islet cells might be potentially detrimental, because calcium
      plays a fundamental role in the control of a variety of cellular functions,
      including insulin secretion, in beta cells.

PMID- 12605108
TI  - Improvement of microvascular graft equilibration and preservation in non-heart
      beating donors by warm preflush with streptokinase.
AB  - Using in situ fluorescence microscopy with Sprague Dawley rats, we studied the
      hypothesis of compromised microvascular kidney perfusion on organ harvest in non
      heart-beating donors (NHBDs), and we evaluated the potential benefit of an
      additional preflush with saline solution containing streptokinase. Aortal flush
      of NHBD kidneys solely with University of Wisconsin solution resulted in a
      significantly (P <0.05) reduced functional capillary density (FCD) with increased
      perfusion heterogeneity compared with kidneys of heart-beating controls. This was
      associated with an increased lactate dehydrogenase (LDH) release on 24 hr
      postpreservation rinse of the grafts (76.7+/-18.9 U/L). Warm preflush with low
      viscosity Ringer's lactate (RL) solution alone did not influence the decreased
      renal FCD and the postpreservation LDH release (76.2+/-29.1 U/L). In contrast,
      the addition of streptokinase to the RL preflush solution resulted in a
      significant (P <0.05) improvement of FCD with values not statistically different
      from those of heart-beating controls. This was associated with an attenuation of
      perfusion heterogeneity and a significantly lowered postpreservation LDH release
      (17.0+/-2.5 U/L). Furthermore, in transplanted and reperfused NHBD kidney grafts,
      the use of streptokinase-supplemented RL for preflush during organ harvest
      significantly (P <0.05) reduced early manifestation of tubular necrosis (29%+/
      8%) when compared with kidneys preflushed exclusively with University of
      Wisconsin solution (56%+/-4%). Thus, we conclude that kidney harvest from NHBDs
      is prone to severe microvascular perfusion deficits, which are likely to preclude
      successful preservation of organ integrity during cold storage. Temporary
      fibrinolytic preflush with streptokinase may represent a feasible tool to improve
      microvascular graft equilibration, which effectively protects the renal integrity
      during both cold storage and posttransplant reperfusion.

PMID- 12605109
TI  - Pediatric renal transplantation with mycophenolate mofetil-based
      immunosuppression without induction: results after three years.
AB  - BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the
      acute rejection rate in adults and in children in the early posttransplantation
      period. Three-year posttransplantation results have been reported for adults but
      not for children thus far. In the present open-labeled study, patients 18 years
      old and younger were evaluated prospectively for up to 3 years after renal
      transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination
      with cyclosporine and prednisone without induction were evaluated for patient
      survival, transplant survival, renal function, arterial blood pressure, adverse
      events, and opportunistic infections. These patients were compared with a
      historic control group (n=54) receiving azathioprine (AZA) instead of MMF.
      RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in
      the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated
      superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes
      occurred in 47% of patients in the MMF group versus 61% in the AZA group
      (P<0.05). Renal function was not significantly different, neither after 3 years
      nor in the long-term calculation. Antihypertensive medication was administered to
      73% to 84% of patients, similar in both groups. Opportunistic infections were
      recorded only for MMF. Infection rates were comparable to those reported in
      adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a
      longer term maintenance immunosuppressive drug in children and adolescents.

PMID- 12605110
TI  - Evaluation of Pefabloc as a serine protease inhibitor during human-islet
      isolation.
AB  - BACKGROUND: Recent evidence has suggested that inconsistencies in human-islet
      yields after collagenase digestion are attributed to the activation of endogenous
      enzymes of the cadaveric donor pancreas. Inhibition of protease activity by
      Pefabloc (0.4 mM; Roche Biochemicals Inc., Indianapolis, IN) has recently been
      shown to improve human-islet isolation after prolonged cold storage of the
      pancreas. In this study, we have hypothesized that this improvement was because
      of the inhibition of three key serine proteases. METHODS: Twenty cadaveric
      pancreases were perfused in the presence (n=12) and absence (n=8) of Pefabloc
      added at the time of distention using a customized perfusion device. Samples were
      collected throughout the digestion process and were assayed for trypsin,
      chymotrypsin, elastase, and total protease activity. RESULTS: In all cases, the
      enzyme activity levels remained lower in the presence of Pefabloc as compared
      with the control samples. There was significantly higher chymotrypsin and
      elastase activity in the control group, but not trypsin or total protease
      activity, from the time following loading of the enzyme onto the pancreas until
      the stopping of the enzymatic digestion phase (dilution). CONCLUSIONS: Pefabloc
      was shown to be an effective protease inhibitor throughout the entire digestion
      process. Pefabloc supplementation did not significantly effect the dilution time
      or the islet yield in this study; however, these data show that serine proteases
      are effectively inhibited by Pefabloc during the clinical islet process.

PMID- 12605111
TI  - Activation of protein C during reperfusion in clinical liver transplantation.
AB  - BACKGROUND: Activated protein C (APC) exhibits anticoagulant and antiinflammatory
      properties. We studied the kinetics and magnitude of protein C activation in
      clinical liver transplantation and the interaction of this activation with
      neutrophil and monocyte activation. METHODS: In 10 patients undergoing liver
      transplantation, we measured plasma protein C and APC levels, neutrophil and
      monocyte CD11b and L-selectin expression, and leukocyte differential counts pre-,
      intra-, and postoperatively. Samples of blood entering and leaving the liver were
      obtained simultaneously to assess changes across the liver. RESULTS: Protein C
      level was low preoperatively (65%, range 39%-141%) and remained low throughout
      surgery. Compared with the preoperative level (107%, range 78%-161%), APC level
      increased during liver reperfusion (471%, range 183%-917%, P=0.05). A
      transhepatic decrease in protein C level (-16%, range -45%-5%, P=0.007), but not
      in APC level, occurred during initial liver reperfusion. At the same time,
      neutrophil and monocyte activation took place in the liver. CONCLUSIONS: Despite
      protein C deficiency, patients with liver insufficiency are able to maintain
      normal APC levels. During reperfusion, protein C consumption occurs in the liver
      without concomitant hepatic release of APC, indicating a shortage of APC in the
      reperfused liver. The process consuming protein C and APC may be related to the
      simultaneous ongoing neutrophil and monocyte activation within the liver graft,
      indicating a regulatory role for APC in inflammation.

PMID- 12605112
TI  - Comprehensive cost comparison of adult-adult right hepatic lobe living-donor
      liver transplantation with cadaveric transplantation.
AB  - BACKGROUND: An important long-term consideration for living-donor liver
      transplantation (LDLT) is the expense compared with cadaveric-liver
      transplantation. LDLT is a more complex procedure than cadaveric transplantation
      and the cost of donor evaluation, donor surgery, and postoperative donor care
      must be included in a cost analysis for LDLT. In this study, we compare the
      comprehensive cost of LDLT with that of cadaveric-liver transplantation. METHODS:
      All costs for medical services provided at our institution were recorded for 24
      LDLT and 43 cadaveric recipients with greater than 1 year follow-up transplanted
      between August 1997 and April 2000. The donor costs include donors evaluated and
      rejected, donors evaluated and accepted, donor right hepatectomy costs, and donor
      follow-up costs (365 days postdonation). LDLT and cadaveric recipient costs
      include medical care 90 days pre-LDLT, recipient transplant costs, and recipient
      follow-up costs (365 days posttransplant) including retransplantation. Cost is
      expressed as an arbitrary cost unit (CU) that is a value between $500 to $1,500.
      RESULTS: Total LDLT costs (evaluations of rejected donors+evaluations of accepted
      donors+donor hepatectomy+donor follow-up care for 1 year+pretransplant recipient
      care [90 days pretransplant]+recipient transplantation+recipient 1-year
      posttransplant care)= 162.7 CU. Total mean cadaveric transplant costs
      (pretransplant recipient care [90 days pretransplant]+recipient transplantation
      [including organ acquisition cost]+recipient 1-year posttransplant care)= 134.5
      CU, (P =ns). CONCLUSIONS: The total comprehensive cost of LDLT is 21% higher than
      cadaveric transplantation, although this difference is not significant.

PMID- 12605113
TI  - Identification of the antibodies involved in B-cell crossmatch positivity in
      renal transplantation.
AB  - BACKGROUND: The significance of a positive B-cell crossmatch (BCM) in kidney
      transplantation has always been controversial in the evaluation of its
      implications on graft survival and specificity of the antibodies involved.
      METHODS: We have investigated the sera of 62 recipients of a kidney allograft
      transplanted across a positive BCM (T negative) for the presence of
      autoantibodies and anti-human leukocyte antigen (HLA) class I and II antibodies,
      using a combination of lymphocytotoxicity, enzyme-linked immunosorbent assay
      (ELISA), and flow cytometry tests. The controls were the 930 patients
      transplanted over the same period of time with a negative T and BCM. RESULTS:
      Autoantibodies were detected in 16%, and donor specific anti-HLA class II
      antibodies, mainly DQ, in 23% of the patients. None had antibodies against donor
      HLA class I. The target of the antibodies was not identified in 61%. Graft
      survival was comparable in the controls and in the +BCM patients, with nondonor
      specific HLA reactivity. Patients with donor-specific anti-HLA class II
      antibodies had lower early graft survival and a higher incidence of vascular
      rejection. However, long-term allograft survival was similar to that of the other
      groups. CONCLUSION: These data suggest that in 77% of the patients, BCM
      positivity was not related with anti-HLA antibodies, and, in this case, graft
      survival was similar to that of the -BCM controls. In a minority of patients,
      anti-HLA class II antibodies were responsible for the +BCM, and their presence
      was associated with lower early, but not long-term, graft survival. Consequently,
      a +BCM should not systematically contraindicate kidney transplantation.

PMID- 12605114
TI  - Aggressive pharmacologic donor management results in more transplanted organs.
AB  - BACKGROUND: Brain death results in adverse pathophysiologic effects in many
      cadaveric donors, resulting in cardiovascular instability and poor organ
      perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve
      cardiac function in brain-dead donors. The goal of this study was to examine the
      effect of HR on the brain-dead donor on the number of organs transplanted per
      donor. METHODS: A retrospective analysis of all brain-dead donors recovered in
      the United States from January 1, 2000, to September 30, 2001, was conducted. HR
      consisted of a methylprednisolone bolus and infusions of vasopressin and either
      triiodothyronine or L-thyroxine. Univariate analyses and multivariate logistic
      regression analyses were used to detect differences between the HR group and
      those donors who did not receive HR. RESULTS: Of 10,292 consecutive brain-dead
      donors analyzed, 701 received three-drug HR. Univariate analysis showed the mean
      number of organs from HR donors (3.8) was 22.5% greater than that from
      nonhormonal resuscitation donors (3.1) (P <0.001). Multivariate analyses showed
      that HR was associated with the following statistically significant increased
      probabilities of an organ being transplanted from a donor: kidney 7.3%, heart
      4.7%, liver 4.9%, lung 2.8%, and pancreas 6.0%. Extrapolation of these
      probabilities to the 5,921 brain-dead donors recovered in 2001 was calculated to
      yield a total increase of 2,053 organs. CONCLUSION: HR stabilizes certain brain
      dead donors and is associated with significant increases in organs transplanted
      per donor.

PMID- 12605115
TI  - Administration of rabbit antithymocyte globulin (thymoglobulin) in ambulatory
      renal-transplant patients.
AB  - BACKGROUND: Antilymphocyte globulins have been used for the treatment and
      prevention of acute rejection in renal-allograft recipients. Thymoglobulin,
      rabbit antithymocyte globulin (RATG), has been shown to be effective for these
      indications and has been used primarily on an inpatient basis because of the
      recommendation that it be administered through a central line. METHODS: We
      retrospectively reviewed the charts of all patients treated with RATG since its
      first use in 1999. After premedication, the dose of RATG was administered over 4
      to 6 hours, with 1,000 units of heparin and 20 mg of hydrocortisone to reduce the
      incidence of thrombosis and local tissue reaction. All adverse reactions were
      recorded. RESULTS: Eighteen patients underwent a total of 57 outpatient
      infusions. Of the 57 infusions, 52 (91%) were without complication. Five
      infusions (9%) were complicated by infiltrates. No serious reactions were noted.
      CONCLUSIONS: These data confirm that peripheral, outpatient administration of
      RATG is safe.

PMID- 12605116
TI  - Renal allograft loss as the result of polyomavirus interstitial nephritis after
      simultaneous kidney-pancreas transplantation: results with kidney
      retransplantation.
AB  - BACKGROUND: Polyomavirus (PV) infection in kidney transplant patients has been
      reported to cause interstitial nephritis and subsequent graft loss. The
      cornerstone of current therapy is a reduction in immunosuppression, which can
      subsequently lead to kidney allograft rejection. This dilemma becomes even more
      challenging in the setting of simultaneous kidney-pancreas transplantation,
      because a reduction in immunosuppression may result in rejection of the pancreas
      allograft. Antiviral therapy has not been shown to be clinically successful in
      decreasing the risk of graft loss secondary to PV infection. Furthermore, because
      of limited experience, the decision to perform retransplantation in patients who
      lost their primary kidney grafts to PV interstitial nephritis becomes a difficult
      one. METHODS: Retrospective review and case studies. RESULTS: We report two
      successful living donor kidney retransplants in simultaneous kidney-pancreas
      transplant patients who lost their first kidney grafts to PV infection. Both
      patients are receiving rimantadine therapy and performing well, with functioning
      kidney and pancreas grafts and no evidence of recurrent PV interstitial nephritis
      22 and 37 months after retransplantation. CONCLUSIONS: Although follow-up is
      limited, our initial experience would indicate that graft loss secondary to PV
      interstitial nephritis is not an absolute contraindication for kidney
      retransplantation.

PMID- 12605117
TI  - Does cadaveric donor renal transplantation ever provide better outcomes than live
      donor renal transplantation?
AB  - BACKGROUND: Live donor renal transplantation (LRT) now comprises more than 40% of
      all kidney transplants performed in the United States. Many patients on the
      cadaveric waiting list have a prospective live kidney donor. This study
      determines whether cadaveric donor renal transplantation (CRT) can demonstrate
      better outcomes than LRT. METHODS: From the United States Renal Data System
      registry, 31,909 adult recipients of a first-time kidney transplant from 1995 to
      1998 were analyzed. Recipients were followed until December 31, 2000. RESULTS:
      CRT, more human leukocyte antigen (HLA) mismatches, increased donor age, cold
      ischemia time greater than 24 hr, African American recipient, and a history of
      diabetic nephropathy all increased the risk of graft failure, return to dialysis,
      and death. Nevertheless, in specific circumstances, CRT could provide better
      outcomes than LRT. For example, in recipients aged 18 to 59 years with a
      hypothetical live kidney donor aged 50 years and four HLA mismatches, the
      relative risk of graft loss with LRT is comparable or increased compared with CRT
      if the cadaveric kidney donor is much younger or with fewer HLA mismatches. On
      the other hand, for recipients aged 60 years or older, CRT never provides better
      outcomes than LRT. All analyses were adjusted for recipient race, gender, and
      history of diabetic nephropathy. There were no significant interactions among
      donor type, HLA mismatches, donor age, and cold ischemia time. CONCLUSIONS: The
      elderly recipient with an imminent LRT should never be offered CRT. A combination
      of recipient and donor factors can make CRT preferable to LRT in younger
      patients.

PMID- 12605118
TI  - Positive remote crossmatch: impact on short-term and long-term outcome in cadaver
      renal transplantation.
AB  - BACKGROUND: A positive crossmatch with a "current" recipient serum (drawn shortly
      before the proposed transplant) is a contraindication to renal transplantation
      because of the risk of hyperacute rejection. Conflicting data have been reported
      concerning the significance of a positive crossmatch with "remote" sera (obtained
      months or years earlier) when the current crossmatch is negative. METHODS:
      Recipients of a first or second cadaver transplant between June 1988 and April
      1994 were studied. All transplants were performed with a negative "current"
      crossmatch. Retrospective crossmatches using "remote" sera were performed for all
      sensitized recipients. RESULTS: Recipients with a positive remote crossmatch
      (RXM) demonstrated a higher incidence of delayed graft function and of acute
      rejection and graft loss occurring in the first year posttransplant than did
      sensitized recipients with a negative RXM or unsensitized recipients. In
      multivariate analysis, only recipients with both a positive RXM and delayed graft
      function were at significantly higher risk for graft loss. Grafts surviving the
      first year demonstrated similar half-lives whether the RXM was positive or
      negative. CONCLUSIONS: The positive RXM, possibly in conjunction with other
      factors leading to very early graft damage, is a significant predictor of
      unfavorable transplant outcome in first and second renal transplants. This effect
      is seen early in the transplant course, and there seems to be no impact on
      outcome after the first year. Newer immunosuppressive modalities may help to
      reduce the early negative impact.

PMID- 12605119
TI  - Tubulitis in renal allograft rejection: role of transforming growth factor-beta
      and interleukin-15 in development and maintenance of CD103+ intraepithelial T
      cells.
AB  - BACKGROUND: Renal tubules normally show no lymphocyte infiltration, but tubulitis
      is a feature of renal allograft rejection with many intratubular T cells
      expressing CD8 and CD103 (the alphaEbeta7 integrin). We investigated the
      development and maintenance of allospecific CD103 T cells within the tubular
      microenvironment. METHODS: Mixed lymphocyte cultures were supplemented with
      transforming growth factor (TGF)-beta1 to model the expression and function of
      CD103 observed in situ on intratubular lymphocytes. Immunocytochemical techniques
      were used to identify cells coexpressing CD8 and interleukin (IL)-15Ralpha, to
      enumerate proliferating intratubular T cells, and to quantify IL-15 expression
      within the tubules of control and rejection-graded transplant biopsy specimens.
      These results were compared with a parallel analysis of the phenotype and
      proliferation of allospecific T cells expanded in vitro in the presence of TGF
      beta1 and IL-15. RESULTS: TGF-beta1 only induced the expression of adhesive CD103
      after at least one cycle of alloantigen-specific cell division in vitro. In the
      renal allograft, a similar proportion of intratubular T cells was observed to
      proliferate during and after acute rejection. Tubular epithelial cells expressed
      IL-15 constitutively, whereas intratubular CD8 T cells expressed IL-15 receptor
      alpha. IL-15 and TGF-beta1 synergized to promote expansion and survival of
      allospecific CD8 CD103 T cells in vitro, but IL-15 down-regulated perforin
      expression. CONCLUSIONS: These results suggest that activated, allospecific CD8 T
      cells are recruited to tubules during acute rejection where they encounter TGF
      beta, up-regulate CD103 expression, and bind E-cadherin. A proportion of these
      cells proliferates and is maintained in a state of low perforin expression by the
      combined action of TGF-beta and IL-15.

PMID- 12605120
TI  - T-cell receptor beta-chain usage in directly activated alloreactive CD4+ T cells:
      unrestricted Vbeta gene usage with CDR3 size limitations.
AB  - BACKGROUND: Alloreactive immune responses may engage both direct and indirect
      antigen allorecognition. This study focuses on T-cell receptor (TCR) beta-chain
      usage by in vitro generated alloreactive CD4+ T cells involved in direct
      allorecognition pathway. METHODS AND RESULTS: We have established Lewis anti
      Brown Norway rat CD4+ T-cell lines and confirmed their reactivities against cell
      surface, but not soluble, alloantigens. TCR Vbeta-specific reverse-transcriptase
      polymerase chain reaction detected all 22 Vbeta genes in these cell lines at all
      stages, regardless of the lengths of in vitro stimulation. By using
      spectrotyping, we found that Vbeta complementarity determining region (CDR)3
      length distribution pattern altered dramatically after repeated allostimulation.
      Such a skewed CDR3 distribution occurred in most Vbeta genes without any obvious
      preference, indicating that expansion occurred in all Vbeta expressing cells by
      allostimulation. Fluorescence-activated cell sorter analysis of Vbeta expression
      in alloreactive CD4+ T-cell lines with anti-Vbeta-specific monoclonal antibodies
      showed, quantitatively, similar percentages of individual Vbeta-expressing cells
      in the alloreactive pool after repeated allostimulation. To test whether
      preferential TCR Vbeta gene usage occurred in "high responder" cells, we sorted
      CD4+ T cells that underwent three or more divisions from primary mixed leukocyte
      reactions. Unlimited Vbeta usage with CDR3 alterations was observed, as in
      unsorted alloreactive T cells. CONCLUSION: TCR Vbeta gene usage in directly
      alloreactive CD4+ T-cell population is unrestricted. Clonal expansion occurs in
      all Vbeta expressing T cells by allostimulation.

PMID- 12605121
TI  - Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage
      colony stimulating factor prolong donor-specific rat cardiac allograft survival.
AB  - BACKGROUND: Because the differential polarization of T cells in response to
      antigen presentation is dependent on the maturational state of dendritic cells
      (DCs), we hypothesized that the adoptive transfer of immature myeloid DCs (iMDCs)
      would prolong graft survival. METHODS: To evaluate this hypothesis, we studied
      the effects of transfer of iMDCs and mature myeloid DCs (mMDCs) on rat cardiac
      allograft survival. RESULTS: Whereas iMDCs that do not express costimulatory
      molecules induce allogeneic T-cell hyporesponsiveness in coculture studies, mMDCs
      that express high levels of major histocompatibility complex class II
      costimulatory and maturation molecules induce a robust allostimulatory T-cell
      response. Adoptive transfer of Wistar Furth iMDCs, unlike mMDCs, 7 days before
      cardiac transplantation significantly prolonged graft survival. It was important
      that adoptive transfer of iMDCs combined with 0.5 mL antilymphocyte serum (ALS)
      transient immunosuppression on day -7 led to donor-specific permanent graft
      survival in 50% of recipients. In contrast, adoptive transfer of mMDCs combined
      with ALS led to graft survival similar to that in recipients treated with ALS
      alone. Stimulation of CD4 T cells isolated from the spleen of unresponsive
      allograft recipients with donor antigen resulted in donor-specific
      hyporesponsiveness and production of interleukin (IL)-10 and transforming growth
      factor-beta but not IL-4 and interferon-gamma. The tolerant T-cell
      unresponsiveness was reversed by the addition of IL-2. CONCLUSION: Our data
      confirming the immunoregulatory effect of immature DCs indicate that induction of
      transplant tolerance by iMDCs is partly dependent on in vivo generation of
      regulatory T cells. This finding suggests that immunization with immature donor
      DCs has therapeutic potential for the induction of transplant tolerance and
      treatment of autoimmune diseases.

PMID- 12605122
TI  - T-cell mediated induction of allogeneic endothelial cell chemokine expression.
AB  - BACKGROUND: The goal of the current study was to test the ability of T cells to
      stimulate allogeneic endothelial cells to express chemokines, particularly the T
      cell recruiting factors monokine induced by interferon-gamma (Mig) and inducible
      protein (IP)-10. METHODS: Lymph node cells from C57BL/6 (H-2b) recipients of C3H
      (H-2k) skin grafts or from naive mice were added to monolayers of C3H-derived
      endothelial cell line 2F-2B. After 5 or 24 hr, the lymph node cells were removed,
      and RNA was prepared from the endothelial cells and tested by ribonuclease
      protection assay or Northern blot hybridization for endothelial cell expression
      of chemokines. RESULTS: Alloantigen-primed T cells induced endothelial cell
      expression of regulated on activation normal T-cell expressed and secreted
      (RANTES), IP-10, Mig, monocyte chemotactic protein-1, macrophage inflammatory
      protein-1alpha, and macrophage inflammatory protein-1beta within 5 hr of
      coculture. In vitro chemotaxis assays demonstrated the production of T-cell
      chemoattractants by the endothelial cells. With the exception of low levels of
      monocyte chemotactic protein-1 and RANTES, culture with naive C57BL/6 lymph node
      T cells did not induce endothelial cell chemokine expression. Alloantigen-primed
      CD4 T cells induced endothelial expression of IP-10 and RANTES but none of the
      other chemokines tested, whereas primed CD8 T cells induced all of the chemokines
      tested. Expression of IP-10 and Mig was not induced when alloantigen-primed T
      cells from interferon-gamma deficient recipients of C3H skin grafts were cultured
      with the endothelial cells. This expression was blocked by addition of
      intercellular adhesion molecule-1 or lymphocyte function-associated antigen-1
      specific antibodies to the cultures. CONCLUSIONS These results demonstrate the
      ability of alloantigen-primed CD8 T cells to quickly and directly stimulate
      endothelial cells to express and produce chemokines, including those recruiting T
      cells.

PMID- 12605123
TI  - Syngeneic bone marrow transduced with a recombinant retroviral vector to express
      endoplasmic reticulum signal-sequence-deleted major histocompatibility complex
      class-I alloantigen can induce specific immunologic unresponsiveness in vivo.
AB  - BACKGROUND: Long-term survival of fully allogeneic cardiac grafts can be induced
      in mice through transduction of recipient bone marrow cells (BMCs) with a
      recombinant retroviral vector encoding a single full-length major
      histocompatibility complex (MHC) class I alloantigen. This study investigated
      whether cell surface expression of the transduced MHC antigen was necessary for
      the induction of specific unresponsiveness. METHOD The signal sequence for
      translocation into the endoplasmic reticulum was deleted from H-2K (SDELKb).
      Syngeneic BMCs from CBA.Ca (H2k) recipients were transduced with an MFG
      retroviral vector encoding either wild-type Kb or the mutant SDELKb and reinfused
      in conjunction with an anti-CD4 therapy. Four weeks later, the recipients
      underwent transplantation with a fully allogeneic C57BL/10 cardiac graft. Graft
      survival and the development of transplant arteriosclerosis were assessed.
      RESULTS: Expression of both the wild-type Kb or SDELK in recipient CBA mice
      before transplantation resulted in prolonged survival of C57BL/10 grafts. Grafts
      from recipients pretreated with SDELKb developed 48%+/-22% intimal proliferation
      compared with 61%+/-21% in grafts from recipients pretreated with wild-type Kb.
      However, this difference did not reach statistical significance. CONCLUSION Cell
      surface expression, and therefore direct recognition, of an MHC class I
      alloantigen is not required to induce long-term survival of fully allogeneic
      cardiac grafts after retroviral transduction of recipient BMCs.

PMID- 12605124
TI  - An engineered bifunctional recombinant molecule that regulates humoral and
      cellular effector functions of the immune system.
AB  - BACKGROUND: Humoral and cellular defense mechanisms mediate the rejection of
      transplanted cells, tissues, and organs after allogeneic or xenogeneic
      transplantation. Inhibition of complement and T-cell costimulation are strategies
      aimed at increasing transplant survival. METHODS: Engineered novel fusion
      proteins that contain the functional domains of human CD152 (hCTLA4) or porcine
      CD152 (pCD152) and human CD59 (hCD152-hCD59, pCD152-hCD59) were developed to form
      bifunctional chimeric proteins that retain the effector functions of both
      moieties. Porcine aortic endothelial cells and murine Balb/3T3 cells were
      transduced or transfected to express the novel fusion proteins. RESULTS:
      Fluorescence-activated cell sorter analysis of hCD152-hCD59 transduced primary
      porcine aortic endothelial cells or hCD152-hCD59 and pCD152-hCD59 transfected
      Balb/3T3 cells determined that the molecules were expressed on the cell surface,
      and that they retained conformational epitopes. We demonstrate that hCD152-hCD59
      and pCD152-hCD59 chimeric proteins inhibit complement-mediated cell lysis. In
      addition, hCD152-hCD59 or pCD152-hCD59 expression resulted in a significant
      reduction in T-cell activation as the result of CD152 engagement of porcine CD86
      or murine CD80 in when Jurkat cells were cocultured with the hCD152-hCD59 or
      pCD152-hCD59 expressing cells. Antibody-blocking experiments or
      phosphatidylinositol phospholipase C removal of the glycosyl-phosphatidylinositol
      linked molecules resulted in increased serum-mediated cytolysis and eliminated
      the costimulatory blockade. CONCLUSIONS: These data illustrate that a single
      molecule can confer resistance to humoral and cellular immune attack.

PMID- 12605125
TI  - Posttransplant administration of allochimeric major histocompatibility complex
      class-I-molecules induces true transplantation tolerance.
AB  - BACKGROUND: Allochimeric class-I major histocompatibility complex (MHC) molecules
      that contain donor-type immunogenic epitopes displayed on recipient-type
      sequences were shown to induce transplantation tolerance when administered at the
      time of transplantation. Here, we investigated the ability of posttransplant
      allochimeric administration to induce tolerance and concomitantly inhibit chronic
      rejection. METHODS: Allochimeric (alpha1h(1/u))-RT1.Aa class-I MHC antigenic
      extracts were administered by way of the portal vein into ACI recipients of
      Wistar-Firth (WF) hearts at days +3, +7, and +10 posttransplantation in
      conjunction with subtherapeutic oral cyclosporine. RESULTS: Delayed
      posttransplant allochimeric administration induced donor-specific transplantation
      tolerance to rat cardiac allografts. In contrast, delayed delivery of unaltered
      donor- or recipient-type MHC extracts failed to prolong allograft survival. In
      addition, histopathologic examination or estimation of transplant vascular
      sclerosis by neointimal index assessment, following delayed allochimeric therapy,
      revealed intact global architecture and minimal intimal thickening, respectively.
      CONCLUSION: Allochimeric MHC class-I therapy is a unique and novel clinically
      applicable approach for induction of "true" transplantation tolerance where
      chronic rejection is concomitantly abrogated.

PMID- 12605126
TI  - Facilitation of tacrolimus-induced heart-allograft acceptability by pretransplant
      host treatment with granulocyte colony-stimulating factor: interleukin-12
      restricted suppression of intragraft monokine mRNA expression.
AB  - BACKGROUND: Because recombinant human granulocyte colony-stimulating factor (rhG
      CSF) is known to modulate function of antigen-presenting cells, we examined
      effects of pretransplant host treatment with rhG-CSF on allograft survival.
      METHODS: In DA-to-Lewis rat heart transplantation, hosts were given pretransplant
      injections of rhG-CSF (250 microg/kg/day subcutaneously from day -5-0) and/or
      posttransplant injections of tacrolimus (2 mg/kg/day intramuscularly from day 0
      3). Cytokine mRNA levels in grafts were measured by real-time reverse
      transcription polymerase chain reaction. RESULTS: rhG-CSF pretreatment was
      effective in prolonging allograft survival only in tacrolimus-treated hosts (P
      <0.001). Intragraft mRNA expression of interleukin (IL)-12 subunits (p35, p40) at
      24 hours after transplantation was significantly (P <0.05) down-regulated by the
      addition of rhG-CSF and was associated with suppression of interferon-gamma
      levels on day 6, although other proinflammatory cytokines (tumor necrosis factor 
      alpha, IL-1beta, IL-6, IL-18) and anti-inflammatory cytokines (IL-10,
      transforming growth factor-beta) were not. CONCLUSIONS: rhG-CSF pretreatment down
      regulates intragraft expression of the type-1 T-helper cell (Th1)-driving
      cytokine IL-12 and facilitates tacrolimus-induced graft acceptance.

PMID- 12605127
TI  - Feasibility of duct-to-duct biliary reconstruction in left-lobe adult-living
      donor liver transplantation.
AB  - A Roux-en-Y choledochojejunostomy (CDJ) has been the sole method of choice for
      the reconstruction of the bile duct in living-donor liver transplantation (LDLT)
      using left-lobe grafts. In this study, we evaluated the feasibility of duct-to
      duct (DD) biliary reconstruction in adult-to-adult LDLT using left-lobe grafts.
      Between October 1996 and October 2001, 46 adult-to-adult LDLTs using the left
      lobe were performed at our institution. The DD biliary reconstruction
      (hepaticocholedochostomy) over a T-tube was performed for seven of the last nine
      recipients (DD group, n=7), whereas the conventional Roux-en-Y CDJ was used for
      the remaining cases (CDJ group, n=39). The technical problems and the incidence
      of biliary complications were compared between the groups. Bile leakage developed
      in only 1 of 7 (14%) in the DD group (leakage from a T-tube exit site), whereas
      it occurred in 8 of 39 (20%) in the CDJ group. Up to now, no patients from the DD
      group developed anastomotic stricture, whereas twelve (30.7%) patients from the
      CDJ group did. Other complications included bleeding from the Roux-en-Y
      jejunojejunostomy (n=1) and anastomotic occlusion caused by an internal stent
      (n=1), and both complications were associated with CDJ. In conclusion, DD
      anastomosis is a simple and viable option for biliary reconstruction in left-lobe
      LDLTs. A long-term follow-up, especially regarding the incidence of biliary
      stricture, is thus warranted in such patients.

PMID- 12605128
TI  - Orthotopic liver transplantation for hereditary fibrinogen amyloidosis.
AB  - Systemic amyloidosis results from the deposition of insoluble protein fibrils in
      various organs and tissues. To date, several different proteins have been
      associated with amyloid fibril formation, including immunoglobulin light chain,
      serum amyloid A protein, and transthyretin. Recent reports have shown that
      variant fibrinogen chains can form amyloid in certain kindreds. Hepatic
      transplantation has previously been reported in the treatment of hereditary
      amyloidosis associated with variant transthyretin proteins, which are mainly
      synthesized in the liver. This article reports the first use and long-term follow
      up of combined hepatic and renal transplantation in the successful treatment of
      two patients with hereditary fibrinogen amyloidosis. Both patients experienced
      sustained improvement in renal function and nutritional status at 61/2 years and
      28 months of follow-up, respectively. Orthotopic liver transplantation is
      effective and potentially curative treatment of hereditary fibrinogen
      amyloidosis.

PMID- 12605129
TI  - Simultaneous pancreas-kidney transplantation in patients with antiphospholipid
      syndrome.
AB  - BACKGROUND: Graft thrombosis is one of the main reasons of graft loss following
      simultaneous pancreas-kidney transplantation (SPK). Although antiphospholipid
      syndrome (APLS) is known as a high risk for graft thrombosis in kidney
      transplants alone, little is known about APLS in SPK. METHODS: Between September
      2000 and December 2001, 45 SPK were performed. The treatment and clinical course
      of 2 patients with APLS is presented. RESULTS: In one patient, APLS was known
      before transplantation. After SPK, she was treated by systemic heparin followed
      by coumarin. Both grafts are doing well 5 months posttransplant. The second
      patient underwent SPK without knowledge of APLS. The patient developed a deep
      vein thrombosis 5 weeks posttransplant. Hypercoagulability screening revealed
      APLS. Treatment consisted of systemic anticoagulation. Grafts were not affected.
      CONCLUSION: SPK can successfully be performed in APLS patients if anticoagulation
      is performed consistently. To reduce the risk of graft thrombosis, a
      pretransplant screening for APLS would probably be of benefit.

PMID- 12605130
TI  - Noncomposite simultaneous liver and intestinal transplantation.
AB  - Patients with short-gut syndrome may develop total parenteral nutrition
      associated liver disease, which may preclude them from isolated intestinal
      transplantation and require combined liver and intestinal transplantation.
      Traditionally, these multiorgan transplantations are performed using en bloc
      liver and intestinal grafts that share portal, hepatic, and mesenteric blood
      supplies. In the event that severe intestinal rejection occurs, it is prohibitive
      in these cases to remove the intestinal portion of the graft. Herein we present
      the case of a patient with short-gut syndrome caused by volvulus and severe
      cholestatic liver disease who underwent simultaneous intestinal and liver
      transplantation using separate grafts from the same cadaveric donor. We discuss
      the technical aspects of the case and the benefit of such an approach.

PMID- 12605131
TI  - Feasibility of acute physiology and chronic health evaluation (APACHE) II and III
      score-based screening in patients receiving allogeneic hematopoietic stem-cell
      transplantation.
AB  - Patients who require management in the intensive care unit (ICU) for
      complications after allogeneic hematopoietic stem-cell transplantation (HSCT)
      generally have a poor outcome. We retrospectively studied whether the risk
      prediction stratification systems commonly used for patients admitted to the ICU,
      that is, the Acute Physiology and Chronic Health Evaluation (APACHE) II and
      APACHE III systems, could be useful for identifying patients who should receive
      intensive care earlier. We reviewed the medical records of 210 patients who
      underwent allogeneic HSCT and found that 18 (8.6%) had been admitted to the ICU
      for acute respiratory failure (n=9), acute renal failure (n=7), and septic shock
      (n=2). The median APACHE II and III scores were, respectively, 16 (10-27) and 55
      (22-87) at the onset of complications and 26 (15-43) and 101 (65-157) upon
      admission to the ICU. Thus, both the APACHE II and APACHE III scores at ICU
      admission were higher than those at the onset of complications (P <0.0001).
      Seventeen patients (94%) subsequently died, with a median ICU stay of 7.5 days (1
      51 days), as a result of multiorgan failure (n=14), respiratory failure (n=2),
      and septic shock (n=1). The APACHE II and III scores of the sole surviving
      patient were, respectively, 21 and 71 at the onset and 24 and 86 upon transfer to
      the ICU. Thus, the APACHE scores in this study were lower than those reported for
      other surgical or medical patients treated in the ICU, despite their uniform poor
      prognosis. Although nine patients had developed grade III to IV acute graft
      versus-host disease, which is the most common cause of morbidity and mortality
      after allogeneic HSCT, this was not fully evaluated in the current scoring
      systems. Application of these systems to HSCT will require adequate modification,
      with particular attention to organ dysfunction secondary to graft-versus-host
      disease.

PMID- 12605132
TI  - Living kidney donors and hypoxia-inducible factor-1alpha.
AB  - BACKGROUND: Hypoxia inducible factor (HIF)-1, a heterodimeric transcription
      factor composed of alpha and beta subunits, is induced in the adaptive response
      to hypoxia and is critical for initiating the transcriptional activation of
      growth factors. We speculate that prolonged ischemia and hypoxia time leads to
      the production of HIF-1alpha, which in turn induces the production of fibrogenic
      cytokines in the graft. METHODS: To investigate our hypothesis, we measured the
      expression of HIF-1alpha in time-zero biopsy specimens from living-donor kidneys
      (< or =2.5 hr of ischemia) and cadaveric donor kidneys (12-32 hr of ischemia).
      RESULTS: By real time reverse-transcriptase polymerase chain reaction analysis,
      the mRNA expression level of HIF-1alpha was fivefold lower in time-zero biopsy
      specimens from living-donor kidneys than in specimens from cadaveric donor
      kidneys. In these time-zero biopsy specimens, the mRNA expression level of the
      fibrogenic cytokine transforming growth factor-beta was also significantly lower
      (twofold). CONCLUSIONS: Low HIF-1alpha mRNA expression levels correlate with
      short ischemia times and prevent the transcription of fibrogenic cytokines that
      initiate the irreversible process of graft fibrosis.

PMID- 12605133
TI  - Outcomes of African-American kidney-transplant recipients treated with sirolimus,
      tacrolimus, and corticosteroids.

PMID- 12605135
TI  - MELD score for selection of patients to receive a left liver graft.

PMID- 12605136
TI  - Terminal ileitis secondary to Mycobacterium gordonae in a renal transplant.

PMID- 12605137
TI  - [Therapeutic management of acne: some reflections].

PMID- 12605138
TI  - [What's new concerning the pathophysiology of acne?].

PMID- 12605139
TI  - [Neonatal, infantile and pre-puberty acne].

PMID- 12605140
TI  - [Polymorphous juvenile acne and adult acne].

PMID- 12605141
TI  - [Severe acne].

PMID- 12605142
TI  - [Diagnostic pitfalls].

PMID- 12605143
TI  - [Treatment of mild to moderate acne].

PMID- 12605144
TI  - [Treatment of severe acne].

PMID- 12605146
TI  - [Acne: skin care].

PMID- 12605145
TI  - [Hormonal treatments of acne].

PMID- 12605147
TI  - [An algorithm for the treatment of acne].

PMID- 12605148
TI  - [Could the blue of the blues be the color of hope?].

PMID- 12605149
TI  - [Cell therapy for leg ulcers. Results and perspectives].

PMID- 12605150
TI  - [Treatment of pemphigus vulgaris by azathioprine and low doses of prednisone
      (Lever scheme)].
AB  - INTRODUCTION: The so-called "Lever scheme" therapeutic regimen has been proposed
      in the borderline forms of pemphigus to reduce the side effects of systemic
      corticosteroids. PATIENTS AND METHODS: A retrospective study was conducted in 8
      hospital centers. The criteria for inclusion were the clinical diagnosis of
      pemphigus, confirmed by histological examination and direct immunofluorescence
      and first line therapy using the "Lever scheme" protocol, combining 40 mg of
      prednisone on alternate days and 100 mg/day of azathioprine. RESULTS: Twenty-two
      patients, seen between January 1990 and December 2000 were included in the study.
      Eighteen patients (82 p. 100) exhibited complete healing of their cutaneous
      buccal lesions after a mean delay of 4.3 months. The lesions of 4 patients did
      not heal. Three of these patients died: a bed-ridden patient, a patient
      exhibiting a metastatic bronchial carcinoma and a hypertensive patient who died
      following a hemorrhagic cerebral vascular accident. Twelve patients (54 p. 100)
      were weaned off treatment after a mean duration of 2.9 years. Five severe adverse
      events were observed: one pneumonia, 2 unbalanced diabetes, one hepatitis and one
      pulmonary embolism. DISCUSSION: This study showed that the healing of the
      cutaneous-buccal lesions was obtained using the "Lever scheme" in 18 cases out of
      22 (82 p. 100). The delay to healing was relatively long in view of the delayed
      effect of azathioprine. This limits the use of the "Lever scheme" protocol to non
      extensive and/or early stage pemphigus. The severe adverse events occurred in low
      weight patients in whom the dose related to weight was the highest. Hence the
      doses of azathioprine and prednisone should be adapted to patients' body weight.

PMID- 12605151
TI  - [Mycetoma: 130 cases].
AB  - BACKGROUND: Mycetoma is a pathological process in which eumycotic (fungal) or
      actinomycotic causative agents from exogenous source produce grains. It follows
      penetrating injury inoculating soil organisms, occurring preferentially in rural
      areas usually among labourers who work barefoot. Mycetoma is a localized chronic,
      and deforming infectious disease of subcutaneous tissues, skin and bones. We
      report 130 cases of mycetoma in Senegal from 1983 to 2000. PATIENTS AND METHODS:
      There were 130 patients with mycetoma. Clinical diagnosis of mycetoma was based
      on open tract sinuses, tumefaction or discharge of grain. Diagnosis confirmation
      was based on mycology and histology. An X-ray was preformed to detect bone
      lesions. Treatment was medical for actinomycetoma and surgical for eumycetoma.
      RESULTS: We observed 76 actinomycetoma and 54 eumycetoma (Sex ratio M/F=6.6; mean
      age=34.7 +/- 14.8 years). The mean duration before the first medical evaluation
      was 4.8 +/- 5.6 years. Actinomycetoma was due to Actinomadura pelletieri, (54
      cases), Actinomadura madurae (17 cases) and Streptomyces somaliensis (5 cases).
      Eumycetoma was due to Madurella mycetomatis (38 cases), Leptospahria senegalensis
      (9 cases), Pseudoallescheria boydii (6 cases) and Rhinoclediella atrovirens (1
      case). Clinical inflammatory features significantly associated with actinomyces
      (p<0.001 OR=2.64) were predominant (85 cases). Tumoral and cystic features were
      found in the others forms. Lesions were located on the foot in 81 patients. Bone
      lesions, depending on the duration, were observed in 68 patients. Neurological
      damage occurred in 3 patients with dorsolumbar actinomycetoma. Sixty-six patients
      with actinomycetoma were cured by medical treatment. DISCUSSION: The 130 cases of
      mycetoma were remarkable by the long duration of the disease before the first
      medical evaluation. Pain and tumor were the two main symptoms which brought the
      patients to the hospital and had appeared after 5 years duration and the
      predominance of actinomadura pelletieri actinomycetoma was responsible for 41.3
      p. 100 of our cases. In Niger and Mauritania, mycetoma were actinomycetoma in
      respectively 71.2 p. 100 and 25 p. 100 of cases. The geographic distribution of
      pathogenic mycetoma agents was determined by the annual rainfall. Distinction
      between eumycetoma and actinomycetoma is very important for the treatment.

PMID- 12605152
TI  - [Frequency, severity and treatment of ocular rosacea during cutaneous rosacea].
AB  - INTRODUCTION: We have tried to assess the incidence and disclosing factors of
      ocular rosacea and its treatment in patients presenting with cutaneous rosacea.
      PATIENTS AND METHODS: We conducted a prospective study over two years of all the
      patients consulting the Dermatology department of the University hospital in
      Saint-Etienne for cutaneous rosacea, and signs of the ocular form using a
      questionnaire and clinical examination. Each patient's case report was then
      studied individually when the patient presented signs of ocular rosacea. RESULTS:
      Three hundred eighteen patients consulted for cutaneous rosacea. Only 19 patients
      (6%) exhibited an ocular rosacea. Erythrocouperose was the predominant cutaneous
      stage. Conjunctivitis and keratitis were the predominating ophthalmologic
      symptoms. Tetracyclines were the treatment generally used with 72% of good
      response. Among the patients presenting with ocular rosacea, 52% had been
      referred by their general practitioner. DISCUSSION: The severity of the ocular
      damage is not correlated with the stage of cutaneous involvement. Ocular rosacea
      in its most developed form still remains the domain of the ophthalmologist. This
      study confirms cyclines as the treatment of choice in this disease.

PMID- 12605153
TI  - [Mucosal localization of leishmaniasis in Tunisia: 5 cases].
AB  - INTRODUCTION: Three epidemic-clinical forms of leishmaniasis are found in
      Tunisia: the sporadic cutaneous form due to L. Infantumin in the North, the
      zoonotic cutaneous form due to L. Major in the Center and South-West, and the
      chronic cutaneous form due to L. Tropica in the South. We report 5 cases of
      mucosal leishmaniasis diagnosed in a Dermatology unit in Tunis. OBSERVATIONS:
      Four women and one man, from the North-west of Tunisia, with a mean age of 42.4
      years (range: 8-75 years) presented with leishmaniasis. The lesions were
      localized on the mucosa of the lips in 4 patients and on the endonasal mucosa
      with infiltration and nasal obstruction in a 75 year-old female patient.
      Diagnosis of leishmaniasis was established on direct examination in 4 cases and
      histological examination in 3 cases and by culture in NNN milieu for one patient
      exhibiting a MON5 L. Major leishmaniasis. All the patients responded well to
      treatment with intramuscular meglumine antimoniate (Glucantime). In our 5
      patients, the mucosal involvement was not as mutilating, nor resistant to
      treatment, as that described for the cutaneous-mucosal forms in the New World.
      COMMENTS: Mucocutaneous leishmaniasis, endemic in Central and South America, are
      due to L. Braziliensis. They provoke mutilating and disfiguring lesions,
      resistant to treatment. In Tunisia, the forms of the disease observed are
      dermotropic, usually responsible for cutaneous leishmaniasis. However, mucosal
      involvement is not uncommon and is characterized by the absence of mutilating
      lesions and the excellent response to treatment.

PMID- 12605154
TI  - [A whole family affected by xeroderma pigmentosum: clinical and genetic
      particularities].
AB  - INTRODUCTION: Xeroderma pigmentosum is a relatively frequent genodermatosis in
      North Africa. It is characterized by abnormal sensitivity to ultraviolet light,
      responsible for the early occurrence of multiple cutaneous neoplasms. We present
      the results of the clinical and biological investigations in a family in which
      all its members exhibited xeroderma pigmentosum. PATIENTS AND METHODS: Since
      1962, the father, mother, the 5 children and the maternal uncle were all followed
      up in the dermatology department in Tunis for a variant of xeroderma pigmentosum.
      Clinical (dermatological, neurological and ophthalmologic), biological,
      photobiological and molecular biology investigations were carried out. RESULTS:
      Diagnosis of a variant of xeroderma pigmentosum was established on the delayed
      appearance (after the age of 4) of poikiloderma and the early onset of multiple
      carcinomas, without neurological disorders. Fifty-eight squamous cell and 3 basal
      cell carcinomas were diagnosed and treated by surgical exeresis or radiotherapy.
      The third child, treated with etretinate for 6 years, had developed 38
      carcinomas. Contrary to the parents, whose first carcinomas had appeared at the
      age of 34 and 40 years, the cutaneous cancers in the children appeared early,
      between the ages of 17 and 24. The minimal erythematous dose was normal in all
      these patients. Conversely, the phototest revealed persistent erythema and the
      delayed appearance of multiple dyskeratosis cells. Molecular biology confirmed
      the diagnosis of xeroderma pigmentosum with the presence of a low level DNA
      repair. The third child, the father and the uncle respectively exhibited DNA
      repair rates of 32, 57 and 72%, compared with normal controls. The results of the
      complementarity tests conducted in the third child suggested that this family
      belonged to the genetic F group. Discussion The clinical and molecular data
      confirmed the diagnosis of xeroderma pigmentosum in this family and their genetic
      F group profile. However, this family exhibited clinical (the cutaneous
      involvement was more severe in the children) and molecular heterogeneity and the
      level of DNA repair was high in comparison with the levels (between 12 and 15%)
      reported by Japanese authors in group F xeroderma pigmentosum. The third child
      exhibited 10-fold more carcinomas that his siblings. This high rate of carcinoma
      may be explained by excessive exposure to sun and/or the retinoid treatment,
      particularly since his DNA repair rate (32%) was relatively high compared with
      that of severe (0-5%) and moderate (5-15%) forms of the disease.

PMID- 12605156
TI  - [Photo-induced sarcoidosis].
AB  - INTRODUCTION: Among the multiple forms of clinically atypical cutaneous
      sarcoidosis, lesions limited to light-exposed areas are rare. We describe a
      fourth observation. CASE REPORT: A phototype V 51-year-old woman, born in Tunisia
      presented with papular erythema on the face. Treatment with topical steroids did
      not result in any improvement. Biopsy specimen revealed a non caseating granuloma
      according with sarcoidosis. Assessment for systemic sarcoidosis was negative.
      Phototesting showed no abnormalities. The patient was successfully treated with
      chloroquine. DISCUSSION: Only three similar observations are reported in the
      literature. The role of light exposure despite the negative phototesting seems to
      be real. The tallying of these four observations permits one to isolate photo
      induced sarcoidosis as a single entity.

PMID- 12605155
TI  - [Successful treatment of haemodialysis-related porphyria cutanea tarda with
      deferoxamine].
AB  - BACKGROUND: End-stage renal failure and long-term hemodialysis treatment promote
      porphyria cutanea tarda. Iron overload is often associated with this disease and
      is thought to play a role in its pathogenesis. We report a case of hemodialysis
      related-porphyria cutanea tarda improved by deferoxamine. CASE REPORT: A 45-year
      old man, with end-stage renal failure and who had received hemodialysis treatment
      since 1993, presented a several months-history of blisters of the face and the
      dorsum of the hands. Laboratory analysis showed: hemoglobin 10 g/dl; a moderate
      hepatic cytolysis; ferritin 195 ng/l. HIV, HBV, HCV serologies were negative.
      Porphyries analyses showed a porphyria cutanea tarda pattern. The cutaneous
      histology was non specific; direct immunofluorescence was negative. The patient
      received deferoxamine (40 mg/kg intravenously every week for 6 weeks) which led
      to dramatic improvement of the symptoms. DISCUSSION: Several treatments are
      proposed in the management of dialysis-related porphyria cutanea tarda. This case
      confirms that deferoxamine can induce rapid and prolonged remission.

PMID- 12605157
TI  - [Juvenile hyaline fibromatosis: 2 twin brothers affected].
AB  - INTRODUCTION: Juvenile hyaline fibromatosis is a rare hereditary genetic disease
      characterized by a cutaneous tumoral fibroblastic proliferation with joint
      involvement. CASE-REPORT: We report the case of 2 homozygous twin brothers both
      presenting a diffuse and invalidating form of juvenile hyaline fibromatosis. The
      2 boys' born of a twin pregnancy' presented at the age of 2 months a clinical
      picture made up by the classic association: infiltrated papulo-nodules, gingival
      hyperplasia and joint contracture. The diagnosis of juvenile hyaline fibromatosis
      suggested clinically was confirmed by the histological study of the skin.
      DISCUSSION: These observations of juvenile hyaline fibromatosis's are particular
      in the involvement of 2 twin brothers, which to our knowledge has never been
      reported, the resemblance of the clinical features, and the severity of the
      functional handicap.

PMID- 12605158
TI  - [Cutaneous T-cell lymphoma following renal transplantation].
AB  - INTRODUCTION: Post-transplant cutaneous lymphomas are the second skin cancer
      after cutaneous carcinoma and are usually of the B-cell type. Post-transplant
      cutaneous T-cell lymphomas are extremely rare. We described a case of a cutaneous
      T-cell lymphoma in a renal transplant recipient. CASE REPORT: A 52-year-old woman
      was hospitalized for an erythematous infiltrated eruption. Seven years earlier,
      she had undergone kidney transplantation. No palpable lymphadenopathy or
      hepatosplenomegaly was present. The patient's skin biopsy specimen was
      histologically suggestive of CD30- fungoid mycosis. The same clonal TCR
      rearrangement was identified in the blood and in the skin. No EBV was detected
      within the cutaneous lesion on immunohistochemical analysis or by PCR in the
      blood. Chlorambucil (Chloraminophene) was associated with a topical treatment
      with chlormethine (Caryolysine) and corticosteroids while tacrolimus (Prograf)
      was reduced and stopped. There was no evidence of recurrence of the lymphoma
      after 12 months of follow-up. DISCUSSION: The particularity of our observation is
      the apparition, 7 years after transplantation, of a CD30-, EBV-fungoid mycosis
      with a blood and cutaneous clonal TCR-rearrangement. Despite this poor prognosis
      factor, the cutaneous lymphoma regressed after reduction of the immunosuppressive
      treatment reduction and institution of topical corticosteroids, chlormethine and
      chlorambucil.

PMID- 12605159
TI  - [Sub-total hereditary leukonychia, histopathological and electron microscopy
      study of "milky" nails].
AB  - INTRODUCTION: Leuconychia is the most common of ungueal discoloration or
      dyschromia. The hereditary form, sub-total or total, is very rare. We report the
      observation of a family in which thirteen members, distributed over four
      generations, presented a partial or subtotal leukonychia of all nails. On the
      basis of this observation and histopathological analysis of the propositus nail,
      we discuss the different hypotheses proposed to account for white nails.
      OBSERVATION: A 45 year-old man without previous medical history, showed partial
      or sub-total leukonychia of his twenty nails. Clinical examination revealed soft
      nails with slow growth. Discoloration or dyschromia was associated with
      koilonychia on the fingers without other cutaneous or visceral abnormalities. A
      longitudinal biopsy of the whole ungueal apparatus of the large toe was
      performed. Histopathological analysis showed parakeratosis and an abnormal
      granular layer thickened on the proximal and ventral womb. These abnormalities
      were responsible for heterogeneous HES coloration, lamellar and dissociated
      aspect of the nail plates. Electron microscopy revealed dissociated keratin
      bundles and the existence of intracytoplasmic clear vacuoles probably of lipid
      origin. This aspect was observed on the proximal part of the dorsal tablet and
      disappeared in the distal portion of the nail. DISCUSSION: According to Newton's
      theorem, a surface appears white when it reflects all the radiation of visible
      light. This mechanism can be proposed to explain leukonychia. On histological
      level, parakeratosis and dissociation of the keratin bundles may play a role in
      the modification of the solar light reflection by ungueal plates. In our case,
      parakeratosis and disorganization of keratin bundles were present in the white
      part of the nail, but also in the distal, pinkish crescent (distal dorsal plate).
      Electron microscopy analysis showed clear vacuoles located in the white part of
      the nail, whereas they were not seen in the distal part. These observations
      confirm the probable participation of parakeratosis and keratin abnormalities in
      this pathology but also suggest an important role of lipid vacuoles. Therefore,
      some white nails may in fact be "milky" nails. Finally, disorganization of the
      keratin bundles observed, was also reported in other genodermatosis e.g.:
      epidermolysis bullosa simplex. In this latter pathology, some hard keratin genes
      mutations (K5 and K14) have been demonstrated. According to these results, a
      genetic study is on going in this family in order to search for a mutation in one
      of the hard keratin genes.

PMID- 12605160
TI  - [Verrucous carcinoma of the tongue occurring on lesions of lichen planus].
AB  - BACKGROUND: Verrucous carcinoma of the oral cavity is a rare entity that was
      formerly controversial. Etiopathogenesis remains unclear, notably as for its
      possible association with lichen planus. We report a case of verrucous carcinoma
      occurring in lesions of lichen planus of the tongue. CASE REPORT: A 78-year old,
      non smoking patient, with past history of cutaneous lichen planus presented for
      lesions of oral lichen planus affecting both the tongue and the palate. A
      treatment by topical tretinoin improved him in a spectacular way and brought
      about a remission which lasted 5 years. A recurrence occurred when the treatment
      was stopped; new whitish, warty cauliflower-like lesions appeared on the tongue.
      A biopsy confirmed the clinical suspicion of verrucous carcinoma. A laser
      resection was performed. Three months later, another recurrence was observed. A
      chemotherapy associating isotretinoin and methotrexate eliminated all lesions.
      The patient's condition is considered stable, under treatment, one year later.
      DISCUSSION: Verrucous carcinoma is a rare slow-growing oral tumor that is chiefly
      exophytic and does not metastasize, but it can invade and destroy oral tissues.
      Its clinical presentation contrasts with benign histologic features:
      papillomatosis, acanthosis, dysplasia in variable degrees. The occurrence on
      lesions of lichen planus, although "classic", is very rarely found in the
      literature. The treatment is not well codified. An additional chemotherapy seems
      necessary to prevent recurrences.

PMID- 12605161
TI  - [Impetigo in a child in a tropical environment].

PMID- 12605162
TI  - [Generalized acute exanthematic pustulosis induced by Boldoflorine].

PMID- 12605163
TI  - [Pruriginous and purpuric eruption].

PMID- 12605165
TI  - [Xanthomas].

PMID- 12605164
TI  - [A reticulated, pigmented, erythematous eruption].

PMID- 12605166
TI  - [Xeroderma pigmentosum].

PMID- 12605168
TI  - [Alginates].

PMID- 12605167
TI  - [Nails of the newborn and infants].

PMID- 12605169
TI  - [How to read a survival curve?].

PMID- 12605170
TI  - [Edema of the eyelids caused by sirolimus in renal transplant recipients].

PMID- 12605172
TI  - Jonathan E. Rhoads, 1907-2002.

PMID- 12605174
TI  - Dispositional pessimism predicts delayed return to normal activities after
      inguinal hernia operation.
AB  - BACKGROUND: The traditional outcome measure to assess effectiveness of inguinal
      hernia operation was recurrence. Open mesh repair has reduced recurrence rates
      and attention is now turning to outcomes other than recurrence. The factors
      influencing the large variation in reported times of resumption of normal
      activities after inguinal hernia repair are many and diverse. The human factors
      influencing resumption of normal activity are rarely reported. METHODS: We
      undertook a prospective study of 206 patients undergoing primary inguinal hernia
      repair in an ambulatory setting in a public hospital to ascertain whether
      dispositional outlook on life affected resumption of normal activity after hernia
      repair. Outlook on life was assessed using the life orientation test. An
      independent observer assessed the patients preoperatively and determined timing
      of resumption of normal activities. RESULTS: Regression analysis showed a highly
      significant relationship between delayed return to normal activity and
      dispositional pessimism (P =.0004). DISCUSSION: Dispositional pessimism
      correlates strongly with delayed return to normal activities. Further studies of
      this kind will help to elucidate the human factors that affect recovery after
      operation. Studies which use return to normal activities as a measure of the
      outcome of a surgical technique should include an assessment of the patient's
      preoperative outlook on life. Surgeons should consider the personality of the
      patient presenting for groin hernia repair and may wish to tailor their
      counseling accordingly.

PMID- 12605173
TI  - Progressive improvement of prognosis for patients with gastric cancer (dynamic
      stage grouping) with increasing survival interval from initial staging: how much
      longer can a given survivor expect to live?
AB  - BACKGROUND: The prognosis in gastric cancer is usually defined at the time of
      presentation. Prognosis, however, is a variable that alters with time. Once a
      patient has survived for 1 year, the prognosis will change. This study examines
      this variable in patients who have survived from 1 to 5 years after operation.
      METHODS: Of 1468 patients with gastric cancer, the next 5-year survival (5YS) of
      patients who already survived for 1, 2, 3, 4, and 5 years after the initial
      operation was examined, ie, for patients who have survived 1 year, the 5YS (the 6
      year survival from operation) was calculated. Similar survival was determined for
      patients who had survived more than 2, 3, 4, or 5 years and reported according to
      stage. RESULTS: In patients who survived 2 years, the next 5YS from that time of
      patients in stage III a stage was similar to that in stage II, and was similar to
      the 5YS of patients in stage II at the time of diagnosis. In patients who
      survived 3, 4, or 5 years, the next 5YS from that time of patients in stage III b
      and stage III a was similar to that of stage II, and subsequently improved.
      Similarly, the relationship between stage and survival was disordered
      subsequently with the passage of time. Similar improvement in survival such that
      5YS from the 3rd, 4th, and 5th postoperative year approximated that of the
      survival of patients at an earlier stage at the time of diagnosis. CONCLUSIONS:
      Survival is not only stage-dependent at the time of diagnosis but dependent on
      the length of survival from the initial operation. Progressive improvement in
      subsequent 5YS appears to approximate survival of lower-stage disease with the
      passage of time.

PMID- 12605171
TI  - Surgical genomics is here.

PMID- 12605176
TI  - The effects of an awareness-raising program for patients and primary care
      physicians on the early detection of gastro-oesophageal cancer.
AB  - OBJECTIVE: To test the efficacy of education by home letter, together with
      improved specialist/GP liaison, in promoting the detection of treatable gastro
      oesophageal cancer in patients over 40. DESIGN: Prospective non-randomized trial
      with matched control group. PARTICIPANTS: 37,500 individuals over 40, registered
      with 12 general practices, were sent yearly letters for 3 consecutive years,
      advising them to consult a doctor with 4 specific symptoms. A matched control
      population of 60,500 received no intervention. MAIN OUTCOME MEASURES: Cancer
      cases were identified from cancer registry data, and the stage distribution and
      operability rates calculated from review of hospital case notes. RESULTS: Twenty
      of 59 cancer patients in the study group (34%) and 42 of 125 in the control group
      (34%) underwent resections; 24% (14/59) of study group and 18% (23/125) of
      control patients had "curable" disease (odds ratio [OR]= 1.51 [95%CI 0.71-3.23],
      X(2) = 1.164, P = 0.28). In year 1 of the study, 11 of 20 (55%) study group
      patients underwent resection compared to P 10 of 38 (26%) control group patients
      (P = 0.045, Fisher's exact test, OR = 3.4 [95% CI 1.09-0.7]). In year 1, 8 of 20
      study patients (40%) had "curable" disease compared to 10.5% (4/38) control
      patients (P = 0.0128 Fisher's exact test, OR = 5.67 [95% CI 1.44 - 22.3]). There
      was no difference in survival between the groups overall or on comparing each
      year of study. CONCLUSION: This intervention caused a transient marked
      improvement in resection rate and curability, but the longer term impact on stage
      and resection rate was nonsignificant, and survival was not affected. Improving
      the detection of curable upper GI cancer is likely to require more complex and
      intensive interventions.

PMID- 12605175
TI  - Trends in surgery for gastroesophageal reflux disease: the effect of laparoscopic
      surgery on utilization.
AB  - BACKGROUND: In addition to substituting for open surgery, minimally invasive
      surgery may lower thresholds for intervention and thus increase overall
      utilization rates. The degree to which laparoscopy may have lowered the threshold
      for elective anti-reflux surgery is unknown. METHODS: Using the Uniform Hospital
      Discharge Dataset and ICD-9 procedure and diagnosis codes, we identified all
      laparoscopic and open anti-reflux procedures performed on adults in
      Massachusetts, New Hampshire, and Vermont for each year from 1993 to 1998. We
      then examined secular trends and regional variation in the use of laparoscopic
      and open anti-reflux surgery. RESULTS: The population-based rate of anti-reflux
      surgery more than doubled between 1993 (4.8 per 100,000) and 1998 (11.7 per
      100,000). Laparoscopic anti-reflux procedures increased more than 6-fold between
      1993 and 1998, from 1.2 to 8.9 procedures per 100,000 adults, with accompanying
      declines in overall length of stay and mortality. However, the number of open
      anti-reflux procedures decreased only modestly (22%) over this time period. In
      the year hospitals performed their first laparoscopic anti-reflux operation,
      procedure rates nearly tripled, on average, and then increased slowly in
      subsequent years. In 1997 and 1998, rates of anti-reflux surgery varied nearly 5
      fold across hospital referral regions, ranging from 5.4 to 24.5 per 100,000.
      CONCLUSIONS: With the growth of minimally invasive surgery, rates of anti-reflux
      surgery have increased substantially, with wide regional variation in
      intervention rates. Further research is needed to determine the appropriate
      threshold for surgical treatment in patients with gastroesophageal reflux.

PMID- 12605177
TI  - Clinical significance of circulating tumor cells in blood by molecular detection
      and tumor markers in esophageal cancer.
AB  - BACKGROUND: The clinical significance of circulating tumor cells in the blood
      during surgery has not been elucidated in esophageal squamous cell carcinoma
      (ESCC). We evaluated the relationship between circulating tumor cells and
      clinicopathologic findings, compared with that of serum squamous cell carcinoma
      (SCC) antigen and carcinoembryonic antigen (CEA), in ESCC. METHODS: Blood samples
      from 54 consecutive patients were obtained from the peripheral artery and the
      superior vena cava at three points in time: immediately before surgery, and
      before and after tumor resection. CEA-specific reverse transcriptase-polymerase
      chain reaction (RT-PCR), which can quantify circulating tumor cells in blood, was
      performed. The preoperative values of serum SCC antigen and CEA were also
      obtained for all patients. RESULTS: CEA messenger RNA (CEA mRNA) was detected in
      the blood of 31 out of 54 patients (57.4%). CEA mRNA positivity was detected most
      frequently after tumor resection and correlated with nodal status and stage
      grouping. The incidence of total recurrence and blood-borne recurrence was
      significantly greater in patients with CEA mRNA positivity than in those with CEA
      mRNA negativity (P =.036 and.0026, respectively). Preoperative serum levels of
      SCC antigen and CEA did not correlate with clinicopathologic findings and tumor
      recurrence. CONCLUSIONS: CEA mRNA detected by RT-PCR was more predictive of tumor
      recurrence than serum tumor markers. Effective adjuvant therapy is recommended
      for patients with CEA mRNA positive expression.

PMID- 12605178
TI  - Interstitial CT lymphography-guided localization of breast sentinel lymph node:
      preliminary results.
AB  - BACKGROUND: Accurate localization of the breast sentinel lymph node (SLN) can be
      challenging as a minimally invasive approach to the treatment of early-stage
      breast cancer. We tested the potential capability of interstitial computed
      tomographic lymphography (CT-LG) using a conventional contrast agent (iopamidol)
      for SLN mapping. METHODS: In 14 female dogs, 0.5 and 1 mL of undiluted iopamidol
      was injected subcutaneously into the 2 skin areas overlying the mammary gland.
      Contiguous, 2 mm-thick multidetector helical CT images were obtained through the
      upper breast and axilla before, and for 60 minutes after, gentle massage at the
      injection site. Three-dimensional (3D) CT images were obtained from the
      postcontrast images showing the greatest SLN enhancement. This CT-LG with 2 mL of
      iopamidol was also evaluated in 5 human female volunteers. RESULTS: The direct
      connection of SLN and lymphatic vessels draining from the injection sites in the
      animal models was clearly visualized, even with 0.5 mL of iopamidol. With this
      dose, the SLN attenuation was maximally enhanced, with a mean of 274 Hounsfield
      units (HU) on the first postcontrast images. The topographic 3D images provided
      the comprehensive anatomy of these lymphatic pathways. Of the 28 SLNs and 184
      distant nodes visualized on CT images, all of the SLNs (100%) and 161 (87.5%) of
      the distant nodes could be resected at premortem and/or postmortem, with a good
      correlation in the locations and sizes with those on the CT images. The CT-LG
      effectively localized 5 SLNs with averaged maximum attenuation of 223 HU in the
      human volunteers, without any significant adverse effects. CONCLUSION:
      Interstitial CT-LG using small volumes of iopamidol can sufficiently visualize
      breast lymphatic drainage and may have potential utility for breast SLN mapping.

PMID- 12605180
TI  - Diminished lung injury with vascular adhesion molecule-1 blockade in choline
      deficient ethionine diet-induced pancreatitis.
AB  - BACKGROUND: Lung injury in severe acute pancreatitis is mediated by infiltrating
      leukocytes. Our laboratory has previously demonstrated that acute lung injury in
      acute pancreatitis results in an up-regulation of vascular adhesion molecule-1
      (VCAM-1) cell surface receptor expression on pulmonary vascular endothelium and
      neutrophil sequestration. The objective of this study was to determine whether
      blocking expression of VCAM-1 in acute pancreatitis would modify acute pulmonary
      injury. METHODS: Young female mice were fed a choline-deficient ethionine (CDE)
      supplemented diet to induce acute pancreatitis. After initiation of the diet, one
      group (acute pancreatitis treated [n = 18]) was treated with blocking doses (2.35
      mg/kg) of monoclonal anti-VCAM-1 receptor antibody (Ab) at 48, 96, and 120 hours.
      A second group (acute pancreatitis treated control [n = 5]) was treated with a
      similar dose of an isotypic control for VCAM-1 (nonbinding Ab) at the same time
      points. A third group (acute pancreatitis untreated [n = 12]) received a CDE
      diet, and a fourth group (control [n = 11]) received standard food with no Ab
      treatment. All animals were killed at 144 hours. The dual radiolabeled monoclonal
      Ab method was used to quantitate VCAM-1 cell surface expression in lung tissue.
      Lung injury was assessed histologically, and apoptosis was detected by
      transferase-mediated deoxyuridine triphosphate nick end labeling assay. Pulmonary
      leukocyte sequestration was determined by myeloperoxidase (MPO) assay and CD18
      staining. RESULTS: Pulmonary VCAM-1 cell surface expression was significantly
      increased in animals with acute pancreatitis when compared to controls (P <.001)
      and was reduced to near control levels in acute pancreatitis treated animals. On
      histologic examination, treated animals with acute pancreatitis exhibited
      significantly less lung injury and apoptosis than did untreated animals with
      acute pancreatitis. Leukocyte sequestration and MPO activity were significantly
      reduced in the treated animals with pancreatitis compared to untreated animals
      with pancreatitis (P <.0001) or acute pancreatitis treated controls (P <.03).
      CONCLUSIONS: Blocking VCAM-1 on pulmonary vascular endothelium decreases
      leukocyte adherence and recruitment into the lung, hence reducing lung injury in
      severe acute pancreatitis. Clinically, VCAM-1 antagonism may be an important
      adjunct to evolving therapy for distant organ injury in severe acute
      pancreatitis.

PMID- 12605179
TI  - The impact of surgical technique on postoperative hypoparathyroidism in bilateral
      thyroid surgery: a multivariate analysis of 5846 consecutive patients.
AB  - BACKGROUND: Limited information exists about risk factors for postoperative
      hypoparathyroidism after bilateral thyroid surgery. METHODS: Between January 1
      and December 31, 1998, bilateral thyroid surgery was performed on 5846 patients
      for benign and malignant thyroid disease. Data were prospectively collected by
      questionnaires from 45 hospitals. A logistic regression model was used to
      determine independent risk factors. RESULTS: The overall incidence of transient
      and permanent hypoparathyroidism was 7.3% and 1.5%, respectively. On logistic
      regression analysis, total thyroidectomy (odds ratio [OR], 4.7), female gender
      (OR, 1.9), Graves' disease (OR, 1.9), recurrent goiter (OR, 1.7), and bilateral
      central ligation of the inferior thyroid artery (OR, 1.7) constituted independent
      risk factors for transient hypoparathyroidism. When the multivariate analysis was
      confined to permanent hypoparathyroidism, total thyroidectomy (OR, 11.4),
      bilateral central (OR, 5.0) and peripheral (OR, 2.0) ligation of the inferior
      thyroid artery, identification and preservation of no or only a single
      parathyroid gland (OR, 4.1), and Graves' disease (OR, 2.4) emerged as independent
      risk factors. CONCLUSIONS: Extent of resection and surgical technique had a
      greater impact on the rates of permanent postoperative hypoparathyroidism than
      thyroid pathologic condition. In bilateral thyroid surgery, peripheral ligation
      of the inferior thyroid artery at the thyroid capsule should be favored over
      central ligation, and at least 2 parathyroid glands should be identified and
      preserved. High-risk procedures, such as total thyroidectomy and Graves' disease,
      require special surgical training and expertise.

PMID- 12605182
TI  - Real-time visualization of partial liquid ventilation in a model of acute lung
      injury.
AB  - BACKGROUND: To clarify the effects of partial liquid ventilation, we visualized
      and morphologically analyzed real-time alveolar recruitment in a model of acute
      lung injury. METHODS: Male Wistar rats were divided into 3 groups: a group that
      underwent hydrochloric acid aspiration and mechanical gas ventilation (ALI group,
      n = 15), a group that underwent acid aspiration and partial liquid ventilation
      beginning 90 minutes after acid aspiration (PLV group, n = 15), and a group that
      underwent mechanical ventilation without acid aspiration (control group, n = 5).
      The number of ventilated alveoli and the diameter of the largest ventilated
      alveolus in each of 10 high-power fields observed on fluorescence micrographs
      with a tracer of labeled albumin were determined and averaged from 90 to 210
      minutes after acid aspiration. RESULTS: The number of alveoli in the PLV group
      significantly increased in comparison to that in the ALI group. The diameter of
      the largest alveolus in the PLV group decreased from 103.7 +/- 16.3 microm to
      76.3 +/- 6.5 microm until the end of the experiment. This diameter was equivalent
      to that in the control group. CONCLUSIONS: The excellent alveolar recruitment
      suggests that liquid ventilation ameliorates ventilator-associated lung injury.

PMID- 12605181
TI  - A novel inhibitor of Rho-associated protein kinase, Y-27632, ameliorates hepatic
      ischemia and reperfusion injury in rats.
AB  - BACKGROUND: A Rho-ROCK signal system induces vascular contraction and neutrophil
      migration, both of which are characteristic features found with ischemia and
      reperfusion injury of the liver. We tested our hypothesis that a novel ROCK I
      inhibitor, Y-27632, attenuates hepatic ischemia and reperfusion injury. METHODS:
      Rats underwent 70% partial hepatic ischemia for 120 minutes and subsequent
      reperfusion. Y-27632 of 10mg/kg was given orally 1 hour before ischemia, while
      distilled water was given to the control animals. One week animal survival,
      systemic hemodynamics, hepatic tissue blood flow, liver function tests, plasma
      endothelin-1, serum hyaluronic acid levels, myeloperoxidase activity and
      malondialdehyde level in liver tissue, membrane attack complex-1 and
      intracellular adhesion molecule-1 staining, and histological architecture were
      analyzed. RESULTS: Y-27632 prolonged 1-week animal survival from 25% of untreated
      animals to 75% accompanied with significant amelioration of hepatic tissue blood
      flow, liver function tests and histological architecture without any adverse
      effects on systemic hemodynamics. In addition, plasma endothelin-1 and serum
      hyaluronic acid levels decreased markedly compared to the control, concomitant
      with remarkable suppression of membrane attack complex-1 stain positive
      neutrophils infiltration, myeloperoxidase activity and malondialdehyde level.
      CONCLUSION: Present study suggests that activation of a Rho-ROCK signal system is
      associated with ischemia and reperfusion injury of the liver, and that Y-27632
      may be an attractive agent for application in major liver resection using
      temporary inflow occlusion and hepatic preservation.

PMID- 12605183
TI  - Video-assisted thoracoscopic surgery for intralobar pulmonary sequestration.

PMID- 12605184
TI  - Prognostic value of the combination of epidermal growth factor receptor and c
      erbB-2 in breast cancer.
AB  - BACKGROUND: Epidermal growth factor receptor (EGFR) and c-erbB-2 are 2 of the 4
      members of the erbB receptor family that play a role in signaling by forming
      heterodimers between family members. METHODS: The immunohistochemical expression
      of EGFR and c-erbB-2 was determined on 670 women who underwent operation for
      primary breast cancer. RESULTS: According to the combination of EGFR and c-erbB
      2, 670 patients were classified into 4 groups: EGFR(-)/c-erbB-2(-) (417
      patients); EGFR(+)/c-erbB-2(-) (136 patients); EGFR(-)/c-erbB-2(+) (72 patients);
      and EGFR(+)/c-erbB-2(+) (45 patients). Univariate analyses on disease-free and
      overall survival showed a significant difference among these 4 groups, whereas
      the difference between patients with positive and negative expression of EGFR was
      not statistically significant in patients with positive expression of c-erbB-2. A
      multivariate analysis indicated the combination of EGFR and c-erbB-2 to be an
      independently significant prognostic factor for disease-free and overall
      survival. CONCLUSIONS: Breast cancer with both a positive EGFR and c-erbB-2
      expression had the worst prognosis, whereas the prognostic value of c-erbB-2 was
      stronger than that of EGFR in breast cancer.

PMID- 12605186
TI  - J. V. H.: what a unique teacher.

PMID- 12605185
TI  - Cytomegalovirus infection as a cause of acute superior mesenteric vein thrombosis
      with jejunal infarction.

PMID- 12605187
TI  - Transverse sternal approach for thymectomy.

PMID- 12605188
TI  - Suicidal crossbow bolt cardiac injury.

PMID- 12605189
TI  - Endoscopic management of Bouveret's syndrome.

PMID- 12605191
TI  - Idiopathic segmental infarction of the omentum mimicking acute appendicitis:
      report of 3 cases and literature review.

PMID- 12605192
TI  - Simulation incision using an oil pen as a method of risk management.

PMID- 12605193
TI  - Congenital cytomegalovirus infection.

PMID- 12605195
TI  - Declining payments for emergency department care, 1996-1998.
AB  - STUDY OBJECTIVE: We describe recent trends in payments from different payer
      classes and assess their relative importance to the financial solvency of
      emergency departments. METHODS: We used Medical Expenditure Panel Survey data
      from 1996 and 1998. The unit of analysis was the ED visit. Primary outcome
      measures were ED charges and payments. The independent variable of interest was
      payer class, and therefore, we limited our analysis to those either uninsured or
      covered by Medicare, Medicaid, or private insurance. RESULTS: From 1996 to 1998,
      a declining percentage of total charges were paid, from 60.3% to 53.0%
      (difference -7.3%; 95% confidence interval [CI] -11.3% to -3.5%). Although the
      percentage of total charges paid by Medicaid, Medicare, and the uninsured
      remained constant, the percentage of total charges paid by the privately insured
      declined from 75.1% to 63.4% (difference -11.7%; 95% CI -16.6% to -6.7%).
      Overall, adjusted mean ED charge increased from 695 dollars to 798 dollars
      (difference 103 dollars; 95% CI 61 dollars to 146 dollars). Two payer classes
      experienced statistically significant increases in adjusted mean charge: the
      uninsured, from 544 dollars to 740 dollars (difference 196 dollars; 95% CI 62
      dollars to 330 dollars), and the privately insured, from 658 dollars to 813
      dollars (difference 151 dollars; 95% CI 103 dollars to 199 dollars). Although the
      adjusted mean payment rate for the uninsured remained stable, the adjusted mean
      payment rate for the privately insured declined from 77.7% to 65.7% (difference 
      12.0%; 95% CI -13.4% to -10.7%). CONCLUSION: The ability of EDs to provide
      emergency care to all regardless of ability to pay is increasingly threatened by
      declining overall payment rates. Cost shifting to fund care for the uninsured is
      an increasingly untenable financing strategy.

PMID- 12605196
TI  - Frequent attenders to an emergency department: a study of primary health care
      use, medical profile, and psychosocial characteristics.
AB  - STUDY OBJECTIVE: We describe, in comparison with a control group, frequent
      attenders to an emergency department in terms of their general health service use
      and their clinical, psychological, and social profiles. METHODS: One hundred
      frequent attenders (those who had made > or =4 visits in the previous year) and
      100 nonfrequent attenders matched for sex, age, and triage category were
      interviewed in the ED. Data were gathered on health service use, mental health
      (by using the General Health Questionnaire-12 item), and perceived social support
      (by using the Multidimensional Scale of Perceived Social Support). Patients'
      general practitioners were contacted to validate attendance data. Medical charts
      were searched for evidence of psychological problems and alcohol or drug abuse.
      RESULTS: In the overall sample of 200 patients, 32% were female, and the mean age
      was 55 years (SD 20). Frequent attenders had made more visits to their general
      practitioner in the past year compared with control patients (median 12 versus 3
      visits); a higher proportion of frequent attenders had used public health nursing
      services, community welfare services, social work services, addiction counseling,
      and psychiatric services in the past year. Frequent attenders had made more other
      hospital visits and had spent more nights in the hospital than control patients.
      General Health Questionnaire-12 item scores were higher for frequent attenders
      than control patients, indicating poorer mental health. Frequent attenders had
      lower levels of perceived social support. CONCLUSION: Frequent attenders to the
      ED are also heavy users of general practice services, other primary care
      services, and other hospital services. General Medical Services-eligible patients
      (84% of frequent attenders) frequently attend the ED, even though they have free
      access to primary care. Frequent attenders are a psychosocially vulnerable group,
      and service providers and policy makers need to take account of this vulnerable
      patient profile as they endeavor to meet their service needs.

PMID- 12605197
TI  - How many emergency department visits are there?

PMID- 12605198
TI  - Head-elevated laryngoscopy position: improving laryngeal exposure during
      laryngoscopy by increasing head elevation.
AB  - STUDY OBJECTIVE: The objective of this study was to determine the effect of
      increasing head elevation and neck flexion on the quality of laryngeal view
      during laryngoscopy. METHODS: Laryngoscopy with a straight blade was performed on
      7 fresh human cadavers. Laryngeal views were recorded with the direct
      laryngoscopy video system, and the laryngoscopy angle was measured throughout the
      procedure with an angle finder attached to the handle of the laryngoscope. Each
      cadaver had laryngoscopy initiated with the head lying flat on the table and with
      atlanto-occipital extension. The head was then progressively elevated as much as
      possible (the head-elevated laryngoscopy position), increasing neck flexion and
      the laryngoscopy angle. Three physicians blinded to the laryngoscopy angle graded
      the quality of laryngeal view using the percentage of glottic opening (POGO)
      score. RESULTS: The laryngoscopy angle ranged from a mean of 32 degrees +/-8
      degrees (1 SD) with the head flat on the table to a mean of 67 degrees +/-8
      degrees with the head-elevated laryngoscopy position. The mean midposition
      laryngoscopy angle was 49 degrees +/-6 degrees. Comparing the 3 positions, mean
      POGO scores+/-1 SD significantly increased from 31%+/-10% (flat position) to
      64%+/-12% (midposition) to 87%+/-13% (head-elevated laryngoscopy position). Both
      the midposition and the head-elevated laryngoscopy position compared with the
      flat position were statistically significant at a P value of less than.0001. The
      midposition also differed significantly from the head-elevated laryngoscopy
      position (P <.0007). Additionally, there was a significant linear relationship
      among the 3 positions (P <.0001). CONCLUSION: Increasing head elevation and
      laryngoscopy angle (neck flexion) significantly improves POGO scores during
      laryngoscopy on fresh human cadavers.

PMID- 12605199
TI  - Cricoid ring integrity: implications for cricothyrotomy.
AB  - STUDY OBJECTIVES: The rapid 4-step technique for cricothyrotomy was originally
      described as making use of a single traction hook on the cricoid ring. However,
      it is possible that such hook placement could lead to damage of the cricoid ring.
      As an alternative, a double-hook device was developed to augment the rapid 4-step
      technique by dispersing forces applied to the cricoid ring. The objectives of
      this study were to compare the requisite forces for intubation and the structural
      tolerances of the cricoid ring between the single- and double-hook techniques.
      METHODS: We randomized 56 human cadaver specimens to undergo either
      cricothyrotomy with intubation followed by cricoid ring breakage or cricoid ring
      breakage alone. We randomized those cadaver specimens undergoing cricothyrotomy
      with intubation with respect to the initial hook technique used and then crossed
      over to the alternate technique for repeat intubation and subsequent cricoid ring
      breakage. We performed all cricothyrotomies in a similar manner with a consistent
      technique. We measured the intubation and breakage forces for the single- and
      double-hook techniques and calculated 95% confidence intervals (CIs). RESULTS:
      The mean force to intubate with the single-hook technique was 18 N (95% CI 14 to
      22 N), and the mean force to intubate with the double-hook technique was 23 N
      (95% CI 17 to 29 N). There was a significant difference between the mean forces
      required to break the cricoid ring with the single-hook technique (54 N; 95% CI
      47 to 62 N) versus with the double-hook technique (101 N; 95% CI 89 to 113 N;
      difference in means 47 [95% CI 34 to 60 N]). CONCLUSION: When applying the rapid
      4-step technique for cricothyrotomy, the force required to intubate with either
      the single- or double-hook technique is small. The cricoid ring, however,
      tolerates significantly more force without breakage when the double-hook
      technique is used.

PMID- 12605200
TI  - Bringing the larynx into view: a piece of the puzzle.

PMID- 12605201
TI  - Continuous 12-lead electrocardiographic monitoring in an emergency department
      chest pain unit: an assessment of potential clinical effect.
AB  - STUDY OBJECTIVES: Continuous 12-lead serial ECG monitoring has been proposed to
      assist in the evaluation of patients with acute coronary syndrome and
      nondiagnostic ECG in an emergency department chest pain unit. However, the
      ability of serial ECG to detect acute coronary syndrome and its benefit in
      addition to a standard protocol has not been established. We evaluate the ability
      of continuous 12-lead ECG to detect acute coronary syndrome, assess the
      incremental benefit of the serial ECG in association with a set protocol in an ED
      chest pain unit, and evaluate whether serial ECG changes could be considered as
      prognostic factors. METHODS: Patients who met Agency for Health Care Policy and
      Research guidelines for intermediate risk for short-term cardiovascular event
      unstable angina were prospectively studied in the chest pain unit. Patients were
      monitored with the Mortara Instruments ELI 100 STM continuous 12-lead ECG system
      with ST-segment analysis. ST-segment changes of greater than 100 microV in 2 or
      more contiguous leads or greater than 200 microV in 1 lead were considered
      positive. Data were compared with serial serum cardiac markers, cardiac function
      study results, angiographic results, and 30-day outcome results. RESULTS: One
      hundred nineteen patients had serial ECG applied. The median duration of
      monitoring was 4.2 hours. Forty patients were given a diagnosis of acute coronary
      syndrome. Chest pain unit protocol detected 52 patients, and 23 were given a
      diagnosis of acute coronary syndrome (sensitivity 58%; specificity 63%). Sixteen
      patients had ST-segment changes of greater than 100 microV or greater than 200
      microV, and 9 were given a diagnosis of acute coronary syndrome. The addition of
      the serial ECG to the chest pain unit protocol increased the sensitivity to 65%
      and decreased the specificity to 58%. Two patients with ST-segment changes but
      none without ST-segment changes had an adverse cardiac event, yielding a
      sensitivity of 100% and a specificity of 88%. CONCLUSION: Serial ECG is of
      limited value in the diagnostic evaluation of intermediate-risk patients managed
      in the chest pain unit with a standard protocol. However, when ST-segment changes
      are present, they indicate an increased likelihood for an adverse cardiac event.

PMID- 12605202
TI  - Evaluation of the patient with chest pain: are the bells and whistles evidence
      based?

PMID- 12605203
TI  - 2002 update to the ACC/AHA guidelines for the management of patients with
      unstable angina and non-ST-segment elevation myocardial infarction: implications
      for emergency department practice.
AB  - The publication of comprehensive evidence-based guidelines for the management of
      non-ST-segment elevation acute coronary syndrome by the American College of
      Cardiology and the American Heart Association in September 2000 marked a sentinel
      event in the evolution of managing this challenging patient population. Many of
      the recommendations included in the guidelines have relevance to the emergency
      department care of patients with non-ST-segment elevation acute coronary syndrome
      and were summarized in Annals of Emergency Medicine in September 2001. New
      clinical data in this area continue to accumulate at a remarkably rapid rate,
      prompting the American College of Cardiology and the American Heart Association
      to publish an update of the 2000 guidelines in October 2002. Several of the
      modified and new recommendations again potentially affect ED management. These
      are presented and discussed here.

PMID- 12605204
TI  - The frequency of complications associated with the use of multiple-dose activated
      charcoal.
AB  - STUDY OBJECTIVE: The objective of this study was to determine the frequency of
      complications associated with the use of multiple-dose activated charcoal.
      METHODS: The study population was drawn from 8 tertiary care hospitals in 4 North
      American cities. Medical records of all inpatients between March 1993 and March
      1998 with a discharge diagnosis of poisoning (International Classification of
      Diseases, 9th edition, Clinical Modification codes 960-989.9) were reviewed to
      select patients who had received multiple-dose activated charcoal (defined as >
      or =2 doses administered within 12 hours). Medical records of patients who
      received multiple-dose activated charcoal were reviewed for patient demographics
      and clinical information regarding the occurrence of pulmonary aspiration,
      gastrointestinal obstruction, hypernatremia, hypermagnesemia, corneal abrasion,
      and other complications associated with the use of multiple-dose activated
      charcoal. RESULTS: We reviewed 6,258 medical records, identifying 878 patients
      who received multiple-dose activated charcoal. We judged 5 (0.6%; 95% confidence
      interval [CI] 0.1% to 1.1%) patients to have had clinically significant pulmonary
      aspiration and none (0%; upper 95% CI 0.3%) to have had gastrointestinal
      obstruction. None of the patients with pulmonary aspiration died or had residual
      sequelae recorded. Hypernatremia (peak serum sodium >145 mEq/L [145 mmol/L]) was
      documented in 53 (6.0%; 95% CI 4.4% to 7.6%) patients, of whom 5 (0.6%; 95% CI
      0.1% to 1.1%) had a serum sodium concentration of greater than 155 mEq/L (155
      mmol/L). Hypermagnesemia (peak serum magnesium >2.5 mg/dL [1.0 mmol/L]) was
      documented in 27 (3.1%; 95% CI 2.0% to 4.2%) patients, of whom 3 (0.3%; 95% CI
      0.1% to 1.0%) had peak values that were greater than 3.75 mg/dL (1.5 mmol/L). One
      patient had a corneal abrasion (0.1%; 95% CI 0% to 0.6%). No other complications
      were identified. CONCLUSION: Clinically significant complications associated with
      the use of multiple-dose activated charcoal occur infrequently.

PMID- 12605205
TI  - British anti-Lewisite (dimercaprol): an amazing history.
AB  - Emergency physicians are familiar with British anti-Lewisite (BAL) because it is
      a heavy metal-chelating agent that is recommended in some cases of metal
      poisoning, especially arsenic. Although there are more modern chelating agents,
      the fact that BAL is still recommended and stocked by hospital pharmacies more
      than 60 years after its initial synthesis is itself remarkable. During World War
      II, BAL minimized the risk to the Allied infantry of injury or death from
      Lewisite, a very potent arsenic-based chemical warfare agent. Once developed, BAL
      revolutionized the treatment of heavy metal poisonings, both accidental and
      iatrogenic (eg, toxicity from treatment of arthritis with gold salts). In 1951,
      BAL was used to treat Wilson's disease with striking success. Today, BAL might
      again become prominent should terrorists or governments use Lewisite against
      civilians or military forces.

PMID- 12605206
TI  - Crotalidae polyvalent immune Fab antivenom limits the decrease in perfusion
      pressure of the anterior leg compartment in a porcine crotaline envenomation
      model.
AB  - STUDY OBJECTIVE: Crotalidae Polyvalent Immune Fab (CroFab; FabAV) antivenom
      prevents a decrease in perfusion pressures in intramuscular crotaline
      envenomation compared with normal saline solution. METHODS: We used a randomized,
      blinded, controlled acute animal preparation. Twenty anesthetized and
      instrumented swine were injected intramuscularly with 6 mg/kg Crotalus atrox
      venom into the anterior tibialis muscle of each hind limb (time 0). One hour
      after envenomation (time 1 hour), animals were randomized to receive 8 vials of
      reconstituted FabAV or an equal volume of normal saline solution (control)
      through a central venous line. The main outcome variable was the area under the
      perfusion-time curve (AUC) of the anterior compartment of the hind limb measured
      from time 1 hour to time 8 hours. Perfusion pressure was defined as mean arterial
      pressure-compartment pressure. Additionally, physiologic variables, including
      pulse rate, prothrombin time, fibrinogen level, platelet count, hemoglobin level,
      and hematocrit level, were monitored. RESULTS: Venom injection resulted in a
      decrease in average perfusion pressures from 54.1 mm Hg (time 0) to 31.7 mm Hg
      (time 1 hour). Comparison of AUC between groups from time 1 hour (time of
      treatment) to the completion of the study at time 8 hours revealed a 57% greater
      AUC in animals that received FabAV (mean+/-SD: 211.1+/-67.9 versus 134.5+/-55.8
      mm Hg/h; P =.036; 95% confidence interval for difference 5.9 to 147.3).
      Comparison of the time curves for the mean prothrombin time from time 1 hour to
      the completion of the study by means of repeated-measures analysis of variance
      revealed a significant increase in the control group (P =.02). No significant
      difference was detected in the time curves for the means of mean arterial
      pressure, compartment pressure, pulse rate, hemoglobin level, hematocrit level,
      fibrinogen level, or platelet count over the course of the study. FabAV was found
      to significantly increase survival time when compared with the effect of the
      normal saline solution control from time 1 hour to time 8 hours, as determined by
      means of Kaplan-Meier estimation and the log-rank test (P =.029). CONCLUSION:
      FabAV limits the decrease in perfusion pressures in the anterior leg compartment
      after intramuscular crotaline venom injection in swine compared with saline
      solution. In addition, FabAV might prevent the development of coagulopathy and
      increase survival time in this model.

PMID- 12605207
TI  - Efficacy of Crotalidae polyvalent antivenin for the treatment of hognosed viper
      (Porthidium nasutum) envenomation.
AB  - Envenomation from pit vipers native to North America can be treated successfully
      with either of the 2 commercially available antivenoms licensed in the United
      States. However, envenomations from imported snakes held in zoos or private
      collections often pose unique challenges to management because of the lack of
      specific antivenom and the unclear efficacy of the available licensed products.
      We report the case of a 37-year-old man who was envenomated on his left hand by
      his pet hognosed viper (Porthidium nasutum ). He had swelling at the wound site
      that progressively worsened over 3 to 4 hours. His symptom progression included
      the structural motor impairment of his fingers and a sensory deficit. Treatment
      with 8 vials of Antivenin (Crotalidae) polyvalent was associated with a halt of
      extremity swelling and restoration of neurologic and motor function of his hand.
      Limited experimental evidence provides support for antigenic cross-reactivity
      between Antivenin (Crotalidae) polyvalent and P nasutum venom.

PMID- 12605208
TI  - Cardioactive steroid poisoning from an herbal cleansing preparation.
AB  - We describe a case of unintentional poisoning from a cardioactive steroid and the
      subsequent analytic investigation. A 36-year-old woman with no past medical
      history and taking no conventional medications ingested an herbal preparation
      marketed for "internal cleansing." Its ingredients were neither known to the
      patient nor listed on the accompanying literature. The next morning, nausea,
      vomiting, and weakness developed. In the emergency department, her blood pressure
      was 110/60 mm Hg, and her pulse rate was 30 beats/min. Her ECG revealed a
      junctional rhythm at a rate of 30 beats/min and a digitalis effect on the ST
      segments. After empiric therapy with 10 vials of digoxin-specific Fab (Digibind),
      her symptoms resolved, and she reverted to a sinus rhythm at a rate of 68
      beats/min. Her serum digoxin concentration measured by means of the fluorescence
      polarization immunoassay (Abbott TDx) was 1.7 ng/mL. Further serum analysis with
      the Tina Quant digoxin assay, a more digoxin-specific immunoassay, found a
      concentration of 0.34 ng/mL, and an enzyme immunoassay for digitoxin revealed a
      concentration of 20 ng/mL (therapeutic range 10 to 30 ng/mL). Serum analysis by
      means of high-performance liquid chromatography revealed the presence of active
      digitoxin metabolites; the parent compound was not present. When the diagnosis of
      cardioactive steroid poisoning is suspected clinically, laboratory analysis can
      confirm the presence of cardioactive steroids by using immunoassays of varying
      specificity. An empiric dose of 10 vials of digoxin-specific Fab might be
      beneficial in patients poisoned with an unknown cardioactive steroid.

PMID- 12605209
TI  - The effects of consecutive night shifts on neuropsychological performance of
      interns in the emergency department: a pilot study.
AB  - STUDY OBJECTIVE: We obtain preliminary information on the neuropsychological
      performance of house officers at the beginning and end of a shift while they
      worked consecutive night shifts in the emergency department. METHODS: We
      prospectively studied interns working 12-hour consecutive night shifts in an
      urban Level I trauma center ED. All consecutive non-emergency medicine interns
      rotating for 1 month were eligible except those older than 40 years and those
      with sleep disorders or depression (identified by using the Profile of Mood
      Scale, Sleep Diagnostic Questionnaire). We tested research subjects at the
      beginning of a day shift and at the beginning and end of night shifts 1 and 3 of
      4 consecutive night shifts at times of estimated baseline wakefulness (10 PM) and
      maximum fatigue (3 AM). We used 3 standardized neuropsychological tests: (1)
      Delayed Recognition Span Test (visual memory capacity); (2) Continuous
      Performance Test (attentional function, vigilance); and (3) Santa Ana Form Board
      Test (psychomotor speed, coordination). We analyzed data with mixed-model
      analysis, with research subject as a random effect. RESULTS: Thirteen interns
      were eligible, and 1 declined. Twelve interns (6 men and 6 women; age range 25 to
      35 years) were enrolled. The Delayed Recognition Span Test (number correct before
      first error) revealed significant deterioration from the beginning of the shift
      to the end of the shift (mean difference -2.2; 95% confidence interval -3.1 to 
      1.3). This represents an 18.5% decrease in visual memory capacity. There were no
      significant differences found for the other tests. CONCLUSION: Interns working
      nights demonstrated a significant reduction in visual memory capacity across the
      night shift. Research involving neuropsychological performance during night
      shifts in the ED is important. It might provide valuable insights into ways to
      improve our performance during night shifts.

PMID- 12605210
TI  - Evidence-based emergency medicine/systematic review abstract. Use of antibiotics
      in patients with acute bacterial conjunctivitis.

PMID- 12605211
TI  - Evidence-based emergency medicine/systematic review abstract. Are corticosteroids
      effective in traumatic spinal cord injury?

PMID- 12605212
TI  - Update on emerging infections: news from the Centers for Disease Control and
      Prevention. Syndromic surveillance for bioterrorism following the attacks on the
      World Trade Center--New York City, 2001.

PMID- 12605213
TI  - My brother and I.

PMID- 12605214
TI  - The news and you.

PMID- 12605215
TI  - Structural lessons in DNA replication from the third domain of life.

PMID- 12605217
TI  - Co-translocational misfolding in the ER of living cells.

PMID- 12605216
TI  - The decline of induced transcription: a case of enzymatic symbiosis.

PMID- 12605218
TI  - An ACE structure.

PMID- 12605219
TI  - Taking myc to the max.

PMID- 12605220
TI  - Ready to partner.

PMID- 12605222
TI  - Dealing with potential dangers.

PMID- 12605223
TI  - Observing the invisible: successful tumor immunity in humans.

PMID- 12605224
TI  - My T's gone cold, I'm wondering why.

PMID- 12605225
TI  - The suicide in the thymus, a twisted trail.

PMID- 12605226
TI  - Il2 transcription unleashed by active DNA demethylation.

PMID- 12605227
TI  - Tuning the immune system: competing positive and negative feedback loops.

PMID- 12605228
TI  - Memory lanes.

PMID- 12605229
TI  - Angiogenin: an antimicrobial ribonuclease.

PMID- 12605231
TI  - The nature of molecular recognition by T cells.
AB  - Considerable progress has been made in characterizing four key sets of
      interactions controlling antigen responsiveness in T cells, involving the
      following: the T cell antigen receptor, its coreceptors CD4 and CD8, the
      costimulatory receptors CD28 and CTLA-4, and the accessory molecule CD2.
      Complementary work has defined the general biophysical properties of interactions
      between cell surface molecules. Among the major conclusions are that these
      interactions are structurally heterogeneous, often reflecting clear-cut
      functional constraints, and that, although they all interact relatively weakly,
      hierarchical differences in the stabilities of the signaling complexes formed by
      these molecules may influence the sequence of steps leading to T cell activation.
      Here we review these developments and highlight the major challenges remaining as
      the field moves toward formulating quantitative models of T cell recognition.

PMID- 12605234
TI  - A journey through two lumens!
AB  - This account describes studies from the Institute of Medical Physiology in the
      University of Copenhagen, starting in the mid 1970's, which included some of the
      earliest European laboratory investigations on human female genital function. The
      measurements involved vaginal pH, pO2, blood flow, motility, fluid and its ionic
      concentrations, amino-acid concentrations and electrical activity (transvaginal
      potential difference) usually in both the basal and sexual aroused states. The
      blood flow monitoring pioneered the use of the heated oxygen electrode. Other
      studies examined the effects of arousal to orgasm on cervical secretion, on the
      heart rate as an objective indicator of orgasmic excitement and investigated the
      actions of TRH and the cholinergic antagonist atropine on a number of vaginal
      parameters. The work was part of the scientific watershed that divided the
      previous descriptive era of human genital mechanisms from the now prevalent
      quantitative assessments.

PMID- 12605235
TI  - The efficacy and safety of a topical alprostadil cream, Alprox-TD, for the
      treatment of erectile dysfunction: two phase 2 studies in mild-to-moderate and
      severe ED.
AB  - In two multicenter, placebo controlled, phase 2 studies, patients with mild-to
      moderate (n=161, Study 1) or severe (n=142, Study 2) erectile dysfunction (ED)
      were randomized to receive placebo, 0.05, 0.1, or 0.2 mg (Study 1) or placebo,
      0.1, 0.2, or 0.3 mg (Study 2) of topically applied alprostadil (containing a
      proprietary skin permeation enhancer). The primary efficacy end point in both
      studies was the change in erectile function (EF) score from baseline to final
      visit. The changes from baseline for EF scores were -0.8+/-1.1, 1.8+/-1.1, 0.7+/
      1.2, and 3.7+/-1.2 (P<0.01; Study 1) and 2.7+/-1.3, 6.29+/-1.4, 6.49+/-1.5, and
      9.44+/-1.5 (P<0.001; Study 2) for ascending dose groups in each study. Topical
      alprostadil was well tolerated with the most common adverse event being
      urogenital pain. These results suggest this topical alprostadil formulation may
      be a potentially useful agent for the treatment of ED.

PMID- 12605236
TI  - Antimicrobial activity of antibiotic-soaked, Resist-coated Bioflex.
AB  - This study investigates whether a hydrophilic coating (Resist), designed to
      inhibit bacterial adherence, applied to inflatable penile prostheses can prolong
      the effect of intraoperative antibiotics. The activity of antibiotic-soaked
      Bioflex (penile prosthetic substrate material) discs with and without Resist was
      examined by measuring the zone of inhibition following in vivo exposure in four
      groups of rabbits: 1, 2, 3 and 5 days' duration of disc implantation. Coated and
      uncoated discs were soaked in an aqueous solution of gentamicin and bacitracin.
      The implanted antibiotic-soaked discs were extracted, and the zone of inhibition
      against four microorganisms in vitro demonstrated that the Resist coating was
      especially effective against Staphylococcus epidermidis, and statistically
      significant improvements were observed for the coated over the uncoated substrate
      up to 3 days following implantation. This effect, and the anti-adherence
      properties of Resist, may prevent adhesion and colonization of some
      microorganisms to penile implants and reduce chances for infection.

PMID- 12605237
TI  - Inflatable penile prosthesis: site-specific malfunction analysis.
AB  - The purpose of this study was to analyze retrospectively the exact site(s) of
      device failure of a large series of Mentor Alpha I inflatable penile prostheses.
      The study consisted of 442 patients implanted over a 12-year period. Only those
      patients who developed a device malfunction and returned for re-evaluation by the
      author were included. The exact site(s) of device malfunction were obtained from
      a review of operative reports. The average length of follow-up in this series was
      63 months, ranging from 1 to 138 months. In all, 22 (4.98%) patients developed
      device malfunction and returned for evaluation, including six (3.9%) of the 154
      infrapubic devices and 16 (5.6%) of the 288 scrotal devices. Of these 22
      patients, three declined revision and 19 were reoperated on by the author. The
      exact site of malfunction differed in the infrapubic vs scrotal implants. Most
      malfunctions of the scrotal device involved tubing fractures at the pump strain
      reliefs, whereas infrapubic device malfunctions typically involved the cylinders
      or the reservoir. A review of these malfunction patterns may assist the
      manufacturer in further improving the reliability of this prosthesis, and may
      assist implanting surgeons in planning operative procedures.

PMID- 12605238
TI  - Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno
      associated virus-mediated VEGF gene therapy prevent and reverse venogenic
      erectile dysfunction in rats.
AB  - Penile veno-occlusive dysfunction (venogenic erectile dysfunction) is a common
      cause of erectile dysfunction (ED). We investigated whether vascular endothelial
      growth factor (VEGF) can be used to prevent and reverse venogenic ED in a rat
      model. Pharmacological cavernosometry was developed and validated using adult
      male rats with either arteriogenic or venogenic ED. Castrated animals were
      treated with intracavernous VEGF as either a recombinant protein (C+VEGF) or
      adeno-associated virus (AAV)-mediated VEGF gene therapy (C+VEGF gene) in an
      attempt to prevent the development of venogenic ED. Other animal groups received
      testosterone replacement (C+testosterone) or intracavernous AAV-LacZ gene
      (C+LacZ). Animals with documented venogenic ED were treated with intracavernous
      VEGF in an attempt to reverse their ED. Functional analysis (pharmacological
      infusion cavernosometry) was performed following treatment. Penile specimens were
      harvested for immunohistochemistry and electron microscopic evaluation. Castrated
      rats showed a decrease in papaverine-induced intracavernous pressure and an
      increase in maintenance and drop rates during pharmacological cavernosometry.
      These changes were prevented by systemic testosterone and intracavernous VEGF or
      AAV-VEGF therapy. Moreover, intracavernous VEGF was able to reverse the venogenic
      ED produced by castration. The quantity of penile smooth muscle detected by alpha
      actin staining decreased after castration but not in the C+T, C+VEGF, or C+VEGF
      gene groups. Transmission electron microscopy revealed atrophy of penile smooth
      muscle cells and nerves in the castrated rats. In VEGF-treated rats, regeneration
      of smooth muscle and nerves as well as endothelial cell hypertrophy and
      hyperplasia were the prominent features. In our animal model, systemic
      testosterone replacement or intracavernous VEGF (protein and VEGF gene) prevented
      the veno-occlusive dysfunction in castrated animals. In rats with established
      venous leakage, VEGF treatment reversed the cavernosometric findings of leakage.
      Intracavernous injection of either VEGF protein or VEGF gene may be a preferred
      therapy to preserve erectile function in patients in whom testosterone therapy is
      contraindicated.

PMID- 12605239
TI  - Oestrogen-mediated hormonal imbalance precipitates erectile dysfunction.
AB  - Declining testosterone (T) in an aging male offsets the equilibrium between
      androgen and oestrogen (oestradiol, E(2)) with a resultant increase in E(2)-T
      ratio. Similar functional hormone imbalance is existent in clinical states of
      hypogonadism and is likely to arise from exposure of males to environmental
      oestrogens. The pathophysiological significance of this derangement on erectile
      function, hitherto unknown, was estimated in sexually mature male rats following
      acute and chronic treatment with oestrogen. A total of 60 male Sprague-Dawley
      rats (200-250 g) were divided into control and two treatment groups, administered
      0.01 and 0.1 mg of oestradiol through oral gavage daily for 1 week (n=30, acute
      study) and 12 weeks (n=30, long-term study), respectively. Sexual activity in the
      presence of hormonally primed female rats and intracavernous pressure (ICP)
      response to electrical stimulation estimated treatment-induced changes, which
      were correlated with hormone levels and penile morphology at 12 weeks. Following
      two to five-fold elevation in serum E(2) levels (and simultaneous reduction in
      testosterone), there was a significant prolongation of mount, intromission,
      ejaculation latencies and some decrease in frequencies. The ICP response to nerve
      stimulation was also impaired in all the treated groups. Histologically,
      trichrome staining highlighted the cavernosal connective tissue hyperplasia in
      the long-term study groups. Results of this investigation indicate that
      oestradiol causes pathophysiological changes in erectile function. These
      observations provide an indirect evidence for the possible sexual health hazards
      in man upon inadvertent exposure to environmental oestrogens, ageing and
      derangement of E(2)-T ratio.

PMID- 12605240
TI  - Prognostic factors for the vascular components of erectile dysfunction in
      patients on renal replacement therapy.
AB  - A total of 76 male patients on renal replacement therapy (RRT) were investigated.
      Erectile dysfunction (ED) was defined as insufficient erection during visual
      erotic stimulation (VES) or during sleep as measured with Rigiscan and
      Erectiometer. Data on medical history, physical examination, and laboratory
      variables were collected. Furthermore, penile pharmacological duplex
      ultrasonography (PPDU) was performed. Univariate and multivariate logistic
      regressions were used to determine prognostic values and to develop prognostic
      models. Independent prognostic factors for ED were the number of cardiovascular
      events, waist-hip ratio, body mass index, and acceleration time (AT) as measured
      with PPDU. Independent prognostic factors for an abnormal AT (>100 ms) were
      number of cardiovascular events, age category, and the presence of carotid
      bruits. Independent prognostic factors for insufficient veno-occlusion during
      PPDU were number of cardiovascular events and supine diastolic blood pressure.
      The vascular contribution to ED in patients on RRT is substantial. Data from
      medical history, limited physical examination, and PPDU contribute to the
      prediction of the vascular contribution to ED.

PMID- 12605241
TI  - Increased contractility of diabetic rabbit corpora smooth muscle in response to
      endothelin is mediated via Rho-kinase beta.
AB  - Corpus cavernosum smooth muscle (CCSM) from rabbits made diabetic for 6 months as
      a result of alloxan injection exhibited increased sensitivity (3vs 9 nM EC(50))
      and generated 20-50% greater force to endothelin-1 (ET-1) compared to CCSM from
      normal rabbits. In contrast, the force produced by the CCSM in response to KCl
      and phenylephrine was not significantly altered in diabetic CCSM. The increased
      ET-1 sensitivity is associated with a two to three-fold upregulation of ET
      receptor A at both mRNA and protein levels in diabetic CCSM. ET-1-induced CCSM
      contraction is largely dependent upon Rho-kinase (ROK), since it is almost
      completely blocked by Y-27632 (a highly selective ROK inhibitor). Furthermore,
      expression of ROKbeta isoform is selectively upregulated in CCSM from diabetic
      rabbits. Thus, an increased CCSM tone, modulated by sensitization of the
      endothelin-mediated contractile pathway via ROK, may be a key component of the
      molecular mechanism of diabetes-induced erectile dysfunction.

PMID- 12605242
TI  - Epidemiology of erectile dysfunction.
AB  - This review of the current epidemiological literature on erectile dysfunction
      (ED) suggests that approximately 5-20% of men have moderate-to-severe ED.
      Different definitions of ED, age distributions and concomitant medical
      conditions, as well as methodological differences, may explain much of the
      variance in reported prevalence rates. Various chronic disorders are associated
      with elevated rates of ED including depression, diabetes, and cardiovascular and
      neurological diseases. Such disorders are more common in the elderly, which may
      partially explain the elevated prevalence of ED in men over 60 y of age.
      Currently, up to 70% of men with ED are not treated. However, so many men
      experience considerable distress from their condition, that the increasing
      awareness of ED as well as the availability of noninvasive treatments may result
      in a greater proportion of patients seeking treatment, and eventually regaining
      satisfaction with their sex life.

PMID- 12605243
TI  - The false organic-psychogenic distinction and related problems in the
      classification of erectile dysfunction.
AB  - The traditional distinction between organic and psychogenic erectile dysfunction
      (ED) was maintained in the recent report of the Nomenclature Committee of the
      International Society for Sexual and Impotence Research. Among the major problems
      with this distinction are that it is based on an obsolete view of mind-body
      distinctions, does not take into account knowledge of the neurobiology of
      'psychological' disorders, disregards the fundamental meaning of 'psychosomatic,'
      is too often diagnosed by exclusion, and may imply to the patient that his ED is
      'all in the mind.' As a result, the distinction has become counterproductive in
      the diagnosis, classification, and treatment of ED, and in research into the
      causes of ED. An alternative taxonomy, based on that proposed by the Nomenclature
      Committee, reclassifies as organic several of the causes of ED now considered to
      be psychogenic, and considers others as situational ED, a class reserved for
      episodic occurrences of ED clearly due to particular attributes of sexual
      encounters.

PMID- 12605244
TI  - Tumour markers and cirrhosis: the CA-125 who came in from the cold.

PMID- 12605245
TI  - Impact of protocol-based guidelines on the management and outcome of acute upper
      gastrointestinal hemorrhage in a district general hospital.
AB  - A prospective audit of acute upper gastrointestinal (GI) hemorrhage was conducted
      between January and September 2000 at Frimley Park Hospital to determine the
      impact of introducing an upper GI bleeding protocol based on Rockall's initial
      risk scoring system. Fifty-seven patients and 52 patients were in the pre- and
      postprotocol phases of the study respectively. Fifty per cent (28) of the
      patients in the first phase and 40% (21) of the patients in the second phase
      belonged to the high risk group. In the preprotocol phase, endoscopy was
      performed in 86% (49) of cases with 60% of patients having an
      esophogastroduodenoscopy within 24 h. Thirty-three per cent of the high risk
      group failed to have an endoscopic examination within 24 h. Only two of 57
      patients required surgery and the mortality was 14%. In the postprotocol phase,
      endoscopy was performed in 79% (42) of patients and 68% (36) patients had
      endoscopy within 24 h. Only four of 21 patients belonging to the high risk group
      had their endoscopy after 24 h of the admission. Patients were better monitored
      and mortality was reduced to 7.5%. Reduction of mortality from upper GI
      hemorrhage followed the introduction of an agreed protocol based on risk scoring.

PMID- 12605246
TI  - Comparision of endoscopy-based and serum-based methods for the diagnosis of
      Helicobacter pylori.
AB  - Available commercial tests for the diagnosis of Helicobacter pylori infection are
      based on different types of antigen preparations and hence the diagnostic utility
      differs substantially. OBJECTIVE: To assess the diagnostic value of the
      determination of Immunoglobulin (Ig) A and IgG antibodies to H pylori whole cell
      (WC) and IgG antibodies to cytotoxin associated gene A (CagA) using an in-house
      ELISA in relation to the results obtained with different invasive methods.
      METHODS: The study population consisted of 251 Mexican adults, mean age 53 years,
      age range 15 to 92 years and female to male ratio of 1.5. Peptic ulcer disease
      was present in 10.8% of these patients, 5.2% had gastric cancer, 11.2% had
      esophagitis and 72.9% had nonulcer dyspepsia. Biopsy specimens from the body and
      the antrum of the stomach were obtained for culture, histology and rapid urease
      test. ELISAs to detect IgA and IgG WC and CagA antibodies were performed using
      serum. RESULTS: H pylori status was established by the results of the invasive
      tests. Eighty (31.9%) patients positive to the three tests and 38 (15.1%)
      negative to all the tests were identified. Based on this result, the sensitivity
      and specificity of the serology assays were 97.5% and 78.9% for the IgG WC and
      70% and 73.7% for the IgA WC, respectively. However, if H pylori status was
      defined by the positive result of at least one or two invasive diagnostic tests,
      the sensitivity for the IgG WC decreased to 87.3% and 66.7% respectively, but the
      specificity was essentially the same. Similar results were obtained for the
      sensitivity and specificity of IgA using the same criteria. A low CagA prevalence
      was observed (39%). CONCLUSIONS: Testing for serological IgG antibodies to H
      pylori WC was the best to assess whether infection by H pylori was present.
      Neither the IgA WC nor the IgG CagA ELISAs add significant value in the diagnosis
      of H pylori.

PMID- 12605247
TI  - The establishment of a national tissue bank for inflammatory bowel disease
      research in Canada.
AB  - The Crohn's and Colitis Foundation of Canada (CCFC) has established a national
      bank for tissue, serum and blood from patients with inflammatory bowel disease
      (IBD). Investigators from across the country submit material to the bank together
      with clinical data. Investigators may access their own patient information from
      the bank for their own study purposes, but the distribution of tissue is
      restricted to specific CCFC-funded projects. Currently, tissues are being
      collected from newly diagnosed, untreated IBD patients to support a recent
      initiative aimed at characterizing microbes in colonic and ileal biopsies from
      such patients. In the future, criteria for the submission of tissue will be
      tailored to specific research questions. This bank is believed to be the first
      national bank of its kind dedicated to research in Crohn's disease and ulcerative
      colitis

PMID- 12605248
TI  - Abdominal pain as the initial and sole clinical presenting feature of systemic
      lupus erythematosus.
AB  - Classically, a diagnosis of systemic lupus erythematosus (SLE) is dependent on
      renal, rheumatological, cutaneous and neurological target organ damage with
      supporting serological markers. A previously healthy 26-year-old Japanese woman
      whose only manifestation of otherwise occult SLE was severe abdominal pain is
      reported. A computed tomographic scan of the abdomen revealed thickened loops of
      small bowel, endoscopic findings were nonspecific and jejunal biopsy revealed a
      nonspecific enteritis. Laboratory studies revealed lymphopenia,
      hypocomplementemia, a positive antinuclear antibody, a weakly positive anti-Smith
      and a strongly positive anti-double stranded DNA. There was a prompt symptomatic
      recovery with immunosuppressive therapy. The authors' experiences, and a review
      of the literature suggest that a diagnosis of SLE should be considered in young
      Asian women who present with significant but clinically enigmatic
      gastrointestinal illness.

PMID- 12605249
TI  - Esophageal foreign body causing direct aortic injury.
AB  - Foreign bodies in the esophagus are uncommon causes of esophageal perforation.
      Many nonperforating cases are successfully managed by flexible gastroscopy.
      However, complicated foreign bodies such as those that result in esophageal
      perforation and vascular injury are best managed surgically. Gastroscopy remains
      the primary method of diagnosis. A case of a 59-year-old woman who developed
      retrosternal and intrascapular pain, odynophagia and hematemesis after eating
      fish is reported. Flexible gastroscopy showed arterial bleeding from the
      midthoracic esophagus. Computed tomography scan localized a 3 cm fish bone
      perforating the esophagus with surrounding hematoma. An aortogram did not reveal
      an actively bleeding aortoesophageal fistula. The fish bone was surgically
      removed and the patient recovered with no postoperative complications. This case
      illustrates the importance of early consideration for surgical intervention when
      confronted with a brisk arterial bleed from the esophagus with suggestive history
      of foreign body ingestion.

PMID- 12605250
TI  - Motion - colonoscopic surveillance is more cost effective than colectomy in
      patients with ulcerative colitis: Arguments for the motion.
AB  - Patients with ulcerative colitis (UC) are at increased risk for colorectal cancer
      (CRC), especially those with longstanding disease, pancolitis or primary
      sclerosing cholangitis. The incidence of colitis- associated cancer is
      increasing, and the mortality rates from CRC are higher in UC patients than in
      the general population. Case control studies have demonstrated that surveillance
      colonoscopy reduces the risk of dying from CRC. A well conducted decision
      analysis found that surveillance colonoscopy decreases cancer-related mortality
      and increases life expectancy. The results with surveillance programs were almost
      as good as with prophylactic colectomy. A subsequent cost effectiveness analysis
      using the same model found that, compared with a policy of no surveillance,
      colonoscopic surveillance was more effective at preventing death from CRC and was
      less costly. The best strategy appears to be to perform colonoscopies every three
      years. The analysis also showed that colectomy should be recommended in patients
      with low-grade dysplasia. Patients at very high risk for CRC should undergo
      yearly colonoscopy, and patients who are concerned about the limitations of this
      technique should be offered prophylactic colectomy.

PMID- 12605251
TI  - Motion - colonoscopic surveillance is more cost effective than colectomy in
      patients with ulcerative colitis: arguments against the motion.
AB  - There are insufficient data upon which to base recommendations about surveillance
      colonoscopy and prophylactic colectomy for the prevention of colorectal cancer in
      patients with ulcerative colitis. Case series, analyses of intermediate results
      and extrapolations from other patient groups do not constitute reliable evidence.
      Available studies are susceptible to several biases: the 'healthy worker' effect,
      surveillance bias and selection bias. Patients who are enrolled in surveillance
      programs are more likely to be thoroughly evaluated beforehand, are more likely
      to be given a diagnosis of dysplasia or neoplasm even when asymptomatic and are
      more likely to comply with medical treatment, including maintenance anti
      inflammatory medication. Comparisons of the rates of neoplasia or death between
      surveyed and nonsurveyed patients are, therefore, of questionable validity.
      Prophylactic colectomy, unlike surveillance colonoscopy, prevents death from
      colorectal cancer. Moreover, it is difficult to keep patients in surveillance
      programs, and those who withdraw from programs appear to be at high risk of
      developing cancer. Prophylactic colectomy should be strongly considered for
      patients with dysplasia, sclerosing cholangitis, longstanding pancolitis
      (especially if it began early in life) or a positive family history of colorectal
      cancer. This procedure is underused in clinical practice and is a good
      alternative to colonoscopic surveillance in high risk patients.

PMID- 12605252
TI  - Motion - computerized tomographic colography is a better method for screening for
      polyps: arguments for the motion.
AB  - Colorectal cancer is an important public health problem that is amenable to
      prevention and early treatment. Traditional screening techniques - fecal occult
      blood testing, flexible sigmoidoscopy, barium enema and colonoscopy - each have
      limitations in terms of diagnostic accuracy, cost and/or patient acceptability.
      Compliance with recommendations for screening has been poor, in part, because of
      negative perceptions about the available modalities. Virtual colonoscopy, or
      computerized tomographic colography, is a minimally invasive technique that
      safely evaluates the entire colon and does not require sedation. Thorough
      cleansing as well as immobilization and air insufflation of the colon is crucial
      to a successful examination. Sensitivity and specificity rates are reasonable,
      compared with conventional colonoscopy, and it has been shown that the latter
      technique can be averted in over two-thirds of cases, with few false-negative
      examinations. Most patients find virtual colonoscopy more acceptable than the
      conventional technique, and would prefer it if a repeat procedure were warranted.
      An economic analysis that found that computerized tomographic colography was less
      cost effective than conventional colonoscopy did not consider the indirect costs
      of the latter, which is an important limitation. Virtual colonoscopy is a novel
      radiological technique that may revolutionize screening for colorectal cancer.

PMID- 12605253
TI  - Motion - computerized tomographic colography is a better method for screening for
      polyps: arguments against the motion.
AB  - Computerized tomographic (CT) colography is an exciting technique whereby images
      of the colonic wall and lumen can be obtained without colonoscopy. It is not as
      good as conventional colonoscopy, however, because of both inherent and
      performance limitations. Among the former is the inability to visualize subtle
      mucosal lesions, such as alterations in colour or pliability. More importantly,
      CT colography is strictly a diagnostic technique, and does not allow biopsy or
      removal of polyps. The vigorous bowel preparation required for this procedure can
      be very unpleasant for the patient, and includes purgatives followed by
      distension of the colon with air. Unlike with colonoscopy, adherent stool can be
      difficult to distinguish radiologically from polyps or cancers; as a result, many
      patients require colonoscopy anyway. The major performance limitations of CT
      colography are poor sensitivity and specificity compared with conventional
      colonoscopy. Rectal lesions, flat adenomas and diminutive adenomas are especially
      difficult to detect, and false-positive results are also common. In addition, the
      procedure is expensive and less cost effective than colonoscopy. CT colography
      takes relatively little patient time, but a substantial amount of time is needed
      for the radiologist to interpret the images. Interobserver variability is high.
      For all of these reasons, CT colography cannot be recommended as a screening test
      for colorectal neoplasia.

PMID- 12605254
TI  - The Canadian Association of Gastroenterology position on colon cancer screening.

PMID- 12605255
TI  - Characterization of a [2Fe-2S] protein encoded in the iron-hydrogenase operon of
      Thermotoga maritima.
AB  - Thermotoga maritima grows optimally at 80 degrees C by fermenting carbohydrates
      to organic acids, CO(2), and H(2). The production of H(2) is catalyzed by a
      cytoplasmic, heterotrimeric (alphabetagamma) Fe-hydrogenase. This is encoded by
      three genes, hydC (gamma), hydB (beta) and hydA (alpha), organized within a
      single operon that contains five additional open reading frames (ORFs). The
      recombinant form of the first ORF of the operon, TM1420, was produced in
      Escherichia coli. It has a molecular mass of 8537+/-3 Da as determined by mass
      spectrometry, in agreement with the predicted amino acid sequence. Purified
      TM1420 is red in color, has a basic p I (8.8), and contains 1.9 Fe atoms/mol that
      are present as a single [2Fe-2S] cluster, as determined by UV-visible absorption
      and EPR spectroscopy. The protein contains five cysteine residues, but their
      arrangement is characteristic of a subunit or domain rather than of a ferredoxin
      type protein. The reduction potential of the [2Fe-2S] cluster (-233 mV at pH 6.5
      and 25 degrees C) is pH independent but decreases linearly with temperature to 
      296 mV (-1.15 mV/ degrees C) at 80 degrees C. TM1420 is not reduced, in vitro, by
      the Fe-hydrogenase nor by a pyruvate ferredoxin oxidoreductase. The protein was
      unstable at 70 degrees C under anaerobic conditions with a half-life of
      approximately 30 min. The basic nature of TM1420, its instability at the growth
      temperature of T. maritima, and the unusual spacing of its cysteine residues
      suggest that this protein does not function as a ferredoxin-type electron carrier
      for the Fe-hydrogenase. Instead, TM1420 is more likely part of a thermostable
      multi-protein complex that is involved in metal cluster assembly of the
      hydrogenase holoenzyme.

PMID- 12605256
TI  - Field-dependent proton relaxation in aqueous solutions of some manganese(II)
      complexes: a new interpretation.
AB  - Field-dependent measurements of the paramagnetic relaxation enhancement for water
      protons in the presence of Mn(II) complexes ( S=5/2), reported recently, are re
      interpreted using theoretical models that take into consideration the fact that
      the relaxation of the electron spin for S>1 is multiexponential (even in the
      Redfield limit) and that are valid for an arbitrary relation between the
      electronic Zeeman interaction and the zero-field splitting in the complex.

PMID- 12605257
TI  - Elucidating thermodynamic parameters for electron transfer proteins using
      isothermal titration calorimetry: application to the nitrogenase Fe protein.
AB  - Establishing thermodynamic parameters for electron transfer reactions involving
      redox proteins is essential for a complete description of these important
      reactions. While various methods have been developed for measuring the Gibbs free
      energy change (Delta G(HR) or E(m)) for the protein half-reactions, deconvolution
      of the respective contributions of enthalpy (Delta H(HR)) and entropy (Delta
      S(HR)) changes is much more challenging. In the present work, an approach is
      developed using isothermal titration calorimetry (ITC) that allows accurate
      determination of all of these thermodynamic parameters for protein electron
      transfer half-reactions. The approach was validated for essentially irreversible
      and reversible electron transfer reactions between well-characterized mediators
      and between mediators and the protein cytochrome c. In all cases, the measured
      thermodynamic parameters were in excellent agreement with parameters determined
      by electrochemical methods. Finally, the calorimetry approach was used to
      determine thermodynamic parameters for electron transfer reactions of the
      nitrogenase Fe protein [4Fe-4S](2+/+) couple in the absence or presence of MgADP
      or MgATP. The E(m) value was found to change from -290 mV in the absence of
      nucleotides to -381 mV with MgATP and -423 mV with MgADP, consistent with earlier
      values. For the first time, the enthalpy (Delta H(HR)) and entropy (Delta S(HR))
      contributions for each case were established, revealing shifts in the
      contribution of each thermodynamic parameter induced by nucleotide binding. The
      results are discussed in the context of current models for electron transfer in
      nitrogenase.

PMID- 12605259
TI  - Level of glucocorticoid receptor mRNA expression in iris tissue and postoperative
      ocular inflammation in patients with uveitis.
AB  - BACKGROUND: Glucocorticoids (GC) are widely used to treat uveitis, but their
      efficacy is known to vary substantially among patients. In this retrospective
      preliminary study, we measured the level of GC receptor (GCR) expression in
      ocular tissue taken from uveitis patients during cataract surgery as an indicator
      of their sensitivity to GC, divided the patients into comparatively high- and low
      sensitivity groups on this basis, and compared the two groups with respect to the
      frequency of ocular inflammation attacks observed after operation. METHODS: Iris
      samples were obtained from 13 patients during surgery for cataract associated
      with uveitis. From each sample, RNA was extracted and used as template for cDNA
      construction. The cDNA was exposed to GCR gene-detecting and TaqMan probes. The
      level of GCR mRNA expression was determined by real-time PCR and compared with
      the frequency of postoperative ocular inflammation attacks that occurred despite
      daily temporal and, as required, subconjunctival glucocorticoid injection or
      other therapy. The level of 18SrRNA expression was measured and taken as the mRNA
      expression baseline, and the ratio between the number of GCR and housekeeping
      gene18SrRNA copies was calculated as the normalized ratio. RESULTS: The mean
      normalized ratio was 13.7 for the uveitis patients and 7.3 for the uveitis-free
      control patients. The median normalized ratio in the uveitis patient group was
      1.5. The mean frequency of inflammation attacks was 0.24/month in the uveitis
      patients with a normalized ratio of 1.5 or higher and 0.53/month in those with a
      normalized ratio of less than 1.5, a significant difference. CONCLUSION: The
      level of GCR expression may relate to the response to steroids in the clinical
      course of inflammation. Further investigation is warranted.

PMID- 12605258
TI  - Optic disc excavation in the atrophic stage of Leber's hereditary optic
      neuropathy: comparison with normal tension glaucoma.
AB  - BACKGROUND: Abnormal optic disc excavations are reportedly seen in patients with
      Leber's hereditary optic neuropathy (LHON), a mitochondrial dysfunction disease.
      We examined the disc morphology in the eyes of patients with LHON at the atrophic
      stage and compared it to that in eyes with normal-tension glaucoma (NTG).
      METHODS: We studied 15 LHON patients with the 11778 mutation, 15 patients with
      NTG, and 25 normal subjects. The optic disc morphology was analyzed by Heidelberg
      retinal tomography (HRT). Ten parameters of the optic disc obtained by HRT were
      evaluated, including the diagnostic classification of glaucoma. RESULTS: Six of
      the nine morphological HRT parameters of the LHON patients, the exceptions being
      disc area, mean cup depth, and maximum cup depth, differed significantly from
      those of the normals. NTG patients had a significantly greater mean and maximum
      cup depth than LHON patients. The HRT glaucoma diagnostic software classified 22
      (73%) of the 30 optic discs in LHON patients as glaucomatous. CONCLUSION: The
      optic discs at the atrophic stage of LHON eyes have glaucoma-like morphological
      changes. However, the cups were significantly deeper in NTG than LHON. The
      similarity in the optic disc findings in LHON and NTG suggests that alterations
      in mitochondrial function may be related to optic disc excavations.

PMID- 12605260
TI  - Diurnal variation in group IIa phospholipase A2 content in tears of contact lens
      wearers and normal controls.
AB  - PURPOSE: To study the diurnal rhythm in group IIA phospholipase A(2) (GIIAPLA(2))
      content of tears and the effect of the wearing time of soft contact lenses (CL)
      on the content of GIIAPLA(2 )in tears. METHODS: The GIIAPLA(2 )content of tears
      was measured by a time-resolved fluoroimmunoassay in 22 healthy controls at 8
      a.m., noon, 4 p.m. and 8 p.m. and in 20 CL wearers at 4 p.m. 1-2 days before
      using CLs and after 4 h (at noon), 8 h (4 p.m.) and 12 h (8 p.m.) use of soft
      CLs. RESULTS: The GIIAPLA(2 )content of tears of healthy controls was 80.6+/-47.8
      micro g/ml (mean+/-SD). The GIIAPLA(2 )content was lower at 8 a.m. than at noon
      (p=0.006) and higher at 4 p.m. than at 8 p.m. ( P=0.003). There was no
      statistically significant difference in the GIIAPLA(2 )content of tears between
      the CL wearers without CLs (69.47+/-31.2 micro g/ml) and the normal subjects
      (92.3+/-48.2 micro g/ml) measured at 4 p.m. Compared with healthy controls, the
      GIIAPLA(2) values in subjects wearing CLs were statistically significantly lower
      at noon ( P=0.0001) and at 4 p.m. ( P=0.0002). CONCLUSION: In normal subjects,
      the GIIAPLA(2) content of tears increased from 8 a.m. to noon and decreased from
      4 p.m. to 8 p.m. The use of CLs for 4 h and 8 h caused a decrease in the
      GIIAPLA(2) content of tears. This difference was not seen at 4 p.m. the day when
      the CL wearers did not use CLs.

PMID- 12605261
TI  - Sine Amsler Charts: a new method for the follow-up of metamorphopsia in patients
      undergoing macular pucker surgery.
AB  - PURPOSE: To evaluate our new method for the follow-up of metamorphopsia in
      patients with a macular pucker. METHODS: Sine Amsler Charts (SAC) are a set of
      eight modified Amsler charts where we have replaced the straight lines by sine
      curves of the same frequency but with different amplitudes (grades I-VIII). The
      patient first examines a regular Amsler chart with the affected eye; subsequently
      the SAC are presented in random order to the fellow eye. With this eye the
      patient then selects the SAC with the amplitude that best corresponds to the
      metamorphopsia observed with the affected eye. After 30 min the test was
      repeated. A comparison of pre- and postoperative SAC scores was made in 63
      patients. The correlations between preoperative visual acuity, membrane type,
      leakage on fluorescein angiography, preoperative SAC score, postoperative SAC
      score and postoperative visual acuity were analyzed. RESULTS: Preoperative repeat
      testing with the SAC revealed 100% reproducibility in the grading of
      metamorphopsia. Postoperative SAC was unchanged in 16% of cases, one grade lower
      in 54%, two grades lower in 21% and more than two grades lower in 7%.
      Postoperative visual acuity was unchanged (i.e., within two EDTRS lines of the
      preoperative value) in 49% of cases, improved in 48% and decreased in 3%. A
      decrease in SAC score with a two-line increase in visual acuity occurred in 43%
      of cases. CONCLUSION: The SAC examination is a reproducible and rapid method for
      the comparison of the preoperative and postoperative metamorphopsia in patients
      undergoing pucker surgery and it may serve as an additional outcome measure.

PMID- 12605262
TI  - Endoscopically controlled erbium:YAG goniopuncture versus trabeculectomy: effect
      on intraocular pressure in combination with cataract surgery.
AB  - PURPOSE: . To compare the efficacy of endoscopic erbium:YAG laser goniopuncture
      in glaucoma treatment to trabeculectomy, both methods as adjuncts to cataract
      surgery. METHODS: . Fifty-nine eyes of 59 glaucoma patients with coexistent
      cataract were treated by phacoemulsification and endoscopic Er:YAG goniopuncture
      in a combined fashion. The primary study endpoints were intraocular pressure
      (IOP), number of antiglaucomatous drugs, postoperative complications,
      hospitalisation time and visual acuity at 1 year after surgery. To date, 24 eyes
      have finished the 1-year follow-up. This prospective treatment arm was compared
      to a retrospective inclusion-matched control group treated by trabeculectomy and
      cataract surgery in a single procedure. RESULTS: . In the laser-treated group,
      the mean IOP dropped by 30% from 23.4+/-3.7 mmHg to 16.3+/-6 mmHg ( P<0.0001)
      after 12 months. Without reoperation, treatment was successful in 71% of these
      eyes. In the control group, the IOP decreased by 33.5% from 22.7+/-3.3 mmHg to
      15.1+/-3.8 mmHg ( P<0.0001). The success rate without reoperation was 46%. The
      number of antiglaucomatous drugs needed decreased from 1.48+/-0.95 to 0.48+/-0.7
      ( P<0.0001) in the laser-treated group and from 2.0+/-0.9 to 0.39+/-0.6 (
      P<0.0001) in the control group. Postoperative complications were found more
      frequently in the control group ( P<0.0001). Hospitalisation was shorter in the
      laser group ( P<0.0001). Postoperative visual acuity was lower in the control
      group ( P=0.004). CONCLUSION: . Combined Er:YAG goniopuncture and cataract
      surgery lowers the IOP to an extent comparable to combined trabeculectomy and
      cataract surgery. Due to fewer postoperative complications, Er:YAG goniopuncture
      seems to be superior to standard fistulation surgery as the primary approach
      within the first year.

PMID- 12605263
TI  - Presbyopia among normal individuals.
AB  - BACKGROUND: To define ocular variables that might affect the need for early use
      of reading glasses. METHODS: A retrospective, non-randomized clinical trial was
      conducted at an aero-medical center. The charts of 100 healthy male pilots who
      suffered from presbyopia were reviewed. All subjects had undergone a complete eye
      examination every year for 30 years. Ocular parameters measured at the ages of
      20, 30, 40, 45, and 50 years were recorded. Individuals were divided into two
      groups: those who needed reading glasses at the age of 45 years or earlier (group
      1) and those who had needed reading glasses after 45 years of age (group 2).
      RESULTS: Of all the ocular variables examined each year, two differed
      significantly between the two groups. Refraction at age 20 was 0.1+/- 0.3 D in
      group 1 and 0.0 +/- 0.3 D in group 2 ( P <0.05). Amplitude of accommodation at
      age 20 was 9.5 +/- 1.2 D in group 1 and 9.9 +/- 1.0 D in group 2 ( P <0.05).
      CONCLUSION: Hyperopia and low amplitude of accommodation at the age of 20 might
      predispose to early development of presbyopia in normal individuals.

PMID- 12605264
TI  - Five-year results of trabeculectomy with mitomycin C.
AB  - BACKGROUND: The long-term efficacy and safety of primary trabeculectomy with
      mitomycin C were retrospectively studied. METHODS: Sixty eyes of 60 patients with
      severe glaucoma, 25 female and 35 male, with a mean age of 72.5 years who
      underwent primary trabeculectomy with mitomycin C between 1993 and 1995 were
      included. Glaucoma subtypes consisted of 42 patients with primary open-angle
      glaucoma, 10 patients with normal-pressure glaucoma, 2 patients with chronic
      narrow-angle glaucoma, 5 patients with pigment dispersion syndrome and 1 patient
      with pseudoexfoliation syndrome. During surgery, mitomycin C 0.2 mg/ml was
      applied under the scleral flap for 3 min. RESULTS: Mean intraocular pressure
      (IOP) decreased from 22.3+/-9.3 preoperatively to 12.6+/-3.5 mmHg
      postoperatively. With success defined as an IOP level of 15 mmHg or less, a
      success rate of 83.3% was obtained in the 1st year, dropping to 60% in the 6th
      year following trabeculectomy. Visual fields remained stable in 73.3% of cases
      during the follow-up period. LogMAR visual acuity increased from 0.2 to 0.4. Four
      eyes underwent cataract surgery prior to trabeculectomy. Thirteen eyes underwent
      cataract surgery during the follow-up period. Long-term complications were
      relatively mild and consisted of two cases of blebitis. Bleb reconstruction was
      performed in five eyes with overfiltration or bleb-related complaints.
      CONCLUSIONS: The present findings indicate that the additional use of mitomycin C
      may be justified in trabeculectomies in patients with severe glaucoma.

PMID- 12605265
TI  - Chemokine and chemokine receptor expression during experimental autoimmune
      uveoretinitis in mice.
AB  - BACKGROUND: Chemokines act as chemoattractants and activators of specific
      leukocytes at the site of inflammation. In this study, we investigated serial
      expression of chemokines and chemokine receptors in the eye with experimental
      autoimmune uveoretinitis (EAU) using RNAse protection assay, and confirmed their
      expression by immunohistochemical staining. METHODS: B10.A mice were immunized
      with 50 micro g of interphotoreceptor retinoid binding protein (IRBP) emulsified
      in complete Freund's adjuvant in order to induce EAU. The eyes were enucleated 0,
      7, 14 and 21 days after IRBP immunization to analyze mRNA expression of
      chemokines and chemokine receptors in the posterior segment. In addition,
      expression of IP-10 and CXCR3 was analyzed by immunohistochemistry. RESULTS: The
      gene expression of RANTES, IP-10, and MCP-1 was upregulated on day 14 after
      immunization (early stage of EAU). The expression of chemokine receptors (CCR2
      and CCR5) associated with Th1-type T cells correlated with their appropriate
      ligands. Furthermore, immunohistochemical study showed that IP-10 and CXCR3, the
      receptor for IP-10, were strongly expressed in the posterior segment of the eyes
      from mice with EAU. CONCLUSION: These results suggest that RANTES, IP-10 and MCP
      1 may contribute to the recruitment of Th1-type T cells into the eye during the
      development of EAU in mice.

PMID- 12605266
TI  - Effects of interferon-gamma on human subconjunctival fibroblasts in the presence
      of TGFbeta1: reversal of TGFbeta-stimulated collagen production.
AB  - BACKGROUND: We examined the effects of interferon-gamma (IFN-gamma) on protein
      production of extracellular matrix (ECM) components in cultured human
      subconjunctival fibroblasts or those stimulated by exogenous transforming growth
      factor beta1 (TGFbeta1). IFN-gamma reportedly up-regulates Smad7, an inhibitory
      mediator of TGFbeta-Smad signaling, and blocks TGFbeta effects. METHODS:
      Proliferation and migration as well as the ultrastructure of these cells were
      examined in the presence and absence of IFN-gamma. Cell migration was examined
      using an in vitro wound healing model in monolayer fibroblast cultures. RESULTS:
      The results showed that IFN-gamma reduced ECM production in normal
      subconjunctival fibroblasts, as well as in those treated with TGFbeta1, below the
      control levels. IFN-gamma had no effect on cell proliferation and fibroblast
      ultrastructure. On the other hand, IFN-gamma delayed defect closure in monolayer
      cell sheets in a dose-dependent manner. Immunohistochemistry also revealed that
      the addition of IFN-gamma attenuated the translocation of Smads2/4 into the
      nuclei of TGFbeta1-treated subconjunctival fibroblasts. CONCLUSION: These
      findings suggest that IFN-gamma may be clinically effective in attenuating
      excessive ECM accumulation in conjunctiva after ocular surgery and in the
      presence of inflammatory ocular surface disorder. IFN-gamma modulates the
      Smads2/4 pathway of TGFbeta1 signal transduction toward the up-regulation of ECM
      components.

PMID- 12605267
TI  - Influence of arterial hypertension and diet-induced atherosclerosis on macular
      drusen.
AB  - PURPOSE: To evaluate whether development of macular drusen is influenced by
      experimentally induced chronic arterial hypertension and atherosclerosis.
      METHODS: The prospective experimental study included 93 eyes of 51 elderly rhesus
      monkeys. The total study group was divided into groups with experimental arterial
      hypertension ( n=22), diet-induced atherosclerosis ( n=10), or both arterial
      hypertension and atherosclerosis ( n=29) and a control group without arterial
      hypertension or atherosclerosis ( n=32). Using color wide-angle fundus
      photographs taken at the beginning and the end of the study, age-related macular
      degeneration was graded by counting the number and estimating the mean size of
      drusen in the macular region. RESULTS: In the monkeys with arterial hypertension,
      the count and area of the macular drusen and the change in number and size of
      macular drusen during the follow-up period were significantly ( P<0.05) higher
      than in the monkeys of the control group. Correspondingly, the count and size of
      macular drusen were significantly ( P<0.05) correlated with the duration of
      arterial hypertension. In contrast, monkeys with only atherosclerosis did not
      vary significantly ( P>0.10) from monkeys of the control group in number and size
      of drusen. The macular drusen parameters were statistically ( P>0.20) independent
      of the duration of atherosclerosis. Similarly, the atherosclerotic monkeys and
      the monkeys of the control group did not vary significantly ( P>0.30) in the
      change of the macular drusen parameters during the follow-up period. CONCLUSIONS:
      Development of macular drusen as part of age-related macular degeneration in
      rhesus monkeys may be associated with experimentally induced arterial
      hypertension. It does not seem to be influenced by diet-induced atherosclerosis.

PMID- 12605269
TI  - Blockers of carbonic anhydrase can cause increase of retinal capillary diameter,
      decrease of extracellular and increase of intracellular pH in rat retinal organ
      culture.
AB  - BACKGROUND: At least in normal-pressure glaucoma a vascular genesis with
      hypoperfusion and regulation impairment is discussed. This may lead to
      malnutrition of retinal ganglion cells and apoptosis. The retinal
      microvasculature has a small functional reserve. In addition, the retinal
      microvessels lack the autonomic nerves that are normally found in other tissues.
      Thus, no systemic influences reach the retinal capillaries apart from circulating
      hormones or transmitters. Blockers of carbonic anhydrase (CA) may modulate
      regional blood flow by mediating changes in extra- and intracellular pH. However,
      it is still unclear (1) whether blockers of CA really change the pH near the
      retinal capillaries and (2) how changes in the local pH affect the capillary tone
      in situ. Therefore, we tested dorzolamide and acetazolamide in our model of the
      freshly enucleated rat retina. METHODS: Adult Sprague-Dawley rats (of both sexes,
      250-350 g) were killed and retinae were prepared. The retinae were gently
      separated from the retinal pigmented epithelium and were observed in a chamber
      for electronic light microscopy or were fixed for immunohistochemistry.
      Electronic light microscopy of the retinal cells was performed with a Zeiss
      Axiovert microscope equipped with differential interference contrast (DIC)
      optics. Changes in capillary diameter were measured using an Openlab acquisition
      system and analyzed statistically using ANOVA. In addition to light microscopy
      the intracellular pH was analyzed in the whole mounts by ratio imaging of the pH
      using the special dye BCECF-AM (2,7 -bis-(2-carboxyethyl)-5-(and -6)
      carboxyfluoresceinacetoxymethyl ester) and the extracellular pH using BCECF (2,7 
      bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein). RESULTS: Pericytes of most
      segments of retinal capillaries are immunoreactive for alpha-smooth muscle actin
      (SMA). The SMA immunostaining is strong around the nucleus; the endothelial tube
      is visible by virtue of the slight immunoreactivity of the surrounding pericyte
      processes. Acetazolamide and dorzolamide showed statistically significant
      vasoactive effects in retinal capillaries. Vasodilation increased by up to 105%
      of that in control capillaries after 5, 10 and 15 min. CA inhibitors were found
      to be able to induce intracellular alkalization in retinal cells. After addition
      of dorzolamide or acetazolamide the extracellular pH decreased from 7.4 to 7.2
      concomitant with diameter changes. CONCLUSIONS: The tube-like pattern of SMA
      immunoreactivity demonstrates the presence of contractile elements within the
      pericyte processes of the rat retina. Thus, pericytes may act as a regulation
      element within the retinal microcirculation. Our results further suggest that CA
      inhibitors are able to decrease pH in the extracellular space; however, the pH
      within the cells increases. The increase in capillary diameter is concomitant
      with these pH changes. Thus, we may conclude that CA inhibitors can relax
      pericytes and might improve the retinal blood supply.

PMID- 12605268
TI  - Connective tissue growth factor in pterygium: simultaneous presence with vascular
      endothelial growth factor - possible contributing factor to conjunctival
      scarring.
AB  - BACKGROUND: Various growth factors have been detected in pterygium and been
      associated with its vasculogenesis. The basic pathophysiological mechanisms
      responsible especially for the fibrotic activity in pterygium are, however, not
      yet known. Connective tissue growth factor (CTGF) has been shown to be
      substantially involved in various processes of fibrosis. We report on the
      presence of CTGF in pterygium and its simultaneous presence with vascular
      endothelial growth factor (VEGF). METHODS: Samples of pterygium were collected
      during surgery with informed consent of the patients. Specific, non-commercial
      primary antibodies against CTGF were used to detect CTGF using
      immunohistochemistry. Specificity of antibodies was confirmed with Western-blot
      analysis. The same specimens were stained with commercial antibodies for VEGF.
      Additionally RT-PCR analysis was performed from pterygium samples. RESULTS: CTGF
      was detected in the epithelium of all samples as well as in some stromal
      keratocytes. The RT-PCR confirmed the identity of CTGF in these samples. The
      staining pattern differed slightly from that of VEGF, which was detected in all
      samples. The control sections were negative. CONCLUSION: CTGF is present in the
      epithelium of a majority of pterygia and probably contributes to fibrosis.
      Simultaneous presence with VEGF suggests growth factor interaction and possible
      involvement in apoptotic dysregulation.

PMID- 12605270
TI  - Impact of head advance and oscillation rate on the flap parameter: a comparison
      of two microkeratomes.
AB  - PURPOSE: To compare flap quality and thickness in an experimental setting using
      the Amadeus and Carriazo/Barraquer microkeratomes. METHODS: One hundred and sixty
      three fresh porcine cadaver eyes were used to cut corneal flaps. One hundred and
      thirty-five eyes were cut using the Amadeus microkeratome with various settings
      of head advance and oscillation rate, 28 eyes using the Carriazo/Barraquer
      microkeratome (Supratome). Flap diameter and hinge width were measured by
      planimetry and flap thickness by ultrasound pachymetry. Descriptive statistical
      analysis was based on medians and quartiles, graphical representation on box
      plots. The measurement devices were compared by two sample Wilcoxon tests, their
      deviation from the distributors' reference measurement values by sign tests.
      RESULTS: Variation of oscillation rate and head advance led to significant
      differences in flap thickness. Optimal cut quality was achieved with 1 mm/s head
      advance and 8,000 rpm in the Amadeus microkeratome. With this setting the
      smallest target deviations in flap thickness were obtained among the results with
      lowest range (median 170 micro m, interquartile range 18 micro m, target 160
      micro m). The Amadeus microkeratome demonstrated a statistically significant
      lower deviation from the target thickness ( P<0.001) and also a lower range than
      the Supratome (median 127 micro m, interquartile range 30 micro m, target 140
      micro m; P<0.001). CONCLUSIONS: Optimization of microkeratome settings leads to
      minimized deviation from target thickness and improved parameter. The Amadeus
      microkeratome achieved a statistically significant lower deviation in flap
      thickness than the Carriazo/Barraquer microkeratome. Individualization of the
      microkeratome settings may help to decrease flap complications and improve
      refractive outcome.

PMID- 12605271
TI  - Benzodiazepine and kainate receptor binding sites in the RCS rat retina.
AB  - BACKGROUND: The effect of age and photoreceptor degeneration on the kainate
      subtype of glutamate receptors and on the benzodiazepine-sensitive gamma
      aminobutyric acid-A receptors (GABA(A)) in normal and RCS (Royal College of
      Surgeons) rats were investigated. METHODS: [(3)H]Kainate and [(3)H]flunitrazepam
      were used as radioligands for kainate and GABA(A)/benzodiazepine()receptors,
      respectively, using the quantitative receptor autoradiography technique. RESULTS:
      In both normal and RCS rat retina we observed that [(3)Eta]flunitrazepam and
      [(3)Eta]kainate binding levels were several times higher in inner plexiform layer
      (IPL) than in outer plexiform layer (OPL) at all four ages studied (P17, P35, P60
      and P180). Age-related changes in receptor binding were observed in normal rat
      retina: [(3)Eta]flunitrazepam binding showed a significant decrease of 25%
      between P17 and P60 in IPL,and [(3)Eta]kainate binding showed significant
      decreases between P17 and P35 in both synaptic layers (71% in IPL and 63% in
      OPL). Degeneration-related changes in benzodiazepine and kainate receptor binding
      were observed in RCS rat retina. In IPL, [(3)Eta]flunitrazepam and
      [(3)Eta]kainate binding levels were higher than in normal retina at P35 (by 24%
      and 86%, respectively). In OPL, [(3)Eta]flunitrazepam binding was higher in RCS
      than in normal retina on P35 (74%) and also on P60 (62%). CONCLUSIONS: The
      results indicate that postnatal changes occur in kainate and benzodiazepine
      receptor binding sites in OPL and IPL of the rat retina up to 6 months of age.
      The data also suggest that the receptor binding changes observed in the RCS
      retina could be a consequence of the primary photoreceptor degeneration.

PMID- 12605272
TI  - A case of angle-closure glaucoma, cataract, nanophthalmos and spherophakia in
      oculo-dento-digital syndrome.
AB  - BACKGROUND: We report a new case of oculo-dento-digital syndrome. METHODS: Case
      report. RESULTS: We saw a 34-year-old women with oculo-dento-digital syndrome.
      Visual acuity was no perception of light (RE) and 1/35 (LE). Biomicroscopy
      revealed a flat anterior chamber and an advanced cataract. The intraocular
      pressure (IOP) was 60 mmHg in both eyes. Ultrasonographic biomicroscopy
      demonstrated a closed chamber angle in both eyes. Measurements of the axial
      length and of the diameter of the lens were 18.7 mm/6.0 mm for the RE and 18.7
      mm/5.8 mm for the LE respectively. In the time following we conducted a
      cyclodestructive procedure in the RE and a cataract extraction with implantation
      of an intraocular lens in the LE. This led to a considerable reduction of the IOP
      in the RE and combined with local therapy to IOP regulation in the LE.
      CONCLUSION: In this patient nanophthalmos, cataract and spherophakia led to angle
      closure glaucoma in both eyes. We recommend early monitoring of IOP, axial length
      and lens diameter. This case demonstrates that an early cataract extraction might
      beneficially influence the natural course of the disease.

PMID- 12605273
TI  - PET imaging with yttrium-86: comparison of phantom measurements acquired with
      different PET scanners before and after applying background subtraction.
AB  - Quantitative imaging with the positron emitter (86)Y is the method of choice to
      determine the uptake and dosimetry of (90)Y-labelled radiopharmaceuticals. To
      examine the quantitative accuracy of positron emission tomography findings with
      (86)Y, this non-pure positron emitter was evaluated in a cylindrical phantom with
      rods of Teflon, water and air and measured with three different scanners: ECAT
      EXACT (2D/3D), ECAT HR+ (2D/3D) and PC4096+ (2D). After standard reconstruction,
      (86)Y radioactivity measured with the ECAT EXACT and related to the true
      radioactivity varied between 0.84 and 0.99 in 2D and between 0.93 and 1.20 in 3D
      from the first to the last acquisition (eight half-life times later). The water
      and Teflon rods exhibited considerable amounts of reconstructed radioactivity-21%
      in 2D and 67% in 3D for water and 65% and 147%, respectively, for Teflon-compared
      with the actual (86)Y radioactivity of the phantom. For the ECAT HR+ similar
      results were obtained in 3D, but there were even greater overestimations in 2D.
      Measurements with the PC4096+ showed rather small errors, with 10% for water and
      20% for Teflon. To correct for the background of gamma-coincidences, sinograms
      were analysed and an experimental percentage of the background was subtracted
      from the sinograms. In order to minimise the errors in reconstructed
      radioactivity, the subtraction value had to be different for the individual
      scanners and modes. Our results demonstrate that (90)Y/(86)Y-based dosimetry for
      bone and red marrow must be regarded with caution if it is derived from regions
      of interest over the bone, the density of which is similar to that of Teflon. To
      obtain more reliable estimates, an appropriate background correction must be
      applied and tailored individually with respect to the scanner and acquisition
      mode.

PMID- 12605274
TI  - The acrophysis: a unifying concept for enchondral bone growth and its disorders.
      I. Normal growth.
AB  - In order to discuss and illustrate the common effects on normal and abnormal
      enchondral bone at the physes and at all other growth plates of the developing
      child, the term "acrophysis" is proposed. Acrophyses include the growth plates of
      secondary growth centers including carpals and tarsals and apophyses, and the
      growth plates at the non-physeal ends of small tubular bones. The last layer of
      development of both physes and acrophysis is the cartilaginous zone of
      provisional calcification (ZPC). The enchondral bone abutting the ZPC shares
      similar properties at physes and acrophyses, including the relatively lucent
      metaphyseal bands of many normal infants at several weeks of age. The bone-in
      bone pattern of the normal vertebral bodies and bands of demineralization of the
      tarsal bones just under the ZPC are the equivalent of those bands. The growth
      arrest/recovery lines of metaphyses similarly have equivalent lines in growth
      centers and other acrophyseal sites. Nearly the same effects can also be
      anticipated from the relatively similar growth plate at the cartilaginous cap of
      benign exostoses ("paraphysis"). The companion article will explore abnormalities
      at acrophyseal sites, including metabolic bone disease and dysplasias.

PMID- 12605275
TI  - Comparison of fixed-flexion positioning with fluoroscopic semi-flexed positioning
      for quantifying radiographic joint-space width in the knee: test-retest
      reproducibility.
AB  - OBJECTIVE: To compare fixed-flexion radiography of the knee with fluoroscopic
      semi-flexed radiography in terms of the reproducibility of measurements of
      minimum joint-space width (JSW) in the medial femorotibial joint. METHODS:
      Posteroanterior radiographs of the right knees of 18 normal volunteers were
      acquired with the patients standing on an upright fluoroscopy table, the feet
      externally rotated 10 degrees and the toes touching the vertical table. Knees
      were positioned and radiographed with two different techniques: (1) semi-flexed
      positioning under fluoroscopic guidance using a horizontal X-ray beam; and (2)
      fixed-flexion positioning, with the knees and thighs touching the vertical table,
      using 10 degrees caudal beam angulation without fluoroscopy. Foot maps were drawn
      in each case. Subjects were repositioned and radiographed twice using each
      technique. The posteroanterior beam angle that optimally projected the medial
      tibia plateau with the patient in the fixed-flexion position was also determined
      for each subject in a separate examination using fluoroscopy. Ten patients with
      osteoarthritis were also examined with the fixed-flexion technique using a
      conventional radiographic unit. Minimum medial joint-space width (JSW) in the
      medial femorotibial joint was measured manually with a graduated lens and also
      with a semi-automated computer algorithm. RESULTS: Reproducibility errors (root
      mean-square SD) for manual and automated JSW measurement were 0.2 mm and 0.1 mm,
      respectively, for fluoroscopic semi-flexed positioning in volunteers; 0.3 mm and
      0.1 mm, respectively, for fixed-flexion positioning in volunteers; and 0.2 mm and
      0.1 mm, respectively, for fixed-flexion positioning in osteoarthritic patients.
      The optimal beam angle for visualizing the joint space was 9.0 degrees +/-3.6
      degrees. CONCLUSION: Fixed-flexion, non-fluoroscopic radiography of the knee can
      provide reproducible JSW measurement using widely available X-ray equipment. This
      technique is more feasible for multicenter clinical studies and routine clinical
      use than are methods that rely on fluoroscopic alignment of the tibial plateau.

PMID- 12605276
TI  - FDG-PET for preoperative differential diagnosis between benign and malignant soft
      tissue masses.
AB  - OBJECTIVE: To evaluate the standardized uptake value (SUV) of [(18)F]2-deoxy-2
      fluoro- d-glucose at positron emission tomography (FDG-PET) for preoperative
      differential diagnosis between benign and malignant soft tissue masses. DESIGN:
      One hundred and fourteen soft tissue masses (80 benign, 34 malignant) were
      examined by FDG-PET prior to tissue diagnosis. The SUVs were calculated and
      compared between benign and malignant lesions and among different histologic
      subgroups which included three or more cases. RESULTS: There was a statistically
      significant difference in SUV between benign (1.80+/-1.42 [SD]) and malignant
      (4.20+/-3.16) soft tissue masses in total (P<0.0001). However, a considerable
      overlap in SUV was observed between many benign and malignant lesions.
      Liposarcomas (2.16+/-1.72) and synovial sarcomas (1.60+/-0.43) did not show
      significantly higher SUV than any benign lesions. Metastases (4.23+/-2.35) showed
      no statistically significant difference in SUV as compared with schwannomas
      (1.75+/-0.84), desmoids (2.77+/-1.32), sarcoidosis (3.62+/-1.53), or giant cell
      tumors of tendon sheath (GCT of TS; 5.06+/-1.63). Even malignant fibrous
      histiocytomas (5.37+/-1.40) could not be differentiated from sarcoidosis or GCT
      of TS, based on the SUV. CONCLUSIONS: A large accumulation of FDG can be observed
      in both benign and malignant histiocytic, fibroblastic, or neurogenic lesions.
      SUV at conventional FDG-PET is limited to differentiating benign from malignant
      soft tissue masses, when all kinds of histologic subtypes are included.

PMID- 12605277
TI  - FDG PET imaging guided re-evaluation of histopathologic response in a patient
      with high-grade sarcoma.
AB  - [(18)F]fluorodeoxyglucose positron emission tomography (FDG PET) is used to
      evaluate the metabolic activity of intermediate- to high-grade soft tissue
      sarcomas prior to the initiation of chemotherapy. FDG PET and MRI are repeated
      after chemotherapy to assess treatment response and to correlate this with the
      histologic response. This case report highlights discrepant results between the
      final histologic diagnosis (tumor response) and the percent change in maximum
      standard uptake variable (SUV(max)). Further investigation of the resected
      specimen identified the significant difference in tumor response assessment to be
      due to the heterogeneity of the tumor and heterogeneity in its response to
      treatment. FDG PET imaging has an important role in evaluating tumor metabolic
      activity and has played an increasingly important part in evaluating the response
      to neoadjuvant chemotherapy in sarcomas. Evaluating the heterogeneity of the
      tumor at baseline and after response to therapy can provide insight into
      prognosis and treatment planning.

PMID- 12605279
TI  - Multifocal, metachronous, giant cell tumor of the lower limb.
AB  - A case of multifocal giant cell tumor in a skeletally immature male with
      documented metachronous disease of the lower limb is described followed by a
      review of the literature including treatment options and their outcomes.

PMID- 12605278
TI  - Malignancy in giant cell tumor.
AB  - Malignant giant cell tumor is a confusing term that in the past has been used to
      describe different types of giant cell-rich tumors. We try to clarify this term
      in this report. We consider two types of malignancy in giant cell tumor of bone:
      "primary" when it arises in juxtaposition to a benign giant cell tumor and
      'secondary' when it arises at the site of a previously treated giant cell tumor.
      Here we present a case of primary malignancy in giant cell tumor that was
      initially not recognized as a malignancy. On radiography and histology of frozen
      sections the lesion had the appearance of a conventional giant cell tumor of
      bone. After curettage, the permanent histology slides showed areas of highly
      malignant osteosarcoma juxtaposed to areas of benign giant cell tumor. The
      patient was treated with chemotherapy and wide resection of the tumor.

PMID- 12605280
TI  - Giant cell reparative granuloma of the occipital bone.
AB  - Giant cell reparative granuloma (GCRG) is a non-neoplastic fibrous lesion with
      unevenly distributed multinucleated giant cells, areas of osseous metaplasia and
      hemorrhage. The small bones of the hands and feet are the most common sites,
      followed by the vertebral bodies and craniofacial bones. In the craniofacial
      bones GCRG has been reported in the temporal bone, in the frontal bone and
      paranasal sinus. However, to the best of our knowledge no case has been reported
      in the occipital bone. We report on the imaging findings and pathological
      features of a GCRG of the occipital bone and discuss the differential diagnosis
      of this entity in this particular location, especially with giant cell tumor
      because of the therapeutic and prognostic implications.

PMID- 12605281
TI  - Intracortical chondromyxoid fibroma of humerus.
AB  - The clinicoradiologic and pathologic aspects of an intracortical, diaphyseal
      chondromyxoid fibroma of the humerus are reported. Because of the location of the
      lesion, the possibility of chondromyxoid fibroma was not considered
      radiologically. The diagnosis was made only after histologic examination of
      tissue obtained via an open biopsy, which led to the appropriate treatment,
      surgical curettage.

PMID- 12605282
TI  - Low-grade osteosarcoma of the maxillary sinus.
AB  - Low-grade osteosarcomas of the paranasal sinus are extremely rare. Most reported
      cases of maxillary sinus osteosarcoma are high-grade. We present a 51-year-old
      man with a low-grade osteosarcoma which was histologically difficult to diagnose
      in isolation since it had bland features. The presence of an aggressive
      destructive lesion on imaging influenced the final pathological diagnosis as
      often appears to be the case with this rare tumor. We briefly discuss paranasal
      sinus osteosarcomas.

PMID- 12605283
TI  - A low-grade extraskeletal osteosarcoma.
AB  - The case of a 35-year-old woman with low-grade extraskeletal osteosarcoma of the
      left leg is presented. Radiographs showed peripheral ossification of the lesion,
      suggesting myositis ossificans. Most of the tumor was composed of cartilage, and
      the cellularity and cell atypia of the proliferating chondrocytes were mild to
      moderate. In the periphery, bone formation with a relatively clear margin and
      proliferation of spindle cells with minimal nuclear atypia were observed. The
      average percentage of cells positive for MIB-1 was 9.0%. A diagnosis of low-grade
      extraskeletal osteosarcoma was made on the basis of these histologic findings.
      The clinical course 47 months after a wide excision was uneventful.

PMID- 12605284
TI  - Fibromyxoma of the iliac wing.
AB  - Myxoma/fibromyxoma of extragnathic bone is a rare, benign tumor. We report the
      case of a 19-year-old man with a myxoma/fibromyxoma of the pelvic bone, who
      presented with abdominal pain in the right lower quadrant. Radiographs
      demonstrated a tumor with central scattered calcifications and ossification in
      the left ilium. CT scans disclosed a solitary ellipsoid tumor with sclerotic
      borders and no evidence of cortical disruption. MRI showed homogeneous signal
      enhancement of the bone marrow with slight thinning of the medial iliac cortex.
      Final diagnosis by radiological characteristics was not conclusive and
      histopathological examination suggested the diagnosis of a myxoma/fibromyxoma.

PMID- 12605285
TI  - Leiomyosarcoma of the popliteal vein.
AB  - Primary vascular leiomyosarcomas are rare tumors arising from the media of vessel
      walls, involving the extremities in about one third of reported cases, and the
      popliteal vein even less frequently. We report a case of popliteal vein
      leiomyosarcoma in a 62-year old man who presented with leg pain and edema 4 weeks
      following spine surgery. Findings on ultrasound, MRI and CT angiography are
      reviewed, with particular emphasis on the value of CT angiography in fully
      evaluating the extent of the mass and in assisting percutaneous biopsy.

PMID- 12605286
TI  - MRI of mycetoma of the foot: two cases demonstrating the dot-in-circle sign.
AB  - Radiological and histological findings of two patients with fungal mycetoma of
      the foot are presented. MRI revealed multiple 2-5 mm lesions of high signal
      intensity interspersed within a low-intensity matrix. Within many of the lesions
      a minute low-intensity focus was identified. Ultrasound showed distinct
      hyperechoic foci within a hypoechoic mass. We speculate that the low-signal
      matrix represents fibrous tissue, the high-intensity lesions correspond to
      granulomata and the central low-signal focus to the characteristic organised
      fungal elements (grains) present in this condition. This "dot-in-circle sign" on
      MRI reflects the unique pathological features of mycetoma and is likely to be a
      highly specific sign for this lesion.

PMID- 12605288
TI  - A preliminary investigation into the relationship between anabolic-androgenic
      steroid use and the symptoms of reverse anorexia in both current and ex-users.
AB  - RATIONALE: To establish whether the symptoms of reverse anorexia continue with
      the cessation of anabolic-androgenic steroid (AAS) use in male body builders.
      OBJECTIVE: To determine whether current and ex-AAS-using body builders score
      higher on the modified (for reverse anorexia) eating disorders inventory (EDI)
      than both non-AAS-using body builders and regular aerobic exercisers. METHODS: A
      random sample of regular aerobic exercisers, current, ex-, and non-AAS-using body
      builders were recruited from four local gyms and a syringe exchange in the
      Merseyside area. A total of 137 male subjects with an average age of 29 years
      (range 17-49 years) were recruited. Fifty subjects were classed as aerobic
      exercisers, 39 subjects were classed as non-AAS-using body builders, 29 subjects
      were current AAS users and 19 subjects were ex-AAS users. All subjects undertook
      an anonymous questionnaire consisting of the modified EDI, the severity of
      dependence scale (SDS) for both exercising and AAS use, and questions about body
      weight, dieting, and substance use. RESULTS: AAS-using bodybuilders were striving
      towards an exaggerated mesomorphic physique. Both current and ex-AAS users had
      higher scores on all sections of the EDI than both groups of non-AAS users. There
      was a significant positive correlation between the SDS scores for AAS and scores
      on the EDI for current AAS users. CONCLUSIONS: AAS use, but not body building per
      se, was associated with increased symptoms of reverse anorexia, and this
      symptomatology was higher in those who had higher scores on the SDS for AAS. It
      remains to be determined whether symptoms of reverse anorexia are either a cause
      or an effect of AAS use.

PMID- 12605287
TI  - Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is
      modulated by, but not dependent on, adrenal hormones.
AB  - RATIONALE: AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to
      improve memory in both animals and humans. In animals, adrenal hormones modulate
      the efficacy of many memory-enhancing compounds, including piracetam and tacrine
      (Cognex). OBJECTIVE: To investigate the role of adrenal hormones in the memory
      enhancing action of AIT-082. METHODS: Plasma levels of adrenal hormones
      (corticosterone and aldosterone) in mice were significantly reduced by surgical
      or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral
      administration of corticosterone. The effects of these hormone level
      manipulations on the memory-enhancing activity of AIT-082 and piracetam were
      evaluated using a cycloheximide-induced amnesia/passive avoidance model. RESULTS:
      As previously reported by others, the memory enhancing action of piracetam was
      abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT
      082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP)
      that did not improve memory in control animals did improve memory in
      adrenalectomized animals. These data suggested that, similar to piracetam and
      tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels
      of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the
      action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the
      activity of AIT-082. CONCLUSIONS: These data suggest that while AIT-082 function
      is not dependent on adrenal hormones, it is modulated by them. That memory
      enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may
      have positive implications for its clinical utility, given that many Alzheimer's
      disease patients have elevated plasma cortisol levels.

PMID- 12605290
TI  - Sporotomaculum syntrophicum sp. nov., a novel anaerobic, syntrophic benzoate
      degrading bacterium isolated from methanogenic sludge treating wastewater from
      terephthalate manufacturing.
AB  - An anaerobic, mesophilic, syntrophic benzoate-degrading bacterium, designated
      strain FB(T), was isolated from methanogenic sludge which had been used to treat
      wastewater from the manufacture of terephthalic acid. Cells were non-motile gram
      positive rods that formed spores. The optimum temperature for growth was 35-40
      degrees C, and the optimum pH was 7.0-7.2. A co-culture with the hydrogenotrophic
      methanogen Methanospirillum hungatei converted benzoate to acetate, carbon
      dioxide, and methane. Butyrate transiently accumulated at a high concentration of
      2.5 mM during degradation. Besides benzoate, no other compound tested supported
      growth of the co-culture. Crotonate supported growth of strain FB(T) in pure
      culture. Furthermore, the strain degraded benzoate in pure culture with crotonate
      as co-substrate to produce acetate and butyrate. The strain was not able to
      utilize sulfate, sulfite, thiosulfate, nitrate, fumarate, or Fe(III) as electron
      acceptor. The G+C content of the DNA was 46.8 mol%. Strain FB(T) contained MK-7
      as the major quinone and C(16:1) as the major fatty acid. 16S rDNA sequence
      analysis revealed that the strain was a member of the genus Sporotomaculum, even
      though it exhibited significant differences, such as the capacity for syntrophic
      growth, to the known member of the genus. Hence, we propose the name
      Sporotomaculum syntrophicum sp. nov. for strain FB(T). The type strain is strain
      FB(T) (DSM 14795, JCM 11475).

PMID- 12605291
TI  - Biodegradation of bis(1-chloro-2-propyl) ether via initial ether scission and
      subsequent dehalogenation by Rhodococcus sp. strain DTB.
AB  - Rhodococcus sp. strain DTB (DSM 44534) grows on bis(1-chloro-2-propyl) ether
      (DDE) as sole source of carbon and energy. The non-chlorinated diisopropyl ether
      and bis(1-hydroxy-2-propyl) ether, however, did not serve as substrates. In ether
      degradation experiments with dense cell suspensions, 1-chloro-2-propanol and
      chloroacetone were formed, which indicated that scission of the ether bond is the
      first step while dehalogenation of the chlorinated C(3)-compounds occurs at a
      later stage of the degradation pathway. Inhibition of ether scission by
      methimazole suggested that the first step in degradation is catalyzed by a flavin
      dependent enzyme activity. The non-chlorinated compounds 1,2-propanediol,
      hydroxyacetone, lactate, pyruvate, 1-propanol, propanal, and propionate also
      supported growth, which suggested that the intermediates 1,2-propanediol and
      hydroxyacetone are converted to pyruvate or to propionate, which can be channeled
      into the citric acid cycle by a number of routes. Total release of chloride and
      growth-yield experiments with DDE and non-chlorinated C(3)-compounds suggested
      complete biodegradation of the chlorinated ether.

PMID- 12605289
TI  - Contrasting effects of citalopram and reboxetine on waking salivary cortisol.
AB  - RATIONALE: Acute administration of antidepressants which potentiate serotonin (5
      HT) and noradrenaline (NA) function stimulates the hypothalamic-pituitary-adrenal
      (HPA) axis and increases salivary free cortisol in healthy subjects. The effects
      of repeated antidepressant administration have been less studied, but the ability
      of such treatment to modulate HPA axis activity may be relevant to therapeutic
      effects. OBJECTIVE: The objective of the study was to assess the effect of short
      term treatment with two different antidepressant medications on HPA axis
      activity. METHODS: We studied the effect of 6-day treatment with the selective
      serotonin re-uptake inhibitor (SSRI) citalopram (20 mg daily) and the selective
      noradrenaline re-uptake inhibitor, reboxetine (8 mg daily), on diurnal salivary
      cortisol in a parallel group, placebo-controlled, double-blind design. RESULTS:
      Citalopram significantly enhanced the increase in salivary cortisol produced by
      waking, while the effect of reboxetine treatment was indistinguishable from
      placebo. There was no change in basal salivary cortisol levels sampled in a
      standard pattern throughout the day. CONCLUSIONS: Short-term treatment with
      citalopram and reboxetine produced strikingly different effects on waking
      salivary cortisol, arguing against a common effect of antidepressant drugs on HPA
      axis function. Waking salivary cortisol may be a more reliable means of assessing
      the effects of antidepressant treatment on the HPA axis than a standard regime of
      basal salivary sampling.

PMID- 12605292
TI  - Characterization and phylogenetic analysis of a thermostable N-carbamoyl- l-amino
      acid amidohydrolase from Bacillus kaustophilus CCRC11223.
AB  - A thermostable N-carbamoyl- l-amino acid amidohydrolase ( l-N-carbamoylase) gene
      composed of an 1,230-bp ORF encoding a 44.3-kDa protein was cloned from the
      thermophile Bacillus kaustophilus CCRC11223. This l-N-carbamoylase contained six
      cysteine residues that form three disulfide bridges. The purified l-N
      carbamoylase was stringently l-specific and exhibited high activity in the
      hydrolysis of N-carbamoyl- l-homophenylalanine. N-carbamoyl derivatives of beta
      alanine, beta-aminoisobutyric acids, l-tryptophan, and d-specific amino acids
      were not recognized as substrates. The l-N-carbamoylase required the divalent
      metal ions Mn(2+), Co(2+), and Ni(2+) for increasing activity. The pH and
      temperature optima of the enzyme were pH 7.4 and 70 degrees C, respectively. This
      enzyme was completely thermostable at 50 degrees C for 36 days in the presence of
      d- and/or l-specific substrates. Phylogenetic analysis of the available amino
      acid sequences of N-carbamoyl and N-acyl amino acid amidohydrolases from the
      three main kingdoms of life showed that they can be divided into four distinct
      families. The B. kaustophilus enzyme could be classified into the family of l-N
      carbamoylases and some beta-ureidopropionases, but did not hydrolyze beta
      ureidopropionates.

PMID- 12605293
TI  - Chloroplast movement: dissection of events downstream of photo- and mechano
      perception.
AB  - The study of chloroplast photorelocation movement is progressing rapidly now that
      mutants for chloroplast movement have become available in Arabidopsis thaliana.
      However, mechanistic approaches in cell biology still stand to elucidate the
      mechanisms and regulations of such movement. The fern Adiantum capillus-veneris
      and the moss Physcomitrella patens are particularly suitable materials for
      analyzing the kinetics of intracellular chloroplast movement. In these plants,
      chloroplast movement is induced by red light as well as blue light, mediated by
      phytochrome and blue light receptor, respectively. In this paper, we review the
      unique force-generating system for chloroplast motility in P. patens. In addition
      to light-induced chloroplast movement, we also summarize mechanically induced
      chloroplast movement in these plants and the motility systems involved. Finally,
      the different dependency of mechano- and photo-relocation movement on external
      Ca(2+) is discussed.

PMID- 12605294
TI  - Time-course of programmed cell death during leaf senescence in Eucommia ulmoides.
AB  - Leaves of Eucommia ulmoidesOliv. harvested between April to November were
      examined for programmed cell death (PCD) during growth and senescence. Leaves
      developed in April, becoming fully expanded in late May, remaining unchanged
      until November when they started to dehisce. Falling leaves retained a green
      color. Our results showed that (1) mesophyll cells gradually reduced their nuclei
      from September to November, (2) positive TUNEL signals appeared on the nuclei
      from August, (3) ladder-like DNA fragmentation occurred in September and October,
      and (4) a 20-kDa Ca(2+)-dependent DNase appeared in these same months. In fallen
      leaves, intact mesophyll cell nuclei could not be detected, but a few cells
      around the vascular bundle had nuclei. Therefore, (1) programmed cell death (PCD)
      of leaf cells occurred in the leaves of E. ulmoides, (2) the progress of
      mesophyll cell PCD lasted for more than 2 months, and (3) PCD of leaf cells was
      asynchronous in natural senescing leaves.

PMID- 12605295
TI  - Stem diameter changes before bud opening in Zelkova serrata saplings.
AB  - It is well known that stems of woody plants shrink and swell diurnally. These
      fluctuations of stem diameter are induced mainly by the changes of water contents
      in plants, which are caused by the combination of leaf transpiration and root
      absorption of water. This implies that dormant-like deciduous broadleaved trees
      in a leafless state should show no or less changes in stem diameter. However,
      some physiological activities in woody plants are also known to precede their
      winter bud opening. Whether and how diameter changes occur in deciduous tree
      stems during winter was investigated using Zelkova serrata saplings in a leafless
      state. Measurements of stem diameter changes were done for more than 4 months
      continuously. The saplings showed distinct diameter changes with periodicities
      from diurnal to a few weeks, and these changes were initiated 2 months before
      winter bud opening. These results indicate that some physiological and/or
      developmental activities occur in the stem of deciduous trees before winter bud
      opening, and do not correspond to changes in water relations as a result of leaf
      transpiration. These internal activities cause fluctuations in stem diameter
      prior to winter bud opening in deciduous trees.

PMID- 12605296
TI  - Notes on the pollination biology of Notylia nemorosa (Orchidaceae): do
      pollinators necessarily promote cross pollination?
AB  - The pollination biology of Notylia nemorosa was elucidated from field and ex situ
      observations. Field observations were carried out in Minas Gerais, southeastern
      Brazil, where this orchid is pollinated by males of Eulaema nigrita(Euglossini).
      Plants cultivated in Campinas (Sao Paulo State, southeastern Brazil) were
      eventually pollinated by males of Eulaema nigrita and Euglossa
      melanothricha(Euglossini). In both cases, Euglossini males collect aromatic
      compounds produced on the surface of the lip, fix the pollinaria on the dorsal
      surface of the labrum and perform pollination. This species is protandrous.
      Recently opened flowers present their stigmatic surfaces blocked and thus flowers
      act only as pollen donors. After 2-3 days the viscidium dries out and pollinaria
      cannot be removed anymore. Then, a narrow slit opens in the stigmatic cavity,
      allowing pollen deposition. Experiments performed with cultivated plants suggest
      that this orchid species is strongly, though not completely self-incompatible.
      Pollination experiments showed that bees tend to stay several minutes in each
      inflorescence. This behavior may promote some degree of geitonogamous pollination
      because flowers in male and female phases coexist in the same inflorescence. The
      combination of self-incompatibility with this specific pollinator behavior may
      explain the rarity of fruits in several neotropical reward-offering Orchidaceae.

PMID- 12605297
TI  - Epidermal and hypodermal characteristics in North American Cactoideae
      (Cactaceae).
AB  - Dermal and hypodermal anatomical features of 70 species representing 21 genera of
      North American Cactoideae were studied. Results show that all species examined
      have parallelocytic stomata and anticlinal wall surface varies from straight to
      undulate. Cuticle thickness is mostly narrow (1-10 microm) contrary to the
      general opinion that cuticle is thick in most cacti; however, few species such as
      Ariocarpus fissuratus and several species of Pachycereus show a distinctive thick
      cuticle. More than 80% of the species studied have a single-layered epidermis.
      Papillae occur in eight species belonging to four genera. Notable papillae are a
      feature shared by all members of Peniocereus subg. Peniocereus. Other species
      show a bullate surface produced by irregular patches of secondary epidermal cell
      divisions. Commonly, the hypodermis is composed of more than two cell layers with
      distinctive collenchymatous walls as reported in many South American species.
      Silica bodies, prismatic crystals, druses, sphaerocrystals, and tannins are the
      most common cellular inclusions that distinguish several genera and appear to
      have taxonomic value. However, a more thorough search in species of
      Cephalocereus, Coryphantha, Echinocereus, Mammillaria, Neobuxbaumia,
      Pilosocereus, and Turbinicarpus is needed to support the previous assertion.

PMID- 12605299
TI  - Karyotypes of metaphase chromosomes in diploid populations of Dendranthema
      zawadskii and related species (Asteraceae) from Korea: diversity and evolutionary
      implications.
AB  - Although the Dendranthema zawadskii complex has been known to comprise a series
      of polyploids (4x, 6x, 8x), we found diploid individuals (with 2 n=18) to occur
      in four populations of D. zawadskii var. latilobum in the southern region of
      Korea. Karyotypes of metaphase chromosomes were diverse because numbers of
      metacentric, submetacentric, and acrocentric chromosomes differ even within a
      population. A total of 17 karyotypes were found in 31 diploid individuals
      collected from the four populations. The karyotypes were also diverse in the
      presence or absence of chromosomes with a secondary constriction on a short or
      long arm and, if present, in the number of such chromosomes. They were further
      diverse in the presence or absence of non-homologous chromosome(s), the presence
      or absence of a chromosome with a satellite, and, if present, how many and where
      satellites are present. Almost the same pattern of diversity was found in diploid
      individuals (with 2 n=18) of D. boreale and D. indicum as well, irrespective of
      whether they occur together with D. zawadskii var. latilobum or not. Structural
      features of chromosomes in the variously different karyotypes suggest that
      reciprocal translocation and the hybridization between individuals with different
      karyotypes had repeatedly occurred not only in D. zawadskii var. latilobum, but
      also in D. boreale and D. indicum. Morphologically intermediate individuals
      between D. zawadskii var. latilobum and D. indicum suggests that the
      hybridization occur with different species as well.

PMID- 12605298
TI  - Lipid composition of mangrove and its relevance to salt tolerance.
AB  - Lipid compositions of mangrove trees were studied in relation to the salt
      tolerance mechanism. Leaves and roots were obtained from seven mature mangrove
      trees on Iriomote Island, Okinawa: Bruguiera gymnorrhiza, Rhizophora stylosa,
      Kandelia candel, Lumnitzera racemosa, Avicennia marina, Pemphis acidula and
      Sonneratia alba. Lipids of mangrove leaves mainly consisted of 11 lipid classes:
      polar lipids, unknown (UK) 1-6, sterols, triacyl glycerols, wax ester and sterol
      ester (UK 3 and 4 were found to be tri-terpenoid alcohol in this study). Of these
      lipid classes, sterol ester was the main lipid in all species comprising 17.6
      33.7% of total lipids. Analysis of the chemical structure found that the sterol
      esters mainly consisted of fatty acid esters of tri-terpenoid alcohols. One major
      tri-terpenoid alcohol was identified to be lupeol by interpretation of infrared
      resonance, nuclear magnetic resonance and mass spectrometry. Because of the
      unique anatomy of the mangrove root, lipid analyses were made separately for
      epidermis, cortex and innermost stele, respectively. The concentration of free
      tri-terpenoid alcohols showed a higher tendency in the outside part than in the
      inside portion of the roots, suggesting their protective roles. Relevance of
      lipid composition to salt tolerance was studied with propagules of K. candel and
      B. gymnorrhiza planted with varied salt concentrations. The proportions of free
      tri-terpenoids increased with salinity in both leaves and roots of K. candel, and
      only in roots of B. gymnorrhiza. No salt-dependent changes were noted in the
      phospholipid and fatty acid compositions in both species. These findings
      suggested that salt stress specifically modulated the terpenoid concentrations in
      mangroves.

PMID- 12605300
TI  - Stages in development of Selaginella diffusa megaspores.
AB  - In mature megaspores of Selaginella diffusa (C. Presl) Spring the units of the
      exospore are ordered and become unordered toward the outer and inner surfaces.
      The exospore surface is coated with silica at maturity. The insertion of the
      future gap begins in early stages with formation of many minigaps within the
      inner part of the exospore distally. The mesospore, like the exospore, is
      resistant to the acetolysis reaction and can, thus, provisionally be considered
      to consist of sporopollenin. Unit structures within the outer part of the
      mesospore are unordered, but become ordered in the middle and inner parts. The
      inner surface of the mesospore appears verrucate. In maturing megaspores, the
      mesospore is mostly disintegrated and the inner exospore, which encapsulated the
      mesospore, remains as a somewhat isolated structure, and is again near the outer
      exospore. There are connecting strands across the gap between the inner surface
      of the outer exospore and the surface of the inner exospore. There are also
      spheres on the outer surface of the inner exospore.

PMID- 12605301
TI  - Photosynthetic limitations of a halophyte sea aster (Aster tripolium L) under
      water stress and NaCl stress.
AB  - To understand the mechanisms of salt tolerance in a halophyte, sea aster ( Aster
      tripolium L.), we studied the changes of water relation and the factors of
      photosynthetic limitation under water stress and 300 mM NaCl stress. The contents
      of Na(+) and Cl(-) were highest in NaCl-stressed leaves. Leaf osmotic potentials
      ( Psi(s)) were decreased by both stress treatments, whereas leaf turgor pressure
      ( Psi(t)) was maintained under NaCl stress. Decrease in Psi(s) without any loss
      of Psi(t) accounted for osmotic adjustment using Na(+) and Cl(-) accumulated
      under NaCl stress. Stress treatments affected photosynthesis, and stomatal
      limitation was higher under water stress than under NaCl stress. Additionally,
      maximum CO(2) fixation rate and O(2) evolution rate decreased only under water
      stress, indicating irreversible damage to photosynthetic systems, mainly by
      dehydration. Water stress severely affected the water relation and photosynthetic
      capacity. On the other hand, turgid leaves under NaCl stress have dehydration
      tolerance due to maintenance of Psi(t) and photosynthetic activity. These results
      show that sea aster might not suffer from tissue dehydration in highly salinized
      environments. We conclude that the adaptation of sea aster to salinity may be
      accomplished by osmotic adjustment using accumulated Na(+) and Cl(-), and that
      this plant has typical halophyte characteristics, but not drought tolerance.

PMID- 12605302
TI  - Characterization of the Selaginella remotifolia MADS-box gene.
AB  - Recent progress in plant molecular genetics has revealed that floral organ
      development is regulated by several homeotic selector genes, most of which belong
      to the MADS-box gene family. Here we report on SrMADS1,a MIKC(c)-type MADS-box
      gene from Selaginella, a spikemoss belonging to the lycophytes. SrMADS1
      phylogenetically forms a monophyletic clade with genes of the LAMB2 group, which
      are MIKC(c) genes of the clubmoss Lycopodium, and is expressed in whole
      sporophytic tissues except roots and rhizophores. Our results and the previous
      report on Lycopodium MIKC(c) genes suggest that the ancestral MIKC(c )gene of
      primitive dichotomous plants in the early Devonian was involved in the
      development of basic sporophytic tissues such as shoot, stem, and sporangium.

PMID- 12605304
TI  - Tumour-inhibiting platinum complexes--state of the art and future perspectives.
AB  - Thirty years after the onset of the first clinical studies with cisplatin, the
      development of antineoplastic platinum drugs continues to be a productive field
      of research. This article reviews the current preclinical and clinical status,
      including a discussion of the molecular basis for the activity of the parent drug
      cisplatin and platinum drugs of the second and third generation, in particular
      their interaction with DNA. Further emphasis is laid on the development of third
      generation platinum drugs with activity in cisplatin-resistant tumours,
      particularly on chelates containing 1,2-diaminocyclohexane (DACH) and on the
      promising and more recently evolving field of non-classic ( trans- and
      multinuclear) platinum complexes. The development of oral platinum drugs and drug
      targeting strategies using liposomes, polymers or low-molecular-weight carriers
      in order to improve the therapeutic index of platinum chemotherapy are also
      covered.

PMID- 12605303
TI  - The phototropin family as photoreceptors for blue light-induced chloroplast
      relocation.
AB  - Blue light-induced chloroplast accumulation and avoidance relocation movements
      are controlled by the blue light photoreceptor phototropin. The Arabidopsis
      thaliana genome has two phototropin genes encoding phot1 and phot2. Each of these
      photoreceptors contains two LOV (light oxygen and voltage) domains and a kinase
      domain. The LOV domains absorb blue light though an associated flavin
      mononucleotide chromophore, while the kinase domain is thought to be associated
      with signal transduction. The phototropins control not only chloroplast
      relocation movement, but also blue light-induced phototropic responses, leaf
      expansion and stomatal opening. Here I review the role of phototropin as a
      photoreceptor for chloroplast photorelocation movement.

PMID- 12605305
TI  - Signal recognition particle-dependent protein targeting, universal to all
      kingdoms of life.
AB  - The signal recognition particle (SRP) and its membrane-bound receptor represent a
      ubiquitous protein-targeting device utilized by organisms as different as
      bacteria and humans, archaea and plants. The unifying concept of SRP-dependent
      protein targeting is that SRP binds to signal sequences of newly synthesized
      proteins as they emerge from the ribosome. In eukaryotes this interaction arrests
      or retards translation elongation until SRP targets the ribosome-nascent chain
      complexes via the SRP receptor to the translocation channel. Such channels are
      present in the endoplasmic reticulum of eukaryotic cells, the thylakoids of
      chloroplasts, or the plasma membrane of prokaryotes. The minimal functional unit
      of SRP consists of a signal sequence-recognizing protein and a small RNA. The as
      yet most complex version is the mammalian SRP whose RNA, together with six
      proteinaceous subunits, undergo an intricate assembly process. The preferential
      substrates of SRP possess especially hydrophobic signal sequences. Interactions
      between SRP and its receptor, the ribosome, the signal sequence, and the target
      membrane are regulated by GTP hydrolysis. SRP-dependent protein targeting in
      bacteria and chloroplasts slightly deviate from the canonical mechanism found in
      eukaryotes. Pro- and eukaryotic cells harbour regulatory mechanisms to prevent a
      malfunction of the SRP pathway.

PMID- 12605306
TI  - Transport of organic anions across the basolateral membrane of proximal tubule
      cells.
AB  - Renal proximal tubules secrete diverse organic anions (OA) including widely
      prescribed anionic drugs. Here, we review the molecular properties of cloned
      transporters involved in uptake of OA from blood into proximal tubule cells and
      provide extensive lists of substrates handled by these transport systems. Where
      tested, transporters have been immunolocalized to the basolateral cell membrane.
      The sulfate anion transporter 1 (sat-1) cloned from human, rat and mouse,
      transported oxalate and sulfate. Drugs found earlier to interact with sulfate
      transport in vivo have not yet been tested with sat-1. The Na(+)-dicarboxylate
      cotransporter 3 (NaDC-3) was cloned from human, rat, mouse and flounder, and
      transported three Na(+) with one divalent di- or tricarboxylate, such as citric
      acid cycle intermediates and the heavy metal chelator 2,3-dimercaptosuccinate
      (succimer). The organic anion transporter 1 (OAT1) cloned from several species
      was shown to exchange extracellular OA against intracellular alpha-ketoglutarate.
      OAT1 translocated, e.g., anti-inflammatory drugs, antiviral drugs, beta-lactam
      antibiotics, loop diuretics, ochratoxin A, and p-aminohippurate. Several OA,
      including probenecid, inhibited OAT1. Human, rat and mouse OAT2 transported
      selected anti-inflammatory and antiviral drugs, methotrexate, ochratoxin A, and,
      with high affinities, prostaglandins E(2) and F(2alpha). OAT3 cloned from human,
      rat and mouse showed a substrate specificity overlapping with that of OAT1. In
      addition, OAT3 interacted with sulfated steroid hormones such as estrone-3
      sulfate. The driving forces for OAT2 and OAT3, the relative contributions of all
      OA transporters to, and the impact of transporter regulation by protein kinases
      on renal drug excretion in vivo must be determined in future experiments.

PMID- 12605307
TI  - Molecular basis of skeletal muscle plasticity--from gene to form and function.
AB  - Skeletal muscle shows an enormous plasticity to adapt to stimuli such as
      contractile activity (endurance exercise, electrical stimulation, denervation),
      loading conditions (resistance training, microgravity), substrate supply
      (nutritional interventions) or environmental factors (hypoxia). The presented
      data show that adaptive structural events occur in both muscle fibres
      (myofibrils, mitochondria) and associated structures (motoneurons and
      capillaries). Functional adaptations appear to involve alterations in regulatory
      mechanisms (neuronal, endocrine and intracellular signalling), contractile
      properties and metabolic capacities. With the appropriate molecular techniques it
      has been demonstrated over the past 10 years that rapid changes in skeletal
      muscle mRNA expression occur with exercise in human and rodent species. Recently,
      gene expression profiling analysis has demonstrated that transcriptional
      adaptations in skeletal muscle due to changes in loading involve a broad range of
      genes and that mRNA changes often run parallel for genes in the same functional
      categories. These changes can be matched to the structural/functional adaptations
      known to occur with corresponding stimuli. Several signalling pathways involving
      cytoplasmic protein kinases and nuclear-encoded transcription factors are
      recognized as potential master regulators that transduce physiological stress
      into transcriptional adaptations of batteries of metabolic and contractile genes.
      Nuclear reprogramming is recognized as an important event in muscle plasticity
      and may be related to the adaptations in the myosin type, protein turnover, and
      the cytoplasma-to-myonucleus ratio. The accessibility of muscle tissue to
      biopsies in conjunction with the advent of high-throughput gene expression
      analysis technology points to skeletal muscle plasticity as a particularly useful
      paradigm for studying gene regulatory phenomena in humans.

PMID- 12605308
TI  - Fibromyalgia: a challenge for modern medicine.

PMID- 12605309
TI  - BCG immunisation and the 'Trojan horse' phenomenon of vaccination.

PMID- 12605310
TI  - Fibromyalgia, a virtual disease.

PMID- 12605311
TI  - Lack of relationships between cumulative methylprednisolone dose and bone mineral
      density in healthy men and postmenopausal women with chronic low back pain.
AB  - The medical use of glucocorticoids (GCs) is related to low bone mineral density
      (BMD). In this study we tested the hypothesis that the cumulative dose of GC is
      not related to BMD outcome. The study was cross-sectional in design and included
      healthy individuals with chronic low back pain resistant to conventional
      treatments. In two steroid-naive subjects cortisol and methylprednisolone (MP)
      concentrations were serially assessed after a single MP depot injection (160 mg
      epidurally). Furthermore, in 14 men and 14 postmenopausal women, previously
      treated with multiple epidural MP depots, endocrine parameters were analysed in
      relation to BMD outcomes. The minimal cumulative MP dose received by all 28
      subjects was 3 g. In the two steroid-naive subjects, cortisol concentrations were
      completely suppressed for at least 6 days and partly recovered over the course of
      30 days. During this period, MP concentrations remained detectable in plasma. In
      the 28 subjects, the cumulative MP dose received was 7.76+/-4.23 g in the men and
      8.50+/-3.13 g in the women (mean+/-1SD). None of the men had osteoporosis, but
      osteopenia was prevalent in 78.5% according to WHO criteria extrapolated to men.
      Half of the women had osteoporosis and half of them had osteopenia. The body mass
      index (BMI) and endogenous oestradiol levels of the men were not related to BMD
      outcomes. Univariate linear relationships in women were found between BMI and
      spinal ( r 0.62; P=0.02) and total hip BMD ( r 0.61; P=0.03), but not femoral
      neck BMD. In women, relationships were also found between the total and, for
      protein binding-corrected oestradiol levels, and spinal BMD ( r 0.70; P=0.01 and
      r 0.72; P=0.01, respectively) and total hip BMD ( r 0.53; P=0.08 and r 0.56;
      P=0.05, respectively). No significance was observed between endogenous oestradiol
      levels and the BMD of the femoral neck. The administration of a single MP depot
      injection (160 mg) resembled a systemic low peak dose GC exposure. The
      administration of multiple MP depots in men and women with chronic low back pain
      revealed no relationship between cumulative GC dose and BMD. These findings
      support the hypothesis of a non-existent relationship between cumulative GC dose
      and BMD outcomes in healthy men and women with a prior GC administration of at
      least 3 g.

PMID- 12605312
TI  - The reliability and validity of the Turkish version of Quality of Life
      Questionnaire of the European Foundation for Osteoporosis (QUALEFFO).
AB  - The purpose of this study was to investigate the reliability and validity of the
      Turkish version of Quality of Life Questionnaire of the European Foundation for
      Osteoporosis (QUALEFFO). The patient group included 43 females aged between 55
      and 78 years with vertebral fractures due to osteoporosis. The control group
      consisted of 43 healthy female volunteers whose ages matched those of the
      patients. All of the participants were evaluated using both QUALEFFO and SF-36.
      In the reliability studies, internal consistency within the domain of QUALEFFO
      was generally good, with Cronbach's alpha values ranging between 0.70 and 0.96.
      Convergent and discriminant validity rates of domains were both found to be
      between 89% and 100%. Significant correlations existed between scores of similar
      domains of QUALEFFO and the SF-36, especially for pain, physical function, social
      function and general health perception. The receiver operating characteristic
      (ROC) curve analysis of QUALEFFO and the SF-36 indicated that all five domains in
      each questionnaire were significantly predictive of vertebral fractures. However,
      when comparing similar domains of the two questionnaires, the social function
      domain of QUALEFFO demonstrated a significantly better performance. In
      conclusion, the Turkish version of QUALEFFO was found to be reliable and valid in
      the evaluation of patients with vertebral fractures due to osteoporosis. Our
      study also suggests that the patients with vertebral fractures due to
      osteoporosis have impairment in quality of life.

PMID- 12605313
TI  - Analysis of risk factors and comorbid diseases in the development of thrombosis
      in patients with anticardiolipin antibodies.
AB  - Our objective was to identify the role of various disease states and additional
      risk factors in the development of thrombosis in patients with anticardiolipin
      antibodies (aCL). We undertook a retrospective chart review of patients with aCL
      (IgG or IgM titres > 20 GPL or 20 MPL by ELISA). Patients with a thrombotic event
      were compared to patients without thrombosis for potential risk factors: age,
      gender, ethnicity, hypertension (HTN), diabetes (DM), hyperlipidaemia, tobacco
      use and sequential aCL determinations. The role of systemic lupus erythematosus
      (SLE), human immunodeficiency virus (HIV), hepatitis C and renal disease was also
      analysed. Statistical analysis was performed using the t-test, the chi(2) test
      and multivariate analysis. Of the 107 patients who had moderately positive aCL
      (IgM and/or IgG), 53 had a thrombotic event. The patients with thrombosis were
      significantly older than patients without thrombosis (mean age 46.6 vs. 38.75
      years, respectively, P=0.014). No significant differences in gender, race, HTN,
      DM, hyperlipidaemia, tobacco use or concomitant diseases were identified in the
      two groups. Thrombosis was more frequent in patients who were seropositive for
      both IgG and IgM ( P=0.027). Thrombosis was observed in equal frequencies in
      patients with aCL on both determinations and in patients with aCL on only one of
      the two determinations. In patients with aCL on two determinations a high-titre
      IgG aCL was associated with thrombosis. Patients with renal disease and aCL on
      only one of the two determinations had fewer thrombotic events ( P=0.0046). Mean
      aCL IgM titres were higher in thrombosis groups containing venous thromboses than
      in the thrombosis group with arterial thrombosis only. We concluded that risk
      factors for thrombosis with a single aCL determination include older age and both
      IgM and IgG aCL. With persistent aCL, high-titre IgG aCL was associated with
      thrombosis.

PMID- 12605315
TI  - Antibodies to ubiquitin in relation to Yersinia infection status in patients with
      ankylosing spondylitis.
AB  - The aim of this study was to investigate IgG and IgM antibodies to ubiquitin in
      relation to Yersinia enterocolitica infection status in patients with AS. Twenty
      eight AS patients (M:F 24:4, mean age 43.9 yrs, range 22-70 yrs, mean disease
      duration 15.9 yrs) and 35 healthy controls (M:F 31:4, mean age 52.1 yrs, range 22
      80 yrs) were included. The levels of antibodies to ubiquitin and Yersinia O:3 and
      O:9 antigens were measured using specific ELISA. The results were expressed as
      optical density (OD) ratio. Antibody levels were assumed increased when the OD
      ratio was higher than mean OD ratio + 3SD in the control group. IgM antibodies to
      ubiquitin were found in five patients and one control ( P < 0.05, Fisher's exact
      test). Anti-ubiquitin antibodies of IgG class were found in two cases, one AS
      patient and one control (NS). IgG antibodies to Yersinia serotypes O:3 and O:9
      were present in eight and five AS patients, respectively ( P < 0.001 and P < 0.05
      vs. controls, Fisher's exact test). No IgM antibodies to Yersinia were found.
      High levels of IgG antibodies to Y. enterocolitica serotype O:3 were found in
      three out of five patients with high levels of IgM antibodies to ubiquitin,
      compared with five out of 23 patients with low levels of anti-ubiquitin
      antibodies ( P=0.1231, NS). Antibodies to Yersinia serotype O:9 were found in
      three out of five patients with IgM antibodies to ubiquitin, compared to two out
      of 23 patients with low serum levels of IgM antibodies to ubiquitin ( P < 0.05).
      The results suggest that Y. enterocolitica infection may induce antibodies to
      ubiquitin in a subset of patients with AS. This may be explained by the
      involvement of a newly discovered ubiquitin-dependent mechanism related to Y.
      enterocolitica virulence.

PMID- 12605314
TI  - Lack of association of Human T-cell lymphotrophic virus type 1(HTLV-1) infection
      and rheumatoid arthritis in an endemic area.
AB  - In South Africa the association of HTLV-1 infection with myelopathy is well
      described in Kwa Zulu Natal, which is an endemic area for HTLV-1 infection. Japan
      also has a high background prevalence of HTLV-1 infection, and a significant
      association of HTLV-1 infection with rheumatoid arthritis has been reported. This
      study was undertaken to determine whether there was an association with HTLV-1
      infection among black Africans with rheumatoid arthritis (RA) in Kwa Zulu Natal,
      South Africa. A randomly selected group of 110 black people with RA were studied.
      The age, sex and duration of disease were recorded and a rheumatoid factor test
      was performed. The presence of antibodies to HTLV-1 was assessed using an enzyme
      linked immunosorbent assay. The integration of proviral DNA in peripheral blood
      monocytes was also studied using the polymerase chain reaction (PCR). Control
      data were available from a previously reported community-based study of 1018
      subjects from the same geographical area. None of the 110 patients studied were
      positive for HTLV-1 infection by serology or by PCR. Although HTLV-1 infection is
      reported as a possible triggering agent for RA in Japan, we failed to detect any
      excess of HTLV-1 infection in black Africans with RA. Our findings are in
      agreement with observations in the USA and Europe.

PMID- 12605316
TI  - Elevated circulating soluble CD40 ligand in patients with mixed connective tissue
      disease.
AB  - Abnormalities of CD40 ligand have been demonstrated in various kinds of diseases.
      Our objective was to determine serum soluble CD40 ligand (sCD40L) levels in
      patients with mixed connective tissue disease (MCTD). Serum sCD40L levels of 23
      patients with MCTD and 21 healthy individuals were measured with specific enzyme
      linked immunosorbent assays. Serum levels of sCD40L were significantly higher in
      patients with MCTD than in healthy individuals (median 0.179 ng/ml vs 0.99 ng/ml,
      25th-75th percentile; 0.117-0.296 ng/ml vs 0.82-1.70 ng/ml, P<0.005), whereas
      there were no significant correlation between elevated serum sCD40L levels and
      clinical or serological features in patients with MCTD. These results suggest
      that sCD40L plays a role in the pathogenesis of MCTD. Further studies are needed
      to clarify this.

PMID- 12605317
TI  - Reduction of factor XII in antiphospholipid antibody-positive patients with
      thrombotic events in the rheumatology clinic.
AB  - Although rheumatological diagnosis often includes an assessment of
      antiphospholipid (aPL) antibodies, the significance of other prothrombotic
      factors has not been established in thrombotic patients who are not afflicted
      with either arteriosclerosis or vasculitis syndrome. We have observed both the
      presence of antiphospholipid antibodies and a reduction of factor XII in such
      patients. Our results identified both lupus anticoagulant-positive (50%) and
      anticardiolipin antibody-positive (58%) patients. In addition, 83% of patients
      showed factor XII antigen level reduction. Furthermore, 70% of aPL-positive
      thrombotic patients showed factor XII antigen level reduction. Only two cases had
      antiphospholipid antibody alone, and 4/12 showed just factor XII antigen
      reduction. Recently, it has been reported that the presence of antiphospholipid
      antibodies induces factor XII reduction, and that anti-factor XII autoantibody
      can be detected in thrombotic patients. However, our results indicate that there
      are smaller factor XII reductions in non-thrombotic controls who are positive for
      antiphospholipid antibodies. Furthermore, anti-factor XII autoantibody was not
      detected in patients with decreased factor XII levels. Kindred research suggested
      that in two patients there was a genetic component to factor XII reduction. We
      concluded that the presence of both antiphospholipid antibodies and reduced serum
      factor XII was observed in most thrombotic patients from our rheumatology clinic.
      It is therefore possible to consider that the coexistence of these prothrombotic
      factors can contribute to the onset of thrombosis.

PMID- 12605318
TI  - A case of dermatomyositis complicated with pneumomediastinum successfully treated
      with cyclosporin A.
AB  - We describe a rare case of a 46-year-old Japanese man with dermatomyositis (DM)
      and interstitial lung disease who developed spontaneous pneumomediastinum and
      subcutaneous emphysema. Relatively mild myositis, mild elevation of CK values and
      the absence of anti-Jo-1 antibody were observed and the case was similar to
      amyopathic DM. Treatment of this patient with oral prednisolone and cyclosporin A
      (CsA) was effective for the myositis and interstitial lung disease. The
      administration of CsA enabled rapid tapering of the dose of prednisolone without
      aggravating the disease. Pneumomediastinum and subcutaneous emphysema disappeared
      5 months later without recurrence. The serum levels of KL-6 were monitored every
      2 weeks to help determine whether this may have contributed to the recurrence of
      interstitial pneumonitis. This is a rare case of pneumomediastinum in a patient
      with DM.

PMID- 12605319
TI  - Diffuse scleroderma occurring after the use of paclitaxel for ovarian cancer.
AB  - Acase of diffuse scleroderma in a 56-year-old woman who received paclitaxel for
      the treatment of a metastatic ovarian cancer is presented. The clinical cutaneous
      alterations, as well as the capillaroscopic and histological findings, were
      indistinguishable from those encountered in definite systemic sclerosis (SSc). In
      contrast to SSc, Raynaud's phenomenon and cutaneous calcinosis were absent and
      antinuclear antibodies were negative. The temporal relationship between the onset
      of skin involvement and administration of the drug may indicate an effect of
      paclitaxel.

PMID- 12605320
TI  - Silica-related rheumatoid arthritis without lung involvement.
AB  - We report a young male with recent onset of rheumatoid arthritis (RA) in whom the
      remarkable severity of the disease led to additional investigations. The only
      significant finding was mediastinal lymphadenopathy, without lung involvement.
      Biopsy of the mediastinal lymph node revealed pathological findings typical of
      silicosis. To our knowledge, this is the first report of silicosis apparent
      solely in the mediastinal lymph node of an RA patient. This suggests that lung
      involvement is not crucial for the development of silica-related arthritis.

PMID- 12605321
TI  - Anti-TNF-alpha-induced systemic lupus syndrome.
AB  - Anti-TNF-alpha therapies are promising new strategies in the treatment of
      rheumatoid arthritis (RA). Despite good clinical efficacy and tolerance, the
      possible occurrence of drug-induced autoimmune disorders remains a matter of
      concern. Induction of antinuclear (ANA) and anti-DNA antibodies is observed in
      some patients treated with TNF-alpha inhibitors (anti- TNF-alpha antibodies) or
      soluble TNF-alpha receptor. Of concern is the possibility of induction of true
      lupus erythematosus by TNF blockers. Few cases without major organ involvement
      were reported to be associated with infliximab treatment that resolved after anti
      TNF discontinuation. Only four cases have been described with the use of
      etanercept. We report a new case of infliximab-induced lupus syndrome and two new
      cases of etanercept-induced lupus syndrome in three patients with RA, all of whom
      had previous isolated positive ANA.

PMID- 12605322
TI  - Transient panhypogammaglobulinaemia and B-lymphocyte deficiency in a patient with
      neuropsychiatric systemic lupus erythematosus after immunosuppressive therapy.
AB  - Panhypogammaglobulinaemia is a rare complication of systemic lupus erythematosus
      (SLE), but its cause and mechanism are unclear. We observed transient
      panhypogammaglobulinaemia in a patient with neuropsychiatric SLE after treatment
      with prednisolone and cyclophosphamide. After the patient developed recurrent
      infections, laboratory findings disclosed panhypogammaglobulinaemia with B
      lymphocyte deficiency. The serum immunoglobulin level returned to the normal
      range after the prednisolone was tapered off. Because lupus patients are
      susceptible to infections associated with disease exacerbation or
      immunosuppressive treatment, recurrent infections might be expected during the
      disease course without need for further evaluation of the immunodeficiency.
      However, this reversible, probably drug-induced case of hypogammaglobulinaemia
      highlights the need for immunoglobulin measurements when immunodeficiency is
      suspected in lupus patients.

PMID- 12605323
TI  - Association of spondylarthropathies with lumbar synovial cysts.
AB  - Intraspinal synovial cysts presenting with lower back pain and radiculopathy are
      well known but rare. They are associated with facet joint arthopathy, generally
      degenerative in nature. Spinal synovial cysts have not been described in
      spondyloarthropathies (SpA). We report a case of a 66-year-old man with a chronic
      undifferentiated SpA who presented with severe weakness of both legs. A centrally
      located spinal cyst was encountered on MRI and led to excision of a highly
      inflammatory synovial cyst. This association may not be fortuitous and be related
      to inflammation of the facet joint in SpA.

PMID- 12605324
TI  - Antitopoisomerase I antibody in patients with systemic lupus erythematosus/sicca
      syndrome without a concomitant scleroderma: two case reports.
AB  - We describe two female patients with classic systemic lupus erythematosus (SLE)
      and secondary sicca syndrome associated with topoisomerase I (topo-I, Scl-70)
      antibody, a specific marker for scleroderma (SSc), which is rarely found in other
      collagen diseases. During the course of the disease, the sera of these two
      patients were repeatedly found to be positive for topo-I antibody following a
      positive screening by ANA-EIA. Neither patient had clinical evidence of
      scleroderma. One patient remains well nearly 4 years from the first positive
      serological test. The progression to sicca syndrome in that patient occurred 2
      years after having tested positive for antitopo-I antibody. Her frozen serum also
      tested positive for anti-Scl-70 by the Western blot technique. The other patient,
      however, died after developing renal and cardiopulmonary complications of lupus,
      including Libman Sachs endocarditis and pulmonary hypertension. Contrary to the
      previous patient, the onset of sicca syndrome in this case had preceded the
      expression of positive antitopo-I antibody. The present cases and other similar
      previously reported ones are therefore unique in the sense of being a serological
      challenge to the high specificity of antitopo-I to scleroderma. In addition, they
      may also represent a new subset of SLE with or without sicca syndrome, which is
      characterised by the absence of features of scleroderma despite the presence of
      antitopo-I antibody.

PMID- 12605325
TI  - Long-term remission from gout associated with fenofibrate therapy.
AB  - Short-term studies with fenofibrate, an established treatment for
      hyperlipidaemia, have shown that its unique side effect of urate lowering is
      mediated through enhanced renal urate clearance. The long-term effects of
      fenofibrate on hyperuricaemia and gout have not previously been reported. We
      report two patients with hyperlipidaemia in association with hyperuricaemia in
      whom long-term fenofibrate therapy was associated with a sustained reduction in
      serum urate and lipid levels, together with remission from recurrent attacks of
      acute gout. The mechanisms involved in these effects and the potential role for
      fenofibrate in the management of gout are discussed.

PMID- 12605327
TI  - [Long-term results after uni- and bilateral high tibial osteotomies].
AB  - AIM: This study compares the long-term results of uni- and bilateral high tibial
      osteotomies. METHOD: 94 osteotomies (72 patients) were followed for 12.7 +/- 2.4
      years after osteotomy. Long-term results of 21 patients with bilateral
      osteotomies (42 osteotomies) were compared with 52 patients who had a unilateral
      high tibial osteotomy. Endpoint of survival, was defined as implantation of a
      knee endoprosthesis (Kaplan-Meier analysis). At follow-up clinical results were
      evaluated by the knee society score and X-rays were analysed for axis and grade
      of arthrosis. RESULTS: Out of 94 high tibial osteotomies 22 (23 %) ended 1 - 13
      years later in a knee endoprosthesis. In 11 of the 42 bilateral high tibial
      osteotomies (26 %; after 2 - 13 years, median 8 years) and 11 of 52 (21 %; after
      1 - 11 years, median 8 years) unilateral osteotomies an endoprosthesis was
      implanted. Kaplan-Meier analysis resulted in no statistical difference in
      survival between the two groups (p = 0.6517). Additionally, clinical and
      radiological results were equal. CONCLUSIONS: We conclude that there is no long
      term difference between uni- and bilateral high tibial osteotomies and both
      indications can be recommended due their satisfactory long-term results.

PMID- 12605326
TI  - [Quality of life five years after total or partial knee arthroplasty].
AB  - AIM: Multiple aspects of health-related quality of life were assessed in elderly
      patients after total or partial knee arthroplasty. METHOD: 187 subjects who had
      undergone knee arthroplasty 5 years ago were asked to fill out 3 questionnaires,
      the Nottingham Health Profile, the SF-36 Health Survey and the
      Funktionsfragebogen Hannover. Results were compared to standard data. The impact
      of gender and age was analyzed, and 3 different types of prostheses were
      compared. RESULTS: Response rate was 74 % (n = 138). Regarding the main symptoms
      pain and subjective function, as well as almost all other aspects, quality of
      life proved to be significantly reduced compared to the age-matched general
      population. Correlations between age and quality of life scales were low.
      Different types of implants led to similar results in all scales but one.
      CONCLUSION: 5 years after knee arthroplasty the quality of life is markedly
      reduced compared to the general population. The impact of age, gender, and type
      of implant is low. In our sample, the SF-36 showed methodological advantages
      compared to the NHP for the measurement of subjective pain and function.

PMID- 12605328
TI  - [Analysis of two different techniques of osteosynthesis in high tibial
      osteotomy].
AB  - AIM: High tibial osteotomy is an accepted method for varus osteoarthritis. This
      study intended to compare the technique of plate osteosynthesis with the
      technique of staple osteosynthesis, as a less invasive procedure. METHOD: 61
      patients (65 knees) were included in this retrospective study evaluating the HSS
      score, patient's satisfaction, non weight bearing period, radiological stage of
      osteoarthritis, bone healing and complications after a follow up period of 5.7 (5
      - 9) years. 26 patients (27 knees) were treated with plates and 37 patients (38
      knees) with staples after osteotomy. RESULTS: Patients treated with plates showed
      62.2 % excellent and good, 27.8 % moderate and poor results in the HSS score,
      77.8 % were very satisfied and satisfied, 22.2 % less or not satisfied. Patients
      who received staple osteosynthesis showed 80.8% excellent and good, 19.2 %
      moderate and poor results in the HSS score and were very satisfied and satisfied
      in 86.9 %, less and nor satisfied in 13.1 %. The periods of non weight bearing
      and bone healing were slightly longer for patients treated with staples. There
      was no significant difference in complications. CONCLUSION: The data of the
      present study suggest that staples as a less invasive osteosynthesis after high
      tibial osteotomy seem to be justified compared to plate osteosynthesis having no
      significant difference in clinical results.

PMID- 12605329
TI  - [Ten year follow-up after single incision anterior cruciate ligament
      reconstruction using patellar tendon autograft].
AB  - AIM: We evaluated 74 patients 10 years after arthroscopically assisted ACL
      reconstruction using the central third of the patellar tendon as autograft.
      METHOD: IKDC, Tegner and Lysholm scores were used for clinical evaluation.
      Ligament stability was tested using the Rolimeter instrument. For statistics we
      used the Chi square test. RESULTS: At follow-up the Tegner activity level was
      5.2, the Lysholm score was 93.6 points. Subjective assessment for function was
      rated normal or nearly normal in 83.7 %, for stability in 71.6 %. The side-to
      side difference measured with the Rolimeter was normal in 87.8% and nearly normal
      in 12.2 %. Pivot shift was proven to be negative in 94.6 %. 29.7 % of patients
      showed degenerative changes in X-rays at follow-up. There was a significant
      correlation between time interval from injury to surgery and the grade of
      degenerative changes. Arthrosis significantly correlates with the rate of
      meniscus injury. Acute operative treatment increases the rate of arthrofibrosis
      significantly. CONCLUSION: To avoid osteoarthrosis we recommend an early
      (subacute) ACL reconstruction and meniscus refixation in the case of meniscus
      injury.

PMID- 12605330
TI  - [5-year follow-up study of total knee arthroplasty by means of EMG mapping].
AB  - AIM: The objective of the present study was to evaluate the long-term functional
      results after implantation of a total knee arthroplasty (TKA) objectively and
      quantitatively. METHOD: Functional parameters (muscular coordination, strength
      and range of motion) and the subjective satisfaction of the patients were
      measured by means of EMG mapping, isokinetics, ultrasound and a questionnaire in
      21 patients with TKA 5.1 years after implantation of the TKA. RESULTS: 81 % of
      the investigated patients were subjectively satisfied. The isokinetic results
      showed a significant improvement of the extensor strength and of the relation
      between flexors and extensors. Patients who had been more physically active over
      these 5 years reached significantly better results. The results of EMG mapping
      showed good overall retention of the satisfactory coordination levels resulting
      from the initial in-patient rehabilitation. But the coordination patterns
      demonstrated clear changes showing highly activated areas in the region of the M.
      vastus medialis. The range of motion and the contraction capacity showed no
      further improvement compared with the results 26 weeks after implantation of the
      TKA. CONCLUSION: Long-term results after implantation of a TKA showed a good
      muscular coordination, strength and range of motion. A higher physical activity
      level led to better functional results and greater overall satisfaction of TKA
      patients 5 years after implantation.

PMID- 12605331
TI  - [Treatment of foot deformities in patients with Duchenne muscular dystrophy].
AB  - AIM: There are different approaches to treat foot deformities in Duchenne
      muscular dystrophy. Some authors recommend conservative, others only surgical
      means. The purpose of this study was to compare the outcome of both non-surgical
      and surgical treatment. METHOD: The records of 91 boys with DMD were
      retrospectively evaluated. The three treatment groups studied included group 1,
      those who had no surgery, group 2, those who had surgery to correct foot
      position, and group 3, those who had surgery to maintain ambulation and correct
      foot position. RESULTS: Although conservative treatment of the feet in group 1
      was carried out, severe equinovarus deformities developed. Surgery for the foot
      deformity including posterior tibial transfer was successful in 94 % at mean 8.5
      years post-operative follow-up. The mean age of cessation of ambulation for those
      who had surgery to maintain ambulation was 11.2 years versus 10.3 years of those
      who did not have surgery (p < 0.05). CONCLUSION: In patients with DMD, lower
      extremity surgery including posterior tibial tendon transfer can successfully
      correct and maintain foot position, as well as prolong ambulation. Early surgical
      treatment is required since conservative means can not prevent progression to
      severe equinovarus deformities.

PMID- 12605332
TI  - [One- or two-step instrumentation for thoracolumbar scoliosis due to
      myelomeningocele?].
AB  - AIM: This investigation evaluates patients with MMC who underwent a two-stage
      anterior-posterior correction and stabilisation of thoracolumbar scoliosis due to
      myelomeningocele. The data were compared with the few reported series of one
      stage versus two-stage surgery in the literature. METHOD: From 1.7.1992 to
      30.6.1995, 11 consecutive patients with severe thoracolumbar scoliosis due to
      myelomenigocele were admitted at our hospital. The mean age at operation was 12
      years nine months (range nine years nine to 14 years six months). All patients
      underwent a two-stage anterior and posterior spinal instrumentation. The patients
      were pre- and postoperatively evaluated. RESULTS: All patients were followed for
      a mean of 4 years 11 months (range 42 months to 88 months) from the time of the
      second stage procedure. Preoperatively the mean scoliosis angle was 82 degrees
      (range 55 degrees to 110 degrees ), this was reduced to a mean of 31 degrees
      (range 8 degrees - 70 degrees ), at final follow-up, the correction had
      deteriorated slightly to a mean of 35 degrees (range 12 degrees - 80 degrees ).
      No patient had increased neurological deficit or showed other major
      complications, i. e., infection, sepsis due to immunologic disorders at the time
      of the operation. CONCLUSION: We believe that with the two-stage anterior and
      posterior instrumentation an effective correction of the scoliosis can be
      achieved. Compared to other studies this report confirms the low morbidity rate
      and emphasise the good results of a two staged procedure.

PMID- 12605334
TI  - [Biomechanical study on lumbar spondylodeses using an internal fixateur
      consisting of a titanium alloy].
AB  - OBJECTIVE: Biomechanical properties of an internal fixateur manufactured of a
      titanium alloy (Ti-6Al-4V-alloy) to be evaluated in an in vitro setting. METHOD:
      Internal fixateurs were inserted into six (four female and two male specimens)
      human lumar spine segments L2 to L4. Only dorsal instrumentations were performed.
      Physiological loads were applied (2.0 to 10.0 Nm for torque, 2.0 to 7.5 Nm for
      extension/flexion and lateral bending). Biomechanical investigations were
      performed in four settings: Intact specimen without instrumentation, instrumented
      specimen, instrumented specimen after corpectomy of the middle vertebral body,
      instrumented specimen after corpectomy of the middle vertebral body with an
      additional transverse connector. RESULTS: Stability after instrumentation was
      increased by 84.7 % for flexion/extension, by 78.2 % for lateral bending and by
      43 % for axial torsion. Axial torsion was already less distinct in the
      physiological specimen. The stability of instrumented specimen after corpectomy
      was superior to that of intact vertebral segments without internal fixation.
      Additional application of transverse connectors did not significantly enhance the
      stiffness of the implant. CONCLUSION: For the clinical use there is no difference
      in the biomechanical properties of the titanium fixateur compared to similar
      constructions made of stainless steel. The possibility of performing MRI- or CT
      scans after implantation of titanium implants is a main clinical advantage. The
      stabilisation after corpectomy is remarkable, so that a sufficient fracture
      stabilisation is possible. Based on the data, the application of transverse
      connectors cannot be recommended.

PMID- 12605333
TI  - [Selective ventral derotation spondylodesis in idiopathic thoracic scoliosis: a
      prospective study].
AB  - AIM: Radiometric curve analysis of instrumented primary and spontaneous secondary
      curve correction after anterior correction and fusion of idiopathic thoracic
      scoliosis. METHOD: Sixty-four patients with idiopathic thoracic scoliosis were
      prospectively evaluated. All patients were operated either with the Zielke-VDS or
      with a primary stable double rod instrumentation with selective fusion of the
      thoracic curve from end-to end-vertebra. Follow-up averaged 29 months (24 - 52
      months). RESULTS: The Cobb angle of the primary curve averaged 63.2 degrees
      preoperatively and was corrected to 21.4 degrees postoperatively with an average
      loss of correction of 5.3 degrees (58 % final curve correction). Apical thoracic
      vertebral rotation was corrected by 48 %. The secondary lumbar curve measured
      38.2 degrees preoperatively (72 % correction on the bending films) and was
      spontaneously corrected by 57 % to 16.4 degrees without significant loss of
      correction in the final follow-up. Apical vertebral rotation averaged 11.3
      degrees in the lumbar curve and was corrected spontaneously by 24 % to 8.6
      degrees without significant loss of correction. Lumbar apex vertebra deviation
      showed no significant reduction. There was no case of lumbar curve decompensation
      in either frontal or sagittal plane. Implant related complications were observed
      in 7 patients (rod breakage), but no pseudarthrosis occurred. There were no
      neurological complications noted. CONCLUSION: Selective anterior correction and
      fusion in idiopathic thoracic scoliosis enables a satisfactory correction of both
      primary and lumbar secondary curves. The advantage of selective anterior
      correction and fusion of thoracic scoliosis is the short fusion length, better
      derotation and satisfactory correction of the secondary lumbar curve. The
      disadvantages of single threaded rod techniques in terms of lack of primary
      stability and a kyphogenic effect have been eliminated by the development of a
      primary stable, small size double rod instrumentation.

PMID- 12605335
TI  - [First experience of intraoperative nerve root monitoring with the INS-1-device
      on the lumbosacral spine].
AB  - AIM: The goal of intraoperative nerve root monitoring on the lumbosacral spine is
      to minimize the risk of nerve root injuries during surgery by reducing the
      incidence of misplaced pedicle screws. In this study we hypothesized that the INS
      1 device (Nuvasive) may provide more accurate information about screw placement.
      METHOD: The INS-1 device provides a means for intraoperative EMG stimulation
      through the inside of the pedicles or the implanted screws. The readings from
      relevant muscles serve as a monitoring technique to detect perforated pedicles
      and thus can be used to prevent or detect misplaced pedicle screws and reduce the
      risk of nerve root injuries. We controlled 58 patients with 334 implanted pedicle
      screws. RESULTS: Our first experience with 334 pedicle screws shows that nerve
      root injuries can be avoided by reducing the number of misplaced pedicle screws
      through additional intraoperative information gained by the INS-1 device. Thus we
      corrected 3.9 % of screws intraoperatively in cases without relevant information
      from fluoroscopic control. CONCLUSION: The INS-1 device is a helpful tool to
      obtain additional information on misplaced pedicle drill holes or already
      implanted screws in the lumbosacral spine.

PMID- 12605336
TI  - [Comparative analysis of lumbar spine degeneration documented by x-rays versus
      large specimen cryomicrotome sections].
AB  - AIM OF THE STUDY: The extent of degenerative changes in the lumbar spine as seen
      on conventional radiographs is interpreted on the basis of visualized osseus
      structures and indirect signs such as diminution of disc height. In order to
      analyze the accuracy of these interpretations we compared and correlated
      different stages of degeneration in conventional radiographs with cuts of large
      specimen cryomicrotome sections (LSCS), offering a direct macroscopic vision of
      the degenerative anatomic features. METHOD: A total of 50 human cadaver lumbar
      spines with 251 spine segments (Th 12 - S1) was investigated by plain radiograms
      and LSCS. The degenerative changes were differentiated into 5 stages for both
      diagnostic measures. Criteria for radiological degeneration were: diminution of
      disc space, presence of osteophytes and sclerosis of the endplates. Degenerative
      changes as seen by LSCS were evaluated by the following features: cracks in the
      endplate, bleeding into the intervertebral disc, alignment of the annulus
      fibrosus fibres and osseous alterations in the spine segment. RESULTS: Complete
      matches of the evaluated radiological and macroscopic stages of degeneration were
      observed in 206 cases. A difference of 1 degree on the degeneration scale was
      registered in 42 segments, whereas a difference of 2 degrees was seen in 3 cases.
      The correlation coefficient between the degeneration stages of the two diagnostic
      measures scored rho = 0.883. CONCLUSION: The comparison of the different degrees
      of degeneration in the lumbar spine as evaluated by both plain radiographs and
      LSCS revealed a good correlation.

PMID- 12605338
TI  - [Cement delivery depends on cement gun performance and cement viscosity].
AB  - AIM: Retrograde cement application is considered an integral part of the modern
      femoral cementing technique. Both pressurisation and rapid cement application
      reduce the risk of interface bleeding and blood laminations. In this context
      cement gun performance has received little attention. METHOD: In our study we
      examined the handling characteristics of four different cement delivery systems
      (Syringe, Vaku-Mix, Optivac and MixOR-System). To allow for cement viscosity as
      another variable, six different bone cements (Palacos R, Palamed G, CMW 1
      Radiopak, CMW 2000, Simplex P, VersaBond) were used with each system. We recorded
      cement gun performance and measured extrusion times and maximum cement delivery
      speeds of all possible combinations (gun/mixing system plus cement type).
      RESULTS: The fastest cement application could be achieved with the Vaku-Mix
      cement delivery system and the corresponding cement gun (Mark III). With regard
      to cement type, VersaBond and prechilled Palacos yielded significantly shorter
      extrusion times than most of the other cements due to their lower viscosities.
      CONCLUSION: Our results have shown significantly different efficacies of commonly
      used cement delivery systems/guns in clinical routine. Improved systems should be
      provided by the suppliers.

PMID- 12605339
TI  - [Computer-assisted navigated cup placement in primary and secondary dysplastic
      hips].
AB  - AIM: The positioning of an acetabular implant has great influence on the range of
      motion as well as the charger of dislocation of total hip arthroplasty. Using
      modern CAS systems the reproduction of the cup position after three-dimensional
      planning based on computed tomography is possible. We investigated the
      reliability of the position of the acetabular implant in primary and secondary
      dysplastic cases. METHOD: Within a prospective randomised study in a total of 100
      hip replacements with postoperatively controlled cup position using a computed
      tomography, we reinvestigated especially the 18 dysplastic and two secondary
      dysplastic cases. RESULTS: In the dysplastic cases we could realise nearly the
      same anteversion angles (22.4 degrees to 21.5 degrees) with a bigger standard
      deviation (+/- 7.68 degrees to +/- 7.29) than in the normal collective. Even the
      inclination angles (44.5 degrees +/- 5.47 degrees) could be realized nearly the
      same as in the normal cases (42.3 degrees +/- 4.31 degrees). The depth of the cup
      implantation could be realised in 15 of 18 cases. CONCLUSION: The CAS system is
      helpful even in dysplastic cases. The advantage of three-dimensional preoperative
      CT-based planning is apparent. The surgeon is not able to plan and realise the
      ideal cup position in some individual.

PMID- 12605341
TI  - Successful twins - separated and reunited: German Societies for Endocrinology and
      Diabetology Join.

PMID- 12605337
TI  - [Correction of deformities with conventional and hexapod frames--comparison of
      methods].
AB  - AIM: Distraction osteogenesis for the correction of deformities with an external
      fixator is well established. The hexapod principle of robotic technique was
      invented for the Ilisarov apparatus (e. g. Taylor-Spatial-Frame/TSF). Treatment
      with conventional frames needs a patient-customised frame mounting. This
      demanding procedure is markedly reduced using this technology. The aim of this
      study was to analyse the value of the hexapod principle in external fixation.
      METHOD: The potential of a frame to correct deformities is limited by its work
      space. The geometry of a conventional frame is different from the geometry of a
      hexapod frame, which is the reason for their different work spaces. The work
      space of the hexapod frame is compared to the work space of a conventional frame.
      Important parameters for this analyses are minimal and maximal frame heights and
      the potential of correction. RESULTS: The minimal frame height of hexapod
      fixators is higher compared to conventional Ilisarov fixators. The standard
      hexapod frame (TSF 155 mm ring diameter) can correct 23 degrees of angulation, 36
      mm of shortening, 71 mm of translation and 43 degrees of rotation without
      changing the telescope rods. The standard conventional frame (160 mm ring
      diameter) can correct 90 degrees of angulation, 100 mm of shortening, 25 mm of
      translation and 12.5 degrees of rotation without remounting of the frame.
      CONCLUSION: The different work spaces of the different frames result in
      consequences for their clinical application. The hexapod frame has more power to
      correct translation and rotational deformities than a conventional frame.
      Correction of extensive angulation and shortening deformities almost always needs
      an exchange of telescopic rods. Conventional frames are usually able to correct
      these deformities with the primary mounting. Because of its increased minimal
      frame height, the indication for hexapod constructs in child orthopaedics can be
      limited.

PMID- 12605342
TI  - Leptin resistance - or why leptin fails to work in obesity.
AB  - In experimental models of obesity high serum concentrations of leptin without
      subsequent inhibition of food intake indicate a resistance to the physiological
      effects of leptin. Similar to the animal model leptin concentrations in most of
      the obese patients are higher compared to normal-weight persons. The postulated
      leptin resistance is one major target in the search for a better understanding of
      obesity and the development of pharmacological tools to treat this spreading
      disease.

PMID- 12605340
TI  - [Accuracy of fluoroscopically navigated drilling procedures at the hip].
AB  - AIM: Many orthopaedic procedures require an accurate drilling in bone. The
      outcome is frequently dependent on the geometric accuracy of this surgical step.
      The precision of such a procedure can be improved with the help of fluoroscopic
      navigation. Reliability, accuracy and benefit of this new method for the patient,
      as well as for the surgical staff, need to be analysed. METHOD: In a standardised
      in vitro trial, the drilling of a 5 mm spherical lesion implanted in an
      artificial femoral head was performed using a navigated drill-guide and a
      navigated drill. In groups A and B, the distance of the tip of the drill to the
      center of the lesion was analysed in a 3D CT-generated model and in macroscopic
      cross section. Additionally, in group B the actual direction of the drill canal
      was measured. RESULTS: The mean distance in group A was measured to be 1 mm, with
      all results ranging between 0 and 2.5 mm. In group B the planned direction of the
      canal was reproduced with a deviation of 0 degrees to 7 degrees, the target only
      being missed by a mean distance of 2.5 mm and a maximum of 3.5 mm. Compared to
      the macroscopic and 3D-CT findings, the correlation of the data calculated by the
      navigation system was accurate up to a difference of 4 degrees or 2 mm.
      CONCLUSION: The fluoroscopically assisted freehand navigation used during the
      drilling of bone led to a high accuracy of three-dimensional tip placement while
      reducing radiation exposure to a minimum. It represents a promising and efficient
      application for a variety of procedures in orthopaedic surgery.

PMID- 12605343
TI  - Aspirin and diabetes: inhibition of amylin aggregation by nonsteroidal anti
      inflammatory drugs.
AB  - Islet amyloid polypeptide (amylin), cosecreted with insulin by the pancreatic
      beta-cells, has an important role in the regulation of islet cell hormone
      homeoastasis. Deposition of beta-sheet polypeptide fibrils into amyloid deposits
      is considered to be central to the pathology of a number of amyloidogenic
      disorders, including type-2 diabetes. Amyloid deposits comprised of beta-sheet
      fibrillar amylin observed in type-2 diabetics are cytotoxic and may have a
      prominent role in causing beta-cell dysfunction. The amyloidogenic process may
      impair beta-cell function before cell death and replacement by amyloid.
      Preservation of beta-cell viability and insulin secretion is a major objective in
      diabetic care. Using circular dichroism and Congo red absorption techniques we
      found that clinically relevant doses of aspirin and other nonsteroidal anti
      inflammatory drugs (NSAIDS) prevented and also reversed the beta-sheet
      conformation of human amylin. The specific COX-2 inhibitors were less effective.
      The anti-inflammatory steroid prednisolone or the analgesic acetaminophen had no
      effect on amylin fibrillogenesis. This action of NSAIDS was similar to their
      inhibition of beta-sheet conformation of the Alzheimer protein, amyloid-beta.
      Aspirin, currently recommended for the prevention of cardiovascular complications
      in diabetic patients, may also ameliorate the disease process in diabetes by
      preserving the beta-cell function.

PMID- 12605344
TI  - Endothelial nitric oxide synthase (ecNOS) 4 a/b gene polymorphism and carotid
      artery intima-media thickness in type-1 diabetic patients.
AB  - AIM: To study putative associations of the ecNOS 4 a/b polymorphism with carotid
      artery intima-media thickness (IMT) and diabetic complications in young type-1
      diabetic patients. METHODS: Study participants were 147 type-1 diabetic patients
      (56 men and 91 women), mean age 30.1 +/- 6.6 years (range 14 - 44), with a
      diabetes duration of 13.1 +/- 8.1 years. HbA1c, albuminuria, and lipid status
      were assessed by standard laboratory techniques, the ecNOS 4 a/b genotype was
      determined by polymerase chain reaction with subsequent polyacrylamide gel
      electrophoresis. The patients were categorized according to the presence or
      absence of hypertension, nephropathy and retinopathy. The IMT, which can be used
      to estimate early stages of arteriosclerosis, was measured by high-resolution
      ultrasonography. RESULTS: The ecNOS genotypes were distributed as follows: 7.5 %
      a/a, 30.6 % a/b, and 61.9 % b/b. The IMT values did not differ between the
      patients with various ecNOS genotypes (a/a: 0.62 +/- 0.13; a/b: 0.63 +/- 0.21;
      b/b: 0.63 +/- 0.13; all: 0.63 +/- 0.15 mm). The prevalence of retinopathy was
      significantly higher in patients with the b/b genotype (odds ratio: 2.4 vs.
      a/a+a/b; 95 % CI, 1.1 - 5.3). CONCLUSIONS: Our results do not support the
      hypothesis that the ecNOS 4 a/b polymorphism interacts with the development of
      early carotid arteriosclerosis in young type-1 diabetic patients, but they give
      grounds to assume that in these patients it could influence the occurence of
      diabetic retinopathy.

PMID- 12605345
TI  - The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma
      cells.
AB  - HIV protease inhibitor treatment is associated with insulin resistance. We have
      recently demonstrated that the HIV protease inhibitor indinavir influences
      initial insulin signaling steps in HepG2 cells. Here we investigated in the same
      cell model whether indinavir alters insulin-stimulated glycogen synthesis. Since
      an altered phosphotyrosine phosphatase activity could represent a mechanism by
      which insulin signaling is influenced, we also assessed potential indinavir
      effects on protein tyrosine phosphatase activity directed against tyrosine
      phosphorylated insulin receptor substrate-1. HepG2 cells were incubated for 48 h
      without or with indinavir (100 micro mol/l). Subsequently, the insulin-stimulated
      incorporation of 14C-glucose into glycogen was measured. In indinavir-treated
      cells the insulin effect on glycogen synthesis was reduced by 30 +/- 4.5 %.
      Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor
      substrate-1 by the cell extracts was determined using a microwell plate-based
      method, and indinavir treatment did not alter this dephosphorylation. In
      conclusion, our data suggest that indinavir affects insulin-stimulation of
      glycogen synthesis in liver cells, and this may be related to the previously
      observed alterations in insulin signaling. Direct effects of indinavir on the
      GLUT4 transport system, that have been suggested from data in other cell systems,
      are unlikely in HepG2 cells that express no or almost no GLUT4 transport system.
      Finally, our data do not support the hypothesis that indinavir alters insulin
      signaling by influencing protein tyrosine phosphatase activity directed against
      insulin receptor substrate-1.

PMID- 12605346
TI  - Signaling of the human calcium-sensing receptor expressed in HEK293-cells is
      modulated by protein kinases A and C.
AB  - In this study, the human calcium-sensing receptor (CaR) stably expressed in
      HEK293 cells was investigated with regard to the phosphorylation-induced
      desensitization of its signaling pathway. The receptor is known to activate the
      phospholipase C/inositol-1,4,5-trisphosphate (IP 3 ) signaling cascade, thus
      stimulating protein kinase C (PKC). In contrast, the adenylylcyclase/cAMP
      signaling pathway that activates protein kinase A (PKA) is believed to be coupled
      to the receptor via an inhibitory G-protein. We elucidated the roles of PKC and
      PKA by measuring Ca 2+o -stimulated accumulation of total inositol phosphates and
      by individually and simultaneously inhibiting the two kinases pharmacologically
      in HEK293 cells, which stably expressed the human CaR. Pharmacological inhibition
      of PKC resulted in a 5-fold enhancement of IP 3 signaling, whereas blocking PKA
      had almost no effect. IP 3 signaling activity increased even more (10-fold)
      however, when the two kinases were inhibited simultaneously. Apart from
      validating the role of PKC as a potent down-regulator of signaling of the human
      CaR in this cell system, this study suggests that both kinases synergize in
      inhibiting Ca 2+o -stimulated IP 3 signaling in CaR-transfected HEK293 cells.

PMID- 12605347
TI  - Limited value of serum steroid measurements in identification of mild form of 21
      hydroxylase deficiency.
AB  - BACKGROUND: ACTH stimulation test is widely used as a basic diagnostic method for
      non-classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase
      deficiency (21-OHD). However, the interpretation of this test has not been
      definitely established. To determine the cut-off values of basal and post-ACTH
      serum 17-OHP concentrations, data of patients with suspected 21-OHD has been
      analysed. PATIENTS AND METHODS: Two hundred and eighty-seven patients with
      postnatal/peripubertal virilization were investigated. Serum steroid
      concentrations were measured by RIA, urinary steroid profile was determined by
      capillary gas chromatography and mutation analysis of CYP21 gene was performed by
      allele specific PCR. 21-OHD was diagnosed by elevated serum 17-OHP
      concentrations, high level of the urinary 17-OHP metabolites and/or homozygosity
      for CYP21 mutations. RESULTS: Twenty-one patients of the total of 287 subjects
      (7.3 %) were identified as having 21-OHD. The numbers of 21-OHD patients compared
      to total numbers of patients with different ranges of serum 17-OHP were as
      follows: basal values below 3.5 ng/ml (mean + 1 SD) 0/225; between 3.5 - 6.6
      ng/ml 3/41; above 6.6 ng/ml (mean + 2 SD) 18/21. Post-ACTH values below 6.4 ng/ml
      (mean + 1 SD) 0/226, between 6.4 - 10.3 ng/ml 0/35, above 10.3 ng/ml (mean + 2
      SD) 21/26. CONCLUSION: There are patients with inappropriate peripubertal
      virilization who have slightly elevated 17-OHP concentrations. In this subgroup
      of patients more sensitive and specific methods are needed to establish the
      diagnosis of 21-OHD. Therefore we suggest performing an ACTH stimulation test in
      patients with a morning 17-OHP level above 3.5 ng/ml. Furthermore, urinary
      steroid profile and/or CYP21 gene analysis are needed in patients with a
      stimulated 17-OHP value between 10 and 30 ng/ml. These tests will distinguish
      between patients with non-classical 21-OHD and patients with other disorders.

PMID- 12605348
TI  - Regulation of the VEGF-system in the endometrium during steroid-replacement and
      early pregnancy of pigs.
AB  - Vascular endothelial growth factor (VEGF) and its specific receptors FLT-1 and
      FLK-1 represent an important ligand-receptor system involved in angiogenesis and
      permeability. These factors are supposed to be influenced by ovarian steroids
      involved in developmental changes in female reproductive tissue as oviduct and
      uterus. The aims of this study were to assess the expression of VEGF and its
      receptor mRNAs during the early implantation period in porcine endometrium using
      real-time RT-PCR. Furthermore, effects of estradiolbenzoate (EB) and progesterone
      (P) on endometrium of ovariectomized (ovx) pigs were examined by RT-PCR and
      immunohistochemistry. A complete VEGF system was found in endometrial tissue
      using RT-PCR detecting the main VEGF isoform 188 aa, FLT-1 and FLK-1. A
      significant upregulation of the mRNAs of VEGF and its receptors was observed in
      the endometrium during the peri-implantation when compared with the pre
      implantation period. Regarding endometrium of non-pregnant ovx-pigs an
      application of P led to elevated transcript levels of VEGF whereas mRNA
      expression was reduced after EB treatment compared to non-treated ovx-animals.
      When pigs were administrated EB and P simultanously, a decrease in VEGF mRNA
      concentration was recorded. For FLT-1, none of the steroids increased mRNA
      expression compared to the ovx-group. Analysis of FLK-1 receptor mRNA
      demonstrated that only after EB + P treatment mRNA-expression was stimulated but
      stayed unchanged after P and EB when compared with the ovx-group.
      Immunohistochemistry revealed FLK-1 and VEGF proteins in glandular and luminal
      epithelia of the endometrium with emphasized staining after P and P + EB
      treatment of ovx-pigs. Summarized, altered VEGF and FLK-1 expression during the
      implantation period as well as under steroid hormones suggest this growth factor
      as a potent regulator of hyperpermeability supporting the angiogenic process in
      porcine endometrium.

PMID- 12605350
TI  - Dose-dependent stimulation of melatonin secretion after administration of Agnus
      castus.
AB  - The circadian rhythm of melatonin secretion was measured in 20 healthy males (20 
      32 yrs.) after intake of placebo or various doses of a special extract of Agnus
      castus (AC: 120 - 480 mg/die) for 14 days. A significant (p < 0.05) dose
      dependent increase of the area under the melatonin secretion curve (AUC) was
      found. The pattern of circadian rhythm of melatonin secretion was, however, not
      influenced. It remains to be elucidated whether the AC-stimulated increase of
      melatonin secretion is suitable for treatment of sleep disturbances.

PMID- 12605349
TI  - Unilateral adrenal tumor, erectile dysfunction and infertility in a patient with
      21-hydroxylase deficiency: effects of glucocorticoid treatment and surgery.
AB  - In untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency
      (21OHDS) the presence of adrenal and testicular tumors had been described;
      however little is known about the effect of the enzymatic defect on fertility in
      males. We studied a male adult patient affected by 21OHDS for infertility, after
      a long period of discontinuation of glucocorticoid therapy and then during
      resumption of treatment and 8 months after monoadrenalectomy. The initial
      spermatic count revealed azoospermia and testicular needle aspiration showed a
      cytological picture consistent with prepuberty. The morphofunctional study
      revealed a right adrenal mass with reduced uptake at radioscan. Treatment was
      resumed with onset of impotency, which improved after reduction of the dose of
      glucocorticoids. The patient was monoadrenalectomised and his spermatic count
      increased. The patient shows that corticosteroid therapy in 21OHDS should be
      continued lifelong to avoid adrenal hyperplasia with possible areas of autonomy
      and to allow regular fertility. Impotence during treatment is probably due to a
      decrease of excessive adrenal androgens while testicular androgen production is
      still suppressed.

PMID- 12605351
TI  - Statins can inhibit proliferation of human breast cancer cells in vitro.
AB  - The effect of five statins, i.e. atorvastatin, fluvastatin, lovastatin,
      pravastatin and simvastatin was investigated on the proliferation of the human
      breast cancer cell line MCF-7. All statins except of pravastatin were able to
      inhibit cell proliferation up to 90 % at a concentration of 50 micro M. Between
      the effective statins no significant difference was observed indicating a class
      specific effect. These data suggest that statins may have clinical significance
      in the primary prevention of human breast cancer beyond their cholesterol
      lowering effect. However, clinical proof must be awaited before drawing any
      further conclusions.

PMID- 12605352
TI  - Abnormal pentagastrin response in a patient with pseudohypoparathyroidism.

PMID- 12605354
TI  - Radiotracers for positron emission tomography imaging.
AB  - Over the past 30 years, advances in radiotracer chemistry and positron emission
      tomography instrumentation have merged to make positron emission tomography a
      powerful scientific tool in the biomedical sciences. However, despite the
      increasing reliance of the biomedical sciences on imaging and the new needs for
      functional information created by the sequencing of the human genome, the
      development of new radiotracers with the specificity and kinetic characteristics
      for quantitative analysis in vivo remains a slow process. In this article, we
      focus on advances in the development of the radiotracers involved in
      neurotransmission, amino acid transport, protein synthesis, and DNA synthesis. We
      conclude with a brief section on newer radiotracers that image other molecular
      targets and conclude with a summary of some of the scientific and infrastructure
      needs that would expedite the development and introduction of new radiotracers
      into biomedical research and the practice of medicine.

PMID- 12605353
TI  - Radiopharmaceuticals for single-photon emission computed tomography brain
      imaging.
AB  - In the past 10 years, significant progress on the development of new brain
      imaging agents for single-photon emission computed tomography has been made. Most
      of the new radiopharmaceuticals are designed to bind specific neurotransmitter
      receptor or transporter sites in the central nervous system. Most of the site
      specific brain radiopharmaceuticals are labeled with (123)I. Results from imaging
      of benzodiazepine (gamma-aminobutyric acid) receptors by [(123)I]iomazenil are
      useful in identifying epileptic seizure foci and changes of this receptor in
      psychiatric disorders. Imaging of dopamine D2/D3 receptors ([(123)I]iodobenzamide
      and [(123)I]epidepride) and transporters [(123)I]CIT (2-beta-carboxymethoxy-3
      beta(4-iodophenyl)tropane) and [(123)I]FP-beta-CIT (N-propyl-2-beta
      carboxymethoxy-3-beta(4-iodophenyl)-nortropane has proven to be a simple but
      powerful tool for differential diagnosis of Parkinson's and other
      neurodegenerative diseases. A (99m)Tc-labeled agent, [(99m)Tc]TRODAT (technetium,
      2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1]oct-2-yl]methyl](2
      mercaptoethyl)amino]ethyl]amino] ethanethiolato(3-)]oxo-[1R-(exo-exo)]-), for
      imaging dopamine transporters in the brain has been successfully applied in the
      diagnosis of Parkinson's disease. Despite the fact that (123)I
      radiopharmaceuticals have been widely used in Japan and in Europe, clinical
      application of (123)I-labeled brain radiopharmaceuticals in the United States is
      limited because of the difficulties in supplying such agents. Development of
      (99m)Tc agents will likely extend the application of site-specific brain
      radiopharmaceuticals for routine applications in aiding the diagnosis and
      monitoring treatments of various neurologic and psychiatric disorders.

PMID- 12605355
TI  - Developments in instrumentation for emission computed tomography.
AB  - Instrumentation for emission computed tomography continues to evolve, taking
      advantage of developments in detector technology, data processing and correction
      methods, and reconstruction algorithms. This article reviews the basic principles
      and latest developments in emission computed tomography instrumentation, for both
      positron emission tomography and single-photon emission computed tomography
      applications.

PMID- 12605356
TI  - Normal patterns and variants in single-photon emission computed tomography and
      positron emission tomography brain imaging.
AB  - One of the most important issues in evaluating functional brain scans for
      research or clinical purposes is to be able to identify normal variants.
      Determining the baseline "normal" state of the brain is not easy to characterize
      since many normal brain functions and mental processes affect brain activity.
      This article reviews issues pertaining to the technical and neurophysiological
      aspects of functional brain imaging that might alter "normal" activity and will
      also consider how normal brain activity changes throughout the lifespan.

PMID- 12605357
TI  - Neuroimaging in cerebrovascular disorders: measurement of cerebral physiology
      after stroke and assessment of stroke recovery.
AB  - Nuclear medicine imaging can play an important role in the diagnosis of stroke
      risk, the differential diagnosis of vascular and parenchymal cerebral
      abnormalities, and the understanding and management of poststroke recovery.
      Radionuclide brain-imaging methods can assess hemodynamic, vascular, and
      metabolic status before and after stroke. Several techniques, including
      vasodilatory stress imaging with regional cerebral blood flow (rCBF) single
      photon emission computed tomography (SPECT), oxygen extraction methods with
      positron emission tomography (PET), and spectroscopic imaging with magnetic
      resonance spectroscopic imaging, offer ways to distinguish vascular from
      parenchymal dysfunction and to determine whether any observed abnormalities in
      cerebral blood flow are primary or secondary disease manifestations. The value of
      radionuclide imaging in assessing the efficacy of several interventional surgical
      procedures is presented. Data from several imaging modalities bearing on the
      controversial issue of luxury perfusion and reperfusion injury are analyzed,
      including some of the discrepancies between animal and human clinical data.
      Imaging evidence for white matter disease and microangiopathy is analyzed,
      including a quantitative rCBF pattern analysis that distinguishes between typical
      Alzheimer's disease and microangiopathy by using multivariate analysis of
      variance curve profile analysis, which shows results of significant differences
      in the circumferential cortical blood flow profiles at P =.01. Microangiopathy
      showed rCBF reduction in the frontal and frontotemporal regions as compared with
      the more typical reduction in posterior temporal-parietal rCBF diminution
      characteristic of Alzheimer's disease. Several functional neuroimaging approaches
      to the study of cerebral poststroke reorganization are analyzed in the context of
      2 major models of recovery: the resolution of diaschisis and reorganization in
      spared brain. Research on these issues is presented with SPECT, PET, magnetic
      resonance imaging, and magnetic resonance spectroscopy. Data show how standard
      structural magnetic resonance imaging, (99m)Tc hexamethylpropylene amine oxime
      SPECT, PET imaging, and magnetic resonance spectroscopy can be used to identify
      the extent of permanent damage versus penumbral and remote effects of a stroke.
      The results of the analysis of the pure-diaschisis model show a high correlation
      between the rCBF brain SPECT defect volume in the cortex and the magnetic
      resonance spectroscopic imaging (MRSI) change in the white matter. There is a
      statistically significant positive correlation between the 2 (P <.01; r(2) =
      0.94). The increased creatine/N-acetyl aspartate and reduced rCBF are proposed to
      be due to an increase in the white matter creatine component due to diaschisis
      and the repair mechanisms associated with increased astrocytosis, in addition to
      a reduction of N-acetyl aspartate in diaschitic white matter. Xenon-133 dynamic
      SPECT is shown to be a quantitative and sensitive measure of cerebrovascular
      status and hemodynamic constraints in both spared and affected brain, providing
      evidence for reorganization and cerebral plasticity. Fluorine-18 PET and (31)P
      spectroscopic imaging data show reorganizational changes in the contralesional
      hemisphere after stroke. The phosphocreatine-adenosine triphosphate ratio in the
      contralesional hemisphere was 38% +/- 17% higher than in the ipsilateral
      hemisphere. The phosphocreatine-adenosine triphosphate ratio was highly
      correlated (r = 0.88, P <.05) with increasing (18)F-fluorodeoxyglucose uptake.
      These results showed that there is a parallel change in glucose metabolism and
      high-energy phosphate metabolism associated with poststroke recovery that is
      proposed to be due to cerebral reorganization in the contralateral premotor
      cortex. The value of these results on rehabilitation strategy, including possible
      criteria for the use of facilitatory versus compensatory approaches, is analyzed.

PMID- 12605358
TI  - Positron emission tomography and single-photon emission computed tomography brain
      imaging in the evaluation of dementia.
AB  - The role of PET and SPECT brain imaging in the initial assessment and
      differential diagnosis of dementia is beginning to evolve rapidly. Numerous
      studies confirm the value of functional brain imaging, particularly with FDG-PET
      imaging, as a potentially cost-effective means of establishing an earlier
      diagnosis of Alzheimer's disease. Such an approach should allow for a more
      objective means of establishing which patients will benefit from treatment with
      cholinesterase inhibitors. In the future, neuroreceptor and plaque burden imaging
      studies should further enhance the sensitivity and specificity of dementia
      detection and patient management.

PMID- 12605359
TI  - Acute postinfectious glomerulonephritis: an immune response gone bad?

PMID- 12605360
TI  - Incidental healed postinfectious glomerulonephritis: a study of 1012 renal biopsy
      specimens examined by electron microscopy.
AB  - Glomerulonephritis (GN) characterized by immune complex deposits typical of
      postinfectious GN but with a paucity or absence of overt clinical symptoms and/or
      urinary abnormalities may occur after a group A streptococcus infection. The
      overall incidence of this type of subclinical GN is not known. To address this
      question, electron microscopy findings in 1012 consecutive renal biopsy specimens
      (952 native kidney, 60 transplant) examined by a single renal pathologist from
      August 1999 to April 2002 were retrospectively reviewed for the presence of
      distinct subepithelial and intramembranous deposits indicative of postinfectious
      GN. Such deposits were noted in 83 biopsy specimens, including 26 with a primary
      diagnosis of postinfectious GN (acute, persistent, or latent) and 57 in which
      these deposits were an incidental finding. In each of the latter 57 cases, some
      or all of the deposits showed partial or extensive loss of electron density
      typical of partially or largely resorbed deposits. A diagnosis of incidental
      postinfectious GN was not made in any biopsy specimen exhibiting another immune
      complex-related glomerular disease that could possibly account for the deposits,
      composing 443 of the 1012 biopsy specimens examined. Thirty of the 57 biopsy
      specimens with incidental postinfectious GN showed mesangial hypercellularity,
      although this was focal and segmental in all but 3 cases and was not accompanied
      by the endocapillary hypercellularity typical of acute postinfectious lesions.
      Immunofluorescence microscopy revealed glomerular deposits of C3 in >90% of these
      biopsy specimens and IgM deposits in 66%, but only rare IgG, IgA, and Cq
      deposits. Twenty-three (40%) of these 57 biopsy specimens exhibited diabetic
      nephropathy, either alone or in combination with another lesion; for perspective,
      only 128 (13%) of the 1012 biopsy specimens examined showed evidence of diabetic
      nephropathy. In summary, incidental evidence of resolving or largely healed
      postinfectious GN was noted in up to 10.5% of renal biopsy specimens (57 of 543,
      not including specimens with a primary diagnosis of an immune complex-related
      glomerular disease). The recognition of such lesions is potentially important in
      the interpretation of certain renal biopsy specimens.

PMID- 12605361
TI  - Expression of DNA methyltransferases in multistep hepatocarcinogenesis.
AB  - Hypermethylation of cell cycle regulators and increased DNA methyltransferase 1
      (Dnmt1) mRNA level have been reported in hepatocarcinogenesis. However, the
      expression of Dnmts has not yet been examined in hepatocellular carcinomas
      (HCCs). We examined 13 cases of HCCs in dysplastic nodules (DNs) and 28 cases of
      advanced HCCs for Dnmt1 and Dnmt3a, and compared the results with those of 9
      cases of low-grade DNs, 24 cases of high-grade DNs, and 59 cases of nonneoplastic
      liver tissues from 59 cases of surgically resected livers by immunohistochemical
      staining. Nuclear expression of Dnmt1 was increased significantly in all HCCs in
      DNs and advanced HCCs compared with those of nonneoplastic livers, low-grade DNs,
      and high-grade DNs (P <0.05). Nuclear expression of Dnmt3a was not detectable in
      nonneoplastic liver and low-grade DN, whereas it was observed in high-grade DNs
      (7 of 24, 29.2%), HCCs in DNs (7 of 13, 53.8%), and advanced HCCs (11 of 28,
      39.3%). Different from Dnmt1 immunostaining, cytoplasmic immunoreactivity for
      Dmnt3a was significantly decreased or absent in 13 of 24 cases of high-grade DNs
      (54.1%), 12 of 13 cases of HCCs in DNs (92.3%), and 22 of 28 cases of advanced
      HCCs (78.6%), compared with nonneoplastic livers and low-grade DNs (P <0.05). Our
      data suggest that Dnmt1 and Dnmt3a play a role in the early stage of
      hepatocarcinogenesis and that dysregulation of Dnmt3a may be involved in the
      progression of HCC. Furthermore, the significantly decreased cytoplasmic
      immunoreactivity for Dnmt3a in high-grade DNs and HCCs can be used as a
      diagnostic adjunct.

PMID- 12605362
TI  - Localization of vascular endothelial growth factor and its receptors in digestive
      endocrine tumors: correlation with microvessel density and clinicopathologic
      features.
AB  - Angiogenesis, a process related to tumor growth and malignancy, is stimulated by
      several growth factors. Among these is vascular endothelial growth factor (VEGF),
      which acts on endothelial cells by binding with 2 specific receptors, VEGFR1 and
      VEGFR2. Recent studies have demonstrated that VEGF expression is correlated with
      microvessel density (MVD) and tumor progression. Digestive endocrine tumors are
      heterogeneous neoplasms exhibiting variable biological aggressiveness and
      behavior that often are not predictable on morphologic grounds alone. The aims of
      this study were to evaluate the expression of VEGF, VEGFR1, and VEGFR2 in
      digestive endocrine tumors and to examine its correlation with MVD and
      malignancy. A total of 84 specimens from endocrine neoplasms and normal gut and
      pancreatic tissue were immunohistochemically studied using specific antibodies
      directed against VEGF, VEGFR1, VEGFR2, endothelial antigens, and
      gastroenteropancreatic hormones. Ultrastructural immunocytochemistry was
      performed to identify the cellular localization of VEGF and the VEGFRs. In normal
      tissues, VEGF immunoreactivity was detected in G cells and PP cells.
      Ultrastructurally, VEGF was localized within secretory granules. The VEGFRs were
      not significantly expressed by normal endocrine cells. VEGF-immunoreactive (IR)
      cells were detected in 40 of 83 tumors, mainly G cell and enterochromaffin cell
      neoplasms. VEGFR1-IR cells were found in 44 of 82 tumors, and VEGFR2-IR cells
      were found in 55 of 82 tumors, with no predilection for any specific tumor type.
      The expression of VEGF and its receptors did not correlate with MVD or
      malignancy. These results suggest that in normal tissues, endothelial functions
      may be regulated by VEGF produced by some endocrine cells and that a VEGF/VEGFR
      binding mechanism may be involved in tumorigenesis, but not in tumor progression
      and aggressiveness.

PMID- 12605363
TI  - Diagnostic yield of gastric biopsy specimens when screening for preneoplastic
      lesions.
AB  - The Sydney system recommends sites and numbers of stomach biopsies (mapping) for
      evaluation of Helicobacter pylori-associated lesions. The diagnostic yield of the
      recommended mapping technique in populations at high risk for gastric
      preneoplastic lesions has not been established. We evaluated pathology data from
      733 endoscopies performed as part of an intervention study that assessed the
      effects of H. pylori treatment on preneoplastic conditions. Two pathologists
      assessed whether the mapping sequence of the 7 biopsy specimens obtained during
      each endoscopy was correctly followed and graded the specimens using the Sydney
      classification for gastritis. If the mapping sequence was followed, then we
      evaluated whether the amount of information obtained from 3 biopsy samples
      approximated that obtained from 5 and 7 biopsy samples. The mapping sequence was
      followed in only 239 (33%) endoscopies, indicating that experienced endoscopists
      can inadvertently misidentify sites in the stomach when obtaining specimens. When
      data from 7 specimens were used, H. pylori was found in 205 endoscopies, atrophy
      in 152, metaplasia in 135, and dysplasia in 22. When data from 3 specimens were
      used, the sensitivity was 99% for presence of H. pylori, 82% for atrophy and
      metaplasia, and 81% for dysplasia. When data from 5 specimens were used, the
      sensitivity was 100% for H. pylori, 96% for atrophy, and 95% for metaplasia and
      dysplasia. Although site-specific biopsy mapping is difficult in practice, the
      recommendations of the Sydney system as to the location and number of gastric
      biopsy specimens can adequately identify significant gastric histopathology.

PMID- 12605364
TI  - Cell kinetics and genetic instabilities in differentiated type early gastric
      cancers with different mucin phenotype.
AB  - To clarify the biological impact and molecular pathogenesis of cellular phenotype
      in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and
      genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers
      (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G
      type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n =
      12) based on the combination of HGM, ConA, MUC2, and CD10. Proliferative index
      (PI), apoptotic index (AI), and p53 overexpression were investigated by
      immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl
      transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53
      antibody, respectively. Using a high-resolution fluorescent microsatellite
      analysis system, microsatellite instability (MSI) and loss of heterozygosity
      (LOH) were examined. Frameshift mutation analysis of transforming growth factor
      beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with
      MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10
      for O-type, and 0.13 for CI-type cancers--significantly lower in G type than in O
      and CI types (P = 0.02 and P = 0.001, respectively). No difference in the
      incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the
      major pattern of MSI, which showed drastic and widely dispersed changes and is
      related to an increased risk for cancer, was significantly higher in G and O
      types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX
      were found in CI-type cancers. These results indicate that G-type cancers are
      likely to show more aggressive behaviors than CI-type cancers, and that O-type
      cancers show the intermediate characteristics of both types. However, the
      molecular pathogenesis of each phenotypic cancer is not associated with
      microsatellite alterations.

PMID- 12605365
TI  - Cell cycle regulators in multiple myeloma: prognostic implications of p53 nuclear
      accumulation.
AB  - Multiple myeloma (MM) is characterized by a multistep process of tumorigenesis
      involving genes that control cell cycle progression. The prevalence and clinical
      implications of p53, p21, HDM-2, p27, and cyclin E immunoreactivity in MM
      patients, however, have not been fully elucidated. We evaluated the
      immunoreactivity (IR) for p53, p21, HDM-2, p27, cyclin E, and Ki-67 in bone
      marrow biopsies from 48 patients. In 34 (70.8%) cases, TP53 gene mutations and
      HDM-2 gene amplification were analyzed by polymerase chain reaction-single-strand
      conformation polymorphism (PCR-SSCP) and Southern blot densitometric analyses in
      the corresponding bone marrow aspirates. Nineteen (39.6%) biopsy specimens
      exhibited > or =10% neoplastic cells immunoreactive for p53, 23 (47.9%) for p21,
      28 (58.3%) for HDM-2, 29 (60.4%) for cyclin E, and 16 (33.3%) for Ki-67; 23
      (47.9%) tumors had > or =50% neoplastic cells immunoreactive for p27. TP53 gene
      mutations in exons 5 through 8 were detected in 3 (8.8%) cases, whereas none
      exhibited HDM-2 gene amplification. In the cases bearing a wild-type TP53 gene,
      no association was found between p53 accumulation and HDM-2 or p21 IR. The same
      cases had been previously investigated for the presence of the t(11;14)
      translocation and cyclin D1 IR; interestingly, a significant inverse correlation
      between cyclin D1 and p27 or cyclin E IR was noted. In addition to clinical stage
      and Bartl's histologic stage and grade, p53 accumulation was significantly
      associated with survival, and it maintained its prognostic significance in a
      multivariate analysis adjusted for age, clinical stage, and relapse. Our data
      suggest that the immunohistochemical evaluation of p53 IR in bone marrow biopsies
      may represent an adjunct in MM patient prognostication.

PMID- 12605366
TI  - Expression of p27KIP1 in human gliomas: relationship between tumor grade,
      proliferation index, and patient survival.
AB  - Numerous studies examining the prognostic significance of p27KIP1 expression in
      human cancer have shown that decreased expression often is an independent
      prognostic factor associated with worse survival. However, the prognostic value
      of p27KIP1 expression in gliomas is less well established. To further address
      this issue, we evaluated the relationship between p27KIP1 protein expression in a
      series of 50 astrocytomas with clinicopathologic parameters including age, tumor
      grade, MIB-1 proliferation index, and patient survival using both Western blot
      analysis and immunohistochemistry. The level of p27KIP1 protein expression in 9
      nonneoplastic brain tissue specimens served as a control. Sixteen high-grade
      astrocytomas were analyzed by Western blot, and 26 high-grade astrocytomas were
      analyzed by immunohistochemistry for levels of p27KIP1 protein expression.
      Regardless of the technique used to measure p27KIP1, approximately 50% of the
      high-grade tumors were low expressors and the other 50% were high expressors.
      Thus, expression of p27KIP1 was independent of tumor grade. Loss of p27KIP1
      expression is often associated with an increase in proliferative activity. We
      measured the rate of tumor cell proliferation using MIB-1 immunostaining in 16
      high-grade astrocytomas to determine whether there was an inverse correlation
      between p27KIP1 expression and proliferation. No correlation between p27KIP1
      expression and MIB-1 labeling index or patient survival was found. Using
      immunohistochemistry, we noted that the staining pattern of p27KIP1 in
      glioblastomas was mainly in the pseudopalisading cells that outline areas of
      necrosis. Because p27KIP1 can be up-regulated by hypoxia, this staining pattern
      would be consistent with our observation that hypoxia-inducible factor 1alpha is
      expressed primarily in pseudopalisading tumor cells around necrotic zones. It has
      been shown that a high level of p27KIP1 prevents apoptosis in hypoxic cells.
      Thus, maintenance of high levels of p27KIP1 in gliomas could result from the
      hypoxic microenvironment present within the tumor. No correlation was found
      between p27KIP1 expression and any of the clinicopathologic parameters tested,
      including patient age and tumor grade, the 2 strongest predictors of survival
      among glioma patients.

PMID- 12605367
TI  - Parathyroid neoplasms: clinical, histopathological, and tissue microarray-based
      molecular analysis.
AB  - We studied 45 patients with typical and 8 with atypical parathyroid adenomas as
      well as 20 with parathyroid carcinomas. Clinical, pathological, and molecular
      analyses were conducted on all adenomas. Clinical data were analyzed for 20,
      histopathologic slides for 16, and tissue specimens for 8 patients with
      carcinoma. Molecular expression profiles were investigated by
      immunohistochemistry (IHC) for Ki-67, p53, mdm2, p21, Bcl-2, cyclin D1, and p27
      on paraffin-embedded tissues arrayed on tissue microarrays. Trabecular growth and
      vascular, capsular, and soft-tissue invasion were characteristic of parathyroid
      carcinomas but not of typical adenomas. No adenomas recurred. Seventy-four
      percent of carcinomas recurred, most in the neck. Seventy-nine percent of
      patients with such illness died of disease after an indolent, multiply recurrent
      course responsive to repeated resections; the 5-year survival rate was 50%. High
      Ki-67 proliferative index was seen in 2% of adenomas and 25% of carcinomas,
      whereas p27 expression was present in 80% of adenomas and 18% of carcinomas. The
      molecular phenotype, p27(+)Bcl-2(+)Ki-67(-)mdm2(+), was observed in 76%, 29%, and
      0% of typical and atypical adenomas and carcinomas, respectively. The complexity
      of molecular phenotypes increased with tumor aggressiveness. Parathyroid
      carcinoma is an aggressive disease with a propensity for multiple recurrences. It
      is characterized by capsular, vascular, and soft-tissue invasion. Recurrence
      portends poor outcome. Molecular markers, Ki-67 and p27, may distinguish
      parathyroid carcinoma from adenoma. The molecular phenotype, p27(+)Bcl-2(+)Ki-67(
      )mdm2(+), appears to be unique to nonmalignant parathyroid tumors, and
      multimarker phenotypes are more complex in carcinomas.

PMID- 12605368
TI  - Cell characterization of mononuclear and giant cells constituting pigmented
      villonodular synovitis.
AB  - The aim of this study was to determine the histologic and cellular
      characteristics of 2 cell types, mononuclear cells (Mos) and multinuclear giant
      cells (GCs), that predominantly constitute pigmented villonodular synovitis
      (PVS). Synovial tissues examined in this study were obtained from 10 patients
      with PVS. Five methods were used for cell analysis: (1) enzyme-histochemistry for
      tartrate-resistant acid phosphatase (TRAP); (2) immunohistochemistry using
      antibodies for CD68, macrophage colony-stimulating factor (M-CSF), MIB-1, p53,
      p21, p16, and cathepsin-L (cath L); (3) TdT-mediated deoxyuridine triphosphate
      biotin terminal end labeling (TUNEL) as a measure of apoptosis; (4) fluorescence
      based polymerase chain reaction single-strand conformation polymorphism analyses
      (FPCR-SSCP) to detect p53 gene mutations; and (5) in situ hybridization using
      gene-specific oligoprobes for matrix metalloproteinase (MMP)-2, MMP-9, receptor
      activator of nuclear factor kappaB ligand (RANKL), and calcitonin receptor (CTR).
      Both Mos and GCs were shown to express the macrophage/histiocyte marker CD68. In
      GCs, TRAP and CTR, both of which are known as characteristic phenotype markers of
      osteoclasts, were expressed. M-CSF and RANKL, which are together essential for
      osteoclast differentiation, were expressed in both Mos and GCs. Mos were shown to
      express MIB-1, but GCs were not. Although proliferation-suppressor proteins p53,
      p21, and p16 were expressed in both Mos and GCs, little apoptotic phenomenon of
      lining Mos was detected by TUNEL. In our study, p53 gene mutations for exons 5,
      7, and 8 in PVS synovial tissues were not detected by FPCR-SSCP analysis.
      Furthermore, both types of cells demonstrated the proteolytic enzymes MMP-2 and
      MMP-9 mRNA, and cath L protein. These results suggest that PVS has a hyperplastic
      property consisting of the CD68-positive monocytic cell lineage with
      differentiation of osteoclastic giant cells from monocyte and probably controlled
      against proliferation by wild-type p53, p21, and p16.

PMID- 12605369
TI  - Expression of Fas and FasL in human serous ovarian epithelial tumors.
AB  - The expression of Fas and FasL was studied in 86 patients with benign,
      borderline, and malignant serous ovarian lesions. Four normal ovaries, and
      monolayer epithelial cultures from a human fetal ovary, a borderline, and a
      serous adenocarcinoma were used for comparison. Expression of Fas and FasL was
      studied immunohistochemically and flowcytometrically. Fas was expressed in all 90
      lesions; FasL in 57 lesions, including 2 normal ovaries. Fas expression was
      significantly increased in borderline tumors compared with benign (P = 0.005, t =
      -2.94) or malignant serous tumors (P = 0.0001, t = 4.15). FasL expression was
      significantly increased in malignant tumors compared with benign (P = 0.039, t = 
      2.10) and borderline tumors (P = 0.0016, t = -3.33). Flow cytometry showed a
      range of Fas expression in short-term cultures isolated from normal, borderline,
      and malignant ovarian serous tissue; in the few samples studied, FasL was not
      expressed. Expression in three serous ovarian cell lines was similar. Fas and
      FasL expression differed throughout the spectrum of ovarian lesions. FasL
      expression was increased in malignant tumors, and Fas expression was increased in
      borderline tumors. Changes in Fas/FasL expression in ovarian surface epithelium
      might play a functional role in the biology of ovarian tumors.

PMID- 12605370
TI  - Expression and prognostic significance of matrix metalloproteinases and their
      tissue inhibitors in primary neuroendocrine carcinoma of the skin.
AB  - Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been
      implicated in the development and progression of many tumors, but data for
      primary neuroendocrine carcinoma (PNC) of the skin are lacking. The aim of the
      study was to assess the expression of MMPs and TIMPs in PNC and to evaluate their
      prognostic significance. Expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, MMP
      13, and MMP-14 and TIMP-1, TIMP-2, and TIMP-3 was evaluated by
      immunohistochemistry on 23 samples of PNC of the skin. The results were matched
      with clinical features and patient survival. In the 23 specimens of PNC, high
      (>20% of positive neoplastic cells) MMP-1 expression was found in 13 (56.5%)
      cases. MMP-2 was evidenced in 12 (52.1%) cases, 8 (34.7%) of which showed high
      expression in neoplastic cells. MMP-3 was detected in 11 cases (47.8%), with high
      expression in 9 (39.1%) of them. High MMP-9 expression was observed in 3 (13%)
      cases, whereas high MMP-14 expression was detected in 11 (47.8%) specimens.
      Expression of TIMP-1 by neoplastic cells was found in 8 (34.7%) cases, with high
      expression in 3 cases, whereas high TIMP-3 expression was detected in 21 (91.3%)
      cases. No immunoreactivity for MMP-11, MMP-13, or TIMP-2 was found. Statistical
      analysis failed to identify a significant correlation between MMP/TIMP expression
      and clinical parameters. By univariate analysis, stage >I (P = 0.01), high
      expression of MMP-1 (P = 0.04) and MMP-3 (P = 0.01) resulted significant negative
      prognostic factors, whereas by multivariate analysis, stage was the only factor
      that affected survival (P = 0.02). Our results suggest that MMP-1 and MMP-3 may
      influence the invasive and metastatic potential of PNCs. It is conceivable that
      future attempts to specifically block MMP-1 and MMP-3 activity may provide a
      novel means to inhibit invasiveness and distant spread in selected patients with
      PNC.

PMID- 12605371
TI  - Two cases of unusual acral melanocytic tumors: illustration of molecular
      cytogenetics as a diagnostic tool.
AB  - The differential diagnosis between benign Spitz nevus and malignant melanoma may
      present considerable difficulties in some cases. Here we report 2 unusual
      melanocytic tumors with spitzoid features developing in acral sites of Japanese
      patients to illustrate the use of comparative genomic hybridization (CGH) to
      classify these lesions. Case 1 was a 12-mm-thick, >2 cm-diameter nodule on the
      sole of a 37-year-old man. Case 2 was a subungual tumor of the left index finger
      in a 13-year-old boy. CGH showed absence of chromosomal aberrations in case 1 and
      multiple aberrations in case 2, including focused amplification as previously
      described in acral melanomas. Case 1 was free of disease after 2.5 years of
      follow-up, whereas case 2 developed lymph node metastasis. We conclude that
      molecular techniques such as CGH can be of diagnostic help in the classification
      of histologically ambiguous lesions.

PMID- 12605372
TI  - Fatal parvovirus B19-associated myocarditis clinically mimicking ischemic heart
      disease: an endothelial cell-mediated disease.
AB  - We report the case of a 34-year-old female patient who died 4 days after hospital
      admission of acute heart failure clinically mimicking ischemic heart disease.
      Microscopic examination of the heart showed severe myocarditis. Polymerase chain
      reaction (PCR), including quantitative real-time PCR, disclosed exclusively
      parvovirus B19 (PVB19), with a high viral load of 4.3x10(5) PVB19 viral genome
      equivalents per microg myocardial nucleic acid. Radioactive in situ hybridization
      detected viral genomes in endothelial cells (ECs) predominantly in the venular
      compartment and (to a lesser degree) in small arteries and arterioles of the
      heart, but not in cardiac myocytes or other tissue components. Concomitant with
      EC infection, marked expression of the adhesion molecule E-selectin was noted,
      accompanied by margination, adherence, penetration, and perivascular infiltration
      of T lymphocytes. We speculate that, due to the high viral load in cardiac ECs,
      PVB19 infection of endothelial cells was sufficient to induce impaired coronary
      microcirculation with secondary cardiac myocyte necrosis.

PMID- 12605373
TI  - Recurrence of lymphangioleiomyomatosis after single lung transplantation: new
      insights into pathogenesis.
AB  - Lymphangioleiomyomatosis (LAM) is a rare disease found primarily in white women
      of childbearing age. The present study describes a case of recurrent LAM after
      single lung transplantation. Double-staining nonisotopic in situ hybridization,
      immunohistochemistry, and short tandem repeat loci analysis demonstrated that the
      recurrent LAM lesions originated from the recipient. The data strongly support
      that metastatic spread of LAM cells or migration of progenitor cells plays an
      important role in the pathogenesis of LAM.

PMID- 12605374
TI  - Choledochal cysts and multilocular cysts of the pancreas.
AB  - Choledochal cyst is a rare congenital anomaly of the biliary system that may be
      associated with other abnormalities of the hepatobiliary tract. We report a case
      of an 11-year-old boy in whom the preoperative evaluation revealed a choledochal
      cyst and intraoperative cholangiopancreatography showed a cystic mass in the
      pancreas. Examination of the choledocho-pancreatico-duodenectomy specimen showed
      a multilocular cyst in the pancreas in addition to a segmental dilation of the
      common bile duct. The findings in our case adds pancreatic cyst to the spectrum
      of abnormalities associated with choledochal cyst and may also support the theory
      that choledochal cyst is the predominant abnormality in a widespread spectrum of
      the pancreatobiliary duct dysplasia.

PMID- 12605375
TI  - Distribution of p53 alterations in a case of gliomatosis cerebri.
AB  - Gliomatosis cerebri (GC) is a rare neuroepithelial tumor characterized by diffuse
      infiltration of large parts of the brain. The origin of GC is unknown, and the
      molecular alterations underlying this tumor have not been determined. Because
      mutations in the p53 tumor-suppressor gene are frequent in common gliomas, we
      investigated the distribution of p53 alterations by immunohistochemistry and
      direct sequencing in a GC case with a disease involving both hemispheres and the
      basal ganglia. Nuclear accumulation of p53 protein was detected in a single
      region with features of a high-grade glioma. In the remaining 10 regions,
      corresponding to low-grade gliomas, no p53 accumulation was seen. In 1 low-grade
      tumor sample, a pathogenic splice site mutation was detected. These findings
      suggest that p53 alterations occur in GC, but are no prerequisite of malignant
      progression. The distribution of p53 alterations demonstrates the existence of
      topographically different clones in 1 patient.

PMID- 12605376
TI  - Genotoxicity of a polluted river system measured using the alkaline comet assay
      on fish and earthworm tissues.
AB  - Monitoring genotoxicity in the environment by using endemic organisms as
      sentinels requires sensitive assays. In this study the genotoxic properties of
      water and sediment collected from the Noyyal River, which is polluted with
      industrial effluent and sewage, was determined in fish (Cyprinus carpio) and
      earthworms (Eisenia foetida) using the alkaline comet assay. Upon
      electrophoresis, extensive DNA damage, measured as the DNA length:width ratio of
      the DNA mass, was observed in erythrocytes, liver, and kidney cells of fish
      exposed to polluted water samples and the amount of damage increased with the
      duration of exposure. Similarly, the mean DNA length:width ratio was
      significantly higher in the coelomocytes of earthworms placed in sediment
      samples. The highest levels of DNA damage were obtained with samples taken at and
      immediately downstream of urban centers. The results of this study indicate that
      the Noyyal River system is contaminated with substances that are genotoxic to
      fish and earthworms and that the comet assay has sufficient sensitivity to detect
      the genotoxicity.

PMID- 12605377
TI  - Photomutagenicity of thiabendazole, a postharvest fungicide, in bacterial assays.
AB  - We investigated the photomutagenicity of thiabendazole (TBZ), a postharvest
      fungicide commonly used on imported citrus fruits. Using UVA light (320-400 nm),
      we irradiated bacterial cultures with or without TBZ in a 24-well multiplate. UVA
      irradiation without TBZ was not mutagenic to the tester strains, nor was
      unirradiated TBZ. TBZ was strongly photomutagenic in Escherichia coli WP2uvrA and
      WP2uvrA/pKM101 strains, weakly photomutagenic in Salmonella typhimurium TA100 and
      TA98, and not photomutagenic in S. typhimurium TA1535 and TA1538. The
      photomutagenicity of TBZ was more evident in WP2uvrA/pKM101, which carries the
      trpE65 ochre mutation (TAA), than in TA100, which carries the hisG46 missense
      mutation (CCC). In E. coli WP3101-WP3106 and the corresponding pKM101-containing
      strains, photoactivated TBZ induced predominantly G:C-->A:T transitions and A:T-
      >T:A transversions. In the plasmid-containing strains only, TBZ induced a
      moderate number of A:T-->G:C transitions and a few A:T-->C:G and G:C-->T:A
      transversions. The observation that UVA-irradiated TBZ mutated both G:C and A:T
      basepairs may explain why WP2uvrA/pKM101 was more sensitive to its mutagenicity
      than TA100. TBZ that was irradiated before it was added to the WP2uvrA/pKM101
      cells was not photomutagenic, which suggests that the photomutagenic products of
      TBZ were unstable or rapidly reacted with other molecules before being
      incorporated into cells.

PMID- 12605378
TI  - Etoposide and merbarone are clastogenic and aneugenic in the mouse bone marrow
      micronucleus test complemented by fluorescence in situ hybridization with the
      mouse minor satellite DNA probe.
AB  - The topoisomerase II (topo II) inhibitors etoposide (VP-16) and merbarone (MER)
      were investigated with the in vivo micronucleus test (MN test) combined with
      fluorescence in situ hybridization (FISH) using the mouse minor satellite DNA
      probe to discriminate MN of clastogenic and aneugenic origin. All experiments
      were performed with male (102/ElxC3H/El) F1 mice bred in the mouse colony of the
      GSF Research Center. The sample size per experimental group was five animals and
      2,000 polychromatic erythrocytes (PCE) were scored per animal from coded slides
      in the conventional MN test. A separate set of coded slides was used for the FISH
      analysis. All treatments consisted of single intraperitoneal injections.
      Colchicine (COL, 3 mg/kg) and mitomycin (MMC, 1 mg/kg) were used as a positive
      control aneugen and clastogen, respectively, and these compounds produced the
      expected responses. A dose of 1 mg/kg VP-16 induced 3.44% MNPCE (compared to the
      concurrent solvent control of 0.37%, P < 0.001) and of these 39.9% (1.4% MNPCE)
      showed one or more fluorescent signals. MER (7.5-60 mg/kg) increased the MNPCE
      frequencies in a dose-dependent manner, with 15 mg/kg being the lowest positive
      dose. At the highest dose of 60 mg/kg of MER, a total of 4.26% MNPCE were found
      (compared to 0.31% in the concurrent solvent control, P < 0.001) and of these
      46.2% (2.0% MNPCE) contained one or more fluorescent signals. The data
      demonstrate that VP-16 and MER induced both clastogenic and aneugenic events
      despite their different modes of topo II inhibition.

PMID- 12605379
TI  - Biomonitoring with the comet assay of Greek greenhouse workers exposed to
      pesticides.
AB  - The pesticides in use in Greek greenhouses include a number of agents known to be
      mutagens and carcinogens. In the present study, we evaluated whether occupational
      exposure of agricultural workers to a complex mixture of pesticides resulted in a
      significant increase in DNA damage in human peripheral blood lymphocytes (PBLs).
      A total of 116 healthy individuals were divided into groups based on exposure to
      pesticides, smoking status, and gender. Alkaline comet assays performed on PBLs
      from these individuals indicated no statistically significant differences in
      basal DNA damage between the study groups. In addition, exposure of PBLs to a
      dose of hydrogen peroxide led to a similar degree of DNA damage and subsequent
      repair for all the study populations. The results of the study indicate that the
      agricultural workers who participated in this study had no detectable increase in
      DNA damage or alteration in the cellular response to DNA damage.

PMID- 12605380
TI  - Mouse bone marrow micronucleus test results do not predict the germ cell
      mutagenicity of N-hydroxymethylacrylamide in the mouse dominant lethal assay.
AB  - N-Hydroxymethylacrylamide (NHMA), a mouse carcinogen inactive in the Salmonella
      assay and mouse micronucleus (MN) assay, was tested for reproductive effects in a
      mouse continuous breeding study. In that study, increased embryonic deaths were
      observed after 13 weeks exposure of parental animals to NHMA via drinking water
      (highest dose, 360 ppm); the results indicated the possible induction of
      chromosome damage in germ cells of treated males. An additional mouse MN test was
      conducted using a 31-day treatment period to better match the dosing regimen used
      in the breeding study; the results were negative. Additional studies were
      conducted to explore the germ cell activity of NHMA. A male mouse dominant lethal
      study was conducted using a single intraperitoneal injection of 150 mg/kg NHMA;
      the results were negative. A follow-up study was conducted using fractionated
      dosing, 50 mg/kg/day for 5 days; again, no increase in dominant lethal mutations
      was observed. NHMA (180-720 ppm) was then administered to male mice in drinking
      water for 13 weeks, during which three sets of matings occurred. Two weeks after
      mating, females were killed and the uterine contents were analyzed. Large, dose
      related increases in dominant lethal mutations were observed with increasing
      length of exposure. The magnitude of the increases stabilized after 8 weeks of
      treatment. However, the frequency of micronucleated peripheral blood erythrocytes
      was not elevated in mice treated for 13 weeks with NHMA in drinking water. Thus,
      NHMA appears to be unique in inducing genetic damage in germ cells but not
      somatic cells of male mice.

PMID- 12605381
TI  - Development of a microplate assay for the detection of single plaque-forming
      units of bacteriophage PhiX174 in crude lysates.
AB  - Mice containing the PhiX174 am3 transgene can be used for measuring in vivo
      mutation; however, the single burst analysis method used for distinguishing in
      vivo mutations from mutations generated during sample processing is labor
      intensive. A liquid microplate assay was developed that detects a single mutant
      plaque-forming unit (PFU) of PhiX174 bacterial virus in the presence of excess
      nonmutant virus. The assay is based on inhibiting reduction of the tetrazolium
      dye, MTS, by bacterial cells selective for mutant virus. The assay is performed
      with crude lysates of infected bacteria and is as accurate as scoring viral
      plaques on a bacterial lawn. This microplate assay may have application in
      increasing throughput of the single burst analysis of PhiX174 in transgenic mouse
      mutation assays.

PMID- 12605382
TI  - Analysis of micronuclei in peripheral blood lymphocytes of traffic wardens:
      effects of exposure, metabolic genotypes, and inhibition of excision repair in
      vitro by ARA-C.
AB  - The cytokinesis-block micronucleus (MN) assay in peripheral lymphocytes was used
      to assess the genetic effects of the occupational exposure to traffic fumes in
      policemen from the Municipality of Rome. The study population consisted of 192
      subjects engaged in traffic control (exposed, 134 subjects), or in office work
      (controls, 58 subjects). Groups were balanced for age, gender, and smoking
      habits. The average benzene exposure during the workshift was 9.5 and 3.8
      microg/m(3) in exposed individuals and controls, respectively. All subjects were
      genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, and DT-diaphorase polymorphisms. The
      incidence of micronuclei and micronucleated cells was recorded in 1,000
      binucleated cells harvested 66 hr after mitogen stimulation. Regression analysis
      of data showed that MN frequency was mainly modulated by the age (P = 0.001) and
      gender (P = 0.001) of the study subjects (relatively higher in the elderly and
      females), whereas it was unaffected by the occupational exposure to traffic fumes
      and smoking habits. A weak (P = 0.02) association between lower MN frequency and
      the GSTM1 null genotype was also observed. In order to improve the sensitivity of
      the method to excision-repairable lesions, a modified protocol, with exposure of
      cells to the repair inhibitor cytosine arabinoside (Ara-C) during the first 16 hr
      of growth, was applied to 78 subjects (46 exposed and 32 controls). The results
      confirmed the higher MN frequency in females (P < 0.05), but failed to
      demonstrate any significant effect of chemical exposure (occupational or related
      to smoking habits). When the frequency of MN induced by Ara-C (i.e., spontaneous
      values subtracted) was considered, a significant inverse correlation with age was
      observed (P = 0.005), possibly related to the age-dependent decrease in repair
      proficiency.

PMID- 12605383
TI  - Mutations induced by (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of
      dibenzo[a,l]pyrene in the coding region of the hypoxanthine
      phosphoribosyltransferase (Hprt) gene in Chinese hamster V79 cells.
AB  - The polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P) is an
      exceptionally potent carcinogen. Its direct DNA-reactive metabolite, the fjord
      region (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide [(-)-anti-DB[a,l]PDE], was
      used to investigate induction of mutations in the coding region of the
      hypoxanthine phosphoribosyltransferase (Hprt) gene in Chinese hamster V79 cells.
      Cells exposed to 1-10 nM (-)-anti-DB[a,l]PDE exhibited a close dose-responsive
      increase in the frequency of mutant clones resistant to 6-thioguanine. RNA was
      isolated from mutant clones and cDNAs were prepared by reverse transcription. The
      coding region of the cDNA of the Hprt gene was amplified by polymerase chain
      reaction and sequenced. Analysis of the DNA base sequence changes induced by (-)
      anti-DB[a,l]PDE indicated that base substitutions were the most prevalent
      mutations, followed by exon deletions. Among the groups of V79 cells treated with
      low concentrations of (-)-anti-DB[a,l]PDE, most displayed high selectivity for
      both A:T-->T:A transversions and A:T-->G:C transitions, while cells exposed to a
      higher dose (10 nM) formed predominantly G:C-->T:A transversions. Also, the
      number of base substitutions per mutant clone increased with dose. In general,
      the mutation profiles induced by (-)-anti-DB[a,l]PDE exhibited a wide spectrum;
      in addition to base substitutions, deletions, insertions, frameshift mutations,
      as well as tandem mutations were detected. Analysis of the DNA adduct levels
      induced by (-)-anti-DB[a,l]PDE revealed that a concentration-dependent increase
      in the level of adduct formation preceded the concentration-dependent increase in
      mutational events in these cells and that an increasing proportion of DNA adducts
      at deoxyadenosine were formed with dose. The results of this study demonstrate a
      correspondence between the concentration and types of DNA adducts and the
      frequency and types of mutations induced by (-)-anti-DB[a,l]PDE in V79 cells.

PMID- 12605384
TI  - Variability in human sensitivity to 1,3-butadiene: Influence of the allelic
      variants of the microsomal epoxide hydrolase gene.
AB  - The carcinogenic effects of 1,3-butadiene (BD), a chemical widely used in the
      rubber industry, are thought to be due to its epoxide metabolites. In humans,
      these epoxides are detoxified predominantly by hydrolysis, a reaction mediated by
      the microsomal epoxide hydrolase (mEH) enzyme. The mEH gene is polymorphic and
      the most common mEH coding-region variants detected in human populations are the
      two amino acid polymorphisms Tyr113His and His139Arg. Polymorphic amino acid
      substitutions at residues 113 and 139 in the human mEH protein can associate in
      four distinct combinations: Tyr113/His139, Tyr113/Arg139, His113/His139, and
      His113/Arg139. In vitro studies have shown that each of these genotypes has a
      unique mEH protein level that can affect net mEH enzymatic activity. In the
      current study, we examined the relationships among the genotypes involving these
      two polymorphisms and the mutagenic responses associated with occupational
      exposure to BD. We studied 49 nonsmoking workers from two styrene-butadiene
      rubber facilities in southeast Texas using the autoradiographic HPRT mutant
      lymphocyte assay as a biomarker of genotoxic effect. We genotyped the study
      participants simultaneously for both polymorphisms, using a multiplex PCR assay
      developed in our laboratory, and the subjects were assigned to a specific group
      based on the predicted mEH activity associated with their genotypes (low,
      intermediate, and high). In the study population, 67% were exposed to low BD
      levels of <150 ppb (measured by personal badge dosimeters) and 33% were exposed
      to >150 ppb (mean 2,244 ppb). In the BD low-exposure group, the mEH genotypes had
      no significant effect on the HPRT variant (mutant) frequency (Vf). In the high
      exposure group (BD > 150 ppb), individuals with genotypes associated with low mEH
      activity had a significant (P < 0.05) 3-fold increase in HPRT Vf (Vf +/- SEM =
      13.95 +/- 2.15 x 10(-6)) compared to high-activity individuals (4.41 +/- 1.19 x
      10(-6)), and a 2-fold increase in Vf compared to intermediate-activity
      individuals (6.44 +/- 2.09 x 10(-6)). Our results indicate that mEH genotypes may
      play a significant role in human sensitivity to the genotoxic effects of exposure
      to BD.

PMID- 12605386
TI  - High serum transferrin receptor level in anemia of chronic disorders indicates
      coexistent iron deficiency.
AB  - Blood transferrin receptor (TR) level is largely determined by the quantum of
      erythropoiesis and by intracellular iron content of the cells of the erythroid
      lineage. Hence, a high serum TR level has been found to be useful in
      distinguishing iron deficiency anemia (IDA) from anemia of chronic disorders
      (ACD). In order to examine its potential role in the diagnosis of concomitant
      iron deficiency in ACD, we determined serum TR levels in 130 cases of ACD, in 25
      cases of IDA, and in 40 normal adults. As expected, all patients of IDA had
      significantly higher serum TR levels compared to the normal subjects (4.2-19.2
      microg/dL vs. 1.3-3.0 microg/dL) (P < 0.002). In 11/25 cases of IDA, the total
      iron-binding capacity (TIBC) was in the normal range although bone marrow iron
      store was absent and serum TR levels were high, thereby highlighting the
      superiority of TR level in the diagnosis of iron deficiency compared to TIBC.
      Although 54% (70/130) patients of ACD had normal or low serum TR levels (0.9-3.0
      microg/dL) as expected, in 46% (60/130) of ACD patients, serum TR levels were
      high (3.2-11.0 microg/dL). Mean corpuscular volume, red cell distribution width,
      and transferrin saturation were significantly lower (P < 0.001) in the latter
      group of patients compared to the former, and these parameters resembled those in
      IDA patients. Also, serum iron was lower and TIBC was higher in this group of ACD
      patients compared to those with normal or low serum TR. All these features point
      to an "IDA-like" profile of ACD patients with high TR and support the possibility
      of co-existent iron deficiency in this subgroup of ACD patients. In light of
      these observations it would be prudent to treat ACD patients with high serum TR
      levels with iron replacement therapy.

PMID- 12605387
TI  - Alterations in sensitivity to calcium and enzymatic hydrolysis of membranes from
      sickle cell disease and trait erythrocytes.
AB  - Normally, human erythrocytes display several responses to elevated intracellular
      calcium levels. These include a shape transition from discocyte to spherocyte,
      shedding of microvesicles into the extracellular fluid, and enhanced
      susceptibility to the hydrolytic action of secretory phospholipase A(2). These
      responses to elevated intracellular calcium were all blunted in erythrocytes
      containing hemoglobin S. The reduction of both the shape transition and the
      shedding of microvesicles were greater than the impairment of phospholipase
      susceptibility, and both correlated strongly with the intracellular content of
      hemoglobin S. In contrast to the response to elevated intracellular calcium,
      erythrocytes containing hemoglobin S displayed a 2.5-fold increase in basal
      susceptibility to phospholipase A(2) compared to control erythrocytes in the
      absence of ionophore. The effect was more prominent among samples from patients
      heterozygous for hemoglobin S than in samples from homozygous individuals. These
      results reveal additional abnormalities in the membranes of sickle cell
      erythrocytes beyond those described previously and demonstrate that red blood
      cells from both heterozygous and homozygous are affected. Furthermore, they
      suggest a possible means by which sickle cell disease and trait patients may
      display enhanced vulnerability to inflammatory stimuli.

PMID- 12605388
TI  - High incidence of autoimmune alterations in chronic myeloid leukemia patients
      treated with interferon-alpha.
AB  - Interferon-alpha is the frontline therapy of the majority of chronic myeloid
      leukemia (CML) patients who are not eligible for bone marrow transplantation.
      Many patients are treated for long periods, and there is concern about the long
      term immune effects of its use. Autoimmune disorders in patients treated with IFN
      alpha may be related to the direct immunomodulating properties of IFN or may be
      linked to a possible toxic effect in target organs, triggering autoimmunity. On
      the other hand, the immune effects of IFN may play a role in its therapeutic
      actions. The aims of our study were to assess the incidence of autoimmune
      phenomena in these patients, and to measure the possible association between the
      generation of autoimmune phenomena and the antileukemic effect of IFN alpha.
      Therefore, 46 patients with Ph1(+) CML in the first chronic phase were studied
      for the appearance of immune complications, their connection to IFN dose, time of
      appearance, and the possible association with the response to treatment.
      Autoimmune abnormalities have been found in 28% of our patients. Moreover, a
      significant association was found between autoimmune alterations and female sex
      (P = 0.02, OR 4.5, 95% CI 1.13-17.9) and a longer treatment time (1.6 vs. 4.1
      years) (P = 0.02; OR 1.01, 95% CI 1-1.02). The Kaplan-Meier estimated probability
      of obtaining a cytogenetic response was significantly higher in patients who
      developed autoimmune alterations (P = 0.049), and this difference was also
      evident in Cox's analysis when controlling with other potentially confounding
      variables (P = 0.078). We conclude that CML patients treated with IFN alpha have
      a high incidence of autoimmune phenomenon.

PMID- 12605390
TI  - Clinical presentation of severe anemia in pediatric patients with sickle cell
      anemia seen in Enugu, Nigeria.
AB  - Anemia is a major cause of morbidity and mortality among patients with sickle
      cell anemia. In this study, 108 episodes of severe anemia were prospectively
      evaluated in 108 patients with hemoglobin SS disease attending the pediatric
      sickle cell clinic of the University of Nigeria Teaching Hospital, Enugu,
      Nigeria. Young children between the ages of 2 and 4 years were found to be at the
      greatest risk of developing anemic crises (severe anemia). There was a gradual
      but progressive decline in the incidence of severe anemia in the age range 8-16
      years old. Upper respiratory tract infections are the most commonly associated
      infections in patients with severe anemia. Others included malaria, septicemia,
      urinary tract infection, acute chest syndrome, and osteomyelitis. Their role in
      precipitating episodes of severe anemia among the patients studied could not be
      fully evaluated. Pallor, jaundice, and fever were the most commonly encountered
      symptoms in patients with severe anemia on admission. About half of the
      parents/guardians failed to notice severe anemia among the patients studied,
      perhaps due to the dark color of the African skin. Caregivers need to be educated
      on how to recognize anemia among patients with sickle cell anemia when they
      develop febrile episodes.

PMID- 12605389
TI  - Decreased exhaled nitric oxide in sickle cell disease: relationship with chronic
      lung involvement.
AB  - A deficiency in airway nitric oxide (NO) could contribute to pulmonary vaso
      occlusion in sickle cell disease (SCD). We measured the fractional expired
      concentration of NO (FE(NO)) by chemiluminescence during a slow vital capacity
      maneuver against a positive pressure of 16 cm H(2)O at an expiratory flow rate of
      50 mL/sec in 44 stable ambulatory adults with SCD and 30 healthy controls. A
      history of acute chest syndrome was present in 29 patients, and 22 complained of
      dyspnea. Mean +/- SD FE(NO) was significantly reduced in the SCD group compared
      with controls (14.8 +/- 8.4 vs. 24.9 +/- 13.5 ppb, P < 0.001). SCD patients with
      dyspnea had lower FE(NO) than those without dyspnea (10.1 +/- 5.7 vs. 19.6 +/- 8
      ppb, P < 0.001) and those with a history of ACS had lower values than those no
      episodes of ACS (13.0 +/- 8.3 vs. 18.4 +/- 7.6 ppb, P < 0.05). There was a weak
      correlation between FE(NO) and percent-predicted DLCO (r = 0.4, P = 0.02) among
      the SCD patients. We conclude that exhaled NO is reduced in adults with SCD, and
      this may play a role in the pathogenesis of acute chest syndrome and chronic
      sickle cell lung disease.

PMID- 12605391
TI  - Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase
      (MTHFR), and venous thromboembolism: Longitudinal Investigation of
      Thromboembolism Etiology (LITE).
AB  - We sought to examine prospectively the association of serum homocysteine and the
      methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of
      venous thromboembolism (VTE). We studied these relationships in a nested case
      control study of 303 VTE cases and 635 matched controls from a population-based
      cohort of 21,680 adults from six U.S. communities. The highest quintile of serum
      homocysteine carried a non-statistically significant adjusted odds ratio of 1.55
      (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a
      significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10
      3.83) and an inverse association in those > or = 65 years of age. Carriers of the
      MTHFR C677T polymorphism were not at higher risk for VTE than those with normal
      genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a
      weak relationship between homocysteine and VTE risk, with associations larger
      among younger participants. MTHFR C677T was not a risk factor for VTE.

PMID- 12605392
TI  - Frequent and prolonged hospitalizations: a risk factor for early mortality in
      sickle cell disease patients.
AB  - A subset of patients with sickle cell disease (SCD) has frequent and prolonged
      hospitalizations. Clinical outcomes for this subset of patients are not known. We
      analyzed mortality data in 71 such patients enrolled in a case management study.
      Adult patients (mean age 32 years) with SCD and > or = 50 hospitalization
      days/year or > or = 6 admissions/year were enrolled. Clinical and psychosocial
      data were obtained. During a mean 24-month follow up, 11 of 71 patients died
      (15.5%). Patients who died had a higher mean number of hospitalization days in
      the year before study entry (116 vs. 40, P < 0.000008) and were also more
      depressed than those who survived (mean score 17.8 vs. 11.9, P = 0.031). Frequent
      and prolonged hospitalizations are a risk factor for early mortality in patients
      with SCD.

PMID- 12605393
TI  - Fatal Bacillus cereus sepsis following resolving neutropenic enterocolitis during
      the treatment of acute leukemia.
AB  - Bacillus cereus is increasingly being acknowledged as a serious bacterial
      pathogen in immunosuppressed hosts. We report a case of fatal B. cereus sepsis in
      a patient with newly diagnosed acute leukemia following resolving neutropenic
      enterocolitis. Gastrointestinal complaints are common during induction
      chemotherapy, yet some antimicrobial coverage suitable for generalized
      neutropenia is not optimal for the eradication of B. cereus. This case
      demonstrates that, in the neutropenic patient with gastrointestinal complaints or
      in the setting of resolving neutropenic enterocolitis, it is important to
      anticipate possible B. cereus infection and sepsis.

PMID- 12605394
TI  - Use of plasma exchange in methotrexate removal in a patient with osteosarcoma and
      acute renal insufficiency.
AB  - Acute renal failure induced by methotrexate (MTX) can be lethal because renal
      excretion of the drug can be delayed. Pre-existing renal impairment, abstention,
      or underdosage of folinic acid and inadequate hydration facilitate toxicity. The
      prolonged high serum levels of MTX result in severe mucositis and pancytopenia,
      but strategies useful to accelerate MTX removal have not been universally
      accepted. We report a case of a 13-year-old girl with osteosarcoma who was
      treated with high-dose MTX because of thoracic tumor recurrence. No side effects
      were observed after 2 cycles of high-dose MTX; however, after the third cycle
      there was a delayed MTX elimination followed by clinical toxicity. Forty hours
      post-MTX infusion the serum level of MTX was 5.39 x 10(-4) mol/L. Treatment was
      based on symptomatic measures, such as maintenance of an abundant and alkaline
      diuresis and parenteral administration of folinic acid. Concomitantly, plasma
      exchange was employed to accelerate MTX removal and reduce its toxicity. After 24
      days, she was discharged from the hospital, and her renal function recovered
      gradually.

PMID- 12605395
TI  - Tumor lysis syndrome (TLS) following fludarabine therapy for chronic lymphocytic
      leukemia (CLL): case report and review of the literature.
AB  - Adenosine deaminase inhibitors have proven superior to alkylating agent-based
      therapies in inducing clinical and hematologic remissions in treated and
      previously untreated chronic lymphocytic leukemia (CLL) patients, and they have
      become increasingly accepted as a standard for therapy. We report the case of a
      66-year-old patient with a 7-year history of CLL who had been previously treated
      with alkylating agents. Upon presentation with abdominal lymphadenopathy, a 5-day
      course of the nucleoside analogue, fludarabine, was administered. Two days after
      completion, the patient developed acute tumor lysis syndrome (TLS) that induced
      renal failure with hyperkalemia and hyperuricemia. This resulted in critical,
      life-threatening complications requiring hospitalization, aggressive hemodialysis
      and fluid replacement therapy. While only 5 other cases of TLS associated with
      fludarabine therapy have been reported since 1989, we recommend that adenosine
      deaminase inhibitor therapy be initiated with the addition of allopurinol, and
      that hydration with copious amounts of oral fluids during therapy be encouraged
      in order to help protect against the renal effects of potential TLS induced by
      these agents.

PMID- 12605396
TI  - HIV-related Hodgkin's disease with central nervous system involvement and
      association with Epstein-Barr virus.
AB  - Central nervous system (CNS) involvement is a rare occurrence in the course of
      human immunodeficiency virus (HIV)-related Hodgkin's disease (HD). We report the
      clinical course of a patient with HIV infection who developed systemic HD, mixed
      cellularity subtype, later complicated by leptomeningeal involvement. The patient
      died from his illness, and autopsy was performed. Examining the brain lesion,
      Epstein-Barr virus (EBV) presence was demonstrated in Reed-Sternberg cells by
      immunohistochemistry using an EBER probe for EBV RNA. This is the second case
      report in the English literature of HD involving the CNS in an HIV-positive
      individual, and the first demonstrating EBV presence. Extranodal presence of
      Hodgkin's disease in patients with HIV infection is probably related to
      immunosuppression, and physicians treating this illness should be alert to the
      potential of unusual sites of involvement.

PMID- 12605397
TI  - Reduced-intensity bone marrow transplantation from an alternative unrelated donor
      for myelodysplastic syndrome of first-donor origin.
AB  - A male patient had a relapse of myelodysplastic syndrome (MDS) 2 years after BMT
      from a female matched unrelated donor. Conventional cytogenetics, FISH, and short
      tandem repeat chimerism analysis proved a relapse of donor origin. He underwent
      reduced-intensity BMT after a conditioning with fludarabine and busulfan, since
      he had impaired renal, liver, and pulmonary functions. Chimerism analysis on day
      28 after the second BMT showed mixed chimerism of the first and the second
      donors, which later turned to full second-donor chimerism on day 60. He developed
      grade II acute GVHD of the skin and cytomegalovirus reactivation, but both were
      improved with methylprednisolone and ganciclovir, respectively. He remains in
      complete remission 6 months after the second BMT. Reduced-intensity second BMT
      from an alternative donor appeared to be a tolerable treatment option for donor
      derived leukemia/MDS after the first conventional transplantation.

PMID- 12605398
TI  - Hairy cell leukemia with concurrent cryptococcus infection.

PMID- 12605399
TI  - Simple fluorescent PCR method for detection of large deletions in the beta-globin
      gene cluster.
AB  - We developed a semi-automated approach to detect large deletions in the beta
      globin gene cluster, based on the quantitative differences in the amplifications
      of samples by a fluorescent PCR. With this strategy, we were able to detect the
      presence of HPFH-2 in an African-Brazilian subject, confirmed by sequencing
      analysis. Differently from other PCR strategies, GAP-PCR for example, it has the
      potential to identify new deletions.

PMID- 12605400
TI  - Variations in spare electron transport chain capacity: The answer to an old
      riddle?
AB  - Several neurological diseases involve focal injury of specific brain structures.
      Poisons of the electron transport chain complexes (ETCC) can also produce
      selective injury of brain structures when given systemically and have been
      implicated in the development of neurological disease. Why ETCC poisons damage
      particular brain regions is unclear. Calculations of the relative ETCC expression
      level to glucose utilization rate (GUR) ratio from published observations here
      reveal that a low ETCC/GUR ratio predisposes a brain structure to injury by a
      poison of that complex. While GUR can rise with increased neuronal activity, ETCC
      expression is fixed in the short term. A high ETCC/GUR therefore represents
      surplus ETCC capacity, allowing for increased ATP generation with short-term
      increases in demand. A low ETCC/GUR indicates the opposite and will lead to
      energy failure when the specific ETCC is poisoned. These observations may explain
      why cyanide, a specific ETCC (IV) inhibitor, can produce selective injury of
      white matter, which has the lowest ETCC (IV)/GUR found in the brain. They are
      also consistent with the selective damage of the striatum produced by poisons
      such as rotenone, a form of injury implicated in Parkinson's disease. The
      striatum has a low ETCC (I)/GUR ratio, whereas rotenone is a selective ETCC (I)
      inhibitor.

PMID- 12605402
TI  - Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem
      cells and involved in cell proliferation.
AB  - BRCA-1 is a tumor suppressor gene that plays a role in DNA repair and cellular
      growth control. Here we show that BRCA-1 mRNA is expressed by embryonic rat brain
      and is localized to the neuroepithelium containing neuronal precursor cells. The
      expression of BRCA-1 decreases during rat brain development, but BRCA-1 is
      expressed postnatally by proliferating neuronal precursor cells in the developing
      cerebellum. Neural stem cells (NSC) prepared from embryonic rat brain and
      cultured in the presence of epidermal growth factor were positive for BRCA-1.
      Induction of NSC differentiation resulted in down-regulation of BRCA-1 expression
      as shown by RNA and protein analyses. In addition to embryonic cells, BRCA-1 is
      also present in NSC prepared from adult rat brain. In adult rats, BRCA1 was
      expressed by cells in the walls of brain ventricles and in choroid plexus. The
      results show that BRCA-1 is present in embryonic and adult rat NSC and that the
      expression is linked to NSC proliferation.

PMID- 12605401
TI  - Genes regulated by learning in the hippocampus.
AB  - The enduring changes in long-term memory probably depend on regulation of gene
      expression in the hippocampus. To seek genes regulated by learning, we used
      microarray technology to compare hippocampal gene expression in mice undergoing
      training in the Morris water maze and control mice forced to swim for the same
      period in the absence of a hidden platform. ANOVA was employed to prioritize
      genes for further study, and three genes were confirmed by real-time PCR as being
      regulated during learning. One of the genes was the alpha subunit of the platelet
      derived growth factor receptor (Pdgfra); another showed homology to DnaJ and cAMP
      response element-binding protein 2 (CREB2); and a third was novel. These genes
      may provide useful insights into the molecular mechanisms of hippocampal
      learning.

PMID- 12605404
TI  - BDNF-induced survival of auditory neurons in vivo: Cessation of treatment leads
      to accelerated loss of survival effects.
AB  - Neurotrophic factors are important for the development and maintenance of the
      auditory system. They have also been shown to act as survival factors for
      auditory neurons in animal deafness models. Studies have demonstrated recently
      that these neurotrophic factors not only maintain survival of auditory neurons,
      but that these surviving neurons retain functionality. It remains to be
      determined, however, if a single administration of a neurotrophic factor is
      sufficient to maintain auditory neuron survival after loss of hair cells, or if
      sustained delivery is required. This study investigated the longevity of the
      survival effects of BDNF on auditory neurons in deafened guinea pigs. Briefly,
      the left cochleae of deafened guinea pigs were infused with BDNF for 28 days via
      a mini-osmotic pump, and neuronal survival was analyzed at various stages after
      the completion of treatment. BDNF treatment prevented the degeneration of
      auditory neurons that normally is seen after a loss of hair cells, supporting
      previous studies. Our results indicate, however, that cessation of BDNF treatment
      leads to an accelerated decline in auditory neuron survival as compared to that
      observed in deafened, untreated cochleae. These findings indicate that much work
      remains to be done to establish a technique for the long-term survival of
      auditory neurons in the deaf ear.

PMID- 12605403
TI  - Expression and properties of the recombinant murine Golli-myelin basic protein
      isoform J37.
AB  - A recombinant form of the murine Golli-myelin basic protein (MBP) isoform J37
      (rmJ37) has been expressed in Escherichia coli and isolated to 95% purity via
      metal chelation and ion exchange chromatography. The protein did not aggregate
      lipid vesicles containing acidic phospholipids, unlike the 18.5 kDa isoform of
      MBP. This result is consistent with J37 having a functional role prior to the
      assembly of compact myelin. Circular dichroic spectroscopy showed that rmJ37 had
      a large proportion of random coil in aqueous solution but gained alpha-helix and
      beta-sheet in the presence of monosialoganglioside G(M1) and PI(4)P. Thus, like
      "classic" MBP, J37 is intrinsically unstructured, and its conformation depends on
      its environment and bound ligands. Analyses of the amino acid sequence of rmJ37
      predicted an N-terminal calmodulin (CaM)-binding site. It was determined via a
      gel-shift assay and fluorescence spectroscopy that rmJ37 and CaM interacted in a
      1:1 ratio in a Ca(2+)-dependent manner. However, the interaction was weak
      compared with 18.5 kDa MBP.

PMID- 12605406
TI  - Estrogen receptor-alpha is required for estrogen-induced mu-opioid receptor
      internalization.
AB  - Endogenous opioid circuits are pivotal for the regulation of sexual receptivity.
      Treatment of mice with morphine, a preferential mu-opioid receptor (MOR) agonist,
      severely attenuates lordosis. Estrogen induces internalization of MOR in cell
      groups of the limbic-hypothalamic lordosis-regulating circuit. Because rapid MOR
      internalization is mediated by estrogen release of endogenous opioid peptides,
      internalization has been used as a neurochemical signature of estrogen action in
      the central nervous system. Together these results indicate that estrogen induces
      a MOR mediated inhibition of sexual receptivity. To determine which estrogen
      receptor, estrogen receptor-alpha (ERalpha) or estrogen receptor-beta (ERbeta),
      mediates MOR internalization, ERalpha knockout (ERalphaKO), ERbeta knockout
      (ERbetaKO) and wild-type (WT) mice were used in the present study. WT, ERalphaKO
      and ERbetaKO mice had similar MOR distributions in the limbic-hypothalamic
      lordosis-regulating circuit. Estrogen treatment internalized MOR in the medial
      preoptic nucleus of ovariectomized WT and ERbetaKO, but not ERalphaKO mice.
      Treatment of ERalphaKO mice with the selective endogenous MOR ligand, endomorphin
      1, induced levels of MOR internalization similar to WT mice suggesting that MOR
      in ERalphaKO mice could be activated and were probably functional. The results of
      the present experiments indicate that ERalpha is required for estrogen-induced
      MOR internalization and suggest that ERalpha can mediate rapid actions of
      estrogen.

PMID- 12605405
TI  - Monoaminergic control of vasopressin and VIP expression in the mouse
      suprachiasmatic nucleus.
AB  - We studied the effects of serotonin and noradrenaline on the expression of
      arginine-vasopressin (AVP) and vasoactive intestinal peptide (VIP) in the
      suprachiasmatic nucleus (SCN). We used transgenic Tg8 mice knockout for the MAO-A
      (monoamine oxidase A) gene, which are characterized by increased amounts of
      serotonin and noradrenaline in brain compared to wild-type mice (C3H). The MAO-A
      deficiency caused an increase in AVP and VIP expression (determined by
      immunohistochemistry, enzyme immunoassay, and in situ hybridization) compared to
      C3H mice. The number of peptidergic neurons was also increased. Inhibiting
      serotonin or noradrenaline synthesis in Tg8 mice by the administration of
      parachlorophenylalanine or alpha-methylparatyrosine, respectively, the amounts of
      AVP, VIP and their mRNAs were decreased, but not the number of peptidergic
      neurons. This study indicates that serotonin and noradrenaline stimulate AVP and
      VIP expression, and could participate in the differentiation of the neurochemical
      phenotype in the mouse SCN.

PMID- 12605407
TI  - Influence of serum-free medium on the expression of glutamate transporters and
      the susceptibility to glutamate toxicity in cultured cortical neurons.
AB  - The presence of glia and glial glutamate transporters seems to modify glutamate
      mediated toxicity in neuronal cultures. In this work we cultured cortical cells
      in serum-containing medium and in a serum-free medium (Neurobasal medium + B27
      supplement) and studied the expression of the glutamate transporters GLAST, GLT,
      and EAAC by immunocytochemistry and RT-PCR. The proportion of glial cells was
      below 10% in the Neurobasal medium and 46% in the serum-containing medium.
      Semiquantitative evaluation of the mRNA for the glutamate transporters showed
      similar amounts in cells grown in serum-free and serum-containing media. We
      detected immunoreactivity for the three transporters in both media, but EAAC was
      coexpressed with the neuronal marker MAP2, whereas GLAST and GLT predominated in
      nonneuronal cells. When the cultures were treated with glutamate for 15 min, the
      cultures in serum-containing medium showed a clear concentration-dependent
      neuronal death, whereas cells primed in this medium and switched to Neurobasal
      medium, as well as cells grown only in the latter, were less sensitive to
      glutamate concentrations up to 1 mM. A similar difference in the sensitivity to
      excitotoxicity was observed when the glutamate uptake inhibitor L-trans-2,4
      pyrrolidine-dicarboxylate was applied during 6 hr, although the accumulation of
      extracellular glutamate was similar in the two media. We conclude that glutamate
      transporters with the culture conditions studied are sensitive to glutamate
      uptake inhibition and that Neurobasal/B27 medium protects cells against
      excitotoxicity.

PMID- 12605408
TI  - Differential regulation of 5' splice variants of the glutamate transporter EAAT2
      in an in vivo model of chemical hypoxia induced by 3-nitropropionic acid.
AB  - Defective glutamate uptake has been implicated as a pathogenic event of neuronal
      damage related to cerebral ischemia and hypoxia. In several models of ischemia
      hypoxia, a reduced immunoreactivity and altered RNA expression of excitatory
      amino acid transporter 2 (EAAT2), the major excitatory amino acid transporter,
      have been reported. However, the gene regulation of EAAT2 under these conditions
      is incompletely understood. In this study, we investigated alternative splicing
      of EAAT2 in an in vivo mouse model of chemical hypoxia as induced by 3
      nitropropionic acid (3-NP). The neurotoxin 3-NP is an inhibitor of mitochondrial
      energy production. Furthermore, it is known to inhibit glutamate reuptake
      directly, representing at least one of the mechanisms responsible for 3-NP
      induced neurodegeneration. Here we report an expression analysis of five known
      (mEAAT2/5UT1-5) and two novel (mEAAT2/5UT6, -7) 5' splice variants of EAAT2 using
      semiquantitative PCR. The RNA expression was studied at 2, 12, 24, 48, and 72 hr
      and 7 days after 3-NP administration. mEAAT2/5UT4 and mEAAT2/5UT5 were up
      regulated in the frontal cortex and down-regulated in the hippocampus 12-72 hr
      after chemical hypoxia. In the cerebellum, there was an increased expression of
      mEAAT2/5UT4 and a down-regulation of mEAAT2/5UT5. mEAAT2/5UT3 show a different
      regional expression pattern, being regulated in the cerebellum only. mEAAT2/5UT1
      7 encoded distinct 5' regulatory sequences, including conserved elements of
      translational control. It is easily conceivable that expression alterations of 5'
      splice variants of EAAT2 are related to glutamate transporter malfunction after
      chemical hypoxia. Our findings contribute to the hypothesis that RNA splicing
      events can serve as a molecular mechanism of posthypoxic gene regulation.

PMID- 12605409
TI  - Normal metabolism but different physical properties of myelin from mice deficient
      in proteolipid protein.
AB  - Proteolipid protein (PLP) is the primary protein component of CNS myelin, yet
      myelin from the PLP(null) mouse has only minor ultrastructural abnormalities.
      Might compensation for a potentially unstable structure involve increased myelin
      synthesis and turnover? This was not the case; neither accumulation nor in vivo
      synthesis rates for the myelin-specific lipid cerebroside was altered in
      PLP(null) mice relative to wild-type (wt) animals. However, the yield of myelin
      from PLP(null) mice, assayed as levels of cerebroside, was only about 55% of wt
      control levels. Loss of myelin occurred during initial centrifugation of brain
      homogenate at 20,000g for 20 min, which is sufficient to sediment almost all
      myelin from wt mice. Cerebroside-containing fragments from PLP(null) mice
      remaining in the supernatant could be sedimented by more stringent
      centrifugation, 100,000g for 60 min. Both the rapidly and the more slowly
      sedimenting cerebroside-containing membranes banded at the 0.85/0.32 M sucrose
      interface of a density gradient, as did myelin from wt mice. These results
      suggest at least some myelin from PLP(null) mice differs from wt myelin with
      respect to physical stability (fragmented into smaller particles during
      dispersion) and/or density. Alternatively, slowly sedimenting cerebroside
      containing particles could be myelin precursor membranes that, lacking PLP, were
      retarded in their processing toward mature myelin and thus differ from mature
      myelin in physical properties. If this is so, recently synthesized cerebroside
      should be preferentially found in these "slower-sedimenting" myelin precursor
      fragments. Metabolic tracer experiments showed this was not the case. We conclude
      that PLP(null) myelin is physically less stable and/or less dense than wt myelin.

PMID- 12605411
TI  - Paracetamol effectively reduces prostaglandin E2 synthesis in brain macrophages
      by inhibiting enzymatic activity of cyclooxygenase but not phospholipase and
      prostaglandin E synthase.
AB  - Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs
      (NSAIDs) are neuroprotective, although the mechanisms underlying their beneficial
      effect remain largely unknown. Given their well-known adverse effects, which of
      the NSAIDs is the best for neurodegenerative disease management remains a matter
      of debate. Paracetamol is a widely used analgesic/antipyretic drug with low
      peripheral adverse effects, possibly related to its weak activity as inhibitor of
      peripheral cyclooxygenase (COX), the main target of NSAIDs. As microglia play an
      important role in CNS inflammation and pathogenesis of neurodegenerative
      diseases, we investigate the effect of paracetamol on rat microglial cultures.
      Although less potent than other NSAIDs, (indomethacin approximately NS-398 >
      flurbiprofen approximately piroxicam > paracetamol approximately acetylsalicylic
      acid), paracetamol completely inhibited the synthesis of prostaglandin E(2)
      (PGE(2)) in lipopolysaccharide-stimulated microglia, when used at concentrations
      comparable to therapeutic doses. The drug did not affect the expression of the
      enzymes involved in PGE(2) synthesis, i.e., COX-1, COX-2, and microsomal PGE
      synthase, or the release of the precursor arachidonic acid (AA). Paracetamol
      inhibited the conversion of exogenous AA, but not PGH(2), into PGE(2) indicating
      that the target of the drug is COX activity. Consistently, paracetamol inhibited
      with similar IC(50) the synthesis of PGF(2alpha) and thromboxane B(2), two other
      COX metabolites. Finally, none of the NSAIDs affected the productions of nitric
      oxide and tumor necrosis factor(alpha), two inflammatory mediators released by
      activated microglia. As paracetamol was reported to inhibit PG synthesis in
      peripheral macrophages with an IC(50) at least three orders of magnitude higher
      than in microglia, we suggest that this drug represents a good tool for treating
      brain inflammation without compromising peripheral PG synthesis.

PMID- 12605410
TI  - Altered expression of CHL1 by glial cells in response to optic nerve injury and
      intravitreal application of fibroblast growth factor-2.
AB  - The close homologue of L1 (CHL1) is a member of the L1 family of cell recognition
      molecules. The protein is expressed by a variety of nerve cell types and
      subpopulations of glial cells in vivo and promotes elongation of neurites and
      survival of nerve cells in vitro. Here we demonstrate that glial cells up
      regulate expression of CHL1 in response to an intraorbital crush of the adult
      mouse optic nerve. We also demonstrate that a single intravitreal application of
      fibroblast growth factor-2 (FGF-2) increases expression of CHL1 in retinal
      astrocytes and Muller cells. Elevated expression of CHL1 by glial cells in
      injured optic nerves and astrocytes and Muller cells in FGF-2-treated retinas
      suggests a role of the protein in the lesioned central nervous system. Results
      also suggest that trophic factors might exert part of their biological function
      by modifying expression of cell recognition molecules.

PMID- 12605412
TI  - Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit
      hippocampus but does not prevent oxidative damage and tau phosphorylation.
AB  - The goal of this study was to assess the in vivo effect of Abeta on apoptosis
      pathways involving the endoplasmic reticulum and mitochondria, and its
      relationship to the induction of tau phosphorylation and DNA oxidative damage. In
      rabbits treated intracisternally with aggregated Abeta(1-42), clear evidence of
      endoplasmic reticulum stress was observed by the activation of caspase-12 and
      cleavage of caspase-3 in the endoplasmic reticulum. Mitochondrial injury was
      evident from the release of cytochrome c into the cytosol and the induction of
      oxidized mitochondrial DNA. Tau phosphorylation and nuclear translocation of NF
      kappaB and GSK-3beta were also observed. Treatment with lithium, an inhibitor of
      GSK-3beta, inhibited caspase activation but did not prevent mitochondrial DNA
      damage or tau hyperphosphorylation, suggesting that the translocation of GSK
      3beta may represent an upstream event that leads to caspase activation but is
      unrelated to tau hyperphosphorylation or mitochondrial DNA oxidative damage. We
      propose that treatment by lithium alone is not sufficient to protect against the
      multiple adverse effects of Abeta, and the use of agents that prevent oxidative
      DNA damage and tau hyperphosphorylation, together with lithium, may provide
      better protection from the neurotoxic effect of Abeta.

PMID- 12605414
TI  - High level of amyloid precursor protein expression in neurite-promoting olfactory
      ensheathing glia (OEG) and OEG-derived cell lines.
AB  - During all the life of a mammal, olfactory ensheathing glia (OEG) permit the
      entry and navigation of olfactory neuron axons from peripheral to central nervous
      system (CNS) territory. This physiological characteristic of OEG has been
      successfully used for promotion of axonal regeneration after CNS injury in animal
      models. However, cellular and molecular properties responsible for OEG
      regenerative ability remain to be unveiled. Two approaches may be followed: to
      carry out genomic or proteomic analysis to detect secreted and/or membrane bound
      molecules or to examine the expression of molecules previously described as
      neuritogenic. This is the case of amyloid precursor protein (APP), a neurite
      promoting molecule. We have studied the expression of APP by OEG and OEG-derived
      clonal lines, immortalised with the large T antigen of SV40 (TEG lines). OEG
      express high levels of APP in vivo and in culture. TEG lines maintained high
      expression of APP. Western blot analysis showed the presence of high molecular
      weight forms of APP in OEG, corresponding probably to glycosylated forms and/or
      to higher expression of the full length APPs. The main APP isoforms present in
      OEG cultures were APP770 and 751. L-APP isoforms without the exon 15, which are
      those corresponding with proteoglycan forms, are predominant in glial cells. Our
      data showed that OEG had three times as much L-APP as astrocytes, which may
      correlate with OEG neuritogenic capacity. In conclusion APP, a neurite-promoting
      molecule, is produced by OEG. Its nexin activity, dependent on the Kunitz family
      of serine protease inhibitors (KPI) domain and/or in combination with its
      glycosylation level might contribute with other factors to the ability of these
      cells to foster axonal elongation.

PMID- 12605413
TI  - Effect of the lipid peroxidation product acrolein on tau phosphorylation in
      neural cells.
AB  - A hallmark of several neurodegenerative disorders, including Alzheimer's disease
      and tauopathies, is the hyperphosphorylation of the microtubule-associated
      protein tau. Tau phosphorylation by proline-directed and non-proline-directed
      protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The
      effect of the lipid peroxidation product acrolein on these modes of
      phosphorylation has been assayed. We have found that acrolein, a peroxidation
      product from arachidonic acid, increases the phosphorylation of tau at the site
      recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of
      mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein
      at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3
      (which is also activated in response to Abeta peptide), the acrolein-induced tau
      hyperphosphorylation at the same site is also due to p38 stress-activated kinase.
      These results support the view that oxidative stress and subsequent formation of
      lipid peroxidation products may contribute to tau protein phosphorylation in
      Alzheimer's disease and tauopathies.

PMID- 12605415
TI  - Hydroxyl radical formation is greater in striatal core than in penumbra in a rat
      model of ischemic stroke.
AB  - Although hydroxyl radical ((*)OH) formation has been implicated in the
      pathophysiological changes of ischemic stroke, (*)OH production in the core and
      penumbra regions is not clear. It is extremely important to distinguish penumbra
      from ischemic core in focal cerebral ischemia studies, because the penumbra
      contains viable tissue, which can be salvaged by appropriate treatment. This
      study evaluated (*)OH production in both core and penumbra regions of ischemic
      striatum during ischemia and reperfusion. Microdialysis probes were placed in
      striatal tissue of rats subjected to the middle cerebral artery occlusion model
      of ischemic stroke. The (*)OH-trapping agent 4-hydroxybenzoic acid (4-HBA) was
      administered by both i.v. and probe infusion. Dialysate levels of the 4-HBA
      oxidation products, 3,4-dihydroxybenzoic acid (3,4-DHBA), were determined by HPLC
      ECD. After microdialysis probe delivery of 4-HBA, (*)OH production was
      significantly increased in the striatal core during both ischemia and
      reperfusion. Penumbra (*)OH production increased only during reperfusion.
      Alterations of 3,4-DHBA concentration in dialysate following i.v. 4-HBA
      administration were likely related to alterations in tissue blood flow. The
      findings were confirmed by a greater oxidation of dihydroethidium in the ischemic
      core than in the penumbra as determined by fluorescent microscopy. The findings
      of (*)OH production in ischemic striatum are the opposite of those reported for
      ischemic cortex and suggest critical regional variations in (*)OH production that
      may have significant clinical implications in the treatment of ischemic stroke.

PMID- 12605416
TI  - Neurotoxicity from glutathione depletion is dependent on extracellular trace
      copper.
AB  - Glutathione (GSH) is an important antioxidant, and its depletion in neurons has
      been implicated in several neurodegenerative disorders. Aberrant copper
      metabolism is also implicated in neurodegeneration and may result in the
      generation of toxic free radicals. However, little is known about the
      relationship between GSH depletion and copper homeostasis. In the present study,
      we examined the role of extracellular trace biometals in neuronal cell death
      induced by GSH depletion. Treatment of primary cortical neurons with buthionine
      sulfoximine (BSO), an inhibitor of GSH synthesis, induced a rapid loss of
      intracellular GSH, leading to decreased neuronal cell viability. Neuronal cell
      death induced by GSH depletion was dependent on trace levels of extracellular
      copper in the culture medium (1.6 microM). Neurons were protected against GSH
      depletion-mediated toxicity when cultured in Chelex 100-treated medium containing
      tenfold less copper (0.16 microM) than normal medium. The addition of copper, but
      not iron or zinc, to Chelex 100-treated medium restored the neurotoxicity induced
      by GSH depletion. Moreover, BSO toxicity in normal medium was inhibited by copper
      chelators. The neurotoxic effects of copper in GSH-depleted neurons involved
      generation of copper(I) and subsequent free radical-mediated oxidative stress.
      These studies demonstrate a critical role for extracellular trace copper in
      neuronal cell death caused by GSH depletion and may have important implications
      for the understanding of toxic processes in neurodegenerative diseases.

PMID- 12605417
TI  - Treatment of acute lymphoblastic leukemia in Hong Kong children: HKALL 93 study.
AB  - A population-based multicentre study for childhood acute lymphoblastic leukemia
      (ALL) was conducted in Hong Kong from 1993 to 1997. One hundred and forty-five
      newly diagnosed ALL patients were treated by the HKALL 93 protocol. Patients were
      stratified into three risk groups according to age, presenting white cell count,
      immunophenotyping and cytogenetic study. The patients received the same induction
      and early and late intensification at week 5 and week 20. Fifty-eight standard
      risk (SR) patients received regular intrathecal methotrexate as CNS preventive
      therapy, while 49 intermediate risk (IR) patients received high dose intravenous
      methotrexate and regular intrathecal methotrexate. Thirty-eight high risk (HR)
      patients were treated with prophylactic cranial irradiation and an additional
      intensification block at week 35. The induction remission rate was 97.2% with 2%
      induction death. Two patients died during first complete remission. Relapse
      occurred in 20.7, 42.9 and 42.1% of SR, IR and HR patients respectively. By
      multivariate logistic regression, age> or =10 years and white cell count> or =100
      x 10(9)/l were the two significant variables accounting for mortality. The 5-year
      overall and event-free survival of the whole group was 81.3 and 62.6%
      respectively. According to risk groups, the event-free survival was 79, 49 and
      61% for SR, IR and HR patients respectively, while the overall survival was 96,
      73 and 68% for SR, IR and HR patients respectively. In conclusion, the treatment
      protocol had low treatment-related mortality but was associated with a rather
      high relapse rate, especially in IR patients. Salvage therapy achieved sustained
      second remission in some patients. More intensive treatment especially a late
      intensification is required to improve the outcome.

PMID- 12605418
TI  - Superoxide radical generation and Mn- and Cu-Zn superoxide dismutases activities
      in human leukemic cells.
AB  - Mn- and Cu-Zn superoxide dismutase (SOD) activities and generation of superoxide
      radicals (O(2) (-)) were assessed in leukemic cells from 10 patients with acute
      myeloid or monocytic leukemia (AML) and 10 patients with acute lymphoblastic
      leukemia (ALL), using a sensitive, specific chemiluminescence method. Leukemic
      cells were classified according to the French-American-British classification. M4
      AML cells from two patients produced some O(2) (-) upon stimulation with
      opsonized zymosan (OZ), phorbol myristate acetate (PMA) or N-formyl-methionyl
      leucyl-phenylalanine (FMLP), but less than normal granulocytes or monocytes. M5b
      AML cells from one patient produced as much O(2) (-) in response to these
      stimulants as normal monocytes. No O(2) (-) generation was induced in other types
      of leukemic cells. Total SOD activity in AML cells was significantly greater in
      normal granulocytes, but was only half of the activity in ALL cells. Mn-SOD in
      AML cells was very low or undetectable. These results suggest that except in M5b
      cells, decreased O(2) (-) production may contribute to susceptibility to
      infections in AML patients. Decreased Mn-SOD activity in AML cells may predispose
      them to oxidative stress.

PMID- 12605419
TI  - Urinary N-telopeptide levels in multiple myeloma patients, correlation with Tc
      99m-sestaMIBI scintigraphy and other biochemical markers of disease activity.
AB  - Urinary cross-linked N-telopeptide of type I collagen (NTx) has been reported to
      be a sensitive and specific marker of bone resorption in multiple myeloma (MM).
      In this study, we measured the levels of NTx in 30 newly diagnosed MM patients
      and 25 controls. We examined its association with the overall score of skeletal
      involvement measured by Tc-99m-MIBI scintigraphy and other biochemical markers of
      bone disease (tumour necrosis factor a (TNF-a), serum calcium and creatinine). We
      further studied the correlation of NTx with the stage of disease (according to
      Durie-Salmon criteria) and bone marrow infiltration by plasma cells. High levels
      of NTx, bone marrow infiltration, TNF-alpha, calcium and creatinine were noted at
      advanced stages of disease (p < 0.05). NTx and TNF-a were found at significantly
      higher concentrations in patients with a high overall score (3 and 4) in Tc-99m
      sestaMIBI in comparison to a low score (0, 1 and 2; p < 0.05). Positive
      correlations were found between NTx and TNF-a, as well as between bone
      infiltration and TNF-a or calcium. In conclusion, NTx is a useful marker for the
      monitoring of bone resorption in MM and correlates with imaging findings on Tc
      99m-sestaMIBI and other biochemical markers of disease activity.

PMID- 12605420
TI  - Detection and monitoring of clonality in peripheral blood and bone marrow of
      patients with B-cell lymphoproliferative disorders.
AB  - Bone marrow (BM) is accepted as the tissue of choice for the detection of
      monoclonal populations in leukemias and lymphomas; however, obtaining BM can be
      painful and traumatic for the patients. Although it is possible to detect
      clonality in peripheral blood (PB) samples, there are no reports comparing the
      results observed from BM with those from PB. Lymphoblastic leukemias and
      lymphomas are derived from B-lymphocytes in 80% of cases. In the early stages of
      their maturation, the immunoglobulin heavy chain genes (IgH) undergo
      rearrangements among their V, D, and J segments, giving rise to the
      Complementarity Determining Regions (CDR). Of these, CDR3 is unique for each
      lymphocyte and therefore it can be used as a tumour-specific marker in these
      malignant disorders. Among the 104 patients from whom we obtained pre-treatment
      paired samples of PB and BM, 94 (90.4%) showed concordant results. Similarly, at
      the end of treatment, 40 of 44 patients (90.9%) showed this concordance. During
      treatment only 24 patients were monitored and monoclones disappeared in 12
      patients; in the other half, they persisted either partial or totally. We
      demonstrate that the detection and monitoring of monoclonal populations in the
      PB, in comparison with BM, was achieved with a statistical sensitivity of 90% and
      specificity of 92%.

PMID- 12605421
TI  - T cells in myeloma.
AB  - The current trend to develop immunotherapy strategies for patients with myeloma
      and other B cell malignancies has stimulated considerable interest in the
      functional state of the T cell population in these patients. Expanded clones of T
      cells exist in many patients with myeloma and their presence is associated with
      an improved survival. However, isolating T cells with tumour specificity has
      proven to be a difficult task and clinical immunization trials have so far failed
      to achieve a significant response. There is now evidence that tumour specific T
      cells are either tolerized or deleted following antigen presentation and that
      idiotype-derived, immunodominant tumour peptides may not exist in all patients.
      In order to develop more effective immunotherapy strategies for patients with
      myeloma, further studies are urgently required to identify the most appropriate
      tumour antigen, the nature of the interactions which take place during antigen
      presentation, and how to promote the cytotoxicity of autologous T cells.

PMID- 12605422
TI  - Koebnerization of reactive perforating collagenosis induced by laser hair
      removal.
AB  - Laser hair removal, due to demonstrated efficacy and safety, has become a
      commonly performed office procedure. We report an unusual occurrence after laser
      hair removal with the 800 nm diode laser that previously has never been
      described. After laser hair removal treatment to the ventral surface of the ears,
      a patient developed lesions of previously diagnosed reactive perforating
      collagenosis. Interestingly, the lesions appeared on the dorsal surface of the
      ears. Perhaps the koebner phenomenon was invoked as the laser energy penetrated
      to the untreated dorsal surface, which was not protected by epidermal contact
      cooling.

PMID- 12605423
TI  - Cancer "photo-chemoprevention" with pulsed dye laser and celecoxib.
AB  - BACKGROUND AND OBJECTIVES: Our previous study demonstrated the efficacy of pulsed
      dye laser (PDL) in inhibiting cancer growth. This study is to determine the
      synergic effect of PDL and Celecoxib, when they are combined for treatment of
      oral cancer. STUDY DESIGN/MATERIALS AND METHODS: Fifteen mice were inoculated
      with oral cell carcinoma and divided into three groups of five each (30 seeding
      sites/group): (1) control (no treatment), (2) PDL only, and (3) treatment with
      combined PDL and Celecoxib (1,500 ppm). The number and volume of tumors were
      counted and measured for 21 days. RESULTS: The combined treatment developed tumor
      at the slowest rate. On day 21, the average tumor volumes were (1) 483.6 mm(3)
      (control), (2) 312.1 mm(3) (PDL only), and (3) 151.4 mm(3) (combined treatment).
      CONCLUSIONS: A synergic effect was found in the combined treatment group. This
      study provides the first evidence of the efficacy of a new strategy for the
      treatment of oral cancer, namely, cancer "photo-chemoprevention."

PMID- 12605424
TI  - Acceleration of ALA-induced PpIX fluorescence development in the oral mucosa.
AB  - BACKGROUND AND OBJECTIVES: The development of 5-aminolevulinic acid (ALA)-induced
      tissue fluorescence is optimal 2-4 hours after ALA application. Goal of this work
      was to develop a means of accelerating oral topical ALA-induced tissue
      fluorescence. STUDY DESIGN/MATERIALS AND METHODS: In 300 hamsters, DMBA (9,10
      dimethyl-1,2-benzanthracene) cheek pouch carcinogenesis produced dysplasia in 3-5
      weeks. Topical application of 20% ALA in Eucerin was followed by localized
      ultrasound treatment (1, 3.3 MHz) in 150 animals. In 75 animals, ALA was applied
      in an Oral Pluronic Lecithin Organogel (OPLO-an absorption enhancer) vehicle.
      Seventy-five animals received only topical ALA in Eucerin. Hamsters were
      sacrificed and cryosections underwent fluorescence measurements, histological
      evaluation, 20-180 minutes after ALA application. One-way ANOVA detected
      independent effects of pathology on laser-induced fluorescence (LIF). Two-way
      ANOVA tested for independent effect of pathology and of OPLO, ultrasound, and
      interaction effects. RESULTS: Ultrasound significantly (P < 0.05) accelerated
      tissue fluorescence development. CONCLUSIONS: Low-frequency ultrasound can
      accelerate ALA-induced fluorescence development.

PMID- 12605426
TI  - Factors affecting the antibacterial effects of Nd:YAG laser in vivo.
AB  - BACKGROUND AND OBJECTIVES: One of the main advantages of laser surgery is it's
      bactericidal effect which reduces the risk of postoperative infections. Several
      study designs have been set to investigate this effect. Aim of this study was to
      research if the bactericidal effect of laser tool was affected from several
      factors in vitro studies. STUDY DESIGN/MATERIALS AND METHODS: To determinate and
      investigate the bactericidal effect of laser in an original model, alpha
      hemolytic streptococcus, Bacterioides fragilis, Neisseria, Streptococcus
      salivarius, Staphylococcus aureus, and Candida albicans were prepared in 10(4),
      10(6) and 10(8) inoculum and placed in Mueller-Hinton Broth which have five
      different proportions of sheep blood. Samples which exposed with various energy
      levels of Nd:YAG laser were spread on agar plates, and at the end of an
      incubation time the colonization counted comparatively. The lowest energy level
      without colonization was accepted as minimal bactericidal energy level. RESULTS:
      Highest minimum bactericidal energy level is used for alpha-hemolytic
      streptococcus and lowest values for neisseria. Bactericidal effect decreased on
      suspensions, of which population of microorganisms are high and hemoglobin
      concentration was high in the broth. CONCLUSIONS: These findings suggest that the
      Nd:YAG laser has a higher bactericidal effect when sheep blood is added to the
      media. Factors like population and type of bacteria in the irradiated suspension
      affect minimum bactericidal energy level.

PMID- 12605425
TI  - Efficacy of NaOCl/H2O2 irrigation and GaAlAs laser in decontamination of root
      canals in vitro.
AB  - BACKGROUND AND OBJECTIVES: To investigate the bactericidal effect of an 809 nm
      semiconductor laser alone, and in combination with NaOCl/H(2)O(2) irrigation in
      root canals in vitro. STUDY DESIGN/MATERIALS AND METHODS: A total of 72 human
      single-rooted teeth extracted for periodontal reasons were included. The crowns
      were removed, the roots shortened to a length of 12 mm, and the canals enlarged
      up to an apical size of #50 file. The specimens were autoclaved and incubated
      with a suspension of Streptococcus sanguinis (ATCC 10556). Laser irradiation was
      performed on a PC-controlled XY translation stage. A 200 micron optic fiber was
      used. Twelve specimens were irradiated at a power output of 1.5, 3.0, and 4.5 W
      in the cw-mode. The total irradiation time was 60 seconds per canal. Twelve
      specimens were rinsed with NaOCl and H(2)O(2) only, 12 were rinsed and laser
      treated, and 12 served as untreated controls. After laser treatment, the
      specimens were sonicated and the bacterial growth was examined by counting colony
      forming units on blood agar plates. Temperature changes at the outer root surface
      during irradiation were registered by means of thermocouples. Treated and control
      specimens were investigated by means of scanning electron microscopy. RESULTS:
      Mean bacterial reductions of 0.35 log steps at a power output of 1.5 W, 1.44 at
      3.0 W, and 2.84 at 4.5 W were calculated. Bacterial reduction by the
      NaOCl/H(2)O(2) solution alone was 1.48 and comparable to that achieved by
      irradiation at 3.0 W. With a log kill 2.85, the combination of rinsing and laser
      irradiation at 3.0 W resulted in a further significant bacterial reduction as
      compared to rinsing alone (P = 0.004). Irradiation did not result in excessive
      heat generation at the root surface. Carbonization of the root canal wall was
      observed in single teeth at 3.0 and 4.5 W and no controlled sealing of the
      dentinal tubules could be achieved in the root canal. CONCLUSIONS: The
      application of the diode laser might be an adjunct to conventional endodontic
      treatment when used in combination with a NaOCl/H(2)O(2) solution.

PMID- 12605427
TI  - Pulpal response to Er:YAG laser drilling of dentine in healthy human third
      molars.
AB  - BACKGROUND AND OBJECTIVES: Maintenance of pulpal health is a critical
      prerequisite for successful application of light amplification by stimulated
      emission of radiations (lasers) in the hard tissue management of vital teeth. The
      purpose of this study was to investigate the short- and long-term pulpal effects
      to cavity-preparations in healthy human teeth using erbium-doped:yttrium,
      aluminum, and garnet (Er:YAG) laser. MATERIALS AND METHODS: A total of seven
      healthy third molars that were to be removed due to space-problem were used.
      Following the laser excavation, the cavities in dentine were closed temporarily
      and the teeth were extracted after 7 days (n = 5) and 3 months (n = 2) post
      operation. The specimens were fixed, decalcified, subdivided, and processed for
      light and transmission electron microscopy. RESULTS: In the short-term group,
      four of the five laser-drilled teeth did not reveal any pathological changes in
      the pulp-dentine complex. One tooth showed mild disruption of odontoblasts (OB)
      and vascular dilatation subjacent to the deepest point of the cavity-preparation
      with a remaining dentine thickness (RDT) of less than 80 microm. The two teeth
      under long-term observation revealed distinct apposition of tertiary dentine
      (TD), lined predominantly with cuboidal cells on its pulpal aspect. CONCLUSIONS:
      These results would allow a conclusion to be drawn that the Er:YAG laser under
      investigation is a pulp preserving hard-tissue drilling tool when used with the
      specific energy settings and emitting radiation at a wavelength of 2.94 microm.

PMID- 12605428
TI  - Raman spectroscopy for optical diagnosis in normal and cancerous tissue of the
      nasopharynx-preliminary findings.
AB  - BACKGROUND AND OBJECTIVES: Raman spectroscopy (RS), which can detect molecular
      changes associated with cancer, was explored as a means of distinguishing normal
      and cancerous nasopharyngeal tissue. STUDY DESIGN/PATIENTS AND METHODS: Tissue
      from six patients with normal and cancerous biopsies was studied using a rapid
      acquisition Raman spectrometer. RESULTS: Spectra were obtainable within 5
      seconds. Consistent differences were noted between normal and cancer tissue in
      three bands 1,290-1,320 cm(-1) (P = 0.005), 1,420-1,470 cm(-1) (P = 0.006), and
      1,530-1,580 cm(-1) (P = 0.002). CONCLUSIONS: Spectral differences appear to exist
      between normal and cancerous nasopharyngeal tissue. The ability to obtain spectra
      rapidly supports the potential for future in vivo application.

PMID- 12605429
TI  - Preliminary biocompatibility experiment of polymer films for laser-assisted
      tissue welding.
AB  - BACKGROUND AND OBJECTIVES: The purpose of this study was to examine the impact of
      a polymer film for liquid solder strength reinforcement on the short term healing
      of a wound closed by laser-tissue soldering. MATERIALS AND METHODS: Full
      thickness incisions created on the dorsum of Sprague-Dawley rats were closed by
      laser-tissue soldering: albumin solder with Indocyanine Green (ICG) dye was
      inserted between the incision edges and photothermally coagulated with a diode
      laser. A poly(DL-lactic-co-glycolic acid) (PLGA) polymer film was implanted
      subcutaneously in the bottom of the incision (controls had no film). Specimens
      were harvested at 0, 3, 7, and 14 days for breaking strength testing and
      histological analysis. RESULTS: Breaking strengths of the controls at 0 and 14
      days were statistically stronger than the specimens with the implanted films (t
      test, P < 0.05). A slight difficulty in apposing the wound edges due to the film
      presence may have contributed to the low acute strengths. Interference with the
      wound contraction process by the films possibly contributed to the lower breaking
      strength at 14 days. Wound histology indicated a mild foreign body reaction to
      the polymer film material. CONCLUSIONS: The polymer film was well tolerated by
      the tissue, and the tissue response to the material was consistent with that seen
      in the literature. The breaking strength differences between control and film
      implanted specimens at 0 and 14 days were probably the result of mechanical
      complications (tissue apposition and wound contraction) due to the presence of
      the film, and not due to the film material itself. The use of polymer film
      patches for liquid solder reinforcement and breaking strength enhancement may
      have certain application specific issues that need to be addressed. Strategies to
      account for these issues require further research.

PMID- 12605430
TI  - A multispectral fluorescence imaging system: design and initial clinical tests in
      intra-operative Photofrin-photodynamic therapy of brain tumors.
AB  - BACKGROUND AND OBJECTIVES: Intra-operative identification of tumor by
      fluorescence may improve surgical resection or photodynamic therapy (PDT). A
      novel instrument was designed, constructed, and tested for this purpose. STUDY
      DESIGN/MATERIALS AND METHODS: The instrument was designed to provide high
      resolution, multi-spectral (five band) fluorescence imaging, and non-contact
      point spectroscopy, with long working distance ( approximately 50 cm), large
      field-of-view ( approximately 3 cm diameter), large depth of view ( approximately
      2 cm), and 'point-and-shoot' operation. Its performance was determined in tissue
      simulating phantoms and in pilot studies in brain tumor resection patients, with
      or without intra-operative Photofrin-PDT. RESULTS: In phantoms the imaging
      resolution was approximately 150 microm, while Photofrin concentrations as low as
      0.05 or 0.1 microg/g could be detected at the tissue surface or at 0.5 mm depth,
      respectively. Red Photofrin fluorescence could be clearly visualized post radical
      resection in all PDT patients, with biopsy confirmation of residual tumor tissue
      in regions that were not seen as tumor under white light. Photobleaching of
      Photofrin during PDT was also demonstrated. CONCLUSIONS: The system performed to
      specification under realistic operating conditions and could reveal unresected
      residual tumor tissue. It may be used for either PDT dosimetry/monitoring and/or
      for surgical guidance.

PMID- 12605431
TI  - Efficacy of low power laser therapy and exercise on pain and functions in chronic
      low back pain.
AB  - BACKGROUND AND OBJECTIVES: The aim of this study was to determine whether low
      power laser therapy (Gallium-Arsenide) is useful or not for the therapy of
      chronic low back pain (LBP). STUDY DESIGN/MATERIALS AND METHODS: This study
      included 75 patients (laser + exercise-25, laser alone-25, and exercise alone-25)
      with LBP. Visual analogue scale (VAS), Schober test, flexion and lateral flexion
      measures, Roland Disability Questionnaire (RDQ) and Modified Oswestry Disability
      Questionnaire (MODQ) were used in the clinical and functional evaluations pre and
      post therapeutically. A physician, who was not aware of the therapy undertaken,
      evaluated the patients. RESULTS: Significant improvements were noted in all
      groups with respect to all outcome parameters, except lateral flexion (P < 0.05).
      CONCLUSIONS: Low power laser therapy seemed to be an effective method in reducing
      pain and functional disability in the therapy of chronic LBP.

PMID- 12605432
TI  - Influence of low level laser therapy on wound healing and its biological action
      upon myofibroblasts.
AB  - BACKGROUND AND OBJECTIVE: In re-evaluating the effects of laser therapy in wound
      healing, the role of extracellular matrix elements and myofibroblasts, was
      analyzed. STUDY DESIGN/MATERIALS AND METHODS: Cutaneous wounds were inflicted on
      the back of 72 Wistar rats. Low level laser was locally applied with different
      energy densities. Lesions were analyzed after 24, 48, 72 hours and 5, 7, and 14
      days. Tissues were studied by histology, immunohistochemistry, and electron
      microscopy. RESULTS: In treated animals, the extent of edema and the number of
      inflammatory cells were reduced (P < 0.05), but the amount of collagen and
      elastic fibers appeared slightly increased. Desmin/smooth muscle alpha-actin
      phenotype myofibroblasts were statistically more prominent on the 3rd day after
      surgery (P < 0.05) in treated wounds than in controls. Treatment with a dosage of
      4 J/cm(2) was superior to that with 8 J/cm(2). CONCLUSIONS: Laser therapy reduced
      the inflammatory reaction, induced increased collagen deposition and a greater
      proliferation of myofibroblasts in experimental cutaneous wounds.

PMID- 12605433
TI  - Personality profiles of children and adolescents with neurofibromatosis type 1.
AB  - The personality profile of 44 youngsters (24 males, 20 females; mean age 11
      years, 3 months) with neurofibromatosis type 1 (NF1) was compared with a group of
      220 non-NF1 control youngsters (matched on age and gender). Personality
      characteristics of each youngster were rated by both parents, using the
      California Child Q-set (CCQ); [Block and Block, 1980]. The scores on eight
      personality dimensions were compared, i.e., Extraversion, Agreeableness,
      Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability,
      and Dependency. Moreover, personality of NF1 youngsters was related to IQ level,
      severity of medical problems, the presence or absence of visible cosmetic
      disfiguring, and de novo versus familial origin of NF1. The personality profile
      of NF1 youngsters was markedly different from the non-NF1 youngsters. Compared to
      the 220 control children, they were equally agreeable, but less conscientious,
      less emotionally stable, less open for new experience, with less motor activity,
      and more extravert, more dependent, and more irritable. Personality
      characteristics were similar for children with maternally or paternally inherited
      NF1, or for children with a new mutation. There was no association with gender,
      the severity of medical and cosmetic problems, and IQ.

PMID- 12605434
TI  - Further delineation of the behavioral and neurologic features in Costello
      syndrome.
AB  - To describe clinical and neurodevelopmental phenotypes of Costello syndrome, we
      performed a retrospective review of the clinical records and findings in 10
      children with Costello syndrome. All patients showed significant postnatal growth
      retardation and severe feeding difficulties leading to failure to thrive from
      early infancy. All required tube feeding and some needed high-calorie formulas
      for variable periods. Developmental quotients/IQs in seven children were 50 or
      less, and three were in the mildly retarded range. Five had seizures. Remarkable
      manifestations not previously reported were the characteristic behavior in
      infancy. Although happy and sociable personality was always emphasized in the
      genetic literature, all children showed significant irritability, including
      hypersensitivity to sound and tactile stimuli, sleep disturbance, and excess
      shyness with strangers in infancy. Those symptoms usually disappeared around age
      2-4 years. Other clinical signs included cardiac abnormalities (8),
      musculoskeletal abnormalities (10), ophthalmological manifestations (5),
      increased urinary vanillymandelic acid (VMA) and homovanillic acid (HVA) (3),
      rhabdomyosarcoma (1), laryngomalacia (1), and cryptorchidism (1). Only three
      girls had papillomata. Family histories were negative for Costello syndrome. In
      conclusion, we confirm the wide spectrum of mental function in patients with
      Costello syndrome, which ranges from severe to mild. During infancy Costello
      syndrome showed remarkable irritability with severe feeding problems, which
      attributes significant difficulties to the parents of affected children.

PMID- 12605435
TI  - Complex chromosomal rearrangement and associated counseling issues in a family
      with Pelizaeus-Merzbacher disease.
AB  - We report cytogenetic and molecular findings in a family in which Pelizaeus
      Merzbacher disease has arisen by a sub-microscopic duplication of the proteolipid
      protein (PLP1) gene involving the insertion of approximately 600 kb from Xq22
      into Xq26.3. The duplication arose in an asymptomatic mother on a paternally
      derived X chromosome and was inherited by her son, the proband, who is affected
      with Pelizaeus-Merzbacher disease. The mother also carries a large interstitial
      deletion of approximately 70 Mb extending from Xq21.1 to Xq27.3, which is present
      in a mosaic form. In lymphocytes, the mother has no normal cells, having one
      population with three copies of the PLP1gene (one normal X and one duplication X
      chromosome) and the other population having only one copy of the PLP1 gene (one
      normal X and one deleted X chromosome). Her karyotype is 46,XX.ish dup (X) (Xpter
      --> Xq26.3::Xq22 --> Xq22::Xq26.3 --> Xqter)(PLP++)/46,X,del(X)(q21.1q27.3).ish
      del(X)(q21.1q27.3)(PLP-). Both ends of the deletion have been mapped by
      fluorescence in situ hybridization using selected DNA clones and neither involves
      the PLP1 gene or are in the vicinity of the duplication breakpoints. Prenatal
      diagnosis was carried out in a recent pregnancy and the complex counseling issues
      associated with these chromosomal rearrangements are discussed.

PMID- 12605436
TI  - Cytogenetic analysis of obsessive-compulsive disorder (OCD): identification of a
      FRAXE fragile site.
AB  - Obsessive-compulsive disorder (OCD) is a chronic psychiatric disease
      characterized by recurrent obsessions, compulsions, or both. The prevalence rate
      of OCD is 2.1% in the general population. Here we report cytogenetic analysis of
      26 patients affected with OCD. In one male patient (OCD-K33), we identified a
      fragile X chromosome by cytogenetic analysis with 21% of cells demonstrating a
      fragile site at Xq27-q28. Polymerase chain reaction (PCR) and Southern blot
      analysis demonstrated that the molecular basis of the OCD-K33 fragile X
      chromosome was expansion of the CCG repeat at FRAXE. The number of the expanded
      repeats was estimated to be more than 300 copies, qualifying it as a full FRAXE
      mutation. Further analysis of the family members of OCD-K33 revealed another
      member with a full FRAXE mutation (630-1,200 copies of the CCG repeat), who had
      the clinical phenotype of speech impairment, and two other members with normal
      phenotypes and no FRAXE expansion. The two FRAXE expansions lead to complete
      methylation at the CCG repeat. The co-segregation of the full FRAXE mutation with
      apparent neurologic disorders in the same family provides further support to the
      notion that FRAXE is a genetic neurologic condition. Our findings expand the
      spectrum of clinical phenotypes associated with FRAXE mutations.

PMID- 12605437
TI  - X-chromosome inactivation (XCI) patterns in placental tissues of a paternally
      derived bal t(X;20) case.
AB  - Non-random X-chromosome inactivation (XCI) is often seen in female carriers of
      balanced X-autosome translocations and is generally attributed to a selective
      growth of cells that inactivate the normal X chromosome. However, little is known
      concerning when in development the selection acts, and thus whether skewed XCI
      would also be seen in placental tissues. Furthermore, as males with X-autosome
      translocations are normally infertile, all translocations studied to date for XCI
      skewing have been either maternal or de novo in origin. We now present an
      analysis of XCI status in cord blood, umbilical cord and four different
      extraembryonic tissues from a female carrier of a paternally derived balanced
      (X;20) translocation. Using methylation based assays to determine XCI status, we
      found preferential inactivation of the non-translocated X in cord blood,
      umbilical cord and amnion samples of the propositus. Remarkably, random XCI was
      evident in several placental tissues analyzed (chorion, and chorionic villi
      trophoblast and mesenchyme). While these findings support the hypothesis of
      strong selection against cells with an inactive translocated X-chromosome in most
      embryonic/fetal tissues, they also suggest weaker selective forces taking place
      during placental development. Additionally, the finding of normal placental
      development in the present case, rules out the possibility of a parental bias to
      XCI in human extraembryonic tissues as a requisite for normal development. The
      finding of hypomethylation in extraembryonic tissues for two out of three markers
      used in the study is consistent with previous findings demonstrating low levels
      of methylation in these tissues.

PMID- 12605438
TI  - Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with
      autosomal dominant hypodontia.
AB  - We describe the molecular analysis of three families with hypodontia involving
      primarily molar teeth and report two novel mutational mechanisms. Linkage
      analysis of two large families revealed that the hypodontia was linked to the
      PAX9 locus. These two families revealed missense mutations consisting of a
      glutamic acid substitution for lysine and a proline substitution for leucine
      within the paired domain of PAX9. A pair of identical twins affected with
      hypodontia in a third family demonstrated a 288-bp insertion within exon 2 that
      resulted in a putative frameshift mutation and a premature stop codon. The
      insertion was associated with the loss of 7-bp from exon 2. A block of 256-bp of
      sequence within the insertion was completely identical to downstream sequence
      from the second intron of the PAX9 gene. These studies extend the spectrum of
      mutations in PAX9 associated with hypodontia to include heretofore undescribed
      categories, including missense mutations.

PMID- 12605439
TI  - Rapid detection of 17p11.2 rearrangements by FISH without cell culture (direct
      FISH, DFISH): a prospective study of 130 patients with inherited peripheral
      neuropathies.
AB  - Charcot-Marie-Tooth (CMT) disease and hereditary neuropathy with pressure palsies
      (HNPP) are two frequent hereditary motor and sensory neuropathies. CMT is
      characterized by slowly progressive weakness and atrophy, primarily in peroneal
      and distal leg muscles. The most frequent form, CMT1A, is due, in most cases, to
      the duplication of a 1.5 Mb region on chromosome 17p11.2 containing the
      peripheral myelin protein 22 gene (PMP22). The phenotype seems to result from
      dosage of the PMP22 gene. This hypothesis is reinforced by the existence of HNPP,
      which is clinically characterized by various recurrent truncular palsies or
      sensory loss precipitated by minor trauma, which is caused by deletion of the
      same 1.5 Mb region in 17p11.2. In clinical practice, the detection of the
      duplication or the deletion in 17p11.2, which permits a positive diagnosis, is
      still performed by time consuming methods (Southern blot or various combinations
      of molecular tools). We developed a method for the rapid detection of 17p11.2
      rearrangements, using "direct FISH" and PRINS analyses, which does not require
      cell culture. In a prospective study of 92 patients with CMT and 38 with
      suspected HNPP, we compared this new technique to classical strategies like
      Southern blot. The results demonstrate the high sensitivity and specificity of
      the new FISH technique for the diagnosis of CMT1A and HNPP. Moreover, because of
      its simplicity and rapidity, this technique provides a useful alternative to the
      molecular approaches that have been used to diagnose segmental aneusomies,
      especially in the case of duplications that often go undetected.

PMID- 12605441
TI  - Satoyoshi syndrome in a Caucasian girl improved with glucocorticoids--a clinical
      report.
AB  - Satoyoshi syndrome (OMIM 600705) is a rare disorder of unknown cause
      characterized by progressive painful intermittent muscle spasms, amenorrhea,
      alopecia, malabsorption, and skeletal abnormalities mimicking a skeletal
      dysplasia. In this report, we describe a Caucasian 12-year-old girl that
      presented with characteristic manifestations, including alopecia, muscle cramps,
      and short stature with onset at age 7. Prednisone 60 mg/m(2) every other day and
      amytriptiline 25 mg QD were administered. After 2 months, alopecia had
      significantly improved and muscle cramps had almost disappeared, so that
      glucocorticoid treatment was tapered. Follow-up, 9 months later, showed a normal
      looking and asymptomatic girl.

PMID- 12605440
TI  - Shashi XLMR syndrome: report of a second family.
AB  - This report describes a family with mental retardation in two brothers. The
      pedigree is consistent with either X-linked mental retardation or autosomal
      recessive inheritance. The clinical features consist of coarse face, prominent
      lower lip, large testes, and obesity. This same constellation of findings was
      observed in a family with X-linked mental retardation (XLMR) reported by Shashi
      et al. [2000: Am J Hum Genet 66:469-479]. Furthermore, haplotype analysis was
      consistent with localization of the Shashi XLMR syndrome in Xq26-q27. Thus, the
      family likely represents a second occurrence of the Shashi XLMR syndrome.

PMID- 12605442
TI  - Cranio-cerebello-cardiac (3C) syndrome: follow-up study of the original patient.
AB  - In 1987, Ritscher et al. described two sisters with brain malformations of the
      posterior fossa, congenital heart defects, and similar craniofacial dysmorphisms.
      Subsequently, more than 20 cases have been reported and the syndrome became known
      as 3C (cranio-cerebello-cardiac) or Ritscher-Schinzel syndrome. The majority of
      patients were younger than six years of age at the time of observation. Here we
      present a follow-up study of one of the two sisters described by Ritscher et al.
      in 1987. At 21 years of age she is the oldest patient reported to date. We
      delineate growth, intellectual development, and evolution of her congenital
      developmental defects. We also provide evidence that the originally reported
      immune deficiency in this patient is not a primary B-cell defect but a secondary
      loss of IgG via the gastrointestinal system.

PMID- 12605443
TI  - Prenatal diagnosis of a trisomy 7/maternal uniparental heterodisomy 7 mosaic
      fetus.
AB  - Chromosomal segregation anomalies often result in trisomy of a single chromosome,
      which can lead to a disastrous phenotype in the fetus. However, this trisomy is
      often "rescued" via loss of one of the triploid chromosomes. Depending on which
      chromosome is eliminated in the rescue, a condition known as uniparental disomy
      may arise where both copies of a particular chromosome pair originate from the
      same parent. Here we describe the case of a 32-year-old woman who was prenatally
      diagnosed with trisomy 7 mosaicism via amniocentesis. Forty-one percent of the
      colonies analyzed displayed trisomy 7 (two maternal chromosomes and one paternal
      chromosome); whereas, 59% of the colonies demonstrated a normal, disomic
      karyotype. Further analysis revealed that the "normal" cell lineage displayed
      maternal uniparental heterodisomy. Chorionic villus tissue was homogeneously
      trisomic, and cord blood cells were uniformly disomic. This is the first case of
      trisomy 7/uniparental disomy 7 mosaic fetus reported in the literature. It is
      important to note that not all such cases will result in lethality or a fetus
      with major anatomic, developmental, or cognitive abnormalities. In addition, the
      benefit of pre- and post-screening test counseling and support is discussed in
      reference to fetuses with chromosomal abnormalities in general and our case in
      particular.

PMID- 12605444
TI  - Thanatophoric dysplasia type II with encephalocele and aortic hypoplasia
      diagnosed in an anatomical specimen.
AB  - A hitherto unknown combination of congenital anomalies was found in an anatomical
      specimen of a female neonate. External examination and additional CT and MRI
      studies showed thanatophoric dysplasia type II with cloverleaf skull and
      concomitant parietal meningoencephalocele and hypoplasia of the descending aorta.
      The possibilities of causal correlations are discussed.

PMID- 12605445
TI  - A new patient with Lowry-Wood syndrome with mild phenotype.
AB  - Lowry-Wood syndrome (LWS) is a rare condition characterized by multiple
      epiphyseal dysplasia (MED), microcephaly, and congenital nystagmus. A variable
      degree of mental retardation can also be present. It is probably inherited as an
      autosomal recessive trait. We report a new case of MED and microcephaly, without
      other additional features, suggesting a mild form of LWS. Molecular analysis of
      the cartilage oligomeric matrix protein (COMP) gene was performed and failed to
      find mutations.

PMID- 12605446
TI  - Progressive osseous heteroplasia in the face of a child.
AB  - We describe a rare case of progressive osseous heteroplasia of the face in a
      child. Biopsy showed osteoma cutis superficially with ectopic bone formation in
      the deeper tissues including skeletal muscle. Analysis of DNA from peripheral
      blood leukocytes showed mutations in the gene encoding the alpha subunit of the
      stimulatory G protein of adenylyl cyclase (GNAS1), confirming the diagnosis of
      progressive osseous heteroplasia.

PMID- 12605447
TI  - Leukodystrophy associated with oligodontia in a large inbred family: fortuitous
      association or new entity?
AB  - We describe a large inbred Syrian pedigree with an autosomal recessive
      neurodegenerative disorder. The clinical picture of the affected patients is
      oligodontia, and a degenerative neurological condition with onset around age 12,
      characterized by progressive ataxia and pyramidal syndrome. Abnormalities in the
      white matter and cortical atrophy were assessed by magnetic resonance imaging.
      Differential diagnosis and the possibility of a fortuitous association or the
      report of a hitherto unreported dento-leukoencephalopathy are discussed.

PMID- 12605448
TI  - Child with De Novo t(1;6)(p22.1;p22.1) translocation and features of ectodermal
      dysplasia with hypodontia and developmental delay.
AB  - We report on a 6.5-year-old girl with a balanced translocation between the short
      arms of chromosomes 1 and 6. She was referred for genetics evaluation because of
      developmental speech delay and congenital absence of several deciduous and
      permanent teeth. She was very sensitive to noise (hyperacusis), had poor hair and
      nail growth, decreased sweating, and turned very red with high fever. She had
      microcephaly (head circumference at the second centile; weight and height were at
      25th centile), short palpebral fissures, epicanthal folds, sparse eyelashes,
      large ears, partial anodontia, short finger and toenails, and dry skin. She had
      mild developmental delay. Family history was significant for learning problems in
      two paternal uncles, one paternal aunt, and several paternal cousins. Thyroid
      studies, calcium, phosphorus, and alkaline phosphatase levels were normal. Her
      karyotype was 46,XX,t(1;6)(p22.1;p22.2), and parental karyotypes were normal.
      This apparently balanced translocation may have resulted in either a
      submicroscopic loss or disruption of a gene or genes involved in ectodermal
      dysplasia. There are no reported cases of ectodermal dysplasia associated with
      this chromosome rearrangement.

PMID- 12605450
TI  - Unexpected survival in a case of prenatally diagnosed non-mosaic trisomy 22:
      Clinical report and review of the natural history.
AB  - Over 30 cases of complete non-mosaic trisomy 22 have been reported in the
      literature in the last 20 years [Crowe et al., 1997: Am J Med Genet 71:406-413].
      Twenty-two infants were liveborn with an average life expectancy of four days. Of
      these, nine survived beyond the first two weeks of life. The life span ranged
      from minutes to 3 years of age. We report a case of an infant diagnosed
      prenatally with complete non-mosaic trisomy 22. Options such as aggressive
      medical/surgical intervention or limiting interventions to symptomatic care
      including home hospice were discussed openly. Given this information, the family
      elected to provide minimal supportive measures with pediatric hospice. The infant
      lived for 2 months with her family before her death. Numerous medical and
      surgical complications are associated with this disorder. Both the family and the
      medical team must be prepared for in utero fetal demise, stillbirth, or for
      limited life expectancy. Proper management, therefore, depends upon an
      understanding of the diagnosis.

PMID- 12605449
TI  - Broad thumbs and halluces with deafness: a patient with Keipert syndrome.
AB  - Clinical, radiological, and audiological features are described in a boy whose
      condition closely parallels the profile of patients previously described with
      Keipert syndrome. This case represents the fourth report of this rare disorder.

PMID- 12605451
TI  - One froggy evening.

PMID- 12605452
TI  - Bilateral renal dysplasia and situs inversus totalis in an infant girl.

PMID- 12605453
TI  - Bilateral Poland anomaly: does it exist?

PMID- 12605454
TI  - Taste, movement, and death: varying effects of new prospero mutants during
      Drosophila development.
AB  - The PGal4 transposon inserted upstream of the pan-neural gene prospero (pros)
      causes several neural and behavioral defects in the Voila(1) strain. The precise
      excision of the transposon simultaneously rescued all these defects whereas its
      unprecise excision created new pros(V) alleles, including the null allele
      pros(V17). Here, we describe the relationship between the genetic structure of
      pros locus, larval locomotion, and larval gustatory response. These two behaviors
      showed varying degrees of variation depending upon the pros allele. We also found
      a good relation between behavioral alteration, the level of Pros protein in the
      embryo, and the degree of disorganization in the larval neuromuscular junction.
      These data suggest that the complete development of the nervous system requires a
      full complement of Pros, and that a gradual decrease in the levels of this
      protein can proportionally alter the development and the function of the nervous
      system.

PMID- 12605455
TI  - MAPK signal transduction pathway mediates agrin effects on neurite elongation in
      cultured hippocampal neurons.
AB  - We have previously shown that agrin regulates the rates of axonal and dendritic
      elongation by modulating the expression of microtubule-associated proteins in
      cultured hippocampal neurons. However, the mechanisms by which agrin-induced
      signals are propagated to the nucleus where they can lead to the phosphorylation,
      and hence the activation, of transcription factors, are not known. In the present
      study, we identified downstream elements that play essential roles in the agrin
      signaling pathway in developing central neurons. Our results indicate that agrin
      induces the combined activation of the extracellular signal-regulated kinases
      (ERK1/ERK2) and p38 in central neurons. In addition, they showed that PD98059 and
      SB202190, synthetic inhibitors of ERK1/ERK2 and p38 respectively, prevented the
      changes in the rate of neurite elongation induced by agrin in cultured
      hippocampal neurons. Collectively, these results suggest that agrin might
      modulate the expression of neuron-specific genes involved in neurite elongation
      by inducing CREB phosphorylation through the activation of the MAPK signal
      transduction pathway in cultured hippocampal neurons.

PMID- 12605456
TI  - Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to
      beta-amyloid1-40 and beta-amyloid1-42.
AB  - The beta-amyloid peptides (Abeta), Abeta(1-40) and Abeta(1-42), have been
      implicated in Alzheimer's disease (AD) pathology. Although Abeta(1-42) is
      generally considered to be the pathological peptide in AD, both Abeta(1-40) and
      Abeta(1-42) have been used in a variety of experimental models without
      discrimination. Here we show that monomeric or oligomeric forms of the two Abeta
      peptides, when interact with the neuronal cation channel, alpha7 nicotinic
      acetylcholine receptors (alpha7nAChR), would result in distinct physiologic
      responses as measured by acetylcholine release and calcium influx experiments.
      While Abeta(1-42) effectively attenuated these alpha7nAChR-dependent physiology
      to an extent that was apparently irreversible, Abeta(1-40) showed a lower
      inhibitory activity that could be restored upon washings with physiologic buffers
      or treatment with alpha7nAChR antagonists. Our data suggest a clear
      pharmacological distinction between Abeta(1-40) and Abeta(1-42).

PMID- 12605457
TI  - Myopodia (postsynaptic filopodia) participate in synaptic target recognition.
AB  - Synaptic partner cells recognize one another by utilizing a variety of molecular
      cues. Prior to neuromuscular synapse formation, Drosophila embryonic muscles
      extend dynamic actin-based filopodia called "myopodia." In wild-type animals,
      myopodia are initially extended randomly from the muscle surface but become
      gradually restricted to the site of motoneuron innervation, a spatial
      redistribution we call "clustering." Previous experiments with prospero mutant
      embryos demonstrated that myopodia clustering does not occur in the absence of
      motoneuron outgrowth into the muscle field. However, whether myopodia clustering
      is due to a general signal from passing axons or is a result of the specific
      interactions between synaptic partners remained to be investigated. Here, we have
      examined the relationship of myopodia to the specific events of synaptic target
      recognition, the stable adhesion of synaptic partners. We manipulated the
      embryonic expression of alphaPS2 integrin and Toll, molecules known to affect
      synaptic development, to specifically alter synaptic targeting on identified
      muscles. Then, we used a vital single-cell labeling approach to visualize the
      behavior of myopodia in these animals. We demonstrate a strong positive
      correlation between myopodia activity and synaptic target recognition. The
      frequency of myopodia clustering is lowered in cases where synaptic targeting is
      disrupted. Myopodia clustering seems to result from the adherence of a subset of
      myopodia to the innervating growth cone while the rest are eliminated. The data
      suggest that postsynaptic cells play a dynamic role in the process of synaptic
      target recognition.

PMID- 12605458
TI  - Dendritic morphology is altered in hippocampal neurons following prenatal
      compromise.
AB  - Chronic placental insufficiency (CPI), a known cause of intrauterine growth
      restriction, can lead to structural alterations in the developing brain that
      might underlie postnatal neurological deficits. We have previously demonstrated
      significant reductions in the volumes of hippocampal neuropil layers in fetal
      guinea pig brains following experimentally induced growth restriction. To
      determine the components of the neuropil affected in the brains of growth
      restricted (GR) fetuses, the dendritic morphology of CA1 pyramidal neurons and
      dentate granule cells was examined. CPI was induced by unilateral uterine artery
      ligation in pregnant guinea pigs at midgestation (term approximately 67 days).
      Hippocampi from control and GR fetuses were stained using the Rapid Golgi
      technique and the growth and branching of the dendritic arbors were quantified
      using the Sholl method. In addition, the density of dendritic spines was
      determined on the apical arbors of each population. In GR brains (n = 7) compared
      to controls (n = 7), there was a reduction in dendritic elongation (p < 0.005)
      and an alteration in the branch point distribution in CA1 basal arbors, and a
      reduction both in the outgrowth (p < 0.05) and branch point number (p < 0.05) of
      CA1 apical arbors. Dentate granule cells from GR brains also demonstrated reduced
      dendritic outgrowth (p < 0.05). There was an increase in dendritic spine density
      in both neuronal populations; this might be due either to altered synaptic
      pruning or as a compensatory mechanism for reduced dendritic length. These
      findings demonstrate that a chronic prenatal insult causes selective changes in
      the morphology of hippocampal cell dendrites and may lead to alterations in
      hippocampal function in the postnatal period.

PMID- 12605460
TI  - Molecular characterization, functional expression, and developmental profile of
      an ether a-go-go K+ channel in the tobacco hornworm Manduca sexta.
AB  - A very large number of evolutionarily conserved potassium channels have been
      identified but very little is known about their function or modulation in vivo.
      Metamorphosis of the tobacco hornworm, Manduca sexta, is a compelling model
      system for such studies because it permits analysis to be conducted at the level
      of identified neurons whose roles in simple behaviors and endocrine regulation
      are known. We present here the characterization of the first ion channel to be
      cloned from this animal. Partial genomic sequence for Manduca sexta ether a-go-go
      (Mseag) and a cDNA clone encoding the Mseag open reading frame were obtained.
      Genomic Southern analysis indicates that Manduca contains a single member of the
      eag subfamily per haploid genome. When expressed in Xenopus oocytes, MsEag
      channels conduct a voltage-dependent, K+ selective outward current with an
      inactivating component that closely resembles the Drosophila eag current. Mseag
      transcripts were restricted to the nervous system, adult antenna, and one set of
      larval skeletal muscles. Steroid hormonal regulation of Mseag expression is
      suggested by the temporal correlation of developmental changes in transcript
      expression with the changing steroid titers that promote metamorphosis. These
      results provide the foundation for functional and modulatory studies of the Eag
      family of K+ channels in Manduca, which will complement the genetic analysis in
      Drosophila.

PMID- 12605459
TI  - A gene necessary for normal male courtship, yellow, acts downstream of fruitless
      in the Drosophila melanogaster larval brain.
AB  - The fruitless (fru) gene is a member of the Drosophila melanogaster somatic sex
      determination genetic pathway. Although it has been hypothesized that the primary
      function of fru is to regulate a genetic hierarchy specifying development of
      adult male courtship behavior, genes acting downstream of fru have not yet been
      identified. Here we demonstrate that the yellow (y) gene is genetically
      downstream of fru in the 3(rd)-instar larval brain. Yellow protein is present at
      elevated levels in neuroblasts, which also show expression of male-specific FRU
      proteins, compared to control neuroblasts without FRU. A location for y
      downstream of fru in a genetic pathway was experimentally demonstrated by
      analysis of fru mutants lacking transcription of zinc-finger DNA binding domains,
      and of animals with temporal, spatial, or sexual mis-expression of male-specific
      FRU. A subset of fru and y mutants is known to reduce levels of a specific
      behavioral component of the male courtship ritual, wing extension, and FRU and
      Yellow were detected in the general region of the brain whose maleness is
      necessary for development of that behavior. We therefore hypothesized that
      ectopic expression of Yellow in the 3(rd)-instar brain, in a y null background,
      would rescue low levels of wing extension and male competitive mating success,
      and this was found to be the case. Overall, these data suggest that y is a
      downstream member of the fru branch of the D. melanogaster sex determination
      hierarchy, where it plays a currently unknown role in the development of adult
      male wing extension during courtship.

PMID- 12605461
TI  - The expression of methyl CpG binding factor MeCP2 correlates with cellular
      differentiation in the developing rat brain and in cultured cells.
AB  - Mutations in the MeCP2 gene cause Rett syndrome, a neurologic condition affecting
      primarily young girls. To gain insight into the normal function of MeCP2, we
      examined its temporal and spatial expression patterns, and immunoreactive
      prevalence, during late embryonic and perinatal brain development. MeCP2 mRNA was
      detected in most regions of the developing rat brain by the late embryonic stage.
      Regions displaying the strongest mRNA expression include the hippocampus, cortex,
      and cerebellum, and moderate expression was observed in most other brain regions.
      At the protein level, MeCP2 was strongly expressed in adult forebrain neurons,
      but was not detected in astrocytes. The nonubiquitous expression of MeCP2 was
      also observed in the embryonic cortex, as about one-third of acutely dissociated
      embryonic day 14 neuroepithelial cells failed to stain with MeCP2. To test
      whether MeCP2 expression correlates with neuronal differentiation, colocalization
      of MeCP2 expression with either the precursor cell marker nestin or the young
      neuronal marker beta-III tubulin was examined in the same acutely dissociated
      cortical cells. Although strong MeCP2 expression was detected in approximately
      75% of beta-III tubulin-positive cells, only about 25% of nestin-positive
      precursor cells were MeCP2 positive. Further support for a correlation of MeCP2
      expression with cell differentiation was observed in culture, where Western blot
      analysis during the in vitro differentiation of PC12, NG108-15, and SH-SY5Y cells
      revealed that MeCP2 levels increased as the cells acquired a more differentiated
      phenotype. This increase was associated with differentiation, as MeCP2 expression
      levels did not vary within different phases of the cell cycle. Taken together,
      these data support a role for MeCP2 in the establishment and/or maintenance of
      neuronal maturity.

PMID- 12605462
TI  - Amputation-induced activity of progenitor cells leads to rapid regeneration of
      olfactory tissue in lobsters.
AB  - Lobsters have a self-renewing olfactory system and, like many animals,
      continuously replace old or dying olfactory receptor neurons. In addition,
      lobsters are able to regenerate the peripheral olfactory system even after
      complete loss. The olfactory sensors in lobsters are located distally on a pair
      of antennules. These antennules are often damaged, but this has little impact on
      the lobster's sense of smell because damaged olfactory tissue is rapidly
      replaced. In this study, we investigated damage-induced regeneration of the
      olfactory system by measuring cell proliferation following controlled amputation.
      We show that amputation-induced regeneration occurs as a result of up-regulating
      the normal development of olfactory sensors. A unique feature of up-regulated
      development is the formation of patches of proliferating cells within the
      antennular epithelium. Epithelial patches were typically formed between 3 and 10
      days postamputation on the amputated side. They were characterized by their:
      proximal position with respect to developing clusters of olfactory receptor
      neurons (ORNs); tendency to form two discrete patches within the borders of each
      existing annulus; cell size, which was approximately twice that of mature ORNs;
      and location within the ventral epithelium. The development of epithelial patches
      was immediately followed by proliferation of clusters of ORNs and associated
      glial cells, and the level of this proliferation increased significantly during
      the premolt stage of the lobster's molt cycle. These epithelial patches may
      represent populations of precursor cells, because they develop in response to
      amputation and immediately precede development of cell clusters composed of ORNs
      and glia. Possible regulatory signals controlling epithelial patch development
      are discussed.

PMID- 12605463
TI  - An exploratory instrumental variable analysis of the outcomes of localized breast
      cancer treatments in a medicare population.
AB  - This study is motivated by the potential problem of using observational data to
      draw inferences about treatment outcomes when experimental data are not
      available. We compare two statistical approaches, ordinary least-squares (OLS)
      and instrumental variables (IV) regression analysis, to estimate the outcomes
      (three-year post-treatment survival) of three treatments for early stage breast
      cancer in elderly women: mastectomy (MST), breast conserving surgery with
      radiation therapy (BCSRT), and breast conserving surgery only (BCSO). The primary
      data source was Medicare claims for a national random sample of 2907 women (age
      67 or older) with localized breast cancer who were treated between 1992 and 1994.
      Contrary to randomized clinical trial (RCT) results, analysis with the
      observational data found highly significant differences in survival among the
      three treatment alternatives: 79.2% survival for BCSO, 85.3% for MST, and 93.0%
      for BCSRT. Using OLS to control for the effects of observable characteristics
      narrowed the estimated survival rate differences, which remained statistically
      significant. In contrast, the IV analysis estimated survival rate differences
      that were not significantly different from 0. However, the IV-point estimates of
      the treatment effects were quantitatively larger than the OLS estimates,
      unstable, and not significantly different from the OLS results. In addition, both
      sets of estimates were in the same quantitative range as the RCT results.We
      conclude that unadjusted observational data on health outcomes of alternative
      treatments for localized breast cancer should not be used for cost-effectiveness
      studies. Our comparisons suggest that whether one places greater confidence in
      the OLS or the IV results depends on at least three factors: (1) the extent of
      observable health information that can be used as controls in OLS estimation, (2)
      the outcomes of statistical tests of the validity of the instrumental variable
      method, and (3) the similarity of the OLS and IV estimates. In this particular
      analysis, the OLS estimates appear to be preferable because of the instability of
      the IV estimates.

PMID- 12605464
TI  - Preferences and person trade-offs: forcing consistency or inconsistency in health
      related quality of life measures?
AB  - We consider assumptions about preferences implicit in the person trade-off
      exercises used to derive health-related quality of life measures for the Global
      and US Burden of Disease Projects. Because these methods and their results have
      the potential of being adopted by other researchers, a critical review of this
      methodology and its assumptions is warranted. Exercise participants are told that
      quality of life valuation is approached using two different questions to reveal
      logical inconsistencies in each person's responses. An inconsistency is claimed
      to exist if a participant's two responses violate a particular mathematical
      relationship, and participants are forced to modify their responses to satisfy
      that relationship. We demonstrate that this supposed 'logical' relationship need
      not hold for logically consistent, rational individuals, and we prove that the
      relationship will in fact hold only for a particular class of social value
      functions exhibiting two characteristics that may not be consistent with the
      preferences of some participants. These results imply that the forced
      modification may invalidate some responses, as it may require some participants
      to provide final answers that are inconsistent with their true preferences. We
      then discuss preference characterizations in the existing person trade-off
      literature, from which this relationship may have been derived.

PMID- 12605465
TI  - The interaction between cost-management and learning for major surgical
      procedures - lessons from asymmetric information.
AB  - The theory of the learning curve states that learning effects are of particular
      importance in industries, where human skills play an important role.
      Consequently, one would expect to find large learning effects for surgical
      procedures because the physician's experience is quite important for this type of
      work. For hospitals, there exists indeed a well-documented effect that shows a
      positive relationship between the number of a certain type of surgery being
      performed and its resulting quality (volume-outcome relationship). Empirical
      analyses of the impact of learning on the average cost of a procedure, however,
      have noted a conspicuous absence of learning effects. Using a mechanism design
      approach, the paper analyzes a model of quality and cost-management for a
      hospital, where learning effects are included into the cost function and
      asymmetric information exists between management and physician. It seeks to
      answer the question, whether recommendations from a symmetric information
      scenario with respect to learning carry over to a health care setting, where
      informational problems tend to be pronounced and severe. If surgery volume
      interacts with physicians' informational rents, an optimal management reaction to
      the presence of learning may result in a policy, which is the exact opposite of
      the one under symmetric information.

PMID- 12605466
TI  - The effect of cigarette prices on youth smoking.
AB  - Prior economic research provides mixed evidence on the impact of cigarette prices
      on youth smoking. This paper empirically tests the effects of various price
      measures on youth demand for cigarettes using data collected in a recent
      nationally representative survey of 17 287 high school students. In addition to
      commonly used cigarette price measures, the study also examined the effect of
      price as perceived by the students. This unique information permits the study of
      the effect of teen-specific price on cigarette demand. The analysis employed a
      two-part model of cigarette demand based on a model developed by Cragg (1971) in
      which the propensity to smoke and the intensity of the smoking habit are modeled
      separately. The results confirm that higher cigarette prices, irrespective of the
      way they are measured, reduce probability of youth cigarette smoking. There is
      also some evidence of negative price effect on smoking intensity, but it is
      sensitive to the price measure used in the model. The largest impact on cigarette
      demand has the teen-specific, perceived price of cigarettes.

PMID- 12605467
TI  - Medical care use and selection in a social health insurance with an equalization
      fund: evidence from Colombia.
AB  - This paper studies the relationship between health status and insurance
      participation, and between insurance status and medical use in the context of a
      social health insurance with an equalization fund (SHIEF). Under this system,
      revenues from a mandatory payroll tax are collected into a single pool
      (equalization fund) that reimburses for-profit insurance companies according to a
      capitated formula. Although competition should induce insurers to control costs
      without reducing the quality of service necessary to attract consumers,
      limitations in the capitation formula might induce insurers to select against bad
      risks, and limitations in the contribution system might induce more healthy
      individuals to evade enrollment. A three-equation model having social health
      insurance, private health insurance, and using medical services is estimated
      using a 1997 Colombian household survey. Consistent with similar studies,
      participation in SHIEF increases medical care use. On the other hand, the
      evidence on selection is somewhat mixed: individuals who report good health
      status are more likely to participate in SHIEF, while those without a chronic
      condition are less likely to participate in SHIEF.

PMID- 12605468
TI  - A note on cost-value analysis.
AB  - We discuss 'cost-value analysis', a method for health care resource allocation
      suggested by Nord et al. (Nord E et al. Incorporating societal concerns for
      fairness in numerical valuations of health programmes. Health Econ 1999; 8: 25
      39). Some difficulties and issues for future research are pointed out.

PMID- 12605470
TI  - How do ring currents affect (1)h NMR chemical shifts?
AB  - Conventional explanations of proton NMR chemical shifts need fundamental
      revisions. Ab initio (IGLO) analyses reveal that the downfield delta (1)H of
      benzene is not due to deshielding ring current effects; the shielding is less
      than the pi contribution to vinyl delta (1)Hs. Enhanced deshielding sigma CC
      influences are responsible for the more downfield delta (1)Hs of the inner
      protons of naphthalene and anthracene. Double pi effects shield ethynyl Hs; there
      is no evidence for a special "ring current influence."

PMID- 12605473
TI  - First synthesis of perfluorinated corrole and its mn=o complex.
AB  - A novel perfluorinated corrole, 2,3,7,8,12,13,17,18-octafluoro-5,10,15
      tris(pentafluorophenyl)corrole, and its manganese(III) and oxomanganese(V)
      derivatives have been synthesized. The perfluorinated manganese corrolate
      exhibited excellent reactivity and stability in the catalytic oxidation of
      alkenes with iodosylbenzene.

PMID- 12605471
TI  - Diazotrifluoropropionamido-containing prenylcysteines: syntheses and applications
      for studying isoprenoid-protein interactions.
AB  - Photoaffinity-labeled prenylcysteines (1 and 2) incorporating a
      diazotrifluoropropionamide-based photophore have been prepared. Photolyses of 2
      in the presence of RhoGDI, a protein that interacts with prenylated proteins, and
      prenylcysteine-containing competitors demonstrate the effectiveness of this
      photoaffinity-labeled analogue as a tool for studying isoprenoid binding sites.

PMID- 12605472
TI  - A solid-phase synthetic strategy for labeled peptides: synthesis of a
      biotinylated derivative of the delta opioid receptor antagonist TIPP (Tyr-Tic-Phe
      Phe-OH).
AB  - A general solid-phase synthetic strategy for labeled peptides was developed and
      used to prepare a biotinylated derivative of the delta opioid receptor antagonist
      TIPP (Tyr-Tic-Phe-Phe-OH). A monoprotected hydrophilic diamine linker was
      attached to an aldehyde-containing solid-phase resin by reductive amination,
      followed by introduction of biotin and peptide synthesis to yield Tyr-Tic-Phe-Phe
      Asp-NH(CH(2)CH(2)O)(2)CH(2)CH(2)NH-biotin (2). The high delta receptor affinity
      and selectivity of 2 demonstrate the applicability of this design approach for
      labeled peptide derivatives.

PMID- 12605474
TI  - Extensively stereodiversified scaffolds for use in diversity-oriented library
      synthesis.
AB  - The syntheses of stereodiverse libraries of 12 and 19 are reported, where each
      asterisk represents an independently varied stereocenter. These scaffolds provide
      additional templates for investigations of geometric diversity in library
      syntheses. Libraries of these N-Fmoc-amino acids were further functionalized by
      incorporation into a peptide sequence, demonstrating the utility of 12 and 19 as
      building blocks for diversity oriented synthesis.

PMID- 12605475
TI  - Stereoselective synthesis of alkynyl C-2-deoxy-beta-d-ribofuranosides via
      intramolecular nicholas reaction: A versatile building block for nonnatural C
      nucleosides.
AB  - The reaction of 3,5-di-O-benzyl-2-deoxy-d-ribofuranose with various
      alkynyllithium reagents afforded diastereomeric mixtures of the corresponding
      ring-opened alkynyldiols. The resulting diastereomeric mixtures were successively
      treated with Co(2)(CO)(8), a catalytic amount of TfOH, Et(3)N, and iodine in one
      pot to give alkynyl C-3,5-di-O-benzyl-2-deoxy-beta-d-ribofuranosides with high
      beta-selectivities. The cobalt-mediated cyclization (intramolecular Nicholas
      reaction) is reversible; thus, thermodynamically more stable beta-anomers were
      obtained preferentially. The alkynyl C-deoxyribofuranosides were converted to a
      variety of C-deoxyribofuranoside derivatives.

PMID- 12605476
TI  - Reformatsky-type reaction of chiral nonracemic alpha-bromo-alpha'-sulfinyl
      ketones with aldehydes. Synthesis of enantiomerically pure 2-methyl-1,3-diol
      moieties.
AB  - Chiral nonracemic alpha-bromo-alpha'-sulfinyl ketones were shown to react with
      aldehydes in the presence of SmI(2) in a Reformatsky-type reaction to give the
      corresponding adduct with excellent syn diastereoselectivity. Further reduction
      of the Reformatsky adducts furnished anti- and syn-2-methyl-1,3-diol moieties in
      excellent yields and diastereoselectivities.

PMID- 12605479
TI  - Controlled incorporation of water molecules into carboxy hydrogen-bond networks:
      a designed approach.
AB  - The incorporation of water molecules into the hydrogen-bonded pattern of
      condensed organic materials implies an unfavorable entropic tradeoff resulting
      from water ordering. Here we show for a family of diacids of general structure
      (+/-)-1 that extended chains of anhydrous or hydrated structures can be prepared
      by controlling the steric factors that lead to the closest packing of individual
      components.

PMID- 12605477
TI  - Unpredictable stereochemical preferences for mu opioid receptor activity in an
      exhaustively stereodiversified library of 1,4-enediols.
AB  - Using olefin cross-metathesis, we synthesized a novel stereodiversified library
      of compounds 3 containing a trans-1,4-enediol. Screening this library for mu
      opioid receptor (MOR) affinity identified multiple high-affinity ligands and
      revealed that the stereochemical configuration varied widely among those ligands
      having the highest affinity. It was not possible to predict the configurations of
      the most active compounds 3 on the basis of the configuration of endomorphin-2, a
      known MOR peptide ligand, validating the diversity-based approach to ligand
      discovery.

PMID- 12605478
TI  - Synthesis of 7-hydroxy(phenyl)ethylguanines by alkylation of 2-amino-6
      chloropurine with allyl-protected bromohydrins.
AB  - Protecting the hydroxyl group in both 2-bromo-2-phenylethanol and 2-bromo-1
      phenylethanol enhanced the alkylation of 2-amino-6-chloropurine to give
      corresponding 7- and 9-alkylated products. Subsequent hydrolysis and deprotection
      led to 7- and 9-hydroxy(phenyl)ethylguanines. 7-Hydroxy(phenyl)ethylguanines are
      major guanine adducts formed by interaction of styrene 7,8-oxide with DNA.

PMID- 12605480
TI  - Bis-1,4-(p-diarylaminostryl)-2,5-dicyanobenzene derivatives with large two-photon
      absorption cross-sections.
AB  - Synthesis and physical properties of novel multibranched two-photon materials are
      reported. The compound with three units of 4-(p-diphenylaminostyryl)-2,5
      dicyanostyryl moieties attached to the central triphenylamine core exhibits a
      very large two-photon absorption cross-section.

PMID- 12605481
TI  - The effect of solvent on a Lewis acid catalyzed Diels-Alder reaction, using
      computed and experimental kinetic isotope effects.
AB  - A new transition structure for the Diels-Alder reaction between isoprene and
      acrolein catalyzed by Et(2)AlCl is found to reconcile reported discrepancies
      between computed and observed secondary kinetic isotope effects (KIEs). Including
      the effect of solvent realigns the computed results with experiment demonstrating
      the importance of nonbond interactions at transition structures. Comparison of
      experimental and newly predicted KIE data reaffirms the ability of theory and
      experiment to probe the mechanism and transition structure geometry of organic
      reactions.

PMID- 12605482
TI  - Regioselective reductive coupling of alkynes and aldehydes leading to allylic
      alcohols.
AB  - Treatment of a mixture of a terminal alkyne and an aldehyde with CrCl(2) and a
      catalytic amount of NiCl(2) and triphenylphosphine in the presence of water in
      DMF at 25 degrees C gives a 1,2-disubstituted allylic alcohol regioselectively.

PMID- 12605483
TI  - Aldol- and Mannich-type reactions via in situ olefin migration in ionic liquid.
AB  - An aldol-type and a Mannich-type reaction via the cross-coupling of aldehydes and
      imines with allylic alcohols catalyzed by RuCl(2)(PPh(3))(3) was developed with
      ionic liquid as the solvent. The solvent/catalyst system could be reused for at
      least five times with no loss of reactivity.

PMID- 12605484
TI  - Biomimetic synthesis of the crispatene core.
AB  - The biomimetic synthesis of the crispatene core is reported. The core framework
      was efficiently generated from an easily synthesized all (E)-tetraene precursor
      in one step, in good yield.

PMID- 12605485
TI  - Unprecedented reactivity of N-heterocyclic carbenes toward DMAD and aldehydes
      leading to novel multicomponent reactions.
AB  - A facile synthesis of highly functionalized 2-oxymaleate and furanone derivatives
      by the multicomponent reaction of 1,3-dimesityl imidazolin-2-ylidene/imidazol-2
      ylidene, DMAD, and aldehydes is described.

PMID- 12605486
TI  - Synthesis of C-19-functionalized 1alpha-hydroxyvitamin D(2) analogues via ring
      closing metathesis.
AB  - A heteroatom-tethered regioselective ring-closing metathesis reaction was used
      for the C-19 functionalization of 1alpha-hydroxy-5,6-trans-vitamin D(2)
      analogues. Applications of the reaction to form a range of analogues by
      manipulation of the tether using both organolithium reagents and Diels-Alder
      cycloadditions are described.

PMID- 12605487
TI  - Simplakidine A, a unique pyridinium alkaloid from the Caribbean sponge plakortis
      simplex.
AB  - Simplakidine A, a unique 4-alkyl-substituted pyridiunium alkaloid, has been
      isolated from the Caribbean sponge Plakortis simplex. The stereostructure of
      simplakidine A has been determined using MS and NMR data, molecular mechanics,
      and an extension of the J-based configuration analysis. Data about the growth
      inhibition activity of simplakidine A are reported.

PMID- 12605488
TI  - Facile synthesis of optically pure 1,2-diaryl (and 1-Alkyl-2-aryl) ethyl and
      propylamines.
AB  - A concise high-yielding route to synthetically useful 1,2-diaryl (and 1-alkyl-2
      aryl) ethyl and propylamines in high enantiomeric purity is described. The key
      step of this route is the completely stereoselective addition of lithium (R)
      ortho-(p-toluenesulfinyl)benzylic carbanions to (S)-N-p-toluenesulfinylimines,
      which takes place in very high or quantitative yields. N-Desulfinylation and C
      desulfinylation of the resulting adducts can be achieved with no loss of optical
      purity employing conventional methods (TFA and Raney-Ni, respectively).

PMID- 12605489
TI  - Rhodium-catalyzed asymmetric conjugate additions of boronic acids using
      monodentate phosphoramidite ligands.
AB  - Monodentate phosphoramidites have been used for the first time as chiral ligands
      in the Rh-catalyzed enantioselective conjugate addition of arylboronic acids to
      enones, unsaturated esters, lactones, and nitro alkenes. High reaction rates and
      ee's up to 89% have been obtained.

PMID- 12605490
TI  - Dehydrative reduction: a highly diastereoselective synthesis of syn-bisaryl(or
      heteroaryl) dihydrobenzoxathiins and benzodioxane.
AB  - TFA/Et(3)SiH-mediated cyclization of thioketones 5 derived from the reaction of
      functionalized thiophenols (catechols) with bromo ketones gave syn 2,3-bisaryl(or
      heteroaryl) dihydrobenzoxathiins and benzodioxane 1 with total
      diastereoselectivity (>99:1), in excellent yields.

PMID- 12605491
TI  - Hydrogen bond-assembled fullerene molecular shuttle.
AB  - A novel [2]rotaxane has been prepared in which fullerene C(60) behaves as both a
      stopper and a photoactive unit. The amphiphilic nature of the rotaxane thread can
      be used to shuttle the macrocycle from close to the fullerene spheroid (in
      nonpolar solvents) to far away (in polar solvents). The differing location of the
      macrocycle in dichloromethane and dimethyl sulfoxide gives rise to effects
      detectable by (1)H NMR and time-resolved spectroscopy.

PMID- 12605492
TI  - Selective inhibition of engineered receptors via proximity-accelerated
      alkylation.
AB  - A new approach for creating allele-specific inhibitors is demonstrated. In this
      approach, a receptor and ligand are engineered to contain complementary reactive
      groups that form a covalent bond via a proximity-accelerated reaction upon
      formation of the receptor-ligand complex, irreversibly modulating the biological
      function of the receptor. This approach is demonstrated in the cyclophilin
      cyclosporin receptor-ligand system by introducing thiol and acrylamide functional
      groups in the receptor and ligand, respectively.

PMID- 12605493
TI  - Delocalizations in sigma-radical cations: the intriguing structures of ionized
      [n]rotanes.
AB  - Highly symmetric aliphatic hydrocarbons such as D(4h)-[4]rotane do not
      necessarily have degenerate HOMOs. According to our predictions based on high
      level computations, its radical cation should display a highly delocalized D(4h)
      symmetric structure, in contrast to its Jahn-Teller distorted cousin, the radical
      cation of [3]rotane, which exists in two distonic localized forms with C(2v) and
      C(s) symmetry.

PMID- 12605495
TI  - Probing the diastereotopicity of methylene protons in strychnine using residual
      dipolar couplings.
AB  - Residual dipolar couplings were successfully used to distinguish between the two
      diastereotopic protons on C-20 of strychnine dissolved in an organic liquid
      crystal (PBLG/CDCl(3)). The results presented here strongly suggest that this
      method will be of help in organic structure determination, making the
      determination of relative stereochemistry in the absence of NOE data possible.

PMID- 12605494
TI  - Enantioselective syntheses of ring-C precursors of vit. B(12). Reagent control.
AB  - Enelactones of the general structure S-(-)-I were prepared in three steps from
      alcohol 21 and acids 22 (ee approximately 85%). Lactones S-(-)-I are versatile
      precursors to enelactams II of the type found in Vitamin B(12).

PMID- 12605496
TI  - Redox inversion of helicity in propeller-shaped molecules derived from s-methyl
      cysteine and methioninol.
AB  - One-electron reduction inverts the helicity of copper complexes formed from
      derivatives of S-methylcysteine and methioninol. The change in conformation of
      the organic ligand is followed in the exciton-coupled circular dichroism (ECCD)
      spectra of the complexes.

PMID- 12605497
TI  - Synthesis and properties of sym-pentasubstituted derivatives of corannulene.
AB  - Alkyl, aryl, and alkynyl as well as heteroatom derivatives of sym
      pentasubstituted corannulenes have been synthesized from sym
      pentachlorocorannulene. These units form potential building blocks for future
      work on superstructures based on corannulene. Absorption/emission properties
      follow expected trends from the parent 1. sym-Pentasubstitution gives rise to
      variations in the chemical dynamics of bowl inversion. van der Waals attraction
      is cited to explain an anomalously high barrier to bowl inversion in 10.

PMID- 12605498
TI  - Dihydropyridine-based multicomponent reactions. Efficient entry into new
      tetrahydroquinoline systems through Lewis acid-catalyzed formal [4 + 2]
      cycloadditions.
AB  - The three-component reaction of dihydropyridines, aldehydes, and p-methylaniline
      efficiently forms highly substituted tetrahydroquinolines in a stereoselective
      manner through a Lewis acid-catalyzed formal [4 + 2] cycloaddition. InCl(3) and
      Sc(OTf)(3) are the catalysts of choice for this process. The in situ generation
      of a reactive 1,4-dihydropyridine through the regioselective nucleophilic
      addition of cyanide to pyridinium salts allows a one-pot four-component
      transformation.

PMID- 12605499
TI  - Alternative solvents for elevated-temperature solid-phase parallel synthesis.
      Application to thionation of amides.
AB  - A new class of higher-boiling solvents was investigated for elevated-temperature
      solid-phase parallel synthesis. Extremely low vapor pressures at high temperature
      and a broader range of solvent effect tuning make this new class of solvents an
      ideal choice for high-temperature parallel solid-phase synthesis. Benzyl benzoate
      is identified as a superior high-boiling solvent for parallel solid-phase
      Lawesson's thionation reactions.

PMID- 12605501
TI  - Synthesis of (e)- and (z)- alkenylphosphonates using vinylboronates.
AB  - (E)- and (Z)-alkenylphosphonates have been prepared stereospecifically via the
      reaction of vinylboronate esters with triethyl phosphite in the presence of
      palladium acetate.

PMID- 12605500
TI  - Highly efficient catalytic asymmetric epoxidation of allylic alcohols by an
      oxovanadium-substituted polyoxometalate with a regenerative TADDOL-derived
      hydroperoxide.
AB  - The oxovanadium(IV) sandwich-type POM catalyzes the chemo-, regio-, and
      stereoselective epoxidation of allylic alcohols by chiral hydroperoxides with
      very high catalytic efficiency (up to 42 000 TON), a potentially valuable
      oxidation for the development of sustainable processes. By using the sterically
      demanding, TADDOL-derived hydroperoxide TADOOH as the chiral oxygen source,
      enantiomeric ratios (er) of up to 95:5 have been achieved.

PMID- 12605503
TI  - Solid-phase synthesis of peptide vinyl sulfones as potential inhibitors and
      activity-based probes of cysteine proteases.
AB  - Peptide vinyl sulfones were prepared from 2-chlorotrityl resin-bound phenolic
      amino vinyl sulfones in high yield and purity. This method enables the convenient
      synthesis of peptide vinyl sulfones having different amino acids at the P(1)
      position. It also allows efficient synthesis of vinyl sulfone-containing,
      activity-based probes of cysteine proteases used in a proteomic experiment.

PMID- 12605502
TI  - Formal catalytic asymmetric total synthesis of fostriecin.
AB  - The common synthetic intermediate of a potent and promising anticancer agent,
      fostriecin, was synthesized using a unique method that combines four catalytic
      asymmetric reactions as shown above.

PMID- 12605504
TI  - Efficient synthesis of macrocyclic paracyclophanes by ring-closing metathesis
      dimerization and trimerization reactions.
AB  - Ring-closing metathesis reactions of para-disubstituted aromatic substrates
      produced macrocyclic [n.n]-, and [n.n.n]paracyclophanes efficiently through
      dimerization and trimerization reactions. Sufficiently long alkyl chains allowed
      direct monocyclizations to yield [n]paracyclophanes. A small library of
      paracyclophanes were generated by the combinatorial cross-metathesis approach.

PMID- 12605505
TI  - Convenient synthesis of polyfunctionalized beta-fluoropyrroles from rhodium(II)
      catalyzed intramolecular N-H insertion reactions.
AB  - Polyfunctionalized beta-fluoropyrrole can be readily prepared from rhodium(II)
      acetate-catalyzed intramolecular N-H insertion reaction of delta-amino
      gamma,gamma-difluoro-alpha-diazo-beta-ketoesters. A cyanomethylene group can be
      introduced at C-3 of the pyrrole ring through the Wittig reaction of the diazo
      compounds followed by rhodium(II)-catalyzed intramolecular N-H insertion
      reactions.

PMID- 12605506
TI  - Total synthesis of (-)-aspidospermine via diastereoselective ring-closing olefin
      metathesis.
AB  - An enantiocontrolled total synthesis of (-)-aspidospermine has been achieved. The
      key element of the strategy is the diastereoselective construction of the
      quaternary stereogenic center employing 1,4-asymmetric induction during the ring
      closing olefin metathesis.

PMID- 12605507
TI  - Primary 1-arylcyclopropylamines from aryl cyanides with diethylzinc and titanium
      alkoxides.
AB  - 1-Aryl-substituted primary cyclopropylamines are conveniently prepared from
      aromatic nitriles and diethylzinc. The yields range from 40 to 56% for donor
      substituted (five examples) to 62-82% for non- and acceptor-substituted
      substrates (nine examples).

PMID- 12605508
TI  - The first preparation of beta-lactones by radical cyclization.
AB  - beta-Lactones have, for the first time, been prepared by 4-exo-trig radical
      cyclization. Thus, alpha-ethenoyloxy radicals react in the presence of
      tributylstannane in a photothermal process to give beta-lactones. Highest yields
      were obtained when groups capable of stabilizing a carbon-centered radical were
      present at the 3-position of the alkenoate acceptor.

PMID- 12605509
TI  - Total synthesis of (+)-spongistatin 1. An effective second-generation
      construction of an advanced EF Wittig salt, fragment union, and final
      elaboration.
AB  - A stereocontrolled, total synthesis of (+)-spongistatin 1 (1) has been achieved.
      Union of a second-generation EF Wittig salt (+)-3 with the advanced ABCD aldehyde
      (-)-4, followed by regioselective macrolactonization and global deprotection
      afforded (+)-spongistatin 1 (1). The longest linear sequence, 29 steps, proceeded
      in 0.5% overall yield.

PMID- 12605510
TI  - Synthesis of (+/-)-phloeodictine A1.
AB  - The antitumor antibiotic phloeodictine A1 (2) has been synthesized by a
      convergent seven-step route in 8% overall yield. The key step was the Eguchi aza
      Wittig reaction of 6 to give 13 followed by a retro Diels-Alder reaction to
      liberate 5. Addition of 11-dodecenylmagnesium bromide to 5 to give 4b, alkylation
      with 18b, and deprotection completed the first synthesis of 2.

PMID- 12605511
TI  - Novel method for incorporating the CHF(2) group into organic molecules using
      BrF(3).
AB  - 2-Alkyl-1,3-dithiane derivatives, easily made from alkyl bromides and the parent
      1,3-dithiane, were reacted with BrF(3) to form the corresponding 1,1
      difluoromethyl alkanes (RCHF(2)) in 60-75% yield. The reaction proceeds well with
      primary alkyl halides. The limiting step for secondary alkyl halides is the
      relatively low yield of the dithiane preparation. The two sulfur atoms of the
      dithiane are essential for the reaction.

PMID- 12605513
TI  - An efficient palladium-catalyzed synthesis of cinnamaldehydes from acrolein
      diethyl acetal and aryl iodides and bromides.
AB  - The reaction of aryl iodides and bromides with acrolein diethyl acetal in the
      presence of Pd(OAc)(2), (n)()Bu(4)NOAc, K(2)CO(3), KCl, and DMF, at 90 degrees C
      until the disappearance of the acetal followed by the addition of 2 N HCl to the
      crude reaction mixture, affords cinnamaldehydes in good to high yields. A variety
      of functional groups are tolerated in the aryl halides, including ether,
      aldehyde, ketone, ester, dialkylamino, nitrile, and nitro groups. The presence of
      substituents close to the oxidative addition site does not hamper the reaction.

PMID- 12605512
TI  - Novel antiinsectan oxalicine alkaloids from two undescribed fungicolous
      Penicillium spp.
AB  - 15-Deoxyoxalicine B (1) and decaturins A (2) and B (3) have been isolated from
      Penicillium decaturense and Penicillium thiersii, two previously undescribed
      species obtained as colonists of wood-decay fungi. The structures were determined
      by 2D NMR experiments and/or single-crystal X-ray diffraction analysis. These
      compounds are members of a rare structural class, and decaturins A and B feature
      a new polycyclic ring system. Decaturin B (3) exhibited potent antiinsectan
      activity against the fall armyworm (Spodoptera frugiperda).

PMID- 12605514
TI  - Direct synthesis of the beta-l-rhamnopyranosides.
AB  - The direct formation of beta-l-rhamnopyranosides by means of thioglycoside donors
      protected with a 2-O-sulfonate ester and, ideally, a 4-O-benzoyl ester, is
      reported. Activation is achieved with the combination of 1-benzenesulfinyl
      piperidine and triflic anhydride in the presence of 2,4,6-tri-tert
      butylpyrimidine. Selectivities vary from moderate to good, and the sulfonyl group
      is easily removed post-glycosylation with sodium amalgam in 2-propanol.

PMID- 12605515
TI  - The endoscopically assisted pharyngeal flap.
AB  - OBJECTIVE: To describe a modification of the Hogan lateral port control technique
      for pharyngeal-flap surgery. RESULTS AND CONCLUSIONS: Use of a 70-degree nasal
      endoscope to assist in the determination of lateral port diameter allows for
      better control of flap and port construction.

PMID- 12605516
TI  - Nerve growth factor receptor immunolocalization during human palate and tongue
      development.
AB  - OBJECTIVE: To investigate the temporospatial pattern of nerve growth factor
      receptor (NGFR) immunolocalization during human palatal closure. MATERIALS: Human
      palate and tongue tissues from 33 embryos/fetuses, 9 to 22 weeks of fertilization
      age. METHODS: Tissues were divided according to developmental stage and palatal
      development (before, during, and after closure) and then subjected to
      decalcification, paraffin embedding, serial sectioning, survey staining, and
      p75NGFR immunohistochemical staining. RESULTS: Specific temporospatial patterns
      of p75NGFR reactivity were observed; reactivity was intense in the soft tissue
      palatal shelves before and during palatal closure and was weaker in the palate
      after palatal closure. In the tongue, intense reactivity was seen throughout 9 to
      22 weeks. CONCLUSION: The observed patterns suggest that p75NGFR may enable the
      visualization of physiological events in palatal closure during normal human
      development.

PMID- 12605517
TI  - Influence of early hard palate closure in unilateral and bilateral cleft lip and
      palate on maxillary transverse growth during the first four years of age.
AB  - OBJECTIVE: To evaluate and compare the effects of early primary closure of the
      hard palate on the anterior and posterior width of the maxillary arch in children
      with bilateral (BCLP) and unilateral (UCLP) cleft lip and palate during the first
      4 years of life. DESIGN: A retrospective, mixed-longitudinal study. SETTING:
      Cleft Palate Center of the University of Erlangen-Nuremberg. SUBJECTS AND
      METHODS: The present investigation analyzes longitudinally 42 children with UCLP
      and 8 children with BCLP between 1996 and 2000 with early simultaneous primary
      closure of lip and hard palate (4 to 5 months). Palatal arch width was measured
      on dental casts with a computer-controlled three-dimensional digitizing system,
      and their growth velocities were calculated from consecutive periods (mean follow
      up 39 months). Differences in growth velocities were compared with those of 25
      children with UCLP and 15 children with BCLP with delayed closure of hard palate
      (12 to 14 months). RESULTS AND CONCLUSIONS: There was no significant difference
      in terms of anterior and posterior maxillary width between early and delayed
      closure of hard palate within the first 4 years of life.

PMID- 12605518
TI  - Early craniofacial morphology and growth in children with nonsyndromic Robin
      Sequence.
AB  - PURPOSE: Craniofacial morphology and growth comparisons in children with
      untreated nonsyndromic Robin Sequence (RS) and a control group with unilateral
      incomplete cleft lip (UICL) in which the lip was surgically closed at 2 months of
      age. MATERIAL: The 52 children (7 RS and 45 UICL) included in the study were
      drawn from a group representing all Danish cleft children born 1976 through 1981.
      The ages of the children were 2 and 22 months at the time of examination 1 and 2,
      respectively. METHOD: The method of investigation was three-projection
      cephalometry. Craniofacial morphology was analyzed by means of linear, angular,
      and area variables. Growth at a specific anatomical location in a patient was
      defined as the displacement vector from the coordinate of the corresponding
      landmark at examination 1 to its coordinate at examination 2. RESULTS: The most
      striking findings in the RS group were markedly increased posterior maxillary
      width, increased width of the nasal cavity, short maxilla with reduced posterior
      height, short mandible, bimaxillary retrognathia, and severe reduction in size of
      the pharyngeal airway. The amount of facial growth was similar in the two groups;
      however, a tendency toward a more vertical growth direction was observed in the
      RS group. CONCLUSION: Facial morphology in children with RS differed
      significantly from that of children with UICL at both 2 and 22 months of age. The
      magnitude of facial growth was similar in the two groups, whereas a tendency
      toward a more vertical facial growth direction was observed in the RS group.

PMID- 12605519
TI  - Influence of lip repair on craniofacial morphology of patients with complete
      bilateral cleft lip and palate.
AB  - OBJECTIVE: The aim of this study was to compare two groups of adult male patients
      with complete bilateral cleft lip and palate (BCLP) on the basis of lateral
      cephalometric radiographs. PATIENTS: The first group of adult male patients with
      complete BCLP was comprised of 13 unoperated patients with an average age of 21
      years. The second group was comprised of 14 patients with an average age of 21
      years 7 months, who had been operated only on the lip prior to 2 years of age.
      DESIGN: The following measurements were evaluated: angle and length of cranial
      base; maxillary spatial positioning and length; mandibular spatial positioning;
      morphology and length; maxillomandibular relationship; vertical facial length;
      dental positioning; interdental arch relationship; and soft profile. RESULTS: The
      results suggest that lip repair has a significant influence on certain areas of
      the craniofacial complex, mainly the premaxilla and the upper incisors.
      CONCLUSIONS: The most significant findings consequent to lip repair consisted of
      reduction of the premaxillary anterior projection and lingual tipping of the
      upper incisors. Retropositioning of the premaxilla, especially in the alveolar
      part, is a desired effect of lip repair in complete BCLP. Such effect on the
      projected premaxilla is usually beneficial, except when the exceedingly severe
      lip pressure, unfavorable growth pattern, or both retropositions the midface
      profile beyond acceptable sagittal limits.

PMID- 12605520
TI  - Do the reading disabilities of children with cleft fit into current models of
      developmental dyslexia?
AB  - OBJECTIVE: The purpose of this study was to determine whether the reading
      problems of children with cleft fit models of developmental dyslexia. DESIGN: The
      study compared children with nonsyndromic cleft lip and palate who had reading
      disability (n = 46) with those who did not have reading disability (n = 46). The
      children were matched for age, sex, and grade. The two groups were compared (t
      tests) on measures of verbal expression, phonemic awareness, and rapid naming.
      Also, regression analyses compared the relative relationships of these variables
      to reading disability. PARTICIPANTS: Children were selected from 154 patients
      originally screened. RESULTS: Children with reading disability scored
      significantly lower on rapid naming and verbal expression, with no differences
      found on phonemic awareness. Rapid naming was shown to have the most significant
      association with reading disability. CONCLUSION: Children with nonsyndromic cleft
      lip and palate show symptoms similar to a naming-memory deficit model of
      developmental dyslexia. Reading treatment should avoid sight word approaches and
      focus on oral phonics treatment.

PMID- 12605521
TI  - Pressure-flow measurements for selected nasal sound segments produced by normal
      children and adolescents.
AB  - OBJECTIVE: The purpose of this prospective study was to: (1) report simultaneous
      oral-nasal pressures, nasal airflow rates, and velopharyngeal orifice areas for
      nasal sounds produced by children and adolescents; (2) determine whether data
      could be statistically classified by age, sex, or utterance type; and (3) provide
      guidelines for determining typical from atypical productions. PARTICIPANTS: The
      study involved 56 subjects, with two boys and two girls representing each age
      from 5 to 18 years. Subjects had no history of speech therapy, were judged as
      having normal speech and resonance at the time of testing, and had no upper
      respiratory tract infections or allergies at the time of testing. METHODS: All
      subjects repeated /mphaaa;/ and "hamper" at normal pitch and loudness after an
      examiner model. Mean oral-nasal pressures, nasal airflow rates, and
      velopharyngeal orifice areas were calculated for each subject's utterances. A
      discriminate function analysis determined whether data could be grouped by age
      and sex. RESULTS: Significant differences in mean data for age groups of 5 to 9
      years, 10 to 13 years, and 14 to 18 years were observed. Data showed decreases in
      pressures and increases in nasal airflow and orifice areas with age. Variability
      in pressure stayed consistent or decreased with age, but variability in nasal
      airflow and orifice areas increased with age. CONCLUSION: We propose a scheme for
      categorizing velopharyngeal function for oral and nasal sound production to be
      used in clinical testing.

PMID- 12605522
TI  - Perceived social support of mothers of children with clefts.
AB  - OBJECTIVE: To identify factors that may predict perceived social support in
      mothers of children with clefts. DESIGN: A comparison was conducted from a sample
      of mothers of children with oral clefts identified from a single institution
      (multidisciplinary craniofacial clinic). The Interpersonal Support Evaluation
      List and Beck Depression Inventory were completed by all participants. RESULTS:
      Mothers of children with visible clefts were more likely to report higher
      perceived social support than mothers of children with clefts that were not
      visible (p =.005). Mothers of female children reported higher levels of perceived
      social support than mothers of male children (p =.02). Mothers who had completed
      more years of education reported significantly higher levels of perceived social
      support than mothers who had completed fewer years of school (p =.03). Mothers
      with more children were more likely to report lower levels of perceived social
      support (p =.009). Maternal depression was highly correlated with perceived
      social support (p <.0001). CONCLUSIONS: Cleft visibility, family size, child sex,
      and maternal education level were important factors in predicting perceived
      social support in mothers of children with clefts. Child age, syndrome status,
      and cleft family history were not significant predictors.

PMID- 12605523
TI  - Dental anomalies of the permanent lateral incisors and prevalence of hypodontia
      outside the cleft area in complete unilateral cleft lip and palate.
AB  - OBJECTIVE: To determine in complete unilateral cleft lip and palate (UCLP)
      subjects the characteristics (location, shape) of the cleft-side lateral incisor.
      The presence of a supernumerary tooth at the cleft side and the prevalence of
      hypodontia outside the cleft area were evaluated. A comparison was made of the
      shape of the cleft side lateral incisor to its contralateral incisor. SETTING:
      Hospital for Rehabilitation of Craniofacial Anomalies (HRCA), Sao Paulo, Brazil.
      PATIENTS: Orthopantomograms of 203 subjects with UCLP and without syndromes were
      chronologically selected from the HRCA data bank, within an age range of 5 to 10
      years. OUTCOME MEASURE: Orthopantomograms were analyzed by the same observer
      according to established criteria. RESULTS: There were no statistically
      significant differences between sexes for any of the criteria studied. The cleft
      side lateral incisor was present in 50.2%, and it was more commonly located at
      the distal side (76.5%). The congenital absence of the cleft-side lateral incisor
      was observed in 49.8% of the sample, and its antimere was congenitally missing in
      10.9%, this difference being statistically significant. The most commonly missing
      tooth outside the cleft area was the maxillary second premolar. CONCLUSIONS: The
      high prevalence of hypodontia of the permanent lateral incisor in the cleft side
      showed that the cleft could play an important role in this absence. There were
      different patterns for the presence of the cleft-side lateral incisor.

PMID- 12605524
TI  - Is isolated palatal anomaly an indication to screen for 22q11 region deletion?
AB  - OBJECTIVE: Velocardiofacial syndrome (VCFS) is the most common multiple anomaly
      disorder associated with palatal clefting. Cytogenetic hemizygous deletion of
      22q11 region is found in 80% of patients. The frequency of 22q11 deletion in
      patients presenting with isolated palatal anomalies has not been fully assessed.
      Our objective was to determine the frequency of the deletion in patients with
      isolated palatal anomalies. DESIGN: Patients were referred because of
      velopharyngeal insufficiency because of isolated congenital palatal anomalies.
      Diagnosis of palatal anomalies was confirmed by videonasopharyngoscopy, multiview
      videofluoroscopy and cephalometry. Other clinical findings suggestive of VCFS
      were sought, and subjects with these characteristics were excluded from the
      study. Peripheral blood samples from all patients were analyzed cytogenetically
      utilizing fluorescent in situ hybridization for the 22q11 region. RESULTS: Thirty
      eight patients aged 3 to 31 years were included in the study. Nine had cleft
      palate, 7 cleft lip and palate, 10 overt and 11 occult submucous cleft palate,
      and 1 had a deep nasopharynx. No deletion of 22q11 region was detected in any of
      the evaluated patients. CONCLUSIONS: A routine screening for the 22q11 deletion
      in older children and adults presenting with an isolated palatal anomaly may not
      be required. Because other signs related to VCFS such as facial dysmorphism and
      behavioral or psychiatric disorders may evolve at an older age, young patients
      should be followed up and reevaluated for additional relevant symptoms that may
      lead to deletion evaluation. In light of the fact that the current literature is
      inconsistent, the relative small size of this study and the significant
      consequences of missed 22q11.2 deletion, more information is needed before
      definitive recommendations can be made.

PMID- 12605526
TI  - Prenatal diagnosis of cleft lip and palate.
AB  - OBJECTIVE: The use of ultrasound for the prenatal diagnosis of cleft lip and
      palate has aided considerably in the early diagnosis of orofacial clefting. The
      impact and consequences of this need to be considered as the reliability and
      validity of ultrasound diagnosis increases. This review article considers a
      number of these issues as well as up-to-date information on the quality of the
      technique.

PMID- 12605525
TI  - Management of infants with Pierre Robin sequence.
AB  - OBJECTIVE: Several methods of treating babies with Pierre Robin sequence have
      been described since the condition itself was first documented in 1923. The main
      aim of treatment has been to relieve upper airway obstruction. Treatment methods
      used range from positioning of the baby to invasive surgery. The aim of this
      article was to describe the assessment, treatment, and monitoring methods used
      for babies referred with Pierre Robin sequence (PRS). SETTING/PATIENTS: From
      December 1995 to May 2000, 22 consecutive patients were admitted to Birmingham
      Children's Hospital with PRS. Their airway and nutritional status were assessed
      and continuously monitored. INTERVENTIONS: Treatment concentrated on the relief
      of airway obstruction with a nasopharyngeal airway (NPA) and nutritional support
      of the babies until they grew out of their respiratory and feeding difficulties.
      MAIN OUTCOME MEASURES: Outcome measures were oxygen saturation, growth of the
      babies, and the need for surgery. RESULTS: All babies were managed successfully
      with an NPA and nutritional support. No baby required surgery, and the majority
      showed good weight gain. CONCLUSION: Relieving airway obstruction by NPA is an
      effective and safe treatment for babies with PRS until they have grown out of
      their respiratory and feeding difficulties. It avoids the need for surgery and
      can be used on neonatal wards using the monitoring described.

PMID- 12605527
TI  - Specific language impairment in children with velocardiofacial syndrome: four
      case studies.
AB  - OBJECTIVE: To describe specific language impairment in four children with
      velocardiofacial syndrome (VCFS). DESIGN: A descriptive, retrospective study of
      four cases. SETTING: University Hospital Groningen, tertiary clinical care.
      PATIENTS: Of 350 patients with cleft plate, 18 children were diagnosed with VCFS.
      Four children are described. INTERVENTIONS: In all children, cardiac and plastic
      surgery was carried out in the first year of life. Afterward, interventions
      consisted of hearing improvement, pharyngoplasty, and speech therapy. MAIN
      OUTCOME: Inadequate and uncharacteristic development of articulation and
      expressive language in four children with VCFS were observed. They differed from
      the majority in two ways: their nonverbal IQ was in the normal range, and their
      language skills were below expectations for their IQ. RESULTS: Four of 18
      patients with VCFS (22%) showed poor response to therapy and did not develop
      language in accordance with their normal learning abilities (nonverbal learning
      capacities and language comprehension). Persistent hypernasal resonance and
      severe articulation problems remained in all four children. In two children the
      expressive language profile was also not in agreement with the nonverbal profile:
      they produced only two- and three-word utterances at the age of 6.0 and 5.3
      years. The other two children at the age of 6.8 and 6.4 years produced very long
      sentences, but they were unintelligible. CONCLUSIONS: The speech and language
      impairment of the four children may be characterized as a phonological or verbal
      programming deficit syndrome and as such can be described as a specific language
      impairment in conjunction with VCFS.

PMID- 12605528
TI  - Report of a patient with hypoglossia-hypodactylia syndrome and a review of the
      literature.
AB  - OBJECTIVE: To present the morphology of the extremities, craniofacial structures,
      and the oral cavity based on roentgencephalometry and three-dimensional computed
      tomography and magnetic resonance imaging scanning in a patient with hypoglossia
      hypodactylia syndrome, discuss the orthodontic treatment method, and review the
      literature for the syndrome. PATIENT: The patient was a 6-year-old boy diagnosed
      with hypoglossia-hypodactylia syndrome at birth. He had hypodactylia as well as
      micrognathia with steep inclination of the anterior surface of the mandible in
      relation to the lower mandibular plane. He had missing mandibular incisors with
      concomitant bone defect limited to the associated alveolar ridge and an absence
      of any malformations in the mandibular ramus and condylar head. The patient had a
      bilateral scissors bite with an extremely constricted mandibular dental arch,
      skeletal Class II jaw relationship with an average mandibular plane angle and
      maxillary incisors inclined palatally. He had extremely reduced tongue size and
      hypertrophy of the floor of the mouth. Anomalies of the central nervous system
      were not observed. There was no evidence of hearing loss.

PMID- 12605529
TI  - Submucous cleft palates presenting with a perforation.
AB  - OBJECTIVE: The development of a perforation in a submucous cleft palate (SMCP) is
      a rare occurrence, with only a few cases reported in the literature. We describe
      and illustrate four cases of SMCPs with a perforation in the palate. RESULTS AND
      CONCLUSIONS: Recognition of the symptoms and signs of an SMCP should enable early
      diagnosis and treatment of this condition in symptomatic patients. However, in
      patients in whom the diagnosis has been missed or in those who have been
      asymptomatic, the development of a perforation may be the presenting feature of
      an SMCP. A history of possible trauma to the palate was found in two cases.
      Relatively minor trauma may cause perforation of the thin translucent central
      mucosa in an SMCP. In neonates, perforations surrounded by very thin mucosa may
      increase in size. The perforation can be closed at the same time as the SMCP
      repair and does not significantly alter the surgical treatment of an SMCP.

PMID- 12605530
TI  - Rigid external distraction osteogenesis for a patient with maxillary hypoplasia
      and oligodontia.
AB  - OBJECTIVE: In this report, the orthodontic treatment combined with rigid external
      distraction osteogenesis in a 5.5-year-old girl with midfacial hypoplasia and
      oligodontia is described. PATIENT: The child presented with a reduced maxilla,
      protruding lower lip, skeletal Class III jaw relationship with a low mandibular
      plane angle, a short and flattened nose, anterior crossbite, and aplasia of 16
      permanent teeth. The patient was treated with rigid external maxillary
      distraction osteogenesis, maxillary protraction headgear, and Class III elastics.
      Following treatment, the maxilla was displaced in a forward direction with new
      bone formation at the tuberosities and the mandible rotated backward in relation
      to the anterior cranial base. The anterior crossbite was corrected, and the
      skeletal jaw relationship changed from a Class III to a Class I skeletal pattern.
      The soft tissue facial profile showed that the nasal projection had been
      increased, the nasolabial angle increased, and the lower lip protrusion was
      reduced. Postoperative treatment results were acceptable. CONCLUSION: This report
      documents that early maxillary advancement with rigid external osteogenesis
      offers a promising treatment alternative for a very young patient with maxillary
      hypoplasia and oligodontia.

PMID- 12605531
TI  - Repair of congenital nasal anomalies involving redundancy of structures.
AB  - OBJECTIVE: Rare congenital nasal anomalies include symmetric complete nasal
      duplication and asymmetric supernumerary nostrils. Complete nasal duplication may
      be either vertically stacked or horizontally oriented. It is a result of
      duplication of the nasal placode pair. Supernumerary structures include nostrils
      (with or without accessory cartilage) or fistulas that result from a fissure of
      the lateral nasal process. A case report is described whereby an adult accessory
      nostril, complete with an extra lower lateral cartilage, is repaired through
      direct excision and tip suturing. The importance of removing superfluous
      structures and reconstructing the normal anatomy by using an open rhinoplasty
      technique is stressed to achieve an aesthetic outcome.

PMID- 12605534
TI  - Isolated soft tissue cleft lip: the influence on the nasal cavity and
      supernumerary laterals.

PMID- 12605536
TI  - Three-dimensional binding of epidermal growth factor peptides in colonic tissues
      produced from rotating bioreactor.
AB  - Epidermal growth factor peptide binding was analyzed on primary cultures of
      colonic cells and along crypts by fluorescent laser-scanning confocal microscopy,
      using a three-dimensional image analysis software (Quant3D, Linux/Unix).
      Structural, proliferative units from primary cultures grown in rotating
      bioreactor for 41 d were arranged according to a tubular symmetry or on a
      parallelepiped sheet. Mean width, height, and depth of 23 tissue-like masses (+/-
      standard error) were 125 microm (+/-16), 152 microm (+/-23), and 29 microm (+/
      3), respectively. Mean density of nuclei in tissue-like masses, expressed as the
      number of nuclei per cubic millimeter (+/- standard error of the mean), was 1.8 x
      10(5) (+/-0.7 x 10(5)) nuclei per cubic millimeter, which corresponded to a
      density that was five to six times lower than that estimated for the colonic
      crypt isolated by chelation. Spots of high epidermal growth factor (EGF) peptide
      binding that corresponded to microlesions in crypt monolayers or to active
      colonization of microcarriers by epithelial and stromal cells in tissue-like
      masses were observed. The relative intensities of EGF peptide binding that were
      obtained below cell position 8 on crypts were very homogeneous and were
      representative of the profile obtained with crypts isolated from adult rats
      adapted to a normal diet and used to develop primary cultures of colonocytes in
      our laboratory. A microscopic multidimensional analytic system to record the
      expression profiles of biomarkers along intestinal tissues should enhance the use
      of primary cultures of colonocytes for in vitro testing of new food products.

PMID- 12605537
TI  - Colony-forming capacity of porcine liver epithelial cells in culture.
AB  - Previously, we reported the presence of certain nonparenchymal epithelial cells
      (NPECs) in adult porcine livers that demonstrate differentiation patterns
      including an emergence of duct-like structures (DLSs) in the colonies. In the
      present study, we examined the effect of supplements to the NAIR-1 medium
      (Dulbecco modified Eagle medium [DMEM]-F12 containing 5% fetal bovine serum [FBS]
      and 11 supplements) used in these cultures on formation of DLSs-emerged colonies
      (type I colonies). No type I colonies were observed in the cultures of the
      nonparenchymal cell fraction when Roswell Park Memorial Institute-1640 medium or
      DMEM-F12 (1:1) supplemented with 5% FBS was used as the culture medium. NAIR-1
      medium without each component did not produce any significant results. No type I
      colonies were formed when epidermal growth factor, and hydrocortisone and insulin
      mixture (A) or nicotinamide and l-ascorbic acid phosphate magnesium salt (Asc2P)
      mixture (B) was added to the DMEM-F12 medium supplemented with 5% FBS. However,
      when a combination of A and B was added, colonies were formed at a significant
      level. Together, the number of type I colonies was increased in the combination
      of A and B containing a higher concentration of Asc2P. We conclude that NPECs
      need a mixture of Asc2P and other components as supplements for type 1 colony
      formation.

PMID- 12605539
TI  - Biochemical and electrophysiological differentiation profile of a human
      neuroblastoma (IMR-32) cell line.
AB  - A human neuroblastoma cell line (IMR-32), when differentiated, mimics large
      projections of the human cerebral cortex and under certain tissue culture
      conditions, forms intracellular fibrillary material, commonly observed in brains
      of patients affected with Alzheimer's disease. Our purpose is to use
      differentiated IMR-32 cells as an in vitro system for magnetic field exposure
      studies. We have previously studied in vitro differentiation of murine
      neuroblastoma (N1E-115) cells with respect to resting membrane potential
      development. The purpose of this study was to extend our investigation to IMR-32
      cells. Electrophysiological (resting membrane potential, V(m)) and biochemical
      (neuron-specific enolase activity [NSE]) measurements were taken every 2 d for a
      period of 16 d. A voltage-sensitive oxonol dye together with flow cytometry was
      used to measure relative changes in V(m). To rule out any effect due to
      mechanical cell detachment, V(m) was indirectly measured by using a slow
      potentiometric dye (tetramethylrhodamine methyl ester) together with confocal
      digital imaging microscopy. Neuron-specific enolase activity was measured by
      following the production of phosphoenolpyruvate from 2-phospho-d-glycerate at 240
      nm. Our results indicate that in IMR-32, in vitro differentiation as
      characterized by an increase in NSE activity is not accompanied by resting
      membrane potential development. This finding suggests that pathways for
      morphological-biochemical and electrophysiological differentiations in IMR-32
      cells are independent of one another.

PMID- 12605538
TI  - Heterocellular cultures of pulmonary alveolar epithelial cells grown on laminin-5
      supplemented matrix.
AB  - The pulmonary alveolar epithelium consists of alveolar type I (AT1) and alveolar
      type II (AT2) cells. Interactions between these two cell types are necessary for
      alveolar homeostasis and remodeling. These interactions have been difficult to
      study in vitro because current cell culture models of the alveolar epithelium do
      not provide a heterocellular population of AT1 and AT2 cells for an extended
      period of time in culture. In this study, a new method for obtaining
      heterocellular cultures of AT1- and AT2-like alveolar epithelial cells maintained
      for 7 d on a rat tail collagen-fibronectin matrix supplemented with laminin-5 is
      described. These cultures contain cells that appear by their morphology to be
      either AT1 cells (larger flattened cells without lamellar bodies) or AT2 cells
      (smaller cuboidal cells with lamellar bodies). AT1-like cells stain for the type
      I cell marker aquaporin-5, whereas AT2-like cells stain for the type II cell
      markers surfactant protein C or prosurfactant protein C. AT1/AT2 cell ratios,
      cell morphology, and cell phenotype-specific staining patterns seen in 7-d-old
      heterocellular cultures are similar to those seen in alveoli in situ. This
      culture system, in which a mixed population of phenotypically distinct alveolar
      epithelial cells are maintained, may facilitate in vitro studies that are more
      representative of AT1-AT2 cell interactions that occur in vivo.

PMID- 12605540
TI  - Chondrogenic differentiation of human mesenchymal stem cells within an alginate
      layer culture system.
AB  - Human mesenchymal stem cells (hMSCs) derived from bone marrow have the capacity
      to differentiate along a number of connective tissue pathways and are an
      attractive source of chondrocyte precursor cells. When these cells are cultured
      in a three-dimensional format in the presence of transforming growth factor-beta,
      they undergo characteristic morphological changes concurrent with deposition of
      cartilaginous extracellular matrix (ECM). In this study, factors influencing hMSC
      chondrogenesis were investigated using an alginate layer culture system.
      Application of this system resulted in a more homogeneous and rapid synthesis of
      cartilaginous ECM than did micromass cultures and presented a more functional
      format than did alginate bead cultures. Differentiation was found to be dependent
      on initial cell seeding density and was interrelated to cellular proliferation.
      Maximal glycosaminoglycan (GAG) synthesis defined an optimal hMSC seeding density
      for chondrogenesis at 25 x 10(6) cells/ml. Inclusion of hyaluronan in the
      alginate layer at the initiation of cultures enhanced chondrogenic
      differentiation in a dose-dependent manner, with maximal effect seen at 100
      microg/ml. Hyaluronan increased GAG synthesis at early time points, with greater
      effect seen at lower cell densities, signifying cell-cell contact involvement.
      This culture system offers additional opportunities for elucidating conditions
      influencing chondrogenesis and for modeling cartilage homeostasis or
      osteoarthritic changes.

PMID- 12605545
TI  - 'Differential Gene Expression 2002'.

PMID- 12605542
TI  - The effects of epidermal growth factor on gene expression in human fibroblasts.
AB  - A better understanding of the molecular effects of epidermal growth factor (EGF)
      on target cell can help to reveal important aspects of cellular proliferation,
      transformation, and apoptosis, as well as embryonic and fetal development. In
      this study, we examined the differences in gene expression of cultured
      fibroblasts with EGF stimulation for 48 h by using high-density complementary
      deoxyribonucleic acid (cDNA) arrays. We found that EGF could cause widespread
      alteration in gene expression. Eight hundred and fifty-five genes, more than 20%
      of those assayed, showed changed expression, which are involved in various
      cellular processes, such as energetic metabolism, biosynthesis, the progress of
      cell cycle, and the signaling pathways of receptor tyrosine kinase (RTKs) and G
      protein-coupled receptors (GPCRs). The most striking finding is that long-term
      EGF treatment on cultured fibroblasts resulted in down-regulation of the genes
      encoding membrane receptors and ion channels and desensitized RTKs and GPCRs to
      their physiological and nonphysiological stimuli, which seems to be a slow
      acting, but permanent, effect of EGF on RTK and GPCR signaling pathways and to
      play important roles in embryonic and fetal development.

PMID- 12605541
TI  - Isolation and characterization of canine satellite cells.
AB  - Satellite cells were isolated from biopsies of the biceps femoris of adult dogs.
      Virtually all cells expressed muscle-specific proteins. Proliferation of
      satellite cells increased as the concentration of fetal calf serum (FCS) was
      increased from 1 to 10% of the basal medium. The addition of mitogenic growth
      factors resulted in greater proliferation than that of cells cultured in basal
      medium alone. Maximum proliferation was obtained when fibroblast growth factor
      basic (FGF2) was added to the medium, but differences existed between sources or
      types. Proliferation did not plateau when the concentration of recombinant human
      FGF2 was 75 ng/ml but reached maximum levels when 50 ng/ml of bovine FGF2 or 10
      ng/ml of growth hormone or insulin-like growth factor-1 were added to the medium.
      Proliferation of satellite cells decreased when more than 5 ng/ml of transforming
      growth factor-alpha was included in the medium. Exposure of canine satellite
      cells to chemically defined media induced greater fusion of total nuclei (ODM
      34%; 4F, ITT-CF, and SFG-23%) than exposure to other treatments, such as basal
      medium plus 2 mg/ml of 1-beta-d-arabinofuranosylcytosine, 5% chick embryo
      extract, 1% horse serum (average 9% fused nuclei), or 1% FCS (2% fused nuclei).
      Actin, myosin, desmin, neural cell adhesion molecule, MyoD1, and myogenin were
      expressed by canine satellite cells, but expression of major histocompatibility
      complex class II antigen was not detected. Reverse transcriptase-polymerase chain
      reaction detected expression of messenger ribonucleic acid for interleukin-6 (IL
      6), IL-15, and leukemia inhibitory factor by canine satellite cells.
      Collectively, these data suggest that isolated canine satellite cells display
      properties of other types of myogenic cells and may be useful for further study
      of the regulation of postnatal myogenesis.

PMID- 12605543
TI  - Privacy issues in personalized medicine.
AB  - Pharmacogenomics is the emerging study of why individuals respond differently to
      drugs. It aims to replace the current 'one size fits all' therapeutic approach
      with 'personalized medicine' that will use pharmacogenomic tests to predict drug
      response. In a simple conceptualization, these tests challenge privacy as a
      result of two factors: how comprehensive is the test and how is the access to
      samples or digital information controlled. Point-of-care tests are likely to be
      limited in scope, fit seamlessly into medical records and do not raise
      qualitatively new ethical and privacy challenges. In order to define practically
      relevant pharmacogenomic predictive patterns however, large-scale clinical trials
      and research on human specimens will be required, resulting in large databases of
      genomic information. The genomic scans' magnitude, stability, implications to kin
      and ease of dissemination together represent a qualitatively different challenge
      compared to traditional, self-limited and often temporally transient medical
      information.

PMID- 12605546
TI  - Lab-on-a-chip and microarrays: discovery and development.

PMID- 12605547
TI  - Candidate gene case-control studies.
AB  - Two main approaches to the identification of genes are involved in polygenic
      diseases. Use of family studies has generally been the preferred approach up
      until recently, but this is only feasible if the genetic component of the disease
      is relatively strong and DNA samples are available from other family members.
      Population case-control studies are useful both as an alternative and an adjunct
      to family studies. These can involve either whole genome scanning or candidate
      gene approaches. While whole genome scanning is likely to be widely used in the
      future once more information on genome-wide single nucleotide polymorphism
      distributions is available, at present, candidate gene studies are more feasible.
      When performing candidate gene case-control studies factors such as study design,
      methods for recruitment of case and controls, selection of candidate genes,
      functional significance of polymorphisms chosen for study and statistical
      analysis require close attention to ensure that only genuine associations are
      detected. Some examples of the successful use of candidate gene case-control
      studies are discussed and, to illustrate some potential problems in the design
      and interpretation of association studies, some specific examples of association
      studies on cancer are considered.

PMID- 12605549
TI  - Pharmacogenomics of angiotensin converting enzyme inhibitors in renal disease-
      pathophysiological considerations.
AB  - Angiotensin converting enzyme (ACE) inhibitors preserve native kidney function in
      patients with renal disease better than other antihypertensive drugs, most likely
      because they more effectively reduce proteinuria. The plasma concentration of the
      ACE inhibitors target is, at least in part, under genetic control. A polymorphism
      of the ACE gene based on the presence or absence of a 287 base pair element in
      intron 16 accounts for 47% of the total phenotypic variance in the plasma ACE
      levels of healthy individuals. Unfortunately, pharmacogenetic studies performed
      so far do not provide a clear answer as to whether the efficacy of the reduction
      of proteinuria by ACE inhibitors is influenced by the ACE genotype - probably
      because these studies were not primarily designed to answer this question. This
      paper will try to outline some aspects that should be considered before an
      appropriate study on this topic is initiated.

PMID- 12605548
TI  - Predicting inductive drug-drug interactions.
AB  - Until recently, inductive drug-drug interactions have proved difficult to predict
      prior to formal pharmacokinetic studies in man. Even then, important interactions
      have often gone unrecognized until clinical sequelae have occurred in the
      postmarketing phase. Recent advances in the molecular and cellular biology of
      nuclear receptors have revealed that there are 'sensors' for xenobiotics, which
      in turn transactivate genes involved in drug metabolism and excretion. Knowledge
      of these mechanisms has allowed the development of assay systems that detect the
      potential of drugs to cause gene induction, well before human studies are
      contemplated.

PMID- 12605550
TI  - Applications of pharmacogenomics in general dental practice.
AB  - The human oral cavity represents a complex ecology of approximately 500 microbial
      species existing as commensals, and interacting with human/host factors.
      Perturbation of this ecosystem can lead to diseases of the oral cavity. The oral
      cavity also acts as a mirror of complex systemic diseases. Unique challenges and
      opportunities in oral healthcare exist in the diagnosis and treatment of primary
      disorders of the oral cavity or manifestations of systemic diseases. The
      completion of human and microbial genome projects has provided a wealth of
      information that will permit the application of pharmacogenomics - how genetic
      variations within the commensal and the host will impact the efficacy of drugs,
      and the diagnosis and treatment of oral disease. This review highlights
      opportunities focusing on oral health where pharmacogenomics can be applied.

PMID- 12605551
TI  - Haplotype analysis in population genetics and association studies.
AB  - Several studies of haplotype structures in the human genome in various
      populations have been published recently. Such knowledge may provide valuable
      information on human evolutionary history and lead to the development of more
      efficient strategies to identify genetic variants that increase susceptibility to
      human diseases. In this review, we summarize the current understanding of
      haplotype structure, diversity, and distribution in the human genome, with a
      focus on statistical issues in using haplotypes for studies of population
      genetics and evolutionary history, as well as to identify genetic variants
      underlying complex human traits.

PMID- 12605552
TI  - From microarrays to new therapeutic approaches in bladder cancer.
AB  - Bladder cancer is a model tumor progressing from superficial to locally invasive
      and finally metastatic disease. The likelihood of progression is determined to a
      large extent by the molecular profile of the tumor. From the pre-genomic era only
      p53 emerged as the molecular prognostic factor able to add value to existing
      clinical and pathological features of bladder cancer, however it was not
      introduced to the clinic. Microarray technologies enable us to study expression
      of thousands of genes in the tumor tissue. This method has already proven to add
      information to clinical classifiers, to find new tumor suppressor genes and to
      define p53 related pathways of cell-cycle regulation. In the last decade,
      progress in the treatment of locally invasive and metastatic bladder cancer was
      minimal; large Phase III trials with neo/adjuvant chemotherapy were inconclusive.
      The new paradigm of treatment tailored to an individual patient could be realized
      in bladder cancer for his chronic clinical course with opportunities to obtain
      tumor samples for microarray studies. Molecular profiling of two samples taken at
      the superficial stage and at cystectomy should enable us to study the
      microevolution of the tumor, to tailor existing treatment options, and to
      introduce new biologicals to the clinic.Introduction

PMID- 12605553
TI  - Non-invasive prenatal diagnosis: on the horizon?
AB  - The launch of the genomics and postgenomics era has greatly expanded our
      understanding of the genetic basis of many diseases. In conjunction with the
      sociocultural trend to delay childbirth and to maintain smaller family units,
      extra demand may be placed on the existing prenatal diagnostic services. The
      inherent risk of fetal loss associated with current prenatal diagnostic
      procedures, such as amniocentesis and chorionic villus sampling, has spurred
      research into non-invasive prenatal diagnosis. Much research has been conducted
      on the exploitation of fetal genetic material present in the maternal
      circulation. The initial focus was on the isolation of intact fetal cells and
      subsequently, the existence of extracellular fetal DNA in maternal plasma was
      realized. Exciting developments have been achieved in recent years. A large-scale
      trial to evaluate the clinical utility of fetal cell isolation from maternal
      blood for fetal aneuploidy diagnosis was launched and data were recently
      published. Much has taken place in the research of fetal DNA analysis in maternal
      plasma and in one example, namely prenatal RhD determination, this type of
      analysis has been used in the clinical setting. This paper reviews the
      technological developments in non-invasive prenatal diagnosis.

PMID- 12605554
TI  - Regression to the truth: replication of association in pharmacogenetic studies.
AB  - Large, prospective trials demonstrating the value of genotyping in patient
      management will be required to support the introduction of pharmacogenetics into
      routine medical practice. However, such studies will be costly and can be
      justified only if there is a reproducible association between genotype and a
      clinically relevant phenotype. Unfortunately, non-replication is prevalent among
      genetic association studies. In some cases non-replication may reflect real
      population differences but multiple comparisons, biases and other design
      limitations suggest that many initial positive associations represent Type I
      errors. Successful detection of a true genetic effect requires not only an
      informed and careful selection of candidate genes but also the assiduous
      application of sound principles of study design. Most important, independent and,
      ideally, prospective confirmation of the hypothesized genetic effect in a
      population similar to the one originally studied is required. In selected
      situations, pharmacogenetic studies in healthy volunteers may support a decision
      to perform such prospective association studies. When the potential health or
      economic consequences of therapy are significant and the results of
      pharmacogenetic association studies are convincing, it is reasonable to consider
      a major clinical trials program to assess the usefulness of genetically targeted
      therapy.

PMID- 12605555
TI  - deCODE genetics, Inc.
AB  - deCODE genetics, Inc. has compiled the world's most comprehensive collection of
      population data on genealogy, genotypes and phenotypes. This combination of
      resources provides an effective system for identifying key genes linked to common
      diseases and to the regulation of drug response. deCODE has successfully mapped
      genes in over 25 common complex diseases and isolated genes in eight of these.
      The methodology used to map these genes is based upon the company's genealogical
      database of the Icelandic population, which enables deCODE scientists to
      efficiently conduct population- and genome-wide linkage studies to identify key
      genetic factors involved in phenotypes ranging from diseases to drug response. In
      its growing pharmacogenomics program, deCODE has combined this linkage approach
      with high-throughput expression profiling to develop accurate tests that can
      predict individual responsiveness to virtually any drug of interest. deCODE is
      applying its unrivaled discovery capabilities to bring to market new drugs, DNA
      based diagnostic products and pharmacogenomic tests. The company believes that
      such tests will play a crucial role in delivering personalized medicine -
      contributing to the development of more effective means of diagnosing and
      treating disease by matching each patient with the most suitable drug.

PMID- 12605556
TI  - Pyrosequencing AB.
AB  - Pyrosequencing AB develops, manufactures and sells research products that enable
      life sciences researchers to add utility to the massive amount of genomic
      information available, with the goal of improving human health. As more genomic
      information becomes available, research efforts are shifting toward implementing
      practical applications of this genetic information. Pyrosequencing has developed
      comprehensive genotyping solutions that provide researchers with rapid and
      accurate technology for assessing individual genetic variation. Genotypic
      information is anticipated to play an important role in the emerging field of
      applied genomics and as a result, significant opportunities may be derived from
      analyzing genetic variation in individuals and across populations. These data
      will be key to understanding how genetic differences may be used to determine an
      individual's predisposition to disease, detect and monitor disease progression,
      and select the most appropriate therapy and dose and to avoid adverse events.
      This is pharmacogenomics, an area in which Pyrosequencing technology is being
      applied and will no doubt continue to enable researchers to ultimately improve
      human health.

PMID- 12605557
TI  - Insulin sensitisation in the treatment of Type 2 diabetes.
AB  - Type 2 diabetes is reaching epidemic proportions worldwide, fueled by the
      increasing prevalence of obesity as many populations adopt a western lifestyle.
      Secondary complications affecting both the microvascular and macrovascular
      systems are responsible for premature mortality in Type 2 diabetes, with two
      thirds or more dying of cardiovascular disease. Two interacting metabolic
      defects, insulin resistance and beta-cell dysfunction are present in Type 2
      diabetes. It is now recognised that insulin resistance is central to a cluster of
      metabolic abnormalities--called the insulin resistance syndrome--that are
      responsible for the excess of cardiovascular disease. Older antidiabetic agents
      such as the sulfonylureas, metformin and insulin are more effective than
      lifestyle modification in reducing microvascular complications of Type 2
      diabetes, but overall do not reduce cardiovascular risk. Metformin, although no
      more effective as a glucose-lowering agent than sulfonylureas or insulin, does
      significantly reduce cardiovascular disease, probably as a result of its weak
      insulin-sensitising action. The newly-marketed thiazolidinedione insulin
      sensitising antidiabetic agents also improve multiple biomarkers of
      cardiovascular risk, suggesting that novel approaches to insulin sensitisation
      will not only provide effective long-term glycaemic control but improve
      cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within
      the insulin signalling cascade are being explored, together with follow-up
      compounds to the first generation thiazolidinediones. These initiatives, together
      with developments in beta(3)-adrenoceptor agonists, 11 beta-hydroxysteroid
      dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1
      axis, all of which also potentially enhance insulin sensitivity, are critically
      evaluated.

PMID- 12605558
TI  - New lipid-modifying therapies.
AB  - Lipid abnormalities are central among the risk factors for the development of
      cardiovascular disease and their correction remains a major target for the
      medical community. Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase
      (statins) are the most widely prescribed and best tolerated of the currently
      available lipid-modifying therapies. Newer agents in this class (e.g.,
      rosuvastatin) have proven to be more effective at lowering levels of low-density
      lipoprotein cholesterol. New formulations of drugs such as nicotinic acid, which
      improve treatment regimens and reduce unpleasant side effects, may result in
      improved patient compliance with this therapy. The development of novel drugs
      such as cholesterol absorption inhibitors (e.g., ezetimibe) and acyl-coenzyme A
      cholesterol acyltransferase inhibitors (e.g., avasimibe) will provide clinicians
      with therapeutic options that exploit different pathways to those currently being
      utilised. By combining these agents with statins, greater improvements in the
      lipid profile than those seen to date could be produced. In addition, advances in
      our understanding of the pathophysiology of dyslipidaemia have enabled other
      novel therapeutic targets to be identified and studies with experimental drugs
      underscore the potential of these approaches.

PMID- 12605560
TI  - Aromatase inhibitors for the treatment of infertility.
AB  - Ovarian stimulation during infertility treatment is used either alone or in
      conjunction with intrauterine insemination and assisted reproductive
      technologies. At the present time, the two main medications used for ovarian
      stimulation include an oral antioestrogen, clomiphene citrate and injectable
      gonadotrophins. In spite of the high ovulation rate, the use of clomiphene
      citrate is associated with adverse side effects and low pregnancy rates. In
      clomiphene citrate failures, gonadotrophin injections are generally the next
      treatment option but, especially in polycystic ovarian syndrome, are associated
      with increased risk of severe ovarian hyperstimulation syndrome and high multiple
      pregnancies. Therefore, an effective oral treatment that could be used without
      risk of ovarian hyperstimulation syndrome and with minimal monitoring is
      preferred. It was hypothesised that aromatase inhibitors can be administered
      early in the follicular phase to induce ovulation by releasing the hypothalamus
      and/or pituitary from oestrogen negative feedback. The success of aromatase
      inhibitors in induction and augmentation of ovulation has been reported. In
      addition, increased intraovarian androgen levels may synergise with central
      effects of decreased oestrogen to enhance ovarian response to gonadotrophin
      stimulation. This increased sensitivity to follicle-stimulating hormone may be
      especially useful in poor responders. The potential future applications for
      aromatase inhibitors in infertility management are also discussed.

PMID- 12605559
TI  - The therapeutic potential of aromatase inhibitors.
AB  - The third generation aromatase inhibitors are both remarkably potent and specific
      endocrine agents inhibiting aromatase activity and reducing circulating oestrogen
      levels in postmenopausal women to levels never previously seen. Their therapeutic
      potential is consequently much greater than the earlier prototype drugs. Their
      excellent side-effect profile also allows for potential wider indications in the
      treatment of oestrogen-related diseases, including breast cancer. It still
      remains to determine whether their potent endocrine effects translate into
      increased therapeutic benefit. In advanced breast cancer, aromatase inhibitors
      have been shown to have improved efficacy and toxicity profiles when compared
      with progestins, aminoglutethimide and tamoxifen. Aromatase inhibitors have also
      been used in the neoadjuvant setting, where they have been shown to achieve
      higher response rates than tamoxifen and to be more successful at downstaging
      tumours. Early results comparing an aromatase inhibitor with tamoxifen in the
      adjuvant setting in early breast cancer show anastrozole to be superior to
      tamoxifen in terms of both disease-free survival and a lower incidence of new
      contralateral tumours. There was also a more favourable side-effect profile,
      which has implications for potential future prophylactic treatment. Additionally,
      since aromatase inhibitors have different mechanisms of action, unlike
      antioestrogens, they may be particularly useful as chemopreventive agents if
      oestrogens are themselves genotoxic. Aromatase inhibitors have been used to date
      almost exclusively in postmenopausal women. The potential of combining them with
      luteinising hormone-releasing hormone analogues allows the possibility of
      treating premenopausal women with either oestrogen receptor-positive breast
      cancer or benign conditions such as cyclical breast pain, fibroadenomata,
      recurrent cystic disease or endometriosis. There is also the potential for their
      use in men with conditions such as gynaecomastia or prostate cancer. These new
      generation aromatase inhibitors may well have an increasing role in the future
      management of a number of conditions in addition to breast cancer.

PMID- 12605561
TI  - The therapeutic potential of leptin.
AB  - Many studies have reported the difficulty most subjects have in maintaining
      weight loss. Leptin is a cytokine-like protein made in adipose tissue and is
      transported into the brain by the blood-brain barrier where it inhibits food
      intake by altering the expression of hypothalamic neurotransmitters. The
      discovery of leptin raised the hope that a natural compound had been found that
      could cause weight loss without adverse effects. However, the majority of obese
      people have high levels of circulating leptin and it is not surprising that
      clinical trials published so far have shown that leptin only works effectively to
      suppress food intake in subjects who are hyperphagic as a result of low leptin
      levels. Obesity secondary to leptin deficiency is rare, most being associated
      with leptin insensitivity. To overcome leptin insensitivity, higher leptin levels
      in the CNS may be required. However, there is evidence that the leptin transport
      mechanism is saturated at low plasma leptin concentrations, limiting the
      effectiveness of peripherally-administered hormone. It is concluded that for
      leptin to have therapeutic potential, it either needs to be modified or the
      transport system by which leptin enters the brain needs to be upregulated to
      allow leptin to enter the brain more easily. To achieve effective weight loss, it
      may also be necessary to overcome central leptin insensitivity by developing
      agents that act downstream of leptin action.

PMID- 12605562
TI  - Novel antibacterial agents for the treatment of serious Gram-positive infections.
AB  - With the continuing development of clinical drug resistance among bacteria and
      the advent of resistance to the recently released agents quinupristin
      dalfopristin and linezolid, the need for new, effective agents to treat multi
      drug-resistant Gram-positive infections remains important. This review focuses on
      agents presently in clinical development for the treatment of serious multidrug
      resistant staphylococcal, enterococcal and pneumococcal infections, including
      methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and
      penicillin-resistant Streptococcus pneumoniae. Agents to be discussed that affect
      the prokaryotic cell wall include the antimethicillin-resistant S. aureus
      cephalosporins BAL9141 and RWJ-54428, the glycopeptides oritavancin and
      dalbavancin and the lipopeptide daptomycin. Topoisomerase inhibitors include the
      fluoroquinolones gemifloxacin, sitafloxacin and garenoxacin. Protein synthesis
      inhibitors are represented by the ketolides telithromycin and cethromycin, the
      oxazolidinones and the glycylcycline tigecycline. Although each of these
      compounds has demonstrated antibacterial activity against antibiotic-resistant
      pathogens, their final regulatory approval will depend on an acceptable clinical
      safety profile.

PMID- 12605563
TI  - The role of pharmacological enhancement in protease inhibitor-based highly active
      antiretroviral therapy.
AB  - Having changed the landscape in the treatment of HIV infection, the functional
      efficacy of current protease inhibitors (PIs) remains limited by their
      pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the
      cytochrome P450 system (particularly the 3A4 isoenzyme), action of membrane drug
      transporter elements (such as P-glycoprotein and multi-drug resistance-associated
      proteins) and activation of the nuclear receptor steroid xenobiotic receptor may
      alter exposures and compromise the antiretroviral activity of these drugs. These
      factors, as well as inadequate adherence, can facilitate the emergence of PI
      resistance and lead to regimen failure. Coadministration of ritonavir can enhance
      exposures of a primary PI by inhibiting CYP3A4 metabolism, P-glycoprotein
      activity and multi-drug resistance protein-1-mediated efflux. Adding ritonavir,
      however, is not without cost. Dyslipidaemia (possibly increasing the risk of
      cardiovascular events), gastrointestinal intolerance, multiple drug-to-drug
      interactions and activation of steroid xenobiotic receptor can all result and
      must be balanced against the pharmacokinetic improvement rendered by the addition
      of ritonavir. Understanding the pharmacological origins for the variations in
      exposures of PIs, both between and within patients, is important for the
      successful use of these agents.

PMID- 12605564
TI  - Farnesyl transferase inhibitors in the treatment of breast cancer.
AB  - Until recently, the therapeutic treatment of breast cancer has been dominated by
      endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.)
      and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.).
      However, the advent of new generation signal transduction inhibitor drugs
      targeted against the molecular abnormalities of breast cancer (e.g., the antibody
      trastuzumab, directed against the cERBB2 receptor) has the promise of providing a
      new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl
      transferase (FTIs) are now undergoing early-stage clinical trials, including in
      patients with advanced breast cancer. Although originally developed as inhibitors
      of RAS signal transduction pathways, it is now apparent that these drugs are
      better described as prenylation inhibitors; the addition of a 15-carbon prenyl or
      farnesyl moiety by farnesyl transferase being critical to the function of a
      number of proteins, including RAS. At least three FTIs are currently undergoing
      clinical evaluation; R115777 (tipifarnib, Zarnestra), SCH66336 (lonafarnib,
      Sarasar) and BMS-214662. In terms of their potential use in the chemotherapeutic
      treatment of advanced breast cancer, a Phase II trial of R115777 (using either
      continuous or intermittent twice-daily oral dosing) has demonstrated promising
      activity (approximately 10% partial response rate). Overall, however, the single
      agent activity of FTIs in various Phase II trials has been rather modest (as well
      as the above mentioned breast cancer trial, some responses have been seen in
      patients with acute and chronic myeloid leukaemias). The main dose-limiting
      toxicities that have been reported are myelosuppression and fatigue and
      neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal
      (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have
      failed to show a survival benefit. It is likely that the future clinical
      direction of FTIs will be as combination therapy, especially with the taxanes,
      where synergy has been seen in a variety of preclinical studies.

PMID- 12605566
TI  - Antiarrhythmic drugs: new agents and evolving concepts.
AB  - Properties of several new antiarrhythmic drugs are summarised in this review
      article. Recent concepts concerning their safety and efficacy of antiarrhythmics
      are discussed. A brief perspective on possible future strategies for
      pharmacotherapy of arrhythmias is provided.

PMID- 12605565
TI  - Recent advances in the pharmacological treatment of colorectal cancer.
AB  - Recent advances in the treatment of colorectal cancer have lead to significant
      gains in response rates and survival. The combination of newer agents such as
      irinotecan and oxaliplatin with 5-fluorouracil/leucovorin using various dosing
      schedules in the metastatic setting has resulted in a steady improvement in the
      outcome of patients with colorectal cancer. Experimental therapies such as
      epidermal growth factor receptor inhibitors, vascular endothelial growth factor
      inhibitors and cyclooxygenase-2 inhibitors, have shown promise in early clinical
      trials and have acceptable toxicity profiles. Efforts towards improving risk
      stratification of stage II colorectal cancer patients and optimising therapy in
      patients with advanced disease, have focused on molecular and genetic markers. It
      is hoped that the addition of new therapies to existing drug combinations, as
      well as further advances in the understanding of colorectal cancer biology, will
      lead to further improvement in survival and quality of life for patients.

PMID- 12605567
TI  - The potential of nitric oxide therapeutics in stroke.
AB  - The therapeutic modulation of the nitric oxide (NO) system has generated
      considerable interest as a new way for managing many disease processes. In
      stroke, a useful strategy is to increase NO availability and thereby exploit its
      beneficial antiplatelet, antiatherosclerotic, haemodynamic and neuroprotective
      properties. Pharmacologically, this can be achieved by providing NO substrate,
      using NO donors or by upregulating nitric oxide synthase. Alternatively, one can
      reduce NO availability by inhibiting NO synthase and thereby limiting its pro
      inflammatory and neurotoxic properties. This article reviews developments in NO
      related therapeutics for treatment of stroke, with a particular emphasis on
      compounds that are in the clinical research and development pipeline. Although
      the routine use of NO therapeutics for the prevention or treatment of stroke
      cannot currently be recommended, we are evidently at an exciting stage in their
      pharmacological development. Definitive randomised controlled trials in stroke
      patients are required as a matter of urgency.

PMID- 12605568
TI  - Treatment of scleroderma: an update.
AB  - The goal of this article is to update the reader and focus on novel therapies and
      clinical trials published since our last review [6]. Evidence suggests that drug
      intervention should target one or all of three biological processes: vascular
      disease, autoimmunity and tissue fibrosis. Efforts should be made to classify the
      subtype of scleroderma, to determine the activity of the disease process and the
      degree of specific organ involvement before specific treatment decisions are
      made. Cyclophosphamide in fibrosing alveolitis, intravenous prostaglandins and
      other vasodilators for the vascular disease, endothelin-1 inhibition in pulmonary
      hypertension and immunosuppressive therapy for early inflammatory disease, all
      appear to have benefit. Several agents used in vitro and in animal models of
      fibrosis also show promise including anti-transforming growth factor-beta, the
      statins and anti-integrins. More experience in well-designed clinical trials is
      needed to define the role of these agents in treating scleroderma.

PMID- 12605569
TI  - Novel therapies in the treatment of ulcerative colitis.
AB  - Ulcerative colitis is a chronic inflammatory disease of the colon of unknown
      cause. Its course is one of relapse and remission and requires therapy for both
      the induction and maintenance of remission. Progress in the fields of genetics
      and immunology affords important advances in our understanding of the
      inflammatory process. Traditional therapy for ulcerative colitis with nonspecific
      anti-inflammatories remains our gold standard. This review examines the most
      recent compounds in development for the treatment of ulcerative colitis,
      including data from early clinical trials and the potential clinical impact of
      future entities.

PMID- 12605570
TI  - Investigational drugs for eating disorders.
AB  - The eating disorders anorexia nervosa, bulimia nervosa and binge eating disorder
      are common, significant public health problems which are treated with
      nutritional, psychotherapeutic and pharmacological interventions. A number of
      drugs (mostly antidepressant drugs) are currently used in their treatment to some
      benefit, but there is substantial room for improvement. A wide variety of
      compounds are listed as under investigation for the treatment of eating
      disorders. They have a diverse variety of mechanisms of action, reflecting the
      complex nature of the control of food intake. While none of these compounds are
      close to release at present, the diversity of mechanisms under study lend some
      optimism that more effective approaches will be identified.

PMID- 12605571
TI  - Clinical trials evaluating angiotensin-converting enzyme inhibitors and
      angiotensin receptor blockers in the setting of acute myocardial infarction.
AB  - There is strong evidence from controlled clinical trials that in the setting of
      acute myocardial infarction complicated by heart failure or isolated left
      ventricular dysfunction, angiotensin-converting enzyme inhibitors started late
      during hospitalisation and continued in the long term, significantly reduced
      mortality and improved the prognosis. On the other hand, administration of
      angiotensin-converting enzyme inhibitors during the first 24 h in unselected
      patients with acute myocardial infarction provided only a slight benefit in terms
      of mortality. Angiotensin-II receptor blockers have and are being examined in the
      setting of acute myocardial infarction with left ventricular dysfunction and can
      provide an alternative for patients who cannot tolerate angiotensin-converting
      enzyme inhibitors. In this article, an evidence-based review of these major
      trials and suggestions for clinical application are presented.

PMID- 12605572
TI  - Expanding indications of statins; implications of the Heart Protection Study.
AB  - The Heart Protection Study is the largest trial of statin therapy conducted to
      date. It provides important new information on the use of statins in women, the
      elderly, diabetics and people with low baseline cholesterol pretreatment and
      those with prior occlusive non-coronary vascular disease. In this report, the
      paper is discussed with the significance of the results outlined in view of
      existing evidence from previously published trials. In addition, ongoing trials
      and future directions are explored.

PMID- 12605573
TI  - Effects of breathing air containing 3% carbon dioxide, 35% oxygen or a mixture of
      3% carbon dioxide/35% oxygen on cerebral and peripheral oxygenation at 150 m and
      3459 m.
AB  - The effects of gas mixtures comprising supplementary 3% carbon dioxide, 35%
      oxygen or a combination of 3% CO(2) plus 35% O(2) in ambient air have been
      compared on arterial blood gases, peripheral and cerebral oxygenation and middle
      cerebral artery velocity (MCAV) at 150 m and on acute exposure to 3459 m in 12
      healthy subjects. Breathing 3% CO(2) or 35% O(2) increased arterial blood oxygen
      at both altitudes, and the CO(2)/O(2) combination resulted in the most marked
      rise. MCAV increased on ascent to 3459 m, increasing further with 3% CO(2) and
      decreasing with 35% O(2) at both altitudes. The CO(2)/O(2) combination resulted
      in an increase in MCAV at 150 m, but not at 3549 m. Cerebral regional oxygenation
      fell on ascent to 3459 m. Breathing 3% CO(2) or 35% O(2) increased cerebral
      oxygenation at both altitudes, and the CO(2)/O(2) combination resulted in the
      greatest rise at both altitudes. The combination also resulted in significant
      rises in cutaneous and muscle oxygenation at 3459 m. The key role of carbon
      dioxide in oxygenation at altitude is confirmed, and the importance of this gas
      for tissue oxygenation is demonstrated.

PMID- 12605574
TI  - Obesity, Type II diabetes and the beta 2 adrenoceptor gene Gln27Glu polymorphism
      in the Tongan population.
AB  - As there is a high prevalence of obesity in Tonga, we aimed to determine the
      distribution of the beta2 adrenoceptor gene Gln(27)Glu polymorphism and to assess
      its relevance to obesity and to Type II diabetes, known to be prevalent in that
      population. A random sample of 1022 individuals from Tonga were genotyped for the
      Gln(27)Glu polymorphism in the beta 2 adrenoceptor gene. To assess the prevalence
      of obesity we measured body-mass index (BMI), fat-free mass, percentage fat and
      waist-to-hip ratio (WHR). To assess glucose metabolism we measured HbA(1c),
      fasting blood glucose, fasting serum insulin, and 1- and 2-h glucose; we also
      measured serum lipid and creatinine levels. We found that 84% of the Tongan men
      and 93% of the women were overweight or obese (BMI > or = 25 kg/m(2)) and 15.1%
      had Type II diabetes. Genotype frequencies among the 1022 Tongans were: Gln/Gln
      90.3% and Gln/Glu 9.6%; we found one Glu/Glu homozygote. The mean BMI (+/-S.D.)
      for men was not significantly different for those who were homozygous (30.2+/-5.4
      kg/m(2)) or heterozygous (30.1+/-5.5 kg/m(2)) for the Gln allele; this was also
      true for women (33.7+/-6.2 kg/m(2) for homozygous and 34.0+/-5.6 kg/m(2) for
      heterozygous). The Glu allele was not associated with other measures of obesity
      or abnormal glucose metabolism in this generally overweight population. There is
      a unique frequency of the Gln/Glu beta 2 adrenoceptor polymorphism among Tongans.
      We found no association of the polymorphism with obesity measures or Type II
      diabetes-related variables in the Tongan population among whom we documented a
      high prevalence of obesity and Type II diabetes and a low frequency of the Glu
      allele.

PMID- 12605575
TI  - The isolated C-terminus of polycystin-1 promotes increased ATP-stimulated
      chloride secretion in a collecting duct cell line.
AB  - Cyst expansion in autosomal dominant polycystic kidney disease (ADPKD) requires
      accumulation of fluid into the cyst lumen, which is probably driven by aberrant
      chloride secretion by the cyst lining epithelium. Extracellular ATP is a potent
      stimulus for chloride secretion in many epithelial systems, and provides a
      plausible mechanism for secretion in ADPKD. Therefore the link between polycystin
      1 and ATP-stimulated chloride secretion was investigated in the M1 cortical
      collecting duct cell line. M1 cells were stably transfected with a glucocorticoid
      inducible cytoplasmic C-terminal polycystin-1 construct fused to a membrane
      expression cassette. Induction of fusion protein expression was associated with
      augmentation of ATP-stimulated transepithelial chloride secretion. After nystatin
      induced permeabilization of the basolateral membrane, it was determined that
      expression of the polycystin fusion protein modulated an ATP-responsive apical
      chloride conductance. It is concluded that up-regulation of ATP-stimulated
      chloride secretion might play a significant role in cyst expansion in ADPKD.

PMID- 12605577
TI  - Augmented sympathetic neural response to simulated obstructive apnoea in human
      heart failure.
AB  - Sleep apnoea in heart failure increases mortality risk, possibly as a result of
      greater activation of the sympathetic nervous system. In healthy subjects,
      simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller
      manoeuvres) increase muscle sympathetic activity equally, primarily through
      chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause
      greater reductions in blood pressure than breath holds. We hypothesized that in
      heart failure, the summation of arterial baroreceptor unloading and chemoreceptor
      stimulation would increase sympathetic activity more during obstructive than
      central apnoeas. Healthy human subjects and heart failure patients (seven of
      each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds
      evoked a progressive increase in muscle sympathetic nerve activity in both
      groups, but had no effect on blood pressure. In healthy subjects, breath holds
      and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast,
      in heart failure patients, Mueller manoeuvres caused a progressive decrease in
      blood pressure (P < 0.05) and greater increases in sympathetic activity than
      breath holds (P < 0.01). In heart failure, simulated obstructive apnoea elicits
      greater increases in sympathetic activity than simulated central apnoea, due to
      its additional hypotensive effect. These present findings offer novel insight
      into the potential role of sleep apnoea in augmenting sympathetic activity and
      accelerating disease progression in heart failure.

PMID- 12605576
TI  - Free insulin-like growth factor 1 in the vitreous fluid of diabetic patients with
      proliferative diabetic retinopathy: a case-control study.
AB  - The aim of the study was to evaluate the vitreous levels of free insulin-like
      growth factor 1 (IGF-1) in patients with proliferative diabetic retinopathy
      (PDR). For this, a total of 36 diabetic patients with PDR (group A) and 28 non
      diabetic patients (group B) in whom a vitrectomy was performed were compared.
      Both groups were matched by age, sex and serum-free IGF-1. In a subgroup of
      diabetic patients (n =21) and non-diabetic patients (n =13), vitreous and serum
      total IGF-1, IGF-binding protein 1 (IGFBP-1) and IGFBP-3 were also determined.
      Serum and vitreous levels of free IGF-1, total IGF-1, IGFBP-1 and IGFBP-3 were
      measured by immunological methods. Vitreal proteins were assessed by a
      turbidimetric method and adjusted for vitreous haemoglobin. Vitreous levels of
      free IGF-1 were elevated in group A (median, 0.16 ng/ml; range 0.06-0.57 ng/ml)
      in comparison with group B (median, 0.12 ng/ml; range 0.06-0.22 ng/ml; P <0.001);
      however, after adjusting for vitreal proteins, free IGF-1 levels were
      significantly lower in group A in comparison with group B [0.05 ng/mg (0.01-0.45
      ng/mg) versus 0.15 ng/mg (0.07-0.66 ng/mg); P <0.001]. The relatively lower free
      IGF-1 level observed in group A could not be attributed to differences in the
      distribution of intravitreous IGFBP-1 and IGFBP-3 in relation to total IGF-1.
      Notably, the contribution of free IGF-1 to total IGF-1 in vitreous fluid was 10%
      in group A and 42% in group B; these percentages largely exceed that obtained in
      serum (<1%). Our results suggest that although there is an enhancement of
      intravitreous free IGF-1 in diabetic patients due to serum diffusion, a deficit
      in its intraocular production also exists. In addition, these findings support
      the concept that intraocular-produced free IGF-1 plays a relevant role in retinal
      homoeostasis.

PMID- 12605578
TI  - Tracking of cardiac output from arterial pulse wave.

PMID- 12605580
TI  - 5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter
      polymorphisms in acute myocardial infarction.
AB  - This study was designed to analyse possible associations between DNA
      polymorphisms in the 5-hydroxytryptamine (5-HT; serotonin) 5-HT(2A) receptor and
      the 5-HT transporter (5-HTT) genes, and myocardial infarction (MI). 5-HT has been
      shown to be involved in cardiovascular pathophysiology. In addition to platelet
      aggregation and vascular contraction, 5-HT induces hyperplasia of artery smooth
      muscle cells. Recently, a 5-HT transporter gene polymorphism has been associated
      with MI. To determine the influence of genetic variation at the 5-HT(2A) receptor
      (T102C polymorphism) and the 5-HTT (insertion/deletion polymorphism) on the risk
      of developing early MI, we genotyped 210 MI patients of < 55 years old and 238
      healthy control subjects for DNA polymorphisms in these genes. In addition, we
      genotyped 95 patients with late-onset MI (> 60 years old) to analyse the effects
      of these polymorphisms on the age at which the first MI episode occurred. The 5
      HT(2A) receptor polymorphism was not associated with MI in our population. In
      addition, since the 5-HT(2A) receptor gene and genotype frequencies did not
      differ between patients with early and late onset of MI, this polymorphism does
      not appear to have an effect on age at the first MI episode. Gene and genotype
      frequencies for the 5-HTT promoter did not differ between patients < 55 years old
      and healthy controls (independent of smoking status). However, homozygotes for
      the deletion (the ss genotype, where s denotes the short allele) were present at
      a significantly higher frequency in patients >60 years old compared with patients
      < 55 years old (P = 0.009; P = 0.004 when only smokers were compared). According
      to our data, the ss genotype would seem to have a protective role against MI,
      delaying the age of onset of the first episode, especially among smokers. This
      could be a consequence of the lower 5-HTT levels linked to the s allele, so that
      individuals homozygous for the ss genotype may have lower 5-HT re-uptake by
      platelets.

PMID- 12605581
TI  - Cigarette smoking is associated with an acute impairment of microvascular
      function in humans.
AB  - An effect on microvascular function has been proposed as a possible mechanism
      explaining the association of acute smoking with increased blood pressure and
      decreased insulin sensitivity. However, the effects of smoking on microvascular
      function have not been studied. We have investigated the acute effects of smoking
      on microvascular function in 12 healthy smokers. Before and after smoking a
      cigarette, we measured heart rate, blood pressure and capillary recruitment
      during peak reactive hyperaemia. We also measured endothelium-dependent and
      endothelium-independent vasodilatation of the skin microcirculation with
      iontophoresis of acetylcholine and sodium nitroprusside respectively combined
      with laser Doppler fluxmetry. To exclude non-specific changes, a control study
      with sham smoking was performed. The smoking and sham smoking studies were
      conducted in a randomized order. Compared with sham smoking, acute smoking caused
      increases in heart rate (smoking, 9.3+/-4.1 beats/min; sham, -1.3+/-3.0
      beats/min; P < 0.001) and systolic blood pressure (smoking, 6.3+/-8.8 mmHg; sham,
      0.8+/-4.4 mmHg; P < 0.05); decreases in absolute (smoking, -4.9+/-6.9 per mm(2);
      sham, 0.8+/-2.1 per mm(2); P = 0.01) and relative (smoking, -13.8+/-21.4%; sham,
      1.9+/-6.9%; P = 0.02) capillary recruitment during peak reactive hyperaemia; and
      decreases in absolute [smoking, -62.4+/-47.7 perfusion units (PU); sham, -30.8+/
      32.6 PU; P = 0.04] and relative (smoking, -147+/-163%; sham, 32+/-225%; P = 0.07)
      vasodilatation caused by acetylcholine. Absolute (smoking, -31.6+/-58.5 PU; sham,
      -8.4+/-44.0 PU; P = 0.3) and relative (smoking, -50.2+/-219.0%; sham, -17.1+/
      139%; P = 0.7) vasodilatation caused by sodium nitroprusside were not affected.
      Thus acute smoking is associated with impaired capillary recruitment during peak
      reactive hyperaemia and impaired microvascular endothelium-dependent
      vasodilatation. These findings may explain the increased blood pressure and
      decreased insulin sensitivity that have been observed after acute smoking.

PMID- 12605583
TI  - Acute pulmonary oedema: rare causes and possible mechanisms.
AB  - Acute pulmonary oedema usually has a fatal outcome. In this clinical report, we
      present rare cases of pulmonary oedema that were associated with Japanese B
      encephalitis, lymphangitis in breast carcinoma, fat embolism due to long-bone
      fracture, and the rupture of cerebral mycotic aneurysms. A total of 18 patients
      in the four disease categories were collected in two teaching hospitals in Taipei
      and Hualien. Upon admission, routine and specific examinations were taken and all
      patients showed clear lungs by chest X-ray; however, signs of acute pulmonary
      oedema occurred within 7 days. After resuscitation, all patients died of acute
      pulmonary oedema. In patients with fat embolism, the levels of non-esterified
      plasma fatty acids, cGMP, 5-hydroxytryptamine (serotonin) and nitrates/nitrites
      were increased during pulmonary oedema. Immunohistochemical staining revealed
      virus infection and neuronal death, predominantly in the medial, ventral and
      caudal medulla in cases of Japanese B encephalitis. The pulmonary oedema due to
      central sympathetic activation in Japanese B encephalitis may be related to
      destruction of depressor mechanisms in the medulla. The rupture of mycotic
      aneurysms is known to cause cerebral compression that results in acute pulmonary
      oedema. Blockade of lymphatics, capillaries and venules in breast carcinoma with
      lymphangitis causes the development of rapid lung oedema. The pathogenesis of
      pulmonary oedema is much more complicated in fat embolism. Mediators such as
      cGMP, 5-hydroxytryptamine, nitric oxide and presumably other chemical substances
      may also be involved.

PMID- 12605582
TI  - Detection of glucagon receptor mRNA in the rat proximal tubule: potential role
      for glucagon in the control of renal glucose transport.
AB  - Glucagon is known to affect glomerular filtration rate and renal tubular solute
      and fluid transport, although it is only thought to act directly on the thick
      ascending limb (TAL) and collecting duct (CD). Indeed, previous studies have
      detected glucagon-sensitive adenylate cyclase exclusively in these nephron
      segments, suggesting the presence of glucagon receptors. In the present study, we
      have demonstrated for the first time that glucagon receptor mRNA is expressed in
      the rat proximal tubule, as well as in the TAL and CD. By autoradiography, we
      have also shown that specific binding of glucagon occurs in both the renal cortex
      and medulla. In addition, using proximal tubule brush-border membrane (BBM)
      vesicles for studies of glucose transport, we have established that glucagon
      stimulates glucose uptake via a facilitative GLUT-mediated transport process (by
      58%; P < 0.005), whereas cAMP stimulates only the sodium glucose-linked
      transporter ('SGLT')-mediated glucose uptake (by 53%; P < 0.05). Taken together,
      these findings suggest that glucagon could have a role in controlling proximal
      tubular transport function, including glucose reabsorption, but unlike in the TAL
      and CD, the proximal tubule glucagon receptor might not be coupled primarily to
      adenylate cyclase.

PMID- 12605584
TI  - Unusual causes of acute pulmonary oedema.

PMID- 12605585
TI  - Short-term aerobic training and circulatory function in women: age and hormone
      replacement therapy.
AB  - The physiological basis of training responses in women, and particularly older
      women, is not well understood. Short-term aerobic training (STAT) was used to
      probe the effects of age and hormone-replacement therapy (HRT) on women's ability
      to rapidly change peak uptake ( VO(2max)), plasma volume and cardiac function. A
      total of 39 females participated in the STAT programme: 15 younger (Y; aged 19-29
      years), 12 postmenopausal women undergoing HRT and 12 non-medicating
      postmenopausal (PM) women (aged 60-75 years). Training consisted of ten sessions
      of cycling over a 2-week period, which progressed in duration from 20 to 60 min
      and in intensity from 60-75% of maximum heart rate. Plasma volume (PV; as
      determined by Evan's Blue dye dilution), VO(2max) (cycle ergometry) and cardiac
      function (radionuclide ventriculography) were analysed using analysis of
      covariance or repeated measures ANOVA. All groups demonstrated similar increase
      in VO(2max) (Y, 13%; PM, 17%; HRT, 13%), but without a significant change in left
      ventricular ejection fraction and diastolic function or volumes during supine
      exercise. PV expansion was observed among the Y group (7%; P <0.05) but not the
      PM group (2%; P >0.05) or women undergoing HRT (1%; P >0.05). Age and hormone
      replacement status did not affect the magnitude of VO(2max) change. This study
      suggests that STAT improves VO(2max), independent of central adaptations.

PMID- 12605586
TI  - Glutamine attenuates post-traumatic glutathione depletion in human muscle.
AB  - Glutathione is quantitatively the most important endogenous scavenger system.
      Glutathione depletion in skeletal muscle is pronounced following major trauma and
      sepsis in intensive care unit patients. Also, following elective surgery,
      glutathione depletion occurs in parallel with a progressive decline in muscle
      glutamine concentration. The present study was designed to test the hypothesis
      that glutamine supplementation may counteract glutathione depletion in a human
      trauma model. A homogeneous group of patients (n = 17) undergoing a standardized
      surgical procedure were prospectively randomly allocated to receive glutamine
      (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric
      nutrition. Percutaneous muscle biopsies and blood samples were taken pre
      operatively and at 24 and 72 h after surgery. The concentrations of muscle
      glutathione and related amino acids were determined in muscle tissue and plasma.
      In the control (unsupplemented) subjects, total muscle glutathione had decreased
      by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and
      45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in
      the glutamine-supplemented group, no significant post-operative decreases in
      total or reduced glutathione were seen following surgery. Muscle free glutamine
      had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in
      the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control
      group. In conclusion, the present study demonstrates that intravenous glutamine
      supplementation attenuates glutathione depletion in skeletal muscle in humans
      following standardized surgical trauma.

PMID- 12605587
TI  - Interpretation of the digital volume pulse: its relationship with large and small
      artery compliance.

PMID- 12605589
TI  - Chronic alpha-tocopherol supplementation in rats does not ameliorate either
      chronic or acute alcohol-induced changes in muscle protein metabolism.
AB  - Chronic alcohol muscle disease is characterized by reduced skeletal muscle mass
      precipitated by acute reduction in protein synthesis. The pathogenic mechanisms
      remain obscure, but several lines of evidence suggest that increased oxidative
      stress occurs in muscle in response to alcohol and this may be associated with
      impaired alpha-tocopherol status. Potentially, this implies a therapeutic role
      for alpha-tocopherol, especially as we have shown that supplemental alpha
      tocopherol may increase the rate of protein synthesis in normal rats [Reilly,
      Patel, Peters and Preedy (2000) J. Nutr. 130, 3045-3049]. We investigated the
      therapeutic effect of alpha-tocopherol on plantaris muscle protein synthesis in
      rats treated either acutely, chronically or chronically+acutely with ethanol.
      Protein synthesis rates were measured with a flooding dose of L-[4
      (3)H]phenylalanine. Protein, RNA and DNA contents were determined by standard
      laboratory methods. Ethanol caused defined metabolic changes in muscle, including
      decreased protein, RNA and DNA contents in chronically treated rats. In acute or
      chronic+acute studies, ethanol suppressed fractional rates of protein synthesis.
      alpha-Tocopherol supplementation did not ameliorate the effects of either acute,
      chronic or chronic+acute alcohol on plantaris muscle protein content or rates of
      protein synthesis. In control animals (not treated with alcohol), alpha
      tocopherol supplementation decreased muscle protein content owing to increases in
      protein turnover (both synthesis and degradation). alpha-Tocopherol
      supplementation is not protective against the deleterious effects of alcohol on
      protein metabolism in skeletal muscle.

PMID- 12605590
TI  - Heart rate variability and baroreflex sensitivity are reduced in chronically
      undernourished, but otherwise healthy, human subjects.
AB  - Alterations in autonomic nerve activity in subjects in a chronically
      undernourished state have been proposed, but have been inadequately documented.
      The present study evaluated heart rate and systolic blood pressure variability in
      the frequency domain in two underweight groups, one of which was undernourished
      and recruited from the lower socio-economic strata [underweight, undernourished
      (UW/UN); n =15], while the other was from a high class of socio-economic
      background [underweight, well nourished (UW/WN); n =17], as well as in normal
      weight controls [normal weight, well nourished (NW/WN); n =27]. Baroreflex
      sensitivity, which is a determinant of heart rate variability, was also assessed.
      The data indicate that total power (0-0.4 Hz), low-frequency power (0.04-0.15 Hz)
      and high-frequency power (0.15-0.4 Hz) of RR interval variability were
      significantly lower in the UW/UN subjects ( P <0.05) than in the NW/WN controls
      when expressed in absolute units, but not when the low- and high-frequency
      components were normalized for total power. Baroreflex sensitivity was similarly
      lower in the UW/UN group ( P <0.05). Heart rate variability parameters in the
      UW/WN group were generally between those of the UW/UN and NW/WN groups, but were
      not statistically different from either. The mechanisms that contribute to the
      observed differences between undernourished and normal-weight groups, and the
      implications of these differences, remain to be elucidated.

PMID- 12605591
TI  - Abnormal rhythmic oscillations of atrial natriuretic peptide and brain
      natriuretic peptide in heart failure.
AB  - The purpose of this study was to clarify whether the secretions of atrial
      natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are pulsatile in
      patients with chronic heart failure (CHF), and whether the rhythmic oscillations
      for ANP and BNP are abnormal in patients with CHF. Several reports have shown
      that ANP and especially BNP are valuable indicators of the prognosis in CHF.
      Previously, a pulsatile secretion has been described for ANP and BNP in healthy
      humans and for ANP in CHF patients. More information about the secretion pattern
      of BNP in heart failure is necessary to increase the clinical usefulness of BNP
      in patients with CHF. Patients with left ventricular systolic dysfunction and CHF
      ( n =12) and controls ( n =12) were investigated. Plasma ANP and BNP levels were
      determined every 2 min during a 2-h period by radioimmunoassay and analysed for
      pulsatile behaviour by Fourier transformation. All patients and controls had
      significant rhythmic oscillations in plasma ANP levels, and 11 patients with CHF
      and 10 controls had significant rhythmic oscillations in plasma BNP levels. The
      amplitude of the main frequency was considerably higher in patients with CHF than
      in controls (ANP: CHF, 4.76 pmol/l; controls, 0.75 pmol/l; P <0.01. BNP: CHF,
      3.24 pmol/l; controls, 0.23 pmol/l; P <0.001; all values are medians), but the
      main frequency did not differ significantly between the group with CHF and the
      control group for either ANP or BNP. Patients with CHF demonstrate pulsatile
      secretion of ANP and BNP with a much higher absolute amplitude, but with the same
      main frequency as healthy subjects.

PMID- 12605592
TI  - P-selectin blockade fails to improve acute lung injury in sheep.
AB  - Accumulation of neutrophils in the lung contributes to the endothelial damage in
      the tissue associated with acute respiratory distress syndrome. This initial
      recruitment of neutrophils within the pulmonary microvasculature may involve P
      selectin. Thus we hypothesized that an antibody against P-selectin would reduce
      pulmonary damage. Sheep were chronically instrumented and prepared. The first
      group received 40% body surface area third-degree burns with 48 breaths of cotton
      smoke and 1 mg/kg of anti-(P-selectin) antibody (termed 3D4) 1 h post injury (n =
      5). The second group (non-treated) received the same injury but no antibody
      treatment (n = 6). The third group comprised of sham animals without any injury
      or antibody treatment (n = 6). Sheep were studied for 48 h during which they were
      uniformly resuscitated with Ringer's lactate solution by following the Parkland
      formula. All the animals were mechanically ventilated. In the non-treated injured
      group, the arterial partial pressure of O(2) ('PaO(2)')/inspired fraction of O(2)
      ('F(i)O(2)') ratio dropped to 168+/-30 at 48 h, whereas the lung lymph flow
      increased to an average of 46+/-9 ml/h (10-fold of baseline). These changes were
      not prevented by an anti-(P-selectin) antibody. The plasma and lymph
      nitrate/nitrite levels were lower in the antibody-treated group than in the non
      treated group. The lymph conjugated dienes were significantly lower in the
      treated animals. However, lung myeloperoxidase activity and lung tissue
      conjugated dienes were significantly increased in the treated animals compared
      with the non-treated injured controls. In conclusion, although the anti-(P
      selectin) antibody did not protect against lung injury during the initial 48 h of
      burn and smoke, it decreased some aspects of injury in the peripheral
      microcirculation.

PMID- 12605593
TI  - Sodium/lithium countertransport and intracellular calcium concentration in
      patients with essential hypertension and coronary heart disease.
AB  - The present study was designed to test the hypothesis that enhanced intracellular
      calcium signalling and increased sodium/lithium countertransport (Na(+)/Li(+) CT)
      activity may be associated with coronary heart disease (CHD) in non-diabetic
      patients with essential hypertension. Platelet-activating factor (PAF)-evoked
      rises in the intracellular calcium concentration ([Ca(2+)](i)) were measured in
      Epstein-Barr-virus-immortalized lymphoblasts from 62 hypertensive patients with
      CHD and 34 patients without CHD. Na(+)/Li(+) CT activity was assessed in
      erythrocytes from 80 hypertensive patients with CHD and 46 patients without CHD.
      Baseline values of unstimulated and PAF-stimulated [Ca(2+)](i) were not
      significantly different between hypertensive subjects with (baseline, 126+/-5
      nmol/l; stimulated, 550+/-43 nmol/l) and without (baseline, 125+/-5 nmol/l;
      stimulated, 654+/-105 nmol/l) CHD. Similarly, Na(+)/Li(+) CT activity was not
      significantly different between the two groups (patients with CHD, 219+/-8
      micromol x l(-1) x h(-1); patients without CHD, 234+/-10 micromol x l(-1) x h(
      1)). We conclude that intracellular signal transduction, as indicated by PAF
      induced rises in [Ca(2+)](i) and Na(+)/Li(+) CT activity, is not associated with
      an increased risk of CHD in non-diabetic patients with essential hypertension.

PMID- 12605594
TI  - Increased mRNA expression of tumour necrosis factor-alpha and its converting
      enzyme in circulating leucocytes of patients with acute myocardial infarction.
AB  - Tumour necrosis factor-alpha (TNF-alpha) plays an important role in myocardial
      damage in acute myocardial infarction (AMI). It has recently been discovered that
      TNF-alpha-converting enzyme (TACE) cleaves precursor TNF-alpha into its mature
      form. However, it remains unknown whether TNF-alpha expression is related to TACE
      expression in circulating leucocytes in AMI. Blood samples were obtained from 37
      patients with AMI within 24 h of onset and eight healthy controls. Plasma TNF
      alpha levels were measured by ELISA. Total mRNA was then extracted from
      circulating leucocytes, and the expression levels of TACE and TNF-alpha mRNAs
      were determined by reverse transcriptase-PCR. Plasma TNF-alpha levels were
      significantly higher in patients with Killip's classes III and IV AMIs (17.1+/
      5.0 pg/ml, n =11) than in those with Killip's classes I and II AMIs (13.7+/-4.2
      pg/ml, n =26), or controls (13.0+/-1.7 pg/ml, n =8) ( P <0.05). There was a
      significant increase in expression (arbitrary units) of TACE and TNF-alpha mRNAs
      in circulating leucocytes obtained from patients with Killip's classes I and II
      AMIs [TACE/glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 2.770+/-0.303; TNF
      alpha/GAPDH, 2.123+/-0.475] compared with controls (TACE/GAPDH, 1.498+/-0.209;
      TNF-alpha/GAPDH, 1.283+/-0.274) ( P <0.01). This increase was even greater in
      patients with Killip's classes III and IV AMIs (TACE/GAPDH, 3.086+/-0.354; TNF
      alpha/GAPDH, 2.808+/-0.422) ( P <0.01). Moreover, there was a significant
      positive relationship between these mRNA expression levels ( r =0.60, P <0.01).
      The TACE-TNF-alpha system in circulating leucocytes is stimulated and may have a
      negative impact on clinical outcome in AMI.

PMID- 12605595
TI  - Ethnic differences in circulating soluble adhesion molecules: the Wandsworth
      Heart and Stroke Study.
AB  - The aim of this study was to investigate whether soluble adhesion molecule levels
      differ by ethnic group. Soluble plasma adhesion molecules [soluble P-selectin (sP
      selectin), soluble E-selectin (sE-selectin), soluble intercellular adhesion
      molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1)]
      were measured in 261 white (120 females), 188 African origin (99 females) and 215
      South Asian (99 females) individuals living in England. All were free from
      coronary heart disease, stroke and other cardiovascular disease, diabetes, drug
      therapy for hypertension or high lipids, hormone-replacement therapy or oral
      contraceptive pill. The results of the study indicated that there were important
      differences in the levels of adhesion molecules by sex and smoking. However, when
      adjusting for these and other potential confounders, there were no differences in
      levels between white subjects and individuals of South Asian origin. In contrast,
      people of African origin had significantly lower levels of sICAM-1 [Caribbean 
      30% (-36 to -23%); West African -22% (-29 to -15%), values are means (95%
      confidence intervals)], sVCAM-1 [Caribbean -14% (-19 to -8%); West African -10% (
      17 to -3%)] and sP-selectin [Caribbean -10% (-17 to -2%); West African -24% (-31
      to -16%)] than white individuals. In conclusion, circulating levels of some
      soluble adhesion molecules are lower in individuals of Caribbean or West African
      origin compared with white or South Asian individuals. These relationships may
      contribute to the low risk of coronary heart disease seen in people of African
      origin living in England.

PMID- 12605596
TI  - Endothelium-dependent vasodilatory effect of vitisin C, a novel plant
      oligostilbene from Vitis plants (Vitaceae), in rabbit aorta.
AB  - We investigated the pharmacological properties of vitisin C, a novel plant
      oligostilbene from Vitis plants. Vitisin C (1-10 microM) dose-dependently
      inhibited the contractile responses of endothelium-intact rabbit thoracic aorta
      induced by phenylephrine (1 microM). These inhibitory effects were abolished in
      the presence of N (G)-nitro-L-arginine methyl ester (L-NAME; 300 microM), a
      potent inhibitor of nitric oxide synthase, but not atropine (1 microM), a non
      selective muscarinic cholinoceptor antagonist. In endothelium-denuded rabbit
      aorta, vitisin C was ineffective in attenuating phenylephrine-induced
      contraction. Moreover, vitisin C (10 microM) increased cGMP production in
      endothelium-intact, but not endothelium-denuded, aorta, and this increase was
      abolished in the presence of L-NAME (300 microM). To assess Ca(2+) movement
      across the endothelial cell membrane induced by vitisin C, we further
      investigated (45)Ca(2+) influx into cultured rabbit aortic endothelial cells in
      the presence of vitisin C (3 microM), carbachol (1 microM) or A23187 (10 nM).
      Vitisin C and carbachol significantly enhanced (45)Ca(2+) influx, which was
      inhibited by nifedipine (10 microM), a blocker of L-type Ca(2+) channels. In the
      presence of SK&F96365, a blocker of receptor-operated Ca(2+) channels, (45)Ca(2+)
      influx induced by carbachol was significantly inhibited, whereas that induced by
      vitisin C was not affected. On the other hand, A23187 enhanced (45)Ca(2+) influx
      in the presence and absence of nifedipine and SK&F96365. These results suggest
      that vitisin C evokes endothelium-dependent vasorelaxation through enhancing
      nitric oxide release, which is facilitated by Ca(2+) influx into endothelial
      cells via nifedipine-sensitive Ca(2+) channels.

PMID- 12605597
TI  - Nitric oxide donors inhibit formation of the Apaf-1/caspase-9 apoptosome and
      activation of caspases.
AB  - Caspases are critical for the initiation and execution of apoptosis. Nitric oxide
      (NO) or derived species can prevent programmed cell death in several cell types,
      reportedly through S-nitrosation and inactivation of active caspases. Although we
      find that S-nitrosation of caspases can occur in vitro, our study questions
      whether this post-translational modification is solely responsible for NO
      mediated inhibition of apoptosis. Indeed, using Jurkat cells as a model system,
      we demonstrate that NO donors block Fas- and etoposide-induced caspase activation
      and apoptosis (downstream of mitochondrial membrane depolarization) and
      cytochrome c release. However, caspase activity was not restored by the strong
      reducing agent dithiothreitol, as predicted for S-nitrosation reactions, thereby
      excluding active-site-thiol modification of caspases as the only anti-apoptotic
      mechanism of NO donors in cells. Rather, we observed that processing of
      procaspases-9, -3 and -8 was decreased due to ineffective formation of the Apaf
      1/caspase-9 apoptosome. Gel-filtration and in vitro binding assays indicated that
      NO donors inhibit correct assembly of Apaf-1 into an active approx. 700 kDa
      apoptosome complex, and markedly attenuate caspase-recruitment domain (CARD)-CARD
      interactions between Apaf-1 and procaspase-9. Therefore we suggest that NO or a
      metabolite acts directly at the level of the apoptosome and inhibits the
      sequential activation of caspases-9, -3 and -8, which are required for both
      stress- and receptor-induced death in cells that use the mitochondrial subroute
      of cell demise.

PMID- 12605598
TI  - Protective effect of creatine against inhibition by methylglyoxal of
      mitochondrial respiration of cardiac cells.
AB  - Previous publications from our laboratory have shown that methylglyoxal inhibits
      mitochondrial respiration of malignant and cardiac cells, but it has no effect on
      mitochondrial respiration of other normal cells [Biswas, Ray, Misra, Dutta and
      Ray (1997) Biochem. J. 323, 343-348; Ray, Biswas and Ray (1997) Mol. Cell.
      Biochem. 171, 95-103]. However, this inhibitory effect of methylglyoxal is not
      significant in cardiac tissue slices. Moreover, post-mitochondrial supernatant
      (PMS) of cardiac cells could almost completely protect the mitochondrial
      respiration against the inhibitory effect of methylglyoxal. A systematic search
      indicated that creatine present in cardiac cells is responsible for this
      protective effect. Glutathione has also some protective effect. However, creatine
      phosphate, creatinine, urea, glutathione disulphide and beta-mercaptoethanol have
      no protective effect. The inhibitory and protective effects of methylglyoxal and
      creatine respectively on cardiac mitochondrial respiration were studied with
      various concentrations of both methylglyoxal and creatine. Interestingly, neither
      creatine nor glutathione have any protective effect on the inhibition by
      methylglyoxal on the mitochondrial respiration of Ehrlich ascites carcinoma
      cells. The creatine and glutathione contents of several PMS, which were tested
      for the possible protective effect, were measured. The activities of two
      important enzymes, namely glyoxalase I and creatine kinase, which act upon
      glutathione plus methylglyoxal and creatine respectively, were also measured in
      different PMS. Whether mitochondrial creatine kinase had any role in the
      protective effect of creatine had also been investigated using 1-fluoro-2,4
      dinitrobenzene, an inhibitor of creatine kinase. The differential effect of
      creatine on mitochondria of cardiac and malignant cells has been discussed with
      reference to the therapeutic potential of methylglyoxal.

PMID- 12605600
TI  - A strategic study using mutant-strain entrapment in calcium alginate for the
      production of Saccharomyces cerevisiae cells with high invertase activity.
AB  - Entrapped cells and entrapped cells grown inside of a calcium alginate matrix as
      well as free cells have been investigated using Saccharomyces cerevisiae mutant
      strains with regard to their pattern of growth and invertase activity. The
      repression of invertase by glucose and glucose-consumption ability were
      considered in the selection process of the mutants. Efficient sucrose
      bioconversion due to high invertase activity was obtained when entrapped mutant
      strain Q6R2 cells were grown within calcium alginate gel beads using sucrose plus
      glucose as the carbon source. Under these conditions, 1 mg (dry weight) of
      entrapped cells is able to produce 20 micromol of inverted sugar in 3 min (the
      maximum activity obtained was 20 units x mg(-1)). The experiments were carried
      out for 6 months without appreciable loss of either bead integrity or invertase
      activity. The biocatalyst was also stored at 4 degrees C for 6 months without
      appreciable loss of the invertase activity. This work shows that entrapped yeast
      cells with a weak ability to consume sugar may be used to produce inverted sugar.

PMID- 12605599
TI  - SEA (sea-urchin sperm protein, enterokinase and agrin)-module cleavage,
      association of fragments and membrane targeting of rat intestinal mucin Muc3.
AB  - In a previous study we showed, by transient expression studies in COS-1 cells,
      that the C-terminal domain of rat intestinal membrane mucin Muc3 was cleaved
      between glycine and serine within a GSIVV (one-letter) amino acid sequence during
      its residence in the endoplasmic reticulum. The extracellular domain fragment
      remained linked to the membrane-associated fragment by non-covalent interactions.
      The present study demonstrates that cleavage depends not only on the presence of
      the G/SIVV site (where G/S is the glycine downward arrow serine cleavage site),
      but also on more distant C-terminal sequences in the SEA (sea-urchin sperm
      protein, enterokinase and agrin) module. Inhibition of N-glycosylation by
      tunicamycin treatment of transfected cells did not prevent re-association of
      fragments, although cleavage was partially impaired, as some of the non
      glycosylated, non-cleaved products were seen to accumulate in cells. Membrane
      targeting of the Muc3 domain and its cleavage products occurred in transfected
      cells and was not impaired in mutants in which the cleavage site was mutated.
      Targeting was also not impaired for products devoid of N-linked oligosaccharides.
      Our studies thus indicate that (a) cleavage within the SEA module of rat Muc3
      requires participation of peptide sequences located C-terminal of and distant
      from the cleavage site, (b) re-association of the fragments requires the SEA
      module, but is independent of N-linked oligosaccharides, and (c) membrane
      targeting of the mucin is independent of the SEA-module-cleavage reaction.

PMID- 12605601
TI  - Prediction of beta-turns from amino acid sequences using the residue-coupled
      model.
AB  - We evaluated the prediction of beta-turns from amino acid sequences using the
      residue-coupled model with an enlarged representative protein data set selected
      from the Protein Data Bank. Our results show that the probability values derived
      from a data set comprising 425 protein chains yielded an overall beta-turn
      prediction accuracy 68.74%, compared with 94.7% reported earlier on a data set of
      30 proteins using the same method. However, we noted that the overall beta-turn
      prediction accuracy using probability values derived from the 30-protein data set
      reduces to 40.74% when tested on the data set comprising 425 protein chains. In
      contrast, using probability values derived from the 425 data set used in this
      analysis, the overall beta-turn prediction accuracy yielded consistent results
      when tested on either the 30-protein data set (64.62%) used earlier or a more
      recent representative data set comprising 619 protein chains (64.66%) or on a
      jackknife data set comprising 476 representative protein chains (63.38%). We
      therefore recommend the use of probability values derived from the 425
      representative protein chains data set reported here, which gives more realistic
      and consistent predictions of beta-turns from amino acid sequences.

PMID- 12605602
TI  - Utility of peptide-protein affinity complexes in proteomics: identification of
      interaction partners of a tumor suppressor peptide.
AB  - We used a N-biotinylated peptide analog of the C-terminal domain of the tumor
      suppressor protein, p21cip1/waf1 to elucidate peptide/protein interacting
      partners. The C-terminal domain of p21cip1/waf1 protein spanning 141-160 amino
      acid residues is known to bind PCNA and this interaction is important in many
      biological processes including cell-cycle control. This C-terminal 20-mer
      efficiently extracts PCNA in the presence of a variety of N- or C-terminally
      attached affinity tags. Using difference silver stained 2D gels combined with in
      gel tryptic digests, we identified the difference spots using MALDI-TOF mass
      spectrometry-based peptide mass fingerprinting followed by a database search
      using PROFOUND against NCBIs human nonredundant protein sequence data bank.
      Identified spots include the p48 subunit of chromatin assembly factor-1, the heat
      shock 70 protein analog BiP, calmodulin, nucleolin and a spot similar in size to
      dimeric PCNA. In contrast, microcapillary ion-trap LC-MS/MS analysis of a tryptic
      digest of entire affinity extracts derived from both control and experimental
      runs followed by database searches using SEQUEST confirmed the presence of most
      of the above proteins. This strategy also identified hnRNPA1, HPSP90alpha, HSP40
      and T-complex protein 1, a protein similar to prothymosin, and a possible allelic
      variant of the p21cip1/waf1 protein. The use of N-biotinylated peptide derived
      from the C-terminal domain of p21cip1/waf1 protein in proteomic analysis
      exemplified here suggests that peptides obtained from intracellular functional
      screens could also potentially serve as efficient baits to discover new drug
      targets.

PMID- 12605603
TI  - Insights into the determinants of beta-sheet stability: 1H and 13C NMR
      conformational investigation of three-stranded antiparallel beta-sheet-forming
      peptides.
AB  - In a previous study we designed a 20-residue peptide able to adopt a significant
      population of a three-stranded antiparallel beta-sheet in aqueous solution (de
      Alba et al. [1999]Protein Sci.8, 854-865). In order to better understand the
      factors contributing to beta-sheet folding and stability we designed and prepared
      nine variants of the parent peptide by substituting residues at selected
      positions in its strands. The ability of these peptides to form the target motif
      was assessed on the basis of NMR parameters, in particular NOE data and 13Calpha
      conformational shifts. The populations of the target beta-sheet motif were lower
      in the variants than in the parent peptide. Comparative analysis of the
      conformational behavior of the peptides showed that, as expected, strand residues
      with low intrinsic beta-sheet propensities greatly disfavor beta-sheet folding
      and that, as already found in other beta-sheet models, specific cross-strand side
      chain-side chain interactions contribute to beta-sheet stability. More
      interestingly, the performed analysis indicated that the destabilization effect
      of the unfavorable strand residues depends on their location at inner or edge
      strands, being larger at the latter. Moreover, in all the cases examined,
      favorable cross-strand side chain-side chain interactions were not strong enough
      to counterbalance the disfavoring effect of a poor beta-sheet-forming residue,
      such as Gly.

PMID- 12605604
TI  - Dipole interaction model predicted pi-pi* circular dichroism of cyclo(L-Pro)3
      using structures created by semi-empirical, ab initio, and molecular mechanics
      methods.
AB  - Cyclo(l-Pro)3 (CP3) is a synthetic peptide created to model cis and torsionally
      strained peptide bonds that also exhibits a strong distinctive UV circular
      dichroic (CD) spectrum. Circular dichroic spectra were computed for the amide pi
      pi* transition using the dipole interaction model for various conformations of
      the peptide. Conformations of CP3 were created initially from crystal data, and
      followed by energy minimizations via molecular mechanics using the cvff force
      field; the effects of additional geometric optimizations by semi-empirical and ab
      initio quantum mechanics were investigated. The CD spectra for each conformation
      were calculated using a variety of different parameters, and each result was
      compared with the published experimental spectrum [Deber, C.M., Scatturin, A.,
      Vaidya, V.M. & Blout, E.R. (1970) Small cyclic proline peptides: UV absorption
      and CD. In: Peptides: Chemistry and Biochemistry, Proceedings of the First
      American Peptide Symposium (Weinstein, B., ed.), Marcel Dekker, New York pp. 163
      173]. Herein, two distinct conformations, a C3 symmetric and an asymmetric form,
      gave CD predictions that separately did not resemble the experimental spectrum.
      Energy differences were predicted at various theoretical levels, including MP2
      and density functional theory. When the predicted CD spectra for each
      conformation were multiplied by Boltzmann weighting factors created using heats
      of formation determined by the AM1 optimizations, the weighted composite CD
      spectrum created did resemble experiment for the pi-pi* transition indicating
      that both conformations may exist simultaneously in solution.

PMID- 12605605
TI  - Detergent-assisted oxidative folding of delta-conotoxins.
AB  - Conotoxins comprise a diverse group of disulfide-rich peptides found in venoms of
      predatory Conus species. The native conformation of these peptides is marginally
      stable in comparison with alternative conformations, often resulting in low
      folding yields. The oxidative folding of hydrophobic delta-conotoxins was found
      to produce less than 1% of the native peptide [Bulaj, G. et al. (2001)
      Biochemistry 40, 13201]. In order to identify factors that might improve folding
      yields, we screened a number of additives including water-soluble polymers,
      detergents and osmolytes for their ability to increase steady-state accumulation
      of the native delta-conotoxin PVIA. The presence of a non-ionic detergent Tween
      and low temperature appeared to be the most effective factors in improving the
      oxidative folding. The detergent was also effective in promoting folding of other
      hydrophobic delta-conotoxins. Based on our findings, we discuss a possible
      mechanism for detergent-assisted folding and the general applicability of this
      mechanism to facilitating the proper folding of hydrophobic, cysteine-rich
      peptides.

PMID- 12605606
TI  - Biophysical studies and anti-growth activities of a peptide, a certain analog and
      a fragment peptide derived from alpha-fetoprotein.
AB  - A chemically synthesized 34-amino acid peptide, an analog, and a fragment of the
      peptide have been purified and studied. Biophysical studies were carried out to
      determine some of the metal ion binding properties of the original peptide and an
      analog of this parent peptide, in which the two histidine residues were replaced
      by alanines. As shown by visible absorption spectroscopy, Co (II) forms a complex
      with the parent peptide, but not with the analog peptide, and one or two
      histidines in the parent peptide are ligands for Co (II) ion binding. The effects
      on disulfide bond formation in the peptide by Zn (II) and Co (II) ions were also
      examined for this analog. Anti-growth assays were performed using the original
      cysteine-containing peptide with Zn (II) ion complexed to the peptide through the
      two cysteine residues. These rat uterine growth assays showed that the complexing
      of Zn (II) ion to the peptide maintained the anti-growth activity of the peptide,
      while gel-filtration experiments showed the zinc ions maintained the peptide in
      its anti-growth form indefinitely in solution. A saliently important part of this
      research was the discovery that a fragment of the peptide consisting of a middle
      sequence of 14 amino acids was found to have significant anti-growth activity in
      the rat uterine assay. Its activity suggested that this fragment might be
      considered a viable candidate for testing in anti-cancer protocols.

PMID- 12605607
TI  - Shopping trolley-related accidents in the UK: a preventable cause of morbidity.

PMID- 12605608
TI  - Recurrent parotitis and Sjogren's syndrome.

PMID- 12605609
TI  - Nasogastric rehydration in acute gastroenteritis.

PMID- 12605610
TI  - Randomized controlled clinical trials.

PMID- 12605612
TI  - Coronary artery disease--more disease, more patients, better treatment.

PMID- 12605613
TI  - The effects of Panax ginseng on quality of life.
AB  - Panax ginseng is marketed and used to maintain natural energy, increase mental
      and physical abilities, improve mood and promote general health and well-being.
      Panax ginseng has been studied in a number of randomized clinical trials
      investigating its effect on physical and psychomotor performance, cognitive
      function, immunomodulation, diabetes mellitus and herpes simplex type-II
      infections. Equivocal results have been demonstrated for many of these
      indications. P. ginseng is also commonly used to promote quality of life (QoL).
      As a result, ginseng's effect on QoL has become an increasingly important
      endpoint in clinical trials. We reviewed all studies (n = 9) that determined the
      effect of P. ginseng on QoL. P. ginseng's has been evaluated at dosages of 80-400
      mg. Study duration has spanned from 2 to 9 months. Several QoL measures have been
      used, ranging from widely accepted core instruments to unpublished investigator
      derived questionnaires. In addition, many of the investigators utilized ginseng
      extracts that were supplemented with vitamins and minerals while others used only
      standardized ginseng extract. Populations evaluated also differed in terms of
      underlying morbidity. Nearly every study evaluated (n = 8) demonstrated some
      degree of QoL improvement. Beneficial effects were evident within instrument
      summary component scores but improvement in overall composite scores of QoL was
      rarely seen. However, findings were equivocal. While populations evaluated varied
      in terms of underlying morbidity, there did not appear to be a substantial
      difference in their response to ginseng with respect to QoL. Despite some
      positive results, improvement in overall health-related quality of life cannot,
      given the current research, be attributed to P. ginseng. However, the possibility
      that various facets of QoL may have improved and the potential of early transient
      effects cannot be discounted.

PMID- 12605614
TI  - High-performance liquid chromatographic method for mycophenolic acid and its
      glucuronide in serum and urine.
AB  - OBJECTIVE: To develop a simple analytical method for monitoring serum and urine
      concentrations of mycophenolic acid (MPA), an active metabolic constituent of the
      immunosuppressive pro-drug mycophenolate mofetil, and its glucuronide. METHODS:
      Serum samples were prepared by solid-phase extraction (SPE), while urine samples
      were simply diluted with water. Serum was added to an SPE cartridge, then washed
      twice with 5% methanol solution. The analytes were eluted with methanol
      containing benzoic acid as internal standard for mycophenolic acid glucuronide
      (MPAG). The resultant eluate was directly injected into a high-performance liquid
      chromatograph (HPLC) to determine MPAG. For the assay of MPA, the remaining
      eluate was dried under nitrogen and resolved in a mixture of acetonitrile and 20
      mM phosphate buffer (pH 3.0). RESULTS: The present methods were reproducible and
      accurate based on the intra- and inter-assay, and had detection limits of 0.225
      microg/mL for MPA and 9.0 microg/mL for MPAG. The present methods enabled us to
      monitor the time course of changes in the concentrations of MPA and MPAG in serum
      and urine in a patient with a renal transplant during 12 h after ingestion of
      mycophenolate mofetil. CONCLUSION: The HPLC method described should be useful for
      the routine monitoring of serum and urine concentrations of MPA and MPAG during
      immunosuppressive medication for renal transplantation.

PMID- 12605615
TI  - Developing prevalence-based prescribing units for analysing variations in general
      practitioner prescribing: a case study using statins.
AB  - OBJECTIVE: To develop regionally specific prevalence-, age- and sex-standardized
      prescribing units (PASS-PUs) and to relate these to statin prescribing. DESIGN:
      Cross-sectional. SETTING: Ninety-four general practitioner (GP) practices within
      one health authority in the north-west of England. MAIN OUTCOME MEASURES:
      Comparisons between specific therapeutic group age-sex-related prescribing units
      (STAR-PUs) and PASS-PUs for statin prescribing. RESULTS: STAR-PUs and PASS-PUs
      were calculated for all GP practices and there was a high degree of correlation
      (Spearman's rank coefficient 0.88; P < 0.001). Using actual prescribing data for
      statins for a 12-month period, a statistically significant correlation was found
      between net ingredient cost per patient and STAR-PUs per patient (Spearman's rank
      coefficient 0.36; P < 0.01). However, the correlation between average daily
      quantities per patient and PASS-PUs per patient was not statistically
      significant. A scatter plot revealed a pattern whereby GP practices with high
      proportions of patients aged over 75 years exhibited low statin prescribing in
      relation to the expected prevalence of treated coronary heart disease (CHD) in
      their patient population. CONCLUSIONS: Low weightings for patients aged over 75
      years in calculating STAR-PUs lead to a much lower number of prescribing units
      within GP practice populations when compared with PASS-PUs. Current statin
      prescribing across GP practices in this study correlates with national
      prescribing cost patterns (as measured by STAR-PUs) although not with expected
      prevalence of treated CHD (as measured by PASS-PUs). PASS-PUs reflect prevalence
      of treated CHD and may therefore be used to monitor and predict GP prescribing
      arising from the implementation of the National Service Framework targets for
      CHD. In addition, PASS-PUs maybe derived for a wide range of therapeutic areas.

PMID- 12605616
TI  - Perioperative infusions in paediatric patients: rationale for using Ringer
      lactate solution with low dextrose concentration.
AB  - To assess the usefulness of Ringer-lactate solution with 0.9% dextrose, fluid
      therapy during surgery in paediatric patients was reviewed. From the literature,
      the need for intravenous (i.v.) infusion and water could be established. The need
      for sodium was also evident and use of normonatraemic i.v. solutions should be
      recommended to avoid hyponatraemia. Little data were found about the value of the
      other electrolytes. Dextrose requirements have been the subject of debate for the
      last two decades. The choice of dextrose concentration is a compromise between
      avoiding hypoglycaemia and hyperglycaemia. Four clinical trials assessing the use
      of Ringer-lactate solution with 0.9 or 1% dextrose in paediatric patients suggest
      that it is appropriate for routine infusion in paediatric patients during the
      perioperative period. However, fluid therapy during surgery has rarely been
      studied, probably because it is inexpensive, rarely leads to problems and is used
      in very different clinical settings. Development of consensus clinical guidelines
      on the use of electrolyte infusions in paediatric surgery would be helpful.

PMID- 12605617
TI  - Identification of medication-related attendances at an A & E department.
AB  - BACKGROUND: The use of medication is the most common medical intervention, but it
      has associated risks. These have been described as drug-related problems (DRPs).
      Other non-UK studies have reported DRPs to be the cause of 3-16% of hospital
      admissions and around 4% of attendances at emergency departments. The size of the
      problem in the UK has not been quantified. AIM: The aim of this study was to
      identify the number of patients attending a central London accident and emergency
      (A & E) department with symptoms or conditions caused by DRPs. METHOD: A 2-week
      retrospective, case-review study was conducted in the A & E department of St
      Thomas' Hospital, London, during March 1999. DRPs were identified using
      recognized criteria. Statistical analysis identified patient characteristics
      which could be associated with the incidence of DRPs. The types of DRP and the
      drugs involved were identified. RESULTS: During the study period, 106 patients
      attended the A & E department with a DRP. This equates to 4% of the A & E
      population. During this period the demographics of the A & E attenders were no
      different to the annual A & E cohort. The most common DRPs were adverse drug
      reactions and overdose. The most frequently involved drugs included analgesics,
      antibiotics, those with narrow therapeutic indices and illegal drugs. The mean
      age of this patient group was 38 years (non-significant). They attended
      significantly more frequently during the early hours of the morning and on
      Saturdays than the A & E general population (chi-squared P = 0.004 and P = 0.003,
      respectively). DISCUSSION: The incidence of DRP as a cause of attendance at A & E
      reflects that in the literature. No statistical association with a specific age
      group of patients could be made, but the mean age of 38 years is younger than
      previously reported. The demographic differences which were statistically
      significant can be explained by the increased incidence of DRP associated with
      the use of illegal drugs than reported in other studies. Other drug groups
      identified by this study are representative of other reports. CONCLUSION: DRPs
      account for 4% of attendances at a central London A & E Department.

PMID- 12605618
TI  - Effect of intravenous infusions of thiamine on the disposition kinetics of
      thiamine and its pyrophosphate.
AB  - BACKGROUND: Thiamine supplementation is necessary in patients with thiamine
      deficiency syndromes. Experimental evidence suggests that tissue uptake and the
      elimination of thiamine are dose-dependent. AIM: The aim of the present study was
      to investigate the effect of different i.v. infusion rates of thiamine on blood
      concentrations of thiamine and its active metabolite thiamine pyrophosphate (TPP)
      and on renal excretion of thiamine. METHODS: Twelve healthy subjects received in
      a two-period block randomized study 150 mg thiamine intravenously over either 1
      or 24 h. RESULTS: The maximum blood concentrations (Cmax) of thiamine were
      significantly higher after the more rapid infusion (RI; 2300 ng/mL) than after
      the slower infusion (SI; 177 ng/mL). The AUC of thiamine was identical after both
      infusion protocols. There was a slightly (10%) increased AUC of TPP (P < 0.08)
      after SI, whereas C(max) values were comparable. Urinary excretion of thiamine
      was significantly decreased from 83.6% of the applied dose after RI to 57.6%
      after the SI. CONCLUSIONS: Our data suggest an increased tissue uptake of
      thiamine when it is given as an SI compared with a RI of the same dose. It is
      concluded, therefore, that an SI of thiamine may be superior to RI or bolus
      injections to treat severe deficiency syndromes.

PMID- 12605619
TI  - Salvia officinalis extract in the treatment of patients with mild to moderate
      Alzheimer's disease: a double blind, randomized and placebo-controlled trial.
AB  - BACKGROUND: Alzheimer's disease is characterized by a slow, progressive decline
      in cognitive function and behaviour. Acetylcholine esterase inhibitors are the
      only agents approved by the Food and Drug Administration for the treatment of
      Alzheimer's disease. All other agents prescribed for the treatment of Alzheimer's
      disease are used on an off-label basis. Current research into new drugs is
      focused on agents that will prevent, slow down and/or halt the progress of the
      disease process. Salvia officinalis has been used in herbal medicine for many
      centuries. It has been suggested, on the basis of traditional medicine, its in
      vitro cholinergic binding properties and modulation of mood and cognitive
      performance in humans, that Salvia officinalis might potentially provide a novel
      natural treatment for Alzheimer's disease. The objective of this study was to
      assess the efficacy and safety of Salvia officinalis extract using a fixed dose
      (60 drops/day), in patients with mild to moderate Alzheimer's disease, over a 4
      month period. METHODS: This was a 4-month, parallel group, placebo-controlled
      trial undertaken in three centres in Tehran, Iran. Patients with mild to moderate
      Alzheimer's disease aged between 65 and 80 years (n = 42, 18 women) with a score
      of > or = 12 on the cognitive subscale of Alzheimer's Disease Assessment Scale
      (ADAS-cog) and < or = 2 on the Clinical Dementia Rating (CDR) were randomized to
      placebo or fixed dose of S. officinalis extract. Over the 16 weeks, the main
      efficacy measures were the change in the ADAS-cog and CDR-Sum of Boxes scores
      compared with baseline. In addition, side-effects were systematically recorded
      throughout the study using a checklist. RESULTS: At 4 months, S. officinalis
      extract produced a significant better outcome on cognitive functions than placebo
      (ADAS-cog: F = 4.77, d.f. = 1, P = 0.03) (CDR-SB: F = 10.84, d.f. = 1, P <
      0.003). There were no significant differences in the two groups in terms of
      observed side-effects except agitation that appears to be more frequent in the
      placebo group (P = 0.09). CONCLUSIONS: The results of this study indicate the
      efficacy of S. officinalis extract in the management of mild to moderate
      Alzheimer's disease. Moreover, S. officinalis may well reduce agitation of
      patients but this needs to be confirmed.

PMID- 12605621
TI  - Reassessing the contraindication of zolmitriptan and serotonin reuptake
      inhibitors: an evidence-based pharmacotherapeutic case report.

PMID- 12605620
TI  - Factors associated with the consumption of psychotropic drugs in a cohort of men
      and women aged 50 and over.
AB  - OBJECTIVES: The use of psychotropic drugs has increased continuously over recent
      years in industrialized countries. In Europe, France has the highest consumption
      of such drugs. The aim of this study was to identify the sociodemographic and
      medical factors associated with the use of psychotropic agents. METHODS: Data,
      collected as part of the SUVIMAX (SUpplementation en VItamines et sels Mineraux
      AntioXydants) prevention trial, from a self- administered questionnaire involving
      7299 subjects aged 45-60 years, were subjected to logistic regression analysis.
      RESULTS: A total of 467 subjects used psychotropic drugs (8.4% of the women, 4.6%
      of the men). Use of psychotropic drugs increased in subjects of both sexes with
      past history of depression, perception of poor health and use of other drug
      treatments. Widowhood in men [odds ratio (OR) = 3.4; 95% CI = 1.6-7.3] and
      divorce in women (OR = 2; 95% CI = 1.2-3.2) were also associated with an
      increased use of psychotropic drugs. Interaction was demonstrated between
      educational level and occupational satisfaction in men (OR = 2.9; 95% CI = 1.5
      5.8) and between perception of health status and use of other types of medication
      in women (OR = 6.5; 95% CI = 4.6-9.5). CONCLUSION: The results of our study are
      consistent with those of others in demonstrating that specific socio-occupational
      factors in men and specific medical factors in women influence extent of use of
      psychotropic drugs.

PMID- 12605622
TI  - Use of pharmacoeconomics in prescribing research. Part 1: costs--moving beyond
      the acquisition price for drugs.
AB  - This paper addresses pharmacoeconomics in prescribing research and reflects the
      increasing use of techniques of economic evaluation to aid drug purchasing
      decisions in a variety of settings -- for national drug subsidization programmes,
      provincial purchasing plans, insurance programmes, and for hospital and area
      health authority formulary decisions. First, we focus on the cost component of an
      economic evaluation and discuss methodological issues that are relevant to all
      pharmacoeconomic analyses.

PMID- 12605624
TI  - The power of children over adults when obtaining sweet snacks.
AB  - BACKGROUND: There is evidence to suggest that the family is becoming a more
      democratic unit and that children are spending more on sweet snack items than
      ever before. A study was thus undertaken to investigate the influence of children
      on parental decision-making in relation to the use of sugary snacks. METHODS: A
      cross sectional interview study; children aged 7-8 years from 20 inner-city
      Manchester primary schools were asked about their sweet eating, their pocket
      money and their perceived levels of influence or autonomy within the household.
      The parents of these children were also asked to fill in a questionnaire that
      mirrored the children's questions. RESULTS: There was a moderate but significant
      correlation between the opinion of the parents and that of the children on the
      extent of influence (Pearson coefficient r = 0.25, P = 0.001). When the adults (n
      = 181) were split into age groups, <or= 29 years (n = 33), 30-35 years (n = 61)
      and >or= 36 years (n = 87), the study showed that the older the adult, the less
      the child seemed to get his or her own way. Spearman's rho = 0.16, P = 0.03
      (children's view) and rho = 0.17, P = 0.02 (adult's view). The dominant factors
      were related to money in the children's opinion, although the adults' data
      suggested that older mothers (>or= 36 years) may be trying to limit their
      children's access to sweet snacks. CONCLUSIONS: Adults' efforts to limit their
      children's intake of sweet snacks and drinks are being undermined by earlier and
      earlier influences in the child's life and by access to money, which allows the
      child to out-manoeuvre his or her parents. This is compounded by the provision of
      additional income, mostly from grandparents.

PMID- 12605625
TI  - The prevalence and severity of dental fluorosis among 12-year-old schoolchildren
      in Jordan.
AB  - OBJECTIVES: To assess dental fluorosis, provide base-line data among Jordanian
      children and to compare fluorosis in incisor teeth between areas with different
      fluoride levels. DESIGN: Cross-sectional study among school children. SAMPLE AND
      METHODS: A sample of 1878 subjects aged 12 years, 940 boys and 938 girls, were
      randomly selected from 128 schools in urban (69 schools) and rural (59 schools)
      areas. The Thylstrup & Fejerskov (TF) index was used to record the dental
      fluorosis on the labial surfaces of incisors. RESULTS: A total of 18.5% of the
      children examined showed dental fluorosis. The difference in fluorosis between
      males (17%) and females (20%) was not statistically significant (P > 0.05).
      Children in rural areas had a higher prevalence of fluorosis (31.8%) than their
      counterparts in urban areas (11.3%), a difference that was statistically
      significant (P < 0.01). CONCLUSIONS AND RECOMMENDATIONS: Findings suggest that
      there is a need for continued monitoring of mottling and further investigation
      into the fluoride intake from all sources in Jordan. However, there is a need to
      change the drinking water supplies in the southern region of Jordan. Active steps
      should also be taken to suppress emissions of vapours high in fluoride from
      phosphate plants to within acceptable limits.

PMID- 12605626
TI  - Pain relief for paediatric dental chair anaesthesia: current practice in a
      community dental clinic.
AB  - AIM: A review of different modes of pain relief for simple dental extractions
      under general anaesthesia in a community dental setting. PATIENTS AND METHODS:
      Different analgesia regimens are used by different anaesthetic teams working in a
      single community clinic. A total of 72 patients were reviewed post-operatively in
      the recovery room and followed up with a telephone survey 24 h later to assess
      pain experienced by the patients. The efficacy of different analgesia regimens
      was analysed. RESULTS: The majority of patients were pain free in recovery,
      independent of the method of pain relief used. Local anaesthetic injections
      appear superior to systemic analgesia, and patients with local anaesthetic
      injections were more settled in recovery. DISCUSSION: Simple dental extractions
      cause pain and efficient administration of appropriate analgesia should be an
      integral part of the community dental service.

PMID- 12605627
TI  - Dental erosion -- changing prevalence? A review of British National childrens'
      surveys.
AB  - OBJECTIVES: To investigate the change in the prevalence of dental erosion, over
      time, by a review of the data from the published national dental surveys of young
      people in the UK. A subsidiary objective was to investigate the relationship
      between erosion and possible associated risk factors. DESIGN: The review was
      based on cross-sectional prevalence studies incorporating a clinical dental
      examination and structured interviews. SAMPLE: The data were collated from the
      1993 UK childrens' dental health survey and the dental report of the two National
      Diet and Nutrition Surveys (NDNS) of children aged 1(1/2)-4(1/2) in 1992/3 and 4
      18 years in 1996/7. The criteria used for data collection were comparable between
      the three different studies. RESULTS: Comparing the data from the different
      studies, the prevalence of erosion was seen to increase from the time of the
      childrens' dental health survey in 1993 and the NDNS study of 4-18-year-olds in
      1996/7. There was a trend towards a higher prevalence of erosion in children aged
      between 3(1/2) and 4(1/2) and in those who consumed carbonated drinks on most
      days compared with toddlers consuming these drinks less often. Drinks overnight
      were associated with an increased prevalence of erosion. More 4-6-year-olds with
      reported symptoms of gastro-oesophageal reflux had erosion compared with symptom
      free children. On multivariate analysis, the strongest independent association
      with erosion was geography, with children living in the North having twice the
      odds of having erosion compared with those in London and the South-east.
      CONCLUSIONS: Comparing prevalence data from cross-sectional national studies
      indicates that dental erosion increases between different age cohorts of young
      people over time. Dietary associations with erosion are present but weak.
      Similarly, there is an association apparent between erosion, symptoms of gastro
      oesophageal reflux and socio-demographic variables such as region of domicile,
      social class, and receipt of social benefits.

PMID- 12605628
TI  - The cause of drooling in children with cerebral palsy -- hypersalivation or
      swallowing defect?
AB  - OBJECTIVE: To determine whether or not drooling in children with cerebral palsy
      is due to hypersalivation. POPULATION AND METHODS: The study population consisted
      of 10 children with cerebral palsy who were identified as having severe drooling,
      and a matched control group composed of 10 unaffected children who had no known
      physical or mental disabilities. Salivary flow rate was compared between the
      cerebral palsied children and the control group using the chin-cup collection
      drool quantification method described by Sochanjwskyj. Components of the system
      included a cup-like collection device, a vacuum pump, plastic tubing, an airtight
      collection chamber, and calibrated test tubes held against the subject's chin
      with elastic straps attached to an orthodontic head bonnet. Statistical analysis
      was completed using the Student's t-test and Fisher's Exact Probability test.
      RESULTS: The ages of the population ranged from 5.2 to 15.6 years, mean age (+/-
      SE) of 10.56 +/- 1.13 years. There was no statistically significant difference in
      the rate of salivary flow rate between the two groups' mean +/- SE: cerebral
      palsy group 0.220 +/- 0.018; control group 0.334 +/- 0.052 (P = 0.053). The
      results were further confirmed by comparing the buffering capacity (P = 1.00) and
      concentrations of the sodium (P = 0.065) and potassium ions (P = 0.058) in the
      saliva of the study groups. CONCLUSIONS: Children with cerebral palsy who drool
      do not appear to produce excess saliva. Their salivation is similar to the
      control children.

PMID- 12605629
TI  - Radiographic assessment of congenitally missing teeth in orthodontic patients.
AB  - OBJECTIVE: To estimate the prevalence of congenitally missing teeth (CMT) in
      patients evaluated for orthodontic care. A sample of 668 panoramic radiographs
      from Mexican population was reviewed from orthodontic healthy patients, 9-20
      years old. METHOD: Statistical tests were used to compare maxillary and
      mandibular hypodontia in right and left quadrants between males and females.
      RESULTS: Prevalence was 27% when all teeth were included, and was 2.7% when third
      molars were excluded. A significant difference was found between maxillary and
      mandibular symmetrical CMT in third maxillary molars, lateral incisors and second
      premolars (P < 0.001), and in mandibular third molars and central incisors (P <
      0.001). CONCLUSIONS: We confirmed that occurrence of CMT in the permanent
      dentition of a Mexican population most often affects third molars, followed by
      maxillary lateral incisors and then mandibular second premolars.

PMID- 12605630
TI  - Eruption of a permanent mandibular canine in a 5-year-old boy.
AB  - The premature eruption of a mature mandibular permanent canine is described in a
      healthy 5-year-old boy with developmental absence of the primary predecessor. The
      effects of early loss or missing primary teeth on eruption timing of the
      permanent successors are discussed. The very early maturation of the permanent
      canine appears to be a unique oddity, and there are no reports in the literature
      of eruption of this type of secondary tooth at such an early chronological age.

PMID- 12605631
TI  - Focal dermal hypoplasia -- oral and dental findings.
AB  - This report describes the case of an 8-year-old girl with focal dermal
      hypoplasia. As well as deformities affecting her hands and feet she had marked
      facial asymmetry, one diminutive eye and coloboma affecting the other.
      Intraorally, the patient had papillomas at the base of the tongue and tonsils.
      Her teeth showed irregular spacing, hypodontia, enamel hypoplasia, anomalous
      tooth form and delayed development. Radiographically, several teeth showed
      abnormal form. The patient's previous surgical experiences had adversely affected
      her behaviour and treatment has been limited to patient motivation and oral
      hygiene instructions, acclimatization, and simple restorative care.

PMID- 12605632
TI  - Congenital epulis of the newborn: a case report.
AB  - This paper describes the case of a day old baby who was admitted to hospital
      because of the presence of a large intraoral swelling that was preventing her
      from breast feeding. Clinical examination showed a firm, pedunculated, lobulated
      nodule protruding from the mouth and attached to the maxillary alveolus to the
      left of the midline. The mucosa was normal in appearance. The growth was excised
      under local anaesthesia and showed a histological appearance consistent with a
      congenital epulis of the newborn. Healing was complete and no recurrence was seen
      at review after two weeks. Conservative treatment of congenital epulis is often
      sufficient but in this case, the nodule prevented feeding. Excision was
      incomplete but, as in other cases treated in the same way, there has been no
      obvious tendency to recur.

PMID- 12605633
TI  - Factitial oral lesions in an autistic paediatric patient.
AB  - Self Injurious Behaviour (SIB) is a deliberate harm to the body that may lead to
      factitial injuries. Its origin may be functional or biological and it has a
      higher prevalence in females and in psychologically impaired individuals. Seventy
      per cent of autistic patients have SIB. Seventy-five per cent of factitial
      injuries are located in the head and neck region. A paediatric case report
      concerning a 4-year-old autistic female is presented. Detailed medical history,
      physical examination, clinical intraoral and radiographic examination, incisional
      biopsy, neuropaediatrical, psychological and speech evaluation were undertaken.
      Diagnosis included hypochromic macrocytic anaemia, caries, coronal fracture,
      factitial ulcer, factitial periodontitis, self-extraction of primary teeth and
      permanent teeth buds, non-specific oral ulcer with inflammatory reaction, mild
      mental retardation, speech impairment, autistic syndrome and self injurious
      behaviour consisting of putting fingers and foreign objects in the gingiva,
      fingernail biting and hair pulling. Differential diagnosis included hystiocitosis
      X, prepuberal periodontitis and leukocyte adhesion deficiency. Dental preventive
      and restorative treatment was performed. Non-contingent reinforcement therapy was
      successfully used to diminish SIB. Treatment of factitial oral injuries must be
      interdisciplinary and requires cooperation of the patient, the parents, health
      care providers, and medical team.

PMID- 12605639
TI  - Recent advances in the pathology of the vulva.
AB  - This review addresses recent and important advances in our knowledge of several
      uncommon or rare disorders of the vulva including Paget's disease, vulva
      intraepithelial neoplasia, lichen sclerosus and squamous hyperplasia and their
      relationship to squamous carcinoma. Emphasis is placed on the two biologically
      different types of squamous carcinoma related and unrelated to human
      papillomavirus infection. Finally, the relatively recent concept of the sentinel
      node as applied to vulva carcinoma is discussed.

PMID- 12605641
TI  - How accurate are subjective judgements of a continuum?
AB  - AIMS: To assess the accuracy of subjective judgements of a uni-dimensional
      continuum. METHODS AND RESULTS: Twenty-four observers were asked to estimate the
      position of a dot placed between two lines using a 100-point scale. Each observer
      judged 20 different positions. Ninety-five percent of observations were between 
      7 and +9 of the true value. The median and the mean value of the estimates for
      each position were within one or two points of the true value in most cases with
      a maximum deviation of five. There was perfect correlation between the ranks of
      the median and the mean and the true value (correlation coefficient +1, P <
      0.00001). The kappa values for interobserver agreement varied from 0.98 for two
      categories to 0.55 for 10 categories and 0.39 for 20 categories. Information
      transmitted increased from 0.98 bits with two categories to 2.83 bits with 20
      categories. CONCLUSIONS: The experiment indicates that subjective judgements can
      be accurate but it is necessary to use a large number of categories. One hundred
      point scales allow confidence intervals to be calculated and the intervals are
      reduced if the results from several observers are pooled. The mean and the median
      of the judgements of a large number of observers are close to objective reality
      and this approach could be used to define a gold standard of rankings of
      pathological continua such as cervical dyskaryosis or tumour differentiation.
      There is a reciprocal relationship between kappa values and information
      transmitted which demonstrates the fallacy of using kappa statistics in studies
      of continua.

PMID- 12605642
TI  - H-caldesmon expression in myofibroblastoma of the breast: evidence supporting the
      distinction from leiomyoma.
AB  - AIMS: The ultrastructural detection of leiomyomatous rather than myofibroblastic
      features in some cases of myofibroblastoma of the breast led some electron
      microscopically orientated pathologists to doubt the commonly accepted
      myofibroblastic nature of such a tumour, so the alternative terms 'myogenic
      stromal tumour' or 'variant of leiomyoma' have been proposed. The aim of this
      study was to analyse the immunohistochemical expression of h-caldesmon, a
      reliable marker in distinguishing smooth muscle versus myofibroblastic cellular
      differentiation, in a large series of myofibroblastomas of the breast to clarify
      whether these tumours are basically leiomyomatous. Moreover, cases from primary
      myofibroblastic lesions of the breast, such as fibromatosis and inflammatory
      myofibroblastic tumour, were analysed to assess whether h-caldesmon expression
      parallels that observed in their soft tissue counterparts. METHODS AND RESULTS:
      Paraffin-embedded sections from 12 cases of myofibroblastoma, seven cases of
      fibromatosis, and one case of inflammatory myofibroblastic tumour were evaluated
      immunocytochemically for the expression of h-caldesmon. As expected, all
      myofibroblastic lesions failed to express h-caldesmon. Conversely, focal
      staining, ranging from 2% to 10% of neoplastic cells, was detected in
      myofibroblastomas, even though it was restricted to 50% of analysed cases.
      CONCLUSIONS: Our results, indicating that smooth muscle differentiation occurs in
      a minority of the myofibroblastoma cells exclusively in half of the analysed
      cases, support the separation of myofibroblastoma from leiomyoma. The detection
      of smooth muscle cells in breast myofibroblastoma is easily explained if we
      postulate its histogenesis from the CD34+ fibroblasts of mammary stroma capable
      of multidirectional mesenchymal differentiation, including smooth muscle. We
      recommend retention of the term myofibroblastoma for all the desmin-positive
      and/or alpha-smooth muscle actin-positive spindle cell tumours of the breast
      consistent with the previously well-established morphological criteria for such
      neoplasms, unless one is dealing with a typical leiomyoma easily recognizable at
      light microscopy.

PMID- 12605640
TI  - The immunohistochemical expression pattern of Chk2, p53, p19INK4d, MAGE-A4 and
      other selected antigens provides new evidence for the premeiotic origin of
      spermatocytic seminoma.
AB  - AIMS: Spermatocytic seminoma is a rare germ cell derived tumour of the testis
      that occurs mainly in older men. We analysed the expression of recently
      discovered markers for germ cell differentiation and the mitosis-meiosis
      transition in order to define the antigen profile for diagnostic purposes and to
      clarify the biology and histogenesis of spermatocytic seminoma. METHODS AND
      RESULTS: Twenty-five spermatocytic seminomas were examined for
      immunohistochemical expression of germ cell-specific onco-fetal antigens and
      proteins involved in regulation of germ cell division, DNA repair and
      differentiation. The panel included Chk2, p19INK4d, p53, MAGE-A4, KIT, TRA-1-60,
      neurone-specific enolase and placental-like alkaline phosphatase. Four of these
      proteins/antigens have never before been investigated in spermatocytic seminoma.
      Proteins highly expressed in gonocytes and spermatogonia, such as Chk2, MAGE-A4
      and neurone-specific enolase, were consistently present in spermatocytic
      seminoma. Antigens expressed in embryonic germ cells but not in the normal adult
      testis, e.g. TRA-1-60, were undetectable, with the exception of p53 protein,
      which was demonstrated in 80% of cases. A proto-oncogene p19INK4d, which is
      involved in the transition from mitotic to meiotic division in germ cells, was
      not detected in spermatocytic seminoma. CONCLUSIONS: The investigation provided
      new information concerning the expression of Chk2, MAGE-A4, neurone-specific
      enolase and p19INK4d in spermatocytic seminoma. The pattern of expression is
      highly consistent with the origin of spermatocytic seminoma from a premeiotic
      germ cell, which has lost embryonic traits and has committed to spermatogenic
      lineage but has not yet passed the meiotic checkpoint, most probably from the
      spermatogonium of the adult testis.

PMID- 12605643
TI  - Association of histochemical expression of Maackia amurensis leukoagglutinin
      positive glycoconjugates with behaviour of human gastric cancer.
AB  - AIMS: To investigate the relationship between sialylation of glycoconjugates and
      clinicopathological characteristics of gastric cancer. METHODS AND RESULTS:
      Sialylation of glycoconjugates was examined histochemically in 71 gastric cancers
      using Maackia amurensis leukoagglutinin (MAL), a lectin that recognizes the
      trisaccharide sequence NeuAc alpha 2,3Gal beta 1,4GlcNAc/Glc. Positive staining
      with MAL was observed in the tumour region of all of the samples, but the
      populations of MAL-positive tumour cells in the tumour region varied among the
      samples. In the corresponding non-cancerous regions, however, no positive
      staining was observed. Calculating the percentage of MAL-positive tumour cells as
      part of the total tumour cells with respect to the MAL-staining index (MI)
      allowed the gastric cancer to be classified into two distinct groups: high and
      low levels of MI, with a cut-off level of 40% of MI. Furthermore, statistical
      analyses using the MI level and clinicopathological characteristics of the tumour
      indicated that a high MI level in gastric tumour tissues is related to a poorer
      prognosis. CONCLUSIONS: The appearance of MAL-positive glycoconjugates in gastric
      tumour cells is associated with the behaviour of gastric cancer.

PMID- 12605645
TI  - Clinicopathological features of nine cases of non-cirrhotic portal hypertension:
      current definitions and criteria are inadequate.
AB  - AIMS: The clinicopathological features of nine patients with non-cirrhotic portal
      hypertension were studied and an attempt was made to apply the descriptive
      criteria of experts to the morphological alterations of the livers in order to
      classify them adequately. METHODS AND RESULTS: Clinical and biochemical data and
      the alterations in livers resected at transplantation (n=7) or at autopsy (n=2)
      were gathered in five males and four females (ages 15-78 years) without
      aetiological factors for chronic hepatic disease who had oesophageal varices and
      splenomegaly in the absence of typical cirrhosis. Noting the luminal obstruction
      of the three hepatic vascular trees, hyperplastic nodule size and distribution,
      and the density of fibrosis, an attempt was made to assign each case to one of
      the following diagnostic categories: idiopathic portal hypertension, diffuse
      nodular regenerative hyperplasia, partial nodular transformation and incomplete
      septal cirrhosis. When a case could not be categorized into one of these groups,
      it was listed as non-cirrhotic irregular architectural transformation. Only three
      cases could be assigned to one pure diagnostic category (two diffuse nodular
      regenerative hyperplasias and one incomplete septal cirrhosis). Three other cases
      could not be classified due to the heterogeneity of their lesions. In the
      remaining three cases, the hepatic morphology was a mixture of hilar partial
      nodular transformation combined with another abnormal architectural pattern in
      the peripheral parenchyma: diffuse nodular regenerative hyperplasia in two cases
      and idiopathic portal hypertension in the other. In seven cases, old thromboses
      in the hilar portal tree were observed. Stenoses were observed in some of the
      arterial branches in five cases and in some hepatic venous branches in four.
      However, no obstructions could be discovered in small or large portal veins in
      the two classical diffuse nodular regenerative hyperplasia cases. CONCLUSIONS:
      The hepatic morphology in this group of non-cirrhotic portal hypertension
      patients was an abnormal remodelling of the liver associated with the frequent
      development of irregular hyperplastic nodules and frequent obstructions of the
      pre- and intrahepatic vascular lumens. It was very difficult to apply the
      nomenclature proposed by international experts.

PMID- 12605644
TI  - Erythropoietin as an angiogenic factor in gastric carcinoma.
AB  - AIMS: Previous studies have shown that increased vascularity is associated with
      haematogenous metastasis and poor prognosis in gastric cancer. The role of
      erythropoietin (Epo) in angiogenesis has not been completely clarified, although
      its involvement has been reported. In this study we correlated microvascular
      density and Epo receptor (Epo-R) expression in endothelial and tumour cells with
      histopathological type in gastric cancer. METHODS AND RESULTS: Specimens of
      primary gastric adenocarcinomas obtained from 40 patients who had undergone
      curative gastrectomy were investigated immunohistochemically by using anti-CD31
      and anti-Epo-R antibodies. Stage IV gastric carcinoma had a higher degree of
      vascularization than other stages, and Epo-R expression in both endothelial and
      tumour cells increased in parallel with malignancy grade and was highly
      correlated with the extent of angiogenesis. CONCLUSIONS: Epo-R level correlates
      with angiogenesis and progression of patients with gastric carcinoma and we
      suggest that Epo might have a trophic effect on the vasculature of the
      gastrointestinal tract. Understanding mechanisms of gastric cancer angiogenesis
      provides a basis for a rational approach to the development of an anti-angiogenic
      therapy in patients with gastric cancer.

PMID- 12605646
TI  - The pathology of acute hepatic disintegration in hereditary haemorrhagic
      telangiectasia.
AB  - AIMS: Hereditary haemorrhagic telangiectasia is a rare inherited disease in which
      telangiectases affect skin, mucous membranes and the gastrointestinal tract.
      Hepatic involvement is common but usually asymptomatic. We report a case of acute
      hepatic disintegration in hereditary haemorrhagic telangiectasia, document the
      histopathological findings and present a hypothesis to explain them. METHODS AND
      RESULTS: The patient presented at the age of 34 years with abdominal pain,
      leading to the surgical removal of a severely inflamed gallbladder. Signs of
      liver damage became increasingly apparent over the next few weeks, with
      disruption of the intrahepatic biliary tree and marked vascular shunting,
      necessitating liver transplantation. Six months after the transplant a diagnosis
      of hepatic hereditary haemorrhagic telangiectasia was made. The principal
      features of hepatic hereditary haemorrhagic telangiectasia are periportal
      telangiectases and sinusoidal congestion and dilatation. Acute hepatic
      disintegration is characterized by disruption of liver structure, hepatocyte
      necrosis, haemorrhage and extravasation of bile. CONCLUSIONS: Periportal
      telangiectases in a liver biopsy are highly suggestive of hereditary haemorrhagic
      telangiectasia. Acute hepatic disintegration is likely to be a consequence of
      rupture of telangiectases and ischaemic necrosis of intrahepatic bile ducts.
      Patients with hereditary haemorrhagic telangiectasia are at risk of acute hepatic
      disintegration following intra-abdominal sepsis.

PMID- 12605647
TI  - Sarcomatoid mesothelioma and its histological mimics: a comparative
      immunohistochemical study.
AB  - AIMS: Differentiating sarcomatoid mesothelioma from other pleural-based spindle
      cell tumours by light microscopy can be challenging, especially in a biopsy. The
      role of immunohistochemistry in this differential diagnosis is not as well
      defined as it is for distinguishing epithelioid mesothelioma from adenocarcinoma.
      In this study, we investigate the utility of diagnostic immunohistochemistry for
      distinguishing sarcomatoid mesothelioma from its histological mimics, high-grade
      sarcoma and pulmonary sarcomatoid carcinoma. METHODS: We stained 20 mesotheliomas
      with sarcomatoid components (10 biphasic and 10 sarcomatoid mesotheliomas) for
      pan-cytokeratin, cytokeratin 5/6, calretinin, WT-1, thrombomodulin, and smooth
      muscle actin. Intensity and distribution of staining were assessed using a
      semiquantitative scale. Only tumours with unequivocal staining were considered
      positive for tabulation. We compared the immunophenotypic profiles of these
      tumours with 24 high-grade sarcomas, 10 pulmonary sarcomatoid carcinomas, and 16
      epithelioid mesotheliomas. The sarcomatoid carcinomas were also stained for
      thyroid transcription factor-1 (TTF-1). RESULTS: Pan-cytokeratin stained 70% of
      sarcomatoid mesotheliomas, 17% of sarcomas, 90% of sarcomatoid carcinomas, and
      100% of epithelioid mesotheliomas. Cytokeratin 5/6 and WT-1 stained most
      epithelioid mesotheliomas, but rarely stained sarcomas, sarcomatoid carcinomas,
      or the sarcomatoid components of mesothelioma. Calretinin and thrombomodulin each
      stained 70% of sarcomatoid mesotheliomas. However, calretinin was also positive
      in 17% of sarcomas and in 60% of sarcomatoid carcinomas, while thrombomodulin was
      positive in 38% of sarcomas and in 40% of sarcomatoid carcinomas. Smooth muscle
      actin was expressed in 60% of sarcomatoid mesotheliomas and in 58% of sarcomas,
      but in only 10% of sarcomatoid carcinomas. All 10 sarcomatoid carcinomas were
      negative for TTF-1. CONCLUSIONS: Mesothelioma shows decreased expression of
      epithelial and mesothelial epitopes in its sarcomatoid components. A wide
      immunophenotypic overlap exists among sarcomatoid mesotheliomas, sarcoma, and
      sarcomatoid carcinomas. Cytokeratin and calretinin have the most value in
      differentiating sarcomatoid mesothelioma from sarcoma. However, because
      sarcomatoid mesothelioma can occasionally be cytokeratin-negative, the
      distinction between it and sarcoma may become arbitrary. With the exception of
      smooth muscle actin, all the markers studied showed similar distributions in
      sarcomatoid mesothelioma and sarcomatoid carcinoma, including frequent calretinin
      and thrombomodulin expression in both tumours. Thus, immunohistochemistry plays a
      more limited role in the differential diagnosis of sarcomatoid tumours compared
      with epithelioid tumours. For sarcomatoid tumours involving the pleural lining,
      clinicopathological data, especially information about the gross appearance of
      the tumour (i.e. localized versus diffuse pleural-based mass), should be noted
      and carefully correlated with microscopic and immunohistochemical findings.

PMID- 12605648
TI  - Over-expression of tenascin-C in malignant pleural mesothelioma.
AB  - AIMS: Tenascin-C is an extracellular matrix glycoprotein known to have anti
      adhesive characteristics and to be expressed in various human malignant
      neoplasms. We hypothesized that the expression of tenascin-C would be increased
      in human malignant pleural mesothelioma, and its accumulation associated with the
      prognosis of the patients with this disease. METHODS AND RESULTS: Thirty-seven
      cases of mesothelioma were studied by immunohistochemically using a monoclonal
      antibody against tenascin-C, and with a semiquantitative scoring system for
      tenascin-C in different areas of the tumours. In 10 selected cases tenascin-C
      mRNA in-situ hybridization was also analysed. Since transforming growth factor
      beta (TGF-beta) is known to induce both the synthesis of tenascin-C and the
      growth of mesotheliomas, an immunohistochemical analysis of TGF-beta 1, -beta 2
      and -beta 3 was also performed. Normal pleura (n = 7) and metastatic pleural
      adenocarcinomas (n = 7) were used as controls. Tenascin-C protein was expressed
      in every histological subtype of malignant mesothelioma, being most prominent in
      the fibrotic stroma of a tumour, around tumour cells and at the invasive border,
      whereas tenascin-C mRNA was scarce in tumour cells. The patients with less
      immunohistochemical expression for tenascin-C tended to live longer (P = 0.028 by
      Fishers' exact probability test). All mesotheliomas showed positivity for at
      least one isoform of TGF-beta. CONCLUSIONS: In conclusion, high expression of
      tenascin-C protein in malignant pleural mesotheliomas may play a role in its
      invasive growth, and might serve as a prognostic marker of the disease.

PMID- 12605649
TI  - Follicular lymphoma with marginal zone differentiation: cytogenetic findings in
      support of a high-risk variant of follicular lymphoma.
AB  - AIMS: The pathogenesis and clinical significance of marginal zone differentiation
      in follicular lymphoma remains to be determined, although genetic alterations are
      likely to be important determinants of both. We therefore report the cytogenetic
      findings in three cases of follicular lymphoma with marginal zone differentiation
      studied by routine karyotyping and in-situ hybridization. METHODS AND RESULTS:
      The morphology and immunophenotype of each case was typical of follicular
      lymphoma displaying marginal zone differentiation. Karyotyping, performed on GTL
      banded preparations of cell cultures derived from fresh lymph node tissue,
      revealed a complex karyotype in all three cases, including t(14;18)(q32;q21) and
      abnormalities associated with progression and/or transformation of follicular
      lymphoma. In addition, trisomy 3 was found in one case and translocations between
      the q27-29 region of chromosome 3 and chromosome 2 in the other two cases; the
      latter was identified only in subclones derived from less complex stem lines
      possessing t(14;18). In-situ hybridization, performed on sections cut from
      routinely processed paraffin-embedded tissue blocks, localized cells possessing
      these abnormalities of chromosome 3 to both the follicular and marginal zone
      components of two lymphomas studied in this way. CONCLUSIONS: Trisomy 3 and
      alterations involving the q27-29 region of chromosome 3 are implicated in the
      pathogenesis of de novo marginal zone lymphoma. Their presence in the current
      cases indicates that they may also be responsible for marginal zone
      differentiation in follicular lymphoma when cells harbouring these genetic
      alterations are exposed to the appropriate microenvironment. Our findings are
      consistent with follicular lymphoma with marginal zone differentiation as a high
      risk variant of follicular lymphoma.

PMID- 12605650
TI  - Utility of immunohistochemistry for CD99 in the identification of matrix
      producing carcinoma of the breast.

PMID- 12605651
TI  - Cervical polyp with eccrine syringofibroadenoma-like features.

PMID- 12605652
TI  - Foamy cells in endometrial stromal tumours: not all of them are histiocytes.

PMID- 12605653
TI  - Intrapulmonary lipomas: report of four cases.

PMID- 12605654
TI  - The role of mast cells in glomus tumours: report of a case of an intramuscular
      glomus tumour with a prominent mastocytic component.

PMID- 12605656
TI  - Longitudinal trends of hemoglobin levels in a Japanese population--RERF's Adult
      Health Study subjects.
AB  - Conflicting results have been reported on the long-term relationship between
      hemoglobin (Hb) level and age. We analyzed that relationship over a 40-yr period
      in a Japanese population, adjusting for the effects of sex, birth cohort,
      smoking, and anemia-associated diseases. We used Hb levels measured biennially
      between 1958 and 1998 for 4858 Adult Health Study subjects of the Radiation
      Effects Research Foundation. Using the mixed-effects model, we showed that the
      aging Hb profile varied by sex (P < 0.001) and birth cohort (P < 0.001). Male Hb
      levels peaked in the third and fourth decades and then decreased while female Hb
      levels dipped slightly in the third decade, peaked in the sixth and seventh, and
      then decreased. Levels were higher in younger cohorts. The rate of Hb decline
      after the sixth decade of life was greater for subjects with anemia-associated
      diseases (P = 0.002). The annual rate of decline between 70 and 80 yr of age for
      disease-free men ranged from 0.083 to 0.042 g/dL and for disease-free women from
      0.049 to 0.036 g/dL. Levels were higher for ever-smokers (P < 0.001), more so for
      women than men. A decreasing trend in Hb concentration with advancing age was
      detected for elderly men and women after controlling for anemia-associated
      diseases, suggesting that anemia in the elderly is due not only to disease but
      also to aging. Cohort and smoking effects on Hb levels were also observed.

PMID- 12605657
TI  - Effect of recombinant human deoxyribonuclease on the expression of cell adhesion
      molecules of thawed and processed cord blood hematopoietic progenitors.
AB  - BACKGROUND AND OBJECTIVES: The integrity of granulocytic cells and platelets is
      compromised within cryopreserved stem cell transplants, and consequent DNA
      release during the thawing procedure can therefore lead to clotting phenomena or
      microaggregate formation and that in turn may cause loss of progenitor cells. To
      circumvent this problem a new processing protocol was introduced using
      recombinant human deoxyribonuclease (rhDNase) to prevent cell aggregate
      formation. In addition, the impact of this new processing protocol on CD34+
      umbilical cord blood (UCB) cells was assessed. MATERIALS AND METHODS: Fifty
      samples derived from 7 buffy coat (BC) volume reduced UCB units were
      cryopreserved, thawed, and processed with washing solutions that were
      supplemented with rhDNase in various concentrations. Thereafter, clotting and
      microaggregate formation was scored microscopically. In addition, expression of
      the adhesion molecules leukocyte function-associated antigen 1 (LFA-1, n = 6),
      intercellular adhesion molecule-1 (ICAM-1, n = 11), and L-selectin (n = 11) on
      CD34+ UCB cells was analyzed by flow cytometry after incubating the samples with
      either dimethyl sulfoxide (DMSO) 5.5%, rhDNase 10 or 50 U/mL, or a combination of
      DMSO 5.5% and rhDNase 50 U/mL. RESULTS: At a minimal concentration of 10 U
      rhDNase/mL, clotting or microaggregate formation could be prevented for all
      tested samples, whereas cell clots could be observed for concentrations up to 8
      U/mL. The expression of adhesion molecules on untreated CD34+ UCB cells (L
      selectin: 64.6 +/- 18.8%; LFA-1: 62.6 +/- 7.5%; ICAM-1: 14.8 +/- 4.1%) did not
      show any significant difference compared with cells that were incubated with up
      to 50 U/mL rhDNase (L-selectin: 62.2 +/- 19.3%; LFA-1: 63.1 +/- 5.9%; ICAM-1:
      17.5 +/- 6.7%). However, after a combined treatment with DMSO 5.5% and rhDNase 50
      U/mL, a slight but significant decrease in L-selectin expression could be
      observed (P < 0.03). CONCLUSION: The supplementation of rhDNase to a final
      concentration of 10 U/mL cell suspension proved to be effective in preventing
      clot formation under the conditions examined and did not lead to decreased
      expression levels of adhesion molecules. We therefore recommend the use of
      rhDNase for the prevention of clot formation and cell loss during the processing
      of thawed UCB transplants.

PMID- 12605658
TI  - Expression of genes regulating angiogenesis in human circulating hematopoietic
      cord blood CD34+/CD133+ cells.
AB  - OBJECTIVES: Human CD34+ cells represent a heterogeneous population of immature
      cells which may differentiate to various cell types. The aim of the study was to
      determine angiogenesis regulating genes expression in CD34+ cells, their
      subpopulations, and during their differentiation induced by hematopoietic growth
      factors. MATERIAL AND METHODS: We have measured the expression of angiogenesis
      regulating genes angiopoietin-1 (Ang-1), angiopoietin-1 (Ang-2) and their
      receptor Tie-2, vascular endothelial growth factor (VEGF) and its receptors VEGFR
      1 and VEGFR-2 in sorted population of CD34+ and CD34+/CD133+ cells from human
      cord blood and bone marrow, and in their differentiating progeny, using real time
      reverse transcriptase polymerase chain reaction. The hematopoietic
      differentiation of CD34+ cells was induced in semisolid or liquid differentiation
      supporting media containing appropriate hematopoietic growth factors. RESULTS: A
      higher expression of Ang-1, Ang-2, and Tie-2 mRNAs was detected in CD34+/CD133+
      cord blood cells as compared with CD34-/CD133- fraction, but no expression of
      these genes was detected in burst-forming unit erythroid (BFU-E) nor colony
      forming unit granulocyte macrophage (CFU-GM) colonies. The level of Ang-1 and Tie
      2 mRNAs, but not that of Ang-2 mRNA gradually decreased during a 14-d incubation
      of cord blood CD34+ cells in a liquid culture. A significantly higher expression
      of VEGF mRNA was in BFU-E as compared with CFU-GM cell colonies and CD34+/CD133+
      cells. VEGFR-1 mRNA was equally expressed in CD34+/CD133+ and CD34-/CD133- cells
      as well as in BFU-E and CFU-GM colonies. Expression of VEGFR-2 mRNA was detected
      at the borderline of method sensitivity only in CD34+/CD133+ cells. CONCLUSION:
      CD34+/CD133+ cord blood cells express Ang-1, Ang-2 and VEGF as well as their
      receptor mRNAs, suggesting a role of these cells in regulation both angiopoiesis
      and hematopoiesis.

PMID- 12605659
TI  - Long-term hydroxyurea therapy in beta-thalassaemia patients.
AB  - OBJECTIVE: The study aimed to investigate the use of hydroxyurea (HU) for the
      treatment of beta-thalassaemia (beta-thal) patients. METHODS: We examined the
      haematological effects of orally administered HU (10-20 mg/kg/d) in 11 patients,
      including four beta-thal major and seven beta-thal intermedia patients. Complete
      blood count and levels of foetal haemoglobin (HbF), liver enzymes and serum
      creatinine were evaluated before and during HU. Response to therapy was evaluated
      at 6 months of treatment. RESULTS: A substantial increase in haemoglobin (Hb)
      level (4.1 g/dL), leading to complete withdrawal from a regular transfusion
      programme, was observed in one unique beta-thal major patient. In the beta-thal
      intermedia patients, increases in Hb level of 1.3, 1.9 and 2.0 g/dL were observed
      in three of seven (42.9%) patients during HU therapy. The mean values of Hb, mean
      corpuscular haemoglobin (MCH), and HbF were higher during HU treatment than
      baseline values (8.7 vs. 7.7 g/dL, P = 0.05; 26.7 vs. 22.9 pg, P = 0.05; 57.2 vs.
      44.9%, P = 0.04; respectively). In contrast, the mean reticulocyte count measured
      during therapy decreased (97.0 x 10(9) vs. 632.0 x 10(9)/L, P = 0.03). No
      correlations were observed between levels of Hb and HbF (r = 0.77, P = 0.10), and
      levels of Hb and reticulocyte counts (r = 0.26, P = 0.31). No significant
      toxicity was observed in our patients. CONCLUSION: These results suggest that HU
      may improve Hb levels in beta-thal. Thus, we may conclude that a large trial
      concerning the response to HU in these patients should be carried out to clarify
      this issue.

PMID- 12605660
TI  - CD95 (APO-1/FAS) deficiency in infant acute lymphoblastic leukemia: detection of
      novel soluble Fas splice variants.
AB  - Fas (APO-1/CD95) is a 45-kDa membrane protein which regulates apoptosis in many
      lymphoid cell types. In the present study, FAS expression was examined in primary
      leukemic cells from infants with acute lymphoblastic leukemia (ALL). The cells
      were resistant to apoptosis induction by an anti-FAS antibody and expressed
      nearly undetectable amounts of FAS protein. Molecular analysis of FAS transcripts
      in these cells revealed no detectable expression of full-length Fas mRNA after a
      single round of reverse transcription and polymerase chain reaction (PCR)
      amplification (RT-PCR). However, a more sensitive nested RT-PCR analysis revealed
      alternatively spliced Fas transcripts in three of five infants (60%) with the
      remaining two infants showing no detectable Fas mRNA expression. The primary
      sequence variation of Fas mRNA seen in the samples was a previously described
      variant lacking exon 6 encoding soluble FAS. However, we also detected the
      presence of several novel alternatively spliced FAS transcripts in the ALL cells.
      In one patient, we observed a novel spliced form of soluble Fas, which not only
      lacked exon 6 but also contained an insertion of an alternative exon 7 (exon 7B).
      In another, a novel exon 4Del FAS mRNA variant was observed, which contained an
      additional 4-bp deletion at the exon 5/6-splice junction. These variants lack
      intact transmembrane domains and thus are predicted to encode soluble FAS
      variants. The low level of expression of functional full length FAS transcripts
      with corresponding low level of FAS protein expression in the ALL cells
      contribute to their resistance to CD95-mediated apoptosis.

PMID- 12605661
TI  - Early and intermediate stage Hodgkin's lymphoma--report from the Swedish National
      Care Programme.
AB  - In Sweden a National Care Programme provides treatment principles for Hodgkin's
      lymphoma (HL) since 1985, for early and intermediate stages often less extensive
      than international recommendations. The purpose is to evaluate long-term results
      of these principles. A total of 308 patients (167 men and 141 women), 17-59 yr
      old (median 31), diagnosed during 1985-92, pathological stage (PS) I-III1A and I
      IIB and clinical stage (CS) I-IIA, mean follow-up 8.8 yr, were studied. Staging
      laparotomy was recommended in CS IIA. Recommended treatment was mantle or mini
      mantle radiotherapy (RT) alone in CS IA, and PS I-IIA and subtotal nodal
      irradiation in PS III1A if the disease was not bulky. Patients in PS I-IIA and
      III1A with bulky disease, and PS I-IIB received one cycle of mechlorethamine,
      vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine,
      lacarbazine (MOPP/ABVD) before irradiation. The remaining patients received three
      to four cycles of MOPP/ABVD with RT to bulky disease. Relapse-free (RFS), Hodgkin
      specific (HLS), and overall survival (OS) at 10 yr were 74%, 92% and 85%. In the
      individual stages, RFS ranged from 53% (PSIII1A) to 90% (PS IA). RFS (P = 0.006),
      HLS, and OS were significantly better in patients treated with chemotherapy
      compared with those treated with RT alone, especially in patients with bulky
      disease (P = 0.0005). The international prognostic score did not provide any
      prognostic information. The OS rates are in agreement with results from
      international centres during that time. The recommended treatment was sufficient
      to produce the desired results of <20-30% recurrences, except in PS III1A. Most
      relapses could be salvaged. Patients with risk factors treated with one MOPP/ABVD
      and RT had an excellent outcome, superior to those without risk factors treated
      with RT alone. These results favour the trend to treat early and intermediate
      stages with a short course of chemotherapy followed by limited RT.

PMID- 12605662
TI  - Acquired haemophilia in HIV negative, HHV-8 positive multicentric Castleman's
      disease: a case report.
AB  - Multicentric Castleman's Disease (MCD) is an atypical lymphoproliferative
      disorder, related to human herpesvirus 8 (HHV-8) infection and often associated
      with autoimmune diseases such as haemolytic anaemia and thrombocytopenia.
      Acquired haemophilia (AH) is a rare, life-threatening disease, which can occur in
      association with lymphoproliferative disorders, although only one case of AH in
      MCD has been described so far. We report the case of a human immuno deficiency
      virus negative 71-yr-old woman referred to our hospital for prolonged bleeding on
      surgical site following a lymph node biopsy. Lymph node histology revealed MCD,
      while the screening for the bleeding disorder showed prolonged activated partial
      thromboplastin time (APTT) (ratio: 1.89, normal value <1.24), low factor VIII
      (FVIII:C) levels (6%) with anti-factor VIII antibodies (2.3 Bethesda units),
      leading to a diagnosis of AH. Virological studies on plasma, lymphocyte and
      bronchoalveolar wash showed positivity for HHV-8 infection. Treatment with
      steroids (metilprednisolone 1-1.5 mg/kg/d) and cyclophosphamide (100 mg/d orally)
      was unsuccessful, and then antiviral therapy with cidofovir (5 mg/kg/wk) was
      started. A transient normalisation of APTT was seen after two administrations of
      cidofovir, but then coagulation parameters worsened and a large haematoma of the
      arm appeared. Bleeding was successfully stopped with two boluses of recombinant
      activated factor VII (Novoseven 90 microg/kg). Therapy with anti-CD 20 monoclonal
      antibody rituximab (Mabthera 375 mg/m2 once a week for 4 wk) was started, and
      following two administrations APTT normalised once again. Cardiological and
      neurological complications arose before the third dose of rituximab and the
      patient died shortly afterwards.

PMID- 12605663
TI  - Rituximab induces remission of cerebral ischemia caused by thrombotic
      thrombocytopenic purpura.
AB  - OBJECTIVE: This report describes the experience of a case of atypical thrombotic
      thrombocytopenic purpura (TTP) whose diagnosis was based on severe deficiency of
      the von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13. METHODS: The
      level of ADAMTS13 activity, the titer of the inhibitors of this protease and the
      size distribution of vWF multimers in plasma samples were analysed in a patient
      with recurrent episodes of dizziness and blurred vision. RESULTS: In the absence
      of thrombocytopenia or microangiopathic hemolysis, diagnosis of TTP was
      established by demonstration of very low ADAMTS13 activity levels and the
      presence of inhibitors of this protease. After rituximab therapy decreased the
      inhibitor titer and increased the ADAMTS13 level, the patient has had no relapse
      of ischemic symptoms in the following 16 months. CONCLUSIONS: Acute neurological
      deficits may occur in TTP without concurrent thrombocytopenia or microangiopathic
      hemolysis. The role of rituximab for patients with TTP deserves further
      exploration.

PMID- 12605665
TI  - Granulocytic sarcoma of the pancreas successfully treated with intensive
      chemotherapy and stem cell transplantation.
AB  - A case of preleukemic granulocytic sarcoma of pancreas is presented. Pancreas is
      a well described site of secondary metastasis of solid tumors, but occasionally
      it has been reported as the primary site of leukemia. Like other cases reported
      in the literature, the present case was initially misdiagnosed as malignant
      lymphoma. We highlight the importance of an accurate immunohistochemical
      diagnosis and of an early and intensive acute myeloid leukemia-like treatment for
      these cases representing an uncommon and aggressive form of acute leukemia.

PMID- 12605664
TI  - Complete remission of pure white cell aplasia associated with thymoma, autoimmune
      thyroiditis and type 1 diabetes.
AB  - Pure white cell aplasia (PWCA) is a rare disorder of unknown origin, often
      associated with thymoma, characterized by selective neutropenia or pure
      agranulocytosis, and absence of granulocyte precursors in the bone marrow, but
      with normal erythroblasts and megakaryocytes. We report a case of PWCA associated
      with thymoma. Unusual findings in this case report included simultaneous presence
      of autoimmune thyroiditis, type 1 diabetes, anti-striated muscle antibodies, and
      the presence in the peripheral blood of CD8+ T cells that expressed a homogeneous
      naive phenotype. Neutrophil count became normal on immunosuppressive therapy
      after thymectomy.

PMID- 12605666
TI  - Lymphoma-associated haemophagocytic syndrome with jaundice and generalised skin
      involvement.

PMID- 12605667
TI  - Hepatitis C virus-related adult chronic idiopathic thrombocytopenic purpura:
      experience from a single Chinese center.

PMID- 12605668
TI  - Can thalidomide be effective to treat plasma cell leptomeningeal infiltration?

PMID- 12605669
TI  - The -148 to -124 region of c-jun interacts with a positive regulatory factor in
      rat liver and enhances transcription.
AB  - The c-jun gene encodes the protein Jun, a component of the essential
      transcription factor, AP1. Jun/AP-1 occupies a central position in signal
      transduction pathways as it is responsible for the induction of a number of genes
      in response to growth promoters. However, the exact mechanisms leading to an
      enhanced expression of the c-jun gene itself during proliferation,
      differentiation, cell growth and development are not fully understood. Cell
      culture studies have given some insight in the mechanisms involved in the up
      regulation of c-jun expression by UV irradiation and phorbol esters. However, it
      is well known that transformed cells do not accurately reflect the biology of a
      normal cell. We now report the identification of a positive regulatory factor
      from normal rat liver that activates transcription from the c-jun promoter by
      binding to the -148 to -124 region of c-jun. Preincubation of fractionated rat
      liver nuclear extract with an oligonucleotide encompassing this region of the
      gene significantly reduced transcription from cloned c-jun promoter. In vitro
      transfection studies using green fluorescent protein as a reporter gene under the
      control of the c-jun promoter with (-148 to +53) and without (-123 to +53) this
      region further confirmed its role in transcription. A DNA-binding protein factor,
      interacting with this region of c-jun was identified from rat liver by using
      electrophoretic mobility shift assays. This factor binds to its recognition
      sequence only in the phosphorylated form and exhibits high affinity and
      specificity. UV cross-linking studies, South-Western analysis and affinity
      purification collectively indicated the factor to be approximately 40 kDa and to
      bind to its recognition sequence as a dimer.

PMID- 12605670
TI  - Proteomic identification of all plastid-specific ribosomal proteins in higher
      plant chloroplast 30S ribosomal subunit.
AB  - Six ribosomal proteins are specific to higher plant chloroplast ribosomes
      [Subramanian, A.R. (1993) Trends Biochem. Sci.18, 177-180]. Three of them have
      been fully characterized [Yamaguchi, K., von Knoblauch, K. & Subramanian, A. R.
      (2000) J. Biol. Chem. 275, 28455-28465; Yamaguchi, K. & Subramanian, A. R. (2000)
      J. Biol. Chem. 275, 28466-28482]. The remaining three plastid-specific ribosomal
      proteins (PSRPs), all on the small subunit, have now been characterized (2D PAGE,
      HPLC, N-terminal/internal peptide sequencing, electrospray ionization MS,
      cloning/ sequencing of precursor cDNAs). PSRP-3 exists in two forms (alpha/beta,
      N-terminus free and blocked by post-translational modification), whereas PSRP-2
      and PSRP-4 appear, from MS data, to be unmodified. PSRP-2 contains two RNA
      binding domains which occur in mRNA processing/stabilizing proteins (e.g. U1A
      snRNP, poly(A)-binding proteins), suggesting a possible role for it in the
      recruiting of stored chloroplast mRNAs for active protein synthesis. PSRP-3 is
      the higher plant orthologue of a hypothetical protein (ycf65 gene product), first
      reported in the chloroplast genome of a red alga. The ycf65 gene is absent from
      the chloroplast genomes of higher plants. Therefore, we suggest that Psrp
      3/ycf65, encoding an evolutionarily conserved chloroplast ribosomal protein,
      represents an example of organelle-to-nucleus gene transfer in chloroplast
      evolution. PSRP-4 shows strong homology with Thx, a small basic ribosomal protein
      of Thermus thermophilus 30S subunit (with a specific structural role in the
      subunit crystallographic structure), but its orthologues are absent from
      Escherichia coli and the photosynthetic bacterium Synechocystis. We would
      therefore suggest that PSRP-4 is an example of gene capture (via horizontal gene
      transfer) during chloro-ribosome emergence. Orthologues of all six PSRPs are
      identifiable in the complete genome sequence of Arabidopsis thaliana and in the
      higher plant expressed sequence tag database. All six PSRPs are nucleus-encoded.
      The cytosolic precursors of PSRP-2, PSRP-3, and PSRP-4 have average targeting
      peptides (62, 58, and 54 residues long), and the mature proteins are of 196, 121,
      and 47 residues length (molar masses, 21.7, 13.8 and 5.2 kDa), respectively.
      Functions of the PSRPs as active participants in translational regulation, the
      key feature of chloroplast protein synthesis, are discussed and a model is
      proposed.

PMID- 12605671
TI  - Upstream and intronic regulatory sequences interact in the activation of the
      glutamine synthetase promoter.
AB  - Glutamine synthetase (GS) is expressed at high levels in subsets of cells in some
      tissues and at low levels in all cells of other tissues, suggesting that the GS
      gene is surrounded by multiple regulatory elements. We searched for such elements
      in the 2.5-kb upstream region and in the 2.6-kb first intron of the GS gene,
      using FTO-2B hepatoma and C2/7 muscle cells as representatives of both cell types
      and transient transfection assays as our tools. In addition to the entire
      upstream region and entire intron, an upstream enhancer module at -2.5 kb, and
      5', middle and 3' modules of the first intron were tested. The main effects of
      the respective modules and their combinatorial interactions were quantified using
      the analysis of variance (anova) technique. The upstream enhancer was strongly
      stimulatory, the middle intron module strongly inhibitory, and the 3'-intron
      module weakly stimulatory in both hepatoma and muscle cells. The 5'-intron module
      was strongly stimulatory in muscle cells only. The major new finding was that in
      both cell types, the upstream enhancer and 5'-intron module needed to be present
      simultaneously to fully realize their transactivational potencies. This
      interaction was responsible for a pronounced inhibitory effect of the 5'-intron
      module in the absence of the upstream enhancer in hepatoma cells, and for a
      strong synergistic effect of these two modules, when present simultaneously in
      muscle cells. The main difference between hepatoma and muscle cells therefore
      appeared to reside in tissue-specific differences in activity of the respective
      regulatory elements due to interactions rather than in the existence of tissue
      specific regulatory elements.

PMID- 12605672
TI  - Presence of melanocortin (MC4) receptor in spiny dogfish suggests an ancient
      vertebrate origin of central melanocortin system.
AB  - We report the cloning, expression, pharmacological characterization and tissue
      distribution of a melanocortin (MC) receptor gene in a shark, the spiny dogfish
      (Squalus acanthias) (Sac). Phylogenetic analysis showed that this receptor is an
      ortholog of the MC4 subtype, sharing 71% overall amino acid identity with the
      human (Hsa) MC4 receptor. When expressed and characterized by radioligand binding
      assay for the natural MSH (melanocyte-stimulating hormone) peptides alpha-, beta
      , and gamma-MSH, the SacMC4 receptor showed pharmacological properties very
      similar to the HsaMC4 receptor. Stimulation of SacMC4 receptor transfected cells
      with alpha-MSH caused a dose-dependent increase in intracellular cAMP levels. The
      SacMC4 receptor has Ala in position 59 where all other cloned MC receptors have
      Glu. We confirmed that this was not due to individual polymorphism and
      subsequently mutated the residue 'back' to Glu but the mutation did not affect
      the pharmacological properties of the receptor. SacMC4 receptor mRNA was detected
      by RT-PCR in the optic tectum, hypothalamus, brain stem, telencephalon and
      olfactory bulb but not in cerebellum or in peripheral tissues. This study
      describes the first characterization of an MC receptor in a cartilaginous fish,
      the most distant MC receptor gene cloned to date. Conservation of gene structure,
      pharmacological properties and tissue distribution suggests that this receptor
      may have similar roles in sharks as in mammals and that these were established
      more than 450 million years ago.

PMID- 12605673
TI  - Effects of various N-terminal addressing signals on sorting and folding of
      mammalian CYP11A1 in yeast mitochondria.
AB  - Topogenesis of cytochrome p450scc, a resident protein of the inner membrane of
      adrenocortical mitochondria, is still obscure. In particular, little is known
      about the cause of its tissue specificity. In an attempt to clarify this point,
      we examined the process in Saccharomyces cerevisiae cells synthesizing cytochrome
      p450scc as its native precursor (pCYP11A1) or versions in which its N-terminal
      addressing presequence had been replaced with those of yeast mitochondrial
      proteins: CoxIV(1-25) and Su9(1-112). We found the pCYP11A1 and CoxIV(1-25)
      mCYP11A1 versions to be effectively imported into yeast mitochondria and
      subjected to proteolytic processing. However, only minor portions of the imported
      proteins were incorporated into mitochondrial membranes, whereas their bulk
      accumulated as aggregates insoluble in 1% Triton X-100. Along with previously
      published data, this suggests that a distinguishing feature of the import of the
      CYP11A1 precursors into yeast mitochondria is their easy translocation into the
      matrix where the foreign proteins mainly undergo proteolysis or aggregation. The
      fraction of CYP11A1 that happens to be inserted into the inner mitochondrial
      membrane is effectively converted into the catalytically active holoenzyme.
      Experiments with the Su9(1-112)-mCYP11A1 construct bearing a re-export signal
      revealed that, after translocation of the fused protein into the matrix and its
      processing, the Su9(67-112) segment ensures association of the mCYP11A1 body with
      the inner membrane, but proper folding of the latter does not take place. Thus it
      can be said that the most specific stage of CYP11A1 topogenesis in adrenocortical
      mitochondria is its confinement and folding in the inner mitochondrial membrane.
      In yeast mitochondria, only an insignificant portion of the imported CYP11A1
      follows this mechanism.

PMID- 12605674
TI  - A functional polymorphism at the transcriptional initiation site in beta2
      glycoprotein I (apolipoprotein H) associated with reduced gene expression and
      lower plasma levels of beta2-glycoprotein I.
AB  - Human beta2-glycoprotein I (beta2GPI), also known as apolipoprotein H, has been
      implicated in haemostasis and the production of anti-phospholipid antibodies.
      There is a wide range of interindividual variation in beta2GPI plasma levels that
      is thought to be under genetic control, but its molecular basis remains unknown.
      To understand the genetic basis of beta2GPI variation, we analyzed the 5'
      flanking region of the beta2GPI gene for mutation detection by DHPLC and
      identified a point mutation at the transcriptional initiation site (-1C-->A) with
      a carrier frequency of 12.1%. The mutation was associated with significantly
      lower beta2GPI plasma levels (P < 0.0001) and low occurrence of anti-phospholipid
      antibodies in lupus patients (4.8% antibody-positive group vs. 16.6% in the
      antibody-negative group; P = 0.019). Northern blot analysis confirmed that the 
      1C-->A mutation was associated with lower mRNA levels and it reduced the reporter
      (luciferase) gene expression by twofold. Electrophoretic gel mobility shift assay
      (EMSA) revealed that the -1C-->A mutation disrupts the binding for crude hepatic
      nuclear extracts and purified TFIID. These results suggest that the substitution
      of C with A at the beta2GPI transcriptional initiation site is a causative
      mutation that affects its gene expression at the transcriptional level and
      ultimately beta2GPI plasma levels and the occurrence of anti-phospholipid
      antibodies.

PMID- 12605676
TI  - The influence of temperature and osmolyte on the catalytic cycle of cytochrome c
      oxidase.
AB  - The influence of temperature on cytochrome c oxidase (CCO) catalytic activity was
      studied in the temperature range 240-308 K. Temperatures below 273 K required the
      inclusion of the osmolyte ethylene glycol. For steady-state activity between 278
      and 308 K the activation energy was 12 kcal x mol-1; the molecular activity or
      turnover number was 12 s-1 at 280 K in the absence of ethylene glycol. CCO
      activity was studied between 240 and 277 K in the presence of ethylene glycol.
      The activation energy was 30 kcal x mol-1; the molecular activity was 1 s-1 at
      280 K. Ethylene glycol inhibits CCO by lowering the activity of water. The rate
      limitation in electron transfer (ET) was not associated with ET into the CCO as
      cytochrome a was predominantly reduced in the aerobic steady state. The activity
      of CCO in flash-induced oxidation experiments was studied in the low temperature
      range in the presence of ethylene glycol. Flash photolysis of the reduced CO
      complex in the presence of oxygen resulted in three discernable processes. At 273
      K the rate constants were 1500 s-1, 150 s-1 and 30 s-1 and these dropped to 220 s
      1, 27 s-1 and 3 s-1 at 240 K. The activation energies were 5 kcal.mol-1, 7
      kcal.mol-1, and 8 kcal.mol-1, respectively. The fastest rate we ascribe to the
      oxidation of cytochrome a3, the intermediate rate to cytochrome a oxidation and
      the slowest rate to the re-reduction of cytochrome a followed by its oxidation.
      There are two comparisons that are important: (a). with vs. without ethylene
      glycol and (b). steady state vs. flash-induced oxidation. When one makes these
      two comparisons it is clear that the CCO only senses the presence of osmolyte
      during the reductive portion of the catalytic cycle. In the present work that
      would mean after a flash-induced oxidation and the start of the next
      reduction/oxidation cycle.

PMID- 12605675
TI  - Genomic structure, expression and characterization of a STAT5 homologue from
      pufferfish (Tetraodon fluviatilis).
AB  - The STAT5 (signal transducer and activator of transcription 5) gene was isolated
      and characterized from a round-spotted pufferfish genomic library. This gene is
      composed of 19 exons spanning 11 kb. The full-length cDNA of Tetraodon
      fluviatilis STAT5 (TfSTAT5) contains 2461 bp and encodes a protein of 785 amino
      acid residues. From the amino acid sequence comparison, TfSTAT5 is most similar
      to mouse STAT5a and STAT5b with an overall identity of 76% and 78%, respectively,
      and has < 35% identity with other mammalian STATs. The exon/intron junctions of
      the TfSTAT5 gene were almost identical to those of mouse STAT5a and STAT5b genes,
      indicating that these genes are highly conserved at the levels of amino acid
      sequence and genomic structure. To understand better the biochemical properties
      of TfSTAT5, a chimeric STAT5 was generated by fusion of the kinase-catalytic
      domain of carp Janus kinase 1 (JAK1) to the C-terminal end of TfSTAT5. The fusion
      protein was expressed and tyrosine-phosphorylated by its kinase domain. The
      fusion protein exhibits specific DNA-binding and transactivation potential toward
      an artificial fish promoter as well as authentic mammalian promoters such as the
      beta-casein promoter and cytokine inducible SH2 containing protein (CIS) promoter
      when expressed in both fish and mammalian cells. However, TfSTAT5 could not
      induce the transcription of beta-casein promoter via rat prolactin and Nb2
      prolactin receptor. To our knowledge, this is the first report describing
      detailed biochemical characterization of a STAT protein from fish.

PMID- 12605677
TI  - Expression of MsPG3-GFP fusions in Medicago truncatula'hairy roots' reveals
      preferential tip localization of the protein in root hairs.
AB  - Tip growth is a specialized type of polar growth where new cell wall is deposited
      in a localized region of the cell, the growing tip. These cells show a
      characteristic zonation, with a high accumulation of secretory vesicles
      containing cell wall components at the tip, followed by an organelle-enriched
      zone. MsPG3 is a Medicago sativa polygalacturonase gene isolated in our
      laboratory, specifically expressed during the interaction of this plant with its
      symbiotic partner Sinorhizobium meliloti and which might participate in tip
      growth processes during symbiosis. We have used MsPG3-GFP fusions to study in
      vivo protein transport processes and localization during root hair growth.
      Different MsPG3-GFP fusions were expressed in Medicago truncatula'hairy roots'
      following a protocol developed for this study and also tested by transient
      expression in onion epidermal cells. Preferential accumulation of an MsPG3-GFP
      fusion protein in the tip of the growing root hair at different developmental
      stages was found, confirming the delivery of MsPG3 to the newly synthesized cell
      wall. This indicates that this protein may participate in tip growth processes
      during symbiosis and, in addition, that this fusion could be a useful tool to
      study this process in plants.

PMID- 12605679
TI  - Cleavage of nonphenolic beta-1 diarylpropane lignin model dimers by manganese
      peroxidase from Phanerochaete chrysosporium.
AB  - Purified manganese peroxidase (MnP) from Phanerochaete chrysosporium oxidizes
      nonphenolic beta-1 diarylpropane lignin model compounds in the presence of Tween
      80, and in three- to fourfold lower yield in its absence. In the presence of
      Tween 80, 1-(3',4'-diethoxyphenyl)-1-hydroxy-2-(4'-methoxyphenyl)propane (I) was
      oxidized to 3,4-diethoxybenzaldehyde (II), 4-methoxyacetophenone (III) and 1
      (3',4'-diethoxyphenyl)-1-oxo-2-(4'-methoxyphenyl)propane (IV), while only 3,4
      diethoxybenzaldehyde (II) and 4-methoxyacetophenone (III) were detected when the
      reaction was conducted in the absence of Tween 80. In contrast to the oxidation
      of this substrate by lignin peroxidase (LiP), oxidation of substrates by MnP did
      not proceed under anaerobic conditions. When the dimer (I) was deuterated at the
      alpha position and subsequently oxidized by MnP in the presence of Tween 80,
      yields of 3,4-diethoxybenzaldehyde, 4-methoxyacetophenone remained constant,
      while the yield of the alpha-keto dimeric product (IV) decreased by approximately
      sixfold, suggesting the involvement of a hydrogen abstraction mechanism. MnP also
      oxidized the alpha-keto dimeric product (IV) to yield 3,4-diethoxybenzoic acid
      (V) and 4-methoxyacetophenone (III), in the presence and, in lower yield, in the
      absence of Tween 80. When the reaction was performed in the presence of 18O2,
      both products, 3,4-diethoxybenzoic acid and 4-methoxyacetophenone, contained one
      atom of 18O. Finally, MnP oxidized the substrate 1-(3',5'-dimethoxyphenyl)-1
      hydroxy-2-(4'-methoxyphenyl)propane (IX) to yield 3,5-dimethoxybenzaldehyde (XI),
      4-methoxyacetophenone (III) and 1-(3',5'-dimethoxyphenyl)-1-oxo-2-(4'
      methoxyphenyl)propane (X). In sharp contrast, LiP was not able to oxidize IX.
      Based on these results, we propose a mechanism for the MnP-catalyzed oxidation of
      these dimers, involving hydrogen abstraction at a benzylic carbon, rather than
      electron abstraction from an aromatic ring.

PMID- 12605678
TI  - The heterogeneity of mast cell tryptase from human lung and skin.
AB  - There has long been conjecture over the degree to which there may be structural
      and functional heterogeneity in the tetrameric serine protease tryptase (EC
      3.4.21.59), a major mediator of allergic inflammation. We have applied 2D gel
      electrophoresis to analyze the extent, nature, and variability of this
      heterogeneity in lysates of mast cells isolated from lung and skin, and in
      preparations of purified tryptase. Gels were silver stained, or the proteins
      transferred to nitrocellulose blots and probed with either tryptase-specific
      monoclonal antibodies or various lectins. Tryptase was the major protein
      constituent in mast cell lysates, and presented as an array of 9-12 diffuse
      immunoreactive spots with molecular masses ranging from 29 to 40 kDa, and pI
      values from 5.1 to 6.3. Although the patterns obtained for lung and skin tryptase
      were broadly similar, differences were observed between tissues and between
      individual donors. Lectin binding studies indicated the presence of mono
      antennary or bi-antennary complex-type oligosaccharide with varying degrees of
      sialylation. Deglycosylation with protein-N-glycosidase F (PNGase F) reduced the
      size of both lung and skin tryptase, while incubation with PNGase F or
      neuraminidase narrowed the pI range, indicating variable degrees of glycosylation
      as a major contributor to the size and charge heterogeneity. Comparison of
      different purified preparations of lung and skin tryptase revealed no significant
      difference in pH profiles, but differences were seen in reactivity towards a
      range of chromogenic substrates, with substantial differences in Km, kcat and
      degree of cooperativity. Mathematical modeling indicated that the variety in
      kinetics parameters could not result solely from the sum of varying amounts of
      isoforms obeying Michaelis-Menten kinetics but with different values of Km and
      kcat. The heterogeneity demonstrated for tryptase in these studies suggests that
      there are important differences in tryptase function in different tissues.

PMID- 12605681
TI  - A single amino acid substitution of Leu130Ile in snake DNases I contributes to
      the acquisition of thermal stability.
AB  - We purified pancreatic deoxyribonucleases I (DNases I) from three snakes, Elaphe
      quadrivirgata, Elaphe climacophora and Agkistrodon blomhoffii, and cloned their
      cDNAs. Each mature snake DNase I protein comprised 262 amino acids. Wild-type
      snake DNases I with Leu130 were more thermally unstable than wild-type mammalian
      and avian DNases I with Ile130. After substitution of Leu130Ile, the thermal
      stabilities of the snake enzymes were higher than those of their wild-type
      counterparts and similar to mammalian wild-type enzyme levels. Conversely,
      substituting Ile130Leu of mammalian DNases I made them more thermally unstable
      than their wild-type counterparts. Therefore, a single amino acid substitution,
      Leu130Ile, might be involved in an evolutionally critical change in the thermal
      stabilities of vertebrate DNases I. Amphibian DNases I have a Ser205 insertion in
      a Ca2+-binding site of mammalian and avian enzymes that reduces their thermal
      stabilities [Takeshita, H., Yasuda, T., Iida, R., Nakajima, T., Mori, S., Mogi,
      K., Kaneko, Y. & Kishi, K. (2001) Biochem. J.357, 473-480]. Thus, it is plausible
      that the thermally stable wild-type DNases I of the higher vertebrates, such as
      mammals and birds, have been generated by a single Leu130Ile substitution of
      reptilian enzymes through molecular evolution following Ser205 deletion from
      amphibian enzymes. This mechanism may reflect one of the evolutionary changes
      from cold-blooded to warm-blooded vertebrates.

PMID- 12605680
TI  - Functional characterization of Drosophila melanogaster PERK eukaryotic initiation
      factor 2alpha (eIF2alpha) kinase.
AB  - Four distinct eukaryotic initiation factor 2alpha (eIF2alpha) kinases
      phosphorylate eIF2alpha at S51 and regulate protein synthesis in response to
      various environmental stresses. These are the hemin-regulated inhibitor (HRI),
      the interferon-inducible dsRNA-dependent kinase (PKR), the endoplasmic reticulum
      (ER)-resident kinase (PERK) and the GCN2 protein kinase. Whereas HRI and PKR
      appear to be restricted to mammalian cells, GCN2 and PERK seem to be widely
      distributed in eukaryotes. In this study, we have characterized the second
      eIF2alpha kinase found in Drosophila, a PERK homologue (DPERK). Expression of
      DPERK is developmentally regulated. During embryogenesis, DPERK expression
      becomes concentrated in the endodermal cells of the gut and in the germ line
      precursor cells. Recombinant wild-type DPERK, but not the inactive DPERK-K671R
      mutant, exhibited an autokinase activity, specifically phosphorylated Drosophila
      eIF2alpha at S50, and functionally replaced the endogenous Saccharomyces
      cerevisiae GCN2. The full length protein, when expressed in 293T cells, located
      in the ER-enriched fraction, and its subcellular localization changed with
      deletion of different N-terminal fragments. Kinase activity assays with these
      DPERK deletion mutants suggested that DPERK localization facilitates its in vivo
      function. Similar to mammalian PERK, DPERK forms oligomers in vivo and DPERK
      activity appears to be regulated by ER stress. Furthermore, the stable complexes
      between wild-type DPERK and DPERK-K671R mutant were mediated through the N
      terminus of the proteins and exhibited an in vitro eIF2alpha kinase activity.

PMID- 12605682
TI  - High activity of human butyrylcholinesterase at low pH in the presence of excess
      butyrylthiocholine.
AB  - Butyrylcholinesterase is a serine esterase, closely related to
      acetylcholinesterase. Both enzymes employ a catalytic triad mechanism for
      catalysis, similar to that used by serine proteases such as alpha-chymotrypsin.
      Enzymes of this type are generally considered to be inactive at pH values below
      5, because the histidine member of the catalytic triad becomes protonated. We
      have found that butyrylcholinesterase retains activity at pH <or= 5, under
      conditions of excess substrate activation. This low-pH activity appears with wild
      type butyrylcholinesterase as well as with all mutants we examined: A328G, A328I,
      A328F, A328Y, A328W, E197Q, L286W, V288W and Y332A (residue A328 is at the bottom
      of the active-site gorge, near the pi-cation-binding site; E197 is next to the
      active-site serine S198; L286 and V288 form the acyl-binding pocket; and Y332 is
      a component of the peripheral anionic site). For example, the kcat value at pH
      5.0 for activity in the presence of excess substrate was 32900 +/- 4400 min(-1)
      for wild-type, 55200 +/- 1600 min(-1) for A328F, and 28 700 +/- 700 min(-1) for
      A328W. This activity is titratable, with pKa values of 6.0-6.6, suggesting that
      the catalytic histidine is protonated at pH 5. The existence of activity when the
      catalytic histidine is protonated indicates that the catalytic-triad mechanism of
      butyrylcholinesterase does not operate for catalysis at low pH. The mechanism
      explaining the catalytic behaviour of butyrylcholinesterase at low pH in the
      presence of excess substrate remains to be elucidated.

PMID- 12605683
TI  - The tungsten-containing formate dehydrogenase from Methylobacterium extorquens
      AM1: purification and properties.
AB  - NAD-dependent formate dehydrogenase (FDH1) was isolated from the alpha
      proteobacterium Methylobacterium extorquens AM1 under oxic conditions. The enzyme
      was found to be a heterodimer of two subunits (alpha1beta1) of 107 and 61 kDa,
      respectively. The purified enzyme contained per mol enzyme approximately 5 mol
      nonheme iron and acid-labile sulfur, 0.6 mol noncovalently bound FMN, and
      approximately 1.8 mol tungsten. The genes encoding the two subunits of FDH1 were
      identified on the M. extorquens AM1 chromosome next to each other in the order
      fdh1B, fdh1A. Sequence comparisons revealed that the alpha-subunit harbours
      putative binding motifs for the molybdopterin cofactor and at least one iron
      sulfur cluster. Sequence identity was highest to the catalytic subunits of the
      tungsten- and selenocysteine-containing formate dehydrogenases characterized from
      Eubacterium acidaminophilum and Moorella thermoacetica (Clostridium
      thermoaceticum). The beta-subunit of FDH1 contains putative motifs for binding
      FMN and NAD, as well as an iron-sulfur cluster binding motif. The beta-subunit
      appears to be a fusion protein with its N-terminal domain related to NuoE-like
      subunits and its C-terminal domain related to NuoF-like subunits of known NADH
      ubiquinone oxidoreductases.

PMID- 12605684
TI  - Antioxidant protein 2 prevents methemoglobin formation in erythrocyte
      hemolysates.
AB  - Antioxidant protein 2 (AOP2) is a member of a family of thiol-specific
      antioxidants, recently renamed peroxiredoxins, that evolved as part of an
      elaborate system to counteract and control detrimental effects of oxygen
      radicals. AOP2 is found in endothelial cells, erythrocytes, monocytes, T and B
      cells, but not in granulocytes. AOP2 was found solely in the cytoplasm and was
      not associated with the nuclear or membrane fractions; neither was it detectable
      in plasma. Further experiments focused on the function of AOP2 in erythrocytes
      where it is closely associated with the hemoglobin complex, particularly with the
      heme. An investigation of the mechanism of this interaction demonstrated that the
      conserved cysteine-47 in AOP2 seems to play a role in AOP2-heme interactions.
      Recombinant AOP2 prevented induced as well as noninduced methemoglobin formation
      in erythrocyte hemolysates, indicating its antioxidant properties. We conclude
      that AOP2 is part of a sophisticated system developed to protect and support
      erythrocytes in their many physiological functions.

PMID- 12605685
TI  - The resident endoplasmic reticulum protein, BAP31, associates with gamma-actin
      and myosin B heavy chain.
AB  - BAP31 is a 28-kDa integral membrane protein of the endoplasmic reticulum whose
      cytosolic domain contains two caspase recognition sites that are preferentially
      cleaved by initiator caspases, such as caspase-8. Recently, we reported that the
      caspase-resistant BAP31 inhibited Fas-mediated apoptotic membrane fragmentation
      and the release of cytochrome c from mitochondria in KB epithelial cells (Nguyen
      M., Breckenridge G., Ducret A & Shore G. (2000) Mol. Cell. Biol.20, 6731-6740).
      We describe here the characterization by capillary liquid chromatography
      microelectrospray tandem MS of a BAP31 immunocomplex isolated from a HepG2 cell
      lysate in the absence of a death signal. We show that BAP31 specifically
      associates with nonmuscle myosin heavy chain B and nonmuscle gamma-actin, two
      components of the cytoskeleton actomyosin complex. Collectively, these data
      confirm that BAP31, in addition to its potential role as a chaperone, may play a
      fundamental role in the structural organization of the cytoplasm. Here we also
      show that Fas stimulation of apoptosis releases BAP31 associations with these
      motor proteins, a step that may contribute to extranuclear events, such as
      membrane remodelling, during the execution phase of apoptosis.

PMID- 12605686
TI  - The 3'-UTR of the mRNA coding for the major protein kinase C substrate MARCKS
      contains a novel CU-rich element interacting with the mRNA stabilizing factors
      HuD and HuR.
AB  - The expression of the major protein kinase C substrate MARCKS (myristoylated
      alanine-rich C kinase substrate) is controlled by the stability of its mRNA.
      While the MARCKS mRNA is long living in quiescent fibroblasts (t1/2 = 14 h), its
      half-life time is drastically reduced (t1/2 = 2 h) in cells treated with phorbol
      esters to activate protein kinase C (PKC) or treated with growth factors. In a
      first step to study the underlying mechanism we identified both a cis-element on
      the MARCKS mRNA and the corresponding trans-acting factors. Fusing the complete
      3'-UTR or specific regions of the 3'-UTR of the MARCKS gene to a luciferase
      reporter gene caused a drastic decrease in luciferase expression to as low as 5
      10% of controls. This down-regulation was a result of destabilization of the
      chimeric transcript as shown by RNA run-off and Northern blot-assays. By
      RNase/EMSA and UV-cross-linking experiments, we identified a stretch of 52
      nucleotides [(CUUU)11(U)8] in the 3'-UTR of the MARCKS mRNA specifically
      recognized by two RNA-binding proteins, HuD and HuR. These trans-acting factors
      are members of the ELAV gene family and bind the MARCKS CU-rich sequence with
      high affinity. Overexpression of HuD and HuR in murine fibroblasts caused a
      striking stabilization of the endogenous MARCKS mRNA even under conditions when
      the MARCKS mRNA is normally actively degraded, i.e. after treating cells with
      phorbol ester. These data imply, that the identified CU-rich cis-element of the
      MARCKS 3'-UTR is involved in conferring instability to mRNAs and that members of
      the ELAV gene family oppose this effect. Based on its structural and functional
      properties, the (CUUU)11(U)8 sequence described here can be grouped into class
      III of AU-rich elements.

PMID- 12605687
TI  - Plasmodium falciparum merozoite surface protein 1.
AB  - In addition to the major carbohydrate moieties of the
      glycosylphosphatidylinositol (GPI) anchor, we report that Plasmodium falciparum
      merozoite surface protein 1 (MSP-1) bears O-GlcNAc modifications predominantly in
      beta-anomeric configuration, in both the C- and N-terminal portions of the
      protein. Subcellular fractionation of parasitized erythrocytes in the late
      trophozoite/schizont stage reveals that GPI-anchored C-terminal fragments of MSP
      1 are recovered in Triton X-100 resistant, low-density membrane fractions. Our
      results suggest that O-GlcNAc-modified MSP-1 N-terminal fragments tend to
      localize within the parasitophorous vacuolar membrane while GPI-anchored MSP-1 C
      terminal fragments associate with low-density, Triton X-100 resistant membrane
      domains (rafts), redistribute in the parasitized erythrocyte and are eventually
      shed as membrane vesicles that also contain the endogenous, GPI-linked CD59.

PMID- 12605688
TI  - Identification and characterization of B"-subunits of protein phosphatase 2 A in
      Xenopus laevis oocytes and adult tissues.
AB  - Protein phosphatase 2A is a phosphoserine/threonine phosphatase implicated in
      many cellular processes. The core enzyme comprises a catalytic and a PR65/A
      subunit. The substrate specificity and subcellular localization are determined by
      a third regulatory B-subunit (PR55/B, PR61/B' and PR72/130/B"). To identify the
      proteins of the B" family in Xenopus laevis oocytes, a prophase Xenopus oocyte
      cDNA library was screened using human PR130 cDNA as a probe. Three different
      classes of cDNAs were isolated. One class is very similar to human PR130 and is
      probably the Xenopus orthologue of PR130 (XPR130). A second class of clones
      (XN73) is identical to the N-terminal part of XPR130 but ends a few amino acids
      downstream of the putative splicing site of PR130. To investigate how this
      occurs, the genomic structure of the human PR130 gene was determined. This novel
      protein does not act as a PP2A subunit but might compete with the function of
      PR130. The third set of clones (XPR70) is very similar to human PR48 but has an N
      terminal extension. Further analysis of the human EST-database and the human PR48
      gene structure, revealed that the human PR48 clone published is incomplete. The
      Xenopus orthologue of PR48 encodes a protein of 70 kDa which like the XPR130,
      interacts with the A-subunit in GST pull-down assays. XPR70 is ubiquitously
      expressed in adult tissues and oocytes whereas expression of XPR130 is very low
      in brain and oocytes. Expression of XN73 mainly parallels XPR130 with the
      exception of the brain.

PMID- 12605689
TI  - Innately moving away from the Th1/Th2 paradigm in pregnancy.

PMID- 12605690
TI  - Lupus autoantibodies 101: one size does not fit all; however, specificity
      influences pathogenicity.

PMID- 12605692
TI  - Xenobiotic metal-induced autoimmunity: mercury and silver differentially induce
      antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice.
AB  - Xenobiotic-metals such as mercury (Hg) and silver (Ag) induce an H-2 linked
      antinucleolar autoantibody (ANolA) production in susceptible mice. The mechanism
      for induction of ANolA synthesis is not well understood. However, it has been
      suggested that both metals interact with nucleolar proteins and reveal cryptic
      self-peptides to nontolerant autoreactive T cells, which in turn stimulate
      specific autoreactive B cells. In this study, we considered this suggestion and
      asked if mercury and silver display, if not identical, similar cryptic self
      peptides, they would induce comparable ANolA responses in H-2 susceptible mice.
      We analysed the development of ANolA production in mercury- and/or silver-treated
      mice of H-2s, H-2q and H-2f genotypes. We found that while mercury stimulated
      ANolA synthesis in all strains tested, silver induced ANolA responses of lower
      magnitudes in only H-2s and H-2q mice, but not in H-2f mice. Resistance to silver
      in H-2f mice was independent of the dosage/time-period of silver-treatment and
      non-H-2 genes. Further studies showed that F1 hybrid crosses between silver
      susceptible A.SW (H-2s) and -resistant A.CA (H-2f) mice were resistant to silver,
      but not mercury with regard to ANolA production. Additionally, the magnitudes of
      mercury-induced ANolA responses in the F1 hybrids were lower than those of their
      parental strains. The above differential ANolA responses to mercury and silver
      can be explained by various factors, including the different display of nucleolar
      cryptic peptides by these xenobiotics, determinant capture and coexistence of
      different MHC molecules. Our findings also suggest that the ability of a
      xenobiotic metal merely to create cryptic self-peptides may not be sufficient for
      the induction of an ANolA response.

PMID- 12605691
TI  - Oxygen free radicals and systemic autoimmunity.
AB  - Reactive oxygen species generated during various metabolic and biochemical
      reactions have multifarious effects that include oxidative damage to DNA leading
      to various human degenerative and autoimmune diseases. The highly reactive
      hydroxy radical (*OH) can interact with chromatin and result in a wide range of
      sugar and base-derived products, DNA-protein cross-links and strand breaks.
      Studies from our laboratory have demonstrated that after modification the DNA
      becomes highly immunogenic and the induced antibodies exhibit variable antigen
      binding characteristics. Systemic lupus erythematosus, a prototype autoimmune
      disease, is characterized by the presence of autoantibodies to multiple nuclear
      antigens. The detection of 8-hydroxyguanosine in the immune complex derived DNA
      of systemic lupus erythematosus patients reinforces the evidence that reactive
      oxygen species may be involved in its pathogenesis. Increased apoptosis and
      decreased clearance of apoptotic cells as observed in systemic lupus
      erythematosus (SLE) might well be a contributory factor in systemic autoimmunity.
      Clinically, titres of autoantibodies are closely related to the degree of renal
      inflammation. Anti-DNA antibodies may combine with circulating antigen and
      contribute to the deposition of immune complexes in renal glomeruli.

PMID- 12605693
TI  - Silica accelerated systemic autoimmune disease in lupus-prone New Zealand mixed
      mice.
AB  - The genetic backgrounds of lupus-prone murine models are a valuable resource for
      studying the influence of environmental exposure on autoimmune diseases in
      sensitive populations. Epidemiological studies have shown associations between
      silica exposure and several autoimmune diseases, including scleroderma and
      systemic lupus erythematosus. To determine whether silica exposure can exacerbate
      systemic autoimmunity in genetically predisposed animals, New Zealand mixed mice
      were intranasally instilled twice with saline or saline suspensions of 1 mg
      silica or 500 micro g TiO2, a dose equivalent in surface area, and were evaluated
      with respect to health and immune status. Survival in silica exposed NZM mice was
      decreased compared to saline and TiO2 exposed mice. Proteinuria levels were
      elevated in silica exposed mice. Levels of circulating immune complexes,
      autoantibodies to nuclear antigen (ANA), histone, and double stranded DNA were
      measured every two weeks by ELISA. Circulating immune complexes showed a trend
      towards an increased acceleration in levels in the silica exposed mice compared
      to saline and TiO2 exposed mice. ANA levels were significantly higher in silica
      exposed animals compared to saline and TiO2 exposed animals (0.237 +/- 0.03
      versus 0.140 +/- 0.029 and 0.125 +/- 0.03, P < 0.05) 16 weeks postexposure.
      Autoantibodies to histone were also significantly elevated after 16 weeks in
      silica exposed animals compared to saline and TiO2 exposed animals (0.227 +/-
      0.03 versus 0.073 +/- 0.015 and 0.05 +/- 0.03, P < 0.05). In contrast, serum IgG
      levels were decreased in silica exposed NZM mice compared to the saline controls,
      however, IgM levels were unaffected. Lungs of the silica-exposed mice had
      increased inflammatory infiltrates as well as fibrotic lesions characterized by
      excess collagen deposition. Therefore, although NZM mice are susceptible to SLE,
      silica exposure significantly exacerbated the course of disease.

PMID- 12605694
TI  - Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies
      inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes.
AB  - Human immunodeficiency virus (HIV) infection leads to a profound T cell
      dysfunction well before the clinical onset of acquired immunodeficiency syndrome
      (AIDS). We have been accumulating evidence that one of the mechanisms responsible
      for this T cell deficiency may be the dysregulation of signal transduction via
      the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have
      observed previously that viral envelope (env) glycoproteins induce IL-2
      unresponsiveness and the down-regulation of the three chains making up the IL-2R
      (alpha, beta, gamma) in vitro. We have now established further that this
      disruption of the IL-2/IL-2R system manifests itself in defective signal
      propagation via the Janus kinase (Jak)/signal transducer and activator of
      transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells
      with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies
      inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their
      targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the
      crippling of CD4 T cell responses to a cytokine central to the immune response by
      HIV.

PMID- 12605695
TI  - Selective up-regulation of functional CXCR4 expression in erythroid cells by HIV
      1 Tat protein.
AB  - CXCR4 is the high affinity receptor for the SDF-1 alpha chemokine and represents
      the main coreceptor for HIV-1 T-tropic strains. The surface expression of CXCR4
      was analysed in CD34+ haematopoietic progenitors, induced to differentiate along
      the erythroid or granulocytic lineages, in liquid cultures supplemented or not
      with HIV-1 Tat protein. At concentrations as low as 1-10 ng/ml, synthetic Tat
      protein significantly increased the surface expression of CXCR4 in erythroid but
      not in granulocytic cells. The Tat-mediated up-regulation of surface CXCR4 was
      accompanied by a concomitant increase of CXCR4 mRNA and total CXCR4 protein
      content in cells developing along the erythroid lineage after 6-10 days of
      culture. Moreover, addition of SDF-1 alpha (200 ng/ml) induced a significant
      higher rate of apoptosis in Tat-treated erythroid cells in comparison with
      control cells. These results demonstrated for the first time a direct positive
      role in haematopoietic gene regulation of Tat protein, and suggest the possible
      involvement of Tat in HIV-1-induced anaemia.

PMID- 12605696
TI  - Analysis of gene expression in peripheral blood eosinophils from patients with
      atopic dermatitis and in vitro cytokine-stimulated blood eosinophils.
AB  - Investigation of differentially expressed genes in eosinophils of patients with
      allergic diseases such as atopic dermatitis (AD) will provide important
      information for elucidating possible mechanisms of pathology. To identify novel
      genes that are expressed in AD, we compared gene expression in samples of
      peripheral blood eosinophils from AD patients and healthy volunteers. RNA was
      extracted from peripheral blood eosinophils. The expression of various genes,
      such as those for cytokine receptors, eosinophil activation marker, platelet
      activating factor (PAF) receptor, eosinophil-specific granular proteins and
      apoptosis-related genes, was confirmed using real-time reverse transcription
      polymerase chain reaction (RT-PCR). Peripheral blood eosinophils of healthy
      volunteers were also isolated and stimulated for introduction of various
      cytokines. RNA was extracted and gene expression was monitored. Several genes,
      such as those for cytokine receptors (granulocyte-macrophage colony-stimulating
      factor (GM-CSF) receptor alpha and beta chain and interleukin (IL)-3 receptor
      alpha chain), CD44 and PAF receptor were expressed at significantly higher levels
      in AD patients than in healthy volunteers. In addition, the anti-apoptotic genes,
      bcl-2 and bcl-xL, were expressed at increased levels in AD patients. No single
      gene expression correlated with clinical markers, such as eosinophil count or IgE
      levels. Expression of GM-CSF receptor beta chain and IL-3 receptor alpha chain in
      isolated blood eosinophils of healthy volunteers was stimulated by IL-5, IL-4,
      interferon (IFN)-gamma and GM-CSF. Expression of bcl-2 and bcl-xL was also
      increased after stimulation with IL-5, IL-4 or IFN-gamma. The in vitro
      enhancement of cytokine-stimulated gene expression correlated well with the
      enhancement observed in clinical samples of eosinophils, suggesting that
      cytokines may affect gene expression in vivo in eosinophils of patients with AD.

PMID- 12605697
TI  - Signal transducer and activator of transcription 6 gene G2964A polymorphism and
      inflammatory bowel disease.
AB  - Signal transducer and activator of transcription 6 (STAT6) is a key transcription
      factor involved in interleukin 4 (IL-4) and IL-13-mediated Th2 response. The
      STAT6 gene is located on chromosome 12q13.3-14.1 (IBD2 region) and is therefore a
      positional and functional candidate gene for study in inflammatory bowel disease.
      We investigated the G2964A polymorphism in the 3' untranslated region of the
      STAT6 gene in Dutch patients with inflammatory bowel disease and healthy
      controls. The G2964A polymorphism in the STAT6 gene was genotyped in 141
      unrelated Dutch Caucasian patients with ulcerative colitis, 183 patients with
      Crohn's disease and 173 healthy individuals by PCR and the amplification-created
      restriction site method. Patients with Crohn's disease were classified according
      to the Vienna classification and the patients with ulcerative colitis were
      classified with the age at onset, extent of disease and colectomy. We did not
      find significant differences in genotype and allele frequencies of the G2964A
      polymorphism in the STAT6 gene between ulcerative colitis, Crohn's disease and
      healthy controls. Subgroups of the patients with Crohn's disease classified
      according to the Vienna classification and those with ulcerative colitis
      classified according to age of onset, disease extension and colectomy did not
      differ in the distribution of this polymorphism. The STAT6 G2964A gene
      polymorphism is not involved in the overall susceptibility or in determining the
      phenotype of IBD.

PMID- 12605698
TI  - The antibody response to HBs antigen is regulated by coordinated Th1 and Th2
      cytokine production in healthy neonates.
AB  - A proportion of healthy neonates fail to produce protective levels of anti-HBs
      antibody following vaccination with recombinant hepatitis B vaccine. This study
      was undertaken to investigate contribution of Th1 and Th2 responses to anti-HBs
      antibody production and to explore the mechanism(s) of unresponsiveness to HBsAg
      in human neonates. Peripheral blood manonuclear cells (PBMCs) were isolated form
      28 nonresponder (anti-HBs antibody <10 IU/l) and 25 responder neonates. The cells
      were stimulated in vitro with recombinant HBsAg and PHA mitogen and
      concentrations of IL-4, IL-10 and IFN-gamma were quantified in culture
      supernatants by sandwich ELISA. Our results demonstrated significantly increased
      production of all cytokines, including IL-4 (P < 0.001), IL-10 (P < 0.002) and
      IFN-gamma (P < 0.01) in responder compared to nonresponder vaccinees. No
      significant differences, however, were observed between the two groups of
      neonates in the levels of cytokines induced by PHA or secreted in absence of
      antigen and mitogen. Our findings suggest that unresponsiveness to recombinant
      HBsAg in healthy neonates is linked to inadequate secretion of both Th1 and Th2
      cytokines.

PMID- 12605699
TI  - Live Leishmania promastigotes can directly activate primary human natural killer
      cells to produce interferon-gamma.
AB  - Natural killer (NK) cells have been implicated in the natural protection and
      healing of leishmaniasis by their ability to secrete the macrophage activating
      cytokine interferon (IFN)gamma. Previous studies have demonstrated that early
      production of interleukin (IL)-12 triggers IFN gamma secretion by NK cells. Here
      we report that live Leishmania promastigotes (the form that is injected by the
      vector) can directly induce human peripheral blood NK cells from healthy donors
      to IFN gamma secretion in the absence of IL-12 and professional antigen
      presenting cells. Killing of promastigotes abolishes this property. This novel
      mechanism of activation of the innate immune response may be relevant for
      establishment of infection and thus also the design of vaccines against
      leishmaniasis.

PMID- 12605700
TI  - Streptococci and Actinomyces induce antibodies which cross react with epithelial
      antigens in periodontitis.
AB  - Perturbation of epithelial structure is a prominent but poorly understood feature
      of the immunopathological response to bacterial antigens which characterizes the
      destructive lesion of periodontitis. Western analysis of sera from 22 patients
      with periodontitis detected multiple antigens in extracts of epithelial cells
      whereas sera from 12 periodontally healthy subjects displayed only trace reaction
      with epithelial antigens. To investigate a possible relationship between the
      bacterial flora adjacent to diseased sites and the presence of antibodies
      reactive with epithelium, subgingival plaque samples were taken from deep
      periodontal pockets and cultured anaerobically. Gram positive bacteria containing
      antigens cross-reactive with epithelial cells were reproducibly isolated by
      probing membrane colony-lifts with affinity-isolated (epithelium-specific)
      antibodies and identified by 16S rDNA sequence homology as streptococci (S.
      mitis, S. constellatus and two S. intermedius strains) and Actinomyces (A.
      georgiae, and A. sp. oral clone). Conversely, when serum from patients with
      periodontitis was absorbed with the captured bacterial species the number of
      epithelial antigens recognized was specifically reduced. It was concluded that
      development of cross-reactive antibodies related to these organisms may
      contribute to perturbation of the epithelial attachment to the tooth and the
      progression of periodontitis. These autoreactive antibodies could also be a
      contributing factor in other diseases affecting epithelia.

PMID- 12605701
TI  - Monocyte-derived RANTES is intrinsically elevated in periodontal disease while
      MCP-1 levels are related to inflammation and are inversely correlated with IL-12
      levels.
AB  - Bacteria colonizing tooth surfaces are essential in the induction of an
      inflammatory response in the periodontal tissues, but do not cause periodontitis
      in everyone, implicating differences in the host immune response. These possible
      differences were studied using lipopolysaccharide (LPS)-stimulated whole blood
      cell cultures (WBCC), which revealed a down regulation of monocyte derived
      interleukin-12 (IL-12p70) in untreated periodontitis patients and an up
      regulation after therapy. IL-12p70 is a crucial factor in the differentiation of
      Th1 cell responses. Since CC chemokines are able to influence the T cell
      differentiation via cytokine secretion in antigen-presenting cells, the
      production of CC chemokines in periodontitis was evaluated. Therefore WBCC were
      stimulated with LPS from Escherichia coli for 18 h and the levels of IL-12p70 and
      CC chemokines were measured in the supernatants by ELISA. Untreated periodontitis
      patients released 2 fold more RANTES (regulated on activation normal T cell
      expressed and secreted) (P = 0.01) and lower levels of IL-12p70 in comparison to
      controls (P < 0.05). A trend towards higher levels of macrophage chemoattractant
      protein-1 (MCP-1) (P = 0.07) was also seen in untreated periodontitis patients;
      while similar levels of monocyte derived chemokine (MDC) and macrophage
      inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha and -1 beta) were found.
      After periodontal therapy no changes were seen with regard to MDC, MIP-1 alpha,
      MIP-1 beta and RANTES, whereas the MCP-1 levels decreased (P < 0.05) and the IL
      12p70 levels strongly increased (P < 0.01). The data showed a consistent inverse
      correlation between the levels of MCP-1 and IL-12p70, and their proportional
      changes after therapy correlated with the clinical inflammatory response after
      therapy. This indicates that the disease state regulates the release of IL-12p70
      and MCP-1 in E. coli LPS-stimulated WBCC. In contrast, the persistent augmented
      levels of RANTES after therapy are suggestive for an intrinsic behaviour.

PMID- 12605702
TI  - Transient elevation of interleukin-16 levels at the initial stage of meningitis
      in children.
AB  - IL-16 is an immunomodulatory cytokine that is characterized by chemotactic
      activity and stimulation of proinflammatory cytokine expression in monocytic
      cells. We studied IL-16 using ELISA in children with meningitis. When meningeal
      symptoms existed, IL-16 levels were high in the cerebrospinal fluid (CSF) of both
      bacterial (939 +/- 877 ng/l, n = 20) and aseptic (341 +/- 371 ng/l, n = 23)
      meningitis. The values in the CSF were significantly higher than those in non
      meningitis controls (29 +/- 8 ng/l, n = 22, P < 0.0001). After meningeal symptoms
      disappeared, IL-16 levels in bacterial (191 +/- 149 ng/l, n = 10, P = 0.0042) and
      aseptic (159 +/- 188 ng/l, n = 13, P = 0.0118) meningitis were lower than those
      during the symptomatic stage. IL-16 levels were the highest before day 5 of the
      illness and then gradually fell. Significant correlations were found between IL
      16 levels and both G-CSF levels (r = 0.783, n = 11, p = 0.0029) and IL-6 levels
      (r = 0.818, n = 12, P = 0.0005) in the CSF of bacterial and aseptic meningitis.
      IL-16 levels in all CSF samples from non-meningitis controls were lower than
      those in serum. In contrast, IL-16 levels in the CSF in six of 16 samples from
      bacterial meningitis and two of 18 samples from aseptic meningitis were higher
      than those in serum. Serum levels of IL-16 did not fluctuate throughout the
      course of meningitis. These data indicate that IL-16 levels rise transiently in
      CSF at the initial stage of meningitis. We speculate that IL-16 may promote
      inflammatory responses during meningitis in concert with other proinflammatory
      cytokines.

PMID- 12605703
TI  - Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human
      pregnancy: an intracellular flow cytometric analysis of peripheral blood
      mononuclear cells.
AB  - This paper considers both monocytes and peripheral blood lymphocytes as potential
      targets for maternal immunological modulation in pregnancy. Peripheral blood
      mononuclear cells (PBMCs) from non-pregnant and normal pregnant donors were
      stimulated in vitro, and cytokine production detected intracellularly by flow
      cytometry. It was found that monocyte production of TNF-alpha was unaltered in
      pregnancy, while production of IL-12 was significantly enhanced. In contrast,
      production of the Th1 type cytokine IFN-gamma was suppressed in the lymphocyte
      subsets: CD4+ T helper cells and CD56+ NK cells. Production of the Th2 type
      cytokine IL-4 in CD4+ cells was not significantly altered in pregnancy. These
      data suggest that the concept that pregnancy is a 'Th2 phenomenon' cannot be
      generalized to the function of all aspects of maternal cellular immunity as,
      paradoxically, circulating monocytes are 'primed' to produce the Th1 cytokine IL
      12. Furthermore, these data support the hypothesis that components of maternal
      innate immunity are activated in normal pregnancy.

PMID- 12605704
TI  - Phenotypic characterization of human decidual macrophages.
AB  - Pregnancy is a challenge to the immune system, which not only has to protect the
      mother and the fetus from invading pathogens but to also maintain immunological
      tolerance against the fetus. However, the mechanisms inhibiting local immune
      responses in the maternal decidual tissue are poorly understood. We have studied
      decidual CD14+ macrophages, which may be important in the maintenance of a
      tolerance against the developing fetus. Decidual macrophages expressed HLA-DR,
      but lower levels of costimulatory molecule CD86 than peripheral blood CD14+
      monocytes from pregnant and non-pregnant women. Decidual macrophages produced
      spontaneously high levels of interleukin-10. Our findings suggest that decidual
      macrophages could represent an inhibitory type of APCs. Supporting this
      conclusion indoleamine 2,3-dioxygenase (IDO), suggested to have an
      immunosuppressive role in pregnancy, was expressed in decidual macrophages.
      Furthermore, decidual macrophages were not able to differentiate into dendritic
      cells under the influence of IL-4 + GM-CSF. These results suggest an
      immunoinhibitory function of decidual macrophages at the maternal-fetal
      interface.

PMID- 12605705
TI  - Anti-SSB/La is one of the antineutrophil autoantibodies responsible for
      neutropenia and functional impairment of polymorphonuclear neutrophils in
      patients with systemic lupus erythematosus.
AB  - Decreased number and impaired functions of polymorphonuclear neutrophils (PMN)
      due to the presence of anti-PMN autoantibodies in the serum render patients with
      systemic lupus erythematosus (SLE) susceptible to bacterial infections. However,
      the cognate antigens and pathological mechanisms of anti-PMN autoantibodies in
      SLE are rarely reported in the literature. In this study, we found approximately
      20% of SLE sera contained anti-PMN autoantibodies detected by human PMN-coated
      cellular ELISA. A membrane protein with molecular weight of 50 kDa was identified
      as the cognate antigen of anti-PMN in Western blot after membrane-biotinylation
      and streptavidin column elution. The 50 kDa molecule was proved to be SSB/La
      after immunoscreening, molecular cloning and nucleotide sequencing of the gene
      from the human leucocyte cDNA library. Human anti-SSB/La autoantibodies purified
      from active SLE sera passing through the recombinant SSB/La conjugated Sepharose
      4B affinity column could bind and penetrate into normal human PMN. Functional
      analysis revealed that the anti-SSB/La autoantibodies exerted a number of potent
      effects on human PMN, including suppressed phagocytosis, accelerated apoptosis
      and enhanced IL-8 production. These in vitro results suggest that anti-SSB/La is
      one of the anti-PMN autoantibodies capable of penetrating into PMN and
      responsible for neutropenia and functional impairment of PMN in patients with
      SLE.

PMID- 12605706
TI  - T cell Vbeta repertoires in childhood vasculitides.
AB  - Superantigens (SAgs) are potent stimulators of T cells bearing specific Vbeta T
      cell receptors (TCR) and may play a role in the aetiopathogenesis of systemic
      vasculitis, although this remains contentious. To investigate the possible
      aetiological role of SAgs, this study examined peripheral blood T cell Vbeta
      repertoires in children with systemic vasculitis. FACS analysis of 17 different
      peripheral blood T cell Vbeta families was performed in 20 healthy control
      children, 27 disease control children with nonvasculitic inflammatory disease, 25
      children with primary systemic vasculitis, six patients with Kawasaki disease
      (KD) and six patients with Henoch-Schonlein purpura (HSP). There was a
      significantly increased variance of CD4 Vbeta12 and Vbeta17, and CD8 Vbeta1 in
      the primary systemic vasculitis group compared to control and disease controls.
      Moreover, 80% of the primary systemic vasculitis children had one or more CD4
      Vbeta expansions or deletions, compared with 30% of controls (P < 0.002), and 37%
      of the disease controls (P < 0.002). In the KD group, the mean percentage of CD4
      Vbeta2 T cells was higher than in controls or disease controls. In the HSP group,
      there was no consistent skewing of the T cell Vbeta repertoire. We have observed
      changes in the T cell Vbeta repertoire in children with vasculitis over and above
      those observed in disease controls. While these data provide impetus for further
      research into this contentious field, they do not resolve unequivocally the
      question of the role of SAgs in childhood vasculitic syndromes.

PMID- 12605707
TI  - Increased circulating levels of proteinase 3 in patients with anti-neutrophilic
      cytoplasmic autoantibodies-associated systemic vasculitis in remission.
AB  - In systemic small vessel vasculitides, patients form autoantibodies against
      neutrophil granular proteins, anti-neutrophilic cytoplasmic autoantibodies
      (ANCA). Some correlation is seen between ANCA titre and disease activity, but
      whether this is cause or effect is still unknown. It has been reported that
      levels of proteinase 3 (PR3), one of the main ANCA antigens, are increased in
      patients with active disease. An increased level of circulating antigen could
      mean a predisposition to autoimmunity. In order to explore this we measured PR3
      levels in patients with stable disease. In addition we measured neutrophil
      gelatinase-associated lipocalin (NGAL) as a specific marker of neutrophil
      degranulation, cystatin C as a marker of renal function as well as C-reactive
      protein (CRP), IL-6 and sTNFr1 as markers of inflammation. PR3, NGAL, IL-6 and
      sTNFr1 were measured in plasma by the ELISA technique. In the PR3 ELISA, we used
      anti-PR3 monoclonal antibodies as capture-antibodies and affinity-purified rabbit
      anti-PR3 antibodies for detection. PR3-ANCA, myeloperoxidase (MPO)-ANCA, CRP and
      cystatin C were measured by routine methods. PR3 was significantly raised (P <
      0.0001) in vasculitis patients (median 560 micro g/l, range 110-3,940, n = 59)
      compared with healthy blood donors (350 micro g/l, 110-580, n = 30) as well as
      disease controls (360, 110-580, n = 46). No correlation was seen with disease
      activity, inflammation or renal function. The raised NGAL levels correlated
      strongly with decreased renal function (r = 0.8, P < 0.001). After correcting for
      this, slightly increased levels (110, 42-340, n = 59) were observed compared with
      healthy blood donors (81, 38-130, n = 25), but not compared with the disease
      controls (120, 57-260, n = 48). In the disease controls, there was a significant
      correlation between NGAL and proteinase 3 (r = 0.3, p < 0.05), but this was not
      the case in the vasculitis patients. Whether patients had PR3-ANCA or MPO-ANCA
      was of no significance. In our measurements, we found significantly raised levels
      of PR3 in plasma from patients with small vessel vasculitis, regardless of ANCA
      specificity. This was not due to decreased renal function, ongoing inflammation
      or neutrophil activation. Plausible mechanisms for this include defects in the
      reticuloendothelial system, genetic factors and selective neutrophil
      degranulation or leakage.

PMID- 12605709
TI  - Not-only-a-title.

PMID- 12605708
TI  - Circulating endothelial cells in Kawasaki disease.
AB  - Recent reports have demonstrated that circulating endothelial cells (CECs) are
      observed in several diseases with vascular injury. Because Kawasaki disease (KD)
      is one type of systemic vasculitis, we hypothesized that an increased number of
      CECs may be associated with the appearance of complicated coronary artery lesions
      (CAL). In the present study we investigated the enumeration and origin of CECs in
      20 patients with KD, using an immunohistochemical method with monoclonal
      antibodies: clone P1H12 against ECs and clone AC133 against endothelial
      progenitor cells (EPCs), which were derived from the bone marrow. The mean number
      of CECs increased significantly (P < 0.05) from the acute through the subacute
      phases of KD compared with both the convalescent phase of KD and healthy
      children. The mean number of CECs was significantly (P < 0.05) higher in six KD
      patients with CAL than in 14 KD patients without CAL. The population of EPCs in
      the total CECs in KD was 4.4 +/- 1.2% (range 0-18%). The number of EPCs during
      the subacute phase was also significantly higher (P < 0.05) in KD patients with
      CAL than in those without CAL. Our findings indicate that the number of CECs
      increase in KD vasculitis and suggest that the increased numbers of CECs and EPCs
      may reflect the EC damage of this disease.

PMID- 12605711
TI  - Carcinogenesis and cancer prevention: the process and the disease deserve a
      better understanding.

PMID- 12605710
TI  - Carcinogenesis: The more we seek to know the more we need to know - Challenges in
      the post Genomic Era.

PMID- 12605712
TI  - The effects of aging and activity on muscle blood flow.
AB  - BACKGROUND: Our purpose was to determine if aging had an influence on muscle
      blood flow independent of habitual physical activity levels. METHODS: Blood flow
      was measured in the femoral artery by Doppler ultrasound after cuff occlusion of
      10 minutes. Active and inactive older subjects (73 +/- 7 years) were compared to
      active and inactive young subjects (26 +/- 6 years). RESULTS: Peak blood flow
      capacity when normalized to lean muscle mass was related to activity level (p <
      0.001), but not to age. Specifically, the young active group had higher peak
      blood flows than the young inactive (p = 0.031) or older inactive (p = 0.005)
      groups. Resting blood flow and conductance were not significantly different
      between groups. Mean arterial pressure was significantly higher in the older
      compared to young group (p = 0.002). Conductance was related to both activity (p
      = 0.002) and age (p = 0.003). A prolonged time for blood flow to recover was
      found in the older compared to the young group (p = 0.038) independent of
      activity status. CONCLUSIONS: The prolonged recovery time in the older subjects
      may suggest a reduced vascular reactivity associated with increased
      cardiovascular disease risk. Peak blood flow capacity is maintained in older
      subjects by physical activity. In summary, maximal flow capacity and prolonged
      recovery of blood flow are influenced by different mechanisms in young and older
      active and inactive subjects.

PMID- 12605714
TI  - Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C3F1
      mice: effect on apoptosis, expression of oncogenes and the tumor suppressor gene
      p53.
AB  - BACKGROUND: Glucocorticoids inhibit hepatocellular proliferation and modulate the
      expression of oncogenes and tumor suppressor genes via mechanisms involving the
      glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated
      inhibitory effect on both basal and hormone-stimulated expression of a newly
      discovered family of molecules important for shutting off cytokine action. We
      therefore hypothesized that inhibiting glucocorticoid receptors may disturb
      hepatocellular growth and apoptosis. Consequently, we investigated the effect of
      RU486, a potent antagonist of the glucocorticoid receptor, on basal levels of
      hepatocellular proliferation and apoptosis in male B6C3F1 mice. Furthermore, we
      evaluated the effect of this compound on cellular genes involved in the
      regulation of these important processes. RESULTS: Data show that treatment of
      male B6F3C1 mice with RU486 (2 mg/kg/d, ip) for 7 days dramatically inhibited
      liver cell proliferation by about 45% and programmed hepatocellular death by
      approximately 66%. RU 486 also significantly increased hepatic expression of the
      oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53.
      CONCLUSION: Exposure to RU486 may ultimately enhance the susceptibility of the
      liver to cancer risk by diminishing its ability to purge itself of pre-cancerous
      cells via apoptosis. This effect may be mediated through increases in the hepatic
      expression of the oncogene mdm2, coupled with decreases in that of the tumor
      suppressor gene p53. The decrease in hepatocellular proliferation caused by RU
      486 may be related to effects other than its anti-glucocorticoid activity.

PMID- 12605716
TI  - Genetic alterations in pancreatic carcinoma.
AB  - Cancer of the exocrine pancreas represents the fifth leading cause of cancer
      death in the Western population with an average survival after diagnosis of 3 to
      6 months and a five-year survival rate under 5%. Our understanding of the
      molecular carcinogenesis has improved in the last few years due to the
      development of novel molecular biological techniques. Pancreatic cancer is a
      multi-stage process resulting from the accumulation of genetic changes in the
      somatic DNA of normal cells. In this article we describe major genetic
      alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the
      tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic
      changes leads to a profound disturbance in cell cycle regulation and continuous
      growth. The knowledge of the underlying molecular mechanisms will offer new
      therapeutic and diagnostic options and hopefully improve the outcome of this
      aggressive disease.

PMID- 12605717
TI  - Invasion and metastasis in pancreatic cancer.
AB  - Pancreatic cancer remains a challenging disease with an overall cumulative 5-year
      survival rate below 1%. The process of cancer initiation, progression and
      metastasis is still not understood well. Invasion and tumor metastasis are
      closely related and both occur within a tumour-host microecology, where stroma
      and tumour cells exchange enzymes and cytokines that modify the local
      extracellular matrix, stimulate cell migration, and promote cell proliferation
      and tumor cell survival. During the last decade considerable progress has been
      made in understanding genetic alterations of genes involved in local and systemic
      tumor growth. The most important changes occur in genes which regulate cell cycle
      progression, extracellular matrix homeostasis and cell migration. Furthermore,
      there is growing evidence that epigenetic factors including angiogenesis and
      lymphangiogenesis may participate in the formation of tumor metastasis. In this
      review we highlight the most important genetic alterations involved in tumor
      invasion and metastasis and further outline the role of tumor angiogenesis and
      lymphangiogenesis in systemic tumor dissemination.

PMID- 12605713
TI  - Apoptosis: targets in pancreatic cancer.
AB  - Pancreatic adenocarcinoma is characterized by poor prognosis, because of late
      diagnosis and lack of response to chemo- and/or radiation therapies. Resistance
      to apoptosis mainly causes this insensitivity to conventional therapies.
      Apoptosis or programmed cell death is a central regulator of tissue homeostasis.
      Certain genetic disturbances of apoptotic signaling pathways have been found in
      carcinomas leading to tumor development and progression. In the past few years,
      the knowledge about the complex pathways of apoptosis has strongly increased and
      new therapeutic approaches based on this knowledge are being developed. This
      review will focus on the role of apoptotic proteins contributing to pancreatic
      cancer development and progression and will demonstrate possible targets to
      influence this deadly disease.

PMID- 12605719
TI  - Arthritis and osteomyelitis due to Aspergillus fumigatus: a 17 years old boy with
      chronic granulomatous disease.
AB  - BACKGROUND: Invasive Aspergillus infections are frequently seen in
      immunocompromised patients but arthritis is a rare complication of Aspergillus
      infections in the absence of immune suppressive therapy, trauma or surgical
      intervention. CASE PRESENTATION: A 17 years old male patient with arthritis and
      patellar osteomyelitis of the left knee whose further investigations revealed
      chronic granulomatous disease as the underlying disease is followed. Aspergillus
      fumigatus was isolated from the synovial fluid and the tissue samples cultures.
      He was treated with Amphotericin B deoxicolate 0.7 mg/kg/day. Also surgical
      debridement was performed our patient. Amphotericin B nephrotoxicity developed
      and the therapy switched to itraconazole 400 mg/day. Itraconazole therapy were
      discontinued at the 6th month. He can perform all the activities of daily living
      including. CONCLUSION: We think that, chronic granulomatous disease should be
      investigated in patients who have aspergillar arthritis and osteomyelitis.

PMID- 12605720
TI  - Gender and power: Nurses and doctors in Canada.
AB  - BACKGROUND: The nurse-doctor relationship is historically one of female nurse
      deference to male physician authority. We investigated the effects of physicians'
      sex on female nurses' behaviour. METHODS: Nurses at an urban, university based
      hospital completed one of two forms of a vignette-based survey in January, 2000.
      Each survey included four clinical scenarios. In form 1 of the questionnaire the
      physicians described were female, male, female, and male. In form 2, vignettes
      were identical but the physician sex was changed to male, female, male, and
      female. Differences in responses to questions based on the sex of the physician
      in each vignette were studied RESULTS: 199 self-selected nurses completed the
      survey. The responses of 177 female respondents and 11 respondents who did not
      specifiy their sex, and were assumed to be female based on the overall sex ratio
      of respondents, were analysed. Persistent sex-role stereotypes influenced the
      relationship between female nurses and physicians. Nurses were more willing to
      serve and defer to male physicians. They approached female physicians on a more
      egalitarian basis, were more comfortable communicating with them, yet more
      hostile toward them. CONCLUSION: When nurses and doctors are female, traditional
      power imbalances in their relationship diminish, suggesting that these imbalances
      are based as much on gender as on professional hierarchy. The effects of this
      change on the authority of the medical profession, the role of nurses, and on
      patient care merit further exploration.

PMID- 12605718
TI  - Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer.
AB  - As with other solid tumors, the growth and metastasis of pancreatic cancer is
      critically dependent on tumor angiogenesis. A major stimulus for a tumor's
      recruitment of additional blood vessels is cellular hypoxia, a condition which is
      especially pronounced in this neoplasm. Hypoxia induces transcriptional
      activation of genes that alter cellular metabolism and promote neoangiogenesis.
      Pancreatic cancer cells have demonstrated activation of such adaptive pathways
      even in the absence of hypoxia. A highly-angiogenic response in this neoplasm
      correlates with increased tumor growth, increased metastasis, and decreased
      survival. Pancreatic cancers expressing high levels of vascular endothelial
      growth factor, a potent pro-angiogenic cytokine, also have a higher incidence of
      metastasis and poorer prognosis. Pancreatic cancer cells uniquely express
      receptors for vascular endothelial growth factor, indicating a role for an
      autocrine loop in tumor proliferation and invasion. Multiple experimental anti
      angiogenic strategies, many of which target vascular endothelial growth factor,
      reduce pancreatic cancer growth, spread, and angiogenesis. Anti-angiogenic
      treatments for pancreatic cancer will likely be most effective when used as an
      integral part of a combination chemotherapeutic regimen.

PMID- 12605722
TI  - Final report of the Conference on the eradicability of Onchocerciasis.
AB  - Sixty-four experts from a variety of disciplines attended a Conference on the
      Eradicability of Onchocerciasis at The Carter Center, in Atlanta GA, held January
      22-24, 2002. The Conference, which was organized by The Carter Center and the
      World Health Organization, with funding from the Bill & Melinda Gates Foundation,
      addressed the question: "Is onchocerciasis (River Blindness) eradicable with
      current knowledge and tools?" Former US President Jimmy Carter attended part of
      the final plenary proceedings on January 24.The Conference consisted of a series
      of presentations by invited expert speakers (Appendix C) and further
      deliberations in four workgroups (Appendix D) followed by plenary discussion of
      major conclusions. The presentations underlined epidemiological and entomological
      differences between onchocerciasis in Africa and the Americas. Whilst
      onchocerciasis in Africa covers extensive areas and is associated with striking
      human and fly population migrations and remarkably efficient black fly vectors,
      in the Americas onchocerciasis is found in limited foci. Human and fly population
      migration are not major problems in the Americas, where most black fly species
      are inefficient, though some efficient black flies are also found there. Vector
      control has been effectively applied in the Onchocerciasis Control Program in
      West Africa (OCP) with remarkable results, interrupting transmission in most
      parts of the original Program area. The use of ivermectin has given variable
      results: while ivermectin treatment has been effective in all endemic areas in
      controlling onchocerciasis as a public health problem, its potential for
      interrupting transmission is more promising in hypo- and mesoendemic areas. The
      African Program for Onchocerciasis Control (APOC), which supports onchocerciasis
      control in endemic African countries outside the OCP, applies ivermectin, its
      principal control tool, to communities in high-risk areas as determined by rapid
      epidemiological mapping of onchocerciasis (REMO) and Geographic Information
      Systems (GIS). In the Americas, through support of the Onchocerciasis Elimination
      Program in the Americas (OEPA), a strategy of bi-annual ivermectin treatment of
      at least 85% of the eligible populations in all endemic communities is showing
      very good results and promises to be effective in eliminating onchocerciasis in
      the region.The Conference concluded that onchocerciasis is not eradicable using
      current tools due to the major barriers to eradication in Africa. However, the
      Conference also concluded that in most if not all the Americas, and possibly
      Yemen and some sites in Africa, transmission of onchocerciasis can be eliminated
      using current tools. The Conference recommended that where interruption of
      transmission is feasible and cost effective, programs should aim for that goal
      using all appropriate and available interventions so that the Onchocerca volvulus
      can eventually be eliminated and interventions halted. Although interruption of
      transmission of onchocerciasis cannot currently be achieved in most of Africa,
      the Conference recommended that efforts be made to preserve areas in West Africa
      made free of onchocerciasis transmission through the Onchocerciasis Control
      Program over the past 25 years. In the remaining hyper and mesoendemic foci in
      Africa, continued annual distribution of ivermectin will keep onchocerciasis
      controlled to a point where it is no longer a public health problem or constraint
      to economic development.

PMID- 12605721
TI  - From wavelets to adaptive approximations: time-frequency parametrization of EEG.
AB  - This paper presents a summary of time-frequency analysis of the electrical
      activity of the brain (EEG). It covers in details two major steps: introduction
      of wavelets and adaptive approximations. Presented studies include time-frequency
      solutions to several standard research and clinical problems, encountered in
      analysis of evoked potentials, sleep EEG, epileptic activities, ERD/ERS and
      pharmaco-EEG. Based upon these results we conclude that the matching pursuit
      algorithm provides a unified parametrization of EEG, applicable in a variety of
      experimental and clinical setups. This conclusion is followed by a brief
      discussion of the current state of the mathematical and algorithmical aspects of
      adaptive time-frequency approximations of signals.

PMID- 12605723
TI  - Impact on the quality of life of lymphoedema patients following introduction of a
      hygiene and skin care regimen in a Guyanese community endemic for lymphatic
      filariasis: A preliminary clinical intervention study.
AB  - BACKGROUND: Hygiene and skin care are effective and important interventions in
      the management of lymphoedema secondary to lymphatic filariasis. We analyzed the
      impact on the quality of life that education and introduction of a designated
      nurse had on lymphoedema patients in a community that was endemic for lymphatic
      filariasis. METHODS: Patients' life quality was assessed using a Dermatology Life
      Quality Index (DLQI) questionnaire. At the same time they received education on
      appropriate hygiene, skin care techniques and simple exercises that encourage
      lymph drainage. A designated nurse was provided with educational materials and
      treatments. The DLQI life quality measure was repeated one year later. RESULTS:
      The DLQI improved for all patients and reported acute attacks were reduced. A
      paired t-test showed the improvement in DLQI to be highly significant (P = <
      0.0001). CONCLUSIONS: A nurse-led service combined with patient education in
      communities endemic for lymphatic filariasis is an effective intervention in
      improving the quality of life of patients with lymphoedema.

PMID- 12605724
TI  - Sex-specific and blood meal-induced proteins of Anopheles gambiae midguts:
      analysis by two-dimensional gel electrophoresis.
AB  - BACKGROUND: Anopheles gambiae is the main vector of Plasmodium falciparum in
      Africa. The mosquito midgut constitutes a barrier that the parasite must cross if
      it is to develop and be transmitted. Despite the central role of the mosquito
      midgut in the host/parasite interaction, little is known about its protein
      composition. Characterisation of An. gambiae midgut proteins may identify the
      proteins that render An. gambiae receptive to the malaria parasite. METHODS: We
      carried out two-dimensional gel electrophoresis of An. gambiae midgut proteins
      and compared protein profiles for midguts from males, sugar-fed females and
      females fed on human blood. RESULTS: Very few differences were detected between
      male and female mosquitoes for the approximately 375 silver-stained proteins.
      Male midguts contained ten proteins not detected in sugar-fed or blood-fed
      females, which are therefore probably involved in male-specific functions;
      conversely, female midguts contained twenty-three proteins absent from male
      midguts. Eight of these proteins were specific to sugar-fed females, and another
      ten, to blood-fed females. CONCLUSION: Mass spectrometry analysis of the proteins
      found only in blood-fed female midguts, together with data from the recent
      sequencing of the An. gambiae genome, should make it possible to determine the
      role of these proteins in blood digestion or parasite receptivity.

PMID- 12605727
TI  - [Cytosolic cathepsin D levels in squamous carcinomas of the lung].
AB  - BACKGROUND AND OBJECTIVES: Cathepsin D is an aspartyl proteinase involved in
      tumoral invasion. The aim of this work was to study cathepsin D cytosolic levels
      in squamous carcinomas of the lung and their correlation with several clinical
      and biological parameters. PATIENTS AND METHOD: The study group included 95
      squamous lung carcinomas and 38 normal tissue samples from the same patients.
      Cathepsin D cytosolic concentrations were determined using an immunoradiometric
      assay (CIS BioInternational. France). EGFR, erbB2 protein, CD44s, CD44v5 and
      CD44v6 levels at cell surfaces were determined. The clinical stage, histological
      grade, ploidy and S-phase cellular fraction (SP) were also considered as
      variables of the study. RESULTS: Cathepsin D cytosolic levels oscillated between
      7.7 and 576 (median: 38.8) pmol/mg protein and were lower (p = 0.001) than those
      observed in 38 normal lung samples from the same patients. When tumors were
      classified according to different clinical and biological parameters, we noticed
      that cathepsin D levels were higher in carcinomas with lower proliferation rates
      and no nodal involvement, reaching statistical significance in both cases.
      Moreover, when lung carcinomas were classified according to cathepsin D
      concentrations, tumors with higher cathepsin D concentrations had lower EGFR
      levels (p = 0.011) and small global SP values (p = 0.025) and DNA index (p =
      0.023). Likewise, they were found to be CD44s positive more frequently (p =
      0.001) and SP positive less frequently (p = 0.022). CONCLUSIONS: These results
      lead us to suggest the following: a) in squamous carcinomas of the lung,
      cathepsin D cytosolic levels are lower than those observed in normal lung samples
      from the same patients, and b) in this subtype of lung carcinomas, high cathepsin
      D levels are associated with tumors without nodal involvement, with low
      proliferation rates, lower EGFR levels, and a reduced positivity for CD44s,
      pointing to a possible role of this proteinase as a parameter of good outcome.

PMID- 12605726
TI  - Current pharmacologic options for patients with Alzheimer's disease.
AB  - BACKGROUND: The aim of the current study was to provide general practitioners
      with an overview of the available treatment options for Alzheimer's disease (AD).
      Since general practitioners provide the majority of medical care for AD patients,
      they should be well versed in treatment options that can improve function and
      slow the progression of symptoms. DESIGN: Biomedical literature related to
      acetylcholinesterase inhibitors (AChEIs) was surveyed. In the United States,
      there are four AChEIs approved for the treatment of AD: tacrine, donepezil,
      rivastigmine, and galantamine. There are other agents under investigation, but at
      present, AChEIs are the only approved drug category for AD treatment.
      MEASUREMENTS AND MAIN RESULTS: AD is becoming a major public health concern and
      underdiagnosis is a significant problem (with only about half of AD patients
      being diagnosed and only half of those diagnosed actually being treated).
      Clinical trials have demonstrated that patients with AD who do not receive active
      treatment decline at more rapid rates than those who do. CONCLUSIONS: Given that
      untreated AD patients show decline in three major areas (cognition, behavior, and
      functional ability), if drug treatment is able to improve performance, maintain
      baseline performance over the long term, or allow for a slower rate of decline in
      performance, each of these outcomes should be viewed a treatment success.

PMID- 12605725
TI  - The production of antibody fragments and antibody fusion proteins by yeasts and
      filamentous fungi.
AB  - In this review we will focus on the current status and views concerning the
      production of antibody fragments and antibody fusion proteins by yeasts and
      filamentous fungi. We will focus on single-chain antibody fragment production
      (scFv and VHH) by these lower eukaryotes and the possible applications of these
      proteins. Also the coupling of fragments to relevant enzymes or other components
      will be discussed. As an example of the fusion protein strategy, the 'magic
      bullet' approach for industrial applications, will be highlighted.

PMID- 12605728
TI  - [An assessment of the effect of helmet use among cyclists and the risk of head
      injury and death in Spain, 1990 to 1999].
AB  - BACKGROUND AND OBJECTIVE: This study aimed to assess the protective effect of
      helmet use by cyclists on risk of suffering head injury or dying as a consequence
      of a traffic crash. SUBJECTS AND METHOD: 26,832 cyclists involved in traffic
      crashes with victims registered in the Direccion General de Trafico database from
      1990 to 1999 in Spain were studied. From this database, variables relating to
      each cyclist (i.e., age, sex, presence of head trauma, severity of lesions) and
      those related with the crash (i.e., place, date, type of crash), were collected.
      The odds ratio and the proportion of the population attributable risk for non-use
      of a helmet by cyclist were estimated. RESULTS: An adjusted odds ratio of 2.45
      (2.19-2.73) for the association between non-use of a helmet and the risk of head
      injury was obtained. As death of the cyclist as the outcome, the corresponding
      odds ratio was 1.35 (1.09-1.67). The values of proportion of the population
      attributable risk were 0.51 (0.47-0.55) and 0.22 (0.07-0.36), for head injury and
      death, respectively. CONCLUSIONS: This study confirms that helmet use among
      cyclists significantly decreased the risk of head injury and, to a lesser extent,
      death. These results constitute a strong argument for increasing in the frequency
      of helmet use among cyclists in Spain.

PMID- 12605729
TI  - [Adaptation and validation of the Health Utilities Index Mark 3 into Spanish and
      correction norms for Spanish population].
AB  - BACKGROUND AND OBJECTIVE: The Health Utilities Index Mark III (HUI-3) is a
      psychometric instrument developed to assign utilities to patients' health states.
      We present its Spanish adaptation and validation. Moreover, we estimate its
      utility in the Spanish population and compare it to Canadian patients. PATIENTS
      AND METHOD: The Adaptation process has been carried out following the original
      protocol by Furlong. A panel of experts was selected in order to warrant the
      process, the questionnaire translation and the training of interviewers. Two
      different samples were used: a modelling sample to develop the Multi Attribute
      Utility function (MAUF) and a directed measure sample to validate the MAUF. Both
      samples are representative of the Spanish population according to gender and age
      quota. In order to estimate the utilities associated with each health state,
      Visual Analogue Scale (VAS) and Standard Gamble (SG) procedures were used. The
      instrument's dimensionality was assessed by means of Factor Analysis, and the
      convergent validity was checked against EuroQoL. RESULTS: The HUI-3 Spanish
      version is feasible (< 2% missing values and 7.34 1.27 minutes completion time)
      and reliable (Cronbach's (= 0.792 in modelling sample, 0.707 in direct measure
      sample, and 0.760 as a whole), showing a good test-retest correlation (0.909, p <
      0.001). Convergent validity is good (correlation with EuroQoL: within 0.788 and
      0.793). Factor solution met 5 factors: Speech & Dexterity, Ambulation & Pain,
      Vision, Emotion & Cognition, and Hearing. The Spanish and Canadian utility
      function differed significantly; 0.07 pts, p < 0.001). CONCLUSIONS: This
      questionnaire can be applied to individuals or collectively, either self
      administered or through an interview. Psychometric indexes are good. Differences
      between Spanish and Canadian utility functions suggest the need of using the
      specific function for each population.

PMID- 12605731
TI  - [Epidemic of metabolic diseases. A warning call].

PMID- 12605732
TI  - [Pharmacogenetic studies: evaluation guidelines for research ethics committees.
      Study protocol and patient information sheet (II)].

PMID- 12605733
TI  - [Current treatment of hypertension].

PMID- 12605730
TI  - [Prevalence of antibodies against Francisella tularensis in Castilla y Leon
      (Spain) before 1997].
AB  - BACKGROUND AND OBJECTIVES: The aim of this paper was determine the prevalence of
      antibodies against Francisella tularensis in the representative sample of people
      from Castilla-Leon (Spain) before epidemic outbreak of end 1997. SUBJECTS AND
      METHOD: We obtain 4,825 sera (between april-1996 and april-1997) of people from
      Castilla-Leon. All sera were tested by a microagglutination technique to detect
      antibodies against Francisella tularensis. The positive sera were tested to
      determine cross-reaction with Brucella, Yersinia enterocolitica and Proteus in
      the tube agglutination tests. RESULTS: We detected antibodies against Francisella
      tularensis in 9 (0,19%) of the 4,825 sera. Only one serum from the 9 seropositive
      was positive in the tube agglutination against Brucella. None of the 9 sera were
      positive against the remaining bacterial antigen tested. CONCLUSIONS: In the
      people of Castilla-Leon before 1997 the prevalence of antibodies against
      Francisella tularensis was 0,19%.

PMID- 12605734
TI  - [GM-CSF: a therapeutic alternative to the bronchoalveolar lavage in the treatment
      of alveolar proteinosis].

PMID- 12605735
TI  - [Haloperidol induced pemphigus foliaceus].

PMID- 12605737
TI  - [Syncope in a patient with Wolff-Parkinson-White syndrome].

PMID- 12605736
TI  - [Hepatotoxicity induced by terazosin].

PMID- 12605738
TI  - [The future of the disability benefit].

PMID- 12605740
TI  - [Evolution of the prevalence of smoking among female physicians and nurses in the
      Autonomous Community of Madrid, Spain].
AB  - BACKGROUND: Smoking is a major cause of mortality in Spain. Tobacco smoking by
      health care workers has a negative influence on the general population. In Spain,
      the prevalence of smoking is high and is increasing among women. The aim of this
      study was to identify tobacco consumption among female physicians and nurses in
      the Community of Madrid, as well as to determine their knowledge about smoking
      and whether smoke-free areas are available in health centers. METHODS: A cross
      sectional, descriptive study was performed in 1998 and 2001 through survey of
      smoking habits in the female medical staff in the Community of Madrid. Multi
      stage sampling with conglomerates was used. RESULTS: We studied 1235 health
      professionals (435 doctors and 800 nurses) in 1998 and 1000 in 2001 (400 doctors
      and 600 nurses); 43.1% were smokers in 1998 and 43% were smokers in 2001. In both
      years smoking was more prevalent among nurses (47.6% and 47%) than doctors (34.7%
      and 37%). Smoking was also more prevalent among health professionals working in
      hospitals (46.6% and 46.7%) than in those working in primary care (35.3% and
      37.3%). When both years were compared, no significant differences in smoking
      prevalence according to profession were found. In both surveys, the prevalence of
      smoking was lowest among younger (< 30 years) doctors (22.9% and 23.6%). A
      similar situation was found in 2001 among nurses (43.8% of those aged < 30 years
      smoked). The percentage of exsmokers was higher in 2001 (18.9% vs. 27.8%). The
      percentage of health workers who smoked in front of patients decreased (2.9% vs.
      1%) as did the percentage of those who thought smoking should be allowed smoke in
      waiting rooms (14.9% vs. 7.4%). The percentage of workers who smoked in staff
      rooms decreased (90.6% vs. 87.1%) and that of health professionals who worked in
      centers with a specific smoking area increased (30.4% vs. 59.4%). CONCLUSIONS:
      The prevalence of smoking among female physicians and nurses in the Community of
      Madrid is very high, and in the case of nurses, it higher than among the general
      population. No substantial changes were observed between the two surveys. Smoking
      is more frequent among nurses than among doctors, and is more frequent in
      hospitals than in primary care. In the second survey, those who smoked less were
      the younger members of both professions, which allows a certain optimism.
      Although it has improved, observance of current legislation in health centers
      continues to be very low.

PMID- 12605741
TI  - [Physical sports activity in a representative sample of the population of Region
      de Murcia, Spain].
AB  - OBJECTIVE: To estimate the prevalence of intense physical activity according to
      age and sex in the region of Murcia, Spain, and to analyze its association with
      major demographic and socioeconomic determinants and other cardiovascular risk
      factors. METHODS: Survey of a representative sample of the population aged
      between 18 and 65 years from Murcia was performed using multistage random
      sampling with definition of the sample quotas. A total of 3091 individuals were
      surveyed. The frequency and duration of intense physical sports activity during
      the two weeks prior to the survey was obtained using a validated questionnaire.
      Information was also collected on socioeconomic variables, smoking, blood
      pressure, weight and height and a blood test was performed to determine plasma
      lipids. Intense or vigorous physical activity (> or = 6 Metabolic Equivalents
      [MET]) was measured in kcal/day and reduced to hours/week to give three
      categories: no vigorous physical activity, less than 2 hours/week, and 2
      hours/week or more. RESULTS: Overall, 17.8% (95% CI: 16.6-19.0) of the adult
      population of the region of Murcia performed intense physical activity for > or =
      2 hours/week. The figures were twice as high in men (23.1%; 95% CI: 21.0-25.2)
      than in women (12.5%; 95% CI: 10.9-14.1). In the logistic regression analysis, a
      higher frequency of intense physical activity was associated with age, level of
      education and employment situation. In men it was also associated with occupation
      and residence in urban areas. CONCLUSIONS: During the study period, one in five
      adults in the region of Murcia took intense physical sports activity with a
      frequency and duration that were compatible with the prevention of episodes of
      coronary ischemia.

PMID- 12605742
TI  - [Variation in the prevention of cardiovascular risk factors. A population-based
      study].
AB  - BACKGROUND: Published studies on clinical practice variability have mainly
      focussed on variability in the rates of hospitalization and surgical procedures.
      The objective of this study was to evaluate variability in the measurement of
      cholesterolemia and blood pressure in four professional groups and in the general
      population. METHODS: A cross-sectional survey was performed by mail in the city
      of Valencia (Spain). Five population groups were selected: physicians, nurses,
      lawyers, architects and the general population. The sample was obtained by random
      sampling of each group. RESULTS: Of all the questionnaires returned, only those
      returned by individuals surveyed (1,755) and their partners (1,296) were used
      (total: 3,050). The frequency of preventive cholesterolemia measurement was
      greater among nurses (55.7%) and physicians (54.1%) than among architects
      (38.9%), lawyers (38.2%) and the general population (35.1%). The frequency of
      preventive blood pressure measurement was also greater among physicians (47.7%)
      and nurses (42.2%) followed by architects (39.4%) and lawyers (38.8%) and was
      lower among the general population (32.2%). After adjusting by sex, age group,
      marital status, level of education, and employment, only lawyers (RR = 0.79; 95%
      CI, 0.6-0.9) and architects (RR = 0.77; 95% CI, 0.68-0.88) showed a significantly
      lower probability of determining cholesterol levels than physicians (basal
      category) and nurses (RR = 1.05; 95% CI, 0.93-1.18). The general population
      showed the lowest probability of measuring blood pressure (RR = 0.8; 95% CI, 0.65
      0.97), although the differences were statistically significant only when compared
      with physicians. CONCLUSIONS: Preventive practices should be increased among
      groups in which they are less frequently performed until they are performed with
      the same frequency as among physicians and nurses. Efforts should be directed to
      increasing cardiovascular prevention programs in health centers.

PMID- 12605743
TI  - [Cost-effectiveness analysis of the use of celecoxib for the treatment of
      osteoarthritis].
AB  - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs), used for the
      treatment of osteoarthritis, can produce serious gastrointestinal (GI) adverse
      reactions.Celecoxib, a specific COX-2 inhibitor, has a proven efficacy equivalent
      to that of traditional NSAIDs with an improved tolerance and safety profile.
      OBJECTIVE: The objective of this study was to perform a cost-effectiveness
      analysis on the use of celecoxib versus traditional NSAIDs in the treatment of
      osteoarthritis. MATERIAL AND METHODS: This cost-effectiveness analysis was
      designed through a pharmacoeconomic model; each effectiveness unit was defined as
      each year of life gained after the ingestion of celecoxib or NSAIDs. The
      probability of different clinical results appearing was obtained from published
      articles and incorporated assumptions. Only direct medical costs were evaluated
      (medication, hospitalization, additional tests, analyses, extra visits, etc.) and
      other costs were excluded. The study perspective was the national health system
      and the time horizon chosen was 6 months. RESULTS: The additional cost for each
      year of life gained through the use of celecoxib compared with that of
      traditional NSAIDs amounted to 8017; (1,333,834 ptas). Sensitivity analysis
      demonstrated how these values were sensitive to changes in the costs of NSAIDs
      and gastroprotective agents as well as to the inclusion of younger population
      groups. CONCLUSION: Celecoxib can be considered as a cost-effective option in the
      treatment of osteoarthritis because its use prevents deaths and increases
      survival rate and the additional cost is reasonable and moderate compared with
      that of NSAIDs. Its efficiency increases in proportion to its use in younger
      patients and probably in those at high risk for developing GI complications.

PMID- 12605744
TI  - [KEZKAK: a new bilingual questionnaire to measure nursing students' stressors in
      clinical practice].
AB  - OBJECTIVE: To develop a bilingual questionnaire (Basque-Spanish) to measure
      nursing students' stressors in clinical practice. METHODS: Ideas were gathered
      from nursing students in group discussions. Initially, 287 nursing students from
      the School of Nursing in San Sebastian (Spain) completed the State-Trait Anxiety
      Inventory (STAI) and the 55-item version of our questionnaire. After analyzing
      the items, we selected 41 items for the final version. Some of the subjects
      completed this final version two (198 = 198) and six months (n = 211) later.
      RESULTS: The questionnaire presented high internal consistency (Cronbach's alpha:
      0.95), considerable reliability (Spearman's correlation: 0.72 at two months and
      0.68 at six months), and acceptable concurrent validity (Spearman's correlation
      with anxiety: 0.39). Factor analysis produced nine factors, with high internal
      consistency, which explained 64.4% of the variance. Based on these factors, the
      main stressors for nursing students in the workplace were produced by lack of
      competence (11.2%), contact with suffering (9.1%), relationships with tutors,
      workmates and classmates (8.9%), uncertainty and impotence (7.7%), lack of
      control in relationships with patients (7.6%), emotional involvement (5.8%),
      relationships with patients [being harmed by the relationship (5.2%) and patients
      seeking a close relationship (4.6%)], and overwork (4.3%). Methodological and
      practice aspects of the questionnaire are discussed, as well as its utility in
      planning the training of future nurses. CONCLUSION: The KEZKAK questionnaire is a
      useful instrument for measuring nursing students' stressors in clinical practice.

PMID- 12605745
TI  - [Words and things].

PMID- 12605746
TI  - [Health professionals' opinion of the Catalan Health Plan. Basis for a reflexion
      on the future].
AB  - OBJECTIVES: To know health professional's opinion of the Health Plan for
      Catalonia (Spain) in order to get news elements for the formulation and
      management of new plans. DESIGN: Combination of quantitative and qualitative
      methodologies. Postal survey to doctors and nurses (multistage randomised
      sample). 3.223 questionnaires were obtained (response rate: 34,1%). Interview to
      a selected sample of 41 health care professionals and managers. MEASUREMENTS AND
      MAIN RESULTS: 78,8% (IC95%: 1,4) of health professionals are familiar with the
      Health Plan, and for most of them it is valued as important. 28,9% (IC95%: 1,7)
      of the professionals who know the Plan consider that it has repercussions in
      their daily work and 51,8% (IC95%: 1,9) declare that it doesn't have any
      repercussions. Different issues such as the planning process, the contents, the
      dissemination strategy, as well as a the poor impact on the health budget are
      critised. Differences by age group and sex, care setting and type of health
      professional are observed. CONCLUSIONS: The implication of health professionals
      in the discussion, formulation and implementation of the Health Plan proposals
      needs to be improved. It will be necessary to make progress in identifying health
      problems and needs, in setting priorities and in the allocation of resources. To
      increase the multisectorial involvement and to develop marketing strategies
      directed to politicians, managers and health professionals will also be needed in
      order to increase the impact of the Health Plan on both the Health System and the
      other sectors involved in health. The role to be played by the Health Plan in the
      health system must be redefined and this will lead to redesigning the planning
      process and the implementation of health strategies.

PMID- 12605747
TI  - [The genome and its metaphors. Detectives, heroes or prophets?].
AB  - The new genetics, or the impetus given to this discipline by the Genome Project,
      aims to a change of paradigm of the Health Sciences. This change is postulated
      from a phenotypic approach to a genotypic one, thereby excluding the influence of
      the environment, which could seriously undermine the grounds for the development
      and exercise of Public Health. Since the beginning of the genome project,
      information on genetic discoveries has frequently been reported in the mass
      media. Metaphors are often used by geneticists and journalists to convey the
      complex concepts of genetic research for which there are no equivalents in the
      lay language. The media do not merely shape the social agenda but also provide
      the space in which health culture is constructed. We present the results of a
      preliminary study exploring the metaphors used in the three most widely-read
      national daily newspapers in Spain, namely ABC, El Pais and El Mundo, when
      reporting news of the new genetics. The possible consequences of the natural
      history of these metaphors, or the process through which figurative terms acquire
      a literal meaning, are discussed. A preliminary taxonomy for the metaphors
      identified was developed. Fifty-one out of 342 identified headings (14.8%)
      contained metaphors. Strategic metaphors such as program, control, code, map, and
      puzzle, were the most commonly used, followed by teleological ones such as
      mystery or God language and finally war-like metaphors such as attack, defeat,
      and capture. The three groups of metaphors are characterized by an attempt to
      giving intentionality to genes. Strategic metaphors predominated over
      teleological and war-like ones and thus a technocratic perspective could form the
      basis of the future construction of health culture.

PMID- 12605748
TI  - [Prevalence of mobile phone use while driving vehicles].
AB  - OBJECTIVE: To estimate the prevalence of mobile telephone use while driving
      vehicles in the city of Lleida (Spain). METHODS: A random sample of 1536 cars
      passing through six intersections regulated by traffic lights in Lleida were
      selected (three with urban traffic and three with interurban traffic). Cyclists,
      motorcyclists and driving school cars were excluded. The variables studied were
      mobile telephone use, age, (18-40; 41-60; >61), sex, the presence of passengers,
      type of intersection (urban traffic/interurban traffic), day of the week (working
      day/weekend or holiday) and hour of the day (rush hour/non-rush hour). The
      prevalence of mobile telephone use was calculated in percentages with a 95% CI.
      The relationship among the dependent variable (mobile telephone use) and the
      other independent variables was studied using odds radios (OR) and 95% CI.
      RESULTS: A total of 1536 direct observations were made and mobile telephone use
      was detected in 50 drivers. The prevalence was 3.3 (95% CI, 2.4-4.3). The
      prevalence was higher in men (OR = 2.2; 95% CI, 1.0-5.7), in drivers aged more
      than 60 years old (OR = 2.2; 95% CI, 0.5-8,4) and in those aged 18-40 years old
      (OR =1.5; 95% CI, 0.8-3.0), in unaccompanied drivers (OR = 3.0; 95% CI, 1.5-6.3),
      in urban intersections (OR = 2.7; 95% CI, 1.2-5.9), on workdays (OR = 2.0; 95%
      CI, 0.9-4.4) and at the rush hour (OR =1.4; 95% CI, 0.8-2.4). CONCLUSIONS: The
      prevalence of mobile telephone use while driving vehicles can be considered high,
      because of the increase in car accidents. The profile of drivers using mobile
      telephones corresponds to men aged 18-40 years or more than 61 years, in urban
      intersections, without passengers, during workdays and at the rush hour. We
      recommend the implementation of measures to decrease the use of mobile telephones
      while driving.

PMID- 12605749
TI  - [Odds ratio or prevalence ratio? Their use in cross-sectional studies].
AB  - BACKGROUND: The most commonly used measures of association in cross-sectional
      studies are the odds ratio (OR) and the prevalence ratio (PR). Some cross
      sectional epidemiologic studies describe their results as OR but use the
      definition of PR. The main aim of this study was to describe and compare
      different calculation methods for PR described in literature using two situations
      (prevalence < 20% and prevalence > 20%). MATERIAL AND METHODS: A literature
      search was carried out to determine the most commonly used techniques for
      estimating the PR. The four most frequent methods were: 1) obtaining the OR using
      non-conditional logistic regression but using the correct definition; 2) using
      Breslow-Cox regression; 3) using a generalized linear model with logarithmic
      transformation and binomial family, and 4) using the conversion formula from OR
      into PR. The models found were replicated for both situations (prevalence less
      than 20% and greater than 20%) using real data from the 1994 Catalan Health
      Interview Survey. RESULTS: When prevalence was low, no substantial differences
      were observed in either the estimators or standard errors obtained using the four
      procedures. When prevalence was high, differences were found between estimators
      and confidence intervals although all the measures maintained statistical
      significance. CONCLUSION: All the methods have advantages and disadvantages.
      Individual researchers should decide which technique is the most appropriate for
      their data and should be consistent when using an estimator and interpreting it.

PMID- 12605750
TI  - [Reporting new HIV cases in Catalonia, Spain: is technical consensus feasible?].
AB  - OBJECTIVE: To describe the process performed in Catalonia (Spain) to design an
      information system for monitoring new cases of HIV infection. METHODS: A survey
      was used to evaluate perception of the need for notification of HIV infection by
      health care professionals (n = 106), as well as their opinions of the various
      possibilities for the implementation of the notification system. As a result of
      this evaluation, a specific technical report defining the objectives and
      technical characteristics of the new notification system was produced. The
      feasibility of the system in health centres was evaluated through discussions
      with health care professionals, health authorities and Non-Governmental
      Organizations, and a second survey was designed to evaluate the use of a personal
      identification code (PIC) from the individual health card (IHC). This process
      took plabe between 1998 and 2000. RESULTS: A total of 84.5% of the health care
      professionals believed that HIV notification should be mandatory and
      confidential; 90.4%, were of the opinion that notification would enable
      identification of the epidemiological characteristics of infected individualos,
      and 75% believed that these individuals would have to be identified by name.
      Finally, 66% of the health care professionals believed that the use of the PIC
      from the IHC would be feasible as the personal identifier in HIV notification. A
      final proposal was draw up and 1 January, 2001 was set as the date to initiate
      the pilot phase of the new HIV notification system. CONCLUSIONS: Most of the
      health care professionals surveyed expressed the need for notification of HIV
      infection, and for such notification to receive institutional endorsement. They
      also believed that, as with other diseases of individualized mandatory reporting,
      notification should be carried out with a single personal identifier. The
      information obtained from notification of HIV infection is essential for the
      optimal planning of preventive programs and the provision of health services. The
      main difficulties observed were that HIV infection has not been included among
      the diseases of mandatory reporting, as well as the low implantation of the PIC
      in the hospitals' clinical registries. All the sectors involved have an important
      role to play in creating the conditions necessary for the notification system of
      new cases of HIV infection to be feasible and useful.

PMID- 12605751
TI  - [Open letter to the president of the Spanish government on health professionals
      and the consequences of a possible war in Iraq].

PMID- 12605752
TI  - [Young people, alcohol and advertising].

PMID- 12605753
TI  - [To write or to publish? The rules of the game].

PMID- 12605754
TI  - [Present and future of antithrombotic therapy in acute coronary syndromes].
AB  - Antithrombotic therapy in the management of an acute coronary syndrome is
      designed to inhibit both the coagulation cascade and platelet activation, thus
      preventing the development of the pathophysiological consequences of these
      processes. The main therapeutic approaches used for this purpose are
      unfractionated heparin, low-molecular-weight heparins, or direct antithrombins,
      all of them being molecules that interfere with the formation of a thrombin clot.
      Numerous clinical studies have investigated the advantages and disadvantages of
      each of these strategies and the benefits and risks of combined therapy with
      these drugs or their association with platelet inhibitors. The difficulty of
      establishing the relative benefits of different therapeutic approaches is due in
      part to the enormous number of possible combinations and the different clinical
      situations in which they can be used. In addition, the need for antithrombotic
      agents with a more specific inhibitor activity and a broader therapeutic range is
      motivating active investigation in laboratories worldwide. This has lead to the
      design of recombinant molecules and monoclonal antibodies that interrupt the
      activation of the coagulation cascade in several strategically important points.
      The relation between the clinical benefits obtained from this new generation of
      molecules and the increased health care costs generated by their design and
      development remains to be seen.

PMID- 12605755
TI  - [Facts and fiction about endothelial function: a new tool for the clinician?].

PMID- 12605756
TI  - [Radial artery access: should it be used more often?].

PMID- 12605757
TI  - [Analysis of differences in flow-mediated dilation in relation to the treatment
      of coronary patients].
AB  - INTRODUCTION: Flow-mediated dilation (FMD) is thought to be related to the
      development of coronary disease. We were interested in knowing the degree of FMD
      in a large sample of coronary patients in relation to the therapy they were given
      in clinical practice. PATIENTS AND METHOD: We studied 1,081 coronary patients
      (age 68 +/- 12 years, 73% male) in which FMD was evaluated in the brachial
      artery. The patients were classified into 5 treatment groups (416 who receive 2
      or more treatments were excluded): group A: 81 controls treated with aspirin,
      group B: 198 treated with ACE inhibitors, group C: 106 with calcium antagonists,
      group D: 145 with beta-blockers, and group E: 135 with lipid lowering medication
      (93% statins). RESULTS: ANOVA was used to analyze the differences between groups.
      With regard to the number of risk factors present in each group, the patients
      treated with ACE inhibitors (2.44 +/- 0.79 vs 2.14 +/- 0.89; p < 0.05) and
      statins (3.45 +/- 0.70 vs 2.14 +/- 0.89; p < 0.05) had more risk factors than GrA
      and higher levels of LDL-cholesterol (ACE inhibitors 145.0 +/- 33.5 vs 128.5 +/-
      32.2 and statins 157.8 +/- 45.3 vs 128.5 +/- 32.2; p < 0.05). GrB had a higher
      glycemia than controls (123.4 +/- 32.2 vs 114.7 +/- 33.7; p < 0.05). The control
      group was younger than the therapeutic groups (p < 0.05). Compared with the
      control group, FMD was significantly higher only in the group treated with ACE
      inhibitors (3.42 +/- 6.01 vs 0.82 +/- 6.04; p < 0.05). Multivariate logistical
      regression showed that treatment with ACE inhibitors and statins (p < 0.05) were
      independent predictors of FMD > 4%. CONCLUSION: Treatment with ACE inhibitors or
      statins was predictive of the normalization of FMD in coronary patients in
      clinical practice.

PMID- 12605758
TI  - [Endothelial adhesion molecules ICAM-1, VCAM-1 and E-selectin in patients with
      acute coronary syndrome].
AB  - INTRODUCTION AND OBJECTIVES: The acute inflammatory response is an important
      phenomenon in the pathogenesis of myocardial damage during acute coronary
      syndrome. Endothelial dysfunction has been found in unstable angina and acute
      myocardial infarction, although the results are controversial. The purpose of
      this study was to determine the levels of the soluble endothelial adhesion
      molecules ICAM-1, VCAM-1 and E-selectin, in patients with unstable angina and
      acute myocardial infarction, compare the results in both groups, and analyze
      their relation with the degree of myocardial injury. METHODS: Serum
      concentrations of ICAM-1, VCAM-1, and E-selectin were measured in 37 control
      subjects and 43 patients (32 with acute myocardial infarction and 11 with
      unstable angina). Measurements were made at the time of admission and ten days
      later using commercial enzyme-linked immunoabsorbent assay (ELISA) kits (R&D
      Systems, UK). RESULTS: There was a significant increase in E-selectin (p < 0.05)
      in patients with unstable angina at admission and ten days later. In contrast,
      patients with acute myocardial infarction showed no significant differences in E
      selectin compared with the control group at admission or ten days later. A
      significant increase in VCAM-1 levels was demonstrated in both groups of patients
      and ICAM-1 levels in acute myocardial infarction, but the concentrations of VCAM
      1 and ICAM-1 in both groups of patients at admission and ten days later did not
      differ significantly. There was no relation between soluble endothelial adhesion
      molecule levels and the severity of myocardial damage estimated by cardiac
      enzymes or electrocardiographic changes. CONCLUSION: This study indicates that
      serum levels of E-selectin, measured at time of admission and ten days later,
      could be a marker for unstable angina and might be useful in the differential
      diagnosis with myocardial infarction.

PMID- 12605759
TI  - [Coronary angiography with 4 f catheters by the radial: minimally invasive
      catheterization].
AB  - INTRODUCTION AND OBJECTIVES: Experience with 4 F catheters in cardiac
      catheterization is limited. These devices appear to be more suitable for the
      radial artery approach than conventional 6 F catheters. METHODS: We analyze our
      preliminary experience with diagnostic catheterization of the radial artery with
      4 F catheters. Angiographic images were evaluated using a predefined scale (1.
      poor; 2. acceptable; 3. optimal). In a subgroup of patients who underwent
      coronary angioplasty, the quantitative angiographic data obtained with the 4 F
      catheter were compared to those obtained with the 6 F guide catheter. In all
      cases the patients were clinically followed-up at 24 h and 7 days. RESULTS: Two
      hundred and six studies performed over a 12-month period were reviewed. In 6
      cases (2.9%) the femoral vein had to be used instead and in 4 cases (1.9%) the 4
      F catheters were replaced by 6 F catheters. The left coronary angiography was
      graded as optimal in 83% and as acceptable in 15%. Right coronary artery images
      were considered optimal in 93% and acceptable in 7%. There was an excellent
      correlation between the reference diameter obtained by quantitative angiography
      with the 4 F catheter and values obtained with a 6 F guide catheter (r = 0.92; p
      < 0.01). No major vascular complications occurred. CONCLUSION: 4 F catheters are
      appropriate for systematic use in diagnostic procedures using the radial access.

PMID- 12605760
TI  - [Transradial approach to coronary angiography and angioplasty: initial experience
      and learning curve].
AB  - INTRODUCTION: The transradial approach has emerged as an attractive alternative
      to the femoral approach for coronary angiography and interventions. We describe
      our experience with the transradial approach and analyze the influence of the
      learning curve. PATIENTS AND METHODS: The transradial approach was attempted in
      patients with a good radial pulse and normal Allen test. When feasible and
      clinically indicated, we attempted ad hoc intervention. We divided the study
      population into two groups: Group A (the first 200 cases) and B (all other
      patients). We compared the radial group with a matched femoral control group.
      RESULTS: We attempted the transradial approach in 526 patients (77.6% male; age
      63.5 +/- 11.51), and obtained a success rate of 93.7%. We found differences
      between group A and B in the success rate (91.0 vs 95.4%, p = 0,04), duration of
      procedure [23 (16-29) vs. 19 (15-24) minutes; p < 0.001], and fluoroscopy time
      [6.4 (4.2-10) vs. 5.0 (3.0-7.7) minutes; p < 0,001]. At 24 h of follow-up, we
      found small hematomas in 9.4%, bleeding in 4.9%, and radial artery obstruction in
      2.8%, with no cases of arteriovenous fistula, pseudoaneurysm, or need for
      vascular surgery. We attempted intervention in 169 patients with 258 lesions,
      achieving angiographic success in 96.1%. We found no differences in the
      characteristics of the lesions and patients, or in the angiographic success rate
      of the radial and femoral PTCA groups. CONCLUSIONS: The transradial approach is a
      safe and effective alternative to femoral catheterization. There is a significant
      learning curve associated with the successful performance of transradial
      procedures.

PMID- 12605761
TI  - [Prognostic value of serum levels of tumor necrosis factor-alpha in patients with
      heart failure].
AB  - INTRODUCTION AND OBJECTIVE: Tumor necrosis factor-alpha is an inflammatory
      cytokine which rises in heart failure and has prognostic value in severe cases.
      Its value is less established in moderate cases. Our aim was to determine its
      prognostic value in cases from a community hospital. PATIENTS: We studied 50
      patients, average age 59.5 12.3 years, with dilated cardiomyopathy (72% non
      ischemic) and moderate heart failure (59% functional class II). METHODS: Patients
      were evaluated with an echocardiogram and cardiopulmonary treadmill stress test
      (Naughton), muscular strength measurements (hand dynamometer), blood tumor
      necrosis factor levels, and an average follow-up of 17.5 9 months (range, 1-29
      months). All causes of mortality, cardiac transplantation, and readmissions for
      heart failure were recorded. RESULTS: Twenty-three patients experienced events.
      These patients were older (63 +/- 12.7 vs 55.7 +/- 11.4 years; p = 0.042), had a
      lower peak VO2 (13.7 +/- 3.9 vs 16 +/- 3.3 ml/kg/min; p = 0.035), and higher peak
      VE/VCO2 and factor levels [41.9 +/- 10.6 vs 33.2 +/- 5.7; p = 0.001 and 4.3 (3.1
      7.9) vs 3.3 (2.4-4.3) pg/ml; p = 0.021, respectively]. In the Cox model, the only
      variable with independent prognostic value was peak VE/VCO2 [HR 1.13 (1.07-1.19);
      p < 0.001]. The best cutoff point was 34.5 (sensitivity, 86.4%; specificity,
      58.3%; p = 0.0007). The cytokine had no independent prognostic value.
      CONCLUSIONS: Our patients with events were older, had a lower peak VO2, and
      higher peak VE/VCO2 and serum tumor necrosis factor levels. However, only peak
      VE/VCO2 had independent prognostic value.

PMID- 12605762
TI  - [Analysis of factors that can influence the appearance of acute heart transplant
      failure].
AB  - INTRODUCTION AND OBJECTIVE: Acute graft failure (AGF) is defined as significant
      failure of myocardial function in a newly implanted heart. The aim of the present
      study was to investigate a series of factors related to heart transplantation
      (HT) in relation to AGF. MATERIAL AND METHOD: In a study of 287 consecutive HTs
      performed over a 14-year period, AGF was defined when: a) the surgeon observed
      ventricular dysfunction before closing the sternotomy; b) various inotropic drugs
      were required at high doses in the first days after surgery, or c) ventricular
      dysfunction was identified by routine echocardiography in the immediate
      postoperative period. Statistical analysis comprised a descriptive and univariate
      comparative study, followed by multivariate analysis based on application of a
      logistical regression model. RESULTS: The incidence of AGF was 22%. Predictors of
      AGF were female donor status (OR = 2.2; 95% CI, 1.2-4.4; p = 0.02), a
      disproportion of more than 20% in donor-recipient body weight (OR = 2.2; 95% CI,
      1.1-4.3; p = 0.02), and background ischemic heart disease (OR = 2.5; 95% CI, 5.5
      1.1; p = 0.03) or valve pathology (OR = 5.0; 95% CI, 7.0-1.5; p = 0.01).
      CONCLUSIONS: AGF is a frequent pathology, which was present in 22% of our heart
      transplantation patients. Among the modifiable factors related to AGF was a clear
      disproportion in body weight and the size of grafts from female donors.
      Unmodifiable factors related to AGF were ischemic heart disease and valvular
      heart disease as a cause of heart transplantation.

PMID- 12605763
TI  - [Assessment of right ventricular function using contrast echocardiography in
      patients with myocardial infarction].
AB  - OBJECTIVE: To evaluate right ventricular size, motility, and ejection fraction
      (RVEF) by contrast echocardiography. METHODS: We studied consecutive patients
      admitted to the coronary intensive care unit with acute inferior myocardial
      infarction, without prior infarction and with or without right ventricle
      involvement, according to accepted electrocardiographic findings. Polygelin, 3.5%
      solution, was used for contrast echocardiography. The reference standard was
      equilibrium radionuclide angiography. RESULTS: We studied 44 patients using
      contrast echocardiography, average patient age 60.8 +/- 10.6 years, 38 men and 6
      women. Abnormal right ventricular size (more than 25 mm) yielded a sensitivity of
      79%, specificity of 87%, positive and negative predictive values of 92 and 68%,
      respectively, and a likelihood ratio of 6. Abnormal right ventricular motility
      had a sensitivity of 70%, specificity of 94%, positive and negative predictive
      values of 95 and 67%, respectively, and a likelihood ratio of 11.6. Right
      ventricular ejection fraction < 30% with contrast echocardiography had a
      sensitivity of 69%, specificity of 97%, positive and negative predictive values
      of 90 and 88% respectively, and a likelihood ratio of 6.9. CONCLUSION: In
      patients with acute inferior myocardial infarction, contrast echocardiography
      with the area-length method is a valid and reproducible technique for evaluating
      right ventricular ejection fraction, which is easy to perform and can be done at
      the patient's bedside.

PMID- 12605764
TI  - [Cardiovascular syndrome X and endothelial dysfunction].
AB  - Up to 30% of patients with chest pain who undergo coronary arteriography, have
      completely normal coronary angiograms. The subgroup with typical angina and a
      positive response to stress testing is generally included under the diagnosis of
      cardiovascular syndrome X. Several causes and mechanisms have been investigated
      in the past twenty years, to explain both chest pain and ischemic angina-like ST
      segment depression that are commonly observed in these patients. Clinical and
      pathogenic heterogeneity appears to be the main features of the syndrome. Among
      the suggested pathophysiological mechanisms, endothelial dysfunction of the
      coronary microcirculation features prominently. In this review, we present the
      available evidence regarding endothelial dysfunction in cardiovascular syndrome
      X.

PMID- 12605765
TI  - [Imaging techniques in modern cardiovascular medicine].

PMID- 12605767
TI  - [Extreme levocardia].

PMID- 12605766
TI  - [Clinical decision making based on cardiac diagnostic imaging techniques (I).
      Diagnosis and therapeutic management of patients with cardiac tamponade and
      constrictive pericarditis].
AB  - Echocardiography, thoracic computed tomography, and magnetic resonance imaging
      are three valuable imaging techniques for the management and pathophysiological
      understanding of cardiac tamponade and constrictive pericarditis. However, these
      techniques should not be used independently from clinical findings. In this
      article we describe the findings that can be obtained with these imaging
      techniques, emphasizing how they should be integrated in the clinical context of
      the patient. Only the proper use of these imaging techniques can optimize the
      management of patients with pericardial disease.

PMID- 12605768
TI  - [Successful ablation of an automatic rhythm originating from his bundle].
AB  - Automatic junctional tachycardias are rare supraventricular tachyarrhythmias
      observed mainly in infants and children. This arrhythmia has a high mortality
      rate. We report the case of a 22-month-old infant in which the
      electrophysiological study disclosed an incessant junctional tachycardia
      originating from an automatic focus located in the His bundle region.
      Radiofrequency pulse delivery to the His bundle with controlled progressive
      heating of this region resulted in a definitive ablation of the ectopic focus
      without complications.

PMID- 12605769
TI  - [Congenital aortic supravalvular stenosis. Frequency and results of surgical
      treatment in a third level hospital].
AB  - In a prospective study made between 1 September 1996 and 31 December 2001,
      pediatric patients with a diagnosis of supravalvular aortic stenosis confirmed by
      a reduction in the aortic inner diameter and a gradient > or = 50 mmHg were
      detected. Of 83 patients with aortic stenosis, only 7 (8.4%) had supravalvular
      aortic stenosis. All 7 patients underwent surgical treatment consisting of
      resection of fibrous tissue and reconstruction of the ascending aorta with a
      preclotted Dacron patch. One patient with severe, diffuse stenosis died and the
      another had perioperative heart failure, cardiac arrest and reversible
      neurological sequelae. A significant decrease in the postoperative gradient was
      obtained (p < 0.05). At present all surviving patients are free of symptoms. It
      was concluded that supravalvular aortic stenosis is infrequent in Mexico. In our
      experience, surgical treatment produced good results and success depended on the
      magnitude and type of stenosis.

PMID- 12605770
TI  - [Valvular heart disease associated with benfluorex].
AB  - We report the first case of valvular heart disease due to benfluorex. A 50-year
      old woman who had been taking the anorectic agent benfluorex intermittently for
      one year developed severe fibrosis and regurgitation of the mitral, aortic and
      tricuspid valves. Clinical, echocardiographic and histopathological findings were
      analogous to those reported with fenfluramine and dexfenfluramine. The similarity
      between the histopathological lesion documented in patients treated with the
      appetite suppressants fenfluramine, dexfenfluramine and benfluorex and the
      valvular lesions reported in valve disease associated with ergot alkaloid use and
      carcinoid heart disease suggest a common pathophysiological mechanism and a
      central role for serotonin in the development of the disease.

PMID- 12605771
TI  - [Chest pain units and emergency departments].

PMID- 12605772
TI  - [Chest pain units: is it urgent its implementation?].

PMID- 12605775
TI  - [Individualization of anti-hypertensive therapy. Past, present and future].

PMID- 12605776
TI  - [Ponderal evolution in the Girona population, 1989-1999].
AB  - BACKGROUND AND OBJECTIVE: Despite the number of plans leading to lose weight
      among individuals in the developed countries, the prevalence of obesity has
      increased since 1980. The knowledge of ponderal evolution in a given population
      is very important because the adverse effects of obesity vary greatly among
      individuals and populations. The objective of the present paper was to determine
      the modifications in the different degrees of body adiposity in a population in
      Catalunya. PATIENTS AND METHODS: A measurement was made of weight and height of
      24554 users aged over 14 years (10595 males and 13959 females) attended at four
      basic health areas (BHA): Girona 1, Girona 4, Salt and Camprodon, and a Primary
      Health Center (PHC) in the Girona province, for a five-year period, 1995-1999.
      The prevalence of the different degrees of obesity was compared with that
      obtained in a previous study with 6373 individuals during the 1986-1989 period
      (4,579 males and 1794 females). RESULTS: The prevalence of women with overweight
      (defined as a body mass index [BMI] > 25 kg/m2) increased from 7.3% (1986-1989,
      study 0) to 17.6% (1995-1999, study 1) for women aged 15 to 24 years ( p <
      0.001), from 17.9 % to 28.1% for women aged 25 to 34 years (p < 0.001), and from
      37.5% to 44.7 % for women aged 35 to 44 years (p < 0.001). In the latter age
      group, the proportion of women with obesity (BMI > 30 kg/m2) increased from 6.9%
      to 12.9%. Similar trends were observed among men, and the change in the 35-44
      year age group (from 10.5 % of obese men to 16% [p < 0.001]), and 55 to 65 years
      (from 16.6% of obese men to 22.7% [p < 0.001] was particularly significant. And
      lastly, it is also noteworthy the proportion of individuals with low weight (BMI
      < 18.5 kg/m2) which increased from 7.3% to 11.6% for women aged 15 to 24 years,
      and from 0.3% to 2.2% for women aged 35 to 44 years. This trend was also observed
      for men aged 15 to 24 years (11% to 17.2%). CONCLUSIONS: The relative increase in
      the prevalence of overweight and obesity runs in parallel to that found in other
      surrounding countries. Also, it is worth mentioning that among women aged 15 to
      24 years the increase in the prevalence of low weight and obesity is almost
      identical, which invalidates the mean and median values as a means to assess the
      ponderal evolution in this population. The current compartmentalization between
      the extreme BMIs, particularly among the youngest portion of population should be
      addressed from a multidisciplinary perspective.

PMID- 12605777
TI  - [Community-acquired pneumonia in inpatients: mortality, comorbidity and risk
      classes].
AB  - BACKGROUND: It is necessary to determine what patients with community acquired
      pneumonia (CAP) are at highest risk of death and which characteristics allow such
      determination. OBJECTIVE: To analyze the risk classes in the CAP. To verify what
      was the associated comorbidity and whether age, sex or residence area of
      inpatients with CAP increased the proportion of deceased patients. METHODS: A
      total of 113 patients were studied (68 males and 45 females) and 15 died (13.3%).
      The mean age of the deceased patients was 82.5 years (standard error [SE]: 6.63
      years) significantly higher than that in survivors (70.5 years, SE: 17.3 years).
      There were no significant differences concerning age or sex between the deceased
      patients and survivors belonging to the most severe class. Most patients had
      comorbidities (82 patients, 72.6%). Seventeen (15%) of the inpatients came from a
      nursing home, more frequently among the deceased (5 patients, 33%) than among
      survivors (12 patients, 12%), a statistically significant difference (p < 0.05).
      CONCLUSIONS: No differences were observed between patients regarding age or sex,
      once patients were stratified by risk classes. There was a high proportion of
      concomitant diseases, and the mortality rate was higher among patients with some
      associated disease. In our series, patients from a nursing home had a higher
      mortality rate.

PMID- 12605778
TI  - [Computerized registry of patients with thromboembolic disease in Spain (RIETE):
      background, objectives, methods, and preliminary results].
AB  - BACKGROUND: Venous thromboembolic disease (VTD) is a common and severe condition.
      Its anticoagulation-based treatment is not without complications and failures.
      OBJECTIVE: To create in Internet a broad database of patients with venous
      thromboembolic disease attended at spanish hospitals which might be helpful in
      the clinical practice. METHODS: Computerized registry of all incident cases of
      patients with objective diagnosis of VTD attended at 27 spanish hospitals since
      March, 1st, 2001. All data related to diagnosis, treatment and follow-up during
      at least a 3-month period were collected. RESULTS: Since March 1st to August
      31st, 2001, 573 patients were included (399 with VTD, 108 with PE and 66 with VTD
      and PE). The mean age of patients was 65.8 years. 10.5 % of patients had at least
      one risk factor: 5.2% hypoprothrombinemia (< 50%), 3% history of recent
      hemorrhage, 1.8% creatinine higher than 3 mg/dl, 1.3% hemodynamic unstability,
      1.1% pregnancy, and 1% thrombopenia lower than 60000 platelets/mm3. The three
      month follow-up period was completed by 35.4% of patients, 21.8 % of them with
      events (death [4.7%], hemorrhage [12.5%], and VTD relapse [4.2%]).
      Hypoprothrombinemia was significantly associated with increased risk of
      complications and history of recent hemorrhage with relapse. CONCLUSIONS: It is
      feasible to create a database containing information on a relevant number of VTD
      patients, 10.5% of them with complications. Such information will allow its
      utilization at short-term for the decision-marking process, particularly for
      patients with complications.

PMID- 12605779
TI  - [Pseudotumor cerebri and systemic lupus erythematosus].
AB  - Pseudotumor cerebri (PC) is a syndrome characterized by intracranial hypertension
      in the absence of any space-occupying lesion, hydrocephalus, cerebral sinus
      thrombosis and biochemical or cytological abnormalities in the CSF. PC has ben
      associated with several factors such as systemic conditions or drugs. We report
      here the case of a patient who presented with headache, vomiting and blurred
      vision accompanied by bilateral papilledema and had been diagnosed with systemic
      lupus erythematosus (SLE) seven years before. Treatment was started with high
      dose corticosteroids with rapid resolution of the clinical symptoms and
      papilledema of the patient.

PMID- 12605780
TI  - [Heterotopic pancreatic transplantation with whole vascularized graft (whole
      organ)].

PMID- 12605781
TI  - [Clinical management of hypertension in the elderly].

PMID- 12605782
TI  - [Therapeutic criteria in acute coronary syndrome].

PMID- 12605783
TI  - [The paradoxical action of bisphosphonates at the bone level].

PMID- 12605784
TI  - [Neurologic impairment and seizures].

PMID- 12605785
TI  - [Simultaneous threatening hemoptysis and hemothorax].

PMID- 12605786
TI  - [Patient with right chest pain].

PMID- 12605787
TI  - [Forty-eight year oldmale with dysphagia, general syndrome and finger clubbing].

PMID- 12605788
TI  - [Quality of hospital discharge reports in Internal Medicine].

PMID- 12605789
TI  - [Carcinomatous meningitis with polimorphonuclear pleocytosis as presentation of
      gastric adenocarcinoma].

PMID- 12605790
TI  - [Staphylococcus lugdunensis endocarditis. Case report and review of the
      literature].

PMID- 12605791
TI  - [Lipodystrophic syndrome associated with infection with the human
      immunodeficiency virus and mediastinal lipomatosis].

PMID- 12605792
TI  - [Improving medical training: small steps with great benefits].

PMID- 12605793
TI  - [Utility of perindopril in mild-moderate heart failure in daily clinical
      practice. METRICA trial].
AB  - INTRODUCTION AND OBJECTIVES: Angiotensin II converting enzyme inhibitors have an
      unquestionable utility in heart failure, although these drugs are underused and
      rarely used at the recommended doses in the clinical practice. The objective of
      this investigation was to study the simplicity of perindopril use in the
      treatment of heart failure and to confirm its clinical and radiological efficacy.
      MATERIAL AND METHODS: Perindopril was orally administered at 2-4 mg/day doses to
      180 patients with heart failure and functional class I-III who were not being
      treated with angiotensin II converting enzyme inhibitors. The percentage of
      patients who reached the target dose (4 mg/day) was studied as well as clinical
      (functional class of the NYHA) and radiological efficacy of this treatment in
      these patients. RESULTS: The target dose (4 mg/day) in heart failure was reached
      in 87.5% patients, with a rate of adverse effects of 18.9%. Eighty-nine percent
      of patients in the functional class III and 38.3% of patients in class II had
      clinical improvement. The cardio-thoracic index decreased from 0.57 to 0.54 (p <
      0.05). A minimal irrelevant change was observed in the analytical levels of
      creatinine and potassium. Only three patients (1.7%) abandoned the trial early in
      its course. CONCLUSIONS: An efficient dose for heart failure is simply and safely
      obtained with perindopril, with a significant improvement in the NYHA functional
      class and in the radiological cardio-thoracic index.

PMID- 12605794
TI  - [Oral or sublingual nifedipine: utility and long-term effectiveness of medical
      education to decrease its use in increased blood pressure].
AB  - OBJECTIVES: Despite the severe side effects reported, short acting nifedipine
      compounds (oral or sublingual) are still widely used for the considered
      hypertensive emergencies. The objective of this study was to study the effect of
      simple medical education measures on the prescription of such compounds in our
      institution. METHODS: In a previous survey we found that 67% of physicians
      involved in the care of hypertensive emergencies at our institution considered
      oral/sublingual nifedipine the therapy of choice. The recommendations in the JNC
      VI document were reviewed in a Clinical Session and each participating physician
      was provided with a translated copy and a letter with the reasoned answer. The
      Pharmacy Department provided a list of patients with the prescriptions of
      nifedipine upon request and programmed in the Emergency Department, Medical and
      Surgical Departments. Four time periods were considered: first or control (pre
      session): September 1997-March 1998; second (immediately post-session): June 1998
      December 1998; third (9-12 months post-session): January 1999-June 1999, and
      fourth (28-34 months post-session): September 2000-March 2001. At a later session
      the results were presented and a summary of results was submitted to Departments
      with a consensus note on the prescription of short acting nifedipine compounds.
      RESULTS: There were significative decrements in urgent and total doses and
      treated patients during the periods considered. This effect was sustained and in
      a three-year period reductions of 78% (Emergency Room), 91% (Medical Services)
      and 79% (Surgical Services) of prescriptions were noted. CONCLUSIONS: Simple
      measures of continuous medical education (scientific meetings, personal letters
      and facilitated access to scientific evidence) were highly effective in reducing
      prescriptions of short-acting nifedipine at our centre.

PMID- 12605795
TI  - [Utility of verapamil in the treatment of diastolic dysfunction in patients with
      acromegaly].
AB  - INTRODUCTION: Diastolic dysfunction is a common complication in patients with
      acromegaly. By using the metabolic treatment for acromegaly, an improvement in
      diastolic function is not always achieved and a group of these patients could
      obtain some benefit from a specific treatment for such a condition. The objective
      of the present study was to evaluate the utility of verapamil therapy in
      acromegalic patients with diastolic dysfunction. METHODS: Fourteen patients (7
      males and 7 females) with the diagnosis of acromegaly and diastolic dysfunction
      confirmed by echocardiogram were studied. After six months of treatment with
      verapamil (240 mg/day) the echo-cardiographic parameters and the functional class
      (NYHA) of patients were reevaluated. RESULTS: All patients showed an increased
      basal measurement of the cardiac mass (mean [percentiles 25-75]: 149 g/m2 [128
      264]) and no improvement was observed after treatment (182 g/m2 [123-328]). Also,
      no improvement was found regarding the studied diastolic function parameters: E/A
      relationship of left ventricle (0.70 [0.54-0.83] versus 0.61 [0.54-0.86]) and
      isovolumetric relaxation time (146 [119-193] versus 120 [97-169]). A trend
      towards improvement was indeed found in the functional class, although no
      statistical differences were observed. CONCLUSION: Our results did not
      demonstrate a benefit derived from the treatment with verapamil upon the
      diastolic function in patients with acromegaly.

PMID- 12605797
TI  - [Tuberculin testing and therapy of latent tuberculosis infection].

PMID- 12605796
TI  - [Diagnostic utility of D-dimer measurement in patients with clinical suspect of
      pulmonary thromboembolism in the setting of an Internal Medicine Department].
AB  - BACKGROUND: The diagnosis of pulmonary thromboembolism (PTE) may be a challenge
      in many cases, particularly among the elderly patients. OBJECTIVE: To establish
      the diagnostic utility of D-dimer measurement by a rapid semi-quantitative
      immunoassay (NycoCard, D-Dimer, normal value < or =0.3 mg/l) in a series of
      patients with suspected PTE admitted to an Internal Medicine Department. METHODS:
      Retrospective review of 48 patients admitted to our Department with the clinical
      suspect of PTE and D-dimer assay, in whom a lung ventilation/perfusion scan was
      conclusive (high or normal/very low/low probability of PTE). RESULTS: The median
      age of patients was 67.4 years and 79.2% were older than 60 years. For the
      diagnosis of PTE, the values of sensitivity, specificity, positive predictive
      value, and negative predictive value were 95.2%, 55.5%, 62.5% and 93.7%,
      respectively. When patients with potential confounding factors in the measurement
      of D-dimer (surgery and/or trauma in the 2 previous weeks, or neoplasm) were
      excluded, similar results were obtained. CONCLUSIONS: When a normal D-dimer (< or
      =0.3 mg/l) measurement by a rapid semi-quantitative immunoassay (NycoCard) is
      obtained, the presence of PTE is very unlikely. An increased D-dimer should lead
      to additional complementary tests to confirm or rule out PTE. These results apply
      for patients aged over 60 years and are not influenced by potential confounding
      factors.

PMID- 12605798
TI  - [Utility of angiotensin receptor blockers in heart failure].

PMID- 12605799
TI  - [Thiazolidinediones: effect of the pioglitazone on hyperglycemia, dyslipidemia
      and cardiovascular risk].

PMID- 12605800
TI  - [Fifty-three year old woman with chylothorax and mediastinal and abdominal lymph
      node enlargement].

PMID- 12605801
TI  - [Inflammatory nodule after insect bite].

PMID- 12605802
TI  - [Septic gonarthritis in a patient with femur fracture 13 years later].

PMID- 12605803
TI  - [Immigrant with unilateral hyperpigmentation in the lower limbs and
      eosinophilia].

PMID- 12605804
TI  - [Favorable evolution with conservative therapy in spontaneous spleen rupture
      during infectious mononucleosis].

PMID- 12605805
TI  - [Cytomegalovirus pneumonia in a patient with thymoma-associated
      immunodeficiency].

PMID- 12605806
TI  - [AA amyloidosis in an HIV-seropositive patient: case report and review of the
      literature].

PMID- 12605808
TI  - [Socioeconomic circumstances and premature mortality from chronic diseases].
AB  - BACKGROUND AND OBJECTIVE: Our aim was to investigate the association between
      socioeconomic factors in childhood or adolescence and adulthood and premature
      mortality from various causes of death. SUBJECTS AND METHOD: Men and women aged
      25-74 years residing on May 1, 1996, in the Autonomous Community of Madrid. For
      the next 19 months, information on individuals who died and the cause of death
      were obtained from the Mortality Register. We estimated the mortality from 5
      types of cancer and from 4 chronic diseases by the educational level--as an
      indicator of the socioeconomic circumstances in childhood or adolescence--and by
      income--as an indicator of the socioeconomic circumstances in adulthood. RESULTS:
      When both variables were included in the analysis simultaneously, the relative
      mortality ratio for men with second grade first phase and lower educational level
      versus those with second grade, second phase and higher educational level and the
      relative mortality ratio for men belonging to income quartiles 3 and 4 (lowest)
      versus those belonging to quartiles 1 and 2 were, respectively: 1.15 (95%
      confidence interval 1.01-1.31) and 1.22 (1.09-1.36) for lung cancer; 1.46 (1.19
      1,93) and 1.13 (0.90-1.41) for gastric cancer; 1.80 (1.32-2.44) and 1.46 (1.18
      1.80) for chronic obstructive pulmonary disease; and 1.18 (0.77-1.81) and 0.68
      (0.47-0.98) for diabetes mellitus. For women the relative mortality ratios were,
      respectively: 0.63 (0.43-0.92) and 0.72 (0.52-0.99) for lung cancer; 1.68 (0.99
      2.83) and 1.17 (0.86-1.60) for gastric cancer; 0.76 (0.61-0.94) and 0.98 (0.82
      1.16) for breast cancer; 1.36 (0.95-1.95) and 1.20 (0.97-1.48) for ischemic heart
      disease; 1.72 (1.19-2.50) and 0.93 (0.75-1.16) for stroke; and 2.23 (0.94-5.27)
      and 1.51 (1.02-2.25) for diabetes mellitus. CONCLUSIONS: Premature mortality in
      adulthood is associated with several socioeconomic factors acting across the
      whole course of life. The contribution of these socioeconomic circumstances to
      mortality varies regarding the cause of death and gender.

PMID- 12605809
TI  - [Clinical trials with rofecoxib: analysis of the information from the gender
      perspective].
AB  - BACKGROUND AND OBJECTIVE: There is evidence if the low rate of participation or
      even exclusion of women in clinical trials (CT), and that sex-differences are not
      considered in the design and analysis of the CT. The objectives of the study were
      to determine whether women are properly represented in the CT with rofecoxib and
      to analyze the information of CT with rofecoxib from a gender perspective.
      MATERIAL AND METHOD: Twenty eight rofecoxib CT in adults have been reviewed, all
      indexed in Medline and published between 1999-2001. The FDA Guideline for the
      Study and Evaluation of Gender Differences in the Clinical Evaluation Drugs was
      used to analyze the information. RESULTS: An 80% of the trials do not describe
      efficacy results by sex, and only one reports side effects by sex. A 78.3% does
      not report stratified analysis by sex. In the discussion the possible difference
      by sex of the results is mentioned in 3 occasions. Only 8% of the CT considers
      the influence of hormonal variation in the results. The pharmacokinetics issues
      related specifically to women are poorly followed: in 60% of the CT it is not
      specified the influence of oral contraceptives in the results of the trial, and
      in 88.9% of CT it is not specified the influence of estrogen treatment in the
      results of the trial. Pregnancy as exclusion criteria is only considered in 50%
      of the trials. CONCLUSIONS: CT with rofecoxib has included more women than men.
      Important information on specific situation related to gender, recommends by FDA
      Guideline for the Study and Evaluation of Gender Differences in the Clinical
      Evaluation Drugs, have not been followed.

PMID- 12605810
TI  - [Two first years' bacteremia incidence and impact in a new hospital].
AB  - BACKGROUND AND OBJECTIVE: We pursued here to determine the incidence of blood
      stream infections. PATIENTS AND METHOD: Longitudinal descriptive study. All
      patients admitted to hospital from January 1999 to December 2000 were included.
      Blood-stream infection episodes were defined according to CDC criteria. Blood
      stream infection prevalence and incidence density (ID), nosocomial primary blood
      stream infection attributable to intravascular devices intravascular devices and
      population attributable fraction were estimated. RESULTS: Overall blood-stream
      infection ID was 1.3 por 1,000 patient-years. Nosocomial blood-stream infection
      represented 1.1 per 1,000 patient-days. Nosocomial primary blood-stream infection
      attributable risk was 54.3%, population attributable risk was 49.8% and
      population attributable fraction was 86.6%. CONCLUSIONS: The incidence of blood
      stream infection was similar to that reported by other centers. The impact of
      intravascular devices on nosocomial blood-stream infections in our hospital was
      high

PMID- 12605811
TI  - [Thymus: old gland, new ideas].

PMID- 12605812
TI  - [Primary trimethylaminuria or fish odor syndrome. A novel mutation in the first
      documented case in Spain].
AB  - BACKGROUND AND OBJECTIVE: Trimethylaminuria or fish odor syndrome is a metabolic
      disorder characterized by a failure in the oxidation route from trimethylamine
      (TMA) to trimethylamineN-oxide (TMA-O). Primary trimethylaminuria is an inherited
      autosomic recessive disease due to mutations in the human FMO3 gene. High levels
      of free TMA in urine and other body fluids confer an unpleasant body odor
      resembling that of fish. Here we report a case of primary trimethylaminuria in a
      4-year-old girl. PATIENT AND METHOD: A 4-year-old girl who presented with a
      strong corporal scent resembling that of fish from the age of 9 months agreeing
      with the introduction of fish in the diet. The patient did not have other
      relevant personal history and had a correct psychomotor and growing development.
      Liver function, urea and creatinine levels were normal. The biochemical diagnosis
      was done by spectrometry, measuring the amount of TMA and TMA-O prior to and
      after fish intake. RESULTS: Genetic analysis evinced that the patient was
      homozygous for a novel mutation in exon 3, R51G (c. 151A > G). Both parents were
      heterozygous. CONCLUSIONS: R51G (c. 151 A > G) mutation had not been found in
      other patients with trimethylaminuria.

PMID- 12605813
TI  - [Attention deficit hyperactivity disorder: diagnosis and drug therapy].

PMID- 12605814
TI  - [Pharmacoeconomic analyses in clinical trials. Principles and practice].

PMID- 12605815
TI  - [Antiphospholipid antibodies, avascular bone necrosis and HIV infection].

PMID- 12605817
TI  - [Creutzfeldt-Jakob disease and nonconvulsive status epilepticus].

PMID- 12605818
TI  - [Composite lymphoma].

PMID- 12605819
TI  - [Occupational asthma due to iroko].

PMID- 12605820
TI  - [Acute hepatitis due to montelukast].

PMID- 12605821
TI  - [Predictive factors for transfusion requirements in patients over 65 years old
      with subcapital hip fracture].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to know the patient's clinical and
      hematologic characteristics that could influence the use of blood in subcapital
      hip fracture (SCHF). PATIENTS AND METHOD: A prospective study of all patients
      affected by SCHF having surgery during 1998. Patients younger than 65 years, with
      primary blood diseases or under anticoagulation therapy were excluded. Age,
      gender, elapsed time, type of SCHF (international AO classification), surgical
      procedure (nail vs. hip arthroplasty), transfusional procedure and total used;
      hemoglobin (Hb) and hematocrit (Hct) levels at days 0 and + 2 (if surgical
      procedure was not performed) and after surgery were studied. Also we analyzed
      different hematimetric parameters: VCM, HCM, and RDW, transfusional act and blood
      consume. Statistical univariant analysis included T-Student test for numeric
      variables and Pearson X2 test for string variables. Statistical significance
      differences were considered when p < 0.05. A multivariate stepwise logistic
      regression model was carried out. RESULTS: 75 patients with SCHF were studied: 18
      B1, 8 B2 and 49 B3 according to AO classification. Male/female: 12/63; age 81(SD:
      8) years (range 65-99). At the admission day, the Hb level was 128 (SD: 23) g/L;
      Hct 0.39 L/L (SD: 0.06) (range 13-52), HCM 30.3 pg, VCM 91.4 fL and RDW 14.3%.
      The elapsed time was 5 (SD: 2.8) days. 22 patients (29.3%) had anemia on
      admission. Surgery consisted of: nails in 23 (31%) and hip arthroplasty in 52
      (69%) patients. At day + 2 (n: 36) Hb was 119 g/L (SD: 12) and Hct 0.36 L/L (SD:
      0.04). 34 (45%) patients were not transfused. On the statitiscal univariant
      study, Hb and Hct levels at admission and after surgery, RDW (anisocytosis), type
      of fracture and the surgical act were all associated with a transfusional
      procedure. In the transfused patients the Hb level (119.9 g/L) was lower than in
      non-transfused ones (138 g/L) (p < 0.01). 71% hip arthroplasty patients were
      transfused vs 17% nail patients (p < 0.01). On the logistic regression only the
      preoperative Hb level (p < 0.01) was identified as an independent predictor of
      transfusion. CONCLUSIONS: These results invite us to improve the hematological
      parameters in this elderly population and to promote earlier and less aggressive
      surgical procedures (nails) and to promote the use of alternatives methods to
      reduce the use of allogenic blood.

PMID- 12605822
TI  - [Dietary variety and diversity of Spanish children: Four Provinces Study].
AB  - BACKGROUND AND OBJECTIVE: Diet variety is claimed for ensuring a healthy eating.
      Our objective was to analyze the relationship between the variety and diversity
      of the diet and its nutritional quality among Spanish children. SUBJECTS AND
      METHOD: Cross-sectional study where information on food and nutrition was
      obtained through a food frequency questionnaire. The sample included 1,112
      children aged 6-7 years from 4 cities. Children were selected by random cluster
      sampling in schools and stratified by sex and socioeconomic level. We calculated
      a diet variety index (DVI)--count of food items--and a diet diversity index (DDI)
      -count of food groups. To measure the overall diet quality, the Healthy Eating
      Index (HEI-f) was used. RESULTS: The percentage of children eating less than one
      daily food serving varied between 0% for the grain and 11.3% for the fruit
      groups. Diet variety and diversity were positively associated with the intake of
      fiber, vitamines B6 and E and folic acid, and the percentage of caloric intake
      resulting from polyinsaturated fatty acids and carbohydrates. In contrast,
      intakes of lipis and saturated fatty acids, vitamine C, sodium and calcium were
      all negatively associated with diet variety and diversity. Although both DVI and
      DDI were possitively associated with the HEI-f, the results from a regression
      model showed that it was only DDI that contributed significantly to the model
      fitting (p < 0.001). CONCLUSIONS: These results support the goodness of a varied
      diet that includes ingredients from different food groups and, at the same time,
      maintains the energy energy within recomended levels.

PMID- 12605824
TI  - [Are old people well nourished?].

PMID- 12605823
TI  - [Prevalence of the metabolic syndrome in the population of Canary Islands,
      Spain].
AB  - BACKGROUND AND OBJECTIVE: The program for the detection of high blood cholesterol
      in adults (ATP III) has recently published diagnostic criteria for the metabolic
      syndrome. Its prevalence in the Canarian population is reported here. SUBJECTS
      AND METHOD: 578 adults, who participated in the Nutritional Survey of the Canary
      Islands (ENCA 1997-1998) were selected. Metabolic syndrome was fined as the
      presence of 3 or more criteria. RESULTS: Three out of every four individuals
      fulfilled at least one of the criteria. In men, hypertriglyceridemia,
      hypertension and hyperglycemia predominated. In women, abdominal obesity and low
      HDL-cholesterol were more common. The global prevalence of the syndrome was 24.4%
      (95%CI: 19.6-29.8), increasing with age and decreasing with the educational
      level. CONCLUSIONS: The prevalence of the metabolic syndrome among adults from
      the Nutritional Survey of the Canary Islands is high and similar to that observed
      in the USA (21.8%).

PMID- 12605825
TI  - [Hemolytic anemia due to ABO or Rh antibodies in recipients of solid organ
      transplants].
AB  - BACKGROUND AND OBJECTIVE: Hemolysis due to ABO or Rh unmatched transplants in
      solid organ recipients owes to the passage of lymphocytes with immunologic
      information. The development of antibodies and hemolysis is directly related to
      the amount of lymphocytes that goes with the transplanted organ. We present five
      cases of hemolytic anaemia, 2 by ABO and 3 by Rh systems. PATIENTS AND METHOD:
      From January 1991 to June 2001, 22 liver transplants ABO-unmatched, 236 renal
      transplants Rh-unmatched and 240 liver transplants Rh-unmatched were performed in
      our center. Both in donors and recipients, we performed an hematologic study with
      determination of indirect antiglobulin test (IAT). When IAT was positive, the
      antibody was determined through different methods. If hemolysis was suspected
      after transplantation, direct antiglobuline test (DAT) and antibody specifity
      were determined. RESULTS: Two liver transplants ABO-unmatched and three Rh
      unmatched developed hemolysis. It was severe in all them and appeared between the
      8th and 40th post-transplant day. Screening for irregular antibodies was negative
      in all pre-transplant patients. In donors, anti-D was recognized in two cases.
      Among post-transplant patients, DAT and IAT were positive in all them, anti-A was
      found in two, anti-D in two and anti-E in one case. All patients were treated
      with IV steroids. Four required transfusion with compatible packed red blood
      cells. CONCLUSION: Hemolysis in the context of a solid organ transplantation with
      minor unmatched ABO or Rh must alert us about the possibility of passage of donor
      lymphocytes.

PMID- 12605826
TI  - [Unified report from committes on Ethics and Clinical Investigations in
      multicenter trials].

PMID- 12605827
TI  - [Helicobacter pylori, cyclooxygenase-2 and gastric cancer].

PMID- 12605828
TI  - [Treatment of primary pulmonary hypertension with vasodilator drugs].

PMID- 12605830
TI  - [About limitations (and subterfuges) of evidence based medicine].

PMID- 12605831
TI  - [Controversies on the abreviated form of millimeters of mercury].

PMID- 12605833
TI  - [Arthritis by Candida tropicalis in an HIV-infected patient].

PMID- 12605834
TI  - [Clinical, metabolic, immunologic and genotypic characteristics in non-pediatric
      patients with type 1A diabetes mellitus. Onset and short-term prognosis].
AB  - BACKGROUND AND OBJECTIVE: Around 50% of new cases of type 1 diabetes mellitus
      (DM1) are seen in subjects aged above 15 years. It is of particular interest the
      characterization of such a population. THE AIMS OF OUR STUDY WERE: a) to
      characterize a group of non-pediatric subjects with DM1 at the onset of the
      disease; b) to evaluate the prognosis of the disease under conventional intensive
      insulin therapy, and c) to investigate the presence of mutations in the HNF-1*
      gene in those subjects who did not display pancreatic autoimmune markers.
      SUBJECTS AND METHOD: All subjects with an age >= 15 and 35 years recently
      diagnosed DM1 (1998-2001) were included in the study. Pancreatic cell function
      was assessed by glucagon test (at onset and at 12 months). The presence of
      pancreatic autoantibodies, GAD, IA2 and IAA was evaluated. HLA class II genes and
      the 10 exons of HNF-1* gene were analyzed from genomic DNA. RESULTS: We studied
      86 subjects (32 women, 23.9 [5.3] year-old). Eighty percent of subjects were
      positive for any of the studied autoantibodies. Alone or in combination, GAD was
      positive in 68.6% of subjects, IA2 in 45.3% and IAA in 27.9% of them. Most
      frequent haplotype was DRB1*0301-DQA1*0501-DQB*0201. There were no differences
      with regard to clinical, metabolic or genetic characteristics among those
      subjects with or without presence of pancreatic autoantibodies (at onset and at
      12 months). We did not find mutations in the HNF-1* gene in any of the subjects
      included in our study. After 12 months of follow-up, cell function remained
      unaltered in comparison with that observed at the onset of the disease.
      CONCLUSIONS: Clinical, immunological and HLA characteristics of a non-pediatric
      DM1 population are in agreement with expected results. The absence of pancreatic
      autoimmune markers neither rules out the existence of type 1A diabetes mellitus
      nor is associated with mutations in the MODY-3 gene. A therapeutic programme
      using conventional intensified insulin treatment prevents the impairment of
      insulin secretory capacity for a short-term follow-up.

PMID- 12605835
TI  - [Bacteremia due to Escherichia coli: epidemiological analysis and sensitivity to
      antibiotics in a county hospital].
AB  - BACKGROUND AND OBJECTIVE: There are few studies analyzing the epidemiological
      characteristics of Escherichia coli bacteremia including the susceptibility to
      antibiotics and outcome. PATIENTS AND METHOD: E. coli bacteremia episodes were
      recorded from January 1989 to December 1998. Clinical variables, setting
      acquisition, source of bacteremia, outcome and susceptibility to antibiotics were
      included. The study was prospective and comparative. Descriptive and univariate
      analysis were performed. RESULTS: 330 episodes of E. coli bacteremia were
      recorded: 117 in women. The most frequent source was the urinary tract (68%),
      followed by an abdominal and biliary focus. E. coli bacteremia appeared mostly in
      groups II and III of McCabe & Jackson. In 46 cases (14%), E. coli bacteremia was
      nosocomial. Crude and related mortality was 6.6 and 4.2%, respectively. A
      significant increase in the resistance to ciprofloxacin was observed.
      CONCLUSIONS: The epidemiological characteristics of E. coli bacteremia have not
      changed, yet the mortality was lower in our series. Preventive measures in the
      hospital and a rational use of antibiotics, principally quinolones, are
      necessary.

PMID- 12605837
TI  - [Screening of celiac disease in first-degree relatives].
AB  - BACKGROUND AND OBJECTIVE: Our aim was to analyze the prevalence of celiac disease
      (CD) in first-degree relatives of patients diagnosed with this disorder in
      Cantabria (Northern Spain). SUBJECTS AND METHOD: A questionnaire was administered
      and a complete biologic study was performed in 184 relatives. When serum CD
      related antibodies were detected, relatives were asked to undergo a jejunal
      biopsy to confirm the diagnosis. RESULTS: Thirteen relatives had autoantibodies
      yet only 4 were diagnosed with CD. The biopsy was suggestive of CD in 3 relatives
      who underwent it. A further relative was diagnosed with CD by the clinical and
      serological response to a gluten-free diet. CONCLUSIONS: The prevalence found in
      our study is high enough so that we recommend the screening of autoantibodies,
      especially anti-gliadin and anti-transglutaminase antibodies, in this risk
      population of celiac disease.

PMID- 12605838
TI  - [New ways of medical attention in heart failure].

PMID- 12605836
TI  - [Effect of phenolic compounds of virgin olive oil on LDL oxidation resistance].
AB  - BACKGROUND AND OBJECTIVE: Several epidemiological and experimental studies have
      associated the intake of antioxidants, which are abundant in the Mediterranean
      diet, with a low incidence of cardiovascular disease. One possible mechanism of
      this action is the oxidative protection in low density lipoproteins (LDL). The
      aim of our study was to compare the antioxidative activity of diverse phenolic
      compounds present in virgin olive oil on these lipoproteins. SUBJECTS AND METHOD:
      LDL was isolated from blood plasma of healthy volunteers by sequential
      ultracentrifugation. This was followed by oxidation with CuC12 in the presence of
      different concentrations of phenolic compounds and virgin olive oil extract.
      Production of conjugated dienes was determined by the continuous monitoring of
      increased absorbency at 234 nm as an indicator of LDL oxidation. RESULTS: Virgin
      olive oil extract prolonged the latency phase and significantly lowered the
      progression rate (p < 0.05) at low concentrations (2 g/ml). This antioxidative
      effect was also observed with low concentrations (2 M) of caffeic acid and
      oleuropein (p < 0.05). However, it was necessary to increase the concentration of
      flavone up to 50 times to observe a similar effect (p < 0.05). CONCLUSION: Both
      virgin olive oil extract enriched in phenolic compounds and phenolic compounds
      present in olive oil (caffeic acid and oleuropein) are potent antioxidants at
      very low concentrations. Thus, the beneficial effects of a Mediterranean diet may
      be partly due to the protective action of these compounds.

PMID- 12605839
TI  - [A secure job for ever].

PMID- 12605840
TI  - [Allergy to corticosteroids, a paradox?].

PMID- 12605841
TI  - [WHI study on the attention of menopause in Spain: significance of its results].

PMID- 12605842
TI  - [Menopause hormone replacement therapy: controversial, accuracy and outlook
      issues].

PMID- 12605843
TI  - [Venous thromboembolism in patients with previous cancer: a marker of tumor?].

PMID- 12605845
TI  - [Hormonal replacement therapy in postmenopausal women in Spain].

PMID- 12605844
TI  - [Clopidogrel-induced hepatotoxicity].

PMID- 12605846
TI  - [Diabetic ketoacidosis and cocaine use].

PMID- 12605847
TI  - [Protein losing enteropathy in association with Fontan operation. Report of a
      case].

PMID- 12605848
TI  - On the need for a control line in selection experiments: a likelihood analysis.
AB  - The question of whether selection experiments ought to include a control line, as
      opposed to investing all facilities in a single selected line, is addressed using
      a likelihood perspective. The consequences of using a control line are evaluated
      under two scenarios. In the first one, environmental trend is modeled and
      inferred from the data. In this case, a control line is shown to be highly
      beneficial in terms of the efficiency of inferences about heritability and
      response to selection. In the second scenario, environmental trend is not
      modeled. One can imagine that a previous analysis of the experimental data had
      lent support to this decision. It is shown that in this situation where a control
      line may seem superfluous, inclusion of a control line can result in minor gains
      in efficiency if a high selection intensity is practiced in the selected line.
      Further, if there is a loss, it is moderately small. The results are verified to
      hold under more complicated data structures via Monte Carlo simulation. For
      completeness, divergent selection designs are also reviewed, and inferences based
      on a conditional and full likelihood approach are contrasted.

PMID- 12605849
TI  - A Bayesian analysis of the effect of selection for growth rate on growth curves
      in rabbits.
AB  - Gompertz growth curves were fitted to the data of 137 rabbits from control (C)
      and selected (S) lines. The animals came from a synthetic rabbit line selected
      for an increased growth rate. The embryos from generations 3 and 4 were frozen
      and thawed to be contemporary of rabbits born in generation 10. Group C was the
      offspring of generations 3 and 4, and group S was the contemporary offspring of
      generation 10. The animals were weighed individually twice a week during the
      first four weeks of life, and once a week thereafter, until 20 weeks of age.
      Subsequently, the males were weighed weekly until 40 weeks of age. The random
      samples of the posterior distributions of the growth curve parameters were drawn
      by using Markov Chain Monte Carlo (MCMC) methods. As a consequence of selection,
      the selected animals were heavier than the C animals throughout the entire growth
      curve. Adult body weight, estimated as a parameter of the Gompertz curve, was 7%
      higher in the selected line. The other parameters of the Gompertz curve were
      scarcely affected by selection. When selected and control growth curves are
      represented in a metabolic scale, all differences disappear.

PMID- 12605850
TI  - Pedigree analysis of eight Spanish beef cattle breeds.
AB  - The genetic structure of eight Spanish autochthonous populations (breeds) of beef
      cattle were studied from pedigree records. The populations studied were: Alistana
      and Sayaguesa (minority breeds), Avilena - Negra Iberica and Morucha ("dehesa"
      breeds, with a scarce incidence of artificial insemination), and mountain breeds,
      including Asturiana de los Valles, Asturiana de la Montana and Pirenaica, with
      extensive use of AI. The Bruna dels Pirineus breed possesses characteristics
      which make its classification into one of the former groups difficult. There was
      a large variation between breeds both in the census and the number of herds.
      Generation intervals ranged from 3.7 to 5.5 years, tending to be longer as the
      population size was larger. The effective numbers of herds suggest that a small
      number of herds behaves as a selection nucleus for the rest of the breed. The
      complete generation equivalent has also been greatly variable, although in
      general scarce, with the exception of the Pirenaica breed, with a mean of 3.8.
      Inbreeding effective population sizes were actually small (21 to 127), especially
      in the mountain-type breeds. However, the average relatedness computed for these
      breeds suggests that a slight exchange of animals between herds will lead to a
      much more favourable evolution of inbreeding. The effective number of founders
      and ancestors were also variable among breeds, although in general the breeds
      behaved as if they were founded by a small number of animals (25 to 163).

PMID- 12605851
TI  - Sources of variation and genetic profile of spontaneous, out-of-season ovulatory
      activity in the Chios sheep.
AB  - Organising the breeding plan of a seasonally breeding species, such as sheep,
      presents a challenge to farmers and the industry as a whole, since both
      economical and biological considerations need to be carefully balanced.
      Understanding the breeding activity of individual animals becomes a prerequisite
      for a successful breeding program. This study set out to investigate the sources
      of variation and the genetic profile of the spontaneous, out-of-season ovulatory
      activity of ewes of the Chios dairy sheep breed in Greece. The definition of the
      trait was based on blood progesterone levels, measured before exposing the ewes
      to rams, which marks the onset of the usual breeding season. Data were 707
      records, taken over two consecutive years, of 435 ewes kept at the Agricultural
      Research Station of Chalkidiki in northern Greece. When all available pedigree
      was included, the total number of animals involved was 1068. On average, 29% of
      all ewes exhibited spontaneous, out-of-season ovulatory activity, with no
      substantial variation between the years. Significant sources of systematic
      variation were the ewe age and live weight, and the month of previous lambing.
      Older, heavier ewes, that had lambed early the previous autumn, exhibited more
      frequent activity. Heritability estimates were 0.216 (+/-0.084) with a linear and
      0.291 with a threshold model. The latter better accounts for the categorical
      nature of the trait. The linear model repeatability was 0.230 (+/-0.095). The
      results obtained in this study support the notion that spontaneous out-of-season
      ovulatory activity can be considered in the development of a breeding plan for
      the Chios sheep breed.

PMID- 12605852
TI  - Detection of genes influencing economic traits in three French dairy cattle
      breeds.
AB  - A project of QTL detection was carried out in the French Holstein, Normande, and
      Montbeliarde dairy cattle breeds. This granddaughter design included 1 548
      artificial insemination bulls distributed in 14 sire families and evaluated after
      a progeny-test for 24 traits (production, milk composition, persistency, type,
      fertility, mastitis resistance, and milking ease). These bulls were also
      genotyped for 169 genetic markers, mostly microsatellites. The QTL were analysed
      by within-sire linear regression of daughter yield deviations or deregressed
      proofs on the probability that the son receives one or the other paternal QTL
      allele, given the marker information. QTL were detected for all traits, including
      those with a low heritability. One hundred and twenty QTL with a chromosome-wise
      significance lower than 3% were tabulated. This threshold corresponded to a 15%
      false discovery rate. Amongst them, 32 were genome-wise significant. Estimates of
      their contribution to genetic variance ranged from 6 to 40%. Most substitution
      effects ranged from 0.6 to 1.0 genetic standard deviation. For a given QTL, only
      1 to 5 families out of 14 were informative. The confidence intervals of the QTL
      locations were large and always greater than 20 cM. This experiment confirmed
      several already published QTL but most of them were original, particularly for
      non-production traits.

PMID- 12605853
TI  - Haplotype diversity of the myostatin gene among beef cattle breeds.
AB  - A total of 678 individuals from 28 European bovine breeds were both phenotyped
      and analysed at the myostatin locus by the Single Strand Conformation
      Polymorphism (SSCP) method. Seven new mutations were identified which contribute
      to the high polymorphism (1 SNP every 100 bp) present in this small gene; twenty
      haplotypes were described and a genotyping method was set up using the
      Oligonucleotide Ligation Assay (OLA) method. Some haplotypes appeared to be
      exclusive to a particular breed; this was the case for 5 in the Charolaise
      (involving mutation Q204X) and 7 in the Maine-Anjou (involving mutation E226X).
      The relationships between the different haplotypes were studied, thus allowing to
      test the earlier hypothesis on the origin of muscular hypertrophy in Europe:
      muscular hypertrophy (namely nt821(del11)) was mainly spread in different waves
      from northern Europe milk purpose populations in most breeds; however, other
      mutations (mostly disruptive) arose in a single breed, were highly selected and
      have since scarcely evolved to other populations.

PMID- 12605854
TI  - A mutation in the MATP gene causes the cream coat colour in the horse.
AB  - In horses, basic colours such as bay or chestnut may be partially diluted to
      buckskin and palomino, or extremely diluted to cream, a nearly white colour with
      pink skin and blue eyes. This dilution is expected to be controlled by one gene
      and we used both candidate gene and positional cloning strategies to identify the
      "cream mutation". A horse panel including reference colours was established and
      typed for different markers within or in the neighbourhood of two candidate
      genes. Our data suggest that the causal mutation, a G to A transition, is
      localised in exon 2 of the MATP gene leading to an aspartic acid to asparagine
      substitution in the encoded protein. This conserved mutation was also described
      in mice and humans, but not in medaka.

PMID- 12605855
TI  - The identification of hydrophobic sites on the surface of proteins using
      absorption difference spectroscopy of bromophenol blue.
AB  - Hydrophobic sites on the surface of protein molecules are thought to have
      important functional roles. The identification of such sites can provide
      information about the function and mode of interaction with other cellular
      components. While the fluorescence enhancement of polarity-sensitive dyes has
      been useful in identifying hydrophobic sites on a number of targets, strong
      intrinsic quenching of Nile red and ANSA dye fluorescence is observed on binding
      to a cytochrome c('). Fluorescence quenching is also observed to take place in
      the presence of a variety of other biologically important molecules which can
      compromise the quantitative determination of binding constants. Absorption
      difference spectroscopy is shown not to be sensitive to the presence of
      fluorescence quenchers but sensitive enough to measure binding constants. The dye
      BPB is shown to bind to the same hydrophobic sites on proteins as polarity
      sensitive fluorescence probes. The absorption spectrum of BPB is also observed to
      be polarity sensitive. A binding constant of 3x10(6)M(-1) for BPB to BSA has been
      measured by absorption difference spectroscopy. An empirical correlation is
      observed between the shape of the absorption difference spectrum of BPB and the
      polarity of the environment. The results indicate that absorption difference
      spectroscopy of BPB provides a valuable supplement to fluorescence for
      determining the presence of hydrophobic sites on the surface of proteins as well
      as a method for measuring binding constants.

PMID- 12605856
TI  - Positional mapping of specific DNA sequences relative to the nuclear substructure
      by direct polymerase chain reaction on nuclear matrix-bound templates.
AB  - Nuclear DNA of higher eukaryotes is organized in supercoiled loops anchored to a
      proteinaceous substructure commonly known as the nuclear matrix. Current evidence
      suggests that important processes of nuclear physiology, such as replication,
      transcription, and processing of primary transcripts, take place at
      macromolecular complexes located at discrete, well-defined sites upon the nuclear
      matrix. A number of authors have reported that actively transcribed genes are
      closely associated with the nuclear matrix. The topological relationship between
      the gene sequences located in the DNA loops and the nuclear matrix appears to be
      very important for appropriate nuclear physiology. Here, we describe a polymerase
      chain reaction-based method for directly mapping any DNA sequence position
      relative to the nuclear matrix that avoids the problem posed by DNA fragments
      nonspecifically bound to the nuclear matrix, without the need of purifying the
      specifically nuclear matrix-bound DNA.

PMID- 12605857
TI  - UV measurements in microplates suitable for high-throughput protein
      determination.
AB  - An UV spectrophotometric method for protein determination using microplates is
      described. Using the SPECTRAmax PLUS reader, the UVStar 96- and 384-well
      microplates and a 96 or 384 parallel channel liquid handling technique, large
      scale determinations can be performed with intraassay precision better than 3% CV
      (coefficient of variation) in the range from 1 to 8000 microg of protein/ml,
      measuring at 205, 215, and 280 nm and using different volume-dependent light-path
      lengths. Since the absorbance coefficient at 205 nm is found to be 30 ml/(mgxcm)
      for eight different proteins with a CV of 5.6% only with the Path Check option of
      the reader, protein concentration can be determined without any individual
      calibration. Samples in the volume range of 60-250 microl can be analyzed without
      time-consuming and expensive treatment and without sample loss. Using a special
      96 or 384 parallel dialyzing device, low molecular weight substances which
      interfere with the analysis by their UV absorbance, such as buffers and
      detergents, can effectively be removed. Application examples for serum protein
      separation are also shown in the presence of the strongly UV absorbing detergent
      Triton X-100.

PMID- 12605858
TI  - Protein surface mapping by chemical oxidation: structural analysis by mass
      spectrometry.
AB  - The solvent-accessible surface area of proteins is important in biological
      function for many reasons, including protein-protein interactions, protein
      folding, and catalytic sites. Here we present a chemical technique to oxidize
      amino acid side chains in a model protein, apomyoglobin, and subsequent
      elucidation of the effect of solvent accessibility on the sites of oxidation.
      Under conditions of low protein oxidation (zero to three oxygen atoms added per
      apomyoglobin molecule), we have positively identified five oxidation sites by
      liquid chromatography-tandem mass spectrometry and high-resolution Fourier
      transform mass spectrometry. Our results indicate that all oxidized amino acids,
      with the exception of methionine, have highly solvent-accessible side chains, but
      the rate of oxidation may not be dictated solely by solvent accessibility and
      amino acid identity.

PMID- 12605859
TI  - Positive cooperativity induces multimodal site and thermodynamic affinity
      distributions in multivalent proteins.
AB  - The characterization of the stoichiometric and site-affinity distributions for
      the reaction of hemoglobin with O(2) and CO is presented as an example of a
      multivalent receptor system which exhibits positive site-site interactions. The
      distributions of stoichiometric constants, T(i)(K(i))'s, are obtained assuming
      that the distribution of site constants, N(k), is known. The importance of these
      distributions is that they can be directly related to quantities measured
      experimentally and that they represent affinity distributions for each ligation
      step. In hemoglobin, positive site-site interactions generate both stoichiometric
      and site-affinity distributions with complex and previously unrecognized
      multimodal patterns that are very different from the theoretical distributions
      obtained in the absence of interactions. These distributions are related to the
      generation of heterogeneity during the ligand binding process. Experimental
      binding data show that these complex distributions can be related to the
      physiological functions of uptake, transport, and release of gaseous ligands by
      hemoglobin.

PMID- 12605860
TI  - Nonradioactive methods for the assay of phosphoinositide 3-kinases and
      phosphoinositide phosphatases and selective detection of signaling lipids in cell
      and tissue extracts.
AB  - We describe a novel approach to quantitation of phosphoinositides in cell
      extracts and in vitro enzyme-catalyzed reactions using suitably tagged and/or
      labeled pleckstrin homology (PH) domains as probes. Stable complexes were formed
      between the biotinylated target lipid and an appropriate PH domain, and
      phosphoinositides present in samples were detected by their ability to compete
      for binding to the PH domain. Complexes were detected using AlphaScreen
      technology or time-resolved FRET. The assay procedure was validated using
      recombinant PI 3-kinase gamma with diC8PtdIns(4,5)P(2) as substrate and general
      receptor for phosphoinositides-1 (GRP1) PH domain as a PtdIns(3,4,5)P(3)-specific
      probe. This PI 3-kinase assay was robust, was suitable for high-throughput
      screening platforms, and delivered expected IC(50) values for reference
      compounds. The approach is adaptable to a wide range of enzymes as demonstrated
      by assays of the tumor suppressor protein, PTEN, a phosphoinositide 3
      phosphatase, which was measured using the same reagents but with
      diC8PtdIns(3,4,5)P(3) as substrate. PtdIns(3,4,5)P(3) present in lipid extracts
      of Swiss 3T3 and HL60 cells stimulated with platelet-derived growth factor and
      fMLP, respectively, was also detectable at picomole sensitivity. The versatility
      and general utility of this approach were demonstrated by exchanging the GRP1 PH
      domain for that of TAPP1 (which binds PtdIns(3,4)P(2) and not PtdIns(3,4,5)P(3)).
      This system was used to monitor the accumulation of PtdIns(3,4)P(2) in Swiss 3T3
      cells exposed to an oxidative stress. It is therefore proposed that similar
      procedures should be capable of measuring any known phosphoinositide present in
      cell and tissue extracts or produced in kinase and phosphatase assays by using
      one of several well-characterized protein domains with appropriate
      phosphoinositide-binding specificity.

PMID- 12605861
TI  - Identification of metabotropic glutamate receptor antagonists using an automated
      high-throughput screening system.
AB  - Antagonists to the human metabotropic glutamate receptor subtype 5a(mGluR(5a))
      have been implicated as potential therapeutics for the treatment of a variety of
      nervous system disorders, including pain, anxiety, and Parkinson's disease. To
      discover novel antagonists to the mGluR(5a), a functional assay measuring agonist
      induced intracellular calcium release was developed. The assay was used for the
      high-throughput screening of a large collection of compounds in single wells
      using a fully automated robotic platform. Primary high-throughput screening hits
      were subjected to a combination of data analysis and counterscreening assays to
      identify several compounds with both efficacy and selectivity for the
      metabotropic glutamate receptor target.

PMID- 12605862
TI  - Hybridization biosensor using di(2,2'-bipyridine)osmium (III) as electrochemical
      indicator for detection of polymerase chain reaction product of hepatitis B virus
      DNA.
AB  - A novel hepatitis B virus (HBV) DNA biosensor was developed by immobilizing
      covalently single-stranded HBV DNA fragments to a gold electrode surface via
      carboxylate ester to link the 3(')-hydroxy end of the DNA with the carboxyl of
      the thioglycolic acid (TGA) monolayer. A short-stranded HBV DNA fragment (181bp)
      of known sequence was obtained and amplified by PCR. The surface hybridization of
      the immobilized single-stranded HBV DNA fragment with its complementary DNA
      fragment was evidenced by electrochemical methods using [Os(bpy)(2)Cl(2)](+) as a
      novel electroactive indicator. The formation of double-stranded HBV DNA on the
      gold electrode resulted in a great increase in the peak currents of
      [Os(bpy)(2)Cl(2)](+) in comparison with those obtained at a bare or single
      stranded HBV DNA-modified electrode. The mismatching experiment indicated that
      the surface hybridization was specific. The difference between the responses of
      [Os(bpy)(2)Cl(2)](+) at single-stranded and double-stranded DNA/TGA gold
      electrodes suggested that the label-free hybridization biosensor could be
      conveniently used to monitor DNA hybridization with a high sensitivity. X-ray
      photoelectron spectrometry technique has been employed to characterize the
      immobilization of single-stranded HBV DNA on a gold surface.

PMID- 12605863
TI  - A quantitative diffraction-based sandwich immunoassay.
AB  - It is shown that diffraction-based sensing can be enhanced for diagnostic
      purposes through the use of a secondary label. The limit of detection for anti
      rabbit IgG was reduced more than 40-fold by using a gold-conjugated secondary
      antibody. The response to secondary antibody binding was linear for
      concentrations from 25 to 500 ng/ml of anti-rabbit IgG, suggesting that
      quantitative determinations can be readily done. Moreover, the binding of the
      secondary antibody was observed as soon as 1 min after its introduction to the
      surface-bound primary complex.

PMID- 12605864
TI  - Enrichment of low-abundance brain proteins by preparative electrophoresis.
AB  - Detection of low-copy-number gene products is essential for the development of
      novel drugs, however, it represents a major drawback of proteomics and
      simultaneously a scientific challenge. We studied the enrichment of rat brain
      cytosolic proteins by preparative electrophoresis using the PrepCell apparatus.
      The electrophoresis was performed in the presence of 0.1% lithium dodecyl
      sulfate. The proteins eluted from the gel were analyzed by two-dimensional gel
      electrophoresis and identified by matrix-assisted laser desorption ionization
      mass specrometry. Lithium dodecyl sulfate was easily exchanged against agents
      compatible with isoelectric focusing. Low-abundance proteins, which had not been
      found before, including neuronal-specific and calcium-binding proteins, were
      detected. In particular, low-molecular-mass proteins, such as hippocalcin,
      visinin-like proteins, and 14-3-3 proteins were strongly enriched by preparative
      electrophoresis.

PMID- 12605865
TI  - Aberrant 3H in Ehrlich mouse ascites tumor cell nucleotides after in vivo
      labeling with myo-[2-3H]- and L-myo-[1-3H]inositol: implications for measuring
      inositol phosphate signaling.
AB  - After in vivo radiolabeling of Ehrlich cells for 24h with conventional myo-[2
      3H]inositol we previously demonstrated an aberrant 3H-labeling of ATP that
      interfered in the HPLC analysis of inositol trisphosphates. This aberrant 3H
      labeling was accounted for by the extensive kidney catabolism of myo-[2-3H]
      inositol with delivery of 3H-labeled metabolites to extrarenal tissues. As
      expected, the aberrant labeling of ATP is markedly reduced with the use of 3H-myo
      inositol labeled at L-C1 rather than at C2, reflecting that the 3H at L-C1
      disappears in the first step of the myo-inositol catabolism: the oxidative
      conversion to D-glucuronate. In contrast, with the 3H at C2 of myo-inositol, the
      3H-C2 passes into the pentose phosphate conversions with resulting labeling of
      nucleotides. The extent of catabolism to 3H-labeled water, the cellular
      accumulation of 3H-myo-inositol, the incorporation into cellular inositol
      phospholipids, and the labeling pattern of cellular phosphoinositides were all
      found to be similar for the two labeled myo-inositol moieties. With the use of L
      myo-[1-3H]inositol an aberrant 3H-labeling at about 25% remained, for which a
      presumptive mechanism is proposed. L-myo-[1-3H]Inositol appears nevertheless to
      be a preferable alternative to myo-[2-3H]inositol for tracing the intact myo
      inositol molecule after in vivo labeling, with minimized interference from
      aberrant 3H-labeling of nucleotides.

PMID- 12605866
TI  - Rapid analysis of metabolic stability of dopamine receptor antagonists and
      detection of their metabolites by liquid chromatography/tandem mass spectrometry.
AB  - In vitro metabolic stability of dopamine D(3)/D(4) receptor antagonists and
      identification of their metabolites by high-performance liquid chromatography
      (HPLC) coupled with ion-trap mass spectrometry (ITMS) were assessed in rat liver
      microsomes. The compounds were divided into three cassette groups for rapid
      quantitative analysis of multiple drugs and simultaneous detection of their
      metabolites. The samples from incubation with rat liver microsomes were pooled
      into designed cassette groups and analyzed by HPLC/electrospray ITMS in full-scan
      mode. The metabolic stability of the drugs was determined by comparing their
      signals after incubation for 0 and for 30min. The metabolic stability of the
      examined dopamine receptor antagonists was in the range of 9.9-84.4%. In
      addition, the present cassette analysis allowed the simultaneous detection of
      metabolites formed during the same incubation without having to reanalyze the
      samples. The metabolites were first characterized by nominal mass measurement of
      the corresponding protonated molecules. Subsequent multistage tandem mass
      spectrometry on the ion-trap instrument allowed characterization of the structure
      of the detected metabolites. N,O-dealkylation and ring hydroxylation reactions
      were identified as major metabolic reactions in piperazinylalkylisoxazole
      derivatives. These results suggested that the present approach is useful for the
      rapid evaluation of metabolic stability and structural characterization of
      metabolites within a short period in new drug discovery.

PMID- 12605867
TI  - A spectrophotometric method to quantify linear DNA.
AB  - A spectrophotometric method for quantification of linear DNA is described. The
      assay measures ADP produced following digestion of linear DNA by an ATP-dependent
      deoxyribonuclease. Cleavage of the phosphodiester bond of the DNA substrate is
      proportional to ADP formed in the reaction which follows typical Michaelis-Menten
      kinetics (K(m) of 0.6 microM, and a V(max) of 30 nmol/min/mg). The enzyme
      requires Mg(2+)-ATP and Mg(2+)-DNA as substrates, although the results suggest a
      requirement for yet another metal ion which may be enzyme bound. Both single
      stranded and double-stranded linear DNA are substrates, as demonstrated by
      comparable initial velocity measurements. However, covalently closed circular
      (CCC) and nicked open circular DNA are not substrates for the enzyme. The rate of
      hydrolysis of ATP is not inhibited by 1 microg RNA or covalently closed circular
      DNA. The product (ADP) formed in the reaction is coupled to NADH oxidation using
      pyruvate kinase and lactate dehydrogenase. NAD formed in the reaction is
      monitored spectrophotometrically as a loss in absorbance at 340 nm. This assay
      directly measures the amount of linear DNA present in preparations of supercoiled
      (CCC) plasmid DNA, and has direct utility for monitoring the quality of plasmid
      preparations for gene therapy.

PMID- 12605868
TI  - Continuous spectrophotometric assay amenable to 96-well plate format for
      prostaglandin E synthase activity.
AB  - The measurement of prostaglandin E synthase (PGES) activity is cumbersome because
      the product of the reaction, PGE(2), is not readily quantitated by spectral
      means. The activity of isolated PGES is typically determined by PGE(2)
      immunoassay or by high-performance liquid chromatography using radiolabeled
      substrate. A relatively rapid continuous spectrophotometric assay which uses 15
      hydroxyprostaglandin dehydrogenase (PGDH) to couple the oxidation of the 15
      hydroxy group of PGE(2) to the formation of NADH was developed. PGDH is
      relatively specific for PGE(2) over the substrate for the PGES reaction, PGH(2),
      allowing a highly reproducible assay of PGES activity to be obtained.

PMID- 12605869
TI  - Scintillation proximity assay of inositol phosphates in cell extracts: high
      throughput measurement of G-protein-coupled receptor activation.
AB  - The phosphatidylinositol turnover assay is used widely to measure activation, and
      inhibition, of G(q)-linked G-protein-coupled receptors. Cells expressing the
      receptor of interest are labeled by feeding with tritiated myo-inositol. The
      label is incorporated into cellular phosphatidylinositol 4,5-bisphosphate, which,
      upon agonist binding to the receptor, is hydrolyzed by phospholipase C to
      inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol. In the presence of
      Li(+), dephosphorylation of IP(3) to inositol is blocked, and the mass of soluble
      inositol phosphates is a quantitative readout of receptor activation. Current
      protocols for this assay all involve an anion-exchange chromatography step to
      separate radiolabeled inositol phosphates from radiolabeled inositol, making the
      assay cumbersome and difficult to automate. We now describe a scintillation
      proximity assay to measure soluble inositol phosphate mass in cell extracts, thus
      obviating the need for the standard chromatography step. The method uses
      positively charged yttrium silicate beads that bind inositol phosphates, but not
      inositol. We have used this assay to measure activation of recombinant and
      endogenous muscarinic acetylcholine receptors and activation of recombinant
      neuropeptide FF2 receptor coupled to IP(3) production by coexpression of a
      chimeric G protein. Further, we demonstrate the use and functional validity of
      this assay in a semiautomated, 384-well format, by characterizing the muscarinic
      receptor antagonists pirenzepine and atropine.

PMID- 12605870
TI  - Specificity of the ferrous oxidation of xylenol orange assay: analysis of
      autoxidation products of cholesteryl arachidonate.
AB  - Autoxidation of polyunsaturated fatty acids and esters leads to a complex mixture
      containing hydroperoxides and cyclic peroxides. The oxidation mixture of
      cholesteryl arachidonate, which has been characterized by a variety of mass
      spectrometry techniques, was subject to analysis by conventional thiobarbituric
      acid-reactive substance (TBARS) and ferrous oxidation in xylenol orange (FOX)
      assays. Our results indicate that the FOX assay is not specific for
      hydroperoxides. Cyclic peroxides, such as monocyclic peroxides and serial-cyclic
      peroxides, give a positive FOX response even after triphenylphosphine reduction.
      We suggest that bicyclic endoperoxides are the major TBARS active compounds
      present in cholesteryl arachidonate oxidation mixtures. These compounds give a
      positive FOX assay before reaction with triphenylphosphine but negative TBARS and
      FOX assays after this reaction. Caution should be exercised when the FOX assay is
      used to analyze highly oxidized lipids, especially arachidonyl-containing lipids.

PMID- 12605871
TI  - On-line preconcentration of in-gel digest by ion-exchange chromatography for
      protein identification using high-performance liquid chromatography-electrospray
      ionization tandem mass spectrometry.

PMID- 12605872
TI  - Use of microfluidics chips for the detection of human telomerase RNA.

PMID- 12605873
TI  - A simultaneous colorimetric assay of free and protein-coupled polyethylene
      glycol.

PMID- 12605874
TI  - Interference in MTT cell viability assay in activated macrophage cell line.

PMID- 12605875
TI  - Simple solutions to problems encountered in quantitative analysis of tocopherols
      and tocotrienols using silica columns.

PMID- 12605876
TI  - Cytotoxicity of pEGFP vector is due to residues encoded by multiple cloning site.

PMID- 12605877
TI  - Neurodegenerative disorders of protein aggregation.
AB  - In recent years, it has become increasingly clear that many neurodegenerative
      diseases involve aggregation and deposition of misfolded proteins such as amyloid
      beta, tau, alpha-synuclein and polyglutamine containing proteins. This abnormal
      deposition of misfolded proteins produce malfunctioning of a distinctive set of
      neurons. It may also induce oxidative and endoplasmic reticulum stress and
      proteosomal and mitochondrial dysfunction that ultimately leads to neuronal
      death. While hereditary forms of disorders are caused by genetic mutations, many
      sporadic cases are likely to be due to genetic and environmental factors. These
      disorders are progressive in nature. Therefore, treatment is difficult. However,
      for some diseases, a growing number of treatment options such as drugs,
      antioxidants, cell transplantation, surgery, rehabilitation procedures and
      preimplantation diagnosis is available. It should be noted that many of these
      treatments produce unacceptable risks or adverse effects and they are of only
      minimal benefit for patients. In future, an understanding of the causes of
      protein aggregation and genetic and environmental susceptibility factors of a
      specific individual (or specific individual determinants) may provide a better
      opportunity for an effective therapeutic intervention.

PMID- 12605878
TI  - [3H]-DA release evoked by low pH medium and internal H+ accumulation in rat
      hypothalamic synaptosomes: involvement of calcium ions.
AB  - The pH fluctuations have been often interpreted as an insufficient regulation or
      as a consequence of the onset of pathological events, such as ischemia, in which
      a significant decrease in pH levels occurs. Neurotransmitter release appears to
      be affected by pH drop significantly. In this study, we investigated the effect
      of an extracellular and an intracellular acidification on tritiated dopamine
      release ([3H]-DA release), from superfused rat hypothalamic synaptosomes. When
      compared to basal release, extracellular acidification, due to a reduction in the
      external pH of the nominally carbonic-free superfusion media, provoked a
      significant increase in [3H]-DA release that showed a sensitiveness to calcium
      omission. Intraterminal acidification, obtained blocking the Na(+)/H(+) exchanger
      by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) and 5-(N,N-dimethyl)-amiloride (DMA),
      induced a significant increase in [3H]-DA outflow which occurred in a calcium
      dependent manner (80% inhibition in absence of calcium from superfusion media).
      To further promote an intraterminal acidification through a H(+) inner
      accumulation, the proton ionophore nigericin was used. At every dose employed (10
      microM), this compound induced a significant increase in [3H]-DA outflow,
      compared to basal release. Nigericin-evoked [3H]-DA release showed a 50% decrease
      when calcium was omitted from superfusion media. When BAPTA-AM, a chelator of
      intracellular calcium, was added, nigericin-evoked [3H]-DA was completely
      abolished. These data indicate that [3H]-DA release can be induced by
      extracellular acidification due to a lowering of external pH and by an
      intraterminal acidification due to an internal proton accumulation. The mechanism
      that can trigger this exocytotic process appears to depend on calcium presence,
      and in particular, on an increased intraterminal calcium availability.

PMID- 12605879
TI  - Inducible expression and pharmacology of recombinant NMDA receptors, composed of
      rat NR1a/NR2B subunits.
AB  - An ecdysone-inducible mammalian expression system was used to study expression of
      recombinant N-methyl-D-aspartate (NMDA) receptors. Human embryonic kidney (HEK)
      293 cells expressing the regulatory vector pVgRXR (EcR 293 cells) were
      transfected with rat NR1a and NR2B cDNAs using the inducible vector pIND
      (Invitrogen). Inducible expression of the NR2B subunit in cell clone designated
      EcR/rNR1a2B was investigated using quantitative RT-PCR and flow cytometry based
      immunocytochemical methods. The mRNA level of the NR2B subunits in EcR/rNRa2B
      cells was dependent on the concentration of the ecdysone analogue inducing agent,
      muristerone A (MuA). Similarly, NR2B subunit protein expression was higher in
      cells pre-treated with the inducing agent. Functionally active NMDA receptors
      were also detected in EcR/rNR1a2B cells after MuA induction. In presence of the
      inducing factor, NMDA-evoked ion currents as well as increase in cytoplasmic
      calcium-concentrations were measured using whole-cell patch clamp and
      fluorometric calcium measuring techniques. The pharmacological profile of the
      expressed NMDA receptors was characterised by comparing the inhibitory activity
      of several NR2B subunit selective NMDA antagonists in EcR/rNR1a2B cells with that
      observed in primary cultures of rat cortical neurones. Whereas the efficacies of
      the NR2B subunit selective NMDA antagonists were similar in EcR/rNR1a2B cells and
      in neurones, their maximal inhibitory effects were significantly higher in cells
      expressing NR1a/NR2B recombinant receptors. This study demonstrates that
      recombinant NMDA receptors can be expressed in an inducible way in non-neuronal
      cell lines using the ecdysone-inducible mammalian expression system. Such cell
      lines can be suitable tools in high throughput functional screening for potential
      subtype selective modulators of the NMDA receptor.

PMID- 12605880
TI  - Pyrrolidinedithiocarbamate induces apoptosis in cerebellar granule cells:
      involvement of AP-1 and MAP kinases.
AB  - Pyrrolidinedithiocarbamate (PDTC) is a compound displaying antioxidant, pro
      oxidant and metal chelator properties in different cell types. It has been
      described that PDTC may exert either anti-apoptotic or apoptotic activity.
      Moreover it is known that this agent regulates the activity of redox-sensitive
      transcription factors, such as AP-1 and NF-kappaB. Using cerebellar granule cells
      (CGCs), a well-described model of neuronal primary cultures, we investigated the
      effects of different concentrations of this compound on cell viability and the
      intracellular mechanisms involved. PDTC used at concentrations, as low as 1
      microM, exerts cytotoxic effects on CGC through the activation of the apoptotic
      machinery with a maximal efficacy for concentration of 10 microM. The PDTC
      dependent apoptosis is correlated to a biphasic and long-lasting increase of AP-1
      binding to the DNA, apparently without affecting the NF-kappaB whose activity was
      reduced only at much higher concentrations (100 microM). PDTC treatment enhanced
      ERK phosphorylation (maximal effect 1h) and p38 phosphorylation (maximal effect
      7h) that was accompanied by an increase of both mRNA and protein of c-Jun. In
      conclusion the results presented show that PDTC exerts apoptotic effects on CGC,
      that are correlated to the activation of stress-pathways, involving mainly AP-1
      and MAPKs.

PMID- 12605882
TI  - Differential expression of N-methyl-D-aspartate receptor subunit messenger
      ribonucleic acids and immunoreactivity in the rat neostriatum during postnatal
      development.
AB  - The present study was performed to investigate the patterns of gene expression of
      N-methyl-D-aspartate (NMDA) receptors (NRs) in the rat neostriatum during
      postnatal development. Reverse transcriptase-polymerase chain reactions (RT-PCR)
      indicated that levels of NR1, NR2A and NR2D mRNAs reached peak levels between
      postnatal days 7 (PND 7) and PND 14. The levels of NR2B and NR2C mRNAs were low
      at PND 1 and their levels increased at PND 7 and remained high in adults.
      Immunofluorescence combined with image analysis revealed that the levels of NR1
      immunoreactivity rose to its maximum at PND 14. In contrast, NR1 immunoreactivity
      rose progressively in perikarya of striatal neurons. Levels of NR2A
      immunoreactivity in the neostriatum were highest in adults. However, levels of
      NR2A immunoreactivity were higher in striatal neurons at PND 1 and PND 7. Levels
      of NR2B immunoreactivity were highest at PND 7. In the perikarya of striatal
      neurons however, the highest levels of NR2B immunoreactivity were detected at PND
      14 and adult striatal neurons. In addition, double immunofluorescence revealed
      that the levels of NR1 immunoreactivity increased but the levels of NR2A
      immunoreactivity were the same in parvalbumin (PV)-positive striatal interneurons
      of PND 14 and adult rats. NR2B immunoreactivity was not detected in PV-positive
      neurons of PND 14 rats, but intense NR2B labeling was seen in PV-positive neurons
      of adult rats. Last but not least, in choline acetyltransferase (ChAT)-positive
      striatal interneurons of PND 14 and adult rats, levels of NR1 and NR2A
      immunoreactivity was seen to increase. Level of NR2B immunoreactivity remained
      the same in ChAT-positive neurons of PND 14 and adult rats. The present results
      indicate that there are differential patterns of expression of NR mRNAs and
      immunoreactivity in the neostriatum during different stages of postnatal
      development. Different combinations of NR have been found in different
      subpopulations of striatal neurons at different developmental stages. NR1, NR2A
      and NR2B are the major NMDA receptor subunits expressed during development. The
      change in patterns of expression of NR may be related to the functional
      maturation of neurons in the neostriatum.

PMID- 12605881
TI  - Altered corticotropin-releasing factor (CRF) receptor immunoreactivity in the
      gerbil hippocampal complex following spontaneous seizure.
AB  - Considerable attention has been focused on the role of corticotropin-releasing
      factor (CRF) in neuropsychiatric disorders and neurodegenerative diseases
      including epilepsy. Therefore, in the present study, we investigated the temporal
      and spatial alteration of CRF receptor in the gerbil hippocampal complex in order
      to characterize the possible changes and associations with different sequelae of
      spontaneous seizure in these animals. Thirty minutes postictal, a decline in CRF
      receptor immunoreactivity was observed in the granule cells and hilar neurons. In
      the subiculum, CRF receptor immunoreactivity was also significantly decreased at
      this time point. Twenty-four hours after seizure onset, the immunoreactivity in
      these regions recovered to the pre-seizure level. Moreover, 30 min after seizure
      in the entorhinal cortex, the density of CRF receptor immunoreactivity began to
      decrease, particularly in the layers II and III, compared to pre-seizure group.
      Nevertheless, 24h after seizure onset, CRF receptor immunodensity had recovered
      to its seizure-sensitive (SS) level. These results suggest that altered CRF
      receptor expression in the hippocampal complex may affect tissue excitability and
      seizure activity in SS gerbils.

PMID- 12605883
TI  - Analysis of glucose and lactate in hippocampal dialysates of rats during the
      operant conditioned reflex using microdialysis.
AB  - Changes of extracellular glucose and lactate in hippocampus for freely moving
      rats during the operant conditioned reflex were examined simultaneously. Samples
      of the dialysate were assayed for both glucose and lactate using in vivo
      microdialysis and a microbore flow injection analysis-immobilized enzyme reactor
      electrochemical detection (FIA-IMER-ECD) system. Microdialysis samplings were
      conducted in a Skinner box where lights were delivered as conditioned stimuli
      (CS) paired with foot shocks as unconditioned stimuli (US). In the treatment
      group the concentration of glucose and lactate showed no fluctuations during the
      whole process. However, in the control group in which the rats were exposed to
      many foot shocks, lactate levels decreased by 19% below baseline during the
      behavioral session and glucose showed a delayed decrease (by 18%). Compared with
      glucose, lactate can immediately indicate the dynamic changes in brain.

PMID- 12605884
TI  - Change in muscarinic modulation of transmitter release in the rat urinary bladder
      after spinal cord injury.
AB  - Muscarinic facilitation of 14C-ACh release from post-ganglionic parasympathetic
      nerve terminals was studied in bladder strips prepared from spinal intact (SI)
      and spinal cord transected (SCT) rats. The spinal cord was transected at the
      lower thoracic spinal segments 3 weeks prior to the experiments. Using non
      facilitatory stimulation (2 Hz) the release of ACh in spinal intact rats did not
      change in the presence of a non-specific muscarinic antagonist, atropine (100
      nM), an M(1) specific antagonist (pirenzepine, 50 nM) or an M(1)-M(3) specific
      antagonist (4-DAMP, 5 nM). However, during a facilitatory stimulation paradigm
      (10 Hz or 40 Hz, 100 shocks) atropine and pirenzepine, but not 4-DAMP inhibited
      the release of ACh in bladders from spinal intact rats, indicating an M(1)
      receptor-mediated facilitation. In spinal cord transected rats, 2 Hz stimulation
      induced release was significantly inhibited by atropine or 4-DAMP but not by
      pirenzepine indicating that a pre-junctional facilitatory mechanism mediated via
      M(3) muscarinic receptors could be induced by a non-facilitatory stimulation
      paradigm after spinal injury. In bladders of spinal cord transected rats, 10 Hz
      stimulation-evoked release of ACh was also inhibited by atropine and 4-DAMP (5
      nM) but not by pirenzepine (50 nM). These results indicate that pre-junctional
      muscarinic receptors at cholinergic nerve endings in the bladder change after
      chronic spinal cord injury. It appears that low affinity M(1) muscarinic
      receptors are replaced by high affinity M(3) receptors. This change in modulation
      of ACh release may partly explain the bladder hyperactivity after chronic spinal
      cord injury.

PMID- 12605885
TI  - Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation
      and DNA-fragmentation in the human hippocampus after cerebral ischemia.
AB  - Reports on non-neural cells have shown that enhanced activity of the Ca(2+)
      dependent/ATP-independent phospholipid scramblase (PLSCR1) is, at least in part,
      responsible for surface exposure of phosphatidylserine and the collapse of plasma
      membrane asymmetry in injured or apoptotic cells. To shed some light on
      mechanisms with a potential to lead to apoptotic death of human neurones
      following ischemic/hypoxic injury, we examined the immunoreactivity of
      hippocampal neurones for PLSCR1, caspase-3, cytochrome c and DNA-fragmentation in
      22 individuals with clinically symptomatic cerebral ischemia after cardiac arrest
      or severe hypotension. WE FOUND: (1) significant differences in the percentage of
      PLSCR1-immunoreactive neurones between controls and short survivors;
      statistically strong differences between the frequency of immunoreactive neurones
      among the subfields studied with lowest levels in the CA3; preferential
      distribution of immunoreactive neurones in controls within the regio
      entorhinalis, subfield CA1, and hilum. Additionally, these areas exhibited
      staining of fibre bundles which probably correspond to perforant path, alvear
      path and collateral's of Schaffer, (2) caspase-3 was upregulated in a region
      specific manner with marked activation in the selectively vulnerable hippocampal
      areas, (3) cytochrome c was redistributed, (4) DNA-fragmentation represented by
      scattered TUNEL-positive cells increased predominantly during the first 3 days
      after ischemia, and particularly in the regions of greatest susceptibility to
      hypoxic injury. This study presents the first evidence that PLSCR1, and probably
      remodelling of plasma membrane phospholipids (PL), plays a role in ischemic
      injury in the human hippocampus.

PMID- 12605886
TI  - Differential distribution of vesicular glutamate transporters in the rat
      cerebellar cortex.
AB  - The chemical organization of excitatory axon terminals in the rat cerebellar
      cortex was examined by immunocytochemistry and in situ hybridization
      histochemistry of vesicular glutamate transporters 1 and 2 (VGluT1 and VGluT2).
      Chemical depletion of the inferior olivary complex neurons by 3-acetylpyridine
      treatment almost completely removed VGluT2 immunoreactivity from the molecular
      layer, leaving VGluT1 immunoreactivity apparently intact. On the other hand,
      neuronal deprivation of the cerebellar cortex by kainic acid injection induced a
      large loss of VGluT1 immunoreactivity in the molecular layer. In the cerebellar
      granular layer, both VGluT1 and VGluT2 immunoreactivities were found in mossy
      fiber terminals, and the two immunoreactivities were mostly colocalized in single
      axon terminals. Signals for mRNA encoding VGluT2 were found in the inferior
      olivary complex, and those for VGluT1 and VGluT2 mRNAs were observed in most
      brainstem precerebellar nuclei sending mossy fibers, such as the pontine, pontine
      tegmental reticular, lateral reticular and external cuneate nuclei. These results
      indicate that climbing and parallel fibers selectively use VGluT2 and VGluT1,
      respectively, whereas mossy fibers apply both VGluT1 and VGluT2 together to
      accumulate glutamate into synaptic vesicles. Since climbing-fiber and parallel
      fiber terminals are known to make depressing and facilitating synapses,
      respectively, VGluT1 and VGluT2 might have distinct properties associated with
      those synaptic characteristics. Thus, it would be the next interesting issue to
      determine whether mossy-fiber terminals co-expressing VGluT1 and VGluT2 show
      synaptic facilitation or depression.

PMID- 12605887
TI  - Developmental maturation of synaptic vesicle cycling as a distinctive feature of
      central glutamatergic synapses.
AB  - The formation of chemical synapses in the mammalian brain involves complex pre-
      and postsynaptic differentiation processes. Presynaptically, the progressive
      accumulation of synaptic vesicles is a hallmark of synapse maturation in the
      neocortex [J Neurocytol 12 (1983b) 697]. In this study, we analyzed the
      functional consequences of presynaptic vesicle-pool maturation at central
      glutamatergic and GABAergic synapses. Using (N-(3-triethylammoniumpropyl)-4-(4
      (dibutylamino)styryl)pyridinium dibromide (FM1-43) staining of recycling synaptic
      vesicles, we demonstrate a pronounced developmental increase in presynaptic
      vesicle accumulation during differentiation of neocortical neurons in culture.
      Using electrophysiological methods to study functional synaptic maturation, we
      found an improved recovery from hypertonic solution-induced depletion. As
      supported by the FM1-43 staining results, this change is most likely caused by a
      developmental increase in the number of reserve-pool vesicles. In addition,
      assuming a rapid reuse of freshly recycled vesicles, a developmental maturation
      of the endocytosis process may also contribute. The observed presynaptic
      maturation process occurred selectively at glutamatergic synapses, while
      GABAergic synapses did not show similar developmental alterations. Furthermore,
      we used high-frequency stimulation (HFS) of glutamatergic and GABAergic synapses
      to reveal the physiological consequences of reserve-pool maturation. As expected,
      recovery from HFS-induced depletion was incomplete at immature glutamatergic
      synapses and strongly improved during synapse maturation. Again, GABAergic
      synapses did not show similar developmental changes. Taken together, our study
      characterizes the functional consequences of a pronounced accumulation of reserve
      pool vesicles occurring selectively at glutamatergic synapses.

PMID- 12605888
TI  - Overexpression of wild-type presenilin 2 or its familial Alzheimer's disease
      associated mutant does not induce or increase susceptibility to apoptosis in
      different cell lines.
AB  - Programmed cell death, or apoptosis, has been implicated in Alzheimer's disease.
      Mutations in the presenilin (PS) genes, PS1 and PS2, are a major cause of early
      onset familial Alzheimer's disease (FAD). Previous studies have suggested that
      the PS play a role in apoptosis. However, the mechanisms whereby presenilins
      affect apoptosis and the relationship of FAD-associated presenilin mutants to the
      apoptotic effect have not been elucidated. In the present study, in an attempt to
      further explore the effect of PS2 on apoptosis we examined whether overexpression
      of wild-type or mutant PS2 can directly induce apoptosis or increase cell
      susceptibility to apoptosis in various cell lines, such as N2a, CHO, and HEK
      293T. Wild-type or mutant PS2 was transiently transfected into these cell lines
      and the viability of the transfected cells was evaluated by their morphology, DNA
      fragmentation and condensation, appearance of sub-G(1/0) cells, and caspase
      activation. We also examined the susceptibility of the PS2-transfected cells to
      apoptosis induced by the apoptotic inducers staurosporine and H(2)O(2). Our
      results showed that overexpression of either wild type or mutant PS2 in these
      cell lines did not directly induce apoptosis or increase the susceptibility to
      apoptosis induced by staurosporine or H(2)O(2). Taken together, these results
      suggest that overexpression of PS2 does not cause pro-apoptotic effects, at least
      not in the cellular systems and conditions employed in this study, and therefore
      it seems unlikely that apoptosis plays a prominent role in the neuropathological
      effects of PS2 in Alzheimer's disease.

PMID- 12605889
TI  - The role of HCO3(-)-dependent mechanisms in pHi regulation during O2 deprivation.
AB  - We have reported in our previous work that, in the absence of HCO(3)(-),
      Na(+)/H(+) exchanger is responsible for an anoxia-induced alkalinization in
      hippocampal CA1 neurons. HCO(3)(-)-dependent mechanisms have been reported to
      play a key role in pH(i) regulation in nerve cells, but how their function is
      affected by O(2) deprivation has not been well studied. In this work, pH(i)
      measurements (obtained from dissociated neurons loaded with carboxy
      seminaphthorhodafluor-1 and using confocal microscopy) and whole-cell patch clamp
      recording techniques were used to investigate the role of HCO(3)(-)-dependent
      membrane exchangers on CA1 neurons during O(2) deprivation. Anoxia (5 min)
      induced a small acidification in neurons in the presence of HCO(3)(-) and this
      acidification was changed to a significant alkalinization when neurons were
      bathed with Hepes buffer or when 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid
      was applied in a HCO(3)(-) solution, indicating that HCO(3)(-)-dependent
      mechanisms were involved. A marked anoxia-induced acidification (0.33+/-0.11 pH
      unit) was seen when the Na(+)/H(+) exchange was blocked with 3-(methylsulfonyl-4
      piperidino-benzoyl)-guanidine methanesulfonate in the presence of HCO(3)(-), but
      the same anoxia did not cause a significant pH(i) change in a Na(+) free, HCO(3)(
      ) solution, suggesting that the anoxia-induced acidification in the presence of 3
      (methylsulfonyl-4-piperidino-benzoyl)-guanidine methanesulfonate is dependent on
      both Na(+) and HCO(3)(-). Furthermore, anoxia did not cause a significant pH(i)
      change when both 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and 3
      (methylsulfonyl-4-piperidino-benzoyl)-guanidine methanesulfonate were present.
      Current clamp recordings showed a significant membrane depolarization following
      anoxia in HCO(3)(-) solution but not in Hepes buffer. Our data suggest that, in
      hippocampal neurons: a) pH(i) regulation during O(2) deprivation is affected not
      only by metabolism but also by membrane exchangers, and b) besides the activation
      of Na(+)/H(+) exchange, anoxia activates a 4,4'-diisothiocyanostilbene-2,2'
      disulfonic acid-sensitive, Na(+)-dependent acid loader (possibly electrogenic).

PMID- 12605890
TI  - Potentiation by ATP of lipopolysaccharide-stimulated nitric oxide production in
      cultured astrocytes.
AB  - The functional changes of astrocytes are deeply involved in neurodegenerating
      processes of various CNS diseases. ATP is released during various neuronal
      damages such as brain ischemia and may control astrocyte functions. We examined
      the effect of ATP on the production of nitric oxide in the cultured astrocytes
      from rat embryo. The astrocytes were stimulated by lipopolysaccharide instead of
      pathological activation in vivo. Nitric oxide production was evaluated by the
      fluorometric assay of nitrite accumulated in the medium. The expression of
      inducible nitric oxide synthase was analyzed by Western blotting. Nitric oxide
      production induced by 1 ng/ml lipopolysaccharide was enhanced by ATP with maximal
      enhancement of three- to four-fold; a half-effective concentration was about 0.3
      mM. In the absence of ATP, half-effective concentration of lipopolysaccharide on
      nitric oxide production was about 3 ng/ml; however, half-effective concentration
      shifted to 0.3 ng/ml in the presence of 1.5-mM ATP. Several other P2 receptor
      agonists (uridine triphosphate, ADP, adenosine monophosphate, 2'- and 3'-O - (4
      benzoylbenzoyl)-ATP, and 2-methylthioATP) showed a similar enhancing effect, and
      an antagonist, ATP-2',3'-dialdehyde, showed an inhibiting effect. Western
      blotting analysis revealed that the extent of lipopolysaccharide-induced
      expression of nitric oxide synthase increased several-fold by the addition of
      ATP; half-effective concentration was about 0.5 mM. These results suggest that
      the extracellular ATP plays an important role as a transmitter and regulates
      astrocyte functions via a certain P2 receptor and that such a change in astrocyte
      function is involved in either protection or aggravation in neurodegenerative
      processes.

PMID- 12605891
TI  - Neuronal injury in hippocampus with human immunodeficiency virus transactivating
      protein, Tat.
AB  - Patients with human immunodeficiency virus infection may develop a dementing
      illness. Using both in vitro and in vivo models, we investigated the
      susceptibility of the hippocampal formation to the Tat protein of human
      immunodeficiency virus. We also determined the pattern of hippocampal injury in
      patients with human immunodeficiency virus encephalitis. Following exposure of
      hippocampal slices to Tat, marked susceptibility of CA3 region with relative
      insensitivity of the CA1/2 region was observed. Injection of Tat into different
      regions of the rat hippocampus produced similar neuronal loss in both CA3 region
      and the dentate gyrus. In animals administered Tat, lesions were dose-dependent
      and immunohistochemical staining showed marked gliosis and loss of microtubule
      associated protein-2 in the affected areas at 3 days post-injection.
      Interestingly, synaptophysin staining was relatively preserved. In hippocampal
      tissue from patients with human immunodeficiency virus encephalitis, loss of
      microtubule-associated protein-2 staining was reduced in the molecular layer of
      the dentate gyrus. The results of our experiments demonstrate a unique pattern of
      hippocampal injury in organotypic culture and rats exposed to Tat. Our
      observations that patients with human immunodeficiency virus reveal a similar
      pattern of damage suggests that Tat protein may be pathophysiological relevant in
      human immunodeficiency virus encephalitis.

PMID- 12605892
TI  - Lithium stimulates progenitor proliferation in cultured brain neurons.
AB  - The number of neurons in the brain is controlled by production of new neurons and
      neuronal death. Neural progenitor proliferation in the developing and adult brain
      plays a prominent role in the production of new neurons. Here, we examined the
      effects of lithium, a mood-stabilizing drug, on neuronal proliferation in rat
      primary neuronal cultures. The incorporation of 5-bromo-2'-deoxyuridine (BrdU)
      into replicating DNA was used to label proliferating cells. BrdU incorporation
      was detected by immunocytochemistry in cerebellar granule cells prepared from
      postnatal rats and cerebral cortical cultures prepared from embryonic rats.
      Quantification of BrdU incorporation into cultures was performed by counting BrdU
      positive cells and BrdU-coupled enzyme-linked immunosorbent assay. Both methods
      revealed that lithium increased BrdU incorporation in cerebellar granule cells
      and cerebral cortical cultures. Most BrdU-positive cells colocalized with nestin,
      a neuroblast cell marker, in cerebral cortical cultures. Blockade of DNA
      replication by cytosine arabinoside almost completely abolished BrdU
      incorporation, suggesting that lithium-induced BrdU incorporation was mainly due
      to enhanced DNA replication. Glutamate, glucocorticoids and haloperidol were
      found to markedly reduce neural progenitor proliferation in cerebellar granule
      cells. The presence of lithium prevented the loss of proliferation induced by
      these agents. Lithium-induced neural progenitor proliferation in vitro suggests
      that similar effects might occur in vivo and this action could also be related to
      its clinical efficacy. Cultured brain neurons may provide a valuable model for
      studying the molecular mechanisms underlying lithium-induced up-regulation of
      neural proliferation.

PMID- 12605893
TI  - Neurotoxicity of an endogenous brain amine, 1-benzyl-1,2,3,4
      tetrahydroisoquinoline, in organotypic slice co-culture of mesencephalon and
      striatum.
AB  - Organotypic slice co-culture of the ventromedial portion of the mesencephalon and
      striatum was used to evaluate the neurotoxicity of 1-benzyl-1,2,3,4
      tetrahydroisoquinoline, an endogenous brain amine related to Parkinson's disease.
      1-Benzyl-1,2,3,4-tetrahydroisoquinoline is specifically increased in the
      cerebrospinal fluid of patients with Parkinson's disease and induces parkinsonian
      features in the monkey and mouse. Here, it decreased the dopamine content of the
      cultured mesencephalon in both dose- (10-100 microM) and time- (24 h to 7 days)
      dependent manners. This result suggests that the neurotoxicity of 1-benzyl
      1,2,3,4-tetrahydroisoquinoline is correlated with the overall exposure
      (concentration multiplied by exposure time). Culture with 100 microM 1-benzyl
      1,2,3,4-tetrahydroisoquinoline for 24 h irreversibly reduced the dopamine
      content. Furthermore, culture with 100 microM 1-benzyl-1,2,3,4
      tetrahydroisoquinoline for 10 days caused morphological changes, including cell
      body shrinkage and distortion of dendritic morphology, in tyrosine hydroxylase
      positive cells in the mesencephalon and reduced the number of cells by half. The
      increase in lactate dehydrogenase activity in the media produced by 1-benzyl
      1,2,3,4-tetrahydroisoquinoline was significant in culture of the mesencephalon
      alone or its co-culture with striatum, but not in cultures of other brain
      regions. We suggest that 1-benzyl-1,2,3,4-tetrahydroisoquinoline is toxic to
      tyrosine hydroxylase-positive cells in the ventral mesencephalon and that it is
      correlated with the integral of the concentration by time of exposure. Thus a low
      concentration of 1-benzyl-1,2,3,4-tetrahydroisoquinoline may first induce a
      decrease in the dopamine content then shrinkage of the cell body, followed by the
      slow death of dopaminergic neurons over a long period. This is the first report
      that indicates 1-benzyl-1,2,3,4-tetrahydroisoquinoline exerts neurotoxicity at
      the cellular level, and reveals in part the character of its neurotoxicity.

PMID- 12605894
TI  - Plurisegmental vestibulocerebellar projections and other hindbrain cerebellar
      afferents in midterm chick embryos: biotinylated dextranamine experiments in
      vitro.
AB  - The vestibular neuronal groups that project to the cerebellum were mapped in
      midterm chick embryos (10-11 days in "ovo") through "in vitro " retrograde
      tracing experiments. Massive unilateral deposits of biotin-dextranamine were
      placed at the basis of the cerebellum to label the cerebellar peduncles. Separate
      rostral and caudal vestibulo-cerebellar groups were identified, with predominance
      of contralateral neurons. We tentatively identified the rhombomeric location of
      both groups, as well as their topography within the conventional
      cytoarchitectonically-defined vestibular nuclei, by comparison with previously
      established segmental fate maps. The rostral group extended from rhombomeres 1-4
      (r1-r4) and was restricted mainly to the superior vestibular nucleus. The caudal
      group stretched from r6 to pseudorhombomere "r8" and was related to the
      descending and medial vestibular nuclei. The less abundant ipsilateral
      vestibulocerebellar neurons had a similar topography. The crossing axons of the
      rostral vestibulocerebellar neurons formed a distinct rostral vestibulocerebellar
      decussation, restricted to the floorplate of rhombomere 2. The axons of the
      caudal vestibulocerebellar population mostly decussated associated to the deep
      cochlear commissure. The present results extend the "segmental hodological
      mosaic" of defined projection-neuron groups identified within the avian
      vestibular nuclear complex: The vestibulocerebellar projecting neurons as a type
      appear iterated from r1 to r4 and from r6 to pseudorhombomere "r8," albeit
      showing in their arrangement peculiarities related to single segmental domains,
      particularly rostrally. In contrast, the vestibulospinal groups are located more
      restrictedly in r4-r6, while the vestibulo-ocular projecting neurons extend from
      r1 to "r7." Only r4 and r6 contain elements of all three hodological types. The
      organization of the three vestibular projection populations studied to date seems
      comparable in chicken and frogs and may be a conserved feature in vertebrates.

PMID- 12605895
TI  - Impact of perinatal asphyxia on the GABAergic and locomotor system.
AB  - Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters
      within the striatum. The striatum plays an important role in motor control,
      sensorimotor integration and learning. In the present study we investigated
      whether perinatal asphyxia leads to motor deficits related to striatal damage,
      and in particular to the loss of GABAergic neurons. Perinatal asphyxia was
      induced in time-pregnant Wistar rats on the day of delivery by placing the uterus
      horns, containing the pups, in a 37 degrees C water bath for 20 min. Three motor
      performance tasks (open field, grip test and walking pattern) were performed at 3
      and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to
      stain GABAergic striatal projection neurons and interneurons, respectively. The
      motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in
      motor activity. Analysis of the walking pattern revealed an increase in stride
      width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss
      of calbindin-immunoreactive (-22%) and parvalbumin-immunoreactive (-43%) cells
      was found in the striatum following perinatal asphyxia at two months of age.
      GABA(A) receptor autoradiography revealed no changes in GABA binding activity
      within the striatum, globus pallidus or substantia nigra. We conclude that
      perinatal asphyxia resulted in a loss of GABAergic projection neurons and
      interneurons in the striatum without alteration of GABA(A) receptor affinity.
      Despite a considerable loss of striatal neurons, only minor deficits in motor
      performance were found after perinatal asphyxia.

PMID- 12605896
TI  - Age, diet and injury affect the survival of facial motoneurons.
AB  - Using the model of facial nerve avulsion, we have compared the effects of injury,
      age and diet on motoneuronal survival. One to four weeks after nerve avulsion, 50
      75% motoneuron loss was quantified in ad libitum-fed rats aged 7 days (neonate),
      6 months (adult) and 24 months (aging) at the time of injury. Evidence of
      apoptosis was found for neonatal rats at 3 days post-injury, but not for neonates
      examined 7 days or adult or aging rats examined 1 month after injury. Non
      operated, ad libitum-fed rats showed no significant loss of facial motoneurons by
      24 months. Surprisingly, non-operated rats whose food intake was restricted to 15
      g standard rat chow per day from the age of 6 months lost 50% of their
      motoneurons by 24 months. Facial nerve avulsion of 24-month-old rats raised on
      this restricted diet did not result in any additional loss of motoneurons one
      month after injury. These results challenge the common view that aging results in
      neuronal loss and that dietary restriction is universally beneficial.

PMID- 12605897
TI  - Distribution and regulation of galanin receptor 1 messenger RNA in the forebrain
      of wild type and galanin-transgenic mice.
AB  - To learn more about molecular alterations in the brain that occur as a
      consequence of either the chronic excess or absence of peptide neurotransmitters,
      we examined the impact of genetically manipulating the neuropeptide galanin on
      the expression of one of its cognate receptors, galanin receptor 1. First, we
      examined the distribution of galanin receptor 1 messenger RNA in the mouse
      forebrain, and found it to be abundantly expressed in many brain regions,
      including in numerous hypothalamic and other forebrain regions associated with
      neuroendocrine function. The distribution of galanin receptor 1 messenger RNA in
      the mouse was similar to previous reports in the rat, with additional expression
      noted in the caudate putamen and in several midbrain regions. Next, using
      quantitative in situ hybridization, we measured cellular levels of galanin
      receptor 1 messenger RNA in the brains of mice that either overexpress galanin
      (galanin transgenic) or lack a functional galanin gene (galanin knockout). We
      report that relative to wild-type controls, the expression of galanin receptor 1
      messenger RNA was increased in discrete areas of the brain in galanin-transgenic
      mice, but that depletion of galanin/noradrenergic innervation to the hypothalamus
      with the neurotoxin 6-hydroxydopamine did not alter levels of galanin receptor 1
      messenger RNA. We also report that levels of galanin receptor 1 messenger RNA
      were not different between galanin-knockout and wild-type mice. These results
      suggest that compensatory adjustments in the expression of cognate receptors
      represent one mechanism by which the developing nervous system attempts to
      maintain homeostasis in response to overexpression of a peptidergic transmitter.
      However, the lack of significant changes in galanin receptor 1 messenger RNA in
      galanin-knockout mice suggests that developmentally programmed levels of receptor
      expression are maintained even in the complete absence of ligand.

PMID- 12605898
TI  - Activation of cholinergic and adrenergic receptors increases the concentration of
      extracellular adenosine in the cerebral cortex of unanesthetized rat.
AB  - Adenosine is an inhibitory neuromodulator in the CNS. For extracellular adenosine
      to play a physiological role in the brain, it must be present at effective
      concentrations. Acetylcholine and noradrenaline are known to play an important
      role in modulating the activity of cortical neurons, and they might have a role
      also in the release of adenosine in the cerebral cortex in vivo. We examined
      whether activation of cholinergic and adrenergic receptors affects extracellular
      adenosine levels in the cerebral cortex of unanesthetized rats using in vivo
      microdialysis. All drugs were administered locally within the cortex by reverse
      dialysis. Both acetylcholine and the acetylcholinesterase inhibitor neostigmine
      increased extracellular adenosine levels, and the effect of neostigmine was
      blocked by the nicotinic receptor antagonist mecamylamine. Both nicotine and the
      nicotinic receptor agonist epibatidine increased the concentration of
      extracellular adenosine. Activation of muscarinic receptors using the
      nonselective agonist oxotremorine and a selective M1 receptor agonist also
      increased extracellular adenosine levels. Noradrenaline and the noradrenergic
      reuptake inhibitor desipramine increased extracellular adenosine levels. The
      alpha(1)-adrenergic receptor agonist phenylephrine and the beta-adrenergic
      agonist isoproterenol increased extracellular adenosine levels, whereas the
      alpha(2)-adrenergic receptor agonist clonidine did not have an effect. These
      findings indicate that activation of specific cholinergic and adrenergic
      receptors can increase extracellular levels of adenosine in the cortex, and
      suggest that cholinergic and adrenergic receptor-mediated regulation of adenosine
      levels may represent a mechanism for controlling the excitability of cortical
      neurons.

PMID- 12605899
TI  - CRF1-receptor antagonist CP-154526 reduces alerting-related cutaneous
      vasoconstriction in conscious rabbits.
AB  - Cutaneous vasoconstrictor responses elicited by salient stimuli in conscious
      rabbits may be a sensitive physiological index of emotional arousal/anxiety. Ear
      pinna blood flow was measured by preimplanted laser Doppler probes, and animals
      were exposed to situations involving different types of potentially salient
      stimuli before and after i.v. administration of CP-154526 (15 mg/kg) or diazepam
      (4 mg/kg). At rest, ear-pinna blood flow was stable (coefficient of varition=11+/
      2) and remained at high level 93+/-13% of test time. Exposure to novel
      environment elicited flow fluctuations (coefficient of variation=79+/-8) and
      reduced amount of time spent at high level to 25+/-6%. Defined unconditioned
      stimuli caused rapid falls in ear-pinna flow, with nociceptive stimulation
      producing more vigorous and consistent effects (flow response index 0.66+/-0.02)
      compared with non-nociceptive (flow response index 0.49+/-0.04). CP-154526
      slightly raised mean arterial pressure (from 81+/-2 to 93+/-3 mmHg), increased
      heart rate (from 198+/-1 to 220+/-4 beats/min) and produced a mild
      vasoconstriction in the ear-pinna bed (flow fell from 46+/-10 to 25+/-6 cm/s). CP
      154526 substantially reduced cutaneous vasoconstrictor responses elicited by the
      exposure to novel environment and by defined non-nociceptive stimuli, with flow
      response index fall from 0.53+/-0.10 to 0.17+/-0.09 and from 0.47+/-0.04 to
      0.24+/-0.04, respectively, without affecting responses to nociceptive stimuli.
      Diazepam reduced only vasoconstrictor responses elicited by the exposure to novel
      environment, with flow-response index fall from 0.40+/-0.12 to 0.27+/-0.07.
      Sensitivity of rapid changes in rabbit ear-pinna blood flow to anxiolytic drugs
      supports the idea that increased cutaneous vascular tone reflects enhanced
      arousal in rabbits.

PMID- 12605900
TI  - Ventral root avulsion leads to downregulation of GluR2 subunit in spinal
      motoneurons in adult rats.
AB  - It has been observed that motor neuron death is induced in adult rats by ventral
      root avulsion which involves pulling out the spinal cord root. Since motor
      neurons are reported to be selectively vulnerable to alpha-amino-3-hydroxy-5
      methyl-4-isoxazole propionate receptor-mediated injury in vitro, we investigated
      changes in the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole
      propionate-receptor subunits in rat spinal motor neurons after ventral root
      avulsion. The L4-L5 ventral roots of adult Sprague-Dawley rats were avulsed by an
      extravertebral extraction procedure. After an appropriate survival time, alpha
      amino-3-hydroxy-5-methyl-4-isoxazole propionate-receptor subunits were detected
      immunohistochemically in the L4-L5 segments. Ventral root avulsion resulted in a
      60% loss of motor neurons by 14 days after surgery. GluR2 labeling in motor
      neurons was markedly decreased after avulsion, but before the onset of motor
      neuron death, while the GluR1 and GluR4 labeling of motor neurons remained
      unchanged. Intrathecal administration of alpha-amino-3-hydroxy-5-methyl-4
      isoxazole propionate-receptor antagonists rescued a significant number of injured
      motor neurons from cell death. In contrast, N-methyl-D-aspartate-receptor
      antagonists did not prevent motor neuron death. Since the presence of GluR2
      subunit renders heteromeric alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate
      receptors Ca(2+)-impermeable, the downregulation of GluR2 may result in increased
      formation of GluR2-lacking, Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4
      isoxazole propionate receptors in motor neurons and could contribute to motor
      neuron death after ventral root avulsion.

PMID- 12605901
TI  - Tyrosine kinase B and C receptors in the neostriatum and nucleus accumbens are co
      localized in enkephalin-positive and enkephalin-negative neuronal profiles and
      their expression is influenced by cocaine.
AB  - Single- and double-label immunohistochemistry were used to determine the extent
      to which the tyrosine kinase B and C receptors, are expressed in enkephalin
      immunopositive or enkephalin-immunonegative neuronal profiles in the rat
      neostriatum and nucleus accumbens. Results indicate that tyrosine kinase B and C
      receptors are co-localized in both enkephalin-positive and enkephalin-negative
      neurons in both of these nuclei, which suggests that these receptors influence
      both the striatal-pallidal (enkephalin) and striatal-ventral mesencephalic
      (substance P/dynorphin) pathways. We also examined the influence of acute or
      repeated injections of cocaine on the number of tyrosine kinase B and C receptors
      immunoreactive neuronal profiles in the rat neostriatum and nucleus accumbens.
      Following an acute injection of cocaine (15 mg/kg, i.p.), there were significant
      decreases in the number of tyrosine kinase B and C receptors immunoreactive
      profiles in specific regions of the neostriatum and nucleus accumbens relative to
      saline-pretreated rats. One or 14 days following the last of seven daily
      injections of 15 mg/kg cocaine or saline there were no differences in the numbers
      of tyrosine kinase B or C receptors immunoreactive neuronal profiles between
      these treatment groups.Collectively, the present results indicate that tyrosine
      kinase B and C receptors in the neostriatum and nucleus accumbens are co
      localized in enkephalin-positive and enkephalin-negative neuronal profiles, which
      suggests that the striatal medium spiny neurons expressing tyrosine kinase B and
      C receptors include those that project to the pallidum or the ventral
      mesencephalon. The current results also show that an acute injection of cocaine
      results in a decrease in the number of tyrosine kinase B and C receptors
      immunoreactive neuronal profiles in specific regions of the nucleus accumbens and
      neostriatum, indicating that cocaine-induced increases in extracellular dopamine
      in the striatal complex result in compensatory decreases in the expression of
      tyrosine kinase B and C receptors.

PMID- 12605903
TI  - Different patterns of synaptic transmission revealed between hippocampal CA3
      stratum oriens and stratum lucidum interneurons and their pyramidal cell targets.
AB  - Stratum lucidum (SL) interneurons likely mediate feedforward inhibition between
      the dentate gyrus mossy fibers and CA3 pyramidal cells, while stratum oriens (SO)
      interneurons likely provide both feedforward and feedback inhibition within the
      CA3 commissural/associational network. Using dual whole-cell patch-clamp
      recordings between interneurons and CA3 pyramidal cells, we have examined SL and
      SO interneurons and their synapses within organotypic hippocampal slice cultures.
      Biocytin staining revealed different morphologies between these interneuron
      groups, both being very similar to those found previously in acute slices. The
      kinetics of IPSCs were similar between the two groups, but the reliability of
      synaptic transmission of SL interneuron (SL-INT) IPSCs was significantly lower
      than the virtually 100% reliability (non-existent failure rates) of SO-INT IPSCs.
      The SL-INT IPSCs also had a lower quantal content than the SO-INT IPSCs. In
      addition, SL-INTs were less likely than SO-INTs to innervate or to be innervated
      by nearby CA3 pyramidal cells. Paired-pulse stimulation at 100 ms interstimulus
      intervals produced similar paired-pulse depression in both interneuron synapses,
      despite the significantly higher failure rate of IPSCs produced by the SL-INTs
      compared with SO-INTs. CV analysis supported the hypothesis that paired-pulse
      depression was presynaptic. During repetitive, high frequency stimulation (>10 Hz
      for 500 ms) the two different synapses exhibited distinctly different forms of
      short-term plasticity: all SL interneurons displayed significant short-term
      facilitation (mean 113% facilitation, n=4), while, by contrast, SO interneuron
      synapses displayed either short-term depression (mean 42% depression, n=5 of 8)
      or no net facilitation or depression (n=3 of 8). These results indicate that the
      synaptic properties of interneurons can be quite different for interneurons in
      different hippocampal circuits.

PMID- 12605902
TI  - Nociceptin/orphanin FQ knockout mice display up-regulation of the opioid receptor
      like 1 receptor and alterations in opioid receptor expression in the brain.
AB  - The opioid receptor-like 1 receptor is a novel member of the opioid receptor
      family and its endogenous peptide ligand has been termed nociceptin and orphanin
      FQ. Activation of the opioid receptor-like 1 receptor by nociceptin/orphanin FQ
      in vivo produces hyperalgesia when this peptide is given supraspinally but
      analgesia at the spinal level. Nociceptin/orphanin FQ also reverses stress
      induced analgesia, suggesting that the peptide has anti-opioid properties.
      Nociceptin/orphanin FQ knockout mice show alterations in pain sensitivity and
      stress responses and display increased morphine dependence, suggesting an
      interaction of the nociceptin/orphanin FQ system with classical opioid receptor
      function. To determine if the behavioural phenotype of nociceptin/orphanin FQ
      knockout mice reflects changes in either opioid receptor-like 1 or classical
      opioid receptor expression, we have carried out quantitative autoradiography of
      the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains
      of these animals. Receptor density was measured on coronal sections from wild
      type, heterozygous and homozygous mice using [(3)H]nociceptin, [(3)H][D-Ala(2)-N
      methyl-Phe(4)-Gly(5) ol] enkephalin, [(3)H]deltorphin-I, or [(3)H](-)-N-methyl-N
      [7-(1-pyrrodinyl)-1-oxospiro[4,5]dec-8-yl]-4-benzofuranacetamide to label opioid
      receptor-like 1, mu-, delta- and kappa-receptors, respectively. A region-specific
      up-regulation of the opioid receptor-like 1 receptor (up to 135%) was seen in
      brains from homozygous mice. Mu-Receptors also showed significant differences
      between genotypes whilst changes in delta- and kappa- receptors were minor. In
      conclusion the region-specific up-regulation of the opioid receptor-like 1
      receptor indicates a tonic role for nociceptin/orphanin FQ in some brain
      structures and may suggest the peptide regulates the receptor expression in these
      regions. The changes in the opioid receptor-like 1 receptor may relate to the
      anxiogenic phenotype of these animals but the observed change in mu-receptors
      does not correlate with altered morphine responses.

PMID- 12605904
TI  - Tissue PO2 and the effects of hypoxia on the generation of locomotor-like
      activity in the in vitro spinal cord of the neonatal mouse.
AB  - The neonatal mouse en bloc spinal cord-brainstem preparation used in combination
      with advances in mouse genomics provides a novel strategy for studying the spinal
      control of locomotion. How well the mouse en bloc preparation is oxygenated
      however, is unknown. This is an important consideration given that (a) other
      superfused mammalian en bloc preparations have anoxic cores and (b) hypoxia can
      have profound effects on neuronal activity. Here we measure the level of tissue
      oxygenation in the mouse preparation and determine how neuronal activity within
      the spinal cord is influenced by poor superfusion and/or low oxygen. To measure
      tissue oxygenation, oxygen depth profiles were obtained (P0-1 and P2-3; Swiss
      Webster mice). At P0-1, spinal cords were oxygenated throughout under resting
      conditions. When fictive locomotor activity was evoked (5-HT 10 microM, dopamine
      50 microM, NMA 5 microM), there was a substantial reduction in tissue PO(2)
      starting within 5 min of drug application. Following washout, the PO(2) slowly
      returned to control levels over a period of 30 min. The experiments described
      above were repeated using P2-3 preparations. In this older age group, the spinal
      cord preparations had a hypoxic/anoxic core that was exacerbated during
      metabolically demanding tasks such as drug-evoked rhythmic activity. To examine
      how an anoxic core affects neuronal activity within the spinal cord we either
      altered the flow-rate or manipulated superfusate PO(2). When the flow-rate was
      reduced a transient disruption in the rhythmicity of drug-induced locomotion
      occurred during the first 15 min (P0-1 preparations). However, the motor output
      adapted and stabilized. During prolonged superfusion with hypoxic artificial
      cerebrospinal fluid on the other hand, both the motor bursts in spinal nerves and
      the activity of most neurons near the center of the tissue were
      abolished.Overall, this study suggests that while oxygenation of P0-P1
      preparations is adequate for studies of locomotor function, oxygenation of older
      preparations is more problematic. Our data also show that neonatal spinal neurons
      require oxygen to maintain activity; and the spinal locomotor rhythm generator
      continues to function providing the peripheral tissue of the cord is oxygenated.
      Together, these results are consistent with the results of a previous study which
      suggest that the locomotor pattern generator is located close to the surface of
      the spinal cord.

PMID- 12605905
TI  - Sleep modulates cannabinoid receptor 1 expression in the pons of rats.
AB  - Endocannabinoids seem to play a role in the modulation of alertness. Therefore,
      we measured cannabinoid receptor 1 (CB1R) protein by Western blot and messenger
      RNA (mRNA) by reverse transcription-polymerase chain reaction in the pons of rats
      across the 24-h period. We performed evaluations every 4 h beginning at 09:00 h.
      Rats were under a controlled light/dark cycle 12:12 (lights on at 08:00 h). Our
      data suggest that the expression of CB1R gene depends on diurnal variations, with
      maximum expression at 13:00 h for protein and 21:00 h for mRNA, and minimum
      expression at 01:00 and 09:00 h, respectively. We also analyzed CB1R protein and
      mRNA levels in the pons of rats deprived of total sleep for 24 h and in rats with
      a 24-h period of sleep deprivation plus a 2-h period of sleep rebound. Unlike
      sleep deprivation, sleep rebound significantly increased CB1R protein while
      decreasing mRNA. Despite the fact that we used gentle manipulation to deprive the
      animals of sleep, there may be a potential influence of stress on this effect,
      too. However, these facts suggest that CB1R gene expression is modulated by the
      light/dark cycle and by sleep.

PMID- 12605906
TI  - Dynamic regulation of polysialylated neural cell adhesion molecule in the
      suprachiasmatic nucleus.
AB  - The suprachiasmatic nucleus (SCN) prominently expresses polysialic acid (PSA), a
      carbohydrate polymer that is attached to neural cell adhesion molecule (NCAM) and
      promotes changes in cell interactions. Previous studies have shown that
      expression of PSA is important for circadian rhythm stability under constant
      darkness, and for photic entrainment of the SCN circadian clock. In the present
      study, immunoblot analyses of the Syrian hamster SCN revealed marked diurnal
      fluctuations in PSA under a 24-h light/dark cycle. PSA levels were reduced by
      >90% during the mid-to-late dark phase, and were elevated to maximal daytime
      levels approximately 1 h after lights-on. A similar pattern of PSA fluctuation
      persisted under constant darkness. Exposure of animals under a 24-h light/dark
      cycle to a 30-min light pulse during the late dark phase dramatically increased
      SCN contents of PSA within 60 min, and these values returned to basal levels 1-2
      h later. There was no effect of light-on expression of PSA in the hippocampus.
      Parallel studies revealed changes in the NCAM-180 isoform that carries PSA in the
      brain, suggesting that regulation of PSA may include protein as well as
      carbohydrate-associated mechanisms. Immunohistological analysis revealed light
      induced enhancement of PSA in the SCN subregion containing calbindin D(28K)
      cells. PSA staining was also closely associated with the majority of SCN cells
      expressing light-inducible Fos protein. This rhythmic, light-inducible expression
      of PSA within the SCN suggests that dynamic cell interactions are important for
      the photic regulation of circadian clock phase.

PMID- 12605907
TI  - Pyramidal cell heterogeneity in the visual cortex of the nocturnal New World owl
      monkey (Aotus trivirgatus).
AB  - Recent studies have revealed marked variation in pyramidal cell structure in the
      visual cortex of macaque and marmoset monkeys. In particular, there is a
      systematic increase in the size of, and number of spines in, the arbours of
      pyramidal cells with progression through occipitotemporal (OT) visual areas. In
      the present study we extend the basis for comparison by investigating pyramidal
      cell structure in OT visual areas of the nocturnal owl monkey. As in the diurnal
      macaque and marmoset monkeys, pyramidal cells became progressively larger and
      more spinous with anterior progression through OT visual areas. These data
      suggest that: 1. the trend for more complex pyramidal cells with anterior
      progression through OT visual areas is a fundamental organizational principle in
      primate cortex; 2. areal specialization of the pyramidal cell phenotype provides
      an anatomical substrate for the reconstruction of the visual scene in OT areas;
      3. evolutionary specialization of different aspects of visual processing may
      determine the extent of interareal variation in the pyramidal cell phenotype in
      different species; and 4. pyramidal cell structure is not necessarily related to
      brain size.

PMID- 12605908
TI  - Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin
      receptor 1 receptors.
AB  - The neuropeptide galanin may have a role in modulation of nociception,
      particularly after peripheral nerve injury. The effect of galanin is mediated by
      at least three subtypes of receptors. In the present study, we assessed the
      nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and
      the development of neuropathic pain-like behaviours after photochemically induced
      partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out
      (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail
      flick and paw radiant heat, tests. The mechanical sensitivity was not different
      between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was
      moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+)
      controls developed mechanical and heat hypersensitivity after partial sciatic
      nerve injury. The duration of such pain-like behaviours was significantly
      increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ
      in their recovery from deficits in toe-spread after sciatic nerve crush. The
      results provide some evidence for an inhibitory function for the neuropeptide
      galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain
      after peripheral nerve injury in mice.

PMID- 12605909
TI  - The impact of corticothalamic feedback on the output dynamics of a
      thalamocortical neurone model: the role of synapse location and metabotropic
      glutamate receptors.
AB  - The spatio-temporal integration of cortical excitatory postsynaptic potentials
      was investigated in a multi-compartment model of a thalamocortical neurone.
      Consistent with experimental data, cortical excitatory postsynaptic potentials
      contained a metabotropic glutamate receptor-mediated component and were generated
      by synapses located on distal dendrites. Within this framework, three synaptic
      distributions (each with equal maximal synaptic conductances) were compared:
      symmetric, with synapses distributed equally between all dendritic trees, single
      dendrite, where synapses were allocated on all distal segments of one dendrite,
      and single-segment, which comprised one synapse on a single dendritic
      compartment. We addressed three main issues: (1) the propagation of cortical
      excitatory postsynaptic potentials to the soma, (2) the interaction of cortical
      excitatory postsynaptic potentials with proximally generated retinal excitatory
      postsynaptic potentials, and (3) the effectiveness of cortical excitatory
      postsynaptic potentials in entraining and perturbing the delta oscillation. The
      somatic and dendritic amplitudes of the cortical excitatory postsynaptic
      potentials depended on the distribution of the synapses, being largest and
      smallest, respectively, for the symmetric distribution, and smallest and largest,
      respectively, for the single-segment distribution. When a retinal excitatory
      postsynaptic potential followed a subthreshold cortical excitatory postsynaptic
      potential with a short (2-200 ms) delay, its ability to evoke action potentials
      was increased, with single-segment cortical excitatory postsynaptic potentials
      having the longest-lasting facilitatory effect. When a retinal excitatory
      postsynaptic potential arrived with a longer delay (210-400 ms), the effect of
      the cortical excitatory postsynaptic potential was to decrease the number of
      retinally evoked action potentials. These facilitatory and depressant effects of
      the cortical excitatory postsynaptic potentials were dependent on the presence of
      their metabotropic glutamate receptor, and were enhanced by increasing the
      strength of this glutamate receptor component. Axial resistivity and distal
      dendritic A-type current had little qualitative effect on these modulatory
      actions of the cortical excitatory postsynaptic potential. Cortical excitatory
      postsynaptic potentials were more effective than retinal excitatory postsynaptic
      potentials in perturbing the phase of the delta oscillation, indicating that they
      are ideally suited to entraining this form of rhythmic activity. Again, this
      effect was closely dependent on the presence of metabotropic glutamate receptor
      but was largely independent of synapse distribution. These results indicate that
      the distribution of activated synapses and the presence of metabotropic glutamate
      receptor are crucial factors in determining the effect of cortical feedback
      excitation on thalamocortical neurons. Moreover, the distinct postsynaptic
      receptor composition of cortical inputs renders them ideally suited to
      synchronising low-frequency oscillatory activity in thalamocortical neurons.

PMID- 12605913
TI  - Toxic risk of surface water pollution--six years of experience.
AB  - Assessment of an ecological quality of surface water is necessary for effective
      protection, abatement and successive revitalisation of river ecosystems. This
      quality is primarily given by biological impact of surface water pollution.
      Substances contained in pollution are frequently toxic to aquatic organisms. Risk
      of chronic impact of surface water pollution is very often underestimated due to
      hidden long time action of pollutants. Proper estimation of the risk is not
      possible from results of chemical analyses and data of substances' toxicity.
      Chemical analyses are not able to detect all substances presented in water
      including the products of reactions between them. In addition, a simultaneous
      presence of substances can modify their final effect on aquatic organisms.
      Therefore, a complex method of assessment of toxic risk of surface water
      pollution based on ecotoxicological approach was developed. The toxic risk of
      surface water pollution is determined from results of evaluation of toxic risk of
      organic part and inorganic part of surface water pollution. Resultant degree of
      toxic risk of total pollution is given by the highest degree detected in any part
      of the water pollution. Presented method, which is routinely used for monitoring
      in the Czech part of the Odra river basin, was fully standardised and published
      in the form of the Czech branch technical norm of water management (TNV) in the
      year 2000.

PMID- 12605912
TI  - The changes of T-PAH levels and health status of mussels in Izmit bay (Turkey)
      after Marmara earthquake and subsequent refinery fire.
AB  - As is well known, a powerful earthquake along the North Anatolian Fault struck
      the eastern part of the Marmara region on August 17, 1999. Izmit Bay, which is
      known as one of the most polluted sites of Turkey, was also affected by the quake
      and the subsequent refinery fire. The measurements performed just before and
      after the earthquake showed that T-PAH levels increased significantly after the
      event [Okay OS, Tolun L, Telli-Karakoc F, Tufekci V, Tufekci H, Morkoc E. Izmit
      Bay (Turkey) ecosystem after Marmara earthquake and subsequent refinery fire: the
      long-term data. Marine Pollution Bulletin 2001;42:361-9]. In the framework of
      ecotoxicological studies, the Bay ecosystem was continuously monitored for T-PAH
      levels in seawater, sediments and mussels (Mytilus galloprovincialis) to find out
      whether change occurred during the 2-year period following the earthquake. For
      that purpose, after the earthquake, the samples were collected six times between
      the period of September 1999 and March 2001 at coastal stations of the Bay
      situated away from the mouth of main discharges. The responses of the mussels
      were also measured by means of the lysosomal stability of the blood cells and
      feeding rate biomarker techniques at two different sites of the bay. Although the
      T-PAH levels in all matrices generally showed a decreasing trend, they were found
      to be still high especially at stations near the refinery. Both biomarker results
      showed that the health status of the mussels is very poor in the Bay ecosystem,
      based on the results obtained from the two sites monitored.

PMID- 12605915
TI  - An assessment of the toxicity of pyridinium chlorides and their biodegradation
      intermediates.
AB  - Toxicity investigations were conducted for four pyridinium chlorides belonging to
      cationic surface-active substances (CSAS), which differed from each other in the
      numbers of methyl groups (CH(3)) in pyridinium ring. The crustacean Daphnia
      magna, the fish Lebistes reticulatus and the alga Scenedesmus quadricauda were
      chosen as biotests. Toxicity of examined preparations appeared to be very high
      but did not depend on their chemical structure. S. quadricauda was the most
      sensitive organism. Toxicity of intermediate products obtained in biological
      oxidation process was also examined. Biodegradation was conducted according to
      the "river water test". It was found that only partial degradation took place
      while pyridinium chlorides constituted main energy and carbon source. Presence of
      biodegradation intermediate products was shown on the basis of 1H NMR analysis.
      Intermediates were not toxic to any biotests.

PMID- 12605914
TI  - Activity of glutathione S-transferase in Spodoptera exigua larvae exposed to
      cadmium and zinc in two subsequent generations.
AB  - The aim of our study was to establish changes in activity of important in
      detoxification enzyme-glutathione S-transferase (GST): in alimentary tract, fat
      body and Malpighian tubules of Spodoptera exigua larvae being under cadmium and
      zinc exposure through the first as well as the second generation. There was
      registered enhancement of the enzyme activity in the fat body and the Malpighian
      tubules caused by zinc as well as its decrease in the Malpighian tubules under
      cadmium action. Amounts of metals in the alimentary tract were either several
      times higher than in the diet ingested by larvae or than in the fat body. Metal
      concentration in the fat body correlated with the level of the enzyme activity
      (positive correlation for zinc and negative for cadmium). The effect of metal
      action differentiated dependently on time exposition.

PMID- 12605916
TI  - Input of heavy metals to the forest floor as a result of Cracow urban pollution.
AB  - The influence of Cracow's urban pollution on small forest ecosystems was studied
      during 1998-2000. Seven sites located at different distances from the Cracow
      conurbation and from busy road were selected. Two sites were situated 26 and 31
      km from Cracow town along an eastern transect, the other five-3, 8, 14, 26 and 35
      km respectively, from Cracow-along a southern transect. At the beginning of
      September, five litter traps were set at each site. The quantity of litter fall,
      along with percentage composition of each species, were estimated for an area of
      1 m(2). The concentration of Cd, Pb, Cu, Zn and Fe in the litter fall and the
      input of these metals to the forest floor were determined. The input of cadmium
      ranged from 84 microg m(-2) at Kornatka in 1998 to 382 microg m(-2) at Bonarka in
      2000. The input of lead was about 10 times higher than cadmium and varied from
      406 microg m(-2) at Weglowka in 1998 to 3717 microg m(-2) at Bonarka in 2000.
      Input of Cu, Zn and Fe to the forest floor showed the similar tendency. During
      1998-2000, the highest heavy metal concentrations in the litter fall and their
      impact on the forest floor were always found at sites close to the Cracow
      conurbation and, in the eastern transect, close to a steel works. Input of metals
      to the forest floor tended to decrease with increasing distance from the centre
      of Cracow.

PMID- 12605917
TI  - The problem of allergy in ecotoxicology of polymeric materials.
AB  - In the program of initial toxicological test, the estimation of allergenic
      activity of some names of polymeric compositions, which are used in the
      polygraphic industry and when painting and decorating dwelling houses and social
      purpose premises, had been carried out. Most of the investigated compositions
      have different degrees of allergenicity. In order to unify the works in this
      field, we suggest the basic circuit of the estimation of allergenicity of
      polymeric materials, the final stage of which provides for the compiling of
      register of potentially allergenic polymeric materials.

PMID- 12605918
TI  - Diet monitoring for assessment of human exposure to environmental pollutants.
AB  - Daily intake of lead, cadmium, aluminium, radiocaesium, DDT and metabolites, and
      lindane in the whole-day food rations collected in hospital canteens in Krakow,
      Lodz, Olsztyn and Poznan in winters of 1993-1994, 1995 and 1996 were determined.
      The diets contained almost 40 microg of cadmium, corresponding to 70% of PTWI,
      and compared to the levels recognised as safe (ADI or PTWI) small amounts of the
      other contaminants. The highest content of Pb, Cd, Al and lindane was determined
      in the diets collected in Krakow, that of radiocaesium in Lodz, and DDT level was
      the highest in Poznan. The whole-day food rations from Olsztyn, situated in a
      region called "green lungs of Poland", were not statistically less contaminated
      than the diets from the other towns. The Pb and radiocaesium levels decreased
      significantly with time.

PMID- 12605919
TI  - Biomarkers and community indices as complementary tools for environmental safety.
AB  - Research on biomarkers as early bioindicators of perturbation in populations and
      individuals has been gaining ground over the last decade. This ecotoxicological
      approach relies on the fact that changes occur at low levels of organization
      before the community is affected and thus they can be monitored to assess
      environmental safety. Changes may concern behavior, physiology, biochemistry, or
      genomic structure and functioning, and may impair population dynamics in the long
      term. Ecotoxicity studies based on biomarkers allow us to measure the impact of
      environmental stressors and to easily follow the evolution of the systems towards
      degradation or restoration. Over and above their use as simple indices of
      exposure to specific pollutants, biomarkers can give an insight into ecosystem
      health. The results of our experience in field studies involving ecotoxicologists
      and ecologists will be presented in order to illustrate the relevance of such an
      integrating strategy for environmental quality assessment.

PMID- 12605920
TI  - Habitat function of agricultural soils as affected by heavy metals and polycyclic
      aromatic hydrocarbons contamination.
AB  - Ecotoxic activity of soils polluted with polycyclic aromatic hydrocarbon (PAH)
      and heavy metals (HM) was evaluated in pot and laboratory experiments. Plants and
      soil microorganisms were chosen as test organisms and six different soil
      materials were used in the study. The applied levels of HM and PAH were aimed to
      reflect environmental conditions in the "worst case" situation. Zn(2+), Pb(2+)
      and Cd(2+) were introduced to the soils as an aqueous solution of the mixture of
      salts at the concentrations corresponding to 1000, 500 and 3 mg kg(-1),
      respectively. Mixture of four PAH compounds (flourene, anthracene, pyrene and
      chrysene) as a CH(2)Cl(2) solution was applied at levels of 10-100 mg summation
      operator 4PAH kg(-1). Population and activity of soil microflora was evaluated as
      measured of total bacteria counts, intensity of respiration and enzyme activity
      (dehydrogenases and phosphatases). Effect on plants was evaluated on the base of
      the growth (plant at an early stage of their development) and yield (mature
      plant) measurements. The results indicate that combined effect of PAH and heavy
      metals on soil microorganisms activity and on some plants at an early stage of
      their development can be stronger than in soils amended with HM or PAH
      separately. Reaction of tested organisms was related to soil properties, PAH
      concentration, time and plant species. Mature plants (maize) were insensitive to
      the applied levels of both group of contaminants.

PMID- 12605921
TI  - Water and sediment toxicity assessment by use of behavioural responses of
      medicinal leeches.
AB  - Behaviour has been shown to be a sensitive indicator of chemically induced stress
      and pathology in aquatic organisms. However, ecotoxicological investigations on
      medicinal leech are restricted because of scarce leech resources in natural
      waters. We used artificially bred medicinal leech (Hirudo medicinalis L.) of two
      different ages: young (1-2 weeks old) and adult leeches (1 year old). Animals
      were exposed to: (1) waters of Lake Drukshiai-the cooler of Ignalina Nuclear
      Power Plant, (2) sediments of the river Nemunas and (3) solution of heavy metal
      model mixture (HMMM). The following behavioural responses of leech were
      investigated: mobility (number of moving individuals within certain periods of
      time), avoidance response (number of individuals escaping the tested water or
      sediments) changes in body shape (contractions of some muscles, abnormal position
      of suckers) and feeding activity (longevity of attachment process, interruptions
      of feeding bouts, size of blood meal). Mobility of young leeches was increased in
      the tested waters of Lake Drukshiai, whereas adult leeches showed no changes of
      this index. Avoidance response as well as impaired feeding activity (prolonged
      attachment process or completely suppressed attachment reflex, decreased size of
      blood meal) was observed in young leeches exposed to the waters from Lake
      Drukshiai and in adult animals exposed to all three kind of trials mentioned
      above. Avoidance response and changes in mobility were recorded during the first
      hour of exposure to tested samples; therefore, these responses can be used as an
      express method for water and sediment pollution assessment. Impaired feeding
      activity was recorded after 1-3-week exposure: this response may be used in
      assessing a chronic toxicity of pollution. Medicinal leech, due to its
      sensitivity, simplicity of measured indices and ease of laboratory maintenance,
      can be used as a test organism in ecotoxicity studies.

PMID- 12605922
TI  - Effects of cadmium and zinc on larval growth and survival in the ground beetle,
      Pterostichus oblongopunctatus.
AB  - Carabid beetles, like Pterostichus oblongopunctatus, living in metal contaminated
      areas may be exposed to elevated levels of metals within their diets. However,
      when compared to other second order consumers, they have one of the lowest
      observed levels of metals, indicating methods of detoxification to deal with such
      toxicants. In this study, we investigated if chronic, multigenerational exposure
      to metals leads to resistance to toxic metal concentrations, and if so, what are
      the costs associated with them. Adult organisms were collected from two sites, a
      polluted and a reference site near Olkusz, in southern Poland. These adults were
      immediately mated, and eggs were collected twice weekly to assess the effects in
      the larvae of the F(1) generation. Larvae were randomly exposed to one of four
      artificial mediums: control, 50 mg kg(-1) Cd, 500 mg kg(-1) Zn, and a combined
      treatment of 50 mg kg(-1) Cd and 500 mg kg(-1) Zn to investigate possible
      interactions. Individuals were sacrificed at 10, 30, and 40 days. Although metals
      were not accumulated in larvae (p>0.05), larvae fed the Cd or the Zn treatment
      grew significantly slower, and had the lowest survival rate (p<0.05) in respect
      to control. Out of metal treated animals, those on the combined treatment of CdZn
      grew the quickest and had the highest observed survival (p<0.05). Although
      previous studies have demonstrated changes in adult population parameters under
      chronic, multigeneration exposure to toxic metal concentrations, our study did
      not reveal any changes in the larval stage.

PMID- 12605923
TI  - Imposex as a biomonitoring tool for marine pollution by tributyltin: some further
      observations.
AB  - Imposex, i.e., the imposition of male sexual characteristics on female
      neograstropods, has been used worldwide as a bioindicator of pollution by the
      antifouling agent TBT as well as to assess the related ecological impact. The
      recent total ban on the use of TBT in the maritime industry has been partly based
      on the use of such a biomarker. This is mainly based on the assumption that no
      other pollutant, or environmental stress, is able to induce such a biological
      response. Nonetheless, several authors had challenged this idea. The present
      paper will present further field observations on imposex in Hexaplex trunculus
      from Malta (Central Mediterranean) which may help clarify this issue.
      Furthermore, the incidence of imposex in this species will be related to body
      burdens and to the environmental levels of organotins as measured analytically.
      First histological observations will also be presented which may help clarify the
      ecological significance of this response in this species. Finally a number of
      alternative scenarios regarding the relationship between imposex and TBT will be
      discussed.

PMID- 12605924
TI  - Determination of potentially bioaccumulating complex mixtures of organochlorine
      compounds in wastewater: a review.
AB  - Organic chlorine compounds can be persistent environmental contaminants and may
      be accumulated through the food chain to the aquatic organisms, to fish and
      humans, depending basically on their hydrophobic properties. Consequently, there
      is an interest to measure these organic compounds from both the scientific and
      regulatory communities. The analytical essays have been improved for measuring
      specific organic chlorine compounds that present the most toxicological potential
      (polychlorinated biphenyls [PCBs], certain pesticides and dioxins), although they
      are tedious and time-consuming procedures. The existing tests to measure
      adsorbable organic halogens (AOX) or extractable organic halogens (EOX) do not
      distinguish the more hydrophobic organic chlorine matter. The intention of this
      paper is to make a review of the existing methods to measure the potentially
      bioaccumulating organochlorine compounds (OCs) from wastewater and propose a
      methodology to a standardisation procedure for complex mixtures of OCs in
      wastewater, such as pulp mill effluents. A new method has been proposed for
      determining the most hydrophobic part of the extractable organic halogens
      (EOX(fob)), the lowest reported value is 0.6 microg/l, expressed as chloride, and
      the relative standard deviation at 20 microg/l is 7% on laboratory samples and
      30% on real effluents. This new procedure could be a valuable tool to complement
      environmental risk assessment studies of wastewater discharges.

PMID- 12605925
TI  - Toxicity of copper in sewage sludge.
AB  - Sewage sludge is a source of organic matter and nutrients, but a major obstacle
      for its recycling is that the municipal wastewater sludge has low but significant
      levels of contaminants. This investigation, on the acute toxicity of copper in
      sewage sludge, was conducted with three organisms, Daphnia magna, Lemna minor and
      Raphanus sativus (seeds). The toxicity of the leakage water from sewage sludge
      spiked with CuSO(4) was studied for 64 days. The toxicity increased during the
      first 8-16 days and then started to decrease. The first increase in toxicity was
      due to ammonia, but after 32 days, a dose-related effect of copper was found.
      After 64 days, L. minor had an EC50 of 3800 mg Cu/kg dw for 7 days growth
      inhibition, a LOEC of 3200 mg Cu/kg dw and a NOEC of 1600 mg Cu/kg dw. D. magna
      had an EC50 of 18100 mg Cu/kg dw (24-h immobility) and a NOEC of 12800 mg Cu/kg
      dw. Root elongation of R. sativus was reduced at 25600 mg Cu/kg dw. Both for
      Daphnia and Lemna, the pH of the leakage water had an effect of the toxicity.
      This means that chemical speciation and bioavailability is very important for the
      hazard assessment of copper in sludge and soil.

PMID- 12605926
TI  - Novel approach to monitoring of the soil biological quality.
AB  - In this study, a new approach to interpretation of results of the simple
      microbial biomass and respiration measurements in the soil microbiology is
      proposed. The principle is based on eight basal and derived microbial parameters,
      which are standardized and then plotted into sunray plots. The output is visual
      presentation of one plot for each soil, which makes possible the relative
      comparison and evaluation of soils in the monitored set. Problems of soil
      microbiology, such as the lack of benchmarking and reference values, can be
      avoided by using the proposed method. We found that eight parameters provide
      enough information for evaluation of the status of the soil microorganisms and,
      thus, for evaluation of the soil biological quality. The usage of rare parameters
      (potential respiration PR, ratio of potential and basal respiration PR/BR,
      biomass-specific potential respiration PR/C(bio), available organic carbon
      C(ext), and biomass-specific available organic carbon C(ext)/C(bio)) can be
      recommended, besides classical and well-known parameters (microbial biomass
      C(bio), basal respiration BR, metabolic coefficient qCO(2)). The combination of
      basal parameters and derived coefficients can also extend our knowledge about the
      condition of the soil microorganisms. In monitoring the case studies presented,
      we observed that soils evaluated to possess good biological quality displayed
      generally higher values of organic carbon, total nitrogen, clay, and cation
      exchange capacity. The soils of good biological quality can display higher levels
      of contaminants. This is probably related with the higher content of organic
      carbon and clay in these soils.

PMID- 12605927
TI  - Effect of heavy metals and PAH on soil assessed via dehydrogenase assay.
AB  - Dehydrogenase enzyme activity (DHA) assay method using resazurin was accommodated
      for measuring of toxicity of compound contaminants on uncharacterized microbial
      communities present in any given soil. The method was used to compare the toxic
      effect of heavy metal and polycyclic aromatic hydrocarbon (PAH) contaminant
      mixture (Cr, Pb, Cu, Cd, Pyrene) on four typical Estonian soils covering a range
      of compositions. The method proved to be useable on all soils; the sensitivity of
      soil microbiology to toxic effect of contaminants was found to have a negative
      correlation with Ca and organic matter (OM) content and a positive correlation
      with amorphous phase content of soils.

PMID- 12605928
TI  - Sorption of metals onto natural organic matter as a function of complexation and
      adsorbent-adsorbate contact mode.
AB  - The effect of complexing anion and adsorbate-adsorbent contact mode (static
      equilibrium or dynamic non-equilibrium) on binding and partition of Cu(2+),
      Cd(2+) and Zn(2+) onto organic matter (exemplified in a low-moor peat) was
      studied. The study comprised comparative batch and column flow-through sorption
      experiments on monometallic solutions of Me-Cl and Me-SO(4) salts, at pH 4.0, and
      sequential fractionation of sorbed metals with respect to binding strength. Both
      the presence of an anion having complexing properties (Cl(-)) as well as a
      contact mode was found to quantitatively and qualitatively affect the sorption
      capacity and binding strength of organic matter (peat) for metal ions. Complexing
      effect of Cl(-) on metal ions resulted mostly in reduction of metal ability to
      form strongly bound metal-organic compounds, in accordance with the order of
      stability constant of complex ions log K: Cd>Zn>Cu. Flow-through (dynamic)
      contact mode, which is the most appropriate to simulate environmental conditions,
      appeared to strongly attenuate the complexing effect of chloride ions on Cd and
      Zn sorption, and significantly enhance sorption capacity also in the absence of
      complexing ions. For Cd, it was mainly due to the enrichment in the strongly
      bound "insoluble organic" fraction, while for Zn the quantitative increase of
      sorption capacity did not alter significantly its partitioning. Neither a
      quantitative nor qualitative effect of contact mode on Cu binding was observed.
      Complex and diverse effects of different environmental parameters on metal
      sorption capacity and binding strength onto organic matter, which strongly
      influence metal mobility, leads to the conclusion that the correct simulation of
      these parameters for ecotoxicological testing is crucial for the reliable
      predicting of metal bioavailability under actual terrestrial environmental
      conditions.

PMID- 12605929
TI  - Environmental risk assessment of metals: tools for incorporating bioavailability.
AB  - In this paper, some of the main processes and parameters which affect metal
      bioavailability and toxicity in the aquatic environment and its implications for
      metal risk assessment procedures will be discussed. It has become clear that,
      besides chemical processes (speciation, complexation), attention should also be
      given to physiological aspects for predicting metal toxicity. The development of
      biotic ligand models (BLMs), which combine speciation models with more
      biologically oriented models (e.g. GSIM), has offered an answer to this need. The
      various BLMs which have been developed and/or refined for a number of metals
      (e.g. Cu, Ag, Zn) and species (algae, crustaceans, fish) are discussed here.
      Finally, the potential of the BLM approach is illustrated through a theoretical
      exercise in which chronic zinc toxicity to Daphnia magna is predicted in three
      regions, taking the physico-chemical characteristics of these areas into account.

PMID- 12605930
TI  - Toxicity assessment of wood preservatives.
AB  - The article describes the influence of wood preservatives on water bioceonosis.
      The "battery" of toxicology tests was used to cover luminescent bacteria test,
      algae growth inhibition test, crustacean and fish lethal tests. The test samples
      used were pure wood preservative and water after the wood preservative leaching
      from wood sample. It was observed that the wood preservative is leaching from the
      wood sample in 10% within 1 month of exposition. Achieved results indicate the
      necessity of toxic assessment of wood preservative after wood element protection.

PMID- 12605931
TI  - Precaution, uncertainty and causation in environmental decisions.
AB  - What measures of uncertainty and what causal analysis can improve the management
      of potentially severe, irreversible or dreaded environmental outcomes?
      Environmental choices show that policies intended to be precautionary (such as
      adding MTBE to petrol) can cause unanticipated harm (by mobilizing benzene, a
      known leukemogen, in the ground water). Many environmental law principles set the
      boundaries of what should be done but do not provide an operational construct to
      answer this question. Those principles, ranging from the precautionary principle
      to protecting human health from a significant risk of material health impairment,
      do not explain how to make environmental management choices when incomplete,
      inconsistent and complex scientific evidence characterizes potentially adverse
      environmental outcomes. Rather, they pass the task to lower jurisdictions such as
      agencies or authorities. To achieve the goals of the principle, those who draft
      it must deal with scientific casual conjectures, partial knowledge and variable
      data. In this paper we specifically deal with the qualitative and quantitative
      aspects of the European Union's (EU) explanation of consistency and on the
      examination of scientific developments relevant to variability and uncertain data
      and causation. Managing hazards under the precautionary principle requires
      inductive, empirical methods of assessment. However, acting on a scientific
      conjecture can also be socially unfair, costly, and detrimental when applied to
      complex environmental choices. We describe a constructive framework rationally to
      meet the command of the precautionary principle using alternative measures of
      uncertainty and recent statistical methods of causal analysis. These measures and
      methods can bridge the gap between conjectured future irreversible or severe harm
      and scant scientific evidence, thus leading to more confident and resilient
      social choices. We review two sets of measures and computational systems to deal
      with uncertainty and link them to causation through inductive empirical methods
      such as Bayesian Networks. We conclude that primary legislation concerned with
      large uncertainties and potential severe or dreaded environmental outcomes can
      produce accurate and efficient choices. To do so, primary legislation should
      specifically indicate what measures can represent uncertainty and how to deal
      with uncertain causation thus providing guidance to an agency's rulemaking or to
      an authority's writing secondary legislation. A corollary conclusion with legal,
      scientific and probabilistic implications concerns how to update past information
      when the state of information increases because a failure to update can result in
      regretting past choices. Elected legislators have the democratic mandate to
      formulate precautionary principles and are accountable. To preserve that mandate,
      imbedding formal methods to represent uncertainty in the statutory language of
      the precautionary principle enhances subsequent judicial review of legislative
      actions. The framework that we propose also reduces the Balkanized views and
      interpretations of probabilities, possibilities, likelihood and uncertainty that
      exists in environmental decision-making.

PMID- 12605932
TI  - Water quality and impacts of pollution sources for Eymir and Mogan Lakes
      (Turkey).
AB  - Mogan and Eymir Lakes are two shallow lakes, interconnected hydrologically in the
      close vicinity of Ankara, Turkey. A total of 245 km(2) of the total 971.4 km(2)
      watershed is under environmental protection status as "Golbasi Specially
      Protected Area". Potential impacts from extensive agriculture, recreation,
      incomplete infrastructure and other human activities, such as residential
      settlements, are discussed with reference to previous and more recent pollution
      monitoring. Six monitoring stations enabling follow-up of previous work were
      selected in this study. These were on the creeks feeding the lake systems.
      Generally, summer months showed heavier pollution loads, with Eymir Lake
      concentrating the pollutants due to flow from Mogan Lake. When compared with the
      1995 study; COD, total-P, Kjeldahl-N in the six stations were close or slightly
      decreased in the present study. Suspended solids significantly decreased;
      possibly due to erosion control measures and decreased domestic wastewater. The
      improvement in the pollution state of the lakes is attributed to the construction
      of a sewage system going around Mogan Lake and collecting wastewater discharges
      and restrictions to urban settlement development around the lakes brought by the
      1/25,000 land use plan controlling further impact from residential developments
      within the protected area boundaries. The study, while addressing water quality
      and interactions due to human activities in shallow lakes, also discusses
      problems associated with human impacts in protected areas with the aim of
      presenting a complicated case study.

PMID- 12605933
TI  - The contamination with organochlorine pesticides and heavy metals in surface
      water in Kucuk Menderes River in Turkey, 2000-2002.
AB  - This study was conducted from 2000 to 2002 to determine the residues of
      organochlorine pesticides (OCP) and metals in surface water of Kucuk Menderes
      River in Turkey. The results showed that Kucuk Menderes River was still polluted
      with organochlorine pesticide despite the existence of bans over a long time. The
      concentrations of pesticides depended on the sampling season and the tendency was
      not the same for all detected pesticides. The DDTs (DDT, DDD, DDE) were detected
      in most water samples. DDD showed a high concentration among DDTs. The highest
      concentration among organochlorine pesticides was heptachlor epoxide by 281 ng/l.
      However, the residues were lower than most polluted water from other sources in
      the world. In most cases, they were not detectable. The studied surface water
      metals varied from not detected to 0.258 mg/l, and the residues were low except
      for Ni, Cu, and Zn.

PMID- 12605934
TI  - Iodine uptake by spinach (Spinacia oleracea L.) plants grown in solution culture:
      effects of iodine species and solution concentrations.
AB  - A hydroponic experiment was carried out to investigate the effects of iodine
      species and solution concentrations on iodine uptake by spinach (Spinacia
      oleracea L.). Five iodine concentrations (0, 1, 10, 50 and 100 microM) for iodate
      (IO(3)(-)) and iodide (I(-)) were used. Results show that higher concentrations
      of I(-) (> or =10 microM) had some detrimental effect on plant growth, while
      IO(3)(-) had little effect on the biomass production of spinach plants. Increases
      in iodine concentration in the growth solution significantly enhanced I
      concentrations in plant tissues. The detrimental effect of I(-) on plant growth
      was probably due to the excessively high accumulation of I in plant tissues. The
      solution-to-spinach leaf transfer factors (TF(leaf), fresh weight basis) for
      plants treated with iodide were between 14.2 and 20.7 at different solution
      concentrations of iodide; TF(leaf) for plants treated with iodate decreased
      gradually from 23.7 to 2.2 with increasing solution concentrations of iodate. The
      distribution coefficients (DCs) of I between leaves and roots were constantly
      higher for plants treated with iodate than those treated with iodide. DCs for
      plants treated with iodide increased with increasing solution concentrations of
      iodide, while DCs for plants treated with iodate (around 5.5) were similar across
      the range of solution concentrations of iodate used in this experiment. The
      implications of iodine accumulation in leafy vegetables in human iodine nutrition
      are also discussed.

PMID- 12605935
TI  - Impact of different pollutant sources on Shiraz air pollution using SPM elemental
      analysis.
AB  - Weekly average suspended particulate matter (SPM) concentrations were measured in
      four locations in Shiraz, Iran. Sampling was carried out from July 1999 and
      continued until July 2000. Instrumental neutron activation analysis (INAA) and
      atomic absorption spectrometry (AAS) methods were employed to obtain the weekly
      concentrations of Pb, Br, V, Ca, Al, Fe, Cu, Cr, Mn, Sc and Zn. The mean annual
      concentrations (in microg/m(3)) of 11 elements were found to be: Pb 0.545 (+/-
      33.8%), Br 0.413 (+/- 34.1%), V 0.009 (+/- 28.2%), Ca 13.36 (+/- 24.5%), Al 2.56
      (+/- 46.3%), Fe 2.62 (+/- 38.7%), Cu 0.122 (+/- 41.4%), Cr 0.015 (+/- 35.8%), Mn
      0.053 (+/- 35.5%), Sc 0.0008 (+/- 37.5%) and Zn 0.085 (+/- 25.2%). The results of
      the study show that vehicle (traffic) pollution in Shiraz is higher than WHO and
      EPA standards and natural and industrial pollution is exceeding international
      guidelines in some seasons. The findings of the study confirm that the nearby
      cement factory has a major pollution impact on Shiraz air.

PMID- 12605936
TI  - Inactivation of coliform bacteria in Black Sea waters due to solar radiation.
AB  - The effects of solar radiation and temperature on bacterial die-off rates in
      Black Sea coastal waters using total coliform as the indicator organism were
      studied. Coliform die-off experiments were carried out in seawater samples
      collected along the coastline. The experiments were conducted in beakers filled
      with seawater that were kept at constant temperatures and exposed to solar
      radiation. The membrane filter technique was used for the coliform analysis.
      Temperature ranging between 9 and 26 degrees C and solar radiation between 20 and
      60 cal/cm(2) h were tested. Experiments in the dark were also conducted to
      isolate the effect of solar radiation from the other factors and, furthermore, to
      determine the effect of temperature on bacterial die-off. The solar radiation was
      found to be the most significant factor affecting the mortality of coliform
      bacteria.

PMID- 12605938
TI  - Geochemical speciation of heavy metals in semiarid soils of the central Ebro
      Valley (Spain).
AB  - This study describes the chemical speciation of Fe, Mn, Zn and Cr in four
      selected soil types representative of the more abundant agricultural soils in the
      central Ebro river valley in Aragon. Gypsisols, Calcisols, Solonchaks and
      Solonetzs represent around 20% of the total soil surface in the region. A total
      of 12 selected sites have been sampled and five subsamples were taken in each
      site to create a composite sample. The four elements have been analysed by the
      sequential extraction procedure of Tessier et al. [Anal. Chem. 51 (1979) 844.] by
      emission atomic spectrometry of solid state (ICP OES). Very little amounts of Fe
      and Mn were retrieved from the exchangeable phase, the ready available for
      biogeochemistry cycles in the ecosystems. Therefore, low quantities of Fe and Mn
      can be taken up by plants in these alkaline soils. Cr was not detected in the
      bioavailable forms as well as Zn that was only present in negligible amounts in
      very few samples. The absence of mobile forms of Cr in all soils eliminates the
      toxic risk both in the trophic chain and from its migration downwards the soil
      profile. The largest contents of Fe, Zn and Cr were retrieved from the residual
      phase where metals are strongly bound to minerals, whereas Mn from the carbonate
      and oxide phases amounts 80% of its total content. Gypsisols and Calcisols have
      the lowest metal contents while the highest are found in Solonetzs and
      Solonchaks.

PMID- 12605937
TI  - Odiel River, acid mine drainage and current characterisation by means of
      univariate analysis.
AB  - Water pollution caused by sulfide oxidation responds to two geochemical
      processes: a natural one of temporal patterns, and the 'acid mine drainage', an
      accelerated process derived from the extractive activity. The Odiel River is
      located in Southwestern Spain; it flows to the south and into the Atlantic Ocean
      after joining the Tinto River near its mouth, forming a common estuary. There are
      three kinds of metallic mining in the Odiel River Basin: manganese, gold and
      silver, and pyrite mining, the latter being the most important in this basin,
      which is the object of this study. The main objective of the present study is
      centred in the characterisation of the sources responsible for the 'acid mine
      drainage' processes in the Odiel River Basin, through the sampling and subsequent
      chemical and statistical analyses of water samples collected in three types of
      sources: mine dumps, active mines and abandoned mines. The main conclusion is
      that mean pH values in the target area are remarkably lower than those in other
      active and abandoned mines outside of the study zone. On the contrary, mean
      values for heavy metal sulfates are much higher. Regarding mine dumps, mean
      values for pH, sulfates and heavy metals are within a similar range to those data
      known for areas outside the study zone.

PMID- 12605939
TI  - Spatial variations of heavy metals contamination in sediments from Odiel river
      (Southwest Spain).
AB  - The presence of heavy metal concentrations was examined in surface sediments from
      27 sites within the Odiel river in the southwest Spain suffering inputs from
      industrial and mining activities. The interest is specially focused on the final
      delta located in the Odiel Natural Park, which constitutes a feeding ground of
      international importance for migrating birds. The behavior of 10 heavy metals
      (Zn, Cd, Pb, Cu, Cr, Mn, Ni, Fe, Hg) is conditioned by chemical properties of
      sediments such as acidity and carbonate or the presence of sulfate Very acidic
      sediments in the medium course of river contribute to the lower presence of metal
      as a consequence of leaching process. However, tidal action raises the pH in the
      marshes of the delta with correlative metal accumulation. In accordance with the
      Muller [Umschan 79 (1979) 133-149] scale for geoaccumulation index, the entire
      watercourse could be considered polluted by Zn and Pb, while Cu exhibits a high
      presence in the delta marshes of the river.

PMID- 12605941
TI  - Use of geographic information systems for assessing groundwater pollution
      potential by pesticides in Central Thailand.
AB  - This study employed geographic information systems (GIS) technology to evaluate
      the vulnerability of groundwater to pesticide pollution in Thailand. The study
      area included three provinces, Kanchana Buri, Ratcha Buri, and Suphan Buri,
      located in west-central Thailand. Factors used for the vulnerability assessment
      included soil texture, slope, land use, well depth, and rainfall. These
      vulnerability factors were reclassified to a common scale, and a weighted average
      was computed to yield a vulnerability score. Vulnerability factors and weights
      were assigned considering pesticide concentrations in 90 wells throughout the
      study area. Well depth was the most significant vulnerability factor. Groundwater
      vulnerability maps were generated for several pesticides. The eastern,
      agricultural part of the study area has relatively deep wells and fine soils.
      Shallow wells are present in the mountainous west; however, fewer pesticides are
      applied in that region. Consequently, much of the study area had a medium
      groundwater vulnerability rating, although there were pockets of high
      vulnerability, for example, in agricultural areas with shallow wells. The
      groundwater vulnerability maps are effective for identifying locations warranting
      more detailed groundwater pollution and vulnerability investigations.

PMID- 12605940
TI  - Volatile organic compounds concentrations in residential indoor and outdoor and
      its personal exposure in Korea.
AB  - To date, personal volatile organic compounds (VOCs) exposure and residential
      indoor and outdoor VOCs levels have not been characterized in Korea. In this
      study, residential indoor and outdoor VOCs concentrations were measured and
      compared simultaneously with the personal exposure for each of 30 participants in
      a medium city, Asan, and in a metropolitan city, Seoul. Factors that influence
      personal VOCs exposures were assessed in relation to house characteristics and
      time activity information. All VOC concentrations were measured using passive
      samplers during a 24-h period and analyzed using GC-MS. Ten target VOCs were
      benzene, trichloroethylene, toluene, o-xylene, p-xylene, ethylbenzene, MIBK, n
      octane, styrene, and 1,2-dichlorobenzene. Residential indoor and outdoor VOCs
      concentrations measured in Seoul were significantly higher than those in Asan.
      Indoor/outdoor (I/O) ratios for all target compounds ranged from 0.94 to 1.51 and
      I/O ratios of Asan were a little higher than those of Seoul. Results indicate
      that time activity information can be used to predict personal exposures,
      although such predictions will result in an over estimation compared to measured
      exposures. Factors which influence the indoor VOCs level and its personal
      exposure in relation to house characteristics included house age, indoor smoking,
      and house type.

PMID- 12605942
TI  - Simulation of pollution buffering capacity of wetlands fringing the Lake
      Victoria.
AB  - Lake Victoria has undergone substantial and most negative changes, especially
      over the last 30 years. One of the driving factors is nutrient enrichment from
      human activities in the catchment, which is causing eutrophication. This has been
      associated with, among others, the rapid proliferation of water hyacinth, alga
      blooms, and with general disruption of the lake ecosystem. Most of pollution to
      the lake flow via the natural wetlands. In order to understand how wetlands
      function within the Lake Victoria ecosystem a wetland model has been developed.
      The main objective of the model is to establish and simulate the buffering
      processes and capacity of individual wetlands (that is, their ability to absorb
      sediments, nutrients and pollutants) within the Lake Victoria basin. It was found
      that in both seasonal and permanent swamp there is a net export of organic matter
      produced in the wetlands. Most of the inorganic phosphorous were retained in the
      wetlands (60% to 90% removal) while there was a negative retention of nitrates
      probably due to the export of organic matter which associate very much with
      nitrates.

PMID- 12605943
TI  - Progress in renewable energy.
AB  - This paper provides an overview of some of the key technological and market
      developments for leading renewable energy technologies--wind, wave and tidal,
      photovoltaics (PV) and biomass energy. Market growth, innovation and policy are
      closely interrelated in the development of renewables and the key issues in each
      area are explored for each of the main types of renewable energy technology. This
      enables the prospects for future development and cost reduction to be considered
      in detail. Key issues for policy are outlined.

PMID- 12605944
TI  - Predictive accuracy of severity scoring system: a prospective cohort study using
      APACHE III in a Korean intensive care unit.
AB  - AIM: To evaluate the discrimination, calibration, and uniformity of fit by age
      group, operative status, and location before ICU admission of APACHE III in a
      single-center ICU population. DESIGN AND SETTING: Prospective data collection in
      a 25 bed mixed (surgical and medical) ICU of 850-bed teaching hospital in Pusan,
      South Korea. SUBJECTS AND METHODS: The worst values on APACHE III variables
      during 24h following ICU admission were collected from the patient's charts and
      clinical flow sheets of 284 consecutively admitted subjects. RESULTS: The
      mortality rate was 31.0%, and showed a strong positive correlation between APACHE
      III score (r=0.97, p<0.0001 for entire population, r=0.97, p<0.0001 for medical
      patients, r=0.91, p<0.0001 for surgical patients). Hospital mortality was
      significantly higher for medical patients than surgical patients (OR=7.23, 95%
      CI=3.76-13.88), and for patients located in the operating room than at ward
      before admitting ICU (OR=0.09, 95% CI=0.04-0.23). At the predicted risk of 0.5
      (66 of APACHE III score), sensitivity was 0.72, specificity 0.91, and correct
      classification rate 0.85. Area under the ROC curve was 0.905 (95% CI=0.867
      0.943). Correlation coefficient (r) between observed and expected mortality rate
      was 0.99. The value (chi-square) of Lemeshow-Hosmer (L-H) goodness-of-fit
      statistic was 6.54 (p=0.59). In patients stratified according to age groups,
      operative status, and location in the hospital before ICU admission,
      discrimination was generally good in all subgroups (area under the ROC curve
      >0.85), and the chi-squared of L-H goodness-of -fit statistic showed a good fit
      for all subgroup, especially for operative status. CONCLUSIONS: The predictive
      accuracy of the APACHE III scoring system showed better discrimination, as well
      as uniformity of fit. So, it was thought that could be utilized for the subject
      hospital.

PMID- 12605945
TI  - Incontinence impact, symptom distress and treatment-seeking behavior in women
      with involuntary urine loss in Southern Taiwan.
AB  - Urinary incontinence (UI) in women is common worldwide, but is studied more often
      in the West. This correlational study conducted in southern Taiwan employed two
      frequently used instruments, which were translated into Chinese. Incontinence
      impact, symptom distress, and treatment-seeking behavior were studied in 106
      women with UI of whom 76 (72%) had not received UI treatment. Incontinence impact
      (mean=49.75; range=30-120) was significantly correlated (r=0.76, p<0.01) with
      symptom distress (mean=18.38; range=2-68). Women with high incontinence impact
      and symptom distress were more likely to seek treatment than those with lower
      impact and symptom distress.

PMID- 12605946
TI  - An exploratory study of continence care services worldwide.
AB  - Urinary incontinence (UI) is a complex symptom of underlying disorders that
      affects over one and a half million Canadians. Although there is good evidence
      that incontinence can be treated effectively, the most efficient and cost
      effective method for delivery of treatment is uncertain. The purpose of this
      study was to explore and describe the continence services that exist
      internationally and in Canada in order to provide the background for a Canadian
      model of continence service. Data were collected by communication with
      international health care professionals with expertise in UI, and distribution of
      a questionnaire to international and Canadian continence care providers. Findings
      suggest that although physicians, nurses, and/or physiotherapists currently
      provide continence care, services are scattered and inconsistent and
      discrepancies exist in how they are funded. The major themes that emerged are the
      need for enhanced accessibility of continence care and the importance of
      multidisciplinary teamwork.

PMID- 12605947
TI  - Thai mothers and children and the home observation for measurement of the
      environment (home inventory): pilot study.
AB  - The HOME Inventory is a measure of home stimulation available to children. The
      purposes of the study were to: (a) examine the psychometric properties of a Thai
      translated HOME (Infant/Toddler), (b) compare Thai mean HOME scores with three
      groups (Hmong, Eskimo, HOME normative sample in the state of Washington) reported
      in the literature. A convenience sample from Mahasarakham public health centers
      in northeastern Thailand was assessed using 36 dyads of mothers and toddlers, 13
      35 months. The internal consistency was 0.81 for the total scale; F-tests of the
      HOME total scale and subscale means showed significant differences between Thai
      and three other groups. Scheffe tests which showed Thai means on three subscales
      (Maternal Involvement, Responsivity, Restriction) were not significantly
      different from the Washington sample, but were significantly lower on three
      subscales (Play, Organization, Stimulation). Further study is needed on the use
      of home assessment instruments by nurses and others working in multicultural
      settings.

PMID- 12605948
TI  - Envy in a nurse education community.
AB  - The definition of envy is based on views of anthropology, sociology, psychology
      and nursing science. According to these definitions, a nurse education community
      consists of shared values, customs and beliefs common in the nursing community.
      The purpose of this paper was to describe envy in the reciprocal relations
      between student nurses in a polytechnic of health and welfare in Finland. The
      sample consisted of 110 student nurses in one faculty of health and welfare in a
      Finnish polytechnic. They were selected from among the available (attending
      classes) students, who had been studying in the same group for 1-3 years in 1996.
      The response percentage was 85.5 (n=94). The data were processed by various
      statistical methods. The findings of envy in a nurse education community were
      defined through the student nurses' views of their sense of self, their relations
      with their fellow students, the objects of envy and also the influence of the
      lecturers. The ways of coping with envy were also identified. The most common
      object of envy was a fellow student who worked part-time while studying. Another
      object of envy consisted of fellow students successful in examinations and
      skills, such as listening, friendships and good ideas. The students coped with
      their envy by sharing their own success and by denying envy. These results
      highlight some essential points of envy in a nurse education community and
      underline the need for open discussion, as emotions and envy are important to
      understand as part of nurse education. If envy is not identified, it may cause
      learning problems and even problems in patient care.

PMID- 12605949
TI  - Agency-nursing work: perceptions and experiences of agency nurses.
AB  - This paper explores agency-nursing work from the perspective of agency nurses to
      gain in-depth understanding of their clinical practice, their relationships with
      the employing agency, hospitals and permanent nurses, and their professional
      status. For this study, individual interviews were conducted with ten agency
      nurses who were registered with one of three nursing agencies in Melbourne,
      Australia. Five major themes emerged from interview data: orientation, allocation
      of agency nurses, reasons for doing agency-nursing work, experiences with
      hospital staff, and professionalism. The findings reveal that the primary reason
      for nurses engaging in agency-nursing work is for the flexibility it offers.
      While agency nurses described a commitment to professionalism, the findings
      emphasise the need to establish effective communication networks between agency
      nurses, nursing agencies and hospital institutions. Such communication between
      stakeholders is important to facilitate discussion of issues such as appropriate
      notification of shift availability, appropriate assignment of work and
      recognition of the agency nurse as a valuable member of the health care team. In
      particular, the findings highlight the importance of comprehensive orientation
      and education for agency nurses to shift the focus of their daily work from task
      completion to more comprehensive patient care.

PMID- 12605950
TI  - Preparing patients for urological surgery.
AB  - There is consensus among health care professionals that patients need and use
      written and oral patient education to prepare for hospitalisation. The purpose of
      this study was to re-design information for patients preparing for transurethral
      surgery (TUR P-B) and describe the effect of this change. A quasi-experimental
      design was used to answer the research questions. The findings showed that
      patients did benefit in some areas. The patients found a correspondence between
      what they were told to expect and what actually happened in the hospital. Nurses
      need to evaluate written materials to see that they are current and reflect best
      practice.

PMID- 12605951
TI  - The assessment and management of pain among older people in care homes: current
      status and future directions.
AB  - Pain is highlighted as a significant, yet neglected problem among older people,
      particularly in long-term care settings. The effects of inadequate assessment and
      treatment of pain among older people may lead to multiple problems. Problems
      arise due to cognitive impairment of clients and inadequate assessment by
      healthcare professionals. Analgesics are under-used and there is a need for
      improved education of both healthcare professionals and older people regarding
      attitudes to pain and ageing. Research is needed into the prevalence of pain
      among older people in United Kingdom (UK) care homes, how best to further educate
      healthcare professionals regarding pain management and how to enable older people
      to be facilitative partners in this process.

PMID- 12605952
TI  - Communicating with culturally and linguistically diverse patients in an acute
      care setting: nurses' experiences.
AB  - Communication with culturally and linguistically diverse (CLD) patients has been
      shown to be difficult. This study describes nurses' experiences of communicating
      with CLD patients in an acute care setting. A purposive sample of registered
      nurses and certified midwives (n=23) were interviewed. Main findings were:
      interpreters, bilingual health workers and combinations of different strategies
      were used to communicate with CLD patients; some nurses showed empathy, respect
      and a willingness to make an effort in the communication process with others
      showing an ethnocentric orientation. Main recommendations were: prioritising
      access to appropriate linguistic services, providing nurses with support from
      health care workers, e.g., bilingual health care workers who are able to provide
      more in-depth information, increasing nurses' understanding of legal issues
      within patient encounters, supporting nurses to translate their awareness of
      cultural diversity into acceptance of, appreciation for and commitment to CLD
      patients and their families.

PMID- 12605954
TI  - Peer support within a health care context: a concept analysis.
AB  - Peer support, and the integration of peer relationships in the provision of
      health care, is a concept of substantial significance to health scientists and
      practitioners today, as the focus shifts from the treatment of disease to health
      promotion. If the nursing profession is to effectively incorporate peer
      relationships into support-enhancing interventions as a means to improve quality
      care and health outcomes, it is essential that this growing concept be clearly
      explicated. This paper explores the concept of peer support through the
      application of Walker and Avant's (Strategies for Theory Construction in Nursing,
      3rd Edition, Prentice-Hall, Toronto, 1995) concept analysis methodology. This
      analysis will provide the nursing profession with the conceptual basis to
      effectively develop, implement, evaluate, and compare peer support interventions
      while also serving as a guide for further conceptual and empirical research.

PMID- 12605953
TI  - Nurse-led inpatient care: opening the 'black box'.
AB  - With recent evaluations contradicting early reports of improved outcomes from
      nurse-led inpatient care, the 'black box' of nurse-led care must be opened in
      order to examine the model of treatment. We present findings on the processes of
      care in one nurse-led unit (NLU), compared with an acute ward. Patterns and
      quality of nursing care were quantified using bar-code technology to measure
      type, frequency and duration of nursing activities and Quality Patient Care Scale
      to measure the quality of care. NLU quality matched, but did not exceed, quality
      on the acute ward. Patterns of care differed between wards, but activities
      associated with therapeutic nursing were no more frequent on the NLU. These
      findings support the hypothesis that disappointing outcomes in recent evaluations
      may be linked to failure to implement a therapeutic model of nursing.

PMID- 12605956
TI  - The search for type 2 diabetes genes.
AB  - Type 2 diabetes (T2DM) is a serious disease with severe complications. Around one
      in 10 people alive today suffer from type 2 diabetes or are destined to develop
      it before they die. Inheritance plays an important role in the cause of type 2
      diabetes. A considerable amount of research is devoted to defining the genes
      involved in the aetiology of this widespread disease. This information is crucial
      if we are to improve our methods of preventing and treating diabetes. Over the
      last 25 years there have been considerable advances in our understanding of the
      genetics of diabetes. Important discoveries have been made in dissecting the
      genes involved in rare monogenic forms of type 2 diabetes which has become a
      paradigm for genetic studies of type 2 diabetes. This review focuses on the main
      approaches currently adopted and our current understanding of the genes involved
      in susceptibility to type 2 diabetes.

PMID- 12605957
TI  - Mammalian longevity under the protection of PARP-1's multi-facets.
AB  - Given the presence of continuous endogenous and exogenous sources of stress,
      mammalian species have evolved complex systems of protection, detoxification and
      repair, in order to maintain homeostasis during development and until
      reproductive maturity for the sake of the species. However, since no system is
      perfect, complete prevention of damage is unlikely to occur. Accumulation of
      macromolecular damage, including damage to DNA and genomic instability, is
      considered a driving force for the ageing process and age-related diseases. One
      of the immediate eukaryotic cellular responses to DNA breakage is the covalent
      post-translational modification of nuclear proteins with poly(ADP-ribose) from
      NAD+ as precursor, mostly catalysed by poly(ADP-ribose) polymerase-1 (PARP-1).
      Poly(ADP-ribosyl)ation is involved in DNA base-excision repair (BER), DNA-damage
      signalling and regulation of genomic stability. In recent years, many groups have
      become involved in PARP field, shedding light on new partners for PARP-1, new
      members of the PARP family and new physiological and pathophysiological
      properties for the founding member of the poly(ADP-ribose) polymerase super
      family. The present review focuses on PARP-1 and its role in the maintenance of
      genome stability and in mammalian longevity.

PMID- 12605959
TI  - Age-related changes in vascular adrenergic signaling: clinical and mechanistic
      implications.
AB  - A large and growing segment of the general population are age 65 or older, and
      this percentage will continue to rise. Primary care of this population has, and
      is becoming a priority for clinicians. Hypertension, orthostatic hypotension,
      arterial insufficiency, and atherosclerosis are common disorders in the elderly
      that lead to significant morbidity and mortality. One common factor to these
      conditions is an age-related decline in beta-adrenergic receptor (beta-AR)
      mediated function and subsequent cAMP generation. Presently, there is no single
      cellular factor that can explain this age-related decline, and thus the primary
      cause of this homeostatic imbalance is yet to be identified. However, the
      etiology is clearly associated with an age-related change in the ability of beta
      AR receptor to respond to agonist at the cellular level. This article will review
      what is presently understood regarding the molecular and biochemical basis of age
      impaired beta-AR receptor-mediated signaling. A fundamental understanding of why
      beta-AR-mediated vasorelaxation is impaired with age will provide new insights
      and innovative strategies for the management of the multiple clinical disorders
      that effect older people.

PMID- 12605958
TI  - Microvascular plasticity in aging.
AB  - Understanding the bases of aging-related cognitive decline remains a central
      challenge in neurobiology. Quantitative studies reveal little change in the
      number of neurons or synapses in most of the brain but their ongoing replacement
      is reduced, resulting in a significant loss of neuronal plasticity with
      senescence. Aging also may alter neuronal function and plasticity in ways that
      are not evident from anatomical studies of neurons and their connections. Since
      the nervous system is dependent upon a consistent blood supply, any aging-related
      changes in the microvasculature could affect neuronal function. Several studies
      suggest that, as the nervous system ages, there is a rarefaction of the
      microvasculature in some regions of the brain, as well as changes in the
      structure of the remaining vessels. These changes contribute to a decline in
      cerebral blood flow (CBF) that reduces metabolic support for neural signaling,
      particularly when levels of neuronal activity are high. In addition to direct
      effects on the microvasculature, aging reduces microvascular plasticity and the
      ability of the vessels to respond appropriately to changes in metabolic demand.
      This loss of microvascular plasticity has significance beyond metabolic support
      for neuronal signaling, since neurogenesis in the adult brain is regulated
      coordinately with capillary growth.

PMID- 12605960
TI  - Aging, lipid modifications and phospholipases--new concepts.

PMID- 12605961
TI  - Age-related trends in gene expression in the chemosensory-nasal mucosae of
      senescence-accelerated mice.
AB  - We have utilized high-density GeneChip oligonucleotide arrays to investigate the
      use of the senescence-accelerated mouse (SAM) as a biogerontological resource to
      identify patterns of gene expression in the chemosensory-nasal mucosa. Gene
      profiling in chronologically young and old mice of the senescence-resistant
      (SAMR) and senescence-prone (SAMP) strains revealed 133 known genes that were
      modulated by a three-fold or greater change either in one strain or the other or
      in both strains during aging. We also identified known genes in our study which
      based on their encoded proteins were identified as aging-related genes in the
      aging neocortex and cerebellum of mice as reported by Lee et al. (2000) [Nat.
      Genet. 25 (2000) 294]. Changes in gene profiles for chemosensory-related genes
      including olfactory and vomeronasal receptors, sensory transduction-associated
      proteins, and odor and pheromone transport molecules in the young SAMR and SAMP
      were compared with age-matched C57BL/6J mice. An analysis of known gene
      expression profiles suggests that changes in the expression of immune factor
      genes and genes associated with cell cycle progression and cell death were
      particularly prominent in the old SAM strains. A preliminary cellular validation
      study supported the dysregulation of cell cycle-related genes in the old SAM
      strains. The results of our initial study indicated that the use of the SAM
      models of aging could provide substantive information leading to a more
      fundamental understanding of the aging process in the chemosensory-nasal mucosa
      at the genomic, molecular, and cellular levels.

PMID- 12605962
TI  - Biochemical failure after definitive therapy of prostate cancer: defining the
      chicken switch.

PMID- 12605963
TI  - Radiographic pulmonary and pleural changes after carbon ion irradiation.
AB  - PURPOSE: For the treatment of Stage I non-small-cell lung cancers, a Phase I/II
      study of carbon ion irradiation was undertaken. In the present study, we focus on
      posttreatment radiographic lung damage: specifically, its timing, features, and
      relation to dose-volume factors. MATERIALS AND METHODS: Forty-three patients with
      44 Stage I non-small-cell lung cancers were treated with carbon ion irradiation
      ranging from 59.4 to 95.4 photon Gy equivalent dose (GyE) in 18 fractions over 6
      weeks, according to our dose escalation protocols. Primary lesions were
      irradiated by 2-4 portals. Follow-up evaluation with computed tomography (CT) was
      sequentially performed to assess changes in the lung. CT findings were classified
      into two categories: pulmonary reaction and pleural reaction. A dose-volume
      histogram for each patient was calculated, using a three-dimensional CT planning
      system. Statistical analysis was conducted using Spearman's rank test. RESULTS:
      The median appearance period of pulmonary reactions was 3 months after the start
      of carbon ion irradiation, whereas the maximum period was 6 months. The severity
      of pulmonary reactions statistically correlated with lung volumes irradiated no
      less than 20 GyE (vol. 20) and 40 GyE (vol. 40) (p = 0.017 and p = 0.0089).
      Geometrically unique findings in the irradiated fields were observed in 7
      patients (16%). The median appearance period of pleural reactions was 4 months
      after the start of carbon ion irradiation. The occurrence of pleural reactions
      significantly correlated with planning target volume (p = 0.000098), vol. 20 (p =
      0.00011), and vol. 40 (p = 0.00097). CONCLUSIONS: Lung damage after carbon ion
      irradiation was observed in the parenchyma and in the pleura. The severity of
      pulmonary reactions was correlated with dose-volume factors. These findings might
      provide useful information in the planning and management of carbon ion
      irradiation.

PMID- 12605964
TI  - Eye retention after proton beam radiotherapy for uveal melanoma.
AB  - PURPOSE: To analyze the long-term results of eye retention after conservative
      treatment of uveal melanoma with proton beam radiotherapy, and to analyze the
      causes leading to enucleation after this conservative treatment approach.
      MATERIALS AND METHODS: This was a prospective, noncomparative, interventional,
      consecutive case series. A total of 2645 patients (2648 eyes) with uveal melanoma
      were treated between 1984 and 1999 with proton beam radiotherapy. Data were
      analyzed as of February 2001. Patients' age ranged from 9 to 90 years, 1284 were
      men, and 1361 were women. Largest tumor diameter ranged from 4 to 27.5 mm, and
      tumor height from 0.9 to 15.6 mm. Median follow-up time was 44 months. RESULTS:
      The overall eye retention rate at 5, 10, and 15 years after treatment was 88.9%,
      86.2%, and 83.7%, respectively. In total, 218 eyes had to be enucleated.
      Enucleation was related to larger tumor size, mainly tumor height, proximity of
      posterior tumor margin to optic disc, male gender, high intraocular pressure, and
      large degree of retinal detachment at treatment time. After optimization of the
      treatment technique, the eye retention rate at 5 years was increased from 97.1%
      to 100% for small tumors, from 86.7% to 99.7% for medium, and from 71.1% to 89.5%
      for large tumors. CONCLUSIONS: The treatment technique as used today results in
      excellent eye retention rates, even in less favorable cases such as large tumors
      and tumors located close to the optic disc. The experience and a continuous
      quality control program allowed us to improve the 5-year eye retention rate for
      all tumor sizes. These findings demonstrate the positive impact of experience and
      quality control-based efforts for treatment technique optimization.

PMID- 12605965
TI  - Impact of a micromultileaf collimator on stereotactic radiotherapy of uveal
      melanoma.
AB  - PURPOSE: To evaluate the impact of a micro multileaf collimator (mMLC) on Linac
      based stereotactic radiotherapy (SRT) of uveal melanoma by comparing circular arc
      with static conformal, dynamic arc, and intensity-modulated SRT. MATERIALS AND
      METHODS: Forty uveal melanoma patients were selected from approximately 100
      patients treated with SRT since 1996. For each patient, four treatment plans
      (BrainSCAN XL, V5.0) were made: conventional arc, static conformal, dynamic arc
      plan, and intensity-modulated radiotherapy (IMRT). The goal of treatment planning
      was to fully encompass the planning target volume (PTV) by the 80% isodose while
      minimizing doses to the optic nerve and lens. The following parameters were
      evaluated: target conformity; target homogeneity; ratio of the target volume and
      50% isodose volume; normal tissue receiving doses >/=80%, >/=50%, and >/=20%;
      central nervous system volume irradiated to >/=20%; optical nerve volume
      irradiated >/=50%, D(max) of the lens; lens volume receiving >/=20%; and monitor
      units. RESULTS: PTVs ranged from 0.68 to 4.90 cm(3) (mean 1.97 +/- 0.97 cm(3)).
      The average reduction of the prescription isodose volume was 1-1.5 cm(3) for
      conformal (range 2.6-0.3 cm(3)), dynamic arc (range 2.5-0.3 cm(3)), and IMRT
      plans (range 3.9-0.1 cm(3)), compared with conventional arc therapy. Central
      nervous system volumes irradiated to doses >/=20% were smallest for conventional
      or dynamic arc treatments. Average target dose homogeneity values were 1.74 +/-
      0.50 for arc, 1.27 +/- 0.02 for static mMLC, 1.26 +/- 0.01 for dynamic arc, and
      1.15 +/- 0.03 for IMRT plans. IMRT helped to reduce doses to the lens but did not
      provide an advantage for optical nerve sparing. When applying IMRT, the monitor
      units increased by approximately one-third compared with static mMLC-based SRT.
      CONCLUSIONS: Conformal mMLC and dynamic arc SRT are the treatment options of
      choice for Linac-based SRT of uveal melanoma. They present dosimetric advantages,
      while being highly efficient in treatment planning and delivery.

PMID- 12605967
TI  - Long-term efficacy, curative potential, and prognostic factors of radiotherapy in
      primary cutaneous B-cell lymphoma.
AB  - PURPOSE: Primary cutaneous B-cell lymphomas (PCBCL) are rare and constitute
      approximately 5-10% of all cutaneous lymphomas. In the literature, conflicting
      data exist on the optimal treatment modality regarding the efficacy and the
      relapse rate after radiotherapy (RT) or polychemotherapy. To evaluate the
      efficacy of RT, patient data from two centers were analyzed and compared with
      recent reports in the literature. MATERIALS AND METHODS: Between April 1984 and
      June 2001, 35 patients with PCBCL, 17 men and 18 women ages 27-86 years, were
      treated with RT alone (29/35 patients) or postoperative RT (6/35 patients).
      According to the European Organization for Research and Treatment of Cancer
      classification for PCBCL, this study group included 21 patients (60%) with
      primary cutaneous follicle center-cell lymphoma, 7 (20%) with primary cutaneous
      immunocytoma, 4 (11%) with primary cutaneous large B-cell lymphoma (PCLBCL) of
      the leg, and 3 (9%) provisional types. RESULTS: A total of 34/35 patients
      achieved an initial complete response after RT. In one additional patient, RT was
      interrupted after 16 Gy because of fulminant pneumonia. A total of 11/35 (31%)
      patients developed cutaneous relapse after a median of 11 months. Three patients
      developed an in-field response and 8 patients an out-field relapse. After a
      median follow-up of 52 months, 27/35 patients are alive, whereas 8/35 patients
      died (three deaths resulting from PCBCL and five unrelated to PCBCL). The 5-year
      overall survival rate was 75% (95% CI: 55-95%). The 5-year relapse-free survival
      was 50% (95% CI: 32-68%). Univariate and multivariate analysis revealed
      disseminated primary lesions in at least two noncontiguous anatomic sites and the
      histologic subtype PCLBCL as unfavorable prognostic factors. CONCLUSIONS: RT of
      all visible skin lesions is an effective treatment for localized PCBCL. In
      patients with cutaneous relapses, RT is an effective treatment option as well.

PMID- 12605966
TI  - Outcome and prognostic factors in orbital lymphoma: a Rare Cancer Network study
      on 90 consecutive patients treated with radiotherapy.
AB  - PURPOSE: To assess the outcome and prognostic factors in patients with orbital
      lymphoma treated by radiotherapy (RT). METHODS AND MATERIALS: Between 1980 and
      1999, 90 consecutive patients with primary orbital lymphoma were treated in 13
      member institutions of the Rare Cancer Network. A full staging workup was
      completed in 56 patients. Seventy-eight patients had low-, 6 intermediate-, and 6
      high-grade lymphoma, and 75 had a single orbital localization. All patients
      underwent RT with a median dose of 34.2 Gy (range 4.0-50.4). Eleven patients
      received chemotherapy in addition to RT. RESULTS: After RT, local control was
      achieved in 97% of the patients. Local progression occurred in 2% and local
      relapse 1%. The rate of systemic relapse was 20%, and 9% of the patients
      developed metachronous contralateral eye involvement. The 5-year disease-free
      survival, overall survival, and cause-specific survival rate was 65%, 78%, and
      87%, respectively. In univariate analyses, the statistically significant
      favorable prognostic factors were younger age, low grade, normal erythrocyte
      sedimentation rate, absence of muscular infiltration, complete response to
      treatment, conjunctival localization, and normal lactate dehydrogenase value for
      overall survival, disease-free survival, and freedom from treatment failure. In
      multivariate analysis, the favorable factors were younger age and low grade for
      overall and disease-free survival; a favorable response, conjunctival
      localization, and complete staging were highly significant for disease-free
      survival and freedom from treatment failure. Neither the RT technique nor the
      total dose influenced the outcome. Cataract and xerophthalmia were the most
      prominent late toxicities. CONCLUSION: Moderate- to low-dose RT alone is able to
      control primary orbital lymphoma with low morbidity. A full staging workup is
      warranted in these patients. Prognostic factors were identified that could be
      useful in the overall management of this uncommon site of primary lymphoma.

PMID- 12605968
TI  - Posttherapy surveillance monitoring of cervical cancer by FDG-PET.
AB  - PURPOSE: To evaluate the effect of irradiation and chemotherapy for carcinoma of
      the uterine cervix on posttreatment tumor uptake of the glucose analog (18)F
      fluorodeoxyglucose (FDG) imaged by positron emission tomography (PET) and to
      assess the utility of FDG-PET for surveillance monitoring. MATERIALS AND METHODS:
      This was a retrospective review of 76 patients with a new diagnosis of carcinoma
      of the uterine cervix who underwent pre- and posttreatment whole-body FDG-PET.
      Posttreatment FDG-PET was performed 2.4-10.4 months (median 4.2) after
      irradiation completion. RESULTS: After treatment, persistent abnormal FDG uptake
      in the cervix was found in 18% (14 of 76), in the pelvic lymph nodes in 16% (9 of
      55), in the paraaortic lymph nodes in 45% (5 of 11), and in the supraclavicular
      lymph nodes in 75% (3 of 4). Eleven patients developed new sites of increased FDG
      uptake. In relation to the findings on posttreatment PET, the 2-year progression
      free survival rate was 86% for patients with no abnormal FDG uptake at any site
      and 40% for those with persistent abnormal uptake; there were no survivors at 2
      years among patients who developed new sites of abnormal FDG uptake (p <0.0001).
      A multivariate analysis of prognostic factors demonstrated that any posttreatment
      abnormal FDG uptake (persistent or new) was the most significant prognostic
      factor (p <0.0001) for death from cervical carcinoma. CONCLUSIONS: FDG-PET is a
      valuable tool to evaluate the response of primary cervical carcinoma and lymph
      node metastasis to treatment and for the surveillance of patients after initial
      therapy.

PMID- 12605969
TI  - Myocardial perfusion changes in patients irradiated for left-sided breast cancer
      and correlation with coronary artery distribution.
AB  - PURPOSE: To evaluate postradiation regional heart perfusion changes with single
      photon emission tomography (SPECT) myocardial perfusion imaging in 69 patients
      treated with tangential photon beams radiation therapy (RT) for left-sided breast
      cancer. To correlate SPECT changes with percent irradiated left ventricle (LV)
      volume and risk factors for coronary artery disease (CAD). METHODS AND MATERIALS:
      Rest SPECT of the LV was acquired pre-RT and at 6-month intervals post-RT. The
      extent of defects (%) with a severity > 1.5 standard deviations below the mean
      was quantitatively analyzed for the distributions of the left anterior descending
      (LAD) artery, left circumflex (LCX) artery, and right coronary artery (RCA) based
      on computer assisted polar map reconstruction (i.e., bull's-eye-view). Changes in
      perfusion were correlated with percent irradiated LV receiving > 25 Gy (range 0
      32%). Data on patient- and treatment-related factors were collected prospectively
      (e.g., cardiac premorbidity, risk factors for CAD, chemotherapy, and hormonal
      treatment). RESULTS: In the LAD distribution, there were increased perfusion
      defects at 6 months (median 11%; interquartile range 2-23) compared with baseline
      (median 5%; interquartile range 1-14) (p < 0.001). There were no increases in
      perfusion defects in the LCX or RCA distributions. In multivariate analysis, the
      SPECT perfusion changes in the LAD distribution at 6 months were independently
      associated with percent irradiated LV (p < 0.001), hormonal therapy (p = 0.005),
      and pre-RT hypercholesterolemia (p = 0.006). The SPECT defects in the LAD
      distribution at 12 and 18 months were not statistically different from those at 6
      months. The perfusion defects in the LAD distribution were limited essentially to
      the regions of irradiated myocardium. CONCLUSION: Tangential photon beam RT in
      patients with left-sided breast cancer was associated with short-term SPECT
      defects in the vascular distribution corresponding to the radiation portals.
      Factors related to the extent of perfusion defects included the percent
      irradiated LV, hormonal treatment, and pre-RT hypercholesterolemia.

PMID- 12605970
TI  - Do dose-volume metrics predict pulmonary function changes in lung irradiation?
AB  - PURPOSE: To examine the ability of standard dose-volume metrics to predict
      pulmonary function changes as measured by pulmonary function tests (PFTs) in a
      group of patients with non-small-cell lung cancer treated with nonconventional
      beam arrangements on a Phase I dose-escalation study. In addition, we wanted to
      examine the correlation between these metrics. MATERIALS AND METHODS: Forty-three
      patients received a median treatment dose of 76.9 Gy (range 63-102.9). Eight
      patients also received induction chemotherapy with cisplatin and vinorelbine.
      They all had pre- and posttreatment PFTs >/=3 months (median 6.2) after
      treatment. The volume of normal lung treated to >20 Gy, effective volume, and
      mean lung dose were calculated for both lungs for all patients. Linear regression
      analysis was performed to determine whether correlations existed between the
      metrics and changes in the PFTs. Additionally, the three metrics were compared
      with each other to assess the degree of intermetric correlation. RESULTS: No
      correlation was found between the volume of normal lung treated to >20 Gy,
      effective volume, and mean lung dose and changes in the PFTs. Subgroup analyses
      of patients without atelectasis before irradiation, Stage I and II disease, or
      treatment without induction chemotherapy were also performed. Again, no
      correlation was found between the dose-volume metrics and the PFT changes. The
      intermetric correlation was good among all three dose-volume metrics.
      CONCLUSIONS: In this relatively small series of patients, dose-volume metrics
      that correlate with the risk of pneumonitis did not provide a good model to
      predict early changes in pulmonary function as measured with PFTs.

PMID- 12605971
TI  - Combined modality radiotherapy and chemotherapy in nonsurgical management of
      localized carcinoma of the esophagus: a practice guideline.
AB  - PURPOSE: To make recommendations regarding combined radiotherapy (RT) and
      chemotherapy (RTCT), compared with RT alone, when a nonsurgical approach is used
      for patients with localized esophageal carcinoma. MATERIALS AND METHODS: The
      Medline, Cancerlit, Cochrane Library databases, and abstracts published in the
      American Society of Clinical Oncology and the American Society for Therapeutic
      Radiology and Oncology proceedings were searched for evidence. Evidence was
      evaluated by two members of the Gastrointestinal Cancer Disease Site Group and
      methodologists. RESULTS: Pooling seven randomized trials detected a statistically
      significant survival benefit at 1 year for concomitant RTCT compared with RT
      alone (1-year mortality odds ratio 0.61; 95% confidence interval 0.44-0.84; p
      <0.00001). Local control also significantly improved with concomitant RTCT
      compared with RT alone for the available data (odds ratio 0.52; 95% confidence
      interval 0.31-0.89; p = 0.004), but a significant increase in adverse effects,
      including life-threatening toxicities, was shown. CONCLUSIONS: Concomitant RT and
      cisplatin-based CT is recommended over RT alone. Patients should be aware of the
      increased acute toxicity associated with this approach, and this recommendation
      should only be made after consideration of the potential risks and benefits and
      the patient's general condition. Sequential RTCT is not recommended as standard
      practice.

PMID- 12605972
TI  - Evidence for efficacy without increased toxicity of hypofractionated radiotherapy
      for prostate carcinoma: early results of a Phase III randomized trial.
AB  - PURPOSE: We performed a randomized trial to compare the GI and urogenital
      toxicity of radiotherapy (RT) for localized (confined to the organ), early-stage
      (T1-T2N0M0, TNM classification) carcinoma of the prostate, using a conventional
      (64 Gy in 32 fractions within 6.5 weeks) vs. a hypofractionated (55 Gy in 20
      fractions within 4 weeks) schedule and to determine the efficacy of the
      respective treatment schedules. METHODS AND MATERIALS: This report is based on an
      interim analysis of the first 120 consecutive patients in this Phase III trial
      after a median follow-up of 43.5 months (range 23-62). RT planning was based on
      two-dimensional CT data, and the treatment was delivered using a three- or four
      field 6-23-MV photon technique. GI and urogenital toxicity (symptom
      questionnaires incorporating the subjective elements of the late effects of
      normal tissues-subjective, objective, management, analytic classification of late
      effects and the European Organization for Research and Treatment of Cancer sexual
      function questionnaire) were evaluated before RT and 1 month, 1 year, and 2 years
      after RT completion. The efficacy of RT was assessed clinically (digital rectal
      examination and radiologic imaging) and biochemically (prostate-specific antigen
      assay) at baseline, and every 3 months for 2 years after RT and every 6 months
      subsequently. RESULTS: RT, whether conventional or hypofractionated, resulted in
      an increase in all six symptom categories used to characterize GI toxicity and in
      four of five symptom categories used to document urinary morbidity 1 month after
      therapy completion. Sexual dysfunction (based on limited data), which existed in
      more than one-third of patients before RT, also increased to just more than one
      half of patients 1 month after RT. The increase in urinary toxicity after RT was
      not sustained (diurnal urinary frequency had decreased significantly at 2 years).
      In contrast, all six symptom categories of GI toxicity remained increased 1 year
      after RT. Four of the six GI symptom categories (rectal pain, mucous discharge,
      urgency of defecation, and rectal bleeding) were still increased at 2 years
      compared with baseline. Except for a slightly greater percentage of patients
      experiencing mild rectal bleeding at 2 years among those who received
      hypofractionated RT, no differences were noted in toxicity between the
      conventional and hypofractionated RT schedule. The mean prostate-specific antigen
      level was 14.0 +/- 1.0 ng/mL at baseline and declined to a nadir of 1.3 +/- 0.2
      ng/mL at a median of 16.8 months (range 0.8-28.3) after RT completion. However,
      it then rose in 17 patients (8 in the hypofractionated and 9 in the conventional
      treatment group). Only 8 of these 17 patients were found to have signs of
      clinical relapse (5 local, 1 regional lymph node, and 2 systemic [bony
      metastases]) after histopathologic and radiologic reassessment). The remaining 9
      patients had biochemical relapse only (defined as three consecutive rises in
      prostate-specific antigen after nadir). The 4-year biochemical relapse-free
      survival rate was 85.8% for all patients and did not differ significantly between
      the two radiation dose schedules (86.2% for the hypofractionated and 85.5% for
      the conventional fractionation group). CONCLUSION: RT for prostate carcinoma,
      using a three- or four-field 6-23-MV photon technique without posterior shielding
      of the lateral fields, is an underestimated cause of persistent GI morbidity. The
      incidence of clinically significant GI and urogenital toxicity after conventional
      and hypofractionated RT appears to be similar. Hypofractionated RT for carcinoma
      of the prostate seems just as effective as conventional RT after a median follow
      up approaching 4 years.

PMID- 12605973
TI  - Improved conformality and decreased toxicity with intraoperative computer
      optimized transperineal ultrasound-guided prostate brachytherapy.
AB  - PURPOSE: We have developed an intraoperative three-dimensional (3D) conformal
      treatment planning system for permanent prostate implantation in an effort to
      reduce toxicity further and improve the accuracy of this procedure. We report the
      preliminary outcome of patients with localized prostate cancer treated with this
      approach. METHODS AND MATERIALS: Two hundred forty-eight patients with clinically
      localized prostate cancer were treated with transperineal ultrasound-guided
      permanent prostate implantation using a real-time intraoperative 3D conformal
      technique (I-3D) between 1997 and 2001. A genetic algorithm optimization program
      intraoperatively evaluated the dose deposited throughout the entire 3D volume for
      multiple seed configurations to identify which seed-loading pattern adhered best
      to the predetermined target, urethral and rectal dose constraints. The median
      follow-up time in these patients was 27 months (range 12-51). The dosimetric
      outcome and acute toxicity profile of these 248 patients were compared with those
      of patients who were treated between 1988 and 1996 at our institution with a
      preplanned transperineal implantation technique (PP). RESULTS: Postimplantation
      dosimetric analysis of the I-3D group demonstrated that the median value of the
      percentage of the target volume treated to at least the prescription dose
      (V(100)) was 96%, and the target coverage with the prescription dose (PD) was
      </=90% in only 3% of these patients. In contrast, among patients treated with the
      PP method, the median V(100) was 88% and the target coverage with the PD was
      </=90% in 60% of these patients (p < 0.001). For the I-3D patients, the median
      and maximal dose to the urethra was 140% and 170% of the PD, respectively,
      compared with 263% and 532%, respectively, for patients treated with the PP
      technique. The percentage of urinary symptom resolution at 6, 12, 18, and 24
      months for the I-3D cohort was 39%, 72%, 90%, and 97%, respectively. In contrast,
      the percentage of symptom resolution at the same intervals for patients treated
      with the PP technique was 12%, 20%, 31%, and 42% (p < 0.001). Multivariate
      analysis demonstrated that the I-3D technique was an independent predictor of
      improved target coverage, reduced urethral dose, and more rapid resolution of
      urinary-related symptoms. The improved dosimetric conformity with the I-3D
      technique did not compromise the biochemical outcome, as the 4-year actuarial
      prostate-specific antigen relapse-free survival rate for this group was 97%.
      CONCLUSION: The integration of an intraoperative optimization program with 3D
      dose evaluation throughout the target volume for prostate brachytherapy has
      consistently achieved excellent target coverage with the PD, and the dose levels
      to normal tissues were effectively restricted to tolerance ranges. These changes
      have led to a more favorable acute toxicity profile for patients treated with
      this technique without compromising biochemical control.

PMID- 12605975
TI  - Role of IMRT in reducing penile doses in dose escalation for prostate cancer.
AB  - PURPOSE: In three-dimensional conformal radiotherapy (3D-CRT), penile tissues
      adjacent to the prostate are exposed to significant doses of radiation. This is
      likely to be a factor in development of posttreatment erectile dysfunction. In
      this study, we investigate whether intensity-modulated radiation therapy (IMRT)
      leads to lower radiation exposure to proximal penile tissues (PPT) when compared
      with 3D-CRT. MATERIALS AND METHODS: Ten randomly selected patients with
      clinically localized prostate cancer constituted the study group. Using identical
      structure sets, 3D-CRT and IMRT plans were designed for each patient. For IMRT,
      both tomographic (TOMO) and step-and-shoot (SS) techniques were used. Treatment
      plans were developed using 18 MV photons for 3D-CRT, 6 MV photons for TOMO, and 6
      MV and 18 MV photons for SS plans. The PPT up to the beginning of the penile
      shaft (usually measuring 2-3 cm) was outlined by a team composed of a board
      certified urologist and a radiation oncologist. The outlined PPT was subdivided
      into three segments (P1, P2, P3), and the radiation dose to each segment and to
      the entire structure was calculated. In addition, PPT was subdivided into
      corporal cavernosa (CC) and corpus spongiosum (bulb). The prostate dose was
      escalated from 73.8 Gy to 81 Gy to 90 Gy. Target D(95) (dose to 95% volume),
      critical structure D(5) (dose to 5% volume), and D(mean) (mean dose) were used in
      the comparison among treatment plans. Because 3D-CRT uses larger field margins
      than does IMRT, target and critical structure doses were recalculated in 3D-CRT
      plans employing field margins obtained from IMRT plans. Planning target volumes
      in original and modified 3D-CRT plans were the same. RESULTS: Compared with 3D
      CRT plans, the mean PPT doses were reduced by 40.2%, 43.6%, and 46.2%,
      respectively, at the three prescription dose levels in TOMO plans. The average
      D(mean) for CC was lower by 46.4%, 48.4%, and 51.4%, whereas the average bulb
      D(mean) was reduced by 44.2%, 44.9%, and 47.9%, respectively. There was also
      considerable sparing of P1, with a reduction in average D(mean) of 41.9%, 45.5%,
      and 48.5% compared with 3D-CRT. All differences between 3D-CRT and IMRT doses
      were statistically significant (p < 0.001). Similar improvements were noticed in
      maximum doses (D(5)) for penile structures. The percent dose reduction with IMRT
      plans improved as prostate dose was escalated. When compared with 3D-CRT plans
      with reduced fields, IMRT plans showed slightly smaller but still significant
      improvements in critical structure doses (p < 0.001). Compared with SS plans,
      TOMO plans produced improved sparing of dose to critical structures. CONCLUSIONS:
      IMRT allows for dose escalation in prostate cancer while keeping penile tissue
      doses significantly lower compared to conformal radiotherapy. This may result in
      improved potency rates over current results observed with 3D-CRT.

PMID- 12605974
TI  - Effect of age on biochemical disease-free outcome in patients with T1-T3 prostate
      cancer treated with definitive radiotherapy in an equal-access health care
      system: a radiation oncology report of the Department of Defense Center for
      Prostate Disease Research.
AB  - PURPOSE: It has traditionally been a common perception that young age is a
      negative prognostic factor in prostate cancer (CaP). Furthermore, many urologists
      believe that younger patients are better suited to surgery rather than
      radiotherapy (RT) because of this perception. However, the data on the effect of
      age on outcome in patients with CaP are unclear. The records of the Department of
      Defense Center for Prostate Disease Research were queried for the biochemical
      disease-free results of patients after definitive RT and analyzed by age.
      MATERIALS AND METHODS: The records of 1018 patients with T1-T3 CaP treated with
      definitive RT between 1988 and 2000 were reviewed. The records of patients
      receiving adjuvant hormonal therapy or adjuvant or salvage RT postoperatively
      were excluded. Biochemical failure was calculated by the American Society for
      Therapeutic Radiology and Oncology criteria. The median potential follow-up was
      85.3 months as of December 31, 2001. RESULTS: Age did not affect biochemical
      disease-free survival significantly when considered as <60 vs. >/=60 years (p =
      0.646), by decade (p = 0.329), or as a continuous variable (correlation
      coefficient r = 0.017, regression slope = 0.007, with p = 0.588 and R(2) <
      0.001). Using multiple regression analysis, age was still not significant (p =
      0.408). Other variables analyzed were pretreatment prostate-specific antigen
      level (p < 0.001), Gleason sum (p = 0.023), stage (p = 0.828), and RT dose (p =
      0.033). CONCLUSIONS: Age and biochemical disease-free survival after RT for CaP
      are not related. Age may not be a valid factor in choosing between primary
      treatment options for CaP.

PMID- 12605976
TI  - Dysuria after permanent prostate brachytherapy.
AB  - PURPOSE: Although numerous prostate cancer quality-of-life studies have been
      reported, a paucity of data exists regarding brachytherapy-related dysuria. In
      this study, we evaluated the incidence and temporal resolution of dysuria, along
      with the influence of multiple treatment, clinical, and dosimetric parameters.
      MATERIALS AND METHODS: Five hundred eighty-one consecutive patients without a
      preimplant history of transurethral resection of the prostate underwent
      brachytherapy between January 1998 and December 2001 for clinical T1c-T3a (1997
      AJCC) adenocarcinoma of the prostate gland. The evaluated population consisted of
      the 546 patients who had completed at least two postimplant dysuria evaluations.
      The median patient follow-up was 26.4 months. In all patients, alpha-blocker
      therapy was initiated before implantation and continued at least until the
      International Prostate Symptom Score (IPSS) returned to baseline. The frequency
      of dysuria was assessed on a 1-5 scale using the IPSS scoring criteria. The
      dysuria severity was scored on a 1-10 scale. The clinical parameters evaluated
      included age, T stage, preimplant IPSS, ultrasound volume, and elapsed time since
      implantation. The treatment parameters included the use of neoadjuvant hormonal
      manipulation, use of supplemental external beam radiotherapy, isotope, and total
      implanted seed strength. The dosimetric parameters included values of the minimal
      dose received by 90% of the prostate, the percentage of prostate volume receiving
      100%, 150%, and 200% of the prescribed minimal peripheral dose, and the median
      and maximal urethral doses. RESULTS: The incidence of dysuria peaked at 52% 1
      month after implantation. The median dysuria frequency score was 0 of 5 for all
      patients and 2 of 5 for those reporting dysuria. The median severity score was 0
      of 10 for the entire cohort and 3 of 10 for those reporting dysuria. For the
      entire group, both the frequency and the severity of dysuria steadily improved
      with time, with near complete resolution of dysuria at 45 months. For those
      patients reporting dysuria, neither the frequency nor the severity revealed any
      durable improvement for approximately 36 months. Patients with dysuria displayed
      higher postimplant IPSSs. Of the 7 IPSS questions, nocturia and incomplete
      voiding were the best surrogates for dysuria. The isotope, supplemental external
      beam radiotherapy, hormonal status, minimal dose received by 90% of the prostate,
      and urethral dose did not predict for dysuria. CONCLUSIONS: After permanent
      prostate brachytherapy, dysuria is a relatively common event, but only rarely
      severe in frequency or intensity. At approximately 45 months after brachytherapy,
      dysuria appears to resolve in almost all patients.

PMID- 12605977
TI  - What to do for prostate cancer patients with a rising PSA?--A survey of
      Australian practice.
AB  - PURPOSE: To document current Australian management of asymptomatic prostate
      cancer patients with prostate-specific antigen (PSA) relapse after radical
      treatment or considered unsuitable for radical treatment. MATERIALS AND METHODS:
      Four case scenarios-postprostatectomy PSA relapse, postradiotherapy (RT) with a
      slow or a rapidly rising PSA level, or no radical treatment-were presented.
      Management preferences, including (where relevant) RT, androgen ablation either
      immediate or delayed until a PSA rise or symptomatic progression, and other
      approaches, were identified. The preferred methods of androgen ablation were
      noted. RESULTS: One hundred eighteen informative replies out of 324 e-mailed
      surveys were received. For postprostatectomy PSA relapse, 59% of respondents
      favored salvage RT. For post-RT with a slow or a rapidly rising PSA level and
      treatment of nonradical patients, there was no clear consensus of opinion, with
      respondents divided among the different options. A diverse range of PSA levels
      was cited for delayed intervention, with values ranging from 0.8 to 100 ng/mL.
      PSA doubling time proved a more consistent criterion for determining
      intervention. Most respondents favored the use of a luteinizing hormone-releasing
      hormone agonist as first-line androgen ablation, although patient choice was
      recognized as important in all decision making. CONCLUSIONS: A lack of available
      evidence underlies the diversity of opinion regarding the management of
      asymptomatic prostate cancer patients with a rising PSA. The need for randomized
      controlled trials in this area is highlighted.

PMID- 12605978
TI  - Prospective study of neuropsychologic testing and quality-of-life assessment of
      adults with primary malignant brain tumors.
AB  - PURPOSE: To identify the characteristics of adult patients with newly diagnosed
      primary brain tumors associated with identifiable deficits in neuropsychologic
      function to target interventions to improve function and quality of life (QOL).
      MATERIALS AND METHODS: Adult patients with newly diagnosed primary brain tumors
      and their caregivers were enrolled and underwent a battery of standardized
      neuropsychologic tests, allowing for qualitative and quantitative assessment and
      sensitive to the effects of the brain tumor, QOL, or caregiver stress. RESULTS:
      We enrolled 68 patients with no prior radiotherapy. Patients with left hemisphere
      tumors reported significantly more memory problems and depressive symptoms. They
      also exhibited poorer attention and were more distractible, with poorer verbal
      fluency and poorer verbal learning. Patients with glioblastoma multiforme
      demonstrated poorer psychomotor speed and visual tracking than patients with non
      glioblastoma multiforme histologic features. Patients and caregivers perceived
      QOL in a similar fashion, with significant correlation between patient and
      caregiver on hope testing and general QOL on the Linear Analog Self-Assessment
      Scale. CONCLUSIONS: Patients with left hemisphere tumors and glioblastoma
      multiforme histologic features demonstrated testable differences in
      neuropsychologic function and QOL that may be amenable to improvement with
      medical therapy or tailored rehabilitation programs. Caregiver assessments can
      predict patient QOL, which may be useful in patients with declining status.

PMID- 12605979
TI  - Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1
      resection for patients with small- to medium-size meningiomas.
AB  - PURPOSE: To compare tumor control rates after surgical resection or stereotactic
      radiosurgery for patients with small- to medium-size intracranial meningiomas.
      MATERIALS AND METHODS: Between 1990 and 1997, 198 adult meningioma patients
      treated at our center underwent either surgical resection (n = 136) or
      radiosurgery (n = 62) as primary management for benign meningiomas <35 mm in
      average diameter. Tumor recurrence or progression rates were calculated by the
      Kaplan-Meier method according to an independent radiographic review. The mean
      follow-up was 64 months. RESULTS: The tumor resections were Simpson Grade 1 in 57
      (42%), Grade 2 in 57 (42%), and Grade 3-4 in 22 (16%). The mean margin and
      maximal radiation dose at radiosurgery was 17.7 Gy and 34.9 Gy, respectively.
      Tumor recurrence/progression was more frequent in the surgical resection group
      (12%) than in the radiosurgical group (2%; p = 0.04). No statistically
      significant difference was detected in the 3- and 7-year actuarial progression
      free survival (PFS) rate between patients with Simpson Grade 1 resections (100%
      and 96%, respectively) and patients who underwent radiosurgery (100% and 95%,
      respectively; p = 0.94). Radiosurgery provided a higher PFS rate compared with
      patients with Simpson Grade 2 (3- and 7-year PFS rate, 91% and 82%, respectively;
      p <0.05) and Grade 3-4 (3- and 7-year PFS rate, 68% and 34%, respectively; p
      <0.001) resections. Subsequent tumor treatments were more common after surgical
      resection (15% vs. 3%, p = 0.02). Complications occurred in 10% of patients after
      radiosurgery compared with 22% of patients after surgical resection (p = 0.06).
      CONCLUSIONS: The PFS rate after radiosurgery was equivalent to that after
      resection of a Simpson Grade 1 tumor and was superior to Grade 2 and 3-4
      resections in our study. If long-term follow-up confirms the high tumor control
      rate and low morbidity of radiosurgery, this technique will likely become the
      preferred treatment for most patients with small- to moderate-size meningiomas
      without symptomatic mass effect.

PMID- 12605980
TI  - Value of external irradiation for locally advanced papillary thyroid cancer.
AB  - PURPOSE: To look for the possible efficacy of external beam irradiation (EBRT)
      for locally advanced papillary thyroid cancers. MATERIALS AND METHODS: Between
      August 1981 and September 1997, 91 patients with locally advanced papillary
      thyroid cancers (pathologic Stage T4 or N1) were treated with surgical resection.
      After surgery, 23 patients received postoperative EBRT with or without ablative
      radioiodine therapy, and 68 patients were treated with ablative radioiodine
      therapy alone. The distribution of age, gender, and stage was comparable in both
      groups. RESULTS: The overall survival rates at 7 years were not significantly
      different statistically between the two groups at 98.1% for the no-EBRT group and
      90% for the EBRT group (p = 0.506). The locoregional control rates at 5 years
      were significantly different (EBRT 95.2% and no EBRT 67.5%; p = 0.0408). Analysis
      of the prognostic factors, age, gender, stage, and use of radioiodine ablative
      therapy, indicated these were not significant variables, except for EBRT.
      CONCLUSIONS: Adjuvant postoperative EBRT did not affect overall survival, but
      significantly improved locoregional control in patients with locally advanced
      papillary thyroid cancer (Stage pT4 or lymph node involvement).

PMID- 12605981
TI  - Increasing the rate of late toxicity by changing the score? A comparison of
      RTOG/EORTC and LENT/SOMA scores.
AB  - PURPOSE: The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal
      Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA)
      scores were compared in a group of breast cancer patients. The impact of the
      classification system on grading late effects was evaluated. MATERIALS AND
      METHODS: Telangiectasia, skin pigmentation, and fibrosis were scored according to
      both LENT/SOMA and RTOG criteria. The results were compared with respect to up-
      or downgrading and correlated (Spearman's rho). Other side effects were recorded
      using LENT/SOMA criteria. Interobserver variability was calculated with Cohen's
      kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent
      breast-conserving therapy between 1981 and 1995 were examined. The median dose of
      radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31
      patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG
      skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were
      used. Two doctors examined 45 patients jointly. RESULTS: Of all patients, 20% had
      telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77%
      retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were
      used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively,
      and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearman's
      rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy
      were observed in 226 patients using LENT/SOMA criteria. Interobserver variability
      was similar for both classification systems and ranged from Cohen's kappa 0.3
      (retraction) to 0.91 (telangiectasia). CONCLUSIONS: LENT/SOMA criteria seem to be
      the better tool in grading and recording late radiation toxicity compared with
      the RTOG scale. There was some upgrading with the RTOG score when skin toxicity
      is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of
      the LENT/SOMA scoring system should be considered to standardize reporting of
      late radiation morbidity.

PMID- 12605982
TI  - Reno, a European postmarket surveillance registry, confirms effectiveness of
      coronary brachytherapy in routine clinical practice.
AB  - PURPOSE: To assess, by a European registry trial, the clinical event rate in
      patients with discrete stenotic lesions of coronary arteries (de novo or
      restenotic) in single or multiple vessels (native or bypass grafts) treated with
      beta-radiation. MATERIALS AND METHODS: Between April 1999 and September 2000,
      1098 consecutive patients treated in 46 centers in Europe and the Middle East
      with the Novoste Beta-Cath System were included in Registry Novoste (RENO).
      RESULTS: Six-month follow-up data were obtained for 1085 patients. Of 1174 target
      lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7%
      were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic
      lesions. Intravascular brachytherapy was technically successful in 95.9% of
      lesions. Multisegmental irradiation, using a manual pullback stepping maneuver to
      treat longer lesions, was used in 16.3% of the procedures. The in-hospital rate
      of major adverse cardiac events was 1.8%. At 6 months, the rate was 18.7%.
      Angiographic follow-up was available for 70.4% of the patients. Nonocclusive
      restenosis was seen in 18.8% and total occlusion in 5.7% of patients. A combined
      end point for late (30-180 days) definitive or suspected target vessel closure
      was reached in 5.4%, but with only 2% of clinical events. Multivariate analysis
      was performed for major adverse cardiac events and late thrombosis. CONCLUSIONS:
      Data obtained from the multicenter RENO registry study, derived from a large
      cohort of unselected consecutive patients, suggest that the good results of
      recent randomized controlled clinical trials can be replicated in routine
      clinical practice.

PMID- 12605983
TI  - Inhibition of hypoxia inducible factor 1alpha causes oxygen-independent
      cytotoxicity and induces p53 independent apoptosis in glioblastoma cells.
AB  - PURPOSE: Hypoxia, which activates the hypoxia inducible factor-1 alpha (HIF
      1alpha) pathway, is a common feature in malignant gliomas and has been linked
      with tumor cell survival and therapy resistance. In this study, we examined the
      effect of antisense inhibition of HIF-1alpha on the survival, apoptosis and
      responses to chemotherapy in U-87 malignant glioma cells. MATERIALS AND METHODS:
      Hypoxia (1% oxygen) was achieved in a tri-gas incubator with intermittent N(2)
      gas flushing or in a gas tight-module sealed with 94% N(2), 1% O(2) and balance
      CO(2). HIF-1alpha inhibition was achieved with antisense phosphorothioate
      oligodeoxynucleotide (AS-HIF ODN), delivered using cytofectin GSV3815. HIF-1alpha
      expression level was monitored by a hypoxia-responsive luciferase reporter assay
      and verified by northern blot and immunoblot analyses. Cell viability was
      quantified by a colorimetric microtiter plate MTS [3-(4,5-dimethylthiazol-2-yl)-5
      (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay.
      Apoptotic cell death was detected with a colorimetric caspase-3 assay, as well as
      using terminal transferase-catalyzed in situ end labeling (TUNEL) staining.
      RESULTS: Antisense HIF-1alpha phosphorothioate oligodeoxynucleotide (AS-HIF ODN)
      treatment suppressed HIF-1alpha expression by up to 80% under both normoxic and
      hypoxic conditions as measured by a hypoxia-responsive reporter assay and
      confirmed by northern and western blot analyses. Antisense knockdown of HIF
      1alpha resulted in significant reduction in U-87 cells survival and an
      acceleration of apoptosis, which did not involve p53 transactivation.
      Pretreatment of cells with Z-Val-Ala-Asp (-OCH(3))-fluoromethylketone (Z-VAD), a
      broad-spectrum caspase inhibitor largely eliminated this effect of AS-HIF.
      Caspase-3 specific activity was markedly induced 3 days after AS-HIF treatment
      when increased cell death was also noted. Transient overexpression of HIF-1alpha
      in U-87 cells neutralized apoptosis-inducing effect of AS-HIF. AS-HIF treatment
      did not affect viability of primary astrocytes and was selectively more toxic to
      U-87 glioma cells than normal human fibroblasts. The HIF-1alpha antisense
      treatment exerted an oxygen-independent, and additive but not synergistic effect
      to the cytotoxicity of cisplatin, etoposide, and vincristine. CONCLUSIONS: These
      results together indicate that suppression of HIF-1alpha-expression may be a
      promising strategy that is selective for reducing the survival and facilitating
      chemotherapeutic efficacy of malignant glioma.

PMID- 12605984
TI  - An adenovirus encoding proapoptotic Bax synergistically radiosensitizes malignant
      glioma.
AB  - PURPOSE: We explore the utility of the adenovirus-mediated delivery of
      proapoptotic Bax for enhancing the cytotoxicity of radiotherapy (RT) in RT
      refractory glioma cells. MATERIALS AND METHODS: Cell lines D54 MG and U87 MG (p53
      wild-type), and U251 MG and U373 MG (p53 mutant), and patient-derived astrocytes
      were evaluated. Cells were irradiated and infected with an inducible adenovirus
      encoding Bax. Cell proliferation, colony formation assay, quantification of early
      apoptotic alteration in the plasma membrane by fluorescence-activated cell sorter
      using annexin V, and nuclear staining with H33258 were used to evaluate
      apoptosis. The capacity of the combined treatment to induce regression of
      subcutaneous D54 MG tumors was tested in nude mice. A dose of 5 Gy was
      administered every other day, four times, for a total dose of 20 Gy. One day
      after each irradiation, tumors were injected with 1 x 10(9) plaque-forming units
      (PFU). RESULTS: Apoptotic death was enhanced by the combination of Ad/Bax and RT.
      In D54 MG, levels of apoptosis after RT alone, Ad/Bax alone, or the combination
      were, respectively, 12.3%, 32.1%, and 78.5%. In contrast, treatment of astrocytes
      did not significantly induce apoptosis. A colony-formation assay showed a 2-log
      inhibition with respect to controls after combined treatment, irrespective of the
      endogenous levels of p53. The other apoptosis assays also showed the defining
      characteristics of apoptosis in the combination group. Remarkably, combined
      treatment induced regression of tumors in mice. CONCLUSIONS: Ad/Bax
      synergistically radiosensitizes glioma, with a seemingly favorable therapeutic
      index.

PMID- 12605985
TI  - Radiation therapy depletes extrachromosomally amplified drug resistance genes and
      oncogenes from tumor cells via micronuclear capture of episomes and double minute
      chromosomes.
AB  - PURPOSE: To determine if clinically relevant doses of ionizing radiation are
      capable of inducing extrachromosomal DNA loss in transformed human cell lines.
      MATERIALS AND METHODS: The multidrug-resistant (MDR) human epidermoid KB-C1 cell
      line and the human neuroendocrine colon carcinoma line COLO320, which contain
      extrachromosomally amplified MDR1 drug resistance genes and MYCC oncogenes, were
      irradiated with 2 Gy fractions up to a total dose of 28 Gy. To track the fate of
      extrachromosomally amplified genes, cells surviving radiation therapy and
      unirradiated control cells were analyzed by fluorescent in situ hybridization of
      chromosomes using MDR1 and MYCC-specific cosmid DNA probes. In addition, total
      DNA and protein isolated from irradiated and control cells was subjected to
      Southern and Western blotting procedures, respectively, to determine amplified
      gene copy number and protein expression levels. Dose-response assays to follow
      loss of function of the MDR1 gene from KB-C1 cells were also performed. RESULTS:
      A significant reduction in extrachromosomal DNA, amplified gene copy number, and
      expression was detected in surviving cells after relatively low doses of
      radiation. Entrapment of extrachromosomal DNA into micronuclei was a consistent
      feature of irradiated cells. CONCLUSIONS: Clinically relevant doses of radiation
      can deplete extrachromosomal DNA in viable human malignant cells and alter their
      phenotype. Depletion of extrachromosomally amplified genes from tumor cells
      occurs via entrapment in radiation-induced micronuclei.

PMID- 12605986
TI  - Nitric oxide-mediated increase in tumor blood flow and oxygenation of tumors
      implanted in muscles stimulated by electric pulses.
AB  - PURPOSE: Oxygen deficiency in tumors reduces the efficacy of nonsurgical
      treatment modalities. We tested the hypothesis that electrical stimulation of the
      sciatic nerve could modify the oxygenation status and the blood flow of tumors
      implanted in the thigh of mice. MATERIALS AND METHODS: The sciatic nerve was
      electrically stimulated at 5 Hz. Local transplantable liver tumor (TLT) and
      fibrosarcoma (FSaII) tumor oxygen pressure (pO(2)) and perfusion measurements
      were carried out using electron paramagnetic resonance (EPR) oximetry and the
      OxyLite/OxyFlo technique. The radiosensitizing effect of the protocol was
      assessed by irradiating FSaII tumors with X-rays. RESULTS: Tumor pO(2) increased
      from approximately 3 mm Hg to approximately 8 mm Hg, and relative tumor blood
      flow was increased by 241% and 162% for TLT and FSaII tumor models, respectively.
      The effect on the tumor oxygenation was inhibited by a nitric oxide synthase
      (NOS) inhibitor, and an increase in the tumor nitric oxide (NO) content was
      observed using EPR spin-trapping. The tumor oxygen consumption rate was decreased
      after the stimulation protocol. In addition, the electrical stimulation of the
      host tissue increased regrowth delays by a factor of 1.65. CONCLUSIONS: This
      increase in tumor oxygenation is due to the temporary increase in tumor blood
      flow, but particularly to a decrease in the tumor oxygen consumption rate
      (inhibition of respiration) that is mediated by a local production of NO during
      the protocol. Those tumor hemodynamic changes resulted in a radiosensitizing
      effect.

PMID- 12605987
TI  - Tumor cell repopulation during conventional and accelerated radiotherapy in the
      in vitro megacolony culture.
AB  - PURPOSE: To analyze the repopulation rate of cancer cells in vitro during
      conventional and accelerated irradiation, using the megacolony culture. MATERIALS
      AND METHODS: Two cell lines-murine squamous cell carcinoma AT478 and human
      adenocarcinoma A549-were grown as epithelial megacolonies in vitro, and they were
      irradiated using Co-60 gamma source at the dose rate of 0.82 Gy/min. Single-dose
      irradiation, conventional fractionation, and continuous accelerated irradiation
      (CAIR) were applied to determine the dose-response relationship and to calculate
      the repopulation balancing dose. Radiosensitivity parameters and the rate of
      repopulation were calculated from the colony cure rates using direct maximum
      likelihood regression and a linear-quadratic model. Cytogenetic radiation damage
      was measured as frequency of necrotic, apoptototic cells and cells with
      micronuclei. Mitotic index was used as a simple measure of cell proliferation
      kinetics. RESULTS: When treatment time was increased, a significant drop in tumor
      control probability was detected. The loss of radiation dose calculated from LQ
      model parameters was equal to 0.8 Gy/day for both human and mouse cell lines.
      There was no evidence of a lag period for accelerated proliferation or altered
      proliferation during weekends. There were no significant differences in
      morphologic presentation of cellular radiation damage. CONCLUSIONS: In present in
      vitro experiments, we did not find any significant differences in repopulation or
      radiosensitivity between accelerated CAIR and conventional fractionation.
      Different mechanisms may be important for tumor cells repopulation in vitro and
      in vivo.

PMID- 12605988
TI  - Clinical significance of atomic inner shell ionization (ISI) and Auger cascade
      for radiosensitization using IUdR, BUdR, platinum salts, or gadolinium porphyrin
      compounds.
AB  - PURPOSE: Halogenated pyrimidines (iododeoxyuridine [IUdR] and bromodeoxyuridine
      [BUdR]), platinum salts, and gadolinium porphyrins are heavy atom compounds used
      as radiosensitizers. For IUdR, it has been hypothesized that iodine inner shell
      ionizations (ISI) and Auger cascades could be one of the primary
      radiosensitization mechanisms. The purpose of this paper is to estimate the
      number of ISI produced per tumor cell and per 2 Gy irradiation in clinically
      relevant modelings. MATERIALS AND METHODS: ISI were evaluated using a two-step
      method. Photon-induced ISI were calculated using the MCNP-4C Monte Carlo code,
      heavy atom concentrations from clinical data published in the literature, and at
      various depths in a water phantom irradiated with 6-MV, (60)Co, (137)Cs, or
      (192)Ir sources. Electron knock-on induced ISI on K, L, and M atomic shells were
      evaluated with an hybrid method, using simulated electron spectra and cross
      sections derived from the Moller formalism. Using a biological dose equivalence
      of 0.05 Gy per cell ISI, relative biological effectiveness (RBE) values were
      calculated for each situation. RESULTS: For platinum and gadolinium, ISI occurs
      in far less than 0.1% of the cell, whichever is the configuration. For IUdR and
      BUdR, ISI occurs in between 45% to 483% of the cell. Due to spectrum degradation,
      about 3 times more photoelectric ISI are generated at greater than shallower
      depths, and 10 times more for (192)Ir compared with (60)Co or 6-MV X-rays.
      Photoelectric ISI are about 3 times more frequent for iodine than bromine, but
      electron knock-on ISI are more frequent on bromine, and at the end about the same
      number of ISI are generated for both elements. RBEs were found to be between 1.01
      and 1.12 for clinically relevant irradiation settings. CONCLUSIONS: The
      mechanisms of radiosensitization for platinum and gadolinium are clearly not
      related to an Auger cascade. For halogenated pyrimidines, however, clinically
      relevant numbers of ISI are generated within each cell. For IUdR, ISI appears to
      be strongly tied to the photon spectra. Halogenated pyrimidines should be
      evaluated again clinically, but using lower energy photons like a (192)Ir
      implant.

PMID- 12605989
TI  - Ultrasound-guided extracranial radiosurgery: technique and application.
AB  - PURPOSE: Stereotactic radiosurgery is an effective treatment modality for many
      intracranial lesions, but target mobility limits its utility for extracranial
      applications. We have developed a new technique for extracranial radiosurgery
      based on optically guided three-dimensional ultrasound (3DUS). The 3DUS system
      provides the ability to image the target volume and critical structures in real
      time and determine any misregistration of the target volume with the linear
      accelerator. In this paper, we describe the system and its initial clinical
      application in the treatment of localized metastatic disease. METHODS AND
      MATERIALS: The extracranial stereotactic system consists of an ultrasound unit
      that is optically tracked and registered with the linear accelerator coordinate
      system. After an initial patient positioning based on computed tomographic (CT)
      simulation, stereotactic ultrasound images are acquired and correlated with the
      CT-based treatment plan to determine any soft-tissue shifts between the time of
      the planning CT and the actual treatment. Optical tracking is used to correct any
      patient offsets that are revealed by the real-time imaging. RESULTS: Preclinical
      testing revealed that the ultrasound-based stereotactic navigation system is
      accurate to within 1.5 mm in comparison with an absolute coordinate phantom.
      Between March 2001 and March 2002, the system was used to deliver extracranial
      radiosurgery to 17 metastatic lesions in 16 patients. Treatments were delivered
      in 1 or 2 fractions, with an average fractional dose of 16 Gy (range 12.5-24 Gy)
      delivered to the 80% isodose surface. Before each fraction, the target
      misalignment from isocenter was determined using the 3DUS system and the
      misalignments averaged over all patients were anteroposterior = 4.8 mm, lateral =
      3.6 mm, axial = 2.1 mm, and average total 3D displacement = 7.4 mm (range = 0
      21.0 mm). After correcting patient misalignment, each plan was delivered as
      planned using 6-11 noncoplanar fields. No acute complications were reported.
      CONCLUSIONS: A system for high-precision radiosurgical treatment of metastatic
      tumors has been developed, tested, and applied clinically. Optical tracking of
      the ultrasound probe provides real-time tracking of the patient anatomy and
      allows computation of the target displacement before treatment delivery. The
      patient treatments reported here suggest the feasibility and safety of the
      technique.

PMID- 12605990
TI  - A novel support system for patient immobilization and transportation for daily
      computed tomographic localization of target prior to radiation therapy.
AB  - PURPOSE: To develop a method for quick and smooth transportation of patients from
      a computed tomography (CT) table to a linear accelerator (linac) table for
      confirming tumor center before radiation therapy. MATERIALS AND METHODS: We
      developed a system using a subtable for patient immobilization that is
      transported via a customized stretcher. The patient lies on the subtable and is
      immobilized by a vacuum cushion and thermoplastic body cast. The subtable
      stretcher is used to carry the subtable from the CT table to the linac table.
      During transportation, the subtable is kept flat and shock to the subtable is
      carefully avoided. Between August 2001 and September 2002, a total of 9 patients
      with solitary upper lung tumors (superior to carina) were treated using this
      system. RESULTS: Intrafractional tumor motion along the x (left-right), y
      (anterior-posterior), and z axis (superior-inferior) ranged from -2 mm to 2 mm, 
      2 mm to 2 mm, and -5 mm to 3 mm, respectively. The standard deviation of
      intrafractional tumor motion along the x, y, and z axis ranged from 0.5 mm to 1.5
      mm, 0 mm to 1.7 mm, and 0.6 mm to 3.5 mm, respectively. Interfractional setup
      errors along the x, y, and z axis ranged from -5 mm to 4 mm, -6 mm to 8 mm, and 
      6 mm to 6 mm, respectively, and we could reduce interfractional setup errors in
      the majority of treatment sessions. CONCLUSIONS: We developed a system that
      allows patients to be immobilized and transported to verify tumor location on a
      daily basis. This system is highly useful for reducing setup errors.

PMID- 12605992
TI  - Incorporating leaf transmission and head scatter corrections into step-and-shoot
      leaf sequences for IMRT.
AB  - PURPOSE: Leaf transmission and head scatter are two important factors that
      influence intensity-modulated radiation therapy (IMRT) delivery and should be
      correctly taken into account when generating multileaf collimator (MLC)
      sequences. Significant discrepancies between the desired and delivered intensity
      profiles could otherwise result. The purpose of this article is to propose a
      reliable algorithm to minimize the dosimetric effects caused by the two factors
      in step-and-shoot mode. MATERIALS AND METHODS: The goal of the algorithm is to
      minimize the difference between the desired fluence map and the fluence map
      actually delivered. For this purpose, an error function, defined as the least
      square difference between the desired and the delivered fluence maps, is
      introduced. The effects of transmission and head scatter are minimized by
      adjusting the fractional monitor units (MUs) in the initial MLC sequences,
      created by using the desired fluence map without inclusion of the contributions
      from the two factors. Computationally, a downhill simplex optimization method is
      used to minimize the error function with respect to the fractional MUs. A three
      source model is used to evaluate the relative head scatter distribution for each
      segment at the beginning of the calculation. The algorithm has been assessed by
      comparing the dose distributions delivered by the corrected leaf sequence files
      and the theoretic predication, calculated by Monte Carlo simulation using the
      desired fluence maps, for an intuitive test field and several clinical IMRT
      cases. RESULTS: The deviations between the desired fluence maps and those
      calculated using the corrected leaf sequence files are <0.3% of the maximum MU
      for the test field and <1.0% for the clinical IMRT cases. The experimental data
      show that both absolute and relative dose distributions delivered by the
      corrected leaf sequences agree with the desired ones within 2.5% of the maximum
      dose or 2 mm in high-dose gradient regions. Compared with the results obtained by
      using the leaf sequences in which only the transmission or none of the two
      effects is corrected, significant improvements in the fluence and dose
      distributions have been observed. CONCLUSIONS: Transmission and head scatter play
      important roles in the dosimetric behavior of IMRT delivery. A larger error may
      result if only one factor is considered because of the opposite effects of the
      two factors. We noted that the influence of the two effects is more pronounced in
      absolute dose than in the relative dose. The algorithm proposed in this work
      accurately corrects for these two effects in step-and-shoot delivery and provides
      a reliable tool for clinical IMRT application.

PMID- 12605991
TI  - Class solutions for conformal external beam prostate radiotherapy.
AB  - PURPOSE: To determine a class solution coplanar plan from comparisons of three
      field (3F), four-field (4F), and six-field (6F) plans in conformal non-intensity
      modulated prostate radiotherapy. METHODS AND MATERIALS: Doses to two clinical
      target volumes, prostate only (PO) and prostate plus seminal vesicles (PSV) were
      evaluated in each of 10 patients using a variety of 3F, 4F, and 6F plans with a
      planning target volume margin of 10 mm. All plans were prescribed to 64 and 74
      Gy. The class solution plan for each of 3F, 4F, and 6F was chosen from a variety
      of symmetrical and asymmetrical field arrangements that had been previously
      assessed. The class solution plans, 3F (0, 90, 270 degrees ), 4F (35, 90, 270,
      325 degrees ), and 6F (50/lat/25) were compared with reference plans: 3F (0, 120,
      240 degrees ), 4F (0, 90, 180, 270 degrees ), and 6F (55, 90, 125, 235, 270, 305
      degrees ). Rectal volumes irradiated to greater than 50% (V(50)), 80% (V(80)),
      and 90% (V(90)) of the prescribed dose, normal tissue complication probabilities
      (NTCP) for rectum, bladder, and femoral heads (FH), and tumor control
      probabilities (TCP) were assessed. FH tolerance was set at 52 Gy to 10% volume.
      RESULTS: The field arrangement that gave the lowest irradiated rectal volume with
      acceptable bladder and FH doses was a 3F (0, 90, 270 degrees ) class solution
      plan. This plan gave a reduction in rectal V(80) of 1.2-12.4% for the PO group
      and 2.3-23.8% for the PSV group compared with the other plans. The reduction in
      rectal V(90) was 0.2-11.9% for the PO group and 1.5-23.3% for the PSV group using
      the 3F (0, 90, 270 degrees ) plan. This plan provided one of the lowest rectal
      NTCPs, but the difference was not significant when compared with the 4F class
      solution plan. When target volumes with 10-mm margins remain unchanged to 74 Gy,
      the irradiated rectal volumes for all plans were higher and rectal NTCPs can be
      trebled. CONCLUSION: The use of appropriate beam arrangements can provide a class
      solution plan using only 3 fields compared with 4 or 6 fields for the parameters
      considered. Both 3F (0, 90, 270 degrees ) and 4F (35, 90, 270, 325 degrees )
      plans can be used as a class solution plan. Other practical issues that may
      influence the choice of class solution include delivery time with smaller number
      of fields, ease of verification, the use of 10-mm multileaf collimation vs.
      conformal blocks, and field shape fitting limitations when using dynamic wedges.

PMID- 12605993
TI  - Clinical implications of incorporating heterogeneity corrections in mantle field
      irradiation.
AB  - PURPOSE: Patient dose calculations for mantle-field irradiation have
      traditionally been performed using homogeneous, water phantom data. The advent of
      computed tomography (CT)-based treatment planning now permits dose calculations
      to be corrected for actual patient density. Incorporation of full heterogeneity
      corrections is desirable, because calculations performed in this fashion more
      closely represent the actual dose delivered to the patient. In preparation for
      full clinical implementation of heterogeneity corrections in mantle irradiation,
      an evaluation of possible changes in dosimetry when transitioning from treatment
      plans generated without heterogeneity corrections to treatment plans that
      incorporated full heterogeneity corrections is presented. MATERIALS AND METHODS:
      A retrospective analysis was performed of treatment plans with and without
      heterogeneity corrections for 15 consecutive patients who had undergone full
      mantle-field irradiation. Comparisons were made of the absolute delivered doses
      (in cGy per monitor unit) and the absolute volume (in cubic centimeters) enclosed
      by the isodose surface of the 30.6 Gy prescription line and the surface
      representing 90% of the prescribed dose. Dose-volume histograms (DVHs) were
      generated and studied to evaluate differences in the doses received by the lungs,
      heart, and spinal cord between corrected and uncorrected plans. Comparisons were
      made of the volumes of lung receiving at least 20 Gy, the volumes of heart
      receiving at least 25.2 Gy, and the maximum cord dose. RESULTS: Dosimetric
      differences between heterogeneity-corrected and heterogeneity-uncorrected
      calculations were small. The mean total ratio of corrected-to-uncorrected dose
      per monitor unit was 1.01, with a standard deviation (SD) of 0.02. The mean
      corrected-to-uncorrected treated volume ratio (30.6 Gy) was 0.97, SD 0.14, and
      the mean corrected-to-uncorrected volume ratio of the 90% isodose surface was
      0.99, SD 0.02. The ratio of the volume of lung receiving at least 20 Gy was 1.03,
      SD 0.02; the ratio of the volume of heart receiving at least 25.2 Gy was 1.01, SD
      0.03; and the maximum spinal cord dose ratio was 1.02, SD 0.02. CONCLUSIONS: In
      all patient treatment plans evaluated, no significant dosimetric differences were
      observed between heterogeneity-corrected and heterogeneity-uncorrected treatment
      plans. However, unpredictable differences in the prescription isodose (30.6 Gy)
      were observed. The differences in coverage at the 90% isodose volume were
      negligible. The dose administered to lung in heterogeneity-corrected plans
      demonstrates a higher dose overall, with the greatest increase occurring at
      volumes receiving at least 20 Gy. In light of these small dosimetric differences,
      we believe that heterogeneity corrections can be incorporated into full mantle
      field treatment planning.

PMID- 12605994
TI  - Performance of different radiotherapy workload models.
AB  - PURPOSE: The purpose of this study was to evaluate the performance of different
      radiotherapy workload models using a prospectively collected dataset of patient
      and treatment information from a single center. METHODS AND MATERIALS:
      Information about all individual radiotherapy treatments was collected for 2
      weeks from the three linear accelerators (linacs) in our department. This
      information included diagnosis code, treatment site, treatment unit, treatment
      time, fields per fraction, technique, beam type, blocks, wedges, junctions, port
      films, and Eastern Cooperative Oncology Group (ECOG) performance status. We
      evaluated the accuracy and precision of the original and revised basic treatment
      equivalent (BTE) model, the simple and complex Addenbrooke models, the equivalent
      simple treatment visit (ESTV) model, fields per hour, and two local standards of
      workload measurement. RESULTS: Data were collected for 2 weeks in June 2001.
      During this time, 151 patients were treated with 857 fractions. The revised BTE
      model performed better than the other models with a mean [observed -predicted] of
      2.62 (2.44-2.80). It estimated 88.0% of treatment times within 5 min, which is
      similar to the previously reported accuracy of the model. CONCLUSION: The revised
      BTE model had similar accuracy and precision for data collected in our center as
      it did for the original dataset and performed the best of the models assessed.
      This model would have uses for patient scheduling, and describing workloads and
      case complexity.

PMID- 12605995
TI  - In regard to Lee et al., IJROBP 2002;53:630-637.

PMID- 12605997
TI  - A commentary on dose escalation and bNED in prostate cancer.

PMID- 12605999
TI  - Radiation oncology health care professional shortages.

PMID- 12606000
TI  - Two more contributions of Dorothy Reed: in regard to Zwitter et al, IJROBP
      2002;53:366-375.

PMID- 12606001
TI  - Synthesis and conformation of four 16,17-diols in the 3-methoxy-13alpha-estra
      1,3,5(10)-triene series.
AB  - All four diasteromeric 16,17-diols in the 3-methoxy-13alpha-estra-1,3,5(10)
      triene series have been synthesized. The trans-diols 1 and 2 can be obtained by
      hydroborating the 17-enol acetate 6 (61%, ratio 27:73, preferred alpha attack).
      OsO(4) dihydroxylation of the olefin 7 yielded the cis-diols 3 and 4 (ratio
      13:87). The dihydroxylation proceeds with preference for beta attack caused by a
      C-ring twist-boat form of 7. The conformations of the diols 2 and 4, the 17
      benzyl-17-hydroxy compounds 9 and 10 (obtained by Grignard reaction), and the
      16alpha-bromo-17beta-hydroxy compound 8 were determined by X-ray analysis and by
      1H NMR spectroscopy in solution. Some compounds, in spite of a 17beta-hydroxy
      group, had a conformation with a ring C chair form (4, 8, 9) caused by
      intermolecular interaction in the solid state. The rest of the compounds studied
      here (2, 10) possessed a conformation with a ring C twist-boat form, which has
      been also found for all 17beta-substituted compounds in solution. The preferred
      conformation of the D-ring with 17beta-substituents seems to be the 16beta
      envelope form or near this form, but the existence of the 16alpha-envelope form
      (inversion of the ring D) for some compounds showed great variance in the
      conformation of ring D, which is substituent dependent.

PMID- 12606002
TI  - Synthesis and antiviral activity of sulfated and acetylated derivatives of
      2beta,3alpha-dihydroxy-5alpha-cholestane.
AB  - Five new steroid sulfates, sodium 2beta,3alpha-dihydroxy-5alpha-cholestane 3
      sulfate (6), sodium 2beta,3alpha-dihydroxy-5alpha-cholestane 2-sulfate (7),
      disodium 2beta,3alpha-dihydroxy-5alpha-cholestane disulfate (8), sodium 3alpha
      acetoxy-2beta-hydroxy-5alpha-cholestane 2-sulfate (12), and sodium 2beta-acetoxy
      3alpha-hydroxy-5alpha-cholestane 3-sulfate (13), have been synthesized starting
      from 3beta-hydroxy-5alpha-cholestane (1). The synthetic steroids were completely
      characterized by one-dimensional and two-dimensional NMR and FABMS spectra.
      Sulfation was performed using triethylamine-sulfur trioxide complex in
      dimethylformamide as the sulfating agent. The sulfated steroids were
      comparatively evaluated for their inhibitory effect on the replication of herpes
      simplex virus type 2 (HSV-2). Compounds 7 and 8 were the most effective in their
      inhibitory action against HSV-2. The disulfated steroid 8 also proved to be
      active against DEN-2 and JV.

PMID- 12606003
TI  - Circadian rhythm characteristics of serum cortisol and dehydroepiandrosterone
      sulfate in healthy Chinese men aged 30 to 60 years. A cross-sectional study.
AB  - The relation of adrenal function and aging has been the subject of intense
      interest in recent years. The circadian variations of plasma cortisol have been
      described in Caucasians, but little information is available on such hormone
      variations among the Chinese population, especially its changes with age. This
      study was, therefore, designed to examine the effects of age on the circadian
      variations of serum cortisol, dehydroepiandrosterone sulfate (DHEAS) and the
      molar ratio of cortisol/DHEAS in Chinese men, stratified by 10-year age-groups
      (i.e. men in their 30-60s, aged from 31 to 63 years old). Circadian variations of
      serum cortisol and DHEAS were documented at 2-h intervals from 8:00 to 22:00 and
      hourly from 22:00 to 8:00 in 26 healthy Chinese men. We found that the serum
      levels of both hormones showed a statistically significant circadian rhythmicity
      in all age-groups. The circadian pattern of serum cortisol was characterized by
      peaks (04:00-06:00) and troughs (18:00-24:00) occurring approximately 2h earlier
      than those usually reported in Caucasians. Aging did not significantly influence
      serum cortisol concentrations, but serum DHEAS levels declined significantly with
      age: subjects in their 60s had significantly lower levels, and their
      cortisol/DHEAS molar ratios were significantly higher than those in the younger
      age-groups.

PMID- 12606004
TI  - A straightforward chemical synthesis of 17-ketosteroids by cleavage of the C-17
      dihydroxy acetone side chain in corticosteroids.
AB  - A facile and convenient approach to 17-ketosteroids is described. Treatment of
      steroids containing the C-17-dihydroxy acetone side chain with an excess of
      sodium methoxide in dry 1,4-dioxane under reflux, affords high yields of the
      corresponding 17-ketosteroids that are recovered as pure products, without the
      need of further purification.

PMID- 12606005
TI  - Evaluation of 17alpha-E-(trifluoromethylphenyl)vinyl estradiols as novel estrogen
      receptor ligands.
AB  - As part of our program to develop novel ligands for the estrogen receptor, we
      synthesized the series of isomeric 17alpha-(trifluoromethyl)phenylvinyl
      estradiols using our solid-phase organic synthesis methodology. The compounds
      were evaluated for their relative binding affinity (RBA) using the ERalpha-LBD
      and in vivo potency using the immature rat uterotrophic growth assay. The ortho
      isomer had the highest RBA values, 48-223, and the highest estrogenicity in vivo.
      The other isomers had significantly lower affinities and were weaker agonists in
      the uterotrophic assay. The results suggest that introduction of substituents at
      the 17alpha-position of estradiol is tolerated by the ER-LBD and permit agonist
      responses in the intact animal, however, the effect is sensitive to the position
      of groups on the phenyl ring. This study demonstrates that the 17alpha-position
      of estradiol is a reasonable site for modification but the position and
      physicochemical properties of such modifications may significantly affect the
      affinity and efficacy of the ligand.

PMID- 12606006
TI  - Synthesis of two new haptens of 16alpha-hydroxydehydroepiandrosterone
      (3beta,16alpha-dihydroxyandrost-5-en-17-one).
AB  - Synthetic routes leading to 19E and 7Z O-(carboxymethyl)oximes derived from
      16alpha-hydroxydehydroepiandrosterone were developed using two independent
      methods for introduction of the 16alpha-hydroxy group. Firstly, the oxime moiety
      was built, and then, either epoxidation of the enol acetate followed by the boron
      trifluoride mediated rearrangement or alkaline hydrolysis of the corresponding
      alpha-bromide in aqueous N,N-dimethylformamide were employed. The last step in
      both methods was removal of the protecting groups, which consisted of acid
      deprotection of the acetates and gentle alkaline hydrolysis of the methyl ester.
      Final haptens were designed as components for immunoanalytical kits.

PMID- 12606007
TI  - First synthesis of ent-desmosterol and its conversion to ent-deuterocholesterol.
AB  - We report the first synthesis of the unnatural enantiomer of desmosterol (ent
      desmosterol). The sterol nucleus was constructed enantiospecifically, followed by
      stepwise addition of the side chain. Beginning with ent-androst-4-ene-3,17-dione,
      ent-desmosterol was synthesized in 13 steps and 20% yield. Protected ent
      desmosterol was subjected to catalytic deuteration to afford ent
      deuterocholesterol. Ent-desmosterol and ent-deuterocholesterol will be used to
      study the importance of sterol absolute configuration for sterol-lipid
      interactions in biophysical studies and in biological systems.

PMID- 12606008
TI  - Evaluation of 11beta-HSD activities in vivo following oral administration of
      cortisol-13C4,2H1 to a human subject.
AB  - This study is concerned with an oral administration of 5mg of [1,2,4,19
      13C(4),11alpha-2H]cortisol (cortisol-13C(4),2H(1)) to a human subject to reliably
      evaluate the individual activities of two isozymes of 11beta-HSD. The use of a GC
      MS method allowed the simultaneous measurement of the plasma concentrations of
      cortisol-13C(4),2H(1), cortisone-13C(4), and cortisol-13C(4) together with
      endogenous cortisol and cortisone. The loss of 11alpha-2H during the conversion
      of cortisol-13C(4),2H(1) to cortisone-13C(4) by 11beta-HSD2 and the regenerated
      cortisol-13C(4) from cortisone-13C(4) by 11beta-HSD1 provided a direct and
      accurate means of distinguishing the activities of the two isozymes. The kinetic
      analysis associated with the metabolism of orally administered cortisol
      13C(4),2H(1) was of great importance in assessing the 11beta-HSD activities. From
      a viewpoint of the chemical stability and much less pronounced kinetic isotope
      effect of the 13C-label and the 2H-labeling in the 11alpha-position, cortisol
      13C(4),2H(1) used in this study served as an appropriate tracer for elucidating
      the kinetics of the interconversion of cortisol to cortisone in man.

PMID- 12606009
TI  - Synthesis of novel arylpyrazolo corticosteroids as potential ligands for imaging
      brain glucocorticoid receptors.
AB  - Corticosteroids regulate a variety of essential physiological functions, such as
      mineral balance and stress. The great interest in these steroids, especially the
      glucocorticoids, stems from roles they are thought to play in neuropsychiatric
      disorders, such as severe depression and anxiety.The development of
      glucocorticoid receptor (GR) ligands which are appropriately labeled with short
      lived positron-emitting radioisotopes would allow the non-invasive in-vivo
      imaging and mapping of brain GRs by means of positron emission tomography (PET).
      In this context we have synthesized a series of novel arylpyrazolo steroids
      exhibiting different substitution patterns at the D-ring of the steroid skeleton,
      as ligands for brain GRs. Special attention was given to 4-fluorophenyl pyrazolo
      steroids, which are known to display high binding affinity toward the GR. The
      compounds were evaluated in a competitive radiometric receptor binding assay to
      determine their relative binding affinities (RBA) to the GR. Some compounds show
      good binding affinities of up to 56% in comparison to dexamethasone (100%). In
      initial experiments, selected candidates were labeled with the positron emitter
      fluorine-18 and in one case with the gamma-emitter iodine-131.

PMID- 12606010
TI  - Synthesis of (20S)-[7,7,21,21-2H4]-3beta-(tert-butyldimethylsilanyloxy)-20-methyl
      pregn-5-en-21-ol, a useful intermediate for the preparation of deuterated
      isotopomers of sterols.
AB  - (20S)-[7,7,21,21-2H(4)]-3beta-(tert-Butyldimethylsilanyloxy)-20-methyl-pregn-5-en
      21-ol, an intermediate for the preparation of deuterated isotopomers of sterols
      to be used as standards for biomedical studies, was prepared by reduction with
      dichloroaluminum deuteride of ethyl (20S)-3beta-(tert-butyldimethylsilanyloxy)-7
      oxo-pregn-5-en-20-carboxylate. Using controlled experimental conditions, it has
      also been shown that the dichloroaluminum hydride reduction of a 7-keto steroid
      affords the corresponding 7beta-hydroxy derivative in a highly stereoselective
      manner.

PMID- 12606011
TI  - Regioselective cleavage of rings E and F in sarsasapogenin.
AB  - Sapogenins from the 25R and 25S series show a marked difference on the E/F
      regioselectivity of the spiroketal cleavage with BF(3)/Ac(2)O. In contrast to the
      high yield of single E-ring cleavage products from diosgenin (3) and hecogenin
      (5), sapogenins of the 25R series (equatorial C-27 methyl), sarsasapogenin (1,
      25S series, axial C-27 methyl) yields the corresponding acetyldihydropyran, (25S)
      23-acetyl-22,26-epoxy-5beta-cholest-22-ene-3beta,16beta-diyl diacetate (8), two
      isomeric furostenes: (E)- and (Z)-(25S)-23-acetyl-5beta-furost-22-ene-3beta,26
      diyl diacetate (9 and 10) and a third one bearing an additional acetyl group: (E)
      (20S,25S)-20,23-diacetyl-5beta-furost-22-ene-3beta, 26-diyl diacetate (11). The
      structures of the compounds were unambiguously established using two dimensional
      NMR techniques. The lower E/F selectivity in the cleavage of 1 is attributed to
      steric hindrance resulting from the axial methyl in F ring on a beta elimination
      forming the dihydropyran double bond in the major product 8.

PMID- 12606012
TI  - Expression of human aromatase (CYP19) in Escherichia coli by N-terminal
      replacement and induction of cold stress response.
AB  - CYP19 (P450arom) catalyzes the aromatization reaction of C19 steroids leading to
      estrogens. While readily expressed in insect cells, the human P450arom has been a
      difficult P450 to express in Escherichia coli at useful levels. In the present
      study, we replaced the N-terminal sequence in human CYP19 with the corresponding
      sequences of other microsomal P450s (CYP2C11 and CYP17) that are efficiently
      expressed in E. coli. Although the N-terminal replacement alone was not
      sufficient for the expression, human P450arom was successfully expressed up to
      the level of 240nmol/l culture by the combination of the N-terminal replacement
      and the induction of cold stress response by 1 microg/ml chloramphenicol.
      Membrane fractions containing the expressed P450arom catalyzed aromatization of
      androstenedione with a specific activity of 4.9 nmol/min/nmol P450. Our results
      are important to provide large quantities of human P450arom as an active form for
      structure-function studies.

PMID- 12606013
TI  - The relations between cognition and the independent living skill of shopping in
      people with schizophrenia.
AB  - A great deal of interest has developed regarding the impact of cognitive deficits
      on the everyday functioning of people with schizophrenia. This study examined the
      relationships between cognitive functioning and the performance of a specific
      independent living skill (grocery shopping) in a sample of 73 individuals with
      schizophrenia or schizoaffective disorder. Cognitive variables included tests of
      verbal memory, executive functioning, verbal fluency, sustained attention and
      visual motor skill. Functional outcome was measured with the Test of Grocery
      Shopping Skills, which is an ecologically based performance measure that requires
      participants to shop for 10 items within an actual grocery store. Accuracy on the
      shopping task was significantly associated with fewer perseverative responses on
      the Wisconsin Card Sorting Test, better verbal memory and faster processing
      speed. Shopping efficiency (i.e. less redundancy) was associated with better
      performance on several cognitive tasks, including verbal memory, verbal fluency,
      sustained attention and executive functioning. Results of this study extend
      previous research by examining the relation between cognition and the actual
      performance of daily living skills under natural circumstances.

PMID- 12606015
TI  - Prospective analysis of premature mortality in schizophrenia in relation to
      health service engagement: a 7.5-year study within an epidemiologically complete,
      homogeneous population in rural Ireland.
AB  - While premature death in schizophrenia is well recognised, mortality risk has
      received little longitudinal study in relation to population representativeness
      and patient engagement with health services. Within a rural Irish catchment area
      of socioeconomic, ethnic and geographical homogeneity and low residential
      mobility, an epidemiologically complete population of 72 patients with
      schizophrenia was followed up over 7.5 years in order to quantify mortality
      prospectively. Information was obtained in relation to 99% of the cohort, with
      94% of those surviving retained in engagement with psychiatric care. There were
      25 deaths (35% of cohort). A relative risk of 2.06 (95% CI, 1.40-2.80; P < 0.001)
      among this epidemiologically complete population may constitute an estimate of
      risk for mortality inherent to schizophrenia when disengagement from health
      services, residential mobility and socioeconomic, ethnic and geographical
      diversity are minimised. On long-term prospective evaluation, risk for death in
      schizophrenia was doubled on a background of enduring engagement in psychiatric
      care with increasing provision of community-based services and introduction of
      second-generation antipsychotics.

PMID- 12606014
TI  - A comparison study of early non-psychotic deviant behavior in Afrikaner and US
      patients with schizophrenia or schizoaffective disorder.
AB  - In a previous study early non-psychotic deviant behaviors in US adult
      schizophrenic patients recruited for a large-scale genetic study were examined
      (Psychiatry Research, 101, 101). Early deviance characterized a distinct subgroup
      of patients at rates that were consistent with earlier reports. In addition,
      specific early non-psychotic deviant behaviors were meaningfully associated with
      later disease outcomes. In the present study, we examined the demographic,
      syndrome course, symptom and early deviant behavior history of 109 Afrikaner
      probands who met criteria for DSM schizophrenia or schizoaffective disorder, and
      compared them to 109 age- and gender-matched US probands. Consistent with past
      findings, 68% of Afrikaner probands, as compared to 67% of age- and gender
      matched US probands, reported one or more forms of early non-psychotic deviance,
      including poor socialization, extreme fears/chronic sadness, and/or
      attention/learning impairment. The remaining 32 and 33% of probands,
      respectively, were without behavioral deviance until the onset of schizophrenia
      or schizoaffective disorder. The frequency and distribution of individual deviant
      behaviors were strikingly consistent between the samples. However, logistic
      regression analyses revealed different patterns of associations between the early
      deviant behaviors manifested and disease outcome. Afrikaner participants with
      early fears/chronic sadness were 3 times more likely to attempt suicide, while
      among US participants, this form of early deviance conferred 3.5 times more risk
      for later schizoaffective disorder, and 3 times greater likelihood of later
      sensory (tactile and/or olfactory) hallucinations. Afrikaner participants with
      attention/learning impairment were 2.5 times more likely to experience later
      auditory hallucinations, while US participants with these early difficulties were
      3 times more likely to experience thought disorder. We concluded that early non
      psychotic childhood deviance in this independently collected Afrikaner population
      distinguished a distinct subtype of patients and that the forms of early deviance
      manifested were meaningfully linked to later disease outcome. Possible reasons
      for the association pattern differences in these two populations are considered.

PMID- 12606016
TI  - The cognitive and anatomo-functional basis of reality distortion in
      schizophrenia: a view from memory event-related potentials.
AB  - This study investigated the neural and cognitive correlates of reality distortion
      in schizophrenia by using event-related potentials (ERPs) recorded in a
      recognition memory task for face. This task has been chosen because previous
      studies have shown that it provides distinct indices related to specific
      cognitive processes and to the functioning of specific brain regions. ERPs have
      been recorded in controls and schizophrenia patients separated into high scorers
      (RD+) and low-scorers (RD-) according to their Reality Distortion score
      (hallucination and delusion SAPS subscales). The results indicate that RD+
      presents abnormalities on various cognitive processes. First, RD+ are deficient
      at interference inhibition and knowledge integration (reduced P2a and N400
      effect). The similar impairments found in RD- suggest that they represent basic
      traits of the illness. Second, RD+ showed inappropriate stimulus categorization
      and contextual integration (larger N300 and fronto-central effect). Third, RD+
      showed a late index (P600 effect) not different from controls, but larger than in
      RD-. This result is consistent with a qualitative, rather than quantitative,
      impairment of mnemonic binding processes (inappropriate binding) in RD+. Since
      each of the ERP abnormalities observed represents associated with distinct brain
      dysfunction, the results are further discussed in regard of the respective
      contribution of the parietal, frontal and hippocampal structures to reality
      distortion symptoms.

PMID- 12606017
TI  - Lifetime comorbidity of antisocial personality disorder and anxiety disorders
      among adults in the community.
AB  - The association between lifetime anxiety disorders, conduct disorder (CD), and
      antisocial personality disorder (ASPD) among adults in the community was
      explored. Data were drawn from the National Comorbidity Survey (n = 5,877), a
      representative community sample of adults aged 15-54 in the 48 contiguous US
      states. Multiple logistic regression analyses were used to determine the
      association between anxiety disorders, CD and ASPD, and between the co-occurrence
      of anxiety disorders and ASPD in the likelihood of comorbid substance use and
      affective disorders, suicidal ideation (SI) and suicide attempt (SA). Out of the
      3.3% of adults with ASPD, over half (54.33%) had a comorbid anxiety disorder
      (lifetime). Similarly, 42.31% of adults with a history of CD (9.4%) who did not
      meet criteria for ASPD had a lifetime anxiety disorder. Social phobia [OR = 1.65
      (1.01, 2.7)] and post-traumatic stress disorder [OR = 2.28 (1.3, 4.0)] were
      associated with significantly increased odds of ASPD, after adjusting for
      differences in sociodemographic characteristics and other psychiatric
      comorbidity. Major depression was no longer significantly associated with ASPD
      after adjusting for anxiety disorders. The comorbidity of anxiety disorders and
      ASPD was associated with significantly higher odds of major depression, substance
      use disorders, and SI and SA compared with odds among those without both
      disorders. These data provide initial evidence of an association between PTSD and
      social phobia and an increased likelihood of ASPD among adults in the community,
      after adjustment for comorbid affective and substance use disorders. Adults with
      ASPD and comorbid anxiety had significantly higher levels of comorbid major
      depression, alcohol dependence, and substance dependence and substantially higher
      rates of lifetime suicidal ideation and suicide attempts compared to adults with
      ASPD or anxiety disorders alone or with neither disorder. Future studies are
      needed to replicate this finding using longitudinal data and to investigate the
      possible mechanisms of the observed links between anxiety disorders and ASPD.

PMID- 12606018
TI  - Clinician ratings vs. global ratings of symptom severity: a comparison of symptom
      measures in the bipolar disorder module, phase II, Texas Medication Algorithm
      Project.
AB  - This study compares ratings obtained with an itemized, clinician-rated, symptom
      severity measure--the 24-item Brief Psychiatric Rating Scale (BPRS(24))--to a
      Physician Global Rating Scale (PhGRS), a Patient Global Rating Scale (PtGRS) and
      the clinician-completed Multnomah Community Ability Scale (MCAS) in patients with
      bipolar disorder (BPD). A total of 69 patients (25 inpatients and 44 outpatients)
      with BPD were enrolled in a feasibility study of the use of medication algorithms
      in the treatment of BPD. Clinicians at each visit completed the BPRS(24), PhGRS
      and MCAS, and patients completed the PtGRS. Analyses compared the BPRS(24) and
      BPRS subscales with the PtGRS, PhGRS and MCAS. PtGRS scores correlated poorly
      with BPRS(24) and with PhGRS scores at baseline, although PtGRS change scores
      correlated moderately with BPRS(24) change scores. Baseline BPRS(24) and PhGRS
      scores correlated moderately at baseline with somewhat stronger correlations
      found on change scores for the two measures. MCAS scores showed moderate
      correlations with BPRS(24) scores both at baseline and with change over time.
      Global assessments by patients or physicians only moderately or poorly reflected
      BPRS(24) scores. Itemized symptom measures to gauge severity of illness or change
      over time are preferred over patient or physician global judgments.

PMID- 12606019
TI  - Nonlinear measures of QT interval series: novel indices of cardiac repolarization
      lability: MEDqthr and LLEqthr.
AB  - In this study, we investigated nonlinear measures of chaos of QT interval time
      series in 28 normal control subjects, 36 patients with panic disorder and 18
      patients with major depression in supine and standing postures. We obtained the
      minimum embedding dimension (MED) and the largest Lyapunov exponent (LLE) of
      instantaneous heart rate (HR) and QT interval series. MED quantifies the system's
      complexity and LLE predictability. There was a significantly lower MED and a
      significantly increased LLE of QT interval time series in patients. Most
      importantly, nonlinear indices of QT/HR time series, MEDqthr (MED of QT/HR) and
      LLEqthr (LLE of QT/HR), were highly significantly different between controls and
      both patient groups in either posture. Results remained the same even after
      adjusting for age. The increased LLE of QT interval time series in patients with
      anxiety and depression is in line with our previous findings of higher QTvi (QT
      variability index, a log ratio of QT variability corrected for mean QT squared
      divided by heart rate variability corrected for mean heart rate squared) in these
      patients, using linear techniques. Increased LLEqthr (LLE of QT/HR) may be a more
      sensitive tool to study cardiac repolarization and a valuable addition to the
      time domain measures such as QTvi. This is especially important in light of the
      finding that LLEqthr correlated poorly and nonsignificantly with QTvi. These
      findings suggest an increase in relative cardiac sympathetic activity and a
      decrease in certain aspects of cardiac vagal function in patients with anxiety as
      well as depression. The lack of correlation between QTvi and LLEqthr suggests
      that this nonlinear index is a valuable addition to the linear measures. These
      findings may also help to explain the higher incidence of cardiovascular
      mortality in patients with anxiety and depressive disorders.

PMID- 12606020
TI  - Blue cone electroretinogram amplitudes are related to dopamine function in
      cocaine-dependent patients.
AB  - The objective of the study was to examine the relationship between an index of
      central dopamine function and electroretinographic (ERG) blue cone amplitudes in
      cocaine-dependent patients. Thus, 17 recently abstinent cocaine-dependent
      patients had an ERG performed. They also had a lumbar puncture for determination
      of cerebrospinal (CSF) concentrations of the dopamine metabolite homovanillic
      acid (HVA). It was found that patients who had reduced ERG blue cone b-wave
      amplitudes (<0.5 microV) had significantly lower concentrations of CSF HVA than
      patients who had ERG blue cone b-wave amplitudes greater than 0.5 microV. There
      was also a significant positive correlation between ERG blue cone amplitudes and
      CSF HVA concentrations. These results suggest the possibility that ERG blue cone
      amplitudes may be a neurobiologic marker related to central dopamine function in
      cocaine-dependent patients.

PMID- 12606021
TI  - A novel testis-specific RAG2-like protein, Peas: its expression in pachytene
      spermatocyte cytoplasm and meiotic chromatin.
AB  - We report a novel gene Peas that constitutes an overlapping gene complex in
      mammalian genome. We have cloned human and mouse Peas cDNAs (hPEAS/mPeas) and
      analyzed their tissue and stage-specific expressions. Peas protein contains six
      repeated kelch motifs, structurally similar to RAG2, a V(D)J recombination
      activator, and is evolutionarily conserved among mammals, birds, insects, and
      nematodes. Northern, RNA in situ hybridization and immunohistochemical analyses
      showed that mPeas is specifically transcribed in testis, particularly in
      pachytene spermatocytes in which it is localized to the cytoplasm and meiotic
      chromatin. It is suggested that Peas may be involved in meiotic recombination
      process.

PMID- 12606022
TI  - Binding and retention of polycationic peptides and dendrimers in the vascular
      wall.
AB  - Extracellular matrix (ECM) of tissues, vascular tissue in particular, contains a
      high concentration of negatively charged glycosaminoglycans (GAGs), which are
      involved in the regulation of cell motility, cell proliferation and the
      regulation of enzyme activities. Previously, we have shown that the vascular ECM
      is capable of binding an extremely high concentration of positively charged
      molecules, such as polylysine. Vascular ECM can be used therefore as a substrate
      for binding and retention of drugs delivered intravascularly, if these drugs are
      endowed with an ability to bind to the vascular ECM. In this study, we evaluated
      a number of positively charged molecules as potential affinity vehicles for
      delivery of drugs to the vascular ECM. We labelled the molecules of interest with
      fluorescence and compared them ex vivo in terms of binding and retention in the
      de-endothelialised rat carotid artery after intravascular delivery under
      pressure. High molecular weight polylysine (84 kDa) and polyamidoamine (PAMAM)
      dendrimers accumulated in the wall of the artery up to a concentration of 10
      mg/ml and were not washed away significantly after 4 h of perfusion of the
      artery. A 24-mer peptide containing a consensus sequence for binding to GAGs
      (ARRRAARA)(3), 2.7 kDa, was comparable to high molecular weight polylysine and
      dendrimers in terms of binding and retention. A 14-mer GAG-binding peptide from
      vitronectin and low molecular weight polylysine, 3 kDa, accumulated in the
      vascular wall up to about 3 mg/ml and was washed away after 30 min of perfusion.
      A 10-mer consensus GAG-binding peptide did not bind significantly to the vascular
      tissue. We conclude that the consensus 24-mer GAG-binding peptide is by far
      superior to polylysine of a similar molecular weight in terms of binding to
      vascular tissue, and can provide high accumulation and long-term retention of a
      low molecular weight compound (fluorescein, as a model molecule) in the vascular
      wall. Rationally designed GAG-binding peptides can be useful as affinity vehicles
      for targeting drugs to the vascular ECM.

PMID- 12606023
TI  - The spontaneous polymerization of plasminogen activator inhibitor type-2 and Z
      antitrypsin are due to different molecular aberrations.
AB  - The wild-type form of plasminogen activator inhibitor type-2 (PAI-2) and the
      pathogenic Z-mutant of alpha(1)-antitrypsin (alpha(1)AT) are serpins that
      spontaneously polymerize by the loop-sheet mechanism. Compared to the consensus
      serpin sequence, both PAI-2 and Z-alpha(1)AT have deviations in the so-called
      breach region located at the top of the A beta-sheet. In the case of Z
      alpha(1)AT, conformational perturbations caused by a single amino acid
      substitution result in polymerization in vivo and predisposes to disease. To test
      whether the polymerization of PAI-2 is due to aberrations in the breach region,
      we constructed substitution mutants of PAI-2 with conserved residues in this
      region. Analysis of the mutants revealed that deviations in the breach region
      modulate but are not the major cause of PAI-2 polymerization. Rather, PAI-2
      exists in a highly polymerogenic conformation and does not require conformational
      rearrangements before polymerization can take place.

PMID- 12606024
TI  - Complement component anaphylatoxins upregulate chemokine expression by human
      astrocytes.
AB  - The complement (C) system, a major component of the innate immune system, has
      been described as a factor implicated in some brain disorders. C activation leads
      to the release of anaphylatoxins, two proinflammatory polypeptides acting through
      specific receptors that have been detected on brain cells. Here, we examined the
      effect of anaphylatoxins on chemokine expression by human astrocytes. We showed
      that anaphylatoxins significantly increase chemokine mRNA expression. However,
      anaphylatoxin-induced chemokine secretion (interleukin-8) was observed only in
      the presence of interleukin-1beta. Thus, anaphylatoxins could initiate a
      chemokine cascade and, at least in part, be involved in pathogenesis of the
      brain.

PMID- 12606025
TI  - Heparin-like dextran derivatives as well as glycosaminoglycans inhibit the
      enzymatic activity of human cathepsin G.
AB  - Some synthetic dextran derivatives that mimic the action of heparin/heparan
      sulfate were previously shown to inhibit neutrophil elastase and plasmin. Here we
      report that these derivatized dextrans also inhibit cathepsin G (CatG). Dextran
      containing carboxymethyl and benzylamide groups (RG1150) as well as those
      containing carboxymethyl, sulfate and benzylamide groups (RG1192), were the most
      efficient inhibitors of CatG activity. RG1192 and RG1150 bind CatG with a K(i) of
      0.11 and 0.17 nM, respectively, while carboxymethylated sulfated dextran (RG1503)
      as well as heparin, heparan sulfate and dermatan sulfate bind CatG with a 7- to
      30-fold lower affinity. Variation of K(i) with ionic strength indicates that
      ionic interactions account for 26% of the RG1503-CatG binding energy, while
      binding of RG1192 or RG1150 to CatG is mainly governed by non-electrostatic
      interactions. This, together with the fact that these compounds both protect
      fibronectin and laminin against CatG-mediated degradation, suggest that specific
      dextran derivatives can contribute to the regulation of CatG activity.

PMID- 12606026
TI  - Trans-acting factors may cause dystrophin splicing misregulation in BMD skeletal
      muscles.
AB  - We analyzed dystrophin alternative splicing events in a large number of Becker
      muscular dystrophy (BMD) affected individuals presenting major hot-spot
      deletions. Evidence is shown that altered splicing patterns in these patients do
      not directly result from the gene defect but probably derive from modifications
      in trans- rather than cis-acting factors. Several potential CUG-binding protein 2
      (CUG-BP2) binding sites were found to be located in the dystrophin gene region
      encompassing exons 43-60 and CUG-BP2 transcript analysis indicated that not only
      expression levels are increased in dystrophic muscles but also that different CUG
      BP2 isoforms are expressed. The possibility that CUG-BP2 might have a role in
      dystrophin splicing regulation is discussed.

PMID- 12606027
TI  - Bsp1p/Ypr171p is an adapter that directly links some synaptojanin family members
      to the cortical actin cytoskeleton in yeast.
AB  - In this study we identified a novel protein, Bsp1p, that interacts directly with
      two yeast synaptojanins, Sjl2p and Sjl3p, but not with Sjl1p. The interaction
      takes place via the Sac1/polyphosphoinositide phosphatase domain, whose conserved
      C-terminal region is important for binding. Subcellular localization and genetic
      interactions revealed a function of Bsp1p in the cortical actin cytoskeleton. A
      fraction of Bsp1p was found to be membrane-associated. Studies with mutants of
      phosphatidylinositol 4-kinase, PIK1, suggested that the interaction with
      membranes is facilitated by phosphoinositides. We propose that Bsp1p is an
      adapter that links Sjl2p and Sjl3p to the cortical actin cytoskeleton.

PMID- 12606028
TI  - Identification of key regions within the Escherichia coli TatAB subunits.
AB  - The twin-arginine translocation (Tat) system catalyzes the transport of folded
      proteins across the bacterial plasma membrane or the chloroplast thylakoid
      membrane. In Escherichia coli and most other species, three important tat genes
      have been identified but the structure and mechanism of this system are poorly
      understood; the role and location of TatA are particularly unclear. In this
      report we have used site-specific mutagenesis to probe the significance of
      conserved features of the related TatA/B subunits. We find that an apparent
      'hinge' region between the transmembrane (TM) span and an adjacent amphipathic
      region is important in both proteins, in that substitution of turn-inducing
      residues inhibits the export of a natural Tat substrate. Surprisingly, large
      scale mutagenesis of the conserved amphipathic regions of TatA and TatB leads
      only to minor effects on Tat-dependent export suggesting that this particular
      feature is not central to the translocation mechanism. This domain is, however,
      critical for the translocation process and we identify Gly/Pro residues in these
      regions of TatA/B that are essential for efficient export.

PMID- 12606029
TI  - The pp60c-Src inhibitor PP1 is non-competitive against ATP.
AB  - Glutathione-S-transferase (GST)-pp60(c-Src) (GST-Src) expressed in Escherichia
      coli is as catalytically active as purified, activated pp60(c-Src) protein
      derived from human platelets. We utilized the bacterially expressed enzyme,
      together with information about the structures of Src family kinases in complex
      with their inhibitors PP1 and PP2, to modify PP1 in a quest for improved
      inhibitors. Despite the detailed structural information on Hck-PP1 and Lck-PP2
      complexes, which shows that PP1 and PP2 bind to the adenosine triphosphate (ATP)
      pocket, we were unable to improve the affinity between modified PP1 and Src.
      Puzzled, we examined in detail the mechanism by which PP1 inhibits the kinase
      activity of Src. Here we report that PP1 is non-competitive with ATP for the
      inhibition of Src, at variance with what is currently accepted, and is a 'mixed
      competitive inhibitor' vis-a-vis the substrate. These findings shed new light on
      the mechanism whereby PP1-like molecules inhibit Src. Examination of the homology
      between the kinase domain of Src and those of Hck and Lck reveals significant
      differences outside the ATP binding pocket, whereas they are identical within the
      ATP binding domain. These results suggest that PP1 may be a leading compound for
      ATP non-competitive inhibitors of Src family kinases. Since Src in its active
      form is the hallmark of numerous cancers, understanding how PP1 inhibits
      activated Src will aid in the discovery of potent and selective Src kinase
      inhibitors.

PMID- 12606030
TI  - Maltodextrin-binding proteins from diverse bacteria and archaea are potent
      solubility enhancers.
AB  - Escherichia coli maltose-binding protein (MBP) is frequently used as an affinity
      tag to facilitate the purification of recombinant proteins. An important
      additional attribute of MBP is its remarkable ability to enhance the solubility
      of its fusion partners. MBPs are present in a wide variety of microorganisms
      including both mesophilic and thermophilic bacteria and archaea. In the present
      study, we compared the ability of MBPs from six diverse microorganisms (E. coli,
      Pyrococcus furiosus, Thermococcus litoralis, Vibrio cholerae, Thermotoga
      maritima, and Yersinia pestis) to promote the solubility of eight different
      aggregation-prone proteins in E. coli. In contrast to glutathione S-transferase
      (GST), all of these MBPs proved to be effective solubility enhancers and some of
      them were even more potent solubilizing agents than E. coli MBP.

PMID- 12606031
TI  - Interaction of NF-Y with the 3'-flanking DNA sequence of the CCAAT box.
AB  - NF-Y, also referred to as CCAAT-binding factor, is a major CCAAT-binding
      transcription factor. The present study demonstrated that the 3'-flanking region
      of the CCAAT box is involved in the formation of a stable NF-Y.DNA complex. An
      electrophoretic mobility shift assay showed that the interaction of NF-Y with DNA
      15 bp downstream of the CCAAT box alters not only the affinity of NF-Y for its
      binding site but also the electrophoretic mobility of the NF-Y.DNA complex. This
      interaction is accompanied by a conformational change of NF-Y as demonstrated by
      a change in the reactivity of an anti-NF-YA antibody to the NF-Y.DNA complex.

PMID- 12606032
TI  - Oxidized glutathione stimulated the amyloid formation of alpha-synuclein.
AB  - alpha-Synuclein is the major filamentous constituent of Lewy bodies found in
      Parkinson's disease (PD). The amyloid formation of alpha-synuclein was
      significantly facilitated by oxidized glutathione (GSSG) as the lag period of the
      aggregation kinetics was shortened by 2.5-fold from its absence. Reduced
      glutathione (GSH), on the other hand, did not influence the lag phase although it
      increased the final amyloid formation. The GSSG stimulation was specific for not
      only alpha-synuclein but also its intactness. The preferred GSSG interaction of
      alpha-synuclein to GSH was also demonstrated with dissociation constants of 0.53
      and 43.5 mM, respectively. It is suggested that the oxidative stress favoring the
      GSSG generation from GSH could result in the augmented amyloid formation of alpha
      synuclein, which ought to be related to the pathogenesis of PD.

PMID- 12606033
TI  - Reconstitution of water channel function of an aquaporin overexpressed and
      purified from Pichia pastoris.
AB  - The aquaporin PM28A is one of the major integral proteins in spinach leaf plasma
      membranes. Phosphorylation/dephosphorylation of Ser274 at the C-terminus and of
      Ser115 in the first cytoplasmic loop has been shown to regulate the water channel
      activity of PM28A when expressed in Xenopus oocytes. To understand the mechanisms
      of the phosphorylation-mediated gating of the channel the structure of PM28A is
      required. In a first step we have used the methylotrophic yeast Pichia pastoris
      for expression of the pm28a gene. The expressed protein has a molecular mass of
      32462 Da as determined by matrix-assisted laser desorption ionization-mass
      spectrometry, forms tetramers as revealed by electron microscopy and is
      functionally active when reconstituted in proteoliposomes. PM28A was efficiently
      solubilized from urea- and alkali-stripped Pichia membranes by octyl-beta-D
      thioglucopyranoside resulting in a final yield of 25 mg of purified protein per
      liter of cell culture.

PMID- 12606034
TI  - Immunohistochemical and biochemical analyses of GD3, GT1b, and GQ1b gangliosides
      during neural differentiation of P19 EC cells.
AB  - In an earlier study, we showed that expressions of GD3, GT1b, and GQ1b
      gangliosides in P19 embryonic carcinoma (EC) cells were enhanced during their
      neural differentiation induced by retinoic acid. We now further demonstrated that
      this increase of the b-series gangliosides is due to an increase in their
      corresponding synthases (sialyltransferase-II, -IV, and -V) in the Golgi. Of the
      three gangliosides studied, GQ1b appeared to be the best candidate for monitoring
      such differentiation process. We also used fluorescence-labeled monoclonal
      antibodies and confocal fluorescence microscopy to obtain direct visual
      information about the relationship of gangliosides and neural specific proteins
      in neuron development. Again, GQ1b is the most interesting as it localizes with
      synaptophysin and neural cell adhesion molecules (NCAMs) on synaptic boutons or
      dendritic spines in RA-induced neurons (R/N). This suggests that GQ1b could be
      used as a marker for synapse formation during construction of the neural network.

PMID- 12606035
TI  - In bafilomycin A1-resistant cells, bafilomycin A1 raised lysosomal pH and both
      prodigiosins and concanamycin A inhibited growth through apoptosis.
AB  - In bafilomycin A(1)-resistant cells (Vero-317 and MC-3T3-E1), bafilomycin A(1)
      neither inhibited cell growth, induced cell death, nor activated caspase-3.
      However, 100 nM bafilomycin A(1) did raise the lysosomal pH similar to 10 mM
      NH(4)Cl. Prodigiosins, H(+)/Cl(-) symporters that raise the lysosomal pH,
      inhibited cell growth through apoptosis and caused the activation of caspase-3.
      Concanamycin A also inhibited the growth of these cells through apoptosis. 10 mM
      NH(4)Cl inhibited the growth of these cells as well, but cytostatically. These
      results suggest that plecomacrolides inhibited cell growth apoptotically through
      specific site(s), in contrast to the cytostatic effect of 10 mM NH(4)Cl, besides
      raising the lysosomal pH.

PMID- 12606037
TI  - Arfaptin 1 inhibits ADP-ribosylation factor-dependent matrix metalloproteinase-9
      secretion induced by phorbol ester in HT 1080 fibrosarcoma cells.
AB  - Matrix metalloproteinase-9 (MMP-9) is a collagenolytic enzyme secreted by cancer
      cells and involved in invasiveness and metastasis. Its secretion from human
      fibrosarcoma HT 1080 cells is markedly enhanced by phorbol 12-myristate 13
      acetate (PMA) and abolished by brefeldin A, an inhibitor of ADP-ribosylation
      factor (ARF) activation. These results support a role for ARF in PMA-stimulated
      MMP-9 secretion. Overexpression of arfaptin 1, a 39 kDa ARF-binding protein that
      inhibits in vitro activation of cholera toxin ADP-ribosyltransferase and
      phospholipase D (PLD) by ARF, inhibited PMA-stimulated MMP-9 and PLD activation.
      These data are in agreement with previous results demonstrating a significant
      role for PLD in regulating MMP-9 secretion.

PMID- 12606036
TI  - CD36-mediated endocytic uptake of advanced glycation end products (AGE) in mouse
      3T3-L1 and human subcutaneous adipocytes.
AB  - Interaction of advanced glycation end products (AGE) with AGE receptors induces
      several cellular phenomena potentially relating to diabetic complications. We
      here show that AGE-modified bovine serum albumin (BSA) is endocytosed by
      adipocytes via CD36. Upon differentiation, 3T3-L1 and human subcutaneous adipose
      cells showed marked increases in endocytic uptake and subsequent degradation of
      [(125)I]AGE-BSA, which were inhibited effectively by the anti-CD36 antibody.
      Ligand specificity of CD36 for modified BSAs was compared with that of LOX-1 and
      scavenger receptor class A. Effect of fucoidan on [(125)I]AGE-BSA binding showed
      a sharp contrast to that on [(125)I]-oxidized low density lipoprotein. These
      results implicate that CD36-mediated interaction of AGE-modified proteins with
      adipocytes might play a pathological role in obesity or insulin-resistance.

PMID- 12606038
TI  - Proteomic identification of divalent metal cation binding proteins in plant
      mitochondria.
AB  - Divalent metal binding proteins in the Arabidopsis mitochondrial proteome were
      analysed by mobility shifts in the presence of divalent cations during two
      dimensional diagonal sodium dodecyl sulphate-polyacrylamide gel electrophoresis.
      Tandem mass spectrometry and searches of the predicted Arabidopsis protein
      dataset were used in an attempt to identify 34 of the proteins which shifted.
      This analysis identified a total of 23 distinct protein spots as the products of
      at least 11 different Arabidopsis genes. A series of proteins known to be
      divalent cation-binding proteins, or to catalyse divalent cation-dependent
      reactions, were identified. These included: succinyl CoA ligase beta subunit, Mn
      superoxide dismutase (SOD), an Fe-S centred component of complex I and the REISKE
      iron-sulphur protein of the b/c(1) complex. A further set of four proteins of
      known function but without known divalent binding properties were also
      identified: the Vb subunit of cytochrome c oxidase, a subunit of ATP synthase
      (orfB), the acyl carrier protein, and the translocase of the outer membrane
      (TOM20). Three other proteins, of unknown function, were also found to shift in
      the presence of divalent cations. This approach has broad application for the
      identification of sub-proteomes based on the metal interaction of polypeptides.

PMID- 12606039
TI  - Inhibition of the plant cytokinin transduction pathway by bacterial histidine
      kinase inhibitors in Catharanthus roseus cell cultures.
AB  - We describe the isolation of two Catharanthus roseus cDNAs encoding proteins
      putatively involved in the final steps of a 'histidine-to-aspartate' phosphorelay
      in cytokinin (CK) signaling. The expression of one of these genes, CrRR1, was
      specifically up-regulated by CKs in C. roseus cell suspensions. We used this
      system as a biological model to test the activity of bacterial histidine kinase
      inhibitors. Our data demonstrate that these inhibitors are active on the CK
      transduction pathway and represent powerful chemical tools to study hormone
      signal transduction in plants. Moreover, these data suggest a strong conservation
      of functional features between prokaryotic and plant signaling pathways utilizing
      histidine kinases.

PMID- 12606040
TI  - Further enhancement of baculovirus insecticidal efficacy with scorpion toxins
      that interact cooperatively.
AB  - We have studied whether the cooperative insecticidal effect of certain scorpion
      toxin pairs, namely either a combination of excitatory and depressant, or alpha
      and depressant scorpion toxins, would improve the efficacy of Autographa
      californica nucleopolyhedrovirus (AcMNPV) over a virus expressing only a single
      toxin, towards Heliothis virescens, Helicoverpa armigera, and Spodoptera
      littoralis larvae. The best result was achieved by combined expression of the
      excitatory toxin, LqhIT1, and the depressant toxin, LqhIT2, that provided an
      ET(50) value of 46.9 h on H. virescens neonates, an improvement of 40% over the
      efficacy of wild-type AcMNPV, and of 18% and 22% over baculoviruses that express
      each of the toxins independently. These results demonstrate that significant
      improvement in efficacy of recombinant baculoviruses is obtainable with toxins
      that exhibit a cooperative effect, and may contribute to employ baculoviruses to
      replace hazardous chemicals in insect control.

PMID- 12606041
TI  - Evidence for glycosylphosphatidylinositol (GPI)-anchored eosinophil-derived
      neurotoxin (EDN) on human granulocytes.
AB  - Eosinophil-derived neurotoxin (EDN) is one of the four basic proteins stored in
      specific eosinophil granules. Here we demonstrate that EDN can also be detected
      at the surface of granulocytes. Reduction of EDN membrane expression after
      phosphatidylinositol-specific phospholipase C treatment suggests that a
      glycosylphosphatidylinositol (GPI) anchor is involved in the membrane association
      of EDN. The presence of a GPI anchor was confirmed by a lower expression of
      membrane EDN on granulocytes from patients with paroxysmal nocturnal
      hemoglobinuria which present cells lacking GPI anchor proteins. Furthermore,
      metabolic labeling with GPI anchor components supports biochemical evidence of
      GPI anchoring of EDN.

PMID- 12606042
TI  - Preliminary characterisation of mechanoresponsive regions of the c-fos promoter
      in bone cells.
AB  - Preliminary analysis of the mechanisms involved in induction of stretch-mediated
      transcriptional activity in the c-fos promoter of bone has been undertaken using
      a series of c-fos promoter-reporter constructs. UMR-106 osteoblastic cells
      transfected with reporter constructs were subjected to cyclical physiological
      loading. The major determinants in the resulting transcriptional
      mechanoactivation are within the sequence between -356 and -151 which contains
      the serum response element and a consensus shear stress response element.
      Elements beyond this region also play a role as deletion of this region does not
      eliminate mechanoinduction. These results suggest that the mechanical induction
      of c-fos in osteoblastic bone cells is mediated by multiple response elements.

PMID- 12606043
TI  - Exceptional pairs of amino acid neighbors in alpha-helices.
AB  - Amino acids seem to have specific preferences for various locations in alpha
      helices. These specific preferences, called singlet local propensity (SLP), have
      been determined by calculating the preference of occurrence of each amino acid in
      different positions of the alpha-helix. We have studied the occurrence of amino
      acids, single or pairs, in different positions, singlet or doublet, of alpha
      helices in a database of 343 non-homologous proteins representing a unique
      superfamily from the SCOP database with a resolution better than 2.5 A from the
      Protein Data Bank. The preference of single amino acids for various locations of
      the helix was shown by the relative entropy of each amino acid with respect to
      the background. Based on the total relative entropy of all amino acids occurring
      in a single position, the N(cap) position was found to be the most selective
      position in the alpha-helix. A rigorous statistical analysis of amino acid pair
      occurrences showed that there are exceptional pairs for which, the observed
      frequency of occurrence in various doublet positions of the alpha-helix is
      significantly different from the expected frequency of occurrence in that
      position. The doublet local propensity (DLP) was defined as the preference of
      occurrences of amino acid pairs in different doublet positions of the alpha
      helix. For most amino acid pairs, the observed DLP (DLP(O)) was nearly equal to
      the expected DLP (DLP(E)), which is the product of the related SLPs. However, for
      exceptional pairs of amino acids identified above, the DLP(O) and DLP(E) values
      were significantly different. Based on the relative values of DLP(O) and DLP(E),
      exceptional amino acid pairs were divided into two categories. Those, for which
      the DLP(O) values are higher than DLP(E), should have a strong tendency to pair
      together in the specified position. For those pairs which the DLP(O) values are
      less than DLP(E), there exists a hindrance in neighboring of the two amino acids
      in that specific position of the alpha-helix. These cases have been identified
      and listed in various tables in this paper. The amount of mutual information
      carried by the exceptional pairs of amino acids was significantly higher than the
      average mutual information carried by other amino acid pairs. The average mutual
      information conveyed by amino acid pairs in each doublet position was found to be
      very small but non-zero.

PMID- 12606044
TI  - Phosphate-deficient oat replaces a major portion of the plasma membrane
      phospholipids with the galactolipid digalactosyldiacylglycerol.
AB  - The plasma membranes of oat normally resemble those of other eukaryotes in
      containing mainly phospholipids and sterols. We here report the novel finding
      that the galactolipid digalactosyldiacylglycerol (DGDG) can constitute a
      substantial proportion of oat plasma membrane lipids, in both shoots and roots.
      When oat was cultivated under severe phosphate limitation, up to 70% of the
      plasma membrane phosphoglycerolipids were replaced by DGDG. Our finding not only
      reflects a far more developed potential for plasticity in plasma membrane lipid
      composition than often assumed, but also merits interest in the context of the
      limited phosphate availability in many soils.

PMID- 12606045
TI  - Increasing D4Z4 repeat copy number compromises C2C12 myoblast differentiation.
AB  - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy
      associated with deletions of a subtelomeric repeat (D4Z4). A reduction in D4Z4
      copy number coincides with increased expression of neighboring 4q35 genes,
      implying a normal repressive role for the repeats. Here we examine the effect of
      increasing D4Z4 repeat number on reporter gene activity in C2C12 cells. Repeat
      size had only a minor cis-effect on reporter gene activity but greatly
      compromised myotube formation. This latter trans-effect did not result from
      expression of a gene within the repeat (DUX4) but likely results from squelching
      of the D4Z4 recognition complex.

PMID- 12606046
TI  - Tissue-specific expression, heat inducibility, and biological roles of two hsp16
      genes in Caenorhabditis elegans.
AB  - In this report we have examined two new heat shock protein (HSP16) proteins in
      the nematode Caenorhabditis elegans encoded by the open reading frames F08H9.3
      and F08H9.4. The F08H9.3 and F08H9.4 genes are oriented in the same direction
      next to each other on the chromosome, not sharing any promoter region, unlike
      other hsp16 genes that share common promoters in pairs. The F08H9.3 and F08H9.4
      proteins were expressed in a tissue-specific manner, unlike the other four HSP16
      proteins. F08H9.3 was expressed in the pharynx, and F08H9.4 in the excretory
      canal and a few neuronal cells. While F08H9.3 was weakly induced by heat shock
      only in the same tissue as under the normal condition, F08H9.4 was newly induced
      in the intestine. RNA interference experiments showed that these two proteins are
      required for survival under the heat shock condition.

PMID- 12606047
TI  - Myeloperoxidase/nitrite-mediated lipid peroxidation of low-density lipoprotein as
      modulated by flavonoids.
AB  - In the presence of a H(2)O(2)-generating system, myeloperoxidase (MPO) caused
      conjugated diene formation in low-density lipoprotein (LDL), indicating lipid
      peroxidation which was dependent on nitrite but not on chloride. The oxidation of
      LDL was inhibited by micromolar concentrations of flavonoids such as (-)
      epicatechin, quercetin, rutin, taxifolin and luteolin, presumably via scavenging
      of the MPO-derived NO(2) radical. The flavonoids served as substrates of MPO
      leading to products with distinct absorbance spectra. The MPO-catalyzed oxidation
      of flavonoids was accelerated in the presence of nitrite.

PMID- 12606048
TI  - Hypertonic activation of phospholemman in solitary rat hepatocytes in primary
      culture.
AB  - Under hypertonic conditions, solitary rat hepatocytes in primary culture shrink
      and subsequently exhibit a distinct regulatory volume increase (RVI). Reverse
      transcribed polymerase chain reaction and 5' and 3' RACE (rapid amplification of
      cDNA ends) techniques reveal that these cells express phospholemman (PLM). In
      whole-cell recordings, the hypertonic activation of a channel is observed that
      resembles PLM with respect to unitary conductance (600-700 pS), gating pattern,
      and non-selectivity for Na(+) over K(+). In Xenopus oocytes expressing hepatocyte
      PLM, hypertonic stress induces a non-selective cation conductance and noise
      analysis reveals the activation of a channel with a unitary conductance of
      approximately 700 pS. These results suggest a role of PLM in the RVI of rat
      hepatocytes.

PMID- 12606049
TI  - Nicotinamide adenine dinucleotide stimulates oligomerization, interaction with
      adenovirus E1A and an intrinsic dehydrogenase activity of CtBP.
AB  - The C-terminal region of adenovirus E1A interacts with the transcriptional
      corepressor, CtBP. The mechanism of transcriptional regulation by CtBP is not
      known. CtBP shares a significant homology with NAD(+)-dependent D2-hydroxy acid
      dehydrogenases. CtBP binds to NAD(+) and NADH. Both forms of the dinucleotide
      stimulate oligomerization of native CtBP and enhance complex formation with E1A.
      CtBP also has a slow dehydrogenase activity. Interaction of CtBP with E1A reduces
      the dehydrogenase activity. Our results raise the possibility that the
      oxidation/reduction reactions of CtBP may regulate transcription. Thus, CtBP is a
      unique transcriptional regulator with an enzymatic activity similar to metabolic
      dehydrogenases. The levels of intracellular nicotinamide adenine dinucleotide may
      modulate transcriptional activity of CtBP.

PMID- 12606050
TI  - Photoreduction of the quinone pool in the bacterial photosynthetic membrane:
      identification of infrared marker bands for quinol formation.
AB  - The photoreduction of the quinone (Q) pool in the photosynthetic membrane of the
      purple bacterium Rhodobacter sphaeroides was investigated by steady-state and
      time-resolved Fourier transform infrared difference spectroscopy. The results are
      consistent with the existence of a homogeneous Q pool inside the chromatophore
      membrane, with a size of around 20 Q molecules per reaction center. IR marker
      bands for the quinone/quinol (Q/QH(2)) redox couple were recognized. QH(2) bands
      are identified at 1491, 1470, 1433 and 1388-1375 cm(-1). The 1491 cm(-1) band,
      which is sensitive to (1)H/(2)H exchange, is assigned to a C-C ring mode coupled
      to a C-OH mode. A feature at approximately 1743/1720 cm(-1) is tentatively
      related to a perturbation of the carbonyl modes of phospholipid head groups
      induced by QH(2) formation. Complex conformational changes of the protein in the
      amide I and II spectral ranges are also apparent during reduction and reoxidation
      of the Q pool.

PMID- 12606051
TI  - Detection of novel truncated forms of human serum amyloid A protein in human
      plasma.
AB  - Serum amyloid A protein (SAA) is a human plasma protein that has been recognized
      as potential biomarker of multiple ailments including myocardial infarction,
      inflammatory disease and amyloiosis. Presented here is the application of a novel
      immunoassay technique, termed mass spectrometric immunoassay for the detection
      and identification of SAA present in human plasma. Results demonstrate the
      ability to readily detect known SAA isotypes, and to identify novel truncated
      forms of SAA, in the plasma of healthy individuals and those suffering from acute
      and chronic inflammation. The approach represents a rapid and sensitive means for
      the routine structural characterization of known SAA isotypes and the discovery
      of associated post-translational modifications.

PMID- 12606053
TI  - Concurrent increase of cholesterol, sphingomyelin and glucosylceramide in the
      spleen from non-neurologic Niemann-Pick type C patients but also patients
      possibly affected with other lipid trafficking disorders.
AB  - Niemann-Pick type C disease (NPC) is a neurovisceral (or, extremely rarely, only
      visceral) lipidosis caused by mutations in the NPC1 gene or, in a few patients,
      the HE1 gene, which encode sterol regulating proteins. NPC is characterised by a
      complex lipid anomaly including a disturbed cellular trafficking of cholesterol
      but also multi-lipid storage in visceral organs and brain. Lipids were studied
      using conventional methods in enlarged spleens that had been removed from five
      patients for different therapeutic and diagnostic reasons and found to have
      microscopic signs of lysosomal storage disease not suspected clinically. The
      spleen lipid findings with a concurrent accumulation of cholesterol,
      sphingomyelin and glucosylceramide (Acc-CSG) allowed us to suggest NPC diagnoses
      for these patients, who were free of neurologic symptoms. From two patients no
      material for confirmatory studies was available, but in two other patients NPC
      diagnoses could be confirmed with the filipin cytochemical cholesterol assay and
      NPC1 gene analysis, respectively. However, these tests and also HE1 gene analysis
      were negative in a third patient. Since the Acc-CSG lipid pattern seems to
      indicate a multi-lipid trafficking defect rather than being highly specific for
      NPC, this patient, if not affected with very atypical NPC, may be a candidate for
      a different lipid trafficking disorder. The Acc-CSG pattern was considered to be
      similar to the lipid pattern known for the lipid rafts, these functional cell
      structures being probably disorganised and accumulated in late endosomes and
      lysosomes of NPC cells.

PMID- 12606052
TI  - Crystal structure of GGA2 VHS domain and its implication in plasticity in the
      ligand binding pocket.
AB  - Golgi-localized, gamma-ear-containing, ARF binding (GGA) proteins regulate
      intracellular vesicle transport by recognizing sorting signals on the cargo
      surface in the initial step of the budding process. The VHS (VPS27, Hrs, and
      STAM) domain of GGA binds with the signal peptides. Here, a crystal structure of
      the VHS domain of GGA2 is reported at 2.2 A resolution, which permits a direct
      comparison with that of homologous proteins, GGA1 and GGA3. Significant
      structural difference is present in the loop between helices 6 and 7, which forms
      part of the ligand binding pocket. Intrinsic fluorescence spectroscopic study
      indicates that this loop undergoes a conformational change upon ligand binding.
      Thus, the current structure suggests that a conformational change induced by
      ligand binding occurs in this part of the ligand pocket.

PMID- 12606054
TI  - Analytical model for determination of parameters of helical structures in
      solution by small angle scattering: comparison of RecA structures by SANS.
AB  - The filament structures of the self-polymers of RecA proteins from Escherichia
      coli and Pseudomonas aeruginosa, their complexes with ATPgammaS, phage M13 single
      stranded DNA (ssDNA) and the tertiary complexes RecA::ATPgammaS::ssDNA were
      compared by small angle neutron scattering. A model was developed that allowed
      for an analytical solution for small angle scattering on a long helical filament,
      making it possible to obtain the helical pitch and the mean diameter of the
      protein filament from the scattering curves. The results suggest that the
      structure of the filaments formed by these two RecA proteins, and particularly
      their complexes with ATPgammaS, is conservative.

PMID- 12606055
TI  - Role of iron and ferritin in TNFalpha-induced apoptosis in HeLa cells.
AB  - We found that tumor necrosis factor alpha (TNFalpha)-induced apoptosis in HeLa
      cells was accompanied by a approximately 2-fold increase in H- and L-ferritin and
      a decrease in transferrin receptor, two indices of increased iron availability.
      Iron supplementation and overexpression of H-ferritin or its mutant with an
      inactivated ferroxidase center reduced by about approximately 50% the number of
      apoptotic cells after TNFalpha-treatment, while overexpression of L-ferritin was
      ineffective. The data indicate that H-ferritin has an anti-apoptotic activity
      unrelated to its ferroxidase activity and to its capacity to modify cellular iron
      metabolism.

PMID- 12606056
TI  - Preproinsulin mRNA engineering and its application to the regulation of insulin
      secretion from human hepatomas.
AB  - Cell-based therapies for treating insulin-dependent diabetes (IDD) can provide a
      more physiologic regulation of blood glucose levels in a less invasive fashion
      than daily insulin injections. Promising cells include non-beta cells genetically
      engineered to secrete insulin in response to physiologic cues; responsiveness can
      be introduced at the transcriptional level to regulate preproinsulin (PPI) mRNA
      biosynthesis. However, these cells exhibit sluggish secretion dynamics, which is
      not appropriate for achieving euglycemia in higher animals and, eventually,
      humans. In this work, we have engineered the PPI mRNA so as to destabilize it
      through nonsense-mediated mRNA decay (NMD). When expressed under transcriptional
      regulation in HepG2 hepatomas, the engineered PPI mRNA level and of the insulin
      secretion rate declined faster upon switching off transcription, compared to the
      one-copy non-engineered control. Our work provides a simple and straightforward
      method to improve the dynamics of transcriptionally regulated insulin secretion,
      which can be a useful tool in developing cell-based therapies for IDD.

PMID- 12606057
TI  - Involvement of three pathogenicity factors of Erwinia amylovora in the oxidative
      stress associated with compatible interaction in pear.
AB  - Erwinia amylovora, the causal agent of fire blight of Maloideae, induces in its
      susceptible host plants an oxidative burst as does an incompatible pathogen. In
      this paper we present evidence that the elicitation of this phenomenon is the
      result of the combined action of two Hrp effectors of the bacteria, HrpN and
      DspA. We also confirmed that desferrioxamine, the siderophore of E. amylovora, is
      necessary for the bacteria to tolerate high levels of hydrogen peroxide. Two
      other pathogenicity factors of the bacteria, the HrpW effector and the capsule,
      do not seem to play any role in the elicitation of the oxidative burst nor in the
      protection of the bacteria.

PMID- 12606059
TI  - Perturbation of protein kinase CK2 uncouples executive part of phosphate
      maintenance pathway from cyclin-CDK control.
AB  - The budding yeast Saccharomyces cerevisiae encounters phosphate starvation by the
      transcription-regulated PHO pathway. We find that genetic perturbation of protein
      kinase CK2, a conserved tetrameric Ser/Thr phosphotransferase with links to cell
      cycle and transcription, affects expression of PHO pathway genes in a subunit-
      and isoform-specific manner. Remarkably, the genes encoding phosphate supplying
      phosphatases and transporters are significantly repressed, while the genes
      encoding components of the central pathway regulator complex, a cyclin-dependent
      kinase (CDK), a cyclin, and a CDK inhibitor, remain unaltered. Thus, perturbation
      of CK2 uncouples the executive part of the PHO pathway from its cyclin-CDK
      control complex.

PMID- 12606060
TI  - Role of molecular chaperones in inclusion body formation.
AB  - Protein misfolding and aggregation are linked to several degenerative diseases
      and are responsible for the formation of bacterial inclusion bodies. Roles of
      molecular chaperones in promoting protein deposition have been speculated but not
      proven in vivo. We have investigated the involvement of individual chaperones in
      inclusion body formation by producing the misfolding-prone but partially soluble
      VP1LAC protein in chaperone null bacterial strains. Unexpectedly, the absence of
      a functional GroEL significantly reduced aggregation and favoured the incidence
      of the soluble protein form, from 4 to 35% of the total VP1LAC protein. On the
      other hand, no regular inclusion bodies were then formed but more abundant small
      aggregates up to 0.05 microm(3). Contrarily, in a DnaK(-) background, the amount
      of inclusion body protein was 2.5-fold higher than in the wild-type strain and
      the average volume of the inclusion bodies increased from 0.25 to 0.38 microm(3).
      Also in the absence of DnaK, the minor fraction of soluble protein appears as
      highly proteolytically stable, suggesting an inverse connection between
      proteolysis and aggregation managed by this chaperone. In summary, GroEL and DnaK
      appear as major antagonist controllers of inclusion body formation by promoting
      and preventing, respectively, the aggregation of misfolded polypeptides. GroEL
      might have, in addition, a key role in driving the protein transit from the
      soluble to the insoluble cell fraction and also in the opposite direction.
      Although chaperones ClpB, ClpA, IbpA and IbpB also participate in these
      processes, the impact of the respective null mutations on bacterial inclusion
      body formation is much more moderate.

PMID- 12606058
TI  - Molecular cloning and characterization of TPP36 and its isoform TPP32, novel
      substrates of Abl tyrosine kinase.
AB  - We have molecularly cloned TPP36, a novel 36 kDa protein with 281 amino acids
      that was identified as a protein phosphorylated in B progenitor cells following
      stimulation with pervanadate/H(2)O(2). Analysis with anti-TPP36 antiserum
      revealed that TPP36 was expressed ubiquitously and had an isoform with 236 amino
      acids, designated TPP32. TPP36/32 were localized mainly in cytoplasm despite the
      presence of a typical nuclear localization signal sequence. These proteins were
      phosphorylated preferentially by Abl among a panel of tyrosine kinases examined.
      Phosphorylation of tyrosine 120 in TPP36/32 led to an apparent mobility shift in
      sodium dodecyl sulfate-polyacrylamide gel electrophoresis, suggesting
      conformational change in the phosphorylated protein. Thus, TPP36/32 appear to be
      novel substrates of Abl tyrosine kinase.

PMID- 12606061
TI  - A surface EMG electrode for the simultaneous observation of multiple facial
      muscles.
AB  - With previous surface electromyography (sEMG) electrodes it has been difficult to
      combine small outer dimensions and secure skin attachment. We resolved this
      problem by developing a new skin attachment technique that yields firm electrode
      fixation without requiring an acrylic housing. Consequently, we could reduce the
      outer electrode dimensions to 4-mm diameter and only 1.5-mm thickness. In a
      bipolar montage, this electrode allows an inter-electrode distance of 8 mm. This
      improves measurement selectivity and, because of the small dimensions, makes
      possible the non-invasive observation of multiple facial muscles with a minimum
      of obstruction. Our new technique was tested on a group of 11 professional
      trumpeters. They were instructed to perform a series of muscle-specific facial
      poses and to play exercises on their instruments while EMG signals were recorded
      simultaneously from seven different perioral muscles. Although the skin
      attachment was subjected to high stress during trumpet playing, more than 98% of
      electrode placements yielded a secure mechanical and electrical connection.
      Muscle selectivity of the signals recorded during the facial poses was similar to
      that obtained in a previous investigation using intra-muscular fine-wire
      electrodes. Crosstalk in the perioral area was estimated to be lower than 25%.
      The availability of an unobstructive sEMG electrode for simultaneously observing
      multiple facial muscles opens up a wide range of applications (e.g. in speech
      research, psychophysiology and orthodontics).

PMID- 12606062
TI  - Visual and electrical evoked response recorded from subdural electrodes implanted
      above the visual cortex in normal dogs under two methods of anesthesia.
AB  - Sensitive methods are required to record electrical evoked potentials over the
      visual cortex to evaluate the efficacy and safety of a retinal prosthesis before
      it can be implanted on the retinal surface of patients afflicted by outer retinal
      diseases. This study was designed to examine subdural electrodes as a mean to
      evaluate cortical evoked potentials in response to light and electrical
      stimulation of the retina in three dogs under two methods of anesthesia-halothane
      and propofol. Results showed that subdural electrodes could be stabilized over
      the visual cortex for several (3-5) months, and that they were 6.95 times more
      sensitive than subdermal electrodes in recording cortical visual evoked
      potentials (VEPs) and 4.31 times more sensitive in recording cortical electrical
      evoked potentials under both methods of anesthesia. The waveforms' shape changed
      for each electrode in the subdural array during 6/6 (100%) and 20/38 (52%) multi
      channel recording sessions under halothane and propofol, respectively. This
      change could point to a cortical retinotopic organization versus hierarchical
      organization of different cortical areas for a given retinal stimulus. In
      summary, subdural electrodes show promising results for recording visual and
      electrical evoked responses (EERs) and thus for evaluation of the retinal
      prosthesis.

PMID- 12606063
TI  - Functional imaging of the retinal layers by laser scattering: an approach for the
      study of Leao's spreading depression in intact tissue.
AB  - This paper presents a novel optical approach for the study of spreading
      depression in isolated retina. The method makes it possible to register the laser
      light scattered from each layer of the tissue, yielding a functional image of the
      retina during spreading depression. The tissue is kept intact, since histological
      cuts are not necessary. Measurements of other variables, such as extracellular
      potential, are also allowed by the described method. This is done simultaneously
      with the functional image in a high spatial resolution, with the positioning of
      the microelectrode tip being easily monitored. The information about temporal and
      spatial evolution of light was compacted in a single image. The image-processing
      technique used here enables the visualization of the light scattered by the inner
      plexiform layer (IPL), which is the most prominent scatter layer during spreading
      depression. The wavefront velocity and its increase as two wavefronts approach
      each other can then be determined, and it is also possible to observe the
      thickness variation of the tissue during the wave travel. The relationship
      between two peaks of light-scattering sequence during the phenomenon was studied
      at two wavelengths (632.8 and 543.5 nm). This relationship is shown to be
      dependent on the wavelength.

PMID- 12606064
TI  - The motion reverse correlation (MRC) method: a linear systems approach in the
      motion domain.
AB  - We introduce the motion reverse correlation method (MRC), a novel stimulus
      paradigm based on a random sequence of motion impulses. The method is tailored to
      investigate the spatio-temporal dynamics of motion selectivity in cells
      responding to moving random dot patterns. Effectiveness of the MRC method is
      illustrated with results obtained from recordings in both anesthetized cats and
      an awake, fixating macaque monkey. Motion tuning functions are computed by
      reverse correlating the response of single cells with a rapid sequence of
      displacements of a random pixel array (RPA). Significant correlations between the
      cell's responses and various aspects of stimulus motion are obtained at high
      temporal resolution. These correlations provide a detailed description of the
      temporal dynamics of, for example, direction tuning and velocity tuning. In
      addition, with a spatial array of independently moving RPAs, the MRC method can
      be used to measure spatial as well as temporal receptive field properties. We
      demonstrate that MRC serves as a powerful and time-efficient tool for quantifying
      receptive field properties of motion selective cells that yields temporal
      information that cannot be derived from existing methods.

PMID- 12606065
TI  - Magnetic cell sorting for enriching Schwann cells from adult mouse peripheral
      nerves.
AB  - We have devised a simple method to purify mitotically active Schwann cells (SC)
      from peripheral nerves of adult mice. Nerves were predegenerated in vitro for 7
      days and after dissociation cells were plated on poly-L-lysine/laminin coated
      dishes in N2 serum-free culture medium supplemented with forskolin and heregulin
      beta1. Primary cultures were purified from contaminating fibroblasts by magnetic
      cell sorting (MACS) based on SC membrane specific expression of p75(NGFR) and
      enriched to about 99% of SC after MACS from 34 to 91% before sorting. After
      sorting, purified adult mouse SC were propagated for three passages until
      confluent to a total surface of 160 cm(2) per mouse (two sciatic and two
      trigeminal nerves). In addition, we show that this method can be used to purify
      tumoral SC from mouse NF2-related schwannomas.

PMID- 12606066
TI  - A simple measure of correlation across time, frequency and space between
      continuous brain signals.
AB  - This paper introduces a simple but systematic method to estimate correlations
      between the spectral energy of two continuous electrophysiological signals in
      such a way that it can detect relationships between different frequencies and
      different latencies. From two series of signals (e.g. electroencephalogram,
      magnetoencephalogram or local field potentials) recorded from two sites in
      response to repeated sensory stimulations, the method computes the time-frequency
      energy of each signal. Then, it computes the Spearman rank order correlation
      coefficient across all the trials between the energy of the first signal series
      in one time-frequency region and the energy of the second signal series in a
      second time-frequency region. The method was designed to analyze interactions
      between frequency bands, in an effort to describe how the main brain rhythms
      interact with each other across time and space. It was applied to two simulations
      and to intracranial electro-encephalogram (EEG) recordings obtained from an
      epileptic patient performing two verbal discrimination tests (a phonological and
      a semantic task). It led to the identification of different correlations patterns
      in the gamma band depending on the level of semantic analysis performed by the
      patient.

PMID- 12606067
TI  - Grid performance test to measure behavioral impairment in the MPTP-treated-mouse
      model of parkinsonism.
AB  - Behavioral impairments in mice following administration of the dopaminergic
      neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) require large
      depletions in striatal dopamine content and are often transient. In this paper,
      we describe a simple and inexpensive test that measures long-term behavioral
      deficits in mice treated with moderate doses of MPTP. These measures are
      significantly correlated with the loss of striatal dopamine and immunoreactivity
      of the dopamine transporter, vesicular monoamine transporter and tyrosine
      hydroxylase. In addition, behavioral impairments on the measures were reversed
      following L-DOPA administration. Employment of this test will allow for more
      efficacious use of mice in PD research, as well as provide more sensitive
      measures of behavioral improvement following potential therapeutic or
      neuroprotective interventions.

PMID- 12606068
TI  - Traumatic brain injury in piglets of different ages: techniques for lesion
      analysis using histology and magnetic resonance imaging.
AB  - Quantitation of lesions in large gyrencephalic brains presents a variety of
      technical challenges. Specific techniques are required when comparing lesions in
      subjects of different ages in order to assess maturational effects. We have
      modified existing techniques to attain reliable, consistent and reproducible
      paraffin-embedded histological sections for volumetric lesion analysis and
      correlation with magnetic resonance imaging (MRI) in piglets of different ages
      following focal traumatic brain injury. Twenty-four Yorkshire domestic piglets at
      three different ages (5 days, 1 month, and 4 months old) underwent scaled
      cortical impact injury to the fronto-parietal cortex. This contusion model
      utilizes a rapid volume of indentation scaled proportionally to the growth of the
      brain, allowing for examination of maturational influences on the brain's
      response to focal mechanical trauma. To overcome problems with differential
      processing and embedding of brains ranging from 43 to 107 g, we developed a
      piglet parallel brain slicing apparatus. Along with specific methods for
      processing, embedding, mounting, and slide preparation, these techniques enabled
      excellent quality 10-microm serial coronal sections to be obtained for histology
      and immunohistochemical analysis. Accurate co-registration of histologic,
      immunohistochemical and radiologic images at different ages was possible, which
      may enhance understanding of developmental aspects of brain injury
      pathophysiology.

PMID- 12606069
TI  - A robust, efficient and flexible method for staining myelinated axons in blocks
      of brain tissue.
AB  - Previous studies have demonstrated the utility of the gold chloride method for en
      bloc staining of a bisected brain in mice and rats. The present study explores
      several variations in the method, assesses its reliability, and extends the
      limits of its application. We conclude that the method is very efficient, highly
      robust, sufficiently accurate for most purposes, and adaptable to many
      morphometric measures. We obtained acceptable staining of commissures in every
      brain, despite a wide variety of fixation methods. One-half could be stained 24 h
      after the brain was extracted and the other half could be stained months later.
      When staining failed because of an exhausted solution, the brain could be stained
      successfully in fresh solution. Relatively small changes were found in the sizes
      of commissures several weeks after initial fixation or staining. A half brain
      stained to reveal the mid-sagittal section could then be sectioned coronally and
      stained again in either gold chloride for myelin or cresyl violet for Nissl
      substance. Uncertainty, arising from pixelation of digitized images was far less
      than errors arising from human judgments about the histological limits of major
      commissures. Useful data for morphometric analysis were obtained by scanning the
      surface of a gold chloride stained block of brain with an inexpensive flatbed
      scanner.

PMID- 12606070
TI  - A simple method for reconditioning epoxy-coated microelectrodes for extracellular
      single neuron recording.
AB  - Epoxy-insulated tungsten microelectrodes can be used once or twice in our lab
      before the impedance becomes too low. Dipping the electrodes in epoxy followed by
      curing restores their initial high impedance which is associated with good
      isolation of single neurons. It is a cost effective and simple procedure.

PMID- 12606071
TI  - The extent of codon usage bias in human RNA viruses and its evolutionary origin.
AB  - Revealing the determinants of codon usage bias is central to the understanding of
      factors governing viral evolution. Herein, we report the results of a survey of
      codon usage bias in a wide range of genetically and ecologically diverse human
      RNA viruses. This analysis showed that the overall extent of codon usage bias in
      RNA viruses is low and that there is little variation in bias between genes.
      Furthermore, the strong correlation between base and dinucleotide composition and
      codon usage bias suggested that mutation pressure rather than natural
      (translational) selection is the most important determinant of the codon bias
      observed. However, we also detected correlations between codon usage bias and
      some characteristics of viral genome structure and ecology, with increased bias
      in segmented and aerosol-transmitted viruses and decreased bias in vector-borne
      viruses. This suggests that translational selection may also have some influence
      in shaping codon usage bias.

PMID- 12606073
TI  - Characterization of the caprine arthritis encephalitis virus (CAEV) rev N
      terminal elements required for efficient interaction with the RRE.
AB  - The Caprine Arthritis Encephalitis Virus (CAEV) genome encodes three structural
      (gag, pol, and env) and three accessory (rev, tat, and vif) genes. The Rev-C
      protein regulates Gag, Pol and Env expression by transporting their mRNAs to the
      cytoplasm. Rev trans-activation requires binding of Rev to an RNA structure
      called the Rev Response Element (RRE-C). Previous mutational analyses have shown
      that two domains of Rev are required for its function. The basic domain mediates
      RRE binding and multimer formation, and the nuclear export signal (NES) mediates
      trans-activation. Preliminary experiments demonstrate that Rev-C N-terminal
      deletion mutants bind the RRE less avidly than does wildtype Rev. As a result, it
      was hypothesized that an additional domain located in the N-terminal exon of Rev
      C was required for optimal RRE binding. To test this hypothesis, Rev-C alanine
      scanning mutants were generated and in vitro RRE binding assays were performed.
      Alteration of Rev-C amino acids K13, E14, N15, V19, T20, M21 and R27 dramatically
      decreased affinity for RRE-C. These data demonstrate that Rev-C N-terminal amino
      acids are required for optimal RRE-C binding and suggest that a third functional
      domain exists within the N-terminus of Rev-C.

PMID- 12606072
TI  - Reciprocal effects of varicella-zoster virus (VZV) and AP1: activation of jun,
      fos and ATF-2 after VZV infection and their importance for the regulation of
      viral genes.
AB  - Varicella-zoster virus, an alpha-herpesvirus that is pathogenic for man, encodes
      its own transcription activators, but ubiquitous cellular transcription factors
      are of great importance, too. Performing quantitative reverse transcriptase
      polymerase chain reaction (RT-PCR) we found an increase of transcription of AP1
      components jun, fos and of ATF-2 at different times post infection (p.i.). Jun
      and ATF-2 proteins were detected in infected cells. To study general effects of
      AP1 in the regulation of VZV encoded genes, oligonucleotide transfections were
      performed to knockout jun and ATF-2 transcription followed by infection with cell
      free VZV. RT-PCR analyses of ORFs 4, 9, 21, 29 and 68 belonging to all three
      kinetic classes of genes and containing different combinations of AP1/TRE and
      ATF/CREB sites in their respective promoters were carried out. In all cases a
      reduction of viral transcription was found. Virions produced after this procedure
      were still infectious, but the amount of newly synthesized virions was clearly
      reduced.

PMID- 12606074
TI  - Non-covalent interaction between nucleocapsid protein of Tula hantavirus and
      small ubiquitin-related modifier-1, SUMO-1.
AB  - To find cellular binding counterparts for the nucleocapsid protein (N) of Tula
      hantavirus (TULV), two cDNA libraries were screened using yeast two-hybrid
      systems based on LexA and Gal4 transcription factors. Five cDNA clones encoding
      SUMO-1 (Small Ubiquitin-related MOdifier, also known as sentrin) were selected in
      the LexA system. Confocal microscopy revealed that, in infected cells, TULV N
      protein and SUMO-1 colocalize at the perinuclear area providing further evidence
      for interaction between the two proteins. Neither endogenous nor transiently
      expressed SUMO-1 was found to be covalently linked to the N protein. Additional
      evidence that the interaction is non-covalent was obtained in immunoprecipitation
      experiments: N protein-specific antibodies precipitated SUMO-1 from TULV-infected
      Vero E6 cell lysate. By using a pepscan assay, two basic amino acid stretches in
      the N-terminal part of SUMO-1 were shown to be involved in the interaction.

PMID- 12606075
TI  - Efficient replication of cloned African cassava mosaic virus in cassava leaf
      disks.
AB  - A transient viral replication assay for cloned African cassava mosaic virus
      (ACMV) was developed using cassava leaf disks. TMS60444 leaf disks were
      transfected using biolistic-mediated inoculation with ACMV clones pKACMVA and
      pKACMVB, which originate from West Kenya ACMV isolate 844 (ACMV-KE). Viral DNA
      synthesized de novo was monitored by Southern hybridization with an AV1 DNA
      probe. By using the methylation-sensitive restriction enzymes DpnI and MboI, it
      was possible to distinguish between the input DNA (dam-methylated) and the de
      novo synthesized viral DNA (not methylated). Different media used for pre- and
      post-culture of inoculated leaf disks significantly affected the efficiency of
      viral DNA accumulation. Without pre-culture, replicated viral DNA was not
      detectable. Culture time in optimized medium also affected the accumulation of
      nascent viral DNA, and the best results were obtained after 4 days pre-culture on
      CIM medium followed by 4-6 days post-culture in SH medium. Time-course analysis
      showed that viral DNA replication can persist for 5-6 days post-inoculation. Our
      results also confirmed that DNA B of ACMV could assist the accumulation of viral
      DNA in the leaf disks. The novel protocol described here has also been used
      successfully with other cassava cultivars (MCol22, MCol1505, TME282 and
      TMS92/0326) and ACMV clones from the ACMV Nigeria isolate (ACMV-NOg).

PMID- 12606076
TI  - Sites of phosphorylation of P and V proteins from Hendra and Nipah viruses: newly
      emerged members of Paramyxoviridae.
AB  - Hendra (HeV) and Nipah (NiV) viruses are newly emerged, zoonotic viruses and
      their genomes have nucleotide and predicted amino acid homologies placing them in
      the subfamily Paramyxoviridae. The polymerase-associated phosphoproteins (P
      proteins) of paramyxoviruses have been shown, by direct and indirect methods, to
      be highly phosphorylated. In this study, a comprehensive comparison of in vivo
      phosphorylation of HeV and NiV P proteins, derived from virus particles, was
      achieved by a direct approach using electrospray ionization ion trap mass
      spectrometry (ESI-IT-MS). Phosphorylation sites for the P proteins were
      determined at Ser-224 and Thr-239 in HeV and at Ser-240 and Ser-472 in NiV. These
      phosphorylation patterns do not appear to be consistent with those reported for
      other paramyxoviruses. Protein V, a product of a frame shift in the P protein
      gene, was identified by specific antibodies in HeV preparations but not in NiV.
      HeV V protein was found to contain phosphoserine but not phosphothreonine. In
      addition, P proteins from both viruses were found to be modified by N-terminal
      acetylation.

PMID- 12606077
TI  - Genetic diversity of ruminant pestiviruses from Spain.
AB  - The genetic diversity of ruminant pestiviruses from Spain was investigated by
      sequencing analysis of the 5' non-coding region (5'NCR) from 10 ovine and 41
      bovine samples collected along 4 years (1999-2002) from different farms. The
      5'NCR amplicons generated by a one-tube RT-PCR using primers 324/326 were
      sequenced and phylogenetically analyzed. When compared with strains from GenBank
      database, Spanish viruses clustered into three genotypes: BVDV 1, BDV and CSFV.
      No BVDV 2 strains were identified. The 41 bovine samples were all BVDV 1
      genotype, but they were further subdivided into subgroups 1b (35) and 1e (6).
      There was no apparent association between the genotype and clinical symptoms, or
      the geographic area of origin. However, subgroup 1e has been recently described
      for isolates from France and, interestingly, subgroup 1e viruses were collected
      from areas close to the French border. Nine of the ten ovine samples formed a
      tight cluster within BDV type but clearly differed from BDV subgroups A and B
      sustaining the need to define a new subgroup as BDV-C in which these ovine
      strains would be included. Finally, although further studies are needed, the
      grouping of an ovine sample with CSFV strains would be the first description of a
      CSFV genotype for ovine pestiviruses.

PMID- 12606078
TI  - Budding and secretion of HIV Gag-Env virus-like particles from recombinant human
      adenovirus infected cells.
AB  - We have characterized the assembly, budding and extra-cellular release of human
      immunodeficiency virus (HIV) Gag-Env virus-like particles (VLPs) from human
      embryonic kidney cells (293 cells expressing the E1a protein of adenovirus)
      infected with recombinant replication-defective human adenovirus type 5.
      Recombinant human adenovirus vectors expressing the chimeric Gag-Env protein were
      constructed by inserting the gag-env fusion gene into the E1a region of the human
      adenovirus type 5. Biochemical and immunological analyses of VLPs recovered from
      the culture supernatant revealed that these particles contain the HIV-2 Gag
      protein and segments of Env protein from the HIV-1 gp120. This chimeric Gag-Env
      protein interacted with HIV-1 positive patient sera and with HIV-2 Gag monoclonal
      antibody. Immunoelectron microscopy of the 293 cells infected with the
      recombinant adenoviruses showed that the HIV Gag-Env antigen is present in the
      VLPs. Thin-section electron microscopy (EM) revealed that the Gag-Env VLPs bud
      through the cytoplasmic membrane, as well as through membranes of intracellular
      vacuoles. The thin-section EM showed that the Gag-Env VLPs have a spherical
      morphology with an electron-dense ring. The size of VLPs range from 110 to 140 nm
      in diameter, which is slightly larger than that of the Gag particles without Env
      protein fusion. Mice immunized with recombinant adenoviruses generated antibodies
      that specifically reacted with Gag-Env chimeric proteins. Our results support the
      idea that the replication-defective adenovirus could be used to induce immune
      responses that might be useful in a vaccine against HIV/AIDS.

PMID- 12606079
TI  - Glucocorticoid regulation of lactate dehydrogenase-elevating virus replication in
      macrophages.
AB  - Lactate dehydrogenase-elevating virus (LDV) is a macrophage-tropic arterivirus
      which generally causes a persistent viremic infection in mice. LDV replication in
      vivo seems to be primarily regulated by the extent and dynamics of a virus
      permissive macrophage population. Previous studies have shown that glucocorticoid
      treatment of chronically LDV-infected mice transiently increases viremia 10-100
      fold, apparently by increasing the productive infection of macrophages. We have
      further investigated this phenomenon by comparing the effect of dexamethasone on
      the in vivo and in vitro replication of two LDV quasispecies that differ in
      sensitivity to immune control by the host. The single neutralizing epitope of LDV
      P is flanked by two N-glycans that impair its immunogenicity and render LDV-P
      resistant to antibody neutralization. In contrast, replication of the
      neuropathogenic mutant LDV-C is suppressed by antibody neutralization because its
      epitope lacks the two protective N-glycans. Dexamethasone treatment of mice 16 h
      prior to LDV-P infection, or of chronically LDV-P infected mice, stimulated
      viremia 10-100-fold, which correlated with an increase of LDV permissive
      macrophages in the peritoneum and increased LDV infected cells in the spleen,
      respectively. The increase in viremia occurred in the absence of changes in total
      anti-LDV and neutralizing antibodies. The results indicate that increased viremia
      was due to increased availability of LDV permissive macrophages, and that during
      a chronic LDV-P infection virus replication is strictly limited by the rate of
      regeneration of permissive macrophages. In contrast, dexamethasone treatment had
      no significant effect on the level of viremia in chronically LDV-C infected mice,
      consistent with the view that LDV-C replication is primarily restricted by
      antibody neutralization and not by a lack of permissive macrophages. beta-Glucan,
      the receptor of which is induced on macrophages by dexamethasone treatment, had
      no effect on the LDV permissiveness of macrophages.

PMID- 12606080
TI  - Elucidation of Nipah virus morphogenesis and replication using ultrastructural
      and molecular approaches.
AB  - Nipah virus, which was first recognized during an outbreak of encephalitis with
      high mortality in Peninsular Malaysia during 1998-1999, is most closely related
      to Hendra virus, another emergent paramyxovirus first recognized in Australia in
      1994. We have studied the morphologic features of Nipah virus in infected Vero E6
      cells and human brain by using standard and immunogold electron microscopy and
      ultrastructural in situ hybridization. Nipah virions are enveloped particles
      composed of a tangle of filamentous nucleocapsids and measured as large as 1900
      nm in diameter. The nucleocapsids measured up to 1.67 microm in length and had
      the herringbone structure characteristic for paramyxoviruses. Cellular infection
      was associated with multinucleation, intracytoplasmic nucleocapsid inclusions
      (NCIs), and long cytoplasmic tubules. Previously undescribed for other members of
      the family Paramyxoviridae, infected cells also contained an inclusion formed of
      reticular structures. Ultrastructural ISH studies suggest these inclusions play
      an important role in the transcription process.

PMID- 12606081
TI  - Isolation and characterisation of segment 1 of the infectious salmon anaemia
      virus genome.
AB  - The isolation and characterisation of the largest genomic segment of infectious
      salmon anaemia virus (ISAV) is reported. Following identification of ISAV
      specific clones from a cDNA library, a rapid amplification of cDNA ends-PCR
      strategy was designed to obtain the sequence of the full length mRNA transcript.
      The full length open reading frame (ORF) of this gene was shown to be 2169
      nucleotides in length, encoding a putative protein of 722 aa. This sequence was
      demonstrated by RT-PCR to be specific to ISAV-infected cell cultures. The start
      codon of this ORF was preceded by the ISAV consensus sequence 5' GCTAAGA 3'
      indicating the full 5' end of the gene to have been obtained. Based on protein
      size and amino acid composition, this protein was shown to be similar to the PB2
      protein of other orthomyxoviruses. Furthermore, a bipartite nuclear localisation
      signal was identified in the C-terminus of the protein as is found on all of the
      influenza virus P proteins. Expression of the putative PB2 as a green fluorescent
      marker protein-fusion protein confirmed that this protein exhibited nuclear
      localisation in a fish cell line. Sequences of the ISAV segment 1 gene were
      obtained from Scottish, Norwegian and Canadian ISAV isolates. Analyses confirmed
      the close genetic relationship between Norwegian and Scottish ISAV and indicated
      that this segment was among the most conserved of the ISAV genes identified to
      date. Thus, this evidence strongly suggests that the genomic segment 1 of ISAV
      encodes a polymerase protein which is thought to be analagous in function to the
      PB2 protein of influenza viruses.

PMID- 12606082
TI  - Functional interaction between Cydia pomonella granulovirus IAP proteins.
AB  - Cydia pomonella granulovirus (CpGV) encodes for three inhibitor of apoptosis
      (IAP) proteins. One of them, CpIAP3, was previously identified based on its
      capacity to substitute for the p35 gene in blocking Autographa californica
      nucleopolyhedrovirus (AcMNPV)-induced apoptosis in SF21 cells. In this paper, the
      function of the other two CpGV IAP proteins, Cp94 and CpIAP5, was studied.
      Neither Cp94 nor CpIAP5, independently or together, can block actinomycin D
      induced apoptosis in transient expression experiments. However, CpIAP5 has a
      significant stimulatory effect on the ability of CpIAP3 to block apoptosis. The
      mechanism of this stimulation remains to be elucidated. This is the first
      evidence of functional interactions between IAPs encoded by a single baculovirus.

PMID- 12606083
TI  - Sequence and phylogenetic analysis of genome segments S1, S2, S3 and S6 of Mal de
      Rio Cuarto virus, a newly accepted Fijivirus species.
AB  - Mal de Rio Cuarto virus (MRCV) is a newly described species of the genus
      Fijivirus, family Reoviridae. The nucleotide sequence of four MRCV genome
      segments was determined. MRCV S1, S2, S3 and S6 were predicted to encode proteins
      of 168.4, 134.4, 141.7 and 90 kDa, respectively. MRCV S1 encodes a basic protein
      that contains conserved RNA-dependent RNA polymerase motifs, and is homologous to
      Rice black streaked dwarf virus (RBSDV), Fiji disease virus (FDV) and Nilaparvata
      lugens reovirus (NLRV) polymerases as well as to corresponding proteins of
      members of other genera of the Reoviridae. MRCV S2 codes for a protein with
      intermediate homology to the ones coded by RBSDV S4 and FDV S3 'B' spike, which
      is presumably the B-spike protein. MRCV S3 most probably encodes the major core
      protein and is highly homologous to corresponding proteins of RBSDV S2 and FDV
      S3. MRCV S6-encoded protein has low homology to the proteins of unknown function
      coded by RBSDV S6 and FDV S6. The identity levels between all analyzed MRCV coded
      proteins and their RBSDV counterparts varied between 84.5 and 44.8%. The analysis
      of the reported sequences allowed a phylogenetic comparison of MRCV with other
      reovirus and supported its taxonomic status within the genus.

PMID- 12606086
TI  - New Dimensions in Hydatidology in the New Millennium. Proceedings of the 20th
      International Congress of Hydatidology. June 4-8, 2001, Kusadasi, Turkey.

PMID- 12606087
TI  - Past to present: echinococcosis in Turkey.
AB  - Echinococcosis is a zoonotic infection caused by Echinococcus spp. and is one of
      the most important helminthic diseases worldwide. Two forms of echinococcosis
      occur in Turkey, i.e. Echinococcus granulosus and E. multilocularis. The life
      cycle of E. granulosus is predominantly in dogs and sheep, and most sheep farmers
      in Turkey keep a dog or two. Stray dogs are numerous and prevention or treatment
      of infection in these dogs is very difficult. Cystic echinococcosis (CE) occurs
      throughout Turkey whereas alveolar echinococcosis (AE) predominantly occurs in
      the eastern Anatolian region of the country. Both CE and AE are known to be
      endemic but few surveys have been performed. Most data on human CE and AE have
      been collected from hospital records. The first reference of echinococcosis,
      "Kyste hydatique multiloculaire", in Turkey dates as far back to 1872 by an
      Ottoman Physician, C.R. Katibian. The results of the first Turkish study on E.
      granulosus were published in 1928. According to Ministry of Health records, 21303
      patients had operations to treat or confirm CE in the period 1987-1994 which
      corresponds to approximately 2663 patients per year. The estimated surgical case
      rate of CE is 0.87-6.6 per 100000 in Turkey. The prevalence of E. granulosus
      infection in dogs in Turkey is between 0.32 and 40% and varies widely with
      geographical location. The reported prevalence of CE in domestic animals in
      Turkey has ranged from 11.2 to 50.7% and has varied widely with geographical
      location. Although no detailed information has been published on AE in domestic
      and wild animals in Turkey, the main definitive and intermediate hosts of E.
      multilocularis are assumed to be rodents and red foxes, respectively. However,
      there has been only a single published report of E. multilocularis in a wild
      animal (fox) in the northwest in 1965 by Merdivenci. The first human case of AE
      in Turkey was reported by Mutlu in 1939, and total cumulative reported case
      number is 202 between 1980 and 1998.

PMID- 12606088
TI  - Economic effects of echinococcosis.
AB  - Cystic echinococcosis (CE) has a number of important economic effects. The most
      tangible of these is the cost of expensive medical treatment for human cases.
      Each confirmed case of CE can cost the health services or individual several
      thousand dollars. In addition to these costs, the additional cost of loss of
      edible offal from agricultural animals is well known. This may result in the
      entire loss of an infected organ or at least the trimming and downgrading of that
      organ, depending on local legislature. However, these losses may only be a
      relatively small percentage of the economic losses attributed to CE. Recent
      evidence suggests, through quality of life surveys, that patients treated for CE
      never fully recover and have a significant and permanent decreased quality of
      life. This has yet to be translated into monetary terms, but it almost certainly
      will result in the loss of income, possibly through a lower paid job, and/or the
      additional expense of increased ill health. Furthermore, in most reports, between
      1 and 2% of CE cases are fatal. The death of these individuals results in the
      loss of the potential lifetime's economic output of these individuals. With
      alveolar echinococcosis the mortality rate is much higher and such consequences
      more severe. There is also a considerable amount of Soviet literature, and small
      amounts published elsewhere which suggests that CE also significantly affects
      animal productivity. Thus, infected sheep tend to give birth to fewer lambs, have
      lower levels of food conversion, produce less milk and have poorer quality
      fleeces then non-infected sheep. The total cost of the disease is the sum of the
      various costs to the health services, costs of morbidity and losses in animal
      productivity. Due to the uncertainty of many of these costs, it is appropriate to
      model these losses using techniques that can give a range of cost estimates. By
      using analytical techniques such as Monte-Carlo analysis, on parameters that are
      difficult to determine accurately, all such variables can be randomly varied
      simultaneously along likely frequency distributions. The results of this give a
      useful sensitivity analysis of economic costs. In addition, the purchasing power
      of money in the local economy must also be taken into account. One US $ buys much
      more in a developing country than in an industrialized economy. Consequently,
      each lost $ will be more acutely felt in poor countries. Estimates of the
      financial burden of disease are beneficial in deciding priorities for control.
      They are also potentially useful tools to lobby donors or non-governmental
      organizations to fund control programs in poor countries.

PMID- 12606089
TI  - The ambiguous role of immunity in echinococcosis: protection of the host or of
      the parasite?
AB  - In Echinococcus infection, at the metacestode stage, studies of the immune
      responses in the experimental murine model as well as in humans have shown that
      (1) cellular immunity induced by a Th1-type cytokine secretion was able to
      successfully kill the metacestode at the initial stages of development; (2)
      antigenic proteins and carbohydrates (and perhaps non-antigenic, mitogenic
      components) of the oncosphere/metacestode were able to interfere with antigen
      presentation and cell activation so that host lymphocytes and other immune cells
      could produce cytokines (especially IL-10) and other mediators able to inhibit
      the effector phase of cellular immune reaction; and (3) immunogenetic
      characteristics of the host were essential to this parasite-induced deviation of
      the immune response. In E. multilocularis infection, a combined Th1 and Th2
      cytokine profile appears crucial for prolonged metacestode growth and survival.
      It may be hypothesized that Th1 cytokines promote the initial cell recruitment
      around the metacestode and are involved in the chronicity of the cell infiltrate
      leading to a fully organized periparasitic granuloma and its consequences,
      fibrosis and necrosis. The Th2 cytokines, on the other hand, could be responsible
      for the inhibition of a successful parasite killing especially because of the
      'anti-inflammatory' potency of IL-10. This combination of various arms of the
      immune response results in a partial protection of both Echinococcus metacestode
      and host. However, it may also be considered responsible for several
      complications of the disease. The Th2-related IgE synthesis and mast cell
      activation, well known to be responsible for anaphylactic reactions in cystic
      echinococcosis, are more rarely involved in 'allergic' complications in alveolar
      echinococcosis (AE). However, the partial but chronic effects of the efficient
      Th1-related cellular immune response are responsible for cytotoxic events which
      both help metacestode growth and dissemination and lead to the central necrosis
      of the lesions and clinical complications of AE. Moreover, the Th-1 response is
      responsible for the major and irreversible fibrosis which leads to bile duct and
      vessel obstruction. In addition, the peri-parasitic fibrosis may be one of the
      reasons for the relative lack of efficacy of antiparasitic drugs. Modulation of
      the host immune response, by using Interferon alpha for instance, may be a new
      tool to generate an effective immune response against the parasite and to prevent
      AE and its complications.

PMID- 12606090
TI  - Progress in control of hydatidosis using vaccination--a review of formulation and
      delivery of the vaccine and recommendations for practical use in control
      programmes.
AB  - A vaccine to protect sheep, goats, and bovines against hydatid disease caused by
      the cysts of Echinococcus granulosus is prepared as a recombinant fusion protein
      expressed in Escherichia coli. Solubilised inclusion bodies are injected,
      together with Quil A, subcutaneously on two occasions 1 month or more apart, and
      induce protection against infection which lasts for at least 12 months. A third
      injection given 6-12 months after the second injection induces a high and long
      lasting protection against artificial or natural challenge infections. This
      review describes work carried out on the formulation, safety and efficacy of the
      vaccine under laboratory and field conditions, using artificial or natural
      challenges with E. granulosus eggs, followed by necropsy. Hydatid control
      programmes based on regular treatment of all dogs with the correct dose of a
      highly-efficient anthelmintic have sometimes not been successful in Continental
      environments. Access to dogs is difficult in summer because of the distances to
      summer pastures, and is often impossible in winter because of snow. A control
      program using strategic twice-yearly anthelmintic treatment of dogs is likely to
      be successful provided grazing animals are vaccinated as well. Vaccination as a
      control tool only requires the veterinarians to visit two times a year, and while
      the veterinarian is present, the dogs can be treated with anthelmintic for little
      additional cost. One visit should take place after the autumn kill of animals for
      winter consumption, and this is a good time to vaccinate animals born in the
      summer, and also all other animals while they are healthy and immunologically
      responsive. The other visit should take place in the spring, at which time
      animals born during winter can be vaccinated. Although a single immunization has
      been shown to induce a useful degree of protection, where possible it is best to
      give two initial injections, 1 month apart. If it is possible for veterinarians
      to stay in the field for 2 months in November/December and March/April, in order
      to give the two injections, a more rapid onset of full protective immunity will
      initially be achieved than if the injections are given 6 months apart. A large
      scale safety and efficacy trial involving 50,000 and 100,000 lambs in Qinghai and
      Xinjiang Provinces of China has taken place. Results have confirmed safety and
      efficacy. In most countries, prevalence of infection increases with age. The
      vaccine has no effect on established cysts, and therefore, in order to prevent
      the biomass of Echinococcus spp. from increasing, it might be an effective
      strategy to begin a control programme by vaccinating all animals. Because many of
      the older stock will already be infected, they will remain a source of infection
      for dogs for the average lifetime of the stock. Dogs will still be able to be
      infected from the older stock, and will continue to infect humans. We advocate
      that a vaccination programme be accompanied by education about hydatid disease,
      and anthelmintic treatment of dogs in late autumn and early spring.

PMID- 12606091
TI  - In vitro culture of Echinococcus multilocularis and Echinococcus vogeli
      metacestodes: studies on the host-parasite interface.
AB  - The larval stage of Echinococcus multilocularis causes alveolar echinococcosis
      (AE) in various mammalians including humans, while Echinococcus vogeli larvae
      cause a related disease which is also occasionally found in man. Traditionally,
      Echinococcus metacestodes have been maintained in the laboratory by serial
      transplantation passages into susceptible animals such as mice or gerbils,
      enabling the parasite to proliferate asexually. These experimental animal models
      have been used extensively to investigate host-parasite interactions and to study
      immunological events occurring at the host-parasite interface. However, with the
      use of laboratory animals it has always been difficult to investigate in more
      detail those factors modulating metacestode differentiation, and investigations
      on gene expression and respective regulation have been hampered by the complexity
      of the host-parasite interplay. There has been a need for an in vitro culture
      model which would enable researchers to dissect specific parasite compartments
      involved in the host-parasite relationship in more detail. This review summarises
      the studies leading to the development and application of a suitable in vitro
      culture model for the maintenance and proliferation of E. multilocularis and E.
      vogeli metacestodes, including the formation of protoscoleces, in a chemically
      defined medium devoid of host influence. These culture models have been used to
      study the basic parameters of metacestode in vitro proliferation and
      differentiation, and for the dissection of the ultrastructure and composition of
      the acellular laminated layer, the structure of which is predominantly involved
      in the physical interaction between the parasite and host immune and non-immune
      cells and tissues. For E. multilocularis, in vitro cultured parasites have been
      more extensively employed to study the localisation of several antigens, and to
      generate defined antigens for immunological studies. Although in vitro culture
      will not completely eliminate the need of animal experimentation, a wider
      application of this technique could significantly reduce the use of animals, and
      thus the costs and time required for respective experimental investigations.

PMID- 12606092
TI  - Predictive values and quality control of techniques for the diagnosis of
      Echinococcus multilocularis in definitive hosts.
AB  - By the end of the 1980s the only reliable technique for diagnosing the intestinal
      Echinococcus multilocularis infection of definitive hosts was parasite detection
      at necropsy. Currently, several techniques for the post mortem and in vivo
      diagnosis are available, including classical and modern methods. The
      sedimentation and counting technique (SCT) is used for the exact determination of
      the worm burden in the intestine after necropsy. The SCT has high sensitivity and
      specificity values (both close to 100%) and can be regarded as 'gold standard'.
      The principle of the intestinal scraping technique (IST) is the stereomicroscopic
      examination of at least 15 intestinal thick smears. This technique has a
      sensitivity of 78% and a specificity approximating 100%. In recent years, the IST
      has been successfully used in large post mortem surveys of foxes for E.
      multilocularis. The newer techniques for detecting coproantigens by ELISA (CA
      ELISA) exhibit rather high sensitivities between 84 and 95%, combined with very
      high specificities of >96%, the latter regarding non-Echinococcus cestodes and
      other parasites. However, cross-reactivity may occur with E. granulosus. Copro
      DNA detection by PCR is also highly sensitive (89-94%) and specific (100%). With
      the SCT, IST and Copro-PCR one person can only examine about 10-20 animals per
      day, whereas the CA-ELISA allows the examination of 200 samples. Therefore, the
      latter test is suited for mass-screening of definitive host populations. Both the
      CA-ELISA and the Copro-PCR allow the examination of materials from dead and
      living animals, including faecal samples collected in the field. Quite often
      diagnostic techniques have been used without adequate quality control and proper
      definition of their performance characteristics, including diagnostic
      sensitivity, specificity, predictive values and some other parameters. Examples
      are presented with the aim to demonstrate the need and the value of calculating
      the predictive values for assays used to diagnose the E. multilocularis infection
      in individual animals and in definitive host populations.

PMID- 12606093
TI  - An update on immunodiagnosis of cystic echinococcosis.
AB  - Immunological parameters are increasingly investigated as possible markers for
      the development of cystic echinococcosis. Among the newer immunologic tests for
      assessing the host-parasite relationship, assay of immunoglobulin isotypes with
      the use of distinct parasite antigens and detection of Th1/Th2 cytokine
      expression are an interesting new approach. The findings upon which we have
      constructed our immunological hypothesis of the host-parasite relationship are:
      (1) immunoglobulin isotype profiles differ in patients with distinct clinical
      outcomes of the disease; in particular, antigen B is the antigen of choice to
      detect specific IgG4, which is the immunoglobulin isotype most clearly associated
      with the progression of the disease; (2) the isolation and characterisation of
      recombinant parasite proteins that behave as molecular markers of allergic
      reactions associated with cystic echinococcosis; (3) Th1/Th2 cell activation is
      involved in the clinical outcome of Echinococcus granulosus infection and, in
      particular Th2 response, is associated with susceptibility to the disease,
      whereas a Th1 response is associated with protective immunity.

PMID- 12606094
TI  - Development of Em18-immunoblot and Em18-ELISA for specific diagnosis of alveolar
      echinococcosis.
AB  - Extensive experience has documented that Em2(plus)-ELISA, Em10-ELISA and Em18
      immunoblot and Em18-ELISA are reliable serologic methods for detection of
      alveolar echinococcosis (AE) caused by the metacestodes of Echinococcus
      multilocularis. Among these, tests based on detection of antibodies to the
      specific Em18 antigen, either immunoblot or ELISA, appears to be the most
      specific for AE. Between 90 and 97% of AE cases with characteristic hepatic
      lesions detectable by image analysis have been positive in Em18-serology. In
      contrast Antigen B (8 kDa)-immunoblot is the most sensitive for all forms of
      echinococcosis, although it can not differentiate AE from cystic echinococcosis
      (CE). Primary serologic screening for echinococcosis, especially for CE using
      hydatid cyst fluid of Echinococcus granulosus appears to be highly sensitive in
      endemic areas. Glycoproteins (GPs) purified from cyst fluid of Taenia solium are
      highly specific for diagnosis of T. solium neuorcysticercosis (NCC). Using
      currently available antigens it is not difficult to differentiate these three
      larval cestodiases serologically. We recommend that (1) primary screening of CE
      in endemic areas should be carried out using hydatid cyst fluid of E. granulosus
      prepared from cysts in either sheep, human or mouse for immunoblot and from sheep
      or mouse for ELISA, (2) both primary screening and confirmation of AE in endemic
      areas should be carried out using Em18-ELISA, Em18-immunoblot or Em2(plus)-ELISA.
      Serodiagnosis in areas where both AE and CE are endemic, such as in China, should
      be carried out as a combination of (1) and (2), and (3) serology of NCC should be
      carried out using GP-ELISA or GP-immunoblot. All samples showing antibody to Em18
      are exclusively from echinococcosis cases. There have been no false positive test
      reactions with sera from other diseases. Strongest Em18 responders are all from
      patients with AE but some weaker responses may be found in sera of persons with
      advanced complex lesions of CE. These highly reliable serodiagnostic methods
      using native, recombinant and synthetic antigens are briefly summarized and
      experiences with these methods in Japan is reviewed. We believe that use of these
      specific antigens in screening and confirmation programs for AE in Japan will
      improve specificity and reduce the confusion, anxiety and expense in persons
      whose sera give false positive reactions with crude echinococcal antigens.

PMID- 12606095
TI  - Statistics and sample design in epidemiological studies of Echinococcus
      multilocularis in fox populations.
AB  - In this paper possible sampling strategies for estimating the prevalence of
      Echinococcus multilocularis infections in foxes are discussed. To draw valid
      conclusions from the analysis of fractions of a total fox population, each member
      of the total population must have the same chance of being selected for the
      investigation (random sampling), the sample must be representative with respect
      to all epidemiologically relevant conditions in the population (e.g. age, endemic
      status, seasonal effects, population density), and it must be large enough to
      obtain results with the required precision. For detection/exclusion of infections
      at a pre-specified prevalence threshold and confidence level (e.g. 99%), the
      required sample is rather small, but the information obtained from the data is
      limited. For prevalence estimates, the required sample sizes depend on the
      expected prevalence, the desired precision of the estimate and the chosen
      confidence level (e.g. 90, 95, or 99%). The samples need to be taken in spatial
      units where the variation of the conditions potentially influencing the infection
      can be neglected. A first impression of the spatial distribution of E.
      multilocularis infections in foxes can also be obtained by mapping the
      investigated sample (infected and uninfected animals) using the municipalities
      where they were shot or found as a spatial grid. To analyse the local influence
      of environmental factors, data on the geographical positions where the animals
      were sampled need to be collected and analysed in the context of a Geographic
      Information System (GIS).

PMID- 12606096
TI  - Overview of the epidemiological situation on echinococcosis in the Mediterranean
      region.
AB  - Cystic echinococcosis due to its considerable morbidity rates, in the populations
      of the Mediterranean region, give rise to high economic losses both in the public
      health sector and the animal production industry. Medium to high infection rates
      in man are recorded in most of the Mediterranean countries. Public awareness of
      hydatid disease is rather low in most of these countries. Difficulties in early
      diagnosis, the prevalent occurrence in rural areas with weak systems of health
      care, the favourable conditions created by man, as well as the climatic and
      ecological ones, are factors contributing to the prevalence of the infection.
      Small, ill-equipped and unsupervised slaughter-houses, illegal slaughtering, high
      population of stray dogs, etc., are known to be the main sources of infection.
      Echinococcus granulosus is the species present in nearly all countries of the
      regions while E. multilocularis infection is limited to a few of them. Accurate
      data on the incidence of human hydatid disease in the region are not available as
      it is notifiable in only a few countries.

PMID- 12606097
TI  - Hydatidosis-echinococcosis in Greece.
AB  - Hydatidosis/echinococcosis (Echinococcus granulosus infection) is considered to
      be a serious problem for both public health and the livestock economy in Greece.
      The present paper reviews and summarizes all data available on this disease since
      1970. The disease was widely prevalent long before the 1970s. At that time the
      annual surgical incidence rate was 12.9 per 100000 inhabitants. As a result of
      the seriousness of the disease, the Greek Department of Veterinary Services
      initiated an anti-echinococcosis campaign in 1984. When the program started, the
      prevalence of infection in farm animals was 82% in cattle, 80% in sheep, 24% in
      goats and 5% in pigs. Data obtained in a survey in Northern Greece in 1994,
      recorded the prevalence of CE as 100% in sheep, 56.6% in cattle, 15.4% in goats
      and 9.3% in pigs; sheep had not only more cysts but significantly higher rates of
      fertile cysts (e.g. contained viable protoscolices) than intermediate host
      species examined. Serologic surveys (specific IgG) in humans carried out between
      1988 and 1999 had shown seroprevalence up to 29%. Surveillance in livestock
      species, since 1998, carried out as part of an European Union (E.U.) project,
      have documented the prevalences of CE in sheep (31.3%), in goats (10.3%), in pigs
      (0.6%) and in cattle (0%). The official campaign against this zoonosis in Greece
      is ongoing. It is concluded that since hydatidosis/echinococcosis is still
      present, surveillance and intervention measures should be continued to track the
      course of the infection and to eliminate risk to humans.

PMID- 12606098
TI  - Performance characteristics and quality control of community based ultrasound
      surveys for cystic and alveolar echinococcosis.
AB  - The probability of disease given the results of a test, is called the predictive
      value of the test. The predictive value of a test is not a property of the test
      itself but will vary according to the prevalence of the disease in the studied
      population. The positive predictive value (PPV) is the probability that the
      subject tested has the disease given that a positive result is obtained. The
      negative predictive value (NPV) is the probability that the subject tested is
      normal given that a negative result is obtained. As the prevalence of a disease
      in a population approaches zero so does the PPV and most of the positive cases
      will be 'false positives'. Conversely the NPV will be very high at low
      prevalences and there will be few 'false negative' results. The sensitivity and
      specificity of a test are properties of the test and do not vary with prevalence.
      The higher the sensitivity and specificity of a particular test the greater the
      predictive values will be at any given prevalence of the disease. Ultrasound (US)
      is increasingly used for detecting lesions due to cystic and alveolar
      echinococcosis (CE and AE) and portable US scanners facilitate community based
      mass screening surveys in remote rural communities. Screening is justified with
      AE and CE in endemic areas as diagnosis at an early stage can lead to a better
      prognosis following treatment. The sensitivity and specificity of US has been
      reported to be between 88-98% and 95-100% respectively for CE and the sensitivity
      is a little higher for AE. Both species have pathognomonic signs on US and the
      technique is considered to be the 'gold standard' although it is still an
      imperfect test. Clinical, laboratory and epidemiological data also play an
      important role in the diagnosis of CE and AE. US results where possible, should
      be evaluated in relation to these findings. Suspected CE and AE images, may
      benefit from the use of other imaging techniques such as magnetic resonance
      imaging, computerised tomography and in the case of AE angiography or
      cholangiography. Immunological tests or molecular biological techniques also
      provide a useful back up, especially for AE. As sensitivity and specificity are
      properties of the US diagnostic test they should not vary if the case mix
      reported in different studies remains the same. The use of the WHO standardised
      US classifications for CE and AE should be used so that the properties of the
      test are standardised. Quality control of field based studies will depend on
      geographical variations in the case mix and the relative proportions of cyst
      types without pathognomonic signs. The latter will have the most bearing on
      variations in specificity, as would the use of different classifications. Inter-
      and intra-observer variability and differences in prevalence will affect the
      performance of US in different endemic settings. Community based surveys must
      adhere to the highest ethical standards and the outcome of surveys should result
      in appropriate treatment and follow-up strategies for all infected individuals
      and suspected cases found during the surveys.

PMID- 12606100
TI  - Morphological and genetic characterization of Echinococcus granulosus in the
      Slovak Republic.
AB  - The present study was undertaken to characterize more thoroughly aetiological
      agent of cystic echinococcosis that still represents a health problem in the
      Slovak Republic. Sequencing of the mitochondrial ND1 gene, Random Amplified
      Polymorphic DNA (RAPD) analysis and isoenzyme analyses were used to characterize
      genetically protoscolices of 37 isolates from pigs and cattle and two isolates
      from humans collected in different regions of the Slovak Republic. Solely the G7
      genotype (pig strain) was identified by ND1 sequences in all 14 pigs isolate
      examined by this method. This genotype was also found in two human patients and
      in two cattle. The exclusive finding of the G7 variant has implications for the
      implementation of control strategies given its unique developmental and
      biological properties. Despite striking morphological variability, a low degree
      of the intra-strain variability was found in the Slovak Echinococcus granulosus
      isolates with the genetic methods used. This was particularly associated with the
      shape and size of hooks, number of testes and shape of ovaries and uterus. GPI
      and MDH enzymes were found suitable for the discrimination of G7 and G1
      (=cosmopolitan sheep strain) variant.

PMID- 12606099
TI  - The use of mathematical models to simulate control options for echinococcosis.
AB  - In many parts of the world Echinococcus granulosus is a widespread infection in
      sheep and dogs with a consequential spill over into the human population. In the
      past, mathematical models have been derived to define the transmission dynamics
      of this parasite, principally in the sheep-dog life cycle. These models have
      characterized the cycles of infection as lacking in density dependent constraints
      in both the definitive or intermediate hosts. This suggested that there was
      little, if any, induced host immunity by the parasite in either host in natural
      infections. However, recent evidence from both Tunisia and Kazakhstan, where
      young dogs are the most heavily parasitised, suggests the possibility of
      significant definitive host immunity. This may have an effect on the control
      effort needed to destabilize the parasite. A preliminary computer simulation
      model (based on an Excel spreadsheet) to attempt to predict the results of a
      control programme has been written. This demonstrates that there could be
      significantly different results if there is indeed protective immunity in the dog
      than in the absence of immunity. In the former the parasite needs a greater
      control effort to push the parasite towards extinction than in the latter. The
      computer simulation is based on a mathematical model of the parasite's life cycle
      and is flexible so that different values of parameters can be used in different
      situations where the transmission of the parasite may be at different levels.
      Because of the flexibility of the computer simulation it is anticipated that this
      programme can be applied in most situations, although initial parameters for a
      particular location or strain of the parasite will have to be first predetermined
      with base line field surveys and possibly experimental infections. The programme
      also has an additional flexibility to enable simulations if some parameters
      cannot be accurately estimated through Monte-Carlo techniques. In the latter
      situation, worst and best case scenarios can be estimated and likely frequency
      distributions of the unknown parameters can be included in the model.

PMID- 12606101
TI  - Profile of cytokine production within the periparasitic granuloma in human
      alveolar echinococcosis.
AB  - Th2 responses, especially IL-10 secretion by circulating mononuclear cells are
      associated with the progressive form of AE and Th1 responses with resistance. The
      HLA B8, DR3, DQ2 haplotype is associated with the severity of AE in humans
      through immune-mediated mechanisms including an elevated production of
      Interleukin-10 (IL-10). Granulomatous infiltration of mononuclear cells around
      the parasitic vesicles is a hallmark of this disease; however, cytokine
      production by granuloma cells has never been studied. Tissue samples were taken
      in the periparasitic area and in the central area of the periparasitic
      granulomatous lesions from a patient with a progressive AE at surgery. Six pieces
      for each zone were incubated in culture medium with antibiotics and IL-2,
      together with irradiated autologous peripheral blood mononuclear cells as feeder
      cells. After four days the dead feeder cells were removed by density gradient
      centrifugation. Lymphocytes were stimulated with Echinococcus multilocularis
      vesicular fluid antigen (Emf) or PHA to study IL-10, IFN-, and IL-4 production in
      the supernatant. Emf-stimulated mononuclear cells from the central part of the
      lesions secreted more IL-10 and less IFN-gamma than cells from the periphery of
      the granuloma. At the basal level, IL-10 secretion by the locally infiltrating
      cells was also high and this confirms at the local granuloma level our previous
      results obtained from cultures of circulating mononuclear cells. The present
      study confirms that IL-10 secretion is a key feature of the immune response
      against E. multilocularis in humans. The location of the cells which produce the
      highest amount of IL-10, those in contact with parasitic structures, suggests
      that the parasite itself is able to modulate the immune response of the host so
      that the infiltrating cells cannot participate in the effector phase of the
      cellular immune response. The nature of the parasitic structures involved and the
      mechanisms which lead to an imbalanced cytokine production remain to be
      elucidated.

PMID- 12606102
TI  - Hydatid cyst of the liver-criteria for the selection of appropriate treatment.
AB  - The appropriate treatment of hydatid cysts of the liver is determined by several
      factors, namely the patient, the cyst, the therapeutic resources and the
      physician. Characteristics of cysts, can be described by ultrasonography (US).
      Based on US images, we can classify hydatid cysts, according the evolutionary
      phase of the larval parasite and to choose the most appropriate therapeutic
      approach. US is also important to evaluate the efficacy of the treatment.
      Concerning the therapeutic methods, surgery had long been the only treatment
      available for the hydatid cyst of the liver. Beginning the 1970s benzimidazoles,
      Mebendazole and Albendazole, have been used for the treatment of the hydatid
      disease and in the early 1980s, with the development of diagnostic US, the
      deliberate puncture of abdominal cysts, particularly those in the liver, was
      evaluated this lead to puncture/aspiration, followed by injection of a scolicide
      which became a therapeutic method known as puncture, aspiration, injection and re
      aspiration (PAIR). So, according to the cyst's characteristics based on US
      evaluation we can establish a therapeutic strategy: cysts type 1 and 3 may be
      treated by chemotherapy. Alternative treatment should be PAIR but only if the
      cysts cannot be treated with benzimidazoles. If there are contraindications for
      PAIR and chemotherapy the treatment should be surgical. Type 2 hydatid cysts can
      be treated by PAIR following initial treatment with benzimidazoles. If PAIR is
      not feasible or there is no evidence of degenerative changes after chemotherapy,
      surgery is indicated. Type 4 cysts are usually inactive and, in these cases,
      treatment is not indicated. If there is evidence that the cysts contents are
      still viable PAIR may be indicate. If PAIR is not possible, surgery is the method
      of choice. Cysts type 5 do not require treatment.

PMID- 12606103
TI  - Benzimidazole treatment of cystic echinococcosis.
AB  - Hydatidosis (cystic echinococcosis, CE) constitutes a serious public health
      problem worldwide. Total surgical removal of a hydatid cyst is still considered
      the gold standard treatment for CE. Percutaneous treatment (PAIR), using either
      hypertonic saline or alcohol as a larvacidal agent, appears to be an additional
      effective form of treatment. Benzimidazoles (albendazole, ABZ; mebendazole, MBZ),
      given either alone or combined with praziquantel (PZ) are currently used for the
      treatment of non-surgical cases and as a supplementary treatment prior and post
      surgery. Combined chemotherapy was found to be more effective than either of the
      agents given alone. ABZ is easily absorbed and more effective than MBZ. ABZ (12
      15 mg/kg/day) and MBZ (30-70 mg/kg/day) given for 14-20 days prior to surgery and
      continued for an additional 3-24 months in a cyclic monthly form were found
      effective against the disease. Either increased or decreased circulating antigen
      levels, which consequently cause changes in the humoral (IgG, IgG1, IgG4, IgE)
      immune responses, have a prognostic value in successfully treated CE cases.
      However, although the cellular immune response to echinococcal antigens decreased
      in improved or cured CE patients, it was not considered of practical use in
      determining treatment efficacy. In certain cases successful treatment was also
      followed by elevated eosinophilia and erythrocyte sedimentation rates. In the
      present article, the mechanism of drug activities as well as the development of
      resistance against the drugs available are further discussed.

PMID- 12606104
TI  - International classification of ultrasound images in cystic echinococcosis for
      application in clinical and field epidemiological settings.
AB  - The increased knowledge of the natural history of cystic echinococcosis (CE) by
      the recent expansion in the use of ultrasound (US) in field and clinical studies
      has necessitated the development of a new WHO standardised classification of US
      images. Use of such a classification will enable clinicians to examine
      recommended clinical procedures for the different cyst types. It will also allow
      scientists to compare data on the occurrence of cyst types in different parts of
      the world providing evidence to examine strain differences in the causative
      organism Echinococcus granulosus. The classification proposed follows that of the
      first classification developed by Gharbi et al. [Radiology 139 (1981) 459] which
      has been widely used, but in modified forms, since its publication. The
      classification presented here is intended for use in field epidemiological
      studies as well as for clinical investigators. The classification is intended to
      follow the natural history of CE and starts with undifferentiated simple cysts,
      as presumably hydatid cysts evolve from these structures. These simple cysts,
      however, may be due to a number of different aetiologies (parasitic lesions,
      congenital disorders, biliary cysts or neoplasms) and, therefore, require further
      diagnostic tests to reveal their identity. As their origin is uncertain they are
      not given the designation of a CE type lesion, and, in the proposed
      classification, should be recorded as cystic lesions (CL). The first clinical
      group starts with cyst types CE 1 and 2 and such cysts are active, usually
      fertile cysts containing viable protoscoleces. CE Type 3 are cysts entering a
      transitional stage where the integrity of the cyst has been compromised either by
      the host or by chemotherapy and this transitional stage is assigned to the second
      clinical group. The third clinical group comprises CE Types 4 and 5 which are
      inactive cysts which have normally lost their fertility and are degenerative. The
      use of the standardised US classification will facilitate the application of
      uniform standards and principles of treatment currently recommended for each cyst
      type.

PMID- 12606105
TI  - Public health education/importance and experience from the field. Educational
      impact of community-based ultrasound screening surveys.
AB  - The public health educational impact of community-based ultrasound (US) surveys
      for cystic echinococcosis (CE) can form an important part of the development
      about the awareness of the importance of the disease in an endemic area. In
      addition to identifying asymptomatic carriers and thereby facilitating early
      diagnosis and treatment, such surveys can be used to impart important educational
      messages at the individual, household, community, regional and national levels.
      US surveys are usually appealing to rural communities where such services are not
      available but where the technique is generally appreciated by its application in
      a wide field of medical applications. The qualities of the test (painless, non
      invasive and gives instant recordable results) are also attractive to
      participants during such surveys and the majority of the population in a selected
      study area choose to be screened. Two such surveys were carried out amongst the
      Berber people of the mid-Atlas mountains in central Morocco in May 2000 and 2001.
      Over 11,000 people were screened in the two 10-day surveys. Informed consent had
      been obtained through community meetings and with the chiefs of villages prior to
      the surveys being conducted. Individuals who volunteered to be screened entered
      the study and as far as is known there were no refusals. The concept of voluntary
      participation, the explanation of the life cycle and clinical manifestations of
      the disease and its prevention are all-important educational messages. The
      occurrence of CE is almost always known in an endemic community but is usually
      very poorly understood leading in many cases to a fear of the disease, especially
      amongst families with an infected individual who has previously undergone
      surgery. During the US survey considerable attention was paid to provide
      educational input before, during and after the survey. Information was provided
      at the start of the survey to local leaders, doctors, veterinarians and school
      teachers on the aims of the study and to obtain informed consent. At the start of
      the study everyone was individually schooled about the route of transmission of
      the parasite and how this may be best prevented. The knowledge level of those
      screened was assessed by showing hydatid cysts, either freshly obtained from the
      abattoir of from photographs. Animal cysts were recognised by almost everyone but
      its transmission and link to human disease was invariably unknown. Patients found
      to be infected with CE were always confidentially counselled and followed up for
      treatment, if required. Treatment options were explained to the individual or to
      parents in the case of a child. Local physicians participated in discussions on
      the WHO guidelines for the treatment of CE and all cases were fully discussed
      providing an educational element for the local doctors. The 1% US prevalence
      found sent an important message to the local politicians and the perceived
      importance of the disease had an impact at the leadership level. Local leaders
      made calls for a control programme. The long term educational impact remains to
      be evaluated as does the role such surveys play in the future collaboration of
      communities with the implementation of a control programme.

PMID- 12606106
TI  - Immunohistochemical observations on cellular response in unilocular hydatid
      lesions and lymph nodes of cattle.
AB  - As we believe the immunohistochemistry of the hydatid lesions and draining lymph
      nodes has never been studied, we collected them from the liver and lungs of
      cattle in Uruguay for such a study. Frozen sections of the tissues were
      immunohistochemically stained using monoclonal antibodies against surface markers
      CD2, CD4, CD5, CD8, B cell and granulocyte-monocyte/macrophage and antiserum
      against specific granules of bovine eosinophils. The adventitial layer of the
      cyst wall consists of a layer of epithelioid cells and connective tissue. The
      cells from the epithelioid cell layer were a kind of macrophage. In most cases
      having progressive hydatid cysts, CD8+ cells were predominant in the pericystic
      adventitia, and a relatively small number of CD4+ cells were in the same area. In
      the adventitial layer surrounding the regressive and involutional hydatid cysts,
      infiltrating lymphocytes were composed mostly of CD4+ cells. An eosinophil
      mediated destruction of the laminated layer was recognized in the regressive and
      involuted hydatid cysts. The subpopulations of T cells in the local lymph nodes
      tended to be similar to T cells in the adventitial layer of hydatid lesions. From
      our findings, we consider that infiltration of eosinophils and the subpopulations
      of lymphocytes infiltrating the hydatid lesions in the liver and lungs are
      derived from cells in the draining lymph nodes of both organs.

PMID- 12606107
TI  - National prevalence of larval echinococcosis in sheep in slaughtering plants Ovis
      aries as an indicator in control programmes in Uruguay.
AB  - Diagnostic surveys carried out on ovine larval echinococcosis in slaughtering
      plants at a national level in 1998 made it possible to meet several objectives,
      i.e. to estimate the existing levels of prevalence, to evaluate the effectiveness
      of the control actions applied by the Programme against Hydatidosis and to
      contribute to the improvement of the health information systems for
      epidemiological surveillance. The work included sheep (Ovis aries), both lambs (2
      4 teeth) and adults (6-8 teeth). A random sample was performed among sheep from
      the plants that slaughter the majority of animals in the country. The sample
      included 22 animals per herd, and it involved removing their offal (liver, lungs
      and heart) and processing serial sections at the laboratory. The
      histopathological studies were performed on the lesions that could not be
      adequately identified at gross examination, and those that were so small that had
      to be submitted for confirmation of the diagnosis. Of the 2035 animals that were
      examined, 1019 were lambs (2-4 teeth) and 1016 were adults (6-8 teeth). The
      prevalence of larval echinococcosis was 7.7% in lambs and 18.0% in adults. The
      overall prevalence in the liver was 8.5 and 8.0% in the lungs. As to the
      characteristics of the morphologic structures of the larvae, in younger animals
      29% of the lesions were calcified, and 71.0% were hyaline, while in older animals
      the proportions were 34.4% calcified versus 65.6% hyaline. Other conditions found
      in the liver parenchyma included: white stain (0.8%), caseous lymphadenitis
      (3.0%), abscess (0.4%), larvae of Taenia hydatigena (5.1%), Fasciola hepatica
      (3.9%). And 1.7% of the animals presented larvae of Taenia ovis in the cardiac
      muscle. Previous surveys carried out in 1994 using the same methodology showed a
      prevalence of 15.2% in 2-4 teethed animals and 33.9% in 6-8 teethed animals, thus
      confirming that rates have decreased by 49.6 and 47.0%, respectively. The data
      obtained reflect the reduction of areas contaminated with eggs of Echinococcus
      granulosus, which would cause a loss in immunity against this parasite after a
      certain time. Prevalence of larvae T. hydatigena and T. ovis could change if more
      sites were considered, a fact that was confirmed in studies carried out in our
      country. The species O. aries must be used as an indicator in the control
      programmes, especially in the category of 2-4 teethed lambs. The fact they are
      not as frequent in our market must be considered; in 1998 they accounted for only
      3.0% of the total numbers of animals.

PMID- 12606108
TI  - The changing epidemiology of echinococcosis in Kazakhstan due to transformation
      of farming practices.
AB  - In recent years there has been a substantial increase in cystic echinococcosis in
      Kazakhstan. There are several factors that have contributed to this change in the
      epidemiology of the disease. The primary reason was the degradation of
      traditional nomadic system of livestock breeding and closing of large collective
      farms. Small private farms have started to keep stock year round in closer
      proximity to permanent human habitation. Furthermore, routine anthelmintic
      prophylaxis of dogs has been abandoned and there is inadequate control over the
      use and disposal of animal carcasses. Large mechanized slaughterhouses are no
      longer operational. Now more people (7-8 times) and more dogs (8-10 times)
      participate in the husbandry of 1000 sheep, than during Soviet administration.
      Because of the close association of dogs with man there is the potential for a
      substantial increase in eggs and of Echinococcus in immediate environment of
      inhabited houses. Soil samples taken from 61% of yards of village homes contained
      taeniid eggs and from 35% of yards from around farmsteads. During an examination
      of 1464 village dogs the average rate of infection with Echinococcus granulosus
      was 5.8%, whilst the prevalence in 607 shepherd dogs was 23.2%. At present, these
      dogs represent a major source of infection for people with this dangerous
      parasite. Examination of hospital records suggested that children and people in
      occupations associated with animal husbandry were at most risk of infection.

PMID- 12606110
TI  - Youth development programs: risk, prevention and policy.

PMID- 12606111
TI  - Mucosal immunity of the adolescent female genital tract.
AB  - This study sought to characterize mucosal immunity of the adolescent genital
      tract during the cycle and determine if adolescents have more suppressed
      immunoglobulin levels in the follicular phase than adults. Daily from cycle day 9
      until ovulation, then every other day until menses, cervical secretions for IgA,
      IgG, and cytokines were collected via Weck-Cel sponge and serum for luteinizing
      hormone (LH), estradiol, and progesterone was obtained from three adolescent
      girls (mean age 16.8 years). Immunoglobulin and cytokine levels varied during the
      menstrual cycle, reaching their nadir around ovulation. Compared with 13 adults,
      adolescents had a greater drop in IgG in the follicular phase (mean beta-953 vs. 
      269 microg/mL/day, p = .045), but a similar rate of rise in IgG in the luteal
      phase (mean beta +118 vs. +100 microg/mL/day, p = .252). Rates of change in IgA
      did not differ between adolescents and adults for either phase. Although limited
      by the small sample size, these findings suggest that adolescents may be more
      sensitive to unopposed estrogen and warrant further investigation.

PMID- 12606112
TI  - Do differences in relationship and partner attributes explain disparities in
      sexually transmitted disease among young white and black women?
AB  - Using data from 1695 respondents aged 15 to 24 years to the 1995 National Survey
      of Family Growth, we examined black/white differences in marital history and sex
      with older, casual, and nonmonogamous partners, as well as the associations of
      these differences with self-reported bacterial sexually transmitted disease (STD)
      history. Although characteristics of sexual partners and relationships often
      differed by race, this did not explain racial disparities in STDs.

PMID- 12606113
TI  - Recruitment and retention of adolescent participants in HIV research: findings
      from the REACH (Reaching for Excellence in Adolescent Care and Health) Project.
AB  - PURPOSE: To evaluate the importance of 13 items in the recruitment and retention
      of HIV-positive and HIV-negative adolescent participants in a longitudinal study
      (REACH study). METHODS: A confidential, self-administered, visual analog, cross
      sectional survey was offered to active participants (November 1999-August 2000)
      with 438 subjects (86%) participating. Sixty-six percent of the cohort were HIV
      positive and 34% were HIV-negative with a mean age of 17 years, and 76% were
      female. Subjects were asked to recall the importance they placed on 13 items in
      deciding to join the REACH study (recruitment) and to remain on study
      (retention). Factors that might explain the judgment placed on the items were
      analyzed using the nonparametric Wilcoxon Rank-Sum test or the Kruskall-Wallis
      test. RESULTS: The five most important factors for study recruitment were
      identical to those chosen for retention by participants. The factors were: (a)
      quality medical care, (b) caring staff, (c) health education, (d)
      privacy/confidentiality, and (e) altruism. Items judged least important were
      social activities, compensation, transportation, and food/meals. Subject
      characteristics (gender, age, HIV status) were not associated with statistically
      different mean judgment scores at recruitment and retention, although clinical
      site showed significant variation. Factors that could render subjects vulnerable
      (health insurance, family finances) were not associated with related items.
      CONCLUSIONS: Adolescents found quality health care and care team characteristics
      critically important in considering research participation. Attention to privacy
      and the opportunity to be altruistic were also important. Compensation for
      participation was not a significant factor for recruitment and retention of this
      adolescent cohort. This study demonstrates that adolescents apply sound criteria
      in evaluating research participation and do not appear to be unduly affected by
      compensation.

PMID- 12606115
TI  - Examining trajectories of adolescent risk factors as predictors of subsequent
      high-risk driving behavior.
AB  - PURPOSE: To examine the effects on early high-risk driving behavior of changes
      over time (trajectories) in adolescent alcohol use, friends' support for
      drinking, susceptibility to peer pressure, and tolerance of deviance. METHODS:
      Statewide driving data were obtained for 4813 subjects who had completed at least
      two previous school-based questionnaires. The self-administered questionnaire
      data provided predictor measures from 5th through 10th grades. Trajectory
      information on predictor measures was summarized using each measure's slope over
      time and level at the 10th grade data collection (last value). Regression models
      used serious offenses, alcohol-related offenses, serious crashes, and alcohol
      related crashes as outcomes, trajectory measures as predictors, and produced
      parameter estimates adjusted for demographic measures. Probabilities of having a
      serious offense or serious crash for five sample trajectories on each measure
      were obtained from the estimated regression models. RESULTS: All four predictor
      measures were important, particularly in predicting serious offenses, alcohol
      related offenses, and alcohol-related crashes. The highest probabilities for
      young adult high-risk driving were found among those with consistently high or
      increasingly high trajectories of friends' support for drinking, susceptibility
      to peer pressure, and tolerance of deviance. CONCLUSIONS: Programs to prevent
      adolescent risk behavior should take into account environmental and personality
      influences. Prevention efforts need to emphasize preserving low levels,
      preventing increases, and promoting decreases over time of adolescent risk
      factors for unhealthy behaviors, such as high-risk driving.

PMID- 12606114
TI  - Utility of cervicography in HIV-infected and uninfected adolescents.
AB  - PURPOSE: To compare cytology with cervicography in HIV-infected and uninfected
      adolescent females. METHODS: At the time of analysis, 334 girls aged 13-19 years
      from 13 U.S. cities were participating in a prospective study of HIV infection.
      All subjects had cytology and a Cervigram (cervicography) performed at two
      consecutive visits 6 months apart, referred to as visit (V) 1 and 2. Cervigrams
      were sent to the parent company for diagnosis and were categorized as: "negative"
      or "positive" (compatible with low-grade or high-grade squamous intraepithelial
      lesions [SIL]). Cytology was considered abnormal if the subject had SIL at either
      V1 or V2. Sensitivity, specificity, and positive predictive value (PPV) of the
      Cervigram were calculated compared with repeat Papanicolaou (Pap) smears.
      RESULTS: Two consecutive adequate Pap smears were available for analysis in 200
      adolescents; 51% (95% CI, 43-59) of the 142 HIV-positive youth and 19% (95% CI, 9
      29) of the 58 HIV-negative youth had SIL on at least one Pap smear (p < .001). A
      positive Cervigram was observed in 44% (95% CI, 36-53) of the HIV-infected group
      and 29% (95% CI, 17-41) of the HIV-uninfected group (p =.06). For the HIV
      infected group, the sensitivity, specificity, and PPV of the Cervigram to detect
      SIL were 58% (95% CI, 45-71), 69% (95%CI, 57-80), and 64% (95%CI, 52-77),
      respectively. For the HIV-uninfected group, the sensitivity, specificity, and PPV
      were 64% (95% CI, 31-89), 80% (95% CI, 65-90), and 44% (95% CI, 19-68),
      respectively. The combined sensitivity, using both the Pap smear and Cervigram
      result from V1 to detect SIL, was 82% (95% CI, 71-91 for HIV+ and 48-98 for HIV-)
      in both groups. However, the PPV based the performance of the Cervigram in Pap
      smear-negative women as 33% (95% CI, 17-53) and 15% (95% CI, 2-45) for the HIV
      infected and uninfected group, respectively (p = not significant [ns]).
      CONCLUSIONS: Although the sensitivity of a single Pap smear increased
      significantly when the Cervigram was used as an adjunct, the low PPV in both HIV
      infected and uninfected groups, suggests that cervicography has a limited utility
      for precancer and cervical cancer screening in high-risk adolescent populations.

PMID- 12606116
TI  - Understanding the role of health care providers during the transition of
      adolescents with disabilities and special health care needs.
AB  - PURPOSE: To evaluate the role of health care providers in the transition from
      pediatric to adult health care for adolescents with disabilities and special
      health care needs (SHCN) from both the families' and providers' perspectives.
      METHODS: A total of 753 parents of adolescents with SHCN (e.g. developmental,
      physical, behavioral/emotional, learning, or health-related disabilities) were
      surveyed by questionnaire to assess their perceptions of their health care
      provider's level of involvement in various transition activities and the extent
      to which they felt it was the provider's responsibility to assist in a particular
      activity. One hundred forty-one health care providers (primarily pediatricians)
      completed a parallel survey to assess their level of participation in the same
      transition activities and the extent to which they felt it was their
      responsibility to assist with each transition activity. The questionnaire listed
      13 different transition activities health providers may engage in to help young
      people prepare for adulthood and also asked questions about areas such as
      employment and health insurance. To investigate whether parents and providers
      share the same views regarding the involvement and responsibility of providers
      across the 13 transition activities, two sets of Student's t-tests were
      calculated. RESULTS: There were significant differences between providers and
      parents concerning both the level of provider involvement and the extent to which
      it was the provider's responsibility to assist in various transition activities
      (e.g., health providers reported significantly more involvement than did parents
      for 11 of the 13 transition activities and, compared with parents, providers
      reported that it was more within their role to assist in these 11 transition
      activities). CONCLUSIONS: The findings suggest a need for health care providers
      and parents to have open discussions about the nature and extent to which
      providers assist families in key transition activities.

PMID- 12606117
TI  - Gender differences in juvenile violence: a report from Add Health.

PMID- 12606118
TI  - Cleavage of cellular DNA by calicheamicin gamma1.
AB  - It is assumed that the efficient antitumor activity of calicheamicin gamma1 is
      mediated by its ability to introduce DNA double-strand breaks in cellular DNA. To
      test this assumption we have compared calicheamicin gamma1-mediated cleavage of
      cellular DNA and purified plasmid DNA. Cleavage of purified plasmid DNA was not
      inhibited by excess tRNA or protein indicating that calicheamicin gamma1
      specifically targets DNA. Cleavage of plasmid DNA was not affected by incubation
      temperature. In contrast, cleavage of cellular DNA was 45-fold less efficient at
      0 degrees C as compared to 37 degrees due to poor cell permeability at low
      temperatures. The ratio of DNA double-strand breaks (DSB) to single-stranded
      breaks (SSB) in cellular DNA was 1:3, close to the 1:2 ratio observed when
      calicheamicin gamma1 cleaved purified plasmid DNA. DNA strand breaks introduced
      by calicheamicin gamma1 were evenly distributed in the cell population as
      measured by the comet assay. Calicheamicin gamma1-induced DSBs were repaired
      slowly but completely and resulted in high levels of H2AX phosphorylation and
      efficient cell cycle arrest. In addition, the DSB-repair deficient cell line
      Mo59J was hyper sensitive to calicheamicin gamma. The data indicate that DSBs is
      the crucial damage after calicheamicin gamma1 and that calicheamicin gamma1
      induced DSBs are recognized normally. The high DSB:SSB ratio, specificity for DNA
      and the even damage distribution makes calicheamicin gamma1 a superior drug for
      studies of the DSB-response and emphasizes its usefulness in treatment of
      malignant disease.

PMID- 12606119
TI  - Transcription, nucleosome positioning and protein binding modulate nucleotide
      excision repair of the Saccharomyces cerevisiae MET17 promoter.
AB  - We have assessed how transcription, chromatin structure and protein binding
      modulate nucleotide excision repair in the upstream regulatory region and early
      coding region of the endogenous Saccharomyces cerevisiae gene MET17. Removal of
      UV-induced cyclobutane pyrimidine dimers was measured from these regions, in
      which transcription and chromatin structure could be regulated independently of
      each other. Distinct repair trends were apparent depending on transcriptional
      state. When transcription was repressed nucleosome positioning and protein
      binding as determined by chromatin immunoprecipitation and quantitative real-time
      PCR, were significant factors. Nucleosome positioning and/or protein binding
      effects were most apparent on the strand that becomes transcribed, with repair
      occurring fastest in a nucleosome free region but being retarded where regulatory
      proteins bound within this region. When transcription was derepressed the rate of
      repair increased on both strands in a region beginning 200 bp upstream of the
      TATA box and extending downstream into the coding region. This effect overrode
      the influences of nucleosome positioning and protein binding.

PMID- 12606121
TI  - Independent roles of XRCC1's two BRCT motifs in recovery from methylation damage.
AB  - XRCC1 is known to be involved in base excision repair (BER)/single-strand break
      repair (SSBR) through interaction with other BER enzymes. Hypersensitivity of
      XRCC1-deficient cells against alkylating agents has been explained by loss of
      interaction with BER proteins. XRCC1 is a unique DNA repair protein containing
      two BRCT motifs, recently identified in several DNA repair and cell cycle
      regulating proteins. To study the function(s) of the two BRCT motifs of the XRCC1
      protein, we established CHO EM9 (XRCC1-null) cells expressing XRCC1 protein
      altered in either one of the two BRCT motifs. Colony-forming ability after methyl
      methanesulfonate (MMS) treatment was dependent on the BRCT-a motif, but not on
      the BRCT-b motif. Surprisingly, reduced BER/SSBR rate in vivo, measured by an
      alkaline comet assay, was observed in the BRCT-b motif-deficient cells, while the
      BRCT-a motif-deficient cells showed the repair rate comparable with the wild-type
      (WT) cells. The BRCT-a motif-mutated cells, instead, showed deficiency in
      initiation of DNA replications after MMS treatment. Furthermore, we found that
      XRCC1 is multiply phosphorylated in vivo and hyperphosphorylation of XRCC1 after
      MMS treatment is dependent on the BRCT-a motif. These data suggest a new function
      dependent on the integrity of the BRCT-a motif of XRCC1 in recovery from MMS
      induced damage.

PMID- 12606120
TI  - In vitro and in vivo studies of MutS, MutL and MutH mutants: correlation of
      mismatch repair and DNA recombination.
AB  - We have used the recently determined crystal structures of Escherichia coli (E.
      coli) MutS, MutL and MutH to guide construction of 47 amino-acid substitutions in
      these proteins and analyzed their behavior in mismatch repair and recombination
      in vitro and in vivo. We find that the active site of the MutH endonuclease is
      composed of regions from two separate structural domains and that the C-terminal
      5 residues of MutH influence both DNA binding and cleavage. We also find that the
      non-specific DNA-binding activity of MutL is required for mismatch repair and
      probably functions after strand cleavage by MutH. Alteration of residues in
      either the mismatch recognition domain, the ATPase active site, or the domain
      interfaces linking the two activities can diminish the differential binding of
      MutS to homoduplex versus heteroduplex and results in the loss of mismatch
      specific MutH activation. Finally, every mutation that abolishes mismatch repair
      is deficient in blocking homeologous recombination, suggesting that mismatch
      repair and prevention of homeologous recombination use the same MutS-MutL
      complexes for signaling in E. coli.

PMID- 12606123
TI  - Mammalian DNA mismatch repair protects cells from UVB-induced DNA damage by
      facilitating apoptosis and p53 activation.
AB  - DNA mismatch repair (MMR) is integral to the maintenance of genomic stability and
      more recently has been demonstrated to affect apoptosis and cell cycle arrest in
      response to a variety of adducts induced by exogenous agents. Comparing Msh2-null
      and wildtype mouse embryonic fibroblasts (MEFs), both primary and transformed, we
      show that Msh2 deficiency results in increased survival post-UVB, and that UVB
      induced apoptosis is significantly reduced in Msh2-deficient cells. Furthermore,
      p53 phosphorylation at serine 15 is delayed or diminished in Msh2-deficient
      cells, suggesting that Msh2 may act upstream of p53 in a post-UVB apoptosis or
      growth arrest response pathway. Taken together, these data suggest that MMR
      heterodimers containing Msh2 may function as a sensor of UVB-induced DNA damage
      and influence the initiation of UVB-induced apoptosis, thus implicating MMR in
      protecting against UV-induced tumorigenesis.

PMID- 12606122
TI  - Polymorphism of genes encoding SOS polymerases in natural populations of
      Escherichia coli.
AB  - High fidelity replicative DNA polymerases can be blocked during DNA replication
      by various base damages, which represents a potentially lethal event. Escherichia
      coli possesses three DNA polymerases, PolII, PolIV and PolV, that can continue
      replication over such lesions in template DNA, thus allowing for cell survival.
      Genes coding for these enzymes, polB, dinB, and umuCD respectively, belong to the
      stress-inducible SOS regulon. We have analyzed the patterns of nucleotide
      sequence variability of genes encoding for three SOS polymerases from E. coli
      natural isolates in order to identify the nature of selective forces that
      determine their evolution. The frequency of inferred inter-strain recombination
      events, and the frequency of synonymous and non-synonymous base substitutions
      within these genes do not deviate significantly from those observed for the
      control group composed of 2 genes coding for DNA polymerases PolI and PolIII and
      10 metabolic genes. This suggests that the loci coding for SOS polymerases are
      subject to selective pressure for the maintenance of their function and
      specificity. The fact that genes coding for translesion-synthesis (TLS)
      polymerases, particularly dinB and umuC homologs, have been conserved during
      evolution and the present analysis suggest that their activity is essential for
      the cellular survival and fitness.

PMID- 12606124
TI  - Choice between death by senescence or by cancer?

PMID- 12606125
TI  - Steroid hormone genotypes ARStuI and ER325 are linked to the progression of human
      prostate cancer.
AB  - Steroid hormones and their receptors are involved as initiators or promoters in
      prostate carcinogenesis. The intrauterine-perinatal period and maternal estrogen
      and testosterone levels have been proposed to be of etiologic importance in
      prostate tumorigenesis and cancer progression. The objective of this study was to
      analyze genetic polymorphisms in the androgen receptor ARStuI by polymerase chain
      reaction-restriction fragment length polymorphism (PCR-RFLP) and in the estrogen
      receptor ER325 by PCR-single-strand conformational polymorphism (PCR-SSCP). In
      our study of 170 prostate cancer patients, ARStuI and ER325 genotypes and their
      association with disease progression and metastasis were analyzed. Age-adjusted
      logistic regression analysis indicates the association of ARStuI S1 allele with
      high-grade tumor (P = 0.033; OR = 3.0, 95% CI = 1.1-8.3) and the association of
      ER325 with high-grade tumor (P = 0.003; OR = 3.0, 95% CI = 1.4-6.4), advanced
      disease (P = 0.020; OR = 2.4, 95% CI = 1.1-5.1), risk of progression (P = 0.027;
      OR = 2.5, 95% CI = 1.1-5.7) and the presence of metastatic disease (P = 0.006; OR
      = 3.1, 95% CI = 1.4-6.8). In summary, this study has demonstrated androgen
      receptor (ARStuI) and estrogen receptor (ER325) genetic polymorphisms in prostate
      cancer patients and its association with disease progression and metastasis. Our
      results support the hypothesis that genetic factors related to steroid hormone
      receptors may influence the behavior of human prostate cancer.

PMID- 12606127
TI  - Molecular analysis of region t(5;6)(q21;q21) in Wilms tumor.
AB  - We have previously described the physical localization of a constitutional
      t(5;6)(q21;q21) in a patient (tumor cell sample designated as MA214) with
      bilateral Wilms tumor (WT). We have now physically refined the breakpoints and
      identified putative gene targets within this region. The translocation
      breakpoints are contained within a 2.5-Mbp region on 5q21 containing four
      candidate genes and a 1.3-Mbp region on 6q21 that contains three candidate genes.
      To explore the role of this region in WT genesis, we have performed loss of
      heterozygosity (LOH) analysis with markers flanking the translocation breakpoints
      in tumor from MA214 and a panel of sporadic WT. Alleles were retained for all
      informative markers used in the MA214 tumor. In sporadic tumors LOH was found in
      6 of 63 (9.5%) and 5 of 62 (8%) informative cases for flanking markers D6S301 and
      D6S1592 on 6q21. LOH was found in 3 of 58 (5.2%) and 2 of 54 (3.6%) for flanking
      markers D5S495 and D5S409 on 5q21. These preliminary data suggest LOH at the
      t(5;6)(q21;q21) region is unlikely to be a mechanism for tumor development in
      MA214, but may be important for a subgroup of sporadic WT.

PMID- 12606126
TI  - Satellite DNA hypomethylation in karyotyped Wilms tumors.
AB  - Previously, a high percentage of Wilms tumors was found to be hypomethylated in
      the unusually long region of pericentromeric satellite DNA on chromosome 1. We
      now show that these pediatric cancers are also frequently hypomethylated in
      centromeric satellite DNA throughout the genome and compare satellite DNA
      hypomethylation with chromosome rearrangements. Relative to normal somatic
      tissues, 83% of the tumors were hypomethylated in centromeric satellite alpha
      DNA. This was assessed by blot hybridization under low-stringency conditions
      after digestion with CpG methylation-sensitive restriction endonucleases. Similar
      results were obtained with different enzymes, indicating generalized
      hypomethylation of centromeric DNA. Hypomethylation of another heterochromatic
      sequence, juxtacentromeric satellite 2 DNA of chromosome 1, was observed in 51%
      of the tumors. By cytogenetic analysis, rearrangements in the centromeric or
      juxtacentromeric heterochromatin of chromosome 1 were the most frequent
      structural aberration and were seen in 14% of the tumors. Tumors with such
      rearrangements had hypomethylation of satellite DNA in the pericentromeric
      region. These results show a high degree of targeting of DNA hypomethylation to
      centromeric and juxtacentromeric satellite DNA sequences in cancer and are
      consistent with satellite DNA hypomethylation contributing to, but not sufficing
      for, karyotypic instability in cancer and possibly playing other roles in
      carcinogenesis.

PMID- 12606128
TI  - Chimeric BCR/ABL gene detected by fluorescence in situ hybridization in three new
      cases of Philadelphia chromosome-negative chronic myelocytic leukemia.
AB  - Three new cases are reported of cytogenetically Philadelphia-negative (Ph-)
      chronic myelocytic leukemia (CML), with positive BCR/ABL gene rearrangement
      according to a reverse transcriptase polymerase chain reaction technique.
      Fluorescence in situ hybridization (FISH) studies using different probes showed
      three different situations involving chromosomes 9 and 22 for the masked BCR/ABL
      fusion gene. With the use of BCR/ABL-extra signal and CEP 9 probes (Vysis,
      Downers Grove, IL, USA), FISH studies detected the BCR/ABL fusion gene at the end
      of chromosome 9 in patient 1, a BCR/ABL fusion gene on both chromosomes 22 in
      patient 2 (who was in an accelerated phase of CML), and a BCR/ABL fusion signal
      on chromosome 22 in patient 3. Interestingly, FISH interphase signals showed the
      same pattern in patients 1 and 3, but the BCR/ABL fusion gene was located on
      different chromosomes. Careful interpretation of the results and a simultaneous
      study of nuclei and metaphases are therefore recommended in each case. In
      conclusion, in cases of Ph- CML, FISH studies are of paramount importance since
      they can detect chromosomal reorganization and its location, and can also provide
      quantitative follow-up of these patients.

PMID- 12606129
TI  - Combined cytogenetic and array-based comparative genomic hybridization analyses
      of Wilms tumors: amplification and overexpression of the multidrug resistance
      associated protein 1 gene (MRP1) in a metachronous tumor.
AB  - Tumor samples from a variety of Wilms tumors (WT) obtained from three patients
      were analyzed by cytogenetic and array-based comparative genomic hybridization
      (CGH) methods. The tumors represented different stages of tumorigenesis and
      included a unilateral primary WT and contralateral nephrogenic rest (case 1), a
      primary WT and a contralateral metachronous WT (case 2), and a recurrent WT with
      lung metastases (case 3). All six specimens exhibited abnormal karyotypes
      characteristic of different WT levels of progression. Array-based CGH
      examinations of 57 genes that are commonly amplified in various cancers revealed
      a 2.6-fold genomic amplification of the multidrug resistance-associated protein 1
      (MRP1) gene in the metachronous WT, but no amplification in the primary tumor.
      This sole amplification event in our series was also confirmed by Southern blot
      analysis. Furthermore, quantitative reverse transcriptase polymerase chain
      reaction showed a sixfold overexpression of the MRP1 gene in this metachronous WT
      relative to the primary tumor. Our findings suggest that for most of the genes
      examined in this series genomic amplification does not play a role in WT
      pathogenesis. Isolated amplification and overexpression of the MRP1 gene in the
      metachronous WT, however, suggest that this gene may be an important factor in
      the development and progression of metachronous tumors.

PMID- 12606130
TI  - A comprehensive karyotypic analysis on Korean hepatocellular carcinoma cell lines
      by cross-species color banding and comparative genomic hybridization.
AB  - Chromosomal aberrations were investigated in hepatitis B virus integrated into
      the hepatocellular carcinoma (HCC) cell lines SNU-368, SNU-449, SNU-398, SNU-182,
      and SNU-475 using Giemsa-banding, cross species color banding, and comparative
      genomic hybridization (CGH). The origins of the marker chromosomes were confirmed
      by fluorescence in situ hybridization with constructed chromosome painting
      probes. Each cell line had unique modal karyotypic characteristics and showed
      variable numbers of numerical and structural clonal cytogenetic aberrations. The
      gains were commonly detected on chromosome 1, and chromosome regions 6p, 7q, 8q,
      10p, 17q, and 20; the losses were often found on 4q21 approximately qter, 13,
      18q21 approximately qter, and Y. In particular, the breakpoints on 1p36, 1p13
      approximately q21, 2p13 approximately q11, 6q10 approximately q11, 7q11, 7q22,
      14q10, 16q10 approximately q13, 17q21, 18q21, and 19p11 approximately q11 were
      involved frequently at the multiple rearranged lesions. CGH analysis further
      confirmed the cytogenetic data, and the nonrandom rearrangements data suggested
      the candidate regions for the genes to be isolated which were related to HCC.

PMID- 12606131
TI  - Characterization of the A673 cell line (Ewing tumor) by molecular cytogenetic
      techniques.
AB  - The A673 cell line was established from a patient with a primary rhabdomyosarcoma
      (RMS), which is referred to in the literature either as a Ewing tumor (ET) or as
      RMS. Although the two tumoral types are associated with specific and well
      characterized translocations, no cytogenetic report on this cell line has been
      published. We characterized the A673 cell line using a combination of spectral
      karyotyping (SKY), fluorescence in situ hybridization (FISH), and reverse
      transcriptase polymerase chain reaction (RT-PCR), which revealed the presence of
      a complex karyotype and a translocation involving chromosomes 11 and 22 and the
      fusion of EWS and FLI1 genes, both events being specific to ET. Neither
      cytogenetics nor molecular alterations specific to RMS were found.

PMID- 12606132
TI  - Unusual aberration involving the short arm of chromosome 11 in an 8-month-old
      patient with a supratentorial primitive neuroectodermal tumor.
AB  - An 8-month-old baby girl with a supratentorial primitive neuroectodermal tumor
      showed an unusual aberration involving the short arm of chromosome 11. Seven
      abnormal metaphase cells had 49 chromosomes with trisomies of chromosomes 9 and
      13, and partial trisomies of 1q and 18p. One homologue chromosome 11 was
      strikingly abnormal showing a long acrocentric-like form, which was composed of
      the long arm of chromosome 1 and an addition to the short arm of chromosome 11.
      This was characterized by fluorescence in situ hybridization using a partial arm
      chromosome-painting probe.

PMID- 12606133
TI  - Molecular profiles of invasive mucinous and ductal carcinomas of the breast: a
      molecular case study.
AB  - Expression profiling using cDNA microarrays have redefined the molecular
      classification of some cancers. The comprehensive genetic analysis also permits
      the identification of novel pathways that might determine subtle differences in
      tumor phenotype. Herein, we analyzed the tissues from a patient with bilateral
      cancer of different histologies in each breast (pure invasive mucinous and pure
      invasive ductal), thus providing a unique opportunity to assess the expression
      profiles determined by histology in an isogenic human background. Our results
      show that the mucinous phenotype is associated with the expression of
      immunostimulatory and inhibitory genes, consistent with the cellular infiltration
      of lymphocytes and with the expression of enzymes involved in mucin production.
      Moreover, the panel of matrix metallo-proteinases are distinctly different
      between the mucinous and the invasive tumors, suggesting that therapeutic targets
      to this class of compounds may need to be tailored for the varying histologies.
      Taken together, these data suggest that expression profiling can be used
      diagnostically to distinguish individual histologic subclassifications and may
      guide the selection of target therapeutics.

PMID- 12606135
TI  - Multiple endocrine neoplasia type 2A: an unusual clinical presentation and
      association with renal dysplasia.
AB  - We report what we believe to be the first case of a patient with multiple
      endocrine neoplasia type 2A (MEN 2A) and renal dysplasia associated with an RET
      634 mutation. The proband presented at the age of 29 with medullary thyroid
      carcinoma (MTC), bilateral pheochromocytomas, and primary hyperparathyroidism.
      Screening of family members identified the syndrome in his father. Both the
      proband and his father carry RET 634 germline mutation resulting in cysteine to
      arginine amino acid substitution. The proband had a left nephrectomy at the age
      of 10 years. Histologic examination of the resected kidney revealed severe
      dysplasia. His father had normal renal tract on ultrasonography. The proband's
      clinical presentation was unusual, and initially thought to be an atypical
      pneumonia. Surgical management after pharmacologic alpha- and beta-blockage
      consisted of bilateral adrenalectomy, total thyroidectomy, and subtotal
      parathyroidectomy as a single procedure.

PMID- 12606134
TI  - Multiple myeloma with monosomy 13 developed in trisomy 13 acute myelocytic
      leukemia: numerical chromosome abnormality during chromosomal segregation
      process.
AB  - We report here an acute myelocytic leukemia (AML-M2) patient with trisomy 13 as
      the sole cytogenetic anomaly, who had relapse of AML with a normal karyotype and
      developed multiple myeloma. Fluorescence in situ hybridization analysis using the
      RB gene probe revealed the plasma cells of multiple myeloma (MM) to have monosomy
      13 anomaly, whereas relapsed blast cells of AML carried disomy of chromosome 13.
      To our knowledge, this is the first case showing clonal evolution of trisomy 13
      AML and monosomy 13 MM, which might be derived from the leukemic clone at
      relapse.

PMID- 12606136
TI  - Cytogenetic findings in a case of nodular fasciitis of subclavicular region.
AB  - We report a case of nodular fasciitis with a reciprocal translocation involving
      both homologues of chromosome 15 [46,XX,t(15;15)(q13;q25)]. This is the third
      case of nodular fasciitis with involvement of chromosome 15. Two genes that are
      involved in either wound healing and/or tumorigenesis have been mapped to
      chromosome 15. One of the genes, the keratinocyte growth factor or fibroblast
      growth factor 7 (KGF or FGF7) was mapped to the 15q22 region, which was involved
      in a cytogenetic rearrangement in one case of nodular fasciitis. KGF is
      implicated in wound healing, healing lung injuries and tumorigenesis of various
      cancers such as breast and prostate. The second gene involved is TRKC or NTRK3
      mapped to the 15q25 region. TRKC is implicated in congenital fibrosarcoma, a
      benign proliferation of fibroblasts. The breakpoint and overexpression of the
      protein in our case further suggest a possible involvement of TRKC.

PMID- 12606137
TI  - Cytogenetic findings in benign cartilaginous neoplasms.
AB  - Cytogenetic analysis has improved our understanding of the histopathogenesis of
      many benign and malignant bone and soft tissue tumors, as well as served as an
      important diagnostic adjunct for these pathologic entities. Cytogenetic reports
      of benign cartilaginous tumors, however, are relatively few. This is unfortunate,
      as distinguishing benign and malignant cartilaginous neoplasms can often be
      difficult. In this study, the cytogenetic findings of two enchondromas, two
      periosteal chondromas, and one soft part chondroma and a review of the literature
      are reported. Abnormal diploid or near-diploid clones were detected in all
      specimens analyzed. Although a tumor-specific anomaly did not emerge from these
      studies, involvement of certain chromosomes/chromosomal regions appears
      recurrent.

PMID- 12606138
TI  - Translocation (X;20)(q13.1;q13.3) as a primary chromosomal finding in two
      patients with myelocytic disorders.
AB  - Reports of X chromosome translocations, as primary chromosomal changes associated
      with hematologic disorders, remain relatively uncommon. Herein, we report the
      detection, by conventional cytogenetic methods, of a cytogenetically identical
      t(X;20) in two different patients with hematologic disorders (probable
      myelodysplasia and polycythemia vera/acute myelocytic leukemia). In both cases,
      this translocation appeared as the primary clonal chromosome abnormality, with
      breakpoints occurring in the long arms of both the X chromosome and chromosome 20
      (Xq13.1 and 20q13.3, respectively). Further characterization and comparison of
      the translocation chromosome products of these two cases by use of fluorescence
      in situ hybridization techniques is also described. Similar previously reported
      cytogenetically cases and the potential that this specific rearrangement may
      represent a nonrandom chromosomal finding are discussed.

PMID- 12606139
TI  - The BRCA2 sequence variant IVS19+1G-->A leads to an aberrant transcript lacking
      exon 19.

PMID- 12606140
TI  - A brief commentary on "Refractory anemia with ring sideroblasts associated with
      i(17q) and mutation of the TP53 gene".

PMID- 12606141
TI  - Translocation (6;14) in childhood acute mixed lineage leukemia.

PMID- 12606142
TI  - The price of innovation: new estimates of drug development costs.
AB  - The research and development costs of 68 randomly selected new drugs were
      obtained from a survey of 10 pharmaceutical firms. These data were used to
      estimate the average pre-tax cost of new drug development. The costs of compounds
      abandoned during testing were linked to the costs of compounds that obtained
      marketing approval. The estimated average out-of-pocket cost per new drug is 403
      million US dollars (2000 dollars). Capitalizing out-of-pocket costs to the point
      of marketing approval at a real discount rate of 11% yields a total pre-approval
      cost estimate of 802 million US dollars (2000 dollars). When compared to the
      results of an earlier study with a similar methodology, total capitalized costs
      were shown to have increased at an annual rate of 7.4% above general price
      inflation.

PMID- 12606143
TI  - Technological development and medical productivity: the diffusion of angioplasty
      in New York state.
AB  - A puzzling feature of many medical innovations is that they simultaneously appear
      to reduce unit costs and increase total costs. We consider this phenomenon by
      examining the diffusion of percutaneous transluminal coronary angioplasty (PTCA)-
      a treatment for coronary artery disease--over the past two decades. We find that
      growth in the use of PTCA led to higher total costs despite its lower unit cost.
      Over the two decades following PTCA's introduction, however, we find that the
      magnitude of this increase was reduced by between 10 and 20% due to the
      substitution of PTCA for CABG. In addition, the increased use of PTCA appears to
      be a productivity improvement. PTCAs that substitute for CABG cost less and have
      the same or better outcomes, while PTCAs that replace medical management appear
      to improve health by enough to justify the cost.

PMID- 12606144
TI  - Socio-economic inequality in ill-health amongst the elderly. Should one use
      current or permanent income?
AB  - In Belgium, income-related inequality in ill-health among the 65- is present, but
      reduces significantly as soon as one restricts the analysis to the 65+. The main
      goal of this paper is to check whether these findings (based on current income)
      are robust to the income concept used. The analysis is repeated using estimates
      of permanent income. Measured inequality among the 65+ remains very limited,
      suggesting that the observed findings are not heavily dependent upon the income
      concept. Finally, I suggest an explanation for the observed difference in
      inequality between the 65- and the 65+. I argue that this difference is likely to
      be correlated with differences across income groups of (1) sample attrition; and
      (2) mortality.

PMID- 12606145
TI  - The effect of financial pressure on the quality of care in hospitals.
AB  - This paper examines the effect of financial pressure on hospital quality, using
      health outcomes after treatment for acute myocardial infarction (AMI) as quality
      indicators. The financial pressure variables are: fiscal pressure from the
      Prospective Payment System (PPS) for inpatient care, and changes in health
      maintenance organization (HMO) penetration at the county level. The study shows
      that both types of financial pressures adversely affect short-term health
      outcomes, but do not affect patient survival beyond 1 year after patients'
      hospital admissions. Furthermore, the impact of HMO penetration appears to differ
      from that of Medicare payment changes for certain hospitals because HMO
      penetration encourages price competition.

PMID- 12606146
TI  - Decomposing world health inequality.
AB  - This study explores global inequality in health status and decomposes it into
      within- and between-country inequality. We rely on standardized height as our
      health indicator since it avoids the measurement pitfalls of more traditional
      measures of health such as morbidity, mortality, and life expectancy. It also
      avoids measurement problems associated with using monetary variables such as
      income or expenditure across time or place to compare welfare. Our calculation of
      world height inequality indicates that, in contrast with similar research on
      income inequality, within-country variation is the source of most inequality,
      rather than the differences between countries.

PMID- 12606147
TI  - Income related inequalities in mental health in Great Britain: analysing the
      causes of health inequality over time.
AB  - Using regression techniques this paper estimates the level of income related
      health inequality in GB in 1992 and 1998. Inequality is decomposed to investigate
      which socio-demographic factors are important contributors to health differences.
      The paper includes a range of measured and subjective income variables to control
      for absolute income. A relative deprivation measure is included to test the
      impact of income inequality on health inequality. It is found that subjective
      financial status is a major determinant of ill-health and makes a major
      contribution to income related inequalities in health. Relative deprivation is an
      important contributor for women but not for men.

PMID- 12606148
TI  - Stationarity of health expenditures and GDP: evidence from panel unit root tests
      with heterogeneous structural breaks.
AB  - This paper re-examines the stationarity of national health care expenditures and
      GDP in a panel setting utilizing data from 20 OECD countries over the period from
      1960 to 1997. Previous research in this area has recognized the drawback of not
      allowing for structural breaks in their unit root tests and noted that their
      empirical results may not be robust. We advance the literature by utilizing a
      recently developed panel LM unit root test that allows for heterogeneous level
      shifts. In contrast to previous analyses that did not consider breaks, our
      results reject the unit root null hypothesis for both series.

PMID- 12606149
TI  - New estimates of drug development costs.

PMID- 12606150
TI  - 2,3,7,8-tetrachlorodibenzo-p-dioxin induces lecithin: retinol acyltransferase
      transcription in the rat kidney.
AB  - Vitamin A (retinoids) has an essential role in development and throughout life of
      humans and animals. Consequently, effects of the environmental pollutant 2,3,7,8
      tetrachlorodibenzo-p-dioxin (TCDD) on retinoid metabolism may be contributory to
      its toxicity. This study was performed to clarify the mechanism behind dioxin
      induced retinyl ester formation in the rat kidney. In addition we investigated
      the possible role of CYP1A1 in dioxin-induced all-trans-retinoic acid (atRA)
      formation. Male Sprague-Dawley rats were exposed to a single oral dose of TCDD in
      a combined dose-response and time-course study, with doses ranging from 0.1 to
      100 microg/kg bw and time points from 1 to 28 days. Levels of atRA and the
      expression of two potentially retinoic acid (RA)-controlled proteins critically
      involved in retinoid storage regulation, lecithin: retinol acyltransferase (LRAT)
      and cellular retinol binding protein I (CRBP I), were analyzed in liver and
      kidney. The expression and activity of cytochrome P4501A1 (assayed as
      ethoxyresorufin-O-deethylase activity) was assessed to gain insight into its
      potential role in RA synthesis. There was a significant increase in LRAT mRNA
      expression in the kidney, whereas no such increase could be observed in the
      liver, despite significantly increased atRA levels in both tissues. This suggests
      a tissue-specific regulation of LRAT by TCDD that may be dependent on other
      factors than atRA. Neither CRBP I mRNA nor protein levels were altered by TCDD.
      The time-course relationship between CYP1A1 activity and atRA levels in liver and
      kidney does not exclude a role of CYP1A1 in TCDD-induced RA synthesis. The
      observed altered regulation of the retinoid-metabolizing enzyme LRAT, together
      with the low doses and short time required by TCDD to change tissue RA levels,
      suggest that enzymes involved in retinoid metabolism are specific and/or direct
      targets of TCDD.

PMID- 12606151
TI  - The metabolism of formyl-substituted benzanthracenes to hydroxymethyl metabolites
      in rat liver in vitro and in vivo.
AB  - Hydroxylation of benzylic methyl carbon atoms on drugs and carcinogenic
      polycyclic aromatic hydrocarbons (PAHs) forms benzylic alcohols. Many
      carcinogenic and mutagenic PAHs bear a primary or secondary benzylic hydroxyl
      group attached to the meso-region of the molecule. According to the unified
      theory, PAHs bearing a benzylic hydroxyl group are proximate carcinogenic
      metabolites. This paper demonstrates that carcinogenic benz[a]anthracenes bearing
      a formyl group at the meso-region undergo enzymatic reductive metabolism to the
      corresponding carcinogenic benzylic alcohol in vitro and in vivo. The unified
      theory would then predict sulfuric acid esterification of such benzylic alcohols
      as the final common step in their metabolic activation to generate ultimate
      electrophilic benzylic carbocations. Finally, oxidative metabolism of 7
      formylbenz[a]anthracenes gives rise to corresponding carboxylic acids and other
      oxygenated metabolites that are carcinogenically inert. Thus, oxidative
      metabolism of meso-region formyl compounds represents an avenue for the
      elimination of the carcinogen in a detoxified form.

PMID- 12606152
TI  - Superoxide dismutase: the balance between prevention and induction of oxidative
      damage.
AB  - Cu,Zn-superoxide dismutase (SOD1) has been shown to be effective in several free
      radical mediated diseases, although some studies have pointed toward SOD1
      toxicity at a high concentrations. In the present study, the balance between
      prevention and induction of damage by SOD1 has been investigated both in vitro
      and in vivo. In vitro superoxide was generated using xanthine/xanthine oxidase.
      In vivo superoxide was generated using the redox cycling compound doxorubicin.
      Furthermore, we determined the pharmacokinetics of lecithinized SOD1 (PC-SOD) in
      order to compare the results obtained in vivo with those obtained in vitro. It
      was found that in vitro high concentrations of SOD1 induce hydroxylation of
      coumarin 3-carboxylic acid (3-CCA). This could be caused by a peroxidative action
      of SOD1 or formation of the highly reactive hydroxyl radicals. Any signs of
      toxicity are absent in vivo because these concentrations are not reached. It can
      be concluded that SOD1 possesses a large therapeutic window and application of
      SOD1 or its derivatives for strengthening the body's defenses against oxidative
      stress in a variety of pathologies seems safe.

PMID- 12606154
TI  - Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces
      apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple
      stress inducer, deoxycholate: relevance to colon carcinogenesis.
AB  - Epidemiologic studies indicate that environmental (smoking) and dietary factors
      (high fat) contribute to carcinogenesis in many organ systems. The aim of our
      study was to test the hypothesis that nicotine, a component of cigarette smoke,
      and sodium deoxycholate (NaDOC), a cytotoxic bile salt that increases in
      concentration in the gastrointestinal tract after a high fat meal, induce similar
      cellular stresses and that nicotine may enhance some of the NaDOC-induced
      stresses. We found that nicotine, at 0.8 microM, the very low sub-micromolar
      level occurring in the tissues of smokers: (1). increases oxidative stress; (2).
      activates NF-kappaB, a redox-sensitive transcription factor; (3). activates the
      78 kD glucose regulated protein promoter, an indication of endoplasmic reticulum
      stress; (4). induces apoptosis; (5). enhances the ability of NaDOC to activate
      the 153 kD growth arrest and DNA damage promoter, an indication of increased
      genotoxic stress; and (6). enhances the ability of NaDOC to activate the
      xenobiotic response element. Our findings have applicability to G.I. cancer, in
      general, since smoking is a risk factor in the development of esophageal,
      pancreatic, gastric and colon cancer, and these cancers are also promoted by bile
      acids.

PMID- 12606153
TI  - Responses of tumorigenic and non-tumorigenic mouse lung epithelial cell lines to
      electrophilic metabolites of the tumor promoter butylated hydroxytoluene.
AB  - A model system to investigate the promotion phase of pulmonary carcinogenesis
      involves chronic exposure of carcinogen-initiated mice to the food additive,
      butylated hydroxytoluene (BHT). Previous studies strongly suggested that this
      activity is due to the cytochrome p450-catalyzed formation of quinone methides
      2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM) and 6-tert-butyl-2
      (1',1'-dimethyl-2'-hydroxy)ethyl-4-methylenecyclohexa-2,5-dienone (BHTOH-QM). The
      effects of these electrophiles on non-tumorigenic C10 and E10 epithelial cell
      lines derived from a normal mouse lung explant were compared with effects on
      their corresponding neoplastic siblings, the A5 and E9 spontaneous transformants,
      respectively. The tumorigenic cells were more resistant to cell killing, with
      LC(50) values of 165-180 microM for BHT-QM and 12-22 microM for BHTOH-QM, versus
      LC(50) values in the non-tumorigenic cells of 105-118 microM and 5.0-6.0 microM,
      respectively. Constitutive glutathione (GSH) concentrations were 12-20 nmol/10(6)
      cells, and BHT-QM toxicity was enhanced >2-fold by depleting GSH with buthionine
      sulfoximine (BSO). Formation of the GSH conjugate of BHT-QM accounted for a
      substantial fraction of the cellular GSH lost by quinone methide exposure.
      Enhanced lipid peroxidation and superoxide formation occurred in all cell lines
      treated with BHT-QM, but both tumorigenic lines contained higher levels of GSH S
      transferase and superoxide dismutase (SOD) activities. These data suggest the
      possibility that BHT-derived quinone methides may exert their promoting effects
      by inducing oxidative stress; such stress is better tolerated by tumorigenic
      cells, which have higher levels of antioxidant enzymes. Normal cells are
      destroyed more readily which allows neoplastic cells to expand their
      proliferation.

PMID- 12606155
TI  - Inactivation of mitochondrial succinate dehydrogenase by adriamycin activated by
      horseradish peroxidase and hydrogen peroxide.
AB  - Although human cancers are widely treated with anthracycline drugs, these drugs
      have limited use because they are cardiotoxic. To clarify the cardiotoxic action
      of the anthracycline drug adriamycin (ADM), the inhibitory effect on succinate
      dehydrogenase (SDH) by ADM and other anthracyclines was examined by using pig
      heart submitochondrial particles. ADM rapidly inactivated mitochondrial SDH
      during its interaction with horseradish peroxidase (HRP) in the presence of
      H(2)O(2) (HRP-H(2)O(2)). Butylated hydroxytoluene, iron-chelators, superoxide
      dismutase, mannitol and dimethylsulfoxide did not block the inactivation of SDH,
      indicating that lipid-derived radicals, iron-oxygen complexes, superoxide and
      hydroxyl radicals do not participate in SDH inactivation. Reduced glutathione was
      extremely efficient in blocking the enzyme inactivation, suggesting that the SH
      group in enzyme is very sensible to ADM activated by HRP-H(2)O(2). Under
      anaerobic conditions, ADM with HRP-H(2)O(2) caused inactivation of SDH,
      indicating that oxidized ADM directly attack the enzyme, which loses its
      activity. Other mitochondrial enzymes, including NADH dehydrogenase, NADH oxidase
      and cytochrome c oxidase, were little sensitive to ADM with HRP-H(2)O(2). SDH was
      also sensitive to other anthracycline drugs except for aclarubicin. Mitochondrial
      creatine kinase (CK), which is attached to the outer face of the inner membrane
      of muscle mitochondria, was more sensitive to anthracyclines than SDH. SDH and CK
      were inactivated with loss of red color of anthracycline, indicating that
      oxidative activation of the B ring of anthracycline has a crucial role in
      inactivation of enzymes. Presumably, oxidative semiquinone or quinone produced
      from anthracyclines participates in the enzyme inactivation.

PMID- 12606156
TI  - Prenatal expression of N-acetyltransferases in C57Bl/6 mice.
AB  - Exposure to carcinogens such as 4-aminobiphenyl (4ABP), found in tobacco smoke
      and other combustion products, results in the formation of detectable levels of
      4ABP-hemoglobin adducts in cord blood and 4ABP-DNA adducts in conceptal tissue.
      The presence of these adducts requires that the parent compound undergo
      biotransformation. When exposure occurs in utero, the maternal, placental and
      conceptal tissues are all possible sites for the formation of DNA-reactive
      products. One step in the activation of 4ABP is catalyzed by N-acetyltransferases
      (NAT). The expression of NAT was evaluated in gestational day (GD) 10-18
      conceptal tissues from C57Bl/6 mice. There was a quantitative increase in NAT1
      and NAT2 mRNAs with increasing gestational age that was also reflected in age
      related changes in functional protein measured as 4ABP-NAT activity. The ability
      to acetylate 4ABP increased from GD10 to 18 and was lower in conceptal tissue
      than in adult liver. The potential toxicologic significance of prenatal NAT
      expression was assessed by formation of 4ABP-DNA adducts. At GD 15 and 18, 4ABP
      DNA adducts were detected by immunohistochemistry 24 h following a single oral
      dose of 120 mg 4ABP/kg. Based on nuclear fluorescence, conceptual 4ABP-DNA
      adducts were present at similar levels at GD15 and 18. Levels of 4ABP-DNA adducts
      were significantly higher in maternal liver compared with the conceptus. Results
      from this study show that both NAT genes were expressed prenatally and that
      functional enzymes were present. These data support the possible in situ
      generation of reactive products by the conceptus. The relative contributions of
      maternal activation of 4ABP and that by the conceptus remain to be determined.

PMID- 12606157
TI  - Apoptosis enzyme-linked immunosorbent assay distinguishes anticancer drugs from
      toxic chemicals and predicts drug synergism.
AB  - The effects of anticancer drugs and toxic compounds on leukemic cells in culture
      were evaluated by enzyme-linked-immunosorbent assay (ELISA) based on the
      detection of apoptotic cells by a monoclonal antibody against single-stranded
      DNA. The concentrations of 13 anticancer drugs, which increased apoptosis ELISA
      absorbance, were similar to the concentrations decreasing long-term cell
      survival. Short-term metabolic tetrazolium-based 3-(4,5-dimethylthiazol-yl)-2,5
      diphenyformazan bromide (MTT) assay was significantly less sensitive than
      apoptosis ELISA and the cell survival assay. In contrast to anticancer drugs, 12
      toxic chemicals did not increase apoptosis ELISA absorbance at cytotoxic
      concentrations. The difference between two groups of compounds by apoptosis ELISA
      was especially large in cultures treated with twofold of concentrations producing
      50% inhibition of cell growth: all anticancer drugs induced intense reaction
      (mean absorbance 2.0), while none of the toxic chemicals induced apoptosis. The
      application of apoptosis ELISA to chemosensitivity testing was evaluated by its
      ability to detect synergism of anticancer drug combinations. Among 66 drug
      combinations tested, only combination of nitrogen mustard with mithramycin was
      highly synergistic by the apoptosis ELISA, as defined by apoptosis induction with
      the combination containing each drug at 50% of effective concentration. This
      combination was also synergistic in the cell survival assay, producing
      significant cell kill while each drug alone had no effect on cell survival. This
      synergism was not detected by MTT assay. We conclude that apoptosis ELISA could
      be useful for drug development and chemosensitivity assessment as it can
      distinguish clinically useful anticancer drugs from toxic compounds, is as
      sensitive as the long-term cell survival assay and can detect anticancer drug
      synergism by rapid evaluation of apoptosis induction.

PMID- 12606158
TI  - Protective effects of flavonoids on the cytotoxicity of linoleic acid
      hydroperoxide toward rat pheochromocytoma PC12 cells.
AB  - The protective effects of nine flavonoids, including apigenin, eriodictyol, 3
      hydroxyflavone, kaempherol, luteolin, quercetin, rutin, and taxifolin (Table 1),
      on the cytotoxicity of linoleic acid hydroperoxide (LOOH) toward rat
      pheochromocytoma PC12 cells were examined. The cytotoxicity was assessed by the
      trypan blue exclusion test and so-called MTT assay. When cells were preincubated
      with each flavonoid prior to LOOH exposure, quercetin, 3-hydroxyflavone, or
      luteolin decreased LOOH cytotoxicity toward undifferentiated cells, while only
      luteolin decreased efficiently LOOH cytotoxicity toward differentiated cells. On
      the other hand, when cells were coincubated with each flavonoid and LOOH,
      kaempherol, eriodictyol, quercetin, 3-hydroxyflavone, luteolin, or taxifolin
      decreased LOOH cytotoxicity toward undifferentiated and differentiated cells. On
      both preincubation prior to LOOH exposure and coincubation with LOOH, luteolin
      acted as the most efficiently protective agent against LOOH cytotoxicity.
      Further, these flavonoids showed protective effects on coincubation rather than
      preincubation. Flow cytometry using the fluorescence probe 2',7'
      dichlorofluorescin diacetate revealed that LOOH increases the intracellular level
      of reactive oxygen species in undifferentiated cells in a dose-dependent manner,
      and that desferrioxamine mesylate suppresses the LOOH-induced increase in the
      level. These flavonoids suppress the LOOH-induced increase. Further, the
      protective effect of flavonoids on LOOH cytotoxicity correlates with the
      suppression of the LOOH-induced increase. These results suggest that such
      flavonoids are beneficial for neuronal cells under oxidative stress.

PMID- 12606159
TI  - Analysis of the recent storm record in the southwestern Spanish coast:
      implications for littoral management.
AB  - This work compares the geomorphologic evolution of the Huelva coast (SW Spain),
      some climatic-oceanographic data of the Cadiz Gulf and the recent storm record of
      this zone, covering the last 4 decades (1956-1996). An interesting correlation
      was found between the southwestern wind periodicity, the number of storm periods
      and the beach ridges observed in the main spits (El Rompido and Donana). The
      spectral analysis of the wind time series permits to establish two most probable
      levels of periodicity: 6 and 9-10 years. Both periods coincide with the storm
      record and the creation of new beach ridges after a high-energy period. Beach
      damage, another storm-induced effect, was analysed by deducing different
      implications for the future management of tourist localities.

PMID- 12606160
TI  - Trace element differentiation in ferruginous accumulation soil patterns under
      tropical rainforest of southern Cameroon, the role of climatic change.
AB  - Regions under tropical rainforest cover, such as central Africa and Brazil are
      characterised by degradation and dismantling of old ferricrete structures. In
      southern Cameroon, these processes are relayed by present-day ferruginous
      accumulation soil facies, situated on the middle and the lower part of hill
      slopes. These facies become progressively harder towards the surface, containing
      from bottom to top, mainly kaolinite, kaolinite-goethite and Al-rich goethite
      hematite, and are discontinuous to the relictic hematite-dominated ferricrete
      that exist in the upper part of the hill slope. These features were investigated
      in terms of geochemical differentiation of trace elements. It appears that, in
      contrast to the old ferricrete facies, the current ferruginous accumulations are
      enriched in transitional trace elements (V, Cr, Co, Y, Sc) and Pb, while alkali
      earth elements are less differentiated. This recent chemical accumulation is
      controlled both by intense weathering of the granodiorite bedrock and by
      mobilisation of elements previously accumulated in the old ferricrete. The
      observed processes are clearly linked to the present-day humid climate with
      rising groundwater tables. They slowly replace the old ferricretes formed during
      Cretaceous time under more seasonal climatic conditions, representing an
      instructive case of continuos global change.

PMID- 12606161
TI  - Benzene emitted from glowing charcoal.
AB  - Benzene was assessed as the predominant aromatic compound emitted from glowing
      charcoal and firewood embers. Concentrations measured above charcoal used for
      grilling exceeded 10 mg m(-3) at a 5% carbon dioxide level. Charcoal with a high
      carbon content released less benzene. Glowing wood pellets emitted less benzene
      than glowing firewood remainders. The emissions of ethene and propene relative to
      benzene were low for commercial charcoal and wood-pellet embers, but high for
      firewood ember. The proportions of methylbenzene and naphthalene from charcoal
      were typically only 10% relative to benzene, and those of benzofuran,
      dibenzofuran and benzonitrile were typically below 5%. The polycyclic aromatic
      hydrocarbon (PAH) indicator phenanthrene was below the 1% level. Adsorbent
      sampling and GC-MS were used for assessing all the aromatic compounds. Earlier
      studies of charcoal emissions have focused on carbon monoxide, PAH and dioxins.
      It is concluded that the carcinogenic benzene may be an even more severe health
      hazard to be addressed by exposure-decreasing measures.

PMID- 12606162
TI  - Effect of industrial pollution on the distribution of 137Cs in soil and the soil
      to-plant transfer in a pine forest in SW Finland.
AB  - The objective of this study was to evaluate the effect of industrial pollution on
      the distribution of radiocaesium in soil and on its transfer from soil to plants.
      The study was started in September 2000 in four Scots pine stands located at
      distances of 0.5, 2, 4 and 8 km along a transect running SE from the Cu-Ni
      smelter at Harjavalta in SW Finland. Annual emissions from the smelter in 1990
      were 80 t of Cu, 31 t of Ni and 9000 t of SO(2), and in 1999 these were 5.9, 0.8
      and 3400 t, respectively. At each site, soil profiles were sampled with a corer,
      and samples were separated into litter (L), organic soil layer (O) and mineral
      soil layers (B, E). Mushrooms, lichens (Cladina spp. and Cetraria islandica),
      lingonberry (Vaccinium vitis-idaea) and crowberry (Empetrum nigrum) plants were
      collected at each site, except at a distance of 0.5 km, where only mushrooms were
      available. In the organic soil layer, 137Cs activity decreased from 8000 Bq/m(2)
      at a distance of 8 km from the smelter to 1500 Bq/m(2) at a distance of 0.5 km;
      in litter, 137Cs concentration increased from 6300 Bq/m(2) at 8 km to 14000
      Bq/m(2) at 0.5 km. 137Cs activity concentration decreased significantly in
      plants, mushrooms and lichens as the pollution load increased. In lichens, 137Cs
      activity decreased from 910 Bq/kg at 8 km to 170 Bq/kg at 2 km, while in
      lingonberry it decreased from 1470 to 20 Bq/kg and in crowberry from 310 to 20
      Bq/kg. Aggregated transfer factors for 137Cs decreased in a similar way in
      lingonberry from 7.6x10(-2) m(2)/kg at 8 km to 7.7x10(-4) m(2)/kg at 2 km and in
      crowberry from 1.6x10(-2) to 7.9x10(-4) m(2)/kg.

PMID- 12606163
TI  - Methods for comparing gridded inventories of atmospheric emissions--application
      for Milan province, Italy and the Greater Athens Area, Greece.
AB  - A set of methods has been compiled to compare gridded air emission inventories
      that have been derived, on the same spatial grid, using widely differing
      techniques. Top-down and bottom-up inventories for Milan, Italy and for the
      Greater Athens area (GAA), Greece were used to test and apply these methods. The
      applicability of each method to certain source sectors was assessed by conducting
      sensitivity analyses. Whilst some of the methods (such as regression calculations
      or the Moran coefficient) appeared very sensitive to variations of point source
      emissions, others (e.g. the construction of difference maps) proved more
      appropriate for characterizing line source differences. Area sources could best
      be dealt with by using the newly developed acceptability criterion. The
      development of these tools allows a reproducible comparison of sets of emission
      inventories and consequently supports developments towards improvement.

PMID- 12606164
TI  - Ambient air quality for the territory of the Czech Republic in 1996-1999
      expressed by three essential factors.
AB  - A new method for spatial interpretation and visualisation of measured air quality
      data developed and introduced in 1998 is used for ambient air quality assessment
      in the Czech Republic. The data from a countrywide air quality monitoring network
      is collated into the least possible number of factors describing the overall air
      quality in 1996-1999. The factors identified as 'ambient air pollution', 'ground
      level ozone' and 'wet atmospheric deposition' represent three different aspects
      of ambient air quality and their impact on receptors' evaluation. The monitoring
      stations are classified for each factor using five categories clearly
      distinguishing the sites over the Czech Republic territory within the 'best
      worst' scale range. The results are presented in maps with spot symbols produced
      in Arc/View system. The problem areas within the country are identified clearly
      for each factor. The air quality picture differs considerably for the respective
      factors within one calendar year. Categorisation of each factor for the entire
      period under review, however, remains strikingly similar, indicating that in
      spite of partial improvement and some decreases in air pollutant concentration,
      the problem areas have remained more or less the same for each factor. Comparison
      of all three factors shows that the southern part of the country is in a certain
      simplification very clean as to the 'ambient air pollution' and 'wet atmospheric
      deposition' factors, while it is impacted as to the 'ground-level ozone' factor.
      In contrast, the northern part of the country impacted as to the 'ambient air
      pollution' along with the 'wet atmospheric deposition' and 'ground-level ozone'
      factors at the higher elevations.

PMID- 12606169
TI  - Execution: an unwanted side-effect.

PMID- 12606165
TI  - Gastric response to acute copper exposure.
AB  - Early effects of acute copper exposure consist mainly of nausea and altered
      gastric permeability. To assess copper effects on gastric response 30 apparently
      healthy volunteers underwent two controlled trials receiving a solution with (10
      mg Cu/l) and without (<0.01 mg Cu/l) copper sulfate after overnight fasting, in
      random order. Ultrasonography was chosen to follow indirectly the gastric
      emptying pattern for 120 min. Measurements were expressed as z scores [z=(mean
      Xi)/S.D.]. Results showed that nobody presented symptoms after drinking water
      without added copper while 9 subjects presented nausea after receiving the 10 mg
      Cu/l solution. The group receiving drinking water with 10 mg Cu/l presented
      greater antral areas during the first 60 min of observation. Individual and mean
      fitted curves for antral area, calculated and compared using the linear mixed
      effects model fit by REML, showed a group effect of copper on antral area over
      time (L. Ratio=23.98, P<0.0001); the effect was due to delay in decreasing antral
      area in the copper treated group during the first hour after ingestion. No
      differences were found by gender or nausea. Results show a copper effect on
      gastric response suggesting that acute exposure to copper in water modify the
      first phase of gastric emptying.

PMID- 12606170
TI  - Whipple's disease--from enigma to genomics.

PMID- 12606171
TI  - Evaluating interventions for HIV prevention in Africa.

PMID- 12606172
TI  - Maintenance buprenorphine for opioid users.

PMID- 12606173
TI  - Light and shade in proposed revision of EU drug-regulatory legislation.

PMID- 12606174
TI  - Sequencing and analysis of the genome of the Whipple's disease bacterium
      Tropheryma whipplei.
AB  - BACKGROUND: Whipple's disease is a rare multisystem chronic infection, involving
      the intestinal tract as well as various other organs. The causative agent,
      Tropheryma whipplei, is a Gram-positive bacterium about which little is known.
      Our aim was to investigate the biology of this organism by generating and
      analysing the complete DNA sequence of its genome. METHODS: We isolated and
      propagated T whipplei strain TW08/27 from the cerebrospinal fluid of a patient
      diagnosed with Whipple's disease. We generated the complete sequence of the
      genome by the whole genome shotgun method, and analysed it with a combination of
      automatic and manual bioinformatic techniques. FINDINGS: Sequencing revealed a
      condensed 925938 bp genome with a lack of key biosynthetic pathways and a reduced
      capacity for energy metabolism. A family of large surface proteins was
      identified, some associated with large amounts of non-coding repetitive DNA, and
      an unexpected degree of sequence variation. INTERPRETATION: The genome reduction
      and lack of metabolic capabilities point to a host-restricted lifestyle for the
      organism. The sequence variation indicates both known and novel mechanisms for
      the elaboration and variation of surface structures, and suggests that immune
      evasion and host interaction play an important part in the lifestyle of this
      persistent bacterial pathogen.

PMID- 12606175
TI  - Syndromic management of sexually-transmitted infections and behaviour change
      interventions on transmission of HIV-1 in rural Uganda: a community randomised
      trial.
AB  - BACKGROUND: Treatment of sexually-transmitted infections (STIs) and behavioural
      interventions are the main methods to prevent HIV in developing countries. We
      aimed to assess the effect of these interventions on incidence of HIV-1 and other
      sexually-transmitted infections. METHODS: We randomly allocated all adults living
      in 18 communities in rural Uganda to receive behavioural interventions alone
      (group A), behavioural and STI interventions (group B), or routine government
      health services and community development activities (group C). The primary
      outcome was HIV-1 incidence. Secondary outcomes were incidence of herpes simplex
      virus type 2 (HSV2) and active syphilis and prevalence of gonorrhoea, chlamydia,
      reported genital ulcers, reported genital discharge, and markers of behavioural
      change. Analysis was per protocol. FINDINGS: Compared with group C, the incidence
      rate ratio of HIV-1 was 0.94 (0.60-1.45, p=0.72) in group A and 1.00 (0.63-1.58,
      p=0.98) in group B, and the prevalence ratio of use of condoms with last casual
      partner was 1.12 (95% CI 0.99-1.25) in group A and 1.27 (1.02-1.56) in group B.
      Incidence of HSV2 was lower in group A than in group C (incidence rate ratio
      0.65, 0.53-0.80) and incidence of active syphilis for high rapid plasma reagent
      test titre and prevalence of gonorrhoea were both lower in group B than in group
      C (active syphilis incidence rate ratio, 0.52, 0.27-0.98; gonorrhoea prevalence
      ratio, 0.25, 0.10-0.64). INTERPRETATION: The interventions we used were
      insufficient to reduce HIV-1 incidence in rural Uganda, where secular changes are
      occurring. More effective STI and behavioural interventions need to be developed
      for HIV control in mature epidemics.

PMID- 12606176
TI  - Relapse prevention with antidepressant drug treatment in depressive disorders: a
      systematic review.
AB  - BACKGROUND: Antidepressant drugs can promote remission from acute depressive
      episodes. Our aim was to establish how long such treatments should be continued
      to prevent relapse. METHOD: We did a systematic overview of evidence from
      randomised trials of continuing treatment with antidepressants in patients with
      depressive disorders who have responded to acute treatment. Medline, Embase,
      Cinahl, PsycLIT, Psyndex, and Lilacs were searched. FINDINGS: Data were pooled
      from 31 randomised trials (4410 participants). Continuing treatment with
      antidepressants reduced the odds of relapse by 70% (95% CI 62-78; 2p<0.00001)
      compared with treatment discontinuation. The average rate of relapse on placebo
      was 41% compared with 18% on active treatment. The treatment effect seemed to
      persist for up to 36 months, although most trials were of 12 months' duration,
      and so the evidence on longer-term treatment requires confirmation. Significantly
      more participants allocated antidepressants withdrew from the trials than did
      those allocated to placebo (18% vs 15%, respectively; odds ratio 1.30, 95% CI
      1.07-1.59): the treatment effect could be even greater in adherent patients. The
      two-thirds reduction in risk of depressive relapse seemed to be largely
      independent of the underlying risk of relapse, the duration of treatment before
      randomisation, or the duration of the randomly allocated therapy. INTERPRETATION:
      Antidepressants reduce the risk of relapse in depressive disorder, and continued
      treatment with antidepressants would benefit many patients with recurrent
      depressive disorder. The treatment benefit for an individual patient will depend
      on their absolute risk of relapse with greater absolute benefits in those at
      higher risk. Further trials are needed to establish the optimum length of therapy
      and should include patients who were not well represented in these trials,
      including those at low risk of relapse.

PMID- 12606177
TI  - 1-year retention and social function after buprenorphine-assisted relapse
      prevention treatment for heroin dependence in Sweden: a randomised, placebo
      controlled trial.
AB  - BACKGROUND: The partial opiate-receptor agonist buprenorphine has been suggested
      for treatment of heroin dependence, but there are few long-term and placebo
      controlled studies of its effectiveness. We aimed to assess the 1-year efficacy
      of buprenorphine in combination with intensive psychosocial therapy for treatment
      of heroin dependence. METHODS: 40 individuals aged older than 20 years, who met
      DSM-IV criteria for opiate dependence for at least 1 year, but did not fulfil
      Swedish legal criteria for methadone maintenance treatment were randomly
      allocated either to daily buprenorphine (fixed dose 16 mg sublingually for 12
      months; supervised daily administration for a least 6 months, possible take-home
      doses thereafter) or a tapered 6 day regimen of buprenorphine, thereafter
      followed by placebo. All patients participated in cognitive-behavioural group
      therapy to prevent relapse, received weekly individual counselling sessions, and
      submitted thrice weekly supervised urine samples for analysis to detect illicit
      drug use. Our primary endpoint was 1-year retention in treatment and analysis was
      by intention to treat. FINDINGS: 1-year retention in treatment was 75% and 0% in
      the buprenorphine and placebo groups, respectively (p=0.0001; risk ratio 58.7
      [95% CI 7.4-467.4]). Urine screens were about 75% negative for illicit opiates,
      central stimulants, cannabinoids, and benzodiazepines in the patients remaining
      in treatment. INTERPRETATION: The combination of buprenorphine and intensive
      psychosocial treatment is safe and highly efficacious, and should be added to the
      treatment options available for individuals who are dependent on heroin.

PMID- 12606178
TI  - What you want to see.

PMID- 12606180
TI  - A boy with a disabling cough.

PMID- 12606179
TI  - Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as
      a regulator of body iron homoeostasis.
AB  - BACKGROUND: The mechanisms responsible for disturbed iron homoeostasis in
      hereditary haemochromatosis are poorly understood. However, results of some
      studies indicate a link between hepcidin, a liver-derived peptide, and intestinal
      iron absorption, suggesting that this molecule could play a part in hepatic iron
      overload. To investigate this possible association, we studied the hepatic
      expression of the gene for hepcidin (HAMP) and a gene important in iron transport
      (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe
      knockout mice. METHODS: We extracted total RNA from the liver tissue of 27
      patients with HFE-associated haemochromatosis, seven transplant donors
      (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were
      examined by ribonuclease protection assays and expressed relative to the
      housekeeping gene GAPD. FINDINGS: There was a significant decrease in HAMP
      expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3
      7.5; p<0.0001) despite significantly increased iron loading. Similarly, we noted
      a decrease in Hamp expression in iron-loaded Hfe-knockout mice. Hepatic IREG1
      expression was greatly upregulated in patients with haemochromatosis (1.8-fold,
      95% CI 1.5-2.2; p=0.002). There was a significant correlation between hepatic
      iron concentration and expression of HAMP (r=0.59, p=0.02) and IREG1 (r=0.67,
      p=0.007) in untreated patients. INTERPRETATION: Lack of HAMP upregulation in HFE
      associated haemochromatosis despite significant hepatic iron loading indicates
      that HFE plays an important part in the regulation of hepcidin expression in
      response to iron overload. Our results imply that the liver is important in the
      pathophysiology of HFE-associated haemochromatosis. Furthermore, the increase in
      hepatic IREG1 expression in haemochromatosis suggests that IREG1 could function
      to facilitate the removal of excess iron from the liver.

PMID- 12606181
TI  - Effectiveness of meningococcal C conjugate vaccine in teenagers in England.
AB  - Meningococcal C conjugate vaccine was introduced into clinical practice in the UK
      before phase 3 trials had been undertaken. We therefore did a case-control study
      in teenagers to assess vaccine effectiveness. All cases (n=31) enrolled had
      laboratory confirmed meningococcal C disease. We also enrolled between one and
      three controls (n=65) per case, matched by age, sex, and general practitioner.
      Three patients and 23 controls had been vaccinated. The protective effectiveness
      of the vaccine, estimated by conditional logistic regression, was 93% (95% CI 39
      99), which is similar to screening method estimates. The estimated protective
      effectiveness varied little when potential confounding risk factors were taken
      into account. Our findings indicate that the vaccine is highly protective against
      invasive meningococcal C disease.

PMID- 12606183
TI  - Umbilical-cord blood for transfusion in children with severe anaemia in under
      resourced countries.
AB  - Shortage of blood for transfusion contributes substantially to mortality of
      children with severe anaemia in sub-Saharan Africa. Umbilical-cord blood could be
      an additional and readily available source of blood. We aimed to show whether it
      is possible to gather cord blood in a busy Ghanaian labour ward. Mean volume of
      each blood sample obtained from the umbilical cord was 85 mL (SD 28.0). This
      amount of blood is sufficient to raise the haemoglobin concentrations of 28 (21%)
      of 131 children needing transfusions in the same hospital, by 30 g/L. Further
      work is needed to improve the sterility of cord blood and to establish the
      resource and logistical implications of scaling-up for sub-Saharan Africa
      transfusion services.

PMID- 12606182
TI  - Low plasma arginine concentrations in children with cerebral malaria and
      decreased nitric oxide production.
AB  - Nitric oxide (NO) production and mononuclear cell NO synthase 2 (NOS2) expression
      are high in healthy Tanzanian children but low in those with cerebral malaria.
      Factors that downregulate NOS2 also diminish factors involved in cellular uptake
      and biosynthesis of L-arginine, the substrate for NO synthesis. We therefore
      postulated that L-arginine concentrations would be low in individuals with
      cerebral malaria. We measured concentrations of L-arginine in cryopreserved
      plasma samples from Tanzanian children with and without malaria. L-arginine
      concentrations were low in individuals with cerebral malaria (mean 46 micromol/L,
      SD 14), intermediate in those with uncomplicated malaria (70 micromol/L, 20), and
      within the normal range in healthy controls (122 micromol/L, 22; p<0.0001).
      Analysis by logistic regression showed that hypoargininaemia was significantly
      associated with cerebral malaria case-fatality. Hypoargininaemia may contribute
      to limited NO production in children with cerebral malaria and to severe disease.

PMID- 12606184
TI  - Rest breaks and accident risk.
AB  - Regular rest breaks are recommended to prevent accumulation of accident risk
      during sustained activities. We examined the effect of rest breaks on temporal
      trends in industrial accident risk, by assessment of accident records from a
      large engineering company, obtained over 3 years. In 2 h of continuous work,
      relative risk of an accident in the last half-hour of a shift was 2.08 (95% CI
      1.73-2.43) higher than in the first half-hour. Trends in risk did not seem to
      differ between three 2-h work periods. Regular rest breaks seem to be an
      effective way to control accumulation of risk during industrial shift-work.

PMID- 12606185
TI  - Cystic fibrosis.
AB  - Cystic fibrosis is the most common autosomal recessive disorder in white people,
      with a frequency of about 1 in 2500 livebirths. Discovery of the mutated gene
      encoding a defective chloride channel in epithelial cells--named cystic fibrosis
      transmembrane conductance regulator (CFTR)--has improved our understanding of the
      disorder's pathophysiology and has aided diagnosis, but has shown the disease's
      complexity. Gene replacement therapy is still far from being used in patients
      with cystic fibrosis, mostly because of difficulties of targeting the appropriate
      cells. Life expectancy of patients with the disorder has been greatly increased
      over past decades because of better notions of symptomatic treatment strategies.
      Here, we summarise advances in understanding and treatment of cystic fibrosis,
      focusing on pulmonary disease, which accounts for most morbidity and deaths.

PMID- 12606186
TI  - Roth spots in diabetes mellitus.

PMID- 12606187
TI  - Itch.
AB  - Itch is a common skin sensation, with substantial effects on behaviour.
      Neurophysiological research has permitted accurate definition of neural pathways
      of itch, and has confirmed the distinctiveness of itch pathways in comparison
      with pain. A clinical classification of itch, based on such improved
      understanding, describes the difference between peripheral (pruritoceptive) and
      central (neurogenic or neuropathic) itch. New specific and sensitive
      investigational methods in people and animals enable us to better understand this
      bothersome symptom, and have important clinical implications. We describe the
      clinical classification of itch, new findings on neuropathophysiology of itch,
      methods for assessment, and improved treatments.

PMID- 12606188
TI  - Mercury in infants given vaccines containing thiomersal.

PMID- 12606189
TI  - Mercury in infants given vaccines containing thiomersal.

PMID- 12606190
TI  - Mercury in infants given vaccines containing thiomersal.

PMID- 12606192
TI  - A holiday in Canada.

PMID- 12606193
TI  - The CAPTIM study.

PMID- 12606194
TI  - The CAPTIM study.

PMID- 12606196
TI  - Benign paroxysmal positional vertigo: are roller coasters really beneficial?

PMID- 12606197
TI  - Coffee consumption and risk of type 2 diabetes mellitus.

PMID- 12606198
TI  - Coffee consumption and risk of type 2 diabetes mellitus.

PMID- 12606200
TI  - Coffee consumption and risk of type 2 diabetes mellitus.

PMID- 12606201
TI  - Coffee consumption and risk of type 2 diabetes mellitus.

PMID- 12606202
TI  - A woman who gained weight and became schizophrenic.

PMID- 12606203
TI  - Old letters, new rules.

PMID- 12606204
TI  - Old letters, new rules.

PMID- 12606206
TI  - A woman who gained weight and became schizophrenic.

PMID- 12606207
TI  - Old letters, new rules.

PMID- 12606208
TI  - Old letters, new rules.

PMID- 12606211
TI  - Old letters, new rules.

PMID- 12606212
TI  - Monica Alvarado interviewed by Marilynn Larkin.

PMID- 12606216
TI  - United Nations reveals aid plans for war in Iraq.

PMID- 12606218
TI  - Mass spectrometric-based approaches in quantitative proteomics.
AB  - Classically, experiments aimed at studying changes in protein expression have
      always followed a small set of proteins. This focused approach was necessary
      since tools to efficiently analyze large numbers of proteins were simply not
      available. Large-scale quantitative proteomics promises to produce reams of data
      that previously would have taken decades to measure with classical methods. Mass
      spectrometry is already a well-established protein identification tool and recent
      methodological developments indicate that it can also be successfully applied to
      extract quantitative data of protein abundance. From the first reports 4 years
      ago, numerous schemes to take advantage of stable isotope nuclei incorporation in
      proteins and peptides have been developed. Here we review the benefits and
      pitfalls of some of the most commonly used protocols, focusing on a procedure now
      being used extensively in our laboratory, stable isotope labeling with amino
      acids in cell culture (SILAC). The basic theory, application, and data analysis
      of a SILAC experiment are discussed. The emerging nature of these techniques and
      the rapid pace of technological development make forecasting the directions of
      the field difficult but we speculate that SILAC will soon be a key tool of
      quantitative proteomics.

PMID- 12606219
TI  - Applying microscopy to the analysis of nuclear structure and function.
AB  - One of the ultimate goals of biological research is to understand mechanisms of
      cell function within living organisms. With this in mind, many sophisticated
      technologies that allow us to inspect macromolecular structure in exquisite
      detail have been developed. Although knowledge of structure derived from
      techniques such as X-ray crystallography and nuclear magnetic resonance is of
      vital importance, these approaches cannot reveal the remarkable complexity of
      molecular interactions that exists in vivo. With this in mind, this review
      focuses on the use of microscopy techniques to analyze cell structure and
      function. We describe the different basic microscopic methodologies and how the
      routine techniques are best applied to particular biological problems. We also
      emphasize the specific capabilities and uses of light and electron microscopy and
      highlight their individual advantages and disadvantages. For completion, we also
      comment on the alternative possibilities provided by a variety of advanced
      imaging technologies. We hope that this brief analysis of the undoubted power of
      microscopy techniques will be enough to stimulate a wider participation in this
      rapidly developing area of biological discovery.

PMID- 12606220
TI  - Visualizing single molecules inside living cells using total internal reflection
      fluorescence microscopy.
AB  - Over the past 10 years, advances in laser and detector technologies have enabled
      single fluorophores to be visualized in aqueous solution. Here, we describe
      methods based on total internal reflection fluorescence microscopy (TIRFM) that
      we have developed to study the behavior of individual protein molecules within
      living mammalian cells. We have used cultured myoblasts that were transiently
      transfected with DNA plasmids encoding a target protein fused to green
      fluorescent protein (GFP). Expression levels were quantified from confocal images
      of control dilutions of GFP and cells with 1-100 nM GFP were then examined using
      TIRFM. An evanescent field was produced by a totally internally reflected, argon
      ion laser beam that illuminated a shallow region (50-100 nm deep) at the glass
      water interface. Individual GFP-tagged proteins that entered the evanescent field
      appeared as individual, diffraction-limited spots of light, which were clearly
      resolved from background fluorescence. Molecules that bound to the basal cell
      membrane remained fixed in position for many seconds, whereas those diffusing
      freely in the cytoplasm disappeared within a few milliseconds. We developed
      automated detection and tracking methods to recognize and characterize the
      behavior of single molecules in recorded video sequences. This enabled us to
      measure the kinetics of photobleaching and lateral diffusion of membrane-bound
      molecules.

PMID- 12606221
TI  - Ultrasensitive investigations of biological systems by fluorescence correlation
      spectroscopy.
AB  - Fluorescence correlation spectroscopy (FCS) extracts information about molecular
      dynamics from the tiny fluctuations that can be observed in the emission of small
      ensembles of fluorescent molecules in thermodynamic equilibrium. Employing a
      confocal setup in conjunction with highly dilute samples, the average number of
      fluorescent particles simultaneously within the measurement volume (approximately
      1 fl) is minimized. Among the multitude of chemical and physical parameters
      accessible by FCS are local concentrations, mobility coefficients, rate constants
      for association and dissociation processes, and even enzyme kinetics. As any
      reaction causing an alteration of the primary measurement parameters such as
      fluorescence brightness or mobility can be monitored, the application of this
      noninvasive method to unravel processes in living cells is straightforward. Due
      to the high spatial resolution of less than 0.5 microm, selective measurements in
      cellular compartments, e.g., to probe receptor-ligand interactions on cell
      membranes, are feasible. Moreover, the observation of local molecular dynamics
      provides access to environmental parameters such as local oxygen concentrations,
      pH, or viscosity. Thus, this versatile technique is of particular attractiveness
      for researchers striving for quantitative assessment of interactions and dynamics
      of small molecular quantities in biologically relevant systems.

PMID- 12606222
TI  - Studying the assembly of multicomponent protein and ribonucleoprotein complexes
      using surface plasmon resonance.
AB  - The assembly of large macromolecular complexes is an important aspect of cellular
      organization and metabolism. Interactions involving such complexes in principle
      follow the same rules as the interactions between single proteins or other
      macromolecules and can therefore be investigated using similar approaches. We
      have developed protocols employing standard surface plasmon resonance technology
      that allow the investigation of interactions involving complex macromolecular
      structures. The principal experimental challenges arise from the possibility of
      parallel reactions where partially assembled or dissociated subcomplexes form a
      significant proportion of the molecule population and from an increased
      likelihood of unspecific binding events owing to the larger surface and
      statistically higher number of charged areas on multisubunit assemblies. Ways to
      experimentally avoid or, where this is not possible, to control for these
      complications are discussed.

PMID- 12606223
TI  - Quantitative characterization of biomolecular assemblies and interactions using
      atomic force microscopy.
AB  - Atomic force microscopy (AFM) has been applied in many biological investigations
      in the past 15 years. This review focuses on the application of AFM for
      quantitatively characterizing the structural and thermodynamic properties of
      protein-protein and protein-nucleic acid complexes. AFM can be used to determine
      the stoichiometries and association constants of multiprotein assemblies and to
      quantify changes in conformations of proteins and protein-nucleic acid complexes.
      In addition, AFM in solution permits the observation of the dynamic properties of
      biomolecular complexes and the measurement of intermolecular forces between
      biomolecules. Recent advances in cryogenic AFM, AFM on two-dimensional crystals,
      carbon nanotube probes, solution imaging, high-speed AFM, and manipulation
      capabilities enhance these applications by improving AFM resolution and the
      dynamic and operative capabilities of the AFM. These developments make AFM a
      powerful tool for investigating the biomolecular assemblies and interactions that
      govern gene regulation.

PMID- 12606224
TI  - Molecular mechanisms of gene regulation studied by site-directed spin labeling.
AB  - The technique of site-directed spin labeling using cysteine substitution
      mutagenesis followed by modification of the sulfhydryl group with a nitroxide
      reagent is emerging as a valuable alternative for the determination of protein
      folds and conformational changes in a variety of systems. The incorporation of
      pairs of nitroxides allows determination of intramolecular distances and distance
      changes with a spatial resolution at the level of the backbone fold under
      conditions relevant to function. The methodology of electron paramagnetic
      resonance spectral data acquisition and interpretation is reviewed with studies
      on conformational changes of Tet repressor (TetR) and the human immunodeficiency
      virus type 1 reverse transcriptase (RT) on interaction with nucleic acid
      substrates or inhibitors in solution. A twisting motion of the DNA reading heads
      of TetR on induction by tetracycline (tc) is observed in solution by changes of
      the interspin distances between interacting nitroxides at positions 22/22(') or
      47/47('). Spin-label side chains located near the tc-binding pocket or at
      position 202 indicate different conformations for the tc- and DNA-complexed
      repressor also in the core of the protein. Interspin distances between spin
      labeled residue positions 24 and 287 in the fingers and the thumb domains of RT
      complexed with dsDNA or a pseudoknot RNA in solution were found to agree with the
      respective crystal data of the so-called open and closed conformations. For the
      unliganded RT a temperature-dependent equilibrium between these two states is
      observed.

PMID- 12606226
TI  - The benefits of ribose in cardiovascular disease.
AB  - Cardiovascular disease still ranks as the leading cause of death in men and
      women. Adults have tried to lower their risk of cardiovascular disease by
      improving their diet, quitting smoking, controlling blood pressure and exercising
      regularly. Additionally, many adults have turned to nutriceutical or natural
      products. Myocardial ischemia, produces a depression in myocardial tissue levels
      of high energy compounds, along with a compromise in myocardial function. Ribose,
      a naturally occurring sugar, has been extensively investigated, both in animal
      and clinical studies, as an agent to enhance the recovery of these depressed
      energy compounds. Results of these studies have been promising in enhancing the
      recovery of these energy molecules along with an improvement in myocardial
      function. Therefore, ribose should be considered as a potential agent in the
      treatment of ischemic cardiovascular disease.

PMID- 12606225
TI  - Vibrational Raman optical activity of proteins, nucleic acids, and viruses.
AB  - Due to its sensitivity to chirality, Raman optical activity (ROA), which may be
      measured as a small difference in vibrational Raman scattering from chiral
      molecules in right- and left-circularly polarized incident light, is a powerful
      probe of biomolecular structure in solution. Protein ROA spectra provide
      information on the secondary and tertiary structures of the polypeptide backbone,
      hydration, side-chain conformation, and structural elements present in denatured
      states. Nucleic acid ROA spectra yield information on the sugar ring
      conformation, the base stacking arrangement, and the mutual orientation of the
      sugar and base rings around the C-N glycosidic linkage. ROA is able to
      simultaneously probe the structures of both the protein and the nucleic acid
      components of intact viruses. This article gives a brief account of the theory
      and measurement of ROA and presents the ROA spectra of a selection of proteins,
      nucleic acids, and viruses which illustrate the applications of ROA spectroscopy
      in biomolecular research.

PMID- 12606227
TI  - Origin of anti-tumor immunity failure in mammals and new possibility for
      immunotherapy.
AB  - There is now much evidence that tumors can be immunogenic. Tumor cells very often
      express antigens in a form recognizable by the host immune system, but most
      frequently without consequences on tumor progression. This has been shown in many
      experimental models and different experimental conditions. Immediate mechanisms
      for the escape of tumors from immune response are very similar with mechanisms
      for the escape of fetoplacental unit (as an allograft) from maternal immune
      response. Similarity between these two mechanisms is so significant that any
      randomness is banished. Mechanisms of anti-tumor immunity in mammals are
      substantially different in comparison with mechanisms of anti-tumor immunity in
      other classes of vertebrates. Moreover, type of most frequently tumors in non
      mammalians vertebrates is also significant different. Incidence of malignant
      tumors in non-mammalians vertebrates is significantly less than incidence of
      malignant tumors in mammals. These facts indicate that immune system of mammals
      during anti-tumor immune response is tricked with similarity between tumor cells
      and trophoblast or other placental cells. It may be a specific evolutionary
      approach in rendering of anti-tumor immunity failure in mammals, and new
      possibility for anti-tumor immunotherapy.

PMID- 12606228
TI  - Free convection schema defines the shape of the human brain: brain and self
      organization.
AB  - As a fundamental rule of nature, the shape of a functioning organ should never be
      considered accidental. Since the principal rules for a self-organizing neural
      network are not sufficient for determining the shape and anatomic features of the
      brain, these must be governed by other rules. Ontogeny of the global shape of the
      brain is guided by radial glial fibers. The rules defining the growth pattern of
      radial glial fibers, therefore, should be the rules for a self-organization for
      the shape of the brain. In this work, the overall shape and structural anatomic
      detail of the human brain was successfully simulated utilizing self-organization
      rules of heat convection represented by Boussinesq partial differential
      equations. The result suggests that radial glial fibers may grow in Markovian
      fashion, guided by gaseous substrates moving miniature distances according to a
      convection schema. The result also holds implication that the shape of the brain
      has specific physical meaning in the creation of a virtual sphere, which in turn
      ensures equivalence of columns within the entire cortex, the well-known vital
      fundamental of brain organization.

PMID- 12606229
TI  - The initiation of multiple sclerosis: a new infectious hypothesis.
AB  - Both genetic and environmental factors cause multiple sclerosis (MS). Few genes
      have been identified, however, and environmental factors remain elusive. Some
      postulate an infectious cause, but no pathogens are reproducibly demonstrable in
      CNS lesions. I postulate that the CNS is not the infectious target in MS, but
      propose a two-hit infectious hypothesis focusing on nai;ve CD4 T-cells that
      initiate demyelination: (1) Various common viruses infect the thymus during
      childhood (first hit) and enhance nai;ve CD4 T-cell reactivity to CNS
      autoantigens; (2) Heterogeneous pathogens fully activate these T-cells during
      adulthood (second hit) to initiate myelin injury. The novel concept of thymic
      infection provides insight into the nature of some susceptibility genes, helps
      explain the high discordance rates in genetically susceptible individuals, and
      suggests it is futile to search for pathogens in MS lesions. Pathogen
      heterogeneity, i.e., the lack of a single infectious cause, implies there can be
      no simple therapies to prevent or treat MS.

PMID- 12606230
TI  - The next step in infectious disease: taming bacteria.
AB  - Except for immunization programs our warfare with bacteria has always been a
      frontal assault with antibiotics. In this warfare we win battles, but with every
      new battle the enemy gets stronger. We need other options. Recent experience
      suggests two alternatives. First, public health measures designed to control the
      spread of infectious disease are associated with the selection of less virulent
      strains of microorganisms. Second, the same selection pressures obtained by
      public health measures outside the body are brought into play when we inhibit the
      adherence of bacteria within the body. Two recent studies using food sugars known
      to inhibit bacterial adherence show long-term benefits best explained by the
      previously observed decreases in bacterial virulence, following chronic exposure
      to the respective substances. Cranberry juice selects for less uropathogenic
      strains of Escherichia coli and xylitol for less caries producing Streptococcus
      mutans. The ability of these substances to reduce bacterial adherence in the
      human host has been known for some time, but poorly utilized. Their in vitro
      ability to decrease virulence has been reported but not clinically studied.

PMID- 12606232
TI  - Our neglect of the normal variation is linked to a reluctance to accept
      multifactorial inheritance and the role of environment.
AB  - One of the most surprising evolutionary discoveries is that wild species similar
      to human contain a vast reservoir of variability. Why are we persistently
      reluctant to discuss normal variation in brain structure and function and label
      any deviation pathological? Despite the failure of Mendelian Genetics to solve
      the genetic puzzle in psychiatry, we refuse to discuss multifactorial inheritance
      and the role of environmental factors. Rising living conditions (high protein
      diet) accelerate maturation, lower pubertal age, shift body-built toward more
      weight for height and cerebral excitability toward higher levels. Another
      environmental factor which has to be provided by diet is marine fat which our
      brain consists of. It normalizes brain function at all levels of excitability and
      possibly prevents psychotic episodes if adequately supplied. As part of Human
      Variation in Growth and Maturation, Schizophrenia and Manic-depressive psychosis
      are multifactorially inherited and share susceptibility loci. They are localized
      at the extremes of variation. Excitability, body-built, clinical picture and CNS
      finding accord with this, their phenotypic characteristics might prove valuable
      in a hunt for genes not common to both disorders.

PMID- 12606231
TI  - Type I interferons induce proteins susceptible to act as thyroid receptor (TR)
      corepressors and to signal the TR for destruction by the proteasome: possible
      etiology for unexplained chronic fatigue.
AB  - In some patients complaining of chronic fatigue such as those suffering from the
      chronic fatigue syndrome (CFS), no underlying physical cause can be clearly
      identified and they typically present a normal thyroid function. Several studies
      indicate a dysregulation in the type I interferons (IFN-alpha/beta) pathway in
      CFS resulting in a sustained upregulation of 2('),5(')-oligoadenylate synthetases
      (2-5OAS). Likewise, patients treated with IFN-alpha/beta usually complain of
      severe fatigue as a limiting side effect. Beside the 2-5OAS, IFN-alpha/beta
      induce also the expression of three closely related proteins of unknown function
      termed the 2-5OAS-like (2-5OASL) proteins. The amino acid sequences of the 2
      5OASL proteins display 96% identity with the partial sequence of the thyroid
      receptor interacting protein (TRIP) 14, further contain two typical thyroid
      hormone receptor (TR) coregulator domains and feature two ubiquitin C-terminal
      domains. From these observations, we raise the hypothesis that the 2-5OASL
      proteins are TRIPs capable of, respectively, repressing TR transactivation and/or
      signaling the receptor for destruction by the proteasome. Such molecular
      mechanisms could explain the development of a clinical hypothyroid state in
      presence of a normal thyroid function.

PMID- 12606234
TI  - The primary restless legs syndrome pathogenesis depends on the dysfunction of EEG
      alpha activity.
AB  - A dopaminergic drug - lisuride exhibited increase in alpha, decrease in beta and
      slow activities on brain function measured by computerized EEG. It was postulated
      that reverse EEG changes might play role in the pathogenesis of RLS. During
      transition from wakefulness to sleep stage 1 changes in alpha activity initiate
      long-lasting alpha arousal responses and they continue increasingly at sleep
      stage 2. This dysfunction is probably due to a genetic vulnerability of EEG alpha
      rhythm and disinhibits the diencephalospinal dopamine system, mostly during sleep
      but also during wakefulness. The disinhibition produces background for activation
      of PLMs, disturbing sensations in brainstem and urge to move, motor restlessness
      at cerebral cortex, generally for legs. All lead to severe insomnia. In RLS
      patients, forced deviations from alpha to theta or beta activity are unsuitable
      and resting EEGs reflect a dopamine receptor-specific 'individual sensitivity.'
      This vulnerability is alleviated after lisuride with suitable CEEG changes.

PMID- 12606233
TI  - Candida albicans and selenium.
AB  - Although low selenium levels have been recorded in infants, no specific human
      disorder has been linked to low selenium status. The incidence of thrush, the
      common enteric fungal infection caused by Candida albicans, has increased
      markedly with antibiotic therapy and research has provided evidence that its
      colonization leads to competition for Coenzyme Q10 (CoQ10) in the host.
      Furthermore it is now known that ubiquinones are essential in heart muscle for
      oxidative phosphorylation in the mitochondrial respiratory chain and considered
      that glutathione peroxidase (GSHPx) in the mitochondria protects ubiquinone from
      oxidation.

PMID- 12606235
TI  - Inaccuracy in cervical dilatation assessment and the progress of labour
      monitoring.
AB  - Cervical dilatation is an essential indicator of the progress of labour and it is
      assessed several times during every vaginal delivery. For a long period of time,
      the size of the error in cervical dilatation assessment was considered of no
      importance and only in the last ten years it was estimated. The hypothesis is
      that the estimated error of +/-1cm in cervical dilatation assessment and
      inaccurate values for the rate of cervical dilatation, influence decisions of
      obstetricians during labour. It is suggested that in labours in which the rate of
      cervical dilatation is 1 cm/h the possibility of drawing incorrect conclusions
      upon progress of these labours is 11 and 33% for time intervals between
      assessments of 4 and 2 h.

PMID- 12606236
TI  - Interleukin-2 and cancer: critical analysis of results, problems and
      expectations.
AB  - The cancer process in a combination of two kinds of events: a multistep cellular
      genetic defects giving cells independent growth and great adaptation capability,
      a multistep interactions profiles with what is called the stromal reaction from
      the original in situ tumor to the invasive metastatic and angiogenic tumor. The
      immune system plays an important role in the control of the cancer process but
      always must be seen as a part integrated in the stromal reaction. In order to
      boost the immune system capability to treat a cancer we must never forget these
      cellular and tissular dimensions. Interleukins, growth factors and monoclonal
      antibodies are new agents are able to bring immunotherapy of cancer to reality.
      Interleukin 2 did not match our dreams of the ideal factor which can stimulate
      the defective immune system and bring the cancer evolution to an end. The little
      but real remissions obtained with the IL-2 high dose protocols still sustains our
      trust of the immune system as a critical barrier to cancer evolution but the
      numerous side effects reminds us that cytokines are not to be used as antibiotics
      and hormones. IL-2 is a regulator of the immune system at the microenvironment
      level, therefore flooding the blood circulation with high IL-2 doses is not
      appropriate. We have also to understand that IL-2 can interact directly with
      cancer cells and also with stromal cells (endothelial and fibroblastic cells),
      the outcome of IL-2 immunotherapy is not restricted to the interactions with
      immune cells.

PMID- 12606238
TI  - Future strategies in psychiatric genetics.
AB  - There is evidence suggesting that the primary (idiopathic) mental disorders are
      due to epimutations involving genes that determine the structure of the brain.
      Although in the past it has been suggested that the genes underlying the primary
      mental disorders may be unidentifiable, recent developments in neuroscience
      suggest otherwise. This paper outlines various epigenetic strategies that may
      help identify the genes underlying these disorders.

PMID- 12606237
TI  - Prion: toxic or infectious agent?
AB  - Prions are proteins that cause a number of invariably fatal neuro-degenerative
      diseases, which can be classified into two groups: genetic or sporadic diseases
      (GSD) and transmissible spongiform encephalopathies (TSE). Both types of disease
      require the development of both normal prion (PrP) and abnormal prion (PrP(sc))
      which differs from PrP in having a tertiary structure rich in beta-sheets. In
      fact, PrP(sc) is a totally dehydrated protein with an anhydrous environment,
      probably a thin carbon dioxide gas gap, that is why it appears highly resistant
      to proteases, to chemical disinfectants in water phase except in certain
      conditions to sodium hydroxide and sodium hypochlorite, to heat and to radiation.
      GSD and TSE diseases differ in incubation time, primary symptoms, and nature of
      CNS lesions. This paper argues that diseases of the GSD type as inherited or
      hereditary metabolic disorders and diseases of the TSE type could be regarded as
      chemical poisonings. TSE is caused by a deficiency in the chemo-defense system
      (CDS), which is unable to destroy or eliminate PrP(sc). As a result, the immune
      defense system (IDS) accommodates PrP(sc) as an inert particle if not a virus
      lure and routes it through to the nervous central system and the brain via the
      body's lymphoreticular system. In TSE PrP(sc) acts inside the cells as a toxic
      disruptor of post-translational phase of PrP biosynthesis. Unfortunately, CDS and
      IDS appear unable to neutralize PrP(sc).

PMID- 12606239
TI  - Breech presentation and tossing a coin: heads or tails.
AB  - Through a retrospective review of our own materials and data from peer-reviewed
      journals, among medical entities a greater probability than 0.5 was not found for
      breech presentation. Submitting the occurrence of breech presentation to the
      classical laws of probability means that each fetus in breech presentation has
      its 'pair' in cephalic presentation. Among medical entities with a probability of
      less than 0.5 for breech presentation, the group of fetuses in cephalic
      presentation consist of two subgroups: (1) fetuses which are by chance in
      cephalic presentation and whose number is identical to the number of fetuses in
      breech presentation, (2) fetuses which are in cephalic presentation because of
      the postural development. Likewise, introducing a medical entity with a small
      number of cases does not allow a conclusion to be drawn about a relationship
      between that entity and breech presentation.

PMID- 12606240
TI  - An association between male homosexuality and reproductive success.
AB  - The existence of homosexuality in humans poses a problem for evolutionary theory.
      Exclusive male homosexuality has a catastrophic effect on reproduction and yet
      inherited factors appear to contribute to it. Previous attempts to resolve this
      conundrum are inconsistent with aspects of evolutionary theory. Additional
      limitations are as follows. Until recently, accounts of homosexuality have paid
      little attention to the probable existence of adaptive bisexuality in ancestral
      populations, from which further variations in sexual orientation may have
      evolved. Secondly, previous explanations have concentrated on the ancestral
      environment of two to three million years ago as the determinant of modern
      sexuality, when more recent influences are likely to have had considerable
      impact. I argue in favour of a longitudinal rather than cross-sectional model of
      the ancestral environment. Thirdly, they have often ignored the possibility of
      variable phenotypic expression, whereby those individuals with a genetic
      propensity for homosexuality exhibit different and adaptive qualities on most
      other occasions. It has been demonstrated in previous studies that homosexual men
      have superior linguistic skills compared to heterosexual men. This may be the
      result of an adaptive feminising effect on the male brain and apply to many
      practising heterosexuals. Other adaptations to the recent ancestral environment
      may include enhanced empathy, fine motor skills and impulse control. By drawing
      together these contributing factors an evolutionary basis for homosexuality can
      be demonstrated.

PMID- 12606241
TI  - Is it healthy to be chaotic?
AB  - The concept of Chaos has proven to be one of the greatest scientific advances
      that have led to radical philosophical implications. It deals with dynamic
      systems whose determining factors are completely unknown to us. Sometimes it
      seems that these dynamic systems exhibit a stochastic behavior while others
      portray simpler or better known behaviors where determinism is obvious. When the
      physician faces chaotic, dynamic systems, he or she wonders if it is healthy for
      these biologic systems to be chaotic. When analyzing the variation in brain and
      heart rates mathematically, the conclusion is that these rates are chaotic,
      complicated and unpredictable. Because each organ regulates its own performance,
      the mathematical variations seem to be the result of the organ's determinism
      rather than fluctuation. This healthy variability is neither a random nor an
      uncontrolled fluctuation. It is a certain, well-harmonized chaos, that 'provides
      the body with the flexibility to respond to different stimuli'.

PMID- 12606242
TI  - Hypothalamic digoxin, geomagnetic fields and human disease--a hypothesis.
AB  - The human hypothalamus synthesis an endogenous membrane Na(+)-K(+) ATPase
      inhibitor, digoxin. A digoxin-mediated model for quantal perception of
      geomagnetic fields is proposed. External geomagnetic fields can produce membrane
      Na(+)-K(+) ATPase inhibition. The inhibition of Na(+)-K(+) ATPase can contribute
      to increase in intracellular calcium and decrease in magnesium, which can result
      in (1) defective neurotransmitter transport mechanism, (2) neuronal degeneration
      and apoptosis, (3) mitochondrial dysfunction, (4) defective golgi body function
      and protein processing dysfunction, (5) immune dysfunction and oncogenesis.
      Geomagnetic fields can thus regulate cellular function and contributing to the
      pathogenesis of disease.

PMID- 12606244
TI  - Genetic chaos and antichaos in human cancers.
AB  - Cancer is considered the genetic disease with the most complex pathogenetic
      mechanism. Contrary to normal human tissues, which function in a highly ordered
      and uniform manner, tumor tissues were considered to develop chaos. Here we
      propose that analysis of human neoplasia according to the concepts of chaos and
      antichaos allowed to distinguish two main types of cancers: the hematopoietic
      cancers, characterized by the orderly antichaos and solid cancers governed by a
      disordered complex of genetic and molecular events characteristic of a chaotic
      pattern. Genetic chaos and antichaos have generated rules that can be applied to
      the diagnosis and therapy of human tumors.

PMID- 12606243
TI  - Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine
      integration and coordination of cellular function--relation to hemispheric
      dominance.
AB  - A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms,
      syndrome-X, rheumatoid arthritis and epilepsy has been described. The
      psychological behavioural patterns of the family were as follows--creativity and
      high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia
      and reduced sleep patterns, increased tendency for spirituality, increased
      tendency for addiction, less of bonding and affectionate behaviour and left
      handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the
      hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase
      activity was found to be reduced in all the disorders and in the indexed family
      studied. Hypothalamic digoxin can modulate conscious perception and its
      dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate
      tryptophan transport over tyrosine resulting in increased levels of depolarising
      tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and
      decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline
      and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the
      above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+)
      ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++)
      levels leading to glutamate excitotoxicity, oncogene activation and immune
      activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and
      increased dolichol can affect glycoconjugate metabolism, membrane formation and
      structure and mitochondrial function leading to the diverse disorders described
      above including those in the indexed family. The isoprenoid pathway and
      neurotransmitter patterns were compared in right-handed/left hemispheric dominant
      and left-handed/right hemispheric dominant individuals. The biochemical patterns
      in the indexed family and the diverse disorders studied correlated with those
      obtained in right hemispheric dominance. The hyperdigoxinemic state indicates
      right hemispheric dominance. Hypothalamic digoxin can thus function as the master
      conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of
      various cellular organelles.

PMID- 12606245
TI  - The role of the parietal lobe in borderline personality disorder.
AB  - Many patients with a diagnosis of borderline personality disorder describe multi
      modal hallucinations. A likely cortical origin for multi-modal hallucinations is
      the inferior parietal lobule. Neuropsychological testing of borderline
      personality disorder reveals deficits of visuospatial capacity; a function which
      is also localised to the inferior parietal lobule. It is hypothesised that this
      brain area is likely to be dysfunctional in those patients with borderline
      personality disorder who have multi-modal hallucinations. A deficit in the
      inferior parietal lobe could plausibly explain a number of other clinical
      features; the gender dimorphism of this disorder, the lack of expressive gesture
      and the specific response to clozapine. More speculatively; the increased concern
      over this disorder over the past 40 years could result from the normal population
      showing an increase in functional ability in the parietal lobe, leaving patients
      with parietal deficits relatively more disabled.

PMID- 12606246
TI  - The experience of Japan as a clue to the etiology of breast and ovarian cancers:
      relationship between death from both malignancies and dietary practices.
AB  - Although breast and ovarian cancers are rare in Japan compared with other
      developed countries, the death rates for both are increasing. In Japan, dramatic
      lifestyle changes occurred after World War II. Over the past 50 years (1947
      1997), the age-standardized death rates of breast and ovarian cancers increased
      about 2- and 4-fold, respectively, and the respective intake of milk, meat, and
      eggs increased 20-, 10-, and 7-fold. The increase in the annual death rates from
      breast and ovarian cancers might be due to the lifestyle changes (increased
      consumption of animal-derived food) that occurred after 1945. Among the food,
      milk and dairy products should receive particular attention since they contain
      considerable amounts of estrogens.

PMID- 12606247
TI  - Homeopathic use of modern medicines: utilisation of the curative rebound effect.
AB  - Homeopathy is a therapeutic method based on the application of the similitude
      principle, utilising medicinal substances that produce effects that are similar
      to the symptoms being treated. In this process, the organism is stimulated to
      react against its own disturbances through a vital (paradoxical, secondary or
      homeostatic) reaction, oriented by the primary effect of the used drug. This
      effect should have properties that are similar to the symptom that is being
      treated. This secondary reaction of the organism to a medicinal stimulus is
      observed in hundreds of modern drugs, and is referred to as a rebound effect. In
      this study we propose the utilisation of modern drugs according to the principle
      of homeopathic cure, employing the rebound effect as a curative reaction. For
      that we suggest the compilation of a Common Materia Medica that would group all
      symptoms produced by the medications in human individuals (therapeutic, adverse
      and side effects), utilising them, a posteriori, following a partial or total
      similitude, in minimal or ponderous doses. By doing that, we can take advantage
      of the numerous modern pharmacological compendiums, amplifying the spectrum of
      homeopathic cure with a wide range of new symptoms and medications.

PMID- 12606248
TI  - Are laboratory animals stressed by their housing environment and are
      investigators aware that this stress can affect physiological data?
AB  - Although stress can affect the behavior and physiology of laboratory animals,
      there has been little investigation into how the quality of animal research is
      affected if the animals are stressed. Even minor perturbations (i.e.,
      environmental noise) can produce a stress response. A pilot survey was designed
      (29/49 responded) to determine the prevalence of noise in animal facilities and
      whether researchers are aware that noise can affect animal physiology. Most
      respondents agreed that environmental factors are stressful to laboratory animals
      (97%) and minor pain/stress causes physiological changes (62%). Of 19/29
      respondents who believed their facility was quiet, 8 identified at least 3-5
      pronounced noise sources. We hypothesize that the level of extraneous noise
      considered acceptable by an investigator depends on their degree of awareness
      that environment can affect an animal's physiology, and their perception of the
      existence of 'mind-body' interactions in an animal.

PMID- 12606249
TI  - Is this the historical 'cancer germ'?
AB  - A highly pleomorphic bacterium, isolated from a canine mammary tumour was found
      to share many characteristics with recently described cancer-related bacteria and
      with the Glover organism, a historically important 'cancer germ'. We suggest that
      both the Glover organism, and possibly other cancer-related bacteria, are likely
      to be a strain of the highly pleomorphic bacterium, Bacillus licheniformis.

PMID- 12606250
TI  - Do retroviruses preferentially integrate within highly plastic regions of the
      human genome?
AB  - Whether retroviral integration is a phenomenon specific to properties of the
      surrounding genomic region is a widely debated question. In this paper we attempt
      to enlight the involvement of genomic regions prone to DNA double strand breaks
      in such process, as well as the more general concept of genome plasticity
      concerning repair, recombination, transposition events. While performing a
      differential display analysis of the promonocytic cell line U937 and clone U42
      HIV infected counterpart, we found, out of about 15 highly dysregulated genes,
      expected according to our previous proteomic analysis, two dysregulated cellular
      transcripts that are shown in the present study to colocalize on band 22q11. The
      LB14 transcript maps within the DiGeorge critical region. Whereas the AG46
      transcript encodes the immunoglobulin-lambda like polypeptide 1 (IGLL1) 4.7Mb
      apart from LB14. The 22q11 band is remarkable for its high plasticity involving
      DNA double strand breaks, that may lead to translocations, large deletions, and
      immunoglobulin rearrangements, frequently observed in this region. We suggest
      that provirus integration preferentially occurs in such genomic regions and that
      the subsequent insertional mutagenesis leads to the present observations.
      Finally, we stress out the possibility that the small size of chromosome 22 is
      associated with this physical property of the genome.

PMID- 12606251
TI  - Correlation of mollicutes and their viruses with multiple sclerosis and other
      demyelinating diseases.
AB  - To identify infectious diseases likely involved in MS, the author previously
      correlated the geographical distribution of MS with the global distribution of
      tick-borne diseases. Tick-borne infectious agents include mollicutes or
      mycoplasmas. The current paper reviews evidence that mollicutes, especially
      spiroplasmas, or their viruses could be the initial exposure that causes MS.
      Mollicute infections, including the effects of their toxins, can be treated or
      prevented with gold salts or tetracyclines. If further research recommended by
      this review finds a role of mycoplasmas in MS, treatment of MS with gold with
      tetracycline should be evaluated.

PMID- 12606252
TI  - Triggering controversy in cardiac excitation-contraction coupling.

PMID- 12606253
TI  - Cardiac sympathetic innervation and control of potassium channel function.

PMID- 12606254
TI  - Imaging the embryonic heart: how low can we go? How fast can we get?

PMID- 12606255
TI  - No role for a voltage sensitive release mechanism in cardiac muscle.
AB  - We have investigated the possibility that some component of calcium release from
      the cardiac sarcoplasmic reticulum (SR) may occur directly in response to the
      surface membrane action potential rather than by calcium induced calcium release
      (CICR). Experiments were performed on rat ventricular myocytes and intracellular
      calcium concentration ([Ca(2+)](i)) measured with fluo-3. In order to mimic
      physiological conditions, experiments were performed at 37 degrees C, using the
      perforated patch technique (to avoid intracellular dialysis) with pulses from -80
      to 0 mV. The addition of 500 microM Cd(2+) to inhibit the L-type Ca current
      reduced the rate of increase of the Ca transient to 2.8 +/- 1% of control. When
      experiments were performed with Na-free solutions in the pipette, Cd(2+)
      abolished the transient completely suggesting that the residual Ca entry was on
      Na-Ca exchange. The addition of Ni(2+) produced a concentration dependent
      inhibition of the Ca transient with 5 mM being sufficient to completely inhibit
      the transient. The inhibitory effects of Ni(2+) were unaffected by prior exposure
      to isoprenaline. These results provide no evidence for a voltage activated
      calcium release mechanism in cardiac muscle and are consistent with SR Ca(2+)
      release being triggered by a process of Ca(2+) induced Ca(2+) release.

PMID- 12606256
TI  - Expression of heart K+ channels in adrenalectomized and catecholamine-depleted
      reserpine-treated rats.
AB  - We studied cardiac outward K currents (transient and sustained) by the whole-cell
      patch-clamp technique and the Kv4.2, Kv4.3, Kv1.4, Kv1.5, Kv1.2 and Kv2.1
      expression of voltage-gated K channel by RT-PCR, in ventricular myocytes from two
      models of catecholamine-depleted adult rats. We induced endogenous catecholamine
      depletion by reserpine treatment and used adrenalectomized rats as a model of
      plasma catecholamine depletion. In reserpine-treated rats (97% decrease in
      endogenous norepinephrine content of the heart), the amplitude of the transient
      outward current was decreased by 48% and Kv4.2 and Kv4.3 mRNA levels were
      decreased by 57% and 34%, respectively. The amount of Kv1.5 mRNA tripled, with no
      change in sustained current density. This increase was not confirmed by
      immunostaining for the Kv1.5 protein. The amplitude of K currents and their
      corresponding mRNA levels returned to control values following recovery from
      reserpine treatment. In contrast, in adrenalectomized rats (98% decrease in
      plasma epinephrine concentration), we observed no change in the amplitude of
      outward K currents or in Kv mRNA levels. These results suggested a role for
      sympathetic innervation and endogenous norepinephrine in the regulation of
      transcription of cardiac outward K currents in physiological and pathological
      situations.

PMID- 12606257
TI  - Protection of ischemic myocardium in dogs using intracoronary 2,3-butanedione
      monoxime (BDM).
AB  - BACKGROUND: Actomyosin ATPase is one of the major ATP consuming enzymes in the
      myocardium. We tested whether 2,3-butanedione monoxime (BDM), a reversible
      inhibitor of actomyosin ATPase, given before coronary occlusion, limits infarct
      size in anesthetized open-chest dogs. METHODS AND RESULTS: After circumflex
      artery catheterization using fluoroscopic guidance, BDM (125 mM) or buffer
      vehicle was infused (12.0 ml/min) for 20 min (BDM-20, n = 5 and Buffer-20, n = 6)
      or for 5 min (BDM-5, n = 6 and Buffer-5, n = 6) prior to 60 min of ischemia and 3
      h of reperfusion. BDM administration increased subendocardial blood flow 271%
      above baseline flow (radioactive microspheres), and systolic wall thickening was
      converted to wall bulging (wall thickening by sonomicrometry was -27 +/- 29% and 
      22 +/- 13% of baseline in BDM-20 and BDM-5, respectively). Adjusted mean infarct
      size (% area-at-risk) was 11.0 +/- 2.8% and 11.9 +/- 2.6% in BDM-20 and BDM-5 vs.
      20.2 +/- 2.5% and 20.5 +/- 2.5% in Buffer-20 and Buffer-5 (ancova, P < 0.05 for
      each BDM vs. Buffer group). Measurement of glycolytic metabolites and the adenine
      nucleotide pool of myocardium paced electronically at 150 beats per minute during
      total ischemia at 37 degrees C following BDM showed a metabolic response similar
      to that seen in ischemic preconditioning. ATP depletion, nucleoside production,
      and lactate accumulation were slowed in ischemic tissue treated with BDM.
      CONCLUSION: BDM given before the onset of ischemia markedly limited infarct size
      and reduced energy demand after the onset of ischemia. The explanation for the
      reduced infarct size induced by BDM treatment is hypothesized to be the
      persistent reduction in energy demand found in ischemic BDM treated myocardium.

PMID- 12606258
TI  - Bone marrow transplantation abolishes inhibition of arteriogenesis in placenta
      growth factor (PlGF) -/- mice.
AB  - We studied the influence of placenta growth factor (PlGF) on arteriogenesis and
      tested the role of bone marrow (BM)-derived cells on PlGF-depleted vascular
      growth. METHODS: Right femoral artery was occluded in wild type (+/+), PlGF k.o.
      (-/-) and (-/-) mice receiving BM from (+/+) mice (-/- BM). Blood supply in paws
      was assessed by laser-Doppler imaging (LDI) measurements before, immediately
      after, as well as 3, 7, 14, 21 and 28 days after surgery. Seven and 28 days after
      occlusion, hindlimbs were perfusion fixed and filled with contrast medium.
      Angiograms were evaluated, collateral arteries were analysed histologically and
      morphometrically. RESULTS: Seven days after occlusion the blood flow and
      collateral growth in (-/-) were delayed in comparison to the (+/+) group. BM
      transplantation from +/+ donors prevented this delay. After 3 weeks the (-/-)
      mice reached values similar to the +/+ control. CONCLUSION: PlGF is an important
      promoter of arteriogenesis. BM transplantation abolishes inhibition of
      arteriogenesis in PlGF -/- mice.

PMID- 12606259
TI  - Bradykinin limits infarction when administered as an adjunct to reperfusion in
      mouse heart: the role of PI3K, Akt and eNOS.
AB  - Attenuation of reperfusion injury by growth factors has recently been linked to
      recruitment of phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), a
      pathway also linked to the phosphorylation of eNOS by bradykinin. We, therefore,
      hypothesised that bradykinin would limit infarct size when given as an adjunct to
      reperfusion. Using an isolated perfused mouse heart model of
      ischaemia/reperfusion injury, we show that 100 nmol/l bradykinin, administered
      upon reperfusion, attenuates infarct size (32 +/- 2% to 22 +/- 2%, P < 0.01).
      This protection was abrogated by concomitant administration of the PI3K
      inhibitor, wortmannin (100 nmol/l), whereas wortmannin alone had no impact upon
      infarct size (31 +/- 3% and 30 +/- 1%, respectively). In eNOS knockout hearts,
      bradykinin was not seen to be protective (31 +/- 2% versus 32 +/- 2%), yet
      knockout hearts could be rescued with the nitric oxide donor, S-nitroso-N-acetyl
      penicillamine (SNAP) (1 micromol/l) (17 +/- 4%, P < 0.01). Using western blot
      analysis, we show that bradykinin administration results in rapid, robust
      phosphorylation of both Akt and eNOS, greater than that seen in control hearts
      upon reperfusion (Akt/eNOS phosphorylation: 68 +/- 7/122 +/- 29 AU versus 32 +/-
      5/47 +/- 10 AU respectively, P < 0.01). This pattern of Akt phosphorylation was
      mimicked in the absence of eNOS, whereas Akt phosphorylation was inhibited by
      wortmannin. Exogenous nitric oxide administration had no impact upon Akt
      phosphorylation. Therefore, we demonstrate that exogenous bradykinin,
      administered at reperfusion, limits infarct size with concomitant rapid
      phosphorylation of Akt and eNOS, and that this protection is dependent upon the
      presence of eNOS. These results may open new avenues for research into clinical
      limitation of reperfusion injury following acute myocardial infarction.

PMID- 12606260
TI  - Microtubules mobility affects the modulation of L-type I(Ca) by muscarinic and
      beta-adrenergic agonists in guinea-pig cardiac myocytes.
AB  - To investigate the interaction of cytoskeleton with the receptor modulation of
      ionic currents, we studied the effect of muscarinic and beta-adrenergic
      stimulation in adult guinea-pig ventricular cardiac myocytes treated with
      paclitaxel and colchicine, two drugs that respectively stabilize or destabilize
      microtubules. We observed that the stabilization of microtubules with paclitaxel
      (1 microM for 1-4 h) did not markedly affect either the kinetics of I(Ca), or the
      stimulatory effect of isoproterenol (Iso, 1 microM); however paclitaxel
      significantly blunted the response to carbachol (CCh, 1 microM). In agreement
      with the electrophysiological measurements, Iso induced a similar enhancement of
      intracellular cAMP levels in both control and paclitaxel-treated cells, while the
      response to CCh 1 microM was significantly reduced in paclitaxel-treated cells.
      The reduction of muscarinic response induced by paclitaxel was also evident in
      atrial cells, in which the stimulation of I(KACh) by CCh 1 microM was reduced to
      about 10%. Compared to the muscarinic response, paclitaxel did not have
      significant effect on the purinergic (adenosine 1-10 microM) modulation of I(Ca).
      In contrast to paclitaxel, in colchicine-treated cells, I(Ca) was not enhanced by
      beta-adrenergic stimulation, but instead reduced by CCh, even in the absence of
      previous stimulation. In conclusion, our data suggest that microtubule
      stabilization significantly affects the muscarinic modulation of I(Ca), by
      interacting with the receptor or the G-protein rather than on the intracellular
      signaling cascade.

PMID- 12606261
TI  - Molecular cloning of calcium channel alpha(2)delta-subunits from rat atria and
      the differential regulation of their expression by IGF-1.
AB  - Calcium channels are multimeric proteins consisting of pore-forming (alpha(1))
      and auxiliary (alpha(2)delta, beta, gamma) subunits. The auxiliary alpha(2)delta
      subunit regulates calcium current density and activation/inactivation kinetics
      when co-expressed with some, but not all, alpha(1)-subunits. Here we report the
      differential expression of three alpha(2)delta-subunit cDNAs in rat atria, atrial
      myocytes and ventricle, and demonstrate that IGF-1 selectively increases the
      expression of the alpha(2)delta-3 mRNA in the atria. mRNA encoding the
      alpha(2)delta-1- and alpha(2)delta-2-subunits, but not the alpha(2)delta-3
      subunit, is detected in the rat ventricle whereas all three transcripts are found
      in atrial tissue. Analysis of the rat alpha(2)delta-1 cDNA sequence indicates
      that the atria express the alpha(2)delta-1e alternatively spliced isoform of this
      gene. The complete cDNA sequences of the alpha(2)delta-2- and alpha(2)delta-3
      subunits from rat atria were determined and found to share 96% and 95% identity,
      respectively, with their counterparts in mouse. Treatment of acutely cultured
      atrial myocytes with IGF-1 caused a significant increase of the amount of
      alpha(2)delta-3, but not alpha(2)delta-1 or alpha(2)delta-2, mRNA. Both L-type
      and T-type calcium currents are recorded from cardiac tissue although their
      expression is regionally specific and changes with age and physiological state.
      Differential regulation of the expression of alpha(2)delta-subunit genes is
      likely to contribute to alterations in the expression of calcium current in the
      mammalian heart.

PMID- 12606262
TI  - Rapid identification and 3D reconstruction of complex cardiac malformations in
      transgenic mouse embryos using fast gradient echo sequence magnetic resonance
      imaging.
AB  - Developmental malformations of the heart in mouse embryos are commonly studied by
      histological sectioning. This is slow, labour intensive, and results in the loss
      of three-dimensional (3D) information. Magnetic resonance studies of embryos
      typically use spin-echo sequences, using prolonged acquisition times (>36 h) or
      perfusion with contrast agents to enhance resolution and contrast. This is
      technically difficult, and requires significant amounts of operator time. We
      imaged paraformaldehyde fixed embryos using a fast spoiled 3D gradient echo
      sequence with T(1)-weighting, in unattended overnight runs of less than 9 h. In
      wild-type embryos, we visualised normal cardiac structures, including cardiac
      chambers, the ventricular septum, primary and secondary atrial septa, valves,
      superior and inferior vena cava, aorta, pulmonary artery, and ductus arteriosus.
      In embryos lacking Cited2 (a transcriptional co-activator required for normal
      heart development), we identified cardiac malformations including atrial and
      ventricular septal defects, cono-truncal defects, and aortic arch malformations.
      We generated 3D reconstructions of normal and mutant hearts using contour
      identification and surface rendering computer software. The malformations were
      confirmed by histological sectioning. Our data indicate that fast gradient echo
      sequence magnetic resonance imaging can be used to rapidly and accurately
      identify complex cardiovascular malformations in transgenic and mutant mouse
      embryos.

PMID- 12606263
TI  - Effects of corticosterone on the proportion of breeding females, reproductive
      output and yolk precursor levels.
AB  - In this study we investigated the role of corticosterone (B) in regulating the
      proportion of laying females, timing of breeding, reproductive output (egg size
      and number), and yolk precursor levels in chronically B-treated female zebra
      finches (Taeniopygia guttata). Corticosterone treatment via silastic implant
      elevated plasma B to high physiological (stress-induced) levels (24.1 +/- 5.3
      ng/ml at 7-days post-implantation). B-treated females had high plasma levels of
      very-low density lipoprotein (VLDL) but low levels of plasma vitellogenin 7-days
      post-implantation, suggesting that corticosterone inhibited yolk precusor
      production and perhaps shifted lipid metabolism away from production of yolk VLDL
      and towards production of generic (non-yolk) VLDL. Only 56% of B-treated females
      (n = 32) initiated laying, compared with 100% of sham-implanted females (n = 18).
      In females that did breed, corticosterone administration delayed the onset of egg
      laying: B-treated females initiated laying on average 14.5 +/- 0.5 days after
      pairing compared to 6.4 +/- 0.5 days in sham-implanted females. B-treated females
      that laid eggs had significantly higher plasma B levels at the 1st-egg stage
      (45.9+/-9.0 ng/ml) than did sham-implanted females (7.9+/-6.8 ng/ml). Despite
      this there was no difference in mean egg mass, clutch size, or egg composition in
      B-treated and sham-implanted females. These results are consistent with the idea
      that elevated corticosterone levels inhibit reproduction, but contrast with
      studies of other oviparous vertebrates (e.g., lizards) in relation to the role of
      corticosterone in regulating egg and clutch size.

PMID- 12606264
TI  - Nitric oxide-mediated arachidonic acid release from perifused Venus verrucosa
      oocytes.
AB  - This study was undertaken in order to investigate the possible interactions
      between nitric oxide and arachidonic acid (AA) in Venus verrucosa oocytes. We
      perifused isolated oocytes to determine the effect of the following substances on
      [3H]arachidonic acid release ([3H]AA): (1) A 23187, a calcium ionophore; (2)
      nitric oxide (NO) donors; (3) 1,1,1-trifluoromethyl-6,9,12,15 heicosatetraen-2
      one (AACOCF(3)), a specific phospholipase A(2) (PLA(2)) inhibitor; (4) [5'
      hydroxymethyl-2'-furyl]-1-benzyl indazole (YC-1) and 1H-[1,2,4]oxadiazolo[4,3
      alpha]quinoxalin-1-one (ODQ), specific soluble guanylyl cyclase activator and
      inhibitor, respectively; (5) L-arginine, the substrate of nitric oxide synthase;
      (6) L-nitroarginine methyl esther (L-NAME), an inhibitor of nitric oxide
      synthase. Our results demonstrated that: (a) the calcium ionophore dose
      dependently increased [3H]arachidonic acid release; (b) the NO donors sodium
      nitroprusside (SNP) and linsidomine (SIN-1) highly increased [3H]arachidonic acid
      output, while S-nitroso-N-acetylpenicillamine (SNAP) was without effect; (c)
      AACOCF(3) completely blocked the [3H]arachidonic acid release induced by SNP and
      SIN-1; (d) YC-1 increased [3H]arachidonic acid release, while ODQ completely
      counteracted SNP response; (e) [3H]arachidonic acid output was also increased by
      L-arginine; (f) a similar effect was, paradoxically, obtained in the presence of
      L-NAME. Furthermore, using RT-PCR we demonstrated in the same cells the presence
      of a nitric oxide synthase (NOS) mRNA, whose expression was not modulated by
      interleukin 1beta (IL-1beta). These results demonstrate the presence of a both
      calcium-dependent and NO-sensitive PLA(2) and of nitric oxide synthase in V.
      verrucosa oocytes. Our data also suggest a co-action of the two pathways in the
      control of reproduction in this bivalve.

PMID- 12606265
TI  - Changes in plasma corticosterone and adrenocortical response to stress during the
      breeding cycle in high altitude flycatchers.
AB  - Plasma corticosterone levels were monitored in a breeding population of Dusky
      Flycatchers (Empidonax oberholseri) at Tioga Pass, in the eastern Sierra Nevada.
      Seasonal changes in baseline plasma corticosterone levels were largely related to
      changes in reproductive status. Levels in both sexes were highest during the
      period preceding the female's initiation of a clutch. Females, alone, incubated,
      but males provided food regularly for their incubating mates. Excepting transient
      peaks in female corticosterone levels that immediately preceded ovipositions,
      steep declines in baseline levels of corticosterone in both sexes corresponded to
      the onset of parental attentiveness. Serial measurements of plasma corticosterone
      levels over a 1-h period of restraint, indicated that these declines originate at
      the level of the hypothalamo-pituitary-adrenal response system. Increases in
      stress-induced plasma corticosterone were significantly greater during the period
      preceding clutch initiation (prenesting) than during the nesting period
      (incubation and nestling periods). Despite the changes in corticosterone between
      prenesting and nesting periods, variability in corticosterone levels during both
      stages was negatively correlated with body condition (body mass and fat,
      corrected for size), and level of parental investment. Highest levels of plasma
      corticosterone were observed in lighter, leaner flycatchers, and during the hours
      when self-foraging activities were highest; lowest levels were seen in heavier,
      fatter birds, and those foraging for chicks. This relationship between
      corticosterone and parental care extended to a small number of accessory males
      that were acting as helpers at the nest. These results suggest that variation in
      the length of the reproductive cycle and degree of parental investment may help
      to explain the level of adaptive modulation of the adrenal stress response in
      species that breed in unpredictable environments.

PMID- 12606266
TI  - Localization of IGF-I, IGF-I receptor, and IGFBP-2 in developing Umbrina cirrosa
      (Pisces: Osteichthyes).
AB  - In this study, the distribution of IGF-I, IGF type I receptor (IGF-IR), and IGF
      binding protein 2 (IGFBP-2) was investigated during larval and post-larval
      developmental stages of the shi drum (Umbrina cirrosa) by immunohistochemistry
      using antisera raised against Sparus aurata IGF-I and IGF-IR, and against mouse
      IGFBP-2. Immunoreactivity of the mitogenic marker PCNA (proliferating cell
      nuclear antigen) was used for assessment of cellular proliferation. Distribution
      of IGF-I mRNA was studied by in situ hybridization. IGF-I immunoreactivity was
      detected in liver and developing intestine already in 1-5 day post-hatching
      larvae. From day 11, immunostaining in the intestine was evident in the
      enterocytes of the anterior intestine and in the apical zone of the epithelium of
      developing posterior intestine. Positive reaction with IGF-I antibody was also
      detected in chondrocytes, in the epithelium of the skin, gills and in the central
      nervous system (CNS), and lateral muscle. At hatching IGF-IR immunoreactivity was
      already detectable in developing CNS, notochord, and skin. From day 6
      immunostaining was evident in the olfactory epithelium, in eyes and from day 11
      in the developing olfactory bulbs and CNS. Positive reaction with IGF-IR antibody
      was also detected in chondrocytes, in the epithelium of the skin, gills, heart,
      and in the lateral muscle. Immunoreactive IGFBP-2, as detected by anti-mouse
      IGFBP-2 antiserum, exhibited generally a similar distribution pattern to that of
      IGF-I and IGF-IR. In situ hybridization, which has been performed by using
      riboprobes from S. aurata cDNA, revealed IGF-I mRNA in skeletal musculature,
      liver, and CNS. These data strongly suggest a role for the IGF system during
      development and growth of U. cirrosa.

PMID- 12606267
TI  - Immunohistochemical localization of gonadotropin releasing hormones in the brain
      and pituitary gland of the Nile perch, Lates niloticus (Teleostei,
      Centropomidae).
AB  - In the present study we investigated the distribution of gonadotropin-releasing
      hormones (GnRH) in the brain of Lates niloticus and their association with
      different pituitary cell types using immunohistochemical techniques. We found
      immunoreactive (ir) chicken GnRH-II (cGnRH-II) and mammalian GnRH (mGnRH) as the
      main components of the GnRH-ir system within the brain of the Nile perch. The
      results indicate that mGnRH and cGnRH are localized in different neurons: mGnRH
      ir perikaria were observed in the preoptic region particularly in the organum
      vasculosum laminae terminalis (OVLT) and in the nucleus lateralis tuberis pars
      posterior (NLTP) of the mediobasal hypothalamus. These cell bodies are located
      along a continuum of ir-fibers that could be traced from the olfactory nerve to
      the pituitary. mGnRH-ir fibers were detected in many parts of the brain
      (olfactory bulbs, ventral telencephalon, hypothalamus, and mesencephalon) and in
      the pituitary. cGnRH-ir cell bodies are restricted to the optic tract, but few
      scattered fibers could be detected in different parts of the brain. The pituitary
      exhibited very few cGnRH-II ir fibers, contrasting with an extensive mGnRH
      innervation. Moreover, mGnRH-ir fibers were targeting the three areas of the
      pituitary gland: rostral pars distalis (RPD), proximal pars distalis (PPD), and
      pars intermedia (PI). Double immunolabeling studies showed GnRH-ir fibers in
      close proximity with prolactin (PRL)- and adrenocorticotropic hormone (ACTH)
      producing cells in the RPD, growth hormone (GH)-producing cells in the PPD,
      gonadotropins (GTHs)-producing cells in the PPD in the external border of the PI,
      and with somatolactin (SL)- and alpha-melanocyte stimulating hormone (alpha-MSH)
      producing cells in the PI. Our results showed direct morphological evidence for a
      close association of GnRH-ir fibers with the different adenohypophysial cell
      types. These results suggest a multiple role of GnRH in the regulation of various
      pituitary hormones' release.

PMID- 12606268
TI  - Cloning and gene expression of P450 17alpha-hydroxylase,17,20-lyase cDNA in the
      gonads and brain of the fathead minnow Pimephales promelas.
AB  - P450 17alpha-hydroxylase,17,20-lyase (P450c17) is a key steroidogenic enzyme in
      the production of androgens and, therefore, is also indispensable for the
      production of oestrogens (that are produced from the aromatisation of androgens).
      In this study, P450c17 cDNA was cloned from the ovary of the fathead minnow (FHM)
      and its gene expression was examined in the gonads and brains of male and female
      FHM at different stages of gonadal development with a view to developing an
      understanding of its involvement in the reproductive physiology in this species.
      The FHM-P450c17 cDNA sequence cloned was 1812 bp in length, with an open reading
      frame of 1554 nucleotides encoding a protein of 518 amino acids. Amino acid
      identity of FHM-P450c17 with P450c17s in other animals was up to 81.8% in other
      teleosts (channel catfish), 62% in elasmobranches (spiny dogfish), 64% in birds
      (chicken), and up to 48.8% in mammals (human). FHM-P450c17 gene expression
      occurred in the ovary, testis, and also in the brain (both male and female) at
      all stages of sexual development studied. Expression in the brain was at least 30
      fold lower than in the gonads, but consistent in all fish life stages studied. In
      the testis, FHM-P450c17 gene expression was negatively correlated with gonadal
      development, but there was no obvious association between P450c17 gene expression
      and sexual development in the ovary, or brain (in both males and females). The
      results from this study demonstrate the expression of P450c17 in the brain for
      the first time in fish. Enzymatic studies are now needed to investigate the
      possible role of P450c17 in neurosteroid production in teleosts.

PMID- 12606269
TI  - Effects of sex and time of day on metabolism and excretion of corticosterone in
      urine and feces of mice.
AB  - Non-invasive techniques to monitor stress hormones in small animals like mice
      offer several advantages and are highly demanded in laboratory as well as in
      field research. Since knowledge about the species-specific metabolism and
      excretion of glucocorticoids is essential to develop such a technique, we
      conducted radiometabolism studies in mice (Mus musculus f. domesticus, strain
      C57BL/6J). Each mouse was injected intraperitoneally with 740 kBq of 3H-labelled
      corticosterone and all voided urine and fecal samples were collected for five
      days. In a first experiment 16 animals (eight of each sex) received the injection
      at 9 a.m., while eight mice (four of each sex) were injected at 9 p.m. in a
      second experiment. In both experiments radioactive metabolites were recovered
      predominantly in the feces, although males excreted significantly higher
      proportions via the feces (about 73%) than females (about 53%). Peak
      radioactivity in the urine was detected within about 2h after injection, while in
      the feces peak concentrations were observed later (depending on the time of
      injection: about 10h postinjection in experiment 1 and about 4h postinjection in
      experiment 2, thus proving an effect of the time of day). The number and relative
      abundance of fecal [3H]corticosterone metabolites was determined by high
      performance liquid chromatography (HPLC). The HPLC separations revealed that
      corticosterone was extensively metabolized mainly to more polar substances.
      Regarding the types of metabolites formed, significant differences were found
      between males and females, but not between the experiments. Additionally, the
      immunoreactivity of these metabolites was assessed by screening the HPLC
      fractions with four enzyme immunoassays (EIA). However, only a newly established
      EIA for 5alpha-pregnane-3beta,11beta,21-triol-20-one (measuring corticosterone
      metabolites with a 5alpha-3beta,11beta-diol structure) detected several peaks of
      radioactive metabolites with high intensity in both sexes, while the other EIAs
      showed only minor immunoreactivity. Thus, our study for the first time provides
      substantial information about metabolism and excretion of corticosterone in urine
      and feces of mice and is the first demonstrating a significant impact of the
      animals' sex and the time of day. Based on these data it should be possible to
      monitor adrenocortical activity non-invasively in this species by measuring fecal
      corticosterone metabolites with the newly developed EIA. Since mice are
      extensively used in research world-wide, this could open new perspectives in
      various fields from ecology to behavioral endocrinology.

PMID- 12606270
TI  - Hysteresis and calcium set-point for the calcium parathyroid hormone relationship
      in healthy horses.
AB  - Abnormalities in calcium (Ca(2+)) homeostasis are reported in horses with several
      pathological conditions; however, there is little information on Ca(2+)
      regulation in horses. The objectives of the present study were to determine the
      Ca(2+) set-point in healthy horses, to determine whether the Ca(2+)/parathyroid
      hormone (PTH) response curves were characterized by hysteresis, and to determine
      if the order of experimentally induced hypocalcemia or hypercalcemia had an
      effect on PTH secretion. The Ca(2+) set-point and hysteresis were determined in
      12 healthy horses by infusing Na(2)EDTA and calcium gluconate. The Ca(2+) set
      point was 1.37 +/- 0.05 mmol/L, which is higher than values reported for humans
      and dogs (1.0-1.2 mmol/L). Hysteresis was present during hypocalcemia and
      hypercalcemia. Horses in which hypocalcemia was followed by hypercalcemia
      secreted more PTH (7440 +/- 740 pmol min/L) than horses in which hypercalcemia
      was followed by hypocalcemia (5990 +/- 570 pmol min/L). This study has
      demonstrated that the Ca(2+) set-point in the horse is higher than in other
      domestic animals and man. We have shown that the Ca(2+)/PTH relationship in
      horses is sigmoidal and displays hysteresis during both hypocalcemia and
      hypercalcemia, and that extracellular Ca(2+) concentrations may affect the
      response of the parathyroid gland to hypocalcemia.

PMID- 12606271
TI  - Monoamines stimulate sex reversal in the saddleback wrasse.
AB  - Monoamine neurotransmitters (norepinephrine, dopamine, and serotonin) play an
      important role in reproduction and sexual behavior throughout the vertebrates.
      They are the first endogenous chemical signals in the regulation of the
      hypothalamo-pituitary-gonadal (HPG) axis. In teleosts with behavioral sex
      determination, much is known about behavioral cues that induce sex reversal. The
      cues are social, processed via the visual system and depend on the ratio of
      females to males in the population. The mechanisms by which these external
      behavioral cues are converted to an internal chemical regulatory process are
      largely unknown. The protogynous Hawaiian saddleback wrasse, Thalassoma duperrey,
      was used to investigate the biological pathway mediating the conversion of a
      social cue into neuroendocrine events regulating sex reversal. Because monoamines
      play an important role in the regulation of the HPG axis, they were selected as
      likely candidates for such a conversion. To determine if monoamines could affect
      sex reversal, drugs affecting monoamines were used in an attempt to either induce
      sex reversal under non-permissive conditions, or prevent sex reversal under
      permissive conditions. Increasing norepinephrine or blocking dopamine or
      serotonin lead to sex reversal in experimental animals under non-permissive
      conditions. Increasing serotonin blocked sex reversal under permissive
      conditions, while blocking dopamine or norepinephrine retarded the process. The
      results presented here demonstrate that monoamines contribute significantly to
      the control sex reversal. Norepinephrine stimulates initiation and completion of
      gonadal sex of reversal as well as color change perhaps directly via its effects
      on the HPG axis. Dopamine exercises inhibitory action on the initiation of sex
      reversal while 5-HT inhibits both initiation and completion of sex reversal. The
      serotonergic system appears to be an integral part of the pathway mediating the
      conversion of a social cue into a neuroendocrine event. The complex organization
      of neurochemical events controlling the psychosocial, physiological, and
      anatomical events that constitute reversal of sexual identity includes monoamine
      neurotransmitters.

PMID- 12606273
TI  - Seasonal variation in plasma catecholamines and adipose tissue lipolysis in adult
      female green sea turtles (Chelonia mydas).
AB  - We investigated three aspects of potential interrenal regulation of reproduction
      in female green sea turtles, Chelonia mydas. First, seasonal trends in plasma
      catecholamines were examined from female C. mydas at different stages of their
      reproductive cycles. Second, variation in catecholamine levels during a nesting
      season were analysed in relation to restraint time, and ecological variables such
      as nesting habitat, body size, and reproductive investment. Third, catecholamine
      and corticosterone (CORT) induced lipolysis was investigated with adipose tissue
      collected from gravid green turtles, using in vitro incubations. Plasma
      epinephrine (EPI) was lowest in non-vitellogenic (1.55 +/- 0.26 ng/ml) and post
      breeding (1.57 +/- 0.22 ng/ml) females, and highest in courting females (2.87 +/-
      0.28). Concentrations of norepinephrine (NE) and EPI were relatively constant
      throughout a nesting season, and not significantly related to restraint time,
      reproductive investment or nesting habitat. In vitro concentrations of CORT (>3
      ng/ml) and NE (2 ng/ml) induced significant release of glycerol after 6h of
      incubation. Epinephrine tended to induce an antilipolytic affect at low
      concentrations (0.25 ng/ml) and a net lipolytic response at higher concentrations
      (>1 ng/ml). Our data suggest that EPI may play a role in regulating body
      condition during vitellogenesis, and maintaining energy stores during prolonged
      aphagia during courtship and nesting in female green sea turtles. Furthermore, we
      provide preliminary evidence that suggests that catecholamine production may be
      either down regulated or de-sensitised in gravid female C. mydas.

PMID- 12606272
TI  - Variation of plasma sex steroid concentrations in wild and captive populations of
      Hermann's tortoise (Testudo hermanni hermanni) in Southern France.
AB  - Plasma levels of sex steroids in both males and females of the endangered
      Hermann's tortoise (Testudo hermanni hermanni) were measured throughout their
      active period in a wild population in the Massif des Maures, France, and in a
      nearby captive population at Le Village des Tortues in Gonfaron. Both plasma
      progesterone and testosterone were elevated in males at emergence from winter
      dormancy, and plasma progesterone levels were significantly higher in wild than
      in captive males. Plasma testosterone in males then fell to the lowest levels (10
      ng ml(-1)) during the nesting season from April to June followed by an elevated
      plateau during summer, with levels reaching 80 ng ml(-1), presumably concomitant
      with spermiogenesis. Plasma testosterone increased in all females during autumn,
      an indication of follicular growth, and remained high on emergence from
      hibernation, to peak during April, although levels were lower in the captive
      population. Plasma progesterone also peaked during April and May, presumably
      related to ovulation, but, again, these changes were less marked in the captive
      than in the wild females. Measurements of testosterone, progesterone and 17beta
      oestradiol in the captive females during their period of oviposition in spring
      suggested that some females did ovulate and lay eggs, whereas others did not.
      Differences in sex steroid levels between captive and wild populations of
      Hermann's tortoise may indicate a problem with ovulation and/or with stress in a
      proportion of captive females.

PMID- 12606274
TI  - Ambient salinity-dependent effects of homologous natriuretic peptides (ANP, VNP,
      and CNP) on plasma cortisol level in the eel.
AB  - The effects of three eel natriuretic peptides (NPs), i.e., ANP, VNP, and CNP on
      plasma cortisol levels were investigated in conscious freshwater (FW)- and
      seawater (SW)-adapted eels with permanent arterial catheter. The experiment was
      performed between 9:00 and 15:00 of the day, when the natural plasma cortisol
      level was relatively stable. After a single intra-arterial injection of ANP, VNP,
      or CNP at 100 pmol/kg, only CNP, but not ANP or VNP, increased plasma cortisol
      concentration in FW eels. In SW eels, however, only ANP at the same dose
      increased plasma cortisol concentration. The effect of CNP in FW eels and that of
      ANP in SW eels were dose-dependent between 10 and 1000 pmol/kg. On the other
      hand, ANP and VNP were equally effective, but CNP was ineffective, in increasing
      hematocrit in both FW and SW eels. These results show that the effect of NPs on
      plasma cortisol level is dependent on the ambient salinity in the eel. Since
      cortisol plays a pivotal role in environmental adaptation of fishes, the results
      suggest a possible involvement of ANP and CNP in the adaptation to SW and FW,
      respectively. Furthermore, this is the first evidence showing that ANP and VNP
      exert different effects in fish despite they share the same receptor, NPR-A.

PMID- 12606275
TI  - Seasonal variation of the three native gonadotropin-releasing hormone messenger
      ribonucleic acids levels in the brain of female red seabream.
AB  - We studied the seasonal variation of the expression of genes encoding the three
      native gonadotropin-releasing hormones (GnRHs), namely salmon(s) GnRH, chicken(c)
      GnRH-II, and seabream(sb) GnRH in red seabream, Pagrus (Chrysophrys) major, in
      order to better understand the regulatory mechanisms of GnRH gene expression by
      environmental and endocrine factors. Female red seabream, reared under natural
      conditions, were collected monthly or bimonthly from October to June, and the
      levels of the three distinct GnRH messenger ribonucleic acids (mRNAs) in the
      brains of those fish (n = 4-6) were determined by ribonuclease (RNase) protection
      analysis. The levels of sbGnRH mRNA correlated well with the observed ovarian
      histology; the levels of sbGnRH mRNA of immature fish in October and December
      were low, and increased in February and March in conjunction with active
      vitellogenesis. The sbGnRH mRNA levels reached a maximum level in April (spawning
      season), after which they rapidly decreased together with the observed ovarian
      regression in June. In contrast, the levels of sGnRH mRNA showed no variation,
      while those of cGnRH-II mRNA were elevated only slightly in March and April. The
      increase in sbGnRH mRNA levels correlates with the increase in day length, water
      temperature and serum steroids levels, suggesting that these factors are
      candidates for regulators of sbGnRH synthesis.

PMID- 12606277
TI  - Identification of proopiomelanocortin-related peptides in the rostral pars
      distalis of the pituitary in coelacanth: evolutional implications.
AB  - The coelacanth fish, genus Latimeria, flourished during the Devonian Period and
      is considered among the closest living relatives of tetrapods. It may therefore
      provide important information on the evolution of fishes into tetrapods. However,
      little is known about the components of the endocrine system in this fish. Here
      we describe the structural characterization of pituitary hormones derived from
      proopiomelanocortin (POMC) in Latimeria chalumnae. We identified alpha-melanocyte
      stimulating hormone (MSH), N-Des-acetyl-alpha-MSH, beta-MSH, N-terminal peptide
      containing gamma-MSH, corticotropin-like intermediate lobe peptide (CLIP), and N
      acetyl-beta-endorpin (END) in an extract from the rostral pars distalis of the
      pituitary by reversed-phase high-performance liquid chromatography, amino acid
      sequence analysis, and mass spectrometry. The occurrence of three different MSHs
      and one beta-END indicates that the structural organization of coelacanth POMC is
      the same as that of lungfish, tetrapods, and primitive ray-finned fish. The
      coelacanth alpha-MSH is identical to its mammalian counterpart. The coelacanth
      beta-MSH shows the highest sequence identity with the amphibian counterpart, and
      gamma-MSH and CLIP show the highest sequence identity with their amphibian and
      bird counterparts, whereas coelacanth beta-END is most similar to the sturgeon
      peptide. The coexistence of tetrapod-type and fish-type characteristics in the
      putative coelacanth POMC molecule reflects the phylogenetic position of this
      fish. When each hormonal segment was compared between coelacanth, lungfish, and
      tetrapod, MSH and CLIP of coelacanth were closer to their tetrapod counterparts
      than those of lungfish, whereas beta-MSH and beta-END of coelacanth are less
      closely related to their tetrapod counterparts than those of lungfish. gamma-MSH
      and CLIP may have evolved at a different rate from beta-MSH and beta-END in both
      the coelacanth and lungfish.

PMID- 12606276
TI  - Effects of angiotensin II and natriuretic peptides of the eel on prolactin and
      growth hormone release in the tilapia, Oreochromis mossambicus.
AB  - The effects of angiotensin II (ANG II) and natriuretic peptides (NPs) of the eel
      (ANP, atrial natriuretic peptide; CNP, C-type natriuretic peptide; and VNP,
      ventricular natriuretic peptide) on prolactin (PRL(188) and PRL(177)) and growth
      hormone (GH) release from the organ-cultured tilapia pituitary were examined. Eel
      ANG II at concentrations greater than 1 nM stimulated the release of PRL(188) and
      PRL(177) in a dose-related manner during the first hour of incubation.
      Significant stimulation by 100 nM ANG II on PRL(177) release was observed until
      4h of incubation, and on PRL(188) release until 12 h. No effect of ANG II was
      seen on GH release. None of the NPs altered the release of PRLs at any time
      point. On the other hand, eel VNP at concentrations greater than 1 nM stimulated
      GH release in a dose-related manner after 4 h, and significant stimulation was
      observed until 48 h. Eel CNP was less effective than eel VNP; significant
      stimulation of GH release was observed at 1 and 10 nM during 24-48 h of
      incubation. No significant effect of eel ANP on GH release was seen at any
      concentration. ANG II had no effect on GH release at any time point. There was no
      change in mRNA levels of PRLs or GH in the pituitaries incubated with ANG II for
      8 h or those incubated with the NPs for 48 h. These results indicate rapid and
      short-lasting stimulation by ANG II on PRL release and slow and long-lasting
      stimulation by VNP and CNP on GH release from the tilapia pituitary.

PMID- 12606278
TI  - Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for
      Shh signaling in taste papilla development and patterning: fungiform papillae
      double in number and form in novel locations in dorsal lingual epithelium.
AB  - From time of embryonic emergence, the gustatory papilla types on the mammalian
      tongue have stereotypic anterior and posterior tongue locations. Furthermore, on
      anterior tongue, the fungiform papillae are patterned in rows. Among the many
      molecules that have potential roles in regulating papilla location and pattern,
      Sonic hedgehog (Shh) has been localized within early tongue and developing
      papillae. We used an embryonic, tongue organ culture system that retains
      temporal, spatial, and molecular characteristics of in vivo taste papilla
      morphogenesis and patterning to study the role of Shh in taste papilla
      development. Tongues from gestational day 14 rat embryos, when papillae are just
      beginning to emerge on dorsal tongue, were maintained in organ culture for 2
      days. The steroidal alkaloids, cyclopamine and jervine, that specifically disrupt
      the Shh signaling pathway, or a Shh-blocking antibody were added to the standard
      culture medium. Controls included tongues cultured in the standard medium alone,
      and with addition of solanidine, an alkaloid that resembles cyclopamine
      structurally but that does not disrupt Shh signaling. In cultures with
      cyclopamine, jervine, or blocking antibody, fungiform papilla numbers doubled on
      the dorsal tongue with a distribution that essentially eliminated inter-papilla
      regions, compared with tongues in standard medium or solanidine. In addition,
      fungiform papillae developed on posterior oral tongue, just in front of and
      beside the single circumvallate papilla, regions where fungiform papillae do not
      typically develop. The Shh protein was in all fungiform papillae in embryonic
      tongues, and tongue cultures with standard medium or cyclopamine, and was
      conspicuously localized in the basement membrane region of the papillae. Ptc
      protein had a similar distribution to Shh, although the immunoproduct was more
      diffuse. Fungiform papillae did not develop on pharyngeal or ventral tongue in
      cyclopamine and jervine cultures, or in the tongue midline furrow, nor was
      development of the single circumvallate papilla altered. The results demonstrate
      a prominent role for Shh in fungiform papilla induction and patterning and
      indicate differences in morphogenetic control of fungiform and circumvallate
      papilla development and numbers. Furthermore, a previously unknown, broad
      competence of dorsal lingual epithelium to form fungiform papillae on both
      anterior and posterior oral tongue is revealed.

PMID- 12606279
TI  - Multiple roles for Hedgehog signaling in zebrafish pituitary development.
AB  - The endocrine-secreting lobe of the pituitary gland, or adenohypophysis, forms
      from cells at the anterior margin of the neural plate through inductive
      interactions involving secreted morphogens of the Hedgehog (Hh), fibroblast
      growth factor (FGF), and bone morphogenetic protein (BMP) families. To better
      understand when and where Hh signaling influences pituitary development, we have
      analyzed the effects of blocking Hh signaling both pharmacologically (cyclopamine
      treatments) and genetically (zebrafish Hh pathway mutants). While current models
      state that Shh signaling from the oral ectoderm patterns the pituitary after
      placode induction, our data suggest that Shh plays a direct early role in both
      pituitary induction and patterning, and that early Hh signals comes from adjacent
      neural ectoderm. We report that Hh signaling is necessary between 10 and 15 h of
      development for induction of the zebrafish adenohypophysis, a time when shh is
      expressed only in neural tissue. We show that the Hh responsive genes ptc1 and
      nk2.2 are expressed in preplacodal cells at the anterior margin of the neural
      tube at this time, indicating that these cells are directly receiving Hh signals.
      Later (15-20 h) cyclopamine treatments disrupt anterior expression of nk2.2 and
      Prolactin, showing that early functional patterning requires Hh signals.
      Consistent with a direct role for Hh signaling in pituitary induction and
      patterning, overexpression of Shh results in expanded adenohypophyseal expression
      of lim3, expansion of nk2.2 into the posterior adenohypophysis, and an increase
      in Prolactin- and Somatolactin-secreting cells. We also use the zebrafish Hh
      pathway mutants to document the range of pituitary defects that occur when
      different elements of the Hh signaling pathway are mutated. These defects,
      ranging from a complete loss of the adenohypophysis (smu/smo and yot/gli2
      mutants) to more subtle patterning defects (dtr/gli1 mutants), may correlate to
      human Hh signaling mutant phenotypes seen in Holoprosencephaly and other
      congenital disorders. Our results reveal multiple and distinct roles for Hh
      signaling in the formation of the vertebrate pituitary gland, and suggest that Hh
      signaling from neural ectoderm is necessary for induction and functional
      patterning of the vertebrate pituitary gland.

PMID- 12606280
TI  - Adenohypophysis formation in the zebrafish and its dependence on sonic hedgehog.
AB  - Formation of the adenohypophysis in mammalian embryos occurs via an invagination
      of the oral ectoderm to form Rathke's pouch, which becomes exposed to opposing
      dorsoventral gradients of signaling proteins governing specification of the
      different hormone-producing pituitary cell types. One signal promoting pituitary
      cell proliferation and differentiation to ventral cell types is Sonic hedgehog
      (Shh) from the oral ectoderm. To study pituitary formation and patterning in
      zebrafish, we cloned four cDNAs encoding different pituitary hormones, prolactin
      (prl), proopiomelancortin (pomc), thyroid stimulating hormone (tsh), and growth
      hormone (gh), and analyzed their expression patterns relative to that of the
      pituitary marker lim3. prl and pomc start to be expressed at the lateral edges of
      the lim3 expression domain, before pituitary cells move into the head. This
      indicates that patterning of the pituitary anlage and terminal differentiation of
      pituitary cells starts while cells are still organized in a placodal fashion at
      the anterior edge of the developing brain. Following the expression pattern of
      prl and pomc during development, we show that no pituitary-specific invagination
      equivalent to Rathke's pouch formation takes place. Rather, pituitary cells move
      inwards together with stomodeal cells during oral cavity formation, with medial
      cells of the placode ending up posterior and lateral cells ending up anterior,
      resulting in an anterior-posterior, rather than a dorsoventral, patterning of the
      adenohypophysis. Carrying out loss- and gain-of-function experiments, we show
      that Shh from the ventral diencephalon plays a crucial role during induction,
      patterning, and growth of the zebrafish adenohypophysis. The phenotypes are very
      similar to those obtained upon pituitary-specific inactivation or overexpression
      of Shh in mouse embryo, suggesting that the role of Shh during pituitary
      development has been largely conserved between fish and mice, despite the
      different modes of pituitary formation in the two vertebrate classes.

PMID- 12606281
TI  - Fluorescent labeling of endothelial cells allows in vivo, continuous
      characterization of the vascular development of Xenopus laevis.
AB  - Appropriate blood supply and vascular development are necessary in development
      and in cancer, heart disease, and diabetes. Here, we report the use of DiI
      labeled acetylated low-density lipoprotein (DiI-Ac-LDL) to label endothelial
      cells and characterize the vasculature of live Xenopus embryos. The atlas we have
      created provides a detailed map of normal vascular development against which
      perturbations of normal patterning can be compared. By following the development
      of the intersomitic vessels in real-time, we show that, while rostrocaudal
      gradient of maturing intersomitic vessels occurs, it is not absolute. In
      addition, the comparative study of the ontogeny of nerve bundles from the spinal
      cord of transgenic Xenopus embryos expressing green fluorescent protein in the
      nervous system and blood vessels demonstrates a strong anatomical correlation in
      neurovascular development. These studies provide the basis for understanding how
      the vascular system forms and assumes its complicated stereotypical pattern in
      normal development and in disease.

PMID- 12606282
TI  - Primary mesenchyme cell patterning during the early stages following ingression.
AB  - Sea urchin primary mesenchyme cells (PMCs) ingress into the blastocoel during an
      epithelial-to-mesenchymal transition (EMT), migrate along the blastocoelar wall
      for a period of time, and then settle into a subequatorial ring to form the
      larval skeleton. Fluorescent-marked blastomeres alone, or in combination with
      blastomere recombination, were used to track the position of PMCs during the
      early phases of this movement. Micromeres expressing Golgi-tethered GFP (galtase
      GFP) were transplanted onto TRITC-stained hosts (in place of the endogenous
      micromere) to observe the progeny of a single micromere. Galtase-GFP as a Golgi
      marker is not transferred between PMCs when the syncytium forms. Thus, the
      position of cells can be followed relative to beginning position for longer
      periods than previously reported. The PMC progeny of a single micromere do not
      disperse upon ingression, but instead remain in a closely associated cluster.
      Generally, progeny of a single micromere remain in the quadrant of origin. In
      total, greater than approximately 94% of labeled PMCs remain within the local
      region of ingression. By contrast, when a transplanted micromere is placed at the
      vegetal plate after removing all 4 host micromeres, the resultant PMCs ingress
      and migrate into all 4 quadrants. Similarly, if 1 blastomere is injected at the 2
      cell stage, and later the 2 unlabeled micromeres are removed at the 16-cell
      stage, the remaining PMCs ingress into all 4 quadrants of the vegetal plate. We
      conclude that the normal restriction of PMCs to a quadrant is due to mechanical
      constraint from other micromere-PMCs. If a labeled micromere is placed
      ectopically at the macromere/mesomere boundary, the PMC progeny ingress
      ectopically and migrate longitudinally along the animal-vegetal axis only.
      Injection of galtase-GFP into one blastomere at the 4-cell stage shows a 2-step
      pattern of localization. At late mesenchyme blastula and early gastrula stages,
      greater than 90% of GFP-expressing PMCs remain in the injected quadrant, while at
      mid- to late-gastrula stage and beyond, more PMCs are found outside the injected
      quadrant. The migration that sets up the asymmetry of the larval skeleton first
      occurs around mid- to late-gastrula stages, when some PMCs from an aboral
      quadrant migrate to the adjacent oral quadrant. In all, these data combined with
      previous data suggest that freshly ingressed PMCs migrate along a longitudinal
      path toward the animal pole and back toward the vegetal pole. Beginning at mid-
      to late-gastrula stage, PMCs utilize oral-aboral cues from the ectoderm for the
      first time. At this time, some aboral PMCs migrate into the adjacent oral
      quadrant to assist in the formation of the ventrolateral cluster.

PMID- 12606283
TI  - Combinatorial expression of Prospero, Seven-up, and Elav identifies progenitor
      cell types during sense-organ differentiation in the Drosophila antenna.
AB  - The Drosophila antenna has a diversity of chemosensory organs within a single
      epidermal field. We have some idea from recent studies of how the three broad
      categories of sense-organs are specified at the level of progenitor choice.
      However, little is known about how cell fates within single sense-organs are
      specified. Selection of individual primary olfactory progenitors is followed by
      organization of groups of secondary progenitors, which divide in a specific order
      to form a differentiated sensillum. The combinatorial expression of Prospero
      Elav, and Seven-up allows us to distinguish three secondary progenitor fates. The
      lineages of these cells have been established by clonal analysis and marker
      distribution following mitosis. High Notch signaling and the exclusion of these
      markers identifies PIIa; this cell gives rise to the shaft and socket. The
      sheath/neuron lineage progenitor PIIb, expresses all three markers; upon
      division, Prospero asymmetrically segregates to the sheath cell. In the
      coeloconica, PIIb undergoes an additional division to produce glia. PIIc is
      present in multiinnervated sense-organs and divides to form neurons. An
      understanding of the lineage and development of olfactory sense-organs provides a
      handle for the analysis of how olfactory neurons acquire distinct terminal fates.

PMID- 12606284
TI  - Nonneuronal expression of the GABA(A) beta3 subunit gene is required for normal
      palate development in mice.
AB  - Cleft palate is one of the most common birth defects in humans, in which both
      genetic and environmental factors are involved. In mice, loss of the GABA(A)
      receptor beta3 subunit gene (Gabrb3) or the targeted mutagenesis of the GABA
      synthetic enzyme (Gad1) leads to cleft palate. These observations indicate that a
      GABAergic system is important in normal palate development. To determine what
      cell types, neuronal or nonneuronal, are critical for GABA signaling in palate
      development, we used the neuron-specific enolase promoter to express the beta3
      subunit in Gabrb3 mutant mice. Expression of this construct was able to rescue
      the neurological phenotype, but not the cleft palate phenotype. Combined with the
      previous observation demonstrating that ubiquitous expression of the beta3
      subunit rescued the cleft palate phenotype, a nonneuronal GABAergic system is
      implicated in palate development. Using immunohistochemistry, we detected GABA in
      the developing palate, initially in the nasal aspect of palatal epithelium of the
      vertical shelves; later in the medial edge epithelium of the horizontally
      oriented palatal shelves and in the epithelial seam during fusion. Based on these
      observations, we propose that GABA, synthesized by the palatal epithelium, acts
      as a signaling molecule during orientation and fusion of the palate shelves.

PMID- 12606285
TI  - Cyclin E expression during development in Caenorhabditis elegans.
AB  - Our interest in the coordination of cell cycle control and differentiation has
      led us to investigate the Caenorhabditis elegans cye-1 gene encoding the G(1)
      cell cycle regulator cyclin E. We have studied the expression and function of cye
      1 by using monoclonal antibodies directed against CYE-1 protein, cye-1::GFP
      reporter genes, and a cye-1 chromosomal deletion mutation. We show that a
      ubiquitous embryonic pattern of expression becomes restricted and dynamic during
      postembryonic development. Promoter analysis reveals a relatively small region of
      cis-acting sequences that are necessary for the complex pattern of expression of
      this gene. Our studies demonstrate that two other G(1) cell cycle genes, encoding
      cyclin D and CDK4/6, have similarly compact promoter requirements. This suggests
      that a relatively simple mechanism of regulation may underlie the dynamic
      developmental patterns of expression exhibited by these three G(1) cell cycle
      genes. Our analysis of a new cye-1 deletion allele confirms and extends previous
      studies of two point mutations in the gene.

PMID- 12606286
TI  - Multiple joint and skeletal patterning defects caused by single and double
      mutations in the mouse Gdf6 and Gdf5 genes.
AB  - Growth/differentiation factors 5, 6, and 7 (GDF5/6/7) represent a distinct
      subgroup within the bone morphogenetic protein (BMP) family of secreted signaling
      molecules. Previous studies have shown that the Gdf5 gene is expressed in
      transverse stripes across developing skeletal elements and is one of the earliest
      known markers of joint formation during embryonic development. Although null
      mutations in this gene disrupt formation of some bones and joints in the
      skeleton, many sites are unaffected. Here, we show that the closely related
      family members Gdf6 and Gdf7 are expressed in different subsets of developing
      joints. Inactivation of the Gdf6 gene causes defects in joint, ligament, and
      cartilage formation at sites distinct from those seen in Gdf5 mutants, including
      the wrist and ankle, the middle ear, and the coronal suture between bones in the
      skull. Mice lacking both Gdf5 and Gdf6 show additional defects, including severe
      reduction or loss of some skeletal elements in the limb, additional fusions
      between skeletal structures, scoliosis, and altered cartilage in the
      intervertebral joints of the spinal column. These results show that members of
      the GDF5/6/7 subgroup are required for normal formation of bones and joints in
      the limbs, skull, and axial skeleton. The diverse effects on joint development
      and the different types of joints affected in the mutants suggest that members of
      the GDF family play a key role in establishing boundaries between many different
      skeletal elements during normal development. Some of the skeletal defects seen in
      single or double mutant mice resemble defects seen in human skeletal diseases,
      which suggests that these genes may be candidates that underlie some forms of
      carpal/tarsal coalition, conductive deafness, scoliosis, and craniosynostosis.

PMID- 12606287
TI  - Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by
      GATA-4 and -6.
AB  - Transcription factors GATA-4, -5, and -6 constitute an evolutionary conserved
      subfamily of vertebrate zinc finger regulators highly expressed in the developing
      heart and gut. Genetic evidence suggests that each protein is essential for
      embryonic development, but their exact functions are not fully elucidated.
      Moreover, because all three proteins share similar transcriptional properties in
      vitro, and because transcripts for two or more GATA genes are present in similar
      tissues, the molecular basis underlying in vivo specificity of GATA factors
      remains undefined. Knowledge of the exact cell types expressing each protein and
      identification of downstream targets would greatly help define their function. We
      have used high-resolution immunohistochemistry to precisely determine the
      cellular distribution of the GATA-4, -5, and -6 proteins in murine embryogenesis.
      The results reveal novel sites of expression in mesodermal and ectodermal cells.
      In particular, GATA-4 and -6 expression was closely associated with yolk sac
      vasculogenesis and early endoderm-mesoderm signaling. Additionally, GATA-6 was
      strongly expressed in the embryonic ectoderm, neural tube, and neural crest
      derived cells. This pattern of expression closely paralled that of BMP-4, and the
      BMP-4 gene was identified as a direct downstream target for GATA-4 and -6. These
      findings offer new insight into the function of GATA-4 and -6 during early stages
      of embryogenesis and reveal the existence of a positive cross-regulatory loop
      between BMP-4 and GATA-4. They also raise the possibility that part of the early
      defects in GATA-4 and/or GATA-6 null embryos may be due to impaired BMP-4
      signaling.

PMID- 12606288
TI  - Alien/CSN2 gene expression is regulated by thyroid hormone in rat brain.
AB  - Alien has been described as a corepressor for the thyroid hormone receptor (TR).
      Corepressors are coregulators that mediate gene silencing of DNA-bound
      transcriptional repressors. We describe here that Alien gene expression in vivo
      is regulated by thyroid hormone both in the rat brain and in cultured cells. In
      situ hybridization revealed that Alien is widely expressed in the mouse embryo
      and also throughout the rat brain. Hypothyroid animals exhibit lower expression
      of both Alien mRNAs and protein levels as compared with normal animals.
      Accordingly, we show that Alien gene is inducible after thyroid hormone treatment
      both in vivo and in cell culture. In cultured cells, the hormonal induction is
      mediated by either TRalpha or TRbeta, while cells lacking detectable amounts of
      functional TR lack hormonal induction of Alien. We have detected two Alien
      specific mRNAs by Northern experiments and two Alien-specific proteins in vivo
      and in cell lines by Western analysis, one of the two forms representing the CSN2
      subunit of the COP9 signalosome. Interestingly, both Alien mRNAs and both
      detected proteins are regulated by thyroid hormone in vivo and in cell lines.
      Furthermore, we provide evidence for the existence of at least two Alien genes in
      rodents. Taken together, we conclude that Alien gene expression is under control
      of TR and thyroid hormone. This suggests a negative feedback mechanism between TR
      and its own corepressor. Thus, the reduction of corepressor levels may represent
      a control mechanism of TR-mediated gene silencing.

PMID- 12606289
TI  - Oligodendroglia in developmental neurotoxicity.
AB  - The developing nervous system has been long recognized as a primary target for a
      variety of toxicants. To date, most efforts to understand the impact of
      neurotoxic agents on the brain have focused primarily on neurons and to a lesser
      degree astroglia as cellular targets. The role of oligodendroglia, the myelin
      forming cells in the central nervous system (CNS), in developmental neurotoxicity
      has been emphasized only in recent years. Oligodendrocytes originate from
      migratory, mitotic progenitors that mature progressively into postmitotic
      myelinating cells. During differentiation, oligodendroglial lineage cells pass
      through a series of distinct phenotypic stages that are characterized by
      different proliferative capacities and migratory abilities, as well as dramatic
      changes in morphology with sequential expression of unique developmental markers.
      In recent years, it has become appreciated that oligodendrocyte lineage cells
      have important functions other than those related to myelin formation and
      maintenance, including participation in neuronal survival and development, as
      well as neurotransmission and synaptic function. Substantial knowledge has
      accumulated on the control of oligodendroglial survival, migration,
      proliferation, and differentiation, as well as the cellular and molecular events
      involved in oligodendroglial development and myelin formation. Recently, studies
      have been initiated to address the role of oligodendrocyte lineage cells in
      neurotoxic processes. This article examines recent progress in oligodendroglial
      biology, focuses attention on the characteristic features of the oligodendrocyte
      developmental lineage as a model system for neurotoxicological studies, and
      explores the role of oligodendrocyte lineage cells in developmental
      neurotoxicity. The potential role of oligodendroglia in environmental lead
      neurotoxicity is presented to exemplify this thesis.

PMID- 12606290
TI  - Breathing and heart rate during experimental solvent exposure of young adults
      with self-reported multiple chemical sensitivity (sMCS).
AB  - This paper deals with the assumption that young adults with self-reported
      multiple chemical sensitivity (sMCS) show a heightened sensitivity of autonomic
      functions during experimental solvent exposure. Male sMCS-subjects were selected
      (out of n=274) on the base of a German questionnaire on chemical and
      environmental sensitivity (CGES). Two independent experiments were carried out,
      each with 12 sMCS-subjects and 12 age-matched control-subjects. In experiment I
      two concentrations of the solvents ethyl benzene (10 and 98 ppm) and 2-butanone
      (10 and 189 ppm) were used. Experiment II investigated 2-propanol (35 and 190
      ppm) and 1-octanol (0.1 and 6.4 ppm). The low concentrations correspond nearly to
      the olfactory thresholds while the high concentrations correspond to the German
      occupational threshold limit values (MAC). The exposure duration under each
      condition was 4h. The sequence of the four exposure conditions was random
      including intervals of at least 2 days without exposure. During the exposure
      physiological changes of breathing rate and heart rate were recorded. Two 30 min
      intervals with a sedentary position of the subjects at the beginning and end of
      exposure were chosen for analyses. Neither in experiment I nor in experiment II
      significant specific reactions to the type or level of the exposures were found.
      The autonomic functions in both experiments revealed alterations within the
      exposure sessions. The heart rate in experiment II and the breathing rate in both
      experiments decreased significantly during the analyzed 30 min intervals.
      Furthermore, in both experiments the heart rates decreased significantly from
      beginning to end of exposure. Only in experiment I the mean breathing rate of
      sMCS-subjects was generally higher compared to the control-subjects. Regarding
      the assumption of a heightened sensitivity of sMCS-subjects the two experiments
      yielded controversial results. Thus, the hypothesis of stronger responses of
      autonomic functions of sMCS-subjects provoked by various exposure scenarios
      remains open.

PMID- 12606291
TI  - Increased [3H]phorbol ester binding in rat cerebellar granule cells and
      inhibition of 45Ca(2+) buffering in rat cerebellum by hydroxylated
      polychlorinated biphenyls.
AB  - Our previous structure-activity relationship (SAR) studies indicated that the
      effects of polychlorinated biphenyls (PCBs) on neuronal Ca(2+) homeostasis and
      protein kinase C (PKC) translocation were associated with the extent of
      coplanarity. Chlorine substitutions at ortho position on the biphenyl, which
      increase the non-coplanarity, are characteristic of the most active congeners in
      vitro. In the present study, we investigated the effects of selected hydroxylated
      PCBs, which are major PCB metabolites identified in mammals, on the same measures
      where PCBs had differential effects based on structural configuration. These
      measures include PKC translocation as determined by [3H]phorbol ester ([3H]PDBu)
      binding in cerebellar granule cells, and Ca(2+) sequestration as determined by
      45Ca(2+) uptake by microsomes isolated from adult rat cerebellum. All the
      selected hydroxy-PCBs with ortho-chlorine substitutions increased [3H]PDBu
      binding in a concentration-dependent manner and the order of potency as
      determined by E(50) (concentration that increases control activity by 50%) is
      2',4',6'-trichloro-4-biphenylol (32 +/- 4 microM), 2',5'-dichloro-4-biphenylol
      (70 +/- 9 microM), 2,2',4',5,5'-pentachloro-4-biphenylol (80 +/- 7 microM) and
      2,2',5'-trichloro-4-biphenylol (93 +/- 14 microM). All the selected hydroxy-PCBs
      inhibited microsomal 45Ca(2+) uptake to a different extent. Among the hydroxy
      PCBs selected, 2',4',6'-trichloro-4-biphenylol is the most active in increasing
      [3H]PDBu binding as well as inhibiting microsomal 45Ca(2+) uptake. 3,5-Dichloro-4
      biphenylol and 3,4',5-trichloro-4-biphenylol did not increase [3H]PDBu binding,
      but inhibited microsomal 45Ca(2+) uptake. This effect was not related to
      ionization of these two hydroxy-PCBs. Hydroxylated PCBs seemed to be as active as
      parent PCBs in vitro. These studies indicate that PCB metabolites such as hydroxy
      PCBs might contribute significantly to the neurotoxic responses of PCBs.

PMID- 12606292
TI  - Dose-dependent biochemical changes in rat central nervous system after 12-week
      exposure to 1-bromopropane.
AB  - 1-Bromopropane is used as a cleaning agent or adhesive solvent in the workplace.
      The present study investigated the long-term effects of exposure to 1
      bromopropane on biochemical components in the central nervous system (CNS) of
      rats. Four groups, each of nine male Wistar rats, were exposed to 200, 400, or
      800 ppm 1-bromopropane or fresh air only, 8h per day, 7 days a week for 12 weeks.
      We measured the levels of neuron-specific gamma-enolase, glia-specific beta-S100
      protein, creatine kinase (CK) subunits B and M, heat shock protein Hsp27 (by
      enzyme immunoassay), enzymatic activity of CK and levels of glutathione (GSH),
      oxidized glutathione (GSSG) and sulfhydrul (SH) base in the cerebrum, cerebellum,
      brainstem and spinal cord. gamma-Enolase decreased dose-dependently in the
      cerebrum, which showed a decrease in wet weight, at 400 ppm or over, but no
      change was noted in beta-S100 protein in any brain region or spinal cord. Hsp27
      decreased in the cerebellum, brainstem and spinal cord. Protein-bound SH base,
      non-protein SH base and total glutathione decreased in every brain region. CK
      activity decreased dose-dependently at 200 ppm or over, and the ratio of CK
      activity to CK-B concentration tended to decrease in all regions. The decrease in
      gamma-enolase in the cerebrum suggests the involvement of biochemical changes in
      neurons with decrease in the wet weight of the cerebrum. Glutathione depletion
      and changes in proteins containing SH base as a critical site might be the
      underlying neurotoxic mechanism of 1-bromopropane. The biochemical changes in the
      cerebrum indicate that long-term exposure to 1-bromopropane has effects on the
      CNS.

PMID- 12606293
TI  - Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters activity
      dependent expression of BDNF mRNA in the neocortex and male rat sexual behavior
      in adulthood.
AB  - Dioxin and its related compounds are suspected to cause neurological and
      nueroendocrinological disruption in human and laboratory animal offspring upon in
      utero and lactational exposure during growth and development. We tested the
      hypothesis by utilizing Long-Evans Hooded rats that perinatal exposure to dioxins
      affects the neocortical function and expression of sexual behavior in adulthood.
      In the sexual behavior test, perinatal exposure to TCDD significantly reduced the
      number of mounts and intromissions. The mRNA semi-quantification in in situ
      hybridization showed that the mating stimulus in control males induced c-fos mRNA
      expression in the preoptic area (POA) and the brain derived neurotrophic factor
      (BDNF) mRNA upregulation in the frontal cortex. In contrast, perinatal exposure
      to TCDD lowered the upregulation of BDNF mRNA in the frontal cortex but not that
      of c-fos mRNA in the POA. The volume of the sexually dimorphic nucleus of the
      preoptic area (SDN-POA) was not affected. The results suggest that perinatal TCDD
      affects the neocortical function independently from the brain sexual
      differentiation and alters the expression of sexual behavior.

PMID- 12606294
TI  - MPP(+) causes inhibition of cellular energy supply in cerebellar granule cells.
AB  - A significant loss in ATP levels was found in cerebellar granule cells with 1
      methyl-4-phenylpyridinium. Exposure of cerebellar granule cells to low
      concentrations of 1-methyl-4-phenylpyridinium (100 microM) resulted in a time and
      dose-dependent decreases in ATP levels and cell death. This neurotoxin caused
      inhibition of the enzymatic activity of NADH-dehydrogenase of mitochondrial
      complex I and consequent impairment of mitochondrial electronic transport with a
      reduction in the depletion of cytosolic NAD(+) levels. Activation of lactate
      dehydrogenase activity (detected by the increase of the lactate in the culture
      medium) partially reduced this depletion. Addition of glucose but not pyruvate to
      the culture medium protected 1-methyl-4-phenylpyridinium-induced cell death.
      These results suggest the 1-methyl-4-phenylpyridinium causes impairment of
      cellular energy metabolism with a major dependence on glycolysis as a source of
      energy. This fact could also explain the partial neuroprotection observed by
      glucose.

PMID- 12606295
TI  - Glutamate and dopamine in nucleus accumbens core and shell: sequence learning
      versus performance.
AB  - This study sought to determine whether neurochemical changes associated with
      chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity
      and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the
      learning impairments also associated with this Pb regimen, and whether core or
      shell subregions of nucleus accumbens would be more important to such effects. If
      so, then mimicking these neurochemical changes in normal (control) rats should
      reproduce these Pb-induced learning impairments. For this purpose, the effects of
      DA (20-80 microg), the non-competitive NMDA antagonist MK-801 (1.0-2.5 microg) or
      DA+MK-801 (40+1.0, 80+2.5 microg) were infused in core or shell of nucleus
      accumbens in normal rats and effects on a multiple schedule of repeated learning
      (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb
      exposure, selectively reducing RL accuracy with no corresponding changes in P
      accuracy, an effect derived from an increased frequency of perseverative errors.
      DA produced non-specific changes, reducing accuracy levels in RL and P
      components. Accuracy and rate effects of DA could be reversed by concurrent
      administration of the higher MK-801 dose. In shell, MK-801, primarily the lower
      dose, reduced accuracy in both the RL and P components, while DA did not produce
      any systematic effects. Collectively, these results point to a greater importance
      of core as compared to shell in the mediation of learning of spatial sequences,
      and suggest that inhibition of glutamatergic NMDA function may play a critical
      role in the selective learning impairments associated with chronic low level Pb
      exposure.

PMID- 12606297
TI  - Effects of methanol on the retinal function of juvenile rats.
AB  - We have investigated the effect of methanol exposure on the retinal function of
      juvenile rats. The electroretinogram (ERG) and oscillatory potentials (OPs) were
      recorded prior to and up to 72 h after the administration of methanol. Data were
      compared to a control group which was only exposed to physiological saline. Our
      findings can be summarized as follows: methanol generally reduced the amplitude
      of all retinal potentials, and in some cases, to baseline levels. The ERG b-wave
      was affected earlier and more prominently than the a-wave. All measured OPs (2-4)
      were decreased but OP2 was less affected, suggesting that the cone pathway may be
      less sensitive to methanol than the rod-mediated pathway. These data indicate
      that juvenile rats (21 days old, i.e. with an immature synaptic development)
      present a sensitivity to methanol comparable to that observed in adult animals.

PMID- 12606296
TI  - Early neuroprotective effect of nitric oxide in developing rat brain irradiated
      in utero.
AB  - Pregnant Wistar rats were exposed on day 17 of gestation to 1 Gy gamma
      irradiation from a Co(60) source. Even though it is established that gamma
      radiation-dependent damage is mainly due to free radical generation neither the
      ascorbyl radical/ascorbate ratio nor the lipid radical content in developing rat
      brain were affected by prenatal irradiation. A distinctive EPR signal for the
      adduct NO-Fe-MGD (g=2.03 and a(N)=12.5 G) was detected in brain homogenates
      prepared from irradiated rats. Nitric oxide (NO)-dependent EPR signal increased
      in a time-dependent manner up to 2h post-irradiation. NO concentration in
      unirradiated brains was 37+/-4 pmol/g brain and 45+/-2, 77+/-5 and 216+/-6 after
      30, 60 and 120 min post-irradiation, respectively. Total nitric oxide synthase
      activity was increased by 77 and 51% after 30 and 60 min post-irradiation,
      respectively, and returned to control values after 120 min. Thus, increased NO
      steady-state concentration could be ascribed to an increase in NOS activity.
      Taken as a whole, these results suggest that NO might act to protect the
      developing brain from the cytotoxicity of reactive species.

PMID- 12606298
TI  - Aluminum disrupts the pro-inflammatory cytokine/neurotrophin balance in primary
      brain rotation-mediated aggregate cultures: possible role in neurodegeneration.
AB  - The etiology of human neurodegenerative diseases including Alzheimer's disease
      (AD) is exceedingly complex and our understanding of the mechanisms involved is
      far from complete. The experimental neurotoxicology of aluminum has been shown to
      recapitulate many of the pathophysiological features of AD and therefore
      represents a useful model to study the mechanisms involved in neurodegeneration.
      The present study investigated the effects of aluminum maltolate (Al-maltol) on
      the delicate balance that exists between pro-inflammatory cytokines and
      neurotrophins using primary brain rotation-mediated aggregate cultures.
      Aggregates were treated with Al-maltol (5-150 microM) on day 15 in vitro for 72
      h. Cell death increased in a time- and concentration-dependent manner reaching
      significance in aggregates treated with 150 microM Al-maltol in 48 h and 50
      microM by 72 h. Analysis of gene expression at 72 h revealed a concentration
      dependent increase in tumor necrosis factor alpha (TNFalpha) and macrophage
      inflammatory protein-1alpha (MIP-1alpha) suggestive of a state of inflammation.
      In contrast, a dramatic concentration-dependent decrease in the expression of
      nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) was
      observed. In fact, NGF expression could not be detected in aggregates treated
      with 50 and 150 microM Al-maltol. These changes in gene expression correlated
      with a decrease in aggregate size and an increase in neurodegeneration as
      indicated by Fluoro-Jade B staining. The results indicated a differential
      regulation of pro-inflammatory cytokines and neurotrophins in brain tissue
      following treatment with Al-maltol. Such findings provide insight into the
      possible involvement of deregulation of the cytokine/neurotrophin balance in the
      etiology of neurodegeneration.

PMID- 12606299
TI  - 20th International Neurotoxicology Conference: Emerging Issues in
      Neurotoxicology.

PMID- 12606301
TI  - Effects of Helicobacter pylori on intracellular Ca2+ signaling in normal human
      gastric mucous epithelial cells.
AB  - In stomach, Helicobacter pylori (Hp) adheres to gastric mucous epithelial cells
      (GMEC) and initiates several different signal transduction events. Alteration of
      intracellular Ca2+ concentration ([Ca2+]i) is an important signaling mechanism in
      numerous bacteria-host model systems. Changes in [Ca2+]i induced by Hp in normal
      human GMEC have not yet been described; therefore, we examined effects of Hp on
      [Ca2+]i in normal human GMEC and a nontransformed GMEC line (HFE-145). Cultured
      cells were grown on glass slides, porous filters, or 96-well plates and loaded
      with fura 2 or fluo 4. Hp wild-type strain 60190 and vacA-, cagA-, and picB-/cagE
      isogenic mutants were incubated with cells. Changes in [Ca2+]i were recorded
      with a fluorimeter or fluorescence plate reader. Wild-type Hp produced dose
      dependent biphasic transient [Ca2+]i peak and plateau changes in both cell lines.
      Hp vacA- isogenic mutant produced changes in [Ca2+]i similar to those produced by
      wild type. Compared with wild type, cagA- and picB-/cagE- isogenic mutants
      produced lower peak changes and did not generate a plateau change. Preloading
      cultures with intracellular Ca2+ chelator BAPTA blocked all Hp-induced [Ca2+]i
      changes. Thapsigargin pretreatment of cultures to release Ca2+ from internal
      stores reduced peak change. Extracellular Ca2+ removal reduced plateau response.
      Hp-induced peak response was sensitive to G proteins and PLC inhibitors. Hp
      induced plateau change was sensitive to G protein inhibitors, src kinases, and
      PLA2. These findings are the first to show that H. pylori alters [Ca2+]i in
      normal GMEC through a Ca2+ release/influx mechanism that depends on expression of
      cagA and picB/cagE genes.

PMID- 12606302
TI  - Active K+ secretion through multiple KCa-type channels and regulation by IKCa
      channels in rat proximal colon.
AB  - Colonic K+ secretion stimulated by cholinergic agents requires activation of
      muscarinic receptors and the release of intracellular Ca2+. However, the precise
      mechanisms by which this rise in Ca2+ leads to K+ efflux across the apical
      membrane are poorly understood. In the present study, Northern blot analysis of
      rat proximal colon revealed the presence of transcripts encoding rSK2 [small
      conductance (SK)], rSK4 [intermediate conductance (IK)], and rSlo [large
      conductance (BK)] Ca2+-activated K+ channels. In dietary K+-depleted animals,
      only rSK4 mRNA was reduced in the colon. On the basis of this observation, a cDNA
      encoding the K+ channel rSK4 was cloned from a rat colonic cDNA library.
      Transfection of this cDNA into Chinese hamster ovary (CHO) cells led to the
      expression of Ca2+-activated K+ channels that were blocked by the IK channel
      inhibitor clotrimazole (CLT). Confocal immunofluorescence confirmed the presence
      of IK channels in proximal colonic crypts, and Western blotting demonstrated that
      IK protein sorted to both the apical and basolateral surfaces of colonic
      epithelia. In addition, transcellular active K+ secretion was studied on
      epithelial strips of rat proximal colon using unidirectional 86Rb+ fluxes. The
      addition of thapsigargin or carbachol to the serosal surface enhanced net 86Rb+
      secretion. The mucosal addition of CLT completely inhibited carbachol-induced net
      86Rb+ secretion. In contrast, only partial inhibition was observed with the BK
      and SK channel inhibitors, iberiotoxin and apamin, respectively. Finally, in
      parallel with the reduction in SK4 message observed in animals deprived of
      dietary K+, carbachol-induced 86Rb+ secretion was abolished in dietary K+
      depleted animals. These results suggest that the rSK4 channel mediates K+
      secretion induced by muscarinic agonists in the rat proximal colon and that
      transcription of the rSK4 channel is downregulated to prevent K+ loss during
      dietary K+ depletion.

PMID- 12606303
TI  - Anion-dependent Mg2+ influx and a role for a vacuolar H+-ATPase in sheep ruminal
      epithelial cells.
AB  - The K+-insensitive component of Mg2+ influx in primary culture of ruminal
      epithelial cells (REC) was examined by means of fluorescence techniques. The
      effects of extracellular anions, ruminal fermentation products, and transport
      inhibitors on the intracellular free Mg2+ concentration ([Mg2+]i), Mg2+ uptake,
      and intracellular pH were determined. Under control conditions (HEPES-buffered
      high-NaCl medium), the [Mg2+]i of REC increased from 0.56 +/- 0.14 to 0.76 +/-
      0.06 mM, corresponding to a Mg2+ uptake rate of 15 microM/min. Exposure to
      butyrate did not affect Mg2+ uptake, but it was stimulated (by 84 +/- 19%) in the
      presence of CO2/HCO(-)3. In contrast, Mg2+ uptake was strongly diminished if REC
      were suspended in HCO(-)3-buffered high-KCl medium (22.3 +/- 4 microM/min) rather
      than in HEPES-buffered KCl medium (37.5 +/- 6 microM/min). After switching from
      high- to low-Cl- solution, [Mg2+]i was reduced from 0.64 +/- 0.09 to 0.32 +/-
      0.16 mM and the CO2/HCO(-)3-stimulated Mg2+ uptake was completely inhibited.
      Bumetanide and furosemide blocked the rate of Mg2+ uptake by 64 and 40%,
      respectively. Specific blockers of vacuolar H+-ATPase reduced the [Mg2+]i (36%)
      and Mg2+ influx (38%) into REC. We interpret this data to mean that the K+
      insensitive Mg2+ influx into REC is mediated by a cotransport of Mg2+ and Cl- and
      is energized by an H+-ATPase. The stimulation of Mg2+ transport by ruminal
      fermentation products may result from a modulation of the H+-ATPase activity.

PMID- 12606304
TI  - Differential changes in human pharyngoesophageal motor excitability induced by
      swallowing, pharyngeal stimulation, and anesthesia.
AB  - We investigated the effects of water swallowing, pharyngeal stimulation, and
      oropharyngeal anesthesia on corticobulbar and craniobulbar projections to human
      swallowing musculature. Changes in pathway excitability were measured via
      electromyography from swallowed intraluminal pharyngeal and esophageal electrodes
      to motor cerebral and trigeminal nerve magnetic stimulation. After both water
      swallowing and pharyngeal stimulation, pharyngoesophageal corticobulbar
      excitability increased (swallowing: pharynx = 59 +/- 12%, P < 0.001; esophagus =
      45 +/- 20%, P < 0.05; pharyngeal stimulation: pharynx = 76 +/- 19%, P < 0.001;
      esophagus = 45 +/- 23%, P = 0.05), being early with swallowing but late with
      stimulation. By comparison, craniobulbar excitability increased early after
      swallowing but remained unaffected by pharyngeal stimulation. After anesthesia,
      both corticobulbar (pharynx =-24 +/- 10%, P < 0.05; esophagus = -28 +/- 7%, P <
      0.01) and craniobulbar excitability showed a late decrease. Thus swallowing
      induces transient early facilitation of corticobulbar and craniobulbar
      projections, whereas electrical stimulation promotes delayed facilitation mainly
      in cortex. With removal of input, both corticobulbar and craniobulbar projections
      show delayed inhibition, implying a reduction in motoneuron and/or cortical
      activity.

PMID- 12606305
TI  - Gastrin-induced gastric adenocarcinoma growth is mediated through cyclin D1.
AB  - Gastrin is a gastrointestinal (GI) peptide that possesses potent trophic effects
      on most of the normal and neoplastic mucosa of the GI tract. Despite abundant
      evidence for these properties, the mechanisms governing gastrin-induced
      proliferation are still largely unknown. To elucidate the mechanisms by which
      gastrin might influence mitogenesis in gastric adenocarcinoma, we analyzed its
      effects on the human cell line AGS-B. Amidated gastrin (G-17), one of the major
      circulating forms of gastrin, induced a concentration-dependent increase in
      [3H]thymidine incorporation of cells in culture, with the maximum effective
      concentration occurring with 20 nM G-17. This effect was significantly attenuated
      by the gastrin-specific receptor antagonist L-365260. In addition, we found that
      G-17 induced a significant increase in the levels of cyclin D1 transcripts,
      protein, and promoter activity. The results of these studies indicate that
      gastrin appears to exert its mitogenic effects on gastric adenocarcinoma, at
      least in part, through changes in cyclin D1 expression.

PMID- 12606306
TI  - Central and noncentral blood volumes in cirrhosis: relationship to
      anthropometrics and gender.
AB  - The size of the central and arterial blood volume (CBV) is essential in the
      understanding of fluid retention in cirrhosis. Previously, it has been reported
      decreased, normal, or increased, but no reports have analyzed CBV with respect to
      gender and lean body mass. The aim of the present study was by means of an
      optimized technique to reassess it in a large group of patients with cirrhosis
      compared with healthy controls and matched controls in relationship to their body
      dimensions and gender. Eighty-three patients with cirrhosis (male/female, 60:23),
      67 patients without liver disease (male/female, 22:45), and 14 young healthy
      controls (male/female, 6:8) underwent a hemodynamic investigation with
      determination of cardiac output, central circulation time, and CBV determined
      according to kinetic principles. Related to gender, CBV was lower in male
      cirrhotics (1.48 +/- 0.30 liter) than in matched and young controls (1.68 +/-
      0.33 and 1.72 +/- 0.33 liter, respectively; P < 0.05-0.01). No significant
      differences in CBV were seen between female cirrhotics and controls. Absolute and
      adjusted CBVs were lower in the females than in men with cirrhosis (P < 0.001),
      and men with cirrhosis had lower absolute and body weight-adjusted CBVs than
      matched controls (P < 0.01). Normalized values of CBV (%total blood volume) were
      significantly lower in patients with cirrhosis (25 +/- 4%) than in matched
      controls (31 +/- 7%) and young controls (28 +/- 4%; P < 0.02). CBV correlated
      significantly with anthropometrics, including lean body mass (r = 0.68-0.82; P <
      0.0001). In conclusion, the CBV of patients with cirrhosis was lower than that of
      controls when adjusted for body dimensions and gender. There are significant
      gender differences, and signs of underfilling are more pronounced in male than in
      female patients. The results emphasize the importance of adjustments of blood
      volumes for anthropometrics and gender.

PMID- 12606307
TI  - Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human
      cholangiocyte cell lines.
AB  - Bile acids transactivate the EGF receptor (EGFR) in cholangiocytes. However, the
      mechanisms by which bile acids transactivate the EGFR remain unknown. Our aims
      were to examine the effects of bile acids on EGFR activation in human
      cholangiocyte cell lines KMBC and H-69. Bile acids stimulated cell growth and
      induced EGFR phosphorylation in a ligand-dependent manner. Although cells
      constitutively expressed several EGFR ligands, only transforming growth factor
      alpha (TGF-alpha) antisera effectively blocked bile acid-induced EGFR
      phosphorylation. Consistent with the concept that matrix metalloproteinase (MMP)
      activity is requisite for TGF-alpha membrane release and ligand function, bile
      acid transactivation of EGFR and cell growth was blocked by an MMP inhibitor. In
      conclusion, bile acids activate EGFR via a TGF-alpha-dependent mechanism, and
      this EGFR activation promotes cellular growth.

PMID- 12606308
TI  - Insulin-stimulated trafficking of ENaC in renal cells requires PI 3-kinase
      activity.
AB  - AlphaENaC-EGFP (enhanced green fluorescent protein-tagged alpha-subunit of the
      epithelial Na(+) channel) stably transfected clonal lines derived from the A6
      parental cell line were used to study the physical mechanisms of insulin
      stimulated Na(+) transport. Within 1 min of insulin stimulation, ENaC migrates
      from a diffuse cytoplasmic localization to the apical and lateral membranes.
      Concurrently, after insulin stimulation, phosphatidylinositol 3-kinase (PI 3
      kinase) is colocalized with ENaC on the lateral but not apical membrane. An
      inhibitor of PI 3-kinase, LY-294002, does not inhibit ENaC/PI 3-kinase
      colocalization but does alter the intracellular site of the colocalization,
      preventing the translocation of ENaC to the lateral and apical membranes. These
      data show that insulin stimulation causes the migration of ENaC to the lateral
      and apical cell membranes and that this trafficking is dependent on PI 3-kinase
      activity.

PMID- 12606309
TI  - Ca2+ transients activate calcineurin/NFATc1 and initiate fast-to-slow
      transformation in a primary skeletal muscle culture.
AB  - The calcineurin-mediated signal transduction via nuclear factor of activated T
      cells (NFATc1) is involved in upregulating slow myosin heavy chain (MHC) gene
      expression during fast-to-slow transformation of skeletal muscle cells. This
      study aims to investigate the Ca2+ signal necessary to activate the calcineurin
      NFATc1 cascade in skeletal muscle. Electrostimulation of primary myocytes from
      rabbit for 24 h induced a distinct fast-to-slow transformation at the MHC mRNA
      level and a full activation of the calcineurin-NFATc1 pathway, although resting
      Ca2+ concentration ([Ca2+]i) remained unaltered at 70 nM. During activation, the
      calcium transients of these myocytes reach a peak concentration of approximately
      500 nM. Although 70 nM [Ca2+]i does not activate calcineurin-NFAT, we show by the
      use of Ca2+ ionophore that the system is fully activated when [Ca2+]i is >or=150
      nM in a sustained manner. We conclude that the calcineurin signal transduction
      pathway and the slow MHC gene in cultured skeletal muscle cells are activated by
      repetition of the rapid high-amplitude calcium transients that are associated
      with excitation-contraction coupling rather than by a sustained elevation of
      resting Ca2+ concentration.

PMID- 12606310
TI  - Adult alveolar epithelial cells express multiple subtypes of voltage-gated K+
      channels that are located in apical membrane.
AB  - Whole cell perforated patch-clamp experiments were performed with adult rat
      alveolar epithelial cells. The holding potential was -60 mV, and depolarizing
      voltage steps activated voltage-gated K(+) (Kv) channels. The voltage-activated
      currents exhibited a mean reversal potential of -32 mV. Complete activation was
      achieved at -10 mV. The currents exhibited slow inactivation, with significant
      variability in the time course between cells. Tail current analysis revealed cell
      to-cell variability in K(+) selectivity, suggesting contributions of multiple Kv
      alpha-subunits to the whole cell current. The Kv channels also displayed steady
      state inactivation when the membrane potential was held at depolarized voltages
      with a window current between -30 and 5 mV. Analysis of RNA isolated from these
      cells by RT-PCR revealed the presence of eight Kv alpha-subunits (Kv1.1, Kv1.3,
      Kv1.4, Kv2.2, Kv4.1, Kv4.2, Kv4.3, and Kv9.3), three beta-subunits (Kvbeta1.1,
      Kvbeta2.1, and Kvbeta3.1), and two K(+) channel interacting protein (KChIP)
      isoforms (KChIP2 and KChIP3). Western blot analysis with available Kv alpha
      subunit antibodies (Kv1.1, Kv1.3, Kv1.4, Kv4.2, and Kv4.3) showed labeling of 50
      kDa proteins from alveolar epithelial cells grown in monolayer culture.
      Immunocytochemical analysis of cells from monolayers showed that Kv1.1, Kv1.3,
      Kv1.4, Kv4.2, and Kv4.3 were localized to the apical membrane. We conclude that
      expression of multiple Kv alpha-, beta-, and KChIP subunits explains the
      variability in inactivation gating and K(+) selectivity observed between cells
      and that Kv channels in the apical membrane may contribute to basal K(+)
      secretion across the alveolar epithelium.

PMID- 12606311
TI  - Microvessel formation from mouse aorta is stimulated in vitro by secreted VEGF
      and extracts from metanephroi.
AB  - We have demonstrated that during culture under 5% O(2,) the addition of
      recombinant human VEGF or FGF2 to mouse embryonic aorta explants (thoracic level
      to lateral vessels supplying the mesonephros and metanephros) stimulates
      microvessel formation. Here we show that microvessel formation is also stimulated
      by addition to explants of supernatants obtained from metanephroi grown in serum
      free organ culture or of metanephroi extracts. Supernatants and extracts from
      metanephroi grown under hypoxic conditions are more stimulatory than
      supernatants/extracts from metanephroi grown in room air. VEGF and FGF2 can be
      detected by using immunohistochemistry in developing nephrons in the cultured
      renal anlagen. Metanephroi supernatants contain more VEGF if renal anlagen are
      grown under hypoxic conditions than if they are grown in room air. Metanephros
      supernatant-stimulated microvessel formation is completely inhibited by soluble
      sFlt-1 fusion protein or anti-VEGF antibodies (alphaVEGF). Extract-stimulated
      microvessel formation is inhibited by alphaVEGF or anti-FGF2 antibodies, or both.
      We conclude that metanephroi produce growth factors including VEGF and FGF that
      enhance microvessel formation from embryonic thoracic aorta in vitro.

PMID- 12606312
TI  - Regulation of K-Cl cotransport during reticulocyte maturation and erythrocyte
      aging in normal and sickle erythrocytes.
AB  - The age/density-dependent decrease in K-Cl cotransport (KCC), PP1 and PP2A
      activities in normal and sickle human erythrocytes, and the effect of urea, a
      known KCC activator, were studied using discontinuous, isotonic gradients. In
      normal erythrocytes, the densest fraction (d approximately 33.4 g/dl) has only
      about approximately 5% of the KCC and 4% of the membrane (mb)-PP1 activities of
      the least-dense fraction (d approximately 24.7 g/dl). In sickle and normal
      erythrocytes, density-dependent decreases for mb-PP1 activity were similar (d50%
      28.1 +/- 0.4 vs. 27.2 +/- 0.2 g/dl, respectively), whereas those for KCC activity
      were not (d50% 31.4 +/- 0.9 vs. 26.8 +/- 0.3 g/dl, respectively, P = 0.004).
      Excluding the 10% least-dense cells, a very tight correlation exists between KCC
      and mb-PP1 activities in normal (r2 = 0.995) and sickle erythrocytes (r2 = 0.93),
      but at comparable mb-PP1 activities, KCC activity is higher in sickle
      erythrocytes, suggesting a defective, mb-PP1-independent KCC regulation. In
      normal, least-dense but not in densest cells, urea stimulates KCC (two- to
      fourfold) and moderately increases mb-PP1 (20-40%). Thus mb-PP1 appears to
      mediate part of urea-stimulated KCC activity.

PMID- 12606313
TI  - Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in
      neonatal rat ventricular myocytes.
AB  - Patients with cardiac hypertrophy and heart failure display abnormally slowed
      myocardial relaxation, which is associated with downregulation of
      sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2) gene expression. We previously
      showed that SERCA2 downregulation can be simulated in cultured neonatal rat
      ventricular myocytes (NRVM) by treatment with the protein kinase C (PKC)
      activator phorbol 12-myristate 13-acetate (PMA). However, NRVM express three
      different PMA-sensitive PKC isoenzymes (PKCalpha, PKCepsilon, and PKCdelta),
      which may be differentially regulated and have specific functions in the
      cardiomyocyte. Therefore, in this study we used adenoviral vectors encoding wild
      type (wt) and kinase-defective, dominant negative (dn) mutant forms of PKCalpha,
      PKCepsilon, and PKCdelta to analyze their individual effects in regulating SERCA2
      gene expression in NRVM. Overexpression of wtPKCepsilon and wtPKCdelta, but not
      wtPKCalpha, was sufficient to downregulate SERCA2 mRNA levels, as assessed by
      Northern blotting and quantitative, real-time RT-PCR (69 +/- 7 and 61 +/- 9% of
      control levels for wtPKCepsilon and wtPKCdelta, respectively; P < 0.05 for each
      adenovirus; n = 8 experiments). Conversely, overexpression of all three dnPKCs
      appeared to significantly increase SERCA2 mRNA levels (dnPKCdelta > dnPKCepsilon
      > dnPKCalpha). dnPKCdelta overexpression produced the largest increase (2.8 +/-
      1.0-fold; n = 11 experiments). However, PMA treatment was still sufficient to
      downregulate SERCA2 mRNA levels despite overexpression of each dominant negative
      mutant. These data indicate that the novel PKC isoenzymes PKCepsilon and PKCdelta
      selectively regulate SERCA2 gene expression in cardiomyocytes but that neither
      PKC alone is necessary for this effect if the other novel PKC can be activated.

PMID- 12606314
TI  - Role of caveolae in signal-transducing function of cardiac Na+/K+-ATPase.
AB  - Ouabain binding to Na(+)/K(+)-ATPase activates Src/epidermal growth factor
      receptor (EGFR) to initiate multiple signal pathways that regulate growth. In
      cardiac myocytes and the intact heart, the early ouabain-induced pathways that
      cause rapid activations of ERK1/2 also regulate intracellular Ca(2+)
      concentration ([Ca(2+)](i)) and contractility. The goal of this study was to
      explore the role of caveolae in these early signaling events. Subunits of
      Na(+)/K(+)-ATPase were detected by immunoblot analysis in caveolae isolated from
      cardiac myocytes, cardiac ventricles, kidney cell lines, and kidney outer medulla
      by established detergent-free procedures. Isolated rat cardiac caveolae contained
      Src, EGFR, ERK1/2, and 20-30% of cellular contents of alpha(1)- and alpha(2)
      isoforms of Na(+)/K(+)-ATPase, along with nearly all of cellular caveolin-3.
      Immunofluorescence microscopy of adult cardiac myocytes showed the presence of
      caveolin-3 and alpha-isoforms in peripheral sarcolemma and T tubules and
      suggested their partial colocalization. Exposure of contracting isolated rat
      hearts to a positive inotropic dose of ouabain and analysis of isolated cardiac
      caveolae showed that ouabain caused 1) no change in total caveolar ERK1/2, but a
      two- to threefold increase in caveolar phosphorylated/activated ERK1/2; 2) no
      change in caveolar alpha(1)-isoform and caveolin-3; and 3) 50-60% increases in
      caveolar Src and alpha(2)-isoform. These findings, in conjunction with previous
      observations, show that components of the pathways that link Na(+)/K(+)-ATPase to
      ERK1/2 and [Ca(2+)](i) are organized within cardiac caveolae microdomains. They
      also suggest that ouabain-induced recruitments of Src and alpha(2)-isoform to
      caveolae are involved in the manifestation of the positive inotropic effect of
      ouabain.

PMID- 12606315
TI  - Adenylyl cyclase expression and modulation of cAMP in rat taste cells.
AB  - cAMP is a second messenger implicated in sensory transduction for taste. The
      identity of adenylyl cyclase (AC) in taste cells has not been explored. We have
      employed RT-PCR to identify the AC isoforms present in taste cells and found that
      AC 4, 6, and 8 are expressed as mRNAs in taste tissue. These proteins are also
      expressed in a subset of taste cells as revealed by immunohistochemistry.
      Alterations of cAMP concentrations are associated with transduction of taste
      stimuli of several classes. The involvement of particular ACs in this modulation
      has not been investigated. We demonstrate that glutamate, which is a potent
      stimulus eliciting a taste quality termed umami, causes a decrease in cAMP in
      forskolin-treated taste cells. The potentiation of this response by inosine
      monophosphate, the lack of response to d-glutamate, and the lack of response to
      umami stimuli in nonsensory lingual epithelium all suggest that the cAMP
      modulation represents umami taste transduction. Because cAMP downregulation via
      ACs can be mediated through Galpha(i) proteins, we examined the colocalization of
      the detected ACs with Galpha(i) proteins and found that 66% of AC8 immunopositive
      taste cells are also positive for gustducin, a taste-specific Galpha(i) protein.
      Whether AC8 is directly involved in signal transduction of umami taste remains to
      be established.

PMID- 12606316
TI  - Na+-dependent phosphate transporters in the murine osteoclast: cellular
      distribution and protein interactions.
AB  - We previously demonstrated that inhibition of Na-dependent phosphate (P(i))
      transport in osteoclasts led to reduced ATP levels and diminished bone
      resorption. These findings suggested that Na/P(i) cotransporters in the
      osteoclast plasma membrane provide P(i) for ATP synthesis and that the osteoclast
      may utilize part of the P(i) released from bone resorption for this purpose. The
      present study was undertaken to define the cellular localization of Na/P(i)
      cotransporters in the mouse osteoclast and to identify the proteins with which
      they interact. Using glutathione S-transferase (GST) fusion constructs, we
      demonstrate that the type IIa Na/P(i) cotransporter (Npt2a) in osteoclast lysates
      interacts with the Na/H exchanger regulatory factor, NHERF-1, a PDZ protein that
      is essential for the regulation of various membrane transporters. In addition,
      NHERF-1 in osteoclast lysates interacts with Npt2a in spite of deletion of a
      putative PDZ-binding domain within the carboxy terminus of Npt2a. In contrast,
      deletion of the carboxy-terminal TRL amino acid motif of Npt2a significantly
      reduced its interaction with NHERF-1 in kidney lysates. Studies in osteoclasts
      transfected with green fluorescent protein-Npt2a constructs indicated that Npt2a
      colocalizes with NHERF-1 and actin at or near the plasma membrane of the
      osteoclast and associates with ezrin, a linker protein associated with the actin
      cytoskeleton, likely via NHERF-1. Furthermore, we demonstrate by RT/PCR of
      osteoclast RNA and in situ hybridization that the type III Na/P(i) cotransporter,
      PiT-1, is also expressed in mouse osteoclasts. To examine the cellular
      distribution of PiT-1, we infected mouse osteoclasts with a retroviral vector
      encoding PiT-1 fused to an epitope tag. PiT-1 colocalizes with actin and is
      present on the basolateral membrane of the polarized osteoclast, similar to that
      previously reported for Npt2a. Taken together, our data suggest that association
      of Npt2a with NHERF-1, ezrin, and actin, and of PiT-1 with actin, may be
      responsible for membrane sorting and regulation of these Na/P(i) cotransporters
      in the osteoclast.

PMID- 12606317
TI  - Contribution of chloride channels to volume regulation of cortical astrocytes.
AB  - The objective of this study was to determine the relative contribution of Cl(-)
      channels to volume regulation of cultured rat cortical astrocytes after hypotonic
      cell swelling. Using a Coulter counter, we showed that cortical astrocytes
      regulate their cell volume by approximately 60% within 45 min after hypotonic
      challenge. This volume regulation was supported when Cl(-) was replaced with Br(
      ), NO(3)(-), methanesulfonate(-), or acetate(-) but was inhibited when Cl(-) was
      replaced with isethionate(-) or gluconate(-). Additionally, substitution of Cl(-)
      with I(-) completely blocked volume regulation. Volume regulation was unaffected
      by furosemide or bumetanide, blockers of KCl transport, but was inhibited by Cl(
      ) channel blockers, including 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB),
      4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and niflumic acid.
      Surprisingly, the combination of Cd(2+) with NPPB, DIDS, or niflumic acid
      inhibited regulation to a greater extent than any of these drugs alone. Volume
      regulation did not differ among astrocytes cultured from different brain regions,
      as cerebellar and hippocampal astrocytes exhibited behavior identical to that of
      cortical astrocytes. These data suggest that Cl(-) flux through ion channels
      rather than transporters is essential for volume regulation of cultured
      astrocytes in response to hypotonic challenge.

PMID- 12606318
TI  - Characterization of a lanosterol 14 alpha-demethylase from Pneumocystis carinii.
AB  - Pneumocystis carinii (PC) causes severe pneumonia in immunocompromised patients.
      PC is intrinsically resistant to treatment with azole antifungal medications. The
      enzyme lanosterol 14 alpha-demethylase (Erg11) is the target for azole
      antifungals. We cloned PCERG11 and compared its sequence to Erg11 proteins
      present in azole-resistant organisms, and performed chromosomal and Northern blot
      analysis for PCERG11. Of 13 potential sites which could confer resistance to
      azoles, two were identical to azole-resistant Candida. By site-directed
      mutagenesis we changed these two sites in PCERG11 to those present in azole
      sensitive Candida to generate PCERG11-SDM (E113D, T125K). We tested the
      susceptibility of ERG11 deletion strains of Saccharomyces cerevisiae (SC)
      expressing PCERG11, PCERG11-SDM, and wild-type SCERG11 to three azole
      antifungals: fluconazole, itraconazole, and voriconazole. PCERG11 required a 2.2
      fold higher dose of voriconazole and 3.5-fold higher dose of fluconazole than
      SCERG11 for a 50% reduction in growth. No difference was observed in the
      sensitivity to itraconazole. PCERG11-SDM has increased sensitivity to fluconazole
      and voriconazole, but not itraconazole. We believe that the molecular structure
      of the lanosterol 14 alpha-demethylase encoded by PCERG11 confers inherent
      resistance to azole antifungals and plays an integral part in the overall
      resistance of this PC to azole therapy.

PMID- 12606319
TI  - Non-cyclic and developmental stage-specific expression of circadian clock
      proteins during murine spermatogenesis.
AB  - The central circadian clock in mammals is housed in the brain and is based on
      cyclic transcription and translation of clock proteins. How the central clock
      regulates peripheral organ function is unclear. However, cyclic expression of
      circadian genes in peripheral tissues is well established, suggesting that these
      tissues have their own endogenous oscillators. Reproduction is a process
      influenced by circadian rhythms in many organisms, thus making the testis an
      attractive model for studying clock function in peripheral organs. However,
      results addressing cyclic expression of clock genes in the mammalian testis are
      inconsistent. To resolve this issue, RNA was extracted from testes of mice at
      various times of day. Expression of the circadian clock genes mPer1, mPer2,
      Bmal1, Clock, mCry1, and Npas2 was constant at all times. Immunohistochemical
      localization of mPER1 and CLOCK proteins revealed restricted expression only in
      cells at specific developmental stages of spermatogenesis. For mPER1, these
      stages are the spermatogonia and the condensing spermatids. In contrast, CLOCK
      expression was restricted to round spermatids, specifically within the developing
      acrosome. Expression of mPER1 and CLOCK was constant at all times of day. These
      results suggest that clock proteins have noncircadian functions in
      spermatogenesis. Noncircadian expression of clock genes was also found in the
      thymus, which, like the testis, is composed primarily of differentiating cells.
      We propose that cyclic expression of clock genes is suspended during cellular
      differentiation.

PMID- 12606320
TI  - Carboxy-terminal proteolytic processing at a consensus furin cleavage site is a
      prerequisite event for quail ZPC secretion.
AB  - In avian species, a glycoprotein homologous to mammalian ZPC is synthesized in
      the granulosa cells of developing follicles. We have previously reported that the
      newly synthesized ZPC (proZPC) in granulosa cells is cleaved at a consensus furin
      cleavage site to generate mature ZPC prior to secretion. In the present study, we
      examined the effect of the proteolytic cleavage of proZPC on ZPC secretion by
      using a specific inhibitor of furin endoprotease and site-directed mutagenesis of
      the furin cleavage site. Western blot analysis demonstrated that the furin
      inhibitor efficiently blocked both the proteolytic cleavage of proZPC and the
      subsequent ZPC secretion. A site-directed mutant that possessed a mutated
      sequence for furin cleavage was not secreted from the cells. The
      immunocytochemical observations indicated that proZPC produced in the presence of
      a furin inhibitor or those produced by the site-directed mutant of the furin
      cleavage site had accumulated in the endoplasmic reticulum. These results
      indicate that proZPC is proteolytically cleaved at the consensus furin cleavage
      site with furin-like protease, and the failure of this cleavage results in its
      accumulation in the endoplasmic reticulum. Therefore, the C-terminal proteolytic
      processing of proZPC at the consensus furin cleavage site is a prerequisite event
      for quail ZPC secretion.

PMID- 12606321
TI  - Demonstration of a tissue factor pathway inhibitor 2 messenger RNA synthesis by
      pure villous cytotrophoblast cells isolated from term human placentas.
AB  - Tissue factor pathway inhibitor 2 (TFPI-2), a Kunitz-type proteinase inhibitor,
      might play an important role during placenta growth by regulating trophoblast
      invasion and differentiation. Many TFPI-2 transcripts have been detected in
      syncytiotrophoblast cells, but conflicting results have been reported concerning
      TFPI-2 synthesis by the cytotrophoblast. To address this issue, we developed a
      method to isolate pure preparations of human villous cytotrophoblast cells from
      normal term placentas, and the synthesis of tissue factor, TFPI-1, and TFPI-2
      mRNAs was then evaluated. Cells were isolated by trypsin-DNase-EDTA digestion,
      followed by Percoll gradient separation and immunodepletion of human leukocyte
      antigen-positive cells. The quality of villous cytotrophoblast cells was verified
      by electron microscopy. Purity of cell preparations was assessed by labeling
      cells with GB25, a monoclonal antibody specific to villous trophoblast cells, and
      by checking the absence of contaminating cells using anti-CD9 antibody. The lack
      of hCG, CD32 mRNA, and tissue factor mRNA also indicated the absence of
      contaminating cells. Using competitive reverse transcription polymerase chain
      reaction, we showed that freshly isolated villous cytotrophoblast cells
      synthesized significant levels of TFPI-1 mRNA and larger amounts of TFPI-2 mRNA.
      TFPI-1 and TFPI-2 mRNA synthesis remained unchanged when cytotrophoblast cells
      were cultured in complete medium and evolved as a multinucleated
      syncytiotrophoblast. These results indicate that the villous cytotrophoblast and
      syncytiotrophoblast are both important sites of TFPI-2 synthesis in the human
      placenta. This study also indicates that tissue factor detection should be used
      systematically to check the purity of cytotrophoblast cell preparations because
      it allows detection of contamination by monocytes/macrophages and by syncytial
      fragments.

PMID- 12606322
TI  - A novel role of luteinizing hormone in the embryo development in cocultures.
AB  - Bovine oviductal epithelium contains LH receptors, which function in the increase
      of synthesis of oviductal glycoprotein (OGP). As with cocultures of embryos with
      oviductal epithelial cells, OGP is thought to promote early embryonic growth and
      development. These findings led us to test the hypothesis that LH treatment of
      cocultures further increases embryo development through OGP mediation. Coculture
      of > or=10 two-cell bovine embryos with bovine oviductal epithelial cells
      increased the development of the embryos into blastocysts. Treatment of these
      cocultures with hCG, used as a surrogate for LH because of its stability and
      purity, further increased embryo development. The hCG effect is dose dependent
      and hormone specific and requires the dimer conformation and the presence of LH
      receptors in oviductal epithelial cells. The inhibition of OGP synthesis and
      prevention of protein kinase A activation blocked the hCG effect in cocultures.
      Reverse transcription polymerase chain reaction and indirect immunofluorescence
      with laser scanning confocal microscopy demonstrated the presence of LH receptors
      in bovine oocytes, embryos, and blastocysts. However, embryo LH receptors may not
      have played any role in the beneficial hCG effects in cocultures. These findings
      suggest that elevated periovulatory LH levels may promote preimplantation embryo
      development in oviducts. These results have important implications for assisted
      reproductive technologies in which cocultures are used to improve pregnancy
      rates.

PMID- 12606323
TI  - Comparison of potassium currents in human decidua before and after the onset of
      labor.
AB  - The human decidua plays a prominent role in the signaling between maternal and
      fetal tissues. It also secretes a plethora of molecules that modulate uterine
      function. Ion-channel activity underpins many cellular functions; however, the
      channels in human decidua have not been characterized in any detail. We have used
      the whole-cell recording mode of the patch-clamp technique to carry out current
      clamp and voltage-clamp recordings of membrane properties and whole-cell
      potassium (K+) currents of freshly isolated decidual stromal cells. Decidual
      tissue was obtained from women after spontaneous vaginal delivery (SVD) or
      elective cesarean section (CS). Cells from both groups generated action
      potentials, the overshoots and durations of which were dependent on extracellular
      calcium levels, inhibited by cobalt and enhanced by barium. Potassium current
      (IK) density was higher in the CS than in the SVD group. Outwardly directed
      currents were heterogeneous with respect to their activation/inactivation
      profiles and exhibited outward rectification. The main difference between the SVD
      and CS group was the presence of a sustained current component in CS cells that
      is tetraethylammonium chloride-resistant and appears to be unaffected by E-4031.
      No evidence for the activation of any calcium-activated K+ currents was obtained.
      We propose that human parturition is associated with subtle changes in K+ channel
      remodeling, reflecting the transition from uterine quiescence to activation and
      stimulation. An understanding of the signal transduction events underlying these
      process may eventually lead to novel approaches to prevent preterm labor via
      decidual rather than myometrial intervention.

PMID- 12606324
TI  - Up-regulation of alpha-inhibin expression in the fetal ovary of estrogen
      suppressed baboons is associated with impaired fetal ovarian folliculogenesis.
AB  - We recently demonstrated that the number of primordial follicles was
      significantly reduced in the ovaries of near-term baboon fetuses deprived of
      estrogen in utero and restored to normal in animals administered estradiol.
      Although the baboon fetal ovary expressed estrogen receptors alpha and beta, the
      mechanism(s) of estrogen action remains to be determined. It is well established
      that inhibin and activins function as autocrine/paracrine factors that impact
      adult ovarian function. However, our understanding of the expression of these
      factors in the primate fetal ovary is incomplete. Therefore, we determined the
      expression of alpha-inhibin, activin beta(A), activin beta(B), and activin
      receptors in fetal ovaries obtained at mid and late gestation from untreated
      baboons and at late gestation from animals in which fetal estrogen levels were
      reduced by >95% by maternal administration of the aromatase inhibitor CGS 20267
      or restored to 30% of normal by treatment with CGS 20267 and estradiol benzoate.
      Immunocytochemical expression of alpha-inhibin was minimal to nondetectable in
      fetal ovaries from untreated baboons. In contrast, in baboons depleted of
      estrogen, alpha-inhibin was abundantly expressed in pregranulosa cells of
      interfollicular nests and granulosa cells of primordial follicles. Thus, the
      number (mean +/- SEM) per 0.08 mm2 of fetal ovarian cells expressing alpha
      inhibin, determined by image analysis, was similar at mid and late gestation and
      increased approximately 8-fold (P < 0.01) near term in baboons treated with CGS
      20267 and was restored (P < 0.01) to normal in baboons treated with CGS 20267
      plus estradiol. Activin beta(A) was detected in oocytes and pregranulosa cells at
      midgestation and in oocytes and granulosa cells of primordial follicles at late
      gestation. Activin beta(B) was also expressed in pregranulosa cells and granulosa
      cells at mid and late gestation, respectively, but was not detected in oocytes.
      Neither the pattern nor the apparent level of expression of activin beta(A) or
      beta(B) were altered in fetal ovaries of baboons treated with CGS 20267 or CGS
      20267 and estrogen. Activin receptors IA, IB, IIA, and IIB were detected by
      Western blot analysis in fetal ovaries at mid and late gestation, and expression
      was not altered by treatment with CGS 20267 or CGS 20267 and estrogen. Activin
      receptors IB and IIA were localized to oocytes and pregranulosa cells at
      midgestation and to granulosa cells and oocytes of primordial follicles at late
      gestation. Thus, the decrease in the number of follicles in the primate fetal
      ovary of baboons deprived of estrogen in utero was associated with increased
      expression of alpha-inhibin. Therefore, we propose that estrogen regulates fetal
      ovarian follicular development by controlling alpha-inhibin expression and, thus,
      the intraovarian inhibin:activin ratio.

PMID- 12606325
TI  - Activin signaling pathways in ovine pituitary and LbetaT2 gonadotrope cells.
AB  - In the pituitary, activin stimulates the synthesis and release of FSH. However,
      the activin receptor signaling pathways that mediate these effects are poorly
      known. We investigated these mechanisms in primary ovine pituitary cells (POP)
      and in the murine LbetaT2 gonadotrope cell line. POP cells and LbetaT2 cells
      express the different activin receptors (types IA, IB, IIA, and IIB) and the Smad
      proteins (Smad-2, -3, -4, and -7). In both POP and LbetaT2 cells, activin
      activated several signaling pathways: Smad-2, extracellular regulated kinase-1/2
      (ERK1/2), p38, and phosphatidylinositol 3'-kinase (PI3K)/Akt. Phosphorylation of
      ERK1/2 and p38 were stimulated (3- to 6-fold) rapidly in 5 min, whereas
      activation of both Smad-2 and Akt (3- to 5-fold) occurred later, in 60 min.
      Activin also increased the association of activin receptor IIB with PI3K. Using
      specific inhibitors, we demonstrated that the activation of Smad-2 was partially
      blocked by the inhibition of PI3K but not by the inhibition of ERK1/2 or p38,
      suggesting a cross-talk between the Smad and PI3K/Akt pathways. In both POP and
      LbetaT2 cells, FSH expression and secretion in response to activin were not
      altered by the inhibition of PI3K/Akt, ERK1/2, or p38 pathways, whereas they were
      reduced by about 2-fold by expression of a dominant negative of Smad-2 or the
      natural inhibitory Smad-7 in LbetaT2 cells. These results indicate that activin
      activates several signaling pathways with different time courses in both POP and
      LbetaT2 cells, but only the Smad-2 pathway appears to be directly implicated in
      FSH expression and release in LbetaT2 cells.

PMID- 12606326
TI  - Analysis of germ cell nuclear factor transcripts and protein expression during
      spermatogenesis.
AB  - Germ cell nuclear factor (GCNF), an orphan receptor in the nuclear receptor
      superfamily, is expressed predominantly in developing germ cells in the adult
      mouse. Two Gcnf transcripts (7.4 and 2.1 kilobase [kb]) encoded by a single copy
      gene are expressed in the testis of several mammalian species. To identify
      features that regulate Gcnf expression, we characterized the structure and
      sequence of the mouse gene and its two transcripts and determined the expression
      profile of the GCNF protein during spermatogenesis. Genomic fragments spanning
      part of the 5'-untranslated region (UTR), the coding sequence, and the complete
      3'-UTR (approximately 80 kb) were isolated and sequenced. The 3'-UTRs of the two
      transcripts are quite distinct. The 7.4 kb transcript, which appears earlier in
      spermatogenesis, has a very long 3'-UTR of 4451 nucleotides. In contrast, the 2.1
      kb transcript, which is expressed predominantly during the haploid phase of
      spermatogenesis, has a 3'-UTR that is only 202 nucleotides in length. Additional
      analyses indicate that both transcripts share the same coding region and are
      associated with polysomes. A single GCNF protein band was detected in testis
      extracts by Western blotting with a specific antiserum. Immunohistochemical
      analysis showed that GCNF is localized in the nuclei of pachytene spermatocytes
      and round spermatids. GCNF is first detectable in early pachytene spermatocytes
      (stage II) and is continuously expressed until spermatids begin to elongate in
      stage IX. Although GCNF is generally distributed throughout the nucleus, it is
      particularly prominent in heterochromatic regions at some stages and in condensed
      chromosomes undergoing the meiotic divisions. This expression profile suggests
      that GCNF plays a role in transcriptional regulation during meiosis and the early
      haploid phase of spermatogenesis.

PMID- 12606327
TI  - Ovarian modulators of 11beta-hydroxysteroid dehydrogenase (11beta HSD) activity
      in follicular fluid from bovine and porcine large antral follicles and
      spontaneous ovarian cysts.
AB  - In the ovary, cortisol is oxidized to cortisone by 11beta-hydroxysteroid
      dehydrogenase (11betaHSD). The present study investigated whether follicular
      fluid (FF) from large antral follicles and spontaneous ovarian cysts, isolated
      from bovine and porcine ovaries, contained modulators of 11betaHSD activity.
      Whereas FF from antral follicles had no significant effect over 1 h on NADP+
      dependent 11betaHSD activity in rat kidney homogenates, enzyme activity was
      inhibited by FF from bovine and porcine ovarian cysts (80.5% +/- 2.3% and 72.8%
      +/- 3.4% of control, respectively). Following C18 reverse-phase chromatography,
      the hydrophilic fractions of FF from bovine and porcine antral follicles
      stimulated NADP+-dependent 11betaHSD activities (111.5% +/- 21.6% and 55.2% +/-
      5.7% respectively). Hydrophobic compounds inhibited NADP+-dependent cortisol
      oxidation by 58.2% +/- 5.1% (bovine) and 45.7% +/- 2.0% (porcine). In both
      species, FF from ovarian cysts appeared to contain less of the hydrophilic
      stimuli to 11betaHSD activity and more of the hydrophobic inhibitors. The FF from
      antral follicles and ovarian cysts, and the C18 fractions thereof, had no
      significant effect on NAD+-dependent cortisol oxidation. The ovarian modulators
      of NADP+-dependent 11betaHSD activities did not coelute with cortisol, cortisone,
      estradiol, testosterone, progesterone, pregnenolone, and cholesterol. However,
      the 11betaHSD stimuli in porcine FF from both antral follicles and cysts coeluted
      with prostaglandin (PG) E2 and PGF2alpha. We conclude that large antral follicles
      and spontaneous ovarian cysts, in both the cow and the pig, contain ovarian
      modulators of the NADP+-dependent 11betaHSD activity. Moreover, FF from
      spontaneous ovarian cysts, because of decreased content of the 11betaHSD stimulus
      accompanied by increased content of the 11betaHSD inhibitors, exerts a net
      inhibitory effect on 11betaHSD activity.

PMID- 12606328
TI  - Timing of blastocyst expansion affects spatial messenger RNA expression patterns
      of genes in bovine blastocysts produced in vitro.
AB  - Blastocyst formation and expansion are dependent on the differentiation and
      function of a proper transport of nutrients through the trophectoderm (TE)
      enclosing the inner cell mass (ICM). Coincident with compaction and cavitation,
      glucose becomes the preferred energy substrate of the early embryo. These
      hallmarks in early development require well-orchestrated gene expression patterns
      specifically with regard to timing and localization. The present study
      investigated the relative abundance (RA) of gene transcripts in the two lineages
      of in vitro-produced expanded bovine blastocysts in relation to timing of
      development, i.e., blastocyst expansion and localization of specific mRNAs.
      Expanded blastocysts from either Day 7 or Day 8 or isolated ICMs derived thereof
      were analyzed with the aid of a semiquantitative reverse transcriptase-polymerase
      chain reaction assay for gene transcripts, which are thought to play a pivotal
      role in blastocyst expansion, i.e., Na/K-ATPase alpha1 subunit (Na/K), E-cadherin
      (E-cad), zonula occludens protein-1 (ZO-1), desmocollin II (Dc II), plakophilin
      (Plako), trophoblastic function (interferon tau [IFtau]), and glucose transport
      (glucose transporter-1, -3, -4 [Glut-1, -3, -4]). Total cell number, ICM cell
      number, or ICM/total cells ratio were similar in Day 7 and Day 8 expanded
      blastocysts. Significant differences were determined in the RA for Na/K, E-cad,
      Dc II, Plako, and ZO-1 transcripts between TE cells of expanded blastocysts
      derived from either Day 7 or Day 8. The RA of Dc II, Glut-1, and Glut-4 was
      significantly decreased in the ICM compared with the TE at Day 7. Similarly, the
      RA of Na/K, Dc II, Glut-1, and Glut-4 at Day 8 of development was significantly
      decreased in the ICM compared with the TE. Interestingly, no differences were
      observed when comparing ICMs originating from blastocysts expanded at either Day
      7 or Day 8. Plako and IFtau transcripts were not detected in isolated ICMs,
      indicating that expression of these mRNAs is restricted to the TE. In contrast,
      similar expression patterns within the ICM and TE were determined for Na/K, E
      cad, ZO-1, and Glut-3 mRNA. Dc II, Glut-1, and Glut-4 were more abundant in the
      TE than in ICM. Results show that expression of developmentally important genes
      is related to the two cell lineages in the early embryo and emphasize the
      critical role of a well controlled spatial gene expression pattern for regular
      preimplantation development.

PMID- 12606329
TI  - Maternal undernutrition from early- to mid-gestation leads to growth retardation,
      cardiac ventricular hypertrophy, and increased liver weight in the fetal sheep.
AB  - Early gestation is critical for placentomal growth, differentiation, and
      vascularization, as well as fetal organogenesis. The fetal origins of adult
      disease hypothesis proposes that alterations in fetal nutrition and endocrine
      status result in developmental adaptations that permanently change structure,
      physiology, and metabolism, thereby predisposing individuals to cardiovascular,
      metabolic, and endocrine disease in adult life. Multiparous ewes were fed to 50%
      (nutrient restricted) or 100% (control fed) of total digestible nutrients from
      Days 28 to 78 of gestation. All ewes were weighed weekly and diets adjusted for
      individual weight loss or gain. Ewes were killed on Day 78 of gestation and
      gravid uteri recovered. Fetal body and organ weights were determined, and
      numbers, morphologies, diameters, and weights of all placentomes were obtained.
      From Day 28 to Day 78, restricted ewes lost 7.4% of body weight, while control
      ewes gained 7.5%. Maternal and fetal blood glucose concentrations were reduced in
      restricted versus control pregnancies. Fetuses were markedly smaller in the
      restricted group than in the control group. Further, restricted fetuses exhibited
      greater right- and left-ventricular and liver weights per unit fetal weight than
      control fetuses. No treatment differences were observed in any gross placentomal
      measurement. However, caruncular vascularity was enhanced in conceptuses from
      nutrient-restricted ewes but only in twin pregnancies. While these alterations in
      fetal/placental development may be beneficial to early fetal survival in the face
      of a nutrient restriction, their effects later in gestation as well as in
      postnatal life need further investigation.

PMID- 12606330
TI  - In vivo effect of epidermal growth factor, interleukin-1beta, and interleukin-1RA
      on equine preovulatory follicles.
AB  - Paracrine factors have significant effects during folliculogenesis. Because of
      various morphological features, the mare is a convenient model to study in vivo
      the effects of factors involved in periovulatory events. In the present work,
      epidermal growth factor (EGF; experiment 1, n = 49 mares) and interleukin-1beta
      and interleukin-1RA (IL-1beta and IL-1RA, respectively; experiment 2, n = 80
      mares) were injected intrafollicularly to evaluate the influence of these factors
      on in vivo maturation of equine preovulatory follicles. A transvaginal ultrasound
      guided injection was performed when the diameter of the dominant follicle reached
      30-34 mm. In experiment 1, the four experimental groups were 1) EGF group,
      intrafollicular (i.f.) injection of EGF (2 ml; 0.5 microg/ml) plus i.v. injection
      of physiological serum; 2) control group, no injection; 3) PBS group, i.f.
      injection of 2 ml of PBS plus i.v. injection of physiological serum; 4) crude
      equine gonadotropins (CEG) group, i.f. injection of PBS plus i.v. injection of
      CEG (20 mg). In experiment 2, groups 3 and 4 were the same as in experiment 1,
      but groups 1 and 2 were changed as follows: 1) IL-1beta group, i.f. injection of
      IL-1beta (2 ml; 0.5 microg/ml) plus i.v. injection of physiological serum; 2) IL
      1RA group, i.f. injection of IL-1RA (2 ml; 0.5 microg/ml) plus i.v. injection of
      physiological serum. In each experiment, cumulus-oocyte complexes from
      dominant/injected follicles were collected by transvaginal ultrasound-guided
      aspiration 38 h after intrafollicular injection. Cumulus morphology and oocyte
      nuclear stage were assessed. Additionally, in experiment 2, 40 mares were used to
      determine the time of ovulation after treatments. Our results indicate that
      intrafollicular injection of EGF or PBS induced lower cumulus expansion and
      oocyte maturation rates compared with the CEG group (P < 0.05). In experiment 2,
      the IL-1beta and CEG groups showed the same expansion rate, the same oocyte
      maturation rate, and the same ovulation distribution. On the other hand, the
      intrafollicular injection of IL-1RA, as PBS, did not induce follicle and cumulus
      oocyte complex (COC) maturation. In conclusion, we confirmed that the technique
      of intrafollicular injection can be used in the mare to study the role of
      specific molecules. We demonstrated for the first time in mares that the
      injection of EGF did not influence in vivo COC maturation. In contrast, IL-1beta
      injection into the dominant follicle induced in vivo oocyte maturation and the
      ovulation process whereas IL-1RA seemed to block these mechanisms.

PMID- 12606331
TI  - Differentiation of monkey embryonic stem cells into neural lineages.
AB  - Embryonic stem (ES) cells are self-renewing, pluripotent, and capable of
      differentiating into all of the cell types found in the adult body. Therefore,
      they have the potential to replace degenerated or damaged cells, including those
      in the central nervous system. For ES cell-based therapy to become a clinical
      reality, translational research involving nonhuman primates is essential. Here,
      we report monkey ES cell differentiation into embryoid bodies (EBs), neural
      progenitor cells (NPCs), and committed neural phenotypes. The ES cells were
      aggregated in hanging drops to form EBs. The EBs were then plated onto adhesive
      surfaces in a serum-free medium to form NPCs and expanded in serum-free medium
      containing fibroblast growth factor (FGF)-2 before neural differentiation was
      induced. Cells were characterized at each step by immunocytochemistry for the
      presence of specific markers. The majority of cells in complex/cystic EBs
      expressed antigens (alpha-fetal protein, cardiac troponin I, and vimentin)
      representative of all three embryonic germ layers. Greater than 70% of the
      expanded cell populations expressed antigenic markers (nestin and musashi1) for
      NPCs. After removal of FGF-2, approximately 70% of the NPCs differentiated into
      neuronal phenotypes expressing either microtubule-associated protein-2C (MAP2C)
      or neuronal nuclear antigen (NeuN), and approximately 28% differentiated into
      glial cell types expressing glial fibrillary acidic protein. Small populations of
      MAP2C/NeuN-positive cells also expressed tyrosine hydroxylase (approximately 4%)
      or choline acetyltransferase (approximately 13%). These results suggest that
      monkey ES cells spontaneously differentiate into cells of all three germ layers,
      can be induced and maintained as NPCs, and can be further differentiated into
      committed neural lineages, including putative neurons and glial cells.

PMID- 12606332
TI  - Gonadotropin-releasing hormone alters the T helper cytokine balance in the
      pregnant rat.
AB  - The interactions between immune-endocrine and reproductive systems are heightened
      during pregnancy as an adaptive mechanism, and are regulated by a complex array
      of hormones and cytokines that control the survival of a semiallogeneic
      conceptus. GnRH can exert direct effects on the immune system via its receptor
      (GnRH-R) on lymphoid cells. In the present study, we employed in vitro, ex vivo,
      and in vivo approaches to investigate the role of GnRH in the modulation of T
      helper cytokines in pregnant rats undergoing termination of pregnancy. Day 8
      pregnant rats were infused with a GnRH agonist (GnRH-Ag) for 24 h using an
      osmotic minipump. Sham control rats were infused with the vehicle, saline.
      Lymphocytes were isolated from sham and treated rats and polyclonally stimulated
      with immobilized anti-CD3 antibody. The levels of the signature T helper 1 (Th-1)
      cytokines (interferon-gamma [IFN-gamma] and interleukin-2 [IL-2]) and Th-2
      cytokines (IL-4 and IL-10) were measured in culture supernatants. Using
      immunoflourescence confocal microscopy, we demonstrated for the first time the
      spatial localization of GnRH-R protein on the surface of lymphocytes. We observed
      a marked increase in IFN-gamma and inhibition of IL-4 production from lymphocytes
      of pregnant rats treated in vitro with different doses of GnRH-Ag. Further, the
      responsiveness of lymphocytes to produce IFN-gamma was markedly increased in
      cells cultured ex vivo from GnRH-Ag infused rats, whereas the capacity of
      lymphocytes to produce IL-4 was significantly inhibited. In addition, GnRH-Ag
      infusion in pregnant rats induced a shift toward Th-1 cytokines in the serum. We
      did not observe any significant difference in IL-2 and IL-10 production in
      response to GnRH-Ag. Our results suggest an additional function for GnRH as a Th
      1 inducer and Th-2 inhibitor. GnRH can thus skew the cytokine balance to
      predominantly Th-1 type in pregnancy, leading to the termination of pregnancy in
      rats.

PMID- 12606333
TI  - A GC-box within the proximal promoter region of the rat cathepsin L gene
      activates transcription in Sertoli cells of sexually mature rats.
AB  - It has been proposed that stage-specific gene expression in Sertoli cells results
      from sequential activation and repression of transcription. However, the exact
      molecular mechanisms are unknown. As a first step in addressing this fundamental
      issue, we recently demonstrated that a 3-kilobase (kb) genomic fragment
      immediately upstream of the rat cathepsin L translation start site directed stage
      specific expression of a reporter gene only in Sertoli cells of transgenic mice
      in a manner comparable to that of the endogenous gene (predominantly in stages VI
      VIII tubules). Supporting the activation/repression model of regulation, an
      upstream domain that mediated an inhibitory effect by male germ cells was
      identified within this 3-kb promoter region. In the present study, we localized
      and characterized the regulatory elements that activate transcription. Analyses
      of a series of 5' deletion constructs demonstrated that a 120-base pair (bp)
      region that spans the transcription start site of the rat cathepsin L gene was
      sufficient to activate transcription in Sertoli cells isolated from sexually
      mature rats. Within this region, electrophoretic mobility shift assays showed
      that one member of the Sp/XKLF family of factors, Sp3, specifically bound to a GC
      box. Furthermore, Sp1-binding activity was not detected in nuclear extracts from
      Sertoli cells of sexually mature rats. Finally, the GC-box was shown to be
      essential for promoter activity since mutating this binding motif abolished
      promoter activity. Collectively, these results suggest that the GC-box is a
      critical regulatory element for the cathepsin L promoter in mature Sertoli cells.

PMID- 12606334
TI  - Mouse oocytes and early embryos express multiple histone H1 subtypes.
AB  - Oocytes and embryos of many species, including mammals, contain a unique linker
      (H1) histone, termed H1oo in mammals. It is uncertain, however, whether other H1
      histones also contribute to the linker histone complement of these cells. Using
      immunofluorescence and radiolabeling, we have examined whether histone H10, which
      frequently accumulates in the chromatin of nondividing cells, and the somatic
      subtypes of H1 are present in mouse oocytes and early embryos. We report that
      oocytes and embryos contain mRNA encoding H10. A polymerase chain reaction-based
      test indicated that the poly(A) tail did not lengthen during meiotic maturation,
      although it did so beginning at the four-cell stage. Antibodies raised against
      histone H10 stained the nucleus of wild-type prophase-arrested oocytes but not of
      mice lacking the H10 gene. Following fertilization, H10 was detected in the
      nuclei of two-cell embryos and less strongly at the four-cell stage. No signal
      was detected in H10 -/- embryos. Radiolabeling revealed that species comigrating
      with the somatic H1 subtypes H1a and H1c were synthesized in maturing oocytes and
      in one- and two-cell embryos. Beginning at the four-cell stage in both wild-type
      and H10 -/- embryos, species comigrating with subtypes H1b, H1d, and H1e were
      additionally synthesized. These results establish that histone H10 constitutes a
      portion of the linker histone complement in oocytes and early embryos and that
      changes in the pattern of somatic H1 synthesis occur during early embryonic
      development. Taken together with previous results, these findings suggest that
      multiple H1 subtypes are present on oocyte chromatin and that following
      fertilization changes in the histone H1 complement accompany the establishment of
      regulated embryonic gene expression.

PMID- 12606335
TI  - Expression and functional characterization of the adhesion molecule spermatogenic
      immunoglobulin superfamily in the mouse testis.
AB  - Spermatogenic immunoglobulin superfamily (SgIGSF) is a mouse protein belonging to
      the immunoglobulin superfamily expressed in the spermatogenic cells of
      seminiferous tubules. We produced a specific polyclonal antibody against SgIGSF.
      Western blot analysis of the testes from postnatal developing mice using this
      antibody demonstrated multiple immunopositive bands of 80-130 kDa, which
      increased in number and size with the postnatal age. Enzymatic N-glycolysis
      caused reduction in the size of these bands to 70 kDa, indicating that SgIGSF is
      a glycoprotein and its glycosylation pattern and extent are developmentally
      regulated. Immunohistochemical analysis of the adult testis demonstrated that
      SgIGSF was present in the spermatogenic cells in the earlier steps of
      spermatogenesis and increased in amount from intermediate spermatogonia through
      zygotene spermatocytes but was diminished in the steps from early pachytene
      spermatocytes through round spermatids. After meiosis, SgIGSF reappeared in step
      7 spermatids and was present in the elongating spermatids until spermiation. The
      immunoreactivity was localized primarily on the cell membrane. Consistent with
      the findings in adult testes, the analysis of the developing testes revealed that
      SgIGSF was expressed separately in the spermatogenic cells in earlier and later
      phases. Sertoli cells had no expression of SgIGSF, whereas both SgIGSF
      immunoprecipitated from the testis lysate and produced in COS-7 cells was shown
      to bind to the surface of Sertoli cells in primary culture. These results
      suggested that SgIGSF on the surface of spermatogenic cells binds to some
      membrane molecules on Sertoli cells in a heterophilic manner and thereby may play
      diverse roles in the spermatogenesis.

PMID- 12606336
TI  - Developmental capacity of ferret embryos by nuclear transfer using G0/G1-phase
      fetal fibroblasts.
AB  - With the ultimate goal of establishing experimental protocols necessary for
      cloning ferrets, the present study has established parameters for the
      reconstruction of ferret embryos by nuclear transfer (NT) using G0/G1-phase donor
      fetal fibroblasts. Cumulus-oocyte complexes were harvested from superovulated
      ferrets and cultured in maturation medium for 24 h. Matured oocytes were then
      enucleated and injected with the fibroblast nuclei derived from 14-16-h serum
      starved cells. Reconstructed embryos were then activated by a combination of
      electric pulses and chemical stimulations. Subsequently, the reconstructed and
      activated embryos were either cultured in vitro or transferred to pseudopregnant
      ferrets to evaluate their developmental capacity in vitro and in vivo. Our
      results demonstrated that 56.3% of reconstructed embryos (n = 187) cleaved, while
      26.0% and 17.6% developed to morula and blastocyst phases in vitro, respectively.
      The blastocysts derived from NT embryos demonstrated normal morphology by
      differentially staining as compared to normal blastocysts developed in vivo
      following fertilization. In vivo developmental studies at 21 days
      posttransplantation demonstrated 8.8% of reconstructed embryos (n = 91) implanted
      into the uterine lining of recipients, while 3.3% formed fetuses. However,
      reconstructed embryos (n = 387) failed to develop to term (42 days). These
      results demonstrate donor nuclei of G0/G1-phase fetal fibroblast cells can be
      reprogrammed to support the development of reconstructed ferret embryos in vitro
      and in vivo; however, a significant third-trimester block occurs preventing full
      term development.

PMID- 12606337
TI  - Expression of foreign DNA is associated with paternal chromosome degradation in
      intracytoplasmic sperm injection-mediated transgenesis in the mouse.
AB  - The efficiency of intracytoplasmic sperm injection (ICSI)-mediated transgenesis
      is often limited by poor embryo development. Because our previous work indicated
      that impairment of embryo development is frequently related to chromosomal
      abnormalities, we hypothesized that foreign DNA and/or conditions used to enhance
      integration of the DNA might induce chromosome damage. Therefore, we examined the
      chromosomes of mouse embryos produced by transgenesis with the EGFP gene.
      Spermatozoa were processed with three methods that cause membrane disruption:
      freeze-thawing, Triton X-100, or Triton X-100 followed by a sucrose wash.
      Membrane-disrupted spermatozoa were mixed with EGFP plasmids and injected into
      metaphase II oocytes. Three endpoints were evaluated: paternal chromosomes of the
      zygote, embryo capacity to develop in vitro, and expression of the transgene at
      the morula/blastocyst stage. In all pretreatments, we observed a significant
      decrease (approximately 2-fold) in the frequency of normal karyoplates when
      spermatozoa were incubated with exogenous DNA as compared with the treatment when
      no DNA was added. As predicted, embryo development was correlated with the
      integrity of the paternal chromosomes of the zygote. Searching for the possible
      mechanism of chromosome degradation, we used the ion chelators EGTA and EDTA and
      found that they neutralize the harmful effect of the transgene and stabilize the
      paternal chromosomes. In the presence of chelating agents, however, the number of
      embryos expressing EGFP produced with ICSI-mediated transgenesis decreased
      significantly. The results suggest that treatment of spermatozoa with exogenous
      DNA leads to paternal chromosome degradation in the zygote. Furthermore, the
      mechanisms of disruption of paternal chromosomes and the integration of foreign
      DNA may be closely related.

PMID- 12606339
TI  - Sex steroids in scleractinian coral, Euphyllia ancora: implication in mass
      spawning.
AB  - The objectives of this study were to investigate the presence and annual cycle of
      sex steroids in scleractinian coral, Euphyllia ancora. The free and conjugated
      forms of sex steroids in coral and spawning seawater were investigated, and
      aromatase activity in the coral tissue was identified. Polyps collected from
      corals and seawater were extracted with diethyl ether, and purified by alumina
      column and reversed-phase HPLC; testosterone and estradiol-17beta (E2) was
      measured by a validated RIA. E2 and testosterone in their free and glucuronide
      forms were consistently detected in coral tissue throughout the year. Peak
      concentrations of free E2, E2 glucuronide, and testosterone glucuronide were
      obtained in the coral tissue just prior to spawning. The presence of specific
      aromatase activity was demonstrated in coral tissue. Free E2 and E2 glucuronide
      concentrations were higher than androgen (testosterone and testosterone
      glucuronide) in coral tissue and spawning seawater. Higher concentrations of free
      E2 than E2 glucuronide were detected in coral tissues throughout the year. In
      contrast, higher concentrations of E2 glucuronide than free E2 and testosterone
      glucuronide were found in seawater during mass coral spawning. No steroid sulfate
      could be detected in the coral tissue and seawater. We suggest that the release
      of E2 glucuronide may play an important role in coral mass spawning.

PMID- 12606338
TI  - Receptor-mediated chicken oocyte growth: differential expression of endophilin
      isoforms in developing follicles.
AB  - Receptor-mediated endocytosis of yolk precursors via clathrin-coated structures
      is the key mechanism underlying rapid chicken oocyte growth. In defining oocyte
      specific components of clathrin-mediated events, we have to date identified
      oocyte-specific yolk transport receptors, but little is known about the oocytes'
      supporting endocytic machinery. Important proteins implicated in clathrin
      mediated endocytosis and recycling are the endophilins, which thus far have been
      studied primarily in synaptic vesicle formation; in the present study, as a
      different highly active endocytic system, we exploit rapidly growing chicken
      oocytes. Molecular characterization of the chicken endophilins I, II, and III
      revealed that their mammalian counterparts have been highly conserved. All
      chicken endophilins interact via their SH3 domain with the avian dynamin and
      synaptojanin homologues and, thus, share key functional properties of mammalian
      endophilins. The genes show different expression patterns: As in mammals,
      expression is low to undetectable in the liver and high in the brain; in ovarian
      follicles harboring oocytes that are rapidly growing via receptor-mediated
      endocytosis, levels of endophilins II and III, but not of endophilin I, are high.
      Immunohistochemical analysis of follicles demonstrated that endophilin II is
      mainly present in the theca interna but that endophilin III predominates within
      the oocyte proper. Moreover, in a chicken strain with impaired oocyte growth and
      absence of egg-laying because of a genetic defect in the receptor for yolk
      endocytosis, endophilin III is diminished in oocytes, whereas endophilin III
      levels in the brain and endophilin II localization to theca cells are unaltered.
      Thus, the present study reveals that the endophilins differentially contribute to
      oocyte endocytosis and development.

PMID- 12606340
TI  - Vascular remodeling and angiogenesis in ectopic ovarian transplants: a crucial
      role of pericytes and vascular smooth muscle cells in maintenance of ovarian
      grafts.
AB  - Cancer patients, treated by either chemo- or radiotherapy, frequently suffer from
      ovarian failure and infertility. One of the new emerging techniques to preserve
      reproductive potential of such patients is cryopreservation of ovarian fragments
      prior to treatment and their retransplantation after healing. A major obstacle in
      survival of the ovarian implants is vascular failure, which leads to tissue
      necrosis. In order to investigate the role of angiogenesis in implant
      preservation, we used a xenograft model in which rat ovaries were transplanted
      into immunodeficient mice. Graft reception and maintenance were monitored by
      magnetic resonance imaging (MRI) and histology. Two transplantation sites were
      explored, i.e., subcutaneous and intramuscular. Comparison between these two
      transplantation sites revealed the importance of vascular smooth muscle cells and
      pericytes in sustaining vascular and tissue integrity. Histological examination
      of the grafts, at different time points and sizes, revealed that loss of
      perivascular cells preceded damage to endothelial cells and was closely
      correlated with loss of follicular and oocyte integrity. Intramuscular
      implantation provided better maintenance of implant perivascular cells relative
      to subcutaneous implantation. Accordingly, follicular integrity was superior in
      the intramuscular implants and the number of damaged follicles was significantly
      lower compared with the subcutaneous transplantation site. These results suggest
      that improving ovarian implant maintenance should be directed toward preservation
      of perivascular support.

PMID- 12606342
TI  - Mouse testin: complementary DNA cloning, genomic organization, and
      characterization of its proximal promoter region.
AB  - Testin is a secretory protein that was initially identified from rat Sertoli cell
      enriched cultures and has been suggested to be a sensitive marker to monitor the
      integrity of Sertoli-germ cell junctions. However, the expression of the testin
      gene in other species and the molecular mechanisms that govern its transcription
      are unknown. To address these issues, we cloned and characterized the mouse
      testin gene. A full-length mouse testin cDNA encoding a polypeptide of 333 amino
      acid residues was isolated by library screening. Sequence analysis revealed that
      mouse testin shares 90.1%, 58.9%, 62.2%, and 64.6% identity with rat testin and
      cathepsin L of mouse, rat, and human, respectively, at the amino acid level.
      Reverse transcription-polymerase chain reaction and Southern blot analysis
      demonstrated that mouse testin transcripts were predominantly expressed in the
      gonads. The mouse testin gene spans over 21 kilobases (kb) and contains eight
      exons interrupted by seven introns. Primer extension analysis and 5' rapid
      amplification of cDNA ends identified a major transcription start site located
      134 base pairs upstream from the translation initiation codon. Analysis of a 2.3
      kb mouse testin 5'-flanking region revealed that it lacked TATA and CAAT boxes,
      and the region was not GC rich. By the use of deletion analysis, in vitro DNase I
      footprinting, and site-directed mutagenesis, we identified within the proximal
      promoter region three closely spaced putative binding sites for GATA, sex
      determining factor, and steroidogenic factor 1 that are important for testin gene
      transcription in mouse Sertoli (MSC-1) cells. These cis-acting elements are also
      present in the conserved Mullerian-inhibiting substance (MIS) proximal promoters,
      raising a possibility that the transcriptions of testin and MIS genes are
      controlled by similar mechanisms.

PMID- 12606341
TI  - Involvement of tumor necrosis factor-alpha in the pathogenesis of autoimmune
      orchitis in rats.
AB  - We studied the testicular macrophages of rats with experimental autoimmune
      orchitis (EAO) and analyzed whether the tumor necrosis factor-alpha (TNFalpha) is
      involved in germ cell apoptosis and in Leydig cell steroidogenesis. The EAO was
      induced in adult male Sprague-Dawley rats by active immunization with testicular
      homogenate and adjuvants. In the experimental group, a severe orchitis was
      observed 80 days after the first immunization. ED1- and ED2-positive macrophages
      were quantified by immunohistochemistry. The TNFalpha concentration of
      conditioned media from testicular macrophages (TMCM) was determined by ELISA. The
      number of apoptotic TNF receptor 1 (TNFR1)-positive germ cells was identified by
      combining in situ end labeling of apoptotic DNA and immunohistochemical
      techniques. The effect of TNFalpha on Leydig cell testosterone production was
      determined by RIA. In rats with EAO, we observed a significant increase in the
      number of TNFalpha-positive testicular macrophages, the TNFalpha concentration in
      TMCM, and the number of TNFR1-positive germ cells. Sixty percent of TNFR1
      positive germ cells were apoptotic. These results suggest that TNFalpha could be
      involved in the pathogenesis of EAO. Acting together with other local factors
      such as Fas-FasL, TNFalpha could trigger germ cell apoptosis. We also
      demonstrated that TNFalpha inhibited in vitro testosterone production in basal
      and hCG-stimulated Leydig cells from rats with orchitis.

PMID- 12606343
TI  - Characterization of fibroblast growth factor receptors expressed in principal
      cells in the initial segment of the rat epididymis.
AB  - Studies from our laboratory support a model in which growth factors produced in
      the testis reach the epididymis via the luminal system and play an important role
      in maintaining the function of epithelial cells, particularly in the initial
      segment. Previous work showed that gamma-glutamyl transpeptidase (GGT) mRNA IV,
      which is highly expressed in the rat initial segment, may be under the control of
      luminal fibroblast growth factor 2 (FGF-2) from the testis. The current studies
      were undertaken to identify which fibroblast growth factor receptors (FGFRs) are
      present in the principal cells of the rat initial segment and to identify other
      potential ligands for these receptors in rat rete testis fluid (RTF). Immunoblot
      analysis revealed that FGFRs 1-4 were present, and reverse transcription
      polymerase chain reaction (RT-PCR) analysis confirmed that both the IIIb and IIIc
      splice variants of FGFRs 1-3 were expressed. However, RT-PCR using RNA isolated
      from principal cells collected by laser capture microdissection revealed only
      FGFR-1 IIIc. Additional PCR analysis established that both the alpha and beta
      forms of FGFR-1 IIIc were expressed in principal cells. Both FGF-4 and FGF-8 were
      present in rat RTF, as determined by immunoblotting. Thus, FGF-2, -4, and -8,
      found in RTF, may act upon FGFR-1 IIIc in the principal cells of the initial
      segment to regulate GGT mRNA IV expression.

PMID- 12606344
TI  - Effect of estrogen on vascular endothelial growth/permeability factor expression
      by glandular epithelial and stromal cells in the baboon endometrium.
AB  - The ovarian steroid hormones, estrogen and progesterone, have important roles in
      establishing the new vascular bed within the endometrium during each menstrual
      cycle; however, little is known about the mechanisms underlying this process. We
      recently showed that mRNA and protein levels for the angiogenic factor vascular
      endothelial growth/permeability factor (VEG/PF) in endometrial glandular
      epithelial and stromal cells of baboons were decreased to very low levels by
      ovariectomy, and we proposed that the levels of estrogen and progesterone
      exhibited during the menstrual cycle regulate endometrial VEG/PF expression in
      the primate. To test this hypothesis, VEG/PF mRNA levels were determined by
      reverse transcription-polymerase chain reaction in glandular epithelial and
      stromal cells isolated by laser-capture microdissection from, and VEG/PF protein
      was determined by immunocytochemistry in the endometrium of baboons after
      ovariectomy and chronic administration of estradiol and progesterone in levels
      designed to replicate the hormonal profiles that are characteristic of the
      proliferative and secretory phases of the menstrual cycle. Administration of
      estradiol to ovariectomized baboons in levels that replicated the late
      proliferative phase of the menstrual cycle (209 +/- 40 pg/ml serum)
      increased/restored VEG/PF mRNA to levels in the glands (5.57 +/- 1.53 amol/fmol
      18S rRNA, P < 0.01) and stroma (2.61 +/- 1.57 amol/fmol 18S rRNA, P < 0.02) that
      were approximately 10-fold greater than those observed after ovariectomy alone
      (0.52 +/- 0.21 and 0.22 +/- 0.11 amol/fmol 18S rRNA, respectively) and were
      similar to those previously shown in intact baboons. Concomitant administration
      of estradiol and progesterone to ovariectomized baboons in levels that replicated
      the midsecretory phase of the menstrual cycle (44 +/- 15 pg/ml serum and 9.8 +/-
      2.2 ng/ml serum, respectively) resulted in glandular epithelial (3.65 +/- 1.42
      amol/fmol 18S rRNA) and stromal (1.25 +/- 0.77 amol/fmol 18S rRNA) VEG/PF mRNA
      levels that were not significantly different from those exhibited after
      ovariectomy or ovariectomy and estradiol treatment. Comparable results were
      obtained for VEG/PF mRNA expression in whole-endometrial tissue, although the
      relative 2-fold increase (P < 0.03) in VEG/PF mRNA levels induced by estrogen in
      mixed endometrial cells of ovariectomized baboons appeared to be less marked than
      that in isolated glandular epithelial and stromal cells. After ovariectomy,
      endometrial width (0.98 +/- 0.09 mm) was approximately one-third of that in
      intact baboons (3.58 +/- 0.32 mm), and endometrial VEG/PF protein expression was
      low. Estradiol restored endometrial width (3.00 +/- 0.12 mm, P < 0.01) and VEG/PF
      protein expression to normal. In summary, estrogen has a significant role in
      regulating and maintaining VEG/PF expression by glandular epithelial and stromal
      cells of the endometrium during the menstrual cycle.

PMID- 12606345
TI  - Development to blastocyst is impaired when intracytoplasmic sperm injection is
      performed with abnormal sperm from infertile mice harboring a mutation in the
      protein phosphatase 1cgamma gene.
AB  - Idiopathic azoospermia, characterized by abnormal spermatogenesis, is commonly
      treated by performing intracytoplasmic sperm injection (ICSI) with sperm
      retrieved from testicular biopsies. However, no controlled experiments have been
      performed using an animal model to assess the efficacy or safety of the
      procedure. We have performed ICSI with testicular sperm obtained in a similar
      manner from testes of male mice homozygous for a null mutation in the protein
      phosphatase 1cgamma gene (PP1cgamma) or those of their wild-type littermates.
      PP1cgamma mutant testicular sperm are less resistant to sonication than are wild
      type sperm and display a range of morphological abnormalities, similar to those
      reported for testicular sperm from idiopathic azoospermic men. PP1cgamma mutant
      sperm are unable to support development to the blastocyst stage, resulting in
      arrested development either before or just after compaction. A comparison of
      testicular and epididymal sperm from wild-type males revealed that the epididymal
      sperm caused embryos to fragment at an elevated rate. These results suggest that
      ICSI with any kind of testicular sperm carries an increased risk of embryo
      fragmentation and that abnormal testicular sperm has an added risk of embryo
      wastage at later preimplantation stages.

PMID- 12606346
TI  - Donor-dependent developmental competence of oocytes from lambs subjected to
      repeated hormonal stimulation.
AB  - An unpredictability of ovarian response still remains the major problem
      concerning ovine reproductive programs. The influence of several environmental,
      genetic, and ovarian cycle effects on oocyte/embryo yield from donor females has
      been previously reported. The present research has been designed to exclude
      aforementioned causes of variability, thus to verify embryogenic competence in
      homogenous groups of animals. For this purpose we used prepubertal ewes kept
      under identical conditions. Initially, we stimulated three groups of prepubertal
      ewes at various ages and used a number of gonadotropin treatments to assess
      differences in oocyte competence between individuals. The results revealed the
      repeatability of response within individual donor lambs throughout the study.
      Moreover, once the variability in both oocyte and embryo yield between homogenous
      groups of donors was revealed alongside the influence of age and type of
      gonadotropin treatment (P < 0.001), we investigated whether the individual donor
      effect persisted among genetically similar animals. Therefore, we compared oocyte
      and subsequent embryo output of sibling lambs derived from the most efficient
      donor. Here the genetic homogeneity of sisters kept under identical conditions
      substantially improved the uniformity of either follicular response or embryo
      production, suggesting that the genotype plays a primary role in establishing
      follicular recruitment and developmental capability of oocytes. This observation
      consents to predict the ovarian performance from a single ewe already in early
      prepuberty (i.e., to qualify the female to breeding programs).

PMID- 12606347
TI  - Characterization of the intracellular calcium store at the base of the sperm
      flagellum that regulates hyperactivated motility.
AB  - Hyperactivated sperm motility is usually characterized by high-amplitude
      flagellar bends and asymmetrical flagellar beating. There is evidence that an
      inositol 1,4,5-trisphosphate (IP3) receptor-gated Ca2+ store in the base of the
      flagellum provides Ca2+ to initiate hyperactivation; however, the identity of the
      store was not known. Ca2+ stores are membrane-bounded organelles, and the only
      two membrane-bounded organelles found in this region of sperm are the redundant
      nuclear envelope (RNE) and mitochondria. Transmission electron micrographs
      revealed two different compartments of RNE, one enriched with nuclear pores and
      the other containing few pores but extensive membranous structures with enlarged
      cisternae. Immunolabeling showed that IP3 receptors and calreticulin are located
      in the region containing enlarged cisternae. In other cell types, mitochondria
      adjacent to Ca2+ stores are actively involved in modulating Ca2+ signals by
      taking up Ca2+ released from stores and also may respond by increasing production
      of NADH and ATP to support increased energy demand. Nevertheless, bull sperm did
      not show an increase in NADH when Ca2+ was released from intracellular stores by
      thapsigargin to induce hyperactivation. Consistently, no net increase in ATP
      production was detected when sperm were hyperactivated, although ATP was
      hydrolyzed at a greater rate. Furthermore, blocking Ca2+ efflux from mitochondria
      by CGP-37157, a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger, did
      not inhibit the development of hyperactivated motility. We concluded that the
      intracellular Ca2+ store is the part of RNE that contains enlarged cisternae and
      that Ca2+ is released directly to the axoneme to trigger hyperactivated motility
      without the active participation of mitochondria.

PMID- 12606348
TI  - Estrogen-induced disruption of neonatal porcine uterine development alters adult
      uterine function.
AB  - In the pig, estradiol-17beta valerate (EV) exposure from birth (Postnatal Day
      [PND] 0) disrupts estrogen receptor-alpha (ER)-dependent uterine development and
      increases embryo mortality in adults. To determine effects of neonatal EV
      exposure on adult uterine morphology and function, 36 gilts received corn oil
      (CO) or EV from PND 0 to PND 13. Cyclic and pregnant (PX) adults from each
      treatment group were hysterectomized on Day 12 after estrus/mating. Treatment and
      pregnancy effects were determined for uterine weight and horn volume, uterine
      luminal fluid (ULF) protein and estradiol content, endometrial incorporation of
      3H-leucine (3H-Leu) into nondialyzable product, and endometrial mRNA levels for
      ER, progesterone receptor (PR), uteroferrin (UF), retinol-binding protein (RBP),
      and keratinocyte growth factor (KGF). Adults cycled normally and had similar
      numbers of corpora lutea. Uteri of PX gilts contained tubular/filamentous
      conceptuses, and ULF estradiol content was unaffected by treatment. However,
      pregnancy increased uterine weight and size only in CO gilts (Treatment x Status,
      P < 0.01). Treatment reduced ULF protein content (P < 0.01), endometrial 3H-Leu
      incorporation (P < 0.05), and the pregnancy-associated increase in ULF protein
      (Treatment x Status, P < 0.01). Treatment did not affect endometrial ER or PR
      mRNA levels but attenuated the pregnancy-associated increase in UF mRNA
      (Treatment x Status; P < 0.01), increased RBP (P < 0.10), and decreased KGF mRNA
      levels (P < 0.05). These results establish that transient postnatal estrogen
      exposure affects porcine uterine responsiveness to potentially embryotrophic
      signals and that estrogen-sensitive postnatal uterine organizational events are
      determinants of uterine size and functionality.

PMID- 12606349
TI  - Sertoli-germ cell adherens junction dynamics in the testis are regulated by RhoB
      GTPase via the ROCK/LIMK signaling pathway.
AB  - During spermatogenesis, cell-cell actin-based adherens junctions (AJs), such as
      ectoplasmic specializations (ESs), between Sertoli and germ cells undergo
      extensive restructuring in the seminiferous epithelium to facilitate germ cell
      movement across the epithelium. Although the mechanism(s) that regulates AJ
      dynamics in the testis is virtually unknown, Rho GTPases have been implicated in
      the regulation of these events in other epithelia. Studies have shown that the in
      vitro assembly of the Sertoli-germ cell AJs but not of the Sertoli cell tight
      junctions (TJs) is associated with a transient but significant induction of RhoB.
      Immunohistochemistry has shown that the localization of RhoB in the seminiferous
      epithelium is stage specific, being lowest in stages VII-VIII prior to
      spermiation, and displays cell-specific association during the epithelial cycle.
      Throughout the cycle, RhoB was localized near the site of basal and apical ESs
      but was restricted to the periphery of the nuclei in elongating (but not
      elongated) spermatids, spermatocytes, and Sertoli cells. However, RhoB was not
      detected near the site of apical ESs at stages VII-VIII. Furthermore, disruption
      of AJs in Sertoli-germ cell cocultures either by hypotonic treatment or by
      treatment with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) also
      induced RhoB expression. When adult rats were treated with AF-2364 to perturb
      Sertoli-germ cell AJs in vivo, a approximately 4-fold induction in RhoB in the
      testis, but not in kidney and brain, was detected within 1 h, at least
      approximately 1-4 days before germ cell loss from the epithelium could be
      detected by histological analysis. The signaling pathway(s) by which AF-2364
      perturbed the Sertoli-germ cell AJs apparently began with an initial activation
      of integrin, which in turn activated RhoB, ROCK1, (Rho-associated protein kinase
      1, also called ROKbeta), LIMK1 (LIM kinase 1, also called lin-11 isl-1 mec3
      kinase 1), and cofilin but not p140mDia and profilin via phosphorylation.
      Immunoprecipitation and immunoblots revealed that the induction of LIMK1 was
      mediated via an increase in its phospho-Ser but not phospho-Tyr content.
      Furthermore, Y-27632 ([(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane
      carboxamide, 2HCl]), a specific ROCK inhibitor, could effectively delay the AF
      2364-induced germ cell loss from the seminiferous epithelium in vivo,
      illustrating that the integrin/RhoB/ROCK/LIMK pathway indeed plays a crucial role
      in the regulation of Sertoli-germ cell AJ dynamics. The fact that the RhoB
      pathway in the kidney and brain was not activated suggests that AF-2364 exerts
      its effects primarily at the testis-specific ES multiprotein complex structures
      between Sertoli cells and spermatids. In summary, this report illustrates that
      Sertoli germ cell AJ dynamics are regulated, at least in part, via the
      integrin/ROCK/LIMK/cofilin signaling pathway.

PMID- 12606350
TI  - Transforming growth factor beta3 regulates the dynamics of Sertoli cell tight
      junctions via the p38 mitogen-activated protein kinase pathway.
AB  - Earlier studies have implicated the significance of transforming growth factor
      beta3 (TGFbeta3) in the regulation of Sertoli cell tight junction (TJ) dynamics,
      possibly via its inhibitory effects on the expression of occludin, claudin-11,
      and zonula occludens-1 (ZO-1). Yet the mechanism by which TGFbeta3 regulates the
      Sertoli cell TJ-permeability barrier is not known. Using techniques of
      semiquantitative reverse transcription-PCR (RT-PCR), immunoblotting,
      immunohistochemistry, and inhibitors against different kinases coupled with
      physiological techniques to assess the Sertoli cell TJ barrier function, it was
      shown that this TGFbeta3-induced effect on Sertoli cell TJ dynamics is mediated
      via the p38 mitogen-activated protein (MAP) kinase pathway. First, the assembly
      of the Sertoli cell-TJ barrier was shown to be associated with a transient but
      significant decline in both the TGFbeta3 production and expression by Sertoli
      cells. Furthermore, addition of TGFbeta3 to Sertoli cell cultures during TJ
      assembly indeed perturbed the TJ barrier with an IC50 at approximately 9 pM.
      Second, the TGFbeta3-induced disruption of the TJ barrier was associated with a
      transient induction in MEKK2 but not the other upstream signaling molecules that
      mediate TGFbeta3 action, such as Smad2, Cdc42, Rac2, and N-Ras, suggesting this
      effect might be mediated via the p38 MAP kinase pathway. This postulate was
      confirmed by the observation that TGFbeta3 also induced the protein level of the
      activated and phosphorylated form of p38 MAP kinase at the time the TJ barrier
      was perturbed. Third, and perhaps the most important of all, this TGFbeta3
      mediated inhibitory effect on the TJ barrier and the TGFbeta3-induced p-p38 MAP
      kinase production could be blocked by SB202190, a specific p38 MAP kinase
      inhibitor, but not U0126, a specific MEK1/2 kinase inhibitor. These results thus
      unequivocally demonstrate that TGFbeta3 utilizes the p38 MAP kinase pathway to
      regulate Sertoli cell TJ dynamics.

PMID- 12606351
TI  - Estrogen receptor, cyclic adenosine monophosphate, and protein kinase A are
      involved in the nongenomic pathway by which estradiol accelerates oviductal
      oocyte transport in cyclic rats.
AB  - This investigation examined the role of estrogen receptor (ER) on the stimulatory
      effect of estradiol (E2) on protein phosphorylation in the oviduct as well as on
      E2-induced acceleration of oviductal oocyte transport in cyclic rats. Estrous
      rats were injected with E2 s.c. and with the ER antagonist ICI 182 780
      intrabursally (i.b.), and 6 h later, oviducts were excised and protein
      phosphorylation was determined by Western blot analysis. ICI 182 780 inhibited
      the E2-induced phosphorylation of some oviductal proteins. Other estrous rats
      were treated with E2 s.c. and ICI 182 780 i.b. The number of eggs in the oviduct,
      assessed 24 h later, showed that ICI 182 780 blocked the E2-induced egg transport
      acceleration. The possible involvement of adenylyl cyclase, protein kinase A (PK
      A), protein kinase C (PK-C), or tyrosine kinases on egg transport acceleration
      induced by E2 was then examined. Selective inhibitors of adenylyl cyclase or PK-A
      inhibited the E2-induced egg transport acceleration, whereas PK-C or tyrosine
      kinase inhibitors had no effect. Furthermore, forskolin, an adenylyl cyclase
      activator, mimicked the effect of E2 on ovum transport and E2 increased the level
      of cAMP in the oviduct of cycling rats. Finally, we measured PK-A activity in
      vitro in the presence of E2 or E2-ER complex. Activity of PK-A in the presence of
      E2 or E2-ER was similar to PK-A alone, showing that E2 or E2-ER did not directly
      activate PK-A. We conclude that the nongenomic pathway by which E2 accelerates
      oviductal egg transport in the rat requires absolute participation of ER and cAMP
      and partial participation of PK-A signaling pathways in the oviduct.

PMID- 12606352
TI  - Interleukin-1beta induces calcium transients and enhances basal and store
      operated calcium entry in human myometrial smooth muscle.
AB  - We have previously reported increased protein expression of sarcoplasmic
      reticulum calcium ATPase (SERCA) 2b in myometrium from women in labor at term,
      but the stimulus for this change is unknown. Proinflammatory cytokines have been
      implicated in the cascade of events leading to preterm and term labor, and we
      hypothesize that interleukin (IL)-1beta may induce changes in key calcium
      homeostatic mechanisms and, in turn, augment myometrial contractility before
      labor. The aim of the present study was to investigate the long-term effects of
      IL-1beta on SERCA 2b protein expression, calcium mobilization from intracellular
      stores, and store-operated calcium entry. Myometrial biopsies were obtained, with
      consent, from women undergoing elective cesarean section at term. Primary
      cultured human myometrial smooth muscle (HMSM) cells were exposed to IL-1beta (10
      ng/ml) for 24 h or to culture medium alone (control). Cells were subsequently
      used in Western blot studies or loaded with fura-2 to assess calcium dynamics
      using fluorescent digital imaging. The present study clearly demonstrated that IL
      1beta significantly increased SERCA 2b protein expression in HMSM cells.
      Cyclopiazonic acid-induced calcium transients were also augmented, predominantly
      by activation of lanthanum-sensitive, store-operated calcium entry. HMSM cell
      excitability was enhanced, as evidenced by increased basal calcium entry and the
      initiation of spontaneous calcium transients in 37% of IL-1beta-treated cells. IL
      1beta modulation of calcium mobilization may be an important mechanism in the
      cascade of events preparing the pregnant uterus for labor.

PMID- 12606353
TI  - Leydig cell-specific expression of DAX1 improves fertility of the Dax1-deficient
      mouse.
AB  - Dax1 is an orphan nuclear receptor expressed in both Leydig and Sertoli cells of
      the testis. Mutation of DAX1 in humans causes adrenal failure and
      hypogonadotropic hypogonadism. Targeted mutagenesis of Dax1 in mice reveals a
      primary gonadal defect characterized by overexpression of aromatase and cellular
      obstruction of the seminiferous tubules and efferent ductules, leading to germ
      cell death and infertility. Transgenic expression of DAX1 under the control of
      the mullerian-inhibiting substance promoter, which is selectively expressed in
      Sertoli cells, improves fertility but does not fully correct the histological
      abnormalities in the testes of Dax1 knockout (Dax1KO) mice. We therefore
      hypothesized that Dax1 may also play a crucial role in other somatic cells of the
      testis, namely the Leydig cells. A 2.1-kilobase fragment of the murine LH
      receptor 5'-promoter (LHR-DAX1) was used to generate transgenic mice that
      selectively express DAX1 in Leydig cells. Expression of the LHR-DAX1 transgene
      caused no observable phenotype in wild-type mice but improved fertility when
      expressed in Dax1KO males (rescue [RS]). Although testicular size was not
      increased in LHR-DAX1 RS animals, aromatase expression was restored to normal
      levels, and sperm production was increased. Testicular pathology was only
      slightly improved in RS mice compared to Dax1KO animals. Taken together with the
      result of previous studies of DAX1 expression in Sertoli cells, we conclude that
      the testis phenotype of Dax1KO mice reflects the combined effects of Dax1
      deficiency in both Sertoli and Leydig cells.

PMID- 12606354
TI  - A triple-stain flow cytometric method to assess plasma- and acrosome-membrane
      integrity of cryopreserved bovine sperm immediately after thawing in presence of
      egg-yolk particles.
AB  - Simultaneously evaluating postthaw viability and acrosome integrity of
      spermatozoa by flow cytometry would provide a valuable testing tool in both
      research and routine work. In the present study, a new triple-stain combination
      was developed for the simultaneous evaluation of viability and acrosome integrity
      of bovine sperm processed in egg yolk-based extender by flow cytometer. SYBR-14
      and propidium iodide (PI) enabled the discrimination of sperm cells from egg yolk
      and debris particles, which was instrumental for the flow cytometric analyses of
      frozen-thawed bovine sperm, because it implied that washing steps to remove egg
      yolk were no longer required. In addition, phycoerythrin-conjugated peanut
      agglutinin (PE-PNA) was used to discriminate acrosome-damaged/reacted sperm cells
      from acrosome-intact cells. Repeatability was calculated using two processed
      ejaculates of 10 bulls. Three straws per batch were analyzed in duplicate
      measurements. Method-agreement analysis between the SYBR-14/PE-PNA/PI and
      fluorescein isothiocyanate (FITC)-conjugated PNA was performed, with FITC-PNA/PI
      staining being carried out on 14 frozen-thawed semen samples immediately after
      thawing and after a 3-h incubation at 37 degrees C. The British Standards
      Institution repeatability index of the SYBR-14/PE-PNA/PI combination was 2.6%. On
      average, the FITC-PNA/PI method showed a 6.3% overestimation of the live and
      acrosome-intact sperm cell subpopulation. In conclusion, the new triple-stain
      combination is highly repeatable and easy to use in routine application, and it
      provides a more precise estimate for the rate of sperm cells with intact head
      membrane and acrosome compared to the generally used and validated FITC-PNA/PI
      staining.

PMID- 12606355
TI  - Up-regulation of glucose metabolism during male pronucleus formation determines
      the early onset of the s phase in bovine zygotes.
AB  - After in vitro fertilization with spermatozoa from bulls with high in vitro
      fertility, a beneficial paternal effect is manifested during the G1 phase of the
      first cell cycle. This benefit determines an earlier onset of the first S phase,
      and then a successful morula-blastocyst transition 7 days later. We hypothesized
      that the origin of the paternal effect could be a shift of the metabolism of the
      fertilized oocyte, because in mice, sperm decondensation is responsible for a
      dramatic increase in glucose metabolism. In this study we investigated the
      interaction between both pronuclei and compared glycolysis and pentose phosphate
      pathway (PPP) activities in bovine oocytes fertilized with spermatozoa from bulls
      of high or low fertility. Here we demonstrate that male pronucleus formation is
      necessary for the onset of the S phase in the female pronucleus, and that the
      component promoting an early S phase in both pronuclei is metabolic and linked to
      an up-regulation of the PPP during the male pronucleus formation. This long
      lasting paternal effect is more evidence of the important role of epigenetic
      control during early embryo development.

PMID- 12606356
TI  - Developmental regulation of follicle-stimulating hormone receptor messenger RNA
      expression in the baboon fetal ovary.
AB  - In the adult ovary, pituitary FSH via interaction with its receptor (FSHR) is
      required for follicular maturation and granulosa cell development. In humans and
      nonhuman primates, the pool of follicles available for adult ovarian function is
      established in utero. However, our understanding of the ontogeny and
      developmental regulation of FSHR in the ovary of the primate fetus is incomplete.
      Our goal was to determine whether the baboon fetal ovary expresses the full
      length FSHR mRNA transcript and whether levels are developmentally regulated.
      Fetal ovaries were obtained at mid (Day 100) and late (Day 165) gestation (term =
      Day 184) from untreated baboons and on Day 165 from baboons in which fetal
      estrogen levels were either decreased by >95% by treatment with the aromatase
      inhibitor CGS 20267 or restored to 30% of normal by treatment with CGS 20267 plus
      estradiol benzoate administered s.c. to the mother on Days 100-164. The full
      length 2088-base pair FSHR mRNA transcript was expressed in ovaries of adult and
      fetal baboons untreated or treated with CGS 20267 or CGS 20267 and estrogen. Mean
      (+/-SEM) FSHR mRNA levels (ratio of FSHR mRNA:18S rRNA), quantified by reverse
      transcription polymerase chain reaction, were increased (P < 0.05) 2-fold between
      mid (0.34 +/- 0.06) and late gestation (0.76 +/- 0.07), an increase prevented (P
      < 0.05) in estrogen-depleted baboons (0.44 +/- 0.10) and partially restored by
      treatment with CGS 20267 and estrogen (0.58 +/- 0.16). We previously showed that
      the number of follicles/0.33 mm2 in fetal ovaries of untreated baboons in late
      gestation was reduced 50% by treatment with CGS 20267 and restored to normal in
      baboons treated with CGS 20267 and estrogen. Thus, when corrected for the number
      of follicles/0.33 mm2, FSHR mRNA levels were similar in baboon fetal ovaries
      untreated (0.010 +/- 0.001) or treated with CGS 20267 (0.009 +/- 0.002) or CGS
      20267 and estrogen (0.007 +/- 0.003). We conclude that estrogen plays a major
      role in regulating ovarian FSHR mRNA expression in the primate fetus, and that
      the developmental increase in FSHR mRNA levels reflects the estrogen-dependent
      increase in folliculogenesis (i.e., increased number of granulosa cells and
      oocytes).

PMID- 12606357
TI  - SPEER--a new family of testis-specific genes from the mouse.
AB  - Differential cloning revealed a partial mRNA sequence expressed in the mouse
      testis, which on further molecular characterization proved to be a member of a
      new family of 14 transcribed genes. Six of the genes appear to be expressed
      pseudogenes. The remainder indicate an open reading frame of approximately 200
      220 amino acids encoding proteins with a very high proportion of alpha helical
      secondary structure, comprising approximately 15% glutamate residues. Because of
      this property, the family has been named SPErm-associated glutamate (E)-Rich
      protein (SPEER). Three members were chosen for more detailed characterization:
      SPEER-1 (pseudogene), SPEER-2, and SPEER-4D. All three are expressed tissue
      specifically in the testis of mice, with only very weak expression evident in the
      rat testis but in no other species tested. Using reverse transcription-polymerase
      chain reaction (RT-PCR), all three transcripts can be detected also in the
      epididymis, presumably due to the presence of spermatozoa. All three transcripts
      are expressed to high levels in haploid germ cells at the spermatocyte-spermatid
      transition. SPEER-1 mRNA is present in the cytoplasm as a sense transcript, SPEER
      2 appears to be made mostly as an antisense transcript, whereas SPEER-4D appears
      to be localized within a subcellular compartment as a conventional sense
      transcript. Codon usage analysis suggests that all but the pseudogenes can be
      expressed as protein, confirmed for SPEER-2 and SPEER-4D by in vitro
      transcription/translation. An antibody raised against a peptide region of SPEER
      4D, which probably cross-reacts with other SPEER members, immunohistochemically
      stains the nuclei of early round spermatids. While there are no true homologies
      to other proteins in the genome databases, some motifs are present that suggest a
      relationship to nuclear matrix proteins, implying that the SPEER family is a new
      group of haploid sperm-specific nuclear factors.

PMID- 12606358
TI  - A 3-kilobase region derived from the rat cathepsin L gene directs in vivo
      expression of a reporter gene in sertoli cells in a manner comparable to that of
      the endogenous gene.
AB  - During mammalian spermatogenesis, the transcription of several genes in Sertoli
      cells is turned on and off as the adjacent male germ cells progress through the
      stages of the cycle of the seminiferous epithelium. A requirement for defining
      how germ cells regulate this process is the identification of a promoter that
      confers, in vivo, accurate, stage-specific gene expression in Sertoli cells. To
      date, such a promoter has not been identified. Using transgenic mice, we show
      that the 3-kilobase genomic fragment immediately upstream of the rat cathepsin L
      translation start site directs expression of the reporter gene, beta
      galactosidase, only in Sertoli cells. The expression pattern of the reporter gene
      recapitulated that of the endogenous gene in Sertoli cells as 75% of the
      seminiferous tubules that contained X-gal positive Sertoli cells were at stages
      VI-VIII and beta-galactosidase enzymatic activity was 4-fold higher in mature
      testes compared with immature testes. This is, to our knowledge, the first
      identification of a promoter region that contains all of the regulatory elements
      required for accurate, stage-specific gene expression in Sertoli cells.

PMID- 12606359
TI  - Gonadotropin-releasing hormone-agonist inhibits synthesis of nitric oxide and
      steroidogenesis by luteal cells in the pregnant rat.
AB  - We have demonstrated that continuous administration of a gonadotropin-releasing
      hormone agonist (GnRH-Ag) in vivo suppressed progesterone production and induced
      apoptosis in the corpus luteum (CL) of the pregnant rat. To investigate the
      mechanism(s) by which progesterone secretion is suppressed and apoptosis is
      induced in the luteal cells, we studied nitric oxide (NO) as a messenger molecule
      for GnRH action. Rats were treated individually on Day 8 of pregnancy with 5
      microg/day of GnRH-Ag for 4, 8, and 24 h. GnRH-Ag decreased the production of
      progesterone and pregnenolone 8 and 24 h after the administration. Corresponding
      with the reduction in these steroid hormones, luteal NO concentrations decreased
      at 8 and 24 h. Western blotting and immunohistochemical studies of endothelial
      nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and
      neuronal nitric oxide synthase (nNOS) in the CL demonstrated that administration
      of GnRH-Ag was associated with a marked decrease in eNOS and iNOS compared with
      sham controls at 4 and 8 h, but nNOS did not change throughout the experimental
      period. We demonstrated, for the first time, the presence of nNOS protein in the
      CL of the pregnant rat. To determine if this suppressive action of GnRH-Ag is
      directly on the CL, luteal cells were treated with GnRH-Ag for 4, 8, 12, and 24 h
      in vitro. Progesterone and NO concentrations in the media decreased at 8 and 12 h
      after the treatment and recovered at 24 h. Western blots revealed that eNOS and
      iNOS decreased in luteal cells treated with GnRH-Ag compared with controls at 4
      and 8 h. These results demonstrate that suppression of luteal NO synthesis by
      GnRH-Ag is direct and leads to a decrease in the luteal production and release of
      progesterone and pregnenolone and thus suggest that GnRH could induce luteolysis
      in pregnant rats via NO.

PMID- 12606360
TI  - Decidual activin: its role in the apoptotic process and its regulation by
      prolactin.
AB  - Successful pregnancy requires profound differentiation and reorganization of the
      uterine tissues including, as pregnancy progresses, extensive apoptosis of
      decidual tissue to accommodate the developing conceptus. We have previously shown
      a positive correlation between expression of activin A and apoptosis in the
      decidua and have also shown that expression of activin A occurs at the time when
      prolactin (PRL) receptors disappear from decidual cells. The goals of this study
      were to examine whether activin A plays a role in decidual apoptosis and whether
      expression of activin A in the decidua is regulated by PRL and placental
      lactogens. Studies were carried out using primary rat decidual cells, a decidual
      cell line (GG-AD), and PRL null mice. Treatment of decidual cells with activin A
      significantly increased DNA degradation, caspase 3 activity, and caspase 3 mRNA
      expression. However, this effect was observed only in the absence of endogenous
      activin production by these cells. Addition of follistatin to decidual cells that
      were producing activin A decreased both caspase 3 activity and mRNA expression.
      Similarly, addition of activin-blocking antibodies to cultures of GG-AD cells,
      which also produce activin A, caused a reduction in both DNA degradation and
      caspase 3 activity. PRL and placental lactogens caused an inhibition of activin A
      mRNA expression in primary decidual cells. Even more convincingly, decidua of PRL
      null mice expressed abundant activin A at a time when no expression of this
      hormone is detected in wild-type mice and treatment of PRL null mice with PRL
      caused a profound inhibition of activin A mRNA expression. In summary, our
      investigations into the role and regulation of decidual activin have revealed
      that activin A can induce cell death in the decidua and that its expression is
      under tight regulation by PRL and placental lactogens.

PMID- 12606361
TI  - Fertilization of oocytes and birth of normal pups following intracytoplasmic
      injection with spermatids in mastomys (Praomys coucha).
AB  - The mastomys is a small laboratory rodent that is native to Africa. Although it
      has been used for research concerning reproductive biology, in vitro
      fertilization (IVF) and intracytoplasmic sperm injection are very difficult in
      mastomys because of technical problems, such as inadequate sperm capacitation and
      large sperm heads. The present study was undertaken to examine whether mastomys
      spermatids could be used to fertilize oocytes in vitro using a microinsemination
      technique, because spermatids are more easily injected than mature spermatozoa
      into oocytes. Most mastomys oocytes (80%-90%) survived intracytoplasmic injection
      with either round or elongated spermatids. Round spermatids had little oocyte
      activating capacity, similar to those of mice and rats, and exogenous stimuli
      were needed for normal fertilization. Treatment with an electric pulse in the
      presence of 50 microM Ca2+ followed by culture in 10 mM SrCl2 led to successful
      oocyte activation. After injection of round spermatids into preactivated oocytes,
      93% of oocytes were normally fertilized (male and female pronuclei formed), and
      100% of cultured oocytes developed to the 2-cell stage. However, none reached
      term after transfer into recipient females. Elongated spermatids, which
      correspond to steps 9-11 in rats, activated oocytes on injection without
      additional activation treatment. After embryo transfer, five offspring (6% per
      transfer) developed to term. These results indicate that microinsemination with
      spermatids is a feasible alternative in animal species that are refractory to IVF
      and sperm injection and that using later-stage spermatids may lead to increased
      production of viable embryos that can develop into normal offspring.

PMID- 12606362
TI  - Long-acting depot formulation of luprolide acetate as a method of hypothalamic
      down regulation for controlled ovarian hyperstimulation and oocyte production in
      Macaca fascicularis.
AB  - Reproductive function in some nonhuman primate species parallels that of the
      human. As a result, studies addressing aspects of reproductive function primarily
      involve the use of nonhuman primate models. The objective of the present study
      was to assess the efficiency of two hypothalamic down-regulation techniques
      combined with a single controlled ovarian hyperstimulation protocol for mature
      oocyte production in the cynomolgus macaque (Macaca fascicularis). Hypothalamic
      GnRH down regulation was first induced using the clinical long protocol of the
      short-acting GnRH-agonist luprolide acetate combined with controlled ovarian
      hyperstimulation and oocyte retrieval. Resulting oocyte yield and maturity with
      this regimen was insufficient for further evaluation of oocyte competency.
      Hypothalamic down regulation was induced in the second experiment using the long
      acting depot formulation of luprolide acetate in conjunction with controlled
      ovarian hyperstimulation. This regimen allowed for the consistently efficient
      production of oocytes (15.5 oocytes per oocyte retrieval) and an oocyte maturity
      rate of 56%. Oocyte competence, as determined by the ability to undergo
      fertilization or parthenogenic activation and to reach specific cleavage stages
      at appropriate time intervals, was evaluated. Intracytoplasmic sperm injection
      resulted in a 59% fertilization rate and a 91% cleavage rate. Parthenogenic
      activation resulted in a 70% activation rate and an 86% cleavage rate. These data
      suggest that use of the long-acting form of luprolide acetate in conjunction with
      controlled ovarian hyperstimulation results in the production of competent,
      mature oocytes and allows the efficient use of nonhuman primate resources in
      studies of reproductive function in cynomolgus macaques.

PMID- 12606364
TI  - Different effects of subnormal levels of progesterone on the pulsatile and surge
      mode secretion of luteinizing hormone in ovariectomized goats.
AB  - This study tested the hypothesis that endocrinological threshold levels of
      progesterone that induce negative feedback effects on the pulsatile and surge
      modes of LH secretion are different. Our approach was to examine the effects of
      subnormal progesterone concentrations on LH secretion. Long-term ovariectomized
      Shiba goats that had received implants of silastic capsules containing estradiol
      were divided into three groups. The high progesterone (high P) group received a
      subcutaneous implant of a silastic packet (50 x 70 mm) containing progesterone,
      and the low progesterone (low P) group received a similar implant of a small
      packet (25 x 40 mm) containing progesterone. The control (non-P) group received
      no treatment with exogenous progesterone. Blood samples were collected daily
      throughout the experiment for the analysis of gonadal steroid hormone levels and
      at 10-min intervals for 8 h on Days 0, 3, and 7 (Day 0: just before progesterone
      treatment) for analysis of the pulsatile frequency of LH secretion. Then
      estradiol was infused into the jugular vein of all animals at a rate of 3
      microg/h for 16 h on Day 8 to determine whether an LH surge was induced. Blood
      samples were collected every 2 h from 4 h before the start of the estradiol
      infusion until 48 h after the start of the infusion. In each group, the mean +/-
      SEM concentration after progesterone implant treatment was 3.3 +/- 0.1 ng/ml for
      the high P group, 1.1 +/- 0.1 ng/ml for the low P group, and <0.1 ng/ml for the
      non-P group, concentrations similar to the luteal levels, subluteal levels, and
      follicular phase levels of the normal estrous cycle, respectively. The estradiol
      concentration ranged from 4 to 8 pg/ml after estradiol capsule implants in all
      groups. The LH pulse frequency was significantly (P < 0.05) suppressed on Day 3
      (6.2 +/- 0.5 pulses/8 h) and on Day 7 (2.6 +/- 0.9 pulses/8 h) relative to Day 0
      (9.0 +/- 0.5 pulses/8 h) in the high P group. In both the low P and non-P groups,
      however, the changes of pulsatile frequency of LH were not significantly
      different, and high pulses (7-9 pulses/8 h) were maintained on each of the 3 days
      they were tested. An LH surge (peak concentration, 100.3 +/- 11.0 ng/ml) occurred
      in all goats in the non-P group, whereas there was no surge mode secretion of LH
      in either the high P or the low P group. The results of this study support our
      hypothesis that the threshold levels of progesterone that regulate negative
      feedback action on the LH pulse and the LH surge are different. Low levels of
      progesterone, around 1 ng/ml, completely suppressed the LH surge but did not
      affect the pulsatile frequency of LH secretion.

PMID- 12606363
TI  - A-kinase anchoring protein 4 binding proteins in the fibrous sheath of the sperm
      flagellum.
AB  - The fibrous sheath is a unique cytoskeletal structure located in the principal
      piece of the sperm flagellum and is constructed of two longitudinal columns
      connected by closely spaced circumferential ribs. Cyclic AMP-dependent protein
      kinases are secured within specific cytoplasmic domains by A-kinase anchoring
      proteins (AKAPs), and the most abundant protein in the fibrous sheath is AKAP4.
      Several other fibrous sheath proteins have been identified, but how the fibrous
      sheath assembles is not understood. Yeast two-hybrid assays and deletion
      mutagenesis were used to identify AKAP4-binding proteins and to map the binding
      regions on AKAP4 and on the proteins identified. We found that AKAP4 binds AKAP3
      and two novel spermatogenic cell-specific proteins, Fibrous Sheath Interacting
      Proteins 1 and 2 (FSIP1, FSIP2). Transcription of Akap4, Akap3, and Fsip1 begins
      in early spermatid development, whereas transcription of Fsip2 begins in late
      spermatocyte development. AKAP3 is synthesized in round spermatids and
      incorporated into the fibrous sheath concurrently with formation of the rib
      precursors. However, AKAP4 is synthesized and incorporated into the nascent
      fibrous sheath late in spermatid development. The AKAP4 precursor is processed in
      the flagellum and only the mature form of AKAP4 appears to bind AKAP3. These
      results suggest that AKAP3 is involved in organizing the basic structure of the
      fibrous sheath, whereas AKAP4 has a major role in completing fibrous sheath
      assembly.

PMID- 12606365
TI  - In vivo hormonal environment leads to differential susceptibility of the corpus
      luteum to apoptosis in vitro.
AB  - We evaluated the involvement of the in vivo hormonal environment on the ability
      of the rat corpus luteum (CL) to undergo apoptosis. Gel electrophoretic DNA
      fragmentation analysis revealed no apoptosis in CL isolated either the 2 last
      days of pregnancy (Days 21 and 22) or throughout the 4 days following
      parturition, suggesting that the number of cells undergoing apoptosis at the same
      time is not sufficient to allow for visualization of DNA breakdown. In contrast,
      CL incubated in serum-free medium underwent significant apoptosis, as evaluated
      by chromatin condensation and DNA fragmentation, regardless of their
      developmental stage in pregnancy. However, CL obtained on Day 7 of pregnancy and
      on Day 4 postpartum demonstrated higher sensitivity to apoptosis in vitro, but
      lactation reduced significantly the capacity of the CL to undergo apoptosis when
      maintained in culture. These data suggest that the exposure of the CL to
      different hormonal environments throughout pregnancy and after parturition is
      responsible for the differential susceptibility to apoptosis observed in vitro.
      We have previously shown that progesterone is a direct factor for survival of the
      CL. Prolactin stimulates luteal progesterone production; therefore, we examined
      whether prolactin prevents apoptosis in luteal cells independently of its
      stimulatory action on progesterone production. We used a luteal cell line (GG-CL)
      that expresses the prolactin receptor but does not produce progesterone. These
      cells undergo apoptosis under conditions of serum starvation, and addition of
      prolactin to the culture medium significantly reduced DNA fragmentation. These
      results indicate that the extent of luteal cell death induced by incubation of CL
      under serum-free conditions depends on the hormonal environment to which this
      endocrine gland is exposed in vivo. These results also indicate an important role
      for lactation in preventing apoptosis, which is further supported by the
      antiapoptotic activity of prolactin observed in luteal cells.

PMID- 12606366
TI  - Metallothionein-1 messenger RNA transcription in steroid-secreting cells of the
      rat ovary during the periovulatory period.
AB  - An increase in metallothionein 1 (MT-1) mRNA was detected in the ovaries of
      immature Wistar rats that were primed with s.c. injection of 10 IU eCG followed
      48 h later by 10 IU hCG s.c. to initiate the ovulatory process. Ovarian RNA was
      extracted at 0, 2, 4, 8, 12, 24, 72, 144, and 288 h after the primed animals were
      injected with hCG. These extracts were used for reverse transcription polymerase
      chain reaction (RT-PCR) differential display and Northern analyses that yielded
      complementary gene fragments for MT-1. Expression of MT-1 mRNA increased
      significantly by 24 h after hCG treatment and reached a peak at 144 h after hCG.
      In contrast, a disintegrin and metalloproteinase with thrombospondin motifs and a
      tissue inhibitor of metalloproteinase 1, which were also detected by the RT-PCR
      differential display procedure, reached a peak at 12 h after hCG and returned to
      control levels in the ovaries by 72 h after hCG. In situ hybridization indicated
      that most of the MT-1 mRNA was expressed in the vicinity of the theca interna of
      preovulatory follicles and in the lutein granulosa of postovulatory follicles.
      Thus, MT-1 mRNA expression is primarily in the vicinity of steroid-secreting
      areas of the ovary. The substantial increase in MT-1 mRNA expression might be
      important in protecting the ovarian tissues from oxidative stress generated by
      ovarian inflammatory events during the ovulatory process and luteinization.

PMID- 12606367
TI  - Osteopontin is synthesized by uterine glands and a 45-kDa cleavage fragment is
      localized at the uterine-placental interface throughout ovine pregnancy.
AB  - Osteopontin (OPN) is a phosphorylated and glycosylated, secreted protein that is
      present in various epithelial cells and biological fluids. On freezing and
      thawing or treatment with proteases, the native 70-kDa protein gives rise to 45-
      and 24-kDa fragments. Secreted OPN functions as an extracellular matrix (ECM)
      protein that binds cell surface receptors to mediate cell-cell adhesion, cell-ECM
      communication, and cell migration. In sheep and humans, OPN is proposed to be a
      secretory product of uterine glandular epithelium (GE) that binds to uterine
      luminal epithelium (LE) and conceptus trophectoderm to mediate conceptus
      attachment, which is essential to maintain pregnancy through the peri
      implantation period. Cell-cell adhesion, communication, and migration likely are
      important at the interface between uterus and placenta throughout pregnancy, but
      to our knowledge, endometrial and/or placental expression of OPN beyond the peri
      implantation period has not been documented in sheep. Therefore, the present
      study determined temporal and spatial alterations in OPN mRNA and protein
      expression in the ovine uterus between Days 25 and 120 of pregnancy. The OPN mRNA
      in total ovine endometrium increased 30-fold between Days 40 and 80 of gestation.
      In situ hybridization and immunofluorescence analyses revealed that the
      predominant source of OPN mRNA and protein throughout pregnancy was the uterine
      GE. Interestingly, the 45-kDa form of OPN was detected exclusively, continuously,
      and abundantly along the apical surface of LE, on conceptus trophectoderm, and
      along the uterine-placental interface of both interplacentomal and placentomal
      regions through Day 120 of pregnancy. The 45-kDa OPN is a proteolytic cleavage
      fragment of the native 70-kDa OPN, and it is the most abundant form in uterine
      flushes during early pregnancy. The 45-kDa OPN is more stimulatory to cell
      attachment and cell migration than the native 70-kDa protein. Collectively, the
      present results support the hypothesis that ovine OPN is a component of
      histotroph secreted by the uterine GE that accumulates at the uterine-placental
      interface to influence maternal-fetal interactions throughout gestation in sheep.

PMID- 12606368
TI  - Differential effects of RU486 and indomethacin on follicle rupture during the
      ovulatory process in the rat.
AB  - Ovulation (i.e., the release of mature oocytes from the ovary) requires spatially
      targeted follicle rupture at the apex. Both progesterone and prostaglandins play
      key roles in the ovulatory process. We have studied follicle rupture and
      ovulation in adult cycling rats treated with a progesterone receptor antagonist
      (RU486), an inhibitor of prostaglandin synthesis (indomethacin, IM), or both. All
      rats were treated with LHRH antagonist on the morning (0900 h) of proestrus to
      inhibit endogenous gonadotropins and with 10 microg of ovine LH (oLH) at 1700 h
      in proestrus to induce ovulation. Animals were treated from metestrus to
      proestrus with 2 mg/day of RU486 or vehicle (olive oil) and on the morning of
      proestrus (1200 h) with 1 mg of IM or vehicle (olive oil). Some rats treated with
      vehicle or RU486 were killed on the morning of proestrus to assess preovulatory
      follicle development. The remaining rats were killed on the morning of estrus to
      study follicle rupture and ovulation. In vehicle-treated rats, oLH induced
      ovulation in 98% of follicles. In IM-treated rats, spatial targeting of follicle
      rupture was disrupted. Most oocytes were released to the ovarian interstitium
      (50%) or to the periovarian space (39%), and a smaller percentage (11%) of
      oocytes remained trapped inside the luteinized follicle. RU486-treated rats
      showed, on the morning of estrus, unruptured luteinized follicles. Only
      occasionally (2.8%), the oocytes were released to the periovarian space. IM
      treatment induced follicle rupture in RU486-treated rats, and 25% of oocytes were
      released to the ovarian interstitium. However, the number of oocytes released to
      the periovarian space (i.e., ovulated) was not increased by IM treatment in rats
      lacking progesterone actions. Overall, these data indicate that RU486 and IM have
      opposite effects on follicle rupture and suggest that both progesterone and
      prostaglandins are necessary for the spatial targeting of follicle rupture at the
      apex.

PMID- 12606369
TI  - A functional genomic study to identify differential gene expression in the
      preterm and term human myometrium.
AB  - The mechanisms that lead to the onset of human parturition are still unknown,
      although selected critical factors have been identified. To investigate the
      changes in myometrial gene expression associated with parturition, we used two
      macroarrays each containing 1176 different complementary human cDNA clones.
      Methods involving hierarchical clustering and conventional statistical analysis
      allowed us to generate a profile of genes expression at three stages of late
      pregnancy: preterm (29 wk amenorrhea); full term, not in labor (38 wk
      amenorrhea); and full term in labor (39 wk amenorrhea). Only 4% of the genes
      investigated were differentially expressed between the preterm and term groups (P
      < 0.05). These genes could be clustered as groups of either down-regulated or up
      regulated transcripts. The changes in transcript abundance were particularly
      marked between the preterm and term stages of gestation, whereas the differences
      between term not in labor and term in labor were less pronounced. The parturition
      was characterized by a massive down-regulation of a large panel of developmental,
      cell adhesion molecule and proliferation-related genes, along with the up
      regulation of inflammatory, contraction and apoptosis associated genes. We
      propose that the mechanisms of parturition consist primarily in the arrest of the
      processes of myometrial development, a step that might be essential to allow the
      uterus to recover appropriate contractile function before delivery.

PMID- 12606370
TI  - Abnormal fertilization is responsible for reduced fecundity following thiram
      induced ovulatory delay in the rat.
AB  - Brief exposure to some pesticides, applied during a sensitive window for the
      neural regulation of ovulation, will block the preovulatory surge of LH and,
      thus, delay ovulation. Previously, we have shown that a single i.p. injection of
      50 mg/kg of thiram, a dithiocarbamate fungicide that decreases norepinephrine
      synthesis, on proestrus (1300 h) suppresses the LH surge and delays ovulation for
      24 h without altering the number of oocytes released. However, when bred, the
      treated dams had a decreased litter size and increased postimplantation loss. We
      hypothesized that the reduced litter size in thiram-delayed rats was a
      consequence of altered oocyte function arising from intrafollicular oocyte aging.
      To test this hypothesis, we examined delayed oocytes, zygotes, and 2-cell embryos
      for evidence of fertilization and polyspermy. In addition, we used confocal laser
      scanning microscopy to evaluate and characterize cortical granule localization in
      oocytes and release in zygotes, because the cortical granule response is a major
      factor in the normal block to polyspermy. Our results demonstrate that a thiram
      induced, 24-h delay in ovulation alters the fertilizability of the released
      oocyte. Although no apparent morphological differences were observed in the
      unfertilized mature oocytes released following the thiram-induced delay, the
      changes observed following breeding include a significant decrease in the
      percentage of fertilized oocytes, a significant increase in polyspermic zygotes
      (21%), and a 10-fold increase in the number of supernumerary sperm in the
      perivitelline space. Importantly, all the polyspermic zygotes exhibited an
      abnormal pattern of cortical granule exudate, suggestive of a relationship
      between abnormal cortical reaction and the polyspermy in the delayed zygotes.
      Because polyspermy is associated with polyploidy, abnormal development, and early
      embryonic death, the observed polyspermy could explain the abnormal development
      and decreased litter size that we observed previously following thiram-delayed
      ovulation.

PMID- 12606371
TI  - Expression and distribution of AP-1 transcription factors in the porcine ovary.
AB  - The activator protein-1 (AP-1) transcription factors are important regulators of
      cell proliferation and differentiation. The developmental distribution of AP-1
      family members in porcine ovary has not been previously investigated. We examined
      the expression of AP-1 factors in porcine ovarian follicles, granulosa cells, and
      corpora lutea at different stages of development. Immunoblot analyses confirmed
      that c-Jun, JunD, JunB, c-Fos, Fra-1, Fra-2, and FosB immunoreactive proteins
      were present in whole-cell extracts (WCE) of all antral follicles and midluteal
      phase corpora lutea (CL) as well as granulosa cells (GC) isolated from different
      sized antral follicles. The intensities of c-Jun and c-Fos protein bands were
      decreased in CL WCE compared to antral follicles. In granulosa cells from
      preovulatory follicles (8-10 mm), Fra-2 exhibited a shift from 43 kDa to 46 kDa
      when compared to granulosa cells from smaller antral follicles. Separation of
      cytoplasmic and nuclear extracts was performed to determine if developmental
      differences between these fractions existed. Most AP-1 factors predominated in
      the nuclear fraction with notable exceptions. c-Fos predominated in the nucleus
      in GC and follicles but predominated in the cytoplasmic fraction of CL. With the
      exception of GC from 1-2-mm follicles, in which expression was similar between
      fractions, Fos-B was found predominantly in the cytoplasmic fraction. Fra-1
      exhibited similar expression between cytoplasmic and nuclear fractions for all
      tissues. Immunohistochemical (IHC) analyses of porcine ovary sections were
      performed to determine the cellular distribution of these factors at different
      follicular stages, and immunopositive nuclei were evaluated. In primordial and
      primary unilaminar follicles, all AP-1 factors studied except for FosB were
      detected in granulosa nuclei. Granulosa cell nuclei of multilaminar preantral
      follicles were immunopositive for all factors, with lower expression of FosB.
      Antral follicles exhibited GC and thecal cell nuclear staining for all factors
      with the exception of FosB in theca. Luteal cells exhibited the most intense
      nuclear staining for JunD and Fra-2, whereas all other factors were present in
      luteal cell nuclei although to a lesser extent. IHC with FosB antibodies yielded
      mostly cytoplasmic staining but only weak luteal nuclear staining. In corpora
      albicantia, low levels of staining were seen for all AP-1 factors. The DNA
      binding abilities of these factors in granulosa cells and CL were evaluated by
      EMSA. Nuclear extracts from granulosa cells from 1-2-mm or 8-10-mm antral
      follicles bound an AP-1 DNA consensus sequence and complexes consisted
      predominantly of c-Jun, JunD, JunB, c-Fos, and Fra-2. In CL, c-Jun, JunD, JunB,
      and Fra-2 were present in DNA-binding complexes, and c-Fos binding was not
      detected. In conclusion, our results suggest that expression and DNA-binding
      activity of AP-1 factors in follicular structures changes with luteinization.
      Differentiation to the luteal phenotype involves a reduction in nuclear c-Jun and
      c-Fos and a predominance of JunD and Fra-2.

PMID- 12606372
TI  - Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl
      coenzyme A (CoA) desaturase 1, and stearoyl-CoA desaturase 2 in rat testis.
AB  - In mammalian cells, essential polyunsaturated fatty acids (PUFAs) are converted
      to longer PUFAs by alternating steps of elongation and desaturation. In contrast
      to other PUFA-rich tissues, the testis is continuously drained of these fatty
      acids as spermatozoa are transported to the epididymis. Alteration of the germ
      cell lipid profile from spermatogonia to condensing spermatids and mature
      spermatozoa has been described, but the male gonadal gene expression of the
      desaturases, responsible for the PUFA-metabolism, is still not established. The
      focus of this study was to characterize the expression and regulation of stearoyl
      CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), and Delta5- and Delta6
      desaturase in rat testis. Desaturase gene expression was detected in testis,
      epididymis, and separated cells from seminiferous tubulus using Northern blot
      analysis. For the first time, SCD1 and SCD2 expression is demonstrated in rat
      testis and epididymis, both SCDs are expressed in epididymis, while testis mainly
      contains SCD2. Examination of the testicular distribution of Delta5- and Delta6
      desaturase and SCD1 and SCD2 shows that all four desaturases seem to be localized
      in the Sertoli cells, with far lower expression in germ cells. In light of
      earlier published results showing that germ cells are richer in PUFAs than
      Sertoli cells, this strengthens the hypothesis of a lipid transport from the
      Sertoli cells to the germ cells. As opposed to what is shown in liver, Delta5-
      and Delta6-desaturase mRNA levels in Sertoli cells are up-regulated by
      dexamethasone. Furthermore, dexamethasone induces SCD2 mRNA. Insulin also up
      regulates these three genes in the Sertoli cell, while SCD1 mRNA is down
      regulated by both insulin and dexamethasone. Delta5- and Delta6-desaturase, SCD1,
      and SCD2 are all up-regulated by FSH. A similar up-regulation of the desaturases
      is observed when treating Sertoli cells with (Bu)2cAMP, indicating that the
      desaturase up-regulation observed with FSH treatment results from elevated levels
      of cAMP. Finally, testosterone has no influence on the desaturase gene
      expression. Thus, FSH seems to be a key regulator of the desaturase expression in
      the Sertoli cell.

PMID- 12606373
TI  - Maintenance of mouse male germ line stem cells in vitro.
AB  - The proliferation and differentiation of a stem cell are regulated intrinsically
      by the stem cell and extrinsically by the stem cell niche. Elucidation of
      regulatory mechanisms of spermatogonial stem cells (SSCs), the stem cell of the
      postnatal male germ line, would be facilitated by in vitro studies that provide a
      defined microenvironment reconstituted ex vivo. We analyzed the effect of in
      vitro environment on the maintenance of adult and immature SSCs in a 7-day
      culture system. Although the number of adult and immature SSCs decreased in a
      time-dependent manner, nearly one in four stem cells (24%) could be maintained in
      vitro for 7 days. Stem cell maintenance was enhanced by coculture with OP9 bone
      marrow stroma or L fibroblast cell lines, addition of glial cell line-derived
      neurotrophic factor, or utilization of specific culture medium. In contrast,
      coculture with TM4 or SF7 Sertoli cell lines and addition of activin A or bone
      morphogenetic protein 4 (BMP4) reduced stem cell maintenance in vitro. Only 4% of
      the stem cells remained when cultured with TM4 cells or activin A, and 6%
      remained when cultured with SF7 cells or BMP4. These results lead to the
      hypothesis that suppression of germ cell differentiation improves in vitro
      maintenance of SSCs by interrupting the unidirectional cascade of spermatogenesis
      and blocking stem cell differentiation.

PMID- 12606374
TI  - Abnormal regulation of DNA methyltransferase expression in cloned mouse embryos.
AB  - Cloning by somatic cell nuclear transfer is inefficient. This is evident in the
      significant attrition in the number of surviving cloned offspring at virtually
      all stages of embryonic and fetal development. We find that cloned
      preimplantation mouse embryos aberrantly express the somatic form of the Dnmt1
      DNA (cytosine-5) methyltransferase, the expression of which is normally prevented
      by a posttranscriptional mechanism. Additionally, the maternal oocyte-derived
      Dnmt1o isoform undergoes little or none of its expected translocation to
      embryonic nuclei at the eight-cell stage. Such defects in the regulation of
      Dnmt1s and Dnmt1o expression and cytoplasmic-nuclear trafficking may prevent
      clones from completing essential early developmental events. Furthermore,
      aberrant Dnmt1 localization and expression may contribute to the defects in DNA
      methylation and the developmental abnormalities seen in cloned mammals.

PMID- 12606375
TI  - Specific binding of nuclear proteins to a bifunctional promoter element upstream
      of the H1/AC box of the testis-specific histone H1t gene.
AB  - The testis-specific histone H1t gene is transcribed exclusively in primary
      spermatocytes during spermatogenesis. Studies with transgenic mice show that 141
      base pairs (bp) of the H1t proximal promoter accompanied with 800 bp of
      downstream sequence are sufficient for tissue-specific transcription. Nuclear
      proteins from testis and pachytene spermatocytes produce footprints spanning the
      region covering the repressor element (RE) from 100 to 125 nucleotides upstream
      of the H1t transcriptional initiation site. Only testis nuclear proteins bind to
      the 5'-end of the element and produce a unique, low-mobility complex in
      electrophoretic mobility shift assays. This testis complex is distinct from the
      complex formed by a repressor protein derived from several cell lines that binds
      to the 3'-end of the element. The testis complex band is formed when using
      nuclear proteins from primary spermatocytes, where the H1t gene is transcribed,
      and band intensity drops 70%-80% when using nuclear proteins from early
      spermatids, where H1t gene transcription ceases. Protein-DNA cross-linking
      experiments using testis nuclear proteins produce electrophoretic bands of 59,
      52, and 50 kDa on SDS/PAGE gels.

PMID- 12606376
TI  - Male sea lampreys, Petromyzon marinus L., excrete a sex pheromone from gill
      epithelia.
AB  - During the period when they are producing sperm, male sea lampreys (Petromyzon
      marinus L.) release a sex pheromone 7alpha, 12alpha, 24-trihydroxy-5alpha-cholan
      3-one-24-sulfate (3 keto-petromyzonol sulfate, 3ketoPZS) that induces search and
      preference behaviors in ovulating females. In this study, we conducted a series
      of experiments to demonstrate that release of this pheromone into water takes
      place exclusively through the gills. In a behavioral maze, water conditioned with
      the anterior region of spermiating males induced an increase of search and
      preference behaviors in ovulating females. Similar behavior was not elicited by
      water conditioned by the posterior region. The anterior region washings and whole
      body washings from spermiating males also elicited large and virtually identical
      electro-olfactogram responses from female sea lampreys, while the posterior
      washings produced negligible responses. Further, mass spectrometry and
      immunoassay confirmed that virtually all the 3ketoPZS released into water was
      through the gills. Immunocytochemistry revealed some gill epithelial cells and
      hepatocytes from spermiating males contained dense immunoreactive 3ketoPZS, but
      not those from prespermiating males. These results demonstrate that 3ketoPZS is
      released through the gill epithelia and suggest that this pheromone or its
      precursor may be produced in the liver.

PMID- 12606377
TI  - Somatic cell-like features of cloned mouse embryos prepared with cultured
      myoblast nuclei.
AB  - Cloning by somatic cell nuclear transfer requires silencing of the donor cell
      gene expression program and the initiation of the embryonic gene expression
      program (nuclear reprogramming). Failure to silence the donor cell program could
      lead to altered embryonic phenotypes. Cloned mouse embryos produced using
      myoblast nuclei fail to thrive in standard embryo culture media but flourish in
      somatic cell culture media favored by the donor myoblasts themselves, forming
      blastocysts at a significant rate, with robust morphologies, high total cell
      number, and a normal allocation of cells to the inner cell mass in most embryos.
      Myoblast cloned embryos continue expressing the GLUT4 glucose transporter, which
      is typically expressed in muscle but not in preimplantation stage embryos.
      Myoblast clones also exhibit precocious enrichment of GLUT1 at the cell surface.
      Both myoblast and cumulus cell cloned embryos exhibit enhanced rates of glucose
      uptake. These observations indicate that silencing of the donor cell genome
      during cloning either is incomplete or occurs progressively over the course of
      preimplantation development. As a result, cloned embryos initially exhibit many
      somatic cell-like characteristics. Tetraploid constructs, which possess a
      transplanted somatic cell genome plus the oocyte-derived chromosomes, exhibit a
      more embryonic-like pattern of gene expression and culture preference. We
      conclude that preimplantation stage cloned embryos have profoundly altered
      characteristics that are donor cell type specific and that exposure of cloned
      embryos to standard embryo culture conditions may lead to disruptions in basic
      homeostasis and inhibition of a range of essential processes including further
      nuclear reprogramming, contributing to cloned embryo demise.

PMID- 12606378
TI  - Late onset of spermatogenesis and gain of fertility in POG-deficient mice
      indicate that POG is not necessary for the proliferation of spermatogonia.
AB  - The germ cell-deficient (gcd) mouse mutation is a recessive, transgenic
      insertional mutation associated with the disruption of two Chr11 genes, Pog
      (proliferation of germ cells) and Vrk2 (vaccinia virus-related protein kinase 2).
      We have recently shown that like gcd/gcd mice, targeted Pog-/- males and females
      show virtually no spermatogenesis or oogenesis at 4-6 wk of age. Because Pog is
      deleted in gcd/gcd and Pog-/- mice, a comparison of the phenotypes of the two
      mouse models is appropriate. Here, we report that unlike in POG-deficient
      females, the germ cells in POG-deficient males eventually populate the
      seminiferous tubules at 9 wk, and fertility can be achieved by 12 wk. Homozygous
      gcd/gcd males did not show a similar degree of germ cell population, and most
      gcd/gcd males remained infertile at 16 and 22 wk of age. A comparison of the
      degree of germ cell deficiency at 13.5 days postcoitum and 1 day postpartum
      between Pog-/- and gcd/gcd males revealed that gcd/gcd males had far fewer germ
      cells than Pog-/- males at both time points. Our data suggest that Pog is
      essential for proper primordial germ cell proliferation in the embryonic stage
      but is not needed for spermatogonial proliferation after birth. Thus, the
      difference in the spermatogenetic potential in adult Pog-/- and gcd/gcd mice may
      result from the severity of germ cell deficiency rather than from the inability
      of gcd/gcd spermatogonia to proliferate efficiently. The greater deficiency of
      germ cells before the onset of spermatogenesis seen in gcd/gcd males compared to
      Pog-/- mice suggests either that the different background affects the outcome of
      Pog deletion or that Vrk2 has additional effects on germ cell development.

PMID- 12606379
TI  - Ligand-activated signal transduction in the 2-cell embryo.
AB  - Platelet-activating factor (PAF) is an autocrine trophic/survival factor for the
      preimplantation embryo. PAF induced an increase in intracellular calcium
      concentration ([Ca2+]i) in the 2-cell embryo that had an absolute requirement for
      external calcium. L-type calcium channel blockers (diltiazem, verapamil, and
      nimodipine) significantly inhibited PAF-induced Ca2+ transients, but inhibitors
      of P/Q type (omega-agatoxin; omega-conotoxin MVIIC), N-type (omega-conotoxin
      GVIA), T-type (pimozide), and store-operated channels (SKF 96365 and econazole)
      did not block the transient. mRNA and protein for the alpha1-C subunit of L-type
      channels was expressed in the 2-cell embryo. The L-type calcium channel agonist
      (+/-) BAY K 8644 induced [Ca2+]i transients and, PAF and BAY K 8644 each caused
      mutual heterologous desensitization of each other's responses. Depolarization of
      the embryo (75 mM KCl) induced a [Ca2+]i transient that was inhibited by
      diltiazem and verapamil. Whole-cell patch-clamp measurements detected a voltage
      gated channel (blocked by diltiazem, verapamil, and nifedipine) that was
      desensitized by prior responses of embryos to exogenous or embryo-derived PAF.
      Replacement of media Ca2+ with Mn2+ allowed Mn2+ influx to be observed directly;
      activation of a diltiazem-sensitive influx channel was an early response to PAF.
      The activation of a voltage-gated L-type calcium channel in the 2-cell embryo is
      required for normal signal transduction to an embryonic trophic factor.

PMID- 12606380
TI  - Functional analysis of the p53 gene in apoptosis induced by heat stress or loss
      of stem cell factor signaling in mouse male germ cells.
AB  - Apoptosis plays an important role in controlling germ cell numbers and
      restricting abnormal cell proliferation during spermatogenesis. The tumor
      suppressor protein, p53, is highly expressed in the testis, and is known to be
      involved in apoptosis, which suggests that it is one of the major causes of germ
      cell loss in the testis. Mice that are c-kit/SCF mutant (Sl/Sld) and cryptorchid
      show similar testicular phenotypes; they carry undifferentiated spermatogonia and
      Sertoli cells in their seminiferous tubules. To investigate the role of p53
      dependent apoptosis in infertile testes, we transplanted p53-deficient
      spermatogonia that were labeled with enhanced green fluorescence protein into
      cryptorchid and Sl/Sld testes. In cryptorchid testes, transplanted p53-deficient
      spermatogonia differentiated into spermatocytes, but not into haploid spermatids.
      In contrast, no differentiated germ cells were observed in Sl/Sld mutant testes.
      These results indicate that the mechanism of germ cell loss in the c-kit/SCF
      mutant is not dependent on p53, whereas the apoptotic mechanism in the
      cryptorchid testis is quite different (i.e., although the early stage of
      differentiation of spermatogonia and the meiotic prophase is dependent on p53
      mediated apoptosis, the later stage of spermatids is not).

PMID- 12606382
TI  - A new subclass of the luteinizing hormone/chorionic gonadotropin receptor lacking
      exon 10 messenger RNA in the New World monkey (Platyrrhini) lineage.
AB  - The luteinizing hormone receptor (LHR) plays an essential role as a mediator of
      LH and CG action during embryonic sexual differentiation and in gametogenesis. In
      a hypogonadal male patient, we recently demonstrated that a genomic deletion of
      exon 10, located in the hinge region of the extracellular domain, results in
      discrimination of LH and hCG action. In the common marmoset (Calltithrix
      jacchus), exon 10 of the LHR is naturally missing at the mRNA level. In order to
      investigate whether this is an isolated species-specific phenomenon, we performed
      a phylogenetic screening, searching for the presence of LHR exon 10 mRNA in a
      number of primate species representative for the major lineages of primate
      evolution. The expressed LHR region encompassing exon 10 was amplified from
      testicular tissue by RT-PCR, cloned, and sequenced. In addition, we performed
      Southern blot analysis of the LHR of selected New World and Old World primates.
      The results revealed that exon 10 mRNA is lacking in the complete New World
      monkey (Platyrrhini) lineage but is present in both more primitive and more
      advanced primates. However, exon 10 seems to be present at the genomic level,
      arguing for a splicing failure possibly due to a genomic mutation or the lack of
      appropriate splicing factors. Considering that, in the human, LH is far less
      active than hCG on the LHR lacking exon 10, we addressed the question whether the
      existence of such a receptor has any consequences on the dual hormone LH/CG
      system present in Platyrrhini. Using primers specific for the known marmoset CG
      beta cDNA, we amplified the CG beta subunit cDNA from male common marmoset
      pituitaries by RT-PCR, while LH beta could not be amplified, suggesting a
      possible physiological role of pituitary CG in this species. In conclusion, we
      demonstrated for the first time that the LH mRNA without exon10 is the natural
      wild-type LHR in the Platyrrhini lineage. We propose that this LHR represents a
      new subclass of receptors that should be named LHR type II. In addition, the high
      expression of CG beta in the marmoset pituitary suggests a physiological role of
      CG in the reproductive function of these primates beyond pregnancy.

PMID- 12606381
TI  - Progeny from sperm obtained after ectopic grafting of neonatal mouse testes.
AB  - Ectopic grafting of testicular tissue is a promising new approach that can be
      used to preserve testicular function. This technique has been used recently to
      differentiate the neonatal testes of different species, up to the level of
      complete spermatogenesis. This approach can be applied successfully to generate
      live progeny using sperm extracted from grafts originating from testes of newborn
      donors. The sperm are capable of supporting normal development and producing
      fertile male and female offspring after intracytoplasmic injection into mouse
      oocytes and embryo transfer into surrogate mothers. The grafted tissue was also
      capable of significantly normalizing reproductive hormone levels in the castrated
      recipients. This technique presents new avenues for experimentation. The
      recipient mouse can be regarded as a living incubator and a culture system of
      testicular tissue, allowing the experimental manipulation of several aspects of
      testis development and spermatogenesis. The successful generation of pups
      indicates that this technique can be used to study the testicular phenotype and
      to breed mutant or transgenic mouse strains with lethal postnatal phenotypes. The
      ability to generate sperm from the germ line ex vivo also paves the way for the
      development of new strategies for preserving fertility in boys undergoing cancer
      therapy.

PMID- 12606383
TI  - Does leptin mediate the effect of photoperiod on immune function in mice?
AB  - Seasonal fluctuations in immune status have been documented for avian and
      mammalian populations. During the late summer and early fall, immune function is
      bolstered to help animals cope with the more physiologically demanding winter.
      The environmental cue for these seasonal changes is apparently decreasing
      photoperiod. In the present study, we determined the potential role of leptin in
      mediating the effect of photoperiod on cell-mediated immune responses in male
      mice. Leptin-deficient (ob/ob) and littermate control mice were housed for 10 wk
      in either a short (8L:16D) or a long (16L:8D) photoperiod beginning at 6 wk of
      age. After the mice were killed, immune and reproductive organs were weighed and
      splenocytes isolated. The proliferative and cytokine responses (interleukin [IL]
      2 and IL-4) of splenocytes to the T-cell mitogen, concanavalin A (Con A; 0-40
      microg/ml), were determined. Body weights were elevated and both testes and
      seminal vesicle weights subnormal in ob/ob mice (by ANOVA, main effect of leptin
      deficiency), but thymuses and spleens were of normal size. Serum leptin levels
      were at minimum detection limits in ob/ob mice, but leptin levels in control mice
      housed at 8L:16D were higher than in control mice housed at 16L:8D. The
      proliferative response of splenocytes from ob/ob mice to Con A was subnormal (by
      ANOVA, main effect of leptin deficiency), but photoperiod had no effect on this
      response. Production of IL-2 in splenocytes of ob/ob mice was subnormal (by
      ANOVA, main effect of leptin deficiency) irrespective of photoperiod, but cells
      from mice housed at 8L:16D (by ANOVA, main effect of photoperiod) produced more
      IL-2 than cells from animals housed at 16L:8D. In contrast, a leptin deficiency
      did not alter IL-4 production, but cells from animals (ob/ob and controls) housed
      at 16L:8D produced less IL-4 than cells from animals housed at 8L:16D (by ANOVA,
      main effect of photoperiod). The present study suggests that both photoperiod and
      leptin have mutually independent effects on the proliferation of lymphocytes and
      cytokine production profiles. The data do not provide definitive support for the
      hypothesis that photoperiod-induced changes in leptin secretion mediate the
      effects of season on immune status.

PMID- 12606384
TI  - Expression of vascular endothelial growth factor isoforms and receptors Flt-1 and
      KDR during the peri-implantation period in the mink, Mustela vison.
AB  - Expression of vascular endothelial growth factor (VEGF) isoforms and its
      receptors, Flt-1 and KDR, was investigated during the period of peri-implantation
      in mink, a species that displays obligate embryonic diapause. Uterine samples
      were collected during diapause, embryo activation, and implantation from
      pseudopregnant and anestrous animals and analyzed by semiquantitative reverse
      transcription polymerase chain reaction and immunohistochemistry. The abundance
      of mRNA of VEGF isoforms 120, 164, and 188 was highest during late embryo
      activation and at implantation. VEGF protein was localized to the glandular
      epithelium at all stages of peri-implantation, whereas the luminal epithelium
      lacked VEGF reactivity during diapause. Endometrial stroma and luminal and
      glandular epithelia were positive for VEGF in implanted uteri. The invasive
      trophoblast cells of the implanting embryo were intensively stained. High levels
      of VEGF mRNA in pseudopregnant uteri indicates that VEGF upregulation leading to
      implantation is dependent upon maternal rather than embryonic factors. The
      abundance of the two receptors, KDR and Flt-1, increased in the uterus during
      implantation. Low levels of the receptors in pseudopregnant uteri compared with
      those containing activated or implanted embryos indicates that the embryo
      regulates receptor expression. These results demonstrate VEGF and VEGF receptor
      expression during early gestation in mink and suggest that maternal and embryonic
      input regulates different aspects of the angiogenic process.

PMID- 12606385
TI  - Characterization of 17beta-hydroxysteroid dehydrogenase type 7 in reproductive
      tissues of the marmoset monkey.
AB  - In contrast to the known rodent enzymes, the physiological significance of 17beta
      hydroxysteroid dehydrogenase type 7 (17HSD7) and its presumed function in
      reproductive biology is not well understood in primates. As a first step, we
      recently cloned the complete coding regions of human and marmoset monkey
      (Callithrix jacchus) 17HSD7 (cj17HSD7). In the present work the complete cDNA of
      marmoset 17HSD1 (cj17HSD1), including the proximal promoter region, and a partial
      sequence of marmoset aromatase (cjARO) were sequenced in order to compare the
      expression of these estradiol synthesizing enzymes with that of 17HSD7 in a
      primate model and to identify tissues where 17HSD7 might participate in the
      pathway of estradiol synthesis. The gene structures of cj17HSD1 and cj17HSD7 were
      determined and proved to be very similar to the human orthologues. Northern
      hybridization showed that cjARO mRNA seems to be coexpressed preferably with
      cj17HSD1 in placenta, whereas in other tissues it is expressed in parallel only
      with cj17HSD7. Especially in corpora lutea, the cj17HSD7 transcript is detectable
      throughout the luteal phase of the ovarian cycle and increases during pregnancy,
      in parallel with the transcript of aromatase. Results were confirmed by
      immunoblots and immunohistochemistry using new polyclonal antisera directed
      against cj17HSD7 and cjARO protein. The enzymatic conversion of estrone to
      estradiol was assessed in marmoset corpora lutea. The pattern of coexpression
      with aromatase supports the hypothesis that luteal 17HSD7 complements placental
      17HSD1, ensuring continued estradiol synthesis throughout pregnancy in primates.

PMID- 12606386
TI  - Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation
      in bicarbonate responsive human sperm cells.
AB  - Only capacitated sperm cells are able to fertilize egg cells, and this process is
      triggered by high levels of bicarbonate. Bicarbonate renders the plasma membrane
      more fluid, which is caused by protein kinase A (PKA)-mediated alterations in the
      phospholipid (PL) bilayer. We studied exposure of phosphatidylserine (PS) and
      phosphatidylethanolamine (PE) in human sperm cells. Surface exposure of PS and PE
      on sperm cell activation in vitro was found to be bicarbonate dependent and
      restricted to the apical area of the head plasma membrane. The PL scrambling in
      bicarbonate-triggered human sperm was not related to apoptosis, because the
      incubated cells did not show any signs of caspases or degeneration of
      mitochondria or DNA. The PL scramblase (PLSCR) gene family has been implicated in
      this nonspecific, bidirectional PL movement. A 25-kDa isoform of PLSCR was
      identified that was homogeneously distributed in human sperm cells. We propose
      that compartment-dependent activation of PKA is required for the surface exposure
      of aminophospholipids at the apical plasma membrane of sperm cells. Bicarbonate
      induced PL scrambling appears to be an important event in the capacitation
      process, because the entire intact scrambling sperm subpopulation showed
      extensive tyrosine phosphorylation, which was absent in the nonscrambling
      subpopulation. The proportion of live cells with PL scrambling corresponded with
      that showing capacitation-specific chlortetracyclin staining.

PMID- 12606387
TI  - Functional assessment of self-renewal activity of male germline stem cells
      following cytotoxic damage and serial transplantation.
AB  - Spermatogenesis is dependent on a small population of stem cells. Although stem
      cells are believed to expand infinitely, there is little functional evidence
      regarding whether spermatogonial stem cells can increase in their number. Using
      the spermatogonial transplantation technique, we evaluated the proliferative
      potential of spermatogonial stem cells in two models of regeneration. After
      busulfan injection to deplete stem cells, the surviving stem cells were able to
      expand by at least 15.8-fold within 2 mo. On the other hand, a serial
      transplantation study indicated that one transplanted stem cell was able to
      expand by 3.8- and 12-fold within 2 and 4 mo, respectively. These results provide
      direct functional evidence for the expansion of stem cells and establish the
      basis for further characterization of the stem cell self-renewal process.

PMID- 12606388
TI  - Human feeder layers for human embryonic stem cells.
AB  - Human embryonic stem (hES) cells hold great promise for future use in various
      research areas, such as human developmental biology and cell-based therapies.
      Traditionally, these cells have been cultured on mouse embryonic fibroblast (MEF)
      feeder layers, which permit continuous growth in an undifferentiated stage. To
      use these unique cells in human therapy, an animal-free culture system must be
      used, which will prevent exposure to mouse retroviruses. Animal-free culture
      systems for hES cells enjoy three major advantages in the basic culture
      conditions: 1). the ability to grow these cells under serum-free conditions, 2).
      maintenance of the cells in an undifferentiated state on Matrigel matrix with
      100% MEF-conditioned medium, and 3). the use of either human embryonic
      fibroblasts or adult fallopian tube epithelial cells as feeder layers. In the
      present study, we describe an additional animal-free culture system for hES
      cells, based on a feeder layer derived from foreskin and a serum-free medium. In
      this culture condition, hES cells maintain all embryonic stem cell features
      (i.e., pluripotency, immortality, unlimited undifferentiated proliferation
      capability, and maintenance of normal karyotypes) after prolonged culture of 70
      passages (>250 doublings). The major advantage of foreskin feeders is their
      ability to be continuously cultured for more than 42 passages, thus enabling
      proper analysis for foreign agents, genetic modification such as antibiotic
      resistance, and reduction of the enormous workload involved in the continuous
      preparation of new feeder lines.

PMID- 12606389
TI  - Gene expression profiles in different stages of mouse spermatogenic cells during
      spermatogenesis.
AB  - During spermatogenesis, diploid stem cells differentiate, undergo meiosis and
      spermiogenesis, and transform into haploid spermatozoa. Various factors have been
      demonstrated to regulate this marvelous process of differentiation, but the
      expression of only a few genes specifically involved in spermatogenesis has been
      studied. In the present study, different types of spermatogenic cells were
      isolated from Balb/c mice testes of different ages using the velocity
      sedimentation method, and we determined the expression profiles of 1176 known
      mouse genes in six different types of mouse spermatogenic cells (primitive type A
      spermatogonia, type B spermatogonia, preleptotene spermatocytes, pachytene
      spermatocytes, round spermatids, and elongating spermatids) using Atlas cDNA
      arrays. Of the 1176 genes on the Atlas Mouse 1.2 cDNA Expression Arrays, we
      detected 181 genes in primitive type A spermatogonia, 256 in type B
      spermatogonia, 221 in preleptotene spermatocytes, 160 in pachytene spermatocytes,
      141 in round spermatids, and 126 in elongating spermatids. A number of genes were
      detected as differential expression (up-regulation or down-regulation). Fourteen
      of the differentially expressed genes have been further confirmed by reverse
      transcription-polymerase chain reaction for their expression characterizations in
      different types of spermatogenic cells. These results provide more information
      for further studies into spermatogenesis-related genes and may lead to the
      identification of genes with potential relevance to spermatogenesis.

PMID- 12606390
TI  - Chemotactic role of neurotropin 3 in the embryonic testis that facilitates male
      sex determination.
AB  - The first morphological event after initiation of male sex determination is
      seminiferous cord formation in the embryonic testis. Cord formation requires
      migration of pre-peritubular myoid cells from the adjacent mesonephros. The
      embryonic Sertoli cells are the first testicular cells to differentiate and have
      been shown to express neurotropin-3 (NT3), which can act on high-affinity trkC
      receptors expressed on migrating mesonephros cells. NT3 expression is elevated in
      the embryonic testis during the time of seminiferous cord formation. A trkC
      receptor tyrophostin inhibitor, AG879, was found to inhibit seminiferous cord
      formation and mesonephros cell migration. Beads containing NT3 were found to
      directly promote mesonephros cell migration into the gonad. Beads containing
      other growth factors such as epidermal growth factor (EGF) did not influence cell
      migration. At male sex determination the SRY gene promotes testis development and
      the expression of downstream sex differentiation genes such as SOX-9. Inhibition
      of NT3 actions caused a reduction in the expression of SOX-9. Combined
      observations suggest that when male sex determination is initiated, the
      developing Sertoli cells express NT3 as a chemotactic agent for migrating
      mesonephros cells, which are essential to promote embryonic testis cord formation
      and influence downstream male sex differentiation.

PMID- 12606391
TI  - Vascular endothelial growth factor in the human oviduct: localization and
      regulation of messenger RNA expression in vivo.
AB  - In this study, we examined the localization of vascular endothelial growth factor
      (VEGF) and the changes in VEGF mRNA expression in various regions of the oviduct
      in fertile women throughout the ovulatory cycle. Oviduct tissue was collected
      from 22 women undergoing laparoscopic tubal sterilization or hysterectomy for a
      benign gynecological condition. Oviduct sections were divided into isthmus,
      ampullary, and infundibular regions. Serial cross sections were analyzed for the
      presence of VEGF by specific immunohistochemical staining. The mucosal layer was
      isolated, and a semiquantitative reverse transcription polymerase chain reaction
      was performed. Immunohistochemical study revealed VEGF in the oviduct luminal
      epithelium, smooth muscle cells, and blood vessels within the oviduct. VEGF mRNA
      expression in oviduct was the highest during the periovulatory stage, and the
      expression in the ampullary and infundibular regions was higher than that in the
      isthmus. There was a significant positive correlation between serum FSH and LH
      concentrations and VEGF mRNA expression. There was no significant correlation
      between serum estradiol and progesterone concentrations and VEGF mRNA expression.
      These results suggest that VEGF in human oviduct may play an important role
      related the early reproductive events, which occur predominantly in the ampulla
      during the periovulatory phase when serum FSH and LH concentrations are high.

PMID- 12606392
TI  - Pregnancy and interferon tau regulate major histocompatibility complex class I
      and beta2-microglobulin expression in the ovine uterus.
AB  - Major histocompatibility complex (MHC) class I molecules, consisting of an alpha
      chain and beta2-microglobulin (beta2MG), play an important role in immune
      rejection responses by discriminating self and nonself and are increased by type
      I interferons during antiviral responses. Interferon tau (IFNtau), the pregnancy
      recognition signal in ruminants, is a type I interferon produced by the ovine
      conceptus between Days 11 and 21 of gestation. In study 1, expression of MHC
      class I alpha chain and beta2MG mRNA and protein was detected primarily in
      endometrial luminal epithelium (LE) and glandular epithelium (GE) on Days 10 and
      12 of the estrous cycle and pregnancy. On Days 14-20 of pregnancy, MHC class I
      and beta2MG expression increased only in endometrial stroma and GE and,
      concurrently, was absent in LE and superficial ductal GE (sGE). Although neither
      MHC class I nor beta2MG proteins were detected in Day 20 trophectoderm, beta2MG
      mRNA was detected in conceptus trophectoderm. In study 2, cyclic ewes were
      ovariectomized on Day 5, treated daily with progesterone to Day 16, received
      intrauterine infusions between Days 11 and 16 of either control serum proteins or
      recombinant ovine IFNtau, and were hysterectomized on Day 17. The IFNtau
      increased MHC class I and beta2MG expression only in endometrial stroma and GE.
      During pregnancy, MHC class I and beta2MG gene expression is inhibited in
      endometrial LE and sGE but, paradoxically, is stimulated by IFNtau in the stroma
      and GE. The silencing of MHC class I alpha chain and beta2MG genes in the
      endometrial LE and sGE during pregnancy recognition and establishment may be a
      critical mechanism preventing immune rejection of the conceptus allograft.

PMID- 12606393
TI  - Early degradation of paternal mitochondria in domestic pig (Sus scrofa) is
      prevented by selective proteasomal inhibitors lactacystin and MG132.
AB  - Ubiquitin-dependent proteolysis has been implicated in the recognition and
      selective elimination of paternal mitochondria and mitochondrial DNA (mtDNA)
      after fertilization in mammals. Initial evidence suggests that this process is
      contributed to by lysosomal degradation of the ubiquitinated sperm mitochondrial
      membrane proteins. The present study examined the role of the proteasome
      dependent protein degradation pathway of the ubiquitin system, as opposed to
      lysosomal proteolysis of the ubiquitinated proteins, in the regulation of sperm
      mitochondrion elimination after fertilization. Boar spermatozoa prelabeled with
      vital fluorescent mitochondrial probes MitoTracker were used to trace the
      degradation of paternal mitochondria after in vitro fertilization (IVF) of
      porcine oocytes. The degradation of sperm mitochondria in the cytoplasm of
      fertilized oocytes started very rapidly, i.e., within 12-20 h after insemination.
      Four stages of paternal mitochondrial degradation were distinguished, ranging
      from an intact mitochondrial sheath (type 1) to complete degradation (type 4). At
      27-30 h postinsemination, 96% of zygotes contained the partially (type 3) or
      completely (type 4) degraded sperm mitochondria. Highly specific peptide
      inhibitors of the ubiquitin-proteasome pathway, lactacystin (10 and 100 microM)
      and MG132 (10 microM), efficiently blocked the degradation of the sperm
      mitochondria inside the fertilized egg when applied 6 h after insemination. Using
      10 microM MG132, only 13.6% of fertilized oocytes screened 27-30 h after IVF
      displayed type 3 sperm mitochondria, and there was no incidence of type 4,
      completely degraded mitochondria. Although lactacystin is not a reversible agent,
      the effect of MG132 was fully reversible: zygotes transferred to regular culture
      medium after 24 h of culture with 10 microM MG132 resumed development and
      degraded sperm mitochondria within the next cell cycle. Surprisingly, penetration
      of the zona pellucida (ZP) was also inhibited by MG-132 and lactacystin when the
      inhibitors were added at insemination. Altogether, these data provide the first
      evidence of the participation of proteasomes in the control of mammalian
      mitochondrial inheritance and suggest a new role of the ubiquitin-proteasome
      pathway in mammalian fertilization.

PMID- 12606394
TI  - Molecular weight forms of inhibin a and inhibin B in the bovine testis change
      with age.
AB  - To investigate alterations in the molecular weight forms of inhibin in bull
      testis from the infantile (4-5 wk of age) to postpubertal (49-56 wk of age)
      periods, testicular homogenates were obtained from animals of various ages and
      fractionated by a combination of immunoaffinity chromatography and SDS-PAGE.
      Subsequently, the fractions eluted from the SDS gels were assayed for total
      inhibin, inhibin A, and inhibin B by fluoroimmunoassay or immunofluorometric
      assays (IFMAs) and for inhibin bioactivity by an in vitro bioassay. The molecular
      mass patterns of inhibin A and inhibin B in the testis, as determined by the
      dimer-specific IFMAs, showed the presence of a peak of approximate 47 kDa until
      21-26 wk of age. However, the peak disappeared after 31-32 wk of age. As bulls
      aged, especially after 31-32 wk of age, inhibin A and inhibin B levels increased
      in the molecular mass region of 27-34 kDa. Total inhibin showed two peaks, of
      between 20 and 26 kDa and at approximately 47 kDa, until 21-26 wk of age and a
      single peak between 20 and 30 kDa after 31-32 wk of age. The eluted fractions
      corresponding to 29, 31, or 47 kDa gave a dose-response curve that was parallel
      to the curve generated with 32-kDa inhibin A or 29-kDa inhibin B standard in the
      IFMA for inhibin A or inhibin B. The fractions corresponding to 29 and 31 kDa
      suppressed basal release of FSH from rat pituitary cells, but the 47-kDa fraction
      had a lower FSH-suppressing activity. In the testes of older bulls, immunoblot
      analysis revealed the presence of a 29-kDa band cross-reacting with inhibin alpha
      and inhibin betaB antibodies and of a 31-kDa band cross-reacting with inhibin
      alpha and inhibin betaA antibodies. The 47-kDa band was recognized by the alpha,
      betaA, and betaB antibodies. Immunohistochemisty of the testis at each age showed
      that inhibin alpha subunits were found exclusively in Sertoli cells, but the
      intensity of immunostaining diminished in older bulls, in parallel with the
      decrease in the testicular concentrations of total inhibin. We conclude that 1)
      bovine Sertoli cells produce both inhibin A and inhibin B, 2) inhibin production
      in Sertoli cells during the prepubertal period is characterized by the 47 kDa
      inhibin-related material that contains precursor forms of inhibin A and inhibin
      B, and 3) the proportion of the mature forms of inhibin A and inhibin B increases
      as bulls age, although total inhibin production in Setroli cells decreases.

PMID- 12606395
TI  - Immunocontraception is induced in BALB/c mice inoculated with murine
      cytomegalovirus expressing mouse zona pellucida 3.
AB  - Immunocontraception, the prevention of oocyte fertilization through immunological
      means, could potentially be used to control plaguing mouse populations in
      Australia. This paper describes the construction of a mouse-specific
      betaherpesvirus, murine cytomegalovirus, which has been engineered to express the
      murine zona pellucida 3 (ZP3) gene. A single inoculation of this recombinant
      virus resulted in almost complete infertility, persistent anti-ZP3 antibody
      production, and profound changes to ovarian morphology in BALB/c mice in the
      absence of significant virus replication during the acute phase of infection.
      Murine cytomegalovirus may prove to be useful as a vector for the delivery of a
      mouse-specific immunocontraceptive agent to target populations of wild mice in
      the field.

PMID- 12606396
TI  - Osteopontin expression in uterine stroma indicates a decidualization-like
      differentiation during ovine pregnancy.
AB  - Osteopontin (OPN) is a component of the extracellular matrix that interacts with
      cell surface receptors, including integrins, to mediate cell adhesion, migration,
      differentiation, survival, and immune function. In pregnant mice and primates,
      OPN has been detected in decidualized stroma and is considered to be a gene
      marker for decidualization. Decidualization involves transformation of spindle
      like fibroblasts into polygonal epithelial-like cells that are hypothesized to
      limit conceptus trophoblast invasion through the uterine wall during invasive
      implantation. Decidualization is not considered characteristic of species with
      noninvasive implantation, such as domestic animals. However, the extent of
      trophoblast invasion between sheep and pigs differs, with sheep exhibiting
      erosion of the uterine luminal epithelium (LE) and fusion of trophectoderm with
      LE to form syncytia, and pigs maintaining an intact LE throughout pregnancy.
      Therefore, the present study measured changes in the decidualization marker genes
      OPN, desmin, and alpha smooth muscle actin (alphaSMA) in ovine and porcine
      uterine stroma throughout pregnancy. The morphology of endometrial stromal cells
      in pregnant ewes changes following conceptus attachment, with cells increasing in
      size and becoming polyhedral in shape by Day 35 of pregnancy. Expression of OPN
      mRNA and protein, as well as desmin and alphaSMA proteins, was observed in this
      same uterine stromal compartment. In contrast, no morphological changes in
      uterine stroma nor induction of OPN mRNA and protein, or desmin protein, were
      detected during porcine pregnancy. Interestingly, alphaSMA protein was absent on
      Day 20, but prominent in uterine stroma of pregnant pigs on Day 45. Collectively,
      these results indicate that the uterine stroma of sheep undergoes a program of
      differentiation similar to decidualization in invasive implanting species,
      whereas porcine stroma exhibits differentiation that is more limited than that in
      sheep, rodents, or primates. Results suggest that uterine stromal decidualization
      is common to species with different types of placentation, but the extent is
      variable and correlates with the depth of trophoblast invasion during
      implantation.

PMID- 12606397
TI  - Mapping quantitative trait loci affecting female reproductive traits on porcine
      chromosome 8.
AB  - An understanding of the genetic control of porcine female reproductive
      performance would offer the opportunity to utilize natural variation and improve
      selective breeding programs through marker-assisted selection. The Chinese
      Meishan is one of the most prolific pig breeds known, farrowing three to five
      more viable piglets per litter than the European Large White breed. This
      difference in prolificacy is attributed to the Meishan's superior prenatal
      survival levels. The present study utilized a three-generation cross in which the
      founder grandparental animals were purebred Meishan and Large White pigs in a
      scan for quantitative trait loci (QTL) on porcine chromosome 8 (SSC8) associated
      with reproductive performance. Reproductive traits, including number of corpora
      lutea (ovulation rate), teat number, litter size, and prenatal survival, were
      recorded for as many as 220 F2 females. Putative QTL for the related traits of
      litter size and prenatal survival were identified at the distal end of the long
      arm of SSC8. A physiological candidate gene, SPP1, was found to lie within the
      95% confidence interval of these QTL. A suggestive QTL for teat number was
      revealed on the short arm of SSC8. The present study demonstrates, to our
      knowledge, the first independent confirmation of QTL for fecundity on SSC8, and
      these QTL regions provide a crucial starting point in the search for the causal
      genetic variants.

PMID- 12606398
TI  - Developmental changes of amino acids in ovine fetal fluids.
AB  - We recently reported an unusual abundance of arginine (4-6 mM) in porcine
      allantoic fluid during early gestation. However, it is not known whether such
      high concentrations of arginine are unique for porcine allantoic fluid or whether
      they represent an important physiological phenomenon for mammals. The present
      study was conducted to test the hypothesis that arginine is also the most
      abundant amino acid in ovine allantoic fluid. Allantoic and amniotic fluids, as
      well as fetal and maternal plasma samples, were obtained from ewes between Days
      30 and 140 of gestation. Glycine was the most abundant amino acid in maternal
      uterine arterial plasma, representing approximately 25% of total alpha-amino
      acids. Alanine, glutamine, glycine, plus serine contributed approximately 50% of
      total alpha-amino acids in fetal plasma. Fetal:maternal plasma ratios for amino
      acids varied greatly, being less than 1 for glutamate during late gestation, 1.5
      3 for most amino acids throughout gestation, and greater than 10 for serine
      during late gestation. Marked changes were observed in amino acid concentrations
      in amniotic and allantoic fluids associated with conceptus development.
      Concentrations of alanine, citrulline, and glutamine in allantoic fluid increased
      by 20-, 34-, and 18-fold, respectively, between Days 30 and 60 of gestation and
      were 24.7, 9.7, and 23.5 mM, respectively, on Day 60 of gestation (compared with
      0.8 mM arginine). Remarkably, alanine, citrulline, plus glutamine accounted for
      approximately 80% of total alpha-amino acids in allantoic fluid during early
      gestation. Serine (16.5 mM) contributed approximately 60% of total alpha-amino
      acids in allantoic fluid on Day 140 of gestation. These novel findings of the
      unusual abundance of traditionally classified nonessential amino acids in
      allantoic fluid raise important questions regarding their roles in ovine
      conceptus development.

PMID- 12606399
TI  - Dexamethasone inhibits transforming growth factor-beta receptor (Tbeta R)
      messenger RNA expression in hamster preantral follicles: possible association
      with NF-YA.
AB  - To evaluate the site(s) and mechanism(s) of glucocorticoid-inhibition of
      transforming growth factor (TGF) beta receptor (TbetaR) mRNA expression in
      ovarian cells, steady-state levels of TbetaR mRNA in hamster preantral follicles
      exposed to FSH or estradiol with or without dexamethasone were determined by
      reverse transcription polymerase chain reaction and Southern hybridization. The
      effect of dexamethasone on follicular DNA and steroid synthesis and the
      expression of NF-Y and Sp3 were also investigated. Dexamethasone differentially
      inhibited FSH- or estradiol-induced expression of TbetaR mRNA in preantral
      follicles at all stages. Dexamethasone also strongly inhibited FSH-induced but
      not TGFbeta2-induced follicular DNA synthesis, and the inhibition was completely
      reversed by TGFbeta2. However, TGFbeta2 markedly attenuated FSH + dexamethasone
      stimulated progesterone and FSH-induced follicular estradiol synthesis. Both FSH
      and estradiol upregulated NF-YA expression, but the effect was significantly
      attenuated by dexamethasone. Our results suggest that suppression of NF-YA levels
      is one of the mechanisms whereby dexamethasone reduces hormone-induced TbetaRI
      and TbetaRII mRNA levels in hamster preantral follicles. Dexamethasone
      potentiates the effect of FSH on granulosa cell steroidogenesis, whereas TGFbeta
      counteracts the effect. These data indicate that glucocorticoid and TGFbeta may
      form an important regulatory loop to modulate FSH regulation of preantral
      follicular growth and differentiation.

PMID- 12606400
TI  - A revised protocol for in vitro development of mouse oocytes from primordial
      follicles dramatically improves their developmental competence.
AB  - The objective of this study was to improve the conditions for oocyte development
      in vitro beginning with the primordial follicles of newborn mice. Previous
      studies showed that oocytes competent of meiotic maturation, fertilization, and
      preimplantation could develop in vitro from primordial follicles. However, the
      success rates were low and only one live offspring was produced (0.5% of embryos
      transferred). A revised protocol was compared with the original protocol using
      oocyte maturation and preimplantation development as end points. The percentage
      of oocytes maturing to metaphase II and developing to the blastocyst stage was
      significantly improved using the revised protocol. In addition, we compared the
      production of offspring from two-cell stage embryos derived from in vitro-grown
      and in vivo-grown oocytes. Of 1160 transferred two-cell stage embryos derived
      from in vitro-grown oocytes, 66 (5.7%) developed to term and 7 pups (10.6%) died
      at birth. The remaining 59 pups (27 females, 32 males) survived to adulthood. By
      comparison, of 437 transferred two-cell stage embryos derived from in vivo-grown
      oocytes, 76 (17.4%) developed to term and 4 (5.3%) died at birth. The remaining
      72 pups (35 females, 37 males) survived to adulthood. These studies provide proof
      of the principle that fully competent mammalian oocytes can develop in vitro from
      primordial follicles and present a significant advance in oocyte culture
      technology.

PMID- 12606401
TI  - Identification of novel isoforms of activin receptor-like kinase 7 (ALK7)
      generated by alternative splicing and expression of ALK7 and its ligand, Nodal,
      in human placenta.
AB  - Members of the transforming growth factor (TGF) beta family play critical roles
      in regulating placental functions. Using polymerase chain reaction (PCR)-based
      strategies, we have cloned four transcripts encoding full-length activin receptor
      like kinase 7 (ALK7) and three novel ALK7 isoforms from the human placenta. The
      full-length ALK7 has 493 amino acids and exhibits all characteristics of TGFbeta
      type I receptors, including an activin receptor-binding domain, a transmembrane
      domain, a GS domain, and a serine/threonine kinase domain. The three ALK7
      isoforms identified include a truncated ALK7 (tALK7) and two soluble proteins
      designated as soluble ALK7a (sALK7a) and soluble ALK7b (sALK7b). The tALK7 lacks
      the first 50 amino acids of the full-length ALK7, resulting in a truncated
      receptor-binding domain. Both sALK7a and sALK7b lack transmembrane and GS
      domains. The ALK7 gene, located on chromosome 2q24.1, is composed of at least
      nine exons and eight introns. The isoforms of ALK7 are generated by alternative
      splicing. Transcripts encoding the sALK7 isoforms differ from the full-length
      transcript by lacking exon III or both exons III and IV in sALK7a and sALK7b,
      respectively. The transcript for tALK7 uses an alternative exon located within
      the first intron of the full-length transcript. These results indicate that four
      distinct proteins are encoded by the human ALK7 gene. Both reverse transcription
      PCR and Western blot analysis showed that ALK7 and its isoforms are expressed in
      human placentae of different stages of pregnancy and that their expression is
      developmentally regulated. In addition, mRNA expression of Nodal, a ligand for
      ALK7, was also detected in placentae of different gestational age. The role of
      Nodal and ALK7 in human placenta is currently under investigation.

PMID- 12606402
TI  - Regulated expression of inhibitor of apoptosis protein 3 in the rat corpus
      luteum.
AB  - We sought to investigate the role inhibitor of apoptosis proteins (IAPs) play in
      the life cycle of the corpus luteum (CL) of the rat. We isolated two clones with
      amino acid homology to rat IAP2 (BIRC 3) and three to rat IAP3 (rIAP3; BIRC 4).
      The expression of rIAP3 mRNA was examined in the rat CL during and after
      pregnancy, in Day 8 pregnant rats after 24-h treatment of gonadotropin-releasing
      hormone-agonist (GnRH-Ag), and in a CL organ culture model of spontaneous
      apoptosis in the absence of tropic support with and without superoxide dismutase.
      We used real-time RT-PCR to quantitate rIAP3 mRNA expression. Interestingly, a
      significant reduction in rIAP3 levels was seen at the time of CL regression in
      the course of natural pregnancy and the GnRH-Ag model. Surprisingly, rIAP3 mRNA
      levels in the CL organ culture model of spontaneous apoptosis failed to show
      significant changes, although TUNEL (terminal deoxynucleotide transferase
      mediated dUTP nick end-labeling) reaction showed 30%-40% of the cells undergoing
      DNA fragmentation after 2 h in culture. In situ hybridization revealed that rIAP3
      expression was localized to the cytoplasm of luteal and granulosa cells. These
      data clearly demonstrate both the presence of IAPs in the rat CL and the
      regulation of rIAP3 during in vivo apoptotic cell death, indicating a role for
      IAPs in the maintenance of CL function and demise.

PMID- 12606403
TI  - Telomerase-immortalized sheep fibroblasts can be reprogrammed by nuclear transfer
      to undergo early development.
AB  - Telomere shortening and lack of telomerase activity have been implicated in
      cellular senescence in human fibroblasts. Expression of the human telomerase
      catalytic reverse transcriptase subunit (hTERT) in these cells reconstitutes
      telomerase activity and immortalizes the cells without tumor transformation. In
      this report, we show that sheep fibroblasts are similar to human cells. They do
      not have detectable telomerase activity and undergo only a finite numbers of cell
      divisions before replicative senescence. Telomere lengths in sheep fibroblasts
      are similar to those reported for human cells and shorten at a rate of 50-200
      base pairs (bp) each cell division. Expression of the human telomerase catalytic
      subunit restored the telomerase activity in the sheep cells and extended their
      proliferative life span. None of the telomerase positive sheep fibroblasts
      exhibited a transformed phenotype after 200 days of continuous culture, and the
      higher hTERT expressing cells maintained their telomere lengths and normal cell
      characteristics for more than 500 days in culture. In cloning experiments using
      one of these cell lines as a nuclear donor, the reconstructed karyoplasts were
      reprogrammed and developed to the blastocyst stage at a similar frequency to that
      observed with the parental, telomerase negative cell line. After embryo transfer
      the blastocysts exhibited a relatively high frequency of implantation, early
      fetal development, and organogenesis. No fetuses survived beyond 40 days of
      development, however, showing that although these cells could be substantially
      reprogrammed, they were not fully competent for nuclear transfer.

PMID- 12606404
TI  - Increment of murine spermatogonial cell number by gonadotropin-releasing hormone
      analogue is independent of stem cell factor c-kit signal.
AB  - Recent studies have demonstrated that GnRH-analogues can stimulate regeneration
      of spermatogenesis of rats when administered after testicular damages. Although
      the mechanism of this phenomenon has not been elucidated yet, stem cell factor
      (SCF) produced by Sertoli cells was proposed to mediate the effects of GnRH
      analogues on spermatogonial proliferation and/or survival. In the present study,
      we quantitatively evaluated the proliferation of spermatogonia and addressed
      whether SCF mediates the effect of GnRH-analogue on spermatogonial proliferation,
      using a novel approach combining spermatogonial transplantation and laser
      confocal microscopic observation. In the first experiment, using wild-type mice
      as recipients for spermatogonial transplantation, the number of donor
      spermatogonia per 100 Sertoli cells in each spermatogenic colony was
      significantly higher in the experimental group of mice treated with leuprorelin,
      a GnRH-agonist, than that of the control group at 4 and 5 wk after
      transplantation. In the second experiment, Steel/Steeldickie (Sl/Sld) mutant
      mice, which lack expression of membrane bound form SCF, were used as recipients.
      As seen in the first experiment, the number of undifferentiated spermatogonia was
      significantly higher in leuprorelin-treated than in the control group. Since
      undifferentiated spermatogonia do not express the receptor of SCF, the present
      study clearly demonstrates that neither membrane-bound nor secreted forms of SCF
      are involved in the mechanism of GnRH-analogue's effect on spermatogonial
      proliferation and/or survival.

PMID- 12606405
TI  - Ovarian dynamics and their associations with peripheral concentrations of
      gonadotropins, ovarian steroids, and inhibin during the estrous cycle in goats.
AB  - Ovarian changes determined by daily transrectal ultrasound and its relationship
      with FSH, LH, estradiol-17beta, progesterone, and inhibin were investigated in
      six goats for three consecutive interovulatory intervals. Estrous cycles were
      synchronized using two injections of prostaglandin F2alpha analogue 11 days
      apart. All follicles 3 mm or greater in diameter and corpora lutea were measured
      daily. A follicular wave was defined as one or more follicles growing to 5 mm or
      greater in diameter. The day that the follicles reached 3 mm in diameter was
      defined as the day of wave emergence, and the first wave after ovulation was
      defined as wave 1. During the interovulatory interval (mean +/- SEM, 21.3 +/- 0.4
      days; n = 18), follicular waves emerged at 0.3 +/- 0.5, 6.5 +/- 0.2, and 12.1 +/-
      0.4 days for wave 1, wave 2, and wave 3, respectively, in goats with three waves
      of follicular development and at -0.6 +/- 0.3, 4.7 +/- 0.2, 9.4 +/- 0.5, and 13.4
      +/- 0.5 days for wave 1, wave 2, wave 3, and wave 4, respectively, in goats with
      four waves of follicular development (Day 0 = the day of ovulation). The mean
      diameter of the largest follicle of the ovulatory wave was significantly larger
      than those of the largest follicles of the other waves. Corpora lutea could be
      identified ultrasonically at Day 3 postovulation and attained 12.1 +/- 0.3 mm in
      diameter on Day 8. Transient increases in plasma concentrations of FSH were
      detected around the day of follicular wave emergence. The level of FSH was
      negatively correlated with that of inhibin. These results demonstrated that
      follicular waves occurred in goats and that the predominant follicular wave
      pattern was four waves with ovulation from wave 4. These results also suggested
      that the emergence of follicular waves was closely associated with increased
      secretion of FSH.

PMID- 12606406
TI  - Porcine spermadhesin PSP-I/PSP-II stimulates macrophages to release a neutrophil
      chemotactic substance: modulation by mast cells.
AB  - The complex of porcine seminal plasma heterodimers I and II (PSP-I/PSP-II), which
      are heterodimers of glycosylated spermadhesins, is the major component of porcine
      seminal fluid. The proinflammatory and immunostimulatory activities of this
      spermadhesin complex suggest its participation in modulation of the uterine
      immune activity that may ensure reproductive success. Spermadhesin PSP-I/PSP-II
      induced the migration of neutrophils into the peritoneal cavity of rats via
      activation of resident cells. In the present study, we have investigated the
      involvement of macrophages and mast cells in the neutrophil chemotactic activity
      of PSP-I/PSP-II and the underlying mechanism. Macrophages and mast cells were
      isolated, cultured, and stimulated with purified PSP-I/PSP-II. Pharmacological
      modulation was performed using the glucocorticoid dexamethasone, indomethacin
      (cyclooxygenase inhibitor), MK886 (leukotriene inhibitor), and the supernatant of
      spermadhesin-stimulated mast cells. Macrophages stimulated with PSP-I/PSP-II
      released into the culture supernatant a neutrophil chemotactic substance. This
      activity was partly inhibited by both dexamethasone (85%) and the supernatant of
      spermadhesin-stimulated mast cells (74%) but not by indomethacin and MK886. An
      anti-tumor necrosis factor (TNF) alpha antibody neutralized (by 68%) the
      neutrophil chemotactic activity of PSP-I/PSP-II-stimulated macrophages. An anti
      interleukin (IL)-4 antibody blocked the inhibitory activity of spermadhesin
      stimulated mast cells on release of a neutrophil chemotactic substance by PSP
      I/PSP-II-stimulated macrophages. As a whole, these data indicate that the
      neutrophil migration-inducing ability of spermadhesin PSP-I/PSP-II involves the
      release of the inflammatory cytokine TNFalpha by stimulated macrophages and that
      this activity is modulated by the lymphokine IL-4 liberated by mast cells. The
      balance between these two cytokines may control onset of the local inflammatory
      reaction, avoiding excessive neutrophil recruitment that would lead to tissue
      damage.

PMID- 12606407
TI  - Evidence suggesting that the mouse sperm acrosome reaction initiated by the zona
      pellucida involves an alpha7 nicotinic acetylcholine receptor.
AB  - The mammalian sperm acrosome reaction (AR) is essential to fertilization and is
      believed to be initiated in vivo by ZP3, a glycoprotein component of the egg zona
      pellucida (ZP). Recently, we reported the results of antagonist studies
      suggesting that a nicotinic acetylcholine receptor (nAChR) containing an alpha7
      subunit (alpha7nAChR) plays a role in the human sperm AR initiated by recombinant
      human ZP3 or by acetylcholine (ACh). Here, we show that ACh can initiate the
      mouse sperm AR and that antagonists of the nAChR inhibit the AR initiated by ACh
      or by ZP obtained from ovarian oocytes (isolated heat-solubilized mouse ZP).
      Preincubation with three antagonists of the nAChR, alpha-bungarotoxin (100 nM),
      alpha-conotoxin IMI (100 nM), and methyllycaconitine (100 nM), significantly
      blocked AR initiation by ACh or by isolated heat-solubilized mouse ZP (P </=
      0.002). Because the only nAChR subunit known to bind all three antagonists is the
      alpha7, an alpha7nAChR appears to be involved in the mouse sperm AR initiated by
      mouse ZP or by ACh. The nAChR antagonists did not inhibit the AR initiated by
      calcium ionophore A23187, suggesting that the role of alpha7nAChR is upstream
      from Ca2+ influx. Pertussis toxin (PTX, 100 ng/ml) did not inhibit the AR
      initiated by ACh, suggesting that the alpha7nAChR might be a candidate for the
      PTX-insensitive, poorly selective cation channel shown previously to play a role
      in ZP-initiated mouse sperm AR. These studies with mouse sperm and ovary-derived
      ZP strongly support our previous conclusion that activation of an alpha7nAChR is
      important to the mammalian AR initiated by the egg ZP.

PMID- 12606408
TI  - Type II and type IX collagen transcript isoforms are expressed during mouse
      testis development.
AB  - Mutations in the transcription factor SOX9 give rise to campomelic dysplasia, a
      syndrome characterized by skeletal abnormalities and XY sex reversal. Sox9 is
      expressed at sites of chondrogenesis and in the developing testis, and, thus, it
      plays a role in two overtly different pathways of differentiation. Previous
      studies have identified the gene for type II collagen, Col2a1, as a target of
      Sox9 in mouse chondrocytes and implicated Col9a3 as a Sox9 target in testis.
      Using differential expression analysis combined with reverse transcription
      polymerase chain reaction and whole-mount in situ hybridization, we have
      identified nonchondrocytic collagen transcript isoforms that are expressed in the
      early male mouse gonad. Male-specific, gonadal expression of nonchondrocytic
      Col2a1 was first seen at 11.5 days postcoitum (dpc) and was undetectable by 13.5
      dpc. This was accompanied by increasing expression of nonchondrocytic Col9a1,
      Col9a2, and Col9a3, first detected at 11.5 dpc. Expression was analyzed in testes
      that had been depleted of germ cells by the cytotoxic drug busulfan. These
      studies showed Col9a3 and Col2a1 to be expressed in Sertoli cells within the
      developing testis cords. Nonchondrocytic type II collagen contains a cysteine
      rich domain that has been shown to bind members of the transforming growth factor
      beta superfamily of signaling molecules. Thus, this interaction may play a role
      in the morphogenesis and differentiation of the testis.

PMID- 12606409
TI  - Male axillary extracts contain pheromones that affect pulsatile secretion of
      luteinizing hormone and mood in women recipients.
AB  - Human underarm secretions, when applied to women recipients, alter the length and
      timing of the menstrual cycle. These effects are thought to arise from exposure
      to primer pheromones that are produced in the underarm. Pheromones can affect
      endocrine (primer) or behavioral (releaser) responses, provide information
      (signaler), or perhaps even modify emotion or mood (modulator). In this study, we
      extracted underarm secretions from pads worn by men and placed the extract under
      the nose of women volunteers while monitoring serum LH and emotion/mood. Pulses
      of LH are excellent indicators of the release of GnRH from the brain's
      hypothalamus. In women, the positive influence of GnRH on LH affects the length
      and timing of the menstrual cycle, which, in turn, affects fertility. Here we
      show that extracts of male axillary secretions have a direct effect upon LH
      pulsing and mood of women. In our subjects, the putative male pheromone(s)
      advanced the onset of the next peak of LH after its application, reduced tension,
      and increased relaxation. These results demonstrate that male axillary secretions
      contain one or more constituents that act as primer and modulator pheromones.

PMID- 12606411
TI  - Endothelial cell proliferation in male reproductive organs of adult rat is high
      and regulated by testicular factors.
AB  - Endothelial cells in the intact adult are, apart from those in the female
      reproductive organs, believed to be quiescent. Systematic examination of
      endothelial cell proliferation in male reproductive organs has not been performed
      and was therefore the aim of the present study. Intact adult rats were either
      pulse labeled or long-term labeled with bromodeoxyuridine to label proliferating
      cells. The roles of Leydig cells and testosterone were examined after castration
      or treatment with the Leydig cell toxin ethane dimethane sulfonate (EDS) and
      testosterone substitution. After perfusion fixation, all blood vessels remained
      open and were easily identified. In all male reproductive organs studied,
      particularly in the testis and epididymis, endothelial cell proliferation was
      considerably higher than in other tissues such as the liver, brain, and muscle.
      Proliferating endothelial cells were observed in all types of blood vessels in
      male reproductive organs, but other characteristics of new blood vessel formation
      were not seen. High endothelial cell proliferation may reflect a continuous high
      turnover of endothelial cells rather than classical angiogenesis. In the
      epididymis, the ventral and dorsolateral prostate lobes, and the seminal
      vesicles, endothelial cell proliferation decreased after testosterone withdrawal
      and increased following testosterone treatment. In the testis, endothelial cell
      proliferation was decreased after Leydig cell depletion but remained low after
      testosterone substitution. High, hormonally regulated endothelial cell
      proliferation is not unique to the female but is also seen in the male
      reproductive organs.

PMID- 12606410
TI  - Nitric oxide regulates the phosphorylation of the threonine-glutamine-tyrosine
      motif in proteins of human spermatozoa during capacitation.
AB  - Reactive oxygen species (superoxide anion, hydrogen peroxide, and nitric oxide)
      are involved in human sperm capacitation and associated tyrosine (Tyr)
      phosphorylation through a cAMP- and protein kinase A-mediated pathway. Recently,
      we evidenced the double phosphorylation of the threonine-glutamine-Tyr motif (P
      Thr-Glu-Tyr-P) in human sperm proteins of 80 and 105 kDa during capacitation. The
      objective of the present study was to investigate the role of reactive oxygen
      species in the regulation of this process and to immunolocalize the P-Thr-Glu-Tyr
      P motif in human spermatozoa. Superoxide dismutase and catalase did not prevent,
      and exogenous addition of superoxide anion or hydrogen peroxide did not trigger,
      the increase in P-Thr-Glu-Tyr-P related to sperm capacitation. However, l-NAME (a
      competitive inhibitor of l-arginine for nitric oxide synthase) prevented, and a
      nitric oxide donor promoted, the increase in P-Thr-Glu-Tyr-P related to sperm
      capacitation. In addition, l-arginine reversed the inhibitory effect of l-NAME on
      capacitation and the associated increase of P-Thr-Glu-Tyr-P. Therefore, the
      regulation of P-Thr-Glu-Tyr-P is specific to nitric oxide and not to superoxide
      anion or hydrogen peroxide. The nitric oxide-mediated increase of P-Thr-Glu-Tyr-P
      involved protein Tyr kinase, MEK or MEK-like kinase, and protein kinase C but not
      protein kinase A. The P-Thr-Glu-Tyr-P motif was immunolocalized to the principal
      piece region of spermatozoa. In conclusion, nitric oxide regulates the level of P
      Thr-Glu-Tyr-P in sperm proteins of 80 and 105 kDa during capacitation. These data
      evidence, to our knowledge for the first time, a specific role for nitric oxide
      in signal transduction events leading to sperm capacitation.

PMID- 12606412
TI  - Demecolcine-induced oocyte enucleation for somatic cell cloning: coordination
      between cell-cycle egress, kinetics of cortical cytoskeletal interactions, and
      second polar body extrusion.
AB  - Studies were designed to further explore the use of pharmacological agents to
      produce developmentally competent enucleated mouse oocytes for animal cloning by
      somatic cell nuclear transfer. Metaphase II oocytes from CF-1 and B6D2F1 strains
      were activated with ethanol and subsequently exposed to demecolcine at various
      times postactivation. Chromosome segregation, spindle dynamics, and polar body
      (PB) extrusion were monitored by fluorescence microscopy using DNA-, microtubule
      , and microfilament-selective probes. Exposure to demecolcine did not affect
      rates of oocyte activation induced by ethanol but did disrupt the coordination of
      cytokinesis and karyokinesis, suppressing the extent and completion of spindle
      rotation and second PB extrusion in a strain-dependent manner. Moreover, strain-
      and treatment-specific variations in the rate of oocyte enucleation were also
      detected. In particular, CF1 oocytes were more efficiently enucleated relative to
      B6D2F1 oocytes, and demecolcine treatments initiated early after activation
      resulted in higher enucleation rates than when treatment was delayed. The
      observed strain differences are possibly caused by a combination of factors, such
      as the time course of meiotic cell-cycle progression after ethanol activation,
      the degree of spindle rotation, and the extent of second PB extrusion. These
      results suggest that developmentally competent cytoplasts can be produced by
      timely exposure of activated oocytes to agents that disrupt spindle microtubules.
      However, the utility of the demecolcine-induced enucleation protocol will require
      further investigation into factors linking karyokinesis to cytokinesis at the
      levels of cell-cycle control and oocyte cytoskeletal remodeling following
      artificial or natural means of egg activation.

PMID- 12606413
TI  - Chronic intermittent cold stress activates ovarian sympathetic nerves and
      modifies ovarian follicular development in the rat.
AB  - We studied the effects of a chronic intermittent cold stress regime on
      sympathetic nerve activation and ovarian physiology. This paradigm (4 degrees C
      for 3 h/day, Monday-Friday, for 3 or 4 wk) does not affect basal plasma levels of
      corticosterone. After 3 wk of stress, we detected a decrease in noradrenaline
      (NA) in the ovary, but after 4 wk, this ovarian neurotransmitter concentration
      increased over that of unstressed control rats. To analyze whether this effect on
      NA is preceded by an activation of the neurotrophic factor system responsible for
      growth and survival of sympathetic neurons, we measured both nerve growth factor
      (NGF) (by enzyme immunoassay) and the intraovarian levels of its low affinity
      receptor mRNA (by reverse transcription-polymerase chain reaction). The
      activation of sympathetic nerves was followed by an increase in NGF concentration
      without affecting the ovarian levels of either NGF or the mRNA of its receptor.
      Interestingly, follicular development changed during the stress procedure; after
      3 or 4 wk of stress, we found a decrease in preantral healthy follicles without a
      compensatory increase in atresia. Concomitantly with the increase in NA and NGF
      in the ovary, we observed that a new population of follicles with hypertrophied
      thecal cell layers appeared after 4 wk of stress. These results suggest that
      chronic stress, through an intraovarian neurotrophin-mediated sympathetic
      activation, produces changes in follicular development that could lead to an
      impairment of reproductive function.

PMID- 12606414
TI  - Clonogenic culture of normal spermatogonia: in vitro regulation of postnatal germ
      cell proliferation.
AB  - The stem cell properties of neonatal germ cells have recently been demonstrated
      by in vivo transplantation. Regulation of proliferation of these cells, however,
      is not yet understood, and an in vitro system is needed for directly testing the
      action of differentiation and proliferation-related factors for germ cells. We
      developed an in vitro model involving micromanipulation and a single-cell
      clonogenic assay in which results from independent experiments on spermatogonia
      and gonocytes have been analyzed and compared. Neonatal germ cells can be
      distinguished by their large size both in vivo and in vitro in a single-cell
      suspension. These cells are picked up singly using a micropipette and deposited
      into a 96-well plate precoated with an extracellular matrix component, e.g.,
      collagen IV. The effect of growth factors or cocultured somatic cells was assayed
      by counting the percentage of wells containing a colony and comparing this
      percentage with that of control cultures. Addition of platelet-derived growth
      factor significantly shifted the modal colony size for gonocytes from >16-64 to
      >64-128 cells/colony (P < 0.001, chi2) but had no effect on spermatogonia-derived
      colony size and number. For testis somatic cell underlays, there was a profound
      inhibition of all colony types, and immunohistochemical staining of testis cell
      underlays showed inhibin/activinbetaA subunit expression. This finding suggests
      that negative regulation of germ cell proliferation is mediated by inhibin.
      Addition of activin A to these cultures resulted in significant recovery (P =
      0.046) of gonocyte-derived colony numbers but not spermatogonia-derived colonies,
      which may reflect the functional regulation by these factors observed in vivo.
      This proliferation assay also highlights many similarities in the regulation of
      gonocyte and spermatogonia proliferation in vitro, suggesting that proliferation
      potential is not noticeably affected by the transition of gonocytes to
      spermatogonia. For example, the average colony cloning efficiency was 80% for
      gonocytes and 76% for spermatogonia. This technology forms a basis for optimizing
      growth of neonatal germ cells for applications such as introduction of genetic
      material into the germ line to produce transgenic mice and to explore gene
      therapy.

PMID- 12606415
TI  - INSL3 ligand-receptor system in the equine testis.
AB  - We employed molecular and immunological techniques to investigate the expression
      of INSL3, a member of the insulin-like superfamily, in prepubertal testis,
      postpubertal testes exhibiting normal and disturbed spermatogenesis, and
      cryptorchid testes of male horses. In addition, the partial cDNA coding sequences
      of the equine homologue of the human relaxin/INSL3-receptor Lgr8 were determined.
      Nonradioactive in-situ hybridization with a cRNA probe for equine Insl3 and
      immunohistochemistry with a specific rabbit INSL3 antiserum localized Insl3
      transcripts and immunoreactive INSL3 ligand to Leydig cells in all types of
      testes investigated. Quantitative polymerase chain reaction analysis revealed a
      down-regulation of Insl3 and an up-regulation of the relaxin/INSL3-receptor
      expression in unilateral cryptorchid versus descended testes. Western blot
      analysis of protein extracts from adult normal and cryptorchid testes and
      prepubertal testes showed a single immunoreactive band at 14.5 kDa, which
      correlates with the predicted size of equine proINSL3. Densitometric analysis of
      Western blot data of adult normal testes revealed significantly stronger
      expression of immunoreactive proINSL3 as compared to extracts derived from
      cryptorchid or prepubertal testes. Thus, decreased expression of immunoreactive
      INSL3 in cryptorchid and prepubertal equine testis is transcriptionally
      regulated. The detection of transcripts for equine Lgr8 in the testis has
      identified the testis as a potential target of INSL3.

PMID- 12606416
TI  - EP2 splicing variants in rhesus monkey (Macaca mulatta) epididymis.
AB  - The expression pattern of EP2 variants was examined in the rhesus monkey (Macaca
      mulatta). Using reverse transcriptase-polymerase chain reaction and rapid
      amplification of complementary cDNA protocols, 11 message variants were
      identified in rhesus epididymis, only three of which (EP2B, EP2C, and EP2E) have
      previously been reported. The most abundant variant found in human, EP2A, was not
      found in rhesus. Seven of the eight new rhesus EP2 variants (EP2J-EP2Q) use
      previously unidentified 5'-splicing sites in exon 3, and four variants use three
      previously unidentified exons whose counterparts are present in the human EP2
      gene. Overall, 3 of the 11 variants, EP2C, EP2E, and EP2Q, code for beta-defensin
      like peptides whose probable physiological role is to protect the male
      reproductive tract against microbial invasions. Because of the complex splicing
      pattern that causes some downstream exons to be read in any of the three reading
      frames, the N-termini of the other eight EP2 peptide variants consist of a
      partial beta-defensin motif with three cysteines, followed by amino acid
      sequences that have no recognizable homology to known proteins.

PMID- 12606417
TI  - Administration of a nitric oxide synthase inhibitor counteracts prostaglandin F2
      induced luteolysis in cattle.
AB  - The objective of this study was to determine whether nitric oxide (NO) is
      produced locally in the bovine corpus luteum (CL) and whether NO mediates
      prostaglandin F2alpha (PGF2alpha)-induced regression of the bovine CL in vivo.
      The local production of NO was determined in early I, early II, mid, late, and
      regressed stages of CL by determining NADPH-d activity and the presence of
      inducible and endothelial NO synthase immunolabeling. To determine whether
      inhibition of NO production counteracts the PGF2alpha-induced regression of the
      CL, saline (10 ml/h; n = 10) or a nonselective NOS inhibitor (Nomega-nitro-l
      arginine methyl ester dihydrochloride [L-NAME]; 400 mg/h; n = 9) was infused for
      2 h on Day 15 of the estrous cycle into the aorta abdominalis of Holstein/Polish
      Black and White heifers. After 30 min of infusion, saline or cloprostenol, an
      analogue of PGF2alpha (aPGF2alpha; 100 microg) was injected into the aorta
      abdominalis of animals infused with saline or L-NAME. NADPH-diaphorase activity
      was present in bovine CL, with the highest activity at mid and late luteal stages
      (P < 0.05). Inducible and endothelial NO synthases were observed with the
      strongest immunolabeling in the late CL (P < 0.05). Injection of aPGF2alpha
      increased nitrite/nitrate concentrations (P < 0.01) and inhibited P4 secretion (P
      < 0.05) in heifers that were infused with saline. Infusion of L-NAME stimulated
      P4 secretion (P < 0.05) and concomitantly inhibited plasma concentrations of
      nitrite/nitrate (P < 0.05). Concentrations of P4 in heifers infused with L-NAME
      and injected with aPGF2alpha were higher (P < 0.05) than in animals injected only
      with aPGF2alpha. The PGF2alpha analogue shortened the cycle length compared with
      that of saline (17.5 +/- 0.22 days vs. 21.5 +/- 0.65 days P < 0.05). L-NAME
      blocked the luteolytic action of the aPGF2alpha (22.6 +/- 1.07 days vs. 17.5 +/-
      0.22 days, P < 0.05). These results suggest that NO is produced in the bovine CL.
      NO inhibits luteal steroidogenesis and it may be one of the components of an
      autocrine/paracrine luteolytic cascade induced by PGF2alpha.

PMID- 12606418
TI  - FOG-2 and GATA-4 Are coexpressed in the mouse ovary and can modulate mullerian
      inhibiting substance expression.
AB  - Transcription factor GATA-4 has been suggested to have a role in mammalian
      gonadogenesis, e.g., through activation of the Mullerian-inhibiting substance
      (MIS) gene expression. Although the expression of GATA-4 during gonadogenesis has
      been elucidated in detail, very little is known about FOG-2, an essential
      cofactor for GATA-4, in ovarian development. We explored in detail the expression
      of FOG-2 and GATA-4 in the fetal and postnatal mouse ovary and in the fetal
      testis using Northern blotting, RNA in situ hybridization, and
      immunohistochemistry. GATA-4 and FOG-2 are evident in the bipotential urogenital
      ridge, and their expression persists in the fetal mouse ovary; this result is
      different from earlier reports of GATA-4 downregulation in the fetal ovary. In
      contrast to ovary, FOG-2 expression is lost in the fetal Sertoli cells along with
      the formation of the testicular cords, leading to the hypothesis that FOG-2 has a
      specific role in the fetal ovaries counteracting the transactivation of the MIS
      gene by GATA-4. In vitro transfection assays verified that FOG-2 is able to
      repress the effect of GATA-4 on MIS transactivation in granulosa cells. In
      postnatal ovary, granulosa cells of growing follicles express FOG-2, partially
      overlapping with the expression of MIS. These data suggest an important role for
      FOG-2 and the GATA transcription factors in the developing ovary.

PMID- 12606419
TI  - Structural features of sterols required to inhibit human sperm capacitation.
AB  - Ejaculated mammalian sperm must undergo a final maturation (capacitation) before
      they can acrosome-react and fertilize eggs. Loss of cholesterol is an essential
      step in the capacitation of human sperm. Experimentally maintaining a high level
      of cholesterol inhibits capacitation, but the mechanism is unknown. The present
      study investigated the structural features that are required for cholesterol's
      inhibitory activity. Human sperm also contain much desmosterol, which is lost
      from sperm during capacitation. Preventing the loss of desmosterol inhibited
      capacitation (as assessed by acrosomal responsiveness), with an effectiveness
      approximately equal to cholesterol's inhibitory activity. Other structural
      analogs were added to the incubation medium to replace sperm cholesterol and
      desmosterol. Most inhibited capacitation, including those that lacked
      cholesterol's 3beta-OH group (cholesteryl methyl ether and epicholesterol) and
      those with modified C17 groups (ergosterol and diosgenin). Two steroids did not
      inhibit capacitation well. Coprostanol, which has a nonplanar steroid nucleus,
      had low inhibitory activity that could be explained by an elevated endogenous
      cholesterol concentration. Epicoprostanol, which has a nonplanar ring structure
      and a 3alpha-OH group, promoted rather than inhibited capacitation. The
      inhibitory activity of the analogs was correlated with their ability to promote
      order of egg phosphatidylcholine as measured by fluorescence anisotropy. In
      summary, a planar ring structure is required for sterol inhibitory activity, but
      a 3beta-OH group and a saturated cholesterol-like aliphatic tail on C17 are not
      required. The present results support the hypothesis that sperm sterols block
      capacitation by increasing order of phospholipids.

PMID- 12606420
TI  - Cloned mice derived from embryonic stem cell karyoplasts and activated cytoplasts
      prepared by induced enucleation.
AB  - Our objective was to induce enucleation (IE) of activated mouse oocytes to yield
      cytoplasts capable of supporting development following nuclear transfer.
      Fluorescence microscopy for microtubules, microfilaments, and DNA was used to
      evaluate meiotic resumption after ethanol activation and the effect of subsequent
      transient treatments with 0.4 micro g/ml of demecolcine. Using oocytes from
      B6D2F1 (C57BL/6 x DBA/2) donors, the success of IE of chromatin into polar bodies
      (PBs) was dependent on the duration of demecolcine treatment and the time that
      such treatment was initiated after activation. Similarly, variations in
      demecolcine treatment altered the proportions of oocytes exhibiting a reversible
      compartmentalization of chromatin into PBs. Treatment for 15 min begun
      immediately after activation yielded an optimized IE rate of 21% (n = 80) when
      oocytes were evaluated after overnight recovery in culture. With this protocol,
      30-50% of oocytes were routinely scored as compartmentalized when assessed 90 min
      postactivation. No oocytes could be scored as such following overnight recovery,
      with 66% of treated oocytes cleaving to the 2-cell stage (n = 80). Activated
      cytoplasts were prepared by mechanical removal of PBs from oocytes whose
      chromatin had undergone IE or compartmentalization. These cytoplasts were
      compared with mechanically enucleated, metaphase (M) II cytoplasts whose
      activation was delayed in nuclear transfer experiments using HM-1 embryonic stem
      cells. Using oocytes from either B6D2F1 or B6CBAF1 (C57BL/6 x CBA) donors, the in
      vitro development of cloned embryos using activated cytoplasts was consistently
      inferior to that observed using MII cytoplasts. Live offspring were derived from
      both oocyte strains using the latter, whereas a single living mouse was cloned
      from activated B6CBAF1 cytoplasts.

PMID- 12606421
TI  - Gonadotropin-releasing hormone receptor gene expression during pubertal
      development of male rats.
AB  - Appropriate expression of the GnRH receptor (GnRH-R) in gonadotropes is critical
      for GnRH signaling and hence for gonadotropin secretion and sexual development.
      In the present work, we have studied the ontogeny of the steady-state GnRH-R mRNA
      levels in pituitaries of male rats from Day 5 to Day 55, when sexual maturity is
      attained. Developmental changes of gonadotropin subunit (alpha, FSHbeta, and
      LHbeta) mRNA levels were also assessed. In addition, the role of the endogenous
      GnRH on the maturational changes of GnRH-R and gonadotropin subunit gene
      expression was investigated. Messenger RNA levels were determined by Northern
      blot analysis of total RNA from anterior pituitaries. Amounts of the most
      abundant (5.0 kb) GnRH-R mRNA increased slowly from Day 5 through the infantile
      and the juvenile periods, to peak at Day 35 (12-fold increase vs. Day 5).
      Thereafter, the levels of the GnRH-R mRNA decline slightly until Day 55 (33%
      decrease vs. Day 35). Parallel changes were observed on the 4.5-kb transcript of
      the GnRH-R gene. Alpha subunit mRNA was easily detected at Day 5, and its levels
      increased progressively through the infantile period (2.5-fold increase) and
      peaked at Day 25 (3.3-fold increase vs. Day 5) with a smooth nonstatistically
      significant increment until Day 35; then it decreased by 41.5% at Day 55. FSHbeta
      and LHbeta mRNA levels rose slowly until Day 25. A sharp rise occurred thereafter
      to reach maximum levels at Day 35 (5.8-fold for FSHbeta and 3.8-fold for LHbeta
      vs. Day 25). Thereafter, the levels of both mRNAs fell until Day 55 (44.1%
      decrease for FSHbeta and 37.1% decrease for LHbeta vs. Day 35). To ascertain
      whether developmental activation of the GnRH-R and gonadotropin subunit gene
      expression is GnRH dependent, we have studied the effect of blocking the
      endogenous GnRH action by treating developing male rats with the specific GnRH
      antagonist cetrorelix (1.5 mg/kg body weight/week, s.c.) through the infantile
      (Days 5-20) and the juvenile periods (Days 20-35). Cetrorelix completely blocked
      the rise of levels of the two most abundant species, 5.0 kb and 4.5 kb, of the
      GnRH-R mRNA, during both the infantile and the juvenile periods. Cetrorelix also
      abolished the developmental rise of the gonadotropin beta subunit mRNAs during
      the two periods of the study. In contrast, the alpha subunit gene expression was
      not altered by cetrorelix treatment during any of the two periods. These data
      demonstrate that sexual maturation of male rats is accompanied by a progressive
      and concerted induction of GnRH-R and gonadotropin subunit gene expression.
      Developmental activation of GnRH-R and gonadotropin beta subunit genes is GnRH
      dependent. The apparent GnRH-independent regulation of the alpha-glycoprotein
      subunit mRNA levels may be due to the contribution of thyrotropes and perhaps to
      the presence of exclusive regulatory signals for this gene.

PMID- 12606422
TI  - Developmental, stage-specific, and hormonally regulated expression of growth
      hormone secretagogue receptor messenger RNA in rat testis.
AB  - Recent evidence from our research suggested the direct role of ghrelin in the
      control of testicular function. However, the pattern of expression and hormonal
      regulation of the gene encoding its cognate receptor (i.e., the growth hormone
      secretagogue receptor [GHS-R]) in the male gonad remains to be fully elucidated.
      In this paper, overall expression of GHS-R mRNA in rat testis was compared with
      that of the functional receptor form, namely GHS-R type 1a, in different
      developmental and experimental settings. In addition, cellular distribution of
      GHS-R within adult testis tissue was assessed. Our analyses demonstrated
      persistent expression of the GHS-R gene in rat testis throughout postnatal
      development. In contrast, testicular expression of GHS-R type 1a mRNA remained
      undetectable before puberty and sharply increased thereafter. In adult testis,
      GHS-R1a mRNA expression presented a scattered pattern of cellular distribution,
      including Sertoli and Leydig cells that also showed specific GHS-R1a
      immunoreactivity. Expression of total GHS-R and specific GHS-R1a mRNAs was
      detected in isolated seminiferous tubule preparations, with varying levels
      throughout the defined stages of the spermatogenic cycle. In addition, testicular
      expression of total GHS-R and GHS-R1a mRNAs was up-regulated by exposure to
      ghrelin in vitro and after stimulation with FSH in vivo. In conclusion, our data
      demonstrate that expression of the GHS-R gene in rat testis takes place in a
      developmental, stage-specific, and hormonally regulated manner. Divergent
      expression of total GHS-R and type 1a specific mRNAs was detected at certain
      stages of postnatal development and spermatogenic cycle, thus raising the
      possibility that, in addition to net changes in GHS-R gene expression, the
      balance between receptor subtypes may represent a novel mechanism for the tuning
      of ghrelin sensitivity in rat testis.

PMID- 12606424
TI  - Failure of male pronucleus formation is the major cause of lack of fertilization
      and embryo development in pig oocytes subjected to intracytoplasmic sperm
      injection.
AB  - The objectives of this study were 1) to compare the efficiency of
      intracytoplasmic sperm injection (ICSI) with and without additional artificial
      stimulation using frozen-thawed sperm and in vitro-matured porcine oocytes and 2)
      to determine the nuclear anomalies of ICSI oocytes that failed to fertilize or
      develop. In experiments 1 and 2, we evaluated the effects of additional
      activation treatments, e.g., electrical stimulus, Ca ionophore (A23187), and/or
      cycloheximide, on fertilization and development of ICSI porcine oocytes.
      Significantly higher fertilization, cleavage, and blastocyst rates were obtained
      for oocytes treated with a combination of ICSI and electrical activation (EA) (P
      < 0.05) than for those treated with ICSI alone. However, different combinations
      of electrical and chemical activation treatments did not further improve the
      rates of fertilization, cleavage, and blastocyst development for ICSI embryos. To
      elucidate the association between sperm head decondensation and oocyte activation
      and to investigate the cause of embryonic development failure, in experiment 3 we
      evaluated the nuclear morphology of oocytes 16-20 h after ICSI. Nearly 100% of
      oocytes showed female pronucleus formation after ICSI regardless of activation
      treatment. However, failure of male pronucleus formation with intact or swelling
      sperm heads was observed in some ICSI embryos, suggesting that these embryos
      underwent cell division with the female pronucleus only. Artificial activation
      (EA and A23187) had a beneficial effect on embryonic development, sperm
      decondensation was independent of the resumption of meiosis, and the failure of
      formation of a male pronucleus was the major cause for fertilization failure in
      porcine ICSI embryos.

PMID- 12606423
TI  - A chemokine, interferon (IFN)-gamma-inducible protein 10 kDa, is stimulated by
      IFN-tau and recruits immune cells in the ovine endometrium.
AB  - Proper distribution of immune cells in the uterus is a prerequisite for
      successful implantation and subsequent placentation, but biochemical signals that
      govern such events have not been well characterized. In the present study, the
      cDNA of a chemokine, interferon (IFN)-gamma-inducible protein 10 kDa (IP-10), was
      identified from a cDNA subtraction study between uterine endometrial tissues from
      Day 17 pregnant and Day 15 cyclic ewes. The effect of IFN-tau on IP-10 expression
      and the involvement of IP-10 in the recruitment of immune cells were then
      investigated. Northern blot analysis revealed that large amounts of IP-10 mRNA
      were present during conceptus attachment to maternal endometrium and early
      placentation. IP-10 mRNA was localized to monocytes distributed in the
      subepithelial stroma of pregnant but not cyclic uteri. This finding was supported
      by the discovery of IP-10 mRNA expression in monocytes but not in lymphocytes,
      uterine epithelial cells, or stromal cells. Moreover, the expression of IP-10
      mRNA by the monocytes was stimulated by IFN-alpha, IFN-gamma, and IFN-tau in a
      dose-dependent manner, but the expression of IP-10 mRNA by the endometrial
      explants was most stimulated by IFN-tau. In a chemotaxis assay, migration of
      peripheral blood mononuclear cells was stimulated by the addition of IFN-tau
      stimulated-endometrial culture medium, and the effect was significantly reduced
      by neutralization with an anti-IP-10 antibody. These results suggest that
      endometrial IP-10 regulated by conceptus IFN-tau regulates recruitment and/or
      distribution of immune cells seen in the early pregnant uterus.

PMID- 12606425
TI  - Hormonal regulation and cell-specific expression of endothelin-converting enzyme
      1 isoforms in bovine ovarian endothelial and steroidogenic cells.
AB  - Endothelin-converting enzyme 1 (ECE-1) is a key enzyme in the biosynthesis of
      endothelin 1 (ET-1), a potent regulator of ovarian function. Different ECE-1
      isoforms are localized in distinct intracellular compartments. Thus, the spatial
      and temporal pattern of ECE-1 expression determines the site of big ET-1
      activation and the bioavailability of ET-1. This study was undertaken to
      investigate the hormonal regulation and cell-specific expression of ECE-1
      isoforms in endothelial and steroidogenic cells of bovine follicles and corpora
      lutea (CL). Using enriched follicular and luteal cell subpopulations and in situ
      hybridization techniques, we showed that the ECE-1 gene is expressed by both
      endothelial and steroidogenic cells; however, the intracellular ECE-1a isoform
      was present only in ET-1-expressing endothelial cells. Steroidogenic cells in
      follicles or in CL, deficient in ET-1, expressed only the plasma membrane ECE-1b
      isoform. The intensity of antisense ECE-1 labeling in the granulosa cell layer
      increased with follicular size; insulin-like growth factor I and insulin
      upregulated ECE-1 expression when cultured with granulosa cells, suggesting that
      these growth factors may increase ECE-1 in growing follicles. In contrast, ET-1
      and LH downregulated ECE-1 in steroidogenic cells. This effect could account for
      low ECE (and ET-1) levels, which characterize the early luteal phase. These
      findings suggest that ECE-1 is regulated during different stages of the cycle in
      a physiologically relevant manner. The hormonal regulation and intracellular
      localization of bovine ECE-1 isoforms revealed in this study may provide new
      insights into ET-1 biosynthesis and mode of action in different cellular
      microenvironments within the ovary.

PMID- 12606426
TI  - 5alpha-reductase isoenzymes 1 and 2 in the rat testis during postnatal
      development.
AB  - The pubertal initiation of spermatogenesis is reliant on androgens, and during
      this time, 5alpha-reduced androgens such as dihydrotestosterone (DHT) are the
      predominant androgens in the testis. Two 5alpha-reductase (5alphaR) isoenzymes
      (5alphaR1 and 5alphaR2) have been identified, which catalyze the conversion of
      testosterone to the more potent androgen DHT. The present study aimed to
      investigate the developmental pattern of 5alphaR isoenzymes and their
      relationship to the production of 5alpha-reduced androgens in the postnatal rat
      testis. Both 5alphaR1 and 5alphaR2 isoenzyme mRNAs were measured by real-time
      polymerase chain reaction, isoenzyme activity levels by specific assays, and
      testicular androgens by radioimmunoassay after high-performance liquid
      chromatographic separation. Both 5alphaR1 and 5alphaR2 mRNAs and activity levels
      were low in the 10-day-old (prepubertal) testis, peaked between Days 20 and 40
      during puberty, and then declined to low levels at 60-160 days of age. The
      developmental pattern of both 5alphaR isoenzyme activity levels was mirrored by
      the testicular production of 5alpha-reduced metabolites. Although 5alphaR1 was
      greater than 5alphaR2 at all ages, it is likely, given the substrate preferences
      of the two, that both isoenzymes contribute to the pubertal peak of 5alpha
      reduced androgen biosynthesis. The peak in 5alphaR isoenzymes and 5alpha-reduced
      metabolite production coincided with the first wave of spermatogenesis in the
      rat, suggesting a role for 5alpha-reduced metabolites in the initiation of
      spermatogenesis. This was explored by acute administration of a 5alphaR inhibitor
      (L685,273) to immature rats. The L685,273 markedly suppressed testicular 5alphaR
      activity during puberty by 75%-86%. However, a marked increase was observed in
      testicular testosterone levels (in the absence of changes in LH), and no decrease
      was observed in the absolute levels of 5alpha-reduced metabolites. Therefore,
      whether the formation of DHT in the presence of low testosterone levels in the
      pubertal testis is required for the initiation of spermatogenesis cannot be
      tested using 5alphaR inhibitors. We conclude that both 5alphaR1 and 5alphaR2
      isoenzymes are involved in the peak of 5alpha-reduced androgen biosynthesis in
      the testis during the pubertal initiation of spermatogenesis.

PMID- 12606427
TI  - Insulin-like growth factor binding protein 4 expression parallels luteinizing
      hormone receptor expression and follicular luteinization in the primate ovary.
AB  - It has been suggested that locally produced insulin-like growth factor binding
      protein 4 (IGFBP4) inhibits ovarian follicular growth and ovulation by
      interfering with IGF action. According to this hypothesis, IGFBP4-expressing
      follicles should demonstrate atresia, whereas healthy dominant follicles should
      be devoid of IGFBP4. Alternatively, according to this view, there could be
      constitutive expression of the inhibitory IGFBP4 but selective expression of an
      IGFBP4 protease in dominant follicles, allowing the follicle to mature and
      ovulate because of degradation of the binding protein. To examine these views
      concerning the role of IGFBP4 in primate follicular selection, we analyzed
      cellular patterns of IGFs 1 and 2, IGFBP4, and the IGFBP4 protease (pregnancy
      associated plasma protein A [PAPP-A]) mRNA expression in ovaries from late
      follicular phase rhesus monkeys using in situ hybridization. The IGF1 mRNA was
      not detected, but the IGF2 mRNA was abundant in theca interna and externa of all
      antral follicles and was present in the granulosa of large preovulatory and
      ovulatory follicles. The IGFBP4 mRNA was selectively expressed by LH receptor
      (LHR) mRNA-positive theca interna cells of healthy antral follicles (defined by
      aromatase and gonadotropin receptor expression) and by LHR-expressing granulosa
      cells found only in large preovulatory and ovulatory follicles (defined by size
      and aromatase expression). The PAPP-A mRNA was abundant in granulosa cells of
      most follicles without obvious relation to IGFBP4 expression. Ovarian IGFBP4 mRNA
      levels were markedly increased after treatment with the LH analog, hCG, whereas
      IGF2 and PAPP-A mRNAs were not significantly altered. In summary, IGFBP4
      expression appears to be associated with follicular selection, not with atresia,
      in the monkey ovary. The IGFBP4 is consistently expressed in healthy theca
      interna and in luteinized granulosa cells, likely under LH regulation. The IGFBP4
      protease, PAPP-A, is widely expressed without apparent selectivity for IGFBP4
      expressing follicles or for dominant follicles. These observations suggest that
      IGFBP4 or an IGFBP4 proteolytic product may be involved with LH-induced
      steroidogenesis and/or luteinization rather than with inhibition of follicular
      growth.

PMID- 12606428
TI  - Nitric oxide synthase production and nitric oxide regulation of preimplantation
      embryo development.
AB  - Nitric oxide (NO) production plays an important role in regulating
      preimplantation embryo development. NO is produced from l-arginine by the enzyme
      nitric oxide synthase (NOS), which has three isoforms: endothelial (eNOS),
      neuronal (nNOS), and inducible (iNOS). It has been previously shown that
      inhibition of NO production by NG-nitro-l-arginine (l-NA) inhibits the
      development of two-cell embryos to the four-cell stage. However, excess NO also
      halts embryo development, possibly through the production of free radicals. We
      hypothesize that multiple NOS isoforms are expressed in order to ensure normal
      preimplantation embryo development and that, in this process, NO acts through the
      cGMP pathway. Using reverse transcription-polymerase chain reaction, mRNA for all
      three NOS isoforms was amplified from two-cell, four-cell, morula, and blastocyst
      embryos. However, blastocyst-stage embryos isolated midmorning on Day 4 of
      pregnancy expressed only nNOS and eNOS, whereas those isolated midafternoon again
      expressed all three NOS isoforms. Culture of one-cell embryos in various
      concentrations of Whitten (positive control), S-nitroso-N-acetylpenicillamine
      (SNP, a NO donor), l-NA, and/or 8-Br-cGMP demonstrated that NO is acting, at
      least in part, through cGMP in preimplantation embryo development. In addition,
      we determined that a critical concentration of NO and cGMP is required for normal
      embryo development and deviations from this concentration lead to developmental
      arrest and/or apoptosis of the embryo. This data provides support for a
      requirement of NO in preimplantation embryo development and one mechanism through
      which it regulates mitotic division in these embryos.

PMID- 12606429
TI  - Effects of luteinizing hormone and follicle-stimulating hormone and insulin-like
      growth factor-I on aromatase activity and P450 aromatase gene expression in the
      ovarian follicles of red seabream, Pagrus major.
AB  - To clarify the mechanism of estradiol-17beta production in the ovarian follicle
      of red seabream, in vitro effects of luteinizing hormone (LH), follicle
      stimulating hormone (FSH), and insulin-like growth factor (IGF-I) on aromatase
      activity (conversion of testosterone to estradiol-17beta) and cytochrome P450
      aromatase (P450arom) mRNA expression in ovarian fragments of red seabream were
      investigated. Of the growth factors used in the present study, only IGF-I
      stimulated both aromatase activity and P450arom gene expression in the ovarian
      fragments of red seabream. LH from red seabream pituitary, but not FSH,
      stimulated both aromatase activity and P450arom gene expression. IGF-I slightly
      enhanced the LH-induced aromatase activity and P450arom gene expression. These
      data and our previous results indicate that LH, but not FSH, stimulates estradiol
      17beta production in the ovarian follicle of red seabream through stimulation of
      aromatase activity and P450arom gene expression and IGF-I enhances the LH
      stimulated P450arom gene expression.

PMID- 12606430
TI  - Vascular endothelial growth factor stimulates preantral follicle growth in the
      rat ovary.
AB  - The regulation of preantral follicle growth in mammals is poorly understood. The
      availability of an adequate vascular supply to provide endocrine and paracrine
      signals may be important during the early states of follicle growth as well as
      the later states of follicle selection and dominance. The objective of the
      present study was to investigate whether vascular endothelial growth factor
      (VEGF) plays a role in preantral follicular development in the rat ovary.
      Immature (age, 21 days) Sprague-Dawley rats were injected with 500 ng of VEGF in
      saline or 50 microg of diethylstilbestrol (DES) in oil under the bursa of one
      ovary. The contralateral ovary was injected with a corresponding volume of
      vehicle. Rats were killed 48 h later, and the ovaries were removed and analyzed
      histologically. Intrabursal administration of VEGF significantly increased the
      number of primary and small secondary, but not of large secondary, preantral
      follicles in the ovary, similar to the effect of DES (P < 0.05). The VEGF
      stimulated preantral follicle growth in a time- and dose-dependent manner.
      Subcutaneous DES administration increased the number of primary and secondary
      follicles, and both s.c. and intrabursal estrogen administration stimulated VEGF
      protein expression in the rat ovary. These data indicate that VEGF stimulates
      preantral follicular development in the rat ovary, is regulated by estrogen, and
      may be one of the factors that participate in the regulation of early follicle
      growth in the rat.

PMID- 12606431
TI  - Regulated expression of osteopontin in the peri-implantation rabbit uterus.
AB  - Blastocyst attachment to the lining of the mammalian uterus during early
      implantation involves the initial apposition of the trophoblast to the uterine
      epithelial surface. Osteopontin (OPN) is a glycoprotein component of the
      extracellular matrix that is secreted by the glandular epithelium of mammalian
      uteri at the time of implantation. This protein is recognized by several members
      of the integrin family and promotes cell-cell attachment and adhesion. In the
      present study, rabbit uteri were examined using Northern and in situ
      hybridization to evaluate the temporal and spatial distribution of OPN mRNA
      during early pregnancy. Northern blot analysis demonstrated a dramatic increase
      in OPN expression on Days 4-7 of pregnancy, corresponding to the rise in
      circulating progesterone and the time of initial embryo attachment in this
      species. In situ hybridization analysis revealed OPN mRNA expression on Day 6.75
      of pregnancy, which was most prominent on endometrial epithelium. Using
      immunofluorescence, OPN protein was present on the glandular epithelium on Day
      6.75 of pregnancy, but was absent on blastocysts. Further, no expression of OPN
      mRNA or protein was found in the nonpregnant endometrium. Induction of
      endometrial OPN expression was observed in unmated rabbits treated with
      progesterone alone and was prevented by cotreatment with the antiprogestin
      ZK137.316. Estradiol-17beta had no effect on OPN expression by itself, and
      estrogen priming was not necessary to demonstrate the stimulatory effect of
      progesterone. In The rabbit uterus, as in other mammalian species studied, OPN is
      expressed in a stage-specific manner by the endometrial glands during the peri
      implantation period and is regulated by progesterone.

PMID- 12606432
TI  - Action of gonadotropin-releasing hormone II on the baboon ovary.
AB  - The content, binding affinity, and bioactivity of chicken II GnRH (GnRH II) and a
      stable analogue of GnRH II (GnRH II analogue) in the baboon ovary were studied.
      Although mammalian GnRH is rapidly degraded by baboon ovarian extracts, we
      designed a GnRH II analogue that is stable to ovarian enzymatic degradation. This
      analogue binds to the ovarian membranes with high affinity (41 +/- 3 nM), having
      20-fold the affinity of a potent mammalian GnRH analogue. The bioactivity of GnRH
      II and this GnRH II analogue on the regulation of ovarian progesterone release
      was compared with that for a potent mammalian GnRH analogue using a baboon
      granulosa cell culture system. Both GnRH II and GnRH II analogue produced
      significant inhibition of progesterone release from the granulosa cells (P < 0.03
      and P < 0.005, respectively), with a greater reduction observed using the GnRH II
      analogue. After 24 h in culture, this GnRH II analogue produced a 59% +/- 5%
      inhibition of progesterone with a concentration as low as 1 nM. Maximal
      inhibition of 75% +/- 1% was attained with 10 nM GnRH II analogue. The endogenous
      GnRH II content in the baboon ovary was 5-14 pmoles/g protein. The release of
      endogenous GnRH II from granulosa cells was observed throughout the 48 h in
      culture. These studies demonstrated the presence of high enzymatic activity for
      the degradation of mammalian GnRH in the ovary, whereas this GnRH II analogue was
      stable. High-affinity binding sites for this GnRH II analogue were also found.
      GnRH II and this GnRH II analogue can regulate progesterone production from
      baboon granulosa cells, suggesting that GnRH II is a potent regulator of ovarian
      function.

PMID- 12606433
TI  - Expression of the scaffolding subunit A of protein phosphatase 2A during rat
      testicular development.
AB  - Previously, we found that the poly(A)+ RNA of the scaffolding subunit A (alpha
      isoform) of protein phosphatase 2A (PP2A-Aalpha) was clearly expressed by fetal
      gonocytes but weakly expressed by adult single (As), paired (Apr), and aligned
      (Aal) A spermatogonia. The scaffolding subunit A of PP2A (PP2A-A) is the major
      subunit in the formation of a functional PP2A holoenzyme. In this study, we
      investigated the expression of PP2A-A during testicular development in more
      detail using in situ hybridization, immunohistochemistry, and Western blot with
      testes of rats of various ages from 16 days postcoitum (pc) to adulthood. The
      expression of PP2A-A was detected in fetal proliferative gonocytes at 16 days pc,
      declining thereafter during the quiescent period of the gonocytes. From the day
      of birth to the start of spermatogenesis (Day 4 postpartum [pp]), the number of
      PP2A-A-immunopositive gonocytes increased. At Day 4 pp, the first A1
      spermatogonia appeared along the basement membrane; all were PP2A-A positive. In
      the adult, PP2A-A was upregulated during the differentiation of the As, Apr, and
      Aal spermatogonia to the A1 spermatogonia and expressed thereafter by all other
      spermatogonia. Spermatocytes from the pachytene stage onward and all spermatids
      in the adult testis also showed clear expression of PP2A-A. In Sertoli cells,
      PP2A-A was detected during their proliferative period at 19 days pc to 15 days
      pp. The presence of a functional enzyme was confirmed by the additional detection
      of the catalytic subunit C of PP2A using Western blot analyses at various ages
      during testicular development. This apparent pattern of expression of PP2A-A
      during testicular development suggests that PP2A may play an important role in
      the proliferation of distinct populations of testicular cells and during meiosis
      and sperm maturation.

PMID- 12606434
TI  - Methoxyacetic acid disregulation of androgen receptor and androgen-binding
      protein expression in adult rat testis.
AB  - Chemical agents can disrupt the balance between survival and apoptosis during
      spermatogenesis and thus give rise to reduced counts of spermatozoa
      (oligospermia). One such agent that produces significant germ cell apoptosis at
      specific stages of the cycle of the seminiferous epithelium is methoxy acetic
      acid (MAA), the active metabolite of a commonly used solvent, methoxyethanol.
      Although MAA gives rise to apoptosis of pachytene spermatocytes, it is not known
      whether MAA exerts a direct effect on germ cells or whether it also affects other
      testicular cell types such as the Sertoli cells. In the present investigation, we
      tested the hypothesis that MAA has direct effects on Sertoli cells in vivo. In
      MAA-treated rats, stage-specific expression of androgen receptor (AR) protein in
      Sertoli cells was significantly altered, as determined by AR
      immunohistochemistry. In MAA-treated animals, high AR expression was found in
      Sertoli cells coincident with the MAA-induced apoptosis of late-stage pachytene
      spermatocytes. The altered expression of AR in MAA-treated animals was also seen
      in seminiferous tubules harvested by laser capture microdissection. In addition
      to effects on AR expression, androgen-binding protein (ABP) mRNA levels were also
      altered in a stage-specific manner. Using a different system for mouse Sertoli
      cell lines TM4 and MSC-1, positive for either AR or ABP, respectively, we found a
      direct effect of MAA on ABP protein and mRNA expression in the MSC-1 cell but did
      not detect an effect on AR protein or mRNA expression in TM4 cells. Mouse
      fibroblasts that express endogenous AR were stably transfected with two AR
      promoter/reporter systems (MMTV-CAT and probasin-luciferase, respectively). We
      used these fibroblasts to examine the ability of MAA to potentiate
      dihydrotestosterone (DHT) activation of AR. Although MAA did not activate AR
      directly, it did potentiate DHT activation of the AR by 2- to 4-fold. MAA altered
      the expression level of AR and ABP in vivo and increased AR transcriptional
      activity in tissue culture cells. The abnormal spermatogenesis generated by MAA
      is at least partly due to direct effects on Sertoli cells. It is still unclear
      whether MAA elicits a proapoptotic signal from Sertoli cells or diminishes a
      prosurvival signal required by germ cells downstream to altering AR and ABP
      expression in a stage-specific fashion.

PMID- 12606435
TI  - Native tesmin is a 60-kilodalton protein that undergoes dynamic changes in its
      localization during spermatogenesis in mice.
AB  - Tesmin is a testis-specific protein. Four mouse tesmin cDNAs so far reported
      encode a testis-specific, metallothionein-like, 30-kDa protein (tesmin-30). An
      antibody against tesmin-30, however, detected a protein of 60 kDa (tesmin-60)
      from the mouse testis. To resolve the relationship between the two, the
      immunoprecipitated native tesmin-60 was sequenced. The result indicated that
      tesmin-30 is not full-length but is part of the C-terminal half of tesmin-60. The
      full-length cDNA (2.2 kilobases [kb]) encoding tesmin-60 (475 amino acid
      residues) and its genomic DNA (23 kb) were cloned and sequenced. A search of
      databases indicated that tesmin is a member of the CXC-hinge-CXC family.
      Immunohistochemistry indicated that tesmin exhibits dynamic subcellular
      localization changes during spermatogenesis. Before meiosis, it was localized in
      the cytoplasm of early to late spermatocytes and then translocated into the
      nucleus just before meiotic division. After meiosis, it appeared in spermatids,
      starting from the acrosomal vesicles, moving to the nuclear membrane and then to
      the caudal end as the spermatids elongated, and finally relocating into the
      cytoplasm. Oxidative stress by cobalt chloride, as well as by diethylmaleate,
      induced both premature translocation of tesmin from the cytoplasm to the nucleus
      and apoptotic signals in spermatocytes. The persistent existence of tesmin and
      its temporally and spatially dynamic localization suggest that tesmin is involved
      in multiple stages of spermatogenesis and spermiogenesis, possibly during sperm
      maturation and/or morphogenesis.

PMID- 12606436
TI  - Differential regulation of the expression of matrix metalloproteinases and tissue
      inhibitors of metalloproteinases by cytokines and growth factors in bovine
      endometrial stromal cells and trophoblast cell line BT-1 in vitro.
AB  - Degradation and reconstitution of extracellular matrix in uterine endometrium is
      a crucial event for embryonic implantation and is regulated by matrix
      metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In
      the present study, we investigated the regulation of MMP and TIMP expression in
      cultured bovine endometrial stromal cells (BESCs) and a bovine trophoblast cell
      line BT-1 (BT-1 cells). The production of proMMP-9 was induced by transforming
      growth factor beta (TGFbeta) and 12-O-tetradecanoylphorbol 13-acetate in the
      stromal cells. The treatment of BESCs with TGFbeta, insulin-like growth factor-I,
      and hepatocyte growth factor (HGF) resulted in a significant increase in the
      level of TIMP-1 in the culture medium. In addition, a significant increase of
      TIMP-2 production was observed in interleukin (IL)-1alpha and HGF-treated BESCs.
      However, the expression of TIMP-1 and TIMP-2 mRNA was not augmented by these
      factors. The treatment of BESCs with 12-O-tetradecanoylphorbol 13-acetate
      resulted in a significant increase in the level of TIMP-1 but a significant
      decrease in the level of TIMP-2 in the stromal cells. Membrane type-1 MMP mRNA
      expression in the stromal cells was augmented by tumor necrosis factor alpha
      (TNFalpha), IL-6, HGF, and 12-O-tetradecanoylphorbol 13-acetate. On the other
      hand, BT-1 cells constitutively produced proMMP-9 and proMMP-2, and the treatment
      of BT-1 cells with TNFalpha, HGF, and 12-O-tetradecanoylphorbol 13-acetate
      resulted in a significant increase in the level of proMMP-9 but not in the level
      of proMMP-2. The production of TIMP-1 in BT-1 cells was also augmented by IL
      1alpha, TNFalpha, and HGF at the level of translation and was transcriptionally
      increased by 12-O-tetradecanoylphorbol 13-acetate. However, the level of TIMP-2
      mRNA in BT-1 cells was not affected by any of the treatments. These results
      suggest that the expression of MMPs and TIMPs is differentially regulated by
      cytokines and growth factors and that the production of TIMP-1 and TIMP-2 may not
      be accompanied by changes in their mRNA expression in bovine endometrium and
      trophoblasts. Furthermore, as in humans and rodents, MMPs and TIMPs may
      contribute to the control of degradation and reconstitution of extracellular
      matrix in bovine endometrium during embryonic implantation and early
      placentation.

PMID- 12606438
TI  - Improved germline transmission in chicken chimeras produced by transplantation of
      gonadal primordial germ cells into recipient embryos.
AB  - In the avian species, germline chimera production could be possible by transfer
      of donor germ cells into the blood vessel of recipient embryos. This study was
      conducted to establish an efficient transfer system of chicken gonadal primordial
      germ cells (gPGCs) for producing the chimeras having a high capacity of germline
      transmission. Gonadal PGCs retrieved from 5.5-day-old embryos (stage 28) of
      Korean Ogol chicken (KOC with i/i gene) were transferred into the dorsal aorta of
      2.5-day-old embryos (stage 17) of White Leghorn chicken (WL with I/I gene).
      Prospective evaluations of whether culture duration (0, 5, or 10 days) and
      subsequent Ficoll separation of gPGCs before transfer affected chimera production
      and germline transmission in the chimeras were made while retrospective analysis
      was conducted for examining the effect of chimera sexuality. A testcross analysis
      by artificial insemination of presumptive chimeras with adult KOC was performed
      for evaluating each treatment effect. First, comparison was made for evaluating
      whether experimental treatments could improve chimera production, but none of the
      treatments were significantly (P = 0.6831) influenced (5.1%-14.4%). Second, it
      was determined whether each treatment could enhance germline transmission in
      produced chimeras. More (P < 0.0001) progenies with black feathers (i/i) were
      produced in the germline chimeras derived from the transfer of 10-day-cultured
      gPGCs than from the transfer of 0- or 5-day-cultured gPGCs (0.6%-7.8% vs. 10.7%
      49.7%). Ficoll separation was negatively affected (P < 0.0001), whereas there was
      no effect in chimera sexuality (P = 0.6011). In conclusion, improved germline
      transmission of more than a 45% transmission rate was found in chicken chimeras
      produced by transfer of 10-day-cultured gPGCs being separated without Ficoll
      treatment.

PMID- 12606437
TI  - Differential effects of natural and environmental estrogens on endothelin
      synthesis in bovine oviduct cells.
AB  - Endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide that plays an
      important role within the endocrine/reproductive system, is synthesized by
      oviduct cells and regulates tubal contractility. Because 17beta-estradiol
      (estradiol) regulates oviduct function by influencing the synthesis of
      autocrine/paracrine factors, estradiol may also regulate ET-1 synthesis.
      Furthermore, environmental estrogens (EEs; phytoestrogens and xenoestrogens),
      which structurally resemble estradiol and possess estrogenic activity, may mimic
      the effects of estradiol on ET-1 synthesis and may influence the reproductive
      system. Using cultures of bovine oviduct cells (epithelial cells:fibroblasts,
      1:1), we investigated and compared the modulatory effects of estradiol,
      phytoestrogens, and xenoestrogens on ET-1 synthesis and determined whether these
      effects were estrogen receptor (ER) mediated. A quantitative ELISA for ET-1 in
      the culture medium revealed that 17beta-estradiol inhibits ET-1 synthesis in a
      concentration-dependent manner (4-400 nmol/L). In contrast to estradiol, ET-1
      synthesis was induced in cell cultures treated with xenoestrogens in the
      following order of potency (0.1 micromol/L): 4-hydroxy-trichlorobiphenyl > 4
      hydroxy-dichlorobiphenyl > trichlorobiphenyl. The stimulatory effects of
      xenoestrogens on ET-1 production were mimicked by the phytoestrogens biochanin-A
      and genistein but not by formononetin, equol, and daidzein. The oviduct cells
      expressed both ERs (alpha and beta), but the modulatory effects of estradiol, but
      not EEs, on ET-1 synthesis were blocked by ICI-182 780 (1 microM), a pure ER
      antagonist. Our results provide evidence that estradiol inhibits ET-1 synthesis
      in oviduct cells via an ER-dependent mechanism, whereas, EEs induce ET-1
      synthesis via an ER-independent mechanism. The contrasting effects of EEs on ET-1
      synthesis suggests that EEs may act as endocrine modulators/disruptors and may
      have deleterious effects on the reproductive system by adversely influencing the
      biology and physiology of the oviduct.

PMID- 12606439
TI  - Maturation-promoting factor governs mitogen-activated protein kinase activation
      and interphase suppression during meiosis of rat oocytes.
AB  - Meiosis is a particular example of a cell cycle, characterized by two successive
      divisions without an intervening interphase. Resumption of meiosis in oocytes is
      associated with activation of maturation-promoting factor (MPF) and mitogen
      activated protein kinase (MAPK). The activity of MPF declines during the
      transition between the two meiotic divisions, whereas the activity of MAPK is
      sustained. Attempts to disclose the interplay between these key regulators of
      meiosis in both amphibian and mammalian oocytes generated contradictory results.
      Furthermore, the enzyme that governs the suppression of interphase in mammals is
      still unidentified. To our knowledge, we provide herein the first demonstration
      in a mammalian system that inhibition of MPF at reinitiation of meiosis abrogated
      Mos expression and MAPK activation. We also show that oocytes, in which
      reactivation of MPF at completion of the first telophase was prevented, exhibited
      an interphase nucleus with decondensed chromosomes. Inhibition of MAPK did not
      interfere with the progression to the second meiotic metaphase but, rather,
      resulted in parthenogenic activation. We conclude that in rat oocytes, MPF
      regulates MAPK activation and its timely reactivation prevents the oocytes from
      entering interphase.

PMID- 12606440
TI  - Effects of a 6-day treatment with medroxyprogesterone acetate after prostaglandin
      F2 alpha-induced luteolysis at midcycle on antral follicular development and
      ovulation rate in nonprolific Western white-faced ewes.
AB  - Medroxyprogesterone acetate (MAP) from intravaginal sponges prolongs the lifespan
      of large ovarian follicles when administered after prostaglandin F2alpha
      (PGF2alpha)-induced luteolysis early in the luteal phase of ewes. The present
      study was designed to determine whether a PGF2alpha/MAP treatment applied at
      midcycle would alter the pattern of antral follicle growth and increase ovulation
      rate in nonprolific ewes. A single injection of PGF2alpha (15 mg, i.m.) was
      given, and an intravaginal MAP (60 mg) sponge was inserted for 6 days, on
      approximately Day 8 after ovulation, in 7 (experiment 1), 8 (experiment 2) or 11
      (experiment 3) ultrasonographically monitored, cycling Western white-faced ewes;
      seven ewes (experiment 1) served as untreated controls. Blood samples were
      collected each day and also every 12 min for 6 h, halfway through the period of
      treatment with MAP (experiment 1), or every 4 h, from 1 day before to 1 day after
      sponging (experiment 2). Seventeen of 26 treated ewes (experiment 1, n = 6;
      experiment 2, n = 5; experiment 3, n = 6) ovulated 1 to 6 days after PGF2alpha,
      but this did not affect the emergence of ensuing follicular waves (experiments 1
      and 2). These ovulations, confirmed by laparotomy and histological examinations
      of the ovaries (experiment 3), were not preceded by an increase in LH/FSH
      secretion and did not result in corpora lutea, as evidenced by transrectal
      ultrasonography and RIA of serum progesterone (experiments 1 and 2). Following
      the removal of MAP sponges, the mean ovulation rate was 3.1 +/- 0.4 in treated
      ewes and 2.0 +/- 0.3 in control ewes (experiment 1; P < 0.05). In experiments 1
      and 2, the ovulation rate after treatment (3.1 +/- 0.4 and 2.8 +/- 0.4) was also
      greater than the pretreatment rate (1.9 +/- 0.3 and 1.9 +/- 0.1, respectively).
      Ovulations of follicles from two consecutive waves before ovulation were seen in
      five treated but only in two control ewes (experiment 1), and in seven ewes in
      experiment 2. There were no significant differences between the MAP-treated and
      control ewes in mean daily serum concentrations of FSH and estradiol, and no
      differences in the parameters of LH/FSH secretion, based on frequent blood
      sampling. Treatment of nonprolific Western white-faced ewes with PGF2alpha and
      MAP at midcycle changed follicular dynamics and increased ovulation rate by
      approximately 50%. These effects of MAP, in the absence of luteal progesterone,
      may not be mediated by changes in gonadotropin secretion.

PMID- 12606441
TI  - Adenosine triphosphate induces Ca2+ signal in epithelial cells of the mouse caput
      epididymis through activation of P2X and P2Y purinergic receptors.
AB  - In the present study, we developed a novel method to analyze the calcium (Ca2+)
      signal in living slices of mouse caput epididymides by applying calcium imaging
      on Fura-2-loaded vibratome slices. The data revealed that in epithelial cells of
      mouse caput epididymides, ATP induces a rapid Ca2+ signal that is sustained after
      60 sec. Preincubating the sections in Ca2+-free medium in the presence of EGTA
      did not affect the amplitude of the ATP-induced Ca2+ signal, indicating the
      presence of P2Y type purinergic receptors and phospholipase C activity.
      Furthermore, ATP induced a similar Ca2+ signal in the different subregions of
      caput epididymides. The P2X type ion-gated purinergic receptors could also be
      responsible for the ATP-induced Ca2+ signal because immunohistochemical and
      reverse transcriptase-polymerase chain reaction analyses showed that P2X1, P2X2,
      P2X4, P2X7, P2Y1, and P2Y2 receptors were expressed in the epididymis. We propose
      that P2X and P2Y receptor expression is vital for the normal function of
      epididymal epithelium and sperm maturation. Furthermore, the method we developed
      allows us to analyze the activity of various G protein-coupled receptors in
      intact epithelial cells of mouse epididymides, and other reproductive tissues as
      well.

PMID- 12606442
TI  - Antioxidant defenses are modulated in the cow oviduct during the estrous cycle.
AB  - The balanced presence of reactive oxygen species and antioxidants has a positive
      impact on sperm functions, oocyte maturation, fertilization, and embryo
      development in vitro. The mammalian oviduct is likely to provide an optimal
      environment for final gamete maturation, sperm-egg fusion, and early embryonic
      development. However, the expression and distribution of antioxidant enzymes in
      the bovine oviduct are poorly characterized. We analyzed the mRNA expression and
      enzymatic activities of major antioxidants glutathione peroxidase (GPx),
      superoxide dismutase (Cu,ZnSOD), and catalase in the bovine oviduct throughout
      the estrous cycle. The high levels of expression for GPx-3 in the isthmus were in
      contrast to expression of GPx-1 and GPx-2, which occurred mostly in the ampulla
      and infundibulum of the oviduct. The highest levels of mRNA expression for GPx-1
      were observed toward the end of the estrous cycle before ovulation, whereas GPx-2
      was mostly expressed at midcycle. Catalase and Cu,ZnSOD mRNA analyses revealed a
      homogenous expression along the oviduct. The highest levels of glutathione and
      enzymatic activities for GPx and catalase occurred at the middle (10-12 days) and
      end (18-20 days) of the estrous cycle, whereas total SOD activity remained
      constant throughout the estrous cycle in the oviductal fluids. These findings
      underscore the importance of hydrogen peroxide and hydroperoxide removal by GPx
      in the oviduct. The heterogeneous expression of antioxidants such as GPx along
      the oviduct is a possible indication of their physiological role in the events
      leading to successful fertilization and implantation in vivo.

PMID- 12606443
TI  - Aryl hydrocarbon receptor regulates growth, but not atresia, of mouse preantral
      and antral follicles.
AB  - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor
      that binds various environmental contaminants. Despite our knowledge regarding
      the role of the AhR in mediating toxicity, little is known about the
      physiological role of the AhR. Previous studies indicate that the AhR may
      regulate folliculogenesis, because AhR-deficient (AhRKO) mice have fewer
      preantral and antral follicles than wild-type (WT) mice during postnatal life.
      Thus, the first objective of the present study was to test the hypothesis that
      AhR deficiency reduces the numbers of preantral and antral follicles by slowing
      growth and/or increasing atresia of follicles. Because alterations in follicular
      growth or atresia can affect the ability to ovulate, the second objective was to
      test whether AhR deficiency reduces the number of ovulated eggs. To test these
      hypotheses, follicular growth was compared in WT and AhRKO ovaries using
      morphometric techniques and by measuring the ability of the ovary and follicles
      to grow in response to eCG. Atresia was compared in WT and AhRKO ovaries using
      morphometric techniques, TUNEL assays, and 3'-end labeling of fragmented DNA.
      Ovulation was compared in WT and AhRKO mice by assessing the number of corpora
      lutea per ovary. The results indicate that follicular growth and ovulation were
      reduced in AhRKO ovaries compared to WT ovaries. The WT ovaries had a 1.5-fold
      increase in the number of preantral and antral follicles between Postnatal Days
      32 and 45, were more responsive to eCG, and contained more corpora lutea than
      AhRKO ovaries. In contrast, no significant difference was observed in the
      incidence of atresia in WT and AhRKO ovaries. Taken together, these results
      suggest that the AhR may regulate growth, but not atresia, of preantral and
      antral follicles in the mouse ovary.

PMID- 12606444
TI  - Genetic variations of gpx-4 and male infertility in humans.
AB  - Phospholipid hydroperoxide glutathione peroxidase (PHGPx), the product of gpx-4,
      is the major selenoprotein in sperm and is considered essential for fertilization
      because of its multiple roles in spermatogenesis, such as hydroperoxide
      detoxification, formation of the mitochondrial capsule, and chromatin
      condensation. Genomic DNA sequences of 3.148 kilobases covering the whole gpx-4
      and its flanking regions were amplified from 63 men using the polymerase chain
      reaction and were analyzed for polymorphisms by direct sequencing. A total of 23
      variant sites were detected; 2 were present only in control men (proven fathers;
      n = 21) and 10 were common to fertile controls and infertile patients (n = 42). A
      further 11 variant sites were seen in five of the infertile men only. Four of the
      gpx-4 variants were considered irrelevant to GPx-4-related fertility problems
      because they occurred homozygously in controls. The majority of the remaining
      variant sites are also of questionable relevance because they are located in
      introns or, as third base exchanges, do not affect the protein sequence. However,
      one of the exon variations leads to an Ala93-Thr exchange that reduces activity
      in a porcine GPx-4 homologue. Two detected promoter variations were shown by
      reporter gene constructs to affect transcription in somatic cell lines. These
      results indicate that gpx-4 polymorphism cannot generally account for the
      correlation of PHGPx content of sperm and fertility-related parameters, but
      further examination of this gene as a potential cause of infertility in
      particular cases is warranted.

PMID- 12606445
TI  - Progesterone induces calcitonin expression in the baboon endometrium within the
      window of uterine receptivity.
AB  - The mammalian uterus can accept a developing blastocyst for implantation only
      within a limited period of time, termed the receptive phase. Our previous studies
      showed that the expression of calcitonin, a peptide hormone that regulates
      calcium homeostasis, is induced by progesterone immediately preceding
      implantation, and is required for the generation of a receptive rat uterus. In
      this study, we investigated the expression and hormonal regulation of calcitonin
      in the baboon endometrium during the window of implantation. We monitored the
      spatio-temporal expression of calcitonin at various days of the menstrual cycle.
      Reverse transcriptase-polymerase chain reaction analysis of the baboon
      endometrium on Days 9 and 10 postovulation revealed stage-specific expression of
      calcitonin mRNA, which overlapped with the window of uterine receptivity.
      Immunocytochemical analysis of baboon endometrium sections localized calcitonin
      expression in the glandular epithelial and stromal cells. Treatment of animals
      with the antiprogestin ZK 137.316 dramatically reduced calcitonin expression,
      indicating that calcitonin expression in the baboon endometrium is under
      progesterone regulation. Collectively, these findings strongly suggest that the
      appearance of calcitonin in progesterone-dominated endometrium is conserved among
      species and may serve as a marker of uterine receptivity for embryo implantation.

PMID- 12606446
TI  - Ontogenesis of leptin receptor in rat Leydig cells.
AB  - There are still many controversies about the role of leptin in reproductive
      function and sexual development. We recently demonstrated that leptin receptors
      are expressed in rodent Leydig cells and that leptin has inhibitory effects on
      hCG-stimulated testosterone production by adult rat Leydig cells in culture. In
      this study, we evaluated the expression of leptin receptor (Ob-R) in rat testes
      from gestational to adult age in comparison with the pattern of expression of
      relaxin-like factor (RLF), a specific marker of Leydig cell differentiation
      status. Immunohistochemical analysis showed that, in prenatal life, Ob-R
      immunoreactivity was absent at early embryonic ages (E14.5) and appeared at a
      late embryonic age (E19.5); in postnatal life, immunoreactivity was evident only
      after sexual maturation (35-, 60-, and 90-days old), whereas it was absent in
      testes from sexually immature rats (7-, 14-, and 21-days old). Immunoreaction was
      always confined to Leydig cells and no signal of Ob-R was detected within the
      tubules. The pattern of expression of Ob-R during testicular development was
      similar with that of RLF immunoreactivity, which was present in mature fetal as
      well as adult-type Leydig cells. In contrast with the findings in the testis, in
      the hypothalamus, the immunohistochemical pattern of Ob-R was very similar
      between pre- and postpubertal life. Reverse transcription-polymerase chain
      reaction studies showed that Ob-R expression was present in embryonic,
      prepubertal, and adult rat testes; semiquantitative analysis showed that mRNA
      levels were much higher in late versus early embryonic testes, as well as in
      mature adults versus sexually immature testes, with a gradual increase from
      younger to older ages. Functional studies showed that, while leptin (150 ng/ml)
      significantly inhibited hCG-stimulated testosterone production in adult rat
      Leydig cells (46% reduction; P > 0.01), it did not modify prepubertal rat Leydig
      cells steroidogenic function in vitro. In conclusion, we showed that, in rat
      testis, Ob-R expression is characteristic of mature Leydig cells (fetal and adult
      type) and it is functional in adult but not prepubertal life.

PMID- 12606447
TI  - Construction of the plasmid pCMV4-rZPC' DNA vaccine and analysis of its
      contraceptive potential.
AB  - Zona pellucida C (ZPC) is a major glycoprotein of the zona pellucida that
      possesses the sperm receptor function. ZPC induces autoantibody that can block
      sperm/oocyte interaction. We selected the partial sequence of rabbit ZPC (amino
      acid 263-415, rZPC') as the target and constructed the pCMV4-rZPC' gene vaccine
      by using DNA recombinant techniques. The total RNA was extracted from the ovaries
      of the sexually healthy female rabbit, and the rZPC' cDNA, which was amplified by
      reverse transcription-polymerase chain reaction, was directly inserted into the
      cloning vector PCR2.1 to construct the PCR2.1-rZPC'. This insertion fragment was
      subcloned into the pCMV4 vector to form the pCMV4-rZPC' prototype DNA vaccine.
      All experimental BALB/C mice and New Zealand rabbits received i.m. injection of
      pCMV4-rZPC' vaccine three times. The results show that 1) the pCMV4-rZPC'
      construct expresses rZPC' cDNA in mice muscle cells, 2) 60% of the immunized
      female mice were infertile at 6 wk after the immunization, 3) the mice immunized
      with pCMV4-rZPC' DNA vaccine developed anti-rZPC antibodies that bound to the
      ovarian ZP in situ, and 4) antibodies against rZPC' were also bound to normal
      animal ovarian ZP in vitro. The results indicate that anti-rZPC antibodies
      developed from pCMV4-rZPC' DNA vaccine can prevent the fertility course and do
      not interfere with normal follicular development. The pCMV4-rZPC' DNA vaccine may
      be possible to develop as a contraceptive vaccine.

PMID- 12606448
TI  - Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys:
      morphometric and ultrastructural studies.
AB  - Our previous studies demonstrated the ability of low doses of antiprogestin ZK
      98.299 (onapristone) to inhibit fertility in bonnet monkeys. In the present study
      cumulative effects of low doses of ZK 98.299 on the endometrial cytoarchitecture
      of bonnet monkeys were analyzed. Treatment with either the vehicle (n = 3) or
      onapristone at 2.5 mg (n = 4) or 5.0 mg (n = 3) was initiated on Day 5 of the
      first menstrual cycle and thereafter repeated every third day for four to seven
      consecutive cycles. The last treatment cycles were anovulatory in two animals
      treated with 2.5 mg and all animals treated with 5.0 mg. Endometrial biopsies
      were collected on Day 8 after the midcycle estradiol peak in ovulatory menstrual
      cycles and on Day 20 in anovulatory menstrual cycles during the last treatment
      cycle. Ultrathin sections of the fixed endometrium were stained with toluidine
      blue for morphometric analysis and uranyl acetate and lead citrate for
      ultrastructural analysis. The ZK 98.299-treated animals showed a dose-dependent
      endometrial atrophy as evident by a decrease in the height and diameter of the
      glands and early signs of compaction in the stroma. Ultrastructural analysis also
      revealed dose-dependent degenerative changes in the subcellular organelles such
      as the nucleus, mitochondria, endoplasmic reticulum, lysosomes, and Golgi
      apparatus. This suggests that long-term treatment with low doses of ZK 98.299
      leads to the suppression of estrogen-dependent endometrial proliferation.
      However, this blockade operates independent of estradiol receptor (ER) and
      progesterone receptor (PR) concentrations as the expressions of these steroid
      receptors did not show any significant changes even after prolonged treatment.
      The study demonstrated an antiestrogenic effect of ZK 98.299 on endometrium after
      prolonged treatment in bonnet monkeys.

PMID- 12606450
TI  - Apoptosis and related proteins in placenta of intrauterine fetal death in
      prostaglandin f receptor-deficient mice.
AB  - The present study investigated whether the increase of apoptosis in the placenta
      is associated with intrauterine fetal death in prostaglandin F receptor-deficient
      mice. Apoptosis was demonstrated within placental and decidual tissue by the
      TUNEL method. The majority of apoptosis was found in syncytiotrophoblast tissues.
      Enhanced TUNEL-positive staining in the syncytiotrophoblast layer was scattered
      in the placental tissues in clusters of apoptotic cells in the death group.
      Marked TUNEL-positive cells were identified in decidua of both groups. The rate
      of apoptosis in the placenta and decidua in the death group was higher than that
      in the survival group (P < 0.05). Immunohistochemical analysis showed that the
      level of active caspase-3 protein expression in the placenta in the death group
      was much higher than that in the survival group. The level of Bcl-2 protein
      expression in the placenta in the death group was much lower than that in the
      survival group. Western blot analysis demonstrated that increased expression of
      the active form of caspase-3 was detected in the placenta and decidua in the
      death group compared with that in the survival group. In contrast, a decrease in
      the expression of Bcl-2 was detected in the placenta and decidua in the death
      group compared with that in the survival group. Enhanced expression of Bax:Bcl-2
      ratio was detected in placenta and decidua in the death group compared with that
      in the survival group. Thus, significantly increased apoptosis in the mouse
      placenta and decidua might be involved in the pathophysiologic mechanism of
      intrauterine fetal death.

PMID- 12606449
TI  - Mouse uterine epithelial apoptosis is associated with expression of mitochondrial
      voltage-dependent anion channels, release of cytochrome C from mitochondria, and
      the ratio of Bax to Bcl-2 or Bcl-X.
AB  - The release of cytochrome c from mitochondria, which is regulated by Bcl-2 family
      members and is considered to take place through voltage-dependent anion channels
      (VDACs) on the outer membranes of mitochondria, results in activation of effector
      caspases, such as caspase-3, which induce apoptosis. We studied the involvement
      of the mitochondrial apoptosis pathway in uterine epithelial apoptosis. Estradiol
      17beta pellets were implanted into ovariectomized mice and removed 4 days later
      (Day 0). The apoptotic index (percentage of apoptotic cells) of the luminal
      epithelium increased markedly, peaking on Day 2, whereas that of the glandular
      epithelium increased much less. Expression of VDAC1, 2, and 3 mRNAs increased in
      the luminal epithelium in correlation with the apoptotic index of the luminal
      epithelium. No increases in VDAC1, 2, and 3 mRNA levels were observed in the
      stroma or muscle, where no apoptosis occurs. VDAC1 protein levels in the uterus
      also correlated well with the apoptotic index of the luminal epithelium. In
      addition, the apoptotic index showed good correlation with the release of
      cytochrome c from mitochondria, activation of caspase-3, which was
      immunohistochemically detected only in the epithelium, and the mRNA and protein
      ratios of Bax:Bcl-2 and Bax:Bcl-X in the uterus. The present results suggest that
      the release of cytochrome c from mitochondria, which is regulated by Bcl-2 family
      members, plays a role in uterine epithelial apoptosis after estrogen deprivation.
      The increase in VDAC expression may facilitate the release of cytochrome c during
      apoptosis.

PMID- 12606451
TI  - The making of "transgenic spermatozoa".
AB  - The processes of making transgenic animals by microinjecting DNA into the
      pronucleus of a fertilized oocyte or after the transfection of embryonic stem
      cells are now well established. However, attempts have also been made, with
      varying degrees of success, to use spermatozoa as a vector for transgenesis in
      mammals and other vertebrates during the last decade. A number of different
      approaches for making transgenic spermatozoa have been developed. These include
      directly incubating mature, isolated spermatozoa with DNA or pretreating mature,
      isolated spermatozoa before assisted fertilization. Microinjection procedures
      have also been established to transfect male germ cells directly in vivo within
      the seminiferous tubules or to reimplant previously isolated male germ cells
      submitted to in vitro transfection into a recipient testis. The latter two
      techniques present the advantage of being able to create transgenic progeny
      simply by mating with wild-type females, which avoids the possibility of
      interference or damage as a result of assisted fertilization or the manipulation
      of embryos. The different aspects of sperm-mediated transgenesis are presented.

PMID- 12606452
TI  - Placenta-specific INSL4 expression is mediated by a human endogenous retrovirus
      element.
AB  - The human insulin-family genes regulate cell growth, metabolism, and tissue
      specific functions. Among these different members, only INSL4 gene shows a
      predominant placenta-specific expression. Here, we show that the human INSL4 gene
      is tightly clustered with three other members of the human insulin superfamily
      (RLN1, RLN2, and INSL6) within a 176-kilobase genomic segment on chromosome
      region 9p23.3-p24.1. We also report evidence that INSL4 is probably the only
      insulin-like growth factor gene to be primate-specific. We identified an
      unexpected human endogenous retrovirus (HERV) element inserted into the human
      INSL4 promoter with a sequence similar to that of env gene, flanked by two long
      terminal repeats(LTRs). The emergence of INSL4 gene and genomic insertion of HERV
      appear to have occurred after the divergence of New World and Old World monkeys (
      approximately 45 million years ago). Transient transfection experiments showed
      that the placenta-specific expression of INSL4 is mediated by the 3' LTR of the
      HERV element, and that the latter may have a major role in INSL4 up-regulation
      during human cytotrophoblast differentiation into syncytiotrophoblast. Finally,
      we identified an INSL4 alternatively spliced mRNA species that encodes putative
      novel INSL4-like peptides. These data support the view that ancient retroviral
      infection may have been a major event in primate evolution, especially in the
      functional evolution of the human placenta.

PMID- 12606453
TI  - Sertoli cell tight junction dynamics: their regulation during spermatogenesis.
AB  - During spermatogenesis, developing preleptotene and leptotene spermatocytes must
      translocate from the basal to the adluminal compartment of the seminiferous
      epithelium so that fully developed spermatids (spermatozoa) can be released to
      the tubular lumen at spermiation. It is conceivable that the opening and closing
      of the inter-Sertoli tight junctions (TJs) that constitute the blood-testis
      barrier are regulated by an array of intriguingly coordinated signaling pathways
      and molecules. Several molecules have been shown to regulate Sertoli cell TJ
      dynamics; they include, for example, transforming growth factor beta3 (TGFbeta3),
      occludin, protein kinase A, protein kinase C, and signaling pathways such as the
      TGFbeta3/p38 mitogen-activated protein kinase pathway. Yet the mechanisms that
      regulate these events are essentially not known. This minireview summarizes some
      of the recent advances in the study of TJ dynamics in the testis and reviews
      several models that can be used to study TJ dynamics. It also highlights specific
      areas for future research toward understanding the precise physiological
      relationship between junction dynamics and spermatogenesis.

PMID- 12606454
TI  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) stimulates gonadotropin secretion in
      the immature female Sprague-Dawley rat through a pentobarbital- and estradiol
      sensitive mechanism but does not alter gonadotropin-releasing hormone (GnRH)
      secretion by immortalized GnRH neurons in vitro.
AB  - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces aberrant release of
      gonadotropins, FSH, and LH and blocks ovulation during induced ovarian follicular
      development in rats by an unknown mechanism. In the current study, TCDD (0, 8, or
      32 microg/kg orally) was administered to immature female Sprague-Dawley rats, and
      synchronous follicular development was induced 24 h later with equine chorionic
      gonadotropin (eCG, 5 IU s.c.). Both doses of TCDD induced a significant premature
      increase in serum FSH and LH (P < 0.05) at 12 h post-eCG. This premature
      gonadotropin surge was facilitated by the administration of a long-acting
      estradiol (estradiol cypionate, 0.01, 0.1, and 0.5 mg/kg s.c.), whereas the
      progesterone and cortisol receptor antagonist RU486 (0, 1, and 10 mg/kg s.c.)
      potentiated the premature release of FSH and LH following TCDD as well.
      Pentobarbital (32 mg/kg i.p.) administered at 6 or 9 h, but not 0 h, post-eCG
      ablated the ability of TCDD to stimulate the release of FSH and LH in vivo. TCDD
      had no significant effect on GnRH accumulation in vitro from immortalized GnRH
      neuronal (GT1-7) cells and failed to alter the cell number. Transfection of these
      cells with a rat GnRH promoter-reporter construct revealed no significant acute
      effect of TCDD on GnRH promoter activity. Aryl hydrocarbon receptor mRNA was not
      detected in the GT1-7 cells by reverse transcription polymerase chain reaction.
      TCDD appears to stimulate premature gonadotropin release in the gonadotropin
      primed immature rat by interacting with an estradiol- and pentobarbital-sensitive
      neural signal for GnRH release but not by acting upon the GnRH neuron directly.

PMID- 12606455
TI  - Down-regulation of the alpha- and beta-subunits of the calcium-activated
      potassium channel in human myometrium with parturition.
AB  - Large-conductance, calcium-dependent potassium (BKCa) channels are implicated in
      maintaining uterine quiescence during pregnancy. The mechanisms whereby calcium
      sensitivity of the BKCa channel is dramatically removed at parturition remain
      unknown. The aim of the present study was to investigate whether this loss of
      calcium sensitivity of the BKCa channel with the onset of labor is associated
      with changes in the protein expression of the alpha- and/or beta-subunit or
      arises from a physical dissociation of the alpha-subunit from the beta-subunit.
      The beta-subunit is a key determinant of BKCa-channel Ca2+ sensitivity. Western
      blot analysis, using alpha- and beta-subunit-specific antibodies, detected bands
      of 110-125 and 36 kDa, respectively. Protein expression levels of the alpha
      subunit in term labor myometrium were significantly reduced compared with term
      pregnancy without labor. Furthermore, alpha-subunit levels at term pregnancy were
      significantly increased relative to the nonpregnant state, whereas levels at
      preterm gestations were unchanged. Densitometric analysis demonstrated
      significantly decreased beta-subunit levels in term and preterm labor samples
      compared with term nonlabor samples. Immunoprecipitation studies revealed the
      presence of both the alpha- and beta-subunits in samples taken before or after
      the onset of labor. We conclude that during labor, the alpha-subunit is not
      physically uncoupled from the beta-subunit, but a decline occurs in the level of
      beta-subunit protein, which may underlie the loss of calcium and voltage
      sensitivity of the BKCa channel with labor. Furthermore, reduced beta-subunit
      protein in preterm labor myometrium implies that ion channels may also contribute
      to pathophysiological labor.

PMID- 12606456
TI  - Peroxisome proliferators disrupt retinoic acid receptor alpha signaling in the
      testis.
AB  - Peroxisome proliferators include a diverse group of chemicals, some of which have
      been demonstrated to be testicular toxicants. However, the mechanism by which
      peroxisome proliferators, such as phthalates, cause testicular damage is not
      clear. It is known that retinoic acid receptor alpha (RARalpha) and its retinoic
      acid ligand, the acid form of vitamin A, are required for spermatogenesis. It has
      been demonstrated that the absence of RARalpha gene or vitamin A in the animal
      leads to testis degeneration and sterility. Therefore, any compound that disrupts
      the action of vitamin A in the testis could potentially be damaging to male
      fertility. The current investigation examined a novel hypothesis that a mechanism
      of degeneration by peroxisome proliferators in the testis is due, in part, to
      disruption of the critical RARalpha signaling pathway. We show that peroxisome
      proliferators were able to disrupt the retinoic acid-induced nuclear localization
      of RARalpha and the retinoic acid-stimulated increase in transcriptional activity
      of a retinoic acid-responsive reporter gene in Sertoli cells. Concomitantly,
      peroxisome proliferators increased the nuclear localization of PPARalpha and the
      transcriptional activity of a peroxisome proliferator-responsive reporter gene in
      these cells. These results indicate that peroxisome proliferators can indeed
      shift the balance of nuclear localization for RARalpha and PPARalpha, resulting
      in deactivation of the critical RARalpha transcriptional activity in Sertoli
      cells.

PMID- 12606457
TI  - Neonatal hypothyroidism alters the localization of gap junctional protein
      connexin 43 in the testis and messenger RNA levels in the epididymis of the rat.
AB  - The objectives of this study were to determine the effects of propylthiouracil
      (PTU)-induced neonatal hypothyroidism on the gap junctional protein Cx43 in rat
      testis and epididymis. PTU (0.02%) was administered via lactation from birth to
      Day 30, and the rats were sampled at 14, 18, 22, 26, 30, and 91 days of age.
      Testicular Cx43 was localized along the plasma membranes and cytoplasm of Sertoli
      cells until Day 22. At Day 30, the immunostaining was localized exclusively along
      the plasma membrane of Sertoli cells. In PTU-treated rats, Cx43 did not localize
      to the plasma membrane and was still cytoplasmic at 30 days of age. Occludin was
      present in tubules of treated rats, but was not localized to the blood-testis
      barrier in 30-day-old rats, as in controls. There were no differences in Cx43
      immunostaining in the adult testis. In the proximal epididymis (initial segment,
      caput, corpus), Cx43 mRNA levels were lower in PTU-treated rats at 14, 18, and 22
      days of age, but no differences were observed in the distal (cauda) epididymis at
      these ages. In 22- and 30-day-old rats, Cx43 was localized along the plasma
      membrane between principal and basal cells throughout the epididymis. In PTU
      treated rats, Cx43 was not detectable in initial segment, caput, or corpus
      epididymidis. In the cauda epididymidis, however, Cx43 immunostaining in PTU
      treated rats was similar to controls. These data suggest that thyroid hormones
      regulate Cx43-dependent gap junctional communication in the testis and
      epididymis.

PMID- 12606458
TI  - Neuronal inputs from the hypothalamus and brain stem to the medial preoptic area
      of the ram: neurochemical correlates and comparison to the ewe.
AB  - The retrograde tracer, FluoroGold, was used to trace the neuronal inputs from the
      septum, hypothalamus, and brain stem to the region of the GnRH neurons in the
      rostral preoptic area of the ram and to compare these imputs with those in the
      ewe. Sex differences were found in the number of retrogradely labeled cells in
      the dorsomedial and ventromedial nuclei. Retrogradely labeled cells were also
      observed in the lateral septum, preoptic area, organum vasculosum of the lamina
      terminalis, bed nucleus of the stria terminalis, stria terminalis, subfornical
      organ, periventricular nucleus, anterior hypothalamic area, lateral hypothalamus,
      arcuate nucleus, and posterior hypothalamus. These sex differences may partially
      explain sex differences in how GnRH secretion is regulated. Fluorescence
      immunohistochemistry was used to determine the neurochemical identity of some of
      these cells in the ram. Very few tyrosine hydroxylase-containing neurons in the
      A14 group (<1%), ACTH-containing neurons (<1%), and neuropeptide Y-containing
      neurons (1-5%) in the arcuate nucleus contained FluoroGold. The ventrolateral
      medulla and parabrachial nucleus contained the main populations of FluoroGold
      containing neurons in the brain stem. Retrogradely labeled neurons were also
      observed in the nucleus of the solitary tract, dorsal raphe nucleus, and
      periaqueductal gray matter. Virtually all FluoroGold-containing cells in the
      ventrolateral medulla and about half of these cells in the nucleus of the
      solitary tract also stained for dopamine beta-hydroxylase. No other retrogradely
      labeled cells in the brain stem were noradrenergic. Although dopamine, beta
      endorphin, and neuropeptide Y have been implicated in the regulation of GnRH
      secretion in males, it is unlikely that these neurotransmitters regulate GnRH
      secretion via direct inputs to GnRH neurons.

PMID- 12606459
TI  - Neonatal estrogen exposure of male rats alters reproductive functions at
      adulthood.
AB  - The effects of neonatal exposure to different doses of diethylstilbestrol (DES)
      on the reproductive functions of male rats at adulthood were evaluated. Sprague
      Dawley rats (5-8/group) received sc injections of 25 microl olive oil containing
      DES (Sigma Chemical Co., St. Louis, MO) at a dose of 10 microg, 1 microg, 100 ng,
      10 ng, or 1 ng per rat on alternate days from Postnatal Days 2-12. Control
      animals received olive oil only. All animals were allowed to develop until 83-91
      days of age; however, when they were 70 to 80 days old, four male rats each from
      the 10 microg, 1 microg, 100 ng, and control groups were cohabited with untreated
      60- to 70-day-old females (1:1) for 12 days. At the end of cohabitation, both
      mated and unmated male rats were weighed, and blood and tissue samples were
      collected and processed. Results revealed that although sperm motility patterns
      and sperm morphology were adversely affected in the 10- microg group, other
      reproductive parameters, including 1). daily sperm production (DSP)/testis; 2).
      absolute and relative weights of the testis, epididymis, and seminal vesicle; and
      3). sperm numbers in both regions of the epididymis declined significantly in a
      dose-dependent manner in the 10- and 1- microg groups. Conversely, in the <1-
      microg groups, none of these parameters (except DSP/testis and weight of the
      epididymis in the 100-ng group, and sperm numbers in the epididymis of the 100-
      and 10-ng groups) was different from controls. Generally, plasma testosterone
      levels decreased in the 10- and 1- microg groups, FSH level increased in the 10
      microg group, and prolactin and LH levels were unaltered. In the fertility study,
      although each male in the 1-microg, 100-ng, and control groups produced a
      copulatory plug and impregnated a female, none could do so in the 10-microg
      group. The mean number of pups per litter was reduced to eight in the 1-microg
      group, in contrast to 15 each in the 100-ng and control groups. In conclusion,
      exposure of neonatal male rats to DES altered sperm motility patterns, sperm
      fertility (as evident from the reduced number of pups in the 1-microg group), and
      sexual behavior (as evident from the absence of copulatory plugs in the 10-microg
      group) and reduced weights of reproductive organs, DSP/testis, and sperm numbers
      in the epididymis. Whether these alterations/reductions persist in older rats (6
      8 mo of age) is under investigation.

PMID- 12606460
TI  - Testis morphometry, seminiferous epithelium cycle length, and daily sperm
      production in domestic cats (Felis catus).
AB  - There is very little information regarding the testis structure and function in
      domestic cats, mainly data related to the cycle of seminiferous epithelium and
      sperm production. The testis weight in cats investigated in the present study was
      1.2 g. Compared with most mammalian species investigated, the value of 0.08%
      found for testes mass related to the body mass (gonadosomatic index) in cats is
      very low. The tunica albuginea volume density (%) in these animals was relatively
      high and comprised about 19% of the testis. Seminiferous tubule and Leydig cell
      volume density (%) in cats were approximately 90% and 6%, respectively. The mean
      tubular diameter was 220 microm, and 23 m of seminiferous tubule were found per
      testis and per gram of testis. The frequencies of the eight stages of the cycle,
      characterized according to the tubular morphology system, were as follows: stage
      1, 24.9%; stage 2, 12.9%; stage 3, 7.7%; stage 4, 17.6%; stage 5, 7.2%; stage 6,
      11.9%; stage 7, 6.8%; and stage 8, 11 %. The premeiotic and postmeiotic stage
      frequency was 46% and 37%, respectively. The duration of each cycle of
      seminiferous epithelium was 10.4 days and the total duration of spermatogenesis
      based on 4.5 cycles was 46.8 days. The number of round spermatids for each
      pachytene primary spermatocytes (meiotic index) was 2.8, meaning that significant
      cell loss (30%) occurred during the two meiotic divisions. The total number of
      germ cells and the number of round spermatids per each Sertoli cell nucleolus at
      stage 1 of the cycle were 9.8 and 5.1, respectively. The Leydig cell volume was
      approximately 2000 microm3 and the nucleus volume 260 microm3. Both Leydig and
      Sertoli cell numbers per gram of testis in cats were approximately 30 million.
      The daily sperm production per gram of testis in cats (efficiency of
      spermatogenesis) was approximately 16 million. To our knowledge, this is the
      first investigation to perform a more detailed and comprehensive study of the
      testis structure and function in domestic cats. Also, this is the first report in
      the literature showing Sertoli and Leydig cell number per gram of testis and the
      daily sperm production in any kind of feline species. In this regard, besides
      providing a background for comparative studies with other fields, the data
      obtained in the present work might be useful in future studies in which the
      domestic cat could be utilized as an appropriate receptor model for preservation
      of genetic stock from rare or endangered wild felines using the germ cell
      transplantation technique.

PMID- 12606461
TI  - Regulation of ipsilateral and contralateral bovine oviduct epithelial cell
      function in the postovulation period: a transcriptomics approach.
AB  - We studied differential gene expression in ipsilateral and contralateral bovine
      oviduct epithelial cells using a combination of subtracted cDNA libraries and
      cDNA array hybridization. Four Simmental heifers were synchronized and
      slaughtered 3.5 days after they entered standing heat. Epithelial cells were
      isolated from ipsilateral and contralateral oviducts. To identify genes that are
      differentially regulated in ipsilateral and contralateral epithelium, subtracted
      cDNA libraries were produced by suppression subtractive hybridization and
      analyzed by cDNA array hybridization. Sequencing of cDNAs showing differential
      expression levels in ipsilateral and contralateral epithelium revealed 35
      different cDNAs, 30 of which matched genes with known functions and 5 of which
      matched genes without a known function. The majority of genes (n = 27) were
      expressed at a higher level in the ipsilateral oviduct, but for some genes (n =
      8), mRNA abundance was higher in the contralateral oviduct. The regulated genes
      or their products include a variety of functional classes such as cell-surface
      proteins, cell-cell interaction proteins, members of signal transduction
      pathways, immune-related proteins, and enzymes. Identification of genes
      differentially regulated in ipsilateral and contralateral oviduct epithelial
      cells is the first step toward a systematic analysis of local mechanisms that
      regulate the function of the bovine oviduct epithelium in the postovulation
      period.

PMID- 12606462
TI  - Smoking enhances oxytocin-induced rhythmic myometrial contraction.
AB  - Although smoking during pregnancy is one of the major risk factors of premature
      delivery, the underlying mechanism by which smoking causes premature delivery is
      unknown. In the present study, we examined the effects of smoking on uterine
      contractility induced by oxytocin and prostaglandin F(2alpha). Rats inhaled
      either cigarette smoke or room air from Day 14 to Day 16 of pregnancy through an
      inhalation apparatus for experimental animals (type "Hamburg II"). After the rats
      were killed on Day 17 of pregnancy, the uterine contractile sensitivity and
      activity on exposure to oxytocin or prostaglandin F2alpha were investigated. The
      expression levels of oxytocin-receptor mRNA and prostaglandin F(2alpha) receptor
      mRNA in the uterus were investigated by reverse transcription-polymerase chain
      reaction. The contractile activity was assessed as the contractile force and the
      frequency of rhythmic contractions of myometrial strips that were treated with
      oxytocin or prostaglandin F(2alpha). The contractile sensitivity to oxytocin was
      significantly higher in the smoking group than in the control group (P < 0.01).
      Although the contractile force of oxytocin-induced contractions did not differ
      between the smoking and control groups, the frequency of contractions was
      significantly higher in the smoking group than in the control group (P < 0.01).
      On the other hand, no significant differences were found in the contractile
      sensitivity and activity in response to prostaglandin F(2alpha) between the
      smoking and control groups. The expression of oxytocin-receptor mRNA in the
      myometrium was significantly increased in the smoking group compared with the
      control group (P < 0.01). However, no significant difference was found in the
      level of expression of prostaglandin F(2alpha)-receptor mRNA between the two
      groups. These results suggest that smoking during pregnancy increases the
      contractile sensitivity and activity of the myometrium in response to oxytocin by
      up-regulating the expression of oxytocin-receptor mRNA. The effects of smoking on
      the contractile sensitivity and activity of the myometrium in response to
      oxytocin may increase the risk of premature delivery in smokers.

PMID- 12606463
TI  - Administration of moderate and high doses of gonadotropins to female rats
      increases ovarian vascular endothelial growth factor (VEGF) and VEGF receptor-2
      expression that is associated to vascular hyperpermeability.
AB  - Convincing evidence supports the role of ovarian-origin vascular endothelial
      growth factor (VEGF) in inducing vascular permeability (VP) and ascites
      associated with ovarian hyperstimulation syndrome (OHSS) in mammals, including
      humans. A circulatory dysfunction has been described in every woman treated with
      gonadotropins for in vitro fertilization. It is not known, however, whether the
      action of gonadotropins also includes up-regulation of the VEGF receptor-2 (VEGFR
      2) and whether increased VP is also found when milder stimulation is used. Thus,
      we applied an OHSS animal model to answer these questions. Immature female rats
      were stimulated with saline (control group) or with high (10 IU of eCG x 4 days +
      30 IU hCG, OHSS group) or mild (10 IU of eCG + 10 IU of hCG, mild-stimulation
      group) doses of gonadotropins. The VP and the expression of whole-VEGF and VEGFR
      2 mRNAs were analyzed through time-course experiments (0, 24, 48, and 96 h after
      hCG). Although eCG increased VP and the expression of VEGF and VEGFR-2 mRNAs in
      the ovaries of both mild- and OHSS-stimulated animals, hCG further augmented
      these parameters and produced the highest values after 48 h. A linear correlation
      was found between increased expression of VEGF and VEGFR-2 mRNAs and enhanced VP
      in both mild and OHSS groups. Immunohistochemistry showed the presence of VEGF
      and VEGFR-2 in the granulosa-lutein and endothelial cells of the entire corpus
      luteum. These studies confirm that in hyperstimulated animals as well as in
      mildly treated rats, VEGF and VEGFR-2 are overexpressed and associated with an
      increase in VP, which may be responsible for the accumulation of ascitic fluid in
      the syndrome.

PMID- 12606464
TI  - Role of tumor necrosis factor-alpha and the modulating effect of the caspases in
      rat corpus luteum apoptosis.
AB  - Tumor necrosis factor-alpha (TNFalpha) is a pleiotropic cytokine that has been
      implicated in apoptosis of many cell systems. However, the signal transduction of
      TNFalpha during the structural and functional regression of the corpus luteum
      (CL) is largely unknown. In this study, we investigate the role of TNFalpha in
      rat CL apoptosis and the involvement of monocyte chemoattractant protein-1 (MCP
      1) and the modulating effect of the caspases in this process. An in vivo study of
      CL during pregnancy and postpartum using immunohistochemistry and Western blot
      analysis indicated that increases in TNFalpha correspond with luteal apoptosis
      approaching term (Day 22) and at postpartum (Day 3). CL apoptosis was further
      investigated using a whole-CL culture model of tropic withdrawal. An increase was
      observed in both low molecular weight (MW) DNA fragmentation and TUNEL staining
      from 0 h to 8 h in culture. CL apoptosis in vitro was associated with increased
      protein expression of both TNFalpha and MCP-1 as measured by immunohistochemistry
      and Western blot analysis. Using a whole-CL culture model, apoptosis was induced
      in vitro by TNFalpha as demonstrated by a dose-dependent increase in DNA
      fragmentation. Treatment of luteal cells with TNFalpha and both specific caspase
      inhibitors (Z-DEVD-FMK, Z-VEID-FMK, Z-IETD-FMK) or a general caspase inhibitor
      (Boc-D-FMK) prevented the effect of TNFalpha. CL regression involves the
      apoptotic deletion of luteal cells; the results of this study suggest that
      TNFalpha is possibly involved in this process. The observed increases in MCP-1
      expression suggest the coordination of TNFalpha expression with the infiltration
      and activation of macrophages. Furthermore, the results demonstrate the
      importance of the caspases in the TNFalpha signal transduction pathway and
      suggest a hierarchy within the caspase family.

PMID- 12606465
TI  - Synergistic expression of Ad4BP/SF-1 and cytochrome P-450 aromatase (ovarian
      type) in the ovary of Nile tilapia, Oreochromis niloticus, during vitellogenesis
      suggests transcriptional interaction.
AB  - Involvement of Ad4BP/SF-1 in the ovarian cytochrome P-450 aromatase (oP450arom)
      gene expression was investigated using ovarian follicles of the Nile tilapia,
      possessing an average 14-day spawning cycle. The promoter region (5' flanking
      region) of oP450arom gene cloned from tilapia contains two Ad4 binding sites.
      Subsequently, a cDNA encoding Ad4BP/SF-1 was cloned from the ovarian follicles.
      It is expressed in gonadal tissues, brain, and kidney. Oligonucleotide probes
      containing putative orphan nuclear receptor binding motifs (derived from promoter
      region of the aromatase gene) formed complexes with in vitro-translated Ad4BP/SF
      1 and nuclear extracts of tilapia ovarian (midvitellogenic) follicles, indicating
      that Ad4BP/SF-1 is one of the transcriptional regulators for aromatase gene
      expression. Northern blot analysis revealed that the expression of both oP450arom
      and Ad4BP/SF-1 increased in parallel with ovarian growth from Day 0 to Day 5
      after spawning and declined sharply from Day 8 to Day 11. On the day of spawning
      (Day 14), the expression of both correlates became undetectable. In vitro
      incubation of post vitellogenic full-grown immature follicles (corresponding to
      Day 11 after spawning) with hCG purged both oP450arom and Ad4BP/SF-1 messenger
      RNA transcripts at 18 h. Conversely, in vitro incubation of late vitellogenic
      follicles (corresponding to Day 8 after spawning) with hCG retained Ad4BP/SF-1
      messenger RNA transcripts more or less steadily and up-regulated oP450arom.
      Ad4BP/SF-1 probably acts as a transcriptional modulator to implement the
      paradoxical actions of gonadotropins on oP450arom gene.

PMID- 12606466
TI  - Improvements in cloning efficiencies may be possible by increasing uniformity in
      recipient oocytes and donor cells.
AB  - The low efficiency of somatic cell cloning is the major obstacle to widespread
      use of this technology. Incomplete nuclear reprogramming following the transfer
      of donor nuclei into recipient oocytes has been implicated as a primary reason
      for the low efficiency of the cloning procedure. The mechanisms and factors that
      affect the progression of the nuclear reprogramming process have not been
      completely elucidated, but the identification of these factors and their
      subsequent manipulation would increase cloning efficiency. At present, many
      groups are studying donor nucleus reprogramming. Here, we present an approach in
      which the efficiency of producing viable offspring is improved by selecting
      recipient oocytes and donor cells that will produce cloned embryos with
      functionally reprogrammed nuclei. This approach will produce information useful
      in future studies aimed at further deciphering the nuclear reprogramming process.

PMID- 12606467
TI  - Porcine SRY promoter is a target for steroidogenic factor 1.
AB  - To study the process of mammalian sex determination and in particular to further
      understand the mechanisms of transcriptional regulation of the SRY gene, we have
      isolated a 4.5-kilobase (kb) pig SRY 5' flanking sequence. To facilitate the in
      vitro analysis of these sequences, we have generated a porcine genital ridge
      (PGR) cell line (9E11) that expresses SRY as well as SOX9, steroidogenic factor-1
      (SF-1), and DAX1. Via primer extension analysis on RNA from this cell line, a
      transcription start site for porcine SRY was identified at -661 base pairs (bps)
      5' from the translation initiation site. Deletion studies of the SRY 5' flanking
      sequences in PGR 9E11 cells demonstrated that -1.4 kb of 5' flanking sequences
      retained full transcriptional activity compared with the -4.5 kb fragment, but
      that transcriptional activity fell when further deletions were made. Sequences
      downstream of the transcriptional start site are important for promoter activity,
      because deleting transcribed but not translated sequences eliminated promoter
      activity. Sequence analysis of the -1.4 kb fragment identified two potential
      binding sites for SF-1, at -1369 and at -290 from the ATG. To address the role of
      SF-1 transactivation in SRY promoter activity, mutagenesis studies of the
      potential SF-1 binding sites were performed and revealed that these sites were
      indeed important for SRY promoter activity. Cotransfection studies in a
      heterologous cell system (mouse CV-1 cells) demonstrated that pig SF-1 was able
      to transactivate the pig SRY promoter. Gel shift assays confirmed that the
      upstream site was recognized by mouse SF-1 protein. We conclude that two sites
      for SF-1 transactivation exist within the pig SRY promoter, at -1369 bp and at 
      290 bp, and that the site at -1369 bp is quantitatively the most important.

PMID- 12606468
TI  - Production of progesterone from de novo-synthesized cholesterol in cumulus cells
      and its physiological role during meiotic resumption of porcine oocytes.
AB  - To investigate the role of factors secreted by cumulus cells during meiotic
      resumption of porcine oocytes, 1, 5, 10, or 20 cumulus-oocyte complexes (COCs)
      were cultured in each well of a culture dish containing 300 microl of maturation
      medium for 20 h. There was a significant positive correlation between the rate of
      germinal vesicle breakdown (GVBD) and the number of COCs cultured in each well
      for 20 h. The level of progesterone in the medium in which COCs had been cultured
      for 20 h also rose significantly with an increase in the number of COCs cultured
      in each well. A significantly small proportion of GVBD in oocytes when one COC
      was cultured in each well for 20 h was improved by the addition of progesterone.
      This proportion of GVBD was fully comparable to that of COCs cultured in the
      absence of additional progesterone with 20 COCs. Thus, progesterone secreted by
      COCs plays a positive role in GVBD induction in porcine oocytes. Furthermore, we
      also examined the role of sterol biosynthesis on progesterone production by
      cumulus cells and in oocyte GVBD. The results showed that the addition of
      ketoconazole, which suppressed the sterol biosynthetic pathway produced by
      demethylation of lanosterol, decreased the rate of GVBD, as well as progesterone
      production in COCs cultured for 20 h. However, the suppression of GVBD by
      ketoconazole was overtaken by the addition of progesterone. These results
      demonstrate that a high level of progesterone produced by cumulus cells was
      responsible for an acceleration of GVBD in porcine oocytes.

PMID- 12606469
TI  - Co-expression of adrenomedullin and adrenomedullin receptors in rat epididymis:
      distinct physiological actions on anion transport.
AB  - Adrenomedullin (AM) has been found in the brain as well as in various peripheral
      tissues, including reproductive organs such as the testis and the prostate. Here,
      we report the expression of AM in the rat epididymis and its role in anion
      secretion. Whole-epididymal extracts had 35.3 +/- 1.4 fmol of immunoreactive AM
      per mg of protein, and immunocytochemical studies showed positive AM
      immunostaining in the epithelial cells. By solution-hybridization-RNase
      protection assay, preproAM mRNA was detected at high levels in the epididymis.
      Gel filtration chromatography of AM showed two peaks, with the predominant one
      eluting at the position of authentic rat AM (1-50). Specific binding of AM to the
      epididymis, which could be displaced by calcitonin gene-related peptide, was
      observed. The epididymis also bound to calcitonin gene-related peptide, and this
      was displaceable by AM. Furthermore, the epididymis was shown to co-express mRNA
      encoding the calcitonin receptor-like receptor and receptor activity-modifying
      proteins, RAMP1/RAMP2. The corpus region had the highest AM level and gene
      expression and the lowest active peptide:precursor ratio. However, mRNA levels of
      the receptor and the receptor activity-modifying proteins were similar in all
      regions. In monolayer cultures derived from the rat epididymal cells, AM
      stimulated short-circuit current on the luminal side in a dose-dependent manner.
      Our results demonstrate the presence of AM, preproAM mRNA, AM receptors, and
      specific-binding sites in the rat epididymis as well as the possible role of AM
      in the regulation of electrolyte and fluid secretion in the epididymis.

PMID- 12606470
TI  - Localization of tyrosine phosphorylated proteins in human sperm and relation to
      capacitation and zona pellucida binding.
AB  - Mammalian sperm must undergo a process known as capacitation before fertilization
      can take place. A key intracellular event that occurs during capacitation is
      protein tyrosine phosphorylation. The objective of this study was to investigate
      and visualize protein tyrosine phosphorylation patterns in human sperm during
      capacitation and interaction with the zona pellucida. The presence of specific
      patterns was also assessed in relation to the fertilizing capacity of the
      spermatozoa after in vitro fertilization. Protein tyrosine phosphorylation was
      investigated by immunofluorescence. Phosphorylation increased significantly with
      capacitation and was localized mainly to the principal piece of human sperm.
      Following binding to the zona pellucida, the percentage of sperm with
      phosphotyrosine residues localized to both the neck and the principal piece was
      significantly higher in bound sperm than in capacitated sperm in suspension. When
      the percentage of principal piece-positive sperm present after capacitation was
      <7%, fertilization rates after in vitro fertilization were reduced. Different
      compartments of human spermatozoa undergo a specific sequence of phosphorylation
      during both capacitation and upon binding to the zona pellucida. Tyrosine
      phosphorylation in the principal and neck piece may be considered a prerequisite
      for fertilization in humans.

PMID- 12606471
TI  - Phosphorylation of protein tyrosine residues in fresh and cryopreserved stallion
      spermatozoa under capacitating conditions.
AB  - Phosphorylation of tyrosine residues on sperm proteins is one important
      intracellular mechanism regulating sperm function that may be a meaningful
      indicator of capacitation. There is substantial evidence that cryopreservation
      promotes the capacitation of sperm and this cryocapacitation is frequently cited
      as one factor associated with the reduced longevity of cryopreserved sperm in the
      female reproductive tract. This study was designed to determine whether stallion
      sperm express different levels of tyrosine phosphorylation after in vitro
      capacitation and whether thawed sperm display similar phosphorylation
      characteristics in comparison with freshly ejaculated sperm. Experiments were
      performed to facilitate comparisons of tyrosine phosphorylation, motility, and
      viability of sperm prior to and following in vitro capacitation in fresh and
      frozen-thawed sperm. We hypothesized that equine spermatozoa undergo tyrosine
      phosphorylation during capacitation and that this phosphorylation is modified
      when sperm have been cryopreserved. We also hypothesized that tyrosine
      phosphorylation could be enhanced by the use of the activators dibutyryl cAMP (db
      cAMP) and caffeine, as well as methyl beta-cyclodextrin-which causes cholesterol
      efflux from the spermatozoa-and inhibited by the protein kinase A (PK-A)
      inhibitor H-89. Our results indicate that equine sperm capacitation is mediated
      by a signaling pathway that involves cAMP-dependent PK-A and tyrosine kinases and
      that cryopreserved sperm may be more sensitive to inducers of capacitation, which
      could explain their limited life span when compared with fresh sperm.

PMID- 12606472
TI  - Insulin-like growth factors-1 and -2, but not hypoxia, synergize with
      gonadotropin hormone to promote vascular endothelial growth factor-A secretion by
      monkey granulosa cells from preovulatory follicles.
AB  - The midcycle gonadotropin surge promotes vascular endothelial growth factor-A
      (VEGF-A) production by granulosa cells in the ovulatory follicle, but it is
      unclear whether primary regulators of VEGF secretion in other tissues, including
      hypoxia and growth factors, are also important in the ovary. To address these
      issues, granulosa cells were collected from rhesus monkeys during controlled
      ovarian stimulation either before (i.e., nonluteinized granulosa cells, NLGCs) or
      27 hours after (i.e., luteinized granulosa cells, LGCs) administration of an
      ovulatory bolus of hCG, and cultured in fibronectin-coated wells containing a
      chemically defined media. When NLGCs were transferred to various O2 environments
      (20%, 5%, or 0% O2) or media containing 100 mM CoCl2, LH (100 ng/ml)-stimulated
      progesterone (P4) levels were markedly (P < 0.05) suppressed by 0% O2 or CoCl2.
      VEGF concentrations also declined (P < 0.05) in control, CoCl2, and CoCl2 + LH
      groups in 0% O2, although CoCl2 modestly increased (75% above control; P < 0.05)
      VEGF levels in 20% and 5% O2. When NLGCs were cultured in the presence of
      recombinant human insulin-like growth factor (IGF)-1, IGF-2, or insulin, there
      was a dose-dependent increase (P < 0.05) in VEGF levels on Day 1 of culture.
      Whereas optimal doses of IGF-1 or IGF-2 (50 ng/ml), hCG (100 ng/ml), and IGF plus
      hCG stimulated VEGF levels on Day 1, only the combination of IGF-1 or IGF-2 plus
      hCG increased VEGF above controls and sustained levels through Day 3 of culture.
      The synergistic effects of IGF and hCG were also evident in P4 levels, and were
      not due to changes in DNA content between treatment groups. LGCs produced much
      higher levels of P4 and VEGF, but the responses to different O2 concentrations
      and insulin-related factors were qualitatively similar to those of NLGCs. These
      results suggest that hypoxia is not a primary regulator of VEGF production in
      primate granulosa cells. However, IGFs may act in concert with the gonadotropin
      surge to promote VEGF secretion in the ovulatory, luteinizing follicle.

PMID- 12606473
TI  - TNFalpha-induced apoptosis and integrin switching in human extravillous
      trophoblast cell line.
AB  - Differentiation of extravillous trophoblast cells (EVT) to an invasive phenotype
      plays an essential role in establishing and maintaining feto-placental
      organization during human pregnancy. A switch in integrin expression occurs
      during this differentiation and is accompanied by changes in the extracellular
      matrix (ECM). Alteration of EVT behavior is also modulated by cytokines. To
      investigate the molecular interactions involved in the EVT differentiation, we
      examined the effects of cytokines and ECM on the human EVT cell line, TCL1 cells.
      We found that tumor necrosis factor alpha (TNFalpha) induced apoptosis in TCL1
      cells but not in JEG3 cells derived from choriocarcinoma while the addition of
      interleukin-1beta, leukemia inhibitory factor, or transforming growth factor had
      no effect on TCL1 cells. This apoptosis was suppressed when TCL1 cells were
      seeded on fibronectin (Fn), collagen type I (C1), collagen type IV (C4), or
      laminin (Ln). Wortmannin, a specific PI3 kinase inhibitor, inhibited this
      suppression. Spreading assays and adhesion blocking assays indicated that TCL1
      cells express integrin-alpha5 and -alpha6 and beta1 and beta4 subunits. Adhesion
      on Fn is mediated by alpha5beta1, and adhesion on C1, C4, or Ln is mediated by
      alpha6beta1 integrins. TNFalpha suppressed alpha6 integrin expression and
      enhanced alpha1 integrin expression in a dose-dependent manner. In addition,
      aggregation of beta1 subunits on C4 was detected after addition of TNFalpha.
      Taken together, these results suggest that TNFalpha and ECM, through activation
      of PI3 kinase mediated by beta1 integrin signaling, might collaboratively
      regulate differentiation of trophoblast cells through integrin signaling in
      establishing and maintaining successful pregnancy.

PMID- 12606474
TI  - Expression of calbindin-D28k (CaBP28k) in trophoblasts from human term placenta.
AB  - Calbindin-D28k (CaBP28k) belongs to a large class of eucaryotic proteins that
      bind calcium (Ca2+) to a specific helix-loop-helix structure. To date, this
      protein was mainly linked to brain, kidneys, and pancreas. Here, we demonstrate
      for the first time the existence of CaBP8k in the human placental trophoblasts of
      the human term placenta. Placental Ca2+ transfer from maternal to fetus is
      crucial for fetal development, although the biochemical mechanisms responsible
      for this process are largely unknown. In the current study, we have investigated
      the 45Ca2+ uptake by human trophoblast cells in correlation with the expression
      CaBP28k. The expression of CaBP28k was determined by Northern blot analysis,
      reverse transcriptase polymerase chain reaction (RT-PCR), immunochemistry, and
      Western blot analysis. Indeed, Northern blot analysis revealed the presence of a
      CaBP28k transcript in syncytiotrophoblasts, cytotrophoblast cells, and HEK-293
      cells. This was further confirmed by RT-PCR analysis followed by sequencing. In
      addition, anti-CaBP28k labeling was associated with cytotrophoblast and
      syncytiotrophoblast tissues in placental tissue sections and in vitro cultured
      cells. The presence of CaBP28k protein in these cells was confirmed by Western
      blotting. Cytotrophoblast cells isolated from human term placenta showed
      differentiation into syncytiotrophoblasts in culture according to the increase in
      hCG secretion. Both Ca2+ uptake and hCG secretion by trophoblasts increased
      gradually and were high at Day 4. Taken together, these data suggest that CaBP28k
      may play a role in Ca2+ transport or cell development in human trophoblast
      possibly trough Ca2+ buffering.

PMID- 12606475
TI  - Desiccation tolerance of spermatozoa dried at ambient temperature: production of
      fetal mice.
AB  - Long-term preservation of mouse sperm by desiccation is economically and
      logistically attractive. The current investigation is a feasibility study of the
      preservation of mouse sperm by convective drying in an inert gas (nitrogen).
      Mouse sperm from the B6D2F1 strain isolated in an EGTA-supplemented Tris-HCl
      buffer were dried using three different drying rates and were stored for 18-24 h
      at 4 degrees C. The mean final moisture content was <5% for all the protocols.
      After intracytoplasmic sperm injection (ICSI), the mean blastocyst formation
      rates were 64%, 58%, and 35% using the rapid-, moderate-, and slow-drying
      protocols, respectively. The slow-drying protocol resulted in a rate of
      development significantly lower than that observed using rapid- and moderate
      drying protocols and indicated that a slower drying rate may be detrimental to
      the DNA integrity of mouse sperm. The transfer of 85 two- or four-cell embryos
      that were produced using rapidly desiccated sperm resulted in 11 fetuses (13%) on
      Day 15 compared with the production of 34 fetuses (40%) produced using the
      transfer of 86 two- or four-cell embryos that were produced using fresh sperm (P
      < 0.05). The results demonstrate the feasibility of using a convective drying
      protocol for the successful desiccation of mouse sperm and identifies some of the
      important parameters required for optimization of the procedure.

PMID- 12606476
TI  - Chemokine receptor expression in human endometrium.
AB  - Chemokines play a role in endometrial physiology and pathology and may affect
      endometrial receptivity and menstrual shedding. Chemokines exert their effect by
      binding to their relevant receptors, the expression levels of which may modulate
      their action. In the present study, we examined the expression of chemokine
      receptors CXCR1 and CXCR2 (receptors for interleukin-8) and CCR5 (receptor for
      RANTES [regulated-on-activation, normal-T-cell-expressed and -secreted],
      macrophage inflammatory protein [MIP]-1alpha, and MIP-1beta) in human
      endometrium. Human endometria (n = 35) were grouped according to the menstrual
      cycle phase and examined by immunohistochemistry for CXCR1, CXCR2, and CCR5. In
      both epithelial and stromal cells, CXCR1 and CXCR2 immunoreactivity was detected.
      Staining was most prominent at the apical and basal aspects of epithelial cells.
      Intense CCR5 immunostaining was observed in epithelial and stromal compartments
      throughout the menstrual cycle. Epithelial and stromal staining for CXCR1 reached
      a peak at the midsecretory phase, during which it was significantly higher than
      the level of staining during the proliferative phase (P < 0.05). Immunostaining
      for CXCR2 and CCR5 showed no significant variation across the menstrual cycle.
      Expression of interleukin-8 and RANTES in endometrium, together with the presence
      of their receptors, suggests that autocrine and paracrine interactions involving
      these chemokines may participate in endometrial physiology.

PMID- 12606477
TI  - Fetal responses to maternal and intra-amniotic lipopolysaccharide administration
      in sheep.
AB  - A link between intrauterine infection and premature labor is widely accepted, yet
      the fetal inflammatory responses to such infections are not well understood. Our
      aim was to use a sheep model in which an inflammatory state was induced by
      lipopolysaccharide (LPS) administration during pregnancy to the maternal
      systemic, intra-amniotic or extra-amniotic compartments. Fetal and maternal blood
      gases and uterine electromyographic activity along with fetal and maternal
      circulating concentrations of prostaglandins PGE2 and PGFM, cortisol, and
      interleukin-6 were determined. Maternal systemic LPS treatment resulted in mild
      maternal hypoxemia, a rise in temperature, greater fetal hypoxemia, and a marked
      rise in fetal cortisol and PGE2 concentrations that persisted for 48 h. Intra
      amniotic administration of LPS at doses higher than those used systemically
      caused an increase in fetal cortisol and PGE2 concentrations as well as a rise in
      uterine activity, but these were lesser in magnitude. Extra-amniotic LPS
      administration caused no overt fetal or maternal inflammatory responses. We
      conclude that maternal LPS treatment markedly elevated fetal cortisol and PGE2
      concentrations. This may be a potential protective mechanism that aids the fetus
      in the event of premature delivery. The attenuated fetal response to intra
      amniotic LPS treatment, despite the much higher dose used, may support a role for
      the amniotic fluid in protecting the fetus from endotoxin exposure during
      pregnancy.

PMID- 12606479
TI  - Regulation of vascular endothelial growth factor production by Leydig cells in
      vitro: the role of protein kinase A and mitogen-activated protein kinase cascade.
AB  - We previously reported the presence of vascular endothelial growth factor (VEGF)
      in testicular cells, and high concentrations of VEGF have been measured in semen,
      although its role in male reproduction remains obscure. In the present study we
      focus on understanding the mechanism of VEGF production by mouse Leydig cells
      cultured in vitro. Production of VEGF protein in medium by testicular cells was
      markedly increased by the addition of hCG in a time- and dose-dependent manner.
      Gonadotropin-stimulated VEGF production was mediated by cAMP-dependent protein
      kinase A (PKA), as evidenced by the effect of hCG being mimicked by 8Br-cAMP and
      being abolished in the presence of a PKA-specific inhibitor, H-89. Protein kinase
      C was not involved, as evidenced by phorbol 12-myristate 13-acetate having no
      influence on VEGF production by Leydig cells. In addition to hCG, atrial
      natriuretic peptide was also able to stimulate VEGF production, suggesting that
      cGMP is able to cross-activate PKA. A specific Src kinase inhibitor, PP2, could
      completely block the stimulatory effects of both gonadotropin and 8Br-cAMP on
      VEGF production by Leydig cells, implying an involvement of the Src kinase
      pathway. Furthermore, addition of U0126, an inhibitor of MEK 1/2, abolished the
      increase in VEGF production stimulated by both hCG and 8Br-cAMP. A similar
      inhibitory effect was observed by the addition of SB203580, a p38 mitogen
      activated protein kinase inhibitor. Thus, in conclusion, Leydig cells are able to
      produce VEGF by a process under gonadotropic control, and PKA plays a key role in
      this process. Downstream of PKA, it appears that both MEK 1/2 and Src kinase
      dependent pathways are involved, although further research will be necessary to
      determine the precise link between PKA and other kinases involved.

PMID- 12606478
TI  - Decysin, a new member of the metalloproteinase family, is regulated by prolactin
      and steroids during mouse pregnancy.
AB  - More than 300 separated actions have been attributed to prolactin (PRL), which
      could be correlated to the quasi-ubiquitous distribution of its receptor. Null
      mutation of the PRL receptor (PRLR) gene leads to female sterility caused by a
      failure of embryo implantation. Using the PRLR knockout mouse model and the mRNA
      differential display method, among 45 isolated genes, we identified UA+4 as a PRL
      and steroids-target gene during the peri-implantation period that encodes the
      decysin. Hormonally regulated in the uterus during pregnancy, this new member of
      disintegrin metalloproteinase is present in the uterus at the site of blastocyst
      apposition in nondifferentiated stromal cells at the antimesometrial pole and,
      interestingly, is colocalized with the PRLR. At midpregnancy, decysin expression
      persists specifically at the foeto-maternal junction around vessels. Although it
      has been previously suggested that decysin expression is related to immune
      function, its function during pregnancy remains to be clearly established.

PMID- 12606480
TI  - Characterization of normal spermiation and spermiation failure induced by hormone
      suppression in adult rats.
AB  - At the end of spermatogenesis, elongated spermatids are released from supporting
      Sertoli cells via the process termed spermiation. Previous studies have shown
      that spermiation failure occurs after hormone suppression, in which spermatids
      are retained instead of releasing. However, the molecular mechanisms involved in
      spermiation and spermiation failure are largely unknown. The aims of the present
      study were, first, to characterize the ultrastructural events associated with
      normal spermiation and spermiation failure using light and electron microscopy
      and, second, to investigate the localization of cell adhesion-associated (beta1
      integrin and cadherins) and junction-associated molecules (integrin-associated
      kinase [ILK], beta-catenin, and espin) during these processes. Four adult Sprague
      Dawley rats received testosterone and estradiol implants and FSH antibody (2 mg
      kg-1 day-1) for 7 days to suppress testicular testosterone and FSH and to induce
      spermiation failure. Four rats treated with saline were used as controls. After
      testosterone and FSH suppression, spermiation at the ultrastructural level
      appeared to be normal until the final disengagement of the spermatids from
      Sertoli cells (stage VIII), at which stage a large number of retained spermatids
      were noted. Immunohistochemical localization of espin showed that during
      spermiation, removal of the ectoplasmic specialization (ES) occurred 30 h before
      spermatid disengagement, suggesting that non-ES junctions mediate the spermatid
      Sertoli cell interaction before and during disengagement. beta1-Integrin and beta
      catenin remained associated with spermatids after ES removal and until
      disengagement; however, ILK was removed along with the ES. Though detectable, N
      cadherin was not associated with the spermatid-Sertoli cell junction. After
      testosterone and FSH suppression, beta1-integrin, but not N-cadherin or beta
      catenin, remained associated with spermatids that failed to spermiate. In
      conclusion, hormone suppression-induced spermiation failure is caused by defects
      in the disengagement of spermatids from the Sertoli cell, and this process likely
      is mediated by beta1-integrin in an ILK-independent mechanism.

PMID- 12606481
TI  - Meiotic competence of equine oocytes and pronucleus formation after
      intracytoplasmic sperm injection (ICSI) as related to granulosa cell apoptosis.
AB  - Follicle atresia and granulosa cell apoptosis may be related to oocyte meiotic
      and developmental competence. We analyzed the relationships among granulosa cell
      apoptosis, initial cumulus morphology, oocyte nuclear maturation in vitro, and
      pronucleus formation after intracytoplasmic sperm injection (ICSI) in the horse.
      For each follicle, the size was measured and granulosa cells were used for DNA
      laddering analysis. Oocytes were evaluated for cumulus morphology, cultured for
      in vitro maturation, and submitted to ICSI. Apoptosis was categorized as absent,
      intermediate, or advanced according to the relative concentrations of two DNA
      fragments at 900 and 360 base pairs (bp). In 98 oocyte-follicle pairs, 52 oocytes
      were classified as expanded (Exp), 39 as compact (Cp), and 7 as having a partial
      (P) cumulus. Advanced apoptosis was detected in 55% (54/98) of follicles; 37%
      (36/98) of follicles showed an intermediate level of apoptosis; and 8 follicles
      (8%) were nonapoptotic. Follicle size was not significantly correlated with
      granulosa cell apoptosis (P > 0.05). Significantly more Exp than Cp oocytes
      originated from follicles with advanced apoptosis (P < 0.001). The proportion of
      oocytes maturing in vitro was significantly higher in oocytes issuing from
      apoptotic follicles than in oocytes issuing from healthy follicles (P < 0.05).
      The proportion of normally (two pronuclei) or abnormally fertilized oocytes (one
      or greater than two pronuclei, or partially decondensed sperm) did not differ in
      relation to granulosa cell apoptosis. We conclude that, in the mare, granulosa
      cell apoptosis is related to cumulus expansion and an increase in oocyte meiotic
      competence but has no effect on the proportion of meiotically competent oocytes
      that activate after ICSI. These results provide selection criteria for horse
      oocytes used in assisted reproductive techniques so that embryo production may be
      maximized.

PMID- 12606482
TI  - Lead reduces messenger RNA and protein levels of cytochrome p450 aromatase and
      estrogen receptor beta in human ovarian granulosa cells.
AB  - Exposure to lead causes decreased fertility in women. In the present study, we
      examined the in vitro effects of lead on cytochrome p450 aromatase (p450 arom)
      and on estrogen receptor beta (ERbeta), two key proteins for the human ovary.
      Aromatase is required for the bioconversion of androgen to estradiol; ERbeta
      mediates estrogen effects in granulosa cells. Granulosa cells were collected from
      women undergoing in vitro fertilization and then cultured with 10 microM lead
      acetate. Using atomic absorption spectrometry, we showed that lead accumulated in
      cells. Aromatase activity as measured by a tritiated water production assay was
      significantly reduced. Using semiquantitative reverse transcription-polymerase
      chain reaction and Western blotting procedures, we showed that p450 arom and
      ERbeta mRNA and protein content were both significantly reduced. Adding 10
      microg/ml of cycloheximide, a protein inhibitor, did not eliminate the effects of
      lead. The present results support the hypothesis that the action of lead on
      fertility in women may result, in part, from the down-regulation of p450 arom and
      ERbeta gene transcription in ovarian granulosa.

PMID- 12606483
TI  - Receptor tyrosine kinase Ron is expressed in mouse reproductive tissues during
      embryo implantation and is important in trophoblast cell function.
AB  - Ron is a receptor tyrosine kinase that is activated by the binding of hepatocyte
      growth factor-like (HGFL) protein. Mutations in the catalytic domain of this
      receptor result in an aggressively invasive phenotype. Conversely, deletion of
      the entire receptor results in an embryonic lethality by Embryonic Day 7.5. The
      specific cellular localization and mechanisms of action of Ron and HGFL during
      embryo implantation are not known. Therefore, this report characterizes the
      temporal and spatial distribution of this receptor during mouse embryo
      implantation and placentation. Reverse transcription-polymerase chain reaction
      analysis demonstrated the presence of Ron transcripts in the uterus, placenta,
      testis, and epididymis, whereas HGFL transcripts were found in the cervix,
      placenta, epididymis, and testis. In situ hybridization and immunohistochemical
      analyses demonstrated that Ron was present in the cells of the ectoplacental cone
      and trophoblast giant cell regions surrounding the implanting embryo. Ron
      expression was also observed in SM9-1, SM9-2, and SM-10 murine trophoblast cell
      lines. To determine the effects of Ron activation on trophoblast function,
      Matrigel invasion and cell survival assays were performed using the SM9-1 and SM
      10 trophoblast cell lines. The HGFL stimulation of these cells increased invasion
      and enhanced cell survival. These observations suggest that activation of the Ron
      receptor by HGFL binding may aid in implantation by way of trophoblast function
      and viability.

PMID- 12606484
TI  - Steroidogenic acute regulatory protein in ovarian follicles of gonadotropin
      stimulated rats is regulated by a gonadotropin-releasing hormone agonist.
AB  - The aim of the present study was to examine the acute and chronic effects of the
      gonadotropin-releasing hormone agonist (GnRH-a) leuprolide acetate (LA) on the
      expression of the steroidogenic acute regulatory protein (StAR), the cytochrome
      P450 side-chain cleavage enzyme (P450scc), and steroid production in antral
      ovarian follicles obtained from prepubertal equine choriogonadotropin (eCG)
      treated rats. Follicular contents of StAR and P450scc proteins were measured by
      Western blotting following in vivo injection of eCG (control) and eCG+LA (LA) to
      prepubertal rats. Treatment with eCG for 2 h resulted in no change in StAR
      protein content, but it was markedly increased at 4 and 8 h after hormone
      treatment. However, coadministration of eCG+LA produced a significant increase (P
      < 0.05) in StAR protein levels at 2, 4, and 8 h when compared with eCG treatment.
      Acute and chronic treatment with either eCG or eCG+LA did not alter the P450scc
      protein levels in freshly isolated follicles. The increase in StAR protein
      expression following LA treatment was qualitatively similar to StAR mRNA
      expression, as determined by quantitative reverse transcription-polymerase chain
      reaction (RT-PCR) analysis. Furthermore, administration of eCG demonstrated a
      time-dependent increase (2-8 h) in the levels of StAR mRNA, and these levels were
      markedly increased by eCG+LA. However, the temporal response pattern of StAR mRNA
      was much greater at 2 h following LA administration when compared with controls.
      In addition, 48 h of LA treatment in eCG-treated rats resulted in a significant
      increase (P < 0.05) in follicular progesterone levels, whereas significant
      decreases in androgen (testosterone and androsterone) and estradiol levels were
      observed. Similar results were obtained when serum androgens and estradiol were
      measured, but serum progesterone levels were unchanged. Collectively, these
      findings demonstrate that the inhibitory effect of LA on ovarian androgen and
      estradiol levels is related to changes in the follicular levels of StAR protein
      and steroid production.

PMID- 12606485
TI  - Tight junction messenger RNA expression levels in bovine embryos are dependent
      upon the ability to compact and in vitro culture methods.
AB  - We have established a transcription map of individual bovine embryos using
      semiquantitative reverse transcriptase-polymerase chain reaction to detect the
      levels of six marker genes involved in early embryo differentiation. The critical
      step of compaction during preimplantation development is often not accomplished
      or it takes place for only a short period in in vitro generated embryos, which
      may result in reduced viability. Compaction is accompanied by the assembly of
      intercellular tight junctions (TJs) as a barrier against the extraembryonic
      environment and as a prerequisite for blastocele formation. In the present study,
      we have related the expression of TJ gene mRNA in individual bovine embryos to
      their developmental stage, their competence to undergo a clear period of
      compaction before blastocyst formation, and their in vitro or in vivo origin. Our
      results indicate that embryos that showed a detectable and well-formed compaction
      period in vitro are of similar quality to their in vivo counterparts. Starting
      from the same amount of maternal message, in vivo and in vitro development differ
      most during the critical period of the major switch from maternal to embryonic
      genomic control before a dramatic increase of TJ mRNAs occurs upon blastocyst
      formation. Failure to compact in vitro results in significant reduction of
      specific transcript levels, in a manner that depends on culture conditions, which
      may contribute to reduced viability. We conclude that TJ mRNA expression levels
      are sensitive to environmental conditions that may influence the developmental
      potential of bovine blastocysts.

PMID- 12606486
TI  - Cloning and spatiotemporal expression of the follicle-stimulating hormone beta
      subunit complementary DNA in the African catfish (Clarias gariepinus).
AB  - The gene and cDNA encoding a putative follicle-stimulating hormone beta subunit
      (cfFSHbeta) from African catfish (Clarias gariepinus) were cloned. Similar to
      other FSHbeta genes, the cfFSHbeta gene consisted of three exons interrupted by
      two introns. The cfFSHbeta cDNA coded for a mature protein of 115 amino acids.
      The 12 cysteines that are required for the typical tertiary folding of
      glycoprotein hormone beta subunits were positionally conserved in cfFSHbeta. The
      cfFSHbeta mRNA expression was exclusively detected in the pituitary and was
      detectable before pubertal development was initiated. The cfFSHbeta transcript
      levels increased in particular during early stages of puberty and reached
      constantly high levels after the first appearance of spermatids in the testis.
      The cfFSHbeta mRNA-positive cells were localized in the proximal pars distalis.
      Castration of mature males caused elevated cfFSHbeta mRNA levels that were
      decreased by steroid replacement. Previous work indicated that the African
      catfish is an interesting model to study the regulation of gonadal functions
      because cfLH is able to activate both the catfish luteinizing hormone receptor
      (cfLH-R) and follicle-stimulating hormone receptor (cfFSH-R). Because cfFSH
      purification has failed so far, ongoing studies are directed toward the
      production of recombinant cfFSH. After all, the developmental and hormonal
      regulation of cfFSHbeta transcript levels opens the possibility for
      physiologically relevant actions of the putative cfFSH, next to the presumptive
      bifunctionally acting cfLH.

PMID- 12606487
TI  - Identification of caspase-6 in rat blastocysts and its implication in the
      induction of apoptosis by high glucose.
AB  - Previous investigations have shown that maternal diabetes impairs rodent embryo
      development during the earliest phase of gestation. Exposure to high
      concentrations of glucose before implantation results in a decrease in the number
      of cells per embryo and in a concomitant increase in two nuclear markers of
      apoptosis: chromatin degradation and nuclear fragmentation. In the present study,
      we show that caspase-6 is expressed in rat blastocysts, using reverse
      transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry. Caspase
      6 is detected in all cells of the blastocyst and is excluded from the nucleus. To
      assess the role of caspase-6 in the glucose-induced apoptosis, rat blastocysts
      were incubated for 24 h in either 6 or 28 mM glucose in the presence or absence
      of a specific inhibitor of caspase-6 (VEID-CHO, 100 nM). After incubation,
      blastocysts were examined for the proportion of nuclei showing signs of chromatin
      degradation and nuclear fragmentation. Addition of VEID-CHO was found to inhibit
      nuclear fragmentation, but did not prevent the increase in chromatin degradation
      triggered by excess glucose. Our data indicate that chromatin degradation and
      nuclear fragmentation are two nuclear damages that are induced separately by high
      glucose in rat blastocysts. Furthermore, nuclear fragmentation in rat blastocysts
      is apparently mediated by the activation of caspase-6.

PMID- 12606488
TI  - Synergistic effects of cystic fibrosis transmembrane conductance regulator and
      aquaporin-9 in the rat epididymis.
AB  - The cystic fibrosis transmembrane conductance regulator (CFTR) and aquaporin-9
      (AQP-9) are present in the luminal membrane of the epididymis, where they play an
      important role in formation of the epididymal fluid. Evidence is accumulating
      that CFTR regulates other membrane transport proteins besides functioning as a
      cAMP-activated chloride channel. We have explored the possible interaction
      between epididymal CFTR and AQP-9 by cloning them from the rat epididymis and
      expressing them in Xenopus oocytes. The effects of the expressed proteins on
      oocyte water permeability were studied by immersing oocytes in a hypo-osmotic
      solution, and the ensuing water flow was measured using a gravimetric method. The
      results show that AQP-9 alone caused an increase in oocyte water permeability,
      which could be further potentiated by CFTR. This potentiation was markedly
      reduced by phloretin and lonidamine (inhibitors of AQP-9 and CFTR, respectively).
      The regulation of water permeability by CFTR was also demonstrated in intact rat
      epididymis luminally perfused with a hypo-osmotic solution. Osmotic water
      reabsorption across the epididymal tubule was reduced by phloretin and
      lonidamine. Elevation of intracellular cAMP with 3-isobutyl-1-methylxanthine
      increased osmotic water permeability, whereas inhibiting protein kinase A with H
      89 (N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline sulfonamide hydrochloride)
      reduced it. These results are consistent with a role for CFTR in controlling
      water permeability in the epididymis in vivo. We conclude that this additional
      role of CFTR in controlling water permeability may have an impact on the genetic
      disease cystic fibrosis, in which men with a mutated CFTR gene have abnormal
      epididymis and infertility.

PMID- 12606489
TI  - B7 family molecules are favorably positioned at the human maternal-fetal
      interface.
AB  - The human placenta utilizes both active and passive mechanisms to evade rejection
      by the maternal immune system. We investigated the pattern of expression of the
      B7 family of immunomodulatory molecules B7-H1 (PD-L1), B7-2 (CD86), and B7-1
      (CD80) at the term maternal-fetal interface. Northern blot and reverse
      transcription-polymerase chain reaction (RT-PCR) analyses showed that B7-H1 mRNA
      is abundant in term placenta and that cytotrophoblasts are sources of this
      message. Immunohistochemistry demonstrated that B7-H1 is constitutively expressed
      by the syncytiotrophoblast and by extravillous cytotrophoblasts, both of which
      are juxtaposed to maternal blood and tissue. By contrast, placental stromal
      cells, including macrophages, lacked the protein. Expression of B7-H1 protein was
      low in first-trimester placenta compared to second- and third-trimester tissue (P
      < 0.05) and was enhanced in cultured cytotrophoblasts by treatment with either
      interferon-gamma or epidermal growth factor (P < 0.05), suggesting that one or
      both of these mediators regulates B7-H1 expression in the placenta. RT-PCR and
      immunofluorescence analysis of term placental tissue revealed different patterns
      of expression of the immunostimulatory protein, B7-2. In contrast to B7-H1, B7-2
      mRNA and protein were absent in cytotrophoblast cells but present in maternal
      macrophages and some fetal macrophages. The B7-1 mRNA and protein were absent at
      the maternal-fetal interface. These studies document expression of the B7 family
      proteins at the maternal-fetal interface and demonstrate that B7-H1 is positioned
      such that it could facilitate protection of fetal cells against activated
      maternal leukocytes. Conversely, B7-2 was absent on trophoblasts and was
      appropriately localized to fetal and maternal macrophages, which may participate
      in antigen presentation.

PMID- 12606490
TI  - Transgene expression of green fluorescent protein and germ line transmission in
      cloned calves derived from in vitro-transfected somatic cells.
AB  - In vitro transfection of cultured cells combined with nuclear transfer currently
      is the most effective procedure to produce transgenic livestock. In the present
      study, bovine primary fetal fibroblasts were transfected with a green fluorescent
      protein (GFP)-reporter transgene and used as nuclear donor cells in oocyte
      reconstructions. Because cell synchronization protocols are less effective after
      transfection, activated oocytes may be more suitable as hosts for nuclear
      transfer. To examine the role of host cytoplasm on transgene expression and
      developmental outcome, GFP-expressing fibroblasts were fused to oocytes
      reconstructed either before (metaphase) or after (telophase) activation.
      Expression of GFP was examined during early embryogenesis, in tissues of cloned
      calves, and again during embryogenesis, after passage through germ line using
      semen from the transgenic cloned offspring. Regardless of the kind of host
      cytoplasm used, GFP became detectable at the 8- to 16-cell stage, approximately
      80 h after reconstruction, and remained positive at all later stages. After
      birth, although cloned calves obtained through both procedures expressed GFP in
      all tissues examined, expression levels varied both between tissues and between
      cells within the same tissue, indicating a partial shutdown of GFP expression
      during cellular differentiation. Moreover, nonexpressing fibroblasts derived from
      transgenic offspring were unable to direct GFP expression after nuclear transfer
      and development to the blastocyst stage, suggesting an irreversible silencing of
      transgenes. Nonetheless, GFP was expressed in approximately half the blastocysts
      obtained with sperm from a transgenic clone, confirming transmission of the
      transgene through the germ line.

PMID- 12606491
TI  - Luteinizing hormone receptor formation in cumulus cells surrounding porcine
      oocytes and its role during meiotic maturation of porcine oocytes.
AB  - We investigated the formation of LH receptor (LHR) in cumulus cells surrounding
      porcine oocytes and the role of LHR in meiotic maturation of oocytes. At least
      three splice variants of LHR mRNA were detected in cumulus cells, in addition to
      the full-length form. Low levels of three types of products were seen in cumulus
      cells from cumulus oocytes complexes (COCs), whereas the full-length form was
      significantly increased by 12-h cultivation with FSH. The addition of FSH also
      significantly increased the binding level of biotinylated hCG to COCs. The
      formation of LHR in FSH-stimulated cumulus cells was not affected by additional
      0.5 mM phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the
      oocytes were synchronized to the germinal vesicle (GV) II stage by exposure to
      0.5 mM IBMX and FSH for 20 h. The binding of LH to its receptor induced a further
      increase in cAMP level and progesterone production and acceleration of meiotic
      progression to the metaphase I stage. The oocytes cultured with LH for 24 h
      following cultivation with FSH and IBMX were used for in vitro fertilization. At
      6 days after in vitro fertilization, blastocyst rate in oocytes matured under
      these conditions was significantly higher than that of oocytes cultured in the
      absence of LH. Treatment of oocytes with FSH and 0.5 mM IBMX to express LH
      receptor in cumulus cells while holding oocytes at the GV II stage is a very
      beneficial way to produce in vitro-matured oocytes, which have high developmental
      competence.

PMID- 12606492
TI  - Maintenance of the inner cell mass in human blastocysts from fragmented embryos.
AB  - The degree of fragmentation during early cleavage is universally used as an
      indicator of embryo quality during human in vitro fertilization treatment.
      Extensive fragmentation has been associated with reduced blastocyst formation and
      implantation. We examined the relationship between early fragmentation and
      subsequent allocation of cells to the trophectoderm and inner cell mass in the
      human blastocyst. We retrospectively analyzed data from 363 monospermic human
      embryos that exhibited varying degrees of fragmentation on Day 2. Embryos were
      cultured from Day 2 to Day 6 in Earle balanced salt solution with 1 mM glucose
      and human serum albumin. Rates of development and blastocyst formation were
      measured. The number of cells in the trophectoderm and inner cell mass and the
      incidence of apoptosis were assessed following differential labeling with
      polynucleotide-specific fluorochromes. Increasing fragmentation resulted in
      reduced blastocyst formation and lower blastocyst cell numbers. For minimal and
      moderate levels of fragmentation, the reduction in cell numbers was confined
      largely to the trophectoderm and a steady number of inner cell mass cells was
      maintained. However, with extensive fragmentation of more than 25%, cell numbers
      in both lineages were reduced in the few embryos that formed blastocysts.
      Apoptotic nuclei were present in both the trophectoderm and inner cell mass, with
      the lowest incidence in blastocysts that had developed from embryos with minor (5
      10%) fragmentation. Paradoxically, higher levels of apoptosis were seen in
      embryos of excellent morphology, suggesting a possible role in regulation of cell
      number.

PMID- 12606494
TI  - Expression and regulation of interferon gamma-inducible proteasomal subunits LMP7
      and LMP10 in the bovine corpus luteum.
AB  - The proteasome is a large, polymeric protease complex responsible for
      intracellular protein degradation and generation of peptides that bind to class I
      major histocompatibility complex (MHC) molecules. Interferon gamma (INFgamma)
      induces expression of alternative proteasomal subunits that affect intracellular
      protein degradation, thereby changing the types of peptides that bind to class I
      MHC molecules. These alterations in class I MHC peptides can influence whether
      cells and tissues are tolerated by the immune system. Expression of two INFgamma
      inducible proteasomal subunits, LMP7 and LMP10, in bovine luteal tissue was
      examined in this study. Northern analysis revealed the presence of mRNA encoding
      LMP7 and LMP10 in luteal tissue. Steady-state amounts of LMP7 mRNA did not change
      during the estrous cycle, but LMP10 mRNA was low in early corpus luteum (CL) and
      elevated in midcycle and late CL. Tumor necrosis factor alpha alone and in the
      presence of LH and/or prostaglandin F2alpha elevated steady-state amounts of
      LMP10 mRNA but did not affect LMP7 mRNA in cultured luteal cells.
      Immunohistochemistry revealed the presence of LMP10 primarily in small luteal
      cells. Numbers of LMP10-positive cells were lower in early CL than in midcycle
      and late CL. The finding that INFgamma-inducible proteasomal subunits are
      expressed in luteal tissue when the CL is fully functional was unexpected and
      suggests that proteasomes in luteal cells may generate peptides capable of
      stimulating a class I MHC-dependent inflammatory response.

PMID- 12606493
TI  - SLLP1, a unique, intra-acrosomal, non-bacteriolytic, c lysozyme-like protein of
      human spermatozoa.
AB  - We report the presence of a unique, non-bacteriolytic, c (chicken or conventional
      type) lysozyme-like protein, SLLP1, in the acrosome of human sperm. C lysozymes
      are bacteriolytic and can also bind to N-acetylglucosamines linked by beta-1,4
      glycosidic bonds. Most of the invariant residues (17 out of 20), including all
      the cysteines, were conserved in SLLP1, but the two catalytic residues E35 and
      D52 of c lysozymes were replaced with T and N, respectively. The full-length cDNA
      encodes a protein of 215 aa with a predicted protease cleavage site between A87
      and K88. The processed form of SLLP1, which showed an exon-intron organization
      similar to human c lysozyme, was the major isoform in the acrosome of ejaculated
      sperm. As expected, based on its sequence, the mature protein secreted from yeast
      showed no bacteriolytic activity. A significant decrease (54%, P < or = 0.001) in
      the number of sperm bound to zona-free hamster eggs was observed in the presence
      of antisera to recombinant SLLP1. SLLP1 mRNA (size, approximately 1 kb) appeared
      to be expressed only in the testis and in the Burkitt lymphoma Raji cell line.
      The gene SPACA3 encodes SLLP1 and contains five exons at locus 17q11.2. Because
      of its typical c lysozyme-like sequence, genomic organization, conservation of
      putative substrate-binding sites even in the absence of catalytic residues, and
      localization in the acrosomal matrix, we hypothesize that, after acrosome
      reaction, SLLP1 could be a potential receptor for the egg oligosaccharide residue
      N-acetylglucosamine, which is present in the extracellular matrix over the egg
      plasma membrane, within the perivitelline space, pores of zona pellucida, and
      cumulus layers.

PMID- 12606495
TI  - Growth hormone-related effects on apoptosis, mitosis, and expression of connexin
      43 in bovine in vitro maturation cumulus-oocyte complexes.
AB  - Pituitary LH and FSH are known to be the major regulators of ovarian function. In
      the last few years, however, there has been evidence that growth hormone (GH) is
      also involved in ovarian regulation. Therefore, the aim of our study was to
      elucidate the mechanisms of GH action during in vitro maturation (IVM) of bovine
      cumulus-oocyte complexes (COCs). As shown by detection of the nuclear cell
      proliferation-associated antigen Ki-67, COCs matured in vitro in the presence of
      GH revealed a significantly (P < 0.05) higher proportion of proliferating cumulus
      cells (12.6%) compared with the COCs matured in the control medium TCM 199
      (9.9%). In contrast, the percentage of proliferating cells was not increased by
      supplementation of the medium with a combination of GH and insulin-like-growth
      factor I (IGF-I). Apoptosis as determined by TUNEL (terminal doxynucleotidyl
      transferase mediated dUTP nick-end labeling) was significantly (P < 0.05) reduced
      in the cumulus cells by GH treatment. COCs matured with a combination of GH and
      IGF-I revealed the lowest percentage of apoptotic cells (11%). The localization
      and quantification of the gap junction protein connexin 43 (Cx 43) demonstrated
      that GH induced a significant decrease in the synthesis of the Cx 43 protein in
      the cumulus cells. Our results imply that GH increases cumulus expansion by
      promotion of cell proliferation and inhibition of apoptosis. Whereas the increase
      in cell proliferation is a direct effect of GH, the antiapoptotic effects of GH
      during in vitro maturation are modulated by IGF-I. Stimulatory effects of GH on
      oocyte maturation are correlated with changes in the synthesis of gap junction
      proteins.

PMID- 12606496
TI  - Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the
      glutathione connection.
AB  - Chronic exposure to hyperglycemia can lead to cellular dysfunction that may
      become irreversible over time, a process that is termed glucose toxicity. Our
      perspective about glucose toxicity as it pertains to the pancreatic beta-cell is
      that the characteristic decreases in insulin synthesis and secretion are caused
      by decreased insulin gene expression. The responsible metabolic lesion appears to
      involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA
      maturation. PDX-1 is a critically important transcription factor for the insulin
      promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic
      beta-cells, improves insulin promoter activity. Because reactive oxygen species
      are produced via oxidative phosphorylation during anaerobic glycolysis, via the
      Schiff reaction during glycation, via glucose autoxidation, and via hexosamine
      metabolism under supraphysiological glucose concentrations, we hypothesize that
      chronic oxidative stress is an important mechanism for glucose toxicity. Support
      for this hypothesis is found in the observations that high glucose concentrations
      increase intraislet peroxide levels, that islets contain very low levels of
      antioxidant enzyme activities, and that adenoviral overexpression of antioxidant
      enzymes in vitro in islets, as well as exogenous treatment with antioxidants in
      vivo in animals, protect the islet from the toxic effects of excessive glucose
      levels. Clinically, consideration of antioxidants as adjunct therapy in type 2
      diabetes is warranted because of the many reports of elevated markers of
      oxidative stress in patients with this disease, which is characterized by
      imperfect management of glycemia, consequent chronic hyperglycemia, and
      relentless deterioration of beta-cell function.

PMID- 12606497
TI  - Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of
      glucose transport and utilization in vitro and in vivo.
AB  - Insulin resistance plays a central role in the development of type 2 diabetes,
      but the precise defects in insulin action remain to be elucidated. Glycogen
      synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin
      signaling, and elevated levels of GSK-3 have been reported in skeletal muscle
      from diabetic rodents and humans. A limited amount of information is available
      regarding the utility of highly selective inhibitors of GSK-3 for the
      modification of insulin action under conditions of insulin resistance. In the
      present investigation, we describe novel substituted aminopyrimidine derivatives
      that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold
      selectivity against 20 other protein kinases. These low molecular weight
      compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO
      cells transfected with the insulin receptor and in primary hepatocytes isolated
      from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of
      both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors
      enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the
      insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats.
      Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered
      blood glucose levels and improved glucose disposal after oral or intravenous
      glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or
      markedly elevating insulin. Collectively, our results suggest that these
      selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the
      treatment of the insulin resistance of type 2 diabetes.

PMID- 12606498
TI  - Disruption of the striated muscle glycogen targeting subunit PPP1R3A of protein
      phosphatase 1 leads to increased weight gain, fat deposition, and development of
      insulin resistance.
AB  - Disruption of the PPP1R3A gene encoding the glycogen targeting subunit
      (G(M)/R(GL)) of protein phosphatase 1 (PP1) causes substantial lowering of the
      glycogen synthase activity and a 10-fold decrease in the glycogen levels in
      skeletal muscle. Homozygous G(M)(-/-) mice show increased weight gain after 3
      months of age and become obese, weighing approximately 20% more than their wild
      type (WT) littermates after 12 months of age. Glucose tolerance is impaired in 11
      month-old G(M)(-/-) mice, and their skeletal muscle is insulin-resistant at > or
      =12 months of age. The massive abdominal and other fat depositions observed at
      this age are likely to be a consequence of impaired blood glucose utilization in
      skeletal muscle. PP1-G(M) activity, assayed after specific immunoadsorption, was
      absent from G(M)(-/-) mice and stimulated in the hind limb muscles of WT mice by
      intravenous infusion of insulin. PP1-R5/PTG, another glycogen targeted form of
      PP1, was not significantly stimulated by insulin in the skeletal muscle of WT
      mice but showed compensatory stimulation by insulin in G(M)(-/-) mice. Our
      results suggest that dysfunction of PP1-G(M) may contribute to the
      pathophysiology of human type 2 diabetes.

PMID- 12606499
TI  - Role of corticotrophin-releasing hormone in the impairment of counterregulatory
      responses to hypoglycemia.
AB  - We have explored the role of individual elements of the hypothalamic pituitary
      adrenal axis on the pathogenesis of hypoglycemia-associated autonomic failure.
      Five groups of male Sprague-Dawley rats were used. Control animals had 3 days of
      sham treatment followed by a hyperinsulinemic/hypoglycemic glucose clamp on day
      4. A second group underwent 3 days of antecedent insulin-induced hypoglycemia
      then a subsequent clamp. Three more groups underwent pretreatment with
      corticosterone, adrenocorticotrophic hormone (ACTH), or corticotrophin-releasing
      hormone (CRH) mirroring the glucocorticoid response of the hypoglycemic group.
      Subsequent counterregulatory responses showed marked differences. CRH- (and
      insulin-treated) animals showed markedly reduced epinephrine responses (CRH 1,276
      +/- 404 pg/ml, controls 3,559 +/- 563 pg/ml; P < 0.05). In contrast, ACTH
      pretreatment augmented epinephrine responses (6,681 +/- 814 pg/ml; P = 0.007
      versus controls); corticosterone pretreatment caused a similar but nonsignificant
      enhancement. The same pattern was seen for norepinephrine. CRH pretreatment also
      suppressed glucagon responses to hypoglycemia (control 157 +/- 21, CRH 68 +/- 10
      pg/ml; P = 0.004). The addition of a CRH receptor 1 (CRHr1) antagonist to the
      antecedent CRH reversed the subsequent suppression of epinephrine. These findings
      suggest that CRH acting via CRHr1 plays an important role in the sympathoadrenal
      downregulation seen in this rodent model of antecedent hypoglycemia; this action
      is not mediated via activation of the hypothalamic-pituitary-adrenal axis.

PMID- 12606500
TI  - Contribution of fatty acids released from lipolysis of plasma triglycerides to
      total plasma fatty acid flux and tissue-specific fatty acid uptake.
AB  - There is controversy over the extent to which fatty acids (FAs) derived from
      plasma free FAs (FFAs) or from hydrolysis of plasma triglycerides (TGFAs) form
      communal or separate pools and what the contribution of each FA source is to
      cellular FA metabolism. Chylomicrons and lipid emulsions were labeled with
      [(3)H]triolein, injected into mice, and appearance in plasma of [(3)H]oleic acid
      was estimated, either through a steady-state approach or by compartmental
      modeling. [(14)C]oleic acid was included to trace plasma FFA. Eighty to 90% of
      triglyceride (TG) label was recovered in plasma, irrespective of tracer method or
      TG source. The contribution of TG lipolysis to total plasma FA turnover was 10
      20%. After infusion of [(3)H]TG and [(14)C]FA, the retention of these labels
      varied substantially among liver, adipose tissue, and skeletal and heart muscle.
      Retention of TG label changed during fasting in the same direction as lipoprotein
      lipase (LPL) activity is regulated. We propose a model that reconciles the
      paradoxical 80-90% loss of TG label into plasma with LPL-directed differential
      uptake of TGFA in tissues. In this model, TGFAs mix locally at the capillaries
      with plasma FFAs, where they would lead to an increase in the local FA
      concentration, and hence, FA uptake. Our data indicate that a distinction between
      TG-derived FA and plasma FFA cannot be made.

PMID- 12606501
TI  - Acute hyperglycemia causes intracellular formation of CML and activation of ras,
      p42/44 MAPK, and nuclear factor kappaB in PBMCs.
AB  - Twenty-three nondiabetic volunteers were divided into three groups. In group A (n
      = 9), the glucose infusion was adjusted to maintain blood glucose at 5 mmol/l
      (euglycemic clamp). In group B (n = 9), the glucose infusion was adjusted to
      maintain blood glucose at 10 mmol/l (hyperglycemic clamp) over 2 h. Group C
      consisted of five volunteers who were studied as the control group. Peripheral
      blood mononuclear cells (PBMCs) were isolated before and at the end of a 2-h
      clamp. In group C, PBMCs were isolated before and after 2 h without performing a
      clamp. The euglycemic clamp as well as "no clamp" had no effects on all
      parameters studied. In contrast, a significant increase in carboxymethyllysine
      (CML) content and p21(ras) and p42/44 mitogen-activated protein kinase (MAPK)
      phosphorylation was observed at the end of a 2-h hyperglycemic clamp. The nuclear
      factor (NF)-kappaB (but not Oct-1) binding activity increased significantly in
      the hyperglycemic clamp. Western blots confirmed NF-kappaB-p65-antigen
      translocation into the nucleus. IkappaBalpha did not change significantly in both
      groups. Hyperglycemia-mediated NF-kappaB activation and increase of CML content,
      p21(ras), and p42/44 MAPK phosphorylation was also seen in ex vivo-isolated PBMCs
      stimulated with 5 or 10 mmol/l glucose. Addition of insulin did not influence the
      results. Inhibition of activation of ras, MAPK, or protein kinase C blocked
      hyperglycemia-mediated NF-kappaB activation in ex vivo-isolated PBMCs stimulated
      with 10 mmol/l glucose. Similar data were obtained using an NF-kappaB-luciferase
      reporter plasmid. Therefore, we can conclude that an acute hyperglycemia-mediated
      mononuclear cell activation is dependent on activation of ras, p42/p44 MAPK
      phosphorylation, and subsequent NF-kappaB activation and results in
      transcriptional activity in PBMCs.

PMID- 12606502
TI  - Enhanced basal activation of mitogen-activated protein kinases in adipocytes from
      type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression.
AB  - Serine and threonine kinases may contribute to insulin resistance and the
      development of type 2 diabetes. To test the potential for members of the mitogen
      activated protein (MAP) kinase family to contribute to type 2 diabetes, we
      examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in
      adipocytes isolated from healthy and type 2 diabetic individuals. Maximal insulin
      stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control
      subjects but not type 2 diabetic patients. Insulin stimulation did not increase
      p38 phosphorylation in either healthy control subjects or type 2 diabetic
      patients. In type 2 diabetic adipocytes, the basal phosphorylation status of
      these MAP kinases was significantly elevated and was associated with decreased
      IRS-1 and GLUT4 in these fat cells. To determine whether MAP kinases were
      involved in the downregulation of IRS-1 and GLUT4 protein levels, selective
      inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated
      chronically with insulin. Inhibition of Erk 1/2, JNK, or p38 had no effect on
      insulin-stimulated reduction of IRS-1 protein levels. However, inhibition of the
      p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. In
      summary, type 2 diabetes is associated with an increased basal activation of the
      MAP kinase family. Furthermore, upregulation of the p38 pathway might contribute
      to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic
      patients.

PMID- 12606503
TI  - Regulation of PGC-1 promoter activity by protein kinase B and the forkhead
      transcription factor FKHR.
AB  - Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) plays a
      major role in mediating hepatic gluconeogenesis in response to starvation, during
      which PGC-1 is induced by the cyclic AMP response element binding protein.
      Although it is observed that insulin counteracts PGC-1 transcription, the
      mechanism by which insulin suppresses the transcription of PGC-1 is still
      unclear. Here, we show that forkhead transcription factor FKHR contributes to
      mediating the effects of insulin on PGC-1 promoter activity. Reporter assays
      demonstrate that insulin suppresses the basal PGC-1 promoter activity and that
      coexpression of protein kinase (PK)-B mimics the effect of insulin in HepG2
      cells. Insulin response sequences (IRSs) are addressed in the PGC-1 promoter as
      the direct target for FKHR in vivo. Coexpression of FKHR stimulates the PGC-1
      promoter activity via interaction with the IRSs, while coexpression of FKHR (3A),
      in which the three putative PKB sites in FKHR are mutated, mainly abolishes the
      suppressive effect of PKB. Whereas deletion of the IRSs prevents the promoter
      stimulation by FKHR, that activity is still partially inhibited by insulin. These
      results indicate that signaling via PKB to FKHR can partly account for the effect
      of insulin to regulate the PGC-1 promoter activity via the IRSs.

PMID- 12606504
TI  - Palmitate-induced activation of the hexosamine pathway in human myotubes:
      increased expression of glutamine:fructose-6-phosphate aminotransferase.
AB  - The nutrient sensing capacity of the hexosamine biosynthetic pathway (HBP) has
      been implicated in the development of insulin resistance of skeletal muscle. To
      study the molecular mechanism of the free fatty acid (FFA)-induced activation of
      the HBP myotubes obtained from muscle biopsies of metabolically characterized,
      subjects were stimulated with different fatty acids for 20 h. Incubation with the
      saturated fatty acids palmitate and stearate (0.5 mmol/l) resulted in a three- to
      fourfold increase in mRNA expression of glutamine:fructose-6-phosphate
      aminotransferase (GFAT), the key and rate-limiting enzyme of the hexosamine
      pathway. Unsaturated fatty acids or 30 mmol/l glucose had little or no effect.
      Palmitate increased the amount of GFAT protein nearly two-fold, and subsequently,
      the concentration of UDP-N-acetylglucosamine, the end product of the HBP, was 1.3
      fold enhanced in the palmitate-stimulated myotubes. The nonmetabolized fatty acid
      bromopalmitate had no effect. The DNA binding activity of the transcription
      factor Sp1, a target downstream of the HBP, was increased by palmitate and
      completely lost after enzymatic removal of O-GlcNAc. No correlation was found
      between the palmitate-induced increase in GFAT protein and the insulin resistance
      in the respective subjects. The findings reveal a new mechanism for how FFAs
      induce the activation of the HBP.

PMID- 12606505
TI  - Effect of short-term fasting and refeeding on transcriptional regulation of
      metabolic genes in human skeletal muscle.
AB  - During short-term fasting, substrate utilization in skeletal muscle shifts from
      predominantly carbohydrate to fat as a means of conserving glucose. To examine
      the potential influence of short-term fasting and refeeding on transcriptional
      regulation in skeletal muscle, muscle biopsies were obtained from nine male
      subjects at rest, after 20 h of fasting, and 1 h after consuming either a high
      carbohydrate (CHO trial) or a low-carbohydrate (FAT trial) meal. Fasting induced
      an increase in transcription of the pyruvate dehydrogenase kinase 4 (PDK4) (10
      fold), lipoprotein lipase (LPL) ( approximately 2-fold), uncoupling protein 3
      (UCP3) ( approximately 5-fold), and carnitine palmitoyltransferase I (CPT I) (
      approximately 2.5-fold) genes. Surprisingly, transcription of PDK4 and LPL
      increased further in response to refeeding (both trials) to more than 50-fold and
      6- to 10-fold, respectively, over prefasting levels. However, responses varied
      among subjects with two subjects in particular displaying far greater activation
      of PDK4 (>100-fold) and LPL (>20-fold) than the other subjects (mean
      approximately 8-fold and approximately 2-fold, respectively). Transcription of
      UCP3 decreased to basal levels after the CHO meal but remained elevated after the
      FAT meal, whereas CPT I remained elevated after both refeeding meals. The present
      findings demonstrate that short-term fasting/refeeding in humans alters the
      transcription of several genes in skeletal muscle related to lipid metabolism.
      Marked heterogeneity in the transcriptional response to the fasting/refeeding
      protocol suggests that individual differences in genetic profile may play an
      important role in adaptive molecular responses to metabolic challenges.

PMID- 12606506
TI  - Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic
      counterregulation.
AB  - We have previously reported that a glucosensor integrating hormonal responses to
      hypoglycemia is located in the ventromedial hypothalamus (VMH) and that local VMH
      glucose perfusion blocks counterregulatory hormone responses. To determine
      whether the by-product of glucose metabolism, lactate, can function within the
      VMH as an alternative for glucose, we delivered lactate locally to the VMH,
      during systemic hypoglycemia. For this purpose, we combined bilateral VMH
      microdialysis perfusion (metabolically active L-lactate or its nonmetabolizable D
      isomer) with a euglycemic-hypoglycemic clamp in conscious chronically
      catheterized Sprague-Dawley rats. Local VMH perfusion with L-lactate decreased
      counterregulatory hormone responses to hypoglycemia by 80-85% as compared with
      the nonmetabolizable D-lactate control. Moreover, hormonal suppression with L
      lactate was accompanied by an approximate fourfold increase in the amount of
      exogenous glucose infused to maintain a stable hypoglycemic plateau (P < 0.05).
      In conclusion, the glucose-sensing mechanism in the VMH responds to lactate and,
      thus, is not specific for glucose. This implies that the VMH may act as a fuel
      sensor rather than as a glucose sensor.

PMID- 12606507
TI  - Modulation of circulating and adipose tissue adiponectin levels by antidiabetic
      therapy.
AB  - The relationship between insulin action and control of the adipocyte-derived
      factor adiponectin was studied in age- and weight-matched obese individuals with
      type 2 diabetes failing sulfonylurea therapy. After initial metabolic
      characterization, subjects were randomized to troglitazone or metformin treatment
      groups; all subjects received glyburide (10 mg BID) as well. Treatment was
      continued for 3 months. The extent of glycemic control after treatment was
      similar in both groups. However, the increase in maximal insulin-stimulated
      glucose disposal rate was greater following troglitazone therapy (+44%) compared
      with metformin treatment (+20%). Troglitazone treatment increased serum
      adiponectin levels nearly threefold. There was no change in serum adiponectin
      with metformin treatment. A positive correlation was found between increases in
      whole-body glucose disposal rates and serum adiponectin levels after
      troglitazone; no such relationship was seen with metformin. The adiponectin
      protein content of subcutaneous abdominal adipocytes was increased following
      troglitazone treatment and unchanged after metformin. Adiponectin release from
      adipocytes was also augmented with troglitazone treatment. Adiponectin was
      present in adipocytes and plasma in several multimeric forms; a trimer was the
      major form secreted from adipocytes. These results indicate that increases in
      adiponectin content and secretion are associated with improved insulin action but
      are not directly related to glycemic control. Modulation of adipocyte function,
      including upregulation of adiponectin synthesis and secretion, may be an
      important mechanism by which thiazolidinediones influence insulin action.

PMID- 12606508
TI  - Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic
      subjects: effects of insulin sensitization therapy.
AB  - Whether free fatty acid (FFA) rate of appearance (R(a)) is increased in type 2
      diabetes is controversial. To characterize nocturnal and postprandial
      abnormalities in FFA kinetics and to determine the effects of treatment with
      insulin sensitizers on lipolysis, we measured palmitate R(a) in control subjects
      (n = 6) and individuals with poorly controlled, sulfonylurea-treated type 2
      diabetes (HbA(1c) = 8.7 +/- 0.2%, n = 20), the latter before and at the end of 12
      weeks of treatment with troglitazone (600 mg/day, n = 4), metformin (
      approximately 2,000 mg/day, n = 8), or placebo (n = 8). Subjects consumed a
      standard breakfast at 0800 h. Results in control subjects and type 2 diabetic
      subjects were compared at baseline. Integrated nocturnal FFA R(a) (AUC(1:00-8:00
      A.M.)) was approximately 50% higher in type 2 diabetic subjects than in control
      subjects (29.4 +/- 3.0 vs. 19.4 +/- 3.9 mmol. m(-2). 7 h(-1), respectively, P <
      0.05), whereas postprandial palmitate R(a) (AUC(0-240 min)) was almost threefold
      higher in type 2 diabetic subjects than in control subjects (14.2 +/- 1.7 vs. 5.3
      +/- 1.0 mmol. m(-2). 4 h(-1), respectively, P < 0.01). After troglitazone
      treatment, nocturnal palmitate R(a) did not change, but postprandial palmitate
      R(a) decreased by approximately 30% (P < 0.05). Palmitate kinetics did not change
      with metformin or placebo treatment. In summary, nocturnal and postprandial FFA
      R(a) is increased in type 2 diabetes. Postprandial lipolysis appears to be
      preferentially improved by thiazolidinediones compared with nocturnal lipolysis.

PMID- 12606509
TI  - Differential sensitivity to central leptin and insulin in male and female rats.
AB  - The distribution of fat in the body differs between the male and female sexes and
      is associated with the relative secretion of the two "adiposity" hormones leptin
      and insulin. We now report that the brains of male and female rats are
      differentially sensitive to the catabolic actions of small doses of these two
      hormones. Leptin (1 or 3.5 microg/2 microl) or saline (2 microl) was administered
      into the third cerebral ventricle of age- and weight-matched male and female
      rats. Leptin significantly reduced food intake in female and male rats over 4 h;
      however, leptin reduced 24-h intake in female but not in male rats. When the same
      rats were administered insulin (1 or 4 mU/2 microl) or saline (2 microl), male
      but not female rats had a robust reduction in food intake over 24 h. Previous
      research demonstrates the melanocortins are a central mediator of the effects of
      both leptin and insulin. However, we found no sex differences in sensitivity to
      the melanocortin agonist MTII (0.01, 0.1, 0.3, and 1.0 nmol/2 microl). These
      results suggest that the sex differences in sensitivity to leptin and insulin at
      the doses that we injected occur upstream of the melanocortin receptors. Because
      insulin and leptin reflect different fat beds and are differentially distributed
      in the male and female sexes, the implication is that the male and female sexes
      regulate adiposity-relevant parameters differently.

PMID- 12606510
TI  - Gene expression profiles of nondiabetic and diabetic obese mice suggest a role of
      hepatic lipogenic capacity in diabetes susceptibility.
AB  - Obesity is a strong risk factor for the development of type 2 diabetes. We have
      previously reported that in adipose tissue of obese (ob/ob) mice, the expression
      of adipogenic genes is decreased. When made genetically obese, the BTBR mouse
      strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes
      resistant. We used DNA microarrays and RT-PCR to compare the gene expression in
      BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and
      pancreatic islets. Our results show: 1) there is an increased expression of genes
      involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene
      expression was lower in adipose tissue of diabetes-susceptible mice, and it
      continued to decrease with the development of diabetes, compared with diabetes
      resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased
      and the hepatic triglyceride content was greatly elevated in diabetes-resistant
      obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the
      prediabetic stage but not at the onset of diabetes; and 5) genes normally not
      expressed in skeletal muscle and pancreatic islets were expressed in these
      tissues in the diabetic mice. We propose that increased hepatic lipogenic
      capacity protects the B6-ob/ob mice from the development of type 2 diabetes.

PMID- 12606511
TI  - Effects of identical weight loss on body composition and features of insulin
      resistance in obese women with high and low liver fat content.
AB  - Our objective was to determine how 8% weight loss influences subcutaneous, intra
      abdominal, and liver fat (LFAT), as well as features of insulin resistance, in
      obese women with high versus low LFAT. A total of 23 women with previous
      gestational diabetes were divided into groups of high (9.4 +/- 1.4%) and low (3.3
      +/- 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy.
      Both groups were similar with respect to age, BMI, and intra-abdominal and
      subcutaneous fat. Before weight loss, women with high LFAT had higher fasting
      serum insulin and triglyceride concentrations than women with low LFAT. At
      baseline, LFAT correlated with the percent of fat (r = 0.44, P < 0.05) and
      saturated fat (r = 0.45, P < 0.05) of total caloric intake but not intra
      abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was
      similar between the groups (high LFAT -7.4 +/- 0.2 vs. low LFAT -7.7 +/- 0.3 kg).
      LFAT decreased from 9.4 +/- 1.4 to 4.8 +/- 0.7% (P < 0.001) in women with high
      LFAT and from 3.3 +/- 0.4 to 2.0 +/- 0.2% (P < 0.001) in women with low LFAT. The
      absolute decrease in LFAT was significantly higher in women with high than low
      LFAT (-4.6 +/- 1.0 vs. -1.3 +/- 0.3%, P < 0.005). The decrease in LFAT was
      closely correlated with baseline LFAT (r = -0.85, P < 0.001) but not with changes
      in the volumes of intra-abdominal or subcutaneous fat depots, which decreased
      similarly in both groups. LFAT appears to be related to the amount of fat in the
      diet rather than the size of endogenous fat depots in obese women. Women with
      initially high LFAT lost more LFAT by similar weight loss than those with low
      LFAT, although both groups lost similar amounts of subcutaneous and intra
      abdominal fat. These data suggest that LFAT is regulated by factors other than
      intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply
      reflect the size of endogenous fat stores.

PMID- 12606512
TI  - Adeno-associated virus-mediated IL-10 gene therapy inhibits diabetes recurrence
      in syngeneic islet cell transplantation of NOD mice.
AB  - Islet transplantation represents a potential cure for type 1 diabetes, yet
      persistent autoimmune and allogeneic immunities currently limit its clinical
      efficacy. For alleviating the autoimmune destruction of transplanted islets,
      newly diagnosed NOD mice were provided a single intramuscular injection of
      recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4
      weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent
      protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that
      received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10
      remained normoglycemic for at least 117 days, whereas diabetes recurred within 17
      days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5
      of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV
      green fluorescent protein-transduced). Serum IL-10 levels positively correlated
      with prolonged graft survival and were negatively associated with the intensity
      of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of
      lymphocytic infiltration as well as induction of antioxidant enzymes manganese
      superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support
      the utility of immunoregulatory cytokine gene therapy delivered by rAAV for
      preventing autoimmune disease recurrence in transplant-based therapies for type 1
      diabetes.

PMID- 12606513
TI  - Processing and presentation of the islet autoantigen GAD by vascular endothelial
      cells promotes transmigration of autoreactive T-cells.
AB  - Type 1 diabetes is characterized by T-cell infiltration of the islets of
      Langerhans and abundant HLA class II molecule expression on islet endothelial
      cells (ECs). The specificity of infiltrating T-cells for islet autoantigens has
      been amply demonstrated in animal models, and is implicit in human diabetes, but
      the processes regulating endothelial transmigration of islet autoantigen-specific
      T-cells into islets are not known. We examined the ability of ECs expressing HLA
      class II molecules to process and present the islet autoantigen GAD65 and
      examined the effects of presentation on transmigration of GAD65-specific T-cells.
      Primary cultures of human vascular ECs expressing the DRB1*0401 (VEC1) and
      DRB1*0301 (VEC2) genotypes were established and de novo expression of HLA class
      II molecules induced with interferon-gamma. Under these conditions, VEC1
      efficiently processed and presented whole GAD65 to the HLA-DR4-restricted murine
      T-cell hybridoma T33.1 that recognizes the 274-286 epitope of GAD65. Using a
      transwell system, we examined the effect of GAD65 presentation on migration of
      GAD65-specific T-cells across EC monolayers. Migration of T33.1 hybridoma cells
      and of the human T-cell clone, PM1#11 (recognizes GAD65 epitope 339-352 presented
      by HLA-DR3) across VEC1 and VEC2, respectively, were greatly enhanced in the
      presence of GAD65, commencing more rapidly and achieving a higher peak migration
      at 3 h. Migrated PM1#11 cells retained full proliferative capacity. These results
      support the hypothesis that presentation of autoantigens by islet endothelium in
      vivo could promote transmigration of circulating islet autoantigen-specific T
      cells primed in regional lymph nodes against islet autoantigens.

PMID- 12606514
TI  - Monounsaturated fatty acids prevent the deleterious effects of palmitate and high
      glucose on human pancreatic beta-cell turnover and function.
AB  - Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function
      observed in type 2 diabetes. Here we examine the effect of saturated and
      monounsaturated fatty acids at different glucose concentrations on human beta
      cell turnover and secretory function. Exposure of cultured human islets to
      saturated fatty acid and/or to an elevated glucose concentration for 4 days
      increased beta-cell DNA fragmentation and decreased beta-cell proliferation. In
      contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA
      fragmentation and induced beta-cell proliferation. Moreover, each monounsaturated
      fatty acid prevented the deleterious effects of both palmitic acid and high
      glucose concentration. The cell-permeable ceramide analogue C(2)-ceramide
      mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in
      proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1
      blocked the deleterious effects of palmitic acid on beta-cell turnover. In
      addition, palmitic acid decreased Bcl-2 expression and induced release of
      cytochrome c from the mitochondria into the cytosol, which was prevented by
      fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved
      beta-cell secretory function that was reduced by palmitic acid and by high
      glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose
      concentration induce beta-cell apoptosis, decrease beta-cell proliferation, and
      impair beta-cell function, which can be prevented by monounsaturated fatty acids.
      The deleterious effect of palmitic acid is mediated via formation of ceramide and
      activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute
      to the protective effect of monounsaturated fatty acids.

PMID- 12606515
TI  - Neonatal exendin-4 prevents the development of diabetes in the intrauterine
      growth retarded rat.
AB  - Uteroplacental insufficiency resulting in fetal growth retardation is a common
      complication of pregnancy and a significant cause of perinatal morbidity and
      mortality. Epidemiological studies show an increased incidence of type 2 diabetes
      in humans who were growth retarded at birth. The mechanisms by which an abnormal
      intrauterine milieu leads to the development of diabetes in adulthood are not
      known. Therefore, a rat model of uteroplacental insufficiency was developed;
      intrauterine growth-retarded (IUGR) rats develop diabetes with a phenotype
      similar to that observed in the human with type 2 diabetes. We show here that
      administration of a pancreatic beta-cell trophic factor, exendin-4 (Ex-4), during
      the prediabetic neonatal period dramatically prevents the development of diabetes
      in this model. This occurs because neonatal Ex-4 prevents the progressive
      reduction in insulin-producing beta-cell mass that is observed in IUGR rats over
      time. Expression of PDX, a critical regulator of pancreas development and islet
      differentiation, is restored to normal levels, and islet beta-cell proliferation
      rates are normalized by the neonatal Ex-4 treatment. These results indicate that
      exposure to Ex-4 in the newborn period reverses the adverse consequences of fetal
      programming and prevents the development of diabetes in adulthood.

PMID- 12606516
TI  - Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and
      islet neogenesis in streptozotocin-induced diabetic rats.
AB  - Recent studies into the physiology of the incretins glucose-dependent
      insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have added
      stimulation of beta-cell growth, differentiation, and cell survival to well
      documented, potent insulinotropic effects. Unfortunately, the therapeutic
      potential of these hormones is limited by their rapid enzymatic inactivation in
      vivo by dipeptidyl peptidase IV (DP IV). Inhibition of DP IV, so as to enhance
      circulating incretin levels, has proved effective in the treatment of type 2
      diabetes both in humans and in animal models, stimulating improvements in glucose
      tolerance, insulin sensitivity, and beta-cell function. We hypothesized that
      enhancement of the cytoprotective and beta-cell regenerative effects of GIP and
      GLP-1 might extend the therapeutic potential of DP IV inhibitors to include type
      1 diabetes. For testing this hypothesis, male Wistar rats, exposed to a single
      dose of streptozotocin (STZ; 50 mg/kg), were treated twice daily with the DP IV
      inhibitor P32/98 for 7 weeks. Relative to STZ-injected controls, P32/98-treated
      animals displayed increased weight gain (230%) and nutrient intake, decreased fed
      blood glucose ( approximately 26 vs. approximately 20 mmol/l, respectively), and
      a return of plasma insulin values toward normal (0.07 vs. 0.12 nmol/l,
      respectively). Marked improvements in oral glucose tolerance, suggesting enhanced
      insulin secretory capacity, were corroborated by pancreas perfusion and insulin
      content measurements that revealed two- to eightfold increases in both secretory
      function and insulin content after 7 weeks of treatment. Immunohistochemical
      analyses of pancreatic sections showed marked increases in the number of small
      islets (+35%) and total beta-cells (+120%) and in the islet beta-cell fraction
      (12% control vs. 24% treated) in the treated animals, suggesting that DP IV
      inhibitor treatment enhanced islet neogenesis, beta-cell survival, and insulin
      biosynthesis. In vitro studies using a beta-(INS-1) cell line showed a dose
      dependent prevention of STZ-induced apoptotic cell-death by both GIP and GLP-1,
      supporting a role for the incretins in eliciting the in vivo results. These novel
      findings provide evidence to support the potential utility of DP IV inhibitors in
      the treatment of type 1 and possibly late-stage type 2 diabetes.

PMID- 12606517
TI  - Development and characterization of a glucagon-like peptide 1-albumin conjugate:
      the ability to activate the glucagon-like peptide 1 receptor in vivo.
AB  - The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl
      peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation
      resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP
      IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to
      albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP
      1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R.
      CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal
      glucose and glycemic excursion following glucose challenge remained significantly
      reduced 10-12 h following a single injection of CJC-1131. Twice daily
      administration of CJC-1131 to db/db mice significantly reduced glycemic excursion
      following oral and IP glucose challenge (P < 0.01 to 0.05) but did not
      significantly lower body weight during the 4-week study period. Levels of random
      fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and
      remained significantly lower even 1 week following discontinuation of CJC-1131
      administration. CJC-1131 increased levels of pancreatic proinsulin mRNA
      transcripts, percent islet area, and the number of bromodeoxyuridine-positive
      islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1
      mimics the action of native GLP-1 and represents a new approach for prolonged
      activation of GLP-1R signaling.

PMID- 12606518
TI  - Role of H1-calponin in pancreatic AR42J cell differentiation into insulin
      producing cells.
AB  - Basic or h1-calponin is a smooth muscle-specific, actin-binding protein that is
      involved in the regulation of smooth muscle contractile activity. We found in
      this study the expression of mRNA and protein for h1-calponin in AR42J-B13 cells,
      which is a useful model for investigating islet beta-cell differentiation from
      pancreatic common precursor cells. Following treatment of AR42J cells with
      activin A and hepatocyte growth factor, the protein levels of h1-calponin
      decreased in a time-dependent manner during the course of the cell
      differentiation. When h1-calponin was continuously overexpressed by utilizing
      recombinant adenovirus-mediated gene transfer, the percentage of cell
      differentiation in h1-calponin overexpressing cells was markedly suppressed as
      compared with that in the cells without overexpression (6.7 +/- 2.5 vs. 28.6 +/-
      3.2%, P < 0.001, Student's t test). Finally, overexpression of h1-calponin (65.6
      +/- 3.4), or that lacking actin-binding domain (55.9 +/- 3.4%), significantly (P
      < 0.001) suppressed the activin A-stimulated transcriptional activity of activin
      responsive element (ARE), whereas calponin homology-domain disruption mutant did
      not (100.6 +/- 1.9%). These results suggest that regulation of h1-calponin is
      involved in the regulation of differentiation of AR42J cells into insulin
      producing cells at least partly through modulating ARE transcriptional activity.

PMID- 12606520
TI  - Metallothionein prevents diabetes-induced deficits in cardiomyocytes by
      inhibiting reactive oxygen species production.
AB  - Many individuals with diabetes experience impaired cardiac contractility that
      cannot be explained by hypertension and atherosclerosis. This cardiomyopathy may
      be due to either organ-based damage, such as fibrosis, or to direct damage to
      cardiomyocytes. Reactive oxygen species (ROS) have been proposed to contribute to
      such damage. To address these hypotheses, we examined contractility, Ca(2+)
      handling, and ROS levels in individual cardiomyocytes isolated from control
      hearts, diabetic OVE26 hearts, and diabetic hearts overexpressing antioxidant
      protein metallothionein (MT). Our data showed that diabetic myocytes exhibited
      significantly reduced peak shortening, prolonged duration of
      shortening/relengthening, and decreased maximal velocities of
      shortening/relengthening as well as slowed intracellular Ca(2+) decay compared
      with control myocytes. Overexpressing MT prevented these defects induced by
      diabetes. In addition, high glucose and angiotensin II promoted significantly
      increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of
      MT or acute in vitro treatment with the flavoprotein inhibitor
      diphenyleneiodonium or the angiotensin II type I receptor antagonist losartan
      eliminated excess ROS production in diabetic cardiomyocytes. These data show that
      diabetes induces damage at the level of individual myocyte. Damage can be
      attributed to ROS production, and diabetes increases ROS production via
      angiotensin II and flavoprotein enzyme-dependent pathways.

PMID- 12606519
TI  - The insulin secretory granule is the major site of K(ATP) channels of the
      endocrine pancreas.
AB  - With ATP sites on K(ir)6.2 that inhibit activity and ADP sites on SUR1 that
      antagonize the inhibition, ATP-sensitive potassium channels (K(ATP) channels) are
      designed as exquisite sensors of adenine nucleotide levels that signal changes in
      glucose metabolism. If pancreatic K(ATP) channels localize to the insulin
      secretory granule, they would be well positioned to transduce changes in glucose
      metabolism into changes in granule transport and exocytosis. Tests for pancreatic
      K(ATP) channels localized to insulin secretory granules led to the following
      observations: fluorescent sulfonylureas that bind the pancreatic K(ATP) channel
      specifically label intracellular punctate structures in cells of the endocrine
      pancreas. The fluorescent glibenclamides colocalize with Ins-C-GFP, a live-cell
      fluorescent reporter of insulin granules. Expression of either SUR1-GFP or
      K(ir)6.2-GFP fusion proteins, but not expression of GFP alone, directs GFP
      fluorescence to insulin secretory granules. An SUR1 antibody specifically labels
      insulin granules identified by anti-insulin. Two different K(ir)6.2 antibodies
      specifically label insulin secretory granules identified by anti-insulin.
      Immunoelectron microscopy showed K(ir)6.2 antibodies specifically label perimeter
      membrane regions of the secretory granule. Relatively little or no labeling of
      other structures, including the plasma membrane, was found. Our results
      demonstrate that the insulin secretory granule is the major site of K(ATP)
      channels of the endocrine pancreas.

PMID- 12606522
TI  - L-arginine-nitric oxide kinetics in normal and type 2 diabetic subjects: a stable
      labelled 15N arginine approach.
AB  - Defective endothelium is a key event in the development of atherosclerosis in
      diabetes: alteration of the L-arginine-nitric oxide (NO) pathway has been
      suggested. We propose a modeling approach of the L-arginine-NO pathway in vivo in
      both control and type 2 diabetic subjects based on the intravenous bolus
      injection of L-[(15)N]arginine and subsequent noncompartmental and compartmental
      model analysis of L-[(15)N] arginine in plasma and [(15)N]nitrate in the urine.
      No differences in arginine kinetics were observed between normal subjects and
      diabetic patients. [(15)N]nitrates were detectable up to 48 h from the L
      (15)[N]arginine administration; no differences were found in the tracer-to-tracee
      ratio in each urine collection. However, the NO synthesis in plasma from arginine
      was lower (P = 0.05 for the noncompartmental and 0.1208 for the compartmental
      analysis, by Mann-Whitney test) in diabetic patients than in control subjects
      when expressed both in absolute terms (50% decrease) and as percentage of NO
      turnover (30% decrease). This new modeling approach of L-arginine-NO pathway
      provides a detailed picture of arginine kinetics and nitrate metabolism. From our
      data, it appears that noncomplicated type 2 diabetic patients have a decreased
      conversion of arginine to NO.

PMID- 12606521
TI  - The focal form of persistent hyperinsulinemic hypoglycemia of infancy:
      morphological and molecular studies show structural and functional differences
      with insulinoma.
AB  - Paternal mutation of ATP-sensitive K(+) (K(ATP)) channel genes and loss of
      heterozygosity (LOH) of the 11p15 region including the maternal alleles of ABCC8,
      IGF2, and CDKN1C characterize the focal form of persistent hyperinsulinemic
      hypoglycemia of infancy (FoPHHI). We aimed to understand the actual nature of
      FoPHHI in comparison with insulinoma. In FoPHHI, the lesion consists in clusters
      of beta-cells surrounded by non-beta-cells. Compared with adjacent islets,
      proinsulin mRNA is similar and proinsulin production higher (P < or = 0.02),
      indicating regulation at a translational level, with slightly lower insulin stock
      and lower ABCC8 peptide labeling (P<0.05). Insulinomas, composed of beta-cell
      nests or cords, have similar proinsulin mRNA compared with adjacent islets,
      highly variable proinsulin production, lower insulin stock (P < or = 0.02), and
      higher ABCC8 peptide labeling (P<0.05). Proinsulin mRNA is lower than in FoPHHI
      (P<0.001). Islets adjacent to FoPHHI appear to be resting, in contrast to those
      adjacent to insulinomas, evidencing intrapancreatic regulation of islet beta-cell
      activity. IGF2 peptide is present inside and outside both lesions, but IGF2 mRNA
      is restricted to the lesions. The 11p15 LOH and absence of CDKN1C peptide
      staining are demonstrated in all FoPHHI but also in three of eight insulinomas.
      Despite some molecular similarities, FoPHHI is thus fundamentally different from
      insulinoma.

PMID- 12606524
TI  - Inflammatory cytokines and the risk to develop type 2 diabetes: results of the
      prospective population-based European Prospective Investigation into Cancer and
      Nutrition (EPIC)-Potsdam Study.
AB  - A subclinical inflammatory reaction has been shown to precede the onset of type 2
      (non-insulin-dependent) diabetes. We therefore examined prospectively the effects
      of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor
      necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We
      designed a nested case-control study within the prospective population-based
      European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study
      including 27,548 individuals. Case subjects were defined to be those who were
      free of type 2 diabetes at baseline and subsequently developed type 2 diabetes
      during a 2.3-year follow-up period. A total of 192 cases of incident type 2
      diabetes were identified and matched with 384 non-disease-developing control
      subjects. IL-6 and TNF-alpha levels were found to be elevated in participants
      with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ
      between the groups. Analysis of single cytokines revealed IL-6 as an independent
      predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip
      ratio (WHR), sports, smoking status, educational attainment, alcohol consumption,
      and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The
      association between TNF-alpha and future type 2 diabetes was no longer
      significant after adjustment for BMI or WHR. Interestingly, combined analysis of
      the cytokines revealed a significant interaction between IL-1beta and IL-6. In
      the fully adjusted model, participants with detectable levels of IL-1beta and
      elevated levels of IL-6 had an independently increased risk to develop type 2
      diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL
      6 but undetectable levels of IL-1beta had no significantly increased risk, both
      compared with the low-level reference group. These results were confirmed in an
      analysis including only individuals with HbA(1c) <5.8% at baseline. Our data
      suggest that the pattern of circulating inflammatory cytokines modifies the risk
      for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6,
      rather than the isolated elevation of IL-6 alone, independently increases the
      risk of type 2 diabetes. These data strongly support the hypothesis that a
      subclinical inflammatory reaction has a role in the pathogenesis of type 2
      diabetes.

PMID- 12606523
TI  - Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate
      in subjects with the metabolic syndrome.
AB  - The metabolic syndrome is characterized by insulin resistance and abnormal
      apolipoprotein AI (apoAI) and apolipoprotein B-100 (apoB) metabolism that may
      collectively accelerate atherosclerosis. The effects of atorvastatin (40 mg/day)
      and micronised fenofibrate (200 mg/day) on the kinetics of apoAI and apoB were
      investigated in a controlled cross-over trial of 11 dyslipidemic men with the
      metabolic syndrome. ApoAI and apoB kinetics were studied following intravenous
      d(3)-leucine administration using gas-chromatography mass spectrometry with data
      analyzed by compartmental modeling. Compared with placebo, atorvastatin
      significantly decreased (P < 0.001) plasma concentrations of cholesterol,
      triglyceride, LDL cholesterol, VLDL apoB, intermediate-density lipoprotein (IDL)
      apoB, and LDL apoB. Fenofibrate significantly decreased (P < 0.001) plasma
      triglyceride and VLDL apoB and elevated HDL(2) cholesterol (P < 0.001), HDL(3)
      cholesterol (P < 0.01), apoAI (P = 0.01), and apoAII (P < 0.001) concentrations,
      but it did not significantly alter LDL cholesterol. Atorvastatin significantly
      increased (P < 0.002) the fractional catabolic rate (FCR) of VLDL apoB, IDL apoB,
      and LDL apoB but did not affect the production of apoB in any lipoprotein
      fraction or in the turnover of apoAI. Fenofibrate significantly increased (P <
      0.01) the FCR of VLDL, IDL, and LDL apoB but did not affect the production of
      VLDL apoB. Relative to placebo and atorvastatin, fenofibrate significantly
      increased the production (P < 0.001) and FCR (P = 0.016) of apoAI. Both agents
      significantly lowered plasma triglycerides and apoCIII concentrations, but only
      atorvastatin significantly lowered (P < 0.001) plasma cholesteryl ester transfer
      protein activity. Neither treatment altered insulin resistance. In conclusion,
      these differential effects of atorvastatin and fenofibrate on apoAI and apoB
      kinetics support the use of combination therapy for optimally regulating
      dyslipoproteinemia in the metabolic syndrome.

PMID- 12606525
TI  - Effect of reinstitution of good glycemic control on retinal oxidative stress and
      nitrative stress in diabetic rats.
AB  - Clinical and experimental studies have shown that reinstitution of good glycemic
      control (GC) after a period of poor glycemic control (PC) does not produce
      immediate benefits on the progression of retinopathy, and hyperglycemia is
      sufficient to initiate the development of diabetic retinopathy. In this study,
      the effect of reinstitution of GC on hyperglycemia-induced increased oxidative
      stress and nitrative stress was evaluated in the retina of rats maintained in PC
      before initiation of GC. In diabetic rats, 2 or 6 months of PC (GHb >11.0%) was
      followed by 7 months of GC (GHb <5.5%). Reinstitution of GC after 2 months of PC
      inhibited elevations in retinal lipid peroxides and NO levels by approximately
      50%, but failed to have any beneficial effects on nitrotyrosine formation.
      However, reversal of hyperglycemia after 6 months of PC had no significant effect
      on retinal oxidative stress and NO levels (P < 0.02 vs. normal). In the same
      rats, inducible nitric oxide synthase expression and nitrotyrosine levels
      remained elevated by >80% compared with normal rats or rats kept in GC for the
      duration. This suggests that oxidative and nitrative modifications in retina
      occur early in the course of development of retinopathy in diabetes. These
      abnormalities are not easily reversed by reinstitution of GC, and the duration of
      PC before initiation of GC influences the outcome of the reversal.
      Characterization of the abnormalities responsible for the resistance of
      retinopathy to arrest after reinstitution of GC will help identify potential
      future therapies to inhibit progression of diabetic retinopathy.

PMID- 12606526
TI  - Latent transforming growth factor-beta binding protein-1, a component of latent
      transforming growth factor-beta complex, accelerates the migration of aortic
      smooth muscle cells in diabetic rats through integrin-beta3.
AB  - Aortic smooth muscle cells (SMCs) of diabetic animals have unique properties,
      including the overexpression of transforming growth factor-beta (TGF-beta) type
      II receptor, fibronectin, and platelet-derived growth factor beta-receptor. TGF
      beta1 is produced and secreted as latent high-molecular weight complex consisting
      of mature TGF-beta1, latency-associated peptide (LAP), and a latent TGF-beta1
      binding protein (LTBP-1). LAP has an important function in the latency of TGF
      beta complex, but the role of LTBP-1 is not known in diabetic angiopathy. SMC
      migration from the medial layer to the intimal layer of an artery is an initial
      major process of the formation of intimal thickening of an artery. Migration
      activities of SMCs from diabetic rat with 1-500 pg/ml of LTBP-1 increased
      significantly compared with that without LTBP-1. LTBP-1 at 10-500 pg/ml
      stimulated the migration of diabetic SMCs more than SMCs from control rat. An
      anti-integrin-beta(3) antibody reduced LTBP-1-stimulated migration of diabetic
      SMCs to 51% compared with no antibody, but it did not reduce that of control
      SMCs. Furthermore, cross-linking experiments show that LTBP-1 binds integrin
      beta(3) in diabetic SMCs much more than in control SMCs in coincidence with the
      increase of integrin-beta(3) in diabetic aorta by immunohistochemistry. Taken
      together, these observations suggest that LTBP-1 plays a critical role in intimal
      thickening of diabetic artery through the acceleration of SMC migration via
      integrin-beta(3).

PMID- 12606527
TI  - Characterization of retinal leukostasis and hemodynamics in insulin resistance
      and diabetes: role of oxidants and protein kinase-C activation.
AB  - Increases in leukostasis/monocyte adhesion to the capillary endothelium
      (leukostasis) and decreases in retinal blood flow may be causally associated and
      are implicated in the pathogenesis of diabetic retinopathy. In this study, we
      demonstrate that increases in leukostasis are observed in insulin-resistant
      states without diabetes, whereas decreases in retinal blood flow require diabetes
      and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary
      obstruction by leukocytes did not affect retinal blood flow. In diabetic rats,
      treatment with the antioxidant alpha-lipoic acid normalized the amount of
      leukostasis but not retinal blood flow. In contrast, treatment with D-alpha
      tocopherol and protein kinase-C beta-isoform inhibition (LY333531) prevented the
      increases in leukostasis and decreases in retinal blood flow in diabetic rats.
      Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic
      rats, but normalized by treatment with antioxidants alpha-lipoic acid and D-alpha
      tocopherol and, surprisingly, PKC beta-isoform inhibition. These findings suggest
      that leukostasis is associated with endothelial dysfunction, insulin resistance,
      and oxidative stress but is not related to retinal blood flow and is not
      sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC beta
      inhibition is effective to normalize diabetes or hyperglycemia-induced PKC beta
      isoform activation and oxidative stress.

PMID- 12606529
TI  - The response of antioxidant genes to hyperglycemia is abnormal in patients with
      type 1 diabetes and diabetic nephropathy.
AB  - Increased flux of glucose through the polyol pathway may cause generation of
      excess reactive oxygen species (ROS), leading to tissue damage. Abnormalities in
      expression of enzymes that protect against oxidant damage may accentuate the
      oxidative injury. The expression of catalase (CAT), CuZn superoxide-dismutase
      (CuZnSOD), glutathione peroxidase (GPX), and Mn superoxide-dismutase (MnSOD) mRNA
      was quantified in peripheral blood mononuclear cells-obtained from 26 patients
      with type 1 diabetes and nephropathy, 15 with no microvascular complications
      after 20 years' duration of diabetes, and 10 normal healthy control subjects-that
      were exposed in vitro to hyperglycemia (HG) (31 mmol/l D-glucose). Under HG,
      there was a twofold increase in the expression of CAT, CuZnSOD, and GPX mRNA in
      the patients without complications and the control subjects versus patients with
      nephropathy (P < 0.0001), and MnSOD did not change in any of the groups. The
      aldose reductase inhibitor zopolrestat partially restored the levels of CAT,
      CuZnSOD, and GPX mRNA in the patients with nephropathy (P < 0.05). There was a
      highly significant correlation between increased aldose reductase (ALR2)
      expression, CAT, CuZnSOD, and GPX mRNA levels under HG conditions and
      polymorphisms of ALR2 in the patients with nephropathy (P < 0.00001). In
      conclusion, these results suggest that high glucose flux through aldose reductase
      inhibits the expression of antioxidant enzymes.

PMID- 12606528
TI  - Role of protein kinase C on the expression of platelet-derived growth factor and
      endothelin-1 in the retina of diabetic rats and cultured retinal capillary
      pericytes.
AB  - Increased expression of endothelin-1 (ET-1) is associated with diabetic
      retinopathy and vasculopathy, although the molecular explanation has not been
      defined. The effects of high glucose and protein kinase C (PKC) activation on
      platelet-derived growth factor (PDGF)-BB and of ET-1 expression in the retina of
      streptozotocin (STZ)-induced diabetic rats and bovine retinal pericytes (BRPC)
      were examined. In 4-week diabetic rats, PDGF-B and prepro-ET-1 (ppET-1) mRNA
      levels increased significantly by 2.8- and 1.9-fold, respectively, as quantified
      by RT-PCR. Treatment with PKC-beta isoform-specific inhibitor (LY333531) or
      insulin normalized retinal ET-1 and PDGF-B expression. In BRPC, high glucose
      levels increased ppET-1 and PDGF-B mRNA expression by 1.7- and 1.9-fold,
      respectively. The addition of PDGF-BB but not PDGF-AA increased expression of
      ppET-1 and vascular endothelial growth factor mRNA by 1.6- and 2.1-fold,
      respectively, with both inhibited by AG1296, a selective PDGF receptor kinase
      inhibitor. A general PKC inhibitor, GF109203X, suppressed PDGF-BB's induction of
      ET-1 mRNA. Thus, increased ET-1 expression in diabetic retina could be due to
      increased expression of PDGF-BB, mediated via PDGF-beta receptors in part by PKC
      activation. The novel demonstration of elevated expression of PDGF-B and its
      induction by PKC activation identifies a potential new molecular step in the
      pathogenesis of diabetic retinopathy.

PMID- 12606530
TI  - Increased serum IGF-I during pregnancy is associated with progression of diabetic
      retinopathy.
AB  - The IGF system has been associated with development and progression of diabetic
      retinopathy. We examined whether a simple measurement of the IGF system (serum
      total IGF-I) correlated with progression of diabetic retinopathy in pregnancy in
      type 1 diabetes. A prospective observational study was performed in 103 pregnant
      women with type 1 diabetes. Serum IGF-I was measured in maternal serum from week
      14, every fourth week until week 30, and every second week until delivery. Twenty
      four-hour blood pressure was measured with a portable oscillometry monitor. The
      women had visual acuity testing and fundus photography before pregnancy, once in
      each trimester, and 4 months after birth. Each eye was assigned an overall
      retinopathy grade on a scale from 1 to 6 independently by two experienced
      graders. During pregnancy, serum IGF-I increased with increasing gestational age
      until a plateau was reached in week 32. Progression of retinopathy was
      significantly associated with a higher level of IGF-I (P < 0.01). Serum IGF-I
      increased with increasing progression of retinopathy. Change of retinopathy was
      significantly associated with level of IGF-I (P < 0.01). During pregnancy, serum
      IGF-I increased with increasing birth weight until a plateau was reached in week
      32. Birth weight was significantly associated with a higher level of serum IGF-I
      (P < 0.01).

PMID- 12606531
TI  - Enhanced recombinant adeno-associated virus-mediated vascular endothelial growth
      factor expression in the adult mouse retina: a potential model for diabetic
      retinopathy.
AB  - Diabetic retinopathy, one of the most serious complications of long-term
      diabetes, could clinically be divided into two stages: 1) background retinopathy
      that does not cause visual impairment and 2) proliferative retinopathy, which is
      a potentially blinding condition. This study aims to investigate the correlation
      between enhancement of vascular endothelial growth factor (VEGF) expression and
      neovascular changes. A binary recombinant adeno-associated virus construct
      producing green fluorescent protein (GFP) and VEGF under the control of the human
      cytomegalovirus promoter, recombinant adeno-associated virus (rAAV).VEGF.GFP, was
      produced and injected into the subretinal space of C57BL mice. GFP expression was
      tracked by fluorescence fundus photography, and VEGF expression was confirmed by
      immunohistochemistry and enzyme-linked immunoassay. Neovascular changes were
      monitored by fluorescein angiography and histology and by quantifying the number
      of inner retinal vessels. GFP expression was found in 100% of injected eyes, and
      vascular changes were detected in 9 of 10 rAAV.VEGF.GFP-injected eyes. Of these,
      four demonstrated microaneurysms and five showed moderate to severe leakage.
      There was a statistically significant increase in blood vessel number in the
      inner nuclear layer (P < 0.03) and dilatation of retinal veins (P < or = 0.05).
      This work has demonstrated that the development of different stages of diabetic
      retinopathy is closely correlated with an increased VEGF level in the retina.

PMID- 12606532
TI  - Aldose reductase inhibitor fidarestat prevents retinal oxidative stress and
      vascular endothelial growth factor overexpression in streptozotocin-diabetic
      rats.
AB  - The study addressed the role for aldose reductase (AR) in 1) retinal oxidative
      stress and vascular endothelial growth factor (VEGF) overexpression in early
      diabetes, and 2) high glucose-induced oxidative stress in retinal endothelial
      cells. In vivo experiments were performed on control rats and diabetic rats
      treated with or without low or high dose of the AR inhibitor (ARI) fidarestat (2
      or 16 mg. kg(-1). day(-1)). In vitro studies were performed on bovine retinal
      endothelial cells (BREC) cultured in either 5 or 30 mmol/l glucose with or
      without 1 micro mol/l fidarestat. Intracellular reactive oxygen species were
      assessed using the 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein
      diacetate (H(2)DCFDA) probe and flow cytometry. Both low and high doses of
      fidarestat (i.e., the doses that partially and completely inhibited sorbitol
      pathway hyperactivity) arrested diabetes-induced retinal lipid peroxidation. This
      was achieved due to upregulation of the key antioxidative defense enzyme
      activities rather than changes in reduced glutathione, oxidized glutathione,
      ascorbate and dehydroascorbate concentrations, and the glutathione and ascorbate
      redox states. Diabetes-associated 2.1-fold VEGF protein overexpression (enzyme
      linked immunosorbent assay; ELISA) was dose-dependently prevented by fidarestat,
      whereas total VEGF mRNA and VEGF-164 mRNA (RT-PCR) abundance were not affected by
      either diabetes or the ARI. In BREC, fidarestat corrected hyperglycemia-induced
      increase in H(2)DCFDA fluorescence but not oxidative stress caused by three
      different pro-oxidants in normoglycemic conditions. In conclusion, increased AR
      activity contributes to retinal oxidative stress and VEGF protein overexpression
      in early diabetes. The findings justify the rationale for evaluation of
      fidarestat on diabetic retinopathy.

PMID- 12606533
TI  - A genome-wide scan in families with maturity-onset diabetes of the young:
      evidence for further genetic heterogeneity.
AB  - Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene
      disorder characterized by non-insulin-dependent diabetes, an early onset and
      autosomal dominant inheritance. Mutations in six genes have been shown to cause
      MODY. Approximately 15-20% of families fitting MODY criteria do not have
      mutations in any of the known genes. These families provide a rich resource for
      the identification of new MODY genes. This will potentially enable further
      dissection of clinical heterogeneity and bring new insights into mechanisms of
      beta-cell dysfunction. To facilitate the identification of novel MODY loci, we
      combined the results from three genome-wide scans on a total of 23 families
      fitting MODY criteria. We used both a strict parametric model of inheritance with
      heterogeneity and a model-free analysis. We did not identify any single novel
      locus but provided putative evidence for linkage to chromosomes 6 (nonparametric
      linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to
      chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score
      1.22 at 175 cM) in 14 more strictly defined families. Our results provide
      evidence for further heterogeneity in MODY.

PMID- 12606534
TI  - Insulin autoantibodies are associated with islet inflammation but not always
      related to diabetes progression in NOD congenic mice.
AB  - Susceptibility to diabetes in humans and nonobese diabetic (NOD) mice is believed
      to arise from the combined effect of multiple genetic loci, resulting in immune
      mediated destruction of the insulin-secreting beta-cells. Insulin autoantibodies
      (IAAs) are often present in humans for years, and in NOD mice for weeks, before
      the onset of diabetes. We have evaluated the expression of IAAs in NOD mice and
      in diabetes-resistant NOD congenic strains to characterize the association of
      autoantibody expression with insulitis and diabetes. In NOD congenic strains with
      genes that contribute to protection from insulitis and diabetes (Idd3, Idd5,
      Idd10, and Idd18), the prevalence of IAAs is reduced relative to NOD mice. In
      contrast, NOD.B10 Idd9 mice have a high prevalence of IAAs and a high degree of
      insulitis, despite a nearly complete resistance to diabetes. These data indicate
      that IAA expression is a phenotype that is associated with insulitis and
      correlates with overall disease progression in some strains of congenic mice but
      not in others. It is likely that patients with type 1 diabetes will also show non
      major histocompatibility complex genetically determined variation in expression
      of autoantibodies and progression to diabetes.

PMID- 12606535
TI  - The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental
      Italy.
AB  - The Arg(972) insulin receptor substrate-1 (IRS-1) variant has been hypothesized
      to play a role in pancreatic beta-cell stimulus-coupled insulin secretion and
      survival. We analyzed the relations between type 1 diabetes and the Arg(972) IRS
      1 variant. The frequency of the IRS-1 Arg(972) variant was investigated in two
      independent sets of unrelated patients: a case-control study and a collection of
      type 1 diabetes simplex families. In the former group, frequency of the IRS-1
      Arg(972) variant was significantly increased in the patients (P = 0.0008),
      conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained
      from the family set revealed that the Arg(972) IRS-1 variant was transmitted from
      heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02).
      Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic
      risk for type 1 diabetes. Arg(972) IRS-1 type 1 diabetic patients also had lower
      fasting plasma concentrations of C-peptide at the time of diagnosis with respect
      to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/-
      0.066, n = 134, respectively [means +/- SE]; P = 0.051). Our findings suggest a
      role for Arg(972) IRS-1 in conferring risk for the development of type 1
      diabetes.

PMID- 12606536
TI  - The functional -374 T/A RAGE gene polymorphism is associated with proteinuria and
      cardiovascular disease in type 1 diabetic patients.
AB  - The hyperglycemic milieu in diabetes results in the formation of advanced
      glycation end products (AGEs) that predominantly act through specific receptors,
      particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the
      promoter of the RAGE gene (-429 T/C and -374 T/A) and one in the AGE binding
      domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In
      patients with poor metabolic control (HbA(1c) >9.5%), the AA genotype of the -374
      T/A polymorphism was more common in those with a normal albumin excretion rate
      than in those with proteinuria (30 vs. 10%, P = 0.01). We observed less coronary
      heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P =
      0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the
      AA genotype of the -374 T/A polymorphism than in those with the TT + TA genotype.
      Thus, the association between the RAGE -374 T/A homozygous AA genotype and
      cardiovascular disease as well as albumin excretion in type 1 diabetic patients
      with poor metabolic control suggests a gene-environment interaction in the
      development of diabetic nephropathy and cardiovascular complications.

PMID- 12606537
TI  - A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor
      gamma coactivator-1 is associated with altered lipid oxidation and early insulin
      secretion in Pima Indians.
AB  - Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) is a
      transcriptional coactivator of peroxisome proliferator-activated receptor gamma
      and alpha, which play important roles in adipogenesis and lipid metabolism. A
      single nucleotide polymorphism within the coding region of the PGC-1 gene
      predicts a glycine to serine substitution at amino acid 482 and has been
      associated with type 2 diabetes in a Danish population. In this study, we
      examined whether this Gly482Ser polymorphism is associated with type 2 diabetes
      or obesity, or metabolic predictors of these diseases, in Pima Indians. There was
      no association of the Gly482Ser polymorphism with either type 2 diabetes or BMI
      (n = 984). However, among nondiabetic Pima Indians (n = 183-201), those with the
      Gly/Gly genotype had a lower mean insulin secretory response to intravenous and
      oral glucose and a lower mean rate of lipid oxidation (over 24 h in a respiratory
      chamber) despite a larger mean subcutaneous abdominal adipocyte size and a higher
      mean plasma free fatty acid concentration. These data indicate that the Gly482Ser
      missense polymorphism in PGC-1 has metabolic consequences on lipid metabolism
      that could influence insulin secretion.

PMID- 12606538
TI  - The mRNA transcription/processing factor Ssu72 is a potential tyrosine
      phosphatase.
AB  - Ssu72 is an essential and highly conserved protein involved in mRNA transcription
      and 3'-end processing. The biochemical function of Ssu72 was so far unknown. We
      report here evidence that Ssu72 is a phosphatase that resembles protein tyrosine
      phosphatases (PTPases). First, recombinant Ssu72 cleaves the phosphotyrosine
      analogue p-nitrophenylphosphate, and this catalytic activity is impaired by
      PTPase-inhibiting agents. Second, the Ssu72 sequence contains the CX(5)R
      signature motif of PTPases; mutation of the catalytic cysteine in this motif
      abolishes Ssu72 activity in vitro and has been shown to confer lethality in vivo.
      Third, secondary structure prediction and site-directed mutagenesis predict that
      Ssu72 adopts the fold of PTPases of the low molecular weight family.
      Distinguishing features, such as a short "aspartate loop" at the active site,
      suggest however that Ssu72 is the founding member of a new phosphatase subfamily.
      The novel Ssu72 activity may regulate coupling events during mRNA biogenesis.

PMID- 12606539
TI  - Production of Bacillus anthracis protective antigen is dependent on the
      extracellular chaperone, PrsA.
AB  - Protective antigen (PA) is a component of the Bacillus anthracis lethal and edema
      toxins and the basis of the current anthrax vaccine. In its heptameric form, PA
      targets host cells and internalizes the enzymatically active components of the
      toxins, namely lethal and edema factors. PA and other toxin components are
      secreted from B. anthracis using the Sec-dependent secretion pathway. This
      requires them to be translocated across the cytoplasmic membrane in an unfolded
      state and then to be folded into their native configurations on the trans side of
      the membrane, prior to their release from the environment of the cell wall. In
      this study we show that recombinant PA (rPA) requires the extracellular chaperone
      PrsA for efficient folding when produced in the heterologous host, B. subtilis;
      increasing the concentration of PrsA leads to an increase in rPA production. To
      determine the likelihood of PrsA being required for PA production in its native
      host, we have analyzed the B. anthracis genome sequence for the presence of genes
      encoding homologues of B. subtilis PrsA. We identified three putative B.
      anthracis PrsA proteins (PrsAA, PrsAB, and PrsAC) that are able to complement the
      activity of B. subtilis PrsA with respect to cell viability and rPA secretion, as
      well as that of AmyQ, a protein previously shown to be PrsA-dependent.

PMID- 12606540
TI  - Distinct transglutaminase 2-independent and transglutaminase 2-dependent pathways
      mediate articular chondrocyte hypertrophy.
AB  - Altered chondrocyte differentiation, including development of chondrocyte
      hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix
      calcification. Similar changes in endochondral chondrocyte differentiation are
      essential for physiologic growth plate mineralization. In both articular and
      growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated
      expression of certain protein-crosslinking enzymes (transglutaminases (TGs))
      including the unique dual-functioning TG and GTPase TG2. Here, we tested if TG2
      directly mediates the development of chondrocyte hypertrophic differentiation. To
      do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from
      recently described TG2 knockout mice, which are phenotypically normal. We treated
      chondrocytes with the osteoarthritis mediator IL-1 beta, with the all-trans form
      of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and
      pathologic calcification, and with C-type natriuretic peptide, an essential
      factor in endochondral development. IL-1 beta and ATRA induced TG transamidation
      activity and calcification in wild-type but not in TG2 (-/-) mouse knee
      chondrocytes. In addition, ATRA induced multiple features of hypertrophic
      differentiation (including type X collagen, alkaline phosphatase, and MMP-13),
      and these effects required TG2. Significantly, TG2 (-/-) chondrocytes lost the
      capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary
      for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide,
      which did not modulate TG activity, comparably promoted Cbfa1 expression and
      hypertrophy (without associated calcification) in TG2 (+/+) and TG2 (-/-)
      chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote
      Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a
      potential site for intervention in pathologic calcification promoted by IL-1 beta
      and ATRA.

PMID- 12606541
TI  - Collagen gene expression and the altered accumulation of scleral collagen during
      the development of high myopia.
AB  - The development of high myopia is associated with reduced scleral collagen
      accumulation, scleral thinning, and loss of scleral tissue, in both humans and
      animal models. Reduced collagen fibril diameter is also observed in the sclera of
      eyes with high myopia. The present study investigated aspects of scleral collagen
      synthesis and degradation, in a mammalian model of high myopia, to elucidate the
      factors underlying scleral changes. General synthesis and degradation of scleral
      collagen was investigated in monocularly deprived tree shrews, through the in
      vivo administration of [(3)H]proline and subsequent assay of scleral tissue for
      [(3)H]collagen. In addition, PCR enriched cDNA, produced from tree shrew scleral
      mRNA, was used to synthesize probes for hybridization to custom gene arrays
      consisting of partial sequences for 11 collagen subtypes. Finally, real-time
      reverse transcriptase-PCR was employed to investigate collagen type I, III, and V
      mRNA expression in the sclera of myopic, contralateral control, and normal tree
      shrew eyes. Scleral [(3)H]proline incorporation was reduced at the posterior pole
      of myopic eyes following 5 days of monocular deprivation (-36 +/- 4%), whereas
      [(3)H]proline content was similar in treated and control eyes before myopia
      induction (-1 +/- 8%) but was reduced in myopic eyes following 5 (-8 +/- 2%), 12
      (-15 +/- 4%), and 24 (-10 +/- 4%) days of myopia induction. The majority of the
      collagens investigated were found to be expressed in the sclera, with 11 subtypes
      being identified. Collagen type I mRNA expression was reduced in the sclera of
      myopic eyes (-20 +/- 7%), however, collagen type III (+2 +/- 9%) and type V (-1
      +/- 6%) expression was unchanged relative to control, resulting in a net increase
      in the ratio of expression of collagen type III/type I and collagen type V/type I
      (22 and 25%, respectively). These results show that reduced scleral collagen
      accumulation in myopic eyes is a result of both decreased collagen synthesis and
      accelerated collagen degradation. Furthermore, changes in collagen synthesis are
      driven by reduced type I collagen production. Short term increases in the ratio
      of newly synthesized collagen type III/type I and type V/type I are likely to be
      important in the increasing frequency of small diameter scleral collagen fibrils
      observed in high myopia and may be important in the subsequent development of
      posterior staphyloma in humans with pathological myopia.

PMID- 12606542
TI  - Signaling mechanism for receptor-activated canonical transient receptor potential
      3 (TRPC3) channels.
AB  - Canonical transient receptor potential 3 (TRPC3) is a receptor-activated, calcium
      permeant, non-selective cation channel. TRPC3 has been shown to interact
      physically with the N-terminal domain of the inositol 1,4,5-trisphosphate
      receptor, consistent with a "conformational coupling" mechanism for its
      activation. Here we show that low concentrations of agonists that fail to produce
      levels of inositol 1,4,5-trisphosphate sufficient to induce Ca(2+) release from
      intracellular stores substantially activate TRPC3. By several experimental
      approaches, we demonstrate that neither inositol 1,4,5-trisphosphate nor G
      proteins are required for TRPC3 activation. However, diacylglycerols were
      sufficient to activate TRPC3 in a protein kinase C-independent manner. Surface
      receptor agonists and exogenously applied diacylglycerols were not additive in
      activating TRPC3. In addition, inhibition of metabolism of diacylglycerol slowed
      the reversal of receptor-dependent TRPC3 activation. We conclude that receptor
      mediated activation of phospholipase C in intact cells activates TRPC3 via
      diacylglycerol production, independently of G proteins, protein kinase C, or
      inositol 1,4,5-trisphosphate.

PMID- 12606543
TI  - Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von
      Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha.
AB  - The hypoxia-inducible factor (HIF) activates the expression of genes that contain
      a hypoxia response element. The alpha-subunits of the HIF transcription factors
      are degraded by proteasomal pathways during normoxia but are stabilized under
      hypoxic conditions. The von Hippel-Lindau protein (pVHL) mediates the
      ubiquitination and rapid degradation of HIF-alpha (including HIF-1alpha and HIF
      2alpha). Post-translational hydroxylation of a proline residue in the oxygen
      dependent degradation (ODD) domain of HIF-alpha is required for the interaction
      between HIF and VHL. It has previously been established that cobalt mimics
      hypoxia and causes accumulation of HIF-1alpha and HIF-2alpha. However, little is
      known about the mechanism by which this occurs. In an earlier study, we
      demonstrated that cobalt binds directly to the ODD domain of HIF-2alpha. Here we
      provide the first evidence that cobalt inhibits pVHL binding to HIF-alpha even
      when HIF-alpha is hydroxylated. Deletion of 17 amino acids within the ODD domain
      of HIF-2alpha that are required for pVHL binding prevented the binding of cobalt
      and stabilized HIF-2alpha during normoxia. These findings show that cobalt mimics
      hypoxia, at least in part, by occupying the VHL-binding domain of HIF-alpha and
      thereby preventing the degradation of HIF-alpha.

PMID- 12606544
TI  - Molecular dissection of GTP exchange and hydrolysis within the ternary complex of
      tubulin heterodimers and Op18/stathmin family members.
AB  - The ubiquitous Op18 and the neural RB3 and SCG10 proteins are members of the
      oncoprotein18/stathmin family of microtubule regulators. These proteins bind two
      tubulin heterodimers via two imperfect helical repeats to form a complex of
      heterodimers aligned head-to-tail. Here we have analyzed GTP exchange and GTP
      hydrolysis at the exchangeable GTP-binding site (E-site) of tubulin heterodimers
      in complex with Op18, RB3, or SCG10. These proteins stimulate a low and
      indistinguishable rate of GTP hydrolysis, and our results show that GTP exchange
      is blocked at both E-sites of the ternary complex, whereas GTP hydrolysis only
      occurs at one of the two E-sites. Results from mutational analysis of clusters of
      hydrophobic residues within the first helical repeat of Op18 suggest that GTP is
      hydrolyzed at the E-site that is interfaced between the head-to-tail arranged
      heterodimers, which is consistent with predicted GTPase productive interactions
      between the two tubulin heterodimers. Our mutational analysis has also indicated
      that Op18/stathmin family members actively restrain the otherwise potent GTPase
      productive interactions that are generated by longitudinal interactions within
      protofilaments. We conclude that tubulin heterodimers in complex with
      Op18/stathmin family members are subject to allosteric effects that prevent
      futile cycles of GTP hydrolysis.

PMID- 12606545
TI  - Variable N-terminal regions of muscle myosin heavy chain modulate ATPase rate and
      actin sliding velocity.
AB  - We integratively assessed the function of alternative versions of a region near
      the N terminus of Drosophila muscle myosin heavy chain (encoded by exon 3a or
      3b). We exchanged the alternative exon 3 regions between an embryonic isoform and
      the indirect flight muscle isoform. Each chimeric myosin was expressed in
      Drosophila indirect flight muscle, in the absence of other myosin isoforms,
      allowing for purified protein analysis and whole organism locomotory studies. The
      flight muscle isoform generates higher in vitro actin sliding velocity and
      solution ATPase rates than the embryonic isoform. Exchanging the embryonic exon 3
      region into the flight muscle isoform decreased ATPase rates to embryonic levels
      but did not affect actin sliding velocity or flight muscle ultrastructure.
      Interestingly, this swap only slightly impaired flight ability. Exchanging the
      flight muscle-specific exon 3 region into the embryonic isoform increased actin
      sliding velocity 3-fold and improved indirect flight muscle ultrastructure
      integrity but failed to rescue the flightless phenotype of flies expressing
      embryonic myosin. These results suggest that the two structural versions of the
      exon 3 domain independently influence the kinetics of at least two steps of the
      actomyosin cross-bridge cycle.

PMID- 12606546
TI  - Transcription cooperation by NFAT.C/EBP composite enhancer complex.
AB  - The nuclear factor of activated T cells (NFAT) group of transcription factors
      regulates gene expression in immune and non-immune cells. NFAT-mediated gene
      transcription is orchestrated, in part, by formation of a composite regulatory
      element. Here we demonstrate that NFAT interacts with transcription factor
      CCAAT/enhancer-binding protein (C/EBP) to form a composite enhancer complex, to
      potentiate expression of the peroxisome proliferator-activated receptor-gamma2
      gene. Formation of a ternary NFAT.C/EBP.DNA complex is required for the
      transcriptional cooperation. A similar NFAT.C/EBP composite element is found in
      the regulatory region of the insulin-like growth factor 2, angiotensin-converting
      enzyme homolog, and transcription factor POU4F3 genes. Thus, the NFAT.C/EBP
      composite element represents a novel regulatory enhancer to direct NFAT-mediated
      gene transcription.

PMID- 12606547
TI  - Protein kinase A intersects SRC signaling in membrane microdomains.
AB  - Regulation of Src kinase activity is tightly coupled to the phosphorylation
      status of the C-terminal regulatory tyrosine Tyr(527), which, when phosphorylated
      by Csk, represses Src. Here, we demonstrate that activation of Csk through a
      prostaglandin E(2)-cAMP-protein kinase A (PKA) pathway inhibits Src. This
      inhibitory pathway is operative in detergent-resistant membrane fractions where
      cAMP-elevating agents activate Csk, resulting in a concomitant decrease in Src
      activity. The inhibitory effect on Src depends on a detergent-resistant membrane
      anchored Csk and co-localization of all components of the inhibitory pathway in
      membrane microdomains. Furthermore, epidermal growth factor-induced activation of
      Src and phosphorylation of the Src substrates Cbl and focal adhesion kinase are
      inhibited by activation of the cAMP-PKA-Csk pathway. We propose a novel mechanism
      whereby G protein-coupled receptors inhibit Src signaling by activation of Csk in
      a cAMP-PKA-dependent manner.

PMID- 12606548
TI  - Cardiac L-type calcium channel beta-subunits expressed in human heart have
      differential effects on single channel characteristics.
AB  - l-Type calcium channels are multiprotein complexes composed of pore-forming
      (CaV1.2) and modulatory auxiliary alpha2delta- and beta-subunits. We demonstrate
      expression of two different isoforms for the beta2-subunit (beta2a, beta2b) and
      the beta3-subunit (beta3a, beta3trunc) in human non-failing and failing ischemic
      myocardium. Quantitatively, in the left ventricle expression of beta2b
      transcripts prevails in the order of > beta3 >> beta2a. The expressed cardiac
      full-length beta3-subunit is identical to the beta3a-isoform, and beta3trunc
      results from deletion of exon 6 (20 nn) entailing a reading frameshift and
      translation stop at nucleotide position 495. In failing ischemic myocardium
      beta3trunc expression increases whereas overall beta3 expression remains
      unchanged. Heterologous coexpression studies demonstrated that beta2 induced
      larger currents through rabbit and human cardiac CaV1.2 pore subunits than beta3
      isoforms. All beta-subunits increased channel availability at single channel
      level, but beta2 exerted an additional, marked stimulation of rapid gating (open
      and closed times, first latency), leading to higher peak current values. We
      conclude that cardiac beta-subunit isoforms differentially modulate calcium
      inward currents because of regulatory effects within the channel protein complex.
      Moreover, differences in the various beta-subunit gene products present in human
      heart might account for altered single channel behavior found in human heart
      failure.

PMID- 12606549
TI  - Tyrosine phosphorylation of the well packed ephrinB cytoplasmic beta-hairpin for
      reverse signaling. Structural consequences and binding properties.
AB  - Tyrosine phosphorylation of the 22-residue cytoplasmic region of ephrinB induces
      its binding to the SH2 domain of Grb4, thus initiating reverse signaling pathways
      controlling cytoskeleton assembly and remodeling. Recently, the region
      corresponding to this 22-residue motif was demonstrated to adopt a well packed
      beta-hairpin structure with a high conformational stability in the
      unphosphorylated cytoplasmic subdomain. However, because the binding to Grb4 is
      phosphorylation-dependent and the hairpin contains three conserved tyrosine
      residues that may be phosphorylated, the key events remain unknown as to how
      tyrosine phosphorylation affects the structure of this well packed beta-hairpin
      and which phosphorylation site is relevant to SH2 domain binding. By
      characterizing the structural and binding properties of six 22-residue SH2 domain
      binding motifs with different phosphorylated sites, the present study reveals
      that, as shown by circular dichroism and NMR, the unphosphorylated 22-residue
      motif adopts a well formed beta-hairpin structure in isolation from the ephrinB
      cytoplasmic subdomain. However, this beta-hairpin is radically abolished by
      tyrosine phosphorylation, regardless of the relative location and number of Tyr
      residues. Unexpectedly, the peptides with either Tyr304 or Tyr316 phosphorylated
      show high affinity binding to SH2 domain, whereas the peptide with Tyr311
      phosphorylated has no detectable binding. This implies that ephrinB with Tyr311
      phosphorylated might have a currently unidentified binding partner distinct from
      the Grb4 protein, because Tyr311 is known to be phosphorylated in vivo. Based on
      the results above, it is thus proposed that the disruption of the tight side
      chain packing by tyrosine phosphorylation in the well structured region of a
      signaling protein may represent a general activation mechanism by which a cryptic
      binding site is disclosed for new protein-protein interactions.

PMID- 12606550
TI  - The trypanosomatid signal recognition particle consists of two RNA molecules, a
      7SL RNA homologue and a novel tRNA-like molecule.
AB  - Trypanosomatids are ancient eukaryotic parasites affecting humans and livestock.
      Here we report that the trypanosomatid signal recognition particle (SRP), unlike
      all other known SRPs in nature, contains, in addition to the 7SL RNA homologue, a
      short RNA molecule, termed sRNA-85. Using conventional chromatography, we
      discovered a small RNA molecule of 85 nucleotides co-migrating with the
      Leptomonas collosoma 7SL RNA. This RNA molecule was isolated, sequenced, and used
      to clone the corresponding gene. sRNA-85 was identified as a tRNA-like molecule
      that deviates from the canonical tRNA structure. The co-existence of these RNAs
      in a single complex was confirmed by affinity selection using an antisense
      oligonucleotide to sRNA-85. The two RNA molecules exist in a particle of
      approximately 14 S that binds transiently to ribosomes. Mutations were introduced
      in sRNA-85 that disrupted its putative potential to interact with 7SL RNA by base
      pairing; such mutants were unable to bind to 7SL RNA and to ribosomes and were
      aberrantly distributed within the cell. We postulate that sRNA-85 may
      functionally replace the truncated Alu domain of 7SL RNA. The discovery of sRNA
      85 raises the intriguing possibility that sRNA-85 functional homologues may exist
      in other lower eukaryotes and eubacteria that lack the Alu domain.

PMID- 12606551
TI  - A phage display-based method for determination of relative affinities of mutants.
      Application of the actin-binding motifs in thymosin beta 4 and the villin
      headpiece.
AB  - We propose phage display combined with enzyme-linked immunosorbent assay as a
      tool for the systematic analysis of protein-protein interactions by investigating
      the binding behavior of variants to a partner protein. Via enzyme-linked
      immunosorbent assay we determine both the amount of fusion protein presented at
      the phage surface and the amount of complex formed, the ratio of which is
      proportional to the affinity. Hence this method enables us to calculate the
      relative affinities of a large number of mutants. As model systems, we
      investigated actin-binding motifs conserved in a number of proteins binding
      monomeric or filamentous actin. The hexapeptide motifs LKKTET, present in
      thymosin beta4, and LKKEKG, present in the villin headpiece, were mutated, and
      the variants were analyzed. Study of the positional tolerance allows postulating
      that the motifs, although similar in primary structures adopt different
      conformations when bound to actin. In addition, our data show that the second and
      the fourth amino acid of the thymosin beta4 motif and the first three residues of
      the villin headpiece motif are most important for actin binding. The latter
      result challenges the charged crown hypothesis for the villin headpiece
      filamentous actin interaction.

PMID- 12606552
TI  - Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function.
AB  - The p53 tumor suppressor is maintained at low levels in normal cells by Mdm2
      mediated degradation and strongly stabilized in response to various types of
      stress including hypoxia. Although hypoxia-inducible factor 1 alpha (HIF-1 alpha)
      has been implicated to be involved in p53 stabilization, the precise mechanism by
      which HIF-1 alpha regulates p53-mediated function remains unknown. Here, we found
      that HIF-1 alpha directly binds Mdm2 both in vitro and in vivo; in contrast, p53
      fails to directly interact with HIF-1 alpha in vitro. Interestingly, Mdm2
      expression can significantly enhance the in vivo association between p53 and HIF
      1 alpha, indicating that Mdm2 may act as a bridge and mediate the indirect
      interaction between HIF-1 alpha and p53 in cells. Furthermore, HIF-1 alpha
      protects p53 degradation mediated by Mdm2, and leads to activation of p53
      mediated transcription in cells. To elucidate the mechanism of HIF-1 alpha
      mediated effect, we also found that HIF-1 alpha can significantly suppress Mdm2
      mediated p53 ubiquitination in vitro and blocks Mdm2-mediated nuclear export of
      p53. These results have significant implications regarding the molecular
      mechanism by which p53 is activated by HIF-1 alpha in response to hypoxia.

PMID- 12606553
TI  - Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C
      dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha
      degradation.
AB  - An imbalance between thrombin and antithrombin III contributed to vascular
      hyporeactivity in sepsis, which can be attributed to excess NO production by
      inducible nitric-oxide synthase (iNOS). In view of the importance of the thrombin
      activated coagulation pathway and excess NO as the culminating factors in
      vascular hyporeactivity, this study investigated the effects of thrombin on the
      induction of iNOS and NO production in macrophages. Thrombin induced iNOS protein
      in the Raw264.7 cells, which was inhibited by a thrombin inhibitor, LB30057.
      Thrombin increased NF-kappaB DNA binding, whose band was supershifted with anti
      p65 and anti-p50 antibodies. Thrombin elicited the phosphorylation and
      degradation of I-kappaBalpha prior to the nuclear translocation of p65. The NF
      kappaB-mediated iNOS induction was stimulated by the overexpression of activated
      mutants of Galpha(12/13) (Galpha(12/13)QL). Protein kinase C depletion inhibited
      I-kappaBalpha degradation, NF-kappaB activation, and iNOS induction by thrombin
      or the iNOS induction by Galpha(12/13)QL. JNK, p38 kinase, and ERK were all
      activated by thrombin. JNK inhibition by the stable transfection with a dominant
      negative mutant of JNK1 (JNK1(-)) completely suppressed the NF-kappaB-mediated
      iNOS induction by thrombin. Conversely, the inhibition of p38 kinase enhanced the
      expression of iNOS. In addition, JNK and p38 kinase oppositely controlled the NF
      kappaB-mediated iNOS induction by Galpha(12/13)QL. Hence, iNOS induction by
      thrombin was regulated by the opposed functions of JNK and p38 kinase downstream
      of Galpha(12/13). In the JNK1(-) cells, thrombin did not increase either the NF
      kappaB binding activity or I-kappaBalpha degradation despite I-kappaBalpha
      phosphorylation. These results demonstrated that thrombin induces iNOS in
      macrophages via Galpha(12) and Galpha(13), which leads to NF-kappaB activation
      involving the protein kinase C-dependent phosphorylation of I-kappaBalpha and the
      JNK-dependent degradation of phosphorylated I-kappaBalpha.

PMID- 12606554
TI  - Purification and characterization of a chimeric enzyme from Haemophilus
      influenzae Rd that exhibits glutathione-dependent peroxidase activity.
AB  - While belonging to the same family of antioxidant enzymes, members of the
      peroxiredoxins do not necessarily employ one and the same method for their
      reduction. Most representatives become reduced with the aid of thioredoxin,
      whereas some members use AhpF, tryparedoxin, or cyclophilin A. Recent research on
      a new peroxiredoxin isoform (type C) from Populus trichocarpa has shown that
      these particular types may also use glutaredoxin instead of thioredoxin. This
      finding is supported by the occurrence of chimeric proteins composed of a
      peroxiredoxin and glutaredoxin region. A gene encoding such a fusion protein is
      enclosed in the Haemophilus influenzae Rd genome. We expressed the H. influenzae
      protein, denoted here as PGdx, in Escherichia coli and purified the recombinant
      enzyme. In vitro assays demonstrate that PGdx, in the presence of dithiothreitol
      or glutathione, is able to protect supercoiled DNA against the metal ion
      catalyzed oxidation-system. Enzymatic assays did, indeed, characterize PGdx as a
      peroxidase, requiring the glutathione redox cycle for the reduction of hydrogen
      peroxide (k(cat)/K(m) 5.01 x 10(6) s(-1) m(-1)) as well as the small organic
      hydroperoxide tert-butylhydroperoxide (k(cat)/K(m) 5.67 x 10(4) s(-1) m(-1)).
      Enzymatic activity as function of the glutathione concentration deviated from
      normal Michaelis-Menten kinetics, giving a sigmoidal pattern with an apparent
      Hill coefficient of 2.9. Besides the formation of a disulfide-linked PGdx dimer,
      it was also shown by mass spectrometric analysis that cysteine 49, which is
      equivalent to the active site cysteine of the peroxiredoxins, undergoes
      glutathionylation during purification under nonreducing conditions. Based on
      these results, we propose a model for the catalytic mechanism.

PMID- 12606555
TI  - Functional characterization and localization of acetyl-CoA hydrolase, Ach1p, in
      Saccharomyces cerevisiae.
AB  - Acetyl-CoA hydrolase (Ach1p), catalyzing the hydrolysis of acetyl-CoA, is
      presumably involved in regulating intracellular acetyl-CoA or CoASH pools;
      however, its intracellular functions and distribution remain to be established.
      Using site-directed mutagenesis analysis, we demonstrated that the enzymatic
      activity of Ach1p is dependent upon its putative acetyl-CoA binding sites. The
      ach1 mutant causes a growth defect in acetate but not in other non-fermentable
      carbon sources, suggesting that Ach1p is not involved in mitochondrial
      biogenesis. Overexpression of Ach1p, but not constructs containing acetyl-CoA
      binding site mutations, in ach1-1 complemented the defect of acetate utilization.
      By subcellular fractionation, most of the Ach1p in yeast was distributed with
      mitochondria and little Ach1p in the cytoplasm. By immunofluorescence microscopy,
      we show that Ach1p and acetyl-CoA binding site-mutated constructs, but not its N
      terminal deleted construct, are localized in mitochondria. Moreover, the onset of
      pseudohyphal development in homozygote ach1-1 diploids was abolished. We infer
      that Ach1p may be involved in a novel acetyl-CoA biogenesis and/or acetate
      utilization in mitochondria and thereby indirectly affect pseudohyphal
      development in yeast.

PMID- 12606556
TI  - Mechanisms of factor Xa-catalyzed cleavage of the factor VIIIa A1 subunit
      resulting in cofactor inactivation.
AB  - Activation of factor VIII by factor Xa is followed by proteolytic inactivation
      resulting from cleavage within the A1 subunit (residues 1-372) of factor VIIIa.
      Factor Xa attacks two sites in A1, Arg(336), which precedes the highly acidic C
      terminal region, and a recently identified site at Lys(36). By using isolated A1
      subunit as substrate for proteolysis, production of the terminal fragment, A1(37
      336), was shown to proceed via two pathways identified by the intermediates A1(1
      336) and A1(37-372) and generated by initial cleavage at Arg(336) and Lys(36),
      respectively. Appearance of the terminal product by the former pathway was 7-8
      fold slower than the product obtained by the latter pathway. The isolated A1
      subunit was cleaved slowly, independent of the presence of phospholipid. The
      A1/A3-C1-C2 dimer demonstrated an approximately 3-fold increased cleavage rate
      constant, and inclusion of phospholipid further enhanced this value by
      approximately 2-fold. Although association of A1 or A1(37-372) with A3-C1-C2
      enhanced the rate of cleavage at Arg(336), inclusion of A3-C1-C2 did not affect
      the cleavage at Lys(36) in A1(1-336). A synthetic peptide 337-372 blocked the
      cleavage at Lys(36) (IC(50) = 230 microm) while showing little if any effect on
      cleavage at Arg(336). Proteolysis at Lys(36), and to a lesser extent Arg(336),
      was inhibited in a dose-dependent manner by heparin. These results suggest that
      inactivating cleavages catalyzed by factor Xa at Lys(36) and Arg(336) are
      regulated in part by the A3-C1-C2 subunit. Furthermore, cleavage at Lys(36)
      appears to be selectively modulated by the C-terminal acidic region of A1, a
      region that may interact with factor Xa via its heparin-binding exosite.

PMID- 12606557
TI  - Novel peptide inhibitors of angiotensin-converting enzyme 2.
AB  - Angiotensin-converting enzyme 2 (ACE2), a recently identified human homolog of
      ACE, is a novel metallocarboxypeptidase with specificity, tissue distribution,
      and function distinct from those of ACE. ACE2 may play a unique role in the renin
      angiotensin system and mediate cardiovascular and renal function. Here we report
      the discovery of ACE2 peptide inhibitors through selection of constrained peptide
      libraries displayed on phage. Six constrained peptide libraries were constructed
      and selected against FLAG-tagged ACE2 target. ACE2 peptide binders were
      identified and classified into five groups, based on their effects on ACE2
      activity. Peptides from the first three classes exhibited none, weak, or moderate
      inhibition on ACE2. Peptides from the fourth class exhibited strong inhibition,
      with equilibrium inhibition constants (K(i) values) from 0.38 to 1.7 microm.
      Peptides from the fifth class exhibited very strong inhibition, with K(i) values
      < 0.14 microm. The most potent inhibitor, DX600, had a K(i) of 2.8 nm. Steady
      state enzyme kinetic analysis showed that these potent ACE2 inhibitors exhibited
      a mixed competitive and non-competitive type of inhibition. They were not
      hydrolyzed by ACE2. Furthermore, they did not inhibit ACE activity, and thus were
      specific to ACE2. Finally, they also inhibited ACE2 activity toward its natural
      substrate angiotensin I, suggesting that they would be functional in vivo. As
      novel ACE2-specific peptide inhibitors, they should be useful in elucidation of
      ACE2 in vivo function, thus contributing to our better understanding of the
      biology of cardiovascular regulation. Our results also demonstrate that library
      selection by phage display technology can be a rapid and efficient way to
      discover potent and specific protease inhibitors.

PMID- 12606558
TI  - Targeting tuberculosis and malaria through inhibition of Enoyl reductase:
      compound activity and structural data.
AB  - Tuberculosis and malaria together result in an estimated 5 million deaths
      annually. The spread of multidrug resistance in the most pathogenic causative
      agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the
      need to identify active compounds with novel inhibitory properties. Although
      genetically unrelated, both organisms use a type II fatty-acid synthase system.
      Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been
      repeatedly validated as an effective antimicrobial target. Using high throughput
      inhibitor screens with a combinatorial library, we have identified two novel
      classes of compounds with activity against the M. tuberculosis and P. falciparum
      enzyme (referred to as InhA and PfENR, respectively). The crystal structure of
      InhA complexed with NAD+ and one of the inhibitors was determined to elucidate
      the mode of binding. Structural analysis of InhA with the broad spectrum
      antimicrobial triclosan revealed a unique stoichiometry where the enzyme
      contained either a single triclosan molecule, in a configuration typical of other
      bacterial ENR:triclosan structures, or harbored two triclosan molecules bound to
      the active site. Significantly, these compounds do not require activation and are
      effective against wild-type and drug-resistant strains of M. tuberculosis and P.
      falciparum. Moreover, they provide broader chemical diversity and elucidate key
      elements of inhibitor binding to InhA for subsequent chemical optimization.

PMID- 12606559
TI  - Activation of muscarinic receptors inhibits beta-amyloid peptide-induced
      signaling in cortical slices.
AB  - Deposition of fibrillar aggregates of the beta-amyloid peptide (Abeta) is a key
      pathologic feature during the early stage of Alzheimer's disease. The initial
      neuronal responses to Abeta in cortical circuits and the regulation of Abeta
      induced signaling remain unclear. In this study, we found that exposure of
      cortical slices to Abeta(1-42) or Abeta(25-35) induced a marked increase in the
      activation of protein kinase C (PKC) and Ca(2+)/calmodulin-dependent kinase II
      (CaMKII), two enzymes critically involved in a variety of cellular functions.
      Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly
      inhibited the Abeta activation of PKC and CaMKII. Increasing inhibitory
      transmission mimicked the M1 effect on Abeta, whereas blocking GABA(A) receptors
      eliminated the M1 action. Moreover, electrophysiological evidence shows that
      application of Abeta to cortical slices induced action potential firing and
      enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently
      increased inhibitory postsynaptic currents. These results suggest that Abeta
      activates PKC and CaMKII through enhancing excitatory activity in glutamatergic
      synaptic networks. Activation of M1 receptors inhibits Abeta signaling by
      enhancing the counteracting GABA(ergic) inhibitory transmission. Thus the
      muscarinic reversal of the Abeta-induced biochemical and physiological changes
      provides a potential mechanism for the treatment of Alzheimer's disease with
      cholinergic enhancers.

PMID- 12606560
TI  - Mapping of a conformational epitope on plasminogen activator inhibitor-1 by
      random mutagenesis. Implications for serpin function.
AB  - The mechanism for the conversion of plasminogen activator inhibitor-1 (PAI-1)
      from the active to the latent conformation is not well understood. Recently, a
      monoclonal antibody, 33B8, was described that rapidly converts PAI-1 to the
      latent conformation (Verhamme, I., Kvassman, J. O., Day, D., Debrock, S.,
      Vleugels, N., Declerck, P. J., and Shore, J. D. (1999) J. Biol. Chem. 274, 17511
      17517). In an attempt to understand this interaction, and more broadly to
      understand the mechanism of the natural transition of PAI-1 to the latent
      conformation, we have used random mutagenesis to identify the 33B8 epitope in PAI
      1. This site involves at least 8 amino acids scattered over more than two-thirds
      of the linear sequence that form a compact epitope on the PAI-1 three-dimensional
      structure. Surface plasmon resonance studies indicate a high affinity interaction
      between latent PAI-1 and 33B8 that is approximately 100-fold higher than
      comparable binding to active PAI-1. Structural modeling results together with
      surface plasmon resonance analysis of parental and site-directed PAI-1 mutants
      with disrupted 33B8 binding suggest the existence of a specific PAI-1
      intermediate structure that is stabilized by 33B8 binding. These analyses
      strongly suggest that this intermediate form of PAI-1 has a partial insertion of
      the reactive center loop into beta-sheet A, and together, these data have
      significant implications for the general serpin mechanism of proteinase
      inhibition.

PMID- 12606561
TI  - Cadherin engagement inhibits RhoA via p190RhoGAP.
AB  - Cadherins are transmembrane receptors that mediate cell-cell adhesion in
      epithelial cells. A number of changes occur during cadherin-mediated junction
      formation, one of which is a rearrangement of the actin cytoskeleton. Key
      regulators of actin cytoskeletal dynamics in cells are the Rho family of GTPases.
      We have demonstrated in previous studies that cadherin signaling suppresses RhoA
      activity and activates Rac1. The signaling events downstream of cadherins that
      modulate the activity of Rho family proteins remain unknown. Here we have
      identified a pathway by which RhoA becomes inactivated by cadherins. To determine
      whether cadherins regulate RhoA through activation of a GTPase-activating protein
      (GAP) for RhoA, we used constitutively active RhoA to isolate activated GAPs.
      Using this assay, we have identified the RhoA-specific GAP, p190RhoGAP,
      downstream from engaged cadherins. We found that cadherin engagement induced
      tyrosine phosphorylation of p190RhoGAP and increased its binding to p120RasGAP.
      The increased precipitation of p190RhoGAP with 63LRhoA was blocked by addition of
      PP2 suggesting that Src family kinases are required downstream from cadherin
      signaling. The inhibition of RhoA activity by cadherins was antagonized by
      expression of a dominant negative p190RhoGAP. Taken together, these data
      demonstrate that p190RhoGAP activity is critical for RhoA inactivation by
      cadherins.

PMID- 12606562
TI  - The Vibrio cholerae porins OmpU and OmpT have distinct channel properties.
AB  - Numerous environmental signals regulate the production of virulence factors and
      the composition of the outer membrane of Vibrio cholerae. In particular, bile
      promotes the ToxR-dependent expression of the porin OmpU. Strains expressing
      solely OmpU are more resistant to bile, are better able to colonize the
      intestine, and produce more cholera toxin than strains expressing solely the OmpT
      porin. To gain some understanding in the physiological relevance and the
      molecular mechanism underlying these porin-dependent phenotypes, we have
      undertaken a thorough electrophysiological characterization of the channel
      properties of the two porins. Purified OmpU or OmpT was reconstituted in
      liposomes suitable for patch clamp and in planar lipid bilayers. The high
      resolution of the patch clamp technique allowed us to analyze in detail the
      behavior of single OmpU and OmpT channels. Both channels exhibit closing
      transitions to various conductance states. OmpT is a much more dynamic channel
      than OmpU, displaying frequent and prolonged closures, even at low transmembrane
      potentials. With a critical voltage for closure V(c) of approximately +/-90 mV,
      OmpT is much more voltage-sensitive than OmpU (with a V(c) of approximately +/
      160 mV), a feature that is also readily apparent in the voltage dependence of
      closing probability observed in patch clamp in the +/-100 mV range. OmpT has low
      ionic selectivity (P(K)/P(Cl) = approximately 4), whereas OmpU is more cation
      selective (P(K)/P(Cl) = approximately 14). The distinct functional properties of
      the two porins are likely to play an integrated role with environmental
      regulation of their expression. For example, the higher selectivity of OmpU for
      cations provides a possible explanation for the protective role played by this
      porin in a bile-containing environment, because this type of selectivity would
      restrict the flux of anionic bile salts through the outer membrane and thus would
      reduce the exposure of the cytoplasmic membrane to this natural detergent.

PMID- 12606563
TI  - A novel role for subunit C in mediating binding of the H+-V-ATPase to the actin
      cytoskeleton.
AB  - Primary proton transport by V-ATPases is regulated via the reversible
      dissociation of the V(1)V(0) holoenzyme into its V(1) and V(0) subcomplexes.
      Laser scanning microscopy of different tissues from the tobacco hornworm revealed
      co-localization of the holoenzyme and F-actin close to the apical membranes of
      the epithelial cells. In midgut goblet cells, no co-localization was observed
      under conditions where the V(1) complex detaches from the apical membrane.
      Binding studies, however, demonstrated that both the V(1) complex and the
      holoenzyme interact with F-actin, the latter with an apparently higher affinity.
      To identify F-actin binding subunits, we performed overlay blots that revealed
      two V(1) subunits as binding partners, namely subunit B, resembling the situation
      in the osteoclast V-ATPase (Holliday, L. S., Lu, M., Lee, B. S., Nelson, R. D.,
      Solivan, S., Zhang, L., and Gluck, S. L. (2000) J. Biol. Chem. 275, 32331-32337),
      but, in addition, subunit C, which gets released during reversible dissociation
      of the holoenzyme. Overlay blots and co-pelleting assays showed that the
      recombinant subunit C also binds to F-actin. When the V(1) complex was
      reconstituted with recombinant subunit C, enhanced binding to F-actin was
      observed. Thus, subunit C may function as an anchor protein regulating the
      linkage between V-ATPase and the actin-based cytoskeleton.

PMID- 12606564
TI  - Structural view of a fungal toxin acting on a 14-3-3 regulatory complex.
AB  - The fungal phytotoxin fusicoccin stabilizes the interaction between the C
      terminus of the plant plasma membrane H(+)-ATPase and 14-3-3 proteins, thus
      leading to permanent activation of the proton pump. This results in an
      irreversible opening of the stomatal pore, followed by wilting of plants. Here,
      we report the crystal structure of the ternary complex between a plant 14-3-3
      protein, fusicoccin and a phosphopeptide derived from the C-terminus of the H(+)
      ATPase. Comparison with the corresponding binary 14-3-3 complexes indicates no
      major conformational change induced by fusicoccin. The compound rather fills a
      cavity in the protein-phosphopeptide interaction surface. Isothermal titration
      calorimetry indicates that the toxin alone binds only weakly to 14-3-3 and that
      peptide and toxin mutually increase each others' binding affinity approximately
      90-fold. These results are important for herbicide development but might have
      general implications for drug development, since rather than inhibiting protein
      protein interactions, which is difficult to accomplish, it might be easier to
      reverse the strategy and stabilize protein-protein complexes. As the fusicoccin
      interaction shows, only low-affinity interactions would be required for this
      strategy.

PMID- 12606565
TI  - Dynamic evidence for metal ion catalysis in the reaction mediated by a flap
      endonuclease.
AB  - On the basis of structural work, metal ions are proposed to play a catalytic role
      in reactions mediated by many phosphoryl transfer enzymes. To gain dynamic
      support for such mechanisms, the role of metal ion cofactors in phosphate diester
      hydrolysis catalysed by a flap endonuclease has been studied. The pH maximal rate
      profiles were measured in the presence of various metal ion cofactors; in each
      case, a single ionic form of the enzyme/cofactor accounts for the pH dependence.
      The kinetic pK(a)s display good correlation with the acidity of the corresponding
      hexahydrated metal ions, which strongly suggests a role for metal-bound
      hydroxide, or its equivalent ionic species, in the reaction. Comparing rates of
      reaction in the pH-independent regions, a small negative beta(nuc) value is
      observed. This suggests that expected trends in the nucleophilicity of the
      various metal-bound hydroxides are balanced by a second form of metal ion
      catalysis that is related to the acidity of the hexahydrated metal ion. This is
      likely to be either electrophilic catalysis or leaving group activation.

PMID- 12606566
TI  - Switching between the two action modes of the dual-affinity nitrate transporter
      CHL1 by phosphorylation.
AB  - To counteract fluctuating nutrient environments, plants have evolved high- and
      low-affinity uptake systems. These two systems were traditionally thought to be
      genetically distinct, but, recently, two Arabidopsis transporters, AtKUP1 and
      CHL1, were shown to have dual affinities. However, little is known about how a
      dual-affinity transporter works and the advantages of having a dual-affinity
      transporter. This study demonstrates that, in the case of CHL1, switching between
      the two modes of action is regulated by phosphorylation at threonine residue 101;
      when phosphorylated, CHL1 functions as a high-affinity nitrate transporter,
      whereas, when dephosphorylated, it functions as a low-affinity nitrate
      transporter. This regulatory mechanism allows plants to change rapidly between
      high- and low-affinity nitrate uptake, which may be critical when competing for
      limited nitrogen. These results demonstrate yet another regulatory role of
      phosphorylation in plant physiology.

PMID- 12606567
TI  - Attenuation of cell adhesion in lymphocytes is regulated by CYTIP, a protein
      which mediates signal complex sequestration.
AB  - An important theme in molecular cell biology is the regulation of protein
      recruitment to the plasma membrane. Fundamental biological processes such as
      proliferation, differentiation or leukocyte functions are initiated and
      controlled through the reversible binding of signaling proteins to phosphorylated
      membrane components. This is mediated by specialized interaction modules, such as
      SH2 and PH domains. Cytohesin-1 is an intracellular guanine nucleotide exchange
      factor, which regulates leukocyte adhesion. The activity of cytohesin-1 is
      controlled by phospho inositide-dependent membrane recruitment. An interacting
      protein was identified, the expression of which is upregulated by cytokines in
      hematopoietic cells. This molecule, CYTIP, is also recruited to the cell cortex
      by integrin signaling via its PDZ domain. However, stimulation of Jurkat cells
      with phorbol ester results in re-localization of CYTIP to the cytoplasm, and
      membrane detachment of cytohesin-1 strictly requires co-expression of CYTIP.
      Consequently, stimulated adhesion of Jurkat cells to intracellular adhesion
      molecule-1 is repressed by CYTIP. These findings outline a novel mechanism of
      signal chain abrogation through sequestration of a limiting component by specific
      protein-protein interactions.

PMID- 12606568
TI  - Intrabodies based on intracellular capture frameworks that bind the RAS protein
      with high affinity and impair oncogenic transformation.
AB  - We have applied in vivo intracellular antibody capture (IAC) technology to
      isolate human intrabodies which bind to the oncogenic RAS protein. IAC
      facilitates the capture of antibody fragments, in this case single-chain Fvs
      (scFvs), which tolerate reducing environments, such as the cytoplasm of cancer
      cells. Three anti-RAS scFvs with different affinity, solubility and intracellular
      binding activity were characterized. The anti-RAS scFvs with highest affinity
      were expressed relatively poorly in mammalian cells, and greater soluble
      expression was achieved by mutating the antibody framework to canonical consensus
      scaffolds, previously derived from IAC, without losing antigen specificity.
      Mutagenesis experiments showed that the consensus scaffolds are functional as
      intrabody fragments without an intra-domain disulfide bond. Furthermore, we could
      convert an intrabody which does not bind RAS in mammalian cells into a high
      affinity reagent capable of inhibiting RAS-mediated NIH 3T3 transformation by
      exchanging VH and VL complementarity-determining regions onto its consensus
      scaffold. These data show that the consensus scaffold is a robust framework by
      which to improve intrabody function.

PMID- 12606569
TI  - A role for N-glycanase in the cytosolic turnover of glycoproteins.
AB  - Successful maturation determines the intracellular fate of secretory and membrane
      proteins in the endoplasmic reticulum (ER). Failure of proteins to fold or
      assemble properly can lead to their retention in the ER and redirects them to the
      cytosol for degradation by the proteasome. Proteasome inhibitors can yield
      deglycosylated cytoplasmic intermediates that are the result of an N-glycanase
      activity, believed to act prior to destruction of these substrates by the
      proteasome. A gene encoding a yeast peptide:N-glycanase, PNG1, has been cloned,
      but this N-glycanase and its mammalian homolog were reported to be incapable of
      deglycosylating full-length glycoproteins. We show that both the yeast PNG1
      enzyme and its mammalian homolog display N-glycanase activity towards intact
      glycoproteins. As substrates, cytosolic PNGase activity prefers proteins
      containing high-mannose over those bearing complex type oligosaccharides.
      Importantly, PNG1 discriminates between non-native and folded glycoproteins,
      consistent with a role for N-glycanase in cytoplasmic turnover of glycoproteins.

PMID- 12606570
TI  - Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor
      targeting for invasion of human erythrocytes.
AB  - The members of the phylum Apicomplexa parasitize a wide range of eukaryotic host
      cells. Plasmodium falciparum, responsible for the most virulent form of malaria,
      invades human erythrocytes using several specific and high affinity ligand
      receptor interactions that define invasion pathways. We find that members of the
      P. falciparum reticulocyte-binding homolog protein family, PfRh2a and PfRh2b, are
      expressed variantly in different lines. Targeted gene disruption shows that
      PfRh2b mediates a novel invasion pathway and that it functions independently of
      other related proteins. Phenotypic variation of the PfRh protein family allows P.
      falciparum to exploit different patterns of receptors on the erythrocyte surface
      and thereby respond to polymorphisms in erythrocyte receptors and to evade the
      host immune system.

PMID- 12606571
TI  - Separation of genetic functions controlling organ identity in flowers.
AB  - Comparative studies on the ABC model of floral development have revealed
      extensive conservation of B and C class genes, but have failed to identify
      similar conservation for A class genes. Using a reverse genetic approach, we show
      that the previous inability to obtain Antirrhinum mutants corresponding to the A
      class gene AP2 of Arabidopsis reflects greater genetic redundancy in Antirrhinum
      . Antirrhinum has two genes corresponding to AP2, termed LIP1 and LIP2, both of
      which need to be inactivated to give a mutant phenotype. Analysis of interactions
      between LIP and class B/C genes shows that unlike AP2 in Arabidopsis, LIP genes
      are not required for repression of C in outer whorls of the flower. However, like
      AP2, LIP genes play a role in sepal, petal and ovule development, although some
      of their detailed effects are different, reflecting the diverse morphologies of
      Antirrhinum and Arabidopsis flowers. The dual functions for which AP2 is required
      in Arabidopsis are therefore separate in Antirrhinum, showing that the genetic
      basis of some aspects of organ identity have undergone major evolutionary change.

PMID- 12606572
TI  - The human chromokinesin Kid is a plus end-directed microtubule-based motor.
AB  - Kid is a kinesin-like DNA-binding protein known to be involved in chromosome
      movement during mitosis, although its actual motor function has not been
      demonstrated. Here, we describe the initial characterization of Kid as a
      microtubule-based motor using optical trapping microscopy. A bacterially
      expressed fusion protein consisting of a truncated Kid fragment (amino acids 1
      388 or 1-439) is indeed an active microtubule motor with an average speed of
      approximately 160 nm/s, and the polarity of movement is plus end directed. We
      could not detect processive movement of either monomeric Kid or dimerizing
      chimeric Kid; however, low levels of processivity (a few steps) cannot be
      detected with our method. These results are consistent with Kid having a role in
      chromosome congression in vivo, where it would be responsible for the polar
      ejection forces acting on the chromosome arms.

PMID- 12606574
TI  - Characterization of Ran-driven cargo transport and the RanGTPase system by
      kinetic measurements and computer simulation.
AB  - Here, we analyse the RanGTPase system and its coupling to receptor-mediated
      nuclear transport. Our simulations predict nuclear RanGTP levels in HeLa cells to
      be very sensitive towards the cellular energy charge and to exceed the
      cytoplasmic concentration approximately 1000-fold. The steepness of the RanGTP
      gradient appears limited by both the cytoplasmic RanGAP concentration and the
      imperfect retention of nuclear RanGTP by nuclear pore complexes (NPCs), but not
      by the nucleotide exchange activity of RCC1. Neither RanBP1 nor the NPC
      localization of RanGAP has a significant direct impact on the RanGTP gradient.
      NTF2-mediated import of Ran appears to be the bottleneck for maximal capacity of
      Ran-driven nuclear transport. We show that unidirectional nuclear transport can
      be faithfully simulated without the assumption of a vectorial NPC passage;
      transport receptors only need to reversibly cross NPCs and switch their affinity
      for cargo in response to the RanGTP gradient. A significant RanGTP gradient after
      nuclear envelope (NE) breakdown can apparently exist only in large cytoplasm.
      This indicates that RanGTP gradients can provide positional information for
      mitotic spindle and NE assembly in early embryonic cells, but hardly any in small
      somatic cells.

PMID- 12606573
TI  - Function of Cdc2p-dependent Bub1p phosphorylation and Bub1p kinase activity in
      the mitotic and meiotic spindle checkpoint.
AB  - Cdc2p is a cyclin-dependent kinase (CDK) essential for both mitotic and meiotic
      cell cycle progression in fission yeast. We have found that the spindle
      checkpoint kinase Bub1p becomes phosphorylated by Cdc2p during spindle damage in
      mitotic cells. Cdc2p directly phosphorylates Bub1p in vitro at the CDK consensus
      sites. A Bub1p mutant that cannot be phosphorylated by Cdc2p is checkpoint
      defective, indicating that Cdc2p-dependent Bub1p phosphorylation is required to
      activate the checkpoint after spindle damage. The kinase activity of Bub1p is
      required, but is not sufficient, for complete spindle checkpoint function. The
      role of Bub1p in maintaining centromeric localization of Rec8p during meiosis I
      is entirely dependent upon its kinase activity, suggesting that Bub1p kinase
      activity is essential for establishing proper kinetochore function. Finally, we
      show that there is a Bub1p-dependent meiotic checkpoint, which is activated in
      recombination mutants.

PMID- 12606575
TI  - Nuclear export of the APC tumour suppressor controls beta-catenin function in
      transcription.
AB  - The adenomatous polyposis coli (APC) protein is inactivated in most colorectal
      tumours. APC loss is an early event in tumorigenesis, and causes an increase of
      nuclear beta-catenin and its transcriptional activity. This is thought to be the
      driving force for tumour progression. APC shuttles in and out of the nucleus, but
      the functional significance of this has been controversial. Here, we show that
      APC truncations are nuclear in colorectal cancer cells and adenocarcinomas, and
      this correlates with loss of centrally located nuclear export signals. These
      signals confer efficient nuclear export as measured directly by fluorescence loss
      in photobleaching (FLIP), and they are critical for the function of APC in
      reducing the transcriptional activity of beta-catenin in complementation assays
      of APC mutant colorectal cancer cells. Importantly, targeting a functional APC
      construct to the nucleus causes a striking nuclear accumulation of beta-catenin
      without changing its transcriptional activity. Our evidence indicates that the
      rate of nuclear export of APC, rather than its nuclear import or steady-state
      levels, determines the transcriptional activity of beta-catenin.

PMID- 12606576
TI  - TACE is required for the activation of the EGFR by TGF-alpha in tumors.
AB  - The factors and mechanisms that transduce the intracellular signals sent upon
      activation of the receptor for the epidermal growth factor (EGFR) and related
      receptors are reasonably well understood and, in fact, are the targets of anti
      tumor drugs. In contrast, less is known about the mechanisms implicated in
      sending the signals that activate these receptors. Here we show that when its
      proteolytic shedding is prevented, the transmembrane form of the transforming
      growth factor-alpha (proTGF-alpha) interacts with, but does not activate, the
      EGFR. Thus, shedding seems to control not only the availability of the soluble
      form of the growth factor (TGF-alpha) but also the activity of the transmembrane
      form. The activity of the protease responsible for the shedding of proTGF-alpha,
      tumor necrosis factor-alpha converting enzyme (TACE), is required for the
      activation of the EGFR in vivo and for the development of tumors in nude mice,
      indicating a crucial role of TACE in tumorigenesis. In agreement with this view,
      TACE is dramatically overexpressed in the majority of mammary tumors analyzed.
      Collectively, this evidence points to TACE as a promising target of anti-tumor
      therapy.

PMID- 12606577
TI  - Structure of Cdc42 in a complex with the GTPase-binding domain of the cell
      polarity protein, Par6.
AB  - Cdc42 is a small GTPase that is required for cell polarity establishment in
      eukaryotes as diverse as budding yeast and mammals. Par6 is also implicated in
      metazoan cell polarity establishment and asymmetric cell divisions. Cdc42.GTP
      interacts with proteins that contain a conserved sequence called a CRIB motif.
      Uniquely, Par6 possesses a semi-CRIB motif that is not sufficient for binding to
      Cdc42. An adjacent PDZ domain is also necessary and is required for biological
      effects of Par6. Here we report the crystal structure of a complex between Cdc42
      and the Par6 GTPase-binding domain. The semi-CRIB motif forms a beta-strand that
      inserts between the four strands of Cdc42 and the three strands of the PDZ domain
      to form a continuous eight-stranded sheet. Cdc42 induces a conformational change
      in Par6, detectable by fluorescence resonance energy transfer spectroscopy.
      Nuclear magnetic resonance studies indicate that the semi-CRIB motif of Par6 is
      at least partially structured by the PDZ domain. The structure highlights a novel
      role for a PDZ domain as a structural scaffold.

PMID- 12606578
TI  - HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with
      erythropoietin.
AB  - An HLF (HIF-1alpha-like factor)/HIF-2alpha-knockout mouse is embryonic lethal,
      preventing investigation of HLF function in adult mice. To investigate the role
      of HLF in adult pathological angiogenesis, we generated HLF-knockdown
      (HLF(kd/kd)) mice by inserting a neomycin gene sandwiched between two loxP
      sequences into exon 1 of the HLF gene. HLF(kd/kd) mice expressing 80-20%
      reduction, depending on the tissue, in wild-type HLF mRNA were fertile and
      apparently normal. Hyperoxia-normoxia treatment, used as a murine model of
      retinopathy of prematurity (ROP), induced neovascularization in wild-type mice,
      but not in HLF(kd/kd) mice, whereas prolonged normoxia following hyperoxic
      treatment caused degeneration of retinal neural layers in HLF(kd/kd) mice due to
      poor vascularization. Cre-mediated removal of the inserted gene recovered normal
      HLF expression and retinal neovascularization in HLF(kd/kd) mice. Expression
      levels of various angiogenic factors revealed that only erythropoietin (Epo) gene
      expression was significantly affected, in parallel with HLF expression. Together
      with the results from intraperitoneal injection of Epo into HLF(kd/kd) mouse,
      this suggests that Epo is one of the target genes of HLF responsible for
      experimental ROP.

PMID- 12606579
TI  - FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts.
AB  - Activation of the transcription factor FKHR (Forkhead in human rhabdomyosarcoma,
      FOXO1a) in various established cell lines induces cell cycle arrest followed by
      apoptosis. These effects are inhibited through activation of the
      phosphatidylinositol 3-kinase/Akt pathway, resulting in FKHR phosphorylation and
      its export from the nucleus, thus blocking its pro-apoptotic activity. Here we
      report that FKHR regulates fusion of differentiating primary myoblasts. We
      demonstrate that FKHR is localized in the cytoplasm of proliferating myoblasts,
      yet translocates to the nucleus by a phosphorylation-independent pathway
      following serum starvation, a condition that induces myoblast differentiation.
      FKHR phosphorylation during terminal differentiation appears to downregulate its
      fusion activity, as a dominant-active non-phosphorylatable FKHR mutant
      dramatically augments the rate and extent of myotube fusion. However, this FKHR
      mutant exerts its effects only after other events initiated the differentiation
      pro cess. Conversely, enforced expression of a dominant-negative FKHR mutant
      blocks myotube formation whereas wild-type FKHR has no effect. We conclude that
      in addition to the role of FoxO proteins in regulating cell cycle progress and
      apoptosis, FKHR controls the rate of myotube fusion during myogenic
      differentiation.

PMID- 12606580
TI  - The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid
      signaling in vivo.
AB  - Hsp90 is required for the normal activity of steroid receptors, and in steroid
      receptor complexes it is typically bound to one of the immunophilin-related co
      chaperones: the peptidylprolyl isomerases FKBP51, FKBP52 or CyP40, or the protein
      phosphatase PP5. The physiological roles of the immunophilins in regulating
      steroid receptor function have not been well defined, and so we examined in vivo
      the influences of immunophilins on hormone-dependent gene activation in the
      Saccharomyces cerevisiae model for glucocorticoid receptor (GR) function. FKBP52
      selectively potentiates hormone-dependent reporter gene activation by as much as
      20-fold at limiting hormone concentrations, and this potentiation is readily
      blocked by co-expression of the closely related FKBP51. The mechanism for
      potentiation is an increase in GR hormone-binding affinity that requires both the
      Hsp90-binding ability and the prolyl isomerase activity of FKBP52.

PMID- 12606581
TI  - HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo.
AB  - Microtubules are cylindrical cytoskeletal structures found in almost all
      eukaryotic cell types which are involved in a great variety of cellular
      processes. Reversible acetylation on the epsilon-amino group of alpha-tubulin
      Lys40 marks stabilized microtubule structures and may contribute to regulating
      microtubule dynamics. Yet, the enzymes catalysing this acetylation/deacetylation
      have remained unidentified until recently. Here we report that beta-tubulin
      interacts with histone deacetylase-6 (HDAC-6) in a yeast two-hybrid assay and in
      vitro. We find that HDAC-6 is a micro tubule-associated protein capable of
      deacetylating alpha-tubulin in vivo and in vitro. HDAC-6's microtubule binding
      and deacetylation functions both depend on the hdac domains. Overexpression of
      HDAC-6 in mammalian cells leads to tubulin hypoacetylation. In contrast,
      inhibition of HDAC-6 function by two independent mechanisms--pharmacological
      (HDAC inhibitors) or genetic (targeted inactivation of HDAC-6 in embryonic stem
      cells)--leads to hyperacetylation of tubulin and microtubules. Taken together,
      our data provide evidence that HDAC-6 might act as a dual deacetylase for tubulin
      and histones, and suggest the possibility that acetylated non-histone proteins
      might represent novel targets for pharmacological therapy by HDAC inhibitors.

PMID- 12606582
TI  - Stress-induced gene expression requires programmed recovery from translational
      repression.
AB  - Active repression of protein synthesis protects cells against protein malfolding
      during endoplasmic reticulum stress, nutrient deprivation and oxidative stress.
      However, long-term adaptation to these conditions requires synthesis of new
      stress-induced proteins. Phosphorylation of the alpha-subunit of translation
      initiation factor 2 (eIF2alpha) represses translation in diverse stressful
      conditions. GADD34 is a stress-inducible regulatory subunit of a holophosphatase
      complex that dephosphorylates eIF2alpha, and has been hypothesized to play a role
      in translational recovery. Here, we report that GADD34 expression correlated
      temporally with eIF2alpha dephosphorylation late in the stress response.
      Inactivation of both alleles of GADD34 prevented eIF2alpha dephosphorylation and
      blocked the recovery of protein synthesis, normally observed late in the stress
      response. Furthermore, defective recovery of protein synthesis markedly impaired
      translation of stress-induced proteins and interfered with programmed activation
      of stress-induced genes in the GADD34 mutant cells. These observations indicate
      that GADD34 controls a programmed shift from translational repression to stress
      induced gene expression, and reconciles the apparent contradiction between the
      translational and transcriptional arms of cellular stress responses.

PMID- 12606583
TI  - Crucial role of CA cleavage sites in the cap-snatching mechanism for initiating
      viral mRNA synthesis.
AB  - In viral cap-snatching, the endonuclease intrinsic to the viral polymerase
      cleaves cellular capped RNAs to generate capped fragments that are primers for
      viral mRNA synthesis. Here we demonstrate that the influenza viral polymerase,
      which is assembled in human cells using recombinant proteins, effectively uses
      only CA-terminated capped fragments as primers for viral mRNA synthesis in vitro.
      Thus we provide the first in vitro system that mirrors the cap-snatching process
      occurring in vivo during virus infection. Further, we demonstrate that when a
      capped RNA substrate contains a CA cleavage site, the functions of virion RNA
      (vRNA) differ from those previously described: the 5' terminal sequence of vRNA
      alone is sufficient for endonuclease activation, and the 3' terminal sequence of
      vRNA functions solely as a template for mRNA synthesis. Consequently, we are able
      to identify the vRNA sequences that are required for each of these two separable
      functions. We present a new model for the influenza virus cap-snatching
      mechanism, which we postulate is a paradigm for the cap-snatching mechanisms of
      other segmented, negative-strand and ambisense RNA viruses.

PMID- 12606584
TI  - Internal initiation drives the synthesis of Ure2 protein lacking the prion domain
      and affects [URE3] propagation in yeast cells.
AB  - The [URE3] phenotype in Saccharomyces cerevisiae is caused by the inactive,
      altered (prion) form of the Ure2 protein (Ure2p), a regulator of nitrogen
      catabolism. Ure2p has two functional domains: an N-terminal domain necessary and
      sufficient for prion propagation and a C-terminal domain responsible for nitrogen
      regulation. We show here that the mRNA encoding Ure2p possesses an IRES (internal
      ribosome entry site). Internal initiation leads to the synthesis of an N
      terminally truncated active form of the protein (amino acids 94-354) lacking the
      prion-forming domain. Expression of the truncated Ure2p form (94-354) mediated by
      the IRES element cures yeast cells of the [URE3] phenotype. We assume that the
      balance between the full-length and truncated (94-354) Ure2p forms plays an
      important role in yeast cell physiology and differentiation.

PMID- 12606587
TI  - Expression of aromatase in human ejaculated spermatozoa: a putative marker of
      motility.
AB  - Cytochrome p450 aromatase (p450arom) is a key enzyme responsible for the
      irreversible transformation of androgens into estrogens. In the present study, we
      have analysed the ability of human ejaculated spermatozoa to produce estrogens
      and for that purpose we have looked for the expression of specific aromatase
      transcript and protein. We have confirmed the presence of p450arom transcript in
      all normospermic purified samples by nested PCR. The sequence of PCR products
      from purified spermatozoa shares 98% identity with published human p450arom
      sequence. Using a semi-quantitative approach, we have observed in immotile sperm
      a significant decrease (28%) of the aromatase/glyceraldehyde-3-phosphate
      dehydrogenase ratio compared with the motile sperm fraction. On Western blot with
      a monoclonal antibody directed against aromatase, we have detected two bands (53
      and 49 kDa) in microsome preparations from purified spermatozoa. In total protein
      extracts of purified spermatozoa (with and without cytoplasmic droplets), we have
      only found the aromatase as a 49 kDa band with a stronger intensity when
      cytoplasmic droplets are present. Moreover, the band seems to be weaker in
      immotile spermatozoa (with and without cytoplasmic droplets). Our data
      demonstrate the expression of aromatase both in terms of mRNA and protein in each
      sample of human purified spermatozoa and in addition, our results suggest that
      aromatase could be concerned with the acquisition of sperm motility.

PMID- 12606585
TI  - BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks
      modulates homologous recombination.
AB  - Diverse functions, including DNA replication, recombination and repair, occur
      during S phase of the eukaryotic cell cycle. It has been proposed that p53 and
      BLM help regulate these functions. We show that p53 and BLM accumulated after
      hydroxyurea (HU) treatment, and physically associated and co-localized with each
      other and with RAD51 at sites of stalled DNA replication forks. HU-induced
      relocalization of BLM to RAD51 foci was p53 independent. However, BLM was
      required for efficient localization of either wild-type or mutated (Ser15Ala) p53
      to these foci and for physical association of p53 with RAD51. Loss of BLM and p53
      function synergistically enhanced homologous recombination frequency, indicating
      that they mediated the process by complementary pathways. Loss of p53 further
      enhanced the rate of spontaneous sister chromatid exchange (SCE) in Bloom
      syndrome (BS) cells, but not in their BLM-corrected counterpart, indicating that
      involvement of p53 in regulating spontaneous SCE is BLM dependent. These results
      indicate that p53 and BLM functionally interact during resolution of stalled DNA
      replication forks and provide insight into the mechanism of genomic fidelity
      maintenance by these nuclear proteins.

PMID- 12606588
TI  - Role of protein tyrosine phosphorylation in the thapsigargin-induced
      intracellular Ca(2+) store depletion during human sperm acrosome reaction.
AB  - During human sperm capacitation, an increase in phosphotyrosine content of
      specific proteins results partially from an increase in the intracellular free
      Ca(2+) concentrations. In the present study, the inter-regulation between protein
      phosphotyrosine content and the intracellular Ca(2+) concentration during the
      thapsigargin treatment of capacitated human sperm was investigated. The
      involvement of a tyrosine kinase pathway in the thapsigargin-induced acrosome
      reaction was also investigated. In response to thapsigargin, two sperm
      subpopulations, called LR (low responsive) and HR (high responsive), according to
      their increase in intracellular Ca(2+), were observed. In addition to their high
      increase in intracellular Ca(2+), sperm from the HR population expressed a higher
      protein phosphotyrosine content, and a higher proportion (P < 0.05) of them
      underwent the acrosome reaction in response to thapsigargin, as compared with LR
      sperm. Although the tyrosine kinase inhibitor PP2 abolished the thapsigargin
      induced increase in protein phosphotyrosine content, it did not affect the
      intracellular Ca( 2+) concentration or the percentage of acrosome-reacted sperm.
      The inability of an src-related tyrosine kinase inhibitor to block the
      thapsigargin-mediated Ca(2+) increase and acrosomal exocytosis suggests that,
      during the acrosome reaction, the signalling pathway mediated by src-related
      tyrosine kinases is involved upstream of the capacitative Ca(2+) entry.

PMID- 12606586
TI  - Localization of DNA polymerases eta and iota to the replication machinery is
      tightly co-ordinated in human cells.
AB  - Y-family DNA polymerases can replicate past a variety of damaged bases in vitro
      but, with the exception of DNA polymerase eta (poleta), which is defective in
      xeroderma pigmentosum variants, there is little information on the functions of
      these polymerases in vivo. Here, we show that DNA polymerase iota (poliota), like
      poleta, associates with the replication machinery and accumulates at stalled
      replication forks following DNA-damaging treatment. We show that poleta and
      poliota foci form with identical kinetics and spatial distributions, suggesting
      that localization of these two polymerases is tightly co-ordinated within the
      nucleus. Furthermore, localization of poliota in replication foci is largely
      dependent on the presence of poleta. Using several different approaches, we
      demonstrate that poleta and poliota interact with each other physically and that
      the C-terminal 224 amino acids of poliota are sufficient for both the interaction
      with poleta and accumulation in replication foci. Our results provide strong
      evidence that poleta targets poliota to the replication machinery, where it may
      play a general role in maintaining genome integrity as well as participating in
      translesion DNA synthesis.

PMID- 12606589
TI  - Expression of apoptosis-related genes during human preimplantation embryo
      development: potential roles for the Harakiri gene product and Caspase-3 in
      blastomere fragmentation.
AB  - In order to resolve the mechanisms and reasons of cellular fragmentation it is
      crucial to understand what genes may be responsible for regulation of this
      process. We report herein that human oocytes and preimplantation embryos possess
      abundant levels of transcripts encoding cell death suppressors, Mcl-1, Bcl-x and
      Bag-1, and the cell death inducer genes, Bax and Caspase-2. Lower but detectable
      levels of mRNA expression for the Bfl-1/a1, Bcl-w, Harakiri (Hrk) and Caspase-3
      genes were also detected during all developmental stages. We also performed
      analysis of gene expression in single human embryos exhibiting various degrees of
      fragmentation at the 2-, 4- and 8-cell stages. At the 4-cell stage, embryos
      displaying 30-50% fragmentation showed a significant increase in Hrk mRNA levels
      (P = 0.016). Immunostaining with anti-Hrk antibody confirmed increased staining
      in some, but not all, fragmented embryos. While Caspase-3 transcripts were
      elevated in both 4- and 8-cell embryos exhibiting a severe degree of
      fragmentation, this difference did not reach statistical significance. However,
      accumulation of Caspase-3 mRNA in fragmented embryos was paralleled by an
      induction of Caspase-3-like activity. These findings suggest that cellular
      fragmentation in a subset of human preimplantation embryos could be regulated by
      certain components of a genetic programme of cell death.

PMID- 12606591
TI  - Leptin regulation of the interleukin-1 system in human endometrial cells.
AB  - We have previously shown that (i). leptin and leptin receptor (Ob-R) are
      expressed in the human endometrium, and (ii). leptin secretion is regulated in
      blastocyst and endometrial epithelial cell (EEC) co-cultures. Interleukin-1beta
      (IL-1beta) up-regulates leptin and Ob-R, and both cytokines up-regulate beta3
      integrin expression in EEC. In the present investigation we examined the effect
      of leptin on the expression of the IL-1 system in EEC and endometrial stromal
      cells (ESC) cultured in a medium containing insulin, leptin or IL-1beta (0-3
      nmol/l). Leptin stimulated IL-1 antagonist (IL-1Ra), IL-1beta secretion and
      expression of IL-1 receptor type I (IL-1R tI) in both cell types. IL-1beta and IL
      1Ra secretion were down-regulated by IL-1R tI blockade using specific antibodies.
      Interestingly, leptin partially neutralized this effect. The blockade of Ob-R
      neutralized the effects of both leptin and IL-1beta on expression of the IL-1beta
      system and beta3 integrin and on phosphorylation of signal transducer and
      activator of transcription 3 (Stat3). These results suggest that leptin regulates
      the IL-1 system and that the blockade of functional Ob-R impairs leptin and IL
      1beta functions at the endometrial level. Leptin could be an important molecule
      for implantation and a molecular mediator for actions of the IL-1 system. The
      fact that leptin, in the absence of IL-1, can trigger the expression of markers
      of endometrial receptivity and of the invasive trophoblast phenotype (as does IL
      1), suggest that leptin could substitute for these IL-1 functions during the
      implantation process.

PMID- 12606590
TI  - Expression and implications of tissue inhibitor of metalloproteinases-4 in mouse
      embryo.
AB  - Matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP),
      and MMP-TIMP interactions may contribute to the highly programmed process of
      embryo implantation. The loss of the delicate MMP-TIMP balance may lead to
      abnormal implantation. The role of TIMP-4 in mouse implantation has not been
      reported. This study examined mRNA and protein expression levels of TIMP-4 in the
      blastocyst and uteri of pregnant mice. We also investigated the effects of a
      specific TIMP-4 antibody on embryo outgrowth and on the gene and protein
      expression levels of two gelatinases. High levels of TIMP-4 mRNA and protein were
      detected in day 3-5 embryos and in the trophoblast cells of mice blastocysts,
      suggesting that TIMP-4 may be involved in embryo implantation. Furthermore, TIMP
      4 antibody promoted blastocyst outgrowth in a dose-dependent manner, but had no
      effect on blastocyst adhesion to extracellular matrix. A specific TIMP-4 antibody
      also increased mRNA and protein expression levels and the enzymatic activities of
      gelatinase A (MMP-2) and gelatinase B (MMP-9). This study suggests that TIMP-4
      may restrict mouse blastocyst outgrowth and embryo implantation by inhibiting the
      activities of MMP-2 and -9.

PMID- 12606593
TI  - Glutathione S-transferase M1 and T1 polymorphisms and the risk of recurrent
      pregnancy loss.
AB  - The aetiology of recurrent pregnancy loss (RPL) remains unclear, but it may be
      related to a possible genetic predisposition together with involvement of
      environmental factors. We examined the relation between RPL and polymorphisms in
      two genes, glutathione S-transferases (GST) M1 and T1, which are involved in the
      metabolism of a wide range of environmental toxins and carcinogens. A case
      control study of 115 cases with RPL and 160 controls was conducted. All cases and
      controls were women resident in Sapporo, Japan and the surrounding area. They
      were genotyped for polymorphisms of GSTM1 and GSTT1 using PCR-based methods. We
      found that 65.2% of the cases with RPL and 45.6% of the controls had the GSTM1
      null genotype [odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.36-3.66].
      On the other hand, 47.0% of the cases and 49.4% of the controls had the GSTT1
      null genotype (OR = 0.95; 95% CI = 0.58-1.55). The results suggest that women
      with GSTM1 null polymorphism may therefore have an increased risk of RPL.

PMID- 12606592
TI  - Effects of L-type Ca(2+)-channel blockade, K(+)(ATP)-channel opening and nitric
      oxide on human uterine contractility in relation to gestational age and labour.
AB  - Relative uterine inactivity during pregnancy changes to vigorous rhythmic
      contractility during labour. We hypothesized that mechanisms involved in the
      regulation of uterine quiescence and contractility differ between term and
      preterm myometrium and in labour and non-labour states. Myometrial strips,
      prepared from biopsies taken at Caesarean section from labouring and non
      labouring women preterm and at term, were mounted in organ chambers for isometric
      tension recording. Oxytocin (10(-9) mol/l) was added to maintain stable
      contractions, and effects of various inhibitors of uterine contractility were
      studied. The inhibitory effects of L-type Ca(2+)-channel blocker nifedipine and
      ATP-sensitive K(+)-channel opener pinacidil were greater in myometrium from the
      non-labour versus the labour group, both preterm and at term. In addition,
      pinacidil's effect was greater at term compared with preterm in the non-labour
      group. Mg(2+) and the nitric oxide donor sodium nitroprusside significantly
      inhibited contractility in all groups without significant differences with regard
      to labour or gestational age. Decreased inhibition of human uterine contractility
      by L-type Ca(2+)-channel blockers and K(+)(ATP)-channel openers in preterm and
      term labour may reflect changes in expression and activity of these channels.
      Effects of nitric oxide and Mg(2+) are not affected by gestational age or labour.

PMID- 12606594
TI  - The N314D polymorphism of the GALT gene is not associated with congenital absence
      of the uterus and vagina.
AB  - The aetiology of anomalous embryonic and fetal development of the female
      reproductive tract, ranging from common uterine abnormalities to the somewhat
      rare congenital absence of the uterus and vagina (CAUV), is unknown. Some have
      proposed that abnormal galactose metabolism might cause CAUV. An association
      between CAUV and the N314D allele of the galactose-1-phosphate uridyl transferase
      (GALT) gene has been proposed as aetiological. We tested this hypothesis further
      by performing a case-control molecular study analysing 32 patients with CAUV for
      the presence of the N314D allele. These patients were compared with 138 normal
      controls. No association between CAUV and the N314D polymorphism was found (P =
      0.32). It is unlikely that either maternal or fetal GALT enzyme activity could
      affect paramesonephric duct development, because neither galactosaemic subjects
      nor their children have an increased incidence of uterine anomalies.

PMID- 12606595
TI  - In vivo CYP3A4 heteroactivation is a possible mechanism for the drug interaction
      between felbamate and carbamazepine.
AB  - Atypical (non-Michaelis-Menten) kinetics are commonly observed with CYP3A4
      substrates in vitro. If relevant in vivo, cytochrome P450 heteroactivation could
      give rise to increased drug clearance. To test the possible in vivo relevance of
      atypical cytochrome P450 kinetics, we investigated the role of heteroactivation
      in the therapeutically relevant drug interaction between the anti-epileptics
      felbamate and carbamazepine. Felbamate heteroactivates CYP3A4-mediated formation
      of carbamazepine-10,11-epoxide (carbamazepine-ep), the major metabolite of
      carbamazepine, in human liver microsomes and recombinant CYP3A4 at relevant in
      vivo concentrations of both drugs (maximum activation 98% at 10 microM
      carbamazepine, 1 mM felbamate). Felbamate (50-500 microM) did not induce CYP3A4,
      as based on mRNA measurements in human liver slices. The further metabolism of
      carbamazepine-ep was inhibited (38% by 500 microM felbamate) in human liver
      slices. We propose a methodology to predict changes in steady-state plasma
      concentrations (Css) of parent drug and metabolite from in vitro heteroactivation
      and inhibition data, including prediction of the increase in fraction
      metabolized. A meta-analysis of reported in vivo effects of felbamate on
      Csscarbamazepine was performed to allow evaluation of this approach. The
      predicted effect of in vitro heteroactivation on Csscarbamazepine corresponds
      well to that observed in vivo. Combining the effect of heteroactivation on the
      fraction metabolized to carbamazepine-ep, and inhibition of its further
      metabolism, predicts a change in Csscarbamazepine-ep that falls within the range
      observed in vivo. Our results strongly suggest that in vivo heteroactivation of
      CYP3A4 is a possible mechanism of the clinically observed drug interaction
      between felbamate and carbamazepine.

PMID- 12606597
TI  - Flavonoid baicalein attenuates activation-induced cell death of brain microglia.
AB  - Baicalein (5,6,7-trihydroxyflavone), a flavonoid originated from the root of
      Chinese medicinal herb Scutellaria baicalensis, has been shown to exert anti
      inflammatory and antioxidant effects, and it is a well known inhibitor of 12
      lipoxygenase. We have previously reported that neuroglia undergo nitric oxide
      (NO)-dependent and NO-independent apoptosis upon inflammatory activation. In the
      current work, we asked how anti-inflammatory baicalein influences autoregulatory
      apoptosis of activated microglia and their NO production. Baicalein attenuated NO
      production and apoptosis of lipopolysaccharide (LPS)-activated, but not
      interferon-gamma-activated, BV-2 mouse microglial cells as well as rat primary
      microglia cultures. The inhibition of NO production by baicalein was due to the
      suppression of inducible NO synthase induction. Moreover, baicalein inhibited LPS
      induced nuclear factor-kappaB (NF-kappaB) activity in BV-2 cells without
      affecting caspase-11 activation, interferon regulatory factor-1 induction, or
      signal transducer and activator of transcription-1 phosphorylation. Transfection
      of BV-2 cells with a p65 subunit of NF-kappaB abolished the apoptosis-attenuating
      effects of baicalein, indicating that the inhibition of NF-kappaB is a major
      mechanism of action. Baicalein, however, did not significantly affect NO donor
      mediated cytotoxicity, and the apoptosis-attenuating effects of baicalein were
      independent of 12-lipoxygenase inhibition. Based on our previous findings that
      activation-induced cell death (AICD) of microglia occurs through two separate
      pathways (NO-dependent pathway and caspase-11-dependent pathway), our current
      results suggest that baicalein selectively inhibits the NO-dependent apoptotic
      pathway of activated microglia by suppressing cytotoxic NO production. Also, the
      AICD-inhibiting effects of baicalein were specific for the inflammatory stimulus
      that activated microglia.

PMID- 12606598
TI  - The delta-isoform of protein kinase C causes inducible nitric-oxide synthase and
      nitric oxide up-regulation: key mechanism for oxidant-induced carbonylation,
      nitration, and disassembly of the microtubule cytoskeleton and hyperpermeability
      of barrier of intestinal epithelia.
AB  - Using intestinal (Caco-2) cells, we found that oxidant-induced disruption of
      barrier integrity requires microtubule disassembly. Protein kinase C (PKC)-delta
      isoform seems to be essential for disruption, but the mechanism is unknown.
      Because inducible nitric-oxide synthase (iNOS) is key to oxidant stress, we
      hypothesized that PKC-delta activation is essential in oxidant-induced iNOS up
      regulation and the consequent cytoskeletal oxidation and disarray and monolayer
      barrier dysfunction. Cells were transfected with an inducible plasmid to
      overexpress native PKC-delta or with a dominant-negative to inhibit the activity
      of native PKC-delta. Clones were then incubated with oxidant (H(2)O(2)) +/-
      modulators. Parental cells were treated similarly. Exposure to oxidant-disrupted
      monolayers by increasing native PKC-delta activity, increasing six iNOS-related
      variables (iNOS activity and protein, nitric oxide, oxidative stress, tubulin
      oxidation and nitration), decreasing polymerized tubulin, disrupting the
      cytoarchitecture of microtubules, and causing monolayer dysfunction. Induction of
      PKC-delta overexpression by itself (3.5-fold) led to oxidant-like disruptive
      effects, including activation of the iNOS-driven pathway. Overexpression-induced
      up-regulation of iNOS was potentiated by oxidants. iNOS inhibitors or oxidant
      scavengers were protective. Dominant inhibition of native PKC-delta activity
      (99.5%) prevented all measures of oxidant-induced iNOS up-regulation and
      protected the monolayer barrier. The conclusions are as follows. 1) Oxidants
      induce loss of epithelial barrier integrity by oxidizing and disassembling the
      cytoskeleton, in part, through the activation of PKC-delta and up-regulation of
      iNOS. 2) Overexpression and activation of PKC-delta are by themselves key for
      cellular injury by oxidative stress of iNOS. 3) We thus report a
      pathophysiological mechanism, activation of iNOS pathway and its injurious
      consequences to the cytoskeleton, including oxidation and nitration, among the
      "novel" subfamily of PKC isoforms.

PMID- 12606600
TI  - Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A
      317920: II. In vivo behavioral and neurophysiological characterization.
AB  - Pharmacological blockade of central histamine H3 receptors (H3Rs) enhances
      cognition in rodents and offers promise for the clinical treatment of
      neurological disorders. However, many previously characterized H3R antagonists
      are either not selective for H3Rs or have potentially significant tolerability
      issues. Here, we present in vivo behavioral and neurophysiological data for two
      novel and selective H3R antagonists with improved safety indices. Functional
      blockade of central H3Rs was first demonstrated for A-304121 [(4-(3-(4-((2R)-2
      aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] (1 mg/kg) and
      A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)
      1-methyl-2-oxo-ethyl)-2-furamide] (0.45 mg/kg) by significantly attenuating an
      acute dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine
      [(R)-alpha-MeHA]. Cognitive performance was improved in a five-trial rat pup
      avoidance test following administration of A-304121 (10 mg/kg) or A-317920 (3
      mg/kg), with efficacy comparable with previously published observations for
      reference H3R antagonists thioperamide (10 mg/kg), ciproxifan (3 mg/kg), and GT
      2331 [(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole] (1 mg/kg).
      Social memory was also significantly enhanced in the adult rat with A-304121 (3,
      10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change
      in electroencephalogram slow-wave amplitude activity. Relative therapeutic
      indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920,
      respectively, by comparing doses producing adverse effects in general observation
      studies with potency in inhibitory avoidance, which were superior to TIs of 8,
      10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and
      GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H3R
      selective piperazine amides that enhance cognition in vivo, which could offer
      advantages over existing H3R antagonists or cognition-enhancing agents.

PMID- 12606602
TI  - Donitriptan selectively decreases jugular venous oxygen saturation in the
      anesthetized pig: further insights into its mechanism of action relevant to
      headache relief.
AB  - The effects of donitriptan on systemic arterial-jugular venous oxygen saturation
      difference were evaluated in pentobarbitone-anesthetized pigs. Oxygen and carbon
      dioxide partial pressures in systemic arterial and jugular venous blood as well
      as hemoglobin oxygen saturation were determined by conventional blood gas
      analysis. Vehicle (40% polyethyleneglycol in saline, n = 9) or donitriptan (0.01,
      0.04, 0.16, 0.63, 2.5, 10, and 40 microg/kg, n = 7) were cumulatively infused
      over 15 min/dose. The involvement of 5-hydroxytryptamine(1B) (5-HT(1B)) receptors
      was assessed in the presence of the 5-HT(1B/1D) receptor antagonist, GR 127935.
      Donitriptan decreased markedly and dose dependently jugular venous oxygen
      saturation [ED(50) 0.5 (0.3-1.1) microg/kg], in parallel with increases in
      carotid vascular resistance [ED(50) 0.9 (0.7-1.1) microg/kg]. Since arterial
      oxygen saturation and partial pressure remained unchanged, donitriptan
      significantly increased arteriovenous oxygen saturation difference from 0.63
      microg/kg (maximal variation: 57 +/- 18%, P < 0.05 compared with vehicle).
      Unexpectedly, donitriptan from 2.5 microg/kg induced marked and significant
      increases in carbon dioxide partial pressure (pVCO(2)) in venous blood (maximal
      increase 18.8 +/- 5.7%; P < 0.05 compared with vehicle). Pretreatment with GR
      127935 (0.63 mg/kg, n = 5) abolished the fall in venous oxygen saturation and the
      increase in carotid vascular resistance and reduced the increases in pVCO(2)
      induced by donitriptan. The results demonstrate that donitriptan, via 5-HT(1B)
      receptor activation, decreases the oxygen saturation of venous blood draining the
      head, concomitantly with cranial vasoconstriction. Since donitriptan also
      increased pVCO(2), an effect upon cerebral oxygen consumption and metabolism is
      suggested in addition to cranial vasoconstriction, which may be relevant to its
      headache-relieving effects.

PMID- 12606603
TI  - Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121
      and A-317920: I. In vitro pharmacological effects.
AB  - Histamine H3 receptor (H3R) antagonists enhance neurotransmitter release and are
      being developed for the treatment of a variety of neurological and cognitive
      disorders. Many potent histamine H3R antagonists contain an imidazole moiety that
      limits receptor selectivity and the tolerability of this class of compounds. Here
      we present the in vitro pharmacological data for two novel piperazine amide
      ligands, A-304121 [4-(3-((2R)-2-aminopropanoyl-1
      piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [N-((1R)-2-(4-(3-(4
      (cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2
      furamide], and compare them with the imidazole H3R antagonists ciproxifan,
      clobenpropit, and thioperamide. Both A-304121 and A-317920 bind potently to
      recombinant full-length rat H3R(pKi values = 8.6 and 9.2, respectively) but have
      lower potencies for binding the full-length human H3R (pKi values = 6.1 and 7.0,
      respectively). A-304121 and A-317920 are potent antagonists at rat H3R in
      reversing R-alpha-methylhistamine [(R)-alpha-MeHA] inhibition of forskolin
      stimulated cAMP formation (pKb values = 8.0 and 9.1) but weak antagonists at
      human H3Rs in cyclase (pKb values = 6.0 and 6.3) and calcium mobilization (pKb
      values = 6.0 and 7.3) assays in cells co-expressing Galphaqi5-protein. Both
      compounds potently antagonize native H3Rs by blocking histamine inhibition of
      potassium-evoked [3H]histamine release from rat brain cortical synaptosomes (pKb
      values = 8.6 and 9.3) and (R)-alpha-MeHA reversal of electric field-stimulated
      guinea pig ileum contractions (pA2 values = 7.1 and 8.3). A-304121 and A-317920
      are also more efficacious inverse agonists in reversing basal guanosine 5'-O-(3
      [35S]thio)triphosphate ([35S]GTP gamma S) binding at the human H3R (pEC50 values
      = 5.7 and 7.0) than are the imidazole antagonists. These novel and selective
      piperazine amides represent useful leads for the development of H3R antagonist
      therapeutic agents.

PMID- 12606604
TI  - Role of prostaglandin I2 in the gene expression induced by mechanical stress in
      spinal ligament cells derived from patients with ossification of the posterior
      longitudinal ligament.
AB  - Ossification of the posterior longitudinal ligament of the spine (OPLL) is
      characterized by ectopic bone formation in the spinal ligaments, and mechanical
      stress has been suggested to play an important role in the progression of OPLL.
      To identify the genes that participate in OPLL, the differential display reverse
      transcription-polymerase chain reaction (RT-PCR) method was used. A 283-base pair
      cDNA fragment corresponding to prostaglandin I2 (PGI2) synthase was highly
      expressed in OPLL cells compared with non-OPLL cells. To examine the effect of
      mechanical stress on the expression of PGI2 synthase, cells were subjected to
      uniaxial cyclic stretch (0.5 Hz, 20% stretch), and PGI2 synthase mRNA expression
      was assessed by quantitative RT-PCR. Cyclic stretch induced an increase in PGI2
      synthase in OPLL cells in a time-dependent manner, whereas no change was observed
      in non-OPLL cells. Cyclic stretch for 9 h also induced a 2.86x increase in PGI2
      production. Beraprost (a stable PGI2 analog) and dibutyryl cAMP (a membrane
      permeable cAMP analog) increased the mRNA expression of alkaline phosphatase
      (ALP) as a marker for osteogenic differentiation up to 240 and 200%,
      respectively, in OPLL cells, whereas no change was observed in non-OPLL cells.
      The increases in ALP mRNA induced by beraprost and cyclic stretch were both
      inhibited by SQ22536, a potent adenylate cyclase inhibitor. These data suggest
      that the increase in PGI2 synthase induced by mechanical stress plays a key role
      in the progression of OPLL, at least in part through the induction of osteogenic
      differentiation in spinal ligament cells via the PGI2/cAMP system.

PMID- 12606605
TI  - Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2
      receptors.
AB  - Neuropeptide FF (NPFF) and prolactin-releasing peptide (PrRP) are two members of
      the RFamide peptide family. In this study we investigated whether these RFamide
      peptides, which have common structural features in their C-terminal RFamide motif
      and share several physiologically important functions, could exert their effects
      through the same set of receptors. The affinity and functional activity of
      several related RFamide peptides were determined at the human neuropeptide FF
      receptor subtype 2 (hNPFF2) and the human prolactin-releasing peptide (hPrRP)
      receptors. The full-length human prolactin releasing peptide 31 (hPrRP31) had
      significantly higher efficacy compared with NPFF and its stable analog,
      (1DMe)Y8Fa, at the hNPFF2 receptor. In contrast, NPFF and (1DMe)Y8Fa were not
      efficacious at the hPrRP receptor. Our study indicated a generally relatively low
      level of discrimination for RFamide peptides at the NPFF receptor, whereas the
      hPrRP receptor clearly preferred PrRP or very closely related peptides. The
      seemingly promiscuous binding of the RFamide peptides to the NPFF receptor was
      further confirmed by receptor autoradiography. PrRP may thus signal through the
      NPFF receptors in vivo.

PMID- 12606608
TI  - Antipsychotic dosing in preclinical models is often unrepresentative of the
      clinical condition: a suggested solution based on in vivo occupancy.
AB  - What is the appropriate dose of an antipsychotic in an animal model? The
      literature reveals no standard rationale across studies. This study was designed
      to use in vivo dopamine D(2) receptor occupancy as a cross-species principle for
      deriving clinically comparable doses for animal models. The relationship between
      dose, plasma levels, and in vivo dopamine D(2) receptor occupancy was established
      in rats for a range of doses administered as a single dose or multiple doses
      (daily injections or osmotic minipump infusions) for five of the most commonly
      used antipsychotics. As a single dose, haloperidol (0.04-0.08 mg/kg), clozapine
      (5-15 mg/kg), olanzapine (1-2 mg/kg), risperidone (0.5-1 mg/kg), and quetiapine
      (10-25 mg/kg) reached clinically comparable occupancies. However, when these
      "optimal" single doses were administered as multiple doses, either by injection
      or by a mini-pump, it led to no or inappropriately low trough (24-h) occupancies.
      This discrepancy arises because the half-life of antipsychotics in rodents is 4
      to 6 times faster than in humans. Only when doses 5 times higher than the optimal
      single dose were administered by pump were clinically comparable occupancies
      obtained (e.g., haloperidol, 0.25 mg/kg/day; olanzapine, 7.5 mg/kg/day). This
      could not be achieved for clozapine or quetiapine due to solubility and
      administration constraints. The study provides a rationale as well as clinically
      comparable dosing regimens for animal studies and raises questions about the
      inferences drawn from previous studies that have used doses unrepresentative of
      the clinical situation.

PMID- 12606609
TI  - Mapping the cerebral monoamine oxidase type A: positron emission tomography
      characterization of the reversible selective inhibitor [11C]befloxatone.
AB  - Befloxatone is a competitive and reversible inhibitor of monoamine oxidase-A
      (MAOI-A). The aim of the study was to characterize the in vivo properties of
      [(11)C]befloxatone and to validate its use as a ligand for the study of MAO-A by
      positron emission tomography (PET). PET studies were performed in baboons after
      i.v. injection of [(11)C]befloxatone (551 +/- 70 MBq, i.e.14.9 +/- 1.9 mCi).
      [(11)C]Befloxatone enters rapidly in the brain with a maximum uptake at 30 min.
      Brain concentration of the tracer is high in thalamus, striatum, pons and
      cortical structures (1.5-1.8% of injected dose per 100 ml of tissue), and lower
      in cerebellum (1.07% injected dose/100 ml). Nonsaturable uptake, obtained after a
      pretreatment with a high dose of nonlabeled befloxatone (0.4 mg/kg), is very low
      and represents only 3% of the total uptake. Brain uptake of [(11)C]befloxatone is
      not altered by a pretreatment of a high dose with lazabemide (0.5 mg/kg i.v.), a
      selective MAOI-B but is completely blocked by a pretreatment with moclobemide
      (MAOI-A; 10 mg/kg). This confirms, in vivo, the selectivity of befloxatone for
      type A MAO. [(11)C]Befloxatone brain radioactivity was displaced by
      administration of unlabeled befloxatone (30 min after the tracer injection). The
      displacement of the tracer from its binding sites is dose-dependent, with an
      ID(50) of 0.02 mg/kg for all studied structures. These results indicate that
      [(11)C]befloxatone will be an excellent probe for the study of MAO-A in humans
      using PET.

PMID- 12606610
TI  - Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated
      withdrawal signs by oral Delta 9-tetrahydrocannabinol.
AB  - Previous studies have demonstrated a functional interaction between cannabinoid
      and opioid systems in the development and expression of morphine tolerance and
      dependence. In these experiments, we examined the effect of a low oral dose of
      Delta 9-tetrahydrocannabinol (Delta 9-THC) on the development of oral morphine
      tolerance and the expression of naloxone-precipitated morphine withdrawal signs
      of jumping and diarrhea in ICR mice. Chronic treatment with high-dose oral
      morphine produced a 3.12-fold antinociceptive tolerance. Tolerance to morphine
      was prevented in groups receiving a daily cotreatment with a nonanalgetic dose
      (20 mg/kg p.o.) of Delta 9-THC, except when challenged with a very high dose of
      morphine. The chronic coadministration of low-dose Delta 9-THC also reduced
      naloxone-precipitated (1 mg/kg s.c.) platform jumping by 50% but did not reduce
      diarrhea. In separate experiments, mice treated chronically with high-dose
      morphine p.o. were not cross-tolerant to Delta 9-THC; in fact, these morphine
      tolerant mice were more sensitive to the acute antinociceptive effects of Delta 9
      THC. Delta 9-THC (20 mg/kg p.o.) also reduced naloxone-precipitated jumping but
      not diarrhea when administered acutely to morphine-tolerant mice. These results
      represent the first evidence that oral morphine tolerance and dependence can be
      circumvented by coadministration of a nonanalgetic dose of Delta 9-THC p.o. In
      summary, cotreatment with a combination of morphine and Delta 9-THC may prove
      clinically beneficial in that long-term morphine efficacy is maintained.

PMID- 12606612
TI  - Maternal vaccination against nicotine reduces nicotine distribution to fetal
      brain in rats.
AB  - Cigarette smoking during pregnancy is associated with a variety of adverse fetal
      outcomes. Nicotine is a likely contributor to these adverse effects, with fetal
      brain as one target organ. Vaccination of adult male rats against nicotine has
      been shown to reduce nicotine distribution to the brain. The current study
      examined whether vaccination of female rats before pregnancy would reduce the
      distribution to fetal brain of a single nicotine dose administered during
      gestation. Female rats immunized with a nicotine conjugate vaccine received a
      single dose of nicotine 0.03 mg/kg i.v. on gestational day 16 to 22. Five minutes
      later, vaccinated rats had substantially higher bound and lower unbound serum
      nicotine concentration and lower brain nicotine concentration than controls.
      Fetal brain nicotine concentration was reduced by 43% in vaccinated rats,
      comparable to the reduction in the maternal brain nicotine concentration. The
      whole-fetus nicotine concentration was not altered by vaccination. A similar
      experiment was performed in which pregnant rats were passively immunized with
      rabbit nicotine-specific IgG 7 or 21 mg/kg just before nicotine dosing. The
      effects of passive immunization on nicotine distribution in the mother were IgG
      dose-related and the higher dose reduced nicotine distribution to fetal brain by
      60%. These data suggest that vaccine effects on nicotine distribution to serum
      and brain are similar in pregnant female rats to those previously reported in
      adult males. Vaccination of female rats before pregnancy, or passive immunization
      during pregnancy, can reduce the exposure of fetal brain to a single dose of
      maternally administered nicotine.

PMID- 12606613
TI  - A tertiary alcohol analog of gamma-hydroxybutyric acid as a specific gamma
      hydroxybutyric acid receptor ligand.
AB  - gamma-Hydroxybutyric acid (GHB) shows great promise as a treatment for sleeping
      disorders but is also increasingly abused. The exact mechanism of action of GHB
      is yet to be delineated, but it is known to interact with specific GHB binding
      sites or receptors, to act as a weak agonist at GABA(B) receptors, and that GHB
      undergoes metabolism to GABA. In drug discrimination studies, GABA(B) agonists,
      and to a lesser extent GABA(A)-positive modulators, substitute for GHB. To
      delineate the relative contributions of each receptor system to the profile of
      GHB, tertiary alcohol analogs of GHB and its homolog, 5-hydroxypentanoic acid
      (UMB58), were prepared (UMB68 and UMB75, respectively), which cannot be
      metabolized to GABA-active compounds. Binding studies against [(3)H]NCS-382 [(2E)
      (5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-ylidene) ethanoic acid]
      showed that the tertiary alcohol analog of GHB (UMB68) has similar affinity to
      GHB, with the longer chain analogs possessing lower affinity. Against [(3)H]GABA,
      UMB68 showed no affinity (IC(50) >100 microM) at GABA(A) or GABA(B) receptors. In
      vivo studies showed that, at behaviorally active doses, rats trained to
      discriminate GHB did not recognize the novel ligands as GHB. Thus, UMB68 is a
      selective GHB receptor ligand in binding assays, will not undergo metabolism to
      GABA-active compounds, and does not show the same effects as GHB in vivo. These
      data suggest that, although UMB68 binds to the GHB receptor, it does not have the
      observed GABA receptor-mediated effects of GHB in vivo and could provide a novel
      tool for studying the pharmacology of the GHB receptor in the absence of
      complicating GABAergic effects.

PMID- 12606616
TI  - Biological characterization of a novel, orally active small molecule gonadotropin
      releasing hormone (GnRH) antagonist using castrated and intact rats.
AB  - Gonadotropin-releasing hormone (GnRH) receptor antagonists have potential in
      treating numerous hormone-dependent pathologies including cancers of the
      prostate, breast, and ovary, endometriosis, and fertility disorders. An unmet
      clinical need exists for an orally available GnRH receptor antagonist. Guided by
      structure-activity relationships, ligand-based targeted library designs, and
      biomarker measurements, our discovery efforts have yielded a novel, small
      molecule GnRH receptor antagonist, 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2
      naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide (CMPD1). CMPD1 bound
      with low nanomolar affinities to human, rat, and mouse GnRH receptors (6.0, 3.8,
      and 2.2 nM, respectively). CMPD1 was more than 100-fold selective for GnRH
      receptors versus various G-protein-coupled receptors and other enzymes and ion
      channels. In cells expressing recombinant rat GnRH receptors, CMPD1 was a
      competitive antagonist of GnRH-stimulated increases in extracellular
      acidification rates in Cytosensor microphysiometer assays. In cells expressing
      recombinant human GnRH receptors, CMPD1 was a potent inhibitor of GnRH-stimulated
      total inositol phosphate accumulation. The effects of CMPD1 on circulating levels
      of luteinizing hormone (LH) and testosterone were studied in castrated and intact
      male rats, respectively. Intravenous and oral administration of CMPD1 dose
      dependently suppressed GnRH-mediated elevations of LH in castrated male rats and
      testosterone in gonad-intact male rats. Moreover, CMPD1, when given at 20 mg/kg
      i.v. to intact male rats, inhibited the elevations of LH and testosterone
      stimulated by the superagonist of GnRH, [d-Ala(6), des-Gly(10)]GnRH (GnRH-A).
      These data suggest that CMPD1 is a potent, selective, orally active GnRH receptor
      antagonist that may have potential application as a therapeutic agent for
      treating hormone-dependent cancers and diseases.

PMID- 12606621
TI  - Interaction of the growth hormone-releasing peptides ghrelin and growth hormone
      releasing peptide-6 with the motilin receptor in the rabbit gastric antrum.
AB  - The structural relationship between the motilin and the growth hormone
      secretagogue receptor (GHS-R), and between their respective ligands, motilin and
      ghrelin, prompted us to investigate whether ghrelin and the GHS-R agonist growth
      hormone-releasing peptide-6 (GHRP-6), could interact with the motilin receptor.
      The interaction was evaluated in the rabbit gastric antrum with binding studies
      on membrane preparations and with contraction studies on muscle strips in the
      presence of selective antagonists under conditions of electrical field
      stimulation (EFS) or not. Binding studies indicated that the affinity (pK(d)) for
      the motilin receptor was in the order of ghrelin (4.23 +/- 0.07) < GHRP-6 (5.54
      +/- 0.08) < motilin (9.13 +/- 0.03). The interaction of ghrelin with the motilin
      receptor requires the octanoyl group. Motilin induced smooth muscle contractile
      responses but ghrelin and GHRP-6 were ineffective. EFS elicited on- and off
      responses that were increased by motilin already at 10(-9) M, but not by 10(-5) M
      ghrelin. In contrast, GHRP-6 also enhanced the on- and off-responses. The motilin
      antagonist Phe-cyclo[Lys-Tyr(3-tBu)-betaAla-] trifluoroacetate (GM-109) blocked
      the effect of GHRP-6 on the off-responses but not on the on-responses. Under
      nonadrenergic noncholinergic conditions, the effects of motilin and GHRP-6 on the
      on-responses were abolished; those on the off-responses were preserved. All
      responses were blocked by neurokinin (NK)(1) and NK(2) antagonists. In
      conclusion, ghrelin is unable to induce contractions via the motilin receptor.
      However, GHRP-6 enhances neural contractile responses, partially via interaction
      with the motilin receptor on noncholinergic nerves with tachykinins as mediator,
      and partially via another receptor that may be a GHS-R subtype on cholinergic
      nerves that corelease tachykinins.

PMID- 12606620
TI  - Thrombin and protease-activated receptor-1 agonists promote lipopolysaccharide
      induced hepatocellular injury in perfused livers.
AB  - Bacterial lipopolysaccharide (LPS) is a potent inflammatory agent capable of
      producing liver injury, the pathogenesis of which depends on numerous mediators,
      including thrombin. Previous studies showed that thrombin promotes LPS-induced
      liver injury independent of its ability to form fibrin clots. In isolated, buffer
      perfused livers from LPS-treated rats, thrombin added to the perfusion buffer
      caused dose-dependent liver injury with an EC(50) value of 0.4 nM, consistent
      with activation by thrombin of a protease-activated receptor (PAR). Actions of
      thrombin at PARs can be mimicked by thrombin receptor-activating peptides
      (TRAPs). TRAPs for PAR-1 reproduced the injury caused by thrombin in isolated
      livers, suggesting that one mechanism by which thrombin promotes LPS-induced
      liver injury is by activating PAR-1. Immunocytochemistry demonstrated the
      presence of PAR-1 on sinusoidal endothelial cells and Kupffer cells but not on
      parenchymal cells or neutrophils. Previous studies showed that thrombin interacts
      with neutrophils in the genesis of liver injury after LPS treatment. To explore
      this interaction further, the influence of thrombin on mediators that modulate
      neutrophil function were evaluated. Inhibition of thrombin in LPS-treated rats
      prevented liver injury but did not prevent up-regulation of cytokine-induced
      neutrophil chemoattractant-1, macrophage inflammatory protein-2, or intercellular
      adhesion molecule-1. Thrombin inhibition did, however, prevent neutrophil (PMN)
      degranulation in vivo as measured by plasma elastase levels. In addition,
      elastase concentration was increased in the perfusion medium of livers isolated
      from LPS-treated rats and perfused with TRAPs. These results suggest that
      activation of PAR-1 after LPS exposure promotes PMN activation and hepatic
      parenchymal cell injury.

PMID- 12606622
TI  - Melphalan antitumor efficacy and hepatotoxicity: the effect of variable infusion
      duration in the hepatic artery.
AB  - The optimum conditions (duration and concentration) of a fixed dose, intra
      arterial melphalan infusion in relation to its antitumor effect and toxicity in
      the liver were investigated in a rat colon tumor model (CC531) of liver
      metastases. We studied the difference in tumor and liver uptake, as well as
      antitumor effect and hepatotoxicity after 5- and 20-min hepatic arterial infusion
      (HAI) of a fixed melphalan dose. Melphalan content in perfusate, liver, and tumor
      tissue was analyzed by high-performance liquid chromatography. The antitumor
      effect and hepatotoxicity in rats treated either systemically or with 5- and 20
      min HAI, with a fixed dose melphalan (4.4 micromol), were assessed 2 weeks after
      treatment. No difference in melphalan content of tumor/liver tissue or antitumor
      effect was observed between rats treated with 5- and 20-min HAI. Hepatotoxicity
      was strongly affected by perfusion duration/concentration, however. Rats treated
      with 5-min HAI weighed significantly less, and liver toxicity parameters were
      significantly increased compared with those of all other groups; eight of nine
      rats showed severe cholangiofibrosis. Body weights and liver toxicity parameters
      of the rats treated with 20-min HAI were not statistically different from the
      control group. In conclusion, duration of HAI with 4.4 micromol of fixed dose
      melphalan did not affect tumor uptake and antitumor effect, but the resulting
      increase in melphalan concentration had major impact on hepatobiliary toxicity.
      Therefore, in a clinical setting, caution should be taken when infusion duration
      and concentration of melphalan are changed.

PMID- 12606624
TI  - Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-1:
      pharmacological characterization and neuroprotective effects in an in vitro model
      of cerebral ischemia.
AB  - Excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme
      catalyzing the transfer of ADP-ribose units from NAD to acceptor proteins,
      induces cellular energy failure by NAD and ATP depletion and has been proposed to
      play a causative role in a number of pathological conditions, including
      ischemia/reperfusion injury. In this study, we used an in vitro enzyme activity
      assay to characterize a series of newly synthesized isoquinolinone derivatives as
      potential PARP-1 inhibitors. Several compounds displayed powerful inhibitory
      activity: thieno[2,3-c]isoquinolin-5-one (TIQ-A) displayed a submicromolar IC50
      of 0.45 +/- 0.1 microM, whereas the 5-hydroxy and 5-methoxy TIQ-A derivatives had
      IC50 values of 0.39 +/- 0.19 and 0.21 +/- 0.12 microM, respectively. We then
      examined the neuroprotective effects of the newly characterized compounds in
      cultured mouse cortical cells exposed to 60 min of oxygen and glucose deprivation
      (OGD). When PARP-1 inhibitors were present in the incubation medium during OGD
      and the subsequent 24-h recovery period, they significantly attenuated neuronal
      injury. TIQ-A provided neuroprotection even when added to the culture 30 min
      after OGD and was able to reduce the early activation of PARP induced by OGD as
      detected by flow cytometry. When the IC50 values observed in the PARP-1 activity
      assay for selected compounds were compared with their IC50 values for the
      neuroprotective activity, a significant correlation (r = 0.93, P < 0.01) was
      observed. Our results suggest that TIQ-A and its derivatives are a new class of
      neuroprotectants that may be helpful in studies aimed at understanding the
      involvement of PARP-1 in physiology and pathology.

PMID- 12606625
TI  - Regulation of the cardiac mitochondrial membrane potential by retinoids.
AB  - Cardiomyocytes suffering irreversible damage under oxidative stress during
      ischemia activate their suicide program. Mitochondria play a key role in this
      process, while they themselves are subject to regulation by a number of signaling
      pathways. We demonstrate here that retinoids influence mitochondrial function in
      cardiomyocytes. Depending on their chemical nature, retinoids can either
      ameliorate or exacerbate stress-related damage. Thus, vitamin A, retinol, was
      protective because retinol deprivation enhanced oxidative damage, as indicated by
      rapid loss of mitochondrial membrane potential. Supplementation with a
      physiological concentration of retinol reversed this effect. Anhydroretinol (AR),
      a known antagonist, which works by displacing retinol from the common binding
      sites on serine/threonine kinases, also caused mitochondrial membrane
      depolarization. The AR effect was both Ca(2+)-dependent and cyclosporin
      sensitive, suggesting an upstream signaling mechanism rather than direct membrane
      effect. Our results agree with a model where retinol supports mitochondrial
      integrity by enabling upstream signaling processes. The consequences of
      disrupting these processes by AR are opening of the permeability transition pore,
      release of cytochrome c, and activation of the suicide program.

PMID- 12606626
TI  - Activation of peroxisome proliferator-activated receptor gamma does not explain
      the antiproliferative activity of the nonsteroidal anti-inflammatory drug
      indomethacin on human colorectal cancer cells.
AB  - The mechanism of the anticolorectal cancer activity of the nonsteroidal anti
      inflammatory drug indomethacin is poorly understood. Indomethacin inhibits both
      cyclooxygenase (COX) isoforms, but it may also act via COX-independent targets.
      Indomethacin can bind and activate the transcription factor peroxisome
      proliferator-activated receptor (PPAR) gamma. Moreover, natural and synthetic
      PPARgamma ligands can induce growth arrest and apoptosis of human colorectal
      cancer cells in vitro. Therefore, we tested the hypothesis that the
      antiproliferative activity of indomethacin on human colorectal cancer cells in
      vitro is explained by a PPARgamma-dependent mechanism of action. Human colorectal
      cancer cell lines SW480 and HCT116 both expressed functional PPARgamma.
      Indomethacin directly activated PPARgamma in both cell lines (HCT116 > SW480). A
      dominant-negative PPARgamma strategy was used to demonstrate that endogenous
      PPARgamma represses proliferation of HCT116 cells (compatible with tumor
      suppressor activity) but that the presence of functional PPARgamma is not
      necessary for the antiproliferative activity (or reduction in cyclin D1 protein)
      associated with indomethacin in vitro. In summary, indomethacin (>100 microM)
      directly activates PPARgamma in human colorectal cancer cells. However, PPARgamma
      activation does not underlie the antineoplastic activity of indomethacin on human
      colorectal cancer cells in vitro.

PMID- 12606627
TI  - Direct interactions between the heterotrimeric G protein subunit G beta 5 and the
      G protein gamma subunit-like domain-containing regulator of G protein signaling
      11: gain of function of cyan fluorescent protein-tagged G gamma 3.
AB  - We used fluorescence resonance energy transfer imaging of enhanced cyan
      fluorescent protein (CFP)-tagged and enhanced yellow fluorescent protein (YFP)
      tagged protein pairs to examine the hypothesis that G protein gamma subunit-like
      (GGL) domain-containing regulators of G protein signaling (RGS) can directly bind
      to the Gbeta5 subunit of heterotrimeric G proteins in vivo. We observed that
      Gbeta5 could interact with Ggamma2 and Ggamma13, after their expression in human
      embryonic kidney 293 cells. Interestingly, although untagged Ggamma3 did not
      interact with Gbeta5, CFP-tagged Ggamma3 strongly interacted with YFP-tagged
      Gbeta5 in FRET studies. Moreover, CFP-Ggamma3 supported Ca(2+) channel inhibition
      when paired with Gbeta5 or YFP-Gbeta5, indicating a "gain of function" for CFP
      Ggamma3. Gbeta5 could also interact with RGS11 and its N-terminal, but not its C
      terminal domain. On the other hand, RGS11 did not interact with Gbeta1. These
      studies demonstrate that the GGL domain-containing N terminus of RGS 11 can
      directly interact with Gbeta5 in vivo and supports the hypothesis that this
      interaction may contribute to the specificity of Gbeta5 interactions with
      cellular effector molecules.

PMID- 12606628
TI  - Endogenous opioid peptides contribute to antinociceptive potency of intrathecal
      [Dmt1]DALDA.
AB  - [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH(2); Dmt = 2',6'-dimethyltyrosine) is a
      dermorphin analog that shows high affinity and selectivity for the mu opioid
      receptor. The intrathecal potency of [Dmt(1)]DALDA far exceeded its affinity at
      mu receptors and suggests that other mechanisms must be involved in its action in
      the spinal cord. The affinity and selectivity of [Dmt(1)]DALDA was determined
      using cell membranes expressing cloned human mu, delta, and kappa opioid
      receptors. Competitive displacement binding with [(3)H][Dmt(1)]DALDA, [(3)H]DPDPE
      (H-Tyr-d-Pen-Gly-Phe-d-Pen), and [(3)H]U69,593 [(5alpha,7alpha,8beta)-(+)-N
      methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec-8-yl)-benzeneacetamide] revealed
      K(i) of 156 +/- 26 pM for mu opioid receptor (MOR), 1.67 +/- 0.04 microM for
      delta opioid receptor (DOR), and K(i) of 4.4 +/- 1.7 nM for kappa opioid receptor
      (KOR), respectively. [Dmt(1)]DALDA increased guanosine 5'-O-(3
      [(35)S]thiotriphosphate) binding in MOR, DOR, and KOR membranes, with EC(50)
      being 17 (8.8-33) nM, 2 (1.2-3.2) microM, and 124 (15-1000) nM, respectively.
      Intrathecal [Dmt(1)]DALDA inhibited the tail-flick response in mice with ED(50) =
      1.22 (0.59-2.34) pmol. Intrathecal administration of an antiserum against
      dynorphin A(1-17) or [Met(5)]enkephalin significantly attenuated the response to
      i.t. [Dmt(1)]DALDA, resulting in ED(50) of 6.2 (3.6-12.6) pmol and 6.6 (3.5-19.6)
      pmol, respectively. Neither antisera had any effect on the response to i.t.
      morphine. Intracerebroventricular (i.c.v.) [Dmt(1)]DALDA was not affected by
      previous i.c.v. administration of anti-Dyn or anti-ME. Pretreatment with
      norbinaltorphimine or naltriben also attenuated the antinociceptive response to
      i.t., but not i.c.v., [Dmt(1)]DALDA. These data suggest that i.t. [Dmt(1)]DALDA
      causes the release of dynorphin and [Met(5)]enkephalin-like substances that act
      at kappa and delta receptors, respectively, to contribute to the extraordinary
      potency of [Dmt(1)]DALDA.

PMID- 12606630
TI  - Structure-activity relations of successful pharmacologic chaperones for rescue of
      naturally occurring and manufactured mutants of the gonadotropin-releasing
      hormone receptor.
AB  - We expressed a test system of wild-type (WT) rat (r) and human (h) gonadotropin
      releasing hormone (GnRH) receptors (GnRHRs), including naturally occurring (13)
      and manufactured (five) "loss-of-function" mutants of the GnRHR. These were used
      to assess the ability of different GnRH peptidomimetics to rescue defective GnRHR
      mutants and determine their effect on the level of membrane expression of the WT
      receptors. Among the manufactured mutants were the shortest rGnRHR C-terminal
      truncation mutant that resulted in receptor loss-of-function (des(325-327)
      rGnRHR), two nonfunctional deletion mutants (des(237-241)-rGnRHR and des(260-265)
      rGnRHR), two nonfunctional Cys mutants (C(229)A-rGnRHR and C(278)A-rGnRHR); the
      naturally occurring mutants included all 13 full-length GnRHR point mutations
      reported to date that result in full or partial human hypogonadotropic
      hypogonadism. The 10 peptidomimetics assessed as potential rescue molecules
      ("pharmacoperones") are from three differing chemical pedigrees (indoles,
      quinolones, and erythromycin-derived macrolides) and were originally developed as
      GnRH peptidomimetic antagonists. These structures were selected for this study
      because of their predicted ability to permeate the cell membrane and interact
      with a defined affinity with the GnRH receptor. All peptidomimetics studied with
      an IC(50) value (for hGnRHR) <or=2.3 nM had measurable efficacy in rescuing GnRHR
      mutants, and within a single chemical class, this ability correlated to these
      IC(50) values. Erythromycin-derived macrolides with IC(50) values as high as
      669.5 nM showed efficacy as rescue compounds. The ability to rescue a particular
      receptor was a reasonable predictor of the ability to rescue others, even across
      species lines, although particular mutants could not be rescued by any of the
      drugs tested.

PMID- 12606629
TI  - Functional and molecular characterization of beta-adrenoceptors in the internal
      anal sphincter.
AB  - The purpose of the present study was to characterize different beta-adrenoceptors
      (beta-ARs) and determine their role in the spontaneously tonic smooth muscle of
      the internal anal sphincter (IAS). The beta-AR subtypes in the opossum IAS were
      investigated by functional in vitro, radioligand binding, Western blot, and
      reverse transcription-polymerase chain reaction (RT-PCR) studies. ZD 7114 [(S)-4
      [2-hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide], a
      selective beta(3)-AR agonist, caused a potent and concentration-dependent
      relaxation of the IAS smooth muscle that was antagonized by the beta(3)-AR
      antagonist SR 59230A [1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1
      naphthalenyl]amino]-(2S)-2-propanol hydrochloride]. Conversely, the IAS smooth
      muscle relaxation caused by beta(1)- and beta(2)-AR agonists (xamoterol and
      procaterol, respectively) was selectively antagonized by their respective
      antagonists CGP 20712 [(+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4
      (trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide
      methanesulfonate salt] and ICI 118551. Saturation binding of
      [(125)I]iodocyanopindolol to beta-AR subtypes revealed the presence of a high
      affinity site (K(d1) = 96.4 +/- 8.7 pM; B(max1) = 12.5 +/- 0.6 fmol/mg protein)
      and a low-affinity site (K(d2) = 1.96 +/- 1.7 nM; B(max2) = 58.7 +/- 4.3 fmol/mg
      protein). Competition binding with selective beta-AR antagonists revealed that
      the high-affinity site correspond to beta(1)/beta(2)-AR and the low affinity site
      to beta(3)-AR. Receptor binding data suggest the predominant presence of beta(3)
      AR over beta(1)/beta(2)-AR. Western blot studies identified beta(1)-, beta(2)-,
      and beta(3)-AR subtypes. The presence of beta(1)-, beta(2)-, and beta(3)-ARs was
      further demonstrated by mRNA analysis using RT-PCR. The studies demonstrate a
      comprehensive functional and molecular characterization of beta(1)-, beta(2)-,
      and beta(3)-ARs in IAS smooth muscle. These studies may have important
      implications in anorectal and other gastrointestinal motility disorders.

PMID- 12606631
TI  - Activation of beta2- and beta3-adrenergic receptors increases brain tryptophan.
AB  - Brain tryptophan concentrations are increased by various stressful treatments, an
      effect that can be prevented by beta-adrenoceptor antagonists. This study aimed
      to determine the beta-adrenergic subtype responsible for the tryptophan response.
      Male CD-1 mice received intraperitoneal injections of nonselective and subtype
      selective beta-adrenergic antagonists 20 min before subtype-selective beta
      agonists. Selected brain regions were dissected for analysis of tryptophan
      content by high-performance liquid chromatography with electrochemical detection.
      The beta(2)-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain
      tryptophan that reached a peak ( approximately 60%) 1 h following injection and
      small but statistically significant increases ( approximately 20%) in 5
      hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The beta(1)
      selective agonist dobutamine (10 mg/kg) produced less robust increases (
      approximately 40%) in brain tryptophan, whereas the beta(3)-selective agonists
      BRL 37344 (0.2 mg/kg (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2
      hydroxyethyl]amino)propyl] phenoxy]acetic acid sodium)) and CL 316243 [0.1 mg/kg
      disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3
      benzodioxole-2,2-dicarboxylate)] resulted in larger increases (80 to 100%).
      Pretreatment with the beta(2)-selective antagonist ICI 118551 (0.5 mg/kg (+/-)-1
      [2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)amino]-2-butanol)
      attenuated the increases in tryptophan induced by both clenbuterol (0.1 mg/kg)
      and dobutamine (10 mg/kg). Pretreatment with the beta(1/2)-selective antagonist
      propranolol (2.5 mg/kg), the beta(3)-selective antagonist SR 59230A [1.5, 2.5, 5,
      or 20 mg/kg (3-(2-ethylphenoxy)-1[1S)-1,2,3,4-tertahydronaphth-1-yl-amino]-(2S)-2
      propanol oxalate)], or ICI 118551 (0.5 mg/kg) did not prevent the BRL 37344
      induced increase in brain tryptophan, whereas the beta(1/2/3)-antagonist
      bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan
      in beta(3)-receptor knockout mice, whereas clenbuterol increased brain
      tryptophan, indicating that beta-adrenergic modulation of brain tryptophan occurs
      in the absence of beta(3)-receptors. We conclude that activation of either
      beta(2)- or beta(3)-adrenergic receptors, but not beta(1)-adrenergic receptors,
      increases mouse brain tryptophan content.

PMID- 12606632
TI  - Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses
      to ethanol and other anesthetics.
AB  - GABA(A) receptors have been implicated in mediating several acute effects of
      ethanol including anxiolysis, ataxia, sedation/hypnosis, and anticonvulsant
      activity. Ethanol sensitivity of neurons has been associated with expression of
      alpha1 subunit-containing receptors. The objective of this study was to determine
      the contribution of alpha1 subunit containing receptors to ethanol responses in
      comparison to neurosteroids and other anesthetics using GABA(A) receptor alpha1
      subunit knockout mice. Deletion of alpha1 subunit-containing receptors did not
      alter the anxiolytic, ataxic, anticonvulsant, or hypnotic effects of ethanol or
      acute functional tolerance to ethanol but did increase sensitivity to the
      locomotor-stimulating effects of ethanol. The ability of ethanol to potentiate
      muscimol-stimulated chloride uptake and ethanol clearance was also not altered
      following alpha1 subunit deletion. The anticonvulsant and hypnotic effects of
      neurosteroids as well as their potentiating effect on GABA-mediated Cl(-) uptake
      were unaltered in alpha1(-/-) mice. The hypnotic effect of pentobarbital,
      etomidate, and midazolam were reduced, whereas the effect of ketamine was
      enhanced in alpha1(-/-) mice. Thus, GABA(A) receptor alpha1 subunit-containing
      receptors appear to influence the motor-stimulating effect of ethanol and the
      sedative/hypnotic effects of some anesthetics, but not ethanol. These receptors
      do not appear to be necessary for most ethanol responses, suggesting involvement
      of other GABA(A) receptor subtypes or other targets altogether.

PMID- 12606633
TI  - Insights into gender bias: rat cytochrome P450 3A9.
AB  - Some members of the CYP3A subfamily show gender-dependent expression. Using
      quantitative real-time polymerase chain reaction, we report that female rats have
      28-fold higher CYP3A9 mRNA levels than males in liver and 3.8-fold higher in
      lung. Furthermore, the CYP3A9 expression profile in kidney exhibits a regio
      specific distribution, i.e., a 10-fold higher expression in cortex compared with
      medulla. Also, we observed tissue-specific estrogen regulation of the CYP3A9
      message. Estrogen treatment caused a significant up-regulation in liver and a
      marked down-regulation both in the cortex and medulla of the kidney. Upon
      ovariectomy, hepatic and brain CYP3A9 expression were reduced significantly, but
      a modest increase in kidney expression was observed. The effects of ovariectomy
      on CYP3A9 gene expression were reversed upon exogenous estrogen treatment. CYP3A
      protein levels and hepatic microsomal activity toward benzphetamine after various
      treatments showed changes parallel to CYP3A9 mRNA levels. We report for the first
      time that CYP3A9 levels change dramatically during the course of pregnancy.

PMID- 12606634
TI  - Distinct recognition of OX1 and OX2 receptors by orexin peptides.
AB  - In this study, we have compared the abilities of orexin-A and orexin-B and
      variants of orexin-A to activate different Ca(2+) responses (influx and release)
      in human OX(1) and OX(2) receptor- expressing Chinese hamster ovary cells.
      Responses mediated by activation of both receptor subtypes with either orexin-A
      or -B were primarily dependent on extracellular Ca(2+), suggesting similar
      activation of Ca(2+) influx as we have previously shown for orexin-A and OX(1)
      receptors. Amino acid-wise truncation of orexin-A reduced its ability to activate
      OX(1) and OX(2) receptors, but the response mediated by the OX(2) receptor was
      more resistant to truncation than the response mediated by the OX(1) receptor. We
      also performed a sequential replacement of amino acids 14 to 26 with alanine in
      the truncated orexin-A variant orexin-A(14-33). Replacement of the same amino
      acids produced a fall in the potency for each receptor subtype, but the reduction
      was less prominent for the OX(2) receptor. The most marked reduction was produced
      by the replacement of Leu20, Asp25, and His26 with alanine. Interestingly,
      extracellular Ca(2+) dependence of responses to some of the mutated peptides was
      different from those of orexin-A and -B. The mutagenesis also suggests that
      although the determinants required from orexin-A for binding to and activation of
      the receptor are highly conserved between the orexin receptor subtypes, the OX(2)
      receptor requires fewer determinants. This might in part explain why orexin-B has
      the affinity and potency equal to orexin-A for this subtype, although it has 10-
      to 100-fold lower affinity and potency for the OX(1) receptor.

PMID- 12606635
TI  - Effect of ursodeoxycholic acid on the impairment induced by maternal cholestasis
      in the rat placenta-maternal liver tandem excretory pathway.
AB  - We investigated the effects of ursodeoxycholic acid (UDCA; 60 microg/day/100 g
      b.wt.) on the impairment induced by maternal obstructive cholestasis during
      pregnancy (OCP) in the rat placenta-maternal liver tandem excretory pathway. A
      blunted catheter was implanted in the common bile duct on day 14 of pregnancy,
      and the tip was cut on day 21. [(14)C]Glycocholate (GC) was then administered
      through the umbilical artery of "in situ" perfused placenta (placental transfer
      test) or through the maternal jugular vein (biliary secretion test), and GC bile
      output was measured. OCP impaired both GC placental transfer and maternal biliary
      secretion. UDCA moderately improved the latter but had a more marked beneficial
      effect on GC placental transfer. Histological examination revealed trophoblast
      atrophy and structural alterations, e.g., loss of apical membrane microvilli in
      OCP placentas. Gene expression level was investigated by real-time quantitative
      reverse transcription-polymerase chain reaction and Western blot analysis. OCP
      reduced both placental lactogen II (a trophoblast-specific gene) mRNA and the
      functional amount of epithelial tissue, determined by transplacental diffusion of
      antipyrin. Using a rapid filtration technique, impairment in the ATP-dependent GC
      transport across trophoblast apical plasma membranes obtained from OCP placentas
      was found. UDCA partially prevented all these changes. The expression level of
      organic anion transporters Oatp1, Oatp2, and Oatp4, and multidrug resistance
      associated proteins Mrp1, Mrp2, and Mrp3 in whole placenta were not affected or
      were moderately affected by OCP but greatly enhanced by UDCA. In summary, UDCA
      partially prevents deleterious effects of OCP on the rat placenta-maternal liver
      tandem excretory pathway, mainly by preserving trophoblast structure and
      function.

PMID- 12606636
TI  - Allosteric adenosine receptor modulation reduces hypersensitivity following
      peripheral inflammation by a central mechanism.
AB  - Activation of adenosine A1 receptors by endogenous adenosine or synthetic
      agonists produces antinociception in animal models of acute pain and also reduces
      hypersensitivity in models of inflammatory and nerve-injury pain. Allosteric
      adenosine modulators facilitate and potentiate the action of adenosine agonists
      at the A1 receptors. The purpose of the current study was to examine the effect
      and site of action for an allosteric adenosine modulator, T62 [2-amino-3-(4
      chlorobenzoyl)-5,6, 7,8-tetrahydrobenzothiophene], in rat models of acute pain
      and inflammation. Intrathecal (i.t.) T62 did not change the withdrawal latency or
      threshold of normal rats to acute heat or to acute paw pressure. In contrast,
      i.t. T62 reversed thermal hypersensitivity in carrageenin-inflamed rats.
      Subcutaneous (s.c.) injection of T62 into the inflamed paw had no such effect. To
      investigate a potential site of action on nociceptors, single-unit afferent
      activity to mechanical stimuli on A delta- and C-fibers was examined in normal or
      carrageenin-inflamed rats before and after intravenous (i.v.) T62 administration.
      Intravenous T62, 3 mg/kg, had no significant effect in either normal or inflamed
      conditions. These results support previous studies to suggest that adenosine
      receptor modulators lack efficacy to acute nociceptive stimuli in the normal
      condition, but reduce hypersensitivity during inflammation through a central
      mechanism.

PMID- 12606637
TI  - The heritability of antinociception II: pharmacogenetic mediation of three over
      the-counter analgesics in mice.
AB  - Chromosomal loci containing genes affecting antinociceptive sensitivity to
      morphine have been identified, but virtually nothing is known about the genetic
      mediation of sensitivity to over-the-counter analgesics. Such knowledge would be
      of great clinical interest, as prodigious interindividual variability has been
      noted in the efficacy of these ubiquitously used drugs. In the present study, we
      assessed heritability and genetic correlations among three over-the-counter
      analgesics in mice of 12 inbred mouse strains on the 0.9% acetic acid (i.p.)
      writhing test. Analgesics included the centrally acting analgesic, acetaminophen
      (150 mg/kg, s.c.), and the nonsteroidal anti-inflammatory drugs (NSAIDs),
      indomethacin (40 mg/kg, s.c.) and lysine-acetylsalicylic acid (800 mg/kg, s.c.).
      Significant strain differences in sensitivity to each of the drugs were observed,
      with narrow-sense heritability estimates ranging from 23 to 45%. Similar strains
      were sensitive and resistant, respectively, to the two NSAIDs (r(s) = 0.64). In
      contrast, a completely different pattern of sensitivities was observed for
      acetaminophen, implying genetic dissociation (r(s) = 0.29 and 0.02) compared with
      the NSAIDs. Additional experiments were performed on two strains, C57BL/6 and
      DBA/2, with extreme sensitivities to acetaminophen. Plasma acetaminophen levels
      in these strains were not significantly different during the time of
      antinociception assessment, suggesting the existence of genetic factors affecting
      acetaminophen pharmacodynamics rather than pharmacokinetics.

PMID- 12606638
TI  - Rac1 and superoxide are required for the expression of cell adhesion molecules
      induced by tumor necrosis factor-alpha in endothelial cells.
AB  - Oxidative signals play an important role in the regulation of endothelial cell
      adhesion molecule expression. Small GTP-binding protein Rac1 is activated by
      various proinflammatory substances and regulates superoxide generation in
      endothelial cells. In the present study, we demonstrate that adenoviral-mediated
      expression of dominant negative N17Rac1 (Ad.N17Rac1) suppresses tumor necrosis
      factor-alpha (TNF-alpha)-induced vascular cell adhesion molecule-1 (VCAM-1),
      intercellular adhesion molecule-1 (ICAM-1), and E-selectin gene expression in a
      dose-dependent manner. Ad.N17Rac1 did not inhibit TNF-alpha-induced activation of
      nuclear factor-kappaB (NF-kappaB) binding activity or inhibitor of NF-kappaB
      alpha degradation. In contrast, Ad.N17Rac1 inhibited TNF-alpha-induced NF-kappaB
      driven HIV(kappaB)(4)-CAT and p288VCAM-Luc promoter activity, suggesting that
      N17Rac1 inhibits TNF-alpha-induced VCAM-1, E-selectin, and ICAM-1 through
      suppressing NF-kappaB-mediated transactivation. In addition, expression of
      superoxide dismutase by adenovirus suppressed TNF-alpha-induced VCAM-1, E
      selectin, and ICAM-1 mRNA accumulation. However, adenoviral-mediated expression
      of catalase only partially inhibited TNF-alpha-induced E-selectin gene expression
      and had no effect on VCAM-1 and ICAM-1 gene expression. These data suggest that
      Rac1 and superoxide play crucial roles in the regulation of expression of cell
      adhesion molecules in endothelial cells.

PMID- 12606639
TI  - The role of GABAB receptors in the discriminative stimulus effects of gamma
      hydroxybutyrate in rats: time course and antagonism studies.
AB  - gamma-Hydroxybutyrate (GHB) is a neurotransmitter in brain and an emerging drug
      of abuse, although its mechanism of action is poorly understood. This study
      characterized the role of GABA(A), GABA(B), and other receptors in the
      discriminative stimulus effects of GHB. Eight rats reliably discriminated 200
      mg/kg GHB from saline after a median of 35 (range: 23-41) training sessions. GHB,
      a metabolic precursor 1,4-butanediol (1,4-BDL), and the GABA(B) agonist (+/
      )baclofen all occasioned greater than 83% responding on the GHB lever. The onset
      of action was similar for GHB and 1,4-BDL; however, 1,4-BDL exhibited a longer
      duration of action than GHB. The GHB precursor gamma-butyrolactone, the
      benzodiazepine diazepam, the neuroactive steroid pregnanolone, the opioid agonist
      morphine, and the N-methyl-d-aspartate antagonist ketamine elicited substantial
      GHB-appropriate responding, although none occasioned greater than 66% drug-lever
      responding. The barbiturate pentobarbital and the GABA(A) receptor agonist
      muscimol did not occasion greater than 17% drug-lever responding at any dose
      tested. The benzodiazepine antagonist flumazenil attenuated GHB-lever responding
      occasioned by diazepam, but not GHB. The GABA(B) receptor antagonist CGP 35348
      antagonized GHB-lever responding occasioned by baclofen or GHB. Small doses of
      the purported GHB receptor antagonist (2E)-(5-hydroxy-5,7,8,9-tetrahydro-6H
      benzo[a][7]annulen-6-ylidene ethanoic acid (NCS-382) attenuated partially the
      effects of GHB, whereas larger doses of NCS-382 alone occasioned partial GHB
      lever responding. These results implicate GABA(B) mechanisms in the
      discriminative stimulus effects of GHB and further suggest that the effects of
      1,4-BDL under these conditions result from its conversion to GHB. That NCS-382
      shares effects with GHB could explain the lack of antagonism reported for NCS-382
      in some studies.

PMID- 12606640
TI  - Pharmacological characterization of a novel antiglaucoma agent, Bimatoprost (AGN
      192024).
AB  - Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a
      nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with
      unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel
      PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide
      substituent. Bimatoprost potently contracted the feline lung parenchymal
      preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a
      variety of PG-sensitive tissue and cell preparations. Its activity seemed
      unrelated to FP receptor stimulation according to the following evidence. 1)
      Bimatoprost exhibited no meaningful activity in tissues and cells containing
      functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is
      not species-specific because its potent activity in this preparation could not be
      reproduced in cells stably expressing the feline FP receptor. 3) Radioligand
      binding studies using feline and human recombinant FP receptors exhibited minimal
      competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost
      pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3
      cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist
      effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular
      normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single
      dose and multiple-dose ocular distribution/metabolism studies using
      [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost
      concentrations were 10- to 100-fold higher in anterior segment tissues compared
      with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular
      species identified at all time points in ocular tissues, indicating that the
      intact molecule reduces intraocular pressure.

PMID- 12606641
TI  - Kinin-induced anion-dependent secretion in porcine ileum: characterization and
      involvement of opioid- and cannabinoid-sensitive enteric neural circuits.
AB  - The intestinal secretory actions of the proinflammatory peptide kallidin (lysyl
      bradykinin) are mediated partially by enteric neurons. We hypothesized that
      kallidin produces neurogenic anion secretion through opioid- and cannabinoid
      sensitive enteric neural pathways. Changes in short-circuit current (I(sc))
      across sheets of porcine ileal mucosa-submucosa mounted in Ussing chambers were
      measured in response to kallidin (1 microM) or drugs added to the contraluminal
      bathing medium. Kallidin transiently increased I(sc), an effect reduced after
      inhibition of neuronal conduction by 0.1 microM saxitoxin, cyclooxygenase
      inhibition by 10 microM indomethacin, or kinin B(2) receptor blockade by 1 microM
      d-arginyl-l-arginyl-l-prolyl-trans-4-hydroxy-l-prolylglycyl-3-(2-thienyl)-l
      alanyl-l-seryl-d-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-l
      (2alpha,3beta,7alphabeta)-octahydro-1H-indole-2-carbonyl-l-arginine (HOE-140).
      Its action was dependent upon extracellular Cl(-) or HCO(3)(-) ions, but was
      resistant to 10 microM bumetanide or 0.3 mM 4,4'-diisothiocyanatostilbene-2,2'
      disulfonic acid, and seemed to involve luminal alkalinization as measured by pH
      stat titration. Kallidin-induced I(sc) elevations were sensitive to saxitoxin in
      tissues bathed in Cl(-)-, but not HCO(3)(-)-deficient media. Tissues pretreated
      with 0.1 microM [d-Pen(2,5)]-enkephalin, a selective delta-opioid agonist,
      displayed reduced I(sc) responses to kallidin; this effect was prevented by the
      delta-opioid antagonist naltrindole. At a contraluminal concentration of 1
      microM, the cannabinoid receptor agonist (6aR)-trans-3-(1,1-dimethylheptyl)
      6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol (HU
      210) also attenuated responses to kallidin. Proinflammatory kinins seem to
      stimulate neurogenic anion secretion in porcine ileum by activating enteric
      neural circuits expressing inhibitory opioid and possibly cannabinoid receptors.

PMID- 12606642
TI  - Early mitochondrial hyperpolarization and intracellular alkalinization in
      lactacystin-induced apoptosis of retinal pigment epithelial cells.
AB  - We investigated the induction and underlying mechanism of apoptosis in retinal
      pigment epithelial cells by the inhibition of proteasome activity using
      lactacystin. Rat retinal pigment epithelial cell line retinal pigment epithelial
      (RPE)-J was used in this study. Apoptosis was evaluated by light and electron
      microscopies, DNA electrophoresis, and terminal deoxynucleotidyl transferase dUTP
      nick-end labeling assay. The apoptosis-related proteins were localized in the
      cells by immunofluorescent microscopy, and the changes of their protein contents
      and the enzyme activation were monitored by Western blot. Mitochondrial membrane
      potential was quantified by measuring J aggregate (5,5',6,6'-tetrachloro
      1,1',3,3'-tetraethylbenzimidazol carbocyanine iodide) fluorescence. To measure
      changes in intracellular pH, cells were loaded with 2',7'-bis(carboxyethyl)-5(6')
      carboxyfluorescein and assayed by flow cytometry. To elucidate the type of
      transport system involving intracellular pH regulation, several transporter
      inhibitors were used, and their effect on pH and membrane potential was assayed
      as described above. Lactacystin treatment significantly induced apoptosis in RPE
      J cells. During the RPE cell apoptosis, 1) cytochrome c and Smac/DIABLO were
      released into cytosol from mitochondria, 2) translocation of apoptosis-inducing
      factor to the nucleus was evident, 3) Bax protein seemed to translocate to
      mitochondria, 4) procaspase-3 and poly(ADP-ribose) polymerase were cleaved, and
      5) nuclear condensation and DNA fragmentation were clearly observed. Noticeably,
      a transient increase of mitochondrial membrane potential was coincidentally
      detected with the intracellular alkalinization after lactacystin administration.
      Furthermore, the lactacystin-induced early alkalinization was inhibited by 4
      acetamido-4'-isothiocyanostilbene-2,2'-disulfonate, an inhibitor of Cl(-)/HCO(3)(
      ) anion exchanger, which also prevented early mitochondrial hyperpolarization and
      apoptosis. Lactacystin-induced apoptosis in RPE-J cells is closely associated
      with an early mitochondrial hyperpolarization induced by intracellular
      alkalinization.

PMID- 12606643
TI  - Distinct effects of dinuclear ruthenium(III) complexes on cell proliferation and
      on cell cycle regulation in human and murine tumor cell lines.
AB  - We have examined the biological and antitumor activity of a series of dinuclear
      ruthenium complexes. The aim of this study was to compare the in vitro effects of
      these new compounds on cell proliferation, cell distribution among cell cycle
      phases, and the expression of some proteins involved in cell cycle regulation.
      Results obtained show a mild cytotoxic activity against human and murine cell
      lines, more evident after prolonged exposure of cell challenge. Two of the eight
      dinuclear complexes [namely, compounds D3 (Na(2)[(RuCl(4)(dmso-S))(2)(mu-bipy)])
      and D7 ([NH(4)][(RuCl(4)(dmso-S))(mu-pyz)(RuCl(3)(dmso-S)(dmso-O))]) modify cell
      cycle distribution similarly to imidazolium trans
      imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A), whereas the others have
      a low or negligible effect on this parameter. If we correlate the induction of
      cell cycle modifications with ruthenium uptake by tumor cells and with the
      modulation of proteins regulating cell cycle, we may stress that the induction of
      G(2)-M cell cycle arrest is related to the achievement of a threshold
      concentration of ruthenium inside the cells, which is dependent on the cell line
      being used, and that only cyclin B, among cell cycle regulating proteins examined
      by immunoblotting assays, appears to be significantly modified. This in vitro
      study shows that dinuclear ruthenium complexes may have a behavior similar to
      that of the monomer NAMI-A. These results encourage the future experimentation of
      their pharmacological properties in in vivo models.

PMID- 12606644
TI  - Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)
      tramadol in the rat: role of cytochrome P450 2D activity.
AB  - In this study the role of cytochrome P450 2D (CYP2D) in the
      pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been
      explored in rats. Male Wistar rats were infused with (+)-T in the absence of and
      during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining
      plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and
      measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was
      affected by Q pretreatment: early after the start of (+)-T infusion, levels of
      (+)-M1 were significantly lower (P < 0.05). However, at later times during Q
      infusion those levels increased continuously, exceeding the values found in
      animals that did not receive the inhibitor. These results suggest that CYP2D is
      involved in the formation and elimination of (+)-M1. In fact, results from
      another experiment where (+)-M1 was given in the presence and in absence of Q
      showed that (+)-M1 elimination clearance (CL(ME0)) was significantly lower (P <
      0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance
      (CL(M10)) and CL(ME0) were modeled by an inhibitory E(MAX) model, and the
      estimates (relative standard error) of the maximum degree of inhibition (E(MAX))
      and IC(50), plasma concentration of Q eliciting half of E(MAX) for CL(M10) and
      CL(ME0), were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively.
      The modeling of the time course of antinociception showed that the contribution
      of (+)-T was negligible and (+)-M1 was responsible for the observed effects,
      which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D
      activity is a major determinant of the antinociception elicited after (+)-T
      administration.

PMID- 12606646
TI  - Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of
      electrophysiological mechanisms.
AB  - (E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) is a
      novel Na(+)/K(+) pump inhibitor with positive inotropic effects. Compared with
      digoxin in various experimental models, PST2744 was consistently found to be less
      arrhythmogenic, thus resulting in a significantly higher therapeutic index. The
      present work compares the electrophysiological effects of PST2744 and digoxin in
      guinea pig ventricular myocytes, with the aim to identify a mechanism for their
      different toxicity. The work showed that 1) the action potential was transiently
      prolonged and then similarly shortened by both agents; 2) the ratio between
      Na(+)/K(+) pump inhibition and inotropy was somewhat larger for PST2744 than for
      digoxin; 3) both agents accelerated inactivation of high-threshold Ca(2+) current
      (I(CaL)), without affecting its peak amplitude; 4) the transient inward current
      (I(TI)) induced by a Ca(2+) transient in the presence of complete Na(+)/K(+) pump
      blockade was inhibited (-43%) by PST2744 but not by digoxin; 5) the conductance
      of Na(+)/Ca(2+) exchanger current (I(NaCa)), recorded under Na(+)/K(+) pump
      blockade, was only slightly inhibited by PST2744 (-14%) and unaffected by
      digoxin; and 6) both agents inhibited delayed rectifier current I(Ks) (<or=-21%);
      delayed rectifier current I(Kr) was inhibited by PST2744 only, but the effect was
      marginal (-6%). Thus, 1) the higher therapeutic index of PST2744 may be accounted
      for by inhibition of I(TI), a current directly involved in digitalis-induced
      arrhythmias. Indeed, the other differences observed concern quantitatively small
      effects; and 2) I(TI) suppression by PST2744 may be only partly accounted for by
      inhibition of the Na(+)/Ca(2+) exchanger.

PMID- 12606647
TI  - Acute mechanism of medium chain fatty acid-induced enhancement of airway
      epithelial permeability.
AB  - The localization of viral receptors to the basolateral surface of airway
      epithelia is an obstacle to the effectiveness of luminal viral-mediated gene
      transfer to the lung. The tight junction (TJ) serves as a rate-limiting barrier
      to the penetration of viral vectors. We have previously identified the sodium
      salt of the medium chain fatty acid (MCFA) capric acid (C10) as an agent that can
      enhance the ability of adenoviral vectors to transduce well differentiated (WD)
      primary human airway epithelial (HAE) cells. Previous studies have suggested that
      intracellular calcium (Ca(i)2+) levels may play a central role in the long-term
      C10-mediated increases in junctional permeability. In this study, we investigated
      the effects of C10 and lauric acid (C12) on Ca(i)2+ in WD primary HAE cells and
      determined whether these effects were necessary for the acute MCFA-induced
      reduction in transepithelial resistance (R(T)) and increased permeability. In
      addition, we characterized the effects of C10 and C12 on components localized to
      the TJ, including ZO-1, junctional adhesion molecule (JAM), and the claudin
      family of transmembrane proteins. In addition to rapidly decreasing R(T), C10 and
      C12 increased cellular and paracellular permeability. C10 induced a rapid,
      sustained increase in Ca(i)2+. However, buffering Ca(i)2+ did not block the
      effects of C10 on R(T). Both C10 and C12 caused reorganization of claudins-1, -4,
      JAM, and beta-catenin, but not ZO-1. These data suggest that C10 and C12 exert
      their acute effects on airway TJs via a Ca(2+)-independent mechanism of action
      and may alter junctional permeability via direct effects on the claudin family of
      TJ proteins.

PMID- 12606648
TI  - alpha 2-Adrenoceptors potentiate angiotensin II- and vasopressin-induced renal
      vasoconstriction in spontaneously hypertensive rats.
AB  - Hypertension in spontaneously hypertensive rats (SHRs) is due in part to enhanced
      effects of vasoactive peptides on the renal vasculature. We hypothesize that the
      G(i) signal transduction pathway enhances renovascular responses to vasoactive
      peptides in SHRs more so than in normotensive Wistar-Kyoto (WKY) rats. To test
      this hypothesis, we examined in isolated perfused kidneys from SHRs and WKY rats
      the renovascular responses (assessed as changes in renal perfusion pressure in mm
      Hg) to angiotensin II (10 nM) and vasopressin (3 nM) in the presence and absence
      of UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; an
      agonist that selectively activates the G(i) pathway by stimulating alpha(2)
      adrenoceptors]. In SHR, but not WKY, kidneys, UK-14,304 (10 nM) enhanced (P <
      0.05) renovascular responses to angiotensin II (control WKY, 43 +/- 6; UK-14,304
      treated WKY, 52 +/- 19; control SHR, 66 +/- 17; UK-14,304-treated SHR, 125 +/-
      16) and vasopressin (control WKY, 42 +/- 17; UK-14,304-treated WKY, 36 +/- 11;
      control SHR, 16 +/- 8; UK-14,304-treated SHR, 83 +/- 17). Pretreatment of SHRs
      with pertussis toxin (30 microg/kg, intravenously, 3-4 days before study) to
      inactivate G(i) blocked the effects of UK-14,304. Western blot analysis of
      receptor expression in whole kidney and preglomerular microvessels revealed
      similar levels of expression of AT(1), V(1a), and alpha(2A) receptors in SHRs
      compared with WKY rats. We conclude that activation of alpha(2)-adrenoceptors
      selectively enhances renovascular responses to angiotensin II and vasopressin in
      SHRs via an enhanced cross talk between the G(i) signal transduction pathway and
      signal transduction pathways activated by angiotensin II and vasopressin.

PMID- 12606650
TI  - Block of Na+,K+-ATPase and induction of hybrid death by 4-aminopyridine in
      cultured cortical neurons.
AB  - K(+) channel blockers such as 4-aminopyridine (4-AP) can be toxic to neurons; the
      cellular mechanism underlying the toxicity, however, is obscure. In cultured
      mouse cortical neurons, we tested the hypothesis that the toxic effect of 4-AP
      might result from inhibiting the Na(+),K(+)-ATPase (Na(+),K(+)-pump) and
      thereafter induction of a hybrid death of concomitant apoptosis and necrosis. The
      Na(+),K(+)-pump activity, monitored as whole-cell membrane currents, was markedly
      blocked by 4-AP in concentration- and voltage-dependent manners in low millimolar
      ranges. At similar concentrations, 4-AP induced a neuronal death sensitive to
      attenuation by the caspase inhibitor Z-VAD-FMK (Z-Val-Ala-Asp(OMe)-fluoromethyl
      ketone) or Ca(2+) chelator BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'
      tetraacetic acid-acetoxymethyl ester). Electron microscopy confirmed hybrid
      ultrastructural features of coexisting apoptotic and necrotic components in same
      cells. We suggest that 4-AP is a potent antagonist of the Na(+),K(+)-ATPase and
      an inducer of the hybrid death of central neurons.

PMID- 12606657
TI  - The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol.
AB  - It has been suggested that the cannabinoid receptor type 1 (CB1), a G protein
      coupled receptor, is internalized after agonist binding and activation of the
      second messenger pathways. It is proposed that phosphorylation enhances the down
      regulation of the CB1 receptor, thus contributing to tolerance. Alterations in
      phosphorylation of proteins in the signal transduction cascade after CB1receptor
      activation could also alter tolerance to cannabinoids. We addressed our
      hypothesis by evaluating the role of several kinases in antinociceptive tolerance
      to Delta(9)-tetrahydrocannabinol (THC). We evaluated cAMP-dependent protein
      kinase (PKA) using KT5720, a PKA inhibitor; protein kinase C (PKC) using
      bisindolylmaleimide I, HCl (bis), a PKC inhibitor; cGMP-dependent protein kinase
      (PKG) using KT5823, a PKG inhibitor; beta-adrenergic receptor kinase (beta-ARK)
      using low molecular weight heparin (LMWH), a beta-ARK inhibitor; and
      phosphatidylinositol-3 kinase (PI3-K) using 2-(4-morpholinyl)-8-phenyl-4H-1
      benzopyran-4-one (LY294002), a PI3-K inhibitor and PP1, a Src family tyrosine
      kinase inhibitor. The cAMP analog used was dibutyryl-cAMP and the cGMP analog
      used was dibutyryl-cGMP. Our data indicate that selective kinases may be involved
      in cannabinoid tolerance. Mice and rats were rendered tolerant to Delta(9)-THC.
      The PKG inhibitor KT5823, the beta-ARK inhibitor LMWH, the PI3-K inhibitor
      LY294002, and inhibition of PKC by bis had no effect on tolerance. At a higher
      dose, bis attenuated the antinociceptive effect of delta(9)-THC in nontolerant
      mice. PP1, the Src family tyrosine kinase inhibitor, and KT5720, the PKA
      inhibitor, reversed THC-induced tolerance. In addition, inhibition of PKA
      reversed a decrease in dynorphin release shown to accompany THC tolerance in
      rats. These data support a role for PKA and Src tyrosine kinase in
      phosphorylation events in delta(9)-THC-tolerant mice.

PMID- 12606659
TI  - Biochemical and pharmacological characterization of 2-(9-(2-piperidinoethoxy)-4
      oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2
      benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a novel, orally active elastase
      inhibitor.
AB  - Human leukocyte elastase (HLE) is a proteinase capable of degrading a variety of
      proteins. Under normal circumstances, the proteolytic activity of HLE is
      effectively controlled by its natural inhibitors. However, an imbalance between
      elastase and its endogenous inhibitors may result in several pathophysiological
      states such as chronic obstructive pulmonary disease, asthma, emphysema, cystic
      fibrosis, and chronic inflammatory diseases. It is anticipated that an orally
      active HLE inhibitor could be useful for the treatment of these diseases. 2-(9-(2
      Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1
      methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071) is a
      potent inhibitor of HLE, with the inhibition constant (K(i)) and the constant for
      inactivation process (k(on)) being 0.0168 +/- 0.0014 nM and 0.183 +/- 0.013
      10(6)/mol sr, respectively. The dissociation rate constant, k(off), was 3.11 +
      0.37 10(-6)/s. SSR69071 displays a higher affinity for human elastase than for
      rat (K(i) = 3 nM), mouse (K(i) = 1.8 nM), and rabbit (K(i) = 58 nM) elastases.
      Bronchoalveolar lavage fluid from mice orally treated with SSR69071 inhibits HLE
      (ex vivo), and in this model, SSR69071 has a dose-dependent efficacy with an
      ED(50) = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung
      hemorrhage induced by HLE (ED(50) = 2.8 mg/kg p.o.) in mice. Furthermore,
      SSR69071 prevents carrageenan- (ED(30) = 2.2 mg/kg) and HLE-induced (ED(30) = 2.7
      mg/kg) paw edema in rats after p.o. administration. In conclusion, SSR69071 is a
      selective, orally active, and potent inhibitor of HLE with good penetration in
      respiratory tissues.

PMID- 12606661
TI  - The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation:
      implications for TRH-based therapeutics.
AB  - The functions of thyrotropin-releasing hormone (TRH) in the central nervous
      system (CNS) can be conceptualized as performed by four anatomically distinct
      components that together comprise a general TRH homeostatic system. These
      components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the
      brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the
      chronobiological system. We propose that the main neurobiological function of TRH
      is to promote homeostasis, accomplished through neuronal mechanisms resident in
      these four integrated systems. This hypothesis offers a unifying basis for
      understanding the myriad actions of TRH and TRH-related drugs already
      demonstrated in animals and humans. It is consistent with the traditional role of
      TRH as a regulator of metabolic homeostasis. An appreciation of the global
      function of TRH to modulate and normalize CNS activity, along with an
      appreciation of the inherent limitations of TRH itself as a therapeutic agent,
      leads to rational expectations of therapeutic benefit from metabolically stable
      TRH-mimetic drugs in a remarkably broad spectrum of clinical situations, both as
      monotherapy and as an adjunct to other therapeutic agents. The actions of TRH are
      numerous and varied. This has been viewed in the past as a conceptual and
      practical impediment to the development of TRH analogs. Herein, we alternatively
      propose that these manifold actions should be considered as a rational and
      positive impetus to the development of TRH-based drugs with the potential for
      unique and widespread applicability in human illness.

PMID- 12606672
TI  - Genetics and susceptibility to toxic chemicals: do you (or should you) know your
      genetic profile?
AB  - This review is based on a symposium/roundtable session, sponsored by the Division
      of Toxicology of the American Society for Pharmacology and Experimental
      Therapeutics, that was held at the 2002 Experimental Biology meeting in New
      Orleans, LA. The focus is on the role of pharmacogenomics in determining
      individual susceptibility to chemically induced toxicity. An individual's risk of
      disease from exposure to toxic chemicals is determined by a complex interplay
      between genetics, physiology, and concurrent or prior exposures to drugs and
      other chemicals. The first section of the review defines the basics of
      pharmacogenetics and pharmacogenomics and assesses the current state of the
      science. Selected applications to specific enzyme systems are summarized by way
      of example. New, state-of-the-art approaches to studying genetic determinants of
      susceptibility, including analytical methods and transgenic technology, are then
      discussed. Finally, ethical and legal concerns with the application of this
      knowledge and methodology to human health will be discussed.

PMID- 12606674
TI  - The specific type-4 phosphodiesterase inhibitor mesopram alleviates experimental
      colitis in mice.
AB  - Mesopram, a specific inhibitor of type-4 phosphodiesterase, decreases the
      synthesis of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN
      gamma). In the present study, we investigated the effect of mesopram in dextran
      sulfate sodium (DSS)-induced murine colitis. In the preventive model, colitis was
      induced by DSS simultaneously with the application of mesopram in BALB/c mice. In
      the therapeutic model, colitis was induced in BALB/c mice by DSS over 7 days. At
      day 8, DSS was discontinued, and treatment was started. Mesopram was applied
      intraperitoneally or orally. The clinical score was calculated daily during the
      course of each study. Post mortem, colon length, histologic score, and expression
      of TNF-alpha and IFN-gamma in colons were determined. In the preventive model,
      mesopram significantly reduced the maximal clinical score, decreased colon
      shortening, and the histologic score. A dose finding study, using the preventive
      model, showed that most clinical and post mortem benefit was achieved with 50
      mg/kg mesopram compared with 2 and 10 mg/kg. In the therapeutic model, i.p.
      mesopram treatment led to a significant reduction of clinical score. Both, i.p.
      and p.o. mesopram significantly reversed DSS-induced colon shortening and reduced
      the ex vivo colonic production of IFN-gamma. We conclude that the specific type-4
      phosphodiesterase inhibitor mesopram ameliorates murine colitis both in a
      preventive and a therapeutic setting.

PMID- 12606673
TI  - Norepinephrine evoked by potassium depolarization increases interstitial
      adenosine concentration via activation of ecto-5'-nucleotidase in rat hearts.
AB  - We examined whether the increase of the extracellular potassium ion
      concentration, [K(+)](o), can increase the production of interstitial adenosine
      in the ventricular myocardium, with the use of microdialysis techniques in in
      situ rat hearts. A microdialysis probe was implanted in the left ventricular
      myocardium of anesthetized rat hearts, and the tissue in the vicinity of the
      dialysis was perfused with Tyrode's solution containing AMP through the dialysis
      probe at a rate of 1.0 microl/min to assess the activity of ecto-5'-nucleotidase.
      When the K(+) concentration of the perfusate ([K(+)](o)) was increased stepwise
      from 5.4 mM (control) to up to 140.4 mM, the level of dialysate adenosine
      significantly increased, in a [K(+)](o)-dependent manner. The presence of CsCl or
      BaCl(2) (20 mM), which markedly depolarized the resting potential, significantly
      increased the level of adenosine in the dialysate. Equivalent increases in the
      osmotic concentration of the perfusate, made by adding sucrose (270 mM), did not
      change the dialysate adenosine concentration. Introduction of high [K(+)](o)
      (140.4 mM) significantly increased the level of norepinephrine (NE) in the
      dialysate, and this increase was abolished in the reserpinized rats hearts. In
      the presence of an antagonist of alpha(1)-adrenoceptor (prazosin, 50 microM) or
      protein kinase C (PKC) (chelerythrine, 10 microM) and in reserpinized rats, an
      introduction of high [K(+)](o) failed to increase the AMP-primed dialysate
      adenosine concentration. We conclude that high [K(+)](o)-induced NE release from
      sympathetic nerve terminals increases adenosine by stimulating the PKC-ecto-5'
      nucleotidase cascade through alpha(1)-adrenoceptors.

PMID- 12606677
TI  - Dendritic glutamate-induced bursting in the prefrontal cortex: further
      characterization and effects of phencyclidine.
AB  - To understand the role of N-methyl-d-aspartate (NMDA) receptors in the prefrontal
      cortex (PFC) and to investigate how the psychotomimetic drug phencyclidine (PCP)
      may alter PFC function, we made whole-cell recordings from PFC neurons in rat
      brain slices. Our result showed that most deep layer pyramidal neurons in the PFC
      were regular spiking cells. They could fire repetitive bursts, however, when
      activated by glutamate focally applied to the apical dendrite. Application of
      NMDA to the same dendritic spot also induced bursting, whereas application of
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) evoked single
      spikes only. Coapplication of AMPA with NMDA evoked more single spikes and
      decreased NMDA-induced bursting. Experiments with NMDA and AMPA antagonists
      further showed that dendritic glutamate (dGlu)-induced bursting required NMDA
      receptor activation and was enhanced when AMPA receptors were blocked. At
      subanesthetic concentrations, PCP decreased dGlu-induced bursting and altered the
      temporal characteristics of the bursts by decreasing spikes per burst and
      increasing interspike intervals within bursts. The latter two changes were not
      observed when AMPA receptors were blocked, suggesting that they are secondary to
      the increased AMPA receptor contribution to glutamate responses evoked in the
      presence of PCP. These results suggest that NMDA receptors are essential for PFC
      pyramidal cells to fire in bursts in response to dGlu input and that PCP
      suppresses dGlu-induced bursting. Since bursting is necessary for pyramidal cells
      to activate GABA interneurons, the suppression effect of PCP may further lead to
      a weakening of the connections from pyramidal cells and GABA interneurons,
      thereby contributing to PCP's psychotomimetic effects.

PMID- 12606680
TI  - In vivo pain-inhibitory role of nociceptin/orphanin FQ in spinal cord.
AB  - Because nociceptin/orphanin FQ (N/OFQ) has both pronociceptive (hyperalgesia) and
      antinociceptive actions in pharmacological experiments, and there is no
      significant difference in the nociceptive responses between NOP(-/-) mice and
      their wild-type (NOP(+/+)) littermates, the physiological role of N/OFQ in pain
      regulation remains to be determined. Under the hypothesis that the use of
      molecularly distinct nociception test may reveal the pain modality-specific role
      of N/OFQ, we attempted to examine the physiological role of N/OFQ in pain
      transmission by using newly developed algogenic-induced nociceptive flexion test
      in NOP(-/-) and NOP(+/+) mice or NOP antagonist-treated mice. The nociceptive
      flexor responses upon intraplantar injection of bradykinin or substance P, which
      stimulates polymodal substance P-ergic fibers, were markedly potentiated in NOP(
      /-) mice, compared with those in its NOP(+/+) mice. However, there were no
      significant changes in NOP(-/-) mice with adenosine triphosphate or prostaglandin
      I(2) agonist, which stimulates glutamatergic but not substance P-ergic fibers.
      The nocifensive responses induced by substance P (i.t.) were also potentiated in
      NOP(-/-) mice. On the other hand, there were no significant differences in NK1
      like immunoreactivity, [(3)H]substance P binding, or NK1 gene expression in the
      dorsal horn of the spinal cord between NOP(-/-) and NOP(+/+) mice. In addition,
      NOP antagonists decreased the threshold in nociception tests driving spinal
      substance P neurotransmission. All these findings suggest that the N/OFQ-ergic
      neuron may play an in vivo inhibitory role on the second-order neurons for
      primary polymodal substance P-ergic fibers in the spinal cord.

PMID- 12606683
TI  - Streptozotocin-induced diabetes increases disulfide bond formation on cardiac
      ryanodine receptor (RyR2).
AB  - In a previous study, we showed that after 6 weeks of streptozotocin-induced
      diabetes (6D), expression of type 2 ryanodine receptor calcium-release channels
      (RyR2) did not change significantly in rat hearts. However, the ability of this
      protein to bind [3H]ryanodine was compromised. Loss in activity therefore
      resulted from diabetes-induced increases in post-translational modifications on
      RyR2. In the present study, the effects of diabetes on one type of modification,
      namely, changes in oxidative state of reactive sulfhydryls was investigated. RyR2
      protein from 6D bound 42.3 +/- 7.6 less [3H]ryanodine than RyR2 from controls
      (6C). The loss in binding was minimized with 2 weeks of insulin treatment
      initiated after 4 weeks of diabetes (77.8 +/- 5.5% of 6C). Pretreating RyR2 from
      6D with 2 mM dithiothreitol in vitro increases [3H]ryanodine binding by 60.8 +/-
      5.3%. Dithiothreitol pretreatment of RyR2 from 6C increased [3H]ryanodine binding
      by 16.8 +/- 4.3%. The reagent pyrocoll interacts with distinct classes of free
      sulfhydryl groups on 6C RyR2 to induce two major effects. At concentrations < or
      = 10 microM, it deactivates RyR2 (decreases [3H]ryanodine binding), whereas at
      higher concentrations it activates them (increases [3H]ryanodine binding). This
      reagent was unable to activate RyR2 from 6D. Although RyR2 from insulin-treated
      animals was deactivated by low concentrations of pyrocoll, it was only partially
      activated at higher concentrations. These data suggest that the dysfunction of
      RyR2 induced by diabetes may be due in part to formation of disulfide bonds
      between adjacent sulfhydryl groups and that these changes were attenuated with
      insulin treatment.

PMID- 12606686
TI  - Iberiotoxin-induced block of Ca2+-activated K+ channels induces dihydropyridine
      sensitivity of ACh release from mammalian motor nerve terminals.
AB  - The role which Ca(2+)-activated K(+) (K(Ca)) channels play in regulating
      acetylcholine (ACh) release was examined at mouse motor nerve terminals. In
      particular, the ability of the antagonist iberiotoxin to recruit normally silent
      L-type Ca(2+) channels to participate in nerve-evoked release was examined using
      conventional intracellular electrophysiological techniques. Incubation of cut
      hemidiaphragm preparations with 10 microM nimodipine, a dihydropyridine L-type
      Ca(2+) channel antagonist, had no significant effect on quantal content of end
      plate potentials. Nevertheless, 1 microM S-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4
      (2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester (Bay K 8644)
      enhanced quantal content to 134.7 +/- 3.5% of control. Iberiotoxin (150 nM)
      increased quantal content to 177.5 +/- 9.9% of control, whereas iberiotoxin plus
      nimodipine increased quantal content to only 145.7 +/- 10.4% of control.
      Coapplication of 1 microM Bay K 8644 with iberiotoxin did not significantly
      increase quantal content further than did treatment with iberiotoxin alone. The
      effects of iberiotoxin and nimodipine alone or in combination on the miniature
      end-plate potential (MEPP) frequency following KCl-induced depolarization were
      examined using uncut hemidiaphragm preparations. Nimodipine alone had no effect
      on MEPP frequency from preparations incubated in physiological saline containing
      5 to 20 mM KCl. Moreover, iberiotoxin alone or combined with nimodipine also had
      no effect on MEPP frequency in physiological salines containing 5 to 15 mM KCl.
      At 20 mM KCl, however, iberiotoxin significantly increased MEPP frequency to
      125.6% of iberiotoxin-free values; combined treatment with nimodipine and
      iberiotoxin prevented this increase in MEPP frequency. Thus, loss of functional
      K(Ca) channels unmasks normally silent L-type Ca(2+) channels to participate in
      ACh release from motor nerve terminals, particularly under conditions of intense
      nerve terminal depolarization.

PMID- 12606689
TI  - Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons.
AB  - The properties of delta2 receptors, which have homology to glutamate receptors
      but are not gated by glutamate, were studied using the constitutively active
      Lurcher mutant delta2(A654T) expressed in Xenopus oocytes. The macroscopic
      current through delta2(A654T) channels in voltage-clamped oocytes was defined as
      the difference between the holding current measured in the presence of
      extracellular Na(+) and that in the presence of the large impermeant cation N
      methyl-d-glucamine. A-to-T mutations in the delta1 subunit and in NMDA (N-methyl
      d-aspartate) receptor subunits, at positions equivalent to delta2(A654T), did not
      produce constitutively active channels. The current through delta2(A654T)
      channels was reduced by pentamidine and 9-tetrahydroaminoacridine, antagonists
      that also inhibit NR1/NR2B NMDA receptors but not AMPA (alpha-amino-3-hydroxy-5
      methyl-4-isoxazolepropionic acid) receptors. Block of delta2(A654T) currents by
      these two antagonists was incomplete and weakly voltage-dependent, in contrast to
      the block of NR1/NR2B receptors, which was complete and strongly voltage
      dependent. Pentamidine inhibited a constitutively active NR1(T648A)/NR2B NMDA
      receptor in a manner similar to its inhibition of a glutamate-gated wild-type
      NMDA receptor, but different from its inhibition of constitutively active
      delta2(A654T) receptors. Currents gated by delta2(A654T) were sensitive to the
      extracellular pH, being smaller at acidic than at alkaline pH, with a pH IC(50)
      value of 7.47 and a maximum inhibition of 70%. It is concluded that delta2(A654T)
      channels have some properties in common with NMDA channels but also have
      characteristics that are different from these receptors. Compounds such as
      pentamidine may be useful for studies of native delta2 receptors.

PMID- 12606693
TI  - Melatonin nocturnal surge modulates nicotinic receptors and nicotine-induced
      [3H]glutamate release in rat cerebellum slices.
AB  - In mammals, the most important synchronizer for endogenous rhythms is the
      environmental light/dark cycle. In this report we have explored the ability of
      light/dark cycle and melatonin, the pineal hormone released during the night, to
      modulate cerebellar cholinergic input by interfering with the nicotinic
      acetylcholine receptors' (nAChRs) availability. Through the analysis of the
      response to selective cholinergic agonists and antagonists, we observed that
      nAChRs containing the alpha7 gene product mediate the release of [(3)H]glutamate
      from rat cerebellum slices. The [(3)H]glutamate overflow induced by alpha7 nAChR
      activation was higher during the dark phase, although the number of alpha
      [(125)I]bungarotoxin binding sites, but not the [(3)H]nicotine binding sites
      (B(max)), was reduced. On the other hand, glutamate-evoked [(3)H]glutamate
      release was not modified by the hour of the day. Finally, we show that the
      nocturnal increase in nicotine-evoked [(3)H]glutamate release is imposed by a
      nocturnal surge of melatonin, as it is abolished when pineal melatonin production
      is inhibited by either maintaining the animals in constant light for 48 h or by
      injecting propranolol just before lights off for 2 days. The difference between
      light and dark [(3)H]glutamate-evoked release is restored in propranolol-treated
      animals that received melatonin during the dark period. In conclusion, we show
      that nicotine-evoked [(3)H]glutamate release in rat cerebellum presents a diurnal
      variation, driven by nocturnal pineal melatonin surge.

PMID- 12606694
TI  - Differential regulation of the human kappa opioid receptor by agonists: etorphine
      and levorphanol reduced dynorphin A- and U50,488H-induced internalization and
      phosphorylation.
AB  - We previously observed that (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)
      cyclohexyl]benzeneacetamide (U50,488H) promoted internalization and
      phosphorylation of the FLAG-tagged human kappa opioid receptor (FLAG-hkor) stably
      expressed in Chinese hamster ovary (CHO) cells. In this study, we compared
      regulation of the FLAG-hkor expressed in CHO cells by U50,488H, dynorphin A,
      etorphine, and levorphanol, which were potent full agonists as determined by
      stimulation of guanosine 5'-O-(3-[(35)S]thio)triphosphate binding. Using
      fluorescence flow cytometry, we found that dynorphin A(1-17), like U50,488H,
      promoted internalization of the FLAG-hkor in a time- and dose-dependent manner.
      The antagonists naloxone and norbinaltorphimine, having no effect on FLAG-hkor
      internalization, effectively blocked dynorphin A(1-17)- and U50,488H-induced
      internalization. Interestingly, the full agonists etorphine and levorphanol did
      not cause internalization of the FLAG-hkor but significantly reduced dynorphin
      A(1-17)- and U50,488H-induced internalization in a dose-dependent manner.
      Immunofluorescence staining of FLAG-hkor yielded similar results. Dynorphin A(1
      17) and U50,488H enhanced phosphorylation of FLAG-hkor to a greater extent than
      etorphine, but levorphanol did not increase FLAG-hkor phosphorylation. Etorphine
      or levorphanol decreased dynorphin- or U50,488H-induced phosphorylation. It is
      likely that conformations of the hkor required for phosphorylation and initiation
      of internalization are different from those for activation of G proteins. We also
      examined whether the four agonists had differential effects on superactivation of
      adenylate cyclase. Pretreatment with U50,488H, dynorphin A(1-17), or etorphine
      enhanced forskolin-stimulated adenylate cyclase activity to approximately 200 to
      250% of the control, whereas levorphanol pretreatment did not result in
      significant adenylate cyclase superactivation. Thus, the degree of
      superactivation caused by an agonist is unrelated to its ability to promote
      internalization of the hkor.

PMID- 12606697
TI  - The effects of chronic treatment with the mood stabilizers valproic acid and
      lithium on corticotropin-releasing factor neuronal systems.
AB  - Corticotropin-releasing factor (CRF) plays a preeminent role in coordinating the
      endocrine, autonomic, and behavioral responses to stress. Dysregulation of both
      hypothalamic and extrahypothalamic CRF systems have been reported in patients
      with major depression and post-traumatic stress disorder. Moreover, effective
      treatment of these conditions leads to normalization of these CRF systems.
      Although there is virtually no data concerning alterations of CRF systems in
      bipolar disorder (manic depressive illness), previous work indicates that
      valproic acid, an anticonvulsant also effective in the treatment of acute mania,
      alters central CRF neuronal systems. In the current studies, we chronically
      administered valproic acid and lithium, two clinically effective mood
      stabilizers, in nonstressed rats to extend our previous findings. Chronic
      valproic acid administration decreased CRF mRNA expression in the paraventricular
      nucleus of the hypothalamus; lithium administration increased CRF mRNA expression
      in the central nucleus of the amygdala. Although valproic acid increased CRF(1)
      receptor mRNA expression in the cortex, CRF(1) receptor binding was decreased in
      both the basolateral amygdala and cortex, suggesting that chronic valproate
      treatment may in fact dampen the overall tone in this central stress pathway.
      Valproate treatment decreased CRF(2A) mRNA expression in both the lateral septum
      and hypothalamus, although CRF(2A) receptor binding was unchanged. Lithium
      administration decreased CRF(1) mRNA expression in both the amygdala and frontal
      cortex, but CRF(1) receptor binding also remained unchanged. These results
      suggest that the therapeutic actions of these mood stabilizers may, in part,
      result from their actions on central CRF neuronal systems. The distinct actions
      of each drug on CRF systems may underlie their synergistic clinical effects.

PMID- 12606698
TI  - An unusual form of the association binding kinetics of N-[3H]methylscopolamine to
      the split muscarinic M2trunk/M2tail receptor.
AB  - The muscarinic M(2) receptor was split at the third cytoplasmic loop into two
      fragments: the one containing the first five transmembrane regions and the N
      terminal part of the third cytoplasmic loop was named M(2trunk), while the other,
      which contained the last two transmembrane regions and the C-terminal part of the
      third cytoplasmic loop, was named M(2tail). As seen in many other G protein
      coupled receptors, when these two fragments were transfected together in COS-7
      cells they rescued the pharmacological profile and the functional activity of the
      wild-type M(2) receptor. Conversely, N-[(3)H]methylscopolamine ([(3)H]NMS)
      association binding experiments showed a substantial difference between the wild
      type M(2) and the split M(2trunk)/M(2tail) receptors. The progression of the
      association binding kinetic of the M(2trunk)/M(2tail) receptor was strictly
      dependent upon the amount of the fragment DNA transfected. When the amount of
      transfected DNA was 4 microg/plate and the B(max) of [(3)H]NMS at equilibrium was
      around 200 fmol/mg protein the form of the association was that of classical
      saturation, but when the amount of transfected DNA was lower the [(3)H]NMS
      association reached a maximum binding point and then declined to a lower
      equilibrium binding level. The form of the association was temperature-dependent:
      as the temperature was lowered, the maximum binding point tended to be higher. We
      suggest that this peculiar form of the [(3)H]NMS association binding to the
      muscarinic M(2trunk)/M(2tail) receptor is attributable to a less stable
      interaction between the trunk and the tail fragments of the split receptor.

PMID- 12606703
TI  - Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA
      receptor pharmacology in adult rats.
AB  - Acute exposure to progesterone or its neurosteroid derivative allopregnanolone
      (3alpha,5alpha-THP) is anxiolytic, consistent with the GABA modulatory effects of
      3alpha,5alpha-THP at the GABA(A) receptor. However, continuous exposure to
      progesterone increases anxiety in association with increased expression of the
      benzodiazepine-insensitive GABA(A) receptor alpha4 subunit. Furthermore, negative
      mood symptoms and altered GABA(A) receptor pharmacology in patients with
      premenstrual dysphoric disorder occur in the early luteal phase in association
      with peak circulating levels of progesterone and 3alpha,5alpha-THP. Because sex
      differences have been reported in steroid-regulated anxiety responses, the
      present study investigated the role of sex and development in the regulation of
      anxiety after short-term exposure to 3alpha,5alpha-THP. To this end, we compared
      the effects of hormone administration in adult male, adult female, and juvenile
      female rats. Increased anxiety in the elevated plus maze was evident in all
      groups after 48-h exposure to either 3alpha,5alpha-THP or progesterone. At this
      time point, alterations in the anxiolytic profile of benzodiazepine agonists and
      antagonists were also observed in both adult males and females in the elevated
      plus maze. However, sex differences in the acoustic startle response were
      observed after short-term hormone treatment such that only female rats displayed
      an increased response indicative of higher anxiety levels. These results suggest
      that although neurosteroid exposure may influence both the pharmacological
      properties of the GABA(A) receptor and the manifestation of anxiety in both
      sexes, the effects of neurosteroids may be modulated in a sex- and task-specific
      manner.

PMID- 12606705
TI  - The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction
      during inflammation and host defense.
AB  - The signal transduction pathways activated by the proinflammatory cytokine
      interleukin-1 (IL-1) have been the focus of much attention because of the
      important role that IL-1 plays in inflammatory diseases. A number of proteins
      have been described that participate in the post-receptor activation of the
      transcription factor nuclear factor kappaB (NF-kappaB), and stress-activated
      protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also
      emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding
      receptor superfamily. These related receptors all have sequence similarity in
      their cytosolic regions. The family includes the Drosophila melanogaster protein
      Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to
      TLR-10, which bind to microbial products, activating host defense responses.
      Because of the similarity of IL-1RI to Toll, the conserved sequence in the
      cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR)
      domain. The same proteins activated during signaling by IL-1RI also participate
      in signaling by other receptors with TIR domains. The receptor superfamily is
      evolutionarily conserved; members also occur in plants and insects, where they
      also function in host defense. The signaling proteins that are activated are also
      conserved across species. Differences are, however, starting to emerge in
      signaling pathways activated by different receptors. This receptor superfamily,
      therefore, represents an ancient signaling system that is a critical determinant
      of the innate immune and inflammatory responses.

PMID- 12606706
TI  - Plasma fibronectin promotes thrombus growth and stability in injured arterioles.
AB  - Mice lacking both of the best-known platelet ligands, von Willebrand factor and
      fibrinogen, can still form occlusive thrombi in injured arterioles. The platelets
      of these animals accumulate excessive amounts of fibronectin (FN). These
      observations led us to examine the contribution of plasma FN (pFN) to thrombus
      formation. Inactivation of the FN gene in FN conditional knockout mice reduced
      pFN levels to <2% and platelet FN to approximately 20% of the levels in similarly
      treated control mice. The mice were then observed in a model of arterial injury
      to evaluate their capacity to form thrombi. The deficiency of pFN did not affect
      the initial platelet adhesion, but a delay of several minutes in thrombus
      formation was observed in the arterioles of pFN-deficient mice as compared with
      control mice. The thrombi that formed in the absence of pFN were stably anchored
      to the vessel wall but continuously shed platelets or small platelet clumps, thus
      slowing their growth significantly; the platelet/platelet cohesion was apparently
      diminished. Consequently the occlusion of pFN-deficient vessels was delayed, with
      the majority of vessels remaining patent at the end of the 40-min observation
      period. We conclude that, in addition to von Willebrand factor and fibrinogen, FN
      plays a significant role in thrombus initiation, growth, and stability at
      arterial shear rates and that deficiency in each of the three platelet ligands
      has its own specific impact on platelet plug formation.

PMID- 12606707
TI  - Interaction of FK506-binding protein 13 with brefeldin A-inhibited guanine
      nucleotide-exchange protein 1 (BIG1): effects of FK506.
AB  - BIG1 and BIG2 are brefeldin A-inhibited guanine nucleotide-exchange proteins that
      activate ADP-ribosylation factors (ARFs), critical components of vesicular
      trafficking pathways. These proteins can exist in macromolecular complexes and
      move between Golgi membranes and cytosol. In the BIG1 molecule, a centrally
      located Sec7 domain is responsible for ARF activation, but functions of other
      regions are largely unknown. Yeast two-hybrid screens of a human placenta cDNA
      library with BIG1 cDNA constructs revealed specific interaction of the N-terminal
      region (amino acids 1-331) with FK506-binding protein 13 (FKBP13). The
      association was confirmed by immunoprecipitation of both endogenous BIG1 and
      FKBP13 from Jurkat T cells with antibodies against either one. Binding of BIG1,
      BIG2, and ARF to cell membranes in vitro was increased by guanosine 5'-[gamma
      thio]triphosphate, and further increases were induced by FK506. Incubation of
      Jurkat T cells with FK506 increased binding of BIG1, BIG2, and ARF to Golgi and
      other membranes in a time- and concentration-dependent manner, without effects on
      clathrin or gamma-adaptin binding. Binding of BIG1, BIG2, and ARF to membranes
      was also increased by L-732,531, an agonist structurally related to FK506, but
      was not increased by a related antagonist, L-685,818, nor by cyclosporin A or
      rapamycin. These findings are consistent with a role for FKBP13 and FK506 in
      vesicular trafficking, influencing ARF activity through their guanine nucleotide
      exchange proteins.

PMID- 12606708
TI  - A global representation of the protein fold space.
AB  - One of the principal goals of the structural genomics initiative is to identify
      the total repertoire of protein folds and obtain a global view of the "protein
      structure universe." Here, we present a 3D map of the protein fold space in which
      structurally related folds are represented by spatially adjacent points. Such a
      representation reveals a high-level organization of the fold space that is
      intuitively interpretable. The shape of the fold space and the overall
      distribution of the folds are defined by three dominant trends: secondary
      structure class, chain topology, and protein domain size. Random coil-like
      structures of small proteins and peptides are mapped to a region where the three
      trends converge, offering an interesting perspective on both the demography of
      fold space and the evolution of protein structures.

PMID- 12606710
TI  - Stochastic gene expression as a many-body problem.
AB  - Gene expression has a stochastic component because of the single-molecule nature
      of the gene and the small number of copies of individual DNA-binding proteins in
      the cell. We show how the statistics of such systems can be mapped onto quantum
      many-body problems. The dynamics of a single gene switch resembles the spin-boson
      model of a two-site polaron or an electron transfer reaction. Networks of
      switches can be approximately described as quantum spin systems by using an
      appropriate variational principle. In this way, the concept of frustration for
      magnetic systems can be taken over into gene networks. The landscape of stable
      attractors depends on the degree and style of frustration, much as for neural
      networks. We show the number of attractors, which may represent cell types, is
      much smaller for appropriately designed weakly frustrated stochastic networks
      than for randomly connected networks.

PMID- 12606709
TI  - Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the
      AMPA receptor GluR2 subunit after forebrain ischemia.
AB  - Brief forebrain ischemia in rodents induces selective and delayed neuronal death,
      particularly of hippocampal CA1 pyramidal neurons. Neuronal death is preceded by
      down-regulation specific to CA1 of GluR2, the alpha-amino-3-hydroxy-5-methyl-4
      isoxazolepropionic acid (AMPA) receptor subunit that limits Ca(2+) influx. This
      alteration is hypothesized to cause neurodegeneration by permitting a lethal
      influx of Ca(2+) and/or Zn(2+) through newly formed GluR2-lacking AMPA receptors.
      Two days of mild hypothermia induced 1 h after ischemia potently and lastingly
      protects against ischemic injury. We examined molecular mechanisms underlying
      hypothermia-induced neuroprotection. We report that hypothermia rescues most
      hippocampal CA1 neurons from ischemia-induced cell death and attenuates ischemia
      induced down-regulation of mRNA encoding the AMPA receptor subunit GluR2.
      Ischemia induced a marked down-regulation of GluR2 mRNA and a small down
      regulation of GluR1 mRNA in CA1 at 2 days, as assessed by quantitative in situ
      hybridization. The ischemia-induced changes in gene expression were cell-specific
      in that GluR2 was not significantly altered in CA3 or dentate gyrus. After
      ischemia treated by hypothermia GluR2 mRNA expression was modestly reduced at 2
      days and exhibited complete recovery to control levels at 7 days. Hypothermia
      prevented ischemia induced changes in GluR1 mRNA expression. These findings
      suggest that intervention at the level of transcriptional regulation of the GluR2
      gene may be a mechanism by which prolonged postischemic cooling rescues CA1
      neurons otherwise "destined to die."

PMID- 12606711
TI  - Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding
      domains: a structural prototype for diversity in integrin signaling.
AB  - The cytoplasmic domains (tails) of heterodimeric integrin adhesion receptors
      mediate integrins' biological functions by binding to cytoplasmic proteins. Most
      integrin beta tails contain one or two NPXYF motifs that can form beta turns.
      These motifs are part of a canonical recognition sequence for phosphotyrosine
      binding (PTB) domains, protein modules that are present in a wide variety of
      signaling and cytoskeletal proteins. Indeed, talin and ICAP1-alpha bind to
      integrin beta tails by means of a PTB domain-NPXY ligand interaction. To assess
      the generality of this interaction we examined the binding of a series of
      recombinant PTB domains to a panel of short integrin beta tails. In addition to
      the known integrin-binding proteins, we found that Numb (a negative regulator of
      Notch signaling) and Dok-1 (a signaling adaptor involved in cell migration) and
      their isolated PTB domain bound to integrin tails. Furthermore, Dok-1 physically
      associated with integrin alpha IIb beta 3. Mutations of the integrin beta tails
      confirmed that these interactions are canonical PTB domain-ligand interactions.
      First, the interactions were blocked by mutation of an NPXY motif in the integrin
      tail. Second, integrin class-specific interactions were observed with the PTB
      domains of Dab, EPS8, and tensin. We used this specificity, and a molecular model
      of an integrin beta tail-PTB domain interaction to predict critical interacting
      residues. The importance of these residues was confirmed by generation of gain-
      and loss-of-function mutations in beta 7 and beta 3 tails. These data establish
      that short integrin beta tails interact with a large number of PTB domain
      containing proteins through a structurally conserved mechanism.

PMID- 12606713
TI  - Structural basis of two-stage voltage-dependent activation in K+ channels.
AB  - The structure of the voltage sensor and the detailed physical basis of voltage
      dependent activation in ion channels have not been determined. We now have
      identified conserved molecular rearrangements underlying two major voltage
      dependent conformational changes during activation of divergent K(+) channels,
      ether-a-go-go (eag) and Shaker. Two conserved arginines of the S4 voltage sensor
      move sequentially into an extracellular gating pocket, where they interact with
      an acidic residue in S2. In eag, these transitions are modulated by a divalent
      ion that binds in the gating pocket. Conservation of key molecular details in the
      activation mechanism confirms that voltage sensors in divergent K(+) channels
      share a common structure. Molecular modeling reveals that structural constraints
      derived from eag and Shaker specify the unique packing arrangement of
      transmembrane segments S2, S3, and S4 within the voltage sensor.

PMID- 12606712
TI  - Crystal structure of the receptor-binding domain of human B7-2: insights into
      organization and signaling.
AB  - B7-1 and B7-2 are homologous costimulatory ligands expressed on the surfaces of
      antigen-presenting cells. Their interactions with CD28/CTLA-4 receptors expressed
      on T cell surfaces are crucial for the proper regulation of T cell activity. B7-1
      and B7-2 display distinct roles in immune regulation, although they are usually
      considered to have redundant functions. Here, we report the crystal structure of
      the receptor-binding (Ig V-type) domain of human B7-2 at 2.7-A resolution.
      Structures of unliganded and liganded B7-1 and B7-2 suggest a physical-chemical
      basis for the observed functional similarities and differences between these two
      costimulatory ligands. Of particular note, whereas the majority of the residues
      mediating B7-1 dimerization are hydrophobic, the B7-2 dimer observed in the B7
      2/CTLA-4 complex displays a very hydrophilic dimer interface. These differences
      provide a mechanism for preventing the formation of B7-1/B7-2 heterodimers. The
      divergence at the putative dimer interface is also consistent with the lower
      tendency of B7-2 to dimerize, as shown by the monomeric state of unliganded B7-2
      both in solution and crystalline form, and may result in detailed differences in
      signaling mechanisms associated with B7-1 and B7-2.

PMID- 12606714
TI  - Control region mtDNA variants: longevity, climatic adaptation, and a forensic
      conundrum.

PMID- 12606715
TI  - The hemodynamic inverse problem: making inferences about neural activity from
      measured MRI signals.

PMID- 12606716
TI  - Clefts, grooves, and (small) pockets: the structure of the retinoblastoma tumor
      suppressor in complex with its cellular target E2F unveiled.

PMID- 12606717
TI  - Crystal structure of Mycobacterium tuberculosis SecA, a preprotein translocating
      ATPase.
AB  - In bacteria, the majority of exported proteins are translocated by the Sec
      system, which recognizes the signal sequence of a preprotein and uses ATP and the
      proton motive force to mediate protein translocation across the cytoplasmic
      membrane. SecA is an essential protein component of this system, containing the
      molecular motor that facilitates translocation. Here we report the three
      dimensional structure of the SecA protein of Mycobacterium tuberculosis. Each
      subunit of the homodimer contains a "motor" domain and a translocation domain.
      The structure predicts that SecA can interact with the SecYEG pore and function
      as a molecular ratchet that uses ATP hydrolysis for physical movement of the
      preprotein. Knowledge of this structure provides a framework for further
      elucidation of the translocation process.

PMID- 12606718
TI  - Lineage-restricted retention of a primitive immunoglobulin heavy chain isotype
      within the Dipnoi reveals an evolutionary paradox.
AB  - The lineage leading to lungfishes is one of the few major jawed vertebrate groups
      in which Ig heavy chain isotype structure has not been investigated at the
      genetic level. In this study, we have characterized three different Ig heavy
      chain isotypes of the African lungfish, Protopterus aethiopicus, including an IgM
      type heavy chain and short and long forms of non-IgM heavy chains. Northern blot
      analysis as well as patterns of V(H) utilization suggest that the IgM and non-IgM
      isotypes are likely encoded in separate loci. The two non-IgM isotypes identified
      in Protopterus share structural features with the short and long forms of
      IgX/W/NARC (referred to hereafter as IgW), which were previously considered to be
      restricted to the cartilaginous fish. It seems that the IgW isotype has a far
      broader phylogenetic distribution than considered originally and raises questions
      with regard to the origin and evolutionary divergence of IgM and IgW. Moreover,
      its absence in other gnathostome lineages implies paradoxically that the IgW-type
      genes were lost from teleost and tetrapod lineages.

PMID- 12606719
TI  - Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for
      an antiinflammatory role for lipoprotein lipase.
AB  - Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in
      the artery wall, triggering early inflammatory responses central to
      atherosclerosis like endothelial adhesion molecule expression. The endogenous
      mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase
      (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich
      lipoproteins and releasing fatty acids. We found that LPL treatment reversed
      tumor necrosis factor alpha and very low-density lipoprotein (VLDL)-stimulated
      endothelial vascular cell adhesion molecule 1 (VCAM1) induction and VCAM1
      promoter responses, thus recapitulating effects reported with synthetic
      peroxisome proliferator-activated receptor (PPAR) agonists. In fact, these LPL
      effects on VCAM1 were absent in endothelial cells isolated from PPAR alpha
      deficient mice. This finding suggests a novel antiinflammatory role for LPL.
      Further studies reveal specificity for PPAR activation through lipolysis in
      regards to lipoprotein substrate (VLDL >> LDL > HDL), PPAR isoform (PPAR alpha >>
      PPAR delta > PPAR gamma), and among fatty acid-releasing lipases. These PPAR
      responses required intact LPL catalytic activity. In vivo, transgenic mice
      overexpressing LPL had increased peroxisome proliferation, but not in the genetic
      absence of PPAR alpha. Although human plasma possesses minimal PPAR alpha
      activation despite containing abundant free fatty acids, marked PPAR alpha
      activation is seen with human plasma after LPL is added in vitro or systemically
      released in vivo. These data suggest a previously uncharacterized pathway in
      which the key lipolytic enzyme LPL can act on circulating lipoproteins to
      generate PPAR alpha ligands, providing a potentially important link between
      lipoprotein metabolism and distal PPAR alpha transcriptional effects.

PMID- 12606720
TI  - A human peripheral blood monocyte-derived subset acts as pluripotent stem cells.
AB  - We have identified, cultured, characterized, and propagated adult pluripotent
      stem cells (PSC) from a subset of human peripheral blood monocytes. These cells,
      which in appearance resemble fibroblasts, expand in the presence of macrophage
      colony-stimulating factor and display monocytic and hematopoietic stem cell
      markers including CD14, CD34, and CD45. We have induced these cells to
      differentiate into mature macrophages by lipopolysaccharide, T lymphocytes by IL
      2, epithelial cells by epidermal growth factor, endothelial cells by vascular
      endothelial cell growth factor, neuronal cells by nerve growth factor, and liver
      cells by hepatocyte growth factor. The pluripotent nature of individual PSC was
      further confirmed by a clonal analysis. The ability to store, expand, and
      differentiate these PSC from autologous peripheral blood should make them
      valuable candidates for transplantation therapy.

PMID- 12606721
TI  - Nuclear and cytosolic calcium are regulated independently.
AB  - Nuclear calcium (Ca(2+)) regulates a number of important cellular processes,
      including gene transcription, growth, and apoptosis. However, it is unclear
      whether Ca(2+) signaling is regulated differently in the nucleus and cytosol. To
      investigate this possibility, we examined subcellular mechanisms of Ca(2+)
      release in the HepG2 liver cell line. The type II isoform of the inositol 1,4,5
      trisphosphate (InsP(3)) receptor (InsP(3)R) was expressed to a similar extent in
      the endoplasmic reticulum and nucleus, whereas the type III InsP(3)R was
      concentrated in the endoplasmic reticulum, and the type I isoform was not
      expressed. Ca(2+) signals induced by low InsP(3) concentrations started earlier
      or were larger in the nucleus than in the cytosol, indicating higher sensitivity
      of nuclear Ca(2+) stores for InsP(3). Nuclear InsP(3)R channels were active at
      lower InsP(3) concentrations than InsP(3)R from cytosol. Enriched expression of
      type II InsP(3)R in the nucleus results in greater sensitivity of the nucleus to
      InsP(3), thus providing a mechanism for independent regulation of Ca(2+)
      dependent processes in this cellular compartment.

PMID- 12606723
TI  - Kiss-and-run, fuse-pinch-and-linger, fuse-and-collapse: the life and times of a
      neurosecretory granule.

PMID- 12606722
TI  - The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and
      interacts with Nix and the Myt1 kinase.
AB  - The p53 tumor suppressor protein plays a crucial role in tumorigenesis by
      controlling cell-cycle progression and apoptosis. We have previously described a
      transcript designated tumor suppressor activated pathway-6 (TSAP6) that is up
      regulated in the p53-inducible cell line, LTR6. Cloning of the murine and human
      full-length TSAP6 cDNA revealed that it encodes a 488-aa protein with five to six
      transmembrane domains. This gene is the murine and human homologue of the
      recently published rat pHyde. Antibodies raised against murine and human TSAP6
      recognize a 50- to 55-kDa band induced by p53. Analysis of the TSAP6 promoter
      identified a functional p53-responsive element. Functional studies demonstrated
      that TSAP6 antisense cDNA diminished levels of the 50- to 55-kDa protein and
      decreased significantly the levels of p53-induced apoptosis. Furthermore, TSAP6
      small interfering RNA inhibited apoptosis in TSAP6-overexpressing cells. Yeast
      two-hybrid analysis followed by GST/in vitro-transcribed/translated pull-down
      assays and in vivo coimmunoprecipitations revealed that TSAP6 associated with
      Nix, a proapoptotic Bcl-2-related protein and the Myt1 kinase, a negative
      regulator of the G(2)/M transition. Moreover, TSAP6 enhanced the susceptibility
      of cells to apoptosis and cooperated with Nix to exacerbate this effect. Cell
      cycle studies indicated that TSAP6 could augment Myt1 activity. Overall, these
      data suggest that TSAP6 may act downstream to p53 to interface apoptosis and cell
      cycle progression.

PMID- 12606725
TI  - Lake sediments record large-scale shifts in moisture regimes across the northern
      prairies of North America during the past two millennia.
AB  - Six high-resolution climatic reconstructions, based on diatom analyses from lake
      sediment cores from the northern prairies of North America, show that shifts in
      drought conditions on decadal through multicentennial scales have prevailed in
      this region for at least the last two millennia. The predominant broad-scale
      pattern seen at all sites is a major shift in moisture regimes from wet to dry,
      or vice versa (depending on location), that occurred after a period of relative
      stability. These large-scale shifts at the different sites exhibit spatial
      coherence at regional scales. The three Canadian sites record this abrupt shift
      between anno Domini 500 and 800, and subsequently conditions become increasingly
      variable. All three U.S. sites underwent a pronounced change, but the timing of
      this change is between anno Domini 1000 and 1300, thus later than in all of the
      Canadian sites. The mechanisms behind these patterns are poorly understood, but
      they are likely related to changes in the shape and location of the jet stream
      and associated storm tracks. If the patterns seen at these sites are
      representative of the region, this observed pattern can have huge implications
      for future water availability in this region.

PMID- 12606724
TI  - The further redefining of steroid-mediated signaling.

PMID- 12606727
TI  - Five components of the ethylene-response pathway identified in a screen for weak
      ethylene-insensitive mutants in Arabidopsis.
AB  - Five ethylene-insensitive loci (wei1-wei5) were identified by using a low-dose
      screen for "weak" ethylene-insensitive mutants. wei1, wei2, and wei3 seedlings
      showed hormone insensitivity only in roots, whereas wei4 and wei5 displayed
      insensitivity in both roots and hypocotyls. The genes corresponding to wei1,
      wei4, and wei5 were isolated using a positional cloning approach. The wei1 mutant
      harbored a recessive mutation in TIR1, which encodes a component of the SCF
      protein ubiquitin ligase involved in the auxin response. wei4, a dominant mutant,
      resulted from a mutation in the ethylene receptor ERS, whereas wei5, a
      semidominant mutant, was caused by a mutation in the EIN3-related transcription
      factor gene EIL1. The simultaneous loss of functional WEI5EIL1 and EIN3 nearly
      completely abolished the ethylene response in etiolated seedlings, and adult
      plants were highly susceptible to infection by the necrotrophic fungal pathogen
      Botrytis cinerea. Moreover, wei5eil1 ein3 double mutants were able to fully
      suppress constitutive signaling caused by ctr1, suggesting a synergistic
      interaction among these gene products. Unlike previously known root ethylene
      insensitive mutants, wei2 and wei3 were not affected in their response to auxin
      and showed a normal response to gravity. Genetic mapping studies indicate that
      wei2 and wei3 correspond to previously unidentified ethylene pathway genes that
      may control cell-elongation processes functioning at the intersection of the
      ethylene and auxin response pathways.

PMID- 12606726
TI  - Hypoxic neuronal necrosis: protein synthesis-independent activation of a cell
      death program.
AB  - Hypoxic necrosis of dentate gyrus neurons in primary culture required the
      activation of an orderly cell death program independent of protein synthesis.
      Early mitochondrial swelling and loss of the mitochondrial membrane potential
      were accompanied by release of cytochrome c and followed by caspase-9-dependent
      activation of caspase-3. Caspase-3 and -9 inhibitors reduced neuronal necrosis.
      Calcium directly induced cytochrome c release from isolated mitochondria. Hypoxic
      neuronal necrosis may be an active process in which the direct effect of hypoxia
      on mitochondria may lead to the final common pathway of caspase-3-mediated
      neuronal death.

PMID- 12606728
TI  - Differentiation, cell fusion, and nuclear fusion during ex vivo repair of
      epithelium by human adult stem cells from bone marrow stroma.
AB  - To investigate stem cell differentiation in response to tissue injury, human
      mesenchymal stem cells (hMSCs) were cocultured with heat-shocked small airway
      epithelial cells. A subset of the hMSCs rapidly differentiated into epithelium
      like cells, and they restored the epithelial monolayer. Immunocytochemistry and
      microarray analyses demonstrated that the cells expressed many genes
      characteristic of normal small airway epithelial cells. Some hMSCs differentiated
      directly after incorporation into the epithelial monolayer but other hMSCs fused
      with epithelial cells. Surprisingly, cell fusion was a frequent rather than rare
      event, in that up to 1% of the hMSCs added to the coculture system were recovered
      as binucleated cells expressing an epithelial surface epitope. Some of the fused
      cells also underwent nuclear fusion.

PMID- 12606729
TI  - A new look at cardiac exercise testing.

PMID- 12606730
TI  - Inappropriate advertising of dietary supplements.

PMID- 12606731
TI  - Can growth hormone prevent aging?

PMID- 12606732
TI  - Frequent ventricular ectopy after exercise as a predictor of death.
AB  - BACKGROUND: Exercise-induced ventricular ectopy predicts an increased risk of
      death in population-based cohorts. We sought to examine in a clinical cohort the
      prognostic importance of ventricular ectopy immediately after exercise, when
      reactivation of parasympathetic activity occurs. We hypothesized that ventricular
      ectopy after exercise (i.e., during the recovery phase) would predict an
      increased risk of death better than ventricular ectopy during exercise. METHODS:
      We studied 29,244 patients (mean [+/-SD] age, 56+/-11 years; 70 percent men) who
      had been referred for symptom-limited exercise testing without a history of heart
      failure, valve disease, or arrhythmia. Frequent ventricular ectopy was defined by
      the presence of seven or more ventricular premature beats per minute, ventricular
      bigeminy or trigeminy, ventricular couplets or triplets, ventricular tachycardia,
      ventricular flutter, torsade de pointes, or ventricular fibrillation. RESULTS:
      Frequent ventricular ectopy occurred only during exercise in 945 patients (3
      percent), only during recovery in 589 (2 percent), and during both exercise and
      recovery in 491 (2 percent). There were 1862 deaths during a mean of 5.3 years of
      follow-up. Frequent ventricular ectopy during exercise predicted an increased
      risk of death (five-year death rate, 9 percent, vs. 5 percent among patients
      without frequent ventricular ectopy during exercise; hazard ratio, 1.8; 95
      percent confidence interval, 1.5 to 2.1; P<0.001), but frequent ventricular
      ectopy during recovery was a stronger predictor (11 percent vs. 5 percent; hazard
      ratio, 2.4; 95 percent confidence interval, 2.0 to 2.9; P<0.001). After
      propensity matching for confounding variables, frequent ventricular ectopy during
      recovery predicted an increased risk of death (adjusted hazard ratio, 1.5; 95
      percent confidence interval, 1.1 to 1.9; P=0.003), but frequent ventricular
      ectopy during exercise did not (adjusted hazard ratio, 1.1; 95 percent confidence
      interval, 0.9 to 1.3; P=0.53). CONCLUSIONS: Frequent ventricular ectopy during
      recovery after exercise is a better predictor of an increased risk of death than
      ventricular ectopy occurring only during exercise.

PMID- 12606733
TI  - Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line
      mutations in MYH.
AB  - BACKGROUND: Germ-line mutations in the base-excision-repair gene MYH have been
      associated with recessive inheritance of multiple colorectal adenomas. Tumors
      from affected persons displayed excess somatic transversions of a guanine
      cytosine pair to a thymine-adenine pair (G:C-->T:A) in the APC gene. METHODS: We
      screened for germ-line MYH mutations in 152 patients with multiple (3 to 100)
      colorectal adenomas and 107 APC-mutation-negative probands with classic familial
      adenomatous polyposis (>100 adenomas). Subgroups were analyzed for changes in the
      related genes MTH1 and OGG1. Adenomas were tested for somatic APC mutations.
      RESULTS: Six patients with multiple adenomas and eight patients with polyposis
      had biallelic germline MYH variants. Missense and protein-truncating mutations
      were found, and the spectrums of mutations were very similar in the two groups of
      patients. In the tumors of carriers of biallelic mutations, all somatic APC
      mutations were G:C-->T:A transversions. In the group with multiple adenomas,
      about one third of patients with more than 15 adenomas had biallelic MYH
      mutations. In the polyposis group, no patient with biallelic MYH mutations had
      severe disease (>1000 adenomas), but three had extracolonic disease. No clearly
      pathogenic MTH1 or OGG1 mutations were identified. CONCLUSIONS: Germ-line MYH
      mutations predispose persons to a recessive phenotype, multiple adenomas, or
      polyposis coli. For patients with about 15 or more colorectal adenomas-
      especially if no germ-line APC mutation has been identified and the family
      history is compatible with recessive inheritance--genetic testing of MYH is
      indicated for diagnosis and calculation of the level of risk in relatives.
      Clinical care of patients with biallelic MYH mutations should be similar to that
      of patients with classic or attenuated familial adenomatous polyposis.

PMID- 12606734
TI  - Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic
      hepatitis B.
AB  - BACKGROUND: Adefovir dipivoxil, a nucleotide analogue, demonstrated clinically
      significant antiviral activity in patients with chronic hepatitis B in phase 1
      and 2 clinical trials. METHODS: We randomly assigned 185 patients with chronic
      hepatitis B who were negative for hepatitis B e antigen (HBeAg) to receive either
      10 mg of adefovir dipivoxil or placebo once daily for 48 weeks in a 2:1 ratio and
      a double-blind manner. The primary end point was histologic improvement. RESULTS:
      At week 48, 64 percent of patients who had base-line liver-biopsy specimens
      available in the adefovir dipivoxil group had improvement in histologic liver
      abnormalities (77 of 121), as compared with 33 percent of patients in the placebo
      group (19 of 57, P<0.001). Serum hepatitis B virus (HBV) DNA levels were reduced
      to fewer than 400 copies per milliliter in 51 percent of patients in the adefovir
      dipivoxil group (63 of 123) and in 0 percent of those in the placebo group (0 of
      61, P<0.001). The median decrease in log-transformed HBV DNA levels was greater
      with adefovir dipivoxil treatment than with placebo (3.91 vs. 1.35 log copies per
      milliliter, P<0.001). Alanine aminotransferase levels had normalized at week 48
      in 72 percent of patients receiving adefovir dipivoxil (84 of 116), as compared
      with 29 percent of those receiving placebo (17 of 59, P<0.001). No HBV polymerase
      mutations associated with resistance to adefovir were identified. The safety
      profile of adefovir dipivoxil was similar to that of placebo. CONCLUSIONS: In
      patients with HBeAg-negative chronic hepatitis B, 48 weeks of adefovir dipivoxil
      treatment resulted in significant histologic, virologic, and biochemical
      improvement, with an adverse-event profile similar to that of placebo. There was
      no evidence of the emergence of adefovir-resistant HBV polymerase mutations.

PMID- 12606735
TI  - Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic
      hepatitis B.
AB  - BACKGROUND: In preclinical and phase 2 studies, adefovir dipivoxil demonstrated
      potent activity against hepatitis B virus (HBV), including lamivudine-resistant
      strains. METHODS: We randomly assigned 515 patients with chronic hepatitis B who
      were positive for hepatitis B e antigen (HBeAg) to receive 10 mg of adefovir
      dipivoxil (172 patients), 30 mg of adefovir dipivoxil (173), or placebo (170)
      daily for 48 weeks. The primary end point was histologic improvement in the 10-mg
      group as compared with the placebo group. RESULTS: After 48 weeks of treatment,
      significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per
      day than who received placebo had histologic improvement (53 percent [P<0.001],
      59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA
      levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per
      milliliter, respectively), undetectable levels (fewer than 400 copies per
      milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0
      percent, respectively), normalization of alanine aminotransferase levels (48
      percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg
      seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent,
      respectively). No adefovir-associated resistance mutations were identified in the
      HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir
      dipivoxil was similar to that of placebo; however, there was a higher frequency
      of adverse events and renal laboratory abnormalities in the group given 30 mg of
      adefovir dipivoxil per day. CONCLUSIONS: In patients with HBeAg-positive chronic
      hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in
      histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase
      levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a
      favorable risk-benefit profile for long-term treatment. No adefovir-associated
      resistance mutations were identified in the HBV DNA polymerase gene.

PMID- 12606736
TI  - Images in clinical medicine. Fatal cerebral hypoxemia after cardiac arrest.

PMID- 12606737
TI  - A survey of liver transplantation from living adult donors in the United States.
AB  - BACKGROUND: The transplantation of the right lobe of a liver from a living adult
      donor into an adult recipient has been performed increasingly frequently in the
      United States. Although the use of grafts from living donors is standard practice
      in transplantation in children, their use in adults remains controversial.
      METHODS: To study the use of liver transplantation from a living donor, we sent a
      24-item questionnaire to all liver-transplantation programs in the United States.
      Data on indications, evaluation, and outcomes were analyzed with the use of
      univariate and multivariate methods. Data on recent transplantations were
      gathered from the Scientific Registry of Transplant Recipients and directly from
      the transplantation programs. RESULTS: Questionnaires were returned by 84 of the
      122 programs (69 percent) describing the results of 449 adult-to-adult
      transplantations of partial livers from living donors that were performed in 42
      centers. Fourteen centers had performed more than 10 such transplantations each
      and together accounted for 80 percent of such transplantations. Centers that
      performed such transplantations also performed more transplantations of livers
      from cadaveric donors and more transplantations from living donors in children
      than centers that did not perform the adult-to-adult procedure (P=0.002 and
      P=0.001, respectively). A total of 45 percent of potential donors who were
      evaluated eventually donated a lobe of their liver; 99 percent of these donors
      were genetically or emotionally related to the recipient. Complications in the
      donor were more frequent in the centers performing the fewest transplantations
      from living donors in adults and included biliary complications requiring
      intervention (in 6.0 percent), reoperation (in 4.5 percent), and death (in one
      donor [0.2 percent]). Among the recipients, 1.6 percent did not meet criteria for
      receipt of a cadaveric transplant; cancer, retransplantation, and acute liver
      failure were uncommon indications for transplantation from a living donor.
      Biliary complications occurred in 22.0 percent of recipients, and vascular
      complications occurred in 9.8 percent. CONCLUSIONS: Adult-to-adult liver
      transplantation from a living donor is increasingly performed in the United
      States but is concentrated in a few large-volume centers. Mortality among donors
      is low, but complications in the donor are relatively common.

PMID- 12606738
TI  - Clinical practice. Occupational exposure to HIV in health care settings.

PMID- 12606739
TI  - Case record of the Massachusetts General Hospital. Weekly clinicopathological
      exercises. Case 7-2003. A 43-year-old man with fever, rapid loss of vision in the
      left eye, and cardiac findings.

PMID- 12606740
TI  - Multiple colorectal adenomas--is their number up?

PMID- 12606742
TI  - Residents' suggestions for reducing errors in teaching hospitals.

PMID- 12606741
TI  - Suppressing hepatitis B without resistance--so far, so good.

PMID- 12606743
TI  - Outcomes after total versus subtotal abdominal hysterectomy.

PMID- 12606744
TI  - Miltefosine for Indian visceral leishmaniasis.

PMID- 12606745
TI  - Hemofiltration and peritoneal dialysis in infection-associated acute renal
      failure.

PMID- 12606746
TI  - The Olivieri case.

PMID- 12606747
TI  - Industrial collaboration.

PMID- 12606748
TI  - Moral progress, mental retardation, and the death penalty.

PMID- 12606749
TI  - Long-term histologic findings in pulmonary arteries reconstructed with autologous
      pericardium.

PMID- 12606750
TI  - Prolonged shedding of multidrug-resistant influenza A virus in an
      immunocompromised patient.

PMID- 12606751
TI  - Calmodulin-regulated adenylyl cyclases: cross-talk and plasticity in the central
      nervous system.
AB  - Gene disruption studies have shown that the Ca(2+)-stimulated adenylyl cyclases,
      AC1 and AC8, are critical for some forms of synaptic plasticity, including long
      term potentiation as well as long-term memory formation (LTM). It is hypothesized
      that these enzymes are required for LTM to support the increased expression of a
      family of genes regulated through the cAMP/Ca(2+) response element-binding
      protein/cAMP response element transcriptional pathway. In contrast to AC1 and
      AC8, AC3 is a Ca(2+)-inhibited adenylyl cyclase that plays an essential role in
      olfactory signal transduction. Coupling of odorant receptors to AC3 stimulates
      cAMP transients that function as the major second messenger for olfactory
      signaling. These cAMP transients are caused, at least in part, by Ca(2+)
      inhibition of AC3, which is mediated through calmodulin-dependent protein kinase
      II. The unique structure and regulatory properties of these adenylyl cyclases
      make them attractive drug target sites for modulation of a number of
      physiological processes including memory formation and olfaction.

PMID- 12606752
TI  - A new endothelial target for cannabinoids.

PMID- 12606753
TI  - Expression and characterization of a 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid
      receptor highly expressed on human eosinophils and neutrophils.
AB  - Using a bioinformatics approach, we have isolated a novel G-protein-coupled
      receptor (GPCR), R527, and have demonstrated that this receptor shows no
      significant homology to previously deorphanized GPCRs. Quantitative reverse
      transcription-polymerase chain reaction analysis of the expression of GPCR R527
      indicated a very high level of mRNA expression in eosinophils, with high
      expression also detected in neutrophils and lung macrophages. Stable cell lines
      were generated expressing this receptor together with the G-protein alpha-subunit
      G alpha(16). These cells were used to screen an agonist collection in a calcium
      mobilization assay and 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) was
      identified as a putative ligand. 5(S)-hydroxyperoxy-6E,8Z,11Z,14Z
      eicosatetraenoic acid was also shown to activate the receptor, whereas the
      leukotrienes LTB(4), LTC(4), LTD(4), and LTE(4) failed to elicit a response. In
      cAMP assays, pertussis toxin reversed the inhibitory effects of 5-oxo-ETE on cAMP
      production, indicating that the receptor is G alpha(i)-coupled. The GPCR R527
      shows pharmacological properties similar to those of the previously described 5
      oxo-ETE receptor expressed on eosinophils, neutrophils, and monocytes. These cell
      types show chemotactic responses to 5-oxo-ETE, and this eicosanoid has been
      proposed to play a key role in the inflammatory response. The molecular
      identification of a receptor binding 5-oxo-ETE will expand our understanding of
      the physiological role of this mediator and may provide new therapeutic
      opportunities.

PMID- 12606754
TI  - Differential requirement of G alpha12, G alpha13, G alphaq, and G beta gamma for
      endothelin-1-induced c-Jun NH2-terminal kinase and extracellular signal-regulated
      kinase activation.
AB  - In the present study, we examined the roles of G(12), G(13), G(q), and G(i) in
      endothelin-1-induced hypertrophic responses. Endothelin-1 stimulation activated
      extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK)
      in cultured rat neonatal myocytes. The activation of JNK, but not ERK, was
      inhibited by the expression of carboxyl terminal regions of G alpha(12) and G
      alpha(13). JNK activation was also inhibited by expression of the G alpha(12)/G
      alpha(13)-specific inhibitor regulator of G protein signaling (RGS) domain of
      p115RhoGEF and the G alpha(q)-specific inhibitor RGS domain of the G protein
      coupled receptor kinase 2 (GRK2-RGS). JNK activation was not, however, inhibited
      by expression of the carboxyl terminal region of G protein-coupled receptor
      kinase 2 (GRK2-ct), which is a G beta gamma-sequestering polypeptide.
      Additionally, JNK activation but not ERK activation was inhibited by the
      expression of C3 exoenzyme that inactivates small GTPase Rho. These results
      suggest that JNK activation by G alpha(12), G alpha(13), and G alpha(q) is
      involved in Rho. On the other hand, ERK activation was inhibited by pertussis
      toxin treatment, the receptor-G(i) uncoupler, and GRK2-ct. Thus, ERK was
      activated by G alpha(i)- and G beta gamma-dependent pathways. These results
      clearly demonstrate that differential pathways activate JNK and ERK.

PMID- 12606756
TI  - Molecular modeling of interactions of dihydropyridines and phenylalkylamines with
      the inner pore of the L-type Ca2+ channel.
AB  - Domains IIIS5, IIIS6, and IVS6 transmembrane segments of L-type Ca(2+) channels
      participate in dihydropyridine (DHP) and phenylalkylamine (PAA) binding. The
      inner pore structure of the Ca(v)1.2 channel was reconstructed from coordinates
      of the transmembrane alpha-helices of the KcsA channel. S6s were aligned with M2
      by comparative analysis of the pore-facing M2 side chains and those required for
      drug binding. Two neighboring tilted S6 helices of domains III and IV below the
      selectivity filter formed an interdomain crevice. Docking of DHPs inside this
      crevice located the DHP ring between Phe-1159 of IIIS6 and Ala-1467 of IVS6,
      parallel to the pore axis, whereas the 4-aryl ring participated in aromatic and
      polar interactions with the side chains of Tyr-1152 and Tyr-1463. Nonpolar
      interactions of the port side ester group with hydrophobic side chains of Ile
      1156, Ile-1163, and Ile-1471 on the bottom of the binding cavity, formed by the
      crossover of IIIS6 and IVS6, could stabilize the channel's closed/inactivated
      state. Similar arrangements were found for DHP agonist drugs, except for the
      absence of hydrophobic interactions with the helical crossing. In this
      arrangement, DHPs do not physically block the pore. Locating the central amine
      group of desmethoxyverapamil near the selectivity filter domain III glutamic acid
      allows one aromatic ring through its CH(2)CH(2) linker to interact with the side
      chain of Tyr-1463 inside the DHP binding site, whereas the opposite aromatic ring
      is in contact with the side chain of Ile-1470 of IVS6, blocking the pore.

PMID- 12606755
TI  - Influence of molecular structure on substrate binding to the human organic cation
      transporter, hOCT1.
AB  - Organic cation transporters play a critical role in the elimination of
      therapeutic compounds in the liver and the kidney. We used computational
      quantitative structure activity approaches to predict molecular features that
      influence interaction with the human ortholog of the organic cation transporter
      (hOCT1). [(3)H]tetraethylammonium uptake in HeLa cells stably expressing hOCT1
      was inhibited to varying extents by a diverse set of 30 molecules. A subset of 22
      of these was used to produce, using Catalyst, a pharmacophore that consisted of
      three hydrophobic features and a positive ionizable feature. The correlation
      coefficient of observed versus predicted IC(50) was 0.86 for this training set,
      which was superior to calculated logP alone (r = 0.73) as a predictor of hOCT1
      inhibition. A descriptor-based quantitative structure-activity relationship study
      using Cerius(2) resulted in an equation relating five molecular descriptors to
      log IC(50) with a correlation coefficient of 0.95. Furthermore, a group of
      phenylpyridinium and quinolinium compounds were used to investigate the spatial
      limitations of the hOCT1 binding site. The affinity for hOCT was higher for 4
      phenylpyridiniums > 3-phenylpyridiniums > quinolinium, indicating that substrate
      affinity was influenced by the distribution of hydrophobic mass. In addition,
      supraplanar hydrophobic mass was found to increase the affinity for binding
      hOCT1. These results indicate how a combination of computational and in vitro
      approaches may yield insight into the binding affinity of transporters and may be
      applicable to predicting these properties for new therapeutics.

PMID- 12606757
TI  - Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2
      ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer
      binding protein beta in macrophages.
AB  - Ceramide, formed by sphingomyelinase, is involved in the expression of
      cyclooxygenase-2 (COX-2). This study examines the effect of C2-ceramide (C2), a
      cell-permeable ceramide analog, on the lipopolysaccharide (LPS)-inducible COX-2
      expression and signaling pathways. C2 did not induce COX-2 but potentiated LPS
      inducible COX-2 expression in Raw264.7 cells, whereas dihydro-C2 was inactive.
      Treatment of cells with C2 notably increased LPS-inducible CCAAT/enhancer binding
      protein (C/EBP) DNA binding. Antibody supershift experiments revealed that LPS
      induced C/EBP DNA binding activity depended on C/EBP beta and C/EBP delta but not
      C/EBP alpha, C/EBP epsilon or CBP/p300. C/EBP beta contributed to C2-enhanced DNA
      binding activity. 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H
      imidazole (SB203580), a p38 kinase inhibitor, completely inhibited LPS-inducible
      and C2-potentiated LPS-inducible COX-2 expression. Enhancement of LPS-inducible
      COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative
      mutant of JNK1 [JNK1(-)] cells. 2'-Amino-3'-methoxyflavone (PD98059) or stable
      transfection with dominant-negative mutant of MKK1 decreased COX-2 induction by
      LPS but failed to inhibit C2-enhanced LPS induction of COX-2. Transfection with
      dominant-negative mutant of C/EBP inhibited the ability of C2 to potentiate the
      induction of COX-2 by LPS. In LPS-treated cells, C2 enhanced both the nuclear
      translocation and the expression of LPS-inducible C/EBP beta with an increase in
      AP-1 DNA binding activity. These enhancements were abolished by JNK1(-)
      transfection. AP-1 decoy oligonucleotide suppressed C2-potentiated C/EBP beta
      expression, indicating that AP-1 was responsible for C2-mediated C/EBP beta
      expression. These results demonstrate that C2 increases C/EBP beta-mediated COX-2
      induction by LPS and that the pathway of JNK1 but not ERK1/2 is responsible for
      C/EBP beta activation involving activator protein-1-mediated enhanced C/EBP beta
      expression.

PMID- 12606758
TI  - Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR.
AB  - The steroid and xenobiotic receptor (SXR) is an orphan nuclear receptor that
      plays a key role in the regulation of xenobiotic response by controlling the
      expression of drug metabolizing and clearance enzymes. We observed that pregnane
      X receptor (PXR), the mouse ortholog of SXR, was retained in the cytoplasm of
      hepatic cells of untreated mice, whereas PXR was translocated to the nucleus
      after administration of a ligand, pregnenolone 16 alpha-carbonitrile. To
      understand the molecular mechanisms underlying the xenochemical-dependent nuclear
      translocation of SXR, we identified the signal sequence of SXR that regulates its
      nuclear translocation; using an in vitro expression system, we allocated the
      nuclear localization signal (NLS) to amino acid residues 66 to 92 within the DNA
      binding domain of SXR. The NLS of SXR is characterized as the bipartite type, and
      is recognized by the three molecular species of importin alpha: Rch1 (PTAC58),
      NPI1, and Qip1, in the presence of PTAC97 of importin beta to target the nuclear
      pore. The nuclear translocation of SXR was observed as an essential regulatory
      event for transcription of its target genes such as CYP3A4. These results
      strongly suggest that the molecular mechanism of the nuclear import of SXR was
      different from that of another xenosensor, the constitutively active receptor,
      whose translocation into the nucleus is mediated by a leucine-rich xenochemical
      response signal in its ligand binding domain.

PMID- 12606759
TI  - In vitro study of the functional expression of organic anion transporting
      polypeptide 3 at rat choroid plexus epithelial cells and its involvement in the
      cerebrospinal fluid-to-blood transport of estrone-3-sulfate.
AB  - The cerebrospinal fluid-to-blood efflux transport of estrone-3-sulfate (E(1)S)
      via the blood-cerebrospinal fluid barrier (BCSFB) may play an important role in
      regulating E(1)S levels in the brain. Here, we investigated the efflux transport
      of E(1)S at the BCSFB using conditionally immortalized rat choroid plexus
      epithelial cells (TR-CSFB) and identified the responsible transporter. The
      [(3)H]E(1)S uptake by TR-CSFB cells was composed of saturable and nonsaturable
      components, and the K(m) and V(max) values of the saturable component were
      determined to be 16.8 +/- 5.1 microM and 12.3 +/- 2.3 pmol/min/mg of protein,
      respectively. [(3)H]E(1)S uptake was inhibited by probenecid, cholate,
      taurocholate, sulfobromophthalein, dehydroepiandrosterone sulfate,
      triiodothyronine, thyroxin, and digoxin but not by p-aminohippuric acid, gamma
      aminobutyric acid, or methotrexate, suggesting the involvement of organic anion
      transporting polypeptide (oatp) in the uptake. Reverse transcription-polymerase
      chain reaction analysis revealed that oatp3 was expressed in TR-CSFB cells and
      isolated rat choroid plexus, although oatp1 was not detected in either. Xenopus
      laevis oocytes expressing oatp3 exhibited [(3)H]E(1)S uptake activity with a K(m)
      of 8.09 +/- 2.83 microM and V(max) of 8.02 +/- 0.87 pmol/h/oocyte. Moreover,
      oatp3 is localized at the brush-border membrane of choroid plexus epithelial
      cells. These results suggest that oatp3 is involved in the E(1)S efflux transport
      at the BCSFB.

PMID- 12606760
TI  - Structural analysis of the activation of ribavirin analogs by NDP kinase:
      comparison with other ribavirin targets.
AB  - Ribavirin used in therapies against hepatitis C virus (HCV) is potentially
      efficient against other viruses but presents a high cytotoxicity. Several
      ribavirin triphosphate analogs modified on the ribose moiety were synthesized and
      tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse
      transcriptase. Modified nucleotides with 2'-deoxy, 3'-deoxy, 2',3'-dideoxy, 2',3'
      dideoxy-2',3'-dehydro, and 2',3'-epoxy-ribose inhibited the HCV enzyme but not
      the other two polymerases. They were also analyzed as substrates for nucleoside
      diphosphate (NDP) kinase, the enzyme responsible for the last step of the
      cellular activation of antiviral nucleoside analogs. An X-ray structure of NDP
      kinase complexed with ribavirin triphosphate was determined. It demonstrates that
      the analog binds as a normal substrate despite the modified base and confirms the
      crucial role of the 3'-hydroxyl group in the phosphorylation reaction. The 3'
      hydroxyl is required for inhibition of the initiation step of RNA synthesis by
      HCV polymerase, and both sugar hydroxyls must be present to inhibit elongation.
      The 2'deoxyribavirin is the only derivative efficient in vitro against HCV
      polymerase and properly activated by NDP kinase.

PMID- 12606761
TI  - Molecular site of action of the antiarrhythmic drug propafenone at the voltage
      operated potassium channel Kv2.1.
AB  - The effects of the antiarrhythmic drug propafenone at Kv2.1 channels were studied
      with wild-type and mutated channels expressed in Xenopus laevis oocytes.
      Propafenone decreased the Kv2.1 currents in a time- and voltage-dependent manner
      (decrease of the time constants of current rise, increase of block with the
      duration of voltage steps starting from a block of less than 19%, increase of
      block with the amplitude of depolarization yielding a fractional electrical
      distance delta of 0.11 to 0.16). Block of Kv2.1 appeared with application to the
      intracellular, but not the extracellular, side of membrane patches. In
      mutagenesis experiments, all parts of the Kv2.1 channel were successively
      exchanged with those of the Kv1.2 channel, which is much more sensitive to
      propafenone. The intracellular amino and carboxyl terminus and the intracellular
      linker S4-S5 reduced the blocking effect of propafenone, whereas the linker S5
      S6, as well as the segment S6 of the Kv1.2 channel, abolished it to the value of
      the Kv1.2 channel. In the linker S5-S6, this effect could be narrowed down to two
      groups of amino acids (groups 372 to 374 and 383 to 384), which also affected the
      sensitivity to tetraethylammonium. In segment S6, several amino acids in the
      intracellularly directed part of the helix significantly reduced propafenone
      sensitivity. The results suggest that propafenone blocks the Kv2.1 channel in the
      open state from the intracellular side by entering the inner vestibule of the
      channel. These results are consistent with a direct interaction of propafenone
      with the lower part of the pore helix and/or residues of segment S6.

PMID- 12606762
TI  - Differential regulation of nonsteroidal anti-inflammatory drug-activated gene in
      normal human tracheobronchial epithelial and lung carcinoma cells by retinoids.
AB  - In this study, we analyze the effect of several retinoids on the expression of
      nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in normal human
      tracheobronchial epithelial (HTBE) cells and several lung carcinoma cell lines.
      The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid
      (AHPN) greatly enhances the expression of NAG-1 mRNA and protein in a time- and
      dose-dependent manner in human lung adenocarcinoma H460 cells and several other
      carcinoma cell lines. This induction was specific for AHPN because retinoic acid,
      a retinoic acid receptor-, and a retinoid X receptor pan-agonist were unable to
      induce NAG-1, suggesting that this induction is not mediated through activation
      of retinoid receptors. Although NAG-1 is a p53-responsive gene, AHPN-induced NAG
      1 expression does not require p53. The induction of NAG-1 expression by AHPN is
      caused at least in part by an 8-fold increase in the stability of NAG-1 mRNA. In
      contrast to carcinoma cells, NAG-1 expression is effectively induced by retinoic
      acid and the RAR-selective pan-agonist in normal HTBE cells and accompanies the
      inhibition of squamous differentiation and the initiation of normal
      differentiation. In vivo, NAG-1 expression was observed in the normal
      tracheobronchial epithelium, whereas no expression was found in either squamous
      metaplastic tracheal epithelium or in sections of human lung tumors. Our results
      suggest that the induction of NAG-1 expression by retinoids in normal HTBE and
      lung carcinoma cells is regulated by distinct mechanisms and is associated with
      different biological processes. The linkage between AHPN treatment and NAG-1
      expression revealed in this study provides a new mechanism for the
      antitumorigenic activity of AHPN.

PMID- 12606763
TI  - N-(4-hydroxyphenyl)retinamide inhibits retinoblastoma growth through reactive
      oxygen species-mediated cell death.
AB  - Retinoblastoma arises from a subset of developing retinal cells lacking the RB-1
      gene product pRB, which have lost the ability to respond to apoptotic signals. A
      better understanding of retinoblastoma biological response to therapeutic agents
      with low toxicity could improve the development of novel approaches for treatment
      and prevention of the disease. Naturally occurring retinoids inhibit growth and
      induce differentiation of Y79 human retinoblastoma cells in vitro. The synthetic
      retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has been shown to induce apoptosis
      and/or necrosis of tumor cells of neuroectodermal origin. We examined the
      sensitivity of Y79 retinoblastoma cells to 4HPR in vitro, and in a xenograft
      model of tumor growth in nude mice in vivo. 4HPR treatment in the range 2.5 to 10
      microM induced a loss of Y79 cell viability, as determined by crystal violet,
      trypan blue exclusion, and long-term clonogenic assays, and impairment of
      mitochondrial function detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
      tetrazolium bromide assay. Reactive oxygen species were elevated in 4HPR-treated
      cells and antioxidants rescued cell viability, indicating that 4HPR-induced cell
      death was mediated by oxidative stress. 4HPR inhibited growth of Y79 xenografts
      in vivo in both chemoprevention and intervention settings. Tumor growth
      inhibition by 4HPR was also associated with significant inhibition of
      angiogenesis in vivo. These findings could have an important translational value
      for chemoprevention or early intervention in the treatment of retinoblastoma.

PMID- 12606764
TI  - Deficiency of nicotinic acetylcholine receptor beta 4 subunit causes autonomic
      cardiac and intestinal dysfunction.
AB  - Neuronal nicotinic acetylcholine receptors (nAChR) are composed of 12 subunits
      (alpha 2-alpha 10 and beta 2-beta 4), which play the central role in autonomic
      transmission. beta 4 subunits are abundantly expressed in autonomic ganglia,
      forming acetylcholine binding sites and ion channels with alpha 3 or alpha 3 and
      alpha 5 subunits as pentameric receptors. To investigate the physiological and
      pharmacological properties of beta 4 subunits in autonomic ganglia, we measured
      autonomic functions in knockout mice lacking nAChR subunit beta 4 (beta 4(-/-))
      and wild-type mice. beta 4(-/-) mice had an attenuated bradycardiac response to
      high frequency (60 pulse/s) vagal stimulation, as well as an increased
      sensitivity to hexamethonium blockade at low dose (3 mg/kg) and a reduced ileal
      contractile response to the nicotinic agonists cytisine,
      dimethylphenylpiperazinium iodide, nicotine (10 mg/kg each), and epibatidine (0.1
      mg/kg). The results suggest that beta 4 subunits are important components of
      nAChRs in autonomic ganglia. Deficiency of beta 4 subunits altered ion channel
      properties, conductance, and sensitivity and affinity of receptors to agonists
      and antagonists, affecting ganglionic transmission.

PMID- 12606765
TI  - Differential effects of catalase on apoptosis induction in human promonocytic
      cells. Relationships with heat-shock protein expression.
AB  - The administration of the H(2)O(2)-specific scavenger catalase attenuated the
      generation of apoptosis by the antitumor drugs etoposide, camptothecin,
      doxorubicin, and cisplatin in U-937 human promonocytic cells. By contrast, the
      antioxidant potentiated the generation of apoptosis by the inducers of the stress
      response, heat shock and cadmium, in this and other myeloid cell types. Catalase
      also increased the heat shock-provoked stimulation of caspase-3 and -9
      activities, as well as the release of cytochrome c from mitochondria to the
      cytosol. The potentiation of cell death by catalase correlated with its capacity
      to inhibit the stress response, as demonstrated by the suppression of 70- or 27
      kDa heat-shock protein expression and the inhibition of heat-shock transcription
      factor 1 binding activity. Conversely, the toxicity of catalase plus heat shock
      was attenuated when the cells were preconditioned with a soft heating, which
      elevated the 70-kDa heat-shock protein levels. By contrast with catalase, the
      antioxidants superoxide dismutase and probucol did not inhibit heat-shock protein
      expression or affect apoptosis in U-937 cells. Finally, it was observed that the
      antitumor drugs did not activate the stress response in U-937 cells and that
      catalase failed to inhibit HSP expression and to potentiate apoptosis in heat
      shock-treated RPMI 8866 lymphoblastic cells. Taken together, these results
      provide the first demonstration of a proapoptotic action of catalase, suggest
      that H(2)O(2) is a critical regulator of both apoptosis and the stress response,
      and corroborate the antiapoptotic action of heat-shock proteins in myeloid cells.

PMID- 12606766
TI  - Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric
      thiol conjugates in Madin-Darby canine kidney cells.
AB  - Mercuric ions are highly reactive and form a variety of organic complexes or
      conjugates in vivo. The renal proximal tubule is a primary target for mercury
      uptake and toxicity, and circumstantial evidence implicates organic anion
      transporters in these processes. To test this hypothesis directly, the transport
      and toxicity of mercuric-thiol conjugates were characterized in a Madin-Darby
      canine kidney cell line stably transfected with the human organic anion
      transporter 1 (hOAT1). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-terazolium
      bromide assays (for mitochondrial dehydrogenase) confirmed that mercuric
      conjugates of the thiols N-acetylcysteine (NAC), cysteine, or glutathione were
      more toxic in hOAT1-transfected cells than in the nontransfected cells. The NAC
      Hg(2+) conjugate was most cytotoxic, inducing greater than 50% cellular death
      over 18 h at a concentration of 100 microM. The cytotoxic effects were fully
      reversed by probenecid (an OAT1 inhibitor) and partially reversed by p
      aminohippurate (an OAT1 substrate). Toxicity of this conjugate was reduced by the
      OAT1-exchangeable dicarboxylates alpha-ketoglutarate, glutarate, and adipate, but
      not by succinate, a nonexchangeable dicarboxylate. (203)Hg-uptake studies showed
      probenecid-sensitive uptake of mercury-thiol conjugates in the hOAT1-transfected
      cells. The apparent K(m) for the NAC-Hg(2+) conjugate was 44 +/- 9 microM. Uptake
      of the NAC-Hg(2+) conjugate was cis-inhibited by glutarate, but not by
      methylsuccinate, paralleling their effects on toxicity. Probenecid-sensitive
      transport of the NAC-Hg(2+) conjugate was also shown to occur in Xenopus laevis
      oocytes expressing the hOAT1 or the rOAT3 transporters, suggesting that OAT3 may
      also transport thiol-Hg(2+) conjugates. Thus, renal accumulation and toxicity of
      thiol-Hg(2+) conjugates may depend in part on the activity of the organic
      transport system.

PMID- 12606767
TI  - Functional analysis of murine aryl hydrocarbon (AH) receptors defective in
      nuclear import: impact on AH receptor degradation and gene regulation.
AB  - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor
      that is also a substrate for the 26S proteasome. However, the subcellular
      location of the degradation events or the requirement for nuclear transport has
      not been resolved. To gain insight into both ligand-dependent and independent
      degradation of the AHR, studies were designed to evaluate the relationship
      between AHR localization, stability, and gene regulation in a defined cell
      culture model system. The strategy of these studies was to generate stable cell
      lines expressing murine AHR proteins that were defective in nuclear import and
      then to assess the location of the AHR, the time course of AHR degradation, and
      the level of induction of endogenous CYP1A1 protein after exposure to 2,3,7,8
      tetrachlorodibezo-p-dioxin (TCDD), geldanamycin (GA), or the protease inhibitor
      carbobenzoxy-L-leucyl-L-leucyl-leucinal (MG-132). Mutation within the putative
      nuclear localization sequence (NLS) resulted in AHR mutants that were severely
      defective in nuclear import as evaluated by immunocytochemical staining after
      exposure to TCDD, GA, or MG-132. Importantly, the NLS mutants exhibited identical
      levels of degradation along a similar time course as wild-type AHR after exposure
      to TCDD or GA when stably expressed in either murine hepatoma cells (Hepa-1) or
      hamster lung cells (E36). In contrast, the NLS mutants were severely defective in
      ligand-mediated induction of CYP1A1 expression. These findings imply that the
      proteolytic machinery present in the cytoplasmic compartment is sufficient to
      degrade the AHR and that nuclear translocation, binding with ARNT, or DNA binding
      are not necessary for efficient degradation of the AHR.

PMID- 12606768
TI  - Activation of p38 mitogen-activated protein kinase and activator protein-1 during
      the promotion of neurite extension of PC-12 cells by 15-deoxy-delta12,14
      prostaglandin J2.
AB  - 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15-deoxy-PGJ(2)), a naturally occurring
      ligand, activates the peroxisome proliferator-activated receptor-gamma (PPAR
      gamma). Activation of PPAR-gamma has been found to induce cell differentiation in
      such cells as adipose cells and macrophages. Herein, we investigated whether 15
      deoxy-PGJ(2) has neuronal cell differentiation and possible underlying molecular
      mechanisms. Dopaminergic differentiating PC-12 cells treated with 15-deoxy-PGJ(2)
      (0.2 to 1.6 microM) alone showed measurable neurite extension and expression of
      neurofilament, a marker of cell differentiation. However, a much greater extent
      of neurite extension and expression of neurofilament was observed in the presence
      of NGF (50 ng/ml). In parallel with its increasing effect on the neurite
      extension and expression of neurofilament, 15-deoxy-PGJ(2) enhanced NGF-induced
      p38 MAP kinase expression and its phosphorylation in addition to the activation
      of transcription factor AP-1 in a dose-dependent manner. Moreover, pretreatment
      of 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole
      (SB203580), a specific inhibitor of p38 MAP kinase, inhibited the promoting
      effect of 15-deoxy-PGJ(2) (0.8 microM) on NGF-induced neurite extension. This
      inhibition correlated well with the ability of SB203580 to inhibit the enhancing
      effect of 15-deoxy-PGJ(2) on the expression of p38 MAP kinase and activation of
      AP-1. The promoting ability of 15-deoxy-PGJ(2) did not occur through PPAR-gamma
      because synthetic PPAR-gamma agonist and antagonist did not change the neurite
      promoting effect of 15-deoxy-PGJ(2). In addition, contrast to other cells
      (embryonic midbrain and neuroblastoma SK-N-MC cells), PPAR-gamma was not
      expressed in PC-12 cells. Other structure-related prostaglandins (PGD(2) and
      PGE(2)) acting via a cell surface G-protein-coupled receptor (GPCR) did not
      increase basal or NGF-induced neurite extension. Moreover, GPCR (PGE(2) and
      PGD(2) receptors) antagonists did not alter the promoting effect of 15-deoxy
      PGJ(2) on neurite extension and activation of p38 MAP kinase, suggesting that the
      promoting effect of 15-deoxy-PGJ(2) may not be mediated by GPCR either. These
      data demonstrate that activation of p38 MAP kinase in conjunction with AP-1
      signal pathway may be important in the promoting activity of 15-deoxy-PGJ(2) on
      the differentiation of PC-12 cells.

PMID- 12606769
TI  - Erythromycin, roxithromycin, and clarithromycin: use of slow-binding kinetics to
      compare their in vitro interaction with a bacterial ribosomal complex active in
      peptide bond formation.
AB  - In a cell-free system derived from Escherichia coli, it is shown that
      clarithromycin and roxithromycin, like their parent compound erythromycin, do not
      inhibit the puromycin reaction (i.e., the peptide bond formation between
      puromycin and AcPhe-tRNA bound at the P-site of 70S ribosomes programmed with
      heteropolymeric mRNA). Nevertheless, all three antibiotics compete for binding on
      the ribosome with tylosin, a 16-membered ring macrolide that behaves as a slow
      binding, slowly reversible inhibitor of peptidyltransferase. The mutually
      exclusive binding of these macrolides to ribosomes is also corroborated by the
      fact that they protect overlapping sites in domain V of 23S rRNA from chemical
      modification by dimethyl sulfate. From this competition effect, detailed kinetic
      analysis revealed that roxithromycin or clarithromycin (A), like erythromycin,
      reacts rapidly with AcPhe-tRNA.MF-mRNA x 70S ribosomal complex (C) to form the
      encounter complex CA which is then slowly isomerized to a more tight complex,
      termed C*A. The value of the overall dissociation constant, K, encompassing both
      steps of macrolide interaction with complex C, is 36 nM for erythromycin, 20 nM
      for roxithromycin, and 8 nM for clarithromycin. Because the off-rate constant of
      C*A complex does not significantly differ among the three macrolides, the
      superiority of clarithromycin as an inhibitor of translation in E. coli cells and
      many Gram-positive bacteria may be correlated with its greater rate of
      association with ribosomes.

PMID- 12606770
TI  - Small ligands modulating the activity of mammalian adenylyl cyclases: a novel
      mode of inhibition by calmidazolium.
AB  - Molecular cloning of membrane-spanning mammalian adenylyl cyclases (ACs) has led
      to the discovery of nine different isotypes, making ACs potentially useful
      therapeutic targets. This study investigated the mechanism by which fungicidal
      nitroimidazole compounds modulate AC activity. Current evidence indicates that
      biological control of AC activity occurs through the cytosolic domains. Hence,
      full-length ACII, ACIX, and recombinant fusion proteins composed of the
      cytoplasmic loops of human ACIX or the first and second cytoplasmic loops of rat
      ACV and ACII, respectively, were expressed in human embryonic kidney 293 cells.
      The AC activities of the respective proteins were characterized, and their
      modulation by nitroimidazoles was investigated. Calmidazolium inhibited the
      activities of both full-length ACs and soluble fusion proteins (IC(50),
      approximately 10 microM). Inhibition of ACIX by calmidazolium was mediated by
      direct interaction with the catalytic core in a noncompetitive fashion. ACIX was
      essentially insensitive to 2'-deoxyadenosine 3'-monophosphate, a known blocker of
      AC activity. The ACV-ACII fusion protein was inhibited by calmidazolium (IC(50),
      approximately 20 microM) as well as by 2'-deoxyadenosine 3'-AMP (IC(50),
      approximately 2 microM), in a manner indicating independent mechanisms of action.
      Taken together, the data demonstrate that ACIX is insensitive to adenosine
      analogs and that calmidazolium inhibits AC activity by a novel, noncompetitive
      mechanism.

PMID- 12606771
TI  - Telomere dysfunction increases cisplatin and ecteinascidin-743 sensitivity of
      melanoma cells.
AB  - The aim of this study was to investigate the role of telomerase function on the
      chemosensitivity of melanoma cells. To this end, ecteinascidin-743 (ET-743) and
      cisplatin [cis-diamminedichloroplatinum(II) (CDDP)], two DNA-interacting drugs
      that invariably cause an arrest in the G(2)/M phase, and 1-(2,4-dichlorobenzyl)
      1H-indazole-3-carboxylic acid (LND), a mitochondria-targeting drug inducing a
      G(1) block, were used. As experimental model, human melanoma clones showing
      reduced human telomerase reverse transcriptase (hTERT) expression and telomerase
      activity and characterized by telomere dysfunction were used. Reconstitution of
      telomerase activity by exogenous hTERT expression improved telomere function and
      reduced the sensitivity to CDDP and ET-743 without affecting LND susceptibility.
      The decreased sensitivity to CDDP and ET-743 was mainly caused by the ability of
      cells to recover from drug-induced damage, evaluated in terms of both chromosomal
      lesions and cell survival. The ability of hTERT-reconstituted cells to recover
      from drug-induced damage was attributable to the restoration of cell cycle
      progression. In fact, the cells without hTERT restoration remained for a
      prolonged time in the G(2)/M phase, and this cell cycle alteration made
      irreversible the drug-induced S-G(2)/M block and led to the activation of
      apoptotic program. On the contrary, the hTERT-reconstituted cells progressed
      quickly through the cell cycle, thus acquiring the capacity to recover from drug
      induced block and to protect themselves from the G(2)/M phase-specific drug
      triggered apoptosis.

PMID- 12606772
TI  - Purinergic P2Y12 receptor blockade inhibits shear-induced platelet
      phosphatidylinositol 3-kinase activation.
AB  - Pathologically elevated shear stress triggers aspirin-insensitive platelet
      thrombosis. Signaling mechanisms involved in shear-induced platelet thrombosis
      are not well understood. To investigate these, we examined the hypothesis that
      functionally important platelet phosphatidylinositol 3-kinase (PI3-K) activity is
      stimulated by an in vitro shear stress of 120 dynes/cm(2) (shear rate of 6,000
      sec(-1)). Phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) production was
      examined in washed human platelets subjected to pathological shear stress in a
      cone-plate viscometer. PIP(3) production peaks 30 s after shear begins and is
      initiated by von Willebrand factor (VWF) binding to the glycoprotein (Gp) Ib-IX-V
      complex. Inhibiting PI3-K with wortmannin or 2-(4-morpholinyl)-8-phenyl-4H-1
      benzopyran-4-one (LY294002) results in the inhibition of shear-induced platelet
      aggregation. In resting platelets, class IA PI3-K associates with the tyrosine
      kinase Syk. Within 30 s of beginning shear, PI3-K-associated Syk becomes tyrosine
      phosphorylated. Inhibiting Syk activation with piceatannol results in the
      inhibition of PIP(3) production and aggregation. Selective blockade of the
      P2Y(12) receptor results in the inhibition of Syk phosphorylation, PIP(3)
      production, and aggregation. These results indicate that shear-induced VWF
      binding to platelet GpIb-IX-V stimulates functionally important PI3-K activity.
      PI3-K activation is signaled by rapid feedback amplification that involves
      P2Y(12) receptor-mediated activation of Syk.

PMID- 12606773
TI  - Ruthenium red inhibits TASK-3 potassium channel by interconnecting glutamate 70
      of the two subunits.
AB  - TASK channels are highly pH-sensitive two-pore-domain background potassium
      channels expressed in the central nervous system and in some peripheral tissues.
      Their current can be regulated by receptor-mediated activation of phospholipase C
      and also by pharmacological means. We have reported previously that the cationic
      dye, ruthenium red (RR), inhibited homodimeric TASK-3 (kcnk9), whereas TASK-1
      (kcnk3) homodimer and TASK-1/TASK-3 heterodimer were not affected by this
      compound. In the present study, we identify the molecular determinant of the RR
      mediated TASK-3 inhibition. Mutation of the negatively charged Glu 70 of TASK-3
      to Arg (E70R) or Cys (E70C) abolished the inhibitory action of RR. When two TASK
      3 coding sequences were concatenated, and the entire homodimer was expressed as a
      single polypeptide chain, the resulting tandem channel was also sensitive to RR.
      Mutation of Glu 70 in either the first (E70R) or the second (E465R) linked
      subunit prevented the action of the inhibitor. Together with the Hill coefficient
      of 1.0 for TASK-3 inhibition, these data indicate that simultaneous binding of
      one polycationic RR molecule to Glu 70 of both subunits is required for the
      inhibitory action. The pivotal role of this residue in the inhibitory mechanism
      of RR is confirmed by the gained RR sensitivity of the mutant TASK-1 in which Lys
      70 was changed to Glu. Our results indicate that RR inhibits TASK-3 by tethering
      its two subunits and identify amino acid 70 as a possible target for designing
      selective inhibitors against the different TASK channels.

PMID- 12606774
TI  - Cocaine affinity decreased by mutations of aromatic residue phenylalanine 105 in
      the transmembrane domain 2 of dopamine transporter.
AB  - Dopamine transporter (DAT) is a major target of cocaine, one of the most abused
      drugs. Major efforts have been focused on defining residues in DAT involved in
      cocaine binding. We have isolated the Drosophila melanogaster DAT (dDAT) cDNA,
      which is 10-fold less sensitive to cocaine than the mammalian DATs. Replacing
      transmembrane domain 2 (TM2) of mouse DAT (mDAT) with dDAT sequence reduced
      cocaine sensitivity. The reciprocal construct exhibited increased cocaine
      sensitivity. Switching residue 105 in TM2, a phenylalanine conserved in all
      mammalian DATs, to methionine, the corresponding residue in dDAT, resulted in a
      functional transporter with cocaine sensitivity 4-fold lower. Replacing F105 with
      alanine, leucine, isoleucine, serine, threonine, asparagine, or glutamine
      resulted in transporters with low transport activity. In contrast, changing F105
      to the other aromatic residues tyrosine or tryptophan retained more than 75%
      transport activity and high cocaine sensitivity. Most significantly, the
      reciprocal construct, switching the methionine in dDAT at the corresponding
      residue to phenylalanine, increased cocaine sensitivity 3-fold. Finally, the mDAT
      mutant with a cysteine at this position had normal transport activity but
      exhibited cocaine sensitivity that was 15-fold lower. These results suggest that
      F105 in mDAT contributes to high-affinity cocaine binding. The functional cocaine
      insensitive mutants provide tools for the study of the mechanism of cocaine
      addiction.

PMID- 12606775
TI  - Different ability of clenbuterol and salbutamol to block sodium channels predicts
      their therapeutic use in muscle excitability disorders.
AB  - Activation of muscle beta(2)-adrenergic receptors successfully counteracted
      sarcolemma inexcitability in patients suffering from hyperkalemic periodic
      paralysis (HPP), a hereditary disease caused by mutations in the gene encoding
      the skeletal muscle sodium channel. Looking for potential modulation of these
      channels by beta(2)-adrenergic pathway using patch-clamp technique, we found that
      clenbuterol blocked sodium currents (I(Na)) in rat skeletal muscle fibers and in
      tsA201 cells transfected with the human channel isoform, whereas salbutamol did
      not. The effects of clenbuterol were independent of beta-adrenoceptor
      stimulation. Instead, clenbuterol structure and physicochemical characteristics
      as well as I(Na) blocking properties resembled those of local anesthetics,
      suggesting direct binding to the channels. Similar experiments with the
      chemically similar beta-antagonists propranolol and nadolol, suggested the
      presence of two hydroxyl groups on the aromatic moiety of the drugs as a
      molecular requisite for impeding sodium channel block. Importantly, clenbuterol
      use-dependently inhibited action potential firing in rat skeletal muscle fibers,
      owing to beta-adrenoceptor-independent I(Na) block. From a clinical point of
      view, our study defines the rationale for the safe use of salbutamol in HPP
      patients, whereas clenbuterol may be more indicated in patients suffering from
      myotonic syndromes, a condition characterized by sarcolemmal overexcitability,
      because use-dependent I(Na) block can inhibit abnormal runs of action potentials.

PMID- 12606777
TI  - Increased antiviral activity of 1-O-hexadecyloxypropyl-[2-(14)C]cidofovir in MRC
      5 human lung fibroblasts is explained by unique cellular uptake and metabolism.
AB  - Recently, there has been renewed interest in finding orally active drugs against
      smallpox. Cidofovir (CDV) given by parenteral injection has been shown to protect
      against lethal poxvirus infection. We have been interested in the synthesis and
      evaluation of orally active derivatives of CDV. Previous studies showed that the
      CDV and cyclic cidofovir (cCDV) analogs 1-O-hexa-decyloxypropyl-CDV (HDP-CDV) and
      1-O-hexadecyloxypropyl-cCDV (HDP-cCDV), show >100-fold increases in antiviral
      activity versus the unmodified nucleosides against cells infected with
      orthopoxviruses, cowpox, and vaccinia virus. In contrast to CDV, HDP-CDV is
      orally bioavailable and has been reported to be orally active in lethal cowpox
      virus infection in mice. To assess the metabolic basis for the increased
      antiviral activity of HDP-CDV in vitro, we studied the cellular uptake and
      anabolic metabolism of (14)C-labeled CDV, cCDV, and their alkoxyalkanol esters
      HDP-CDV and HDP-cCDV. HDP-CDV and HDP-cCDV were taken up rapidly by MRC-5 human
      lung fibroblasts in vitro, but uptake of CDV and cCDV was much slower. Analysis
      of cellular metabolites showed that levels of cidofovir diphosphate (CDV-DP), the
      active antiviral compound, were >100 times greater with HDP-CDV than levels
      observed with CDV. When cells were exposed to HDP-CDV, the intracellular half
      life of CDV-DP was 10 days versus 2.7 days reported when cells are exposed to
      CDV. HDP-CDV seems to circumvent poor cellular uptake by rapid association with
      cellular membrane phospholipids, whereas CDV uptake proceeds via the slow process
      of fluid endocytosis.

PMID- 12606776
TI  - Selective inhibitors of cyclooxygenase-2 delay the activation of nuclear factor
      kappa B and attenuate the expression of inflammatory genes in murine macrophages
      treated with lipopolysaccharide.
AB  - The effect of rofecoxib, a selective cyclooxygenase-2 inhibitor, on inflammatory
      signaling has been investigated in elicited murine peritoneal macrophages.
      Macrophages treated with 10 microM rofecoxib exhibited an important inhibition in
      the early activation of nuclear factor kappa B (NF-kappa B) and the mitogen
      activated protein kinase p38, the extracellular-regulated kinase p44, and the c
      Jun N-terminal kinase. Moreover, this drug decreased the protein levels of nitric
      oxide synthase-2 and cyclooxygenase-2 in lipopolysaccharide (LPS)-treated
      macrophages. Rofecoxib delayed and attenuated NF-kappa B activation, which
      impaired significantly the expression of kappa B-dependent genes. This drug and
      related coxibs did not affect cell viability and protected against LPS-induced
      apoptosis through the impairment of the inflammatory response. These data show an
      additional anti-inflammatory mechanism of selective cyclooxygenase-2 inhibitors
      through the attenuation of macrophage activation.

PMID- 12606778
TI  - Pharmacological interference with dimerization of human neuronal nitric-oxide
      synthase expressed in adenovirus-infected DLD-1 cells.
AB  - A recombinant adenovirus containing the cDNA of human neuronal nitric-oxide
      synthase (nNOS) was constructed to characterize the interaction of nNOS with N
      [(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazole-1-yl)pyrimidin-4-yl]-4
      (methoxycarbonyl)-piperazine-2-acetamide (BBS-1), a potent inhibitor of inducible
      NOS dimerization [Proc Natl Acad Sci USA 97:1506-1511, 2000]. BBS-1 inhibited de
      novo expression of nNOS activity in virus-infected cells at a half-maximal
      concentration (IC(50)) of 40 +/- 10 nM in a reversible manner. Low-temperature
      gel electrophoresis showed that BBS-1 attenuated the formation of SDS-resistant
      nNOS dimers with an IC(50) of 22 +/- 5.2 nM. Enzyme inhibition progressively
      decreased with increasing time of addition after infection. BBS-1 did not
      significantly inhibit dimeric nNOS activity (IC(50) > 1 mM). Long-term incubation
      with BBS-1 of human embryonic kidney cells stably transfected with nNOS or
      endothelial NOS revealed a slow time- and concentration-dependent decrease of NOS
      activity with half-lives of 30 and 43 h and IC(50) values of 210 +/- 30 nM and 12
      +/- 0.5 microM, respectively. These results establish that BBS-1 interferes with
      the assembly of active nNOS dimers during protein expression. Slow inactivation
      of constitutively expressed NOS in intact cells may reflect protein degradation
      and interference of BBS-1 with the de novo synthesis of functionally active NOS
      dimers. As time-dependent inhibitors of NOS dimerization, BBS-1 and related
      compounds provide a promising strategy to develop a new class of selective and
      clinically useful NOS inhibitors.

PMID- 12606779
TI  - Cyclic AMP inhibition of tumor necrosis factor alpha production induced by
      amyloidogenic C-terminal peptide of Alzheimer's amyloid precursor protein in
      macrophages: involvement of multiple intracellular pathways and cyclic AMP
      response element binding protein.
AB  - In the present study, we focused on the molecular events involved in tumor
      necrosis factor-alpha (TNF-alpha) production in response to the amyloidogenic 105
      amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a
      candidate alternative toxic element in Alzheimer's disease pathology, and the
      mechanisms by which cyclic AMP regulates the relating inflammatory signal
      cascades. CT105 at nanomolar concentrations strongly activated multiple signaling
      pathways involving tyrosine kinase-dependent extracellular signal-regulated
      kinase and p38 mitogen-activated protein kinases. Moreover, phosphatidylinositol
      3-kinase/Akt signal was required for excess TNF-alpha production in human
      macrophages derived from THP-1 cells. Interferon-gamma significantly potentiated
      the induction of the CT105-mediated signal cascade. These multiple signaling
      pathways in turn converged, at least in part, at the nuclear transcription factor
      known as cAMP response element binding protein (CREB), which acts on the TNF
      alpha gene promoter through the cAMP response element. The cell-permeable cAMP
      analog dibutyryl cAMP partially and almost simultaneously suppressed all of these
      CT105-induced signaling pathways through excessive CREB phosphorylation, which
      led to decreased CREB DNA binding activity and reduced TNF-alpha expression.
      Furthermore, dibutyryl cAMP decreased the interaction of the p65 nuclear factor
      kappa B with CREB binding protein, thus further inhibiting CT105-mediated TNF
      alpha expression. Collectively, the detailed molecular mechanisms of
      amyloidogenic CT-induced TNF-alpha production as negatively regulated by cAMP may
      advance the possibility of targeted treatment in Alzheimer's disease.

PMID- 12606780
TI  - Selective ligands and cellular effectors of a G protein-coupled endothelial
      cannabinoid receptor.
AB  - The cannabinoid analog abnormal cannabidiol [abn-cbd; (-)-4-(3-3,4-trans-p
      menthadien-[1,8]-yl)-olivetol] does not bind to CB(1) or CB(2) receptors, yet it
      acts as a full agonist in relaxing rat isolated mesenteric artery segments.
      Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive,
      and is inhibited by the BK(Ca) channel inhibitor charybdotoxin, but not by the
      nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester or by the
      vanilloid VR1 receptor antagonist capsazepine. The cannabidiol analog O-1918 does
      not bind to CB(1) or CB(2) receptors and does not cause vasorelaxation at
      concentrations up to 30 microM, but it does cause concentration-dependent (1-30
      microM) inhibition of the vasorelaxant effects of abn-cbd and anandamide. In
      anesthetized mice, O-1918 dose-dependently inhibits the hypotensive effect of abn
      cbd but not the hypotensive effect of the CB(1) receptor agonist (-)-11-OH
      Delta(9)-tetrahydrocannabinol dimethylheptyl. In human umbilical vein endothelial
      cells, abn-cbd induces phosphorylation of p42/44 mitogen-activated protein kinase
      and protein kinase B/Akt, which is inhibited by O-1918, by pertussis toxin or by
      phosphatidylinositol 3 (PI3) kinase inhibitors. These findings indicate that abn
      cbd is a selective agonist and that O-1918 is a selective, silent antagonist of
      an endothelial "anandamide receptor", which is distinct from CB(1) or CB(2)
      receptors and is coupled through G(i)/G(o) to the PI3 kinase/Akt signaling
      pathway.

PMID- 12606781
TI  - Poly(ADP-ribose) polymerase activation and changes in Bax protein expression
      associated with extracellular ATP-mediated apoptosis in human embryonic kidney
      293-P2X7 cells.
AB  - Extracellular ATP is a potent signaling factor that modulates a variety of
      cellular functions through the activation of P2 purinergic receptors.
      Extracellular ATP at higher concentrations exerts cytostatic as well as cytotoxic
      effects in a variety of cell systems, the mechanism of which is not fully
      understood. In this study, we used cultured human embryonic kidney (HEK) cells
      stably transfected with human P2X(7) receptors (HEK-P2X(7)) to investigate the
      mechanism of ATP-induced cell death. The cytotoxic effects of ATP in HEK-P2X(7)
      cells were dose- and time-dependent, whereas ADP, AMP, and UTP had no effect. ATP
      treatment induced a significant increase in apoptotic HEK-P2X(7) cells as
      ascertained by the terminal deoxynucleotidyl transferase dUTP nick-end labeling
      technique and flow cytometry. An ATP-induced decrease in the pro-apoptotic bax
      gene expression was detected by apoptosis-related cDNA microarray analysis, which
      correlated with a decrease of Bax protein expression. Western blot analysis
      revealed that ATP treatment resulted in the processing of pro-caspase 3 to its
      active form and cleavage of the nuclear enzyme, poly(ADP-ribose) polymerase
      (PARP). Both ATP-induced molecular alterations in HEK-P2X(7) cells (i.e.,
      decrease of Bax expression and increase of PARP cleavage) were blocked by the
      purinergic P2X(7) receptor antagonist oxidized ATP. In conclusion, we
      demonstrated the importance of the P2X(7) receptor in ATP induced cell death of
      HEK-P2X(7) cells, which seems to be independent of bax expression; however, the
      activation of caspases is required.

PMID- 12606782
TI  - Tumor necrosis factor-alpha-induced activation of RhoA in airway smooth muscle
      cells: role in the Ca2+ sensitization of myosin light chain20 phosphorylation.
AB  - Tumor necrosis factor-alpha (TNF), an inflammatory cytokine, has a potentially
      important role in the pathogenesis of bronchial asthma and may contribute to
      airway hyper-responsiveness. Recent evidence has revealed that TNF can increase
      the Ca(2+) sensitivity of agonist-stimulated myosin light chain(20) (MLC(20))
      phosphorylation and contractility in guinea pig airway smooth muscle (ASM). In
      the present study, the potential intracellular pathways responsible for this TNF
      induced Ca(2+) sensitization were investigated. In permeabilized cultured guinea
      pig ASM cells, recombinant human TNF stimulated an increase in Ca(2+)-activated
      MLC(20) phosphorylation under Ca(2+) "clamp" conditions. This increased MLC(20)
      phosphorylation was inhibited by preincubation with the Rho-kinase inhibitor
      Y27632. TNF also increased the proportion of GTP-bound RhoA, as measured using
      rhotekin Rho-binding domain, in a time course compatible with a role in the TNF
      induced Ca(2+) sensitization. In cultured human ASM cells, recombinant human TNF
      also activated RhoA with a similar time course. In addition, TNF stimulated
      phosphorylation of the regulatory subunit of the myosin phosphatase, which was
      inhibited by Y27632. Although human ASM cells expressed both receptor subtypes,
      TNF-R1 and TNF-R2, the activation of RhoA was predominantly via stimulation of
      the TNF-R1, although RhoA did not immunoprecipitate with the TNF-R1. In
      conclusion, the TNF-induced increase in the Ca(2+) sensitivity of MLC(20)
      phosphorylation is through stimulation of the TNF-R1 receptor and via a RhoA/Rho
      kinase pathway leading to inhibition of the myosin light chain phosphatase. This
      intracellular mechanism may contribute to TNF-induced airway hyper
      responsiveness.

PMID- 12606783
TI  - Dehydroepiandrosterone affects the expression of multiple genes in rat liver
      including 11 beta-hydroxysteroid dehydrogenase type 1: a cDNA array analysis.
AB  - Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid precursor to the gonadal
      steroids. In humans, circulating levels of DHEA, as its sulfated conjugate, are
      high at puberty and throughout early adulthood but decline with age. Dietary
      supplementation to maintain high levels of DHEA purportedly has beneficial
      effects on cognitive memory, the immune system, and fat and carbohydrate
      metabolism. In rodents, DHEA is a peroxisome proliferator that induces genes for
      the classical peroxisomal and microsomal enzymes associated with this response.
      These effects are mediated through activation of peroxisome proliferator
      activated receptor alpha (PPAR alpha). However, DHEA can affect the expression of
      genes independently of PPAR alpha, including the gene for the major inducible
      drug and xenobiotic metabolizing enzyme, cytochrome P450 3A23. To elucidate the
      biochemistry associated with DHEA treatment, we employed a cDNA gene expression
      array using liver RNA from rats treated with DHEA or the classic peroxisome
      proliferator nafenopin. Principal components analysis identified 30 to 35 genes
      whose expression was affected by DHEA and/or nafenopin. Some were genes
      previously identified as PPAR-responsive genes. Changes in expression of several
      affected genes were verified by quantitative reverse transcriptase-polymerase
      chain reaction. These included aquaporin 3, which was induced by DHEA and to a
      lesser extent nafenopin, nuclear tyrosine phosphatase, which was induced by both
      agents, and 11 beta-hydroxysteroid dehydrogenase 1, which was decreased by
      treatment with DHEA in a dose-dependent fashion. Regulation of 11 beta
      hydroxysteroid dehydrogenase 1 expression is important since the enzyme is
      believed to amplify local glucocorticoid signaling, and its repression may cause
      some of the metabolic effects associated with DHEA.

PMID- 12606784
TI  - Hypersensitivity reactions to carbamazepine: characterization of the specificity,
      phenotype, and cytokine profile of drug-specific T cell clones.
AB  - Administration of carbamazepine (CBZ) causes hypersensitivity reactions
      clinically characterized by skin involvement, eosinophilia, and systemic
      symptoms. These reactions have an immune etiology; however, the role of T cells
      is not well defined. The aim of this study was to characterize the specificity,
      phenotype, and cytokine profile of CBZ-specific T cells derived from
      hypersensitive individuals. Proliferation of blood lymphocytes was measured using
      the lymphocyte transformation test. CBZ-specific T cell clones were generated by
      serial dilution and characterized in terms of their cluster of differentiation
      and T cell receptor V beta phenotype. Proliferation, cytotoxicity, and cytokine
      secretion were measured by [(3)H]thymidine incorporation, (51)Cr release, and
      enzyme-linked immunosorbent assay, respectively. HLA blocking antibodies were
      used to study the involvement of antigen-presenting cells. The specificity of the
      drug T cell receptor interaction was studied using CBZ metabolites and other
      structurally related compounds. Lymphocytes from hypersensitive patients
      (stimulation index: 32.1 +/- 24.2 [10 microg ml(-1)]) but not control patients
      (stimulation index: 1.2 +/- 0.4 [10 microg ml(-1)]) proliferated upon stimulation
      with CBZ. Of 44 CBZ-specific T cell clones generated, 10 were selected for
      further analysis. All 10 clones were either CD4+ or CD4+/CD8+, expressed the
      alpha beta T cell receptor, secreted IFN-gamma, and were cytotoxic. T-cell
      recognition of CBZ was dependent on the presence of HLA class II (DR/DQ)-matched
      antigen-presenting cells. The T cell receptor of certain clones could accommodate
      some CBZ metabolites, but no cross-reactivity was seen with other anticonvulsants
      or structural analogs. These studies characterize drug-specific T cells in CBZ
      hypersensitive patients that are phenotypically different from T cells involved
      in other serious cutaneous adverse drug reactions.

PMID- 12606785
TI  - Usefulness of liposomes loaded with cytostatic bile acid derivatives to
      circumvent chemotherapy resistance of enterohepatic tumors.
AB  - We have investigated the sensitivity of the cisplatin-resistant enterohepatic
      tumor cell lines LS174T/R (human colon adenocarcinoma), WIF-B9/R (rat hepatoma
      human fibroblast hybrid), and Hepa 1-6/R (mouse hepatoma) to free and liposome
      encapsulated cytostatic bile acid derivatives Bamet-R2 and bamet-UD2. Expression
      of resistance associated genes was measured by quantitative reverse transcription
      polymerase chain reaction or Western blotting. Drug uptake was determined by
      atomic absorption spectrophotometry. In resistant cells, overexpression of MRP1
      and MRP2 was accompanied by reduced accumulation of cisplatin. The expression of
      MDR1 and GST-P was only enhanced in LS 174T/R. A higher expression of p53 was
      seen in LS 174T/R and Hepa 1-6/R cell lines but not in WIF-B9/R cells. In wild
      type counterparts, uptake and cytostatic ability of Bamets were markedly higher
      (UD2 > R2) than that of cisplatin. Both effects were further enhanced by liposome
      formulation. Bamets were able to overcome cisplatin resistance in all cell lines.
      Cisplatin prolonged the survival time of nude mice in whose livers a Hepa 1-6
      tumor had been implanted, but failed to exert a beneficial effect when the tumor
      was Hepa 1-6/R. In both cases, tissue distribution of cisplatin was: kidney >>
      liver > tumor. Survival was markedly longer in animals receiving Bamet-UD2, even
      if the implanted tumor was resistant. The accumulation of Bamet-UD2 in tissues
      was: liver > tumor > kidney. Liposome formulation further enhanced the beneficial
      properties of Bamet-UD2. Thus, the amount of drug in the tumor was increased and
      that in liver and kidney was reduced (tumor > liver > kidney), and life span was
      prolonged. In conclusion, liposomal Bamet-UD2 may be a useful tool to circumvent
      resistance to chemotherapy, particularly in tumors of the enterohepatic circuit.

PMID- 12606786
TI  - Mechanism of corticotropin-releasing factor type I receptor regulation by
      nonpeptide antagonists.
AB  - Mechanisms of nonpeptide ligand action at family B G protein-coupled receptors
      are largely unexplored. Here, we evaluated corticotropin-releasing factor 1
      (CRF(1)) receptor regulation by nonpeptide antagonists. The antagonist mechanism
      was investigated at the G protein-coupled (RG) and uncoupled (R) states of the
      receptor in membranes from Ltk(-) cells expressing the cloned human CRF(1)
      receptor. R was detected with the antagonist (125)I-astressin with 30 microM
      guanosine 5'-O-(3-thiotriphosphate present, and RG detected using (125)I
      sauvagine. At the R state, nonpeptide antagonists antalarmin, NBI 27914, NBI
      35965, and DMP-696 only partially inhibited (125)I-astressin binding (22-32%
      maximal inhibition). NBI 35965 accelerated (125)I-astressin dissociation and only
      partially increased the IC(50) value of unlabeled sauvagine, CRF, and urocortin
      for displacing (125)I-astressin binding (by 4.0-7.1-fold). Reciprocal effects at
      the R state were demonstrated using [(3)H]NBI 35965: agonist peptides only
      partially inhibited binding (by 13-40%) and accelerated [(3)H]NBI 35965
      dissociation. These data are quantitatively consistent with nonpeptide antagonist
      and peptide ligand binding spatially distinct sites, with mutual, weak negative
      cooperativity (allosteric inhibition) between their binding. At the RG state the
      compounds near fully inhibited (125)I-sauvagine binding at low radioligand
      concentrations (79-94 pM). NBI 35965 did not completely inhibit (125)I-sauvagine
      binding at high radioligand concentrations (82 +/- 1%, 1.3-2.1 nM) and slowed
      dissociation of (125)I-sauvagine and (125)I-CRF. The antagonist effect at RG is
      consistent with either strong allosteric inhibition or competitive inhibition at
      one of the peptide agonist binding sites. These findings demonstrate a novel
      effect of R-G interaction on the inhibitory activity of nonpeptide antagonists:
      Although the compounds are weak inhibitors of peptide binding to the R state,
      they strongly inhibit peptide agonist binding to RG. Strong inhibition at RG
      explains the antagonist properties of the compounds.

PMID- 12606788
TI  - Magnetic X-ray absorption fine structure for Ni-Mn alloys.
AB  - Magnetic X-ray absorption fine-structure (XAFS) spectra have been measured for Ni
      Mn alloys. The magnetic XAFS in the near-edge region (X-ray absorption near-edge
      structure, XANES) and X-ray magnetic circular dichroism (XMCD) of the Mn and Ni K
      edge for Ni(1-x)Mn(x) (x = 0.25, 0.24 and 0.20) show that (i) the local magnetic
      structure around the Mn atom is quite different from that around the Ni atom, and
      (ii) the peak intensity in the magnetic XANES of the Mn K-edge depends on the
      magnetization of the sample in contrast to the Ni K-edge. The Mn K-edge magnetic
      EXAFS (extended XAFS) for Ni(0.76)Mn(0.24) is also measured. The second and
      fourth peaks in the Fourier transform are observed to be enhanced in comparison
      with the non-magnetic EXAFS, indicating that the second- and fourth-shell Ni
      atoms are replaced by Mn atoms due to heat treatment (atomic ordering). Semi
      relativistic theoretical calculation explains the observed magnetic EXAFS.

PMID- 12606787
TI  - Genotoxic profiling of MCF-7 breast cancer cell line elucidates gene expression
      modifications underlying toxicity of the anticancer drug 2-(4-amino-3
      methylphenyl)-5-fluorobenzothiazole.
AB  - A candidate antitumor agent, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F
      203), was empirically discovered through the National Cancer Institute's
      Anticancer Drug Screen from a unique growth inhibitory-response profile,
      indicating a novel mechanism of action. 5F-203 activates the CYP1 family of
      cytochrome P450, involving aryl hydrocarbon receptor translocation into the
      nucleus. To characterize more completely the pathways involved in 5F-203
      toxicity, cDNA microarrays were used to determine gene expression changes in MCF
      7, a 5F-203-sensitive breast cancer cell line, after treatment with 1 microM 5F
      203. The mRNA expression of CYP1A1 and CYP1B1 were both increased approximately
      20-fold after 24 h, but less after 6 h of treatment, confirming previous results.
      However, the most pronounced drug-induced change was in the PLAB gene, encoding
      one of the bone morphogenic proteins in the transforming growth factor-beta (TGF
      beta) superfamily. Other induced gene expressions included the apoptosis
      initiating receptor TNFRSF6 (CD95/FAS), the DNA-damage response genes CDKN1A
      (p21/Cip1), p53-induced gene-3, and DNA binding protein 2. In contrast, the
      transcription factor c-Myc showed reduced expression. Western blot analysis also
      showed induction of p53 protein expression in response to 5F-203 treatment. In
      contrast to the MCF-7 data, MDA-MB-435, a cancer cell line resistant to 5F-203,
      showed no change in expression of any of these genes or the p53 protein under the
      same conditions of 5F-203 treatment. These data are consistent with the idea that
      CYP1A1 and CYP1B1 activation leads to 5F-203 toxicity through DNA damage-induced
      apoptosis, as well as signaling through a variant member of the TGF-beta
      superfamily.

PMID- 12606789
TI  - Multiple-electron excitation in X-ray absorption: a screened model of the core
      hole-photoelectron potential.
AB  - The probability of secondary electron shake-off in X-ray absorption is calculated
      using a model form for the time- and energy-dependent core-hole-photoelectron
      potential, screened by the single plasmon pole dielectric function of the
      surrounding material. The resultant excitation probabilities are related to the
      energy-dependent intrinsic loss function in EXAFS data analysis and compared with
      experiment. Reasonable agreement is obtained close to the absorption edge
      although the calculation is less accurate at higher photon energies. The theory
      described allows the losses to be calculated with little computational effort,
      making the method suitable for routine EXAFS data analysis.

PMID- 12606790
TI  - Interferometer-controlled scanning transmission X-ray microscopes at the Advanced
      Light Source.
AB  - Two new soft X-ray scanning transmission microscopes located at the Advanced
      Light Source (ALS) have been designed, built and commissioned. Interferometer
      control implemented in both microscopes allows the precise measurement of the
      transverse position of the zone plate relative to the sample. Long-term
      positional stability and compensation for transverse displacement during
      translations of the zone plate have been achieved. The interferometer also
      provides low-distortion orthogonal x, y imaging. Two different control systems
      have been developed: a digital control system using standard VXI components at
      beamline 7.0, and a custom feedback system based on PC AT boards at beamline
      5.3.2. Both microscopes are diffraction limited with the resolution set by the
      quality of the zone plates. Periodic features with 30 nm half period can be
      resolved with a zone plate that has a 40 nm outermost zone width. One microscope
      is operating at an undulator beamline (7.0), while the other is operating at a
      novel dedicated bending-magnet beamline (5.3.2), which is designed specifically
      to illuminate the microscope. The undulator beamline provides count rates of the
      order of tens of MHz at high-energy resolution with photon energies of up to
      about 1000 eV. Although the brightness of a bending-magnet source is about four
      orders of magnitude smaller than that of an undulator source, photon statistics
      limited operation with intensities in excess of 3 MHz has been achieved at high
      energy resolution and high spatial resolution. The design and performance of
      these microscopes are described.

PMID- 12606791
TI  - Scanning X-ray microdiffraction with submicrometer white beam for strain/stress
      and orientation mapping in thin films.
AB  - Scanning X-ray microdiffraction (microSXRD) combines the use of high-brilliance
      synchrotron sources with the latest achromatic X-ray focusing optics and fast
      large-area two-dimensional-detector technology. Using white beams or a
      combination of white and monochromatic beams, this technique allows for the
      orientation and strain/stress mapping of polycrystalline thin films with
      submicrometer spatial resolution. The technique is described in detail as applied
      to the study of thin aluminium and copper blanket films and lines following
      electromigration testing and/or thermal cycling experiments. It is shown that
      there are significant orientation and strain/stress variations between grains and
      inside individual grains. A polycrystalline film when investigated at the
      granular (micrometer) level shows a highly mechanically inhomogeneous medium that
      allows insight into its mesoscopic properties. If the microSXRD data are averaged
      over a macroscopic range, results show good agreement with direct macroscopic
      texture and stress measurements.

PMID- 12606792
TI  - Absorption and extinction correction in quantitative DAFS analysis.
AB  - An approach to X-ray attenuation correction for diffraction anomalous fine
      structure (DAFS) measurements is presented, taking into account energy-dependent
      secondary extinction effects. A numerical model based on the kinematical theory
      of diffraction is presented. This model is exemplified by DAFS measurements of
      the Zr 0002 reflection intensities for energies in the vicinity of the Zr K
      absorption edge of a Co/Zr multilayer exhibiting strong fibre texture. X-ray
      absorption fine-structure (XAFS) measurements proved to be a necessary auxiliary
      for DAFS amplitude correction.

PMID- 12606793
TI  - Formation and relaxation of coherency strain in the nickel-base superalloy SC16.
AB  - An in situ study of the kinetics of relaxation of the gamma-gamma' lattice
      mismatch in the single-crystal Ni-base superalloy SC16 was carried out by means
      of high-energy synchrotron radiation diffraction. The high resolution achievable
      was exploited to measure the time variation of the gamma and gamma' lattice
      parameters during isothermal ageing at several temperatures, starting from the
      gamma' solvus point. On cooling from the solvus temperature (1523 K) the gamma'
      precipitate phase nucleates and grows following concurrent mechanisms. The
      variations of the gamma and gamma' peak position and integrated intensity could
      be followed by means of fundamental and superstructure reflections. At each
      temperature T < 1473 K the integrated intensity follows an Avrami time law. The
      gamma' Volume fraction increases as a function of time at each temperature. It
      increases with cooling, until saturation occurs at temperatures as low as 1075 K.
      The lattice mismatch follows an exponential time decay, while having larger
      values at high temperatures. The pArticles are born fully coherent, and the
      coherency strains the set-up. Over time, long-term ageing shows a stabilization
      of the misfit value, while the precipitates are supposed to lose their coherency
      to the matrix (within 3-4 h) and the strains relax.

PMID- 12606794
TI  - Dynamics of phase transformations and microstructure evolution in carbon
      manganese steel arc welds using time-resolved synchrotron X-ray diffraction.
AB  - Phase transformations that occur in both the heat-affected zone (HAZ) and the
      fusion zone (FZ) of a carbon-manganese steel spot weld have been investigated
      using time-resolved X-ray diffraction (TRXRD) with time resolutions down to 50
      ms. It is found that in both zones the gamma(f.c.c.) --> alpha(b.c.c.)
      transformation on cooling is twice as fast as the forward transformation of alpha
      --> gamma on heating. Profile analysis of the major Bragg reflections recorded in
      the TRXRD patterns reveals similarities and differences in the microstructural
      evolution with time in the HAZ and in the FZ. The latter undergoes melting and
      solidification in addition to solid-state transformations. With increasing
      temperature, the (110) d-spacing of the alpha phase prior to and during the alpha
      --> gamma transformation and the (111) d-spacing of the gamma phase just after
      the same transformation exhibit a decrease. The observed (and unusual) lattice
      contraction with temperature rise may be attributed to chemical effects, such as
      carbide precipitation in the alpha matrix, and/or mechanical effects due to
      stress relief. In the FZ, the gamma-Fe that forms has a preferential (200)
      texture on solidification of the liquid, whereas, on cooling in the HAZ, the
      gamma-Fe retains largely a (111) texture that is induced in the alpha --> gamma
      transformation on heating. On cooling in the HAZ, the width of the gamma(111)
      reflection increases initially, which is indicative of microstrain developing in
      the f.c.c. lattice, but decreases as expected, with a reduction of thermal
      disorder, on further cooling until the completion of the gamma --> alpha
      transformation. In the FZ, however, the microstrain in the gamma phase increases
      steadily on solidification and more rapidly for the duration of the gamma -->
      alpha transformation on further cooling. The final microstructure of the FZ is
      likely to consist of a single alpha phase dispersed in two morphological
      entities, whereas in the HAZ the alpha phase persists in one morphological entity
      in the final microstructure.

PMID- 12606795
TI  - Diamond planar refractive lenses for third- and fourth-generation X-ray sources.
AB  - The fabrication and testing of planar refractive hard X-ray lenses made from bulk
      CVD diamond substrates is reported. The lens structures were generated by
      electron-beam lithography and transferred by reactive-ion etching into the
      diamond. Various lens designs were fabricated and tested at 12.4 and 17.5 keV
      photon energy. Efficiencies of up to 71% and gains of up to 26 were achieved. A
      line focus of 3.2 micro m (FWHM) was measured. These lenses should be able to
      withstand the extreme flux densities expected at the planned fourth-generation X
      ray sources.

PMID- 12606796
TI  - Performance of phase plates on the XMaS beamline at the ESRF.
AB  - Two phase plates, a 0.78 mm-thick natural diamond and a 0.3 mm-thick synthetic
      diamond, were used to convert linearly polarized X-rays into a circularly
      polarized beam, to cover an energy range of 3-9 keV. The performance of these
      plates followed theoretical predictions as indicated by polarization analyses and
      X-ray magnetic circular dichroism measurements. The use of the device is
      illustrated by resonant magnetic reflectivity measurements on UAs/Co multilayers.

PMID- 12606797
TI  - Time-resolved X-ray powder diffraction on a three-way catalyst at the GILDA
      beamline.
AB  - Time-resolved X-ray diffraction experiments carried out at the beamline BM08
      GILDA of ESRF allowed a study of the structural modifications taking place in a
      Pt/ceria-zirconia catalyst while the CO oxidation reaction was in progress. The
      capillary tube in which the sample is stored acts effectively as a chemical
      microreactor that ensures homogeneity of the sample treatments and minimization
      of diffusion effects. During the flowing of the reactant CO/He mixture, the
      investigated catalyst undergoes a fast Ce(IV)-Ce(III) partial reduction that
      involves the release of one O atom for every two reduced Ce cations. Because
      Ce(III) has a larger ionic radius than Ce(IV), the structural modification
      produces an increase of the lattice constant of the ceria-zirconia mixed oxide,
      and this increase is monitored by the translating imaging-plate device
      implemented at GILDA. The CO(2) resulting from the oxidation of the fluxed CO is
      monitored by a quadrupole mass spectrometer during the recording of the time
      resolved X-ray diffraction pattern. The chemical and structural information was
      combined to show that the CO(2) yield is nearly constant until the catalytic
      system can provide oxygen for the reaction, while the structural rearrangement of
      the catalyst is delayed with respect to the switching on of the CO/He flux. After
      this induction time, during which CO(2) is produced with no structural
      modification of the catalyst, a fast increase of the lattice constant takes
      place.

PMID- 12606798
TI  - Software for automatic calibration of synchrotron powder diffractometers.
AB  - An automatic procedure to calibrate angular-dispersive monochromatic diffraction
      instruments has been developed at the Daresbury Synchrotron Radiation Source. The
      procedure uses a macro Language to control the powder diffraction instruments to
      locate Bragg reflections and perform peak-centre refinement from a standard
      reference material. The information obtained is used to refine the wavelength of
      the radiation used and the angular offset of the detector arm. The concept and
      implementation of the new software are described with applications to demonstrate
      its viability. The results of a reliability and accuracy study are also
      presented.

PMID- 12606799
TI  - Miniature ionization chamber detector developed for X-ray microprobe
      measurements.
AB  - A windowless small ionization chamber detector has been developed for monitoring
      the intensity of the microbeam at the ID18F microprobe end-station of the
      European Synchrotron Radiation Facility. The small dimensions of the ionization
      chamber (10 mm along the beam direction and 5 mm perpendicular to it) make it
      possible to place it very close to the sample. A pinhole of diameter 50 microm
      was used for defining the entrance window of the ionization chamber; thus the
      small counter can be used as an order-selecting aperture while measuring
      simultaneously the intensity after the aperture. In the present work the
      technical characteristics, such as the current-voltage curve, stability and
      linearity, of the small monitor have been tested.

PMID- 12606800
TI  - A comment on 'A new ray-tracing program RIGTRACE for X-ray optical systems' [J.
      Synchrotron Rad. (2001), 8, 1047-1050].
AB  - Some points concerning the characteristics of the X-ray simulation code SHADOW
      [Welnak et al. (1994). Nucl. Instrum. Methods, A347, 344-347] are clarified which
      are not correctly mentioned by Yamada et al. [J. Synchrotron Rad. (2001), 8, 1047
      1050]. It is shown that, contrary to the Authors' statement, some functionality
      of their new program is not original. In particular, we show that SHADOW can deal
      correctly with crystal monochromators.

PMID- 12606801
TI  - SAXSANA: an interactive program for the analysis and monitoring of static and
      time-resolved small-angle X-ray solution scattering measurements.
AB  - An interactive analytical program, SAXSANA, for small-angle X-ray scattering
      measurements of solutions is described. The program processes scattered data
      without disciplined knowledge of small-angle scattering. SAXSANA also assists in
      finding the best experimental conditions, thus avoiding blind runs of
      experiments. SAXSANA consists of the following procedures: (i) determination of
      the centre of scattered X-rays and moment transfer Q (Q = 4pisintheta/lambda,
      where 2theta is the scattering angle and lambda is the wavelength) for each
      measured channel; (ii) conversion of the data format to the format of Q versus
      scattered intensities J(Q); (iii) truncation of unnecessary data and smoothing of
      scattering curves by cubic-spline function; (iv) correction of the absorption
      effect and subtraction of the scattered intensity of the buffer (solvent)
      solution from that of the sample solution; (v) creation of a data file for a
      three-dimensional representation of time-resolved scattering curves; (vi)
      determination of radii of gyration by Guinier plots; (vii) determination of
      persistent lengths by Kratky plots; (viii) extrapolation of the small-angle part
      by Guinier plots; (ix) extrapolation of the wide-angle part by Porod's &
      Luzzati's laws for the Hankel transformation in order to obtain the distance
      distribution function p(r); (x) calculation of p(r) and computation of the
      invariant, the chord length, the Volume, the spherical radius, the maximum
      dimension D(max) and the radius of gyration (Rg). SAXSANA also serves as an on
      site monitor for the validity of an experimental result during the measurements.

PMID- 12606804
TI  - Comments on Synchrotron fibre diffraction identifies and locates foetal
      collagenous breast tIssue associated with breast carcinoma by V. J. James (2002).
      J. Synchrotron Rad. 9, 71-76.

PMID- 12606805
TI  - Comments on Synchrotron fibre diffraction identifies and locates foetal
      collagenous breast tIssue associated with breast carcinoma by V. J. James (2002).
      J. Synchrotron Rad. 9, 71-76.

PMID- 12606811
TI  - Extracellular signals and pancreatic beta-cell development: a brief review.
AB  - Cell lineage development is a finely tuned process of proliferation and
      differentiation, survival and apoptosis, that is regulated by numerous
      extracellular signals. Here we review some of the extracellular signals-
      including insoluble cell-cell and extracellular matrix-cell interactions, as well
      as soluble factors--that appear critical for pancreatic beta-cell development.
      Knowledge of how these signals control the development of pancreatic endocrine
      stem/precursor cells into fully functional insulin-secreting beta cells is a
      platform for the restoration of beta-cell function and the cure therapy of type 1
      diabetes.

PMID- 12606812
TI  - The role of insulin-like growth factor 2 and its receptors in human tumors.
AB  - Insulin-like growth factor 2 (IGF-2) is important for normal development and
      growth of an organism. In humans it is encoded by 11p15.5 paternally expressed
      imprinted gene. It binds at least two different types of receptors: IGF type 1
      (IGF-1R) and IGF-2/mannose 6-phosphate receptors (IGF-2R/M6P). Ligand binding to
      IGF-1R provokes mitogenic and anti-apoptotic effects. IGF-2R/M6P has tumor
      suppressor function; it mediates IGF-2 degradation. When the IGF-2 gene/protein
      is overexpressed, mostly as a consequence of loss of heterozygosity resulting in
      paternal allele duplication (LOH) or by loss of imprinting (LOI), it is involved
      in the development and progression of many tumors and overgrowth syndromes by
      autocrine or paracrine mechanisms.

PMID- 12606813
TI  - Anx7 is required for nutritional control of gene expression in mouse pancreatic
      islets of Langerhans.
AB  - BACKGROUND: Gene expression in islets of Langerhans is profoundly sensitive to
      glucose and other nutrients. Islets of Langerhans in the Anx7(+/-) knockout mouse
      exhibit a profound reduction in ITPR3 protein expression, defective intracellular
      calcium signaling, and defective insulin secretion. Additional data presented
      here also show that mRNA for ITPR3 is virtually undetectable in isolated Anx7(+/
      ) islets. IP3Receptor type 3 (ITPR3) expression in islets of Langerhans is
      closely regulated by secretory stimuli, and it has been suggested that the level
      of the ITPR3 expression controls the ability of the islets to respond to
      nutritional signals. We report that although control islets respond to glucose in
      vitro by a transient increment in ITPR3 mRNA, the islets from the Anx7(+/-) mouse
      remain low. We therefore hypothesized that the Anx7/IP3 Receptor(3)/Ca(2+)
      signaling pathway plays a role in beta cell responses to glucose, and that in the
      absence of the Anx7/ITPR3 signaling system, the islets would be unable to
      discriminate between fed or fasted states in vivo. MATERIALS AND METHODS: To test
      this hypothesis, we subjected Anx7(+/-) and control mice to either food and water
      ad libidum or to an overnight fast with access to water only. We then isolated
      the respective islets and compared nutrient-dependent changes in global gene
      expression under the four conditions using genome-based microarray technology.
      RESULTS: Anx7 protein expression in these islets is only about 50% of control
      levels in normal littermate controls, and IPTR3 message and protein are virtually
      zero. cDNA microarray analyses show that in control animals gene expression is
      significantly affected by the fasting state. Many of the affected genes have
      historical relevance to development and differentiation of islets. These include
      preproglucagon, APOJ, cadherin2, phosphoglucoisomerase, oncostatin M, PAX6, HGF,
      and cytokeratin 18. However, there are also many other nutritionally sensitive
      genes in control islets that are principally associated with cell division and
      DNA repair. The latter genes have not specifically been associated with islet
      physiology in the past. By contrast, Anx7(+/-) mouse islets exhibit a greatly
      reduced ability to discriminate genomically between fed and fasted states for all
      classes of identified genes. Many of the validated genes are specific to islets
      in comparison to liver tissue examined. Real-time quantitative RT-PCR analysis of
      islets from Anx7 heterozygous mice and littermate controls revealed remarkable
      down-regulation in PTEN, Glut-2, PDX-1, IGF-1, and Neuro D1 expression, but not
      in liver. CONCLUSIONS: We conclude that reduced gene dosage in the Anx7(+/-)
      islet, with concomitant loss of ITPR3 expression and consequent defects in Ca(2+)
      signaling, may substantially contribute to the mechanism of the loss of genomic
      discrimination, in vivo, between the fed and fasted states. We believe that the
      requirement for complete Anx7 gene dosage and IPTR3 expression in islets of
      Langerhans will prove to be of fundamental importance for understanding the
      mechanism of nutritional sensing in health and disease.

PMID- 12606814
TI  - Computer-based design of an HLA-haplotype and HIV-clade independent cytotoxic T
      lymphocyte assay for monitoring HIV-specific immunity.
AB  - BACKGROUND: Human immunodeficiency virus (HIV)- specific CD8-positive cytotoxic T
      lymphocytes (CTL) play a key role in controlling HIV infection. Monitoring CTL
      response could be clinically relevant during structured therapy interruption
      (STI), HIV exposure, and vaccine trials. However, HLA patients' restriction and
      HIV variability limited the development of a CTL assay with broad specificity.
      MATERIALS AND METHODS: We designed an HLA-class I/HIV-1 clade independent assay
      for assessing HIV- specific CTL by using a computer-assisted selection ofthe CTL
      epitopes. Twenty-eight 15-mers were selected by peptide-binding motifs analysis
      using different databases (HIV-Immunology Database, SYFPEITHI, BIMAS). Altogether
      they putatively bind to more than 90% of HLA haplotypes in different populations,
      with an overall HIV-1 variability below 9%. The peptide pool was used as an
      antigen in an intracellular cytokine staining (ICS) assay for quantifying HIV
      specific CTL response. RESULTS: The test can be performed using both fresh and
      cryopreserved peripheral blood mononuclear cells (PBMC), whereas GAG protein as
      antigen works only on fresh PBMC. A significantly higher CTL response with
      respect to HIV-negative controls was detected in all HIV-1 infected subjects of
      two groups of patients with different ethnicities (Caucasians and Africans) and
      coming from areas with different HIV-1 clade prevalences (clade B and A/G,
      respectively). In Caucasian patients, after month of STI, the number of HIV-1
      specific CTL (2,896 +/- 2,780 IFN-gamma specific CD8 cells/ml) was significantly
      higher than that found at enrolment (2,125 +/- 4,426 IFN-gamma specific CD8
      cells/ml, p< 0.05). CONCLUSIONS: These data indicate that this CTL assay is
      broadly specific and could represent a useful clinical tool for HIV
      immunodiagnostic independent of HLA-haplotype and HIV-clade variabilities.

PMID- 12606815
TI  - Modulation of balance between apoptosis and proliferation by lipid peroxidation
      (LPO) during rat liver regeneration.
AB  - BACKGROUND: This work aims to investigate the role of lipid peroxidation (LPO) at
      early stages of liver regeneration and to evaluate the balance between apoptosis
      and cell proliferation during this process. METHODS: Sham and partial
      hepatectomized (PH) male Wistar rats were randomized in seven groups: Control
      (untreated), E-Control (injected with vitamin E-vehicle), C-Control (injected
      with vitamin C-vehicle), E1 (vitamin E 100 mg/kg body weight), E2 (vitamin E 600
      mg/kg body weight), C1 (vitamin C 30 mg/kg body weight), C2 (vitamin C 100 mg/kg
      body weight). RESULTS: Vitamin treatments attenuated the increase of LPO level
      observed in total homogenate and microsomes at 3 and 5 hr after PH. Both
      antioxidant vitamins attenuated the increase in Bax pro-apoptotic protein and
      augmented Bcl-xL antiapoptotic protein levels (35%) at 3 and 5 hr post-PH; Bcl
      xL/Bax ratio was, therefore, increased. A direct linear relationship between LPO
      levels and Bax mitochondrial protein levels was seen. Vitamin-treatments
      diminished the apoptosis index with respect to PH-Control values, so that this
      parameter showed a linear relationship with LPO levels. At 24 hr after PH, the
      vitamin treatments increased the peak of [(3) H]-thymidine incorporation into DNA
      and the proliferative index (PI), measured as PCNA expression; an inverse
      relationship between PI and LPO levels could be demonstrated. CONCLUSION: Our
      data show that the diminution of LPO levels by vitamin-treatment post-PH produces
      both an attenuation of cellular apoptosis and a marked increase in the
      proliferation process, suggesting that the modulation of LPO has a role in liver
      regeneration process.

PMID- 12606816
TI  - Visualization of irreparable ischemic damage in brain by selective labeling of
      double strand blunt-ended DNA breaks.
AB  - BACKGROUND: Double-strand DNA breaks with blunt ends represent the most serious
      type of DNA damage, and cannot be efficiently repaired by cells. They are
      generated in apoptosis or necrosis and are absent in normal or transiently
      damaged cells. Consequently, they can be used as a molecular marker of
      irreparable cellular damage. We evaluated the effects of focal brain ischemia
      using selective labeling of blunt-ended DNA breaks as a marker of irreversible
      tissue damage. A new approach permitting such analysis in situ is introduced.
      MATERIALS AND METHODS: Rat brain sections taken 6, 24, 48 and 72 hr after the
      onset of focal brain ischemia were used. Double-strand DNA breaks were detected
      directly in the tissue sections via ligation of blunt-ended hairpin-shaped
      oligonucleotide probes. The probes were attached to the ends of the breaks by T4
      DNA ligase. Conventional cresyl violet co-staining and terminal transferase based
      labeling (TUNEL) were employed to analyze the distribution of labeled cells.
      RESULTS: Double-strand blunt-ended DNA breaks rapidly accumulate in brain cells
      after focal brain ischemia. At 24 hr, they concentrate in the peripheral areas of
      stroke, which are prone to ischemia-reoxygenation. By 48-72 hr, this type of DNA
      damage spreads inward, covering the internal areas of the ischemic zone.
      CONCLUSIONS: Selective labeling of blunt-ended DNA breaks delineates the dynamics
      of stroke-induced irreversible DNA damage and provides highly specific detection
      of brain cells with irreparable DNA injury. It can be used for comparing the
      efficiency of various anti-ischemic drugs, particularly those that target DNA
      damage, as well as for monitoring stroke-induced damage.

PMID- 12606817
TI  - Semicarbazide-sensitive amine oxidase (SSAO) gene expression in alloxan-induced
      diabetes in mice.
AB  - BACKGROUND: Plasma activity of semicarbazide-sensitive amine oxidase (SSAO) has
      been reported to be significantly higher in diabetic patients compared to healthy
      controls. Due to the production of highly angiotoxic substances in SSAO-catalyzed
      reactions, it has been speculated that this could be a cause for the vascular
      complications frequently associated with diabetes. Little is known about how the
      enzyme activity is regulated, and why it is high in these patients. In the
      present study, we assessed the possibility of transcriptional regulation by
      analyzing SSAO activity and SSAO-mRNA levels in mice with alloxan-induced
      diabetes. MATERIALS AND METHODS: Diabetes was induced in NMRI mice by a single
      intravenous injection of alloxan. The enzyme activity was analyzed by a
      radiometric assay using (14) C-benzylamine as a substrate, and the mRNA-levels
      were analyzed by real-time PCR. RESULTS: We found that the enzyme activity was
      increased in lung and adipose tissue 1 day after induction, as the glucose levels
      start to rise. Seven days after the injection of alloxan, the activity in serum
      was increased, and this activity was positively correlated with blood glucose
      levels in the alloxan-treated animals. Although the enzyme activity was increased
      in adipose tissue as a result of the treatment, SSAO-mRNA levels in this tissue
      were decreased, possibly suggesting a negative feedback on the gene expression.
      CONCLUSIONS: The main conclusion from this study is that the increased enzyme
      activity observed in diabetes is not a result of increased SSAO gene
      transcription. We speculate that the enzyme activity is controlled by
      posttranslational modifications of the protein, and that the catalytic activity
      controls the gene expression.

PMID- 12606819
TI  - Peripheral benzodiazepine binding sites in platelets of patients affected by
      mitochondrial diseases and large scale mitochondrial DNA rearrangements.
AB  - BACKGROUND: The peripheral-type benzodiazepine receptors (PBR) are localized on
      the outer mitochondrial membrane, as a constituent of mitochondrial permeability
      transition (MPT)-pore. Among its hypothesized functions, the regulation of the
      mitochondrial respiratory chain and apoptosis have been suggested; in addition
      alterations of PBR site density have been shown in some neuropathologic
      conditions with putative mitochondrial involvement. The aim of this work has been
      to evaluate PBR kinetic binding parameters in platelets from patients affected by
      mitochondrial disorders (MD) with large-scale mitochondrial DNA deletions and
      reduced cytochrome c oxidase activity. MATERIALS AND METHODS: Using the specific
      PBR radioligand [(3) H] PK 11195, the kinetic binding parameters of PBR sites
      were determined in platelet membrane of 15 healthy subjects and 11 patients
      affected by different form of MD. RESULTS: Significant changes of dissociation
      constant (K(d)) and maximal number of binding sites (B(max)) values were
      evidenced in platelets of patients versus controls. In all patients the B(max)
      values were decreased (2,387.0 +/- 305.6 fmol/ mg proteins versus 4889.0 +/-
      357.8 fmol/mg proteins, p< 0.05), whereas the K(d) values were higher in patients
      than controls (13.18 +/- 2.06 nM versus 5.63 +/- 0.46 nM, p< 0.05). CONCLUSIONS:
      These data suggest that the kinetic binding parameters of PBR are altered in MD
      and that the observed changes might be related to the mitochondrial dysfunction
      associated with MD.

PMID- 12606818
TI  - Angiotensin II-induced mesangial cell apoptosis: role of oxidative stress.
AB  - BACKGROUND: Angiotensin II (ANG II) has been shown to play a role in the
      induction of glomerular injury. In the present study, we evaluated the effects of
      ANG II on mesangial cell apoptosis and the involved molecular mechanism.
      MATERIALS AND METHODS: The effect of ANG II on apoptosis of mouse mesangial cells
      (MC) was evaluated by morphologic, DNA fragmentation and TUNEL assays. To
      evaluate the role of oxidative stress and involved mechanisms, we studied the
      effect of antioxidants, anti-TGF-beta antibody, inhibitors of nitric oxide
      synthase and modulators of cytosolic calcium/heme oxygenase (HO) activity. In
      addition, we studied the effect of ANG II on the generation of reactive oxygen
      species (ROS) by MCs. RESULTS: ANG II promoted apoptosis of MCs in a dose
      dependent manner. This effect of ANG II was not only associated with ROS
      production, but also inhibited by antioxidants. Both Anti-TGF-beta antibody and
      propranolol inhibited ANG II-induced ROS generation and apoptosis. BAPTA
      inhibited both ANG II- and TGF-beta-induced apoptosis. On the other hand,
      thapsigargin stimulated MC apoptosis under basal as well as ANG II/TGF-beta
      stimulated states. ANG II receptor types 1 and 2 antagonists attenuated the
      proapoptotic effect of ANG II. Hemin inhibited but zinc protoporphyrin enhanced
      the proapoptotic effect of ANG II. Propranolol increased HO activity; whereas pre
      treatment with propranolol prevented ANG II-induced apoptosis. CONCLUSIONS: ANG
      II promotes MC apoptosis. This effect of ANG II is mediated through downstream
      signaling involving TGF-beta, phospholipase D, and Ca(2+), contributing to the
      activation of NADPH oxidase and generation of ROS. HO activity plays a modulatory
      role in ANG II- induced MC apoptosis.

PMID- 12606820
TI  - Modulation of trophoblast cell death by oxygen and EGF.
AB  - BACKGROUND: Preeclampsia, a maternal hypertensive disease, is characterized by
      shallow invasion of the maternal spiral arterioles resulting in
      hypoxia/reperfusion type insult; however, the molecular mechanism is unknown. The
      aim of this study was to determine the mechanism of altered oxygen tension or
      inhibition of phosphatidyl-inositol-3-kinase (PI3K) on trophoblast survival and
      to investigate the effect of epidermal growth factor (EGF) on maintaining
      cellular integrity. MATERIALS AND METHOD: We have used flow cytometry,
      immunoblotting, and fluoroimmunocytochemistry to study apoptosis in a
      characterized, spontaneously transformed first trimester extravillous-like
      trophoblast cell line that exhibits many characteristics of in vivo trophoblast.
      RESULTS: Time-dependent exposure of first trimester extravillous-like trophoblast
      to all oxygen tensions tested promoted dissipation of the mitochondrial membrane
      potential (psi(m)) and resulted in a significant increase in celldeath by 48 hr
      as determined by dual staining flow cytometry. Western blot analysis revealed
      expression ofcleaved caspase-3 and caspase-9 increased with time with hypoxia and
      hyperoxia promoting the greatest elevation indicating that longer duration of
      exposure to a change inoxygen tension causes increased apoptosis via a
      mitochondrial-mediated pathway. Disruption of the anti-apoptotic PI3K pathway by
      LY294002 (40 microM), its specific inhibitor, caused further significant
      dissipation of the psi(m) (p< 0.01) and cleavage of caspase-3. EGF was able to
      maintain the psi(m) and to prevent cleavage of caspase-3 even in the presence of
      LY294002, indicating that its survival effects were independent of the PI3K
      pathway. CONCLUSIONS: These results suggest that inhibition of the PI3K/Akt
      pathway can sensitize first-trimester trophoblast-like cells into oxygen-induced
      cell death and that EGF exerts its anti-apoptotic effect independently of
      PI3K/Akt.

PMID- 12606821
TI  - Farnesyl protein transferase inhibition interferes with activation of MAP kinase
      family members in human peripheral blood monocytes.
AB  - BACKGROUND: Farnesyl protein transferase inhibitors have emerged as promising
      novel agents for combating cancerous disease. Nevertheless, the importance for
      farnesyl protein transferase enzymatic activity for cellular physiology of
      untransformed cells remains poorly investigated. MATERIALS AND METHODS:
      Peripheral blood monocytes, isolated from the blood of eight healthy volunteers,
      were treated with a farnesyl protein transferase inhibitor (FTI 744,832) or
      vehicle control for 16 hr. Subsequently cells were challenged with different
      concentrations of lipopolysaccharide (LPS), colony stimulating factor-1 (CSF-1),
      or phorbol esters for 10 min, after which the activation state of p42/p44 MAP
      kinase, p38 MAP kinase, and Jun-N-terminal kinase was investigated using Western
      blotting and phosphospecific antibodies. RESULTS: We observed that farnesyl
      protein transferase inhibition abrogated activation of p38 MAP kinase by LPS, CSF
      1, and phorbol esters. Also the activation of Jun-N-terminal kinase by LPS was
      not seen after farnesyl protein transferase inhibition. Finally, stimulation of
      p42/p44 MAP kinase with CSF-1 was strongly reduced by farnesyl protein
      transferase inhibition, whereas activation of p42/p44 MAP kinase by phorbol ester
      was only slightly effected. CONCLUSIONS: Farnesyl protein transferase enzymatic
      activity is required for proper activation of all major members of the MAP kinase
      family. The observation that activation the p38 MAP kinase and Jun-N-terminal
      kinase is sensitive to farnesyl protein transferase inhibition raises the
      possibility that, in addition to cancerous disease, farnesyl protein transferase
      inhibitors may be useful compounds in combating inflammatory disease.

PMID- 12606822
TI  - Effects of free fatty acid on polymerization of islet amyloid polypeptide (IAPP)
      in vitro and on amyloid fibril formation in cultivated isolated islets of
      transgenic mice overexpressing human IAPP.
AB  - BACKGROUND: Islet amyloid polypeptide (IAPP) is deposited as amyloid in the
      islets of Langerhans in type 2 diabetes. The mechanism behind the formation of
      the cytotoxic fibrils is unknown. Islet amyloid develops in a mouse IAPP null
      mouse strain that expresses human IAPP (+hIAPP/-mIAPP) after 9 months on a high
      fat diet. Herein we investigate the effect that individual free fatty acids
      (FFAs) exert on formation of amyloid-like fibrils from synthetic IAPP and the
      effects of FFAs on IAPP polymerization in +hIAPP/-mIAPP islets cultivated in
      vitro. MATERIALS AND METHODS: In the study myristic acid, palmitic acid, stearic
      acid, oleic acid, and linoleic acid were used together with albumin. Thioflavin T
      (Th T) assay was used for quantification of amyloid-like fibrils. Islets were
      isolated from the +hIAPP/-mIAPP transgenic strain and cultured in the presence of
      the FFAs for 2 days. Immuno-electron microscopy was used for evaluation. RESULTS:
      The Th T assay showed that all studied FFAs potentiated fibril formation but that
      myristic acid revealed the highest capacity. In some cells from cultured islets,
      intragranular aggregates were present. These aggregates had a filamentous
      appearance and labeled with antibodies against IAPP. In some cells cultured in
      the presence of linoleic acid, large amounts of intracellular amyloid were
      present. Earlier, this has not been observed after such a short incubation
      period. CONCLUSIONS: Our studies suggest that FFAs can potentiate amyloid
      formation in vitro, probably without being integrated in the fibril. Cultivation
      of +hIAPP/-mIAPP transgenic mouse islets with FFAs results in altered morphology
      of the secretory granules with appearance of IAPP- immunoreactive fibrillar
      material. We suggest that such fibrillar material may seed extracellular amyloid
      formation after exocytosis.

PMID- 12606823
TI  - Adenoviral transfer of mda-7 leads to BAX up-regulation and apoptosis in
      mesothelioma cells, and is abrogated by over-expression of BCL-XL.
AB  - BACKGROUND: Malignant pleural mesothelioma (MPM) is unresponsive to conventional
      therapies. Forced expression of the novel tumor suppressor mda-7 gene in other
      cell types has resulted in decreased growth and apoptosis. We evaluated cell
      growth, apoptosis and tumor suppressor characteristics following forced
      expression of this gene in mesothelioma cell lines. METHODS: MDA-7 expression in
      human MPM cells at baseline, following pharmacologic differentiation and viral
      mda-7 transduction (Ad-mda7) were evaluated with Western blot. Cell viability was
      evaluated with a colorimetric (XTT) assay, and apoptosis with subG1 FACS and
      Hoescht. Caspase-3 expression was evaluated by functional assay. These parameters
      were also evaluated in a stable bcl-xl hyper-expressing MPM cell line. Bax mRNA
      levels were evaluated with real-time PCR. RESULTS: No baseline or differentiated
      MPM MDA7 expression was found, but was noted following Ad-mda7 exposure. More
      than 50% of MPM cells were killed at 5 days following Ad-mda7 exposure (p <
      0.001). Apoptosis was accompanied by caspase-3 cleavage and increased BAX
      expression at both the protein (translational) and mRNA (transcriptional) level.
      These findings were reduced in a bcl-xl hyper-expressing cell line (P < 0.01).
      CONCLUSIONS: Although mda-7 does not appear to be a MPM suppressor gene,
      adenoviral-mediated expression in cell lines induces apoptotic cellular death
      related to BAX upregulation and caspase cleavage. This is supported by abrogation
      of effect in a bcl-xl hyper-expressing cell line.

PMID- 12606824
TI  - Betulinic acid-induced Mcl-1 expression in human melanoma--mode of action and
      functional significance.
AB  - BACKGROUND: Currently there is no information on the regulation of expression and
      physiological role of the anti-apoptotic protein Mcl-1 in cells of the
      melanocytic lineage. This study investigates the regulation and expression of Mcl
      1 in human melanoma cells, which was recently found to be induced by betulinic
      acid, a compound with anti-melanoma and apoptosis-inducing potential. MATERIALS
      AND METHODS: Mcl-1 phosphorthioate antisense oligonucleotides were used to
      investigate the effect of downregulating the expression of Mcl-1. Regulation of
      Mcl-1 expression was analyzed with the specific PI3-kinase inhibitors LY294002
      and wortmannin and the inhibitor of MAP-kinase activation, PD98059. Western blot
      analysis was performed with anti ERK1/2, Mcl-1, Bak, Bcl-x and Bax antibodies.
      Activation status of PI-3 kinase and MAP-kinase pathways was investigated using
      phospho-Akt and phosphorylation-state independent Akt as well as phospho-MAP
      kinase, phospho-MEK and phospho-GSK-3alpha/beta antibodies. RESULTS: Upregulation
      of Mcl-1 in human melanoma cells by betulinic acid is mediated via a signal
      transduction pathway that is inhibited by LY294002 and wortmannin. Betulinic acid
      induced phosphorylation and activation of the Akt protein kinase was inhibited by
      LY294002. The inhibitor PD98059 reduced expression levels of Mcl-1 in melanoma
      cells and this effect was counteracted by betulinic acid. Downregulation of Mcl-1
      by antisense oligodeoxynucleotides in combination with betulinic treatment led to
      a synergistic effect regarding growth inhibition. CONCLUSIONS: These results
      suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for
      survival and (ii) subject to dual regulation by the MAP- kinase pathway and a
      pathway involving protein kinase B/Akt, the latter of which is modulated in
      response to betulinic acid. This study provides an experimental foundation for
      future therapeutic strategies using anti-Mcl-1 antisense oligonucleotides in
      human melanoma.

PMID- 12606825
TI  - Importance of National Institute of Infectious Diseases and Institutes of Public
      Health on control of infectious diseases in the new century.
AB  - As the incidence of infectious diseases has recently decreased, we are faced with
      new problems, such as emerging and re-emerging infectious diseases, food
      poisoning, zoonosis, and bio-terrorism. In light of these new conditions, the
      National Institute of Infectious Diseases, the Local Institutes of Public Health,
      public health offices, and other medical organization must maintain close
      relationship in order to protect the health and safety of the citizens.

PMID- 12606826
TI  - Diarrheagenic Escherichia coli isolated from stools of sporadic cases of
      diarrheal illness in Osaka City, Japan between 1997 and 2000: prevalence of
      enteroaggregative E. coli heat-stable enterotoxin 1 gene-possessing E. coli.
AB  - Diarrheagenic Escherichia coli (DEC) represents an elusive target, since they are
      not easily distinguished from fecal coliforms. To clarify if DEC are prevalent
      among sporadic cases of diarrheal illness in Osaka City, Japan, diarrheal
      specimens were examined for E. coli that were enterohemorrhagic (EHEC),
      enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroinvasive (EIEC), or
      enteroaggregative (EAggEC). EAST1EC, a strain of E. coli that does not possess
      any diarrheagenic characteristics except the EAggEC heat-stable toxin 1 (EAST1)
      gene, was also included as a possible DEC. A total of 924 specimens were examined
      between July 1997 and March 2000. DEC and Salmonella were isolated from 7.3%
      (67/924) and 6.8% (63/924) of specimens, respectively. DEC was therefore as
      prevalent as Salmonella among sporadic cases. The 67 strains were composed of 17
      EPEC (26%), 10 EHEC (15%), four ETEC (6%), 13 EAggEC (20%), and 23 EAST1EC (35%),
      including two strains of EAST1EC O166:H15. Although PCR and tissue culture
      adhesion tests were useful to detect DEC, the effectiveness of serotyping was
      limited: only 40 strains (17.5%) out of 229 isolates that had been assumed to be
      enterovirulent on the basis of their O antigen were recognized to be
      diarrheagenic. In conclusion, not only EHEC but also the other subgroups of DEC,
      including EAST1EC, seem to play an important role in causing sporadic diarrheal
      illnesses. Methods to detect and unified criteria to identify various kinds of
      DEC are strongly desired.

PMID- 12606827
TI  - Intestinal myiasis due to Musca domestica: a report of two cases.
AB  - Myiasis is the infestation of live human and vertebrate animals with dipterous
      larvae, which, at least for a certain period, feed on the host's dead or living
      tissue, liquid body substances, or ingested food. Intestinal myiasis is usually
      an accidental phenomenon, which occurs due to the ingestion of eggs or larvae
      present in food. Usually the patient is asymptomatic and the larvae are excreted
      harmlessly in the feces. In some cases, however, the passage of larvae may be
      associated with symptoms. The present paper describes two such cases.

PMID- 12606828
TI  - An urban outbreak of leptospirosis in Mumbai, India.
AB  - An outbreak of leptospirosis occurred during the rainy season in the city of
      Mumbai, India. Out of 169 suspected cases, 74 (43.7%) were determined
      serologically positive by microagglutination test (MAT) carried out with a
      battery of eight pathogenic serovars, while 78 (46.1%) were shown positive for
      IgM antibodies to leptospira by enzyme-linked immunosorbent assay. On the basis
      of MAT, serovar Copenhageni accounted for 66 (89.1%) out of the 74 cases admitted
      during the period of the outbreak. Myalgia, conjunctival suffusion, cough with
      hemoptysis, icterus, and oliguria were significantly more common in patients
      whose samples were determined positive by MAT. The presence of pulmonary signs
      and symptoms and renal failure were significantly associated with mortality in
      patients presumed to be suffering from leptospirosis.

PMID- 12606829
TI  - Evaluation of National Tsutsugamushi Disease Surveillance--Japan, 2000.
AB  - In Japan, Tsutsugamushi disease, which is caused by Orientia tsutsugamushi, is re
      emerging with newly recognized strains and is now endemic in all prefectures
      except Hokkaido and Okinawa. We analyzed recent surveillance data to describe the
      epidemiology of Tsutsugamushi disease and to evaluate the newly implemented
      national surveillance system according to the CDC guidelines for evaluating
      surveillance systems. In 2000, 756 cases of Tsutsugamushi disease were reported
      from 37 of 47 prefectures; two of these cases were fatal. The median age of case
      patients was 64 years (range: 2 - 94 years); 414 (54.8%) were male. In northern
      Japan, most cases were diagnosed in the months of May through July and in the
      months of October through December, and in southern Japan, cases were diagnosed
      almost year-round with a peak from October through December and in January.
      Reporting and transfer of surveillance information from the prefecture to the
      national level was effective and timely, but the completeness and quality of case
      reporting could still be improved. The current system for Tsutsugamushi disease
      surveillance is useful for describing epidemiologic patterns by time, prefecture,
      and demographic characteristics. However, collection of additional information on
      suspected place of transmission, activity performed at the place of transmission,
      or the case-patient's profession would likely make the system more valuable for
      outbreak detection and for better defining populations at risk.

PMID- 12606830
TI  - Neuraminidase subtyping of human influenza a viruses by RT-PCR and its
      application to clinical isolates.

PMID- 12606831
TI  - An outbreak of heat-stable enterotoxin-producing Escherichia coli O25:HNM
      resistant to nalidixic acid caused by ingestion of contaminated box-lunch in
      September-October 2002 in Hyogo and Shiga Prefectures.

PMID- 12606832
TI  - Phylogenetic analysis of Salmonella enterica serovar Enteritidis isolated from
      food poisoning outbreaks and sporadic infections in 2001-2002 in Hyogo
      prefecture: existent of predominant genotypes in the epidemic.

PMID- 12606833
TI  - Molecular epidemiology of methicillin-resistant Staphylococcus aureus in a Tokyo
      hospital in 2002.

PMID- 12606834
TI  - Pulmonary Mycobacterium avium infection in an immunocompetent aged woman related
      to use of home bath with a circulating water system.

PMID- 12606836
TI  - A questionnaire investigation regarding the neglect of hand washing, assessed by
      nurses in hospitals in Japan.

PMID- 12606837
TI  - A clonal expansion of methicillin-resistant Staphylococcus aureus (MRSA) in a
      tuberculosis ward.

PMID- 12606838
TI  - Do obsessive-compulsive patients and abstinent heroin addicts share a common
      psychophysiological mechanism?
AB  - BACKGROUND/AIM: Working memory (WM) and attentional deficits have been implicated
      in the pathophysiology of both obsessive-compulsive disorder (OCD) and opioid
      addiction. The P300 component of event-related potentials (ERPs) is considered as
      an index of on-line updating of WM and/or attentional operations involved in this
      function. The present study aimed at comparing the P300 elicited during a WM test
      in patients with prolonged heroin abstinence, those with OCD and healthy
      controls, in order to demonstrate possibly common underlying psychophysiological
      mechanisms. METHODS: The P300 component was evaluated during the anticipatory
      period of a WM test in 20 patients characterized by a past history of opioid
      dependence (6 months abstinence), in 18 OCD patients, and 20 healthy subjects
      matched for age, sex and educational level. RESULTS: The two patient groups
      showed a considerable reduction of the P300 amplitudes, located at the right
      frontal area as compared with healthy controls. The abstinent heroin addicts
      exhibited a significantly lower P300 amplitude at central frontal areas and a
      significantly higher P300 amplitude at the left occipital region relative to the
      other two groups. Furthermore, the abstinent group showed a notable delay of P300
      latency relative to controls and OCD patients at the right occipital region.
      Moreover, the OCD patients manifested a significant prolongation of P300 located
      at the central prefrontal area, relative to addicts and healthy controls.
      CONCLUSIONS: These findings point to considerable WM and/or attentional deficits
      in the long-term abstinent syndrome of heroin misuse and OCD associated with
      distributed and prefrontal cortical circuits, respectively. Furthermore, the
      present findings suggest that both OCD and long-term abstinent heroin addicts may
      share a common impairment of WM and/or attention involving or affecting the right
      prefrontal areas.

PMID- 12606835
TI  - Detection of dengue virus-infected patients among passengers at the quarantine
      station of the New Tokyo International Airport.

PMID- 12606840
TI  - No evidence for an association between the T102C and 1438 G/A polymorphisms of
      the serotonin 2A receptor gene in attention deficit/hyperactivity disorder in a
      Turkish population.
AB  - Disturbances in the serotonergic neurotransmission system have been implicated in
      the etiology of attention deficit/hyperactivity disorder (ADHD). As the
      importance of genetic factors is well established, genes encoding for proteins of
      the serotonergic pathway are important candidates to unravel the underlying
      genetic contribution. We previously demonstrated that the polymorphisms of the
      serotonin transporter gene promoter and regions of variable number of tandem
      repeats were involved in the pathogenesis of ADHD. The purpose of this study was
      to examine the relationship between ADHD and two polymorphisms (T102C and 1438
      G/A) in the 5-HT2A gene in a sample of Turkish children. Using the PCR technique,
      these polymorphisms were assessed in 70 patients with ADHD and in 100 healthy
      controls. There was no significant difference between the frequencies of the T,
      C, G and A alleles of both groups. No association was found between the studied
      polymorphisms of the 5-HT2A gene and ADHD in this sample consisting of Turkish
      children. Overall, our results suggest that the investigated 5-HT2A polymorphisms
      are not major susceptibility factors in the etiology of ADHD.

PMID- 12606841
TI  - Attenuated left prefrontal activation during a verbal fluency task in patients
      with depression.
AB  - Functional neuroimaging studies on patients with depression have found abnormal
      activity in the left prefrontal and anterior cingulate cortex compared with
      healthy controls. Other studies have shown that these regions become active in
      healthy subjects during verbal fluency tasks, while patients with depression show
      impaired performance on such tasks. We used functional magnetic resonance imaging
      to investigate changes in cerebral blood oxygenation associated with a verbal
      fluency task in depressed patients and healthy volunteers. In contrast to 10 age-
      and sex-matched healthy control subjects who activated the left prefrontal cortex
      and the anterior cingulate cortex during word generation, 10 depressed subjects
      showed attenuated activation in the left prefrontal cortex and did not show
      significant activation in the anterior cingulate cortex. These findings suggest
      that impaired performance during verbal fluency task in depressed patients is
      associated with abnormal neural responses within these regions.

PMID- 12606842
TI  - T102C polymorphisms at the 5-HT2A receptor gene in Turkish schizophrenia
      patients: a possible association with prognosis.
AB  - BACKGROUND: Serotonergic system abnormalities have been implicated in the
      pathogenesis of schizophrenia. The 5-HT2A receptor gene polymorphism has long
      been implicated to play a role in the pathogenesis of schizophrenia. AIM: In this
      study, we assessed the relationship of schizophrenia and its subgroups with 5
      HT2A receptor gene polymorphism, and attempted to evaluate a possible correlation
      between the severity and prognosis of the illness and 5-HT2A receptor gene
      polymorphism. METHOD: Our study comprised 141 unrelated subjects who strictly met
      DSM-IV criteria for schizophrenia, and 79 healthy unrelated controls, all of
      Turkish origin. A clinical evaluation of all patients was accomplished applying
      the Brief Psychiatric Rating Scale (BPRS) test. The analysis of 5-HT2A receptor
      gene polymorphism was performed using the polymerase chain reaction technique.
      RESULTS: Regarding 5-HT2A receptor gene polymorphisms, no statistically
      significant difference was found between schizophrenic patients and control
      subjects (p > 0.05). There was no significant difference between the average of
      BPRS points of the patients and 5-HT2A receptor gene polymorphisms (p > 0.05).
      Although there was no correlation between the duration of illness and
      polymorphism (p > 0.05), the frequency of hospitalization was found to be higher
      in the patients with T/C and T/T genotypes compared with the patients with C/C
      genotype (p < 0.05). CONCLUSION: Our findings indicate that the T102C
      polymorphisms of the 5-HT2A receptor gene does not play a substantial role in
      schizophrenia nor help evaluate susceptibility to schizophrenia. Since the 5-HT2A
      receptor gene polymorphism is associated with the frequency of hospitalization of
      the patients, it may be an indicator of prognosis in schizophrenia or help
      differentiate the patients who are somewhat refractory to antipsychotic
      treatment.

PMID- 12606839
TI  - Jealousy and subthreshold psychopathology: a serotonergic link.
AB  - BACKGROUND: A few studies suggest that different neurotransmitters may play a
      role in the expression of jealousy. Our study aimed to explore the serotonergic
      system by means of the specific binding of (3)H-paroxetine ((3)H-Par) to platelet
      membranes of healthy subjects with and without excessive jealousy concerns,
      according to a specific self-administered questionnaire [Questionnaire for
      affective relationships (QAR)]. SUBJECTS AND METHODS: The study sample includes
      21 subjects concerned by jealousy thoughts and 21 control subjects without
      jealousy concerns, as shown by their QAR scores. Subjects of the first group were
      administered a battery of self-report instruments designed to detect the presence
      of typical, atypical and subthreshold psychopathology. Platelet membranes and
      (3)H-Par binding were carried out according to standardized protocols. RESULTS:
      Subjects with excessive jealousy concerns had a reduced density of (3)H-Par
      binding as compared with control subjects without jealousy concerns and had one
      or more psychiatric spectrum conditions. CONCLUSIONS: Our findings suggest that
      excessive jealousy is associated with various forms of psychopathology and may be
      underlain by alteration of the serotonergic system, as reflected by the lower
      density of the platelet serotonin transporter.

PMID- 12606843
TI  - Influence of mirtazapine on salivary cortisol in depressed patients.
AB  - Unlike other antidepressants, mirtazapine does not inhibit the reuptake of
      norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2)
      receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1
      receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol
      secretion in healthy subjects. In the present study, the impact of mirtazapine
      treatment on salivary cortisol secretion was investigated in 12 patients (4 men,
      8 women) suffering from major depression according to DSM-IV criteria. Patients
      were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0,
      30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21).
      Response to mirtazapine treatment was defined by a reduction of at least 50% in
      the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary
      cortisol concentrations were measured before treatment (day -1), at the beginning
      of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of
      treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until
      20.00 h. The area under the curve values served as parameter for the salivary
      cortisol secretion. Following analysis of variance with a repeated measures
      design, tests with contrasts revealed a significant reduction of cortisol
      concentrations already after 1 day of mirtazapine treatment that was comparable
      in responders and nonresponders. In addition to new pharmacological approaches
      such as CRH1 receptor antagonists, mirtazapine therefore appears to be an
      effective strategy to decrease hypercortisolism and restore HPA system
      dysregulation in depression. However, the importance of the acute inhibitory
      effects of mirtazapine on cortisol secretion for its antidepressant efficacy has
      to be further clarified.

PMID- 12606845
TI  - The effects of Ginkgo biloba extracts on the memory and motor functions of rats
      with chronic cerebral insufficiency.
AB  - The main goal of the current study was to investigate the effects of two Ginkgo
      leaf extracts, EGb 761 and an extract of local Ginkgo leaf (LGb), on the memory
      and motor functions of rats with chronic cerebral insufficiency (produced by
      bilateral common carotid artery ligation). After the operation, spatial memory
      and motor functions were tested for over 80 days. Tests included (1) radial-arm
      maze test for testing spatial memory and locomotor activity and (2) muscle force
      and hind limbs for escape. The results indicate that both EGb 761 and LGb
      improved spatial memory from the second week after operation, but only EGb 761
      delayed deterioration of motor functions from the fifth week after operation.

PMID- 12606844
TI  - Flupenthixol versus risperidone: subjective quality of life as an important
      factor for compliance in chronic schizophrenic patients.
AB  - OBJECTIVE: The primary aim of this paper was to compare the effects of
      flupenthixol and risperidone on subjective quality of life and attitude towards
      medication in chronic schizophrenic patients with mainly negative symptoms. In a
      spectrum ranging from its typical end "haloperidol" to its atypical end
      "clozapine", flupenthixol has typical and atypical characteristics. METHODS: The
      effects of flupenthixol versus risperidone were investigated in a multicenter,
      double-blind trial, whereas subjective quality of life was assessed by means of
      the EuroQuol-Visual Analogue Scale and the patient satisfaction questionnaire.
      The attitude towards medication was assessed by means of the Drug Attitude
      Inventory-30 (DAI-30). RESULTS: Mean daily dose of study medication was 6.6 (SD
      2.9) mg/day flupenthixol and 3.6 (SD 1.2) mg/day risperidone. Both groups showed
      a significant improvement regarding subjective quality of life and positive
      attitude towards medication. Especially the categories "control of their
      thoughts", concentration and "feeling better in general" ameliorated in both
      groups. In the flupenthixol group, the "ability to cope with stress", "feel more
      relaxed" and the "ability to achieve something" improved significantly more than
      in the risperidone group. CONCLUSIONS: (1) The spectrum of schizophrenia can be
      treated effectively with different neuroleptic treatments. (2) Flupenthixol
      especially improves the ability to cope with stress, the ability to achieve
      something and feeling more relaxed. (3) Subjective quality of life significantly
      increased with no difference between the groups.

PMID- 12606846
TI  - Lack of association between polymorphisms of the dopamine D4 receptor gene and
      personality.
AB  - Recent studies have suggested a role of two polymorphisms of the dopamine D(4)
      receptor gene (DRD4 exon III and -521C/T) in the modulation of personality traits
      such as "novelty seeking" or "extraversion", which are supposed to be modulated
      by individual differences in dopaminergic function. However, several replication
      studies have not provided positive findings. The present study was performed to
      further investigate whether DRD4 exon III and -521C/T are associated with
      individual differences in personality. One hundred and fifteen healthy German
      volunteers completed the NEO-Five-Factor Inventory (NEO-FFI) and were genotyped
      for the two DRD4 polymorphisms. We found no association between DRD4 exon III and
      -521C/T, respectively, and estimated novelty seeking, NEO-FFI extraversion or
      other personality factors. Our findings are in line with several earlier studies
      which have failed to replicate the initial association results. Hence, our data
      do not provide evidence for a role of DRD4 exon III and the -521C/T polymorphism
      in the modulation of novelty seeking and extraversion.

PMID- 12606847
TI  - Explaining variation in affiliative relationships among male white-faced
      capuchins (Cebus capucinus).
AB  - Relationships among coresident male white-faced capuchins are highly variable,
      ranging from affiliative to aggressive. In this paper I examine the affiliative
      relationships of all adult and subadult males residing in four social groups in
      Santa Rosa National Park, Costa Rica. Relationships among males in two study
      groups were neutral and tolerant, while in the remaining two groups males were
      highly affiliative. Male-male dyadic affiliative interactions were examined to
      determine which variables (group size, sex ratio, age relationship, relationship
      duration, and rank distance) influence the quality of male relationships within
      the study groups. Group size explained much of the variation, with males in small
      groups being more affiliative. However, the duration and history of the
      relationship among coresident males appears to be the most important variable in
      understanding male-male relationships within social groups.

PMID- 12606848
TI  - Differentiation between fore- and hindlimb bones and locomotor behaviour in
      primates.
AB  - Primate appendicular limb bones were measured on the cross-sectional geometry at
      the mid-length of the humerus and femur and on the external dimensions of long
      bones of the same individuals. Cross sections were directly measured by means of
      computer tomography or direct sectioning. The morphometry of bones and locomotor
      behaviour is discussed from the viewpoint of the functional differentiation
      between the fore- and hindlimbs. The primate group which daily adopted a
      relatively terrestrial locomotor type demonstrates robust forelimb bones compared
      with the group which adopted a fully arboreal locomotor type. In contrast, the
      arboreal group showed relatively large and long hindlimb bones. The difference
      resembled the previously reported comparison between terrestrial and arboreal
      groups among wholly quadrupedal mammals. Humans were more similar to the arboreal
      group than to the terrestrial group. Parameters of the cross-sectional geometry
      showed a slightly positive allometry in total primate species. Slopes of the
      parameters were explained by the influence of muscle force.

PMID- 12606849
TI  - Seed dispersal by sympatric tamarins, Saguinus mystax and Saguinus fuscicollis:
      diversity and characteristics of plant species.
AB  - In a comparative study of Saguinus mystax and Saguinus fuscicollis, we examined
      the spectrum of plant species whose seeds are dispersed by these two tamarin
      species. We characterize these plants in terms of life form, fruit colour, pulp
      consistency and seed dimensions. The tamarins disperse a much broader spectrum of
      plant species than previously reported (88 of the total of 155 species exploited
      for fruit). While the distribution over plant life form, fruit colour and pulp
      consistency is identical between dispersed plant species and the overall spectrum
      of consumed plant species, clear differences exist in all seed parameters
      (length, width, height, volume, mass) except specific weight between dispersed
      and non-dispersed plant species for both tamarin species. Plant and fruit
      characteristics and seed parameters of dispersed plant species do not differ
      between S. mystax and S. fuscicollis, suggesting that their ecological and
      evolutionary interaction with plants is very similar or identical.

PMID- 12606850
TI  - Infanticide and cannibalism in wild common marmosets.
AB  - Infanticide has been observed in many different species [1], including common
      marmosets [2-4], due to sexual selection, reproductive strategies or resource
      competition [3, 5, 6], which may ultimately lead to exploitation (cannibalism)
      [1, 7]. Wild callithrichids have a very flexible mating system, including
      monogamy, polygynandry, polyandry and polygyny [4, 8, 9], with Monteiro da Cruz
      [10] finding all these patterns within the same population. This results from the
      high degree of deforestation of their habitat [4], but non-monogamous groups
      cannot ensure successful rearing of infants, since helpers are crucial and should
      be present in high numbers [11]. In this study, we show for the first time that
      cannibalism can follow infanticide, and we hypothesise that it is a result of
      both competition for scarce resources and the need for animal protein,
      exacerbated by forest degradation.

PMID- 12606851
TI  - A note on an interaction between Rhinopithecus bieti and a buzzard at Baima Snow
      Moutain.
AB  - Predation avoidance relies primarily on behavioural mechanisms [van Schaik and
      van Hooff, 1983]. Primates alarm call at predators, including most birds and
      mammals [Cheney and Wrangham, 1987]. Alarm calls could be used to signal to the
      predator that it has been spotted [Zuberbuhler et al., 1999], thereby probably
      decreasing the likelihood of an attack [Schultz, 2001], and they also inform prey
      of the presence of the predator, thereby increasing overall attention levels
      [Schulke, 2001]. Although eagles are reported to be one of the predators of
      Rhinopithecus bieti [Bai et al., 1987], few interactions between these monkeys
      and raptors have been documented to date. Here I document an interaction
      witnessed between R. bieti and a buzzard [Buteo sp., Yang X-J, pers. comm.].

PMID- 12606852
TI  - Seasonal variation in the testicular volume of capuchin monkeys (Cebus apella) in
      captivity.
AB  - The study of the reproductive strategy developed by different species in order to
      adapt to their environmental conditions and their meaning in an evolutionary
      perspective is essential for understanding the mechanisms involved in the process
      of reproduction. Non-human primates are very interesting models for this purpose.
      Some species show a typical seasonal reproductive pattern, such as rhesus
      macaques (Macaca mulatta) [Sade, 1964; Conaway and Sade, 1965] and ring-tailed
      lemurs (Lemur catta) [Zuckerman, 1953], while others, such as gorillas (Gorilla
      gorilla) and chimpanzees (Pan troglodytes) [Puschmann, 1975], show relative
      independence of the environment. Neotropical primates display many different
      breeding strategies. Female capuchin monkeys (Cebus apella), for instance, having
      reached puberty, have fertile cycles year-round [Hamlett, 1939; Nagle and Denari,
      1983]. Interestingly, there are reports of a clear peak of births in free-living
      [Hamlett, 1939] and captive colonies [Welker et al., 1983] in the dry season,
      i.e. May-June in the southern hemisphere. Some authors suggest that a seasonal
      variation in spermatogenesis could explain the birth peak [Freese and
      Oppenheimer, 1981]. The aim of this study was to investigate this theory,
      measuring seasonal variation in total testicular volume in a captive group of
      male capuchin monkeys and assessing its temporal correlation with the birth
      season as an indirect indication of variation in male fertility.

PMID- 12606855
TI  - Organizing primary care for an integrated system.
AB  - During the past decade, many changes have occurred in the Canadian healthcare
      delivery system but few, if any, of these changes have specifically addressed the
      role of the family physician. This paper proposes a number of changes to the
      infrastructure that supports the role of family physicians, including family
      physician accountability for delivering twenty-four-hour, seven-days-per-week
      services to a defined population of patients. The infrastructure needed to
      support family physicians as the coordinators of care across the continuum of
      healthcare services includes family-medicine group practices or practice networks
      linked by electronic networks. Family medicine is the key to health-system
      integration. Systems to integrate family medicine with other primary healthcare
      providers and with secondary- and tertiary-care systems are proposed, as well as
      quality-improvement systems for family medicine.

PMID- 12606856
TI  - Building on one of the best delivery systems in the world.
AB  - Rosser and Kasperski build upon and consolidate several earlier reports to put
      forward a "bottom-up" model for the integration of health services for Ontario
      that establishes the family physician as the focal point of entry to the
      healthcare system. The essential features of this model are as follows: 1. Each
      person in the province should choose a family physician and formalize a
      partnership with this physician. 2. Each family physician should be in some form
      of group practice or practice network ranging in size from 7 to 30 physicians. 3.
      Urgent care would be provided by the members of the physician group on a 24-hour
      a-day/7-days-per-week basis. 4. The family physician would be responsible for
      maintaining a comprehensive record for each patient through the use of
      information technology. 5. All providers in the system with whom a patient had
      contact would be required to forward copies of all reports and associated
      information from that contact to the family physician. 6. The group model will be
      characterized by collaboration, with the use of nurse practitioners and family
      practice nurses to provide preventative and chronic care, the use of midwives to
      augment the provision of obstetrical, prenatal and postnatal care, and community
      access and hospital-in-the-home services. 7. Family physicians would be supported
      by a geographically defined group of specialists providing secondary care, such
      as psychiatrists, pediatricians and obstetricians, who would also coordinate
      tertiary care. 8. Every family physician should be an active staff member of his
      or her local hospital. 9. At some level of aggregation a family physician would
      be responsible for facilitating/implementing quality-improvement programs for
      community physicians. 10. Family physicians would be supported through a blended
      funding model.

PMID- 12606857
TI  - Primary care and primary health care for an integrated system.
AB  - The article by Rosser and Kasperski, "Organizing Primary Care for an Integrated
      System," provides an important stimulus for examining issues surrounding
      healthcare reform in Canada. As the "Guidelines for Commentary" of
      HealthcarePapers indicate, healthy debate can foster "constructive change. " The
      Canadian Nurses Association welcomes the opportunity to engage in such a debate
      and it is within this spirit that we offer a number of challenges, both at a
      theoretical/conceptual as well as a factual level, to the ideas presented by
      Rosser and Kasperski. Although there are a number of points in the article that
      warrant attention, this commentary will address only a selected few.

PMID- 12606858
TI  - Moving healthcare reform forward: a complex and challenging transition.
AB  - As a long-time advocate of primary-care reform and a participant in the present
      implementation of the Ontario Primary Care Reform (PCR) pilot projects, I am
      sympathetic to the perspectives of Rosser and Kasperski. The model for reform
      that they propose has added fuel to the debate on PCR initiatives. However, the
      future strategic direction for primary care will be determined at the conclusion
      of the implementation and testing period for the pilot sites and after evaluating
      models in other provincial jurisdictions. Although the investment of resources
      over the past four years by government and the profession has clearly been
      significant, the methodical planning and breadth of consultation and review on
      many issues may not be apparent to observers.

PMID- 12606859
TI  - Viewing the kaleidoscope of health systems through a patient-centred prism.
AB  - I ought to start by giving my credentials for writing this commentary. I have a
      marked aversion to outsiders with limited first-hand experience telling me about
      the British National Health Service. This is especially so when their questions
      and comments raise issues that make me feel uncomfortable.

PMID- 12606860
TI  - Making best use of every healthcare provider's knowledge and skills.
AB  - In "Organizing Primary Care for an Integrated System" Rosser and Kasperski
      propose changing the way family physicians practice to address deficiencies in
      the current primary-care delivery system in Canada. These deficiencies include a
      growing shortage of physicians, particularly in rural areas of Canada; the
      growing dependence of Canadians on acute hospital emergency units or "walk- in
      clinics" for primary care; fragmentation and unnecessary duplication in the
      delivery of primary-care services; lack of understanding on the part of the
      community and hospital sectors of the role of the family-practice physician; a
      fee-for-service funding model that does not reward prevention and health
      promotion initiatives by physicians and makes high-problem visits the most
      lucrative; and lack of clarity with regard to what the public should expect from
      their physicians.

PMID- 12606861
TI  - Rhetoric, reality and revolution in family practice and primary care.
AB  - It is distressing to an observer from south of Canada to read the paper from the
      Ontario College of Family Physicians (Rosser and Kasperski). It indicates
      disruption and confusion within an admirable healthcare system - a system with a
      reputation of getting things right when it comes to family practice and primary
      care. Apparently, all is not well.

PMID- 12606862
TI  - Implementing primary care reform and the impact on physicians and their
      practices.
AB  - The paper by Rosser and Kasperski represents the positions of the Ontario College
      of Family Physicians. Their rostering proposal has been taken up by the Ministry
      of Health and the Ontario Medical Association. My comments will be largely on the
      ideas as seen in the light of their planned implementation.

PMID- 12606863
TI  - The pharmacist's role in primary care within an integrated health system.
AB  - I read, with interest, the paper by Rosser and Kasperski. I was struck by how
      similar and applicable the problems and issues identified for family physicians
      are to those pharmacists face today in Canada's health system. There is a need
      for a coordinated and systematic approach to address infrastructure support for
      all primary-care providers. In this companion article, I will provide evidence to
      support the Ontario College of Family Physicians' position on strengthening
      family physicians' abilities to provide excellent primary care. In addition, I
      will make a case for support of greater involvement of pharmacists in community
      based primary-care teams.

PMID- 12606866
TI  - Protocols in sports magnetic resonance imaging.
AB  - Magnetic resonance imaging, with its multiplanar imaging capability and superior
      soft-tissue contrast, has become the preferred method for imaging sports-related
      injuries. Advances in gradient technology, receiver coils, and imaging software
      have allowed the imaging of the injured athlete to take place quickly and at high
      resolution. Understanding the tissues being imaged, the underlying anatomy, and
      the capabilities of today's scanners is crucial to the design of intelligent and
      efficient protocols.

PMID- 12606867
TI  - Indirect magnetic resonance arthrography: applications in sports imaging.
AB  - Indirect magnetic resonance (MR) arthrography is an imaging tool with several
      advantages over both direct MR arthrography and unenhanced musculoskeletal
      magnetic resonance imaging. It is based upon the idea that paramagnetic contrast
      agents injected intravenously into the plasma compartment ultimately will perfuse
      the articular space. Advantages of indirect MR arthrography include enhancement
      of both intra-articular and extra-articular pathology without the need for an
      invasive, fluoroscopically guided arthrogram, as well as high sensitivity for
      reinjury in postoperative patients. Some potential disadvantages of this
      technique are enhancement of normal vascular tissues and difficulty in making a
      diagnosis dependent upon joint space distension in the absence of an effusion.
      Important technical issues when performing indirect arthrography include choosing
      an appropriate delay between contrast injection and imaging, as well as the
      potential use of patient exercise to improve image quality. In sports medicine,
      indirect MR arthrography is most useful in and about small joints such as the
      wrist and ankle; in articulations with potential internal derangements, as well
      as bony or osteochondral injuries; and in injured joints that have been altered
      surgically.

PMID- 12606868
TI  - Shoulder: labrum and bicipital tendon.
AB  - Shoulder instability can be due to a single, acute traumatic event, generalized
      joint laxity, or repeated episodes of microtrauma. The later occurs in the
      throwing athlete. The most common lesion involving the labrum is the anterior
      inferior labral tear, associated with capsuloperiosteal stripping (classic
      Bankart lesion). A number of variants of the Bankart lesion have been described
      recently and include the ALPSA lesion, SLAP lesion, and HAGHL lesion, among
      others. Lesions of the long head of the biceps tendon can be seen in isolation
      (tears, tendinosis, dislocation) or in association with rotator cuff and labral
      lesions. Conventional MR and MR arthrography have been extensively used for the
      preoperative diagnosis of these lesions, with reportedly good accuracy. An
      understanding of the normal anatomy and biomechanics of the shoulder joint is
      essential for proper interpretation of the MRI manifestations of these
      conditions.

PMID- 12606869
TI  - Magnetic resonance imaging of the shoulder: rotator cuff.
AB  - Magnetic resonance imaging has proven to be useful in the assessment of rotator
      cuff injuries. Improvements in magnetic resonance techniques, including fast spin
      echo imaging and fat saturation, have facilitated demonstration of tendinous
      abnormalities of the rotator cuff. Rotator cuff disease is multifactorial.
      Primary impingement within the coracoacromial arch, degeneration of the rotator
      cuff tendons, trauma, and glenohumeral instability may be contributing factors.
      Shoulder pain in athletes can be related to acute myotendinous and muscle
      injuries, which can be easily detected using magnetic resonance imaging.

PMID- 12606870
TI  - Magnetic resonance imaging of sports injuries of the elbow.
AB  - Many abnormalities seen in the elbow result from trauma, often from sports such
      as baseball and tennis. Elbow problems are frequently related to the medial
      tension-lateral compression phenomenon, where repeated valgus stress produces
      flexor-pronator strain, ulnar collateral ligament sprain, ulnar traction
      spurring, and ulnar neuropathy. Lateral compression causes osteochondral lesions
      of the capitellum and radial head, degenerative arthritis, and loose bodies.
      Other elbow abnormalities seen on magnetic resonance imaging include radial
      collateral ligament injuries, biceps and triceps tendon injuries, other nerve
      entrapment syndromes, loose bodies, osseous and soft-tissue trauma, arthritis,
      and masses, including bursae.

PMID- 12606871
TI  - Magnetic resonance imaging of sports injuries of the spine.
AB  - Spinal injuries are relatively frequent events in professional athletes. Greater
      popularity of recreational athletic activities has increased the occurrence of
      sports-related spinal injuries in the general population. The demand of high
      intensity sports places a constant load on the vertebral column. Several studies
      have demonstrated higher prevalence of spinal abnormalities in athletes than
      nonathletes. Direct correlation of the number and extent of injuries with the
      length in years of sports activity has been established. Diagnostic imaging,
      particularly magnetic resonance imaging (MRI), plays a crucial role in evaluating
      and detecting sports-related spinal injuries. Subtle bone marrow, soft-tissue,
      and spinal cord abnormalities, which may not be apparent on other imaging
      modalities, can be readily detected on MRI. Early detection often leads to prompt
      accurate diagnosis and expeditious management, in many cases avoiding unnecessary
      procedures. This article reviews the technical aspects of MRI for evaluation of
      the spine and the role of MRI in the assessment of sports-related spinal
      injuries.

PMID- 12606872
TI  - Musculoskeletal ultrasound: an alternative imaging modality for sports-related
      injuries.
AB  - Advanced technology and increasing clinical experience have established
      sonography as a reliable imaging modality for sports-related injuries. Tears of
      muscles and tendons, tendinosis, and tenosynovitis are promptly diagnosed using
      ultrasound. Dynamic assessment of joints can be performed, allowing diagnoses of
      conditions that may remain undetected when evaluated with conventional magnetic
      resonance imaging. Sonography provides expeditious image guidance for procedures
      such as drainage of fluid collections and cysts. This article reviews the
      applications of sonography to sports-related injuries in which its diagnostic
      performance may be comparable to magnetic resonance imaging.

PMID- 12606874
TI  - Chlamydia pneumoniae and multiple sclerosis: the latest etiologic candidate.

PMID- 12606875
TI  - Putting prenatal effects on sex-dimorphic behavior in perspective: an absolutely
      complete theory.

PMID- 12606876
TI  - On the determination of sample size.

PMID- 12606877
TI  - Pregnancy and protection from hormonally associated tumor development.

PMID- 12606878
TI  - Infection with Chlamydia pneumoniae and risk of multiple sclerosis.
AB  - BACKGROUND: Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic
      agent for multiple sclerosis (MS), but results of previous studies are
      conflicting. METHODS: Using a nested case-control design, we examined the
      association between Cpn infection and MS in the Nurses' Health Study (NHS) and
      Nurses' Health Study II (NHS II) cohorts. Among 32,826 women in the NHS and
      29,722 women in the NHS II with blood samples, 141 incident cases of definite or
      probable MS were documented. Each case was matched to two healthy controls on
      year of birth and NHS cohort. Serum samples were tested for the presence of Cpn
      specific immunoglobin G antibodies using microimmunofluorescence. RESULTS: Cpn
      immunoglobin G seropositivity was positively associated with risk of MS (odds
      ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1-2.7). This association did
      not change after adjusting for age at blood collection, ancestry, latitude of
      residence at birth, and smoking (OR = 1.9; CI = 1.1-3.1). Seropositivity for Cpn
      was only moderately associated with risk of relapsing-remitting MS (OR = 1.7; CI
      = 0.9-3.2), but it was strongly associated with risk of progressive MS (OR = 7.3;
      CI = 1.4-37.2). Geometric mean titers of Cpn-specific immunoglobin G antibody
      were similar in women with relapsing-remitting MS as compared with matched
      controls (44 vs 39), but they were elevated in women with progressive MS (99 vs
      40). CONCLUSIONS: These results support a positive association between Cpn
      infection and progressive MS.

PMID- 12606879
TI  - Hormonally active agents in the environment and children's behavior: assessing
      effects on children's gender-dimorphic outcomes.
AB  - BACKGROUND: Early sex hormone exposure contributes to gender-dimorphic behavioral
      development in mammals, including humans. Environmental toxicants concentrated in
      contaminated sport fish can interfere with the actions of sex steroids. METHODS:
      This study developed an outcome variable by combining gender-dimorphic behaviors
      that differentiates boys and girls. Offspring of participants in the New York
      State Angler Cohort Study (NYSACS) were targeted in a parent-report postal
      survey. Instruments were selected based on findings of gender differences in the
      general population. RESULTS: A linear discriminant function model incorporating
      three gender behavior scales correctly classified the sex of 97.7% of children
      (252 boys and 234 girls) from a random NYSACS sample. The discriminant function
      was cross-validated by correctly classifying the sex of 98.4% of children (457
      boys and 425 girls) from the remaining NYSACS cases and 97.6% of children (154
      boys and 142 girls) from an independent school sample. Within-sex stepwise
      multiple regression analyses revealed that masculine behavior increased among
      boys with age and with the number of years of maternal sport fish consumption. In
      girls, older age and previous live-born siblings were associated with more
      masculine behavior, whereas feminine behavior increased with the duration of
      breast feeding. These associations were replicated in an independent sample.
      CONCLUSIONS: A linear discriminant function effectively transformed the binary
      classification of sex (male-female) to a bipolar continuum of gender (masculinity
      femininity). Findings from this study are consistent with the hypothesis that
      environmental contaminants contribute to shifts in gender-role behavior. Future
      investigations will need to account for competing explanations of this effect.

PMID- 12606880
TI  - Psychosexual characteristics of men and women exposed prenatally to
      diethylstilbestrol.
AB  - BACKGROUND: Between 1939 and the 1960s, the synthetic estrogen diethylstilbestrol
      (DES) was given to millions of pregnant women to prevent pregnancy complications
      and losses. The adverse effects of prenatal exposure on the genitourinary tract
      in men and the reproductive tract in women are well established, but the possible
      effects on psychosexual characteristics remain largely unknown. METHODS: We
      evaluated DES exposure in relation to psychosexual outcomes in a cohort of 2,684
      men and 5,686 women with documented exposure status. RESULTS: In men, DES was
      unrelated to the likelihood of ever having been married, age at first
      intercourse, number of sexual partners, and having had a same-sex sexual partner
      in adulthood. DES-exposed women, compared with the unexposed, were slightly more
      likely to have ever married (odds ratio [OR] = 1.1; confidence interval [CI] =
      1.0-1.4) and less likely to report having had a same-sex sexual partner (OR =
      0.7; CI = 0.5-1.0). The DES-exposed women were less likely to have had first
      sexual intercourse before age 17 (OR = 0.7; CI = 0.6-0.9) or to have had more
      than one sexual partner (OR = 0.8; CI = 0.7-0.9). There was an excess of left
      handedness in DES-exposed men (OR = 1.4; CI = 1.1-1.7) but not in DES-exposed
      women. DES exposure was unrelated to self-reported history of mental illness in
      women. CONCLUSIONS: Overall, our findings provide little support for the
      hypothesis that prenatal exposure to DES influences the psychosexual
      characteristics of adult men and women.

PMID- 12606881
TI  - On the use of population attributable fraction to determine sample size for case
      control studies of gene-environment interaction.
AB  - Most methods for calculating the sample size needed to detect gene-environment
      interactions use odds ratios to measure the effect size. We show that for any
      combination of susceptible genotype prevalence and exposure prevalence and their
      associated risks, the odds ratio measuring strength of interaction corresponds to
      a population attributable fraction (PAF) because of interaction and vice versa.
      Simultaneous consideration of odds ratio for interaction and the associated PAF
      attributable to interaction provides additional insight to investigators
      evaluating the feasibility and public health relevance of a proposed study. We
      considered gene-environment interactions on a multiplicative scale, and assumed a
      dichotomous environmental exposure variable and a single two-allele disease
      susceptibility locus. Our results show, for example, that for studies of
      exposures and genotypes that are common in a population (30%-50%), the PAF for
      interaction is large (>27%) even if the odds ratio for interaction is only
      moderate (approximately 2). If simultaneous estimates of interaction odds ratio
      and PAF indicate that the PAF is so large as to be implausible, the investigator
      may decide to reevaluate the study design based on detecting a more reasonable
      PAF. In this case, the associated odds ratio for interaction will be weaker and a
      considerably larger sample size may be needed.

PMID- 12606882
TI  - Does pregnancy induce the shedding of premalignant ovarian cells?
AB  - BACKGROUND: High parity is associated with reduced risk of ovarian cancer. One
      hypothesis is that pregnancy is associated with clearance of a fraction of the
      genetically modified (premalignant) cells from the ovaries. METHODS: We evaluated
      this hypothesis using a model that estimates the cell clearance fraction at first
      and second pregnancy according to age at pregnancy. The model was fitted using
      reproductive history data from a cohort of 1.5 million Danish women born between
      1935 and 1978 and followed for 28.7 million person-years. During this follow-up
      period, 2,035 developed invasive ovarian cancer. RESULTS: We found the model to
      have a satisfactory fit despite the very few parameters involved. The model
      estimated similar cell clearance fractions for the first and second pregnancy and
      decreasing clearance with later age at pregnancy. CONCLUSION: The relation of
      pregnancy history to risk of ovarian cancer can be well described by a cell
      clearance model that allows the cell clearance fraction to decrease with age at
      pregnancy.

PMID- 12606883
TI  - Arsenic in drinking water and skin lesions: dose-response data from West Bengal,
      India.
AB  - BACKGROUND: Over 6 million people live in areas of West Bengal, India, where
      groundwater sources are contaminated with naturally occurring arsenic. The key
      objective of this nested case-control study was to characterize the dose-response
      relation between low arsenic concentrations in drinking water and arsenic-induced
      skin keratoses and hyperpigmentation. METHODS: We selected cases (persons with
      arsenic-induced skin lesions) and age- and sex-matched controls from participants
      in a 1995-1996 cross-sectional survey in West Bengal. We used a detailed
      assessment of arsenic exposure that covered at least 20 years. Participants were
      reexamined between 1998 and 2000. Consensus agreement by four physicians
      reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases
      clinically diagnosed in the field. RESULTS: The average peak arsenic
      concentration in drinking water was 325 microg/liter for cases and 180
      microg/liter for controls. The average latency for skin lesions was 23 years from
      first exposure. We found strong dose-response gradients with both peak and
      average arsenic water concentrations. CONCLUSIONS: The lowest peak arsenic
      ingested by a confirmed case was 115 microg/liter. Confirmation of case diagnosis
      and intensive longitudinal exposure assessment provide the basis for a detailed
      dose-response evaluation of arsenic-caused skin lesions.

PMID- 12606884
TI  - Nitrate in public water supplies and risk of bladder cancer.
AB  - BACKGROUND: Nitrate is a precursor compound in the formation of N-nitroso
      compounds, most of which are potent animal carcinogens. N-nitroso compounds and
      their precursors have not been extensively evaluated as bladder cancer risk
      factors. METHODS: We conducted a population-based case-control study of bladder
      cancer in Iowa. Cases were men and women newly diagnosed with bladder cancer in
      1986-1989. Nitrate data for Iowa public water supplies were sparse before the
      1960s. To reduce misclassification by unknown nitrate levels, we included only
      those who used public supplies with nitrate data for 70% or more of their person
      years since 1960 (808 cases, 1259 controls). RESULTS: Among controls, the median
      average nitrate level for their Iowa residences with public water supplies was
      1.3 mg/liter nitrate-nitrogen (interquartile range = 0.6-3.0). After adjustment
      for confounders, we found no increased risk of bladder cancer with increasing
      average nitrate levels in drinking water; the highest quartile odds ratio for
      women was 0.8 (95% confidence interval = 0.4-0.8), and for men 0.5 (0.4-0.8). We
      observed no association among those with high water nitrate exposure (>median)
      and low (<median) vitamin C intake compared with those who had low water nitrate
      and high vitamin C intake. CONCLUSIONS: Our data suggest that long-term exposure
      to nitrate in drinking water at levels in this study (90th percentile 5.5
      mg/liter nitrate-nitrogen) is not associated with risk of bladder cancer.

PMID- 12606885
TI  - Trihalomethane exposures from municipal water supplies and selected congenital
      malformations.
AB  - BACKGROUND: Concerns about potential health effects of trihalomethanes (THMs)
      have prompted investigations on whether infants whose mothers were
      periconceptionally exposed to drinking water containing THMs are at greater risk
      of congenital malformations. METHODS: We used two large case-control maternal
      interview studies that were conducted among California deliveries from 1987
      through 1991. One study comprised 538 infants/fetuses with neural tube defects
      (NTDs) and 539 nonmalformed control infants. The second study included an
      additional 265 infants with NTDs, 207 infants with conotruncal heart defects, 409
      infants with orofacial clefts, and 481 control infants. Expert personnel from
      municipal water companies estimated THM levels for a particular residence and
      specific periconceptional time period using quarterly monitoring measurements.
      Estimates were also made for four individual THM levels and for the total THM
      level. RESULTS: NTD risk in the first study was inversely associated with total
      THM exposure. Although the second study did not show the same inverse
      relationship for NTDs, there were no positive associations of NTDs or the other
      malformations with total THM as estimated from continuous models. Elevated risks
      were observed for the lowest category of exposure (1-24 ppb), but risks were
      either not substantially elevated or were imprecise for higher exposure levels.
      Thus no evidence was observed for an exposure-response relation. CONCLUSIONS: Our
      results do not provide a clear pattern of association between THM exposure and
      risks of specific congenital malformations. Imprecise exposure measures coupled
      with a lack of information about other possible sources of THM exposure may have
      caused associations to be underestimated.

PMID- 12606886
TI  - Folate intake and the risk of neural tube defects: an estimation of dose
      response.
AB  - BACKGROUND: Studies have shown that folic acid supplementation in early pregnancy
      markedly reduces the risk of neural tube defects (NTDs). Investigation of the
      relation between relative dose of supplemental folic acid or total folate intake
      and NTD risk is limited. METHODS: We used data from 23,228 women, predominantly
      from the northeastern United States, enrolled between October 1984 and June 1987
      in a prospective study of early prenatal exposures and pregnancy outcomes. Diet
      and vitamin intake data were gathered in the early second trimester. NTDs were
      ascertained through prenatal testing and by report of the delivering physician.
      Data analyses included multiple logistic regression and restricted spline
      regression modeling. RESULTS: For each additional 500 dietary folate equivalents
      consumed per day, the prevalence of NTDs decreased by 0.78 cases (95% confidence
      interval [CI] = 0.47-1.09) per 1,000 pregnancies. Compared with women having the
      lowest total folate intakes (0-149 folate equivalents per day), the prevalence of
      NTDs declined by 34%, 30%, 56% and 77% among the offspring of those women
      consuming 150-399, 400-799, 800-1199 and > or = 1200 folate equivalents per day,
      respectively (P-value for linear trend = 0.016). CONCLUSIONS: Our results suggest
      that NTD risk declines markedly with modest increases of total folate in early
      pregnancy. Total folate dose, rather than supplemental folate alone, should be
      considered in formulating public health guidelines for NTD prevention.

PMID- 12606887
TI  - Dietary calcium supplements to lower blood lead levels in lactating women: a
      randomized placebo-controlled trial.
AB  - BACKGROUND: Pregnancy and breastfeeding mobilize lead stored in bone, which may
      be a hazard for the fetus and infant. We tested the hypothesis that in lactating
      women a dietary calcium supplement will lower blood lead levels. METHODS: Between
      1994 and 1995 we conducted a randomized trial among women in Mexico City.
      Lactating women (N = 617; mean age = 24 years; mean blood lead level = 8.5 ug/dL)
      were randomly assigned to receive either calcium carbonate (1200 mg of elemental
      calcium daily) or placebo in a double-blind trial. Blood samples were obtained at
      baseline, and 3 and 6 months after the trial began. Blood lead was determined by
      graphite furnace atomic absorption spectroscopy. Bone lead was measured at
      baseline with a 109cd K x-ray fluorescence instrument. The primary endpoint was
      change in maternal blood lead level, which was analyzed in relation to supplement
      use and other covariates by multivariate generalized linear models for
      longitudinal observations. RESULTS: An intention-to-treat analysis showed that
      women randomized to the calcium supplements experienced a small decline in blood
      lead levels (overall reduction of 0.29 ug/dL; 95% confidence interval = -0.85 to
      0.26). The effect was more apparent among women who were compliant with
      supplement use and had high bone lead levels (patella bone lead > or =5 microg/gm
      bone). Among this subgroup, supplement use was associated with an estimated
      reduction in mean blood lead of 1.16 ug/dL (95% confidence interval = -2.08 to 
      0.23), an overall reduction of 16.4%. CONCLUSIONS: Among lactating women with
      relatively high lead burden, calcium supplementation was associated with a modest
      reduction in blood lead levels.

PMID- 12606888
TI  - Validation of a food frequency questionnaire in preschool children.
AB  - BACKGROUND: Support for the validity of food frequency questionnaires (FFQ) in
      preschool children using parental report is limited. METHODS: We obtained dietary
      information for 68 children age 1-3 years using three or four 24-hour recalls and
      a FFQ regarding the child's diet covering one year from families in Denver, CO
      from 1997 to 1999. FFQs were completed by the parents, and recalls were collected
      via interviews with the parents and alternate caregivers, where applicable.
      Nutrient biomarkers were measured in the plasma of 38 of the children. All
      nutrients were adjusted for energy intake using residuals, and log-transformed
      where necessary. RESULTS: Correlations (Pearson r) between the FFQ and the
      average of the recalls were 0.33 for protein, 0.41 for carbohydrate, 0.39 for
      fat, 0.42 for vitamin C, 0.27 for alpha-tocopherol, and 0.08 for total energy
      intake. We found no substantial changes in these correlations after
      stratification by whether or not meals and snacks were provided by caregivers
      other than the parents. The highest correlations (Spearman r) with biological
      measures were 0.51 between plasma ascorbic acid and FFQ vitamin C, and 0.48
      between plasma and FFQ alpha-tocopherol. CONCLUSIONS: The FFQ shows mostly good
      agreements with multiple 24-hour recalls and biomarkers in preschool children. In
      addition, the validity of the FFQ using parental report does not appear to be
      compromised when there are meal providers in addition to the parents.

PMID- 12606889
TI  - Time of birth and risk of intrapartum and early neonatal death.
AB  - BACKGROUND: Previous studies have found that infants born at night and during
      weekends and holidays have an increased risk of perinatal mortality. However,
      these associations may be confounded by the distribution of high-risk deliveries
      according to time of birth. METHODS: We undertook a population-based cohort study
      of 694,888 singleton births without elective cesarean section in Sweden between
      1991 and 1997. We estimated relative risks of intrapartum and early neonatal
      death according to the hour, day and month of delivery. Estimated risk ratios
      were adjusted for gestational age, birth weight for gestational age,
      malformations, induction of labor, breech presentations and year of birth.
      RESULTS: Infants of high-risk deliveries were more often delivered during daytime
      (8:00 am to 7:59 pm). Compared with infants born during daytime, infants born at
      night were at increased risk of early neonatal death (adjusted risk ratio = 1.28;
      95% confidence interval = 1.13-1.46), but not intrapartum death (1.05; 0.71
      1.54). If this association is causal, 12% of early neonatal deaths can be
      attributed to the increased risk among nighttime births. There was no association
      of weekend or holiday births with risks of intrapartum or early neonatal death.
      CONCLUSIONS: Infants born at night may be at increased risk of early neonatal
      death.

PMID- 12606890
TI  - A relation between blood pressure and stiffness of joints and skin.
AB  - BACKGROUND: Blood pressure, particularly pulse pressure, is associated with
      arterial wall stiffness, but little is known about its relation to stiffness of
      other parts of the body. We examined the extent to which blood pressure levels in
      young healthy children are related to stiffness of various tissues. METHODS: In
      November 2000, we studied 95 healthy prepubertal children (41 boys and 54 girls,
      within age range 8-10 years) from two primary schools in the city of Zeist, The
      Netherlands. Systolic and diastolic blood pressure and pulse pressure were
      analyzed in relation to various tissue indicators of stiffness, including active
      joint mobility and skin extensibility. All results were adjusted for age, sex,
      body height, body weight and muscle strength as possible confounders. RESULTS:
      Diastolic blood pressure was lower with increased active joint mobility
      (multivariate generalized linear regression coefficient = -4.5 mmHg per standard
      deviation [SD] joint mobility; 95% confidence interval [CI] = -7.8 to -1.2).
      Pulse pressure was lower with increased skin extensibility (-3.2 mmHg per SD skin
      extensibility; CI = -5.2 to -1.1), through a higher diastolic blood pressure (2.0
      mmHg per SD skin extensibility; CI = 0.2-3.9) and possibly lower systolic blood
      pressure (-0.8 mmHg per SD skin extensibility; CI = -3.5 to 1.9). These
      associations were mutually independent. Additional adjustment for reported
      musculoskeletal problems or physical activity levels did not materially change
      the findings. CONCLUSIONS: Our findings support the hypothesis that
      constitutional stiffness of body tissues may be associated with blood pressure
      levels and eventually cardiovascular risk.

PMID- 12606891
TI  - Estimating long-term average particulate air pollution concentrations:
      application of traffic indicators and geographic information systems.
AB  - BACKGROUND: As part of a multicenter study relating traffic-related air pollution
      with incidence of asthma in three birth cohort studies (TRAPCA), we used a
      measurement and modelling procedure to estimate long-term average exposure to
      traffic-related particulate air pollution in communities throughout the
      Netherlands; in Munich, Germany; and in Stockholm County, Sweden. METHODS: In
      each of the three locations, 40-42 measurement sites were selected to represent
      rural, urban background and urban traffic locations. At each site and fine
      particles and filter absorbance (a marker for diesel exhaust particles) were
      measured for four 2-week periods distributed over approximately 1-year periods
      between February 1999 and July 2000. We used these measurements to calculate
      annual average concentrations after adjustment for temporal variation. Traffic
      related variables (eg, population density and traffic intensity) were collected
      using Geographic Information Systems and used in regression models predicting
      annual average concentrations. From these models we estimated ambient air
      concentrations at the home addresses of the cohort members. RESULTS: Regression
      models using traffic-related variables explained 73%, 56% and 50% of the
      variability in annual average fine particle concentrations for the Netherlands,
      Munich and Stockholm County, respectively. For filter absorbance, the regression
      models explained 81%, 67% and 66% of the variability in the annual average
      concentrations. Cross-validation to estimate the model prediction errors
      indicated root mean squared errors of 1.1-1.6 microg/m for PM(2.5) and 0.22-0.31
      *10(-5) m for absorbance. CONCLUSIONS: A substantial fraction of the variability
      in annual average concentrations for all locations was explained by traffic
      related variables. This approach can be used to estimate individual exposures for
      epidemiologic studies and offers advantages over alternative techniques relying
      on surrogate variables or traditional approaches that utilize ambient monitoring
      data alone.

PMID- 12606892
TI  - Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure.
AB  - BACKGROUND: Two recent studies estimated that users of nonsteroidal
      antiinflammatory drugs (NSAIDs) have a two-fold increase in risk of
      hospitalization for congestive heart failure and that this effect is larger among
      patients with preexisting cardiovascular diseases. METHODS: To evaluate the
      association between NSAID use and the risk of first-diagnosed episode of heart
      failure, we conducted a case-control study nested in a population-based cohort of
      individuals 40-84 years of age and registered in the U.K. General Practice
      Research Database at 1 January 1996. We excluded patients with a diagnosis of
      heart failure or cancer before that time and followed source members until a
      first-time recorded diagnosis of heart failure or cancer, or until 31 December
      1996 if no disease occurred. The analysis included 857 confirmed cases and 5000
      controls frequency-matched to cases by age (interval of 1 year) and sex. RESULTS:
      The estimated adjusted relative risk of heart failure associated with
      prescription of NSAIDs was 1.6 (95% confidence interval = 1.2-2.1). The relative
      risk was greater during the first month of therapy and was independent of
      treatment indication. The relative risk was 1.9 (1.3-2.8) among patients with
      prior history of hypertension, diabetes or renal failure and 1.3 (0.9-1.9) among
      individuals without these conditions. CONCLUSIONS: Initiation of NSAID therapy
      may double the risk of developing heart failure in susceptible individuals.
      Patients with renal failure, diabetes or hypertension when taking NSAIDs might be
      at a greater risk of developing heart failure than patients without those
      conditions.

PMID- 12606893
TI  - Why is parity protective for uterine fibroids?
AB  - Uterine fibroids are benign tumors, the etiology of which is not understood.
      Symptoms can be debilitating, and the primary treatment is surgery, usually
      hysterectomy. Epidemiologic data show that pregnancy is associated with reduced
      risk of fibroids. We hypothesize that this association is attributable to a
      protective effect of postpartum involution of the uterus. After each pregnancy
      the uterus rapidly returns to prepregnancy size by dramatic remodeling of the
      tissue. We hypothesize that small fibroids are eliminated during this process. We
      present preliminary epidemiologic evidence that is consistent with this
      hypothesis. If the hypothesis is supported by more direct evidence, it may have
      broader implications, supporting the idea that tissue remodeling may be a general
      mechanism for limiting tumor development.

PMID- 12606895
TI  - Banking of urine sediments as DNA source in epidemiologic studies.

PMID- 12606894
TI  - Placental genes and breast cancer: can the offspring's or father's genotypes
      predict mother's risk?
AB  - Half of the placental genes to which a woman is exposed during pregnancy come
      from her mating partner. Placental hormones, especially human chorionic
      gonadotropin and human placental lactogen, are considered to mediate the
      protective effects of full-term pregnancy and lactation on breast cancer risk. In
      this paper, variants in a woman's placental human chorionic gonadotropin or human
      placental lactogen genes, which are easily measurable through her offspring's
      genotypes, are associated with her breast cancer risk. If this hypothesis is true
      it would indicate that genotype of a woman's mating partner can affect her breast
      cancer risk and that offspring's genotype may be useful in predicting such risk.
      Because the placenta produces a wide range of hormones and enzymes (in addition
      to human chorionic gonadotropin and human placental lactogen), results supporting
      this hypothesis could open new dimensions to genetic research for diseases beyond
      breast cancer (including gynecologic tumors and reproductive and pregnancy
      related disorders).

PMID- 12606898
TI  - Child assent and parental permission: a comment on Tait's "Do they understand?".

PMID- 12606899
TI  - Organ donation after cardiac death: what role for anesthesiologists?

PMID- 12606900
TI  - Donation after cardiac death: non-heart-beating organ donation deserves a green
      light and hospital oversight.

PMID- 12606901
TI  - Do they understand? (part I): parental consent for children participating in
      clinical anesthesia and surgery research.
AB  - BACKGROUND: Central to the tenet of informed consent is the quality of disclosure
      of information by the investigator and the understanding thereof by the research
      subject or his or her surrogate. This study was designed to measure parents'
      understanding of the elements of informed consent for clinical studies in which
      their children had been approached to participate. METHODS: The study sample
      consisted of 505 parents who had been approached for permission to allow their
      child to participate in a clinical anesthesia or surgery study. Regardless of
      whether the parent consented (consenters, n = 411) or declined (nonconsenters, n
      = 94) to their child's participation in a study, they were interviewed to
      determine their understanding of 11 elements of consent. Two independent
      assessors who were familiar with the study protocols scored the parents' levels
      of understanding. RESULTS: Parents perceived their overall understanding of the
      elements of consent as high (8.7 +/- 1.6; 0-10 scale); however, this represented
      a significant overestimation compared with the assessors' measures of parental
      understanding (7.3 +/- 1.8; P< 0.0001). Furthermore, consenters had greater
      understanding than nonconsenters (7.6 +/- 1.6 vs 6.1 +/- 1.9; P< 0.001). Several
      predictors of understanding were identified, including whether the parent
      consented, education level, clarity of disclosure, child in previous study, age
      of parent, parent listened to disclosure, and degree to which parent read the
      consent document. The day on which consent was sought had no impact on the level
      of understanding. CONCLUSIONS: Parents approached for permission to allow their
      child to participate in a research study had less than optimal understanding of
      the elements of consent. As such, investigators must make every effort to enhance
      understanding and ensure that parents have sufficient information to make
      informed decisions regarding their child's participation in research studies.

PMID- 12606902
TI  - Do they understand? (part II): assent of children participating in clinical
      anesthesia and surgery research.
AB  - BACKGROUND: Participation of children in clinical research requires not only
      parental permission but also the assent of the child. Although there is no fixed
      age at which assent should be sought, investigators should obtain assent from
      children considered able to provide it. This study was designed to determine
      children's understanding of the elements of disclosure for studies in which they
      had assented to participate. METHODS: The study population included 102 children
      aged 7-18 yr who had given their assent to participate in a clinical anesthesia
      or surgical study. Children were interviewed using a semistructured format to
      determine their understanding of eight core elements of disclosure for the study
      to which they had agreed to participate. Two independent assessors scored the
      children's levels of understanding of these elements. RESULTS: The children's
      perceived level of understanding of the elements of disclosure was significantly
      greater than their measured understanding (7.0 +/- 2.4 vs 5.3 +/- 2.7, 0-10
      scale; P< 0.0001). Complete understanding of the elements of disclosure for all
      children ranged from 30.4 to 89.4%. Children aged more than 11 yr had
      significantly greater understanding compared with younger children, particularly
      with respect to understanding of the study protocol, the benefits, and the
      freedom to withdraw. CONCLUSIONS: Children approached for their assent to
      participate in a clinical anesthesia or surgery study have limited understanding
      of the elements of disclosure and their role as a research participant,
      particularly if they are aged less than 11 yr.

PMID- 12606903
TI  - Teaching with a video system improves the training period but not subsequent
      success of tracheal intubation with the Bullard laryngoscope.
AB  - BACKGROUND: The Bullard laryngoscope is useful for the management of a variety of
      airway management scenarios. Without the aid of a video system, teaching
      laryngoscopy skills occurs with indirect feedback to the instructor. The purpose
      of this study was to determine if use of a video system would speed the process
      of learning the Bullard laryngoscope or improve the performance (speed or
      success) of its use. METHODS: Thirty-six anesthesia providers with no previous
      Bullard laryngoscope experience were randomly divided into two groups: initial
      training (first 15 intubations) with looking directly through the eyepiece (n =
      20), or with the display of the scope on a video monitor (n = 16). The subjects
      each then performed 15 Bullard intubations by looking directly through the
      eyepiece. RESULTS: There was not an overall significant difference in
      laryngoscopy or intubation times between the groups. When only the first 15
      intubations were considered, the laryngoscopy time was shorter in the video group
      (26 +/- 24) than in the nonvideo group (32 +/- 34; P< 0.04). In the first 15
      patients, there were fewer single attempts at intubation (67.9% vs 80.3%; P<
      0.002) and more failed intubations (17.2% vs 6.0%; P< 0.0001) in the nonvideo
      group. CONCLUSIONS: In conclusion, the authors have shown that use of a video
      camera decreases time for laryngoscopic view and improves success rate when the
      Bullard laryngoscope is first being taught to experienced clinicians. However,
      these benefits are not evident as more experience with the Bullard laryngoscope
      is achieved, such that no difference in skill with the Bullard laryngoscope is
      discernible after 15 intubations whether a video system was used to teach this
      technique.

PMID- 12606904
TI  - Correlation of approximate entropy, bispectral index, and spectral edge frequency
      95 (SEF95) with clinical signs of "anesthetic depth" during coadministration of
      propofol and remifentanil.
AB  - BACKGROUND: Several studies relating electroencephalogram parameter values to
      clinical endpoints using a single (mostly hypnotic) drug at relatively low levels
      of central nervous system depression (sedation) have been published. However, the
      usefulness of a parameter derived from the electroencephalogram for clinical
      anesthesia largely depends on its ability to predict the response to stimuli of
      different intensity or painfulness under a combination of a hypnotic and an
      (opioid) analgesic. This study was designed to evaluate the predictive
      performance of spectral edge frequency 95 (SEF95), BIS, and approximate entropy
      for the response to increasingly intense stimuli under different concentrations
      of both propofol and remifentanil in the therapeutic range. METHODS: Ten healthy
      male and ten healthy female volunteers were studied during coadministration of
      propofol and remifentanil. After having maintained a specific target
      concentration for 10 min, the depth of sedation-anesthesia was assessed using the
      responsiveness component of the Observer's Assessment of Alertness/Sedation
      (OAA/S) rating scale, which was modified by adding insertion of a laryngeal mask
      and laryngoscopy. The electroencephalogram derived parameters approximate
      entropy, bispectral index, and SEF95 were recorded just before sedation level was
      assessed. RESULTS: The prediction probability values for approximate entropy were
      slightly, but not significantly, better than those for bispectral index, SEF95,
      and the combination of drug concentrations. A much lower prediction ability was
      observed for tolerance of airway manipulation than for hypnotic endpoints.
      CONCLUSION: Approximate entropy revealed informations on hypnotic and analgesic
      endpoints using coadministration of propofol and remifentanil comparable to
      bispectral index, SEF95, and the combination of drug concentrations.

PMID- 12606905
TI  - Risk factors for adverse postoperative outcomes in children presenting for
      cardiac surgery with upper respiratory tract infections.
AB  - BACKGROUND: Otherwise healthy children who present for elective surgery with an
      upper respiratory infection (URI) may be at risk for perioperative respiratory
      complications. This risk may be increased in children with congenital heart
      disease who undergo cardiac surgery while harboring a URI because of their
      compromised cardiopulmonary status. Therefore, this study was designed to
      determine the incidence of peri- and postoperative complications in children
      undergoing cardiac surgery while harboring a URI. METHODS: The study population
      consisted of 713 children scheduled to undergo cardiac surgery. Of these, 96 had
      symptoms of URI, and 617 were asymptomatic. Children were followed prospectively
      from induction of anesthesia to discharge from the hospital to determine the
      incidence of postoperative respiratory, cardiovascular, neurologic, and surgical
      adverse events. Duration of postoperative ventilation, time in the intensive care
      unit (ICU), and length of hospital stay were also recorded. RESULTS: Children
      with URIs had a significantly higher incidence of respiratory and multiple
      postoperative complications than children with no URIs (29.2 vs 17.3% and 25 vs
      10.3%, respectively; P< 0.01) and a higher incidence of postoperative bacterial
      infections (5.2 vs 1.0%; P= 0.01). Furthermore, logistic regression indicated
      that the presence of a URI was an independent risk factor for multiple
      postoperative complications and postoperative infections in children undergoing
      open heart surgery. Children with URIs also stayed longer in the intensive care
      unit than children with no URIs (75.9 +/- 89.8 h vs 57.7 +/- 63.8, respectively;
      P< 0.01). However, the overall length of hospital stay was not significantly
      different (8.4 vs 7.8 days, URI vs non-URI groups; P> 0.05). CONCLUSIONS: The
      presence of a URI was predictive of postoperative infection and multiple
      complications in children presenting for cardiac surgery. Despite this, the
      presence of a URI does not appear to affect the patient's overall length of
      hospital stay nor the development of long-term sequelae.

PMID- 12606906
TI  - Combined effects of nitrous oxide and propofol on the dynamic cerebrovascular
      response to step changes in end-tidal PCO2 in humans.
AB  - BACKGROUND: Nitrous oxide (N2O) and propofol exhibit directionally opposite
      effects on the cerebral circulation, vasodilation and vasoconstriction,
      respectively. The authors investigated an interaction between the two anesthetic
      agents on the dynamic cerebrovascular response to step changes in end-tidal
      pressure of carbon dioxide (PetCO2) in humans. METHODS: Participants with no
      systemic diseases were allocated into two groups, each of which was anesthetized
      sequentially with two protocols. Patients in group 1 were anesthetized with 30%
      O2 + 70% N2O. A continuous intravenous infusion of propofol (7-10 mg x kg(-1) x
      h(-1)) was then added to the N2O. Patients in group 2 were anesthetized first
      with continuous infusion of propofol (10 mg x kg(-1) h(-1)), and then 30% O2 +
      70% N2O was added to the propofol anesthesia. Using transcranial Doppler
      ultrasonography, blood flow velocity at the middle cerebral artery (FV(MCA)) was
      measured during a step increase (on-response) followed by a step decrease (off
      response) in PetCO2, with PetCO2 ranging between approximately 28 and 50 mmHg.
      The dynamic FV(MCA)-PetCO2 relationship was analyzed using a mathematical model
      that was characterized with a pure time delay, and a time constant and a gain
      each for the on- or off-response. RESULTS: The addition of propofol to the N2O
      anesthesia increased the on-response time constant (P < 0.01), whereas the
      addition of N2O to the propofol anesthesia increased the time constants for on-
      (P < 0.01) and off-responses (P < 0.05). However, the addition of either
      anesthetic did not affect the gains. CONCLUSIONS: Propofol and N2O, when one is
      added to the other, produce similar dynamic FV(MCA) responses to sudden changes
      in PetCO2. Addition of each anesthetic slows the dynamic response and produces
      the response whose magnitude is proportional to the baseline FV(MCA).

PMID- 12606907
TI  - Sustained prolongation of the QTc interval after anesthesia with sevoflurane in
      infants during the first 6 months of life.
AB  - BACKGROUND: Sevoflurane, an inhalational anesthetic frequently administered to
      infants, prolongs the QT interval of the electrocardiogram in adults. A long QT
      interval resulting in fatal arrhythmia may also be responsible for some cases of
      sudden death in infants. As the QT interval increases during the second month of
      life and returns to the values recorded at birth by the sixth month, we evaluated
      the effect of sevoflurane on the QT interval during and after anesthesia in this
      particular population. METHODS: In this prospective two-group trial we examined
      pre-, peri-, and postoperative electrocardiograms of 36 infants aged 1 to 6
      months scheduled for elective inguinal or umbilical hernia repair. Anesthesia was
      induced and maintained with either sevoflurane, or the well-established pediatric
      anesthetic halothane. Heart rate corrected (c) QTc and JTc interval (indicator of
      intraventricular conduction delays) were recorded from electrocardiograms before
      and during anesthesia, and at 60 min after emergence from anesthesia. RESULTS:
      Prolonged QTc was observed during sevoflurane anesthesia (mean [+/-SD], 473 +/-
      19 ms, P< 0.01). Sixty minutes after emergence from anesthesia, QTc was still
      prolonged (433 +/- 15 ms) in infants treated with sevoflurane compared with those
      treated with halothane (407 +/- 33 ms, P< 0.01). Analogous differences were found
      for the JTc interval. CONCLUSIONS: Despite a shorter elimination time than better
      known inhalational anesthetics, sevoflurane induction and anesthesia results in
      sustained prolongations of QTc and JTc interval in infants in the first 6 months
      of life. Electrocardiogram monitoring until the QTc interval has returned to
      preanesthetic values may increase safety after sevoflurane anesthesia.

PMID- 12606908
TI  - Comparative analysis of apoptosis-inducing activity of codeine and codeinone.
AB  - BACKGROUND: There are relatively few studies about the antiproliferative effects
      of codeine-related compounds on human cancer cell lines, compared with those of
      morphine-related compounds. The authors previously found that codeinone, an
      oxidation metabolite of codeine, among 10 opioids, showed the highest cytotoxic
      activity (DNA fragmentation-inducing activity) against human promyelocytic
      leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L
      cysteine (NAC). These findings prompted us to perform a more detailed study of
      apoptosis induction after codeinone treatment. METHODS: Apoptosis was induced by
      treating HL-60 cells for 1-6 h with codeine or codeinone. DNA fragmentation was
      assessed by both agarose gel electrophoresis and fluorometric determination of
      the fragmented DNA after staining with diamidinophenylindole (DAPI). The
      appearance of apoptotic cells was monitored by microscopic observation after
      staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS)
      after staining with Annexin. The release of cytochrome c and cytochrome oxidase
      from mitochondria and activation of caspase 3 were monitored by Western blot
      analysis. Intracellular caspase 3-like activity was confirmed by FACS, using cell
      permeable substrate. Mitochondrial manganese-containing superoxide dismutase
      (MnSOD) activity and mRNA expression were assayed by activity staining after
      separation on the polyacrylamide gel electrophoresis, and reverse transcriptase
      polymerase chain reaction (RT-PCR), respectively. RESULTS: Codeinone induced
      internucleosomal DNA fragmentation and production of Annexin-positive apoptotic
      cells more potently than codeine in HL-60 cells. Codeinone stimulated the release
      of both cytochrome c and cytochrome oxidase, and cleavage of procaspase 3 without
      significant changes in both the activity and expression of MnSOD. CONCLUSIONS:
      Codeinone was found to possess both apoptosis and necrosis-inducing activity, in
      addition to the reported antinociceptive activity, further substantiating its
      antitumor potential.

PMID- 12606909
TI  - Randomized assessment of resource use in fast-track cardiac surgery 1-year after
      hospital discharge.
AB  - BACKGROUND: The authors assessed the safety and resource use associated with fast
      track cardiac anesthesia (FTCA) after coronary artery bypass graft surgery (CABG)
      over a 1-yr period. METHODS: One hundred twenty patients were initially
      randomized to FTCA (n = 60) or conventional anesthetic (n = 60) for primary
      elective CABG surgery. Patients were followed for 1-yr after index surgery
      through linkage to universal administrative databases. Acute care hospital
      readmission rates and length of stay (LOS) and the downstream use of health
      resources were compared. Resource use was analyzed as use of hospital and
      rehabilitation center bed-days, expenditures on physician services, and use of
      cardiac drugs. RESULTS: There were no deaths during the 1-yr follow-up after
      initial discharge; 15 (25%) patients from both groups were readmitted to acute
      care hospitals in the follow-up period. The mean LOS for acute care readmission
      was 0.3 (1.0) in the FTCA and 1.6 (6.3) days in the conventional group at 3
      months; P= 0.01, 95% CI (0.1, 5.7) and 0.8 (1.8) and 2.9 (9.6) days at 12 months;
      P= 0.01, 95% CI (0.2, 7.5). Two (3.3%) patients in the FTCA group and 9 (15%)
      patients in the conventional group were transferred to rehabilitation facilities.
      The LOS was 0.3 (1.5) and 2.3 (5.7) days respectively; P= 0.001, 95% CI (0.6,
      4.0). Specialist visits were more frequent in the FTCA group 6.2 (13.2) versus
      1.9 (2.2) visits respectively; P= 0.002, 95% CI (-9.0, -1.3). Percentage
      reduction of FTCA cost was 68% at 3 months, P= 0.0002 and 49.5% at 1-yr, P= 0.004
      after index hospital discharge. CONCLUSIONS: Fast-track cardiac anesthesia is a
      safe practice that decreases resource use for a 1-yr period after index
      hospitalization.

PMID- 12606910
TI  - Redistribution of microcirculatory blood flow within the intestinal wall during
      sepsis and general anesthesia.
AB  - BACKGROUND: Hypoperfusion of the intestinal mucosa remains an important clinical
      problem during sepsis. Impairment of the autoregulation of microcirculatory blood
      flow in the intestinal tract has been suggested to play an important role in the
      development of multiple organ failure during sepsis and surgery. The authors
      studied microcirculatory blood flow in the gastrointestinal tract in anesthetized
      subjects during early septic shock. METHODS: Eighteen pigs were intravenously
      anesthetized and mechanically ventilated. Regional blood flow in the superior
      mesenteric artery was measured with ultrasound transit time flowmetry.
      Microcirculatory blood flow was continuously measured with a six-channel laser
      Doppler flowmetry system in the mucosa and the muscularis of the stomach,
      jejunum, and colon. Eleven pigs were assigned to the sepsis group, while seven
      animal served as sham controls. Sepsis was induced with fecal peritonitis, and
      intravenous fluids were administered after 240 min of sepsis to alter hypodynamic
      sepsis to hyperdynamic sepsis. RESULTS: In the control group, all monitored flow
      data remained stable throughout the study. During the hypodynamic phase of
      sepsis, cardiac output, superior mesenteric artery flow, and microcirculatory
      blood flow in the gastric mucosa decreased by 45%, 51%, and 40%, respectively,
      compared to baseline (P < 0.01 in all). Microcirculatory blood flow in the
      muscularis of the stomach, jejunum, and colon decreased by 55%, 64%, and 70%,
      respectively (P < 0.001 in all). In contrast, flow in the jejunal and colonic
      mucosa remained virtually unchanged. During the hyperdynamic phase of sepsis,
      there was a threefold increase in cardiac output and superior mesenteric artery
      flow. Blood flow in the gastric, jejunal, and colonic mucosa also increased (22%,
      24%, and 31% above baseline, respectively). Flow in the muscularis of the stomach
      returned to baseline, while in the jejunum and colon, flow in the muscularis
      remained significantly below baseline (55% and 45%, respectively, P< 0.01).
      CONCLUSIONS: It appears that in early septic shock, autoregulation of
      microcirculatory blood flow is largely intact in the intestinal mucosa in
      anesthetized pigs, explaining why microcirculatory blood flow remained virtually
      unchanged. This may be facilitated through redistribution of flow within the
      intestinal wall, from the muscularis toward the mucosa.

PMID- 12606911
TI  - Isoflurane but not mechanical ventilation promotes extravascular fluid
      accumulation during crystalloid volume loading.
AB  - BACKGROUND: The combination of isoflurane anesthesia and mechanical ventilation
      reduces urinary output and promotes redistribution of a crystalloid bolus into
      the extravascular space. The authors hypothesized that mechanical ventilation
      rather than isoflurane causes this alteration. METHODS: The fate of a 25-ml/kg,
      20-min, 0.9% saline fluid bolus was studied in four different experiments per
      sheep: while conscious and spontaneously ventilating (CSV), while conscious and
      mechanically ventilated (CMV), while anesthetized with isoflurane and mechanical
      ventilated (ISOMV), and while anesthetized with isoflurane and spontaneously
      ventilating (ISOSV). RESULTS: By calculations based on the indicator dilution and
      mass balance principles, plasma expansion was similar between protocols.
      Isoflurane but not mechanical ventilation reduced urinary output and increased
      interstitial fluid volume (P < 0.001): At 180 min, mean total urinary outputs
      were 15.6 +/- 2.1 and 15.9 +/- 2.9 ml/kg in the CSV and CMV protocols and 2.7 +/-
      0.6 and 3.1 +/- 1.1 ml/kg in the ISOSV and ISOMV protocols, respectively. The net
      changes in extravascular volume, assumed to be interstitial fluid volume, were
      8.6 +/- 3.3 and 8.1 +/- 3.1 ml/kg, and 22.5 +/- 1.5 and 22.1 +/- 1.6 ml/kg in the
      corresponding protocols. Volume kinetic analysis demonstrated extravascular fluid
      accumulation associated with isoflurane anesthesia similar to the calculated
      interstitial accumulation of 20.2 +/- 0.5 and 26.5 +/- 0.3 ml/kg in the ISOSV and
      ISOMV protocols, respectively. CONCLUSION: Isoflurane, but not mechanical
      ventilation, decreased urinary excretion and increased interstitial fluid volume.
      Volume kinetic analysis indicated "third-space" losses due to isoflurane.
      Perioperative fluid retention may be associated not only with surgical tissue
      manipulation, but with anesthesia per se.

PMID- 12606912
TI  - Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent
      glutamatergic transmission in rat substantia gelatinosa neurons.
AB  - BACKGROUND: Although intrathecal administration of norepinephrine is known to
      produce analgesia, cellular mechanisms for this action have not yet been fully
      understood. METHODS: The actions of norepinephrine (50 microm) on glutamatergic
      transmission were examined by using the whole cell patch clamp technique in
      substantia gelatinosa neurons of an adult rat spinal cord slice with an attached
      dorsal root. RESULTS: Norepinephrine inhibited the amplitude of monosynaptically
      evoked A delta-fiber and C-fiber excitatory postsynaptic currents in a reversible
      manner. When compared in magnitude between the A delta-fiber and C-fiber
      excitatory postsynaptic currents, the former inhibition (50 +/- 4%, n = 20) was
      significantly larger than the latter one (28 +/- 4%, n = 8). Both actions of
      norepinephrine were mimicked by an alpha2 adrenoceptor agonist, clonidine (10
      microm), and an alpha 2A agonist, oxymetazoline (10 microm), but not by an alpha1
      agonist, phenylephrine (10 microm), and a beta agonist, isoproterenol (40
      microm). The inhibitory actions were antagonized by an alpha 2 antagonist,
      yohimbine (1 microm), all of the results of which indicate an involvement of
      alpha 2 adrenoceptors. Norepinephrine did not affect the amplitude of miniature
      excitatory postsynaptic current and of a response of substantia gelatinosa
      neurons to AMPA, indicating that its action on evoked excitatory postsynaptic
      currents is presynaptic in origin. CONCLUSIONS: Norepinephrine inhibits A delta
      fiber- and C-fiber-mediated sensory transmission to substantia gelatinosa neurons
      through the activation of the alpha 2 adrenoceptor (possibly alpha2A type, based
      on the current, published behavioral and anatomical data) existing in primary
      afferent terminals; this action of norepinephrine is more effective in A delta
      fiber than C-fiber transmission. This could contribute to at least a part of
      inhibitory modulation of pain sensation in the substantia gelatinosa by
      intrathecally administered norepinephrine.

PMID- 12606913
TI  - Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive
      dysfunction in the rat.
AB  - BACKGROUND: With clinical data suggesting a role for excitatory amino acid
      neurotransmission in the pathogenesis of cardiopulmonary bypass (CPB)-associated
      brain injury, the current study was designed to determine whether xenon, an N
      methyl-D-aspartate receptor antagonist, would attenuate CPB-induced neurologic
      and neurocognitive dysfunction in the rat. METHODS: Following surgical
      preparation, rats were randomly divided into four groups: (1) sham rats were
      cannulated but did not undergo CPB; (2) CPB rats were subjected to 60 min of CPB
      using a membrane oxygenator receiving a gas mixture of 30% O2, 65% N2, and 5%
      CO2; (3) CPB + MK801 rats received MK801 (0.15 mg/kg intravenous) 15 min prior to
      60 min of CPB with the same gas mixture; and (4) CPB + xenon rats underwent 60
      min of CPB using an oxygenator receiving 30% O2, 60% xenon, 5% N2, and 5% CO2.
      Following CPB, the rats recovered for 12 days, during which they underwent
      standardized neurologic and neurocognitive testing (Morris water maze). RESULTS:
      The sham and CPB + xenon groups had significantly better neurologic outcome
      compared to both the CPB and CPB + MK801 groups on postoperative days 1 and 3 (P
      < 0.05). Compared to the CPB group, the sham, CPB + MK801, and CPB + xenon groups
      had better neurocognitive outcome on postoperative days 3 and 4 (P < 0.001). By
      the 12th day, the neurocognitive outcome remained significantly better in the CPB
      + xenon group compared to the CPB group (P < 0.01). CONCLUSION: These data
      indicate that CPB-induced neurologic and neurocognitive dysfunction can be
      attenuated by the administration of xenon, potentially related to its
      neuroprotective effect via N-methyl-D-aspartate receptor antagonism.

PMID- 12606914
TI  - Vasopressin, but not fluid resuscitation, enhances survival in a liver trauma
      model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.
AB  - BACKGROUND: The authors compared the effects of vasopressin fluid resuscitation
      on survival in a liver trauma model with uncontrolled and otherwise lethal
      hemorrhagic shock in pigs. METHODS: A midline laparotomy was performed on 23
      domestic pigs, followed by an incision, and subsequent finger fraction across the
      right medial liver lobe. During hemorrhagic shock, animals were randomly assigned
      to receive either 0.4 U/kg vasopressin (n = 9), or fluid resuscitation (n = 7),
      or saline placebo (n = 7), respectively. A continuous infusion of 0.08 U x kg(-1)
      x min(-1) vasopressin in the vasopressin group, or normal saline was subsequently
      administered in the fluid resuscitation and saline placebo group, respectively.
      After 30 min of experimental therapy, bleeding was controlled by surgical
      intervention, and blood transfusion and rapid fluid infusion were subsequently
      performed. RESULTS: Maximum mean arterial blood pressure during experimental
      therapy in the vasopressin-treated animals was significantly higher than in the
      fluid resuscitation and saline placebo groups (mean +/- SD, 72 +/- 26 vs 38 +/-
      16 vs 11 +/- 7 mmHg, respectively; P< 0.05). Subsequently, mean arterial blood
      pressure remained at approximately 40 mmHg in all vasopressin-treated animals,
      whereas mean arterial blood pressure in all fluid resuscitation and saline
      placebo pigs was close to aortic hydrostatic pressure (approximately 15 mmHg)
      within approximately 20 min of experimental therapy initiation. Total blood loss
      was significantly higher in the fluid resuscitation pigs compared with
      vasopressin or saline placebo after 10 min of experimental therapy (65 +/- 6 vs
      42 +/- 4 vs 43 +/- 6 ml/kg, respectively; P< 0.05). Seven of seven fluid
      resuscitation, and seven of seven saline placebo pigs died within approximately
      20 min of experimental therapy, while 8 of 9 vasopressin animals survived more
      than 7 days (P < 0.05). CONCLUSIONS: Vasopressin, but not fluid resuscitation or
      saline placebo, ensured survival with full recovery in this liver trauma model
      with uncontrolled and otherwise lethal hemorrhagic shock in pigs.

PMID- 12606915
TI  - Morphine enhances pharmacological preconditioning by isoflurane: role of
      mitochondrial K(ATP) channels and opioid receptors.
AB  - BACKGROUND: Adenosine triphosphate-regulated potassium channels mediate
      protection against myocardial infarction produced by volatile anesthetics and
      opioids. We tested the hypothesis that morphine enhances the protective effect of
      isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium
      channels and opioid receptors. METHODS: Barbiturate-anesthetized rats (n = 131)
      were instrumented for measurement of hemodynamics and subjected to a 30 min
      coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size
      was determined using triphenyltetrazolium staining. Rats were randomly assigned
      to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration
      [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane
      (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before
      coronary occlusion. In eight additional groups of experiments, rats received 5
      hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or
      absence of isoflurane, morphine, and morphine plus isoflurane. RESULTS:
      Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n
      = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to
      control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further
      decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not
      affect infarct size, but abolished cardioprotection produced by isoflurane,
      morphine, and morphine plus isoflurane. CONCLUSIONS: Combined administration of
      isoflurane and morphine enhances the protection against myocardial infarction to
      a greater extent than either drug alone. This beneficial effect is mediated by
      mitochondrial adenosine triphosphate-regulated potassium channels and opioid
      receptors in vivo.

PMID- 12606916
TI  - Neutrophils pretreated with volatile anesthetics lose ability to cause cardiac
      dysfunction.
AB  - BACKGROUND: Volatile anesthetics can precondition the myocardium against
      functional depression and infarction following ischemia-reperfusion. Neutrophil
      activation, adherence, and release of superoxide play major roles in reperfusion
      injury. The authors tested the hypothesis that pretreatment of neutrophils with a
      volatile anesthetic, i.e., simulated preconditioning, can blunt their ability to
      cause cardiac dysfunction. METHODS: Studies were performed in 60 buffer-perfused
      and paced isolated rat hearts. Left ventricular developed pressure served as an
      index of myocardial contractility. Polymorphonuclear neutrophils and/or drugs
      were added to coronary perfusate for 10 min, followed by 30 min of recovery.
      Platelet-activating factor was used to stimulate neutrophils. Pretreatment of
      neutrophils consisted of incubation with 1.0 minimum alveolar concentration (MAC)
      isoflurane or sevoflurane for 15 min, followed by washout. Additional studies
      were performed with 0.25 MAC isoflurane. Effects of superoxide dismutase were
      compared to those of volatile anesthetics. Superoxide production was measured by
      spectrophotometry. Neutrophil adherence to coronary vascular endothelium was
      estimated from the difference between neutrophils administered and recovered in
      coronary venous effluent. RESULTS: Activated neutrophils caused marked,
      persistent reduction (> 50%) in left ventricular developed pressure. Isoflurane
      and sevoflurane at 1.0 MAC and superoxide dismutase abolished this effect.
      Isoflurane and sevoflurane reduced superoxide production of activated neutrophils
      by 29% and 33%, respectively, and completely prevented the platelet-activating
      factor-induced increases in neutrophil adherence. Isoflurane at 0.25 MAC blunted,
      but did not abolish, the neutrophil-induced decreases in left ventricular
      developed pressure. CONCLUSION: Neutrophils pretreated with 1.0 MAC isoflurane or
      sevoflurane lost their ability to cause cardiac dysfunction, while those
      pretreated with a concentration of isoflurane as low as 0.25 MAC were partially
      inhibited. This action of the volatile anesthetics was associated with reductions
      in superoxide production and neutrophil adherence to the coronary vascular
      endothelium. Our findings suggest that inhibitory actions on neutrophil
      activation and neutrophil-endothelium interaction may contribute to the
      preconditioning effects of volatile anesthetics observed in vivo during
      myocardial ischemia-reperfusion.

PMID- 12606917
TI  - Caudal ropivacaine and neostigmine in pediatric surgery.
AB  - BACKGROUND: Neostigmine has been added to local anesthetics for different nerve
      blocks. This study was conducted to evaluate effects of neostigmine when added to
      ropivacaine for caudal anesthesia. METHODS: We studied children, aged 1-5 yr,
      undergoing inguinal hernia and hypospadias surgery. After standard induction of
      anesthesia, Group I received 0.2% ropivacaine 0.5 ml/kg and Group II received
      0.2% ropivacaine 0.5 ml/kg with 2 microg/kg neostigmine via the caudal route.
      Heart rate, mean arterial pressure, and pulse oximetry were recorded before
      induction, after induction, and then every 10 min after caudal anesthesia.
      Hemodynamic, Toddler-Preschooler Postoperative Pain Scale pain score, and
      sedation score values were recorded 30 min after extubation and at hours 2, 4, 6,
      12, and 24. A pain score greater than 3/10 resulted in administration of rectal
      paracetamol. RESULTS: There were no differences between the groups in demographic
      and hemodynamic data, duration of surgery and anesthesia, time to extubation, or
      sedation scores. The pain scores were significantly lower in Group II at 6 and 12
      h (P < 0.05). Time to first analgesic requirement was statistically prolonged in
      Group II (19.2 +/- 5.5h) when compared with Group I (7.1 +/- 5.7 h) (P < 0.05).
      Total analgesic consumption was statistically larger in Group I (174 +/- 96 mg)
      when compared with Group II (80 +/- 85.5 mg) (P < 0.05). The incidence of
      vomiting (3 patients in Group II and 1 patient in Group I) was not statistically
      significantly different. CONCLUSIONS: The authors found that a single caudal
      injection of neostigmine when added to ropivacaine offers an advantage over
      ropivacaine alone for postoperative pain relief in children undergoing
      genitourinary surgery.

PMID- 12606918
TI  - Posterior approach to the sciatic nerve in adults: is euclidean geometry still
      necessary?
AB  - BACKGROUND: Every approach to the sciatic nerve in the buttocks currently
      requires the identification of pelvic bone structures. The large size of the
      nerve and its constant trajectory suggest that a simplified approach is possible.
      METHODS: During the first stage, 24 sciatic nerves in adult cadavers were
      dissected. The most significant findings were, (1) caudal to the piriformis
      muscle the sciatic nerve runs parallel to the midline (intergluteal sulcus); (2)
      the distance between the nerve and the intergluteal sulcus during this course is
      approximately 10 cm in adults, regardless of their gender, size, or body habits.
      In the clinical stage 20 blocks were performed at 10 cm from the midline of the
      buttocks using a nerve stimulator and insulated needles. RESULTS: All blocks were
      accomplished in less than 8.5 min. The technique proved easy to teach. Residents
      performed most of the blocks. Incision time, measured from the time of the
      injection, was less than 29 min in all cases. There were 18 successful blocks and
      2 failures. CONCLUSIONS: Because of the intimate relationship of the sciatic
      nerve to the bony pelvis, the position of this nerve in the buttocks is constant.
      Caudal to the piriformis muscle the nerve runs vertically between the ischium and
      the greater trochanter. The location of this narrow passage, not the buttocks'
      size, determines the position of the nerve. While the size of the buttocks is
      variable among different individuals and in the same individual at different
      stages of adult life, the relationship of the sciatic nerve to the pelvis is
      constant throughout life. Using this relationship to our advantage, a sciatic
      block in adults can be accomplished at 10 cm lateral to the intergluteal sulcus
      without a need for identification of buried structures or line tracings.

PMID- 12606919
TI  - Gabapentin markedly reduces acetic acid-induced visceral nociception.
AB  - BACKGROUND: Gabapentin has recently been used clinically as an antihyperalgesic
      agent to treat certain neuropathic pain states. The aim of this study is to test
      whether gabapentin is able to inhibit responses to peritoneal irritation-induced
      visceral pain and to examine the effect of gabapentin on spinal cord amino acid
      release. METHODS: The acetic acid-induced writhing assay was used in rats to
      determine the degree of antinociception. The rats received an intraperitoneal
      injection of acetic acid 40 min after intraperitoneal administration of vehicle
      or gabapentin (50, 100, or 200 mg/kg). Cerebrospinal fluid dialysate was
      collected by microdialysis from the spinal subarachnoid space in anesthetized
      rats. Acetic acid-induced release of amino acids into the dialysate, including
      glutamate, aspartate, serine, glutamine, and glycine, following intraperitoneal
      injection of acetic acid was evaluated by measurements of changes in the
      concentrations of these amino acids. The effects of pretreatment with saline or
      gabapentin (100 mg/kg intraperitoneal) on amino acid release were compared.
      RESULTS: Gabapentin reduced writhing responses in a dose-related fashion.
      Dialysate concentrations of glutamate, aspartate, and serine increased
      significantly following intraperitoneal injection of acetic acid, while glutamine
      and glycine concentrations were not increased significantly. When compared to
      saline-treated rats, animals pretreated with 100 mg/kg gabapentin showed
      suppression of the acetic acid-induced increases in glutamate, aspartate, and
      serine concentrations. CONCLUSIONS: These data demonstrate that gabapentin
      effectively inhibits acetic acid-induced nociception, and the antinociceptive
      effect of gabapentin correlates with the suppression of noxious-evoked release of
      excitatory amino acids in the spinal cord.

PMID- 12606920
TI  - Intrathecal coadministration of D-APV and morphine is maximally effective in a
      rat experimental pancreatitis model.
AB  - BACKGROUND: Many studies have demonstrated that either glutamate -methyl-d
      aspartate (NMDA) receptor antagonists or opioid receptor agonists provide
      antinociception. Spinal coadministration of an NMDA receptor antagonist and
      morphine has an additive action for control of various pain states in animal
      models. The current study examined spinal coadministration of low doses of NMDA
      receptor antagonist, D-(-)-2-Amino-5-phosphonovalerate (D-APV), and mu-opioid
      receptor agonist, morphine sulfate (MS), in reducing visceral nociception using
      an acute bradykinin induced pancreatitis model in rats. METHODS: An intrathecal
      catheter was surgically inserted into the subarachnoid space for spinal drug
      administration in Sprague-Dawley rats. A laparotomy was performed for ligation
      and cannulation of the bile-pancreatic duct. Rats were pretreated intrathecally
      with artificial cerebrospinal fluid (aCSF), D-APV, MS, or combined administration
      of D-APV and MS. These treatments were given 30 min before noxious visceral
      stimulation with bradykinin injected through the bile-pancreatic catheter.
      Spontaneous behavioral activity tests, including cage crossing, rearing, and hind
      limb extension, were conducted before and after bradykinin injection into the
      bile-pancreatic duct to assess visceral nociception. RESULTS: Spinal pretreatment
      of D-APV or low doses of MS partially reduced visceral pain behaviors in this
      model. Pretreatments with combinations of low doses of MS (0.05-0.5 microg) and D
      APV (1 microg) were maximally effective in returning all spontaneous behavioral
      activities to baseline. CONCLUSIONS: Spinal administration of combined doses of
      NMDA receptor antagonist, D-APV, and MS reversed three behavioral responses to
      induction of an acute pancreatitis model. These results suggest that in the
      clinical management of visceral pain, such as pancreatitis, restricted usage of
      glutamate antagonists might be useful as adjuvant potentiation at the onset of
      morphine therapy.

PMID- 12606921
TI  - The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic
      administration of acetaminophen.
AB  - BACKGROUND: It has been proposed that serotonin participates in the central
      antinociceptive effect of acetaminophen. The serotonin activity in the brainstem
      is primarily under the control of 5-HT1A somatodendritic receptors, although some
      data also suggest the involvement of 5-HT1B receptors. In the presence of
      serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei
      leads to an increase in serotonin release in terminal areas, thus improving
      serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors
      in the antinociceptive effect of acetaminophen in mice. METHODS: The effects of
      acetaminophen (600 mg/kg intraperitoneal) followed by different doses of
      antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg
      subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129
      [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively,
      were determined in the hot-plate test in mice. RESULTS: Acetaminophen (300-800
      mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in
      mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the
      antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose
      related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the
      antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B
      antagonist) induced a dose-related increase in the antinociceptive effect of
      acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased
      the antinociceptive effect of acetaminophen. CONCLUSIONS: These results suggest
      that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B
      antagonist properties could be a new strategy to improve the analgesia of
      acetaminophen, thanks to its mild serotonergic properties.

PMID- 12606922
TI  - Clonidine-induced neuronal activation in the spinal cord is altered after
      peripheral nerve injury.
AB  - BACKGROUND: Alpha 2 adrenoceptor agonists produce antinociception in normal
      animals and alleviate mechanical allodynia in animals with nerve injury, although
      their mechanism of action may differ in these situations. The purpose of this
      study was to examine the location and number of cells in the spinal cord
      activated by intrathecal clonidine in these two circumstances and to test whether
      one class of interneurons, cholinergic, express alpha 2 adrenoceptors. METHODS:
      Intrathecal saline or clonidine, 10 and 30 microg, was injected in normal rats or
      those with mechanical allodynia following partial sciatic nerve section. Two
      hours later, animals were anesthetized and pericardially perfused. The number of
      cells in superficial and deep dorsal horn laminae at the L4-L5 level
      immunostained for phosphorylated cAMP response element binding protein (pCREB)
      were quantified. In separate studies, the authors colocalized alpha2C
      adrenoceptors with cholinergic neurons. RESULTS: Intrathecal clonidine increased
      pCREB immunoreactive cells in both superficial and deep laminae by 50-100% in
      normal animals. The number of pCREB immunoreactive cells increased in nerve
      injured compared to normal rats. Intrathecal clonidine decreased pCREB
      immunoreactive cells in the deep dorsal horn of injured animals. Alpha2C
      adrenoceptors colocalized with cholinergic neurons in both superficial and deep
      dorsal horn. DISCUSSION: Previous studies suggest a shift in alpha 2 adrenoceptor
      subtype and the involvement of cholinergic interneurons in antinociception in the
      spinal cord after nerve injury. The current results suggest that intrathecal
      clonidine, by direct or indirect methods, increases neuronal activation in normal
      animals, presumably leading to net inhibition of pain signaling, whereas it
      reduces the increase in neuronal activity induced by nerve injury.

PMID- 12606923
TI  - Preoperative cardiology consultation.

PMID- 12606924
TI  - Another matter of life and death: what every anesthesiologist should know about
      the ethical, legal, and policy implications of the non-heart-beating cadaver
      organ donor.

PMID- 12606926
TI  - Saddle block using 10-20% tetracaine for patients with perineal pain due to
      recurrent rectal cancer.

PMID- 12606925
TI  - Modifying cardiovascular risk in diabetes mellitus.

PMID- 12606927
TI  - Combined infraclavicular plexus block with suprascapular nerve block for humeral
      head surgery in a patient with respiratory failure: an alternative approach.

PMID- 12606928
TI  - Lhermitte sign associated with postdural puncture headache in a parturient.

PMID- 12606929
TI  - Thoracic epidural infusion complicated by epidural compartment syndrome.

PMID- 12606930
TI  - Does xenon anesthesia inhibit cholinesterases? An in vitro radiometric
      assessment.

PMID- 12606931
TI  - Does vasopressin infusion improve the outcome of severe septic-shock without any
      adverse effects?

PMID- 12606932
TI  - Depth of anesthesia monitors: status quo.

PMID- 12606933
TI  - Anesthesia should not be blamed for all perioperative complications.

PMID- 12606934
TI  - Anesthetic preconditioning: target the right patients.

PMID- 12606935
TI  - Continuous spinal anesthesia redux.

PMID- 12606936
TI  - A preventable cause of brachial plexus injury.

PMID- 12606937
TI  - A rash decision.

PMID- 12606938
TI  - Buprenorphine contains glucose.

PMID- 12606939
TI  - BRCA2-dependent and independent formation of RAD51 nuclear foci.
AB  - The formation of RAD51 foci in response to ionizing radiation (IR) represents an
      important step in the repair of DNA double-strand breaks. RAD51 foci also appear
      during S phase and are thought to be required for the restart of stalled or
      broken replication forks. The RAD51 recombinase interacts directly with the
      breast cancer-associated tumour suppressor BRCA2, an interaction that is required
      for normal recombination proficiency, radiation resistance and genome stability.
      In CAPAN-1 cells, which express a truncated form of BRCA2 that is cytoplasmic
      because of loss of the nuclear localization signal, the formation of IR-induced
      RAD51 foci is impaired. In this work, we show that S-phase RAD51 foci form
      normally in CAPAN-1 cells expressing truncated BRCA2. Moreover, we find that
      RAD51 specifically associates with chromatin at S phase in a reaction that is
      BRCA2-independent. The observed BRCA2-dependent and independent formation of
      RAD51 foci shows that intact BRCA2 is not required for RAD51 focus formation per
      se, leading us to suggest that S phase and IR-induced RAD51 foci assemble by
      distinct pathways with defined protein requirements.

PMID- 12606940
TI  - Role for RhoB and PRK in the suppression of epithelial cell transformation by
      farnesyltransferase inhibitors.
AB  - Recent genetic investigations have established that RhoB gain-of-function is
      sufficient to mediate the antitransforming effects of farnesyltransferase
      inhibitors (FTIs) in H-Ras-transformed fibroblast systems. In this study, we
      addressed the breadth and mechanism of RhoB action in epithelial cells
      transformed by oncoproteins which are themselves insensitive to FTI inactivation.
      Rat intestinal epithelial (RIE) cells transformed by activated K-Ras or Rac1 were
      highly sensitive to FTI-induced actin reorganization and growth inhibition,
      despite the inability of FTI to block prenylation of either K-Ras or Rac1.
      Ectopic expression of the geranylgeranylated RhoB isoform elicited in cells by
      FTI treatment phenocopied these effects. Analysis of RhoB effector domain mutants
      pointed to a role for PRK, a Rho effector kinase implicated in the physiological
      function of RhoB in intracellular receptor trafficking, and these findings were
      supported further by experiments in a fibroblast system. We propose that FTIs
      recruit the antioncogenic RhoB protein in the guise of RhoB-GG to interfere with
      signaling by pro-oncogenic Rho proteins, possibly by sequestering common exchange
      factors or effectors such as PRK that are important for cell transformation.

PMID- 12606941
TI  - The transcriptional response after oxidative stress is defective in Cockayne
      syndrome group B cells.
AB  - Cockayne syndrome (CS) is a human hereditary disease belonging to the group of
      segmental progerias, and the clinical phenotype is characterized by postnatal
      growth failure, neurological dysfunction, cachetic dwarfism, photosensitivity,
      sensorineural hearing loss, and retinal degradation. CS-B cells are defective in
      transcription-coupled DNA repair, base excision repair, transcription, and
      chromatin structural organization. Using array analysis, we have examined the
      expression profile in CS complementation group B (CS-B) fibroblasts after
      exposure to oxidative stress (H2O2) before and after complete complementation
      with the CSB gene. The following isogenic cell lines were compared: CS-B cells
      (CS-B null), CS-B cells complemented with wild-type CSB (CS-B wt), and a stably
      transformed cell line with a point mutation in the ATPase domain of CSB (CS-B
      ATPase mutant). In the wt rescued cells, we detected significant induction (two
      fold) of 112 genes out of the 6912 analysed. The patterns suggested an induction
      or upregulation of genes involved in several DNA metabolic processes including
      DNA repair, transcription, and signal transduction. In both CS-B mutant cell
      lines, we found a general deficiency in transcription after oxidative stress,
      suggesting that the CSB protein influenced the regulation of transcription of
      certain genes. Of the 6912 genes, 122 were differentially regulated by more than
      two-fold. Evidently, the ATPase function of CSB is biologically important as the
      deficiencies seen in the ATPase mutant cells are very similar to those observed
      in the CS-B-null cells. Some major defects are in the transcription of genes
      involved in DNA repair, signal transduction, and ribosomal functions.

PMID- 12606942
TI  - Detailed computational study of p53 and p16: using evolutionary sequence analysis
      and disease-associated mutations to predict the functional consequences of
      allelic variants.
AB  - Deciding whether a missense allelic variant affects protein function is important
      in many contexts. We previously demonstrated that a detailed analysis of p53
      intragenic conservation correlates with somatic mutation hotspots. Here we refine
      these evolutionary studies and expand them to the p16/Ink4a gene. We calculated
      that in order for 'absolute conservation' of a codon across multiple species to
      achieve P<0.05, the evolutionary substitution database must contain at least 3(M)
      variants, where M equals the number of codons in the gene. Codons in p53 were
      divided into high (73% of codons), intermediate (29% of codons), and low (0
      codons) likelihood of being mutation hotspots. From a database of 263 somatic
      missense p16 mutations, we identified only four codons that are mutational
      hotspots at P<0.05 (8 mutations). However, data on function, structure, and
      disease association support the conclusion that 11 other codons with > or =5
      somatic mutations also likely indicate functionally critical residues, even
      though P0.05. We calculated p16 evolution using amino acid substitution matrices
      and nucleotide substitution distances. We looked for evolutionary parameters at
      each codon that would predict whether missense mutations were disease associated
      or disrupted function. The current p16 evolutionary substitution database is too
      small to determine whether observations of 'absolute conservation' are
      statistically significant. Increasing the number of sequences from three to seven
      significantly improved the predictive value of evolutionary computations. The
      sensitivity and specificity for conservation scores in predicting disease
      association of p16 codons is 70-80%. Despite the small p16 sequence database, our
      calculations of high conservation correctly predicted loss of cell cycle arrest
      function in 75% of tested codons, and low conservation correctly predicted wild
      type function in 80-90% of codons. These data validate our hypothesis that
      detailed evolutionary analyses help predict the consequences of missense amino
      acid variants.

PMID- 12606943
TI  - Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces
      growth suppression, apoptosis and radiosensitization in malignant gliomas in a
      p53-independent manner.
AB  - Malignant gliomas are extremely aggressive cancers currently lacking effective
      treatment modalities. Gene therapy represents a promising approach for this
      disease. A requisite component for improving gene-based therapies of brain cancer
      includes tumor suppressor genes that exhibit cancer constrained inhibitory
      activity. Subtraction hybridization identified melanoma differentiation
      associated gene-7 (mda-7) as a gene associated with melanoma cell growth,
      differentiation and progression. Ectopic expression of mda-7 by means of a
      replication-incompetent adenovirus (Ad), Ad.mda-7, induces growth suppression and
      apoptosis selectively in diverse human cancers, without producing any apparent
      harmful effect in normal cells. We presently demonstrate that Ad.mda-7 induces
      growth inhibition and apoptosis in malignant human gliomas expressing both mutant
      and wild-type p53, and these effects correlate with an elevation in expression of
      members of the growth arrest and DNA damage (GADD) gene family. In contrast,
      infection with a recombinant Ad expressing wild-type p53, Ad.wtp53, specifically
      affects mutant p53 expressing gliomas. When tested in early passage normal and
      immortal human fetal astrocytes, growth inhibition resulting from infection with
      Ad.mda-7 or Ad.wtp53 is significantly less than in malignant gliomas and no
      toxicity is evident in these normal cells. Moreover, infection of gliomas with
      Ad.mda-7 or treatment with purified GST-MDA-7 protein sensitizes both wild-type
      and mutant p53 expressing tumor cells to the growth inhibitory and antisurvival
      effects of ionizing radiation, and this response correlates with increased
      expression of specific members of the GADD gene family. Since heterogeneity in
      p53 expression is common in evolving gliomas, the present findings suggest that
      Ad.mda-7 may, in many instances, prove more beneficial for the gene-based therapy
      of malignant gliomas than administration of wild-type p53.

PMID- 12606944
TI  - Exchange of catenins in cadherin-catenin complex.
AB  - beta-Catenin is an intracellular multifunctional protein. In complex with the
      transmembrane adhesive receptor E-cadherin, it becomes plasma membrane-associated
      and mediates intercellular adhesion. A cytosolic pool of beta-catenin interacts
      with DNA-binding proteins and participates in signal transduction. To reveal the
      possible cross-talk between these two pools, we studied whether beta-catenin is
      exchanged between its free and cadherin-bound states. We found that pulse-labeled
      beta-catenin replaces the beta-catenin bound to the cell surface prebiotinylated
      E-cadherin immediately after synthesis. Approximately 25% of all pulse-labeled
      beta-catenin destined for E-cadherin associates with this protein via this
      mechanism. The rest of the newly synthesized beta-catenin arrives at the plasma
      membrane in a complex with the E-cadherin precursor. Immediately after arrival,
      this beta-catenin pool is transferred to the prebiotinylated E-cadherin. beta
      Catenin released from E-cadherin may participate in new exchange cycles. This
      beta-catenin exchange is strongly affected in cells that contain mutations in the
      tumor suppressor gene APC. This process may contribute significantly to both cell
      cell adhesion and beta-catenin-dependent signaling.

PMID- 12606945
TI  - Suppression of RelA/p65 nuclear translocation independent of IkappaB-alpha
      degradation by cyclooxygenase-2 inhibitor in gastric cancer.
AB  - Selective cyclooxygenase-2 (COX-2) inhibitors are promising anti-inflammatory
      drugs with potential antitumor activities. The nuclear factor-kappa B (NF-kappaB)
      family of proteins is important transcriptional regulators of genes involved in
      immunity, inflammation, and carcinogenesis. In the present study, we investigated
      whether and by which molecular mechanism the selective COX-2 inhibitors inhibit
      NF-kappaB activation in gastric cancer. The effects of SC236 and its derivative,
      but devoid of COX-2 enzyme inhibition activity on NF-kappaB signaling, were
      evaluated using electromobility shift, transfection, and reporter gene assay. The
      translocation of RelA/p65 was investigated using Western blotting and
      immunocytochemistry. We showed that SC236 suppressed NF-kappaB-mediated gene
      transcription and binding activity in gastric cancer. This effect occurred
      through a mechanism independent of cyclooxygenase activity and prostaglandin
      synthesis. Furthermore, unlike aspirin, SC236 affected neither the
      phosphorylation, degradation, nor expression of IkappaB-alpha, suggesting that
      the effects of SC236 are independent of IKK activity and IkappaB-alpha gene
      transcription. Instead, SC236 worked directly through suppressing nuclear
      translocation of RelA/p65. It is possible that SC236 directly targets proteins
      that facilitate the nuclear translocation of NF-kappaB. Our study suggests an
      important molecular mechanism by which COX-2 inhibitors reduce inflammation and
      suppress carcinogenesis in gastrointestinal tract.

PMID- 12606946
TI  - Osteopontin-induced migration of human mammary epithelial cells involves
      activation of EGF receptor and multiple signal transduction pathways.
AB  - Osteopontin (OPN) is a secreted, integrin-binding glycophosphoprotein that has
      been implicated in breast cancer. We previously showed that OPN-induced cell
      migration of mammary epithelial cells (MEC) depends on binding to cell surface
      integrins and involves activation of the hepatocyte growth factor (HGF) receptor,
      Met. Here, we show that OPN-induced migration of MEC also requires activation of
      the epidermal growth factor (EGF) pathway. Synergism was seen between EGF and OPN
      in inducing cell migration. Furthermore, incubation of cells with exogenous OPN
      increased ligand (TGFalpha> EGF) and EGF receptor (EGFR) mRNA expression, as well
      as EGFR kinase activity. Treatment of cells with anti-TGFalpha or anti-EGFR
      antibody, or with tyrphostin-25 (EGFR inhibitor), significantly impaired the cell
      migration response to OPN. Other more broad-spectrum tyrosine kinase inhibitors
      and the growth factor/ receptor interaction inhibitor, suramin, also inhibited
      OPN-induced migration. Using specific signal transduction pathway inhibitors, we
      have screened for involvement of MEK (MAP kinase kinase), phosphatidylinositol 3
      kinase, phospholipase C (PLC), and protein kinase C (PKC). Results implicated all
      of these pathways in OPN-induced cell migration, the most pronounced effect being
      seen with PLC and PKC inhibitors. These results suggest that induction of MEC
      migration by OPN involves a cascade of events including at least two growth
      factor/receptor pathways and multiple downstream signal transduction pathways. A
      number of potential targets are thus provided for strategies aimed at blocking
      the malignancy-promoting effects of OPN.

PMID- 12606947
TI  - Adenosine suppresses activation of nuclear factor-kappaB selectively induced by
      tumor necrosis factor in different cell types.
AB  - Adenosine is an endogenous immunomodulator that has been shown to exhibit anti
      inflammatory and immunosuppressive properties through a mechanism that is not
      fully established. Owing to the pivotal role of nuclear factor (NF)-kappaB in
      these responses, we tested the hypothesis that adenosine mediates its effects
      through suppression of NF-kappaB activation. We investigated the effects of
      adenosine on NF-kappaB activation induced by various inflammatory agents in human
      myeloid KBM-5 cells. The treatment of these cells with adenosine suppressed TNF
      induced NF-kappaB activation, but had no effect on activation of another redox
      sensitive transcription factor, AP-1. These effects were not restricted to
      myeloid cells, as NF-kappaB activation in other lymphocytic and epithelial cell
      types was also inhibited. The effect on TNF-induced NF-kappaB activation was
      selective as adenosine had minimal effect on NF-kappaB activation induced by
      H(2)O(2), PMA, LPS, okadaic acid, or ceramide, suggesting differences in the
      pathway leading to NF-kappaB activation by different agents. Adenosine also
      suppressed NF-kappaB-dependent reporter gene expression activated by TNF or by
      overexpression of TNFR1, TRAF 2, NIK, and p65 subunit of NF-kappaB. The
      suppression of TNF-induced NF-kappaB activation by adenosine was found not to be
      because of inhibition of TNF-induced IkappaBalpha phosphorylation and degradation
      or IkappaBalpha kinase activation. The suppression of TNF-induced NF-kappaB
      activation was unique to adenosine, as neither its metabolites (inosine, AMP, and
      ATP) nor pyrimidines (thymidine and uridine) had any effect. Overall, our results
      clearly demonstrate that adenosine selectively suppresses TNF-induced NF-kappaB
      activation, which may contribute to its role in suppression of inflammation and
      of the immune system.

PMID- 12606948
TI  - Apoptosis protection and survival signal by the CD53 tetraspanin antigen.
AB  - The CD53 antigen is a tetraspanin protein of the lymphoid-myeloid lineage, but
      its implication in biological effects is hardly known. Radioresistant tumor cells
      express very high levels of this antigen. We have studied the effect of CD53
      antigen ligation on the survival response of tumor cells to serum deprivation, a
      well-known stimulator of cell death that may mimic the tumor environment; for
      this aim IR938F and Jurkat cells, a B- and T-cell lymphoma, were used. Ligation
      of CD53 triggers a survival response and reduces the number of cells that enter
      apoptosis. In CD53- stimulated cells there is a significant reduction in caspase
      activation, measured by caspase processing of poly ADP-ribose polymerase, as well
      as a reduction in the fragmentation of DNA. CD53- stimulated cells also have an
      increase in the level of bcl-X(L) and a reduction of bax protein, two components
      of the mitochondrial apoptotic pathway, changing their ratio by 24-fold in the
      direction of survival. This survival signal appears to be mediated by activation
      of the AKT, as detected by its phosphorylation in Ser473 upon CD53 ligation. The
      CD53 antigen interactions might contribute to cell survival in poorly
      vascularized regions of the tumor mass.

PMID- 12606949
TI  - Common fragile sites are preferential targets for HPV16 integrations in cervical
      tumors.
AB  - The development of cervical cancer is highly associated with human papillomavirus
      (HPV) infection. HPV integration into the genome of infected cervical cells is
      temporally associated with the acquisition of the malignant phenotype. A
      relationship between the sites of HPV integration in cervical cancer and the
      position of the common fragile sites (CFSs) has been observed at both the
      cytogenetic and molecular levels. To further explore this relationship at the
      molecular level, we used RS-PCR to rapidly isolate cellular sequences flanking
      the sites of HPV16 integration in 26 primary cervical tumors. Human bacterial
      artificial chromosome clones were isolated based on these flanking sequences and
      used as probes for fluorescence in situ hybridization on aphidicolin-stimulated
      metaphases. Our data demonstrate that 11/23 HPV16 integrations in cervical tumors
      occurred within CFSs (P&<0.001). In addition, we show that deletions and complex
      rearrangements frequently occur in the cellular sequences targeted by the
      integrations and that integrations cluster in FRA13C (13q22), FRA3B (3p14.2), and
      FRA17B (17q23). Finally, our data suggest that cellular genes, such as Notch 1,
      are disrupted by the HPV16 integrations, which may contribute to the malignant
      phenotype.

PMID- 12606950
TI  - Adrenomedullin antagonist suppresses in vivo growth of human pancreatic cancer
      cells in SCID mice by suppressing angiogenesis.
AB  - Since it is reported that adrenomedullin (AM) upregulated by hypoxia inhibits
      hypoxic cell death, we examined the effects of AM antagonist (AM C-terminal
      fragment; AM(22-52)) on the growth of pancreatic cancer cells. We, for the first
      time, demonstrated that AM antagonist significantly reduced the in vivo growth of
      the pancreatic cancer cell line. Immunohistochemical analysis demonstrated that
      the mean diameter of blood vessels was significantly smaller in the tumor tissues
      treated with AM antagonist than in those treated with AM N-terminal fragment
      (AM(1-25)), and that the PCNA-labeling index was lower in the former than in the
      latter. Then we demonstrated that AM antagonist showed no effect on the in vitro
      growth of the pancreatic cancer cell line. These results showed that AM played an
      important role in the growth of pancreatic cancer cells in vivo, suggesting that
      AM antagonist might be a useful tool for treating pancreatic cancers.

PMID- 12606952
TI  - Genome-wide screening for complete genetic loss in prostate cancer by comparative
      hybridization onto cDNA microarrays.
AB  - We demonstrate that comparative genomic hybridization (CGH) onto cDNA microarrays
      may be used to carry out genome-wide screens for regions of genetic loss,
      including homozygous (complete) deletions that may represent the possible
      location of tumour suppressor genes in human cancer. Screening of the prostate
      cancer cell lines LNCaP, PC3 and DU145 allowed the mapping of specific regions
      where genome copy number appeared altered and led to the identification of two
      novel regions of complete loss at 17q21.31 (500 kb spanning STAT3) and at 10q23.1
      (50-350 kb spanning SFTPA2) in the PC3 cell line.

PMID- 12606951
TI  - LOH of chromosome 12p correlates with Kras2 mutation in non-small cell lung
      cancer.
AB  - Previous observation has shown that the wild-type Kras2 allele is a suppressor of
      lung cancer in mice. Here we report that loss of heterozygosity (LOH) of
      chromosome 12p was detected in approximately 50% of human lung adenocarcinomas
      and large cell carcinomas, and Kras2 mutations were detected at codon 12 in
      approximately 40% of adenocarcinomas and large cell carcinomas. Interestingly,
      all of the lung adenocarcinomas and large cell carcinomas containing a Kras2
      mutation exhibited allelic loss of the wild-type Kras2 allele when a correlation
      between LOH of the region on chromosome 12p and Kras2 mutation was made. These
      results from human lung cancer tissues provide a strong evidence in support of
      our previous observation in mouse models that the wild-type Kras2 is a tumor
      suppressor of lung cancer.

PMID- 12606953
TI  - Allelic imbalance and altered expression of genes in chromosome 2q11-2q16 from
      rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a compound found in
      cooked meat, is a mammary gland carcinogen in rats. Comparative genomic
      hybridization of PhIP-induced rat mammary gland carcinomas revealed loss in the
      centromeric region of 2q, a region known to carry the mammary carcinoma
      susceptibility 1 (Mcs1) gene and several other genes relevant to carcinogenesis.
      Allelic imbalance, specifically microsatellite instability and loss of
      heterozygosity, was examined in mammary gland carcinomas induced by PhIP in
      Sprague-Dawley (SD)xWistar Furth F1 hybrid rats. In a polymerase chain reaction
      (PCR)-based assay with 34 microsatellite markers coinciding to 2q11-2q16, nine
      markers revealed allelic imbalance. The frequency of imbalance in the tumors
      varied from 10 to 100% depending on the specific marker. However, none of the
      markers coinciding with the Mcs1 gene locus showed allelic imbalance, suggesting
      that alterations at this locus were not associated with PhIP-induced rat mammary
      gland cancer. The expression of several genes physically mapped to 2q11-2q16 and
      potentially involved in carcinogenesis including Ccnb (cyclin B1), Ccnh (cyclin
      H), Rasa (Ras GAP), Rasgrf2, Pi3kr1 (p85alpha), and Il6st (gp130) was also
      examined by quantitative real-time PCR and immunohistochemistry (IHC) across a
      large bank of PhIP-induced SD rat mammary gland carcinomas. By quantitative real
      time PCR, the mRNA expression of Rasa, Pi3kr1, Ccnh, and Il6st in carcinomas was,
      respectively, 22-, 20-, three- and threefold higher in carcinomas than in control
      mammary gland tissues (P<0.05, Student's t-test). A statistically sixfold lower
      expression of Rasgrf2 was detected in carcinomas whereas no significant change in
      Ccnb1 expression was observed. The findings from quantitative real-time PCR were
      confirmed by IHC for each gene. In addition, the proliferation index in mammary
      gland carcinomas as assessed by PCNA was found to correlate with the
      overexpression of Cyclin H by IHC analysis (P<0.05, Spearman Rank Order
      Correlation). The findings from the current study implicate molecular alterations
      in the proximal region of 2q in PhIP-induced rat mammary gland carcinomas.

PMID- 12606954
TI  - Gene profiling and promoter reporter assays: novel tools for comparing the
      biological effects of botanical extracts on human prostate cancer cells and
      understanding their mechanisms of action.
AB  - The use of botanical mixtures is commonplace in patients with prostate cancer,
      yet the majority of these products have not been rigorously tested in clinical
      trials. Here we use PC-SPES, a combination of eight herbs that has been shown to
      be effective in clinical trials in patients with prostate cancer, as a model
      system to demonstrate 'proof of principle' as to how gene expression profiling
      coupled with promoter assays can evaluate the effect of herbal cocktails on human
      prostate cancer. In addition, we demonstrate how such approaches may be used for
      standardization of herbal extract activity by comparing the gene profile of PC
      SPES with that of PC-CARE, a product with a similar herbal composition. Since
      prior studies have shown that PC-SPES contains estrogenic organic compounds, and
      such compounds are known to affect prostate cancer, an important issue is whether
      these are the primary drivers of the gene profile. Our data suggest that gene
      expression profiles of LNCaP human prostate cancer cells in response to PC-SPES
      are different from those found when diethylstilbestrol (DES), a synthetic
      estrogen, is used, suggesting that the estrogenic moieties within PC-SPES do not
      drive this expression signature. In contrast, the expression profile of PC-CARE
      was almost identical to that of DES, highlighting that mixtures containing
      similar herbal compositions do not necessarily result in similar biological
      activities. Interestingly, these three agents cause similar in vitro
      morphological changes and growth effects on LNCaP. To validate the expression
      profiling data, we evaluated the protein expression and promoter activity of
      prostate-specific antigen (PSA), a gene induced by PC-SPES but repressed by DES.
      In order to gain a mechanistic understanding of how PC-SPES and DES affect PSA
      expression differently, LNCaP cells were transiently transfected with wild-type
      and mutagenized PSA promoter, ARE concatemers and appropriate controls. We
      provide evidence that androgen response elements (ARE) II and III within the
      promoter region are responsible for the suppressive effects of DES and
      stimulatory effects of PC-SPES. In addition, we show that the effects on PSA
      transcription are ARE specific in the case of DES while PC-SPES affects this
      promoter nonspecifically. In conclusion, expression profiling coupled with
      mechanistic target validation yield valuable clues as to the mode of action of
      complex botanical mixtures and provides a new way to compare objectively mixtures
      with similar components either for effect or quality assurance prior to their use
      in clinical trials.

PMID- 12606955
TI  - Sacrifice for the greater good?

PMID- 12606956
TI  - Draft guidelines ease restrictions on use of genome sequence data.

PMID- 12606957
TI  - Mixed results win HIV vaccine a guarded response.

PMID- 12606958
TI  - Physicists fail to find saving grace for falsified research.

PMID- 12606959
TI  - NASA seeks inspiration from microscopic views of life.

PMID- 12606960
TI  - Climate panel to seize political hot potatoes.

PMID- 12606961
TI  - Experts cast doubt on Britain's green energy ambitions.

PMID- 12606962
TI  - Genomes take pole position in the icy wastes.

PMID- 12606963
TI  - Canada boosts spending on science.

PMID- 12606964
TI  - NASA pins hopes on nuclear-powered orbiter.

PMID- 12606965
TI  - Europe draws up plans for funding agency.

PMID- 12606967
TI  - Tissue engineering: The beat goes on.

PMID- 12606968
TI  - Disaster planning: Avalanche!

PMID- 12606969
TI  - Switzerland's role as a hotspot of type specimens.

PMID- 12606970
TI  - Novel and conventional paths to a better banana.

PMID- 12606971
TI  - Objective assessment of transgenic salmon.

PMID- 12606972
TI  - Liability for climate change.

PMID- 12606978
TI  - Ecological footprints: A blot on the land.

PMID- 12606979
TI  - Gravity: The weight of expectation.

PMID- 12606982
TI  - Geochemistry: Lost terrains of early Earth.

PMID- 12606980
TI  - Ecology: The how and why of biodiversity.

PMID- 12606984
TI  - Oceanography: The brawniest retroflection.

PMID- 12606983
TI  - Developmental biology: A twist in a mouse tale.

PMID- 12606985
TI  - Cell polarity: From embryo to axon.

PMID- 12606987
TI  - Environment: A pre-industrial source of dioxins and furans.

PMID- 12606988
TI  - Sociobiology: Worker nepotism among polygynous ants.

PMID- 12606989
TI  - Sociology: The puzzle of human cooperation.

PMID- 12606990
TI  - Audiovisual perception: Implicit estimation of sound-arrival time.

PMID- 12606992
TI  - Fire science for rainforests.
AB  - Forest fires are growing in size and frequency across the tropics. Continually
      eroding fragmented forest edges, they are unintended ecological disturbances that
      transcend deforestation to degrade vast regions of standing forest, diminishing
      ecosystem services and the economic potential of these natural resources.
      Affecting the health of millions, net forest fire emissions may have released
      carbon equivalent to 41% of worldwide fossil fuel use in 1997-98. Episodically
      more severe during El Nino events, pan-tropical forest fires will increase as
      more damaged, less fire-resistant, forests cover the landscape. Here I discuss
      the current state of tropical fire science and make recommendations for
      advancement.

PMID- 12606993
TI  - Energetic neutral atoms from a trans-Europa gas torus at Jupiter.
AB  - The space environments--or magnetospheres--of magnetized planets emit copious
      quantities of energetic neutral atoms (ENAs) at energies between tens of electron
      volts to hundreds of kiloelectron volts (keV). These energetic atoms result from
      charge exchange between magnetically trapped energetic ions and cold neutral
      atoms, and they carry significant amounts of energy and mass from the
      magnetospheres. Imaging their distribution allows us to investigate the structure
      of planetary magnetospheres. Here we report the analysis of 50-80 keV ENA images
      of Jupiter's magnetosphere, where two distinct emission regions dominate: the
      upper atmosphere of Jupiter itself, and a torus of emission residing just outside
      the orbit of Jupiter's satellite Europa. The trans-Europa component shows that,
      unexpectedly, Europa generates a gas cloud comparable in gas content to that
      associated with the volcanic moon Io. The quantity of gas found indicates that
      Europa has a much greater impact than hitherto believed on the structure of, and
      the energy flow within, Jupiter's magnetosphere.

PMID- 12606994
TI  - Upper limits to submillimetre-range forces from extra space-time dimensions.
AB  - String theory is the most promising approach to the long-sought unified
      description of the four forces of nature and the elementary particles, but direct
      evidence supporting it is lacking. The theory requires six extra spatial
      dimensions beyond the three that we observe; it is usually supposed that these
      extra dimensions are curled up into small spaces. This 'compactification' induces
      'moduli' fields, which describe the size and shape of the compact dimensions at
      each point in space-time. These moduli fields generate forces with strengths
      comparable to gravity, which according to some recent predictions might be
      detected on length scales of about 100 microm. Here we report a search for
      gravitational-strength forces using planar oscillators separated by a gap of 108
      micro m. No new forces are observed, ruling out a substantial portion of the
      previously allowed parameter space for the strange and gluon moduli forces, and
      setting a new upper limit on the range of the string dilaton and radion forces.

PMID- 12606995
TI  - Ultra-high-Q toroid microcavity on a chip.
AB  - The circulation of light within dielectric volumes enables storage of optical
      power near specific resonant frequencies and is important in a wide range of
      fields including cavity quantum electrodynamics, photonics, biosensing and
      nonlinear optics. Optical trajectories occur near the interface of the volume
      with its surroundings, making their performance strongly dependent upon interface
      quality. With a nearly atomic-scale surface finish, surface-tension-induced
      microcavities such as liquid droplets or spheres are superior to all other
      dielectric microresonant structures when comparing photon lifetime or,
      equivalently, cavity Q factor. Despite these advantageous properties, the
      physical characteristics of such systems are not easily controlled during
      fabrication. It is known that wafer-based processing of resonators can achieve
      parallel processing and control, as well as integration with other functions.
      However, such resonators-on-a-chip suffer from Q factors that are many orders of
      magnitude lower than for surface-tension-induced microcavities, making them
      unsuitable for ultra-high-Q experiments. Here we demonstrate a process for
      producing silica toroid-shaped microresonators-on-a-chip with Q factors in excess
      of 100 million using a combination of lithography, dry etching and a selective
      reflow process. Such a high Q value was previously attainable only by droplets or
      microspheres and represents an improvement of nearly four orders of magnitude
      over previous chip-based resonators.

PMID- 12606996
TI  - Logarithmic rate dependence of force networks in sheared granular materials.
AB  - Many models of slow, dense granular flows assume that the internal stresses are
      independent of the shearing rate. In contrast, logarithmic rate dependence is
      found in solid-on-solid friction, geological settings and elsewhere. Here we
      investigate the rate dependence of stress in a slowly sheared two-dimensional
      system of photoelastic disks, in which we are able to determine forces on the
      granular scale. We find that the mean (time-averaged) stress displays a
      logarithmic dependence on the shear rate for plastic (irreversible) deformations.
      However, there is no perceivable dependence on the driving rate for elastic
      (reversible) deformations, such as those that occur under moderate repetitive
      compression. Increasing the shearing rate leads to an increase in the strength of
      the force network and stress fluctuations. Qualitatively, this behaviour
      resembles the changes associated with an increase in density. Increases in the
      shearing rate also lead to qualitative changes in the distributions of stress
      build-up and relaxation events. If shearing is suddenly stopped, stress
      relaxations occur with a logarithmic functional form over long timescales. This
      slow collective relaxation of the stress network provides a mechanism for rate
      dependent strengthening.

PMID- 12606997
TI  - Early history of Earth's crust-mantle system inferred from hafnium isotopes in
      chondrites.
AB  - The 176Lu to 176Hf decay series has been widely used to understand the nature of
      Earth's early crust-mantle system. The interpretation, however, of Lu-Hf isotope
      data requires accurate knowledge of the radioactive decay constant of 176Lu
      (lambda176Lu), as well as bulk-Earth reference parameters. A recent calibration
      of the lambda176Lu value calls for the presence of highly unradiogenic hafnium in
      terrestrial zircons with ages greater than 3.9 Gyr, implying widespread
      continental crust extraction from an isotopically enriched mantle source more
      than 4.3 Gyr ago, but does not provide evidence for a complementary depleted
      mantle reservoir. Here we report Lu-Hf isotope measurements of different Solar
      System objects including chondrites and basaltic eucrites. The chondrites define
      a Lu-Hf isochron with an initial 176Hf/177Hf ratio of 0.279628 +/- 0.000047,
      corresponding to lambda176Lu = 1.983 +/- 0.033 x 10-11 yr-1 using an age of 4.56
      Gyr for the chondrite-forming event. This lambda176Lu value indicates that
      Earth's oldest minerals were derived from melts of a mantle source with a time
      integrated history of depletion rather than enrichment. The depletion event must
      have occurred no later than 320 Myr after planetary accretion, consistent with
      timing inferred from extinct radionuclides.

PMID- 12606998
TI  - Patterns and processes in reef fish diversity.
AB  - A central aim of ecology is to explain the heterogeneous distribution of
      biodiversity on earth. As expectations of diversity loss grow, this understanding
      is also critical for effective management and conservation. Although explanations
      for biodiversity patterns are still a matter for intense debate, they have often
      been considered to be scale-dependent. At large geographical scales,
      biogeographers have suggested that variation in species richness results from
      factors such as area, temperature, environmental stability, and geological
      processes, among many others. From the species pools generated by these large
      scale processes, community ecologists have suggested that local-scale assembly of
      communities is achieved through processes such as competition, predation,
      recruitment, disturbances and immigration. Here we analyse hypotheses on
      speciation and dispersal for reef fish from the Indian and Pacific oceans and
      show how dispersal from a major centre of origination can simultaneously account
      for both large-scale gradients in species richness and the structure of local
      communities.

PMID- 12606999
TI  - Mechanism of genetic exchange in American trypanosomes.
AB  - The kinetoplastid Protozoa are responsible for devastating diseases. In the
      Americas, Trypanosoma cruzi is the agent of Chagas' disease--a widespread disease
      transmissible from animals to humans (zoonosis)--which is transmitted by exposure
      to infected faeces of blood-sucking triatomine bugs. The presence of genetic
      exchange in T. cruzi and in Leishmania is much debated. Here, by producing hybrid
      clones, we show that T. cruzi has an extant capacity for genetic exchange. The
      mechanism is unusual and distinct from that proposed for the African trypanosome,
      Trypanosoma brucei. Two biological clones of T. cruzi were transfected to carry
      different drug-resistance markers, and were passaged together through the entire
      life cycle. Six double-drug-resistant progeny clones, recovered from the
      mammalian stage of the life cycle, show fusion of parental genotypes, loss of
      alleles, homologous recombination, and uniparental inheritance of kinetoplast
      maxicircle DNA. There are strong genetic parallels between these experimental
      hybrids and the genotypes among natural isolates of T. cruzi. In this instance,
      aneuploidy through nuclear hybridization results in recombination across far
      greater genetic distances than mendelian genetic exchange. This mechanism also
      parallels genome duplication.

PMID- 12607000
TI  - Water transport in plants obeys Murray's law.
AB  - The optimal water transport system in plants should maximize hydraulic
      conductance (which is proportional to photosynthesis) for a given investment in
      transport tissue. To investigate how this optimum may be achieved, we have
      performed computer simulations of the hydraulic conductance of a branched
      transport system. Here we show that the optimum network is not achieved by the
      commonly assumed pipe model of plant form, or its antecedent, da Vinci's rule. In
      these representations, the number and area of xylem conduits is constant at every
      branch rank. Instead, the optimum network has a minimum number of wide conduits
      at the base that feed an increasing number of narrower conduits distally. This
      follows from the application of Murray's law, which predicts the optimal taper of
      blood vessels in the cardiovascular system. Our measurements of plant xylem
      indicate that these conduits conform to the Murray's law optimum as long as they
      do not function additionally as supports for the plant body.

PMID- 12607001
TI  - Extra-embryonic function of Rb is essential for embryonic development and
      viability.
AB  - The retinoblastoma (Rb) gene was the first tumour suppressor identified.
      Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis
      and widespread developmental defects, leading to embryonic death by day 14.5
      (refs 2-4). However, the actual cause of the embryonic lethality has not been
      fully investigated. Here we show that loss of Rb leads to excessive proliferation
      of trophoblast cells and a severe disruption of the normal labyrinth architecture
      in the placenta. This is accompanied by a decrease in vascularization and a
      reduction in placental transport function. We used two complementary techniques
      tetraploid aggregation and conditional knockout strategies-to demonstrate that Rb
      deficient embryos supplied with a wild-type placenta can be carried to term, but
      die soon after birth. Most of the neurological and erythroid abnormalities
      thought to be responsible for the embryonic lethality of Rb-null animals were
      virtually absent in rescued Rb-null pups. These findings identify and define a
      key function of Rb in extra-embryonic cell lineages that is required for
      embryonic development and viability, and provide a mechanism for the cell
      autonomous versus non-cell autonomous roles of Rb in development.

PMID- 12607002
TI  - Role for antisense RNA in regulating circadian clock function in Neurospora
      crassa.
AB  - The prevalence of antisense RNA in eukaryotes is not known and only a few
      naturally occurring antisense transcripts have been assigned a function. However,
      the recent identification of a large number of putative antisense transcripts
      strengthens the view that antisense RNAs might affect a wider variety of
      processes than previously thought. Here we show that in the model organism
      Neurospora crassa entrainment of the circadian clock, which is critical for the
      correct temporal expression of genes and their products, is controlled partly by
      an antisense RNA arising from a clock component locus. In a wild-type strain,
      levels of antisense frequency (frq) transcripts cycle in antiphase to sense frq
      transcripts in the dark, and are inducible by light. In mutant strains in which
      the induction of antisense frq RNA by light is abolished, the time of the
      internal clock is delayed relative to the wild-type strain, and resetting of the
      clock by light is altered. These data provide an unexpected link between
      antisense RNA and circadian timing and provide a new example of a eukaryotic
      cellular process regulated by naturally occurring antisense RNA.

PMID- 12607003
TI  - MDC1 is required for the intra-S-phase DNA damage checkpoint.
AB  - MRE11, RAD50 and NBS1 form a highly conserved protein complex (the MRE11 complex)
      that is involved in the detection, signalling and repair of DNA damage. We
      identify MDC1 (KIAA0170/NFBD1), a protein that contains a forkhead-associated
      (FHA) domain and two BRCA1 carboxy-terminal (BRCT) domains, as a binding partner
      for the MRE11 complex. We show that, in response to ionizing radiation, MDC1 is
      hyperphosphorylated in an ATM-dependent manner, and rapidly relocalizes to
      nuclear foci that also contain the MRE11 complex, phosphorylated histone H2AX and
      53BP1. Downregulation of MDC1 expression by small interfering RNA yields a radio
      resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced
      focus formation by the MRE11 complex. However, downregulation of MDC1 does not
      abolish the ionizing radiation-induced phosphorylation of NBS1, CHK2 and SMC1, or
      the degradation of CDC25A. Furthermore, we show that overexpression of the MDC1
      FHA domain interferes with focus formation by MDC1 itself and by the MRE11
      complex, and induces an RDS phenotype. These findings reveal that MDC1-mediated
      focus formation by the MRE11 complex at sites of DNA damage is crucial for the
      efficient activation of the intra-S-phase checkpoint.

PMID- 12607004
TI  - MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways.
AB  - Forkhead-homology-associated (FHA) domains function as protein-protein modules
      that recognize phosphorylated serine/threonine motifs. Interactions between FHA
      domains and phosphorylated proteins are thought to have essential roles in the
      transduction of DNA damage signals; however, it is unclear how FHA-domain
      containing proteins participate in mammalian DNA damage responses. Here we report
      that a FHA-domain-containing protein-mediator of DNA damage checkpoint protein 1
      (MDC1; previously known as KIAA0170)--is involved in DNA damage responses. MDC1
      localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This
      association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of
      CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after
      DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent
      with this hypothesis, suppression of MDC1 expression results in defective S-phase
      checkpoint and reduced apoptosis in response to DNA damage, which can be restored
      by the expression of wild-type MDC1 but not MDC1 with a deleted FHA domain.
      Suppression of MDC1 expression results in decreased p53 stabilization in response
      to DNA damage. These results suggest that MDC1 is recruited through its FHA
      domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage
      responses.

PMID- 12607007
TI  - Ground control.

PMID- 12607005
TI  - MDC1 is a mediator of the mammalian DNA damage checkpoint.
AB  - To counteract the continuous exposure of cells to agents that damage DNA, cells
      have evolved complex regulatory networks called checkpoints to sense DNA damage
      and coordinate DNA replication, cell-cycle arrest and DNA repair. It has recently
      been shown that the histone H2A variant H2AX specifically controls the
      recruitment of DNA repair proteins to the sites of DNA damage. Here we identify a
      novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain
      containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which
      works with H2AX to promote recruitment of repair proteins to the sites of DNA
      breaks and which, in addition, controls damage-induced cell-cycle arrest
      checkpoints. MDC1 forms foci that co-localize extensively with gamma-H2AX foci
      within minutes after exposure to ionizing radiation. H2AX is required for MDC1
      foci formation, and MDC1 forms complexes with phosphorylated H2AX. Furthermore,
      this interaction is phosphorylation dependent as peptides containing the
      phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner. We
      have shown by using small interfering RNA (siRNA) that cells lacking MDC1 are
      sensitive to ionizing radiation, and that MDC1 controls the formation of damage
      induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX
      phosphorylation. In addition, cells lacking MDC1 also fail to activate the intra
      S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing
      radiation, which was associated with an inability to regulate Chk1 properly.
      These results highlight a crucial role for MDC1 in mediating transduction of the
      DNA damage signal.

PMID- 12607008
TI  - The data busters.

PMID- 12607009
TI  - [Learning from others].

PMID- 12607010
TI  - [Cost-benefit analysis of the implementation of automated drug-dispensing systems
      in Critical Care and Emergency Units].
AB  - OBJECTIVE: To determine monetary impact when traditional drug floor stocks are
      replaced by Automated Drug Dispensing Systems (ADDS) in the Medical Intensive
      Care Unit, Surgical Intensive Care Unit and the Emergency Room. METHODS: We
      analysed four different flows considered to be determinant when implementing ADDS
      in a hospital environment: capital investment, staff costs, inventory costs and
      costs related to drug use policies. RESULTS: Costs were estimated by calculation
      of the current net value. Its analysis shows that those expenses derived from
      initial investment are compensated by the three remaining flows, with costs
      related to drug use policies showing the most substantial savings. Five years
      after initial investment, global cash-flows have been estimated at 300.525 euros.
      CONCLUSION: Replacement of traditional floor stocks by ADDS in the Medical
      Intensive Care Unit, Surgery Intensive Care Unit and the Emergency Room produces
      a positive benefit/cost ratio (1.95).

PMID- 12607011
TI  - [Pharmacotherapy and costs of DRD 88. Chronic obstructive pulmonary disease in
      hospital].
AB  - BACKGROUND: Diagnosis-Related Group (DRG) 88 -chronic obstructive pulmonary
      disease is one of the most frequent groups of patients in hospital case-mix and
      accounts for substantial health-care costs. Our purpose was to determine drug
      utilization pattern and related costs for this DRG and to analyse their
      relationship with several factors. METHODS: 288 patients treated at a tertiary
      referral hospital between january and december 1997 were studied. We analysed
      demographic, clinical, and administrative data, as well as drugs prescription and
      cost for every patient. RESULTS: Most patients received antibiotics (n=267)
      which, in addition, represented 46% of total pharmacy cost of this DRG.
      Cephalosporines were the most frequently prescribed. 67% of patients were treated
      with inhaled B-agonists and theophillyne, whereas the combination of B-agonists
      and Ipratropium Bromide was less frequent (n=152). Oral or parenteral
      corticosteroids were used in 233 patients. This treatment regime presented
      differences according to main diagnosis and to department responsible for patient
      discharge. Cost per episode was 116,6 +/- 110,5 euros. Cost per hospital stay was
      13,1+/- 15,5 euros. Correlation of pharmacy costs with length of stay was
      moderate. CONCLUSION: Pharmacy costs are mainly determined by the use of
      antibiotics. Treatment pattern shows a certain variability that can be attributed
      to patients clinical features as well as to physician prescribing habits.

PMID- 12607012
TI  - [The elaboration, use and evaluation of eye-drops with autologous serum in
      corneal lesions].
AB  - OBJECTIVES: To expose the elaboration process, microbiological control and
      effectiveness of an eyewash prepared with the patient's serum, for the treatment
      of injure corneas of different etiology. METHOD: It was edited an elaboration
      protocol and microbiological control, following the norms of correct elaboration
      picked up in the real Ordinance 175/2001. The clinical answer was valued
      objectively and subjectively. RESULTS: The eyewashes got ready under sterile
      conditions, using the patient's serum diluted to 20% with physiologic. None of
      the containers conserved in the Service of Pharmacy were contaminated, while the
      contamination in those already used, varied according to the patient. Of the
      eleven evaluated cases, six experienced a total recovery of its corneal lesions,
      three improved partially, and in the remaining ones the treatment was not
      effective. CONCLUSIONS: The elaboration of the eyewash doesn't present technical
      problems if we have the appropriate equipment for the realization under sterile
      conditions. The contamination of the containers seems to be due to the inadecuate
      use by the patients. The results, in spite of the even scarce number of treated
      patients, justify the treatment in serious cases of dry eye and corneal
      ulceration.

PMID- 12607013
TI  - [Validation of triiodothyronine sodium analysis method].
AB  - OBJECTIVE: To validate the ultraviolet spectrophotometry analytical method for
      triiodothyronine sodium in order to use this method in the quality control
      process of a diluted powder of said active principle for the manufacturing of 25
      mcg capsules. MATERIAL AND METHODS: An ultraviolet spectrophotometry analysis is
      performed on triiodothyronine sodium to obtain its spectrum. Subsequently, a
      mother solution of triiodothyronine sodium is made, from which 5 different
      concentration dilutions are prepared in order to obtain a calibration line
      allowing the study of the method's linearity. Then 3 of these 5 dilutions are
      selected for repeatability and reproducibility studies. Two pattern solutions
      with differing concentrations are prepared for the accuracy study. Three
      different-concentration dilutions are prepared from each of them. The
      absorbencies of controls for both pattern solutions are measured to compare
      results obtained. RESULTS: A scan is performed between 350 and 200 nm, and an
      experimental peak of 319 nm is obtained. The method proves linear for the
      considered range of concentrations (r(2) = 0.9985). Variation coefficients are
      around 2%, thus indicating good repeatability and reproducibility. The mean
      percentage of recovery in known-concentration samples does not significantly
      differ from the theoretical 100%. CONCLUSION: The studied analytical method is
      adequately reliable to result in a foreseen result within defined intervals.

PMID- 12607014
TI  - [Evolution of antimicrobial use during the years 1996-2000 in a general hospital.
      A detailed ICU study].
AB  - PURPOSE: Antimicrobials are a mayor part of hospital pharmacy budgets and must be
      considered in resource planning and spending projections. This study describes
      the profile of antibiotic use at a medium-sized hospital (by examining the ICU
      separately) and analyses its evolution over the period 1996-2000. METHODS:
      Descriptive and retrospective study. Pharmacy records were reviewed to identify
      oral and parenteral antimicrobial agents administered to inpatients. Results were
      expressed in Daily Defined Doses (DDD) per 100 stays and day. RESULTS: During the
      five-year study period 176.162 DDD / 100 s-d of antibiotics were consumed in the
      ICU, whereas in the rest of the hospital usage was much lower (54.540 DDD / 100 s
      d). Aminoglycosides, cephalosporins, penicillins, glycopeptides and carbapenems
      were the most commonly used groups of antimicrobials in the ICU, and penicillins,
      cephalosporins, trimethoprim/sulfonamide combinations, aminoglycosides and
      quinolones in the rest of the hospital. CONCLUSIONS: ICUs have some special
      features which make them different to the rest of inpatient areas. Because of
      that fact we consider important to study this specific patient-care area
      separately.

PMID- 12607016
TI  - [In-hospital Radio-Pharmacy Unit: creation and development].
AB  - Regarding the creation of an In-Hospital Radio-Pharmacy Unit within Clinica
      Puerta de Hierro University Hospital, as well as the compliance with Real Decreto
      479/1993 on the regulation of radio-drugs for human use, the steps to be taken to
      bring it service are laid out and discussed. An overall review of the
      differential characteristics of radio-drugs is undertaken. The adequate
      distribution of spaces and the Unit's functioning regulations are presented, and
      the responsibilities of the person in charge of the ionisation chamber are
      clearly placed on record. The professional responsible of the Unit should define
      performance and quality control protocols for each test. The responsibility for
      coordinating the Unit's operation is assigned to the Heads of Nuclear Medicine
      and Pharmacy Departments, within the Pharmacy and Therapeutics Committee and the
      Nuclear Medicine Quality Committee.

PMID- 12607015
TI  - [Factor VII, a therapeutic alternative in the treatment of severe haemoghage
      disorders].
AB  - Plasmatic coagulation has like purpose the formation of a stable clot of fibrina,
      this process is possible thanks to the intervention of the factors of the
      coagulation that are plasmatic proteins. Some of these factors are vitamin K
      dependent (factors II, VII, IX and X) and all except for the factors VIII, XII
      and XIII which are synthesized in the liver. Three clinical cases of patients are
      described who present serious hemorrhagic disorders, associated to different
      hepatic alterations, which do not respond to conventional treatments. As a
      measure of urgency and therapeutic alternative, the administration of recombinant
      factor VII is used with the aim of activating the extrinsic pathway of the
      coagulation and of obtaining a positive answer in the control of the hemorrhage.

PMID- 12607018
TI  - [Comment on: Opportunities, challenges and themes pending on the correct
      normative elaboration of quality control formulas, by Dr. Jose Maria Sune].

PMID- 12607017
TI  - [Medicinal gases].

PMID- 12607019
TI  - [Lidocaine, is it an excipient?].

PMID- 12607020
TI  - [Drug safety. Notes about surveillance].

PMID- 12607023
TI  - Late outcome following central nervous system injury in child abuse.
AB  - OBJECTIVE: The object of this study was to increase our understanding of the
      social, clinical, radiographic and psychological consequences of child abuse
      after the initial insult and to describe the role of neurosurgery and other
      specialties in this context. METHODS: A review of the literature on child abuse
      (using scientific journals, textbooks, and internet reports) was conducted, with
      special attention given to child abuse in infants. The biomechanical patterns of
      injury, the long-term neurological, psychological, and social outcomes and
      methods of rehabilitation are reviewed. CONCLUSIONS: Head injury associated with
      physical abuse carries a significantly worse clinical outcome than accidental
      trauma. Late findings in CT scans and MRI show evidence of cerebral atrophy in
      100% and cerebral ischemia in 50% of physical abuse cases. Abuse and neglect have
      a strong impact in developing children, producing emotional, cognitive, and
      social problems that may persist throughout the rest of their lives. Outcome
      cannot be improved without an integrated rehabilitation strategy encompassing
      early field management, hospital therapy, precise targeting of educational and
      cognitive needs, and finally return to the community. New ancillary tests have
      emerged that are aimed at improving rehabilitation and illuminating the long-term
      physiological and functional impact of abuse.

PMID- 12607024
TI  - Lumbar disc herniation and tight hamstrings syndrome in adolescence.
AB  - BACKGROUND: Lumbar intervertebral disc herniation is infrequently encountered in
      children and adolescents. Additional signs and symptoms such as postural
      deformities and abnormal gait accompany the classical findings of lumbar root
      irritation. These unusual signs have been described in the literature as "tight
      hamstrings syndrome". Waddling gait with flexed knees is considered as
      pathognomonic for this condition and may be masked by the signs of root
      irritation due to prolapsed intervertebral disc material. CASE REPORT AND
      DISCUSSION: We report an adolescent patient with lumbar disc herniation in whom
      gait abnormality and limitation of lumbar movements persisted after surgical
      intervention. A review of the literature on tight hamstrings is presented.

PMID- 12607025
TI  - Complete surgical resection in children with low-grade astrocytomas after
      neoadjuvant chemotherapy.
AB  - INTRODUCTION: Low-grade astrocytomas constitute the majority of pediatric central
      nervous system neoplasms. Gross total resection is desirable as the initial
      therapeutic approach and is curative in most cases. In the past, radiation
      therapy was often recommended for patients in whom complete resection was not
      achieved, although there are special concerns about secondary malignancy and
      cognitive impairment. There has been increasing interest in the use of
      chemotherapy to treat these tumors, but appropriate indications still need to be
      defined. CASE REPORTS: The use of neoadjuvant chemotherapy to ease surgical
      resection in two children with inoperable pilocytic astrocytomas who presented
      with extrinsic compression of mesencephalic structures is described. DISCUSSION:
      This paper also emphasizes and discusses the therapeutic approach for very
      selected cases of low-grade gliomas in children presenting with inoperable giant
      lesions, in whom the use of chemotherapy may be considered initially.

PMID- 12607026
TI  - Distribution of intracellular and extracellular water molecules in developing
      rat's midbrain: comparison with fraction of multicomponent T(2) relaxation time
      and morphological findings from electron microscopic imaging.
AB  - OBJECTIVE: In the present study, we examined the behavior and state of water
      molecules in immature and mature rat brains by measuring the components of
      magnetic resonance (MR) water proton transverse relaxation time ( T(2)). We also
      performed morphological examination of immature and mature rat brains using
      electron microscopy (EM). We then compared the fraction of T(2) component and the
      EM findings. METHODS: Midbrains of male Wistar rats were examined at various time
      points ranging from 4 h to 12 weeks after birth. T(2) was measured by MR, and the
      ratios of intra- to extracellular spaces were determined by EM in each stage.
      RESULTS: T(2) consisted of two components: fast T(2) (<100 ms), and slow T(2)
      (>100 ms). During maturation, values of fast T(2) decreased dramatically, but
      slow T(2) remained constant. However, the fraction accounted for by slow T(2)
      decreased from 59% to 9% during maturation. Morphological examination showed that
      the extracellular space fraction of the midbrain decreased from 49% to 5% during
      maturation. Thus, morphological change correlated well with changes in slow T(2);
      in other words, multicomponent T(2) results showed a close correlation with
      tissue compartmentalization. CONCLUSION: MR relaxation times obtained by means of
      multicomponent analysis can thus be used to measure intra- and extracellular
      space fractions.

PMID- 12607027
TI  - Split spinal cord malformations: report of 22 cases and review of the literature.
AB  - OBJECT: The aims of this study were to describe the embryological changes that
      drive the formation of a split spinal cord malformation, analyse the forms of
      presentation, evaluate the diagnostic procedures and discuss the indications for
      the different forms of therapy for each case. METHODS: Clinical and radiological
      features of 22 cases of split spinal cord malformations (SSCM) are reported.
      Three groups of patients are considered: group a, patients with signs of tethered
      cord or scoliosis; group b, patients with midline cutaneous stigmata and group c,
      patients with a meningocele or meningomyelocele. CONCLUSION: While CT scan is
      particularly useful for the evaluation of vertebral bodies and posterior arch
      abnormalities and spur characteristics in SSCM, MRI gives complementary
      information on the anatomy of spinal cord, dural sac, conus and filum terminale
      and permits the exclusion of associated lesions such as hydro-syringomyelia,
      dermal sinus or dermoid and epidermoid cysts. Surgery should be considered
      indicated in all cases of SSCM, even the asymptomatic ones, except in very badly
      handicapped meningomyelocele patients with nonprogressive disability and type II
      SSCM.

PMID- 12607028
TI  - Split spinal cord malformation.

PMID- 12607029
TI  - Progression of terminal syrinx in occult spina bifida after untethering.
AB  - OBJECT: The association of spinal dysraphism and terminal syringomyelia is a well
      known entity, and untethering with or without syrinx drainage is usually the
      surgery of choice. However, progression of the previously existing syrinx after
      an untethering procedure is an uncommon course. The objective of this study was
      to discuss the diagnostic, surgical, and follow-up consequences of such an
      occurrence. METHODS: Four children with occult spina bifida associated with
      terminal syrinx at the time of initial presentation are included in this study.
      After the primary releasing procedure, all developed enlargement of the syrinx.
      Two of them were operated on for placement of a syringo-subarachnoid shunt, while
      the other two were followed up conservatively. One of the shunted patients also
      had a second releasing procedure. CONCLUSION: Progression of the pre-existing
      terminal syrinx after the primary untethering procedure should be kept in mind
      even in the absence of overt neurological progression.

PMID- 12607030
TI  - The role of cine flow MRI in children with Chiari I malformation.
AB  - INTRODUCTION: Since the introduction of MRI, the incidence of Chiari I
      malformations (cerebellar tonsils ectopia) has increased. The clinical
      significance of this finding remains questionable in some instances. Recently,
      cine flow MRI has added to the understanding of the dynamics of cerebrospinal
      fluid at the craniocervical junction and to the pathophysiology of the Chiari I
      malformation. The present study attempts to analyze the role of cine flow MRI in
      Chiari I malformations. MATERIALS AND METHODS: Between January 1990 and December
      2000, 24 patients were identified who met the following inclusion criteria:
      patients diagnosed with Chiari I malformation who had had an MRI of the brain
      including the craniocervical junction, clinical follow-up for at least six
      months, and cine flow studies had to have been performed pre- and
      postoperatively. The cine flow studies were repeated during follow-up if the
      patients were not surgical candidates. Patients harboring intracranial space
      occupying lesions or lumboperitoneal shunts were excluded. Sixteen of the 24
      selected patients underwent 18 operations and 8 were followed conservatively.
      There was a wide variation in clinical presentations. Twelve patients had
      cerebellar tonsils protruding more than 5 mm below the foramen magnum, and in 12
      patients the descent of the cerebellar tonsils was less than 5 mm. Despite this
      difference in the degree of protrusion, there was no significant difference in
      clinical presentation. The cisterna magna was small or absent in 20 patients with
      sluggish cine flow posteriorly, 19 of whom were symptomatic, in contrast to 1
      symptomatic patient who had satisfactory cine flow. RESULTS: All patients with
      Chiari I malformation and an associated cervical syrinx had absent cine flow at
      the craniovertebral junction, and this finding was statistically significant.
      There was a good correlation between the clinical presentation and cine flow
      preoperatively, and between clinical improvement and cine flow postoperatively.
      Patients with Chiari I malformation, cervical syrinx, and absent cine flow
      preoperatively improved after suboccipital decompression and duroplasty. Patients
      with Chiari I malformations without syrinx and absent cine flow underwent
      suboccipital bony decompression alone and had satisfactory outcomes.

PMID- 12607031
TI  - Lower extremity spasticity as an early marker of ambulatory recovery following
      traumatic brain injury.
AB  - METHODS: A consecutive series of 107 children and young persons with traumatic
      brain injury (TBI) admitted to a hospital-based inpatient rehabilitation program
      was assessed to determine whether lower extremity spasticity could be utilized as
      an early clinical marker for recovery of ambulation. Presence of spasticity was
      determined by clinical examination at admission, and the ability to ambulate
      safely indoors (15.24 m) was evaluated at discharge. Sensitivity, specificity and
      positive and negative predictive values for spasticity were calculated. RESULTS:
      Lower extremity spasticity is a sensitive (71.4%) and specific (81.5%) predictor
      of the inability to ambulate at discharge. The absence of lower extremity
      spasticity, however, was a better predictor of ambulation recovery than the
      presence of spasticity was a predictor of nonambulatory status at hospital
      discharge. DISCUSSION: Implications for spasticity assessment and prognosis in
      terms of ambulation and recovery are discussed.

PMID- 12607032
TI  - Latent abscess formation adjacent to a non-functioning intraventricular catheter.
AB  - CASE REPORT: A 16-year-old male patient who had been treated at the age of 13
      months with a ventriculoperitoneal (VP) shunt due to obstructive hydrocephalus
      was presented to our department for a routine follow-up examination. The patient
      had tolerated well a shunt disconnection in 1990 and the distal part had been
      removed. Six years later radiological evaluation revealed an intracerebral mass
      adjacent to the remaining intraventricular catheter. The mass, histologically
      classified as an abscess, had to be removed 3 years later due to disease
      progression, although the patient remained asymptomatic. DISCUSSION: This case is
      of particular interest because it demonstrates the extremely delayed onset and
      progressive course of a well-known complication of VP shunt systems in an
      asymptomatic patient. In addition, the reported case raises the question of
      whether a non-functioning shunt needs to be removed or not.

PMID- 12607033
TI  - Hemicerebellitis mimicking a tumour on MRI.
AB  - CASE REPORT: We report a case of hemicerebellitis in a 13-year-old girl
      presenting with symptoms of intracranial hypertension with acute onset. RESULTS:
      MRI of the brain revealed a unilateral cerebellar swelling with foliaform
      enhancement. The patient was still symptomatic even with high doses of
      intravenous steroids, so we decided to operate on her for diagnosis and
      decompression. The pathology showed leptomeningitis. She had a good postoperative
      outcome and a normal brain MRI 2 months later. DISCUSSION: It is unusual to have
      a unilateral cerebellitis; only two cases have been published so far. CONCLUSION:
      Although cerebellitis is considered to be benign and self limited, surgical
      intervention is sometimes mandatory.

PMID- 12607034
TI  - Epidural thoracal teratoma in a 7-month-old girl.
AB  - CASE REPORT: We report a rare case of epidural thoracal teratoma in a 7-month-old
      girl. A total laminectomy was performed via T6-T8 and the lesion was totally
      excised. RESULTS AND DISCUSSION: We describe the radiological, surgical and
      pathological findings in this patient and review the findings in other reported
      cases.

PMID- 12607036
TI  - The photoreceptor localization confirms the spectral heterogeneity of ommatidia
      in the male small white butterfly, Pieris rapae crucivora.
AB  - The compound eye of Pieris rapae crucivora contains ventrally three types of
      histologically distinct ommatidia. An ommatidium contains nine photoreceptors,
      four of which (R1-4) construct the distal tier of the rhabdom. We determined the
      sensitivity spectra of the R1-4 distal photoreceptors in each type of ommatidia
      by intracellular electrophysiology and identified UV, blue, double-peaked blue,
      green, and a green receptor with depressed sensitivity in the violet. We
      localized these receptors in each type of ommatidia by injecting dye after the
      recording. In type I ommatidia the R1 and R2 cells are UV and blue receptors.
      When R1 is UV sensitive, R2 is always blue sensitive, or vice versa. R3 and R4 in
      type I are both green receptors. In type II, R1 and R2 are both double-peaked
      blue receptors and R3 and R4 are both green receptors with depressed sensitivity
      in the violet. In type III, R1 and R2 are both UV, and R3 and R4 are green
      receptors. The double-peaked blue, and green receptors with depressed sensitivity
      in the violet in type II ommatidia have depressed sensitivity at 420 nm, which is
      probably due to the filtering effect of a fluorescing material present in the
      type II ommatidia. Spectral heterogeneity of ommatidia seems to be a common
      design of insect compound eyes.

PMID- 12607037
TI  - The antennal system and cockroach evasive behavior. I. Roles for visual and
      mechanosensory cues in the response.
AB  - Cockroaches escape from predators by turning and then running. This behavior can
      be elicited when stimuli deflect one of the rostrally located and highly mobile
      antennae. We analyzed the behavior of cockroaches, under free-ranging conditions
      with videography or tethered in a motion tracking system, to determine (1) how
      antennal positional dynamics influence escape turning, and (2) if visual cues
      have any influence on antennal mediated escape. The spatial orientation of the
      long antennal flagellum at the time of tactile stimulation affected the direction
      of resultant escape turns. However, the sign of flagellar displacement caused by
      touch stimuli, whether it was deflected medially or laterally for example, did
      not affect the directionality of turns. Responsiveness to touch stimuli, and
      escape turn performance, were not altered by blocking vision. However, because
      cockroaches first orient an antenna toward stimuli entering the peripheral visual
      field, turn direction can be indirectly influenced by visual input. Finally, when
      vision was blocked, the run phase of escape responses displayed reduced average
      velocities and distances traveled. Our results suggest that tactile and visual
      influences are integrated with previously known wind-sensory mechanisms to
      achieve multisensory control of the full escape response.

PMID- 12607038
TI  - The antennal system and cockroach evasive behavior. II. Stimulus identification
      and localization are separable antennal functions.
AB  - Cockroaches ( Periplaneta americana) orient their antennae toward moving objects
      based on visual cues. Presumably, this allows exploration of novel objects by the
      antennal flagellum. We used videographic and electrophysiological methods to
      determine if receptors on the flagellum are essential for triggering escape, or
      if they enable cockroaches to discriminate threatening from non-threatening
      objects that are encountered. When a flagellum was removed, and replaced with a
      plastic fiber, deflection of a "prosthetic flagellum" still activated the
      descending mechanosensory interneurons associated with escape and produced
      typical escape responses. However, escape was essentially eliminated by
      constraining the movement of the scape and pedicel at the antennal base. When
      cockroaches approached and briefly explored the surface of a spider or another
      cockroach with the flagellum, they produced escape significantly more often in
      response to subsequent controlled contact from a spider than from a cockroach.
      This discrimination did not depend on visual or wind-sensory input, but required
      flagellar palpation of the surface. The crucial sensory cues appear to involve
      texture rather than surface chemicals. These results indicate that cockroaches
      acquire basic information on stimulus identity during exploration of surfaces
      with flagellar receptors, but that basal receptors are triggers for escape
      behavior.

PMID- 12607039
TI  - Octopamine modulates spermathecal muscle contractions in Locusta migratoria.
AB  - Octopamine was identified in the spermathecal tissue of Locusta migratoria using
      HPLC and immunohistochemical techniques. Octopamine-like immunoreactive unpaired
      median neurons were identified in the VIIth and VIIIth (terminal) abdominal
      ganglia and octopamine-like immunoreactive axons were present in the ventral
      ovipositor nerve (branches from this nerve innervate the spermatheca).
      Stimulatory actions of octopamine on myogenic and neurogenic contractions were
      observed. Dose-dependent increases in the frequency of myogenic contractions and
      the amplitude of neurogenic contractions were elicited by the application of
      octopamine to the spermathecal muscle. Non-sustained basal tension increases were
      noted in some preparations, although these were not found to be dose-dependent.
      SchistoFLRFamide (PDVDHVFLRFamide) inhibited octopamine-induced contractions by a
      maximum of about 30%. In the presence of 3-isobutyl-1 -methylxanthine, octopamine
      increased cAMP levels in all regions of the spermathecal. The largest increase in
      cAMP content was found in the spermathecal sac, followed by the straight duct and
      coil duct. Phentolamine blocked octopamine-induced increases in cAMP levels and
      abolished the actions of octopamine on myogenic contractions.

PMID- 12607041
TI  - Trophallaxis in forager honeybees (Apis mellifera): resource uncertainty enhances
      begging contacts?
AB  - Trophallaxis among adult worker honeybees is the transfer of liquid food by mouth
      from one individual to another. Within the colony, nectar foragers perform
      offering contacts (as food-donors) to transfer the contents of their crops to
      recipient nest-mates and, in addition, they also perform begging contacts (as
      food-receivers). The biological relevance of these last interactions remains
      unknown. Previous evidence suggests that begging may be involved in the exchange
      of information on food resources that occurs naturally between employed foragers
      and nest-mates. This work was aimed to reveal possible connections between the
      information obtained while foraging and the begging behavior displayed inside the
      nest. Experiments were intended to (1) analyze whether chemosensory information
      obtained while foraging, i.e., odors and sucrose concentrations, affects begging
      behavior, and (2) determine whether resource uncertainty enhances begging
      contacts. Results showed that: (1) most begging contacts lasted less than 1 s, a
      duration which only allows receiving food samples from nest-mates; (2) the
      diversity of odors and sucrose concentrations at the feeding place enhances the
      occurrence of begging contacts; and (3) an increased resource uncertainty
      enhances the forager begging behavior. In addition, results suggest that foragers
      may direct their begging contacts frequently to other employed nectar foragers.

PMID- 12607040
TI  - Orientation and spatiotemporal tuning of cells in the primary visual cortex of an
      Australian marsupial, the wallaby Macropus eugenii.
AB  - The metatherians (marsupials) have been separated from eutherians (placentals)
      for approximately 135 million years. It might, therefore, be expected that
      significant independent evolution of the visual system has occurred. The present
      paper describes for the first time the orientation, direction and spatiotemporal
      tuning of neurons in the primary visual cortex of an Australian marsupial, the
      wallaby Macropus eugenii. The stimuli consisted of spatial sinusoidal gratings
      presented within apertures covering the classical receptive fields of the cells.
      The neurons can be classified as those with clear ON and OFF zones and those with
      less well-defined receptive field structures. Seventy-percent of the total cells
      encountered were strongly orientation selective (tuning functions at half height
      were less than 45 degrees ). The preferred orientations were evenly distributed
      throughout 360 degrees for cells with uniform receptive fields but biased towards
      the vertical and horizontal for cells with clear ON-OFF zones. Many neurons gave
      directional responses but only a small percentage of them (4%) showed motion
      opponent properties (i.e. they were excited by motion in one direction and
      actively inhibited by motion in the opposite direction). The median peak temporal
      tuning for cells with clear ON-OFF zones and those without were 3 Hz and 6 Hz,
      respectively. The most common peak spatial frequency tuning for the two groups
      were 2 cycles per degree and 0.5 cycles per degree, respectively. Spatiotemporal
      tuning was not always the same for preferred and antipreferred direction motion.
      In general, the physiology of the wallaby cortex was similar to well studied
      eutherian mammals suggesting either convergent evolution or a highly conserved
      architecture that stems from a common therian ancestor.

PMID- 12607042
TI  - The roles of receptor noise and cone oil droplets in the photopic spectral
      sensitivity of the budgerigar, Melopsittacus undulatus.
AB  - Individual budgerigars (Melopsittacus undulatus) were taught to detect narrow
      bands of wavelengths under ambient illumination of known spectral composition.
      Because the cone pigments of this species of bird have been identified and data
      on carotenoid absorbance present in the cone oil droplets are available,
      predictions of the Vorobyev-Osorio equations can be calculated with reasonable
      confidence. Based on more than 27,600 individual choices made by several birds at
      10 wavelengths, the photopic sensitivity (i.e., color thresholds) of these birds
      is found to be consistent with the hypothesis that threshold discrimination of
      colored targets is limited by receptor noise and that high sensitivity to near
      ultraviolet wavelengths is in harmony with the relatively small number of
      ultraviolet cones present in the retina. The pronounced fine structure of the
      sensitivity spectrum is caused by the absorption of cone oil droplets. Under
      natural sunlight, containing more energy in the near-ultraviolet than is present
      in artificial indoor lighting, the birds' peak of sensitivity in the ultraviolet
      should be much less prominent than it is in laboratory experiments.

PMID- 12607043
TI  - Sensory cues for sound localization in the cricket Teleogryllus oceanicus:
      interaural difference in response strength versus interaural latency difference.
AB  - Two potential sensory cues for sound location are interaural difference in
      response strength (firing rate and/or spike count) and in response latency of
      auditory receptor neurons. Previous experiments showed that these two cues are
      affected differently by intense prior stimulation; the difference in response
      strength declines and may even reverse in sign, but the difference in latency is
      unaffected. Here, I use an intense, constant tone to disrupt localization cues
      generated by a subsequent train of sound pulses. Recordings from the auditory
      nerve confirm that tone stimulation reduces, and sometimes reverses, the
      interaural difference in response strength to subsequent sound pulses, but that
      it enhances the interaural latency difference. If sound location is determined
      mainly from latency comparison, then behavioral responses to a pulse train
      following tone stimulation should be normal, but if the main cue for sound
      location is interaural difference in response strength, then post-tone behavioral
      responses should sometimes be misdirected. Initial phonotactic responses to the
      post-tone pulse train were frequently directed away from, rather than towards,
      the sound source, indicating that the dominant sensory cue for sound location is
      interaural difference in response strength.

PMID- 12607044
TI  - Diversity in the structure of electrocommunication signals within a genus of
      electric fish, Apteronotus.
AB  - Some gymnotiform electric fish modulate their electric organ discharge for
      intraspecific communication. In Apteronotus leptorhynchus, chirps are usually
      rapid (10-30 ms) modulations that are activated through non- N-methyl- d
      aspartate (non-NMDA) glutamate receptors in the hindbrain pacemaker nucleus.
      Males produce longer chirp types than females and chirp at higher rates. In
      Apteronotus albifrons, chirp rate is sexually monomorphic, but chirp structure
      (change in frequency and amplitude during a chirp) was unknown. To better
      understand the neural regulation and evolution of chirping behavior, we compared
      chirp structure in these two species under identical stimulus regimes. A.
      albifrons, like A. leptorhynchus, produced distinct types of chirps that varied,
      in part, by frequency excursion. However, unlike in A. leptorhynchus, chirp types
      in A. albifrons varied little in duration, and chirps were all longer (70-200 ms)
      than those of A. leptorhynchus. Chirp type production was not sexually dimorphic
      in A. albifrons, but within two chirp types males produced longer chirps than
      females. We suggest that species differences in chirp duration might be
      attributable to differences in the relative proportions of fast-acting (non-NMDA)
      and slow-acting (NMDA) glutamate receptors in the pacemaker. Additionally, we map
      species difference onto a phylogeny and hypothesize an evolutionary sequence for
      the diversification of chirp structure.

PMID- 12607045
TI  - Decline in popularity of general surgery as a career choice in North America:
      review of postgraduate residency training selection in Canada, 1996-2001.
AB  - There has been a perception that fewer medical students are currently pursuing
      careers in general surgery. To investigate the validity of this premise we
      reviewed the Canadian Residency Matching Service (CaRMS) database from 1996 to
      2001 and identified recent trends in graduates' selections. Three surgical
      specialties--general surgery, orthopedic surgery, obstetrics and gynecology--were
      chosen for analysis as "poor lifestyle" specialties. They were compared to
      anesthesia, diagnostic radiology, and ophthalmology, which were chosen as
      representative "good lifestyle" specialties. Linear regression and chi-square
      analyses were performed to identify significant changes in applications to each
      specialty. A negative trend in first-choice applications to all three "poor
      lifestyle" specialties was observed, whereas all three "good lifestyle"
      specialties experienced increased first-choice applicants. Potential factors
      influencing medical student residency selection are discussed, emphasizing the
      reduced number of first-choice applicants to general surgery.

PMID- 12607046
TI  - Nitric oxide-mediated liver injury in the presence of experimental bile duct
      obstruction.
AB  - We investigated the possible mechanism of common bile duct (CBD) obstruction
      related liver cell necrosis in a guinea pig model during a 24-hour period of
      biliary occlusion. A total of 30 male albino guinea pigs were randomly and
      equally assigned to two groups. Group 1 underwent sham laparotomy (SL), and group
      2 underwent common bile duct ligation (CBDL). All the animals were followed for
      the first 24-hours after operation. The liver antioxidant defense was examined by
      measuring liver total superoxide dismutase (TSOD), copper/zinc-containing
      superoxide dismutase (Cu-ZnSOD), manganese superoxide dismutase (MnSOD), and
      glutathione peroxidase (GPx) activities as well as the reduced glutathione (GSH)
      concentration. Severity of necrosis was assessed by blind quantitation of liver
      specimens using a histologic scoring system. Histologic evidence of grade +2
      hepatocellular necrosis was observed in the CBDL group, as was a more than
      fourfold increase in plasma nitrite plus nitrate [NOx] concentrations in these
      animals. Although no significant difference was found between the two groups for
      liver Cu-ZnSOD activity, the CBDL group showed a marked decrease in MnSOD
      activity. Concomitant increases in liver GPx activity and the GSH level were
      measured in the CBDL group. These data supported the hypothesis that excessive
      production of [NOx] and its derivative peroxynitrite contribute to a coexisting
      MnSOD deficiency in the mitochondria and lead to liver cell necrosis in
      cholestatic animals.

PMID- 12607047
TI  - Timing of cholecystectomy for acute biliary pancreatitis: outcomes of
      cholecystectomy on first admission and after recurrent biliary pancreatitis.
AB  - Biliary stones are the leading cause of acute pancreatitis. Although
      cholecystectomy and selective endoscopic retrograde cholangiography (ERC)
      comprise the current treatment in patients with acute biliary pancreatitis (ABP),
      the time of intervention is still controversial. In this study we evaluated the
      outcomes of cholecystectomy on first admission for ABP and in patients with
      recurrent biliary pancreatitis. A series of 43 patients with ABP between January
      1997 and November 2000 were evaluated retrospectively. Patients were classified
      into two groups. Group I included 27 patients who underwent cholecystectomy on
      first admission before discharge from the hospital. Group II comprised 16
      patients who had recurrent biliary pancreatitis and then underwent
      cholecystectomy. The severity of the pancreatitis was determined by Ranson's
      criteria. Age, gender, length of hospital stay, severity of pancreatitis, amylase
      level, and complications of cholecystectomy were evaluated in both groups.
      Patients in group I underwent cholecystectomy during the original hospital
      admission and patients in group II during an admission for a recurrence. There
      were 24 patients with a Ranson's score </= 3 in group I and 12 in group II. The
      mean hospital stays were 15.29 days (range 4-48 days) and 36.66 days (range 15
      123 days) in groups I and II, respectively ( p = 0.006). Morbidity was 11%
      without mortality in group I and 43% with one mortality in group II ( p = 0.023).
      Definitive treatment of ABP can be accomplished effectively and safely by
      cholecystectomy following clinical improvement, with selective ERC performed
      during the first admission (delayed cholecystectomy). Waiting to perform
      cholecystectomy (interval cholecystectomy) may result in recurrent biliary
      pancreatitis, which may increase morbidity and the length of the hospital stay.

PMID- 12607048
TI  - Hepatoduodenal ligament invasion by gallbladder carcinoma: histologic patterns
      and surgical recommendation.
AB  - A consensus for the optimal management of hepatoduodenal ligament (HDL) invasion
      by gallbladder carcinoma has yet to be reached. We retrospectively correlated the
      patterns of HDL invasion with the surgical outcome. From 1985 to 2000, 59
      patients underwent combined resection of the extrahepatic bile duct and
      gallbladder and contiguous organs if required. Pathologic staging (UICC) was
      stage II, 4; stage III, 14; stage IVa, 10; and stage IVb, 31. Hepatoduodenal
      ligament invasion was subdivided into lymph node involvement (LNI) and bile duct
      infiltration (BDI). Patterns of HDL invasion were compared with bile duct
      morphology, resectability, and outcome. Bile duct infiltration ( n = 32) caused
      stenosis of the bile duct in all cases, whereas LNI ( n = 40) caused stenosis in
      only 4 cases. Resection was complete after extended cholecystectomy ( n = 22) in
      36%; 4b/5 segmentectomy ( n = 10) in 90%; major hepatectomy ( n = 2) in 50%; and
      hepatopancreatoduodenectomy ( n = 17) in 53% of cases. Surgery was curative in
      75% of patients without BDI, and was < 30% with BDI. The most common factor
      preventing curative resection in BDI was perineural invasion around the HDL.
      Perineural invasion occurred in over 70% of cases at either the cut end of the
      bile duct or in the margin of dissection. The 3-year survival rates, excluding
      patients with R2 resection (residual cancer) and death in hospital, were LNI(
      )BDI(-) ( n = 8), 65.6%; LNI(+)BDI(-) ( n = 17), 35.3%; LNI(-)BDI(+) ( n = 7),
      14.3%; and LNI(+)BDI(+) ( n = 17), 5.9%. There were no 5-year survivors with BDI.
      In conclusion, perineural invasion in BDI is an important obstacle to complete
      resection. Hepatopancreatoduodenectomy is a feasible strategy only for LNI(+)BDI(
      ) disease.

PMID- 12607049
TI  - Completion radical surgery after cholecystectomy for accidentally undiagnosed
      gallbladder carcinoma.
AB  - Survival time of 73 patients with undiagnosed gallbladder carcinoma incidentally
      found after cholecystectomy treated between 1982 and 2000 was evaluated in
      relation to various variables, with special reference to the significance of the
      radical second resection. The most significant prognostic factor was the depth of
      tumor invasion as assessed by univariate and multivariate analyses (odds ratio
      3.40, 95% CI 1.65-7.00, p < 0.001). None of the 23 pT1 patients received radical
      second resection, and all of them were doing well without recurrence at their
      last follow-up examination. The 3-year survival rate was 68% for patients with
      pT2 and 14% for patients with pT3. Patient characteristics for the 18 pT2
      patients who underwent radical second resection were similar to the
      characteristics of the 25 pT2 patients who did not; nor did postoperative
      survival times differ significantly. Survival time was not correlated with the
      interval from initial to second surgery or the type of initial cholecystectomy
      (open vs laparoscopic). In 11 patients with pT2 whose surgical margin was judged
      positive at initial cholecystectomy, the radical second resection significantly
      lengthened survival time. Radical second resection tended to prolong the median
      survival period from 7 to 15 months in 7 patients with pT3, although the
      difference was not significant. In conclusion, patients with pT1 undiagnosed
      carcinoma need no further treatment. The redo surgery was found to prolong
      survival only in patients with pT2 with positive surgical margin at initial
      cholecystectomy.

PMID- 12607050
TI  - Factors influencing postoperative hospital mortality and long-term survival after
      radical resection for stage IV gallbladder carcinoma.
AB  - Factors influencing postoperative hospital mortality and long-term survival after
      radical resection of stage IV gallbladder carcinoma remain unclear. The objective
      of this study was to identify characteristics of patients who are good candidates
      in terms of surgical risk and long-term survival for radical resection of stage
      IV gallbladder carcinoma. A retrospective study was made of attempted surgical
      cure in 72 patients with stage IV gallbladder carcinoma. There were 14
      postoperative hospital deaths (19%). Eleven (19%) of the 58 patients discharged
      from hospital survived for more than 3 years. Multivariate analysis indicated
      male gender, extended right hepatic lobectomy in a cholestatic liver, and portal
      vein resection as independent risk factors that correlated with hospital death.
      Distant metastasis was the sole independent factor that related negatively with
      long-term survival by multivariate analysis. Subset analysis was performed with
      combinations of the four independent factors obtained by multivariate analyses.
      The hospital mortality rate and the 3-year survival rate in the 44 patients
      without portal vein involvement were 9% and 28%, respectively, and were 3% and
      27%, for the 31 women in this group. The highest 3-year survival rate (39%) was
      observed in the 26 patients without distant metastasis and portal vein
      involvement, despite a hospital mortality rate of 12%. Better patient selection
      may improve the outcome of radical surgery for stage IV gallbladder carcinoma.
      These data may be useful in designing future trials of the surgical treatment of
      advanced gallbladder carcinoma.

PMID- 12607051
TI  - Preoperative evaluation of hilar cholangiocarcinoma with contrast-enhanced three
      dimensional fast imaging with steady-state precession magnetic resonance
      angiography: comparison with intraarterial digital subtraction angiography.
AB  - We sought to evaluate the image quality of double-dose, contrast-enhanced 3D fast
      imaging with steady-state precession (FISP) magnetic resonance (MR) angiography
      in patients with hilar cholangiocarcinoma, and to compare its efficacy with
      intraarterial digital subtraction angiography (DSA). Thirty-six patients were
      studied to determine the visibility of the hepatic artery and portal vein with
      contrast-enhanced MR angiography. Determination of hepatic arterial and/or portal
      invasion from cholangiocarcinoma was compared between MR angiography and DSA as
      well. 0.2 mmol/kg gadolinium chelates were administrated at a rate of 4 ml/s. The
      hepatic artery was diagnostically visible in 28 patients (78%); the portal vein,
      in 34 patients (94%). The sensitivities, specificities, and accuracies in
      distinguishing arterial invasion, were 58%, 93%, and 89%, respectively, with MR
      angiography; 75%, 99%, and 96%, respectively, with DSA. In distinguishing portal
      venous invasion, these were 78%, 91%, and 89%, respectively, with MR angiography;
      78%, 92%, and 90%, respectively, with DSA. There were no significant differences
      between imaging methods ( p >.05); however, DSA was superior in specificity
      regarding hepatic arterial invasion ( p =.0143). The data presented here indicate
      that noninvasive contrast-enhanced 3D FISP MR angiography has the potential to
      replace DSA in the preoperative evaluation of hilar cholangiocarcinoma.

PMID- 12607052
TI  - Evaluating the hilar bifurcation territory in the human liver caudate lobe to
      obtain critical information for delimiting reliable margins during caudate lobe
      surgery: anatomic study of livers with and without the external caudate notch.
AB  - The hilar bifurcation (HB), a wedged portion between the left and right portal
      vein origins, often issues the caudate branch. However, the HB territory in the
      caudate lobe has not been well recognized during liver surgery. In 50% of 48
      human livers (25 usual livers and 23 with the external caudate notch), the HB
      gave off thick portal branches (> 1 mm) to supply the caudate lobe. Using minute
      dissections, we identified four cross-sectional configurations of three
      subdivisions of the caudate lobe (i.e., left, right, and HB portal territories).
      The HB territory was consistently located in the paracaval portion, although it
      sometimes (29.2%: type A) extended slightly or deeply into Spiegel's lobe. This
      leftward HB territorial extension was seen more frequently in livers with the
      notch (43.6%) than in those without it ("usual" livers) (16.0%). Moreover, in
      livers with the notch the caudate lobe (usually its right portal territory)
      tended to extend upward and rightward to attach or surround the terminal portion
      of the right hepatic vein. Our results suggested that in many cases subdivisions
      of the caudate lobe cannot be divided simply into right and left portions. The HB
      branch or territory should be examined to determine the real principal border as
      well as the subdivisional configuration of the caudate lobe. Combined evaluation
      of the HB branch(es) and external notch could provide critical information for
      anatomically sophisticated caudate lobe surgery.

PMID- 12607053
TI  - Aggressive surgical resection for hilar-invasive and peripheral intrahepatic
      cholangiocarcinoma.
AB  - The clinicopathology and surgical outcome of intrahepatic cholangiocarcinomas are
      not fully understood. The objective of this study was to clarify the
      clinicopathologic features of intrahepatic cholangiocarcinoma and evaluate
      prognostic factors influencing survival. Forty consecutive patients with
      intrahepatic cholangiocarcinomas undergoing surgical resection at Chiba
      University Hospital between October 1981 and October 1997 were analyzed
      retrospectively. Intrahepatic cholangiocarcinomas were classified as hilar
      invasive type ( n = 26) or peripheral type ( n = 14). Patients with peripheral
      type tumors had a significantly ( p = 0.005) better 5-year survival rate (43%)
      than those with the hilar-invasive type (4%). Hilar-invasive-type tumors had
      perineural invasion (100%) and nodal involvement (85%) more frequently than did
      peripheral-type tumors. Despite aggressive surgical resection, the surgical
      margin was positive in 88% of patients with hilar-invasive type tumors (23/26)
      and 29% of patients with peripheral-type tumors (4/14). There was no evidence of
      a survival benefit of vascular resection for patients with a hilar-invasive
      intrahepatic cholangiocarcinoma. Patients with lymph node metastasis had a
      significantly worse prognosis ( p = 0.0004). No patients with nodal involvement
      survived more than 38 months. Negative perineural invasion ( p = 0.008) and a
      negative microscopic margin ( p = 0.008) were significantly associated with
      improved survival. Better survival results could be achieved by curative
      resection with a free margin for hilar-invasive and peripheral intrahepatic
      cholangiocarcinoma.

PMID- 12607054
TI  - Clinicopathologic features and factors related to survival of patients with small
      hepatocellular carcinoma after hepatic resection.
AB  - Hepatic resection for small hepatocellular carcinomas (HCCs) offers patients a
      chance of cure but is associated with a significant tumor recurrence rate. We
      characterized 145 resected small HCCs and defined patients who would most benefit
      from hepatic resection. A retrospective study was conducted of 485 HCC patients
      who had undergone curative resection. The clinical features and survival rates of
      patients with HCCs </= 3 cm (group 1, n = 145) were compared with those of
      patients with HCCs > 3 cm (group 2, n = 340). Compared with group 2 patients,
      group 1 had worse liver function, a higher frequency of hepatitis C infection,
      and a lower alpha-fetoprotein level. The 1-, 3-, and 5-year disease-free survival
      rates of group 1 were better than those of group 2 (82%, 59%, and 42% vs. 56%,
      39%, and 31%, respectively) ( p < 0.001). From the sixth postoperative year
      onward, the proportions of disease-free survivors were not significantly
      different between the two groups (32% vs. 31%). By multivariate analysis, factors
      influencing small-HCC patients' outcomes were tumor centrally located ( p =
      0.003), indocyanine green retention rate > 10% ( p = 0.017), and albumin level <
      3.7 g/dl ( p = 0.004). A clinical risk scoring system incorporating these factors
      correlated closely with the patients' outcomes and it may be used to select
      patients who would most benefit from hepatic resection.

PMID- 12607055
TI  - Hepatic resection for colorectal metastasis with macroscopic tumor thrombus in
      the portal vein.
AB  - Metastatic lesions in the liver derived from colorectal cancer rarely invade the
      portal vein macroscopically. Little is known about the clinical characteristics
      and outcome of surgical treatment in patients with tumor thrombus in the portal
      vein. Medical charts of 142 consecutive patients who underwent hepatic resection
      for colorectal metastasis were reviewed retrospectively. Of the 142 patients, 4
      (2.8%) had macroscopic portal vein invasion. The most prominent characteristic on
      preoperative imaging was segmental staining in the arterial phase shown by
      dynamic computed tomography (CT) or by CT arteriography. This finding was
      positive in all four of the patients. All patients underwent anatomic liver
      resection and were alive with no evidence of disease for an average of 52.3
      months (range 21-102 months). Macroscopic tumor thrombus in the portal vein is
      rare with colorectal metastasis. It is accurately detected by CT by checking for
      signs of segmental staining. In this setting, anatomic major resection of the
      liver is essential for curative treatment.

PMID- 12607056
TI  - Delay in treatment of colorectal cancer: multifactorial problem.
AB  - The stage of a colorectal carcinoma represents the most important prognostic
      factor regarding the probability of survival. The primary objective of this study
      was to document the management of patients with colorectal carcinoma after onset
      of symptoms. Factors influencing the delay in definitive therapy should thus be
      determined. Anthropometric, social, and operative data were obtained by
      standardized questionnaires from 40 patients with colonic cancer and 30 patients
      with rectal cancer. The influence of delayed treatment on outcome was analyzed. A
      significant correlation was found for the time between onset of first symptoms
      and definitive surgical therapy with tumor stage (colon cancer: r = 0.52, p <
      0.05; colorectal cancer: r = 0.62, p < 0.05). The time delay in rectal carcinoma
      patients averaged 224 days and in patients with colonic carcinoma 149 days.
      Social influences such as profession, type of education, marital status, and
      quality of health insurance had a significant influence on treatment delay, as
      did the clinical experience of the physician first contacted. The leading symptom
      in patients with rectal cancer was peranal hemorrhage, and in patients with
      colonic cancer it was abdominal pain. The main causes of iatrogenic delay were
      insufficient clinical investigation and a lack of awareness when typical first
      symptoms were present. Delayed treatment of colorectal cancer seems to be a
      multifactorial problem. Causes for such delay are found not only in the patients
      and their social environments but also in the type and quality of their medical
      care systems. Intensified education and earlier prevention are the major aims for
      patients and their physicians.

PMID- 12607057
TI  - Etiology of the resting myoelectric activity of the levator ani muscle:
      physioanatomic study with a new theory.
AB  - Of all the striated muscles in the bodies of mammals, only the pelvic floor
      muscles, which include the levator ani (LA), have resting electric activity. The
      cause and function of this resting myoelectric activity are not exactly known.
      The current study investigated the effect of intraabdominal pressure (IAP) and
      visceral weight on the electromyographic (EMG) activity of the LA, seeking to
      elucidate its cause and function. A series of 18 subjects (12 women, 6 men, mean
      age 38.6 years) were subjected to laparoscopic cholecystectomy for calcular
      cholecystitis. Prior to cholecystectomy, the resting LA EMG and IAP were recorded
      with the patient in the recumbent and erect positions. During laparoscopic
      cholecystectomy, the IAP was elevated by CO2 insufflation in increments of 5 cm
      of H(2)O, and the LA EMG activity was recorded for the recumbent and vertical
      positions during inflation and after deflation at the end of the operation. In
      5/18 patients in whom laparoscopic cholecystectomy was extended to open
      cholecystectomy, the IAP and LA EMG were also registered. The study also included
      histologic examination of the LA muscle from 15 cadavers (7 adults, 8 neonates).
      Levator ani EMG increased ( p < 0.05) on standing. At operation, IAP elevation
      was associated with a significant increase of LA EMG activity. On deflation, the
      IAP and LA EMG activity level returned to the pre-insufflation state. In open
      cholecystectomy, the IAP was zero and the LA EMG recorded no activity for the
      recumbent position, but there was an activity for the vertical position.
      Histologically, the lateral part of the LA in the adult cadavers consisted solely
      of skeletal muscle fibers. Proceeding medially, smooth muscle fibers started to
      appear and gradually increase until, at the midportion, the LA split into two
      layers, a deep layer consisting of smooth muscle fibers and a superficial layer
      consisting of skeletal fibers. In neonates, the LA was composed of purely
      skeletal muscle fibers. The LA EMG activity seems to be related to both the IAP
      and the visceral weight. It is probably attributable to the presence of smooth
      muscle bundles in the LA muscle. The LA EMG activity increased with the elevation
      of the IAP and visceral weight, which resulted in increased muscle tone to oppose
      the augmented pressure or weight. This effect seems to be mediated through the
      straining-levator reflex. A chronic increase of IAP or visceral overload is
      suggested to affect muscle integrity and function.

PMID- 12607058
TI  - Possibilities of chromoesophagoscopy for diagnosis of Barrett's esophagus.
AB  - When the distal esophagus is covered with columnar gastric mucosa up to 2 cm from
      the esophagogastric junction it is considered normal. If the distal esophagus is
      covered with columnar epithelium more than 2 cm from the esophagogastric
      junction, it is called Barrett's esophagus. We have developed a new
      chromoesophagoscopic method to improve diagnostic testing for Barrett's
      esophagus. The distinctive feature of this method is that 4 to 5 ml of a 1%
      solution of neutral red is administered intravenously, after which excretion of
      the stain by the esophageal mucosa is examined by endoscopy. Chromoesophagoscopy
      has been carried out in 11 patients with reflux esophagitis. It revealed
      Barrett's esophagus in four patients, which was proved by histologic evaluation
      of biopsy specimens obtained from the stained zone of the esophageal mucosa.
      These observations suggest that chromoesophagoscopy is an effective, accessible,
      feasible, safe method for diagnosing Barrett's esophagus. It allows us to
      determine the length of the metaplastic epithelium and the topography of gastric
      glands; it also allows us to examine parietal cells in the esophagus and estimate
      the functional activity of these parietal cells in metaplastic epithelium.

PMID- 12607059
TI  - Management of 100 consecutive cases of pancreatic serous cystadenoma: wait for
      symptoms and see at imaging or vice versa?
AB  - Pancreatic serous cystadenomas have a low malignancy rate. When nonsymptomatic,
      in selected patients, they can be managed without surgery; however, a high degree
      of diagnostic reliability is crucial. We admitted 100 consecutive cases (87 women
      with a median age of 51.86 years). Of these, 44 were symptomatic and 56 were
      diagnosed incidentally. Ultrasound correctly diagnosed 53% of the cases,
      incorrectly 31%, and was nondiagnostic in 16%. Computed tomography scan had
      similar rates (54%, 34% and 12%, respectively), while magnetic resonance imaging
      improved diagnostic accuracy to 74% and reduced incorrect diagnoses to 26%. In 21
      cases, exploratory needle aspiration of the cyst was carried out; only 8 samples
      (38%) resulted in a diagnosis; in 12 patients (57%) insufficient material was
      acquired to allow for diagnosis, one case demonstrated epithelial dysplasia. In 1
      patient an exploratory puncture resulted in a very serious bleeding. Sixty-eight
      patients were treated surgically, the 44 symptomatic cases and another 24
      patients with ill-defined oligocystic lesions that could not be differentiated as
      serous or mucinous in the preoperative period. Two patients underwent resection
      because of frank tumor growth. In the two time periods analyzed (the first 7
      years and the subsequent 6.5 years) the relationship between cases
      observed/operated on did not significantly change. Twenty-one (30.8%) distal
      pancreatectomies, 14 (20.5%) intermediate resections, 10 (14.7%)
      pancreaticoduodenectomies 4 (5.8%) enucleations, and 1 (1.4%) duodenum-preserving
      pancreatic head resection were carried out. Nine patients (13.2%), underwent
      exploratory laparotomy with a diagnostic biopsy. Another 9 underwent
      decompressive interventions with cystojejunostomies. The morbidity was 27.9%,
      with a reoperation rate of 7.3% and zero mortality. In general the patient's pain
      resolved in the postoperative period. Median follow-up was 43 months (range, 4
      191 months). One patient died from other causes, and all others are currently
      alive. In the group of 32 patients who did not undergo operation, the median
      follow-up is 69 months (range, 8-164 months). Until more sophisticated
      technologies can be developed, the current diagnostic work-up will not result in
      increased preoperative diagnosis of serous-cystic tumors of the pancreas. This is
      mainly relevant to the oligocystic forms, which account for about one fourth of
      all serous tumors observed.

PMID- 12607060
TI  - Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of
      the pancreatic head: 25-year experience.
AB  - The prognosis of patients who undergo resection for pancreatic ductal
      adenocarcinoma with curative intention is generally poor unless they have early
      stage disease. Based on our 25-year experience, the results of 194 patients after
      a standardized Kausch-Whipple resection for adenocarcinoma of the pancreatic head
      were analyzed and the prognostic factors were evaluated. Between 1972 and 1998 a
      total of 221 patients were diagnosed for ductal adenocarcinoma of the pancreatic
      head, and 194 of them subsequently underwent a standardized Kausch-Whipple
      resection. Long-term results and prognostic factors were examined by multivariate
      and univariate analyses. The overall postoperative mortality was 3.09%, and the
      morbidity was 29.9%. By multivariate analysis only curative resection (R0) was
      significantly related to a favorable prognosis ( p < 0.0001). Furthermore, in
      case of a curative resection, the presence of lymph node metastases showed
      prognostic significance in the multivariate analysis ( p = 0.005). Cumulative
      survival analysis revealed a 5-year survival rate of 25.4%, a 7-year survival
      rate of 12.3%, and a 10-year survival rate of 8.2% for patients who underwent
      curative resection (R0) for adenocarcinoma of the pancreatic head. We
      demonstrated that the R0 status is the only independent prognostic factor after
      surgery for adenocarcinoma of the pancreatic head. In the case of a curative
      resection, the presence of lymph node metastases is of prognostic relevance. In
      view of considerable surgical morbidity and mortality, resection for cancer of
      the pancreatic head is the only option if the lesion is resectable. We concluded
      that surgical treatment is "as good as it gets," as extended techniques have not
      proved to produce better results.

PMID- 12607061
TI  - Minimum number of lymph nodes that should be examined for the International Union
      Against Cancer/American Joint Committee on Cancer TNM classification of gastric
      carcinoma.
AB  - The classification of lymph node metastasis based on the number of positive nodes
      has been adopted in the International Union Against Cancer/American Joint
      Committee on Cancer (UICC/AJCC) TNM classification of gastric carcinoma. However,
      the N classification (for condition of the regional lymph nodes) would be
      underestimated when the number of examined nodes were too small. To determine the
      minimum number of lymph nodes to examine for a correct classification, we
      analyzed 926 patients undergoing curative resection for gastric carcinoma. The
      number of metastatic lymph nodes correlated significantly with the number of
      examined lymph nodes. The pN0 patients with 10 to 14 examined nodes showed a
      significantly higher survival rate than did those with 5 to 9 examined nodes, and
      they had as good a prognosis as those with 15 or more examined nodes. In the pN1
      and pN2 categories, patients with 29 or fewer examined nodes tended toward lower
      survival rates than did patients with 30 or more examined nodes. Among the
      patients who were classified as stage IA, the survival rate for those with 5 to 9
      examined nodes was significantly lower than that for patients with 30 or more
      examined nodes. Among the patients classified as stage III, those with 10 to 19
      examined nodes and those with 20 to 29 examined nodes had lower survival rates
      than did patients with 30 or more examined nodes. In conclusion, the minimum
      number of lymph nodes examined for a correct pN0 classification can be reduced
      from 15 to 10. For pN1-3 classifications, 20 or more nodes should be examined,
      and examining 30 or more lymph nodes may be desirable.

PMID- 12607062
TI  - Is adenocarcinoma of the gastric cardia a distinct entity independent of
      subcardial carcinoma?
AB  - Cardia carcinoma has been defined diversely. The purpose of this study was to
      determine whether cardia carcinoma should be categorized as a distinct entity
      independent of subcardial carcinoma. We retrospectively analyzed 65 patients
      undergoing resection for adenocarcinoma involving the esophagogastric junction
      (EGJ) with the tumor center within 5 cm of the EGJ. Adenocarcinomas of the EGJ
      were classified into Type I, Type II, and Type III according to Siewert's
      criteria. There was only one Type I adenocarcinoma, and it was associated with
      Barrett's esophagus. No tumors had their center between 1 cm and 2 cm proximal to
      the EGJ. Clinicopathologic features and prognosis were compared among patients
      with Type II adenocarcinomas ( n = 31), patients with Type III adenocarcinomas (
      n = 33), and patients with adenocarcinomas in the upper third of the stomach not
      invading the EGJ ( n = 153). Siewert's Type II adenocarcinoma was associated with
      a higher male/female ratio and with higher incidences of well-demarcated
      appearance and differentiated histology than carcinoma of the upper third of the
      stomach without esophageal invasion. Lymph nodes along the greater curvature and
      parapyloric nodes were rarely involved in Type II tumors. Within the pT2
      category, patients with Siewert's Type II tumors showed a higher incidence of
      lymph node metastasis and a significantly lower survival rate than did patients
      with tumors of the upper third of the stomach without esophageal invasion. In
      conclusion, cardia carcinoma, appropriately defined as adenocarcinoma with its
      epicenter between 1 cm proximal and 2 cm distal to the EGJ, should be categorized
      as a distinct entity.

PMID- 12607063
TI  - Long-term outcome of unilateral parathyroid exploration for primary
      hyperparathyroidism due to presumed solitary adenoma.
AB  - Unilateral cervical exploration for primary hyperparathyroidism (PHPT) remains
      controversial. Critics of unilateral exploration have argued that this surgical
      strategy results in an unacceptably large number of patients with persistent or
      recurrent hypercalcemia following the initial operation due to undetected
      additional parathyroid pathology on the contralateral, unexplored side of the
      neck. We have reviewed retrospectively a large cohort of patients who were
      submitted to scan-directed unilateral cervical exploration for PHPT following
      dual-isotope subtraction scintigraphy and according to a standard protocol.
      Between January 1, 1985 and June 30, 1999 a series of 184 patients underwent scan
      directed unilateral neck exploration for PHPT. Following the initial operation
      three individuals (1.6%) demonstrated persistent hypercalcemia. At a mean follow
      up of 59 months (range 6-168 months) none of the patients had developed recurrent
      hypercalcemia. Scan-directed unilateral cervical exploration represents a valid
      surgical strategy for a significant proportion of patients with PHPT; and in this
      group of patients it does not lead to an increased incidence of persistent or
      recurrent hypercalcemia.

PMID- 12607064
TI  - Fractures in patients with primary hyperparathyroidism: nationwide follow-up
      study of 1201 patients.
AB  - Parathyroid hormone (PTH) increases bone turnover and may thus increase fracture
      risk. As PTH secretion is increased in primary hyperparathyroidism, surgical cure
      may prevent fractures. We studied fracture risk before and after diagnosis in
      patients treated surgically and conservatively for primary hyperparathyroidism.
      All 1201 patients with newly diagnosed primary hyperparathyroidism (PHPT) between
      1982 and 1996 in Denmark were identified through the Danish Hospital Discharge
      Register. Each patient was compared with three age- and gender-matched controls
      randomly drawn from the background population. Those who were treated surgically
      ( n = 841; mean age 58.6 +/- 14.6 years) were significantly younger than those
      who were not ( n = 360; 65.5 +/- 16.8 years; 2 p < 0.01); they had higher plasma
      ionized calcium (1.58 +/- 0.16 vs. 1.50 +/- 0.10 mmol/L; 2 p = 0.03) and tended
      to have lower lumbar spine bone mineral Z-scores (-0.72 +/- 1.35 vs. 0.05 +/-
      1.05; 2 p = 0.06). Before diagnosis, fracture risk was elevated in both those who
      subsequently underwent surgery [incidence rate ratio (IRR) 1.45, 95% CI 1.05
      1.99] and in those who did not (IRR 1.59, 95% CI 1.10-2.29). After diagnosis, no
      difference in fracture risk was present between surgically and nonsurgically
      treated patients. The risk of death was significantly lower in the operated
      patients than in those who did not have surgery (RR 0.58, 95% CI 0.47-0.73). No
      differences in fracture risk could be demonstrated between those who had and
      those who did not have surgery, taking age, gender, and previous fractures into
      account.

PMID- 12607065
TI  - Surgical therapy and histological abnormalities in functional isolated small
      bowel obstruction and idiopathic gastrointestinal perforation in the very low
      birth weight infant.
AB  - We examined surgical treatment, outcome, and histological findings in very low
      birth weight (VLBW) infants with functional isolated small bowel obstruction
      (FISBO) and idiopathic gastrointestinal perforation (IGIP). The files of 18
      neonates (average gestational age 27.5 weeks; average birth weight 880 g),
      surgically treated for IGIP ( n = 12) or FISBO ( n = 6), were retrospectively
      reviewed. In both groups segmental or diffuse dilatation of the small bowel was
      seen. All but two perforations were localized in the small bowel. In half of the
      patients a discontinuous absence of the internal layer of the muscularis propria
      or muscularis mucosae was found. Signs of necrotizing enterocolitis (NEC) were
      absent. Most of the patients were treated with an enterostomy (IGIP: n = 11;
      FISBO: n = 4). Overall survival in both groups was 83%. Follow-up after
      enterostomy closure (mean 23 months) shows normal gastrointestinal function
      without failure to thrive in 67% of the survivors. Muscular wall abnormalities
      and small bowel distension are found in both FISBO and IGIP. Although the
      underlying etiology remains unclear, segmental muscular wall absence may be a
      major predisposing factor in both conditions. Creation of a temporary enterostomy
      is a valid surgical option in VLBW infants with minimal risk for recurrent
      obstruction and/or perforation. Survival and long-term gastrointestinal function
      is excellent. IGIP should be distinguished from NEC.

PMID- 12607066
TI  - Analysis of failure in living donor liver transplantation: differential outcomes
      in children and adults.
AB  - Over the past decade we have reported excellent outcomes in pediatric living
      donor liver transplantation (LDLT) with recipient survival exceeding 90%.
      Principles established in these patients were extended to LDLT in adults. To
      compare outcomes in donors and recipients between adult and pediatric LDLT in a
      single center, we reviewed patient records of 45 LDLT performed between 1/98 and
      2/01: 23 adult LDLT (54 +/- 6.5 yr) and 22 pediatric LDLT (33.7 +/- 53.5 months).
      Preoperative liver function was worse in adults (International Normalized Ratio
      [INR] 1.5 +/- 0.4 vs. INR 1.2 +/- 0.5; p = 0.032). 4 adults (17%) met criteria
      for status 1 or 2A. Only 1 child was transplanted urgently. Analysis included
      descriptive statistics and Kaplan-Meier estimation. Donor mortality was 0% with 1
      re-exploration, 2.4%. Median hospital stay (LOS) was 6.0 days (range, 4-12 days).
      Donor morbidity and LOS did not differ by sex, extent of hepatectomy, or adult
      and pediatric LDLT ( p = 0.49). In contrast, recipient outcomes were worse for
      adults. Adult 1 year graft survival was 65% (3 retransplants [ReTx], 5 deaths)
      vs. 91% for children (1 ReTx, 1 death) p = 0.02. Graft losses in adults were due
      to sepsis (n = 3), small for size (n = 2), suicide, and hepatic artery thrombosis
      (HAT), whereas in children graft losses were due to portal thrombosis and total
      parenteral nutrition (TPN) liver failure. Biliary leaks occurred in 22% of adults
      and 9% of children. Hepatic vein obstruction occurred in 17% of adults and in
      none of the children. Median LOS was comparable (adult, 16.5 days (range, 7-149
      days); child, 17 days (range, 10-56 days), p = 0.2). Graft function (total
      bilirubin (TBili) < 5mg/dl, INR < 1.2, aspartate aminotransferase (AST) < 100
      U/l) normalizing by day 4 in children and by day 14 in adults. Adults fared
      worse, with an array of problems not seen in children, in particular, hepatic
      vein obstruction and small-for-size syndrome. Biliary leaks were diagnosed later
      in adults and were lethal in 3 cases; this was later avoided with biliary
      drainage in adult recipients. Finally, use of LDLT in decompensated adults led to
      death in 3 of 4 patients, and should be restricted to elective use.

PMID- 12607067
TI  - Effects of a femoral shaft fracture on multiply injured patients with a head
      injury.
AB  - To study the effects of a femoral shaft fracture and its early stabilization on
      the morbidity, mortality, and outcome of patients with multiple injuries and a
      concomitant head injury, we analyzed the clinical course of patients using a
      prospectively gathered database. A series of 42 patients with multiple injuries,
      including head injuries and femoral fractures, formed the study group. A series
      of 133 patients with multiple injuries and head injuries but without femoral
      fractures formed the control group. The parameters examined included injury
      severity, injury pattern, hemodynamics at admission, mortality, duration of
      ventilation, length of intensive care unit (ICU) stay, and outcome. There were no
      significant differences regarding the demographics, injury severity score (ISS),
      injury pattern except the extremity Abbreviated Injury Scale (AIS) between the
      study and control groups. No significant differences were found in terms of
      mortality, duration of ventilation/ICU stay, and outcome. Injury severity (ISS),
      severity of the head injury (AIS), and hemodynamics at admission were shown to
      have a significant effect on the examined parameters. The present study suggests
      that a femoral fracture and its early stabilization in a multitrauma patient with
      a concomitant head injury do not adversely affect mortality and outcome and
      supports aggressive surgical management for these patients.

PMID- 12607073
TI  - Preferences for cocaine- or pup-associated chambers differentiates otherwise
      behaviorally identical postpartum maternal rats.
AB  - RATIONALE AND OBJECTIVES: Our previous work uncovered a differential preference
      of maternal female rats for cues associated with pups versus cues associated with
      cocaine at three different postpartum time points. Our current study examines the
      preference for these cues in conjunction with an assessment of the capacity to
      express the maternal behavior at one of these time points. We examined dams at
      day 10 postpartum using a procedure that included two additional controls, and a
      complete assessment of the expression of maternal behavior and locomotor
      activity. METHODS: A conditioned place-preference procedure was used to determine
      the preference for cocaine- or pup-associated cues. The two controls were (1) a
      preconditioning test to verify no initial chamber preference and (2) a separate
      control group of postpartum day-10 dams exposed to chambers and cues but not to
      unconditioned stimuli. The expression of maternal behavior was determined by
      measurement of maternal nest building, retrieval of pups to the nest, grooming,
      crouching over pups, nursing, and maternal aggression. Locomotor activity was
      measured with an automated apparatus. RESULTS: Dams conditioned with cocaine or
      pups showed a preference for either the cocaine-associated chamber or the pup
      associated chamber, confirming the existence of two similar-sized preference
      groups at this time point. Regardless of preference, dams had equal and robust
      expression of maternal behavior and similar locomotor capacity. The pre
      conditioning test showed no initial chamber preferences and did not alter the
      conditioned preference response. The use of unconditioned stimuli in the place
      preference conditioning procedure was effective and necessary for the preference
      response. CONCLUSION: Our current study has revealed that differences in the
      motivational state of the maternal dam emerge even while the expression of
      maternal behavior is constant and substantial. The data suggest that the
      difference in preference is a very specific appetitive response that is not
      linked to expression of maternal behavior or locomotor capacity.

PMID- 12607075
TI  - [Rachitic knock knees in children].
AB  - Knee malpositions, for example valgus or varus deformations or flexion
      contractures, were often cited in the historical literature. In earlier times,
      clinical pictures such as rickets were often the reason for this kind of
      deformity. A causal therapy did not exist until the twentieth century. In most
      cases of rickets, genu valgum was reported as the typical knee deformation. The
      differential diagnosis for genu valgum caused by rickets was genu valgum
      traumaticum, paralyticum, and inflammatorium. The most important reports on the
      pathogenesis of valgus deformation can be found in publications by Hueter and von
      Mikulicz. The causal therapy of rickets was introduced at the beginning of the
      twentieth century.Vitamin therapy and UV phototherapy were developed during this
      period. Using these therapies, rickets decreased dramatically. Kurt Huldschinsky,
      a pediatrician from Berlin,was one of the main inventors of UV phototherapy in
      Germany. At the end of the nineteenth century, the operative correction of knee
      deformities increased while conservative treatment continued to be applied.
      Plaster casts,orthoses, and osteoclast therapy were the main noninvasive
      therapeutic possibilities. Positive aspects of the conservative techniques were
      mostly the good results and easy, timesaving technique compared with the
      operative treatment. The operative therapy increased with the knowledge of
      antisepsis and asepsis as well as advances in anesthetic procedures. Operative
      treatment modalities, for example tibial and femoral osteotomies, were more
      precise, but connected with multiple complications and greater time expenditure.
      Sufficient vitamin prophylaxis rendered knee deformations caused by rickets a
      rarity.

PMID- 12607076
TI  - [Anterior knee pain in children and adolescents. Diagnosis and conservative
      treatment].
AB  - Anterior knee pain is a common problem in childhood and adolescence with a
      prevalence of 4-30% in regional surveys. Although different etiologic theories
      are discussed in a large number of published studies, most cases are probably
      attributed to lower extremity malalignment, muscular imbalance, or physical
      overactivity (or even a combination of all three). Thorough clinical
      investigation should result in a definition of relevant static or functional
      problems as underlying causes of the disease. Radiographic analysis is mainly
      performed to exclude severe pathology (i.e., malignancies), as the correlation
      between described morphometric variables and clinical problems is weak. Prior to
      therapeutic recommendations, the benign natural course of the disease should be
      discussed with patients and their parents. In a large number of published studies
      with different conservative treatment protocols, positive results for many
      regimens are reported. The size,however, is not always large enough to prove
      superior outcome when compared to the natural course of the disease. There is
      also no evidence to support the superiority of one physiotherapy intervention
      over others.

PMID- 12607077
TI  - [Inserts and shoes for foot deformities].
AB  - Prevention of habitual or shoe-induced foot and toe deformities in children and
      treatment of congenital or developing malformations require a change of view
      towards functional aspects and the use of modern technical possibilities based on
      our traditional knowledge.Statics, functional anatomy, biomechanics, neuromotor
      and psychomotor activity, and developmental physiology have to be considered as
      well as the broad variety of physiological interindividual differences. Modern
      materials and fabrication techniques make it easier to produce anatomically and
      functionally correct and appealing shoes, inserts, and orthoses. New means of
      invasive treatment improve the preconditions for orthotic management. Cultural
      and cosmetic expectations and the real extent of disability, impairment, and
      handicap have to be carefully differentiated for the sake of every single child.

PMID- 12607074
TI  - Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and
      antagonists in non-human primates.
AB  - RATIONALE: Dopamine D(1) receptor agonists and antagonists attenuate
      reinstatement of cocaine seeking in a non-human primate model of relapse. The
      mechanisms by which these different classes of D(1) receptor drugs produce these
      similar effects on cocaine seeking are unknown. OBJECTIVES: This study
      investigated how D(1) receptor agonists and antagonists alter the shape and
      position of the dose-response function for reinstatement of drug seeking induced
      by a cocaine prime accompanied by restoration of the cocaine-paired stimulus.
      METHODS: Squirrel monkeys were given extensive histories of cocaine self
      administration under a second-order fixed-interval, fixed-ratio schedule of i.v.
      drug injection. Drug seeking was then extinguished by replacing cocaine with
      vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions,
      in which the cocaine-paired stimulus was re-introduced, priming injections of
      cocaine alone or combined with the different D(1) receptor high- and low-efficacy
      agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per
      drug condition) were tested for their ability to reinstate extinguished cocaine
      seeking. RESULTS: Cocaine priming accompanied by the restoration of the cocaine
      paired stimulus induced a dose-dependent reinstatement of drug seeking. When
      combined with cocaine, all D(1) receptor agonists and antagonists produced
      rightward and downward shifts in the cocaine dose-response function. However,
      combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited
      cocaine seeking less than either drug individually. CONCLUSIONS: These findings
      suggest that D(1) receptor high- and low-efficacy agonists as well as antagonists
      attenuate reinstatement of cocaine seeking in part via pharmacologically opposing
      actions at a common population of D(1) receptors.

PMID- 12607072
TI  - Atypical antipsychotics and mood stabilization in bipolar disorder.
AB  - The available literature on the use of atypical antipsychotics for the treatment
      of bipolar disorder was reviewed. All uncontrolled and controlled reports were
      identified through a comprehensive Medline search. Based on the available
      evidence, olanzapine was found to be the most appropriate atypical antipsychotic
      agent utilized for the treatment of manic bipolar patients, although there is
      also preliminary data suggesting the efficacy of risperidone and clozapine. The
      preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar
      disorder are still very limited. Double-blind controlled studies with atypical
      antipsychotics in the long-term treatment of bipolar disorder are still largely
      not available, but will be critical to determine the effectiveness of these
      agents in the maintenance treatment of bipolar disorder. There are recent
      uncontrolled suggestions that olanzapine may have beneficial effects in depressed
      bipolar patients, which deserve further investigation in controlled studies. In
      conclusion, atypical antipsychotics, due to lower potential for neurotoxicity and
      preliminary evidence suggesting better efficacy than typical antipsychotics, are
      increasingly having a more prominent role in the pharmacological management of
      bipolar patients. Nonetheless, until there is systematic data from long-term
      controlled follow-up studies on the comparative efficacy of these agents with
      mood stabilizers, atypical antipsychotics should be cautiously utilized, and
      preferably in combination with a mood stabilizer for the maintenance phase of
      treatment.

PMID- 12607078
TI  - [Nonsurgical treatment of congenital dysplasia and dislocation of the hip].
AB  - Despite general ultrasound screening of the newborn,congenital dysplasia and
      dislocation of the hip are still among the most common congenital skeletal
      diseases.A differentiated and stage-adjusted therapy must be the aim because
      inadequate therapy can lead to necrosis of the femoral head or a residual
      dysplasia that both require further treatment. Now as before a correct and early
      diagnosis is absolutely necessary for the treatment of dysplasia of the hip.A
      once treated hip should be observed until completion of growth.

PMID- 12607079
TI  - [Nonoperative treatment in Legg-Calve-Perthes disease].
AB  - There is still discussion about the indication for and modalities about treatment
      of Perthes'disease. The main objective of treatment in Perthes'disease is
      prevention of deformation and malalignment of the hip joint. Most important for
      the evaluation of any therapy is the long term outcome, therefore we present this
      retrospective study on nonoperative treatment of perthes disease with orthoses
      compared to the natural history. 54 Patients with 59 involved hips, treated
      between 1945-1975 were clinically and radiologically evaluated. We divided the
      patients into two subgroups: Group 1 with nonoperative therapy. Group 2 with no
      therapy. The outcome shows correlation of the results with the degree of
      malalignment and necrosis. There was no statistically significant correlation
      between the two groups, but a slightly better outcome in the non-operative group
      compared to the natural history. The use of orthosis may be justified if there is
      improvement of the containment and reduction of the femoral head, otherwise
      surgical treatment like pelvic- and hip osteotomies to realign the hip joint
      should be considered.

PMID- 12607080
TI  - [Conservative treatment of idiopathic scoliosis with physical therapy and
      orthoses].
AB  - Opinions differ in the international literature about the efficacy of
      conservative approaches to scoliosis treatment. Because this divergence of
      opinion corresponds to a great discrepancy in the standards applied to
      conservative treatment methods, it is not astonishing that the results of
      conservative treatment as described in the literature also differ. Scoliosis
      normally does not have such dramatic effects that immediate surgery would be
      indicated.Moreover, it is clear from the published literature that it is the
      functional and physiological impairments of scoliosis patients--including pain,
      torso deformity, psychological disturbance, and pulmonary dysfunction--which
      require therapeutic intervention. In Germany the triad of outpatient
      physiotherapy, intensive inpatient rehabilitation, and bracing has proven
      effective in conservative scoliosis treatment.Indication, content, and results of
      the individual treatment procedures are described and discussed. The positive
      outcomes of this practice validate a policy of offering conservative scoliosis
      treatment as an alternative to patients, including those for whom surgery is
      indicated.

PMID- 12607081
TI  - [Conservative and functionally oriented treatment of idiopathic clubfoot].
AB  - The article describes current conservative treatment of idiopathic clubfoot,
      especially plaster cast manipulation, functional mobilization, and orthosis. New
      procedures such as mobilization of the foot on a continuous passive motion
      machine and the use of botulinum toxin are presented and discussed.

PMID- 12607082
TI  - [Myoelectric prostheses for kindergarten age children. Analysis of first
      reactions and experiences].
AB  - During the last few decades myoelectric prostheses were generally provided for
      adolescent or adult patients. Since 1991 the availability of smaller sized
      electric hands in conjunction with technical improvements enabled the
      introduction of myoelectric prostheses for preschool children.However, this
      progress remained widely unnoticed in Germany. This study presents the authors'
      experiences with prosthetic devices for preschool children with unilateral upper
      limb deficiency (congenital and traumatic). Twenty children received a
      myoelectric prosthesis between the ages of 2 and 5 years (3.9+/-1.1 years). The
      follow-up period was 1.7 years. The prosthesis was worn for an average of 5.6
      h/day. Our hospital-based intensive training program positively influenced the
      acceptance rate. All children with a below-hand amputation rejected their
      prosthesis.However, the general dropout rate in preschool children is
      conspicuously lower compared to adults. In this study 2.4+/-2.9 repairs per year
      per patient were required. The susceptibility for repairs in this age group is
      much higher for myoelectric prostheses compare to body-powered devices. Since the
      correct indication and the intensive training program significantly influence the
      acceptance rate, the introduction of myoelectric prostheses to preschool children
      should take place at specialized centers with an interdisciplinary team composed
      of orthopedists,occupational therapists,and technicians.

PMID- 12607083
TI  - [MRI-guided musculoskeletal biopsy].
AB  - MRI-guided musculoskeletal biopsy has been mentioned to be a minimally invasive
      method to obtain specimens for diagnostic purposes in bone tumors. To evaluate
      the viability, to assess the accuracy, and to record possible complications of
      this method, clinical data of 19 MRI-guided biopsies were analyzed. Interventions
      were performed on 18 patients (1-78 years) as an outpatient procedure: 15
      skeletal and 4 soft tissue biopsies were taken from the pelvis, upper limb,or
      lower limb. We used T1-weighted gradient echoes (GE) for locating the puncture
      site and T2-weighted turbo spin echoes (TSE) for visualization of needle
      position. In 14 of 18 MRI-guided biopsies, a definite histological diagnosis was
      obtained. According to the pathologist, the inadequate size of the specimen was
      the main reason for missing the diagnoses in four cases.Long intervention time
      and inappropriate biopsy tools proved to be the main disadvantages of MRI-guided
      biopsy, but technical improvement might solve these technical problems in
      future.A postbiopsy hematoma was the only complication observed. Once technically
      improved, MRI-guided biopsy could be a precise alternative routine method for
      musculoskeletal biopsies in future.

PMID- 12607084
TI  - [Performance of an open low-field MR unit in routine examination of knee lesions
      and comparison with high field systems].
AB  - The purpose of this study was to analyze the diagnostic value of a low-field open
      MR system in the diagnosis of knee lesions and to compare it with that of high
      field MR systems. In 139 knees,arthroscopic investigations were used as the gold
      standard to calculate sensitivity, specificity, predictive values and accuracy of
      the low-field open MR system. Figures for high field systems were taken from the
      literature. The values for the open MR system relative to arthroscopy were as
      follows: sensitivity 66%,specificity 95%,positive predictive value 64%,negative
      predictive value 92%, and accuracy 82%. The corresponding values taken from 10
      relevant publications for highfield systems were: sensitivity 81%, specificity
      90%, accuracy 90%. A lower diagnostic performance has to be expected using open
      low field MR units for knee lesions in comparison to high field units. Sedative
      drugs can make it possible for claustrophobic patients to be investigated in high
      field units. The use of open low-field scanners may still be indicated in very
      adipose patients who do not fit into closed units.

PMID- 12607085
TI  - [Endoprostheses of the ankle joint. Indications, development, current status and
      trends].

PMID- 12607086
TI  - [Modern imaging modalities in renal disease: CT and MRI].
AB  - Considerable technical advances have been made in computed tomography (CT) and
      magnetic resonance imaging (MRI) over the last 10 years. Both modalities allow
      for high-resolution imaging of the entire abdomen before as well as during the
      arterial and parenchymal perfusion phase after intravenous contrast medium
      administration. Multiplanar reconstructions of the three-dimensional source data
      sets yield views in any spatial orientation. Maximum intensity projections enable
      the generation of CT or MR angiographies as well as CT or MR urographies from
      delayed images. Thus, both modalities today allow for comprehensive diagnostic
      evaluation of renal disease by a single examination comprising detailed
      visualization of the parenchyma as well as of arterial and venous vessels and
      assessment of excretion. CT and MRI thus enable efficient preoperative diagnostic
      assessment in particular in patients with renal masses.

PMID- 12607087
TI  - [Laparoscopic vs. open nephrectomy. 10 years' results of a nonrandomized
      comparative study of 549 patients with benign kidney diseases].
AB  - We report the results from a nonrandomized comparison of open flank vs
      laparoscopic nephrectomy in patients with benign renal disease. Between 1993 and
      2002, 549 nephrectomies for benign renal disease were performed at the Department
      of Urology of the Medical University of Lubeck and the Urological Department of
      the Martin Luther University in Halle/Wittenberg. There were 236 patients in the
      open flank nephrectomy group and 313 patients in the laparoscopic nephrectomy
      group. Clinical parameters were compared among both groups. Median operative time
      in the open flank nephrectomy group was 90 min (range: 30-240 min) and also 90
      min in the laparoscopic nephrectomy group (range: 41-210 min). There were 54
      complications (17.2%) in the laparoscopic nephrectomy group compared to 60
      complications (25.4%) in the open flank nephrectomy group. Patients in the
      laparoscopy group demonstrated clear advantages in terms of analgesic use for
      pain control, hospital stay, and convalescence. Laparoscopic nephrectomy results
      in a significantly briefer postoperative course when compared to open flank
      nephrectomy. However, due to a limited number of patients, a laparoscopic
      nephrectomy is mainly reserved for laparoscopic centers. Nevertheless, the
      laparoscopic approach should be offered to the majority of patients with benign
      renal disease requiring nephrectomy.

PMID- 12607088
TI  - [Laparoscopic radical nephrectomy: indications, techniques, and oncological
      outcome].
AB  - Renal cell carcinoma is likely to become one of the most important indications
      for laparoscopic surgery worldwide. The laparoscopic technique combines the
      benefits of the minimally invasive approach with established surgical principles.
      In our institution the laparoscopic transperitoneal approach with intact specimen
      extraction has become the standard technique for radical nephrectomies. We report
      the indications, techniques, and oncological outcome in a single center
      experience in 100 cases. The mean tumor size was 5.9 cm (range: 2-11 cm), the
      blood loss was 220 ml, and the mean surgical time was 211 min, including the
      learning curves of five surgeons. Histological findings were pT1 in 66 (66%), pT2
      in 11 (11%), and pT3 in 19 (19%) patients with an increasing tumor size according
      to the experience of the surgeons. In four cases (4%) histology did not prove
      malignant disease. Positive lymph nodes were detected in three cases (3%) and
      surgical margins were negative for tumor in all patients. To date 61 patients
      were available for follow-up; patients with primary metastatic disease were
      excluded from this analysis. Follow-up was between 1 and 30 months with an
      average of 12.9 months. Progressive disease occurred in two cases in patients
      with pT3G3 tumors. No cases of local recurrence or port metastasis occurred
      during observation. Laparoscopic radical nephrectomy is a routine, effective
      treatment for patients with renal cell carcinoma. Our follow-up data up to 30
      months confirm the effectiveness of laparoscopic radical nephrectomy in terms of
      surgical principles and oncological outcome.

PMID- 12607089
TI  - [Renal carcinoma with invasion of the suprahepatic vena cava (Staehler stage III
      and IV): surgical treatment and results].
AB  - The operative treatment of patients with renal cell carcinoma (RCC) and
      suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion
      (Staehler stage III and IV) is still an interdisciplinary challenge. The
      potential high complication rate and the enormous operative-technical efforts
      have to be brought into line with the individual benefit for the patient. In this
      study, we have retrospectively analyzed the operative results of 24 patients. We
      have further compared the patients during follow-up and immunotherapy due to
      metastasis with a control group of 75 patients without vena cava invasion.
      Perioperative mortality in the 24 patients was 4%. Four patients had metastasis
      at presentation and 14 further patients developed metastatic disease during
      median follow-up of 23.5 months. Median survival was 45 months with a 1-, 3-, and
      5-year survival rate of 92, 57, and 33%, respectively. In a multivariate
      analysis, only the presence of metastasis (p=0.002) and marginal immunotherapy
      (p=0.1), but not vena cava invasion (p=0.259) or a positive lymph node status
      (p=0.624) were significant predictors of a poor survival. For patients with RCC
      and suprahepatic infradiaphragmatic or supradiaphragmatic vena cava invasion
      (Staehler stage III and IV), the combination of an aggressive surgical treatment
      combined with subsequent immunotherapy in the presence of metastatic disease
      offers a realistic therapeutic option with reasonable survival rates.

PMID- 12607090
TI  - [Laparoscopic transperitoneal donor nephrectomy. Technique and results].
AB  - Living donor kidney transplantation is one possibility to meet the growing demand
      for organs in patients with chronic renal failure. In 1995 the first laparoscopic
      living donor nephrectomy (LDN) was performed in the United States. More than 100
      transplant centers worldwide perform LDN. The expectations of a larger number of
      willing organ donors were fulfilled due to the less traumatic operation.
      Meanwhile, several techniques exist to retrieve a kidney laparoscopically,
      including the trans- or retroperitoneal, strictly laparoscopic, or hand-assisted
      approach. From February 1999 to September 2002, 63 strictly laparoscopic,
      transperitoneal LDNs were performed at the Department of Urology of the Charite
      University Hospital, Berlin. Warm ischemic time was 148 s (105-360) and operating
      time was 203 min (110-305). Intraoperative complications were due to insufficient
      closure of the vessels in four patients. Mean postoperative hospital stay was 5.7
      days (3-9). One year after LDN, renal function as well as creatinine levels of
      the recipient showed no difference compared to the organs harvested via the
      approach at our department prior to implementation of LDN. Strictly laparoscopic
      transperitoneal donor nephrectomy is a safe method for kidney retrieval and
      ensures excellent graft function.

PMID- 12607091
TI  - [Laparoscopic living donor nephrectomy of kidneys with multiple renal vessels].
AB  - Due to the increasing waiting time for transplantation of a cadaveric kidney,
      living donor kidney transplantation is an increasingly oncoming issue.
      Laparoscopic donor nephrectomies (LDN) have been performed since 1995 and
      presently more than 100 transplant centers offer this minimally invasive surgical
      approach. The advantages for the donor of less pain, shorter hospital stay,
      earlier return to work, better cosmetic results in combination with an organ
      function equal to open donor nephrectomy are the reasons for an enormous increase
      in LDN. Since up to 30% of the donor kidneys have multiple vessels for blood
      supply, an increase of these organs for LDN can be expected. We performed a
      retrospective study of LDN at our center and compared donors with multiple vs
      single vessel supply. From February 1999 to September 2002, 63 LDN were performed
      at the department of Urology, Charite University Hospital, Berlin. A comparison
      between 18 donor kidneys with multiple vessel supply and 45 donor organs with
      single vessels showed no difference for the time of laparoscopic explantation
      (207 vs 201 min, p=0.4) or the warm (166 vs 148 s, p=0.2) and cold ischemic times
      (117 vs 103 min, p=0.66). As could be expected, the mixed ischemic time, i.e.,
      the time for anastomosis of the kidney with the recipient's vessels, showed a
      significant difference (53 vs 46 min, p=0.02). Intra- and postoperative
      complication rates for donors and recipients were not different in both groups.
      Laparoscopic donor nephrectomy for kidneys with multiple vessels is feasible and
      safe for donor and recipient.

PMID- 12607092
TI  - [Effect of P fimbriae on pyuria and bacterial colonization of the human urinary
      tract].
AB  - This study investigated the role of P fimbriae in colonization of Escherichia
      coli, host response, and bacterial persistence in humans. Human volunteers were
      inoculated intravesically with the nonadherent ABU isolate E. coli 83972 and with
      P fimbriated transformants of the same strain. During the following 24 h all
      urine samples, and thereafter daily samples, were collected for urine culture,
      analysis of neutrophil numbers, and cytokine concentrations (IL-6 and IL-8). The
      P fimbriated transformants showed enhanced bacterial colonization in comparison
      to E. coli 83972 and lowered the bacterial numbers needed for persistent
      bacteriuria. The P fimbriated transformants also lowered the bacterial numbers
      needed for a significant neutrophil and cytokine host response. We conclude that
      P fimbriae enhance bacterial colonization and trigger the host response in the
      human urinary tract.

PMID- 12607093
TI  - [Four-glass or two glass test for chronic prostatitis].
AB  - Chronic pelvic pain syndrome is still an important clinical problem. The NIH
      prostatitis classification introduced in 1998 for diagnosis and treatment
      measures is based on extended microbiological analysis of urine and expressed
      prostate secretion (4-glass test). In 1997 J.C. Nickel proved that the culture
      and microscopic examination of urine before and after prostatic massage leads to
      the same results as the 4-glass test. In our prospective study on 143 patients
      with a diagnosis of chronic prostatitis, we analyzed this statement and came to
      the same results. We therefore recommend replacing the expensive and time
      consuming 4-glass test by a simple preprostatic and postprostatic massage urine
      culture. Further examinations should only be performed in special cases.

PMID- 12607094
TI  - [Monitoring of the treatment of calcium-oxalate stone formers with the Bonn-Risk
      Index].
AB  - Cost-effective metaphylaxis and monitoring is becoming more and more focused in
      the treatment of urinary stones. Therefore, medical practitioners are asked to
      reduce the analytical efforts necessary for evaluation and to control the actual
      biochemical risk of stone formation in the patients. The most common strategy
      available is based on chemical urinalysis and the calculation of theoretically
      derived risk parameters. However, this covers--in the best case--the analysis of
      the most prominent low molecular urinary constituents. No information about the
      fraction of the important macromolecular urinary components is obtained.
      Crystallization experiments in unprepared, native urine samples, carried out
      according to the Bonn-Risk-Index approach (BRI), allow the determination of a
      more realistic measure of a urine's crystallization risk since the entire urinary
      composition influences the experimental result. As only two parameters have to be
      analyzed, the BRI is a fast and cost-effective risk evaluation method. The
      results show a high selectivity between stone-formers and non-stone-forming
      persons. The changes in the BRI-risk of three calcium oxalate stone-formers after
      a 1 week stay in our hospital are presented and discussed in detail. In one of
      these patients, a follow up examination was performed in order to control the
      therapy's success and, additionally, to obtain information about the patient's
      compliance with the therapy. During hospitalization, the patients received a
      standardized and "stone-neutral" diet. All persons showed a distinct decrease in
      their individual crystallization risk.

PMID- 12607095
TI  - [Functional results and early experience with the Hautmann neobladder.
      Comparative analysis of the Toulouse series and the Ulm series].
AB  - Orthotopic ileal urinary bladder replacement is an established method after
      radical standard cystectomy for both genders. In 1986 Hautmann described for the
      first time the technique of bladder reconstruction using the ileum at the
      University of Ulm. The W shape of the ileum buffers the coordinated peristaltic
      waves. The detubularized orthotopic ileal reservoir has been used worldwide ever
      since because of its technical simplicity, its reduced risk, and its good
      functional results. The good results published in the literature for this
      technique were reported by larger centers. With regard to these results, we
      wondered in 1994 if our smaller department with fewer patients might also offer
      this technique for male and female patients who had undergone cystectomy. The
      question was if this method would produce the same results as in large series,
      provided that patients were adequately selected and surgery carefully performed.
      This would provide the evidence that the surgical technique is simple,
      reproducible, and has the same complication rates, such as mortality and
      morbidity, also for departments with less experience.

PMID- 12607096
TI  - Isolation of cytomegalovirus and foamy virus from the drill monkey (Mandrillus
      leucophaeus) and prevalence of antibodies to these viruses amongst wild-born and
      captive-bred individuals.
AB  - Drill monkeys (Mandrillus leucophaeus) are an endangered species whose indigenous
      viral flora is largely unknown. We report here the isolation and characterization
      of both a cytomegalovirus (DrCMV) and a foamy virus (SFV-drl) from drill monkeys.
      Phylogenetic analysis of DNA sequence data placed the DrCMV within a primate CMV
      clade, and showed that SFV-drl was closely related to baboon foamy viruses. ELISA
      analysis demonstrated that DrCMV shared common epitopes with other primate CMVs
      but was distinct from human and baboon CMVs. ELISA testing of sera from wild-born
      and captive-bred drills indicated that the prevalence of antibodies reactive with
      these two viruses was 93.2% for DrCMV and 20.3% for SFV-drl.

PMID- 12607097
TI  - CpG immuno-stimulatory motifs enhance humoral immune responses against hepatitis
      C virus core protein after DNA-based immunization.
AB  - Chronic HCV infection is associated with a high morbidity and mortality rate, and
      currently a prophylactic or therapeutic vaccine is not available. DNA-based
      immunization is a powerful method to generate cellular and humoral immune
      responses. However, DNA immunization against HCV core results only in a weak
      humoral immune response demonstrated in several studies. Therefore, co
      immunization with a novel adjuvant may enhance such potentially important immune
      responses. We examined whether unmethylated CpG motifs in the form of
      oligodeoxynucleotides (ODN) or E. coli DNA can act as adjuvants for a DNA
      vaccination approach, since CpG motifs have been shown to stimulate the innate
      immune system as well as B and T cell immune reactivity. The present study
      demonstrates that CpG motifs enhance in vivo antibody levels after DNA
      immunization against HCV core. However, despite some in vitro activity of CpG
      motifs, no enhancement of T cell responses in vivo was observed after
      immunization with HCV plasmid DNA and CpG motifs in mice. Our results suggest
      that co-immunization with CpG-ODN may strengthen humoral immune responses but
      show no potential effect as an adjuvant to induce cellular immunity against HCV
      core.

PMID- 12607098
TI  - Stem-loop structures II-IV of the 5' untranslated sequences are required for the
      expression of the full-length hepatitis C virus genome.
AB  - The 5' and 3' untranslated regions (UTR) of the hepatitis C virus (HCV) genome
      contain stem-loop structures, which are important in viral gene expression and
      replication. In this study, the functional roles of the predicted stem-loop
      structures of HCV 5' UTR and 3' UTR in viral gene expression were examined using
      a chimeric clone of full-length HCV genomic cDNA clone and the gene for green
      fluorescent protein (GFP). High level expression of the HCV-GFP chimera in Huh-7
      cells was accomplished by using a replication defective adenovirus that expresses
      T7 RNA polymerase and transcription plasmid containing full-length HCV-GFP
      chimera under the control of a T7 promoter. The HCV-GFP clone, with deletion of
      stem-loop I, expressed proteins in transfected Huh-7 cells at comparable levels
      to the wild type HCV clone. Other mutations of the 5' UTR, which either deleted
      or altered the base pairing of stem-loops II to IV, completely abolished the
      expression of HCV-GFP chimera. In contrast, deletion of 3' UTR sequences had no
      effect on HCV protein expression. These findings suggest that the stem-loop
      structures II to IV of HCV 5' UTR are necessary for protein expression, but that
      stem loop I is dispensable for protein translation. The stem-loop structures of
      3' UTR of HCV genome appear to have no direct role in viral gene expression.

PMID- 12607099
TI  - Inhibition of fusion activity of influenza A haemagglutinin mediated by HA2
      specific monoclonal antibodies.
AB  - The effect of seven monoclonal antibodies (MAbs) specific to the light chain
      (HA2) of influenza A haemagglutinin (HA) on its fusion activity was investigated.
      These MAbs, which are non-virus neutralizing, defined four distinct antigenic
      sites on HA2 glycopolypeptide and the corresponding epitopes were attributed to
      the sequence stretches on HA2. The accessibility of all seven HA2 epitopes
      significantly increased after trypsin cleavage and pH 5 treatment of the HA (X
      31). The influence of anti-HA2 MAbs on the fusion process was followed by cell
      cell fusion of CHO cells expressing precursor HA, virus-liposome fusion assay,
      and haemolysis mediated by virus. MAb CF2, which bound directly to the fusion
      peptide 1-35 of HA2, was positive in all three fusion-inhibition assays and was
      the only one inhibiting the polykaryon formation of CHO-X-31 cells. Two other
      MAbs belonging to the same antigenic site but not binding directly to the fusion
      peptide inhibited virus to liposome fusion (EB12) or inhibited haemolysis (BB8).
      Moreover, MAb IIF4 binding to distinct antigenic site within 125-175 HA2
      inhibited haemolysis, too. Thus, fusion activity of HA may be inhibited by anti
      HA2 MAbs, mainly those binding to or near the fusion peptide. These antibodies
      represent useful probes for studies of influenza virus to cell membrane fusion.

PMID- 12607100
TI  - Sequence variability within the 3'-proximal part of the Sweet potato mild mottle
      virus genome.
AB  - Sweet potato mild mottle virus (SPMMV) is the type member of the genus Ipomovirus
      (family Potyviridae) and is only known to occur in East Africa. In Uganda, SPMMV
      is the third most prevalent virus infecting sweet potato. The sequence
      variability of SPMMV was studied by cloning and sequencing a 1.8-kb fragment
      representing the 3'-end of the genome of eight SPMMV isolates collected from
      different districts of Uganda. Sequence comparisons indicated 85.9-99.9%
      nucleotide sequence identity and 92.8-100% amino acid sequence similarity for the
      coat protein (CP) encoding region. The nucleotide sequence identity within the 3'
      untranslated region (3' UTR) was 84.7-100%, and the region was variable in length
      (303-308 nucleotides) due to some deletions within the 5'-proximal part of the 3'
      UTR. Phylogenetic analysis of the CP amino acid sequences revealed significant
      clustering, indicating the existence of distinguishable sequence variants or
      strains. The low CP amino acid sequence similarity of SPMMV isolates with other
      characterised viruses of the family Potyviridae and the unusual putative
      proteolytic cleavage site at the NIb/CP junction further demonstrate SPMMV as a
      very distinct virus in the family Potyviridae.

PMID- 12607101
TI  - Generation of chicken single chain antibody variable fragments (scFv) that
      differentiate and neutralize infectious bursal disease virus (IBDV).
AB  - Phage-displayed recombinant antibody libraries derived from splenic mRNA of
      chickens immunized with an Australian strain of infectious bursal disease virus
      (IBDV) were constructed as single chain variable fragments (scFv) by either
      overlap extension polymerase chain reaction (PCR) or sequential ligation of the
      individual heavy (V(H)) and light (V(L)) chain variable gene segments. Sequential
      cloning of the individual V(H) and V(L) genes into a newly constructed pCANTAB
      link vector containing the synthetic linker sequence (Gly(4)Ser)(3) was more
      efficient than cloning by overlap extension PCR, increasing the library size 500
      fold. Eighteen IBDV specific antibodies with unique scFv sequences were
      identified after panning the library against the immunizing antigen. Eight of the
      clones contained an identical V(H) gene but unique V(L) genes. In ELISA analysis
      using a panel of Australian and overseas IBDV strains, one scFv antibody was able
      to detect all strains, whilst 3 others could discriminate between Australian and
      overseas strains, classical and variant strains and Australian field strains and
      vaccine strains. In addition, some scFvs showed significant neutralization titres
      in vitro. This report shows that generation of chicken antibodies in vitro by
      recombinant means has considerable potential for producing antibodies of diverse
      specificity and neutralizing capacity.

PMID- 12607102
TI  - Prevalence and genetic diversity of TT virus genotype 21 (YONBAN virus) in
      Brazil.
AB  - Isolates of the newly characterized, single-stranded DNA virus TTV, have been
      tentatively classified into four major phylogenetic groups and at least 28
      genotypes. Four Japanese isolates, designated as YONBAN viruses, belong to the
      fourth group and to genotype 21. In this study, a genotype 21-specific PCR assay
      was standardized. With this assay, 48/184 (26%) serum samples and 76/167 (46%)
      saliva samples, collected from unselected ambulatory patients (aged 2 to 82) of a
      Brazilian public hospital, were positive. A total of 110 (66%) patients had TTV
      genotype 21 DNA in serum, saliva, or both fluids. Furthermore, 18/37 (49%) serum
      samples, collected from Indians belonging to three ethnic groups of the Western
      Brazilian Amazon, were also positive. Nucleotide sequences (253 bases at the 3'
      end of the non-coding region of the genome) were determined, that derived from 25
      individuals, i.e. 17 patients and eight Indians. Phylogenetic analysis showed
      that three isolates from Indians of a particular ethnic group formed a separate
      subgroup within genotype 21. Among non-Indians, a clustering of strains was
      observed according to their country of origin (Japan or Brazil), with all 17
      sequences derived from Brazilian patients located in a unique subgroup.

PMID- 12607103
TI  - Oxytocin and prostaglandins F2alpha and E2 do not enhance HIV antigen production
      in vitro.
AB  - Oxytocin and prostaglandins (PGs) are hormones involved in labor and are used
      clinically for its induction. In this study the effect of oxytocin, PGF(2alpha),
      and PGE(2) on Humour immunodeficiency virus-1 production in acutely and
      persistently infected cells was measured. No significant effect on p24 antigen
      production was found with oxytocin or PGs, except for a transient decrease in
      persistently infected cells treated with 1 micro M PGF(2alpha). These results
      showed that oxytocin and PGs could be used clinically for labor induction without
      any direct enhancement in viral production. Besides, the results with PGF(2alpha)
      at the highest concentration studied may indicate a pharmacological effect.

PMID- 12607104
TI  - Characterization of the simian varicella virus glycoprotein C, which is
      nonessential for in vitro replication.
AB  - The simian varicella virus (SVV) glycoprotein C (gC), which may play an important
      role in viral pathogenesis, shares extensive homology to the varicella-zoster
      virus (VZV) gC. The SVV gC gene includes two identical 83 base pair repeat
      elements which are conserved within the gC genes of epidemiologically distinct
      SVV isolates. Expression of the gC gene was confirmed by detection of viral gene
      products. Deletion of the gC gene and replacement with the green fluorescent
      protein (GFP) gene yields a SVVgC(-)/GFP mutant which replicates as efficiently
      as wild type virus, demonstrating the SVV gC gene is nonessential for in vitro
      replication.

PMID- 12607105
TI  - Human cytomegalovirus glycoprotein B genotypes in immunocompetent,
      immunocompromised, and congenitally infected Italian populations.
AB  - Human cytomegalovirus (HCMV) strains, obtained from immunocompetent and
      immunocompromised Italian hosts, were typed with glycoprotein B (gB) gene
      restriction analysis. A predominant circulation of HCMV strains with gB type 2
      and 3 was detected in both the immunocompetent host with a primary HCMV infection
      and the immunocompromised host with or without HCMV disease. No association
      between gB types and subjects with different risks of developing HCMV disease was
      found. All four gB genotypes were capable of causing congenital infection in
      Italian babies, with gB type 1 accounting for 50% of the strains examined in
      symptomatic infants and a remarkable incidence of gB type 4 viruses.

PMID- 12607106
TI  - Construction of a recombinant orf virus that expresses an Echinococcus granulosus
      vaccine antigen from a novel genomic insertion site.
AB  - The potential of recombinant poxviruses as expression vectors has been
      extensively studied using Vaccinia virus but there has been only limited transfer
      of this technology to the Parapoxvirus genus. We detail here the construction of
      a recombinant Orf virus that expresses an antigenic peptide (EG95) of the
      causative agent of cystic hydatid disease, Echinococcus granulosus. Expression of
      this foreign antigen was regulated by a synthetic early/late poxvirus
      transcriptional promoter and levels of expression comparable to that achieved by
      a similar vaccinia virus recombinant were observed. The expression cassette was
      inserted into a unique orf virus gene (G1L) thereby confirming the non-essential
      nature of that gene and identifying a novel genomic insertion site. This
      recombinant will be a valuable tool with which to assess the potential of
      recombinant orf viruses to deliver vaccine antigens to sheep.

PMID- 12607107
TI  - Infectivity of in vitro transcripts of Johnsongrass mosaic potyvirus full-length
      cDNA clones in maize and sorghum.
AB  - In vitro transcripts of full-length cDNA clones of the Johnsongrass strain of
      Johnsongrass mosaic potyvirus (JGMV-Jg) were infectious on maize and sorghum when
      inoculated by mechanical or by biolistic bombardment. Two of the cDNA clones with
      spontaneous mutations in the coat protein were not infectious. Sequence
      differences between infectious and non-infectious transcripts revealed that
      alteration of inferred amino sequences, near or in the N-terminus of the coat
      protein, profoundly affected the infectivity of transcripts. Transcripts of
      chimeric full-length cDNA of JGMV-Jg, containing coat protein sequences from the
      Krish-infecting strain of JGMV, were infectious in Krish resistant sorghums.

PMID- 12607108
TI  - Nodavirus infection in freshwater ornamental fish, guppy, Poicelia reticulata-
      comparative characterization and pathogenicity studies.
AB  - Biochemical, genomic and serological studies were carried out to characterize a
      virus obtained from diseased guppy, Poicelia reticulata. The SDS-PAGE analysis of
      CsCl purified virus showed two distinct bands with molecular weight of 42 kDa and
      110 kDa. A 1367 nucleotide region of the coat protein gene was sequenced, which
      includes one full open reading frame of 1017 nucleotides and a region of 350
      nucleotides at the 3'end. The nucleotide identity of this strain with the
      nodavirus isolated from Epinephelus tauvina (Singapore strain) is 98% and with
      other strains of fish nodaviruses the identity is more than 75%. Western blot
      analysis using rabbit antisera raised against the nodavirus from marine fish, E.
      tauvina confirmed its antigenic similarity to the marine nodavirus isolate.
      Asymptomatic infection in guppy fry was observed following experimental infection
      with this virus and the marine nodavirus isolate (Singapore strain) implying the
      spread of virus from marine fish to freshwater fish. This report forms the first
      description of a nodavirus infection in freshwater fish.

PMID- 12607109
TI  - DNA microarrays of baculovirus genomes: differential expression of viral genes in
      two susceptible insect cell lines.
AB  - We describe, for the first time, the generation of a viral DNA chip for
      simultaneous expression measurements of nearly all known open reading frames
      (ORFs) in the best-studied members of the family Baculoviridae, Autographa
      californica multiple nucleopolyhedrovirus (AcMNPV) and Bombyx mori
      nucleopolyhedrovirus (BmNPV). In this study, a viral DNA chip (Ac-BmNPV chip) was
      fabricated and used to characterize the viral gene expression profile for AcMNPV
      in different cell types. The viral chip is composed of microarrays of viral DNA
      prepared by robotic deposition of PCR-amplified viral DNA fragments on glass for
      ORFs in the NPV genome. Viral gene expression was monitored by hybridization to
      the DNA fragment microarrays with fluorescently labeled cDNAs prepared from
      infected Spodoptera frugiperda, Sf9 cells and Trichoplusia ni, TnHigh-Five cells,
      the latter a major producer of baculovirus and recombinant proteins. A comparison
      of expression profiles of known ORFs in AcMNPV elucidated six genes (ORF150, p10,
      pk2, and three late gene expression factor genes lef-3, p35 and lef- 6) the
      expression of each of which was regulated differently in the two cell lines. Most
      of these genes are known to be closely involved in the viral life cycle such as
      in DNA replication, late gene expression and the release of polyhedra from
      infected cells. These results imply that the differential expression of these
      viral genes accounts for the differences in viral replication between these two
      cell lines. Thus, these fabricated microarrays of NPV DNA which allow a rapid
      analysis of gene expression at the viral genome level should greatly speed the
      functional analysis of large genomes of NPV.

PMID- 12607110
TI  - Nucleotide sequence and infectious transcripts from a full-length cDNA clone of
      the carmovirus Melon necrotic spot virus.
AB  - We have studied the biological and molecular characteristics of a MNSV isolate
      collected in Spain (MNSV-Malpha5) and generated a full-length cDNA clone from
      which infectious RNA transcripts can be produced. The host range of MNSV-Malpha5
      appeared to be limited to cucurbits and did not differ from that of MNSV-Dutch
      [4, 21]. However, differences were observed in the type of symptoms that both
      isolates could induce. A full-length cDNA of MNSV-Malpha5 was directly amplified
      by reverse-transcription polymerase chain reaction (RT-PCR) using a 5'-end primer
      anchoring a T7 RNA promoter sequence and a 3'-end primer, and cloned. Uncapped
      RNAs transcribed from this cDNA clone were infectious and caused symptoms
      indistinguishable from those caused by viral RNA when mechanically inoculated
      onto melon, cucumber or watermelon plants. The complete genome sequence of MNSV
      Malpha5 was deduced from the full length cDNA clone. It is 4271 nt long and,
      similarly to MNSV-Dutch, consists of 5' and 3' untranslated regions (UTRs) and
      five open reading frames (ORFs) coding for 29, 89, 42 and two small 7 kDa
      proteins. One notable difference between MNSV-Malpha5 and other sequenced MNSV
      isolates was found, as for MNSV-Malpha5 the first of the two small ORFs, which
      are contiguous in the genome, terminates with a genuine stop codon, whereas for
      MNSV-Dutch and other sequenced MNSV isolates it terminates with an amber codon.
      This suggested that the putative p14 readthrough protein that could be expressed
      from the MNSV-Dutch and other MNSV genomes could not be expressed from the MNSV
      Malpha5 genome. Also, the nucleotide and amino acid sequences comparisons showed
      a distant relationship of MNSV-Malpha5 with other known MNSV isolates.

PMID- 12607111
TI  - Taxonomic proposals on the Web: new ICTV consultative procedures.

PMID- 12607114
TI  - Genetic linkage of Francois-Neetens fleck (mouchetee) corneal dystrophy to
      chromosome 2q35.
AB  - Francois-Neetens fleck (mouchetee) corneal dystrophy is an autosomal dominant
      corneal dystrophy characterized by scattered small white flecks occurring at all
      levels of the corneal stroma. We report linkage of the CFD locus to D2S2289
      (Z(max)=4.46, theta=0), D2S325 (Z(max)=3.28, theta=0), D2S317 (Z(max)=3.1,
      theta=0), D2S143 (Z(max)=3.8, theta=0.03), and D2S2382 (Z(max)=5.0, theta=0) on
      chromosome 2q35. Multipoint analysis confirmed linkage to the region between
      D2S117 and D2S126 with a maximum multipoint lod score of 5.0 located midway
      between D2S2289 and D2S325. Analysis of CFD in these same families assuming a 90%
      penetrance increased the maximum lod score to 6.28 at D2S157.

PMID- 12607113
TI  - Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is
      associated with low HDL cholesterol.
AB  - Type A and B forms of Niemann-Pick disease (NPD) are lipid storage disorders
      caused by deficient activity of the enzyme acid sphingomyelinase (aSMase) and the
      resulting accumulation of sphingomyelin in tissues. In the present study, we
      investigated two family members who had been diagnosed with Type B NPD and who
      had a severe decrease in plasma high density lipoprotein cholesterol (HDL-C). The
      proband (a 48-year-old male) had an HDL-C of 0.30 mmol/l (12 mg/dl) and his
      sister had values of 0.45 mmol/l (17 mg/dl) with severe premature coronary artery
      disease (CAD). Hypertriglyceridemia was found in both cases. aSMase activity
      measured in skin fibroblasts appeared markedly depressed. The SMPD1 gene, coding
      for aSMase, was sequenced in affected subjects and all family members. Compound
      heterozygosity (DeltaR608 and R441X) was identified in both affected patients.
      Carriers of the DeltaR608 mutation tended to have moderately to severe decreased
      HDL-C levels, whereas carriers of the R441X mutation, although present only in
      young subjects (<20 years of age) had normal HDL-C levels. To investigate the
      cause of the low HDL-C level in these patients, we studied apoA-I-mediated
      cellular cholesterol efflux in fibroblasts. Unlike patients with Tangier disease,
      cholesterol efflux was found to be normal under the experimental conditions used
      in the present study. On the other hand, we observed a significant increase in
      the free cholesterol:esterified cholesterol ratio in HDL fraction from these
      patients and a decrease in endogenous lecithin-cholesterol acyltransferase (LCAT)
      activity, as determined by the fractional esterification rate. Taken together,
      these results suggest that (1) compound heterozygosity at the SMPD1 gene causes a
      severe decrease in aSMase activity and in HDL-C and increases the risk of CAD,
      (2) this lipoprotein abnormality is not attributable to defective cellular
      cholesterol efflux, (3) abnormal HDL composition might cause a decrease in LCAT
      activity and a lack of HDL maturation.

PMID- 12607115
TI  - PA26 is a candidate gene for heterotaxia in humans: identification of a novel
      PA26-related gene family in human and mouse.
AB  - Heterotaxia is an aetiologically heterogeneous condition caused by an abnormal
      left-right axis formation, resulting in reversed left-right polarity of one or
      more organ systems. In a patient with heterotaxia and a de novo reciprocal
      translocation t(6;18)(q21;q21), we found that the PA26 gene was disrupted by the
      6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26
      gene in an Epstein-Barr virus-transformed cell line of this patient. During early
      embryogenesis of Xenopus, the orthologue of PA26, XPA26 is exclusively expressed
      in the notochord, a midline structure. This further supports a possible role of
      PA26 in human situs determination. Mutation analysis of human PA26 gene in 40
      unrelated individuals with unexplained heterotaxia failed to identify mutations,
      indicating that PA26 mutations are not a frequent cause of heterotaxia in humans.
      Analysis of the PA26 gene structure resulted in the identification of a novel
      PA26-related gene family, which we have named the sestrin family, and which
      comprises three closely related genes in human and in mouse.

PMID- 12607116
TI  - No evidence of fetal DNA persistence in maternal plasma after pregnancy.
AB  - Short- and long-term persistence of fetal DNA in maternal plasma has been
      investigated. Short-term persistence at very low concentration was detected in 47
      out of 105 women within two days after delivery. Twelve out of 13 samples re
      tested within three days scored negative. No long-term persistence was detected
      in 172 women who had previous sons or abortions. Molecular microchimerism due to
      circulating fetal DNA persisting from previous pregnancies should not hamper non
      invasive plasma-based prenatal testing.

PMID- 12607117
TI  - Prediction of clinical outcome with microarray data: a partial least squares
      discriminant analysis (PLS-DA) approach.
AB  - Partial least squares discriminant analysis (PLS-DA) is a partial least squares
      regression of a set Y of binary variables describing the categories of a
      categorical variable on a set X of predictor variables. It is a compromise
      between the usual discriminant analysis and a discriminant analysis on the
      significant principal components of the predictor variables. This technique is
      specially suited to deal with a much larger number of predictors than
      observations and with multicollineality, two of the main problems encountered
      when analysing microarray expression data. We explore the performance of PLS-DA
      with published data from breast cancer (Perou et al. 2000). Several such analyses
      were carried out: (1) before vs after chemotherapy treatment, (2) estrogen
      receptor positive vs negative tumours, and (3) tumour classification. We found
      that the performance of PLS-DA was extremely satisfactory in all cases and that
      the discriminant cDNA clones often had a sound biological interpretation. We
      conclude that PLS-DA is a powerful yet simple tool for analysing microarray data.

PMID- 12607118
TI  - Different immune responses to abdominal surgery in men and women.
AB  - BACKGROUND: Animal experiments reveal significant gender differences in the
      immunological response to surgical trauma. This raises the possibility that
      gender differences may also exist in patients after major abdominal surgery.
      PATIENTS AND METHODS: This prospective study included 40 patients (20 men, 20
      women) with colorectal diseases requiring surgical intervention. To evaluate the
      immune response to surgery circulating lymphocyte populations and natural killer
      cells were determined by flow-cytometry, and IL-6 serum levels were measured by
      enzyme-linked immunosorbent assay. Blood samples were taken before and on days 1,
      2, and 5 after surgery. RESULTS: Despite comparable preoperative cell counts we
      detected significant postoperative gender differences regarding B-lymphocyte, T
      lymphocyte, T-helper cell counts, and NK cell counts. While only a short,
      insignificant depression of these immune competent cells was detected in women,
      men suffered long-lasting (5 days) depression of these cells. Furthermore, women
      showed a more pronounced immediate (day 1) proinflammatory response (circulating
      IL-6) after abdominal surgery. CONCLUSIONS: Significant immunological gender
      differences following major abdominal surgery were observed in this prospective
      clinical study. Our findings support the experimental observations of better
      posttraumatic immune competence in women than in men. These gender differences
      may be of relevance for short- and long-term results after surgery for colorectal
      diseases. Future studies will address the use of sex-steroids and/or their
      antagonists as a therapeutic option for the improvement in perioperative immune
      dysfunction in patients with major surgery.

PMID- 12607119
TI  - Prospective trial comparing bilateral and unilateral varicose vein surgery.
AB  - BACKGROUND: This study compared bilateral and unilateral varicose vein surgery in
      primary varicosis of the long or short saphenous vein with respect to blood loss.
      PATIENTS AND METHODS: The prospective trial assessed postoperative pain,
      analgesic consumption, blood loss, return to physical activity and work, cosmetic
      result, complications, hospitalization, patient satisfaction, and hospital cost
      in 73 consecutive patients undergoing unilateral ( n=40) or bilateral ( n=33)
      varicose vein surgery. RESULTS: There were no statistically significant
      differences between the two groups in postoperative pain, postoperative analgesic
      consumption immediately postoperatively and after 8 h, median postoperative stay,
      return to work and physical activity, or cosmetic result. All patients but one
      were either satisfied or very satisfied 6 weeks postoperatively. CONCLUSIONS:
      Patients undergoing a bilateral stripping operation did not differ from those
      undergoing unilateral operation. Therefore we recommend bilateral operation when
      indicated.

PMID- 12607120
TI  - Does anastomotic leakage affect functional outcome after rectal resection for
      cancer?
AB  - BACKGROUND: Anastomotic leakage is the most threatening early complication in
      sphincter-preserving rectal cancer surgery. While the oncological consequences
      have been well examined, only few data exist about the functional outcome.
      PATIENTS AND METHODS: We investigated continence function in 150 patients after
      curative sphincter-preserving rectal cancer surgery. Functional results were
      compared in 22 patients with a clinically relevant anastomotic leakage, confirmed
      radiologically or endoscopically, and 128 patients with uneventful recovery.
      Evaluation of continence function was based on the Cleveland Clinic Continence
      Score and was examined in all patients with anastomotic leakage and in 111
      patients without complications 107+/-46 weeks postoperatively. Additionally, 14
      patients with anastomotic leakage and 58 patients with uneventful recovery
      underwent anorectal manometry 26+/-15 weeks postoperatively. RESULTS: The
      continence score in patients after anastomotic leakage did not differ
      significantly from that in patients without complications. Sphincter function was
      similar. Maximum tolerable volume and rectal compliance were slightly but not
      significantly worse after leakage. CONCLUSIONS: Continence function remained
      undisturbed after anastomotic leakage due to rectal resection

PMID- 12607121
TI  - Robot-assisted laparoscopic partial posterior fundoplication with the DaVinci
      system: initial experiences and technical aspects.
AB  - BACKGROUND: This pilot study evaluated the role of the DaVinci operation robot
      for laparoscopic antireflux surgery. PATIENTS AND METHODS: A robot-assisted
      laparoscopic Toupet-fundoplication was performed on nine consecutive patients
      with severe gastroesophageal reflux disease using the DaVinci robot system. The
      operative procedure was performed in the same way as for the conventional
      laparoscopic procedure. Clinical assessment and endoscopic and manometric follow
      up investigations were performed 6 months after surgery in six of the patients.
      RESULTS: The mean robotic operative time was 173 min (120-235). A mean of 25 min
      (12-45) was required to establish the pneumoperitoneum, to set the trocars, and
      to place the robot arms. There were no intraoperative complications. Six months
      after surgery none of the patients suffered from reflux symptoms and none of the
      patients had acute esophagitis. Postoperatively one patient complained of mild
      transient dysphagia. However, persistent dysphagia was not found in any of the
      patients. One further patient complained of mild bloating. No other side effects
      occurred. Manometrically there was a significant improvement in the function of
      the lower esophageal sphincter. CONCLUSIONS: The robot-assisted partial posterior
      fundoplication is a safe procedure and provides a high-quality three-dimensional
      camera image that is superior to that with the conventional laparoscopic device.
      The handling of the instruments is precise, and intracorporeal suturing and knot
      tying is much easier than without the robotic technique. The procedure allows for
      an accurate approximation of the hiatal crura and for precise construction of the
      fundic wrap. However, robotic surgery is expensive and the setup of the system is
      time consuming at present.

PMID- 12607122
TI  - Inguinal hernia: obligatory indication for elective surgery? A prospective
      assessment of quality of life before and after plug and patch inguinal hernia
      repair.
AB  - BACKGROUND: Incarcerated inguinal hernia may be treated effectively by recent
      surgical techniques with a low rate of complications, but it is unclear whether
      quality of life is improved by elective inguinal hernia repair. Therefore we
      investigated the quality of life before and after inguinal hernia repair using
      plug and patch technique. PATIENTS AND METHODS: Quality of life was prospectively
      assessed in 123 patients before and 3 months after plug and patch inguinal hernia
      repair using the Short Form 36 questionaire and a visual analog scale. All
      patients complained preoperatively of pain associated with the clinical findings
      of inguinal hernia (visual analog scale: reduced quality of life 6.8+/-2.7;
      reduced daily activity: 5.5+/-2.6). Clinical characteristics (operation times, in
      hospital stay, complications, need for pain medication) were documented.
      Inclusion criteria were patients with symptomatic inguinal hernia, scheduled for
      elective unilateral inguinal hernia repair by plug and patch technique. RESULTS:
      There were no major in-hospital complications. At 3 months no recurrences of
      inguinal hernia or late onset complications were observed; seven patients
      complained of dumbness, and eight felt pressure at the operation site with a
      tendency for resolving pain within this time. At 3 months patients had a
      significantly improved quality of life regarding freedom from pain, vitality, and
      physical activity compared to preoperatively. CONCLUSIONS: Plug and patch repair
      of unilateral inguinal hernia improves quality of life with a very low rate of
      procedural complications. Regarding freedom from pain, vitality, and physical
      activity there is significant improvement as compared to preoperatively.
      Therefore inguinal hernia repair should be intended in all elective cases and
      plug and patch repair appears as an excellent technique to improve quality of
      life.

PMID- 12607123
TI  - Partial splenic embolization: long-term outcome.
AB  - BACKGROUND: Partial splenic embolization (PSE) was introduced in the 1980s. We
      studied the long-term follow-up results of a PSE-treated patient cohort. PATIENTS
      AND METHODS: Twenty-six severely ill patients (median age 63.5 years) were
      treated with a graded PSE a total of 52 times, mainly due to bleeding esophageal
      varices and thrombocytopenia. The aggregated follow-up time was 1715 months.
      RESULTS: The mean values of hemoglobin, leukocytes and thrombocytes increased
      significantly after PSE. The frequency of bleeding episodes from esophageal
      varices was significantly reduced. No effect was observed concerning blood liver
      parameters in cirrhotic patients. The integrated PSE effect was judged as
      improvement in 19 patients, status quo in 5, and deterioration in 2. Median
      survival time was 50.5 months (range 0.5-272 months). Two patients underwent
      liver transplantation. Complications consisted mainly of fever, atelectasis, and
      abdominal pain. Two patients died of PSE-related complications. CONCLUSIONS: A
      standardized and graded PSE is reasonably safe even in patients with advanced
      disease in whom it is hazardous to splenectomize. It gives a long-term effect on
      the hematological parameters, bleedings from esophageal varices and good
      palliation, and improved clinical status contributing to symptomatic control.

PMID- 12607124
TI  - Analysis of collagen-interacting proteins in patients with incisional hernias.
AB  - BACKGROUND: In recent years a disorder of the collagen metabolism has been
      suggested for the pathogenesis of abdominal wall hernias. Previous investigations
      of skin specimens revealed a reduction in the collagen I/III ratio and
      alterations in matrix metalloproteinases in patients with incisional hernias. We
      investigated known collagen-interacting proteins to further characterize
      connective tissue in these patients. PATIENTS AND METHODS: Skin scars from
      patients with either primary or recurrent incisional and recurrent inguinal
      hernias, as a subgroup of incisional hernias, were analyzed for overall collagen
      content and for the distribution of collagen types I and III by crosspolarization
      microscopy. The expression of collagen type V, collagen receptor discoidin domain
      receptor 2, matrix metalloproteinase 1, connective tissue-like growth factor, and
      tenascin was determined by immunohistochemistry. Mature abdominal skin scars from
      patients without evident hernia served as controls. RESULTS: Patients with
      recurrent incisional hernia showed lowest ratios of collagen types I to III.
      Contents of overall collagen and of collagen type V did not differ between the
      groups. In patients with either primary or recurrent incisional hernias the
      proportion of collagen receptor discoidin domain receptor 2 positive cells was
      increased. Matrix metalloproteinase 1 expression was more pronounced in patients
      with recurrent incisional or inguinal hernias than in controls. Connective tissue
      like growth factor was significantly increased in recurrent inguinal hernia
      patients. The expression of tenascin was notably decreased in all hernia groups.
      CONCLUSIONS: The observed alterations in the expression of collagen-interacting
      proteins again indicate the possibility of a fundamental connective tissue
      disease as the causal factor in the pathogenesis of (recurrent) incisional
      hernias.

PMID- 12607125
TI  - Interfragmentary movements in the early phase of healing in distraction and
      correction osteotomies stabilized with ring fixators.
AB  - BACKGROUND: Experimental analyses have demonstrated the impact of mechanical
      conditions on bone healing. In critical clinical cases the mechanical conditions
      may be even more demanding than those in experimental studies. This study set out
      to examine the gap movements in distraction and correction osteotomies and to
      determine the suitability of initial fixation. PATIENTS AND METHODS:
      Interfragmentary movements, ground reaction forces, and stability (ground
      reaction force divided by interfragmentary movement) were measured in 18 patients
      with tibial osteotomies stabilized by Ilizarov hybrid constructs until either
      bone union or conversion to internal fixation occurred (9 distraction treatments,
      9 correction osteotomies). Consolidation was determined by clinical evaluation
      and standard radiographic techniques. RESULTS: In both groups cocontraction led
      to gap movements comparable to level walking. Although the in vitro stiffness was
      slightly increased in the correction constructs, the interfragmentary movement in
      vivo was initially comparable between the groups. Patients undergoing distraction
      returned later to full weight bearing than patients undergoing correction
      treatment. In the correction group the stability increased with treatment time,
      while in the distraction group the stability remained relatively small.
      CONCLUSIONS: The in vivo mechanical conditions in challenging clinical cases
      appear far more demanding than those in experimental studies. In distraction,
      mechanical conditions at the defect appear to be more critical than during
      correction osteosynthesis. According to the persistence of shear motion, even
      after 80 days of treatment, it may from the clinical point of view be important
      to maintain interfragmentary compression during the whole healing process and
      thereby reduce shear.

PMID- 12607126
TI  - Benefits and limitations of enteral nutrition in the early postoperative period.
AB  - BACKGROUND: Preexisting malnutrition has been shown to be a major clinical
      problem in surgical patients. Surgical stress itself increases the energy
      expenditure and protein loss making necessary the early nutritional support.
      Although there is strong evidence that "nil by mouth" is not justified, the data
      are still conflicting over the role of early enteral nutrition compared with the
      traditional methods of postoperative feeding including total parenteral nutrition
      support. METHODS AND FOCUS: This paper deals with the various trials related to
      early enteral feeding. It also compares this with the possible advantages of
      total parenteral nutrition as a method of perioperative nutritional support in
      patients undergoing gastrointestinal surgery.

PMID- 12607127
TI  - Role of human GTP cyclohydrolase I and its regulatory protein in
      tetrahydrobiopterin metabolism.
AB  - OBJECTIVE: GTP cyclohydrolase I (GTPCH I) catalyzes the de novo biosynthesis of
      tetrahydrobiopterin (BH(4)), an essential cofactor of NO-synthase. The enzyme
      underlies negative feedback regulation by the end product BH(4). This feedback
      inhibition is mediated through complex formation with the GTP cyclohydrolase I
      feedback regulatory protein (GFRP). To further classify the mechanism involved in
      the regulation of BH(4) synthesis, we measured expression of GTPCH I and GFRP in
      different human tissues. Furthermore, we looked for the influence of
      phenylalanine that is known to reverse BH(4)-mediated feedback inhibition of
      GTPCH I, and of immunostimulation with interferon gamma on the expression of
      GTPCH I and GFRP. METHODS AND RESULTS: Using RT-PCR and northern blot technique,
      coexpression of GFRP and GTPCH I could be demonstrated in a number of different
      tissues such as endothelial cells and peripheral blood cells. Following
      stimulation of human umbilical vein endothelial cells (HUVEC) with phenylalanine
      (1 mM), there was no change of GFRP mRNA. In contrast, the mRNA level of GTPCH I
      was significantly upregulated with a maximum after 6 hours (p = 0.04). Incubation
      of HUVEC with interferon-gamma (100 U/ml) showed an increase of GTPCH I mRNA and
      a significant downregulation of GFRP mRNA after 24 hours (p = 0.03). CONCLUSION:
      This study shows for the first time the expression of GFRP in different human
      tissues. The biosynthesis of BH(4) is not only regulated on the substrate level
      but also through transcription of the interacting proteins. Phenylalanine
      stimulates the biosynthesis of BH(4) not only by reversing the negative feedback
      inhibition of GTPCH I but also by increasing the mRNA level of GTPCH I.
      Immunostimulation alters protein expression of GTPCH I and GFRP in a way that
      favors BH(4) synthesis.

PMID- 12607128
TI  - Impact of hypercholesterolemia on acidosis-induced coronary microvascular
      dilation.
AB  - An increase in coronary flow conductance during acidosis is an important
      compensatory mechanism in various diseased conditions. On the other hand,
      hypercholesterolemia causes microvascular dysfunction as well as macrovascular
      disorders. We investigated the impact of hypercholesterolemia on the coronary
      microvascular response to acidosis. Coronary arterioles (< 150 microm) isolated
      from rabbit hearts were cannulated to micropipettes in a vessel chamber and the
      microvascular responses were observed. After preconstriction was established, the
      extravascular pH was gradually reduced from 7.4 to 7.0. The effects of
      glibenclamide, ATP-sensitive K(+) (K(ATP)) channel blocker, (1 microM, n = 4) or
      pertussis toxin (100 ng/mL, n = 7) on the acidosis-induced microvascular
      responses were examined. In another set of experiments, rabbits were randomly
      assigned to normal chow (NC group, n = 18) or high cholesterol (2 %) diet (HC
      group, n = 20). After 8 weeks of feeding, the responses of isolated coronary
      arterioles to acidosis, ADP, nitroprusside, and levcromakalim were examined in
      the two groups. Coronary arterioles significantly dilated as the pH was reduced
      and the dilation was significantly inhibited by glibenclamide or pertussis toxin.
      Acidosis-induced dilation in the HC group was significantly attenuated compared
      to the NC group (36.5 +/- 2.1 % vs 73.7 +/- 4.8 % at pH = 7.0 P < 0.05). There
      were no significant differences in the dilations by ADP, nitroprusside and
      levcromakalim between the two groups. In conclusion, acidosis-induced dilation of
      rabbit coronary arterioles is mediated by the activation of the pertussis toxin
      sensitive G protein and K(ATP) channels, and the dilation of coronary arterioles
      is impaired in hypercholesterolemia. The impairment occurs upstream of K(ATP)
      channel opening.

PMID- 12607129
TI  - Direct biochemical evidence for eNOS stimulation by bradykinin in the human
      forearm vasculature.
AB  - OBJECTIVE: Although it has been shown recently that acetylcholine (ACh)-induced
      vasodilation of forearm resistance vessels is predominantly mediated by nitric
      oxide, direct biochemical evidence for eNOS stimulation by bradykinin (BK) in the
      human arterial circulation is still lacking. Therefore, the present study was
      designed to test the hypothesis that in the human forearm vasculature eNOS
      stimulation significantly contributes to BK-induced vasodilation. METHODS: BK was
      infused in the presence and absence of the NOS inhibitor L-NMMA (8 micromol/min)
      into the brachial artery of 16 healthy volunteers and the effects compared to
      muscarinergic eNOS stimulation following acetylcholine infusion. Forearm blood
      flow (FBF) was measured by venous occlusion plethysmography, and plasma nitrite
      (NO(2)(-)), which represents a sensitive and specific marker of regional eNOS
      activity, was determined in the antecubital vein and brachial artery by flow
      injection analysis. Nitric oxide production was calculated as product of the veno
      arterial difference of NO(2)(-) concentration times FBF. RESULTS: Kininergic (BK:
      20, 60, 200 ng/min) as well as muscarinergic (ACh: 1, 3, 10 microg/min)
      stimulation resulted in a dose-dependent increase in FBF and NO(2)(-) in each
      individual. The relationship between FBF and NO production upon BK infusion was
      comparable to that obtained with ACh (r = 0.98; n = 64, p < 0.01). Moreover, NOS
      inhibition reduced both flow responses and NO production (BK: 54 and 75 %; ACh:
      57 and 72 %) to a similar extent. CONCLUSIONS: These data provide direct
      biochemical evidence for the involvement of eNOS in bradykinin-induced
      vasodilation of forearm resistance vessels in humans.

PMID- 12607131
TI  - Differential G protein receptor kinase 2 expression in compensated hypertrophy
      and heart failure after myocardial infarction in the rat.
AB  - The onset of heart failure is associated with characteristic changes in
      myocardial expression of G protein receptor kinase 2 (GRK2). Although, GRK2
      significantly contributes to the regulation of myocardial function in the failing
      heart, the GRK2 expression during cardiac hypertrophy without heart failure
      remains to be explored. We here report a differential expression of GRK2 in
      cardiac hypertrophy with or without heart failure in response to a myocardial
      infarction in the rat. Postmyocardial infarction animals were divided into two
      groups depending on the absence or presence of pulmonary edema, which is a
      manifestation of heart failure. Remarkably, cardiac GRK2 expression and activity
      were inhibited in animals with cardiac hypertrophy without heart failure, whereas
      animals with heart failure had elevated GRK2. Thus, three weeks after the
      infarction cardiac GRK2 expression in animals with hypertrophy alone was
      decreased to 0.34 of control, whereas in the group of animals with heart failure
      GRK2 expression was 1.89-fold higher than in sham-operated animals. GRK2 activity
      was affected in a similar way, three and nine weeks after the infarction cardiac
      GRK2 activity was reduced to 0.58 and 0.62 in animals with hypertrophy without
      heart failure when compared to sham operated animals. By contrast, GRK2 activity
      was increased by 1.32- and 1.21-fold three and nine weeks postinfarction in
      animals with heart failure when compared to sham animals. These data suggest that
      GRK2 expression is differentially regulated in hypertrophic, non-failing and
      hypertrophic, failing hearts.

PMID- 12607130
TI  - Longer term effects of ouabain on the contractility of rat isolated
      cardiomyocytes and on the expression of Ca and Na regulating proteins.
AB  - Cardiac glycosides like ouabain are used in the therapy of heart failure and
      atrial fibrillation. They exert a positive inotropic effect on cardiomyocytes by
      inhibiting the plasma membrane sodium pump (Na,K-ATPase), decreasing the Ca
      extrusion by the sarcolemmal cardiac sodium/calcium exchanger (NCX) and
      increasing the intracellular Ca-concentration and Ca-release during subsequent
      contraction cycles.The longer term effects of ouabain treatment on the expression
      of proteins important for Ca- and Na-homeostasis are not well known and were
      investigated in this study. Isolated adult rat cardiomyocytes were cultured in
      the presence or absence of ouabain (30 microM). In these cells, the expression of
      the Na,K-ATPase, Na,Ca-exchanger (NCX), the sarcoplasmic reticulum Ca-ATPase
      (SERCA 2a) and phospholamban (PLB) were studied by Western blot. In addition, the
      contractile function of these cells was studied after electrical stimulation.
      After 2 days of ouabain treatment immunoreactivity of the NCX was increased
      significantly relative to control which was set 1 (1.78 +/- 0.16 vs. 1 +/- 0.13;
      n = 8; P = 0.003) and at day 4 (1.96 +/- 0.35 vs. 1 +/- 0.20; n = 6; P = 0.02).
      All other proteins (SERCA 2a, PLB and Na,K-ATPase a1 and b1) remained unchanged
      (n >/= 4). Ouabain treatment increased the fractional shortening of isolated
      cardiomyocytes at day 0 (1 Hz: 9.64 +/- 0.73 %, n = 24, vs. 7.18 +/- 0.60 %; n =
      21; P = 0.01), whereas at day 2 the contractility was unchanged (1 Hz: 7.23 +/-
      1.08 %, n = 9 vs. 7.70 +/- 0.63 %; n = 10, P = 0.71). The inhibition of SERCA 2a
      (10 microM cyclopiazonic acid (CPA)) decreased contractility in both the ouabain
      treated group and in controls, at day 0 and at day 2. These results show that
      chronic ouabain treatment increases the protein expression of the NCX. The
      positive inotropic effect of ouabain can no longer be observed after a chronic
      treatment for 2 days. Thus, both protein expression and contractile function of
      the cells are specifically altered by longer term cardiac glycoside exposure.
      Whether such regulation can be found in human cardiomyocytes and the resulting
      consequences in the clinical setting remain to be determined.

PMID- 12607132
TI  - Ischemic preconditioning promotes a transient, but not sustained translocation of
      protein kinase C and sensitization of adenylyl cyclase.
AB  - OBJECTIVE: Brief periods of ischemia precondition the heart and reduce the size
      of infarction caused by a subsequent sustained ischemia. The molecular memory of
      preconditioning, i.e., the molecule persistently activated by the preconditioning
      ischemia exhibiting protection during the infarct-inducing event, is subject to
      debate. Protein kinase C, adenylyl cyclase and beta-adrenergic receptors are
      candidates for this memory, supposedly their activation persists during several
      cycles of ischemia and reperfusion. The goal of this study was, therefore, to
      determine the activation of those signaling molecules after 1 - 3 cycles of
      myocardial ischemia and reperfusion. METHODS: Rat hearts were perfused according
      to the method of Langendorff with 1 - 3 cycles of ischemia (5 min) and
      reperfusion (10 min). In the particulate fraction of these hearts, densities of b
      adrenergic receptors, activities of adenylyl cyclase, and the activities and
      isozyme distributions of PKC-alpha, PKC-beta, and PKC- epsilon were determined.
      RESULTS: The ischemia-induced upregulation of beta-adrenergic receptors is not
      influenced by preconditioning. In contrast, the sensitization of adenylyl cyclase
      observed after 5 min of ischemia is lost after repetitive periods of ischemia and
      reperfusion. Translocation of protein kinase C to the particulate fraction could
      be shown after 1 and 2 periods of ischemia including all major cardiac isozymes,
      with a rapid relocation to the cytosol after every cycle of reperfusion. A third
      period of ischemia was unable to promote a repeated translocation of protein
      kinase C. CONCLUSION: The ischemia-induced regulation process of beta-adrenergic
      receptors is not influenced in preconditioning. Moreover, a sustained
      translocation of protein kinase C and a sustained sensitization of adenylyl
      cyclase are obviously no prerequisite for preconditioning after various cycles of
      ischemia and reperfusion. Thus, those signaling molecules do not seem to be
      operative for the preconditioning's memory. It is suggested that the initial,
      synergistic burst of sensitization of the adenylyl cyclase and of protein kinase
      C translocation induces myocardial protection very early in ischemia and
      reperfusion.

PMID- 12607133
TI  - Skeletal muscle abnormalities in rats with experimentally induced heart
      hypertrophy and failure.
AB  - BACKGROUND: In congestive heart failure (CHF), function and metabolism of
      skeletal muscles are abnormal. AIM: To evaluate whether the reduced oxidative
      capacity of skeletal muscles in CHF is due to impaired O(2) utilisation. METHODS:
      CHF was induced in rats by injecting 50 mg/Kg monocrotaline. Several animals
      received the same dose of monocrotaline but only compensated right ventricular
      hypertrophy and no sign of congestion resulted. Two age- and diet-matched groups
      of control animals were also studied. In soleus and extensor digitorum longus
      (EDL) muscles, we studied skeletal muscle blood flow, oxidative capacity and
      respiratory function of skinned muscle fibres. RESULTS: In CHF, we observed a
      decrease of muscle blood flow (statistically significant in the soleus, p < 0.05
      vs. controls). In compensated rats, a similar trend in blood flow was observed.
      In both soleus and EDL, a significant reduction of high energy phosphate and a
      shift of the redox potential towards accumulation of reducing equivalents were
      observed. The reduction of energy charge was not correlated to the decrease of
      blood flow. In skinned myofibres, the ratio of O(2) utilised in the presence and
      in absence of ADP (an index of phoshorilating efficiency) was reduced from 8.9 +/
      1.9 to 2.7 +/- 0.2 (p < 0.001) and from 5.7 +/- 1.0 to 2.0 +/- 0.3 (p < 0.01) in
      soleus and EDL, respectively. Activity of the different complexes of respiratory
      chain was investigated by means of specific inhibitors, showing major
      abnormalities at the level of complex I. In fact, inhibition of VO(2) by rotenone
      was decreased from 83.5 +/- 3.2 to 36.4 +/- 9.6 % (p < 0.005) and from 81.8 +/-
      6.1 to 38.2 +/- 7.4 % (p < 0.005) in soleus and EDL, respectively. CONCLUSIONS:
      In rats with CHF, abnormalities of oxidative phosphorylation of muscles occur and
      complex I of the respiratory chain seem to be primarily affected. The metabolic
      alterations of skeletal muscles in CHF may be explained, at least in part, by an
      impaired O(2) utilisation.

PMID- 12607134
TI  - A new screening method to diagnose coronary artery disease using multichannel
      magnetocardiogram and simple exercise.
AB  - BACKGROUND: Magnetocardiography (MCG) is a non-contact mapping technique to
      record cardiac action currents. The Master's two-step electrocardiogram (ECG)
      test is a simple exercise method for screening coronary artery disease (CAD), but
      it is inadequate concerning the sensitivity. Our aim was to develop a new
      screening method using multichannel MCG instead of ECG. METHODS: Thirty subjects
      (aged 54 +/- 16 years, 27 males), 17 of whom had CAD confirmed by coronary
      angiography, underwent the Master's exercise ECG test. After the exercise, MCG
      signals were acquired every minute during recovery with a 64-channel MCG system
      (MC-6400, Hitachi Ltd). We integrated tangential components of the MCG signals
      within QRS (during 20, 40, 80, and 120 ms centering on R-wave peak) immediately
      after exercise (Iex) and 5 minutes after exercise (Irec). The exercise-induced
      change of currents [(Iex-Irec)/Irec] was determined and normalized for each
      channel, and the maximal change among 64 channels, maximal QRS integral change,
      was used as a diagnostic index for myocardial ischemia. RESULTS: The maximal QRS
      integral change during 40 ms was significantly higher in the CAD group than in
      the control group (0.81 +/- 0.51 vs. 0.36 +/- 0.19, p < 0.01). A sensitivity and
      specificity for predicting CAD by the change > 0.44 were 82 % and 85 %,
      respectively, yielding a diagnostic accuracy of 83 %. The conventional Master's
      ECG test identified the CAD patients with a diagnostic accuracy of 63 %
      (sensitivity 47 %, specificity 85 %). CONCLUSION: The Master's two-step exercise
      test with a 64-channel MCG system showed the high diagnostic accuracy, despite of
      non-contact recording and simple exercise. The magnetic field in the
      depolarization process has the potential to detect the subtle myocardial ischemia
      induced by exercise.

PMID- 12607135
TI  - National survey of clinical neuropsychology postdoctoral fellows.
AB  - The present study was designed to survey postdoctoral fellows in clinical
      neuropsychology about their perceptions of a variety of training standards and
      recommendations. Survey packets were mailed to the 78 training directors listed
      in Cripe's (1998) most recent listing of postdoctoral training programs at the
      time of survey. A response rate of 44% was achieved. Results were notable in that
      most fellows had been trained in clinical psychology, and mostly in Ph.D.
      programs. Approximately half had been trained and/or supervised by diplomates in
      clinical neuropsychology from the American Board of Professional Psychology.
      Continuing education was judged by respondents to be an insufficient substitute
      for formal training. Most respondents completed internships and postdoctoral
      residencies in a hospital setting, with greater than 50% of their time devoted to
      clinical neuropsychology.

PMID- 12607136
TI  - Fine tuning of the digit symbol paired associate recall test for practitioner
      purposes in clinical and research settings.
AB  - Guidelines are presented to facilitate the use of the WAIS Digit Symbol measure
      of paired associate recall as a neuropsychological instrument. Currently three
      formal variants of the test exist with accompanying normative data (the original
      WAIS-R-NI form; a WAIS-R Short Form; a longer WAIS-III form), providing a
      potential source of confusion which may limit its application. To circumvent
      this, the present article critically evaluates: (i) variations in test forms and
      their advantages; (ii) available norms in terms of age and education, with
      pointers for more differentiated guidelines in this regard; and (iii) the
      desirability of incorporating a delayed recall variant of the test. Finally, a
      synopsis of data is presented that supports the screening potential of Digit
      Symbol paired associate recall in cases of mild neurocognitive dysfunction. For
      the purposes of this paper, the term WAIS is used with broad reference to all
      variations of the original Wechsler Adult Intelligence Scale (1955) upon which
      they were based, including the WAIS-R (1981) and WAIS-III (1997) updated
      editions, and the South African WAIS (1969). The terms South African WAIS (South
      African Wechsler Adult Intelligence Scale), WAIS-R (Wechsler Adult Intelligence
      Scale - Revised), and WAIS-III (Wechsler Adult Intelligence Scale-III), refer to
      these specific versions of the test.

PMID- 12607137
TI  - Re-examination of a Rey auditory verbal learning test/Rey complex figure
      discriminant function to detect suspect effort.
AB  - Bernard (1990), and Bernard, Houston, and Natoli (1993) identified a discriminant
      function, derived from Rey figure recall score and RAVLT trial 1 and recognition,
      which discriminated simulators and controls with 77--85% accuracy. However, in
      the current study, application of the discriminant function to patients with
      suspect effort, brain injured patients, and controls, revealed excellent
      sensitivity (95%) but low specificity (33% for patients, 61% for controls). A new
      discriminant function using the same Rey figure and RAVLT scores, derived from
      actual patients with documented suspect effort and patients with confirmed brain
      injury, resulted in an overall classification of 85% correct, with only 16% of
      suspect effort and 15% of brain injured patients misidentified. Use of a
      discriminant function score of </=-.40 resulted in sensitivity of 71% while
      maintaining specificity of >/=91%.

PMID- 12607138
TI  - The Key Behaviors Change Inventory and executive functioning in an elderly clinic
      sample.
AB  - The Key Behaviors Change Inventory (KBCI) was developed to assess executive,
      behavioral, and emotional functioning following brain insults and to track the
      course of recovery. The purpose of this study was to investigate, in an elderly
      memory disorder clinic sample, the convergent and discriminant validity of the
      KBCI by examining the relationships between various measures of executive
      functioning and the KBCI scales that theoretically relate to executive functions.
      The KBCI was administered to the caregivers of 97 consecutive patients who came
      to a memory disorders clinic seeking services. The KBCI scales of Inattention,
      Apathy, Unawareness of Problems, and Communication Problems were significantly
      correlated with cognitive measures of executive functioning but not with measures
      of memory, visuospatial abilities or global cognitive functioning. In contrast,
      KBCI scales of Interpersonal Difficulties, Somatic Difficulties, and Emotional
      Adjustment were not related to any cognitive measures, either executive or
      nonexecutive. Contrary to predicted findings, the Impulsivity Scale was not
      associated with cognitive measures of executive functioning. This lack of
      relationship most likely reflects the failure to include executive measures of
      orbitofrontal functioning in this study. Results provide convergent and
      discriminant validity support for the KBCI. The KBCI may be a useful tool for
      assessing and tracking the executive, behavioral, and emotional sequelae of
      neurologic disorders.

PMID- 12607139
TI  - Age and educational influences on RBANS index scores in a nondemented geriatric
      sample.
AB  - Research has indicated the Repeatable Battery for the Assessment of
      Neuropsychological Status (RBANS; Randolph, 1998) to be sensitive to the effects
      of brain dysfunction and capable of accurately discriminating cortical from
      subcortical dementias (Randolph, Tierney, Mohr, & Chase, 1998). It recently has
      been demonstrated, however, that certain indices of the measure are susceptible
      to educational influences (Lineweaver, Zone, Chelune, Hermann, & Dow, 2001). The
      present investigation examined the effects of age and education on the six RBANS
      indices in a sample of nondemented older adults. Education accounted for a
      statistically significant proportion of the variance across all RBANS indices for
      this group (range=1.9-7.6%), while age increased the variance accounted for on
      four of six indices (range=0.5-2.2%). Regression-based educational corrections
      for index scores were derived to allow for appropriate adjustment. Effects of
      age, although statistically significant, were too small to make clinical
      adjustment on three of the four index scores worthwhile. On the Delayed Memory
      Index, however, correction for age for persons 80 years old and higher should be
      considered.

PMID- 12607141
TI  - Diagnostic utility of attention measures in postconcussion syndrome.
AB  - Neuropsychological evaluation may be of particular relevance in the detection of
      subtle cognitive impairments after mild traumatic brain injury (MTBI), including
      the subgroup of MTBI patients with a persistent postconcussion syndrome (PCS).
      Attention measures may be the most sensitive indicators of dysfunction associated
      with MTBI; however, previous studies have typically relied on the analysis of
      overall group differences, which may not reflect the diagnostic accuracy of
      attention measures when applied to individuals with MTBI. In the present study,
      subjects with persistent symptoms at least 3 months following a mild traumatic
      brain injury were compared with a sample of community living, normal control
      subjects in order to evaluate the sensitivity, specificity, and diagnostic
      accuracy of attention measures. Patients with PCS, screened with conservative
      inclusion and exclusion criteria, and a matched normal control group were
      administered six clinical tests of attention: Digit Span, Trail Making Test, Part
      A and Part B, Stroop Color-Word Test, Continuous Performance Test of Attention
      (CPTA), Paced Auditory Serial Addition Test (PASAT), and Ruff 2 & 7 Selective
      Attention Test. Consistent with prior research, these measures exhibited a wide
      range of sensitivity and specificity to possible cognitive impairment among
      patients. Attention measures may be the most sensitive indicators of dysfunction
      associated with PCS. Measures with high specificity (e.g., Stroop Color, and 2 &
      7 Processing Speed) were shown to have strong positive predictive value, while
      measures with high sensitivity (e.g., CPTA) demonstrated strong negative
      predictive value for diagnosing PCS. Examination of the Odds Ratios indicated
      that measures assessing processing speed had a reliable, positive association
      with PCS, while measures without a processing speed component did not.
      Implications for making informed clinical decisions are discussed.

PMID- 12607140
TI  - Intraindividual variability in physical and emotional functioning: comparison of
      adults with traumatic brain injuries and healthy adults.
AB  - Recent research has shown that individuals with certain neurological conditions
      demonstrate greater intraindividual variability on cognitive tasks compared to
      healthy controls. The present study investigated intraindividual variability in
      the domains of physical functioning and affect/stress in three groups: adults
      with mild head injuries, adults with moderate/severe head injuries, and healthy
      adults. Participants were assessed on 10 occasions and results indicated that (a)
      individuals with head injuries demonstrated greater variability in dominant
      finger dexterity and right grip strength than the healthy controls; (b) increased
      variability tended to be associated with poorer performance/report both within
      and across tasks; and (c) increased variability on one task was associated with
      increased variability on other tasks. The findings suggest that increased
      variability in physical function, as well as cognitive function, represents an
      indicator of neurological compromise.

PMID- 12607142
TI  - The impact of American content on California Verbal Learning Test performance: a
      New Zealand illustration.
AB  - The assessment of verbal memory is a core component of neuropsychological
      assessment, and is often assessed through the use of list-learning tasks. As with
      other neuropsychological tests, list-learning tasks may be impacted by cultural
      relevance of test content. This study examined the extent to which the American
      content of the California Verbal Learning Test (CVLT) impacts upon the verbal
      memory performance of New Zealanders. Participants included 90 healthy New
      Zealand adults who ranged in age from 17 to 81 years. Each participant completed
      the CVLT and a new version of this test that was modified to reflect New Zealand
      content (NZ-VLT). Performance on the two measures was not significantly impacted
      by gender, cultural identity (European/Pakeha; Maori or Pacific Islander), or
      version of the test administered first. Poorer performances on all scores for
      both measures were significantly related to increased age, with larger
      correlation coefficients produced for the New Zealand version of the task. Within
      subject comparisons revealed that participants performed significantly better on
      the New Zealand version of the task for short-delay free recall, long-delay free
      recall, and recognition trials. Implications of these findings are presented to
      aid clinicians in future applications of the CVLT in New Zealand.

PMID- 12607143
TI  - Relationship between neuropsychological and emotional functioning in severe
      chronic alcoholism.
AB  - Previous studies of patients with severe chronic alcoholism have shown a high
      prevalence of emotional distress such as anxiety and depression, and
      neuropsychological impairments such as executive deficits, but few have examined
      the relationship between these disorders. We addressed this issue in 51 abstinent
      patients with histories of severe chronic alcoholism utilizing the Minnesota
      Multiphasic Personality Inventory (MMPI) and the Halstead-Reitan
      Neuropsychological Test Battery (HRNTB). Applying factor analysis to the MMPI
      clinical and validity scales, we derived four dimensions accounting for 78% of
      the available variance. We found that Factor 1, which loaded on most clinical
      scales of the MMPI, was significantly correlated (p <.01) with performance on the
      Halstead Category Test (HCT), a measure of executive functioning. Further, group
      analysis with MANOVA using HCT (impaired and nonimpaired) as the independent
      variable revealed a significant main effect for Factor 1 (p <.004), which was
      maintained and strengthened when age and education were controlled as covariates
      (p <.001). The results suggest a relationship between emotional distress and
      executive functioning as measured by the HCT, reflecting differing facets of
      frontal lobe dysfunction common to cognitive and affective domains in patients
      with severe chronic alcoholism.

PMID- 12607145
TI  - Functional equivalence of WAIS-III/WMS-III digit and spatial span under forward
      and backward recall conditions.
AB  - The purpose of the current study was to examine the performance characteristics
      of the Wechsler Spatial Span subtest in a mixed clinical sample. Contrary to
      expectation, differential patterns of performance were obtained on the Digit and
      Spatial Span tasks. Forward Digit Span scores were significantly higher than
      backward recall scores, but this was not the case for Spatial Span. There were no
      differences between forward and backward raw Spatial Span scores at the mean
      level. Further, about one third of the sample showed better performance on
      backward compared to forward Spatial Span. In addition, performance on the
      Spatial Span backward task correlated unexpectedly with that of the WMS-III
      Immediate and Delayed Auditory Index scores. Overall, the findings suggest that
      clinicians should be hesitant when interpreting the Spatial Span task, and the
      backward condition in particular, as a measure of working memory. Finally,
      methodological concerns with the Spatial Span task are noted, raising additional
      concerns regarding the meaning of this task.

PMID- 12607144
TI  - Neuropsychological findings in combat-related posttraumatic stress disorder.
AB  - Previous research investigating whether combat-related Posttraumatic Stress
      Disorder (PTSD) is associated with impaired neuropsychological functioning has
      yielded inconsistent findings. The present study addressed many methodological
      limitations of previous research. Neuropsychological measures of intellectual
      ability, learning, memory, attention, visuospatial ability, executive
      functioning, language, and psychomotor speed were compared in four groups of
      early middle-aged community dwelling veterans. The four demographically
      comparable groups were: (a) those with current PTSD symptoms (n=80); (b) those
      with a prior history of PTSD but not currently experiencing active PTSD symptoms
      (n=80); (c) a non-PTSD psychiatrically matched control group (n=80); and (d) a
      normal control group (n=80). Results indicated that the four groups did not
      statistically differ on the neuropsychological measures and that veterans with
      PTSD perform similarly to demographically matched controls. Results further
      suggested that the cognitive difficulties previously linked to PTSD may actually
      have been secondary to preexisting individual differences or other clinical
      conditions coexisting with PTSD.

PMID- 12607146
TI  - Functional ability in executive variant Alzheimer's disease and typical
      Alzheimer's disease.
AB  - A frontal, or executive, variant of Alzheimer's disease (EAD) has been described
      in the literature in which frontal dysfunction accompanies temporal and parietal
      changes in the early stages of the illness. However, no study has empirically
      investigated associated aspects, such as neuropsychiatric symptoms, instrumental
      activities of daily living, or caregiver burden in this EAD subgroup. We compared
      the performance of two subgroups of mild Alzheimer's disease patients (e.g., EAD
      and typical Alzheimer's disease; TAD) on neuropsychological and associated
      measures. Results revealed that the EAD group, selected based on poor executive
      scores, did not significantly differ from the TAD group on nonexecutive
      neuropsychological tests of intelligence, language, verbal and nonverbal memory,
      or visual-spatial abilities. However, the EAD group evidenced more severe
      neuropsychiatric symptoms, impaired activities of daily living, and greater
      caregiver distress than the TAD group. Thus, the EAD subgroup is characterized by
      executive dysfunction, neuropsychiatric symptoms, and functional disability in
      excess of that seen in TAD. Whether our EAD subgroup represents an actual frontal
      variant of Alzheimer's disease awaits replication in a larger sample including
      neuroimaging and pathological confirmation, as well as longitudinal assessment of
      cognition and neuropsychiatric symptoms.

PMID- 12607147
TI  - Relationship between coping, cognitive dysfunction and depression in multiple
      sclerosis.
AB  - Given its relatively high prevalence, one possible source of stress for patients
      with multiple sclerosis (MS) is cognitive dysfunction. The authors' study was
      guided by a new theoretical model suggesting that cognitive dysfunction in MS may
      be most likely to lead to depression when patients use high levels of avoidance
      coping and/or low levels of active coping. To test this model, 55 patients with
      definite MS were administered a neuropsychological battery and measures of
      depression and coping. Consistent with predictions, regression analyses showed
      that coping significantly moderated the relationship between cognitive
      dysfunction and depression. Specifically, cognitive dysfunction was most likely
      to be associated with depression when patients used either high levels of
      avoidance or low levels of active coping. Implications of these data for clinical
      applications and for our theoretical conceptualization are discussed and
      limitations of the model explored.

PMID- 12607148
TI  - Hopkins Verbal Learning Test-Revised: norms for elderly African Americans.
AB  - The Hopkins Verbal Learning Test-Revised (HVLT-R) is a memory test commonly used
      in neuropsychological evaluations, but for which there are currently no normative
      data for elderly African Americans. The current study examined the influence of
      demographic characteristics on HVLT-R performance measures in a community
      dwelling sample of 237 African American older adults (60-84 years). Age, gender,
      and education accounted for moderate amounts of variance in HVLT-R performance.
      Based on these results, normative tables for HVLT-R scores, stratified by age and
      with score adjustments for education and gender, are provided.

PMID- 12607149
TI  - Normative data for a working memory test: the four word short-term memory test.
AB  - A number of tests of short-term memory based on the Brown-Peterson paradigm
      (recall of either trigrams or short words after varying distractor intervals)
      have been utilized by neuropsychologists in both clinical practice and in
      research protocols. The present study provides normative data for a large group
      of subjects (N=350) aged 18-65 on the Four Word Short-Term Memory Test, a measure
      of working memory based on the Brown-Peterson paradigm. The Four Word Short-Term
      Memory Test presents subjects with four words at the rate of one word per second
      and subjects are then asked to recall the words following a distractor interval
      of counting backwards by threes for 5, 15 or 30 s. Normative data is stratified
      by age and education and presented in overlapping midpoint intervals. Percentile
      rankings based on age and education are also provided.

PMID- 12607150
TI  - Minimal neuropsychological assessment of MS patients: a consensus approach.
AB  - Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in
      MS clinics and neurologic practices are not routinely assessed
      neuropsychologically. In part, poor utilization of NP services may be attributed
      to a lack of consensus among neuropsychologists regarding the optimal approach
      for evaluating MS patients. An expert panel composed of neuropsychologists and
      psychologists from the United States, Canada, United Kingdom, and Australia was
      convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives
      were to: (a) propose a minimal neuropsychological (NP) examination for clinical
      monitoring of MS patients and research, and (b) identify strategies for improving
      NP assessment of MS patients in the future. The panel reviewed pertinent
      literature on MS-related cognitive dysfunction, considered psychometric factors
      relevant to NP assessment, defined the purpose and optimal characteristics of a
      minimal NP examination in MS, and rated the psychometric and practical properties
      of 36 candidate NP measures based on available literature. A 90-minute NP
      battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged
      from this discussion. The MACFIMS is composed of seven neuropsychological tests,
      covering five cognitive domains commonly impaired in MS (processing speed/working
      memory, learning and memory, executive function, visual-spatial processing, and
      word retrieval). It is supplemented by a measure of estimated premorbid cognitive
      ability. Recommendations for assessing other factors that may potentially
      confound interpretation of NP data (e.g., visual/sensory/motor impairment,
      fatigue, and depression) are offered, as well as strategies for improving NP
      assessment of MS patients in the future.

PMID- 12607151
TI  - Detecting exaggeration and malingering with the trail making test.
AB  - The purpose of this study was to examine whether unusual performance on the Trail
      Making Test could be indicative of deliberate exaggeration. Participants were 571
      patients seen as part of a hospital trauma service who had acute traumatic brain
      injuries, and 228 patients involved in head injury litigation. As expected, the
      hospital patients with more severe traumatic brain injuries performed more poorly
      than the patients with less severe brain injuries on Trails A and Trails B.
      Cutoff score tables were developed for the patients with acute traumatic brain
      injuries for the total sample and by injury severity groups. Scores falling at or
      below the 5th percentile were considered suspicious for possible exaggeration.
      The performances of the head injury litigants who exaggerated on at least one
      well-validated symptom validity test were compared to these cutoffs. Very high
      positive predictive values for individuals with very mild head injuries on Trails
      A and B were identified (i.e., both 100%); lower positive predictive values were
      obtained for individuals with more severe head injuries (55.6-60%). The negative
      predictive values were only moderate (range=66.4-78.2%), and the sensitivity was
      very low (range = 7.1-18.5%) for all groups. Scores that fall in the range of
      possible biased responding should be considered "red flags" for the clinician
      because they likely do not make biological or psychometric sense. However, the
      sensitivity of the test for deliberate exaggeration is very low, so clinicians
      who rely on this test in isolation to identify deliberately poor performance will
      fail to identify the vast majority of cases.

PMID- 12607152
TI  - When the third party observer of a neuropsychological evaluation is an audio
      recorder.
AB  - The presence of third parties during neuropsychological evaluations is an issue
      of concern for contemporary neuropsychologists. Previous studies have reported
      that the presence of an observer during neuropsychological testing alters the
      performance of individuals under evaluation. The present study sought to
      investigate whether audio-recording affects the neuropsychological test
      performance of individuals in the same way that third party observation does. In
      the presence of an audio-recorder the performance of the participants on memory
      tests declined. Performance on motor tests, on the other hand, was not affected
      by the presence of an audio-recorder. The implications of these findings in
      forensic neuropsychological evaluations are discussed.

PMID- 12607154
TI  - Visual impairment and nursing home placement in older Australians: the Blue
      Mountains Eye Study.
AB  - PURPOSE: To assess whether visual impairment at baseline is an independent
      contributor to subsequent nursing home placement during a 6-year follow-up.
      METHODS: 3654 non-institutionalised people aged 49+ years (82.4% of those
      eligible) who participated in baseline examinations of the Blue Mountains Eye
      Study (1992-94) were followed during 1997-99. Presenting visual acuity was
      measured with current glasses and a standardised refraction performed. We defined
      visual impairment as visual acuity reduced to <or=20/40. Permanent nursing home
      admissions during follow-up were confirmed by the regional Aged Care Assessment
      Team and government subsidy payment records. RESULTS: At baseline, 511
      participants had presenting visual impairment. After refraction, vision improved
      to 20/30 or better in 346 persons (68%, "correctable"), while 165 (32%) remained
      visually impaired. During follow-up, 162 study participants (5.0%) were admitted
      permanently to a nursing home. The age-adjusted 6-year incidence was 3.6% for
      participants with normal vision, 16.2% for those with visual impairment after
      best correction and 8.1% for those with "correctable" visual impairment. After
      adjusting for non-cognitive factors that predicted nursing home placement, the
      relative risk (RR) for nursing home admission among persons with visual
      impairment after best correction was 1.8 (95% CI 1.1-2.9). A similar magnitude of
      association was found among persons with "correctable" visual impairment (RR 2.1,
      95% CI 1.4-3.1). For each line of reduction in presenting visual acuity at
      baseline, there was a 7% increased risk of subsequent nursing home placement.
      CONCLUSIONS: This study suggests that decreased vision may be a marker or
      contributing factor to subsequent nursing home placement in general older
      populations.

PMID- 12607155
TI  - Refractive errors and cataract as causes of visual impairment in Brazil.
AB  - PURPOSE: To identify the main causes of visual impairment (VA <or= 0.2) within
      the population over 50 years of age examined in "Cataract Free Zone" projects
      sponsored by the University of Campinas from 1986 to 1995. METHODS: A
      retrospective review of the ophthalmic forms used for 60,404 patients examined in
      74 Cataract Projects was performed. Through mass media information, adults of the
      target region or city were asked to self-test their vision. Patients with VA <or=
      0.2 in the better eye were to come to a visual acuity test. Using Snellen charts,
      visual acuity testing was done by trained auxiliaries and medical students. The
      positive cases were then examined by ophthalmologists Criteria were established
      for the classification of the diagnoses and statistical analysis was performed.
      RESULTS: After the self-test of visual acuity, 60,404 patients came to have their
      visual acuity tested; 11,462 (18.97%) cases were considered positive and were
      submitted to complete eye examination; 5447 (42.7%) received spectacles for
      vision improvement, and 2704 (23.59%) had cataract surgery done. Other important
      causes of visual impairment were senile macular degeneration (5.4%) and glaucoma
      (4.02%). CONCLUSION: The main causes of visual impairment were non-corrected
      refractive errors and senile cataract. Ophthalmic community-based campaigns to
      serve the older population are recommended in order to detect and treat the
      identified cases and to indicate possible changes in the health care system.

PMID- 12607156
TI  - Severe ocular injuries in Greek children.
AB  - OBJECTIVE: To determine the epidemiological characteristics of severe eye
      injuries in childhood, in a mixed urban and rural Greek setting. METHODS:
      Retrospective analysis of 95 cases (103 eyes) of eye injuries in children younger
      than 17 years of age admitted to the Department of Ophthalmology, University
      Hospital of Patras, Greece, during a five-year period. The data were analyzed
      with respect to age, sex, type, cause and mode of injury, method of management,
      duration of hospitalization and final visual deficit. RESULTS: The average age
      was 9.8 years and males were involved in 80% of the cases. The most common type
      of eye injury was mechanical closed-globe injury (71.8%). Mechanical open-globe
      injuries were found in 21.3% of the eyes, while burns comprised 6.7% of the
      injuries. Most injuries were agent-related, with blows and falls being
      responsible most often. Multiple operations were part of the treatment in 11.6%
      of the eyes; 14.5% of the eyes were blinded and 15.5% had significant final
      visual acuity loss. CONCLUSIONS: These hospital-based data suggest that there is
      a need for health education of both parents and children, since some injuries in
      children could easily have been prevented.

PMID- 12607157
TI  - Pattern of antibiotic use in a trachoma-endemic region of Nepal: implications for
      mass azithromycin distribution.
AB  - PURPOSE: To investigate antibiotic utilization in a rural district of western
      Nepal that is currently receiving azithromycin as part of a trachoma program and
      is being monitored by the Centers for Disease Control and Prevention (CDC) for
      drug resistance. METHODS: Antibiotic purchase receipts were collected for 3
      months from all medicine halls, pharmacies, and government sub-health posts in a
      sub-district of Western Nepal. Supplementary surveys of antibiotic sales were
      performed in different seasons. RESULTS: Macrolides account for 3.9% of total
      antibiotic use, far less than quinolones, penicillins, tetracyclines, and
      sulfonamides. CONCLUSIONS: If trachoma programs in Western Nepal generate
      transient macrolide resistance in pneumococcus and other bacteria, the
      epidemiological impact may not be great, as macrolides are not commonly used in
      the area.

PMID- 12607158
TI  - Systemic use of anti-inflammatory medications and age-related maculopathy: the
      Blue Mountains Eye Study.
AB  - PURPOSE: To assess whether an association exists between systemic use of anti
      inflammatory medications at baseline and the prevalence or incidence of either
      late or early age-related maculopathy (ARM) in a population-based cohort.
      METHODS: 3654 participants of the Blue Mountains Eye Study baseline examination
      (1992-94) were followed during 1997-99. Use of anti-inflammatory medication was
      recorded during the baseline interview. After excluding 543 persons who died
      since baseline, 2334 (75% of the surviving participants) attended 5-year follow
      up examinations. Retinal photographs taken during both examinations were graded
      using the Wisconsin Age-Related Maculopathy Grading System. Prevalence refers to
      the proportion of participants having ARM at baseline. Incidence refers to the
      proportion of participants without ARM at baseline who developed it over the 5
      year period. Known ARM risk factors were adjusted for when assessing the
      relationship between use of anti-inflammatory medications and ARM. RESULTS: At
      baseline, 1010 (27.6%) of 3654 participants were current users of non-steroidal
      anti-inflammatory drugs (NSAIDs), 514 (14.1%) were past users and 1282 (35.1%)
      were ever users. The corresponding numbers of subjects reporting current, past or
      ever use of corticosteroids (including inhaled steroids) were 225 (6.2%), 519
      (14.2) and 564 (15.4), respectively. Late ARM was present in 72 participants
      (2.0%) and early ARM was present in 171 participants (4.9%) at the baseline
      examination. During the follow-up period, 25 participants (1.1%) developed
      incident late ARM and 192 (8.7%) developed incident early ARM. After adjusting
      for age, sex, family history of ARM and smoking, no significant associations were
      evident for the use of NSAIDs or corticosteroids and the prevalence of either
      late or early ARM. There were also no associations found between use of these
      medications at baseline and the 5-year incidence of either late or early ARM.
      CONCLUSIONS: No association was found between use of systemic anti-inflammatory
      medications and either the cross-sectional prevalence or longitudinal incidence
      of ARM in this population.

PMID- 12607159
TI  - The development and validation of a questionnaire to assess visual
      symptoms/dysfunction and impact on quality of life in cataract patients: the
      Visual Symptoms and Quality of life (VSQ) Questionnaire.
AB  - The aim of the study was to develop a new questionnaire to assess visual
      symptoms/dysfunction and impact on vision-specific quality of life for those
      undergoing second eye cataract extraction. Items for the VSQ questionnaire were
      devised with reference to existing literature and following consultation with eye
      care experts (n = 18) and interviews with cataract patients (n = 40). Piloting
      work conducted with 53 patients indicated that the questionnaire was promising,
      with a high level of internal consistency, low levels of missing data and
      indications that it was responsive to surgery. A modified version of the
      questionnaire was completed by 105 patients having received 'early' surgery and
      103 scheduled for routine surgery within a randomised controlled trial evaluating
      the effectiveness of second eye cataract surgery. Analyses showed that the
      internal consistency of both the visual symptoms/dysfunction and quality of life
      areas was high (Cronbach's alpha 0.82 and 0.83, respectively). Highly significant
      improvements were found for early surgery patients (p < 0.0001), with little
      change among routine surgery patients. Two final versions of the VSQ
      questionnaire have been produced for future use in assessing visual
      symptoms/dysfunction and impact on vision-specific quality of life: a scoreable
      short form and more detailed and sensitive long form.

PMID- 12607161
TI  - Defending principlism well understood.
AB  - After presenting the current version of principlism, in the process repudiating a
      widespread deductivist misinterpretation, a fundamental metaethical disagreement
      is developed by outlining the deductivistic critique of principlism. Once the
      grounds for this critique have been understood, the dispute between casuistry,
      deductivism and principlism can be restructured, and the model of "application"
      proven to be the central difference. In the concluding section it is argued that
      principlism is the most attractive position, if the perceptual model of weak
      intuitionism is made more explicit.

PMID- 12607162
TI  - On the triad disease, illness and sickness.
AB  - The point of departure for this article is a review of the discussion between
      Twaddle and Nordenfelt on the concepts of disease, illness, and sickness, and the
      objective is to investigate the fruitfulness of these concepts. It is argued that
      disease, illness, and sickness represent different perspectives on human ailment
      and that they can be applied to analyze both epistemic and normative challenges
      to modern medicine. In particular the analysis reveals epistemic and normative
      differences between the concepts. Furthermore, the article demonstrates, against
      Nordenfelt's claim, that the concepts of disease, illness, and sickness can exist
      without a general theory of health. Additionally, the complexity of different
      perspectives on human ailment also explains why it is so difficult to give strict
      definitions of basic concepts within modern health care.

PMID- 12607163
TI  - Reconstructionist Confucianism and health care: an Asian moral account of health
      care resource allocation.
AB  - In this article, I offer an abridged reconstruction of the foundational elements
      of Confucian moral commitments, which, I will argue, still provide the background
      moral substance for moral reflection in mainland China, Hong Kong, Taiwan,
      Singapore, and Korea. The essay presents implications of Confucianism for
      establishing an appropriate health care system and critically assesses the
      features of current health polices in mainland China, Hong Kong, and Singapore.
      The goal is to offer a family-oriented, non-individualist account of resource
      allocation that takes family authority and responsibility seriously.

PMID- 12607164
TI  - The search for a global bioethics: fraudulent claims and false promises.

PMID- 12607167
TI  - Speed of information processing after unilateral stroke.
AB  - Speed of information processing in the subacute stage after stroke was studied in
      88 first ever, unilateral, ischemic stroke patients. The patient group included
      42 right and 46 left hemisphere patients. Seventy-one control subjects were also
      examined. Four reaction time tasks with different levels of complexity were used:
      two visuomotor, and two semantic categorisation tasks. The results showed that
      stroke causes a decrease in decision making speed, but that the effect is
      different for right and left hemisphere patients. The right hemisphere group were
      slower than the control group on all reaction time tasks, and slower than the
      left hemisphere patients on the visuomotor tasks. The left hemisphere patients
      were slower than the healthy controls, only on the most complex tasks, the
      categorisation tasks.

PMID- 12607168
TI  - Verbal memory impairment in congestive heart failure.
AB  - Cognitive dysfunction, mainly memory impairment, characterizes congestive heart
      failure (CHF). Aim of this study was to verify whether: (1) CHF has differential
      effects on primary and secondary memory; (2) memory dysfunction can be diagnosed
      by a screening instrument. In a multicenter study we enrolled 369 patients with
      stable CHF who underwent a structured assessment of verbal memory mechanisms and
      selected cognitive functions. Performance on some verbal memory indexes (Recency,
      Rey's immediate and delayed recall, Learning efficiency) progressively decreased
      from II to IV New York Heart Association (NYHA) class. Rate of forgetting was
      uniformly high across NYHA classes II-IV. Verbal memory indexes were highly
      correlated with most nonverbal scores. The Mini Mental State Examination (MMSE)
      had poor sensitivity and specificity versus primary or secondary verbal memory
      dysfunction. Therefore, a deficit of both primary and secondary memory is
      relatively common in CHF but cannot be accurately recognized by a screening
      neuropsychological test.

PMID- 12607169
TI  - Memory and executive functions in aneurysms of the anterior communicating artery.
AB  - The cognitive outcome of three groups of patients, who had undergone surgery for
      repair of a single ruptured intracranial aneurysm, was evaluated. We assessed
      performance on tests of executive functions and memory in a group of 15 patients
      tested at least 3 months after an aneurysm of the anterior communicating artery
      (ACoA) and in a group of 12 patients tested in the first month after the same
      pathology. Acute patients were more impaired overall than chronic ones, but the
      two groups significantly differed on two executive and one memory test. The
      performance of the ACoA patients was also compared to the performance of a group
      of 10 patients who had undergone surgery for an aneurysm located on the posterior
      communicating artery (PCoA) at least 3 months before the examination. Chronic
      ACoA and PCoA patients significantly differed in two memory and in two executive
      tests performance, with posterior patients being more impaired than anterior. An
      unexpected finding was the impairment of semantic memory in ACoA patients.

PMID- 12607170
TI  - Lateralized-temporal-lobe-lesion effects on learning and memory: examining the
      contributions of stimulus novelty and presentation mode.
AB  - Previous studies have attributed poor memory for words after left temporal
      lobectomy (LTL) to a verbal memory deficit and poor memory for abstract designs
      after right temporal lobectomy (RTL) to a difficulty in remembering
      nonverbal/visual stimuli. In this investigation, the contribution of stimulus
      novelty to lateralised-lesion-effects was evaluated by testing list learning in
      11 LTL, 8 RTL and 14 normal control subjects, using four types of material
      (familiar verbal, novel verbal, familiar designs and novel designs). In addition,
      the effect of presentation modality (spoken vs. written) on word-list learning
      was examined. We found that novelty enhanced material-specific-side-of lesion
      effects and that the LTL group had greater difficulty in learning spoken than
      written words.

PMID- 12607171
TI  - Spacing of repetitions improves learning and memory after moderate and severe
      TBI.
AB  - Extensive research has determined that new learning in healthy individuals is
      significantly improved when trials are distributed over time (spaced
      presentation) compared to consecutive learning trials (massed presentation). This
      phenomenon known as the "spacing effect" (SE) has been shown to enhance verbal
      and nonverbal learning in healthy adults of different ages and in different
      memory paradigms (e.g., recognition, recall, etc.). The purpose of this study was
      to examine whether learning in adults with moderate and severe traumatic brain
      injury (TBI) is improved using a spacing-of-repetitions procedure. Using a within
      groups design, participants with TBI (n = 20) were presented a list of 115 words
      that were presented either once (single condition), twice consecutively (massed
      condition), or twice with 11 words between presentations (spaced condition).
      Participants were required to rank each word from 1 to 10 according to their
      familiarity with the word; they were not asked to "memorize" words for a later
      test. Word list learning was measured with a free recall test immediately
      following list presentation and with free recall and recognition tests after a 30
      min delay. Participants recalled and recognized significantly more spaced words
      than massed words during this word list learning task. These results strongly
      indicate that the spacing of repetitions improves learning and memory in
      individuals who have sustained moderate to severe TBI. Implications for
      rehabilitation are discussed.

PMID- 12607172
TI  - A confirmatory factor analysis of the WAIS-III in patients with traumatic brain
      injury.
AB  - Maximum likelihood confirmatory factor analysis was performed on the WAIS-III
      data of a sample of 166 patients with traumatic brain injury (TBI). Four
      competing hypothetical models were tested for model fit and parsimony. A four
      factor model composed of Verbal Comprehension, Perceptual Organization, Working
      Memory, and Processing Speed, identical to that proposed for the standardization
      sample, provided the best fit to the clinical data. The results support the
      construct validity of these four factors in patients with TBI.

PMID- 12607173
TI  - Attention in adult intracranial tumors patients.
AB  - This study investigated the neuropsychological effects of intracranial tumors on
      attention, prior to irradiation and chemotherapy. Subjects (n = 55) being treated
      for low-grade, supratentorial brain tumors were administered tests of attention
      and working memory. We divided the tumor patients into a "superficial" regional
      group (e.g., gliomas that infiltrate white matter and meningiomas attached to the
      cortical surface) and classified them into four brain regions: anterior left
      side, anterior right side, posterior left side, posterior right side. The groups
      were also classified into either a combined anterior group or combined posterior
      group, and either a combined left hemispheric group or combined right hemispheric
      group. All groups were compared to deep tumor (DT) patients (e.g., pituitary and
      pineal tumors) and a demographically normal control (NC) group (n = 63). While
      the NC group primarily outperformed the brain tumor groups on the
      neuropsychological measures, there were instances where the individual brain
      tumor groups demonstrated higher scores than the NC group. Significant
      differences among the brain tumor groups were only found on Digits Forward. The
      DT group performed significantly worse than the superficial regional groups and
      the combined anterior and combined posterior groups on Digits Forward. The DT
      group was also worse than the combined left hemispheric and right hemispheric
      groups on Digits Forward. The fact that the DT group performed similarly to the
      other patient groups on the remaining attention measures suggests that these
      tumors are associated with especially poor attentional performance.

PMID- 12607174
TI  - Sensitivity and specificity of memory dysfunction in schizophrenia: a comparison
      with major depression.
AB  - Fifty-three schizophrenic subjects were compared to 50 patients with major
      depression and 50 normal controls on measures of working memory, declarative
      memory and malingering. The schizophrenic group scored 1-2 SDs below controls on
      all measures, while depressive patients exposed only lesser deficits in working
      memory and free recall. The memory deficit of the schizophrenic subjects was
      disproportionately greater than their intellectual decline. Differences between
      clinical groups could not be explained by differences in IQ, clinical symptom
      load or demographic characteristics. This indicates that impaired memory is a
      particular sensitive symptom of schizophrenia and that the impairment is specific
      to the illness. Working memory failure was prominent in both clinical groups. The
      schizophrenic subjects displayed primarily an acquisition failure, while the
      depressed group showed retrieval difficulties.

PMID- 12607175
TI  - Relation between clinical characteristics of Parkinson's disease and cognitive
      decline.
AB  - This study examined how cognitive impairments in Parkinson's disease (PD) are
      related to clinical characteristics such as age at testing, duration of illness,
      motor impairment, and especially age at disease onset. To address these issues,
      we administered 14 tests of memory, language, visuospatial, and frontal lobe
      capacities to 104 PD patients and 60 healthy volunteers of comparable age and
      education. The participants completed 1-9 test sessions over 1-10 years. Duration
      of PD was associated with deteriorating performance on most cognitive tests,
      independent of age-related decline. Severity of motor impairment, indexed by
      Hoehn and Yahr stages, was positively related to impairment on almost all
      cognitive tests, holding age and duration constant. For some tests, especially
      those that were motorically demanding and those that assessed language skills,
      cognitive deficits appeared earlier in the disease course for late-onset than for
      early-onset PD patients. These late onset deficits were synergistic effects
      beyond the additive contributions of disease duration and normal aging. These
      findings may assist physicians in advising PD patients and their families about
      the future course of the illness.

PMID- 12607176
TI  - Clustering and switching in phonemic fluency following pallidotomy for the
      treatment of Parkinson's disease.
AB  - Phonemic fluency impairments have been reported as one of the most consistent
      cognitive declines following pallidotomy for the treatment of Parkinson's
      disease. In 39 pallidotomy patients, we evaluated two dissociable processes
      involved in phonemic fluency: (1) clustering, the ability to generate words
      within clusters or subcategories, which has been related to intact temporal lobe
      functioning; and (2) switching, the ability to shift between clusters, which has
      been related to frontostriatal integrity. We also correlated the location of the
      lesion in the pallidum and adjacent structures with the effect on phonemic
      fluency. Pallidotomy patients generated significantly fewer words on phonemic
      fluency for up to a year following surgery, with a decline in the total number of
      switches made, rather than a decline in the number of clusters generated.
      Patients whose lesions on postoperative neuroimaging fell entirely or mostly
      within the GPi performed worse on switching than patients whose lesions fell half
      outside of the GPi, either within the GPe or the internal capsule. However, no
      significant differences were found for lesion location 6 months following
      surgery. The findings support the hypothesis that the GPi plays a role in
      cognitive functioning.

PMID- 12607177
TI  - The functional impact of HIV-associated neuropsychological impairment in Spanish
      speaking adults: a pilot study.
AB  - Among English-speaking adults, HIV-associated neuropsychological (NP) impairments
      have been associated with problems in everyday functioning, including ability to
      function at work and drive an automobile. Latinos account for a disproportionate
      number of HIV/AIDS cases nationwide, and a significant segment of this population
      is primarily Spanish speaking. We have previously developed an assessment that
      evaluates English-speakers on a variety of instrumental activities of daily
      living. In this pilot study, we used Spanish-language translations of our
      functional battery to investigate the cultural relevance of such measures, and to
      explore relationships between NP status and ability to perform important everyday
      tasks in HIV-infected Spanish-speakers. Sixteen HIV-infected monolingual Spanish
      speaking adults received comprehensive, Spanish language NP testing and
      functional assessments included the following domains: Medication Management,
      Cooking, Finances, Shopping, and Restaurant Scenario. Results revealed that most
      of the functional tasks appeared culturally relevant and appropriate with minor
      modifications. NP-impaired participants were significantly more functionally
      impaired compared to NP-normals (88% vs. 13%, p <.01). Performances on the
      functional assessment and the NP battery were also related to indicators of real
      world functioning, including employment status and quality of life. These
      results, though preliminary, suggest that Spanish language functional assessments
      are potentially valid tools for detecting everyday functioning deficits
      associated with NP impairments in HIV-infected Spanish-speakers.

PMID- 12607178
TI  - Healthy older adult performance on a modified version of the Cognistat (NCSE):
      demographic issues and preliminary normative data.
AB  - Normative data for a healthy sample of older adults (n = 108) ranging in age from
      60 to 96 are provided for the Cognistat, a mental status exam previously known as
      the Neurobehavioral Cognitive Status Examination (NCSE). A Cognistat Composite
      Score is also introduced that is intended to be used as a marker of general
      cognitive impairment, allowing the Cognistat to be used to match patients in
      terms of the severity of their cognitive dysfunction. The "screen and metric"
      approach of the Cognistat was abandoned in order to improve the reliability and
      standardization of this measure by administering the entire metric to all
      patients. The impact of demographic variables on Cognistat performance was
      examined, demonstrating that both age and education contribute uniquely to a
      number of Cognistat subtests as well as to the Cognistat Composite Score. This
      study highlights the importance of matching an examinee's demographic background
      to the normative sample with which his or her test score is being compared.
      Normative data were stratified accordingly by age and by both age and education.
      Current results indicate that the Cognistat is sensitive to normal aging and
      promises greater sensitivity to the impact of age than the commonly employed Mini
      Mental State Examination (MMSE).

PMID- 12607179
TI  - Cognitive impairment in systemic lupus erythematosus and neuropsychiatric
      systemic lupus erythematosus: a population-based neuropsychological study.
AB  - We present a cross-sectional, population-based neuropsychological study of
      systemic lupus erythematosus (SLE) patients identified within Tampere University
      Hospital district, Finland with 440,000 inhabitants. Patients with definite SLE
      in the age range of 16-65 years (n = 46) and matched controls (n = 46) underwent
      neurological examination and comprehensive neuropsychological testing. On the
      basis of medical examination, the SLE patients were divided into neuropsychiatric
      (NP+; n = 15) and nonneuropsychiatric (NP-; n = 31) cases. The neuropsychological
      test results revealed more prevalent cognitive impairment in the NP+ patients,
      indicating that this subgroup mostly accounts for neuropsychological changes in
      SLE. Most characteristic changes in NP+ were observed in domains of memory,
      psychomotor speed, and complex attention. This suggests nonspecific CNS
      involvement, which is in line with neurological manifestations of the disease.

PMID- 12607180
TI  - Straw man walking: reply to Varney (2002).

PMID- 12607182
TI  - Ocular torsion produced by unilateral chemical inactivation of the cerebellar
      flocculus in alert cats.
AB  - PURPOSE: Vertical eye movements are executed by the vertical recti and oblique
      muscle pairs. Since each of these pairs rotates the eye in both vertical and
      torsional directions, torsional components must be controlled to execute
      appropriate, purely vertical eye movements. To test whether the cerebellar
      flocculus is involved in the control of torsional eye position, we examined the
      effects of unilateral chemical inactivation of the flocculus on ocular torsion in
      alert cats. METHODS: Pitch-responding floccular regions were first identified,
      then the GABA agonist muscimol was injected unilaterally into the identified
      regions. Ocular torsion was examined photographically. RESULTS: Unilateral
      muscimol infusion into pitch-responding areas in the rostral and middle parts of
      the flocculus resulted in significant intorsion of the eye ipsilateral to the
      infusion. Gaze-holding was also impaired following downward saccades induced by
      visual stimuli. Although the contralateral eye showed a tendency towards
      extorsion, the effects were not significant. Muscimol infusion into the caudal
      flocculus did not induce consistent effects on ocular torsion. CONCLUSION: The
      cerebellar flocculus plays a key role in the maintenance of torsional eye
      position.

PMID- 12607183
TI  - Immunolocalization and quantification of advanced glycation end products in
      retinal neovascular membranes and serum: a possible role in ocular
      neovascularization.
AB  - PURPOSE: Earlier studies have revealed the association of advanced glycation end
      products (AGE) with the pathogenesis of various micro and macro vascular
      complications. The purpose of the present study is to localize AGEs, namely
      carboxy methyl lysine (CML-AGE) and methyl glyoxal-derived AGEs (MG-AGE), in
      retinal neovascular membranes and to quantify them in serum samples. METHODS:
      Surgically excised retinal neovascular membranes and serum samples obtained from
      patients with diabetic retinopathy, Eales' disease and nondiabetics were studied.
      Immunolocalization of AGEs namely CML-AGE and MG-derived AGEs was done using
      avidin biotin complex method and quantification was done by enzyme linked
      immunosorbent assay (ELISA). RESULTS: CML-AGE immunoreactivity was detected in
      all cases of Eales' disease and 61% cases of diabetic retinopathy and none in
      idiopathic epiretinal membrane (ERM). MG-AGE immunoreactivity was observed in
      approximately 15% of diabetic retinopathy and none in Eales' disease and and
      idiopathic ERM. Quantification of AGEs in serum samples revealed statistically
      significant increased levels of MG-AGE in diabetes, in relation to nondiabetics
      with idiopathic ERM and CML-AGE in Eales' disease, in relation to diabetics and
      nondiabetics with idiopathic ERM. CONCLUSION: Results from this study suggest
      that AGEs formed through glycation and glycoxidation may play an important role
      in the development of retinal neovascularization. The immunoreactivity of CML
      AGEs in neovascular membrane and its increased levels in serum suggest that
      inspite of the normoglycemic status, glycoxidation and lipid peroxidation due to
      oxidative stress may trigger retinal neovascularization in Eales' disease, while
      MG-AGEs in diabetic membrane and serum suggest the role of glycation. Thus the
      mechanism of neovascularization in different pathological conditions could be
      different.

PMID- 12607184
TI  - TGF-beta-induced apoptosis and reduction of Bcl-2 in human lens epithelial cells
      in vitro.
AB  - PURPOSE: TGF-beta has been shown to induce lens epithelial cells to undergo an
      aberrant growth and transdifferentiation that mimic some characteristics of
      anterior subcapsular cataract, and posterior capsular opacification. Here we
      sought to examine whether TGF-beta induces apoptotic cell death in human lens
      epithelial cells in vitro. METHODS: Cell death of human lens epithelial cells HLE
      B3 cell line was measured by TUNEL assay, FACS analysis, and DNA fragmentation
      assay. The expression of Bcl-2 and Bax was examined using reverse transcription
      polymerase chain reaction and Western blot analysis. The expression of poly (ADP
      ribose) polymerase (PARP) and caspase-3 was examined using Western blot analysis.
      RESULTS: TGF-beta-induced cell death was detected in human lens epithelial cells
      by TUNEL assay. DNA fragmentation assay showed the characteristic laddering
      pattern from the genomic DNA from human lens epithelial cells treated with TGF
      beta. The expression of Bcl-2 mRNA and its protein was markedly decreased in
      human lens epithelial cells treated with TGF-beta. Caspase-3 and PARP were not
      activated in this process. CONCLUSIONS: This study suggests that TGF-beta induces
      apoptotic cell death in human lens epithelial cells and that decreased expression
      of Bcl-2 might play a role in this process.

PMID- 12607185
TI  - Black-line formation and the "perched" human tear film.
AB  - Introduction. McDonald and Brubaker(1) observed that after instillation of
      fluorescein, dark lines appear near the upper and lower lid margins of the human
      eye immediately following a blink. Methods. This paper numerically models the
      dynamic black-line formation under the lubrication approximation at low Reynolds
      number, including gravity and surface tension forces. Results. The hydrodynamic
      model predicts that menisci at the lid margins draw liquid from the tear film,
      resulting in local thinning close to the lids (i.e., black lines) due to
      capillary suction. Once the film thins locally, resistance to further thinning
      increases. No vertical gravity-induced drainage occurs between blinks, and the
      tear film is trapped in its initially deposited state or "perched" between the
      two black lines. Conclusions. We demonstrate quantitatively that due to rapid
      formation of black lines, the tear film is trapped for extended periods. Lid
      action is therefore required to disturb the perched tear film.

PMID- 12607186
TI  - Mechanisms for sickle red blood cell retention in choroid.
AB  - PURPOSE: Although sickle (SS) red cell-mediated vaso-occlusion in retina and
      resultant retinopathy is well documented, the effects of SS red cells on
      choroidal vasculature are poorly understood. The intent of this study was to
      determine, using a rat model, the conditions under which retention of sickle
      erythrocytes in choroid occur and if that retention can be inhibited. METHODS:
      Sickle red cells were density separated into high density (SS4) or normal
      density, reticulocyte-enriched fractions (SS2). Red cells were labeled with FITC
      and administered IV to anesthetized Sprague Dawley rats. Rats were made either
      hypoxic or were given TNF-alpha intraperitoneally 5 hours before intravenous
      administration of red cells. Five minutes after administration of red cells, rats
      were exsanguinated, the retinas removed, and choroids prepared as flatmounts. The
      number of red cells retained in five high power fields of choroid was then
      determined. In other experiments, SS red cells were preincubated with the cyclic
      peptide TBC772 [inhibits binding of alpha4beta1 (VLA-4) and alpha4beta7 to their
      ligands], a control peptide TBC1194, or a VLA-4 neutralizing antibody before
      administration to the rat or antibodies against VLA-4 ligands were delivered IV
      before administration of SS red cells. RESULTS: Hypoxic conditions before
      administration of SS red cells significantly stimulated retention of SS4 cells (P
      = 0.0003), but did not significantly increase retention of SS2 cells.
      Administration of TNF-alpha significantly increased retention of all types of SS
      red cells (P < 0.001). Preincubation of cells with anti-VLA-4 or TBC 772
      inhibited retention of SS red cells in choriocapillaris of TNF-alpha-treated rats
      (P < 0.0001). Complete inhibition of cytokine-stimulated retention was also
      accomplished by IV administration of monoclonal antibodies against fibronectin or
      its CS-1 domain, a ligand for VLA-4. CONCLUSIONS: The mechanisms for retention of
      SS red cells in retina and choroid appear identical: hypoxia-mediated retention
      of dense red cells and adherence of red cells in reticulocyte-rich fractions
      after cytokine stimulation. TNF-alpha-stimulated retention of SS red cells in
      choroid appears to be mediated by VLA-4, presumably on the surface of some
      reticulocytes. This increased retention was inhibited by a VLA-4 antagonist
      (TBC772), a VLA-4 neutralizing antibody or by blocking one of VLA-4's ligands,
      the CS-1 portion of fibronectin.

PMID- 12607187
TI  - Magnetic resonance imaging studies of the volume of the rabbit eye with
      intravenous mannitol.
AB  - PURPOSE: Changes in the volume of rabbit eyes after intravenous mannitol
      injection were studied non-invasively using 3D-magnetic resonance imaging (MRI).
      METHODS: Images of eight rabbit eyes were obtained using a 3D-gradient echo
      technique before and at 30, 60 and 90 minutes after mannitol injection at 4 g/kg.
      To evaluate the volume, the cross-sectional area of the eye in the central 5
      slices was traced and totaled. The intraocular pressure (IOP) of five rabbits was
      measured before and after administration. RESULTS: The total area of the eyeball
      decreased significantly at 60 minutes. The total area of the anterior chamber,
      iris plus ciliary body decreased rapidly and then recovered. The decrease in the
      vitreous and the IOP was consistently significant during the 90-minute
      observation period. CONCLUSIONS: Consecutive MRIs enabled us to measure the
      changes in eye volume of the same rabbit before and after mannitol injection in a
      non-invasive manner.

PMID- 12607188
TI  - Demonstration of the nerve distribution of the extraocular muscles in rabbits
      (Oryctolagus cuniculus).
AB  - PURPOSE: The intramuscular nerve distribution of the extraocular muscles may be
      of utmost importance for better understanding of their physiologic and pathologic
      reactions. The aim of this study was to determine the entire intramuscular nerve
      distribution pattern of rabbit extraocular muscles by utilizing Sihler's staining
      technique. METHODS: Six New Zealand rabbits were used in order to demonstrate the
      intramuscular nerve distribution of the extraocular muscles by using Sihler's
      staining method. RESULTS: The number of extramuscular and intramuscular major
      nerve branches were higher in the inferior oblique muscle while the number of
      intramuscular minor nerve branches were higher in the superior oblique muscle
      when compared with the other extraocular muscles. The smallest number of
      extramuscular branch and intramuscular both major and minor branches were found
      in the medial rectus muscle. More complex anastomoses and a branching pattern
      were observed in the superior oblique and superior rectus muscle. The
      anastomosing nerve branches were observed to run in a "Y", "I" or "U"-shaped
      pattern in all of the extraocular muscles. Of all the extraocular muscles, the
      longest major nerve branches were observed in the retractor bulbi muscles.
      However, these branches had the smallest diameter. No morphological difference
      was observed between the two sides with regard to all the characteristics of the
      extraocular muscles. CONCLUSION: Sihler's neural staining technique could be
      quite useful in the demonstration of the intramuscular nerve distribution of
      extraocular muscles.

PMID- 12607189
TI  - Histamine-induced cytokine production and ICAM-1 expression in human conjunctival
      fibroblasts.
AB  - PURPOSE: Conjunctival fibroblasts stimulated with histamine (H) may be directly
      involved in the inflammatory and remodeling processes of chronic allergic
      conjunctival diseases. METHODS: Proinflammatory cytokine and growth factor
      production, and the expression of intercellular adhesion molecule-1 (ICAM-1) were
      studied in conjunctival fibroblast cultures challenged with different
      concentrations of H (from 10(-9) M to 10(-) (4) M). Interleukin (IL)-1, IL-4, IL
      6, IL-8, tumor necrosis factor-alfa (TNF-alpha), fibroblast growth factor (FGF),
      epidermal growth factor (EGF) and transforming growth factor-beta (TGFbeta-1)
      were measured in supernatants. ICAM-1 expression was evaluated by a fluorescence
      activated cell sorter (FACS). Inhibitory effects of the H-1 antagonists (antiH):
      emedastine, levocabastine, and azelastine, and of the antiH-2, cimetidine, on H
      stimulated fibroblasts were evaluated by measuring both cytokines in supernatants
      and the cellular expression of ICAM-1. RESULTS: Histamine increased the
      production of IL-1, IL-6 and IL-8, and ICAM-1 expression. TNF-alpha, IL-4 and
      growth factor production were not modified by histamine. The antiH-1, emedastine,
      significantly reduced H-induced production of IL-1, IL-6 and IL-8, while
      azelastine reduced only IL-1. Levocabastine and cimetidine were less effective.
      The histamine-induced increase in ICAM-1 expression was inhibited by emedastine
      but not by azelastine and levocabastine. CONCLUSIONS: Histamine has pro
      inflammatory effects on conjunctival fibroblasts, inducing the production of
      cytokines and the expression of ICAM-1. Emedastine significantly reduced cytokine
      and ICAM-1 expression from H-stimulated fibroblasts. Conjunctival fibroblasts may
      contribute to the maintenance of inflammation in chronic allergic diseases.

PMID- 12607190
TI  - Impaired left ventricular function is associated with increased recovery time
      dispersion in patients with previous myocardial infarction.
AB  - Left ventricular (LV) dysfunction after myocardial infarction is associated with
      higher risk of serious ventricular arrhythmias and sudden death. We suspected
      that heterogeneity in ventricular repolarization contributes to these
      arrhythmias. To quantify this heterogeneity, we measured the recovery time (the
      interval between QRS onset and the time of maximum dV/dt in the ST-T segment)
      using an 87-lead body surface mapping electrocardiogram and estimated recovery
      time dispersion (the difference between maximum recovery time and minimum
      recovery time) in each lead. Differences between 110 patients with previous
      myocardial infarction and 31 healthy controls were compared. Recovery time
      dispersion [medians (25th, 75th percentiles)] was greatest in patients with a
      dilated LV [169 ms (154, 201) vs. 155 ms (137, 172), P <.005], impaired ejection
      fraction [173 ms (155, 202) vs. 152 ms (138, 165), P <.0005] and LV dyskinesis
      [175 ms (159, 201) vs. 155 ms (137, 161), P <.0005]. This study suggests that LV
      dysfunction associated with myocardial infarction leads to heterogeneous
      ventricular repolarization and may provide the electrical substrate for
      ventricular arrhythmias.

PMID- 12607191
TI  - Clinical utility of ST-segment depression in lead AVR in acute myocardial
      infarction.
AB  - The present study evaluated the prevalence and significance of ST-segment
      depression (STD) in lead aVR on the admission 12-lead electrocardiogram in 307
      consecutive patients with an acute myocardial infarction (AMI) with ST-segment
      elevation. STD in aVR was present in a significantly higher proportion of
      patients with inferior/posterior AMIs. Within inferior/posterior AMIs those with
      STD in aVR had significantly more concomitant STD in V(1), V(2), V(3) and more
      concomitant STesegment elevation in V(5), V(6) and right precordial leads. These
      data suggests that STD in aVR may point to a coronary artery with a large area of
      supply as the culprit vessel responsible for the AMI.

PMID- 12607192
TI  - Combination of QT variability and signal-averaged electrocardiography in
      association with ventricular tachycardia in postinfarction patients.
AB  - The authors investigate incidence of ventricular tachycardia/ventricular
      fibrillation (VT/VF) in relationship with combination of noninvasive arrhythmia
      risk markers as left ventricular ejection fraction (LVEF), late potentials (LP),
      and QT variability index (QTVI) and compare the utility of their combination in
      association with sustained ventricular arrhythmias in patients after myocardial
      infarction (MI). Fifty-four patients with old MI, among them 27 with documented
      spontaneous sustained VT/VF entered the study. All of them underwent evaluation
      for arrhythmias and noninvasive risk stratification. Logistic regression analysis
      demonstrated that the highest association with ventricular tachyarrhythmia had
      combination of LP and increased QTVI (13.8, P<.0002), followed then by
      combination of LVEF and LP (12.2, P<.0005), LP alone (P<.001), QTVI (P<.002) and
      LVEF (P<.003) alone and age (P<.01). After stepwise regression analysis showed
      that the model including association of LP and QTVI, age and EF is the best one
      for delineating patients having the risk of ventricular tachyarrhythmia
      development. In conclusion, patients with combination of positive LP and
      increased QTVI after MI have high likelihood for development of serious sustained
      arrhythmia.

PMID- 12607193
TI  - Comparison of waveforms in conventional 12-lead ECGs and those derived from EASI
      leads in children.
AB  - To investigate the possibility of simplifying electrocardiogram (ECG) recording
      in children, we compared waveforms in conventional 12-lead ECGs to those derived
      from EASI leads in 221 children of various ages. The conventional 12-lead ECGs
      and the ECGs using EASI electrode positions were collected simultaneously. We
      developed and determined the value of age-specific transformation coefficients
      for use in deriving 12-lead ECGs from the signals recorded at the EASI sites. We
      compared the results of using age-specific coefficients to the results of using
      adult coefficients and studied the "goodness-of-fit" between the conventional and
      the derived 12-lead ECGs. The age-specific coefficients performed slightly better
      than the adult coefficients, and good agreement was usually attained between the
      conventional 12-lead ECG and the EASI-derived 12-lead ECG. Our conclusion is that
      EASI leads in children have the same high levels of "goodness-of-fit" to
      replicate conventional 12-lead ECG waveforms, as reported earlier in adults.

PMID- 12607194
TI  - P wave morphology during spontaneous and paced pulmonary vein activity:
      differences between patients with atrial fibrillation and normal controls.
AB  - P wave morphology (PWM) has been used to predict the location of ectopic foci
      responsible for triggering atrial fibrillation (AF). With bi-atrial mapping, this
      study examined PWM during spontaneous ectopy and during pulmonary vein (PV)
      pacing, comparing the results with published algorithms in 40 AF patients and 15
      controls. PWM during PV pacing is similar to spontaneous ectopy, if performed at
      similar coupling intervals. PWM during ectopic activity from the PVs is affected
      by cycle length and the presence of underlying atrial electrical and structural
      abnormalities. Changes in PWM during decremental pacing were observed in 5% of
      controls but in over 25% of persistent AF patients. The algorithms are accurate
      in over 90% of controls and paroxysmal AF patients with normal atria, but less
      than 60% in those with persistent AF or electrical or structural atrial
      abnormalities. The accuracy of non-invasive localization of arrhythmogenic PV is
      limited.

PMID- 12607195
TI  - Logit50: a nonlinear transformation of pNN50 with improved statistical
      properties.
AB  - The traditional time domain heart rate variability index pNN50 is a percentage
      scale-based measure of large beat-to-beat changes in heart period that may
      reflect parasympathetic neural activity impinging on the sino-atrial node.
      However, pNN50 exhibits nonlinear saturation effects near 0% and 100% that may
      adversely affect its statistical properties. The purpose of this paper is to
      propose a revision of pNN50, Logit50, that is the natural logarithm of the odds
      of the occurrence of large beat-to-beat differences in R-R interval. Using five
      clinical and normal sample data sets, the revised Logit50 index is shown to
      retain the computational simplicity and interpretability of the pNN50, but to
      have better metric properties in statistical and clinical applications. In
      particular, the Logit50 is demonstrated to be relatively unaffected by the
      positive distributional skew that is common in most statistical applications of
      pNN50.

PMID- 12607196
TI  - Characteristics of the electrical activity within the persistent left superior
      vena cava: comparative view with reference to the ligament of Marshall.
AB  - We sought to characterize the electrical activity within the persistent left
      superior vena cava (LSVC), which normally becomes the ligament of Marshall (LOM)
      that is known to be related to the genesis of atrial tachyarrhythmias. A 20-pole
      electrode catheter was used to record the entire activation sequence in the LSVC
      in a patient with Wolff-Parkinson-White syndrome. Electrical activity
      representing the musculature of the LSVC could be recorded up to a level as high
      as the pulmonary artery. Multiple electrical connections between the LSVC and
      left atrium were shown, and one of the connections exhibited unidirectional
      conduction block. It might be important to take into account the presence of
      multiple electrical connections when we consider the LOM as a target for
      radiofrequency catheter ablation or its role in clinical arrhythmias.

PMID- 12607197
TI  - Diminution of QRS complexes caused by anasarca after an acute myocardial
      infarction: a case report and a discussion of the plausible underlying
      pathophysiological mechanisms.
AB  - We describe the case of an 81-year-old man with an acute anterior myocardial
      infarction (MI), complicated by anoxic encephalopathy, respiratory, and acute
      renal failure, who developed gradually marked reduction in the QRS complexes of
      his electrocardiogram (ECG) in the process of gaining 44 pounds, due to anasarca.
      Such ECG pattern has been recently associated with marked peripheral edema in the
      context of critical illness of varying etiologies. Our patient did not have a
      pericardial effusion, and his gradually increasing weight values correlated
      strongly with the corresponding sums of the amplitudes of the QRS complexes of
      the 12-lead ECGs (r =.92, P =.0029). The mechanism of this ECG phenomenon is
      attributed to a reduction of the overall transfer impedance of the conducting
      volume surrounding the heart, which leads to an attenuation of the potentials
      recorded on the body surface, due to a shunting effect of the edematous
      subcutaneous connective tissues. This reduction of the composite transfer
      impedance of the conducting medium is being mediated by the low resistivity of
      the water of the retained anasarca fluid.

PMID- 12607198
TI  - Safe right bundle branch block pattern during permanent right ventricular pacing.
AB  - It is known that an electrocardiogram (ECG) after transvenous right ventricular
      (RV) pacing should yield left bundle branch block (LBBB) QRS patterns. When right
      bundle branch block (RBBB) pacing morphology appears in a patient with a
      permanent or temporary transvenous RV pacemaker, myocardial perforation or
      malposition of the pacing lead must be ruled out, even though the patient may be
      asymptomatic. We report a case of a 77-year-old man who underwent permanent
      transvenous VDD pacemaker implantation for symptomatic heart block. The
      postoperative ECG revealed a RBBB pacing configuration, but his chest X-ray and
      echocardiographic studies confirmed uncomplicated RV pacing. We review and
      discuss the literature concerning the differential diagnosis of such a safe RBBB
      ECG pattern.

PMID- 12607199
TI  - Atypical atrioventricular Wenckebach periodicity caused by conduction through
      triple atrioventricular junctional pathway as a probable mechanism.
AB  - Electrocardiograms were taken from an 84-year-old man with right bundle branch
      block in whom atypical atrioventricular Wenckebach periodicity was frequently
      occurred. The electrocardiographic findings as mentioned below suggested that the
      atypical periodicity was caused by conduction through triple atrioventricular
      junctional pathways as a probable mechanism. When a P wave was blocked after a
      markedly prolonged PR interval of 0.64 s, the RP interval containing this blocked
      P wave ranged between 0.84 s and 0.86 s, and the next P wave was followed by a
      QRS complex of the same configuration, with the PR interval of 0.35 s. On the
      other hand, when a P wave was blocked after a PR interval of 0.49 s or 0.52 s,
      the RP interval containing this blocked P wave was comparatively long, ie, 0.95 s
      or 0.98 s, and the next P wave was followed by a QRS complex of somewhat
      different configuration showing borderline left axis deviation, with a shorter PR
      interval of 0.21 s or 0.23 s. These findings suggest that longitudinal
      dissociation occurred not only in the atrioventricular junction but also in the
      His bundle. This is the first report suggesting triple atrioventricular
      junctional pathways probably associated with longitudinal dissociation in the His
      bundle.

PMID- 12607200
TI  - Alternating reversed wenckebach periodicity: Concealed electrotonic conduction as
      a possible mechanism.
AB  - Electrocardiograms were taken from a 67-year-old man with 2:1 atrioventricular
      block in whom alternating reversed Wenckebach periodicity was found. Long PR
      intervals of alternately conducted P waves progressively shortened until an
      alternate P wave was blocked. After an alternate P wave was blocked, the next
      alternate P wave was conducted to the ventricles with a markedly long PR
      interval. Then long PR intervals of alternately conducted P waves progressively
      shortened again until an alternate P wave was blocked. This is the first report
      on alternating reversed Wenckebach periodicity. It seems that concealed
      electrotonic conduction of alternately blocked impulses occurred as a possible
      mechanism.

PMID- 12607202
TI  - What is to be done? Controversies in the diagnosis and treatment of manic
      depressive illness.
AB  - BACKGROUND: In recent years, much progress has been made in the diagnosis and
      treatment of schizophrenia and depression. Bipolar disorder, however, remains
      frequently misunderstood, leading to inconsistent diagnosis and treatment. Why is
      the case? What is to be done about it? METHODS: We critically review studies in
      the nosology of bipolar disorder and the effects of antidepressant agents.
      RESULTS: Bipolar disorder is underdiagnosed and frequently misdiagnosed as
      unipolar major depressive disorder. Antidepressants are probably overused and
      mood stabilisers underused. Reasons for underdiagnosis include patients' impaired
      insight into mania, failure to involve family members in the diagnostic process,
      and inadequate understanding by clinicians of manic symptoms. We propose using a
      mnemonic to aid in diagnosis, obtaining family report, and utilising careful
      clinical interviewing techniques given the limitations of patients' self-report.
      We recommend aggressive use of mood stabilisers, and less emphasis on
      antidepressants. CONCLUSIONS: The state of diagnosis and treatment in bipolar
      disorder is suboptimal. More diagnostic attention to manic criteria is necessary
      and the current pattern of use of antidepressant use in bipolar disorder needs to
      change.

PMID- 12607203
TI  - Definition, psychopharmacological basis and clinical evaluation of novel/atypical
      neuroleptics: methodological issues and clinical consequences.
AB  - High expectations have been put into new/atypical neuroleptics for the treatment
      of schizophrenia: the higher extrapyramidal-motor tolerability and better
      efficacy in treating negative symptoms supposedly result in a more favourable
      influencing of the overall course of the disease and in a higher quality of life
      for the patients. This article will report about the state of evaluation and
      therapeutic advantages of new/atypical neuroleptics, and thereby deal with
      problems of definition and methodology. It also describes differences in the
      unwanted adverse events profile of the different new/atypical antipsychotics.

PMID- 12607204
TI  - Obsessive compulsive disorder: serotonin and beyond.
AB  - OCD was considered a rare, treatment refractory disorder of psychological origin,
      up until 20 years ago. Research in the last two decades has altered the
      perspectives regarding OCD. It is now clear that OCD is a prevalent disorder-
      about 2% of the population suffer from OCD--and that it is amenable both to
      psychological (cognitive-behavioural approach) and pharmacological intervention
      (with serotonergic medication). The biochemical and neuroanatomical (the frontal
      basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to
      emerge. OCD is unique with regards to its specific response to serotonergic
      medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine,
      paroxetine, sertraline and citalopram were all found to be effective treatments
      for OCD based on large, multicentre, double-blind, placebo-controlled studies. As
      only serotonergic medications appear to be effective in OCD, the serotonergic
      hypothesis has been formulated and tested. Indeed, pharmacological challenges
      with specific serotonin agonists such as mCPP and sumatriptan, which were
      associated with transient exacerbation of OCD symptoms, are in line with the
      specific role of 5HT in the pathogenesis of OCD. However, this serotonergic
      hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic
      and autoimmune mechanism are also implicated in the pathogenesis of OCD. Further
      studies are required to understand the relevance of the serotonergic and non
      serotonergic systems in OCD, and to highlight the various possible subtypes of
      this intriguing disorder.

PMID- 12607205
TI  - Effects of fluoxetine, indomethacine and placebo on 3 alpha, 5 alpha
      tetrahydroprogesterone (THP) plasma levels in uncomplicated alcohol withdrawal.
AB  - OBJECTIVE: The purpose of this study was to investigate the effects of fluoxetine
      (F) and indomethacine (I), two drugs that regulate the synthesis of the GABAergic
      neurosteroid 3 alpha, 5 alpha tetrahydroprogesterone (allopregnanolone, THP) on
      THP plasma levels and on symptoms of anxiety and depression in alcoholics during
      ethanol withdrawal. METHOD: Patients who met DSM-IV criteria for alcohol abuse
      were randomly assigned to treatment with F (40 mg/day) plus misoprostol (M) (500
      mg/day) or I (100 mg/day) plus M or placebo (PL) plus M. Patients were rated with
      the Hamilton Anxiety (14-HAS) and Depression (17-HDS) scales on days 1, 5, 7, 15
      and 28 of ethanol withdrawal and with a Visual Analogue Scale for Depression
      (VASD) and a Visual Analogue Scale for Anxiety (VASA) on days 1, 2, 4, 5, 7, 15
      and 28 of withdrawal. On the same days a plasma sample was collected to measure
      the concentrations of THP by means of a very sensitive gas chromatographic mass
      spectrometric method. RESULTS: During withdrawal at days 1, 2, 4 and 5, THP
      plasma values were lower and symptoms of anxiety and depression were
      significantly higher compared to the late withdrawal phase at days 15 and 28. In
      the F or I treatment, the depression and anxiety score, measured by VASD and
      VASA, decreased significantly at day 5-7 whereas THP plasma levels significantly
      increased compared to PL condition CONCLUSIONS: Treatment of alcohol withdrawal
      either with F or I reduced the extent of anxiety and depression and normalised
      THP plasma levels that were decreased during withdrawal.

PMID- 12607206
TI  - Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review
      of recent research strategies in depression.
AB  - Depressed patients show a variety of alterations in hypothalamic-pituitary
      adrenocortical (HPA) system regulation which is reflected by increased pituitary
      adrenocortical hormone secretion at baseline and a number of aberrant
      neuroendocrine function tests. The latter include the combined dexamethasone
      (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which
      CRH was able to override DEX induced suppression of ACTH and cortisol secretion.
      Whereas the abnormal HPA activation in these patients improved in parallel with
      clinical remission, persistent HPA dysregulation was associated with an increased
      risk of relapse. Moreover, healthy subjects at high genetic risk for depression
      also showed this phenomenon as a trait marker. In consequence, it has been
      concluded that HPA alteration and development as well as course of depression may
      be causally related. As evidenced from clinical and preclinical studies,
      underlying mechanisms of these abnormalities involve impairment of central
      corticosteroid receptor function which leads to enhanced activity of hypothalamic
      neurons synthesising and releasing vasopressin and CRH. These neuropeptides
      mediate not only neuroendocrine but also behavioural effects. Recent research
      provided evidence that CRH can induce depression-like symptoms in animals and
      that these signs are mediated through the CRH1 receptor subtype. Hence,
      therapeutical application of new compounds acting more specifically on the HPA
      system such as CRH1 receptor antagonists appear to be a promising approach for
      future treatment options of depression. In conclusion, research in
      neuroendocrinology provided new insights into the underlying pathophysiology of
      depression and, in consequence, may lead to the development of new therapeutic
      tools.

PMID- 12607207
TI  - Identifying psychiatric patients with serotonergic dysfunctions by event-related
      potentials.
AB  - The increasing knowledge concerning anatomical structures and cellular processes
      underlying event-related potentials (ERP) as well as methodological advances in
      ERP data analysis (e.g. dipole source analysis) is beginning to bridge the gap
      between ERP and neurochemical aspects. Reliable indicators of the serotonin
      system are urgently needed because of its role in pathophysiology and as target
      of pharmacotherapeutic interventions in psychiatric disorders. Converging
      arguments from preclinical and clinical studies support the hypothesis that the
      loudness dependence of the auditory evoked N1/P2-response (LDAEP) is regulated by
      the level of central serotonergic neurotransmission. Dipole source analysis
      represents an important methodological advance in this context, because the two
      N1/P2-subcomponents, generated by the primary and secondary auditory cortex known
      to be differentially innervated by serotonergic fibres, can be separated. A
      pronounced LDAEP of primary auditory cortices is supposed to reflect low central
      serotonergic neurotransmission, and vice versa. LDAEP is a parameter with
      potential clinical value since subgroups of patients with a serotonergic
      dysfunction can be identified and can be treated more specifically. In depressed
      patients, a significant relationship between strong LDAEP, indicating low
      serotonergic function, and a favourable response to SSRI has been found.
      Additionally, there is evidence from several studies with patients with affective
      disorders that a strong LDAEP predicts favourable response to a preventive
      lithium treatment.

PMID- 12607208
TI  - Treatment and recovery rate in depression: a critical analysis.
AB  - The objective of this study was to evaluate the frequency and consequences of the
      presence of residual symptoms in patients treated for major depression. The
      literature specifically focused on recovery and residual symptomatology of
      depression was reviewed. Thirty per cent or more of treated patients present
      residual symptoms. These symptoms appear to be associated with a higher frequency
      and larger number of relapses and equally affect the outcome of depression in
      different age groups. They also seem to have a major impact on work and
      psychosocial functioning because of cognitive dysfunction and a reduction in
      social interaction affecting patients' quality of life. We found that there is
      scant literature on residual symptoms contrasting with the profuse reports on
      single or multiple antidepressant drug trials. Studies focusing on this important
      issue in the treatment of depression are needed.

PMID- 12607209
TI  - Treatment of mitral valve prolapse and panic disorder with metoprolol.
AB  - The prevalence of mitral valve prolapse (MVP) and panic disorder (PD) has been
      reported to range from 0-50% depending on the respective diagnostic manuals and
      described selection criteria. We report the case of a 44-year-old patient
      suffering from both panic disorder and mitral valve prolapse. While
      antidepressants did not result in any improvement of panic symptoms, a fast
      remission was achieved by treating the patient with metoprolol. This case report
      suggests that betablockers might represent a useful tool in the treatment of
      panic disorder and mitral valve prolapse.

PMID- 12607210
TI  - Toward a remarriage of psychiatry and neurology.

PMID- 12607211
TI  - Wine and psychiatry.

PMID- 12607212
TI  - Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation.
AB  - Immune alterations in schizophrenia have been described for decades. However,
      modern immunological methods and new insights into the highly developed and
      functionally differentiated immune system allow an integrative view of both the
      older and also more recent findings of immunological abnormalities in
      schizophrenia. The conceptual advances in immunology require the re-evaluation of
      elder immunological findings in schizophrenia. In this overview, recent advances
      in immunological research regarding the differentiation between T-Helper-1 and T
      Helper-2 cells and between the so-called specific and unspecific arms of the
      immune system are discussed. The unspecific "innate" immune system shows signs of
      an over-activation in unmedicated schizophrenic patients, as increased monocytes
      and gamma delta-cells point to. Increased levels of Interleukin-6 (IL-6) and the
      activation of the IL-6 system in schizophrenia might be the result of the
      activation of monocytes/macrophages, too. In contrast, several parameters of the
      specific cellular immune system are blunted, e.g. the decreased T-helper-1 (TH-1)
      related immune parameters in schizophrenic patients, both in vitro and in vivo.
      It seems that a TH-1-TH-2 imbalance with a shift to the TH-2 system is associated
      with schizophrenia. During therapy with antipsychotics, the specific TH-1 related
      immune answer becomes activated, but the B-cell system and the antibody
      production become activated too.

PMID- 12607213
TI  - Sleep in depression and sleep deprivation: a brief conceptual review.
AB  - Risk factors for somnipathies are psychological stress or psychiatric illness.
      More severe sleep difficulties have been found to be clearly related to
      psychiatric illness such as depression and phobias, as well as to addiction.
      Somnipathies can objectively be identified by means of polygraphy. Overall,
      polysomnographic measures in patients with affective disorders differ most
      frequently and significantly from those in normal control subjects. Persistent
      sleep disturbances are associated with significant risk of both relapse and
      recurrence in mood disorders and an increased risk of suicide. In addition to
      changes in sleep architecture, patients with major depression show profoundly
      altered patterns of nocturnal hormone secretion, possibly through mechanisms that
      link regulation of sleep with neuroendocrine activity. Basic and clinical
      approaches of sleep research established neurobiological models into the
      underlying pathophysiology associated with psychiatric disorders.

PMID- 12607214
TI  - Predominant polarity of bipolar patients in Israel.
AB  - Studies in European and American populations have suggested that the course of
      bipolar illness is most often characterised by a predominance of depressions over
      manias. The current chart review study suggests that among manic-depressive
      patients in Southern Israel, a predominately manic course of illness is more
      common. Unlike some previous studies, no sex differences were noted in type of
      illness course. Possible explanations for the main finding, including climate
      related factors, are discussed.

PMID- 12607215
TI  - In-vitro immunomodulatory effects of haloperidol and perazine in schizophrenia.
AB  - There are some reports describing concurrent changes in lymphocytic and monocytic
      activities in schizophrenia. In this study we investigated T cell activity in
      schizophrenic patients by measuring the release of interleukin-2 (IL-2) and
      soluble interleukin-2 receptor (sIL-2R) by T cells and the percentages of CD4+
      and CD8+ cells in blood. The release of IL-2 and sIL-2R by T cells was evaluated
      in dilute whole blood after in-vitro stimulation with phytohemagglutinin. IL-2
      levels and the percentage of CD4-cells tended to decrease and sIL-2R levels
      decreased significantly in schizophrenic patients. Haloperidol and perazine
      significantly decreased IL-2 levels and increased sIL-2R levels and the
      percentage CD4-cells. IL-2 and sIL-2R levels were lower in patients with a
      predominance of positive symptoms. The neuroleptic-induced increase in sIL-2R
      levels was higher in patients with a predominance of positive symptoms compared
      with those in whom both positive and negative symptoms were severe. The study has
      shown that T-cell activity is reduced in schizophrenia and that neuroleptics may
      have immunomodulatory properties.

PMID- 12607216
TI  - Negative outcome after neurosurgery for refractory obsessive-compulsive spectrum
      disorder.
AB  - OBJECTIVE: The authors sought to determine the long-term outcome of patients with
      severe and refractory obsessive-compulsive disorder spectrum (OCDS) following
      neurosurgery. METHOD: Five patients who underwent neurosurgery as a last-resort
      treatment for refractory OCDS were evaluated. On all patients, posttest data was
      obtained from the Yale-Brown Obsessive-Compulsive Scale, The Overvalued Ideas
      Scale, the Beck Depression Inventory and the Beck Anxiety Inventory. Pretest
      scores were available on three patients as well. RESULTS: All patients failed to
      maintain initial improvements after surgery and relapsed. In addition, they
      became depressed with suicidal ideation or attempt. CONCLUSION: Complications of
      neurosurgery are discussed, notably relapse and depression.

PMID- 12607217
TI  - State of the art of drug treatment of schizophrenia and the future position of
      the novel/atypical antipsychotics.
AB  - Neuroleptic medication is the most important part of the treatment regimen for
      schizophrenic patients. The efficacy of neuroleptics in the acute and long-term
      treatment of schizophrenia is very well proven and the effect size is
      comparatively high. After more than 40 years of clinical practice with the
      classical neuroleptics, several more or less generally accepted rules for the
      management of drug treatment in schizophrenia have been established. The paper
      aims to describe these standards, discussing, among other things, developments
      which have appeared in the last 10 to 20 years, e.g. the tendency to a lower
      daily dose during acute treatment and the tendency to alternative strategies
      during long-term treatment. The paper especially also takes into consideration
      the benefits of the novel/atypical antipsychotics as compared to the classical
      neuroleptics, which will change the current treatment standards under several
      aspects--a change which is already ongoing. The novel/atypical antipsychotics
      will be much better accepted by patients, thus leading to increased compliance,
      will be associated with a better quality of life and will possibly change the
      long-term outcome of schizophrenic patients in a very important manner. It should
      be considered that the so-called novel/atypical neuroleptics do not constitute a
      homogeneous group but are a group of individual drugs, each with their own
      advantages and disadvantages. As was the situation with the classical
      neuroleptics, the physician also has to choose the most adequate drug under
      consideration of the risk/benefit profile of each drug in relation to the
      disposition of the individual patient.

PMID- 12607218
TI  - PET and SPECT findings in alcohol hallucinosis: case report and super-brief
      review of the pathophysiology of this syndrome.
AB  - Alcohol hallucinosis is a rare complication of chronic alcoholism with
      schizophreniform symptomatology. The pathophysiology is basically unclear. We
      report the case of a 48-year-old, never-medicated, long-term alcoholic suffering
      from alcohol hallucinosis with pure acoustic hallucinations for at least six
      months. Current FDG PET data suggest a hypofrontality and possibly a thalamic
      hypofunction in alcohol hallucinosis, findings similar to those reported in
      unmedicated schizophrenics. Current IBZM SPECT data do not support a dopamine
      receptor dysfunction in alcohol hallucinosis but TRODAT SPECT showed reduced
      dopamine transporter binding. Possible implications of these findings are
      discussed.

PMID- 12607219
TI  - Controversies in the diagnosis and treatment of manic-depressive illness.

PMID- 12607220
TI  - Secondary amenorrhoea induced by antipsychotics.

PMID- 12607221
TI  - New perspectives in the acute treatment of bipolar depression.
AB  - In contrast to mania, bipolar depression is usually characterised by longer
      lasting episodes and a higher incidence of treatment refractoriness.
      Additionally, the risks of antidepressive standard treatment regimens are
      increasingly recognised, especially the risk of a switch into mania or induction
      of a rapid cycling course. Mood stabilisers, e.g. lithium, and some
      anticonvulsants, appear to have at least some antidepressant efficacy, which,
      however, may not be sufficient for treating severe depression. Currently, their
      use as a monotherapy of mild depression and at the start as a co-medication to
      antidepressants in severe depression is under consideration. The potential
      usefulness and risks of currently applied antidepressive treatment strategies as
      well as potential future developments will be reviewed in this article. At this
      stage, at least in severe depression, the use of true antidepressants still
      appears to be mandatory, especially because of the risk of suicide. However,
      initial combination with a mood stabiliser can be recommended. The treatment of
      depressive episodes only responsive to ECT should include combination with a mood
      stabiliser, in this case lithium, right from the start. In patients with lithium
      refractoriness, mood stabilising anticonvulsants should be initiated directly
      after the end of the ECT cycle. In order to reach sufficient plasma levels and
      thus reduce the risk of a switch, a loading therapy is recommended.

PMID- 12607223
TI  - Effects of various anions on serotonin transport in human platelets.
AB  - A survey is given of some results from the author's studies on serotonin (5HT)
      uptake in human blood platelets in vitro. These findings are relevant also for
      serotonin reuptake at serotonergic synapses, since it has been shown that the
      serotonin transporter (5HTT) in platelets is identical to that in the brain. The
      main findings: 5HT uptake is dependent on the presence of Cl-, which shows simple
      saturation kinetics in relation to 5HT uptake rate, probably by acting on a
      hypothetical "anion site". Chloride can, however, be partly replaced by other
      small anions like bromide, iodide and nitrite. Unexpectedly, increasing
      concentrations of nitrite gives a sigmoidal 5HT uptake curve, indicating a double
      effect: being able to replace chloride in the "anion site", and exerting an
      allosteric effect by being bound to a separate "activating site". It was later
      found that the monocarboxylic acids acetate, lactate and pyruvate, which can not
      replace chloride, have an allosteric stimulatory effect on 5HT uptake in the
      presence of chloride, presumably by acting at the same activating site as shown
      for nitrite. The chloride concentration, as well as lactate and puruvate, may
      exert a regulatory effect on serotonin reuptake in the brain.

PMID- 12607222
TI  - Pharmacological characterisation of cortical gamma-aminobutyric acid type A
      (GABAA) receptors in two Wistar rat lines selectively bred for high and low
      anxiety-related behaviour.
AB  - Two Wistar rat lines that have been selectively bred for high-anxiety-related
      behaviour (HAB) and low-anxiety-related behaviour (LAB) in the elevated plusmaze
      test may be considered as a genetically prone animal model to study the
      neurochemical correlates of anxiety-related behaviour. Because there are
      pronounced differences between the two lines both in baseline levels of open-arm
      exploration in the elevated plus-maze test and in sensitivity to the anxiolytic
      effects of 1 mg/kg diazepam, we used these lines to investigate the pharmacology
      of the benzodiazepine binding site and the GABA binding site of cortical GABAA
      receptors. No difference in characteristics of flunitrazepam, zolpidem or
      muscimol binding to cortical GABAA receptors could be detected between the two
      lines. Although there was an increase in the brain concentration of the
      anxiolytic neuroactive steroid allopregnanolone, a potent positive allosteric
      modulator of GABAA receptors, both in HAB and LAB animals after a forced swim
      stress, allopregnanolone concentrations did not differ between the two lines.
      Moreover, plasma dehydroepiandrosterone (DHEA) concentrations were similar in HAB
      and LAB animals. We conclude that anxiety-related behaviour and benzodiazepine
      sensitivity in these rat lines are likely to be independent of the pharmacology
      of cortical GABAA receptors.

PMID- 12607224
TI  - Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic
      disorder.
AB  - Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise
      panic disorder. The influence of genetic factors on liability to the disease has
      been the object of several linkage and association studies and appears to relate
      to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently,
      an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was
      found in female patients with panic disorder. An analysis of possible synergistic
      effects of the MAO-A gene promoter variant and the short serotonin transporter (5
      HTT) gene promoter variant in panic disorder was performed in a German and an
      Italian sample (combined panic disorder n = 144, combined controls n = 175).
      There was no significant difference in odds ratios, suggesting that the observed
      increase of genetic liability by the long MAO-A gene promoter allele is not
      modified by the 5-HTT gene promoter polymorphism.

PMID- 12607225
TI  - Nosologomania: a disorder of psychiatry.
AB  - For many years, psychiatry has been devoted to nosology. This disease model
      conceives psychiatric conditions as discrete entities, with a particular
      pathophysiology and predictable relations between phenomenology, course and
      outcome. This model witnessed a true revival with the introduction of the DSM
      III. Its foundations, however, are weak. Many of the disorders, so delineated,
      are of doubtful validity. This is demonstrated, taking major depression as a
      paradigm. The nosological way of thought, moreover, carries with it harmful side
      effects, such as proliferation of new diagnoses, magnification of comorbidity,
      border problems and neglect of the factor psychogenesis. The question is raised
      of a possible alternative disease model and the reaction form model is considered
      to be just that. This model is defined and discussed and the conclusion is
      reached that it fits clinical practice and biological research better than the
      nosological disease model. A reconstruction of the diagnostic process in
      psychiatry is proposed, in such a way that it gains in sophistication and at the
      same time creates opportunities for comparative studies of the merits of the
      nosological and the reaction form model for psychiatric practice and research.

PMID- 12607226
TI  - Cognitive function and language of a child with an arachnoid cyst in the left
      frontal fossa.
AB  - The authors inspected the cognitive function of a boy with a congenital arachnoid
      cyst in the left frontal fossa. Neuropsychological tests described his cognition,
      including language, memory, and frontal functions, as mildly retarded overall.
      The boy's verbal ability was delayed, but his frontal function was intact. We
      supposed that the cyst would not affect his cognitive function. SPECT images
      showed low perfusion in the left temporal lobe. Dysfunction of the left temporal
      lobe should cause delayed language leading to learning difficulty.
      Neuropsychological evaluation of cognitive function concurrent with rCBF imaging
      was necessary not only for describing the influence of the cyst but also in
      discriminating its psychological aspects.

PMID- 12607228
TI  - Information processing and attentional dysfunctions as vulnerability indicators
      in schizophrenia spectrum disorders.
AB  - The schizotypal personality disorder is believed to be part of the schizophrenic
      spectrum of disorders including schizophrenic patients as well as some of their
      seemingly unaffected relatives with discreet symptoms. Spectrum-individuals are
      characterised by a genetic vulnerability for schizophrenia. The vulnerability is
      connected with neurocognitive deficits independent of clinical state. Some
      cognitive dysfunctions are unspecific and probably related to non-genetic brain
      damage. A consistent finding has, however, been poor performance in tasks
      involving information processing and attention. The findings point to the
      existence of specific sensory-perceptual deficits or a general attentional
      dysfunction. Identification of cognitive disturbances characteristic not only of
      schizophrenics, but also of schizotypal disordered and their relatives in the
      boundaries of schizophrenia, is relevant in order better to understand the
      pathogenetic mechanisms and treatment of schizophrenia. In the present review
      clinical data are analysed based on models of vulnerability and information
      processing with reference to a characterisation of the neuro-integrative deficits
      that form the core abnormalities of the spectrum.

PMID- 12607227
TI  - Report of three cases of Alzheimer's disease with focal motor symptoms: clinical
      correlates of neuroimaging findings.
AB  - We report clinical and neuroimaging findings for three patients suffering from
      Alzheimer's disease (AD) with focal motor symptoms. These patients initially
      showed cognitive deficits and subsequently featured myoclonus and awkward
      movements in the unilateral upper limb while progressing to paresis. Paresis was
      noted in the unilateral upper limb. All patients held the unilateral arm flexed
      at the wrist and elbow, closely adducted to the body and the hand fisted and
      pronated. No signs of cerebellar ataxia, sensory disturbance or long tract signs
      were observed, nor any of the initial non-cognitive behavioural changes typical
      of frontotemporal dementia. EEGs of these patients showed marked slowing of basic
      activity without epileptic discharges. MRIs showed progressive brain atrophy in
      the contralateral frontoparietal lobes as well as the hippocampal formation.
      Cases 2 and 3 featured extensive long T2 lesions on MRI. 99mTc-HMPAO-SPECT
      revealed blood flow hypoperfusion in the corresponding regions. The cerebellum
      and brain stem showed neither morphological abnormalities nor blood flow
      hypoperfusion. On the basis of these clinical and neuroimaging observations, the
      focal motor symptoms were attributed to contralateral frontoparietal cortical
      atrophy with or without white matter lesion.

PMID- 12607229
TI  - Stress, depression and the activation of the immune system.
AB  - Both stress and depression have been associated with impaired immune function and
      increased susceptibility of the patient to infectious diseases and cancer. While
      it was initially thought that the hypercorticosolaemia caused a suppression of
      immune function, it is now apparent that adaptive changes result from chronic
      stress and depression that lead to a hypoactivity of the glucocorticoid receptors
      on immune cells and in limbic regions of the brain. Thus depression is now
      thought to be associated with activation of some aspects of cellular immunity
      resulting in the hypersecretion of proinflammatory cytokines and the
      hyperactivity of the hypothalamic-pituitary-adrenal axis. There is also
      experimental evidence to show that such immune activation induces "stress-like"
      behavioural and neurochemical changes in rodents which supports the hypothesis
      that the hypersecretion of proinflammatory cytokines are involved in the
      pathology of depression. This review attempts to show how the immune, endocrine
      and neurotransmitter systems are integrated and how the result of such
      integration may be causally involved in the aetiology of depression.

PMID- 12607230
TI  - A review of 19 double-blind placebo-controlled studies in social anxiety disorder
      (social phobia).
AB  - Nineteen double-blind placebo-controlled studies on the treatment of Social
      Anxiety Disorder (Social Phobia) are reviewed. Initial trials yielded a high
      degree of efficacy for phenelzine, a large difference between drug and placebo
      and a low rate of placebo response. Controlled studies with RIMAs (moclobemide
      and brofaromine) yielded more moderate levels of efficacy and more pronounced
      placebo effects. Results of the Liebowitz Social Anxiety Scale (LSAS) permit a
      comparison of the outcomes of the different controlled trials. Overall, the
      reduction in the mean total score with various drugs is inferior to 50%, probably
      because the chronic nature of the disorder is not amenable to drastic changes in
      short-term trials. Results with the LSAS and other scales justify a ranking of
      the efficacy of the drugs: Classical MAOIs > SRIs > RIMAs. Two controlled studies
      with benzodiazepines (clonazepam and bromazepam) would position them together
      with the SRIs relative to efficacy but with problems associated with unwanted
      effects and dependence. Controlled studies with SRIs (paroxetine and fluvoxamine)
      demonstrated very significant differences from placebo. Paroxetine is the SRI
      most extensively studied in Social Anxiety Disorder with positive therapeutic
      results.

PMID- 12607231
TI  - The genetic heterogeneity of "schizophrenia".
AB  - The main reason for the inconsistent findings in schizophrenia research is the
      lack of diagnostic conformity. This has not changed markedly following the
      introduction of modern operational diagnostic systems. Taking schizophrenia as a
      disease entity or assuming schizophrenia spectrum psychoses to represent a
      continuum of diseases without any clear dividing lines, the results of family and
      twin studies point to a multifactorial etiology based on a polygenic mode of
      transmission. Further, then it has to be assumed a familial continuum from
      schizophrenia to affective psychosis and other spectrum disorders. However, in
      family and twin studies based on Leonhard's classification, there is clearcut
      evidence that schizophrenic spectrum psychoses have to be divided into clinical
      and etiological subgroups with a completely different genetic background. For
      example, systematic catatonia is, for the most part, a sporadic disease, whereas
      periodic catatonia aggregates in families in a manner consistent with a major
      gene effect. Further, the results indicate that schizophrenic spectrum psychoses
      consist of three main valid categories: cycloid psychoses, unsystematic
      schizophrenias and systematic schizophrenias. In the case of cycloid psychosis
      and systematic schizophrenias, genetic loading seem to be very low, while
      "environmental" factors, for example, birth complications, may play an important
      etiological role. Unsystematic schizophrenias, however, are predominantly
      inherited and "environmental" factors are not very prominent.

PMID- 12607232
TI  - Reappraisal of Dementia Praecox: focus on clinical psychopathology.
AB  - One century of investigation in schizophrenia is still not enough to elucidate
      all the complex issues related to the essential symptomatology, clinical
      boundaries, aetiology, pathogenesis, outcome, treatment and prevention. Despite
      the extraordinary progress in the neuroscience field, no definitive data is
      available for schizophrenia. On the other hand, after the successful activity of
      the psychopharmacological era, the clinical psychopathological investigations
      were reduced and almost replaced by the mechanistic operational diagnosis. This
      has caused an impoverishment in psychiatry. Tracing some historical aspects of
      schizophrenia since the kraepelinian Dementia Praecox, this article intends to
      demonstrate the failure of the current model of diagnosis and current limitation
      of neuroscience. It advocates the reinforcement of Clinical Psychopathology as
      the foundation for correct and appropriate first steps in the investigation of
      schizophrenia. The splitting disease is still a challenge to biological
      psychiatry.

PMID- 12607233
TI  - Psychopathological changes preceding motor symptoms in Huntington's disease: a
      report on four cases.
AB  - Neurodegenerative disorders often exhibit "classical" psychiatric symptoms as an
      initial presentation of the disease. Here we present four patients with different
      psychopathological abnormalities who were later diagnosed as having Huntington's
      disease. The range of symptoms covered affective and psychotic symptoms,
      antisocial behavior, cognitive problems reminiscent of dementia and suicidal
      idealisation. The pattern of progress of neuronal degeneration may be helpful in
      explaining the antecedent manifestation of psychiatric symptoms.

PMID- 12607234
TI  - [Assessment of biventricular function using gated blood pool SPECT with QBS
      software: comparison with planar radionuclide ventriculography].
AB  - Quantitative blood pool SPECT (QBS) is a new application for the quantitative
      assessment of biventricular function from gated blood pool SPECT (TMUGA). In this
      study, we compared biventricular function between planar radionuclide
      ventriculography and TMUGA. The reproducibility of measuring biventricular
      ejection fraction with QBS was also evaluated. MATERIALS AND METHODS: Thirty-five
      patients with cardiac disease were enrolled. Following intravenous bolus
      injection of 740 MBq of 99mTc human serum albumin-DTPA, first-pass radionuclide
      angiography (FP) and 25-gated interval planar multi-gated blood pool scintigraphy
      (PMUGA) were performed for the measurement of right ventricular ejection fraction
      (RVEF; %) and left ventricular ejection fraction (LVEF; %), respectively.
      Subsequently TMUGA data set was acquired with a dual-head gamma camera (16 gated
      intervals). Then, alternative LVEF and RVEF were measured using TMUGA with QBS.
      Regional left ventricular wall motion for both PMUGA and TMUGA were assessed with
      a 4-point scoring system respectively. RESULTS: Automatic biventricular border
      detection using QBS was feasible in 27 of 35 patients (70.7%). Measurements of
      TMUGA LVEF and RVEF were well reproducible, with interobserver correlation
      coefficient of 0.98 and 0.97, respectively. TMUGA LVEF showed excellent
      correlation with PMUGA LVEF (r = 0.98, SEE = 3.92%). The agreement of LV wall
      motion score between TMUGA and PMUGA was 88.1% (214 of 243 segments), with a
      kappa value of 0.82. On the other hand, RVEF determined by QBS had a 12.4%
      average overestimate compared to the same value obtained by FP. Moreover 95%
      confidential interval of TMUGA RVEF (-28.8 to +4.0%) was wider than that of TMUGA
      LVEF (-10.7 to +10.7%). CONCLUSION: TMUGA with QBS analysis provided accurate and
      reproducible data for global and regional left ventricular function. However, the
      results of RVEF with TMUGA were not satisfying as a replacement for those with FP
      and modifying the algorithm were needed to improve accuracy of quantification.

PMID- 12607235
TI  - [Clinical significance of exercise-induced ST segment depression in patients with
      lateral myocardial infarction involving the left circumflex artery: evaluation by
      exercise 99mTc-MIBI myocardial scintigraphy].
AB  - PURPOSE: The aim of this study is to clarify the causes of exercise-induced ST
      segment depression in patients with broad lateral old myocardial infraction
      involving LCX (LCX-OMI) without ischemia on exercise scintigraphy. METHOD: Twenty
      one patients (M/F = 11/10, age = 62 +/- 19 years) with myocardial infraction
      involving LCX (LCX-MI), but without fill-in on exercise and rest MIBI
      quantitative gated SPECT (QGS), were selected. They were divided into two groups
      of Group ST(+) (n = 11, with significant ST depression (max -2.8 +/- 0.4 mm),
      Group ST(-) (n = 10) without ST depression. On 20 SPECT segments of both exercise
      and rest SPECT, we scored uptake score as DS (0 = normal to 3 = defect) and wall
      motion as WMS (0 = normal to -5 = dyskinesis) and summed DS (TDS) and WMS (TWMS)
      in LCX region, furthermore, calculated the difference of TWMS (delta TWMS
      [exercise-rest]), end diastolic volume (EDV) and ejection fraction (EF) during
      exercise were compared between the two groups. RESULT: Group ST(+) showed
      significantly (p < 0.01) lower EF (35.4 +/- 9.2% vs. 60.2 +/- 6.2%), larger EDV
      (146 +/- 53 ml vs. 93 +/- 15 ml), higher TDS (5 vs. 7 +/- 3), lower TWMS (-25 +/-
      9 vs. -6 +/- 5), furthermore lower delta TWMS (-6.9 +/- 4.0 vs. -2.0 +/- 0.8)
      than Group ST(-). CONCLUSION: Exercise-induced significant ST depression in V2-4
      without ischema in LCX-MI was observed in patients with broad LCX-MI, low EF, and
      was related to impaired wall motion in LCX region. ST depression in V2-4 was
      considered to appear as miller image of ST elevation at postero-inferior wall due
      to disturbed wall motion on exercise.

PMID- 12607236
TI  - [A possibility of the prognosis factor of serum cross-linked carboxyterminal
      telopeptide region of type I collagen (ICTP) as a marker of bone metastasis].
AB  - We measured ICTP in 126 patients suffering from cancer in our palliative care
      unit to investigate the clinical significance of serum cross-linked
      carboxyterminal telopeptide region of type I collagen (ICTP) and divided them
      into 2 groups according to the absence or presence of bone metastasis. 1) There
      was a relationship that of ICTP = -22.6Loge (Ccr) + 111.4 (r = 0.63, p < 0.01)
      between ICTP and creatinine clearance (Ccr) in non-metastasis group. The ICTP
      increased as renal function deteriorated. 2) In cancer patients with normal renal
      function of 40 ml/min/1.73 m2, ICTP was significantly higher in the group of
      metastasis than non-metastasis group. 3) In cancer patients who died, ICTP was
      high in both metastasis and non-metastasis groups and no difference was found
      between 2 groups. Duration of disease was significantly short in non-metastasis
      group than in metastasis group. These results suggest that ICTP is one of markers
      of bone metastasis, but higher value of ICTP is influenced by various factors
      such as renal function and may reflect the prognosis.

PMID- 12607237
TI  - [Effect of the respiratory movements on the intensity of FDG accumulation in PET
      inspection image].
AB  - PURPOSE: With chest PET examination, expansion of an image showing a small
      accumulation and reduction in the radiation count due to breathing movements are
      anticipated. The purpose of this paper is to analyze movement in the chest region
      when breathing and to clarify effects of the movement on expansion of the image
      of a small accumulation and intensity of the radiation count. METHODS: Movements
      around the hilum of the lung under resting respiration are analyzed in X-rays, CT
      images and MR images. Based on results of the analysis, breathing movements are
      reproduced by means of a phantom of our own design. The phantom is adjusted to
      the PET apparatus so as to change in accordance with the magnitude and movement
      of a small accumulation to obtain expansion of the image of this part and the
      intensity of the radiation count. RESULTS: It was found that movements around the
      hilum of the lung under resting respiration are of a reciprocative kind in the
      cranio-caudal direction which can be approximated by the fundamental wave. The
      extent of the image with average amplitude (8.2 +/- 2.8 mm, n = 30) was 6 mm in
      the cranio-caudal direction. The average amplitude of the radiation count was
      lowered 38% at 3 mm phi and 22% at 6 mm phi. CONCLUSIONS: It is considered that
      breathing movement results in a reduction in the radiation count in small
      accumulations and this may cause underestimation of SUV.

PMID- 12607238
TI  - [The mechanism of neurally mediated syncope assessed by an ambulatory
      radionuclide monitoring system and heart rate variability indices during head-up
      tilt].
AB  - PURPOSE: Previously, we tested the hypothesis that the great decline in left
      ventricular volume during head-up tilt test could trigger ventricular mechano
      receptor activation, using ambulatory radionuclide monitoring system (C-VEST
      system). The aim of this study is to investigate the mechanism of tilt-induced
      syncope further, based on our previous report. METHOD: We measured the temporal
      changes in left ventricular volume, ejection fraction, cardiac output, and heart
      rate variability indices during head-up tilt test in 34 patients with syncope of
      an underdetermined etiology. RESULT: Twenty-two patients had a positive response
      (P group). Twelve patients showed a negative response (N group). Before syncope,
      left ventricular volume declined (P group, diastolic volume; -7.9 +/- 6.8%:
      systolic volume; -23.3 +/- 33.8%: N group, diastolic volume; -2.5 +/- 1.9%:
      systolic volume; 0.6 +/- 9.5%: p < 0.05), ejection fraction increased (P group,
      3.9 +/- 2.5%; N group, -3.5 +/- 7.2%; p < 0.005), and high frequency spectra
      increased (P group, 12.0 +/- 20.3%; N group, 3.1 +/- 9.7%; p < 0.05), more
      extremely in the P group than in the N group. The value of the high frequency
      spectra before the head-up tilt test was significantly higher in the P group than
      in the N group (P group, 5.8 +/- 0.9 ms; N group, 5.0 +/- 1.1 ms; p < 0.05).
      CONCLUSIONS: (1) The precise evaluation of left ventricular volume by ambulatory
      radionuclide monitoring system combined with a heart rate variability analysis is
      considered to be useful for clarifying the pathophysiology of neurally mediated
      syncope. (2) Patients with neurally mediated syncope have higher baseline
      parasympathetic tone than normal population.

PMID- 12607239
TI  - [A case of "Takotsubo" cardiomyopathy observed with myocardial scintigraphy from
      the acute phase].
AB  - A 57-year-old woman was emergently admitted to our hospital because of chest
      oppression. On examination, blood pressure was 174/96 mmHg, pulse rate was 90/min
      and coarse crackle and third heart sound were audible. On laboratory data, the
      levels of LDH and CPK-MB were mildly elevated. Electrocardiogram (ECG)
      demonstrated elevation of the ST segment in leads I, aVL and V2-V5. 99mTc
      tetrofosmin myocardial SPECT (TF) showed severely reduced uptake in the apex and
      anterior wall. Emergent coronary angiography (CAG) did not show any stenotic
      lesion. Left ventriculography (LVG), however, demonstrated akinesis of the apex,
      anterior, and inferior walls, and basal hyperkinesis. On the second hospital day,
      ECG demonstrated inverted T wave in leads I, aVL and V2-V5. 123I-BMIPP myocardial
      SPECT (BMIPP) and 123I-MIBG myocardial SPECT (MIBG) were performed on the second
      and fourth hospital days, respectively. These cardiac images showed severely
      reduced uptake equally. TF, BMIPP, and MIBG were re-examined on the eighth,
      tenth, and twelfth hospital days, respectively. MIBG, BMIPP, and TF showed
      reduced uptake in order of severity. On the fourteenth hospital day, CAG and LVG
      were re-examined. Coronary vasospasm provocation test was negative using
      ergonovine and acetylcholine, and LVG did not demonstrated any sign of asynergy.
      We considered that this case was "Takotsubo" cardiomyopathy and might be caused
      by microvascular spasm.

PMID- 12607240
TI  - [Predicting of the period of recurrent for a post-operative glioblastoma after
      radiochemotherapy using 201TlCl SPECT].
AB  - After radiochemotherapy for a post-operative glioblastoma multiforme (GB), the
      majority of patients return at a later date with a recurrent. To assess whether
      201TlCl uptake can be used as a prognostic indicator in patients with GB, we
      measured the ratio of 201TlCl uptake in tumor to 201TlCl uptake in normal brain
      (TL index) in 10 patients at the end of radiochemotherapy and followed all the
      patients until they returned with a recurrent. The TL indices at the end of
      radiochemotherapy indicated 1.36 to 6.82 (mean +/- SD; 3.59 +/- 1.84), and the
      terms of tumor recurrent were 3-12 months (5.55 +/- 3.10 month). There was a
      significant negative correlation between the TL indices and the terms of tumor
      recurrent (y = -1.28x + 10.14, r = 0.760, p < 0.01). Especially, three cases
      indicated less than 2.0 did not returned with a recurrent in 8 months and 7 cases
      more than 2.0 returned with a recurrent in 5 months. This study resulted that
      201TlCl SPECT was clinically useful to predict the period of recurrent for GB.

PMID- 12607241
TI  - [Performance evaluation of continuous blood sampling system for PET study:
      comparison of three detector-systems].
AB  - OBJECTIVES: To measure cerebral blood flow with 15O'PET, it is necessary to
      measure the time course of arterial blood radioactivity. We examined the
      performance of three different types of continuous blood sampling system.
      METHODS: Three kinds of continuous blood sampling system were used: a plastic
      scintillator-based beta detector (conventional beta detector (BETA)), a bismuth
      germanate (BGO)-based coincidence gamma detector (Pico-count flow-through
      detector (COINC)) and a Phoswich detector (PD) composed by a combination of
      plastic scintillator and BGO scintillator. Performance of these systems was
      evaluated for absolute sensitivity, count rate characteristic, sensitivity to
      background gamma photons, and reproducibility for nylon tube geometry. RESULTS:
      The absolute sensitivity of the PD was 0.21 cps/Bq for 68Ga positrons at the
      center of the detector. This was approximately three times higher than BETA, two
      times higher than COINC. The value measured with BETA was stable, even when
      background radioactivity was increased. The count rate characteristic of the PD
      and COINC was linear up to 8 kcps. The reproducibility of sensitivity for nylon
      tube geometry of COINC was the smallest (C.V. = 1.00%) among the three. PD was
      the weights the least (3.5 kg) among the three, which is convenient for clinical
      use. CONCLUSIONS: Each detector has unique characteristics derived from its own
      structure. Although the performance of all three detectors meets clinical
      requirement, PD had the highest physical performance.

PMID- 12607242
TI  - [Cardiac pool scintigraphy using the solid-state Digirad 2020tc Imager-
      comparison with the conventional anger-type gamma camera using moving cardiac
      phantom].
AB  - Movable gamma camera, 2020tc Imager, was light miniaturized using Si photodiode
      as a semiconductor sensor instead of photomultiplier tubes. To validate
      performance of this new camera in cardiac pool scintigraphy, multigated
      equilibrium radionuclide ventriculography using the moving cardiac phantom was
      performed with 2020tc Imager and a conventional Agner-type gamma camera (PRISM
      3000). METHOD: Both measured cardiac functional values were compared with the set
      up ones for the phantom. Five-, 7.5-, and 10-minute-multigated data were acquired
      using both cameras under constant contractile condition. Constant 5-minute
      multigated data acquisitions using 2020tc Imager were also carried out with
      varied contractile conditions. RESULTS: Measured ejection fraction (EF) derived
      from 2020tc Imager and an Anger-type camera were 68.5 +/- 0.6 and 70.3 +/- 1.4%,
      respectively. Both of these values were absolutely close to the set-up EF value
      of 70%. Both of end-diastolic volume and EF showed excellent correlation between
      set-up and measured values with the correlation coefficient of 0.97 and 0.99,
      respectively. CONCLUSION: This new movable camera could provide comparative
      cardiac functional values with an Anger-type camera and it can be useful to
      evaluate acute cardiac function in a coronary care unit.

PMID- 12607243
TI  - [Short time bacterial endotoxins test for positron emission tomography by means
      of positively charged filters].
AB  - Positron emission tomography (PET) radiotracers have very short physical half
      lives. It is hard to complete a bacterial endotoxins test prior to release from
      medical institutes. For endotoxin quantitative determination, limulus amebocyte
      lysate (LAL) reagent and kinetic-turbidimetry system were previously developed.
      We investigated the possibility of a short time test by means of positively
      charged filters. As a result of this study, the effects of positively charged
      filters on endotoin removal were over 99.5% for [18F]FDG and [18F]NaF, which were
      contaminated with the indicated concentration of endotoxin. Combining this filter
      and the kinetic-turbidimetric method, it was possible to complete a bacterial
      endotoxins test in 5 min prior to the patient's administration. This test should
      be required prior to release for PET radiopharmaceutical quality control. It has
      been suggested that this combination is a good method for this purpose.

PMID- 12607244
TI  - [Evaluation of efficiency of a semiconductor gamma camera].
AB  - We evaluation basic characteristics of a compact type semiconductor gamma camera
      (eZ-SCOPE AN) of Cadmium Zinc Telluride (CdZnTe). This new compact gamma camera
      has 256 semiconductors representing the same number of pixels. Each semiconductor
      is 2 mm square and is located in 16 lines and rows on the surface of the
      detector. The specific performance characteristics were evaluated in the study
      referring to NEMA standards; intrinsic energy resolution, intrinsic count rate
      performance, integral uniformity, system planar sensitivity, system spatial
      resolusion, and noise to the neighboring pixels. The intrinsic energy resolution
      measured 5.7% as FWHM. The intrinsic count rete performance ranging from 17 kcps
      to 1,285 kcps was evaluated, but the highest intrinsic count rate was not
      observed. Twenty percents count loss was recognized at 1,021 kcps. The integral
      uniformity was 1.3% with high sensitivity collimator. The system planar
      sensitivity was 33,330 cpm/MBq with high resolution collimator and 766,767
      cpm/MBq with high sensitivity collimator. The system spatial resolution (FWHM)
      was 2.0 mm and 2.2 mm when the distance between source and collimator was 0 cm
      and 3 cm respectively.

PMID- 12607245
TI  - [Prognosis for the cases after resection of pulmonary metastasis of
      osteosarcoma].
AB  - Osteosarcoma commonly metastasize to the lungs. Sixty-six cases with surgical
      treatment for pulmonary metastasis of osteosarcomas have been experienced for
      past 25 years in our hospital. Disease free interval (DFI) and the number of
      metastatic lesions were assessed in relation to their prognosis. As a result of
      our assessment, fewer metastasis (3 or less), and longer DFI (1 year or more) had
      relations to longer post-thoracotomy survival. And the relations between the
      number of metastatic lesions and DFI were found. Fewer metastasis were associated
      with longer DFI, and multiple metastasis were associated with short DFI. The
      cases with fewer metastasis (3 or less) and longer DFI (1 year or more) might
      have a survival advantage.

PMID- 12607246
TI  - [Results of surgical treatment of pulmonary metastatic tumors and analysis of
      prognostic factors].
AB  - We evaluated surgical outcome and prognostic factors in 35 patients who underwent
      surgery for pulmonary metastatic tumors. Overall 5-year survival rate was 55.3%.
      Size of lesions and disease free interval were considered as affecting factors
      for survival, but not statistically significant. Because number of resected
      tumors, surgical procedure, laterality (unilateral or bilateral) did not
      significantly affect survival, we considered that partial resection was
      appropriate for pulmonary metastases if tumors were complete resected. Tumor size
      and preoperative serum carcinoembryonic antigen (CEA) levels were significant
      factors influencing survival for patients of colorectal carcinoma, Ki-67 positive
      cell ratio for patients of colorectal and breast carcinoma.

PMID- 12607247
TI  - [The outcome of surgical treatment and prognostic factors of pulmonary
      metastases; differences between carcinomas, sarcomas and germ cell tumors].
AB  - We have performed pulmonary metastasectomy on 97 patients with various malignant
      tumors. We analyzed the outcome of surgical treatment and prognostic factors.
      Survival of patients undergoing metastasectomy was significantly different
      according to the type of malignant tumor. The patients with carcinomas had a good
      survival when they had 3 years or longer disease free interval (DFI) and no other
      lesion except the lungs. Those with sarcomas were good survivors, who had a
      solitary pulmonary lesion, 1 years or longer DFI, and had no symptom originating
      from pulmonary metastases. Survival of patients with germ cell tumors was
      significantly superior to other 2 types, and factors such as an existence of
      extra-pulmonary metastatic lesions, respiratory symptoms and a length of DFI had
      no impact on the chance of their survival. These results suggest that we should
      decide the indication for metastasectomy on patients according to their types of
      malignant tumor.

PMID- 12607248
TI  - [Video-assisted thoracic surgery for the resection of pulmonary metastases].
AB  - We report the use of video-assisted thoracic surgery (VATS) as a treatment or
      pulmonary metastases. Between July 1994 and March 2002, 75 patients were treated
      for metastatic lung tumor by VATS. These patients included 45 males and 30
      females with an average age of 60.6 years. Their primary diseases were Colon
      cancer (38), renal cell carcinoma (12), breast cancer (6), seminoma (3), thyroid
      carcinoma (3), parotid cancer (2), pharyngeal cancer (2) and the others (9).
      Tumor size ranged from 6 to 62 mm in diameter. A preoperative high resolution
      spiral computed tomography (CT) scan was used to locate the nodule in all
      patients. Ten recurrence cases were performed re-resection by VATS approach with
      an average period was 22 month. We conclude that VATS is a good candidate for the
      resection of lung metastases in the selected cases.

PMID- 12607249
TI  - [Thoracoscopic surgery for metastatic lung tumors: computed tomography-guided
      localization with use of a needle with a suture].
AB  - When a metastatic lung tumor is found to be deep to the visceral surface of the
      pleura, or when it is found to be a small lesion, it may important to help
      identify the lesion by preoperative methods in order to localize it at the time
      of thoracoscopic operation. We performed computed tomography-guided localization
      of metastatic lung tumors with use of a needle with a suture in 11 cases prior to
      thoracoscopic resection. Placement of the needle, immediately before moving to
      the operation room were successfully performed in all patients. It took from 16
      to 25 minutes (20.3 minutes on average). Complications included minimal
      pneumothorax in 8 patients, mild airway bleeding in 2, and penetration through
      the middle lobe to the lower lobe of the right lung in 1. However, treatment was
      not necessary in any of the patients. Thoracoscopic resections were successfully
      achieved in all patients. Our technique may be a simpler technique and
      advantageous for identification of small lesions and lesions deep to the visceral
      surface of the pleura during the thoracoscopic operation for metastatic lung
      tumors.

PMID- 12607250
TI  - [Surgery for metastatic lung tumors at our department during the last ten years].
AB  - We report on 86 cases (112 operations) who underwent surgery for metastatic lung
      tumors at our department during the last 10 years. The study subjects comprised
      53 men and 33 women, and the average age was 51 (+/- 19) years. Of the 112
      metastatectomies performed, 53 were conducted by video-assisted thoracic surgery
      (VATS), and 59 were performed via thoracotomy. The procedures employed for
      metastatectomy were lobectomy (22 cases), segmentectomy (4 cases), and partial
      resection. wedge resection (86 cases). The primary origin of the metastatic
      tumors was colorectal carcinoma in 22 cases, osteosarcoma in 13 cases, renal
      carcinoma in 10 cases, and breast carcinoma in 6 cases. The 5-year survival rates
      in subjects undergoing first and second resection for pulmonary metastases were
      46% and 44%. Metastatectomy was performed 1, 2, 3, 4, 5, and 7 times in 73, 7, 1,
      2, 2, 1 cases, respectively. The average number and maximum diameter of the
      metastatic pulmonary lesions at first metastatectomy were 1.9 and 27.6 mm.
      Metastatectomy is performed, as a rule, by VATS at our department, because the
      more highly invasive thoracotomy procedure influences the activity of the cancer
      cells in a suspended phase in an unfavorable manner. Furthermore, we believe that
      to the maximum extent possible, re-metastatectomy should also be performed by
      VATS. The survival rates at our institution have been satisfactory, and we
      attribute this to our following strict indications for metastatectomy. Re
      metastatectomy should always be considered, as the survival rates are as
      favorable as those following the first metastatectomy.

PMID- 12607251
TI  - [Surgical treatment for pulmonary metastases from colorectal cancer].
AB  - Blalock first reported pulmonary resection for metastatic colorectal cancer in
      1944. Since then, surgical resection of pulmonary metastases has been generally
      accepted as a standard therapeutic procedure in properly selected cases.
      Recently, the criteria of eligibility have been progressively expanded according
      to the development of radiological diagnosis using helical computed tomography
      (CT), widespread of minimum invasive video-assisted thoracic surgery. In this
      review summarized the surgical treatment of pulmonary metastases from colorectal
      cancer based on the recent literatures. Major areas of controversy remain with
      respect to the following aspects: prognostic factors (i.e., number of metastases,
      size of tumor, disease free interval, preoperative serum carcinoembryonic antigen
      level), procedure of operation (i.e., role of video-assisted thoracic surgery,
      lymphonode dissection), indication of surgical treatment on metastases both lung
      and liver, role of repeat thoracotomy for recurrence. For all above-mentioned
      points it appeared reasonable to try to the cooperative multicentric clinical
      prospective study.

PMID- 12607252
TI  - [Consideration of the prognostic factors influencing survival after lung
      metastasectomy of renal cell carcinoma].
AB  - From 1989 to 2002, 9 patients with metastatic renal cell carcinoma to lung
      underwent lung resections for curative removal of metastatic disease in our
      department. Disease free interval (DFI), number and size of metastases resected
      (at first metastasectomy), and number of metastasized regional lymph nodes were
      studied after resection of pulmonary metastases. DFI were 0 to 60 months with
      mean value of 23 months. At first operation, single metastases accounted for 4
      cases and multiple lesions more than 2 metastases accounted for 5 cases with mean
      value of 2.1. Maximal diameter of metastases was 10 to 50 mm with mean value of
      24 mm. Regional lymph nodes metastases were demonstrated only 1 patient in 2 of
      No. 12 lymph nodes adjacent to metastases. At subsequent relapse, 1 patient had
      second-stage metastasectomy, 2 patients went on to a third phase. Four patients
      were lost, 2 are under treatment for newly relapsed lesions, and 3 are now free
      of metastases. Analysis was performed by Cox proportional hazards model of
      survival using these factors. Though lacking the statistical significance, only
      maximal diameter of metastases was prone to have influencing factor on prognosis.
      Survival was not related to DFI between 0 to 21 months and more than 21 months
      and numerous lung metastases between single metastasis and with 2 or more. In
      general, estimated survival rate of these patients according to Kaplan-Meier was
      0% at 67 months. Considering the above results, surgical treatment for patients
      with metastatic renal cell carcinoma to lung should be planned carefully.

PMID- 12607253
TI  - [Metastatic lung tumor: report of two cases].
AB  - We herein report 2 cases of metastatic lung tumor. The first case was a 59-year
      old female, who had undergone a left radical mastectomy for the treatment of
      breast cancer 18 years before. She was found to have a pulmonary nodule in the
      left lower lobe on the routine chest radiograph. She underwent a video-assisted
      thoracic surgery (VATS) partial resection of the left lower lobe. Tumor was
      diagnosed as a lung metastasis of the breast cancer microscopically. The second
      case was a 77-year-old man, who had undergone a right nephrectomy for the
      treatment of renal cell carcinoma. He was found to have 2 nodules in the right
      lung (1 in the middle lobe and the other in the lower lobe) on the follow-up
      computed tomography (CT) scan of the chest. He underwent VATS partial resections
      of the right middle and lower lobes. While the tumor in the lower lobe was
      diagnosed as a lung metastasis of the renal cell carcinoma, the tumor in the
      middle lobe turned out a primary lung cancer.

PMID- 12607254
TI  - [Surgical treatment for pulmonary metastasis from submandibular gland cancer].
AB  - We reviewed surgical result of 5 patients with pulmonary metastasis from
      submandibular gland cancer. Pathological diagnosis was adenoid cystic carcinoma
      in 2 patients, carcinoma in pleomorphic adenoma in 1, epidermoid carcinoma in 1,
      and mucoepidermoid tumor in 1. Disease free interval from resection of the
      primary lesion to diagnosis of pulmonary metastasis was ranging from 7 to 76
      months. Lobectomy was performed in 2 patients and partial lung resection in 3.
      Three patients died of tumor recurrence 12 to 28 months after lung resection and
      2 patients with a single metastatic lesion have survived as long as 42 and 150
      months after the operation. This study suggests that surgical treatment may be
      effective for pulmonary metastasis, especially for a single metastatic lesion,
      from submandibular gland cancer.

PMID- 12607255
TI  - [Pneumothorax due to pulmonary metastasis of gingival carcinoma: report of a
      case].
AB  - A 72-year-old woman developed left pneumothorax 14 months after the first
      operation of a gingival carcinoma. The chest X-ray films and computed tomographic
      scans on admission revealed left pneumothorax and 2 lesions with a thin-walled
      cavity in the upper lung field. They seemed to be pulmonary metastasis from a
      carcinoma of gingiva and one of them ruptured into the pleural cavity. As airleak
      continued after tube thoracostomy, wedge resections of 2 lesions were performed
      through thoracotomy. Postoperative histological examination revealed that both of
      the lesions were moderately differentiated squamous cell carcinoma and they were
      the same histological findings as the gingival carcinoma excised previously.
      Pulmonary metastasis from a carcinoma of gingiva is rare, while it may be thought
      1% of metastatic lung tumors. And also pulmonary metastasis is unusual cause of
      pneumothorax, especially without chemotherapy for it. We reported the very rare
      case of pneumothorax due to pulmonary metastasis from a carcinoma of gingiva.

PMID- 12607256
TI  - [Off-pump coronary artery bypass grafting for restenosis after coronary
      angioplasty in the patient with left main shock syndrome].
AB  - A case of left main shock syndrome due to total occlusion of left main trunk was
      reported. A 65-year-old man with acute myocardial infarction developed
      cardiogenic shock shortly after admission. An emergency coronary angiogram
      revealed total occlusion of the left main trunk without collaterals. Immediately,
      a stent was implanted in the left main trunk and the lesion was successfully
      improved. However, the left coronary angiogram revealed 90% restenosis of the
      left main trunk in a coronary angiogram examined 6 months after stent placement.
      Since the patient suffered from poor cardiac function, off-pump coronary artery
      bypass grafting (left internal thoracic artery to left descending coronary
      artery) was successfully performed using an intracoronary shunt. No complications
      were observed.

PMID- 12607257
TI  - [Clinical experience of gelatin-resorcin-formal (GRF) glue for acute empyema with
      bronchopleural fistula].
AB  - Gelatin-resorcin-formal (GRF) glue is a new biological adhesive agent with the
      advantage of sealing efficacy. We report a successful closure of bronchopleural
      fistula using this agent. A 77-year-old man underwent cavernostomy for lung
      aspergillosis. After surgery, he developed methicillin-resistant staphylococcus
      aureus (MRSA)-empyema with bronchopleural fistula. Thoracoplasty and muscular
      plombage were performed for filling up the cavity and closure of bronchial
      fistula. But the fistula relapsed 3 days after surgery. GRF glue was injected
      into the residual cavity, then air-leakage was completely disappeared with tight
      adhesion of cavity wall. We consider this agent is useful material for the
      closure of bronchopleural fistula.

PMID- 12607258
TI  - [Structure of the bacterial RNA polymerase holoenzyme].

PMID- 12607259
TI  - [Molecular switch for mRNA synthesis rate].

PMID- 12607260
TI  - [Identification of a novel urate transporter URAT1 and current status on urate
      research].

PMID- 12607261
TI  - [Crystal structure of bacterial multidrug efflux transporter AcrB].

PMID- 12607262
TI  - [Archael molecular chaperones: protein folding mechanism of the archael
      chaperonin].

PMID- 12607263
TI  - [Examination of models for vertebrate limb development].

PMID- 12607264
TI  - [PRC(Protein Research Communication) No. 2002. 68].

PMID- 12607265
TI  - [Max Perutz elucidating the three dimensional structure of protein].

PMID- 12607266
TI  - [Introduction to gene ontology].

PMID- 12607267
TI  - [The effects of intrathecally administered neostigmine on somato-sympathetic
      reflex potentials].
AB  - BACKGROUND: Antinociceptive effect of intrathecal neostigmine has been
      investigated using withdrawal responses in laboratory experiments. However,
      neostigmine administered in this route can induce muscle weakness or sedation. As
      a result, these effect can modify withdrawal responses. In this study we
      investigated the antinociceptive effect of intrathecally administered neostigmine
      bromide (NB) in cats objectively and quantitatively using somato-sympathetic
      reflex potentials. METHODS: Anesthetized cats were inserted with a spinal
      catheter via atlanto-occipital membrane and 10 micrograms (n = 5), 50 micrograms
      (n = 5), 250 micrograms (n = 8) or 2 mg (n = 5) of NB was administered through
      this route. Somato-sympathetic reflex potentials (A and C reflex) derived from
      lumbar sympathetic ganglion by stimulation of the femoral nerve and mean arterial
      blood pressure (MAP) and heart rate (HR) in each dose were monitored and
      recorded. RESULTS: Reflex potential was reduced in a dose dependent fashion by NB
      but these changes were not significant. On the other hand, 250 micrograms and 2
      mg of NB maximally reduced C reflex potential to 55.2% and 24.0% of control
      values respectively 20 minutes after the administration (P < 0.01), and this
      reduction was reversed by 250 to 2 mg of intrathecal administration of atropine
      sulfate to 89.4%, 68.6% of control values respectively. MAP and HR decreased in
      dose dependent fashion by NB to 57.6%, 65.2% of control values after the
      administration of 2 mg of NB and these cardiovascular changes recovered by
      intrathecally administered atropine sulfate. CONCLUSION: These results
      objectively indicate that intrathecally administered neostigmine bromide shows
      antinociceptive effect and this inhibition is partially mediated by cholinergic
      mechanism.

PMID- 12607268
TI  - [Transcutaneous carbon dioxide and oxygen measurement in patients undergoing
      microlaryngosurgery with high frequency jet ventilation].
AB  - BACKGROUND: High frequency jet ventilation (HFJV) via thin tracheal tube is a
      convenient method of ventilation in microlaryngosurgery, but the problem of the
      assessment of oxygen and carbon dioxide status during HFJV is yet to be studied.
      METHODS: Fifteen patients undergoing microlaryngosurgery under total intravenous
      anesthesia with HFJV were studied. The combined transcutaneous carbon dioxide
      (PtcCO2) and oxygen (PtcO2) levels were compared with arterial blood gas values
      (PaCO2, PaO2). RESULTS: The PtcCO2 values demonstrated a high degree of
      correlation with PaCO2 before intubation (r = 0.97), during HFJV (r = 0.96), and
      after anesthesia (r = 0.93). The PaO2 values demonstrated a generally good
      correlation with PaO2 before intubation (r = 0.78) and during HFJV (r = 0.83),
      but not after anesthesia (r = 0.54). CONCLUSION: Capnography values are invalid
      during HFJV, and an arterial catheter is not always indicated and feasible in
      microlaryngoscopy. The transcutaneous devices provide an effective method for non
      invasive monitoring of PaCO2 in situations where continuous and precise control
      of CO2 levels is desired such as in perioperative period of microlaryngosurgery
      with HFJV.

PMID- 12607269
TI  - [A clinical study of total intravenous anesthesia by using mainly propofol,
      fentanyl and ketamine--with special reference to its safety based on 26,079
      cases].
AB  - During a period of five years from January 1996 through December 2000 total
      intravenous anesthesia with mainly propofol, fentanyl and ketamine was
      administered to 26,079 patients including cardiac and neurosurgical patients at
      the University of Hirosaki Hospital and five other affiliated hospitals. The
      patients studied ranged from 1 year 8 months to 93 years in age, 9.2 kg to 135.0
      kg in body weight and from 18 min to 22 hours 50 min in anesthetic time. With
      adequate monitoring, fentanyl 1-2 micrograms.kg-1 was given at first, then total
      dose of ketamine 1 mg.kg-1 and propofol 1-2 mg.kg-1 were administered for the
      induction of anesthesia in adult patients. A total dose of fentanyl 3-15
      micrograms.kg-1 was given combined with propofol 5-10 mg.kg-1 and ketamine 0.3
      1.0 mg.kg.h-1. In craniotomy patients, ketamine was excluded. For pediatric
      patients, sevoflurane anesthesia was employed to establish i.v. route, and
      intravenous agents were given almost same as in the same manner as in adult
      patients. None of them developed either cardiac arrest or severe cardiovascular
      insufficiencies due to anesthesia alone. Their postoperative hepatic and renal
      functions evaluated by various biochemical indices and urine output were
      adequately maintained during anesthesia and for a week postoperatively. They were
      followed up to 3 months postoperatively only to fail to detect any adverse events
      related directly to this method of anesthesia. These data suggest that total
      intravenous anesthesia with propofol, fentanyl and ketamine has a very wide
      margin of safety.

PMID- 12607270
TI  - [The effect of ketamine on reducing postoperative agitation after sevoflurane
      anesthesia in pediatric strabismus surgery].
AB  - We investigated the effect of ketamine on reducing postoperative agitation after
      sevoflurane anesthesia in children undergoing elective strabismus surgery. Fifty
      five children, 3-9 years of age, were randomly assigned to the following three
      groups; ketamine (group K, n = 18), pentazocine (group P, n = 19), and
      flurbiprofen axetil(group F, n = 18). Group K received ketamine 1 mg.kg-1
      intravenously, followed by infusion of ketamine 1 mg.kg-1.hr-1 during surgery,
      group P received pentazocine 0.2 mg.kg-1 intravenously after induction of
      anesthesia, and Group F received intravenous flurbiprofen axetil, 1 mg.kg-1 5
      minutes before the end of surgery. Agitation (evaluated by Aono's four-point
      scale; AFPS) and awareness (evaluated by Steward score) were assessed just before
      tracheal extubation(T 1), 5 minutes after tracheal extubation(T 2), arrival at
      the ward(T 3), and 60 minutes after arrival at the ward(T 4). We considered AFPS
      > or = 3 patients as "agitated" and APFS < or = 2 patients as "not agitated". At
      T 1 and T 2, the incidence of agitation(AFPS > or = 3) in group K was less than
      that of group F and group P. However, in group K, more patients needed oxygen
      supplement after extubation. We concluded that coadministration of ketamine could
      be beneficial for reducing postoperative agitation after sevoflurane anesthesia
      in pediatric strabismus surgery.

PMID- 12607271
TI  - [Anesthetic management for elective cesarean section due to placenta previa in a
      patient with moyamoya disease].
AB  - We report the anesthetic management of a 31-year-old female patient with moyamoya
      disease using general anesthesia combined with epidural anesthesia for a cesarean
      section due to placenta previa. Epidural anesthesia with 10 ml of 2% lidocaine
      was first used. Then general anesthesia was induced with thiamylal 200 mg and
      succinylcholine 60 mg just before starting operation and was maintained with 60%
      nitrous oxide in oxygen. After the delivery, propofol was administered at 3-5
      mg.kg-1.hr-1. Except for temporary hypotension due to massive bleeding, systolic
      blood pressure was maintained between 100 and 120 mmHg. Arterial carbon dioxide
      tension was maintained at about 40 mmHg. Intracranial blood velocity and regional
      oxygen saturation were also measured to monitor cerebral blood flow. There was no
      postoperative pain, and no postoperative neurological defects. On the basis of
      these findings, it was concluded that general anesthesia combined with epidural
      anesthesia for elective cesarean section due to placenta previa is effective for
      perioperative management of a patient with moyamoya disease.

PMID- 12607272
TI  - [Sequential changes of various parameters of arterial blood samples].
AB  - BACKGROUND: Since the values of various parameters in arterial blood samples
      changes with time, they should be measured without delay. There are some
      situations, however, where it is quite difficult to carry out the measurement
      immediately. In this study, we aim to obtain a series of parameters by which we
      can estimate true values from stale blood samples. METHODS: Arterial blood gases
      (PaCO2, PaO2, pH), electrolytes, blood sugar and lactate were measured at 0 min,
      30 min, 60 min after collecting the samples. Cytometry was done at 0 min. We
      calculated proton ion concentration ([H+]) and oxygen content (CaO2).
      Relationships between the change of various parameters in arterial blood samples
      and the numbers of red blood cell (RBC), white blood cell (WBC) and platelet were
      analyzed using multiple regression analysis. RESULT: The values of PaCO2, lactate
      and [H+] increased, and those of PaO2, blood sugar and CaO2 decreased with time.
      Electrolytes changed little. There were significant relationships between the
      number of RBC and the change of blood sugar, and between the number of WBC and
      the change of CaO2 value. CONCLUSION: From these result, we found a series of
      expression by which we can estimate appropriate values from stale blood samples.

PMID- 12607273
TI  - [A case of cardiac arrest at induction of anesthesia for postpartum
      hysterectomy].
AB  - Although peripartum cardiac arrest is rare, the prognosis of the event may be
      worse than in nonpregnant patients because the events is often associated with
      pulmonary or amniotic embolisms. The following report is a case of cardiac arrest
      which occurred at the induction of anesthesia for the postpartum hysterectomy. A
      31-year-old woman was treated with infusion of ritodrine chloride for preterm
      labor and placenta previa. Elective cesarean section was performed at 37 weeks'
      gestation for her delivery under epidural anesthesia. Following the operation,
      the total hysterectomy was scheduled due to the continuous massive bleeding. She
      rapidly developed ventricular tachycardia, following trachea intubation with
      propofol and suxamethonium. Since she was not resuscitated with cardiac massage,
      we started intravenous epinephrine, electronic cardioversion, the percutaneous
      cardiopulmonary support and intra-aortic balloon pumping with epinephrine and
      dopamine infusions leading to a successfully outcome. In this case, we believe
      that the combination of propofol and suxamethonium had the most impact on
      producing the cardiac arrest. Therefore, the case emphasizes the potential danger
      of using these combination for patients who have been treated with ritodrine.

PMID- 12607275
TI  - [A case of monoplegia from conversion disorder after spinal anesthesia].
AB  - Neurological complications related to spinal anesthesia are exceptional, but
      their consequences are serious. We report a case of conversion disorder, which
      was initially diagnosed as monoplegia caused by spinal anesthesia. The patient
      was a 36-year-old, 88 kg woman with a history of psychogenic aphonia. She
      underwent plastic surgery for both toes under spinal anesthesia. On the following
      day, her left leg remained paralyzed with loss of sensation below the knee level.
      She practiced walking according to rehabilitation program, but paralysis became
      worse gradually. As the hospitalization was prolonged, she refused to be
      discharged from the hospital and began to demand the compensation. Her symptoms
      had not been correlated with the correct anatomical patterns of neurological
      deficit. The reflexes and muscle's tonus were normal and EMG gave normal
      findings. The result of neurological diagnosis, confirmed the diagnosis of
      conversion disorder causing her monoplegia because she was under psychic
      stressful circumstances from her family. Conversion disorder as a cause of
      monoplegia after surgery under spinal anesthesia should be kept in mind.

PMID- 12607274
TI  - [Does a high inspired oxygen concentration consistently play a key role in
      developing combustion in the airway during fiberoptic bronchoscopy guided laser
      treatment?--A case of firing in the airway under total intravenous anesthesia].
AB  - We experienced combustion of a fiberoptic bronchoscope and an endotracheal tube,
      as well as tracheo-bronchial burn during a diode laser treatment in a hypoxemic
      patient requiring continuous oxygen administration. Total intravenous anesthesia
      and a high concentration of inspired oxygen (FIO2 0.60) were used for the
      procedure. The complication occurred abruptly at the beginning of the second
      treatment after the first uneventful 15 min treatment. Several reports suggest
      that laser treatment can be performed even under FIO2 1.0 without firing in the
      airway, and a high FIO2 itself would not consistently play a key role in
      developing combustion in the airway, even though combustion is more vigorous when
      a higher FIO2 is used. Based on our experience and reports of firing in the
      airway during laser treatment, the following recommendations are presented. The
      laser treatment should be done (1) at the FIO2 just enough to maintain adequate
      oxygenation in each individual patient, (2) at the greatest possible distance
      between a bronchoscope and an endotracheal tube, and (3) after removing small
      pieces of carbonized tissues produced by each laser treatment.

PMID- 12607276
TI  - [Oxygen embolism after intraoperative use of hydrogen peroxide].
AB  - Hydrogen peroxide is widely used for irrigation of surgical wounds. However, its
      administration has been associated with gas embolism. We report a case of gas
      embolism after wound irrigation with hydrogen peroxide in a 11-year-old boy
      undergoing extraction of the extra-traumatic splint under general anesthesia.
      When 3% hydrogen peroxide 12 ml was applied to wound of the left femur after
      extraction of the splint, the patient showed clinical signs of pulmonary
      embolism. Symptomatic treatment was initiated immediately. When the patient awoke
      from anesthesia, he showed tonic convulsion. But he recovered without any
      complications. The administration of hydrogen peroxide into a closed tissue is
      contraindicated during surgery.

PMID- 12607277
TI  - [A case of acute myocardial infarction during laparoscopic rectal amputation].
AB  - An 80-year-old man with chronic bronchitis and hypertension was admitted with
      rectal cancer and cholecystolithiasis. Under general and epidural anesthesia,
      laparoscopic cholecysytectomy was performed with slightly elevated EtCO2. He
      underwent head-down tilt for laparoscopic rectectal amputation. Twenty five
      minutes after positioning, he developed ventricular tachycardia and died. Autopsy
      showed acute myocardial infarction super-imposed on the scar of lateral wall from
      old infarction. The laparoscopic operating techniques have become popular, but we
      do not know the safety limits of the pneumoperitoneal pressure and the angle of
      head-down tilt position. In our case, the cardiac event occurred 25 minutes after
      head-down tilt, and the head-down tilt position when combined with
      pneumoperitoneum may have a fatal influence on high-risk cardiac patients.

PMID- 12607278
TI  - [Survey Report on International Cooperation 2001--report of the Japanese Society
      of Anesthesiologists Committee on International Affairs].
AB  - A survey was conducted in November 2001 with a questionnaire entitled "Survey
      Report on International Cooperation" compiled by the International Affairs of the
      Japanese Society of Anesthesiologists (JSA). The survey focused on member
      awareness of the importance of international cooperation by sending the
      questionnaire to its entire membership. Replies were received from approximately
      15.6% of the membership or, to be exact, 1,353 JSA members. The survey produced
      several remarkable findings, which are as follows: 57.8% of the respondents are
      interested in international cooperation, 86.8% regard international cooperation
      as necessary, and 38.4% are willing to participate in international cooperation.
      Those who have actually engaged in international cooperation in the past account
      for only 7.5%, indicating that there are a good number of members who have not
      had a chance to provide assistance in international cooperation, their
      willingness notwithstanding. Regarding their employers' levels of understanding
      of this issue, 30.6% responded that their managements either recommend active
      participation or approve of the respondents' intention. Another 24.9% replied
      that their managements agreed to their participation on condition that they do so
      privately. Thus, a total of 55.5% of the respondents have permission to
      participate in international cooperation. Regarding the level of understanding
      from family members, 41.2% replied that their families agree to their desire
      irrespective of whether or not their services overseas are relevant to their
      profession. This figure became 72.4% when their services abroad would be relevant
      to their profession. On the other hand, 16.0% of the respondents (216 members)
      stated that they have no interest in international cooperation. For the reasons,
      38.8% replied that the issue cannot be viewed as a matter worthy of immediate
      attention, 10.2% replied that it is not their problem, and 24.1% replied that
      this will involve dangers. When questioned about their overall impressions from
      actual participation in international cooperation in the past, among the 102
      members responding, 88.2% said they are satisfied with what they have done, 4.9%
      were undecided as to whether or not they are satisfied, while none of them
      responded negatively about their services. Of those who are satisfied with their
      services, as many as 54.4% found their services "worthy of the time spent because
      of all the excitement involved and because each activity involved work other than
      their own profession," and 40.0% found them "worthy of their time and labor."
      Particularly noteworthy is the fact that 6.7% now consider activities in
      international cooperation "their divinely appointed work in life," and 65.7% hope
      to participate in international cooperation again. From these findings, it can be
      deduced that there are few obstacles to the members' international cooperation
      and that JSA's potential as a promoter of international cooperation may be highly
      estimated.

PMID- 12607279
TI  - [Nationwide investigation of insect allergy in patients with allergic rhinitis].
AB  - To clarify the role of insects as allergens in allergic rhinitis (AR), specific
      IgE antibodies (sIgE) to the moth, midge, and cockroach together with 10 other
      allergens were measured using sera from 560 AR patients, who visited 20
      otolaryngological clinics nationwide from Hokkaido to Kyushu. Nasal challenge
      tests were also conducted with allergen disks of these 3 insects in 65 AR
      patients. Frequencies of sIgE positive to the moth, midge, and cockroach were
      32.5%, 16.1%, and 13.4%. Frequencies of sIgE positive to these insects were not
      affected by patients' residential location, age, medication, or association with
      bronchial asthma. The prevalence of patients with positive nasal challenge
      increased depending on the RAST class to the insects. Among the patients whose
      RAST class were 3 and 4, nasal challenges with cockroach or moth extracts were
      positive in 55.6% or 61.5%. A strong correlation of sIgE titers was observed
      between the moth and midge, but the correlation between the cockroach and moth,
      and between the cockroach and midge were weak. No correlation of sIgE titers was
      found between house dust mites and these 3 insects. These results show that the
      moth, midge, and cockroach are inhalant allergens causing allergic rhinitis in
      Japan.

PMID- 12607280
TI  - [Therapeutic effect of roxithromycin on chronic sinusitis with nasal -- polyps
      clinical, computed tomography, and electron microscopy analysis].
AB  - To evaluate the therapeutic effect of Roxithromycin (RXM), we studied 56 chronic
      sinusitis patients with nasal polyps using computed tomography (CT) and electron
      microscopy in addition to conventional clinical assessment. The paranasal sinus
      of subjects was observed clinically before and after daily administration of RXM
      at 300 mg for 3 months all underwent allergy testing for possible complications
      of allergic rhinitis based on subjective symptoms and objective findings.
      Improvement after RXM treatment was seen in 50.3% based on subjective symptoms
      and 59.1% based on objective findings. Overall improvement was seen in 53.6%. In
      41 cases (73.2%) of all patients with chronic sinusitis and complications of
      allergic rhinitis, no significant difference was seen between patients with and
      without complications (53.7% in those with complications and 53.3% in those
      without). In CT analysis the paranasal sinus in 51.8% of all posttreated patients
      showed obvious improvement. In electron microscopy in chronic sinusitis patients
      with complications of allergic rhinitis, pretreated ethmoidal sinus tissues
      showed high mucous epithelial cell apoptosis in addition to common histological
      lesions, while posttreatment patients showed only eosinophil apoptosis in the
      interstitium and no apoptotic epithelial cells. We divided ethmoidal sinus
      lesions in patients without complications into 3 types and evaluated them as
      follows: In type 1, pretreated ethmoidal sinus tissues showed plasma cell
      infiltration and posttreatment cell apoptosis. In type 2, pretreated tissues
      showed lymphocyte and plasma cell infiltration and posttreated showed only some
      lymphocytes and no plasma cells. In type 3, proliferation of fibroblasts, most of
      which showed apoptosis, was seen in addition to apoptotic epithelial cells before
      treatment, while after treatment, these lesions remained with some apoptotic
      bodies phagocytosed by macrophages. In type 3 patients relapsed after surgery.
      Our findings indicate that RXM treatment had a significant therapeutic effect on
      chronic sinusitis with nasal polyps with and without complications of allergic
      rhinitis. We clarify the morphological mechanism of therapeutic effect of RXM on
      each type of ethmoidal sinus lesion divided by light and electron microscopy.

PMID- 12607281
TI  - [Study of allergic fungal sinusitis in 40 surgical cases of chronic paranasal
      sinusitis].
AB  - Allergic fungal sinusitis is chronic and paranasal, related to fungal allergy.
      Many papers on allergic fungal sinusitis have been reported in the United State,
      and the incidence is 5% to 10% among patients with chronic paranasal sinusitis.
      Although cases of allergic fungal sinusitis have been reported in Japan, the
      incidence is unclear. We studied allergic fungal sinusitis in 40 consecutive
      patients--26 men and 14 women--undergoing endoscopic sinus surgery at Keiyukai
      Sapporo Hospital December 2000 to July 2001. We checked for allergic rhinitis and
      asthma, a history of surgery for nasal polyps and chronic sinusitis, the presence
      of nasal polyps, grading of sinusitis via computed tomography, nonspecific IgE
      and allergen-specific IgE for fungi in serum, eosinophilia in nasal smears,
      paranasal eosinophilic mucin, and histology and fungal culture of paranasal sinus
      mucus. None had typical allergic fungal sinusitis, but 1 had eosinophilic
      paranasal mucin, high IgE, and false-positive IgE for fungi. We studied clinical
      data and histology of fungi and paranasal mucosa in 9 cases with fungal maxillary
      sinusitis, but none had allergy or eosinophilic mucin. This suggested that few
      patients with allergic fungal sinusitis exist among those with chronic paranasal
      sinusitis.

PMID- 12607282
TI  - [Outcome of neonatal screening for hearing loss in neonatal intensive care unit
      and well-born nursery infants].
AB  - A newborn hearing screening was conducted on 319 neonatal intensive care unit
      (NICU) and 1200 well-born nursery (WBN) infants. Mean NICU birth weight was 1997
      g and mean gestational age 34 weeks. Auditory brainstem response was studied in
      screening in NICU infants. Otoacoustic emission (OAE) or automated auditory
      brainstem response (AABR) was used in primary WBN screening. All infants not
      bilaterally passing hearing screening before discharge were recalled for
      outpatient retesting. If the outcome was still failure, ABR screening was
      conducted. The prevalence of infants diagnosed with hearing loss was 1.1% (16 of
      1519). Of these 16, 75% were from the NICU and 75% were at risk for hearing loss.
      Mean age at hearing loss identification was 12.9 weeks in the WBN and mean age at
      hearing aid fitting was 16.1 weeks. Mean age at hearing aid fitting was lower for
      WBN than for NICU infants. Hearing loss identification and hearing aid fitting
      are thus feasible in NICU and WBN infants in universal newborn hearing screening.

PMID- 12607283
TI  - [Navigation-aided surgery for congenital cholesteatoma at the petrous apex].
AB  - Computer-aided navigation in otolaryngology has been used mainly for nasal
      operation and rarely for ear surgery. The reason for its limited use in ear
      surgery appears to be that microscopic observation may be sufficient in most
      cases of ear surgery. We report a case of congenital cholesteatoma at the petrous
      apex operated on using navigation. A 65-year-old man with facial palsy, deafness,
      and canal paresis in caloric test on the left ear was found in preoperative
      computed tomograph (CT) showed a large mass at the apex with an expansively
      eroded skull base and inner ear. Navigation used for the operation was magnetic
      (Insta Trak). A probe 3.2 mm in diameter was moved in the operative field and 3
      axial CTs were simultaneously monitored on a workstation to show the tip
      location. With this image-guided system, cholesteatoma was thoroughly and safely
      removed. We concluded that navigation should be used for safe surgery, especially
      in ear surgery at the petrous apex, because anatomical identification is very
      easy and damage to vital areas around the inner ear, nerve, brain, and internal
      carotid artery could be avoided.

PMID- 12607284
TI  - [Changes in the nasal NO level, nasal resistance, and nasal patency before and
      after exercise in normal subjects].
AB  - The nasal mucosa plays an important role in human disease resistance by
      repeatedly constricting and expanding. The nasal membrane also shrinks after
      exercise and thereafter recovers gradually. We studied exercise-induced changes
      in nasal NO, nasal resistance, and a minimal cross-sectional area in normal
      subjects and discuss the role of nasal NO. Subjects were 11 healthy adults (5 men
      and 6 women 24-52 years of age). They underwent a 6-minute fixed-load treadmill
      exercise, walking about 6 km/hr for 6 minutes. The nasal NO level, nasal
      resistance, and minimal cross-sectional area were measured consecutively before
      exercise, immediately after exercise, and at 5, 10, 15, 20, 25, and 30 minutes
      after exercise. Nasal resistance is known to decrease immediately after exercise
      and thereafter gradually increases until it reaches baseline levels. The minimal
      cross-sectional area increases immediately after exercise, but returns to
      baseline levels thereafter. The nasal NO level decreases immediately after
      exercise, but does not show changes parallel to nasal resistance or minimal cross
      sectional area. The nasal NO level increases gradually, but then suddenly
      decreases at around 20 or 25 minutes after exercise. Its level thus shows 2 dips.
      This pattern is caused by a depletion of the NO substrate. As a result, NO is
      required by the various exercise-induced changes in many parts of the body. These
      findings suggest that NO production is related to the maintenance of homeostasis.

PMID- 12607285
TI  - [Social movement in the Japanese society of child neurology].

PMID- 12607286
TI  - [Tracks and perspectives of child neurology in Japan. Interview by Toshiaki Abe].

PMID- 12607288
TI  - [Usefulness of EEG recording for delirium in children with high fever].
AB  - Delirium in children associated with high fever is defined as an acute and
      transient confusional state. Clinically it is most important to differentiate
      delirium from encephalitis or encephalopathy. Electroencephalographic (EEG)
      tracings were obtained from 17 children with fever and delirium, consisting of 12
      boys and 5 girls, aged from 2 to 13 years. The initial recording was done from 2
      to 36 hours (mean: 15 hours) after the last episode of delirium. The causes of
      fever were upper respiratory infections in 14 patients, acute bronchitis in 1,
      measles in 1 and exanthema subitum in 1. The body temperature ranged from 38.0 to
      41.0 degrees C, when delirium was noticed by their parents. On 15 EEG tracings
      obtained during waking, the alpha rhythm showed a frequency normal for age, but
      it was interrupted by posterior slow waves in 2 of them. Eight tracings showed
      abnormal occipital delta activities. These slow waves were blocked by eye
      opening, and disappeared within 1 to 5 days. Two of the 6 tracings during sleep
      showed high voltage irregular slow wave bursts mixed with spikes lasting for 7
      minutes, which also disappeared within 1 to 2 days. Our results indicate that EEG
      is useful in differentiating delirium from encephalitis or encephalopathy; in
      delirium, the occipital delta waves are blocked by eye opening and abnormal
      activities disappear within a few days.

PMID- 12607287
TI  - [Serotonin 2A receptor gene polymorphism and clinical efficacy of fluvoxamine in
      children with autistic disorder].
AB  - Fluvoxamine, a selective serotonin reuptake inhibitor which modulates
      serotoninergic activities, is a useful drug for patients with an autistic
      disorder. Genetic variation of the serotonin receptor may influence the efficacy
      of fluvoxamine treatment. We studied the correlation between clinical responses
      to fluvoxamine and serotonin receptor gene polymorphism (5-HT2AR) in children
      with an autistic disorder. Eighteen patients completed a 12-week double-blind,
      placebo-controlled, randomized crossover study. Clinical global impression (CGI)
      by child neurologists and interviews for parents were assessed after 12 weeks of
      fluvoxamine treatment. Behavioral assessments consisting of 20 items by newly
      created Behavioral Assessment Scale (BAS) were obtained before as well as 6 and
      12 weeks after treatment. For genotyping of 5-HT2AR, 102 T/C polymorphism was
      analyzed by the PCR method. Seven cases of T/T, 6 of T/C and 5 of C/C were
      identified. The patients with the genotype T/C responded more favorably when
      estimated by CGI and parents' report at 12 weeks of treatment. Although not
      significant statistically (p = 0.0578), the number of improved BAS items in these
      patients were larger after fluvoxamine than placebo treatment. On analyses of
      individual BAS items, the patients with the genotype C/C showed improvement of
      unnatural facial expression, which was significant at 6 weeks, but not at 12
      weeks, of fluvoxamine treatment. In the patients with the genotype T/C, eye
      movements and emotional changes were significantly improved at 12 weeks of
      treatment. Our results suggested that genetic polymorphism of 102 T/C in the 5
      HT2AR gene may have influence on the response to fluvoxamine treatment for
      patients with an autistic disorder. Because of the small numbers of subject
      studied here, further studies are needed. The methods of fluvoxamine treatment,
      such as appropriate dosage and treatment duration, should also be clarified.

PMID- 12607289
TI  - [Juvenile myoclonic epilepsy misdiagnosed as focal epilepsy: variability of
      myoclonic seizures].
AB  - We report two male patients with juvenile myoclonic epilepsy. They had been
      diagnosed as having partial epilepsy for three years. They had various myoclonic
      seizures characterized by truncal and head torsion, stepping backward, and
      inability to reach objects, as well as asymmetric myoclonic jerks of the upper
      extremities. For early diagnosis of juvenile myoclonic epilepsy, it is important
      to take account of the variability of myoclonic seizures.

PMID- 12607290
TI  - [Three cases with severe motor and intellectual disabilities presenting the
      severest condition caused by prolonged non-convulsive status epilepticus].
AB  - Three patients with severe motor and intellectual disabilities presented
      deterioration of the activities of daily living, which was revealed to be caused
      by prolonged non-convulsive status epilepticus (NCSE). Their condition improved
      by the treatment with antiepileptics. Case 1, a 4-year-old girl with profound
      psychomotor retardation and past history of West syndrome of unknown etiology,
      became unable to sit and eat orally above age of two years. EEG showed continuous
      generalized slow spike and wave bursts indicating NCSE. Continuous intravenous
      infusion of midazolam abolished EEG abnormalities of NCSE, and she regained the
      ability of oral feeding. Case 2, a 3-year-old boy with Angelman syndrome and past
      history of West syndrome, presented decreased mental response, poor oral intake
      and somnolence. EEG showed continuous slow spike and wave bursts, indicating
      NCSE. High-dose phenobarbital therapy and continuous intravenous injection of
      vitamin B6 were effective, and remarkably improved his psychomotor activities.
      Case 3, a 3-year-old boy with Lennox-Gastaut syndrome, developed decreased
      psychomotor activity and loss of vocalization and walking. He could not sit by
      himself and became nearly bed-ridden. EEG showed very frequent generalized spike
      and wave bursts, showing NCSE. Continuous infusion of thiopental diminished NCSE,
      and he could walk again. Psychomotor deterioration in patients with severe motor
      and intellectual disabilities may be caused by NCSE, which should not be
      overlooked.

PMID- 12607291
TI  - [Two cases of Costello syndrome].
AB  - We report two unrelated cases of Costello syndrome, presenting with poor
      postnatal growth, mild mental retardation, poor feeding, curly hair, coarse
      characteristic face, loose skin, hypotonia, and cardiac involvement. Nasal
      papilloma and acanthosis nigricans were the most characteristic features of this
      syndrome. Both cases had atrial fibrilation from infancy to early childhood. One
      patient had hypertonia in the lower extremities and pes equinovarus, while the
      other had hypotonia and pes planovalgus.

PMID- 12607292
TI  - [Adverse effects of dichloroacetate in a girl with mitochondrial disorder].
AB  - We present the effects and adverse effects of dichloroacetate (DCA) in a girl
      with mitochondrial disorder. Oral administration of DCA 50 mg/kg per day, reduced
      the elevated levels of lactate to below the normal range. Treatment with DCA
      ameliorated electroencephalogram abnormalities, but caused the adverse effects
      with hepatomegaly and decreased activity, which were improved by reduction or
      withdrawal of DCA. The decreased activity may be an adverse effect on the central
      nervous system. The dosage of DCA should be adjusted for each patient.

PMID- 12607293
TI  - [A case of acute encephalitis with refractory, repetitive partial seizures
      (AERRPS) showing transient disappearance of the seizure with occurrence of choreo
      ballistic movement].
AB  - We present here a 5-year-old girl with acute encephalities with refractory,
      repetitive partial seizures (AERRPS), a new clinical entity defined by the
      following five criteria: 1. acute encephalitis with a prolonged acute phase of
      more than 2 weeks, 2. persistent partial seizures with identical phenotype both
      in the acute and recovery phase, 3. seizures frequently evolving into convulsive
      status especially during the acute phase, 4. extremely intractable, and 5. no
      causative lesion or agent is identified. Interestingly, her seizures had
      completely diminished from the fifty-sixth day of her illness with concomitant
      appearance of choreo-ballistic involuntary movements. After the 120th day of the
      illness, seizures evolved again, though the involuntary movements persisted. This
      transient disappearance of intractable seizures might provide a clue to the
      pathophysiology of seizures in AERRPS.

PMID- 12607294
TI  - [A case of hypothalamic hamartoma with refractory seizures: successful treatment
      with gamma knife surgery].
AB  - Hypothalamic hamartomas are associated with precocious puberty and gelastic
      epilepsy. The seizures are often refractory to antiepileptic medications. The
      treatment of hamartoma is not well established. We report a 3-year-6-month-old
      boy was admitted because of intractable seizures occurring several times a day.
      The findings on magnetic resonance imaging and his characteristic seizure led to
      the diagnosis of hypothalamic hamartoma. The seizures were resistant to multiple
      antiepileptic drugs, and persisted for about 3 years, during which his cognition
      deteriorated. Focal radiosurgery by a gamma knife of the hamartoma successfully
      controlled the seizures with no neurological complications, and his mental
      function improved.

PMID- 12607295
TI  - [Effects of midazolam on acute phase of stroke in two patients with mitochondrial
      encephalopathy, lactic acidosis and stroke-like episodes].

PMID- 12607296
TI  - [Home oxygen therapy for terminal lung cancer cases].
AB  - Home oxygen therapy (HOT) was introduced as part of the terminal care of 52 lung
      cancer patients attending our hospital from 1997 to 2000, all of whom
      subsequently died from their illnesses. We administered a questionnaire about HOT
      to their bereaved family members. The results confirmed that many of those
      interviewed thought that HOT improved their quality of life, but probably made
      the patients more aware of the progression of their disease. As the incidence of
      lung cancer has been increasing, lung cancer patients have begun to form an
      increasing proportion of patients receiving HOT in recent years. In addition, the
      number of patients with a PaO2 of > or = 60 torr at rest at the start of HOT has
      been increasing. It may be necessary when dealing with terminal lung cancer
      patients, in whom PaO2 can decrease rapidly over a relatively short period of
      time, to explore indication criteria for HOT different from those conventionally
      employed.

PMID- 12607297
TI  - [Clinical analysis of chronic hypersensitivity pneumonitis].
AB  - Chronic hypersensitivity pneumonitis (CHP) has a poor prognosis because of the
      difficulties in its diagnosis and treatment. Recently, we have encountered six
      cases of CHP (4 patients with the home-related type, a patient with bird
      fancier's lung, and one with flour-induced CHP), and we examined the clinical
      characteristics of these cases. Environmental provocation testing has been
      considered useful for diagnosing HP, but all patients gave negative results in
      short-term environmental exposure tests performed routinely for the diagnosis of
      HP. However, 5 patients had a positive response in long-term environmental
      exposure tests. Two patients died of respiratory failure after ten years'
      observation despite improvement of the causative environment, and were given
      steroid therapy. Radiographically and pathologically, the process of progressive
      and irreversible lesions were recognized in our series of CHP patients. The
      diagnosis of CHP should be carried out on the basis of the comprehensive findings
      including the detailed history, clinical course, radiography, and histology.

PMID- 12607298
TI  - [Dynamic analysis of airway temperature in dogs breathing cold air].
AB  - Exercise in cold, dry air induces bronchoconstriction. However, the time course
      of airway cooling during the breathing of cold air has not been investigated. In
      this study in dogs, the temperatures of tracheal gas and the tracheal wall were
      measured continuously while the animal was breathing cold air at approximately
      4.5 degrees C. The temperature of the tracheal gas decreased during the
      inspiratory phase, increase slightly early in the expiratory phase, and then
      decreased to the level at end-expiration. The lowest temperature of the tracheal
      gas decreased significantly, from 29.7 +/- 2.4 degrees C (mean +/- SD) to 25.7 +/
      2.8 degrees C. The highest temperature also changed significantly, but the
      decrease was less than 1 degree C. The lowest temperature of the tracheal wall
      decreased from 31.1 +/- 2.6 degrees C to 30.5 +/- 2.5 degrees C during cold-air
      breathing, but the difference was not significant. When a dog inspired deeply
      during a cough, the temperature of tracheal gas did not decrease linearly with
      the progression of inspiration. However, the decrease in the tracheal wall
      temperature was almost directly proportional to inspiratory volume. We concluded
      that both the tracheal gas and the tracheal wall temperatures were resistant to
      cooling with cold-air breathing. It remains uncertain whether rapid, deep
      breathing during exercise decreased the tracheal wall temperature.

PMID- 12607299
TI  - [A case of successful pulmonary embolectomy for massive acute pulmonary
      thromboembolism].
AB  - A 54-year-old man was admitted to our hospital complaining of sudden-onset
      dyspnea in shock. Chest computed tomography(CT) showed thrombi in the right main
      and left intermediate pulmonary arteries. The case was diagnosed as a massive
      acute pulmonary thromboembolism. Although his hemodynamic status was stable after
      catecholamine infusion, his dyspnea was still in progress. Emergency pulmonary
      embolectomy was performed and the life of patient was saved. It is thought that
      progressive dyspnea is an important sign of a deteriorating hemodynamic status
      and the predictive symptom indicating a surgical procedure in patients with
      massive acute pulmonary thromboembolism.

PMID- 12607300
TI  - [NSIP group III treated with the first cadaveric single lung transplantation in
      Japan].
AB  - A 43-year-old woman developed dyspnea on effort in January 1996. She was treated
      with various antibiotics but developed dyspnea and pretibial edema. She was
      referred to our hospital and admitted on February 20, 1996. On the basis of the
      clinical course and radiological findings, she was diagnosed as having idiopathic
      pulmonary fibrosis with right-side heart failure. After high-dose steroid therapy
      (methylprednisolone, 1,000 mg/day for 3 days) and the administration of a
      diuretic, oral prednisolone therapy was initiated. Her condition gradually
      recovered. To obtain a definite diagnosis, an open lung biopsy was recommended
      but the patient refused the procedure. She was discharged from the hospital and
      placed on home oxygen therapy. After her informed consent was obtained, she
      became a candidate recipient for the nationwide Central Lung Transplant
      Evaluation Committee on August 7, 1998. Her name was then listed in the Japan
      Organ Transplant Network. The patient was admitted to our hospital in October
      1998 because of respiratory failure. She underwent left lung transplantation at
      Osaka University Hospital on March 29, 2000. After the lung transplantation, she
      was discharged and is presently doing well without the need for supplementary
      oxygen. A differential diagnosis of the removed lung as nonspecific interstitial
      pneumonia (NSIP) group III or UIP was required. We finally diagnosed NSIP group
      III because of the temporal uniformity and diffuse distribution of the fibrosis.
      In this report, we also describe the background of the clinical diagnosis, the
      indications for lung transplantation and the clinical course before and after
      transplantation.

PMID- 12607301
TI  - [Acute exacerbation of interstitial pneumonia associated with active systemic
      lupus erythematosus in a patient with rheumatoid arthritis].
AB  - A 36-year-old woman with rheumatoid arthritis was admitted to our hospital for
      evaluation of newly developed active systemic lupus erythematosus (SLE). After
      hospitalization, she showed progressive respiratory failure. Chest CT revealed
      exacerbation of interstitial pneumonia, showing acute development of air-space
      consolidation and ground-glass opacity in addition to intensified reticular
      shadows. Administration of high-dose corticosteroids and cyclosporine A resulted
      in recovery from respiratory failure, accompanied by obvious improvement in the
      chest radiographs and CT, as demonstrated by the disappearance of air-space
      consolidation and ground-glass opacity. Clinically, the exacerbation of her
      interstitial pneumonia was compatible with acute lupus pneumonitis, a rare
      complication with active SLE.

PMID- 12607302
TI  - [A patient with mediastinal liposarcoma showing dedifferentiation].
AB  - A 70-year-old man visited our hospital with fever and general malaise. Chest CT
      scanning showed a large tumor shadow in the anterior mediastinum. The tumor was
      resected. It consisted of a portion rich in fat on the anterior mediastinal side
      and a solid portion on the left thoracic cavity side. Pathological examination
      demonstrated liposarcoma (myxoid type). The solid portion was considered to have
      resulted from dedifferentiation of the cystic portion. Mediastinal liposarcoma
      accounts for less than 1% of all mediastinal tumors. To our knowledge, there have
      been no previous reports of patients with myxoid-type mediastinal liposarcoma
      showing dedifferentiation.

PMID- 12607303
TI  - [A case of Japanese summer-type hypersensitivity pneumonitis: monitoring with
      serum KL-6 and examination of the phenotype of HLA].
AB  - A 55-year-old woman was admitted with a cough and fever in August. A diagnosis of
      Japanese summer-type hypersensitivity pneumonitis was made on the basis of
      radiological, serological and pathological findings, in addition to positive
      returning home provocation. Serum KL-6 was monitored during the clinical course.
      Although KL-6 fluctuated slowly in comparison with the clinical symptoms and HRCT
      findings, it was considered useful for confirming the effects of treatment. Serum
      anti-Trichosporon antibody and the phenotype of HLA were studied in both the
      patient and her asymptomatic roommate, with whom she had no blood relationship.
      Though both were sensitized immunologically, HLA-DQ 3, which was reported to be
      associated with Japanese summer-type hypersensitivity pneumonitis, was detected
      in the patient but not in her roommate. It was suggested that HLA plays a role in
      the development of this disease.

PMID- 12607304
TI  - [A case of multicentric Castleman's disease with multiple pulmonary nodules].
AB  - A 55-year-old woman visited our hospital for further examination of abnormal
      shadows on chest radiographs. Her routine chest radiograph showed two nodular
      shadows in the right lower lung field. A chest CT scan revealed other nodules,
      small patchy shadows in both lung fields, and enlargement of the mediastinal
      lymphnodes (#2, 3). Laboratory data showed polyclonal hyperimmunoglobulinemia.
      This case was initially considered on the basis of a transbronchial lung biopsy
      to be a plasma cell granuloma. However, serum gammaglobulin levels gradually
      increased, and video-assisted thoracoscopic surgery was performed to aid in
      making a definite diagnosis. Biopsy specimens revealed lymphoid follicles with
      plasma cells which were stained with both anti-kappa chain and anti-lambda chain
      antibodies. The patient was treated with prednisolone (50 mg/day), and the serum
      gammaglobulin level and the shadows on the chest CT were temporarily slightly
      improved. During the clinical course, her laboratory data and histological
      specimens were re-examined, and the final diagnosis was multicentric Castleman's
      disease.

PMID- 12607305
TI  - [An autopsy case of protein-losing enteropathy due to gastrointestinal
      amyloidosis, occurring in empyema].
AB  - On August 14, 2001, a 76-year-old woman with a history of rheumatoid arthritis
      was admitted to our hospital with fever, cough, dyspnea and diarrhea. On
      admission, her chest radiography showed pleural effusion on the right side, and
      thoracocentesis was used to diagnose empyema. The patient underwent pleural
      drainage and received antibiotics. Alpha-Streptococcus was detected in both
      aerobic and anaerobic cultures of the pleural effusion. After 2 weeks of therapy,
      her empyema had improved; but her diarrhea, which had started 1 week before
      admission, had worsened, and her hypoproteinemia had progressed. Examination of
      the fecal clearance of alpha-1-antitrypsin and biopsied rectal material revealed
      that the diarrhea was caused by protein-losing enteropathy due to
      gastrointestinal amyloidosis secondary to rheumatoid arthritis. The patient was
      treated with steroids, but developed an additional infectious disease and died on
      September 29, 2001. In this case, she suffered from various infectious diseases
      including empyema and fungus infections. It has been reported that protein-losing
      enteropathy accompanies abnormalities in the immune system, by the loss of
      immunoglobulins and lymphocytes from the gut. We therefore suspect that protein
      losing enteropathy due to gastrointestinal amyloidosis caused this patient's
      empyema.

PMID- 12607306
TI  - [Gastric mucosal injury induced by H. pylori infection].

PMID- 12607308
TI  - [Discussion for gastric cancer treatment guidelines in Japan].
AB  - The Japan Gastric Cancer Association issued the first version of Gastric Cancer
      treatment guidelines in March 2001 and those for patients in December 2001. These
      guidelines aim to reduce differences in treatment selection by institutions and
      doctors by to provide standard indication for doctors and patients. This
      guidelines show treatment indications according to the clinical stages of
      disease. If doctors are planning to offer treatments different from those in the
      guidelines, they are expected to explain the reasons for this difference to
      patients. The advantages and disadvantages of the guidelines had been discussed
      in developing committee and symposium of Japanese gastric cancer association. In
      these guidelines for patients, [there is no evidence to prevent gastric cancer by
      Helicobacter pylori eradication.]. But, many studies have yielded a positive
      relationship between Helicobacter pylori and gastric cancer. These gastric cancer
      treatment guidelines are significant in every respect, especially medical care
      and informed consent. Treatment guidelines should be revised associated with
      developments in the treatment of gastric cancer.

PMID- 12607307
TI  - [Guidelines in the management of Helicobacter pylori infection in Japan--in
      comparison with the guidelines published in other countries].
AB  - Helicobacter pylori(H. pylori) is a causative agent for chronic gastritis and is
      an important risk factor for peptic ulcers, gastric carcinomas, and gastric MALT
      lymphomas. In 2000, the Japanese Society for Helicobacter Research published a
      guideline on the diagnosis and treatment of H. pylori infection for physicians in
      routine medical practice. In this guideline, H. pylori eradication therapy is
      recommended in gastric or duodenal ulcer patients. H. pylori eradication is also
      recommended in gastric MALT lymphoma patients but the guideline says it should be
      done at specialist institutions. Considering the high prevalence of gastric
      carcinomas in Japan. H. pylori eradication for the prevention of gastric
      carcinomas should be discussed urgently.

PMID- 12607309
TI  - [Epidemiology of Helicobacter pylori infection in Japan].
AB  - The prevalence of H. pylori infection in Japan is extremely low at an early age,
      as in other developed countries, and subsequently shows a rapid increase until it
      reaches a plateau of about 70% at 50 years of age. This phenomenon is thought to
      occur because people about 50 years old were born soon after World War II and
      spent their childhood in conditions of poor hygiene. It is suggested that H.
      pylori infection leads to histological chronic gastritis regardless of the strain
      of this organism, and after that the course of the disease does depend on the
      environmental factors such as diet, duration of or age at H. pylori infection,
      the virulence of H. pylori strains, and host factors including genetic make-up in
      Japan.

PMID- 12607310
TI  - [H. pylori infection and the development of gastric cancer in Japan].
AB  - In Japan, where the incidence of gastric cancer is the highest in the world due
      to its different health care insurance system from Europe and the US, early-stage
      gastric cancer is more often discovered by endoscopy. This paper describe the
      relationship between H. pylori infection and development of gastric cancer in
      Japan. Our study shows that, during the 8 year follow-up, gastric cancer
      developed in 36 of the 1,246 H. pylori-infected patients(2.9%), but in none of
      the 280 uninfected patients. In terms of the development status of gastric cancer
      over time, our study estimated the risk of gastric cancer in H. pylori-positive
      patients to be about 5% at ten years. Epidemiologically, just as cancer of the
      liver is closely associated with hepatitis C viral infection, a majority of
      gastric cancers are known to develop from the persistent inflammation of the
      gastric mucosa caused by H. pylori infection. It is therefore considered rare for
      clinical gastric cancer to develop in uninfected patients--rigorously diagnosed
      after taking into account the possibility of false negative results occurring in
      various test methods--or, in other words, in gastric mucosa having no persistent
      inflammation.

PMID- 12607311
TI  - [Helicobacter pylori infection in gastric remnant cancer after gastrectomy].
AB  - Patients who have undergone distal gastrectomy for peptic ulcer are at higher
      risk of developing gastric remnant cancer, and chronic bile reflux is believed to
      increase the risk of cancer in remnant stomach. In remnant stomach,
      carcinogenesis may be prevented by selecting the anastomosis method with a few
      reflux of intestinal juice including a bile acid. How Helicobacter pylori(H.
      pylori) infection participate in stomal gastritis and gastric remnant cancer,
      same as early gastric cancer in the intact stomach, is attended. H. pylori
      positive rate of remnant stomach is different by examination method and a report,
      but its rate is decreased every year after gastrectomy and in particular low in
      Billroth-II(B-II) anastomosis. B-II anastomosis is followed by a significantly
      lower rate than B-1. This may reflect the role of bile reflux because bile reflux
      interferes with colonization by H. pylori. Gastric cancer excision usual increase
      complicates gastric remnant stomach and H. pylori infection, but while H. pylori
      infection lasts after gastrectomy for gastric cancer, cell proliferation increase
      in remnant stomach. In remnant stomach after gastrectomy for gastric cancer,
      while H. pylori infection continues, H. pylori infection may cause remnant
      gastritis and a second cancer of remnant stomach. H. pylori infection and bile
      reflux seem to have a synergistic effect on cell proliferation in remnant stomach
      and may explain the increased risk of gastric remnant cancer. The cancer-causing
      dominant role might changed from H. pylori infection predominance to bile reflux
      every year after gastrectomy. Furthermore, a prophylactic effect to
      carcinogenesis by H. pylori eradication therapy is expected. Eradication of H.
      pylori after gastrectomy for gastric cancer has been recommended.

PMID- 12607312
TI  - [Effect of high salt diet and Helicobacter pylori infection on gastric
      carcinogenesis].
AB  - Helicobacter pylori(Hp) infection and a high salt diet are considered important
      enhancing factors in gastric carcinogenesis. A high salt diet is considered to
      cause temporary tissue damage, alteration of the viscosity of the protective
      mucous barrier, and to facilitate colonization of Hp, resulting in gastric tumor
      progression. The high prevalence of Hp infection and high salt diets might have
      greatly affected the rates of gastric carcinogenesis, especially in Japan. In
      Mongolian gerbils treated with a chemical carcinogen, the highest incidence of
      adenocarcinoma was observed in animals with both a high salt diet and Hp
      infection. The two factors of Hp infection and a high salt might interact to
      produce gastric cancers, and thus have implications for cancer prevention.

PMID- 12607313
TI  - [cag PAI and gastric carcinogenesis-association with p53 gene mutation].
AB  - It is widely accepted that carcinogenesis is a multistep process in which
      regulation of both cell proliferation and apoptosis is disturbed. p53, which is
      considered the cellular gatekeeper for growth and division, induces apoptosis.
      Helicobacter pylori(Hp) infection is an accepted risk factor for the development
      of gastric cancer, but not all infected individuals develop gastric cancer.
      Because CagA+ Hp induces increased cell proliferation, the CagA+ strain is
      believed to play an important role in the pathogenesis of gastric cancer. We have
      reported that p53 alteration were more frequently found in the CagA+ Hp infection
      in gastric cancer patients. In this chapter, we summarized recent findings of the
      relation among p53, CagA and cag PAI.

PMID- 12607314
TI  - [The roles of H. pylori infection and K-ras gene mutation in gastric
      carcinogenesis].
AB  - To elucidate the significance of K-ras gene mutations in gastric carcinogenesis,
      we examined the mutations in gastric cancers and in Helicobacter pylori
      associated chronic gastritis(H. pylori-CG). In gastric cancers, K-ras gene
      mutations were detected in intestinal type cancers, but not in diffuse type
      cancers. K-ras gene mutations in H. pylori-CG were significantly more frequent in
      gastric cancer patients than in cancer-free patients. These data suggest that K
      ras gene mutations may be involved in the early stages of gastric carcinogenesis
      of the intestinal type. Recently, Uemura, et al. reported that H. pylori
      eradication suppressed gastric cancer development(Cancer Epidemiol Biomarkers
      Prev, 1997; N Engl J Med, 2001). Further examination is necessary to clarify the
      mechanism of suppression of gastric cancer development after H. pylori
      eradication.

PMID- 12607315
TI  - [Present state of Japanese intervention trial of H. pylori].
AB  - To prove a 'causal link' between H. pylori infection and gastric cancer, the
      intervention study called JITHP was planned in 1994 under the auspices of Second
      Term Comprehensive Strategies for Cancer Control in Japan organized by Ministry
      of Health and Welfare. Although the trial was performed by affiliated 145
      institutions scattered all over Japan, we were confronted with the difficulties
      of patients accrual for this trial. As a result, the initial two principal items
      for evaluation in this study were reduced to one. That is, we decided to conduct
      a comparative study on only prevention of the onset and progression of atrophy of
      gastric mucosa by H. pylori elimination' and not evaluate the other 'comparative
      study on the frequency of stomach cancer'. Finally, a total of 682 patients, with
      342 in H. pylori eradicated group and 340 in un eradicated group were enrolled.
      The final outcome of this trial will be obtained in March 2004.

PMID- 12607316
TI  - [Mechanism of Helicobacter pylori induced stomach carcinogenesis--analysis using
      animal models].
AB  - Helicobacter pylori is known to infect a half of the world's population and has
      been closely linked to an increased risk of the development of gastric
      adenocarcinoma, making it a pathogen of potentially great significance. The
      IARC/WHO in 1994 designated H. pylori a class I carcinogen based on
      epidemiological evidence. A direct association between H. pylori infection and
      the induction of gastric carcinoma has been recently demonstrated in a Mongolian
      gerbil model with use of chemical carcinogens, giving further credence to the
      role of this organism as a promoter in gastric carcinogenesis. However, the exact
      mechanisms underlying the link between H. pylori infection and gastric
      carcinogenesis still remain to be elucidated. To approach this issue, it is
      necessary to find environmental factors and to clarify genetic events during
      carcinogenesis in in vivo models.

PMID- 12607317
TI  - [Histological diagnosis of Helicobacter pylori using biopsy specimens].
AB  - Helicobacter pylori(H. pylori) are an organism that can be confidently recognized
      by histology. Using histological specimens, we can both identify infection and
      assess pathological condition associated with H. pylori. For the precise
      diagnosis, biopsies should be taken from suitable sites(greater curvature of
      antrum and corpus) and the valuable requirements are to recognize several
      pathologic findings of H. pylori--infected gastric mucosa(epithelial changes and
      neutrophilic infiltration together with mononuclear cell infiltration) and to use
      special staining methods for H. pylori(i.e. Giemsa staining, Gimenez staining,
      silver staining, and immunostaining) in addition to HE staining.

PMID- 12607318
TI  - [13C-urea breath test].
AB  - Infection with Helicobacter pylori(H. pylori) is thought to be an important
      factor in the pathogenesis of gastritis, peptic ulcer and gastric cancer, and the
      13C-urea breath test (13C-UBT) is a convenient and non-invasive method for the
      detection of H. pylori in the stomach. We have examined the sensitivity,
      specificity and accuracy of 13C-UBT, comparing it with histology. The 13CO2/12CO2
      ratio was measured by using infra-red spectroscopy(IR) and gas
      chromatography/mass spectrometry(GC-MS). The IR analyzer should be particularly
      useful for the diagnostic test of H. pylori infection using 13C-UBT.

PMID- 12607319
TI  - [Rapid urease test].
AB  - Rapid urease test(RUT) is one of the invasive methods for detection of H. pylori
      infection. H. pylori in the biopsy specimen splits the urea to ammonia in the
      test container. Elevation of pH by ammonium hydroxide are detected as color
      change of pH indicator. The advantage of RUT are low-priced, easy-to-use, and
      rapid time to diagnosis. The disadvantage of RUT are necessity of endoscopy
      performance and occurrence of false negative. RUT is useful for diagnosis of H.
      pylori infection before and after eradication treatment. However, the sensitivity
      of RUT is comparatively low within 6 months after completion of eradication.

PMID- 12607320
TI  - [The antimicrobial susceptibility test of Helicobacter pylori].
AB  - Now that treatment of H. pylori associated disease is becoming common in Japan,
      drug resistant--H. pylori has emerged as a problem to be solved. There is no
      standard method of H. pylori drug susceptibility test in Japan yet. There are
      several methods available: Disk test, E-test, microplate method and agar plate
      dilution method. The E-test is being the standard method in European countries
      and USA. However the microplate method has been reported as a same accuracy as
      the agar dilution method, and thought as being a new standard method in Japan. In
      2000, The Japanese Society of Chemotherapy proposed that drug susceptibility test
      be standardized and listed the break point of MIC of amoxicillin(AMPC) and
      clarithromycin(CAM).

PMID- 12607321
TI  - [Culture method for H. pylori].
AB  - In the five diagnostic tests for H. pylori infection recommended by the Japanese
      guideline, culture method may be the most difficult in clinical use, because of
      taking 3 to 5 days for growth, requiring a lot of skill and equipment, and having
      a possibility of false negative. On the other hand, it has merits of having a
      specificity of 100%(direct demonstration of the presence of H. pylori), allowing
      further investigation of the organism (determining its sensitivity to
      antibiotics, investigating its virulence factors, and typing it for
      epidemiological purposes). This method is necessary for the cases in whom strains
      are needed its sensitivity to antibiotics. Considering of increase of CAM
      resistant H. pylori in the future, culture method should be necesary in the
      diagnosis of H. pylori.

PMID- 12607322
TI  - [Detection of H. pylori by serum and urine-based ELISA].
AB  - Detection of H. pylori infection by serum antibody to H. pylori using ELISA is a
      popular method. Several ELISA kits are available in Japan. However, the
      sensitivity and specificity of ELISA kits are different among these kits.
      Recently urine-based ELISA kit for detection of antibody to H. pylori has been
      developed in Japan. It has been reported that the sensitivity and specificity of
      ELISA may be higher using the Japanese strain of H. pylori as antigen.

PMID- 12607323
TI  - [Serum pepsinogen I/II ratio test].
AB  - Serum pepsinogen levels were measured in 137 stomach cancer patients and compared
      with those of 288 normal cancer-free subjects. The serum pepsinogen levels of
      stomach cancer patients, especially pepsinogen I and the pepsinogen I/pepsinogen
      II ratio were significantly lower than those of normal controls and correlated
      well with the extent of chronic gastritis associated with the cancerous stomach.
      These results were in good accordance with the results of previous studies
      indicating that the cancer derived from the stomach where chronic
      gastritis/intestinal metaplasia is extensive. The initial step of the screening
      procedure can be completed rapidly. Our results indicate that serum pepsinogen
      screening(pepsinogen test method) is a valuable method to detect gastric cancers
      in the Japanese population.

PMID- 12607324
TI  - [Indication of H. pylori eradication therapy].
AB  - In the guideline, for H. pylori the Japanese Society of Helicobacter published
      diagnosis and treatment in July 2000. Only peptic ulcers and low grade MALT
      lymphomas are recommended as an indication of H. pylori eradication and other
      diseases such as atrophic gastritis, post EMR state for early gastric cancer and
      post-operated stomach due to gastric cancer, hyperplastic polyps and non-ulcer
      dyspepsia, were not included. In addition, Japanese social security foundation
      approves only peptic ulcers for indication of H. pylori eradication treatment.
      However, eradication therapy for atrophic gastritis should be considered in
      aspect of decreasing gastric cancer risk. Since accumulated epidemiological,
      experimental and clinical data strongly support its positive correlation with
      cancer risk, patients in high risk group for gastric cancer should be included
      for a target eradication therapy. Indication of the treatment should be expanded
      to histological gastritis caused by H. pylori in our country, where prevalence of
      gastric cancer is very high.

PMID- 12607325
TI  - [Suitable diagnostic methods for H. pylori infection after eradication therapy].
AB  - Urease test, histology, culture, urea breath test(UBT) and stool antigen test are
      accurate tests for Helicobacter pylori diagnosis. General practitioners are now
      going to test peptic ulcer disease patients with these tests before and after in
      Japan. To test with high accuracy after eradication therapy, it is important that
      examination should be done over 4 weeks after cessation of treatment with PPI and
      antibiotics. UBT and stool antigen test are suitable tests for diagnosis of
      Helicobacter pylori infection after treatment.

PMID- 12607326
TI  - [New triple therapy for Helicobacter pylori infection in Japan].
AB  - In Japan, a phase 3 trial of 1-week triple therapy with lansoprazole(L),
      amoxicillin(A), and clarithromycin(C) was finished in March, 2000. Patients were
      randomized into three groups: L 30 mg bid and placebos, and L 30 mg bid, A 750 mg
      bid and C 200 mg bid or 400 mg bid. Eradication rates were high in group
      LAC200(88-91%) and group LAC400 (84-89%). Next, a phase 3 trial of 1-week triple
      therapy with omeplazole (O), A and C was finished in 2001. Eradication rates were
      78.8% in the group of O 20 mg, A 750 mg and C 400 mg bid, and 83.0% in the group
      of O 20 mg, A 1,000 mg, and C 500 mg bid.

PMID- 12607327
TI  - [A strategy for second-line anti-Helicobacter pylori therapy in eradication
      failure patients].
AB  - Although available H. pylori eradication regimens in Japan fail to cure 10-20% of
      patients, an optimal re-treatment therapy for eradication-failure patients has
      still not been established. Since patient compliance, bacterial resistance and
      genotypic differences in CYP2C19 influence the eradication rate, re-eradication
      therapy should be selected, taking them into consideration. In the West, meta
      analysis of the second-line treatment of H. pylori infection showed therapies
      comprising ranitidine bismuth and two antimicrobials are very effective re
      treatment therapies irrespective of factors influencing H. pylori eradication.
      However ranitidine bismuth is not available in Japan and re-eradication therapy
      consisting of PPI, amoxicillin and metronidazole have been often undertaken and
      have achieved high eradication rate, even including patients with metronidazole
      resistant H. pylori.

PMID- 12607328
TI  - [Problems occurred after Helicobacter pylori eradication and their
      countermeasures].
AB  - Acute esophagogastroduodenal mucosal lesions are the demonstrable adverse events
      occurred after H. pylori eradication. In our study, acute duodenal erosions were
      observed in 13.5% of the eradicated patients. Duodenal erosions which occurred
      mainly at the early phase after eradication were temporal and asymptomatic. Acute
      gastric erosion showed the same clinical manner. However, it needs to pay
      attention for rare occurrence of acute ulcers with severe symptoms. On the other
      hand, mild but persistent reflux esophagitis occurred at relatively late phase
      after eradication. Their occurrence rates were 9.8% after 1 year and 11.4% after
      3 years. Acute mucosal lesions occurred probably due to the increase of acid
      output accompanied with the recovery of gastritis. Symptomatic treatment with
      antacids were need occasionally for acute ulcer and reflux esophagitis.

PMID- 12607329
TI  - [The prospects of vaccination against H. pylori infection].
AB  - H. pylori causes numerous gastroduodenal diseases including malignancies.
      Although eradication of H. pylori using antibiotics is clinically performed, it
      is sometimes unsuccessful because of resistant bacteria and patient non
      compliance with treatment. Therefore prophylactic and therapeutic vaccination
      against H. pylori infection is necessary for clinical use but it is still under
      study. H. pylori is widely believed to be transmitted in childhood. If long and
      chronic H. pylori infection causes gastric cancer, vaccination should be targeted
      at children for the prophylaxis of cancer. Systemic immunization with aluminum
      hydroxide which has been already proved to be safe for human child, deserve
      attention.

PMID- 12607330
TI  - [Tailor-made medicine in Helicobacter pylori eradication therapy].
AB  - Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with
      the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly
      different from the homozygote, but there was no statistically significant
      difference. The CYP2C19 genotype dependence found for lansoprazole was not
      obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile
      was independent of the CYP2C19 genotype. CYP2C19 genotyping can provide a new
      strategy to choose an optimal regimen, and this genotyping is especially useful
      for Japanese, as the frequency of poor metabolizers is five times greater than
      that found among Caucasians. However, we should be aware that the increase of
      antimicrobial-resistant strains of H. pylori may force us to examine
      antimicrobial susceptibility of all patients in order to achieve a more than 80%
      eradication rate at first-line therapy in the near future. We should also have
      proper knowledge of the influence of the CYP2C19 genetic polymorphism on
      treatment efficacy according to the variety of PPI and the combination with other
      drugs.

PMID- 12607331
TI  - [The present status and problems of Helicobacter pylori eradication therapy with
      a special reference to gastric cancer].
AB  - Since the eradication therapy of Helicobacter pylori(H. pylori) for peptic ulcer
      was covered by Japanese health insurance at 2000 November, this therapy has been
      generalized in Japan. However, some problems have cropped up at the time, for
      example, emergence of clarithromycin resistant bacterium etc. On the other hand,
      investigation of relation between H. pylori and gastric cancer is making
      progress. Uemura, et al. demonstrated H. pylori had an important role for gastric
      carcinogenesis by the elegant prospective study in 2001. Under the present
      circumstances, the Japanese society of Helicobacter Research has to reconsider
      the guideline for eradication therapy. In this paper, we would like to state the
      present status and problems of eradication therapy of the current guideline for
      eradication therapy, especially focusing on gastric cancer.

PMID- 12607332
TI  - [Economic evaluation of H. pylori eradication].
AB  - A review of economic evaluation studies of Helicobacter pylori eradication was
      performed. As a result of the high quality and quantity of data emerging, the
      eradication therapy for patients with gastric or duodenal ulcer was considered to
      be less costly and more effective than conventional therapy in a Japanese
      clinical setting. Furthermore, population-based Helicobacter pylori screening was
      seemed to have the potential to produce important health benefits at a reasonable
      cost, especially in Japan. Controlled studies are needed to quantify the impact
      of Helicobacter pylori eradication on the risk of gastric cancer to confirm it.

PMID- 12607333
TI  - [A new horizon of tuberculosis control and research].
AB  - In the 1990s, tuberculosis (TB) came to be recognized as one of re-emerging
      diseases and as a serious health issue worldwide. This has brought about many
      innovations for TB control and care. These include a series of bacteriological
      examination methods based on the nucleic acid amplification, immunological
      diagnostics for TB infection or active disease. The completion of the whole
      genome analysis of Mycobacterium tuberculosis opened the way to the development
      of novel modalities for therapeutics, diagnostics and vaccines. For TB control,
      WHO developed the DOTS strategy as a standard TB treatment programme that has
      been being expanded globally, in both developed and developing nations. Japan's
      TB control programme is being revised drastically in order to meet the change in
      the TB epidemiology, aiming at realization of the DOTS concept adapted into the
      Japanese setting of patient care.

PMID- 12607334
TI  - [Clinical evaluation of the cause of death in patients with active pulmonary
      tuberculosis].
AB  - We made a clinical analysis of the cause of death of forty deceased patients with
      active pulmonary tuberculosis who were admitted to Kawasaki Medical School
      Hospital, Kawasaki Medical School Kawasaki Hospital, and Asahigaoka Hospital
      during the period from January 1996 to December 2001. The age of 40 deceased
      patients (29 males/11 females) ranged from 55 to 93 years old, and were mostly
      bedridden. Underlying diseases existed in all except one case, and they were
      respiratory diseases in 9 patients and non-respiratory diseases in 34 patients.
      Laboratory findings revealed poor nutritional conditions. The diagnosis of
      pulmonary tuberculosis was established within one month from the appearance of
      symptoms in over half of these patients because most of them were smear positive
      for Mycobacterium tuberculosis. None of the strains of Mycobacterium tuberculosis
      isolated from these patients were multidrug resistant for antituberculous drugs
      and only one strain was completely resistant for Rifampicin. Radiological
      findings of the tuberculosis were bilateral in 30 patients. Consolidation shadows
      without cavity were noted in 22 patients, and extension within the unilateral
      lung field was observed in 24 patients. Regarding the cause of death, advanced
      pulmonary tuberculosis was the cause in 17 patients and non-tuberculous diseases
      were the cause in 23 patients. There were 15 patients with bacterial
      superinfections such as bacterial pneumonia, 4 with malignancy, and 4 with other
      disease. The number of pulmonary tuberculosis patients in poor general and
      nutritional condition has been increasing with the aging of the Japanese
      population. Treatment for pulmonary tuberculosis has been successful in most
      cases, however, the number of the deaths unrelated to tuberculosis including
      those due to bacterial superinfection has been increasing. Therefore, treatment
      should be considered against resistant microoganisms such as MRSA.

PMID- 12607335
TI  - [Smear-positive pulmonary tuberculosis diagnosed in a general hospital].
AB  - In Japan, patients with smear-positive pulmonary tuberculosis (SPTB) are
      hospitalized in a sanatorium because of the law for the prevention of
      tuberculosis, and not in a general hospital. According to our experience,
      however, some of the patients with SPTB are hospitalized in a general hospital.
      In order to study if it is possible to prevent the admission of patients with
      SPTB to a general hospital, we retrospectively reviewed and compared the medical
      records of pulmonary TB patients whose sputum was smear-positive for
      Mycobacterium tuberculosis at our outpatient clinic (Group B; n = 61), and
      patients whose sputum was smear-positive after the admission to our hospital
      (Group A; n = 17). The Group A patients were significantly older than the Group B
      patients [mean age, Group A, 67 years vs Group B, 56 years; (p = 0.01)]. Compared
      with the Group B patients, the Group A patients more often suffered from
      underlying diseases [percentage of patients with underlying disease, Group A,
      88.2% vs Group B, 37.7%; p < 0.001]; more often showed atypical infiltrative
      patterns of pulmonary tuberculosis [percentage of cases showing atypical chest
      roentgenograms, 70.6% vs 19.7%; p < 0.001]; and were in a more serious condition
      [percentage of deaths during treatment, 47.1% vs 1.7%; p < 0.001]. We conclude
      that hospitalization of SPTB patients in general hospitals is inevitable, because
      SPTB can not always be accurately diagnosed before admission, and because it is
      sometimes difficult to send severely ill SPTB patients to a sanatorium which is
      inconveniently located in the countryside. We propose to provide facilities for
      the treatment of SPTB at all general hospitals in Japan.

PMID- 12607336
TI  - [Molecular epidemiologic study of tuberculosis--a study on isolates of M.
      tuberculosis in southern half of Osaka Prefecture].
AB  - Restriction fragment length polymorphism, RFLP or DNA fingerprinting technique
      provides a very useful tool for the study of epidemiology of tuberculosis
      transmission in human. We performed RFLP analysis with the IS6110 insertion
      sequence of the organisms isolated from culture-positive patients who visited our
      Hospital during the period from January to December 2001. Our Hospital covers
      patients living in southern half of Osaka Prefecture including a part of Osaka
      City, which is the highest TB prevalence area in Japan. The number of copies of
      IS6110 per isolate ranged from 1 to 21. Most isolates (67%) carried 10 to 15
      copies. Of 410 available isolates during the year of 2001, 131 (32%) belonged to
      a cluster and 279 (68%) did not. The clusters comprised one matching isolate in
      minimum to 13 isolates in maximum and had a total of 49 distinct RFLP patterns.
      The average age of the clustered cases was 52.1 years and 64% cases belonged to
      patients with ages younger than 60 years. Above findings suggest that many cases
      of tuberculosis in southern part of Osaka Prefecture result from recent
      transmission. It remains to be elucidated, however, how and where these recent
      infections occurred in these clustered cases.

PMID- 12607337
TI  - [A study on low performance status cases of pulmonary tuberculosis in the
      elderly].
AB  - The subjects consisted of 42 patients aged over 60 years, whose performance
      status (PS) was grade 3 or 4, and who had been admitted for pulmonary
      tuberculosis at National Chiba-Higashi Hospital between 1997 and 1998. The
      average age (+/- SD) of the 34 men and 8 women was 77.6 (+/- 8.5) years (range,
      60-91 years). The mean stay in the hospital of the improved patients was 166.6
      days (range, 57-303 days), and the mean survival period from admission to death
      was 43.4 days (range, 2-179 days in died patients). On admission to our hospital,
      26 cases were sputum smear positive, 8 cases were smear negative and culture
      positive, and 8 were negative both on smear and culture. The cavity was observed
      in 30 cases (71.4%) on the chest X-ray. The laboratory data on admission revealed
      low nutritional condition. The mean serum total protein, albumin, and cholesterol
      level on admission were 6.2 (+/- 0.82) g/dl, 2.7 (+/- 0.62) g/dl, and 143.0 (+/-
      41.9) mg/dl. Most of the patients had a difficulty in taking foods, and 20 cases
      (47.6%) were performed parenteral nutrition by central venous catheter. 23 cases
      (54.8%) received oxygen therapy by facial mask or nasal tube. The most common
      cause of low PS on admission was pulmonary tuberculosis in 14 cases (33.3%),
      followed by cerebrovascular diseases in 11 cases, and orthopedic disease in 8
      cases. The proportion of patients whose cause of low PS was not due to lung
      tuberculosis increased with age. Observing the mortality by the route of
      administration of antituberculosis medications on admission, 19 (55.9%) of 34
      cases who could take drugs per oral route died. One (50.0%) of 2 cases who were
      administered drugs through gastric tube died, and all (100.0%) of 5 cases who
      could not take drugs per oral route and were injected isoniazid and streptomycin
      died. One case who could not administer any drug died. 16 cases improved and 26
      cases died, of whom the most common cause of death was pulmonary tuberculosis in
      11 cases (42.3%), followed by bacterial pneumonia in 5 cases, and cerebrovascular
      disease in 3 cases. The mortality by the PS on admission were as follows: 10
      (47.6%) of 21 cases with PS 3 died. 16 (76.2%) of 21 cases with PS 4 died. 16
      (6.4%) of 249 cases aged over 60 years with PS 0, 1 or 2, and were admitted for
      pulmonary tuberculosis at the same hospital during the same period died. This
      study confirms that the prognosis of low performance status patients of pulmonary
      tuberculosis in the elderly was significantly poor. We have to detect
      tuberculosis patients in the early stage, and give them antituberculosis
      medications per oral route as far as possible.

PMID- 12607338
TI  - [A case of Pneumocystis carinii pneumonia during treatment for miliary
      tuberculosis].
AB  - A 30-year old man of Myanmar origin was admitted to our hospital because of
      productive cough, anorexia, weight loss and fever. Sputum smear was strongly
      positive for M. tuberculosis (Gaffky 6) and sputum culture proved M.
      tuberculosis. Caseous necrosis with Langhans giant cells was observed in the
      biopsied specimens of the liver and bone marrow. He was diagnosed as miliary
      tuberculosis. Treatment with combined use of isoniazid, rifampicin, ethambutol
      and streptomycin was started. After one month, his cough resolved, fever subsided
      and chest X-ray findings improved. Two months later, non-productive cough and
      fever recurred. Chest radiograph and computed tomographic scan of the chest
      revealed diffuse ground-glass opacity. Specimens taken by transbronchial biopsy
      showed pneumocystis carinii in alveoli. Pulsed use of methyprednisolone with
      Trimethoprim-sulfamethoxazole was started. The symptoms and chest X-ray findings
      disappeared and he recovered uneventfully. Tests for HIV infection were negative.
      Anti-HTLV antibody was negative. There were no other suggestive evidences of
      immune suppression. CD4+T cell count was low, when Pneumocystis carinii pneumonia
      occurred. The relation between miliary tuberculosis, Pneumocystis carinii
      pneumonia and CD4-T lymphocytopenia has remained unelucidated.

PMID- 12607339
TI  - [Medical risk factors of tuberculosis and countermeasures].
AB  - We describe the actual situation of and measures for medical risk factors of
      tuberculosis in compromised hosts and elderly people. Cases of diabetes mellitus,
      collagen disease and lung cancer administered corticosteroid preparations are
      taken up as compromised hosts. The frequency of TB patients having diabetes
      mellitus concurrently tends to increase, and the relative risk of diabetics
      developing tuberculosis is also high. Physicians giving diagnosis and treatment
      of diabetes mellitus should understand that diabetics belong to the high risk
      group of developing tuberculosis and perform chest X-ray examination
      periodically. In order to prevent the development of tuberculosis from diabetics,
      it is considered preferable to give chemoprophylaxis where there is no history of
      TB treatment and healing of TB has been found on the chest X-ray films. Where
      corticosteroid preparation, more than 10 mg in terms of prednisolone is
      administered over a long period of time for collagen diseases except rheumatoid
      arthritis and lung cancer, chemoprophylaxis is considered desirable. As for the
      present situation of the elderly TB patients among in-patients at our hospital,
      the elderly often had serious complications, their prognosis was poor and they
      often died of the diseases other than tuberculosis. To strengthen the measures to
      deal with tuberculosis in the elderly, early discovery and prophylaxis of
      pulmonary tuberculosis are considered. For the early discovery when the patient
      is symptomatic, the examination of sputum along with chest X-ray examination is
      important. As for the periodical health examination, the patients with the risk
      of infection to those around them being high need to undergo the health
      examination for sure. As the prophylactic measures, chemoprophylaxis is
      recommended where there is no history of TB treatment and healing of tuberculosis
      has been found on chest X-ray films.

PMID- 12607340
TI  - [Treatment for multidrug-resistant tuberculosis in Japan].
AB  - INTRODUCTION: Multidrug-resistant (MDR) tuberculosis is now refractory against
      standard chemotherapy for tuberculosis. The curability of medical treatments for
      it has been up to 50-75%. In Japan several hundreds new MDR tuberculosis cases
      are supposed to occur every year. This review is the outline of Japanese
      preliminary guideline of treatment for MDR tuberculosis. DRUG SUSCEPTIBILITY
      TEST: One of the most important points to manage MDR tuberculosis is the drug
      usages according to drug susceptibility. Recently some susceptibility tests with
      liquid media were introduced in our country, but Japanese new standard test of
      Ogawa method (using absolute concentration with proportion method) is still
      important from point of true evaluation of susceptibility. MEDICAL CHEMOTHERAPY:
      In MDR tuberculosis one-half of two-third cases are cured by suitable resume of
      anti-tuberculosis chemotherapy. If patients would prove to be suffered from MDR
      tuberculosis, chemotherapy resume must be changed from standard resume to special
      one, that are made from effective and stronger four or five (at least three) anti
      tuberculosis drugs including new quinolons. Those drugs should be changed at the
      same time, not one by one. Although CPM and Tb1 cannot be available in Japan, but
      sometimes we have to try administrations of those drugs, beta-lactam antibiotics,
      interferon. The duration of treatment will be 18-24 months usually. If decreasing
      of tuberculosis bacilli in sputa is failed under new effective resume through
      four months treatment, surgical treatment may be indicated. SURGICAL TREATMENT:
      (1) In Fukujuji Hospital, Japan Anti-Tuberculosis Association, surgical
      treatments for seventy four cases of MDR tuberculosis were undergone from 1983 to
      2001 March. 85 surgical interventions for them were performed in 71 pulmonary
      resections (pneumonectomy in 20, lobectomy in 44, segmentectomy in 7) for 64
      cases, 8 thoracoplasties alone for 8 cases, 5 cavernostomies for 5 cases, 1
      phrenic nerve avulsion for 1. The result of pulmonary resections was as follows;
      early negative conversion rate of tuberculosis expectorations was 97.2%,
      reexpectoration rate of sputa tuberculosis bacilli was 13.8%, final success rate
      of pulmonary resections was 91.7%. The factors significantly correlated to
      reexpectoration of tuberculosis bacilli were preoperative positive bacilli in
      sputa, few sensitive drugs, other cavitary lesions remained, postoperative
      prolonged bronchopleural fistula. The result of thoracoplasty alone revealed 75%
      success rate. In postoperative complications of 85 interventions, there was no
      operative death, prolonged bronchopleural fistula in 17.6%, respiratory failure
      in 8.7%, pyothorax in 5.9%. (2) Recently results of surgical treatment for MDR
      tuberculosis were reported in several literatures. Those success rates were
      almost same 85-95% as our result. They seemed to be very excellent for refractory
      cases against vigorous medical treatments. So any surgical treatment for MDR
      tuberculosis should be indicated more constructively in its earlier course. (3)
      Indication of surgical treatment is as follows; Main target lesions that should
      be removed are cavitary ones in pulmonary or pleural foci. And any capsulated
      localized tuberculosis foci more than 2 cm in diameter is better to be resected
      because of the possibility of later cavitation. Surgically it is the best that
      all tuberculosis foci are within a resected lobe, effective drugs remained as
      many as possible and no cardiopulmonary risks. But even if patient's state are
      over those criteria, resections of more extended pulmonary foci including in
      opposite sides can be tried within tolerable cardiopulmonary function. OTHER
      COMMENTS: Treatment for HIV-positive MDR tuberculosis and protection for
      nosocomial transmission of MDR tuberculosis are discussed briefly in this
      article. Preventive therapy for newly infected persons with MDR tuberculosis is
      controversial. At this time just in MDR tuberculosis cases no preventive therapy,
      careful following up, and drastic treatment with remained effective drugs after
      developping of disease will be recommended.

PMID- 12607341
TI  - [Diagnosis and treatment of pulmonary nontuberculous mycobacteriosis].
AB  - Pulmonary non-tuberculous mycobacteriosis in Japan occurs more than about 5,000
      cases annually. Among them, about 70% are occupied by Mycobacterium avium complex
      (MAC) infection. Considering the frequency and the difficulty of treatment, we
      discuss mainly on pulmonary MAC infection on this report. At National Tokyo
      hospital, secondary MAC infection after tuberculosis sequelae were 46.5% out of
      170 pulmonary MAC cases since 1969 to 1985, but it decreased to 19.4% out of 268
      cases since 1986 to 2000. In this same period, a type of MAC infection like
      middle lobe syndrome without recognizing preceding pulmonary disease, increased
      to 69.8% out of all pulmonary MAC cases (Fig. 1). Recently, this type of
      pulmonary MAC infection, which consists with scattered nodular lesion and local
      bronchiectasis in middle lobe or lingula, attracts attention. Why is there much
      frequency in women? Why does it originate from middle lobe or lingula? Although,
      it shows a characteristic X-ray pattern, ant it is still an interesting problem,
      the origin of the disease cannot be clarified. First diagnostic standard of
      nontuberculous mycobacteriosis in Japan was submitted in 1967, and the current
      diagnostic standard was made in 1985, through several times improvements. These
      contents are almost similar to that of American diagnostic standard in 1997, but
      the new revision that reflected chest CT findings and bronchoscopic sampling etc,
      is pressed now. In the treatment, INH or PZA, which is a key drug in tuberculous
      chemotherapy, is not a key drug in MAC chemotherapy. MAC chemotherapy is
      multidrugs combination chemotherapy including EB, CAM, RFP, and aminoglycosides.
      However, it is difficult to achieve complete regression with current drugs
      combinations, and an early surgical resection is the most effective in case of
      localized MAC lesion. We propose a guidance of treatment selection with age and
      disease severity (Table). Fig. 2 shows survival curves of 104 cases pulmonary MAC
      infection at National Tokyo Hospital.

PMID- 12607342
TI  - [New diagnostic methods for tuberculosis and their clinical utilities].
AB  - The clinical utilities of new diagnostic methods for Mycobacterium tuberculosis,
      such as primary isolation and drug susceptibility testing using MGIT,
      identification using anti-MPB 64 monoclonal antibodies and nucleic acid
      amplification assay, were studied. It was shown that these new diagnostic methods
      were more rapid and more accurate than currently available approaches and useful
      for the early and aggressive case findings. Questionnaire survey indicated that
      most of the laboratories had been ready to introduce these new diagnostic
      methods. Thus, the diagnosis for active tuberculosis along the "CDC
      recommendation in 1993" has become realizable in Japan. Now, Japanese TB control
      program is under revision due to the current stagnation of the decline in
      notification rates. The importance of rapid and accurate diagnosis of active
      tuberculosis should be declared in the new Japanese TB control program by
      indicating the guideline of rapid diagnostic methods for Mycobacterium
      tuberculosis.

PMID- 12607343
TI  - [Current topics on classification and nomenclature of bacteria. 15. Candidatus-
      the provisional status for prokaryotes that were not yet cultivable].

PMID- 12607344
TI  - [A rapid screening method for the detection of E. coli O157 by an automated
      enzyme-linked fluorescent immunoassay].
AB  - VIDAS ECO is useful as a rapid method for detecting E. coli O157 from food
      samples, because one can obtain the results within 1 hour by examining the
      enrichment broth after a 18 hour incubation. In addition, one can handle a large
      amount of sample, owing to its simplicity. No false negative were recognized in
      the present experiment and diffuse outbreak samples cases, which confirmed the
      usefulness of ECO as a screening method. Besides, regarding ECO positive samples,
      we could confirm by the following day, that they were false positive, by a
      combined test using an isolation medium after a bead-enzyme-linked immunosorbent
      assay.

PMID- 12607345
TI  - [Evaluation of Streptococcus pneumoniae-urinary antigen detection kit in patients
      with community acquired pneumonia].
AB  - We evaluated a new rapid urinary antigen detection kit. NOW Streptococcus
      pneumoniae (Binax Inc., USA) that detected S. pneumoniae antigen by
      immunochromatographic membrane assay, with 66 Japanese adult patients of
      community acquired pneumonia. Twenty-two (33.3%) patients were found to be
      positive with the kit and S. pneumoniae was isolated from six patients (27.3%) of
      these 22 patients. S. pneumoniae was not isolated from eight of the 22 patients
      by blood or sputum culture. Analysis of clinical laboratory data showed that the
      levels of C-reactive protein (CRP) in the serum were significantly higher in the
      urine-antigen positive group than those in the urine-antigen negative group.
      There were no significant difference between the two groups including renal
      function, urinalysis, clinical symptom, and severity of pneumonia. Our study
      suggests that more cases of community acquired pneumonia are caused by S.
      pneumoniae than conventional tests can currently confirm. Since it is not
      technically complex, does not require equipment, and detects within as quickly as
      in 15 minutes, the S. pneumoniae urinary antigen kit is useful for rapid
      diagnosis of community acquired pneumonia in adults.

PMID- 12607346
TI  - [The utility of the Pneumonia PORT prediction rule for evaluating the severity of
      community-acquired pneumonia in Japan. The relationship between disease severity
      and drug-resistant Streptococcus pneumoniae].
AB  - To examine the utility of the Pneumonia PORT prediction rule for evaluating the
      severity of community-acquired pneumonia (CAP) in Japan, 127 consecutive patients
      with CAP admitted during one-year period were recruited and stratified by the
      rule. The relationship between CAP severity determined by the rule and drug
      resistant Streptococcus pneumoniae was also investigated. The number of the
      patients classified into each class was 20 (15.7%) in class I, 32 (25.2%) in
      class II, 32 (25.2%) in class III, 31 (24.4%) in class IV, and 12 (9.4%) in class
      V, respectively. Risk class-specific mortality rate was 0% in class I and II,
      3.1% in class III, 3.2% in class IV, and 41.7% in class V, respectively. Twenty
      seven patients (21.3%) were diagnosed as pneumococcal pneumonia. In terms of
      penicillin-susceptibility of Streptococcus pneumoniae, 19 strains (70.4%) were
      penicillin-susceptible Streptococcus pneumoniae (PSSP). Five (18.5%) were
      penicillin-intermediate Streptococcus pneumoniae (PISP), and 3 (11.1%) were
      penicillin-resistant Streptococcus pneumoniae (PRSP). Highly resistant
      pneumococci with penicillin MIC > or = 4.0 micrograms/mL was not observed. For
      severity of drug-resistant pneumococcal pneumonia, 3 patients infected with PISP
      were classified as class IV, 2 with PISP were as class V, 2 with PRSP were as
      class IV, and 1 with PRSP was as class V. The patients with drug-resistant
      pneumococcal pneumonia were classified as high risk classes (class IV to V),
      however, the mortality rate was low (0%). In conclusion, the Pneumonia PORT
      prediction rule is effective for evaluating the severity of CAP in Japan,
      especially in classifying the class V patients who are related to high mortality.
      The mortality rate of the patients with drug-resistant pneumococcal pneumonia was
      low.

PMID- 12607347
TI  - [Effect of the pretreatment with organic acid buffer solutions on the recovery of
      Legionella species from environmental water samples].
AB  - Anti-microbial effect of the pretreatment with various organic acid buffer
      solutions against co-existing microorganisms which were isolated from cooling
      tower water samples along with Legionella spp. was examined. Among several buffer
      solutions, a 0.1 M potassium citrate-citric acid buffer solution (hereafter,
      citrate buffer solution, pH 2.2) hardly affected the recovery of Legionella spp.,
      but effectively inhibited the growth of co-existing microorganisms. To evaluate
      the buffer action of these buffer solutions, pHs of 9 cooling-tower water samples
      were evaluated after addition of an equal volume of each buffer solution. When a
      citrate buffer solution. pH 2.2 was combined to a 200-fold concentrated solution
      of each cooling-tower water sample, the pH of the combined solution became 2.5 to
      2.7 and maintained a stably low pH value than that (pH 3.0 to 7.4) obtained after
      mixture of a 0.2 M HCl-KCl buffer solution (hereafter, HCl buffer solution, pH
      2.2), suggesting strong buffer action of the citrate buffer solution, pH 2.2 in
      the combined solutions. Furthermore, when cooling-tower water samples were
      pretreated with a citrate buffer solution, pH 2.2, the recovery of Legionella
      spp. was successful in 7 out of 9 cooling-tower water samples, suggesting 3 times
      higher recovery rate than that obtained by addition of a HCl buffer solution, pH
      2.2 (3 out of 9 cooling-tower water samples).

PMID- 12607348
TI  - [Patient assessment for zanamivir therapy (second report) -- a survey of patients
      with influenza who were prescribed zanamivir during the 2001/2002 season in
      Japan].
AB  - Patients diagnosed as influenza who were prescribed zanamivir were surveyed from
      December 2001 to April 2002 in Japan as the same 2000/2001 influenza season. A
      total of 751 survey questionnaires were returned. We analyzed the efficacy of
      zanamivir against 367 patients who were diagnosed as influenza by rapid diagnosed
      kit and took zanamivir within 48 hours after onset of symptoms. Following the
      first zanamivir treatment, symptom relief was reported by 24.0% of the patients
      within 12 hours, 52.6% within 24 hours and 79.6% within 48 hours. The patients
      reported that the severest influenza symptom was fever, 28.4% of the patients
      started to feel reduction of fever within 12 hours, 62.2% within 24 hours. All of
      the 751 patients, 98.8% reported that the Diskhaler could be used as instructed
      by the doctor or pharmacist and 91.3% found the device easy or very easy to use.
      These results showed that the effect of zanamivir started very fast and the
      diskhaer was well accepted. This was the same as the previous results.

PMID- 12607349
TI  - [An elderly case with Listeria monocytogenes sepsis and pulmonary non-tuberculous
      mycobacterial infection].
AB  - A 88-year-old woman, who had lived in a nursing home, was admitted to our
      hospital because of the suspicion of pulmonary tuberculosis. She had a cough,
      fever and diarrhea on admission. She suffered from sepsis because Listeria
      monocytogenes was isolated from only the blood culture twice. We immediately
      administered imipenem/cilastatin to her on admission. She simultaneously had
      pulmonary non-tuberculous mycobacterial infection because the chest roentgenogram
      showed a cavity in the right upper lung field and Mycobacterium intracellulare
      was isolated from the sputum many times. She was treated with isoniazid,
      rifampicin and clarithromycin for the pulmonary non-tuberculous mycobacterial
      infection. Her condition improved soon after the administration of IPM/CS but a
      low grade fever and cough persisted. L. monocytogenes and M. intracellulare are
      important pathogens in the elderly because cell-mediated immunity mainly works as
      host defenses against both organisms.

PMID- 12607350
TI  - [Three imported cases of acute Q fever after an inspection tour to Australia and
      New Zealand].
AB  - After an inspection tour to farms and abattoirs in Australia and New Zealand,
      three Japanese persons simultaneously developed febrile illnesses in Japan. They
      generally had slight fever and general fatigue, followed by thrombocytopenia and
      hepatic dysfunction. However, no respiratory symptoms were observed. In one of
      the cases, severe thrombocytopenia (1.3 x 10(4)/microliter) and high fever up to
      40 degrees C were observed. These clinical symptoms were compatible with Q fever.
      All of the cases showed four hold-elevations of IgM and IgG against Coxiella
      burnetii phase II between acute and convalescent sera by a serological test. C.
      burentii-DNA was also detected in the serum of one patient. Minocycline was
      highly effective in all cases. This report illustrates the typical clinical
      courses of acute Q fever.

PMID- 12607351
TI  - [A critical pneumonia by multidrug-resistant Enterococcus faecium in a chronic
      hemodialysis patient. A case report].
AB  - Enterococcus faecium is usually known as a pathogen of nosocomial infections in
      compromised patients. Recently it is a problem that some of the E. faecium become
      resistant to many antibiotics. It is not usual that this pathogen causes
      pneumonia. We report a community-acquired pneumonia by multidrug-resistant E.
      faecium in an outpatient who had been receiving hemodialysis for the past year.
      The patient recovered from pneumonia with vancomycin, but had nosocomial
      pneumonia caused by MRSA later but recovered.

PMID- 12607352
TI  - [Mycoplasma pneumonia of identical twin sisters with different clinical courses
      depending on the treatment].
AB  - Mycoplasma pneumoniae (M. pneumoniae) pneumonia is a common disease which usually
      shows a good prognosis, however, it can develop a very serious state such as
      respiratory distress syndrome. We experienced 2 cases with M. pneumoniae
      pneumonia from identical twin sisters. Case 1, who was 22 years-old and was the
      senior sister of the twin, complained of fever and cough on August 1st, 1999. Her
      chest radiograph revealed consolidation in the right lung. When she was admitted
      to our hospital on August 11, she revealed severe hypoxemia and the titer to M.
      pneumoniae was markedly elevated. She was diagnosed as M. pneumoniae pneumonia
      with acute respiratory distress syndrome and treated with clarithromycin and
      methylprednisolone. Although it was necessary for her to be in the intensive care
      unit for 8 days, her condition gradually improved and was discharged on the 30th
      of September. Case 2, who was the younger sister of Case 1, complained cough and
      fever on August 21, 1999. Her chest radiograph showed consolidation in the left
      lung. She was treated by sparfloxacin because the intrafamilial infection of M.
      pneumoniae was most likely. The diagnosis was confirmed by the increased antibody
      titer to M. pneumoniae later. There have been several reports that hyperimmune
      reaction may be related with the worse course of M. pneumoniae pnuemonia.
      However, the clinical courses of twin sisters, who should be very similar in
      their immune response to the same antigen, were very different from each other.
      The time of administration of effective antibiotics seemed to be a crucial factor
      to determine their courses. These results emphasized the importance of early
      diagnosis of the patients with M. pneumoniae pneumonia and the adequate
      chemotherapy to prevent developing severe respiratory failure.

PMID- 12607353
TI  - Relation between hospitalization and the resistance of enterobacteria to beta
      lactam antimicrobial agents.

PMID- 12607354
TI  - [The cloning and sequencing of H-2Kk gene cDNA of 615 mice].
AB  - OBJECTIVE: The purposes of this study were to clone and sequence the major
      histocompatibility complex type I (MHC I) molecular antigen recognizing gene (H
      2Kk) of 615 mice, and to provide the functional gene for transgenic therapy.
      METHODS: The 1.4 kb full-length fragment of H-2Kk gene complementary DNA (cDNA)
      was amplified from the total RNA of 615 mouse liver by using reverse
      transcription polymerase chain reaction (RT-PCR). The cDNA was inserted into
      PGEM3Zf(+) vector directionally, and the competent E. coli JM109 was transformed
      with the ligated product. The recombinant PGEM3Zf(+)-H-2Kk cDNA plasmid was
      obtained using restricted enzyme analysis of the transfectants. The complete
      sequence of 615 mouse H-2Kk cDNA was determined by using Sanger's method.
      RESULTS: The sequences of 615 mouse H-2Kk cDNA were 99% similar with those of H
      2Kk cDNA which were reported by other researchers, and the sequences encoding
      antigen recognizing regions (ARS) were identical with each other. CONCLUSION: The
      authors cloned the MHC I molecular antigen recognizing gene (H-2Kk) of 615 mice
      successfully and got the functional gene of MHC I.

PMID- 12607355
TI  - [Effects of cryotreat on the corrosion resistance of the medium melting-point
      castable alloy].
AB  - OBJECTIVE: The purpose of this study was to investigate effects of cryotreat on
      the corrosion resistance of SDA-II medium melting-point castable alloy. METHODS:
      12 samples were divided into three groups, including the control group, the
      cryotreated group and the cryotreated & post-cryogenic treated group. The
      cryotreating process was firstly dropping the temperature from room temperature
      to -170 degrees C with dropping rate 3 degrees C/min, maintaining -170 degrees C
      for 2 hrs, and then returning to ambient temperature with an increasing rate of 1
      degree C/min. The post-cryogenic process was maintaining the samples in 300
      degrees C for 1 hr. Finally, all samples were subjected to the electrochemical
      potentiodynamic polarization after immersed in the artificial saliva (ISO/TR
      10271: 1993 (E), pH 6.8) for 24 hrs at ambient temperature. The exposing area of
      each sample was 10 mm x 10 mm. The electrochemical tests were carried out in the
      artificial saliva under 37 degrees C, with the scanning rate of 20 mV/min,
      starting potential -200 mV below OCP and stopping current 10(-3) A. The corrosion
      currents (Icorr), the pitting corrosion potentials (Eb) and the potentiodynamic
      polarization curves were observed using the 283 electrochemical corrosion
      measuring system automatically. RESULTS: For SDA-II medium melting-point castable
      alloy, cryotreat reduced corrosion rate of the alloy, but had no effect on the
      pitting corrosion potential. As far as the post-cryogenic treatment, it didn't
      affect the corrosion resistance. CONCLUSION: The results suggested that cryotreat
      was an effective procedure in enhancing the corrosion resistance of SDA-II medium
      melting-point castable alloy, and it may be applicable in prosthetic dentistry.

PMID- 12607356
TI  - [A study on the correlation between facial growth pattern and posterior-anterior
      ratio].
AB  - OBJECTIVE: This study aimed at finding sensitive indicators in diagnosing facial
      growth pattern by studying the relationship between the indicators which can
      reflect facial growth pattern according to the previous studies and posterior
      anterior ratio. METHODS: The cephalometric radiographs of 61 teenage children
      were measured, the posterior-anterior ratio and the other 12 indicators including
      Y-axis angle, facial axis angle, cranial basal angle, and the four angles (The
      sagittal horizontal planes were analyzed using statistic methods. RESULTS: The MP
      SN angle was significantly coincided with the posterior-anterior ratio and
      Pearson coefficient is -0.922, and little correlation was found between the
      angles of four sagital horizontal planes and the posterior-anterior ratio. The
      positive correlation was found between the length of mandibular ramus and
      posterior-anterior ratio. CONCLUSION: The sensitive indicators for confirming
      facial growth pattern are the posterior-anterior ratio and the MP-SN angle.

PMID- 12607357
TI  - [Distribution of neuropeptide Y-like immunoreactive fiber in rat
      temporomandibular joint].
AB  - OBJECTIVE: This investigation aimed at explore the total distribution of
      neuropeptide Y-like immunoreactive (NPY-LI) fibers and their changes post-trauma
      in rat temporomandibular joints (TMJs). METHODS: Six groups of rats were killed
      individually before trauma, 1, 3, 7, 14 and 28 days after trauma. TMJs were
      extracted totally, and the avidin-biotin-peroxidase complex method and image
      analysis were employed to detect NPY-LI fibers in frozen sections of TMJs.
      RESULTS: NPY-LI fibers were distributed extensively in TMJs, except the central
      disc band and bone, and they were mainly located around blood vessels, especially
      arteries. The densities of fibers in the six groups were 160.4 +/- 27.5, 95.8 +/-
      16.4, 88.6 +/- 14.5, 114.3 +/- 17.0, 135.0 +/- 20.7, 158.6 +/- 19.5 (unit:mm2).
      CONCLUSION: NPY-LI nerve fibers are distributed extensively in the periphery of
      blood vessels of TMJs and densities changed dynamically when TMJs were impacted.
      NPY may play an important role in pathologic change of TMJ by regulating local
      blood circulation.

PMID- 12607358
TI  - [A histological study on healing process of palatal wound with denuded bone
      restored with transplanted buccal or palatal mucosa].
AB  - OBJECTIVE: The purpose of this study was to observe the healing process of palate
      wound with denuded bone restored with transplanted buccal or palatal mucosa and
      to elucidate the mechanism of maxillary growth inhibition following palate
      repair. METHODS: 32 Japan white rabbits, 5 weeks old, were selected as the
      subjects for this study. They were divided into 4 groups at random. The rabbits
      in group I was the control without receiving any treatment. The rabbits in group
      II, III, IV was surgically denuded the bone of palate, and afterwards, the
      rabbits in group II were not received further restoration, but rabbits in group
      III and IV were restored with transplanted buccal and palatal mucosa
      respectively. From 2 to 14 weeks after surgery, at regular intervals, palatal
      wounds were observed by using a light microscope. Histological changes were also
      compared among different groups. RESULTS: It was found in group II that dense
      connective tissue was formed 2 weeks after the surgery, and Sharpey's fibers was
      formed between the scar and bone tissue 4 weeks after the surgery. However, no
      Sharpey's fiber was found in group III and group IV, and in the latter two
      groups, the histological character of tissue was similar to that of the control.
      CONCLUSION: Prevention of the attachment of Sharpey's fibers to the palatal bone
      could be effectively accomplished by covering the denuded palatal bone with the
      transplanted buccal or palatal mucosa.

PMID- 12607359
TI  - [A study on papain-induced osteoarthritis in rabbit temporomandibular joint].
AB  - OBJECTIVE: The aim of this study was to set up an animal model of osteoarthritis
      (OA) in the rabbit temporomandibular joint (TMJ). METHODS: 0.3 ml of 1.6% papain
      solution was injected into the upper compartment of each left TMJ of six Japanese
      big ear white rabbits, and the same volume of saline was injected into the upper
      compartment of left TMJ as control. The rabbits were sacrificed 2, 4, 6 weeks
      respectively after injections and the TMJ specimens were pathologically examined.
      RESULTS: The degenerative changes were demonstrated in the TMJs injected with
      papain, such as thinner articular cartilage, fibrillation and destroyed cartilage
      matrix, and inflammation, proliferation, and degeneration of the synovial tissue.
      All these changes were much worse with prolonged observation time. Some kinds of
      reparative changes appeared in the sixth week after papain injection. CONCLUSION:
      Pathological similarities between papain induced rabbit TMJ osteoarthritis and
      human TMJ osteoarthritis were observed. This animal model has good
      reproducibility and hence can be used for exploring pathogenesis of this disease
      and selection of treatments for osteoarthritis of TMJ.

PMID- 12607360
TI  - [A histomorphologic and enzyme histochemical study of masticatory muscles
      affected by distraction osteogenesis of mandible].
AB  - OBJECTIVE: The purpose of this study was to study the masticatory muscles
      affected by distraction osteogenesis of the mandible. METHODS: The distraction
      osteogenesis (DO) was applied to distract the left mandible of 6 mongrel dogs
      that were divided into three experimental groups. After different distraction
      phase and consolidation phase, the masseter and the digastric muscle were taken
      out. The specimens were stained using hematoxylin/eosin and enzyme
      histochemistry. Afterwards, the specimens were observed with a light microscope
      to study the morphologic changes of the muscles. The contents of enzyme in the
      different groups were measured by VIDAS. RESULTS: The masseter showed
      consequently atrophy, but the digastric muscle showed a progress of
      histomorphologic reconstruction, including atrophy and hypertrophy. The changes
      of the contents of enzyme and histomorphology were identical in the masticatory
      muscles. CONCLUSION: The digastric muscle parallel to the vector of mandibular
      distraction adapts the distraction by the way of atrophy, regeneration and
      hypertrophy. And the contents of enzyme appear to decrease at the beginning,
      increase afterwards, and return to the normal level finally. But the masseter
      perpendicular to the vector of mandibular distraction shows consequent atrophy,
      and the contents of enzyme consequently decrease, which means the metabolism
      decrease.

PMID- 12607361
TI  - [A study of oral epithelial cells cultured with L929 cells as seed cells in
      vitro].
AB  - OBJECTIVE: To purpose of study aimed at investigating the technique of culturing
      oral epithelia in vitro and to set up an experimental model for further
      reconstructing oral mucosa in vitro. METHODS: The oral mucosa was taken from
      young New Zealand rabbits, and the mucosa was digested with enzyme and suspended
      in liquid to form cellular suspension. Being seeded, the cells were cultured
      motionlessly. The medium was changed regularly and the cells were subcultured.
      RESULTS: The cultured cells were all epithelial cells without fibroblasts, and
      they were proved to be diploid cells. The cells were subcultured in 1-13
      generations which survived for 50-60 days. CONCLUSION: The oral epithelium of
      young New Zealand rabbit can be cultured in vitro, maintaining the ability to
      proliferate in a certain period. It is a pilot study to reconstruct oral tissue
      in vitro.

PMID- 12607362
TI  - [The utility of vascularized free fibula flap in mandibular reconstruction: a
      clinical report of 25 cases].
AB  - OBJECTIVE: The purpose of this study was to evaluate the advantages and
      disadvantages of vascularized free fibula flap as a new method for mandibular
      reconstruction. METHODS: 25 cases (17 male to 8 female) who have received
      mandibular reconstruction with free vascularized fibular flaps in our hospital
      were studied retrospectively. The average length of the fibula grafts is 10.0 cm
      (range from 5.5 to 16 cm). 3 cases received primary insertion of osteointegrated
      dental implants into the free fibula flap, and all these 5 implants survived.
      RESULTS: All flaps except 1 were viable. 62% of the cases took normal diet
      postoperatively, and the remainder took soft diet as well. All patients spoke
      clearly. No ankle unstability was reported. And the aesthetic assessments in all
      patients were good or fair. CONCLUSION: Vascularized free fibular flap takes its
      distinct advantages to other autogeneous free bone flaps and is confirmed to be
      one of the optimal methods for mandible reconstruction by our study.

PMID- 12607364
TI  - [A study on morphology and distribution of mast cells in oral lichen planus].
AB  - OBJECTIVE: The aim of this study was to investigate the features of mast cell
      subtypes and relationship between mast cells and pathogenesis of oral lichen
      planus. METHODS: Mast cells in the tissue of oral lichen planus were stained with
      Alcian blue/safranine in order to demonstrate mature and immature mast cells, and
      the constituent ratio of these two subtypes was calculated. Afterwards, LUZEX-F
      image pattern analysis system was applied to demonstrate the size of these two
      subtypes and their morphological features. RESULTS: The constituent ratio of
      mature and immature types of mast cells in the tissue of oral lichen planus was
      significantly different from that in the normal tissue (P < 0.01), and such
      difference was also demonstrated among different types of this malady, including
      papule-, net- and erosion-type of oral lichen planus (P < 0.05). There was
      significant difference between the sizes of mature and immature mast cells (P <
      0.01) and also the sizes, amount and distribution of the plasma granules within
      these two mast cells. CONCLUSION: It could be implied that mast cells might play
      a role in the pathogenesis of oral lichen planus.

PMID- 12607363
TI  - [Effects of exogenous IL-10 on IL-6 and ICAM-1 expression in inflammatory
      gingival tissue].
AB  - OBJECTIVE: This study aimed at investigating effects of exogenous interleukine-10
      (IL-10) on IL-6 and intercellular adhesion molecular (ICAM-1) expression in
      inflamed gingival tissue. METHODS: The expression of IL-6 and ICAM-1 was examined
      using immunohistochemical techniques. Inflammatory gingival tissue treated with
      IL-10 was taken as the experimental group and the same patient's inflammatory
      gingival tissue without treatment of IL-10 was included into the control group.
      RESULTS: IL-6 expression was found mainly in monocytes, macrophages, lymphocytes,
      endotheliocytes and fibroblasts. The expression of ICAM-1 was found mainly in
      epithelial cells, monocot-macrophages, lymphocytes, endotheliocytes and
      fibroblasts. The immunohistochemical optical density (IOD) of the expression of
      IL-6 and ICAM-1 was detected by using Image-Proplus software, and the results
      showed that the expression in the experimental group differed significantly from
      that in the control group. CONCLUSION: The exogenous IL-10 may down-regulate IL-6
      and ICAM-1 expression in inflammatory gingival tissue.

PMID- 12607365
TI  - [Quantitative changes of microflora on stress-bearing areas relating to bases of
      removable partial dentures].
AB  - OBJECTIVE: This study was designed to find out the changes in microflora on the
      stress-bearing areas after insertion of removable partial dentures, and in turn
      to explore the difference between such changes caused by metal bases and acrylic
      resin bases respectively. METHODS: Sixteen patients who were ready to accept
      removable partial dentures were selected and divided into two groups. Eight
      patients used metal bases while the other eight patients used acrylic resin
      bases. Then at the following three points: before dentures were inserted, one
      month after wearing and three months after wearing, the total cultivable flora
      were counted and the proportions of bacteria detected on the stress-bearing areas
      were calculated. RESULTS: No matter what type of bases was selected, the wearing
      of removable partial denture enhanced the accumulation of microflora on stress
      bearing areas. The percentages of Candida albicans and Lactobacilli detected on
      stress-bearing areas also increased significantly (P < 0.05). When such changes
      were compared, the authors found that the increment of Candida albicans caused by
      acrylic resin bases was higher than that caused by metal bases (P < 0.05).
      CONCLUSION: The wearing of removable partial dentures forms new retention areas
      between the bases and the stress-bearing areas, as a result enhances the deposit
      of microbe and facilitate the growth of Candida albicans and Lactobacilli.
      Compared with increment of Candida albicans caused by metal bases, the increment
      relating to acrylic resin bases is more evident.

PMID- 12607366
TI  - [Combined rapid palatal expansion (RPE), edgewise technique and protraction
      headgear in correction of skeletal Class III malocclusion].
AB  - OBJECTIVE: The skeletal Class III malocclusion often occurs in ethnic Asia
      population, and it is difficult to obtain an ideal results if only treated with
      protraction headgear (PH). However, the combined rapid palatal expansion (RPE),
      Edgewise Technique and PH can reach it, so the authors investigated the methods
      and characteristics of combined RPE, Edgewise Technique and PH in the treatment
      of skeletal Class III malocclusion. METHODS: Fifteen patients, aged 8.5-12 years,
      including six males and 9 females, with skeletal Class III malocclusion and
      maxillary retrusion were selected for this study. Radiographs of left hand and
      wrist showed that all patients were at the pre-pubertal stage. The duration of
      treatment was nine months on average. RESULTS: The SNA and A-ptm increased with a
      mean of cephalometric analysis, which showed significant difference (P < 0.05).
      CONCLUSION: Obvious skeletal and profile changes can be achieved with combined
      RPE, Edgewise Technique and PH in the treatment of early skeletal Class III
      malocclusion.

PMID- 12607367
TI  - [Oral microflora of 42 patients with oral squamous cell carcinoma].
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of squamous cell
      carcinoma on oral bacteria. METHODS: This study investigated the microbial
      contents of the plaque on the surfaces of oral squamous cell carcinomas. Samples
      were obtained from the central surface of lesions, contiguous healthy mucosa and
      saliva of 42 patients with oral squamous carcinoma before and after operation.
      RESULTS: The median of bacterial colony forming units per milliliter (CFUs/ml) of
      saliva before operation was 8.10 x 10(8) CFUs/ml. The median of CFUs per square
      centimeter of the tumor surface was 5.21 x 10(5) CFUs/cm2 which was significantly
      higher than that of the healthy (the control) mucosa (1.77 x 10(4) CFUs/cm2, P =
      0.0001). The CFUs per square centimeter of mucosa surface at the operative zone
      was 4.34 x 10(5) CFUs/cm2 which was also significantly higher than that of the
      healthy (control) mucosa(7.24 x 10(4) CFUs/cm2, P = 0.0001). CONCLUSION: Oral
      carcinoma can break the balance of oral microflora, which may be one of the
      reasons leading to the high susceptivity of these compromised patients to
      systemic infection.

PMID- 12607368
TI  - [Transfection of the exogenous PTEN-induced growth inhibition of the highly
      metastatic mucoepidermoid carcinoma cell line M3SP2 in vitro].
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects of the exogenous
      phosphatase and tensin homology deleted on chromosome 10 (PTEN) gene on in vitro
      growth of the highly metastatic mucoepidemoid carcinoma cell line M3SP2. METHODS:
      The growth of the exogenous PTEN transfected mucoepidemoid carcinoma cells M3SP2
      PTEN gene was studied by analyzing cell growth curves, mitosis index and clone
      formation efficiency and compared with its parental cell line M3SP2 and the
      vector pBabepuro-transfected cell line M3SP2-pBp. RESULTS: The doubling time (h)
      of M3SP2, M3SP2-pBp and M3SP2-PTEN were 24.50, 24.76 and 31.74; the mitosis index
      (@1000) were 53.0 +/- 6.20, 49.0 +/- 5.24 and 16.2 +/- 3.2; the clone formation
      efficiency (%) were 37.37, 35.01 and 10.40, respectively. The M3SP2-PTEN cells
      also revealed 57.05%-71.46% inhibition of growth from day 3 to 7 and 65%-72%
      inhibition of clone formation compared with the parental cells. CONCLUSION: These
      data provide evidence that the exogenous wild-type PTEN have remarkably
      inhibitory effects on in vitro proliferation of the highly metastatic
      mucoepidermoid carcinoma cell line M3SP2.

PMID- 12607369
TI  - [Properties of GI-II glass/alumina composite infiltrated with GI-II tinted
      infiltration glass].
AB  - OBJECTIVE: The purpose of this study was to determine the thermal, mechanical
      properties and density of the composite infiltrated with GI-II tinted
      infiltration glass. METHODS: The bar-shaped aluminum oxide and glass/alumina
      composite specimens with the size of 20 mm x 5 mm x 5 mm were prepared, with two
      free-end surfaces perpendicular to the long axis of the specimens and parallel to
      each other. The thermal expansion curves were obtained on a TMA2940 thermal
      analyzer with heating rate of 5 degrees C/min and temperature range of 25 degrees
      C to 1000 degrees C. The bar-shaped specimens with the size of 25 mm x 5 mm x 2
      mm were fabricated and employed to test the density using Archmede's method. The
      flexural strength, elastic modulus were measured by means of 3-point bending test
      with the same specimens. The fractured specimens were indented with Vicker's
      diamond pyramid under load of 49 N for 15 seconds to determine the hardness and
      indentation fracture toughness. RESULTS: The thermal expansion coefficient of the
      glass/alumina composite was 7.620 x 10(-6) degrees C-1 (25-500 degrees C), which
      was higher than that of Vitadur alpha veneering porcelain. The 3-poit flexural
      strength, elastic modulus, Vicker's hardness, indentation fracture toughness and
      density were 389.6 MPa, 92 GPa, 9.409 GPa, 3.2425 MNm-3/2 and 3.662 g/cm3
      respectively. CONCLUSION: The thermal expansion of the GI-II glass/alumina
      composite is compatible with that of Vitadur alpha veneering porcelain, and the
      material could meet the strength demands for clinical use.

PMID- 12607370
TI  - [Spectral transmittance of GI-II glass/alumina composite].
AB  - OBJECTIVE: The purposes of this study were to determine the spectral
      transmittance of GI-II glass/alumina composites and to explore the effects of
      different specimen thickness and fining arts of glass infiltration on the
      transmittance. Data were compared with those of Vita In-Ceram Alumina materials.
      METHODS: Plate-shaped specimens 12.5 mm in diameter, with 3 thickness (0.5, 1.0,
      1.5 mm), 6 color groups for GI-II and 4 color groups for Vita In-Ceram Alumina
      were fabricated. Specimens of color AL2 for In-Ceram and IG2 for GI-II were
      selected in the study of relationship between different infiltration arts and
      transmittance. Five infiltration time duration and three temperatures were
      studied. A spectrophotometer with standard A light source paralleled light beam 5
      mm in diameter and spectra range 380-780 nm was employed to measure the spectral
      transmittance. RESULTS: The range of spectral transmittance were 2.7%-4.5% for GI
      II and 2.4%-5.2% for Vita In-Ceram Alumina. Transmittance decreased with specimen
      thickness, but they were not linearly related. Transmittance of GI-II tended to
      increase and that of Vita In-Ceram Alumina decreased as the infiltration
      temperature elevated. The transmittance increased with infiltration time less
      than 4 hours and reduced with prolonged time over 6 hours for both materials.
      CONCLUSION: GI-II glass/alumina composite has comparatively lower translucency.
      Influences of factors as color, thickness and infiltration arts on translucency
      of restorations should be considered in the clinical selection of the all-ceramic
      materials.

PMID- 12607371
TI  - [Expression of plasmid pcDNA3-gtfB in mammalian cell].
AB  - OBJECTIVE: This study aimed at investigating the transcription and expression of
      recombined plasmid pcDNA3-gtfB which encoding multiple glucosyltransferase-B
      antigenic gene, and the feasibility of the pcDNA3-gtfB used as gene vaccine.
      METHODS: The pcDNA3-gtfB was transfected into mammalian cell COS-1 with liposome.
      The total RNA of COS-1 cell transfected by pcDNA3-gtfB was extracted and
      purified. Using the total RNA as template, the transcription of pcDNA3-gtfB was
      assayed by reverse transcription polymerase chain reaction (RT-PCR). The
      expression product of pcDNA3-gtfB was identified with 5% SDS-PAGE, and then
      assayed using Western-blotting. The expression product of pcDNA3-gtfB was also
      assayed by using LSAB method, and cell transfected by pcDNA3 as the negative
      control. RESULTS: Identified by agarose gel electrophoresis, the target gene
      fragment had the same molecular size (3.6 kb) as it was predicted, and it
      indicated that pcDNA-3gtfB was correctly transcribed into mammalian cells. Proved
      by SDS-PAGE, the molecular weight of the expression product (116-212 kD) was also
      the same as it was supposed to be. It was also indicated by Western-blotting and
      LSAB assay that the expression product induced immunizing response. CONCLUSION:
      As gene vaccine, it is importance that the recombined plasmid could be correctly
      transcribed and expressed in mammalian cells. It was suggested by RT-PCR, LSAB
      and Western-blotting that recombined plasmid pcDNA3-gtfB could be correctly
      transcribed and expressed in mammalian cells, and the expression product could
      induce immunizing response, which support its use as gene vaccine candidates in
      the development of anticaries vaccines.

PMID- 12607373
TI  - [Establishment of two-dimensional magnetic field finite element analysis model of
      cup-yoke-type magnetic attachment].
AB  - OBJECTIVE: The purpose of this study was to establish two-dimensional magnetic
      field finite element analysis model of cup-yoke-type magnetic attachment for
      optmizing the design of magnetic attachments. METHODS: Because the magnetic field
      of cup-yoke-type magnetic attachment is stable axial-symmetrical, the authors
      only analyzed two-dimensional magnetic field of 1/2 section. The Maxwell stress
      between magnet and keeper was integral analyzed using the finite element method,
      and the attractive force between magnetic attachments was obtained. RESULTS:
      Compared the value of calculated attractive force with that of examined, the
      authors found that the procedure veritably reflected influencing trend of
      variable factors on attractive force, and the value of former one was 10% less
      than the later one. CONCLUSION: This procedure can be used in magnetic field
      calculation of cup-yoke-type magnetic attachments.

PMID- 12607372
TI  - [A study on screening effective immunization route of anticaries DNA vaccine
      pcDNA3-gtfB].
AB  - OBJECTIVE: Glucosyltransferase-B (GTF-B) of Streptococcus mutans has been
      implicated as a principal virulent factor in the development of dental caries.
      The objective was to use recombined plasmid pcDNA-gtfB expressing multiple
      antigen of glucosyltransferase-B as gene vaccine to immunize rats through
      different route, and to investigate the immunization effects of immunization
      routes. METHODS: A total of 18 Wistar rats were divided into 3 groups, including
      the quadriceps injection group, the intransal irrigation group and the
      submandibular gland-targeted injection group. The serum IgG and salivary IgA were
      assayed by using ELISA after pcDNA3-gtfB immunization. The serum IgG and salivary
      IgA in different groups were compared using statistical one-way ANOVA. RESULTS:
      Compared these 3 groups, the serum IgG in the quadriceps injection group was much
      higher than those of other two groups (P < 0.01), while the salivary IgA of the
      submandibular gland-targeted injection was much higher than those of other two
      groups (P < 0.01). CONCLUSION: It is indicated pcDNA3-gtfB is good candidate for
      anticarious gene vaccine, and submandibular gland-targeted injection is an
      effective immunization route for stimulating salivary IgA.

PMID- 12607374
TI  - [Levels of volatile sulfur compounds and the analysis of related factors in oral
      cavities of 384 health subjects in Chengdu].
AB  - OBJECTIVE: The purpose of the study was to investigate the prevalence of oral
      malodor in a group of health cohorts in Chengdu, China by using different
      diagnostic methods. METHODS: Volatile sulfur compounds (VSCs) level was evaluated
      by using Halimeter. The organoleptic score and tongue coating index were also
      evaluated. A questionnaire interview was conducted at the same time. RESULTS:
      There were 21.61% subjects whose oral VSCs level were more than 300 ppb. No
      significant difference was found between male and female for the VSCs values. The
      subjects with malodor (score > or = 6) evaluated by organoleptic score were
      28.91%, and the difference between the male and female was significant (P <
      0.05). Further, a significant correlation could be detected between the VSCs
      level, organoleptic score and tongue coating index (P < 0.05). CONCLUSION: The
      study indicates that nearly one of fourth people suffer from oral malodor.
      Malodor has significant correlation with tongue coating, so cleaning of tongue
      dorsum is very important to reduce oral malodor.

PMID- 12607375
TI  - [Implantable defibrillators after myocardial infarction. Expensive palliation or
      therapeutic breakthrough?].

PMID- 12607376
TI  - [Open prioritization in health care is necessary for confidence in the welfare
      model. A gap between citizens', decision makers' and health personnel's values].

PMID- 12607377
TI  - [The most comprehensive survey of the treatment of infections in primary health
      care. Prescription of antibiotics is not always according to the guidelines].

PMID- 12607378
TI  - [The Internet a good web for gathering data for clinical trials and registries.
      Traditional paper data forms are soon completely "out"].
AB  - With the development of the Internet technology, clinicians have got a valuable
      tool for solving some of the logistic problems affecting multicenter studies and
      registers. Web based solutions enhance efficiency and quality of multicenter
      studies. Data can be entered continuously without any time and geographical
      limitations. On-line connection to a central database improves involvement of
      participants, and information and alterations can easily be disseminated. The
      central database enables optimal randomization and stratification. Furthermore,
      web based IT solutions for studies and registers enable the patients to report
      their data directly into the database. Until now web based IT solutions have been
      rather expensive but may gradually come down in price.

PMID- 12607379
TI  - [Ladies prefer to contact their doctor by e-mail. Experiences based on data from
      an e-mail mail-box of a community health center in a sparsely-populated area].

PMID- 12607380
TI  - [Supervisor training in psychosomatic approach to work--a successful pilot
      project. Communication increases trust in the professional].
AB  - A question from the Director of Health and Social Security--"What happens when so
      many patients seek help, and apparently don't get any?"--resulted in an enquiry,
      which mapped how the medical staff thought about "psychosomatic" problems. One
      consequence was the pilot project discussed in this article: a training programme
      with two aims--to increase knowledge of psychosomatic illness, and to offer
      training in a method for supervision. The training included theory and practise.
      The course lasted for one and a half years, two days once a month. Participants
      (n = 18) included physicians, physiotherapists, nurses, medical social workers
      and occupational therapists. The course evaluation showed that working on
      different levels (theoretical, practical, personal) was appreciated, meeting the
      needs of working with complex health issues. The evaluation of the supervision
      given by the course participants that reached about 85 persons showed that the
      supervision brought increased trust to professional ability with the participants
      in the supervision groups.

PMID- 12607381
TI  - [Increased commercial financing of national Medical Product Agencies within the
      EU].

PMID- 12607382
TI  - [The Medical Product Agency's work and economics--a comment].

PMID- 12607383
TI  - [Five direct questions to Josef Milerad concerning credibility].

PMID- 12607384
TI  - [A bizarre debate aimed to divert criticism against mediocre research and
      alarming reports in mass media].

PMID- 12607385
TI  - [Who does sponsor Lakartidningen to keep secrets?].

PMID- 12607386
TI  - [In case you will be reported--some good advice].

PMID- 12607387
TI  - [Microhematuria--how does the HSAN reason?].

PMID- 12607388
TI  - [What is reliable in therapy].

PMID- 12607389
TI  - [Pulmonary hypertension].

PMID- 12607390
TI  - [Barrett esophagus. Endoscopic and/or surgery therapy in place of an observation
      program?].

PMID- 12607391
TI  - [Emergencies in long distance flights].

PMID- 12607392
TI  - [Osteoporosis].

PMID- 12607393
TI  - [Current therapeutic strategies in Hodgkin lymphoma].

PMID- 12607394
TI  - [Partial liver transplantation and living donation from the viewpoint of internal
      medicine].

PMID- 12607395
TI  - [After care of patients after kidney transplantation].

PMID- 12607396
TI  - [Botulinum toxin: indications in internal medicine].

PMID- 12607397
TI  - [Autopsy].

PMID- 12607398
TI  - [31-year-old woman with colicky epigastric pain and eosinophilia. Fascioliasis].

PMID- 12607399
TI  - [64-year-old patient with dyspnea at risk and ankle edema in recurrent
      tachycardia. Heart failure].

PMID- 12607400
TI  - [Malpractice in determination of INR value in ambulatory care].

PMID- 12607401
TI  - [Atrial fibrillation: a domain of pharmacotherapy?].

PMID- 12607402
TI  - [Report of the 14th World AIDS Conference 07 July - 12 July, 2002].

PMID- 12607403
TI  - [Prevention of thrombosis in internal medicine].

PMID- 12607404
TI  - [Radial segmentation of lymphocytes in peripheral blood of patients with non
      small cell lung cancer ].
AB  - The term radial segmentation (RS) is applied to a characteristic nuclear
      deformation observed in peripheral blood in vitro in some neoplastic and normal
      cells. It concerns al mononuclear cells. RS positive lymphocytes were found as CD
      4 cells. Different conditions and substances, i.e. anticoagulant or cyclosporin
      can induce the formation of RS nuclei in vitro. Elevated ratio of RS nuclei in
      peripheral blood has been observed in patients with some autoimmunological
      diseases i.e. rheumatoid arthritis, diabetes mellitus insulin-dependent,
      sarcoidosis. Reduced ratio of RS nuclei was observed in neoplastic diseases. The
      aim of the study was to analyze the incidence of RS nuclei of lymphocytes in
      vitro in peripheral blood (induced by cyclosporin) in patients with non-small
      cell lung cancer (NSCLC). Heparinized peripheral blood was obtained from controls
      and patients with primary NSCLC. The blood was incubated with cyclosporin, and
      then lymphocytes were isolated by Lymphoprep. RS positive lymphocytes were
      counted in smears stained with MGG stain. In peripheral blood from healthy donors
      the average incidence of lymphocytes RS was 3.314% and in patients with NSCLC
      4.481% respectively. The difference between controls and patients with NSCLC was
      not significant. No correlation was found between incidence of RS and stadium of
      lung cancer.

PMID- 12607405
TI  - [Lung function tests and bronchoalveolar lavage (BAL) findings in patients with
      primary biliary cirrhosis].
AB  - Primary biliary cirrhosis (PBC) is a rare cholestatic liver disease with an
      autoimmune etiology. The present study was done to estimate the frequency of
      occurrence of pulmonary disturbances and to analyse the results of
      bronchoalveolar lavage (BAL) findings in patients with PBC. Thirteen patients
      (only women) aged 50.4 with histologically proved PBC were investigated. Mean
      values of lung function tests in the study group were within normal range. In 38%
      of patients the impairment of DICO was observed. Only in one patient decrease of
      lung compliance (Cdyn) was observed. BAL findings showed the increase of
      lymphocytes ratio (> 15%) in 5 patients (38%). The disturbances in lung function
      and BAL were observed in patients with different stage of PBC and without
      clinical symptoms of lung disease.

PMID- 12607406
TI  - [The factors inducing status asthmaticus and changes in physical examination on
      admission to intensive care unit].
AB  - During the last 10 years 342 patients with status asthmaticus were admitted (mean
      age 42 years, 63% female) to ICU of Pneumonology Department in Warsaw Medical
      University. After admission respiratory rate (mean 28/min), heart rate (mean 121
      beats/min), blood pressure (mean 139/83 mmHg), pulsus paradoxus (mean 19.9 mmHg)
      and peak expiratory flow rate (mean 109.3 L/min) were recorded. Arterial blood
      gas tension was analyzed as well. Mean PaO2 was 65.7 mmHg (range 31.4-128 mmHg)
      and mean PaCO2 was 39.1 mmHg (range 18-130.9 mmHg). Electrocardiography showed p
      pulmonale in 24.4% of cases. 18.9% of the patients had ST-T changes and rotation
      of heart axis in 9% of cases. X-ray examination performed on admission showed
      changes characteristic for pneumonia in 15 patients. Status asthmaticus was
      caused by infection in 57.6%, exercise 6.1%, emotion and stress 3.2%, allergens
      2.3% of cases. Underlying factors were unknown in 24.3%.

PMID- 12607407
TI  - [Analysis of the cardiac arrhythmias in premature infants throughout the 24 hours
      following birth using Holter method].
AB  - The aim of the study was to determine the heart rhythm (the frequency and
      disturbances) in premature infants in satisfactory clinical condition throughout
      the 24 hours following birth using Holter method. The influence of some maternal
      parameters (number of previous pregnancies, delivery mode, usage of pregnancy
      maintaining drugs) on newborn's heart rhythm and the influence of child's
      parameters (sex, birthweight, gestational week, clinical state according to Apgar
      score) were studied. Digital Holter registration system with two channels real
      time recording Silicon Beat 2000 version 3.2 by Medea (Poland) was used. Sixty
      two premature infants were studied. Cardiac arrhythmias were found in 38 cases.
      They were mainly benign disturbances. The most frequent ones were
      supraventricular extrasystolic beats. The analysis of the influence of definitive
      features of mothers and children on arrhythmias and the values of heart rate
      revealed, that in naturally born infants naturally born and in these ones with
      low Apgar score the supraventricular extrasystolic beats were significantly more
      common as compared with those born by Caesarean section and with higher Apgar
      score. In younger subjects (< 30 gestation weeks) and with lower birthweight (<
      2000 g) the sinus tachycardia was significantly more frequent as compared with
      older and heavier ones.

PMID- 12607408
TI  - [The frequency of coeliac disease occurrence in patients with recurrent aphthous
      stomatitis (RAS)-preliminary report].
AB  - The aim of this study was to determine the frequency of non-diagnosed coeliac
      disease in patients with recurrent aphthous stomatitis, admitted to the
      Department of Oral Medicine, Dental Institute, Warsaw Medical School in the years
      1999-2000. The examination comprised 20 subjects (10 females and 10 males), mean
      age: 40 years. In one patient anti-endomysial antibody, the markers of coeliac
      disease (IgAEmA-80j) were detected.

PMID- 12607409
TI  - [The influence of three-months weight reducing treatment on eating behavior in
      obese women].
AB  - The effectiveness of weight reducing treatment and maintaining of reduced weight
      depends in great extend on changing patient's food preferences and it can be
      achieved through nutritional education and through patients self-esteem.
      Estimation of changes in eating behaviour in obese women during 3 months of
      weight reducing treatment carried by doctors, dietician and psychotherapist. 3
      months of weight reducing treatment resulted in weight loss of 9.1%. Percentage
      of animal fats in the meals was significantly reduced and the percentage of
      complex carbohydrates (fruit and vegetables) and low-fat protein products was
      increased. The change of a diet structure was accompanied by a symptomatic
      decrease of preferences of simple carbohydrates and animal fats as well as
      protein products. 3 months of weight reducing group treatment resulted not only
      in a reduction of weight but also in modification of eating behaviour. The
      beneficial change of food preferences which influenced the composition of the
      consumed meals seems to be good predictor of a long-term effect of the treatment.
      The most favourable results of the weight reducing treatment can be obtained by
      group therapy using eating education and psychotherapy.

PMID- 12607410
TI  - [Individual sensitivity of jejunal mucosa to small doses of gluten in coeliac
      disease ].
AB  - In coeliac patients the age of development of symptoms, clinical picture of the
      disease and complications depend on the dose of ingested gluten. The aim of the
      study was the evaluation of individual sensitivity to small doses of gluten in
      the group of 60 patients aged 2.65 to 17.92 (mean age 7.49) treated with gluten
      free diet for at least 12 months due to coeliac disease diagnosed according to
      ESPGAN criteria (food allergy to gluten excluded). Gluten challenge with dose of
      10 mg/kg body mass/day was controlled with serological tests (IgAEmA, IgAAGA, and
      IgGAGA antibodies) carried out every 3 to 6 months. Jejunal biopsy was performed
      before gluten challenge (normal mucosa), and after positive EmA/AGA antibodies
      tests to confirm diagnosis (flat mucosa). After 35 months of observation 53.7% of
      all patients presented of jejunal villious atrophy, and positive IgAEmA. In this
      group 3.7% presented symptoms after 3 months of gluten challenge, 5.5% after 6
      months, 3.7% after 9 months, and 3.7% after 12 months. In some coeliac patients
      ingestion of small amounts of gluten (10 mg/kg/day) can lead to small intestinal
      villious atrophy.

PMID- 12607411
TI  - [Heart rate variability in patients with hypertrophic cardiomyopathy and in their
      close relatives].
AB  - The results of HRV analysis in patients with hypertrophic cardiomyopathy (HCM)
      are conflicting. We evaluated short-term HRV in patients with familiar HRV and in
      their close relatives. 31 families of patients with HCM were examined. There were
      43 patients with HCM confirmed by 2D-echo (HCM-group, 23 f, 20 m, aged 46 +/- 14
      ys), and 157 family members (REL-group, 75 f, 82 m, aged 29 +/- 17 ys). The
      control group consisted of 180 healthy subjects (80 f, 100 m, aged 33 +/- 12 ys).
      In each subject 512 consecutive sinus beats were recorded in supine position
      during spontaneous breathing using computer-assisted amplifier (A/D 12 bit, 1
      kHz). Mean RR interval (RRI, ms), its standard deviation (SDRR, ms) and spectral
      measures (FFT, Blackman-Harris window): PSD of high frequency (HF) and low
      frequency (LF) [ms2/Hz], as well as respiratory rate (BPM) were measured.
      Patients with HCM had significantly shorter RRI (867 +/- 121) as compared to the
      controls (919 +/- 138, p < 0.05). The RRI was also shorter in the relatives (851
      +/- 150, p < 0.01). In HCM and REL groups the respiratory rate was faster (16.7
      +/- 3.0 and 17.1 +/- 3.4, respectively), as compared to the controls (14.5 +/-
      2.9, both p < 0.01). The HRV measures were reduced in the HCM-group (SDRR 31.4 +/
      10.6, lnHF 7.71 +/- 0.65, lnLF 8.22 +/- 0.65 and LF/HF 1.07 +/- 0.10), as
      compared to the controls (SDRR 64.8 +/- 23.9, lnHF 8.79 +/- 0.61, lnLF 8.87 +/-
      0.65, all p < 0.001 and LF/HF 1.01 +/- 0.07, p < 0.01). In the REL-group SDRR and
      lnHF were significantly reduced (SDRR 52.4 +/- 24.1, lnHF 8.48 +/- 0.78, p <
      0.001), while the remaining parameters were comparable. The HRV reduction was
      more expressed in HCM-patients and family-members < 30 years of age. A
      significantly reduced age-, sex- and RRI-adjusted SDNN was observed in 54% pts in
      HCM-group and in 42% subjects in members-group. Reduced heart rate variability is
      frequently seen not only in patients with diagnosed HCM, but also in a
      substantial number of their kindred.

PMID- 12607412
TI  - [Brachytherapy--own, preliminary experiences in the treatment of head and neck
      neoplasms with the use of pulsed brachytherapy].
AB  - The historical development of brachytherapy from the beginning of the 20th
      century until nowadays is presented. On the basis of the literature the authors
      presented indications, advantages and the technical aspects of brachytherapy.
      Early own experience with the use of pulsed brachytherapy was also reported.

PMID- 12607413
TI  - [The influence of gastroesophageal reflux on asthma].
AB  - The association of gastroesophageal reflux (GER) and respiratory symptoms has
      been investigated for a long time. The results of large number of studies are
      often conflicting. It seems, however, that with present knowledge an agreement
      concerning causal relationship between GER and asthma is possible to achieve.
      This article is to clarify available information related to the subject. It
      presents current views on pathogenesis of GER, its extra esophageal
      manifestations, suggested mechanisms linking reflux and respiratory symptoms. We
      analyzed diagnostic methods used when reflux is suspected as a cause of asthma
      exacerbations. The treatment recommended in such cases and its efficacy is
      discussed. Other diseases of the respiratory system connected with GER are also
      presented.

PMID- 12607414
TI  - [Clinical classification of tremor].
AB  - This paper is a review of up-to-date literature regarding on tremor with a
      special attention paid to classification and clinical types. The division has
      been based on new, uniform classification established in 1998 by Movement
      Disorder Society.

PMID- 12607415
TI  - [Airways remodeling in bronchial asthma--heparin as a potential factors
      suppressing the remodeling].
AB  - In this study we have described current opinions concerning the pathogenesis of
      airways remodeling in bronchial asthma. The participation of different cells and
      their mediators in airways remodeling induction and multiplication have been
      presented as well as the potential role of heparin in suppression of this
      processes.

PMID- 12607416
TI  - [Current principles of Wilson's disease--diagnosis and treatment].
AB  - Wilson's disease defined also as hepatolenticular degeneration is an important
      clinical problem of young adults still causing diagnostic difficulties. In the
      course of the last decade, genetic background of the disease has been definitely
      established and elucidated, confirming the variety of genetic mutations,
      responsible for its origin. The current scheme of the disease treatment has been
      elaborated and established. It aims to eliminate the excess of toxic copper ions
      from the organism as fast as possible. In the initial phase of the treatment,
      traditional and recently introduced chelating agents administration usually
      results in prompt tissue copper deposits excretion and copper metabolism balance
      maintenance. In the chronic therapy, zinc compounds, inducing intestinal and
      hepatic metallothionein synthesis, have been gaining more common application.
      Life-long, constant, pharmacological Wilson's disease therapy, administered after
      its early diagnosis, allows for long periods of patients survival, frequently
      comparable to the normal population.

PMID- 12607417
TI  - [Present view on malignant melanoma treatment].
AB  - Malignant melanoma is a tumor arising from melanocytes. Epidemiological data
      indicate rapid and progressive increase of malignant melanoma cases in Poland and
      other countries. Early diagnosis in malignant melanoma is the most important for
      the prognosis. Therefore the best treatment is ultraviolet prevention--sunscreen
      prophylactic, educational campaigns. Early diagnosis of malignant melanoma is
      based on ABCDE rules, seven point check Glasgow scale, dermatoscopy (a modern
      method in the differential diagnostics) and the knowledge of predisposing
      factors. There are several methods of treatment of malignant melanoma
      (chemotherapy, radiotherapy, immunotherapy etc.) among them surgical procedure is
      still a treatment of choice.

PMID- 12607418
TI  - [The efficacy of intraventricularly administered vancomycin in the case of
      central nervous system infection caused by enterococcus faecalis].
AB  - The case of 40 years old man with subarachnoid hemorrhage with intraventricular
      bleeding and with consecutive cerebro-meningitis is presented. The bacterial
      pathogen was Enterococcus faecalis sensitive only to glycopeptide antibiotics.
      The standard therapy with intravenously administered Vancomycin and Teicoplanin
      was not effective. Because of the worsening of patient's clinical status and
      clinical symptoms of sepsis the intraventricular Vancomycin (20 mg/day) was
      introduced. At the second day of the therapy the gradual patient's recovery was
      observed. The symptoms typical for meningitis diminished as well as cerebro
      spinal fluid (CSF) parameters normalized. There was no bacterial growth in the
      blood serum and in CSF. As we can observe the intraventricular administration of
      Vancomycin is efficient method of cerebro-meningitis treatment. In our opinion
      the blood-brain barrier, even pathologically changed by infection, do not allow
      antibiotics to penetrate CSF, even in the maximal intravenous doses. In the cases
      of cerebro-meningitis caused by bacteria sensitive only to glycopeptide
      antibiotics, the intraventricular administration of the drug might be an
      alternative way of therapy especially when the doses of intravenous antibiotics
      need to be reduced.

PMID- 12607419
TI  - [Ovarian cancer during pregnancy--two case reports].
AB  - Authors presented two different cases of ovarian cancer during pregnancy. The
      first case in the stage IA had favourable course. We performed ovariectomy in the
      second trimester. At the term of delivery cesarean section with total
      hysterectomy and omentectomy with following chemotherapy (PC) were carried out.
      The second case (IIIC stage) had a poor course and diagnosis (Cystadenocarcinoma
      papillary GIII). The management comprised of total hysterectomy and omentectomy
      with following chemotherapy (PAC + Bleomycin + Mitomycin). Despite our treatment
      the development of cancer was observed. The patient died after 8 months since
      operation. Early diagnosis and lower stage of cancer give better prognosis,
      however, clinical management is still discussed.

PMID- 12607420
TI  - [Giant posttraumatic cyst of the left adrenal gland ].
AB  - A case of 31 years old female with giant, posttraumatic cyst of the left adrenal
      gland is presented. It was not possible to make a proper diagnosis
      preoperatively. The correct diagnosis in our patient was based on the results of
      the postoperative microscopic examination of the resected tissues. The diagnostic
      difficulties are discussed.

PMID- 12607422
TI  - [Patient's or doctor's values?].

PMID- 12607421
TI  - [Asphyxiating thoracic dysplasia (Jeune's Syndrome) in 15-years-old boy--6 years
      of observation].
AB  - Asphyxiating thoracic dysplasia (Jeune's Syndrome) is a genetically determined
      dysplasia of thoracic bones usually leading to death during intrauterine life or
      in early childhood. Other osseous dysplasias as well as renal, hepatic and
      pancreatic failure may coexist with Jeune's syndrome. About one hundred cases of
      the syndrome were reported till now. The aim of the study is to describe the
      disease in a 15-year-old boy observed till the age of 20. The disease started in
      the second year of life and was manifested by limitation of thorax development
      and respiratory tract infections. At the age of 15 he was hospitalized due to
      dyspnoea. Short stature, weight deficiency and long, flat chest with significant
      stenothorax as well hypoxemia, pulmonary restriction and obstruction were found
      on admission. Moreover symmetrical decline in isoptic marker uptake without
      regional ventilatory disturbances were detected by ventilation--perfusion
      scintigraphy. The lack of bronchial epithelium and basement membrane thickening
      with present in and under the membrane numerous collagen fibres and fibroblasts
      were revealed in electron microscopy. As it is the first in literature
      description of bronchial mucosa electronogram in Jeune's syndrome we cannot have
      an unequivocal attitude to the described microscopic changes. The increase of
      body weight, height and some anthropometric parameters of the thorax as well as
      the maintenance of pulmonary restriction and obstruction, respiratory failure
      stagnation and circulatory failure deterioration were observed after 6 years of
      follow-up.

PMID- 12607423
TI  - [Arthroscopic surgery for osteoarthritis of the knee is seldom needed].

PMID- 12607424
TI  - [The improved diagnostics of adenomyosis].

PMID- 12607425
TI  - [Imaging techniques in the diagnostics of pulsating tinnitus].

PMID- 12607426
TI  - [Radiation risks and their prevention].

PMID- 12607427
TI  - [Treatment outcome and overall costs of femoral neck fractures].

PMID- 12607428
TI  - [Diagnostics and therapy of cervical lymphoma].

PMID- 12607429
TI  - [Cramp fever?].

PMID- 12607430
TI  - [Oral cancer].

PMID- 12607431
TI  - [ALLHAT--the most comprehensive antihypertensive treatment trial in the world.
      The significance of thiazide diuretics for patients older than 55 years is
      confirmed].

PMID- 12607432
TI  - [Consequences of ALLHAT: Thiazides rehabilitated--time to change prescription
      patterns].

PMID- 12607433
TI  - [An announcement from the ALLHAT: Thiazide diuretics are medically and
      economically superior].

PMID- 12607434
TI  - [Winter vomiting disease--a winter season's curse for health care].

PMID- 12607435
TI  - [Difficult to motivate intravenous addicts for vaccination against hepatitis. The
      campaign in Blekinge was not successful: it reached only 10 percent of the
      group].

PMID- 12607436
TI  - [The consensus development conferences at the National Institutes of Health are
      impressing--powerful discussions focused on knowledge barriers and future
      research].

PMID- 12607437
TI  - [Muhimbili Medical Center in Dar-es-Salaam. Excellent medical education in spite
      of insufficient resources].

PMID- 12607438
TI  - [A comment to the proposal of the Protos group: We recommend a united primary
      health care with team work and the listing system].

PMID- 12607439
TI  - [The family practice platform makes the thoughts in the national handling plan
      concrete].

PMID- 12607440
TI  - [Swedish primary health care needs a national family practitioner system].

PMID- 12607441
TI  - [Cloning of children--a step toward anti-humanism and racial hygiene].

PMID- 12607442
TI  - [Following the National Board of Health and Welfare's criticism of the long
      leaves granted to committed mentally ill patients: Change the psychiatric care
      for something better or change the legislation!].

PMID- 12607443
TI  - [Five answers to Holmgren's crooked questions].

PMID- 12607444
TI  - [From "Robocop" to "Care-O-bot"].

PMID- 12607445
TI  - [Living with dementia quality manual: Lady Di and Dr. Zhivago--or--he who
      searches, finds].

PMID- 12607446
TI  - [The European Pressure Ulcer Advisory Panel: no scale is perfect].

PMID- 12607447
TI  - [Therapy with expertise and psychology: "better nursing care" for insulin
      dependent diabetic patients].

PMID- 12607448
TI  - [Otorhinolaryngology--1: Earache is often only a symptom].

PMID- 12607449
TI  - [Preparation for capital financing contracts--2: Mastering raging with the
      balanced scoreboard].

PMID- 12607450
TI  - [Diagnostic related groups: from legislation to reality].

PMID- 12607451
TI  - [On the path to a diagnostic related groups system: consequences will eventually
      become clearer].

PMID- 12607452
TI  - [The challenges with DRG: making nursing care visible].

PMID- 12607453
TI  - [Determining personnel staffing in nursing care: no real alternative to the
      Nursing Personnel Regulation].

PMID- 12607454
TI  - [Personnel development in nursing--I: Complex responsibilities require complex
      support].

PMID- 12607455
TI  - [New forms of team management: cooperation instead of conflict].

PMID- 12607456
TI  - [Team-oriented scheduling: flexible work times in general practice].

PMID- 12607457
TI  - [Consumer orientation in the hospital: trendy expressor or absolute necessity?].

PMID- 12607458
TI  - [Planning and organization of graduate and continuing education: a check-up for
      more personalized orientation].

PMID- 12607459
TI  - [Learning in nursing care: support in a crisis].

PMID- 12607460
TI  - [Introduction to "nursing consultation" methodology--on the logic of planned
      nursing].

PMID- 12607461
TI  - New surgical procedures diagnose, cure, and palliate cancer.

PMID- 12607465
TI  - [Specialties are changing--is the expertise vanishing?].

PMID- 12607462
TI  - ONS seeks support, action from Congress.

PMID- 12607466
TI  - [Treatment of short bowel patients has to be centralized].

PMID- 12607467
TI  - [Matti Ayrapaa Award to Kai Simons].

PMID- 12607468
TI  - [Possibilities to preserve the fertility of a cancer patient].

PMID- 12607469
TI  - [Using isotopes with short half-life in the diagnostics of oncological diseases].

PMID- 12607470
TI  - [Woman and von Willebrand disease].

PMID- 12607471
TI  - [Other mental disorders presenting together with schizophrenia].

PMID- 12607472
TI  - [Treatment of cervical dysplasia with colposcopy in Finland].

PMID- 12607474
TI  - [Transdural herniation of the spinal cord due to dural tear].

PMID- 12607473
TI  - [The Lemierre syndrome--a rare complication of pharyngitis].

PMID- 12607475
TI  - [Treatment resistant nodules in the arm of an officer].

PMID- 12607476
TI  - An infant with heart murmur and dysmorphic face.

PMID- 12607477
TI  - Optimal use of phototheraphy.

PMID- 12607478
TI  - Serum gamma-glutamyl transpeptidase activity and bile acids in normal Taiwanese
      infants.
AB  - To facilitate making a diagnosis of cholestatic liver disease in Taiwan, we have
      established reference ranges for serum gamma-glutamyl transpeptidase (gamma-GT)
      activity and bile acids in normal Taiwanese infants. The serum level of gamma-GT
      activity was assayed in 90 normal Taiwanese infants and children aged between 2
      days and 2 years old. These data were analyzed in twenty-three 0-3-month-old,
      twenty-four 4-6-month-old, and forty-three 7-24-month-old infants. The mean
      values of serum gamma-GT activity were 47.4 +/- 26.6, 21.5 +/- 7.3, and 14.0 +/-
      3.2 IU/L for the respective age groups. The highest reference gamma-GT values
      were 99.5, 35.8, and 20.3 IU/L for the respective age groups. The mean values of
      serum gamma-GT activity were highest in infants younger than 3 months, and these
      gradually decreased to the adult level with age (p < 0.01). Serum bile acids were
      measured in 24 premature and 56 full-term infants. The mean values of serum bile
      acids were 34.5 +/- 34.5 mumol/L in preterm infants and 18.7 +/- 21.9 mumol/L in
      full-term babies. The bile acid levels of preterm infants were higher than those
      in full-term babies (p < 0.01).

PMID- 12607479
TI  - Serum leptin levels in preterm, healthy and sick-term newborns.
AB  - Leptin, a hormone that signals the brain about the status of body (fat) energy
      stores, has recently been shown to play a role in the regulation of several
      hypothalamic pituitary axes, including the growth hormone axis. To investigate a
      potential association of serum leptin concentrations and clinical condition in
      preterm, sick term and healthy term newborns, serum leptin concentrations were
      evaluated in 104 newborns. Twenty-eight of them were healthy term (18 males and
      10 females; gestational age, 37-42 weeks), 21 were sick term (12 males and 9
      females; gestational age, 37-42 weeks) and 55 were preterm neonates (35 males and
      20 females; gestational age: 26-37 weeks). Leptin values correlate positively
      with birth weight, birth length, head circumference, waist circumference, hip
      circumference, body surface, weight/length ratio, and gestational age (r = 0.38,
      0.42, 0.29, 0.21, 0.29, 0.40, 0.31 and 0.28), respectively. The concentrations of
      leptin are statistically significantly higher (p < 0.05) in term neonates (3.02
      +/- 2.94 ng/ml) than preterm neonates (1.93 +/- 2.21 ng/ml). Female infants also
      have significantly higher (p < 0.05) serum leptin values than male infants in
      preterm and healthy term groups. We also found leptin present in venous blood
      after 26 weeks of gestation.

PMID- 12607480
TI  - Changing position does not improve the efficacy of conventional phototherapy.
AB  - The aim of this study was to compare the efficacy of position-changing
      phototherapy with conventional fixed-position phototherapy. Clinically well, term
      infants with nonhemolytic hyperbilirubinemia were enrolled in the study. After
      entry into the study, infants were randomly assigned to receive single-direction
      phototherapy with or without changing from a supine to a prone position or vice
      versa every 2 h. Phototherapy was initiated when the serum bilirubin
      concentration was greater than 15 mg/dl and was discontinued when the bilirubin
      level had declined below 10 mg/dl. Total serum bilirubin concentrations were
      measured just prior to initiation of phototherapy and at 12-h intervals until
      phototherapy was discontinued. The rate of bilirubin decline expressed by the
      first and secondary 24-h declines and overall bilirubin concentration decrease
      per hour were comparable between the two groups. The rebound in bilirubin levels
      after cessation of phototherapy was negligible, and none of the infants needed re
      phototherapy. We conclude that changing an infant's position at 2-h intervals
      does not improve the efficacy of conventional single-direction phototherapy.

PMID- 12607481
TI  - Inhaled nitric oxide in persistent pulmonary hypertension of the newborn: four
      year experience in a single medical center.
AB  - Forty-eight infants with persistent pulmonary hypertension of the newborn (PPHN)
      from July, 1997 to June, 2001 were enrolled for a prospectively study to
      determine the role of inhaled nitric oxide (NO) treatment and to determine an
      appropriate weaning strategy of NO. The initial dose of NO was started at 10 ppm
      for 10 minutes. If the infant's symptoms did not improve, we used a rapid dose
      ladder schedule for increasing the dose of NO to 20, 40 and 80 ppm every 10
      minutes until we achieved the desired response. When oxygenation improved for 30
      minutes, NO was decreased by 5 ppm every 10 minutes until reaching 5 ppm which
      was maintained for 2-3 hours. During the NO weaning period, if the SpO2 decreased
      by 10% or fell below 85%, the NO was increased to the previous higher dose and
      maintained this lowest effective dose for 2-3 hours. During this period, FiO2 was
      decreased by 10% every 10 minutes and peak inspiratory pressure was decreased
      gradually as the infant tolerable to avoid a decrease in saturation; we then
      tried to repeat the weaning procedure of NO. Inhaled NO was discontinued at 5 ppm
      if the infants were stable for 2-3 hours, and at the same time FiO2 was permitted
      to raise 10-20%. If SpO2 decreased by 10% or fell below 85% within 5 minutes, NO
      was reinstated at 5 ppm. A second attempt at weaning NO was made 2-3 hours later
      when the infants were stable. Thirty-four infants (70.8%) survived. Forty infants
      (83.3%), including 34 who survived and 6 who died, had good responses to inhaled
      NO. The mean effective NO concentration was 37 (5-80) ppm. The mean duration of
      inhaled NO treatment was 43 (6-153) hours. This study has demonstrated that
      inhaled NO is an effective rescue treatment for infants with severe PPHN, but the
      final outcome of infants depends not only on the response to inhaled NO but also
      on the associated complications. Using our weaning strategy, we shortened the
      duration of inhaled NO treatment as compared with a previous study (43 vs. 87
      hours). Beginning inhaled NO therapy early in severe PPHN may be an important
      factor in shortening the duration of NO therapy. Further controlled trials of
      this weaning strategy are warranted.

PMID- 12607482
TI  - Specific IgE to 5 different major house dust mites among asthmatic children.
AB  - Asthma is one of the most commonly occurring manifestation of allergy in Taiwan.
      Sensitivity to house dust mites is closely related to childhood asthma. This
      study was designed to investigate sensitized rates and average concentrations of
      specific IgE antibodies to 5 major house dust mites (HDMs) among asthmatic
      children. A total of 93 asthmatic children aged from 3 to 15 years were enrolled
      to measure their specific IgE concentrations in response to 5 different species
      of mites: Dermatophagoides pteronyssinus (Dp), Dermatophagoides farinae (Df),
      Dermatophagoides microceras (Dm), Euroglyphus maynei (Em), and Blomia tropicalis
      (Bt). The severity of hypersensitivity was classified based on the concentration
      of specific IgE as mild (0.35-3.5 kuA/L), moderate (3.5-50 kuA/L), and severe (>
      50 kuA/L). Sixty-three asthmatic children were found to have specific IgE to at
      least one mite. The percentage of these 63 children who had specific IgE to Dp,
      Df, Dm, Em and Bt were 87%, 85%, 84%, 77%, and 65%, respectively. Patients with
      specific IgE to Dp, Df, Dm, and Bt, had a high percentage of moderate and severe
      hypersensitivity (83.6%, 83.4%, 81.4%, 70.6%, respectively). However, patients
      sensitized to Em have relatively lower concentration of specific IgE Ab, with 75%
      of them in the mild range. Some patients had positive IgE antibody to Em (3.2%),
      and Bt (3.2%) even though they had none to Dp and Df. We conclude that Dm and Bt
      are also important mite allergens in atopic children. Conventional testing that
      assays only for sensitivity to Dp and Df would fail to demonstrate 6.4% of mite
      sensitized asthmatic children.

PMID- 12607483
TI  - Clinical spectrum of bronchiectasis in children.
AB  - The prevalence of bronchiectasis decreased due to the effective use of vaccines
      and advances of antibiotic therapy after 1970. However, it remains an important
      long-term morbidity of lower respiratory tract infection in developing country.
      To evaluate the clinical features of bronchiectasis in a tertiary hospital, we
      collected 21 patients with a diagnosis of bronchiectasis in Taipei Veterans
      General Hospital from May, 1984 to Dec, 2001 in pediatric outpatient with the
      admission of age below 18 years old. The diagnosis was based on the history of
      recurrent cough with fetid sputum, hemoptysis, or recurrent lobar pneumonia for
      months at least and radiological findings of lobar infiltration, tram-track like
      patterns, bronchiolar dilatation or honeycomb patterns. The diagnostic
      examinations included chest plain radiography, bronchography and chest computed
      tomography (CT) scans. Respiratory tract infections were the commonest cause
      predisposing to bronchiectasis in our study. Tuberculosis is not rare in this
      study. In recent years, immunodeficiency disorders have been recognized. Most
      patients suffered from recurrent cough and fetid sputum for years before
      diagnosis was established. Hemoptysis was the second common symptom in our study.
      The plain chest radiograph of bronchiectasis revealed dilatation of bronchial
      trees with honeycomb pattern or infiltration only. In recent years, chest CT
      became the most accurate and being noninvasive diagnostic tool. The initial
      treatment was primarily medical conservative therapy. Only five patients in our
      cases underwent pulmonary resection due to persistent hemoptysis, recurrent
      bacterial pneumonia or pulmonary parenchyma destruction. Most patients still
      suffered from recurrent pneumonia or occasional exacerbation in the long-term
      follow-up. In conclusion, bronchiectasis is not uncommon in pediatric population
      in northern Taiwan. The history of recurrent cough with fetid sputum, hemoptysis,
      or recurrent pneumonia were the most important clues to early diagnosis of this
      disease. Early diagnosis and appropriate treatment are effective in order to
      prevent lung abscess, empyema and pneumothorax, bronchopleural fistula,
      hemoptysis or cor pulmonale.

PMID- 12607484
TI  - Total anomalous pulmonary venous return complicated by progressive pulmonary
      venous stenosis after total repair: report of one case.
AB  - Total repair of an infracardiac type total anomalous pulmonary venous return was
      performed on a 3-day-old female newborn. Echocardiogram study showed a smooth
      connection between the pulmonary veins and the left atrium one week after the
      operation, however, later echocardiograms showed a progressive obstruction of the
      pulmonary veins. The patient died at 50 days of age due to lung congestion. The
      autopsy revealed severe intima hypertrophy and upstream obstruction in every
      pulmonary vein, while the anastomosis between the left atrium and the pulmonary
      venous confluence remained well patent. In view of the high rate of progressive
      pulmonary venous stenosis after total repair in patients with infracardiac type
      total anomalous pulmonary venous return, it is advised that the operator should
      try to mobilize every pulmonary vein, make larger areas of anastomosis with
      pericardial patch augmentation and avoid using continuous suture. When the
      progressive pulmonary venous stenosis occurred during the follow-up period, a
      'sutureless neoatrium' procedure can be used to resolve the obstructions.

PMID- 12607485
TI  - Management of acute decompensation of neonatal maple syrup urine disease with
      continuous arteriovenous haemofiltration: report of one case.
AB  - A 22-day-old female infant was referred to our hospital due to unusual urine odor
      suspecting inborn error of metabolism. Physical examination revealed a stuporous
      and hypotonic infant with poor reflexes. Intravenous thiamine and high glucose
      along with appropriate protein were given under the suspicion of maple syrup
      urine disease (MSUD), which was confirmed by blood and cerebrospinal fluid amino
      acid assays, and urinary organic acid assay. Progressive neurological
      deterioration was observed despite the non-invasive treatment. So, we performed
      pump assisted continuous arteriovenous haemofiltration (CAVHF). Dramatic
      improvement in neurological function was observed hours after initiation of
      CAVHF, along with decrease in the level of isoleucine, leucine and valine. In our
      experience, CAVHF is a well-tolerated procedure for managing the acute phase of
      neonatal MSUD. Further study on indications, duration of treatment, and
      preventing complications is needed.

PMID- 12607486
TI  - Hypersensitivity to vitamin preparation in parenteral nutrition: report of one
      case.
AB  - We report an 8-year-old girl with adhesion ileus complicated with jejunal
      perforation. The patient developed an anaphylactic reaction to parenteral
      nutrition. The anaphylactic reaction was caused by the vitamin B complex
      solution.

PMID- 12607487
TI  - Bacterial meningitis of an infant with Currarino triad.
AB  - Currarino triad is a rarely hereditary condition including: (1) an anorectal
      malformation, (2) an anterior sacral defect, and (3) a presacral mass. Autosomal
      dominant transmission is suggested. We reported one case of Currarino triad, who
      was a 3-month-old male with sacral dysgenesis, imperforated anus and enteric
      cyst. This case presented with acute lower limbs paralysis due to bacterial
      meningitis complicated with acute arachnoiditis. The diagnosis of this condition
      led to a work-up of his sibling, who was found to have an incomplete type. The
      purpose of this case is to emphasize that a high index of suspicion for timely
      diagnosis and treatment of Currarino triad could prevent devastating
      complications.

PMID- 12607489
TI  - [Free choice].

PMID- 12607488
TI  - Necrotizing pneumonia caused by Streptococcus pneumoniae in a child with systemic
      lupus erythematosus.
AB  - Necrotizing pneumonia caused by Streptococcus pneumoniae is not an uncommon
      disease in children. Here we report a case of necrotizing pneumonia caused by
      Streptococcus pneumoniae in a 13-year-old girl. She was a case of systemic lupus
      erythematosus (SLE), and has long been treated with corticosteroids and
      azathioprine. She acquired pneumococcal necrotizing pneumonia later on. After
      appropriate antimicrobial therapy and surgical intervention, her condition
      stabilized and she recovered gradually. The present case suggests the need for a
      comprehensive diagnostic approach in patients with SLE who are undergoing
      immunosuppressive therapy, in order to screen for the possibility of infections
      if a new pulmonary pathologic process is present, even if the patient has no
      symptoms/signs indicating severe pulmonary infections.

PMID- 12607490
TI  - [Clinical medical research--from wrong to worse?].

PMID- 12607491
TI  - [New impetigo--new therapeutic recommendations].

PMID- 12607492
TI  - [Hereditary antithrombin deficiency and pregnancy--what is the effective
      thromboprophylaxis?].

PMID- 12607493
TI  - [Diagnosis of hypertension in general practice--are office pressure measurements
      sufficient?].

PMID- 12607494
TI  - [Primary coronary angioplasty or thrombolytic therapy for acute myocardial
      infarction?].

PMID- 12607496
TI  - [Cortical blindness and pre-eclampsia].

PMID- 12607495
TI  - [National guidelines for treatment of chronic myelogenous leukemia].

PMID- 12607497
TI  - [Who seeks counseling with the foundation Alternative to Abortion in Norway?].

PMID- 12607498
TI  - [Nutritional status and post-transplantation risks].

PMID- 12607499
TI  - [Fulminant liver failure in acute hepatitis B virus infection].

PMID- 12607500
TI  - [Methanol poisoning--an update].

PMID- 12607501
TI  - [Intracytoplasmic sperm injection and congenital syndromes because of imprinting
      defects].

PMID- 12607502
TI  - [Drugs against urinary incontinence].

PMID- 12607503
TI  - [Biological mechanisms and some clinical effects of alcohol].

PMID- 12607504
TI  - [The contribution of alcohol to common clinical symptoms].

PMID- 12607505
TI  - [Alcohol and the European Union--free flow?].

PMID- 12607506
TI  - [Physician as patients' attorney--loyalty limitations].

PMID- 12607507
TI  - [PCI as emergency treatment--where and how?].

PMID- 12607508
TI  - [The first heart surgery in the world].

PMID- 12607509
TI  - [Anticholesteremic agents and omega-3 fatty acids].

PMID- 12607510
TI  - [Analytic epidemiology--patient-control studies and cohort studies].

PMID- 12607511
TI  - [Methanol analyses].

PMID- 12607512
TI  - A matter of life or death: mortality in Crohn's disease.

PMID- 12607513
TI  - Safety of selective cyclooxygenase-2-inhibitors in inflammatory bowel disease.

PMID- 12607514
TI  - Making the grade: should patients with UC and low-grade dysplasia graduate to
      surgery or be held back?

PMID- 12607515
TI  - [Obstetrics--new developments].

PMID- 12607516
TI  - [Prevention, skin care and avoiding pressure. Prevention of decubitus ulcers, 2].

PMID- 12607517
TI  - [Erection disorders--significance for partnership].

PMID- 12607518
TI  - [Abbott Symposium. New developments in management of tumor-induced weight loss].

PMID- 12607519
TI  - [Living with psychiatric patients--self-confidence and solidarity].

PMID- 12607520
TI  - Insights into the functional organisation of the respiratory and cardiovascular
      systems - are lesions deficit models useful?

PMID- 12607521
TI  - What causes autonomic dysreflexia after spinal cord injury?

PMID- 12607522
TI  - Why do we measure baroreflex sensitivity the way we do?

PMID- 12607523
TI  - [High risk patient profit from early treatment with interferon beta 1a].

PMID- 12607524
TI  - [Parkinson disease: effective treatment of sleep disturbances].

PMID- 12607525
TI  - What's new on the dental scene? Browsing through the dental literature.

PMID- 12607527
TI  - [Regulations. MDS Expert Forum: Evidence and value of early detection measures
      need to be proven].

PMID- 12607528
TI  - Death receptors on reactive astrocytes: a key role in the fine tuning of brain
      inflammation?
AB  - Immune responses protect the CNS against pathogens. However, the fact that there
      is little dispensable tissue in the brain makes regulation necessary to avoid
      disastrous immune-mediated damage. Astrocytes respond vigorously to any brain
      injury (e.g., tumor, stroke, AD, MS, HIV) and are postulated to play an important
      role in the fine tuning of brain inflammation. The authors propose that
      astrocytes use death receptors to modulate pro- and anti-inflammatory effects.

PMID- 12607529
TI  - MR venography.

PMID- 12607530
TI  - Immune haemolytic anaemia due to visceral leishmaniasis in a young child.

PMID- 12607531
TI  - Renal function in patients with Menkes disease.

PMID- 12607532
TI  - Spectrum of arterial obstructions caused by one elastin gene point mutation.

PMID- 12607533
TI  - Enhanced compositional contrast in imaging of nanoprecipitates buried in a
      defective crystal using a conventional TEM.
AB  - In this article, we show that nanometer-sized precipitates of atomic numbers
      higher than those of the surrounding crystalline matrix can be clearly revealed
      in a conventional transmission electron microscope by high-angle, centered dark
      field imaging after minimizing the diffraction contrast. The effect is similar to
      that of Z-contrast STEM, albeit with a spatial resolution limited to 1 nm. Its
      sensitivity to atomic number differences between precipitates and matrix is about
      10, which is demonstrated for precipitates formed after Er, Ge, Cr, and Si ion
      implantation into SiC.

PMID- 12607536
TI  - Prenatal and post-natal imaging of an hepatic mesenchymal hamartoma.

PMID- 12607535
TI  - Rectal bleeding in a preterm infant as a symptom of allergic colitis.

PMID- 12607534
TI  - Induction of nitric oxide synthase in RAW 264.7 macrophages by lipoteichoic acid
      from Staphylococcus aureus: involvement of protein kinase C- and nuclear factor
      kB-dependent mechanisms.
AB  - This study investigates the signaling pathway involved in inducible nitric oxide
      synthase (iNOS) expression and nitric oxide (NO) release caused by Staphylococcus
      aureus lipoteichoic acid (LTA) in RAW 264.7 macrophages. A phosphatidylcholine
      phospholipase C (PC-PLC) inhibitor (D-609) and a phosphatidylinositol
      phospholipase C (PI-PLC) inhibitor (U-73122) attenuated LTA-induced iNOS
      expression and NO release. Two PKC inhibitors (Go 6976 and Ro 31-8220), an NF
      kappaB inhibitor (pyrrolidine dithiocarbamate; PDTC), and long-term (24 h) 12
      phorbol-13-myristate acetate (PMA) treatment each also inhibited LTA-induced iNOS
      expression and NO release. Treatment of cells with LTA caused an increase in PKC
      activity; this stimulatory effect was inhibited by D-609, U-73122, or Ro 31-8220.
      Stimulation of cells with LTA caused IkappaB-alpha phosphorylation and IkappaB
      alpha degradation in the cytosol, and translocation of p65 and p50 NF-kappaB from
      the cytosol to the nucleus. Treatment of cells with LTA caused NF-kappaB
      activation by detecting the formation of NF-kappaB-specific DNA-protein complexes
      in the nucleus; this effect was inhibited by Go 6976, Ro 31-8220, long-term PMA
      treatment, PDTC, L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), and
      calpain inhibitor I. These results suggest that LTA might activate PC-PLC and PI
      PLC to induce PKC activation, which in turn initiates NF-kappaB activation, and
      finally induces iNOS expression and NO release in RAW 264.7 macrophages.

PMID- 12607537
TI  - Successful treatment of pharmacoresistent continuous spike wave activity during
      slow sleep with levetiracetam.

PMID- 12607538
TI  - Safety and efficacy of ibuprofen versus indomethacin in preterm infants.

PMID- 12607540
TI  - [Mass lesion on the tongue. Ulcerous eosinophilic granuloma of the tongue].

PMID- 12607539
TI  - Epstein-barr virus latent membrane protein-1 mediates upregulation of tumor
      necrosis factor-alpha in EBV-infected T cells: implications for the pathogenesis
      of hemophagocytic syndrome.
AB  - The infection of human T cells by Epstein-Barr virus (EBV) may result in a fatal
      hemophagocytic syndrome (HS). We have previously shown that EBV can selectively
      upregulate the tumor necrosis factor-alpha (TNFalpha) gene and lead to activation
      of macrophages in a manner similar to the pathobiology of HS in EBV-infected T
      lymphoproliferative disorders (LPDs). This study was designed to further clarify
      the specific EBV gene product(s) responsible for TNFalpha upregulation. RT-PCR
      analysis of EBV gene expression was performed on 2 CR2-transfected EBV-infected T
      lymphoma lines and 2 EBV-infected B cell lines. To identify the EBV gene
      responsible for upregulation of TNFalpha, 2 reporter recombinant plasmids, pTNF
      CAT and pTNFalpha-Luc, were then constructed and cotransfected with the
      expression plasmids of the EBV latent and lytic genes (EBNA-1, EBNA-2, LMP-1, LMP
      2A, and BZLF-1) in both T and B cell lines. Analyses using ELISA and Western
      blotting were further performed to detect the secreted TNFalpha. The results
      revealed that EBNA-1 and LMP-1 were consistently expressed in EBV-infected T cell
      lines (type II latency), while a type III latency with expression of EBNA-1, EBNA
      2, LMP-1, and lytic BZLF transcripts was detected in EBV-infected B cell lines.
      LMP-1 was demonstrated to be the only EBV gene product to transactivate the
      TNFalpha gene, and this phenomenon was observed only in T, not in B, cells.
      Enhanced secretion of TNF-alpha protein was also detected in LMP1-transfected T
      cell lines. We concluded that LMP1 is the candidate protein in the upregulation
      of the TNFalpha gene in T cells and is probably responsible for the pathogenesis
      of HS in EBV-infected T lymphoproliferative disorders.

PMID- 12607541
TI  - Evaluation of antibody response after vaccination with conjugate Haemophilus
      influenzae type b vaccine in infants and toddlers in Slovakia.

PMID- 12607542
TI  - Complications of varicella requiring hospitalisation before and after the
      introduction of varicella vaccine in a children's hospital in Taiwan.

PMID- 12607543
TI  - Hair changes in congenital disorders of glycosylation (CDG type 1).

PMID- 12607544
TI  - Ptosis in patients with hemispheric strokes.

PMID- 12607545
TI  - Diffusion abnormalities and Wernicke encephalopathy.

PMID- 12607546
TI  - Diffusion abnormalities and Wernicke encephalopathy.

PMID- 12607547
TI  - Estimated folic acid intakes from simulated fortification of the New Zealand food
      supply.
AB  - AIM: To identify a folic acid food fortification programme that will maximise the
      percentage of women of child-bearing age receiving at least 400 microg folic
      acid/day, the amount shown to reduce the risk of neural tube defect-affected
      pregnancies, while not putting population groups at risk of excessive intakes.
      METHODS: 1997 New Zealand National Nutrition Survey data and a computer modelling
      programme were used to estimate folic acid intakes from simulated fortification
      scenarios. RESULTS: Breads fortified with folic acid at 150 microg/50 g, white
      flour at 100 microg/35 g and liquid milk at 200 microg/200 ml, were found to be
      the best fortification scenarios. Thirty one percent, 21% and 18% of women of
      child-bearing age received > or = 400 microg folic acid/day from the
      fortification of bread, white flour and milk respectively. CONCLUSIONS: The most
      effective scenario for folic acid fortification is bread fortified at 150
      microg/50 g. However, it is impossible to fortify food at a level that ensures
      the majority of women of child-bearing age receive more than 400 microg folic
      acid/day without exposing some people to excessive amounts of folic acid. The
      current public health message encouraging women to select folic acid fortified
      foods and take folic acid supplements, needs to continue.

PMID- 12607548
TI  - [Rayer's studies on the contagion of glanders (1837-1843)].
AB  - P. Rayer (1795-1867) had never thoroughly published his experimental studies on
      the contagion of glanders. His recently un-earthed hand written papers allow us
      to depict his experimental approach and its results. He was not the first who
      transmitted glanders from a patient to horses or donkeys. But he did it
      systematically with glander secretions from acute and chronic cases. Whatever was
      the disease of the donors the transmitted forms were unpredictably either chronic
      or acute. His conclusion was that the two forms were two symptomatic aspects of a
      unique disease. Clinically dormant states were shown to be also contagious. He
      demonstrated it through deliberately altering healthy and sick horses inside the
      stable and by using saddles, bridles and brushes of sick horses on healthy ones.
      Moreover he excluded other causative factors tentatively proposed, peculiarly
      food products. The systematically logical and rigorous experimental approach used
      by Rayer for this research is a mile stone, 30 years before Pasteur. This
      methodology is still nowadays used to study the epidemiology of diseases such as
      Prion Diseases, Mad Cow for instance.

PMID- 12607550
TI  - Inappropriate examination.

PMID- 12607549
TI  - Time for gastroscopy.

PMID- 12607551
TI  - Failure to provide the necessaries of life.

PMID- 12607553
TI  - An infrarenal abdominal aortic aneurysm.

PMID- 12607552
TI  - [Second consensus statement on the use of antimicrobial drugs in chronic
      obstructive pulmonary disease exacerbations].

PMID- 12607554
TI  - Retraction.

PMID- 12607555
TI  - [Nurses in the first times of World War one].
AB  - The First World War originated in new and huge problems for both military
      authorities and military health service. The modern war which begun in 1914
      overflowed this Service reformed in 1912. Famous journalists and political men
      such as Barres and Clemenceau took part against dramatic conditions encountered
      by wounded soldiers. The First World War saw the introduction of many new
      technologies to the art of killing one's enemy among them the machine gun and the
      heavy use of artillery. It resulted in massive amount of wounded and ill soldiers
      which overflowed the military health service and every evacuation mean to the
      rear front. From August 2nd, 1914 to December 31st, 1914, 798. 833 French wounded
      soldiers and 322.672 ill soldiers were treated by the French Army 7th direction,
      in charge of the military health service. In such circumstances, a voluntary,
      parallel and the efficient sanitary organisation took an importance unknown until
      yet. This organisation, the Red Cross, associated the Societe francaise de
      secours aux blesses militaires (French society for help to the wounded soldiers),
      the Union des Femmes de France (French Women Union) and the Association des Dames
      francaises (French Ladies Association). These three organisations, associated to
      many religious ones, brought a real sanitary structure so necessary in the
      troubled period as the beginning of the First World War. Everywhere in France,
      health service structures such as the hopital temporaire no. 103 (Temporary
      Hospital number 103) in Paris, model hospital from the Union des Femmes de
      France, associated volunteers civilian doctors and surgeons. To increase the
      professional value of the paramedical staffs, a very specific effort was done for
      the formation of nurses in number, as correctly and as quickly as possible.
      During the first year of the First World War, nurses will be estimated since they
      had been able by their action to balance the disorder of the very first time of
      the conflict.

PMID- 12607557
TI  - [Broca and the beginning of modern neuro-surgery].
AB  - This article deals with Broca's pioneering efforts on cerebral localizations and
      craniotopography and their implementation for the first craniotomy.

PMID- 12607558
TI  - [German Galerant: September 8, 1914-March 17, 2001].

PMID- 12607556
TI  - [Prophylaxis and treatment of fungal infections in oncohematological patients].

PMID- 12607559
TI  - [Dissections places and mortuaries in Paris from 1200 to 1980].
AB  - Before French Revolution of 1789, Church and University forbid dissections for
      clerks and Doctors. The first, old Faculty in Bucherie street had three
      amphitheatres in 1608 (Jabot), 1617 (Riolan), 1744 (Winslow). Two men taught
      anatomy, a latin speaking professor and a operating barber-surgeon. To learn
      anatomy, surgeons students had to hide for dissections in Hotel-Dieu, masters'
      houses, or had to steal corpses. The better learning place was the Surgery's
      College 1515, at 5 medical school street, where two successive amphitheatres were
      built in 1615 (Pineau) and 1691, and finally at the Royal Surgical Academy at the
      12 of the same street. French kings, in order to avoid the Church and
      University's bad power, created also in 1529 the French College and King's garden
      in 1673 with Dionis. The chiefly problem was the lack of corpses.

PMID- 12607560
TI  - Son of a mother against decapentaplegic.

PMID- 12607561
TI  - Evidence-based practice in psychosocial intervention in early dementia: how can
      it be achieved?

PMID- 12607562
TI  - [The pharmacist's actions and responsibilities during regular professional
      activities (I). Study conducted in 1999-2000 by the French National Academy of
      Pharmacy (Report by Francis Puisieux)].

PMID- 12607563
TI  - Growing pains for environmental justice movement.

PMID- 12607564
TI  - Dust busters gather.

PMID- 12607565
TI  - GHA remains focused in new political landscape.

PMID- 12607566
TI  - Preventing mental illness, 1882.

PMID- 12607567
TI  - Actinomycotic tubo-ovarian abscess mimicking pelvic malignancy.
AB  - A 39-year-old multipara was admitted to hospital with lower abdominal pain. She
      had used an intrauterine device (IUD) for 10 years. Three years ago, her tubes
      were ligated. Ultrasound examination revealed a 9.5 x 6 cm multiloculated cystic
      mass in the right part of her lower abdomen. CA-125 was also found to be
      increased. Since ovarian malignancy was suspected, laparotomy was performed.
      Pathologically, an actinomycotic tubo-ovarian abscess with sulfur granules was
      disclosed.

PMID- 12607568
TI  - HMOs lost 3 million enrollees in 2001.

PMID- 12607570
TI  - Behaviour of insomniacs and implication for their management.

PMID- 12607569
TI  - Building a framework for improving oral health: National Oral Health Conference.

PMID- 12607571
TI  - Zolpidem "as needed" for the treatment of primary insomnia: a double-blind,
      placebo-controlled study.

PMID- 12607572
TI  - Polysomnographic findings during non-continuous administration of zolpidem.

PMID- 12607573
TI  - Zolpidem "as needed" versus continuous administration: Pan-European study
      results.

PMID- 12607574
TI  - The caudate lobe of the liver: implications of embryology and anatomy for
      surgery.
AB  - The anatomy of the caudate lobe has technical and possibly oncologic implications
      for surgeons. The complex anatomy of the lobe is clarified by embryologic and
      anatomic analysis. This posterior sector is embryonically and anatomically
      independent of the right and left liver and the main portal fissure. The caudate
      lobe represents the only part of the liver that is in contact with the vena cava,
      except at the entrance of the main hepatic veins into the vena cava, and provides
      an anastomosis between the hepatic veins and vena cava. The entire caudate lobe
      is a single anatomic segment that is defined by the presence of portal venous and
      hepatic arterial branches, which supply the lobe, draining biliary ducts, and
      hepatic veins. Because no separate veins, arteries, or ducts can be defined for
      the right paracaval portion of the posterior liver and because pedicles cross the
      proposed division between the right and left caudate, the concept of segment IX
      is abandoned. The significance of caudate anatomy is reflected in the increase in
      the frequency and safety of major hepatic resection for primary and metastatic
      tumors in the liver. Right hepatic lobectomy routinely involves resection of the
      right portion of the caudate lobe (C. Couinaud, unpublished data, 1999). In the
      case of hilar bile duct cancer, which may extend into the dorsal ducts
      (especially the right lateral duct), partial or total caudate lobectomy is often
      necessary for complete extirpation of the tumor. Isolated caudate lobectomy can
      be performed for hepatocellular carcinoma that arises in the caudate lobe or for
      other tumors that arise in the lobe. The caudate lobe can be resected as part of
      the donor liver in preparation for a living related donor transplantation.
      Knowledge of the surgical anatomy of the caudate lobe is an essential part of the
      repertoire for surgeons who perform liver transplants or treat hepatobiliary
      cancer.

PMID- 12607575
TI  - A scientist revisits the atrophy-hypertrophy complex: hepatic apoptosis and
      regeneration.
AB  - In 1898, Cantlie demonstrated his deep insight into the AHC when he wrote. "It is
      theoretically possible to tie the vessels of one side at the gate of the
      liver...leaving the other side to do the work. That one-half of the liver can
      hypertrophy, so as to perform the function of the whole, is attested by
      pathological study...I commend this subject to all those who are working on the
      surgery of the liver; and I believe that if, in the hands of future observers,
      the statements I have made receive closer investigation, surgery of the liver
      will be advanced a step." More than 100 years later, his foresight is coming to
      fruition, but the understanding of the AHC remains rudimentary. Further insight
      into the cellular and molecular mechanisms that initiate hepatocyte replication
      after contralateral atrophy may allow the development of novel therapeutic
      treatments or adjuncts.

PMID- 12607576
TI  - Preoperative imaging of biliary tract cancers.
AB  - Many imaging techniques are available for the evaluation of patients with
      malignant obstructive jaundice. Ultrasonography, in experienced hands, is
      valuable for evaluating the local extent of the disease, but its usefulness for
      staging distant metastases is limited. When used properly, CT and MR imaging can
      provide valuable information about the extent of local tumor involvement and
      distant metastases. These noninvasive techniques provide images of the bile ducts
      and vascular images that are comparable in quality to those obtained with more
      invasive procedures, such as PTC, ERCP, and angiography, and do not have the risk
      for complications of these invasive techniques.

PMID- 12607577
TI  - Role of laparoscopy in the evaluation of biliary tract cancer.
AB  - Patients with malignancies of the biliary tract have a dismal prognosis. As in
      most abdominal cancers, resection is the only effective treatment with potential
      for cure. Preoperative staging is not completely accurate, however, and a
      significant number of patients with biliary carcinoma undergo unnecessary
      laparotomy. As imaging technology improves, more patients with unresectable
      disease will be identified, avoiding the need for a laparotomy. Laparoscopy is a
      major addition, but its usefulness in staging of abdominal malignancies continues
      to evolve. The importance of laparoscopy to better predict the resectability in
      liver malignancies increasingly has been recognized. Conversely, the use of
      staging laparoscopy for other cancers has shown little benefit. For hilar
      cholangiocarcinoma and gallbladder cancer, the authors' analysis of 100 patients
      supports the use of staging laparoscopy for assessing these tumors. In this
      series, staging laparoscopy correctly identified unresectable disease and
      prevented unnecessary laparotomy in one third of patients. Patients with
      unresectable disease that was not detected at laparoscopy most often had locally
      advanced tumors. LUS did not contribute to the assessment of resectability in
      these patients. The yield of laparoscopy was lower for hilar cholangiocarcinoma,
      but could be improved by targeting patients who are at higher risk for occult
      unresectable disease, such as patients with T2 or T3 lesions. These patients and
      patients with primary gallbladder carcinoma have a high incidence of metastatic
      disease and should undergo laparoscopic staging before attempting at resection.

PMID- 12607578
TI  - Hepatic resection in the treatment of perihilar cholangiocarcinoma.
AB  - Proximal bile duct cancer poses a difficult surgical problem in hepatobiliary
      surgery because of its location, patterns of spread, and required extent of
      resection for complete excision. This article focuses on the anatomic and
      pathologic issues that are associated with proximal bile duct cancer and assesses
      the roles of partial hepatectomy and bile duct resection in the surgical
      management of this cancer. It is hoped that this article provides clinical
      evidence that supports hepatic resection as an essential and efficacious
      component of the surgical management of perihilar cholangiocarcinoma in selected
      patients.

PMID- 12607580
TI  - Palliative treatment of unresectable bile duct cancer: which stent? which
      approach?
AB  - Nonsurgical options for the palliative treatment of unresectable bile duct cancer
      are discussed. Despite all of the available approaches, the disease remains
      uniformly fatal. The goal of managing unresectable bile duct cancer is to treat
      the symptoms that still contribute to significant morbidity and mortality.
      Further development of new treatment strategies and modalities is needed to
      improve the quality of life and survival of patients with this disease.

PMID- 12607579
TI  - Preliminary experience with liver transplantation in selected patients with
      unresectable hilar cholangiocarcinoma.
AB  - Previous experience with OLT for hilar CCA has been discouraging, and survival
      was dismal. This study demonstrates that carefully selected patients with
      unresectable hilar CCA can achieve long-term survival after OLT. The survival
      rate obtained with this protocol (5-year actuarial survival of 87%) is comparable
      with the overall survival rate of liver-transplant recipients at the authors'
      institution. In comparison, the best survival rate after OLT for hilar CCA
      reported in the literature is 64.8% at 5 years in a subset of nine patients with
      negative lymph nodes. In the absence of a control group, it is difficult to
      assess with certainty the role of a combination of chemotherapy and radiotherapy,
      but in some patients it seems to prevent or slow progression of the disease while
      waiting for an available organ. Treatment-related morbidity, although
      significant, is not prohibitive. Nevertheless, a considerable proportion of
      treated patients ultimately was found to have advanced disease precluding
      transplantation. This finding confirms the importance of the staging laparotomy
      as an essential component of the protocol.

PMID- 12607581
TI  - Palliative and postoperative radiotherapy in biliary tract cancer.
AB  - Local failure is the primary limitation for cure in patients with BTC. whether or
      not they have been resected. The use of radiotherapy with or without chemotherapy
      in the postoperative setting is controversial, but some studies have reported
      improvement in 5-year survival. In patients with unresectable BTC, EBRT offers
      effective palliation of symptomatic disease and has resulted in improved median
      and long-term survival in a small number of patients in most studies. Novel
      approaches, including neoadjuvant chemoradiotherapy combined with OLT, and
      escalated conformal irradiation, seem to be promising and warrant further
      investigation.

PMID- 12607583
TI  - Extent of resection and outcome after curative resection for intrahepatic
      cholangiocarcinoma.
AB  - According to the classification from the Liver Cancer Study Group of Japan, ICC
      can be classified into three major macroscopic types: MFCC, periductal
      infiltrating, and intraductal-growth [19]. Although most ICC cases in the
      literature seem to be cases of MFCC, they are actually mixtures of MFCC and non
      MFCC. Subtypes of ICC should be specified in future studies. Radiologic findings
      of MFCC are similar to those of secondary liver cancer, and the preoperative
      diagnosis of MFCC is sometimes difficult. The outcome after surgical treatment
      for MFCC is slightly worse than that for HCC. Among patients with MFCC, almost
      all recurrences occur within a year, and most patients with recurrence die within
      2 years after hepatic resection. Lymph node metastasis is the most distinctive
      prognostic factor, and the presence of lymph node metastasis in MFCC may be a
      sign of disseminated disease.

PMID- 12607582
TI  - Indications for and limitations of portal vein embolization before major hepatic
      resection for hepatobiliary malignancy.
AB  - Portal vein embolization is a promising adjunctive tool in liver surgery;
      however, the understanding of liver regeneration and PVE is still in its infancy.
      Refinement in patient selection criteria and methods to evaluate hepatic
      hypertrophy and function should increase the potential indications for PVE and
      expand the field of major liver surgery.

PMID- 12607584
TI  - Surgical indications and extent of resection in gallbladder cancer.
AB  - Gallbladder cancer often is diagnosed at an advanced stage when the prognosis is
      dismal. Early tumors (T1) that are recognized incidentally are curable with
      simple cholecystectomy alone. All other tumors should be resected with an
      extended cholecystectomy (T2) or with an extensive liver resection that obtains
      the negative margins. Patients with tumors greater than T1 should undergo
      lymphadenectomy that includes the porta hepatis and superior pancreatic nodes.
      Long-term survival with this approach is possible, even with T3 and T4 tumors.
      The role of extended lymphadenectomy, including the retropancreatic and
      aortocaval basins, is unclear and should be attempted only in selected cases.

PMID- 12607585
TI  - Cellular and molecular biology of biliary tract cancers.
AB  - Cancer of the biliary tract has been associated with point mutations of K-ras and
      beta-catenin proto-oncogenes; alterations of p53, p16, APC, and DPC4 tumor
      suppressor genes by a combination of chromosomal deletion, mutation, or
      methylation; and infrequently microsatellite instability. The frequencies of
      these alterations vary by location and race of the patient, tumor subsite,
      histology, and associated disease. Advances in the understanding of the genetics
      of this disease will help in diagnosing biliary tract cancer, screening at-risk
      patients, and developing therapies.

PMID- 12607586
TI  - Are prognostic factors in rheumatoid arthritis of any use in daily clinical
      practice?

PMID- 12607587
TI  - Anticitrullinated protein/peptide antibody and its role in the diagnosis and
      prognosis of early rheumatoid arthritis.

PMID- 12607588
TI  - Collapse after moderate exercise. Hypertrophic cardiomyopathy.

PMID- 12607589
TI  - Pathogenesis of renal microvascular complications in diabetes mellitus.

PMID- 12607590
TI  - Single-centre experience with tunnelled central venous catheters in 150 cancer
      patients.
AB  - BACKGROUND: Tunnelled venous catheters improve venous access in cancer patients,
      but are associated with complications. We retrospectively analysed the outcome of
      Hickman catheter and Port-A-Cath (PAC) insertion in cancer patients from a
      department of medical oncology and compared these results with the literature.
      METHODS: The files of patients in whom insertion of a Hickman or PAC was planned
      in the period March 1992 to August 1999 were analysed. RESULTS: In total, 150
      files were evaluated. In 149 patients, 128 Hickman catheters and 38 PACs were
      inserted successfully. Complications occurred in 44.6% of the catheters inserted
      successfully. Infection (24.1%) and thrombosis (7.2%) were observed most
      frequently. In 66.7% of patients with thrombosis, the catheter tip was positioned
      incorrectly. Removal for catheter-related complications occurred in 47.7%. Of 146
      catheter insertions for which the name of the responsible (resident) surgeon
      could be traced, 48 different names were identified. CONCLUSIONS: In comparison
      with other studies, we found a high incidence of infections and a high removal
      rate for catheter-related complications. We confirmed the relationship between
      thrombosis and an inadequate position of the catheter tip. The level of
      experience of the (resident) surgeon performing the catheter insertion may have
      played a role in the high complication rate.

PMID- 12607591
TI  - Treatment of primary Sjogren's syndrome with D-penicillamine: a pilot study.
AB  - BACKGROUND: Up to now no satisfying systemic treatment is available for patients
      with primary Sjogren's syndrome. METHODS: In a prospective, open study we
      investigated the effect of D-penicillamine (first three months 250 mg/day, next
      three months 500 mg/day) on clinical and immunological parameters in 19 patients
      with primary Sjogren's syndrome and a mean disease duration of 3.8 years.
      RESULTS: Eight patients had to stop treatment mainly due to severe (reversible)
      loss of taste. Clinically, a statistically significant increase in basal salivary
      flow was observed after three months (p<0.05). In addition, improvement was noted
      in the Schirmer test and stimulated parotid salivary flow after six months, but
      these differences were not statistically significant. Laboratory values showed a
      decrease in ESR (p<0.05) and levels of IgA and IgM (both p<0.02) after six
      months, a decrease in levels of IgA-Rf and IgM-Rf after three months (both
      p<0.05), and an increase in haemoglobin level (p<0.05). CONCLUSION: From this
      pilot study we conclude that the treatment of primary Sjogren's syndrome with D
      penicillamine has only marginal beneficial effects. Together with its clear side
      effects this means that D-penicillamine is unsuitable for this indication.

PMID- 12607592
TI  - Renal graft failure due to type 1 primary hyperoxaluria.
AB  - Primary hyperoxaluria type 1 (PH1) usually presents with recurrent urolithiasis,
      nephrocalcinosis and progressive renal failure at a relatively young age. This
      report describes a patient who, due to the late onset of end-stage renal disease,
      had been diagnosed with PH1 only after failure of his second kidney graft.
      Retrospectively, his vascular problems, skeletal abnormalities and cardiac
      arrhythmias fit the picture of severe systemic oxalosis. Possible therapeutic
      options are discussed.

PMID- 12607593
TI  - Reversible migratory osteoporosis in renal oncocytoma mimicking renal cell
      carcinoma with bone metastases.
AB  - We report a case in which initially the wrong diagnosis of renal cell carcinoma
      with bone metastases was made. Nephrectomy and bone biopsy led to the right
      diagnosis of oncocytoma with transient osteoporosis. This report stresses the
      importance of pathological investigation and points to oncocytoma in the
      differential diagnosis of solid renal masses. In addition, the possible
      relationship between this tumour and migratory osteoporosis, which disappeared
      after surgery, is described.

PMID- 12607594
TI  - A young woman with fever and a pericardial effusion.
AB  - A 19-year-old woman is presented with high-spiking fever, pericardial tamponade
      and respiratory failure. A diagnosis of adult onset Still's disease was made.
      This is a rare inflammatory disease with an unknown aetiology. The diagnosis is
      made by exclusion and with the help of diagnostic criteria. Treatment with
      corticosteroids met with a good response.

PMID- 12607595
TI  - Expression of vascular endothelial growth factor in invasive ductal carcinoma of
      the breast and the relation to angiogenesis and p53 and HER-2/neu protein
      expression.
AB  - The vascular endothelial growth factor (VEGF) appears to play an important role
      in tumor angiogenesis. The p53 and HER-2/neu genes have been thought to regulate
      VEGF expression. Although the most common genetic alterations described in human
      breast cancer are p53 gene mutations and HER-2/neu gene amplification, there is a
      paucity of reports concerning a possible association between VEGF expression and
      p53 and HER-2/neu expression. Ninety-nine invasive ductal carcinoma cases were
      examined by immunohistochemical studies with anti-VEGF, anti-p53, anti-HER-2/neu,
      and anti-CD34 antibodies. Computerized image analysis was used to evaluate the
      microvessel density (MVD). Eighty-eight tumors (88.9%) were classified as being
      VEGF positive. Twenty-five tumors (25.3%) showed p53 protein expression, while 36
      tumors (35.4%) expressed the HER-2/neu protein. The MVD ranged from 22.0 to
      197.0, with a median value of 58.5 (65.4 +/- 27.9). The tumors expressing VEGF
      had a significantly higher MVD than those that did not (P < 0.05). VEGF
      expression was significantly associated with p53 protein expression (P < 0.01).
      In double VEGF and p53 immunohistochemical stained sections, the two markers were
      generally expressed in the same tumor cells. The cancer stage was the only
      independent prognostic factor of disease-free and overall survival. The authors'
      results suggest that VEGF expression plays a role in promoting angiogenesis in
      invasive ductal carcinoma of the breast, and p53 is likely to be involved in
      regulating VEGF expression.

PMID- 12607596
TI  - Immunohistochemical evaluation of sentinel lymph nodes in breast carcinoma
      patients.
AB  - Sentinel lymph node sampling has become an alternative to axillary lymph node
      dissection to provide prognostic and treatment information in breast cancer
      patients. The role of immunohistochemistry has yet to be established. A total of
      241 sentinel lymph nodes (in 270 slides) from 91 patients with invasive carcinoma
      (73 ductal, 9 lobular, 8 mixed lobular/ductal, 1 NOS) were studied for presence
      of macrometastases (> 0.2 cm), identified in hematoxylin and eosin sections, and
      occult metastases (micrometastases [< or = 0.2 cm], clusters of cells, isolated
      carcinoma cells), identified only by immunohistochemistry. Intraoperative touch
      preparations, frozen sections, seven hematoxylin and eosin levels (L1-L7), and
      two AE1-3 cytokeratin immunohistochemistries (L1, L4-5) of the entire bisected or
      trisected sentinel lymph node were examined. Thirty-one (34%) patients had 50
      positive sentinel lymph nodes. Twenty-six (33%) sentinel lymph nodes had
      metastatic carcinoma (11 macrometastases, 11 micrometastases, 3 clusters of
      cells, 1 isolated carcinoma cells) by touch preparations, frozen sections, and
      one hematoxylin and eosin (L1). Thirty-eight (43%) were positive by AE1-3
      immunohistochemistry (L1) (11 macrometastases, 8 micrometastases, 13 clusters of
      cells, 6 isolated carcinoma cells), significantly more than by touch
      preparations, frozen sections, hematoxylin and eosin L1, or hematoxylin and eosin
      L2-7. Cytokeratin immunostain on L4-5 demonstrated 31 (34%) positive sentinel
      lymph nodes, a similar frequency to cytokeratin immunostain on L1. Size of
      sentinel lymph node metastasis did not correlate with size, histologic grade, or
      type of primary breast carcinoma. AE1-3 (L1) immunohistochemistry is highly
      sensitive in delineating sentinel lymph node metastasis, especially clusters of
      cells and isolated carcinoma cells. The prognostic significance of clusters of
      cells and isolated carcinoma cells and the value of AE1-3 immunohistochemistry on
      frozen sections need to be determined.

PMID- 12607597
TI  - Relationship between the thymidine labeling and Ki-67 proliferative indices in
      126 breast cancer patients.
AB  - Proliferative activity has been proposed as a prognostic and predictive marker
      for breast cancer; Ki-67 is one of the most frequently used markers to assess
      proliferative activity. In the current study, Ki-67 immunoreactivity was
      comparatively assessed, even in terms prognostic relevance, with 3H-thymidine
      labeling index as a reference standard for proliferation in 126 patients with
      stage I and II breast cancer. There was a significant but weak correlation
      between Ki-67 values and the 3H-thymidine labeling index (r = 0.19, P = 0.03).
      Analysis of variance showed that the mean 3H-thymidine labeling index values were
      not statistically different in terms of pathologic size (T1, T2. T3, T4), number
      of pathologically positive axillary nodes (neg, pos 1-3, pos > 3), and grading
      classes (1, 2, 3), but significantly and inversely correlated with estrogen
      receptor status (P = 0.033) and progesterone receptor status (P = 0.08). The Ki
      67 values significantly correlated with N status (P = 0.041), estrogen receptor
      status (P < 0.001), progesterone receptor status (P < 0.001), and grading (P <
      0.001). The median follow-up was 37 months. In terms of prognosis, Ki-67 was
      associated significantly with overall survival (P = 0.01) and marginally with
      disease-free survival (P = 0.095). A significant difference in prognosis was
      found for both disease-free survival (P = 0.024) and overall survival (P = 0.040)
      when a 3H-thymidine labeling index cut-off of 6.5% was used (P = 0.024). The
      results suggest that, although both are indicators of proliferative activity, 3H
      thymidine labeling index and Ki-67 seem to identify breast cancers with different
      phenotypes.

PMID- 12607598
TI  - Frequent loss of BRCA1 nuclear expression in young women with breast cancer: an
      immunohistochemical study from an area of low incidence but early onset.
AB  - Young women with breast cancer have a more unfavorable outcome and advanced
      disease than older women. This study was initiated to determine the difference in
      tumor biology between younger and older groups. One hundred fifty-five patients
      with invasive ductal carcinoma, not otherwise specified, comprised the study
      group, including 50 women aged less than 35 years, 50 aged 36 to 50 years, and 55
      aged more than 50 years. Histopathologic parameters, including tumor size,
      combined histologic grade, and axillary lymph node status, were studied.
      Biomarkers, including estrogen receptor status, tumor proliferation rate as
      determined by Ki-67, and gene expressions of c-erbB-2, p53, bcl-2, and BRCA1,
      were determined by immunohistochemistry. Comparisons of the distribution of these
      parameters in three age groups were performed. Breast cancer occurring in women
      aged less than 35 years had a significantly higher incidence of large tumor, high
      proliferation rate, and loss of nuclear BRCA1 expression (44.0% versus 22.0% or
      23.6%) than in the two older age groups. Breast cancer in women aged less than 35
      years also had higher histologic grade and higher frequency of bcl-2-negative
      tumor than that found in the 36- to 50-year age group. No difference was found in
      lymph node status and c-erbB-2 and p53 gene expressions between the age groups.
      Loss of BRCA1 nuclear expression significantly correlated with higher histologic
      grade and high Ki-67 index (P < 0.05) in group A. These findings suggested that
      women aged less than 35 years have frequent loss of nuclear BRCA1 expression,
      which may be responsible for the specific tumor biology different from older
      women. However, c-erbB-2 and p53 gene expressions seem to have no important role
      in the adverse tumor behavior of breast cancer in young women.

PMID- 12607599
TI  - Immunohistochemical expression of basic fibroblast growth factor, vascular
      endothelial growth factor, and their receptors in stage IV non-Hodgkin lymphoma.
AB  - Angiogenesis is increased in hematologic malignancies, including non-Hodgkin
      lymphoma (NHL). Elevated serum levels of two important angiogenic factors,
      vascular endothelial growth factor (VEGF) and basic fibroblast growth factor
      (bFGF), are associated with a poor prognosis. Immunohistochemistry was used to
      evaluate 27 patients with NHL and bone marrow involvement (17 with low-grade B
      cell NHL, including 7 with higher grade transformation; 6 with intermediate-grade
      B-cell NHL; and 4 with T-cell lymphoma). Among the 17 patients with low-grade B
      cell NHL, results for 7 were positive for VEGF stain (41.2%), and results were
      negative for all other stains for VEGF receptors, bFGF, and bFGF receptors. In
      the 10 patients with intermediate-grade B-cell NHL and T-cell lymphoma, all VEGF
      staining was positive (100%), but bFGF staining was only weakly positive in 2.
      Staining results for seven patients who had low-grade B-cell NHL with higher
      grade transformation showed that VEGF staining was positive in large lymphoid
      cells of 5 patients and in small lymphoid cells of one patient. Staining for the
      receptors VEGFR-1 and VEGFR-2 was positive in large lymphoid cells in four and
      two cases, respectively. Staining for bFGF was positive in two cases of large
      lymphoid cells. We concluded that VEGF, but not bFGF, was associated with higher
      tumor grading of NHL and high-grade transformation of low-grade lymphoma.

PMID- 12607600
TI  - Immunohistochemical expression of the transcription factor DP-1 and its
      heterodimeric partner E2F-1 in non-Hodgkin lymphoma.
AB  - DP-1 is a G1 cell cycle-related protein that forms heterodimers with E2F, a
      family of transcriptional factors regulating the expression of genes important
      for G1 to S progression. Although the exact role of DP-1 is not well understood,
      it has been shown to stabilize DNA binding of E2F proteins. By
      immunohistochemistry, the authors examined the expression of DP-1 in lymphoid
      tissues, including 8 cases of reactive follicular hyperplasia and 69 cases of B
      cell non-Hodgkin lymphoma. The expression of the cell cycle-related proteins E2F
      1 and Ki-67 was also assessed. Scoring was based on the proportion of labeled
      nuclei (1-10%, 11-25%, 26-50%, and > 50%). In reactive follicular hyperplasia,
      staining for DP-1, E2F-1, and Ki-67 was largely confined to the germinal centers.
      All 25 cases of follicular lymphoma, regardless of grade, had a high proportion
      (> 50%) of DP-1-positive cells but a lower proportion of cells marking for E2F-1
      and Ki-67 (P < 0.001). The diffuse large B-cell lymphomas (n = 24) had high DP-1
      and Ki-67 scores but low E2F-1 scores (P < 0.001). Small lymphocytic (n = 10),
      marginal zone (n = 3), and mantle cell lymphomas (n = 5) contained relatively low
      proportions of cells labeled for all three markers. Precursor B-cell
      lymphoblastic lymphoma (n = 2) displayed high proportions of cells positive for
      DP-1, Ki-67, and E2F-1 (> 50% in both cases). Except in follicular center cell
      lesions, DP-1 expression generally correlated with that of Ki-67. However, the
      expression of DP-1 was discordant with that of E2F-1 in benign and malignant
      follicular center cells, suggesting that DP-1 may have functions other than
      facilitating E2F-1-dependent gene regulation and cell cycle progression in these
      neoplasms.

PMID- 12607601
TI  - p53 protein and Ki-67 overexpression in urothelial dysplasia of bladder.
AB  - Mutated tumor suppression gene p53 is a common genetic abnormality in most
      papillary or invasive transitional cell carcinomas (TCC). In these cases,
      overexpression of p53 protein is detectable in nuclei by immunohistochemical
      methods. Nuclear antigen Ki-67, a marker of cellular proliferation, has been
      shown to correlate with the growth of many human neoplasms, including TCC. Since
      overexpression of p53 protein and increased Ki-67 proliferative activity have
      been a consistent finding in TCC, p53 and Ki-67 expression may be used as markers
      of urothelial cells with significant genetic alterations. In this study, the
      authors have investigated whether there is increased p53 and Ki-67 expression in
      varying grades of urothelial dysplasia. Staining for p53 and Ki-67 using formalin
      fixed, paraffin-embedded sections was performed using a Dako Autostainer,
      followed by counting positive cells using an automatic cellular imaging system
      (ACIS). The high-grade dysplasia/CIS group (n = 16) had a similar high percentage
      and intensity of p53 staining (45.3 +/- 4.3%; 28.2 +/- 6.1 arbitrary units [AU])
      as the TCC group (n = 16. 53.6 +/- 3.9%; 36.8 +/- 5.7 AU), but revealed a
      significantly higher percentage and intensity of p53 staining than the low-grade
      dysplasia (n = 14, 25.6 +/- 3.3%; 12.2 +/- 2.0 AU) and benign group (n = 10, 10.0
      +/- 3.3%; 5.8 +/- 1.7 AU). Percentage of p53-positive cells counted by ACIS was
      similar to that obtained by manual counting. In addition, expression of Ki-67 in
      all four groups paralleled p53 expression. The authors' data showing
      overexpression of p53 and Ki-67 in high-grade urothelial dysplasia/CIS similar to
      that observed in TCC support the notion that high-grade urothelial dysplasia/CIS
      is a precursor of invasive TCC.

PMID- 12607602
TI  - Appraisal of differentiation markers in urothelial cells.
AB  - The expression, subcellular localization, and supramolecular organization of
      structural and differentiation-related proteins were studied in differentiating
      superficial cells during regeneration of the rat urothelium. Cytokeratin 17 and
      epidermal growth factor receptor were expressed in undifferentiated cells,
      whereas in differentiated superficial cells, this expression ceased. beta-Actin
      was expressed in undifferentiated and in differentiated cells, but subcellular
      localization markedly changed by its withdrawal from apical region during
      differentiation. In differentiating cells, cytokeratin 20 was first observed as
      diffusely arranged spots distributed throughout the cytoplasm; later, it became
      organized as a network in the apical part of the cells. Urothelium specific
      proteins, uroplakins, were weakly expressed at early states of differentiation,
      but only in terminally differentiated cells did they organize into asymmetric
      unit membrane plaques. These findings show that in some cases, expression is a
      sufficient marker of cell differentiation. In other cases, however, the specific
      subcellular localization and supramolecular organization of proteins should be
      considered. It is evident that choosing the appropriate methods is crucial for
      precise evaluation of the urothelial differentiation states.

PMID- 12607603
TI  - Expression of p27 and VHL in renal tumors.
AB  - Renal tumors, in particular clear cell renal cell carcinomas, have an unclear
      prognosis and metastatic potential. Cell cycle regulators play a key role in
      cellular proliferation and have been implicated in neoplasia. The cell cycle
      inhibitor p27 has been associated with prognosis in various tumor types. Recently
      a reported association between p27 and Von Hippel-Lindau (VHL) gene function has
      also been noted. We have examined p27 and VHL expression by immunohistochemistry
      in a panel of kidney tumors and have noted specific and unique patterns of p27
      expression in various tumor types. In addition, we have analyzed p27 expression
      in clear cell type renal cell carcinomas and have noted a significant association
      between decreasing p27 expression and increasing tumor size, suggesting a
      relation between renal cell proliferation and loss of p27 function. These
      findings suggest a role for p27 in the development of various types of renal
      tumors.

PMID- 12607604
TI  - Comparative study in the expression of p53, EGFR, TGF-alpha, and cyclin D1 in
      verrucous carcinoma, verrucous hyperplasia, and squamous cell carcinoma of head
      and neck region.
AB  - Verrucous carcinoma (VC) is a locally invasive, nonmetastasizing variant of
      squamous cell carcinoma (SCC) with distinct clinical and histologic features.
      Molecular alterations detectable by immunohistochemical analyses in VC have not
      been extensively studied. This study investigates the expression of p53,
      epidermal growth factor receptor (EGFR), transforming growth factor-alpha (TGF
      alpha), and cyclin D1 in VC, verrucous hyperplasia (VH), and classic SCC of the
      head and neck. Twenty-six cases of VC, 12 cases of SCC of various
      differentiations, and 4 cases of VH were studied. Formalin-fixed, paraffin
      embedded archival material was used for immunohistochemistry (avidin-biotin
      immunoperoxidase technique) to study the expression of oncogenes and their tumor
      markers. Identification of p53 protein was found in 100% of VH, 88% of VC, and
      100% of SCC. EGFR expression was noted in 25% of VH, 54% of VC, 40% of well
      differentiated SCC (WDSCC), and 100% of moderately and poorly differentiated SCC
      (MDSCC/PDSCC). TGF-alpha was detected in 25% of VH, 88% of VC, 80% WDSCC, and
      100% of MDSCC/PDSCC. Cyclin-D1 expression was seen in 75% of VH, 35% of VC, 100%
      of WDSCC, 67% of MDSCC, and 50% of PDSCC. Correlation between the level of
      expression of all markers and the grade of this group of squamous lesions
      revealed statistically significant correlation coefficients for p53 and EGFR but
      not for TGF-alpha and cyclin D1.

PMID- 12607605
TI  - Expression of metallothionein in synovial sarcoma cells.
AB  - Other authors have demonstrated earlier that cells of normal synovium contain
      metallothionein. The protein was also detected in several other normal cell types
      and in tumors derived from the cells. Metallothionein content is thought to
      reflect proliferative activity of neoplastic cells. Therefore, it was decided to
      demonstrate metallothionein expression in various types of synovial sarcoma. The
      present study aimed to determine metallothionein cellular expression by
      immunocytochemical techniques in nine cases of biphasic, six cases of monophasic
      (spindle cell), and five cases of poorly differentiated synovial sarcoma, and to
      compare the expression with those of vimentin and cytokeratin 19. Metallothionein
      expression was demonstrated in epithelioid cells in all cases of biphasic type
      sarcoma and in spindle cells in all cases of monophasic type tumors. In poorly
      differentiated tumors, metallothionein expression was detected in four of five
      cases (80%). Expression of cytokeratin 19 was typical for epithelioid cells and
      expression of vimentin for spindle cells of synovial sarcoma. A much less
      pronounced expression of the proteins was observed in poorly differentiated
      tumors. The results indicate that metallothionein expression may prove useful in
      differential diagnosis and for defining prognosis in cases of synovial sarcomas.

PMID- 12607606
TI  - Heat-induced antigen retrieval restores electrostatic forces: prolonging the
      antibody incubation as an alternative.
AB  - The term antigen retrieval was introduced by Shi et al. (1) to describe a process
      of heating formalin-fixed paraffin-embedded tissue sections for improved
      immunoreactivity of tissue antigens with their specific antibodies. Although it
      has currently become an essential part of immunohistochemistry, the exact nature
      of this process remains unknown. The following report will describe the rationale
      and results of experiments that associate the restoration of electrostatic
      (coulombic) forces with the functional basis of antigen retrieval. Critical
      support for this was derived by the application of relevant tenets regarding the
      sensitivity of immune reactions to pH and ionic strength and through the use of
      prolonged antibody incubations. For the majority of the investigated tissue
      antigens, prolonging the antibody incubation time from a standard 10 minutes to
      60 minutes represented an effective alternative to heat-induced antigen
      retrieval. The report will carefully weigh the advantages and disadvantages of
      prolonged antibody incubations versus antigen retrieval procedures.

PMID- 12607608
TI  - Comprehensive evaluation of carboxylesterase-2 expression in normal human tissues
      using tissue array analysis.
AB  - Carboxylesterases play an important role in the hydrolytic biotransformation of a
      number of structurally diverse endogenous compounds and medications. Several
      distinct carboxylesterase isoforms have been described in human liver, brain, and
      placenta. Carboxylesterase-2 has been identified as the key enzyme in the
      metabolic activation of the irinotecan, a topoisomerase I inhibitor commonly used
      in the treatment of many solid tumors. The tissue distribution and intensity of
      protein expression of carboxylesterase-2 have not been defined in any organ or
      tissue. This study used a carboxylesterase-2-specific antibody and tissue array
      analysis to detect carboxylesterase-2 expression in human normal tissues by
      immunohistochemistry. Carboxylesterase-2 is present in a wide variety of organs
      and tissues. The highest carboxylesterase-2 expression occurs in hepatocyte,
      small intestine mucosa, kidney proximal convoluted tubule, and adrenal cortex
      cells. The results suggest that liver and gastrointestinal tract with
      carboxylesterase-2 are likely the most important sites of conversion of
      irinotecan to the active metabolite SN-38, but carboxylesterase-2 within the
      other tissues may be contributive to this process. In the central nervous system,
      carboxylesterase-2 expression was confined to capillary endothelial cells,
      consistent with the enzyme having a role to protect the central nervous system
      from toxic esters and perhaps being a component of a blood-brain barrier system.

PMID- 12607607
TI  - A modified reduced-temperature antigen retrieval protocol effective for use with
      a polyclonal antibody to cyclooxygenase-2 (PG 27).
AB  - Antigen retrieval is now a standard procedure in immunohistochemical studies of
      tissues for diagnosis and research. While the most commonly used protocol (20
      minutes at 100 degrees C in citrate buffer pH 6.0) is effective for many
      antibody/antigen combinations, experience has shown that in some instances, this
      standard approach fails. Under these circumstances, a successful antigen
      retrieval protocol may still be established by varying key conditions in the
      antigen retrieval process. The authors previously have advocated a test battery
      approach to determine the optimal conditions for antigen retrieval, illustrated
      here with respect to a polyclonal antibody to cyclooxygenase-2 (PG-27) that
      failed to give a positive staining result after orthodox antigen retrieval. The
      key feature of this modified antigen retrieval protocol is heating the
      deparaffinized tissue sections at a reduced temperature (90 degrees C as opposed
      to 100 degrees C). For this particular antibody, a boiling condition yields a
      negative result, a principal reason why previous investigators have used a
      tyramide signal amplification system to achieve satisfactory immunohistochemical
      results with this antibody. The optimal antigen retrieval protocol established in
      the authors' laboratory for this polyclonal antibody to cyclooxygenase-2 (PG-27)
      was evaluated in a study of formalin-fixed, paraffin-embedded cell lines and 31
      bladder cancer tissue blocks using the tissue microarray technique, with side-by
      side comparison between the results obtained by a tyramide signal amplification
      method (without antigen retrieval) and a standard immunohistochemical method with
      the optimized antigen retrieval protocol. The reduced temperature antigen
      retrieval protocol yielded a comparable or superior immunostaining for
      cyclooxygenase-2 both in cell lines and tissue blocks. In conclusion, use of the
      test battery approach allowed development of a modified antigen retrieval
      technique that provides a more reliable, much simpler approach for the
      demonstration of cyclooxygenase-2 in archival tissues.

PMID- 12607609
TI  - Equipment testing and tuning: the cold-knife cryomicrotome microm HM-560.
AB  - A major innovative feature of the Microm HM-560 cryomicrotome is the independent
      control of specimen and knife temperatures. We used such equipment with a variety
      of tissues, and fixation and freezing procedures. High-quality sectioning was
      reproducibly obtained using 1) a low temperature setting for the sectioning blade
      ("cold knife," about -33 degrees C); 2) a comparatively high temperature for the
      specimen; and 3) a suitable mounting medium, which would remain solid up to about
      0 degrees C. Specimen temperature was set between -8 degrees and -15 degrees C
      for 4-microm sectioning, higher temperatures (-1 degrees to -8 degrees C) being
      appropriate when cutting at 10 to 20 microm. Under such conditions, disposable
      blades were effective throughout, while a modified antiroll plate profile further
      enhanced usability. After intensive use for almost 3 years, by more than 15
      different users, the cryomicrotome is in excellent working order.

PMID- 12607611
TI  - Power of the written word.

PMID- 12607610
TI  - Increased expression of adenylyl cyclase isoforms in the adrenal gland of
      diabetic Goto-Kakizaki rat.
AB  - The spontaneously diabetic Goto-Kakizaki rat harbors the same defects expressed
      in human type 2 diabetes. It is not clear, however, whether stress factors
      emanating from the adrenal glands are involved in causing the diabetic state. For
      that reason, the authors studied gland size and expression of adenylyl cyclase
      isoforms in adrenal glands from Goto-Kakizaki and normal rats. Goto-Kakizaki rat
      adrenals were found to weigh only about half as much as those of control rats.
      This decrease was the result of a reduction of the cortex, especially of the zona
      fasciculata, whereas the medulla was unaffected. Cell density measurements showed
      that the total number of medullary cells in Goto-Kakizaki rats was lower than
      that in controls. In the cortex, the cell density did not differ between the two
      groups; thus, our results point to a marked hypotrophy. In the medulla of Goto
      Kakizaki rats, the nuclear size was significantly increased, and there was also
      an overexpression of adenylyl cyclase 1, 2, 4, 6, and 8 isoforms in the adrenalin
      producing cells, indicating an increased functional capacity. In the cortex,
      despite the cortical hypotrophy, adenylyl cyclase 5 immunoreactivity was markedly
      increased in Goto-Kakizaki rats, especially in the zona reticularis. It is
      unclear whether this morphologic change in the diabetic adrenal glands together
      with the overexpression of different adenylyl cyclase isoforms plays a role in
      the pathogenesis of this diabetic state or is a genetic defect or compensatory
      mechanism of diabetes in this spontaneous rodent model of type 2 diabetes.

PMID- 12607612
TI  - Occupational health services for dental practices.

PMID- 12607613
TI  - Wars on warfarin.

PMID- 12607614
TI  - Retired list.

PMID- 12607615
TI  - Options for change.

PMID- 12607616
TI  - Glove wearing necessary?

PMID- 12607617
TI  - NICE guidelines?

PMID- 12607618
TI  - What is the role of dentists in smoking cessation?
AB  - The associations between tobacco use and diseases affecting the oral cavity, such
      as periodontal disease and cancer, are now well recognised. This has lead to
      proposals from some members of the profession and the BDA that members of the
      dental team should provide smoking cessation services. Many dentists have
      positive attitudes towards the idea of dentists encouraging patients to stop
      smoking. However the belief that members of the dental team should engage in
      delivering smoking cessation interventions is not held by all parties. More
      dentists believe that they should offer smoking cessation support than actually
      do provide it and reasons for not providing it include time and reimbursement
      issues, need for further training and poor co-ordination of dental and smoking
      cessation services.

PMID- 12607619
TI  - Further statistics in dentistry, Part 5: Diagnostic tests for oral conditions.
AB  - A diagnostic test is a simple test, sometimes based on a clinical measurement,
      which is used when the gold-standard test providing a definitive diagnosis of a
      given condition is too expensive, invasive or time-consuming to perform. The
      diagnostic test can be used to diagnose a dental condition in an individual
      patient or as a screening device in a population of apparently healthy
      individuals.

PMID- 12607620
TI  - Ethics: how the Apothecaries Act of 1815 shaped the dental profession. Part 1.
      The Apothecaries and the emergence of the profession of dentistry.
AB  - The Apothecaries Act of 1815, (revised by the Act of 1825) has been credited with
      being the most important forward step in the education of the general medical
      profession in the nineteenth century, although a closely argued revisionist view
      of its significance by S W F Holloway makes clear his view that it was also a
      successful and deeply reactionary political move by the physicians to emasculate
      a rival group growing rapidly in numbers and power. This paper demonstrates that
      the Act also created a distance between the true dentists and others, like the
      chemists and druggists, who carried out dental functions. By so doing the Act
      defined the social identity of the profession of dentistry, in its numbers,
      status, nineteenth century reform and pattern of education. The paper proposes
      the apothecary/general medical practitioner as a social as well as ethical role
      model for the general dental practitioner.

PMID- 12607621
TI  - A view from the bodies corporate. 3. Ora Dental Group Ltd. Interview by F.Stuart
      Wilson.
AB  - Julian Perry does not strike one as being the sort of man that would set off a
      fire alarm deliberately when there was no fire. The fact that he did and the
      reason that he did comes out quite late in our discussion over coffee one bright
      morning in central London.

PMID- 12607622
TI  - A cross sectional study of water quality from dental unit water lines in dental
      practices in the West of Scotland.
AB  - OBJECTIVE: To determine the microbiological quality of water from dental units in
      a general practice setting and current practice for disinfection of units.
      DESIGN: A cross-sectional study of the water quality from 40 dental units in 39
      general practices and a questionnaire of the disinfection protocols used in those
      practices. SETTING: NHS practices in primarydental care. SUBJECTS: Thirty-nine
      general practices from the West of Scotland. METHODS: Water samples were
      collected on two separate occasions from dental units and analysed for
      microbiological quality by the total viable count (TVC) method. Water specimens
      were collected from the triple syringe, high speed outlet, cup filler and surgery
      tap. Each participating practitioner was asked to complete a questionnaire.
      Results Microbial contamination was highest from the high speed outlet followed
      by the triple syringe and cup filler. On average, the TVC counts from the high
      speed water lines at 37 degrees C and for the high speed lines, triple syringe
      and cup filler at 22 degrees C were significantly higher than that from the
      control tap water specimens. The study included units from 11 different
      manufacturers with ages ranging from under one year to over eight years. The age
      of the dental unit analysed did not appear to influence the level of microbial
      contamination. Five of the practices surveyed used disinfectants to clean the
      dental units but these had no significant effect on the microbiological quality
      of the water. The majority of dental units (25 out of 40) were never flushed with
      water between patients. A number of different non-sterile irrigants were used for
      surgical procedures. CONCLUSION: The microbiological quality of water from dental
      units in general dental practice is poor compared with that from drinking water
      sources. Suitable sterile irrigants should be used for surgical procedures in
      dental practice. Further work is required for pragmatic decontamination regimens
      of dental unit water lines in a general dental practice setting

PMID- 12607623
TI  - The relationship between socio-demographic characteristics and dental health
      knowledge and attitudes of parents with young children.
AB  - OBJECTIVE: To determine if parental socio-demographic characteristics are
      associated with dental knowledge and attitude. DESIGN: A questionnaire survey of
      500 consecutive parents with children aged approximately 8-months, attending
      clinics in 1999/2000, in Burnley, Pendle and Rossendale, for health visitor
      distraction-hearing tests. OUTCOME MEASURES: Scores were obtained for dental
      knowledge and attitudes. The socio-demographic variables of parental ethnicity,
      age, education and area of residence were used to determine any associations.
      RESULTS: Parental age ranged between 16-46 years. Child age ranged between 7-11
      months. Significant differences were detected for parental dental knowledge
      according to ethnicity (P = 0.003), educational status (P = 0.000), and area of
      residence (P = 0.016). Significant differences were also found in dental
      attitudes; ethnicity (P = 0.000), educational status (P = 0.004) and area of
      residence (P = 0.005). Parental age was not significant for either knowledge or
      attitude. CONCLUSIONS: Lack of further education, being Asian and living in a
      deprived area means parents have less chances of high dental knowledge and
      positive dental attitudes.

PMID- 12607624
TI  - The nature and quality of periodontal related patient information on the world
      wide web.
AB  - BACKGROUND: The internet provides a potentially invaluable source of health
      education material for members of the public. OBJECTIVES: This study aimed to
      investigate the nature and quality of periodontal-related patient information on
      the world-wide web. METHODS: The search term ' "gum disease" AND "patient
      information" ' was entered into three common internet search engines. The top 50
      sites identified by each search engine were downloaded and assessed for
      authorship, content, accord with accepted dental practice, currency, and
      references to peer reviewed data. RESULTS: The search term returned in excess of
      3,615 hits across the three search engines. Of the top 150 identified, 68 were
      deemed relevant to patients seeking information on periodontal disease. Of these,
      17 were duplicated either within or between search engines, therefore the
      following analysis is based on the remaining 51 sites. The majority of sites (25)
      were authored by individual dental practitioners, with sites originating in the
      USA predominating (80%). Information on the aetiology, signs and symptoms, and
      treatment options for periodontal disease was provided by 38, 38, and 29 sites
      respectively. This information was deemed in accordance with conventional
      periodontal practice in 27, 33, and 23 cases respectively. Only seven sites
      indicated the currency of the information and five provided peer-reviewed
      references for further reading. The rank order identified by the search engines
      meant that sites providing comprehensive and authoritative information, were not
      readily differentiable from sites whose primary objective was promoting
      attendance at specific dental practices. CONCLUSIONS: Judicious and active
      support from professionals is required to aid patients' interpretation of the
      information identified and to direct them to the most instructive sites.

PMID- 12607625
TI  - The dark side of complementary and alternative medicine.

PMID- 12607626
TI  - Clinical trials, industrial sponsoring, and ethics--a never ending story?

PMID- 12607627
TI  - Clinical trials in jeopardy.
AB  - BACKGROUND: The controlled clinical trial, the gold standard for clinical
      research, is in jeopardy. The pharmaceutical industry is rapidly expanding its
      command over clinical trials but scientific rigor requires independence and
      objectivity. Safeguarding such criteria is hard because industrial sponsors,
      benefit directly from favorable results and are virtually in complete control.
      OBJECTIVE: To review flawed procedures jeopardizing the credibility of trials and
      to look for possible solutions to the conflict between sponsored industry and
      scientific independence. RESULTS: Flawed procedures jeopardizing current clinical
      trials can be listed as follows. Industries, at least in Europe, are allowed to
      choose their own independent protocol review board prior for approval. The
      independent protocol review board approves protocols even when the research is
      beyond the scope of its expertise. Health institutions hosting multicenter trials
      are requested to refrain from scientific or ethic assessment of the trial. Trial
      monitors are often employees of industry. Data control is predominantly in the
      hands of the sponsor. Interim analyses are rarely performed by independent
      groups. The scientific committee of the trial consists largely of prominent but
      otherwise uninvolved physicians attached to the study. The analysis and report of
      the trial is generally provided by clinical associates of the pharmaceutical
      companies and, after a brief review, co-signed by prominent physicians attached
      to the study. POSSIBLE SOLUTIONS: Possible solutions to the conflict between
      sponsored industry and scientific independence could include the following.
      Surveillance by independent observers during each stage of the trial is
      desirable. In contrast, tight control of study data, analysis, and interpretation
      by the commercial sponsor is undesirable. If, instead, the pharmaceutical
      industry allows the profession to more actively participate in different stages
      of the trial, scientific research will be better served, reasonable biological
      questions will be better answered, and, because the profession will be more
      convinced of the objective character of the research, it will not be
      counterproductive to the sales.

PMID- 12607628
TI  - Bupropion: pharmacological and clinical profile in smoking cessation.
AB  - Chemistry, pharmacokinetics, pharmacology, clinical efficacy, adverse effects and
      dosage of bupropion hydrochloride (BP), an aminoketone antidepressant used in
      smoking cessation, are reviewed. The nicotinergic acetylcholine receptors are
      inhibited at clinically relevant concentrations of BP. BP does not inhibit
      monoamine oxidase, and it has minimal inhibitory effects on presynaptic
      noradrenaline and dopamine uptake. BP is rapidly absorbed after oral
      administration and demonstrates biphasic elimination with an elimination half
      life of 11 - 14 hours. BP is extensively metabolized by oxidation and reduction
      to at least 6 metabolites, 2 of which may be active. The plasma levels of the
      erythro-amino alcohol of BP correlate with several side effects such as insomnia
      and dry mouth. Efficacy of BP(SR) in smoking cessation has been examined in
      several double-blind, randomized trials in which daily doses of 150 or 300 mg
      have been administered for 7 or 9 weeks. In addition, 1 study examined the
      combination of BP(SR) plus nicotine patch. The point prevalences of stopping
      smoking reached values between 21.2 and 38%, but they did not exceed those after
      nicotine replacement therapy alone. Long-term administration (52 weeks) of BP did
      not improve abstinence compared with placebo after a 2-year follow-up period.
      Thus, the efficacy of BP in smoking cessation is comparable to that of nicotine
      replacement therapy. However, BP possesses a broad spectrum of infrequent adverse
      effects and interferes with the degradation of several drugs such as tricyclic
      antidepressants, beta-recpetor blocking agents, class Ic-antiarrhythmics etc. As
      the risk-benefit ratio of BP is smaller than that of nicotine replacement, BP
      should be considered as a second-line treatment in smoking cessation.

PMID- 12607629
TI  - Prospective observational cohort safety study to monitor the introduction of a
      non-CFC formulation of salbutamol with HFA134a in England.
AB  - OBJECTIVE: To monitor the safety of a salbutamol MDI with a hydrofluoroalkane
      propellant (Ventolin Evohaler) during its introduction into primary care use in
      England. METHODS: Prospective observational cohort study. 1,365 GPs in England
      submitted data on 10,472 regular users of Ventolin MDI, over five 3-month periods
      of observation between October 1, 1998 and December 31, 1999. The primary aim was
      to compare event rates occurring before and after the introduction of Ventolin
      Evohaler. The secondary aim was a comparison of event rates between users of
      Ventolin Evohaler and Ventolin MDI. The main outcome measures were: indication
      for use of Ventolin MDI, assessment of disease severity, event rates during each
      period of observation; deaths, pregnancies, reported adverse drug reactions and
      reasons for discontinuation of MDI. Event rates were adjusted using a ratio for
      under-reporting derived from a validation study on 4.6% of the study population
      and stratified by severity of indication. RESULTS: The primary indication was
      asthma in 94%, distributed by severity as 47% mild, 44% moderate and 9% severe;
      13% were children. By October 1999, 52.7% of the 8,973 remaining patients had
      transitioned to Ventolin Evohaler. There was no increase in major or minor events
      observed following the introduction of Ventolin Evohaler. No serious adverse
      events, abnormal pregnancy outcomes or deaths have been related to Ventolin MDI
      or Ventolin Evohaler. The validation study showed a degree of under-reporting.
      CONCLUSION: These results on a large cohort of community patients in England
      indicate that Ventolin Evohaler is well tolerated among asthmatics.

PMID- 12607631
TI  - AAPP meeting report: Navigating the biotechnology revolution. Report on the 9th
      National Conference of the American Academy of Pharmaceutical Physicians (AAPP).
      San Diego, California, October 28-30, 2002.

PMID- 12607630
TI  - Frequency and predictors of drug therapy interruptions after hospital discharge
      under physician drug budgets in Germany.
AB  - OBJECTIVE: We sought to study how frequently prescription drug therapy at
      hospital discharge was discontinued or changed by general practitioners under
      physician drug budgets in Germany and explore reasons and predictors for such
      discontinuations. METHODS: This cohort study was part of a larger project on
      clinical outcomes of acute hospital care in patients with 5 groups of medical
      diagnoses, including conditions of the heart, lung and brain, gastroduodenal
      ulcer disease and diabetes. Patients entered the study cohort at hospital
      admission and were followed throughout their stay until they had their first
      encounter with a primary care physician responsible for follow-up treatment after
      hospital discharge. Nurse practitioners and physicians assessed patient
      characteristics at admission and discharge. A 1-page questionnaire on continuity
      of care, including drug therapy, was provided to primary care physicians at the
      first patient encounter. The primary study endpoint was discontinuation of drug
      therapy by the primary care physician. Data were analyzed by multivariate
      logistic regression. RESULTS: A total of 3,267 patients in 22 primary care
      hospitals were eligible for the study. Standardized questionnaires on
      continuation of drug therapy were returned by 890 patients (27%); 846 patients
      (95%) used prescription drugs at discharge. Of those, drug therapy was
      interrupted in 122 (14%). Reasons for discontinuations included excessive costs
      of drugs in 66 patients (54%), excessive number of drugs prescribed (32, 26%) and
      differences in judgment on the clinical appropriateness of a drug (23, 19%). In a
      multivariate logistic regression, gastroduodenal ulcer disease was a significant
      predictor for discontinuation (OR = 3.1; 95% CI 1.5 - 6.5). Discontinuation
      tended to be more likely in older patients (69 - 76 years vs. < or = 58: OR =
      2.0; 1.0 - 3.9) but slightly less likely in male patients (OR = 0.7; 0.4 - 1.1).
      CONCLUSION: Discontinuation of drug therapy after hospital discharge is common.
      The high costs of prescription drugs were the most common reason. Elderly
      patients seem to be particularly affected.

PMID- 12607632
TI  - Publication of unethical research studies: the importance of informed consent.

PMID- 12607633
TI  - Alternative energy sources for atrial ablation: judging the new technology.

PMID- 12607634
TI  - Value of radiotherapy after radical surgery for esophageal carcinoma: a report of
      495 patients.
AB  - BACKGROUND: Despite three decades of debate, no conclusion has been reached
      concerning the effectiveness of postoperative radiotherapy for resected
      esophageal carcinoma. From 1986 through 1997, a prospective randomized study was
      carried out with 495 patients in an attempt to define the value of this
      therapeutic modality. METHODS: A total of 495 patients with esophageal cancer who
      had undergone radical resection were randomized by the envelope method into a
      surgery-alone group (S) of 275 patients and a surgery plus radiotherapy group (S
      + R) of 220 patients. Radiation treatment was started 3 to 4 weeks after the
      operation. The portals encompassed the entire mediastinum and bilateral
      supraclavicular areas. A midplane dose of 50 to 60 Gy in 25 to 30 fractions was
      delivered over 5 to 6 weeks. RESULTS: The overall 5-year survival rate was 31.7%
      for the S group and 41.3% (p = 0.4474) for the S + R group. The 5-year survival
      rates of patients who were lymph node positive were 14.7% and 29.2% (p = 0.0698),
      respectively. Five-year survival rates of stage III patients were 13.1% and 35.1%
      (p = 0.0027), respectively. CONCLUSIONS: Postoperative prophylactic radiotherapy
      improved the 5-year survival rate in esophageal cancer patients with positive
      lymph node metastases and in patients with stage III disease compared with
      similar patients who did not receive radiation therapy. These results were almost
      significant for patients with positive lymph node metastases and highly
      significant for patients with stage III disease.

PMID- 12607636
TI  - Infectious necrotizing esophagitis: outcome after medical and surgical
      intervention.
AB  - BACKGROUND: Immunodeficiency predisposes to invasive esophageal infections. The
      treatment of perforation, respiratory fistula, and necrosis due to transmural
      esophageal infection is guided by anecdote. We wish to determine treatment and
      outcome of local complications of necrotizing esophagitis. METHODS: We report our
      experience over a 7-year period and review published reports since 1976. We
      treated 4 patients and found 21 reported patients with perforation (11/25),
      fistula (8/25), and necrosis (6/25) at a mean age of 35 years. Twenty-one
      patients were immunodeficient (84%) due to acquired immunodeficiency syndrome in
      8, acute leukemia in 6, renal transplant in 3, diabetes mellitus, renal failure,
      and corticosteroids in 1 each. Pathogenic organisms were fungal in 15 cases,
      viral in 7, and bacterial in 7. RESULTS: Treatment consisted of antibiotic
      therapy in 13 patients and surgical intervention combined with antibiotic therapy
      in 12: esophagectomy in 6, esophageal stenting and drainage in 2, drainage alone
      in 2, and salivary diversion in 2. Overall mortality was 48% (12/25). Mortality
      without surgical intervention was 90% (9/10) and with surgical intervention 27%
      (3/11). One of 6 patients undergoing esophagectomy (17%) died. The difference in
      mortality was due to sepsis, which was the cause of death in 8 patients treated
      with medical intervention and only 1 treated with surgical intervention.
      CONCLUSIONS: Local complications of necrotizing esophagitis have a high mortality
      due to sepsis. Surgical intervention, in particular esophagectomy, controls
      sepsis in published case reports and should be considered in selected patients.
      Further study is required to determine the true prevalence of these complications
      and the outcome of intervention.

PMID- 12607635
TI  - Surgical volume and quality of care for esophageal resection: do high-volume
      hospitals have fewer complications?
AB  - BACKGROUND: Previous studies have shown that high-volume hospitals (HVHs) have
      lower mortality rates than low-volume hospitals (LVHs). However, little is known
      regarding the relationship of morbidity to hospital volume. The objective of the
      current study was to investigate the relative incidence of postoperative
      complications after esophageal resection at HVHs and LVHs. METHODS: All patients
      discharged from a nonfederal, acute-care hospital in Maryland after esophageal
      resection from 1994 to 1998 were included (n = 366). Rates of 10 postoperative
      complications were compared at HVHs and LVHs. Risk-adjusted analyses were
      performed using multiple logistic regression. RESULTS: High-volume hospitals had
      a mortality rate of 2.5% compared with 15.4% at LVHs (p < 0.001), with a case
      mixed adjusted odds ratio (OR) of death equal to 5.7 (95% confidence interval
      [CI], 2.0 to 16; p < 0.001). Low-volume hospitals had a profound increase in the
      risk of several complications after adjusting for case-mix: renal failure (OR,
      19; 95% CI, 1.9 to 178; p = 0.01), pulmonary failure (OR, 4.8; 95% CI, 1.6 to 14;
      p = 0.002), septicemia (OR, 4.0; 95% CI, 1.1 to 15; p = 0.04), reintubation (OR,
      2.9; 95% CI, 1.4 to 6.1; p = 0.004), surgical complications (OR, 3.3; 95% CI, 1.6
      to 6.9; p = 0.001), and aspiration (OR, 1.8; 95% CI, 1.0 to 3.3; p = 0.04).
      CONCLUSIONS: Patients undergoing esophageal resection at LVHs were at a markedly
      increased risk of postoperative complications and death. Pulmonary complications
      are particularly prevalent at LVHs and contribute to the death of patients having
      surgery at those centers.

PMID- 12607637
TI  - Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine
      morphology of the lung: prognosis after complete resection and systematic nodal
      dissection.
AB  - BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) and large cell carcinoma
      with neuroendocrine morphology of the lung are both currently classified as
      subtypes of large cell carcinomas according to the World Health Organization
      IASLC classification system for lung and pleural tumors. Prognosis is reported as
      similar to that of small cell carcinomas. There is no consensus on management of
      this subset and adjuvant chemotherapy is recommended by some for early stage
      LCNEC to impact long-term prognosis. We retrospectively reviewed a cohort of
      patients at our institution who had this type of tumor to determine factors that
      might influence survival. METHODS: Twenty-one cases of LCNEC and large cell
      carcinoma with neuroendocrine morphology were identified in the files of the
      Royal Brompton Hospital between 1986 and 1999. All patient data were reviewed,
      and complete follow-up was achieved with 20 of these patients. RESULTS: Of the 21
      patients identified, 20 underwent resection with systematic nodal dissection in
      18. There was no in-hospital mortality. Of those patients fully staged by
      systematic nodal dissection, 9 were stage I, 5 were stage II and 4 were stage
      III. Median follow-up was 25 months (range, 2 to 120 months). At the time of
      review, 11 patients were alive and free of disease. One patient was alive and
      free of disease when lost to follow-up. Nine patients had died, 7 related and 2
      unrelated to disease. The 5-year actuarial survival for the entire group was 47%.
      The actuarial survival of accurately staged, stage I patients at 5 years was 88%.
      The actuarial survival of patients in stage II and III was 28% at 5 years.
      CONCLUSIONS: LCNEC and large cell carcinoma with neuroendocrine morphology are
      aggressive tumors, but patients with completely resected disease after systematic
      nodal dissection have a better prognosis than previously described. Patients with
      more advanced disease have a poor prognosis.

PMID- 12607638
TI  - Visceral pleura invasion and pleural lavage tumor cytology by lung cancer: a
      prospective appraisal.
AB  - BACKGROUND: Despite an early-stage diagnosis, lung cancer presenting with
      visceral pleura invasion (VPI) or malignant pleural lavage cytology (PLC) has a
      poor prognosis. The purpose of this study was to correlate VPI to malignant PLC.
      METHODS: One hundred forty-three consecutive patients scheduled for surgical lung
      resection having undergone preresectional pleural lavage cytology were reviewed.
      There were 121 malignant and 22 nonmalignant lesions. All cases were studied by
      pathology, histology, previous transthoracic puncture, VPI, and presence of
      pleural lymphatic involvement. RESULTS: PLC was positive (n = 13) or suspected (n
      = 5) for malignant cells in, respectively, 10.7% and 4.1% of patients with lung
      cancer. There was no positive PLC in cases of nonmalignant disease. PLC was
      positive only in pT2 tumors and almost always when the tumor was exposed on the
      pleural surface, thus possibly exfoliating within the pleural space (12/17
      patients, 70.6%; p < 0.01). Positive PLC was obtained whatever the histology but
      did not appear related to previous transthoracic puncture or involvement of
      pleural lymphatics by tumor cells. CONCLUSIONS: VPI and positive PLC are linked,
      and the appearance of tumor cells within the pleural cavity can be explained by
      tumor desquamation. The role that visceral pleura involvement and parietal pleura
      reabsorption play in lung cancer is of paramount importance and deserves further
      research. A better understanding of their relationship could have major
      implications in the therapeutic management of non-small cell lung cancer.

PMID- 12607639
TI  - Survival in primary lung cancer potentially cured by operation: influence of
      tumor stage and clinical characteristics.
AB  - BACKGROUND: Surgical resection is currently standard treatment in early stage
      lung cancer. The aim of the present study was to identify stage-related factors
      and patient characteristics influencing survival after complete resection.
      METHODS: We identified 395 patients with non-small cell lung cancer who had
      undergone potentially radical operation during 1987 to 1999 at one thoracic
      surgery institution in central Sweden. Factors independently related to survival
      were identified in a multivariate analysis. Survival was analyzed in low-, medium
      , and high-risk groups based on a risk score calculated from relative hazards for
      identified risk factors. RESULTS: Overall 5-year survival among the 395 patients
      was 51%. The strongest factor predicting prognosis was positive lymph nodes at
      operation. Higher age, earlier period for operation, impaired lung function,
      current smoking, and major operative complication were all related to poorer
      prognosis. Patients with tumor stage Ia had a 5-year survival of 69%, compared to
      73% in patients in the low-risk group. CONCLUSIONS: Tumor stage is the best
      prognostic indicator after radical operation. Inclusion of other tumor- and
      patient-related variables did not add prognostic information of clinical
      relevance beyond that provided by tumor stage alone.

PMID- 12607640
TI  - Mediastinoscopy in patients with clinical stage I non-small cell lung cancer.
AB  - BACKGROUND: The aim of this study was to investigate the significance of
      mediastinoscopy for clinical stage I non-small cell lung cancer. METHODS: We
      reviewed 291 patients who underwent mediastinoscopy from January 1995 to December
      2001 for clinical stage I non-small cell lung cancer. The patients who presented
      tumor-negative lymph nodes on mediastinoscopy underwent thoracotomy for pulmonary
      resection and mediastinal lymph node dissection in the same operative session.
      Mediastinoscopy-positive patients were referred for neoadjuvant therapy. RESULTS:
      Of the 291 patients, 20 patients (6.9%) were found with N2 or N3 disease on
      mediastinoscopy. Among 271 mediastinoscopy-negative patients, thoracotomy-proven
      N0 was found in 201 patients (74.2%), N1 in 44 patients (16.2%), and N2 in 25
      patients (9.2%). Seventeen of 25 patients with unforeseen N2 disease had positive
      lymph nodes in the station that could be approached by mediastinoscopy only. The
      positive rate of mediastinoscopy was significantly higher in the patients with
      nonbronchioloalveolar-type adenocarcinoma than in squamous cell carcinoma (11.5%
      vs 3.3%, p = 0.013). However, there was no difference in the mediastinoscopy
      positive rate between clinical T1 and T2 status. CONCLUSIONS: Though there are
      still controversies about routine mediastinoscopy in patients without mediastinal
      nodal enlargement on chest computed tomography scan, this study demonstrates that
      routine mediastinoscopy is necessary, especially for nonbronchioloalveolar-type
      adenocarcinoma patients.

PMID- 12607642
TI  - Clinical outcome after coronary artery revascularization and lung
      transplantation.
AB  - BACKGROUND: Presence of coronary artery disease (CAD) in otherwise eligible lung
      transplant candidates is considered a contraindication to lung transplantation.
      We reviewed the clinical outcome of our experience in lung transplant recipients
      with operable coronary artery disease and normal left ventricular function.
      METHODS: Medical records of all transplant recipients with coronary artery
      disease were reviewed. Data analyzed include demographics, coronary angiograms,
      coronary artery revascularization procedure, and clinical outcome after lung
      transplantation. RESULTS: Between April 1992 and August 2001, 354 lung transplant
      procedures were performed. Eighteen patients (5%) had significant CAD (greater
      than 50% stenoses). Six male patients (mean age 59 years) underwent percutaneous
      transluminal coronary angioplasty/stent and after lung transplantation all were
      discharged after a median hospital stay of 8.5 days. All recipients are alive at
      a median follow-up time of 14.5 months after their transplant. Twelve male
      patients (mean age 58 years) had combined coronary artery bypass grafting and
      lung transplantation. All recipients were discharged after a median hospital stay
      of 16 days. Nine recipients are alive at a median follow-up time of 7.5 months
      after transplant. One-year survival by the Kaplan-Meier method is 88% for the 18
      patients with coronary artery disease who underwent revascularization and lung
      transplantation. CONCLUSIONS: Despite the traditional criteria of excluding all
      eligible transplant candidates due to coronary artery disease, coronary
      revascularization in select candidates with favorable anatomy and normal left
      ventricular function can allow patients to undergo lung transplantation with
      acceptable outcomes.

PMID- 12607641
TI  - Bronchogenic carcinoma after solid organ transplantation.
AB  - BACKGROUND: This study assesses the risk of bronchogenic carcinoma after solid
      organ transplantation. Although the overall incidence of malignancy is increased
      after solid organ transplantation, the risk of bronchogenic carcinoma in the
      transplant population has not been systematically studied. METHODS: Among a
      cohort of 3,374 patients transplanted in our institution between 1985 and 2000
      (1,735 kidney recipients, 930 liver, 313 heart, and 396 lung recipients), 9
      patients (0.3%) had a bronchogenic carcinoma develop. Lung carcinoma occurred in
      3 kidney recipients, 3 liver recipients, 2 heart recipients, and 1 lung
      recipient. RESULTS: Time to diagnosis after the transplant procedure ranged from
      9 to 126 months (mean, 63 months). Aside from the lung transplant candidate, all
      recipients had a smoking history. Seven patients underwent thoracotomy and 6 had
      a complete resection. Tumors were classified as stage IA (n = 1), IB (n = 2), IIB
      (n = 2), IIIA (n = 2), IIIB (n = 1), and IV (n = 1). Genotyping demonstrated that
      the carcinoma arising in the lung transplant recipient originated from the donor
      and may have been transmitted at the time of transplantation. Two patients were
      alive without recurrence 21 and 42 months after the operation. CONCLUSIONS: The
      risk of bronchogenic carcinoma is low and occurs mainly in recipients with a
      smoking history. However, bronchogenic carcinoma can also be transmitted from
      donor lungs at the time of transplantation. Hence careful examination of chest
      roentgenograms, and computed tomographic chest scan if available, as well as
      meticulous assessment of the lung, and biopsy of any suspicious lesions, are
      important to limit the risk of lung cancer transmission, especially with the
      liberalization of donor criteria.

PMID- 12607643
TI  - Catamenial pneumothorax: retrospective study of surgical treatment.
AB  - BACKGROUND: Catamenial pneumothorax is a rare entity characterized by recurrent
      accumulation of air in the thoracic space during menstruation. Catamenial
      pneumothorax is also associated with a high rate of postoperative recurrence. The
      aim of this study was to discuss the etiology and to determine the optimal
      surgical treatment of this entity. METHODS: From December 1991 to September 2000,
      10 patients with catamenial pneumothorax were treated at our institution. Median
      age at time of operation was 37 years (range, 21 to 44 years). We retrospectively
      evaluated the pathologic findings, the operation performed, and the results in
      all patients. The mean follow-up was 55.7 months. RESULTS: Pleurodesis alone was
      performed in 5 patients and an associated diaphragmatic procedure was performed
      in 5 patients. In 5 patients, no diaphragmatic anomaly was discovered: 3
      experienced one or more recurrences and all still suffer from chronic catamenial
      chest pain. Hormonal therapy temporarily improved outcome for 6 months in 2
      patients. On the contrary, in 5 patients surgical pleurodesis was associated with
      the repair of diaphragmatic defects (simple closure or coverage by a polyglactin
      mesh): these patients experienced no recurrence (n = 0/5, p = 0.0016) and no
      subsequent catamenial chest pain. CONCLUSIONS: The postoperative outcome is
      influenced by the diagnosis of diaphragmatic defects with or without
      endometriosis. Surgical treatment should be accomplished during menstruation for
      an optimal visualization of pleurodiaphragmatic endometriosis. Because
      diaphragmatic lesion is frequent and may be occult, we propose the systematic
      coverage of the diaphragmatic surface by a polyglactin mesh to prevent catamenial
      pneumothorax recurrence even when the diaphragm appears normal.

PMID- 12607644
TI  - Limited operation for severe multisegmental bilateral bronchiectasis.
AB  - BACKGROUND: Some patients exhibiting severe multisegmental bilateral
      bronchiectasis are no longer improved with antibiotic treatment and drainage and,
      most of the time, operation is contraindicated. In our institution, limited
      operation has been offered to select patients for this indication. We report our
      data regarding the feasibility and utility of such a procedure. METHODS: We
      studied 16 patients who underwent surgical removal of nonlocalized disease
      between 1990 and 1999. We report the mortality and morbidity rates of this
      surgical procedure and the clinical, bacteriological, and functional data for
      each patient. RESULTS: There was no mortality and the morbidity was low (18%, all
      with favorable outcome). Symptoms such as hemoptysis, sputum production, or
      dyspnea were also improved. The recurring infections decreased in frequency in 8
      patients and disappeared completely in 5 others. The bacteriological data
      assessment revealed disappearance of germs in 4 patients and persistence of
      chronic colonization in others. Postoperative spirometric data were not worsened
      and postoperative computed tomographic scans did not show progression of lesions
      not removed. CONCLUSIONS: These results suggest that, in properly selected
      patients, lasting symptomatic improvement can be achieved by resection. Limited
      operation may be indicated in nonlocalized bilateral bronchiectasis, provided
      that a target can be identified. This procedure is supported by physiopathologic
      arguments and is particularly relevant to patients with bronchiectasis with
      cystic and functionless territories.

PMID- 12607645
TI  - Use of three-dimensional computed tomographic angiography of pulmonary vessels
      for lung resections.
AB  - BACKGROUND: Identification and appropriate treatment of the pulmonary artery (PA)
      is a key to successful anatomic resection of the lung. Preoperative
      identification of branching pattern of the PA seems to make pulmonary resection
      easier and safer especially when there is severe adhesion or incomplete fissure
      between the lobes. With the development of the multidetector row spiral computed
      tomography (MDCT), three-dimensional (3D) CT angiography can be obtained easily
      and can provide very useful information about various organs. We studied the
      usefulness of 3D-CT pulmonary angiography (3D-CTPA) in evaluating the PA
      branching pattern before anatomic pulmonary resection. METHODS: Fourteen patients
      with primary lung cancer undergoing anatomic pulmonary resections were the
      subjects of this study. The 3D-CTPA images were obtained using MDCT. The obtained
      images of the PA branching pattern were compared with intraoperative findings in
      each case at the time of thoracotomy. RESULTS: MDCT scanning required
      approximately 15 seconds per patient during a single respiratory pause and the 3D
      images were processed within 10 minutes after scannning. According to
      intraoperative findings, 98% (84 of 86) of PA branches were revealed to be
      successfully identified on preoperative 3D-CTPA. Two missed branches on 3D-CTPA
      were small vessels, which were less than 1.5 mm in actual diameter. Pulmonary
      vessels were clearly identified even when contrast medium was not administered
      intravenously. CONCLUSIONS: Obtaining 3D-CTPA using MDCT is noninvasive yet it
      provides precise preoperative information regarding pulmonary vessels. This
      technique is a far less invasive and an easier investigation than conventional
      pulmonary angiography. The 3D-CTPA navigation may have the potential to increase
      the safety of surgical procedure and to reduce surgical morbidity in anatomic
      lung resection.

PMID- 12607646
TI  - Bronchial fenestration improves expiratory flow in emphysematous human lungs.
AB  - BACKGROUND: The crippling effects of emphysema are due in part to dynamic
      hyperinflation, resulting in altered respiratory mechanics, an increased work of
      breathing, and a pervasive sense of dyspnea. Because of the extensive collateral
      ventilation present in emphysematous lungs, we hypothesize that placement of
      stents between pulmonary parenchyma and large airways could effectively improve
      expiratory flow, thus reducing dynamic hyperinflation. METHODS: Twelve human
      emphysematous lungs, removed at the time of lung transplantation, were placed in
      an airtight ventilation chamber with the bronchus attached to a tube traversing
      the chamber wall, and attached to a pneumotachometer. The chamber was evacuated
      to -10 cm H2O pressure for lung inflation. A forced expiratory maneuver was
      simulated by rapidly pressurizing the chamber to 20 cm H2O, while the expiratory
      volume was continuously recorded. A flexible bronchoscope was then inserted into
      the airway and a radiofrequency catheter (Broncus Technologies) was used to
      create a passage through the wall of three separate segmental bronchi into the
      adjacent lung parenchyma. An expandable stent, 1.5 cm in length and 3 mm in
      diameter, was then inserted through each passage. Expiratory volumes were then
      remeasured as above. In six experiments, two additional stents were then inserted
      and forced expiratory volumes again determined. RESULTS: The forced expiratory
      volume in 1 second (FEV1) increased from 245 +/- 107 mL at baseline to 447 +/-
      199 mL after placement of three bronchopulmonary stents (p < 0.001). With two
      additional stents, the FEV1 increased to 666 +/- 284 mL (p < 0.001). CONCLUSIONS:
      Creation of extra-anatomic bronchopulmonary passages is a potential therapeutic
      option for emphysematous patients with marked hyperinflation and severe
      homogeneous pulmonary destruction.

PMID- 12607648
TI  - Complete atrioventricular septal defect, Down syndrome, and surgical outcome:
      risk factors.
AB  - BACKGROUND: This study was conducted to evaluate surgical outcome and to identify
      risk factors for hospital mortality and reoperation after repair of complete
      atrioventricular septal defect. METHODS: A total of 147 consecutive children
      underwent repair between January 1986 and December 1998. Of those, 106 had Down
      syndrome, 37% had normal chromosomes, and 4 had other syndromes; 108 underwent
      primary repair, 19 had prior pulmonary artery banding, and 20 had additional
      tetralogy of Fallot. The median weight at primary repair was 4.5 kg. A two-patch
      technique was used in 88%. RESULTS: The 30-day mortality was 15% (70% confidence
      interval [CI] 12% to 19%). A double orifice atrioventricular valve was found to
      be a significant risk factor (p = 0.002), with 6 of 11 patients dying. If double
      orifice atrioventricular valve patients are excluded, the mortality rate falls to
      12% (70% CI 9% to 15%). No difference in mortality was found between Down
      syndrome and chromosomally normal children but the latter more commonly required
      reoperation. Chromosomally normal children frequently have a dysplastic common
      atrioventricular valve (24% versus 3% in Down children, p < 0.001). In a
      multivariate Cox model including both variables, the presence of a dysplastic
      atrioventricular valve was a significant risk factor for reoperation. After
      controlling for the presence of a dysplastic atrioventricular valve, Down
      syndrome retained a significant protective effect but the upper limit of the
      confidence interval was close to 1. CONCLUSIONS: The presence of a double orifice
      atrioventricular valve emerged as an unforeseen risk factor for death.

PMID- 12607647
TI  - Late follow-up of 1095 patients undergoing operation for complex congenital heart
      disease utilizing pulmonary ventricle to pulmonary artery conduits.
AB  - BACKGROUND: Pulmonary ventricle (PV) to pulmonary artery (PA) conduits have made
      possible the correction of many complex congenital cardiac anomalies. METHODS:
      Between April 1964 and January 2001, 1270 patients underwent operation with
      conduit placement from the PV to PA. The present study evaluates late outcome of
      1095 patients (612 males, 483 females) having an operation before July 1992. Mean
      age was 9.6 +/- 8.2 years old. Diagnoses included pulmonary atresia/tetralogy of
      Fallot (459), transposition of the great arteries (TGA) (232), truncus arteriosus
      (193), double outlet right ventricle (DORV) (121), corrected TGA (49), septated
      univentricular heart (36), and other (5). A porcine-valved Dacron conduit was
      used in 730, homograft in 239, and non-valved conduit in 126. RESULTS: Early
      mortality decreased from 23.5% prior to 1980 to 3.7% for the most recent decade.
      Mean follow-up was 10.9 years (maximum, 29 years). Actuarial survival for early
      survivors at 10 and 20 years was 77.0% +/- 1.5% and 59.5% +/- 2.6%. On univariate
      analysis, clinical and hemodynamic factors associated with late mortality were
      male gender, older age at operation, higher post-repair PV/systemic ventricle
      (SV) pressure ratio, higher distal PA pressure, and longer bypass time (p < or =
      0.01 for all). On multivariate analysis, independent risk factors for late
      mortality were male gender, older age at operation, diagnosis of TGA, corrected
      TGA, truncus, or univentricular heart, and PV/SV pressure ratio > or = 0.72 (p <
      or = 0.03 for all). Freedom from reoperation for conduit failure at 10 and 20
      years was 55.5% +/- 2.0% and 31.9% +/- 2.7%. On multivariate analysis,
      independent risk factors for conduit failure were homograft conduit, diagnosis of
      TGA, younger age at operation, and smaller conduit size (p < or = 0.007 for all).
      Reoperation for one conduit replacement was performed in 306 patients, two
      conduit replacements in 55 patients, three in 6 patients, and four in 3 patients.
      Overall early mortality for conduit replacement in this series was 4.9%; it was
      1.7% for patients operated on from 1989 through 1992. At follow-up, 84% of
      survivors were in NYHA class I or II. CONCLUSIONS: Operations that include
      conduit placement and replacement can be performed with low early mortality.
      Younger age at operation was associated with improved late survival. The
      diagnosis of TGA was associated with increased risk for conduit failure, and the
      durability of the homograft, in this series, was inferior to the porcine-valved
      Dacron conduit. Quality of life was excellent for most patients despite the need
      for reoperation.

PMID- 12607649
TI  - Sequential diagnosis of coronary arterial anatomy in congenitally corrected
      transposition of the great arteries.
AB  - BACKGROUND: The objective of this study was to analyze coronary arteries (CA) in
      congenitally corrected transposition (CCT) and to determine the influence of
      aortopulmonary rotation on its pattern systematically. Precise CA anatomy is
      surgically needed in the current era of double switch for CCT. METHODS: We
      collected data on 62 patients who had CCT with situs solitus or inversus between
      1981 and 1999. Coronary artery anatomy was analyzed as it related to apical
      position, atrial situs, ventricular looping, and aortopulmonary rotation. Five
      main types with similar variants of epicardial configuration at the base of the
      heart were categorized into five central patterns (patterns X, O, I, II, and IV).
      RESULTS: The right CA coursed to the left in CCT with situs solitus, and to the
      right in CCT with situs inversus; and to the more posterior atrioventricular
      groove in both without apicocaval ipsilaterality. However, in CCT with more
      apicocaval ipsilaterality, the left circumflex might shift posterior to the right
      CA. With the same aortopulmonary rotation, the two groups had similar central
      patterns, and eta-square analysis showed that the evolution from patterns X, O,
      I, II, toward IV (n = 1, 36, 15, 9 to 1) was dependent on clockwise
      aortopulmonary rotation (p < 0.00000). CONCLUSIONS: Peripheral CA pattern in the
      atrioventricular groove was dictated by apicocaval ipsilaterality
      anteroposteriorly and ventricular looping dextrosinistrally, irrespective of
      atrial situs. The central CA pattern near the aortic sinus depended on
      aortopulmonary rotation due to "marriage of convenience" between them, and thus
      was predictable from arterial relations irrespective of its disease category.

PMID- 12607650
TI  - High-dose aprotinin reduces activation of hemostasis, allogeneic blood
      requirement, and duration of postoperative ventilation in pediatric cardiac
      surgery.
AB  - BACKGROUND: Though multiple studies have affirmed the effectiveness of aprotinin
      in reducing blood loss in adult cardiac surgery, the possible benefit in
      pediatric cardiac surgery is controversial. METHODS: In a double-blind,
      randomized, and placebo-controlled study, the efficacy of aprotinin in
      attenuating the hemostatic and inflammatory activation during cardiopulmonary
      bypass in 60 patients weighing less than 10 kg was investigated. Secondary
      endpoints were the influence of aprotinin on the reduction of blood loss and
      allogeneic blood requirement, as well as postoperative oxygenation and length of
      mechanical ventilation. Aprotinin was administered in a high-dose of 3 x 10(4)
      KIU/kg plus a bolus of 5 x 10(5) KIU (not weight adjusted) added to the pump
      prime. RESULTS: Aprotinin plasma concentration at the end of cardiopulmonary
      bypass (CPB) was with 184 +/- 45 KIU/mL, within the targeted range of 200 KIU/mL.
      Coagulation and fibrinolysis were suppressed (F1.2 1 hour after CPB: 5.35 +/- 2.9
      nmol/L vs 14.5 +/- 23.1 nmol/L; D-dimer 1 hour after CPB: 0.63 +/- 0.6 ng/mL vs
      2.3 +/- 3.1 ng/mL; p < 0.05), inflammatory markers (interleukin [IL]-6, IL-8, IL
      10) increased over time without significant differences between the groups, and
      only complement C3a activation was significantly attenuated at the end of CPB in
      the aprotinin group. Chest tube drainage was significantly reduced (24 hours:
      median 13.5 [IQR 12.2] mL/kg vs 19.4 [8.2] mL/kg; p < 0.05). All patients
      received one unit of packed cells to prime the heart lung machine. A second unit
      was needed significantly less often in the aprotinin group (13% vs 47%; p <
      0.05). Postoperative oxygenation (pO2/FIO2 172 [IQR 128] mm Hg vs 127 [74]; p <
      0.05) improved, and the time on ventilator was shorter in the aprotinin group
      (median 45 hours [IQR 94] vs 101 [IQR 74]; p < 0.05). No side effects were
      attributable to the use of aprotinin. CONCLUSIONS: High-dose aprotinin
      effectively attenuated hemostatic activation and reduced blood loss and
      transfusion requirement in pediatric cardiac surgery. Postoperative ventilation
      was also shortened in the aprotinin group.

PMID- 12607651
TI  - Robotic mitral valve repair: experience with the da Vinci system.
AB  - BACKGROUND: As part of a Food and Drug Administration trial, mitral repairs were
      performed in 38 patients using the robotic da Vinci surgical system (Intuitive
      Surgical, Inc, Mountain View, CA). Prospectively, we evaluated safety and
      efficacy in performing both simple and complex mitral repairs. METHODS: Eligible
      patients had nonischemic moderate to severe mitral insufficiency. Operative
      techniques included peripheral cardiopulmonary perfusion, a 4- to 5-cm mini
      thoracotomy, transthoracic aortic occlusion, and antegrade blood cardioplegia.
      Transesophageal echocardiograms were done intraoperatively with three-dimensional
      reconstructions. Successful repairs were defined as mild or less residual
      regurgitation. RESULTS: Enhanced three-dimensional visualization of mitral
      leaflets and the subvalvar apparatus allowed safe, dexterous intracardiac tissue
      manipulation. All patients had successful valve repairs including quadrangular
      resections, sliding plasties, and edge-to-edge approximations, as well as both
      chordal transfers and replacements. There were no operative deaths, strokes, or
      device-related complications. One patient required valve replacement for
      hemolysis and 1 was reexplored for bleeding. There were no incisional
      conversions. Both robotic repair and total operating times decreased
      significantly from 1.9 +/- 0.1 and 5.1 +/- 0.1 hours (mean +/- standard error of
      the mean) for the first 19 patients to 1.5 +/- 0.1 (p = 0.002) and 4.4 +/- 0.1
      hours (p = 0.04) for the last 19 operations, respectively. Total hospital length
      of stay for patients was 3.8 +/- 0.6 days. Of all patients, 31 (82%) had a 4-day
      or less length of stay. Seven patients (18%) had stays between 5 and 9 days (6.4
      +/- 1.0). CONCLUSIONS: This study shows that the da Vinci surgical system
      (Intuitive Surgical, Inc) has few limitations in performing complex valve
      repairs. Articulated wrist-like instruments and three-dimensional visualization
      enabled precise tissue telemanipulation. Future robotic design advances and
      adjunctive suture technologies may promote continuing evolution of robotic
      cardiac operations.

PMID- 12607652
TI  - The initial experience with the ATS Medical mechanical cardiac valve prosthesis.
AB  - BACKGROUND: From May 1994 through October 2000, a total of 1,146 patients
      underwent valve replacement with the ATS Medical mechanical cardiac valve
      prosthesis under a study protocol approved by international ethics committees
      (non-United States participants) or under a United States Food and Drug
      Administration-approved Investigational Device Exemption study. The study took
      place at 19 domestic and three international centers. METHODS: As required by the
      Food and Drug Administration's Heart Valve Guidance Document, only isolated
      implants were included in the study (double-valve implants were excluded), with
      operative and follow-up data collected from each center. RESULTS: Aortic valve
      replacement (AVR) was conducted in 801 patients (309 with coronary bypass) and
      mitral valve replacement (MVR) in 345 patients (78 with coronary bypass). Overall
      operative (< or = 30 days post implant) mortality was 2.1% (17 AVR = 2.1%, 7 MVR
      = 2.0%), 7 of which (AVR = 4, MVR = 3) were valve related. In 2,086 patient-years
      (1,459 AVR patient-years, 627 MVR patient-years) of follow-up, there were an
      additional 50 patient deaths of these, 18 were valve related, 9 due to
      anticoagulant related bleeding, 5 sudden/unexplained, and 1 each after stroke,
      thrombosis, prosthetic valve endocarditis, and thromboembolism. Late (>30 days
      post implant) valve-related complications included: transient and chronic
      thromboembolism (27 AVR (linearized rate 1.85%/patient-year) and 20 MVR
      (3.19%/patient-year), of which 11/47 (0.53%/patient-year) had chronic deficits,
      thrombosis (1 AVR = 0.07%/patient-year and 4 MVR = 0.64%/patient-year),
      paravalvular leak (10 AVR = 0.69%/patient-year and 8 MVR = 1.28%/patient-year),
      anticoagulant related hemorrhage (34 AVR = 2.33%/patient-year and 8 MVR =
      1.28%/patient-year), prosthetic valve endocarditis (3 AVR = 0.21%/patient-year
      and 2 MVR = 0.32%/patient-year), and structural valve failure or dysfunction
      (0%). Echocardiographic gradients were proportional to valve size and did not
      significantly change over the follow-up period. CONCLUSIONS: This study
      documented the ATS Medical mechanical cardiac valve prosthesis to be a valuable
      addition to the surgeon's armamentarium in the treatment of cardiac valvular
      disease.

PMID- 12607653
TI  - Treatment of destructive aortic valve endocarditis with the Freestyle Aortic Root
      Bioprosthesis.
AB  - BACKGROUND: Successful treatment of destructive aortic valve endocarditis with
      annular abscess formation requires extensive surgical debridement and
      reconstruction of the left ventricular outflow tract and aortic root. Homograft
      aortic roots are the conduits of choice, but because they are not available in
      all cases, alternative conduits are needed. METHODS: Owing to its features, which
      are comparable to those of homografts, the Freestyle aortic root xenograft was
      used in 10 consecutive patients aged between 32 and 77 years. All patients had
      extensive abscess formation, 5 presented with prosthetic valve endocarditis, 2
      had additional mitral valve endocarditis requiring partial leaflet resection and
      reconstruction, 1 patient had an additional fistula into the right atrium, and 1
      required coronary bypass. One patient developed a septic ventricular septal
      defect and fistula into the right atrium with tricuspid valve endocarditis.
      RESULTS: None of the patients required reoperation for bleeding. Two (20%)
      patients died in the postoperative period, 1 due to multiorgan failure, and 1 due
      to preexisting invasive pulmonary aspergillosis. At autopsy, neither had evidence
      of intrapericardial hematoma or suture dehiscence. One patient died 13 months
      postoperatively without clinical signs of valve dysfunction or recurrent
      endocarditis. All other patients are well at 12 to 42 months after surgery.
      Clinical examination and echocardiography at the most recent follow-up showed no
      signs of valve dysfunction, recurrent fistulation, or endocarditis. CONCLUSIONS:
      The Freestyle aortic root appears to be an acceptable alternative to homografts
      in the treatment of severe endocarditis. Long-term valve durability in younger
      patients, however, remains to be determined.

PMID- 12607654
TI  - Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic
      valve cusps and promotes aortic valve interstitial cell calcification via
      apoptosis.
AB  - BACKGROUND: Aortic valve stenosis characteristically progresses due to cuspal
      calcification, often necessitating valve replacement surgery. The present study
      investigated the hypothesis that TGF-beta1, a cytokine that causes calcification
      of vascular smooth muscle cells in culture, initiates apoptosis of valvular
      interstitial cells as a mechanistic event in cuspal calcification. METHODS:
      Noncalcified and calcified human aortic valve cusps were obtained at autopsy or
      at the time of cardiac surgery. The distributions within cusps of TGF-beta1,
      latent-TGF-beta1-associated peptide, and TGF-beta receptors were studied using
      immunohistochemistry. The effects of TGF-beta1 on mechanistic events contributing
      to aortic valve calcification were also investigated using sheep aortic valve
      interstitial cell (SAVIC) cultures. RESULTS: Immunohistochemistry studies
      revealed that calcific aortic stenosis cusps characteristically contained within
      the extracellular matrix qualitatively higher levels of TGF-beta1 than
      noncalcified cusps. Noncalcified normal valves demonstrated only focal
      intracellular TGF-beta1. Addition of TGF-beta1 to SAVIC cultures led to a cascade
      of events, including: cellular migration, aggregation, formation of apoptotic
      alkaline phosphatase enriched nodules, and calcification of these nodules. The
      time course of these events in the SAVIC culture system was rapid with nodule
      formation with apoptosis by 72 hours, and calcification after 7 days.
      Furthermore, ZVAD-FMK, an antiapoptosis agent (caspase inhibitor), significantly
      inhibited calcification and apoptosis induced by TGF-beta1, but had no effect on
      nodule formation. However, cytochalasin D, an actin-depolymerizing agent,
      inhibited nodule formation, but not calcification. CONCLUSIONS: TGF-beta1 is
      characteristically present within calcific aortic stenosis cusps, and mediates
      the calcification of aortic valve interstitial cells in culture through
      mechanisms involving apoptosis.

PMID- 12607655
TI  - Valved stentless composite graft: clinical outcomes and hemodynamic
      characteristics.
AB  - BACKGROUND: The valved stentless composite graft has become well established in
      our hospital for replacement of the ascending aorta and aortic valve in elderly
      patients and those with contraindication for lifelong anticoagulation. This study
      was conducted to evaluate the postoperative hemodynamic characteristics and
      clinical outcomes after implantation of this device. METHODS: Between November
      1998 and February 2001, 45 consecutive patients with a mean age of 69 years
      underwent implantation of a composite graft using a stentless valve prosthesis
      (Toronto SPV) incorporated in a collagen-coated Dacron tube (InterGard). The
      indication for surgery was aortic valve disease with an accompanying true
      aneurysm of the ascending aorta in 42 patients and a dissection of the aortic
      wall in 3 patients. Postoperative echocardiographic examinations were performed
      before discharge from the hospital and at the time of the follow-up. Mean follow
      up duration was 18 months (range 3 to 30 months). RESULTS: There was no
      perioperative mortality. During follow-up, there were two noncardiac, nonvalve
      related deaths. Echocardiographic evaluation before discharge and at follow-up
      demonstrated favorable hemodynamics of the valve prosthesis with mean
      transvalvular gradients of 8.5 +/- 2.9 mmHg and 8.0 +/- 3.1 mmHg, respectively.
      No regurgitation across the valve and no contact of the cusps with the Dacron
      tube were seen in any case. CONCLUSIONS: A stentless composite graft for
      replacement of the aortic valve and ascending aorta offers excellent hemodynamic
      results and is a suitable device for patients in whom anticoagulation should be
      avoided.

PMID- 12607656
TI  - Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult
      patients.
AB  - BACKGROUND: Stroke remains a devastating complication after cardiac surgical
      procedures despite advances in perioperative monitoring and management. The
      purpose of this study was to determine the predictors of stroke in a large,
      contemporary cardiac surgery population. METHODS: Prospective data on 16,184
      consecutive patients undergoing cardiac surgery (coronary artery bypass grafting
      [CABG], n = 8,917; beating heart CABG, n = 1,842; aortic valve surgery, n =
      1,830; mitral valve surgery, n = 708; double or triple valve surgery, n = 381;
      CABG and valve surgery, n = 2,506) between April 1996 and August 2001 were
      subjected to univariate and multivariate analysis. Stroke was defined as any new
      permanent (manifest stroke) or temporary neurologic deficit or deterioration
      (transient ischemic attack or prolonged reversible ischemic neurologic deficit)
      and was confirmed by computed tomography or magnetic resonance imaging whenever
      possible. RESULTS: Overall incidence of stroke was 4.6% and varied between
      surgical procedures (CABG 3.8%; beating-heart CABG 1.9%; aortic valve surgery
      4.8%; mitral valve surgery 8.8%; double or triple valve surgery 9.7%; CABG and
      valve surgery 7.4%). Of 63 patient-specific and treatment variables, 54 were
      found to have a significant univariate association with postoperative stroke.
      Multivariable analysis revealed 10 variables that were independent predictors of
      stroke: history of cerebrovascular disease, peripheral vascular disease,
      diabetes, hypertension, previous cardiac surgery, preoperative infection, urgent
      operation, CPB time more than 2 hours, need for intraoperative hemofiltration,
      and high transfusion requirement. Beating heart CABG was associated with a lower
      incidence of stroke in this multivariable analysis. CONCLUSIONS: Identification
      of predictors for stroke is important for understanding the pathogenesis of this
      devastating complication as well as for developing preventative strategies.
      Although retrospective analyses can be subject to selection bias we believe
      beating heart CABG is associated with a lower incidence of stroke and may
      therefore improve patient outcomes.

PMID- 12607657
TI  - Stroke after cardiac surgery: a retrospective analysis of the effect of aprotinin
      dosing regimens.
AB  - BACKGROUND: Half-dose aprotinin (HDA) appears to be equivalent to full-dose
      aprotinin (FDA) in its ability to prevent bleeding. However, data regarding the
      potential effect of aprotinin use and dosage on other outcomes such as the
      occurrence of perioperative stroke are limited. It has been postulated that the
      higher level of kallikrein inhibition obtained with FDA dosing may be required
      for end-organ protection. Therefore, we performed a retrospective study in
      cardiac surgery patients at high risk for developing stroke to determine the
      relative effects of FDA and HDA regimens on the incidence of postoperative
      stroke. METHODS: Records of 1,524 patients undergoing cardiac surgery over a 15
      month period were reviewed. Patients at high risk for stroke were selected if
      they met all of the following predefined criteria: age greater than 70 years,
      history of hypertension, history of diabetes mellitus, history of stroke or
      transient ischemic attack, and presence of aortic atheroma. A validated
      preoperative stroke risk index was calculated for each patient. Postoperative
      stroke required confirmation by computed tomography or magnetic resonance
      imaging. Patients were divided into three groups according to whether they were
      administered no aprotinin, HAD, or FDA. RESULTS: A total of 149 patients
      fulfilled the criteria for being at high risk for stroke. Stroke risk index was
      very similar (p = 0.56) in the three groups: those who received no aprotinin and
      served as a control group (124 +/- 15, n = 56), those who were given HDA (123 +/-
      12, n = 67), and those who received FDA (122 +/- 11 n = 26). Preoperative and
      intraoperative characteristics were also similar between the three study groups.
      Overall, the incidence of stroke was 16% (24/149). The incidence of stroke
      differed (p < 0.05) among the three groups: no aprotinin 16% (9/56), HDA 22%
      (15/67), and FDA 0% (0/26). CONCLUSIONS: In this retrospective study of cardiac
      surgery patients at high risk for postoperative stroke, the administration of FDA
      but not HDA was associated with a lower incidence of stroke.

PMID- 12607658
TI  - Clinical impact of drug-eluting stents in changing referral practices for
      coronary surgical revascularization in a tertiary care center.
AB  - BACKGROUND: The long-term benefits of angioplasty are limited by the occurrence
      of restenosis. Drug-eluting stents with a projected restenosis rate of close to
      0% are soon to become available. The short- and long-term consequences of this
      advance to the cardiac surgical volume remain unclear. METHODS: A total of 196
      consecutive coronary angiograms and medical records of patients referred for
      coronary bypass surgery were reviewed. Considering the hypothetical premise of
      having drug-eluting stents with a near zero restenosis rate, we reviewed each
      case to determine if surgical revascularization was still the preferred option
      for revascularization. RESULTS: The mean age was 60 (+/-10.6) years. Seventy-two
      percent of patients were male. Considering the availability of drug-eluting
      stents 154 (79%) would still have been sent to surgery, representing a 21%
      decrease in the number of surgical revascularizations. Angiographic
      characteristics predicting coronary bypass revascularization were the presence of
      chronic total occlusion (odds ratio [OR]: 9.1; confidence interval [CI]: 2.1 to
      39), left main coronary artery stenosis (OR: 9.6; CI: 1.27 to 73), and need for
      valvular surgery (OR: 7.38; CI: 1.3 to 157). The most common predictors of a
      change in clinical management from surgical to percutaneous revascularization if
      drug-eluting stents were available were diffuse coronary narrowing (OR: 15.78),
      restenotic lesions (OR: 27.86), and small coronary arteries (OR: 26).
      CONCLUSIONS: Drug-eluting stents may have a significant impact on cardiac surgery
      volume (approximately a 21% decrease in our center). It may also direct patients
      with small vessels, diffuse narrowing, or restenotic lesions and diabetic
      patients to percutaneous therapy.

PMID- 12607659
TI  - Pain treatment with a COX-2 inhibitor after coronary artery bypass operation: a
      randomized trial.
AB  - BACKGROUND: Adequate analgesic medication is mandatory after cardiac operations.
      Cyclooxygenase-2 inhibitors represent a new therapeutic option, acting primarily
      on the response to inflammation. METHODS: We compared a cyclooxygenase-2
      inhibitor (etodolac) with two traditional drugs: a nonselective cyclooxygenase
      inhibitor (diclofenac) and a weak opioid (tramadol) on postoperative pain and
      renal function in patients undergoing coronary artery bypass operations. Sixty
      consecutive patients were randomized into three groups: (1) group A patients who
      received tramadol; (2) group B patients who received diclofenac; and (3) group C
      patients who received etodolac. For measurement of analgesic effect, the visual
      analogue scale was assessed up to postoperative day 4. Creatinine-clearance was
      determined before and at the end of study medication, and serum creatinine and
      urea were monitored daily for renal effects. Study medication was given on
      postoperative days 2 and 3. Side effects and additional pain medication were
      recorded. RESULTS: The visual analogue scale was lower in group C (p < 0.05) from
      postoperative days 2 to 4 and in group B (p < 0.05) from postoperative days 3 to
      4 compared with group A. Amount of additional pain medication and incidence of
      side effects were significantly less in group C compared with group A. We
      observed a short-lasting elevation of serum creatinine and urea in groups B and C
      compared with group A (p < 0.05). CONCLUSIONS: At the doses analyzed, etodolac
      and diclofenac produced better postoperative pain relief with less side-effects
      than tramadol. A short-lasting impairment of renal function was found in patients
      treated with etodolac and diclofenac.

PMID- 12607660
TI  - Long-term results of coronary artery bypass grafting in patients with renal
      insufficiency.
AB  - BACKGROUND: There are few published studies on coronary artery bypass grafting in
      patients with renal insufficiency who are not on maintenance dialysis. No details
      of long-term results have been published. METHODS: This retrospective study
      focuses on 117 consecutive coronary artery bypass grafting patients with renal
      insufficiency, but who did not require dialysis (group B: preoperative serum
      creatinine level > or = 1.5 mg/dL). For comparison purposes, patients on
      maintenance dialysis (group C: 84 patients) and patients with normal renal
      function (group A: 794 patients; preoperative serum creatinine level < 1.0 mg/dL)
      were selected. RESULTS: Hospital mortality was 11% (13 of 117) in group B, 5.9%
      (5 of 84) in group C, and 1.6% (13 of 794) in group A, and between groups A and
      B, p < 0.0001, and between groups B and C, p = 0.24. Actuarial survival rates at
      10 years, including all deaths, were 87%, 32%, and 29% in groups A, B and C,
      respectively, and between groups A and B, p < 0.009 and between groups B and C, p
      = 0.63. In 23 patients in group B, the bilateral internal thoracic artery was
      used. No cardiac deaths were observed in these patients during the mean follow-up
      time of 42 months (range, 1 to 128 months). Cox model analysis revealed nonuse of
      arterial grafting (p = 0.03; Hazards ratio 1.7) to be a statistically significant
      factor, and renal insufficiency (p < 0.0001; Hazards ratio 3.3) and maintenance
      dialysis (p < 0.0001; Hazards ratio 5.6) to be major independent risk factors for
      actuarial survival. CONCLUSIONS: Renal insufficiency was shown to be an
      independent risk factor for poor prognosis after coronary artery bypass grafting.
      However, aggressive use of arterial grafts, especially the internal thoracic
      artery, is recommended to improve late outcomes.

PMID- 12607662
TI  - Off-pump coronary artery bypass grafting does not decrease the incidence of
      atrial fibrillation.
AB  - BACKGROUND: Postoperative atrial fibrillation remains a significant source of
      morbidity after coronary artery bypass grafting. We reviewed the data on 2,569
      patients to determine if the absence of cardiopulmonary bypass resulted in a
      lower incidence of atrial fibrillation. METHODS: All patients undergoing coronary
      artery bypass grafting without cardiopulmonary bypass from January 1, 1997
      through June 30, 2001 were evaluated for postoperative atrial fibrillation. The
      data of 252 patients with no cardiopulmonary bypass (group 1) were reviewed and
      compared with three other patient groups. Group 2 consisted of 1,470 patients
      using cardiopulmonary bypass during the same study period. Group 3 consisted of
      841 patients with a similar number of grafts as the study group but using
      cardiopulmonary bypass. Group 4 consisted of historical data for 847 patients
      operated on using cardiopulmonary bypass collected from January 1995 through
      December 1996. Prophylactic beta-blockade was instituted in January 1997. Groups
      1 to 3 received this treatment, but group 4 did not. RESULTS: Group 1 had an
      incidence of atrial fibrillation of 8.8%. Groups 2, 3, and 4 had incidences of
      atrial fibrillation of 11.6%, 9.4%, and 28.0%, respectively. When compared with
      group 1, the incidence of atrial fibrillation in group 4 was statistically
      different (p <. 0001). CONCLUSIONS: Avoiding cardiopulmonary bypass did not aid
      the reduction of atrial fibrillation at our institution.

PMID- 12607661
TI  - Internal thoracic artery grafts for the entire heart at a mean of 12 years.
AB  - BACKGROUND: There is consensus today that the long-term results of bypassing the
      left anterior descending artery with an internal thoracic artery (ITA) graft are
      superior to those of a saphenous vein graft. Our hypothesis for this study was
      that three-vessel revascularization with only ITA grafts would also give
      excellent results. METHODS: Using our previously described techniques to enhance
      the length of ITA grafts by skeletonization and high mediastinal mobilization, we
      were able to perform tension-free, three-vessel revascularization using only ITA
      grafts in 125 (83%) of a consecutive series of 150 patients with three-vessel
      occlusive coronary disease. We followed 100% of these 125 exclusive ITA graft
      patients (average of 3.9 anastomoses per patient) to their time of death (59;
      47.2%) or current living status (66; 52.8%). RESULTS: Combined intraoperative
      graft flows averaged 225 mL/min. Of the 125 patients in this study (average age,
      63.5 years), 121 (96.8%) lived beyond 40 days. Of these 121 patients, 55 (45%)
      died at a mean of 7 years postoperatively and 66 (55%) are still living at a mean
      of 12.1 years. Of these 121 patients, 112 (93%) had angina at baseline. Of these
      112, 92 (85%) were angina free at a mean of 9.1 years postoperatively. Freedom
      from infarction was 100% at 5 years and 97% at 10 years. Freedom from
      reintervention was 90% at a mean of 9.8 years. CONCLUSIONS: Use of ITA grafts for
      three-vessel coronary revascularization provides excellent results and is both
      practical and appropriate for many patients.

PMID- 12607663
TI  - Estimating group mortality and paraplegia rates after thoracoabdominal aortic
      aneurysm repair.
AB  - BACKGROUND: Most clinical studies regarding thoracoabdominal aortic aneurysm
      (TAAA) surgery are retrospective comparisons involving heterogeneous groups of
      patients. Risk models that evaluate susceptibility bias enhance interpretation of
      these intergroup comparisons. The purpose of this analysis was to derive group
      risk models for mortality and paraplegia after TAAA repair. METHODS: Data
      regarding 1,220 consecutive patients undergoing TAAA repair were analyzed via
      multiple logistic regression with stepwise model selection. Categorical
      preoperative risk factors that predicted 30-day mortality and paraplegia were
      used to develop risk models. RESULTS: Fifty-eight patients (4.8%) died within 30
      days and 56 patients (4.6%) developed paraplegia or paraparesis. Predictors of
      mortality were rupture, renal insufficiency, symptomatic aneurysms, and Crawford
      extent II repairs. Extent of repair and acute presentation were predictors of
      paraplegia. The derived risk models estimated mortality and paraplegia rates that
      correlated well with actual frequencies reported in other contemporary series
      (regression slopes = 0.87 and 1.06, respectively). CONCLUSIONS: The derived risk
      models accurately estimate paraplegia and mortality rates in groups of patients.
      Prospective model validation will be required to confirm their accuracy.

PMID- 12607664
TI  - Surgery for acute type A dissection using antegrade selective cerebral perfusion:
      experience with 122 patients.
AB  - BACKGROUND: Antegrade selective cerebral perfusion (ASCP) has proved to be a
      reliable method of brain protection during surgery of the thoracic aorta, but its
      use during aortic dissection surgery still remains controversial. In this study,
      we present our results after the operative repair of acute type A aortic
      dissections using ASCP and moderate hypothermic circulatory arrest. METHODS:
      Between October 1995 and August 2001, 122 patients (76 men, 46 women) underwent
      repair of acute type A aortic dissection with the aid of ASCP and open distal
      anastomosis. The average age of the patients was 61 +/- 12 (mean +/- standard
      deviation). Preoperative complications included cardiac tamponade (n = 34;
      27.0%), aortic regurgitation (n = 27; 22.1%), and new neurological deficits (n =
      11; 9%). RESULTS: Stepwise logistic regression revealed preoperative cardiac
      tamponade (p = 0.018) and new neurological deficits (p = 0.017) to be independent
      determinants for hospital mortality (19.7%). Permanent neurological complications
      occurred in 7% of the patients. Independent risk factors for temporary
      neurological dysfunction (11.2%) included cardiac tamponade (p = 0.019) and
      preoperative neurological deficits (p = 0.000). CONCLUSIONS: In our experience,
      the surgical treatment of acute type A aortic dissection with the aid of ASCP was
      associated with acceptable hospital mortality and neurologic morbidity rates.

PMID- 12607665
TI  - Preoperative shock determines outcome for acute type A aortic dissection.
AB  - BACKGROUND: Acute type A aortic dissection is a life-threatening catastrophe.
      Surgical results have not improved. METHODS: The charts of all 70 patients
      surgically treated for acute type A primary aortic dissection during the period
      of January 1988 through April 2001 were reviewed. RESULTS: Average age was 59 +/-
      2 years. Comorbidities included hypertension (66%), coronary artery disease
      (17%), and Marfan's syndrome (11%). At presentation, 23% were in shock, 17% had
      neurologic dysfunction, and 36% had coronary ischemia. The aortic valve was
      preserved in 55. Distal aortic anastomosis was performed under aortic cross-clamp
      ("closed") in 32 and "open" under circulatory arrest in 38 patients. Operative
      mortality was 18.6% (13 of 70 patients). Patients in shock had an operative
      mortality of 50% compared with stable patients of 9% (p = 0.0002). Mortality was
      similar regardless of technique. Univariate analysis revealed preoperative shock
      (p = 0.0002), tamponade (p = 0.003), and neurologic deficit (p = 0.02) to be
      associated with mortality. Multivariate analysis revealed hemodynamic stability
      (odds ratio = 0.10, p = 0.04) and outside transfer (odds ratio = 0.12, p = 0.03)
      to be negative predictors of mortality. Of 57 survivors, follow-up was 93%
      complete for an average of 46 +/- 6 months. The overall late reoperation rate was
      24.6% (14 of 57 patients) at 50.3 +/- 12.3 months. Twelve patients (21%)
      underwent future aortic aneurysmal repair. No difference in reoperation rate was
      seen comparing "closed" (26%) with "open" (18%; p = 0.46). Of 42 preserved native
      valves, only 3 (7.1%) needed future valve replacement. CONCLUSIONS: In our
      experience, operative mortality was determined by preoperative hemodynamic
      instability. Technique did not impact survival or late reoperation. Early
      diagnosis and repair is critical to improving survival.

PMID- 12607666
TI  - Is extended aortic replacement in acute type A dissection justifiable?
AB  - BACKGROUND: The aim of this study was to evaluate the effectiveness of our
      surgical strategy for acute aortic dissection based on the extent of the
      dissection and the site of the entry, with special emphasis on resection of all
      dissected aortic segments if technically possible. METHODS: Between January 1995
      and March 2001, 43 consecutive patients underwent operations for acute aortic
      dissection. In all patients the distal repair was performed under circulatory
      arrest without the use of an aortic cross-clamp. Fifteen patients underwent
      aortic arch replacement with additional reconstruction of supra-aortic vessels in
      3 patients. Complete replacement of all dissected tissue could be achieved in 21
      patients (group 1). Because of the distal extent of the dissection beyond the
      aortic arch, replacement of all the dissected tissue was not possible in 22
      patients (group 2). RESULTS: Early mortality was 4.7% (2 patients), and the
      incidence of perioperative cerebrovascular events was 7.0% (3 patients). All of
      these events occurred in group 2 (p < 0.025). During the follow-up period of 6
      years or less, 5 patients died, all from causes not related to the aorta or the
      aortic valve. A persisting patent false lumen was observed in 14 of the 36
      surviving patients (39%). CONCLUSIONS: Extended replacement of the dissected
      ascending aorta and aortic arch can be done with good early and midterm results,
      even though it requires a complex surgical technique. Therefore we advocate
      complete replacement of the dissected parts of the aorta in all patients in whom
      this is technically possible.

PMID- 12607667
TI  - Endoluminal repair of aneurysms associated with coarctation.
AB  - BACKGROUND: Late aneurysm formation is a well-recognized complication of surgery
      for aortic coarctation. Open surgery to repair these aneurysms is associated with
      significant morbidity and mortality. Endoluminal repair is an attractive
      alternative to open surgery. METHODS: Data were collected prospectively on
      consecutive patients who presented with aneurysms associated with coarctation
      RESULTS: Between June 1999 and October 2001, 5 patients underwent elective
      endoluminal repair for coarctation aneurysms. All procedures were technically
      successful and no patients died. Four patients previously had open surgery to
      repair aortic coarctation, and 1 presented with an aneurysm associated with a
      previously unrecognized coarctation. The median follow-up was 7 months (range, 3
      to 29 months), and to date, all aneurysms remain excluded. CONCLUSIONS:
      Endoluminal repair is a promising alternative to redo open surgery for thoracic
      aneurysms associated with previous surgery for aortic coarctation. Long-term
      follow-up is required to assess the durability of the stent grafts.

PMID- 12607668
TI  - A tumor necrosis factor gene polymorphism influences the inflammatory response
      after cardiac operation.
AB  - BACKGROUND: The genetic background may influence cytokine release evoked by
      cardiac operation. Thus we determined the allele frequency and genotype
      distribution of a bi-allelic tumor necrosis factor (TNF) gene polymorphism and
      TNF-alpha concentrations in patients undergoing cardiac operations with and
      without cardiopulmonary bypass (CPB). METHODS: The TNF NcoI gene polymorphism was
      identified by polymerase chain reaction followed by restriction analysis of the
      polymerase chain reaction product. Reading the size of the resulting DNA bands
      from the agarose gel defined the genotype as homozygous or heterozygous for the
      two alleles TNFB1 and TNFB2. Blood samples to determine TNF-alpha plasma levels
      were drawn from the patients before induction of general anesthesia after
      termination of CPB or after finishing coronary revascularization on the beating
      heart in non-CPB patients and 12 hours postoperatively. RESULTS: The genotype
      distribution and allele frequencies in 47 patients undergoing cardiac operation
      with CPB were comparable with those found in 36 patients undergoing cardiac
      operation without CPB. The TNF-alpha plasma levels over time were comparable in
      patients with and without CPB. However, patients homozygous for the TNF-B2 allele
      had significantly higher TNF-alpha plasma levels after termination of the CPB
      (40.2 +/- 3.5 pg/mL; mean +/- standard error of the mean; n = 28) compared with
      non-CPB patients (29.8 +/- 2.5 pg/mL; mean +/- standard error of the mean; n =
      15) (p < 0.05). CONCLUSIONS: Patients homozygous for the TNF-B2 allele showed
      significantly higher TNF-alpha plasma levels after termination of CPB compared
      with non-CPB patients. Therefore preoperative TNF genotyping may be useful as
      patients with genetically determined increased proinflammatory cytokine
      expression with multiple comorbidities may in particular benefit from avoiding
      the use of CPB.

PMID- 12607669
TI  - Treatment of recurrent staphylococcal mediastinitis: still a controversial issue.
AB  - BACKGROUND: Although surgical management with early debridement and closed
      mediastinal irrigation has proved successful in reducing early mortality
      following poststernotomy deep sternal wound infection, recurrence rates are still
      up to 20%. This study compared the effectiveness and safety of wound dressing
      with granulated sugar versus early muscle flap surgery in the management of
      recurrent postoperative Staphylococcal mediastinitis. METHODS: Between January
      1995 and January 2002, 25 patients with severe recurrent staphylococcal
      mediastinitis were treated with granulated sugar wound dressing (group A) or with
      wound debridement, v-shape sternectomy and associated muscle flap surgery (group
      B). Clinical outcomes and perioperative data were analyzed. Outcomes were
      compared between the groups evaluating the length of time for normalization of
      white blood cell (WBC) count and of body temperature and length of hospital stay.
      Patient characteristics determining best treatment option were identified.
      Survival and incidence of recurrence at follow-up were also analyzed. RESULTS:
      Study groups proved homogenous as to preoperative characteristics. Complete cure
      was achieved earlier in group A than in group B (defervescence: p = 0.0005; WBC
      normalization: p = 0.0001, respectively). Hospital stay was shorter in group A. A
      statistically significant difference was found in hospital mortality (16%
      overall) between the two groups with better outcomes in group A (p = 0.039). In
      the patient subset with the most severe preoperative profile (hemodialysis,
      tracheostomy, inotropic support) surgical treatment produced worse results than
      the sugar dressing method (p 0.048). No case of recurrence was observed.
      CONCLUSIONS: Both treatments proved effective in recurrent type IV A
      Staphylococcal mediastinitis. Granulated sugar proved a safer option in severely
      compromised patients.

PMID- 12607670
TI  - Comparison of epicardial and endocardial linear ablation using handheld probes.
AB  - BACKGROUND: The optimal technique for producing linear radiofrequency thermal
      lesions in myocardial tissue is unclear. We compared epicardial ablation on the
      beating heart with endocardial ablation after cardioplegia. METHODS:
      Radiofrequency lesions were produced using a multielectrode malleable handheld
      probe in ovine myocardium with three wall thicknesses. Detailed analysis of
      lesion dimensions was used to assess the effects of site of ablation, muscle
      thickness, and duration of ablation. RESULTS: After epicardial atrial ablation,
      myocardial lesions were detected in all sections without macroscopically visible
      epicardial fat (n = 10), but only 43% (6/14) of sections with epicardial fat.
      Three of 24 atrial epicardial sections (13%) and 92% (23/25) of endocardial
      atrial lesion sections were clearly transmural. In thicker tissues lesion depth
      was independent of endocardial (right ventricle: 3.9 +/- 1.1 mm, left ventricle:
      3.8 +/- 0.7 mm) or epicardial (right ventricle: 3.4 +/- 0.6 mm, left ventricle:
      4.3 +/- 0.9 mm) ablation site. Epicardial lesions are less deep in thinner areas
      of myocardium (p = 0.003). Lesions were all wider than they were deep. There was
      no significant increase in lesion depth with the increase in ablation duration
      from 1 to 2 minutes. CONCLUSIONS: Lesions were unlikely to be transmural with
      either technique when the wall thickness was greater than about 4 mm. Epicardial
      fat has an important negative effect on epicardial lesion formation. Where
      epicardial fat is absent epicardially produced lesions penetrate less deeply when
      the wall thickness is small, possibly due to endocardial cooling by circulating
      blood. Prolongation of the duration of ablation from 1 to 2 minutes does not
      significantly increase lesion depth.

PMID- 12607672
TI  - Elimination of fat microemboli during cardiopulmonary bypass.
AB  - BACKGROUND: Fat emboli have been implicated in cerebral dysfunction after
      cardiopulmonary bypass (CPB). We sought to identify the source of fat emboli
      during CPB and devise a technique for their elimination. METHODS: Patients
      undergoing CPB were prospectively randomized to either cardiotomy suction (n = 7)
      or cell-saving suction device (n = 6). Blood was collected at various intervals
      during CPB, and the fat emboli were identified using oil red O stain. These
      emboli were grouped based on their diameter into 10- to 50-microm and more than
      50-microm particles. The number of fat emboli per slide examined was graded
      according to the following scale: 1 (1 to 10), 2 (11 to 20), 3 (21 to 30), and 4
      (> 30 emboli). In the second phase of the experiment, a 21-microm filter was
      attached in series, distal to the cardiotomy reservoir (n = 6), and fat emboli
      were quantified. RESULTS: Blood from the pericardial well was saturated with fat
      emboli of both sizes. Patients randomized to the cardiotomy suction had a
      significantly higher number of fat emboli at the end of CPB when compared with
      those randomized to the cell-saving suction device and dual-filter group.
      Processed blood from both the cardiotomy reservoir and cell-saving device was
      noted to have an abundance of fat emboli when compared with blood processed
      through the dual filters. CONCLUSIONS: Processed blood from both the cardiotomy
      reservoir and cell-saving device appear to have an abundance of fat emboli that
      are completely eliminated by using a 21-microm arterial filter in series with the
      cardiotomy reservoir. This intervention could potentially reduce neurocognitive
      dysfunction associated with CPB.

PMID- 12607671
TI  - Growth factors improve latissimus dorsi muscle vascularization and trophicity
      after cardiomyoplasty.
AB  - BACKGROUND: Dynamic cardiomyoplasty consists of wrapping the electrostimulated
      latissimus dorsi muscle (LDM) around the failed heart. Partial ischemia followed
      by atrophy of the middle and distal part of the LDM were observed in 30% of
      clinical cases after LDM flap elevation from its origin. In the current study, we
      hypothesized that local administration of growth factors at the LDM/epicardial
      interface could improve muscle vascularization and trophicity. METHODS: In 24
      sheep, dynamic cardiomyoplasty was performed using the left LDM. A
      multiperforated catheter was positioned at the LDM/epicardial interface for a
      weekly administration, during a 1-month period, of the following factors: basic
      fibroblast growth factor (bFGF, n = 6), vascular endothelial growth factor (VEGF,
      n = 6), and regenerating agent (RGTA, n = 6). Six sheep injected with phosphate
      buffered saline (used for dilution of the growth factors) were used as a control
      group. At 3 months, angiographic, histologic, and histomorphometric studies were
      performed. RESULTS: Angiographic studies of the animals treated with growth
      factors demonstrated hypervascularization due to the development of new vessels.
      Histomorphometric and histologic studies showed a significant increase in the
      number of capillaries and arterioles (100 fields/muscle) in the groups treated
      with bFGF (443.0 +/- 101.2, p < 0.01), RGTA (293.2 +/- 29.3, p < 0.05), and VEGF
      (246.5 +/- 45.9, p < 0.05), as compared with the control group (81.5 +/- 11.4). A
      significantly lower atrophy score was observed in the groups treated with bFGF
      (1.4 +/- 0.18, p < 0.05), RGTA (1.59 +/- 0.17, p < 0.05), and VEGF (1.96 +/-
      0.14, NS), as compared with the control group (2.48 +/- 0.16). CONCLUSIONS: Local
      administration at the heart/muscle interface of growth factors increases muscle
      vascularization and avoids muscle atrophy in an experimental cardiomyoplasty
      model, both of which are advantageous to the contracting LDM. The local growth
      factors delivery system used in this study appears efficient, easy to implant,
      and manipulate and safe.

PMID- 12607673
TI  - Effect of perfusion flow rate on tissue oxygenation in newborn piglets during
      cardiopulmonary bypass.
AB  - BACKGROUND: Our knowledge of the best perfusion flow rate to use during
      cardiopulmonary bypass (CPB) in order to maintain tissue oxygenation remains
      incomplete. The present study examined the effects of perfusion flow rate and
      patent ductus arteriosus (PDA) during normothermic CPB on oxygenation in several
      organ tissues of newborn piglets. METHODS: The experiments were performed on 12
      newborn piglets: 6 with PDA ligation (PDA-L), and 6 without PDA ligation (PDA
      NL). CPB was performed through the chest at 37 degrees C. During CPB, the flow
      rate was changed at 15-minute intervals, ranging from 100 to 250 ml/kg/min.
      Tissue oxygenation was measured by quenching of phosphorescence. RESULTS: For the
      PDA-L group, oxygen in the brain did not change significantly with changes in
      flow rate. In contrast, for the PDA-NL group, oxygen was dependent upon the flow
      rate. Statistically significant decreases in cortical oxygen were observed with
      flow rates below 175 ml/kg/min. Within the myocardium, liver, and intestine,
      there were no significant differences in the oxygen levels between the PDA-L and
      PDA-NL groups. In these tissues, the oxygen decreased significantly as the flow
      rate decreased below 150 ml/kg/min, 125 ml/kg/min, and 175 ml/kg/min,
      respectively. Oxygen pressure in skeletal muscle was not dependent on either PDA
      ligation or flow rate. CONCLUSIONS: In newborn piglets undergoing CPB, the
      presence of a PDA results in reduced tissue oxygenation to the brain but not to
      other organs. In general, perfusion flow rates of 175 ml/kg/min or greater are
      required in order to maintain normal oxygenation of all organs except muscle.

PMID- 12607674
TI  - Liposarcoma of the thyroid gland mimicking retrosternal goiter.
AB  - Primary liposarcoma of the thyroid gland is extremely rare with only two previous
      reports in the literature. We report two further cases, both patients presenting
      with rapid airways compression. Patient 1 had clinical, radiographic, and biopsy
      appearances suggesting benign goiter. Patient 2 had a long-term history of benign
      goiter, a previous partial thyroidectomy, and more recent biopsies showing
      liposarcoma. The management of such rare conditions is always challenging.

PMID- 12607675
TI  - Mediastinal talcoma masquerading as thymoma.
AB  - We report a young woman with a large, calcified anterior mediastinal mass
      discovered 18 months following a left talc pleurodesis. The lesion was evaluated
      and treated as the thymoma or teratoma that it appeared to be, with excision by a
      transcervical approach. Pathologic examination revealed a giant talc granuloma.
      Awareness of such a possibility following talc pleurodesis may allow surgeons to
      avoid unnecessary mediastinal exploration, and its occurrence suggests that talc
      administration simultaneous with mechanical pleurodesis should be avoided.

PMID- 12607676
TI  - Totally endoscopic robotic thymectomy for myasthenia gravis.
AB  - The current recommendations for treating myasthenia gravis include surgical
      thymectomy for patients between puberty and 60 years of age. This is a report of
      a new method for surgical thymectomy using the robotic da Vinci surgical system
      for a totally endoscopic approach. This new procedure combines the potential
      advantages of minimally invasive methods with the efficacy of open procedures.

PMID- 12607677
TI  - Mediastinal mass evaluation using advanced robotic techniques.
AB  - The diagnosis and management of mediastinal masses frequently necessitates biopsy
      and surgical resection. The use of videothorascopic techniques has broadened the
      surgeon's ability to evaluate and treat such tumors using a minimally invasive
      approach. We describe herein the use of the da Vinci Robotic Surgical System for
      evaluating a mediastinal mass in a young woman.

PMID- 12607678
TI  - Tracheal erosion by an innominate artery graft: presentation and surgical repair.
AB  - This report illustrates the presentation, diagnosis, and successful surgical
      management of a unique case involving erosion of a prosthetic innominate artery
      graft into the trachea.

PMID- 12607679
TI  - Unusual presentation of rib exostosis.
AB  - We report two cases of unusual presentation of rib exostosis. The first patient
      presented acutely with hemorrhagic shock due to massive hemothorax, and the
      second patient presented with repetitive chest infection complicated by empyema.
      In both patients, preoperative computed tomographic (CT) scan of the chest
      revealed rib exostoses, necessitating thoracotomy and rib resection.

PMID- 12607681
TI  - Paroxysmal cold hemoglobinuria and cardiopulmonary bypass.
AB  - Paroxysmal cold hemoglobinuria, a cold-reactive autoimmune disease associated
      with the Donath-Landsteiner antibody, has not been described in patients
      undergoing cardiac surgery. We report a case of mitral valve replacement in a
      woman with a positive Donath-Landsteiner antibody and a history of recurrent
      hemolysis and hemoglobinuria secondary to cold exposure. Successful perioperative
      management is described, as is a discussion of paroxysmal cold hemoglobinuria.

PMID- 12607680
TI  - Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative
      argatroban use.
AB  - Heparin-induced thrombocytopenia (HIT), a serious complication of heparin
      therapy, mandates heparin cessation and alternative anticoagulation. We report a
      patient with a history of HIT who successfully underwent cardiopulmonary bypass
      (CPB) using short-term reexposure to heparin and perioperative therapy with
      argatroban. No bleeding complications or HIT-related problems occurred. The
      pharmacokinetics of argatroban, especially its hepatic rather than renal
      elimination, makes it the drug of choice for some HIT patients in whom other
      alternative anticoagulants (eg, danaparoid and hirudin) are less well suited.
      Because of interference with the international normalized ratio (INR), switching
      from argatroban to oral anticoagulants is not straightforward.

PMID- 12607682
TI  - Pericardial rupture and cardiac herniation after blunt chest trauma.
AB  - Pericardial rupture after blunt chest trauma is rare and is associated with a
      high mortality rate. We describe a patient with traumatic pericardial rupture and
      cardiac herniation who was successfully treated surgically. Traumatic pericardial
      rupture is difficult to diagnose preoperatively but should be suspected whenever
      there is severe blunt chest trauma. If pericardial rupture is not recognized and
      treated promptly it could be fatal owing to cardiac herniation.

PMID- 12607683
TI  - Dislocated wrap after previous reduction aortoplasty causes erosion of the
      ascending aorta.
AB  - We report a patient with bicuspid aortic valve and dilatation of the ascending
      aorta who had previous aortic valve replacement and reduction aortoplasty with
      wrapping. After 4 years, reoperation because of coronary artery disease and
      paravalvular leakage revealed an erosion of the aortic wall due to dislocation of
      the wrap. This complication confirms the need for secure anchoring and good
      fitting of the Dacron wrap to avoid alterations of the underlying aortic wall.

PMID- 12607684
TI  - Left atrial dissection after double valve replacement.
AB  - Left atrial dissection, a rare complication occurring mainly after mitral repair,
      is reported after double valve replacement in a patient with a connective tissue
      disease. A 63-year-old woman with systemic sclerosis underwent double valve
      replacement. Laceration of the tissue between the two mechanical prostheses and
      dissection of the left atrial wall emerged postoperatively and regurgitation
      through the dissection caused heart failure, which later improved without
      surgery. The possible causes of the dissection were thought to be shear forces
      against the tissue between the two prostheses and tissue fragility due to
      systemic sclerosis and corticosteroid therapy.

PMID- 12607685
TI  - Surgical management of double outlet right ventricle with intact ventricular
      septum.
AB  - A very rare case of double outlet right ventricle with intact ventricular septum
      and unrestricted pulmonary flow was successfully palliated with pulmonary banding
      and delayed bidirectional cavopulmonary anastomosis and mitral avulsion. This is
      the only case of pulmonary banding with mitral avulsion reported in the
      literature for this type of heart defect

PMID- 12607686
TI  - Catheter closure of autologous pericardial extracardiac Fontan fenestration.
AB  - We describe two patients who required fenestration of an autologous pericardial
      extracardiac Fontan (APEF), short-medium term angiographic follow-up, and
      subsequent successful transcatheter closure of the fenestration.

PMID- 12607687
TI  - Epicardial pulmonary vein isolation by cryoablation as concomitant cardiac
      operation to treat nonvalvular atrial fibrillation.
AB  - Since Haissagere and colleagues reported that a rapid firing focus in or close to
      the pulmonary veins could be the cause of atrial fibrillation, a transcutaneous
      catheter technique directed at isolating these foci has been developed. How
      should patients with nonvalvular atrial fibrillation who require cardiac
      operation be managed? We developed an epicardial technique that uses cryoablation
      to isolate the left atrial posterior wall and pulmonary veins and used it to
      treat a patient. Because cryoablation is achieved epicardially, the technique
      does not require atriotomy and does not prolong aortic cross-clamp time.
      Isolation of the left atrium was confirmed by electrophyscologic studies, and the
      patient remains in sinus rhythm 16 months after operation. This concomitant
      procedure allows treatment of patients with nonvalvular atrial fibrillation.

PMID- 12607688
TI  - Multiple pulmonary artery aneurysms due to infective endocarditis.
AB  - Bilateral pulmonary artery aneurysms developed in the course of staphylococcal
      endocarditis in a 6-year-old girl with ventricular septal defect. Consecutive
      computed tomography scans revealed the progressive enlargement of one of the
      aneurysms. She underwent an urgent left upper lobectomy because of the impending
      rupture and a possible life-threatening hemorrhage. The second ipsilateral
      aneurysm was plicated in order to exclude the aneurysm sac. In the next operation
      the ventricular septal defect was closed and vegetations located on the tricuspid
      valve were removed. On follow-up spontaneous thrombotic resolution occurred in
      the right-sided aneurysms.

PMID- 12607689
TI  - Unusual cause of a pulmonary mass on computed tomographic scan of the thorax.

PMID- 12607691
TI  - Needlescopic operation for partial lung resection.
AB  - Needlescopic operation using instruments with a diameter of 2 mm has not been
      applied to partial lung resection because of the difficulty in grasping the lung
      firmly or the possibility of injuring the lung easily with 2-mm forceps. We have
      developed a technique using a mini-loop retractor and successfully performed
      partial lung resection in 35 patients with pneumothorax, small lung tumor, or
      interstitial pneumonia.

PMID- 12607690
TI  - Ventricular fibrillation in a heterotopic heart transplant recipient.

PMID- 12607692
TI  - Videothoracoscopic resection of neurogenic tumors of the superior sulcus using
      the harmonic scalpel.
AB  - Resection of neurogenic tumors located in the paravertebral sulcus carries a risk
      of injury to the adjacent nervous structures and also to critical intercostal
      arteries supplying the anterior spinal artery. To avoid such complications, we
      have used the Harmonic Scalpel (Ethicon Endo-Surgery, Cincinnati, OH) for the
      dissection of neurogenic tumors in 2 consecutive patients operated on by
      videothoracoscopy. The Harmonic Scalpel functions with ultrasonic energy,
      producing less heat than a regular electrocautery and allows a safer dissection
      of tumors located in the posterior mediastinum, particularly those located in the
      superior paravertebral sulcus.

PMID- 12607693
TI  - Edge-to-Edge tricuspid repair for redeveloped valve incompetence after DeVega's
      annuloplasty.
AB  - "Edge-to-edge" technique is a well-accepted procedure with excellent results for
      correction of mitral insufficiency. We describe a simple edge-to-edge combined
      with bicuspidalization repair method that was successfully applied in 2 patients
      for the treatment of redeveloped functional tricuspid regurgitation after
      previous annuloplasty. Significant improvement in symptoms and echocardiographic
      results were achieved.

PMID- 12607694
TI  - Off-pump technique for Thoratec left ventricular assist device insertion.
AB  - We present a case of left ventricular assist device (Thoratec; Thoratec
      Laboratories Corp, Pleasanton, CA) insertion performed through a left thoracotomy
      without cardiopulmonary bypass in a patient with severe end-stage congestive
      heart failure with renal and respiratory dysfunction and a history of multiple
      cardiac operations.

PMID- 12607695
TI  - Development of tracheal surgery: a historical review. Part 1: Techniques of
      tracheal surgery.

PMID- 12607696
TI  - Obstructive hypertrophic cardiomyopathy: echocardiography, pathophysiology, and
      the continuing evolution of surgery for obstruction.
AB  - Our understanding of the pathophysiology of obstruction in hypertrophic
      cardiomyopathy has evolved since initial descriptions in the late 1950s. This
      review addresses the cause of obstruction, from early ideas that a muscular
      outflow tract sphincter was the cause, through the discovery of systolic anterior
      motion (SAM) of the mitral valve, to current understanding that flow drag, the
      pushing force of flow, is the dominant hydrodynamic mechanism for SAM. The
      continuing redesign and modification of surgical procedures to relieve outflow
      obstruction have corresponded to ideas about the cause of this condition. In this
      review we discuss the evolution of surgical procedures to relieve obstruction and
      review modern surgical approaches. Medical and nonsurgical methods for reducing
      obstruction are reviewed, as well as efforts to prevent sudden arrhythmic cardiac
      death. Echocardiography has become central to understanding this complex
      phenomenon, and for clinical diagnosis, operative planning and intraoperative
      management.

PMID- 12607697
TI  - Neuroendocrine tumors (carcinoid) of the thymic gland.

PMID- 12607698
TI  - Anterior approach versus posterior approach in apical chest tumor: surgeon's
      choice or oncological need?

PMID- 12607699
TI  - Pulmonary complications following esophagectomy.

PMID- 12607700
TI  - Alveolar recruitment during one-lung ventilation--really "one" lung?

PMID- 12607701
TI  - Another case of metalloptysis after lung volume reduction surgery.

PMID- 12607702
TI  - Reoperative aortic valve replacement with patent internal thoracic artery and
      venous grafts.

PMID- 12607703
TI  - Liberal use of delayed sternal closure: sternal infection does not increase.

PMID- 12607704
TI  - Successful interventional treatment of a large pulmonary artery aneurysm after
      Swan-Ganz catheterization.

PMID- 12607705
TI  - Open technique or Bentall/de Bono technique?

PMID- 12607707
TI  - Tissue factor and thrombin mediate myocardial ischemia-reperfusion injury.
AB  - Reperfusion of the ischemic heart is necessary to prevent irreversible injury of
      the myocardium, which leads to permanent organ dysfunction. However, reperfusion
      in itself leads to myocardial ischemia/reperfusion (I/R) injury, which is
      characterized by an acute inflammatory response mediated by activated
      inflammatory cells, chemokines, cytokines, and adhesion molecules. The molecular
      mechanisms of myocardial I/R injury are not completely known. Tissue factor (TF)
      and thrombin, two potent procoagulant and proinflammatory mediators, are
      recognized to play significant roles in myocardial I/R injury. To investigate the
      role of TF and thrombin in myocardial I/R injury, we used rabbit and murine in
      situ coronary artery ligation models. Increased TF mRNA, antigen, and activity
      were found in ischemic cardiomyocytes. Administration of an inhibitory antirabbit
      TF monoclonal antibody before or during the onset of ischemia resulted in a
      significant reduction in infarct size. Functional inhibition of thrombin with
      hirudin also reduced the infarct size. However, defibrinogenating rabbits with
      ancrod had no effect on infarct size, suggesting a requirement of thrombin
      generation but not fibrin deposition in myocardial I/R injury.

PMID- 12607706
TI  - Cellular mechanisms of ischemia-reperfusion injury.
AB  - As of yet, only a few strategies to prevent myocardial reperfusion injury have
      been tested clinically. In the first minutes of reperfusion, the myocardium can
      be damaged by contracture development, causing mechanical stiffness, tissue
      necrosis, and the "stone heart" phenomenon. Reperfusion-induced contracture can
      have two different causes, namely, Ca2+overload-induced contracture or rigor-type
      contracture. Ca2+ contracture results from rapid re-energization of contractile
      cells with a persistent Ca2+ overload. Strategies to prevent this type of injury
      are directed at cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity. Rigor
      contracture occurs when re-energization proceeds very slowly. It does not depend
      on Ca2+ overload. It may be prevented by strategies improving early mitochondrial
      reactivation

PMID- 12607708
TI  - The basic biology of apoptosis and its implications for cardiac function and
      viability.
AB  - Apoptosis or programed cell death is a continuous process of destruction of
      nonfunctional cells. It is a physiologic process whereby the body disposes of
      unwanted cells by self-destruction and is our utmost defense against damaged
      cells. There are several pathways leading to programed cell death. Apoptosis is
      seen in failing, infarcted, and hibernating human hearts, and during open heart
      surgery. Apoptosis appears to be induced by myocardial ischemia-reperfusion
      injury and this is reduced by ischemic preconditioning. Antiapoptotic
      interventions may be a future target for myocardial protection.

PMID- 12607709
TI  - Mechanisms and alternative methods of achieving cardiac arrest.
AB  - Elective cardiac arrest during surgery can be achieved by inducing
      depolarization, polarization, or influencing calcium mechanisms. Depolarized
      arrest, induced by elevating the extracellular potassium concentration, is
      currently the most commonly used technique. However, injury associated with ionic
      imbalance involving sodium and calcium overload, together with maintained
      metabolic processes aimed at correcting these imbalances, have lead to
      alternatives being sought. "Polarized" arrest, induced by sodium-channel blockers
      or by agents that activate potassium channels, has been shown to exert equal or
      superior protection. Similarly, agents that induce calcium desensitization may
      also prove to enhance protection. These alternative techniques, however, require
      extensive characterization before introduction into routine clinical use can be
      recommended.

PMID- 12607710
TI  - The mitochondrial K(ATP) channel and cardioprotection.
AB  - Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels allow coupling
      of membrane potential to cellular metabolic status. Two K(ATP) channel subtypes
      coexist in the myocardium, with one subtype located in the sarcolemma
      (sarcK(ATP)) membrane and the other in the inner membrane of the mitochondria
      (mitoK(ATP)). The K(ATP) channels can be pharmacologically modulated by a family
      of structurally diverse agents of varied potency and selectivity, collectively
      known as potassium channel openers and blockers. Sufficient evidence exists to
      indicate that the K(ATP) channels and, in particular, the mitoK(ATP) channels
      play an important role both as a trigger and an effector in surgical
      cardioprotection. In this review, the biochemistry and surgical specificity of
      the K(ATP) channels are examined.

PMID- 12607711
TI  - Cardiac cell transplantation: closer to bedside.
AB  - The current treatment for heart failure is inadequate for a large number of
      patients who do not qualify for heart transplantation or innovative surgical
      therapy. Cellular augmentation of damaged myocardium has been actively
      investigated in the past decade. Cells best suited for the task are skeletal
      myoblasts and bone morrow mesenchymal stem cells. Both cell types are autologous,
      abundant, and easy to harvest. The focus of early human trials will be to
      establish the safety of an effective cellular dose. Trials conducted with an
      inadequate cellular dose may discredit cell therapy because of lack of effect
      but, more importantly, may provide a false sense of safety because of a lack of
      adverse events secondary to a small inoculating dose.

PMID- 12607712
TI  - Increased susceptibility of hypertrophied hearts to ischemic injury.
AB  - Cardiac hypertrophy is an adaptive response that compensates for increased
      workload by normalizing wall stress and preserving cardiac contractile function.
      In advanced stages, however, clinical and experimental studies have shown that
      when the high workload is maintained, hypertrophy progresses to ventricular
      dilatation, contractile dysfunction, and decreased tolerance to
      ischemia/reperfusion. Development of hypertrophy is accompanied by distinct
      qualitative and quantitative changes in contractile protein expression and
      isoform switching, cytosolic calcium regulation, and substrate delivery and use.
      We have focused our investigations on changes in substrate delivery and capillary
      density in pressure overload hypertrophy and on the effects that these changes
      have on tolerance to ischemia/reperfusion. This report summarizes our work in
      this area using a model of aortic banding in 10-day-old rabbits, which exhibits
      the same pattern of concentric hypertrophy early, followed by ventricular
      dilatation and contractile dysfunction that is clinically apparent.

PMID- 12607713
TI  - Vascular growth factors and angiogenesis in cardiac surgery.
AB  - Therapeutic angiogenesis, in the form of growth factor protein administration or
      gene therapy, has emerged as a new method of treatment for patients with severe,
      inoperable coronary artery disease. Improved myocardial perfusion and function
      after administration of angiogenic growth factors has been demonstrated in animal
      models of chronic myocardial ischemia. Recently, preliminary clinical trials
      using growth factor proteins or genes encoding these angiogenic factors have
      demonstrated clinical and other objective evidence of relevant angiogenesis. A
      recent study reported beneficial long-term effects of therapeutic angiogenesis
      using fibroblast growth factor (FGF)-2 protein in terms of freedom from angina
      and perfusion on single-photon emission computed tomographic imaging. Thus,
      therapeutic angiogenesis has the potential to extend treatment options to
      patients who are not optimal candidates for conventional methods of myocardial
      revascularization. However, endogenous antiangiogenic influences, intrinsic lack
      of response of patients with severe endothelial dysfunction, and other
      limitations will need to be overcome before angiogenesis becomes a standard
      therapy for the treatment of patients with severe coronary disease.

PMID- 12607714
TI  - Adenosine in myocardial protection in on-pump and off-pump cardiac surgery.
AB  - Adenosine is most well known for its potent vasodilation of the vasculature.
      However, it also promotes glycolysis, and activates potassium-sensitive adenosine
      triphosphate (K(ATP)) channels. Adenosine also strongly inhibits neutrophil
      function such as superoxide anion production, protease release, and adherence to
      coronary endothelial cells. Hence adenosine attenuates ischemic injury as well as
      neutrophil-mediated reperfusion injury. Adenosine has also been implicated in the
      cardioprotective phenomenon of ischemic preconditioning. Accordingly experimental
      evidence shows that adenosine reduces postischemic injury when administered
      before ischemia and at the onset of reperfusion. Clinical studies in cardiology
      and cardiac surgery show cardioprotective trends with adenosine treatment but the
      effects are not as dramatic as those reported by experimental studies.

PMID- 12607715
TI  - Intracellular sodium hydrogen exchange inhibition and clinical myocardial
      protection.
AB  - Although the mechanisms underlying ischemia/reperfusion injury remain elusive,
      evidence supports the etiologic role of intracellular calcium overload and
      oxidative stress induced by reactive oxygen species. Activation of the sodium
      hydrogen exchanger (NHE) is associated with intracellular calcium accumulation.
      Inhibition of the NHE-1 isoform may attenuate the consequences of this injury.
      Although there is strong preclinical and early clinical evidence that NHE
      inhibitors may be cardioprotective, definitive proof of this concept in humans
      awaits the results of ongoing clinical trials.

PMID- 12607716
TI  - Preconditioning and cardiac surgery.
AB  - Preconditioning is in experimental studies the most powerful mode of
      cardioprotection known. The signal transduction pathways involve a variety of
      trigger substances, mediators, receptors, and effectors. The studies of
      preconditioning in cardiac surgery provide conflicting results but the majority
      of studies show that ischemic preconditiong is an effective adjunct to myocardial
      protection. However, ischemic preconditioning with repeated clamping of the aorta
      will never get widespread use. If the "preconditioning response" is to be
      exploited in cardiac surgery, targeting the underlying molecular mechanisms must
      provide easily applicable techniques or drugs, which are shown in large scale
      clinical studies to be beneficial.

PMID- 12607717
TI  - Inflammatory response to cardiopulmonary bypass.
AB  - Inflammation in cardiac surgical patients is produced by complex humoral and
      cellular interactions with numerous pathways including activation, generation, or
      expression of thrombin, complement, cytokines, neutrophils, adhesion molecules,
      mast cells, and multiple inflammatory mediators. Because of the redundancy of the
      inflammatory cascades, profound amplification occurs to produce multiorgan system
      dysfunction that can manifest as coagulopathy, respiratory failure, myocardial
      dysfunction, renal insufficiency, and neurocognitive defects. Coagulation and
      inflammation are also closely linked through networks of both humoral and
      cellular components including proteases of the clotting and fibrinolytic
      cascades, including tissue factor. Vascular endothelial cells also mediate
      inflammation and the cross talk between coagulation and inflammation. Novel
      antiinflammatory agents inhibit these processes by several mechanisms such as
      preventing proteolysis of the protease-activated receptor (aprotinin), inhibiting
      complement-mediated injury (pexelizumab), or inhibiting contact activation
      (kallikrein inhibitors). Surgery alone also activates specific hemostatic
      responses, activation of immune mechanisms, and inflammatory response mediated by
      the release of various cytokines and chemokines. Novel agents are under
      investigation to further improve outcomes in cardiac surgical patients.

PMID- 12607718
TI  - Therapy with insulin in cardiac surgery: controversies and possible solutions.
AB  - Insulin has been used in the treatment of patients undergoing cardiac surgery or
      suffering from acute myocardial infarction. Most of these investigations have
      demonstrated that the metabolic cocktail consisting of glucose-insulin-potassium
      (GIK) improves recovery of function and outcome after cardiac surgery and
      substantially reduces mortality of patients with acute myocardial infarction.
      There is also evidence suggesting that insulin is not effective under these
      conditions, as demonstrated in a recent large randomized trial in cardiac
      surgery. It is therefore not surprising that insulin or GIK is not used routinely
      in clinical practice. Many hypotheses have been advanced to explain the effects
      of insulin and GIK but none of them has enjoyed convincing support. In cardiac
      surgery the many different application protocols described make it difficult to
      compare the results. The application of GIK after cardiac surgery may be
      complicated by severe disturbances in glucose or potassium homeostasis. In this
      article we review the literature in this field, addressing the areas of
      controversy. We discuss the different mechanisms suggested and we propose
      potential solutions. We conclude that a multifactorial mechanism is likely to
      explain the effects of insulin or GIK after ischemia and we propose that in a
      practical sense the application of high-dose insulin during reperfusion,
      utilizing a newly described, direct nonmetabolic effect, is a convincing concept.
      We will further demonstrate our clinical experience in establishing a protocol
      for putting this concept into clinical practice.

PMID- 12607719
TI  - Current strategies for optimizing the use of cardiopulmonary bypass in neonates
      and infants.
AB  - The use of cardiopulmonary bypass is still necessary for the repair of many
      congenital cardiac defects. However, exposure to cardiopulmonary bypass can still
      lead to major morbidity and sometimes mortality, especially in neonates and
      infants, despite a perfect surgical repair. Various research-based strategies
      have been used to minimize some of the complications related to cardiopulmonary
      bypass, including the systemic inflammatory response, hemodilution, and
      transfusion requirement. This overview provides some of the strategies that we
      use in our practice in applying cardiopulmonary bypass in the repair of
      congenital cardiac defects in neonates and infants.

PMID- 12607720
TI  - Aprotinin and preservation of myocardial function after ischemia-reperfusion
      injury.
AB  - Ischemia-reperfusion injury, a complex process involving the generation and
      release of inflammatory cytokines, accumulation and infiltration of neutrophils
      and macrophages, release of oxygen free radicals, activation of proteases, and
      generation of nitric oxide (NO), may result in myocardial dysfunction and
      possible injury to other major organs. Aprotinin, a nonspecific serine protease
      inhibitor used to reduce the blood loss and transfusion requirements accompanying
      cardiac surgery, has dose-dependent effects on coagulation, fibrinolytic, and
      inflammatory variables. Data indicate that aprotinin may provide protection from
      ischemia-reperfusion injury. In myocardial tissue models of ischemia and
      reperfusion, aprotinin has been shown to reduce uptake of tumor necrosis factor
      alpha (TNF-alpha), generation of NO, and accumulation of leukocytes. Improved
      myocardial function has been observed with aprotinin treatment in animal models
      of ischemia-reperfusion injury. In humans, data indicate that integrin expression
      associated with leukocyte transmigration as well as markers of myocardial damage
      are reduced in patients receiving aprotinin. Further, data suggest that patients
      who receive aprotinin may have a reduced need for inotropic support and a
      decreased incidence of postoperative atrial fibrillation. In all, review of this
      topic indicates that aprotinin may reduce aspects of ischemia-reperfusion injury
      and prospective clinical studies are needed to evaluate the impact of aprotinin
      on associated patient outcomes.

PMID- 12607721
TI  - Maintaining hemodynamic stability and myocardial performance during off-pump
      coronary bypass surgery.
AB  - Patients presenting for coronary artery bypass (CAB) surgery are now older and
      have more comorbid conditions. Off-pump (OPCAB) methods may reduce morbidity and
      mortality in these higher risk patients. Multivessel surgery has been limited by
      the difficulty in maintaining hemodynamic stability during lateral wall vessel
      grafting. Techniques for providing safe access to lateral wall vessels were
      applied in a largely unselected group of 665 OPCAB patients with emphasis on the
      avoidance of right ventricular compression. Safe access to essentially all target
      coronary arteries was achieved with very little need for pharmacological or
      mechanical support. No patient required new intraaortic balloon pumping and no
      patient required urgent conversion to cardiopulmonary bypass. Access to
      essentially all target coronary arteries can be achieved and myocardial
      performance can be maintained when strict attention is paid to operative
      strategies designed to minimize right-side heart compression.

PMID- 12607722
TI  - Platinum-induced autoantibodies target nucleoplasmic antigens related to active
      transcription.
AB  - Research on autoimmune diseases has revealed that autoimmunity can be induced by
      heavy metals such as mercury and gold. Following the introduction of platinum
      containing catalytic converters in automobiles, the emission of platinum
      compounds constitutes an abundant environmental pollutant, however, potential
      immunological hazards resulting from platinum-containing emissions were not yet
      examined. In our previous studies on molecular mechanisms of heavy metal-induced
      autoimmunity, we showed a platinum-dependent subcellular redistribution of the
      autoantigen fibrillarin from the nucleolus to the nucleoplasm. Since H-2s mice
      constitute a valuable model to study the role of heavy metals in the development
      of systemic autoimmunity, we treated susceptible B10.S mice with
      hexachloroplatinate (Na2PtCl6, Pt4+) to examine whether platinum induces the
      production of autoantibodies. The present study shows for the first time that
      chronic administration of Pt4+ generated an autoimmune response in mice which
      targets distinct nucleoplasmic antigens. Dual-labeling revealed substantial
      colocalization of these nucleoplasmic autoantigens with (i) nascent RNA, (ii) the
      active, phosphorylated form of RNA polymerase II, and partial overlap with (iii)
      acetylated histone 4 protein, and (iv) 20S proteasomes in dendritic cells
      isolated from platinum-treated mice. The results suggest that platinum elicits
      antibodies against antigens associated with active sites of transcription which
      may be subject to proteasomal processing during heavy metal-induced autoimmunity.

PMID- 12607723
TI  - Simultaneous cytometric analysis of (auto)antigen-reactive T and B cell
      proliferation.
AB  - The detection and characterization of (auto)antigen-specific lymphocytes, both B
      and T cells, is essential to investigate immunopathologic mechanisms. Our aim was
      to perform a CFSE (Carboxyfluorescein diacetate succinimidyl ester)-based
      cytometric analysis of peripheral blood mononuclear cells (PBMC) proliferating in
      response to antigenic provocation. CFSE-labeled PBMC were stimulated with a
      superantigen (SEB), a recall antigen (tetanus toxoid), an allergen (grass pollen)
      and an autoantigen (nucleosomes) and stained after cultivation with CD4-, CD8-
      and CD19-antibodies. Proliferated cells were identified cytometrically by the
      decrease of the CFSE fluorescence intensity due to cell division. Antigen
      reactive, proliferated B cells were further analysed phenotypically, antigen
      specific proliferated Th cells were further characterized functionally regarding
      their cytokine secretion pattern after polyclonal restimulation. Using this
      technique, antigen-specific proliferated B and Th cells were detected even at low
      frequencies. Analyzing the cytokine secretion pattern of allergen-reactive
      proliferated Th cells after polyclonal restimulation we found differences in the
      expression of IL-13 and IL-4 between an atopic and a healthy donor. After
      stimulation of PBMC from TT-vaccinated donors TT-specific proliferated B cells
      were detected in high frequencies and showed a plasmablast-typical CD20(low)
      CD27(high) phenotype with only low frequencies expressing CD138 (= Syndecan-1).
      Proliferation of nucleosome-reactive Th cells and B cells was observed in both
      patients and healthy controls. We have optimized here the cytometric analysis of
      reactive cell proliferation based on CFSE offering various facilities of
      application on the further characterization of both antigen-specific B and T
      cells.

PMID- 12607724
TI  - Treatment of refractory Churg-Strauss-Syndrome (CSS) by TNF-alpha blockade.
AB  - Churg-Strauss-Syndrome (CSS) often takes a mild course and is in many cases
      treated successfully by glucocorticosteroids (GC) alone. However, there are also
      several reports demonstrating the necessity of more intensive treatment in life
      threatening courses with cyclophosphamide and in less severe cases with other
      immunosuppressive or immunomodulatory drugs like azathioprine, methotrexate or
      interferon alpha. Relapses of the CSS are detected clinically and serologically
      and may require cyclophosphamide therapy as well as high-dose GC. We treated 3
      cases between 2000 and 2001 that not only experienced a severe relapse (of the
      heart and the central nervous system) but also proved to be refractory to
      cyclophosphamide and GC therapy. In the absence of other options we decided to
      apply TNF-alpha blockers (etanercept in one case and remicade in the two other).
      This experimental treatment proved to be effective and safe and induced complete
      remission in one patient and partial remission in the second and at least stopped
      disease progression in the third. The BVAS 1 markedly improved after additional
      treatment with TNF-alpha blockers.

PMID- 12607725
TI  - Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency
      (CVID) patients with autoimmune cytopenia.
AB  - Common variable immunodeficiency (CVID) is characterized by a severe
      hypogammaglobulinemia. While the clinical picture is dominated by recurrent
      respiratory and gastrointestinal infections, a subgroup of up to 30% of the
      patients develops additional autoimmune phenomena, including thrombocytopenia and
      autoimmune hemolytic anemia. So far no classification allowed a prediction of the
      coincidence of immunodeficiency and autoimmunity. Here, we propose the size of
      the peripheral CD19(hi)CD2(lo/neg) B cell pool as a marker for CVID patients with
      autoimmune cytopenia and splenomegaly. Interestingly similar B cell populations
      are also found in patients with SLE and may not only be an epiphenomenon of the
      disease.

PMID- 12607726
TI  - A new disorder of lymphocyte apoptosis: combination of autoimmunity, infectious
      lymphadenopathy, double negative T cells, and impaired activation-induced cell
      death.
AB  - A new symptom-complex is described characterized by manifestations of autoimmune
      disease, infectious lymphadenopathy, double negative T cells, and impaired
      activation-induced cell death that developed in late adolescence. Similarities,
      but also significant differences, to autoimmune lymphoproliferative syndromes
      (ALPS, Canale-Smith syndrome) and autoimmune lymphoproliferative disease (ALD,
      Dianzani syndrome), were observed. The main clinical features were recurrent
      bacterial infections with subsequent lymphadenopathy due to autoimmune
      neutropenia. Laboratory results revealed a large proportion of alphabetaTCR
      positive, CD4 negative, CD8 negative, peripheral T cells, and a decreased
      apoptosis upon activation with phytohemagglutinin and interleukin 2, but normal
      Fas-mediated apoptosis. Genetic investigations excluded mutations in Fas gene
      death domain and in the 4 exons of Fas ligand gene. Despite unknown pathogenesis,
      this new syndrome might belong to the growing group of diseases with defects in
      apoptosis.

PMID- 12607727
TI  - Effective B cell depletion with rituximab in the treatment of autoimmune
      diseases.
AB  - In a pilot study four patients with systemic lupus erythematosus (SLE) and
      autoimmune thrombocytopenia (ITP) were treated with rituximab, a B cell depicting
      chimeric human/mouse anti-CD20 antibody. Treatment could be performed without
      serious side effects and resulted in a depletion of B cells from the peripheral
      blood for at least 4 months. Examination of one patient three months after
      treatment revealed a complete depletion of B cells in the bone marrow and in the
      spleen as well. The time point when peripheral B cells returned into the normal
      range varied between 8 months and over one year and could be observed also in the
      spleen. The follow up over more than 12 months revealed no significant treatment
      associated side effects. Total immunoglobulin and specific antibody levels did
      not change except for one SLE-patient receiving additional immunosuppressive
      treatment including cyclophosphamide because of progressive disease. Clinical
      effectiveness cannot be judged by the small number of patients. However, one SLE
      patient with refractory severe thrombocytopenia had a very Favourable response
      with stable platelet numbers over 100.000/microl now for more than 6 months and
      disappearance of anti-DNA antibodies. The treatment failure in another SLE
      patient could be due to the persistence of CD20-negative plasmablasts in
      peripheral blood which are not targeted by anti-CD20 treatment. Further studies
      are needed to assess the clinical benefit of B cell depletion in the treatment of
      autoimmune diseases.

PMID- 12607729
TI  - Casein is an essential cofactor in autoantibody reactivity directed against the C
      terminal SmD1 peptide AA 83-119 in systemic lupus erythematosus.
AB  - The C-terminal peptide SmD1(83-119) has been identified as an important
      autoantigen in systemic lupus erythematosus (SLE). ELISA studies have shown that
      roughly 70% of all sera from patients with SLE react with this peptide. Previous
      findings revealed that the addition of blocking agents and sample dilution
      buffers influences the discrimination between positive and negative anti-SmD1(83
      119) sera in SLE. The aim of the present study was to identify possible cofactors
      in the anti-SmD1(83-119) reactivity. We therefore tested SLE sera (n=6) for anti
      SmD1(83-119) reactivity by ELISA and analysed the effects of different blocking
      agents (1% skim milk, 1% gelatin, and 1% BSA). In our investigation, lipids were
      extracted from skim milk using dichlomethane, and the putative fraction was
      tested to assess the assay's ability to discriminate between positive and
      negative sera. The effects of enzymatic digestion by casein were analyzed, and
      different concentrations of casein were used to determine the role of this
      protein in the detection of anti-SmD1(83-119) antibodies by ELISA. Furthermore,
      rabbits were immunized with SmD1(83-119) adsorbed to casein and control proteins.
      One percent skim milk was the most effective blocking agent and sample dilution
      buffer for the discrimination between positive and negative sera. As demonstrated
      by SDS electrophoresis, the discriminative capacity was influenced by enzymatic
      digestion of skim milk proteins, but not by lipid extraction. Differences in anti
      SmD1(83-119) reactivity upon variation of the casein concentration suggest that
      the protein plays a significant role in the detection of anti-SmD1(83-119)
      antibodies. However, our immunisation studies did not show any effect of casein
      on anti-SmD1(83-119) reactivity, suggesting that it has no immunogenic effect on
      the anti-SmD1(83-119) response. In conclusion, casein seems to be an important
      cofactor in autoantibody reactivity directed against the C-terminal SmD1(83-119)
      peptide and probably functions by changing the conformation of the peptide's
      critical epitope.

PMID- 12607728
TI  - T cell activation induced by cross-linking CD3 and CD28 leads to silencing of
      Epstein-Barr virus/C3d receptor (CR2/CD21) gene and protein expression.
AB  - Complement receptor II (CR2) also known as CD21 is the receptor for C3d on immune
      complexes. In humans it serves as a receptor for the Epstein-Barr virus (EBV).
      CR2 is expressed on B cells and in low density in the T cell lineage. EBV can
      infect T cells and EBV-positive T lymphomas have been described. Although CR2
      mRNA is readily detectable in T cells, the function of CR2 in human T lymphocytes
      remains elusive. Here we have analyzed the expression of CR2 in normal and
      activated T cells. PCR analyses and immunofluorescence/confocal microscopy of
      peripheral blood T cells and of activated T cells shows considerable reduction in
      CR2 mRNA and protein expression upon activation. The downregulation of CR2
      expression may modulate life span or immunological reactivity of T cells and the
      susceptibility of cells to infection by lymphotropic viruses.

PMID- 12607730
TI  - Lamina propria plasma cells in inflammatory bowel disease: intracellular
      detection of immunoglobulins using flow cytometry.
AB  - This is the first application of flow cytometry for the detection of lamina
      propria plasma cells and their intracellular immunoglobulins in patients with
      inflammatory bowel disease compared to healthy controls. The study has been
      focused on the distribution of IgA, IgG, IgM and the four IgG subclasses. Plasma
      cells were detected as high CD38 positive cells. For fixation and
      permeabilisation a single step reagent, Ortho Permeafix, was used. By flow
      cytometry, in patients with inflammatory bowel disease compared to healthy
      controls, a higher percentage of IgG+ cells can be observed, in Crohn's disease
      also a higher percentage of IgM+ cells. Regarding the IgG subclass distribution,
      patients with Crohn's disease show an increase in IgG2+ cells, patients with
      ulcerative colitis an increase in IgG1+ and IgG3+ cells. These results do agree
      with and expand the results of earlier immunohistochemical and functional
      studies, which are favoured today. For the determination of lymphocyte subset
      proportions and the detection of intracellular antigens, flow cytometry provides
      a useful alternative to well-established immunohistochemical methods. By
      analysing a larger number of cells, this method is more reproducible and less
      prone to interobserver variations than immunohistochemistry, which needs the pre
      selection of a mucosal area, the microscopic scoring of a limited number of cells
      and the circumvention of high background staining. The optimized flow cytometric
      protocol used in this study might be a promising tool for further investigations
      of various purposes.

PMID- 12607731
TI  - The role of long-lived plasma cells in autoimmunity.
AB  - Recent results on the biology of plasma cells have shown that these cells can
      survive as long as memory B cells. Possibly, such long-lived plasma cells are
      also involved in the production of autoantibodies. Here, we discuss the potential
      involvement of long-lived plasma cells in the pathogenesis of autoimmune disease
      and the consequences it has for the development of effective therapeutic
      strategies.

PMID- 12607732
TI  - Whitaker wins Wiley Award.

PMID- 12607733
TI  - Use of pi-acceptors for spectrophotometric determination of dicyclomine
      hydrochloride.
AB  - Simple, rapid, accurate, and sensitive spectrophotometric methods are described
      for the determination of dicyclomine hydrochloride. The methods are based on the
      reaction of this drug as an n-electron donor with 2,3-dichloro-5,6-dicyano-p
      benzoqunione (DDQ), p-chloranilic acid (p-CA), and chloranil (CL) as pi-acceptors
      to give highly colored complex species. The colored products are measured
      spectrophotometrically at 456, 530, and 650 nm for DDQ, p-CA, and CL,
      respectively. Optimization of the different experimental conditions were studied.
      Beer's law was obeyed in concentration ranges of 20-100, 50-250, and 80-600
      microg/mL for DDQ, pCA, and CL, respectively. Colored complexes are produced in
      organic solvents and are stable for at least 1 h. The methods were applied to
      Spasmorest antispasmotic tablets and ampoules with good accuracy and precision.

PMID- 12607734
TI  - Simultaneous determination of Zilpaterol and other beta agonists in calf eye by
      gas chromatography/tandem mass spectrometry.
AB  - Adrenergic drugs for growth promotion have been outlawed in European meat
      production; however, molecules such as Ractopamine and Zilpaterol are licensed
      for feeding swine and cattle in the United States, Mexico, and South Africa.
      Analysis of bovine retinal extracts has recently shown considerable extension in
      the detection period following withdrawal. Previous studies demonstrated that
      residual concentrations of Clenbuterol and related substances in retinal tissue
      were > 100 ng/g at day 50 of withdrawal. A method was developed to identify and
      simultaneously quantify Clenbuterol-like substances with anilinic moieties and
      drugs with phenolic and catecholic moieties, such as Ractopamine and Zilpaterol,
      in retinal tissue. The method was validated according to SANCO/1805/2000. After
      extraction in 0.1 N HCl, samples were cleaned up on C18 non-endcapped solid-phase
      extraction columns and analyzed as trimethylchlorosilane derivatives by gas
      chromatography/tandem mass spectrometry, electron impact mode. At concentrations
      of agonists between 62.5 and 250.0 ng/g in bovine retina, mean recoveries ranged
      from 85.3 to 94.8%, repeatability was < 9.6%, and within-laboratory
      reproducibility was < 10.5%. The decision limits (CCalpha) were within the range
      of 66.3-70.4 ng/g, and the detection capability (CCbeta) varied from 73.9 to 79.8
      ng/g. Results are discussed in terms of a multiresidue approach to improve
      reliability of the monitoring strategy.

PMID- 12607735
TI  - Determination of hydroxyurea in capsules and biological fluids by ion-selective
      potentiometry and fluorimetry.
AB  - Two hydroxyurea selective electrodes were investigated with beta-cyclodextrin
      used as ionophore and either tetrakis (p-chlorophenyl) borate (electrode 1), or
      tetrakis [3,4-bis (trifluoromethyl) phenyl] borate (electrode 2), as a fixed
      anionic site in a polymeric matrix of carboxylated polyvinyl chloride. Linear
      responses of hydroxyurea within a concentration range of 10(-5)-10(-)3 M with
      slopes of 51.2 and 58.6 mV/decade with pH 3-6 were obtained by using electrodes 1
      and 2, respectively. Two spectrofluorimetric methods involving the formation of
      drug-AI(III) complex (method 3) and drug-Mg(II) complex (method 4) at pH 5 were
      also investigated. These complexes emit fluorescence at wavelengths of 380 and
      355 nm, after excitation at 305 nm, for AI and Mg complexes, respectively. The
      calibration graphs were rectilinear from 0.5 to 2.5 microg/mL for the AI complex
      and 1 to 5 microg/mL for the Mg complex. The 4 proposed methods display useful
      analytical characteristics for determination of hydroxyurea, with average
      recoveries of 100.2 +/- 0.83 and 99.4 +/- 1.81% in capsules and 99.7 +/- 0.70 and
      99.4 +/- 1.25% in biological fluids for the potentiometric and fluorimetric
      methods, respectively. Results obtained by the proposed procedures were
      statistically analyzed and compared with those obtained by the U.S. Pharmacopeial
      method. The 4 proposed procedures were also used to determine the stability of
      the drug in the presence of its degradate, hydroxylamine.

PMID- 12607736
TI  - Stability of florfenicol in drinking water.
AB  - Florfenicol, a broad-spectrum antibiotic, is being developed for veterinary
      application as an oral concentrate intended for dilution with drinking water.
      When a drug product is dosed via drinking water in a farm setting, a number of
      variables, including pH, chlorine content, hardness of the water used for
      dilution, and container material, may affect its stability, leading to a decrease
      in drug potency. The stability of florfenicol after dilution of Florfenicol
      Drinking Water Concentrate Oral Solution, 23 mg/mL, with drinking water was
      studied. A stability-indicating, validated liquid chromatographic method was used
      to evaluate florfenicol stability at 25 degrees C at 5, 10, and 24 h after
      dilution. The results indicate that florfenicol is stable under a range of
      simulated field conditions, including various pipe materials and conditions of
      hard or soft and chlorinated or nonchlorinated water at low or high pH.
      Significant degradation (> 10%) was observed only for isolated combinations in
      galvanized pipes. Analysis indicated that the florfenicol concentration in 8 of
      the 12 water samples stored in galvanized pipes remained above 90% of the initial
      concentration (100 mg/L) for 24 h after dilution.

PMID- 12607737
TI  - Multilaboratory trial for determination of ceftiofur residues in bovine and swine
      kidney and muscle, and bovine milk.
AB  - A multilaboratory trial for determining ceftiofur-related residues in bovine and
      swine kidney and muscle, and bovine milk was conducted following regulatory
      guidelines of the U.S. Food and Drug Administration, Center for Veterinary
      Medicine. The methods convert all desfuroylceftiofur-related residues containing
      the intact beta-lactam ring to desfuroylceftiofur acetamide to establish
      ceftiofur residues in tissues. Four laboratories analyzed 5 sets of samples for
      each tissue. Each sample set consisted of a control/blank sample and 3 control
      samples fortified with ceftiofur at 0.5 Rm, Rm, and 2 Rm, respectively, where Rm
      is the U.S. tolerance assigned for ceftiofur residue in each tissue/matrix: 0.100
      microg/mL for milk, 8.0 microg/g for kidney (both species), 1.0 microg/g for
      bovine muscle, and 2.0 microg/g for swine muscle. Each sample set also contained
      2 samples of incurred-residue tissues (one > Rm and one < Rm) from animals
      treated with ceftiofur hydrochloride. All laboratories completed the method trial
      after a familiarization phase and test of system suitability in which they
      demonstrated > 80% recovery in pretrial fortified test samples. Results showed
      that the methods met all acceptable performance criteria for recovery, accuracy,
      and precision. Although sample preparation was easy, solid-phase extraction
      cartridge performance must be carefully evaluated before samples are processed.
      The liquid chromatography detection system was easily set up; however, the
      elution profile may require slight modifications. The procedures could clearly
      differentiate between violative (> Rm) and nonviolative (< Rm) ceftiofur
      residues. Participating laboratories found the procedures suitable for ceftiofur
      residue determination.

PMID- 12607738
TI  - Application of thermal desorption to the development of a gas
      chromatographic/mass spectrometric method for the determination of toluene,
      chlorinated aromatic hydrocarbons, and 2,3,7,8-tetrachlorodibenzo-p-dioxin in
      combustion emissions.
AB  - A fast and accurate analytical method, which uses commercially available
      adsorbents (Tenax TA, Carbotrap B and C, and Carbosieve S-III), was developed for
      the sampling and determination of aromatic hydrocarbons, chloroaromatic
      compounds, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. The breakthrough volume data
      show that Carbotrap C has a good capacity for compounds of high molecular weight,
      whereas Carbosieve S-III and Tenax TA are efficient for volatile compounds. The
      organic components are thermally desorbed and transferred to a gas
      chromatograph/mass spectrometer. Importantly, thermal desorption avoids
      conventional solvent extraction procedures and also allows reuse of adsorbent
      tubes. Preliminary results for recovery of analytes from tubes packed with single
      adsorbent prove that a single-adsorbent bed is not capable of sampling a wide
      range of compounds. The best method to obtain the desired collection and
      desorption properties is to use adsorbent tubes containing several different
      materials. The results of optimization studies are summarized.

PMID- 12607739
TI  - Rapid determination of 2,3,7,8-tetrachlorodibenzo-p-dioxin in water samples by
      using solid-phase microextraction followed by gas chromatography with tandem mass
      spectrometry.
AB  - A rapid and simple method of using solid-phase microextraction was developed for
      determination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in water
      samples. In this method, the target analyte is extracted from the sample into the
      polymeric coating of the fused-silica fiber. After exposure, the fiber is
      thermally desorbed in the heated injection port of the gas chromatograph, and a
      chromatographic analysis is performed by using low-resolution tandem mass
      spectrometry. Parameters that may affect the extension of the microextraction
      process, such as sampling mode, sample volume, temperature, agitation, and
      sampling time, were studied. Extraction efficiencies for 3 coating fibers were
      investigated: 100 microm poly(dimethylsiloxane) (PDMS), 65 microm PDMS
      divinylbenzene, and 75 microm carboxen-PDMS. Linearity was evaluated (R = 0.999)
      for a 250-fold concentration range from the fg/mL to the pg/mL level. The 2,3,7,8
      TCDD was detected at the fg/mL level when the headspace over the water sample was
      sampled for 60 min; the limit of detection obtained was better than that of
      Method 8280B of the U.S. Environmental Protection Agency. The proposed method
      performed well when applied to the analysis of tap water, lake water, and
      seawater samples.

PMID- 12607740
TI  - Preparation of a calibrant as certified reference material for determination of
      the Fusarium mycotoxin zearalenone.
AB  - In the field of mycotoxin analysis, substantial problems shown by high between
      laboratory standard deviations and noncomparable and nontraceable results have
      been caused by the lack of proper calibrants for external calibration. During a
      large-scale Standard Measurement and Testing project of the European Commission
      (EC) dealing with preparation and certification of reference materials for
      determination of the mycotoxin zearalenone (ZON) in maize, a ZON calibrant in
      acetonitrile was prepared and checked for purity, homogeneity, and stability.
      Before certification, on the basis of preparation, the calibrant was checked in a
      mini-interlaboratory study by UV spectrophotometric determination. The molar
      absorptivities of ZON in acetonitrile at 236, 274, and 314 nm were established,
      and as a main result, a common reference wavelength of 274 nm with molar
      absorptivity of 12623 +/- 111 L/mol x cm can be recommended for ZON in
      acetonitrile. A concentration and expanded uncertainty of the ZON calibrant of
      9.95 +/- 0.08 microg/mL was calculated as a preliminary value before final
      evaluation through the certification panel of the EC.

PMID- 12607741
TI  - Determination of deoxynivalenol and nivalenol in corn and wheat by liquid
      chromatography with electrospray mass spectrometry.
AB  - The fungus Fusarium graminearum is a pathogen of both wheat and corn. Strains of
      the fungus from the United States produce a toxin, deoxynivalenol (DON); strains
      of the fungus from Asia and Europe produce DON or a related toxin, nivalenol.
      These toxins can cause disease in livestock, and their potential presence in feed
      and foods is a concern for animal and human health. A method was developed to
      detect both toxins in corn and wheat by liquid chromatography/mass spectrometry
      of an extract of ground grain. The method requires no sample cleanup and can
      detect the toxins at 0.05 microg/g.

PMID- 12607742
TI  - Determination of percentage of RoundUp Ready soya in soya flour using real-time
      polymerase chain reaction: interlaboratory study.
AB  - An interlaboratory study was conducted to evaluate a method for determination of
      the percentage of RoundUp Ready (RR) soya in soya flour using Taqman technology.
      The method included DNA extraction from the test portion with
      cetyltrimethylammonium bromide buffer followed by chloroform extraction and
      Wizard resin cleanup steps. The DNA was then assayed with primer and probe sets
      specific for lectin as the endogenous control and the RR insert as the target.
      The percentage of RR soya in the soya fraction of the sample was calculated by
      using a matrix-matched standard curve. Ten samples of split-level blind
      duplicates were sent to 22 laboratories in 12 countries worldwide. Test portions
      contained 0, 0.5, 0.7,1.6, 2, and 3.9% (w/w) RR soya prepared gravimetrically
      from commercially available RR standard reference materials. Based on the results
      for test materials, the relative standard deviation for repeatability (RSDr) for
      the method ranged from 9.3 to 19.3% and, for reproducibility (RSDR), ranged from
      20.3 to 33.7%.

PMID- 12607744
TI  - Determination of acesulfame and sucralose in oral electrolyte maintenance
      solution by liquid chromatography.
AB  - A method was developed for the direct, simultaneous determination of acesulfame
      and sucralose in oral electrolyte maintenance solution (OEMS). Analyte separation
      and quantitation were achieved by gradient reversed-phase liquid chromatography
      (LC) and UV absorbance at 192 nm, respectively. Detection at a second wavelength,
      214 nm, was used to check sucralose peak purity; 20 microL OEMS was injected
      without preparation or dilution. System linearity was demonstrated as 192 nm peak
      area versus analyte concentration at 80-120% OEMS sweetener fortification (r >
      0.999, and all residuals < 0.5%, for both acesulfame and sucralose). Spike
      recoveries for OEMS samples prepared at 3 spiking levels (80, 100, and 120%
      sweetener fortification) ranged from 100.3 to 102.0% for acesulfame, and from
      97.9 to 102.3% for sucralose. In a second assessment of method accuracy, the same
      spiked OEMS samples were tested by 2 alternative methods: acesulfame (LC/UV at
      230 nm) and sucralose (anion exchange-pulsed amperometric detection). Results for
      the alternative acesulfame method were within 1.2%, and for the alternative
      sucralose method within 6.0%, of the corresponding results obtained by the 192 nm
      method. Repeatability and intermediate precision RSD values were < 1 % for
      acesulfame and < 3% for sucralose. The limits of quantitation were 1.6 and 32
      mg/L for acesulfame potassium and sucralose, respectively. Despite the weak UV
      absorptivity of sucralose and the consequent small size of its LC peak, no
      evidence was found for sucralose interference in any of the commercial OEMS
      flavors.

PMID- 12607743
TI  - Determination of isoflavones in ready-to-feed soy-based infant formula.
AB  - An alkaline hydrolysis/liquid chromatography (LC) method was developed for
      determination of isoflavones in ready-to-feed soy-based infant formula. The
      method consists of a 15 min methanol extraction, 10 min alkaline hydrolysis, HCl
      neutralization, gravity filtration, aqueous dilution, and 50 min LC analysis with
      UV detection at 262 and 250 nm to quantify 6 isoflavone analytes: daidzin,
      glycitin, genistin, daidzein, glycitein, and genistein. The concentration
      averages for 10 commercial batches (microg aglycone/g formula) were daidzein,
      6.12 +/- 1.23; glycitein, 1.19 +/- 0.16; genistein, 12.8 +/- 2.35; and total,
      20.1 +/- 3.61. Validation experiments demonstrated extraction completion and
      analyte stability to alkaline hydrolysis. Spike recoveries ranged from 97.6 to
      104.1%, and a series of accuracy assessments showed that isoflavone concentration
      determined by the method was within 5% of the true value. The relative standard
      deviation values for repeatability ranged from 0.4 to 2.2% (n = 10), and from 0.3
      to 2.7% (n = 4) for intermediate precision. Isoflavone peak purity was verified
      by comparing sample and standard peak area ratios (262/250 nm). The limits of
      detection and quantitation (microg/ formula) ranged from 0.02 to 0.05 and 0.08 to
      0.18 microg/g, respectively. The difference between our concentrations and those
      reported by others in 1995-1998 is attributable to the well-established seasonal
      variation in soybean isoflavone levels. Although the method was applied
      exclusively to ready-to-feed formula in the present study, it is equally suitable
      for powder and concentrated liquid infant formulas.

PMID- 12607745
TI  - Determination of total fat in milk- and soy-based infant formula powder by
      supercritical fluid extraction.
AB  - Commercially available simple benchtop systems using CO2 supercritical fluid
      extraction (SFE) eliminate expensive organic solvent disposal problems and offer
      potential to meet a demand for rapid, accurate high-volume gravimetric
      determinations of total fat content of infant formula powders. A Data Quality
      Objectives (DQOs) approach was used to evaluate the performance characteristics
      of instrumental SFE extraction for determination of total gravimetric fat in
      infant formula. The established DQOs included the following: ACCURACY: Correct
      values were obtained for a suitable reference material, SRM 1846 Infant Formula
      [National Institute of Standards and Technology (NIST), Gaithersburg, MD].
      RUGGEDNESS: Variables were defined as (1) extraction time (35 min optimum); (2)
      ratio of sample size to diatomaceous earth support material (1 g sample/2 g
      support); (3) ratio of distilled water to alcohol (50% isopropanol optimum for
      both milk- and soy-based infant formula samples); (4) extraction flow rate was 3
      3.5 mL/min optimum. PRECISION: Relative standard deviations of multiple
      determinations fell within the Horwitz limits of acceptability of < or = 2.8% at
      the level of analyte determined (0.34-2.5% obtained). SCOPE OF APPLICABILITY:
      Includes milk- and soy-based infant formula powders. Research data were obtained
      by use of a commercially available fat analyzer. Samples of the SRM, 2 commercial
      milk-based and 3 commercial soy-based infant formula products were distributed to
      2 additional collaborating laboratories. Very good agreement was obtained among
      the submitting and collaborating laboratories for these samples. The use of
      clearly defined DQOs to establish method performance characteristics, along with
      the commercially available reference material, provided the mechanism for
      verification and validation of analytical methodology.

PMID- 12607746
TI  - Efficacy of glutaraldehyde disinfectant against Cryptosporidium parvum in the
      presence of various organic soils.
AB  - The opportunistic protozoan Cryptosporidium parvum is highly resistant to
      disinfectants, including those specifically used for processing reused medical
      equipment in hospitals. C. parvum oocysts were dried onto glass and steel grooved
      penicylinders and challenged with 2.5% glutaraldehyde solution in the presence of
      3 types of soil with exposures at 10 min, 90 min, and 10 h. The influence of
      organic soils on disinfection was measured with 5% fetal bovine serum (FBS), 10%
      FBS, and 5 mg mucin/mL. An in vitro excystation procedure and cell culture
      infection assay were used to determine survivability of oocysts after the
      germicide challenge. In the presence of organic soil, all oocysts removed from
      carriers excysted and infected cell monolayers after all germicide contact times.
      However, excystation was observed only from oocysts that received no protection
      from organic soil after 10 h exposure. In these samples, no infection was
      observed in the cell monolayers. The results of this research demonstrate the
      importance of thorough cleaning of medical equipment before disinfection.

PMID- 12607747
TI  - Determination of pyrethroid pesticide residues in processed fruits and vegetables
      by gas chromatography with electron capture and mass spectrometric detection.
AB  - A gas chromatographic method was developed for the simultaneous determination of
      12 pyrethroids (tefluthrin, bifenthrin, fenpropathrin, cyhalothrin, permethrin,
      cyfluthrin, cypermethrin, alpha-cypermethrin, flucythrinate, fenvalerate,
      fluvalinate, and deltamethrin) in tomato puree, peach nectar, orange juice, and
      canned peas. A miniaturized extraction-partition procedure requiring small
      amounts of nonchlorinated solvents is used. Samples are extracted with acetone,
      partitioned with ethyl acetate-cyclohexane (50 + 50, v/v), and cleaned up on a
      Florisil cartridge. The final extract is analyzed by gas chromatography with both
      electron capture and mass spectrometric detection modes. Studies at fortification
      levels of 0.010-0.100 mg/kg gave mean recoveries ranging from 70.2 to 96.0% and
      coefficients of variation between 4.0 and 13.9% for all compounds. Quantitation
      limits were < 0.010 mg/kg for electron capture detection.

PMID- 12607748
TI  - The certainty of uncertainty.

PMID- 12607749
TI  - Committee on drugs and related topics. Drug residues in animal tissues.

PMID- 12607750
TI  - Committee on additives, beverages, and food process related analytes. Filth and
      extraneous materials in foods and drugs.

PMID- 12607751
TI  - Committee on natural toxins and food allergens. Mycotoxins.

PMID- 12607752
TI  - Committee on food nutrition. Sugars and sugar products.

PMID- 12607753
TI  - Committee on food nutrition. Nonvitamin micronutrients.

PMID- 12607754
TI  - Committee on food nutrition. Fat-soluble vitamins.

PMID- 12607755
TI  - Committee on food nutrition. Water-soluble vitamins.

PMID- 12607756
TI  - Committee on residues and related topics. Metals and other elements.

PMID- 12607757
TI  - Committee on microbiology and extraneous materials. Food microbiology--non-dairy.

PMID- 12607758
TI  - Committee on microbiological and extraneous materials.

PMID- 12607759
TI  - Postdated pregnancy, amniotic fluid volume and initiation of labor.

PMID- 12607760
TI  - The amniotic fluid index in late pregnancy.
AB  - OBJECTIVE: Our purpose was to examine changes in the amniotic fluid index (AFI)
      in accurately dated term pregnancies both in relation to gestational age and in
      relation to the onset of spontaneous labor. STUDY DESIGN: This was a prospective
      observational study in 137 women with uneventful term pregnancies, in whom 220
      AFI measurements were performed. More than one AFI value was available from 51
      individuals. RESULTS: The AFI did not change significantly between 37 and 42
      weeks' gestation, but a significant reduction was seen during the last 11 days
      before the spontaneous onset of labor (R = -0.37, n = 83, p < 0.001). The AFI
      (corrected for gestational age) within individuals remained stable over periods
      of up to 2 weeks. Meconium staining of the amniotic fluid was related to
      gestational age, but not to the AFI or fetal distress at birth. No significant
      correlation was found between fetal distress and the AFI, or between fetal
      distress and the reduction in AFI during the last two measurements before labor.
      CONCLUSIONS: The reduction of the AFI in pregnancies progressing beyond term is
      related to the labor process itself rather than to the exact gestational age.

PMID- 12607761
TI  - Efficacy of a single dose of antenatal steroid in surfactant-treated babies under
      31 weeks' gestation.
AB  - OBJECTIVES: Antenatal steroids in labor improve the outcome in preterm babies.
      The objective in this retrospective study was to compare the efficacy of one dose
      of antenatal steroid against the standard course in surfactant-treated babies.
      METHODS: A total of 226 babies treated with prophylactic surfactant and under 31
      weeks' gestation were divided into three groups: group 1 (n = 89), no antenatal
      steroids; group 2 (n = 68), one dose of antenatal steroids 4-24 h before
      delivery; and group 3 (n = 69), two or more doses of antenatal steroids 24 h to 7
      days before delivery. The three groups were compared for early clinical well
      being and ultimate clinical outcome. RESULTS: Apgar and Clinical risk index for
      babies (CRIB) scores in groups 2 and 3 were similar and both were significantly
      better than in group 1. Group 2 babies had a 23.5% reduction in serious
      intraventricular hemorrhage (IVH) (p < 0.0001, relative risk (RR) 0.2 (95% CI
      0.07-0.54), numbers needed to treat (NNT) 4.6) and a 22.9% reduction in death (p
      < 0.001, RR 0.28 (95% CI 0.12-0.63), NNT 4.4) and group 3 babies had a 21.1%
      reduction in IVH (p < 0.001, RR 0.25 (95% CI 0.10-0.62), NNT 4.6) and a 24.2%
      reduction in death (p < 0.001, RR 0.23 (95% CI 0.10-0.57), NNT 4.2) compared to
      group 1. For these parameters, there was no significant difference between groups
      2 and 3. CONCLUSIONS: One dose of antenatal steroids given 4-24 h before delivery
      was clinically comparable to the recommended schedule of the National Institutes
      of Health in surfactant-treated preterm infants. Should the findings of this
      study be confirmed in randomized controlled trials, the dosage regimen could be
      simplified, steroid administration reduced and the interval from delivery reduced
      in acute clinical conditions.

PMID- 12607762
TI  - Evidence of participation of soluble CD14 in the host response to microbial
      invasion of the amniotic cavity and intra-amniotic inflammation in term and
      preterm gestations.
AB  - OBJECTIVE: Endotoxin has been implicated in the mechanism responsible for the
      setting of infection in preterm labor. To exert its biological effects, endotoxin
      binds to a circulating protein known as lipopolysaccharide binding protein (LBP)
      and presents endotoxin monomers to CD14, which may be a membrane-bound receptor
      or a soluble molecule. The endotoxin-LBP-CD14 complex interacts with Toll-like
      receptor 4 and other regulatory proteins leading to cellular activation and an
      inflammatory response. The purpose of this study was to determine whether
      microbial invasion of the amniotic cavity (MIAC)/intra-amniotic inflammation
      (both preterm and term) and parturition at term are associated with changes in
      the amniotic fluid and umbilical plasma soluble concentrations of CD14 (sCD14).
      STUDY DESIGN: Amniotic fluid was retrieved by amniocentesis from 88 patients in
      the following groups: group 1, preterm labor with intact membranes with
      MIAC/intra-amniotic inflammation (n = 18) and without these conditions (n = 26);
      group 2, term gestations not in labor without MIAC/intra-amniotic inflammation (n
      = 11), in labor without MIAC/intra-amniotic inflammation (n = 12) and in labor
      with MIAC/intra-amniotic inflammation (n = 13); and group 3, patients who
      underwent genetic amniocentesis at mid-trimester (n = 8). A sample of cord blood
      was obtained after delivery in all patients except those in group 3. sCD14 was
      assayed with a sensitive and specific immunoassay. Non-parametric statistics were
      used for analysis. A p value of < 0.05 was considered significant. RESULTS: sCD14
      was detectable in 97% (85/88) of the amniotic fluid samples. Amniotic fluid sCD14
      concentrations were lower in patients at term than in the mid-trimester of
      pregnancy (mid-trimester: median 482 ng/ml, range 258-838 ng/ml vs. term no
      labor: median 7 ng/ml, range 2-274 ng/ml, p = 0.01). Among patients with preterm
      labor with intact membranes, the median amniotic fluid sCD14 level of patients
      with MIAC/intra-amniotic inflammation was higher than in patients without these
      conditions (median 1568 ng/ml, range 98-5887 ng/ml vs. median 645 ng/ml, range 0
      3961 ng/ml, respectively; p = 0.01). Among women at term in labor, those with
      MIAC/intra-amniotic inflammation had a higher median amniotic fluid sCD14
      concentration than those without these conditions (median 85 ng/ml, range 2-1113
      ng/ml vs. median 17 ng/ml, range 0-186 ng/ml; p = 0.01). MIAC/intra-amniotic
      inflammation in women with preterm labor with intact membranes was associated
      with a higher median umbilical venous plasma sCD14 concentration (median 744
      ng/ml, range 0-3620 ng/ml vs. median 0 ng/ml, range 0-2060 ng/ml; p = 0.04).
      sCD14 was undetectable in plasma from umbilical cords of all neonates born to
      women at term. An increase in amniotic fluid concentration of sCD14 was observed
      in cases of intrauterine infection, not only by gram-negative bacteria, but also
      gram-positive bacteria and Ureaplasma spp. CONCLUSION: sCD14 is a physiological
      constituent of amniotic fluid, and its concentrations at term are lower than in
      the mid-trimester. Intrauterine infection/inflammation is associated with a
      higher median amniotic fluid sCD14 concentration in both preterm and term
      parturition. Neonates born from mothers with preterm labor with intact membranes
      and MIAC/intra-amniotic inflammation had a higher median concentration of sCD14
      in umbilical cord plasma than those without these conditions. sCD14
      concentrations are increased in the amniotic fluid and umbilical cord blood even
      in the absence of a microbiologically proven gram-negative infection. CD14
      appears to participate in the host response to intrauterine infection even in
      cases involving genital mycoplasmas.

PMID- 12607763
TI  - Lipopolysaccharide-binding protein in microbial invasion of the amniotic cavity
      and human parturition.
AB  - OBJECTIVE: Lipopolysaccharide-binding protein (LBP) is an acute-phase protein of
      predominantly hepatic origin, capable of binding the lipid A fraction of
      bacterial lipopolysaccharide (LPS). The complex LBP-LPS binds to CD14, and has
      been implicated in the host response to gram-negative infection. The purpose of
      this study was to determine whether microbial invasion of the amniotic cavity
      (MIAC) and parturition (term and preterm) are associated with changes in the
      amniotic fluid concentration of LBP. STUDY DESIGN: Amniotic fluid was retrieved
      by amniocentesis from 343 patients in the following groups: (1) those in mid
      trimester with a subsequent normal pregnancy outcome (n = 84); (2) those in mid
      trimester with a fetal loss after the procedure (n = 10); (3) those with preterm
      labor and intact membranes without MIAC who delivered at term (n = 36) or
      prematurely (n = 52), and those with preterm labor with MIAC (n = 26); (4) those
      with preterm premature rupture of membranes (PROM) with (n = 26) and without (n =
      26) MIAC; and (5) those delivering at term with intact membranes in the absence
      of MIAC, in labor (n = 52) and not in labor (n = 31). The concentration of LBP in
      amniotic fluid was determined with a specific and sensitive immunoassay. Non
      parametric statistics were used. A p value of < 0.05 was considered significant.
      RESULTS: LBP was detected in 98% (335/343) of the amniotic fluid samples. MIAC
      was associated with a significant increase in amniotic fluid concentration of LBP
      in women with preterm labor and intact membranes, but not in preterm PROM.
      Spontaneous preterm parturition was associated with a significant increase in
      amniotic fluid concentration of LBP. Patients who had a spontaneous fetal loss
      after a mid-trimester amniocentesis had a significantly higher median amniotic
      fluid LBP concentration than those who had a mid-trimester amniocentesis and a
      normal perinatal outcome. CONCLUSION: Preterm labor with MIAC and preterm
      parturition are associated with higher amniotic fluid concentrations of LBP than
      those with sterile amniotic fluid.

PMID- 12607764
TI  - Glutathione peroxidase levels throughout normal pregnancy and in pre-eclampsia.
AB  - OBJECTIVE: Evidence suggests that hemoglobin, in addition to its function as a
      carrier of oxygen, also serves to transport nitric oxide, as S-nitroso cysteine,
      from the lungs to the peripheral circulation, where it can be released.
      Glutathione peroxidase, besides being an important antioxidant, is known to
      catalyze the release of nitric oxide from smaller carrier molecules, and may play
      a role in the distribution of nitric oxide throughout the body. In light of these
      findings, we sought to determine whether glutathione peroxidase levels differed
      throughout gestation, and specifically between pre-eclamptic and normal women.
      METHODS: A nested case-control study of women receiving routine prenatal care was
      conducted. Pre-eclampsia was defined by a blood pressure of at least 140 mmHg
      systolic and/or 90 mmHg diastolic as well as proteinuria > 300 mg/24 h or > 2+ by
      dipstick, both occurring on two occasions at least 6 h apart. Blood was collected
      in heparinized tubes and was then centrifuged in a clinical centrifuge for 10
      min. Plasma was frozen promptly at -80 degrees C for later enzyme-linked
      immunosorbent assay (ELISA), with which plasma glutathione peroxidase was
      determined. RESULTS: The maternal demographics of the pre-eclamptic and non-pre
      eclamptic study groups did not significantly vary with respect to mean maternal
      age, gravidity, parity and gestational age at the time of delivery. The median
      maternal ages were 33 and 34 years, and the median gestational ages at the time
      of birth were 37.5 and 38.1 weeks, respectively. In evaluating the glutathione
      peroxidase levels of all patients across the three trimesters, we found that
      there was essentially no difference in mean levels (83.7, 81.0 and 89.5 ng/ml,
      respectively). There was no difference between the pre-eclamptic and non-pre
      eclamptic patients, again stratified by trimester. A linear regression analysis
      indicated that the plasma glutathione peroxidase concentration did not correlate
      with gestational age or the presence of pre-eclampsia. CONCLUSIONS: Plasma
      glutathione peroxidase expression is similar across all trimesters. There is no
      change in the glutathione peroxidase levels in pre-eclamptic patients.

PMID- 12607765
TI  - The effect of intrapartum magnesium sulfate therapy on fetal cardiac troponin I
      levels at delivery.
AB  - OBJECTIVE: To determine whether intrapartum magnesium sulfate (MgSO4) therapy for
      seizure prophylaxis in pre-eclampsia-eclampsia is associated with biochemical
      evidence of subacute fetal myocardial damage at delivery. STUDY DESIGN: Troponin
      I, a cardiac-specific protein used to detect myocardial injury, was measured from
      the umbilical vein at delivery in term pregnancies complicated by pre-eclampsia
      and uncomplicated control pregnancies. Women with pre-eclampsia received
      intravenous MgSO4 as a 6-g load followed by 2 g/hour until delivery. Clinical
      characteristics and fetal troponin levels were compared between groups. RESULTS:
      There was no difference in troponin I concentrations between term patients with
      intrapartum MgSO4 therapy and controls who did not receive MgSO4 (median 0.86
      ng/ml, range 0.72-1.10 vs. 0.89 ng/ml, range 0.68-1.50; p = 1.0). There was also
      no statistically significant difference in the number of patients with a troponin
      I level of > or = 1.0 ng/ml between groups (30.8% (4/13) vs. 15.4% (4/26); p =
      0.4). CONCLUSIONS: Our findings suggest that, in term fetuses that are not growth
      impaired, exposure to intrapartum MgSO4 is not associated with subacute
      myocardial injury.

PMID- 12607766
TI  - Early changes of pulmonary mechanics to predict the severity of bronchopulmonary
      dysplasia in ventilated preterm infants.
AB  - OBJECTIVES: To verify whether early pulmonary mechanics measurements are useful
      to predict subsequent bronchopulmonary dysplasia (BPD) and its severity. METHODS:
      Pulmonary mechanics were studied at 3, 5, 7 and 10 days of age in 52 preterm
      infants with birth weight < 1250 g, affected by respiratory distress syndrome and
      ventilated for more than 72 h. Pulmonary function was assessed using a previously
      standardized method based on the measurement of airflow with a Fleisch OO
      pneumotachograph and airway pressure with a model P7D differential pressure
      transducer. At 28 days pulmonary outcome was classified into three groups: no
      BPD, mild BPD (oxygen dependency and hazy lung on X-ray) and severe BPD (oxygen
      dependency and Northway stage 3/4). RESULTS: Of the 52 infants, 39 survived to 28
      days: no BPD (11 infants), mild BPD (16 infants) and severe BPD (12 infants). The
      no-BPD group had significantly higher gestational age and birth weight, fewer
      males and a lower incidence of patent ductus arteriosus than both BPD groups,
      while no differences were detected between the BPD groups. Lung compliance was
      significantly higher in the mild-BPD group than in the severe-BPD group at 7 and
      10 days of life (p < 0.01 and p < 0.001, respectively). The corresponding odds
      ratio confirmed that ventilated infants with lower lung compliance values had a
      significantly higher probability of developing severe BPD. Respiratory system
      resistance did not show any predictive value. CONCLUSIONS: Our findings indicate
      that low lung compliance values determined on the 7th and 10th days of life are a
      reliable predictive tool of the severity of later BPD.

PMID- 12607767
TI  - The relationship of fetal eye movements to non-stress test results.
AB  - OBJECTIVE: This study was designed to correlate ultrasound-observed fetal eye
      movements with fetal heart rate reactivity to determine its potential role in
      fetuses with persistent non-reactivity. METHODS: A total of 104 non-stress tests
      (NSTs) were evaluated in 62 patients referred for fetal surveillance for standard
      antepartum indications. Ultrasound-observed eye movements, assessed during
      portions of these NSTs, were categorized as negative (0), intermittent (1-5/min),
      or rapid (> or = 6/min). RESULTS: Of the NSTs, 97 were reactive and seven were
      non-reactive. All studied fetuses were apparently healthy, as the seven patients
      with persistently non-reactive NSTs had biophysical profile scores of 8/10.
      During the NSTs, 120 reactive portions and 81 non-reactive portions were
      evaluated for ultrasound-observed eye movements. During reactive portions, eye
      movements were negative 19% of the time, intermittent 24% of the time and rapid
      56% of the time. During non-reactive portions, eye movements were negative 84% of
      the time, intermittent 7.8% of the time and rapid 7.8% of the time. All fetuses
      demonstrating eye movements during non-reactive periods became reactive shortly
      thereafter, and all of the seven persistently non-reactive fetuses displayed
      negative ultrasound-observed eye movements throughout the entire observation
      period. CONCLUSIONS: Healthy fetuses display a strong relationship between non
      reactive heart rate tracings and absent or diminished eye movements, consistent
      with quiet sleep. Conversely, reactive periods are associated with a high
      incidence of rapid eye movement. Further study is needed in fetuses documented to
      be hypoxic.

PMID- 12607768
TI  - Maternal glycemic control and umbilical artery Doppler velocimetry.
AB  - OBJECTIVE: To determine whether information from umbilical artery Doppler flow
      velocity waveforms significantly improves the prediction of adverse perinatal
      outcome, independently of maternal glycemic control, in pregnancies complicated
      by diabetes. STUDY DESIGN: The medical records of 277 pregnant women with
      diabetes were reviewed. Glycemic control was determined by glycosylated
      hemoglobin concentration and umbilical artery Doppler velocimetry by using
      systolic/diastolic ratios (S:D), both obtained during the third trimester.
      Pregnancies with adverse perinatal outcome were compared to those with good
      outcome. Logistic regression analysis was used to adjust for glycemic control,
      and to test whether an elevated umbilical artery Doppler S:D ratio was
      independently associated with pregnancy outcome. RESULTS: Adverse pregnancy
      outcome occurred in 51.6% of these pregnancies (143/277). The mean third
      trimester glycosylated hemoglobin (7.7 +/- 1.9% vs. 6.7 +/- 1.3%, p < 0.001) and
      the umbilical artery S:D ratio were significantly higher (2.6 +/- 0.6 vs. 2.4 +/-
      0.3, p < 0.001) in the pregnancies with adverse outcome. Logistic regression
      analysis showed that umbilical artery S:D ratio was an independent predictor of
      adverse perinatal outcome after adjusting for the third-trimester glycosylated
      hemoglobin level. Forty per cent of patients with normal Doppler findings (S:D
      ratio of < 3.0) and normal glycemic control values (glycosylated hemoglobin level
      of < 7.5%) had an adverse pregnancy outcome. Sixty-three per cent of patients
      with an abnormal result for one of these tests had an adverse pregnancy outcome.
      Ninety-six per cent of patients with both abnormal Doppler findings and abnormal
      glycemic control had an adverse pregnancy outcome. CONCLUSION: Umbilical artery
      Doppler velocimetry improves the predictive value for adverse perinatal outcome,
      independently of glycemic control, in pregnancies complicated by diabetes. The
      combination of an abnormal umbilical artery S:D ratio and abnormal glycosylated
      hemoglobin was strongly associated with adverse pregnancy outcome.

PMID- 12607769
TI  - Primary hyperparathyroidism, hypercalcemic crisis and subsequent seizures
      occurring during pregnancy: a case report.
AB  - A first-trimester primigravid patient presented with hyperemesis and malaise.
      Work-up was consistent with primary hyperparathryoidism. During acute treatment,
      she developed generalized motor seizures considered to be secondary to
      hypercalcemia. Evaluation and treatment of women with primary hyperparathyroidism
      and hypercalcemia are reviewed, and the pathogenesis of seizures associated with
      hypercalcemia is discussed.

PMID- 12607770
TI  - Chorea gravidarum: a case report.
AB  - Chorea gravidarum is a rare syndrome in pregnancy. The clinical picture is of
      extrapyramidal symptoms such as involuntary movements, lack of coordination and
      slurred speech. Neuroleptics or benzodiazepines can be used for treatment. When
      antiphospholipid antibodies are shown to be present, corticosteroids, and
      sometimes aspirin, are added to the treatment. Movement disorders can also be
      associated with an increased central dopamine level. In this report, we present
      the case of a patient with chorea gravidarum in whom an etiologic factor has not
      been observed. We treated the symptoms with dopamine-blocking agents such as
      haloperidol. We believe that, if chorea gravidarum is not accompanied by other
      etiologic factors (such as antiphospholipid antibodies), there is no elevated
      risk for the mother and the fetus.

PMID- 12607771
TI  - Evaluation of serum CA 125 concentration before and during hormonal induced
      cycles as predictor of IVF/ET outcome.
AB  - PROBLEM: To evaluate the role of CA 125 in prediction of in vitro fertilization
      and embryo transfer (IVF/ET) outcome. METHOD OF STUDY: Serum CA 125
      concentrations were evaluated in the spontaneous and stimulated cycles of 33
      patients. CA 125 was measured using a microparticle enzyme immunoassay (MEIA)
      (Abbott, Diagnostics, USA). Follicular growth, endometrial thickness and
      subendometrial blood flow were evaluated by transvaginal color Doppler
      ultrasound. Statistical analysis was performed by Wilcoxon rank-sum test and
      Friedman test. RESULTS: There was no statistically significant difference (P >
      0.05) of CA 125 values between spontaneous and stimulated cycles, and between
      pregnant and non-pregnant patients. A CA 125 rise from the late proliferative to
      the early secretory phase (P < 0.05) was obtained only in the stimulated cycles.
      There was no relationship between CA 125, follicle number, endometrial thickness
      and resistance index of the subendometrial vessels. CONCLUSION: CA 125 levels are
      not predictive of ovarian and endometrial response. Hormonal stimulation does not
      effect serum CA 125 concentration. There was no influence of CA 125 levels on
      IVF/ET outcome in stimulated cycles.

PMID- 12607772
TI  - Influence of carrier protein conjugation site and terminal modification of a GnRH
      I peptide sequence in the development of a highly specific anti-fertility
      vaccine. Part I.
AB  - PROBLEM: We previously immunoneutralized gonadotrophin releasing hormone (GnRH),
      using an analogue of GnRH (des-1 GnRH-I), conjugated to tetanus toxoid via a
      carbodiimide reaction. The castration effect on the reproductive system was not
      consistent in all the treated animals. Therefore, we examined the possibility
      that conjugation to the carrier protein via the N- or C-terminal could have an
      effect on efficacy. METHOD OF STUDY: GnRH analogue sequences were synthesized
      consisting of an additional cysteine at either terminal and specific conjugation
      was carried out using a bifunctional linker agent. RESULTS: Conjugation of the
      monomer through the N-terminal proved to be a highly effective means of causing
      immunocastration in terms of decreased gonadotrophin and testosterone
      concentrations and testicular size, whereas conjugation through the C-terminal
      proved to be ineffective. This was reflected in the ability of the antibodies to
      bind native GnRH, but not the levels of the anti-GnRH antibodies. CONCLUSION:
      Immunoneutralization efficacy was attributed to the importance of preserving the
      GnRH C-terminal.

PMID- 12607774
TI  - The expressions of intracellular cytokines in the lymphocytes of preeclamptic
      patients.
AB  - PURPOSE: The objective of the study was to investigate the intracellular
      expressions of T helper 1 (Th1) and Th2 cytokines in peripheral blood T
      lymhocytes and natural killer (NK) cells of patients with preeclampsia and women
      with uncomplicated pregnancy. METHOD OF STUDY: Blood samples were taken from 20
      patients with preeclampsia and 16 healthy pregnant women. Mononuclear cells were
      isolated from peripheral blood and stimulated for 5 hr at 37 degrees C and 5%
      CO2. Next, the cells were stained with antibodies against surface markers of T
      cell subsets and NK cells. After fixation and permeabilization processes, the
      cells were stained with antibodies against intracellular cytokines--interleukin-2
      (Il-2) and interferon-gamma (IFN-gamma) as well as Il-10 and Il-4. The
      intracellular expressions of Th1 and Th2 cytokines were determined using the flow
      cytometric method. Statistical analysis was performed using Mann-Whitney U-test.
      RESULTS: We found that in patients with preeclampsia the expressions of Il-2 were
      significantly higher when compared with women with uncomplicated pregnancy.
      Furthermore, in the group of patients with preeclampsia the expressions of Il-2
      were higher in T CD 8+ lymphocytes than in T CD4+ cells. The expressions of IFN
      gamma did not differ in CD4+ cells and CD8+ cells in both studied groups but they
      were higher in NK cells in the study group. The expressions of Il-10 were lower
      in lymphocytes of preeclamptic patients when compared with controls. The
      expressions of Il-4 did not differ in both studied groups. CONCLUSIONS: These
      results suggest that in patients with preeclampsia there is Th1/Th2 imbalance,
      with predominant Th1 immunity.

PMID- 12607773
TI  - Part II: influence of dimerization of a modified GnRH-I peptide sequence on a
      male antifertility vaccine.
AB  - PROBLEM: In the previous paper, we described how the tetanus toxoid (TT)
      conjugated monomer, CHWSYGLRPG-NH2, induced high neutralizing antibody titres,
      which resulted in decreased levels of testosterone and subsequent antifertility.
      However, its counterpart HWSYGLRPGC, induced low avidity antibody titres. We
      wanted to know whether peptide dimerization would improve the efficacy of both
      peptides. METHOD OF STUDY: Male Sprague-Dawley rats were immunized with modified
      dimerized GnRH-I peptides (HWSYGLRPGCCGPRLGYSWH and GPRLGYSWHCCHWSYGLRPG-NH2),
      with or without conjugation to TT. RESULTS: The unconjugated dimers were not
      effective in causing castration, although the first peptide dimer did induce
      production of antibodies. When conjugated to TT, both dimers showed the same
      level of efficacy in causing castration as each other. However, there were
      differences in antibody binding to native GnRH. CONCLUSIONS: Dimerization and
      conjugation to a carrier improved the antifertility efficacy of HWSYGLRPGC,
      whereas the conjugated monomer CHWSYGLRPG-NH2 showed a greater level of
      consistent castration than its conjugated dimer.

PMID- 12607775
TI  - Transforming growth factors beta1, beta2 and beta3 and their receptors are
      differentially expressed in human peritoneal fibroblasts in response to hypoxia.
AB  - PROBLEM: Little is known about the role of peritoneal fibroblasts in adhesion
      formation. This study determines the effect of hypoxia and transforming growth
      factor (TGF)-beta1 treatment on the expression of TGF-beta1-3 and TGF-betaI and
      betaII receptors in human peritoneal fibroblasts (HPF). TGF-beta isoforms and
      their receptors have been implicated as mediators of the healing process and
      adhesion development. METHODS: HPF were cultured under normal and hypoxic
      condition, and treated with and without (1 ng/mL) TGF-beta1 for 24 hr. Total RNA
      from each group was subjected to multiplex reverse transcriptase-polymerase chain
      reaction (RT/PCR) to quantitate TGF-beta1-3 and TGF-betaI and betaII receptors
      messenger RNA (mRNA) levels. RESULTS: Hypoxia resulted in a significant increase
      in TGF-beta1 (26%; P < 0.05), TGF-betaIR (34%; P < 0.05) and TGF-betaIIR (29%; P
      < 0.05) mRNA levels, with no effect on TGF-beta2 or beta3. TGF-beta1 treatment
      resulted in a significant increase in TGF-beta1 (35%; P < 0.05), but a decrease
      in TGF-beta2 (22%; P < 0.05) and no effect on TGF-beta3, TGF-betaIR or TGF
      betaIIR. Combined treatment of hypoxia and TGF-beta1 caused a significant
      increase in TGF-beta1 (37%; P < 0.05), TGF-beta2 (12%; P < 0.05), TGF-betaIR
      (32%; P < 0.05) and TGF-betaIIR (34%; P < 0.05). There is no significant change
      in the mRNA levels of TGF-beta3 in any of the treatments. CONCLUSION: Hypoxia and
      TGF-beta1 treatments of cultured HPF modulate the expression of TGF-beta1, beta2
      and beta3 and their receptors betaIR and betaIIR by increasing the ratio of TGF
      beta1 and beta2 to beta3, thus favoring the development of peritoneal adhesion.

PMID- 12607776
TI  - Effect of ovaric hyper-stimulation on blood lymphocyte subpopulations, cytokines,
      leptin and nitrite among patients with unexplained infertility.
AB  - PROBLEM: To determine the effect of ovarian stimulation on TH1, TH2 and natural
      killer (NK) lymphocytes, plasma cytokines, leptin and nitrite levels. METHODS:
      Women with reproductive failure were studied during the implantation window, at
      baseline (n = 18) and under ovarian stimulation (gonadotropins + progesterone, n
      = 6). CONTROLS: eight fertile women. Lymphocyte subpopulations and NK function
      were determined by flow cytometry. Interleukin-2 (IL-2), IL-4, IL-10, IFN-gamma,
      TNF-alpha, TGF-beta1 and leptin were measured by enzyme immunoassay (EIA);
      nitrite by the Griess reaction. RESULTS: At baseline, patients had higher values
      of NK effectors, NK activity and plasma IFN-gamma and IL-2 than controls.
      Conversely, TGF-beta1 values were lower. Hormones induced leukocytosis. Under
      stimulation, THI CD4+ cells, NK effectors and function and plasma IFN-gamma and
      IL-2 decreased, while transforming growth factor (TGF)-beta1 increased. Other
      variables did not change. CONCLUSION: The abnormal distribution of leukocytes,
      high TH1 cytokines and a low TGF-beta1 associated with reproductive failure,
      respond to ovarian stimulation, achieving total or partial normalization.

PMID- 12607777
TI  - Macrophage migration inhibitory factor in human pregnancy and labor.
AB  - PROBLEM: Macrophage migration inhibitory factor (MIF) is a proinflammatory
      cytokine involved in reproduction. Presently there is no information on the
      possible involvement of MIF in the onset of labor. METHODS: Macrophage migration
      inhibitory factor was assayed, by enzyme-linked immunosorbent assay (ELISA), in
      maternal serum (MS) and amniotic fluid (AF) both, at midtrimester and at term, as
      well as in cord serum (CS) at birth. Extraembryonic membranes were analyzed by
      immunohistochemistry. RESULTS: Amniotic fluid MIF concentrations were
      significantly higher at term (median 62.10 ng/mL) than at midtrimester (median
      20.07 ng/mL) and reached a peak in term labor (median 258.80 ng/mL). The AF/MS
      ratio varied from a median of 4.34 at midtrimester and 33.7 at term labor. The
      MS/CS ratio was 0.4. Migration inhibitory factor immunoreactivity was found in
      different cell layers of the extraembryonic membranes. CONCLUSIONS: The increased
      secretion of MIF in AF at term, particularly at term labor, suggests that MIF
      contributes to the inflammatory events leading to labor.

PMID- 12607778
TI  - Cystic pancreatic neoplasms evaluation by CT and magnetic resonance
      cholangiopancreatography.
AB  - CT provides limited assistance in the differentiation between serous and mucinous
      neoplasms. Because of the variability in the radiographic appearance of serous
      cystadenomas and overlap in CT characteristics with mucinous neoplasms, most
      serous neoplasms still require ancillary testing such as biopsy to reach a
      definitive diagnosis. MRCP is useful in differentiating benign and malignant
      mucinous tumors including IPMT of the pancreas. The presence of mural nodules is
      suggestive of malignancy; however, the absence of mural nodules does not indicate
      that the tumor is benign. A maximum main pancreatic duct diameter of greater than
      15 mm and diffuse dilatation of the main pancreatic duct are suggestive of
      malignancy in main duct-type tumors. Among branch duct-type tumors, malignant
      tumors tend to be larger than benign tumors; however, this finding is variable.
      The presence of main pancreatic duct dilatation may be helpful in determining
      malignancy of branch duct-type tumors.

PMID- 12607779
TI  - Histology of cystic tumors of the pancreas.
AB  - The cystic tumors of the pancreas constitute a considerable diagnostic challenge
      because of their overlapping clinical, radiologic, and pathologic features. They
      may be difficult to differentiate from one another and from benign lesions such
      as pseudocysts. Because many of the tumors in this group are potentially curable,
      correct diagnosis is essential for proper patient management. Even when correctly
      diagnosed, thorough microscopic evaluation is required for the mucin-producing
      tumors to correctly determine their degree of malignant progression in any given
      case. Most recently, molecular analysis of these tumors has demonstrated
      definitively that the serous and mucinous types of cystic neoplasms of the
      pancreas are unrelated pathogenetically. Conversely, molecular data indicate
      similarities between the mucinous types of cystic tumors and ductal
      adenocarcinoma of the pancreas, but the essential molecular differences that
      underlie the differences in biological behavior are as yet undetermined.

PMID- 12607780
TI  - Role of cytology in the diagnosis of cystic and intradcutal papillary mucinous
      neoplasms.
AB  - Cytology may provide valuable information and is diagnostic in many cases, but it
      is limited by sampling difficulties. Performance of mucin stains and analysis of
      the cyst fluid for tumor markers, as described in the article on histology of
      cystic neoplasms elsewhere in this issue, increase detection of MCNs and IPMNs;
      however, as with any other laboratory test, the results of the cyst fluid
      cytologic analysis need to be assessed in light of the clinical and radiologic
      findings, particularly when the cytology is not completely diagnostic.

PMID- 12607781
TI  - Endoscopic ultrasound techniques for pancreatic cystic neoplasms.
AB  - The role of EUS and EUS FNA in the evaluation of cystic pancreatic lesions is
      evolving. The detailed imaging provided by EUS and hence the ability to target
      the biopsy at suspicious areas within the pancreatic cystic lesion may prove to
      be invaluable. Improvements in EUS equipment will further secure the role of this
      technology when evaluating these patients.

PMID- 12607782
TI  - Diagnosis of cystic neoplasms with endoscopic ultrasound.
AB  - From the data that are currently available, it appears that EUS can help to
      reliably distinguish between the majority of benign and neoplastic cystic
      lesions. In equivocal cases, or cases where a high suspicion for malignancy
      exists, the use of EUS-guided FNA for obtaining cytology and cystic fluid for
      analysis of various tumor markers, gives the best diagnostic yield. Occasionally,
      despite a complete evaluation of a cystic mass, the cyst type may not be
      determined. The decision regarding further management of these lesions should be
      based on a combination of factors including symptoms, cyst size, EUS morphology
      and the patient's overall medical condition. In the case of symptomatic, large,
      or suspicious lesions where the patient is a good surgical candidate, surgical
      resection should be performed. However, it becomes more difficult in the case of
      asymptomatic, small cystic lesions where the patient is not an optimal surgical
      candidate. In the latter scenario, applying EUS criteria for follow-up of small
      pancreatic cystic lesions as reported by Ikeda et al can help in the decision
      making process. In this study, Ikeda et al reported on 31 patients with
      pancreatic cystic lesions of unknown etiology that were followed-up with semi
      annual EUS exams over a 3-year period. In 87.1% of these lesions, the size was
      less than 2 cm. Their criteria included 1) a clear thin wall, 2) smooth contour,
      3) round or oval shape, 4) no septum or nodules, 5) asymptomatic clinical
      presentation, and 6) no findings of chronic pancreatitis. The cystic lesions
      remained stable in 30/31 patients, and only one lesion increased in size. This
      lesion was resected and was found to be a retention cyst. We are optimistic that
      the role of EUS in the management of cystic neoplasms will continue to evolve and
      expand as future studies evaluate the clinical utility of imaging modalities for
      the optimal practice algorithm for managing these neoplasms.

PMID- 12607783
TI  - Diagnosis and fine needle aspiration of intraductal papillary mucinous tumor by
      endoscopic ultrasound.
AB  - A recently established clinical entity, intraductal papillary mucinous tumor
      (IPMT) of the pancreas embraces a spectrum of pathology ranging from benign to
      malignant disease. IPMT must be differentiated from other cystic neoplasms of the
      pancreas, as well as inflammatory cystic lesions. As the pancreas lies in close
      proximity to the gastric and duodenal walls, endoscopic ultrasonography (EUS) is
      ideally suited for imaging the pancreas. Additionally, EUS facilitates fine
      needle aspiration of pancreatic cysts and/or a dilated pancreatic duct for
      cytologic and tumor marker analysis. This article presents a brief history of
      IPMT, differential diagnosis, current imaging modalities, findings of cytologic
      and tumor marker analysis, prognosis, and treatment strategy. Special emphasis is
      dedicated to the role of EUS, as well as EUS with fine needle aspiration.

PMID- 12607784
TI  - The role of ERCP and pancreatoscopy in cystic and intraductal tumors.
AB  - ERCP and pancreatoscopy may establish a diagnosis of IPMT and differentiate it
      from a pseudocyst or cystic neoplasm of the pancreas. These techniques may also
      assess risk of malignancy, extent of disease, allow tissue sampling, and provide
      therapeutic intervention.

PMID- 12607785
TI  - The role of laparoscopy and laparoscopic ultrasound in the diagnosis of cystic
      lesions of the pancreas.
AB  - With the widespread use of advanced imaging techniques, cystic lesions of the
      pancreas are now diagnosed relatively frequently. The nature of these lesions
      vary from benign cysts (serous cvstadenoma) or an inflammatory process
      (pseudocyst), to premalignant (mucinous cystadenoma) or frankly malignant lesions
      (cystadenocarcinoma). Differentiation of various types of pancreatic cysts
      presents a diagnostic and therapeutic challenge, as clinical presentation may be
      vague. Laparoscopic ultrasonography (LAPUS), the biopsy of the cystic wall, and
      analysis of the cystic aspirate, although expensive and rather invasive
      procedures, significantly contribute to the differential diagnosis of pancreatic
      cystic lesions.

PMID- 12607786
TI  - Nonmucinous cystic pancreatic neoplasms.
AB  - This article discusses serous cystadenomas, the most common of the nonmucinous
      cystic lesions of the pancreas. These microcystic lesions were previously known
      as "glycogen-rich" cystadenomas because of the presence of glycogen within the
      cyst epithelium. A small percentage of these lesions are macrocystic, and it may
      be difficult to differentiate them from mucinous lesions; however, endoscopic
      ultrasound guided fine needle aspiration can provide diagnostic material from the
      cyst fluid. The second most common nonmucinous cyst, the islet cell tumor, is
      also discussed. These rare cystic tumors may or may not be accompanied by excess
      hormone production. The prognosis for the rare cystic tumors is good if they are
      resected successfully.

PMID- 12607787
TI  - Diagnosis and fine needle aspiration of pancreatic pseudocysts: the role of
      endoscopic ultrasound.
AB  - Pseudocysts are localized collections of pancreatic fluid surrounded by
      nonepithelialized granulation tissue that occur following an insult to the
      pancreas. High image resolution and the ability sample in real-time by fine
      needle aspiration permit accurate distinction between various cystic lesions in
      the pancreas by endoscopic ultrasound (EUS). Other cyst characteristics and
      background pancreatic changes detectable at EUS assist in the diagnostic process.
      The use of Doppler flow ultrasound allows diagnosis of important pseudocyst
      complications such as pseudoaneurysms and varices. Endoscopic approaches to the
      drainage of symptomatic lesions previously relied on the use of cross-sectional
      imaging studies such as computed tomography scanning in combination with stent
      placement using a duodenoscope in the presence of an endoscopically visible cyst
      bulge. EUS facilitates this process allowing accurate imaging of the lesion prior
      to stent placement via the echoendoscope and overcomes many of the drawbacks and
      pitfalls of other endoscopic techniques.

PMID- 12607788
TI  - Role of tumor markers in the diagnosis of cystic and intraductal neoplasms.
AB  - Despite recent advances in imaging procedures, the correct diagnosis of cystic
      lesions of the pancreas is lacking in about one third of cases. Cyst fluid
      analysis can help in the differential diagnosis, particularly in patients with
      unilocular or paucilocular lesions, thus precluding unjustified resection in
      patients with benign cystic lesions of the pancreas. Although use of cystic fluid
      marker analysis is helpful in several situations, it is crucial to carefully
      evaluate the clinical context with appraisal of patient's demographics, clinical
      symptoms, and morphologic data. A multidisciplinary approach is advised and
      should improve the overall diagnostic performance and lead to better management
      strategies in patients presenting with such tumors of the pancreas.

PMID- 12607789
TI  - Gastroesophageal reflux disease in children: an overview of pathophysiology,
      diagnosis, and treatment.

PMID- 12607790
TI  - Safety of lansoprazole in the treatment of gastroesophageal reflux disease in
      children.
AB  - OBJECTIVES: To evaluate the safety of lansoprazole in children between 1 and 11
      years of age. METHODS: In a phase I/II, open-label, multicenter (11 sites) study,
      children with symptomatic gastroesophageal reflux disease (GERD), erosive
      esophagitis (> or = grade 2), and/or esophageal pH < 4 for > 4.2% of the 24-hour
      period were assigned, on the basis of body weight, to lansoprazole 15 mg (< or =
      30 kg) or 30 mg (> 30 kg) once daily for 8 to 12 weeks. At the discretion of the
      investigator, the dosage of lansoprazole was increased up to 60 mg daily in
      children who continued to be symptomatic after 2 weeks of treatment. Safety for
      all study participants was monitored by adverse event reports and laboratory
      evaluations. RESULTS: Sixty-six children were enrolled in the study and were
      included in the safety analysis. Throughout the treatment period, no child
      discontinued therapy because of an adverse event and no clinically significant
      changes in laboratory values were observed. Three of the 32 children (9%) who
      received lansoprazole 15 mg once daily (mean exposure 50.3 days) and 6 of the 34
      children (18%) who received the 30 mg once-daily dose (mean exposure 49.4 days)
      experienced one or more treatment-related adverse events before any dose
      increase. The three children in the lansoprazole 15 mg treatment group were
      treated with doses of 0.6 mg to 1.2 mg/kg/day; those in the lansoprazole 30 mg
      treatment group were treated with doses of 0.7 mg to 0.9 mg/kg/day. Only one
      child experienced a new treatment-related adverse event after an increase in
      lansoprazole dose to 1.3 mg/kg/day. Treatment-related events experienced by two
      or more children were: constipation (lansoprazole 15 mg QD, two children;
      lansoprazole 30 mg QD, one child), and headache (lansoprazole 30 mg QD, two
      children). Mean fasting serum gastrin levels were significantly increased from
      58.0 pg/mL at baseline to 112.4 pg/mL at week 2 and 121.9 pg/mL at the final
      visit (P < or = 0.001 for each comparison). However, the median fasting serum
      gastrin levels at the week 2 and the final visit were within the normal range (25
      111 pg/mL). CONCLUSION: Lansoprazole, when administered on the basis of body
      weight in children between 1 and 11 years of age, is safe and well-tolerated.

PMID- 12607791
TI  - Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in
      children.
AB  - OBJECTIVES: To assess the efficacy of lansoprazole for the relief of symptoms due
      to gastroesophageal reflux disease (GERD) in children 1 to 11 years of age. In
      addition, the efficacy in healing of erosive esophagitis (EE) was determined in
      those children with EE who were enrolled in the study. METHODS: In this phase
      I/II, open-label, multicenter (11 sites) U.S. study, children with symptomatic
      GERD, EE by endoscopy, and/or intraesophageal pH < 4 for greater than 4.2% of the
      time based on 24-hour pH testing were assigned, on the basis of body weight, to
      lansoprazole 15 mg (< or = 30 kg) or 30 mg (> 30 kg) once daily for 8 to 12
      weeks. At the discretion of the investigator, the dosage of lansoprazole was
      increased up to 60 mg daily in children who continued to be symptomatic after 2
      weeks of treatment. Symptom response was assessed by investigator interview and
      daily diary. Esophagitis healing was evaluated by repeat endoscopy after 8 and,
      if applicable, 12 weeks of treatment. RESULTS: Sixty-six children were enrolled.
      At week 8, 78% (21/27) of the children with EE at baseline had healed; the
      remaining six children were healed by week 12 (100%, 6/6). By investigator
      interview, 70% of children experienced resolution or improvement in their overall
      symptoms of GERD by their final visit. Statistically significant reductions from
      baseline in the severity of each symptom were reported with the exceptions of
      wheezing, hematemesis, and melena. Based on daily diary data, improvement in
      overall GERD symptoms was reported in 76% (47/62) of all children. With few
      exceptions, significant (P < 0.05) reductions from baseline occurred during each
      of the 2-week treatment intervals of the study period in the percentage of days
      and the average daily severity of GERD symptoms, the percentage of days antacid
      was used, and the average number of antacid tablets used per day. CONCLUSION: In
      children 1 to 11 years of age, lansoprazole is efficacious in healing EE and in
      relieving GERD-related symptoms.

PMID- 12607792
TI  - Pharmacokinetics and pharmacodynamics of lansoprazole in children with
      gastroesophageal reflux disease.
AB  - OBJECTIVES: To evaluate the pharmacokinetics and pharmacodynamics of lansoprazole
      in children between 1 and 11 years of age with gastroesophageal reflux disease
      (GERD). METHODS: In a multicenter, open-label trial of pediatric patients with
      symptomatic GERD, children were assigned, based on their weight, to receive
      lansoprazole 15 mg (patients weighing < or = 30 kg) or lansoprazole 30 mg
      (patients weighing > 30 kg) once daily. The effects of lansoprazole on 24-hour
      median intragastric pH, the percentages of time intragastric pH was above 3 and
      4, and pharmacokinetic parameters were assessed at the day-5 visit and compared
      to baseline. RESULTS: Sixty-six children were enrolled in the study. Mean
      lansoprazole C(max) values of 790.9 ng/mL and 898.5 ng/mL and T(max) values of
      1.5 hours and 1.7 hours were observed in the < or = 30 kg and the > 30 kg body
      weight treatment groups, respectively. AUC0-24 values of 1707 ng x h/mL and 1883
      ng x h/mL and T1/2 values of 0.68 hours and 0.71 hours were observed in the < or
      = 30 kg and > 30 kg lansoprazole body weight treatment groups, respectively.
      There was no statistical significant difference in AUC0-24 between the two groups
      (P = 0.2571). After 5 days of treatment lansoprazole produced significant
      increases in patients' 24-hour mean intragastric pH and the percentages of time
      intragastric pH was above 3 and 4 compared to baseline. CONCLUSION: The observed
      pharmacokinetic properties of lansoprazole in children between 1 and 11 years of
      age with GERD were similar to those previously observed in healthy adult
      subjects. Lansoprazole significantly increased the mean 24-hour intragastric pH
      and the percentages of time intragastric pH was above 3 and 4 when children were
      dosed with either 15 or 30 mg according to body weight.

PMID- 12607793
TI  - Lansoprazole in adolescents with gastroesophageal reflux disease:
      pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability.
AB  - OBJECTIVES: To evaluate the pharmacokinetics, pharmacodynamics, symptom relief
      efficacy, and tolerability of lansoprazole in adolescents between 12 and 17 years
      of age with gastroesophageal reflux disease (GERD). METHODS: Adolescents with
      symptomatic, endoscopically and/or histologically proven GERD were enrolled in
      this multicenter, double-blind trial and randomized to lansoprazole 15 mg or 30
      mg once daily for 5 days. RESULTS: Sixty-three adolescents were enrolled in the
      study. After lansoprazole administration, T(max) occurred at 1.6 hours in those
      treated with lansoprazole 15 mg and at 1.7 hours in those treated with
      lansoprazole 30 mg. Dose-proportional increases in lansoprazole C(max) and AUC
      were observed in the treatment groups. Age, weight, and gender had no significant
      effect on T(max), C(max), or AUC. Lansoprazole produced significant increases (P
      < or = 0.05) in mean 24-hour intragastric pH and the percentages of time
      intragastric pH was above 3 and 4. The majority of adolescents treated with
      lansoprazole 15 mg (69%, 22/32) or lansoprazole 30 mg (74%, 23/31) demonstrated
      improvement in their reflux symptoms after 5 days of treatment. Adolescents in
      both dosage groups exhibited reductions from baseline in the percentage of days
      and nights with heartburn (or other predominant symptom of GERD), the severity of
      heartburn, the percentage of days antacids were used, and the number of antacid
      tablets used per day. Pharyngitis and headache were the most commonly reported
      side effects among adolescents treated with lansoprazole 15 mg and 30 mg,
      respectively. Five patients experienced adverse events considered to be possibly
      treatment-related. One patient with a history of environmental allergies
      experienced a mild allergic reaction after 3 days of treatment with lansoprazole
      15 mg. Among those treated with lansoprazole 30 mg, 4 patients each reported one
      occurrence of pain (toothache), diarrhea, dizziness, and rash. CONCLUSION: The
      pharmacokinetic parameters of lansoprazole observed in this study of adolescents
      are similar to those observed in studies of healthy adults. Lansoprazole 15 mg or
      30 mg once daily for 5 days produces significant increases in intragastric pH,
      effectively relieves symptoms of reflux disease, and is well tolerated in
      adolescents with GERD.

PMID- 12607794
TI  - Fluctuating lymphocyte chimerism, tolerance and anti-tumor response in a patient
      with refractory lymphoma receiving nonmyeloablative conditioning and a
      haploidentical related allogeneic bone marrow transplant.
AB  - A 51-year-old patient with refractory non-Hodgkin lymphoma (NHL) received non
      myeloablative conditioning and a two of six (A, B, DR) human leucocyte antigen
      (HLA) mismatched donor BMT. Post-BMT lymphocytes showed fluctuating T- and
      natural killer (NK)-cell chimerism, which culminated in mainly donor lymphocytes
      by Day + 100. Changes in lymphocyte chimerism correlated with anti-donor and anti
      host responses in mixed lymphocyte reaction (MLR). On Day + 100, a strong anti
      host response was observed in MLR in the absence of graft-versus-host disease
      (GVHD), together with near complete regression of the patient's lymphoma. A mild
      chronic GVHD later developed and, eventually, by 680 days post-BMT, the lymphoma
      had relapsed and MLR reflected a state of global immune unresponsiveness. These
      observations demonstrate evolving host-versus-graft and graft-versus-host
      tolerance that correlates with fluctuating lymphoid chimerism and graft-versus
      lymphoma (GVL) effects, in the absence of severe GVHD. Eventual lymphoma relapse
      temporally correlated with a generalised immunosuppressed state.

PMID- 12607795
TI  - Pharmacologic and cytokine treatment of commonly encountered anemias.
AB  - Anemia has multiple etiologies: it may be caused by nutritional deficiencies or
      congenital abnormalities, or it may be associated with a number of conditions,
      such as chronic kidney disease, cancer, or human immunodeficiency virus (HIV)
      infection. Anemia is associated with an increase in morbidity and mortality in
      patients with endstage renal disease, cancer, or HIV infection. Each case of
      anemia is different, with different causes, clinical consequences, and treatment
      strategies. Identifying the most appropriate treatment requires an understanding
      of the etiology of the anemia and investigation of the nature of the causative
      medical condition. In some cases, such as anemia associated with chronic kidney
      disease, treatment is well defined and consists of administration of
      erythropoiesis-stimulating agents, accompanied by iron supplementation where
      appropriate. In other instances, such as megaloblastic anemia, which may be
      caused by vitamin or folate deficiency, vitamin supplementation alone may be a
      clinically appropriate treatment. This article gives an overview of the
      etiologies and current therapies of the most commonly encountered types of
      anemia, highlighting both the diverse nature of the condition, and the equally
      diverse pharmacologic and supportive treatment approaches.

PMID- 12607796
TI  - Molecular aspects of glucocorticoid hormone action in rheumatoid arthritis.
AB  - Glucocorticoids (GC) are the most powerful anti-inflammatory drugs used in the
      treatment of autoimmune diseases such as rheumatoid arthritis. In addition,
      endogenous GC are involved in numerous physiological processes. Most of their
      effects are mediated by the glucocorticoid receptor (GR) via activation or
      repression of gene expression. Whereas activation requires DNA binding of the
      receptor, repression is mediated by protein-protein interactions with other
      transcription factors. In particular, most immunosuppressive and anti
      inflammatory effects are exerted by an interaction of GR with the activating
      protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) families of transcription
      factors without DNA binding. Cytokines such as tumor necrosis factor alpha (TNF
      alpha) and interleukin 1 (IL-1) activate the hypothalamus pituitary adrenal (HPA)
      axis, whereas GC inhibit IL-1 and TNF-alpha forming a cytokine-HPA axis feedback
      circuit. The high effectiveness of cytokine-antagonists blocking TNF-alpha or IL
      1 in RA and the understanding of the precise molecular mechanisms of GC function
      will enhance our understanding of autoimmune diseases, such as RA, and could
      suggest new beneficial therapeutic approaches with fewer side-effects.

PMID- 12607799
TI  - The family physician workforce in New York City: implications for family medicine
      predoctoral education.

PMID- 12607798
TI  - Intracellular cytokine analysis of interferon-gamma in T cells of patients with
      chronic myeloid leukemia.
AB  - The role of T cells in eradicating leukemic cells has been well demonstrated for
      chronic myeloid leukemia (CML). Type 1 (T1) T-cell cytokines play a major role in
      this antileukemic immune effect. Studies in cancer patients have demonstrated a
      decreased T1 cytokine production, measured by enzyme-linked immunosorbent assay
      (ELISA), in cultures of peripheral blood mononuclear cells. This observation of
      malignancy-related suppressed T1 cytokines also occurs in untreated chronic-phase
      (CP) CML, raising the question of the influence of different CML treatment
      regimens on this immunosuppression. Intracellular flow cytometry (ICF) has
      facilitated the evaluation of cytokines on a single-cell level. This study
      analyzed T1 (interferon-gamma) cytokine production in purified peripheral blood T
      cells by ICF, comparing different therapy approaches for CML. Twenty-one newly
      diagnosed CP CML patients were compared with 24 patients treated with interferon
      alpha (IFN-alpha) and to 30 allogeneic bone marrow transplant (BMT) recipients
      (BCR-ABL negative by reverse-transcriptase polymerase chain reaction, and free
      of, or having only limited graft-versus-host disease at the time of study).
      Thirty-seven healthy controls were included. Our results showed a significantly
      decreased T-cell IFN-gamma synthesis in CP CML patients in relation to healthy
      controls (P = 0.0007). Treatment with IFN-alpha resulted in a shift from
      immunosuppression--documented for the group of untreated patients--to
      immunopotentiation, with an increase of T-cell IFN-gamma production (P = 0.0266).
      Notably, BMT enhanced IFN-gamma production of T cells to a level not only
      exceeding untreated patients (P < 0.0001) but also healthy volunteers (P <
      0.0001). The observation of T1 cytokine up-regulation with IFN-alpha therapy
      indicates that enhanced T-cell function may be achievable in patients with CML,
      even in the absence of an allo-response.

PMID- 12607797
TI  - Serum levels of melanoma-inhibiting activity do not predict relapse in melanoma
      patients.
AB  - Melanoma-inhibiting activity (MIA) is a 107 amino-acid protein secreted from
      melanoma cells and frequently detectable at high concentration in the serum of
      patients with advanced melanoma. Early studies suggested that MIA may be a useful
      serum tumor-marker for detection of recurrent or progressive disease. We
      evaluated the sensitivity of serum MIA levels in predicting the risk of relapse
      in patients with American Joint Committee on Cancer (AJCC) Stage II, III, and IV
      melanoma. MIA was measured by ELISA in serum from 39 patients with AJCC Stage II,
      III and IV disease at a single time-point 1 month to 5 years after they were
      rendered free of disease. Twenty-three of the 39 patients recurred, with a median
      follow-up of 4.5 months. Only four of the 23 patients who recurred had shown
      elevated MIA values (17% sensitivity). Of the 16 patients who remain free of
      disease (median follow-up 3.5 years, range 11 months to 6.3 years), one patient
      had an elevated MIA. There was no significant difference in the proportion of
      patients with elevated serum MIA between the patients who recurred and those who
      remained free of disease. In this series, serum MIA was not a sensitive marker
      for relapse in patients who were clinically free of disease after treatment.

PMID- 12607800
TI  - Are family physicians willing to use pharmacogenetics for smoking cessation
      therapy?

PMID- 12607801
TI  - Benefits of a preceptor focus group: a model of interaction among academic and
      community faculty.

PMID- 12607802
TI  - Minnesota's rural health school: interdisciplinary community education.
AB  - The Minnesota Rural Health School was established in 1996 and is administered by
      the University of Minnesota School of Medicine, Duluth. The program provides
      rural interdisciplinary clinical experiences for health professions students in
      seven community sites. The core disciplines include medicine, physician
      assistant, pharmacy, nursing, dentistry, and social work. There have been more
      than 230 participants. Students benefit by learning to work in collaborative
      teams and by participating in rural health care delivery. The communities benefit
      from service-learning projects, from the introduction of telecommunication
      technologies, and from the increased potential for recruiting future rural
      practitioners.

PMID- 12607803
TI  - A different kind of life.

PMID- 12607804
TI  - On doing nothing.

PMID- 12607805
TI  - The effects of the 1997 Balanced Budget Act on family practice residency training
      programs.
AB  - BACKGROUND AND OBJECTIVES: This study assessed the impact of the Balanced Budget
      Act (BBA) of 1997 on family practice residency training programs in the United
      States. METHODS: We surveyed 453 active family practice residency programs,
      asking about program closures and new program starts (including rural training
      tracks), changes in the number of residents and faculty, and curriculum changes.
      Programs were classified according to their urban or rural location, university
      or community hospital setting, and rural and/or urban underserved mission
      emphasis. RESULTS: A total of 435 (96%) of the programs responded. Overall, the
      impact of the BBA was relatively small. In 1998 and 1999, nationwide, there were
      11 program closures, a net decrease of only 82 residents, and a net increase of
      52 faculty across program settings and mission emphasis. The rate of family
      practice residency program closures increased from an average of 3.0 per year
      between 1988-1997 to 4.8 per year in the 4 years following passage of the BBA.
      CONCLUSIONS: The 1997 BBA did not have an immediate significant negative impact
      on family practice residency programs. However, there is a worrisome increase in
      the rate of family practice residency closures since 1997. A mechanism needs to
      be established to monitor all primary care program closures to give an early
      warning should this trend continue.

PMID- 12607806
TI  - The relationship of residency performance to match status and US versus
      international graduate status.
AB  - BACKGROUND AND OBJECTIVES: This study compared the performance of family practice
      residents selected through the National Resident Matching Program (NRMP) with
      those selected outside the NRMP and that of US medical graduates (USMGs) versus
      international medical graduates (IMGs). METHODS: Surveys were mailed to all 470
      US family practice residencies asking Match status and USMG versus IMG status of
      graduates accepted into their programs from 1994-1996. RESULTS: Of 3,222
      residents, 2,815 (87.4%) were accepted through the Match, 159 (4.9%) before the
      Match, and 248 (7.7%) after the Match; 2,874 (89.2%) were USMGs, and 348 (10.8%)
      were IMGs. Residents accepted after the Match versus residents selected through
      the Match were more likely to leave their programs early (14.5% versus 4.8%),
      score in the lower 10% of their In-training Assessment Examination (ITE) (11.7%
      versus 2.2%), and require remedial programs (12.9% versus 2.6%). A lower
      proportion of residents accepted after the Match scored in the top 10% on the ITE
      examination (5.6% versus 15.2%). IMGs were more likely than USMGs to leave the
      program be fore graduating (8.0% versus 5.2%), to score within the lower 10% on
      the ITE examination (7.8% versus 2.5%), and to require remedial programs (7.8%
      versus 3.2%). CONCLUSIONS: Although a large majority of the residents studied
      here performed well, somewhat less-favorable performance was seen among residents
      accepted after the Match and among those with international medical degrees.

PMID- 12607807
TI  - Nutrition education in family practice residency programs.
AB  - BACKGROUND AND OBJECTIVES: Nutrition is a required part of family practice
      residency training. Unfortunately, little is known about the quality or
      effectiveness of this nutrition training. This study evaluated the current status
      of nutrition training in family practice residency training programs. METHODS: We
      surveyed 100 randomly selected US family practice residencies about their
      nutrition education curriculum. Surveys were sent by e-mail, mail, fax, or
      administered by phone to individuals identified as responsible for nutrition
      teaching. A response rate of 66% was obtained. RESULTS: Programs varied greatly
      in their emphasis on nutrition. Identified barriers were similar across most
      programs. The presence of at least a part-time faculty member dedicated to
      nutrition was correlated with perceived effectiveness of nutrition education
      efforts. CONCLUSIONS: If family physicians are to be prepared to inform their
      patients regarding nutrition and to make appropriate referrals, improvements in
      the nutrition curriculum offered in many family practice residency programs will
      be required. Readers can evaluate their program's nutrition education efforts and
      see how they compare to our sample. Specific recommendations for potential
      changes are included.

PMID- 12607808
TI  - Aspirin and ibuprofen: potential mediators of the cardiovascular risk due to
      smoking?
AB  - BACKGROUND AND OBJECTIVES: Smokers have elevated C-reactive protein (CRP), an
      indicator of systemic inflammation and a marker for increased risk for
      cardiovascular disease (CVD). This study investigated among smokers the
      relationship between CRP and use of the anti-inflammatories aspirin and
      ibuprofen. METHODS: Data from adults (>17 years) collected in the National Health
      and Nutrition Examination Survey (NHANES III) was analyzed (n = 8,850).
      Regression models were used to determine the independent relationship between
      aspirin and ibuprofen use and elevated CRP, controlling for demographics, body
      mass index, history of CVD, and health status. RESULTS: Frequency of use of
      aspirin and ibuprofen among "ever smokers," a population that includes current
      smokers and quitters, was associated with a decreased likelihood of having
      elevated CRP. Ever smokers with low frequency of use of either aspirin or
      ibuprofen had a lower likelihood of having elevated CRP similar to that for
      "never smokers." In adjusted relationships, aspirin use was not significantly
      related to elevated CRP, while low use of ibuprofen had decreased odds of having
      elevated CRP compared to no use. CONCLUSIONS: These preliminary findings from a
      nationally representative survey suggest that among patients refractory to
      smoking cessation interventions, use of ibuprofen may be useful to decrease CVD
      risk.

PMID- 12607809
TI  - Patient pain: its influence on primary care physician-patient interaction.
AB  - BACKGROUND AND OBJECTIVES: Heightened awareness of the importance of appropriate
      pain management in health care delivery has stimulated researchers to examine the
      impact of patient pain on medical encounters. In this study, we explored how
      patient pain might influence the physician-patient interaction during medical
      visits. METHODS: New adult patients (n = 509) were randomized to see primary care
      physicians in videotaped visits at a university medical center Self-reported
      patient pain was measured before the visit using the Visual Analog Scale and the
      Medical Outcomes Study Short Form-36 (MOS SF-36) pain scale; patient
      sociodemographics were also measured. Physician practice style during the visit
      was analyzed with the Davis Observation Code (DOC). RESULTS: Regression analyses
      revealed that patient pain during the medical visit was associated with the
      physician spending a greater portion of the visit on technical tasks and a
      smaller portion on preventive services and other activities designed to encourage
      the patients' active participation in their own health care. CONCLUSIONS: Patient
      pain may influence the physician-patient interaction and its outcomes. Primary
      care physicians should be aware that there may be less focus on patients' active
      involvement in their own care and less emphasis on providing disease prevention
      when treating patients who are experiencing pain.

PMID- 12607810
TI  - Building capacity for research in family medicine: is the blueprint faulty?
AB  - BACKGROUND AND OBJECTIVES: This study compared the training programs and career
      paths of family medicine graduates in the National Research Service Award (NRSA)
      Program for Research in Primary Medical Care with general internal medicine and
      general pediatric peers. METHODS: We mailed a survey to NRSA fellows graduating
      from 23 programs nationally between 1988-1997. Personal characteristics,
      fellowship experience, current professional activities, and academic productivity
      were compared among primary care disciplines. RESULTS: Of 215 NRSA participants,
      146 (68%) completed the survey. Of the 131 primary care respondents, 25% were
      family physicians. During the fellowship, family physician trainees spent
      significantly less time in hands-on research activity (32% +/- 12%) than
      internists and pediatricians (39% +/- 17%). Family physician graduates also had
      less post-fellowship mentoring and were less likely to hold clinician/researcher
      faculty positions in academic centers. Family physician faculty spent far more
      time on clinical work and less time on research. Only 12.5% of family physician
      fellowship graduates published one or more articles per year, compared with 36.5%
      of their peers, and 30% had published nothing since graduation. CONCLUSIONS:
      Family physician graduates of this research training program did not achieve
      academic success comparable to their peers. Family physicians need more protected
      time for conducting research in their faculty positions and more sustained
      mentorship.

PMID- 12607811
TI  - Best practices research.
AB  - "Best practices research," described in this paper, refers to a systematic
      process used to identify, describe, combine, and disseminate effective and
      efficient clinical and/or management strategies developed and refined by
      practicing clinicians. It involves five steps: development of a conceptual model
      or series of steps, definition of "best" based on values and standards,
      identification and evaluation of potentially effective methods for each component
      or step, combination of most-effective methods, and testing of combined methods.
      The chronological development of this process is described with case examples,
      and the methodological steps are discussed.

PMID- 12607812
TI  - Family medicine soup.

PMID- 12607813
TI  - The importance of track records in developing family medicine research.

PMID- 12607814
TI  - Laser mediated production of reactive oxygen and nitrogen species; implications
      for therapy.
AB  - Laser therapy has gained wide acceptance applications to many medical
      disciplines. The side effect-effects from laser therapy involve the potential for
      interaction with cellular and extracellular matrix molecules to generate reactive
      oxygen species and reactive nitrogen species which in turn can initiate lipid
      peroxidation, protein damage or DNA modification. These issues are addressed in
      this short overview in the context of experimental models of laser-induced
      thrombosis.

PMID- 12607815
TI  - Glycated proteins can enhance photooxidative stress in aged and diabetic lenses.
AB  - This study intends to clarify the ability of different carbonyl-containing lens
      metabolites to form advanced glycation end products, which possess
      photosensitizer activity and to investigate whether these modified proteins could
      be implicated in lens photodamage. Calf lens protein was experimentally glycated
      with either methylglyoxal, glyoxal, ascorbic acid, or fructose to obtain models
      of aged and diabetic cataractous lenses. Being exposed to 200J/cm2 UVA radiation
      the model glycated proteins produced 2-3-fold more singlet oxygen compared to the
      unmodified protein and the superoxide radical formation was 30-80% higher than by
      the native protein. Ascorbylated proteins demonstrated the highest
      photosensitizer activity. Biological responses of glycation-related
      photosensitizers were studied on cultured lens epithelial cells irradiated with
      40J/cm2 UVA. Tissue culture studies revealed a significant increase in
      thiobarbituric acid reactive substances in the culture medium of lens epithelial
      cells after irradiation and treatment with glycated proteins. Lens proteins had a
      protective effect against UVA induced cytotoxicity, however, this protective
      effect decreased with the increasing photosensitizer activity of experimentally
      glycated proteins. The documented glycation-related photosensitization could
      explain the accelerated pathogenic changes in human lens at advanced age and
      under diabetic conditions.

PMID- 12607817
TI  - Measurement of ascorbic acid (vitamin C) induced hydroxyl radical generation in
      household drinking water.
AB  - Ascorbic acid (vitamin C) induced hydroxyl radical formation was measured in
      household drinking water samples using the hydroxyl radical sensitive probe
      coumarin-3-carboxylic acid. Vitamin C, a reducing agent that is commonly used as
      a food additive, triggered a significant hydroxyl radical generating reaction
      when added to the tap-water samples tested. The capacity of ascorbic acid to
      trigger hydroxyl radical formation in the tap-water samples was dependent on the
      flushing time before the samples were taken indicating that the water in the
      copper piping had been contaminated by copper ions. In line with this, high
      concentrations of copper were measured in the hydroxyl radical generating first
      draw samples. Moreover, a strong correlation was found between the hydroxyl
      radical generation capacity seen in the coumarin-3-carboxylic acid based
      microplate assay and the DNA damage seen in an agarose gel assay using the
      pBluescript plasmid. In the water samples showing high capacity to hydroxylate
      coumarin-3-carboxylic acid, a rapid formation of the open circular form of the
      plasmid could also be seen indicating a copper assisted hydroxyl radical attack
      on the DNA. In conclusion, our results show that addition of vitamin C to
      household tap water that is contaminated with copper ions, results in Fenton type
      reactions that continuously generate harmful and reactive hydroxyl radicals.

PMID- 12607816
TI  - Prevention of peroxynitrite-induced renal injury through modulation of
      peroxynitrite production by the Chinese prescription Wen-Pi-Tang.
AB  - The effect of Wen-Pi-Tang extract on renal injury induced by peroxynitrite (ONOO
      ) production was investigated using rats subjected to intravenous
      lipopolysaccharide (LPS) injection and then renal ischemia followed by
      reperfusion. The plasma level of 3-nitrotyrosine, a marker of cytotoxic ONOO
      formation in vivo, was enhanced markedly in control rats subjected to LPS plus
      ischemia-reperfusion, but was significantly reduced by the oral administration of
      Wen-Pi-Tang extract, at doses of 62.5 and 125 mg/kg body weight/day, for 30 days
      prior to LPS plus ischemia-reperfusion. The activities of inducible nitric oxide
      synthase (iNOS) and xanthine oxidase (XOD) in renal tissue of control and Wen-Pi
      Tang extract-treated rats did not change significantly, while those of the
      antioxidant enzymes, superoxide dismutase, catalase and glutathione peroxidase,
      were significantly increased by the administration of Wen-Pi-Tang extract,
      indicating that Wen-Pi-Tang improved the defense system by scavenging free
      radicals, not by directly inhibiting nitric oxide and superoxide production by
      iNOS and XOD. In addition, the levels of the hydroxylated products, m- and p
      tyrosine, declined, whereas that of phenylalanine increased, after oral
      administration of Wen-Pi-Tang extract. Furthermore, the elevated plasma urea
      nitrogen and creatinine levels resulting from LPS plus ischemia-reperfusion
      process were significantly reduced by Wen-Pi-Tang extract, implying amelioration
      of renal impairment. The present study indicates that Wen-Pi-Tang extract
      contributes to the regulation of ONOO- formation and plays a beneficial role
      against ONOO(-) -induced oxidative injury and renal dysfunction in vivo.

PMID- 12607818
TI  - Influences of different stress models on the antioxidant status and lipid
      peroxidation in rat erythrocytes.
AB  - The aim of this study was to investigate the influences of different stress
      models on the antioxidant status and lipid peroxidation (LPO) in erythrocytes of
      rats. Swiss-Albino female rats (3 months old) were used in this study. Rats were
      randomly divided into the following four groups; control group (C), cold stress
      group (CS), immobilization stress group (IS) and cold + immobilization stress
      group (CS + IS). Control group was kept in an animal laboratory (22 +/- 2 degrees
      C). Rats in CS group were placed in cold room (5 degrees C) for 15min/day for 15
      days. Rats in IS group were immobilized for 180 min/day for 15 days. Rats in CS +
      IS group were exposed to both cold and immobilization stresses for 15 days. At
      the end of experimental periods, the activities of glucose-6-phosphate
      dehydrogenase (G-6-PD), Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase (CAT)
      and glutathione peroxidase (GSH-Px), and concentration of reduced glutathione
      (GSH) were measured. LPO was determined by measuring the contents of
      thiobarbituric acid-reactive substances (TBARS). Cu,Zn-SOD activity and TBARS
      concentration were increased after cold and immobilization stresses, but CAT and
      GSH-Px activities and GSH levels were decreased. Immobilization stress decreased
      the activity of G-6-PD. The activities of G-6-PD, CAT and GSH-Px, and the level
      of GSH were lower in CS + IS group than in the control group. Cu,Zn-SOD activity
      and TBARS levels were increased in CS + IS group when compared with the control
      group. From these findings, three stress models are thought to cause oxidative
      stress.

PMID- 12607820
TI  - Pharmacology, genomics, and the evolutionary biology of ageing.
AB  - Aging is a multifold process affected by many genes and thus many biochemical
      pathways. This conclusion is underscored by the failure to find simple central
      controls for the aging process during the 20th Century. This situation poses a
      fundamental challenge to anti-aging medicine: how to develop effective therapies
      for a genomically complex pathology. We propose such a strategy. As a first step,
      we recommend the use of model systems in which significant genetic intervention
      is not proscribed or impractical. Second, we propose that work with such model
      systems begin with selected lines that have genetic enhancements that allow
      increased lifespan. Third, genomic methods should be used to identify a number of
      biochemical pathways for increasing lifespan. Fourth, biochemical pathways that
      have been identified in model systems would then be available for pharmaceutical
      development, first in rodents, eventually in a clinical human population. This
      may seem to be a cumbersome R&D strategy, but starting with human populations or
      inadequately pre-screened compounds would be unlikely to succeed because of the
      complexity of the aging problem.

PMID- 12607819
TI  - 2,3,7,8-tetrachlorobenzo-p-dioxin inhibits proliferation of SK-N-SH human
      neuronal cells through decreased production of reactive oxygen species.
AB  - Oxidative stress has been known to be involved in the mechanism of toxic effects
      of various agents on many cellular systems. In this study we investigated the
      role of reactive oxygen species (ROS) in 2,3,7,8-tetrachlorodibenzo-p-dioxin
      (TCDD)-induced neuronal cell toxicity using SK-N-SH human neuroblastoma cells.
      TCDD inhibited proliferation of the cells in a dose-dependent manner, which was
      revealed by MTT staining, counting of cells stained with trypan blue and
      [3H]thymidine uptake assay. TCDD also suppressed the basal generation of ROS in a
      time- and concentration-dependent manner assessed by 2',7'-dichlorofluorescein
      fluorescence. In addition, TCDD induced a dose-dependent inhibition of lipid
      peroxidation, a biomarker of oxidative stress, whereas it significantly increased
      the level of glutathione (GSH), an intracellular free radical scavenger in the
      cells. Moreover, TCDD altered the activities of major antioxidant enzymes;
      increase in superoxide dismutase (SOD) and catalase, but decrease in glutathione
      peroxidase (GSH-Px) and glutathione reductase (GSH-Red). Pretreatment with L
      buthionine-S,R-sulfoximine (BSO, 50 microM), an inhibitor of GSH synthesis,
      significantly prevented the TCDD-induced reduction in lipid peroxidation and cell
      proliferation. Interestingly, exogenous application of an oxidant, H2O2 (50
      microM) markedly restored the inhibited cell proliferation induced by TCDD. Taken
      together, these results suggest that alteration of cellular redox balance may
      mediate the TCDD-induced inhibition of proliferation in human neuronal cells.

PMID- 12607821
TI  - Clinical trials testing cardiovascular benefits of antioxidant supplementation.
AB  - Self-selected supplementation of vitamin E has been associated with reduced
      coronary events and atherosclerotic progression, but the evidence from clinical
      trials is controversial. ASAP was a 6-year randomized trial to study the effect
      of supplementation with vitamin E plus slow-release vitamin C on carotid
      atherosclerotic progression in 520 hypercholesterolemic men and women aged 45-69
      years. The supplementation reduced the progression of carotid atherosclerosis by
      26% (P = 0.014), by 33% (P = 0.024) in men and 14% (not significant) in women.
      The effect was larger in subjects with low baseline vitamin C or atherosclerotic
      plaques. In the Harvard IVUS trial, the combined supplementation with vitamins E
      and C significantly inhibited the progression of coronary atherosclerosis in one
      year. These data confirm that the supplementation with a combination of vitamins
      E and C can retard atherosclerotic progression. The findings of completed trials
      testing the effect on cardiovascular events are less consistent. The major on
      going clinical trials include the SU.VI.MAX, WHS, WACS and WAVE studies. These
      involve in total over 80,000 subjects, who are treated with antioxidative
      supplements for years. The results of these studies will become available during
      2003-2006. They may provide the necessary additional information concerning the
      effect of antioxidants on cardiovascular events.

PMID- 12607823
TI  - Atherosclerosis, oxidation and endometriosis.
AB  - Endometriosis affects younger women of childbearing age. Atherosclerosis is
      considered as a disease of the old and increases with the ageing process. Both
      diseases are characterized by the increased presence of activated macrophages and
      associated increases in growth promoting activity and the production of
      inflammatory cytokines. In this review, we propose that oxidative stress and the
      presence of forms of oxidized low-density lipoprotein (LDL) might contribute to
      both Atherosclerosis and Endometriosis.

PMID- 12607822
TI  - Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity:
      implications for neurodegeneration in Alzheimer's disease brain. A review.
AB  - Oxidative stress, manifested by protein oxidation, lipid peroxidation, DNA
      oxidation and 3-nitrotyrosine formation, among other indices, is observed in
      Alzheimer's disease (AD) brain. Amyloid beta-peptide (1-42) [Abeta(1-42)] may be
      central to the pathogenesis of AD. Our laboratory and others have implicated
      Abeta(1-42)-induced free radical oxidative stress in the neurodegeneration
      observed in AD brain. This paper reviews some of these studies from our
      laboratory. Recently, we showed both in-vitro and in-vivo that methionine residue
      35 (Met-35) of Abeta(1-42) was critical to its oxidative stress and neurotoxic
      properties. Because the C-terminal region of Abeta(1-42) is helical, and invoking
      the i + 4 rule of helices, we hypothesized that the carboxyl oxygen of lle-31,
      known to be within a van der Waals distance of the S atom of Met-35, would
      interact with the latter. This interaction could alter the susceptibility for
      oxidation of Met-35, i.e. free radical formation. Consistent with this
      hypothesis, substitution of lle-31 by the helix-breaking amino acid, proline,
      completely abrogated the oxidative stress and neurotoxic properties of Abeta(1
      42). Removal of the Met-35 residue from the lipid bilayer by substitution of the
      negatively charged Asp for Gly-37 abrogated oxidative stress and neurotoxic
      properties of Abeta(1-42). The free radical scavenger vitamin E prevented A(beta
      (1-42)-induced ROS formation, protein oxidation, lipid peroxidation, and
      neurotoxicity in hippocampal neurons, consistent with our model for Abeta
      associated free radical oxidative stress induced neurodegeneration in AD. ApoE,
      allele 4, is a risk factor for AD. Synaptosomes from apoE knock-out mice are more
      vulnerable to Abeta-induced oxidative stress (protein oxidation, lipid
      peroxidation, and ROS generation) than are those from wild-type mice. We also
      studied synaptosomes from allele-specific human apoE knock-in mice. Brain
      membranes from human apoE4 mice have greater vulnerability to Abeta(1-42)-induced
      oxidative stress than brain membranes from apoE2 or E3, assessed by the same
      indices, consistent with the notion of a coupling of the oxidative environment in
      AD brain and increased risk of developing this disorder. Using
      immunoprecipitation of proteins from AD and control brain obtained no longer than
      4h PMI, selective oxidized proteins were identified in the AD brain. Creatine
      kinase (CK) and beta-actin have increased carbonyl groups, an index of protein
      oxidation, and Glt-1, the principal glutamate transporter, has increased binding
      of the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE). Abeta inhibits CK
      and causes lipid peroxidation, leading to HNE formation. Implications of these
      findings relate to decreased energy utilization, altered assembly of cytoskeletal
      proteins, and increased excitotoxicity to neurons by glutamate, all reported for
      AD. Other oxidatively modified proteins have been identified in AD brain by
      proteomics analysis, and these oxidatively-modified proteins may be related to
      increased excitotoxicity (glutamine synthetase), aberrant proteasomal degradation
      of damaged or aggregated proteins (ubiquitin C-terminal hydrolase L-1), altered
      energy production (alpha-enolase), and diminished growth cone elongation and
      directionality (dihydropyrimindase-related protein 2). Taken together, these
      studies outlined above suggest that Met-35 is key to the oxidative stress and
      neurotoxic properties of Abeta(1-42) and may help explain the apoE allele
      dependence on risk for AD, some of the functional and structural alterations in
      AD brain, and strongly support a causative role of Abeta(1-42)-induced oxidative
      stress and neurodegeneration in AD.

PMID- 12607824
TI  - Melatonin, longevity and health in the aged: an assessment.
AB  - This brief review considers the potential role of melatonin in the processes of
      aging, the prolongation of life span and health in the aged. Studies completed to
      date generally suggest that exogenously administered melatonin may serve to
      extend life span in invertebrates, but evidence supporting this conclusion in
      mammals is less compelling. Thus, any conclusion regarding a role for melatonin
      in extending normal longevity, particularly in mammals, would be premature. With
      regard to deferring the signs of chemically-induced neurodegenerative conditions
      in experimental animals, the data are remarkably strong and there is a modicum of
      evidence that in humans with debilitating diseases melatonin may have some
      beneficial actions. Indeed, this should be one focus of future research since as
      the number of elderly increases in the population, the frequency of costly age
      related diseases will become increasingly burdensome to both the patient and to
      society as a whole.

PMID- 12607825
TI  - Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha
      tocopherol therapy.
AB  - The diabetic state confers an increased propensity to accelerated atherogenesis.
      In addition to the established risk factors, there is evidence for increased
      oxidative stress and inflammation in diabetes. Increased oxidative stress is
      manifested by increased lipid peroxidation (e.g. increased F2-isoprostanes) and
      increased DNA damage. Evidence for increased inflammation includes increased
      monocyte superoxide and pro-inflammatory cytokine release (IL-1, IL-6, and TNF
      alpha), increased monocyte adhesion to endothelium and increased levels of plasma
      C-reactive protein, the prototypic marker of inflammation. Most importantly,
      alpha tocopherol therapy, especially at high doses, clearly shows a benefit with
      regards to LDL oxidation, isoprostanes and a decrease in inflammatory markers
      such as C-reactive protein, pro-inflammatory cytokines and PAI-1 levels. Thus, it
      appears that, in diabetes, alpha tocopherol therapy could emerge as an additional
      therapeutic modality.

PMID- 12607826
TI  - Optimal marker placement in photogrammetry patient positioning system.
AB  - A photogrammetry-based patient positioning system has been used instead of the
      conventional laser alignment technique for patient set-up in external beam
      radiotherapy. It tracks skin affixed reflective markers with multiple infrared
      cameras. The three-dimensional (3D) positions of the markers provide reference
      information to determine the treatment plan isocenter location and hence provide
      the ability to position the lesion at the isocenter of the treatment linear
      accelerator. However, in current clinical practice for lung or liver lesion
      treatments, fiducial markers are usually randomly affixed onto the patients'
      chest and abdomen, so that the actual target registration error (TRE) of the
      internal lesions inside the body may be large, depending on the fiducial
      registration error (FRE). There exists an optimal marker configuration that can
      minimize the TRE. In this paper, we developed methods to design the patient
      specific optimal configurations of the surface makers to minimize the TRE, given
      the patient's surface contour, the lesion position and the FRE. Floating genetic
      algorithm (GA) optimization was used to optimize the positions of the skin
      markers. The surface curve of the patient body was determined by an automatic
      segmentation algorithm from the planning CT. The method was evaluated using a
      body phantom implanted with a metal ball (a simulated target). By registering two
      CT scans using the surface markers and measuring the displacement of the target,
      the TRE was measured. The TRE was also measured by taking two orthogonal portal
      films after positioning the phantom using the photogrammetry based patient
      positioning system. A 50% reduction in TRE has been achieved by using the optimal
      configuration compared to the random configuration. This result demonstrates that
      the optimization of a fiducial configuration can result in improved tumor
      targeting ability.

PMID- 12607827
TI  - Physical aspects of dynamic stereotactic radiosurgery with very small photon
      beams (1.5 and 3 mm in diameter).
AB  - Stereotactic radiosurgery is often used for treating functional disorders. For
      some of these disorders, the size of the target can be on the order of a
      millimeter and the radiation dose required for treatment on the order of 80 Gy.
      The very small radiation field and high prescribed dose present a difficult
      challenge in beam calibration, dose distribution calculation, and dose delivery.
      In this work the dose distribution for dynamic stereotactic radiosurgery, carried
      out with 1.5 and 3 mm circular fields, was studied. A 10 MV beam from a Clinac-18
      linac (Varian, Palo Alto, CA) was used as the radiation source. The BEAM/EGS4
      Monte Carlo code was used to model the treatment head of the machine along with
      the small-field collimators. The models were validated with the EGSnrc code,
      first through a calculation of percent depth doses (PDD) and dose profiles in a
      water phantom for the two small stationary circular beams and then through a
      comparison of the calculated with measured PDD and profile data. The three
      dimensional (3-D) dose distributions for the dynamic rotation with the two small
      radiosurgical fields were calculated in a spherical water phantom using a
      modified version of the fast XVMC Monte Carlo code and the validated models of
      the machine. The dose distributions in a horizontal plane at the isocenter of the
      linac were measured with low-speed radiographic film. The maximum sizes of the
      Monte Carlo-calculated 50% isodose surfaces in this horizontal plane were 2.3 mm
      for the 1.5 mm diameter beam and 3.8 mm for the 3 mm diameter beam. The maximum
      discrepancies between the 50% isodose surface on the film and the 50% Monte Carlo
      calculated isodose surfaces were 0.3 mm for both the 1.5 and 3 mm beams. In
      addition, the displacement of the delivered dose distributions with respect to
      the laser-defined isocenter of the machine was studied. The results showed that
      dynamic radiosurgery with very small beams has a potential for clinical use.

PMID- 12607829
TI  - A global method based on thin-plate splines for correction of geometric
      distortion: an application to fluoroscopic images.
AB  - Quantitative analysis of biomedical images needs a careful correction of
      geometric distortion. To avoid the discontinuities of the local correction
      techniques and achieve good accuracy in the presence of global and local
      distortion, a novel global correction technique based on thin-plate splines is
      proposed. The technique approximates the grid points by a thin plate minimizing
      the weighted sum of the bending energy and the mean squared residual errors. The
      method proposed is compared with three traditional correction techniques: two
      local and one global. One local technique is linear and takes into account
      translation, rotation, and scaling, the other is nonlinear and includes skewing.
      The global technique is based on a two-dimensional polynomial model. Computer
      based simulations and experimental tests on fluoroscopic images were carried out.
      The local techniques were sensitive to both sigmoidal and radial distortion. The
      polynomial and thin-plate splines global techniques were found sensitive only to
      sigmoidal distortion and to radial distortion, respectively. The two global
      techniques showed better performances with respect to any local on synthetic and
      real images. Where the distortion is predominantly radial or high computational
      efficiency is required, the polynomial global correction technique should be
      preferred. Where the distortion has a local nature or is predominantly sigmoidal,
      the thin-plate splines global correction technique should be chosen.

PMID- 12607828
TI  - Comparison of ionization chambers of various volumes for IMRT absolute dose
      verification.
AB  - IMRT plans are usually verified by phantom measurements: dose distributions are
      measured using film and the absolute dose using an ionization chamber. The
      measured and calculated doses are compared and planned MUs are modified if
      necessary. To achieve a conformal dose distribution, IMRT fields are composed of
      small subfields, or "beamlets." The size of beamlets is on the order of 1 x 1
      cm2. Therefore, small chambers with sensitive volumes < or = 0.1 cm3 are
      generally used for absolute dose verification. A dosimetry system consisting of
      an electrometer, an ion chamber, and connecting cables may exhibit charge
      leakage. Since chamber sensitivity is proportional to volume, the effect of
      leakage on the measured charge is relatively greater for small chambers.
      Furthermore, the charge contribution from beamlets located at significant
      distances from the point of measurement may be below the small chambers threshold
      and hence not detected. On the other hand, large (0.6 cm3) chambers used for the
      dosimetry of conventional external fields are quite sensitive. Since these
      chambers are long, the electron fluence through them may not be uniform
      ("temporal" uniformity may not exist in the chamber volume). However, the
      cumulative, or "spatial" fluence distribution (as indicated by calculated IMRT
      dose distribution) may become uniform at the chamber location when the delivery
      of all IMRT fields is completed. Under the condition of "spatial" fluence
      uniformity, the charge collected by the large chamber may accurately represent
      the absolute dose delivered by IMRT to the point of measurement. In this work,
      0.6, 0.125, and 0.009 cm3 chambers were used for the absolute dose verification
      for tomographic and step-and-shoot IMRT plans. With the largest, 0.6 cm3 chamber,
      the measured dose was equal to calculated within 0.5%, when no leakage
      corrections were made. Without leakage corrections, the error of measurement with
      a 0.125 cm3 chamber was 2.6% (tomographic IMRT) and 1.5% (step-and-shoot IMRT).
      When doses measured by a 0.125 cm3 chamber were corrected for leakage, the
      difference between the calculated and measured doses reduced to 0.5%. Leakage
      corrected doses obtained with the 0.009 cm3 chamber were within 1.5%-1.7% of
      calculated doses. Without leakage corrections, the measurement error was 16%
      (tomographic IMRT) and 7% (step-and-shoot IMRT).

PMID- 12607830
TI  - Dosimetry study of Re-188 liquid balloon for intravascular brachytherapy using
      polymer gel dosimeters and laser-beam optical CT scanner.
AB  - Angioplasty balloons inflated with a solution of the beta-emitter Re-188 have
      been used for intravascular brachytherapy to prevent restenosis. Coronary stents
      are in extensive clinical use for the treatment of de novo atherosclerotic
      stenoses. In this study, the effect of an interposed stent on the dose
      distribution has been measured for Re-188 balloon sources using the proprietary
      BANG polymer gel dosimeters and He-Ne laser-beam optical CT scanner. In polymer
      gels, after ionizing radiation is absorbed, free-radical chain-polymerization of
      soluble acrylic monomers occurs to form an insoluble polymer. The BANG polymer
      gel dosimeters used in these measurements allow high resolution, precise, and
      accurate three-dimensional determination of dosimetry from a given source. Re-188
      liquid balloons, with or without an interposed metallic stent, were positioned
      inside thin walled tubes placed in such a polymer dosimeter to deliver a
      prescribed dose (e.g., 15 Gy at 0.5 mm). After removing the balloon source, each
      irradiated sample was mounted in the optical scanner for scanning, utilizing a
      single compressed He-Ne laser beam and a single photodiode. In the absence of a
      stent, doses at points along the balloon axis, at radial distance 0.5 mm from the
      balloon surface and at least 2.5 mm from the balloon ends, are within 90% of the
      maximum dose. This uniformity of axial dose is independent of the balloon
      diameter and length. Dose rate and dose uniformity for intravascular
      brachytherapy with Re-188 balloon are altered by the presence of stent. The dose
      reduction by the stent is rather constant (13%-15%) at different radial
      distances. However, dose inhomogeneity caused by the stent decreases rapidly with
      radial distance.

PMID- 12607831
TI  - Commissioning, evaluation, quality assurance and clinical application of a
      virtual micro MLC technique.
AB  - Multileaf collimators (MLCs) are a valuable tool in modern radiation therapy,
      offering flexible and convenient field shaping. One disadvantage, however, is the
      undulation of the dose distribution at the edge shaped by the leaves due to the
      finite leaf width. An attempt to reduce the effect of this undulation is the
      objective of the commercial linear accelerator package HD270, which incorporates
      three-dimensional couch translation together with leaf adjustment to emulate
      finer leaf widths. In this paper we report on the commissioning and evaluation of
      this feature, together with the development of a process for quality assurance,
      as well as description of a clinical application of this technique. It is
      concluded that this technique could be applied reliably to situations currently
      utilizing MLC for shielding, with little added cost in treatment time, provided
      that a comprehensive quality assurance program is in place to monitor the
      performance of this complicated procedure.

PMID- 12607832
TI  - Dose verification of an IMRT treatment planning system with the BEAM EGS4-based
      Monte Carlo code.
AB  - Intensity modulated radiation therapy (IMRT) has been increasingly used in
      radiotherapy departments during the last several years. A major advantage of IMRT
      in comparison to traditional three-dimensional conformal radiotherapy is the
      higher capability in providing dose distributions that conform very tightly to
      the target even for very complex shapes such as, for instance, concave regions.
      This results in a significant sparing of adjacent normal tissues. Different types
      of algorithms are employed in the IMRT dose calculation, from the simple pencil
      beam method, such as the finite-size pencil beam algorithm, to the more
      sophisticated algorithms, such as the kernel-based convolution/superposition
      ones. With the latter ones, electronic disequilibrium and inhomogeneities are
      better dealt with in comparison to the correction-based models like pencil beam.
      Nevertheless, even these types of algorithms may have some approximations that
      can potentially affect the dose results, especially considering that in an IMRT
      plan small segments or beamlets may be present for which electronic
      disequilibrium and inhomogeneities effects are of paramount importance. The goal
      of this work was to determine the accuracy in monitor units (MU) and dose
      distribution calculation of the algorithm implemented in the commercial treatment
      planning system PINNACLE3 (P3), for two IMRT plans with 6 MV photon beams. This
      system is based on a convolution/superposition with the Collapsed Cone
      approximation algorithm. The "BEAM" Monte Carlo (MC) code was employed as a
      benchmark in comparing the MU calculation and the dose distribution of P3. The
      model used to calculate the MU, with the separation of collimator scatter from
      the phantom scatter, valid for broad beams, was verified for narrow and irregular
      segments. The attention was focused on the way P3 calculates output factors (OF).
      A difference of 8% compared to MC was found for a particularly narrow segment
      analyzed. A dependence of the results on field size was found. For the complete
      plan, the agreement of dose distribution and MU calculation with MC results
      (affected by a dose uncertainty less than 0.5%) is very good: the dose difference
      at isocenter is 2.1% (1 standard deviation) for a "Prostate" site and 2.9% (1
      standard deviation) for the "Head and Neck" site.

PMID- 12607833
TI  - Topology-based orientation analysis of trabecular bone networks.
AB  - After bone mineral density, orientation is the major determinant of trabecular
      bone strength and is thus of significant interest in understanding the clinical
      implications of osteoporotic bone loss. The methods used to measure orientation
      and anisotropy of the trabecular bone have largely relied on deriving global
      measures along test lines, computing the best-fit ellipsoid, and decomposing to
      eigenvalue-eigenvector pairs that yield the mean orientation and anisotropy of
      the region. These techniques ignore the differences between measuring the
      orientation of trabecular plates versus rods, and do not provide insight into the
      relationship between local orientation and biomechanical stresses. Digital
      topological analysis allows a unique determination of each voxel's topological
      class as belonging to a plate, rod, or junction. The digital topology-based
      orientation analysis (DTA-O) method extracts the voxels belonging to plates and
      determines the local surface normal by fitting a plane through the local
      neighborhood BVF map. Modeling regional distributions of these vectors allows
      assessment of anisotropy measures, such as mean and variance of the orientation
      distribution. High-resolution microcomputed tomography, synthetic, and in vivo
      images were used for a validation of the new method and compare the results with
      the mean intercept length (MIL) technique. The results indicate that DTA-O is a
      better measure of trabecular orientation and anisotropy than MIL. Applying DTA-O
      to a recently completed study on the distal radius of 82 subjects [F.W. Wehrli et
      al., J. Bone Min. Res. 16, 1520 (2001)] shows that the mean orientation and
      anisotropy at the medial and lateral sides in the distal radius mataphyseal
      trabecular network are consistent with the mechanical stresses acting on the
      radius during common tasks.

PMID- 12607834
TI  - Analytical models for multi-slice helical CT performance parameters.
AB  - One of the most recent technological advancements in computed tomography (CT) is
      the introduction of multi-slice CT (MSCT). When combined with the helical scan
      mode, MSCT offers significant improvements in volume coverage, isotropic spatial
      resolution, and contrast utilization. Although experimental studies have been
      conducted on MSCT performance, there is a lack of theoretical analysis on the
      slice sensitivity profile (SSP) and noise performance. In this paper, we derive
      several closed-form expressions, for linear interpolation based helical
      reconstruction algorithms, to characterize these performance parameters under
      different detector configurations and acquisition modes. Following the common
      practice, the expressions are explicitly described for regions near the iso
      center, although the same approach can be used to describe system performances
      away from the iso-center. These models are validated against phantom experiments.

PMID- 12607835
TI  - Calculations for plane-parallel ion chambers in 60Co beams using the EGSnrc Monte
      Carlo code.
AB  - The EGSnrc Monte Carlo simulation system is used to obtain, for 10 plane-parallel
      ionization chambers in 60Co beams, the correction factors Kcomp and Pwall that
      account for the nonequivalence of the chamber wall material to the buildup cap
      and the phantom material, respectively. A more robust calculation method has been
      used compared to that used in previous works. A minor conceptual error related to
      the axial nonuniformity correction factor, Kan, has been identified and shown to
      have an effect of about 0.2%. The assumption that Pwall in-phantom is numerically
      equal to Kcomp calculated for a water buildup cap is shown to be accurate to
      better than 0.06%, thereby justifying the use of Kcomp calculations which are
      much more efficient. The effect on the calculated dose to the air in the cavity
      of the particle production threshold and transport energies used in the
      simulations is studied. Uncertainties in the calculated correction factors due to
      uncertainties in the photon and electron cross-section data are studied. They are
      0.14% and 0.24%, respectively (1 standard deviation), for Kcomp factors. The
      uncertainties on Kwall factors are 0.03% from photon cross-section uncertainties
      and negligible from electron cross-section uncertainties. A comparison with
      previous EGS4/PRESTA calculations shows that present results are systematically
      higher by an average of 0.8%, ranging from 0.4% up to 1.4%. The present results
      are in better agreement with reported experimental values.

PMID- 12607836
TI  - Quantitative evaluation of noise reduction strategies in dual-energy imaging.
AB  - In this paper we describe a quantitative evaluation of the performance of three
      dual-energy noise reduction algorithms: Kalender's correlated noise reduction
      (KCNR), noise clipping (NOC), and edge-predictive adaptive smoothing (EPAS).
      These algorithms were compared to a simple smoothing filter approach, using the
      variance and noise power spectrum measurements of the residual noise in dual
      energy images acquired with an a-Si TFT flat-panel x-ray detector. An estimate of
      the true noise was made through a new method with subpixel accuracy by
      subtracting an individual image from an ensemble average image. The results
      indicate that in the lung regions of the tissue image, all three algorithms
      reduced the noise by similar percentages at high spatial frequencies (KCNR=88%,
      NOC=88%, EPAS=84%, NOC/KCNR=88%) and somewhat less at low spatial frequencies
      (KCNR=45%, NOC=54%, EPAS=52%, NOC/KCNR=55%). At low frequencies, the presence of
      edge artifacts from KCNR made the performance worse, thus NOC or NOC combined
      with KCNR performed best. At high frequencies, KCNR performed best in the bone
      image, yet NOC performed best in the tissue image. Noise reduction strategies in
      dual-energy imaging can be effective and should focus on blending various
      algorithms depending on anatomical locations.

PMID- 12607837
TI  - Physical aspects of yttrium-90 microsphere therapy for nonresectable hepatic
      tumors.
AB  - Administration of yttrium-90 microspheres via the hepatic artery is an attractive
      approach to selectively deliver therapeutic doses of radiation to liver
      malignancies. This procedure allows delivering radiation absorbed doses in excess
      of 100 Gy to the tumors without significant liver toxicity. The microsphere
      therapy involves different specialties including medical oncology, radiation
      oncology, nuclear medicine, interventional radiology, medical physics, and
      radiation safety. We have treated 80 patients with nonresectable hepatic tumors
      with yttrium-90 microspheres during the past two years on an institutional study
      protocol. The nominal radiation absorbed dose to the tumor in this study was 150
      Gy. Required activity was calculated based on the nominal radiation absorbed dose
      and patient's liver volume obtained from the CT scan, assuming a uniform
      distribution of the microspheres within the liver. Microspheres were administered
      via a catheter placed into the hepatic artery. The actual radiation absorbed
      doses to tumors and normal liver tissue were calculated retrospectively based on
      the patient's 99mTc-MAA study and CT scans. As expected, the activity uptake
      within the liver was found to be highly nonuniform and multifold tumor to
      nontumor uptake was observed. A partition model was used to calculate the
      radiation absorbed dose within each region. For a typical patient the calculated
      radiation absorbed doses to the tumor and liver were 402 and 118 Gy,
      respectively. The radiation safety procedure involves confinement of the source
      and proper disposal of the contaminated materials. The average exposure rates at
      1 m from the patients and on contact just anterior to the liver were 6 and 135
      uSv/h, respectively. The special physics and dosimetry protocol developed for
      this procedure is presented.

PMID- 12607838
TI  - Efficient center-line extraction for quantification of vessels in confocal
      microscopy images.
AB  - In this paper we present a novel method for the three-dimensional (3-D)
      centerline extraction of elongated objects such as vessels. This method combines
      the basic ideas in distance transform-based, thinning, and path planning methods
      to extract thin and connected centerlines. This efficient approach needs no user
      interaction or any prior knowledge of the object shape. We used the path planning
      approach, which has exclusively been used in the virtual endoscopy or robotics,
      to obtain the medial curve of the objects. To make our approach fully automated,
      a distance transform mapping is used to identify the end points of the object
      branches. The initial paths are also constructed on the surface of the object,
      traversing the same distance map. Then a thinning algorithm centralizes the
      paths. The proposed approach is especially efficient for centerline extraction of
      the complex branching structures. The method has been applied on the confocal
      microscopy images of rat brains and the results confirm its efficiency in
      extracting the medial curve of vessels, essential for the computation of
      quantitative parameters.

PMID- 12607839
TI  - Automated melanoma detection: multispectral imaging and neural network approach
      for classification.
AB  - Our aim in the present research is to investigate the diagnostic performance of
      artificial neural networks (ANNs) applied to multispectral images of cutaneous
      pigmented skin lesions as well as to compare this approach to a standard
      traditional linear classification method, such as discriminant function analysis.
      This study involves a series of 534 patients with 573 cutaneous pigmented lesions
      (132 melanomas and 441 nonmelanoma lesions). Each lesion was analyzed by a
      telespectrophotometric system (TS) in vivo, before surgery. The system is able to
      acquire a set of 17 images at selected wavelengths from 400 to 1040 nm. For each
      wavelength, five lesion descriptors were extracted, related to the criteria of
      the ABCD (for asymmetry, border, color, and dimension) clinical guide for
      melanoma diagnosis. These variables were first reduced in dimension by the use of
      factor analysis techniques and then used as input data in an ANN. Multivariate
      discriminant analysis (MDA) was also performed on the same dataset. The whole
      dataset was split into two independent groups: i.e., train (the first 400 cases,
      95 melanomas) and verification set (last 173 cases, 37 melanomas). Factor
      analysis was able to summarize the data structure into ten variables, accounting
      for at least 90% of the original parameters variance. After proper training, the
      ANN was able to classify the population with 80% sensitivity, 72% specificity,
      and 78% sensitivity, 76% specificity for the train and validation set,
      respectively. Following ROC analysis, area under curve (AUC) was 0.852 (train)
      and 0.847 (verify). Sensitivity and specificity values obtained by the standard
      discriminant analysis classifier resulted in a figure of 80% sensitivity, 60%
      specificity and 76% sensitivity, 57% specificity for the train and validation
      set, respectively. AUC for MDA was 0.810 and 0.764 for the train and verify set,
      respectively. Classification results were significantly different between the two
      methods both for diagnostic scores and model stability, which was worse for MDA.

PMID- 12607840
TI  - Automatic needle segmentation in three-dimensional ultrasound images using two
      orthogonal two-dimensional image projections.
AB  - In this paper, we describe an algorithm to segment a needle from a three
      dimensional (3D) ultrasound image by using two orthogonal two-dimensional (2D)
      image projections. Not only is the needle more conspicuous in a projected (volume
      rendered) image, but its direction in 3D lies in the plane defined by the
      projection direction and the needle direction in the projected 2D image. Hence,
      using two such projections, the 3D vector describing the needle direction lies
      along the intersection of the two corresponding planes. Thus, the task of 3D
      needle segmentation is reduced to two 2D needle segmentations. For improved
      accuracy and robustness, we use orthogonal projection directions (both orthogonal
      to a given a priori estimate of the needle direction), and use volume cropping
      and Gaussian transfer functions to remove complex background from the 2D
      projection images. To evaluate our algorithm, we tested it with 3D ultrasound
      images of agar and turkey breast phantoms. Using a 500 MHz personal computer
      equipped with a commercial volume-rendering card, we found that our 3D needle
      segmentation algorithm performed in near real time (about 10 fps) with a root
      mean-square accuracy in needle length and endpoint coordinates of better than 0.8
      mm, and about 0.5 mm on average, for needles lengths in the 3D image from 4.0 mm
      to 36.7 mm.

PMID- 12607841
TI  - Three-dimensional diffuse optical tomography in the parallel plane transmission
      geometry: evaluation of a hybrid frequency domain/continuous wave clinical system
      for breast imaging.
AB  - Three-dimensional diffuse optical tomography (DOT) of breast requires large data
      sets for even modest resolution (1 cm). We present a hybrid DOT system that
      combines a limited number of frequency domain (FD) measurements with a large set
      of continuous wave (cw) measurements. The FD measurements are used to
      quantitatively determine tissue averaged absorption and scattering coefficients.
      The larger cw data sets (10(5) measurements) collected with a lens coupled CCD,
      permit 3D DOT reconstructions of a 1-liter tissue volume. To address the
      computational complexity of large data sets and 3D volumes we employ finite
      difference based reconstructions computed in parallel. Tissue phantom
      measurements evaluate imaging performance. The tests include the following: point
      spread function measures of resolution, characterization of the size and contrast
      of single objects, field of view measurements and spectral characterization of
      constituent concentrations. We also report in vivo measurements. Average tissue
      optical properties of a healthy breast are used to deduce oxy- and deoxy
      hemoglobin concentrations. Differential imaging with a tumor simulating target
      adhered to the surface of a healthy breast evaluates the influence of physiologic
      fluctuations on image noise. This tomography system provides robust,
      quantitative, full 3D image reconstructions with the advantages of high data
      throughput, single detector-tissue coupling path, and large (1L) imaging domains.
      In addition, we find that point spread function measurements provide a useful and
      comprehensive representation of system performance.

PMID- 12607842
TI  - Conditioning data for calculation of the modulation transfer function.
AB  - A method for conditioning data used in the measurement of the modulation transfer
      function (MTF) is discussed. This method is based upon imposing the constraint
      that the edge spread function (ESF) is monotonic. The advantages of this
      technique, when applicable, are demonstrated with simulated examples for which
      the true MTF is known. The application of this technique in the measurement of
      the MTF of a digital detector in clinical use is also demonstrated.

PMID- 12607843
TI  - Imaging performance of amorphous selenium based flat-panel detectors for digital
      mammography: characterization of a small area prototype detector.
AB  - Our work is to investigate and understand the factors affecting the imaging
      performance of amorphous selenium (a-Se) flat-panel detectors for digital
      mammography. Both theoretical and experimental methods were developed to
      investigate the spatial frequency dependent detective quantum efficiency [DQE(f)]
      of a-Se flat-panel detectors for digital mammography. Since the K edge of a-Se is
      12.66 keV and within the energy range of a mammographic spectrum, a theoretical
      model was developed based on cascaded linear system analysis with parallel
      processes to take into account the effect of K fluorescence on the modulation
      transfer function (MTF), noise power spectrum (NPS), and DQE(f) of the detector.
      This model was used to understand the performance of a small-area prototype
      detector with 85 microm pixel size. The presampling MTF, NPS, and DQE(f) of the
      prototype were measured, and compared to the theoretical calculation of the
      model. The calculation showed that K fluorescence accounted for a 15% reduction
      in the MTF at the Nyquist frequency (fNy) of the prototype detector, and the NPS
      at fNy was reduced to 89% of that at zero spatial frequency. The measurement of
      presampling MTF of the prototype detector revealed an additional source of
      blurring, which was attributed to charge trapping in the blocking layer at the
      interface between a-Se and the active matrix. This introduced a drop in both
      presampling MTF and NPS at high spatial frequency, and reduced aliasing in the
      NPS. As a result, the DQE(f) of the prototype detector at fNy approached 40% of
      that at zero spatial frequency. The measured and calculated DQE(f) using the
      linear system model have reasonable agreement, indicating that the factors
      controlling image quality in a-Se based mammographic detectors are fully
      understood, and the model can be used to further optimize detector imaging
      performance.

PMID- 12607844
TI  - Magnetic fields with photon beams: planar-current-induced magnetic fields.
AB  - Strong transverse magnetic fields can produce very large dose enhancements and
      reductions in localized regions of a patient under irradiation by a photon beam.
      In this work we consider planar-current-induced magnetic fields ("PCIMFs")
      generated by arbitrary electric currents in one or two parallel planes, and pose
      two questions: how much arbitrariness is there in specifying a PCIMF, and how can
      we solve the "inverse problem" of determining the current distribution which
      generates a chosen PCIMF? We have completely answered both questions, and have
      applied the general formulas which we have developed to the case of cylindrical
      symmetry, giving a concrete example of our method. The present work provides the
      theoretical tools for designing PCIMFs, but a great deal of systematic research
      will be required in order to understand and design magnetic fields which produce
      desired distributions of dose enhancement and dose reduction in photon beams
      treating patients.

PMID- 12607845
TI  - Reference values are de facto regulatory limits for patient exposures. For the
      proposition.

PMID- 12607846
TI  - Reference values are de facto regulatory limits for patient exposures. Against
      the propostion.

PMID- 12607847
TI  - More precisely defined dose distributions are unlikely to affect cancer
      mortality.

PMID- 12607848
TI  - Want to transition your practice?

PMID- 12607849
TI  - Mandibular symphyseal distraction osteogenesis: diagnosis and treatment planning
      considerations.
AB  - Treatment planning decisions in the transverse dimension have historically been
      based on the presenting mandibular arch width and form. Distraction osteogenesis
      (DO), originally developed by Russian orthopedic surgeon Ilizarov, has produced
      significant results in limb lengthening. Mandibular symphyseal DO was introduced
      by Guerrero, providing a new paradigm for patients whose treatment alternatives
      and results were previously limited. Orthodontic and surgical techniques and
      principles will be shown using completed and current cases.

PMID- 12607850
TI  - Study of stress distribution and displacement of various craniofacial structures
      following application of transverse orthopedic forces--a three-dimensional FEM
      study.
AB  - The purpose of this study was to analyze the stress distribution patterns within
      the craniofacial complex during rapid maxillary expansion. Therefore, a finite
      element model of a young human skull was generated using data from computerized
      tomographic scans of a dried skull. The model was then strained to a state of
      maxillary expansion simulating the clinical situation. The three-dimensional
      pattern of displacement and stress distribution was then analyzed. Maximum
      lateral displacement was 5.313 mm at the region of upper central incisors. The
      inferior parts of the pterygoid plates were also markedly displaced laterally.
      But there was minimum displacement of the pterygoid plates approximating the
      cranial base. Maximum forward displacement was 1.077 mm and was seen at the
      region of the anteroinferior border of the nasal septum. In the vertical plane,
      the midline structures experienced a downward displacement. Even the ANS and
      point A moved downward. The findings of this study provide some additional
      explanation of the concept of correlation between the areas of increased cellular
      activity and the areas of dissipation of heavy orthopedic forces. Therefore, the
      reason for the occurrence of sensation of pressure at various craniofacial
      regions, reported by the patients undergoing maxillary expansion could be
      correlated to areas of high concentration of stresses as seen in this study.
      Additionally, the expansive forces are not restricted to the intermaxillary
      suture alone but are also distributed to the sphenoid and zygomatic bones and
      other associated structures.

PMID- 12607851
TI  - Morphometric analysis of the transverse dentoskeletal features of class II
      malocclusion in the mixed dentition.
AB  - The aim of the present study was to evaluate the dentoskeletal features of Class
      II malocclusion in the transverse plane by means of a morphometric analysis (thin
      plate spline analysis [TPS]) applied to posteroanterior cephalograms. A sample of
      49 subjects (24 males, 25 females; mean age 7 years, 9 +/- 5 months) with Class
      II Division 1 malocclusion was compared with a control group of 50 subjects (17
      males, 33 females; mean age 8 years, 4 +/- 3 months) with Class I occlusion.
      Subjects of both groups were in the mixed dentition and had no history of
      orthodontic treatment. Average craniofacial configurations were subjected to TPS
      analysis to compare the differences in shape between the two groups. The results
      of the present study showed that subjects with Class II malocclusion exhibited
      significant shape differences in craniofacial configuration in the frontal plane
      when compared with subjects with normal occlusion; these differences mainly
      consisted of a contraction of the maxilla at both the skeletal and the
      dentoalveolar levels and a narrowing of the base of the nose. The reduction in
      maxillary dentoskeletal width was associated with an increase in the vertical
      height of the maxilla.

PMID- 12607852
TI  - Skeletal changes of maxillary protraction in patients exhibiting skeletal class
      III malocclusion: a comparison of three skeletal maturation groups.
AB  - This cephalometric study evaluated skeletal and dentoalveolar changes produced by
      rapid maxillary expansion and facial mask therapy in 85 subjects exhibiting a
      Class III malocclusion with a retruded maxilla. The skeletal maturity of
      individual patients was assessed on the basis of Fishman's skeletal maturity
      indicator (SMI), using hand-wrist radiographs at the initiation of treatment, to
      determine the relationship between the effect of maxillary protraction and
      skeletal age. Patients were divided into three groups: prepubertal growth peak
      group (SMI 1-3), pubertal growth peak group (SMI 4-7), and postpubertal growth
      peak group (SMI 8-11). The major findings of this cephalometric study were as
      follows: (1) there was no difference in the effects of maxillary advancement
      after maxillary protraction between the prepubertal growth peak and the pubertal
      growth peak group, but there was a decrease in the postpubertal growth peak
      group; (2) in the postpubertal growth peak group, there was a decrease in
      maxillary skeletal advancement, whereas the dentoalveolar effect was increased;
      (3) the posteroinferior rotation of mandible, the increase of lower facial
      height, and the eruption of maxillary molars showed no correlation with skeletal
      age. The results of our study emphasize the importance of performing a biologic
      evaluation of skeletal maturity and pubertal growth peak in individual patients
      in the diagnosis and treatment planning of Class III malocclusions.

PMID- 12607853
TI  - Effects of extraction and nonextraction treatment on class I and class II
      subjects.
AB  - This study aims to examine the profile as well as the dentoalveolar and skeletal
      effects of extraction or nonextraction treatment in a wide range of patients
      including Class I and Class II, division 1 cases. Results achieved with
      extraction and nonextraction modalities have also been compared. The study was
      performed on pretreatment and posttreatment lateral cephalograms of 87
      orthodontic patients. There were no significant differences between the
      pretreatment values of extraction and nonextraction Class I groups, whereas SN
      GoGn (degrees), maxillary incisor to A-Po (degrees), mandibular incisor to A-Po
      (mm), Co-Gn (mm), overjet (mm), and overbite (mm) measurements of extraction
      Class II group were significantly higher before the treatment. After treatment,
      these differences were eliminated in the Class II group; however, incisors were
      significantly protruded in both nonextraction groups. No other differences in
      profile or lip position were found between the extraction and nonextraction
      groups. The results of this study indicate that in successfully treated cases,
      whether by extraction or nonextraction, the same soft and hard tissue profile
      posttreatment end points were reached except for the incisor positioning, which
      is rather easier to anticipate than profile and soft tissue changes. The simple
      statement that extraction means a more retrusive or dished-in profile seems to be
      unacceptable. It seems that a more thorough assessment and investigation
      including pretreatment extent of crowding and factors related to anchorage, soft
      tissue thickness, and strain should be carried out.

PMID- 12607854
TI  - Occupational stress among Canadian orthodontists.
AB  - The occupational stress associated with many professions, including general
      dentistry, has been well researched. An anonymous, self-administered, mail-out
      survey was distributed to Canadian orthodontists. The survey included 67
      potential stressors, an overall occupational stress score, an overall job
      satisfaction scale, and items addressing various characteristics of the
      respondents. The response rate was 51.2% (335/654). Pronounced differences were
      found between the respondents in the evaluation of potential stressors and the
      overall occupational stress score. The category of stressors with the highest
      mean severity of stress scores was time-related stressors. The stressors with
      high mean severity scores and high mean frequency scores were as follows: falling
      behind schedule, trying to keep to a schedule, constant time pressures, patients
      with broken appliances, and motivating patients with poor OH and/or
      decalcification. Stepwise multiple regression determined a model, involving
      overall job satisfaction, age, participation in a study group, hours worked per
      week, part-time academics, days of continuing education per year, and
      participation in stress management, to account for 35.9% of the variation in
      overall occupational stress scores. The results indicate the importance of time
      management skills in reducing occupational stress, but other factors seem to have
      more effect on reported occupational stress than do the characteristics addressed
      by this survey.

PMID- 12607855
TI  - Do failed appointments lead to discontinuation of orthodontic treatment?
AB  - A retrospective case note study was performed on 500 consecutive patients
      attending an orthodontic clinic. The total number of appointments and number of
      failed appointments was ascertained. The outcome of treatment was recorded as one
      of five categories: default before treatment, 46 (9.2%); still under treatment,
      42 (8.4%); transferred elsewhere, 9 (1.8%); default during treatment, 88 (17.6%);
      or completed treatment, 315 (63.0%). Using a chi-square test, the 315 patients
      who completed treatment were compared with the 88 who defaulted during treatment.
      The total number of appointments was significantly fewer, but the number of
      failed appointments was significantly greater in the discontinued treatment
      groups. The standardized failure rate (total number of failed appointments /
      total number of appointments x 100) was used to compensate for the difference in
      the total number of appointments between the groups. The mean standardized
      failure rate was only 10.3% for the completed treatment group compared with 21.4%
      for the discontinued treatment group.

PMID- 12607856
TI  - Bond strength of orthodontic brackets using different light and self-curing
      cements.
AB  - The purpose of the study was to evaluate the shear bond strength of stainless
      steel orthodontic brackets directly bonded to extracted human premolar teeth.
      Fifty teeth were randomly divided into five groups: (1) System One (chemically
      cured composite resin), (2) Light Bond (light-cured composite resin), (3)
      Vivaglass Cem (self-curing glass ionomer cement), (4) Fuji Ortho LC (light-cured
      glass ionomer cement) used after 37% orthophosphoric acid-etching of enamel (5)
      Fuji Ortho LC without orthophosphoric acid-etching. The brackets were placed on
      the buccal and lingual surfaces of each tooth, and the specimens were stored in
      distilled water (24 hours) at 37 degrees C and thermocycled. Teeth were mounted
      on acrylic block frames, and brackets were debonded using an Instron machine.
      Shear bond strength values at fracture (Nw) were recorded. ANOVA and Student
      Newman-Keuls multiple comparison tests were performed (P < .05). Bonding failure
      site was recorded by stereomicroscope and analyzed by Chi-square test, selected
      specimens of each group were observed by scanning electron microscope. System One
      attained the highest bond strength. Light Bond and Fuji Ortho LC, when using an
      acid-etching technique, obtained bond strengths that were within the range of
      estimated bond strength values for successful clinical bonding. Fuji Ortho LC and
      Vivaglass Cem left an almost clean enamel surface after debracketing.

PMID- 12607857
TI  - Effect of self-etching primers on bond strength--are they reliable?
AB  - Currently introduced self-etching primers combine conditioning and priming agents
      into a single product. The purpose of this study was to determine the effects of
      using three self-etching primers on the shear bond strength (SBS) of orthodontic
      brackets and on the bracket/adhesive failure mode. Brackets were bonded to
      extracted human teeth according to one of four protocols. In the control group,
      teeth were etched with 37% phosphoric acid. In the experimental groups, the
      enamel was conditioned with three different self-etching primers, Clearfil SE
      Bond (CSE), Etch & Prime 3.0 (EP3), or Transbond Plus (TBP), as suggested by the
      manufacturer. The brackets were then bonded with Transbond XT in all groups. The
      present in vitro findings indicate that conditioning with TBP before bonding
      orthodontic brackets to the enamel surface resulted in a significantly (P < or =
      .001) higher SBS (mean, 16.0 +/- 4.5 MPa) than that found in CSE, EP3, and the
      control (acid-etched [AE]) groups. CSE produced bond strength values (mean 11.5
      +/- 3.3 MPa) that are statistically comparable to those produced by acid etching
      (mean 13.1 +/- 3.1 MPa). The use of EP3 for enamel conditioning resulted in the
      lowest mean SBS value (mean 9.9 +/- 4.0 MPa). A comparison of the adhesive
      remnant index scores indicated that there was more residual adhesive remaining on
      the teeth that were treated with conventional acid etching than in the CSE and
      EP3 groups. In the TBP group, the failure sites were similar to those of the AE
      group but different from those of the CSE group.

PMID- 12607859
TI  - Temporomandibular joint morphology changes with mandibular advancement surgery
      and rigid internal fixation: a systematic literature review.
AB  - The purpose of this systematic review was to evaluate the effect of bilateral
      sagittal split mandibular osteotomy (BSSO) with rigid internal fixation (RIF) on
      temporomandibular joint (TMJ) morphology. Controlled trials of BSSO with RIF
      treatment of Class II patients using transcranial radiographs, submental vertex
      (SMV) radiographs, tomographic radiography, computed tomography (CT) scan, or
      magnetic resonance imaging (MRI) to assess TMJ morphology were identified by
      Medline (1966-2001) and PubMed. Case reports were excluded. On the basis of our
      search only six studies were included in this review. All studies used internal
      controls with pre- and posttreatment imaging. Two studies used SMV, one used
      transcranial radiographs, one used tomography, two used CT scan and one used MRI.
      Methodological deficiencies prevent major conclusions regarding osseous
      remodeling and disk status. There was a wide range of individual variability in
      condyle position change. The reviewed studies have highlighted the importance of
      further research. Prospective controlled studies using serial MRI and tomography
      or CT scan are required to establish effect of BSSO with RIF on TMJ morphology.

PMID- 12607858
TI  - Comparison of skeletal and dental morphology in asymptomatic volunteers and
      symptomatic patients with bilateral degenerative joint disease.
AB  - The purpose of this study was to evaluate the effect of bilateral degenerative
      joint disease (BDJD) on the skeletal and dental patterns of affected individuals.
      There were 29 symptomatic female patients and 46 asymptomatic normal female
      volunteers. All study participants had bilateral high-resolution magnetic
      resonance scans in the sagittal (closed and open) and coronal (closed) planes to
      evaluate the temporomandibular joints. Linear and angular cephalometric
      measurements were taken to evaluate the skeletal, denture base and dental
      characteristics of the two groups. Analysis of variance was used to compare
      symptomatic subjects with control subjects. There was an overall retrusion of the
      maxilla and mandible with a clockwise mandibular rotation. The upper and lower
      denture bases were retruded. The upper incisor was more protruded, whereas the
      lower incisor was more retroclined in the symptomatic group. The overjet was also
      increased. This study suggests that subjects with BDJD may manifest altered
      craniofacial morphology. Clinicians should be aware of this possibility,
      especially for patients who are growing children and orthognathic surgery
      candidates.

PMID- 12607860
TI  - Optimum force magnitude for orthodontic tooth movement: a systematic literature
      review.
AB  - The aim of this study was to perform a meta-analysis of the literature concerning
      the optimal force or range of forces for orthodontic tooth movement. Over 400
      articles both on human research and animal experiments were found in Medline and
      by hand searching of main orthodontic and dental journals. Articles on animal
      experiments were in the majority. A wide range of animal species such as rat,
      cat, rabbit, beagle dog, monkey, mouse, and guinea pig were used. Besides
      variation in species, there was also a wide range of force magnitudes, teeth
      under study, directions of tooth movement, duration of experimental period, and
      force reactivation. Furthermore, hardly any experiments were reported that
      provide information on the relation between the velocity of tooth movement and
      the magnitude of the applied force. Data from human research on the efficiency of
      orthodontic tooth movement appeared to be very limited. The large variation in
      data from current literature made it impossible to perform a meta-analysis.
      Therefore, we have systematically reviewed the literature. It appeared that no
      evidence about the optimal force level in orthodontics could be extracted from
      literature. Well-controlled clinical studies and more standardized animal
      experiments in the orthodontic field are required to provide more insight into
      the relation between the applied force and the rate of tooth movement.

PMID- 12607861
TI  - Use of a tip-edge stage-1 wire to enhance vertical control during straight wire
      treatment: two case reports.
AB  - Vertical control is one of the problems occasionally encountered in Straight wire
      treatment. Two cases, one with deep overbite and one with anterior open-bite,
      demonstrate the use of a Tip-Edge stage-1 wire to enhance vertical control in
      conjunction with Straight wire brackets and superelastic main arch wires.

PMID- 12607862
TI  - Gamma probe-guided lymph node dissection ('gamma picking') in differentiated
      thyroid carcinoma.
AB  - The prognostic significance and the optimal management of regional lymph node
      metastases in patients with well-differentiated thyroid carcinoma continue to be
      controversial. The current surgical approach for nodal metastases is removal of
      grossly involved lymph nodes ("berry picking"). In patients with papillary
      thyroid cancer, this intraoperative sampling technique reveals tumor in only 15%
      to 60% of excised nodes. However, if a more extensive nodal dissection is
      undertaken, at least 70% of patients are found to have nodal disease. The authors
      have successfully used a gamma probe-guided lymph node dissection technique
      ("gamma picking") to identify visually undetectable micrometastatic lymph nodes
      at the time of surgical exploration. The authors used this technique in a 52-year
      old man with papillary carcinoma of the thyroid that was diagnosed by fine-needle
      aspiration. Eighteen hours before the planned total thyroidectomy, the patient
      was given 1 mCi I-123 orally. Operative exploration revealed multiple tumor
      nodules in both lobes but no palpable lymph nodes in the neck. Total
      thyroidectomy was performed with complete extracapsular removal of both lobes and
      isthmus. The thyroid bed and the central and lateral nodal basins were scanned
      using a gamma probe (Neoprobe). Hot spots were identified, and these counts were
      compared with that of the background activity in the strap muscles. The gamma
      probe revealed four distinct foci of increased activity (10 times more than the
      background). These were resected and labeled separately for histopathologic
      study. Histologic analysis revealed bilateral, multifocal well-differentiated
      papillary carcinoma, with the largest tumor focus measuring 0.6 cm. Two of the
      four hot spots proved to be metastatic foci in small lymph nodes measuring less
      than 0.5 cm. The other two hot spots were thyroid remnants with no associated
      nodal tissue.

PMID- 12607863
TI  - Benign cervical thymoma masquerading as a malignant thyroid nodule.
AB  - A thymoma in the neck region is a rare diagnosis involving a solitary neck nodule
      that moves with deglutition and is contiguous with the thyroid gland. The authors
      report an unusual case of a thymoma that accumulated both Tc-99m pertechnetate
      and Tc-99m MIBI. This is probably the first reported case of a benign neck
      thymoma concentrating these two radiopharmaceuticals. Thymoma should be added to
      the gamut of false-positive findings in the neck for thyroidal (with Tc-99m
      pertechnetate) and malignant (with Tc-99m MIBI) tissue.

PMID- 12607864
TI  - The use of sestamibi imaging in parathyroid hyperplasia.
AB  - The authors describe a 42-year-old man with parathyroid hyperplasia secondary to
      chronic renal failure. Parathyroidectomy was indicated because of persistent
      hypercalcemia and an increasing parathyroid hormone level despite medical
      management. A parathyroid sestamibi scan was performed immediately before
      operation and a gamma-detecting probe was used during operation. Six parathyroid
      glands weighing nearly 21 g were present. Without the use of the gamma-detecting
      probe during operation, one of the glands would have been missed. The efficacy of
      sestamibi scanning with parathyroid hyperplasia is discussed.

PMID- 12607865
TI  - Primary diagnosis of multiple pheochromocytomas in the brother of a MEN-2 patient
      by simultaneous MIBG scintigraphy and low-dose computed tomography.
AB  - Metaiodobenzylguanidine (MIBG) scintigraphy is a well-established functional
      imaging method for localizing pheochromocytomas. However, the morphologic
      information revealed on the scintigram is often too sparse and thus, accordingly,
      supplemental computed tomography (CT) or magnetic resonance imaging are often
      performed. Recently, gamma cameras with built-in low-dose CT were introduced. The
      authors describe a patient with a high likelihood of pheochromocytoma who had
      simultaneous MIBG scintigraphy and low-dose CT performed as the primary
      examinations. The scan revealed pheochromocytomas in both adrenal glands and one
      extra-adrenal pheochromocytoma located in the liver. The combined imaging ensured
      the final diagnosis without any need for further imaging. Based on the findings
      of this case, the authors believe that combined MIBG scintigraphy and low-dose CT
      is a promising future single imaging technique for pheochromocytomas.

PMID- 12607866
TI  - Functional assessment of the right ventricle with gated myocardial perfusion
      SPECT.
AB  - BACKGROUND: The evaluation of right ventricular function can provide valuable
      information in a variety of cardiac and noncardiac conditions. Functional
      assessment of the right ventricle is difficult because of its anatomy and
      geometry. The authors describe a method for assessing right ventricular function
      using gated myocardial perfusion SPECT. METHODS: In 20 patients, right and left
      ventricular ejection fractions (RVEF, LVEF) were determined using gated blood
      pool scintigraphy (GBPS) and gated myocardial perfusion SPECT (GSPECT). To avoid
      contamination with right atrial activity, the two-frame method was adopted for
      gated blood-pool data when RVEF was measured. In nine patients with normal right
      ventricles, an index of wall thickening for the right ventricle was derived from
      the peak systolic and diastolic counts in the free wall. RESULTS: Linear
      correlation between the two methods adopted for calculation of LVEF and RVEF was
      good. Bland-Altman analysis revealed good agreement between the two methods with
      no specific bias. The mean LVEF was 47.9 +/- 12% (GBPS) and 47.3 +/- 12.4
      (GSPECT). The mean RVEF was 43.2 +/- 9.6% (GBPS) and 44.2 +/- 8.5% (GSPECT). In
      both cases, the values were not significantly different. The mean wall motion
      index was 35%. There was no correlation between the wall thickness index and
      ejection fraction, but the index was greater in patients with a normal right
      ventricle compared with those with reduced RVEF. CONCLUSIONS: Gated SPECT offers
      an alternative to GBPS for the functional assessment of the right ventricle.
      Using GSPECT will allow the simultaneous assessment of both the right and left
      ventricles.

PMID- 12607867
TI  - The role of renal scintigraphy in renal arteriovenous malformation treated by
      transcatheter arterial embolization.
AB  - A 41-year-old woman was hospitalized because of gross hematuria. She was found to
      have a renal arteriovenous malformation and was treated with transcatheter
      arterial embolization (TAE). Renal scintigraphy with Tc-99m
      mercaptoacetyltriglycine was performed before and after TAE. Renal scintigraphy
      was useful for evaluating renal function in this patient.

PMID- 12607868
TI  - Migration of Tc-99m DTPA from the cerebral ventricle to the subarachnoid space.
AB  - A 70-year-old woman was examined because of increasing problems with cognition.
      She had a history of a cerebral shunt placed surgically 10 years previously.
      Introduction of Tc-99m DTPA directly into the ventricular cavity revealed good
      ventricular distribution, followed by progression downward, as though into a
      previous ventriculoperitoneal shunt. However, a chest radiograph revealed what
      appeared to be a shunt tube in the right atrium. Delayed lateral images showed
      activity in proximity to the vertebral column, indicating migration of tracer and
      cerebrospinal fluid into the dorsal and lumbar subarachnoid space.

PMID- 12607869
TI  - Detection of rhabdomyolysis associated with compartment syndrome by bone
      scintigraphy.

PMID- 12607870
TI  - Tc-99m HMPAO white blood cell SPECT of an enterovesical fistula complicating
      Crohn's disease.

PMID- 12607871
TI  - A clinical conundrum solved with indium-111 white blood cell scanning.

PMID- 12607872
TI  - Imaging of bone to skin sinus tract from osteomyelitis of the femur by Tc-99m
      HMPAO leukocyte scintigraphy.

PMID- 12607873
TI  - Supernumerary parathyroid tissue hidden by high uptake in the submandibular
      gland.

PMID- 12607874
TI  - I-123 imaging after recombinant human thyroid-stimulating hormone to diagnose
      metastatic disease in an intubated patient with papillary thyroid cancer.

PMID- 12607875
TI  - Retention of iodine-131 in a thoracic esophageal diverticulum mimicking
      metastatic thyroid cancer.

PMID- 12607876
TI  - Misleading Ga-67 uptake in a patient with Hodgkin's disease, mediastinal
      deviation, and pulmonary compression.

PMID- 12607877
TI  - Ga-67 scintigraphy in multicentric Castleman's disease.

PMID- 12607878
TI  - Added value of attenuation-corrected myocardial perfusion scintigraphy in a
      patient with dextrocardia.

PMID- 12607879
TI  - Diaphragmatic paralysis with an elevated hemidiaphragm masquerading as lung
      carcinoma found during myocardial perfusion imaging.

PMID- 12607880
TI  - Lymphoscintigraphy in a patient with polyserositis of unknown origin.

PMID- 12607881
TI  - Spontaneously resolving lymphocele demonstrated on serial renal dynamic
      scintigraphy.

PMID- 12607882
TI  - Sentinel lymph node navigation surgery in Paget's disease of the vulva.

PMID- 12607883
TI  - A dual-energy X-ray absorptiometry artifact and potential pitfall: the
      nonremovable umbilical ring.

PMID- 12607884
TI  - Scintigraphic findings in Gorlin's syndrome.

PMID- 12607885
TI  - Bilateral symmetrically increased Tc-99m MDP cranial uptake in Hurler syndrome.

PMID- 12607886
TI  - Incidental detection of a falx meningioma on post-therapy radioiodide whole-body
      imaging.

PMID- 12607887
TI  - Evaluation of brain perfusion using Tc-99m HMPAO in a patient with a persistent
      vegetative neurologic state and a left ventricular thrombus.

PMID- 12607889
TI  - Positron emission tomographic imaging of Merkel cell carcinoma.

PMID- 12607888
TI  - Ventral hernia resulting in increased fluorodeoxyglucose uptake on positron
      emission tomographic imaging.

PMID- 12607890
TI  - Primary malignant peritoneal mesothelioma: appearance on F-18 FDG positron
      emission tomographic images.

PMID- 12607891
TI  - Entry of urine from a transplanted kidney into the scrotum.

PMID- 12607892
TI  - Scintigraphic visualization of renal fusion anomalies in a possible abdominal
      mass.

PMID- 12607894
TI  - Unusual hepatic visualization after esophageal scintigraphy.

PMID- 12607893
TI  - Severe bladder distortion mimics bone metastasis from pelvic rhabdomyosarcoma.

PMID- 12607896
TI  - Current readings in nuclear medicine.

PMID- 12607895
TI  - Demonstration on Tl-201 scan of a pelvic lymph node metastasis from prostate
      cancer after radical prostatectomy.

PMID- 12607897
TI  - Tobacco: a medical history.

PMID- 12607898
TI  - Infant sleep position and SIDS: a hospital-based interventional study.
AB  - CONTEXT: Avoidance of the prone sleeping position is considered an important
      factor contributing to the decline in the incidence of sudden infant death
      syndrome (SIDS). OBJECTIVES: To determine infant sleep positioning practices and
      SIDS awareness before and after a hospital-based Back to Sleep campaign. DESIGN:
      A questionnaire-based, descriptive, and cross-sectional before-after trial.
      SETTING: The pediatric outpatient department of an inner-city hospital in
      Brooklyn, New York. SUBJECTS: Two consecutive samples of 250 mothers of healthy
      infants younger than 6 months old born in and attending the outpatient clinics of
      the hospital before and after the intervention. INTERVENTION AND MAIN OUTCOME
      MEASURES: Specific policies promoting Back to Sleep were established in our
      newborn nursery and outpatient department. Reduction in prone infant sleep
      positioning was the primary outcome measure. Increased parental SIDS awareness
      was a secondary outcome. RESULTS: The proportion of infants sleeping prone was
      reduced significantly (from 27% to 18%) after the intervention (P < .005). Among
      the mothers who chose the prone sleeping position for their infants, 49.6%
      worried about choking. Older mothers (> 22 years) responded to the intervention
      by a 45.6% reduction in prone placement (P < .005) as opposed to a 11.4%
      reduction among younger mothers (< 22 years) (P = ns). Other factors contributing
      to reduced prone positioning included marriage (adjusted odds ratio [OR] 0.57;
      95% confidence interval [CI] 0.93, 0.34) and breast feeding (adjusted OR 0.66;
      95% CI 1.1, 0.4). SIDS awareness was 79.6% and 82.4% in the preintervention and
      postintervention groups, respectively (P = ns). CONCLUSIONS: The Back to Sleep
      campaign was effective in our hospital setting. Our data indicate the need for
      special targeting of young, unmarried, and non-breast-feeding mothers. Fear of
      choking remains an important deterrent to proper infant sleep positioning.

PMID- 12607900
TI  - Experiences of families that applied for government-sponsored child health
      insurance: report of a follow-up study in New York City.
AB  - CONTEXT: This study followed up on a summer 1997 advocacy project by the
      Children's Defense Fund--New York, which assisted families in New York City in
      enrolling their children in government-sponsored health insurance programs
      (Medicaid and Child Health Plus). OBJECTIVE: To determine how many participants
      from the 1997 project acquired insurance, to document their experiences during
      the application process, and to solicit their suggestions on improving the
      application process. DESIGN: Guided telephone interviews in summer 1998 with all
      families from the 1997 program that could be located. PARTICIPANTS: Fifty-five
      families from New York City that, with the assistance of the Children's Defense
      Fund--New York, applied for Medicaid or Child Health Plus in summer 1997.
      RESULTS: Of the 55 families, 46 acquired insurance for their children at some
      point during the year. A number of families changed insurance status several
      times during the year, and some insured originally through government-sponsored
      programs later acquired private insurance. The families experienced many
      difficulties in dealing with the health insurance bureaucracies. CONCLUSION: The
      process of applying for Medicaid and Child Health Plus is more difficult and time
      consuming than may be realized, and many families may go through the application
      repeatedly. Current efforts to decrease the number of uninsured children in the
      US must take into account the bureaucratic barriers faced by families that are
      eligible for these programs and must consider ways to make the application
      process less formidable.

PMID- 12607899
TI  - Scattering of primary care: doctor switching and utilization of health care by
      children on fee-for-service Medicaid.
AB  - OBJECTIVE: To determine whether children on fee-for-service Medicaid who switch
      primary care doctors use less health care and are less up to date with preventive
      care visits than children who do not switch primary care doctors. DESIGN:
      Retrospective cohort study using Medicaid claims data. SETTING: 51,027 children
      enrolled on Medicaid in Monroe County, New York. PATIENTS: 14,187 children
      enrolled continuously on fee-for-service Medicaid between January 1992 and
      December 1994. MAIN OUTCOME MEASURES: Utilization of primary care, emergency
      department (ED) services, and specialty care and proportion up to date with
      preventive care visits according to American Academy of Pediatrics guidelines.
      RESULTS: During the 2-year study period, 22% of children switched primary care
      doctors. Compared with children who did not switch primary care doctors, those
      who switched had more primary care visits (4.7 vs. 3.2 visits/year, P < .01), age
      adjusted preventive care visits (1.2 vs. 1.0 visits/year), ED visits (0.72 vs.
      0.47 visits/year, P < .01), and specialist visits (0.99 vs. 0.31, P < .01). On
      multivariate analysis, doctor switching was associated with increased odds of
      being up to date with preventive care visits (odds ratio [OR] = 1.7; 95%
      confidence interval [CI] 1.3 to 2.1). However, on multivariate analysis
      stratified by age, the association was significant only for older children (ages
      11 to 14). Altogether, 68% of all children and 44% of infants less than 1 year
      old made the recommended number of preventive care visits during the study
      period. CONCLUSIONS: All groups of children received less preventive care than
      recommended by the American Academy of Pediatrics. Children who switched primary
      care doctors had higher utilization of health care, including primary care, ED,
      and specialty care. Contrary to expectations, they were more likely to be up to
      date with preventive care visits. The heavy utilization of health services by
      doctor switchers indicates that this subgroup of children on Medicaid may not be
      at risk for poor access to health care, but additional research is needed to
      determine whether the quality of care is related to doctor switching.

PMID- 12607902
TI  - Israel's health care system: a US perspective.

PMID- 12607901
TI  - Population characteristics of markets of safety-net and non-safety-net hospitals.
AB  - RESEARCH OBJECTIVES: To compare and contrast the markets of urban safety-net
      (USN) hospitals with the markets of other urban hospitals. STUDY DESIGN: To
      develop profiles of the actual inpatient markets of hospitals, we linked 1994
      patient-level information from hospital discharge abstracts from nine states with
      1990 data at the ZIP code level from the US Census Bureau. Each hospital's market
      was characterized by its racial and ethnic composition, median household income,
      poverty rate, and educational attainment. Measures of hospital competition were
      also calculated for each hospital. The analysis compared the market profiles of
      USN hospitals to those of other urban hospitals. We also compared the level of
      hospital competition and financial status of USN and other urban hospitals.
      PRINCIPAL FINDINGS: The markets of USN hospitals had higher proportions of racial
      and ethnic minorities and non-English-speaking residents. Adults residing in
      markets of USN hospitals were less educated. Families living in markets of USN
      hospitals had lower incomes and were more likely to be living at or below the
      federal poverty level. USN hospitals and other urban hospitals faced similar
      levels of competition and had similar margins. However, USN hospitals were more
      dependent on Medicare disproportionate share payments and on state and local
      government subsidies to remain solvent. CONCLUSION: USN hospitals
      disproportionately serve vulnerable minority and low-income communities that
      otherwise face financial and cultural barriers to health care. USN hospitals are
      dependent on the public subsidies they receive from federal, state, and local
      governments. Public policies and market pressures that affect the viability of
      USN hospitals place the access to care by vulnerable populations at risk. Public
      policy that jeopardizes public subsidies places in peril the financial health of
      these institutions. As Medicare and Medicaid managed care grow, USN hospitals may
      lose these patient revenues and public subsidies based on their Medicaid and
      Medicare patient volumes. The loss of these funds would hinder the ability of USN
      hospitals to finance uncompensated care for uninsured and underinsured patients.

PMID- 12607903
TI  - A personal perspective: caring for homeless people with AIDS.

PMID- 12607904
TI  - Consolidation of municipal hospitals. 1926.

PMID- 12607905
TI  - Surveillance for diarrheal disease in New York City.
AB  - In an effort to document the occurrence of diarrheal disease more fully and to
      hasten recognition of a diarrheal disease outbreak in New York City, three
      special surveillance programs monitor nonspecific indicators of diarrheal
      disease. Twenty-six months of data from the clinical laboratory surveillance
      system are summarized to illustrate the type of data generated by these special
      surveillance programs.

PMID- 12607906
TI  - Role of proliferation in the toxicity of fumonisin B1: enhanced hepatotoxic
      response in the partially hepatectomized rat.
AB  - Fumonisin mycotoxins are common contaminants of maize and cause several fatal
      animal diseases. Liver is a target organ of fumonisins in intact animals, but
      liver slices and primary hepatocytes, which do not proliferate in culture, are
      resistant to fumonisin exposure. Hepatoma cell lines, on the other hand, undergo
      cell division in culture and are sensitive to the toxic effects of fumonisins. It
      was therefore hypothesized that fumonisin cytotoxicity is dependent on cell
      proliferation. To test this hypothesis, the partially hepatectomized rat was used
      as a model to determine whether fumonisin produced greater toxicity in rapidly
      proliferating liver in vivo. Rats were dosed intraperitoneally with fumonisin B1
      (FB1) 24 h after sham operation or partial hepatectomy (PH) and were killed 24 h
      later. The dose-related increase in free sphingoid bases (a biomarker of
      fumonisin exposure) was enhanced in the PH-treated rats. Serum cholesterol and
      enzymes were higher in PH-treated rats dosed with FB1 than in those given PH
      without FB1 or in sham-operated, FB1-dosed rats. Multiple daily doses of FB1
      after surgery elevated the number of apoptotic hepatocytes in both sham-operated
      and PH-treated rats to about the same degree, suggesting that apoptosis is not
      associated with the enhanced cytotoxicity of FB1 in regenerating liver.
      Proliferating cells appear to be more sensitive to the toxic effects of
      fumonisins. This enhanced cytotoxicity may be related to the increased ability of
      fumonisins to disrupt sphingolipid metabolism in hepatectomized rats, but this is
      yet to be determined.

PMID- 12607907
TI  - Factors involved in hepatic glutathione depletion induced by acute ethanol
      administration.
AB  - Factors implicated in changes of the hepatic glutathione concentration following
      acute ethanol administration were examined in rats. Adult female rats were
      treated with either ethanol (4 g/kg, p.o.) or an isocaloric glucose solution. The
      hepatic reduced glutathione (GSH) concentration decreased rapidly after ethanol
      intake with a maximum diminution, approximately 50% of the control value, being
      observed at t = 6 h. The hepatic GSH concentration gradually increased, and
      finally rebounded at 24 h after ethanol ingestion. The dose of ethanol induced a
      transient increase in the oxidized glutathione (GSSG)/GSH ratio, which was
      associated with a significant reduction in GSH rather than elevation in GSSG
      [corrected]. The activity of gamma-glutamylcysteine synthetase (GCS), the rate
      limiting enzyme for glutathione synthesis, and the cysteine concentration in
      liver were also measured. The GCS activity was depressed to approximately 80% of
      the control value at t = 2.5 h followed by rapid recovery, but no difference in
      the hepatic cysteine concentration between control and ethanol treated rats was
      observed for 24 h, suggesting that the reduction in glutathione synthesis may not
      play a major role in the significant depletion of this tripeptide in liver. The
      total glutathione concentration was measured both in prehepatic and posthepatic
      inferior vena cava blood. The glutathione concentration in posthepatic blood was
      approximately twice as high as that of prehepatic blood in control rats. Acute
      ethanol administration doubled the elevation of glutathione in posthepatic blood
      measured at t = 2.5 h. The sinusoidal efflux of glutathione estimated from the
      increase in blood glutathione concentration was greater than the total amount of
      its depletion in the liver of rats treated with ethanol. The results suggest that
      in the liver of rats treated acutely with ethanol, glutathione efflux plays the
      most important role in the reduction of this tripeptide, which would be
      aggravated by a transient decrease in glutathione synthesis and by increased
      consumption in association with its metabolism.

PMID- 12607908
TI  - Chlorination of drinking water and sex ratio at birth in Taiwan.
AB  - Chlorination has been the major strategy for disinfecting drinking water in
      Taiwan. The objective of the present study was to determine whether the
      chlorination of drinking water was associated with abnormal sex ratios, an
      indicator of exposure to pollutants. A "chlorinating municipality" (CHM) was
      defined as one in which more than 90% of the municipality population was served
      with chlorinated water. A "nonchlorinating municipality" (NCHM) was one in which
      less than 5% of the municipality population was served with chlorinated water.
      The results of this study found no association between the use of chlorinated
      drinking water and abnormal sex ratios at birth in Taiwan. The imbibing of
      chlorinated water may not reflect contaminant exposure using sex ratio as a
      biomonitor.

PMID- 12607909
TI  - Lung toxicity of paraquat in the rat.
AB  - In a rat model of paraquat-induced lung injury, pulmonary alveolar lavage fluid
      metabolic parameters were assessed to establish damage, and the use of surfactant
      was employed as a protective agent. Three groups of adult male Sprague-Dawley
      rats received intraperitoneal injection of paraquat (35 mg/kg body weight) in 1
      ml saline, or received 1 ml saline, or no material. On d 3, 7, 14, and 21 after
      injection, pressure-volume curves and pulmonary alveolar lavage fluids were
      obtained. On d 3 paraquat significantly increased the lung wet/dry weight ratio
      and protein content but lowered phosphatidylcholine levels. There were no marked
      changes at other time points in the parameters examined. The pressure-volume
      curves initially moved downward and to the right on d 3 and 7 and then returned
      to control levels in the paraquat-treated rats. Immediate intratracheal
      administration of Survanta after paraquat injection (70 mg/kg body weight) tended
      to increase the survival rate on d 1 compared to rats without Survanta
      administration. Our results suggest that administration of exogenous surfactant
      may play a role in the treatment of patients poisoned with paraquat.

PMID- 12607911
TI  - Violence in the workplace: guidelines for health care facilities.
AB  - For many years, health care workers have faced the risk of job-related violence,
      and the incidence of serious threat to employees continues to increase. This
      Professional Development Series document discusses the elements of an effective
      health care violence evaluation and mitigation program that are necessary to meet
      the objectives of the U.S. Department of Labor's Occupational Safety and Health
      Administration (OSHA) recommendations.  The information is designed to help
      health care employers reduce and prevent the incident of workplace violence as
      well as track the progress of their efforts.

PMID- 12607910
TI  - Toxicity evaluation of petroleum blending streams: inhalation subchronic
      toxicity/neurotoxicity study of a light catalytic reformed naphtha distillate in
      rats.
AB  - A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats
      (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D,
      CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for
      6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were
      maintained after final exposure for a 4-wk recovery period. The highest exposure
      concentration was 75% of the lower explosive limit. Standard parameters of
      subchronic toxicity were measured throughout the study; at necropsy, organs were
      weighed and tissues processed for microscopic evaluation. Neurotoxicity
      evaluations consisted of motor activity (MA) and a functional operational battery
      (FOB) measured pretest, throughout exposure and after the recovery period.
      Neuropathology was evaluated at termination. No test-related mortality or effects
      on physical signs, body weight, food consumption, or clinical chemistry were
      observed. In males exposed to 7500-ppm LCRN-D, a statistically significant
      decrease in white blood cell counts and lymphocyte counts was observed at the
      termination of exposure that was not present in animals after the 4-wk recovery
      period. However, mean corpuscular volume was slightly decreased in high-dose
      males after the recovery period. Statistically significant increases in kidney
      weights relative to body weights in 7500-ppm male rats correlated with
      microscopically observed hyaline droplet formation and renal tubule dilation,
      indicative of light hydrocarbon nephropathy, a condition in male rats that is not
      toxicologically significant for humans. Statistically significant decrease in
      absolute and relative spleen weights in 7500-ppm male rats correlated with
      decreases in hematologic parameters but had no microscopic correlate and was not
      observed in animals after 4 wk of recovery. This mild, reversible effect in white
      blood cell populations may relate to the presence of aromatics in the distillate.
      The only effect of LCRN-D on neurobehavioral parameters was significantly higher
      motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery
      period, suggesting a possible delayed effect of LCRN-D. However, there was no
      evidence of hyperactivity or abnormal behavior from the functional observational
      battery evaluations, and there were no microscopic changes in neural tissue to
      support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN
      D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed
      effects level (NOEL) was 750 ppm.

PMID- 12607913
TI  - [Drug discovery and personalized medicine based on the functional genomics].

PMID- 12607912
TI  - [Ensemble of membrane and cytoskeleton remodelings in cell migration].

PMID- 12607914
TI  - [Theoretical approach to three-dimensional structures and functionality of sugar
      chains].

PMID- 12607915
TI  - [Quality control of proteins in secretory pathway by N-glycans].

PMID- 12607916
TI  - [A novel family of proteinases: structure and function of serine-carboxyl
      proteinases].

PMID- 12607917
TI  - [Toll-like receptor signals and innate immunity].

PMID- 12607918
TI  - [Regulation of chromosomal DNA replication by CDK].

PMID- 12607920
TI  - [Child and adolescent psychiatry its problems and foresight].
AB  - Accompanying the fall in birth rate, problems pertaining to the child's mind such
      as school in attendance, bullying, violence in the school, intrafamilial
      violence, eating disorders, substance abuse, and child abuse have rocketed and
      diversified, in addition to affecting increasingly lower age groups. The
      importance of child and adolescent psychiatry has never been more profound, but
      our country, without a chair in Child and Adolescent Psychiatry in the medical
      school framework, and lacking recognition of Child and Adolescent Psychiatry as a
      clinical department has undoubtedly become an underdeveloped country in terms of
      child and adolescent psychiatric care. The medical schools have been in the
      process of review and reorganization these past few years. The range of mental
      science is wide, and despite being a major discipline constituting one of the two
      arms of medical science together with somatic medicine, it is regarded as a minor
      existence in our country. This is the time to re-establish mental science, with
      areas such as child and adolescent psychiatry, geriatric psychiatry, social
      psychiatry, and crime psychiatry placed on an equal footing with general
      psychiatry. Turning our eyes on the world, the children are being robbed of their
      mental health as refugees, through child labor, starvation, and civil war. The
      demand of this age is true symbiosis, surpassing differences in race, religion,
      language, and culture, which is probably the indispensable element in the quest
      for a happy future for the children of this age.

PMID- 12607919
TI  - [Functional diversity of the synaptotagmin family].

PMID- 12607921
TI  - Integrating mental health into primary health care in Nigeria: management of
      depression in a local government (district) area as a paradigm.
AB  - BACKGROUND: In Nigeria, the primary health care (PHC) manned by non-physician
      health workers, forms the bedrock of the health care system. And mental health
      care has not yet been integrated into primary health care system. OBJECTIVE: To
      demonstrate how the training of primary health care workers in the recognition
      and management of depression can form an example of systematic integration of
      mental health into primary health care. METHODS: The training needs and knowledge
      of 62 primary health care workers were assessed through focus group discussions
      and structured self-administered questionnaire. A two-day training program on the
      recognition and management of depression was conducted using an adapted version
      of the World Psychiatric Association (WPA) guidelines for the management of
      depression in primary health care. The trainees completed a pre and post-training
      assessments to determine the immediate outcome of the training. RESULTS: Pre
      training, the health workers had very poor knowledge of depression. None of the
      participants could mention any antidepressant. There were significant
      improvements in knowledge post training, with the greatest gain in knowledge
      occurring in drug management of depression. General outcome evaluation showed
      significant increase in knowledge and skills for the recognition and management
      of depression. CONCLUSIONS: The training increased PHC workers knowledge about
      the concept, recognition and management of depression. And the methods adopted
      could be helpful means of integrating mental health into PHC.

PMID- 12607922
TI  - [Pharmacogenomics and future antidepressant research].
AB  - Although antidepressants have been used clinically for more than 50 years, no
      consensus has been reached concerning their precise molecular mechanism of
      action. Pharmacogenomics is a powerful tool that can be used to identify genes
      affected by antidepressants or by other effective therapeutic manipulations.
      Using this tool we have previously identified more than 300 cDNA fragments as
      antidepressant-related genes. Some of these candidate genes may encode common
      functional molecules induced by chronic antidepressant treatment. Defining the
      roles of these molecules in drug-induced neural plasticity is likely to transform
      the course of research on the biological basis of antidepressants. Such detailed
      knowledge will have profound effects on the diagnosis, prevention, and treatment
      of depression. Novel biological approaches beyond the "monoamine hypothesis" are
      expected to evoke paradigm shifts in the future of antidepressant research.

PMID- 12607923
TI  - [Recent abuse of 3,4-methylenedioxymethamphetamine ("yaoto-wang", "ecstasy")].
AB  - 3,4-methylenedioxymethamphetamine ("Yaoto(head shifting)-wang", "Ecstasy"),
      designer drugs is popular world wide along with rave party, especially from the
      1980s. Although there is a significant misconception of MDMA as "a safe drug",
      recent findings show its serotonin (5-HT) selective neurotoxity with memory
      disturbance and cognitive disorders, not only during its use but lasting for
      years. Hyperinnervation of 5-HT neurons has also been reported among non-human
      primates. Serotonin syndrome, serious dehydration and acute renal failure are
      reported as serious clinical symptoms and some deaths related to the use of MDMA
      have been reported. Unlike many stimulant users, MDMA users are likely to be
      socially adapted and epidemiological research suggests that, in the United States
      and European countries, 6-8% of students and 0.5-3% of adults have experienced
      MDMA use. Although criminal cases have been reported in Japan since the 1990s,
      there has been no empirical study of MDMA abuse, especially among youth. Based on
      the "Classification of Medicine and Drugs" of the Ministry of Health, Welfare and
      Labor. MDMA is classified as "compound narcotics: hallucinogens and stimulants"
      rather than individually. Another problem is that MDMA users are likely to visit
      emergency rooms rather than psychiatric clinics. The American Psychiatric
      Association has publicized the misconception of MDMA as a safe drug and informed
      people of its dangers. The author offers suggestions for Japanese psychiatrists
      to take steps to cope with this situation and recommends authorities to establish
      an appropriate drug policy.

PMID- 12607924
TI  - [Determination of sucralose in foods by liquid chromatography/tandem mass
      spectrometry].
AB  - A simple method for the determination of sucralose in various foods using liquid
      chromatography-electrospray ionization tandem mass spectrometry (LC/MS/MS) was
      developed. Sucralose was extracted with water or methanol, and the extract was
      cleaned up on a C18 cartridge, and diluted with water for injection into the
      LC/MS/MS. The LC separation was performed with a reversed-phase gradient on an
      ODS column, and the mass spectral acquisition was done in the negative ion mode
      by applying selected reaction monitoring (SRM). The recoveries of sucralose from
      various kinds of foods fortified at 100 micrograms/g and 5 micrograms/g were 88.1
      96.7% and 92.7-98.5%, respectively. The lower limits of quantification were 0.5
      microgram/g in beverage, low-malt beer, yogurt and chocolate and 2.5 micrograms/g
      in other foods. Forty-three commercial foods containing sucralose were analyzed
      by this method. Sucralose was detected in all samples at levels of 3.8-481
      micrograms/g.

PMID- 12607925
TI  - Effect of subchronic feeding of genetically modified corn (CBH351) on immune
      system in BN rats and B10A mice.
AB  - Subchronic animal feeding studies to examine the effect on the immune system of
      genetically modified corn CBH351, which contains the Cry9C protein derived from
      Bacillus thuringiensis subspecies tolworthi, were conducted in female BN rats and
      B10A mice. The studies were designed to compare the effect of a line of
      genetically modified corn CBH351 (GM corn) with that of isoline corn (non-GM
      corn). Heat-treated corn meal was incorporated into the diets of the rats and
      mice at a concentration of 50%. The study duration was 13 weeks. Growth, food
      intake, and organ weights of the thymus, spleen, and liver were compared between
      animals fed the non-GM and GM lines. The histological findings in thymus, spleen,
      mesenteric lymph nodes, Peyer's patches, small intestines, liver, kidney, and
      bone marrow, and the presence of Cry9C-specific IgE, IgG, IgG1 and IgA antibodies
      in serum were also compared. The results showed no significant differences in
      growth, feeding value, or the histological findings in immunity-related organs
      between the animals fed the GM and non-GM lines. Production of Cry9 C-specific
      IgE and IgA was not detected in the serum of either group. Production of Cry9C
      specific IgG and IgG1 was slightly increased in the 50% GM groups of BN rats. No
      Cry9C-specific IgG or IgG1 was detected in the serum of BN rats fed the diet
      containing 5% GM-corn In conclusion, no immunotoxic activity was detected in the
      GM-corn-fed rats and mice in this subchronic dietary study.

PMID- 12607927
TI  - [Determination of sucralose in foods by HPLC using pre-column derivatization].
AB  - The development of a sensitive pre-column derivatization high-performance liquid
      chromatography (HPLC) method for determination of sucralose is reported.
      Sucralose is converted into a strongly ultraviolet (UV)-absorbing derivative,
      possessing strong absorption at 260 nm, by treatment with p-nitrobenzoyl chloride
      (PNBCl). Homogenized samples were dialyzed and washed with a Bond Elut ENV
      cartridge, then the eluate was evaporated to dryness and the residue was
      derivatized. Subsequently, the sucralose derivative was purified with hexane
      ethyl actate (9:1) in a silica cartridge, and then the sucralose derivative was
      eluted with acetone. HPLC was performed on a phenyl column, using acetonitrile
      water (73:27) as a mobile phase with UV detection (260 nm). The calibration curve
      was linear in the range of 1 microgram/mL to 50 micrograms/mL of sucralose. The
      recoveries of sucralose from eight kinds of foods spiked at the levels of 0.20
      and 0.05 g/kg of sucralose were more than 76.2% with SD values in the range from
      0.90% to 4.31%. The quantitative limit of the developed method was 0.005 g/kg for
      sucralose in samples.

PMID- 12607926
TI  - [Study on the determination of pesticide residues in crops by ion-trap GC/MS/MS].
AB  - Ion-trap GC/MS/MS was evaluated for the multi-residue determination of pesticides
      in agricultural products. Matrices were extracted from samples (spinach, carrot,
      onion and brown rice) with acetone and submitted to gel permeation
      chromatography, followed by a clean-up step through a graphite carbon cartridge.
      Thirty-five pesticides were added to either matrix, and analyzed by GC/MS/MS.
      Detection limits of pesticides by GC/MS/MS was almost the same as those by GC/MS
      (SIM). Coefficients of variation of peak area in 5 measurements of each pesticide
      at 0.1 microgram/mL or 0.05 microgram/mL with or without matrices were mostly
      acceptable, though those of 20 pesticides out of 35 were higher than 10% at a
      concentration of 0.02 microgram/mL. It was indicated that matrix artifacts, which
      interfere with GC/MS-Scan analysis, could be eliminated in some cases by using
      GC/MS/MS.

PMID- 12607928
TI  - Determination of low levels of methanol and ethanol in licorice extract by large
      volume injection head-space GC.
AB  - A large volume injection head-space GC method was established for measuring low
      levels of residual methanol and ethanol in licorice extract used a food additive.
      A vial was kept at 50 degrees C in the oven of the head-space sampler. Injection
      of the head-space gas for 0.75 min into a Poraplot Q GC column with a initial
      oven temperature of 35 degrees C, enabled the determination of low levels (5
      micrograms/g) of methanol and ethanol. The standard deviations for five rounds of
      analysis of methanol and ethanol in licorice extracts were between 0.82 and 2.97.
      Methanol was found in 6 samples out of 9 collected in 1999, at concentrations
      exceeding 50 micrograms/g, the limit set by the Japanese Government, established
      in 1999 and coming into force on April 1, 2000. The highest concentration reached
      10,000 micrograms/g. Methanol at a concentration exceeding 50 micrograms/g was
      found in 2 out of 9 samples collected in 2000. The highest concentration was 270
      micrograms/g.

PMID- 12607929
TI  - [A detection method for recombinant DNA from genetically modified potato (NewLeaf
      Y potato)].
AB  - A detection method using the polymerase chain reaction (PCR) was developed to
      detect genetically modified (GM) potato (NewLeaf Y potato; NL-Y), of which the
      mandatory assessment has not yet been completed in Japan. The potato sucrose
      synthase gene was used as an internal control. We designed a primer pair to
      specifically detect NL-Y without false-positive results in processed potato foods
      infected with the potato virus Y (PVY). The DNA introduced into NL-Y using the
      primer pair could be detected from potato powder samples containing 0.05% NL-Y.
      In addition, we designed primer pairs for recognizing the CryIIIA gene to detect
      the NewLeaf potato (NL), NewLeaf Plus potato (NL-P) and NL-Y and for recognizing
      p-FMV in order to detect NL-P and NL-Y. The proposed method was applied to the
      detection of NL-Y in 26 processed potato foods and NL-Y was not detected in any
      samples.

PMID- 12607930
TI  - [Effects of veterinary drugs on beta-hexosaminidase release from rat basophilic
      leukemia cells (RBL-2H3)].
AB  - Little is known about the effects of residual veterinary drugs on the allergic
      reaction, except for the antigenicity of antibiotics and synthetic
      antimicrobials. Therefore, 59 kinds of veterinary drugs were investigated for
      their effects on the IgE receptor-mediated beta-hexosaminidase release from RBL
      2H3 cells as an index of immediate allergic reaction. We found that the
      antibiotics chlorotetracycline, doxycycline, monensin, the synthetic
      antimicrobial pyrimethamine and the steroid hormone testosterone inhibited beta
      hexosaminidase release. Most of the veterinary drugs showed no action, though the
      ionophores lasalocid, salinomycin and the steroid hormone hexestrol promoted beta
      hexosaminidase release from injured cells. Based on the residual levels of these
      drugs and the frequencies of detection in actual food samples, it seems unlikely
      that these drugs have any immediate allergic effect in practice.

PMID- 12607932
TI  - [Current educational status of clinical toxicology in medical schools].

PMID- 12607933
TI  - [Current educational status of clinical toxicology in pharmaceutical sciences].

PMID- 12607934
TI  - [Current educational status of clinical toxicology in the school of veterinary
      medicine].

PMID- 12607935
TI  - [Current educational status of clinical toxicology in school of emergency life
      supporting technology].

PMID- 12607931
TI  - Comparison of sulfuric acid treatment and multi-layer silica gel column
      chromatography in cleanup methods for determination of PCDDs, PCDFs and dioxin
      like PCBs in foods.
AB  - Two typical cleanup methods, sulfuric acid treatment and multi-layer silica gel
      column chromatography, for the determination of polychlorinated dibenzo-p-dioxins
      (PCDDs), dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dioxin
      like PCBs) in seventeen food samples were examined and compared. Vegetables,
      fruits, cereals, fish, meat and dairy foods were extracted by conventional
      methods (shaking with acetone/n-hexane or with n-hexane after alkaline
      treatment). The extracts were cleaned up by sulfuric acid treatment or multi
      layer silica gel column chromatography, followed by several column
      chromatographic steps. Of the samples treated, the vegetable, fruit and cereal
      samples could be directly applied to the multi-layer silica gel column after
      extraction. However, the samples containing fats and oils such as fish, meat and
      dairy foods needed to be treated several times with concentrated sulfuric acid
      before multi-layer column chromatography, because these samples plugged the
      column with oily residues. Both cleanup methods gave similar values of isomeric
      concentrations and showed similar efficiency of purification, and the recoveries
      ranged from 40 to 120%. These results are considered to provide useful data for
      the efficient analysis of dioxins in foods which have wide-ranging compositions.

PMID- 12607936
TI  - [Colchicine poisoning by accidental ingestion of the bulbs of Sandersonia
      aurantiaca: report of a case].
AB  - We report a case of colchicine poisoning in an 82-year-old woman. She had
      suffered from senile dementia and in her confused state ingested two bulbs of
      Sandersonia aurantiaca (Christmas-bells, Chinese lantern lily). She was admitted
      complaining of gastrointestinal symptoms, mainly severe watery diarrhea. The
      duration of her diarrhea was approximately 40 hours. On the 3rd day after
      ingestion, leukopenia and thrombocytopenia occurred. Although 50 micrograms of
      granulocyte-colony stimulating factor was administered from the 5th day to the
      8th day, her white blood cell count did not increase and revealed nadir
      (100/microliter) on the 7th day. Her platelet count also revealed nadir on the
      7th day. She died of respiratory failure in the early morning of the 9th day. The
      bulb of Sandersonia was found to contain colchicine at a concentration of 4.7
      mg/g, and her serum level of colchicine was 6.3 ng/ml on the 6th day. Colchicine
      is an alkaroid extractable from the plants like Colchicum autumnale (meadow
      saffron, autumn crocus), and Gloriosa supra tuber. These plants belong to the
      lily family. Sandersonia aurantiaca also belongs to the lily family and we found
      that its bulb contained colchicine. To our knowledge, this is the first report of
      colchicine poisoning by Sandersonia aurantiaca.

PMID- 12607937
TI  - [A case of fatal chloropicrine poisoning induced by ingestion].
AB  - A case of fatal chloropicrine poisoning induced by suicidal ingestion was
      reported. The patient was found unconsciousness in his room with drinking about
      100 ml of chloropicrine sodium at 8:55 in the morning and brought to a nearby
      hospital. He was transported to our ER at 10:17. 7 hours after ingestion, he died
      from metabolic acidosis and acute cardiac failure. It was difficult to detect
      chloropicrine in his serum and gastric content with GC/MS method. At the present,
      we must be severe to store and use chloropicrine as there is no specific
      treatment of chloropicrine poisoning. It is necessary to protect from exposure to
      volatile agricultural chemicals such as chloropicrine for prevention of secondary
      disaster.

PMID- 12607938
TI  - [Practical analysis of toxic substances useful for clinical toxicology--4-
      Acetaminophen].

PMID- 12607939
TI  - [Studies on the experimental allergic rhinitis induced by Japanese cedar pollen-
      role of cysteinyl leukotrienes in nasal allergic symptoms].
AB  - Cysteinyl leukotrienes (CysLTs: LTC4, LTD4, and LTE4) are a family of potent
      inflammatory mediators that appear to contribute to the pathophysiologic features
      of allergic rhinitis. Because treatment with a CysLT1 receptor antagonist and a 5
      lipoxygenase inhibitor modified allergen-induced nasal blockage in patients with
      allergic rhinitis, and CysLTs were detected in nasal cavity lavage fluid, it has
      been suggested that CysLTs act as significant inflammatory mediators in allergic
      rhinitis. The role of CysLTs was evaluated in our experimental allergic rhinitis
      model in sensitized guinea pigs which shows biphasic nasal blockage, sneezing and
      nasal hyperresponsiveness to LTD4 induced by repetitive inhalation challenge with
      Japanese cedar pollen. In this model, the CysLT1 receptor antagonist pranlukast
      suppressed the late-phase nasal blockage but not early blockage and sneezing.
      Nasal hyperresponsiveness (nasal blockage) to LTD4 was largely blocked by
      pranlukast, naphazoline, and N omega-nitro-L-arginine-methyl ester. The results
      demonstrate that nasal blockage induced by CysLTs is mainly due to dilatation of
      nasal blood vessels, which can be induced by the nitric oxide produced through
      CysLT1 receptor activation. On the other hand, when pollen inhalation challenge
      was performed in the presence of nasal hyperresponsiveness, antigen-induced
      biphasic nasal blockage and sneezing were considerably enhanced and CysLTs
      contributed to both symptoms, suggesting that nasal hyperresponsiveness induces
      aggravation of antigen-induced nasal symptoms. The results presented in this
      study further suggest that our model is a good representative of human allergic
      rhinitis and offer evidence that CysLTs are chemical mediators mainly responsible
      for allergic nasal symptoms.

PMID- 12607940
TI  - Asymmetric conjugate addition of arylthiols to enoates and its application to
      organic synthesis of biologically potent compounds.
AB  - As a part of our studies aimed at asymmetric catalytic reactions by using an
      external chiral ligand, we have developed a catalytic asymmetric addition
      reaction of an arylthiol to alpha,beta-unsaturated esters under the control of an
      external chiral ligand. The characteristic of our technology is a double
      activation of a thiol by lithiation and chelate formation with a chiral
      tridentate amino diether ligand, which simultaneously and effectively controls a
      stereochemistry of the reaction. One significant feature of an arylthiol is a
      bulky 2-substitution on aryl group, which enables the formation of a really
      reactive monomeric thiolate species. s-Cis conformation and capability of
      electron lone pair-differentiating coordination of a carbonyl oxygen to lithium
      are structural requirements of the substrates for high enantioselectivity. The
      enantioselectivity came up to 97% under the cited conditions. Asymmetric
      protonation of a transient enolate, generated by conjugate addition of a lithium
      thiolate to an enoate, was also realized. The stereochemistry of the protonation
      was controlled by the conformation of initially formed transient enolate in a 1,2
      asymmetric induction manner. This technology enabled the asymmetric synthesis of
      (S)-naproxene. Stereoselective tandem C-S and C-C bond-forming reaction was
      developed as a logical extension by trapping the transient enolate intermediate
      with an aldehyde as a carbo-electrophile in the presence of
      phenylthiotrimethylsilane as an equilibrium-shift reagent. This tandem reaction
      was extended to a stereoselective cyclization of omega-oxo-alpha,beta-unsaturated
      esters initiated by a lithium thiolate. Stereoselectivity of both tandem inter-
      and intramolecular reaction is predictable by an allylic strain-controlled
      conformation model of the enolate, in which an approach of aldehyde takes place
      anti to C-S bond through coordination of an aldehyde oxygen to lithium. Total
      synthesis of (-)-neplanocin A was achieved by using the tandem cyclization as a
      key tool for the direct construction of a five-membered carbocycle where every
      carbon is functionalized.

PMID- 12607941
TI  - [Development of analytical methods for residual antibiotics and antibacterials in
      livestock products].
AB  - One of the major roles of public health agencies is to ensure safe products for
      consumers through analysis of residual antibiotics and antibacterials in
      livestock products. In this study, the analytical methods were established for
      tetracyclines (TCs), penicillins (PCs), and sulphonamides (SAs), which are widely
      used as veterinary drugs in livestock. Taking into consideration the inspection
      systems used by prefectural governments, UV-HPLC, which is commonly used in
      health centers, was selected as the determination method, and LC/MS/MS, which is
      used for highly sensitive analyses, was employed as a confirmation method. Based
      on the physicochemical features of TCs, PCs, and SAs, detailed examinations of
      the solid-phase extraction cartridge clean-up and analytical conditions were
      carried out. A simultaneous confirmation method for four types of TCs in bovine
      tissues, both the simultaneous determination method and the highly sensitive
      identification method of six types of weakly acidic PCs in bovine tissues, and
      the simultaneous determination method of SAs in animal liver and kidney were
      established. The development of the analytical method for PCs is described in
      detail in this paper. The combined use of a simple and reproducible determination
      method and the highly sensitive and precise confirmation of residual antibiotics
      and antibacterials in livestock products was successfully established for the
      inspection system. This should provide high-quality analysis and ensure safe
      product improvements.

PMID- 12607942
TI  - [Chemotherapy with hybrid liposomes without any drug in vivo].
AB  - Prolonged survival was seen in a carcinoma model in mice intraperitoneally
      inoculated with B-16 melanoma cells after the intraperitoneal treatment with
      hybrid liposomes composed of L-alpha-dimyristoylphosphatidylcholine (DMPC) and
      polyoxyethylenedodecyl ether (C12(EO)n, n = 10 and 23 respectivery) which had a
      uniform and stable structure. No drug was administered. The therapeutic effects
      of the single-component liposomes composed of lipids with a variety of
      hydrophilic head groups and different hydrophobic alkyl chains were investigated.
      Markedly prolonged survival (248%) of mice was achieved after treatment with DMPC
      liposomes. However, DMPC liposomes have the disadvantage of an unstable
      structure, requiring daily sonication. On the other hand, no life-prolonging
      effects or toxicity occurred with the administration of the other single
      component liposome employed in this study. Next, we successfully prepared stable,
      uniform liposomes composed of 90 mol% DMPC and 10 mol% C12(EO)n (n = 10 and 23,
      respectively), which have diameters of 70 nm and 100 nm, respectively.
      Interestingly, prolonged survival (173-186%) of mice was achieved after treatment
      with hybrid liposomes of 90 mol% DMPC/10 mol% C12(EO)n (n = 10 and 23). Finally,
      we conducted toxicity tests using normal rats to determine hybrid liposome
      stability. There were no abnormal findings in blood chemistry or relative organ
      weights at autopsy of normal rats after hybrid liposome administration. In
      addition, hybrid liposomes were metabolized in the liver after intravenous
      administration to normal mice. These results suggest that hybrid liposomes could
      be used as a new single chemotherapeutic agent in the treatment of carcinoma with
      no side effects.

PMID- 12607943
TI  - Effects of concomitant antiepileptic drugs on serum carbamazepine concentration
      in epileptic patients: quantitative analysis based on extracellular water volume
      as a transforming factor.
AB  - The effects of concomitant antiepileptic drugs on the serum carbamazepine
      concentration (C1) were analyzed quantitatively. Primidone (PRM), phenobarbital
      (PB), phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS), clonazepam (CZP),
      and ethosuximide (ETS) were coadministered with carbamazepine (CBZ). Routine
      therapeutic drug monitoring data, obtained from epileptic patients who were
      treated with the repetitive oral administration of CBZ fine granules/tablets,
      were used for the analysis. A total of 119 patients were administered CBZ alone,
      and 91, 39, 19, and 6 patients were coadministered one, two, three, and more than
      four different antiepileptic drugs, respectively. Using the data obtained from
      the patients administered CBZ alone, Ct could be expressed approximately as a
      function of the daily dose per extracellular water volume (D/VECW) as Ct =
      A(D/VECW)B (A, B: parameter). By comparing the regression line on log Ct vs.
      log(D/VECW) for CBZ alone with that for CBZ plus another concomitant drug, Ct was
      thus found to be affected at each definite ratio by PB and PHT, but not by VPA
      and ZNS. We postulated a model showing that Ct is affected by each concomitant
      antiepileptic drug i at each definite ratio. We defined the parameter Ri(i = 1,
      2, ..., 7) representing the effect of each concomitant antiepileptic drug on Ct.
      A linear polynomial expression, in which both members of this model are converted
      into common logarithms, was used for a multiple regression analysis. The analysis
      clarified that PB and PHT lowered Ct to 0.770 and 0.710 the value of CBZ alone,
      respectively. On the other hand, VPA and ZNS did not affect Ct. The number of
      patients coadministered PRM, CZP, and/or ETS was not sufficient to detect the
      effect on Ct based on a test of significance. In the case of the addition or
      discontinuation of concomitant antiepileptic drugs in the same patient, the
      estimated Ct values were calculated using the value of each Ri and compared with
      the measured Ct values. Both values were in good agreement, and thus our results
      appear valid.

PMID- 12607944
TI  - [Effects of chronic alcohol administration on changes of extracellular dopamine
      and serotonin concentration induced by methamphetamine--comparison of two
      different alcohol preference rat lines].
AB  - We have investigated the effects of single administration of methamphetamine
      (MAP) (1.0 mg/kg, i.p.), and of combined administration of ethanol (EtOH) (2.0
      g/kg, i.v.) and MAP (1.0 mg/kg, i.p.) on striatal extracellular dopamine (DA) and
      serotonin (5-HT) levels in chronic alcohol treated rats using a brain
      microdialysis method. We used two different lines of rats with high and low
      alcohol preferences, (high alcohol preference rat (HAP) and low alcohol
      preference rat (LAP), respectively), which were chronically fed an alcohol
      containing liquid diet for 6 to 8 weeks. The percent change in DA and 5-HT in
      striatum following single administration of MAP was significantly higher in
      control-fed LAP than HAP. However, in the alcohol-fed group, the percent changes
      in DA and 5-HT were significantly elevated in the alcohol-fed HAP compared to
      LAP. There were no significant increases in striatal extracellular DA and 5-HT in
      alcohol-fed LAP. In combined administration of MAP and EtOH, extracellular DA and
      5-HT levels increased slightly following EtOH administration in chronic alcohol
      fed rats, especially in HAP. Dramatic increases of DA and 5-HT levels were
      observed in alcohol-fed HAP following EtOH and MAP administration. The percent
      change in DA and 5-HT in alcohol-fed HAP was further elevated to 4667.7 +/-
      1095.5% and 3116.9 +/- 1162.7% of the maximal change, respectively. These percent
      changes ware higher than that observed with a single administration of MAP.
      Meanwhile, LAP were less sensitive to the influence of chronic EtOH
      administration and to single administration of MAP. These results demonstrate
      that a chronic treatment of EtOH enhances the sensitivity to MAP in a high
      alcohol preference rat line, when two drugs were administrated simultaneously,
      and that a significant difference of responsiveness to abused drugs was indicated
      between these two lines. It is necessary to consider the alcohol preference when
      investigating the interaction of alcohol and/or other abused drugs.

PMID- 12607945
TI  - [A cohort study of Japanese adolescent alcohol use and misuse (1): Observation
      for 2 years].
AB  - Japanese adolescent drinking has increased during the past 20 years. Two national
      surveys on adolescent drinking problems were conducted, but no prospective study
      has been performed in Japan. We started the first longitudinal cohort study on
      Japanese adolescent alcohol use and misuse in 1997. The purpose of the cohort
      study was to show factors that promote adolescent drinking, and whether
      adolescent problem drinkers will develop the early alcohol dependence syndrome.
      Eight hundred and two subjects were recruited from four junior high schools in
      Kanagawa prefecture. They were in grades 7 to 9, and the mean age was 13.5 years
      in 1997. The survey was conducted annually by mail using self reported
      questionnaires concerning adolescent drinking and alcohol-related problems. This
      report indicates the sociodemographic backgrounds of the subjects and showed
      increasing of drinking of the subjects from 1997 to 1999. At 1999 survey from 2
      years after the starting point, the respondents numbered 629, and the follow-up
      rate was 78%. Drinking frequencies and quantities of the subjects increased year
      by year, and alcohol-related problems also increased. We divided the subjects
      into two groups based on changes in drinking status from the 1997 to the 1999
      survey, the increased drinking group and no increased group, and compared these
      two groups concerning their family relationships, first drinking age and drinking
      status of parents with the responses of the 1997 survey. In the comparison of the
      two groups, many factors were significantly different, and logistic regression
      analyses were performed on these factors to determine drink promoting factors.
      Three factors were determined: earlier age of the first drink, not refusing
      friends' temptations to drink and less communication with their parents. We will
      continue the longitudinal cohort study to determine if these three factors
      promote adolescent drinking in the future.

PMID- 12607946
TI  - Increased immunoreactivity of POMC-derived neuropeptides and immediate-early gene
      derived proteins (c-Fos and Egr-1 proteins) as an early step of acute cocaine
      induced stressor effects: comparison with the effects of immobilization stress.
AB  - The effects of an acute toxic dose of cocaine (COC) (60 mg/kg, i.p.) as a
      stressor were examined in rats both neuroendocrinally and behaviorally. The time
      course (5 min, 5, 12, and 24 h) of the alterations in the immunoreactivity of
      POMC (preopiomelanocortin)-derived neuropeptides [ACTH (adrenocorticotropin),
      beta-endorphin, and alpha-MSH (melanocyte stimulating hormone)] and immediate
      early gene-derived proteins (c-fos and egr-1 proteins) was examined in the
      hypothalamus, including the regions reported to be neuroendocrinally sensitive to
      stressor effects, along with the accompanying alterations in the spontaneous
      behaviors in the cage and the forced swimming behaviors. Similar to the
      observations in rats treated with a 30 min immobilization stress (IM), an
      increase in the number of immunoreactive nerve cells for each neuroendocrinal
      product and a delayed depression in the swimming behaviors as compared to the
      alterations in the spontaneous activity, which seemed to be correlated with some
      intermediate steps, were characteristically caused by a toxic dose of COC.
      However, the early enhancement (at 5 h) of the swimming behaviors and the brain
      ACTH level might also be the characteristic acute COC effects, which could be
      differentiated from the effects of other non-psychostimulant stressors.

PMID- 12607947
TI  - [A study of maternal psychological state among women with fetal alcohol effects
      (FAE) infants].
AB  - Frequent alcohol drinking during pregnancy may result in facial dysmorphism,
      growth retardation and central nervous system deficits in infants ranging from
      Fetal Alcohol Effects (FAE) to Fetal Alcohol Syndrome (FAS). However, few studies
      has been done to empirical research the psychosomatic approach among women with
      FAE. In this study, twelve women with FAE infants were selected and interviewed
      at two or three days after delivery with CMI, MAS, and ANS-S, in order to
      elucidate the number of problems with mental health of them. All of women with
      FAE infants drank alcohol during the pregnancy consumed 2 or 3 drinks per week
      (ethanol consumption less than 92.0 gms per week). The mean mother's age of FAE
      infants is 30.2 years (range 27-35) and that of healthy mother is 30.3 years
      (range 24-35). Eleven of 12 (91.7%) infants were identified having the smooth
      philtrum, 9 (75.0%) with thin upper lip, 3 (25%) with hypersensitivity, 3 (25%)
      with sleeping disturbance, 2 (16.7%) with growth retardation. Eighty-three
      percent of infant with FAE had an adequate body weight and height. In comparison
      with the women without FAE, women with FAE infants were noted to have a
      significant difference of the score of CMI (p < 0.0001), MAS (p < 0.0001), ANS-S
      (p < 0.02). Psychosomatic interview revealed that women with FAE infants have
      increased anxiety neurosis and stress state. Seventy-five percent of women with
      FAE infants had an anxiety compared with control group (18.8%). Our findings in
      this study are important because 12 women with FAE infants were not alcoholics
      and did not consider themselves to have alcohol problems. Therefore, obstetrician
      has to cut down women alcohol intake considerably during pregnancy for preventing
      adverse fetal effects. Alcohol consumption and psychometric works also need to be
      done for detecting at risk use of alcohol during the pregnancy.

PMID- 12607948
TI  - [Future perspective of radiation therapy for superficial esophageal cancer].
AB  - Superficial esophageal cancer (SEC) is defined as esophageal cancer limited to
      the submucosal layer, and includes mucosal and submucosal cancer. Based on the
      criteria of the Japanese Society for Esophageal Disease, mucosal and submucosal
      cancer are classified according to location: epithelial layer (m1); proper
      mucosal layer (m2); muscularis mucosa (m3); upper third of the submucosal level
      (sm1); middle third of the submucosal layer (sm2); and lower third of the
      submucosal level (sm3). Irrespective of the treatment method, the depth of
      invasion is one of the most important prognostic factors of SEC because lymph
      node metastasis markedly increases in lesions infiltrating the lamina muscularis
      mucosa (m3). The best management technique for small m1 and m2 esophageal cancers
      is generally endoscopic mucosal resection (EMR). For m3-sm3 SEC, extensive lymph
      node dissection has been the most widely used form of treatment. However, a
      recent study has shown that for m3 and sm1 cancer, EMR seems to be as effective
      as surgery. Therefore, EMR may become the standard therapy for m3 and sm1 cancer.
      The role of radiation therapy in the treatment of SEC has not been established,
      and radiation therapy has tended to be used for SEC patients who are not suitable
      for EMR or surgery. The treatment outcomes of radiation therapy are encouraging
      and seem to be comparable with those of other treatment modalities. Radiation
      therapy is a promising method for treating SEC and may become standard therapy
      for certain subgroups of SEC. However, many problems concerning radiation
      therapy, including optimal radiation dose, optimal radiation field, and the role
      of intracavitary irradiation, remain to be solved. Thus, standardization of
      radiotherapy is an urgent issue.

PMID- 12607949
TI  - [Detection and diagnosis of coronary arteries using multi-detector CT].
AB  - OBJECTIVE: In this study coronary arteries were compared and evaluated in 41
      cases using multidetector CT with slice thicknesses of 2 mm and 1 mm. All 323
      segments including #1-3, 5-8, and 11 [based on the American Heart Association
      (AHA) classification system] were used: 163 segments of 2 mm and 160 segments of
      1 mm. METHODS: The images obtained were separated into fivelevels (0-4 points) of
      cardiac motion artifacts and evaluated based on volume rendering (VR) and partial
      maximum intensity projection (partial MIP). RESULTS: Of the results obtained,
      slice images of 1 mm in thickness were superior to those of 2 mm by 15.4% for
      sensitivity, 7.5% for specificity, and 8.2% for accuracy. On evaluation by
      segment, diagnostic accuracy was 2.88 +/- 0.57 for 2-mm slices and 3.28 +/- 0.59
      for 1-mm slices of the left coronary artery, and 2.11 +/- 0.82 for 2-mm slices
      and 2.33 +/- 0.67 for 1-mm slices of the right coronary artery. Particularly for
      #6, a significantly high value was found for 1-mm slices (p < 0.05). Diagnostic
      accuracy was low in groups #2 and #3. CONCLUSION: On the basis of these findings,
      we were persuaded of the usefulness of MDCT for the evaluation of coronary
      arterial stenosed lesions, and we consider that diagnostic capability is improved
      by using thinner slices. We concluded that further studies would be necessary for
      visualization of the right coronary artery, which was seriously affected by
      cardiac motion artifacts.

PMID- 12607951
TI  - [Radioprotective effects of natural beta-carotene on villi and crypts in
      abdominally radiated mice].
AB  - The protective effect of beta-carotene against radiation injury to the small
      intestine of abdominally radiated mice (15 Gy) was examined with administration
      given pre-radiation, during (pre- and post-) radiation, and post-radiation. In
      the beta-carotene group, the ratio of villus length to crypt was significantly
      greater in comparison with the radiation only group at 2 days after radiation. At
      7 days after radiation, the ratio of necrotic cells in the crypt vs. the total
      was significantly lower, and the ratio of necrotic cells in the villus vs. the
      total was significantly greater with beta-carotene administration, which
      indicated that beta-carotene accelerated recovery from radiation injury. Each
      group administered beta-carotene showed a significant radioprotective effect,
      with pre-radiation administration yielding a smaller effect than administration
      during radiation and post-radiation. It is concluded that pre-, during, and post
      radiation administration of beta-carotene protected against radiation injury of
      the small intestine and accelerated recovery from it.

PMID- 12607950
TI  - [Radiofrequency ablation of rabbit liver: correlation between dual CT findings
      and pathological findings].
AB  - PURPOSE: To present the time-related imaging findings and correlative pathologic
      findings of radiofrequency pulse-irradiated regions of the liver. MATERIALS AND
      METHODS: Radiofrequency (RF) ablation was performed in 22 rabbit livers with 15
      gauge RF probes inserted percutaneously. Regions were imaged with dual-phase CT
      at 3 days (n = 6), 2 weeks (n = 6), 4 weeks (n = 6), and 12 weeks (n = 4) after
      RF ablation. RESULTS: At 3 days, the regions showed a two-zone structure on plain
      CT and peripheral enhancement. The regions presented a three-zone structure on
      pathological study. Hepatocytes appeared as acidophilic bodies, and nuclei were
      pyknotic at the inner necrotic zone. The middle whitish zone showed enlarged
      sinusoids. The marginal zone was a regenerative band. At 2 weeks, the two-zone
      structure was obscured on unenhanced CT. The region showed a two-zone structure
      on pathological study. At the inner zone, acidophilic degeneration had
      progressed, however, cell structure remained. The marginal zone showed fibrous
      tissue bundles. At 12 weeks, the region was obscured on plain CT. Nuclei and cell
      structures had disappeared almost completely at the inner zone. Collagen fiber
      had replaced the marginal zone. CONCLUSION: Zone structural CT findings reflect
      the pathological findings and time-related changes after RF ablation. Peripheral
      enhancement in the arterial phase reflects the granulation tissue layer, and its
      time-related decrease reflects replacement by fibrous tissue.

PMID- 12607952
TI  - [Percutaneous transhepatic central venous port implantation via the middle
      hepatic vein: a case report].
AB  - Percutaneous transhepatic central venous access with a subcutaneous infusion port
      was performed in a 34-year-old woman with extensive third-degree burns whose
      peripheral vessels were not available because of infection or dermatoplastic
      sites. This procedure could be done in the same way as the usual PTCD maneuver
      without serious complications. The infusion system functioned well, and the
      patient's alimentation could be carried out.

PMID- 12607953
TI  - [A case of venipuncture-induced complex regional pain syndrome].
AB  - A case of complex regional pain syndrome (CRPS) secondary to peripheral nerve
      injury occurring during venipuncture for post-contrast CT examination is
      presented. The puncture site was in the left antecubital fossa. Anatomically,
      cutaneous nerves lie close to cutaneous veins, making them vulnerable to injury
      during the procedure. This syndrome is characterized by continuing pain,
      allodynia, or hyperalgesia that is disproportionate to any inciting event in
      severity, and may lead to loss of the involved limb. The syndrome is poorly
      understood by radiologists and is often misdiagnosed. Early recognition and
      appropriate therapy are most important in treating this disorder.

PMID- 12607954
TI  - [Radiofrequency ablation of pulmonary malignancies].
AB  - Radiofrequency ablation (RFA) with a maximum output of < or = 70 W was used under
      CT guidance to treat 14 tumors (median diameter 1.5 cm, range 0.8 to 2.4 cm) in 6
      patients. Primary lung cancer was treated in 2 patients, and metastatic lung
      tumors were treated in 4 patients. Good response was confirmed in 6 tumors on CT
      images, in one tumor on PET images, and in 2 tumors by histologic examination. In
      the other 5 tumors, curative effect was not determined because consolidation
      shadows surrounded the tumors. Complications were mild (pneumothoraces, 5; sputum
      cruentum, 4; subcutaneous emphysema, 3) except for one case of pleurisy. RFA of
      pulmonary malignancies appears to be a safe, effective treatment if a low output
      of less than 70 W is applied.

PMID- 12607955
TI  - [FDG-PET on the day after first chemotherapy in malignant lymphoma].
AB  - Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PE) was performed
      in four patients with non-Hodgkin's lymphoma on the day after initial
      chemotherapy, in an attempt to predict the effects of chemotherapy earlier than
      standard methods. Twelve regions displaying intense uptake on baseline FDG-PET
      were selected, and decreases in the rate for each region were calculated from
      standardized uptake values on the day following chemotherapy. Seven of the 12
      regions demonstrated decrease rates of 60% or more, and two decreased by 100%.
      This study indicates that FDG-PET on the day after first chemotherapy seems to
      reflect the effect of chemotherapy on malignant lymphoma.

PMID- 12607956
TI  - [Function preservation and reconstructive surgery for oral cancer].

PMID- 12607957
TI  - [Fundamental study on the development of a measuring device using an
      accelerometer].
AB  - It is important to clarify stomatognathic functions. To diagnose them, some
      measuring devices, such as MKG and the Gnatho-hexagraph, were developed. Such
      equipment, however, is not widely diffused, due to cost. The purpose of this
      fundamental study was to obtain information on position using an accelerometer.
      This system consists of a micro dual-axis accelerometer and a peripheral
      interface controller. Two-dimensional acceleration, velocity, and movement can be
      calculated by a computer. We examined the accuracy of this system using a laser
      measuring device. The result was as follows: The accuracy of the system was 0.03
      (p-p values) using acceleration of gravity and a frequency of 72.5 Hz. In the
      present study, mandibular movements during chewing raisins were analyzed using
      this system. The new system demonstrated its value for analyzing mandibular
      movements.

PMID- 12607958
TI  - [A study on the relationship between the actual situation of nursing activities,
      in the outpatient section of oral surgery, and medical fees].
AB  - In our outpatient oral surgery section, nurses have performed such nursing
      activities as guidance and consultation for outpatients. The present survey was
      conducted to clarify the actual situation of nursing activities, and that of
      claims for medical fees during fiscal year 2000, the year the claim for medical
      fees was started. At that time, the problems involved were examined to further
      improve nursing activities for outpatients. The nurses gave guidance on
      alimentation, oral hygiene, and breast feeding, from the nurse's record which
      were classified and totalled according to each disease, guidance item, and time
      required (less than 30 minutes or more than 30 minutes). The total numbers of
      patients were 172 persons and 357 cases. Major guidance items were alimentary
      guidance (179 cases), oral hygiene guidance (105 cases), and breast feeding
      guidance (73 cases). The items claimed for medical fees were two: "Athrocytosis
      function therapeutics" (9 cases) and "the guidance fee for the treatment of
      specific dental disease" (32 cases). The problems that discouraged claiming a fee
      for performed chargeable nursing activities are listed as 1. there are no
      exclusive guidance rooms, 2. insufficiency in securing staff, 3. the instructions
      and the requests by dentists have not been made exactly and smoothly. Thus, the
      problems to be considered hereafter would be 1. review and improvement in the
      guidance environment to an appropriate level, 2. make regulations for securing
      necessary staff, 3. construction of a system for exact and smooth instruction and
      requests, and 4. promotion to enrich the content of guidance and to make the
      results public.

PMID- 12607959
TI  - [The influence of medial implant location in three-unit posterior cantilever
      fixed partial dentures on stress distribution in surrounding mandibular bone].
AB  - This study examined the influence of medial implant location in three-unit
      posterior cantilever fixed partial dentures (FPDs) on stress distribution in
      mandibular bone surrounding two implants. A three-dimensional finite element
      model that included three-unit FPD and two cylindrical-type implants (4 mm in
      diameter and 10 mm in length) osseointegrated in the posterior mandible, was
      digitized. Five different models were created according to the medial implant
      location between the missing second premolar and the first molar location. The
      distal implant was fixed at the missing second molar location. Oblique bite force
      of 100 N at 30 degrees buccal to the vertical direction was directed on each of
      three artificial teeth, respectively and simultaneously, while the lower surface
      of the mandible was fixed. The maximum equivalent stress in the cortical and the
      trabecular bone generally increased as the medial implant shifted to a distal
      position. Under the simultaneous bite force, relatively low maximum stresses
      within the cortical bone: between 55 MPa and 57 MPa, were shown in the models
      with the medial implant placed within the range of one implant diameter from the
      most medial position, while higher maximum stresses: between 64 MPa and 73 MPa,
      were demonstrated with more distally placed medial implants. The results suggest
      that reasonably low mechanical stress in the surrounding bone may be assured when
      the medial implant is placed in the range between the missing second premolar
      position and one implant diameter distal from that location.

PMID- 12607960
TI  - [An analysis of mandibular movements before and after a surgical orthodontic
      treatment].
AB  - By the surgical orthodontic treatment for the patient who has a malocclusion,
      scaffold reverse occlusion, it is considered that remarkable change of
      maxillofacial form in the oro-facial region affects the stomatognathic functions.
      The purpose of this study was to analyze stomatognathic functions during border
      movements and masticatory movements before and after surgical orthodontic
      treatment. The lateral border movements were analyzed regarding the symmetry of
      both sides and the change of angle of balancing condylar path. The masticatory
      movements were analyzed during opening and closing phases. We also analyzed cross
      patterns. In consequence, the lateral border movements were extended after the
      surgical orthodontic treatment, and the symmetries of the border-movement were
      improved. The angle of balancing condylar path did not show a large change in the
      sagittal plane by a remarkable change of the anterior guidances during lateral
      movements. However, the balancing condylar path in the horizontal and frontal
      plane had a tendency to change. The cross patterns of the masticatory movements
      tended to decrease after the surgical orthodontic treatment, and each of the
      opening phase and the closing phase tended to separated independently, i.e. each
      movement became stable. It was also suggested that the occlusal relationships of
      the upper and lower jaw including occlusal contacts had particular effect on the
      stomatognathic functions.

PMID- 12607961
TI  - [A clinical application of the T-Scan II system--usefulness for evaluating
      occlusal contacts of complete denture wearers].
AB  - The purpose of this study was to assess the reproducibility of the T-Scan II
      system and its clinical usefulness for evaluating occlusal contacts of complete
      denture wearers. The occlusal contacts of 13 dentate subjects, and 14 complete
      denture wearers, were recorded using a T-Scan II system during maximum voluntary
      clenching. The recordings for complete denture wearers were taken after each
      treatment for the new denture, and continued until the completion of all
      corrections. The recordings for complete denture wearers were analyzed using
      repeated measured ANOVA. In addition, the variables obtained with the system, the
      delta of the occlusal area and load, and the maximum-load time (MLT), which
      represented the time length taken to reach the occlusal load at the maximum
      level, were then compared between dentate subjects and complete denture wearers,
      using a t-test. The conclusions were as follows: 1. The standard errors values
      for both occlusal area and the load recordings for the dentate subjects were
      limited to within 10% of the means. 2. The values of the occlusal area and load
      significantly increased, and delta of the occlusal area and load significantly
      decreased, as the denture corrections were repeated. 3. The means of the MLT were
      about 0.3 seconds for dentate subjects, and 0.8 seconds for complete denture
      subjects. It was revealed that the T-Scan II showed acceptable reproducibility,
      and it was useful to evaluate occlusal contacts of complete denture wearers.

PMID- 12607962
TI  - [A study of oral status of adults who received regular checkups and professional
      care].
AB  - The purpose of this study was to investigate the effect of regular professional
      care on oral health status. We examined the oral health status of 255 adults (76
      males, 179 females; 61.8 +/- 7.8 yrs) who received professional dental care at
      the Dental Hospital of Tokyo Medical and Dental University at least once a year.
      The oral health care included checkups and prevention (oral health education,
      scaling, polishing, topical application of fluoride). We compared the oral health
      status of adults who received regular professional care with the status of
      subjects of similar age reported in national and Tokyo surveys of dental diseases
      in 1999. The following results were obtained. 1. The number of teeth present
      among adults who received regular oral health care was greater than that reported
      in the national and Tokyo surveys of dental diseases in 1999. 2. The number of
      untreated decayed teeth among adults who received regular oral health care was
      smaller than that reported in the national and Tokyo surveys of dental diseases
      in 1999. The results show that the oral health status of adults who received
      regular oral health care was better than the oral health condition of those
      reported in the national and Tokyo surveys of dental diseases in 1999. Therefore,
      it is suggested that regular professional care by a dentist or dental hygienist
      will assist in achieving the objective of the 8020 movement (20 healthy teeth at
      age 80).

PMID- 12607963
TI  - [The relationship among eating habits, lifestyles, and oral health status of
      students].
AB  - A questionnaire survey and oral health examination were conducted in 2000. The
      subjects were students of dental and dental hygiene schools at Tokyo Medical and
      Dental University. Subjects totaled 101 (48 males, 53 females), and the average
      age was 22.0 +/- 3.3. The relationship among eating habits, lifestyles, and oral
      health status of the students was analyzed. The following results were obtained.
      1. Almost half of the students did not eat one of the three main meals; that is,
      breakfast, lunch, or supper. Most of them skipped breakfast. 2. The students who
      ate rice (traditional Japanese-style food) for breakfast had less DMFT compared
      with those who ate other foods, such as bread or noodles, or who did not eat
      breakfast. 3. The amount of stimulated saliva of the students who ate rice for
      breakfast was greater than that of others. 4. The oral health behavior and
      nutrition balance of the students who ate rice for breakfast was better than that
      of others. 5. The students' eating habits were related to their living styles,
      such as living alone or with the family. From these results, it was suggested
      that educational emphasis on nutrition balance and eating habits is needed for
      dental students and dental hygiene students, because in the future they must
      advise patients on good oral health and general health through good eating
      habits, as dental professionals.

PMID- 12607964
TI  - [Guidelines for the management of refractory nephrotic syndrome--from
      investigations between 1997 and 2001--research project team for progressive renal
      lesions in the Ministry of Health, Labor and Welfare, Japan].

PMID- 12607965
TI  - [Historical remarks on nephrology research in Japan. 2. Clinical research on
      nephritis and renal biology(discussion)].

PMID- 12607966
TI  - [Current progress in the diagnosis and treatment of renal cell carcinoma].

PMID- 12607967
TI  - [Pathological analysis of renal diseases with mild proteinuria].
AB  - Proteinuria is an important predictor of renal outcome in a variety of renal
      diseases. Proteinuria exceeding 0.5 g/day is often considered to be a major
      indication of renal biopsy. In this study, we analyzed the clinical and
      histopathological data of 58 patients with mild proteinuria of less than or equal
      to 0.5 g/day. The histopathological diagnosis included 45 cases(77.6%) of
      mesangial proliferative glomerulonephritis, 4 cases(6.9%) of lupus nephritis, one
      case of membranoproliferative glomerulonephritis and only 6 cases(10.3%) of minor
      glomerular abnormality. The percent sclerotic glomeruli exceeded 10% in 17
      cases(29.3%) and reached 71.4% in 2 cases. There were no significant differences
      in histopathological parameters(percent sclerotic glomeruli, tubulointerstitial
      change, arterio-arterio sclerotic change) between the groups with or without
      microhematuria. There was a positive correlation between age and percent
      sclerotic glomeruli. Percent sclerotic glomeruli in our cases were higher than in
      the healthy population reported by Kaplan et al. and the influence of
      glomerulonephropathy was obvious. During the follow-up period(mean 19.7 months),
      one patient progressed to chronic renal failure and 2 patients had increased
      urinary protein excretion, but the others did not. These results suggest the
      importance of clarifying the prognosis by renal biopsy even in cases with mild
      proteinuria.

PMID- 12607968
TI  - [Effect of probucol on the blood concentration of cyclosporin A in patients with
      nephrotic syndrome: a case study with a microemulsion formulation (Neoral)].
AB  - Cyclosporin A(CyA) is used frequently in the treatment of steroid-resistant or
      recurrent cases with nephrotic syndrome. Recently, a new microemulsion
      formulation of CyA(Neoral) has been developed and used preferably because of a
      more stable bioavailability than an oily formulation(Sandimmun). Nephrotic
      syndrome accompanies hyperlipidemia, and probucol is used in cases showing
      inadequate effects or some adverse reactions under therapy with HMG-CoA reductase
      inhibitors. We reported previously that combined use of probucol caused a
      decrease in blood concentrations of CyA to about half of those without probucol.
      In the present study, we evaluated the influence of probucol on the blood
      concentrations of CyA in patients with nephrotic syndrome following Neoral.
      Coadministration of Neoral and probucol decreased the blood concentrations of CyA
      to approximately 75% of the levels before combined use. The change of blood CyA
      concentrations appeared to be smaller compared to those in cases with Sandimmun.
      Based on the present findings, we suggest that Neoral should be used
      preferentially instead of Sandimmun when the concomitant use of probucol is
      required, and that optimal dose adjustment of CyA is needed by frequent
      monitoring of CyA blood concentrations.

PMID- 12607969
TI  - [Investigation of CD68 positive monocytes/macrophage(CD68+ Mo/M phi) in urine and
      infiltrated tissue of various kidney diseases in children].
AB  - In order to investigate the participation of monocytes/macrophages(Mo/M phi) in
      the progression of various kidney diseases of children, Mo/M phi in urine and
      that infiltrating renal tissue were both measured as the number of CD68 positive
      Mo/M phi (CD68+ Mo/M phi), using anti-CD68 antibody. The number of CD68+ Mo/M phi
      infiltrating in one glomerulus was significantly higher in Henoch-Schonlein
      purpura nephritis(HSPN) (p < 0.01) in comparison with that in minimal change
      nephrotic syndrome(MCNS) (p < 0.01), and a high tendency was found in IgA
      nephropathy (IgAN), proliferative glomerulonephritis (non-IgAN), focal segmental
      glomerulosclerosis(FSGS) and membranoproliferative glomerulonephritis (MPGN),
      respectively. The number of CD68+ Mo/M phi infiltrating one mm2 of tubulo
      interstitium area was significantly higher in HSPN(p < 0.05), FSGS(p < 0.01),
      Alport's syndrome(p < 0.01), respectively, than that in MCNS. The number of CD68+
      Mo/M phi in one milliliter of urine correlated significantly with both that
      infiltrating the glomerulus and the tubulo-interstitium(both p < 0.01). Moreover
      the number of urine CD68+ Mo/M phi in a clinically active stage was significantly
      higher than that in an inactive stage in the AGN(p < 0.05), IgAN(p < 0.05),
      HSPN(p < 0.05), non-IgAN(p < 0.01) and MPGN groups(p < 0.05), respectively. From
      these results, 1) It was suggested that the Mo/M phi infiltrating renal tissue
      participated in the development of various kidney diseases. 2) It was predicted
      that CD68+ Mo/M phi in urine reflected both the number of Mo/M phi infiltrating
      the glomerulus and that in the tubulo-interstitium. 3) It was suggested that the
      number of CD68+ Mo/M phi in urine indicated clinical activity in proliferative
      glomerulonephritis groups of children.

PMID- 12607971
TI  - [A unique case of recurrent malignant hypertension after removal of an adrenal
      tumor for primary aldosteronism].
AB  - We report here a unique case of recurrent malignant hypertension after the
      removal of an adrenal tumor for primary aldosteronism. The patient had a history
      of hypertension for 15 years. In 1995, he developed drug-resistant hypertension
      with hyperreninemia, hyperaldosteronemia and hypokalemia. He was diagnosed as
      having primary aldosteronism with a right adrenal tumor. His blood pressure did
      not normalize and renal dysfunction continued after the adrenalectomy. Although
      antihypertensive treatment was continued for residual hypertension, he soon
      refused medication. In 1997, he developed recurrent malignant hypertension. It
      was considered that the different underlying mechanisms might be attributable to
      the two episodes of malignant hypertension in this patient.

PMID- 12607970
TI  - [A case of focal segmental glomerulosclerosis(FSGS) complicated with chronic
      hepatitis B and treated with steroid and LDL apheresis].
AB  - A 52-year-old man was admitted to our hospital because of nephrotic syndrome. He
      had been monitored at our outpatient clinic for chronic hepatitis B, and had
      experienced histologically proven minimal change nephrotic syndrome at the ages
      of 40 and 51 years. Because of HBsAg positivity in his serum, steroid therapy was
      withheld in his earlier episodes and he recovered from nephrotic syndrome
      spontaneously. However, in the most recent episode the nephrotic syndrome was
      found difficult to control and the findings of renal biopsy showed FSGS, which is
      not expected in HBV-associated nephropathy. Finally, prednisolone was
      administered at the dose of 40 mg/day for four weeks, after which the dose was
      tapered. LDL apheresis was also administered three times because of the patient's
      incomplete response to prednisolone. His proteinuria was reduced from > 10 g/day
      to < 1 g/day, but the ALT levels and HBsAg titer increased. With stronger
      neominophagen C induction and very careful tapering of glucocorticoid, ALT levels
      and the HBsAg titer decreased. During the two-year period since the induction of
      glucocorticoid therapy, urinary protein excretion has been maintained at less
      than 1 g/gcr, and ALT levels and HBsAg titer have not increased. We conclude that
      attention must be paid to dose modification of steroid therapy and strategies
      without immunosuppressive agents such as LDL apheresis should be considered in
      the case of treatment of nephrotic syndrome with HB virus.

PMID- 12607973
TI  - [Urine collection and devices for urine collection].

PMID- 12607974
TI  - [A review and commentary on the Clinical Nephrology Board Examination
      WorkingHroup for Education].

PMID- 12607972
TI  - [Two cases of systemic lupus erythematosus accompanied by antiphospholipid
      syndrome nephropathy without immune complex nephritis].
AB  - We report here two interesting cases of systemic lupus erythematosus(SLE)
      accompanied by antiphospholipid syndrome nephropathy(APSN). These cases satisfied
      the criteria for SLE established by the American College of Rheumatology 1997 and
      also satisfied the criteria for antiphospholipid syndrome (APS) established by
      the Sapporo International Workshop of APS 1998. Both cases had high blood
      pressure with elevated plasma renin activity, proteinuria and renal dysfunction.
      Their biopsied renal specimens showed the characteristic findings for APSN, such
      as mesangial proliferation, double contours, thickening of the capillary loops,
      and intimal hyperplasia, but there was no evidence for immune complexes in the
      glomeruli, which were examined by the indirect immunofluorescence methods and the
      electron microscopy method. These results indicated that their renal dysfunction
      was caused by APSN, but not by immune complex nephritis. In addition to treatment
      with prednisolone, they were administered anticoagulants(warfarin, or aspirin, or
      heparin) for APSN and an angiotensin II receptor blocker, candesartan, for the
      hypertension. Subsequently, their conditions recovered with the improvement of
      renal function and hypertension. Our experiences suggest that anticoagulant
      therapy in addition to corticosteroids offers advantages in the treatment of
      patients with SLE accompanied by APSN and renal dysfunction.

PMID- 12607975
TI  - [Masseter strength in patients with motor neuron disease].
AB  - Although masseter muscles play an essential role in digestion, masseter strength
      in patients with motor neuron diseases has not been well studied. The purpose of
      this study is to evaluate the masseter strength in healthy volunteers (n = 13,
      mean age +/- S.D.: 58 +/- 10 years) and in patients with motor neuron diseases (n
      = 16, mean age +/- S.D.: 61 +/- 10 years) using a device for the measurement of
      occlusal forces (Nihon Koden, Co. Ltd., Japan). Masseter strength values in the
      healthy volunteers and the patients with motor neuron diseases including
      amyotrophic lateral sclerosis (ALS) were 24.6 +/- 13.4 kg (mean +/- S.D.) and
      21.9 +/- 16.4 kg (ALS: 26.2 +/- 14.6 kg), respectively, and this difference is
      not statistically significant. Further, there was no relation between masseter
      strength and the severity of clinical signs including bulbar palsy. These results
      suggest that masseter strength is not particularly vulnerable in patients with
      motor neuron diseases.

PMID- 12607976
TI  - [Chronic and predominantly sensory polyneuropathy in Toroku Valley where a mining
      company produced arsenic].
AB  - We report 9 patients (5 males, 4 females, ages 63-77) with chronic
      polyneuropathy. They were exposed to arsenic for about 15-40 years in Toroku
      Valley, Takachiho-Town, Miyazaki Prefecture, Japan, where a mining company
      produced arsenic from 1920-1962. Predominantly sensory polyneuropathy was the
      most significant neurological finding. In 5 of them, superficial and deep
      sensation was equally affected over the entire body, including head, face, and
      mucous membranes of the mouth. The corneal reflexes were absent or sluggish. Pin
      prick and light-touch perception was absent in their hands and legs. Another
      sensory disorder such as glove and stocking-type was seen in 4 of them. All 9
      patients were comfortable with extremely hot water in their beverages, their
      baths, and their wash basins compared with controls. But these patients felt that
      their temperature sensation was normal. Motor involvement was minimal. Although
      motor-nerve conduction velocities were normal or reduced minimally, sensory-nerve
      conduction velocities were moderately reduced. Sural-nerve biopsy revealed
      reduction of both small myelinated and unmyelinated fibers, which occurs with
      axonal degeneration of peripheral nerves. Other main symptoms and signs were
      tension-type headaches, non-painful tonic spasms of limbs, and losses or
      significantly decreased sensations of taste and smell. Dantrolene-sodium was
      effective for the treatment of their non-painful tonic spasms of limbs. As for
      the general medical condition of these patients, all of them had suffered from
      chronic bronchitis and skin eruption during childhood or in their early life or
      in their young adulthood when the mine was producing arsenic. At the time of this
      study only four of them suffered from chronic bronchitis and none of them had
      skin eruptions or discoloration of the skin, 37 years after closure of the mine.
      These 9 patients were diagnosed as having chronic arsenic poisoning and arsenic
      polyneuropathy. The multiplicity of symptoms found in these patients--anosmia,
      ageusia, chronic bronchitis, tension-type headaches, and non-painful tonic spasms
      of limbs--differs from the symptoms previously reported cases with arsenic
      poisoning. This may be due to combined overexposure to environmentally hazardous
      arsenic by effluent gas, dust, and drinking water in Toroku Valley. As concerns
      the sensory disorders described above, it is necessary to investigate sensory
      conduction pathways, including cerebral sensory cortex, spinal cord, and skin
      sensory receptors such as Pacini corpuscles, and Meissner corpuscles.
      Unfortunately, no information has been obtained about this problem because there
      were no autopsy cases.

PMID- 12607977
TI  - [Cerebral circulation and metabolism in the patients with higher brain
      dysfunction caused by chronic minor traumatic brain injury: a study by the
      positron emission tomography in twenty subjects with normal MRI findings].
AB  - Many individuals are affected on their higher brain functions, such as
      intelligence, memory, and attention, even after minor traumatic brain injury
      (MTBI). Although higher brain dysfunction is based on impairment of the cerbral
      circulation and metabolism, the precise relationship between them remains
      unknown. This study was undertaken to investigate the relationship between the
      cerebral circulation or cerebral metabolism and higher brain dysfunction. Twenty
      subjects with higher brain dysfunction caused by chronic MTBI were studied. They
      had no abnormal MRI findings. The full-scale intelligence quotient (FIQ) were
      quantitatively evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS
      R), and the subjects were classified into the normal group and the impaired
      group. Concurrent with the evaluation of FIQ, positron emission tomography (PET)
      was performed by the steady state method with 15O gases inhalation. Regional
      cerebral blood flow (rCBF), oxygen extraction fraction (OEF) and cerebral
      metabolic rate of oxygen (CMRO2) were calculated in the bilateral frontal,
      parietal, temporal, and occipital lobe. First, of all twenty subjects, we
      investigated rCBF, OEF and CMRO2 in all regions. Then we compared rCBF, OEF, and
      CMRO2 between the normal group and the impaired group based on FIQ score. We also
      studied the change of FIQ score of 13 subjects 9.3 months after the first
      evaluation. In addition, we investigated the change of rCBF, OEF and CMRO2 along
      with the improvement of FIQ score. Although rCBF and OEF of all subjects were
      within the normal range in all regions, CMRO2 of more than half of subjects was
      under the lower normal limit in all regions except in the right occipital lobe,
      showing the presence of "relative luxury perfusion". Comparison of rCBF, OEF and
      CMRO2 between normal group and impaired group revealed that CMRO2 of the impaired
      group was significantly lower than that of the normal group in the bilateral
      frontal, temporal, and occipital lobe. After 9.3 months, FIQ scores of 13
      subjects were significantly increased. CMRO2 was significantly increased in the
      bilateral frontal and temporal lobe, as well as in the right occipital lobe,
      along with the improvement of FIQ score. It was concluded that higher brain
      dysfunction caused by chronic MTBI was related to malfunction of neuronal
      networks based on the generalized decrease of brain oxygen metabolism in all
      brain regions. Damage to neuronal networks in the bilateral frontal and temporal
      lobe appeared to play the most important role in higher brain dysfunction.

PMID- 12607978
TI  - [A case of multiple sclerosis with pathological laughing caused by pontine base
      lesions].
AB  - We report a case of multiple sclerosis (MS) with pathological laughing for which
      lesions in pontine bases are considered to be responsible. A 30-year-old man was
      diagnosed as having MS based on left hemiparesis, and pathological laughing, and
      MRI findings showing a plaque in the right pontine base as well as several
      plaques in the bilateral periventricular deep white matter. After remission for 6
      years, his pathological laughing exacerbated in association with development of
      right hemiparesis. A new lesion in the left pontine base was demonstrated by MRI
      studies in addition to a few supratentorial lesions. Steroid pulse therapy was
      effective for both pathological laughing and right hemiparesis. We speculate that
      the anatomical lesion responsible for the pathological laughing is located in the
      pontine base.

PMID- 12607979
TI  - [A case of pharyngeal-cervical-brachial weakness suggestive of the nosological
      continuity between acute oropharyngeal palsy].
AB  - A 68-year-old man without history of antecedent infection experienced nasal voice
      (day 1), and the developed dysphagia on day 9. Eleven days after the onset, he
      developed ophthalmoplegia, and on day 13 mild weakness in the neck and the upper
      limbs. Cerebrospinal fluid examination revealed albuminocytologic dissociation on
      day 19. Motor nerve conduction velocities and compound muscle action potentials
      were normal, but terminal latency was slightly prolonged in the median nerve.
      Enzyme-linked immunosorbent assay showed that the patient's anti-GT1 a IgG
      antibody fiter was high and that the antibody cross-reacts with GQ1b. We
      considered that this patient showed acute oropharyngeal palsy at the onset, and
      then evolved into pharyngeal-cervical-brachial weakness. The presence of this
      case suggested the nosological continuity between acute oropharyngeal palsy and
      pharyngeal-cervical-brachial weakness in both clinical and serological aspects.

PMID- 12607980
TI  - [A case of sensory perineuritis with Bowen disease].
AB  - A 60-year-old man was admitted because of subacutely progressive sensory
      disturbance characterized by fluctuating dysesthesia and light pain on the skin
      of his hands and feet. He exhibited mononeuritis multiplex, and a plaque with
      sloughing was observed on the left side of his back. Sural nerve biopsy revealed
      marked thickening of the perineurium with vascularization, and no necrotizing
      vasculitis. The pathological features of the nerve biopsy were compatible with
      sensory perineuritis. A biopsy from his skin lesion revealed Bowen's disease.
      There have been several reported cases of sensory perineuritis accompanied by
      malignant tumors. In these cases, immune dysfunctions were considered a common
      underlying cause in both diseases. This is the first reported case of sensory
      perineuritis associated with Bowen's disease.

PMID- 12607981
TI  - [Sporadic cerebral amyloid angiopathy presenting with dementia and prominent
      capillary beta-amyloid deposition: a case report].
AB  - We report a sporadic case of unusual cerebral amyloid angiopathy (CAA) with
      prominent capillary involvement. A 67-year-old doctor developed gait disturbance,
      resting tremor and rigidity. He was diagnosed to have Parkinson's disease, for
      which the treatment with levodopa was effective. Four years later he began to
      exhibit progressive cognitive decline and behavioral abnormalities consisting of
      hallucination and agitation. Subsequently, his condition steadily worsened and
      became bedridden with severe dementia, and he died eight years after the disease
      onset. During the clinical course, there had been no episode of stroke.
      Postmortem examinations revealed the typical pathology of Parkinson's disease
      with frequent cortical Lewy bodies in the amygdala. The most striking
      pathological feature of this patient was widespread CAA where prominent beta
      amyloid (A beta) deposition was observed in the capillaries of the neocortex,
      most pronouncedly in the occipital lobe, as well as leptomeningeal and cerebral
      medium-sized and small vessels. Further, perivascular plaques were found in half
      of the amyloid-laden capillaries. Tau-positive dystrophic neurites were only
      sparsely detectable within a few perivascular plaques. Despite the severe A beta
      pathology, there was no microaneurysmal dilatation, fibrinoid necrosis or
      vascular occlusion. There was only one small ischemic lesion in the brain. The
      cerebral white matter was unremarkable. Senile plaques of neuritic type and
      neurofibrillary tangles were mostly limited to the hippocampal regions and, to a
      lesser degree, in the amygdaloid nucleus, which did not meet the
      neuropathological criteria of Alzheimer's disease. On the gene analyses, his
      apolipoprotein E (ApoE) genotyping was verified to be heterozygous epsilon
      3/epsilon 4, and no mutation was seen in exons 16 and 17 of the amyloid precursor
      protein gene. Severe A beta capillary angiopathy as seen in our patient is
      exceptional in sporadic CAA. Further, A beta angiopathy of this patient was
      notable in the absence of an associated cerebrovascular disease despite prominent
      A beta deposition in the vessel walls. Regarding the development of his severe
      dementia, the limbic pathology of Lewy body disease might be one of the potential
      causes, but A beta angiopathy appears more likely because of its severity. We
      speculate that widespread A beta deposition disregulates the blood-brain barrier
      of the capillaries leading to a disturbance of the microcirculation throughout
      the cerebral cortex without obvious ischemic disintegration of the neuropil. We
      should take into consideration that A beta angiopathy can present as progressive
      dementia without cerebrovascular disease.

PMID- 12607982
TI  - [Herpes simplex encephalitis with expanded cerebral cortex lesions on T1-weighted
      MRI after clinical improvement: a case report].
AB  - We described a 58-year-old woman with herpes simplex encephalitis (HSE), who
      initially had fever and developed impaired consciousness. Cerebrospinal fluid
      (CSF) examination showed mononuclear pleocytosis and the existence of herpes
      simplex virus (HSV) DNA. The first T1-weighted MR image showed symmetrical
      swelling and low signal intensity lesions in the medial temporal lobes and
      hippocampus. T2-weighted MR image showed high signal intensity lesions in the
      medial temporal lobes, the amygdala, the hippocampus, the insula and the
      cingulate gyri bilaterally. After the treatment with intravenous acyclovir and
      betamethasone, impaired consciousness and recent memory disturbance gradually
      improved. On the second T1-weighted MR image examination, eighteen days after the
      onset, high signal intensity lesions were demonstrated in the right medial
      temporal lobe, the right hippocampus, the left insula and the bilateral cingulate
      gyri. Although the clinical symptoms had improved significantly over three
      months, the high signal intense lesions on T1-weighted MR images were also
      detected in the left medial temporal lobe, the right insula, and the straight
      gyrus. Brain CT did not demonstrate any abnormalities. The repeated CSF
      examinations showed negative HSV DNA and a decreased number of WBC. However,
      oligoclonal IgG bands were continuously positive. Myelin basic protein level and
      IgG index increased in parallel with the expansion of the cerebral lesions on T1
      weighted MR images. In the present case, the abnormality of T1-weighted MRI was
      thought to indicate hemorrhagic inflammatory lesions that could not be detected
      by CT. The increased level of myelin basic protein, the elevated IgG index and
      the continuous positive oligoclonal IgG indicated continuous immunologic response
      against HSV in these lesions.

PMID- 12607983
TI  - [Disturbance of jaw-opening due to extension of syringobulbia to the pons--a case
      report].
AB  - We report a patient with syringobulbia extending to the pons, who could not open
      his mouth widely. He had been involved in the traffic accident at 16 years of
      age. Since them he had suffered numbness in the left neck and arm. At age 30, he
      became unable to open the mouth widely with pain in the left jaw joint. He also
      noted dysphagia and tinnitus. Neurologically, there were vocal cord paresis,
      dysesthesia of the face, ageusia and cerebellar ataxia all on the left side.
      Brain MRI revealed syringobulbia which extended to the pons. Spinal MRI revealed
      syringomyelia through the entire spinal cord. The syrinx of the spinal cord
      seemed to connect with the brainstem lesion. EMG of the masticatory muscles
      revealed paradoxical activity in the left masticatory muscles. We concluded that
      disturbance of jaw-opening in this case was caused by syringobulbia, the lesion
      of which could involve masticatory central pattern generator in the brainstem.

PMID- 12607984
TI  - [A case of portal-systemic shunt encephalopathy due to congenital portal vein
      hypoplasia presenting with abnormal cerebral white matter lesions on the MRI].
AB  - A 49-year-old woman, without any past history of liver diseases and blood
      transfusion, was admitted to our service because of somnolence, and flapping
      tremor. Neurologically, she was drowsy and disoriented. She had bilateral
      pyramidal tract signs and flapping tremor. Although the laboratory examination
      showed marked hyperammonemia (217 micrograms/dl), neither abdominal CT nor liver
      biopsy showed any evidence of liver cirrhosis. An abdominal angiography showed
      portal vein hypoplasia associated with the portal-systemic shunt. A T2-weighted
      MRI showed the high intensity areas in the bilateral deep cerebral white matter,
      and the posterior limbs of the bilateral internal capsules. This is a rare case
      of portal-systemic shunt encephalopathy due to congenital portal vein hypoplasia
      presenting with abnormal cerebral white matter lesions on the MRI.

PMID- 12607985
TI  - [Measuring utilities for various functional outcomes after stroke. Comparison of
      rating scale and time trade-off methods].
AB  - OBJECTIVES: To elicit utility of various functional outcomes after stroke for
      application in cost-utility analysis for stroke rehabilitation and to analyze the
      effects of demographic characteristics such as age, sex, professional status,
      marital status, or health status and the relationship between rating scale and
      time trade-off methods. METHODS: The respondents were 460 healthy people,
      students (n = 169), rehabilitation staff (n = 134), family caregivers (n = 52)
      and office workers (n = 105). We assessed utility for 5 functional outcomes after
      stroke according to the Ranking scale, employing rating scale and time trade-off
      methods. RESULTS: The mean utilities for Rankin I-V were 0.89-0.18 using rating
      scale, and 0.83-0.09 using time trade-off. Correlations between the two were only
      0.176-0.412. The effect of professional status was clear, with rehabilitation
      staffs and caregivers giving higher utilities than students and office workers
      using time trade-off. However, effects of other characteristics were not
      apparent. CONCLUSIONS: People's preferences for stroke outcomes differ with
      disability level, and correlation between rating scale and time trade-off utility
      is weak. We found that few demographic characteristics had significant influence.

PMID- 12607986
TI  - [Intrapair comparisons of diet and food preference in adult twins].
AB  - OBJECTIVES: An investigation was conducted on the influence of genetic and
      lifestyle factors related to the determination of eating behavior of human
      beings. The objective was to obtain information about lifestyle factors that may
      help health professionals intervene in terms of the prevention of diet-related
      diseases. METHODS: The subjects were 180 pairs of adult twins aged over thirty,
      comprising of 134 monozygotic (MZ) and 46 dizygotic (DZ) pairs. Every subject was
      given an interview concerning dietary habits, food preference, food intake, as a
      part of medical examination. The intake of food containing salt and fat, the
      intake of food meals, the frequency of daily meals, and the frequency of eating
      18 sorts of food were assessed on an individual basis, with a questionnaire on
      nutrition. The expected and observed values of intrapair concordance rates were
      calculated, and compared within each zygosity, using the chi-square test.
      RESULTS: Significant differences between the expected and observed for intrapair
      concordance rates were shown with monozygotic twins, regarding every category of
      question. Comparing MZ pairs who had lived apart before their twenties with the
      other MZ pairs, the latter had a tendency to show significant differences between
      the expected and observed values of intrapair concordance rate, regarding every
      category of question. In each case, the observed values were higher than the
      expected values. CONCLUSIONS: The study implied that both genetic and lifestyle
      factors influence the determinants of eating behavior of human beings. This
      finding shows the importance of understanding individual characteristics of food
      preference and eating behavior for intervention regarding lifestyle factors for
      prevention of diet-related diseases.

PMID- 12607987
TI  - [Anti-rubella virus IgG in urine: epidemiological application of a new enzyme
      liked-immunosorbent assay (ELISA)].
AB  - OBJECTIVES: To evaluate the utility of urinary assessment for epidemiological
      studies of rubella, we measured anti-rubella virus immunoglobulin G (anti-RV IgG)
      using samples from pediatric patients with initial rubella infection, healthy
      volunteers who received a prophylactic inoculation of live rubella vaccine, and 3
      years-old children undergoing a health examination at a community health center.
      METHODS: Blood and urine samples were collected from 12 of spontaneous rubella
      cases treated at 7 local pediatric clinics during acute and convalescent stages.
      In addition, blood and urine samples were collected from 17 healthy volunteers
      receiving prophylactic rubella vaccination immediately before, and 3 and 6-7
      weeks after vaccination. Urine samples for anti-RV IgG measurement were also
      collected from 740 children 3 years of age at Odawara Community Health Center
      after obtaining informed consent from their parents. In addition, a questionnaire
      survey of the past history of prophylactic vaccinations was conducted. Serum
      titers of anti-RV antibody were measured using VIDAS Rubella-IgG and IgM
      (bioMerieux Japan Ltd.) and urinary titers of anti-RV IgG by ELISA (Otsuka
      Pharmaceutical Co., Ltd.). RESULTS: 1) The sensitivity and specificity for anti
      RV IgG measurement in urine were 99.4% and 100%, respectively. 2) Six of 12 cases
      suspected of rubella infection were confirmed as initial rubella infection, and
      showed significantly increased anti-RV IgG titers in convalescent sera. Anti-RV
      IgG titers were also increased in the urine specimens. 3) In 17 subjects who
      received prophylactic inoculation with live rubella vaccine, serum titers of anti
      RV IgG were increased 6-7 weeks after vaccination and anti-RV IgG was also
      detected in urine samples from all cases. 4) Urine samples from 80.9% of the
      children were positive for anti-RV IgG. In addition, 81.7% of the 698 cases,
      whose parents completed the questionnaire had received prophylactic inoculation
      with live rubella vaccine, confirmed by the vaccination records in maternal and
      child health handbooks. Furthermore, urine samples from 12.5% of children who had
      not received prophylactic live rubella vaccination were positive for anti-RV IgG.
      CONCLUSIONS: The results of this study suggest that increased antibody titers
      after spontaneous rubella infection and prophylactic vaccination can be confirmed
      by measuring antibody titers in the urine. The results also suggest that urine
      sampling is useful for epidemiological studies of rubella because collection is
      simple, even from children.

PMID- 12607988
TI  - [A survey of infection control among community home care service providers].
AB  - PURPOSE: This study aimed to explore the current situation of infection control
      by community home care providers. METHODS: We investigated an area managed by one
      of 6 municipal social welfare offices in Fukushima. Two questionnaires were sent
      to all home care agencies providing home help services, visiting bathing care and
      visit-nursing: one to the 82 chiefs of the agencies (response rate of 90.2%) and
      the other to 1024 health care workers working for them (57.2%). The questionnaire
      covered health checkups of employees, maintenance and management of devices,
      infection control education and manuals, and hand hygiene. RESULTS: 1. Medical
      checkups were organized once a year or more at 94.6% of the agencies and employee
      participation of once a year or more was 87.6%. 2. Regarding the management of
      health care devices, personnel were assigned and a registration system was
      introduced at 43.2% and 20.8% of the agencies, respectively. Most agencies
      (94.6%) provided disposable gloves and 82.6% of the employees used them when
      handling body fluids or excretions. However, not many agencies provided hand
      washing equipment (43.2%) and paper towels (39.2%). 3. Infection control
      educational programs were organized at 40.3% of the agencies and attended by
      30.2% of the employees. Among the agencies without such programs, 76.2% gave
      employees' time constraint as a reason for not giving training. On the other
      hand, 78.5% of non-attendants of the program answered that they were not given a
      chance to participate. 4. Infection control manuals were available at 68.9% of
      the agencies, but only 69.4% of their employees were aware of them and only 44.3%
      utilized them. Agencies were aware of the situation and only 42.9% answered that
      their manuals were fully utilized. Among the agencies currently without manuals,
      47.8% are developing manuals. 5. When and how to wash hands and how to use towels
      in home care settings were specified in 73.0%, 78.4% and 35.1% of the agencies,
      respectively. As high as 92.0% of employees washed their hands after caring for
      clients and 74.6% after handling body fluids or excretions, but 52.2% did so
      before caring. It was noted that although 82.7% of the employees washed their
      hands with water and soap (and antiseptic agents), only 7.5% used paper towels to
      dry their hands. CONCLUSION: The chiefs of home care providers should be required
      to develop and implement better infection control strategies with the support of
      local governmental agencies.

PMID- 12607989
TI  - [Study on the effects of telephone counseling for family caregivers of demented
      patients].
AB  - PURPOSE: The purposes of this study were to clarify the impact of telephone
      counseling on the actual state of family caregivers of demented patients, and to
      investigate strategies of public health care for such caregivers. METHODS: We
      classified 206 counseling cases, including 103 cases in 1999 and 103 cases
      through mid-2000, using several checklists, and analyzed date with the chi 2
      test. RESULTS: 1) The most common symptom of demented patients was
      "forgetfulness." (106 cases) 2) 87 caregivers (42.2%) lived separately from
      demented patients, and in 60 cases the caregivers were daughters. 3) 104
      caregivers suffered from stress because of caregiving difficulties, 89 (43.2%)
      having "emotional difficulties in caregiving," 33 (16.0%) "social difficulties
      with caregiving," 28 (13.6%) "physical difficulties with caregiving," and 8
      (3.9%) "financial difficulties." While 102 caregivers (49.5%) reported no
      caregiving difficulties. 42 (40.4%) belonged to more than two of the listed
      categories. 4) The greatest concern of caregivers was "how to care for senile
      patients' mental symptoms." followed by "whether suffering from dementia" in 36
      cases, "how to use welfare services" in 35, "whether the doctor should be
      consulted" in 30, and "expression of emotion" in 30 cases. The caregivers for
      whom "expression of emotion was an issue" had emotional, social and physical
      caregiving difficulties, prompting the contact for telephone counseling. 5)
      Public health nurses who had been working for more than 10 years tended to deal
      with the caregivers' "emotional caregiving difficulties" (P = 0.05). There were
      no differences regarding other items. CONCLUSIONS: 1) The results suggest that
      living apart, especially for daughters, has an effect on caregiving with senile
      patients if the number of family caregivers is reduced. In the future, we should
      consider ways to support families living apart from senile patients. 2) The
      results also reveal that caregivers of senile patients have emotional, social and
      physical caregiving difficulties. Therefore, a necessity for support of
      caregivers' emotional and physical health maintenance, and provision of community
      education is indicated. 3) Caregivers can talk more freely on the telephone than
      face-to-face, and get help when senile patients' symptoms are in the early
      stages. Therefore, it is possible to mitigate caregiving difficulties by
      intervening in their problems before these become serious and entrenched. 4)
      Telephone counseling gives caregivers the opportunity to express their emotions.
      Therefore, it can be expected to mitigate caregiving difficulties through
      appropriate targets of their expressed concerns.

PMID- 12607990
TI  - [A report on medication adherence among outpatients].
AB  - BACKGROUND: Increase in chronic disease and hospital stays of minimal length have
      caused a rise in the number of outpatients receiving long-term medication. The
      authors conducted the present study to examine their adherence to medication.
      METHODS: Self-administered questionnaires covering 20 items related to adherence
      were collected from outpatients who received medication from O university
      hospital on a day in October 1998. The authors examined the relationship between
      adherence to medication and lifestyle and then analyzed predictors of adherence
      using discriminant analysis. RESULTS: The rare of adherence to medication for 943
      outpatients in O university hospital was 87.9%. The major reasons for non
      adherence were "forgetting medication", "leaving home without [one's]
      medication," "suspecting side effects" and "having no symptoms". The patients who
      made a detailed explanation displayed better understanding and adherence to
      medication. Although 94.8% of the patients received an explanation about their
      medications at least once, 76.9% expressed some anxiety about their use.
      Predictors of poor adherence to medication were "no support to remind the patient
      to take medicines correctly," "anxiety about medication," "not receiving a
      detailed explanation about medications," "poor knowledge of medication," and
      "youth (20-29 years of age)." CONCLUSION: Among outpatients in O university
      hospital, the medication adherence rate is 87.9%, but most patients had
      anxieties. The results clarified the need to consider lifestyle in medication
      management in the outpatient setting, since this was the main predictor of
      adherence to medication.

PMID- 12607991
TI  - [Assessment of the Cuban approach to AIDS and HIV].
AB  - OBJECTIVE: The objective of this study was to assess the Cuban AIDS polidy model
      and its possible application to other developing countries through
      epidemiological analyses. METHOD: The author conducted a field study in Cuba from
      March 23 to 31, 2001, and reviewed related articles. RESULTS: (1) The National
      Referral Center of Cuba, the Pedro Couri Institute, detected 3,230 HIV positive
      patients between 1986 and January 2001. Among them, 2,500 were male and 730 were
      female. (2) 45 institutions are responsible for the preliminary screening and the
      Pedro Couri Institute finalizes the diagnosis. (3) Diagnosed patients are
      admitted to a sanatorium for AIDS patients or a day care hospital free of charge.
      (4) The Ministry of Health in Cuba set up a national committee on AIDS in 1983,
      and had screened eight million people by June 1990, all provinces in Cuba started
      building AIDS sanatoriums. From 1993, day care hospitals started treating
      patients. CONCLUSIONS: Cuba has succeeded in controlling the HIV/AIDS epidemic.
      Its success relies on the existing health care system and intervention at early
      stages. Due to the debates on the sanatorium policy and the screening of pregnant
      mothers, direct application of the cuban model to other countries requires
      careful consideration at this stage.

PMID- 12607992
TI  - [Airway hyperreactivity in patients undergoing hematopoietic stem cell
      transplantation].
AB  - Airway hyperreactivity (AHR) was studied with an astograph for 34 sequential
      hematopoietic stem cell transplantation (HSCT) patients before and after HSCT.
      The percentage of Dmin positive patients was 25.0% before HSCT and 25.0-57.1%
      after HSCT, while all normal subjects were negative for Dmin. The mean Dmin of
      post HSCT patients was 22.7 u in days 501-1000 and 19.3 u after 1001 days, which
      was significantly lower than the 45.2 u of normal controls. The patients were
      divided into two groups according to the treatment before HSCT, strongly treated
      (S, acute leukemia and non-Hodgikin lymphoma) and weakly treated (W, chronic
      myelogenous leukemia and aplastic anemia) patients. The ratio of Dmin positive
      patients and mean Dmin in the W group after HSCT (38.9%, 27.8 u), and the S group
      before and after HSCT (55.6%, 20.5 u and 45.5%, 23.8 u, respectively), were
      significantly impaired compared with the findings in the normal controls (0%,
      45.2 u). The mean sGrs/Grs count was higher in the W group before HSCT than in
      the other groups (W before and after HSCT, 0.58 and 0.19, respectively; S before
      and after HSCT, 0.21 and 0.22, respectively). Taken together, AHR was observed in
      HSCT patients, particularly for patients in the S group. These data indicate that
      high dose chemo-radiotherapy including conditioning regimen causes AHR. The
      mechanisms leading to AHR may be infection, inflammation, and remodeling of the
      airway.

PMID- 12607993
TI  - [Thalidomide therapy in patients with refractory or relapsed multiple myeloma].
AB  - We treated seven refractory or relapsed myeloma patients resistant to
      conventional chemotherapy with thalidomide. We started thalidomide at 100 mg
      daily and the dose was increased up to 300 mg if the patient could tolerate it.
      The patients were evaluated at four weeks and 12 mg of dexamethasone was added
      for four days when the patient failed to respond to thalidomide treatment. One
      patient was excluded from the study because of general fatigue. Two of the six
      patients responded to thalidomide alone and three of the remaining four patients
      responded to the combination with dexamethasone. The most common adverse effect
      was sleepiness which was seen in three patients. Two patients showed pancytopenia
      (Grade 3), constipation and skin eruption. Of the six patients four needed
      reduction of the thalidomide dose to 200 mg because of adverse effects. Plasma
      levels of TNF-alpha, IL-6, bFGF and VEGF were measured before and after four
      weeks. High plasma bFGF levels were seen in responding patients. In conclusion,
      treatment with thalidomide alone or in combination with dexamethasone is feasible
      and effective in refractory or relapsed myeloma patients. Further study is
      required to clarify the role of thalidomide in the therapeutic strategy for
      multiple myeloma.

PMID- 12607994
TI  - [Simultaneous development of factor V inhibitor and autoimmune thrombocytopenia
      in a patient with dermatomyositis].
AB  - It has been previously demonstrated that aging, a history of malignancy or
      surgery, and exposure to bovine thrombin may be related to the presence of factor
      V inhibitor. However, dermatomyositis (DM) and autoimmune thrombocytopenic
      purpura (ATP) have rarely been associated with factor V inhibitor. Here we report
      a patient with factor V inhibitor accompanied by DM and ATP. In January 2000, a
      77-year-old woman with DM was hospitalized because of susceptibility to bleeding.
      At the onset of DM, she had suffered from gastric leiomyosarcoma, and had
      undergone gastrectomy and splenectomy without the use of bovine thrombin.
      Thereafter, she had been treated with prednisolone until October 1999. On
      admission, prolongation of both APTT and PT was seen. Her factor V activity had
      fallen to 6%, and factor V inhibitor was positive at 8.9 Bethesda units. Moreover
      her platelet count had dropped to 1.0 x 10(9)/l. A bone marrow aspirate showed a
      cellular marrow with megakaryocytic hyperplasia, and the patient's PA-IgG level
      was elevated at 389 ng/10(7) cells. These findings suggested that ATP was also
      present. Additionally, the patient showed a positive result for Coombs test and
      consumption of complement. After a further course of steroid therapy, the
      patient's condition was markedly improved. This is a very rare case that showed
      factor V inhibitor and ATP simultaneously. Furthermore, the patient's clinical
      course suggests the relationship between the presence of factor V inhibitor and
      the reactivation of her collagen disease activity.

PMID- 12607995
TI  - [ATL (lymphoma type) presented with a mass formation in the heart].
AB  - A 50-year-old man was admitted to another hospital with epigastralgia. Malignant
      lymphoma was suspected because the patient had increased levels of serum LDH and
      an abnormal Ga scintigraphy finding in his chest. When he was transferred to our
      hospital, he underwent a right inguinal lymphadenopathy. The laboratory data
      showed increased levels of serum LDH and soluble IL-2 receptor, but there was no
      appearance of peripheral abnormal lymphocytes. His chest MRI indicated tumors in
      the right atrium (4 cm x 4 cm) and in the head of his left humerus. Those tumors
      were enhanced by Gd-DTPA. There were no other lymphadenopathies.
      Histopathological and immunohistochemical studies showed T-cell type lymphoma in
      the right inguinal lymph node. Furthermore, monoclonal rearrangement of HTLV-I
      proviral DNA was detected from the lymph node by Southern blot analysis. Taken
      together, we diagnosed the patient as having ATL (lymphoma type). His condition
      has improved well with systemic chemotherapy. We report a rare case of lymphoma
      type ATL with initial massive cardiac involvement, although ATL cells sometimes
      involve the heart at the end of the disease course.

PMID- 12607996
TI  - [Acute leukemia in two brothers].
AB  - A 42-year-old man was diagnosed as having refractory anemia in May, 2001. He
      developed overt leukemia and received allogeneic bone marrow transplantation
      (BMT). His younger brother, a 40-year-old man, was diagnosed as having acute
      leukemia with trilineage myelodysplasia in November, 2001. Although he was
      treated with conventional chemotherapy, he failed to achieve complete remission.
      He also received allogeneic BMT. We suggest that environmental factors in
      addition to a genetic defect in the pluripotent hematopoietic stem cells may be
      associated with the occurrence of this familial leukemia.

PMID- 12607997
TI  - [Guidelines on the viral conjunctivitis].

PMID- 12607998
TI  - [Epidemiology].

PMID- 12607999
TI  - [Differential diagnosis of conjunctivitis].

PMID- 12608000
TI  - [Clinical findings in viral conjunctivitis].

PMID- 12608001
TI  - [Laboratory diagnosis of viral conjunctivitis].

PMID- 12608002
TI  - [Treatment of viral conjunctivitis].

PMID- 12608003
TI  - [Nosocomial infection of adenovirus conjunctivitis: prevention and management].

PMID- 12608004
TI  - [Frequently asked questions about adenovirus conjunctivitis].

PMID- 12608005
TI  - Improving network-provider relationships: resolving conflicts and developing
      solutions.

PMID- 12608006
TI  - Measures and systems: a new formulation of managed care?

PMID- 12608007
TI  - Another "solution" to the problem of managed care.

PMID- 12608008
TI  - Smoking, estradiol metabolism and hormone replacement therapy.
AB  - Products for hormone replacement therapy (HRT) in the postmenopause are the
      second most frequently prescribed drugs in the USA. Among the women receiving
      this treatment many are smokers. In the Women's Health Initiative (WHI), one of
      the largest interventional studies on HRT to date and which recently had to be
      discontinued, 50% of the 8,500 women on HRT had smoked before or continued to
      smoke during the study. Remarkably, there is little knowledge about the impact
      smoking has on the efficacy and side effects of HRT. However, it has been proven
      that, depending on the type, duration and intensity of nicotine consumption,
      smoking can reduce or completely cancel the efficacy of orally administered
      estrogens. Not only does smoking diminish the otherwise well-established
      beneficial effects of estrogen on hot flashes and urogenital symptoms and its
      positive effects on lipid metabolism, i.e. by reducing cholesterol, but smoking
      also specifically reduces estrogen's ability to prevent osteoporosis. The
      reduction or loss of therapeutic efficacy is mainly caused by dose-dependently
      elevated hepatic clearance, partially in conjunction with lower estrogen levels,
      and has been demonstrated only with oral estrogen applications. This failure of
      therapeutic action should not be compensated for by increasing the dose in
      smokers as this might result in the production of toxic, even potentially
      mutagenic estrogen metabolites-compounds recently associated with a higher risk
      of breast cancer. The favorable effects of estrogens are not lost in smokers when
      they are applied transdermally. This route enables low dosage and also avoids the
      formation of unphysiological metabolites by bypassing the liver. Women who
      continue to smoke despite all warnings should therefore only be treated via the
      transdermal route. Oral contraceptives, but not HRT, are contraindicated in
      elderly smokers. However, the principal conclusion of the WHI study was that the
      lowest dose possible should be chosen, especially in patients with an increased
      cardiovascular risk, as is the case in smokers.

PMID- 12608009
TI  - Psychopharmacological effects of tianeptine analogous hetero[2,1] benzothiazepine
      derivatives.
AB  - The psychopharmacological effects of a number of thieno and pyrazolo[2,1]
      benzothiazepine derivatives as well as several synthetic intermediate compounds
      were investigated in mice. Previously published studies in mice have shown that
      some of these compounds were effective in the tetrabenazine and Porsolt tests. In
      the present study, 7 of the 15 compounds under study clearly antagonized the
      apomorphine (16 mg/kg s.c.)-induced hypothermia, but no significant potentiation
      of the 5-hydroxytryptophan (5-HTP) and amphetamine actions was found. Five of
      them inhibited the syndrome induced by 5-HTP (250 mg/kg i.p.). Moreover, some of
      them were effective in the plus-maze test and antagonized the apomorphine (3
      mg/kg s.c.)-induced effects. On the other hand, these compounds produced a
      moderate inhibition of exploratory behaviour in the hole-board test, but they had
      no significant muscle relaxant and anticonvulsant activities. The results
      indicate that some of the compounds under study combine a spectrum of
      antidepressant, anxiolytic and neuroleptic properties in mice with a lack of
      muscle relaxant and anticonvulsant activities.

PMID- 12608010
TI  - Effects of imipramine treatment on delta-opioid receptors of the rat brain cortex
      and striatum.
AB  - Imipramine (CAS 113-52-0) is being utilized widely for the treatment of major
      depression. In recent years, there has been evidence of the involvement of the
      endogenous opioid system in major depression and its treatment. There is some
      evidence indicating that opioid receptors could be involved in the antidepressant
      mechanism of action. Regarding this topic, mood-related behavior of endogenous
      enkephalins seems to be mediated by delta-opioid receptors. In this work, the
      effects of subacute (5 day) and chronic (15 day) treatments of imipramine on the
      density and the affinity of the delta-receptors in the striatum and in the
      parietal and frontal cortices of the rat brain are described. Studied parameters
      (Bmax and Kd) were calculated by a saturation binding assay with the delta-opioid
      agonists [3H]-DPDPE (tyrosyl-2,6-3H(N)-(2-D-penicillamine-5-D-penicillamine)
      enkephalin) as specific ligand and DSLET ([D-serine2]-D-leucine-enkephalin
      threonine) as non-radioactive competing ligand. It was found that 15 days
      treatment significantly decreased the delta-opioid receptor density,without
      changing the affinity, in the frontal cortex of the rat brain. That decrease was
      confirmed by delta-opioid receptor immunostaining. These results suggest that
      delta-opioid receptors could play a role in the chronic action mechanism of
      imipramine.

PMID- 12608011
TI  - Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011
      in rats and dogs.
AB  - In this study, the pharmacokinetics of SNI-2011 ((+/-)-cis-2-methylspiro[1,3
      oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS
      153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the
      treatment of Sjogren's syndrome, in rats and dogs were determined following
      intravenous or oral administration using liquid chromatography/mass spectrometry
      (LC/MS). The in vitro metabolism of SNI-2011 was also evaluated with rat and dog
      liver microsomes. After oral administration, plasma concentrations of SNI-2011
      reached to Cmax within 1 h in both species, suggesting that SNI-2011 was quickly
      absorbed, and then decreased with a t1/2 of 0.4-1.1 h. The bioavailability was
      approximately 50% and 30% in rats and dogs, respectively. Major metabolites in
      plasma were both S- and N-oxidized metabolites in rats and only N-oxidized
      metabolite in dogs, indicating that a large species difference was observed in
      the metabolism of SNI-2011. Sex difference was also observed in the
      pharmacokinetics of SNI-2011 in rats, but not in dogs. In the in vitro study,
      chemical inhibition and pH-dependent studies revealed that the sulf-oxidation and
      N-oxidation of SNI-2011 were mediated by cytochrome P450 (CYP) and flavin
      containing monooxygenase (FMO), respectively, in both species. In addition, CYP2D
      and CYP3A were mainly responsible for the sulfoxidation in rat liver microsomes.

PMID- 12608012
TI  - Synthesis and local anaesthetic activity of 2-substituted-N-(2-diethylaminoethyl)
      acetamides.
AB  - The synthesis of 2-substituted-N-(2-diethylaminoethyl)acetamide oxalates (6a, 6b)
      and the evaluation of their in vivo local anaesthetic activities are described.
      The compounds 6a and 6b were obtained starting from 4-acetamidophenol and 1
      naphthol, respectively. The in vivo local anesthetic activity was evaluated by
      infiltration anaesthesia, sciatic nerve block and corneal anaesthesia models. N
      (2-Diethylaminoethyl)-2-(naphthalen-1-yloxy)acetamide oxalate (6b) was found to
      have potency, onset and duration of action comparable to that of lidocaine (2)
      (lidocaine hydrochloride, CAS 6108-05-0). Procaine (1) (procaine hydrochloride,
      CAS 51-05-8) was also used for comparison. Dissociation constants (pKa) of
      compounds 5a and 5b (2-substituted-N-(2-diethylaminoethyl)acetamide) have been
      determined to be 8.9 and 8.6, respectively.

PMID- 12608013
TI  - In vitro release of felodipine from original brand and generic products.
AB  - Eight different felodipine (CAS 72509-76-3) products (nominal content: 5 mg) were
      tested for their in vitro release profile: The generic drugs A-G and the
      reference product Modip. During an incubation period of 7 h in dissolution
      vessels (paddle method in accordance with USP XXII) samples were taken to be
      assayed for the active ingredient concentration within 24 h by means of UV
      spectroscopy. All products examined released at least the content declared. While
      the 6 tablets of the reference differed only slightly in their release kinetics,
      the other products showed considerable variability with the exception of Drug D
      (uniform rapid release) and Drug C. The reference offered the linear controlled
      release profile expected from an extended-release product. Three different time
      profiles could be distinguished in the generics: a) Drugs A, B, F, and D
      practically showed immediate release of the active ingredient, b) Drugs E and G
      showed some extent of controlled release (however, more than 50% of the total
      content was released within 60 min); c) Drug C displayed controlled-release
      properties but a more rapid release than the reference at all sampling times.

PMID- 12608014
TI  - Anti-inflammatory activity of some novel alpha-amino naphthalene derivatives.
AB  - alpha-Acetylamino naphthalene (1) was reacted with different aromatic aldehydes
      and with primary or secondary amines to give alpha-aminonaphthylsubstitutedaryl
      chalkones (2-5) and alpha-(substituted aminoethyl)-amidonaphthalenes (14-25),
      respectively. These substituted chalkones were treated with hydrazinehydrate and
      hydroxylamine hydrochloride to give 1-acetyl-5-substitutedaryl-3-(alpha
      aminonaphthyl)-2-pyrazolines (6-9) and alpha-(2-substitutedaryl-isoxazolin-4-yl)
      aminonaphthalenes (10-13), respectively. Their chemical structures were confirmed
      by IR and 1H-NMR spectral data and elemental analysis. Studies of the anti
      inflammatory and ulcerogenic activities and acute toxicity of these newly
      synthesized compounds were performed in vivo and compared with the standard drug,
      phenylbutazone (CAS 50-33-9). Some of these compounds showed potent anti
      inflammatory activity and less ulcerogenic effects than phenylbutazone.

PMID- 12608015
TI  - Thermodynamic characterization of the binding process of sulindac to human serum
      albumin.
AB  - This study deals with the molecular basis of the binding of the anti-inflammatory
      drug sulindac (CAS 38194-50-2) to human serum albumin (HSA) using high
      performance liquid affinity chromatography. The chromatography was carried out
      using a HSA-immobilized column and a predominantly aqueous mobile phase (67
      mmol/l sodium phosphate buffer/propan-1-ol, 94:6 v/v). A small quantity of
      sulidac was injected onto the column while increasing concentrations of the same
      drug were added to the mobile phase. The capacity factor k' serves as a measure
      for the binding affinity. The experiments were carried out at different
      temperatures in order to establish some thermodynamic parameters of the binding
      process. The values of the binding affinity constants decreased with the
      temperature. The free energy change was almost constant. Its large negative value
      suggests a spontaneous binding of sulidac to HSA. Both enthalpy and entropy
      changes of the binding process were also negative assuming donor-acceptor
      interactions between sulindac and its binding sites in HSA. Hydrogen bonds and
      salt linkages are supposed to make a major contribution to the binding of
      sulindac to HSA, while hydrophobic interactions seem to be of less importance.

PMID- 12608016
TI  - Efficacy of praziquantel and Ro 15-5458, a 9-acridanone-hydrazone derivative,
      against Schistosoma haematobium.
AB  - The efficacy of Ro 15-5458 ([10-(2-diethylamino)ethyl)-9-acridanone(thiazolidin-2
      ylidene)hydrazone, CAS 92928-47-7) as a new antischistosomal drug was studied in
      hamsters using a dose of 20 mg/kg body weight against an Egyptian strain of
      Schistosoma haematobium, in comparison with praziquantel (PZQ, CAS 55268-74-1)
      (full dose 1000 mg/kg body weight). This was carried out at 4, 8 and 12 weeks
      post cercarial exposure of hamsters. The criteria used for the assessment of drug
      efficacy were the worm load, oogram pattern and number of ova/g liver and
      intestine. Results revealed that in earlier stages of infection (4 weeks post
      cercarial exposure), Ro 15-5458 proved to be more effective than PZO, the worm
      load was reduced by 83.2% and 55.6% from the untreated control group,
      respectively. At the same time, treatment with Ro 15-5458 increased the ratio of
      dead ova, while treatment with PZQ showed no change in the oogram pattern
      compared with the untreated control group. The reduction of eggs/g liver and
      intestine was higher in the group treated with Ro 15-5458, being 95.7% and 98.2%,
      compared to 65.3% and 79.2% in the PZQ group, respectively. However, in older
      infection (at 8 and 12 weeks post cercarial exposure) both drugs produced similar
      positive results regarding worm load, oogram pattern and the number of eggs/g
      liver and intestinal tissues. Consequently, Ro 15-5458 proved to be as efficient
      a drug as PZQ in the treatment of mature infection of schistosomiasis
      haematobium. Furthermore it showed much better effect in immature cases of
      infection.

PMID- 12608017
TI  - The struggle to stay outside the gates.

PMID- 12608018
TI  - Those fragile hearts. Who dies from heart attacks? Surprisingly, more women than
      men.

PMID- 12608019
TI  - [Dementia is to be investigated and treated].

PMID- 12608020
TI  - [Frontotemporal dementia--new understanding of Pick disease].
AB  - Frontotemporal dementia is a relatively new term, which encompasses several
      degenerative diseases involving the frontal and anterior temporal lobes. The
      article gives a short overview of new knowledge in this field. Clinical criteria
      are in focus, but neuropathological aspects are also mentioned.

PMID- 12608021
TI  - [Human endogenous retroviruses and disease?].
AB  - Endogenous retroviruses represent sequences descended from ancient virus
      infections integrated in the host genome. They participate in processes, such as
      speciation, recombination, ontogenesis, and regulation of tissue specificity and
      gene expression. It has been suggested in recent years that human endogenous
      retroviruses may play a role in certain types of cancer and autoimmune diseases.
      Human endogenous retroviruses represent both putative susceptibility genes and
      putative pathogenic viruses in diseases like systemic lupus erythematosus,
      Sjogren's disease, rheumatoid arthritis, and possibly type 1 diabetes. Multiple
      sclerosis is specifically associated with expression of human endogenous
      retroviruses as virions. It is not yet known if the human endogenous retroviruses
      also represent causal factors, but several pathogenic mechanisms are possible.

PMID- 12608022
TI  - [Depressive conditions in adolescence (teens): identification, psychopathology
      and therapeutic possibilities].

PMID- 12608024
TI  - [Measuring of preoperative anxiety by three self-reporting scales: State Trait
      Anxiety Inventory, Symptoms CheckList 92 and visual analogue scale].
AB  - INTRODUCTION: Preoperative anxiety is a common phenomenon. It is therefore
      necessary to investigate whether quantitative self-reporting anxiety scales can
      be helpful in the anaesthetic clinic and research. The aim of this study was to
      compare the state trait anxiety inventory (STAI), symptoms checklist 92 (SCL 92),
      the subscales anxiety and phobic anxiety, and a visual analogue scale for anxiety
      (VAS). MATERIAL AND METHODS: Thirty-eight women consecutively referred for
      elective breast surgery filled in the rating scales the day before the operation.
      RESULTS: A statistically significant correlation was found between STAI, SCL 92,
      anxiety, and VAS. The patients' STAI and SCL 92 anxiety scores were markedly
      higher than that of the background population. DISCUSSION: In this study the STAI
      scale, SCL 92 anxiety, and VAS measure all essential features of the phenomenon.
      SCL 92 anxiety is nevertheless considered to be the most appropriate rating
      scale, because it has been validated in a Danish population.

PMID- 12608023
TI  - [Treatment with antidepressants in geriatric departments. Occurrence and record
      keeping].
AB  - INTRODUCTION: The aim of the present study was to describe the occurrence of
      antidepressant treatment in geriatric departments in Denmark and assess the notes
      of the patient records in connection with prescription. MATERIAL AND METHODS:
      Patient records for consecutively referred patients in seven geriatric
      departments were examined and basic information was noted. For users of
      antidepressants further information about the treatment was noted. RESULTS: A
      total of 1211 patients records were examined and out of these 338 patients were
      in treatment with antidepressants (29.7%). The users of antidepressants used more
      drugs on their discharge from the hospital. For 61.8% (209/338) of the users the
      treatment had started before the admission and in more than three-fourths the
      treatment remained unchanged at their discharge, in 9% the treatment was
      discontinued. 38.2% (129/338) started their treatment during the admission.
      Depression was stated as being the main reason in 54% of those who continued an
      ongoing treatment, and in 78% of those who started their treatment during
      admission. In 98.4%, the beginning of treatment with antidepressants was based
      upon the file notes. In 34.8% of the records of ongoing treatment no file notes
      were given. DISCUSSION: Treatment with antidepressants is common in geriatric
      departments and most often it is a question of continuation of a treatment that
      had started before the admission. The study shows that there is a need for an
      optimization of the file notes.

PMID- 12608025
TI  - [Hearing loss in children--epidemiology, age at identification and causes through
      30 years].
AB  - INTRODUCTION: The survey describes paediatric audiology through 30 years within
      Copenhagen City concerning epidemiology, age at identification, and causes of
      permanent hearing impairment in children. MATERIAL AND METHODS: Three
      longitudinal ten years birth-cohorts [table: see text] are included: 1970-1979 (n
      = 69); 1980-1989 (n = 64), and 1990-1999 (n = 104) provided with hearing aids,
      living in the Copenhagen City at the time of the data collection in January 1982,
      1992, and 2002. The cohorts 1970-1979 and 1980-1989 have previously been
      described (1), whereas the 1990-1999 birth cohort is evaluated as part of a
      prospective registry study. The estimated prevalences are based on the age
      matched background population. RESULTS: The estimated prevalence of children
      provided with hearing aids is 1.97/1000 and the estimated prevalence of
      congenital hearing impairment is 1.50/1000--without longitudinal changes from
      1970-1979 over 1980-1989 to 1990-1999. The proportion of at-risk children in the
      three-pooled birth-cohorts is 63.3%. The median age at identification of the
      birth-cohort 1990-1999 was 18 months, 1980-1989 16 months, and 1970-1979 43
      months. Only 6% of children with congenital hearing impairment born 1990-1999 are
      identified at the age of six months, and only 27% at the age of one year. An
      increase in the prevalence of genetic hearing impairment in the cohort 1970-1979
      was demonstrated. DISCUSSION: The prevalence of permanent hearing impairment in
      childhood through three decades is unchanged, and the age at identification of
      children with congenital hearing impairments is still delayed. Factors causing
      hearing impairment demonstrate an increase in genetic factors, which, however,
      are not significant.

PMID- 12608026
TI  - [Hospital costs and benefits of screening for abdominal aortic aneurysm. Results
      from a randomized screening trial].
AB  - INTRODUCTION: The hospital costs and benefits of screening older males for
      abdominal aortic aneurysms (AAA) are unknown. MATERIAL AND METHODS: In 1994, a
      hospital-based screening trial of 12,658 65-73-year-old males in the County of
      Viborg, Denmark, was started. AAA > 5 cm were referred for surgery. The remaining
      AAA were offered annual control scans. Those with aortic ectasia (def.: 2.5-2.9
      cm) were rescreened at 5-year intervals. AAA-operations and deaths of AAA at
      hospital were registered. Finally, costs of screening, surveillance, and
      treatment were registered. Data on causes of death outside hospitals could not be
      obtained. RESULTS: The attendance rate was 76%, of whom 191 (4.0%) had AAA. The
      average observation time was 5.13 years. 60 in the screened and 41 in the control
      group were operated (P = 0.06), 7 and 27 were operated as an emergency (P <
      0.001), and 6 and 19 died at the hospitals due to AAA (p = 0.009). The costs per
      scan were 83.50 DKK, 81,400 DKK per elective operation (71,485 DKK after
      screening), and 117,000 DKK for an emergency operation. The costs per prevented
      hospital death were 67,855 DKK or approx. 7,540 DKK per life year saved (1 GBP =
      12 DKK). DISCUSSION: Screening older males for AAA in Denmark seems very cost
      effective and reduces hospital mortality of AAA by 68% and probably the overall
      AAA-specific mortality by 73%.

PMID- 12608027
TI  - [Pseudoaneurysm in the femoral artery after repeated hip surgery--combined
      thrombolytic and surgical treatment].
AB  - Pseudoaneurysms in the femoral artery seldom occur spontaneously. Commonly they
      occur secondarily to trauma or as a complication to surgery or angiography. This
      study reports the occurrence of a pseudoaneurysm in the left common femoral
      artery. The patient, a 54-year-old woman, had undergone leftsided hip replacement
      five years before and several subsequent operations on the left hip due to
      dislocation and loose cup. She was admitted with a palpable non-pulsating mass in
      her left inguinal region and pain and cyanosis in her left lower limb. Ultrasound
      and angiography showed a pseudoaneurysm with occlusion of the popliteal, the
      tibial, and the peroneal arteries. The patients was successfully treated with
      actilysis for 48 hours and subsequent vascular surgery.

PMID- 12608028
TI  - [Clinical heart arrest after emergency "direct current" cardioversion of atrial
      flutter].
AB  - A rare case of clinical cardiac arrest after acute DC cardioversion is presented.
      The patient was a 64-year-old man with acute haemodynamically unstable atrial
      flutter. He was known to have had episodes of atrial flutter requiring DC
      cardioversion, and he was treated with propafenone (300 mg twice daily).
      Synchronised DC cardioversion resulted in cardiac arrest. Resuscitation was
      initiated and after 2-3 minutes the patient regained sinus rhythm and pulse.
      There were no sequelae. We conclude that cardiac arrest is a rare complication to
      DC cardioversion.

PMID- 12608029
TI  - [Acute idiopathic scrotal edema: a rare or underdiagnosed disease?].
AB  - We present a case of acute idiopathic scrotal oedema diagnosed after surgical
      scrotal exploration and we discuss its incidence, differential diagnoses and
      indication of surgery for acute scrotum with boys.

PMID- 12608030
TI  - [Breast cancer screening--re-evaluation].

PMID- 12608031
TI  - [Awareness-oriented (holistic) medical theory: the purpose of life theory (the
      life mission theory)].

PMID- 12608032
TI  - [Transpalpebral tonometer for measuring intraocular pressure].
AB  - Two new portable instruments--an ophthalmotonometer (TGDc-01) and a pressure
      indicator (IGD-02)--which make it possible to measure the intraocular pressure
      (IOP) through the eyelid, were worked out. The operation of both instruments is
      based on determining the acceleration of freely falling rod after its interaction
      with the elastic eye surface. The readings of TGDc-01 correlate with the genuine
      IOP, and those of IGD-2--with the tonometric pressure for Maklakov's tonometer
      with a weight of 10 g. The accuracy of both instruments is sufficient for
      clinical purposes; there is no need to use anesthetics or to sterilize the
      instruments, which are easy in usage. They can be used not only in ophthalmologic
      examination rooms but also at home.

PMID- 12608033
TI  - [Administration of epithalamine in the treatment of unstable glaucoma of
      different types after normalization of intraocular pressure].
AB  - The treatment effect and clinical efficacy of epithalamine solution was studied
      on 28 patients (42 eyes) with unstable glaucoma and normalized intraocular
      pressure (IOP). Epithalamine belongs to the group of cytomedines and it has a
      modeling effect on the functional activity of the simpatico-adrenaline system,
      adrenal cortex and anti-oxidizing activity. The clinical study showed that the
      use of epithalamine solution resulted in normalization of the biochemical
      activity of the neuro-humoral triphism (adrenaline, norepinephrine, and
      hydrocortisone). It leads to an increased diameter of arterioles of the bulbar
      conjunctiva and of the optic disk as well as to a decreased degree of congestive
      angiopathy and of intravascular aggregation of erythrocytes.

PMID- 12608034
TI  - [Clinical aspects of normal pressure glaucoma].
AB  - A comprehensive ophthalmologic examination of 45 patients (76 eyes) with normal
      pressure glaucoma (confirmed in hospital by using tonography, computer perimetry
      with the "Humphrey-720" field analyzer being applied and by photometry of the
      optic nerve disk with the "Nidec" fundus-chamber being applied) was carried out.
      Polymorphism of clinical manifestations of the disease and specific features of
      such manifestations with regard for an initial level of the ophthalmic tone were
      revealed. Elderly age, the condition of the anterior segment and hydrodynamic
      parameters close to the age norm, a pronounced saucer-shaped or asymmetric
      excavation and segment-type nature of visual field defects were found to be more
      typical for glaucomatous patients with a relatively low intraocular pressure--IOP
      (< or = 20 mm Hg according to Maklakov). Younger age, dystrophic changes in the
      iris and drainage zone similar to those occurring at typical primary open-angle
      glaucoma, low indices of secretion combined with low indices of intraocular fluid
      discharge, predominant symmetric excavation and diffuse reduction of light
      sensitivity along the periphery with a predominant damage of the nasal segments
      were found to be more typical for glaucomatous patients with relatively high IOP
      (< or = 26 mm Hg). The described clinical aspects enable a timely diagnosis of
      the disease and an adequate choice of treatment.

PMID- 12608035
TI  - [Condition of ocular blood supply in patients with primary open-angle glaucoma
      with normal pressure].
AB  - The condition of discharge of intraocular fluid (IOF), the value of systemic
      arterial pressure (AP), the condition of mean dynamic arterial pressure in the
      ocular artery (Pm.ophth.) an the perfusion ocular pressure (Pperf.) were examined
      in patients with normal pressure glaucoma (NPG). A decrease in the IOF discharge
      from 0.16 +/- 0.02 cu mm per 1 mm Hg at the NPG initial stage to 0.11 +/- 0.01 cu
      mm per 1 mm Hg at the NPG deteriorated stage was established. The value of
      decrease of the systemic AP within an interval of 100 to 116 mm Hg is observed in
      patients with NPG by 6.9 times more often as compared to the controls (in 42.2%
      and 6.1% of cases, respectively). A reliable reduction of Pm.ophth. by 4.0 mm Hg
      and of Pperf.--by 4.9 mm Hg was found in patients with NPG as compared with
      Pm.ophth. and Pperf. in the controls with the same systemic AP values; the
      deficit of the ocular volumetric blood flow reached 10.9%. The treatment of NPG
      patients must be related with improving the IOF discharge, with reducing the
      genuine intraocular pressure (Po) to a tolerable level, and with increasing the
      systemic AP, Pm.ophth. and Pperf. to the mean statistically normal level.

PMID- 12608037
TI  - [Complications of trabeculectomy in congenital glaucoma in children].
AB  - Presently, trabeculectomy is being widely used for congenital glaucoma in
      children. The authors established, after examining 92 children, that the efficacy
      of surgical treatment was on the average affirmed in 98.7% of cases during the
      early observation period, and in 89.8% of cases during the late observation
      period (1-5 years). Complications occurred in 12% of eyes during the early and
      late postoperative periods. The complications observed during the early
      postoperative period were not the cause for relapses of elevated intraocular
      pressure. Excessive cicatrization in the surgical intervention zone was the most
      prevalent cause for the instability of the achieved treatment results in the late
      period.

PMID- 12608036
TI  - [Study of circadian (diurnal) rhythm of intraocular pressure in healthy persons
      and patients with glaucoma].
AB  - 35 patients (65 eyes) were examined; 10 patients (18 eyes) were without glaucoma
      or ophthalmic hypertension, and 25 patients (47 eyes) had an open-angle glaucoma
      of stages I-III. Glaucomatous patients were divided into 2 groups: patients of
      one group were examined in hospital (26 clinical studies), and those of another
      group were examined in policlinics (21 clinical studies). The studies resulted in
      elaborating a nearly daily rhythm correlating with the modern chronological-and
      biological recommendations, i.e. 9 measurements during 4 days were made in
      hospital and 11 measurements during 5 days were made in policlinics. Such
      tonometry method was proven to have advantages before Maslennikov's daily
      tonometry. It was established that the cyclic nature of fluctuations of
      intraocular pressure (IOP) is individual not only for each person but also for
      each eye. The obtained data support the advisability of measuring the IOP by
      using the chronological-and-biological method in diagnostically complicated
      situations, at so-called glaucoma with pseudo-normal IOP, and in choosing the
      treatment schemes for patients with glaucoma.

PMID- 12608038
TI  - [Humoral immune response to the retinal S-antigen in premature infants and its
      role in the development and course of retinopathy of prematurity].
AB  - The humoral immune response to the retinal S-antigen was studied in premature
      babies with active and cicatricle stages of retinopathy of the premature (RP) and
      in the controls (102 serum test). The presence of antibodies to the S-antigen of
      classes IgG and IgM was established by the enzyme multiplied analysis and by an
      authors' developed test-system. A definite specific humoral response to the S
      antigen correlated with the nature of the course and prognosis of the disease was
      found in 71% of cases. The first peak of IgM-antibodies was found in babies of
      the risk-group (preretinopathy), it correlated with a poor prognosis (progression
      of RP). The second peak was highly pronounced in babies with the terminal
      cicatricle stages of RP. The wave-like dynamics of IgG-antibodies suggests that
      specific circulating immune complexes shape up. The role of immune responses,
      induced by the retinal S-antigen, in the RP pathogenesis is discussed.

PMID- 12608039
TI  - [Effectiveness of present-day therapy of purulent lesions of the cornea].
AB  - The treatment of 313 patients (317 eyes) with purulent injuries of the cornea was
      studied. The medication therapy was found to be effective in 173 patients (176
      eyes), which made up 56.2%. The purulent process in the cornea was arrested after
      the therapeutic penetrating and lamellar keratoplasty in 62 patients (63 eyes or
      20.1%). 74 patients (74 eyes or 23.7%) were cured through the loss of an organ:
      enucleation was made for 63 patients, evisceroenucleation--for 8 patients and
      evisceration--for 3 persons. Before the onset of purulent pathology, all removed
      eyes were blind due to different diseases and traumas. Pathomorphological
      examinations of 63 enucleated eyes showed, in 76.2% of cases, purulent-and
      inflammatory changes only in anterior eye segment, and in 23.8% of cases they
      showed that the purulent process extended into the posterior segment structures
      of the eyeball; it is noteworthy that the signs of developing endophthalmitis
      were found only in 6.3% of cases. The obtained morphological data are indicative
      of that not all therapeutic possibilities were used to preserve the injured but
      unpromising (in the optic sense) eyes. We conclude that the absolute indication
      for removing an eye with purulent pathology of the cornea is the generalizing
      process, i.e. endophthalmitis or panophthalmitis.

PMID- 12608040
TI  - [Comparative evaluation of treatment methods in posttraumatic ciliary-choroidal
      detachment].
AB  - The detachment of the ciliary body and the choroid (ciliochoroidal detachment-
      CCD) is one of the most severe complications after mechanical trauma of the eye,
      and, according to published data, it is encountered in 1.9% of injured persons.
      The purpose of the study was to compare the efficacy of treatment of
      posttraumatic CCD by applying the traditional methods and those elaborated by the
      authors and based on using the modern laser equipment. The results of treatment
      of 26 patients with dislocated detachment of the choroid and ciliary body were
      analyzed. The conservative treatment for dislocated CCD produces, as a rule, a
      temporary result because it does not eliminate the causes of detachment. The
      traditional surgery for dislocated CCD ensures the adhesion only in one half of
      patients and it is related with a high risk of postoperative complications. The
      transscleral diode-laser cycloplexia is a most promising and low-traumatic method
      for dislocated CCD to be used during the early period after trauma.

PMID- 12608041
TI  - [Fluorescent angiographic evaluation of the iris microcirculation in cataract
      extraction by Nd:YAG laser with wavelength of 1.44 mcm].
AB  - The purpose of the present study is to evaluate the iridial microcirculation by
      fluorescent iridial angiography after laser cataract extraction by using a new
      extraction device, i.e. "RAKOT", based on the Nd:YAG-laser with wave length of
      1.44 mcm. 25 eyes (21 patients) aged 71 to 87 with mature senile cataract were
      examined. The method of laser cataract extraction was used in 14 cases. These
      eyes made up the main examination group. As for the controls (11 eyes), the
      manual technic of cataract extraction was used for them. The results in the main
      group show that the degree of the response of the iridial microvessels to surgery
      is insignificant and the microcirculation restores completely in 1.5-2 months
      after surgery provided there are no initial pathological changes in the iridial
      microcirculation (3 eyes). A short-time intensification of permeability of the
      iridial microcirculation is possible in eyes with a pronounced initial pathology
      in the iris (11 cases), however it restores to the original level during 3-3.5
      months after surgery. The iridial microcirculation restores in the controls
      during 3 months after surgery. The described data demonstrate that the laser
      cataract extraction does not lead to pronounced iridial vascular disorders. A
      comparison with the controls is indicative of a lower trauma in case of laser
      method versus the manual technic of lens extraction.

PMID- 12608042
TI  - [Characteristics of the distribution of major histocompatibility system antigens
      in retinal vasculitis in patients with Behcet's disease].
AB  - The etiology of Behcet's disease (BD) has not been accurately specified until
      now, however, it is a fact of general knowledge that the genetic factors and
      environment have an effect on the pathogenesis of the disease. 21 histological
      antigens (HLA) were typed for 30 Caucasians with BD (14 of them had retinal
      vasculities, and 16 of them were without it). HLA A and HLA B were determined by
      using the standard lymphocyte microcytotoxicity technique. The disease was
      diagnosed in accordance with the criteria of the International Study Group for
      BD. 1000 healthy donors of the Middle European population were in the control
      group. The frequency of occurrence of HLA B-5 was reliably higher in patients
      with retinal vasculitis (85.7%, PR = 5.53) and without retinal vasculitis (68.8%,
      PR = 4.44) as compared to the controls (15.5%, p < 0.0000). The occlusive retinal
      vasculitis was found only in BD patients with HLA B-5 (p = 0.0242). The study
      shows that HLA B-5 is associated with BD and can be a marker of severe retinal
      vasculitis.

PMID- 12608043
TI  - [Methods of the analysis of images in the diagnosis of diseases of the anterior
      eye segment].
AB  - Methods of mathematical computerized analysis of images obtained through the
      microscopy of the eye by the slit lamp were used in examining patients with
      different pathologies of the eye anterior segment. Densitometric and planimetric
      analysis of images of the cornea, lens as well as of the posterior and anterior
      capsules of the lens was made for patients with aphakia and artiphakia. The optic
      corneal density (which depends on a type and degree of refraction and an
      administered medication therapy) was found to change after excimerlaser
      procedures. The corneal transparency, which also depends on an administered
      medication therapy, was examined in cases of its opacities and photokeratitis.
      Examinations of the lens led to elaborating a clinical classification of cataract
      maturity degrees, which can be used during the preoperative period for planning a
      type and tactics of the therapeutic and surgical treatment. Main complications
      occurring after cataract extraction, i.e. opacities in the anterior and posterior
      capsules, were evaluated densitometrically. A classification of opacities in the
      lens capsule was worked out; it was used to determine the optimal time and types
      of the therapeutic and surgical treatment at secondary cataracts.

PMID- 12608044
TI  - [Use of cycloferon in a combined treatment of chlamydial conjunctivitis].
AB  - A high therapeutic efficiency of cycloferon, an interferon inductor, was
      demonstrated when it is combined with antibiotics in the treatment of chlamidial
      conjuctivitis. The use of the mentioned drug for acute chlamidial conjuctivitis
      prevents relapses.

PMID- 12608045
TI  - [Toxic lesions of the organ of vision caused by chloroquine derivatives].
AB  - An analysis of complications resulting from a long-term administration of
      chloroquinine derivatives is presented in the paper. The efficacy of
      chloroquinine derivatives for patients with rheumatological and dermatological
      pathologies was demonstrated. However, the remote results showed, after the
      administration of the above preparations, highly serious complications in
      different organs and primarily in the organ of vision. As for our practice,
      complications of various severity degrees were found in 6 patients with
      rheumatoid arthritis, who received the preparations in question, such
      complications were classified as highly severe in 1 patient. Taking into
      consideration that the chloroquinine derivatives have been widely used, while
      many doctors are not aware of the complications caused by them. We found it
      advisable to compile a literature survey and to enlarge it with our own
      observations. Eventually, we concluded that the pathogenesis of disorders in
      visual functions could be explained by a toxic effect produced by the
      chloroquinine derivatives not only on the retina but also on the optic nerve and
      chiasm. Our opinion is that a thorough and differentiated approach is needed to
      patients with the mentioned pathologies while using the chloroquinine derivatives
      for treatment.

PMID- 12608046
TI  - [Case of Malherbe's epithelioma and lymphocytoma of the eyelid skin].

PMID- 12608047
TI  - [Present-day sports activities among the blind and persons with poor vision in
      different countries of the world].
AB  - The approach of a country to persons with limited physical abilities is an
      important component of country's social-and-cultural policy. Blindness is a most
      severe variety of health disorders leading to social defect and social
      insufficiency. The role of adaptive physical culture is important within the
      system of the social-and-medical rehabilitation of the blind because the
      sedentary life mode has a negative effect on organisms of the disabled due to
      vision. Sports is not only a method for correcting the general somatic condition,
      but it is also an important social-and-physiological factor that enables the
      blind to comprehend their abilities as an example for others. As for our country,
      the information about the modern sports activities among the disabled due to
      vision is absolutely insufficient for the public at large. An analysis of results
      of examination (conducted by using the computer data base of the International
      Blind Sportsmen Association--IBSA) of 2386 blind and impaired vision sportsmen is
      presented in the paper. Data about sport disciplines and types of ophthalmic
      pathologies encountered among the high-class blind and impaired vision athletes
      from different world countries are described. The above data can be helpful in
      elaborating the rehabilitation programs for persons with severe disorders of the
      organ of vision to be used in rehabilitation centers, sport federations and clubs
      of the disabled as well as in other institutions dealing with rehabilitation of
      the disabled due to vision in our country.

PMID- 12608048
TI  - [Pathology of the lateral geniculate body and visual function].

PMID- 12608049
TI  - [Histo-pathogenetic functions of the formation of filtration cushions after anti
      glaucoma operations and methods of their correction].

PMID- 12608050
TI  - [The 110th anniversary of the Eye Clinic of the Medical Department of the Moscow
      University].

PMID- 12608051
TI  - [Russian-German scientific relations in the field of ophthalmology (19th
      century)].

PMID- 12608052
TI  - [Identification of orthopoxvirus species using oligonucleotide micro-chips].
AB  - A method for describing the Orthopoxviruses that are pathogenic both to man and
      animals is described in the article. The method is based on hybridization of a
      fluorescently labelled amplified DNA sample with oligonucleotides, which were
      immobilized in a microchip. Species-specific regions within the crmB gene
      encoding a viral analogue of the tumor necrosis factor receptor, i.e. an
      important gene determining the pathogenicity of the mentioned Orthopoxviruses
      type, were used as a target for identification. The identification procedure
      takes around 6 hours and does not demand any costly equipment (a portable
      fluorescent microscope can be used).

PMID- 12608053
TI  - [Analysis of hepatitis C virus proteins in hepatic cells of patients with chronic
      hepatitis C].
AB  - A correlation between the detection of proteins and an activity of the
      pathological process was analyzed in a study of the content of the C virus
      hepatitis (CVH) proteins in hepatic cells of patients with chronic C hepatitis
      (CCH). The expression of CVH proteins in frozen sections of biopsy samples of 69
      CCH patients was evaluated by using the immune-histological method involving
      original monoclonal antibodies (MCA) to 5 CVH proteins. The results of the
      detection of proteins in patients were compared with an activity and stage of CCH
      (by using histological tests and a level of alanine aminotransferase--AAT). A set
      of the CVH proteins were found in the liver of 74% of patients, i.e. core
      proteins, NS3, NS4A, NS4B and NS5A--in 28, 43, 43, 55 and 58%, respectively. All
      studied proteins were detected in the cytoplasm of hepatocytes. Proteins were
      found in the liver more often as compared with the detection rate of CVH RNA in
      the blood serum (61%). This demonstrates a high sensitivity of the discussed test
      at detecting the CVH infection. The accumulation of the core protein was shown to
      correlate with the presence of the replicative form of CVH RNA in the liver and
      with a higher level of AAT. The quantity of NS5 A-expressing cells correlated
      directly with a CCH stage. The quantity of NSB- and NS3-positive hepatocytes
      correlated negatively with an activity of the inflammatory-and-necrotic processes
      in the liver. Hyper-fermentation was found more often among the antigen-positive
      patients. The CCH histological activity was proven to be reliably higher at a
      simultaneous detection of CCH proteins in the liver and of CVH RNA--in the serum.

PMID- 12608054
TI  - [Screening of birds in the Volga delta (Astrakhan region, 2001) for the West Nile
      virus by reverse transcription-polymerase chain reaction].
AB  - Infection of birds, residing in the Volga lower and middle delta, with West Nile
      Virus (WNV) genome was detected by the RT-PCR method. A total of 315 samples of
      bird organs, collected in the Astrakhan region in August 2001, were examined.
      Positive results, with various severity degrees, were found in coots (15.1%) and
      in cormorants (14.3%) in the lower delta. As for the middle delta, the infection
      rate among coots, herons, sea-gulls and terms was found to be identical and
      amounted to 8-13%, it was essentially higher in cormorants--42%. The infection
      rate of land-based birds did not exceed 5% in synanthropic biocenosis. According
      to a partial sequencing of the 5'-end region of WNV genome, all positive tests
      can be described as belonging to the 1st WNV genotype. The obtained results are
      indicative of a high activity of circulation of WNV among the birds of the water
      and near-water complexes in the mentioned region.

PMID- 12608055
TI  - [Cytokine production during experimental infection of mice with tick-borne
      encephalitis virus].
AB  - An experiment with BALB/c mice, infected with a lethal dosage of the virus of
      tick-borne encephalitis (TE), strain 205, was accompanied by pronounced growing
      concentrations of the IL-1 beta, IL-6, IL-10 and TNF alpha cytokines in the blood
      serum of animals. The maximum values of the above cytokines were determined at
      the infection terminal stage. A reliably less pronounced growth of concentrations
      of IL-1 beta, TNF alpha and IL-10 was found in animals infected with a non-lethal
      TE dosage. The concentration of IL-6 in the blood serum of animals, infected with
      a non-lethal dosage of the virus, changed during the whole observation period.
      The dynamics of cytokines in the blood serum of mice, infected with a lethal
      dosage of the TE virus, suggests the development of SIRS at the infection
      terminal stage.

PMID- 12608056
TI  - [In vitro synthesis of immunoglobulins caused by an inactivated Ebola virus].
AB  - An in vitro model Ebola infection was used to study the humoral response of human
      mononuclear cells to stimulation by purified inactivated Ebola virus antigen.
      Inactivated Ebola virus was cocultivated with human mononuclear cells in the
      presence or absence of B-cell mitogen LPS E. coli: B5. An increase in the rate of
      synthesis of immunoglobulins (both IgG and, to a less extent, other classes) was
      observed. The Ebola virus proteins were suggested to exert no suppression effect
      on B-cells. The IgM/IgG synthesis was evaluated by EIA in supernatants after 7
      days of cultivation. It was concluded that Ebola fever is accompanied by active
      humoral immune response, which provides a promising basis for further search of
      the methods of treatment of this disease.

PMID- 12608057
TI  - [Interaction of human apolipoprotein AI and HIV-1 envelope proteins with the
      native and recombinant CD4 receptors].
AB  - The method of enzyme-linked immunosorbent assay (ELISA) was used to show an
      interaction of soluble recombinant CD4-receptor (rsCD4) with human apolipoprotein
      A-1. Competitive interactions between envelope proteins VIH-1 (gp120 and gp41),
      on the one hand, and human apolipoprotein A-1 with CD4 receptor, present in the
      cellular membranes of line MT4 human lymphocytes, were demonstrated by the method
      of flow cytofluorimetry. It was suggested that the competitive interactions
      between the above proteins could manifest in respect to the apolipoprotein A-1
      receptor, which affects the involvement of the latter in the regulation of
      protein biosynthesis and which leads to a decrease in the body weight of HIV
      infected patients.

PMID- 12608058
TI  - [Antiviral effect of alpha-interferon and cytokine mRNA level in cell cultures
      infected with a cytopathogenic variant of the hepatitis C virus].
AB  - An experimental model of the viral C-hepatitis (VCH) infection was worked out in
      vitro and it was found suitable to study the influence of interferon (IFN)
      preparations produced on the infection caused by an HCV cytopathogenic
      variations, i.e. the SW-13 human adrenocarcinoma cellular culture sensitive to
      the anti-VCH action of alpha-IFN and the MT-4 human lymphoblastoid cellular
      culture non-sensitive to the anti-VCH action of alpha-IFN. The above cellular
      models were employed to study, by using the methods of reverse transcription and
      polymerize chain reaction (RT-PCR), the influence produced by alpha-IFN on the
      VCH infectious activity as well as to study the changes in the activity of the
      below cytokine mRNAs: alpha-IFN, gamma-IFN, IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL
      10, IL-18 and TNF-alpha. A double treatment of the SW-13 alpha-IFN cellular
      cultures 24 and 48 hours after the infection was found to essentially suppress
      (by 4 Ig) reproduction of the VCH cytopathogenic variant. It was detected that
      the VCH reproduction is mediated by the regulation of a number of cytokine genes.
      The study results can be a basis for a more effective use of the alpha-IFN
      preparations in the therapy of VCH-infections.

PMID- 12608059
TI  - [Virus isolated in the human blood leukocyte culture and its interaction with
      hepatitis C and G viruses].
AB  - Electrone-microscopic investigations are indicative of that the cultures of
      healthy donors, stimulated by phytohemagglutinin (PHA), can be successfully used
      to study the etiology of parenterally transmitted hepatitis. An electronic
      microscopic study of a virus, isolated from the blood serum of a patient with
      hepatitis on the basis of the PHA-stimulated human leukocyte cultures and named a
      hepatitis leukocytic virus (HLV), enabled, by using the negative contrasting
      method, to detect viral particles of the hexagonal shape, sized 50-65 nm, with a
      coating divided by a 4-5 nm light space. Therefore, the HLV was described as
      belonging to the Flaviviridae family. RNA of the C hepatitis virus was detected
      in the K HLV strain stored, for 24 years, at the Museum of the Viruses Research
      Institute, Russian Academy of Medical Sciences, in a lyophilizated bed at -5
      degrees C, however, an attempt to genotype the RNA failed. No RNA donor
      leukocytes were found in the materials of further passing of HLV by using the PHA
      stimulated cultures, which can be explained by an inactivation of HLV at storage.
      No RNA of the C hepatitis virus was found in the above materials either, however,
      in 1999, DNA of the TT virus was detected at passing the strain, which indicates
      that the virus is widely spread in the population of healthy donors, whose
      lymphocytes are used preparing the blood leukocyte cultures.

PMID- 12608060
TI  - [Effect of tetracycline on the hepatitis C virus propagation and levels of
      cytokine mRNA in infected SW-13 and MT-4 cells].
AB  - An experimental HCV-infection model was used in vitro to study the influence of
      tetracycline on the reproduction of the HCV-infection accompanied by a
      simultaneous analysis, by using the methods of reverse transcription and
      polymerase chain reaction (RT-PCR), of the mRNA activity, i.e. alpha-IFN, gamma
      IFN, 1 beta-IFN, IL-2, IL-4, IL-6, IL-6, IL-10, IL-12, IL-18 and TNF-alpha. The
      study was made with the SW-13 long-term cellular cultures (human adrenocarcinoma
      cells) and MT-4 cell cultures (human lymphoblastoid cells) infected by HCV. An
      analysis of the obtained data is indicative, in both examined cellular cultures,
      of a differently-oriented induction-suppression reaction of cytokine mRNAs.
      Suppression of the activity of the investigated cytokine mRNAs, except for mRNAs
      IL-18 and TNF-alpha, was observed in the SW-13 cellular culture; while, as for
      the MT-4 cellular culture, the activity of all studied cytokine mRNAs was pointed
      out. The results testify to that tetracycline should be studied more actively in
      experimental infections caused by HCV in vivo.

PMID- 12608062
TI  - [Titration of Ebola and Marburg viruses by plaque formation under semi liquid
      agar].
AB  - The method of titration of Ebola and Marburg viruses using plaque formation under
      semifluid agar cover is considered. Advantages of this method over conventional
      method of titration of these viruses with the use of hard agar cover are
      discussed.

PMID- 12608061
TI  - [Antiviral and anti-stress activity of the gamma-L-glutamyl-histamine and its
      derivatives].
AB  - Effect of gamma-L-glutamylhistamine gamma-L-Glu-HA and some of its derivatives on
      the state of nonspecific resistance and antiviral activity was studied using
      experimental models of influenza virus and herpes simplex virus infections.
      Activities of natural killer (NK) cells and interferon (IFN) system were
      measured. The model of physical-emotional stress in mice was used. It was shown
      that the gamma-L-Glu-HA derivative II can prevent totally or substantially a
      decrease in the NK activity. This agent also prevents inhibition of synthesis of
      alpha- and gamma-IFN during the post-stress period. The gamma-L-Glu-HA
      derivatives II, III, and VII increased the mice resistance to influenza virus
      type A/Aichi at low infection dose (10LD50). The derivative II showed its
      protective effect even at high dose of pathogen (100LD50). However, this gamma-L
      Glu-HA derivative was virtually ineffective under harsh experimental conditions.
      Thus, a number of gamma-L-Glu-HA derivatives tested in this work demonstrated
      immunomodulation activity. These agents were able to normalize parameters of
      nonspecific immunity. They exerted a pronounced antiviral effect against
      influenza virus but were virtually ineffective against encephalitis in mice
      caused by herpes simplex virus, type 1. Of all tested agents, gamma-L-Glu-HA
      derivative II was found to be the most promising.

PMID- 12608063
TI  - [Specific markers for the detection of circulation of Tahyna, Inko and Batai
      viruses (Bunyaviridae, Bunyavirus) in humans, mosquitoes, ticks and cattle of the
      Ul'ianovsk region].
AB  - Comprehensive examinations of the population, sanguivorous arthropoda and
      domestic animals were for the first time held in the territory of the Ulyanovsk
      region. An active circulation of certain arboviruses was detected and a
      predominantly ecological relation of California encephalitis serogroup viruses
      with Aedes mosquitoes, on the one hand, and of Batai viruses with Anopheles
      mosquitoes, on the other hand, was established. The most reliable detection of
      antibodies to California encephalitis viral complex was pointed out.

PMID- 12608064
TI  - [65 years in the vanguard of medical and technical science].

PMID- 12608065
TI  - [An analysis of the prospects for elaboration and production of narcosis and
      respiratory equipment].
AB  - The narcosis-and-respiratory equipment (NRE) is one of the most important
      categories of equipment in health care. The article contains analytical data on
      the structure of NRE and sales statistics; a classification of the methods of
      ventilation support is presented, the appearance of NRE types, developed by ZAO
      "VNIIMP-VITA" and serially manufactured, is described.

PMID- 12608067
TI  - [A new method of high-frequency electrosurgery (coblation technology)].
AB  - A new method of electrosurgical intervention, i.e. a high-frequency cold-plasma
      ablation or coblation-technology, is presented in the article. The method is
      based on an ionic "bombardment" of the biological tissue at the intervention
      site, which leads to ruptures of intermolecular cohesions. The method has been
      widely used in arthrosurgery, cardiosurgery, otorhinolaryngology, spinal surgery
      and cosmetology. The "ArthroCare" Company (USA) was the first to start developing
      the discussed method. As for Russia, the Research Institute for Medical
      Instrument-Making of the Russian Academy of Medical Sciences and Stavropol State
      Medical Academy are the leaders in promoting the technology in question.

PMID- 12608066
TI  - [State of the art and outlook for promoting Russian-made hemodialysis equipment
      with regeneration of dialyzing solution].
AB  - Radical improvements in the physiological features and self-sufficiency of
      hemodialysis equipment, an essential reduction of the volume of dialyzate
      contacting with patient's body and elimination of dependence of the equipment
      operation on the availability of a water-supply network can be ensured by
      applying a regime of circulation of a relatively small volume (3-5 l) of
      dialyzate through the regenerating device. The regeneration unit must eliminate
      the organic products of dialysis from the dialyzate and stabilize the ionic
      composition of the purified dialyzate according to the preset parameters. Modern
      methods and technical means for regenerating the used dialyzate are discussed; a
      regeneration unit, which ensures an electrochemical oxidation (in the used
      dialyzate) of nitrogen-containing organic metabolites with a subsequent sorption
      type additional purification of electrochemically-processed dialyzate, is
      offered. The regeneration unit is made up of an electrolyser, a sorption-type
      additional-purification device and a gas utilizer; it eliminates organic
      metabolites, phosphorus, calcium and potassium from the used dialyzate and
      stabilizes the pH solution.

PMID- 12608068
TI  - [Instruments and equipment for psychophysiological examinations].
AB  - Scientific aspects providing a foundation for working out the instruments and
      equipment systems designed for psychophysiological examinations are presented in
      the article. The already developed instruments and equipment systems for
      psychophysiology are described; projects implemented jointly with the leading
      institutions and experts of the Russian Academy of Medical Sciences and Ministry
      of Health of Russia, and which are already related with the use of the developed
      instruments and equipment systems in the field psychophysiology, are also
      described.

PMID- 12608069
TI  - [Nuclear-medical equipment in the Research Institute for Medical Instrument
      making].
AB  - The activity of the department for emission introscopy of the Research Institute
      for Medical Instrument-Making ("ZAO VNIIMP-VITA") is described in the article. A
      list of developed and commissioned devices and instruments for the field of
      nuclear medicine is presented. Methods of elaboration of some sophisticated
      instruments and units designed for radio-biochemical and radio-immunologic
      examinations as well as methods of elaboration of scintillation gamma cameras,
      tomograph GKS-301T, medical dosimeters and of other devices are also described.

PMID- 12608071
TI  - [Monitoring aspects of safety in anesthesiology and resuscitation].
AB  - Uninterrupted monitoring of the key parameters of blood, breathing, and cardiac
      function in patients is a main factor ensuring safety of the patients. The
      article contains a classification of monitors and requirements applicable to
      their designing. Technical parameters of the monitors developed by the Research
      Institute for Medical Instrument-Making ("ZAO VNIIMP-VITA") are described in the
      article.

PMID- 12608070
TI  - [New implanted electrodes for electric pacemakers].
AB  - Requirements applicable to as well as the construction of electrodes to stimulate
      the cardiac function are presented in the article. The importance of pacemakers
      at a wide range of heart diseases is demonstrated.

PMID- 12608072
TI  - [State of the art and outlook for the development of physical therapy equipment].
AB  - Analytical materials related with the importance of physical therapy in the
      treatment of patients are presented in the article. Physical factors for the
      indication of physical therapy were analyzed. Peculiarities of using the physical
      therapy devices of different types were discussed.

PMID- 12608073
TI  - [Standardization and testing of medical devices].
AB  - The role of standardization of medical devices within the system of health care
      of the Russian Federation was analyzed in the article. The results of activities
      of technical committees for standardization as well as the list of the mentioned
      devices compatible with the international standards are presented. Lists of
      attested and etalon application means and equipment designed for examinations of
      different types are equally described.

PMID- 12608075
TI  - [Lighting and technical elements of medical illuminators and the principles of
      minimal heating of the surgical field].
AB  - Schemes of lighting-and-technical elements of medical illuminators, manufactured
      by leading companies, are presented in the article. The values of the
      energy/light correlation are analyzed for different illumination sources;
      besides, the conditions of a minimal thermal inflow into tissues are described.

PMID- 12608074
TI  - [Certification of medical devices].
AB  - The importance and peculiarities of certification of medical devices are
      analysed. The attention is focused on classification of devices which are
      potentially risky in application. The application aspects of the EU 93/42
      Directive, i.e. a fundamental document in design, elaboration, production, sale
      and maintenance of medical devices are detailed.

PMID- 12608076
TI  - [Anatolii Andreevich Vorob'ev (on his 80th birthday)].

PMID- 12608077
TI  - [Oral vaccination against smallpox (on the return of smallpox vaccination)].

PMID- 12608078
TI  - [Conjugated polymer-subunit immunogens and vaccines].
AB  - A study of fundamental mechanisms regulating the immune response resulted in
      producing a theory explaining the mechanism of immunostimulating properties of
      polyelectrolytes, as well as in working out the principles for creating the
      synthetic immunomodulators and, on the basis of them, polymer-subunit immunogens
      and vaccines. The above theory produced a basis for creating polyoxidonium, a new
      polymer polyelectrolyte, which was used to synthesize the conjugated polymer
      subunit "Grippol" vaccine that, after its commissioning into production, has been
      widely used.

PMID- 12608079
TI  - [Genome-wide non-sequencing strategies for bacterial genome comparison: the
      necessity and an analysis of the variable bacterial world].
AB  - A tremendous success in bacterial genome sequencing has been achieved during the
      recent years; it resulted in making available, for analysis, multiple sequences
      of different bacterial genomes, including such pathogens as causative agents of
      syphilis, typhus, and tuberculosis as well as such organisms like archaebacterias
      living under extreme conditions. A comparative analysis of bacterial genomes
      leads to conclusions, which have a general biological value, and, in particular,
      to the conclusions about mechanisms and evolution rate as well as about the
      variability of genomes and interrelation between organisms and their habitat. On
      the other hand, the analysis reveals specific features of separate bacterial
      species responsible for their pathogenicity and ability to avoid the destruction
      of the host immune system as well as for adaptation to exist within a certain
      ecological niche. However, the variability of bacterial genomes is so high that
      methods, which enable to evaluate the variability without full genome sequencing,
      are needed to depict adequately the evolution and ecological characteristics of
      the prokaryotic world and to develop new effective therapeutics and diagnostic
      tools. The survey covers two approaches to such comparative analysis, i.e. DNA
      arrays and subtractive hybridization. The advantages and disadvantages of each
      approach are discussed and the necessity in a new approach combining the positive
      features of the two mentioned approaches is substantiated.

PMID- 12608080
TI  - [New assumptions in the concept of vaccine prophylaxis of infantile infections].
AB  - An essential reduction in the incidence rate of six infantile infections within
      the Expanded Immunization Program was accompanied by occurrence of new problems
      in vaccine prophylaxis. 1. Vaccine-dependence--the reoccurrence of vaccine
      prevented infections in those cases when vaccination was stopped. 2. A choice of
      strategy in the immune prophylaxis of poliomyelitis during the post-liquidation
      period bearing in mind the elimination of vaccine strains from the human
      population and a possible global refusal from vaccination. 3. Elaboration of
      regional programs for eliminating the measles in big territories. 4. Alteration
      of protective antigens Bordotella pertussis. The relationship of such alterations
      correlates with a rise in the Bordotella pertussis incidence rate with regard for
      multiple comprehensive vaccinations in the USA and Western Europe.

PMID- 12608082
TI  - [Rickettsiosis: state of the art at the turn of the 21st century].
AB  - Information about changes in the modern taxonomy of intracellular bacteria
      conditionally united within the nomination of "Rickettsioses" is presented in the
      paper. Due to a total hobby related with keeping home animals (pets), cats and
      dogs, apart from the cattle, joined the natural ecological cycles of
      rickettsioses stimulation. The morbidity of rickettsioses of the acaroid group
      has been persistently growing; like in case with other pathologies (Lyme's
      disease) involving the acaroid transfer factor, its obvious "urbanization" is
      pronounced. Absolute and relative morbidity indices in respect to rickettsioses,
      which are epidemiologically important for Russia, are presented. The modern
      knowledge database concerning the rickettsioses makes it possible to control the
      epidemic process for this infection category. It is noteworthy, that Prowazek's
      rickettsiosis of its both forms (i.e. the epidemic and relapsing ones), which
      does not have an independent cycle of circulation of its stimulator in wild
      nature, and unlike the acaroid group rickettsioses, turned into a socially
      controllable infection. It will be totally eliminated, during 10-15 years, both
      in Russia and the CIS countries. The practitioners are well supplied with a
      variety of drugs of tetracycline and fluorine-quinol groups, which makes it
      possible to arrest the infection process in patients rapidly and effectively and
      to prevent the lethal cases. A low incidence rate of rickettsioses, including Q
      fever, within the general infection morbidity, and taking into consideration the
      availability of methods for effective therapy and prevention, makes one consider
      a comprehensive vaccination against the discussed group of infections to be
      irrational. Obviously, such vaccination must be still applied in respect to a
      limited number of persons from among high-risk groups and for two or three
      varieties of rickettsioses only (i.e. Prowazek's rickettsioses, Rocky Mountain
      spotted fever and Q fever). Live vaccines, obtained on the basis of attenuated
      and recombined strains (which have a full-scale set of specific antigens), are
      recommended.

PMID- 12608081
TI  - [Artificial anti-HIV immunogens and methods of their delivery].
AB  - Elaboration of an anti-HIV vaccine is a highly important task because there is a
      need to arrest or at least to slow-down the rapid spread of AIDS throughout the
      world. Regrettably, no attempts to create an effective vaccine resulted in
      success. Nonetheless, the available data contribute to building up the confidence
      in that the set purpose can be achieved provided extra resources are found for
      working out a potential anti-HIV vaccine. The paper contains some results of
      research conducted by the "Vector" Research Center for Virology and Biotechnology
      in the field of artificial polyepitope immunogens, which could be potential anti
      HIV vaccines, and in the field of creating various system for their delivery. The
      immunogenic properties of the thus obtained vaccine structures were tested on
      mice BALB/c. The delivery systems were experimentally demonstrated to ensure the
      induction of specific antibodies against HIV-1, with such anti-bodies having a
      virus-neutralizing activity; the above systems also induce the cellular immunity.

PMID- 12608083
TI  - [Veterinary and epidemiologic aspects of prion infections].

PMID- 12608084
TI  - [Adoptive immunotherapy in malignant tumors].
AB  - Presently, the biotherapy for cancer, involving activated cells of the immune
      system has been used on an expanding basis in clinical oncology. The stimulated
      recombinant preparations of interleukin-2 (IL-2) and of interferon on (INF), or
      so-called lymphoquin-activated killers (LAK), were found to be able to lyse the
      freely isolated tumor cells by avoiding any damage to the normal cells. An NCI
      randomized study (181 cases), held in 1990, showed that the combination of IL-2
      with LAK was most effective as compared with the IL-2 therapy alone. Despite the
      fact that the immunotherapy basic research is focused on melanoma, renal cancer,
      colorectal cancer and lymphomas, there are published data related with an
      effective use of IL-2/LAK-therapy in patients with other localizations. The
      administration of IL-2 and LAK for exudative cancer forms in 78 patients led to
      clinical effects in 94.8% of cases. A maximum cytoreduction of tumor is one more
      way to enhance the efficacy of the immunotherapy; it ensures the establishment of
      a maximum correlation between the tumor cells and the killers. A combination of
      the methods of activation of specific and non-specific immunities should be
      regarded as the most promising trend in the development of biotherapy of tumors.

PMID- 12608085
TI  - [Interferon-based immunobiological preparations. An outlook of their use in the
      treatment of patients with infections].
AB  - The paper contains the generalizing results of many-year research related with
      using various ready-made medication forms (RMF) of human genetic-engineering
      interferon-alpha 2 and of methods of its administration into the body. Extensive
      clinical materials were made use of to show convincingly that the most effective
      therapy for infectious diseases is ensured within a short time period and with a
      consequent long-term rehabilitation effect by using separate RMFs and methods of
      application of interferon-alpha 2, when their impact on the lesion focus is
      monitored by the parameters of the cellular-and-humoral chains of the general and
      local immunity. It is noteworthy, that a selection of RMF adequate for an actual
      nosologic form or of an administration method can reduce the medication dose of
      interferon-alpha 2 (thus, the incidence of complications to the drug goes down),
      it can also eliminate the influenza-like syndrome and production of
      autoantibodies related with the intramuscular administration of interferon-alpha
      2, besides, it essentially prolongs the presence of interferon-alpha 2 in the
      body. It is important that the application of interferon-based preparations for
      infectious diseases can eliminate, in a number of cases, the use of antibiotics
      and other antibacterial drugs, it enhances the efficacy of antibacterial and
      antiviral therapy within a comprehensive treatment scheme, it contributes to a
      higher resistance of normal flora to the action of antibiotic and antibacterial
      drugs, and, finally, it arrests quicker the manifestations of dysbacterioses of
      various localizations.

PMID- 12608086
TI  - [Studies of changes in human intestinal micro-biocenosis in health and in
      disease].
AB  - The paper contains the generalized many-year research conducted by staff of the
      chair for microbiology (including virology and immunology) aimed at describing
      the universal principles related with forming an inter-individual diversity of
      gastric-and-intestinal micro-biocenosis. The research demonstrated a high
      dependence of qualitative and quantitative parameters of the analyzed biotope on
      various-genesis factors. It was established that the nature of violations in the
      gastric-and-intestinal micro-biocenosis is not dependent on peculiarities of an
      influencing pathogenetic factor, and its difference is related only with
      quantitative and qualitative (specific) changes in the microbial composition. The
      marked feature makes it possible to regard the gastric-and-intestinal micro
      biocenosis as a non-specific indicator of the condition of a macro-organism and
      that of the environmental quality.

PMID- 12608087
TI  - [Adverse effects following vaccinations and effectiveness of different live
      vaccines against mumps].
AB  - The paper analyses adverse effects with special emphasis on meningitis following
      mumps vaccination with vaccines containing different strains of mumps virus. It
      also provides information on the comparative effectiveness of different types of
      vaccines. Information is based on the review of literature and data collected in
      the Department of Epidemiology, National Institute of Hygiene in Warsaw. Most of
      the data provides evidence that risk of aseptic meningitis following vaccines
      containing Jeryl Lynn strains of the mumps virus is generally smaller than the
      risk following vaccines based on Urabe AM 9 strain. Studies on vaccine
      effectiveness showed moderately higher effectiveness of vaccines based on Urabe
      AM 9. The main aim of this paper was to provide comprehensive information on the
      effectiveness and safety of mumps vaccines registered in Poland for the purpose
      of decisions making on their use.

PMID- 12608088
TI  - [Extra-salivatory glands manifestations of mumps--own observations].
AB  - A total of 808 patients with extra-salivary glands manifestations of mumps were
      treated in the Department of Infectious Diseases, Bytom, Silesian University
      Medical School in the period of 1985-2001. Mumps meningitis, testicular
      involvement (epidydymo-orchitis), and mild mumps pancreatitis were diagnosed in
      762 (529 male; 69.4%), 24, and 22 (14 male; 63.6%) patients respectively. The
      patients' age ranged from 2 to 53 years. Mumps virus infection was the reason of
      transient (behavior disorders, cognition functions impairment) and permanent
      (hypoacusis, deafness) sequelae of the disease.

PMID- 12608089
TI  - [Seroprevalence of Bartonella henselae and Bartonella quintana infections in
      Poland in 1998-2001].
AB  - Bartonella henselae and Bartonella quintana infections result in illnesses with
      symptoms of severity ranging from mild lymphadenopathy (CSD) to systemic disease.
      The aim of the study was to estimate a prevalence of B. henselae and B. quintana
      infections in human in Poland. Serum samples collected from 265 patients in 1998
      2001 were tested for the presence of antibodies specific to B. henselae and B.
      quintana. Levels of serum IgM and IgG antibodies to Bartonella henselae and
      Bartonella quintana were measured with indirect microimmunofluorescence test (MRL
      Diagnostic, USA). Cats' sera were assessed with indirect microimmunofluorescence
      test (MRL Diagnostic, USA) and goat immune serum anti-cat IgG FITC conjugate
      (Sigma, USA). Bartonella henselae specific antibodies were detected in 146
      (57.0%) patients with lymphadenopathy. From that number 11.3% have shown specific
      Bartonella henselae IgM serum antibodies. Bartonella quintana infection was
      detected with serological methods in 4 patients. It has been found that CSD is a
      seasonal infection, with most cases occurring in autumn. Most cases of the
      disease have been recognized in children 8-16 years old. Most of CSD cases
      (30.1%) were detected in Mazowieckie voivodeship. There were no cases of CSD in
      Pomorskie, Podkarpackie, Lubuskie and Opolskie voivodeship. The seroprevalence of
      Bartonella sp. infections in cats was estimated on 86% (31/36). The highest titer
      of specific Bartonella henselae antibodies detected in cats was 1024. The number
      of detected Bartonella henselae infections in Poland is very low. It is very
      probable that the number of cases is underestimated in our country. Cat scratch
      disease is the most frequently clinically and serologically identified
      bartonellosis.

PMID- 12608090
TI  - [Toxoplasmosis in Poznan region, Poland 1990-2000].
AB  - The paper summarizes the results of the interdisciplinary studies on
      toxoplasmosis carried out in Poznan region, Poland. In the years 1990-2000 the
      specific Toxoplasma gondii seropositivity rates in pregnant women decreased from
      58.9% to 43.7%. Significant was an increase in seropositivity in the age group 15
      20 years. Cats were seropositive in 70.6%; relatively high seropositivity rate
      was observed in cats kept at home only (65.7%). Slaughtered pigs were positive in
      13.2% with higher rates in older pigs and those originating from small private
      farms. Screening newborns with noncommercial tests by using Guthrie cards
      revealed that the congenital toxoplasmosis occurs in 0.55/1.000 pregnancies at
      screening for specific IgM and 1.08/1.000 pregnancies at screening for combined
      IgM and IgA. The prenatal screening for toxoplasmosis has not been introduced in
      Poland. However, the frequency of individual serological testing for Toxoplasma
      increased from 2.7% to 4.6% of pregnancies. Active health education was
      introduced in Poznan region and the awareness of toxoplasmosis risk increased
      from 24.3% to 45.2%. Still 54.7% of pregnant women were inadequately informed and
      44.8% of pregnant women, being aware of the risk or not, did not respect specific
      hygienic measures. The rational control of congenital toxoplasmosis in Poznan
      region should be based on a routine newborn screening for congenital
      toxoplasmosis, continuous education of medical personnel and intensive, modern
      health education especially in adolescents and pregnant women from rural areas.

PMID- 12608091
TI  - [Effect of exposure to tick-bites on the course of lyme borreliosis in Bialowieza
      residents].
AB  - The aim of the study was to evaluate relationship between clinical picture of
      Lyme disease and risk of Borrelia burgdorferi infection, expressed as an exposure
      to ticks in an endemic area of the disease. METHODS: Questionnaires regarding
      frequency of tick bites, symptoms of the disease in an acute phase and symptoms
      likely associated with previous infection were collected from 131 residents of
      Bialowieza village, who suffered from Lyme disease in the past. RESULTS: Lower
      prevalence of erythema migrans and significantly higher prevalence of arthritis
      was demonstrated in the group of persons with the highest frequency of tick
      bites. Evaluation of symptoms that can be related to previous Lyme disease showed
      significant increase of arthralgia, myalgia, ischialgia, sleep and concentration
      difficulties in persons with higher frequency of tick bites. CONCLUSIONS: These
      results demonstrate, that multiple exposures to B. burgdorferi promote
      manifestation of the disease in the form of arthritis, and less frequently lead
      to the development of erythema migrans.

PMID- 12608092
TI  - [Evaluation of oxidoreductive potential of patients with neuroborreliosis].
AB  - AIM: The purpose of the study was to evaluate parameters of oxidoreductive system
      in serum and cerebrospinal fluid (CSF) of patients with neuroborreliosis.
      MATERIAL AND METHODS: The cases were 25 patients aged 21 to 64 (x = 42.3)
      hospitalized with diagnosis of neuroborreliosis. Activity of superoxide dismutase
      (Cu, Zn-SOD), glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px) and
      concentration of sulphydryl groups (-SH) and malondialdehyde (MDA) in serum and
      CSF were tested. The control group consisted of 10 patients with diagnosis of
      discopathy. An examination was performed twice: before and after treatment.
      RESULTS: Results of the study showed lack of stability in an oxidoreductive
      system during neuroborreliosis both in serum and in CSF. In CSF activity of SOD
      was increased while activity of GSH-Px and GSSG-R were decreased. Also
      concentration of -SH and lipid peroxidation products measured as MDA were
      increased. The increase of SOD, GSH-Px, GSSG-R activity and concentration of -SH
      and MDA in serum were detected. CONCLUSIONS: Disorders of an oxidoreductive
      system in CSF and serum during neuroborreliosis were observed. These changes
      persisted despite treatment and normalization of inflammatory CSF markers.

PMID- 12608093
TI  - [Clinical and epidemiological analysis of patients with botulism hospitalized at
      the Department of Infectious Disease, Medical University of Lublin in 1990-2000].
AB  - In the paper we presented results of clinical and epidemiological analysis of 32
      patients with botulism hospitalized at the Department of Infectious Diseases,
      Medical University of Lublin in 1990-2000. In the studied group, the
      relationships between botulism incidence and sex and place of residence were not
      significant. The incubation period ranged from 7 hours to 5 days (average 36
      hrs). The clinical manifestations of botulism were typical in all cases. In one
      female patient the course of disease was complicated. She developed right-sided
      bronchopneumonia and left-sided purulent parotitis. The type B botulinum toxin
      occurred more frequently than the other types and the cases without serological
      confirmation (Chi 2 = 6.125 p = 0.01). It was found in serum of 23 patients (in 2
      cases together with the type A toxin). The type E toxin was found in serum of one
      patient. The presence of toxin in serum was not detected in 8 patients. In all
      patients trivalent (types A, B and E) equine antitoxin was administered. The dose
      ranged from 50 to 150 cm3. Symptomatic treatment was given in all cases. Nobody
      required mechanical ventilation. The duration of hospitalization ranged from 5 to
      28 days (average 16.6 days). A few patients complained of long-lasting blurred
      vision or dry mouth.

PMID- 12608094
TI  - [Catheter induced septicaemia].
AB  - The most serious catheter-related infections, such as septicaemia are associated
      with the central venous catheters rather than the peripheral catheters. The main
      sources of microorganisms are the patient's skin and hospital environment.
      Bacteria can gain access to blood via the external or the internal catheter
      surfaces. A number of approaches for the prevention of sepsis associated with
      catheters have been proposed, with limited success. Beside the careful aseptic
      techniques, the development of antibacterial polymers offers the greatest
      potential for further reduction of risk of catheter-related sepsis. However,
      there is evidence suggesting that an appropriate training of staff in the
      management and care of catheters is fundamental to achieve a reduction in the
      incidence of catheter-related infections.

PMID- 12608095
TI  - [Mortality of Polish actors in 1981-1999].
AB  - The objective of this study was to compare the mortality of Polish actors (males
      and females) with the general Polish population for the period 1981-1999 and for
      two sub-periods: 1981-1991 and 1992-1998. Initially the studied cohort included
      3992 dramatic actors (2161 males, 1831 females) of age 18-80 years (at the moment
      of cohort entrance). After detailed data verification statistical analysis was
      made for 2120 actors and 1767 actresses, contributing 29477.1 and 24886.2 person
      years of observation, respectively. A total of 633 deaths (368 males and 265
      females) were noted during the analyzed period. Statistical approach based on the
      follow-up method. Comparison with the reference population (Polish males and
      females from urban areas) was made by means of the standardized mortality ratios
      (SMRs) and their 95% confidence intervals. Direct comparison of the selected
      subgroups' mortality based on the rate ratio analysis. Standardized mortality
      ratios were 0.739 (95%CI: 0.666-0.819) for the actors and 0.887 (95%CI: 0.784
      1.001) for actresses. Mortality of the actors' cohort was found to be
      significantly lower than in the reference population during total analyzed
      period, whereas for actresses no significant differences were found. Age-specific
      SMR dependence was found. Statistically significant lowering of SMR was observed
      for actors up to 80 years old. Finally, it could be concluded that in contrast to
      the actresses' cohort the actors' mortality in 1992-1999 significantly decreased
      in relation to 1981-1991 period. Moreover, the decrease of the actors' mortality
      exceeded tendencies observed for Polish urban population.

PMID- 12608096
TI  - [Characteristics of the elderly in the study on assessment of the activity level
      of health status].
AB  - OBJECTIVE: The aim of the study carried-out in 1999 was to describe and analyse
      the health status and activity forms in elderly subjects (65 and older). METHODS:
      Health status was assessed on self-reported questionnaire information on:
      diseases, hospitalisation, disability, mobility, BMI, level of life enthusiasm,
      relationships and satisfaction. Reported activity has been classified as
      physical, intellectual (mental) and pro-social. Study group health status,
      activity (level, forms) demographic features were presented and analysed with the
      use of Epi-info6. RESULTS: Of this research study are presented in the second
      part of this paper.

PMID- 12608097
TI  - [Assessment of the impact of physical activity on the health status of elderly
      people].
AB  - OBJECTIVE: The aim of this research study carried-out in 1999 was to assess the
      impact of various forms of activity (physical, pro-social and intellectual
      mental) on health status of the group of people aged 65 and more. METHODS: A tool
      used to conduct the research was anonymous questionnaire. After a preliminary
      assessment of 2072 questionnaires for a further analysis, 1910 questionnaires
      (92.6%) have been selected. Health status has been assessed on the basis of the
      following epidemiological parameters: information on illness and health problems,
      hospitalisation, disability, mobility, and body weight, depression, limited life
      enthusiasm, assessment of satisfaction resulting from contacts with other
      persons, identification of problems connected with ageing. Activity has been
      assessed on the basis of responses to the open and closed questions. The
      statistic tests: Chi 2, logistic regression, Pearson's correlation were used.
      RESULTS: Active persons assessed their health condition more positively, they
      suffered from fewer CVD's and their health condition was more stable, many had a
      better psycho-social status, and they less often used medical services
      (hospitalisation). Legal and biological disability, except 1st disability
      category and persons who were immobile did not constitute any barrier to become
      active. Similarly, diseases didn't exclude activity, except very severe
      pathologies. In the group of active persons overweight subjects constituted a
      minority, while no active person was obese. Majority of respondents has admitted
      that their health condition has deteriorated drastically at the age of 63-64.
      CONCLUSION: Activity of persons over 65 year old is one of many independent
      determinants and indicators of positive ageing.

PMID- 12608098
TI  - [Use of regression analysis to determine blood glucose in fasting and two hours
      after glucose administration in the diagnosis of diabetes mellitus].

PMID- 12608099
TI  - [Sample selection in epidemiologic studies].
AB  - Problems with sample selection in epidemiological studies starts with the
      definition of representativeness of the sample. The definition of
      representativeness as a "miniature of the population" is impractical, especially
      for very rare disease, and not suitable for certain types of epidemiological
      studies. More plausible are operational definitions, which refer to certain
      statistical features of the sample or to the sampling method suitable for the
      study design. The article reviews different meanings of representativeness used
      directly or implicitly in epidemiological and statistical studies and gives
      examples of certain methods of sample selection for the specific purposes
      including matching in design. Some important sources of selection bias and
      methods of avoiding it are also addressed in this article.

PMID- 12608100
TI  - [Surveillance].
AB  - The article presents an outline of development of epidemiological surveillance in
      history and basic characteristics of principal types of surveillance being used
      in contemporary epidemiology. The role of disease definition and classification
      of diseases is stressed. The main features of the surveillance system are
      characterized. Basic methods of evaluation of such systems are also presented.

PMID- 12608102
TI  - Cracking the ice.

PMID- 12608103
TI  - Skipping chemo. A lot of breast-cancer survivors are doing it, not always for
      good reasons.

PMID- 12608104
TI  - Dueling diapers.

PMID- 12608105
TI  - Bristol-Myers cleans up its mess.

PMID- 12608106
TI  - When life really stinks.

PMID- 12608107
TI  - Ego.

PMID- 12608108
TI  - [Early post-denervation depolarization: effect of NO, acetylcholine and glutamate
      on chloride transporter].
AB  - Resting non-quantal acetylcholine (ACh) and probably glutamate (Glu) release from
      nerve endings activates M1- and NMDA-receptor mediated Ca2+ entry into the
      sarcoplasm with following activation of NOS and production of NO. This is a
      trophic message from motoneurones which keeps the Cl- transport inactive in the
      innervated sarcolemma. After denervation, the secretion of ACh and Glu at the
      neuromuscular junction is eliminated within 3-4 h and the production of NO in the
      sarcoplasm is lowered. As a result, the Cl- influx is probably activated by
      dephosphorylation of the Cl- transporter with subsequent elevation of
      intracellular Cl- concentration. The equilibrium Cl- potential becomes more
      positive and the muscle membrane becomes depolarized.

PMID- 12608109
TI  - [3-nitrotyrosine--an indicator of changes in the formation of reactive oxygen and
      nitrogen species].
AB  - 3-nitrotyrosine (3NTYR) produced by the reaction of nitrogen and oxygen species
      is used as a suitable marker of radical mediated tissue damage. Free or protein
      bound tyrosin residues are in vivo nitrated most likely by peroxynitrite or
      myeloperoxidase. Processes involved in formation and degradation of 3NTYR are not
      completely clear. It seems that degradation depends on the way in which 3NTYR is
      formed, characteristics of the tissue or organ where 3NTYR was formed and even
      general condition of the organism. Nitration of tyrosine does not only modify the
      biochemical structure of the protein but usually affects its function. Nitrated
      proteins are probably specific for each organ and may influence the pathogenesis
      of the disease. The review also describes the methods of 3NTYR detection and
      summarizes published data on 3NTYR concentration in various human diseases.

PMID- 12608110
TI  - [Experimental research and new concepts of the role of the cerebellum].
AB  - It has been discovered recently--especially thanks to the experimental research
      on animals--that cerebellum is not only a co-ordinator of the motor functions but
      that it also participates in the higher functions of the central nervous system.
      In this research, models with genetically determined cerebellar degeneration
      (Lurcher, pcd. staggerer, hot-foot, weaver) or originally healthy animals after
      partial or complete artificial destruction of cerebellum are often used. The
      animals can be tested by specific methods of motor learning (rotating steel grid,
      rotorod, round wooden beam, bridge, coat-hanger, horizontal crossbar, vertical
      and inclined grid, ladder), spatial learning (Morris water maze, radial maze,
      hole board) and discriminative learning-type of passive avoidance (step through
      and step down). The experiments result in conclusion that an injury or
      degeneration of the cerebellum are associated with worse motor skills and
      cognitive functions. Nevertheless, the disorders of cerebellum do not prevent
      from motor learning completely: motor possibilities of Lurcher and hot-foot
      mutants can be improved by training in spite of the fact that they never reach
      the same level of motor abilities of healthy controls. Drug therapy of cerebellar
      degeneration and substitution of lost cells by transplantation are in the phase
      of new experiments.

PMID- 12608111
TI  - [Amylin--its physiological role in humans].
AB  - Amylin is a polypeptide hormone composed of 37 aminoacids, that is produced in
      pancreatic beta-cells, and that was discovered in 1987. Releasing amylin into the
      circulation is increased postprandially, proportionally to the amount of digested
      food. Daily profile of amylin plasma levels corresponds to the profile of
      insulin. Normal plasma levels of amylin vary from 4 pmol/L (fasting) to 25 pmol/L
      (postprandially). Receptors for amylin are highly concentrated especially in the
      central nervous system--area postrema and nucleus accumbens. There is a 20%
      sequence homology between amylin, calcitonin and adrenomedullin and 44% homology
      with calcitonin gene--related peptide. Amylin contributes to the regulation of
      postprandial glycaemia by suppression of glucagon release and by regulation of
      gastric emptying. Deficit os amylin is typical for diabetes mellitus type 1 or
      for the late stage of diabetes type 2. Insulin resistance in obese patients is
      characterized by increased levels of both insulin and amylin. Amylin decreases
      food intake and participates in the regulation of body weight. Some biochemical
      forms of amylin cause proliferation of osteoblasts and inhibit bone resorption.
      Amylin modulates insulin sensitivity of skeletal muscle, contributes to the
      regulation of blood pressure and causes vasodilatation.

PMID- 12608112
TI  - [ Physiology of consciousness. II].
AB  - At present, no plausible theory or even working hypothesis of the formation of
      human consciousness based on physiological processes of the central nervous
      system has been proposed. An obvious and principal obstacle is, how an immaterial
      process, consciousness, may arise from any material processes, and vice versa.
      For this reason, it is extremely difficult to propose such a hypothesis.
      Therefore, a working hypothesis is proposed based on well known interactions of
      the human consciousness with quantum submicroscopic processes.

PMID- 12608113
TI  - Seeking value in working with pharmacy benefit managers.
AB  - By working with pharmacy benefit managers (PBMs), employers can improve
      prescription drug use and thereby both reduce health care costs and enhance
      patient quality of care. This article educates employers about the importance of
      plan design in pharmacy benefits management, what distinguishes PBMs from other
      benefit intermediaries and how employers can evaluate and audit services provided
      by a PBM. Finally, it discusses upcoming changes in the drug benefit marketplace
      that will affect employers' opportunities and challenges in providing maximum
      prescription drug benefits at the best value.

PMID- 12608114
TI  - Developing an effective generic prescription drug program.
AB  - Pharmacy benefit managers (PBMs) use a variety of pricing strategies. When
      employers have a thorough knowledge of those strategies, they can use them to
      their advantage to help manage pharmacy benefits. This article discusses PBM
      strategies in terms of what employers need to know, the questions employers need
      to ask and goals employers must keep in mind in order to secure the affordable
      cost and quality prescription drug management programs that they and their
      employees need and deserve.

PMID- 12608116
TI  - Supply and demand: negotiating the prescription drug labyrinth to reduce costs.
AB  - Prescription drug costs are increasing at a rate of 15% to 17% a year and a look
      into the future does not bring much better news. Employers can expect to see more
      numbers like these as doctors more aggressively treat diseases using drug
      therapy, the population continues to age and pharmaceutical companies continue to
      spend billions of dollars on direct-to-consumer advertising aimed at consumers
      who are desensitized to the true costs of their prescriptions. In this
      environment, it is unlikely that companies can realistically expect to reverse
      costs of even to avoid cost increases. However, this article provides employers
      with a prudent approach to managing both the supply and demand sides of the
      prescription drug equation in order to reduce their level of increase. Supply
      side management focuses on negotiations with vendors, while the demand side
      focuses on managing employee utilization.

PMID- 12608115
TI  - The tough decisions that no one wants to make.
AB  - This article examines prescription drug benefit plan trends: past, current, short
      term future and long-term future. It includes a brief discussion of each cost
      trend and its drivers, then asks the question, "What can be done to protect the
      pharmacy benefit budget, yet provide what is needed?" from three perspectives:
      (1) business, (2) stakeholders (management, human resource groups, physicians,
      employees) and (3) patients (employees and dependents). The article discusses
      therapeutic guidelines, physician education, reimbursement issues, distribution
      channels and the impact of business decisions on employees, dependents,
      stockholders, shareholder value, management, human resources and decision makers'
      own careers.

PMID- 12608117
TI  - The role of the PBM in total health management strategies for individuals with
      chronic conditions.
AB  - In this article, we examine the multiple data sources and outcomes surrounding
      the management of both pharmacy and medical cost spending for chronic health care
      in one pharmacy benefit manager (PBM). We offer examples of how the complex
      relationship between interventions and spending is utilized in order to bring
      value to PBMs' clients above and beyond the scope of traditional pharmacy trend
      analytics. Additionally, we demonstrate how the implementation of disease
      management programs can effectively impact the largest component of total health
      care costs.

PMID- 12608118
TI  - Managing the intricate Web of prescription drugs.
AB  - Prescription drug costs are the fastest rising component of health care and are
      contributing to the dramatic increase in health care costs. Emergence of generic
      drugs, employer recognition and increased consumer knowledge are already forcing
      enormous change on the industry. This article explains the factors affecting the
      current financial pressure of prescription drugs, solutions and tactics that
      employers can immediately act on and the variables that employers need to be
      aware of in order to take appropriate action.

PMID- 12608119
TI  - Designing long-term disability plans: tax efficiency vs. maximizing wage
      replacement.
AB  - The tax treatment of long-term disability plans raises difficult questions for
      employers and employees, as it necessitates a tradeoff between tax efficiency and
      maximizing wage replacement for disabled workers. By using simplified case
      examples, this article illustrates the advantages and disadvantages of different
      plan design choices. The authors conclude that, in most cases, long-term
      disability coverage should be mandatory but that employees should be given the
      choice to decide whether their coverage is taxable.

PMID- 12608120
TI  - [The cardiologist, the economist and the meteorologist].

PMID- 12608121
TI  - [Cellular mechanism of vasculo-protection induced by polyphenols on the
      endothelium].
AB  - Epidemiological studies have suggested that dietary factors, including moderate
      red wine consumption, might reduce the risk of cardiovascular diseases. The
      beneficial effect of fruits, vegetables, or red wine may be in part explained by
      the presence of polyphenols with a multitude of biological activities, including
      antioxidant and free radical-scavenging properties, anti-aggregatory platelet
      property and inhibition of vascular smooth muscle cell proliferation. Another
      therapeutically relevant effect of polyphenols may be their ability to interact
      with the generation of nitric oxide from vascular endothelium that leads not only
      to vasodilatation but also to the expression of genes protective of the
      cardiovascular system. Finally, polyphenols contribute to the preservation of
      endothelial integrity by acting on the processes implicated in endothelial
      proliferation, migration and apoptosis. All these effects of polyphenols might
      interfere with atherosclerotic plaque development and stability, vascular
      thrombosis and occlusion and therefore might explain their cardio- and vascular
      protective properties.

PMID- 12608122
TI  - [Correlation between aortic atherosclerosis at transesophageal echocardiography
      and coronary atherosclerosis].
AB  - The aim of this study was to test the relationship between atherosclerotic
      plaques in the thoracic aorta detected by transesophageal echocardiography and
      coronary artery disease detected by angiography. A prospective study was carried
      out in 103 patients who underwent coronary angiography. All patients underwent
      transesophageal echocardiography with imaging of the thoracic aorta. Aortic
      intimal changes were classified in 4 grades. The detection of aortic atheroma
      plaques was the strongest predictor of coronary artery disease. The presence of
      aortic plaques on transesophageal study had a sensitivity of 97.6% and a
      specificity of 80% for angiographically proved obstructive coronary artery
      disease. The positive predictive value of aortic plaque for obstructive coronary
      artery disease was 95.3% and the negative predictive value was 88.9%. Compared to
      the other segments, the detection of atherosclerotic plaque in the descending
      aorta has the highest sensitivity but the specificity was the highest in the
      ascending aorta. With older age and in women the specificity decreased, while the
      sensitivity increased.

PMID- 12608123
TI  - [A practical approach to the evaluation of excessive alcohol drinking].
AB  - Epidemiological data show a typical J curve between alcohol intake and coronary
      artery disease mortality. Non drinkers have an increased risk of coronary artery
      disease, and moderate drinking is associated with a risk decrease of about 30%.
      However, this beneficial effect is observed for daily consumptions of 5 g/d to 40
      g/d in men, and 5 g/d to 20 g/d in women. Higher alcohol consumption is
      associated with increased risk and therefore must be sought in each patient. Both
      the amount and type of drinks must be assessed and specialised questionnaires may
      be used to this purpose. In addition, 4 biological markers can be useful: gamma
      GT, mean red blood cells volume, carbohydrate deficient transferring (CDT) and
      HDL cholesterol. A simple intervention in excessive drinkers has proved
      beneficial over the long-term.

PMID- 12608124
TI  - [Recovery from exercise in trained smokers].
AB  - AIM: Assess the influence of tobacco on recovery after exercise in sportsmen.
      METHODS: Sixty-three smokers aged 18-33 years, practising soccer, participated in
      this study. These subjects belonged to second division congolese league clubs.
      Heart rate (HR) was studied during recovery of moderate exercise (Ruffer's test),
      but also recovery index and arterial pressure. Kinetics of the HR was studied for
      7 min for recovery. A control group consisted of 50 non smokers, practising
      soccer at similar level. RESULTS: Smokers showed heart rate values significantly
      higher (P < 0.001). Non smokers presented a low recovery index. The recovery has
      generally two components: the first is slow in smokers, while the second is a
      fast one. However, recovery rate for the smokers was more rapid during the
      alactic phase. There exists also differences with regards to smoking tobacco
      dependence: when compared to great smokers, lower smokers exhibited a faster
      first phase and a slower second phase. These differences were significant.
      DISCUSSION AND CONCLUSION: The smokers and non smokers differences are discussed
      with reference to the effects of nicotinemia and carbon monoxide on sympathetic
      parasympathetic balance. Cardiovascular changes during exercise have a twofold
      control: decrease a vagal tone and increase of sympathetic activity. The
      comparison of smokers and non smokers concerning recovery led to suppose that
      there exists a difference in regards of the catecholaminergic sensitivity. The
      problem of thermoregulation must not be neglected during recovery. As smokers are
      considered, cutaneous thermolysis is perhaps important when these subjects
      perform exercise in ambient hot air. Here against, it is known that thermolysis
      mechanisms are not similar in smokers and non smokers. In conclusion, this study
      showed that smoking tobacco induce a lower physical condition in sportmen.
      Recovery rate after exercise may function as a predictor of fitness in smokers.

PMID- 12608125
TI  - [Holter EKG for the hypertensive heart disease].
AB  - During chronic mechanical overload induced by hypertension, left ventricular
      hypertrophy predisposes to atrial and ventricular arrhythmias. Atrial
      arrhythmias, mainly atrial fibrillation, decrease cardiac output and increase the
      risk of embolism whereas ventricular arrhythmias remain the major cause of sudden
      death. In hypertensive patients, Holter EKG recordings frequently detect atrial
      or ventricular premature beats and more rarely atrial or ventricular tachycardia.
      In these patients, the presence of non-sustained ventricular tachycardia is
      considered as an independent predictor of mortality. Moreover, this non invasive
      method through the assessment of heart rate variability allows the study of the
      autonomic control of the heart, known to modulate occurrence of arrhythmias.

PMID- 12608126
TI  - [Cardio-vascular effects of sildenafil: new data].
AB  - Sildenafil is an inhibitor of phosphodiesterase 5, which has important
      vasodilatory properties. Though sildenafil provokes a decrease in systemic
      arterial pressure, its safety has been confirmed in large series of patients on
      several kinds of anti-hypertensive therapy. Likewise, post-marketing surveys, in
      the US or United Kingdom, have recorded a number of cardio-vascular deaths
      following sildenafil administration which was lower than expected, provided the
      contra-indication with the concomitant use of nitrates is observed. In patients
      with known or suspected coronary artery disease, sildenafil does not modify the
      tolerance or results of echocardiographic exercise testing. However, sildenafil
      does increase coronary flow reserve, both in narrowed or normal coronary
      arteries, with no sign of a "steal" phenomenon. Because of its capacity to retard
      the degradation of cGMP, by the inhibition of phosphodiesterase 5, the effect of
      sildenafil in primary pulmonary hypertension has been evaluated in several
      studies: acutely, sildenafil decreases pulmonary artery pressure, either alone or
      in combination with inhaled iloprost or NO. On the same line, sildenafil
      decreases hypoxia-induced pulmonary hypertension in normal volunteers. These
      findings, together with reports of long-term improvement in symptoms and levels
      of pulmonary artery pressure in patients with primary pulmonary hypertension,
      will warrant further trials to document its potential role in this otherwise
      severe disease.

PMID- 12608127
TI  - [Deleterious role of adipose tissue on cardiovascular disease].
AB  - Obesity corresponds to excessive weight caused by an increase in energetic
      stores. It can be considered a disease of adipose tissue, with an increase of
      triglycerides inside adipose cells. There is a "J" curve between body mass index
      and mortality. Incidence of angina pectoris, sudden death and, to a lesser
      extent, acute myocardial infarction, is increased in obese subjects. However,
      this relation is strongly mediated by the influence of obesity on conventional
      risk factors (diabetes mellitus, dyslipidemia, hypertension, insulin resistance,
      and hemostatic disorders. However, the distribution of body fat mass is also
      important. In particular, excessive abdominal fat is independently associated
      with an increased cardiovascular risk. Regarding therapeutic management, obesity
      must be considered a chronic disorder and justifies long term measures, rather
      than the simple prescription of a diet. Last, prevention of obesity should be one
      of the goals of a health policy in industrialized countries.

PMID- 12608128
TI  - [Cardiovascular benefits and hazard of physical practice].
AB  - The benefits of regular physical activity have been demonstrated in numerous
      epidemiologic studies in primary and secondary prevention of coronary artery
      disease. However, even high level physical activity is not an absolute guarantee
      against complications of coronary artery disease. Sudden death remains a major
      complication of sports. Beyond 35-40 years of age, coronary artery disease is the
      main cause of sudden death during physical activity. In normotensive as well as
      hypertensive subjects, physical activity lowers blood pressure. It also has
      beneficial effects on body fat and increases HDL-cholesterol. Likewise, physical
      activity has documented beneficial effects in diabetic patients, for type 1 as
      well as type 2 diabetes mellitus. Overall, the advantages of regular physical
      activity clearly exceed the potential risk of sudden death which is usually
      caused by heavy exertion in otherwise unaware coronary patients.

PMID- 12608129
TI  - [Smoking cessation in coronary patients].
AB  - Smoking is one of the main risk factors for coronary artery disease and its
      complications, including sudden death. In smokers, smoking cessation is
      associated with improved 5-year outcome. Consequently, smoking cessation should
      be one of the main goals of the clinician in patients hospitalized for a coronary
      event. Any health professional has the capacity to deliver a simple message: "do
      you smoke?" and "are you willing to quit?". Such simple questions have a positive
      impact on the smoker who knows he has coronary artery disease. In addition
      nicotine substitutes and bupropion are particularly useful to help the patient:
      their efficacy has been demonstrated in several well-conducted studies. Last,
      treating tobacco smoking requires long-term follow-up of the patient who will be
      asked to consult regularly to this purpose.

PMID- 12608130
TI  - [Social and professional factors, occupational environmental strain and
      cardiovascular diseases].
AB  - In addition to conventional risk factors, environmental and occupational strain
      is an actor of the development and evolution of cardiovascular diseases. In
      industrialised countries, cardiovascular mortality is inversely correlated with
      the socio-economic level and type of occupation. In the French Ihpaf study,
      systemic hypertension and obesity were correlated with the socio-economic level.
      Among possible explanations for the importance of occupational environment,
      psychological stress at work, sedentary jobs, passive smoking and shift working
      may all play a role. Thus, beyond the conventional approach to individual risk
      factor management, it appears necessary to consider cardiovascular prevention
      through collective actions taking into account occupational environment.

PMID- 12608131
TI  - [Myocardial infarction and abnormal origin of the circumflex coronary artery].
AB  - Abnormal origin of the circumflex coronary artery without any stenosis is
      generally considered benign and without any particular ischemic risk. We report a
      case of a 21 year old man who suffered a posterior lateral myocardial infarction
      with objective criteria: electrocardiographic, echocardiographic and isotopic.
      The patient received thrombolytic therapy at H2. Angiography showed an abnormal
      origin of the circumflex coronary artery which was free of any stenosis. Certain
      cases of the circumflex artery anomaly can, therefore, be complicated by
      myocardial infarction, and the benign nature of the anomaly needs to be re
      examined.

PMID- 12608132
TI  - [Screening of the abdominal aortic aneurysms during an echocardiography].
AB  - We examined the abdominal aorta by ultrasound in 1106 patients during
      transthoracic echocardiography, whatever the reason of the echocardiography, to
      track abdominal aortic aneurysms. The study group comprised 822 men and 284
      women. We found 88 patients having an abdominal aorta with a diameter of more
      than 23 mm and 11 patients with a diameter of more than 35 mm. Ninety sixteen per
      cent of the patients having an aortic ecstasy are more than fifty years old. Ther
      are more smokers among the patients having an aortic ecstasy. In conclusion, the
      track of the ecstasies and the abdominal aortic aneurysms is easily realizable
      during an echocardiography and presents a good rentability.

PMID- 12608133
TI  - [Iodic allergic reaction with vasospasm occluded coronary during coronarography].
AB  - Coronary vasospasm is infrequent during anaphylaxis reaction. The authors
      describe a severe coronary spasm following iodine allergic reaction and then
      should to explain the physiopathology of this complication.

PMID- 12608134
TI  - [Reversible cardiomyopathy induced by psychotropic drugs: case report and
      literature overview].
AB  - A number of psychotropic drugs, including tricyclic antidepressants,
      phenothiazine and lithium, have a well demonstrated risk of cardiotoxicity. Each
      individual therapeutic class has potentially deleterious effects on
      electrophysiology and myocardial function. The authors report a case showing how
      serious side effects may result from the association of these different classes
      in the presence of a coexistent heart disease, even when the underlying disease
      is mild.

PMID- 12608135
TI  - [Brugada here, Brugada there].

PMID- 12608137
TI  - In Roe's shadow.

PMID- 12608136
TI  - Cheating Uncle Sam for mom and dad.

PMID- 12608138
TI  - Out of the time warp.

PMID- 12608139
TI  - [Temporary arterial clipping in surgery for cerebral aneurysms in acute
      subarachnoidal hemorrhage].
AB  - Temporary clipping was used during operations in 69 patients. Of them, 51
      patients underwent temporary arterial clipping, forced temporary arterial
      clipping was used in 18 patients. A total of 104 patients were operated on with
      preventive temporary clipping. Aneurysmal rupture occurred in 18 (17.3%) patients
      of them. The bioelectrical activity of the brain was intraoperatively monitored
      by using EEG and ECG in 12 patients of whom 11 felt rather well on discharge. The
      temporarily arterial clipping technique using EEG and ECG makes it possible to
      monitor the allowable time of temporary arterial clipping, which is in turn
      associated with a less risk for postoperative ischemic complications.

PMID- 12608140
TI  - [Results of endoscopic ventriculostomy of the III ventricle in the treatment of
      occlusive hydrocephalus].
AB  - The paper presents data of a retrospective analysis of the outcomes of endoscopic
      ventriculostomy of the 3rd ventricle, obtained in a consecutive series of 120
      patients aged 5 months to 58 years who had occlusive hydrocephalus and operated
      on at the Research Institute of Neurosurgery, Russian Academy of Medical
      Sciences, in 1995-2000. In most cases (n = 112), hydrocephalus was caused by a
      block at the level of the cerebral aqueduct. In more than 50% of the patients,
      different tumors were responsible for occlusion. In 96 (80%) cases, the operation
      led to the elimination of occlusion and to the regression of symptoms just after
      surgery. Complications were few and observed in 19 patients, ventriculitis (n =
      7) and intracranial hemorrhages (n = 6) being most common. No death occurred.
      Seventy three patients were followed up for 1 month to 5 years (mean 1.5 years).
      Eliminated occlusion and steady-state remission were found in 64 (87.7%) cases.
      Improvement was strongly correlated with an increase in the reserve
      craniovertebral content capacity estimated by measuring the pulse amplitude of
      blood flow in the tentorial sinus in body position-changing tests. In 9 patients,
      the symptoms of hydrocephalus remained or recurred after short-term improvement.
      In 3 of them, this occurred with anatomically competent anastomoses between the
      3rd ventricle and cisterns. In the other 6 cases, the obliteration and anatomic
      incompetence of ventriculostoma were responsible for a relapse. In 8 of the 9
      patients, shunting had to be made subsequently in the period of 1 to 6 months.
      The paper also considers some biophysical aspects of cerebrospinal fluid
      circulation and discusses indications for endoscopy. It is concluded that
      endoscopic ventriculostomy of the 3rd ventricle is the method of choice in the
      treatment of patients with obstructive hydrocephalus.

PMID- 12608141
TI  - [Microvascular decompression as a treatment of essential hypertension].
AB  - Microvascular decompression (MVD) proved to be the method of choice in treating
      trigeminal neuralgia, facial hemispasm, glossopharyngeal neuralgia, and
      torticollis spastica. So did MVD for the left rostral ventrolateral medulla
      oblongata and glossopharyngeal and vagus nerves in association with primary
      arterial hypertension. Five patients with primary essential hypertension were
      treated with MVD. During a longer follow-up, 75% of the patients had lowered
      blood pressure. In 2 patients, MVD was performed for trigeminal nerves due to
      ipsilateral trigeminal neuralgia. This paper presents and analyzes the clinical
      findings in these 5 patients and discusses the global state-of-the-art of MVD for
      arterial hypertension.

PMID- 12608143
TI  - [The features of the brain immune system in brain neoplasms].
AB  - Examining responses of the local immune system of the brain in neurocancer
      patients suggests that the immune system is involved in the neuroimmune
      interaction of both physiological and pathological conditions in the central
      nervous system (CNS). The setting off the local immune system of the brain is of
      functional nature, similar to functional analogy with the local system of the
      mucosae. By functional analogy, the aggregate of immune responses in the nervous
      tissue and cerebrospinal fluid should be called local and the system that
      includes these responses should named the local immune system of the brain. Due
      to the fact that nervous, endocrine, and immune regulatory pathways intersect in
      the CNS (hypothalamus), it is expedient to call this aggregate of defensive
      factors and mechanisms in CNS more broadly--the neuroimmune system.

PMID- 12608144
TI  - [Hematoma of the cerebral peduncle].
AB  - The paper presents a rare case of surgical treatment for hematoma of the cerebral
      peduncle in a 30-year-old woman found to have progressive neurological focal
      disorders due to mesaticephalic and thalamic lesions. Computed tomography and
      magnetic resonance imaging (MRI) revealed a round mass (26 x 3 x 25 mm) in the
      left cerebral peduncle and thalamus without surrounding edema. The focus showed
      characteristic signs of subacute parenchymatous hematoma. The interpeduncular
      cistern was explored via transsylvian approach and hematoma was removed by making
      a small incision of the left cerebral peduncle. Histological examination of a
      surgical specimen demonstrated no vascular malformation. The postoperative period
      was complicated by left oculomotor nerve palsy which regressed following several
      months. A small slit-like cyst communicating with the interpeduncular cistern was
      detected in the left cerebral peduncle by MRI at follow-up.

PMID- 12608142
TI  - [Cerebral low T3 syndrome].
AB  - The authors studied the time course of changes in the parameters of the cerebral
      thyronergic system (total and free triiodthyronine (T3) and thyroxin (T4),
      thyroxine-binding globulin (TBG), thyroid-stimulating hormone (TSH) by
      radioimmunoassay (Immunotech, Czechia; CIS, France), proinflammatory cytokine of
      TNF-alpha by enzyme immunoassay (Innogenetic, Belgium) in the blood and
      cerebrospinal fluid (CSF) in 59 patients (37 males and 22 females whose age
      ranged from 21 to 64 years) in acute subarachnoidal hemorrhage due to arterial
      aneurysmal rupture. On admission, the condition of 47 (79.7%) was rated as grades
      III-VI according to the Hunt-Hess scale, which was responsible for high mortality
      rates (33.89% in the assessment of outcomes according to the Glasgow outcome
      scale). The causes of death were ischemic and hemorrhagic insults, edema of the
      brain, cerebral stem wedging. Laboratory findings were analyzed in relation to
      the clinical condition of patients, outcomes, and the degree of secondary
      vasospasm assessed by Doppler transcranial study by the average blood flow
      velocity in the middle cerebral artery. They revealed a significant depression of
      thyroidal metabolism with developed the total low T3 syndrome just before
      surgical treatment in patients with deterioration in the early postoperative
      period. The significant correlations found by the authors between the decreased
      blood T3 and TSH levels and 1) the severity of neurological disorders; 2) the
      degree of vasospasm, and 3) the outcome of disease, as well as negative
      correlations of elevated TNF-alpha levels not only in the blood, but also in CSF
      with the content of CT3, CT4 and with the severity of neurological symptomatology
      are indicative of the development of isolated syndrome in the brain, which is
      characterized by specific thyroidal metabolic disorders, which the author propose
      to call the cerebral low T3 syndrome (by taking into account the presence of the
      autonomic systems of thyroidal homeostatic provision).

PMID- 12608145
TI  - [Embolization of blood vessels for intracranial neoplasms].

PMID- 12608146
TI  - [Parenteral nutrition of patients in early postoperative and posttraumatic
      periods].

PMID- 12608147
TI  - [Ethical questions in neurosurgery].

PMID- 12608148
TI  - Aggressive lipid reduction provides additional clinical benefit.

PMID- 12608149
TI  - Changes in ATP III focus on diabetes and the metabolic syndrome.

PMID- 12608150
TI  - Statin pharmacology may have important clinical implications.

PMID- 12608151
TI  - Growing body of evidence shows benefits of aggressive lipid management in high
      risk patients.

PMID- 12608152
TI  - Role of hs-CRP in cardiovascular risk prediction.

PMID- 12608153
TI  - Interview: role of managed care in implementing NCEP-ATP III guidelines.

PMID- 12608160
TI  - Epidemiology of single-unit transfusion. A one-year experience in a community
      hospital.
AB  - The transfusion practices of an 850-bed community hospital are reviewed from Jan
      1, 1962, through Jan 1, 1963. Twenty-nine percent (855 of 2,921) transfused
      patients received a single unit of whole blood or packed red blood cells. Eighty
      two percent of single-unit transfusions were given to women, and 93% were related
      to surgical or obstetric situations. In patients undergoing common operative
      procedures, 62% had normal vital signs and hematocrit readings before
      transfusion. Sixty-seven percent of all patients had normal hematocrit readings
      prior to transfusion. One third of the single-unit transfusions were considered
      justified, and two thirds were regarded as questionable or unnecessary.

PMID- 12608161
TI  - Reconstituted collagen and chromic catgut suture for colon anastomoses in dogs.
AB  - Reconstituted collagen sutures demonstrate no advantages over catgut sutures in
      this study, which was designed to observe the physiochemical and morphological
      characteristics of reconstituted collagen after implantation in colon anastomoses
      in dogs. There are three distinct disadvantages of the collagen suture: (1) early
      separation and fragmentation of the suture fiber, (2) evidence of prolonged
      chemical irritation, and (3) hyper-fibrillosis about the suture wound in
      prolonged observations.

PMID- 12608162
TI  - Diagnosis of pain with a graduated spinal block technique.
AB  - The differential spinal examination has been used at Duke University Medical
      Center for approximately 15 years in the evaluation of low-back and lower
      extremity pain. This is a technique of using increasing concentrations of
      procaine hydrochloride to block nerves of various sizes and degrees of
      myelinization. With the ever increasing number of compensation and liability
      cases, there is a corresponding need for this type of diagnostic and prognostic
      test. It is an attempt to give the physician an objective estimate of the pain.
      It must be stressed that this is just another test for diagnostic and prognostic
      evaluation. However, initial results seem to indicate that much weight can be
      placed on the findings in an attempt to objectively categorize the pain as being
      either organic or functional and whether it is medicated by sensory or
      sympathetic pathways.

PMID- 12608163
TI  - The changing face of intussusception.
AB  - Management of intussusception in a pediatric center shows changing patterns over
      the past 26 years. Early and subacute cases of intussusception are now ordinarily
      successfully reduced by hydrostatic pressure (barium enema). A minority, who are
      in shock, who have evidence of significant blood loss or, in whom small
      intestinal obstruction is apparent, are treated by emergency laparotomy, with or
      without confirmatory contrast studies. In the latter group the rate of resection
      is high (16.4% in the present series). Resected segments are microscopically
      infarcted; with unnecessary resection a rarity. Advances in surgical management
      have eliminated a major portion of the mortality formerly associated with
      resection. The use of hydrostatic pressure reduction makes surgery unnecessary in
      a high percentage of infants with intussusception, but does not reduce the
      incidence of infarction requiring resection. Ambulatory or nonhospital management
      of intussusception subjects the infant to the risk of a significant delay in
      definitive treatment and is not to be condoned.

PMID- 12608164
TI  - Neisseria subflava as a cause of meningitis and septicemia in children. Report of
      five cases.
AB  - In five cases of meningitis or septicemia in children, the causative organism was
      Neisseria subflava. The organism is similar to N meningitidis. Only one previous
      case of meningitis caused by N subflava in a child has been found in the
      literature, but this organism may be more commonly pathogenic than has been
      thought. The clinical findings and course are not unlike those of septicemia and
      meningitis due to N meningitidis.

PMID- 12608165
TI  - Simple electrodiagnostic test for Bell's palsy.
AB  - Experience with the use of a simple and practical nerve-excitability test in 56
      cases of Bell's palsy has demonstrated its value in estimating prognosis and
      progress at an early stage of the disease.

PMID- 12608166
TI  - Pyelonephritis in the diabetic. Correlation of open renal biopsies and
      bacteriologic studies.
AB  - In a study of 80 juvenile diabetic patients, chronic pyelonephritis was found
      histologically in seven (9%) of open renal biopsies. Twelve patients (15%) had
      positive urine cultures. No patient had a positive renal-biopsysite culture.
      Three patients (4%) had positive renal-tissue cultures. There was essentially no
      correlation found between the presence of positive urine cultures, positive
      tissue cultures, and the histological diagnosis of chronic pyelonephritis. It is
      suggested that factors other than the continued presence of bacteria in the
      kidney may play a role in the pathogenesis of chronic pyelonephritis.

PMID- 12608167
TI  - Periodic health examinations using an automated multitest laboratory.
AB  - Automated multitest laboratories with automated, electronic, and computer
      equipment are used as an integral part of a routine periodic health examination
      for 4,000 patients a month. The automated multitest laboratory provides
      electrocardiography, anthropometry, chest and breast x-rays, visual acuity tests,
      tonometry, retinal photography, audiometry, vital capacity determinations, a
      health questionnaire on prepunched cards, and laboratory tests including eight
      blood chemistries done simultaneously with direct punched-card output. Before the
      patient leaves the multitest laboratory, additional indicated procedures are
      arranged in accordance with programmed computer "advice" rules. When all test
      reports are received, the computer prints out a summary report for the physician.
      The advent of automation and computers may introduce a new era of preventive
      medicine.

PMID- 12608168
TI  - Carcinoma of the cervix among women in their twenties. A 14% prevalence deserves
      our respect!
AB  - The purpose of this study was to estimate the value of routine vaginal cytology
      in women under 30 years of age. Over a five-year period, 18,160 vaginal
      cytological examinations were made on women aged 20 through 29 years, and 424
      women (2.3%) were found to have Papanicolaou smears class III, IV, or V. Of these
      424 patients, 122 (28.8%) were found to have carcinoma of the cervix. A tissue
      diagnosis of intraepithelial carcinoma was obtained in 103 women. The remaining
      19 patients proved to have invasive carcinoma of the cervix. Approximately one
      third of this group of women with positive cytology failed to return for tissue
      diagnosis so the true prevalence of cancer was probably in the region of 40%. The
      findings suggest that women deserve routine vaginal cytological examinations
      irrespective of age.

PMID- 12608169
TI  - Protein abnormalities in neuromuscular diseases--Part 2.
AB  - Different protein abnormalities have been found in several neuromuscular diseases
      and in some instances seem to be disease-specific. They do not necessarily
      represent "primary" defects and to date have only seldom led to beneficial
      therapy. But at the very least, these protein abnormalities provide handles which
      one may grasp in attempting to devise ways of arresting, curing, and preventing
      neuromuscular diseases.

PMID- 12608170
TI  - Jet injection of insulin vs the syringe-and-needle method.
AB  - A new technique of injecting insulin without a needle employs a jet injector to
      administer a high-pressure stream of medication. This method causes very little
      pain and affords great accuracy, ease of administration, and safety. The
      medication is more widely diffused in the body by jet injection than by the
      needle-and-syringe technique. The control of blood sugar (with similar doses of
      insulin) achieved by the two techniques is similar, and their effect on local
      tissues is also similar. In the patients studied, jet injection appeared to be a
      very satisfactory method of administering insulin and has met with good patient
      acceptance. Jet injection is also a useful method for the visually handicapped.

PMID- 12608171
TI  - Familial aggregation of blood pressure. Preliminary report.
AB  - Familial aggregation of blood pressure levels has been under study in a random
      sample of Buffalo families. Spouse aggregation has been demonstrated for couples
      married more than 15 years. Parent-child aggregation was limited to families in
      which father and mother had the same systolic blood pressure level in a five
      response scale. Aggregation was further limited to parents and sons. In all
      comparisons in which aggregation was present, it was manifested most strongly in
      the lower range of systolic blood pressure values.

PMID- 12608172
TI  - Evaluation of an antispasmodic agent. Methixene hydrochloride (Trest).
AB  - Methixene hydrochloride, an anticholinergic agent, may be useful in the
      symptomatic treatment of functional bowel disorders. Adverse effects reported
      from its use are those of the anticholinergic drugs in general.

PMID- 12608173
TI  - Electrical injuries.

PMID- 12608174
TI  - The superiority of the rotating program.
AB  - In view of the recent trend towards straight internships in many teaching
      hospitals, the Intern Committee of the Henry Ford Hospital has surveyed the
      rotating internship in this institution. It is our belief that many factors
      affecting both the intern and the hospital staff make the rotating program still
      superior to any other type of internship offered.

PMID- 12608175
TI  - Gluten and the small intestine in rheumatoid arthritis.
AB  - A study of the small intestine in patients with rheumatoid arthritis was
      undertaken because it has been suggested that the disease arises secondary to
      hereditary enteropathy. No abnormality of jejunal mucosa was detected
      histologically in five patients with arthritis, and studies of bowel function
      were normal in six patients. No serologic evidence of increased intestinal
      permeability, as indicated by antimilk or antijejunal cell antibodies, was
      detected in sera of 17 arthritic patients. Gluten-free diet, claimed to be
      helpful in treating the disease, proved of no value in a brief, carefully
      controlled, hospital trial in five patients.

PMID- 12608176
TI  - Bone-marrow examination. Technique and diagnostic value of a bone-marrow biopsy
      using a Silverman needle.

PMID- 12608177
TI  - Elusive errors in coronary statistics.

PMID- 12608178
TI  - Significance of thromboangitis obliterans.

PMID- 12608179
TI  - Guillain-Barre syndrome an allergic reaction?

PMID- 12608180
TI  - African handyman.

PMID- 12608181
TI  - Iron deficiency in infants.

PMID- 12608182
TI  - Abreast of the times.

PMID- 12608183
TI  - Sir Henry Halford (1766-1844)--morbid physician.

PMID- 12608184
TI  - Coexistence of chronic lymphocytic leukemia and Hodgkin's disease. A case report.
AB  - In the present case there was coexistence of chronic lymphocytic leukemia and
      Hodgkin's disease. The leukocyte count of 213,000/cu mm, being among the highest
      reported in association with Hodgkin's disease, is unusual. The patient was
      treated for chronic lymphocytic leukemia with an unfavorable response to
      triethylenemelamine, and short-lived response to mechlorethamine and prednisone.
      The autopsy confirmed the existence of Hodgkin's disease and chronic lymphocytic
      leukemia. The coexistence of these two diseases does not imply that one is
      necessarily related to the other. In view of the continued controversy about the
      relationships of lymphoproliferative disorders to each other, this case should
      stimulate interest.

PMID- 12608185
TI  - False-positive reaction to VDRL test with prozone phenomena. Association with
      lymphosarcoma.
AB  - A patient with lymphosarcoma had a VDRL test reactive at 1:256. A prozone
      phenomenon was also present. The nontreponemal test result was shown to be a
      false-positive reaction by nonreactive Treponema pallidum immobilization and
      fluorescent treponemal antibody absorption tests. High-titer serologic tests for
      syphilis are uncommon, and prozone reactions are previously unrecorded in the
      false-positive reactor.

PMID- 12608186
TI  - Rupture of a pancreatic cyst into the portal vein. Report of a case of
      subcutaneous nodular and generalized fat necrosis.
AB  - Nodular subcutaneous and generalized fat necrosis, due to rupture of a pancreatic
      cyst into the portal vein, occurred in a 57-year-old man. No report of a similar
      mechanism causing such a result was found in the literature. Multiple papular
      lesions, with microscopic changes in the skin, although not in themselves
      specific, should lead to a suspicion of systemic dissemination of pancreatic
      secretions into the blood stream.

PMID- 12608187
TI  - Prophylaxis of recurrent lymphangitis complicating lymphedema.
AB  - Antibiotic prophylaxis was employed in 21 patients with secondary lymphedema
      complicated by recurrent episodes of acute lymphangitis. Eighteen were completely
      free of subsequent attacks; the three others showed a marked reduction in the
      frequency and severity of subsequent attacks. Follow-up time averaged 30 months.

PMID- 12608188
TI  - Paget's disease of the breast. Simple method of cytological diagnosis.
AB  - A simple abrasive technique for obtaining cytological material for evaluation of
      lesions of the mammary nipple yields samples which permit a diagnosis of Paget's
      disease without surgical biopsy. The lesion is abraded with the rough surface of
      a glass microscope slide having one frosted face; the sample is fixed with
      polyethylene glycol, and stained with the Papanicolaou technique. The slide is
      rendered transparent by the cover-slip mounting material and is evaluated
      according to usual cytological standards.

PMID- 12608190
TI  - Penrose feeding tubes.

PMID- 12608189
TI  - Fatal blunt injury to the omentum.

PMID- 12608191
TI  - The treatment of the hiccups.

PMID- 12608192
TI  - Photosensitizers in soaps.

PMID- 12608193
TI  - National Oral Health Week: 14-18 August.

PMID- 12608194
TI  - [A powerful storm brewing in the north].

PMID- 12608195
TI  - A retrospective analysis of gunshot injuries to the maxillo-facial region.
AB  - This study analysed the prevalence, demography, soft- and hard-tissue injury
      patterns, management and complications of gunshot injuries to the maxillo-facial
      region in 301 patients treated at Groote Schuur Hospital, Cape Town. The number
      of patients presenting with maxillo-facial injuries caused by gunshot increased
      over the 15-year study period. The majority were caused by civilian type low
      velocity hand-guns and were purposefully and intentionally inflicted by others.
      Males in their third decade of life and of low socioeconomic status were most
      often the victims. The wounding effects of these low-velocity injuries were
      characteristic--small rounded entrance wounds, causing fragmentation of teeth and
      comminution of the underlying bone, usually without any exit wounds. A comminuted
      displaced type of fracture pattern was most frequently observed. Special
      investigations included plain film radiographs with more sophisticated
      investigations being requested where indicated. Definitive surgical management
      was initiated by early soft-tissue debridement. Both the mandibular and maxillary
      fractures had more open than closed reductions. Bone continuity defects as a
      result of the initial injury were usually reconstructed secondarily using free
      autogenous bone grafts. All the patients received anti-tetanus toxoid on
      admission and the majority received antibiotic treatment. The most common
      complications were sepsis, ocular and neurological complications and limitation
      of mouth opening. The postoperative sepsis rate was high (19%). The wounding
      effects of these low-velocity missile injuries are devastating and pose a
      treatment challenge to the maxillo-facial surgeon.

PMID- 12608196
TI  - Clinical evaluation of the ART approach and materials in peri-urban farm schools
      of the Johannesburg area.
AB  - In this study, 1,325 school children from 7 farm schools were examined. Their
      mean age (+/- SD) was 10.5 +/- 3.0 (range 6-11) years. At baseline, the mean DMFT
      score was 1.1 +/- 1.7 and 36.4% of the children had caries. The prevalence of
      fluorosis among the children was 12.6%. Curative treatment was offered to all the
      children. A total of 113 children (8.5%) with one-surface cavities on permanent
      teeth and without fluorosis were treated using the atraumatic restorative
      treatment (ART) approach. A total number of 163 cavities were included in the
      study, of which 82 were treated with Fuji IX glass-ionomer cement and 81 with
      Ketac-MOLAR (hand mix). One year after treatment, restoration and sealant parts
      of ART fillings were examined. Caries status was also determined. The placing of
      the ART fillings and their evaluation were performed by different practitioners.
      A total number of 108 restorations (58 with Fuji IX, 50 with Ketac-MOLAR) were
      evaluated. Results of ART fillings showed a survival rate of 93.1% with Fuji and
      94.0% with Ketac-MOLAR. Retention of the sealant parts of ART fillings was
      observed in 81% of restorations with Fuji IX and 76% with Ketac-MOLAR, not
      connected to the filled cavity. Caries was absent on all teeth restored with Fuji
      IX and noted in only one tooth restored with Ketac-MOLAR, not connected to the
      filled cavity. The retention rate after a 12-month period was acceptable and ART
      approach proved to be an appropriate technique for restoring teeth in this
      population group. There were no statistically significant differences between the
      survival rates of the two glass-ionomer restorative materials (P > 0.05).

PMID- 12608197
TI  - Investigations into the application of electrochemically activated water in
      dentistry.

PMID- 12608198
TI  - Overview of pharmacological aspects of sedation--Part I.

PMID- 12608200
TI  - Opportunities outweigh challenges.

PMID- 12608199
TI  - Transnet-Phelophepa's Colgate dental clinic: prevention and education.

PMID- 12608201
TI  - Fitting restorations from extracted teeth.

PMID- 12608202
TI  - Alcohol contents of dental products.

PMID- 12608203
TI  - Bond strengths and patterns of failure of a zinc polycarboxylate cement on
      surface-treated gold alloys.
AB  - The study investigated the shear strengths and fracture characteristics of a zinc
      polycarboxylate cement on three sets of type III gold alloy bars whose surfaces
      were modified by alumina blasting, heat treatment and tin plating respectively.
      Each set comprised 20 bars with similarly treated surfaces, cemented in pairs
      with the polycarboxylate cement and stored in water at 37 degrees C for 48 hours.
      The cement bond was then stressed to failure by application of forces in shear
      mode and the bond strength was determined. The mean bond strength for each type
      of treated gold alloy surface was calculated and then compared with the others by
      way of statistical analysis. The failed surfaces were observed and photographed
      with a stereophotomicroscope for subjective evaluation of the character of the
      failed surfaces. The strongest bonds were formed on the alumina-blasted surfaces
      where 70% of the bonds failed in an adhesive-cohesive fashion. The weakest bonds
      were formed on the tin-plated surfaces where cement failure was entirely
      adhesive. Bond strengths on the heat-treated surfaces were intermediate and a
      cohesive failure pattern was observed on 80% of the specimens. The differences in
      bond strengths on the three surfaces were statistically significant.

PMID- 12608204
TI  - Prostheses for acquired maxillary defects with emphasis on flexible silicone
      obturators.

PMID- 12608205
TI  - Reviewing the role of educational domains and problem-based learning in dental
      curricula. Part I: The concept of educational domains and their integration.
AB  - This review of educational domains and problem-based learning in dental curricula
      examines the concept of educational domains under the following headings: the
      domains of skills and knowledge within which we expect students to demonstrate
      proficiency whether a course should be integrated, both vertically and
      horizontally between academic disciplines whether these domains are achievable by
      problem-based learning in whole or in part, and the type of learning domain or
      skill which is expected from students, such as cognitive, psychomotor and
      affective. Part I will deal with the first two aspects, while Part II (to be
      published in SADJ September 2000) will deal with problem-based learning (PBL) and
      the skills required of students.

PMID- 12608206
TI  - Context as a critical influence on dental education.
AB  - The problems which beset dental education in many African countries are not
      unique to the African continent. While modified by the continent's history and
      present stage of development many of the difficulties are similar to those in
      developing and industrialised countries throughout the world. The need for oral
      health education programmes to produce, in the most cost-efficient manner,
      competent, high-quality graduates capable of coping in diverse situations is
      universal. This article reviews the limitations that the local context places on
      achieving these dual objectives and highlights the significance of the role of
      consumer demand for dental care in creating viable dental education programmes,
      particularly in poorer countries.

PMID- 12608207
TI  - Overview of pharmacological aspects of sedation. Part 2. Combination
      sedative/analgesics.

PMID- 12608208
TI  - Precis of matters discussed at General Practice Committee meeting held in
      Johannesburg on 24 June 2000.

PMID- 12608209
TI  - The current state of dentine bonding systems: a review of materials and
      techniques.
AB  - The acid-etch technique for bonding composite resin to enamel is a well
      established clinical procedure. Although bonding composite resin to dentine has
      proved to be a difficult challenge, it has become an indispensable link in
      aesthetic dentistry. The purpose of this article is to provide a brief history of
      dentinal bonding as well as an overview of clinical indications and available
      products for the bonding of composites and/or amalgam.

PMID- 12608210
TI  - Cosmetic enhancement of maxillary anterior teeth with bonded resin composite
      onlays.

PMID- 12608211
TI  - Bloodborne viruses and occupational exposure in the dental setting.
AB  - Occupational hazards in dentistry are most commonly associated with physical,
      chemical and biological agents. Bloodborne viruses, notably hepatitis B virus and
      human immunodeficiency virus (HIV), pose a risk for occupational exposure among
      oral health care workers in South Africa. Although post-exposure prophylaxis can
      be prescribed after exposure to either or both these viruses, universal
      precautions and strategies must be implemented in order to protect the oral
      health care professional.

PMID- 12608212
TI  - Reviewing the role of educational domains and problem-based learning in dental
      curricula. Part II: Problem-based learning and skills expected from students.

PMID- 12608214
TI  - Guns in our society.

PMID- 12608213
TI  - Taking your practice to a new level. Part I.
AB  - There is a new game in the dental profession with new rules of competition. The
      new game has to do with creating patient value. With this game, good no longer is
      good enough.

PMID- 12608215
TI  - The elastic limit of nickel-containing and nickel-free cobalt-chromium
      circumferential clasp arms.
AB  - The purpose of this study was to compare the flexibility and rigidity of the
      retentive arms of cast circumferential clasps prepared from two nickel-containing
      alloys (Vitallium and Wironit) with a nickel-free alloy (Biosil). Standardised
      wax patterns were adapted to 30 specially prepared refractory casts. Ten of these
      waxed casts were sent to each of three commercial laboratories that specialize in
      making castings from each of the alloys to be tested. A tensile tester was used
      to test each one of the finished clasps for deflection at the elastic limit and
      for load at 0.5 mm deflection. An exploratory analysis of the data by means of a
      multivariate analysis of variance was followed by Fisher's least significant test
      that identified specific differences between test specimens. It was found that
      nickel-containing and nickel-free alloys were not significantly different in
      respect of flexibility and rigidity.

PMID- 12608216
TI  - The degree of polymerisation shrinkage of adhesive resin cements.
AB  - The degree of polymerisation (DP) of modern resin cements has a significant role
      to play in determining the ultimate physical and mechanical properties of the
      material. This study was undertaken to determine the DP of three adhesive resin
      cements, viz. 3M Opal Cement (3M), Enforce (E, Caulk/Dentsply) and C epsilon tB
      Metabond (CB, Parkell). Spectra of both light-cured (3M and E) and self-cured
      (3M, E and CB) samples were obtained at different time intervals from 3 minutes
      after mixing the cement up to 24 hours, using a Dilor Raman Confocal Microprobe.
      The DP of the different cement specimens was calculated from the spectra and
      statistically analysed (ANOVA). There was a statistically significant difference
      (P < 0.01) between the DP of 3M and E in the two different activation modes. The
      light-cured specimens attained a statistically higher degree of polymerisation.
      CB obtained a statistically significant higher degree of polymerisation (P <
      0.01) compared with 3M and E at 24 hours.

PMID- 12608217
TI  - Action research in the professional development of university staff: a case study
      from operative dentistry.
AB  - Action research has long been used in educational research and increasingly
      features in the professional development of university staff. A brief review of
      the historical development of action research is presented together with the
      range of approaches covered and their common characteristics. To illustrate the
      elements of action research, an example is drawn from operative dentistry. The
      steps taken by a lecturer to improve a pre-clinical course in operative dentistry
      are described in some detail and the outcomes of the action are reported and
      evaluated. The findings support the suitability of action research for
      professional development in dental education. The kinds of problems likely to be
      encountered by teachers using this methodology are reported. The ability of the
      participant investigators to reflect critically on the action taken was found to
      be a key component of action research.

PMID- 12608218
TI  - Taking your practice to a new level. Part II.
AB  - There is a new game in the dental profession with new rules of competition. The
      new game has to do with creating patient value. With this game, good no longer is
      good enough.

PMID- 12608219
TI  - Shaping the profession for the future.

PMID- 12608220
TI  - [Keen on dentistry 50 years old--an historical overview].

PMID- 12608223
TI  - Environmental scanning electron microscopy of hydrated conditioned/etched
      dentine.
AB  - Various etchants/conditioners are used during dental treatment to affect or
      remove the smear layer. The purpose of this study was to evaluate the effect of
      different treatments on moist dentine, using a field emission environmental
      scanning electron microscope (FE-ESEM). Twenty freshly extracted, human molar
      teeth were utilised. The roots and pulps were removed, and the crowns
      horizontally sectioned with a low speed diamond saw (Isomet) (with cooling in a
      saline solution) in order to expose superficial dentine. A smear layer was
      created on these surfaces by using 600 grit silicone carbide paper. Test surfaces
      were then treated in one of the following ways: 1. 37% phosphoric acid liquid 2.
      37% phosphoric acid gel 3. NRC (non-rinse conditioner) without rinsing 4. NRC
      with rinsing. Shallow grooves were cut on the untreated sides, using a thin
      diamond bur. This enabled the samples to be split in half when pressure was
      applied in the grooves. Samples were maintained moist throughout specimen
      preparation. Samples were examined in the FE-ESEM (Philips XL 30) in such a way
      that the effect of the treatment could be viewed occlusally, as well as
      perpendicular to the treated interface. Phosphoric acid liquid and gel removed
      the smear layer, and demineralised the dentine for approximately 5-10
      micrometers. NRC penetrated the smear layer and modified it to a lesser degree.
      However, washing of the NRC treated surface removed part of the smear layer, and
      opened up some dentinal tubules. Excellent resolution was possible with the FE
      ESEM in both the wet and dry modes.

PMID- 12608224
TI  - Prevalence and pattern of snuff dipping in a rural South African population.
AB  - The contradictory results of earlier studies on the role of snuff in the
      aetiology of oral cancer may be due to the heterogeneous composition of snuff and
      to regional and cultural differences in its use. The aim of this study was to
      determine the prevalence and pattern of use of oral snuff in a rural South
      African adult population, and to report on associated oral lesions. A structured
      questionnaire was administered by means of face-to-face interviews with a
      population of 30 randomly selected households (125 adults over the age of 30
      years). Of the respondents, 20.8% were active oral snuff-dippers and 80.8% of
      them had never visited a dentist before. There was no significant difference
      between the genders of the dippers (P > 0.05). The mean age of dippers was 62.7
      years. None of the snuff-dippers chewed or smoked tobacco, but 38.5% used
      alcohol. Mean dipping period was 21.5 years, for about 2 hours per day and an
      average of 35 minutes per dip. Of the snuff-dippers, 84.6% place their snuff in
      the lower labial sulcus and 15.4% in the lower buccal sulcus, 80.8% of the
      dippers demonstrated keratotic lesions at the site of placement. The clinical
      severity of the lesions was significantly associated with the brand of snuff used
      (P < 0.01). The high prevalence of snuff dipping and associated lesion in many of
      the elderly that had never visited a dentist before highlights the importance of
      regular screening of this group at risk.

PMID- 12608225
TI  - Bone resorption and/or osteogenesis of the mandible in implanto-orthognathic
      reconstructive surgery.
AB  - Over a period of 18-48 months, the bone resorption, or bone deposition
      (osteogenesis) of the mandible, in the supero-inferior dimension, was evaluated
      in patients who had had implanto-orthognathic reconstructive surgery (IORS). It
      entails the combination of three different types of surgical involvement for the
      reconstruction of the atrophic (class V), and severely atrophic (class VI)
      mandibular alveolar ridge (Butow and Duvenage, 1993). This type of surgical
      reconstruction combines orthognathic osteotomy, interpositional bone grafting and
      the immediate placement of osseointegrated implants by means of a trans
      mucoperiosteal approach. Evaluation of the mandibular IORS over the long-term,
      has proven that not only is there minimal resorption, but that osteogenesis of
      the alveolar ridge occurs.

PMID- 12608226
TI  - Palatal finger springs in removable orthodontic appliances--an in vitro study.
AB  - Palatal finger springs are often used in removable orthodontic appliances to tip
      teeth in a mesiodistal direction. There is general consensus that a force of 30
      50 g is required to tip a single-rooted tooth, with an activation of about 3 mm
      for a spring with a load/deflection rate (LDR) of 15 g/mm. The purpose of this
      report is to establish the magnitude of forces for finger springs made from
      different types of wires (i.e. those from different manufacturers and of
      different diameters and lengths). The findings were that springs made from
      ordinary 18/8 stainless steel wire showed a lower LDR than previously reported.
      The 18/9 stainless steel springs gave yet a lower LDR. Definite specifications
      are given for forming springs. For example, a Unitek 0.51 x 17 mm spring can be
      used when the traditional activation of 2-4 mm is applied, but should increased
      activation be required (advocated in this report), the spring length would have
      to be increased to 20 mm to keep the force within the specified range.

PMID- 12608227
TI  - Interpretation and management of oral symptoms experienced by scuba divers.

PMID- 12608228
TI  - Drug-induced gingival hyperplasia--a review.

PMID- 12608229
TI  - The new Pretoria curriculum.
AB  - Macro-environmental changes in tertiary education have prompted a review of
      dental curricula in order to address shortcomings in the traditional curriculum.
      This paper defines the philosophical principles that highlight concepts in the
      new innovative curriculum. The stance adopted in the development of the macro- as
      well as the micro-curriculum is described.

PMID- 12608230
TI  - HIV/AIDS: the current confusion.

PMID- 12608231
TI  - Dental education at the crossroads.

PMID- 12608232
TI  - HIV/AIDS: breaking the silence.

PMID- 12608233
TI  - HIV--a personal perspective.

PMID- 12608234
TI  - Time to flex our muscles?

PMID- 12608235
TI  - Charity drive donates R306 000 to six baby homes.

PMID- 12608236
TI  - Oral HIV training and diagnostic workshops.

PMID- 12608238
TI  - [Forensic dentistry].

PMID- 12608237
TI  - Why I cannot vote in favour of SADA's new constitution.

PMID- 12608239
TI  - So what's new?

PMID- 12608240
TI  - Amendment of tariff codes.

PMID- 12608241
TI  - The flexibility of titanium clasps compared with cobalt-chromium clasps.
AB  - Retention of a partial denture depends on the amount of undercut engaged on an
      abutment tooth and the flexibility of the clasp. Flexibility is influenced by
      clasp length and the denture base material. Titanium clasps are purported to have
      greater flexibility than cobalt-chromium cast clasps which should enable them to
      engage deeper undercuts or be used where shorter clasp arms are needed such as on
      premolar teeth. This study investigated the flexibility of cast titanium clasps
      with three commonly used cobalt-chromium clasps through comparative measurements
      of their tip deflections and yield strengths. The results showed that the
      titanium clasps were significantly (P < 0.05) more flexible than the cobalt
      chromium clasps. However, all four materials were found to be flexible enough to
      engage an undercut of 0.25 mm without exceeding their yield strengths.

PMID- 12608242
TI  - Noma (cancrum oris): case report in a 4-year-old HIV-positive South African
      child.
AB  - Cancrum oris (noma) is a gangrenous infection that develops in the mouth and
      spreads rapidly to other parts of the face. The disease occurs mostly in
      conditions of poverty, poor hygiene and malnutrition. In sub-Saharan Africa the
      frequency in several countries is estimated to be 1-7 cases per 1,000 population,
      and as many as 12 cases per 1,000 in the most affected communities. About 90% of
      these children die without receiving any care, yet the disease can, and should,
      be prevented. With increasing numbers of children who are malnourished and who
      have compromised immune systems (compounded by the HIV pandemic) the prevalence
      of conditions such as noma is likely to increase. Among the earliest features of
      noma are excessive salivation, marked fetor oris, facial oedema and a greyish
      black discolouration of the skin in the affected area. This devastating
      gangrenous lesion may involve the cheek, the chin, the infra-orbital margin,
      palate, nose, antrum and virtually any part of the face. This report describes a
      4-year-old HIV-positive African girl, who was abandoned, discharged from the
      Plastics Unit and now lives in a child care sanctuary. Little is known about her
      history prior to her arrival at the home a few weeks previously. The clinical
      examination revealed a delay in growth and physical development equivalent to
      that of a 2-year-old child. The left cheek had a perforating ulcer in a healing
      phase. The perforation, about 1 cm in diameter, was surrounded by oedematous
      tissues showing a mild to moderate erythema. The peripheral oedema extended to
      the lower palpebral, the upper labial, left labial commissural, mandibular and
      pre-parotid regions. Submental, submandibular and cervical lymph nodes were
      mildly painful upon palpation. The child was not pyretic. The intra-oral
      examination revealed the features of acute necrotising gingivitis (ANG). ANG was
      generalised and showed classic interdental crater-like ulcers covered with
      whitish debris. Halitosis was pronounced. Examination of the second quadrant
      revealed a large ulcer extending from the distal aspect of the deciduous canine
      to the distal aspect of the second deciduous molar. The adjacent palatal mucosa
      was severely oedematous. The alveolar bone supporting the first and the second
      molars was completely exposed to the fundus of the vestibulum. It was not
      possible to obtain intraoral photographs or radiographs. Chlorhexidine gluconate
      (0.2% solution) and metronidazole tablets, 200 mg twice daily for 15 days were
      prescribed. The child was seen every alternate day for 10 days and her condition
      improved rapidly. Halitosis had subsided. She was then referred to the
      Johannesburg Hospital for further treatment under general anaesthesia. The
      proposed treatment plan was as follows: removal of dental accretions and
      polishing of all teeth, extraction of the left maxillary teeth supported by non
      vital bone, resection of the necrotic bone in the left maxilla and reconstructive
      surgery in the left cheek.

PMID- 12608243
TI  - Oral HIV lesions and the South African dentist.

PMID- 12608244
TI  - Estimation of dental caries treatment needs--a review of the literature.
AB  - If we wish to achieve a better understanding of the treatment needs in the
      delivery of primary dental services, we need to know why differences in dental
      caries recorded in the general practice and survey settings occur and the reasons
      for these differences. We also need to know how this factor influences the volume
      and type of treatment planned, both for the individual skilled benchmark
      epidemiologist and practitioner, and for mean world extremes on the other hand.
      This paper reviews estimates of dental caries treatment needs from the
      perspective of translation of dental caries status to estimates by need,
      estimation of need for dental care at the time of examination, differences in
      caries diagnosis between the epidemiologist and clinician and the consequences
      thereof, and changes in the presentation of dental caries that have occurred over
      the years. It is evident from this review of dental caries treatment needs that
      although the past record of dental epidemiology and clinical diagnosis can be
      defended, we cannot afford to do what has been done in the past, which was
      appropriate for lesions seen in the 1960s and 1970s, to the disease as it occurs
      in the 1990s.

PMID- 12608245
TI  - Oral candidiasis, switching and antifungal resistance.

PMID- 12608247
TI  - Ethical and legal issues around HIV/AIDS in dentistry in South Africa.

PMID- 12608248
TI  - The controversy of impacted wisdom teeth.

PMID- 12608246
TI  - A continuum from competency to proficiency through postgraduate general dentistry
      training.
AB  - Over the last few decades, the increase in knowledge and advances in dental
      technology have raised oral health care to a new level, and dental educators and
      the profession have put increasing demands on the clinical competencies expected
      of new graduates. The medical profession has reformed radically with its evidence
      based and problem-based curricula, and its extension of the post-qualification
      training of family practitioners has meant universities, colleges and
      postgraduate institutes developing new strategies. This paper reviews the
      development of general dentistry, with special emphasis on the global trend
      towards enhanced postgraduate training.

PMID- 12608250
TI  - Hypohydrotic ectodermal dysplasia: an unusual presentation and management in an
      11-year-old Xhosa boy.
AB  - Ectodermal dysplasia (ED) is an inherited disorder in which two or more
      ectodermally derived structures fail to develop, or are abnormal in development.
      Hypohydrotic ectodermal dysplasia (HED) or Christ-Siemens-Touraine syndrome, is
      an X-linked recessive syndrome with an incidence of 1/10,000 to 1/100,000 births.
      Because of its X-linked inheritance pattern, it is more common in males. HED is
      characterised by hypohydrosis (diminished perspiration), hypotrichosis (decreased
      amount of hair) and microdontia (small teeth), hypodontia (lack of development of
      one or more teeth) or adontia (total lack of tooth development). These patients
      present diagnostic and treatment challenges because of variable oral
      manifestations. This report describes an 11-year-old Xhosa boy, who was referred
      to the University Dental Faculty by his general medical practitioner because of
      hypodontia. General facial features included: frontal bossing, a depressed nasal
      bridge, 'butterfly' pattern of eczema over the nasal bridge to the malar process
      of each cheek, thinned out hair, loss of vertical dimension of face and dry skin.
      Intra-oral examination revealed hypodontia with peg-shaped anterior teeth and
      diastemas. Radiological examination revealed no developing permanent teeth or
      tooth buds. Diagnosis was confirmed by doing a sweat gland count. Management
      included oral hygiene instruction, fluoride treatments, construction of a partial
      lower denture and counselling about his condition with particular reference to
      the danger of hyperthermia and control of allergies.

PMID- 12608249
TI  - Attitudes to water fluoridation in South Africa 1998. Part II. Influence of
      educational and occupational levels.
AB  - The purpose of this report is to investigate the influence of education, income
      and occupation on public perceptions of water fluoridation (WF). A questionnaire
      on current knowledge, sources of information, the purpose of WF and its
      desirability was administered to a representative sample of 2,220 individuals
      over the age of 18 years. Knowledge of WF increased with educational level (range
      from 13.5% in the grade 0-5 group to 59% in the grade 12 plus group). Lack of
      knowledge decreased from 76% to 37% in these groups respectively. Knowledge
      levels varied from 19% to 68% across the occupational spectrum and from 13% to
      88% across the income spectrum. In educational levels up to grade 12, electronic
      media were most frequently cited as dominant sources of information among 40-50%
      of respondents, whereas in the grade 12 plus group print media (37%) dominated.
      Sources of knowledge on fluoridation were largely obtained from print and
      electronic media for both categories. Only 28% in the educational level up to
      grade 5 thought the purpose of WF was to protect teeth against decay. This
      gradually increased to 55% in the grade 12 plus category. More than a quarter of
      the population in both the occupational and income categories indicated that the
      purpose of WF was to purify water and protect teeth from decay. The number of
      respondents who thought that water should be fluoridated increased with level of
      education from 58% to 70%, while those who disagreed decreased as qualifications
      increased. The lower- and middle-income groups were more supportive of WF than
      the very-high-income groups. Persons in high administrative professional and
      executive positions were more opposed (27%) to WF than semi-skilled and unskilled
      workers (5%).

PMID- 12608251
TI  - [The ethics of dental records].
AB  - This article highlights five aspects of necessary record-keeping in practices:
      ethicolegal requirements, confidentiality and disclosure, risk management and
      consent, accounts and practice management, and forensic functions. Patient
      records therefore have ethical, moral, legal and management implications.
      Unfortunately, they are often underestimated or ignored by practitioners. In the
      light of increasing litigation and disciplinary hearings, it is necessary to
      remind practitioners that every clinical action also contains an administrative
      component which has to fulfill many requirements.

PMID- 12608252
TI  - Will things ever get better?

PMID- 12608253
TI  - World renowned couple to speak at Oral AIDS Conference.

PMID- 12608254
TI  - Illegible handwriting of medical practitioners and dentists.

PMID- 12608255
TI  - Attitudes to water fluoridation in South Africa 1998. Part III. An analysis of
      pro- and anti-fluoridation attitudes in South Africa.
AB  - A survey on attitudes to water fluoridation in the South African population (N =
      2,220) was undertaken in 1998. The purpose of this study was to evaluate
      responses to, and underlying reasons for pro- and anti-fluoridation attitudes. In
      response to a structured questionnaire, 61.9% of respondents were in favour of
      fluoride being added to drinking water and 9% were against it. Reasons supporting
      and opposing this measure were as follows. Of those who favoured the measure, 30%
      of respondents said it was because it would reduce tooth decay and 30% said it
      'affects health', presumably positively. Other reasons include, 'it purifies
      water' (10.3%), 'more people will be reached' (9.8%), 'it strenghtens bones'
      (6%), 'it prevents plaque' (4.6%) and it 'improves the taste of water' (3.1%).
      There was a 1.3% 'don't know' response. Those opposed to the measure said, 'water
      should stay as it is' (26.1%), 'if it stays in the system it will create other
      problems' (15.6%), it 'affects health', presumably negatively (12.3%) and 'it
      will increase the cost of water' (8.8%). The 'don't know' response was 10.5%.
      When asked to give reasons for their 'don't know' response in the 'uncertain'
      category, 90% said they did not know. Given the contradictory and variable
      responses in both 'yes' and 'no' categories, the possible reasons for these
      findings could include: the differences between knowledge and beliefs,
      alternative health and lifestyle practices, levels of education, resistance to
      change and personality factors, among others. Understanding the assumption people
      make about fluoridation would help to structure education programmes to provide
      accurate and comprehensive information.

PMID- 12608256
TI  - National pathfinder survey of dental caries prevalence and treatment needs in The
      Gambia.
AB  - OBJECTIVE: The aim of this study was to assess dental caries status and treatment
      needs in The Gambia for the purpose of national planning. MATERIALS AND METHODS:
      1,235 subjects were obtained with a multi-stage stratified random sampling
      technique. Clinical examinations were carried out using the criteria suggested in
      WHO Basic Methods (WHO 1987). The WHO J2 software programme was used for data
      analysis. RESULTS: More than half of the subjects had caries. Mean DMFT increased
      from 1.7 in the 7-year-old group to 8.8 in 65-99-year-olds. Mean DT peaked at 5.1
      in the 30-34-year-old group before declining to 3.2 among the 65-99-year-olds.
      Mean filled teeth (FT) was zero in all ages. Missing teeth (MT) increased from
      0.1 in 13-year-olds to 5.6 among the 65-99-year group. Mean DMFT was 2.3, 2.8,
      and 6.6 in 12-year-olds, 15-year-olds and 35-44-year-olds respectively. Unmet
      treatment need (DT/DMFT) was 90-100% in subjects below 25 years. Need for dental
      extraction increased from 15% to 63% in 65-99-year-olds. Between 0.3 and 2.8
      teeth required extraction, and 46-79% of subjects needed conservative treatment.
      Dental auxiliaries should be trained to carry out extractions and fillings using
      the atraumatic restorative treatment (ART).

PMID- 12608258
TI  - Enough dam rubber--a case report.

PMID- 12608259
TI  - [Dentistry in 1000 A.D].
AB  - This article, written by an American in Afrikaans after having spent a short
      spell in the Department of Psychiatry, Groote Schuur Hospital, Cape Town,
      describes the situation in medicine and dentistry at the beginning of the second
      millennium AD. It traces the history of medicine during the last part of the Dark
      Ages (the first part of the Middle Ages) and the more enlightened second half of
      the Middle Ages. It looks in more detail at the life of St Hildegard and her
      views about, and influence on, the medical knowledge at the time.

PMID- 12608260
TI  - People are as important as programmes.
AB  - The introduction of a clinical management computer system into a dental practice
      involves more than selecting and installing a suitable software package. The
      computer system introduces a new set of dynamics within the dental practice and a
      new set of demands on the practice staff. Research conducted in South African
      practices has identified practice staff as being crucial to the success of the
      system. This article identifies some of the major human-computer interaction
      problems that can occur when a clinical management computer system is installed
      into a dental practice. Recommendations for preventing and solving these problems
      are made.

PMID- 12608261
TI  - Sedation in dental practice.

PMID- 12608262
TI  - [More than a flood in the Waterberg region].

PMID- 12608263
TI  - Permeability of vaginal mucosa to water at normal and elevated temperatures.
AB  - A number of studies have clearly demonstrated that human vaginal mucosa may be
      used as a model of buccal mucosa for a variety of in vitro permeability studies
      on drugs and other chemical compounds. Furthermore, at between 25 degrees and 37
      degrees C, a linear temperature-dependence of water flux across this mucosa,
      which was attributed to an increased fluidity of the principal lipoidal
      permeability barrier, was found to exist. The objective of the present study was
      to examine the behaviour of the above barrier on water fluxes at normal and
      elevated temperatures. Clinically healthy human vaginal mucosa specimens were
      obtained from excess tissue removed during a vaginal hysterectomy from a single
      patient, snap-frozen in liquid nitrogen and stored for 6 months at -85 degrees C.
      Seven sections from the mucosa were thawed in phosphate-buffered saline (PBS) and
      mounted in flow-through diffusion cells (exposed area 0.039 cm2). Their
      permeability to tritiated water was determined using a continuous flow-through
      perfusion system at temperatures of 37 degrees, 39 degrees and 41 degrees C.
      Three permeability experiments were performed at each temperature setting.
      Specimens were subjected to histological examination before and after
      permeability experiments. Mean water flux rates at steady state (10-24 h) were
      found to be 2,356 +/- 71 SEM, 3,020 +/- 38 SEM and 3,659 +/- 116 SEM cpm. cm
      2.min-1, at temperatures of 37 degrees, 39 degrees and 41 degrees C,
      respectively. A linear regression analysis and plot (r2 = 0.99) displayed a slope
      of 325 +/- 4 SEM cpm.cm-2.min-1/degree C. The results of this study showed that,
      notwithstanding cellular damage, the principal physical permeability barrier was
      linearly temperature-dependent between the temperatures studied, providing
      further support for the concept that this barrier is lipoidal in nature.

PMID- 12608264
TI  - Lasers: what they can do and how they do it.

PMID- 12608265
TI  - CPD throughout the world.

PMID- 12608268
TI  - Conscious sedation: making our treatment options safe and sound.

PMID- 12608266
TI  - Occlusal and oral health status of a group of 3-8-year-old South African black
      children.
AB  - This study determined the oral health status of a group of 3-8-year-old South
      African black children, comprising a total of 214 children from the townships of
      Garankuwa, Shosanguwe, Mabopane, Hebron and Erasmus who attended a school in
      Akasia, Greater Pretoria Metropolitan Substructure. The decayed, missing and
      filled teeth (dmft), oral hygiene status, dental IQ and malocclusion status were
      determined. The study found that the children's oral health status and occlusal
      status were unacceptable. The level of their dental IQ scores was low, their oral
      hygiene poor, and they were in urgent need of primary and secondary dental care.
      In addition they were in need of both preventive and interceptive orthodontic
      care. A national strategy to address primary dental health care is recommended.

PMID- 12608269
TI  - Establishment of Committee for Human Rights, Ethics and Professional Practice of
      the Medical and Dental Professional Board.

PMID- 12608270
TI  - Oral health status in an institutionalised elderly Jewish population.
AB  - The oral health status and treatment needs of 95 institutionalised elderly Jewish
      persons were determined. The mean DMFT was 23.4, with the M component increasing
      with age. Untreated carious lesions were identified in men and women of all ages.
      A relatively small percentage (10.5%) of subjects were affected by root caries.
      In 75% of cases of identified periodontal disease, the condition presented as
      bleeding or calculus. All subjects were in need of oral hygiene instruction and
      64 (67.3%) required scaling and root planing. Complex treatment formed only a
      small percentage of the overall treatment needs. A low prevalence of
      temporomandibular joint problems, denture stomatitis and angular cheilitis was
      noted. A relatively high prevalence of untreated oral disease of low severity was
      observed, indicating the need for a comprehensive form of preventive and basic
      oral care.

PMID- 12608271
TI  - The oral health status in Mahonisi: a community with very low levels of dental
      caries.
AB  - The oral health status and treatment needs of the community at Mahonisi were
      determined in order to plan a health care programme. The caries experience,
      occlusal status, fluorosis prevalence and prosthetic status and needs were
      determined according to the WHO pathfinder methodology (1987). The dmft for the 4
      5- and 6-year-old children was 0.33 and 0.67 respectively. The DMFT ranged from
      0 in the 12- and 15-year-old children to 4.2 in the 65-years-and-older age group.
      Among the 12-, 15- and 18-year-old pupils 73% had good occlusions, 18% had slight
      and 9% more serious anomalies. Of the 152 subjects examined for fluorosis only 2
      exhibited very mild dental fluorosis. No soft-tissue lesions were seen in the
      adult sample, but 10 cases were seen in the schoolchildren. No edentulous person
      was seen, but 4 people needed extraction of all their remaining teeth. A need for
      7 partial dentures was recorded. The simplified oral hygiene index (OHI-S) ranged
      from 1.45 in the 4- 5-year-old children to 4.47 in the oldest group. The zero
      DMFT scores for the 12- and 15-year-old children are exceptional and need to be
      further investigated. It is recommended that the teachers in the pre-school and
      some of the primary school be trained to provide oral hygiene instruction to the
      children.

PMID- 12608272
TI  - Extensive endodontic treatment for severe facial pain: a case report.

PMID- 12608273
TI  - The role and functions of dietary antioxidants in relation to human health.

PMID- 12608274
TI  - [Exclusive identification of gene loci of autosomal dominant nonsyndromic hearing
      loss].
AB  - OBJECTIVE: The purpose is to map related genes of an autosomal dominant
      nonsyndromic hearing loss kindred. METHOD: Linkage analysis was carried out using
      screening markers of the 22 reported loci. RESULT: Linkage analysis showed no
      linkages between pedigree gene and reported loci. CONCLUSION: The autosomal
      dominant nonsyndromic hearing loss in the kindred may be resulted from a new
      gene.

PMID- 12608275
TI  - [Study on auditory brainstem response to bone conducted clicks].
AB  - OBJECTIVE: To observe how different vibrator placement and different stimulate
      rates affect the results of bone conduction ABRs. METHOD: Bone conduction ABRs
      with different vibratory placement and different stimulate rates were recorded in
      20 normal hearing young adults and compared with their air conduction ABRs.
      RESULT: The results show that all subjects were recorded reproducible and
      reliable air and bone conduction ABR waveforms under higher intensities(above 40
      dBnHL). The ABR thresholds from air and bone conduction were similar, they are
      both about 5-10 dB higher above their behavioral thresholds to clicks. The
      frontal placement produces significantly longer ABR wave V latencies. Bone
      conduction ABR wave V latencies from different stimulate rates were also
      observed. The results show that temporal placement ABR wave V latencies became
      longer significantly when the stimulate rate increased from 20/s to 52/s.
      CONCLUSION: Although it is affected by different vibrator placement and different
      stimulate rate, bone conduction ABR is a valuable and effective method to detect
      hearing, it plays an important role in newborn auditory screening, assessment of
      cochlear reserve, and identification of hearing loss.

PMID- 12608276
TI  - [The appearance of contralateral otoacoustic emissions with unilateral cochlear
      hearing loss].
AB  - OBJECTIVE: To investigate the latent influence on the contralateral ear when one
      ear was involves by different deaf elements. METHOD: TEOAE and DPOAE were
      recorded from contralateral ears with unilateral cochlear hearing loss, who were
      divided into 5 groups, group S1, sudden deafness last within two months (9 ears),
      group S2, sudden deafness last over one year or so(6 ears), Meniere's disease (13
      ears M1, M2) cochlear hearing loss of unknown etiology(7 ear, UNK), using ILO-96
      analyzer system. RESULT: Response amplitude, wave reproducibility, band
      reproducibility of TEOAE in S1, M2 were significantly lower than normal values.
      Amplitude of DPOAE in S1, M2 were significantly lower than normal values. All
      record were the same with normal in S2, M1. UNK. CONCLUSION: In all sorts of deaf
      elements, some have an effect on binaural ears, the others have an effect on
      unilateral ear.

PMID- 12608277
TI  - [Tympanoplasty in the only hearing ear].
AB  - OBJECTIVE: To evaluate result of tympanoplasty in only hearing ear. METHOD: 15
      cases were analyzed retrospectively. All cases were operated by tympanoplasty for
      middle ear diseases with conductive deafness. The contralateral ears of all cases
      had sensorineural deafness. RESULT: All ears obtained dry ear and 80% ears
      obtained hearing improvement. CONCLUSION: Tympanoplasty is availability in only
      hearing ear with middle ear diseases, but operation must be manipulated by senior
      expert.

PMID- 12608278
TI  - [The treatment of facial nerve palsy related to cholesteatoma otitis media].
AB  - OBJECTIVE: In order to investigate the operative treatment of facial nerve palsy
      which induced by cholesteatoma otitis media. METHOD: To analyse 35 postoperative
      cases with of cholesteatoma otitis media to accompany peripheral facial
      paralysis. Opened technique was performed in 32 cases, closed technique was
      performed in 3 cases. All of them were performed facial nerve decompression.
      RESULT: In opened technique group, the effect of postoperation reached House
      Brackmann I-II degree in 24 patients (24/32), House-Brackmann III-V degree in 8
      patients. In closed technique group, 2 patients reached House-Brackmann II
      degree, but they recoveryed slowly. CONCLUSION: Facial nerve decompression should
      be performed as long as the diagnosis was made, Mastoidectomy by using opened
      technique has satisfactory therapeutic effect.

PMID- 12608279
TI  - [Applied anatomy of abut structures of internal auditory meatus (IAM) through
      middle cranial fossa approach].
AB  - OBJECTIVE: To provide anatomical basis for operation of internal auditory
      meatus(IAM). Correlation structures with IAM were measured according to sign of
      hiatus of facial nerve. METHOD: These structures include spinous foramen,
      superficial geater petrosal nerve, superficial lesser petrosal nerve, hiatus of
      facial nerve were measured on 24 wet cranial bone (48 sides). RESULT: It is
      demonstrated that 8.3% geniculate ganglion and labyrinth segment of facial nerve
      Variation which distance from hiatus of facial nerve to geniculate ganglion is
      distinct. CONCLUSION: Our data will be very holpful for location of IAM during
      operation via middle cranial fossa approach.

PMID- 12608280
TI  - [Influence of foot position in the static posturography].
AB  - OBJECTIVE: To study the effect of position of the feet on posturography. METHOD:
      The quantitative significance of the standing position in posturographic
      measurements was evaluated with 30 healthy volunteers studied under nonvisual
      conditions, using 5 foot positions: heels toghther with the toes 30 degrees apart
      or at an angle of the voleer's own choice, and the feet parallel and 0.5 or 10 cm
      apart were studied respectively. RESULT: Five test methods showed different
      results. The feet parallel and 10 cm apart is the most stable position among 5
      test methods, the most unstable position is feet parallel and together.
      CONCLUSION: Feet position can influence the results of test. For those who can
      hardly stand with the feet parallel and together can choose the feet apart
      position.

PMID- 12608281
TI  - [A study on the effects of contralateral acoustic suppression to transient evoked
      otoacoustic emissions after noise exposure].
AB  - OBJECTIVE: To investigate the effects of contralateral acoustic suppression(CAS)
      on transient evoked otoacoustic emissions(TEOAE) in Noise Exposure Condition, in
      order to explore the effects of efferent positive feedback regulation on the
      cochlear mechanisms and the effects of CAS on the sensitivity of TEOAE measure
      for finding changes of cochlear function condition induced by noise exposure.
      METHOD: Observing the effects of CAS (60 dB SPL WN) on the changes of TEOAE
      parameters, Response Amplitude, Reproducibility, Band SNR and Band
      Reproducibility, before and after noise exposure. RESULT: The values of every
      index of TEOAE were decreased respectively so that the effects of noise exposure
      on cochlear function can be reflected sensitively. A small decrease of values can
      be induced by CAS before noise exposure, of some decrease of indices were
      significant. After noise exposure, the changes of TEOAE parameters become much
      more with CAS than without. CONCLUSION: Noise exposure can effect obviously
      cochlear function condition and decrease OAE measurement values. CAS had
      suppressing action on cochlear activity by a negative feedback and can increase
      obviously the sensitivity of TEOAE measurement in finding the changes induced by
      noise exposure.

PMID- 12608282
TI  - [Establishment of method and evaluated criteria for newborn hearing screening in
      the gross-roots hospital].
AB  - OBJECTIVE: To study a optimal method and pass criterion for newborn hearing
      screening. METHOD: Transient evoked otoacoustic emissions(TEOAE) was used for
      hearing screening in 1,277 (2,554 ears) newborns. The pass criterion was defined
      as signal-noise-ratio(SNR) > or = 3 dB in 3 of 4 frequency bands. RESULT: Pass
      rates were 89.37%. The best tested time at 2-4 days after birth. CONCLUSION:
      TEOAE may be an ideal method for newborn hearing screening, SNR > or = 3 dB for
      frequency bands was the appropriate pass criteria.

PMID- 12608283
TI  - [Analysis of electroglottograph waveform and parameters of benign vocal fold
      diseases].
AB  - OBJECTIVE: To study the sensitivity and specificity and clinical value of
      electroglottograph (EGG) measurement of benign vocal fold diseases. METHOD: 365
      cases of vocal polyp and vocal cyst and vocal leukoplakia pre- and post
      microsurgery were measured, and ECG waveform and their parameters were analyzed,
      respectively. RESULT: EGG waveform of most patients was abnormal with fixed notch
      or steepness in close-opening phase dominantly. After surgery, most of the
      waveform returned to normal. The surgery had significant effects on the EGG
      waveform statistically, while the disease's type did not. Compared with that of
      vocal polyp and vocal cyst, whose parameters were similar, CQ was smaller and CI
      was relatively larger in vocal leukoplakia. After the surgery, jitter, shimmer,
      HNR, CQ and CQP improved in vocal polyp and cyst, while EGG parameters didn't
      improve except of HNR in leukoplakia. CONCLUSION: ECG waveform was sensitive to
      benign vocal fold diseases to a degree, but the specificity was poor. EGG
      parameters were affected by vocal lesion and its intrinsic inflammation.

PMID- 12608284
TI  - [Voice recovery observation of vocal polyp after operation].
AB  - OBJECTIVE: Observing the voice recovery rule of vocal polyp in 20 cases to give
      the reasonable voice method for the patients after operation. METHOD: Follow up
      the voice changes by means of voice assessment for 2 weeks after the operation.
      RESULT: The worst voice of the patients occurred in the day 1 after the
      operation. It recovered significantly in day 10(P < 0.05) and reached to normal
      status in day 14(P < 0.01). CONCLUSION: The patients with vocal polyp should be
      in rest of voice for at least 2 weeks after the operation.

PMID- 12608285
TI  - [Effects of nimodipine on cochlear blood flow with normal and vertebrobasilar
      insufficiency status].
AB  - OBJECTIVE: To study effect of nimodipine (ND) on cochlear blood flow (CBF).
      METHOD: CBF was measured in twenty-two guinea pigs by laser Doppler
      flowmetry(LDF). RESULT: Nimodipine decreased CBF following the decrease of
      systemic BP and present a dose dependent mode, neither the dose of nimodipine is
      lower, normal and higher, nor the animal is under the status of normal supply of
      inner ear blood flow and ischemia of inner ear caused by vertebrobasilar
      insufficiency(VBI). CONCLUSION: It suggested that this compound may be of little
      clinical use to elevate CBF.

PMID- 12608286
TI  - [Expression of EIIIA-fibronectin in injured rat skin used in estimation of wound
      interval].
AB  - OBJECTIVE: To observe the means of fibronectin(FN) alternative splicing and the
      expression of EIIIA-FN variant in rat skin after bruise, for the sake of
      providing some help for forensic estimation of wound interval. METHODS: Total RNA
      was isolated from wounded skin, and reverse transcription polymerase chain
      reaction was conducted to amplify target segments. RESULTS: Detectable EIIIA+(526
      bp) segments, lacked in normal organize, was amplified at 1 h after experimental
      wound, and the levels were increased within 24 h. CONCLUSION: The alternative
      splicing EIIIA-fibronectin variant would be a satisfied criterion for research of
      skin injury.

PMID- 12608287
TI  - [Tryptase and fatal anaphylaxic reaction].
AB  - OBJECTIVE: To investigate the relationship between tryptase in serum and
      anaphylaxis. METHODS: The concentrations of tryptase in the sera of heart blood
      in three persons died from anaphylaxis shock were detected by ELISA. The first
      sample was obtained from a man, aged 38, died of injecting Amikacin. The second
      sample was obtained from a man, aged 42, died of injecting Cephradine. The third
      sample was from a woman, aged 39, died of injecting Lincomycin. All samples were
      stored in -20 degrees C. RESULTS: The concentrations of tryptase in sera were 52
      ng/ml, 121 ng/ml and 0.73 ng/ml. It was unknown why the concentration of tryptase
      in the third sample was normal. CONCLUSION: In fetal anaphylaxia reaction
      tryptase measurement is a useful indicator, but the diagnosis is not to be based
      on the test alone.

PMID- 12608288
TI  - [A preliminary study of epidemiology of sudden manhood death syndrome in the
      peasant derived workers in Dongguan city].
AB  - OBJECTIVE: To study the feature of sudden manhood death syndrome(SMDS) in
      Dongguan city. METHODS: The data of 284 cases of SMDS were analysized by
      retrospective study. RESULTS: The distribution of age, sex, the time of death and
      hometown of the dead in SMDS were described. The clinical or anatomical
      characters of SMDS were also discussed. CONCLUSION: These data will contribute to
      the late epidemical study.

PMID- 12608289
TI  - [Apoptosis in mouse after tetramine poisoning].
AB  - OBJECTIVE: To observe pathological changes and apoptosis in mouse brain, hart,
      liver and kidney after tetramine poisoning, and to provide some references for
      forensic identification. METHODS: An experimental model of mouse tetramine
      poisoning was found, and the technology of apoptosis detection was used. The
      staining results were analyzed by computer image analysis competitive system.
      RESULTS: (1) Quantities of apoptosis in brain, hart, liver and kidney in chronic
      poisoning groups are many more than in acute poisoning groups. As in same organs,
      Quantities of apoptosis are different after different poisoning time. In
      addition, the peak-time of apoptosis is not same in different organs. (2) Poison
      analysis showed that, all organic samples from acute poisoning groups were
      positive, while that from chronic poisoning groups are negative. CONCLUSION:
      Chronic tetramine poisoning can not be detective by clinic or poison analysis
      while can be found changes in apoptosis, which indicate that small amount and
      chronic poisoning still affects the body.

PMID- 12608290
TI  - [Molecular cloning of recombinant fibronectin EDA and EDB fusion protein].
AB  - OBJECTIVE: Construct a recombinant plasmid pET28a-EDA-EDB, prepare the fusion EDA
      EDB protein. METHODS: For the production of recombinant fibronectin EDA-EDB in
      Escherichia coli, the EDA and EDB segments were separated from pGEM2-EDA/EDB and
      recomposed with two additional amino acids, then cloned into the expression
      vector pET28a. pET system to express EDA-EDB fusion protein and 6 x His/Ni-NTA
      system to purify it in a single step were used. Western blotting confirmed the
      purified protein. RESULTS: The EDA and EDB segments were ligated and inserted
      into pET28a vector. EDA-EDB fusion protein was highly expressed in Escherichia
      coli BL21 (DE3). Afterwards, it was purified by Ni-NTA resin and verified by
      western blotting. CONCLUSION: EDA-EDB fusion protein can be expressed in pET
      system and purified by 6 x His/Ni-NTA system.

PMID- 12608291
TI  - [The relationship between postmortem degradation of marrow DNA in bosom bone and
      late postmortem interval estimation].
AB  - OBJECTIVE: To study the relationship between degradation of marrow DNA and late
      postmortem interval (PMI). METHODS: Marrow were left on natural condition for
      0,1,3,5,7 day after death respectively, Marrow DNA were detected by using Feulgen
      staining and computerized image analysis. RESULTS: The content of marrow DNA
      could be detected till 7 days after death yet. CONCLUSION: The degradation of
      marrow DNA may be used on estimation the late PMI.

PMID- 12608292
TI  - [A primary study on the ARP-SRP gene expression profiling of brain injury by cDNA
      microarray].
AB  - OBJECTIVE: To screen the differential expression of apoptosis-related protein and
      stress response protein(APR-SRP) genes after human brain injury by cDNA
      microrarray. METHODS: The total RNAs were isolated from normal and injured brain
      tissues of a car-accident victim, and were purified to obtain mRNAs by Oligotex.
      Both mRNAs from the tissues of the injured and the normal tissue were reversely
      transcribed to cDNAs with the incorporation of fluorescent dUTP to prepare the
      hybridization probes. The probes from normal tissue was labeled with Cy3-dUTP,
      that from the injured tissue with Cy5-dUTP. The mixed probes were hybridized to
      the BioDoor Chip ARP-SRP-1.0S, a cDNA microarray which contains 77 apoptosis
      related protein genes and 23 stress protein related genes. After high-stringent
      washing, the cDNA microarray was scanned for the fluorescent signals and showed
      differences between two tissues. RESULTS: Among the 100 target genes, Only CLN2
      gene (Homo sapiens lysosomal pepstatin insensitive protease gene) showed distinct
      deference in expression level between the brain injury and normal tissues.
      CONCLUSION: cDNA microarray analysis indicated that CLN2 gene, which is
      correlated to a fatal childhood neurodegenerative disease, might be related to
      the brain injury. The expression level of CLN2 gene was significantly decreased
      in brain injured tissue in comparison to normal tissue. Further analysis of this
      gene will be helpful to understand the molecular mechanism of brain injury and
      utilization in forensic medicine.

PMID- 12608293
TI  - [Genetic polymorphism of the STR DXS9898 locus in Han population].
AB  - OBJECTIVE: Studying the genetic polymorphism of X-STR locus DXS9898 in Han
      population. METHODS: 296 unrelated Chinese individuals (199 females and 97 males)
      living in Chengdu were investigated using PCR and PAG electrophoresis followed by
      silver staining. RESULTS: 6 alleles were observed and the range of fragment size
      was 189-214 bp. The genotype distribution of DXS9898 locus was in accordance with
      Hardy-Weinberg equilibrium. Family survey confirmed Mendelian inheritance of
      alleles. The observed heterozygosity in females was 0.5930, the discriminating
      power (Dp) were 0.5667 and 0.9420 for males and females respectively. The power
      of exclusion were 0.5862 and 0.4392 for trio and duo respectively. CONCLUSION:
      The results demonstrated that the locus is highly polymorphic and can be used in
      forensic identification and parentage testing.

PMID- 12608294
TI  - [PGM1 genotyping by PCR-SSCP].
AB  - OBJECTIVE: PGM1 genotyping by PCR-SSCP analysis. METHODS: Amplified genome DNA
      from 156 unrelated Han individuals living in Wuhan, PCR products for exon 4 and
      exon 8 of PGM1 were then analyzed by SSCP to detect the genotypes. RESULTS: 2
      alleles and 3 genotypes were detected in exon 4 and 8 respectively. The
      discrimination power was 0.7318. PCR-SSCP analysis was suitable for determination
      of PGM1 genotypes from old blood and semen stains. CONCLUSION: PGM1 system typed
      by PCR-SSCP is useful for forensic identification.

PMID- 12608295
TI  - [Effect of PCR reaction volume on the accuracy of human identification tests].
AB  - OBJECTIVE: To investigate the effect of different PCR amplification volume on the
      accuracy of human identification test. METHODS: Human genome DNA samples were
      amplified using ABI PRISM Profiler Plus kits in 50 microliters, 25 microliters,
      12.5 microliters, and 6.25 microliters reaction volume, respectively. The
      thermocycle parameters were the same. All PCR products were then
      electrophoresized on ABI PRISM 310 Genetic Analyzer, 377 DNA Sequencer, and 3100
      Genetic Analyzer. Data were processed by ABI PRISM GeneScan and Genotyper
      software. RESULTS: The less reaction volume, the more alleles losing or alleles
      adding observed. CONCLUSION: Non-standard volume of PCR amplification reaction
      should be used carefully in human identification test, especially when the sample
      DNA quality is not so satisfied.

PMID- 12608296
TI  - [Study on the forensic psychiatric examination of the cases of labor disputes].
AB  - OBJECTIVE: To explore the current situation and tendency of the forensic
      psychiatric examination of the cases of labor disputes. METHODS: This study
      reviewed 156 cases examined during the period of 1990-2001, analyzing some
      related factors. RESULTS: It was shown that most of these cases were related to
      the termination and interruption of labor contracts, while the quantity of cases
      related to labor pay increased considerably. The intervals between the beginnings
      of disputes to examinations were prolonged, while 69.2% of the intervals were
      within 12 months. 91.2% conclusions of the examinations were consistent with the
      diagnosis of psychiatric history. The rates of limited civil capability and
      incapability were 23.1% and 52.6%. CONCLUSION: The quantity, type and interval of
      the cases of labor disputes were changing greatly during recent years. More
      attention should be paid to this kind of cases.

PMID- 12608297
TI  - [Interpretation of DNA profiles for mixed stains].
AB  - This article review the advance in interpretation of mixed forensic stains using
      DNA profiling, including autosome STR profiling, sex profiling determined by PCR,
      Y-specific STR profiling, mitochondrial DNA profiling and single nucleotide
      polymorphism profiling. The statistics methods for mixed stain has also been
      reviewed.

PMID- 12608298
TI  - [Medical legal identification of post-transfusion HIV/AIDS].
AB  - This article summarized circumstances and influential factors of post-transfusion
      HIV/AIDS in recent years. Laws and regulations were emphasized in respective
      duties of every blood transfusion related departments. The strictly controlled
      imported blood products, carefully blood screening on donor, standardized blood
      products, tightened control on indication of use of blood, and finally, carefully
      told rare-happened HIV/AIDS to recipients were the key measures to avoid forensic
      cases of post-transfusion HIV/AIDS. Main evidences in Medical legal
      identification of post-transfusion HIV/AIDS were also proposed.

PMID- 12608299
TI  - [Morphologic changes in photoreceptor connecting cilia in experimental phototoxic
      retinopathy].
AB  - PURPOSE: It has been suggested that structural alterations of the photoreceptor
      connecting cilium are a primary defects leading to photoreceptor degeneration in
      some forms of inherited retinal degenerations (5). In a series of 17 eyes with
      retinitis pigmentosa (RP) and with various genetic forms of RP, examined by
      electron microscopy, no structural abnormalities were found in the arrangement of
      the ciliary microtubules. However, a 10% reduction in the ciliary diameter was
      recorded in RP photoreceptors (12). The question arose: is thinning of the cilium
      a primary defect associated with RP, or a secondary abnormality related to
      degenerative processes in photoreceptors irrespective of the cause? The aim of
      this study was to examine the photoreceptor connecting cilia in the early stages
      of experimental light induced retinal degeneration in the rat, by conducting a
      structural and morphometric survey of the relevant electron-micrographs. In
      addition, the effects of various fixation techniques on the ciliary structure
      were compared. MATERIAL AND METHOD: Analysis of 124 transmission electron
      micrographs of 9 controls and 155 transmission electron micrographs of 55 light
      damaged animals was conducted. For the effects of fixation on morphometry 72
      transmission electron micrographs from an additional 4 controls (43 negatives)
      and 8 light damaged animals (29 negatives) were examined. Light damage was
      induced by exposure to 1000 lux of white light for 120 minutes. Retinal samples
      were fixed either in 2.5% glutaraldehyde or by high pressure freezing followed by
      freeze-substitution. RESULTS: This study showed that one of the early
      morphological alterations occurring in rat photoreceptors damaged by light is a
      reduction of ciliary diameter of approximately 10%. It was not associated with
      any apparent ultrastructural changes in the axoneme. It was also found that the
      degree of ciliary shrinkage largely depends on the fixation technique used. Cryo
      fixation followed by freeze substitution shows more shrinkage than chemical
      fixation by immersion in glutaraldehyde. CONCLUSIONS: It is suggested, that
      reduction in photoreceptor cilium diameter is a secondary and non-specific
      change. It is not a unique phenomenon, observed not only in human photoreceptors,
      which are undergoing degeneration in RP. It can be induced in otherwise healthy
      rat retina, in which photoreceptor degeneration was caused by exposure to toxic
      levels of light.

PMID- 12608300
TI  - [Evaluation analysis of blood flow of peripapillary area in glaucoma patients
      using scanning laser Doppler flowmetry].
AB  - PURPOSE: To evaluate capillary blood flow and velocity in retinal peripapillary
      area in primary open angle glaucoma (POAG), normal tension glaucoma (NTG),
      pseudoexfoliation glaucoma (PEXG) and age matched control group (C) using
      scanning laser Doppler flowmetry (Heildelberg Retina Flowmeter). MATERIAL AND
      METHOD: One randomly selected eye of 17 POAG patients (mean age 59.3 +/- 2.6), 18
      NTG patients (mean age 56.4 +/- 2.4), 17 PEXG patients (63.3 +/- 2.8) and 15
      healthy subjects (mean age 55.8 +/- 3.8) underwent examination with scanning
      laser Doppler flowmetry. The measurements were performed at the superior and
      inferior temporal peripapillary retinal area. The measured parameters were
      capillary blood flow and velocity of the moving erythrocytes. Each image was
      analysed using the program AFFPIA. This software calculates the hemodynamic
      parameter flow of each pixel. Comparison of value obtained from patients and
      control participants were made using Student's t test. RESULTS: Scanning laser
      Doppler flowmetry results showed a significant reduction in blood flow at the
      superior and inferior temporal peripapillary area in POAG and NTG patients
      compared to control group (p < 0.04). The POAG and NTG patients had also
      significantly decreased velocity at the inferior temporal peripapillary retinal
      area compared to control group. No statistical difference was found between blood
      flow and velocity in POAG compared with NTG. When compared with the control
      participants, patients with PEXG showed significant decreases in the mean blood
      flow at the inferior temporal quadrant (p < 0.05), while the differences in the
      mean flow and velocity at the superior quadrant between those groups were not
      statistically significant. CONCLUSIONS: Our findings indicate a reduction in
      ocular blood flow at the temporal peripapillary retinal area in patients with
      POAG and NTG compared to age matched control participants. The peripapillary
      retinal microcirculation is not significantly altered in patients with PEXG
      compare with POAG and JNC. The blood flow parameters in the capillaries are lower
      in JNC retinas, the difference however is not significant. Further clinical
      investigation is required having groups homogeneous with respect to stage of
      glaucoma and controlled for factors known to effect perfusion pressure.

PMID- 12608301
TI  - [Retinal nerve fiber layer analysis and evaluation of eye blood flow in patients
      with glaucoma].
AB  - PURPOSE: The aim of this research was to evaluate the changes of blood flow
      velocity in ocular arteries (ophthalmic artery, central retinal artery and short
      posterior ciliary arteries) and the amount of ocular nerve fibers in patients
      with primary open angle glaucoma (POAG) and normal tension glaucoma (NTG).
      MATERIAL AND METHOD: The research was done on 17 patients with diagnosed POAG and
      13 patients with NTG. No ocular surgery was performed on any of these patients
      prior to our examinations. The blood flow measurements were made with ACUSON
      Color Doppler USG 128*P10 type with 7.5 MHz sector phased probe. Parameters of
      diastolic velocity (Vr), systolic flow velocity (Vs), Golsing pulsation index
      (PI) and pourcelate resistivity index (RI) were registered, together with the
      instant spectrography of examined artery. Quantitative retinal nerve fiber layer
      (RNFL) measurements were obtained by scanning laser polarimetry GDx (software
      version 1.0.14). RNFL was measured automatically in each of 256x 256 pixels and
      results were compared to the age-, sex- and race-norms. Approximately 150 wide
      field of view was used. Average thickness, Superior Maximum, Inferior Maximum,
      maximum modulation and GDx Number were analysed. All results were compared to age
      norms. Student's t test was used for statistical analysis. RESULTS: In patients
      with POAG a statistically significant decrease of Vs in ophthalmic artery was
      detected in 27% of eyes, in central retinal artery in 51% of eyes and in short
      posterior ciliary arteries in 45% of eyes. In patients with NTG a statistically
      significant decrease of Vs was detected in ophthalmic artery in 27% of eyes, in
      central retinal artery in 65% of eyes and in short posterior ciliary arteries in
      53% of eyes. RNFL analysis in eyes with POAG showed a decrease in avg. thickness
      in 80% of analysed eyes, decrease of Superior Maximum in 84% of analysed eyes,
      decrease of Inferior Maximum in 77.4% of analysed eyes, decrease in maximal
      modulation in 87% of analysed eyes and increase of GDx Number in 77% of analysed
      eyes. RNFL analysis in patients with NTG showed a decrease in av. thickness in
      73% of analysed eyes, decrease of Superior Maximum in 80.7% of analysed eyes,
      decrease of Inferior Maximum in 65.7% of analysed eyes, decrease in maximal
      modulation in 61.5% of analysed eyes and increase of GDx Number in 57.6% of
      analysed eyes.

PMID- 12608302
TI  - [Eye growth in children with primary congenital glaucoma after trabeculectomy].
AB  - PURPOSE: Evaluation of the influence of intraocular pressure (IOP) after
      trabeculectomy on the axial length and refraction of eyeballs in children with
      primary congenital glaucoma. MATERIAL AND METHODS: Thirty six eyes of 23 children
      at the age from 7 days to 6.5 years (mean 17.1 months), were examined.
      Measurements of corneal diameter, axial length, IOP and refraction were done
      before trabeculectomy and in the long-term follow-up (mean 7.9 years) after
      surgery. RESULTS: Horizontal corneal diameter didn't change and ranged from 10 to
      15 mm, mean 13.22 mm. Mean value of axial length before trabeculectomy was 22.45
      mm and 23.27 mm at last visit. The difference was statistically significant. The
      axis decreased in 3 eyes, was the same in 3 eyes. In the others the eye growth
      changed proportionally to the age of child. IOP values were statistically lower
      after surgery (mean 16 mmHg) than before treatment (mean 35.51 mmHg). There was
      no correlation between IOP and axial length of eyeballs (p = 0.69) and between
      IOP and refraction changes (p = 0.42) in the long-term follow-up. CONCLUSIONS:
      There is small influence of normalised IOP after trabeculectomy on size of
      eyeballs and refraction in children with primary congenital glaucoma. The
      development of eyeballs even buphthalmic is proportionally to the age.

PMID- 12608303
TI  - [The endothelin-1 level in blood serum of patients with primary open angle
      glaucoma abd its influence on the static perimetry abd Gdx changes].
AB  - PURPOSE: The aim of the work was to define the relationships between the
      endothelin-1 level in blood serum of glaucoma patients concerning the visual
      field defects and the number of nerve fibers. MATERIAL AND METHODS: 24 women and
      14 men, aged 38-74 year (mean 53.4 year) with primary open angle glaucoma,
      without any systemic diseases. The control group consisted of 20 healthy women
      and men, aged 34-70 year (mean 52.6 year). The endothelin-1 level was tested with
      the enzymo-immunologic method from the blood serum. The visual field defects were
      examined with the Humphrey static perimetry. The nerve fibers were analyzed with
      the Gdx apparatus. RESULTS: Mean value of ET-1 in blood serum were similar in
      both examined groups, it was 0.51 in group of glaucoma patients and 0.54(fmol/l)
      in the control group. There were no significant correlations between ET-1 level,
      static perimetry, GDx parameters and age in the group of patients with POAG. The
      statistics significances were stated for ET-1 level and MD-parameter in static
      perimetry (p < 0.03) and ET-1 level with The Number--the GDx parameter (p <
      0.03). CONCLUSION: There was no significant level of ET-1 in blood serum in group
      of patients with POAG. There have not been stated any relationships between the
      static perimetry and GDx changes in patients with POAG to endothelin-1 level in
      blood serum. It is the preliminary communication.

PMID- 12608304
TI  - [The influence of silicone oil removal on intraocular pressure].
AB  - PURPOSE: The aim of this study was to evaluate the influence of silicone oil
      removal on intraocular pressure. MATERIAL AND METHOD: Our material consists of 98
      patients (104 eyes), who underwent vitrectomy with silicone oil tamponade.
      Sixteen eyes in this group were aphakic before vitrectomy. The mean duration of
      silicone-oil tamponade was 8.8 months. We examined and compared intraocular
      pressure in all cases before vitrectomy, during tamponade and after silicone oil
      removal. RESULTS: The increased intraocular pressure (> 22 mmHg) was found in 27
      eyes (seven of them were aphakic) during tamponade. We had to remove silicone oil
      due to glaucoma in 6 eyes (three of them were aphakic). In 9 eyes (four aphakic)
      the intraocular pressure was higher than 22 mmHg after silicone oil removal.
      Seven patients required additional topical medication and 2 patients were
      qualified for operation--trabeculectomy. Hypotony (< 10 mmHg) was observed in 11
      eyes, and it coexisted with retinal redetachment in 4 cases. CONCLUSIONS: The
      increased intraocular pressure is a frequent complication of silicone oil
      tamponade, and it normalizes after silicone oil removal in most of these cases.

PMID- 12608305
TI  - [Non-perforating deep sclerectomy ab externo with intrascleral implant in
      juvenile glaucoma].
AB  - PURPOSE: Trabeculectomy, a very well known procedure giving mainly good result,
      may sometimes produce many serious postoperative complications, connected with
      opening of anterior chamber. Another operating technique prepared by Fyodorov,
      Zimmerman and Kozlov, seems to be useful in all cases with open-angle glaucoma
      and does not produce complications like the once caused by trabeculectomy.
      MATERIAL AND METHOD: Non-perforating sclerectomy was performed on 7 children aged
      8 to 15 with juvenile glaucoma /in 4 cases as the first procedure and in 3 cases
      as a secondary technique after trabeculectomy done more than 10 years before/.
      The operative technique was done with an implant to sclera made from natrium
      sodium of hialuronic acid. Observation lasted from 6 to 18 months. RESULTS: In 6
      cases good results were obtained after the first procedure, in one reoperation
      was necessary. The intraocular pressure /less than 20 mmHg/ was low in all eyes
      during 6 months observation, after a year low intraocular pressure decreased in
      72% of cases, but with complimentary local therapy was low in all cases. In 1 eye
      there was intraoperative complication-perforating of Schlemm's canal structures
      but without great outflow of aqueous. All parameters of vision /visual acuity and
      visual field/ were stable. CONCLUSIONS: This operative technique, although
      difficult to perform was not dangerous for the eye and gave good results,
      unfortunately only in some of the eyes.

PMID- 12608306
TI  - [Serum antiretinal antibodies titres in patients with endogenous posterior
      uveitis in 12 months follow-up period].
AB  - PURPOSE: To evaluate changes of serum antiretinal antibodies titres (ARA) in
      patients with idiopathic posterior uveitis in 12 months follow-up period.
      MATERIAL AND METHODS: 50 patients (29 women and 21 men) in age 15-70 yrs with
      endogenous posterior uveitis were examined. In all cases serum ARA titres were
      determined by indirect immunofluorescence test on normal monkey retina as a
      substrate and FITC-labelled anti-human IgA, IgG, IgM serum (Euroimmun-Niemcy).
      ARA were scored in active stage of the disease and 1, 3, 6, 12 months after the
      immunosuppressive therapy was started. RESULTS: Before treatment in active stage
      of the disease, the ARA were present in serum of 40 patients (80%). The range of
      serum ARA titres was 1:10 to 1:320. In 10 patients (20%) the serum ARA levels
      were not detectable. In the last control the ARA were detected in sera of 20% of
      patients in titres 1:10 to 1:40. CONCLUSIONS: 1. The presence of ARA in serum of
      80% patients with active endogenous posterior uveitis indicates their involvement
      in the etiopathogenesis of this disease. 2. The assessment of serum ARA in
      patients with idiopathic posterior can act as an indicator of immunosuppressive
      therapy efficacy. 3. Serum ARA analysis is not a specific diagnostic test for
      endogenous posterior uveitis because ARA can be present in serum of patients with
      other ocular disorders.

PMID- 12608307
TI  - [Serum anti-retinal antibodies and intensity of endogenous posterior uveitis ].
AB  - PURPOSE: To analyse the correlation between the anti-retinal antibodies (ARA) and
      intensity of intraocular inflammation in patients with endogenous posterior
      uveitis. MATERIAL AND METHODS: 50 patients--29 women (58%) and 21 men (42%) in
      age 15-70 yrs with idiopathic posterior uveitis were examined. Intraocular
      inflammation intensity was scored on standard uveitis grading system prepared by
      BenEzra et al. In all cases the ARA were determined by indirect
      immunofluorescence test on normal monkey retina as a substrate and FITC-labelled
      goat's anti-human IgA, G, M serum (Euroimmun-Germany). The control serum was
      obtained from 50 blood donors: 20 women (40%) and 30 men (60%) in age 15-68 yrs.
      RESULTS: The statistical analysis showed a correlation between the ARA serum
      levels and intraocular inflammation intensity. High correlation was found in
      first control between serum ARA level and the degree of vitreous inflammation and
      the presence of fresh vessels sheathing, characteristic for retinal vasculitis.
      In next three controls, this correlation was still present, but only in a case of
      vitreous changes. And at the end of observation no correlation was found, neither
      between serum ARA levels and the activity of vitreous inflammation, nor between
      the ARA levels and retinal vasculitis intensity. CONCLUSIONS: The assessment of
      serum ARA in patients with idiopathic posterior uveitis can act as an indicator
      for intraocular inflammation intensity and can reflect the retinal autoimmunity.

PMID- 12608308
TI  - [The effect of monocytes on early activation of lymphocytes T among children with
      idiopathic uveitis].
AB  - PURPOSE: We have investigated T Lymphocytes ability for CD69 molecule induction
      in presence and absence of monocytes in idiopathic uveitis. MATERIAL AND METHODS:
      Twenty-five children with idiopathic uveitis were studied. The control group
      consisted of 12 healthy children. Peripheral blood mononuclear cells (PBMCs) were
      isolated from heparinised venous blood, by density gradient centrifugation. CD69
      expression was cytometrically assessed on freshly isolated and cultured T
      lymphocytes. RESULTS: CD69 expression on freshly isolated peripheral blood T
      lymphocytes was low in both studied groups. LPS-stimulated monocytes added to
      cultures of T lymphocytes induced increase in CD69 expression but significantly
      lower in children with idiopathic uveitis compare to healthy children.

PMID- 12608309
TI  - [Photodynamic therapy in age-related macular degeneration--results of one year
      observation].
AB  - PURPOSE: To evaluate the efficacy of photodynamic therapy (PDT) with verteporfin
      in reducing the vision loss and progression of choroidal neovascularization (CNV)
      in patients with subfoveal CNV due to age-related macular degeneration (AMD).
      MATERIALS AND METHODS: 46 eyes of 46 patients with subfoveal, predominantly
      classic CNV caused by AMD and best-corrected visual acuity of 5/50 to 5/10 were
      treated with photodynamic therapy with verteporfin (Visudyne, CIBA Vision).
      Verteporfin was administered via intravenous infusion over 10 minutes. Fifteen
      minutes after the start of the infusion, a diode laser light at 689 nm (Opal
      Photoactivator, Coherent) was delivered over 83 seconds. Visual acuity and
      fluorescein angiography were performed before and after the treatment at 7 days
      and 1, 3, 6, 9 and 12 months after the initial-treatment. Retreatment in the same
      manner was applied if at follow-up examination fluorescein leakage from CNV was
      seen. Outcomes were compared with those of control group which consisted of 38
      eyes of 38 patients of the same condition of the disease, not treated with any
      method. RESULTS: The lost of visual acuity was significantly reduced in the
      verteporfin--treated eyes compared--with controls. At the 12 month 73.91% eyes of
      PDT group versus 36.84% of control group (p < 0.001) lost fewer than 3 Snellen
      lines. The vision loss appeared to be more rapid in first 6 months of the study.
      During the study growth of CNV was diminished in PDT group compared with control
      group. CONCLUSIONS: Results show, that photodynamic therapy may be an effective
      method of treatment for predominantly classic subfoveal choroidal
      neovascularization caused by AMD. Further studies are needed to find the best
      modes of PDT procedure.

PMID- 12608310
TI  - [Traumatic injuries to the oculomotor nerve].
AB  - PURPOSE OF THE STUDY: A collective summary of the pathogenesis, character and
      clinical significance of damage to the oculomuscular innervation, arising from
      closed head trauma, based on our own clinical observations, together with a
      review of literature on the topic. MATERIALS AND METHODS: The clinical and
      pathophysiological evaluation of injuries to the oculomotor (III) nerve based on
      a prospective study in our clinic, dating from 1994 onwards: the clinical
      material consisted of 600 patients admitted to our Department of Neurosurgery
      following head trauma, the subgroup consisted of 38 patients, who died following
      major head trauma. RESULTS: Few authors focus on damage to the innervation of
      oculomotor muscles, the diagnosis of damage being difficult due to the usually
      poor clinical condition of such patients, the interdisciplinary nature of the
      resulting damage, and their delayed ophthalmological evaluation. The oculomotor
      (III) nerve is the nerve most frequently damaged amongst the cranial nerves,
      taking into account the innervation of the ocular system nerves (II-VII). Of
      clinical importance is differentiating between the mechanism of damage, paying
      particular attention to intracranial damage. The mechanisms of damage can be
      distinguished by: 1) partial tearing of the parasympathetic fibres contused
      against the petroclinoid ligament, 2) total tearing of the parasympathetic nerve
      root, 3) complete tear of one or both oculomotor nerves at the interpeduncular
      base, 4) nerve root tear, resulting from vessel perforation. The oculomotor nerve
      has the ability to regenerate. The regenerative process should occur within 3 to
      5 months, that is without pathological synkinesis. If this process prolongs, this
      may lead to unpleasant consequences, such as the "misdirection phenomenon".
      CONCLUSIONS: Primary damage to the oculomuscular innervation resulting from
      closed head trauma is an integral component of such conditions. Early diagnosis
      and neuroprotective therapy may prevent pathological regeneration.

PMID- 12608312
TI  - [Results of treatment in congenital esotropia].
AB  - THE AIM: We analyzed results of the operations in congenital esotropia. MATERIAL
      AND METHODS: In paediatric ophthalmology department were treated 42 children in
      age 1.5 to 2.5 years with congenital esotropia. Strabismus angles were from +20
      degrees to +45 degrees. After the operations children were controlled in
      paediatric ophthalmology clinic. The pleoptic-ortoptic therapy was applied when
      children finished 3.5 years old. RESULTS: 28 children had orthoposition after
      primary operations and 20 had binocular vision. 6 children had second operation
      due to excessive functional activity inferior oblique muscle or residual angle.
      CONCLUSION: The operations of children with congenital esotropia between 1.5 to
      2.5 years old provided good functional results.

PMID- 12608311
TI  - [The role of color vision disturbances in diagnostics of early diabetic
      retinopathy].
AB  - PURPOSE: The evaluations of color vision sensitivity in children with type I
      diabetes mellitus without retinopathy. MATERIAL AND METHOD: We examined 96 young
      patients. They was divided into three groups: I: 35 children from 7 to 16 years
      old with insulin-dependent diabetes mellitus duration of 1-8 years, II: 30
      children with type I diabetes lasting more then 8 years, III--31 non-diabetic
      subjects as a control-matched for age and sex, without visual or systemic
      symptoms. The examinations of colour vision sensitivity were done with the IF
      2AII-color Anomaloscope. In all cases were tested the dynamic blue-green equation
      of Moreland and two variables were determined: setting (matching) range (SR),
      calculated mid point (matching mid point) (CMP). RESULTS: In the blue-green
      equation setting range (SR) was significantly (p < 0.01) enlarged in the II group
      (diabetes mellitus duration > 8 years) and calculated mid point (CMP) was shifted
      but no significant. The results indicate a diminution of the colour
      discriminating sensitivity in the short wavelength half of the visible spectrum
      and diminution of the blue cone sensitivity in early diabetic retinopathy.
      CONCLUSIONS: Blue-green colour vision testing with the anomaloscope may serve as
      an additional test in the diagnosis of early diabetic retinopathy in children
      without vascular changes at the eye fundus.

PMID- 12608313
TI  - [Amblyopia in myopia in patients with strabismus and without strabismus].
AB  - PURPOSE: To determine factors, which have influence on presence of strabismus
      among myopic patients with amblyopia. MATERIAL AND METHODS: Material covers 21
      myopic patients with amblyopia, aged 6-15. All children presented have a
      different amount of anisometropia, 12 of them had strabismus. Authors, compared
      the group of patients with amblyopia and strabismus (12) with the group of
      patients with pure anisometropic amblyopia (9), according to the following
      criteria: age of presentation, best corrected visual acuity, mean refraction
      error of amblyopic eye, mean amount of anisometropia, percentage of patients with
      central fixation and binocular vision. RESULTS: Patients with strabismus
      presented oneself earlier than patients without squint. Best corrected visual
      acuity was better in patients without strabismus. Refraction error in both groups
      has similar value. Amount of anisometropia was slightly smaller in the group with
      squint. Central fixation and binocular vision were better preserved among
      patients without strabismus. Authors didn't find the following correlations too:
      correlation between amount of anisometropia and amount of amblyopia in both
      groups, correlation between amount of anisometropia and the amount of the
      deviation of squinting eye, correlation between depth of amblyopia and the amount
      of deviation of the squinting eye. CONCLUSION: It seems, that primary factor
      leading to presence of strabismus among patients with anisometropic myopia, is
      motor dysfunction of extraocular muscles.

PMID- 12608314
TI  - [Evaluation of the visual function in employees working with computers].
AB  - PURPOSE: To evaluate the effects of long-term work with computer monitor on the
      accommodation, convergence, stereopsis, near and distant visual acuity. MATERIAL
      AND METHODS: The studies of the accommodation, convergence, stereopsis, near and
      distant visual acuity have been performed in 50 employees working with the
      computer 6.5 hours daily, 5-6 days weekly and 5 to 12 years. The same studies
      have been performed in 50 white-collar workers, who had no contact with the
      computer in their work. RESULTS: No changes in the accommodation, convergence,
      stereopsis, near and distant visual acuity have been found in the employees in
      both studies groups. CONCLUSION: Long-term work with the computer monitor does
      not cause changes in the visual function of the employees. Reported changes are
      probably cause by the visual fatigue associated with the near work, and not by
      the direct influence of the computer monitor.

PMID- 12608315
TI  - [Massive choroidal hemorrhage as a late trabeculectomy complication ].
AB  - The purpose of this paper was to present the case of an unusual late complication
      of filtering glaucoma surgery. A massive choroidal hemorrhage occurred 5 years
      after trabeculectomy and extracapsular cataract extraction. The diagnosis was
      confirmed by MRI examination. Improvement in choroidal status and in visual
      acuity (from hand motions to 6/12 with aphakic correction of 12 diopters) was
      observed during three weeks of medication. The retina and the choroid remained
      attached during two years of observation.

PMID- 12608316
TI  - [Biotinidase deficiency--a case report].
AB  - Biotinidase deficiency is a disorder of biotin metabolism. Heterogeneity of
      clinical course is presented. A girl with biotinidase deficiency is described.

PMID- 12608317
TI  - [Long acting analogue of somatostatin (Octreotide) for treatment of patients with
      neurochorioretinitis due to ocular sarcoidosis who failed corticosteroids
      therapy].
AB  - Neurochorioretinitis due to the course of ocular sarcoidosis is relatively rare
      case. It usually responds well to conventional treatment with corticosteroids. We
      want to present the patient effectively treated with long acting analogue of
      somatostatin (Octreotide), who failed to respond to previous corticosteroids
      treatment.

PMID- 12608319
TI  - [New methods of treatment of age-related macular degeneration. Photodynamic
      therapy. Part I].
AB  - Neovascular form of Age-related Macular Degeneration is the leading cause of
      blindness in developed countries. There is un urgent need for the effective
      treatment. In the recent years a number of treatment methods has been
      investigated. Photodynamic Therapy (PDT) with verteporfin appears to be an
      exciting approach to treatment which may provide a major breakthrough. The
      benefits of PDT with verteporfin were proved in randomized clinical trials-
      Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP)
      study.

PMID- 12608318
TI  - [Choroidal osteoma--diagnosis and ophthalmic management ].
AB  - Two cases of the long term observation and clinical findings of choroidal osteoma
      are presented. Choroidal osteoma (choroidal osseous choristoma) is a very rare,
      benign, ossifying tumour of the choroid, which typically affects healthy young
      women. The etiology is unknown. Neovascularisation and haemorrhage is a frequent
      associated finding. Subretinal neovascularisation, which tend to develop
      progressive visual loss, may be treated successfully with argon or krypton laser
      photocoagulation.

PMID- 12608320
TI  - [Evaluation vitreous body in idiopathic macular holes--biomicroscropic and
      ultrasonographic picture].
AB  - AIM OF THE STUDY: The aim of our study was to estimate the state of the vitreous
      body and the vitreoretinal interface in patients with idiopathic macular holes.
      MATERIAL AND METHODS: We examined 36 patients (41 eyes), 34 women and 2 men aged
      65-72 with idiopathic macular holes. State of the hole (classified by Gass) was
      established on the biomicroscopical examination using Goldmann lens and double
      aspheric Volk lenses (+60.0, +90.0 D), ultrasonography Compuscan UAB 1000 Storz
      and fluorescein angiography. RESULTS: We classified stage 2 macular hole in 7
      eyes (17%), stage 3 in 28 eyes (68%) and stage 4 in 6 eyes (15%). In the slit
      lamp examination we revealed partial posterior hyaloid detachment with posterior
      hyaloid membrane still attached at optic nerve head in 5 eyes, vitreomacular
      separation in 3 eyes, and vitreofoveal separation of posterior hyaloid membrane
      with the presence of focal condensation of the posterior hyaloid membrane in
      front of the fovea--operculum in 11 eyes, in stage 3 macular hole. In 8 eyes we
      observed lacunaes, and vitreoretinal tractions in 6. Ultrasonography was slightly
      more effective in revealing vitreomacular and partial PVD separation than
      biomicroscopical examination. In the case of vtireoretinal tractions or lacunaes,
      ultrasonography was worse than slit lamp examination. CONCLUSIONS: The exact
      evaluation of condition of the vitreous body and vitreo-retinal relationships are
      crucial for a further surgical treatment.

PMID- 12608321
TI  - [Gene therapy prospects in ophthalmology].
AB  - PURPOSE: Presentation of newest achievements from borderland of ophthalmology and
      molecular biology and their clinical employment areas in the therapy of eye
      diseases. MATERIAL AND METHODS: MEDLINE database has been searched for terms
      gene, gene therapy, ocular, eye in title and summary fields. RESULTS: Based on
      the latest literature eye disorders have been selected that are currently in
      focus of gene therapy. Experimental approaches in vitro as well as in vivo have
      been reviewed. CONCLUSIONS: Modern ophthalmology profits more and more from
      newest achievements in molecular biology such as gene therapy. Transfer of
      additional genes to selected target cells within eye is able to change function
      and allows to achieve required effects. It is performed through employment of so
      called vectors, small particles allowing the gene to be transferred. Presently
      most often used vectors are derived from viruses (retrovirus, adenovirus, viruses
      AAV). Experimental studies have been performed in following eye diseases:
      retinitis pigmentosa, Leber congenital amaurosis, glaucoma, retinoblastoma,
      postoperative posterior capsule opacification, corneal diseases, age related
      macular degeneration, uveal melanoma. In each case the experimental results were
      promising. However, possible side effects of such therapy are not sufficiently
      known. There have been no clinical gene therapy studies in ophthalmology so far.

PMID- 12608323
TI  - [Selected problems of ophthalmological certification in legal proceedings in
      labour court--own experience].
AB  - PURPOSE: Analysis of the appeals to the Appeals Labour Court and estimation of
      visual functions shown in court's decree. MATERIAL AND METHOD: 248 ophthalmic
      court's decree were analysed. RESULTS: In 72% of cases people were qualify as
      able to work. The most frequent reasons to obtain judgement of disability for
      labour were: eye injury, high myopia, strabismus, amblyopia, optical nerve
      atrophy, cataract. 54% persons were monocular. CONCLUSIONS: The most appeals to
      the Appeals Labour Court had no sufficient grounds for stating liability for
      labour.

PMID- 12608322
TI  - [Biotinidase deficiency and eye].
AB  - Biotinidase deficiency is an autosomal recessive disorder depending on the
      deficiency of 4 biotin-containing carboxylases. This disease can lead to variety
      of neurologic, ophthalmologic and cutaneous symptoms, when untreated.

PMID- 12608324
TI  - [The health service in the European Community. What can await in the future EU
      members?].
AB  - The problems of national health system in the European Community member states
      and affiliating countries will be discussed. Particular attention will be paid to
      team doctor model, continuous medical education, social security system and
      disease management programme.

PMID- 12608325
TI  - [History of academic ophthalmology in Wroclaw, Poland in 1812-2002].
AB  - The authors present the history of the Department of Ophthalmology in Wroclaw,
      since 1812. Special attention is paid to following professors of ophthalmology
      and directors of the University Eye Hospital: T.V.G. Benedict, A.T. Mitteldorf,
      R. Foerster, H.L. Cohn, H. Magnus, A. Groenouw, H. Willbrand; W. Uhthoff, Th.
      Axenfeld, G. Lenz, A. Huszcza, L. Baran, A. Bielschowsky, W. Dieter, A.
      Bednarski, M. Grzedzielski, L. Hirschfeld, W.J. Kapuscinski, S. Drozdowska, E.
      Ogielska, P. Hanczyc, M.H. Nizankowska

PMID- 12608326
TI  - Facing the future. Surgical advances are changing the lives of children born with
      severely malformed features.

PMID- 12608327
TI  - A medical battalion.

PMID- 12608328
TI  - A deep-six fix. Could burying fossil-fuel emissions save the climate?

PMID- 12608329
TI  - World beater. Computing power to humble all rivals and forecast Earth's future.

PMID- 12608330
TI  - A new start for stem cells. Can bone marrow seed the brain with fresh neurons?

PMID- 12608331
TI  - [Destruction of the skull during compression].
AB  - The article contains the results of an experimental modeling of the destruction
      of the head of a bio-mannequin by compressing it between two blunt objects with
      the hard, flat and broad surfaces and by using a mechanical press (with slow
      motion) and freely falling object (with fast motion). The obtained results were
      compared with two opposite-direction blows by a similar object. The author
      studied the main regularities of fractures of the skull of the main shapes, i.e.
      ellipsoid or ovoid as well as spheroid and rhomboid shapes, at different
      directions of its compression (sagittal, lateral, diagonal, vertical or moving).
      A comparison of local, constructional and local-and-constructional zones of the
      inflicted fractures made it possible to establish the succession in the formation
      of the destruction of the skull at the static and dynamic compression types.

PMID- 12608332
TI  - [Dynamics of morphological changes in the central nervous system as a criteria
      for lifetime thermal trauma].
AB  - An attempt was made in the present study to specify the signs of a lifetime
      thermal trauma (TT) by examining the dynamics of ultrasound changes in the
      central nervous system (CNS). Derangements of interneuronic bonds and of
      interrelations between the neurons and capillaries are typical for changes in the
      brain at thermal trauma. The former is documented by changes in the synaptic
      apparatus, and the latter--by an edema of the glia cell processes, which account
      for the transportation of substances from the blood flow into neurons. Such
      changes can be regarded as the signs of a lifetime TT, which makes it possible to
      recommend to use the photo-optic and electron-microscopic examinations of the
      cerebral tissues in the forensic medicine for the differential diagnosis of
      lifetime and postmortem TTs.

PMID- 12608333
TI  - [Features of asymmetry of paired sizes of the lower jaw as applied to osteologic
      human identification].
AB  - The article contains craniometric data of 50 lower jaws. An asymmetry of twin
      sizes of the lower jaw as applicable to the tasks of osteologic personality
      identification is evaluated.

PMID- 12608334
TI  - [Methods of achieving group-specific activity of plant extracts].
AB  - Different methods of eliminating the side effects of phytohemagglutinins and of
      enhancing the titer of a needed phytohemagglutinin are described. The importance
      of the above methods for the forensic-medicine serology is demonstrated.

PMID- 12608335
TI  - [Morphofunctional changes of external male genitalia in alcoholism and substance
      abuse].
AB  - The external male genitals (EMG) of male corpses, who abused alcohol and
      narcotics at lifetime, were examined. The objects were stained according to the
      common histological and histochemical methods. The study results are indicative
      of a high frequency rate of pathologic changes of the EMG in persons, who abused
      alcohol and narcotics at lifetime. The inflammatory, fibrosing and atrophic
      changes of the EMG as well as a reduced vascular permeability can be a cause for
      erection malfunction.

PMID- 12608336
TI  - [Organization and implementation of forensic medical expertise at determining the
      degree of loss of ability to work].

PMID- 12608337
TI  - [Accidents related with atypical sexual behavior].
AB  - The article is devoted to the phenomenon of autoerotism, in particular, to sexual
      asphyxia. Published research data and independent observations were used to
      describe lethal and non-lethal incidents of forensic-and-medical importance.

PMID- 12608338
TI  - [Determination of hair group by preserved hair cell bulbs].
AB  - Difficulties appearing in determining hair group were the reason for conducting
      this research for the purpose of finding additional possibilities to solve the
      mentioned problem. It was established that the preliminary cell coloring, related
      with determination of hair sex, does not influence a consequent detection of
      antigens. Methods or the fixation of material were selected. The most suitable
      reagents and their titers as well as different time periods of absorption for
      detecting antigens A and B are offered. All stages of examination are described
      in detail.

PMID- 12608339
TI  - [The problem of conventional criterion of adequacy of genetic information for
      conclusions on genetic individual identity].

PMID- 12608340
TI  - [Significance of general and specific signs in forensic-medical human
      identification by morphologic methods].

PMID- 12608341
TI  - [Laboratory methods of determining old cerebrocranial injuries in forensic
      medicine].

PMID- 12608342
TI  - [Role of histologic study of the liver in forensic medical diagnosis of chronic
      narcotic intoxication].

PMID- 12608343
TI  - [M. I. Avdeev and the chair of Forensic Medicine at Moscow Medical Academy named
      for I. M. Sechenov (on the 100th anniversary of his birth)].

PMID- 12608344
TI  - Demographic and mortality trends in the region of the Americas, 1980-2000.

PMID- 12608345
TI  - Epidemiologic situation of acute pesticide poisoning in Central America, 1992
      2000.

PMID- 12608346
TI  - Standardization: a classic epidemiological method for the comparison of rates.

PMID- 12608347
TI  - Case definitions. Cutaneous leishmaniasis.

PMID- 12608348
TI  - Case definitions.  Visceral leishmaniasis.

PMID- 12608349
TI  - Mercury in vaccines may not pose harm.

PMID- 12608350
TI  - Product recalls. Recall: chocolate covered raisins.

PMID- 12608351
TI  - Diet & nutrition. Risks of herbal therapies...and a caution about "skinny pill
      for kids".

PMID- 12608352
TI  - Product safety. Helping protect children from burns.

PMID- 12608354
TI  - Parent/child. Infant colic--does it affect mother's mental health?

PMID- 12608353
TI  - A new resource to help identify recalled toys.

PMID- 12608355
TI  - Back pain in children--how common is it?

PMID- 12608357
TI  - Gender differences in adverse drug reactions: analysis of spontaneous reports to
      a Regional Pharmacovigilance Centre in France.
AB  - The aim of this study was to investigate putative gender-related differences in
      adverse drug reactions (ADRs). Data were ADRs recorded in the database of the
      French Midi-Pyrenees Pharmacovigilance Centre in 1998. A total of 927 ADRs were
      spontaneously reported to the Centre in 1998, of which 53.1% were in females
      (difference vs. males not statistically significant). There was no statistically
      significant difference in the incidence of reported ADRs in males (3.6/10,000
      inhabitants) vs. females (3.9/10,000 inhabitants) for the total population of the
      Midi-Pyrenees area. The number of reported ADRs was similar across different age
      groups (10-year age ranges). However, 'serious' ADRs were more frequently
      reported in males in the 0-9 and 60-69 age groups (and in females between 20 and
      29 years old). There were significantly more neuropsychiatric (69 vs. 43, P =
      0.05) and fewer cardiovascular (8 vs. 2, P = 0.05) ADRs reported in females than
      in males. ADRs were more frequently reported in females for some classes of drugs
      (such as genito-urinary, sex hormone, antineoplastic, antiparasitic and
      respiratory drugs). These results confirm that female gender is a risk factor for
      the development of ADRs.

PMID- 12608356
TI  - 13CO2/12CO2 isotopic ratio measurements using a difference frequency-based sensor
      operating at 4.35 micrometers.
AB  - A portable modular gas sensor for measuring the 13C/12C isotopic ratio in CO2
      with a precision of 0.8%(+/-1 sigma) was developed for volcanic gas emission
      studies. This sensor employed a difference frequency generation (DFG)-based
      spectroscopic source operating at 4.35 micrometers (approximately 2300 cm-1) in
      combination with a dual-chamber gas absorption cell. Direct absorption
      spectroscopy using this specially designed cell permitted rapid comparisons of
      isotopic ratios of a gas sample and a reference standard for appropriately
      selected CO2 absorption lines. Special attention was given to minimizing
      undesirable precision degrading effects, in particular temperature and pressure
      fluctuations.

PMID- 12608358
TI  - Production of laccase by Coriolus versicolor and its application in
      decolorization of dyestuffs: (I). Production of laccase by batch and repeated
      batch processes.
AB  - The production of laccase by Coriolus versicolor was studied. The effect of
      cultivation conditions on laccase production by Coriolus versicolor was examined
      to obtain optimal medium and cultivation conditions. Both batch and repeated
      batch processes were performed for laccase production. In repeated-batch
      fermentation with self-immobilized mycelia, total of 14 cycles were performed
      with laccase activity in the range between 3.4 and 14.8 U/ml.

PMID- 12608359
TI  - [Deferred appendectomy in a case of appendiceal mass].

PMID- 12608361
TI  - Abstracts of the 2nd Conference on Experimental Tumor Biology. March 14-17, 2002.
      Bovec, Slovenia.

PMID- 12608360
TI  - [Trends of adolescent injury and poisoning mortality].
AB  - OBJECTIVE: To describe the external causes of death and mortality trends due to
      injuries and poisoning in Mexican adolescents, from 1979 to 1997. MATERIAL AND
      METHODS: This is a descriptive study of deaths occurring in Mexico from 1979 to
      1997. Data were abstracted, coded, and entered in electronic format, by Instituto
      Nacional de Estadistica, Geografia e Informatica (National Institute of
      Statistics, Geography, and Informatics, INEGI). Data were analyzed during the
      second half of year 2000, in Jalisco, at the Research Unit of Epidemiologic and
      Adolescent Health Services, of Instituto Mexicano del Seguro Social (Mexican
      Institute of Social Security, IMSS). RESULTS: Injuries and poisoning ranked first
      as causes of adolescent mortality in Mexico (rate = 13.35/100,000), decreasing
      41.4% from 1979 to 1997. However, an increasing trend was observed for homicides
      and suicides (9.5% y 104.0%, respectively). The most frequent mechanisms of
      injury were: motor vehicles, firearms, intoxications, suffocation, and drowning.
      CONCLUSIONS: Injuries and poisoning in developing countries show differences from
      those reported in developed countries. Further studies should be conducted to
      find preventive measures consistent with the sociocultural and environmental
      determinants of injuries and poisoning.

PMID- 12608362
TI  - Proceedings of the Edward M. Copeland III Scientific Symposium. March 1, 2002.
      Gainesville, Florida, USA.

PMID- 12608363
TI  - Proceedings of the Advisory Committee on Infection in Solid Organ
      Transplantation. December 15, 2000. Palm Beach, Florida, USA.

PMID- 12608364
TI  - Proceedings of the 28th Annual Meeting of the International Society of Oxygen
      Transport to Tissue. Nijmegen, The Netherlands. August 20-25, 2000.

PMID- 12608365
TI  - Proceedings of the 3rd International Symposium on Pharmaceutical Chemistry.
      Istanbul, Turkey. September 17-19, 2001.

PMID- 12608366
TI  - From tradition to modernity: Asian therapies for cancer. A first international
      conference. February 28-March 3, 2001, New York, New York, USA.

PMID- 12608367
TI  - Assuring Quality in Emergency Care. Proceedings of the AEM 2002 Consensus
      Conference.

PMID- 12608368
TI  - A punishing pace.

PMID- 12608369
TI  - Isolation of a Pantoea dispersa-like strain fron a 71-year-old woman with acute
      myeloid leukemia and multiple myeloma.

PMID- 12608370
TI  - Prepared to soldier on?

PMID- 12608371
TI  - Clinical quiz: Disseminated infection in an immunocompetent woman after an arm
      injury.

PMID- 12608372
TI  - Up against a brick wall.

PMID- 12608373
TI  - Critical condition. Interview by Nick Edwards.

PMID- 12608374
TI  - West Nile virus-- an emerging pathogen.

PMID- 12608375
TI  - [Fleurs du mal].

PMID- 12608376
TI  - [How to win patients for self-pay options with patient information booklets].

PMID- 12608377
TI  - [Acceptability of slot time contracts to anesthetists with personnel].

PMID- 12608378
TI  - [Cataract: new synthetic lens improves contrast vision in operated patients].

PMID- 12608379
TI  - [Do Hans-Joachim Haase prisms improve stereo vision?]].

PMID- 12608380
TI  - [Chronic fixation disparity doesn't have to result in reduced stereo depth
      perception].

PMID- 12608382
TI  - Physiome 2002. Abstracts of the 70th Annual Meeting of the Societe de
      Physiologie. September 18-20, 2002. Quebec, Canada.

PMID- 12608381
TI  - [Prism correction in vision disparity based on the "H. J. Haase measurement and
      correction methodology"].

PMID- 12608383
TI  - [Mechanical causes of coxarthrosis in young adults].

PMID- 12608384
TI  - Emerging Alzheimer's disease therapies: focusing on the future. Proceedings of a
      symposium. November 7, 2001, Philadelphia, Pennsylvania, USA.

PMID- 12608385
TI  - Mortality trends of all cancer sites in Japan: 1960-2000.

PMID- 12608386
TI  - Arvid Wretlind.

PMID- 12608387
TI  - Total myocardial revascularization without cardiopulmonary bypass. 5th
      International Symposium. March 15-16, 2002. Tampa, Florida, USA.

PMID- 12608388
TI  - [Acute coronary infarcts: close connection between inflammation and thrombosis].

PMID- 12608389
TI  - [Starting light alcohol drinking for prevention of coronary disease: too little
      too late?].

PMID- 12608390
TI  - [Sleep apnea and cardiovascular disease].

PMID- 12608391
TI  - [Suboptimal results of Optimaal: treatment with ACE inhibitors remains the
      preferred therapy in patients with left ventricular dysfunction after acute
      myocardial infarct]].

PMID- 12608393
TI  - [Pierre-Francois Nicolas (1743-1816), apothecary, physician, chemistry teacher on
      the eve of the French Revolution].
AB  - Pierre-Francois Nicolas, was born in Saint-Mihiel in 1743, studied in this town
      and in St-Nicolas-de-Port near Nancy. At first he has been a military apothecary
      during the "Guerre de Sept-Ans". Then he studied pharmacy in Nancy and was
      received in 1768 at the "Maitrise de pharmacie". With the physician Henri Michel
      du Tennatar, he created a teaching of chemistry for medicine students and became
      the professor of chemistry of the Faculty of Medicine in 1781. During these
      years, he published some research results about hydrology, distillery,
      biochemistry (phosphorus in bone), toxicology, dyeing... At the end of 1783, he
      succeeded in the realization of a balloon and he played an important part in
      Nancy during the French Revolution. Professor at the "Ecole de medecine" in
      Strasbourg for some weeks, then in Nancy at the "Ecole centrale" and at the
      "Societe de sante", he left Nancy towards the mid-1798. Staying in Paris for two
      or three years he probably worked with Fourcroy and perhaps Chaptal and
      Berthollet. In the early years of the nineteenth century he was appointed
      professor in the "Ecole centrale" du Calvados" and some years after at the
      "Faculte des sciences" in Caen. His latest significant work with Gueudeville was
      devoted to the detection of sugar in the urine of diabetic patients. Retired in
      1811 Pierre-Francois Nicolas died in Caen in 1816.

PMID- 12608392
TI  - Meniscus repair.

PMID- 12608394
TI  - Pediatric rehabilitation medicine.

PMID- 12608395
TI  - Virtual colonoscopy.

PMID- 12608396
TI  - Outcomes after total versus subtotal abdominal hysterectomy.

PMID- 12608397
TI  - Miltefosine for Indian visceral leishmaniasis.

PMID- 12608398
TI  - Hemofiltration and peritoneal dialysis in infection-associated acute renal
      failure.

PMID- 12608399
TI  - Hemofiltration and peritoneal dialysis in infection-associated acute renal
      failure.

PMID- 12608400
TI  - Hemofiltration and peritoneal dialysis in infection-associated acute renal
      failure.

PMID- 12608401
TI  - The Olivieri case.

PMID- 12608402
TI  - [Glaucoma diagnosis -- photographic analysis].

PMID- 12608403
TI  - Galls on thistles.
AB  - Plant galls - the more we learn, the more there is to know! Approximately 15000
      insect species ( c. 2% of all known insects) form galls, and this habit is
      extremely common over a range of floras and latitudes. Yet, there is still no
      general consensus on why they exist. Thistle-galling insects are relatively well
      known and are used as biological control agents (of thistles) and model
      ecological systems.

PMID- 12608404
TI  - A tribute to Senator Charles E. Grassley.

PMID- 12608405
TI  - [Increased myopia and metaporphosia in a 59-year old patient. Serous retinal
      detachment of the posterior pol after latanoprost administration].

PMID- 12608407
TI  - [Bilateral, progressive deterioration of vision with a concentrically constricted
      field. High grade malignant, small-cell endometrial carcinoma in early stage (G4,
      pT1b, Nx, Mx, Ro].

PMID- 12608408
TI  - Using outcomes & benchmarked data as a competitive advantage.

PMID- 12608410
TI  - A fitting honor.

PMID- 12608411
TI  - [32nd Annual Meeting of DOSAK, Freiburg, 18-20 November 2001. "DOSAK in the
      future--the future of DOSAK"].

PMID- 12608412
TI  - Medicare overpayments can go from bad to worse.

PMID- 12608413
TI  - EU countries 'must harmonise clinical trial regulations'.

PMID- 12608414
TI  - Clinical trials are key to progress.

PMID- 12608415
TI  - Oestrogen receptor positivity is associated with improved response to endocrine
      therapies.

PMID- 12608416
TI  - [Stability of TSH in dried blood spots].

PMID- 12608417
TI  - [Victor Moreau and his son practised the first joint resections].
AB  - Victor Moreau (1746-1799) and his son (1778-1846) were surgeons in Bar-le-Duc
      (French Department of Meuse). Victor Moreau invented the first joint resection
      technique in 1782 and submitted written comments to the "Academie Royale de
      Chirurgie" in 1782 then 1786 and 1789. At that time amputation was the only way
      of saving wounded and injured patients' lives and a conservative technique was an
      actual revolution in bone and joint surgery. His friend Pierre-Francois Percy was
      transmitted the technique in 1792. His son improved the technique and attempted
      to put it into widespread use through his thesis (1803) and the most famous essay
      of his in 1816. However the technique did not immediately succeed till Leopold
      Ollier's works proved the "bone regeneration by the periosteum" and the role of
      the "sub-capsular periosteum resection". Nowadays in spite of prosthesis progress
      some joint resections can be still indicated. At last Victor Moreau can be deemed
      the pioneer of the functional limb surgery.

PMID- 12608418
TI  - Effect of fluoride mouth rinse on fluoride releasing and recharging from
      aesthetic dental materials.
AB  - This study evaluated fluoride-release and recharging with the fluoride mouth
      rinsing technique on fluoridated materials. Three fluoride containing materials
      and one non-fluoride containing composite resin were used for this study. Samples
      for each material consisted of 15 discs, 9 mm diameter with a thickness of 1 mm.
      Initial fluoride release was assessed over a 60-day period. After that, 15 discs
      for each material were divided into 3 groups: distilled water group, 450-ppm and
      900-ppm mouth rinsing groups. Fluoride release increased in combination with
      fluoride mouth rinse, and fluoride was higher in the 900-ppm group than the 450
      ppm group. Moreover, S-PRG or F-PRG fillers materials released fluoride in higher
      than fluoroaluminosilicate glass fillers materials. In addition fluoride release
      from control samples was not observed. Therefore, only fluoride release material
      takes up fluoride. The findings of the present investigation suggest that the
      rate of fluoride release was different for each material, because they contained
      different function fillers. The results showed the importance of the fluoride
      mouth rinsing technique for fluoride-releasing restorative materials for the
      prevention of secondary caries.

PMID- 12608419
TI  - Fluorescent labeling analysis and electron probe microanalysis for alveolar ridge
      augmentation using calcium phosphate cement.
AB  - Our previous histopathological study showed that the augmentation block, prepared
      from a calcium phosphate cement (CPC) mixed with H2O at powder to liquid ratio of
      5 g/mL, placed on the alveolar bone ridge, was gradually replaced by natural
      bone. In the present study, fluorescent labeling analysis (FLA) and electron
      probe microanalysis (EPMA) were performed on the same surgical site of the above
      histopathological study. Fluorescent labeling agents, that would be incorporated
      into newly formed mineralized tissues, were injected into dogs intramuscularly
      twice a week during the 3 week period that ended 1 week before sacrifice. The
      specimens obtained from the block were subjected to FLA for assessing the extent
      of new bone formation and to EPMA for measuring the elemental (Ca, P, Mg)
      distributions. FLA results showed the presence of newly formed bone at 1 month
      after surgery. EPMA results showed that the elemental distributions in the
      augmentation site were similar to those of the residual bone area at 6 months
      after surgery. FLA and EPMA examinations also indicated that the implants were
      surrounded and fixed by natural bone chronologically. A CPC augmentation block is
      clearly useful for alveolar ridge augmentation and osteointegrated implant
      fixation.

PMID- 12608420
TI  - Calcium-ion incorporation into titanium surfaces accompanied by electrochemical
      apatite-deposition.
AB  - The depths of calcium-ion incorporation into a commercially pure titanium and an
      experimental beta-type titanium alloy were determined using Auger electron
      spectroscopy. After the electrochemical deposition of apatite, new compositional
      gradients appeared in the profiles in which the Ca and P concentrations gradually
      decreased as a function of the depth up to 6-8 nm. The relative concentration of
      Ca in the outermost layer was higher than that of P. On the other hand, after the
      soaking in a simulated body fluid, the relative concentration of P was higher
      than that of Ca in the outermost layer. These results suggested that Ca ions were
      well incorporated into the outermost oxide layer of titanium accompanied by the
      electrochemical apatite-deposition on its surface.

PMID- 12608421
TI  - Studies on MMA-tBB resin. I. Comparison of TBB and other initiators in the
      polymerization of PMMA/MMA resin.
AB  - Polymerization characteristics of poly (methyl methacrylate)(PMMA)/(methyl
      methacrylate) (MMA) resin initiated by tributylborane (TBB) were compared with
      those by benzoyl peroxide (BPO)/N,N-dimethyl-p-toluidine and camphorquinone
      (CQ)/N,N-dimethylaminoethyl methacrylate from the aspects of temporal changes of
      residual MMA and molecular weight up to 4 weeks at 37 degrees C. Residual MMA 30
      min after polymerization decreased from 8.15% for TBB resin, 8.39% for the BPO
      resin, and 9.19% for the CQ resin to 0.48%, 3.54%, and 6.79%, respectively, after
      4 weeks. The molecular weights at 30 min and 4 weeks after polymerization were
      409 x 10(3) and 247 x 10(3) for TBB resin, 297 x 10(3) and 282 x 10(3) for the
      BPO resin, and 267 x 10(3) and 231 x 10(3) for the CQ resin, respectively. The
      present results revealed that the TBB-initiated polymerization had unique and
      different characteristics compared with those initiated by the other common
      initiators: (1) The decrease in residual MMA was fast, sustained for a long time
      and resulted in very low value; (2) high molecular weight PMMA was formed first
      and then decreased with time.

PMID- 12608422
TI  - Experimental ammonia-free phosphate-bonded investments using Mg(H2PO4)2 solution.
AB  - In our previous study, we investigated ammonia-free phosphate-bonded investments
      using Mg (H2PO4)2 powder. The purpose of the present study was to attempt usage
      of 50 wt% Mg (H2PO4)2 solution instead of powder. Magnesium oxide (MgO) was
      prepared as a binder and cristobalite was selected as a refractory. After
      arranging six kinds of experimental investments (A-F) with different
      cristobalite/MgO ratios, the fundamental properties of the dental investments
      were examined. The properties of the molds were influenced by the amount of MgO.
      Decreases in MgO showed lower mold strengths, longer setting time and larger
      setting expansion. According to XRD analysis, the peaks of MgH(PO4)3 x 3H2O newly
      formed, cristobalite and MgO were detected in the A set, but MgO peaks in F set
      were reduced. On the other hand, the surface of F was entirely covered by
      phosphorus. From these results, it was found that the usage of Mg(H2PO4)2
      solution was possible for ammonia-free investments.

PMID- 12608424
TI  - Effect of NaOCl treatment on bond strength between indirect resin core-buildup
      and dentin.
AB  - The aim of this study was to investigate the bond strength between indirect resin
      core-buildup and dentin treated with or without hypochlorite (NaOCl) gel. The
      post-space was made in five extracted human molars with obturated root canals,
      and the indirect resin core was produced on a gypsum model. Then, the dentin
      surface was treated with/without NaOCl, followed by luting of the resin core into
      the cavity. After storage for 24 h in 37 degrees C water, the specimens were
      sectioned for measuring bond strength to the root and coronal dentin, and were
      subjected to micro-tensile bond strength (MTBS) testing. Two-way ANOVA showed
      that significant differences in MTBS were revealed for both factors of NaOCl
      treatment and dentin region. It is concluded that, for indirect resin core
      buildup, the proper use of the NaOCl gel to dentin could increase the bond
      strength.

PMID- 12608423
TI  - Effects of Ga addition on the mechanical properties of 35Ag-30Pd-20Au-15Cu alloy.
AB  - Ten 35Ag-30Pd-20Au-15Cu alloys containing 0.00, 0.25, 0.50, 0.75, 1.00, 1.25,
      1.50, 2.00, 4.00, or 6.00% Ga were experimentally prepared to investigate the
      effect of Ga on their mechanical properties in addition to their use for denture
      frameworks, connectors and clasps. The effect of Ga addition on the mechanical
      properties was marked with a significant increase in the tensile strength, 0.2%
      off-set proof stress (proof stress) and Vickers hardness observed at low Ga
      contents (0.25-2.00%). On the other hand, the elongation significantly decreased
      with the addition of Ga at all contents used in this study. The tensile strength,
      proof stress and Vickers hardness of the 35Ag-30Pd-20Au-15Cu alloys containing
      0.25-2.00% Ga were in the range of 809-957 MPa, 669-857 MPa and 260-301 MPa,
      respectively. These values are similar to those of Co-Cr alloys, suggesting that
      0.25-2.00% Ga alloys can be used for denture frameworks, clasps and connectors.

PMID- 12608425
TI  - Surface properties and biocompatibility of nitrided titanium for abrasion
      resistant implant materials.
AB  - Corrosion, other related properties and biocompatibility of surface nitrided
      titanium were investigated to examine its possible use as an abrasion resistant
      implant material. The nitrided layer about 2 microm thick composed of TiN and
      Ti2N was formed on titanium by a gas nitriding method. The dissolved amount of
      titanium ion in SBF was as low as the detection limit of ICP, and that in the 1%
      lactic acid showed no significant difference from titanium. The tissue reaction
      of the cylindrical implant in soft tissue of rats showed no inflammation, and
      fine particles of 1 microm induced phagocytosis, which was similar to titanium.
      The implantation in the femor showed the new bone formed in direct contact with
      implants. All the results suggested that the wettability, corrosion resistance,
      S. mutans adhesion and biocompatibility were nearly equivalent to those of
      titanium. The surface of nitrided titanium was promising, with biocompatibility
      comparable with titanium, as an implant material such as for an abutment part of
      a dental implant, which requires high abrasion resistance.

PMID- 12608426
TI  - Improving a self-curing dental resin by eliminating oxygen, hydroquinone and
      water from its curing process.
AB  - Self-curing dental resins are always manipulated in the presence of curing
      inhibitory factors such as oxygen, hydroquinone, water and another contaminants
      such as saliva and blood. The purpose of this study was to elucidate the effects
      of eliminating these curing inhibitory factors on resin properties. Several
      clinically relevant characteristics of an experimental resin cured in the absence
      of inhibitory factors (purified group) were determined and compared with the
      resin cured conventionally (control group). The purified group showed a
      significantly shorter induction period and higher reaction exotherm. It also
      showed significantly higher tensile strength and lower strain to failure. With
      regard to the amount of residual monomer, fracture toughness and fatigue strength
      the improvements were not significant. These findings suggest that the
      polymerization outcomes and mechanical properties of the purified group resin can
      be improved in general. Dental clinicians should pay attention to the storage and
      curing environments while manipulating the self-curing resin.

PMID- 12608427
TI  - Effect of presilanization filler decontamination on aesthetics and degradation
      resistance of resin composites.
AB  - Filler-matrix coupling determines, to a large extent, the mechanical strength and
      clinical longevity of dental composites. The aim of this study was to examine how
      far a methodology to decontaminate filler prior to silanization may improve
      aesthetic performance in addition to physico-mechanical properties such as
      degradation resistance. It was reported that filler particles are surrounded and
      wrapped by a film that consists of multiple layers of silane molecules. X-ray
      photoelectron spectroscopy, however, revealed that silanization of filler
      particles largely depended upon siloxane bridge (Si-O-Si) formation between the
      silica surface and the silane molecule rather than on intermolecular bonding
      between adjacent silane molecules. In this study, we showed that filler
      decontamination resulted in a higher translucency, thereby providing a better
      aesthetic potential. In addition, experimental composites produced following
      presilanization decontamination of filler revealed a higher Vickers hardness
      value and a diametral tensile strength that was resistant to degradation by
      thermo-cycling.

PMID- 12608428
TI  - Influence of 30% hydrogen peroxide bleaching on compomers in their surface
      modifications and thermal expansion.
AB  - The surface modifications and the coefficient of thermal expansion of compomers
      after treatment with a 30% hydrogen peroxide bleaching agent were investigated.
      Three compomers (Compoglass F, Elan and F2000) were nonbleached and bleached for
      1 and 3 days. The surface modification and the coefficient of thermal expansion
      of each bleached compomer were evaluated using a scanning electron microscope and
      a thermomechanical analyzer, respectively. As a result, Compoglass F and Elan
      showed slight surface degradation, whereas F2000 showed many cracks on its
      surface and these cracks were not observed in Compoglass F and Elan. Bleached
      Elan and F2000 has changed to the extent where their the coefficient of thermal
      expansion increased compared with those of nonbleached specimens. In addition,
      bleached compomers showed a strong inverse correlation between the coefficient of
      thermal expansion and the volume percent of filler.

PMID- 12608429
TI  - Pulmonary infections: what to do when it's a bug that you do not know.

PMID- 12608430
TI  - Inhaled corticosteroids and survival in chronic obstructive pulmonary disease.

PMID- 12608431
TI  - Rapid urinary antigen test for diagnosis of pneumococcal community-acquired
      pneumonia in adults.
AB  - Streptococcus pneumoniae is suspected to cause an important proportion of
      community-acquired pneumonia (CAP) whose aetiology cannot be detected with
      conventional tests. In this study, the authors evaluated the diagnostic yield of
      a new immunochromatographic membrane test (ICT) for the detection of the S.
      pneumoniae antigen in the urine of patients admitted with diagnosed CAP. ICT was
      performed in unconcentrated and concentrated urine from all the patients. ICT was
      repeated 1 month after discharge in a group initially testing positive. The
      authors also studied the ICT in clinically stable human immunodeficiency virus
      type 1 (HIV1)-infected patients. S. pneumoniae antigen was detected in all of the
      68 (100%) patients tested with definitive pneumococcal pneumonia. In five of
      these cases ICT was only positive when it had been performed on the patients. The
      S. pneumoniae antigen was also detected in 36 (69.2%) of 52 patients with
      probable pneumococcal pneumonia and in 50 of 277 (18%) patients without
      pneumococcal pneumonia. ICT remained positive in 16 (69.5%) of 23 patients, 1
      month after hospital discharge. Nasopharyngeal colonisation with S. pneumoniae
      was detected in 8 (12%) of 68 clinically stable HIV1 infected patients, but none
      tested ICT positive. The Binax NOW it immunochromatographic membrane test is a
      rapid, sensitive and specific test for detecting pneumococcal community-acquired
      pneumonia in adults. The test may remain positive for several weeks after
      pneumococcal pneumonia.

PMID- 12608432
TI  - Genomic DNA extraction from small amounts of serum to be used for alpha1
      antitrypsin genotype analysis.
AB  - If laboratory diagnosis of alpha1-antitrypsin (alpha1-AT) deficiency is usually
      based on its phenotype identification by isoelectric focusing, alpha1
      antiprotease inhibitor (Pi)S and PiZ genotypes can also be determined by
      deoxyribonucleic acid (DNA)-based methods. Recently, several methods have been
      described for preparing genomic DNA from serum. The aim of the current study was
      to determine the Pi allele from serum extracted DNA by polymerase chain reaction
      (PCR) and to compare these results with those obtained with whole blood extracted
      DNA. Serum alpha1-AT concentration and phenotypic identification were
      systematically performed in 43 hospitalised patients. Genomic DNA was
      simultaneously purified from whole blood and from serum. The mutation detection
      was found using a PCR-mediated site-directed mutagenesis method. Concerning
      phenotypic identification, 29 patients were MM homozygotes, 11 were heterozygotes
      for S (MS = 7) or for Z (MZ = 4) and three showed a ZZ phenotype. Genotyping
      analyses gave identical results with serum and whole blood extracted DNA and all
      the results were in agreement with the phenotyping results. The authors found
      that the deoxyribonucleic acid-based test proved to be a reliable tool for alpha1
      antitrypsin deficiency diagnosis and appears to be an alternative for the labour
      intensive alpha1-antitrypsin determination by isoelectric focusing. The authors
      also concluded that this method yields good quality deoxyribonucleic acid from
      serum, equal to that extracted from whole blood and is helpful in retrospective
      studies of multiple genetic markers.

PMID- 12608433
TI  - Diagnostic value of adenosine deaminase in nontuberculous lymphocytic pleural
      effusions.
AB  - Adenosine deaminase (ADA) can aid in the diagnosis of tuberculous pleural
      effusions, but false-positive findings from lymphocytic effusions have been
      reported. The purpose of this study is to assess the ADA levels in nontuberculous
      lymphocytic pleural effusions (lymphocyte count > 50%) of different aetiologies.
      Altogether, 410 nontuberculous lymphocytic pleural fluid samples were
      consecutively selected. These included malignant effusions (n = 221), idiopathic
      effusions (n = 76), parapneumonic effusions (n = 35), postcoronary artery bypass
      graft surgery effusions (n = 6), miscellaneous exudative effusions (n = 21) and
      transudative effusions (n = 51). The ADA level reached the diagnostic cut-off for
      tuberculosis (40 U x L(-1)) in seven of the 410 cases (1.71%). The negative
      predictive value of ADA for the diagnosis of pleural tuberculosis was 99% (403 of
      407 cases) in the group of lymphocytic pleural effusions. In five of these seven
      patients ADA1 and ADA2 were measured, and in all these cases (100%) ADA1/ADA(p)
      correctly classified these lymphocytic effusions as nontuberculous (ratio <
      0.42). This prospective study provides additional evidence that adenosine
      deaminase levels in nontuberculous lymphocytic pleural effusions seldom exceed
      the cut-off set for tuberculous effusions. The pleural fluid adenosine deaminase
      levels were significantly higher in different types of exudative effusions than
      in transudates. An adenosine deaminase level < 40 IU x L(-1) virtually excluded a
      diagnosis of tuberculosis in lymphocytic pleural effusions. Adenosine
      deaminase1/adenosine deaminase(p) correctly classified all nontuberculous
      lymphocytic pleural effusions with high adenosine deaminase levels.

PMID- 12608434
TI  - Apoptosis of bronchoalveolar lavage lymphocytes in hypersensitivity pneumonitis.
AB  - The aim of this study was to look at the apoptosis of alveolar lymphocytes in
      hypersensitivity pneumonitis (HP). HP patients and normal unexposed controls were
      studied. The percentage of apoptotic lymphocytes was significantly lower in HP
      patients than in normal patients (37.4 +/- 3.4 versus 56.5 +/- 5.5% for Annexin V
      and propidium iodine detection methods and 0.4 +/- 0.1 versus 1.0 +/- 0.2% for
      dUTP nick end-labelling technique (TUNEL)). The proportion of bronchoalveolar
      lavage (BAL) lymphocytes positive for Fas antigen was significantly higher in HP
      patients than in normal subjects (71.7 +/- 5.4 versus 50.4 +/- 9.0%). However, no
      significant difference was found in the proportion of BAL lymphocytes positive
      for Fas ligand (FasL) between the two groups. Soluble Fas (sFas) levels in the
      BAL fluid of the patients and normals were 80.5 +/- 8.5 pg x mL(-1) and 23.2 +/-
      3.1 pg x mL(-1), respectively. A positive correlation was found between the
      percentage of BAL lymphocytes and the levels of sFas for the total subjects but
      not within the separate study groups. The intracellular quantity of the inducible
      anti-apoptotic gene Bcl-xL product was significantly higher in the pulmonary
      lymphocytes of HP patients than in lymphocytes of the control, while no
      difference was found for constitutive anti-apoptotic protein (Bcl-2). In
      conclusion, the apoptosis of pulmonary lymphocytes is lower in hypersensitivity
      pneumonitis than in normal subjects. This could be explained, at least in part,
      by an increase of soluble Fas, the anti-apoptic gene, and Bcl-xL.

PMID- 12608436
TI  - Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and
      baroreflex.
AB  - This study was undertaken to determine whether abolition of obstructive sleep
      apnoea (OSA) by continuous positive airway pressure (CPAP) could reduce blood
      pressure (BP) in patients with refractory hypertension. In 11 refractory
      hypertensive patients with OSA, the acute effects of CPAP on nocturnal BP were
      studied during sleep and its longer term effects on 24-h ambulatory BP after 2
      months. During a single night's application, CPAP abolished OSA and reduced
      systolic BP in stage 2 sleep from 138.3 +/- 6.8 to 126.0 +/- 6.3 mmHg. There was
      also a trend towards a reduction in average diastolic BP (from 77.7 +/- 4.5 to
      72.9 +/- 4.5). CPAP usage for 2 months was accompanied by an 11.0 +/- 4.4 mmHg
      reduction in 24-h systolic BP. In addition, both the nocturnal and daytime
      components of systolic BP fell significantly by 14.4 +/- 4.4 and 9.3 +/- 3.9
      mmHg, respectively. Diastolic BP was reduced significantly at night by 7.8 +/-
      3.0 mmHg. In patients with refractory hypertension, acute abolition of
      obstructive sleep apnoea by continuous positive airway pressure reduces nocturnal
      blood pressure. These data also suggest that continuous positive airway pressure
      may reduce nocturnal and daytime systolic blood pressure chronically. Randomised
      trials are needed to confirm the latter results.

PMID- 12608435
TI  - Oxidative stress in lung epithelial cells from patients with idiopathic
      interstitial pneumonias.
AB  - Lung epithelial cells are a primary target for reactive oxygen species (ROS). ROS
      can cause oxidative deoxyribonucleic acid modification, such as 8-hydroxy
      deoxyguanosine (8-OHdG). A human homologue of the MutT protein (hMTH1) prevents
      this modification. Mitochondria are the most important cellular source of ROS and
      may be susceptible to oxidative damage. The purpose of this study is to
      investigate oxidative stress and mitochondrial damage in lung epithelial cells
      from idiopathic interstitial pneumonias (IIPs). The authors analysed 8-OHdG,
      hMTH1, and mitochondrial proteins on lung specimens from 13 patients with IlPs
      consisted of eight patients with usual interstitial pneumonia and five patients
      with nonspecific interstitial pneumonia using Western blot analysis and
      immunohistochemistry. Immunoreactivity for 8-OHdG and hMTH1 was significantly
      increased in the lung epithelial cells from patients with IIPs compared with
      controls. The expression of hMTH1 was localised in the nuclear and cytoplasmic,
      but not the mitochondrial, fraction of lung homogenates. Immunoreactivity for
      mitochondrial protein and cytochrome c oxidase complex subunit IV was increased
      in the lung epithelial cells from patients with IIPs compared with controls. The
      current study concludes that oxidative stress may participate in epithelial cell
      damage in idiopathic interstitial pneumonia, and that increased mitochondrial
      mass may associate with increased reactive oxygen species production in
      idiopathic interstitial pneumonia.

PMID- 12608437
TI  - High Mallampati score and nasal obstruction are associated risk factors for
      obstructive sleep apnoea.
AB  - Induced nasal obstruction can cause obstructive apnoeas in healthy subjects
      during sleep, but the relationship between nasal resistance measured during
      wakefulness and obstructive sleep apnoea syndrome (OSAS) is weak. It was
      postulated that if the subjects could not breathe through the nose, the oral
      airway must be used, but if this airway is narrowed as well, then it could
      precipitate sleep-disordered breathing (SDB). Nasal patency, Mallampati score
      (MS), neck circumference and body mass index were measured in 202 subjects
      referred to the authors' hospital to undergo a full-night polysomnography for
      suspicion of SDB. A significant correlation was found between the MS and
      apnoea/hypopnoea index measured during sleep. However, the relationship between
      these parameters was only significant in patients with nasal obstruction. The
      relative risk of having OSAS with a MS of III or IV was 1.95 for the whole group
      and 2.45 in patients with nasal obstruction. In conclusion, a high Mallampati
      score represents a predisposing factor for obstructive sleep apnoea syndrome,
      especially if it is associated with nasal obstruction. These patients merit
      special attention from both the sleep physician and the anaesthetist.

PMID- 12608439
TI  - Inhaled corticosteroids and survival in chronic obstructive pulmonary disease:
      does the dose matter?
AB  - Recent data suggest that inhaled corticosteroids reduce the number of clinical
      exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown
      whether a dose/response relationship exists. The present study was conducted to
      evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD
      mortality. Hospital discharge data were used to identify all patients aged > or =
      65 yrs recently hospitalised due to COPD in Alberta, Canada (n = 6,740). The
      relative risk (RR) for all-cause mortality was compared across different dose
      categories of inhaled corticosteroids (none and low, medium and high doses)
      following hospital discharge. Inhaled corticosteroid therapy after discharge was
      associated with a 25% relative reduction in risk for all-cause mortality (RR
      0.75, 95% confidence interval (CI) 0.68-0.82). Patients on medium- or high-dose
      therapy showed lower risks for mortality than those on low doses (RR 0.77, 95% CI
      0.69-0.86 for low dose; RR 0.48, 95% CI 0.37-0.63 for medium dose; and RR 0.55,
      95% CI 0.44-0.69 for high dose). Use of inhaled corticosteroids following
      hospital discharge for chronic obstructive pulmonary disease was associated with
      a significant reduction in the overall mortality rate. Low- was inferior to
      medium- or high-dose therapy in protecting against mortality in chronic
      obstructive pulmonary disease.

PMID- 12608438
TI  - Evaluation of a portable device for diagnosing the sleep apnoea/hypopnoea
      syndrome.
AB  - Waiting times for hospital-based monitoring of the obstructive sleep
      apnoea/hypopnoea syndrome (OSAHS) are rising. This study tested whether Embletta,
      a new portable device, may accurately diagnose OSAHS at home. A synchronous
      comparison to polysomnography was performed in 40 patients and a comparison of
      home Embletta studies with in-laboratory polysomnography was performed in 61
      patients. In the synchronous study, the mean difference (polysomnography
      Embletta) in apnoeas+hypopnoeas (A+H) x h(-1) in bed was 2 h(-1). In comparison
      to the apnoea/ hypopnoea index (AHI) x h(-1) slept, the Embletta (A+H) x h(-1) in
      bed differed by 8 x h(-1). These data were used to construct diagnostic
      categories in symptomatic patients from their Embletta results: "OSAHS" (> or =
      20 (A+H) x h(-1) in bed), "possible OSAHS" (10-20 (A+H) x h(-1) in bed) or "not
      OSAHS" (<10 (A+H) x h(-1) in bed). In the home study, the mean difference in
      (A+H) x h(-1) in bed was 3 x h(-1). In comparison to the polysomnographic AHI x
      h(-1) slept, the Embletta (A+H) x h(-1) in bed differed by 6 +/- 14 x h(-1).
      Using the above classification, all nine patients categorised as not OSAHS had
      AHI < 15 x h(-1) slept on polysomnography and all 23 with OSAHS on Embletta had
      an AHI > or = 15 on polysomnography, but 18 patients fell into the possible OSAHS
      category potentially requiring further investigation and 11 home studies failed.
      Most patients were satisfactorily classified by home Embletta studies but 29 out
      of 61 required further investigation. The study suggested a 42% saving in
      diagnostic costs over polysomnography if this approach were adopted.

PMID- 12608440
TI  - Minimal important difference of the transition dyspnoea index in a multinational
      clinical trial.
AB  - Dyspnoea is a primary symptom of chronic obstructive pulmonary disease (COPD).
      The baseline (BDI) and transition (TDI) dyspnoea indices are commonly used
      instruments to assess breathlessness and the impact of intervention. Its validity
      and pattern of response in multinational clinical trials has not been
      established. In a retrospective analysis of a cohort of 997 COPD patients who
      received tiotropium, salmeterol or placebo, in addition to usual care, the
      validity and pattern of response of the BDI and TDI were examined. The BDI was
      significantly correlated with the dyspnoea diary (DD) score and the symptom and
      activity components of the St. George's respiratory questionnaire (SGRQ),
      establishing concurrent validity. Furthermore, the TDI was also correlated with
      the changes in DD, SGRQ symptom and activity scores. Construct validity was
      established by the association between baseline forced expiratory volume in one
      second (FEV1) and BDI and AFEVI with TDI. Physician's global evaluation (PGE) was
      significantly associated with BDI as well as APGE with TDI. Significant
      correlations have also been observed when the cohorts were classified according
      to native English and native non-English speaking countries. A change in PGE of 1
      category (i.e. 2 units on an 8-point scale) was associated with a mean TDI of
      approximately 1 unit (0.9-1.3 mean focal score), lending further support to the
      clinical significance of this change inherent in the instrument's descriptors.
      TDI responders (i.e. focal score < or = 1 unit) used less supplemental
      salbutamol, had fewer exacerbations and had significantly improved health status
      as measured by impacts and total SGRQ scores compared with nonresponders. In
      conclusion, the transition dyspnoea index is a valid instrument when used in a
      multinational clinical trial and the patterns of response confirm a 1-unit change
      in the transition dyspnoea index focal score as being clinically important.

PMID- 12608441
TI  - In vitro and in vivo contractile properties of the vastus lateralis muscle in
      males with COPD.
AB  - Peripheral muscle weakness is common in chronic obstructive pulmonary disease
      (COPD) but it is still under debate whether weakness is due to atrophy or
      contractile dysfunction. In vitro and in vivo contractile properties of the
      vastus lateralis muscle were studied in 16 patients with stable COPD (forced
      expiratory volume in one second 39 +/- 16% of predicted, age 67 +/- 4 yrs (mean
      +/- sD)) and nine sedentary control subjects. Isometric knee extensor strength
      was measured while mid-thigh muscle cross-sectional area (MTMCSA) was obtained
      using computed tomography. Muscle strips from the vastus lateralis obtained
      through open biopsy were rapidly suspended in an oxygenated Krebs-Ringer solution
      that was maintained at 35 degrees C with a pH of 7.40 to study their contractile
      properties. The isometric knee extensors strength/MTMCSA ratio was 0.50 +/- 0.08
      versus 0.58 +/- 0.06 kg x cm(-2) for COPD and control subjects, respectively. The
      muscle bundle cross-sectional area (CSA) was 4.6 +/- 2.1 and 4.4 +/- 3.1 mm(-2),
      the length at which active tension was maximum was 15 +/- 4 and 15 +/- 3 mm, and
      maximal isometric peak forces normalised for CSA were 4.3 +/- 2.7 and 4.8 +/- 2.6
      N x cm(-2) for COPD and control subjects, respectively. The force/frequency
      relationship tended to be shifted to the right in patients with COPD, meaning
      that a higher stimulation frequency was necessary to produce the same relative
      force. Patients with COPD had a lower proportion of type I fibre than controls
      (26 +/- 12% versus 39 +/- 11%) with reciprocal significant increase in type IIb
      fibre proportion (20+/-16% versus 8 +/- 4%). The proportion of type IIa fibres
      was similar between the two groups. These results suggest that the contractile
      properties of the vastus lateralis are preserved in patients with chronic
      obstructive pulmonary disease. Therefore, the reduction in the quadriceps
      strength in patients with chronic obstructive pulmonary disease cannot be
      explained on the basis of an alteration of the contractile apparatus.

PMID- 12608442
TI  - Validity and interpretation of mortality, health service and survey data on COPD
      and asthma in England.
AB  - The comparability of asthma and chronic obstructive pulmonary disease (COPD)
      epidemiology in different English routine data sources was examined to explore
      their use and validity in investigating environmental influences on respiratory
      health. National data were obtained for mortality, emergency hospital admissions,
      general practitioner contacts and symptoms in the early 1990s. Age/sex patterns,
      seasonal variations and regional and urban/rural age/sex standardised event
      ratios were examined. Spearman rank correlations were used to describe
      consistency of regional rankings across data sets. Asthma showed inconsistent
      disease patterns in different data sources and weak correlations for regional
      rankings but COPD was notably consistent. Unmeasured confounders may partly
      explain the findings, but individual level adjustment for social class and
      smoking (possible for symptoms) only partially attenuated the higher COPD rates
      in northern and urban areas and did not affect findings for asthma. When
      epidemiological patterns are consistent across data sources as with chronic
      obstructive pulmonary disease in England, healthcare use is likely to reflect the
      underlying prevalence and severity of disease and can be used to study
      environmental influences. When patterns vary, as with asthma, the validity of the
      data in relation to its intended use must be carefully considered.

PMID- 12608443
TI  - The effects of Mycobacterium vaccae on allergen-induced airway responses in
      atopic asthma.
AB  - T-helper (Th)2 cytokines play a central role in asthma. Therefore, a double-blind
      randomised study was conducted to investigate whether heat-killed Mycobacterium
      vaccae (SRL172), a potent downregulator of Th2 cytokines, can reduce allergen
      induced airway responses in patients with atopic asthma. A total 24 male
      asthmatics participated in this study. A bronchial allergen challenge was
      performed along with early (EAR) and late asthmatic responses (LAR) 2 weeks
      before and 3 weeks after a single intradermal injection of SRL172 or placebo.
      Before and after treatment, serum immunoglobulin (Ig)E levels and in vitro
      production of interleukin (IL)-5 by peripheral blood lymphocytes were studied.
      Neither treatment affected the EAR. SRL172 caused a mean 34% reduction of the
      area under the curve of the forced expiratory volume in one second (FEV1) changes
      during the LAR, which failed to reach conventional statistical significance when
      compared with placebo. SRL172 also caused a mean 25% decrease in the maximum fall
      in FEV1 during LAR, but this was not significantly different from placebo. SRL172
      caused a reduction in serum IgE and IL-5 synthesis in vitro 3 weeks post
      treatment (p = 0.07). This study shows a trend toward significance for the
      effects of heat-killed Mycobacterium vaccae (SRL172) on allergen-induced airway
      responses. Further clinical trials, involving multiple dosing, are needed.

PMID- 12608444
TI  - Community-acquired pneumonia in the elderly: Spanish multicentre study.
AB  - Community-acquired pneumonia (CAP) in the elderly has increased as a consequence
      of an overall increase of the elderly population. A controversy about the
      aetiology and outcome of CAP in this population still exists and more
      epidemiological studies are needed. A prospective, 12-month, multicentre study
      was carried out to assess the clinical characteristics, aetiology, evolution and
      prognostic factors of elderly patients (> or = 65 yrs) admitted to hospital for
      CAP. The study included 503 patients (age 76 +/- 7 yrs). The clinical picture
      lasted < or = 5 days in 318 (63%) and the main clinical features were cough (n =
      407, 81%) and fever (n = 380, 76%). Aetiological diagnosis was achieved in 199
      (40%) cases, with a definite diagnosis obtained in 164 (33%). Of the 223
      microorganisms isolated the main agents found were Streptococcus pneumoniae in 98
      (49%) and Haemophilus influenzae in 27 (14%). A total of 53 patients died (11%)
      and the multivariate analysis showed the following factors of bad prognosis:
      previous bed confinement, alteration in mental status, absence of chills, plasma
      creatinine > or = 1.4 mg x dL(-1), oxygen tension in arterial blood/inspiratorv
      oxygen fraction ratio < 200 at the time of admission, and shock and renal failure
      during the evolution. The results of this study may aid in the management of
      empiric antibiotic treatment in elderly patients with community-acquired
      pneumonia and the patients who have a greater probability of bad evolution may be
      identified based on the risk factors.

PMID- 12608445
TI  - A nosocomial outbreak of influenza during a period without influenza epidemic
      activity.
AB  - The objective of this study was to describe a nosocomial outbreak of influenza
      during a period without influenza epidemic activity in the community. Outbreak
      investigation was carried out in an infectious diseases ward of a tertiary
      hospital. Presence of two or more of the following symptoms were used to define
      influenza: cough, sore throat, myalgia and fever. Epidemiological survey, direct
      immunofluorescence, viral culture, polymerase chain reaction, haemagglutination
      inhibition test in throat swabs and serology for respiratory viruses were
      performed. Twenty-nine of 57 healthcare workers (HCW) (51%) and eight of 23
      hospitalised patients (34%) fulfilled the case definition. Sixteen HCW (55%) and
      three inpatients (37%) had a definitive diagnosis of influenza A virus infection
      (subtype H1N1). Among the symptomatic HCW, 93% had not been vaccinated against
      influenza that season. Affected inpatients were isolated and admissions in the
      ward were cancelled for 2 weeks. Symptomatic HCW were sent home for 1 week. On
      the seventeenth day of the outbreak the last case was declared. The incidence of
      cases in this outbreak of influenza, which occurred during a period without
      influenza epidemic activity in the community, was notably high. Epidemiological
      data suggest transmission from healthcare workers to inpatients. Most healthcare
      workers were not vaccinated against influenza. Vaccination programmes should be
      reinforced among healthcare workers.

PMID- 12608446
TI  - Hypertonic saline increases secretory and exudative responsiveness of human nasal
      airway in vivo.
AB  - Hypertonic saline (HS) is used in sputum induction studies. However, little is
      known about the physiological effects of HS on human airways in vivo. The present
      study takes advantage of the fact that the airway effects of topical challenges
      may be accurately examined in the readily accessible nasal airway. The present
      study specifically examines whether exposure to HS affects histamine challenge
      induced exudation of plasma (alpha2-macroglobulin) and methacholine-induced
      secretion of mucin (fucose). Isotonic saline and HS (27 and 45 g x L(-1)), with
      and without concomitant histamine challenges, and with and without preceding
      methacholine challenges, were administered onto the nasal mucosa in 16 healthy
      subjects. Lavage fluid levels of alpha2-macroglobulin and fucose were analysed.
      Histamine produced a significant mucosal output of plasma (alpha2-macroglobulin).
      HS itself did not evoke exudation of alpha2-macroglobulin, but it significantly
      increased the plasma exudation effect of histamine. Methacholine produced a
      significant nasal mucosal output of fucose. HS also increased the mucin secretion
      (fucose), and it enhanced the secretory effect of methacholine. The authors
      concluded that hypertonic saline alone evokes mucinous secretion in human nasal
      airways in vivo and that it also enhances the exudative and secretory effects of
      histamine and methacholine, respectively. Through different mechanisms the HS
      exposure may also improve the recovery of soluble indices in human nasal airways.
      Whether or not the present findings are translatable to human bronchial airways
      remains to be examined.

PMID- 12608447
TI  - The relationship between water vapour saturation of inhaled air and nasal
      patency.
AB  - The nasal cavity volume and the temperature of the nasal mucosa are considered to
      be the most important predictors of nasal conditioning. The aim of this study was
      to assess the relationship between the intranasal degree of water vapour
      saturation of inhaled air and nasal patency. Intranasal humidity values at
      different locations within the nasal cavity of 15 healthy subjects were compared
      to nasal airway resistance detected by active anterior rhinomanometry (AAR).
      Repeated measurements were carried out during one day to obtain varying nasal
      cavity volumes due to the nasal cycle. The end-inspiratory humidity data were
      obtained with a miniaturised capacitive humidity sensor at defined detection
      sites within the anterior nasal segment without interruption of nasal breathing.
      Measurements were carried out at four different times during one day. The degree
      of water vapour saturation did not correlate with the values of the AAR at any
      intranasal detection site and time of detection during one day. The study
      supports the view that there is no correlation between the degree of water vapour
      saturation within the anterior nasal segment and the nasal resistance during the
      nasal cycle over the day. Although nasal patency varies because of the nasal
      cycle, the changes of nasal cavity volume due to the nasal cycle do not seem to
      influence the degree of water vapour saturation of the inspiratory air.

PMID- 12608448
TI  - Mould exposure at home relates to inflammatory markers in blood.
AB  - Living in damp buildings has been associated with airway symptoms, suspected to
      be due to inflammatory reactions. The relationship between home exposure to mould
      and signs of inflammation was, therefore, studied. Nonsmoking subjects with a
      high (G-high, > 4.0 ng x m(-3), n = 17) or low (G-low, < 2.0 ng x m(-3), n = 18)
      amount of airborne beta(1 --> 3)-D-glucan, an indicator of mould biomass, in the
      home were recruited. Blood samples were analysed for granulocytic enzymes, T-cell
      subsets and the secretion of cytokines from in vitro incubated peripheral blood
      mononuclear cells (PBMCs). In the G-high group, the proportion of cytotoxic T
      cells (CD8+S6F1+) was lower and secretion of tumour necrosis factor-alpha from
      PBMCs higher than in the G-low group. There were no significant differences in
      secretion of interferon gamma and interleukin (IL)-4 from PBMCs between the two
      groups. Among nonatopic subjects, the ratio between interferon gamma and IL-4 was
      significantly higher in the G-high group than in the G-low group and was related
      to the amount of beta(1 --> 3)-D-glucan in the home. No significant differences
      were found regarding secretion of IL-10 or IL-Ibeta from PBMCs, eosinophil
      cationic protein or myeloperoxidase in serum, or differential cell counts in
      blood. The effects found on inflammatory markers in relation to beta(1 --> 3)-D
      glucan in the home suggest upregulation of some parts of the
      inflammatory/immunological system due to mould exposure.

PMID- 12608449
TI  - Region-related risk factors for respiratory symptoms in European and Californian
      farmers.
AB  - The aim of this study was to determine the prevalences and regional risk factors
      for respiratory symptoms in European and Californian farmers. Farmers
      participating in the 1993-1997 surveys performed in Europe (n = 7,188) and
      California (n = 1,839) were included in this cross-sectional study. Respiratory
      symptoms and farming characteristics were assessed by questionnaire and risk
      factors associated with symptoms using logistic regression. The prevalences of
      rhinitis and asthma were lower in European (12.7% and 2.8%) than in Californian
      farmers (23.9% and 4.7%), but chronic bronchitis and toxic pneumonitis were more
      prevalent in Europe (10.7% and 12.2%) than in California (4.41% and 2.7%).
      Respiratory symptoms were associated with poultry and rabbit farming, flower
      growing and the cultivation of grain and oil plants. Working in Europe was a
      statistically significant risk factor for chronic bronchitis and toxic
      pneumonitis. Chronic bronchitis was related to toxic pneumonitis, work inside
      confinement buildings and greenhouses. Chronic bronchitis and toxic pneumonitis
      are highly prevalent among European farmers and are mainly attributable to indoor
      work.

PMID- 12608450
TI  - Occupational and nonoccupational factors associated with high grade bronchial pre
      invasive lesions.
AB  - Besides tobacco exposure, factors associated with the development of pre-invasive
      bronchial lesions are not known. Autofluorescence bronchoscopy was used to assess
      the prevalence of severe dysplasia and carcinoma in situ (SD/CIS) of the proximal
      bronchial tree in relation to occupational or nonoccupational carcinogen
      exposure. Among the 241 individuals in this study, the overall prevalence of at
      least one SD/CIS was 9% (21 subjects). Multivariable analysis revealed
      significant and independent associations between presence of SD/CIS and: 1)
      active smoking, relative to former smokers; 2) presence of synchronous invasive
      lung cancer; 3) duration of asbestos exposure and; 4) exposure to other
      occupational carcinogens. The independent associations of synchronous lung cancer
      with severe dysplasia and carcinoma, after adjusting for both occupational and
      nonoccupational carcinogen exposures, suggest other mechanisms than a field
      cancerisation may be involved in the carcinogenesis of these pre-invasive
      lesions. Moreover, active smokers, patients with recently resected invasive lung
      cancer and workers occupationally exposed to bronchial carcinogens may represent
      a population of choice for early cancer endoscopic detection programmes in view
      of their high severe dysplasia and carcinoma prevalence.

PMID- 12608451
TI  - Extracts of lung cancer cells reveal antitumour antibodies in sera of patients
      with lung cancer.
AB  - The objective of the present study was to reveal antitumour antibodies in sera of
      patients with small cell lung cancer (SCLC). The antibodies in sera of patients
      with SCLC and other tumours were detected by immunoblotting with whole extracts
      of SCLC cells as the antigen source. Sera of patients with various pulmonological
      disorders, irradiated during the liquidation of consequences of the Chernobyl
      nuclear power plant incident (a high-risk group in lung cancer), were also
      analysed. The present authors' found that SCLC sera contain a set (pattern) of
      antitumour antibodies which are rarely detected in sera of patients with cancers
      different from SCLC and very rarely, if ever, present in sera of healthy
      individuals. The sensitivity and the specificity of the pattern are equal to 80%
      and 91%, correspondingly. In the high-risk group in lung cancer, the frequencies
      of the antibodies are somewhat lower than the corresponding values in SCLC sera,
      but significantly larger than those in healthy sera. The findings of the present
      study create a basis for clinical application of the antitumour antibodies
      described.

PMID- 12608452
TI  - Systemic effects of chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is characterised by an
      inappropriate/excessive inflammatory response of the lungs to respiratory
      pollutants, mainly tobacco smoking. Recently, besides the typical pulmonary
      pathology of COPD (i.e. chronic bronchitis and emphysema), several effects
      occurring outside the lungs have been described, the so-called systemic effects
      of COPD. These effects are clinically relevant because they modify and can help
      in the classification and management of the disease. The present review discusses
      the following systemic effects of chronic obstructive pulmonary disease: 1)
      systemic inflammation; 2) nutritional abnormalities and weight loss; 3) skeletal
      muscle dysfunction; and 4) other potential systemic effects. For each of these,
      the potential mechanisms and clinical implications are discussed and areas
      requiring further research are highlighted.

PMID- 12608453
TI  - Tularaemia.
AB  - Tularaemia is a zoonotic bacterial disease of the Northern hemisphere. The
      causative agent, Francisella tularensis, is spread to humans by direct contact
      with infected rodents or lagomorphs, aerogenic exposure, ingestion of
      contaminated food or water, or by arthropod bites. The prevalence of tularaemia
      shows a wide geographic variation. In some endemic regions, outbreaks occur
      frequently, whereas nearby rural parts of a country may be completely free. F.
      tularensis is a facultative intracellular pathogen and its primary mammalian
      target cell is the mononuclear phagocyte. When tularaemia is acquired via the
      skin, a primary ulcer is often detected and in general, regional lymph nodes
      become prominently enlarged. When contracted by inhalation, the disease may
      present with pneumonia. Nearly as frequent, however, is the development of fever
      and general illness with no respiratory symptoms and no pulmonary radiological
      changes. When present, the changes vary widely and may sometimes include hilar
      enlargement indistinguishable from that of lymphoma. Within an outbreak, the
      first case of tularaemia is not always readily diagnosed. A decade may have
      lapsed since the disease was encountered and its existence may be more or less
      forgotten. The difficulty refers especially to the respiratory form, in which
      symptoms are less specific. In cases of atypical pneumonia or acute febrile
      disease with no local symptoms, a history of exposure to hares or rodents or
      merely living in an endemic region should be sufficient to include tularaemia
      among differential diagnoses. The microbiological diagnosis of tularaemia relies
      mainly on serology, and the treatment on broad-spectrum antibiotics. For decades,
      a live vaccine has been successfully used in risk groups but is presently not
      available due to difficulties in standardisation.

PMID- 12608454
TI  - eThrombosis: the 21st century variant of venous thromboembolism associated with
      immobility.
AB  - The association between immobility with prolonged sitting and venous
      thromboembolism has been recognised for > 60 yrs, most recently with long
      distance air travel. The case of a 32-yr-old male, in whom immobility associated
      with sitting for long periods at a computer represented the major provoking risk
      factor for his life-threatening venous thromboembolism, is presented. The authors
      propose the term "eThrombosis" to describe this 21st Century variant of venous
      thromboembolism associated with immobility from prolonged sitting. In view of the
      widespread use of computers in relation to work, recreation and personal
      communication, the potential burden of eThrombosis may be considerable.

PMID- 12608455
TI  - Neither questions nor answers, just original data.

PMID- 12608456
TI  - Muscle weakness after short course of steroids.

PMID- 12608457
TI  - Helicobacter pylori and bleeding peptic ulcer: what is the prevalence of the
      infection in patients with this complication?

PMID- 12608458
TI  - Synthesis and localization of pancreatic secretory proteins in pancreatic acinar
      like metaplasia in the distal part of the oesophagus. Pancreatic acinar
      metaplasia: another source of pancreatic enzymes!
AB  - BACKGROUND: Pancreatic acinar-like metaplasia has previously been described in
      the gastric mucosa and in the distal part of the oesophagus. The resemblance to
      pancreatic acinar cells prompted us to study the possible occurrence of secretory
      pancreatic proteins in these cells. METHODS: Seven specimens obtained from the
      distal oesophagus at gastroscopy where routine microscopy showed pancreatic
      acinar-like metaplasia were selected for this study. Sections were subjected to
      immunohistochemical detection of trypsinogen, pancreatic elastase,
      procarboxypeptidase B and pancreatic secretory trypsin inhibitor using specific
      antisera. An alkaline-phosphatase-conjugated oligodeoxynucleotide probe,
      complementary to the transcript for trypsinogen 2 (anionic) was used for in situ
      hybridization. RESULTS: Cells with pancreatic acinar-like metaplasia were
      immunoreactive to all pancreatic secretory proteins studied. In situ
      hybridization showed the presence of trypsinogen 2 mRNA in pancreatic acinar-like
      metaplasia. The pancreatic proteins were not seen in other cells in the distal
      oesophagus. CONCLUSION: Pancreatic acinar-like metaplasia is common in the distal
      oesophagus and pancreatic secretory proteins, including trypsininogen 2, are
      produced in the oesophageal metaplastic acinar cells. The biological significance
      of this finding has yet not been thoroughly studied.

PMID- 12608459
TI  - Cell kinetics of the oesophageal epithelium in the rat: effects of
      hypergastrinaemia.
AB  - BACKGROUND: Hypergastrinaemia stimulates cell proliferation in the oesophageal
      epithelium of the rat. In the present study, we tested whether hypergastrinaemia
      also affected cell turnover time and structure of the oesophageal epithelium.
      METHODS: Seventy-two female adult Sprague-Dawley rats, divided into 12 equal
      groups, were given 3H-thymidine by infusion/injection. Groups 1-6 were control
      rats, groups 7-9 were provided with a minipump releasing synthetic rat gastrin
      17, and groups 10-12 were given injections of omeprazole twice daily. The rats in
      the control groups were killed after 1 h, and after 1, 6, 9, 17 or 25 days. The
      rats given gastrin or omeprazole were killed after 1, 6 or 9 days. Tissue samples
      of oesophagus were processed for light microscopic autoradiography and the
      labelling index (LI) was calculated. Morphometric data of the oesophageal
      epithelium were also obtained, as well as plasma gastrin concentrations. RESULTS:
      LI in the control rats increased continuously up to 9 days when about 90% of the
      cells were labelled. Extrapolation indicates a mean cell turnover time of 10.4 +/
      0.58 days. Plasma gastrin levels were significantly elevated in the rats given
      gastrin or omeprazole. In these animals, average cell turnover times were reduced
      to 9.1 +/- 0.11 and 9.4 +/- 0.18 days, respectively, and the epithelium was
      almost 20% thinner than in the controls. Moreover, in the gastrin-treated rats
      the number of epithelial cells/mm was decreased by almost 20%. CONCLUSION:
      Hypergastrinaemia reduces cell turnover time in rat oesophageal epithelium. This
      is independent of stimulation of acid secretion. The concomitant epithelial
      hypotrophy may be explained by a premature shedding of the epithelial cells or by
      acceleration of cell maturation.

PMID- 12608460
TI  - The course of Helicobacter pylori infection in kidney transplantation patients.
AB  - BACKGROUND: Helicobacter pylori has been found to be only a minor risk factor for
      gastroduodenal complications in kidney transplantation patients. The aim of the
      study was to follow up the course of H. pylori infection in a group of
      immunosuppressed kidney transplantation patients. METHODS: After a median follow
      up of 6.8 years, control serum samples were taken from 93 originally seropositive
      and 88 originally seronegative kidney transplant recipients. H. pylori antibodies
      of the IgG and IgA classes and serum pepsinogen I levels were measured from
      pretransplant and follow-up samples in parallel. In addition, CagA antibodies
      were measured from the baseline samples of the seropositive patients. RESULTS: 83
      of the 93 seropositive patients were also cagA-positive. In addition to the 10
      patients who received H. pylori eradication therapy, 27 (29%) of the 92 patients
      with originally elevated H. pylori IgG antibody titres showed IgG titres at
      normal level or levels decreased by more than 70% and below 2000 (regarded as
      seroreverters) after the follow-up. One of the originally seronegative patients
      seroconverted during the study period. After transplantation, the decrease of
      serum pepsinogen I values was in accordance with improved kidney function.
      Patients with lower serum pepsinogen I levels before the transplantation
      seroreverted more easily. CONCLUSIONS: A spontaneous H. pylori seroreversion
      occurred in 29% of the immunosuppressed kidney transplantation patients. After a
      successful kidney transplantation, serum pepsinogen I values declined
      significantly.

PMID- 12608461
TI  - Controlled mechanical distension of the human oesophagus: sensory and
      biomechanical findings.
AB  - BACKGROUND: The relation between mechanical distension of the gut and the sensory
      response is poorly understood. The current experimental study aimed to examine
      the sensory response in the human oesophagus during on-line recording of the
      luminal pressure, cross-sectional area (CSA) and sensory rating using different
      distension rates before and during relaxation of the smooth muscle. METHODS: An
      impedance planimetric probe for bag distension of the oesophagus was used in 13
      healthy subjects aged 43 +/- 15 years. Ramp distensions were done with an
      electromechanical pump using infusion rates of 10, 25 and 50 ml/min, with and
      without relaxation of the smooth muscle with butylscopolamine. The sensory
      intensity was measured using a 0-10 visual analogue scale (VAS), with 5 as the
      pain threshold. The pump was reversed at 8 on the scale, corresponding to medium
      pain intensity, and the pressure, volume, tension and CSA were evaluated.
      Finally, three isovolumetric experiments where the CSA was held constant for 2
      min at initial VAS ratings of 3, 5 and 7 were performed. RESULTS: A total of 104
      distension profiles were investigated. The volume at maximal pain intensity (VAS
      = 8) increased as a function of the distension rate (P < 0.001), whereas the
      pressure, tension and CSA were not affected. When the smooth muscle was relaxed,
      there was a 29% fall in pressure at maximal pain intensity (P = 0.004), a 27%
      fall in tension (P = 0.003), whereas CSA did not change (P = 0.3). When the
      pressure was recorded as a function of the sensory intensity, there was an
      exponential increase after the pain threshold was reached, whereas the stimulus
      response functions for tension, volume and CSA were nearly linear. In the
      isovolumetric experiments the ratings during the three sensory intensities were
      the same in the individual subjects, but the between-individual pain response was
      variable, probably reflecting individual differences in adaptation/central
      integration. CONCLUSIONS: The study allowed us to assess the strain-rate
      dependency of both perception and biomechanical properties in the oesophagus. It
      was demonstrated that the pain response was related to the CSA (and hence
      strain), independently of the contractile state of the muscle and biomechanical
      behaviour of the tissue. The findings support the fact that the pain-sensitive
      mechanoreceptors in the human oesophagus depend on circumferential wall stretch
      rather than on pressure, tension and volume. The model should be used in future
      studies to investigate whether changes in strain are responsible for the
      oesophageal sensation in health and disease.

PMID- 12608462
TI  - Gender differences in gut transit shown with a newly developed radiological
      procedure.
AB  - BACKGROUND: Gut transit measurements are essential for understanding the
      pathophysiology of many gastrointestinal disorders. The ideal bowel transit test
      should be easy to perform, widely accessible, reproducible, non-invasive and
      inexpensive and the risks should be minimal. These requirements prompted us to
      develop a procedure for simultaneous measurement of gastric emptying, small-bowel
      transit and colonic transit at one visit. We assessed the influence of gender,
      body mass index, age, menopause and smoking on gastrointestinal transit in
      healthy subjects. METHODS: Eighty-three healthy subjects (43 women) were
      included. Colonic transit was based on 10 radiopaque rings given daily for 6 days
      with fluoroscopy on day 7. Then, the subjects had a test meal containing 20
      radiopaque markers. Using fluoroscopy, gastric emptying and small-bowel transit
      of the markers were followed until they reached the colon. RESULTS: Gastric
      emptying, small-bowel transit and colonic transit were significantly slower in
      female healthy subjects compared to males (2.9 (1.6-4.9) h, median and percentile
      10-90, versus 2.4 (0.7-3.7) h, P=0.005; 4.4 (2.1-11.1) h versus 3.2 (1.5-6.0) h,
      P=0.001; 1.5 (1.0-3.7) days versus 1.3 (0.8-1.9) days P=0.002), respectively.
      Small-bowel transit was significantly faster in women with overweight and in
      postmenopausal women compared to lean and premenopausal women, respectively.
      CONCLUSION: This procedure meets most of the requirements of the ideal bowel
      transit test and is easily performed at one visit. Small-bowel transit as well as
      gastric emptying and colonic transit were significantly slower for women.

PMID- 12608463
TI  - Effects of non-steroidal anti-inflammatory drugs on the methotrexate transport in
      rat small intestine.
AB  - BACKGROUND: Methotrexate (MTX) is used in the treatment of rheumatic disease,
      sometimes along with non-steroidal anti-inflammatory drugs (NSAIDs), and is
      actively co-transported with H+ in the small intestine, mediated by a reduced
      folate carrier (RFC). The co-administration of NSAIDs with MTX might cause a
      decrease in MTX absorption through the small intestine, since some NSAIDs are
      uncouplers of oxidative phosphorylation. The present study investigates whether
      flufenamic acid, diclofenac and indomethacin, NSAIDs, decrease the ATP content of
      small intestinal epithelial cells and affect MTX transport (the secondary active
      transport) in the small intestine. METHODS: MTX transport was examined in the
      presence and absence of the NSAIDs, using the everted intestine technique and
      brush border membrane vesicles (BBMVs) from the rat small intestine. The change
      in physical properties of the membrane was studied in BBMVs using the
      fluorescence techniques. RESULTS: MTX absorption in the small intestine with H+
      gradient (mucosal side, pH 6.0; serosal side, pH 7.4) decreased in the presence
      of the NSAIDs, but absorption without H+ gradient (both sides, pH 7.4) was
      unaffected. The intestinal mucosal ATP content decreased in the presence of the
      NSAIDs. The uptake of MTX in BBMVs was unaffected by the NSAIDs. The activity of
      intestinal Na+-K+-ATPase was enhanced in the presence of the NSAIDs. The
      fluorescence measurements showed that membrane fluidity, membrane potential and
      membrane hydrophobicity of BBMVs were unaffected by the NSAIDs. CONCLUSIONS:
      NSAIDs decreased the H+/MTX absorption in the small intestine, but not the
      passive transport. The uncoupling effect of the NSAIDs decreased the ATP content
      in the small intestine, resulting in inhibition of the secondary active
      transport.

PMID- 12608464
TI  - High rate of positive anti-tissue transglutaminase antibodies in chronic liver
      disease. Role of liver decompensation and of the antigen source.
AB  - BACKGROUND: Since the recognition of tissue transglutaminase (tTG) as the target
      antigen of anti-endomysium antibodies, several ELISA assays using either guinea
      pig or human recombinant tTG have been developed. The aim of the study was to
      compare the behaviour of anti-tTG and anti-endomysium antibodies assays in
      coeliacs and in patients with chronic liver disease. METHODS: 34 patients (24
      women, 34.9 +/- 12.5 years) with coeliac disease and 41 with chronic liver
      disease (14 women, 57 +/- 11.2 years), including 19 cirrhotics, were evaluated
      for anti-endomysium antibodies by indirect immunofluorescence and for anti-tTG
      IgA antibodies by ELISA, using guinea pig liver or human recombinant
      transglutaminase. RESULTS: The prevalences of anti-tTG and anti-endomysium
      antibodies were 100% in patients with coeliac disease at diagnosis, 75% and 64.3%
      in patients on a gluten-free diet. All liver disease patients were negative for
      anti-endomysium antibodies, while 11 (26.8%) were positive for anti-tTG. All
      these patients had liver cirrhosis and represented 57.9% of all cirrhotics. The
      presence of anti-tTG was associated with higher Child-Pugh scores. The use of
      human transglutaminase determined a reduction in the rate of positive results;
      however, the rate of positive anti-tTG was still 17.1% in all liver disease
      patients and 31.6% in cirrhotics. CONCLUSIONS: Our data confirm that anti-tTG
      have a similar sensitivity compared with anti-endomysium antibodies assay in
      coeliacs. However, a high prevalence of positive anti-tTG results is observed in
      cirrhotic patients, even when human recombinant tTG is used. The high prevalence
      of positive results among cirrhotic patients is associated with more advanced
      liver disease.

PMID- 12608465
TI  - Increase in nitric oxide urinary products during gluten challenge in children
      with coeliac disease.
AB  - BACKGROUND: Coeliac disease is a gluten-sensitive enteropathy where pro
      inflammatory cytokines and excess nitric oxide (NO) production can contribute to
      mucosal damage. NO urinary products are elevated in coeliac children on a gluten
      diet, but it is not known how rapidly this increase develops after gluten
      exposure. METHODS: Oral gluten challenge was performed in 25 children whose
      families kept a daily record of gluten intake and symptoms. Blood was analysed
      monthly for antigliadin (AGA) and endomysium antibodies (EMA). Urine was analysed
      every second week for NO products, i.e. the sum of nitrite and nitrate was
      measured with a colorimetric method. We performed a third biopsy when clinical
      symptoms indicated a relapse. Median age at the post-challenge biopsy was 3.8
      (2.7-8.8) years. RESULTS: Signs of morphological or serological relapse were seen
      in all children. Mean daily gluten intake was 0.10 (range 0.02-0.26) g/kg
      bodyweight. Median NO level was doubled and significantly higher after 4 weeks of
      challenge but not after 2 weeks. EMA, but not AGA levels, correlated positively
      with NO. Intraepithelial lymphocyte count was significantly higher in the post
      challenge biopsy, but did not correlate with the NO levels. CONCLUSIONS: NO
      products in urine increased during gluten challenge. EMA levels reflected
      severity of mucosal damage, and NO products reflected the inflammatory response,
      which was doubled after 4 weeks of challenge. The NO analysis is simple and non
      traumatic for the child. It can be performed repeatedly during investigation of
      children with suspected coeliac disease.

PMID- 12608466
TI  - Familial prevalence of coeliac disease: a twenty-year follow-up study.
AB  - BACKGROUND: The genetic predisposition of coeliac disease (CD) is well known.
      Previous studies of first-degree relatives of coeliac patients have shown that as
      many as 10% have the disease. In 1981, we published a study in which all first
      degree relatives of 32 index patients with CD were investigated by small-bowel
      biopsy. We found 2 relatives (2%) with CD. The present study is a re
      investigation of all first-degree relatives of the same index patients performed
      20-25 years after the first study to reveal any new cases of CD in this high-risk
      population. METHODS: All 120 first-degree relatives were screened for CD by means
      of serological markers of CD. The relatives with positive markers were submitted
      to small-bowel biopsy. RESULTS: Eight new cases of CD were found among the
      relatives. Two had been investigated by small-bowel biopsy 20 years previously,
      when they had only minor mucosal changes not classified as CD. The other six new
      cases of CD were found among offspring of the index patients and were born after
      completion of the previous study. Thus no new case of CD was found among those
      relatives who had a completely normal small-bowel biopsy 20-25 years previously.
      CONCLUSIONS: The high prevalence of CD among first-degree relatives of coeliac
      patients (8.3% in this study) supports the need to screen for CD in this high
      risk population. Even relatives with only mild enteropathy should be followed
      carefully, since some may subsequently develop CD.

PMID- 12608467
TI  - Luminal nitric oxide and epithelial expression of inducible and endothelial
      nitric oxide synthase in collagenous and lymphocytic colitis.
AB  - BACKGROUND: Colonic nitric oxide (NO) production in collagenous colitis (CC) has
      been studied in a small number of patients and found increased. The cellular
      source of NO is believed to be the colonic epithelial cells. The aim of this
      study was to investigate colonic NO levels in patients with CC and lymphocytic
      colitis (LC), to compare with the histopathological status and with the clinical
      activity, and to assess the epithelial expression of inducible and endothelial
      nitric oxide synthase (iNOS and eNOS). METHODS: We included 19 patients with CC,
      8 patients with LC and 15 controls. During colonoscopy, luminal gas was sampled
      and NO levels were measured using the chemiluminescence technique. Mucosal
      biopsies were obtained for routine histopathologic examination and
      immunohistochemical studies of iNOS and eNOS. Clinical activity, as measured by
      the mean frequency of daily bowel movements during the week prior to colonoscopy,
      was assessed. RESULTS: Luminal NO levels, median (25-75 percentiles), in the
      patients with CC and LC were greatly increased compared to the controls, 1673
      (145-8143) parts per billion (ppb) and 1838 (1065-2694) ppb versus 28 (20-46) ppb
      (P < 0.005, both). A positive association was seen between NO levels and
      histopathological status as well as clinical activity. Strong expression of iNOS
      was seen in the surface epithelium in 5 of 6 patients with CC and in 2 of 5
      patients with LC. CONCLUSIONS: The fact that luminal NO levels are related to
      histopathological status and correlate with clinical activity indicates that NO
      is involved in the pathophysiology of CC and LC. The epithelial cells are the
      most likely source of luminal NO.

PMID- 12608468
TI  - Biological activity of Desulfovibrio desulfuricans lipopolysaccharides evaluated
      via interleukin-8 secretion by Caco-2 cells.
AB  - BACKGROUND: Although Desulfovibrio desulfuricans species, besides existing in the
      natural environment, is also found in the human digestive tract, no information
      is currently available on its role in the intestinal ecosystem and its activity
      in regard to the intestinal mucosa. Bacterial products (lipopolysaccharides,
      LPSs) are generally known for their ability to trigger inflammatory response by
      stimulating cytokine expression, such as interleukin-8 (IL-8). METHODS: Colonic
      Caco-2 cells were exposed to LPSs isolated from the soil type and intestinal wild
      strains of D. desulfuricans bacteria. The amount of IL-8 secreted was measured by
      ELISA. The effects of sodium butyrate and cell preincubation with sodium butyrate
      on the IL-8 secretion in response to LPSs were also analysed. RESULTS: LPSs from
      D. desulfuricans down-regulated IL-8 secretion by the cells. Incubation of these
      cells with butyrate alone resulted in a dose-dependent stimulation of IL-8
      release. Butyrate also modulated IL-8 secretion by cells stimulated with LPSs.
      CONCLUSIONS: Our findings suggest the lack of inflammatory response of intestinal
      mucosa in the presence of LPSs of D. desulfuricans. This response can be
      conditioned by the natural bacterial product, butyrate, which exerts a
      stimulatory effect on the IL-8 secretion and modulates its release in response to
      LPSs.

PMID- 12608469
TI  - Increased farnesyltransferase activity in human colorectal cancer: relationship
      with clinicopathological features and K-ras mutation.
AB  - BACKGROUND: The enzyme farnesyltransferase has emerged as an important target for
      anti-cancer therapies. Farnesyltransferase inhibitors have been introduced in
      clinical trials of subjects with colorectal cancer. We investigated
      Farnesyltransferase activity, beta-subunit Farnesyltransferase protein expression
      and its mRNA in patients with colorectal cancer and its relationship with
      clinicopathological features and K-ras mutation. METHODS: Farnesyltransferase
      activity was determined by Farnesyltransferase [3H] SPA enzyme assay. Beta
      subunit Farnesyltransferase protein expression was investigated by Western
      blotting and its mRNA by reverse transcriptase-polymerase chain reaction. K-ras
      mutation was detected by polymerase chain reaction amplification and restriction
      enzyme analysis. Multiple linear regression analysis was used to analyse
      relationships among age, sex, site of tumour, Dukes' stage, histological
      differentiation, K-ras mutation and Farnesyltransferase activity in normal mucosa
      and cancer. RESULTS: The levels of Farnesyltransferase activity and beta-subunit
      Farnesyltransferase protein expression were significantly higher in cancer than
      in normal mucosa. Moreover, tumours located on the right side, with mucinous
      histological differentiation and with K-ras mutation showed higher levels of
      Farnesyltransferase activity. CONCLUSIONS: Our findings suggest that
      Farnesyltransferase activity may be a potential marker of tumourigenicity. The
      differences in Farnesyltransferase activity in relation to histological grading,
      tumour location and K-ras mutation described here may constitute a starting point
      for investigating the causes of this variation within the large bowel.

PMID- 12608470
TI  - Severe jaundice in Sweden in the new millennium: causes, investigations,
      treatment and prognosis.
AB  - BACKGROUND: The aims of the study were to assess the causes of jaundice in
      Gothenburg, Sweden, to study the types of investigations applied in cholestatic
      and hepatocellular types of jaundice and treatment and to evaluate the prognosis
      of these patients up to a year from the diagnosis. METHODS: Over a 3-month
      period, all adult patients with bilirubin > 100 micromol/l were identified by the
      clinical chemistry laboratory serving all three hospitals in Gothenburg. Relevant
      clinical information was obtained from medical records. Follow-up was performed 9
      12 months later. RESULTS: A total of 173 patients were identified; 40% were under
      surgical care while 38% were in the care of internists. The most common cause of
      jaundice was malignancy in 58 patients, liver metastases in 20,
      cholangiocarcinoma in 16, pancreatic cancer in 13, cancer of papilla Vateri in 2
      and primary liver cancer in 7. Alcoholic liver disease was the second most common
      cause, found in 29 patients, followed by bile duct stones (28 patients). Only 3%
      had viral hepatitis. Ultrasound and/or CT were performed in 95% of those with
      cholestasis and ultrasound had been performed in 75% of those with hepatocellular
      type and CT in almost 50%. Thirty-two patients were operated on, 27 patients were
      treated endoscopically and 17 patients required liver transplantation. Total
      mortality was 51% and in malignancy 82%. CONCLUSION: Malignancy and alcoholic
      liver disease are the most common causes of severe jaundice, whereas viral
      hepatitis is a rare cause. Many patients are under surgical care, probably due to
      historical reasons as surgery is rarely indicated.

PMID- 12608471
TI  - Prevalence and clinical implications of hepatitis B virus genotypes in southern
      Taiwan.
AB  - BACKGROUND: Hepatitis B virus (HBV) infection is a major health problem. HBV
      genotypes may be associated with progression of liver disease. The distribution
      and clinical implications of HBV genotypes in southern Taiwan are evaluated.
      METHODS: We used a polymerase chain reaction-restriction fragment length
      polymorphism genotyping method to determine HBV genotypes. RESULTS: The genotype
      distribution for 265 patients with chronic HBV infection was as follows: A, 3
      (1%); B, 158 (60%); C, 90 (34%); D, 7 (2.5%); E, 0: F, 0; and unclassified, 7
      (2.5%). Compared with genotype B patients, genotype C patients had a higher
      hepatitis B e antigen positive rate and higher fibrosis score. There was no
      significant difference in the mean age between genotype B and genotype C patients
      with hepatocellular carcinoma (HCC). However, when patients were stratified by
      age, the prevalence of genotype C was significantly higher in young HCC patients
      (<50 years of age) than in age-matched asymptomatic carriers (40% versus 10%, P <
      0.001). Using multivariate analysis, the significant risk factors for advanced
      liver disease (cirrhosis or HCC) for patients with chronic HBV infection were old
      age, male gender and genotype C. CONCLUSIONS: These results suggest that genotype
      C is associated with more severe liver diseases than the B variant.

PMID- 12608472
TI  - Aetiology and prognostic implication of severe jaundice in surgical trauma
      patients.
AB  - BACKGROUND: Pronounced postoperative jaundice occurs not infrequently in trauma
      patients. The aim of this study was to elucidate the implication of early,
      pronounced jaundice (serum-bilirubin >100 micromol x l(-1)) for 30-day survival
      of such patients. METHODS: From 1995 through 2001, 53 surgical trauma patients
      developing pronounced postoperative jaundice were identified. Nine were excluded
      from the study because of major hepatobiliary injury or pre-existing liver
      disease. The clinical course and laboratory chemistry profiles of the remaining
      44 patients were analysed. RESULTS: Thirty-one patients survived and 13 died
      within 30 days of trauma. Non-survivors had higher age, higher injury severity
      score (ISS) and lower probability of survival (PS) (P < 0.05) than survivors. ISS
      averaged 34 in survivors and 45 in non-survivors. Survivors and non-survivors
      received a mean of 46 (range 10-97) and 55 units of blood (range 11-128),
      respectively (P = 0.366). Systemic hypotension, local infections and sepsis were
      common in both groups. Bilirubin levels peaked around the 11th day in survivors
      (median 189 micromol x l(-1)). In non-survivors, serum bilirubin values rose
      progressively, reaching maximum levels at time of death (median 231 micromol x l(
      1)). These patients died in a setting of sepsis and multiple organ failure.
      CONCLUSION: Large endogenous production of bilirubin because of rapid breakdown
      of transfused and extravasated blood can cause pronounced jaundice in
      multitransfused trauma patients. In such patients, serum bilirubin rising >100
      micromol x l(-1) does not by itself signal poor outcome. However, progressive
      pronounced jaundice outlasting the trauma incident by 10-12 days portends fatal
      outcome for the patient.

PMID- 12608473
TI  - Diagnostic yield in a biennial Hemoccult-II screening program compared to a once
      only screening with flexible sigmoidoscopy and Hemoccult-II.
AB  - BACKGROUND: Flexible sigmoidoscopy (FS) has a higher degree of sensitivity for
      detecting colorectal neoplasia in the left side of the colon than Hemoccult (H
      II). However, no randomized controlled trial has compared a single FS screening
      with a H-II screening program (annual or biennial) despite the well-documented
      mortality reduction from colorectal cancer (CRC) in the latter. The aim was to
      compare the diagnostic yield of colorectal neoplasia in two aged-matched groups
      from two different randomized screening trials; one group screened by a single
      FS+H-II, the other with biennial H-II over the course of 16 years. METHODS:
      24,465 persons invited to participate in the Funen biennial H-II screening
      program were compared with 4,460 similar persons invited to another Funen trial
      using a single FS+H-II. RESULTS: Compliance in the biennial H-II program was
      65.5% during the first screening round compared to 39.8% for FS+H-II. The
      cumulative number of persons with positive tests was 8.2% (positive H-II) in the
      biennial H-II program during 16 years and 20.3% (polyps > 3 mm in diameter seen
      at FS or positive H-II) for once-only FS+H-II. The diagnostic yield of CRC per
      1,000 screened was 9.9 in the biennial H-II program and 6.6 after FS+H-II (6.5
      and 2.7 per 1,000 invited). The yield of advanced adenomas (> or = 10 mm and/or
      villous structure and/or severe dysplasia) was 2.3% in the H-II program and 3.3%
      after FS+H-II among the screened persons, but this difference disappeared when
      persons invited, but not necessarily screened, were compared (1.5% versus 1.3%).
      CONCLUSION: Screening with H-II in a biennial screening program during 16 years
      detected more CRCs than a single screening with FS+H-II and a similar number of
      advanced adenomas.

PMID- 12608474
TI  - Acute CMV-colitis in a patient with a history of ulcerative colitis.
AB  - A symptomatic cytomegalovirus (CMV) infection usually occurs in patients with
      debilitating diseases, immunosuppression, transplantations and acquired
      immunodeficiency syndrome (AIDS). Gastrointestinal infections with CMV,
      especially colitis, are usually found in immunocompromised patients and rarely
      affect immunocompetent subjects. Here we report the case of a young female
      patient with a history of ulcerative colitis (UC) who presented with an acute
      attack of colitis caused by CMV infection. This was documented by the presence of
      CMV early antigen, antibodies and evidence of CMV in the colonic mucosa. After
      combined anti-inflammatory and antiviral treatment the patient recovered
      completely. As most attention is given to CMV-pathogeneity in immunocompromised
      patients, here we discuss the relationship to inflammatory bowel diseases.

PMID- 12608475
TI  - Internal hernia presenting as obstructive jaundice.

PMID- 12608476
TI  - Haemorrhage from multiple duodenal Dieulafoy lesions or angiodysplasia?

PMID- 12608478
TI  - DSM-IV alcohol and substance abuse and dependence in homeless youth.
AB  - OBJECTIVE: The purpose of this study is to describe endorsement rates of
      substance use criteria among homeless adolescents and to evaluate the reliability
      of diagnostic formulations among a group of adolescents who use more frequently
      and more heavily than other samples of adolescents. METHOD: Substance use rates
      and DSM-IV abuse and dependence criteria were assessed among 198 (109 male)
      homeless youths between the ages of 13 and 19, as part of a larger study.
      Endorsement rates and reliability analyses were completed for diagnostic criteria
      assessed for alcohol, marijuana, amphetamines and heroin. RESULTS: Consistent
      with other studies of homeless youth, data revealed high rates of substance use
      and high rates of substance dependence. Both dependence and abuse diagnoses were
      associated with greater rates of use. DSM-IV criteria showed acceptable internal
      reliability, although variability was observed when applied to different
      substances. Of the drugs assessed, problems with heroin use appeared to be best,
      and marijuana use least, represented by dependence criteria. Criteria pertaining
      to continued use despite interference with role obligations and the experience of
      craving were consistently related to other dependence criteria. CONCLUSIONS: DSM
      IV substance dependence criteria appear to have good internal reliability within
      a sample of adolescents who use at extremely high rates. Continued development of
      diagnostic systems for adolescent substance use should consider the social
      context of use, differential patterns of symptoms across different substances and
      the inclusion of additional criteria found reliable among adolescent samples.

PMID- 12608479
TI  - Patterns of alcohol use among Australian secondary students: results of a 1999
      prevalence study and comparisons with earlier years.
AB  - OBJECTIVE: This study was initiated to estimate the prevalence of alcohol use
      among Australian secondary students in 1999 and to examine changes in that
      prevalence over a 15-year period between 1984 and 1999. METHOD: A randomly
      selected representative sample of approximately 400 secondary schools across
      Australia participated in the study. At each school, up to 80 randomly selected
      students completed a pencil-and-paper questionnaire anonymously. RESULTS: The use
      of alcohol by secondary students was widespread in 1999. By the age of 15, 44% of
      boys and 36% of girls had consumed alcohol in the week before the survey. Among
      16 and 17 year olds, about 50% had consumed alcohol in this time period. Of 16
      and 17 year olds who had consumed alcohol in the past week, around 35% had drunk
      at hazardous levels. Long-term trends in alcohol use showed declines during the
      late 1980s but increases through the 1990s. While the proportion of hazardous
      drinkers among 12-15 year olds had not changed throughout the 1990s, the
      proportion among 16 and 17 year olds had increased over the period of the survey.
      The proportion of current drinkers buying the last alcoholic drink consumed had
      decreased since 1987, although there was no change between 1996 and 1999 among 16
      and 17 year olds. CONCLUSIONS: Alcohol is widely used by secondary students in
      Australia, and significant proportions of the student population drink at
      hazardous levels.

PMID- 12608480
TI  - Age of first intoxication, heavy drinking, driving after drinking and risk of
      unintentional injury among U.S. college students.
AB  - OBJECTIVES: This study explored whether college students who were first
      intoxicated by alcohol at ages younger than 19 are more likely to become alcohol
      dependent and frequent heavy drinkers, drive after drinking, ride with
      intoxicated drivers and be injured after drinking. It also investigated whether
      these results occur because these students believe they can drink more and still
      drive legally and safely. METHOD: In 1999, 14,138 of 23,751 full-time 4-year
      students from a random sample of 119 college and universities nationwide
      completed self-administered questionnaires (response rate: 60%). This analysis
      focused on 12,550 who were aged 19 or older. Respondents were asked the age at
      which they first got drunk, as well as questions about recent alcohol-related
      behaviors and consequences. RESULTS: Compared with respondents first drunk at age
      19 or older, those first drunk prior to age 19 were significantly more likely to
      be alcohol dependent and frequent heavy drinkers, to report driving after any
      drinking, driving after five or more drinks, riding with a driver who was high or
      drunk and, after drinking, sustaining injuries that required medical attention.
      Respondents first intoxicated at younger ages believed they could consume more
      drinks and still drive safely and legally; this contributed to their greater
      likelihood of driving after drinking and riding with high or drunk drivers.
      CONCLUSIONS: Educational, clinical, environmental and legal interventions are
      needed to delay age of first intoxication and to correct misperceptions among
      adolescents first drunk at an early age about how much they can drink and still
      drive safely and legally.

PMID- 12608481
TI  - Alcohol involvement and developmental task completion during young adulthood.
AB  - OBJECTIVE: Relations among young adult alcohol use disorders (AUDs), preadulthood
      variables (gender, family history of alcoholism, childhood stressors, high-school
      class rank, religious involvement, neuroticism, extraversion, psychoticism) and
      young adult developmental tasks (baccalaureate degree completion, full-time
      employment, marriage) were evaluated. METHOD: Participants were 424 first-time
      college students (228 women) who were 18-20 years old; approximately half had a
      history of paternal alcoholism. Participants were assessed on five occasions over
      7 years (Years 1, 2, 3, 4 and 7). RESULTS: Structural equation modeling results
      suggest preadulthood variables were more salient predictors of developmental
      tasks than AUD diagnoses, with the majority of effects due to apparent selection
      processes. In addition, marriage protected against later AUD diagnosis at Year 7.
      CONCLUSIONS: Findings highlight the importance of prospective multivariate models
      that specify potential selection, causation, socialization and reciprocal effects
      in order to fully examine complex relations among variables, including alcohol
      involvement, during major life-transition periods.

PMID- 12608482
TI  - College attendance and risk-related driving behavior in a national sample of
      young adults.
AB  - OBJECTIVE: This study examined and sought to explain the relationship between
      college attendance and indicators of risk-related driving (drinking and driving,
      seatbelt use) among young adults who participated in the 1999 National Household
      Survey on Drug Abuse (NHSDA). METHOD: In-home interview data collected from
      11,549 18-25 year olds were analyzed to examine the relationship between full- or
      part-time college status, drinking and driving and seatbelt use. Logistic
      regression analyses were conducted to determine whether full- or part-time
      college attendance would be associated with drinking and driving and seatbelt use
      when adjusting for demographics and age of onset of alcohol use, and whether
      these relationships would be explained by place of residence (e.g., dormitory),
      psychosocial factors (e.g., propensity for risk taking, disapproval of driving
      after drinking) and past-month heavy drinking. RESULTS: The prevalence of
      drinking and driving in the past year was highest for full-time college students
      (34.2%), followed by part-time students (32.8%) and other young adults (27.9%).
      Full-time students were also more likely to report always wearing a seatbelt as a
      driver (76.1%) or passenger (70.1%) than were part-time students (71.8%, 68.6%)
      and other young adults (62.7%, 56.7%). These relationships persisted when
      adjusting for demographic characteristics and age of onset of alcohol use. The
      higher level of drinking and driving among full-time students was partially
      explained by psychosocial factors and past-month heavy drinking, but the higher
      level of drinking and driving among part-time students was not explained by these
      variables. The higher levels of seatbelt use among full- and part-time college
      students were also not explained by place of residence, psychosocial factors or
      heavy drinking. CONCLUSIONS: College students are more likely than other young
      adults to drink and drive, but are also more likely to wear a seatbelt as a
      driver or passenger. This pattern of drinking and driving behavior may help to
      explain similar rates of fatal alcohol-related traffic crashes among college
      students and other young adults. Additional research is needed to better
      understand why college students are more likely to drink and drive and wear
      seatbelts than other young adults in the same age group.

PMID- 12608483
TI  - Considerations for more effective social norms based alcohol education on campus:
      an analysis of different theoretical conceptualizations in predicting drinking
      among fraternity men.
AB  - OBJECTIVE: Recent alcohol education campaigns targeting college students have
      focused on correcting the erroneous perception students have of the amount of
      alcohol their peers consume. This strategy is based on assumptions that college
      students overestimate the amount of alcohol their peers consume and that
      correcting that misperception will lessen the pressure they feel to consume
      heavily. However, other theoretical constructs of normative influence may be as
      or more valuable in improving effectiveness of social norms based education for
      high-risk college students. This study evaluates the effects of three social
      normative influence factors on alcohol consumption among fraternity men. METHOD:
      Participants were 379 members of randomly selected chapters from two large
      student fraternity organizations. We used hierarchical linear models to analyze
      the predictive value of normative influence variables in explaining alcohol
      consumption differences, both across individuals within chapters and across
      chapters. RESULTS: Perceived consumption norms and perceived subjective norms
      were significant predictors of alcohol consumption levels. Both normative
      influence variables are significant in predicting differences in consumption
      within chapters and across chapters of fraternity men. General approval of
      alcohol use did not account for significant variance within chapters in
      consumption or any unique variance in consumption between chapters. CONCLUSIONS:
      Perceived subjective norms as defined by long-standing behavior theory may
      provide an alternative and potentially more promising intervention target for
      this high-risk student population than does the current focus on correcting
      students' errors in estimating the amount of alcohol their peers consume.

PMID- 12608484
TI  - Rethinking positive and negative aspects of alcohol use: suggestions from a
      comparison of alcohol expectancies and decisional balance.
AB  - OBJECTIVE: Few studies have compared similar alcohol-related constructs such as
      alcohol expectancies and decisional balance: two conceptualizations of the
      positive and negative aspects of alcohol. The purpose of this study was to
      compare these constructs and to examine their ability to predict alcohol use and
      problems. METHOD: A sample of 406 college students recruited from Psychology
      courses at a mid-sized Northeastern University completed a questionnaire that
      included measures of alcohol expectancies, decisional balance, drinking indices
      and drinking problems. Of these students, N = 389 (73% female) were drinkers and
      were included in analyses. RESULTS: Positive expectancies (PE) and the pros were
      more related to one another than were negative expectancies (NE) and the cons.
      The 8-item pros scale outperformed 20 items measuring PE in the prediction of
      alcohol problems and performed equally well in the prediction of alcohol indices.
      The negative relationship of cons to alcohol indices, something not found with
      NE, suggested that the cons scale may include components important to the
      measurement of negative aspects of alcohol. CONCLUSIONS: Although expectancies,
      particularly PE, have been a common choice for use by researchers, these data
      suggest that decisional balance scales may be a better choice because their
      predictive ability is equal to or better than that of expectancies, and their
      response burden on participants is lower. Instruments that aim to measure the
      negative aspects of alcohol use should include severe and distal items to better
      capture this negative attitudinal domain.

PMID- 12608485
TI  - The average ethanol content of beer in the U.S. and individual states: estimates
      for use in aggregate consumption statistics.
AB  - OBJECTIVE: The purpose of this study is to describe the variation in the ethanol
      content of beer and specific categories of beer, and to illustrate the importance
      of accurate assessment of ethanol conversion factors for the calculation of
      apparent ethanol consumption from beer at the state and national levels in the
      U.S. METHOD: Published sources of brand-level ethanol content, national brand
      share of beer categories and state beer category market shares are utilized to
      (1) estimate the mean ethanol content of each beer category in the U.S. for 1995
      and 2000, (2) calculate per capita apparent consumption of ethanol from beer for
      1995 and 2000 and for each state in 2000 and (3) describe trends in ethanol
      content for specific beer brands during the 1990s. RESULTS: The mean ethanol
      content of beer in the U.S. is found to increase from 4.33% (by volume) in 1995
      to 4.66% in 2000. Using these estimates, per capita ethanol from beer is found to
      increase from 1.386 gallons in 1995 to 1.468 gallons in 2000. Use of a constant
      ethanol conversion, however, indicates a decrease. Application of ethanol content
      estimates to state-level per capita consumption for 2000 changes the relative
      rankings of 28 states, compared to the use of a constant 4.5% ethanol conversion.
      CONCLUSIONS: Improved ethanol conversion factor estimates are found to influence
      both time trends and the cross-sectional ranking of states, suggesting that
      analyses of both cross-sectional and time series aggregate ethanol consumption
      data that fail to consider variation in the ethanol content of beer may be
      biased.

PMID- 12608486
TI  - Distribution and dose response of laboratory markers to alcohol consumption in a
      general population: results of the study of health in Pomerania (SHIP).
AB  - OBJECTIVE: Biomarker distributions must be well known for use as screening tools
      for hazardous alcohol consumption in general populations. The aim of this study
      was to investigate characteristics of carbohydrate-deficient transferrin (CDT)
      and to compare it with gamma-glutamyltransferase (GGT) and erythrocyte mean
      corpuscular volume (MCV) in regard to distribution in the general population; the
      dose response relationship between alcohol consumption and biomarkers; and the
      effect of gender, age, body mass index (BMI) and smoking. METHOD: In a cross
      sectional health survey in northeast Germany (1997-2001), a sample of 7,008 men
      and women aged 20-79 years was drawn, following stratification by age and gender.
      Of this sample, 4,310 subjects (2,193 women) took part in the study. Alcohol
      consumption was evaluated by self-reports with a beverage specific quantity
      frequency method. RESULTS: Biomarker distributions differ across age and gender.
      The distribution of drinkers and nondrinking subjects showed considerable
      overlap. The association of alcohol consumption to laboratory markers is weak in
      the general population: strongest for GGT, followed by CDT and MCV For CDT and
      MCV it is weaker in women than in men. We found increasing risk of all three
      elevated marker values with increasing alcohol consumption and significant
      effects of age, gender, smoking and body mass index on the alcohol-biomarker dose
      response curve. CONCLUSIONS: When biomarkers are used for screening, all
      confounding effects have to be taken into account and adjusted normal ranges must
      be used. CDT shows no overall advantage over GGT. Low correlation of biomarkers
      with alcohol consumption, their high variability and widely spread ranges in
      nondrinking subjects limit the usefulness of these markers in general population
      settings.

PMID- 12608487
TI  - Comparative and joint prediction of DUI recidivism from alcohol ignition
      interlock and driver records.
AB  - OBJECTIVE: This work was conducted to find practical predictors that anticipate
      which driving under the influence (DUI) offenders will continue to drink and
      drive after a period of alcohol ignition interlock-controlled driving ends. The
      interlock prevents impaired driving by requiring a low blood alcohol
      concentration (BAC) breath sample before allowing an engine to start. Each breath
      test is recorded. The study evaluated the interlock record as a predictor of
      future DUI offenses relative to driver records and self-report items. METHOD:
      Subjects were 2,273 DUI offenders in Alberta, Canada, who used an interlock to
      gain full reinstatement of driving privileges; for 2,134, the installed periods
      ranged from 5 to 30 months. A median of 8.1 breath tests was logged for each
      installed day; 9.9 tests were taken on each day of vehicle use (4.3 starts plus
      5.6 running retests). Predictors of postinterlock repeat DUI were compared by
      sensitivity and survival analyses. RESULTS: Although 69% of all interlock users
      had at least one BAC test > or = .04% (a "fail" test) within the first 5 months,
      only 9% were reconvicted up to 4 years after interlock removal. Failed interlock
      tests proportional to all BAC tests taken was the best predictor of driver
      recidivism risk during the years following interlock removal. CONCLUSION: The
      interlock record provides new information, particularly about drivers with no
      prior DUI offenses. Prior moving violations and driving while suspended
      convictions, although better predictors than questionnaire data, were poorer than
      interlock records and prior DUI offenses. The alcohol interlock, already
      recognized as a useful control device, warrants attention for DUI prediction as
      well.

PMID- 12608488
TI  - The effects of alcohol on driving-related sensorimotor performance across four
      times of day.
AB  - OBJECTIVE: The effect of alcohol on driving-related tracking tasks at four times
      of day was examined to address concerns that the legal driving alcohol threshold
      in New Zealand (80 mg/dl blood) may have greater effects during the early
      afternoon and early morning than during the evening and midmorning. METHOD: A
      volunteer group of 16 male army personnel provided a homogenous sample with
      respect to time-of-day characteristics. After a formal practice session, members
      of the sample performed lateral (one-dimensional) tracking tasks in eight
      counterbalanced sessions, either with or without alcohol (0.836 g/kg), at 0900,
      1300, 1800 and 0100 hours. The tasks varied in terms of smooth and ballistic
      motor pursuit, unpredictability and availability of target preview. RESULTS:
      Alcohol markedly impaired tracking accuracy (error from target), especially in
      nonpreview conditions. The only evidence for an overall time-of-day effect was on
      a ballistic pursuit nonpreview task, but there was no indication of any alcohol
      by time-of-day interactions. CONCLUSIONS: When tested 30 minutes after
      consumption of alcohol, sensorimotor tracking skills are markedly impaired at
      alcohol levels approaching the New Zealand threshold for legal driving, but these
      effects are not subject to circadian variations.

PMID- 12608489
TI  - The influence of Hispanic ethnicity on long-term outcome in three alcohol
      treatment modalities.
AB  - OBJECTIVE: Prior research has suggested that treatment-seeking Hispanic clients
      are not likely to affiliate with Alcoholics Anonymous (AA). It was hypothesized
      that AA 12-step facilitation therapy (TSF) would therefore be less effective than
      cognitive behavioral therapy (CBT) and motivational enhancement therapy (MET) for
      Hispanics, particularly for those with low acculturation. METHOD: Outcomes for
      non-Hispanic white (n = 105; 70% male) and Hispanic (n = 100; 80% male) clients
      at the New Mexico site within Project MATCH were analyzed for evidence of
      differential treatment response. A pretreatment measure of acculturation to non
      Hispanic white culture was available for 80 of the Hispanic clients. RESULTS:
      Self-identified ethnicity mediated treatment response at distal follow-up, as
      measured by frequency and intensity of alcohol consumption (p < .02). Hispanics
      drank with more intensity than did non-Hispanic whites when assigned to TSF; non
      Hispanic whites in TSF drank with less frequency than those in the combined CBT
      and MET conditions. The modest outcome advantage for TSF observed in Project
      MATCH appears to have been limited to non-Hispanic clients. Contrary to
      prediction, level of acculturation did not mediate treatment response at proximal
      (Months 1-6 after treatment) or distal follow-up (Months 7-12). CONCLUSIONS:
      Ethnic self-identification may interact with treatment outcomes in complex ways
      that are not directly associated with the factors tapped by commonly used
      measures of acculturation.

PMID- 12608491
TI  - The influence of alcohol on the activation of outcome expectancies: the role of
      evaluative expectancy activation in drinking behavior.
AB  - OBJECTIVE: Despite the well-established finding from questionnaire studies that
      positive expectancies are associated with drinking behavior, there is
      comparatively little known about the mechanisms through which they may affect
      drinking behavior. Incentive motivation models suggest that alcohol itself may
      alter the value of the expected outcomes of drinking. The current study was
      designed to examine the influence of low-dose alcohol on the activation of
      alcohol outcome expectancy value. METHOD: Forty-eight hazardous drinkers (34 men)
      between the ages of 21 and 35 years were recruited from advertisements in local
      newspapers for a social drinking study. Participants, whose most frequently
      consumed beverage was beer, were administered a dose of either alcoholic (8.5%)
      beer, based on gender and weight to reach a blood alcohol concentration of 40
      mg/dl, or an equivalent volume of placebo beer. Following an absorption phase, a
      computerized evaluative priming task was completed in which participants made a
      series of judgments about the value of positive and negative outcomes following
      either alcohol or neutral word primes. RESULTS: Those who consumed alcohol made
      faster evaluative responses to positive relative to negative outcomes, compared
      with individuals who consumed the placebo beverage. CONCLUSIONS: These findings
      suggest that moderate doses of alcohol may influence the incentive value of
      positive relative to negative outcome expectancies. It is suggested that these
      processes may play a role in patterns of hazardous alcohol use.

PMID- 12608490
TI  - Effects of self-administered ethanol or water preloads on appetitive and
      consummatory behavior in the alcohol-preferring (P) rat.
AB  - OBJECTIVE: Ethanol intake control in the selected alcohol-preferring lines of
      rats appeared to have shifted in some lines for both increased ethanol seeking
      and increased consumption once ethanol was available. It was unknown whether a
      small preload of ethanol would alter either the seeking or the consumption in a
      selected line. This study examined this issue. METHOD: Alcohol-preferring (P)
      rats from Indiana University School of Medicine were initiated to drink ethanol
      using a sucrose-substitution procedure and a single daily limited-access trial.
      Following 30 responses on a lever, a sipper tube containing 10% ethanol extended
      into the operant chamber for 20 minutes. Self-administered ethanol and water
      preloads were tested prior to either a regular session or an extinction session.
      In extinction sessions, no access to the sipper tube occurred, and the number of
      responses occurring during 20 minutes was taken as a measure of ethanol seeking.
      RESULTS: The ethanol and water preloads had no effect on the following ethanol
      consumption at any time during the experiment. However, the first two ethanol
      preloads significantly reduced extinction responding, which did not recover to
      the levels observed prior to the preload tests. CONCLUSIONS: The data support the
      conclusion that ethanol seeking in the P rat can be influenced by environmental
      history, whereas consummatory behavior appears to be under more explicit genetic
      control. This gene-environment interaction suggests that, in the P rat, seeking
      behavior, initially set at higher levels than observed for nonselected lines, can
      be modified by certain environmental experiences.

PMID- 12608492
TI  - Alcohol craving predicts drinking during treatment: an analysis of three
      assessment instruments.
AB  - OBJECTIVE: The purpose of this investigation was to examine the utility of thee
      craving instruments to predict drinking during treatment. The three assessments
      used were the Penn Alcohol Craving Scale (PACS), the Alcohol Urge Questionnaire
      (AUQ) and Items 1-6 of the Obsessive subscale (OBS) of the Obsessive Compulsive
      Drinking Scale (OCDS). METHOD: The three instruments were administered during the
      course of a 9-month, double-blind, placebo-controlled trial of 100 mg/day of
      naltrexone, and a manual-based psychosocial intervention using the BRENDA manual
      conducted at the University of Pennsylvania's Treatment Research Center.
      Participants (133 men and 50 women at the initiation of the study) used these
      instruments to self-report craving on a weekly or biweekly basis. The weekly
      number of drinks was reported using the Timeline Followback interview. The data
      were analyzed with generalized estimating equations using craving scores at 1
      week as the independent variable and number of drinks in the subsequent treatment
      week as the dependent variable. RESULTS: Each of the three scales predicted
      drinking during the subsequent treatment week. The PACS was the strongest
      predictor followed closely by the OBS and then the AUQ. Most important, craving
      as measured by the three scales was a stronger predictor of subsequent drinking
      than was drinking during the prior treatment week. CONCLUSIONS: Craving
      assessment provides a useful means of predicting drinking during treatment. Such
      information would be helpful in designing clinical trials and for many treatment
      modalities.

PMID- 12608493
TI  - An item response analysis of the Alcohol Dependence Scale in treatment-seeking
      alcoholics.
AB  - OBJECTIVE: In this study we use methods based on Item Response Theory to examine
      in depth the psychometric properties of the Alcohol Dependence Scale (ADS). In
      particular, we examine the ability of each ADS item to discriminate among
      individuals across the continuum of alcohol dependence severity and also examine
      the extent to which item-response options provide useful and reliable information
      about the level of alcohol dependence. METHOD: Participants were 166 alcohol
      dependent patients with elevated depressive symptoms. We conducted a maximum
      likelihood common factors analysis on the ADS, and then used a nonparametric
      kernel smoothing method to create Item Characteristic Curves (ICC) and Option
      Characteristic Curves (OCC) for each ADS item. On the basis of these curves, we
      identified items showing at least fair discrimination and modified the scoring of
      response options where indicated. We then created an empirically derived ADS
      score and correlated it with the original ADS and with other measures of alcohol
      involvement. RESULTS: Replicating previous studies, our results indicated a
      primarily unidimensional factor structure. A total of 12 of the 25 ADS items
      showed good discrimination, and examination of the OCC indicated that dichotomous
      scoring was most appropriate for these items. This 12-item abbreviation of the
      ADS was highly correlated with the original scale (r = 0.91), and showed similar
      patterns of correlations with other measures of alcohol involvement. CONCLUSIONS:
      Results suggest potential gains in measurement efficiency using methods based on
      Item Response Theory and indicate potential ordering of dependence symptoms based
      on item severities.

PMID- 12608494
TI  - Factors associated with partner violence among female alcoholic patients and
      their male partners.
AB  - OBJECTIVE: This study described the extent of partner violence victimization and
      perpetration among married or cohabiting female alcoholic patients and the
      factors associated with it. METHOD: Male-to-female and female-to-male physical
      partner violence were examined for 103 female alcoholic patients seeking couples
      based outpatient alcoholism treatment. Partner violent (PV) and nonpartner
      violent (NPV) groups were compared on hypothesized risk factors. RESULTS: In the
      year before treatment, about two thirds of the women were victimized by their
      male partners, and a similar proportion engaged in violence toward their male
      partners. Severe violence also was high, with 22% victimization and 50%
      perpetration prevalence. Women committed more violent acts overall and were more
      likely to commit severely violent acts than the men in these couples. Risk
      factors for PV in both the victimization and perpetration models were as
      predicted: less education, lower income, greater relationship problems, stronger
      beliefs in the link between relationship problems and the female patient's
      drinking, greater cocaine use by the perpetrator of violence and greater
      emotional distress of the men. Greater alcohol and drug use and more severe
      alcohol problems also distinguished male perpetrators from their nonviolent
      counterparts in the female victimization model. Predictions that female patients
      in the PV group would report greater substance use and problems, childhood
      violence exposure and emotional distress than their female counterparts in the
      NPV group were not supported for either victimization or perpetration models.
      CONCLUSIONS: Partner violence is a serious problem for women in alcoholism
      treatment. More research is needed to increase understanding of risk factors and
      explanatory models for such violence.

PMID- 12608495
TI  - Pathophysiology of anorexia.
AB  - A physiologic decline in food intake occurs with advancing age. The physiologic
      anorexia of aging and its associated weight loss predispose older persons to
      develop protein-energy malnutrition. In older persons a variety of social and
      psychologic factors, diseases, and medications can aggravate the physiologic
      anorexia and lead to severe weight loss. Many of these factors are amenable to
      treatment, resulting in a reversal of the underlying malnutrition. This article
      first reviews the physiologic factors responsible for anorexia in older persons.
      It then reviews the major pathologic processes responsible for producing protein
      energy malnutrition in older persons.

PMID- 12608496
TI  - Regulation of appetite in frail persons.
AB  - Aging is often accompanied by anorexia of aging, described as a decline in
      appetite resulting in a lower dietary intake, followed by unexplained weight loss
      and adverse effects on health. This article discusses the main causes of a lack
      of appetite in frail elderly people. It is clear that appreciation of hedonic
      qualities of foods declines with age, as does the ability to regulate food
      intake. Carefully controlled studies, however, have shown favorable results with
      interventions that stimulate appetite in, frail elderly people.

PMID- 12608497
TI  - Food intake in the real world: implications for nutrition and aging.
AB  - Nutrient intakes are affected by two classes of factors, physiological and
      environmental. In the real world, environmental variables such as social factors,
      palatability, and the time of eating appear to have large influences on amounts
      ingested in the short-term. Physiological control mechanisms also operate to
      regulate intake, and they induce compensatory responses to deviations from the
      norm. These physiological influences only appear to have weak influences on short
      term intake unless there are large deviations from the normal state, but over the
      long-term they act patiently and persistently to rectify the excesses produced by
      environmental fluctuations and thereby tend to maintain a relative balance
      between energy intake and expenditure. As individuals age there is a progressive
      decline in physiological function including the mechanisms that act to control
      intake in the young. This should not produce a problem in a healthy individual in
      a stable environment: however, if that situation should change due to illness or
      an environmental change such as the death of a spouse, which produces decline in
      intake, elderly individuals would not have the physiological mechanisms present
      to compensate. Thus, the deficit in energy intake would not be replaced, and the
      lower level of intake would be maintained as long as the new health condition or
      environment remains stable. Hence, the decline in the effectiveness of the
      physiological systems with age makes the elderly particularly vulnerable and
      unable to rebound from deficits. Although the elderly have difficulty
      compensating for deficits automatically by physiologically-induced adjustments,
      the studies of real world intake reviewed in this article suggest that
      compensation can be produced by adjustments to the environment. The elderly
      appear to be as responsive to environmental factors as younger individuals. In
      particular, they appear to increase intake in response to social facilitation,
      diurnal rhythms, the eating environment, and palatability to the same extent as
      their juniors. These data suggest that alterations in the social, temporal,
      environmental, or hedonic conditions of eating could induce desired alterations
      in the nutrient intakes of the elderly. The study of real world eating behavior
      has produced evidence that suggests that this strategy can work. It remains for
      future applied investigations to ascertain whether or not this strategy is
      effective in treating undernutrition in the elderly.

PMID- 12608498
TI  - Undernutrition in the European SENECA studies.
AB  - The SENECA study, which sampled a cohort of community-dwelling persons born
      between 1913 and 1918 in 12 European countries in baseline (1988), follow up
      (1993), and final (1999) surveys, found a relatively high risk of malnutrition
      despite a low prevalence of actual malnourishment. The results point out the
      importance of monitoring nutritional status in healthy elderly adults.

PMID- 12608499
TI  - Oral health, taste, and olfaction.
AB  - Oral health, taste, and smell are critical components to an older person's
      overall sense of well-being and quality of life. Oral health problems can cause
      pain and discomfort and can hinder the maintenance of a satisfying and nutritious
      diet. Loss of taste and smell interferes with pleasure derived from food and food
      related activities. Attention should be given to preserving teeth and optimizing
      oral function. Likewise, close evaluation of older adults' medications may
      identify the causes of taste and smell disorders. In instances in which nutrient
      intake is inadequate and chemosensory perception is considered a likely
      contributor, a trial of flavor enhancers or monosodium glutamate may improve both
      quality and quantity of intake. Much more information is needed to understand the
      interrelationship between chemosensory perception, food intake regulatory
      mechanisms, and nutritional status. Multidisciplinary studies will be required to
      understand how to improve nutrition through manipulation of oral characteristics,
      taste, and smell.

PMID- 12608500
TI  - Diagnosing undernutrition.
AB  - Because of its wide prevalence and its grave consequences on the health of older
      persons, malnutrition requires immediate attention. Physicians in general have
      been described as being nutritionally blind in their slowness to recognize
      undernutrition. A high degree of suspicion, a thorough history and physical
      examination, and pertinent laboratory data can identify patients at risk. When a
      more comprehensive assessment is needed; screening tools, dietary history, and
      special biochemical parameter can be used.

PMID- 12608501
TI  - Identifying the elderly at risk for malnutrition. The Mini Nutritional
      Assessment.
AB  - In more than 10,000 elderly persons, the mean prevalence of malnutrition is 1% in
      community-healthy elderly persons, 4% in outpatients receiving home care, 5% in
      patients with Alzheimer's disease living at home, 20% in hospitalized patients,
      and 37% in institutionalized elderly persons. In community-dwelling elderly
      persons, the MNA detects risk of malnutrition and life-style characteristics
      associated with nutritional risk while albumin levels and the BMI are still in
      the normal range. In outpatients and in hospitalized patients, the MNA is
      predictive of outcome and cost of care. In home care patients and nursing home
      residents, the MNA is related to living conditions, meal patterns, and chronic
      medical conditions and allows targeted intervention. The MNA has been used
      successfully in follow-up evaluation of outcome, nutritional intervention,
      nutritional education programs, and physical intervention programs in elderly
      persons. The MNA-SF allows quick screening to determine a person's risk of
      malnutrition. Early detection of malnutrition is important to allow targeted
      nutritional intervention and should be a key component of the geriatric
      assessment. The MNA test is a simple, noninvasive, well-validated screening tool
      for malnutrition in elderly persons and is recommended for early detection of
      risk of malnutrition. The MNA, as a two-step procedure (screening with the MNA-SF
      followed by assessment, if needed, by the full MNA), is reliable and can be
      easily administered by general practitioners and by health professionals at
      hospital or nursing home admission for early detection of risks of malnutrition.
      The MNA has the following characteristics: * The MNA is a two step procedure: (1)
      the MNA-SF to screen for malnutrition and risk of mainutrition; (2) assessment of
      nutritional status with the full MNA. * The MNA is an 18-item questionnaire
      comprising anthropometric measurements (BMI, mid-arm and calf circumference, and
      weight loss) combined with a questionnaire regarding dietary intake (number of
      meals consumed, food and fluid intake, and feeding autonomy), a global assessment
      (lifestyle, medication, mobility, presence of acute stress, and presence of
      dementia or depression), and a self-assessment (self-perception of health and
      nutrition). The MNA-SF comprises 6 items from the 18. * The MNA is well
      validated. It correlates highly with clinical assessment and objective indicators
      of nutritional status (albumin level, BMI, energy intake, and vitamin status). *
      A low MNA score can predict hospital-say outcomes in older patients and can be
      used to follow up changes in nutritional status. * Because of its validity in
      screening and assessing the risk of malnutrition, the MNA should be integrated in
      the comprehensive geriatric assessment. * In more than 10,000 elderly persons,
      the prevalence of undernutrition assessed by the MNA is 1% to 5% in community
      dwelling elderly persons and outpatients, 20% in hospitalized older patients, and
      37% in institutionalized elderly patients.

PMID- 12608502
TI  - Undernutrition in medical outpatients.
AB  - This article discusses the epidemiology, predisposing factors, and etiology of
      undernutrition in geriatric patients receiving ambulatory care. It presents the
      major aspects of the clinical evaluation of undernutrition in older adults.
      Interdisciplinary assessment of nutritional risk in the outpatient setting and
      the formulation of an outpatient nutritional intervention model are also
      discussed.

PMID- 12608503
TI  - Vitamin nutrition in older adults.
AB  - Proper vitamin nutrition is essential for all people but especially for elderly
      persons, because they are at higher risk for deficiency than younger adults. A
      review of the clinical effects of vitamin deficiency shows how easily deficiency
      can masquerade as other morbidities, such as skin, neurologic, and gait
      abnormalities. Given the numerous readily available forms and sources of
      supplementation, their low cost, and their rather limited potential for harm, the
      goal of good vitamin nutrition for the elderly is easily attainable. To be
      successful in this goal, physicians must look for patients at risk and for those
      with features of frank vitamin deficiency. Laboratory testing is most helpful
      with respect to vitamin B12 and folate deficiency. Given the great value of
      clinical assessment, the low cost of vitamins, and the higher cost of laboratory
      testing, the authors do not recommend testing before instituting multivitamin use
      or extra supplementation with individual vitamins unless the diagnosis of
      deficiency is in question or the use of supplementation would put the patient at
      risk. The authors' general recommendations are * one multivitamin daily * extra
      vitamin E for patients with cardiovascular risk factors or Alzheimer's dementia *
      extra vitamin D for patients with known osteoporosis, osteoporosis risk factors,
      or strong risk factors for vitamin D deficiency * extra folate for patients with
      cardiovascular risk factors (especially smokers) and alcoholics * extra thiamine
      for alcoholics.

PMID- 12608504
TI  - Trace metals and the elderly.
AB  - The elderly are at nutritional risk as a result of multiple physiological,
      social, psychological, and economic factors. Elderly persons have a higher
      incidence of chronic diseases and associated intake of medications that may
      affect nutrient utilization. Social and economic conditions can adversely affect
      dietary choices and eating patterns. Physiological functions naturally decline
      with age, which may influence absorption and metabolism. Loneliness and
      reluctance to eat may complicate an already marginal situation. This article
      reviews specific trace metals in relation to the elderly. Our objectives are to
      provide Dietary Reference Intakes for older adults, to provide information on
      presenting features and functional consequences of trace metal deficiency, and to
      discuss potential effects and/or benefits of trace metal supplementation in the
      elderly.

PMID- 12608505
TI  - Dietary prescription in atherosclerosis.
AB  - Although the evidence that dietary intervention reduces blood lipid levels is
      strong, evidence linking hypercholesterolemia and heart disease in elderly
      persons is conflicting. Treatment through dietary intervention for secondary
      prevention of heart disease in all elderly individuals and for primary prevention
      in those less than 75 years with risk factors seems to be justified. A more
      flexible dietary approach should be adopted for primary prevention of heart
      disease in the persons over 75 years. "The most reasonable dietary advice in them
      would be moderation, balance and variety".

PMID- 12608506
TI  - Dietary prescription in diabetes mellitus.
AB  - No one specific diet is recommended by the ADA for the management of diabetes.
      The prescribed diet should be based on nutritional assessment, treatment goals,
      and desired outcome. The nutritional therapy should be individualized to meet the
      patient's nutritional requirements. Glycemic control should be maintained by
      monitoring metabolic parameters, adjusting medication, and patient education.

PMID- 12608507
TI  - Dietary prescription for chronic obstructive pulmonary disease.
AB  - Patients with chronic obstructive pulmonary disease (COPD) demonstrate classic
      signs of undernutrition. A low body mass, weight lose, and decrease in lean body
      mass have been associated with impaired functional status and poor outcome. The
      nutritional deficiencies accompanying COPD have been refractory to strategies
      aimed at increasing calorie intake, indicating that the underlying
      pathophysiology is not a simple nutritional defect amenable to correction. The
      association of cytokine-induced inflammatory markers in COPD patients suggests
      that interventions aimed at controlling cytokine production may be required to
      reverse the cachexia syndrome and improve functional status.

PMID- 12608508
TI  - Alternative diet therapy for elderly patients. Unique concerns for a high-risk
      population.
AB  - Many elderly individuals accept or even seek alternative or complementary
      therapies, including dietary and nutritional treatments. Medical practitioners,
      nutritionists, and marketing strategists must recognize the special concerns
      regarding ADT use by the elderly and advise them accordingly. These concerns
      about the use of alternative diet therapies include social, physical, medical,
      psychologic, and ethical factors. Many elderly individuals struggle with chronic
      illnesses that cannot be completely ameliorated by conventional treatments. Thus,
      the possibility that alternative approaches may help reduce these symptoms needs
      to be explored. To do so with an appropriate level of safety, it is recommended
      that these alternative treatments be attempted as part of a complementary
      treatment protocol. That is, the physician, nutritionist, and other traditional
      health care professionals should team with providers of alternative products and
      treatments to offer guidance to elderly patients who wish to use these therapies.

PMID- 12608509
TI  - Orexigenic and anabolic agents.
AB  - Anorexia and weight loss represent a major cause of morbidity and mortality. At
      present in the United States two effective anorectic agents are commonly used,
      namely, megestrol acetate and dronabinol. These two agents are compared in Table
      1. In persons with a large excess cytokine production. megestrol acetate should
      be tried at a does of 800 mg per day for no longer than 3 months. Megestrol
      acetate should be administered with testosterone in men. It should be avoided in
      persons who are bed-bound because of the risk of deep vein thrombosis. Dronabinol
      should be used for most anorectic patients. Dronabinol should initially be given
      in a low dose (2.5 mg) in the evening. The dose should be increased to 5 mg per
      day if no improvement in appetite is seen after 2 to 4 weeks. Dronabinol can be
      continued indefinitely. It seems to have a particularly good profile for persons
      with anorexia who are at the end of life. In persons with depression and
      anorexia. mirtazapine seems to be the antidepressant of choice. In addition, the
      use of taste enhancers can be considered in persons who complain that the food
      does not taste good. The appropriate use of anabolic agents in older persons with
      weight loss is controversial. Certainly all older men who are losing weight
      should have bioavailable testosterone measured and, if the testosterone level is
      low, should receive testosterone replacement therapy. Women who are losing weight
      may benefit from the use of low-dose testosterone (eg, Estratest). Anabolic
      agents, such as oxandrolone, should be reserved for those who have profound
      cachexia. An approach to the management of anorexia and weight loss in older
      persons is given in Fig. 1. Thomas et al have provided a more complex algorithm
      the management of weight loss in nursing home residents.

PMID- 12608510
TI  - Enteral nutrition and enteral tube feeding. Review of the evidence.
AB  - Improvements in delivery systems for enteral feeding, in formulas, and in the
      understanding of complications have made the technology for enteral feeding easy
      to apply. Adequate nutrients can be delivered, and individual tolerance for
      feeding is acceptable. The remaining question is when to apply the technology.
      Formula selection should be as simple as possible. Aspiration and other early
      complications are a serious risk and are not diminished by route of feeding. Long
      term enteral feeding is associated with a high complication rate, with high
      mortality, and may not be effective.

PMID- 12608511
TI  - Distinguishing starvation from cachexia.
AB  - The poor response to hypercaloric feeding in ill adults may be caused by failure
      to distinguish cachexia from starvation (Table 1). The chief difference between
      starvation and cachexia is that refeeding reverses starvation but is less
      effective for cachexia. The ineffectiveness of refeeding in treating cachexia may
      explain some of the poor results from direct nutritional interventions in
      clinical trials. Simple starvation should respond to voluntary or involuntary
      hypercaloric feedings. The failure to demonstrate a more positive response may be
      caused by underlying cachexic states.

PMID- 12608512
TI  - The value of clinicopathological correlation in patient care, teaching and
      research in ophthalmology.

PMID- 12608513
TI  - The Misericordia Health Centre cataract comfort study.

PMID- 12608514
TI  - Current use of dietary supplementation in patients with age-related macular
      degeneration.
AB  - BACKGROUND: The Age-Related Eye Disease Study (AREDS) Research Group recently
      reported significant reduction in the progression of certain categories of age
      related macular degeneration (AMD) with the use of high-dose antioxidant and zinc
      supplementation. We studied the current use of dietary supplementation in our
      patients with AMD to determine whether dosages recommended in the AREDS were
      being achieved. We also evaluated the easiest and most cost-effective method to
      reach recommended dosages using supplements currently available in Canada.
      METHODS: Cross-sectional descriptive study conducted by patient survey from Feb.
      1 to Mar. 31, 2002. All patients with the diagnosis of AMD were surveyed during
      an office visit at a retinal specialty clinic in Edmonton. The following
      information was collected: demographic information, duration of AMD, smoking
      status and current use of dietary supplements. For patients using supplements, we
      also noted duration of use, reason for use, who recommended use, and type and
      dosage of supplements (including vitamin, mineral and herbal supplements). The
      exact dosages were confirmed by follow-up telephone interview. Cost estimates
      were determined by averaging retail prices from several local pharmacies. We
      compared methods of reaching the recommended dosages using various combinations
      of commercially available multivitamin formulations and individual beta-carotene,
      vitamin C and E, and zinc supplements. The goal was to match the dosage
      recommended in the AREDS (without exceeding it if possible) at maximum
      convenience and minimum cost and without increasing the risk of toxic effects.
      RESULTS: Of 108 patients with AMD surveyed, 85 (79%) were taking dietary
      supplements, and 73 (68%) were taking at least one AREDS ingredient. The mean
      dosages of beta-carotene, vitamins C and E, and zinc were all below those
      recommended in the AREDS. None of our patients met the recommended dosages for
      all four ingredients. We identified four methods of reaching recommended dosages
      using various combinations of ICAPS TR, Ocuvite and Vitalux as well as Centrum
      multivitamin and individual supplements. INTERPRETATION: Patients with AMD may
      not be receiving the dosages of beta-carotene, vitamins C and E, and zinc
      recommended in the AREDS. Until new formulations of high-dose antioxidant and
      zinc supplements are available in Canada, patients should be counselled to
      attempt to meet recommended dosages by using combinations of currently available
      supplements.

PMID- 12608515
TI  - Autosomal dominant macular dystrophy in a large Canadian family.
AB  - BACKGROUND: We studied a large Canadian family (178 total family members)
      spanning seven generations with autosomal dominant macular dystrophy. We
      performed a study to identify the gene mutation responsible for the disease in
      the family. METHODS: Participating family members were evaluated clinically.
      Genetic linkage, genotyping, mutation screening and an extensive genealogic
      investigation were performed. RESULTS: The common clinical findings in affected
      family members included progressive early- to mid-onset visual loss and extensive
      areas of central chorioretinal atrophy. Two-point linkage analysis indicated
      linkage to chromosome 6p. Direct DNA sequencing showed a C/T transition in codon
      172 of the retinal degeneration slow (RDS) gene creating an amino acid change to
      Arg172Trp. Haplotype analysis of affected family members using microsatellite
      markers distributed around the RDS gene locus revealed that the markers were not
      conserved when compared to members of British families with the Arg172Trp
      mutation. Genealogic studies indicated the family immigrated to Canada from
      Ireland in 1843. INTERPRETATION: A newly identified large family with autosomal
      dominant macular dystrophy is described. The phenotypic appearance of the fundus
      is similar to that of previously described patients with an Arg172Trp mutation in
      the RDS gene. Haplotype analysis of markers spanning the disease locus identified
      a new founder for this mutation. The identification of the disease-causing gene
      in this family allows for better genetic counselling for patients with this
      condition and provides a basis to distinguish clinically similar types of macular
      dystrophy based on the clinical phenotype.

PMID- 12608516
TI  - Expression of neuropilin-1 in choroidal neovascular membranes.
AB  - BACKGROUND: Neovascularization is a serious consequence of several eye diseases,
      including age-related macular degeneration. Neovascularization is under the
      control of proangiogenic factors, such as vascular endothelial growth factor and
      fibroblast growth factor. Recent work in our laboratory has focused on other,
      novel angiogenic factors, such as neuropilin-1, and their potential role in
      neovascularization. The purpose of this study was to investigate the role of
      neuropilin-1 in choroidal neovascularization (CNV). METHODS: We examined the
      localization of neuropilin-1 by immunohistochemistry in nine choroidal
      neovascular membranes (CNVMs) surgically excised from four patients with age
      related macular degeneration who had not undergone laser photocoagulation, four
      with idiopathic CNV and one with ocular histoplasmosis. We also stained the
      membranes for markers of endothelial and retinal pigment epithelial cells.
      Controls included omission of primary antibody, use of an irrelevant primary
      antibody, and neuropilin-1 staining of the posterior sclera, choroid and retina
      of four healthy donor eyes. RESULTS: Neuropilin-1 was present in eight of the
      nine CNVMs. It was localized mainly to the plasma membrane. The more vascular
      membranes and those consisting of a larger number of retinal pigment epithelial
      cells were associated with greater neuropilin-1 staining. Neuropilin-1 was not
      seen in the posterior segment of the four healthy eyes. INTERPRETATION:
      Neuropilin-1 appears to play an active role in CNV. Further study is needed to
      establish a causal relation.

PMID- 12608517
TI  - Retinopathy in sickle cell trait: does it exist?
AB  - BACKGROUND: Patients with sickle cell trait and concomitant systemic disease are
      known to be at risk for proliferative retinopathy. However, there are reports of
      retinopathy in patients with sickle cell trait without systemic disease. There
      are no population-based studies addressing the risk of sickle cell retinopathy in
      this group. We performed a study to clarify the relation between sickle cell
      trait and retinopathy in healthy subjects. METHODS: We reviewed the medical
      records of 100 children with sickle cell disease who attended the Sickle Cell
      Clinic at the Hospital for Sick Children, Toronto. We then contacted 200 parents
      with sickle cell trait, of whom 32 agreed to participate in the study. All
      participants were proven to have hemoglobin AS status with prior hemoglobin
      electrophoresis. An ophthalmologic history was obtained, and a complete
      ophthalmologic examination was performed. We defined sickle cell retinopathy as
      any salmon patch hemorrhages, iridescent spots, black sunbursts, retinal
      neovascularization or retinal detachment. The evaluation also included attempts
      to identify the more subtle signs of sickle cell retinopathy, such as optic nerve
      head vascular changes, vascular tortuosity, macular changes (e.g., microaneurysms
      and vascular loops) and peripheral arteriovenous anastamoses. Blood samples were
      obtained for complete blood count, reticulocyte count and smear. RESULTS: We
      found no cases of sickle cell retinopathy among the 32 subjects. Ten of 30
      subjects had a high reticulocyte count (greater than 120 x 10(9)/L); however,
      there were no associated eye findings in this subgroup. INTERPRETATION: Our
      results indicate that there is no increased risk of retinopathy in healthy people
      with sickle cell trait.

PMID- 12608518
TI  - Endothelial cell loss after cataract phacoemulsification with Healon5 vs. I-Visc
      Phaco.
AB  - BACKGROUND: Healon5, the first viscoadaptive agent introduced in ophthalmic
      surgery, has been judged to be superior to Healon GV in protecting corneal
      endothelial cells. The purpose of this study was to compare the endothelial
      protective effects of I-Visc Phaco, a newer viscoadaptive agent, with those of
      Healon5 in cataract phacoemulsification. METHODS: A total of 96 unselected
      patients scheduled to undergo cataract surgery at a community-based hospital in
      St. Catharines, Ont., were assigned to receive I-Visc Phaco. This group was
      compared with 112 patients who had received Healon5 in a previous study by the
      author. The technique used to remove the cataract with phacoemulsification and
      insertion of an intraocular lens was the same in the two groups. Endothelial cell
      count and corneal thickness were measured preoperatively and 3 and 8 weeks
      postoperatively with a Konan noncontact specular microscope. One-way analysis of
      variance was used to analyse the data. RESULTS: Preoperatively there was no
      statistically significant difference between the Healon5 and I-Visc Phaco groups
      in age, eye operated, or endothelial cell count or corneal thickness. At 3 weeks
      there was no significant difference between the two groups in mean endothelial
      cell count (2110.2 [standard deviation (SD) 529.9] cells/mm2 vs. 2113.5 [SD
      566.6] cells/mm2) or mean corneal thickness (586.2 microm [SD 46.73 microm] vs.
      583.9 microm [SD 42.23 microm]). Similarly, there was no significant difference
      between the two groups in mean endothelial cell count (2113.3 [SD 496.6]
      cells/mm2 vs. 2145.5 [SD 573.1] cells/mm2) or mean corneal thickness (570.9
      microm [SD 44.09 microm] vs. 574.4 microm [SD 40.73 microm]) at 8 weeks.
      INTERPRETATION: Results at 3 and 8 weeks postoperatively indicate that Healon5
      and I-Visc Phaco protect the endothelium equally well during cataract
      phacoemulsification surgery.

PMID- 12608519
TI  - Radiation-induced chorioretinal degeneration: a clinicopathological report of
      three cases.
AB  - BACKGROUND: With the shift in radiotherapy toward the posterior segment and with
      the use of lead screens to shield the anterior segment, posterior segment lesions
      have become more readily recognized. The purpose of this study is to highlight
      the effects of ionizing radiation on the choroid and to demonstrate how this can
      result in visual loss, particularly if the macula is involved. METHODS:
      Histopathological study of three enucleated eyes of three patients who had
      received ionizing radiation: a 27-year-old woman who had received radiation as a
      child for a hemangioma of the left side of the face, a 16-year-old girl who had
      received radiation at age 11 years for a malignant mesenchymoma of the right
      maxilla, and a 4-year-old girl who had received radiation at age 1 year for a
      retinoblastoma of the right eye. RESULTS: Histopathological examination of the
      three globes showed extensive chorioretinal degeneration, among other ocular
      findings. In all cases the fellow eye did not show similar chorioretinal lesions.
      As all three patients were relatively young, the degree of chorioretinal
      degeneration was considered to be secondary to radiation treatment.
      INTERPRETATION: Vascular damage from ionizing radiation is not limited to the
      retina. It can also affect the choroid in the form of chorioretinal degeneration.
      Since most of the intraocular circulation arises from the uveal vessels,
      chorioretinal degenerative lesions may be extensive and may even involve the
      macula.

PMID- 12608520
TI  - Wegener's granulomatosis: a diagnostic dilemma. case presentation.

PMID- 12608521
TI  - Weight loss and increased mortality: epidemiologists blinded by observations?

PMID- 12608522
TI  - Weight loss causes increased mortality: pros.
AB  - There are many good reasons to expect that weight loss in overweight and obese
      subjects should lead to reduced mortality, not least because the general risk
      factor profile of several diseases responsible for the excess mortality
      associated with overweight and obesity improves with weight loss. However,
      observational long-term population studies have shown that weight loss in
      overweight subjects leads to increased long-term mortality, even if the studies
      are well controlled with regard to known confounding factors, including hazardous
      behaviour and underlying diseases that may lead to both weight loss and increased
      mortality. It seems unfeasible to wait for the multiple randomized clinical
      trials of sufficient quality, size and duration that may resolve this question.
      Therefore, the recommendations about weight loss must be based on the weaker
      evidence that can be obtained in short-term clinical trials and the observational
      population studies. Several studies have tried to address the problem by
      distinguishing intentional from unintentional weight loss, but only few do so by
      gathering information about the intention to lose weight before weight loss is
      observed. These studies suggest that intentional weight loss is associated with
      increased mortality. Recommendations to healthy overweight and obese subjects to
      lose weight must be based on an explicit weighing of the short-term well
      documented benefits of weight loss, including improvement of quality of life,
      against the possible risk of an increased mortality in the long-term

PMID- 12608523
TI  - Weight loss causes increased mortality: cons.
AB  - Short-term studies indicate that intentional weight loss (IWL) among obese
      persons significantly improves health variables that are often precursors or
      markers of chronic diseases (e.g. heart diseases, type-2 diabetes). Hence, it is
      logical to assume that IWL among obese persons would lead to increased longevity.
      On the whole, epidemiological studies, including recent ones that use
      conservative analytic approaches such as distinguishing between apparently IWL
      and unintentional weight loss (UWL), adjusting for potential confounders and
      excluding apparently unhealthy subjects, indicate that apparently IWL appears to
      neither increase nor decrease mortality rate. However, it is important to note
      that none of the existing studies were designed specifically to test the
      hypothesis that IWL reduces mortality rate, and given methodological problems,
      these studies do not provide a satisfactory way to address the body mass index
      (BMI)-mortality question. Several controlled clinical trials suggest that IWL may
      reduce mortality rate. However, even in these studies, it is important to
      acknowledge that subjects are randomized to conditions that produce more or less
      weight loss and not to distinct levels of weight loss per se. Nevertheless, while
      we await additional data from better designed studies, given our incomplete
      knowledge, we conclude that it seems more likely than not that IWL achieved by
      medically recommended methods does not increase and probably decreases mortality
      rate.

PMID- 12608524
TI  - Energy balance and pollution by organochlorines and polychlorinated biphenyls.
AB  - Organochlorines are fat-soluble chemical compounds resistant to degradation, so
      they are stored in the adipose tissue of practically every organism on the
      planet, including humans. Accumulation of these compounds in the body seems to be
      related to fat mass, obese individuals having a higher plasma organochlorine
      concentration than lean subjects. During body weight loss, lipid mobilization and
      a decrease in fat mass result in increased concentrations of organochlorines in
      plasma and adipose tissue. Organochlorines may have adverse health effects. For
      example, they have been associated with altered immune and thyroid functions and
      with some types of cancer. As these compounds may reach their target organs
      whilst in the circulation, their increase in plasma during weight loss might be
      associated with some physiological changes occurring during weight loss.
      Relationships have indeed been reported among weight loss-induced increase in
      plasma organochlorine concentration and decreased triiodothyronine (T3)
      concentration, resting metabolic rate, and skeletal muscle markers for fat
      oxidation. Although further studies are needed to assess the causality of these
      relationships, they raise concern about some potential undesirable effects of
      weight loss. Indeed, the effects of organochlorines on energy balance could
      complicate body weight loss and even favour weight regain. These notions lend
      support for weight-loss strategies favouring a moderate weight loss, which would
      reduce risks for cardiovascular diseases, diabetes and hypertension, without
      resulting in a substantial release of organochlorines.

PMID- 12608525
TI  - Treatment of obesity: an update on anti-obesity medications.
AB  - The information presented in this article provides an overview of physiological
      agents, therapeutics in current use, and medications that have been extensively
      used in the past but are no longer available, or are not classically considered
      as anti-obesity drugs. The authors present an extensive review on the criteria
      for anti-obesity management efficacy, on physiological mechanisms that regulate
      central and/or peripheral action energetic homeostasis (nutrients, monoamines and
      peptides), and on beta-phenethylamine pharmacological-derivative agents
      (fenfluramine, dexfenfluramine, phentermine, diethylpropion, fenproporex and
      sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives
      (ephedrine, phenylpropanolamine), a phenylpropanolamine oxy-tri-fluor-phenyl
      derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine
      derivative (orlistat). An analysis of all clinical trials longer than 10 weeks in
      duration is also presented for medications used in the management of obesity.

PMID- 12608526
TI  - Possible involvement of the adipose tissue renin-angiotensin system in the
      pathophysiology of obesity and obesity-related disorders.
AB  - Angiotensin II (Ang II), acting on the AT1 and AT2 receptors in mammalian cells,
      is the vasoactive component of the renin-angiotensin system (RAS). Several
      components of the RAS have been demonstrated in different tissues, including
      adipose tissue. Although the effects of Ang II on metabolism have not been
      studied widely, it is intriguing to assume that components of the RAS produced by
      adipocytes may play an autocrine, a paracrine and/or an endocrine role in the
      pathophysiology of obesity and provide a potential pathway through which obesity
      leads to hypertension and type 2 diabetes mellitus. In the first part of this
      review, we will describe the production of Ang II, the different receptors
      through which Ang II exerts its effects and summarize the concomitant
      intracellular signalling cascades. Thereafter, potential Ang II-induced
      mechanisms, which may be associated with obesity and obesity-related disorders,
      will be considered. Finally, we will focus on the different pharmaceutical agents
      that interfere with the RAS and highlight the possible implications of these
      drugs in the treatment of obesity-related disorders.

PMID- 12608527
TI  - Childhood obesity: a societal problem to solve.
AB  - In contrast to other threats to American children's health, the treatment and
      prevention of childhood obesity are considered the responsibility of individual
      children and their parents. This pressure exists in the context of the societal
      stigmatization of overweight children and the powerful environmental inducements
      aimed directly at children to eat nutritionally poor foods. Parents of overweight
      children are left in the difficult position of fearing the social and health
      consequences of their child's obesity, and fighting a losing battle against the
      omnipotent presence of the media and constant exposure to unhealthy foods. This
      paper brings together several literatures to provide a comprehensive examination
      of the major challenges facing obese children and their families. In particular,
      this paper documents the extent of stigmatization towards overweight children and
      reviews evidence of the conflicting advice given to parents about how to help
      children develop healthful eating in the face of biological and learned food
      preferences. We conclude with a call for a shift in thinking about the role of
      our society in the aetiology, treatment and prevention of childhood obesity.

PMID- 12608528
TI  - Spirited critique of glycaemic index (GI) and its role in the treatment of
      obesity.

PMID- 12608529
TI  - A systems approach to drug development and to drug therapy.

PMID- 12608530
TI  - Messenger RNA expression of transporter and ion channel genes in undifferentiated
      and differentiated Caco-2 cells compared to human intestines.
AB  - PURPOSE: The purpose of this work was to study the influence of cell
      differentiation on the mRNA expression of transporters and channels in Caco-2
      cells and to assess Caco-2 cells as a model for carrier-mediated drug transport
      in the intestines. METHOD: Gene mRNA expression was measured using a custom
      designed microarray chip with 750 deoxyoligonucleotide probes (70mers). Each
      oligomer was printed four times on poly-lysine-coated glass slides. Expression
      profiles were expressed as ratio values between fluorescence intensities of Cy3
      and Cy5 dye-labeled cDNA derived from poly(A) + RNA samples of Caco-2 cells and
      total RNA of human intestines. RESULTS: Significant differences in the mRNA
      expression profile of transporters and channels were observed upon
      differentiation of Caco-2 cells from 5 days to 2 weeks in culture, including
      changes for MAT8, S-protein, and Nramp2. Comparing Caco-2 cells of different
      passage number revealed few changes in mRNAs except for GLUT3, which was down
      regulated 2.4-fold within 13 passage numbers. Caco-2 cells had a similar
      expression profile when either cultured in flasks or on filters but differed more
      strongly from human small and large intestine, regardless of the differentiation
      state of Caco-2 cells. Expression of several genes highly transcribed in small or
      large intestines differed fourfold or more in Caco-2 cells. CONCLUSIONS: Although
      Caco-2 cells have proven a suitable model for studying carrier-mediated transport
      in human intestines, the expression of specific transporter and ion channel genes
      may differ substantially.

PMID- 12608531
TI  - Novel ethanol-in-fluorocarbon microemulsions for topical genetic immunization.
AB  - PURPOSE: Traditionally, vaccines have been administered by needle injection.
      Topical immunization through the intact skin with either protein- or DNA-based
      vaccines has attracted much attention recently. We sought to enhance the immune
      responses induced by DNA-based vaccines after topical application by developing
      novel ethanol-in-fluorocarbon (E/F) microemulsion systems to aid in the delivery
      of plasmid DNA (pDNA). METHODS: Ten different fluorosurfactants were selected or
      synthesized and screened by pseudo-phase-diagram construction for their ability
      to form E/F microemulsions. Plasmid DNA was successfully incorporated into E/F
      microemulsions using several different fluorosurfactants and perfluorooctyl
      bromide as the continuous fluorocarbon phase. For several reasons, Zonyl FSN-100
      (an ethoxylated nonionic fluorosurfactant) was selected for further studies. In
      vivo studies were performed in mice to assess pDNA expression in skin and
      immunologic responses after topical application of this system using a luciferase
      encoding plasmid (CMV-luciferase) and a CMV-beta-galactosidase-encoding plasmid,
      respectively. RESULTS: Plasmid DNA incorporated into E/F microemulsion using FSN
      100 as the surfactant was found to be stable. After topical application of this
      E/F microemulsion system, significant enhancements in luciferase expression and
      antibody and T-helper type-1 biased immune responses were observed relative to
      those of "naked" pDNA in saline or ethanol. For example, with the E/F
      microemulsion system, the specific serum IgG and IgA titers were increased by 45
      fold and over 1000-fold, respectively. CONCLUSION: A novel fluorocarbon-based
      microemulsion system for potential DNA vaccine delivery was developed.

PMID- 12608532
TI  - Enhanced oral bioavailability of paclitaxel by coadministration of the P
      glycoprotein inhibitor KR30031.
AB  - PURPOSE: In an attempt to improve the oral bioavailability of paclitaxel, a novel
      P-glycoprotein inhibitor, KR30031, which is verapamil analog with fewer
      cardiovascular effects, was coadministered with paclitaxel, and to elucidate
      other possible causes of the low oral bioavailability of paclitaxel, an inhibitor
      of hepatic metabolism, ketoconazole, was also coadministered with paclitaxel.
      METHODS: In vivo oral absorption was tested in rats, and an in vitro study was
      also performed with a Caco-2 cell monolayer to identify the extent of P
      glycoprotein inhibition. RESULTS: After coadministration of paclitaxel with
      ketoconazole, KR-30031, or KR-30031 and ketoconazole, bioavailability was
      increased about 1.6-, 7.5-, or 8.9-fold as compared with control, respectively.
      These results show that P-glycoprotein plays a major role in the oral
      bioavailability of paclitaxel. The effect of ketoconazole on oral bioavailability
      of paclitaxel was limited relative to the P-glycoprotein inhibition effect of KR
      30031. In vitro study of Caco-2 cell transport showed that paclitaxel permeation
      was significantly higher when the drug was given from the basolateral side as
      compared to the permeation from the apical side, indicating the involvement of an
      enzyme reaction in the active efflux mechanism. Apical-to-basolateral transport
      of paclitaxel was increased in the presence of KR-30031. The ability of KR-30031
      to reduce this efflux transport is equal to that of verapamil, a well-known P
      glycoprotein inhibitor. CONCLUSIONS: Our findings suggest that about 54% of a
      paclitaxel oral dose is extruded to the gut lumen by P-glycoprotein. Thus, the
      bioavailability of paclitaxel could be enhanced by coadministration of a P
      glycoprotein inhibitor, KR-30031.

PMID- 12608533
TI  - Impact of Mrp2 on the biliary excretion and intestinal absorption of furosemide,
      probenecid, and methotrexate using Eisai hyperbilirubinemic rats.
AB  - PURPOSE: This study assesses the impact of rat multidrug resistance-associated
      protein 2 (Mrp2) on the biliary excretion and oral absorption of furosemide,
      probenecid, and methotrexate using Eisai hyperbilirubinemic rats (EHBR). METHODS:
      To assess Mrp2-mediated biliary excretion, rats received a 2-h intravenous
      infusion of furosemide, probenecid, or methotrexate. Blood and bile samples were
      collected at specified intervals. To assess Mrp2's impact on oral absorption,
      rats received furosemide, probenecid, or methotrexate orally at 5 mg/kg. Jugular
      and portal blood samples were obtained at timed intervals. All samples were
      analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated using WinNonlin
      and standard pharmacokinetic equations. RESULTS: Thirty seven- and 39-fold
      reductions in biliary clearance were observed in EHBR as compared to control rats
      for probenecid and methotrexate, respectively. Biliary clearance was comparable
      between EHBR and control rats for furosemide. In all cases, no significant
      difference in absorption was observed between EHBR and control rats. CONCLUSIONS:
      This study provides the first evidence that Mrp2 mediates the biliary excretion
      of probenecid but not furosemide. Additionally, Mrp2 apparently has a less
      profound impact on intestinal absorption than biliary excretion of its
      substrates. Furthermore, alteration in systemic clearance in EHBR indicates that
      a potential compensatory mechanism may occur in EHBR.

PMID- 12608535
TI  - Enhanced drug-induced apoptosis associated with P-glycoprotein overexpression is
      specific to antimicrotubule agents.
AB  - PURPOSE: We have reported that overexpression of mdr1 P-glycoprotein (Pgp) is
      associated with a higher sensitivity to paclitaxel-induced apoptosis (1,2). The
      present study examined the substrate specificity of this phenomenon. METHODS: Two
      Pgp substrates (vincristine and doxorubicin) and three nonsubstrates (cisplatin,
      camptothecin. and 5-fluorouracil) were studied. Serum deprivation, known to
      induce apoptosis, was used as a comparison. RESULTS: The Pgp nonsubstrates and
      serum deprivation showed similar overall cytotoxicity and apoptosis in human
      breast MCF7 cells (with negligible Pgp expression) and its mdr1-transfected
      subline BC19 cells (with nine-fold higher Pgp expression). In contrast, the
      overall cytotoxicity and apoptosis of the two Pgp substrates was higher in MCF7
      cells. Cotreatment with a Pgp inhibitor, verapamil, abolished the difference in
      intracellular accumulation of doxorubicin as well as the differences in apoptosis
      between MCF7 and BC19 cells. This finding confirms that the lower apoptosis of
      doxorubicin in BC19 cells, in the absence of verapamil, was a result of lower
      intracellular drug accumulation secondary to high Pgp expression in BC19 cells.
      In contrast, abolishing the difference in intracellular vincristine concentration
      by verapamil cotreatment resulted in significantly higher apoptosis in BC19
      cells. This finding is identical to our previous finding with paclitaxel, where
      equal intracellular drug concentration resulted in greater apoptosis in the Pgp
      rich BC19 cells. CONCLUSIONS: These data, together with the opposite effects of
      paclitaxel and vincristine on microtubules (i.e., polymerization versus
      depolymerization), indicate that the enhanced apoptosis in Pgp-rich cells is
      specific for antimicrotubule agents but is not related to the polymerization of
      microtubules.

PMID- 12608534
TI  - Kinetic analysis of P-glycoprotein-mediated transport by using normal human
      placental brush-border membrane vesicles.
AB  - PURPOSE: P-Glycoprotein (Pgp) plays an important role in drug disposition and
      excretion in various tissues such as the brain, intestine, and kidney. Moreover,
      we have demonstrated that Pgp is expressed on the brush-border membranes of
      trophoblast cells in the placenta and restricts drug transfer from the maternal
      circulation to the fetus. However, the transport kinetics of physiologically
      expressed Pgp has scarcely been investigated. METHODS: In this study, we assessed
      the functional kinetics of transport mediated by Pgp that is physiologically
      expressed in normal tissue by using human placental brush-border membrane
      vesicles (BBMVs). Digoxin and vinblastine were used as typical substrates of Pgp.
      RESULTS: The uptakes of [3H]digoxin and [3H]vinblastine into BBMVs were
      significantly increased in the presence of an ATP-regenerating system. The ATP
      dependent uptakes of [3H]digoxin and [3H]vinblastine into BBMVs exhibited
      saturable kinetics. The Michaelis constants (Kt values) were 2.65 +/- 1.80 microM
      and 21.9 +/- 3.37 microM, respectively. In the presence of a Pgp inhibitor such
      as verapamil, cyclosporine A, or progesterone, the ATP-dependent uptakes of
      [3H]digoxin and [3H]vinblastine into BBMVs were significantly reduced. Anti-Pgp
      monoclonal antibody C219 completely inhibited the uptake of [3H]digoxin.
      CONCLUSIONS: The transport kinetics of [3H]digoxin and [3H]vinblastine by
      physiologically expressed Pgp were successfully evaluated by using BBMVs prepared
      from normal human placenta. The present method enabled us to evaluate the
      function of physiologically expressed Pgp and is superior to the use of cultured
      transfectants in terms of the yield of vesicles. The present method may also be
      applicable to investigating the influence of various factors such as the genotype
      of the MDR1 gene or various pathophysiologic states of neonates on the function
      of Pgp.

PMID- 12608536
TI  - Influence of spacer length on interaction of mannosylated liposomes with human
      phagocytic cells.
AB  - PURPOSE: To improve target specificity and uptake of liposomes by macrophages,
      one can improve high-affinity receptor binding to mannose determinants with their
      175-kDa mannose receptor (MR), which is mainly influenced by the length and
      flexibility of the spacer between the carbohydrate head group and liposome
      surface. Liposomes containing alkylmannosides with hydrophilic spacers 0 to 8
      ethyleneoxy units (EO) long (Man0...Man8) were used to investigate systematically
      the effects of spacer length on liposome-cell interactions. METHODS: Concanavalin
      A (ConA)-induced liposome aggregation was studied by turbidity measurement and
      cell uptake using PMA-induced HL-60 cells or native human macrophages by
      determining 6-CF after cell lysis or NBD-fluorescence with flow cytometry.
      Detection of MR in native cell populations was carried out by an antibody assay
      using flow cytometry; MR-representing cells were selected analytically. RESULTS:
      Liposomes containing mannosides with more than one EO spacer length were
      specifically aggregated by ConA, indicating accessibility of the carbohydrate
      ligands of these derivatives. Increase in EO spacer units of incorporated
      mannosides (two or more EO) led to suppression of cellular uptake of mannosylated
      liposomes by phagocytes lacking MR (HL60, U937). The extent of suppression
      increased with spacer length. Liposome uptake by native macrophages expressing MR
      was, on the contrary, improved, particularly by Man6 and Man8. CONCLUSIONS:
      Uptake of liposomes modified with Man6 or Man8 by native cells was enhanced but
      did not reach an optimum. Thus, Man6, Man8, and mannosides with even longer
      spacer arms are of potential use in receptor-mediated targeting.

PMID- 12608537
TI  - Kinetic analysis of saturable myocardial uptake of idarubicin in rat heart:
      effect of doxorubicin and hypothermia.
AB  - PURPOSE: Little is known of how anthracyclines are transported into the heart.
      Our previous kinetic study suggested saturable myocardial uptake of idarubicin.
      This study sought to determine the effects of temperature reduction and of
      doxorubicin coadministration on the transport process. METHODS: In Langendorff
      perfused rat hearts, a 0.5 mg dose of idarubicin was infused over 10 min. The
      outflow concentration-time curve as well as the residual amounts in cardiac
      tissue of idarubicin and its active metabolite idarubicinol were measured after
      temperature reduction (from 37 degrees C to 30 degrees C) and in the presence of
      doxorubicin (20 microM) in the perfusate. The outflow concentration-time profile
      of idarubicin was analyzed by a four-compartment model and simultaneous nonlinear
      regression. RESULTS: Doxorubicin significantly inhibited the Michaelis-Menten
      like uptake process of idarubicin in the heart (50% decrease in Vmax), leading to
      a decreased net tissue uptake of idarubicin. Kinetic analysis of sensitivity to
      temperature reduction revealed a 2.6-fold increase in KM; however, this
      inhibition of idarubicin uptake was counterbalanced by a decrease in efflux rate.
      CONCLUSIONS: These data confirm the existence of a saturable myocardial uptake
      mechanism for idarubicin and might provide useful information for optimizing
      anthracycline dosage regiments.

PMID- 12608538
TI  - In vitro cellular handling and in vivo targeting of E-selectin-directed
      immunoconjugates and immunoliposomes used for drug delivery to inflamed
      endothelium.
AB  - PURPOSE: Drug targeting to activated endothelial cells is now being explored as a
      new approach to interfere with chronic inflammation. This study compares a
      dexamethasone-anti-E-selectin immunoconjugate (dexa-AbEsel) with anti-E-selectin
      immunoliposomes (AbEsel-immunoliposomes) that contain dexamethasone, regarding in
      vitro binding and internalization as well as in vivo accumulation in activated
      endothelial cells. METHODS: In vitro binding and internalization of dexa-AbEsel
      and the AbEsel-immunoliposomes into TNFalpha-activated HUVECs was studied using
      confocal laser scanning microscopy and radiolabeled compounds. Tissue
      accumulation of both compounds was studied in a murine delayed-type
      hypersensitivity model using immunohistochemistry. RESULTS AND CONCLUSIONS: Both
      preparations were selectively internalized by activated endothelial cells. Dexa
      AbEsel was internalized by activated HUVECs to a larger extent than the AbEsel
      immunoliposomes, although in theory the high drug-loading capacity of the
      liposomes may enable a larger amount of dexamethasone to be delivered
      intracellularly. Both dexa-AbEsel and AbEsel-immunoliposomes accumulated in
      activated endothelial cells in murine inflamed skin. AbEsel-immunoliposomes, but
      not dexa-AbEsel, were additionally detected in control skin, though to a lesser
      extent, and in macrophages of the liver and the spleen. Studies on therapeutic
      effects and side effects in models of chronic inflammation are now necessary to
      establish pharmacodynamics of dexa-AbEsel and/or AbEsel-immunoliposomes in the
      treatment of chronic inflammation.

PMID- 12608539
TI  - Structural studies of EDTA-induced fibrillation of salmon calcitonin.
AB  - PURPOSE: The purpose of this work was to determine the structure of an insoluble
      precipitate formed when mixing approximately equimolar amounts of ethylenediamine
      tetraacetic acid (EDTA) and salmon calcitonin (sCT). METHODS: The interaction
      between EDTA and sCT was examined by measuring solution turbidity kinetics as a
      function of pH, ionic strength, and addition of ferric ions. Fourier
      transformation infrared spectroscopy (FT-IR) identified changes in peptide
      secondary structure in presence of EDTA. Scanning and transmission electron
      spectroscopy revealed the macromolecular structure of the sCT/EDTA precipitate.
      RESULTS: Aggregation of sCT in a time frame up to 1200 min cannot be induced by
      either pH (range 3.0-7.0) or ionic strength (up to 200 mM) alone, but is a
      noncovalent interaction between sCT and EDTA. In the pH range 5.0-7.0, a molar
      binding stoichiometry of sCT/EDTA in the precipitate of 1-3 was determined. We
      suggest coulombic binding of the free acidic groups of the EDTA to the side
      chains of the basic amino acids present in the sCT primary sequence. This results
      in bridging aggregation of the sCT molecules and their precipitation in aqueous
      solution. The aggregation reaction was blocked by the addition of ferric ions,
      which bind preferentially to the acidic groups of the EDTA. The sCT/EDTA
      precipitate redissolves in water in a pH-dependent manner. FT-IR measurements
      showed a progressive loss of the random coil structure of sCT in water in the
      presence of EDTA and a simultaneous strong increase in beta-structure. Scanning
      electron microscopy revealed a fine, sponge-like morphology of the isolated,
      solid sCT/EDTA precipitate. Transmission electron microscopy delivered final
      proof of the existence of extensive fibrillation in the sCT/EDTA mixture.
      CONCLUSIONS: EDTA induces rapid fibrillation of sCT in water and the partially
      reversible formation of a noncovalent, insoluble sCT/EDTA precipitate.

PMID- 12608540
TI  - Microsomal cytochrome P450 levels and activities of isolated rat livers perfused
      with albumin.
AB  - PURPOSE: We recently showed that the perfusion of isolated rat livers with
      perfusates containing bovine serum albumin (BSA) would significantly stimulate
      the release of tumor necrosis factor (TNF)-alpha. Here, we hypothesize that BSA
      induced increase in the release of TNF-alpha, and possibly other cytokines, would
      affect cytochrome P450 (CYP)-mediated drug metabolism. METHODS: Rat livers were
      perfused ex vivo for 1, 2, or 3 h with a physiologic buffer containing or lacking
      1% BSA (n = 4-5/group). At the end of perfusion, liver microsomes were prepared
      and analyzed for their total CYP, CYP2E1, CYP3A2, and CYP2C11 protein contents
      and the activities of cytochrome c reductase, CYP2E1, CYP3A2, CYP2C11, CYP2E1,
      CYP2D1, CYP1A1, and CYP2B1/2. In addition, the concentrations of various
      cytokines and nitric oxide were quantified in the outlet perfusate. RESULTS: In
      the absence of BSA, the perfusate levels of all measured cytokines and nitric
      oxide were low. However, when the perfusate contained BSA, the levels of TNF
      alpha, interleukin-6, and nitric oxide increased significantly (p < 0.005).
      Perfusion of the livers for 3 h with the BSA-containing perfusate resulted in
      significant (p < 0.05) decreases in the total CYP (41%), CYP2E1 (59%), CYP3A2
      (68%), and CYP2C11 (50%) protein contents and activities of cytochrome c
      reductase (31%), CYP2E1 (66%), CYP3A2 (54%), and CYP2G11 (51%). In contrast,
      perfusion of livers for 1 or 2 h with the BSA perfusate did not have any
      significant effect on CYP-mediated metabolism. The CYP1A2, CYP2D1, and CYP2B1/2
      activities were not affected by BSA, regardless of perfusion time. CONCLUSION:
      Addition of BSA to perfusates, which is a routine practice in isolated rat liver
      studies, can reduce CYP-mediated drug metabolism by a mechanism independent of
      protein-binding effect.

PMID- 12608541
TI  - Hepatobiliary transport of a nonpeptidic endothelin antagonist, (+)-(5S,6R,7R)-2
      butyl-7-[2((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)
      cyclopentenol[1,2-b]pyridine-6-carboxylic acid: uptake by isolated rat
      hepatocytes and canalicular membrane vesicles.
AB  - PURPOSE: Hepatobiliary excretions of drugs from the blood to the bile include two
      essential transmembrane processes: uptake into hepatocytes and secretion from
      hepatocytes. The purpose of this study was to clarify the transport mechanisms
      underlying these processes for a new non-peptide endothelin antagonist, (+)
      (5S,6R,7R)-2-butyl-7-[2((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4
      methylenedioxy-phenyl)cyclopentenol[1,2-b]pyridine-6-carboxylic acid (J-104132).
      METHODS: Biliary excretion of J-104132 was assessed in rats after intravenous
      injection. To evaluate the hepatic uptake process, J-104132 was incubated with
      freshly isolated rat hepatocytes and the uptake of J-104132 was calculated. To
      evaluate the biliary secretion process, the uptake of J-104132 into rat
      canalicular membrane vesicles that were isolated from normal Sprague-Dawley rats
      or Eisai hyperbilirubinemic rats was measured. RESULTS: After intravenous
      injection, J-104132 was recovered from the bile quantitatively (99.7 +/- 1.3%) as
      its intact form. J-104132 was taken up by isolated rat hepatocytes in a time- and
      temperature-dependent manner. The uptake was saturable with Km and Vmax of 5.7
      microM and 564 pmol/min/10(6) cells, respectively. The uptake was Na+ independent
      and was reduced in the presence of ATP depleters (rotenone and carbonyl cyanide-p
      (trifluoromethoxy)-phenylhydrazone), organic anions (dibromosulfophthalein,
      indocyanine green, BQ-123, and pravastatin), and bile acids (taurecholate and
      cholate). In Sprague-Dawley rats, J-104132 was taken up by canalicular membrane
      vesicle ATP-dependently with Km and Vmax values of 6.1 microM and 552 pmol/min/mg
      protein, respectively. However, ATP-dependent uptake disappeared in Eisai
      hyperbilirubinemic rats. CONCLUSIONS: These data suggest that energy-dependent
      and carrier-mediated transport systems play important roles in hepatobiliary
      excretion of J-104132 (both uptake and secretion processes), which is the main
      excretion route in rats. As for the secretion process of J-104132, an involvement
      of mrp2 was demonstrated.

PMID- 12608542
TI  - Computer simulation of convective and diffusive transport of controlled-release
      drugs in the vitreous humor.
AB  - PURPOSE: Biodistribution of drugs in the eye is central to the efficacy of
      pharmaceutical ocular therapies. Of particular interest to us is the effect of
      intravitreal transport on distribution of controlled-released drugs within the
      vitreous. METHODS: A computer model was developed to describe the three
      dimensional convective-diffusive transport of drug released from an intravitreal
      controlled release source. Unlike previous studies, this work includes flow of
      aqueous from the anterior to the posterior of the vitreous. The release profile
      was based on in vitro release of gentamicin from poly(L-lactic acid) microspheres
      into vitreous. RESULTS: For small drugs, convection plays a small role, but for
      large (slower diffusing) drugs, convection becomes more important. For the cases
      studied, the predicted ratio of drug reaching the retina to drug cleared by the
      aqueous humor was 2.4 for a small molecule but 13 for a large molecule. Transport
      in neonatal mouse eye, in contrast, was dominated by diffusion, and the ratio
      decreased to 0.39. CONCLUSIONS: The interaction among convection, diffusion, and
      geometry causes significant differences in biodistribution between large and
      small molecules or across species. These differences should be considered in the
      design of delivery strategies or animal studies.

PMID- 12608543
TI  - Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo
      performance of a novel delivery system.
AB  - PURPOSE: The purpose of this work was to characterize in vitro/in vivo delivery
      and pharmacokinetics of oxybutynin (OXY) and its active metabolite. N
      desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS). METHODS:
      Two in vivo, randomized, three-way crossover trials examined single/multiple OXY
      TDS doses. Abdomen, buttock, and hip application sites were compared and dose
      proportionality was evaluated. Model independent pharmacokinetics, elimination
      rate constants, and metabolite/drug ratios were derived from both plasma OXY and
      DEO concentrations. RESULTS: Single/multiple applications of the OXY TDS to the
      abdomen yielded mean Cmax OXY concentrations of 3.4 +/- 1.1/6.6 +/- 2.4 ng/mL and
      median tmax of 36/10 h, with steady state achieved during the second application.
      Plasma OXY and DEO concentrations decreased gradually after Cmax until system
      removal. Buttock and hip applications resulted in bioequivalent OXY absorption.
      AUC ratios of DEO/OXY were 1.5 +/- 0.4 (single dose) and 1.3 +/- 0.3 (multiple
      dose). Mean in vitro OXY skin absorption (186 microg/h) was comparable to the
      estimated in vivo delivery (163 microg/h) over 96 h. CONCLUSIONS: Sustained
      delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice
      weekly OXY TDS dosing. A low incidence of anticholinergic side effects is
      expected during clinical use because of the avoidance of presystemic metabolism
      and low DEO plasma concentrations. The consistent delivery, absorption, and
      pharmacokinetics should result in an effective treatment of patients with
      overactive bladder.

PMID- 12608544
TI  - Microfabricated porous silicon particles enhance paracellular delivery of insulin
      across intestinal Caco-2 cell monolayers.
AB  - PURPOSE: Novel porous silicon microparticles were fabricated and loaded with
      fluorescein isothiocyanate (FITC)-insulin, a model hydrophilic pharmacologically
      active protein, along with varied doses of sodium laurate (C12), a well-known
      permeation enhancer. METHODS: Particle and liquid formulations were compared as a
      function of apical to basolateral flux of FITC-insulin across differentiated
      human intestinal Caco-2 cell monolayers grown on Transwell inserts. RESULTS: The
      flux of FITC-insulin from silicon particles across cell monolayers was nearly 10
      fold higher compared with liquid formulations with permeation enhancer and
      approximately 50-fold compared with liquid formulations without enhancer. By
      increasing C12 dose per particle with a concomitant decrease in total particles
      added per monolayer, the percent of FITC-insulin transport resulted in a linear
      increase up to 25% monolayer coverage. CONCLUSIONS: Although maintaining
      monolayer integrity and transepithelial electrical resistance, maximum drug
      transport (20%/h) was achieved with 0.337 microg C12 dose per particle, and total
      particle loading at 25% monolayer coverage.

PMID- 12608545
TI  - Direct formation of nanospheres from amphiphilic beta-cyclodextrin inclusion
      complexes.
AB  - PURPOSE: The aim of this work was to develop and characterize a highly loaded
      nanoparticulate system based on amphiphilic beta-cyclodextrins (CDs) to
      facilitate the parenteral administration of poorly soluble antifungal model drugs
      bifonazole and clotrimazole. METHODS: Inclusion complexes were characterized with
      spectroscopic techniques. Particle size distribution of nanospheres were
      determined by photon correlation spectroscopy (PCS). Nanospheres were assessed
      for hemolytic activity. Entrapped and released drug quantities were determined
      and minimum inhibitory concentration (MIC) values of drugs, amphiphilic beta-CDs,
      and drug loaded nanospheres were evaluated. RESULTS: 1:1 inclusion complexes of
      model drugs with amphiphilic beta-CDs gave nanospheres <300 nm (polydispersity
      index < 0.15) by nanoprecipitation technique without using surfactants. By direct
      preparation from preformed inclusion complexes, loading was increased 2- to 8
      fold depending on CD type and loading technique. Conventionally loaded CD
      nanospheres displayed immediate release whereas preloaded and highly loaded
      nanospheres liberated model drugs over a period of 1 h reducing the initial burst
      effect. MIC values of bifonazole and clotrimazole were lowered significantly when
      associated to amphiphilic beta-CD nanospheres. CONCLUSION: Amphiphilic beta-CDs
      form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than
      that of natural CDs directly from inclusion complexes. They enhanced solubility
      and subsequently therapeutic efficacy of the model drugs.

PMID- 12608546
TI  - Modifications in lipoprotein surface charge alter cyclosporine A association with
      low-density lipoproteins.
AB  - PURPOSE: The purpose of this study was to examine the influence of lipoprotein
      surface charge on the plasma distribution of cyclosporine A (CSA). METHODS:
      Phosphatidylinositol (PI; 40 micromol) was administered intravenously to rabbits.
      Blood was removed 10 min after injection and plasma was retrieved. Radiolabeled
      CSA ([3H] CSA) at a concentration of 1000 ng/mL was incubated for 60 min at 37
      degrees C in control and PI-treated rabbit plasma. After incubation, plasma was
      separated into its lipoprotein and lipoprotein-deficient plasma (LPDP) fractions
      by density gradient ultracentrifugation, and the percentage of [3H]CSA recovered
      in each fraction was determined by radioactivity. To determine lipoprotein
      surface charge within control and PI-treated plasma, the zeta potential of each
      lipoprotein fraction was measured. The effect of PI on lipoprotein surface charge
      was further confirmed by gel electrophoresis. RESULTS: PI treatment caused low
      density lipoprotein (LDL) fraction to migrate further on the agarose gel,
      indicative of an increased negative surface charge. Zeta potential analysis
      further showed that LDL particles had a surface potential of -11.4 +/- 1.9 mV and
      -17.4 +/- 3 mV in control and PI-treated groups, respectively. A greater
      percentage of [3H]CSA was recovered within the LDL (16.4 +/-1.1% vs. 7.7 +/-
      2.1%; n = 3; p < 0.05) fraction after incubation in PI treated than in control
      plasma, respectively. CONCLUSION: These findings suggest that modifications in
      lipoprotein surface charge alter CSA distribution within the LDL plasma fraction.

PMID- 12608548
TI  - Identification of phase separation in solid dispersions of itraconazole and
      Eudragit E100 using microthermal analysis.
AB  - PURPOSE: To evaluate the phase separation in itraconazole/Eudragit E100 solid
      dispersions prepared by hot-stage extrusion. METHODS: Extrudates were prepared
      using a corotating twin-screw extruder at 180 degrees C. Micro-TA was used to
      evaluate the phase separation, where the AFM mode is used to visualize the
      different phases and local thermal analysis (LTA) to characterize the different
      phases RESULTS: Itraconazole formed a homogeneous mixture with Eudragit E100 with
      drug concentrations up to approximately 20%. Above this concentration, phase
      separation was observed. MTDSC revealed two Tgs and the mesophase of free glassy
      itraconazole. Performing micro-TA on the surface of these dispersions indicated
      an increase in sample roughness in the z-axis piezo signal, which could be an
      indication of free glassy itraconazole. However, thermal conductivity did not
      reveal differences between separate phases. Performing LTA, where only a small
      area (20 x 20 microm) is heated, showed two separate and mixed phases of
      itraconazole and Eudragit E100. Tip penetration in itraconazole and Eudragit E100
      occurred at 332K and 383K respectively. The difference in tip penetration was
      explained in terms of the difference in fragility. CONCLUSION: Micro-TA makes it
      possible to characterize separate phases of itraconazole and Eudragit E100,
      thereby confirming the MTDSC results on phase separation.

PMID- 12608547
TI  - Oral-antigen delivery via a water-in-oil emulsion system modulates the balance of
      the Th1/Th2 type response in oral tolerance.
AB  - PURPOSE: To evaluate the ability of a water-in-oil (W/O) emulsion containing
      ovalbumin (OVA), a model antigen, to induce oral tolerance and to elucidate the
      mechanism for the induction of oral tolerance by the emulsion system. METHODS: A
      W/O emulsion containing OVA was prepared and evaluated its ability to induce oral
      tolerance in mice. Also, the Th1/Th2 balance in the mice tolerized was
      investigated in terms of the ratios of anti-OVA IgG2a titer to anti-OVA IgG1
      titer (IgG2a/IgG1 ratios) and cytokine profiles. RESULTS: Anti-OVA total IgG
      antibody titer of mice administered OVA in saline was approximately 3.5-fold
      higher than that of the mice administered OVA in W/O emulsion at a dose of 0.1
      mg/mouse/day. Similar total IgG responses were observed between the above two at
      a dose of 1 mg/mouse/day. The IgG2a/IgG1 ratios decreased as the dose of OVA in
      W/O emulsion, but not in saline, increased at doses of 0, 0.1, and 1
      mg/mouse/day. Interferon-gamma secretion of PLN cells from the mice administered
      OVA in W/O emulsion decreased, whereas their interleukin-4 secretion remained
      high. Although interferon-gamma secretion for the mice administered OVA in saline
      decreased, interleukin-4 secretion did not change. CONCLUSIONS: The present study
      suggests that oral delivery of OVA via the W/O emulsion system may more
      efficiently enhance the induction of Th2-dominated imbalance than that of OVA in
      saline.

PMID- 12608550
TI  - Hospitalized valvular heart disease in patients on renal transplant waiting list:
      incidence, clinical correlates and outcomes.
AB  - BACKGROUND: Patients with ESRD are at increased risk for heart valve
      calcification. It has not been established whether hospitalized valvular heart
      disease (VHD) is a substantial barrier to renal transplantation (RT) after
      transplant listing, or whether VHD progresses after RT. METHODS: Using data from
      the USRDS, we studied 35,215 patients with ESRD enrolled on the renal transplant
      waiting list from July 1994 to June 1997. Cox non-proportional hazards regression
      models were used to calculate adjusted, time-dependent hazard ratios (HR) for RT
      and VHD. RESULTS: In comparison to maintenance dialysis (2.2/1,000 person years),
      RT was independently associated with a lower hazard for hospitalization for VHD
      (0.7/1,000 person years, HR 0.28, 95% confidence interval 0.17 - 0.47). Renal
      transplant recipients had much lower rates of VHD after transplant than before
      (rate ratio (RR) 0.49, 95% Cl 0.47 - 0.52). Patients with VHD were significantly
      less likely to receive RT (adjusted rate for RT 0.38, 95% CI 0.20 - 0.45) but
      patients who received valve replacement surgeries (VRS) were not affected
      (adjusted rate for RT 1.10, 95% CI 0.52 - 2.32, not significant). CONCLUSIONS:
      VHD is an uncommon but serious barrier to RT after listing, while VRS is not a
      significant barrier to RT. Established VHD does not appear to worsen after RT.
      Clinicians should consider giving increased attention to the detection and
      treatment of VHD during the pre-transplant evaluation.

PMID- 12608549
TI  - Insulin resistance highly associates with hypertension in IgA nephropathy.
AB  - BACKGROUND: Insulin resistance has been reported to induce hypertension. Previous
      studies described that there was no relationship between insulin resistance and
      hypertension in patients with chronic renal diseases with mild to moderate renal
      dysfunction. The aim of the present study is to clarify the relationship between
      insulin resistance and blood pressure, renal function, histopathological changes
      and other characteristics in IgA nephropathy (IgAN). METHODS: Eighty-eight IgAN
      patients were included in this cross-sectional study. Hypertension was diagnosed
      according to the WHO/ISH criteria. Insulin resistance was evaluated by
      homeostasis model assessment (HOMA-IR). RESULTS: Male gender, age, body mass
      index, serum creatinine, urinary protein excretion, triglycerides and HOMA-IR
      were positively correlated with hypertension. C(Cr), serum albumin and HDL
      cholesterol were negatively correlated with blood pressure by Spearman's simple
      correlation test. By logistic multivariate analysis, C(Cr), insulin resistance,
      age and male gender were significantly correlated with hypertension,
      independently of all other variables. CONCLUSIONS: Insulin resistance is not
      directly related to renal dysfunction, but is also independently associated with
      hypertension in IgAN. Since hypertension is considered as a risk factor for renal
      disease progression, insulin resistance may be an indirect deteriorating factor
      for IgAN. To identify and improve insulin resistance may be another therapeutic
      target in the clinical management of IgAN.

PMID- 12608551
TI  - Serum levels of total homocysteine, homocysteine metabolites and of advanced
      glycation end-products (AGEs) in patients after renal transplantation.
AB  - AIMS: Hyperhomocysteinemia has been described as an independent risk factor for
      cardiovascular diseases (CVD) influencing patient outcome. Advanced glycation end
      products (AGEs) are involved in the pathogenesis of vascular damage in uremia.
      This study was undertaken to assess whether high serum levels of total
      homocysteine (tHcy) with its metabolites methylmalonic acid (MMA), methylcitric
      acid (MCA) and cystathionine (CYSTA) as well as elevated serum concentrations of
      the AGEs pentosidine and Nepsilon-carboxymethyllysine (CML) are independent risk
      factors for CVD, left ventricular hypertrophy (LVH) or hypertension as well as
      kidney dysfunction in renal transplant recipients (RTR). METHODS: Serum levels of
      tHCy, MMA, MCA and CYSTA were measured by a gas chromatographic-mass
      spectrometric assay, pentosidine by HPLC and CML using an ELISA assay. RESULTS:
      All measured parameters were significantly higher in RTRs than in healthy
      subjects (p < 0.0001). The levels of pentosidine and CML as well as of tHcy and
      its metabolites correlated significantly with each other, but not with those
      ofMMA and CYSTA. Significant correlations were also found between pentosidine and
      tHcy, MMA or MCA as well as between CML, MMA and MCA, respectively. Acute or
      chronic rejection did not influence these values. No significant differences were
      observed between patients with or without CVD or with hypertension. In RTRs with
      LVH, only the tHcy levels were significantly higher than in those RTRs without
      LVH (p = 0.006). Logistic regression analysis revealed an independent influence
      of tHcy on the presence of LVH. CONCLUSION: These results may indicate an
      association between high tHcy values and LVH. Further investigation is needed to
      determine whether a reduction of tHcy and Hcy metabolites and/or AGE serum
      concentrations would significantly improve patient outcome after undergoing renal
      transplantation.

PMID- 12608552
TI  - Post-renal transplant syndrome of transient lower limb joint pain: description
      under a tacrolimus-based immunosuppression.
AB  - The occurrence of a post-renal transplant syndrome of lower limbs joint pain has
      been reported extensively over the last decade. Clinical examination of the
      symptomatic joints is often unremarkable and magnetic resonance imaging reveals
      abnormalities of the bone marrow suggestive of edema and/or hemorrhage. The main
      striking features of this syndrome are the spontaneous resolution of the symptoms
      within a few weeks as well as of the marrow abnormalities. This syndrome has been
      attributed to cyclosporine, given in the immunosuppression regimen or to
      epiphyseal impactions. We here document the occurrence of this syndrome in 5
      kidney graft recipients given a tacrolimus-based immunosuppression.

PMID- 12608553
TI  - A new system for regional citrate anticoagulation in continuous venovenous
      hemodialysis (CVVHD).
AB  - BACKGROUND: CVVHD is an established renal replacement therapy in hemodynamically
      unstable ICU patients. Various methods for regional citrate anticoagulation have
      been developed to minimize bleeding complications. Metabolic alkalosis, the risk
      of severe hypocalcemia and need for continuous calcium substitution as well as
      treatment-associated hypernatremia have limited the success of systems employed
      so far. We have developed a new technique for regional citrate anticoagulation in
      CVVHD to overcome these deficiencies and have performed a validation study.
      METHODS: One hundred and thirty-three filters with an overall treatment duration
      of 3,324 hours were used in 19 critically ill patients with bleeding
      complications. We used a calcium-containing dialysate (1.81 mmol/l Ca) to avoid
      mandatory systemic calcium supplementation. Sodium bicarbonate was added to the
      dialysate in variable concentrations (13 - 34 mmol/l) to control acid-base status
      and prevent hypernatremia. The resulting dialysate sodium concentrations were
      between 121 and 140 mmol/l. Blood flow was set at 75 ml /min. Infusion of a
      solution containing trisodium citrate and citric acid with an overall citrate
      concentration of 113 mmol/l was started at 250 ml/h. Primary endpoints were pre-
      and post-filter ionized calcium (Ca(i)) concentrations, base excess and serum
      sodium. Filter life was assessed as a secondary end-point. RESULTS: Control of
      electrolyte balance and azotemia was excellent (prefilter serum Ca(i) 1.06 +/-
      0.012 mmol/l (+/- SEM), post-filter Ca(i) 0.23 +/- 0.01 mmol/l, base excess -0.39
      +/- 0.4 mmol/l, serum sodium 137 +/- 4 mmol/l, mean serum creatinine 1.8 +/- 0.07
      mg/dl). Normal base excess was achieved with a mean dialysate bicarbonate
      concentration of 26 mmol/l at a mean citrate infusion rate of 266 +/- 4 ml/h.
      After 48 hours, 25% of filters were still patent, mean filter life was 26 +/- 1.6
      hours. No patient developed serious CVVHD-related adverse events. CONCLUSION: The
      new regional citrate anticoagulation system for CVVHD is safe, feasible and can
      avoid major complications of previously described methods, especially
      hypocalcemia, alkalosis and hypernatremia.

PMID- 12608554
TI  - Content of reticulocyte hemoglobin is a reliable tool for determining iron
      deficiency in dialysis patients.
AB  - BACKGROUND: The evaluation of iron status in dialysis patients provides
      information essential to the planning of adequate recombinant human
      erythropoietin (rHuEPO) treatment. Iron status of the patients can be determined
      from the recently available measurement of content of reticulocyte hemoglobin
      (CHr). METHODS: In this study, to clarify the accuracy of CHr in diagnosing iron
      deficiency in hemodialysis (HD) patients, we initially compared CHr with such
      conventional iron parameters as serum ferritin levels, transferrin saturation and
      serum soluble transferrin receptor levels. Secondly, we investigated the changes
      in CHr during iron supplementation for iron-deficient patients to determine
      whether this marker is a prospective and reliable indicator of iron sufficiency.
      The participants in this study were 149 hemodialysis (HD) patients and 53 age
      matched healthy subjects. Iron deficiency was defined as having a TSAT of less
      than 20% and serum ferritin of less than 100 ng/ml. Conventional parameters of
      red blood cells and CHr were measured by an ADVIA120 autoanalyzer. RESULTS: Mean
      CHr was 32.3 +/- 2.2 pg in the patients undergoing hemodialysis treatment. CHr
      significantly correlated with iron parameters in the dialysis patients. Logistic
      regression analysis was performed to determine the relationship between CHr and
      each outcome measure, and CHr was the significant multivariate predictor of iron
      deficiency. Iron supplements given to the patients with low CHr and hematocrit
      (Hct) significantly increased Hct, resulting in a decrease in the weekly dosage
      of rHuEPO. CONCLUSIONS: CHr, measured simultaneously with Hct, is a sensitive and
      specific marker of iron status in dialysis patients.

PMID- 12608555
TI  - Plasma serotonin and histamine levels in hemodialysis-related pruritus are not
      significantly influenced by 5-HT3 receptor blocker and antihistaminic therapy.
AB  - BACKGROUND: Elevated plasma histamine levels are considered to play a part in the
      pathophysiology of hemodialysis-related pruritus. However, antihistaminic therapy
      often fails to provide sufficient relief. Elevated serotonin levels in patients
      on dialysis therapy have also been described but the effects of 5-HT3 receptor
      antagonists on hemodialysis-related pruritus remain controversial. METHODS: we
      conducted a study to determine plasma histamine and serotonin levels before and
      after treatment with 5-HT3 receptor antagonists (tropisetron 5 mg and ondansetron
      8 mg) and an antihistamine (cetirizine 10 mg). Eleven hemodialysis patients with
      a history of pruritus participated in this study,10 healthy volunteers served as
      control group. RESULTS: Histamine and serotonin values were normal in patients
      and controls. Treatment with cetirizine did not significantly reduce histamine
      levels in patients or in controls. Tropisetron and ondansetron likewise did not
      alter serotonin levels in patients. Tropisetron treatment did not significantly
      change serotonin levels in controls. CONCLUSION: Histamine and serotonin are no
      major mediators of pruritus in hemodialysis patients. Elevated histamine levels
      are occassionally seen and may be due to the increased mast cell number found in
      a subgroup of hemodialysis patients. Our findings explain the only marginal
      relief of antihistamines and the controversial antipruritic effect of serotonin
      receptor antagonists in hemodialysis-related pruritus.

PMID- 12608556
TI  - Increasing blood flow increases kt/V(urea) and potassium removal but fails to
      improve phosphate removal.
AB  - BACKGROUND: Hyperphosphatemia and hyperkalemia are major determinants of
      morbidity and mortality in hemodialysis patients. Half of the dialysis population
      suffers from hyperphosphatemia which is now recognized as an important
      cardiovascular disease risk factor. It is, therefore, necessary to improve the
      removal of these molecules. In this study, we investigated the effect of
      enhancing blood flow on Kt/V for urea (Kt/Vu), potassium and phosphate removal.
      METHODS: Thirteen patients were investigated in a randomized, cross-over,
      prospective study using 3 blood flows (Qb) of 200,250 and 300 ml/min which gave
      39 standardized high-flux hemodialysis treatments. Effective blood flows were
      measured by ultrasonic flow meter. Quantification of delivered dialysis dose was
      performed by partial dialysate and ultrafiltrate collection for the determination
      of potassium and phosphate removal and by blood urea concentrations for
      determination of Kt/Vu. RESULTS: Kt/Vu rose significantly from 1.10 +/- 0.14 to
      1.22 +/- 0.14 and finally to 1.39 +/- 0.16 (p = 0.0001) with increasing Qb
      similar to the increase in potassium removal from 53.0 +/- 2.4 to 63.4 +/- 2.6
      and to 74.2 +/- 3.8 mMol (p = 0.01). Phosphate removal only improved from 28.1 +/
      1.3 to 31.4 +/- 1.5 (p = 0.050) when Qb was increased from 200 to 250 ml/min but
      remained unchanged at 31.2 +/- 1.5 mMol (NS compared to phosphate removal at Qb =
      250 ml/min) when Qb was increased to 300 ml/min. CONCLUSIONS: Increasing
      delivered Kt/Vu and potassium removal with higher Qb fails to produce the same
      desired effect with phosphate removal during high-flux hemodialysis.

PMID- 12608557
TI  - Membranous glomerulopathy and acute interstitial nephritis following treatment
      with celecoxib.
AB  - Both membranous glomerulopathy and acute interstitial nephritis have been
      reported to occur following treatment with non-steroidal anti-inflammatory drugs.
      We report the first cases of membranous glomerulopathy and acute interstitial
      nephritis following treatment with celecoxib (Celebrex), a selective COX-2
      inhibitor. The rapid and complete resolution of both conditions following
      discontinuation of Celebrex strongly implicates this agent in disease
      pathogenesis. These cases enlarge the spectrum of potential renal toxicities of
      the COX-2-specific non-steroidal anti-inflammatory drugs.

PMID- 12608559
TI  - Evolution of bone stiffness in renal transplant patients measured by quantitative
      ultrasound.

PMID- 12608558
TI  - WT-1 and NPHS2 mutation analysis in patients with non-familial steroid-resistant
      focal-segmental glomerulosclerosis.
AB  - BACKGROUND: Familial forms of steroid-resistant nephrotic syndrome with the
      histologic findings of focal-segmental glomerulosclerosis have frequently a
      genetic basis. For the non-familial forms this is still unresolved. PATIENTS AND
      METHODS: Ten children with non-familial steroid-resistant nephrotic syndrome
      along with focal-segmental glomerulosclerosis were tested for mutations in the WT
      1 and NPHS2 genes. RESULTS: In 1 patient, a mutation in intron 9 of the WT-1 gene
      and in 1 patient a heterozygous NPHS2 mutation could be detected. Both
      abnormalities are important for the treatment modalities and prognosis.
      CONCLUSION: Additional studies will have to provide a solid basis for the
      recommendation of mutation analysis in non-familial steroid-resistant focal
      segmental glomerulosclerosis.

PMID- 12608560
TI  - A case of early onset cyclosporine-induced hemolytic uremic syndrome resulting in
      renal graft loss.

PMID- 12608561
TI  - Fluctuating levels of anti-GBM antibodies following a fungal infection in a
      patient with secondary amyloidosis.

PMID- 12608562
TI  - Characterization of a novel ranavirus isolated from grouper Epinephelus tauvina.
AB  - A large icosahedral virus was isolated from diseased grouper Epinephelus tauvina.
      The virus grew well in several cultured fish cell lines, with stable and high
      infectivity after serial passages in grouper cell line (GP). The virus was
      sensitive to both acid and heat treatments. Virus replication was inhibited by 5
      iodo-2-deoxyuridine (IUDR), indicative of a DNA-containing genome. The virus
      infectivity was reduced with ether treatment, suggesting that the virus was lipid
      enveloped. Electron micrographs showed abundant cytoplasmic icosahedral virons in
      the virus-infected GP cells. The size of the intracellular nucleocapsid was 154
      nm between the opposite sides, or 176 nm between the opposite vertices with an
      inner electron-dense core of 93 nm. Virus particles were released through budding
      from plasma membranes with a size of 200 nm in diameter. SDS-PAGE of purified
      virus revealed 20 structural protein bands and a major capsid protein (MCP) of 49
      kDa. A DNA fragment of approximately 500 nucleotides was successfully amplified
      by polymerase chain reaction (PCR) using the primers from conserved regions of
      the MCP gene of frog virus 3 (FV3), the type species of Ranavirus. Subsequent
      multiple alignment and phylogenetic analysis showed that the newly isolated
      grouper virus was closely related to largemouth bass virus (LMBV), FV3 and Regina
      ranavirus (RRV). Our data suggests that the virus isolate is a novel member of
      genus Ranavirus, family Iridoviridae. We tentatively name the virus as Singapore
      grouper iridovirus (SGIV). SGIV was able to cause serious systemic disease
      capable of killing 96% of grouper fry.

PMID- 12608564
TI  - Molecular detection methods developed for a systemic rickettsia-like bacterium
      (RLB) in Penaeus monodon (Decapoda: Crustacea).
AB  - Molecular detection methods were developed to aid in the diagnosis of a
      rickettsia-like bacterium (RLB) which caused severe mortalities of farm-raised
      Penaeus monodon in Madagascar. Using primers derived from the 16S rRNA gene of
      bacteria, a PCR assay was optimized to amplify this region of the genome of the
      RLB, using extracted DNA from infected P. monodon tissue as the template. The
      resulting amplified PCR product was sequenced and 2 novel primers were selected
      from the variable region of the gene. These primers amplified a 532 bp fragment
      of DNA originating from the rickettsia-infected samples. The PCR assay was
      optimized and tested on DNA extracted from specific pathogen-free (SPF) P.
      vannamei tissue and several other strains of bacteria. The PCR assay with the
      rickettsia-specific primers was specific for this RLB and did not amplify the
      other DNA samples tested. The 532 bp PCR-amplified fragment was labeled with
      digoxigenin (DIG) for in situ hybridization assays. This probe was tested on SPF,
      RLB and bacteria-infected shrimp specimens preserved in Davidson's fixative. The
      probe was specific for both natural and experimental rickettsial infections.
      Hybridization with this probe required a stringent temperature of 65 degrees C,
      otherwise cross-reactivity was observed with other types of bacteria.

PMID- 12608563
TI  - Highly conserved sequences of three major virion proteins of a Korean isolate of
      white spot syndrome virus (WSSV).
AB  - In Korea, mass mortality occurred among cultured shrimp with visible macroscopic
      white spots in 2000, and we confirmed the presence of white spot syndrome virus
      (WSSV) in the tissues of moribund shrimp by electron microscopy. In order to
      identify the characteristics of this Korean isolate of WSSV, we cloned and
      characterized its genomic DNA coding for VP24, VP26, and VP28. On the nucleotide
      level, VP24, VP26, and VP28 of the Korean isolate were found to be 100%, 100%,
      and 99% identical to those of Taiwan, Thailand and Chinese isolates,
      respectively. On the deduced amino-acid level, all 3 virion proteins showed 100%
      identity to those of the foreign isolates. The extent of sequence identity
      suggests that the Korean isolate originated from the same ancestor as the
      Taiwanese, Thai and Chinese isolates.

PMID- 12608565
TI  - Characterization of strains of Vibrio splendidus and V. tapetis isolated from
      corkwing wrasse Symphodus melops suffering vibriosis.
AB  - Two vibrio bacteria pathogenic to the corkwing wrasse Symphodus melops were
      isolated. Vibriosis-inducing strain LP1 was isolated as the dominanting bacterium
      in kidney samples of dead and moribund wrasse from a population suffering
      vibriosis and high daily mortality in 1998 on the Norwegian west coast. The other
      vibriosis-inducing strain, LP2, was isolated from wrasse captured the following
      year. Re-infection experiments have confirmed that these strains cause vibriosis
      in corkwing wrasse. Both strains were typical vibrios sharing the traits of
      fermentative Gram-negative curved rods with motility and a positive oxidase
      reaction. Detailed biochemical and genetic characterisation revealed a close
      affiliation to known species of the marine environment. The first isolate, LP1,
      is a form of the ubiquitous seawater organism Vibrio splendidus, while the second
      isolate, LP2, is closely related to V. tapetis (previously only known as the
      brown ring disease agent in clams). Identification of the new wrasse pathogens V.
      splendidus LP1 and V. tapetis LP2 is facilitated by break points observed in this
      study.

PMID- 12608566
TI  - Bacteriophage control of Pseudomonas plecoglossicida infection in ayu
      Plecoglossus altivelis.
AB  - Two previously isolated phages were used to examine the therapeutic effects
      against Pseudomonas plecoglossicida infection in ayu Plecoglossus altivelis.
      Phage PPp-W4 (Podoviridae) inhibited the in vitro growth of P. plecoglossicida
      more effectively than Phage PPpW-3 (Myoviridae), and a mixture (PPpW-3/W-4) of
      the 2 phages exhibited the highest inhibitory activity. In phage therapy
      experiments, ayu were fed P. plecoglossicida-impregnated feed (10(7) CFU fish(
      1)) and then fed phage-impregnated feed (10(7) PFU fish(-1)). Mortalities of fish
      receiving PPpW-3, PPpW-4, PPpW-3/W-4, and a control fish receiving no phages were
      53.3, 40.0, 20.0 and 93.3%, respectively. Phage (PPpW-3/W-4)-receiving fish also
      showed high protection against water-borne infection with P. plecoglossicida. In
      a field trial, when phage (PPpW-3/W-4)-impregnated feed was administered to ayu
      in a pond where the disease occurred naturally, daily mortality of fish decreased
      at a constant level (5% d(-1)) to one-third after a 2 wk period. The causal
      relationship of phages in this phenomenon was verified by the long-lasting
      appearance of administered phages in the kidneys of the fish, and a disappearance
      of P. plecoglossicida from apparently healthy fish. Neither phage-resistant
      organisms nor phage-neutralizing antibodies were detected in diseased fish or
      apparently healthy fish, respectively. These results indicate the potential for
      phage control of the disease.

PMID- 12608567
TI  - Bacteraemia in free-ranging Hawaiian green turtles Chelonia mydas with
      fibropapillomatosis.
AB  - Past studies of free-ranging green turtles Chelonia mydas with
      fibropapillomatosis (FP) in Hawaii have shown that animals become
      immunosuppressed with increasing severity of this disease. Additionally,
      preliminary clinical examination of moribund turtles with FP revealed that some
      animals were also bacteraemic. We tested the hypothesis that bacteraemia in sea
      turtles is associated with the severity of FP. We captured free-ranging green
      turtles from areas in Hawaii where FP is absent, and areas where FP has been
      endemic since the late 1950s. Each turtle was given an FP severity score ranging
      from 0 (no tumours) to 3 (severely affected). A fifth category included turtles
      that were stranded ashore and moribund with FP. We found that the percentage of
      turtles with bacteraemia increased with the severity of FP, and that the majority
      of bacteria cultured were Vibrio spp. Turtles with severe FP were more
      susceptible to bactaeremia, probably in part due to immunosuppression. The
      pattern of bacteraemia in relation to severity of disease strengthens the
      hypothesis that immunosuppression is a sequel to FP.

PMID- 12608568
TI  - Prevalence of a single fish-pathogenic Saprolegnia sp. clone in Finland and
      Sweden.
AB  - Thirty-one isolates of Saprolegnia sp., most originating from infected salmon or
      trout, were characterised genetically and physiologically. The majority (6 of 31)
      of the isolates from several widely separated geographical locations was found to
      be genetically almost identical as assessed by RAPD-PCR. The remaining isolates
      belonged to 3 different groups with 1 to 3 representatives each. It is suggested
      that the first group of isolates represents a virulent form of the organism that
      has been widely spread by clonal propagation. The ability to repeated zoospore
      emergence, as an alternative to direct germination, seems to characterise
      specific Saprolegnia genotypes that may have adapted to certain hosts.

PMID- 12608569
TI  - Ultrastructural aspects of the myxosporean Henneguya astyanax n. sp. (Myxozoa:
      Myxobolidae), a parasite of the Amazonian teleost Astyanax keithi (Characidae).
AB  - This study reports light and electron microscopical aspects of a myxosporean
      found in the gills of the freshwater teleost Astyanax keithi Gery, Planquete & Le
      Bail, 1996 (family Characidae), collected from the estuarine region of the Amazon
      River, near Belem, Brazil. The prevalence of infection was 23%. In interlamellar
      spaces of the gills, ellipsoidal whitish cyst-like plasmodia structures were
      present, which contained spores. The spores had a spermatozoa-like appearance
      (47.8 +/- 0.71 microm in total length) with a fusiform body (15.2 +/- 0.77 pm in
      length, 5.7 +/- 0.71 microm in width and 4.2 +/- 0.31 microm in thickness), and
      each of the 2 valves presented a tapering tail (32.6 +/- 1.11 microm in length).
      The valves surrounded a binucleate sporoplasm cell and 2 polar capsules (5.0 +/-
      0.13 microm in length, 1.5 +/- 0.07 microm in width) that contained 8 to 9 coils
      of the polar filament. In the sporoplasm, several unique sporoplasmosomes were
      visible. A synoptic table of spore measurements of known Brazilian Henneguya
      species is presented. The spores differed from those of previously described
      species. Based on spore morphology, it is concluded that this species belongs to
      the family Myxobolidae, genus Henneguya, and that it constitutes a new species:
      H. astyanax n. sp.

PMID- 12608570
TI  - Molecular analysis of a haplosporidian parasite from cultured New Zealand abalone
      Haliotis iris.
AB  - In the Austral summer and autumn of 2000 and 2001, mortalities of black-footed
      abalone Haliotis iris (Martyn, 1784) occurred in a commercial facility in New
      Zealand. Histological analyses suggested that infection by a haplosporidian
      parasite was responsible. To confirm identification as a haplosporidian and to
      help determine if this parasite represented a new, undescribed species, DNA was
      extracted from infected host tissues scored as positive for infection by
      histological examination. Small-subunit rRNA (SSU rRNA) gene sequences from both
      the host abalone and a parasitic organism were amplified by PCR and
      characterized. Although the sequence for this parasite was novel, not matching
      any known SSU rRNA gene sequences, phylogenetic analyses strongly supported
      grouping this parasite with the haplosporidians. Parsimony analyses placed the
      parasite at the base of the phylum Haplosporidia, ancestral to Urosporidium
      crescens and the Haplosporidium, Bonamia, and Minchinia species. Sequencing of
      multiple parasite DNA clones revealed a single polymorphic site in the
      haplosporidian SSU rRNA gene sequence.

PMID- 12608571
TI  - Monitoring the prevalence of the parasitic dinoflagellate Hematodinium sp. in
      snow crabs Chionoecetes opilio from Conception Bay, Newfoundland.
AB  - Bitter crab disease (BCD) of snow crabs Chionoecetes opilio is caused by a
      parasitic dinoflagellate, Hematodinium sp. In Newfoundland's commercial fishery,
      infected snow crabs are identified using visual, macroscopic signs of disease for
      separation prior to processing. We estimated the sensitivity and specificity of
      gross, macroscopic diagnosis of Hematodinium sp. by comparing these results with
      microscopic examination of prepared hemolymph smears. The sensitivity of a
      diagnostic test is the probability that the test will yield a positive result
      given that the animal has the disease. The specificity is the probability of a
      negative result given the animal is not diseased. In October 1998, we conducted a
      design-based survey using cluster sampling in 2 strata. Over 10 000 snow crabs
      from pot and trawl surveys were examined macroscopically for BCD. In addition,
      over 350 crabs were randomly examined microscopically for disease. The double
      sampling resulted in an estimated sensitivity of 52.7% and an estimated
      specificity of 100%. That is, a positive result from macroscopic examination is
      definitive, if the observer is well trained, but macroscopic examination will
      fail to detect infections in crabs with borderline clinical signs of disease. The
      prevalence estimated from macroscopic observations (p(st) = 2.24%) was corrected
      for misclassification by dividing p(st) by the estimated sensitivity (0.527),
      giving a corrected estimate of 4.25%. The use of double sampling provides for
      efficient estimation of prevalence in that large numbers of crabs can be quickly
      examined for gross signs of infection and the results corrected for
      misclassification based on a limited number of observations with a better, but
      time-consuming test. In addition, the prevalence of macroscopically infected male
      crabs was lower in a trap survey (0.57%) compared to a trawl survey (1.59%). In
      the trawl survey, female crabs had a significantly higher prevalence of
      macroscopically diagnosed infections than males (6.34%). The prevalence of BCD
      has shown an alarming increase since it was first detected in Newfoundland during
      the early 1990s. Transmission and mortality studies are warranted to better
      understand the effect of the disease on its commercially important host.

PMID- 12608572
TI  - Helminth parasites of the southern sea otter Enhydra lutris nereis in central
      California: abundance, distribution and pathology.
AB  - From October 1997 to May 2001, the gastrointestinal tracts from 162 beach-cast
      southern sea otters Enhydra lutris nereis were examined for helminth parasites
      and associated lesions. Carcasses were collected opportunistically in central
      California between Pt. San Pedro and Pt. Arguello. The primary goals of this
      study were to examine spatial and temporal variability in mortality due to
      parasite infection, identify factors associated with increased risk of infection,
      and illustrate the process of intestinal perforation by Profilicollis spp. Two
      genera and 4 species of acanthocephalans (Profilicollis altmani, P. kenti, P.
      major, Corynosoma enhydri) were found in 46.3% (Profilicollis spp.) and 94.4% (C.
      enhydri) of the carcasses examined. Three species of Digenea (Microphallus pirum,
      M. nicolli, Plenosoma minimum) were found in 47% of carcasses, at times in
      massive numbers (> 3000 per cm2). This is the first report of the latter 2
      species from the sea otter. Mortality resulting from infection by Profilicollis
      spp. occurred in 13.0% (n = 21) of sampled carcasses, either directly, due to
      perforation of the intestinal wall and peritonitis (9.9%, n = 16), or indirectly,
      due to inhibition of host nutrient uptake or depletion of host energy reserves to
      fight chronic infections (3.1%, n = 5). The most massive infections (< 8760
      parasites), and all cases of intestinal perforation occurred in carcasses
      infected by P. altmani and/or P. kenti. Mortality due to infection by
      Profilicollis spp. occurred more frequently among juvenile and old-adult females
      (chi2 = 17.479, df = 9, p = 0.045) from sand and mixed habitats in Monterey and
      Santa Cruz in the north of the sea otter range (chi2 = 9.84, df = 4, p = 0.045).
      Spatial differences in sea otter mortality coincided with the relative
      distributions of Profilicollis altmani, P. kenti, and P. major, and may reflect
      differences in sea otter diet, or differences in intensity of infection in
      intermediate hosts. Mortality rate due to infection by Profilicollis spp.
      decreased between 1998 and 2001, though differences were not significant (chi2 =
      3.983, df = 3, p = 0.40), and may vary on multi-year cycles due to environmental
      factors such as density of definitive hosts (e.g. the surf scoter Melanitta
      perspicillata), or El Nino. Corynosoma enhydri did not cause significant damage
      to the intestine of the host, even when present in great numbers.

PMID- 12608573
TI  - Ovacystis-like condition in the eastern oyster Crassostrea virginica from the
      northeastern Gulf of Mexico.
AB  - Histological examination of the eastern oyster Crassostrea virginica from a study
      in Pensacola Bay, Florida, revealed 2 cases of abnormally large, basophilic ova
      that resembled cells characteristic of ovacystis disease previously reported in
      oysters from Maine and Long Island. The hypertrophied gametes measured up to 250
      pm in diameter, had scant cytoplasm and contained granular nuclear-masses of
      Feulgen-positive material. Electron microscopy of reclaimed tissue revealed these
      masses to consist of virus-like particles (average 46 nm) similar to those
      reported in cases of ovacystis.

PMID- 12608574
TI  - Genetic material in the early evolution of bacteria.
AB  - DNA and RNA are nucleic acids that cells and viruses use to produce copies of
      themselves. However, there is an immense paucity of knowledge on how these
      nucleic acids originated and changed as early bacteria became capable of growth
      and cell division. One possibility is that parallel evolution of the genetic code
      and protein synthesis was required for assembly of the first cells capable of
      growth and division. It is also possible that DNA-RNA duplices were intermediate
      genetic material in the early assembly of the first cells. These ideas will be
      discussed as well as other aspects of the assembly of the first cells on the
      Earth.

PMID- 12608575
TI  - An alternative model of the twin arginine translocation system.
AB  - The twin arginine translocation (Tat) system is a machinery which can translocate
      folded proteins across energy transducing membranes. Currently it is supposed
      that Tat substrates bind directly to Tat translocon components before a ApH
      driven translocation occurs. In this review, an alternative model is presented
      which proposes that membrane integration could precede Tat-dependent
      translocation. This idea is mainly supported by the recent observations of Tat
      independent membrane insertion of Tat substrates in vivo and in vitro. Membrane
      insertion may allow i) a quality control of the folded state by membrane bound
      proteases like FtsH, ii) the recognition of the membrane spanning signal peptide
      by Tat system components, and iii) a pulling mechanism of translocation. In some
      cases of folded Tat substrates, the membrane targeting process may require ATP
      dependent N-terminal unfolding-steps.

PMID- 12608576
TI  - Poly(3-hydroxybutyrate) (PHB) synthesis by recombinant Escherichia coli
      harbouring Streptomyces aureofaciens PHB biosynthesis genes: effect of various
      carbon and nitrogen sources.
AB  - Recombinant Escherichia coli (ATCC:PTA-1579) harbouring poly(3-hydroxybutyrate)
      (PHB) synthesising genes from Streptomyces aureofaciens NRRL 2209 accumulates
      PHB. Effects of different carbon and nitrogen sources on PHB accumulation by
      recombinant E. coli were studied. Among the carbon sources used glycerol,
      glucose, palm oil and ethanol supported PHB accumulation. No PHB accumulated in
      recombinant cells when sucrose or molasses were used as carbon source. Yeast
      extract, peptone, a combination of yeast extract and peptone, and corn steep
      liquor were used as nitrogen sources. The maximum PHB accumulation (60% of cell
      dry weight) was measured after 48 h of cell growth at 37 degrees C in a medium
      with glycerol as the sole carbon source, and yeast extract and peptone as
      nitrogen sources. Scanning electron microscopy of the PHB granules isolated from
      recombinant E. coli revealed these to be spherical in shape with a diameter
      ranging from 0.11 to 0.35 pm with the mean value of 0.23 +/- 0.06 pm.

PMID- 12608577
TI  - Fusarium graminearum and deoxynivalenol contamination in the durum wheat area of
      Argentina.
AB  - Fusarium graminearum head blight of wheat is a destructive disease of the world's
      wheat-growing areas. This work was performed to analyze the distribution and
      contamination of deoxynivalenol (DON) and its relationship with F. graminearum
      kernel invasion in Argentina durum wheat area during two consecutive harvests. A
      total of 147 samples (cultivars and lines) of durum wheat from 5 locations of the
      major cropping area (Southern Buenos Aires Province) were analyzed. Percentage of
      F. graminearum kernel infection was evaluated following the blotter test (ISTA
      method) and fusarotoxins were analyzed by thin layer chromatography. None of the
      varieties and lines were free of F. graminearum infection. In the first harvest
      fungal invasion was very low. From 40 samples, 55% showed DON contamination but
      only 4 samples (10%) were higher than 2 ppm. In the second harvest, a crop year
      conducive to scab development, the highest level of F. graminearum kernel
      invasion observed was 42% on a sample from the humid area (eastern Buenos Aires
      Province) DON was detected in 47 (78.2%) of 60 samples analyzed and 19 (31.6%)
      showed levels of DON higher than those established in the guidelines in Canada
      and USA for food and feedstuff. In both years all locations situated in the humid
      area showed levels ranging from 0 to > 8 ppm. Within the durum wheat area
      differences among locations were found. This analysis indicates the need for more
      information on the problem and distribution of Fusarium mycotoxins in durum wheat
      grown in Argentina.

PMID- 12608578
TI  - Cloning of Acinetobacter calcoaceticus chromosomal region involved in catechin
      degradation.
AB  - Acinetobacter calcoaceticus utilizes catechin as sole carbon source. The
      chromosomal region involved in catechin catabolism was cloned in Escherichia coli
      DH5alpha from the genomic DNA of A. calcoaceticus. A recombinant E. coli
      containing 9.2 kb DNA fragment of A. calcoaceticus inserted in pUC19 showed a
      halo zone around the colony in plate assays, indicating the catechin utilizing
      ability of the clone. Enzyme assays revealed the expression of the cloned DNA
      fragment of A. calcoaceticus. High performance thin layer chromatography
      confirmed protocatechuic acid and phloroglucinol carboxylic acid as cleavage
      products of catechin in A. calcoaceticus and the catechin degrading ability of
      the clones. A. calcoaceticus followed the beta-ketoadipate pathway for catechin
      degradation. The sub-clone (pASCI) of this insert was sequenced and analyzed. The
      sequence showed three major ORFs but only ORF 2 showed similarities to other
      aromatic oxygenases and the sequence of ORF 2 was submitted to GenBank
      (AF369935).

PMID- 12608580
TI  - Overexpression and increased DNA topoisomerase II-like enzyme activity in
      arsenite resistant Leishmania donovani.
AB  - Western immunoblot analyses of whole cell lysates probed with a human specific
      monoclonal anti-topoisomerase IIalpha antibody identified a 190 kDa protein over
      expressed in the arsenite resistant Leishmania donovani strain. The crude nuclear
      extract of the resistant strain showed higher topoisomerase II-like enzyme
      activity. suggesting a possible regulatory role of putative topoisomerase II in
      arsenite resistant Leishmania.

PMID- 12608579
TI  - Molecular diversity in the bacterial community and the fluorescent pseudomonads
      group in natural and chlorobenzoate-stressed peat-forest soil.
AB  - Bacterial community shifts in a soil microcosm spiked with 3-chlorobenzoate or
      2,5-dichlorobenzoate were monitored. The V6-V8 variable regions of soil bacterial
      16S rRNA and rDNA were amplified and separated by temperature gradient gel
      electrophoresis (TGGE) profiling. Culturing in the presence of 2.5 mM chlorinated
      benzoates suppressed 10 to 100 fold the total aerobic bacterial community but had
      no effect on the diversity within the group of fluorescent pseudomonads. In
      contrast, the uncultured bacterial community showed a decrease in the number of
      bands in the TGGE profiles of the chlorobenzoate-spiked treatments. Accordingly,
      the Shannon's diversity and equitability indices of these treatments reflected a
      decreasing trend in time. The approach allowed a direct assessment of community
      shifts upon contamination of soil.

PMID- 12608581
TI  - Bioremediation of chromium by the yeast Pichia guilliermondii: toxicity and
      accumulation of Cr (III) and Cr (VI) and the influence of riboflavin on Cr
      tolerance.
AB  - A comparative study has been made on the sensitivity of the yeast Pichia
      guilliermondii to Cr (III) and Cr (VI) as well as on the Cr uptake potential at
      growth-inhibitory concentrations of chromium. The strains used in the study were
      either isolated from natural sources or obtained from a laboratory strain
      collection. The results show that most of the natural strains were more tolerant
      to chromium and were able to grow in the presence of 5 mM Cr (III) or 0.5 mM Cr
      (VI), that is at concentrations which substantially inhibited the growth of
      laboratory strains. The cellular Cr content after treatment was similar for both
      strain types and ranged from 1.2-4.0 mg/g d.w. and 0.4-0.9 mg/g d.w., for Cr
      (III) and Cr (VI) forms, respectively, however, in one case of a natural strain
      it reached the value of 10 mg Cr (III)/g dry mass. Natural-source strains were
      grouped into four groups based on the yeasts' differential response to Cr (III)
      and Cr (VI). Hexavalent Cr-resistant mutants of a P. giuilliermondii laboratory
      strain, which revealed markedly changed capabilities of chromium accumulation,
      were obtained by means of UV-induced mutagenesis. Cr (VI) treatment triggered
      oversynthesis of riboflavin and the addition of exogenous riboflavin increased P.
      guilliermondii resistance to both Cr (III) and Cr (VI). Electrophoretic protein
      profiles revealed the induction and/or suppression of several proteins in
      response to toxic Cr (VI) levels.

PMID- 12608582
TI  - Essential role of magnesium ion in water for colonization of Helicobacter pylori
      in 2-week-old miniature pigs.
AB  - This study was designed to determine whether magnesium ion in water would
      influence the colonization of Helicobacter pylori in 2-week-old miniature pigs.
      Groups A (2 pigs) and B (1 pig) were both fed a milk diet dissolved in drinking
      water, Group C (2 pigs) was fed a milk diet dissolved in deionized distilled
      water (DDW), and Group D (1 pig) was fed a milk diet dissolved in DDW
      supplemented with MgCl2. Groups B, C, and D were all challenged with H. pylori,
      and Group A was not. Necropsy was performed on the pigs on postinfection Day 5,
      and biopsy specimens were taken from 16 sites of the stomach. H. pylori were
      recovered from 11 of 16 sites in Group B, 1 of 32 sites in Group C, and 13 of 16
      sites in Group D. On the other hand, the degree of lymphocyte infiltration
      increased in the order of Group A < Group B < Group C < Group D. These
      observations suggest that magnesium ion in drinking water is essential for the
      colonization of H. pylori in the pig stomach. Possible mechanisms for the
      lymphocyte infiltration are discussed.

PMID- 12608583
TI  - Combat of iron-deprivation through a plant growth promoting fluorescent
      Pseudomonas strain GRP3A in mung bean (Vigna radiata L. Wilzeck).
AB  - Microorganisms and plants sustain themselves under iron-deprived conditions by
      releasing siderophores. Among others, fluorescent pseudomonads are known to exert
      extensive biocontrol action against soil and root borne phytopathogens through
      release of antimicrobials and siderophores. In this study, production and
      regulation of siderophores by fluorescent Pseudomonas strain GRP3A was studied.
      Among various media tested, standard succinate medium (SSM) promoted maximum
      siderophore production of 56.59 mg l(-1). There were low levels of siderophore in
      complex media like King's B medium, trypticase soya medium and nutrient medium
      (41.27, 29.86 and 27.63 mg l(-1)), respectively. In defferrated SSM, siderophore
      level was quantified to be 68.74 mg l(-1). Supplementation with iron (FeCl3)
      resulted in decreased siderophore levels depending on concentration. Siderophore
      production was promoted by Zn2+ (78.94 mg l(-1)), Cu2+ (68.80 mg l(-1)) whereas
      Co2+ (57.33 mg l(-1)) and Fe3+ reduced siderophore production (37.44 mg l(-1) as
      compared to control (55.97 mg l(-1)). Strain GRP3A showed plant growth promotion
      under iron limited conditions.

PMID- 12608584
TI  - Protection against malaria among seafarers.
AB  - Malaria infections contracted by seafarers in ports of malarious countries may
      cause loss of lives and inflict serious suffering and temporary incapacitation.
      The risk of infection varies according to the epidemiological situation in the
      port areas. Infections with Plasmodium falciparum pose the most serious threat.
      In most of the endemic countries this is compounded by the parasite's resistance
      to one or more of the common antimalarial drugs. Malaria risk highlights the need
      for preventive measures consisting of exposure prophylaxis, under conditions of
      moderate and high risk complemented by chemoprophylaxis. This paper provides
      guidelines for the protection of seafarers under various conditions of exposure
      to infection. It also covers action when manifest malaria occurs on board.

PMID- 12608585
TI  - Gas permeable materials improve safety of life saving appliances.
AB  - Spray-hoods are additional items of life jackets. They are very effective in
      reducing water contact of the breathing openings when victims have to stay in
      rough seas without boat or life raft. A life raft is also a very important life
      saving device. But both have a system problem. They consist of a more or less
      encapsulated space in which humans have to breathe. To ensure a sufficient amount
      of oxygen and to reduce the amount of carbon dioxide, spray-hoods have
      ventilation openings which reduce the efficiency of this equipment, but most of
      the life rafts have no ventilation. In a series of tests we used a new gas
      permeable material for the hoods. This reduced the flooding of victims to a very
      little amount, while O2 and CO2 stayed at acceptable levels. Our experiments with
      conventional rafts showed that the O2 level went down to less than 15% within 50
      minutes while CO2 went up to 6%. These are dangerous levels. The canopy of some
      of the life rafts were modified with the above mentioned new gas permeable
      material. Identical rafts were used in comparative trials. The tests showed
      positive results for the new material. The minimum O2 level stayed at 20.2% and
      CO2 reached a maximum of 0.52%. The results prove that this material can lead to
      a much safer rescue system than the systems used so far.

PMID- 12608586
TI  - The evidence base for maritime medical standards.

PMID- 12608587
TI  - Maritime health: a case for preventing influenza on the high seas.
AB  - For decades cruise ships have been recognized as foci for diarrheal illness. More
      recently influenza has been added to the list of diseases for which people on
      cruise ships are at risk. Influenza is a business risk involving cruise ship
      operating and litigation costs and travelers' loss in value. Immunizing the crews
      could be one way to prevent introduction and spread of influenza on cruise ships.
      A cost-effectiveness analysis for vaccination of crews on cruise ships was
      conducted showing that it is not only cost-effective but it is cost savings.

PMID- 12608588
TI  - Mortality from disease among seafarers in British merchant shipping (1976-1995).
AB  - OBJECTIVE: To establish the cause and circumstances of all deaths from disease
      among seafarers who were working in British merchant shipping between 1976 and
      1995. Further aims were to discuss implications for reducing mortality and for
      maritime health care. METHODS: A retrospective study of occupational mortality,
      based upon official mortality files, with a population of 983,119 seafarer-years
      at risk. RESULTS: Out of a total of 600 deaths from disease, 427 (71%) were
      caused by cardiovascular disease; 247 of the 427 (58%) were taken ill at sea and
      180 (42%) in port. Over 60% of the 427 who died from cardiovascular disease were
      off-duty at the time of onset and over 40% were found dead. Rates of evacuation
      to hospital before death from cardiovascular disease were 7% at sea and 9% in
      port. Fifty-five deaths from gastro-intestinal disease (9% of all deaths) were
      largely due to liver cirrhoses and stomach ulcers (14 each) and acute
      pancreatitis (seven). Trends in crude mortality rates for both cardiovascular and
      non-cardiovascular disease declined between 1976 and 1995. CONCLUSIONS: Seafarers
      are at special risks from acute illnesses since they lack direct access to
      specialist medical care. Prevention should be aimed at improvements in the use of
      radio-medical advice and in medical training for ship's officers. Also, since
      many deaths were linked to lifestyle factors such as smoking, obesity and heavy
      alcohol consumption, primary preventative advice would be of benefit.

PMID- 12608589
TI  - Radiomedical services for seafarers in Sweden.

PMID- 12608590
TI  - Travelling diabetics.
AB  - During the past several decades, the number of both business and tourist travels
      has greatly increased. Among them are persons suffering from chronic diseases,
      including diabetics for whom travels pose the additional health-hazard.
      Irrespective of better education, self-control and constantly improving quality
      of specialistic equipment available, diabetics still are the group of patients
      requiring particular attention. In the case of travelling diabetics, problems may
      occur concerning the transport and storage of insulin, as well as control of
      glycaemia, all caused by irregularity of meals, variable diet, physical activity,
      stress, kinetosis (sea voyages), and the change of time zones. The travel may as
      well evoke ailments caused by the change of climate and concomitant diseases such
      as traveller's diarrhoea, malaria, etc. Apart from avoiding glycaemia
      fluctuations, important for retaining health of diabetics is the prevention of
      other diseases and carrying the necessary drugs.

PMID- 12608591
TI  - Validation of diving decompression tables.
AB  - Research on the validation of decompression tables is one of the common subject
      areas of the co-operation undertaken between the Defence and Civil Institute of
      Environmental Medicine, Toronto, Canada, and The Naval Academy of Gdynia, Poland.
      For several years now, a systematic survey of diving technologies has been
      conducted among the target projects financed by the Polish State Committee for
      Scientific Research and the Polish Navy. Among the most important problems
      discussed have been various aspects of decompression safety. The present paper
      shows a study to standardise and unify validation procedures for decompression in
      the Polish Navy.

PMID- 12608592
TI  - Leukotriene-B4 concentrations in exhaled breath condensate and lung function
      after thirty minutes of breathing technically dried compressed air.
AB  - In previous studies it had been shown that leukotriene-B4 [LTB4] concentrations
      in the exhaled breath mirror the inflammatory activity of the airways if the
      respiratory tract has been exposed to occupational hazards. In diving the
      respiratory tract is exposed to cold and dry air and the nasopharynx, as the site
      of breathing-gas warming and humidification, is bypassed. The aim of the present
      study was to obtain LTB4-concentrations in the exhaled breath and spirometric
      data of 17 healthy subjects before and after thirty minutes of technically dried
      air breathing at normobar ambient pressure. The exhaled breath was collected non
      invasively, via a permanently cooled expiration tube. The condensate was measured
      by a standard enzyme immunoassay for LTB4. Lung function values (FVC, FEV1, MEF
      25, MEF 50) were simultaneously obtained by spirometry. The measured pre- and
      post-exposure LTB4- concentrations as well as the lung function values were in
      the normal range. The present data gave no evidence for any inflammatory activity
      in the subjects' airways after thirty minutes breathing technically dried air.

PMID- 12608593
TI  - Evolution of relation P1(P2) describing saturation decompressions after air
      hyperbaric expositions.
AB  - The basic problem in decompression is the limit of maximum tolerable change of
      pressure after diving. Due to the number of parameters involved in decompression
      models (bottom time, ambient pressure, exposition profile, content of breathing
      mixtures, properties of inert gases) the number of possible solutions is
      theoretically unlimited. Since the beginning of modern decompression models the
      starting point has been direct saturation decompression using air. The generally
      accepted form of solution is the linear relation between tolerable pressure P2
      after saturation exposition to pressure P1 described by the equation in the form
      P1 = P2 x A + B, where A and B are parameters obtained by experiments. Since the
      introduction of this equation values of parameters have been changing in order to
      decrease the rate of decompression illness. The aim of this study was to analyse
      and interpret the trend of those changes. Sixteen published models, including the
      one developed in our center, were compared and gradual change of parameters was
      identified. This trend should result in safer decompression systems.

PMID- 12608596
TI  - The German Sea Rescue Service (SAR).
AB  - The German Sea Rescue Service (GSRS) history, organisation and operations are
      presented. The institution was founded in 1865 to provide sea rescue services for
      the German coasts in the North Sea and in the Baltic Sea. Its fleet counts 61
      vessels based in 54 stations of the service. In 2001, the rescue crafts were
      called for assistance 2428 times and 207 lives were saved. The service is
      supported by voluntary donations.

PMID- 12608594
TI  - Changes of selected morphotic parameters and blood plasma proteins in blood of
      divers after a single short-time operational heliox exposure.
AB  - In the Polish Navy, deep-water dives, performed for the needs of the maritime
      industry, are conducted using our own national technology and trimix as a
      breathing medium. In this paper are presented the results obtained during a short
      time deep-water diving test using the principles of US Navy technology, combined
      with the use of diving equipment type AF-2 and heliox-type breathing mixture in
      the open circuit. In the performed examinations changes in clinical parameters
      were assessed viz.: blood morphology, hematocrit level, concentration of C3c, C4,
      IgG, IgA, IgM, CRP, concentration of fibrinogen and factor XII level, obtained 30
      minutes prior to commencement, immediately after completion, and 24 hours after
      termination of the exposure. The results thus generated were subjected to a
      preliminary analysis by the description of trends observed. It was revealed that
      the diving technology employed did not generate substantial changes in the
      examined parameters of blood in divers, and the increase of neutrophils, blood
      platelets and fibrinogen concentration in the blood plasma immediately after
      diving is of temporary character, being a typical reaction observed during
      diving.

PMID- 12608595
TI  - Teleradiology--an integrated solution.
AB  - Successful and clinically relevant teleradiology requires robust technology
      coupled with expert specialist opinion. It also places significant demands on
      ships' medical personnel to produce images of diagnostic quality. There is the
      corresponding need for crew training and continuous quality management to ensure
      that the benefits of an innovative service are maintained and maximised. In the
      context of services provided by the Telemedical partnership, this paper will
      discuss: * Maritime Radiography and Information Technology (IT) * Crew Training-
      shore and computer based * Radiation Protection--recent legislation * Quality
      Standards--medical audit and clinical governance. It will demonstrate how a high
      quality clinical service can be developed and sustained by applying an integrated
      approach to these essential components. (This subject was presented to the 6th
      International Symposium on Maritime Health in Manila, Philippines, in November
      2001).

PMID- 12608597
TI  - Globalization and health: international collaboration in health protection of
      seafarers.

PMID- 12608598
TI  - The health services on board Italian ships.

PMID- 12608599
TI  - The Danish Maritime Occupational Health Service.

PMID- 12608600
TI  - Health services for seafarers in Georgia.

PMID- 12608601
TI  - WHO intercountry training course on maritime occupational health, Gdynia, 6-20
      October 2002.

PMID- 12608602
TI  - Prestige oil ship disaster.

PMID- 12608603
TI  - Morbidity among international seafarers examined at the Port Health Centre in
      Rotterdam in the years 1999 and 2000.

PMID- 12608604
TI  - Increase in mariner deaths in Vanuatu Fleet.

PMID- 12608608
TI  - Determination of beam intensity in a single step for IMRT inverse planning.
AB  - In intensity modulated radiotherapy (IMRT), targets are treated by multiple beams
      at different orientations each with spatially-modulated beam intensities. This
      approach spreads the normal tissue dose to a greater volume and produces a higher
      dose conformation to the target. In general, inverse planning is used for IMRT
      treatment planning. The inverse planning requires iterative calculation of dose
      distribution in order to optimize the intensity profile for each beam and is very
      computation intensive. In this paper, we propose a single-step method utilizing a
      figure of merit (FoM) to estimate the beam intensities for IMRT treatment
      planning. The FoM of a ray is defined as the ratio between the delivered tumour
      dose and normal tissue dose and is a good index for the dose efficacy of the ray.
      To maximize the beam utility, it is natural to irradiate the tumour with
      intensity of each ray proportional to the value of the FoM. The nonuniform beam
      intensity profiles are then fixed and the weights of the beam are determined
      iteratively in order to yield a uniform tumour dose. In this study, beams are
      employed at equispaced angles around the patient. Each beam with its field size
      that just covers the tumour is divided into a fixed number of beamlets. The FoM
      is calculated for each beamlet and this value is assigned to be the beam
      intensity. Various weighting factors are incorporated in the FoM computation to
      accommodate different clinical considerations. Two clinical datasets are used to
      test the feasibility of the algorithm. The resultant dose-volume histograms of
      this method are presented and compared to that of conformal therapy. Preliminary
      results indicate that this method reduces the critical organ doses at a small
      expense of uniformity in tumour dose distribution. This method estimates the beam
      intensity in one single step and the computation time is extremely fast and can
      be finished in less than one minute using a regular PC.

PMID- 12608607
TI  - Intensity-modulated radiotherapy optimization with gEUD-guided dose-volume
      objectives.
AB  - Currently, most intensity-modulated radiation therapy systems use dose-volume
      (DV)-based objectives. Although acceptable plans can be generated using these
      objectives, much trial and error is necessary to plan complex cases with many
      structures because numerous parameters need to be adjusted. An objective function
      that makes use of a generalized equivalent uniform dose (gEUD) was developed
      recently that has the advantage of involving simple formulae and fewer
      parameters. In addition, not only does the gEUD-based optimization provide the
      same coverage of the target, it provides significantly better protection of
      critical structures. However, gEUD-based optimization may not be superior once
      dose distributions and dose-volume histograms (DVHs) are used to evaluate the
      plan. Moreover, it is difficult to fine-tune the DVH with gEUD-based
      optimization. In this paper, we propose a method for combining the gEUD-based and
      DV-based optimization approaches to overcome these limitations. In this method,
      the gEUD optimization is performed initially to search for a solution that meets
      or exceeds most of the treatment objectives. Depending on the requirements, DV
      based optimization with a gradient technique is then used to fine-tune the DVHs.
      The DV constraints are specified according to the gEUD plan, and the initial
      intensities are obtained from the gEUD plan as well. We demonstrated this
      technique in two clinical cases: aprostate cancer and ahead and neck cancer case.
      Compared with the DV-optimized plan, the gEUD plan provided better protection of
      critical structures and the target coverage was similar. However, homogeneities
      were slightly poorer. The gEUD plan was then fine-tuned with DV constraints, and
      the resulting plan was superior to the other plans in terms of the dose
      distributions. The planning time was significantly reduced as well. This
      technique is an effective means of optimizing individualized treatment plans.

PMID- 12608609
TI  - Leaf sequencing algorithms for segmented multileaf collimation.
AB  - The delivery of intensity-modulated radiation therapy (IMRT) with a multileaf
      collimator (MLC) requires the conversion of a radiation fluence map into a leaf
      sequence file that controls the movement of the MLC during radiation delivery. It
      is imperative that the fluence map delivered using the leaf sequence file is as
      close as possible to the fluence map generated by the dose optimization
      algorithm, while satisfying hardware constraints of the delivery system.
      Optimization of the leaf sequencing algorithm has been the subject of several
      recent investigations. In this work, we present a systematic study of the
      optimization of leaf sequencing algorithms for segmental multileaf collimator
      beam delivery and provide rigorous mathematical proofs of optimized leaf sequence
      settings in terms of monitor unit (MU) efficiency under most common leaf movement
      constraints that include minimum leaf separation constraint and leaf
      interdigitation constraint. Our analytical analysis shows that leaf sequencing
      based on unidirectional movement of the MLC leaves is as MU efficient as
      bidirectional movement of the MLC leaves.

PMID- 12608610
TI  - Measurement of image contrast using diffraction enhanced imaging.
AB  - Refraction contrast of simple objects obtained using diffraction enhanced imaging
      (DEI) was studied and compared to conventional radiographic contrast. Lucite
      cylinders and nylon wires were imaged using monochromatic synchrotron radiation
      at the National Synchrotron Light Source (http://nslsweb.
      nsls.bnl.gov/nsls/Default.htm) at the Brookhaven National Laboratory. The DEI
      images were obtained by placing a silicon analyser crystal tuned to the [333]
      diffraction plane in the beam path between the sample and the detector. To
      compare the DEI images with conventional radiographic images requires a
      consistent definition of refraction and absorption contrast. Conventional
      definitions of contrast favour conventional radiography and DEI contrast is
      defined to emphasize the specific characteristics of DEI. The proposed
      definitions were then used to find the DEI gain (the ratio of the DEI contrast
      with respect to the conventional image contrast). The results presented here show
      that the DEI gain is consistently greater than 1, indicating that DEI provides
      more contrast information than conventional radiography.

PMID- 12608611
TI  - Investigation of an image artefact induced by projection noise inhomogeneity in
      multi-slice helical computed tomography.
AB  - The introduction of multi-slice helical computed tomography has fundamentally
      changed the way radiologists view CT images. Increasing numbers of clinical cases
      are examined with advanced visualization tools, such as maximum intensity
      projection, multi-planar reformation and volume rendering. It has been discovered
      that new image artefacts, which do not appear in the traditional two-dimensional
      reconstructed images, become visible in images generated by these new tools. In
      this paper, we investigate the causes of one such artefact, the Venetian blind
      artefact, which appears as bright-and-dark bands superimposed on three
      dimensional images. We demonstrate that such an artefact is caused by the
      periodical noise variation in the reconstructed images. The image noise variation
      is, in turn, caused by the interaction of the noise inhomogeneity in the
      projections with the helical weights. An analytical formula is developed that
      accurately predicts the presence of such artefacts. Based on our analysis,
      several approaches are proposed for the artefact reduction or elimination.

PMID- 12608612
TI  - Poly(vinyl alcohol) gels for use as tissue phantoms in photoacoustic mammography.
AB  - Materials for solid photoacoustic breast phantoms, based on poly(vinyl alcohol)
      hydrogels, are presented. Phantoms intended for use in photoacoustics must
      possess both optical and acoustic properties of tissue. To realize the optical
      properties of tissue, one approach was to optimize the number of freezing and
      thawing cycles of aqueous poly(vinyl alcohol) solutions, a procedure which
      increases the turbidity of the gel while rigidifying it. The second approach
      concentrated on forming a clear matrix of the rigid poly(vinyl alcohol) gel
      without any scattering, so that appropriate amounts of optical scatterers could
      be added at the time of formation, to tune the optical properties as per
      requirement. The relevant optical and acoustic properties of such samples were
      measured to be close to the average properties of human breast tissue. Tumour
      simulating gel samples of suitable absorption coefficient were created by adding
      appropriate quantities of dye at the time of formation; the samples were then cut
      into spheres. A breast phantom embedded with such 'tumours' was developed for
      studying the applicability of photoacoustics in mammography.

PMID- 12608613
TI  - Monte Carlo model of the Elekta SLiplus accelerator: validation of a new MLC
      component module in BEAM for a 6 MV beam.
AB  - A new component module (CM), called MLCE, has been implemented in the BEAM
      program. The CM takes into account the particular 'tongue-and-groove' design of
      the Elekta multi-leaf collimator (MLC) and the air gap between the leaves. The
      model was validated by two series of measurements and simulations. The first
      benchmarking series focuses on the interleaf leakage and the intraleaf
      transmission. The measurement showed a total transmission through the MLC of
      1.42% of the open field dose. Two Monte Carlo (MC) simulations were made, the
      first with the new CM MLCE (inclusive of air gap) and the second with the CM MLCQ
      (exclusive of air gap), which is available in the BEAM distribution. When the air
      gap between the leaves was determined by varying the parameters of the leaf
      geometry within tolerance limits on the technical drawing, the total measured
      transmission of 1.42% was well reproduced by the CM MLCE. In contrast, MC
      simulations with MLCQ showed that the transmission through the MLC calculated
      without the interleaf leakage is only 44% of the total transmitted radiation. The
      relevance of the detailed MLC modelling was demonstrated also by studying the
      'adjacent' tongue-and-groove effect, where two adjacent (not opposing) leaves are
      complementary, opened or closed. The two complementary leaf settings were
      simulated both with the CM MLCE and MLCQ. A comparison with measurements was
      made. In regions covered by two or more leaves, the dose increased by 14% for two
      leaves and by 40% for more than two leaves when the interleaf leakage was
      included in the transmission. The tongue-and-groove effect was perfectly
      reproduced by the MLCE module.

PMID- 12608614
TI  - Should single or distributed parameters be used to explain the steepness of
      tumour control probability curves?
AB  - Linear quadratic (LQ) modelling allows easy comparison of different fractionation
      schedules in radiotherapy. However, estimating the radiation effect of a single
      fractionated treatment introduces many questions with respect to the parameters
      to be used in the modelling process. Several studies have used tumour control
      probability (TCP) curves in order to derive the values for the LQ parameters that
      may be used further for the analysis and ranking of treatment plans.
      Unfortunately, little attention has been paid to the biological relevance of
      these derived parameters, either for the initial number of cells or their
      intrinsic radiosensitivity, or both. This paper investigates the relationship
      between single values for the TCP parameters and the resulting dose-response
      curve. The results of this modelling study show how clinical observations for the
      position and steepness of the TCP curve can be explained only by the choice of
      extreme values for the parameters, if they are single values. These extreme
      values are in contradiction with experimental observations. This contradiction
      suggests that single values for the parameters are not likely to explain
      reasonably the clinical observations and that some distributions of input
      parameters should be taken into consideration.

PMID- 12608615
TI  - A hybrid evolutionary algorithm for multi-objective anatomy-based dose
      optimization in high-dose-rate brachytherapy.
AB  - Multiple objectives must be considered in anatomy-based dose optimization for
      high-dose-rate brachytherapy and a large number of parameters must be optimized
      to satisfy often competing objectives. For objectives expressed solely in terms
      of dose variances, deterministic gradient-based algorithms can be applied and a
      weighted sum approach is able to produce a representative set of non-dominated
      solutions. As the number of objectives increases, or non-convex objectives are
      used, local minima can be present and deterministic or stochastic algorithms such
      as simulated annealing either cannot be used or are not efficient. In this case
      we employ a modified hybrid version of the multi-objective optimization algorithm
      NSGA-II. This, in combination with the deterministic optimization algorithm,
      produces a representative sample of the Pareto set. This algorithm can be used
      with any kind of objectives, including non-convex, and does not require
      artificial importance factors. A representation of the trade-off surface can be
      obtained with more than 1000 non-dominated solutions in 2-5 min. An analysis of
      the solutions provides information on the possibilities available using these
      objectives. Simple decision making tools allow the selection of a solution that
      provides a best fit for the clinical goals. We show an example with a prostate
      implant and compare results obtained by variance and dose-volume histogram (DVH)
      based objectives.

PMID- 12608616
TI  - X-ray micro-diffraction analysis of reconstructed bone at Zr prosthetic surface
      with sub-micrometre spatial resolution.
AB  - The purpose of the present investigation is to demonstrate the power of the x-ray
      micro-diffraction technique in biological studies. In particular the reported
      experiment concerns the study of the interface between a Zr prosthetic device
      implanted in a rat femur and the newly-formed bone, with a spatial resolution of
      0.5 microm. The obtained results give interesting information on the Zr
      deformation and on the crystallographic phase, the grain size and the orientation
      of the new bone. Moreover the study reveals a marked difference in the structure
      of the reconstructed bone with respect to the native bone, which cannot be
      appreciated with other techniques.

PMID- 12608617
TI  - Computer-enhanced stereoscopic vision in a head-mounted operating binocular.
AB  - Based on the Varioscope, a commercially available head-mounted operating
      binocular, we have developed the Varioscope AR, a see through head-mounted
      display (HMD) for augmented reality visualization that seamlessly fits into the
      infrastructure of a surgical navigation system. We have assessed the extent to
      which stereoscopic visualization improves target localization in computer-aided
      surgery in a phantom study. In order to quantify the depth perception of a user
      aiming at a given target, we have designed a phantom simulating typical clinical
      situations in skull base surgery. Sixteen steel spheres were fixed at the base of
      a bony skull, and several typical craniotomies were applied. After having taken
      CT scans, the skull was filled with opaque jelly in order to simulate brain
      tissue. The positions of the spheres were registered using VISIT, a system for
      computer-aided surgical navigation. Then attempts were made to locate the steel
      spheres with a bayonet probe through the craniotomies using VISIT and the
      Varioscope AR as a stereoscopic display device. Localization of targets 4 mm in
      diameter using stereoscopic vision and additional visual cues indicating target
      proximity had a success rate (defined as a first-trial hit rate) of 87.5%. Using
      monoscopic vision and target proximity indication, the success rate was found to
      be 66.6%. Omission of visual hints on reaching a target yielded a success rate of
      79.2% in the stereo case and 56.25% with monoscopic vision. Time requirements for
      localizing all 16 targets ranged from 7.5 min (stereo, with proximity cues) to 10
      min (mono, without proximity cues). Navigation error is primarily governed by the
      accuracy of registration in the navigation system, whereas the HMD does not
      appear to influence localization significantly. We conclude that stereo vision is
      a valuable tool in augmented reality guided interventions.

PMID- 12608618
TI  - Comment on 'A systematic review of the precision and accuracy of dose
      measurements in photon radiotherapy using polymer and fricke MRI gel dosimetry'.

PMID- 12608619
TI  - Markers of pulmonary diseases in exhaled breath condensate.
AB  - Exhaled breath condensate has been more and more extensively used as a novel and
      non-invasive method to study airway inflammation. It is simple to perform, very
      well tolerated by patients and no adverse events have been reported so far.
      Serial measurements can be made with no harmful effects on patients, which is of
      extreme value in occupational medicine. Exhaled breath condensate has been
      obtained from both adult and children patients suffering from various pulmonary
      diseases such as asthma, cystic fibrosis, chronic obstructive pulmonary disease,
      and interstitial lung diseases. Several markers and mediators are detectable in
      breath condensate: hydrogen peroxide, thiobarbituric acid-reactive substances,
      isoprostanes, prostaglandins and leukotrienes. Nitric oxide-related markers have
      also been studied in the condensate. There is increasing body of evidence that
      changes in condensate markers reflect local abnormalities of airway lining fluid.

PMID- 12608620
TI  - Exposure to environmental tobacco smoke and children health.
AB  - This paper reviews the investigations of the effects of pre- and/or postnatal
      exposure to environmental tobacco smoke (ETS) on children health reported in the
      literature. The evidence from epidemiological studies demonstrate that children's
      exposure to ETS is a risk factor for a variety of diseases, including respiratory
      disorders and middle ear disease. However, the current research base on the ETS
      associated risks is still inadequate to fully support strategies, programs and
      policy development in this area. For example, it is not definitively determined
      what methods should be used for assessing ETS exposure and predicting potential
      health risks of exposed children. Based on the available data, we tried to find
      out which methods seem to be most desirable for quantifying ETS exposure in
      children. It is our opinion that among all biomarkers, the measurements of blood,
      saliva or urinary cotinine and hair nicotine are, as for today, the most specific
      and sensitive methods for an objective assessment of ETS exposure in children. A
      combination of the measurement of body fluids cotinine and hair nicotine with the
      questionnaire and interview-derived information seems to be the optimal method
      for assessing ETS exposure in children.

PMID- 12608621
TI  - Occupational diseases in Poland, 2001.
AB  - The Central Register of Occupational Diseases keeps the records of all reported
      and certified occupational diseases in Poland. In this paper the incidence of
      occupational diseases in Poland in 2001 is discussed on the basis of the data
      provided by the Register. The changes in the incidence pattern over the recent 30
      years are also shown. In 2001, 6,007 cases of occupational diseases were
      registered, with the incidence rate of 63.2 per 100,000 employees. The highest
      incidence rates were noted for seven categories of diseases: the vocal organ
      diseases, noise-induced hearing loss, pneumoconioses, contagious and invasive
      diseases, dermatoses, chronic diseases of bronchi, and vibration syndrome.
      Altogether these diseases covered 5,239 cases (87.2% of all registered cases).
      Mining and quarrying, agriculture, hunting and forestry, education, health and
      social works were the economy activities with the highest incidence of
      occupational diseases. The majority of occupational diseases (93.9%) have
      developed after a long-term (over 10 years) exposure to particular harmful
      factors. As much as 58.5% of cases were recorded in males. The predominant
      occupational diseases in males were occupational hearing lesions, while in
      females chronic vocal organ diseases, most common in teachers, were most
      frequently recognized. In Poland, the diseases of the vocal organ poses a serious
      problem from the medical and socio-economic points of view. These pathologies
      show the highest dynamics of the incidence among all registered occupational
      diseases. Over the last five years the vocal organ diseases have moved upwards to
      the top in the ranking, both with respect to the number of cases and the
      incidence rate. Since 1998, the incidence of occupational diseases has been
      continuously showing a downward tendency. Four categories of occupational
      diseases have accounted mostly for this decline: noise-induced hearing loss,
      chronic diseases of vocal organ, contagious and invasive diseases, and dermatoses
      (a decrease by 64%, 54%, 40%, and 51%, respectively). The decreased incidence has
      been also noted for "classical pathologies": chronic poisonings, pneumoconioses
      and vibration syndrome. At least three most important explanatory factors have to
      be pointed out: a) the decrease in employment and liquidation of industrial
      plants with the highest health risk; b) the modernization of plants and
      improvement of working conditions: and c) effective prevention.

PMID- 12608622
TI  - Viral hepatitis in health service workers in the Province of Wielkopolska.
AB  - Viral hepatitis is the most frequent occupational disease in the health service
      workers. On the ground of epidemiological data on certifications of occupational
      diseases, an analysis of morbidity of viral hepatitis was performed. Among
      viruses that can cause occupational hepatitis there are HAV, HBV and HCV.
      However, occupational HDV and HGV infections are also possible. In Poland, the
      number of hepatitis diagnosed as occupational diseases became more stable in the
      years 1996-1998, whereas morbidity of hepatitis C significantly increased. Such
      an epidemiological situation could be observed in the area of Wielkopolska and
      throughout the country. In the former province of Poznan and in the present
      province of Wielkopolska, occupational hepatitis occurred mostly in nurses. In
      the nineteen sixties and seventies, the most dramatic increase in the incidence
      of hepatitis B was noticed in the population of nurses and midwives at the age
      between 21 and 30 years. This can provide evidence of especially high exposure to
      infectious factors in this occupational group and of high HBV infectivity.
      Nowadays, an average age at the time of diagnosis of hepatitis C is somewhat
      higher. Hepatitis C is usually recognized at the age between 30 and 39 years. A
      relatively low infectivity of HCV and mostly asymptomatic course of the
      infection, which delays diagnosis, may provide some explanations of these
      phenomena. The geographical distribution of stated cases of hepatitis C is
      difficult to predict and may suggest that some non-medical factors also play a
      role. Since no specific measures to prevent the incidence of hepatitis C have
      been developed, a good recognition of HCV reservoir in the population of health
      service workers (particularly nurses) is one of possible methods to improve the
      epidemiological situation. It might also be necessary to discuss some limitations
      in work ability of infected persons. In addition, good training in occupational
      hygiene and how to handle infectious materials is essential for health service
      workers.

PMID- 12608623
TI  - The validity of general health questionnaires, GHQ-12 and GHQ-28, in mental
      health studies of working people.
AB  - The purpose of the study was to determine such cut-off points in the scores of
      General Health Questionnaires (GHQ-12 and GHQ-28) that allow for optimal
      identification of people with mental health disorders in the Polish working
      population attending primary health care settings. The groups under the study
      covered 419 and 392 patients for GHQ-12, and GHQ-28, respectively. In the GHQ-12
      group, 90 and in the GHQ-28 group, 80 subjects filled in the questionnaires and
      agreed to participate in the second stage of the study--a psychiatric interview.
      The criterion validity of the GHQs was a mental health diagnosis, based on the
      Munich version of Composite International Diagnostic Interview. The complete
      computerized version of interview, covering all diagnostic sections, has been
      adopted. In the mental health diagnosis only disorders, which currently troubled
      patients were taken into consideration and disorders which created problems in
      the distant past were excluded. In the group covered by GHQ-12 examination, 55.6%
      of persons had at least one type of mental disorder diagnosed, based on the
      criteria of both Diagnostic and Statistical Manual for Mental Disorders (DSM-IV)
      and the International Classification of Diseases (ICD-10). In the GHQ-28 group,
      the percentage of persons with mental disorders was 47.5%. After excluding
      patients with nicotine dependence disorder only, the frequency of mental health
      problems decreased to 45.5% and 33.8%, respectively. The proposed cut-off points,
      2/3 points for GHQ-12 and 5/6 points for GHQ-28, were established at the level of
      the highest possible sensitivity and specificity not lower than 75%. These
      principals have been accepted for a practical reason, as the acceptance of the
      lower level of specificity forces medical practitioners to devote too much time
      to practically healthy people. At the above mentioned cut-off points for GHQ-12
      sensitivity is 64% and specificity--79%, while for GHQ-28 the values are 59% and
      75%, respectively. These validity coefficients were calculated from distributions
      of groups, from which persons with nicotine dependence as the only disorder were
      excluded. Incorporation of these people in the whole sample reduced the
      questionnaires' validity. Modification of responses scoring from the standard one
      -GHQ to CGHQ has not improved the validity of questionnaires. Lower validity
      coefficients of GHQ-28, in comparison to GHQ-12 validity are the effect of
      greater influence of somatic disease on the results acquired in this scale
      version of the questionnaire.

PMID- 12608624
TI  - A prospective-controlled study of pregnant veterinary staff exposed to inhaled
      anesthetics and x-rays.
AB  - Most veterinary staff are women of reproductive age. They are exposed to "waste"
      anesthetic gas and ionizing radiation in their workplace, which may endanger
      fetal safety. Presently, exposure of female veterinary staff to these health
      hazards has not been adequately addressed in the medical literature. Our primary
      objective was to investigate the incidence of major malformations associated with
      occupational exposure to inhaled anesthetics and/or radiation among pregnant
      veterinary staff. The secondary objective was to determine the rates of other
      adverse outcomes. We prospectively collected data on and followed-up women
      occupationally exposed to inhaled anesthetics and/or radiation in veterinary
      practices in Ontario, and compared them to controls matched for maternal age and
      gestational age at the time of call to the Motherisk Program. A total of 95 women
      were prospectively enrolled and followed-up. Among the participants there were 87
      (93.5%) and 88 (92.8%) livebirths in the study and control groups, respectively.
      There were 4 (4.8%) major birth defects in the study group and 3 (3.4%) in the
      control group. The rates of spontaneous abortion were also similar, 6 (6.4%)
      cases in the study group and 7 (7.4%) cases in the control group. These results
      suggest that Ontario female veterinary staff exposed to inhaled anesthetics
      and/or radiation do not seem to be at an increased risk for major malformations
      above baseline risk.

PMID- 12608625
TI  - Comparison of tissue distribution and metabolism of 1,2- and 1,4-dibromobenzenes
      in female rats.
AB  - The distribution, excretion and metabolism of 1,4-dibromobenzene (1,4-DBB) and
      1,2-dibromobenzene (1,2-DBB), following a single intraperitoneal administration
      to female Wistar rats, were investigated using radiotracer 3H and GC-MS
      technique. The maximum level of 3H after 1,4-DBB administration was detected in
      all examined rat tissues between 4 and 24 h foltowing the injection. The highest
      concentrations of 3H were found in fat tissue, muscles, adrenal glands and
      sciatic nerve. About 50% of administered dose was still retained in the rat 72 h
      after injection. For 1,2-DBB, the highest level of 3H was in the liver, kidneys
      and fat tissue 4 and 8 h after administration. Three days after injection, less
      than 2% of the given dose was retained in the rat body. Urine turned out to be
      the main route of 3H excretion following the injection of both compounds (30% and
      82%, after 1,4-DBB and 1,2-DBB, respectively), and about 4% of the given dose was
      excreted in feces. In urine of rats the following substances were identified (in
      sequence 1,4-dBB and 1,2-dBB): (1) unchanged parent compounds (5 and 11%); (2)
      dibromophenols (84 and 73%); (3) dibromothiophenols (5 and 10%) and (4)
      monobromophenols (1.9 and 0.7%). This study suggests that 1,2-DBB is
      characterized by a relatively high turnover rate, whereas 1,4-DBB shows a
      tendency for long-term retention in the body.

PMID- 12608626
TI  - Assessment of long-term neurotoxic effects of exposure to mesitylene (1,3,5
      trimethylbenzene) based on the analysis of selected behavioral responses.
AB  - Trimetylbenzene isomers: pseudocumene, hemimellitene and mesitylene, are major
      components of numerous commercial solvents and high-grade fuels. In our earlier
      research on rats we have proved that inhalation exposure to pseudocumene or
      hemimellitene at concentrations close to the MAC value results in behavioral
      changes detectable many weeks after cessation of the exposure. The aim of our
      present study is to determine whether exposure to mesitylene causes effects
      similar to those observed for pseudocumene and hemimellitene. Male rats were used
      in the experiment. The animals were exposed in the inhalation chambers to
      mesitylene vapors at the following concentrations: 0 ppm--group MES0; 25 ppm (125
      mg/m3)--group MES25; 100 ppm (500 mg/m3)--group MES100 and 250 ppm (1,250 mg/m3)-
      group MES250 for 4 weeks (6 h/day, 5 days/week). The following behaviors were
      tested: 1) ability to find water in a radial maze (14-19 days after the
      exposure); 2) open field locomotor activity (25 days after the exposure); 3)
      acquiring the conditioned reaction of active avoidance (35-45 days after the
      exposure); 4) sensitivity to pain and stress-induced changes of pain sensitivity
      (50-51 days after the exposure); and 5) acquiring the conditioned reaction of two
      way active avoidance (54-60 days after the exposure). Significant between-group
      differences were noted in passive and active avoidance tests and sensitivity to
      pain. In the MES25, MES100 and MES250 rats, the persistence of the passive
      avoidance reaction was shorter, and more trials were required to produce the
      active avoidance reaction than in controls (group MES0), the MES100 group
      appeared to be more fearful on the second day of testing on the hot plate. The
      exposed groups did not differ in the magnitudes of the detected changes (no
      concentration-effect relationship). These results indicate that inhalation
      exposure to mesitylene, like that to pseudocumene and hemimellitene, at
      concentrations close to the current hygiene standard value for trimethylbenzene,
      may produce long-term functional changes in the rat central nervous system.

PMID- 12608627
TI  - Integrated indexes of occupational exposure as predictors of kidney dysfunction.
AB  - The aim of the study was to evaluate the dose-effect and dose-response
      relationships between the integrated indexes Cd-A x t (mg/m3 x years of exposure)
      and Cd-B x t (microg/l x years of exposure), and the increase in retinol binding
      protein excretion in urine (RBP-U) and beta2-microglobulin concentration in serum
      (beta2M-S). The study was carried out in the nickel-cadmium battery factory in
      1998-1999. Exposure to cadmium was formerly very high. The study group consisted
      of 116 persons for whom the results of determinations of Cd-B were available
      during two former observation periods (1983 and 1986-1988). The mean age of the
      group was 49 years and the mean period of exposure was 17 years. The dose-effect
      relationship between Cd-B x t and RBP-U or beta2M-S was much better (r = 0.642
      and 0.513) than between Cd-A x t and RBP-U or beta2M-S (r = 0.173 and 0.127).
      There was also correlation between Cd-U (microg/g creatinine), measured in 1998
      1999, and RBP-U or beta2M-S (r = 0.343 and 0.198). Urinary cadmium should,
      however, be used with caution as a dose estimate because its excretion may
      increase as a result of renal damage. According to the dose-response
      relationship, an increase in RBP excretion above 300 microg/g creatinine can be
      expected in 10% of subjects at the integrated exposure index (Cd-B x t) of about
      450 microg/l x years, and an increase in beta2M-S above the accepted cut-off
      point of 2.4 mg/l can be expected in 10 % of subjects at Cd-B x t of about 190
      microg/l x years. The data obtained confirmed the validity of the recommended at
      present health-based limit for occupational exposure of 5 microg/l of blood, as
      well as the superiority of the biological monitoring of exposure to cadmium over
      the environmental monitoring.

PMID- 12608628
TI  - Application of pylon radon daughter standard for calibration of radiometers.
AB  - Radiometers for measurements of radon daughter potential energy used in the
      surveillance of the work environment need a systematic calibration. This paper
      presents how a commercially available device produced by the Pylon Company can be
      applied. This device allows to produce, simply and directly, standard sources of
      radon daughters, corresponding with the energy, geometry and properties of
      radiation originated from an air sample. The calibration yielded the results that
      proved to be in agreement with those obtained previously by means of radon
      chamber.

PMID- 12608629
TI  - An investigative report on circumstances leading to death among Indian cotton
      farmers.
AB  - Andhra Pradesh, a southern state of India has been in the news for cotton
      farmers' deaths/suicides since 1998. The occurrence of 12 deaths among the
      farmers in the years 2001-2002 clustering around September-October expedited the
      investigation. The objective of our investigation was to identify the
      circumstances leading to death of cotton farmers in Warangal district of Andhra
      Pradesh. Some of the broadly held hypotheses were also analyzed for their
      validity. The socioeconomic-political factors emerge as very strong determinants
      of deaths, given the occupational work environment.

PMID- 12608630
TI  - Polish bibliography of occupational medicine, 2001.

PMID- 12608631
TI  - Effect of ginsenoside Rb1 on long-term potentiation in the dentate gyrus of
      anaesthetized rats.
AB  - Ginsenosides are the major principles of Panax ginseng and have various
      pharmacological actions on the central nervous system. In this report, we
      investigated whether ginsenoside Rb1 (10, 100 nmol(-1), icv) could increase the
      population spike (PS) amplitude in a dose-dependent manner, and accelerate the
      maintenance phase of long-term potentiation (LTP) induced by high frequency
      stimulation (HFS) in the dentate gyrus of anaesthetized rats. However, it had no
      effect on basic synaptic responses evoked by test stimulation. Comparatively,
      ginsenoside Rb1 (10, 100 nmol l(-1), icv) inhibited the induction phase of LTP
      induced by HFS in a dose-dependent manner. This may be one of the mechanisms of
      action of ginsenoside Rb1 on synaptic transmission. The details of the mechanism
      need further investigation.

PMID- 12608633
TI  - Two new triterpenoid saponiins from Adina pilulifera.
AB  - Two new triterpenoid saponins, 3beta-O-beta-D-xylopyranosyl (1 --> 3)-alpha-L
      rhamnopyranosyl-pyrocincholic acid 28-O-beta-D-glucopyranosyl (1 --> 6)-beta-D
      glucopyranosyl ester (1), and 3beta-O-beta-D-xylopyranosyl(l --> 3)-alpha-L
      rhamnopyranosyl-cincholic acid 28-O-beta-D-glucopyranosyl ester (2) were isolated
      from the roots of Adina pilulifera, together with 18 known compounds. The
      structures of 1 and 2 were determined by spectroscopic methods.

PMID- 12608632
TI  - Biotransformation of 4(20),11-taxadienes by cell suspension cultures of
      Platycodon grandiflorum.
AB  - Platycodon grandiflorum cell suspension cultures were employed to biotransform
      the taxane diterpenoids 2alpha,5alpha,10beta,14beta-tetraacetoxy-4(20),11
      taxadiene (1) and 9alpha-hydroxy-2alpha,5alpha,10beta,14beta-tetraacetoxy
      4(20),11-taxadiene (2). One product, 10beta-hydroxy-2alpha,5alpha,14beta
      triacetoxy-4(20),11-taxadiene (3) was obtained from 1 and two products,
      9alpha,10beta-dihydroxy-2alpha,5alpha,14beta-triacetoxy-4(20),11-taxadiene (4)
      and 10beta-hydroxy-2alpha,5alpha,9alpha,14beta-tetraacetoxy-4(20),11-taxadiene
      (5) were obtained from 2 incubated with Platycodon cultured cells respectively,
      among which 5 is characterized as a new taxoid compound. The effects of the
      addition stage for 1 and 2 on the biotransformation were investigated and the
      results revealed that: (1) the optimal addition stage for 1 was in the early
      logarithmic phase (6th day) of the cell growth period, in which 78% of 1 was
      converted and the yield for 3 reached 75%; (2) the optimal addition stage for 2
      was on the mid-logarithmic phase (12th day) of the cell growth period, in which
      25.3% of 2 was converted and the yields for 4 and 5 reached 18.9 and 14.5%,
      respectively.

PMID- 12608634
TI  - Uvamalols D-G: novel polyoxygenated seco-cyclohexenes from the roots of Uvaria
      macrophylla.
AB  - Uvamalols D-F (1-4), novel polyoxygenated seco-cyclohexenes, were isolated from
      the roots of Uvaria macrophylla, and their structures were elucidated by
      interpretation of spectral data.

PMID- 12608635
TI  - Glycosyl flavonoids from the roots and rhizomes of Asarum longerhizomatosum.
AB  - Two new glycosyl flavonoids including a glycosyl aurone, together with six known
      flavonoids were isolated from the roots and rhizomes of Asarum longerhizomatosum.
      The structures of the two new compounds were elucidated as 4,6,4'-trihydroxy
      aurone-4,6-di-O-beta-D-glucopyranoside (7, caulesauroneside) and naringenin-7,4'
      di-O-beta-D-glucopyranoside (8, caulesnarinside). The six known flavonoids were
      identified as naringenin (1), naringenin-5-O-beta-D-glucopyranoside (2),
      naringenin-7-O-beta-D-glucopyranoside (3), chalcononaringenin-2'-O-beta-D
      glucopyranoside (4), naringenin-5,7-di-O-beta-D-glucopyranoside (5),
      chalcononaringenin-2',4'-di-O-beta-D-glucopyranoside (6), respectively. This is
      the first report of the isolation of aurones in the family Aristolochiaceae.

PMID- 12608636
TI  - Two new pterocarpenes from Hedysarum multijugum.
AB  - Two new pterocarpenes were isolated from the roots of Hedysarum multijugum, and
      their structures were elucidated as hedysarimpterocarpene B (1) and
      hedysarimpterocarpene C (2) on the basis of spectroscopic data.

PMID- 12608637
TI  - Irritant potential of some constituents from the seeds of Caesalpinia bonducella
      (L.) fleming.
AB  - The irritant potential of four triterpenoids, isolated for the first time from
      the seeds of Caesalpinia bonducella, identified as alpha-amyrin [12-ursen-3beta
      ol], beta-amyrin [12-oleanex-3beta-ol], lupeol [lup-20(29)-en-3beta-ol] and
      lupeol acetate [lup-20(29)-en-3beta-yl acetate] was investigated by open mouse
      ear assay, evaluating their ID50 (irritant dose in 50% animals) after acute
      effects and by irritant units (IU) after chronic effects. Alpha-Amyrin, lupeol
      acetate and beta-amyrin were the most potent and persistent irritant compounds
      with red weals of 1.5-2.1 cm diameter areas of the animal skin and with lowest
      ID50 = 0.078, 0.186 and 0.190mg/10 microl after 1.5, 2.10 and 3.5h, respectively.
      Their reactions lasted for 24 h with IU = 2.5; 0.312 and 1.25 mg/10 microl,
      respectively. Lupeol was the least irritant and least persistent compound with
      ID50 = 0.603 mg/10 microl after 4.5 h. Its reaction subsided before 24 h.

PMID- 12608638
TI  - Further studies on the synthesis of 7,17-seco norditerpenoid alkaloids.
AB  - Following the report on the synthesis of the 7,17-seco compounds [Wang, F.P.,
      Yang, J.S., Chen, Q.H., Yu, L. and Li, B.G. (2000), Chem. Pharm. Bull. 48, 1912
      1916], further studies on the reaction optimization for cleavage of the
      C(7),C(17) bond led to the 7,17-seco norditerpenoid alkaloids (e.g. 4, 9) in
      nearly 90% yield.

PMID- 12608639
TI  - Bioactive triterpenoids from Symplocos chinensis.
AB  - A new triterpenoid, 2beta,3beta,19alpha,24-tetrahydroxy-23-norurs-12-en-28-oic
      acid (4), together with three known triterpenoids 3-oxo-19alpha,23,24
      trihydroxyurs-12-en-28-oic acid (1), 2alpha,3beta,19alpha,23-tetrahydroxyurs-12
      en-28-oic acid (2), 2alpha,3alpha,19alpha,23-tetrahydroxyurs-12-en-28-oic acid
      (3), was isolated from the roots of Symplocos chinensis. The new triterpenoid
      shows significant cytotoxic activity against B16 and BGC-823 cells.

PMID- 12608641
TI  - Two new methyl chanofruticosinates from Kopsia flavida blume.
AB  - Two new indole alkaloids with the methyl chanofruticosinate skeletal system viz.,
      methyl 3-oxo-12-methoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate (1)
      and methyl 3-oxo-11,12-methylenedioxy-N-decarbomethoxy-14,15
      didehydrochanofruticosinate (2), together with four known compounds, methyl 12
      methoxy-N1-decarbomethoxychanofruticosinate, methyl 12-methoxychanofruticosinate,
      methyl 11,12-dimethoxychanofruticosinate and methyl 11,12-methylenedioxy-N1
      decarbomethoxychanofruticosinate, were isolated in continuing studies on the
      leaves of Kopsia flavida Blume. The structures of the new indole alkaloids were
      assigned by NMR spectral data using various 2D-techniques.

PMID- 12608640
TI  - A new biologically active flavone glycoside from the seeds of Cassia fistula
      (Linn.).
AB  - A new bioactive flavone glycoside 1 [mp 252-254 degrees C, C28H32O16, [M]+ 624
      (EIMS)] was isolated from the acetone soluble fraction of the defatted seeds of
      Cassia fistula (Linn.). It was characterized as a new bioactive flavone glycoside
      5,3',4'-tri-hydroxy-6-methoxy-7-O-alpha-L-rhamnopyranosyl-(1 --> 2)-O-beta-D
      galactopyranoside by several colour reactions, spectral analysis and chemical
      degradations. Compound 1 showed anti-microbial activity.

PMID- 12608642
TI  - Two new monoterpenoid glycosides from Mentha spicata L.
AB  - Two new monoterpenoid glycosides, spicatoside A and spicatoside B, were isolated
      from the whole herbs of Mentha spicata L. which have anti-inflammatory and
      hemostatic activities. Their structures have been determined on the basis of
      spectral and chemical analysis. They are (+)-5-[1-(beta-D
      glucopyranosyloxymethyl)ethenyl]-2-methyl-2-cyclohexen-1-one (1), and (-)-5-[[2
      (beta-D-glucopyranosyloxy)-1-hydroxy-l-methyl]ethyl]-2-methyl-2-cyclohexen-1-one
      (2).

PMID- 12608643
TI  - Effect of fangchinoline in murine models of multiple organ dysfunction syndrome
      and septic shock.
AB  - OBJECTIVE AND DESIGN: To study the effect of the alkaloid fangchinoline on
      zymosan-induced multiple organ dysfunction syndrome (MODS) and Escherichia coli
      (E. coli)-induced septic shock. MATERIAL: Male ICR mice were used. Macrophages
      were isolated from peritoneal cavity for in vitro study. TREATMENT: Fangchinoline
      was administered i.p. at a dose of 1 or 5 mg/kg into the mice. METHODS: MODS was
      induced by intraperitoneal (i.p.) injection of zymosan at a dose 1.0 or 0.8/g
      b.w. E. coli-induced septic shock was provoked by i.p. inoculation of 5 x 10(8)
      bacterial cells into mice. TNF-alpha in serum and supernatants from peritoneal
      macrophages was detected by the use of L-929 cell cytotoxic assay. Alternative
      pathway (AP) complement activity was determined by hemolytic assay. RESULTS:
      Fangchinoline increased the survival rate in lethal MODS and septic shock. The
      alkaloid prevented the loss of body weight and liver enlargement in MODS and
      suppressed serum tumor necrosis factor-alpha (TNF-alpha) accumulation in MODS and
      septic shock. CONCLUSIONS: The result suggest that fangchinoline due mainly to
      its ability to downregulate TNF-alpha production might have protective effect in
      murine models of zymosan-induced MODS and E. coli-induced septic shock.

PMID- 12608645
TI  - CD40 ligation triggers COX-2 expression in endothelial cells: evidence that CD40
      mediated IL-6 synthesis is COX-2-dependent.
AB  - OBJECTIVE: To investigate whether CD40-CD154 interactions on HUVEC can trigger
      COX-2 synthesis as well as PGE2 and PGI2 secretion in vitro and explore whether
      the CD40-triggered prostanoids provide costimulatory signals for IL-6 secretion
      in this cell type. MATERIALS AND METHODS: COX-2 protein expression was examined
      in HUVEC using Western blot analysis. ELISAs were employed to assess PGE2, PGI2
      and IL-6 synthesis. RESULTS: We found that COX-2 expression is upregulated when
      HUVEC are cultured with CD154+ D1.1 cells but not CD154- B2.7 cells. This effect
      was specifically inhibited by anti-CD154 mAb, and was amplified by the presence
      of IFNgamma. Analysis of cell supernatants showed a concomitant rise in PGE2 and
      PGI2 secretion triggered by CD154+ D1.1 cells, or rsCD154. Use of selective (NS
      398) and non-selective (ibuprofen) COX-2 inhibitors effectively inhibited
      prostanoid synthesis triggered by CD40 ligation. Reduction in prostanoid levels
      by NS-398 was accompanied by a reduction in IL-6 secretion levels triggered by
      CD40 ligation. Furthermore, exogenously added PGE2 triggered a dose-dependent IL
      6 secretion, which was unaffected by NS-398. CONCLUSIONS: These studies
      demonstrate that CD40 ligation upregulates HUVEC COX-2 expression and function.
      Moreover, the data strongly suggest that CD154-induced IL-6 secretion in HUVEC is
      dependent on COX-2 activity.

PMID- 12608644
TI  - The effect of inhibiting topoisomerase I and II on the anti-apoptotic response
      associated with pro-inflammatory crystals of calcium pyrophosphate dihydrate in
      human neutrophils.
AB  - OBJECTIVE AND DESIGN: To investigate the ability of various topoisomerase I and
      II inhibitors to reverse the pro-survival effects of calcium pyrophosphate
      dihydrate (CPPD) crystals on human neutrophils, thereby identifying potential
      agents that may promote the resolution of neutrophil accumulation typical of
      crystal associated inflammatory diseases. MATERIALS AND METHODS: Freshly isolated
      human neutrophils incubated in the presence of CPPD crystals, with or without the
      pro-apoptotic cytokine TNF-alpha, were pre-incubated in the presence or absence
      of the topoisomerase I inhibitors camptothecin, nogalamycin or beta-lapachone, or
      topoisomerase II inhibitors etoposide, doxorubicin or mitoxantrone. Neutrophil
      respiratory burst was assessed via chemiluminescence, and two quantitative
      methods were used for the determination of neutrophil apoptosis; cytoplasmic
      histone-associated-DNA fragmentation assessment, and endogenous caspase 3
      substrate (Ac-DEVD-AMC) cleavage. RESULTS: Beta-lapachone and mitoxantrone
      effectively repressed CPPD crystal associated respiratory burst, whereas the
      other topoisomerase inhibitors had no inhibitory or stimulatory effect.
      Camptothecin and all of the topoisomerase II inhibitors induced neutrophil
      apoptosis, even in the presence of the CPPD crystals that normally repress TNF
      alpha-induced and spontaneous apoptosis. CONCLUSIONS: These results suggest that
      although topoisomerase II antagonists are distinctively effective agents at
      reversing the pro-survival effects of crystals on neutrophils, camptothecin was
      unique as a topoisomerase I inhibitor in that it was significantly more effective
      as a pro-apoptosis inducer than the topoisomerase II poisons without affecting
      normal neutrophil activation responses.

PMID- 12608646
TI  - Suppression of tumor necrosis factor-alpha by beta2-adrenoceptor activation: role
      of mitogen-activated protein kinases in renal mesangial cells.
AB  - OBJECTIVE: The present study examined the inhibitory effect of beta2-adrenoceptor
      activation on the mitogen-activated protein kinase (MAPK) cascades and the
      contribution of these pathways to the suppression of tumor necrosis factor (TNF)
      alpha in lipopolysaccharide (LPS)-stimulated rat renal mesangial cells. MATERIALS
      AND METHODS: Experiments were performed using cultured mesangial cells in the
      presence of LPS (1 microg/ml) and/or the beta2-adrenoceptor agonist, terbutaline
      (10(-6) 10(-8) M). The levels of extracellular signal-regulated kinase-1 and
      2(Erk 1/2), p38, c-Jun N-terminal protein kinase (JNK) and TNF-alpha were
      estimated. RESULTS: LPS activated Erk-1/2 and p38 levels, by 4.7-fold and 1.8
      fold, respectively (P < 0.05), which were suppressed by terbutaline (10(-6) - 10(
      8) M) in a dose dependent way. These inhibitory actions of terbutaline were
      prevented by the beta2-adrenoceptor antagonist, ICI 118,551(10(-6) M) but not by
      an inhibitor of the cAMP-PKA pathway, H-89 (5 x 10(-6) M). The selective MAPK/Erk
      1 inhibitor, PD98059 (10(-5) M) and the specific p38 inhibitor SB203580 (10(-5)
      M) significantly decreased LPS-induced TNF-alpha production in the cells.
      CONCLUSIONS: Inhibition of MAPK cascades (Erkl/2 and p38) plays an important role
      in the suppression of TNF-alpha following beta2-adrenoceptor activation but the
      inhibitory effect on MAPK is independent of the cAMP-PKA pathway in the mesangial
      cell.

PMID- 12608647
TI  - 5-Hydroxytryptamine-induced plasma extravasation in the rat knee joint is
      mediated by multiple prostaglandins.
AB  - OBJECTIVE AND DESIGN: This study investigated whether prostaglandins (PGs) are
      involved in 5-hydroxytryptamine (5-HT)-induced synovial plasma extravasation.
      MATERIALS AND METHODS: Male Sprague-Dawley rat knee joints were perfused with 5
      HT and synovial capillary Evans Blue dye leakage was measured using
      spectrophotometry. Cyclooxygenase (COX) inhibitors and PG receptor subtype
      selective antagonists were tested for the ability to reduce 5-HT-induced synovial
      plasma extravasation. RESULTS: 5-HT-induced plasma extravasation was inhibited by
      indomethacin. The COX-1 selective inhibitor SC-560 and the COX-2 selective
      inhibitor NS-398 were equally effective, indicating that both isoforms are
      involved. Antagonists selective for EP1, EP2 and DP receptor subtypes
      significantly attenuated the 5-HT-induced plasma extravasation. However,
      antagonists selective for FP, IP and TP subtypes failed to reduce 5-HT-induced
      plasma extravasation. CONCLUSIONS: These results demonstrate that multiple, but
      selective, subtypes of PGs mediate synovial plasma extravasation produced by 5
      HT, and suggest that PGs act downstream of 5-HT in the inflammatory cascade.

PMID- 12608648
TI  - Dose-dependent effects of corticosteroids on the expression of matrix-related
      genes in normal and cytokine-treated articular chondrocytes.
AB  - OBJECTIVE AND DESIGN: To assess the effects of glucocorticoids on the expression
      of multiple matrix-related genes in normal and cytokine-treated cultured equine
      articular chondrocytes in a phenotypically correct suspension culture. MATERIAL
      OR SUBJECTS: Articular cartilage harvested from the joints of 15 foals, 7
      yearling horses, and 16 adult horses. TREATMENT: Glucocorticoids (dexamethasone,
      prednisolone, triamcinolone) at 10(-10) to 10(-4) M. METHODS: Equine articular
      chondrocytes maintained in suspension cultures were treated with glucocorticoids
      with and without human recombinant interleukin 1-beta (IL1-beta) and tumor
      necrosis factor-alpha (TNF-alpha). Northern blots of total RNA from the treated
      cells were probed with equine specific cDNA probes for a number of cartilage
      matrix-related genes. Zymography, Western blotting, and fluorography were also
      performed to study the effects on protein synthesis. RESULTS: The
      glucocorticoids, dexamethasone, triamcinolone, and prednisolone, markedly
      decreased MMP1, MMP3, MMP13, TIMPI, and ferritin steady-state mRNA levels. There
      were no qualitative differences seen among the tested corticosteroids although
      dexamethasone and triamcinolone appeared to be slightly more potent than
      prednisolone. The effects of the glucocorticoids on MMP transcription occurred
      consistently at lower doses than those required to similarly downregulate type II
      collagen and aggrecan. Link protein and fibronectin mRNA were increased by the
      glucocorticoids, and biglycan and decorin were minimally affected. Fluorography
      of [14-C] proline-labeled media demonstrated that the decrease in type II
      collagen transcription (mRNA levels) was paralleled at the protein level.
      Zymography and Western blotting confirmed the decrease in functional
      metalloproteinases found in chondrocyte cultures following glucocorticoid
      treatment. CONCLUSIONS: The effects of glucocorticoids are complex inasmuch as
      they differentially affect numerous genes involved in the composition of
      cartilage matrix and the degradation of that matrix. This study provides new
      insight into the effects of glucocorticoids on the regulation of extra-cellular
      matrix and matrix-related genes by demonstrating that low doses of
      glucocorticoids can inhibit the degradative metalloproteinases with minimal
      negative effects on the transcription of extracellular matrix genes.

PMID- 12608649
TI  - Revised birth and fertility rates for the United States, 2000 and 2001.
AB  - OBJECTIVES: This report presents revised birth and fertility rates for 2000 and
      2001, based on populations consistent with the April 1, 2000, census. Rates are
      presented by age, race, and Hispanic origin of mother; by age, race, and Hispanic
      origin of mother for unmarried women; and by age and race of father. To put the
      rates for 2000 and 2001 into context, rates are also shown for 1990. METHODS:
      Populations were produced for the Centers for Disease Control and Prevention's
      National Center for Health Statistics under a collaborative arrangement with the
      U.S. Census Bureau. The populations reflect the results of the 2000 census. This
      census allowed people to report more than one race for themselves and their
      household members, and also separated the category for Asian or Pacific Islander
      persons into two groups (Asian; Native Hawaiian or Other Pacific Islander). These
      changes reflected the Office of Management and Budgets 1997 revisions to the
      standards for the classification of Federal data on race and ethnicity. Because
      only one race is currently reported in birth certificate data, the 2000 census
      populations were "bridged" to the single race categories specified in the Office
      of Management and Budget's 1977 guidelines for race and ethnic statistics in
      Federal reporting, which are still in use in the collection of vital statistics
      data. RESULTS: Population-based birth and fertility rates for 2000 and 2001,
      based on the 2000 census, are somewhat lower for Hispanics (11 percent for the
      fertility rate in 2001) and Asian or Pacific Islanders (7 percent) and
      considerably lower for American Indians (18 percent) than the rates previously
      published based on populations projected from the 1990 census. Rates for most
      other population subgroups differ little from those previously published. Because
      of these patterns, the differentials in fertility among population subgroups
      remain, but are somewhat reduced. Between 1990 and 2001, teenage birth rates
      declined, rates for women in their twenties changed little, and rates for women
      in their thirties and forties rose.

PMID- 12608650
TI  - Deflazacort treatment of cystoid macular edema in patients affected by Retinitis
      Pigmentosa: a pilot study.
AB  - BACKGROUND: To investigate the efficacy of a long-term treatment with Deflazacort
      (DFZ), a third generation synthetic glucocorticoid, in patients affected by
      Retinitis Pigmentosa (RP) complicated by Cystoid Macular Edema (CME). METHODS: A
      randomized group of 10 RP subjects were selected for this pilot study and treated
      with DFZ for one year according to a standard protocol. Far and near Best
      Corrected Visual Acuity (BCVA), fluorescein angiography (Heidelberg Retina
      Angiograph) and computerized perimetry (Humphrey Visual Field Analyzer) were
      statistically assessed. RESULTS: Near visual acuities, fluorescein angiographic
      findings and perimetric data improved significantly (p < 0.01) while far BCVA
      varied only slightly (p < 0.05). No ocular or systemic side effects were
      recorded. CONCLUSIONS: Further case-control studies, also involving a larger
      number of patients, are required to confirm these preliminary results. However,
      the present investigation seem to suggest that DFZ could be effective in reducing
      fluorescein angiographic findings and improving perimetric data and near visual
      acuities in RP patients, even though the pathogenesis of CME remains poorly
      understood.

PMID- 12608651
TI  - Coagglutination test for rapid noncultural diagnosis of human Campylobacteriosis.
AB  - Forty diarrhoeic stool samples of domestic animal handlers in a rural area of
      India were cultured and screened for detection of Campylobacter jejuni by Co
      agglutination technique (CoA). Seven C. jejuni strains were isolated by culture
      and 6 faecal samples gave positive CoA test. The specificity and sensitivity for
      negative and positive culture were 96.9% and 85.7% respectively. This is first
      report of detection of Campylobacter enteritis of human beings using CoA
      technique directly from stool samples.

PMID- 12608652
TI  - ERCP and acute pancreatitis.
AB  - Acute biliary pancreatitis (ABP) is a serious complication of biliary stones
      disease and is associated with significant morbidity and mortality. The role of
      ERCP in the management of ABP has been the focus of discussion in recent years.
      In this report, we evaluated a protocol of emergency Endoscopic retrograde
      Cholangiopancreatography (ERCP) (within 24 hours) and early ERCP (within 72
      hours). From July 1997 to July 2000, were observed 45 patients (19 man and 26
      women) with acute biliary pancreatitis. Mean age of patients was 63.4 years
      (range 21-87 years). Diagnosis of ABP was based on anamnesis and clinical
      assessment and was confirmed by specific laboratory data (hyperamylasemia,
      hyperlipasemia, total and fractionated bilirubinemia, gamma-GT, transaminase,
      alkaline phosphatase, hypocalcemia, hyperglycemia, leukocytosis). Ultrasound
      scanning within 24 h of admission was performed in 45 patients (100%) and it
      revealed gallbladder stones and muddy bile in 39 patients (87%). Computed
      tomography (CT) performed in all patients, showed a severe acute pancreatitis in
      the second or subsequent week following admission. The severity of acute
      pancreatitis was established by Glasgow's criteria and by clinical details of
      patients. ERCP and Endoscopic Sphinterotomy (ES) was performed in all 45 patients
      with acute biliary pancreatitis. Twenty-six patients (57%) were classified as
      having a severe attack (> 4) 19 as having a mild attack by Glasgow's criteria.
      ERCP associated with ES was performed within 24 hours in 22 patients (49%), 11
      (50%) showed a severe attack and 11 (50%) showed a mild attack. A total of 2
      complications (4%) occurred and the mortality was of 2 patients (4%). In 23
      patients (51%) ERCP and ES was performed within 72 hours after conservative
      therapy, 8 (35%) showed a mild attack and 15 (65%) showed a severe attack. A
      total of 5 complications (9%) occurred and the mortality was of 3 patients (6%).
      Our study showed that ERCP with endoscopic sphincterotomy can be performed safely
      by skilled endoscopist, without adverse consequences soon after the onset of
      acute biliary pancreatitis even within the first 24 hours and it showed that is
      better than ERCP within 72 hours after conservative therapy.

PMID- 12608653
TI  - Neonatal necrotizing enterocolitis: a focus on.
AB  - Necrotizing enterocolitis (NEC) is a multifactorial worldwide problem,
      representing the most frequent gastrointestinal emergency in neonates. Extremely
      common in preterm infants, it is also registered in fullterm low birth weight
      neonates. Despite extensive research, its etiopathogenesis is not completely
      understood and this neonatal disease remains associated with high morbidity and
      mortality rates. This review proposes an interdisciplinary focus on recent
      developments in NEC etiopathogenesis, diagnosis and management.

PMID- 12608654
TI  - Differential diagnosis of salivary acinic cell carcinoma and adenocarcinoma
      (NOS). A comparison of (immuno-)histochemical markers.
AB  - A correct histologic differential diagnosis between salivary acinic cell
      carcinoma (ACC) and adenocarcinoma not otherwise specified (AC-NOS) is highly
      relevant because of the strikingly different biologic behavior and related
      therapeutical strategies. The distinction between both tumor types can be
      difficult because of an enormous variation in histologic appearance, with either
      type showing partially overlapping morphologic features. Owing to a lack of
      approved markers, the expression of PAS-staining, alpha-Amylase, alpha-1 Anti
      trypsin, cytokeratin (CK)-subtypes 7/18 and Ki-67 was evaluated in 16 cases of
      ACC and 16 cases of AC-NOS. CK 7 is identified as the most reliable marker with
      strong positivity in AC-NOS, and complete or preponderant negativity in ACC. The
      characteristic membranous staining pattern of CK 18 in ACC, in contrast to a
      diffuse cytoplasmic pattern in AC-NOS, proved to be an additional valuable
      criterion. PAS and alpha-Amylase are only of little value when ACC is diagnosed,
      as many cases are only faintly positive or completely negative. The proliferation
      index (Ki-67) proved to be significantly higher in AC-NOS; however, the
      diagnostic usefulness is limited by a relevant overlap. In conclusion, we
      recommend CK 7 and 18 as the most valuable markers in cases with difficult
      differential diagnosis between ACC and AC-NOS.

PMID- 12608655
TI  - Promoter methylations of p16INK4a and p14ARF genes in early and advanced gastric
      cancer. Correlations of the modes of their occurrence with histologic type.
AB  - The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a and
      p14ARF. These share an exon using different reading frames, and act through Rb
      and p53 pathways. Recently, it has been found that silencing of p16INK4a and
      p14ARF expressions by aberrant methylation of the CpG islands in the promoter
      regions is an alternative mechanism that inactivates possible tumor suppressor
      functions in various tumors. To clarify the features of gastric cancers with
      promoter methylation of p16INK4a and p14ARF, we investigated the methylation
      status in gastric cancer cell lines and primary gastric cancers using methylation
      specific PCR (MSP), and correlated the methylation status with microsatellite
      instability (MSI), DNA ploidy pattern, p53 immunohistochemistry, and various
      clinicopathologic factors, paying attention to the correlations with the
      histologic types. Of 10 cell lines studied, silencing of the expression of
      p16INK4a and p14ARF due to promoter methylation was detected by MSP and RT-PCR in
      six (60%) and two (20%) cell lines, respectively. p14ARF silencing was detected
      only in cell lines derived from gastric cancer of the diffuse type, while
      p16INK4a silencing was found in cell lines derived from both diffuse and
      intestinal types. In 59 primary gastric cancers, promoter methylation of p16INK4a
      and p14ARF was found in 10 (17%) and 14 (24%) of the tumors independently, there
      being an association with DNA diploidy, but not with p53 immunohistochemistry.
      p16INK4a methylation was found irrespective of tumor stages and histology.
      Whereas p14ARF methylation was found more frequently in intestinal type cancers
      in an early stage and in diffuse type cancers in an advanced stage, MSI tended to
      be related especially to p14ARF methylation in cancers of the intestinal type.
      Thus, the significance of p14ARF methylation differed between intestinal and
      diffuse types, while such a difference was not observed in p16INK4a methylation.

PMID- 12608656
TI  - Aberrant P-cadherin expression: is it associated with estrogen-independent growth
      in breast cancer?
AB  - Breast carcinomas represent a heterogeneous group of tumors, with a diverse
      biologic behavior, outcome, and response to therapy. Recent studies have
      demonstrated that alterations in the expression of adhesion molecules in cancer
      cells are related to aggressiveness and poor prognosis. The aim of our study was
      to investigate the expression of P-cadherin in breast carcinomas and correlate it
      with estrogen receptor (ER) status. We selected 73 ductal carcinomas in situ
      (DCIS) and 149 invasive carcinomas of the breast, and assessed the expression of
      P-cadherin as well as other biologic markers. P-cadherin expression showed a
      strong inverse correlation with ER expression in both types of breast carcinoma
      (in situ and invasive). P-cadherin-positive and ER-negative tumors were related
      to a higher histologic grade, a high proliferation rate, and expression of c-erbB
      2. We demonstrated that P-cadherin identifies a subgroup of breast carcinomas
      that lacks ER expression, and correlates with higher proliferation rates and
      other predictors of aggressive behavior. We believe that these tumors represent
      an advanced step in cancer progression, and our data support the hypothesis that
      an estrogen-independent pathway regulates P-cadherin expression.

PMID- 12608657
TI  - Immunohistochemical localization of collagen type III and type IV, laminin,
      tenascin and alpha-smooth muscle actin (alphaSMA) in the human liver in peliosis.
AB  - The expression of collagen types III and IV, laminin, tenascin, and hepatic
      stellate cells (HSCs) activation marker alphaSMA was evaluated
      immunohistochemically in the liver of three patients with non-bacilar peliosis.
      Peliosis was attributed to tuberculosis, endometriosis treated with anabolic
      androgenic steroids, and to pheochromocytoma. Ultrastructural examination of the
      lesions of the liver revealed cavities that were sometimes lined with sinusoidal
      endothelial cells or hepatocytic microvilli. In liver sinusoids around cavities,
      cystic dilatation of the space of Disse and an abundance of amorphous matrix were
      observed. At this location, HSCs were transformed into transitional cells or
      myofibroblasts. Extracellular matrix proteins (ECM) were increased in the dilated
      sinusoids around cavities perisinusoidally and in the wall of cavities
      themselves. AlphaSMA was also increased. Ultrastructural immunohistochemistry
      revealed strong intracellular deposits of collagen type IV, laminin, and alphaSMA
      in HSCs. Laminin immunoreactivity was also noted in the endocytic vesicles in the
      cytoplasm of a monocyte. These findings suggest that enhanced ECM accumulation
      and the transformation of HSCs into myofibroblasts constitute a secondary event
      in peliosis and an attempt of the liver to restrict and remove sinusoidal
      dilatation.

PMID- 12608658
TI  - Expression pattern of apoptotic markers in vestibular schwannomas.
AB  - The Fas-Fas-L system plays a major role in the regulation of apoptosis and hence
      in growth in benign and malignant human tumors. As the factors regulating cell
      death in benign schwannomas are not well understood, we investigated the
      immunoexpression of the Fas-Fas-L system, as well as that of the anti-apoptotic
      factor Bcl-2 and the pro-apoptotic factor Bax in 14 sporadic vestibular
      schwannomas, and related the findings to the MIB-1 labeling index as a marker for
      cell proliferation. Whereas cytoplasmic Fas expression was seen in only one tumor
      (7%), Fas-L was found in the nuclei of 12 schwannomas (86%). Bcl-2 expression was
      found in the cytoplasm of 9 tumors (64%), and Bax was found in 10 out of 14
      schwannomas (71%). No significant correlations between different labeling indices
      were observed. However, schwannomas expressing Bax tended to show a higher
      proliferation rate as revealed by the MIB-1 LI, suggesting a balance between cell
      proliferation and cell death. Our study further showed that Fas-L is present in
      most vestibular schwannomas; however, due to the lack of Fas expression,
      apoptosis in vestibular schwannomas does not seem to be mediated via the Fas-Fas
      L system.

PMID- 12608659
TI  - Combined small cell carcinoma and clear cell carcinoma of the gallbladder: report
      of a case and review of the literature.
AB  - We report a case of an incidental combined carcinoma of the gallbladder in a 66
      year-old woman who underwent cholecistectomy for gallstones. The neoplasm was
      mainly constituted by a clear cell component and a small cell, chromogranin
      positive one; it also showed some areas of conventional adenocarcinoma and foci
      of vascular invasion. The patient died after 3 years following treatment with
      combination chemotherapy. The histologic and immunohistochemical profile of the
      lesion is described, together with a brief review of the pertinent bibliography.

PMID- 12608660
TI  - Lymphangioleiomyomatosis associated with pulmonary metastasis from an occult
      papillary carcinoma of the thyroid: report of a case occurring in a patient
      without tuberous sclerosis.
AB  - We report on 50-year-old woman without tuberous sclerosis, presenting with
      recurrent spontaneous pneumothorax. A CT-scan of the chest showed multiple,
      bilateral, thin-walled cysts, consistent with pulmonary lymphangioleiomyomatosis.
      A videothoracoscopic lung biopsy confirmed the diagnosis of
      lymphangioleiomyomatosis, but revealed also a micrometastasis from an occult
      papillary carcinoma of the thyroid gland. The main histologic differential
      diagnosis and the possible correlation between lymphangioleiomyomatosis and
      thyroid diseases are briefly discussed.

PMID- 12608661
TI  - Histopathologic changes in parotid gland parenchyma after fine needle aspiration
      biopsy of a Warthin's tumour. A case report.
AB  - Fine needle aspiration biopsy of a non-tender tumour in the right parotid gland
      was performed in a 63-year-old man. A cytological diagnosis of Warthin's tumour
      was made. Six weeks later, the tumor was removed by a formal parotidectomy.
      During dissection of the marginal mandibular branch of the facial nerve,
      significant fibrosis in the surrounding soft tissues was noted, requiring
      resection of the nerve. We also found a metaplastic (infarcted) Warthin's tumour
      with focal necrosis surrounded by metaplastic squamous epithelium. There was
      extensive fibrosis within the adjacent atrophic parotid parenchyma, striated
      muscle and around peripheral nerves. Small arteries at the periphery of the
      tumour were occluded by thrombi. The authors believe that the fibrosis of the
      tissue adjacent to the tumour was more likely due to the ischemia than to a
      direct puncture trauma caused by the fine needle aspiration.

PMID- 12608663
TI  - Speaking and writing the scientific language.

PMID- 12608662
TI  - Cellular composition of subacute thyroiditis. an immunohistochemical study of six
      cases.
AB  - To clarify the cellular composition of subacute thyroiditis, histologic and
      immunohistochemical studies were performed. Histologically, the lesion presented
      a patchy distribution of non-caseous granulomas comprising colloid, small
      lymphocytes, neutrophils, macrophages with or without epithelioid features, and
      multinucleated giant cells of foreign body type. In addition, numerous
      plasmacytoid monocytes were closely associated with the granulomas. The giant
      cells were CD68+, thyroglobulin- and cytokeratin-. Usually, small lymphocytes in
      the granulomas are CD3+, CD8+, CD45RO+ cytotoxic T-cells. In the non
      granulomatous lesion, the follicles were often infiltrated by CD8+ T-lymphocytes,
      plasmacytoid monocytes and histiocytes, resulting in disrupted basement membrane
      and rupture of the follicles. Lymphoid follicles with or without active germinal
      centers were not observed. Moreover, no residual follicular dendritic cell
      networks were detected by CD23 and CAN.42 immunostains. In the interfollicular
      area, scattered plasma cells were observed among infiltrating cells. Neither
      human herpes virus 8 nor EBER-positive cells were detected in the six patients.
      The findings of our study suggest that cellular immune response may play an
      important role in the pathogenesis of subacute thyroiditis.

PMID- 12608664
TI  - Influence of platelet-rich plasma on osseous healing of dental implants: a
      histologic and histomorphometric study in minipigs.
AB  - PURPOSE: In the present study the time course of local bone formation following
      the application of PRP during implant placement was evaluated
      histomorphometrically and histologically. MATERIALS AND METHODS: The mandibular
      premolars of 12 adult minipigs were removed surgically and 72 sites were prepared
      for implant placement. Before the implants (MK III, Replace, and MK III TiUnite)
      were placed, autogenous PRP (8 x 10(5) to 10 x 10(5) platelets/microL) was
      instilled into the host sites on the left side. The animals were sacrificed at 3,
      6, and 12 weeks, and undecalcified ground sections were prepared. RESULTS: The
      histomorphometric evaluation showed significantly more bone-to-implant contact
      after topical PRP application in the early healing phase (6 weeks), which varied
      as a function of the distance from the implant surface (controls = 24.2% versus
      PRP = 44.21%; P = .013). At 12 weeks, the extent of osteoneogenesis was
      comparable in the 2 groups (controls = 51.3% versus PRP = 44.2%; P = .251).
      Statistical analysis revealed no significant interaction between implant surface
      type and PRP. DISCUSSION: Topical PRP application significantly increased the
      activity of bone regeneration at implant host sites during early healing.
      CONCLUSION: In the present study PRP was found to have a time- and site-dependent
      effect on peri-implant bone healing.

PMID- 12608665
TI  - A new porous hydroxyapatite for promotion of bone regeneration in maxillary sinus
      augmentation: clinical and histologic study in humans.
AB  - PURPOSE: This study was undertaken to evaluate clinically, histologically, and
      immunohistochemically the use of a new porous hydroxyapatite (HA) (B. Agra,
      Cabon, Milan, Italy) as a grafting material for maxillary sinus augmentation with
      simultaneous implant placement. MATERIALS AND METHODS: A total of 28 titanium
      implants were placed in 12 patients with an average of 4.5 mm of bone on the
      sinus floor. HA granules were packed around the implants in the sinus cavity.
      After a healing period of 5 to 6 months, second-stage surgery was carried out. In
      5 patients, bone cores were harvested from grafted areas and processed for
      histology and immunocytochemistry. RESULTS: All implants were clinically stable
      at second-stage surgery and were followed for an average of 3 years. The
      histology showed newly formed bone in direct contact with the HA granules.
      Immunohistochemistry showed the presence of large quantities of bone sialoprotein
      and osteopontin in and around the granules of HA. DISCUSSION AND CONCLUSION: This
      study suggests that a new porous HA accommodated sinus floor augmentation in
      patients with 3 to 5 mm of bone height preoperatively. By possibly attracting
      circulating biocomponents at sites of tissue repair, it may promote bone
      regeneration.

PMID- 12608666
TI  - Immediate placement and provisionalization of maxillary anterior single implants:
      1-year prospective study.
AB  - PURPOSE: This 1-year prospective study evaluated the implant success rate, peri
      implant tissue response, and esthetic outcome of immediately placed and
      provisionalized maxillary anterior single implants. MATERIALS AND METHODS: Thirty
      five patients (8 men, 27 women) with a mean age of 36.5 years (range 18 to 65)
      were included in this study. Thirty-five threaded, hydroxyapatite-coated implants
      were placed and provisionalized immediately after each failing tooth had been
      removed. The definitive restoration was placed 6 months later. The patients were
      evaluated clinically and radiographically at implant placement and at 3, 6, and
      12 months after implant placement. RESULTS: At 12 months, all implants remained
      osseointegrated. The mean marginal bone change from the time of implant placement
      to 12 months was -0.26 +/- 0.40 mm mesially and -0.22 +/- 0.28 mm distally. No
      significant differences in the Plaque Index scores were noted at different time
      intervals. The mean midfacial gingival level and mesial and distal papilla level
      changes from pretreatment to 12 months were -0.55 +/- 0.53 mm, -0.53 +/- 0.39 mm,
      and -0.39 +/- 0.40 mm, respectively. All patients were very satisfied with the
      esthetic outcome and none had noticed any changes at the gingival level.
      DISCUSSION: Although marginal bone and gingival level changes were statistically
      significant from pretreatment to 12 months of follow-up, they were well within
      clinical expectations. CONCLUSION: The results of this study suggest that
      favorable implant success rates, peri-implant tissue responses, and esthetic
      outcomes can be achieved with immediately placed and provisionalized maxillary
      anterior single implants.

PMID- 12608667
TI  - Surface chemistry effects of topographic modification of titanium dental implant
      surfaces: 1. Surface analysis.
AB  - PURPOSE: To analyze the surface composition of 34 different commercially
      available titanium dental implants. MATERIALS AND METHODS: Surface composition
      was evaluated by x-ray photoelectron spectroscopy (XPS). Samples were divided
      into 4 groups, depending on their surface topography (machined, sandblasted, acid
      etched, or plasma sprayed). RESULTS: Statistical analysis of the data showed a
      clear relationship between surface composition and topography, which can be
      easily accounted for by the chemical effects of the surface treatment performed.
      On average, acid-etched and plasma-sprayed surfaces had higher titanium and lower
      carbon concentration than machined surfaces. DISCUSSION AND CONCLUSION: Current
      studies aimed at the evaluation of implants with different topography should not
      implicitly assume that topography is the only variable controlling the biologic
      response. Rather, when comparing different topographies, it should be taken into
      account that surface chemistry may be a variable as well.

PMID- 12608668
TI  - Surface chemistry effects of topographic modification of titanium dental implant
      surfaces: 2. In vitro experiments.
AB  - PURPOSE: To determine, in vitro, cytotoxicity and cell adhesion on 3 different
      implant surfaces. MATERIALS AND METHODS: All samples had machined surfaces, but
      they were subjected to different cleaning procedures, which produced 3 different
      surface chemistries. One of the samples was "as-produced" from the machining
      tools. The other samples were subjected to partial and total cleaning routines.
      Cytotoxicity was evaluated using mouse fibroblast cultures, and cell adhesion was
      evaluated with osteoblast-like SaOS-2 cells. RESULTS: The "as-produced" sample
      showed a pronounced surface contamination by lubricating oils. For partially and
      totally cleaned samples, an increasing amount of titanium and a decreasing
      carbon/titanium ratio was observed as cleaning became more complete. DISCUSSION:
      Differences in surface chemistry such as those normally found on titanium implant
      surfaces (see part 1 of this series) can lead to those same effects which, in in
      vitro experiments, are normally accounted for in terms of surface topography
      alone. CONCLUSION: Effects related to surface chemistry can operate over and
      above surface topography, making it impossible, without proper characterization,
      to make definite statements about the role of topography alone.

PMID- 12608669
TI  - Histologic findings in sinus augmentation with autogenous bone chips versus a
      bovine bone substitute.
AB  - PURPOSE: The aim of this study was to compare a bovine bone substitute (Bio-Oss)
      to autogenous bone with respect to its value as a material for sinus
      augmentation. MATERIALS AND METHODS: In 10 beagle dogs 12 months of age, the 3
      maxillary premolars were extracted on both sides. Six weeks later, 2 cavities of
      predefined size were produced in the region of the nasal cavity. The antral
      window was 25 mm long and had a vertical extension of 7 mm. Two Frialit-2
      implants (3 x 8 mm) were placed in each bone defect (n = 20). Every implant was
      primarily stable because of fixation in native bone. In each maxilla, 1 bone
      defect was filled with autogenous bone harvested from the mandible and 1 was
      filled with Bio-Oss (material selected at random). The animals were sacrificed at
      90 and 180 days, and histologic specimens were examined and the results subjected
      to statistical analysis by the Wilcoxon test for paired observations. RESULTS: No
      healing problems were observed. Histologically, after 90 days the volume of the
      augmentation showed a reduction of 14.6 +/- 4.4% within the Bio-Oss group and 3.8
      +/- 2.5% in the group with autogenous bone. Bone-implant contact of 52.16 +/-
      13.15% in the Bio-Oss group and 60.21 +/- 11.46% in the autogenous bone group was
      observed. At 180 days, the Bio-Oss group showed bony ingrowth of the substitute,
      whereas in the autogenous group a differentiation from original bone could no
      longer be made. The volume reduction was 16.5 +/- 8.67% in the Bio-Oss group and
      39.8 +/- 16.14% in the autogenous group. Bone-implant contact of 63.43 +/- 19.56%
      in the Bio-Oss group and 42.22 +/- 12.80% in the autogenous bone group was
      measured. DISCUSSION AND CONCLUSION: The results indicated that because of the
      nonresorptive properties of the bone substitute Bio-Oss, regeneration of the
      defects is achievable. It was demonstrated that the bone substitute seemed to
      behave as a permanent implant. The volume of the area augmented by autogenous
      bone decreased over the observation period.

PMID- 12608670
TI  - Bicortically stabilized implant load transfer.
AB  - PURPOSE: Questions exist as to the potential advantages of bicortical
      stabilization of implants in the mandible through engagement of the lingual
      cortical plate. The purpose of this investigation was to determine
      photoelastically the effect of lingual cortical plate engagement on implant load
      transfer. MATERIALS AND METHODS: Composite photoelastic models of an edentulous
      posterior segment of a mandible were fabricated using plastics of different
      modulus to simulate cortical and trabecular bone. One model included a 3.75 x 15
      mm threaded implant that engaged the simulated lingual cortical plate, while in
      the other model the implant was centrally located within the simulated trabecular
      bone. A metal superstructure was cast using an abutment cylinder. Simulated
      vertical occlusal loads were applied to the superstructure over the implant and
      at fixed buccal cantilever lengths. Stresses that developed within the model were
      monitored photoelastically and recorded photographically. Peri-implant defects
      were then formed in the models and the loading and recording procedures were
      repeated. RESULTS: Lingual cortical plate engagement generated the highest
      stresses at the lingual cortical plate and the buccal crestal cortical layer at
      the implant neck. Stress intensity within the buccal plate at the implant neck
      was lower than that in the centrally placed implant. In the presence of a peri
      implant defect, for all load conditions, more load was borne by the trabecular
      bone. Increasing cantilever lengths caused asymmetric load transfer with higher
      maximum stresses. DISCUSSION: For both implant placements, a large portion of the
      applied load was taken by the crestal cortical bone simulant. Engagement of the
      lingual cortical plate reduced maximum stress in the crestal cortical bone by
      approximately 25%. With peri-implant defects, the simulated trabecular bone
      provided the main support of the applied load. Longer buccal cantilever lengths
      increased maximum stresses for all placement and crestal bone conditions.
      CONCLUSIONS: The results of this investigation do not indicate a clear load
      transfer advantage to apical engagement of the lingual cortical plate in this
      model.

PMID- 12608671
TI  - Effects of bisphosphonate on bone reaction after placement of titanium implants
      in tibiae of ovariectomized rats.
AB  - PURPOSE: This study was undertaken to investigate the action of bisphosphonate on
      bone reactions after the placement of titanium screw implants into the tibiae of
      ovariectomized rats. MATERIALS AND METHODS: Twelve-week-old female Wistar rats
      were divided into 4 groups of 18 animals each. The first group (Sham) was sham
      operated, the second group (OVX) was ovariectomized only, the third group
      (Estrogen) was ovariectomized and received continuous estrogen with a 17beta
      estradiol pellet, and the fourth group (YM-175) was ovariectomized and received
      bisphosphonate at a dose of 10 microg/kg of body weight. Titanium screw implants
      were placed in the proximal metaphyses of the tibiae 168 days after surgery. The
      animals were sacrificed 7, 14, and 56 days after implant placement. Undecalcified
      sections were prepared and evaluated by light microscopy. Histomorphometric
      measurements were obtained with a computer-based image analyzer to quantify the
      unit bone mass around the implant and the rate of implant-bone contact. RESULTS:
      Ovariectomies significantly reduced implant-bone contact and the bone volume
      around the implants. However, in the YM-175 group, only slight differences in
      both bone contact and bone volume were noted compared with the Sham and Estrogen
      group. The woven structure of new bone in the YM-175 group was also replaced by
      mature lamellar bone, as in the other groups. DISCUSSION AND CONCLUSION: These
      results suggested that bisphosphonate preserved the implant-bone contact and bone
      volume around the implants.

PMID- 12608672
TI  - Sandblasted and acid-etched dental implants: a histologic study in rats.
AB  - PURPOSE: Current literature has revealed that surface etching of endosseous
      implants can improve bone-implant contact. The aim of this study was to evaluate
      the differences in bone-implant contact (BIC) between sandblasted/acid-etched and
      machined-surface implants. MATERIALS AND METHODS: Thirty-two Sprague-Dawley rats
      were used in this study. Two implant surfaces, Ecotek (sandblasted/ acid-etched)
      and machined, were used with 1 implant placed in each tibia of the animals. A
      total of 64 implants were placed. BIC was evaluated at 5, 15, 30, and 60 days.
      Histomorphometry of the BIC was evaluated statistically. RESULTS: The
      sandblasted/acid-etched surface demonstrated a greater BIC percentage than the
      machined surface. This difference was statistically significant only at 30 and 60
      days after healing. DISCUSSION AND CONCLUSION: The sandblasted/acid-etched
      surface demonstrated a stronger bone response than the machined one at a later
      period of healing.

PMID- 12608673
TI  - Prospective study of 429 hydroxyapatite-coated cylindric omniloc implants placed
      in 121 patients.
AB  - PURPOSE: Controversy over the long-term clinical effectiveness of hydroxyapatite
      (HA)-coated dental implants still persists, despite numerous clinical studies
      documenting high survival rates. The Ohio State University College of Dentistry
      undertook a 5-year prospective study of 429 HA-coated cylindric implants placed
      into 121 patients to determine the long-term clinical performance of the
      implants. MATERIALS AND METHODS: All study subjects were patients screened and
      evaluated in the university's dental clinic by one of the principal investigators
      and one member of the surgical team. A total of 429 HA-coated implants were
      placed in 121 patients. The Ohio State University Human Subjects Committee
      approved and reviewed this study. RESULTS: At the time of this report, 375
      implants had completed 5 years of clinical follow-up. Beyond the 5-year limit of
      the study, 282 implants had completed 6 years and 114 implants had completed 7
      years of clinical monitoring. The cumulative survival rate was 96% at 5 years and
      95% at 7 years of follow-up. Mean combined mesial/distal bone loss was 1.2 mm in
      the mandible and 1.4 mm in the maxilla after 5 years of functional loading.
      Implant failures were most commonly associated with short implants or angled
      abutments. DISCUSSION: Prospective clinical data are extremely valuable for
      clinicians evaluating the reliability of dental implant systems. In the present
      study, the implants achieved 100% osseointegration with minimal marginal bone
      loss, and 96% of the implants remained in function at 5 years. CONCLUSION: The HA
      coated cylindric implants in this study provided a predictable means of oral
      rehabilitation.

PMID- 12608675
TI  - Erbium:YAG laser application in the second phase of implant surgery: a pilot
      study in 20 patients.
AB  - PURPOSE: Conventional implant dentistry implies 2 surgical stages. In this
      context, pain is often present in the second stage, despite the fact that it is
      comparatively less aggressive for the patient. The present pilot study proposes
      application of Erbium:YAG (Er:YAG) laser for second-stage implant surgery.
      MATERIALS AND METHODS: Twenty patients were studied with a total of 50 implants
      in which osseointegration was complete. The subjects were divided into 2 groups:
      a control group (10 patients with 25 implants), subjected to conventional second
      stage surgery; and a group of 10 subjects (also with 25 implants) treated with
      the Er:YAG laser at second-stage implant surgery. RESULTS: The use of Er:YAG
      laser obviated the need for local anesthesia and minimized postoperative pain and
      time needed before starting the second stage. With regard to surgical duration,
      quality of hemostasis, and success in implant treatment, no differences were
      reported. DISCUSSION: In the second stage of implant surgery, different types of
      laser have been used, taking advantage of their bacteridal effect; disadvantages
      arise from inducing damage to the implant surface and adverse thermal effects.
      CONCLUSION: The advantages afforded by laser treatment include technical
      simplicity, the possibility of obviating local anesthesia, absence of
      postoperative pain and edema, and complete tissue healing by day 5, thus
      facilitating rapid prosthetic rehabilitation. The technique described can be used
      in all cases except situations where esthetic considerations prevail in anterior
      areas, or in the event of a lack of keratinized gingiva surrounding the implant.

PMID- 12608674
TI  - Is platelet-rich plasma the perfect enhancement factor? A current review.
AB  - Guided bone regeneration is an accepted surgical method employed in implant
      dentistry to increase the quantity and quality of the host bone in areas of
      localized alveolar defects. The lack of predictability in osseous regenerative
      procedures with various grafting materials suggests that improvement in the
      osteoinductive properties of these materials is highly desirable. Platelet-rich
      plasma (PRP), a modification of fibrin glue made from autologous blood, is being
      used to deliver growth factors in high concentration to sites requiring osseous
      grafting. Growth factors released from the platelets include platelet-derived
      growth factor, transforming growth factor beta, platelet-derived epidermal growth
      factor, platelet-derived angiogenesis factor, insulin-like growth factor 1, and
      platelet factor 4. These factors signal the local mesenchymal and epithelial
      cells to migrate, divide, and increase collagen and matrix synthesis. PRP has
      been suggested for use to increase the rate of bone deposition and quality of
      bone regeneration when augmenting sites prior to or in conjunction with dental
      implant placement Only 6 human studies using PRP have been found in the dental
      implant literature and 5 were case series or reports. Thus, there is clearly a
      lack of scientific evidence to support the use of PRP in combination with bone
      grafts during augmentation procedures. This novel and potentially promising
      technique requires well-designed, controlled studies to provide evidence of
      efficacy.

PMID- 12608676
TI  - Patient self-reported satisfaction with maxillary anterior dental implant
      treatment.
AB  - PURPOSE: Dental implants are accepted as a successful alternative to conventional
      fixed and removable prostheses for the treatment of partial or complete
      edentulism. However, there have been few studies of the success of implants from
      the patients' perspective. The purpose of this study was to assess patient
      overall satisfaction with the outcome of treatment with maxillary anterior
      implants. MATERIALS AND METHODS: A self-administered mailed questionnaire, which
      was developed for this project, and a data abstraction form, which was designed
      based on information available from the corresponding dental records of 123
      eligible subjects, were utilized to survey implant patients. RESULTS: Seventy
      eight of 123 eligible subjects responded to the mailed, self-administered,
      structured questionnaire. Twelve of the 24 questionnaire variables demonstrated
      statistically significant bivariate associations with the dependent variable
      "overall patient satisfaction." Five variables--implant position, definitive
      restoration shape, appearance, effect on speech, and chewing capacity--were
      strongly associated with overall satisfaction. No demographic or treatment
      related, dental record-abstracted variable, of the 25 that were examined, was
      statistically significant. DISCUSSION: The practitioner who provides implant
      restorations should be aware of the multidimensional aspects of patient
      satisfaction with implant treatment. This study suggests that patient
      satisfaction with key elements influences the overall acceptance of maxillary
      anterior implant prostheses, which are esthetically critical. Communication
      between dentist and patient is important to achieve optimal results that will be
      satisfactory to both. Discussion of treatment limitations may also help patients
      to develop realistic expectations of the final result. CONCLUSIONS: In this
      limited investigation, patient satisfaction with implant position, restoration
      shape, overall appearance, effect on speech, and chewing capacity were critical
      for patient overall acceptance of the dental implant treatment.

PMID- 12608677
TI  - Osseointegration assessment of dental implants using a synchrotron radiation
      imaging technique: a preliminary study.
AB  - PURPOSE: This study tests the possibility of using synchrotron radiation (SR) x
      ray micro-imaging as a new method to evaluate osseointegration. MATERIALS AND
      METHODS: A simple imaging setup with primarily unmonochromatic SR was used to
      study the interface of a dental implant in contact with bone. The samples were
      prepared by sectioning the undecalcified specimen of a titanium screw implanted
      in the tibia of a New Zealand white rabbit. Radiographs of the interface between
      surrounding tissues and dental titanium implant were imaged using the SR imaging
      system at PLS (Pohang Light Source) 5C1 beamline, a micro-computed tomography
      (microCT) system (SkyScan-1072), and a conventional dental x-ray system (Siemens
      Heliodent MD). RESULTS: The image quality of the osseointegrated titanium implant
      was compared among the 3 imaging systems. The SR imaging technique showed greater
      details than other radiographic modalities for evaluation of the healing stage of
      bone-implant contact. DISCUSSION: The evaluation was especially focused on the
      image quality of the osseous contact at the bone-to-implant interfaces.
      CONCLUSIONS: This SR imaging technique provides finer details and can be expected
      to make an impact in the clinical study of osseointegration.

PMID- 12608678
TI  - Dental implants in reconstructed jaws: patients' evaluation of functional and
      quality-of-life outcomes.
AB  - PURPOSE: To evaluate the quality-of-life aspect of treatment outcome following
      functional jaw reconstruction and dental implants in the maxilla or mandible.
      MATERIALS AND METHODS: This cross-sectional study used a questionnaire interview
      of 28 rehabilitated patients who received autogenous bone grafts from the ilium
      and endosseous implants (14 maxillary and 14 mandibular cases; 134 implants) for
      functional jaw reconstruction between 1988 and 1999. A questionnaire was
      developed to assess the quality-of-life outcome for those patients who had
      finished their rehabilitation at least 6 months prior to the interview. Responses
      to the questions were recorded by means of visual analog scales. RESULTS: In
      general, patients gave positive comments on the restoration of their orofacial
      appearance and function (mastication and speech). The majority (85.7%) found no
      problem in various daily social activities, including dining in public.
      DISCUSSION: The overall level of satisfaction with the treatment outcome and the
      degree of recommendation of the treatment to others were both favorable (mean
      scores 8.6 and 8.7 out of 10, respectively). CONCLUSION: Oral rehabilitation
      using functional jaw reconstruction can reach a satisfactory level of esthetics,
      function, and psychosocial well being of patients, thus improving their quality
      of life.

PMID- 12608679
TI  - Subantroscopic laterobasal sinus floor augmentation (SALSA): an up-to-5-year
      clinical study.
AB  - PURPOSE: The aim of the article was to introduce a new subantroscopic laterobasal
      sinus augmentation (SALSA) tecnique as a minimally invasive approach to maxillary
      peri-implant surgery. MATERIALS AND METHODS: The SALSA technique consists of the
      following steps: (1) microsurgical opening of the subantral space (SAS) with
      detachment of the sinus membrane (SM) under supported videoendoscopy; (2)
      enlargement of the SAS by laterobasal tunnelling; (3) subantroscopic examination
      of the SAS with (4) optional reinforcement or repair of the SM; (5) implant site
      preparation with subantroscopic identification of the cavities; and (6) precise
      stepwise placement of graft material under endoscopic control. RESULTS: Since
      1996, 118 sinus augmentations have been performed on 83 patients using
      particulate alloplastic augmentation material (tricalcium phosphate) with various
      amounts of autogenous bone and blood. Mean augmentation height was 8.6 mm (range,
      1 to 15 mm). Twenty-eight perforations of sinus mucosa were observed without
      further complication (1 case of sinusitis was treated and re-augmented
      endoscopically). Of 211 titanium screw-type implants placed, 11 failures were
      observed. DISCUSSION: SALSA is a predictable surgical technique. With this
      minimally invasive method, adequate bone height can be achieved. CONCLUSION:
      SALSA may offer advantages related to lower morbidity, conservation of bone
      volume and blood supply, optimized view of the surgical field, and high
      acceptance by patients.

PMID- 12608680
TI  - Young people's response to death threat appeals: do they really feel immortal?
AB  - Threat appeals are used frequently in health promotion, with threats of
      (premature) death common in some areas, e.g. 'quit smoking or you'll die'. There
      is a common notion that young people feel they are immortal. Accordingly, we
      investigated whether young people would respond less to threats of death than to
      non-death threats and whether younger people would respond less to death threats
      than older people. This study was conducted with smokers in two age groups (16-25
      and 40-50 years). Each respondent was exposed to one message about the threat of
      emphysema, either a death or non-death message. Younger smokers did not respond
      more to non-death threats than death threats and expressed a higher level of
      response to all threats than older smokers. It would appear that death threats
      are effective with young people and so we conclude that they do not feel
      immortal. An additional finding was that older females responded significantly
      more to non-death threats than older males. Death threats may not be effective
      with older females and a segmentation approach may be advisable when targeting
      older people using death threats in health promotion campaigns.

PMID- 12608681
TI  - Dissemination of heart health promotion in the Ontario Public Health System: 1989
      1999.
AB  - This paper reports the results of an analysis of the dissemination of community
      based heart health promotion strategies. The research draws on diffusion and
      socio-ecological theories to study the first 10 years of heart health promotion
      in the public health system in Ontario, Canada. Using case description and
      interpretive analysis, the study describes developments in five stages of
      dissemination, and examines the interplay of factors operating in the internal
      organizational setting and the external environment in order to explain these
      developments. Findings demonstrate that dissemination of health promotion is a
      long-term, iterative process involving multiple stages. Dissemination is
      influenced by a complex interplay of factors operating within the public health
      system (especially traditional public health practice and champions) and factors
      in the environment in which the public health system operates (especially
      research, practice information and health policies). Implications are that policy
      makers should take a long-term view of dissemination, identify intermediate and
      long-term goals consistent with dissemination stages, and capitalize on internal
      and external forces supporting dissemination goals. Similar case-study research
      in other public health systems and time periods, and in more advanced stages of
      dissemination, will add further insight into the dissemination process.

PMID- 12608682
TI  - Disclosure of HIV infection: how do women decide to tell?
AB  - This descriptive study explores the phenomenon of disclosure of HIV infection by
      women. Specifically, we examined women's level of disclosure to various groups
      and how these disclosure decisions are made. The sample consisted of 322 HIV
      infected women residing in the southern US. Participants were predominantly
      African-American, single women of reproductive age with yearly incomes less than
      $10,000. Data were collected at the first interview of a longitudinal study of
      reproductive decision making. Findings showed that the majority of the women had
      disclosed to some sex partners, close family and friends, and health care
      professionals. However, for a group of women, disclosure of HIV infection is a
      difficult issue supporting the need for health education and counseling.
      Qualitative data were analyzed using content analysis and revealed three major
      categories describing how women make disclosure decisions: full disclosure,
      criteria for disclosure and emotional disclosure. Quantitative analysis revealed
      few demographic differences among women in the three disclosure categories. These
      findings provide insight that can assist those working with HIV-infected women in
      helping them decide not only to whom they disclose, but how best to disclose.

PMID- 12608683
TI  - Utilizing role theory to help employed parents cope with children's chronic
      illness.
AB  - Role theory is utilized to detail a six-step process for developing balanced
      coping through role negotiation. As applied in this paper, the role theory
      framework provides health educators with a useful tool for helping employed
      parents cope with a child's chronic illness. The emphasis is on partnering with
      parents or primary caregivers to identify, understand and manage the multiple
      role demands of working parents with chronically ill children. Role theory
      suggests ways health educators can support balanced coping by educating families
      about the demands of a child's illness, and helping to reduce those demands,
      helping to increase family resources, supporting parents and facilitating role
      negotiation. The ultimate goal is the development of balanced coping strategies
      that (1) meet the medical and emotional needs of the ill child, (2) allow parents
      to maintain their physical and mental health, and (3) enable parents to meet the
      demands of their other roles (e.g. paid employment).

PMID- 12608684
TI  - Validity and reliability of the parental sun protection scales.
AB  - Skin cancer is the most common cancer diagnosed in the US and its incidence
      continues to rise. Epidemiological studies have shown that excessive sun exposure
      received during childhood may increase the risk of developing skin cancer later
      in life. Yet, there are few published reports on the development of reliable and
      valid theory-based scales that assess the factors associated with parental sun
      protection practices to reduce sun exposure in preschool children. To fill this
      gap, the Parental Sun Protection Scales were developed and validated. Two series
      of confirmatory factor analytic models were employed to test the factor structure
      of the scales and to examine the inter-relationships among the proposed
      psychosocial factors. Sunscreen-use and sun-avoidance behavioral models were
      tested in a sample of 384 parents. The results provided a basis for the reliable
      and valid measurement of psychosocial factors related to parental sun-protection
      practices. These scales may be useful in more fully understanding the
      determinants of sun-protection behaviors and in evaluating intervention programs
      designed to improve such behaviors.

PMID- 12608686
TI  - 'You and your skin': a short-duration presentation of skin cancer prevention for
      teenagers.
AB  - The effectiveness of a short-duration presentation of the educational material
      'You and Your Skin' was tested on 184 adolescents (age 13-15) at the Year 7 and 8
      levels. A non-equivalent control group design was used with pre-testing and post
      testing 3 months after the intervention. The intervention increased the students'
      knowledge of known risks factors for skin cancers. However, the students'
      attitudes to abstaining from sunbathing and tanning was not significantly
      affected. The effect of the intervention on the stage of change was primarily a
      progression from the precontemplation stage to the contemplation stage regarding
      avoiding the mid-day sun. We conclude that a brief presentation of the
      educational kit 'You and Your Skin' can be used to increase knowledge, but there
      is a need for a more extensive intervention effort to affect students' readiness
      to change their behavior and attitude towards sunbathing and tanning. Therefore,
      it is important to emphasize the necessity of using the educational kit as a
      multi-lesson programme with its several group exercises.

PMID- 12608685
TI  - One-year follow-up results of the STARS for Families alcohol prevention program.
AB  - This study examined the 1-year follow-up effects of the STARS (Start Taking
      Alcohol Risks Seriously) for Families program, a 2-year preventive intervention
      based on a stage of acquisition model, and consisting of nurse consultations and
      parent materials. A randomized controlled trial was conducted, with participants
      receiving either the intervention or a minimal intervention control. Participants
      included a cohort of 650 sixth-grade students from two urban middle schools-one
      magnet (bused) and one neighborhood. Trained project staff administered
      questionnaires to students following a standardized protocol in the schools. For
      the magnet school sample, significantly fewer intervention students (5%) were
      planning to drink in the next 6 months than control students (18%), chi2 = 11.53,
      1 d.f., P = 0.001. Magnet school intervention students also had less intentions
      to drink in the future, greater motivation to avoid drinking and less total
      alcohol risk than control students, Ps < 0.05. For the neighborhood school,
      intervention students (m = 7.90, SD = 1.87) had less total alcohol risk than
      control students (m = 8.42, SD = 1.83), F(1,205) = 4.09, P = 0.04. These findings
      suggest that a brief, stage and risk/protective factor tailored program holds
      promise for reducing risk for alcohol use among urban school youth 1 year after
      intervention, and has the unique advantage of greater 'transportability' over
      classroom-based prevention programs.

PMID- 12608687
TI  - Consumption of nutritional supplements among adolescents: usage and perceived
      benefits.
AB  - The aim of the study was to obtain rich qualitative data about the type of
      nutritional supplements and drinks consumed by adolescents, and the reasons for
      their consumption, with particular emphasis on the perceived benefits of
      nutritional supplementation. Semi-structured focus group interviews (n = 16) were
      conducted among 78 adolescents aged 11-18 years from a co-educational government
      high school. Participants reported consuming sports drinks, vitamin and mineral
      supplements, energy drinks, herbal supplements, guarana, creatine, high protein
      milk supplements, and coenzyme Q10. Reasons for supplement use included perceived
      short-term health benefits, prevention of illness, improved immunity, parental
      supply of supplements, taste, energy boost, better sports performance and to
      rectify a poor diet. Results suggest that some adolescents consume nutritional
      supplements, sports drinks and energy drinks for their perceived physiological
      benefits, and that they may not be aware of any potential risks. Health educators
      should be aware that adolescents seek specific health benefits from nutritional
      supplements and drinks, which may be better achieved through appropriate
      consumption of a nutritious diet. Health education programmes should incorporate
      the perceptions, aspirations and motivations of young people into the planning of
      interventions and activities in order to make them most relevant and effective.

PMID- 12608688
TI  - Cannabis and smoking research: interviewing young people in self-selected
      friendship pairs.
AB  - This paper will discuss the use of paired interviewing as the main method of
      generating data in a study exploring the social context of young people's smoking
      and cannabis use. The research, conducted as part of an on-going PhD, involved 59
      participants of both genders, aged 13-15 from different socioeconomic
      backgrounds, and with a wide range of cigarette and cannabis use experience.
      Participants were offered the choice of an individual interview or a paired
      interview with a friend of their choice, most opting for the paired format. The
      paper will discuss many of the methodological and ethical features of this
      method. In particular, it will discuss the potential for paired interviewing to
      access accounts generated within close friendship bonds, making this method
      distinctive from larger focus groups. It will also explore how paired
      interviewing facilitates access to interactions between participants, shedding
      light on many aspects of young people's social relationships and allowing
      occasional glimpses into more private territory. It will argue that the paired
      interview method can make a novel and distinctive contribution to health
      education/promotion research, policy and practice, and to any research that aims
      more fully to understand aspects of young people's social worlds.

PMID- 12608689
TI  - Prevalence of asthma in schoolchildren under-represents those from socially
      deprived areas.

PMID- 12608690
TI  - Special issue dedicated to Dr. Anders Hamberger.

PMID- 12608691
TI  - A powerful brain stimulant: Anders Hamberger.

PMID- 12608692
TI  - Erucamide as a modulator of water balance: new function of a fatty acid amide.
AB  - The aim of this study was to isolate a compound from blood plasma that inhibits
      intestinal diarrhea and that appears also to regulate fluid volumes in other
      organs. The isolation procedure included lipid extraction, liquid chromatography,
      and gas chromatography. The active substance was identified by mass spectrometry
      as erucamide (MW 337 Da). The biological effect was reproduced with authentic
      erucamide. Erucamide is a fatty acid amide, such as oleamide and anandamide,
      which modulate other physiological functions in a receptor-mediated fashion. All
      the exact biological functions of erucamide are as yet to be defined, but it is
      already known to stimulate angiogenesis. Erucamide concentrations were determined
      in body organs from the pig. The blood plasma level was 3 ng/g, and those of
      lung, kidney, liver, and brain were 12, 2.5, 1.0, and 0.5 ng/g, respectively.
      Erucamide was below detection level in the intestine, but is known to be present
      in the cerebrospinal fluid. In the rat, 3H-erucamide was accumulated in vivo into
      lung, liver, and spleen and in vitro into lung, liver, brain, and intestine. The
      in vitro uptake was time and temperature dependent, but not saturable.

PMID- 12608693
TI  - Role of PARP under stress conditions: cell death or protection?
AB  - A great deal of increasing evidence designs PARP as a multifunctional protein
      implicated in many cellular functions. Much interest is emerging to understand
      the precise mechanisms by which PARP mediates genome stabilization and protection
      against damage, as well as its involvement in cell death, either apoptotic or
      necrotic. Aside from the clearly established role of PARP hyperactivation in
      necrotic cell death, after excessive DNA damage and energy failure, it appears to
      be actively involved in the phenomenon of apoptosis. However, its exact role is
      still controversial. The identification of several enzymes sharing the poly(ADP
      ribose) polymerase catalytic domain (PARPs), but with different features and
      subcellular localization, has opened a new perspective in the field of poly(ADP
      ribosyl)ation. The picture of the role of PARP in the control of cell homeostasis
      became even more complex after demonstration of its implication in the regulation
      of gene transcription. The notion that energy failure is the sole mechanism by
      which PARP promotes cell death is therefore under reevaluation.

PMID- 12608695
TI  - White matter injury following systemic endotoxemia or asphyxia in the fetal
      sheep.
AB  - White matter injury is the most frequently observed brain lesion in preterm
      infants. The etiology remains unclear, however, both cerebral hypoperfusion and
      intrauterine infections have been suggested as risk factors. We compared the
      neuropathological outcome, including the effect on oligodendrocytes, astrocytes,
      and microglia, following either systemic asphyxia or endotoxemia in fetal sheep
      at midgestation. Fetal sheep were subjected to either 25 minutes of umbilical
      cord occlusion or systemic endotoxemia by administration of Escherichia coli
      lipopolysaccharide (LPS O111:B4, 100 ng/kg, IV). Periventricular white matter
      lesions were observed in 2 of 6 asphyxiated fetuses, whereas the remaining
      animals showed diffuse injury throughout the subcortical white matter and
      neuronal necrosis in subcortical regions, including the striatum and hippocampus.
      LPS-treatment resulted in focal inflammatory infiltrates and cystic lesions in
      periventricular white matter in 2 of 5 animals, but with no neuron specific
      injury. Both experimental paradigms resulted in microglia activation in the white
      matter, damaged astrocytes, and loss of oligodendrocytes. These results show that
      the white matter at midgestation is sensitive to injury following both systemic
      asphyxia and endotoxemia. Asphyxia induced lesions in both white and subcortical
      grey matter in association with microglia activation, and endotoxemia resulted in
      selective white matter damage and inflammation.

PMID- 12608694
TI  - Metabolism and functions of phosphatidylserine in mammalian brain.
AB  - Phosphatidylserine (PtdSer) is involved in cell signaling and apoptosis. The
      mechanisms regulating its synthesis and degradation are still not defined. Thus,
      its role in these processes cannot be clearly established at molecular level. In
      higher eukaryotes, PtdSer is synthesized from phosphatidylethanolamine or
      phosphatidylcholine through the exchange of the nitrogen base with free serine.
      PtdSer concentration in the nervous tissue membranes varies with age, brain
      areas, cells, and subcellular components. At least two serine base exchange
      enzymes isoforms are present in brain, and their biochemical properties and
      regulation are still largely unknown because their activities vary with cell type
      and/or subcellular fraction, developmental stage, and differentiation. These
      peculiarities may explain the apparent contrasting reports. PtdSer cellular
      levels also depend on its decarboxylation to phosphatidylethanolamine and
      conversion to lysoPtdSer by phospholipases. Several aspects of brain PtdSer
      metabolism and functions seem related to the high polyunsaturated fatty acids
      content, particularly docosahexaenoic acid (DHA).

PMID- 12608696
TI  - Atrial natriuretic peptides elevate cyclic GMP levels in primary cultures of rat
      ependymal cells.
AB  - The aim of this study was to examine the effect of atrial natriuretic peptides on
      primary cultures of ependymal cells, as measured by changes in intracellular
      levels of cyclic GMP. Incubation of ependymal cells with rat atrial natriuretic
      peptide-(1-28) (rANP) elicited a 30-fold increase in ependymal cGMP content
      within 1 min and more than a 100-fold increase within 10 min to a plateau value
      of approximately 30 pmol/mg protein. The C-type natriuretic peptide (CNP)
      elicited a similar increase in cGMP levels; however the maximal effect was
      observed within 1 min and the levels subsequently dropped by 90% to a low plateau
      within 10 min. A comparison of the concentration-response curves for rANP, human
      ANP-(1-28) (hANP) and CNP showed that rANP, hANP and CNP had similar effects,
      with regards to elevation of cGMP levels at high concentrations, but with
      differing EC50 values. These results demonstrate the presence of a heterogenous
      population of functional ANP receptors i n cultured ependymalcells suggesting
      that ANP may regulate specific ependymal cell activity.

PMID- 12608697
TI  - Effects of long-term antipsychotic treatment on NMDA receptor binding and gene
      expression of subunits.
AB  - Postmortem studies in schizophrenic patients revealed alterations in NMDA
      receptor binding and gene expression of specific subunits. Because most of the
      patients had been treated with antipsychotics over long periods, medication
      effects might have influenced those findings. We treated animals with haloperidol
      and clozapine in clinical doses to investigate the effects of long-term
      antipsychotic treatment on NMDA receptor binding and gene expression of subunits.
      Rats were treated with either haloperidol (1.5 mg/kg/day) or clozapine (45
      mg/kg/day) given in drinking water over a period of 6 months. Quantitative
      receptor autoradiography with [3H]-MK-801 was used to examine NMDA receptor
      binding. In situ hybridization was performed for additional gene expression
      studies of the NR1, NR2A, NR2B, NR2C, and NR2D subunits. [3H]-MK-801 binding was
      found to be increased after haloperidol treatment in the striatum and nucleus
      accumbens. Clozapine was shown to up-regulate NMDA receptor binding only in the
      nucleus accumbens. There were no alterations in gene expression of NMDA subunits
      in any of the three regions. However, the NR2A subunit was down-regulated in the
      hippocampus and prefrontal cortex by both drugs, whereas only clozapine induced a
      down-regulation of NR1 in the dorsolateral prefrontal cortex. NR2B, 2C, and 2D
      subunits did not differ between treatment groups and controls. Both altered NMDA
      receptor binding and subunit expression strengthen a hyperglutamatergic function
      after haloperidol treatment and may contribute to some of our postmortem findings
      in antipsychotically treated schizophrenic patients. Because the effects seen in
      different brain areas clearly vary between haloperidol and clozapine, they may
      also be responsible for some of the differences in efficacy and side effects.

PMID- 12608698
TI  - Astrocytic amino acid metabolism under control conditions and during oxygen
      and/or glucose deprivation.
AB  - Amino acid contents were measured in 1- and 3-week-old primary cultures of
      astrocytes and in their incubation media, an amino acid-free salt solution with
      or without glucose, during 3-h incubation under normoxic or anoxic conditions.
      Most essential amino acids were rapidly released to the medium during the
      beginning of the incubation. A subsequent slow medium increase reflected
      proteolysis. Glutamate and aspartate were absent from the media during all
      conditions, indicating fueling of their uptake by either glycolytically or
      oxidatively derived energy. The total content of glutamine increased, except
      during incubation in glucose-deprived media, when it declined or remained
      constant. Changes in aspartate were negligible, suggesting oxidative degradation
      of aspartate-derived oxaloacetate during normoxia and its reduction to succinate
      during anoxia, driving regeneration of NAD+ from NADH. An increase of alanine was
      reduced in glucose-free media, whereas serine showed especially large increase
      during isolated glucose deprivation, suggesting its production from glutamine via
      3-phosphoglycerate.

PMID- 12608699
TI  - Homocysteine-evoked 45Ca release in the rabbit hippocampus is mediated by both
      NMDA and group I metabotropic glutamate receptors: in vivo microdialysis study.
AB  - This in vivo microdialysis study compared the effects of NMDA and D,L
      homocysteine (Hcy) administered via dialysis medium on 45Ca efflux from
      prelabeled rabbit hippocampus. Application of these agonists evoked dose
      dependent, and sensitive to MK-801, opposite effects: NMDA decreased the 45Ca
      radioactivity in the dialysate, whereas Hcy induced the release of 45Ca. The
      latter effect was potentiated by glycine, inhibited by the antagonist of group I
      metabotropic glutamate receptors (mGluR) LY367385, and mimicked by t-ADA, an
      agonist of these receptors. Electron microscopic examination of pyramidal
      neurones in the CA1 sector of the hippocampus in the vicinity of the
      microdialysis probe after NMDA application demonstrated swelling of mitochondria,
      which was prevented by cyclosporin A. This study shows, for the first time, Hcy
      induced activation of both group I mGluR and NMDA receptors, which may play a
      role in acute Hcy neurotoxicity. We present new applications of brain
      microdialysis in studies on excitotoxicity and neuroprotection.

PMID- 12608700
TI  - Neuron-specific ablation of PDGF-B is compatible with normal central nervous
      system development and astroglial response to injury.
AB  - Members of the PDGF family have multiple roles during embryogenesis and in a
      variety of pathological situations in the adult. One of the major sites of PDGF-B
      expression in adult mammals are postmitotic CNS neurons. Combined with reported
      neurotrophic and neuroprotective effects of exogenously administered PDGFs, this
      has led to the speculation that PDGF-B may have a role in CNS development, in
      maintenance, or in response to CNS injury. To test these hypotheses, we developed
      mice in which PDGF-B was ablated genetically in postmitotic neurons at sites
      where PDGF-B is normally expressed. We found that these mice develop to adulthood
      without apparent defects. We demonstrate PDGF-B expression in the postnatal mouse
      hippocampus and forebrain cortex. We show that neuron-specific knockout of PDGF-B
      does not influence the astroglial and angiogenic responses to injury in the
      hippocampus or forebrain cortex. We conclude that the role of neuron-derived PDGF
      B remains obscure. A role for neuron-derived PDGF-B, if existing, might be
      redundant with other CNS growth factors. Alternatively, other and more specific
      analyses of CNS functions in the normal and injured states will be required to
      demonstrate such a role.

PMID- 12608701
TI  - Searching for mechanisms of N-methyl-D-aspartate-induced glutathione efflux in
      organotypic hippocampal cultures.
AB  - N-Methyl-D-aspartate (NMDA)-receptor stimulation evoked a selective and partly
      delayed elevated efflux of glutathione, phosphoethanolamine, and taurine from
      organotypic rat hippocampus slice cultures. The protein kinase inhibitors H9 and
      staurosporine had no effect on the efflux. The phospholipase A2 inhibitors
      quinacrine and 4-bromophenacyl bromide, as well as arachidonic acid, a product of
      phospholipase A2 activity, did not affect the stimulated efflux. Polymyxin B, an
      antimicrobal agent that inhibits protein kinase C, and quinacrine in high
      concentration (500 microM), blocked efflux completely. The stimulated efflux
      after but not during NMDA incubation was attenuated by a calmodulin antagonist
      (W7) and an anion transport inhibitor (DNDS). Omission of calcium increased the
      spontaneous efflux with no or small additional effects by NMDA. In conclusion,
      NMDA receptor stimulation cause an increased selective efflux of glutathione,
      phosphoethanolamine and taurine in organotypic cultures of rat hippocampus. The
      efflux may partly be regulated by calmodulin and DNDS sensitive channels.

PMID- 12608703
TI  - The induction of the TNFalpha death domain signaling pathway in Alzheimer's
      disease brain.
AB  - The tumor necrosis factor-alpha death domain pathway contributes to cellular
      degeneration in a variety of conditions. This study investigates the hypothesis
      that this death domain pathway is progressively induced in the brain during the
      progression of Alzheimer's disease (AD). AD cases had increased levels of
      proapoptotic markers including tumor necrosis factor-alpha (TNFalpha), TNF
      receptor type 1 (TNF-R1), TNF receptor-associated death domain (TRADD), and
      caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3
      times higher than transitional cases. In striking contrast, potentially
      neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain
      like interleukin-1beta-converting enzyme (FLICE) inhibitor protein (FLIP) were
      decreased in AD as compared with age-matched control cases (P < .01). Overall,
      there was an elevation in proapoptotic elements, including a 5-fold increase in
      TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate
      to increased degenerative potential because the downstream effector caspase-3 and
      product of the TNF pathway was also increased in parallel with enhanced TNF
      proapoptotic conditions. Our findings suggest that the TNF death receptor pathway
      and caspases are activated in the early stages of neuronal degeneration in AD.

PMID- 12608705
TI  - New aspects on primary aldosteronism.
AB  - The adrenal cortex synthesizes and releases steroid hormones, mainly
      mineralocorticoids and glucocorticoids. There is a functional zonation of the
      adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of
      aldosterone, primary aldosteronism, may be much more common than previously known
      and may be responsible for 10% of essential hypertension. Primary aldosteronism
      is characterized by autonomous production of aldosterone, suppressed renin
      activity, hypokalemia, and hypertension. The two most common forms are unilateral
      adenoma and bilateral hyperplasia. In spite of thorough clinical workup and
      careful histopathology it is often difficult to differentiate between adenoma and
      hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for
      aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol
      production. Most normal controls show expression of CYP11B2 in zona glomerulosa.
      Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis,
      whereas the expression of CYP21 is present in all three cortical layers. Adenomas
      from patients with primary aldosteronism show considerable variation in the
      expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a
      strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of
      primary aldosteronism, 4 patients had small nodules detected with expression of
      CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses
      seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This
      suggests that these small nodules are responsible for the aldosterone production
      and this is characteristic of nodular hyperplasia in patients with primary
      aldosteronism. In conclusion, this method to visualize mRNA gene expression of
      steroidogenic enzymes, and especially expression of CYP11B2, has increased the
      knowledge of adrenal pathophysiology. The results emphasize the value to include
      functional studies (venous sampling and/or scintigraphy) in the preoperative work
      up of patients with primary aldosteronism.

PMID- 12608704
TI  - Discussion of the role of the extracellular signal-regulated kinase-phospholipase
      A2 pathway in production of reactive oxygen species in Alzheimer's disease.
AB  - In this paper we show that exposure of a rat brain synaptosome fraction to the
      amyloid beta peptide fragment betaA(25-35), but not the inverted peptide betaA(35
      25), stimulated production of reactive oxygen species (ROS) in a concentration-
      and time-dependent manner. The ROS formation was attenuated by the tyrosine
      kinase inhibitor genistein, the mitogen-activated protein kinase inhibitor U0126,
      and the phospholipase A2 (PLA2) inhibitor 7,7-dimethyl-(5Z,8Z)-eicosadienoic
      acid. This strongly suggests that betaA(25-35) stimulated ROS production through
      an extracellular signal-regulated kinase-PLA2-dependent pathway. The interaction
      between these enzymes and their possible involvement in free radical formation in
      Alzheimer's disease are discussed.

PMID- 12608702
TI  - Astrocytes and stroke: networking for survival?
AB  - Astrocytes are now known to be involved in the most integrated functions of the
      central nervous system. These functions are not only necessary for the normally
      working brain but are also critically involved in many pathological conditions,
      including stroke. Astrocytes may contribute to damage by propagating spreading
      depression or by sending proapoptotic signals to otherwise healthy tissue via gap
      junction channels. Astrocytes may also inhibit regeneration by participating in
      formation of the glial scar. On the other hand, astrocytes are important in
      neuronal antioxidant defense and secrete growth factors, which probably provide
      neuroprotection in the acute phase, as well as promoting neurogenesis and
      regeneration in the chronic phase after injury. A detailed understanding of the
      astrocytic response, as well as the timing and location of the changes, is
      necessary to develop effective treatment strategies for stroke patients.

PMID- 12608706
TI  - Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine,
      and topiramate.
AB  - Epilepsy, a functional disturbance of the CNS and induced by abnormal electrical
      discharges, manifests by recurrent seizures. Although new antiepileptic drugs
      have been developed during recent years, still more than one third of patients
      with epilepsy are refractory to treatment. Therefore, the search for new
      mechanisms that can regulate cellular excitability are of utmost importance.
      Three currently available drugs are of special interest because they have novel
      mechanisms of action and are especially effective for partial onset seizures.
      Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that
      greatly increases whole-brain levels of GABA. Tiagabine is a potent inhibitor of
      GABA uptake into neurons and glial cells. Topiramate is considered to produce its
      antiepileptic effect through several mechanisms, including modification of Na(+)
      and/or Ca(2+)-dependent action potentials, enhancement of GABA-mediated Cl-
      fluxes into neurons, and inhibition of kainate-mediated conductance at glutamate
      receptors of the AMPA/kainate type. This review will discuss these mechanisms of
      action at the cellular and molecular levels.

PMID- 12608707
TI  - S100B protein and 4-hydroxynonenal in the spinal cord of wobbler mice.
AB  - S100B is a calcium-binding protein that, in the nervous system, is mainly
      concentrated in glial cells. Although its biological role is still unclear, the
      protein is hypothesized, at high concentrations, to act in the pathogenesis of
      neurodegenerative processes, possibly through oxidative stress mechanisms. To
      investigate this hypothesis we studied the spinal cord of wobbler mice, an animal
      model of motor neuron degeneration. Using immunocytochemistry, we detected an
      overexpression of S100B in astrocytes of the cervical spinal cord of these
      animals. We also confirmed this finding by reverse transcriptase polymerase chain
      reaction. In the same spinal cord regions, scattered neurons appeared to be
      immunostained for 4-hydroxynonenal-modified proteins, an indicator of lipid
      peroxidation. This finding constitutes a sign of oxidative stress-induced
      neurodegeneration.

PMID- 12608709
TI  - Metabolic parameters of epilepsy: adjuncts to established antiepileptic drug
      therapy.
AB  - Hughlings Jackson at the turn of the century defined epilepsy as a disorder
      originating in a "morbid nutrition" of the neuron. With the advances in modern
      neurochemistry, it is becoming increasingly clear that a chronic seizure
      predisposition or a lowering of the brain's discharge threshold can be demarcated
      by a number of biochemical markers. They include a tendency for an increased
      release of glutamate with or without GABAergic impairment, (intra)neural tissue
      alterations in water redistribution/osmolarity or other distortions of the
      cytoarchitecture, and an elevation of ionic calcium inside the cell. These
      changes are dominantly shared parameters of the seizure prone brain. Magnetic
      resonance spectroscopy (MRS) shows that cerebral levels of glutamate + glutamine
      (Glx) are increased interictally in epileptogenic regions in human partial
      epilepsy; other findings using this technique suggest damage to
      (cellular/mitochondrial) membranes, denoted by N-acetyl-aspartic acid (NAA)
      changes and a decreased energy capability. The merging of previous in vitro and
      ex vivo findings in neurophysiology and neurochemistry with magnetic resonance
      spectroscopy technology provides a powerful new methodology to interpret and to
      obtain clinical insight into the metabolic alterations that underlie an
      epileptogenic process. In this review some of these basic neurochemical and
      electrophysiological mechanisms are discussed. In addition, certain adjuncts to
      established antiepileptic drug therapy are suggested in the hope that over the
      long term they may help in correcting the primary metabolic deficits.

PMID- 12608710
TI  - Target discovery and validation in the post-genomic era.
AB  - The recent publication of the human genome sequence provides an opportunity both
      to combat diseases that are presently considered as pharmaceutically intractable
      and also to improve current therapies for many common human diseases. The
      identification of every human gene by ongoing bioinformatic efforts has the
      potential, when combined with functional genomic approaches, to pinpoint the
      molecular basis of every human disease, and to discover appropriate intervention
      points. This exciting prospect is directly relevant to the successful development
      of effective therapeutics because the past record of drug discovery suggests that
      30%-40% of experimental drugs fail because an inappropriate biological target was
      pursued. The major impact of genomic information may therefore be to reduce this
      biological failure rate by earlier definition of drug targets related to disease
      susceptibility or progression. This paper briefly reviews some of the approaches
      that can be used to identify biologically relevant drug targets.

PMID- 12608711
TI  - Quantitative analysis of MAP2 immunoreactivity in human neocortex of three
      patients surviving after brain ischemia.
AB  - Transient global ischemia caused by cardiac arrest results in lesions that
      involve all brain structures. The aim of this study was to investigate the
      distribution of MAP2 immunoreactivity in neurons in the brain of patients
      surviving for various times after an ischemic incident, using confocal laser
      scanning microscopy. We performed a quantitative analysis of the distribution and
      density of MAP2-positive structures in human neocortical areas after survival
      times of 1 week, 3 months, and 1 year after the cardiac arrest. Three important
      observations were made in the present study: (i) in all human brain areas
      investigated (motor, temporal, frontal, and visual cortex) a decrease of MAP2
      immunoreactivity was found; (ii) in all studied areas the most significant
      decrease in MAP2 was found in layers II-III, compared with layers V-VII; (iii)
      the decrease of MAP2 immunoreactivity in layers II-III was related to the
      duration of the postischemic period. The maximal decrease, by 66.3% (P < .05), in
      MAP2-positive pyramidal neurons, was observed in layers II-III in the motor
      cortex after 1 year of survival after cardiac arrest.

PMID- 12608708
TI  - Role of astrocytes in the maintenance and modulation of glutamatergic and
      GABAergic neurotransmission.
AB  - The functional activity in the brain is primarily composed of an interplay
      between excitation and inhibition. In any given region the output is based upon a
      complex processing of incoming signals that require both excitatory and
      inhibitory units. Moreover, these units must be regulated and balanced such that
      an integrated and finely tuned response is generated. In each of these units or
      synapses the activity depends on biosynthesis, release, receptor interaction, and
      inactivation of the neurotransmitter in question; thus, it is easily understood
      that each of these processes needs to be highly regulated and controlled. It is
      interesting to note that in case of the most prevailing neurotransmitters,
      glutamate and GABA, which mediate excitation and inhibition, respectively, the
      inactivation process is primarily maintained by highly efficient, high-affinity
      transport systems capable of maintaining transmembrane concentration gradients of
      these amino acids of 10(4)-10(5)-fold. The demonstration of the presence of
      transporters for glutamate and GABA in both neuronal and astrocytic elements
      naturally raises the question of the functional importance of the astrocytes in
      the regulation of the level of the neurotransmitters in the synaptic cleft and
      hence for the activity of excitatory and inhibitory neurotransmission. Obviously,
      this discussion has important implications for the understanding of the role of
      astrocytes in disease states in which imbalances between excitation and
      inhibition are a triggering factor, for example, epilepsy and neurodegeneration.

PMID- 12608712
TI  - Ligand-gated ion channel currents in a nonstationary lyotropic model.
AB  - Transmembrane currents in ligand-gated ion channels are calculated in a
      nonstationary, chemically open whole cell system or patch of a membrane. The
      model is lyotropic in the sense that dynamics, and parameters such as the ligand
      concentration for half-maximal response (scale of response), and threshold for
      firing, such as in neurons, become nonlinear functions of the reactant
      concentrations. The derived total currents fit recorded data significantly better
      than those derived from mass action, Ising, and other stationary type models, in
      which the derived response is often displaced from the assessed response by
      several orders in the ligand concentration. Also, the derived slope of response
      is in perfect agreement with the values assessed.

PMID- 12608714
TI  - Infant botulism--New York City, 2001-2002.
AB  - Infant botulism results from germination of swallowed spores of botulinum toxin
      producing clostridia that colonize the large intestine temporarily. Four cases of
      type B infant botulism in one New York City (NYC) borough were diagnosed within a
      12-month period during 2001-2002. All four patients resided in Staten Island
      (2000 population: 443,728). The annual incidence of infant botulism in the United
      States is two cases per 100,000 live births; incidence in NYC is four cases per
      100,000 live births. Staten Island recorded 5,899 live births in 2000; incidence
      of infant botulism during this 12-month period was 68 cases per 100,000 live
      births. This report summarizes the investigation of these four cases; as expected
      with infant botulism, a common source of exposure was not identified. All four
      patients recovered after treatment and were discharged from local hospitals.
      State and local health departments should be notified promptly when infant
      botulism is suspected to arrange diagnostic testing.

PMID- 12608715
TI  - Outbreak of botulism type E associated with eating a beached whale--Western
      Alaska, July 2002.
AB  - Botulism is a neuroparalytic illness caused by toxins produced by the bacterium
      Clostridium botulinum, an obligate anaerobe found commonly in the environment.
      Intoxication with toxin type E is associated exclusively with eating animal foods
      of marine (salt or fresh water) origin. Persons who eat raw or fermented marine
      fish and mammals are at high risk for botulism from type E toxin. On July 17,
      2002, the Alaska Division of Public Health investigated a cluster of suspected
      botulism cases among residents of a fishing village in Alaska. This report
      summarizes the findings of the outbreak investigation, which linked disease to
      eating raw muktuk (skin and a pink blubber layer) from a beached whale (Figure).
      To avoid delays in treatment, health-care providers evaluating patients suspected
      of having botulism should base treatment decisions on clinical findings. Public
      health authorities should be notified immediately about any suspected botulism
      case.

PMID- 12608713
TI  - Effects of repeated administration of baclofen to rats on GABAB receptor binding
      sites and subunit expression in the brain.
AB  - Repeated stimulation of the GABAB receptor with baclofen frequently produces
      tolerance, the underlying mechanisms of which are poorly understood. The purpose
      of the present work was to determine whether repeated administration of baclofen
      to rats is accompanied by changes in cerebral GABAB receptor binding sites, mRNA
      for the subunits GABAB(1) and GABAB(2), and protein levels for these subunits.
      Rats were injected with placebo or baclofen (20 micromol/kg subcutaneously) once
      daily for 14 days. Decreases in body temperature were measured as an index of
      pharmacological effects of baclofen. Binding of radiolabeled GABA to GABAB
      receptors was quantitated in brain membranes, mRNA levels were determined using
      quantitative real-time PCR, and GABAB receptor protein levels were assessed with
      Western blot analysis. Baclofen caused a decline in temperature amounting to
      approximately 2.5 degrees C after the first dose. This effect was partly lost
      after the fifth and abolished after the seventh injection. Despite the complete
      development of tolerance, there were no significant alterations in GABAB receptor
      binding sites (number or affinity) or mRNA levels for the subtypes GABAB(1a),
      GABAB(1b), or GABAB(2). Receptor protein levels were also unchanged. It is
      concluded that baclofen induces tolerance through mechanisms other than down
      regulation of GABAB receptor transcription or translation.

PMID- 12608716
TI  - Update: Influenza activity--United States, 2002-03 season.
AB  - Although overall influenza activity in the United States remained low from late
      September through early January, it is expected to increase during the coming
      weeks. Laboratory-confirmed influenza infections have been reported from 25
      states. Influenza viruses isolated this season are antigenically well matched by
      this season's influenza vaccine. This report summarizes influenza activity in the
      United States during September 29, 2002-January 4, 2003, and updates the previous
      summary.

PMID- 12608717
TI  - Compensatory bone formation in young and old rats during tooth movement.
AB  - The aim of this study was to investigate compensatory lingual alveolar bone
      formation during tooth movement in young and old rats, using the vital bone
      marker tetracycline. Wistar male rats were separated into the following groups:
      13-week-old rats without appliances (13C: control, n = 5), 60-week-old rats
      without appliances (60C: control, n = 5), 13-week-old rats with appliances (13E:
      experimental, n = 10), and 60-week-old rats with appliances (60E: experimental, n
      = 10). The upper first molars of the 13E and 60E groups were moved lingually
      using fixed appliances. On the third day of tooth movement, tetracycline (TC) was
      intra-peritoneally injected in all animals including the controls. On the 21st
      day of tooth movement, the animals were killed and unfixed, and undecalcified, 5
      microm frozen frontal sections of the rat first molar areas in both control and
      experimental groups were examined under light and fluorescent microscopes. In the
      13C group without tooth movement, tetracycline labelling lines were obvious in
      the alveolar crest, apical areas, and interradicular septum, indicating vertical
      alveolar bone growth. However, in the 60C control group, tetracycline labelling
      was almost undetectable throughout the alveolar bone. Although the lingual
      alveolar crest was resorbed from the periodontal side after lingual tooth
      movement, the sharp, bright labelling lines were still present from the crest to
      the lingual periosteal alveolar bone in the 13E group. In the 60E group the lines
      appeared in the lingual periosteal alveolar bone containing the crest, indicating
      considerable new bone formation. The results indicate that compensatory bone
      formation occurs in the alveolar crest area and, consequently, alveolar bone
      height is maintained, even in aged rats.

PMID- 12608718
TI  - Evaluation of the effects of functional orthopaedic treatment on
      temporomandibular joints with single-photon emission computerized tomography.
AB  - The aims of this investigation were to evaluate the temporomandibular joints
      (TMJs) with single-photon emission computerized tomography (SPECT) in subjects
      treated with a mandibular advancement repositioning splint (MARS), and to compare
      the results with the total effect on dento-facial morphology. The study was
      undertaken on 17 Class II division 1 malocclusion subjects (nine males, eight
      females) with mandibular retrusion. Ten patients (five males, five females)
      formed the treatment group and seven (four males, three females) were used as the
      control. SPECT was performed only in the treatment group. Cephalometric
      evaluation showed significant increases in NAPog (P < 0.001) and SNB (P < 0.05)
      angles. Increased bone formation in theTMJs was analysed with the aid of pre- and
      post-treatment scintigraphic studies. The results indicate that new bone
      formation in the mandibular condyles seems to contribute to the increase in
      mandibular prognathism resulting from functional jaw orthopaedics.

PMID- 12608719
TI  - The Kabuki syndrome: four patients with oral abnormalities.
AB  - The aim of this paper is to report the oral signs and symptoms of four patients
      with Kabuki syndrome. All had oral abnormalities affecting the palate, teeth,
      and/or lips, including wide spacing between the teeth, screwdriver-shaped upper
      incisors, hypodontia, delayed tooth eruption, narrow spacing in the upper canine
      area, large pulp chambers of the upper incisors and permanent molars, external
      root resorption of the upper central incisors and permanent molars, a division of
      the lower third of the root canal in normally one-rooted teeth, tooth retention,
      retrognathia of the upper jaw, a high palate or cleft lip/palate, and microforms
      of lower lip fistula.

PMID- 12608721
TI  - Comparative reproducibility of three methods of radiographic assessment of
      alveolar bone grafting.
AB  - The aims of this study were to compare the reproducibility of three radiographic
      methods of assessing the quality of alveolar bone grafts, namely the Bergland,
      Kindelan and Chelsea Scales, and evaluate their application in the mixed and
      permanent dentitions. Additionally the use of occlusal versus periapical
      radiographs was assessed. Three examiners applied each scale on two occasions to
      the radiographs of 48 cleft lip and palate patients who had received alveolar
      bone grafts in 59 sites (11 had bilateral clefts). The agreement between repeated
      assessments by the same observer at different time points was measured by the
      kappa statistic, for each of the three assessors and each of the types of
      radiographic scale in turn. None of the three scales was found to be more
      reproducible than the others (kappa statistics for intraobserver variation ranged
      from 0.61 to 0.70). The agreement between observers was also similar across the
      three radiographic scales (multiple kappa statistics for inter-observer variation
      ranged from 0.45 to 0.51). Likewise, neither occlusal nor periapical radiographs
      were found to enable greater reproducibility of assessment. Surprisingly there
      was a tendency to greater reproducibility in the mixed than in the permanent
      dentition, which suggests the outcome of alveolar bone grafting may be assessed
      at an earlier stage than currently adopted. The outcome of alveolar bone grafting
      in this group of patients was generally successful.

PMID- 12608720
TI  - Muscle fibre composition and electromyographic features of cervical muscles
      following prolonged head extension in growing rats.
AB  - Soft tissue stretching has been proposed as one of the control factors in
      craniofacial morphogenesis. However, its mechanism remains unclear. The present
      study investigated electromyographic (EMG) activity and muscle fibre composition
      of cervical muscles following prolonged head extension in growing rats. Thirty
      six male Wistar rats were divided into two experimental (E1, E2) and one control
      (C) group at 25 days of age. To induce head extension, the experimental rats were
      raised in cylindrical cages, which were positioned horizontally for group E1 and
      tilted upward at 45 degrees for group E2. At 55 days of age, EMG activity was
      recorded from the anterior digastricus (AD), sternohyoideus (SH),
      sternomastoideus (SM), longus capitis (LC), and biventer cervicis (BC) muscles in
      the rest position and passive head extension. EMG activity was analysed on its
      integrated values (IEMG), and composition of muscle fibres was evaluated by
      myosin ATPase reaction and fibre cross-sectional areas were calculated. Group E1
      showed a higher percentage of type I fibres and lower IEMG during passive head
      extension in AD. In group E2 there was a higher percentage of type I fibres, a
      higher IEMG at rest, and a lower IEMG during passive head extension in BC. The
      experimental groups demonstrated altered proportions of type IIA and IIB fibres
      in SM and LC. They also showed higher percentages of subtype fibres and reduced
      cross-section areas of type II fibres in most of the muscles investigated. These
      findings suggest that head extension affects fibre transition, distribution,
      cross-section area, and recruitment pattern in cervical muscles.

PMID- 12608722
TI  - Maxillary canine displacement; further twists in the tale.
AB  - This report describes two cases seen over a 5-year period, each with a labially
      impacted maxillary canine found in close proximity to the adjacent first
      permanent premolar, which had a deviated palatal root. The issue as to whether
      the premolar root deviation either produced the canine impaction or vice versa is
      discussed, both with reference to the processes considered to be involved in
      normal tooth eruption, and to three previously published similar cases.

PMID- 12608723
TI  - The effect of changes in tooth position of unerupted canines on cephalograms.
AB  - Although many radiographic procedures have been described to localize an impacted
      canine, they all submit the patient to extra radiation. The purpose of the entire
      study was to evaluate if the combined interpretation of cephalograms and dental
      panoramic tomograms (DPTs), which are used in orthodontic practice, can provide
      adequate information as to the position of impacted canines. In a previous study
      the radiographic image of impacted canines on DPTs was evaluated. In this
      investigation, the effect of changes in position and inclination of an impacted
      canine on cephalograms was studied in an experimental set-up. An upper canine was
      removed from a human skull and placed in a positioning device to imitate various
      positions of impaction. Starting from a buccally impacted position, three
      different displacements were simulated: 10 mm frontally, 10 mm sagittally, and 5
      mm vertically. In each of these positions nine different changes in inclination
      (in the sagittal and the frontal plane) were registered, resulting in 36
      different cephalographic exposures. Analysis revealed the following: the degree
      of vertical and sagittal displacement of the incisal point of the impacted
      canine, the angulation of the tooth as well as the tooth length, measured on a
      cephalogram, appeared to give an accurate representation of the experimental set
      up. Combining these findings and those from the previous study, it became
      possible to define a series of points to enable an adequate three-dimensional
      (3D) estimation of the canine's position. A clinical case of an impacted canine
      is used as an illustration of this experimental set-up.

PMID- 12608724
TI  - The value of the aesthetic component of the Index of Orthodontic Treatment Need
      in the assessment of subjective orthodontic treatment need.
AB  - Previous studies carried out using the Index of Orthodontic Treatment Need (IOTN)
      have reported that the Aesthetic Component (AC) has limited use in
      schoolchildren. The purpose of this study was to estimate whether dental concern
      expressed by the grade of the AC chosen by subjects is reliable and whether it
      may be predictive for potential co-operation. Such a correlation would indicate
      if the AC of the IOTN may help to identify individuals interested in orthodontic
      treatment who would co-operate well, and consequently who might derive the
      greatest benefits. The investigation was carried out in north-west Poland among
      84 schoolchildren (42 girls and 42 boys) aged 12 years and was based on a
      questionnaire and clinical examination. The questionnaire contained items
      relating to the subjective assessment of dental appearance, demand for
      orthodontic treatment, the influence of the dentition on the general appearance,
      and any functional disorders (speech, mastication, muscular pain, etc.). Clinical
      examination was carried out at the schools each time by the same dentist. For
      statistical analysis chi-square (Yates corrected) and McNemar tests were used. A
      probability at the 5 per cent level or less (P < 0.05) was considered
      statistically significant. The outcome shows that the AC of the IOTN moderately
      reflects the subjective perception of dental aesthetics and demand for
      orthodontic treatment. The results indicate that using professional rating the AC
      scale does not seem to be more precise or reliable than self-evaluation. The
      correlation between dental concern and the AC would be higher if the 'no
      treatment need' category was split into two parts (e.g. 1-2 'no need', 3-4
      'slight need') or the 'borderline need' category was moved two grades lower. The
      AC would then help to identify patients interested in treatment who would
      potentially be co-operative.

PMID- 12608725
TI  - Maxillary retention: is longer better?
AB  - Two different maxillary retention regimes were compared to ascertain if
      differences in posttreatment relapse existed. The patient pool was derived from
      subjects being treated at two orthodontic departments in the west of Scotland.
      Group 1 (20 patients) followed a 6 month regime using removable upper Hawley
      retainers for a period of 3 months full time and 3 months nights only. Group 2
      (18 patients) followed a 1 year regime of 6 months full time and 6 months nights
      only. The results revealed that maxillary incisor alignment, as determined by
      Little's irregularity index, had relapsed by an average of 50 per cent of the end
      of retention value 3 months out of retention in Group 1 but only 23 per cent in
      Group 2. Although the actual mean values for relapse were 0.77 and 0.23 mm,
      respectively, seven subjects in Group 1 showed relapse of more than 3 mm as
      compared with only one in Group 2. This suggests that retaining a case for 1 year
      rather than 6 months is clinically beneficial.

PMID- 12608726
TI  - The level of cathepsin B in gingival crevicular fluid during human orthodontic
      tooth movement.
AB  - This investigation examined gingival crevicular fluid (GCF) levels of lysosomal
      cystein protease, cathepsin B (CAB), during human orthodontic tooth movement. The
      study included 10 patients (five males, mean age 22.5 +/- 2.8 years and five
      females, mean age 23.4 +/- 3.9 years), each having one tooth undergoing
      orthodontic movement, while the contralateral and antagonist teeth were used as
      the controls. The GCF was sampled at the control and treatment (compression)
      sites before activation and at 1, 24, and 168 hours. Prevention of plaque-induced
      inflammation allowed this study to focus on the dynamics of mechanically
      stimulated CAB levels in GCF. The CAB levels in GCF were determined by
      fluorospectrometry, using Z-Arg-Arg-MCA as the substrate and by Western blotting
      analysis. The GCF levels of CAB for the treated teeth were significantly (P<
      0.001) higher than those of the control teeth at 24 hours. At the control sites,
      CAB levels at 24 hours did not change significantly with time. At the
      experimental site where orthodontic forces were applied, Western blot analysis
      demonstrated that the molecular forms were 29 kDa mature enzymes. These results
      indicate that the amount of CAB in GCF is increased by orthodontic tooth
      movement. This increased CAB may be involved in extracellular matrix degradation
      in response to mechanical stress.

PMID- 12608728
TI  - The effects of activator treatment on the craniofacial structures of Class II
      division 1 patients.
AB  - The aim of the present study was to clarify the skeletal treatment effects
      induced by activator treatment. Fifty actively growing patients with Class II
      division 1 malocclusions were treated with an activator appliance. A control
      group consisting of longitudinal growth data from 20 patients (untreated Class II
      division 1 malocclusions) was used to eliminate possible differences in growth
      pattern. Lateral cephalograms of each patient were taken at the start and end of
      treatment. Final cephalograms were taken after a mean of 16.4 (+/- 2.0) months
      activator treatment, compared with a mean of 14.2 (+/- 2.4) months for the
      control group. Each cephalogram was traced and digitized by the same individual.
      The mean and standard deviations for linear and angular cephalometric
      measurements were analysed statistically, and intra- and inter-group changes were
      evaluated by paired- and independent-sample t-tests. At the end of the study
      period, the overjet was decreased in all patients. Ramus height, corpus length,
      anterior and posterior face height all increased significantly (P < 0.05). In the
      treatment group, ANB angle decreased and the bite was opened. The activator
      appliance caused maxillary incisor lingual tipping and mandibular incisor labial
      tipping. The overjet was decreased as a result of the increased forward growth of
      the mandible and dentoalveolar changes. The results demonstrated that the
      activator appliance has a characteristic skeletal and dental effect on the
      developing craniofacial complex.

PMID- 12608727
TI  - Development of a non-radiographic cephalometric system.
AB  - The purpose of the present study was to develop a three-dimensional (3D) non
      radiographic cephalometric system based on Simon's three planes. In pursuit of
      cephalometry without irradiation of patients, readiness of data and simplicity of
      the system, a portable 3D computer-aided, contact-method cephalometric system,
      equipped with newly developed cephalometric software for chairside use, was
      developed. The feasibility of its clinical use was examined based on comparison
      of the measurements obtained with those from conventional radiographic
      cephalometry on a human dry skull, as well as on three living subjects. From a
      total of nine measurements, a statistically significant difference was seen in
      six measurements: FMPA, U1/FH, FMIA, ANB, IMPA, and A-Np for the dry skull; in
      four measurements: FPA, FMPA, U1/FH, and Pog-Np for subject A; in five
      measurements: FMPA, U1/FH, FMIA, AN/FH, and A-Np for subject B; and in seven
      measurements: FMA, FMPA, U1/FH, FMIA, ANB, IMPA, and AN/FH for subject C. A
      clinically significant difference was found only in one measurement, U1/FH for
      the dry skull, in four measurements FPA, FMPA, U1/FH, and Pog-Np for subject A,
      in one measurement AN/FH for subject B, and in three measurements U1/FH, FMIA,
      and AN/FH for subject C. While demonstrating workability as a chairside tool and
      whilst there is a need for further refinement in measurement accuracy, this newly
      developed cephalometric system shows potential applicability, not only in the
      clinic as an auxiliary to or as a substitute for existing radiographic
      cephalometry, but also outside the clinic as an epidemiological tool.

PMID- 12608729
TI  - Long-term follow-up of early treatment with reverse headgear.
AB  - The purpose of this study was to investigate the long-term outcome of treatment
      with reverse headgear in young individuals with a reverse overjet and a skeletal
      Class III malocclusion due to maxillary deficiency. Lateral cephalograms were
      obtained from 21 subjects (8.4 +/- 1.5 years; 17 girls and four boys) of an
      original sample of 30 consecutively treated young patients who were followed for
      8 years after active treatment. There was a drop-out of nine subjects; their
      dentofacial morphology at start of treatment did not differ from those who
      remained in the study. The remaining subjects were divided into a stable group
      and a relapse group. The results revealed that two out of three patients
      maintained a positive overjet 8 years after active treatment. The immediate
      treatment outcome in the sagittal plane was the same for the stable and relapse
      groups, but lower face height increased (P < 0.08) and the mandibular plane angle
      opened (P < 0.05) more in the relapse group. During the 8-year follow-up period,
      the dental compensation was similar in both groups, but the mandible outgrew the
      maxilla by four times in the relapse group, compared with twice that in the
      stable group. In young individuals diagnosed with maxillary deficiency treated
      with reverse headgear and who have an immediate positive treatment response,
      there is a potential risk that about one-third might be candidates for
      orthognathic surgery later in life, because of an unfavourable growth pattern.

PMID- 12608730
TI  - Salivary metal levels of orthodontic patients: a novel methodological and
      analytical approach.
AB  - The purpose of this study was to qualitatively and quantitatively assess the
      nickel, chromium, and ferrous levels in a population of 17 orthodontic patients
      undergoing treatment, compared with seven untreated individuals, employing a
      novel methodological approach and a new analytical technique. Salivary samples
      obtained from patients before and after rinsing with double distilled water were
      processed for Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES)
      for simultaneous estimation of the concentration of the metallic elements. No
      statistically significant difference was detected between control and patient
      groups with respect to salivary metal content, regardless of element. The range
      of salivary metal levels found did not exceed those of daily intake through food
      and air. The lack of a continuous monitoring scheme for salivary metal
      concentrations in real time may impose substantial obstacles to defining the
      release rate of metals in vivo. The results of this study emphasize the necessity
      of incorporating the dimension of time in assessing the release potential of
      orthodontic alloys.

PMID- 12608731
TI  - Gene expression of transferrin and transferrin receptor in brains of control vs.
      iron-deficient rats.
AB  - The mechanism of the regulation of transferrin (Tf) and transferrin receptor
      (TfR) levels in rat brain by dietary iron status is not fully elucidated. We
      examined Tf and TfR protein and mRNA contents in various brain regions affected
      by dietary iron deficiency, and analyzed the relationships between protein and
      mRNA contents in brains of control vs. iron-deficient rats. In a region-specific
      fashion, iron-deficient diet decreased significantly brain iron concentration by
      22-63%, and increased Tf level by 22-130% and TfR level by 74% in thalamus and
      40% in cortex. Tf mRNA content decreased by 20-50% in most brain regions
      demonstrating inverse correlation of Tf and its mRNA in response to iron
      deficiency. TfR mRNA levels remained unaffected by iron status. The corpus
      callosum, white matter of the cerebellum and lateral ventricles expressed highest
      levels of Tf mRNA, whereas TfR mRNA levels was lowest in these regions, but
      highest in cortex, hippocampus, and the gray matter of the cerebellum. The data
      demonstrate that the cells in brain have the capacity to maintain minimum iron
      levels during iron deficiency. This capacity may be associated with increased
      iron-Tf uptake from plasma, stabilization of TfR mRNA, or increased Tf mRNA
      translation efficiency in specific cell types within the brain.

PMID- 12608732
TI  - The short-term effects of fasting on the neuroendocrine system in patients with
      chronic pain syndromes.
AB  - It is commonly reported that short term fasting leads to mood enhancement and
      emotional harmonisation. We investigated psychosocial well-being and the
      neuroendocrine response, assessed by nightly urinary excretion of cortisol and
      catecholamines, in 28 inpatients with chronic pain syndromes during and after a
      one-week modified fast. Twenty-two of the patients (51.4 +/- 2.7 years, BMI 26.8
      +/- 1.0 kg/m2) participated in a 7-day fast with daily intake of 300 kcal/day,
      six control patients (47.5 +/- 4.0 years; BMI 22.9 +/- 1.1 kg/m2) received a
      vegetarian-based diet. With fasting significant increases of the urinary
      concentration of noradrenaline (17.8 +/- 3.0-27.8 +/- 3.8 microg/ml), adrenaline
      (1.5 +/- 0.2-3.4 +/- 0.7 microg/ml) and cortisol (26.1 +/- 3.7-40.7 +/- 6.1
      microg/ml) were observed, whereas controls showed no significant endocrine
      changes. The neuroendocrine response to fasting was pronounced in younger
      subjects (age <50 years) and in the presence of a BMI >25 kg/m2, moreover the
      increase in cortisol excretion was significantly higher in subjects with lower
      baseline cortisol levels. Mood and well-being increased non-significantly in both
      groups. Fasting was well tolerated, and regarded as beneficial by most fasting
      patients. Our results show that short-term fasting leads to neuroendocrine
      activation and may suggest that the extent of this response is dependent on the
      individual metabolic and endocrine state at baseline.

PMID- 12608733
TI  - Can the pathophysiology of autism be explained by the nature of the discovered
      urine peptides?
AB  - Opioid peptides derived from food proteins (exorphins) have been found in urine
      of autistic patients. Based on the work of several groups, we try to show that
      exorphins and serotonin uptake stimulating factors may explain many of the signs
      and symptoms seen in autistic disorders. The individual symptoms ought to be
      explainable by the properties and behavioural effects of the found peptides. The
      data presented form the basis of an autism model, where we suggest that exorphins
      and serotonin uptake modulators are key mediators for the development of autism.
      This may be due to a genetically based peptidase deficiency in at least two or
      more peptidases and, or of peptidase regulating proteins made manifest by a
      dietary overload of exorphin precursors such as by increased gut uptake.

PMID- 12608734
TI  - Increasing preload volume with water reduces rated appetite but not food intake
      in healthy men even with minimum delay between preload and test meal.
AB  - The role of gastric volume in the short-term control of eating in humans remains
      unclear, with some studies reporting that food volume alone can reduce appetite
      but others finding no such effect. A recent study in our laboratory, found
      effects of preload volume on subjective appetite (hunger, fullness) but not
      intake, and found effects of preload energy on intake but not appetite. That
      study used an interval of 30 min between serving preloads and the test meal, and
      the present study attempted to maximise the effects of the volume manipulation by
      removing the delay between the preload and test meal. We administered four soup
      based preloads varying in volume (150 and 450 ml) using water, and energy density
      (1.4 and 4.2 kJ/ml) using maltodextrin, producing three energy levels (209, 629,
      629 and 1886 kJ; repeated measures). These were followed immediately by an
      unlimited hot pasta lunch, during which food weight was monitored continuously by
      computer. Increasing soup volume at constant energy (629 kJ) reduced appetite
      ratings, but not intake. In contrast, increasing soup energy at constant volume
      (450 ml) reduced intake, without affecting appetite. The discrepancies between
      our results and other reported studies suggest that volume is more influential
      when intakes are large, or that there may be a threshold concentration for
      nutrients in the GI tract before volume alone is tangibly expressed in subsequent
      eating.

PMID- 12608735
TI  - Effect of retinoic acid on ferritin H expression during brain development and
      neuronal differentiation.
AB  - We have previously shown that brain ferritin H expression, which has been
      associated with iron utilization, is developmentally regulated. Because retinoic
      acid (RA) regulates gene expression and is involved in cellular differentiation,
      we tested the hypothesis that RA regulates ferritin H during brain development
      and neuronal differentiation. RA, administered to rats on postnatal day 1,
      produced a 4-fold increase in brain ferritin H mRNA (p < 0.01) after 24 h. To
      examine whether RA-stimulated neuronal differentiation contributed to this up
      regulation, ferritin and ferritin H mRNA were measured in human neuronal
      precursor cells (NTera-2, NT2) before and after 4-weeks of RA-stimulated
      differentiation into post-mitotic neurons. Differentiation resulted in a 2-fold
      increase in both ferritin and ferritin H mRNA (p < 0.05). Immunocytochemistry and
      Northern analysis showed significant elevations in ferritin expression that began
      as early as 24 h after RA treatment. While there was also a significant increase
      in the labile iron pool after RA treatment, this did not occur until 72 h. These
      data show that RA regulates ferritin H expression during rat brain development
      and neuronal differentiation and suggests a new role for RA in brain iron
      metabolism.

PMID- 12608736
TI  - Dietary soy phytoestrogens effects on retinal thickness in rats.
AB  - Naturally occurring estrogen-like molecules in plants (phytoestrogens), present
      via soy, in animal diets are known to alter brain morphology and reproductive
      endocrine parameters. This study characterized dietary phytoestrogens' effect on
      retinal thickness in male and female Long-Evans rats. Experiment 1a and 1b: upon
      arrival (50 day-old) animals received either a phytoestrogen-rich diet
      (containing 600 microg phytoestrogen/g diet; referred to as Phyto-600) or a diet
      low in phytoestrogens (Phyto-free). Males remained on these diets until 140 days
      of age (females until 160 days of age). In both sexes a significant (but
      opposite) diet difference in retinal thickness was identified. Male Phyto-600 and
      female Phyto-free animals had significantly greater retinal thickness compared to
      Phyto-free males and Phyto-600 females, respectively. Experiment 2: male or
      female rats were raised from conception on either the Phyto-600 or Phyto-free
      diet until sacrifice at 75 days of age. Consistent with experiment 1, males
      exposed to the Phyto-600 diet lifelong had significantly greater retinal
      thickness than lifelong fed Phyto-free males (no significant differences were
      identified in females). These data suggest that phytoestrogens influence rat
      retinal characteristics in a sexually dimorphic manner (more robust effect in
      males vs. females) and that this influence can occur even in adulthood.

PMID- 12608737
TI  - Differential dose-dependent effects of central morphine treatment upon food
      intake in male and female rats receiving neonatal hormone manipulations.
AB  - Male rats display significantly greater analgesic responses following morphine
      than female rats, with neonatal gonadal manipulations reversing the sex-dependent
      pattern. The present study assessed whether dose-dependent (0.0005-5 microg, icv)
      effects of morphine-induced feeding were sensitive to sex-dependent and neonatal
      gonadectomy manipulations. Sex differences in morphine-induced feeding varied as
      a function of morphine dose with males showing greater increases at low (0.0005
      microg) doses, and females showing greater increases at high (5 microg) doses.
      Neonatal castration, respectively, enhanced and reduced morphine-induced feeding
      at very low (0.0005 microg) and low (0.005 microg) doses. In contrast, neonatal
      testosterone administered to females enhanced morphine-induced feeding at higher
      (0.5-5 microg) doses. These data indicate that sex and neonatal gonadectomy
      differences in morphine-induced feeding are dependent upon the dose of morphine
      employed.

PMID- 12608738
TI  - Breakfast cereal consumption and subjective reports of health by young adults.
AB  - The aim of the present research was to extend previous research which has shown
      that consumption of breakfast is associated with reports of better health.
      Previous research has confirmed this in samples in the age ranges from mid
      twenties to early eighties. The present study considered young adults (189
      volunteers, aged between 19-21 years, mean age 19.6 years) living at home. The
      results showed that skipping breakfast is associated with reports of poorer
      health and that regular breakfast cereal consumption is associated with better
      reported health. The effects of breakfast could not be explained by other health
      related behaviours or other aspects of diet. Further research is now required to
      determine the mechanisms underlying this robust association to examine whether it
      is observed with objective indicators of health and specific diseases.

PMID- 12608740
TI  - Assessment of specific language impairment in Swedish.
AB  - The results from pre-testings of 42 children selected for a cross-linguistic
      study are discussed to establish the usefulness of the assessment instruments
      used and whether the children selected are similar to children with specific
      language impairment (SLI) from other countries. The results from assessments of
      grammatical production, language comprehension and phonology clearly
      distinguished children with SLI from age-matched controls, while they differed
      from language matched controls only on phonological measures. As a group the
      children with SLI were about 2 years delayed on grammatical production measures
      and about 1 year on language comprehension. The assessment instruments used thus
      seem capable of distinguishing children with SLI. The Swedish children selected
      exhibit the same range of problems as children with SLI selected in other
      countries.

PMID- 12608739
TI  - Advice to eat fish and mood: a randomised controlled trial in men with angina.
AB  - People with high intake of fish have lower reported rates of depression and a
      small trial in psychiatric patients suggested that fish oil supplements reduced
      episodes of depression and mania. As part of a factorial trial of interventions
      to reduce mortality in angina 452 men were randomised to advice to eat more fatty
      fish or no fish advice. Maxepa fish oil capsules were supplied to men who found
      the fish unpalatable. Fish intake and mood were assessed at baseline and six
      months. Most men (83%) had mood assessed using the Derogatis Stress Profile at
      baseline and follow-up. Self reported intake of fish was higher in the fish
      advice group at six months. There was, however, no difference in depression or
      anxiety in those allocated to receive fish advice. After controlling for baseline
      mood, the difference in depression score between those randomised to fish advice
      and those not was 1.29 (95% CI -0.29 to 2.88) and the difference in anxiety was
      0.82 (95% CI -0.57 to 2.22) with positive differences indicating more depression
      or anxiety in those allocated to the fish arm. This trial provides no evidence
      that increased fatty fish intake in people without depressive symptoms has any
      substantial effect on mood.

PMID- 12608741
TI  - Clinician elicitation strategies and child participation. Comparing two methods
      of phonological intervention.
AB  - The focus of this paper is on interaction between clients and clinicians during
      language intervention. Two kinds of phonological interventions are compared, viz.
      Metaphon therapy and traditional therapy. Elicitation strategies used by the
      clinicians and the effects on child participation are analysed. The results show
      that the elicitation strategies used in Metaphon significantly more often
      required a comprehension response, elicited by an indirect rather than a direct
      request. The elicitations in traditional therapy significantly more often
      required direct productions from the child. Both kinds of intervention showed an
      asymmetric pattern where the adults dominated the session, but the asymmetry was
      more pronounced in traditional therapy. Non-focal turns were more frequent in
      traditional therapy; these were instances when clinician and child talked at
      cross-purposes.

PMID- 12608742
TI  - Muscle activity in the classical singer's shoulder and neck region.
AB  - The objective of this study is to characterize the level of use of the trapezius
      (TR) and the sternocleidomastoideus (STM) muscles by singing students. We further
      try to lower the activity in both muscles by use of biofeedback (BF) from
      electromyographic recordings (EMG). We finally examine whether the experiences
      from the BF session can be transferred into regular singing by maintaining a
      mental focus on the experiences made in the BF session. Two groups, each
      consisting of eight conservatory singing students, all in their first or second
      year of study, volunteered as subjects. Two singing procedures were used, a song
      and a sustained tone of maximum possible duration. EMG activity was recorded
      bilaterally from the TR and STM by use of an ambulatory monitoring system. EMG BF
      appeared to lower muscle activity in the two muscles, thus the experiences made
      in the BF session could be transferred into regular singing. We conclude that
      singers, although having an enhanced awareness of posture, still may have overuse
      of especially the TR muscle, but probably also the STM muscle.

PMID- 12608743
TI  - Persistent dysphonia in two performers affecting the singing and projected
      speaking voice: a report on a collaborative approach to management.
AB  - The projected speaking voice and the singing voice are highly sensitive to
      external and internal influences, and teachers of spoken voice and singing are in
      a unique position to identify subtle and more serious vocal difficulties in their
      students. Persistent anomalies may herald early onset of changes in vocal fold
      structure, neurophysiological control, or emotional stability. Two cases are
      presented to illustrate the benefits of a collaborative approach to diagnosis and
      management. The first, a 21-year-old male drama and singing student with an
      abnormally high speaking voice and falsetto singing voice was found to have a
      psychogenic dysphonia referred to as "puberphonia" or "mutational falsetto". The
      second, a 34-year-old female alto with strained phonation and perceived stutter
      of the vocal folds was diagnosed with "adductor spasmodic dysphonia" or "focal
      laryngeal dystonia" of neurological origin.

PMID- 12608744
TI  - Arachidonic acid-induced channel- and carrier-type ion transport across planar
      bilayer lipid membranes.
AB  - Transmembrane ion transport by arachidonic acid (AA) through bilayer lipid
      membranes (BLMs) was investigated by means of electrochemical measurements to
      provide a basis for designing a sensor membrane. We found that AA induces a
      channel-type current, in addition to a carrier-type current, across planar BLMs.
      A linear relation between the logarithmic value of the AA concentration and the
      current responses (given as integrated currents) was observed for a carrier-type
      current, while a sigmoid relation was found for a channel-type current. Although
      AA transports Na+, Ca2+ and Mg2+ and exhibits ion selectivity between Na+ and
      Mg2+ for the carrier-type current, ion transport for the channel-type current was
      non-selective. It was found that ion transport via the channel mechanism occurs
      frequently for AA, while channel-type currents were only occasionally observed
      for y-linolenic acid and prostaglandin D2. No channel-type currents were induced
      by other fatty acids (oleic, linoleic, stearic, myristic, eicosapentanoic and
      docosahexanoic acids) and metabolites of AA (12-HETE and 5-HETE). The carrier
      type ion transport occurs selectively to these compounds if the concentration is
      below 1.0 microM. These results suggest that AA selectively facilitates an ion
      flux through the BLMs, generating channel-type and/or carrier-type currents,
      which can be used as a measure of the AA concentration.

PMID- 12608745
TI  - Adsorption behavior of cytochrome c, myoglobin and hemoglobin in a quartz surface
      probed using slab optical waveguide (SOWG) spectroscopy.
AB  - Slab optical waveguide (SOWG) spectroscopy was used to observe the adsorption
      behavior of three important heme proteins, namely cytochrome c, myoglobin and
      hemoglobin, in a quartz surface. Using prism-coupled polychromatic visible light
      propagated into a quartz waveguide by internal total reflection, the real-time
      monitoring of evanescent wave absorption revealed a strong dependence of the
      protein-surface interaction on the protein concentration, the solution pH and the
      ionic strength. For the three proteins studied, the absorbance-bulk concentration
      ratio was higher at low bulk concentrations, and decreased at higher
      concentrations. For cytochrome c and myoglobin, the absorbance approached a
      limiting value, but buffered hemoglobin surprisingly did not show any indication
      of forming a signal plateau. Moreover, the slow introduction of protein into the
      solution lessened the total adsorbed amount per unit area. These observations
      suggested a possible conformational transition of the protein molecules at the
      quartz surface after adsorption. For a bulkier protein, hemoglobin, adsorption
      onto the quartz surface was enhanced in the presence of a phosphate buffer, while
      the opposite effect was observed for the smaller cytochrome c and myoglobin
      molecules. The results of pH studies concurred with the electrostatic
      interactions predicted from the isoelectric data of proteins and the quartz
      surface.

PMID- 12608746
TI  - Measurement of mouse urinary type IV collagen using time-resolved
      fluoroimmunoassay.
AB  - Urinary level of type IV collagen is an important indicator for early renal
      dysfunction, but there has been no practical system to measure mouse type IV
      collagen adaptable to extremely small amounts of urine samples. We developed a
      highly sensitive time-resolved fluoroimmunoassay (TR-FIA) to measure mouse
      urinary type IV collagen. Based on the structural features of type IV collagen
      molecule, dithiothreitol (DTT) was used for pretreatment of the samples. This
      assay permits measurement of 100 pg/ml type IV collagen in 5 microl urine
      samples. Urinary levels of type IV collagen derived from 12 samples of two
      different mouse strains (KK/Ta and BALB/c) were measured using this assay. The
      results demonstrated very clearly the difference in values of urinary type IV
      collagen between diabetic mice and non-diabetic mice. Compared with the
      conventional enzyme-linked immunosorbent assay (ELISA), this method requires far
      smaller volumes of samples, and is best suited to mouse models in future
      experiments.

PMID- 12608747
TI  - Determination of proteins with Fast Red VR by a corrected resonance light
      scattering technique.
AB  - A simple corrected resonance light-scattering (CRLS) technique was established to
      correct for any distortion of the resonance light scattering (RLS) spectra
      resulting from molecular absorption. By using an absorption cell holder to change
      the propagation direction of the incident light beam of a common
      spectrofluorometer, the molecular absorption was directly measured through a
      spectrofluorometer. With measurements of the CRLS signals of the interaction of
      Fast Red VR (FRV) and proteins, we proved that the present correction for the RLS
      spectra in terms of the molecular absorption of excitation and scattering
      radiation can improve the detection sensitivity by about two fold.

PMID- 12608748
TI  - Hydrogen ion-selective poly(vinyl chloride) membrane electrode based on a
      calix[4]arene.
AB  - A hydrogen ion-selective poly(vinyl chloride) membrane electrode was constructed
      using 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetracyanomethoxycalix[4]arene as a
      neutral carrier. The electrode showed an apparent Nernstian response in the 2
      11.5 pH range with a slope of 54.0 +/- 0.2 mV/pH at 20 +/- degrees C. This
      electrode showed a rapid response of the emf to changes in the pH, high ion
      selectivity with respect to lithium, sodium and potassium, and characteristics
      similar to those reported for the conventional pH glass membrane electrode. It
      can be used as a potentiometric indicator electrode in hydrofluoric acid
      solutions. The effects of iodide, thiocyanate, perchlorate and bromide on the
      characteristics of the electrode were also considered.

PMID- 12608749
TI  - Novel PVC-based copper(II) membrane sensor based on 2-(1'-(4'-(1''-hydroxy-2''
      naphthyl)methyleneamino)butyl iminomethyl)-1-naphthol.
AB  - A copper(II) ion-selective PVC membrane sensor based on 2-(1'-(4'-(1''-hydroxy
      2''-naphthyl)methyleneamino)butyl iminomethyl)-1-naphthol (BHNB) as a novel
      Schiff base containing a sensing material has been successfully developed. The
      sensor exhibits a good linear response of 29 mV per decade within the
      concentration range of 10(-1)-10(-6) M of Cu2+. The sensor shows good selectivity
      for copper(II) ion in comparison with alkali, alkaline earth, transition and
      heavy metal ions. The BHNB-based sensor is suitable for use with aqueous
      solutions of pH 3.5-7.0 and displays minimal interference by Sr(II), Cd(II),
      Hg(II), Zn(II) and Pb(II), which are known to interfere with other previously
      suggested electrodes. The proposed membrane electrode was used as a sensor for
      determining the Cu(II) content in black tea samples. It was also applied as an
      indicator electrode in the potentiometric titration of Cu2+ ions with EDTA.

PMID- 12608750
TI  - Chemically modified carbon paste electrode for iodide determination on the basis
      of cetyltrimethylammonium iodide ion-pair.
AB  - A new carbon paste electrode (CPE) for the determination of iodide ion based on a
      cetyltrimethylammonium iodide (CTMAI) ion pair as an electroactive material is
      described. The electrode shows a linear response for iodide ion over the
      concentration range of 4 x 10(-5) M to 1 x 10(-1) M with a lower detection limit
      of 4 x 10(-5) M at 25 degrees C. The electrode has a Nemstian slope of -55.0 +/-
      0.4 mV/decade and a fast potential response of 45 s, which is almost constant
      over a pH range of 5.0 - 9.0. Selectivity coefficient data of the CTMAI-CPE for
      some common ions show negligible interference, and the electrode has high
      selectivity towards the iodide ion. An average recovery of 101.83% with a
      relative standard deviation of 1.53% has been achieved for the determination of
      iodide in Flaxedil (gallamine triethiodide) ampoules, a muscle relaxant drug. The
      electrode has been examined for the determination of iodide in saline water; the
      results were found to compare favorably with those obtained using Metrohm iodide
      ISE. The electrode has been utilized as an end-point indicator electrode for the
      determination of Hg(II) and phenylmercury(I) in their aqueous solutions using
      potentiometric titration with a potassium iodide standard solution.

PMID- 12608751
TI  - Novel potentiometric membrane sensor for the determination of trace amounts of
      chromium(III) ions.
AB  - A plasticized Cr3+ ion sensor by incorporating 2,3,8,9-tetraphenyl-1,4,7,10
      tetraazacyclododeca-1,3,7,9-tetraene (TTCT) ionophore exhibits a good
      potentiometric response for Cr3+ over a wide concentration range (1.0 x 10(-6)
      1.0 x 10(-1) M) with a slope of 19.5 mV per decade. The sensor response is stable
      for at least three months. Good selectivity for Cr3+ in comparison with alkali,
      alkaline earth, transition and heavy metal ions, and minimal interference are
      caused by Li+, Na+, K+, Co2+, Hg2+, Ca2+, Pb2+ and Zn2+ ions, which are known to
      interfere with other chromium membrane sensors. The TTCT-based electrode shows a
      fast response time (15 s), and can be used in aqueous solutions of pH 3-5.5. The
      proposed sensor was used for the potentiometric titration of Cr3+ with EDTA and
      for a direct potentiometric determination of Cr3+ content in environmental
      samples.

PMID- 12608752
TI  - Micro-phase sorbent extraction for trace analysis via in situ sorbent formation:
      application to the spectrophotometric determination of nitrite in environmental
      waters.
AB  - A micro-phase sorbent in situ formation from an aqueous solution was proposed for
      the sensitive spectrophotometric determination of nitrite in environmental
      waters. Nitrite in a 10 mL sample solution was converted into a cationic azo dye
      by the reaction with 4-trifluoromethylanilinium ion and N-1
      naphthylethylenediammonium ion in an acidic medium. Addition of
      dodecylbenzenesulfonate ion caused the formation of a suspension of ion associate
      in the solution. Centrifugation of the solution led to the isolation of a liquid
      organic phase that extracted the azo dye at the bottom of the centrifuge tube.
      The volume of the new phase was ca. 5 microL. After the aqueous phase was
      discarded, the organic phase was dissolved with 1 mL of 2-methoxyethanol to
      measure the absorbance. Nitrogen as NO2- at concentrations from 1.5 to 30 microg
      L(-1) was determined with sufficient precision. When 0.2 mL of 2-methoxyethanol
      was applied to dissolve the organic phase, 0.3-4.8 microg NO2--N L(-1) was
      determined. The recovery tests for nitrite added to some river water and seawater
      were satisfactory. This method is very simple and rapid. It takes only 30 min
      from the dye formation to the measurement of the absorbance.

PMID- 12608753
TI  - Binding of some environmental pollutants to corn protein zein studied by high
      performance liquid chromatography.
AB  - The strength and the character of the binding of 12 organic solvents to the corn
      protein zein was determined by preparing zein-coated carbon stationary phase and
      by measuring the retention of solvents on a high-performance liquid
      chromatographic column filled with this stationary phase. The relationship
      between the physicochemical parameters and binding characteristics of solvents
      was elucidated by principal component analysis. Various interactive forces are
      involved in the binding of solvent to the protein. The strength of the binding is
      dominantly influenced by the molecular hydrophobicity while the Gaussian or non
      Gaussian distribution of the adsorption strength is markedly dependent on the
      polarity parameters of the solvent. Sterical correspondences exerted considerable
      influence on each binding parameter.

PMID- 12608754
TI  - Improvement of an automatic HPLC system for nitropolycyclic aromatic
      hydrocarbons: removal of an interfering peak and increase in the number of
      analytes.
AB  - An automatic HPLC system for analyzing nitropolycyclic aromatic hydrocarbons
      (NPAHs, nitroarenes) in airborne particulates was previously described (Anal.
      Chim. Acta, 2001, 445, 20). Some problems with this system were that it generated
      a peak originating from an ascorbic acid solution that elutes at a retention time
      close to that of 1,6-dinitropyrene (DNP), and that it was able to analyze only
      1,3-, 1,6-, 1,8-DNPs and 1-nitropyrene (I-NP). Here, we describe an improved
      system that effectively removes the interfering peak by introducing an ODS column
      just after the pump for the ascorbic acid solution, and which is capable of
      analyzing several additional compounds (2-, 4-NPs, 2-nitrofluorene. 6
      nitrochrysene, 7-nitrobenz[a]anthracene, 3-nitroperylene and 6
      nitrobenzo[a]pyrene etc.). The improved sensitivities were achieved by
      concentrating the compounds in a benzene-ethanol extract from airborne
      particulates, by increasing the loading time of the sample solution from 20 to 38
      min, and by increasing the flow rate of an ascorbic acid solution from 1.3 to 1.8
      mL/min.

PMID- 12608755
TI  - Determination of lead, cadmium and mercury in microwave-digested foodstuffs by RP
      HPLC with an on-line enrichment technique.
AB  - A new method for the simultaneous determination of lead, cadmium and mercury ions
      in microwave-digested foodstuffs by reversed-phase high-performance liquid
      chromatography combined with on-line enrichment technique has been developed. The
      foodstuff samples were digested by microwave digestion. The lead, cadmium and
      mercury ions can be precolumn derivatized with 5,10,15,20-tetrakis(3
      aminophenyl)porphine (T3APP) to form color chelates; then, the Hg-T3APP, Cd-T3APP
      and Pb-T3APP chelates can be enriched and separated on a valve switching HPLC
      system combined with on-line enrichment technique. The linearity ranges are 0.01
      120 microg/l for each metal ion. The detection limits (S/N = 3) of lead, cadmium
      and mercury are 1.2 ng/l, 0.5 ng/l and 0.8 ng/l, respectively. This method was
      applied to the determination of lead, cadmium and mercury in foodstuffs with good
      results.

PMID- 12608756
TI  - Speciation of antimony using chromosorb 102 resin as a retention medium.
AB  - The selective retention of the Sb(III) chelate with ammonium pyrrolidine
      dithiocarbamate (APDC) on a column of Chromosorb 102 resin from a buffered sample
      solution including Sb(V) was used for the determination of Sb(III). The retained
      antimony was eluted with acetone. The retention of the Sb(III)-iodide compounds
      with sodium iodide on the Chromosorb 102 resin column from the same solution
      after reducing Sb(V) to Sb(III) by iodide in acidic solution was used to
      preconcentrate the total antimony. The retained antimony was eluted with 0.25 mol
      l(-1) HNO3. The antimony in the effluent was determined by flame atomic
      absorption spectrometry. Also, the total antimony was determined directly by
      graphite-furnace atomic absorption spectrometry. The Sb(V) concentration could be
      calculated by the difference. The recoveries were > or = 95%. The detection
      limits of a combination of the column procedure and flame AAS for antimony were 6
      - 61 microg l(-1) and comparable to 4 microg l(-1) for a direct GFAAS
      measurement. The relative standard deviations were <6%. The procedure was applied
      to the determination of Sb(III) and Sb(V) in spiked tap water, waste-water
      samples and a certified copper metal with the satisfactory results.

PMID- 12608757
TI  - Collection of iron(III) from homogeneous aqueous solutions on membrane filters
      using Chromazurol B with Triton X-100.
AB  - A membrane filtration method was examined concerning the effective collection of
      iron(III) from a homogeneous aqueous solution with Chromazurol B (CAB), one of
      the triphenylmethane dyes, as a precipitating reagent in the presence of a non
      ionic surfactant, polyethylene glycol mono[4-(1,1,3,3
      tetramethylbutyl)phenyl]ether (Triton X-100). A formed blue Fe(III)-CAB complex
      was collected as a precipitate on a membrane filter by filtration under suction
      from a homogeneous aqueous solution in the pH range over about 2. The original
      solution was prepared at a concentration ratio of CAB to Fe(III) of to 10, and
      that of Triton X-100 to CAB of 10 to 100. It was then adjusted to a pH value of
      between 1.0 and 6.5. A linear relationship (r = 0.999) was obtained between the
      initial concentration and the found one of Fe(III) in the range of 2.0 x 10(-5)
      to 4.0 x 10(-4) mol dm(-3) at a fixed concentration ratio of CAB to Fe(III) of 3
      and that of Triton X-100 to CAB of 20. This membrane filtration with CAB and
      Triton X-100 may be utilized for the separation of Fe(III) as a background
      species.

PMID- 12608758
TI  - Superheated water chromatography of phenols using poly(styrene-divinylbenzene)
      packings as a stationary phase.
AB  - A method for the superheated water chromatography of phenols was developed using
      a poly(styrene-divinylbenzene) (PSDVB) stationary phase. The stationary phase of
      superheated water chromatography must be stable against the attack of water. A
      durability test for PSDVB packings and octadecylsilyl (ODS)-silica gels indicated
      that PSDVB packings were stable in superheated water in the temperature range of
      100-150 degrees C, whereas octadecylsilyl groups of ODS-silica gels cleaved even
      at 100 degrees C. The retention of phenols on the PSDVB stationary phase
      decreased with an elevation of the column temperature. The retention mechanism
      was characterized using a thermodynamic theory that has been used for describing
      retention in conventional RP-HPLC. The application of the present method to an
      environmental analysis was also demonstrated, in which a suitable separation with
      good peak shape was obtained for p-chlorophenol in river-water samples.

PMID- 12608759
TI  - Multimethod characterization of the interaction of aluminum ion with alpha
      ketoglutaric acid in acidic aqueous solutions.
AB  - It has recently been reported that aluminum plays a very important role in
      reducing the activity of Krebs-cycle enzymes and glutamate dehydrogenase in rat
      brain homogenate. Therefore, it is necessary to identify the aluminum binding
      ability with the pivotal substrate alpha-ketoglutarate in biological systems. The
      interactions of aluminum with alpha-ketoglutarate were studied with pH
      potentiometry, cyclic voltammetry, UV-vis, 1H, 27Al-NMR and Raman spectra multi
      analytical techniques in acidic aqueous solution to measure the stoichiometries
      and stability constants of the complexes and its keto-enol tautomerism. The alpha
      ketoglutarate was found to bind Al in a bidentate manner at the carboxylate and
      carbonyl moieties. The mononuclear 1:1 (AlLH(-1), AIL+, AlHL2+) and 2:1 (AlL2-,
      AlL2H(-2)3-) species, and dinuclear 2:1 (Al2L4+) species were found in acidic
      aqueous solution. Meanwhile, Al can promote alpha-KG tautomerize to its enolic
      structure compounds in solutions. These findings may help to further understand
      the influence of Al on GDH enzyme reactions in biological systems.

PMID- 12608760
TI  - Spectroscopic analytical study for the charge-transfer complexation of certain
      cephalosporins with chloranilic acid.
AB  - Studies were carried out to develop a simple, rapid and accurate
      spectrophotometric method for the analysis of fifteen cephalosporins. The method
      depends on the charge-transfer complexation reaction between any of these drugs
      as an n-electron donor and p-chloranilic acid (p-CA) as a pi-acceptor to form a
      violet chromogen measured at 520 nm. Different variables affecting the reaction
      were studied and optimized. Under the optimum conditions, linear relationships
      with good correlation coefficients (0.9986-0.9996) were found between the
      absorbances and the concentrations of the studied drugs in the range of 4-1,200
      microg ml(-1). The limits of assay detection ranged from 2.54 to 42.83 microg ml(
      1). The accuracy and precision of the method were satisfactory. The method was
      successfully applied to an analysis of the studied drugs in their pharmaceutical
      formulations; the recovery percentages ranged from 96.76 +/- 0.87% to 100.50 +/-
      1.30%. The interaction sites were confirmed by UV/VIS, IR, 1H-NMR techniques.
      Molecular modeling for the interaction was used for deriving an equation for
      calculating the epsilon value for a particular drug. This equation gave a perfect
      prediction for the degree of interaction of the investigated drugs with the p-CA
      reagent.

PMID- 12608761
TI  - Determination of thiamine in pharmaceutical preparations by sequential injection
      renewable surface solid-phase spectrofluorometry.
AB  - Fluorometric determination of thiamine requires the conversion of the analyte to
      fluorescent thiochrome by hexacyanoferrate(III) oxidation in alkaline solution
      and the isolation of the produced thiochrome from the reaction medium by solvent
      extraction. It was observed that thiochrome could be concentrated and separated
      from the reaction medium by solid-phase extraction. The thiochrome sorpted on the
      surface of octadecyl-alklylated poly[styrene/divinylbenzene] (C18-PS/DP)
      microbeads emitted strong fluorescence upon excitation, the maximum excitation
      and emission wavelengths being 385 nm and 433 nm, respectively. Based on this
      observation, a sequential injection renewable surface solid-phase
      spectrofluorometry was developed for the determination of thiamine. A sequential
      injection system on-line coupled to a chip-based flow-through cell was employed
      to handle the chemical reaction, bead injection and discharging, and adsorption
      of thiochrome. Solid-phase fluorometric detection was realized by coupling the
      chip-based flow-through cell to a spectrofluorometer with a multistrand
      bifurcated optical fiber. Under the optimized condition, a detection limit of
      0.03 microg ml(-1) was achieved at the sample throughput of 30 h(-1) and
      consumption of 1 mg C18-PS/DP microbeads for each run. Eleven runs of a 2 microg
      ml(-1) thiamine standard solution gave a relative standard deviation of 1.0%. The
      developed approach was successfully applied for the determination of thiamine
      contents in pharmaceutical preparations.

PMID- 12608762
TI  - Carbazole as fluorescence carrier for preparation of doxycycline sensor.
AB  - Carbazole is a promising pharmaceutical species. A novel optical sensor for
      determining doxycycline based on the fluorescence quenching of N-allylcarbazole
      immobilized on an quartz glass plate surface by covalent bonding has been
      described. The sensor shows satisfactory virtues in reversibility, repeatability,
      selectivity and sufficient lifetime resulting from its excellent optode membrane.
      Its response time is less than 60 s. The determination range and detection limit
      of the sensor are 6.0 x 10(-7)-2.0 x 10(-3) M and 2.0 x 10(-7) M, respectively.
      The lifetime of each sensor is at least three to four months. The sensor can be
      used for direct determination of doxycycline in pharmaceutical preparations and
      urine samples.

PMID- 12608763
TI  - Solid phase extraction and spectrophotometric determination of silver with 2-(2
      quinolylazo)-5-diethylaminophenol as chromogenic reagent.
AB  - A new chromogenic reagent, 2-(2-quinolylazo)-5-diethylaminophenol (QADEAP), was
      synthesized. A sensitive, selective and rapid method has been developed for the
      determination of microg/L level silver ion based on the rapid reaction of
      silver(l) with QADEAP and the solid phase extraction of the colored chelate with
      C18 cartridge. The QADEAP reacts with Ag(l) to form a violet chelate of a molar
      ratio 1:2 (silver to QADEAP) in pH 3.5-8.0. This chelate was prconcentrated by
      solid phase extraction with C18 cartridge. An enrichment factor of 100 was
      achieved. The molar absorptivity of the chelate is 1.30 x 10(5) L mol(-1) cm(-1)
      at 590 nm in measured solution. Beer's law is obeyed in the range of 0.01-0.6
      microg/ml. The relative standard deviation for eleven replicate samples of 0.01
      microg/ml is 1.15%. The detection limit is 0.02 microg/L in the original samples.
      This method was applied to the determination of microg/L level silver ion in
      water with good results.

PMID- 12608765
TI  - Discrimination of poly(vinyl chloride) samples with different plasticizers and
      prediction of plasticizer contents in poly(vinyl chloride) using near-infrared
      spectroscopy and neural-network analysis.
AB  - In the recycling of poly(vinyl chloride) (PVC), it is required to discriminate
      every plasticizer for quality control. For this purpose, the near-infrared
      spectra were measured for 41 kinds of PVC samples with different plasticizers
      (DINP, DOP, DOA, TOTM and Polyester) and different plasticizer contents (0-49%).
      A neural-network analysis was applied to the near-infrared spectra pretreated by
      second-derivative processing. They were discriminated from one another. The
      neural-network analysis also allowed us to propose a calibration model which
      predicts the contents of plasticizers in PVC. The correlation coefficient (R) and
      the root-mean-square error of prediction (RMSEP) for the DINP calibration model
      were found to be 0.999 and 0.41 wt%, respectively. In comparison, a partial least
      squares regression analysis was carried out. The R and RMSEP of the DINP
      calibration model were calculated to be 0.993 and 1.27 wt%, respectively. It is
      found that a near-infrared spectra measurement combined with a neural-network
      analysis is useful for plastic recycling.

PMID- 12608764
TI  - Simultaneous spectrophotometric determination of uranium and thorium by flow
      injection analysis using selective masking.
AB  - A flow injection system for the simultaneous determination of uranium and thorium
      has been developed by using selective masking and a spectrophotometric detector
      with two flow cells aligned with the same optical path. The injected sample
      solution was first mixed with a reagent solution containing Chromazurol S (CAS)
      and cetyltrimethylammonium chloride (CTMAC), and the total absorbance of uranium-
      and thorium-CAS complexes was measured in the first flow cell at 620 nm. The
      sample stream was then mixed with an EDTA solution in order to convert the
      thorium-CAS complex to a thorium-EDTA complex, and the absorbance of the uranium
      CAS complex was measured in the second flow cell. The detection limits were 10
      microg dm(-3) for uranium and 7 microg dm(-3) for thorium. The calibration graphs
      were linear (r < 0.9998) at least over the ranges of 0.1 to 10 mg dm(-3) for
      uranium and 0.08 to 8 mg dm(-3) for thorium. The RSDs were less than 1.5% (n = 3)
      in the calibration range. Uranium and thorium of up to the 6-fold concentration
      to each other could be determined in admixtures with relative errors of less than
      3.3%. The sample throughput was 24 per hour. The proposed system was successfully
      applied to the analysis of a uranium-thorium ore mock solution by coupling with
      anion-exchange in a magnesium nitrate medium to eliminate interference from
      coexisting elements.

PMID- 12608766
TI  - Determination of cobalt and nickel by graphite-furnace atomic absorption
      spectrometry after coprecipitation with scandium hydroxide.
AB  - Trace amounts of cobalt and nickel in a water sample were quantitatively
      coprecipitated with scandium hydroxide at pH 8.0-10.5. Because the coprecipitant
      could be easily dissolved with 1 mol dm(-3) nitric acid, and the presence of up
      to 10 mg cm(-1) of scandium did not interfere with the graphite-furnace atomic
      absorption spectrometric determination of cobalt and nickel, the volume of the
      final solution prepared for the determination could be minimized down to 0.5 cm3.
      The concentration factor was 400-fold and the detection limits (signal to noise =
      2) were 5.0 pg cm(-3) of cobalt and 10.0 pg cm(-3) of nickel in 200 cm3 of the
      initial sample solution. The 27 diverse ions investigated did not interfere with
      the determination in at least a 500-fold mass ratio to cobalt or nickel. The
      proposed method was successfully applied to the determination of trace amounts of
      cobalt and nickel in river-water samples.

PMID- 12608767
TI  - Determination of midodrine in human plasma by high-performance liquid
      chromatography with fluorescence detection.
AB  - A simple and sensitive fluorometric high-performance liquid chromatographic
      method was developed for the determination of midodrine in human plasma. After
      liquid-liquid extraction from plasma, the drug and 2-phenylglycinol (internal
      standard) were convened into the corresponding fluorescent derivatives by
      reaction with 3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxoquinoxaline-2-carbonyl
      chloride, a fluorescence derivatization reagent for amines. The derivatives were
      separated within 30 min on a reversed-phase column using isocratic elution with
      acetonitrile-methanol-water (10:30:60, v/v) and were detected
      spectrofluorometrically at 485 nm with excitation at 400 nm. The detection limit
      for midodrine was 0.3 pmol (76 pg) per mL plasma at a signal-to-noise ratio of 3.

PMID- 12608768
TI  - "Substituent on benzenesulfonyl group" effect in use of 8
      benzenesulfonamidoquinoline derivatives as chelate extractant.
AB  - "Substituent on benzenesulfonyl group" effect of 8-benzenesulfonamidoquinoline [N
      (8-quinolyl)benzenesulfonamide, Hbsq] as bidentate chelate extractant for
      divalent metal cations was investigated with using Hbsq and its eight
      derivatives. Introduction of electron-withdrawing substituent on the
      benzenesulfonyl group in Hbsq enhanced the extractability that originated from
      its inductive effect. Furthermore, a bulky substituent on an ortho-position of
      the benzenesulfonyl group resulted in no steric effect in extraction, whereas the
      existence of two substituents on each ortho-position caused lower extraction
      performance due to steric hindrance.

PMID- 12608769
TI  - Direct determination of arsenic in steel by glow discharge optical emission
      spectrometry with argon-helium mixed gas.
AB  - In glow discharge optical emission spectrometry, an argon-helium mixed gas plasma
      was investigated to improve the detection sensitivity of arsenic in steel
      samples. The emission line of arsenic was enhanced and the background intensity
      was simultaneously reduced when an Ar-He plasma was employed instead of an Ar
      plasma, which is effective for the sensitive determination of arsenic. The
      detection limits were calculated to be 0.009 mass% for a 700-V Ar plasma, 0.004
      mass% for a 700-V Ar-He plasma, and 0.001 mass% for a 900-V Ar-He plasma.

PMID- 12608770
TI  - Crystal structure of ciprofloxacin hydrochloride 1.34-hydrate.
AB  - Ciprofloxacin belongs to a family of quinolone antibacterial agents. The crystal
      structure of ciprofloxacin hydrochloride 1,34-hydrate was determined. Most of the
      bond lengths and angles of the ciprofloxacin cation are very similar to those of
      ciprofloxacin hexahydrate, which appears in the zwitterionic form. The exceptions
      are the carbon-oxygen bond distances in the carboxylic group, since in the title
      compound this group is not deprotonated. Various inter- and intramolecular
      hydrogen bonds were found in the molecule and are described.

PMID- 12608771
TI  - Crystal structure of [N,N'-bis(5-chlorosalicylidene)-1,3-diaminopropane]iron(II).
AB  - The crystal structure of the title compound has been determined. The coordination
      geometry about the iron(II) center is a tetrahedrally distorted square plane
      formed by the four-coordinate N2O2 donor set of the Schiff-base imine-phenol
      ligand. Molecules of the title compound are not planar. The two Schiff-base
      moieties, which themselves are reasonably planar, are inclined at an angle of
      31.5(1) degrees.

PMID- 12608772
TI  - Crystal structure of the 1:2:2 adduct of piperazine, o-phthalic acid and water.
AB  - The adduct of piperazine, o-phthalic acid and water (1:2:2), C20H26N2O10,
      crystallizes in the monoclinic space group P21/c with a = 6.129(1), b =
      12.810(2), c = 13.137(2)A, beta = 95.87(1) degrees, V = 1026.0(3)A3, Z = 2. The
      piperazinium adopts a chair comformer, and is tied with the hydrogen
      orthophthalate via a hydrogen bond of the N-H...O type. Because of bifurcated
      hydrogen bonding of C(sp3)H-O [3.0801(17) and 3.1408(18)A] and the shortest
      hydrogen bond of C(sp3)H-O [2.9758(17)A], C(sp3)H-O hydrogen bonds play important
      roles in stablizing the title adduct.

PMID- 12608773
TI  - Crystal structure of [2,6-bis(3,5-dimethyl-N-pyrazolyl)pyridine]
      (azido)(chloro)copper(II).
AB  - In the title compound, the coordination around the Cu atom is a distorted square
      pyramid involving three N atoms from the ligand and one N atom from the azido
      group at the basal plane. The Cl atom is located at the apical position. The Cu
      atom is 0.32(5)A above the basal plane. There are three intramolecular and four
      weak intermolecular hydrogen bonds in the structure. IR spectra confirm the
      asymmetric N3 stretching vibrations of the terminal azide group.

PMID- 12608774
TI  - Crystal structure of tetracarbonyl(2,2'-dipyridylamine)tungsten.
AB  - Tetracarbonyl(2,2'-dipyridylamine)tungsten was prepared from W(CO)6 and 2,2'
      dipyridylamine in toluene. The structure was determined by an X-ray diffraction
      analysis. Crystal data: triclinic; space group, P-1 (No.2); a = 8.454(1)A, b =
      13.369(2)A, c = 6.9452(9) A, a= 85.88(1) degrees, beta = 68.28(1) degrees, gamma
      = 80.93(1) degrees, V= 720.0(1)AI; Z = 2.

PMID- 12608775
TI  - Studies in polyphenol chemistry and bioactivity. 4.(1) Synthesis of trimeric,
      tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins
      having all-4beta,8-interflavan connectivity and their inhibition of cancer cell
      growth through cell cycle arrest.
AB  - We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin
      4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'
      tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously
      employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K
      10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, 
      tetramer, and -pentamer were obtained regioselectively from their lower
      homologues, albeit in rapidly decreasing yields. Reaction of 2 with an
      organoaluminum thiolate generated from 2-mercaptobenzothiazole and
      trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2
      benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized
      protected oligomers with 4beta,8-interflavan linkages are obtained in improved
      yields by using this compound as the electrophile and silver tetrafluoroborate as
      activator and are isolated by reversed-phase HPLC. Their deprotection by ester
      saponification followed by hydrogenolysis yielded the free procyanidins, which
      were characterized as their peracetates. The synthetic procyanidins are identical
      by normal-phase HPLC with fractions isolated from cocoa. The principle of chain
      extension by two members was demonstrated using a dimeric electrophile obtained
      by self-condensation of compound 12. Both the synthetic and natural pentamer 32
      inhibit the growth of several breast cancer cell lines. Using the MDA MB 231
      line, it was established that this outcome is based on the induction of cell
      cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic
      rather than apoptotic. Control experiments demonstrate that the polyphenol
      itself, rather than hydrogen peroxide potentially formed by its autoxidation, is
      the causative agent.

PMID- 12608776
TI  - Studies of the biosynthesis of DTX-5a and DTX-5b by the dinoflagellate
      Prorocentrum maculosum: regiospecificity of the putative Baeyer-Villigerase and
      insertion of a single amino acid in a polyketide chain.
AB  - The biosynthetic origins of the diarrhetic shellfish poisoning toxins DTX-5a and
      DTX-5b have been elucidated by supplementing cultures of the producing organism
      Prorocentrum maculosum with stable isotope labeled precursors and determining the
      incorporation patterns by 13C NMR spectroscopy. The amino acid residue in the
      sulfated side chain is found to originate from glycine, and oxygen insertion in
      the chain is shown to occur after polyketide formation.

PMID- 12608777
TI  - Synthesis and reactions of aminoporphyrazines with annulated five- and seven
      membered rings.
AB  - The novel five- and seven-membered ring appended aminoporphyrazines 3 and 12 have
      been prepared via mixed Linstead macrocyclization. The structures of both have
      been unequivocally established by X-ray crystallographic studies. Reductive
      deselenation of selenadiazole 3 in the presence of 9,10-phenanthrenequinone or
      2,3-butanedione results in the formation of pyrazines 6a,b, whereas oxidation of
      porphyrazine 12 gave the corresponding seco derivative 14. seco-Porphyrazine 14
      mediates the generation of singlet oxygen with a quantum yield of 0.74.

PMID- 12608778
TI  - 1H NMR studies of maltose, maltoheptaose, alpha-, beta-, and gamma-cyclodextrins,
      and complexes in aqueous solutions with hydroxy protons as structural probes.
AB  - The (1)H NMR chemical shifts, coupling constants, temperature coefficients, and
      exchange rates have been measured for the hydroxy protons of aqueous solutions of
      alpha-, beta-, and gamma-cyclodextrins, maltose, and maltoheptaose. In
      cyclodextrins (CDs), the high chemical shift of the O(3)H signal and its small
      (3)J(OH,CH) value suggest that O(3)H is involved in a hydrogen bond. The small
      temperature coefficients and rate of exchange values of O(2)H and O(3)H confirm
      the involvement of O(3)H in hydrogen bonding and indicate that O(2)H is the
      hydrogen bond partner. In maltose, two distinct NMR signals with two different
      vicinal coupling constants are found for O(2')H. A cross-peak in the ROESY
      spectrum indicates chemical exchange between the O(2')H and O(3)H protons. The
      existence of two distinct NMR signals with different J values for O(2')H shows
      the influence of anomeric configuration on the O(2')H-O(3)H interaction. The
      effect of complexation with methyl benzoate, adamantane-1-carboxylic acid,
      adamantane-1-ol, and l- and d-tryptophane on the NMR spectra of the hydroxy
      protons of alpha-, beta-, and gamma-cyclodextrins and of maltose has been
      investigated. No significant spectral changes were observed upon addition of
      methyl benzoate and adamantane-1-carboxylic acid. The addition of adamantane-1-ol
      resulted in an upfield shift and a strong broadening of the O(2)H signal from
      alpha-CD, and a small temperature coefficient was measured upon complexation. The
      O(2)H and O(3)H signals in beta-CD were broadened and shifted downfield upon
      addition of l- and d-tryptophane.

PMID- 12608779
TI  - Reverse turn induced pi-facial selectivity during polyaniline-supported
      cobalt(II) salen catalyzed aerobic epoxidation of N-cinnamoyl L-proline derived
      peptides.
AB  - A novel chemo- and diastereoselective aerobic epoxidation of the N-cinnamoyl
      peptides catalyzed by polyaniline-supported cobalt(II) salen (PASCOS) is
      described. The N-cinnamoyl proline derived peptides 1 show a high pi-facial
      selectivity during these epoxidations. The origin of this diastereoselectivity in
      1 has been attributed to (i) the propensity of the N-cinnamoyl proline amide to
      exist predominantly as trans rotamer in CDCl3, DMSO-d6, and CH3CN medium and (ii)
      existence of these peptides as organized structures (gamma- and beta-turns) due
      to the presence of intramolecular hydrogen bonds. An extensive solution NMR and
      MD simulation study on 1d and 1f indicates that the origin of the high pi-facial
      selectivity is due to the well-defined gamma- and beta-turns which result in the
      hindrance of one face of the cinnamoyl double bond in the transition state of the
      epoxidation reaction.

PMID- 12608780
TI  - An approach to the synthesis of the phomoidrides.
AB  - The phomoidrides are a structurally fascinating family of natural products which
      possess moderate inhibitory activity against Ras farnesyl transferase and
      squalene synthase. Since their discovery they have inspired a great deal of
      attention from synthetic chemists. Our own work, culminating in an efficient
      synthesis of the fully elaborated tetracyclic core of phomoidrides B and D, is
      described herein. The synthesis relies on a late stage tandem reaction involving
      a novel carbonylation reaction that delivers the strained bicyclic pseudoester
      system, which strain in turn drives a highly efficient silyloxy-Cope
      rearrangement that delivers the tetracyclic core of phomoidrides B and D. Several
      examples of this powerful tandem reaction are presented that document its
      tolerance of significant structural variation. The application of this
      methodology to the synthesis of a phomoidride D precursor lacking only the maleic
      anhydride is described, and the prospects for the completion of a total synthesis
      are discussed.

PMID- 12608781
TI  - Synthesis of a new chiral bisphospholane ligand for the Rh(I)-catalyzed
      enantioselective hydrogenation of isomeric beta-acylamido acrylates.
AB  - The highly stereoselective synthesis of a chiral silylphospholane has been
      described, which can be advantageously used as a building block under base-free
      conditions for the construction of diphosphines related to DuPHOS. The utility of
      silylphospholane is shown in the synthesis of a new bisphospholane ligand 1
      (MalPHOS), which is characterized by a maleic anhydride backbone. The ligand
      forms with Rh(I) a complex with a larger bite angle P-Rh-P than the analogue Me
      DuPHOS complex. Both complexes have been tested in the asymmetric hydrogenation
      of unsaturated alpha- and beta-amino acid precursors of pharmaceutical relevance.
      In several cases, the new catalyst was superior in comparison to the Me-DuPHOS
      complex, in particular when (Z)-configured beta-acylamido acrylates were used as
      substrates.

PMID- 12608782
TI  - Novel radical compounds bearing mesogenic cores with long alkyl substituents.
AB  - Series of aminoxyl radicals (TEMPO or nitronyl nitroxide radicals) bearing phenyl
      benzoate, troponoid, or biphenylcarbonitrile as mesogenic cores with long alkyl
      substituents were prepared. Although most aminoxyl radicals showed only weak
      antiferromagnetic interactions due probably to the remote spin centers as
      clarified by the X-ray analysis of 4a and no appreciable mesogenic phase was
      observed in each compound, an unusual magnetic transition from an original Curie
      Weiss phase to another magnetic phase well-expressed by a singlet-triplet (ST)
      model was disclosed through the thermal transition in the 4'-undecyloxy-4
      biphenylcarbonitrile derivative with oxocarbonyl-TEMPO 12b.

PMID- 12608783
TI  - Stable simple enols. Self-catalyzed E/Z-isomerization of the sterically crowded 2
      (m-methoxymesityl)-1,2-dimesitylethenol.
AB  - (E)-2-(m-methoxymesityl)-1,2-dimesitylethenol (3a) isomerizes in the absence of a
      catalyst in solution to a 1.0:0.9 E/Z (3a/3b) equilibrium mixture. In CDCl3 the
      isomerization is first order in 3a within a run, but the plot of the rate
      constant k(obs) vs the changing [3a]0 in different runs is a half-parabola,
      indicating self-catalysis by more than one enol molecule. At 0.09 M enol, the
      isotope effect k(3a)/k(3a)-OD = 2.1. In the presence of 0.025-0.25 M pyridine-d5,
      the k(obs) vs [pyridine-d5] plot displays a bell-shaped profile. The change in
      the shape of the OH signals of the 3a/3b mixture at 295-430 K in C6D5NO2 was
      followed by DNMR. The four signals of the diastereomeric 3a/3b mixture observed
      at 330 K coalesce at 350 K with barriers of 18.3 and 18.4 kcal x mol(-1) due to
      the diastereomerization of the vinyl propellers. The resulting two signals
      observed at >360 K further coalesce at 425 K with a barrier of 22.9 kcal x mol(
      1) due either to oxygen-to-oxygen proton exchange or to E/Z isomerization. The
      estimated upper limit for the rate of proton exchange of k(ex) < or = (2-4) x
      10(3) M(-1) x s(-1) at 425 K between the enol molecules is sufficiently slow to
      be a rate-controlling step in the isomerization. A process in which several enol
      molecules catalyze the isomerization is suggested, and several mechanistic routes
      are analyzed.

PMID- 12608784
TI  - A highly chemoselective, diastereoselective, and regioselective epoxidation of
      chiral allylic alcohols with hydrogen peroxide, catalyzed by sandwich-type
      polyoxometalates: enhancement of reactivity and control of selectivity by the
      hydroxy group through metal-alcoholate bonding.
AB  - Sandwich-type polyoxometalates (POMs), namely [WZnM2(ZnW9O34)2]q- [M = Mn(II),
      Ru(III), Fe(III), Pd(II), Pt(II), Zn(II); q = 10-12], are shown to catalyze
      selectively the epoxidation of chiral allylic alcohols with 30% hydrogen peroxide
      under mild conditions (ca. 20 degrees C) in an aqueous/organic biphasic system.
      The transition metals M in the central ring of polyoxometalate do not affect the
      reactivity, chemoselectivity, or stereoselectivity of the allylic alcohol
      epoxidation by hydrogen peroxide. Similar selectivities, albeit in significantly
      lower product yields, are observed for the lacunary Keggin POM [PW11O39]7-, in
      which a peroxotungstate complex has been shown to be the active oxidizing
      species. All these features support a tungsten peroxo complex rather than a high
      valent transition-metal oxo species operates as the key intermediate in the
      sandwich-type POM-catalyzed epoxidations. On capping of the hydroxy functionality
      through acetylation or methylation, no reactivity of these hydroxy-protected
      substrates [1a(Ac) and 1a(Me)] is observed by these POMs. A template is proposed
      to account for the marked enhancement of reactivity and selectivity, in which the
      allylic alcohol is ligated through metal-alcoholate bonding, and the H2O2 oxygen
      source is activated in the form of a peroxotungsten complex. 1,3-Allylic strain
      promotes a high preference for the threo diastereomer and 1,2-allylic strain a
      high preference for the erythro diastereomer, whereas tungsten-alcoholate bonding
      furnishes high regioselectivity for the epoxidation of the allylic double bond.
      The estimated dihedral angle alpha of 50-70degrees for the metal-alcoholate
      bonded template of the POM/H2O2 system provides the best compromise between 1,2A
      and 1,3A strain during the oxygen transfer. In contrast to acyclic allylic
      alcohols 1, the M-POM-catalyzed oxidation of the cyclic allylic alcohols 4 by
      H2O2 gives significant amounts of enone.

PMID- 12608785
TI  - A formal [3 + 3] cycloaddition reaction. Improved reactivity using alpha,beta
      unsaturated iminium salts and evidence for reversibility of 6pi-electron
      electrocyclic ring closure of 1-oxatrienes.
AB  - A detailed account regarding a formal [3 + 3] cycloaddition method using 4
      hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition
      reaction or annulation reaction is synthetically useful for constructing 2H
      pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is
      significant in controlling competing reaction pathways to give exclusively 2H
      pyrans. Most significantly, experimental evidence is provided to support the
      mechanism of this reaction that involves a sequential Knoevenagel condensation
      and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.

PMID- 12608786
TI  - A trifunctional catalyst for one-pot synthesis of chiral diols via Heck coupling
      N-oxidation-asymmetric dihydroxylation: application for the synthesis of
      diltiazem and taxol side chain.
AB  - A heterogeneous bifunctional catalyst composed of OsO4(2-)-WO4(2-) and a
      trifunctional catalyst comprising PdCl4(2-)-OsO4(2-)-WO4(2-), designed and
      prepared by an ion-exchange technique using layered double hydroxides (LDH) as an
      ion-exchanger and their homogeneous bifunctional analogue, K2OsO4-Na2WO4 and
      trifunctional analogue, Na2PdCl4-K2OsO4-Na2WO4, devised for the first time are
      evaluated for the synthesis of chiral vicinal diols. These bifunctional and
      trifunctional catalysts perform asymmetric dihydroxylation-N-oxidation and Heck
      asymmetric dihydroxylation-N-oxidation, respectively, in the presence of
      Sharpless chiral ligand, (DHQD)2PHAL in a single pot using H2O2 as a terminal
      oxidant to provide N-methylmorpholine oxide (NMO) in situ by the oxidation of N
      methylmorpholine (NMM). The heterogeneous bifunctional catalyst supported on LDH
      (LDH-OsW) displays superior activity to afford diols with higher yields over the
      other heterogeneous catalysts developed by the ion exchange on quaternary
      ammonium salts covalently bound to resin (resin-OsW) and silica (silica-OsW) or
      homogeneous catalysts in the achiral dihydroxylation reactions. The LDH-OsW and
      its homogeneous analogue are found to be very efficient in performing a
      simultaneous asymmetric dihydroxylation (AD)-N-oxidation of a wide and varied
      range of aromatic, cyclic, and mono, di-, and trisubstituted olefins to obtain
      chiral vicinal diols with higher yields and ee's using H2O2. Further, the use of
      OsO4(2-)-WO4(2-) catalysts as such or in the supported form offers a simplified
      procedure for catalyst recycling, which shows consistent activity for a number of
      cycles. In this process, Os(VI) is recycled to Os(VIII) by a coupled electron
      transfer-mediator (ETM) system based on NMO-WO4(2-) using H2O2, leading to a mild
      and selective electron transfer. The one-pot biomimic synthesis of chiral diols
      is mediated by a recyclable trifunctional heterogeneous catalyst (LDH-PdOsW)
      consisting of active palladium, tungsten, and osmium species embedded in a single
      matrix. This protocol, which provides prochiral olefins and NMO in situ by Heck
      coupling and N-oxidation of NMM, respectively, required for the AD, unfolds a low
      cost process. We extended the present method to the one-pot synthesis of
      trisubstituted chiral vicinal diols with moderate to excellent ee's by AD of
      trisubstituted olefins that are obtained by in situ Heck arylation of
      disubstituted olefins. The heterogeneous trifunctional catalysts offers chiral
      diols with unprecedented ee's and excellent yields in the AD of prochiral
      cinnamates, which are obtained in situ from acrylates and halobenzenes for the
      first time. The new variants such as LDH support and Et3N*HX inherently composed
      in the heterogeneous multicomponent system and slow addition of H2O2 facilitates
      the hydrolysis of osmium monogylcolate ester to subdue the formation of
      bisglycolate ester to achieve higher ee's. Without resorting to
      recrystallization, the chiral diols of cinnamates thus synthesized with 99% ee's
      and devoid of osmium contamination are directly put to use in the synthesis of
      diltiazem and Taxol side chain with an overall improved yield to demonstrate the
      synthetic utility of the trifunctional heterogeneous catalyst. The high binding
      ability of the heterogeneous osmium catalyst enables the use of equimolar ratio
      of ligand to osmium to give excellent ee's in AD in contrast to the homogeneous
      osmium system in which the excess molar quantities of the expensive chiral ligand
      to osmium are invariably used. Further, the XRD, FT-IR, UV-vis DRS, and XPS
      studies indicate the retention of the coordination geometries of the specific
      divalent anions anchored to LDH matrix in their monomeric form during the ion
      exchange and after the reaction.

PMID- 12608787
TI  - Hydroxylamines as oxidation catalysts: thermochemical and kinetic studies.
AB  - Bond dissociation enthalpies (BDE) of hydroxylamines containing alkyl, aryl,
      vinyl, and carbonyl substituents at the nitrogen atom have been determined by
      using the EPR radical equilibration technique in order to study the effect of the
      substituents on the O-H bond strength of these compounds. It has been found that
      substitution of an alkyl group directly bonded to the nitrogen atom with vinyl or
      aryl groups has a small effect, while substitution with acyl groups induces a
      large increase of the O-H BDE value. Thus, dialkyl hydroxylamines have O-H bond
      strengths of only ca. 70 kcal/mol, while acylhydroxylamines and N
      hydroxyphthalimide (NHPI), containing two acyl substituents at nitrogen, are
      characterized by BDE values of ca. 80 and 88 kcal/mol, respectively. Since the
      phthalimide N-oxyl radical (PINO) has been recently proposed as an efficient
      oxidation catalyst of hydrocarbons or other substrates, the large BDE value found
      for the parent hydroxylamine (NHPI) justifies this proposal. Kinetic studies,
      carried out in order to better understand the mechanism of the NHPI-catalyzed
      aerobic oxidation of cumene, are consistent with a simple kinetic model where the
      rate-determining step is the hydrogen atom abstraction from the hydroxylamine by
      cumylperoxyl radicals.

PMID- 12608788
TI  - Conjugated macrocycles related to the porphyrins. 25. Proton NMR spectroscopic
      evidence for a preferred [18]annulene substructure in carbaporphyrins from the
      magnitude of selected 4J(H,H) CH=C-CH3 coupling constants.
AB  - Two new benzocarbaporphyrins with four or five alkyl substituents have been
      synthesized by the "3 + 1" MacDonald methodology. At lower temperatures, the
      proton NMR spectrum of the asymmetrically substituted carbaporphyrin 8 gave two
      NH resonances, while carbaporphyrin 9, which retains a plane of symmetry, gave
      only one resonance of this kind. As no additional peaks were seen for the
      remaining protons, these data strongly support the proposal that a single
      tautomer predominates in solution where the two NH protons flank the interior CH.
      Carbaporphyrin 8, which has a CH=CMe unit on the pyrrolic ring opposite the
      indene moiety, gave a long-range coupling constant of 4J(Me,H) = 1.3-1.4 Hz. On
      the other hand, the CH=CMe units of 9, which correspond to the pyrrole rings on
      each side of the carbocyclic moiety, gave 4J(Me,H) = 0.9-1.0 Hz. These values are
      in accord with those expected if the exterior carbon-carbon bonds of the pyrrole
      units next to the indene ring are part of a fully delocalized 18pi electron
      system, while the C=C bond of the remaining pyrrole ring retains substantial
      olefinic character.

PMID- 12608789
TI  - Calorimetric and computational study of thiacyclohexane 1-oxide and
      thiacyclohexane 1,1-dioxide (thiane sulfoxide and thiane sulfone). Enthalpies of
      formation and the energy of the S=O bond.
AB  - A rotating-bomb combustion calorimeter specifically designed for the study of
      sulfur-containing compounds [J. Chem. Thermodyn. 1999, 31, 635] has been used for
      the determination of the enthalpy of formation of thiane sulfone, 4, Delta(f)H(o)
      m(g) = -394.8 +/- 1.5 kJ x mol(-1). This value stands in stark contrast with the
      enthalpy of formation reported for thiane itself, Delta(f)H(o) m(g) = -63.5 +/-
      1.0 kJ x mol(-1), and gives evidence of the increased electronegativity of the
      sulfur atom in the sulfonyl group, which leads to significantly stronger C-SO2
      bonds. Given the known enthalpy of formation of atomic oxygen in the gas phase,
      Delta(f)H(o) m(O,g) = +249.18 kJ x mol(-1), and the reported bond dissociation
      energy for the S=O bond in alkyl sulfones, BDE(S=O) = +470.0 kJ x mol(-1), it was
      possible to estimate the enthalpy of formation of thiane sulfoxide, 5, a
      hygroscopic compound not easy to use in experimental calorimetric measurements,
      Delta(f)H(o) m(5) = -174.0 kJ x mol(-1). The experimental enthalpy of formation
      of both 4 and 5 were closely reproduced by theoretical calculations at the
      G2(MP2)+ level, Delta(f)H(o) m(4) = -395.0 kJ x mol(-1) and Delta(f)H(o) m(5) = 
      178.0 kJ x mol(-1). Finally, calculated G2(MP2)+ values for the bond dissociation
      energy of the S=O bond in cyclic sulfoxide 5 and sulfone 4 are +363.7 and +466.2
      kJ x mol(-1), respectively.

PMID- 12608790
TI  - A modular synthesis of annonaceous acetogenins.
AB  - A synthesis of four Annonaceous acetogenins, asiminocin, asimicin, asimin, and
      bullanin, by a modular approach from seven fundamental subunits, A-G, is
      described. The approach employs a central core aldehyde segment, C, to which are
      appended an aliphatic terminus, A or B, a spacer subunit, D or E, and a
      butenolide terminus, F or G. Coupling of the A, B, D, and E segments to the core
      aldehyde unit is effected by highly diastereoselective additions of enantiopure
      allylic indium or tin reagents. The butenolide termini are attached to the ACD,
      BCE, or BCD intermediates by means of a Sonogashira coupling. The design of the
      core, spacer, and termini subunits is such that any of the C30, C10, or C4
      natural acetogenins or stereoisomers thereof could be prepared. IC50 values for
      the four aforementioned acetogenins against H-116 human colon cancer cells were
      found to be in the 10(-3) to 10(-4) microM range. The IC90 activities were ca.
      10(-3) microM for asimicin and asimin but only 0.1-1 microM for bullanin and
      asiminocin.

PMID- 12608791
TI  - Total synthesis and structure confirmation of the annonaceous acetogenins 30(S)
      hydroxybullatacin, uvarigrandin a, and 5(R)-uvarigrandin a (narumicin I?).
AB  - A synthesis of the bistetrahydrofuran Annonaceous acetogenins 30(S)
      hydroxybullatacin, uvarigrandin A, and 5(R)-uvarigrandin A through application of
      a previously disclosed four-component modular approach is described in which
      extended core segments are coupled to a C4- or C5-hydroxy butenolide terminus.
      The butenolide termini segments were prepared from (S)- or (R)-malic acid.
      Spectral properties of synthetic 30(S)-hydroxybullatacin and uvarigrandin A, as
      well as their Mosher ester derivatives, were in close agreement to the reported
      values for the natural substances. The synthetic 5(R)-uvarigrandin A is possibly
      identical to narumicin I, but subtle differences in the reported NMR spectra
      prevented an unambiguous assessment of this point.

PMID- 12608792
TI  - A novel method for the determination of stereochemistry in six-membered chairlike
      rings using residual dipolar couplings.
AB  - A novel method for the determination of the relative stereochemistry of six
      membered chairlike ring molecules by residual dipolar couplings is presented. C-H
      residual dipolar couplings were used to investigate the relative stereochemistry
      of 4,6-O-ethylidene-d-glucopyranose. For this and similar systems it is not
      necessary to acquire redundant dipolar couplings and to calculate the orientation
      order tensor. The presented methodology is a paradigmatic leap for the
      determination of the relative stereochemistry or remote stereochemistry in this
      kind of fused ring system. Residual dipolar coupling data were collected by 1D
      and 2D direct-measurement heteronuclear multiple quantum coherence (HMQC)
      spectroscopy. It was demonstrated that direct measurement of HMQC was quick and
      accurate for small molecules at natural abundance.

PMID- 12608793
TI  - Mechanism of an alcohol-trapping reaction in the direct and benzophenone
      sensitized photodenitrogenation of a spiroepoxy-substituted azoalkane: solvent
      effects and stereochemical deuterium labeling.
AB  - The spin-state-dependent reactivity, singlet versus triplet, of the 2-spiroepoxy
      1,3-cyclopentane-1,3-diyl DR2 has been assessed through alcohol-trapping
      reactions for which the effect of solvent acidity on the product distribution of
      the alcohol trapping products 2 versus 3 + 4 and stereochemical deuterium
      labeling studies have been performed. The proposed mechanism for the solvent
      effect on the product ratio (2/3 + 4) reveals the importance of the hydrogen
      bonded intermediates I1 and I2 in the trapping reactions; the stereochemical
      deuterium-labeling results clarify the dipole structure trapped by the alcohol.
      The dipoles DP1 and DP2, in which the configuration between the epoxide oxygen
      and the deuterium atoms is retained, are inferred for the direct
      photodenitrogenation reactions (singlet state), whereas for the benzophenone
      sensitized photoreactions (triplet state), after ISC, the ring-opened dipole DP3
      is implied as the intermediate that is trapped by the alcohol.

PMID- 12608794
TI  - A comparison of linear optical properties and redox properties in
      chalcogenopyrylium dyes bearing ortho-substituted aryl substituents and tert
      butyl substituents.
AB  - A series of thiapyrylium pentamethine dyes (4 and 12-15) bearing 2,2'-di-tert
      butyl-6,6'-diphenyl, 2,2'-di-tert-butyl-6,6'-bis(2,6-dimethylphenyl), 2,2'-di
      tert-butyl-6,6'-bis(2-methylphenyl), 2,2',6,6'-tetrakis(2,6-dimethylphenyl), and
      2,2',6,6'-tetrakis(2-methylphenyl) substituents, respectively, were prepared and
      their linear optical properties and electrochemical redox properties were
      measured and compared to thiapyrylium pentamethine dyes 3 and 5. The tert-butyl
      and 2,6-dimethylphenyl substituents give nearly identical chromophores with
      respect to values of lambda(max), molar extinction coefficients (epsilon),
      bandwidths at half-height (nu(1/2)), and lack of absorption in the visible
      spectrum. The 2-methylphenyl substituent imparts linear optical properties that
      are intermediate between those of the tert-butyl and phenyl substituents. The 2,6
      dimethylphenyl and 2-methylphenyl substituents impart greater oxidative stability
      based on anodic shifts in oxidation potential.

PMID- 12608795
TI  - The alpha-effect in methyl transfers from S-methyldibenzothiophenium fluoroborate
      to substituted N-methylbenzohydroxamates.
AB  - Studies of the alpha-effect show increased reactivity of nucleophiles having lone
      pairs of electrons on atoms neighboring the lone pair involved in reactivity when
      compared to the basicity of the nucleophiles. Hammett-type plots and Bronsted
      type plots of substituted methylphenyl sulfates vs hydrogen peroxide anions and
      substituted N-methylbenzohydroxanates (NMBH) with substituted
      methylarenesulfonates or substituted arenedimethylsulfonium ions have large rho
      or beta(nuc) values, indicating a putative tightening of the usual S(N)2
      transition states (anti-Hammond effect). Electrochemical studies of S(N)2-SET or
      reactivity indicate that SET character occurs in looser transition states,
      whereas S(N)2 transition states are associated with greater tightness. The alpha
      effects for the series of sulfonium salts in completion reactions for 3-ClNMBH
      anions and 3-nitrophenolate anions are (log k(alpha)/k(normal)) 1.124 for
      dimethylphenyl sulfonium, 1.512 for dimethyl-1-naphthyl sulfonium, 1.835 for
      dimethyl-9-anthracenyl sulfonium, and 1.137 for S-methyldibenzylthiophenium.
      Correlations of the sizes of alpha-effects with typical SET (or ET) experimental
      parameters and the inverse dependence of the size of the alpha-effect on electron
      demand indicate inclusion of SET character in these S(N)2 transition states, vs
      no (or at least diminished) SET character in normal transition states. This
      dichotomy of tighter S(N)2 transition states, but looser SET transition states
      indicated in the alpha-effect, is examined in the present work.

PMID- 12608796
TI  - Conformational studies by dynamic NMR. 93.(1) Stereomutation, enantioseparation,
      and absolute configuration of the atropisomers of diarylbicyclononanes.
AB  - The structure of 9-(4-methoxyphenyl)-9-(3-methylphenyl) bicyclo[3.3.1]nonane (1)
      has been determined by single-crystal X-ray diffraction, and the rotation
      barriers about the two aryl-C9 bonds have been measured by variable temperature
      NMR spectroscopy in solution. In the case of 9-(4-methoxyphenyl)-9-(1
      naphthyl)bicyclo[3.3.1]nonane (3), the barrier involving the naphthyl-C9 rotation
      was found to be so high as to allow the physical separation of the two
      atropisomers by enantioselective HPLC at ambient temperature: the absolute
      configuration could be established on the basis of the corresponding CD spectra.
      It was also observed that the Ar-C9 rotation barriers of monoaryl-substituted
      nonanes are much lower than those of the corresponding diaryl-substituted
      nonanes.

PMID- 12608797
TI  - Efficient desymmetrization of "pseudo"-C2-symmetric substrates: illustration in
      the synthesis of a disubstituted butenolide from arabitol.
AB  - A short synthesis of the homochiral disubstituted butenolide 1 is described in
      four steps from arabitol. The key steps are the selective kinetic protection of
      arabitol and the cyclization of 11 to form the butenolide ring. This last
      transformation represents a rare example of a fully stereoselective cyclitive
      desymmetrization process of a "pseudo"-C2-symmetric substrate.

PMID- 12608798
TI  - Beta-silyl-substituted silaadamantyl, silabicyclo[2.2.2]octyl, silanorbornyl, and
      1-silacyclohexyl cations. A theoretical (DFT and GIAO NMR) study.
AB  - Parent 1-silaadamant-1-yl (1+) and a series of mono-beta-silyl-substituted- (2
      Me+, 2-F+, 2-Cl+, 2-Br+), bis-beta-silyl-substituted- (3-Me+), and tris-beta
      silyl-substituted (4-Me+)-1-silaadamant-1-yl cations were studied by the DFT
      method at the B3LYP/6-31G(d,p) level and by GIAO NMR at the B3LYP/ 6
      31G(d,p)//B3LYP/6-31G(d,p) level. The geometries, relative energies, NMR chemical
      shifts, and charge distribution in the bridgehead silylium ions are discussed and
      compared. The magnitude of the beta-silyl effect (the Si-C-Si+ hyperconjugation)
      is gauged as a function of structure. Related model studies on the
      silabicyclo[2.2.2]octyl (5+, 6+, 5a+, and 6a+), silanorbornyl (7+ and 8+), and
      silacyclohexyl cations (9+ and 10+) were carried out in which the effect of beta
      silyl substitution on geometry, stability, and NMR chemical shifts was probed.
      The acyclic model Me3Si-CH2-Si+(Me)2 (11+) was used to gauge the influence of the
      twist angle between the p-orbital at Si+ and the C-Si bond on relative stability
      and on the changes in the 29Si NMR chemical shifts. Finally, interaction of 1+
      with H2O and MeOH and 2-Me+ with H2O was also examined. The resulting optimized
      structures (12+, 13+, and 14+) and the computed NMR chemical shifts are most
      compatible with the formation of silaoxonium ions.

PMID- 12608799
TI  - Conformation of secondary amides. A predictive algorithm that correlates DFT
      calculated structures and experimental proton chemical shifts.
AB  - The magnetic deshielding caused by the amido group on CON-CHalpha protons of
      secondary amides can easily be correlated with DFT-based structures at the
      B3LYP/6-31G level of theory via a novel algorithm that refines previous models,
      such as the classical McConnell equation. The shift is given by delta = a + 2.16
      cos2(alpha - 35)/d, where alpha denotes the virtual dihedral angle resulting from
      linking the carbonyl and the alpha-carbons and d is the distance (A) between the
      shifted proton and the carbonyl oxygen. Notably, in this equation a is a
      parameter that can be optimized for different solvents, namely, CDCl3, DMSO-d6,
      and D2O. For the development of these correlations, the preferential conformation
      of amides is taken from the optimized structures in the gas phase obtained at the
      DFT level. The deshielding on anti and gauche protons in both rotamers of (Z)
      acetamides and E/Z isomers of formamides has been evaluated. This methodology has
      proved to be highly reliable, allowing us to discard ab initio or DFT
      conformational arrangements when shifts calculated by the above-mentioned
      equation differ from the experimental values. Thus, the anti disposition between
      the CHalpha proton and the N-H bond appears to be the more stable conformation of
      simple amides. For amides bearing only one proton at Calpha, a local syn minimum
      can equally be characterized. The rotational barriers around the CON-alkyl bond
      along with the pyramidalization of the amido group have also been reassessed. As
      the conformation is taken away from anti or local syn minima, the nonplanarity of
      the amido group appears to increase.

PMID- 12608800
TI  - Solid-phase synthesis of an A-B loop mimetic of the Cepsilon3 domain of human
      IgE: macrocyclization by Sonogashira coupling.
AB  - The solid-phase synthesis of a cyclic peptide containing the 21-residue epitope
      found in the A-B loop of the Cepsilon3 domain of human immunoglobulin E has been
      carried out. The key macrocyclization step to form the 65-membered ring is
      achieved in approximately 15% yield via an "on-resin" Sonogashira coupling
      reaction which concomitantly installs a diphenylacetylene amino acid
      conformational constraint within the loop.

PMID- 12608801
TI  - Temperature- and time-dependent stereochemical control in thermally induced keto
      ene cyclizations.
AB  - Reaction conditions determine the stereoselection in the intramolecular keto-ene
      reaction. The thermolysis of chiral 2-acyl-3-allyl-substituted 1,3
      perhydrobenzoxazines derived from (-)-8-aminomenthol gives a mixture of only two
      cis-3-hydroxy-3,4-disubstituted pyrrolidine nuclei. The stereochemistry of the
      major diastereoisomer depends on both the temperature and the reaction time.

PMID- 12608802
TI  - Rearrangement pathways of five-membered ring enlargement in carbocations: quantum
      chemical calculations and deuterium kinetic isotope effects.
AB  - Three plausible routes for the five-membered ring expansion in the equilibrating
      2-cyclopentyl-2-propyl and 1-(2-propyl)cyclopentyl cations 1A/1B were located on
      the PES, all calculated at the MP4/6-31G(d)//MP2/6-31G(d) level of theory. In
      pathway I, the six-membered transition structure (TS-I) connects the less stable
      cyclopentyl cation 1A and the 1,2-dimethylcyclohexyl carbocation (2) via a
      barrier of 16.4 kcal/mol. In pathway II, which has a barrier of 16.3 kcal/mol,
      the methyl migration occurs first in the more stable 1B via transition structure
      TS-II. Pathway III involves the uphill hydride shift and formation of the
      secondary cation 3, which undergoes Wagner-Meerwein 1,2-isopropyl shift via a
      transition structure TS-III and the protonated carbocation intermediate 4. The
      barrier pathway III is for 17.0 kcal/mol. Experimental secondary deuterium
      isotope effects of the rearrangement were measured for the hexadeuterated 1A
      d6/1B-d6 (kH/kD = 2.40) and tetradeuterated 1A-d4/1B-d4 (kH/kD = 0.18) cations by
      means of 1H NMR. Comparison of the experimental data with the theoretical values
      (kH/kD = 2.40 for 1B-d6 and kH/kD = 0.24 for 1B-d4, respectively) obtained with
      QUIVER revealed that pathway II is a major reaction route.

PMID- 12608804
TI  - Stereocontrolled synthesis of bicyclic lactone derivatives via tungsten-mediated
      [3 + 2] cycloaddition of epoxides with a tethered alkynyl group.
AB  - In the presence of BF3*Et2O, alkynyltungsten complexes underwent [3 + 2]
      cycloaddition with tethered epoxides to give bicyclic -lactones efficiently. Only
      one diastereomeric product was formed despite the presence of three stereogenic
      centers. A mechanism is proposed that involves formation of a tungsten
      vinylidenium species via an SN2 attack of the epoxide carbon by an
      alkynyltungsten group to give a tungsten-enol ether species via counterattack at
      the central tungsten-vinylidenium carbon by the OBF3- terminus. Most of the
      tungsten enol ether species were too unstable for isolation and underwent
      hydrolysis to give only cis-fused -bicyclic lactones. This cyclization works for
      both cis- and trans-epoxides and tolerates various functional groups. In the case
      of trans-phenyl epoxide, the reaction led to an addition product via a 6-endo
      attack of epoxide by the tungsten fragment. This method provides a simple
      enantiospecific synthesis of complex bicyclic lactones if a chiral epoxide is
      used in the cyclization. It is also applicable to the one-pot synthesis of
      bicyclic unsaturated gamma-lactones if a suitable alkynyltungsten functionality
      is used.

PMID- 12608803
TI  - A short path synthesis of [13C/15N] multilabeled pyrimidine nucleosides starting
      from glucopyranose nucleosides.
AB  - The synthesis of fully [13C/15N] labeled pyrimidine nucleosides has been achieved
      from 13C-glucose and labeled nucleobases. The reaction scheme leads directly to
      the protected nucleosides without the need for the inversion of configuration of
      C-3 of 13C-glucose. This was achieved by an oxitative ring-opening reaction
      removing the carbon with the wrong configuration.

PMID- 12608806
TI  - Gauging the significance of atomic oxygen [O(3P)] in sulfoxide photochemistry. A
      method for hydrocarbon oxidation.
AB  - A liquid-phase photolysis of 1,2-benzodiphenylene sulfoxide, 1, and
      dibenzothiophene sulfoxide, 2, was used to generate atomic oxygen [O(3P)] or an
      equivalent active oxygen species. The reaction for sulfoxide photodeoxygenation
      was similar to a microwave discharge method for generating O(3P) atoms in the
      condensed phase (Zadok, E.; Rubinraut, S.; Mazur, Y. J. Org. Chem. 1987, 52, 385
      90). Sulfoxide photodeoxygenation is a potentially clean method for O(3P)
      production compared to the microwave discharge method. With Argon purging of the
      sulfoxide sample before photolysis, the method can preclude a secondary oxidation
      process involving molecular oxygen. Our study focused on the results of oxidation
      products in the reaction of styrene, 3, and on the dependence of substrates that
      provided an opportunity to vary the electronic and steric effects. The sulfoxide
      photochemistry is rationalized with the primary formation of O(3P) in which a
      charge-transfer interaction between O(3P) and substrate precedes oxidation.
      Functionalization of hydrocarbons takes place under mild photolysis conditions of
      1 and 2, which leads to an interesting possibility for the synthetic use of
      atomic oxygen, O(3P). Alkanes give principally alcohols. Alkenes give principally
      epoxides and ketones. For comparison, hydroxyl radicals are more reactive and
      less selective toward hydrocarbons compared to O(3P) atoms. On the other hand,
      O(3P) atoms balance reactivity and selectivity and involve the oxidation of inert
      alkanes typically inaccessible to peracid, dioxirane, ozone, and singlet
      molecular oxygen chemistry. The findings from this study may be useful to those
      interested in generating high-value oxygenated compounds from readily available
      petroleum components.

PMID- 12608805
TI  - Ring expansions of beta-keto lactones with zinc carbenoids: syntheses of (+)
      patulolide A and (+/-)-patulolide B.
AB  - A one-pot ring expansion/oxidation/elimination method has been developed in which
      beta-keto lactones are converted efficiently to alpha,beta-unsaturated-gamma-keto
      lactones. The reaction can be successfully applied to a variety of ring sizes.
      Alkene stereochemistry is dependent upon ring size and reaction conditions. The
      method was applied to the synthesis of (+)-patulolide A.

PMID- 12608807
TI  - Synthesis and characterization of beta-trifluoromethyl-meso
      tetraphenylporphyrins.
AB  - Beta-trifluoromethyl-meso-tetraphenylporphyrins were synthesized to investigate
      the electronic and steric effects of the trifluoromethyl groups on the
      macrocycle. Preparation of these novel porphyrins was carried out by copper
      assisted trifluoromethylation of beta-tetrabromo-meso-tetraphenylporphyrin metal
      complexes and in situ generated CF3Cu. For comparison, the beta-methyl analogues
      were also prepared. Analysis of beta-trifluoromethylporphyrins by UV-vis, NMR,
      and cyclic voltammetry (CV) showed that the electron-withdrawing effects of the
      trifluoromethyl groups on the antipodal pyrroles required the macrocycle to take
      a fixed 18pi-electron pathway. UV-vis, CV, and molecular modeling studies suggest
      that the novel porphyrins are distorted following introduction of trifluoromethyl
      groups onto the pyrrolic beta-position of meso-tetraphenylporphyrin. The pK(a)
      difference of beta-tetrakis(trifluoromethyl)-meso-tetraphenylporphyrin from that
      of DBU in CH2Cl2, obtained by spectrophotometric titration, affirms that it is
      one of the most electron-deficient porphyrins so far prepared.

PMID- 12608808
TI  - Generation of chiral boron enolates by rhodium-catalyzed asymmetric 1,4-addition
      of 9-aryl-9-borabicyclo[3.3.1]nonanes (B-Ar-9BBN) to alpha,beta-unsaturated
      ketones.
AB  - Asymmetric 1,4-addition of 9-phenyl-9-borabicyclo[3.3.1]nonane (2m) to 2
      cyclohexenone (1a) proceeded with high enantioselectivity in toluene at 80
      degrees C in the presence of 3 mol % of a rhodium catalyst generated from
      [Rh(OMe)(cod)]2 and (S)-binap to give a high yield of boron enolate (S)-3am,
      which is 98% enantiomerically pure. Reaction of the boron enolate 3am with
      electrophiles, methanol-d, propanal, and allyl bromide, gave the corresponding 2
      substituted (3S)-3-phenylcyclohexanones with perfect regio- and
      diastereoselectivity.

PMID- 12608809
TI  - The pK(a) of the internucleotidic 2'-hydroxyl group in diribonucleoside (3'-->5')
      monophosphates.
AB  - Ionization of the internucleotidic 2'-hydroxyl group in RNA facilitates
      transesterification reactions in Group I and II introns (splicing), hammerhead
      and hairpin ribozymes, self-cleavage in lariat-RNA, and leadzymes and tRNA
      processing by RNase P RNA, as well as in some RNA cleavage reactions promoted by
      ribonucleases. Earlier, the pK(a) of 2'-OH in mono- and diribonucleoside (3'-
      >5') monophosphates had been measured under various nonuniform conditions, which
      make their comparison difficult. This work overcomes this limitation by measuring
      the pK(a) values for internucleotidic 2'-OH of eight different diribonucleoside
      (3'-->5') monophosphates under a set of uniform noninvasive conditions by 1H NMR.
      Thus the pK(a) is 12.31 (+/-0.02) for ApG and 12.41 (+/-0.04) for ApA, 12.73 (+/
      0.04) for GpG and 12.71 (+/-0.08) for GpA, 12.77 (+/-0.03) for CpG and 12.88 (+/
      0.02) for CpA, and 12.76 (+/-0.03) for UpG and 12.70 (+/-0.03) for UpA. By
      comparing the pK(a)s of the respective 2'-OH of monomeric nucleoside 3'-ethyl
      phosphates with that of internucleotidic 2'-OH in corresponding diribonucleoside
      (3'-->5') monophosphates, it has been confirmed that the aglycons have no
      significant effect on the pK(a) values of their 2'-OH under our measurement
      condition, except for the internucleotidic 2'-OH of 9-adeninyl nucleotide at the
      5'-end (ApA and ApG), which is more acidic by 0.3-0.4 pK(a) units.

PMID- 12608810
TI  - Aromatic allylation via diazotization: variation of the allylic moiety and a
      short route to a benzazepine derivative.
AB  - A continued study of the recently discovered diazotizative allylation (DiazAll)
      reaction of aniline derivatives is reported. Several allyl reagents, commonly
      used in radical allylation reactions, were evaluated, and some of these reagents
      resulted in allylation when used in the DiazAll reaction. The best result was
      obtained with allyl bromide. Substituted allylic bromides gave the corresponding
      allyl aromatic compounds in poor to excellent yields. In comparison with an
      established method for aromatic allylation, the DiazAll reaction performed well
      and was superior when a more complex allylic bromide was used. Finally, a new
      allylation-bromocyclization reaction was demonstrated and used in the synthesis
      of a known inhibitor of phenylethanolamine N-methyltransferase (PNMT), an enzyme
      involved in the biosynthesis of adrenaline.

PMID- 12608811
TI  - Enantioselective synthesis of piperidine, indolizidine, and quinolizidine
      alkaloids from a phenylglycinol-derived delta-lactam.
AB  - Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H
      oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of
      2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The
      potential of this approach is illustrated by the synthesis of the piperidine
      alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)
      solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and
      (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.

PMID- 12608812
TI  - Rearrangement of 5-trimethylsilylthebaine on treatment with L-selectride: an
      efficient synthesis of (+)-bractazonine.
AB  - Treatment of 5-trimethylsilylthebaine with L-Selectride gave rise to a
      rearrangement to 10-trimethylsilylbractazonine through migration of the phenyl
      group, whereas treatment of thebaine with strong Lewis acids is known to lead to
      a similar rearrangement through migration of the alkyl bridge to give, after
      reduction, (+)-neodihydrothebaine. It is suggested that the rearrangement of the
      alkyl group of thebaine is favored due to the formation of a tertiary benzylic
      cation. However, for 5-trimethylsilylthebaine, the lithium ion of L-Selectride
      acts as the Lewis acid and the beta-silyl effect dominates in the stabilization
      of any positive charge. This rearrangement provides a clear example of the
      greater relative migratory aptitude of phenyl groups over alkyl groups, and
      provides an efficient synthesis of (+)-bractazonine from thebaine.

PMID- 12608813
TI  - UV band Splitting of chromogenic azo-coupled calix[4]crown upon cation
      complexation.
AB  - Calixcrown-6 compounds carrying a pair of phenylazo moieties on the upper rim and
      two OH groups, one OH group, and two OR groups on the lower rim have been
      prepared in both the cone and partial cone conformations. UV/vis spectral
      measurements showed a red shift upon the addition of Ca2+ to the calixcrown
      carrying two OH groups and a blue shift for the calixcrown carrying two OR
      groups. For the compounds with two OR groups on the lower rim and a fixed partial
      cone conformation, a blue shift caused by electrostatic interaction between the
      oxygen atoms of OR and the metal ion as well as a red shift caused by the pi
      metal complexation between the rotated calix benzene and the metal ion were
      observed.

PMID- 12608814
TI  - Cyclic allene intermediates in intramolecular dehydro Diels-Alder reactions:
      labeling and theoretical cycloaromatization studies.
AB  - A comprehensive theoretical and experimental investigation of dehydro Diels-Alder
      reactions examining the evolution of the cyclic allene intermediates under
      conditions for intramolecular and ionic and radical intermolecular
      cycloaromatization processes is reported. Theoretical calculations showed that
      the most favored intramolecular path for cycloaromatization of 1,2,4
      cyclohexatriene 4 and its benzoannulated derivative 14, strained cyclic allenes,
      consists of a pair of successive [1,2] H shifts rather than a [1,5] shift.
      Cycloaromatization of cyclic allenes may follow both inter- and intramolecular
      pathways, depending on the experimental conditions (use of protic or aprotic
      solvents). For synthetic purposes, the best procedure is to use a protic solvent
      to promote the ionic intermolecular route, the fastest and highest yielding. When
      the reaction is carried out in CCl4, intermolecular radical addition of chlorine
      to the cyclic allene competes with intramolecular aromatization paths.
      Theoretical calculations predict a low barrier for the reaction of cyclic allenes
      with carbon tetrachloride, and that the cyclic allenes act as nucleophiles in
      this reaction.

PMID- 12608815
TI  - Expeditious synthesis of new 1,2,3-thiadiazoles and 1,2,3-selenadiazoles from 1,2
      diaza-1,3-butadienes via Hurd-Mori-type reactions.
AB  - Alpha-substituted hydrazones obtained from 1,2-diaza-1,3-butadienes and
      methylenic or methinic activated substrates gave rise to a wide range of cyclic
      compounds. In particular, in the presence of thionyl chloride as solvent-reagent,
      they were transformed into 1,2,3-thiadiazoles,(1) with selenium oxychloride in
      new 4-substituted 2,3-dihydro-1,2,3-selenadiazoles, while with selenium dioxide,
      they were transformed into 4-substituted 1,2,3-selenadiazoles. We have also
      examined the nucleophilic behavior of 1,2,3-thiadiazole 4a in the reaction with
      1,2-diaza-1,3-butadienes that produced, under basic conditions, 4-hydrazono-1
      (1,2,3-thiadiazolyl)pentane derivatives. This event represents an interesting
      example of stereoselective synthesis because it leads exclusively to the
      formation of the RR/SS racemic mixture. These latter compounds, treated with
      thionyl chloride, gave the corresponding 1,3-di-1,2,3-thiadiazolylpropane
      derivatives, while with sodium methoxide they afforded 1,2,3-thiadiazolyl-2-oxo
      2,3-dihydro-1H-pyrrole systems.

PMID- 12608816
TI  - Dual nucleophilic catalysis with DABCO for the N-methylation of indoles.
AB  - DABCO is an extremely active catalyst for the methylation of indoles in
      conjunction with dimethyl carbonate (DMC). This green chemistry is highly
      effective and produces N-methylindoles in nearly quantitative yields. The
      reaction sequence consists of competing alkylation and acylation pathways and
      involves 1,4-diazabicyclo[2.2.2]octane (DABCO) dually as a nucleophilic catalyst,
      ultimately resulting in a single product: the N-methylated indole.

PMID- 12608817
TI  - Studies on hydrozirconation of 1-alkynyl sulfoxides or sulfones and the
      application for the synthesis of stereodefined vinyl sulfoxides or sulfones.
AB  - The hydrozirconation reaction of 1-alkynyl sulfoxides or sulfones with Cp2Zr(H)Cl
      in THF at room temperature predominantly gave Z-beta-zirconated vinyl sulfoxides
      or sulfones with excellent regioselectivity. Compared with 1-alkynyl sulfoxides,
      the hydrozirconation reaction of 1-alkynyl sulfones exhibits great synthetic
      potential, leading to the efficient preparation of Z-beta-halovinyl sulfones, Z
      beta-sulfonyl alpha,beta-unsaturated ketones, and Z-beta-alkynyl vinyl sulfones.
      Although the reaction mechanisms are still not clear, the neighboring group
      participation of the sulfinyl or sulfonyl group may be playing an important role
      in this unique hydrozirconation reaction.

PMID- 12608818
TI  - Photoenolization as a means to release alcohols.
AB  - We have designed molecules which release alcohols upon exposure to UV light
      independent of the reaction media, making it possible to liberate alcohols in a
      controlled manner in applications. Photolysis of 2-(2-isopropylbenzoyl)benzoate
      ester derivatives 4 in various solvents and in thin films results in the
      liberation of the alcohol moiety from the ester. The reaction mechanism for the
      release of the alcohol has been elucidated by time-resolved laser flash
      photolysis. Upon irradiation the triplet excited state of ketone, 4 is formed,
      and its lifetime can be estimated to be between 0.08 and 0.8 ns. The triplet
      excited state decays by efficient intramolecular H-atom abstraction to form a 1,4
      biradical, 8, that has a lifetime of less than 17 ns and is trapped by molecular
      oxygen. In the absence of oxygen, biradical 8 intersystem crosses to form
      photoenols (Z)-9 and (E)-10 in a ratio of 5:2, respectively. Photoenol (Z)-9 has
      a lifetime of approximately 3000 ns in protic solvents and returns to the
      starting material through 1,5 intramolecular hydrogen transfer. The other isomer,
      (E)-10, is much longer lived (>1 ms) and releases the alcohol moiety through an
      intramolecular lactonization.

PMID- 12608819
TI  - Catalysis of the Michael addition reaction by late transition metal complexes of
      BINOL-derived salens.
AB  - Salen metal complexes incorporating two chiral BINOL moieties have been
      synthesized and characterized by X-ray crystallography. The X-ray structures show
      that this new class of Ni-BINOL-salen catalysts contains an unoccupied apical
      site for potential coordination of an electrophile and naphthoxides that are
      independent from the Lewis acid center. These characteristics allow independent
      alteration of the Lewis acidic and Bronsted basic sites. These unique complexes
      have been shown to catalyze the Michael reaction of dibenzyl malonate and
      cyclohexenone with good selectivity (up to 90% ee) and moderate yield (up to 79%
      yield). These catalysts are also effective in the Michael reaction between other
      enones and malonates. Kinetic data show that the reaction is first order in the
      Ni*Cs-BINOL-salen catalyst. Further experiments probed the reactivity of the
      individual Lewis acid and Bronsted base components of the catalyst and
      established that both moieties are essential for asymmetric catalysis. All told,
      the data support a bifunctional activation pathway in which the apical Ni site of
      the Ni*Cs-BINOL-salen activates the enone and the naphthoxide base activates the
      malonate.

PMID- 12608820
TI  - Development and conformational analysis of a pseudoproline-containing turn mimic.
AB  - The liquid-phase synthesis and the conformational analysis of a small library of
      fully protected tetramers containing L-pyroglutamic acid (L-pGlu), (4S,5R)-4
      methyl-5-carboxybenzyloxazolidin-2-one (L-Oxd), or (4R,5S)-4-methyl-5
      carboxybenzyloxazolidin-2-one (D-Oxd) as residue i + 1 are reported to test the
      tendency of these oligomers to assume a -hairpin conformation. The most promising
      molecule is Boc-L-Val-D-Oxd-Gly-L-Ala-OBn, which assumes a preferential -turn
      conformation in CDCl3, as shown by IR and 1H NMR analysis. These findings have
      been confirmed by DFT calculations, which provide an interpretation for the
      available experimental data and agree with the reported observations.

PMID- 12608821
TI  - Complete control of regioselectivity in the intramolecular [2 + 2]
      photocycloaddition of 2-alkenyl-3(2H)-furanones by the length of the side chain.
AB  - The 2-(omega-alkenyl)-substituted 2-methyl-3(2H)-furanones 2a and 2b were
      prepared from biacetyl (3) in four reaction steps and in overall yields of 20%
      and 21%, respectively. They underwent a clean intramolecular [2 + 2]
      photocycloaddition upon irradiation at lambda = 350 nm. Whereas compound 2a
      reacted in the expected manner and yielded 7-oxabicyclo[3.2.1.0(3,6)]octane 7
      (87% yield), the regioselectivity in the photocycloaddition of compound 2b was
      completely reversed. The reaction led to compound 8 (92% yield) with the unusual
      9-oxabicyclo[4.2.1.0(3,8)]nonane skeleton, the structure of which was established
      by single-crystal X-ray crystallography.

PMID- 12608822
TI  - Kinetic isotope effect evidence for a concerted hydrogen transfer mechanism in
      transfer hydrogenations catalyzed by [p-(Me2CH)C6H4Me]Ru- (NHCHPhCHPhNSO2C6H4-p
      CH3).
AB  - The isotope effects in the reaction of [p-(Me2CH)C6H4Me]Ru(NHCHPhCHPhNSO2C6H4-p
      CH3) (1) with isopropyl alcohol were 1.79 for transfer of hydrogen from OH to N
      and 2.86 for transfer from CH to Ru. The isotope effect for transfer of deuterium
      from doubly labeled material (kCHOH/kCDOD = 4.88) was within experimental error
      of the product of the two individual isotope effects. These isotope effects
      provide convincing evidence for a mechanism involving concurrent transfer of
      hydrogen from oxygen to nitrogen and from carbon to ruthenium.

PMID- 12608823
TI  - Two novel cytotoxic cyclodepsipeptides from a mycoparasitic Cladobotryum sp.
AB  - Two novel cyclodepsipeptides (1 and 2) along with three known compounds (3-5)
      were isolated from a New Zealand isolate of a Cladobotryum sp. The structures of
      1 and 2 were elucidated from NMR and HRESIMS experiments, and the absolute
      stereochemistry of 2 was established by X-ray crystallography and chemical
      degradation. Compounds 1 and 2 were both cytotoxic against murine P388 leukemia
      cells.

PMID- 12608824
TI  - Stereoselective synthesis of 1'-C-branched arabinofuranosyl nucleosides via
      anomeric radicals generated by 1,2-acyloxy migration.
AB  - Stereoselective C-C bond formation at the anomeric position of uracil and adenine
      nucleoside has been accomplished through reaction of the anomeric radical,
      generated by 1,2-acyloxy migration, with a radical acceptor. The present method
      consists of the following steps: (1) electrophilic addition (bromo
      pivaloyloxylation) to 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)
      protected 1',2'-unsaturated nucleoside, (2) tin radical-mediated reaction of the
      resulting adduct with a radical acceptor. The use of allyl(tributyl)tin gave the
      1'-C-allylated uracil nucleoside 14 in 66% yield together with the unrearranged
      2'-C-allylated product 15 (6%). Radical acceptors such as styryl(tributyl)tin and
      3-bromo-2-methylacrylonitrile can also be used in the reaction of 5, giving 16
      (70%) and 17 (76%) without the formation of unrearranged product. The radical
      mediated C-C bond formation of the adenine counterpart 12 was also investigated.

PMID- 12608825
TI  - Practical and high-yield syntheses of dihydromorphine from tetrahydrothebaine and
      efficient syntheses of (8S)-8-bromomorphide.
AB  - A practical method for the conversion of tetrahydrothebaine to dihydromorphine in
      92% yield is described. The procedure should allow more efficient production of
      opium products and may be easily modified for large-scale synthesis. The
      conversion of codeine to (8S)-8-bromomorphide, a potentially valuable
      intermediate to 6-demethoxyoripavine and derivatives, is also described. The
      absolute configuration of (8S)-8-bromomorphide was determined by a single-crystal
      X-ray diffraction study of the hydrobromide salt.

PMID- 12608826
TI  - Brocaenols A-C: novel polyketides from a marine derived Penicillium brocae.
AB  - Chemical investigation of a Penicillium brocae, obtained from a tissue sample of
      a Fijian Zyzyya sp. sponge, yielded two known diketopiperazines and three novel
      cytotoxic polyketides, brocaenols A-C. The brocaenols contain an unusual enolized
      oxepine lactone ring system that to the best of our knowledge is unprecedented in
      the literature. The structures were elucidated by using 2D-NMR methods including
      an INADEQUATE experiment. The absolute stereochemistry of brocaenol A was
      established by using a modified Mosher method. The taxonomy of the producing
      fungus was elucidated by using both morphological and rDNA sequence analysis.

PMID- 12608827
TI  - Highly efficient deprotection of aromatic acetals under neutral conditions using
      beta-cyclodextrin in water.
AB  - Aromatic acetals have been deprotected to the corresponding aldehydes under
      biomimetic conditions for the first time using beta-cyclodextrin in water under
      neutral conditions, thereby overcoming many of the drawbacks associated with
      earlier methodologies. This method, apart from being simple with regard to
      recycling of the catalyst, also has the potential for industrial applications.

PMID- 12608828
TI  - Increased polymer length of oligopeptide-substituted polynorbornenes with LiCl.
AB  - The ring-opening metathesis polymerization (ROMP) reaction is extraordinarily
      useful for the preparation of a large variety of polymers. We report that the
      length (n = 25-50) of high-substituent-density oligopeptide polymers synthesized
      by ROMP is dramatically improved upon addition of LiCl to reduce polymer and
      oligopeptide aggregation. This methodology should significantly expand the
      variety of polymers that may be prepared by ROMP and be of general use with
      norbornyl oligopeptides of any sequence.

PMID- 12608829
TI  - Stereospecific synthesis of polyfunctionalized carbacephams induced by
      titanocene(III) chloride.
AB  - Enantiomerically pure N-substituted epoxyalkene-2-azetidinones reacted with
      titanocene monochloride to give stereospecifically polyfunctionalized bicyclic
      beta-lactams. Four isomeric epoxyaldehydes 2 reacted with TiCp2Cl to give
      exclusively the respective carbacephams 7 while under the same reaction
      conditions the epoxyesters 1, which are more hindered for an intramolecular
      addition, gave the cyclization products 6 (only two isomers) and/or the
      elimination products 5 (all isomers).

PMID- 12608830
TI  - Aminoalkoxide-mediated formation and stabilization of phenylpyridyllithium:
      straightforward access to phenylpyridine derivatives.
AB  - It is shown that lithium aggregates promoted the efficient metalation of
      phenylpyridines and stabilization of phenylpyridyllithium. The BuLi-LiDMAE
      superbase prevented dimerization or nucleophilic addition encountered with t-BuLi
      or n-BuLi. The reported selective pyridine ring lithiation of 2-, 3-, and 4
      phenylpyridine alpha to nitrogen opens a straightforward access to their
      derivatives.

PMID- 12608831
TI  - ortho-metalation of unprotected 3-bromo and 3-chlorobenzoic acids with hindered
      lithium dialkylamides.
AB  - Upon treatment of 3-chloro/bromobenzoic acids with hindered lithium dialkylamides
      (LDA or LTMP) at -50 degrees C, lithium 3-chloro/bromo-2-lithiobenzoates are
      generated. These dianions can be trapped as such to afford after electrophilic
      quenching a variety of simple 2-substituted-3-chloro/bromobenzoic acids. The 3
      bromo-2-lithiobenzoate is less stable than the corresponding 3-chloro derivative
      and partly eliminates lithium bromide, thus setting free lithium 2,3- and 3,4
      dehydrobenzoates that can be intercepted in situ with the hindered base.

PMID- 12608832
TI  - Asymmetric synthesis of highly substituted beta-nitro alcohols and
      enantiomerically enriched 4,4,5-trisubstituted oxazolidinones.
AB  - It is demonstrated that alpha,alpha-disubstituted-alpha-nitroketones are reduced
      to the corresponding trisubstituted nitro alcohols in good to excellent yield and
      enantiomeric excess by borane-dimethyl sulfide in the presence of a chiral
      oxazaborolidine catalyst. Reduction of the nitro alcohols to the corresponding
      amino alcohols and their subsequent conversion to enantiomerically enriched 4,4,5
      trisubstituted oxazoldinones is also reported.

PMID- 12608833
TI  - A practical route to 3'-amino-3'-deoxyadenosine derivatives and puromycin
      analogues.
AB  - 3'-aminoacylamino-3'-deoxyadenosines, analogues of the antibiotic puromycin, have
      been synthesized from adenosine. They key 3'-azido derivative 10 was obtained
      through a 3'-oxidation/reduction/substitution procedure. A modified purification
      protocol on a larger scale was developed for the oxidation step using the Garegg
      reagent. The coupling reaction between an Fmoc-l-amino acid and the fully
      protected form of 3'-amino-3'-deoxyadenosine 11 furnished the aminoacylated
      compounds 12 in high yields. The puromycin analogues were obtained in 10 steps
      and up to 23% (14c) overall yield.

PMID- 12608834
TI  - One-step highly diastereoselective synthesis of gamma-aminoalkyl-substituted
      gamma-butyrolactones by an asymmetric samarium-mediated ketyl-alkene coupling
      reaction.
AB  - The samarium(II) iodide mediated reaction of N,N-dibenzyl-protected (S)-alpha
      amino aldehydes with (1S,2R)-N-methylephedrinyl acrylate gave the (4R,1'S)-gamma
      (aminoalkyl)-gamma-butyrolactones in good yields with high diastereoselectivities
      (up to 80% de); (4R,1'S)-gamma-amino-(2-phenylethyl)-gamma-butyrolactone (6a),
      which should be a potent precursor for gamma-secretase inhibitors, was obtained
      with high de value.

PMID- 12608835
TI  - N-arylation of aziridines.
AB  - A range of N-arylaziridines were prepared by the palladium or copper catalyzed
      amination reaction between N-H aziridines and aryl bromides or arylboronic acids.
      These results showcase the synthetic utility of metal-bound aziridine species in
      nitrogen transfer processes.

PMID- 12608836
TI  - First synthesis of methylated hypocrellin and its fluorescent excited state: a
      cautionary tale.
AB  - Methylated hypocrellins were obtained and characterized by satisfactory 1HNMR, UV
      vis, IR, and mass data, and their absorption and fluorescence emission spectra
      were studied. A previous report of methylated hypocrellin (J. Phys. Chem. A 1999,
      103, 7949) appears to be in error.

PMID- 12608837
TI  - Practical synthesis and elaboration of methyl 7-chloroindole-4-carboxylate.
AB  - A synthesis of a previously unknown indole derivative is presented. The route
      reported herein allows for the preparation of multihundred gram quantities of
      material without any chromatographic purification. Conditions are presented for
      the Pd-catalyzed elaboration of one of the "diversity generating elements" of
      this important pharmacophore.

PMID- 12608838
TI  - Preparation of nitrogen-containing pi-deficient heteroaromatic Grignard reagents:
      oxidative magnesiation of nitrogen-containing pi-deficient
      halogenoheteroaromatics using active magnesium.
AB  - The oxidative magnesiation of nitrogen-containing pi-deficient
      halogenoheteroaromatics using active magnesium was accomplished. Both
      magnesiation followed by addition of a carbonyl compound (Grignard reaction) and
      magnesiation in the presence of a carbonyl compound (Barbier reaction) were
      carried out to afford the corresponding product. Especially, the latter method
      enabled fused halogenodiazines such as 4-chloro-1-phenyl-1H-pyrazolo[3,4
      d]pyrimidine or 2-chloroquinoxaline to magnesiate at a mild temperature (-20 to
      30 degrees C).

PMID- 12608839
TI  - Mild oxidation of alcohols with o-iodoxybenzoic acid (IBX) in water/acetone
      mixture in the presence of beta-cyclodextrin.
AB  - A mild and efficient oxidation of alcohols with o-iodoxybenzoic acid (IBX)
      catalyzed by beta-cyclodextrin in a water/acetone mixture (86:14) has been
      developed. A series of alcohols were oxidized at room temperature in excellent
      yields.

PMID- 12608845
TI  - New flavans, spirostanol sapogenins, and a pregnane genin from Tupistra chinensis
      and their cytotoxicity.
AB  - Seven new compounds, including three new flavans [tupichinol A-C (1-3)], three
      new spirostanol sapogenins [tupichigenin D-F (4-6)], and one new pregnane genin
      [tupipregnenolone (7)], together with 18 known compounds, were isolated from the
      underground parts of Tupistra chinensis. The structures of the new compounds were
      elucidated by spectroscopic analysis and chemical evidence. The structures and
      relative stereochemistry of 1 and 9 were further confirmed by single-crystal X
      ray crystallographic analysis. Compounds Delta(25(27))-pentrogenin, 10, and
      ranmogenin A showed 100%, 96%, and 80% inhibition, respectively, against human
      gastric tumor (NUGC) cells at a concentration of 50 microM. Delta(25(27))
      pentrogenin showed 100% inhibition against human nasopharyngeal carcinoma (HONE
      1) cells at a concentration of 50 microM.

PMID- 12608844
TI  - Oxygenated analogues of gorgosterol and ergosterol from the soft coral Capnella
      lacertiliensis.
AB  - From the dichloromethane solubles of Capnella lacertiliensis five new sterols
      were isolated that are highly functionalized with oxygen-containing substituents:
      12beta-acetoxy-7alpha-hydroxygorgosterol (1), 12beta-acetoxy-7alpha,19
      dihydroxygorgosterol (2), 12beta-acetoxyergost-5-ene-3beta,23-diol (4), 12beta
      acetoxyergost-5-ene-3beta,11beta,16-triol (5), and 11beta-acetoxyergost-5-ene
      3beta,12beta,16-triol (6). The structures of all compounds were deduced from
      interpretation of their spectroscopic data, mainly 1D and 2D NMR spectra and
      HREIMS. Biological activities of the isolates were assessed, and all were found
      to be weakly antifungal. Compounds 5 and 6 were also found to have weak tyrosine
      kinase p56(lck)() (TK) inhibitory activity at the 200 microgram/mL level.

PMID- 12608846
TI  - Synthesis and structure-phytotoxicity relationships of acetylenic phenols and
      chromene metabolites, and their analogues, from the grapevine pathogen Eutypa
      lata.
AB  - Eutypa lata, the fungus responsible for dying-arm disease in grapevines, produces
      a number of structurally related secondary metabolites, of which eutypine (1) has
      been implicated as the principal phytotoxin. However, analysis of an E. lata
      strain from California known to be pathogenic to grapevines showed that eutypine
      was not present, suggesting that other metabolites could be phytotoxic.
      Investigation of the relative phytotoxicities of individual metabolites has been
      limited by insufficient material and lack of a reliable bioassay. Metabolites of
      particular interest and their precursors were therefore synthesized, and a rapid,
      quantitative bioassay via topical application of individual compounds to disks of
      grape leaves and measurement of chlorophyll loss was developed to provide a
      relative measure of tissue damage. The recently reported metabolite
      eulatachromene (2) was found to have phytotoxicity greater than that of eutypine
      (1). The cyclization product, 5-formyl-2-methylvinyl[1]benzofuran (3), also
      showed significant activity, whereas the reduction product, eutypinol (4), was
      inactive, as was the quinol, siccayne (5). These results indicate that before
      strains of Eutypa are incriminated as pathogenic they must be analyzed for the
      presence or absence of specific constituents for which the phytotoxicity has been
      unequivocally established.

PMID- 12608847
TI  - Variation in the alkaloids among indo-pacific Leucetta sponges.
AB  - Nine different Indo-Pacific collections of calcareous Leucetta sp. sponges were
      investigated for variation in their alkaloid constituents. These alkaloids
      consisted of 2-amino imidazoles such as dorimidazole A (1) and a polyunsaturated
      fatty amino alcohol (PUFAA), leucettamol A (3). The nine Leucetta species were
      divided into five different groups based on taxonomy. Significantly, six
      specimens contained leucettamol A (3), while the other three contained
      imidazoles, and these two classes of alkaloids did not occur in the same sponge
      sample. We recently found a Fijian Leucetta sponge that was a source of
      spirocyclopentimidazolidins, including spirocalcaridine A (4). We now show that
      another Fijian collection affords three amino imidazoles consisting of the known
      alkaloid naamine A (6) plus two new structures, N,N-dimethyl naamine D (5) and
      leucettamine C (7).

PMID- 12608848
TI  - Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues.
AB  - The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural
      analogues have been synthesized and evaluated in cell-based assays for both
      cytotoxic and antimitotic activity in order to explore the SAR for this promising
      anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent in
      vitro cytotoxicty and antimitotic activity than the natural product hemiasterlin
      (1), and consequently it has been subjected to thorough preclinical evaluation
      and targeted for clinical evaluation. The details of the synthesis of
      hemiasterlin (1) and the analogues and a discussion of how their biological
      activities vary with their structures are presented in this paper.

PMID- 12608849
TI  - Chemical constituents of Garcinia fusca: structure elucidation of eight new
      xanthones and their cancer chemopreventive activity.
AB  - We describe the isolation and spectrometric structure elucidation of eight new
      xanthones, fuscaxanthone A (1), B (2), C (3), D (4), E (5), F (6), G (7), and H
      (8), together with eight known xanthones from the stem bark of Garcinia fusca
      collected in Thailand. All the new xanthones were shown to have a terpenoid
      (prenyl and/or geranyl) side chain(s) in their molecules. We also present the
      results of a primary screening of the inhibitory effects of eight xanthones (9
      16) isolated as major components of this plant on 12-O-tetradecanoylphorbol-13
      acetate induced Epstein-Barr virus early antigen activation in Raji cells.

PMID- 12608851
TI  - Six new isoflavones and a 5-deoxyflavonol glycoside from the leaves of
      Ateleiaherbert-smithii.
AB  - Six new isoflavones, 5-methoxy-6,7:3',4'-bis(methylenedioxy)isoflavone (1), 3'
      methoxy-6,7:4',5'-bis(methylenedioxy)isoflavone (2), 5,2'-dimethoxy-6,7:4',5'
      bis(methylenedioxy)isoflavone (3), 5,3'-dimethoxy-6,7:4',5'
      bis(methylenedioxy)isoflavone (4), 5-hydroxy-7,3',4'-trimethoxyisoflavone (5),
      and 5,6,7,3',4'-pentamethoxyisoflavone (6), were obtained from diethyl ether
      extracts of the leaves of Ateleia herbert-smithii together with 11 known
      isoflavones and two chalcones. Four of the isoflavones (1-4) are characterized by
      a unique bis-methylenedioxyl substitution pattern. A new flavonol glycoside, 5
      deoxyisorhamnetin 3-O-alpha-l-rhamnopyranosyl(1' " --> 6' ')-beta-d
      glucopyranoside (20), and three known flavonol 3-O-glycosides were obtained from
      aqueous methanol extracts of leaves of the same species. Spectroscopic methods
      were used to determine the structures of the compounds. The significance of their
      occurrence in A. herbert-smithii is discussed from both biosynthetic and
      taxonomic viewpoints.

PMID- 12608850
TI  - Polyprenylated benzophenones from Garcinia assigu and their potential cancer
      chemopreventive activities.
AB  - In a further study on the chemical constituents of Garcinia assigu, two new
      benzophenones corresponding to the 13-O-methyl ethers (1 and 2) of the known
      isogarcinol and garcinol, respectively, were isolated and characterized, along
      with known benzophenones (3-6). Inhibitory effects of the benzophenones isolated
      from this plant on Epstein-Barr virus early antigen (EBV-EA) activation induced
      by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and their radical
      scavenging ability against 1,1-diphenyl-2-picrylhydrazyl (DPPH) were
      demonstrated. The cyclized polyprenylbenzophenones (1-5) showed comparable or
      stronger potential cancer chemopreventive activity when compared to glycyrrhetic
      acid, a known anti-tumor promoter.

PMID- 12608852
TI  - Diverse secondary metabolites from a Puerto Rican collection of Lyngbyamajuscula.
AB  - Extensive fractionation of the crude organic extract from a Puerto Rican
      collection of Lyngbya majuscula led to the discovery of three new secondary
      metabolites: a quinoline alkaloid (1), malyngamide T (2), and a tryptophan
      derivative (3). In addition, several previously reported compounds, including the
      potent neurotoxins antillatoxin, antillatoxin B, and kalkitoxin, were identified.
      The structures of 1, 2, and 3 were deduced by NMR and mass spectral data
      interpretation and suggest the existence of a convergent biosynthetic pathway for
      these new and unusual metabolites.

PMID- 12608853
TI  - Calmodulin inhibitors from Leucophyllum ambiguum.
AB  - Activity-directed fractionation of a CH(2)Cl(2)-MeOH (1:1) extract of
      Leucophyllum ambiguum led to the isolation of two new lignans designated with the
      trivial names of 2'-methoxykobusin (1) and 2'-methoxy-4' '
      hydroxydemethoxykobusin (2). In addition, the known compounds kobusin (3), 2',2'
      '-dimethoxysesamin (4), trans-cinnamic acid, apigenin, and apigetrin were
      obtained. The identification of the novel analogues 1 and 2 was accomplished by
      spectral methods. The structure of 1 was unequivocally confirmed by X-ray
      analysis. Compounds 1-4 interacted with bovine-brain calmodulin and inhibited the
      activation of the calmodulin-dependent enzyme cAMP phosphodiesterase.

PMID- 12608854
TI  - New oplopane and eremophilane derivatives from Robinsonecio gerberifolius.
AB  - A phytochemical study of Robinsonecio gerberifolius afforded six new
      sesquiterpenoids, two oplopane (1and 2) and four eremophilane derivatives (3-6).
      The structures of these compounds were elucidated on spectroscopic grounds, and
      the absolute configurations of compounds 3 and 4 were established from CD
      analysis. The known 3beta-angeloyloxy-1,10-epoxyfuranoeremophilane (7) was also
      isolated, and its stereochemistry was revised. The cytotoxic activities of
      compounds 1-7 were determined against five human cancer cell lines.

PMID- 12608856
TI  - Bufadienolide and spirostanol glycosides from the rhizomes of
      helleborusorientalis.
AB  - The rhizomes of Helleborus orientalis have been analyzed for the bufadienolide
      glycoside and spirostanol saponin constituents, resulting in the isolation of a
      new bufadienolide rhamnoside (1), along with two known bufadienolide glycosides
      (2 and 3) and five new spirostanol saponins (4-8). The structures of the new
      compounds were determined on the basis of extensive spectroscopic analysis,
      including 2D NMR, and the results of hydrolytic cleavage. The isolated compounds
      were evaluated for their cytotoxic activities against cultured tumor and normal
      cells.

PMID- 12608855
TI  - Exploring sponge-derived terpenoids for their potency and selectivity against 12
      human, 15-human, and 15-soybean lipoxygenases.
AB  - To sharpen the search for new lipoxygenase inhibitors, we designed a screen to
      probe for both potency and selectivity. The assay utilized 12-human (12-HLO), 15
      human (15-HLO), and 15-soybean (15-SLO) lipoxygenases. The IC(50) value data
      obtained provided new insights about structure-activity relationships (SAR) for
      redox and nonredox inhibitors. All of the compounds tested were isolated from
      sponges and consisted of a novel terpenoid, hyrtenone A (1), and 12 known
      terpenoids. Potent compounds were defined as those having IC(50) values < 1
      microM, and selectivity was assessed from the three possible IC(50) value ratios.
      One of the four terpenoid redox inhibitors studied, puupehenone (2), was
      equivalent to or better in potency than the well-known redox inhibitor
      nordihydroguarierate acid (NDGA, 14). However, none of the terpene redox
      inhibitors exhibited a selectivity ratio on a par with that of 14. Several potent
      nonredox inhibitors were identified, and one, dimethoxypuupehenol (5), exhibited
      notable selectivity. The structural elucidation of 1 and the SAR results for 13
      natural products are reported. This study suggests that sponge-derived terpenes
      are a promising source for new lipoxygenase inhibitors.

PMID- 12608857
TI  - Antibacterial diterpenes from Calceolaria pinifolia.
AB  - Two new isopimaranes, 19-methylmalonyloxy-ent-isopimara-8(9),15-diene (5) and 19
      malonyloxy-ent-isopimara-8(9),15-diene (6), were isolated using bioassay-guided
      fractionation of the CH(2)Cl(2)-MeOH (1:1) extract of the aerial part of
      Calceolaria pinifolia along with eight other diterpenes (1-4, 7-10) and two
      triterpenes (11, 12). All compounds were assayed against Staphylococcus aureus
      (SA), methicillin-resistant S. aureus (MRSA), Bacillus subtilis (BS), and
      Escherichia coli (EC). 4-Epi-dehydroabietinol (2) and ent-isopimara-9(11),15
      diene-19-ol (8) were found to be active against MRSA with MIC values of 8 and 2
      microgram/mL, respectively. Mechanistic studies of 8 in BS suggested rapid and
      nonspecific inhibition of uptake and incorporation of radiolabeled precursors
      into DNA, RNA, and protein consistent with membrane-damaging effects in bacteria.
      Compound 8 did not afford protection against an acute infection with SA in mice.

PMID- 12608858
TI  - Bistratamides E-J, modified cyclic hexapeptides from the Philippines ascidian
      Lissoclinum bistratum.
AB  - The Philippines ascidian Lissoclinum bistratum contained the known metabolites
      bistratamides C and D, together with six novel modified cyclic hexapeptides,
      bistratamides E-J. The structures of bistratamides E-J were elucidated by
      interpretation of spectral data, and the absolute stereochemistry of the
      constituent amino acids was determined after ozonolysis and acid-catalyzed
      hydrolysis. Bistratamides E-J were moderately cytotoxic in the HCT-116 cell line
      assay.

PMID- 12608859
TI  - New cytotoxic furanosesterterpenes from an Okinawan marine sponge, Ircinia sp.
AB  - Five new sesterterpenes have been isolated from a lipophilic extract of a sponge,
      Ircinia sp., and their structures elucidated by spectroscopic and chemical
      methods. The absolute configurations of two metabolites (1, 3) were established
      by chemical degradation. These compounds showed moderate cytotoxicity against KB
      cells.

PMID- 12608860
TI  - Nitric oxide inhibitory isopimarane-type diterpenes from Orthosiphon stamineus of
      Indonesia.
AB  - A methanolic extract of Orthosiphon stamineus yielded six new highly oxygenated
      isopimarane-type diterpenes, orthosiphols U-Z (1-6), and 15 previously reported
      diterpenes. The isolated diterpenes all showed significant dose-dependent
      inhibitory effects on the nitric oxide (NO) production in lipopolysaccharide
      (LPS)-activated macrophage-like J774.1 cells. Orthosiphols A (7), B (8), D (9),
      and X (4) showed more potent inhibitory activities than a positive control, N(G)
      monomethyl-l-arginine (l-NMMA), and 1 displayed the strongest activity with an
      IC(50) value of 6.4 microM.

PMID- 12608861
TI  - Isolation and structure of palstatin from the Amazon tree Hymeneae palustris(1).
AB  - Bioassay (P388 lymphocytic leukemia cell line and human cancer cell lines) guided
      separation of an extract prepared from the leaves of Hymenaea palustris Ducke led
      to the isolation of six cancer cell growth inhibitory flavonoids (1-6). The
      structures were elucidated by HRMS and 1D and 2D NMR spectral analysis. The new
      flavonolignan 1 designated palstatin proved to be a methoxy structural
      modification of 5'-methoxyhydnocarpin-D (2). Flavones 1-4 inhibited growth of the
      pathogenic bacteria Enterococcus faecalis and/or Neisseria gonorrhoeae.

PMID- 12608863
TI  - New norditerpenoid alkaloids from Aconitum hemsleyanum var. leueanthus.
AB  - Four new norditerpenoid alkaloids, leueantines A (1), B (2), C (3), and D (4),
      were isolated from the roots of Aconitum hemsleyanum var. leueanthus. The
      structures of 1-4 were established by spectroscopic evidence.

PMID- 12608862
TI  - Natural anti-HIV agents. Part IV. Anti-HIV constituents from Vatica cinerea.
AB  - In a continuing search for anti-HIV compounds from plants of Vietnam, 19
      compounds, including a new triterpene, were isolated from an extract of the
      leaves and stem of Vatica cinerea. The new triterpene was determined to be a
      cycloartane triterpenoid with 29 skeletal carbons and was assigned the name
      vaticinone (1). The known triterpenes included three cycloartanes, a lanostane,
      two dammaranes, three lupanes, an ursane, and an oleanane. A chlorophyll isolate
      was identified as pheophorbide a (13). The majority of the triterpenes, the
      sesquiterpene, 1-hydroxycyclocolorenone, and pheophorbide a showed anti-HIV
      activity, with the chlorophyll being the most active, demonstrating an IC(50)
      value of 1.5 microgram/mL (2.5 microM), while being completely devoid of toxicity
      up to a concentration of 20 microgram/mL (33.8 microM). Vaticinone (1) was found
      to inhibit the replication of HIV-1, with an IC(50) value of 6.5 microgram/mL
      (15.3 microM; selective index = 1.4). The structures of these isolates were
      determined by spectral data including 1D and 2D NMR spectra.

PMID- 12608864
TI  - Eudistomins W and X, two new beta-carbolines from the micronesian tunicate
      Eudistoma sp.
AB  - Chemical investigation of the Micronesian ascidian Eudistoma sp. afforded two new
      eudistomin congeners, which were designated eudistomins W (1) and X (2). The
      structures of the new compounds were unambiguously established on the basis of
      NMR spectroscopic ((1)H, (13)C, COSY, (1)H detected direct, and long-range (13)C
      (1)H correlations) and mass spectrometric (EI and ESIMS) data. Compound 2
      exhibited antibiotic activity toward Bacillus subtilis, Staphyloccocus aureus,
      and Escherichia coli and was also found to be fungicidal against Candida albicans
      in an agar diffusion assay. Compound 1 was selectively active against C. albicans
      but showed no antibacterial activity.

PMID- 12608865
TI  - Antineoplastic agents. 488. Isolation and structure of yukonin from a yukon
      territory fungus.
AB  - Cancer cell line bioassay-guided separation of an extract from a Yukon Territory
      fungus resulted in the isolation of a new C(16)-terpene dilactone designated
      yukonin (1) accompanied by two previously known, structurally related
      constituents (2 and 3). The structure of each was determined by X-ray
      crystallographic analysis. Dilactone 2 was found to correspond to LL-Z1271alpha
      isolated from fungi in the genera Oidiodendron, Acrostalagmus, and Holwaya, while
      dilactone 3 had earlier been prepared by reduction of an alpha-lactol derivative.
      Each of the dilactones was found to inhibit growth of human cancer cell lines
      (pancreas, breast, CNS, lung, colon, and prostate) and some pathogenic fungi.

PMID- 12608866
TI  - A novel constituent from Rollinia mucosa, rollicosin, and a new approach to
      develop annonaceous acetogenins as potential antitumor agents.
AB  - Rollicosin (1), a new Annonaceous acetogenin, was isolated from the unripe fruits
      of Rollinia mucosa. Rollicosin (1) is the first compound of this type to contain
      lactone moieties on both sides of the aliphatic chain and to lack either
      tetrahydrofuran or tetrahydropyran rings. Its structure was determined on the
      basis of spectroscopic analyses. This compound may serve as a new prototype
      molecule to develop Annonaceous acetogenins as potential antitumor agents.

PMID- 12608867
TI  - S(R)-podolactone D, a new sulfoxide-containing norditerpene dilactone from
      Podocarpus macrophyllus var. maki.
AB  - S(R)()-Podolactone D (1), a new norditerpene dilactone having a methylsulfoxide
      moiety, was isolated from the leaves of Podocarpus macrophyllus D. Don var. maki
      Endl. along with known podolactone D (2, S(S)()-podolactone D). The structures
      and absolute configurations of compounds 1 and 2 were elucidated by spectral
      methods (HREIMS, IR, (1)H, (13)C, and 2D NMR) and finally confirmed by single
      crystal X-ray analyses. The cytotoxic effects of compounds 1 and 2 on P388 murine
      leukemia cells were also examined.

PMID- 12608868
TI  - 5-Fluorouracil derivatives from the sponge Phakellia fusca.
AB  - 5-Fluorouracil derivatives were isolated from the marine sponge Phakellia fusca
      collected around the Yongxing Island of the Xisha Islands in the South Sea of
      China. Their structures were determined on the basis of spectral analysis and X
      ray diffraction.

PMID- 12608869
TI  - Mycaperoxide H, a new cytotoxic norsesterterpene peroxide from a Thai marine
      sponge Mycale sp.
AB  - Mycaperoxide H, a new cyclic norsesterterpene peroxide, was isolated from a Thai
      marine sponge Mycalesp. The structure of mycaperoxide H was deduced by
      spectroscopic and chemical analysis. Mycaperoxide H was cytotoxic against HeLa
      cells with an IC(50) value of 0.8 microgram/mL.

PMID- 12608870
TI  - Rigidins B-D, new pyrrolopyrimidine alkaloids from a tunicate Cystodytes species.
AB  - Three new pyrrolopyrimidine alkaloids, rigidins B-D (1-3), have been isolated
      from an Okinawan marine tunicate Cystodytes sp., and the structures were
      elucidated on the basis of spectroscopic data.

PMID- 12608871
TI  - New 2'-oxygenated flavonoids from Andrographis affinis.
AB  - Three new 2'-oxygenated flavonoids, (2S)-5,7,2',3',4'-pentamethoxyflavanone (1),
      5-hydroxy-7,8,2',5'-tetramethoxyflavone (2), and echioidinin 2'-O-beta-d-(6' '-O
      acetyl) glucopyranoside (3), together with four known flavonoids, 7-O
      methyldihydrowogonin, 7-O-methylwogonin, skullcapflavone I 2'-methyl ether, and
      skullcapflavone I, and two diterpenoids, andrograpanin and 14-deoxy-11,12
      didehydroandrographolide, were isolated from the whole plant of Andrographis
      affinis. The structures were elucidated by spectral and chemical studies.

PMID- 12608872
TI  - Hemolytic steroid disulfates from the far eastern starfish Pteraster pulvillus.
AB  - Six steroidal ophiuroid-type disulfates, namely, disodium salts of (20R)-cholest
      5-ene-3alpha,4beta,21-triol 3, 21-disulfate (1), (20R)-5alpha-cholestane
      3alpha,4beta,21-triol 3,21-disulfate (2), (20R)-5alpha-cholestane-2beta,3alpha,21
      triol 3,21-disulfate (3), and (20R)-5alpha-cholestane-3alpha,21-diol 3,21
      disulfate (4), the dityrammonium salt of (20R)-5alpha-cholestane-3alpha,21-diol
      3,21-disulfate (5), and a mixture of sodium and tyrammonium salts (1:1) of (20R)
      cholest-5-ene-3alpha,21-diol 3,21-disulfate (6), have been isolated from the
      ethanolic extracts of Far Eastern starfish Pteraster pulvillus. Steroids 2 and 3
      are new compounds. Steroids 1, 2, and 4-6 showed hemolytic activity to mouse
      erythrocytes with HC(50) values of 8.0 x 10(-5), 4.5 x 10(-5), 1.0 x 10(-5), 1.8
      x 10(-5), and 3.3 x 10(-5) M, respectively.

PMID- 12608873
TI  - New briaranes from the Taiwanese gorgonian Junceella juncea.
AB  - In addition to the known junceelolide C (4), three new briaranes, juncenolides B
      (1), C (2), and D (3), have been isolated from the acetone extract of a red
      Gorgonian Junceella juncea collected in Taiwan. The structures of 1-3 were
      elucidated on the basis of FABMS and 2D NMR techniques including COSY, HMQC,
      HMBC, and NOESY experiments. Among them, compound 2 exhibited mild cytotoxicity
      against human liver carcinoma (HEPA 59T/VGH) and oral epidermoid (KB) carcinoma
      cells.

PMID- 12608874
TI  - A new 1-hydroxy-2,6-pyrazinedione associated with hypovirulent isolates of
      Sclerotinia minor.
AB  - A new 1-hydroxy-2,6-pyrazinedione, sclerominol (1), was isolated from cultures of
      hypovirulent isolates of Sclerotinia minor, a fungal plant pathogen associated
      with lettuce drop and other plant diseases. This compound was characterized by
      NMR, mass spectrometry, and X-ray crystallography. One other 1-hydroxy-2,6
      pyrazinedione, flutimide, has been reported. Flutimide has activity as an
      inhibitor of influenza virus endonuclease, and therefore, sclerominol was
      evaluated for related biological activity. Sclerominol (1) displayed some
      activity against cancer cell lines but little activity against three influenza
      virus strains. The role of 1 in the physiology of hypovirulent isolates of S.
      minor has not been determined, but 1 has also been recovered from debilitated
      isolates of S. sclerotiorum.

PMID- 12608875
TI  - Reaction of irofulven with zinc and acid.
AB  - Reaction of antitumor agent irofulven (1) with zinc and acetic acid yielded
      several new indene derivatives (6, 7, 8, 10) as well as the known indene (9).
      These all have greatly reduced toxicity to human leukemia (HL60) cells compared
      to irofulven.

PMID- 12608876
TI  - Diplopyrone, a new phytotoxic tetrahydropyranpyran-2-one produced by Diplodia
      mutila, a fungus pathogen of cork oak.
AB  - A new phytotoxic monosubstituted tetrahydropyranpyran-2-one, named diplopyrone
      (1), was isolated from the liquid culture filtrates of Diplodia mutila, a plant
      pathogenic fungus causing a form of canker disease of cork oak (Quercus suber).
      Diplopyrone was characterized, using spectroscopic and chemical methods, as 6
      [(1S)-1-hydroxyethyl]-2,4a,6,8a-tetrahydropyran[3,2-b]pyran-2-one. The absolute
      stereochemistry of the chiral secondary hydroxylated carbon (C-9), determined by
      application of Mosher's method, proved to be S. Diplopyrone assayed at a 0.01-0.1
      mg/mL concentration range caused necrosis and wilting on cork oak cuttings. On a
      nonhost plant, tomato, diplopyrone caused brown discoloration or stewing on the
      stem.

PMID- 12608877
TI  - cis-Clerodane type diterpenes from Cistus monspeliensis.
AB  - The aerial parts of Cistus monspeliensis yielded 11 cis-clerodane type
      diterpenes. Five of these, 3, 4, 8,9, and 10, are new compounds. Their structures
      have been elucidated on the basis of their spectral data (FABMS, 1D and 2D NMR).

PMID- 12608878
TI  - Two new nor-triterpene glycosides from peruvian "Una de Gato" (Uncaria
      tomentosa).
AB  - Two new 27-nor-triterpene glycosides, tomentosides A (1) and B (2), were isolated
      from Peruvian "Una de Gato" (cat's claw, plant of origin: Uncaria tomentosa), a
      traditional herbal medicine in Peru. Their structures were determined by
      spectroscopic analysis and chemical interconversions. This is the first report of
      naturally occurring pyroquinovic acid glycosides.

PMID- 12608879
TI  - Congenital hypothyroidism: a review of current diagnostic and treatment practices
      in relation to neuropsychologic outcome.
AB  - Because thyroid hormone is essential for normal brain development, children born
      with congenital hypothyroidism who lack thyroid hormone during a circumscribed
      period of early development are at risk of brain damage and mental retardation.
      Since the advent of newborn screening programs in the 1980s, the diagnosis and
      treatment of this condition are now provided in the first 2-3 weeks of birth in
      most regions. While this is usually sufficient to prevent mental retardation, the
      children so identified attain mildly reduced IQs from expectation, and may still
      experience subtle and specific neurocognitive deficits. Their particular deficits
      are related to the brief period of thyroid hormone insufficiency they undergo,
      especially factors reflecting the severity of hypothyroidism at the time of
      diagnosis, the duration of hypothyroidism in infancy, and thyroid hormones at
      time of testing. In this article, we review the specific kinds of deficits
      demonstrated by children with congenital hypothyroidism who were diagnosed by
      screening and treated early, as well as the factors associated with their disease
      and its management that contribute to these deficits. The disease-related factors
      that will be reviewed will include the etiology of hypothyroidism and severity of
      disease at the time of diagnosis, while the treatment-related factors will
      include age at onset of therapy, starting and subsequent dose levels, compliance,
      and treatment-adequacy issues. Also examined will be the effects of hormone
      levels at the time of testing. In addition, the role of moderating variables such
      as social, genetic, and environmental influences, as well as the child's gender,
      will be discussed. Furthermore, several new issues including the quality of
      subsequent management, ultimate outcome, and pregnancy will be additionally
      reviewed. In conclusion, while outcome in congenital hypothyroidism is
      substantially improved by screening, affected children do still experience mild
      neuropsychologic deficits. To reduce the impact of persisting deficits, further
      research is needed to determine the optimal starting dose for the different
      etiologies, guidelines for subsequent management, and alternative therapies.
      Moreover, now that the original samples are reaching adulthood and, in females,
      childbearing age, further research is also needed regarding treatment during
      pregnancy in women with congenital hypothyroidism, as is research to determine
      how this population ultimately fares in adulthood.

PMID- 12608880
TI  - Treatment of infectious diarrhea in children.
AB  - Diarrheal diseases remain an important cause of childhood morbidity and death in
      developing countries, although diarrheal deaths have significantly declined in
      recent years, mostly due to successes in the implementation of oral rehydration
      therapy (ORT), which is the principal treatment modality. Diarrhea may occur for
      varied reasons; however, most episodes of diarrhea in developing countries are
      infectious in origin. Three clinical forms of diarrhea (acute watery diarrhea,
      invasive diarrhea, and persistent diarrhea) have been identified to formulate a
      management plan. Acute diarrhea may be watery (where features of dehydration are
      prominent) or dysenteric (where stools contain blood and mucus). Rehydration
      therapy is the key to management of acute watery diarrhea, whereas antimicrobial
      agents play a vital role in the management of acute invasive diarrhea,
      particularly shigellosis and amebiasis. In persistent diarrhea, nutritional
      therapy, including dietary manipulations, is a very important aspect in its
      management, in addition to rehydration therapy. Rehydration may be carried out
      either by the oral or intravenous route, depending upon the degree of
      dehydration. Oral rehydration salts (ORS) solution (World Health Organization
      formula) is recommended for ORT. Intravenous fluid is recommended for initial
      management of severe dehydration due to diarrhea, followed by ORT with ORS
      solution for correction of ongoing fluid losses. Antimicrobial therapy is
      beneficial for cholera and shigellosis. Antiparasitic agents are indicated only
      if amebiasis and giardiasis are present. Appropriate feeding during diarrhea is
      recommended for nutritional recovery and to prevent bodyweight loss.
      Antidiarrheal agents do not provide additional benefit in the management of
      infectious diarrhea. Although some probiotics have been shown to be beneficial in
      the treatment of acute diarrhea due to rotavirus, their use in the treatment of
      diarrhea is yet to be recommended, even in developed countries. The children of
      developing countries might benefit from zinc supplementation during the diarrheal
      illness, but its mode of delivery and cost effectiveness are yet to be decided.

PMID- 12608881
TI  - Antithrombotic drug treatment of pediatric patients with ischemic stroke.
AB  - Causes of stroke in children include congenital heart malformations, sickle cell
      disease, infections, and metabolic disorders. Up to 80% of children with ischemic
      stroke have cerebrovascular disease, and case control studies demonstrate an
      association of ischemic stroke in children with hereditary prothrombotic risk
      factors. There have been no randomized, clinical trials for primary prevention,
      short-term treatment, or secondary prevention of pediatric ischemic stroke.
      Treatment recommendations are based on small case series or case reports, and
      have mainly been adapted from adult stroke studies. Antiplatelet agents (e.g.
      aspirin [acetylsalicylic acid]) and heparins (e.g. low molecular weight heparin),
      have been used on an individual patient basis. Warfarin is administered in
      children with cardioembolic stroke, arterial dissection, or persistent
      hypercoagulable states. Alteplase has been used in a few patients within 3 hours
      of the onset of symptoms. In each patient treated the benefit of anticoagulation
      has to be weighed up against the individual bleeding risk.

PMID- 12608882
TI  - Strategies for optimizing immunosuppression in adolescent transplant recipients:
      a focus on liver transplantation.
AB  - Adolescence is a difficult time for transplant recipients; they must learn to
      take responsibility for their own behavior and medication, and to balance their
      developing sexuality in a body that has been transformed by the adverse effects
      of immunosuppression. More than 80% of children survive transplantation to
      adolescence and adulthood, thus long-term outcome and tailoring of
      immunosuppression is of great importance. To date, the most experience with long
      term immunosuppression regimens is cyclosporine, which is well tolerated and
      effective. Long-term adverse effects include hypertension, nephrotoxicity, and
      post-transplant lymphoproliferative disease (PTLD). The recent development of
      tacrolimus has improved the cosmetic adverse effects related to cyclosporine, but
      has similar rates of hypertension and nephrotoxicity, and possibly a higher rate
      of PTLD. There has been a recent, welcome development in renal sparing drugs,
      such as mycophenolate mofetil, which has no cosmetic adverse effects, does not
      require drug level monitoring and is thus particularly attractive to teenagers.
      Recent surveys demonstrate recovery of renal function with mycophenolate mofetil,
      if started prior to irreversible renal dysfunction. There are currently little
      published data on the use of sirolimus (rapamycin) in the pediatric population,
      but preliminary studies suggest that the future use of interleukin-2 receptor
      antibodies may be beneficial for immediate post-transplant induction of
      immunosuppression. It is important when planning immunosuppression for
      adolescents to consider the effects of drug therapy on both males and females in
      order to maintain fertility and to ensure safety in pregnancy. Noncompliance is a
      problem in this age group, but adequate practical measures and support should
      reduce noncompliance, and allow good, long-term graft function.

PMID- 12608883
TI  - Autoimmune lymphoproliferative syndrome: etiology, diagnosis, and management.
AB  - Autoimmune lymphoproliferative syndrome (ALPS) is a childhood disorder
      characterized by chronic, nonmalignant lymphoproliferation and autoimmunity, most
      commonly involving cells of hematopoietic origin. Mutations of the tumor necrosis
      factor receptor super family member 6 (TNFRSF6) gene, coding for the apoptosis
      inducing protein Fas (Apo-1, CD95) are involved in the physiopathology of the
      syndrome, although the complete mechanism by which the syndrome is caused has not
      yet been unraveled. Although the syndrome has a benign nature, life-threatening
      complications can demand treatment. Treatment schedules, including
      corticosteroids, low doses of chemotherapy, granulocyte colony stimulating
      factor, or splenectomy, have varying results. Treatment with the antimalarial
      drug pyrimethamine/sulfadoxine (25/500mg per tablet) seems to be a new, well
      tolerated, and efficient approach, although larger studies will have to
      demonstrate the true value of this drug in patients with ALPS.

PMID- 12608885
TI  - Consumer adverse drug reaction reporting: a new step in pharmacovigilance?
AB  - The direct reporting of adverse drug reactions by patients is becoming an
      increasingly important topic for discussion in the world of pharmacovigilance. At
      this time, few countries accept consumer reports. We present an overview of
      experiences with consumer reporting in various countries of the world. The
      potential contribution of patient reports of adverse drug reactions is discussed,
      both in terms of their qualitative and quantitative contribution. The crucial
      question is one of whether patient reports will increase the number and quality
      of the reports submitted and/or lead to a more timely detection of signals of
      possible adverse reactions, thus contributing to an enhancement of the existing
      methods of drug safety monitoring. To date, the data available are insufficient
      to establish such added value.

PMID- 12608884
TI  - Treatment of apnea of prematurity.
AB  - In the last decade, knowledge regarding the neurodevelopment and functional
      aspects of the respiratory centers during postnatal maturation has increased
      substantially. However, an increase in such knowledge has not provided a basis
      for change in practice. The diagnosis of apnea of prematurity (AOP) is one of
      exclusion. All causes of secondary apnea must be ruled out before initiating
      treatment for AOP. Treatment will depend on the etiology as well as effectiveness
      and tolerability of the treatment by the patient. The primary goal of any
      treatment of AOP is to prevent the frequency of apnea lasting >20 seconds, and/or
      those that are shorter, but associated with cyanosis and bradycardia. The
      clinical management of AOP is not much different today than it was two decades
      ago, with pharmacologic and nonpharmacologic treatment options remaining the
      mainstay of therapy. Methylxanthines are still the most widely used pharmacologic
      agents. Due to the wider therapeutic index of caffeine and ease of once daily
      administration, it should be the preferred agent. Doxapram, or nonpharmacologic
      treatment measures such as nasal continuous positive airway pressure, may be
      considered in infants who are unresponsive to methylxanthine treatment alone.
      Treatment should be continued until there is complete resolution of apnea, and
      for some time thereafter. The choice of method for weaning treatment remains one
      of individual physician preference. Discharge from hospital after apnea requires
      close monitoring and some infants will require home apnea monitors. The decision
      to provide a home apnea monitor should be individualized for each patient,
      depending on the effectiveness of treatment and clinical response.

PMID- 12608886
TI  - What can consumer adverse drug reaction reporting add to existing health
      professional-based systems? Focus on the developing world.
AB  - The current system of pharmacovigilance encourages reporting of adverse drug
      reactions (ADRs) mainly from healthcare professionals. Underreporting is a major
      problem, more so in the developing world than in the developed world. Less than
      3% of reports added to the WHO database in the year 2000 originated from
      developing countries, although around 80% of the global population lives in the
      developing world [corrected]. Also a considerable time lag still exists in
      recognition of serious ADRs. Hence, there is a need for a different approach to
      pharmacovigilance. We present an overview of possible reasons for underreporting
      by healthcare professionals with particular emphasis on the developing world, and
      the potential benefits of encouraging consumer reporting. Only a few countries
      accept consumer reports. We suggest an independent consumer reporting system for
      hypothesis generation to complement the present health professional-based system.
      We also highlight the low priority given by multinational pharmaceutical
      companies to the developing countries regarding new safety information. The
      important questions are whether the resources available would be sufficiently
      robust to sustain such a system in the developing world, and whether it will be
      sufficiently robust and sensitive for the early detection of signals.

PMID- 12608889
TI  - Evaluation of the safety of palivizumab in the second season of exposure in young
      children at risk for severe respiratory syncytial virus infection.
AB  - BACKGROUND: Palivizumab reduces respiratory syncytial virus (RSV)
      hospitalisations in high-risk infants. Those with severe bronchopulmonary
      dysplasia may require two seasons of prophylaxis. There is concern that this
      humanised antibody might cause an adverse immune response in a second season of
      use. OBJECTIVE: To evaluate and compare the occurrence of anti-palivizumab
      antibodies and clinical adverse events in subjects receiving monthly palivizumab
      injections for a first and second season, and to assess frequency and severity of
      RSV disease in the two groups. DESIGN AND PATIENTS: Subjects aged <or=2 years at
      severe risk for RSV disease were designated as first season (no previous
      palivizumab exposure) or second season subjects (received palivizumab in previous
      RSV season). Palivizumab injections (15 mg/kg) were administered monthly for up
      to 5 months. Anti-palivizumab antibody titres and serum palivizumab
      concentrations were measured; adverse events were recorded. RESULTS: No first (n
      = 71) or second (n = 63) season subjects experienced a significant anti
      palivizumab antibody response (titre >or=1 : 80). Serum palivizumab
      concentrations were similar for the two groups. Nine (12.7%) first season and 8
      (12.7%) second season subjects experienced one or more serious adverse events;
      most were respiratory and all were considered to be not or probably not related
      to palivizumab. No deaths occurred during the study. CONCLUSIONS: Monthly
      palivizumab injections were not associated with adverse immune responses or
      adverse events in young children receiving palivizumab for one or two seasons.
      Children receiving palivizumab for a second season did not experience more severe
      adverse events than those receiving it for the first time.

PMID- 12608890
TI  - Residual C-peptide secretion and endothelial function in patients with Type II
      diabetes.
AB  - Recent studies have demonstrated that C-peptide exerts beneficial effects on
      endothelial function. To investigate the relationship between residual pancreatic
      C-peptide secretion and endothelial function in patients with well controlled or
      poorly controlled Type II diabetes, we studied 100 patients with Type II diabetes
      that were free from diabetic neuropathy. In all patients, insulin resistance,
      residual pancreatic C-peptide secretion, endothelial function and oxidative
      stress were investigated using the homoeostasis model assessment (HOMA) index,
      glucagon bolus test, brachial reactivity, Trolox equivalent antioxidant capacity
      (TEAC) and thiobarbituric acid-reacting substances (TBARS). The patients were
      categorized into quartiles on the basis of plasma HbA(1c) (glycated haemoglobin)
      concentration. Analysis of the data showed significant increases in plasma
      glucose concentration, HOMA index, microalbuminuria and TBARS, and significant
      decreases in plasma C-peptide, AUC (area under the curve) plasma C-peptide and
      TEAC, through the different quartiles (from the lowest to the highest HbA(1c)
      concentration). With regard to parameters of endothelial function, changes in
      diameter showed a significant declining trend through the different quartiles.
      Endothelial-dependent changes in diameter were independently and significantly
      associated with AUC C-peptide levels, TEAC and TBARS. In conclusion, our study
      demonstrated that patients with Type II diabetes with good residual C-peptide
      secretion are better protected from endothelial dysfunction that those with poor
      C-peptide secretion.

PMID- 12608887
TI  - Benefits and risks of newer treatments for chemotherapy-induced and postoperative
      nausea and vomiting.
AB  - Nausea and vomiting are common adverse effects of chemotherapy, radiation
      therapy, anaesthesia and surgery. The incidence of chemotherapy-induced nausea
      and vomiting (CINV) is estimated to vary from 30 to 90%, depending on the type of
      chemotherapeutic agent used. Radiation-induced emesis varies with anatomical site
      radiated but is estimated to have an overall incidence of approximately 40%. The
      incidence of postoperative nausea and vomiting (PONV) depends on the type of
      anaesthesia and surgery, but overall is estimated to be 20-30%. Evidence-based
      medicine and meta-analysis have been used to direct medical therapy to help
      determine equivalence, optimal dose, timing, safety and efficacy of antiemetic
      medications. Concepts such as the number needed to treat and number needed to
      harm are helpful to guide the clinician regarding the benefits and risks of a
      particular treatment. The serotonin 5-HT(3) receptor antagonists ondansetron,
      granisetron, tropisetron and dolasetron have been important additions to the
      antiemetic armamentarium. The 5-HT(3) receptor antagonists are similar in
      chemical structure, efficacy and adverse effect profile. They appear to have no
      important differences among themselves in clinical outcomes for CINV and PONV.
      Headache, dizziness, constipation and diarrhoea are their most common adverse
      effects, and when they occur they are usually mild and easily managed.
      Haemodynamic changes and extrapyramidal adverse effects are uncommon. ECG changes
      such as prolonged corrected QT (QTc) interval are infrequent, dose-related and
      overall judged to be clinically insignificant. As most studies with the 5-HT(3)
      antagonists have been conducted on relatively healthy patients, caution should be
      exercised when these drugs are used in susceptible patients with co-morbidities.
      The clinician must weigh the benefit of administering an antiemetic for CINV or
      PONV against the risk of occurrence of an adverse event.

PMID- 12608888
TI  - New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and
      zaleplon.
AB  - Insomnia affects 30-35% of people living in developed countries. The impact of
      insomnia on daytime functioning and its relationship with medical and psychiatric
      illnesses necessitate early treatment to prevent insomnia becoming persistent and
      to avoid the development of complications. However, pharmacological strategies
      must achieve a balance between sedative and adverse effects. In the last 30
      years, benzodiazepines have been the preferred drugs for the treatment of
      insomnia. Benzodiazepines act nonselectively at two central receptor sites, named
      omega(1) and omega(2), which are located in different areas of the CNS. The
      sedative action of benzodiazepines is related to omega(1) receptors, whereas
      omega(2) receptors are responsible for their effects on memory and cognitive
      functioning. According to their pharmacokinetic profile, benzodiazepines can be
      classified into three groups: short half-life (<3 hours), medium half-life (8-24
      hours) and long half-life (>24 hours). The newer non-benzodiazepine agents
      zopiclone, zolpidem and zaleplon have a hypnosedative action comparable with that
      of benzodiazepines, but they display specific pharmacokinetic and pharmacodynamic
      properties. These three 'Z' agents all share a short plasma half-life and limited
      duration of action. In addition, these agents are selective compounds that
      interact preferentially with omega(1) receptors (sedative effect), whereas
      benzodiazepines also interact with omega(2) receptors (adverse effects on
      cognitive performance and memory). Zaleplon is characterised by an ultrashort
      half-life (approximately 1 hour). Zolpidem and zopiclone have longer half-lives
      (approximately 2.4 and 5 hours, respectively). These properties, together with
      the low risk of residual effect, may explain the limited negative influences of
      these agents on daytime performance. Psychomotor tasks and memory capacities
      appear to be better preserved by non-benzodiazepine agents than by
      benzodiazepines. When present, cognitive deficits almost exclusively coincide
      with the peak plasma concentration. In particular, impairment can emerge in the
      first hours after drug administration, whereas psychomotor and memory tests
      carried out 7-8 hours later (i.e. in the morning) generally show no relevant
      alterations. As with benzodiazepines, the three 'Z' non-benzodiazepine agents
      should be used for a limited period, even in chronic relapsing conditions.
      Further evaluation is needed of the safety of hypnosedative medications in the
      long-term management of insomnia.

PMID- 12608891
TI  - Biochemical and mass spectrometric characterization of soluble ecto-5'
      nucleotidase from bull seminal plasma.
AB  - Ecto-5'-nucleotidase (ecto-5'-NT) is a glycosylphosphatidylinositol-anchored
      membrane-bound protein that is ubiquitous in mammalian tissues. It is a target
      for a number of therapeutic drugs since increased levels of the enzyme correlate
      with various disease states. In this investigation, we describe the properties of
      a soluble ecto-5'-NT derived from bull seminal plasma. The protein was highly
      heterogeneous as demonstrated by chromatofocusing and two-dimensional PAGE.
      Sequencing analyses revealed a truncated polypeptide lacking the
      glycosylphospatidylinositol attachment site, suggesting that it is produced post
      translationally by cleavage at Gln(547) and/or Phe(548). Heterogeneity was
      largely due to differential glycosylation, especially in the oligosaccharides
      linked to Asn(403). Significant differences in substrate specificity were
      observed between isoforms and, on the basis of molecular-modelling studies, were
      interpreted in terms of variable glycosylation causing steric hindrance of the
      substrate-binding site. Thus the soluble forms of ecto-5'-NT found in bull
      seminal plasma are unique both biochemically and structurally, and have a
      putative role in signalling interactions with spermatozoa following ejaculation
      and capacitation in the female reproductive tract.

PMID- 12608892
TI  - Activation of vanilloid receptor type I in the endoplasmic reticulum fails to
      activate store-operated Ca2+ entry.
AB  - To evaluate interaction of vanilloid receptor type 1 (TRPV1) with endogenous
      Ca(2+) signalling mechanisms, TRPV1 was expressed in Spodoptera frugiperda (Sf 9)
      insect cells using recombinant baculovirus. Stimulation of TRPV1-expressing
      cells, but not control Sf 9 cells, with resiniferatoxin (RTX), capsaicin or
      anandamide, produced an increase in cytosolic free Ca(2+) concentration
      ([Ca(2+)](i)), with EC(50) values of 166 pM, 24.5 nM and 3.89 microM
      respectively. In the absence of extracellular Ca(2+), both capsaicin and RTX
      caused an increase in [Ca(2+)](i) with EC(50) values of approx. 10 microM and 10
      nM respectively. This TRPV1-induced release of Ca(2+) from intracellular stores
      was not blocked by U73122, suggesting that phospholipase C was not involved.
      Substantial overlap was found between the thapsigargin- and RTX-sensitive
      internal Ca(2+) pools, and confocal imaging showed that intracellular TRPV1
      immunofluorescence co-localized with the endoplasmic reticulum targeting motif
      KDEL. To determine if TRPV1-induced mobilization of intracellular Ca(2+)
      activates endogenous store-operated Ca(2+) entry, the effect of 2
      aminoethoxydiphenyl borate (2-APB) on Ba(2+) influx was examined. 2-APB blocked
      thapsigargin-induced Ba(2+) influx, but not RTX-induced Ba(2+) entry. In the
      combined presence of thapsigargin and a store-releasing concentration of RTX, the
      2-APB-sensitive component was essentially identical with the thapsigargin-induced
      component. Similar results were obtained in HEK-293 cells stably expressing
      TRPV1. These results suggest that TRPV1 forms agonist-sensitive channels in the
      endoplasmic reticulum, which when activated, release Ca(2+) from internal stores,
      but fail to activate endogenous store-operated Ca(2+) entry. Selective activation
      of intracellular TRPV1, without concomitant involvement of plasmalemmal Ca(2+)
      influx mechanisms, could play an important role in Ca(2+) signalling within
      specific subcellular microdomains.

PMID- 12608893
TI  - Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in vascular
      smooth muscle cells.
AB  - Keratinocyte growth factor receptor (KGFR), also known as fibroblast growth
      factor receptor (FGFR)2 IIIb, is located in many types of epithelial cells and is
      activated by four known ligands (FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF
      10) that are predominantly synthesized by mesenchymal cells. In the early stage
      of atherosclerosis, vascular smooth muscle cells (VSMC) transform from a
      contractile to a synthetic phenotype, proliferate and migrate into the intima.
      Previously, FGF-7 mRNA expression was reported in VSMC, but KGFR mRNA was not
      detected. In the present study, we attempted to determine whether KGFR is
      localized in VSMC cultured from rat aorta and VSMC in human normal and
      atherosclerotic coronary arteries. Expression of KGFR mRNA and its protein was
      detected in cultured rat VSMC by reverse transcription-polymerase chain reaction
      and western blot analysis, respectively. Immunohistochemically, KGFR was
      localized in the VSMC of the outer layer of the media in normal human coronary
      arteries. Furthermore, it was localized in the VSMC of the media and thickened
      intima of atherosclerotic arteries. Recombinant FGF-7 and/or FGF-10 proteins
      stimulated the growth of cultured rat VSMC. These findings indicate that KGFR
      localized in VSMC may contribute to the proliferation of VSMC in normal and
      atherosclerotic arteries.

PMID- 12608894
TI  - Pulmonary fibrosis: cellular and molecular events.
AB  - Connective tissue remodeling of the interstitium is an important feature of
      chronic lung diseases encompassing interstitial inflammatory changes and
      subsequent pulmonary fibrosis. The early inflammatory phase is usually associated
      with the release of several cytokines and chemokines by activated resident cells
      and infiltrating cells which, in turn, help further recruit inflammatory
      mononuclear cells. Cytokines and growth factors secreted by inflammatory cells
      and by interstitial cells (fibroblasts and myofibroblasts) play an important role
      in the fibrogenic phase of pulmonary fibrosis by inducing matrix synthesis. In
      addition, matrix-degrading enzymes and their inhibitors also contribute to
      extracellular matrix (ECM) remodeling in pulmonary fibrosis. This review
      addresses the pathophysiology of wound healing and different phases of pulmonary
      fibrosis.

PMID- 12608895
TI  - Expression of RET in follicular cell-derived tumors of the thyroid gland:
      prevalence and implication of morphological type.
AB  - Expression of the wild-type RET proto-oncogene has been observed in non
      medullary, follicular cell-derived tumors (FCDT), but the relation with the
      histopathological features has not been fully demonstrated. To assess the
      expression of RET and protein products in relation to morphological types of
      FCDT, including follicular adenoma (FA), papillary carcinoma (PTC), follicular
      carcinoma (FTC) and anaplastic carcinoma (AnC), 58 non-neoplastic and neoplastic
      samples using pathological paraffin sections by immunohistochemistry (IHC),
      reverse transcriptase-polymerase chain reaction (RT-PCR) and laser capture
      microdissection (LCM) methods were analyzed. Expression of RET proto-oncogene was
      detected in 27.3% of FCDT by IHC and 25.5% by RT-PCR using a primer set at a
      regular break point. The present study also found higher expression ratios of RET
      in FA (50.0%) and the follicular variant of PTC (50.0%), in contrast to FTC
      (20.0%), ordinary PTC (20.0%) and poorly differentiated or AnC (14.3%) by RT-PCR.
      One patient with PTC showed a discrepancy in the results by RT-PCR using a
      different primer set at the C-terminus of RET. The study found that the RET proto
      oncogene is often stimulated in FCDT, not only in PTC but also in follicular
      tumors (FA and FTC), and may contribute to tumorigenesis of these tumors.

PMID- 12608896
TI  - Evolution of DNA ploidy state and DNA index in colorectal adenomas and carcinomas
      using the crypt isolation technique: new hypothesis in colorectal tumorigenesis.
AB  - The evolution of DNA diploid, aneuploid and multiploid (diploid and aneuploid)
      states that represent DNA types that are independent of genetic alterations in
      colorectal tumors were examined. Changes in the DNA index (DI) accompanying tumor
      development from adenoma to carcinoma were assessed. In colorectal adenomas and
      early cancers, the DNA was diploid or multiploid. A pure aneuploid state was
      observed in advanced carcinomas only, whereas the aneuploid DI values of adenomas
      were characterized by two distinct peaks. The DI values for the carcinomas were
      randomly distributed. However, in advanced carcinomas, aneuploid carcinomas
      tended to have lower DI whereas aneuploid populations within multiploid
      carcinomas tended to have higher DI. Early cancers were subdivided into two
      groups: a cancer region associated with an adenomatous region (group A tumors)
      and a cancer region that exhibited an absence of or a very limited adenomatous
      region (group B tumors). Group A tumor DI were lower than group B. It is
      suggested that low DI adenomas might transform into group A tumors, which
      consequently progress to advanced aneuploid carcinomas. In addition, group B
      tumors might derive predominantly from high DI adenomas or from group A tumors by
      high DI evolution, and might progress into advanced multiploid carcinomas.
      Therefore, the evolution of the DNA index might play an important role in the
      development of colorectal tumors.

PMID- 12608897
TI  - Cytogenetic and clinicopathological analysis of soft-tissue leiomyosarcomas.
AB  - To identify a characteristic cytogenetic aberration and cytogenetic-morphological
      correlation in soft-tissue leiomyosarcomas, a karyotypic and clinicopathological
      analysis of 15 cases of leiomyosarcoma was performed. The histological type was
      classical in nine cases, pleomorphic in three cases and myxoid in three cases.
      The histological grade was 1 in three cases, 2 in 10 cases and 3 in two cases.
      Nine of 15 tumors displayed an abnormal karyotype, whereas the other six tumors
      displayed a normal karyotype. The relative consistency of involvement of 3p, 3q,
      6q, 7p, 7q, 9p, 10p, 11p, 11q, 12p, 16q, 17p and 19q was recognized, although
      characteristic chromosomal rearrangements were not detected. All six tumors that
      had a normal karyotype were of the classical type, whereas those displaying an
      abnormal karyotype contained another morphological type along with the classical
      type. The results of the present study suggest that chromosomal aberrations
      contribute to morphological changes in soft-tissue leiomyosarcomas.

PMID- 12608898
TI  - Subependymoma of the spinal cord and review of the literature.
AB  - Subependymoma is a tumor of the central nervous system, which frequently occurs
      in the ventricles and rarely in the spinal cord. Most of the intraventricular
      subependymomas are subclinical and thus incidentally encountered at autopsy,
      whereas the spinal ones are inevitably accompanied by myelopathy and are often
      diagnosed clinically as ependymomas or astrocytomas. Two cases of spinal cord
      subependymomas are reported, one of which recurred 9 years after the initial
      operation. All specimens of both cases showed similar microscopic features.
      Within a highly fibrillary background, round to ovoid tumor cells were unevenly
      distributed and arranged in cell clusters. Mitoses were rarely encountered. No
      necrosis was demonstrated in any of the specimens. Ultrastructural examination
      demonstrated many slender processes containing abundant intermediate filaments
      and occasional small lumen-like structures with many microvillous projections and
      cell junctions. Subependymomas arising in the spinal cord should be distinguished
      from other more aggressive gliomas, such as diffuse astrocytomas and ependymomas.
      Characteristic microscopic features and the ultrastructural studies support the
      diagnosis.

PMID- 12608899
TI  - Collagenous gastritis in a young Japanese woman.
AB  - Collagenous gastritis, a counterpart of collagenous colitis, is a rare disorder
      with less than 20 cases reported in the literature. A case of collagenous
      gastritis in a Japanese woman in her early 20s who had been receiving treatment
      for atopic dermatitis and bronchial asthma is reported. The patient complained of
      repeated epigastric pain, and endoscopy revealed multifocal atrophic areas and
      scars in the gastric body. Biopsy specimens showed a thickened eosinophilic band
      like structure with entrapped capillaries approximately 30-70 micro m thick
      beneath the surface epithelium. It was regarded as a collagen band because it was
      positive on Azan staining but negative on amyloid staining. This finding was
      accompanied by marked infiltration of mononuclear cells and eosinophils in the
      lamina propria; however, no evidence of lymphocytic gastritis was found.
      Helicobacter pylori infection was not detected and inflammatory cell infiltration
      was minimal in the mucosa without the collagen band. Immunohistochemical analysis
      revealed that the band was positive for type III and type VI collagen. The size
      of the collagen band did not change for 2 years. These findings suggest that
      subepithelial collagen deposition was due to an abnormal local immune response
      based on generalized allergic disorder.

PMID- 12608900
TI  - Leiomyomatosis peritonealis disseminata with malignant change in a man.
AB  - Leiomyomatosis peritonealis disseminata (LPD) is a rare clinicopathological
      entity typically observed in women of reproductive age. We report a case of LPD
      with malignant change in a man. A 77-year-old man presented with a mass measuring
      10 cm in diameter at the terminal ileum and numerous peritoneal small nodules
      that were revealed by abdominal computed tomography. Right hemicolectomy with
      lymph node dissection was performed. Macroscopically, a tumor of the terminal
      ileum consisted of aggregates of small nodular lesions with calcification and
      necrosis. The wall of the ileum and colon was intact. Microscopically, some of
      the nodular lesions consisted of neoplastic growths of atypical spindle cells
      with cellular atypism and abnormal mitoses. A few of these lesions were
      completely surrounded by smooth muscle bundles. Hemorrhages and necroses were
      found within the tumor nodules. Immunohistochemically, the tumor cells were
      positive for vimentin, desmin, muscle actin, alpha-smooth muscle actin,
      cytokeratin and p53. The remaining nodular lesions, including small peritoneal
      lesions, were composed of hypocellular hyalinizing nodules. This case was thought
      to be LPD with malignant change, although the pathogenesis was uncertain because
      the tumor cells were negative for estrogen and progesterone receptors.

PMID- 12608901
TI  - Localized necrotizing angiitis of the ileum.
AB  - A 20-year-old woman was hospitalized repeatedly because of intermittent bouts of
      intestinal obstruction and the symptoms usually improved with conservative
      treatments. One year after the first admission the patient was hospitalized in
      emergency and a laparotomy revealed a circular stricture with a pinhole
      perforation in the ileum. Histological sections of the stricture showed the
      characteristic features of microscopic polyangiitis varying from active to
      resolving stages, which were localized in the ileum. Fibrinoid necrosis,
      fibroblastic and fibrous proliferation of the intima and fibrous replacement of
      the media with a variable pan- and perivascular inflammatory cell infiltrate were
      characteristic in the muscular arteries and arterioles. Vascular occlusion by
      pale eosinophilic, fibrillar-like materials resembling livedo racemosa of the
      skin, was noticed in the small arterioles and capillaries. Under no prophylaxis,
      the postoperative course was uneventful with no recurrence of the illness at an
      18-month follow up. The pathological alterations were distributed focally,
      occasionally segmentally, and haphazardly, and required detailed examination by
      stepwise sections for the histological diagnosis.

PMID- 12608902
TI  - Ovarian carcinoid exhibiting double function.
AB  - A case of a 58-year-old woman with ovarian carcinoid exhibiting double function
      is reported. She had suffered from constipation and hirsutism before surgery.
      Pathological examination revealed that many carcinoid tumor cells were
      immunohistochemically positive for peptide YY, which inhibits intestinal motility
      and many peripheral steroid cells. After surgery the patient recovered from
      constipation immediately. Although the serum level of testosterone also
      immediately decreased, hirsutism remained for about 2 years. These clinical
      manifestations are considered to be due to peptide hormone-producing tumor
      parenchymal cells and testosterone-producing functioning stromal cells. This is
      the first report of clinically manifested double-functioning ovarian carcinoid;
      one function is due to tumor cells themselves and another function is due to
      stromal cells.

PMID- 12608904
TI  - Activation of MMP-2 by Porphyromonas gingivalis in human periodontal ligament
      cells.
AB  - It has been reported that matrix metalloproteinase (MMP) produced by host cells
      plays a major role in periodontal tissue destruction. In addition, secreted
      virulence factors from Porphyromonas gingivalis can alter MMP secretion and cause
      activation in host cells that lead to the tissue degradation. In this study, we
      examine the effects of P. gingivalis supernatant on matrix metalloproteinase-2
      (MMP-2) activation in human periodontal ligament (HPDL) cells. Cultures of HPDL
      cells were treated with P. gingivalis supernatant for 48 h and the level of MMP-2
      activation was monitored by gelatin zymography. The profound activation of MMP-2
      was seen only in the treated group. The activation of MMP-2 was inhibited by MMP
      inhibitors phenanthroline and EDTA, but not serine protease or cysteine protease
      inhibitors. To study the correlation between the expression of membrane-type-1
      matrix metalloproteinase (MT1-MMP) and the activation of MMP-2, the level of MT1
      MMP was analyzed. The results from reverse-transcription polymerase chain
      reaction (RT-PCR) and Western analysis indicated that P. gingivalis supernatant
      up-regulated the expression of MT1-MMP in both transcription and translation
      levels within 48 h. These results suggest that P. gingivalis supernatant can
      activate MMP-2 in HPDL cells and the mechanism of activation may involve the
      increased amount of MT1-MMP. It is possible that the activation of MMP-2 by P.
      gingivalis plays a role in the process of chronic periodontitis.

PMID- 12608903
TI  - Estimation of interleukin-1beta levels in the gingival crevicular fluid in health
      and in inflammatory periodontal disease.
AB  - Initial research indicated that the levels of interleukin-1beta (IL-1beta) are
      higher in sites of inflammation than in healthy sites. However, subsequent
      studies suggest heterogenous responses and indicate the quantitative levels of IL
      1beta to be the characteristic of an individual rather than simply being the
      reflection of the inflammatory status of the tissues. This study has been
      designed to find out the relationship between IL-1beta levels in the gingival
      crevicular fluid and the inflammatory status of the periodontal tissues in the
      Indian population. Sixty patients were selected for the study. They were
      categorized in to three groups based on their periodontal tissue status as group
      I (clinically healthy gingiva with no loss of attachment), group II (gingivitis
      with no attachment loss) and group III (gingivitis with attachment loss).
      Microcapillary pipettes were used to collect gingival crevicular fluid samples
      from one site in each person and the samples were analysed for IL-1beta using a
      commercially available ELISA kit. The concentration of IL-1beta in the gingival
      crevicular fluid of patients in group III is statistically higher (P < 0.0001)
      than that in group II and the concentration of IL-1beta in groups II and III is
      statistically at much higher levels (P < 0.0001) than in the group I subjects.
      However, there is a significant overlap in the values obtained in groups II and
      III and the values in both the groups range over a wide spectrum. The composite
      values obtained within the groups and the overlapping values in groups II and III
      could indicate the role of genetic polymorphism in determining the quantity of IL
      1beta produced and also the contributory role of other cytokines that share
      similar biologic activity.

PMID- 12608905
TI  - Basic fibroblast growth factor induces the expression of matrix metalloproteinase
      3 in human periodontal ligament cells through the MEK2 mitogen-activated protein
      kinase pathway.
AB  - Basic fibroblast growth factor (bFGF, FGF-2) is one of the potent mitogens for
      periodontal ligament (PDL) cells. However, the role of bFGF on the matrix
      metalloproteinase-3 (MMP-3) expression in PDL cells is unknown. In this study,
      the effect of bFGF on MMP-3 expression in PDL cells and the mechanism of this
      process were examined. Human PDL cells were exposed to bFGF at various
      concentrations (0.01-10 ng/ml) in monolayer cultures. bFGF increased
      [3H]thymidine incorporation and suppressed proteoglycan synthesis concentration
      dependently. However, similar concentration ranges of bFGF increased the release
      of the cell-associated proteoglycans into the medium. Furthermore, bFGF increased
      MMP-3 mRNA levels concentration-dependently as examined by reverse transcription
      polymerase chain reaction (RT-PCR). Induction of MMP-3 after the stimulation with
      bFGF was observed as early as 12 h with maximal at 24 h. Thereafter, the MMP-3
      mRNA level gradually decreased until 72 h. Cycloheximide blocked the induction of
      MMP-3 by bFGF, indicating the requirement of de novo protein synthesis for this
      stimulation. Furthermore, MMP-3 expression induced by bFGF was abrogated by
      U0126, a specific inhibitor of MEK1/2 and ERK1/2 in mitogen-activated protein
      (MAP) kinase pathway, not by PD98059, a specific inhibitor of MEK1. In addition,
      bFGF up-regulated the phosphorylated ERK1/2 in 5 min with the maximal at 20 min
      as examined by Western blotting, and U0126 inhibited the ERK1/2 phosphorylation
      induced by bFGF. These findings suggest that bFGF induces MMP-3 expression in PDL
      cells through the activation of the MEK2 in MAP kinase pathway. bFGF stimulation
      on MMP-3 synthesis may be involved in the control of the cell-associated
      proteoglycans in PDL cells during periodontal regeneration and degradation.

PMID- 12608906
TI  - Effects of safrole on the defensive functions of human neutrophils.
AB  - The effects of safrole on the defensive functions of human neutrophils were
      examined. At the concentrations employed in this study, safrole did not
      significantly affect the viability of peripheral blood neutrophils as verified by
      their ability to exclude trypan blue dye. However, exposure of neutrophils to
      safrole inhibited their bactericidal activity against oral pathogens, including
      Actinobacillus actinomycetemcomitans and Streptococcus mutans, in a dose
      dependent manner. In addition, safrole inhibited the production of bactericidal
      superoxide anion by neutrophils as measured by cytochrome c reduction. In
      conclusion, the results demonstrated that safrole reduced the antibacterial
      activity and the superoxide anion production of neutrophils. Inhibition of the
      defensive functions of neutrophils may be one possible mechanism by which safrole
      compromises the oral health.

PMID- 12608907
TI  - Subjective intensity of pain during the treatment of periodontal lesions with the
      Vector-system.
AB  - The aim of this study was to measure subjective intensities of pain during the
      treatment of periodontal lesions with the Vector-system when compared to pain
      occurring during the treatment with conventional methods. Twenty patients, each
      of whom had three teeth with comparable periodontal pocket depths, were treated
      using three different methods: (i) scaling and root planing with hand
      instruments, (ii) cleaning with a conventional ultrasonic instrument (Siroson S)
      and (iii) cleaning with the Vector-system. The subjective intensities of pain
      during the treatment were measured with an intermodal intensity comparison. A
      visual analog scale was used for the evaluation after the treatment. The results
      of the intermodal intensity comparison during treatment showed that the use of
      the Vector-system caused less pain than the cleaning with hand instruments or the
      conventional ultrasonic system (P < 0.05). The intermodal intensity comparisons
      of cleaning with hand instruments and cleaning with the conventional ultrasonic
      system were not significantly different (P > 0.05). These results could be
      confirmed by the visual analog scale. Using the Vector-system for cleaning
      periodontal lesions it is possible to reduce pain sensations compared to
      conventional methods. Using cleaning methods that cause less discomfort and pain,
      it might be possible to increase the patient's compliance during non-surgical
      periodontal therapy and recall.

PMID- 12608908
TI  - Antibiotic treatment of incipient drug-induced gingival overgrowth in adult renal
      transplant patients.
AB  - BACKGROUND: Drug-induced gingival overgrowth (GO) remains a challenge in
      periodontics. Partial and total regressions of this GO have been reported after a
      short course of antibiotics. METHODS: We conducted a double-blinded controlled
      randomised study to determine the effect of metronidazole (MNZ) or azithromycin
      (AZM) on the regression of incipient cyclosporin A-induced GO in 40 adult renal
      transplanted patients. The quantitation of the GO was performed with Image
      Digital Analysis. RESULTS: None of the patients with GO showed complete remission
      after 30 days. The pretreatment GO index was 0.895 +/- 0.16 in the metronidazole
      treatment group (MNZ group, n = 13), 0.932 +/- 0.11 in the azithromycin treatment
      group (AZM group, n = 14), and 1.073 +/- 0.32 in the controls (placebo group, n =
      13). At the end of the study (30 days), the GO index score was lower in 54.4% and
      62.3% of the MNZ and AZM groups, respectively, and the mean score differences
      were statistically significant between the groups (0.897 +/- 0.28, MNZ group vs.
      0.909 +/- 0.15, AZM group vs. 1.130 +/- 0.3, placebo group, P < 0.05 ANOVA).
      CONCLUSIONS: A 7-day course of MNZ or AZM does not induce remission of CsA
      induced GO, although it acts on concomitant bacterial over-infection and gingival
      inflammation.

PMID- 12608909
TI  - A TEM/SEM study of the microbial plaque overlying the necrotic gingival papillae
      of HIV-seropositive, necrotizing ulcerative periodontitis.
AB  - The purpose of this study was to examine by transmission (TEM) and scanning
      electron microscopy (SEM) the supragingival microbial plaque overlying the
      ulcerated gingival papillae of necrotizing ulcerative periodontitis (NUP) lesions
      in HIV-seropositive patients. The microbiota of NUP and HIV-seropositive patients
      with periodontitis has been reported to be similar to that of conventional
      periodontitis in non-infected subjects, although several investigators have also
      reported high recovery rates of microbes not generally associated with the
      indigenous oral microbial flora. Light and electron microscopic observations and
      microbial culture studies indicate a similar high prevalence of spirochetes in
      both necrotizing ulcerative gingivitis (NUG) and NUP. In addition, several
      studies have reported more frequent isolation of Candida albicans from diseased
      periodontal sites in HIV-seropositive patients than from non-diseased sites. Ten
      male and six female patients, each HIV-seropositive and exhibiting NUP,
      constituted the study population. Two biopsies of involved gingival papillae from
      between posterior teeth were obtained from each patient and processed for
      examination by both TEM and SEM. Microscopic examination revealed a surface
      biofilm comprised of a mixed microbial flora of various morphotypes in 81.3% of
      biopsy specimens. The subsurface flora featured dense aggregations of spirochetes
      in 87.5% of specimens. Zones of aggregated polymorphonuclear leukocytes and
      necrotic cells were also noted. Yeasts were observed in 65.6% of specimens and
      herpes-like viruses in 56.5% of the specimens. Collectively, except for the
      presence of yeast and viruses, the results suggest that the microbial flora and
      possibly the soft tissue lesions of NUP and necrotizing ulcerative gingivitis are
      very similar.

PMID- 12608910
TI  - Periodontal conditions among adults in Southern Thailand.
AB  - OBJECTIVE: To describe the periodontal conditions among 30-39- and 50-59-year-old
      rural Thais from the Province of Songkhla, Southern Thailand. METHODS: A total of
      359 dentate persons were given a clinical examination comprising recordings of
      plaque and calculus in six teeth, and bleeding on probing, attachment level and
      pocket depth in six sites of all teeth present, except third molars. The same
      examiner carried out all examinations. Information on religious faith, smoking
      habits and use of betel was obtained by interview. A subset consisting of 60
      persons was reexamined for attachment level 6 months later by another examiner.
      RESULTS: The oral hygiene conditions were poor with abundant amounts of both
      plaque and calculus. Gingival bleeding was essentially ubiquitous. The prevalence
      of attachment loss > or = 4 mm was 92% among 30-39-year-olds and 100% among 50-59
      year-olds. The average percentage of sites affected in the two age groups was
      23.9% and 63.9%. Pockets > or = 4 mm were seen in 84% of the 30-39-year-olds and
      in 93% of the 50-59-year-olds. Older age, Thai Buddhist faith and a high
      percentage of sites with calculus were significant positive predictors of a high
      percentage of sites with attachment loss > or = 4 mm, whereas older age and Thai
      Buddhist faith were the only statistically significant predictors of a high
      percentage of sites with attachment loss > or = 7 mm. CONCLUSION: The results
      indicate that this Thai population may have more widespread and severe
      periodontal destruction than other Asian populations, but failed to confirm the
      contention that Muslim faith is associated with more severe periodontal
      destruction.

PMID- 12608911
TI  - Emdogain regulation of cellular differentiation in wounded rat periodontium.
AB  - Emdogain is an enamel matrix derivative that may promote periodontal regeneration
      by recapitulating critical events in tooth morphogenesis. We hypothesized that
      Emdogain enhances periodontal regeneration by promoting the differentiation of
      cells required for the synthesis of periodontal ligament, bone and cementum. Cell
      differentiation was examined in rat periodontal window wounds in which there is
      no microbial biofilm or epithelial downgrowth, thereby simplifying the model
      system. Defects were filled with vehicle control or Emdogain (3 mg/ml or 30
      mg/ml). Rats were sacrificed at 7, 14 and 21 d after wounding. Specimens of
      periodontium were immunostained for osteopontin, bone sialoprotein, osteocalcin
      as markers of osteogenic differentiation and for alpha-smooth muscle actin, a
      myofibroblastic marker. Morphometry and 3H-proline radioautography were used for
      assessment of tissue homeostasis and matrix production. Rats treated with
      Emdogain (only at 30 mg/ml) showed widening of the periodontal ligament at 7 d;
      by 14 and 21 d, periodontal ligament width was restored to normal values for all
      groups. Emdogain exerted no effect on cementum thickness, bone volume, osteoid
      deposition rates, or extracellular staining for osteopontin, bone sialoprotein or
      osteocalcin. Further, the percentage of cells with intracellular staining for
      osteopontin, osteocalcin or bone sialoprotein was unaffected by Emdogain.
      Staining for alpha-smooth muscle actin was abundant in the repopulating wound but
      was also unaffected by Emdogain. In conclusion, Emdogain does not apparently
      affect the expression of differentiation markers or bone matrix protein synthesis
      in the repopulation response of wounded rat molar periodontium. Therefore the
      effect of Emdogain on wound healing in the periodontium may be independent of
      differentiation in the cell populations examined in this model.

PMID- 12608912
TI  - Laminin- and fibronectin-like molecules produced by periodontal ligament
      fibroblasts under serum-free culture are potent chemoattractants for gingival
      epithelial cells.
AB  - Previously, we revealed that hepatocyte growth factor (HGF) or an HGF-like factor
      secreted by periodontal ligament fibroblasts (PLF) and gingival fibroblasts
      cultured in the presence of serum was a major chemoattractant for gingival
      epithelial cells, and suggested that it might play a role in epithelial invasion.
      However, our recent study showed that serum-free culture of PLF and gingival
      fibroblasts produced potent chemoattractants other than HGF for gingival
      epithelial cells. To identify these chemoattractants, PLF-conditioned medium (PLF
      CM) from serum-free cultures was obtained, concentrated, and separated by gel
      filtration column chromatography, and the chemotactic activity for gingival
      epithelial cells of each eluted fraction was monitored by a modified Boyden
      chamber assay. The chemoattractant activity was eluted at a molecular mass of
      around 600 kDa, which would include laminin and fibronectin, but not HGF,
      determined by ELISA. The chemotactic activity was reduced by treatment with
      antilaminin and/or antifibronectin polyclonal antibodies. Western blots using
      both antibodies revealed that the PLF-CM contained laminin- and fibronectin-like
      molecules. Along with HGF, these large glycoprotein molecules produced by PLF may
      be involved in the pathogenesis and progression of periodontitis by inducing the
      apical migration of epithelial cells.

PMID- 12608913
TI  - Molecular size distribution analysis of human gingival glycosaminoglycans in
      cyclosporin- and nifedipine-induced overgrowths.
AB  - Glycosaminoglycans are thought to accumulate in formative lesions like drug
      induced gingival overgrowth. Recent evidences, however, suggest that the amounts
      of glycosaminoglycans are comparable in overgrown and healthy gingiva. Besides,
      alterations in the size distribution of glycosaminoglycan molecules isolated from
      phenytoin-induced overgrown samples have also been suggested. Therefore, we
      sought to determine possible differences in molecular size distribution of
      gingival glycosaminoglycans in other types of drug-induced overgrowths. Purified
      gingival glycosaminoglycans from healthy and cyclosporin- and nifedipine-induced
      overgrown gingival tissues were analyzed by agarose gel electrophoresis and their
      molecular-size distribution was evaluated by both gel filtration chromatography
      and polyacrylamide gel electrophoresis. Our results on the gingival
      glycosaminoglycan composition showed presence of chondroitin sulfate, dermatan
      sulfate, heparan sulfate and hyaluronic acid in all types of gingival tissues
      examined. In addition, hyaluronic acid was predominantly of a large size eluting
      near to the void volume of a Superose-6 column, while the sulfated
      glycosaminoglycans were mainly composed of low molecular size glycosaminoglycans.
      Our results show no differences in the molecular-size distribution of hyaluronic
      acid and sulfated glycosaminoglycans among healthy and drug-induced overgrown
      gingival tissues.

PMID- 12608915
TI  - Influence of subcutaneous administration of recombinant TNF-alpha on ligature
      induced periodontitis in rats.
AB  - Proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) was found in
      inflamed periodontal tissues and many studies pointed to its significant role in
      development of periodontal disease. In this study, the influence of
      subcutaneously administered recombinant human TNF-alpha (rhTNF-alpha) on
      inflammatory reaction and periodontal breakdown in rats was analyzed during
      experimental periodontitis, induced by placing silk ligatures around the
      maxillary right second molar tooth. The rats were divided into two groups with
      five animals in each; the first group was infused subcutaneously with rhTNF-alpha
      via osmotic pumps for 2 weeks and the second group was infused with phosphate
      buffered saline (PBS) in the same manner. Inflammatory reaction and periodontal
      breakdown was evaluated morphometrically on hematoxylin and eosin stained
      sections. Serum ionized calcium and inorganic phosphates were monitored
      colorimetrically. Serum calcium and phosphate levels were similar in rats
      receiving rhTNF-alpha and PBS. Ligation resulted in accelerated periodontal
      breakdown, while subcutaneous rhTNF-alpha administration by itself had no
      significant effect. Combined effect of subcutaneous rhTNF-alpha administration
      and ligation resulted in a significantly greater inflammatory reaction and
      periodontal breakdown then either treatment alone. We concluded that the
      subcutaneous administration of rhTNF-alpha accelerates the progression of
      experimental periodontitis in rats.

PMID- 12608914
TI  - Capsular polysaccharide from Actinobacillus actinomycetemcomitans inhibits IL-6
      and IL-8 production in human gingival fibroblast.
AB  - We previously reported that a capsular polysaccharide (CP) from Actinobacillus
      actinomycetemcomitans Y4 induces bone resorption in a mouse organ culture system
      and osteoclast formation in mouse bone marrow cultures. However, the effects of
      A. actinomycetemcomitans Y4 CP on human gingival fibroblasts (HGF) are still
      unclear. The present study was undertaken to test the hypothesis that A.
      actinomycetemcomitans Y4 CP alters the production of inflammatory cytokines, such
      as interleukin-6 (IL-6) and IL-8 by HGF. When HGF were cultured with various
      concentrations of Y4 CP for 24 h, IL-6 and IL-8 production decreased in a
      concentration-dependent manner. Y4 CP (100 microg/ml) suppressed the release of
      IL-6 from 9.09 +/- 0.08 ng/ml to 0.34 +/- 0.21 ng/ml (P < 0.01) and IL-8
      production decreased from 3.76 +/- 0.03 ng/ml to 0.09 +/- 0.01 ng/ml (P < 0.01).
      Y4 CP suppressed 70-80% of the release of IL-6 and IL-8 from HGF stimulated with
      Y4 lipopolysaccharide (LPS), too. Interestingly, anti-A. actinomycetemcomitans Y4
      CP completely inhibited the effect of A. actinomycetemcomitans Y4 CP on IL-6 and
      IL-8 production from HGF. These results indicate that Y4 CP inhibits the release
      of IL-6 and IL-8 from HGF, suggesting that A. actinomycetemcomitans Y4 modulates
      the inflammatory response in periodontitis. Remarkably, this inhibitory effect
      was reversed by specific anti-A. actinomycetemcomitans Y4 CP suggesting an
      important relationship between the organism and the humoral host response.

PMID- 12608916
TI  - The effect of chronic emotional stress on the humoral immune response to
      Porphyromonas gingivalis in mice.
AB  - Previous studies have shown that psychological stress plays a significant role in
      the outcome of infectious diseases, but data related to the effect of stress on
      periodontal infection is limited. The present study was designed to test the
      impact of emotional stress on the humoral immune response to the periodontal
      pathogen Porphyromonas gingivalis in a mouse model of local inflammation.
      Chambers constructed from titanium wire were implanted in the subcutaneous
      dorsolumbar region of mice. All mice were immunized with P. gingivalis followed
      by an intrachamber challenge with the bacteria. One group of mice was used as
      control, while the other two experienced experimental stress conditions
      (isolation/restraint stress). Stress-1 group was stressed during the immunization
      period, while Stress-2 group was stressed during the local challenge period.
      Chamber exudates and serum were collected and analyzed for levels of anti-P.
      gingivalis antibodies (IgG, IgG1 and IgG2a). The levels of serum antibodies to P.
      gingivalis were not different between the three tested groups, excluding
      increased levels of IgG2a in Stress-1 group at baseline. The levels of antibodies
      in the chamber exudates were significantly lower in the stressed groups at
      baseline, but higher at d 7. The IgG1 to IgG2a ratio was significantly higher in
      the control group compared with the two stressed groups. The findings of the
      present study suggest that chronic psychological stress had a marked impact on
      the localized response to P. gingivalis challenge. The lower IgG1/IgG2a ratio
      observed in the stress groups suggests elevated Th1 response during stress.

PMID- 12608917
TI  - Patterns of chemokines and chemokine receptors expression in different forms of
      human periodontal disease.
AB  - Current knowledge states that periodontal diseases are chronic inflammatory
      reactions raised in response to periodontopathogens. Many cell types and
      mediators, including Th1 and Th2 lymphocytes, cytokines and chemokines, appear to
      be involved in the immunopathogenesis of periodontal diseases. Chemokines, a
      family of chemotactic cytokines, bind to specific receptors and selectively
      attract different cell subsets to the inflammatory site. They can also interact
      with classical cytokines and modulate the local immune response. In order to
      study the role of chemokines in periodontal diseases, we examined the expression
      of chemokines, chemokine receptors and cytokines by means of reverse
      transcription-polymerase chain reaction (RT-PCR) techniques. Characteristic
      patterns of such factors' expression were found in gingival biopsies from
      patients presenting with aggressive periodontitis and chronic periodontitis. The
      expression of the chemokines macrophage inflammatory protein-1 alpha (MIP-1alpha)
      and interferon-gamma inducible protein 10 (IP-10) and of their respective
      receptors, CCR5 and CXCR3, were more prevalent and higher in aggressive
      periodontitis, and associated with higher interferon-gamma (IFN-gamma) expression
      and lower interleukin-10 (IL-10) expression. In contrast, chronic periodontitis
      patients exhibited a more frequent and higher expression of monocyte
      chemoattractant protein-1 (MCP-1) and its receptor CCR4, and higher expression of
      IL-10. It is possible that chemokines, in addition to the classical cytokines,
      are involved in the immunopathogenesis of periodontal disease, driving the
      migration and the maintenance of several inflammatory cell types such as
      polymorphonuclear leukocytes, dendritic cells (DCs), natural killer cells,
      macrophages, and subsets of lymphocytes in the gingival tissues. These cells are
      thought to participate in the inflammatory and immune reaction that takes place
      in periodontal disease, killing pathogens, presenting antigens, and producing
      cytokines. The selective recruitment of polarized lymphocyte subsets could result
      in differential cytokine production at the site of response, which is supposed to
      determine the stable or progressive nature of the lesion. Besides, the role of
      chemokines as activators and chemoattracts of osteclasts may be involved in the
      determination of disease severity.

PMID- 12608918
TI  - Centrally mediated reflex vasodilation in the gingiva induced by painful tooth
      pulp stimulation in sympathectomized human subjects.
AB  - This study was designed to determine whether painful electrical stimulation of
      the tooth pulp induces centrally mediated reflex vasomotor changes in human
      gingiva and whether the sympathetic nervous system is involved in the vasomotor
      responses. Dynamic changes in maxillary gingival blood flow (GBF) following
      painful electrical stimulation of the mandibular lateral incisor were
      investigated, by means of laser-Doppler flowmetry, in both healthy volunteers and
      patients undergoing sympathetic blockade for hyperhidrosis. Increases in GBF were
      observed in both healthy volunteers and patients on the ipsilateral side without
      an increase in systemic blood pressure, but the evoked GBF increase disappeared
      when pain sensation was abolished by local anesthetization with 2% xylocaine
      solution. The vasodilator responses did not differ in amplitude between before
      and after the sympathectomy. These results suggest that painful tooth stimulation
      evokes centrally mediated reflex vasodilation, presumably via parasympathetic
      efferent fibers, in the human gingiva and that sympathetic vasomotor mechanisms
      are not involved in these responses.

PMID- 12608919
TI  - Combined TUNEL and TRAP methods suggest that apoptotic bone cells are inside
      vacuoles of alveolar bone osteoclasts in young rats.
AB  - Although it is generally accepted that osteoclasts breakdown and resorb bone
      matrix, the possibility that they may also be able to engulf apoptotic
      osteoblasts/lining cells and/or osteocytes remains controversial. Apoptosis of
      osteoblasts/ lining cells and/or osteocytes and interactions between these cells
      and osteoclasts are extremely rapid events that are difficult to observe in vivo.
      A suitable in vivo model for studying these events is the alveolar bone of young
      rats because it is continuously undergoing intense resorption/remodeling. Thus,
      sections of aldehyde fixed alveolar bone of young rats were stained by the
      combined terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
      (TUNEL) method and the tartrate-resistant acid phosphatase (TRAP) method for the
      simultaneous visualization of apoptotic cells and osteoclasts in the same
      section. The combined TUNEL and TRAP reactions, in the same section, greatly
      facilitated visualization of relationship between osteoclasts and apoptotic bone
      cells during alveolar bone remodeling. Our results showed that several TRAP
      positive osteoclasts exhibited large vacuoles containing TUNEL positive apoptotic
      structures, probably derived from osteoblasts/lining cells and/or osteocytes.
      These results support the idea that alveolar bone osteoclasts are able to
      internalize dying apoptotic bone cells.

PMID- 12608920
TI  - CFD in indoor air.

PMID- 12608921
TI  - Quality control of computational fluid dynamics in indoor environments.
AB  - Computational fluid dynamics (CFD) is used routinely to predict air movement and
      distributions of temperature and concentrations in indoor environments. Modelling
      and numerical errors are inherent in such studies and must be considered when the
      results are presented. Here, we discuss modelling aspects of turbulence and
      boundary conditions, as well as aspects related to numerical errors, with
      emphasis on choice of differencing scheme and computational grid. Illustrative
      examples are given to stress the main points related to numerical errors.
      Finally, recommendations are given for improving the quality of CFD calculations,
      as well as guidelines for the minimum information that should accompany all CFD
      related publications to enable a scientific judgment of the quality of the study.

PMID- 12608922
TI  - Comparison of multiple environmental factors for asthmatic children in public
      housing.
AB  - Nine families of a public housing development in Boston were enrolled in a pilot
      asthma intervention program designed to gather dense environmental data and
      generate hypotheses about the relative importance of different contaminants and
      the viability of interventions. Despite formidable challenges working with this
      inner-city population, the project team succeeded in gaining active support for
      the project by forming a partnership with a community-based organization and by
      building positive relationships between the field team and the residents.
      Families were provided with physical interventions such as air filters,
      industrial cleaning and mattress covers to each apartment. Indoor temperature was
      high and relative humidity low during winter. Insulation of exposed steam pipes
      did not lower temperature. Cockroach, mouse and pet antigen levels were variable
      and frequently high in settled dust. Viable fungal spore levels were variable and
      high in some apartments. Dust-mite allergen levels were below the level of
      concern. Industrial cleaning led to transient reduction in mouse and cockroach
      antigen burden. Mattress and pillow covers lowered dust-mite antigen in bedrooms,
      but not living rooms. Nitrogen dioxide (NO2) levels exceeded ambient
      concentrations due to use of gas stoves and concentrations of particulate matter
      with aerodynamic diameter <2.5 microm (PM2.5) were above ambient levels because
      of smoking. Air filtering systems did not reduce PM levels. Several volatile
      organic compounds (VOCs) were above adverse risk concentrations. We hypothesize
      that our findings are consistent with a multifactorial model for exacerbation of
      asthma in this population and that no single problem dominates.

PMID- 12608923
TI  - Comfort climate evaluation with thermal manikin methods and computer simulation
      models.
AB  - With increasing demand for acceptable environment in the modern workplace is it
      necessary, already in the construction phase, to estimate what effect different
      environmental factors have on the occupants. Thermal sensation is affected by
      many factors in the work place environment, especially thermal factors and
      effects from air movement caused by different ventilation principles. A series of
      full scale measurements as well as numerical calculations have been carried out
      in order to investigate whether Computational Fluid Dynamics (CFD) calculations
      and measurements with a thermal manikin are able to predict the perceived thermal
      climate. When human thermal sensation is linked together in measurements and
      calculations, the thermal situation in the work place environment is visualized.
      The results show relatively good agreement with the measurements made in the real
      environment. However, numerical and experimental methods need to be further
      developed. Evaluation methods of this type, will enable engineers to make better
      predictions and early decisions in the design and construction process. This also
      opens possibilities to use results from a number of full scale tests providing
      means to improve the comfort, health and productivity in working life.

PMID- 12608924
TI  - 'EUROPART'. Airborne particles in the indoor environment. A European
      interdisciplinary review of scientific evidence on associations between exposure
      to particles in buildings and health effects.
AB  - The relevance of particle mass, surface area or number concentration as risk
      indicators for health effects in non-industrial buildings has been assessed by a
      European interdisciplinary group of researchers (called EUROPART) by reviewing
      papers identified in Medline, Toxline, and OSH. Studies dealing with dermal
      effects or cancer or specifically addressing environmental tobacco smoke, house
      dust-mite, cockroach or animal allergens, microorganisms and pesticides were
      excluded. A total of 70 papers were reviewed, and eight were identified for the
      final review: Five experimental studies involving mainly healthy subjects, two
      cross-sectional office studies and one longitudinal study among elderly on
      cardiovascular effects. From most studies, no definite conclusions could be
      drawn. Overall, the group concluded that there is inadequate scientific evidence
      that airborne, indoor particulate mass or number concentrations can be used as
      generally applicable risk indicators of health effects in non-industrial
      buildings and consequently that there is inadequate scientific evidence for
      establishing limit values or guidelines for particulate mass or number
      concentrations.

PMID- 12608925
TI  - Flame retardants in the indoor environment -- Part II: release of VOCs
      (triethylphosphate and halogenated degradation products) from polyurethane.
AB  - Organophosphate esters, halogenated and non-halogenated, are frequently used for
      fire protection of building materials. With regard to toxicological profiles it
      is desired to avoid human exposure in the indoor environment. Moreover, some
      hazardous volatile organic compounds detected in indoor air are directly linked
      to the utilization of flame retardants. In this study, different polyurethane
      (PUR) products for building and indoor use treated with organophosphate flame
      retardants were tested in 1 m(3) emission test chambers. Emissions of flame
      retardants and degradation products were measured under living conditions. A PUR
      hard foam sample showed area-specific emission rates >100 microg/m(2) h for the
      compound triethylphosphate. During the tests several chlorinated degradation
      products of organophophorous flame retardants could be identified in the chamber
      air.

PMID- 12608926
TI  - Indoor air quality, ventilation and health symptoms in schools: an analysis of
      existing information.
AB  - We reviewed the literature on Indoor Air Quality (IAQ), ventilation, and building
      related health problems in schools and identified commonly reported building
      related health symptoms involving schools until 1999. We collected existing data
      on ventilation rates, carbon dioxide (CO2) concentrations and symptom-relevant
      indoor air contaminants, and evaluated information on causal relationships
      between pollutant exposures and health symptoms. Reported ventilation and CO2
      data strongly indicate that ventilation is inadequate in many classrooms,
      possibly leading to health symptoms. Adequate ventilation should be a major focus
      of design or remediation efforts. Total volatile organic compounds, formaldehyde
      (HCHO) and microbiological contaminants are reported. Low HCHO concentrations
      were unlikely to cause acute irritant symptoms (<0.05 ppm), but possibly
      increased risks for allergen sensitivities, chronic irritation, and cancer.
      Reported microbiological contaminants included allergens in deposited dust,
      fungi, and bacteria. Levels of specific allergens were sufficient to cause
      symptoms in allergic occupants. Measurements of airborne bacteria and airborne
      and surface fungal spores were reported in schoolrooms. Asthma and 'sick building
      syndrome' symptoms are commonly reported. The few studies investigating causal
      relationships between health symptoms and exposures to specific pollutants
      suggest that such symptoms in schools are related to exposures to volatile
      organic compounds (VOCs), molds and microbial VOCs, and allergens.

PMID- 12608927
TI  - The relation between growth of four microbes on six different plasterboards and
      biological activity of spores.
AB  - Microbial growth on water-damaged building materials is commonly associated with
      adverse health effects in the occupants. We examined the growth of Stachybotrys
      chartarum, Aspergillus versicolor, Penicillium spinulosum, and Streptomyces
      californicus, isolated from water-damaged buildings, on six different brands of
      plasterboards. The microbial growth was compared with the biological activity of
      the spores, that is the potential to induce cytotoxicity and proinflammatory
      mediators in RAW264.7 macrophages. These results showed that the microbial growth
      on plasterboard depended on both the microbial strain and the brand of
      plasterboard used. The biological activity of spores appeared to be regulated by
      different growth conditions on plasterboards so that good microbial growth was
      associated with a low bioactivity of the spores, whereas the spores collected
      from plasterboard supporting only weak growth usually were biologically active.
      Cytotoxicity of either S. chartarum or A. versicolor did not correlate with any
      particular growth conditions or induced inflammatory responses. Instead, there
      were positive correlations between cytotoxicity and levels of induced
      proinflammatory cytokines for P. spinulosum and S. californicus. These data
      suggest that both the microbial growth on plasterboard and the resulting
      bioactivity of spores vary and might be affected by changing the growth
      conditions provided by the plasterboards.

PMID- 12608928
TI  - Hormone replacement therapy: current controversies.
AB  - Postmenopausal hormonal therapy is used to manage the climacteric symptoms that
      impair the quality of life of a substantial number of women. The difficulty is
      achieving the desired effects with minimal side-effects and no adverse health
      risks. Fundamental to this is understanding the physiology of oestrogen in women
      and the metabolism of the therapeutic compounds. Although the effects of oral
      oestrogen therapy have been studied extensively, there is insufficient evidence
      to assess adequately the independent effects of progestin use, other oestrogen
      compounds, differing doses and duration of treatment. We have reviewed some basic
      concepts of oestrogen physiology and how these relate to exogenous oestrogen
      administration, the risks of greatest concern, and the role of androgens and
      newer treatment alternatives.

PMID- 12608929
TI  - Significant ethnic variation in total and free testosterone concentration.
AB  - OBJECTIVE: Measurement of serum testosterone is an integral part of the
      assessment of men presenting to endocrine clinics. Little is known about the
      variation of total bound or bioavailable testosterone by ethnic group. The
      principal determinant of testosterone bioavailability is SHBG, which itself is a
      marker for insulin sensitivity. Our aim was to examine variations in testosterone
      and SHBG levels across three ethnic groups in relation to ethnic differences in
      insulin sensitivity. DESIGN: Men of three ethnic groups living in Manchester, UK,
      were sampled randomly from population registers being of white European (n = 55),
      Pakistani (n = 50) and African-Caribbean (AfC) origin (n = 75). Circulating serum
      testosterone and SHBG concentrations were measured and free testosterone
      calculated. Insulin sensitivity (HOMA-S) and insulin secretory capacity (HOMA-B)
      were determined from fasting plasma intact insulin and glucose values. RESULTS:
      Testosterone levels were lower in Pakistani men (mean 14.6 nmol/l, 95% confidence
      interval 12.6-16.6 nmol/l) than in Europeans (18.7, 16.8-20.6 nmol/l) or AfCs
      (18.0, 16.4-19.6 nmol/l) (F = 4.8, P = 0.009). Despite SHBG levels also being
      lower in Pakistani men (22.9, 19.4-26.5 nmol/l) compared with Europeans (28.7,
      25.7-31.8 nmol/l) and AfCs (26.9, 23.9-30.0 nmol/l) (F = 3.0, P < 0.05),
      circulating free testosterone was significantly lower in the Pakistani group
      (367, 326-408 pmol/l) than in Europeans (455, 416-494 pmol/l) or AfCs (458, 424
      492 pmol/l) (F = 6.8, P = 0.001). Pakistani men were on average 4 cm shorter than
      other groups. However, the lower free testosterone persisted even when adjusted
      for height or waist-hip ratio. The lower SHBG in the Pakistani men was paralleled
      by a lower HOMA-S (0.40, 0.25-0.56) compared with Europeans (0.77, 0.61-0.93) and
      AfCs (0.80, 0.66-0.93) (F = 8.2, P < 0.0001). SHBG correlated positively with
      HOMA-S (rho = 0.28, P < 0.001) and strongly with total testosterone (rho = 0.54,
      P < 0.001). There was no difference in insulin secretory capacity (HOMA-B) in
      Pakistani men compared with Europeans and AfCs. Multiple linear regression
      analysis showed that total testosterone was independently and negatively related
      to ln fasting insulin (beta = -0.28, P < 0.001) and age (beta = -0.17, P = 0.02)
      and positively to ln SHBG (beta = 0.23, P < 0.001) and height (beta = 0.22, P =
      0.001). There was no relationship with ethnicity or waist-hip ratio. CONCLUSION:
      Both total bound and calculated free testosterone were lower in Pakistani men.
      SHBG levels were also lower in Pakistani men, in keeping with poorer insulin
      sensitivity. We propose that further work is necessary to establish ethnic
      specific ranges for the interpretation of total circulating and free testosterone
      levels in men.

PMID- 12608930
TI  - Final height outcome and value of height prediction in boys with constitutional
      delay in growth and adolescence treated with intramuscular testosterone 125 mg
      per month for 3 months.
AB  - OBJECTIVES: Constitutional delay in growth and adolescence (CDGA) is common in
      boys, some of whom request treatment to accelerate growth and attainment of
      secondary sexual characteristics. The aims of this study were to confirm that a 3
      month course of intramuscular testosterone oenanthate does not impair final
      height in boys with CDGA, and to determine the accuracy of height prediction in
      this condition. DESIGN AND PATIENTS: Boys with CDGA who had attended the growth
      clinic, who were now at or close to final height and who had received either
      testosterone or declined treatment, were identified by retrospective case note
      analysis. Bone age assessment was carried out by a single observer, using the RUS
      (TW2) method of Tanner and Whitehouse. MEASUREMENTS: The following auxological
      data were extracted from the case records: age, bone age, height, pubertal stage,
      parental heights and predicted final height. All subjects were then measured at
      age 19 years or greater. The main outcome measures were comparison of final
      height in treated and untreated boys; final height comparison with mid-parental
      height and with height prediction [RUS (TW2) method] at initial assessment and at
      subsequent review. RESULTS: Sixty-four boys met the inclusion criteria, of whom
      41 subjects had received testosterone and 23 were untreated. There were no
      significant differences between the groups (treated mean/SD vs. untreated
      mean/SD; P-value) in age (14.3/0.7 vs. 14.0/1.1; 0.13), height (144.7/6.2 vs.
      144.2/6.2; 0.79), mid-parental heights (170.4/5.5 vs. 171.1/4.5; 0.59), and bone
      age (12.0/1.2 vs. 12.3/1.3; 0.36). Final heights in both groups (168.9/6.0 vs.
      168.2/3.5; 0.65) were closely related to predicted final heights (170.0/5.0 vs.
      168.1/4.1; 0.15) and only slightly less than mid-parental heights. Only three
      subjects had final heights below the initial height prediction range.
      CONCLUSIONS: Our data support the hypothesis that this treatment regime does not
      adversely affect the final height achieved in constitutional delay of growth and
      adolescence and that height prediction, assessed by a single observer, is a
      useful and accurate tool.

PMID- 12608931
TI  - Bone mineral density, biochemical and hormonal profiles in suboptimally treated
      children and adolescents with beta-thalassaemia disease.
AB  - OBJECTIVE: Thalassaemia/haemoglobinopathy is a hereditary disease causing
      increased erythropoiesis and expansion of the bone marrow cavity. As a
      consequence, there is a reduction in trabecular bone tissue resulting in
      osteopenia/osteoporosis. The present study was performed to assess bone mineral
      density (BMD) in children and adolescents with beta-thalassaemia disease and to
      determine biochemical and hormonal changes that may affect BMD. METHODS: Forty
      eight children and adolescents with beta-thalassaemia were divided into two
      groups, transfusion-dependent (TD) (n = 16) and transfusion-independent (TI) (n =
      32). All patients were treated suboptimally. BMD was determined by dual-energy X
      ray absorptiometry. Bone maturation was assessed by radiographic bone age (BA).
      Blood and urine samples were obtained for the determination of biochemical and
      hormonal profiles, which included PTH, 25-hydroxyvitamin D (25-OHD), osteocalcin,
      bone-specific alkaline phosphatase, IGF-1, fT4, TSH and urine deoxypyridinoline.
      RESULTS: Most of the patients were short and underweight, and they had delayed BA
      with mean Z-scores of -2.77 in the TD and -2.04 in TI groups. The mean Z-scores
      of BMD in the TD vs. TI groups of total body, radius, femoral neck and lumbar
      spine were -2.09 vs.-1.49, -0.73 vs. -0.54, -1.93 vs.-1.17 and -3.45 vs.-2.43,
      respectively. Although the means BMD values in the TD group were lower than those
      in the TI group, they were not significantly different. Mean serum IGF-1 levels
      were lower in the TD than the TI groups, 11.6 and 24.9 nmol/l, respectively (P <
      0.05). Other biochemical and hormonal profiles did not differ between these two
      groups. CONCLUSIONS: Patients with undertransfused severe beta-thalassaemia had
      more bone marrow expansion, lower serum IGF-1 levels and more delayed bone age
      than did patients with untransfused moderately severe beta-thalassaemia.
      Therefore, the severity of the disease appeared to be a primary factor for low
      bone mineral density in undertransfused patients in association with bone age
      delay and low serum IGF-1.

PMID- 12608932
TI  - TSH-R expression and cytokine profile in orbital tissue of active vs. inactive
      Graves' ophthalmopathy patients.
AB  - OBJECTIVE: From in vitro studies using cultures of orbital fibroblasts, it has
      become clear that cytokines play an important role in the orbital inflammation in
      Graves' ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells
      of the autoimmune attack, and they are able to express the TSH receptor (TSH-R).
      In vivo data on the presence of cytokines in orbital tissues are sparse, and
      mostly limited to samples obtained from patients with endstage, inactive GO; the
      same holds true for the presence of the TSH-R. The aim of the present study was
      to determine whether the cytokine profile and TSH-R expression differ in the
      active vs. the inactive stage of GO. DESIGN AND MEASUREMENTS: Orbital
      fat/connective tissue was obtained from six patients with active, untreated GO
      undergoing emergency orbital decompression, and from 11 patients with inactive GO
      subjected to rehabilitative decompressive surgery. The mRNA levels of various
      cytokines and the TSH-R were assessed by real-time polymerase chain reaction
      (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/beta
      actin mRNA). RESULTS: Active GO patients had much higher TSH-R expression than
      inactive patients: 4/0-24 (median value/range) vs. 0/0-9, P = 0.01. TSH-R
      expression was related to the Clinical Activity Score (r = 0.595, P = 0.015).
      Patients with active GO compared to those with inactive GO had higher mRNA levels
      of the proinflammatory cytokines interleukin-1beta (IL-1beta) (445/153-877 vs.
      0/0-455, P = 0.001), IL-6 (1583/968-18825 vs. 559/0-7181, P = 0.01), IL-8
      (1422/38-7579 vs. 32/0-1081, P = 0.046) and IL-10 (145/58-318 vs. 27/0-189, P =
      0.002). In active GO there also existed a trend towards a predominance of T
      helper 1 (Th1)-derived cytokines as evident from higher IL-2 (37/0-158 vs. 0/0
      68, P = 0.043), interferon-gamma (IFN-gamma) (20/0-79 vs. 0/0-16, P = 0.12) and
      IL-12 (2.3/0-14.8 vs. 0/0-1.6, P = 0.10) mRNAs. IL-1 receptor agonist (IL-1RA),
      IL-2 receptor (IL-2R), IL-3, IL-4, IL-5, IL-13, IL-18 and tumour necrosis factor
      alpha (TNF-alpha) mRNAs were similar in both groups. CONCLUSIONS: These data show
      that at the mRNA level, TSH-R expression is largely present only during the
      active stages of GO. The active phase is characterized by the presence of
      proinflammatory and Th1-derived cytokines, whereas other cytokines, among them
      Th2-derived cytokines, do not seem to be linked to a specific stage of GO.

PMID- 12608933
TI  - Sandostatin LAR in acromegaly: a 6-week injection interval suppresses GH
      secretion as effectively as a 4-week interval.
AB  - INTRODUCTION: Depot preparations of long-acting somatostatin analogues are being
      used increasingly in the treatment of GH hypersecretion in patients with
      acromegaly, either as primary treatment or as secondary treatment following
      incomplete surgery. In 60% of these patients, Sandostatin long-acting release
      (LAR), the depot preparation of octreotide, achieves effective suppression of
      serum GH (< 5 mU/l) and IGF-I levels. The advice is to administer Sandostatin LAR
      at 4-week intervals. After injection, serum octreotide shows an initial peak and
      thereafter maximal values between 14 and 42 days. There have been suggestions
      that the dose interval of this preparation could be increased, resulting in
      reduced costs, although this concept has not been confirmed by studies. AIM OF
      THE STUDY: We performed a prospective, cohort study in patients with active
      acromegaly but with normal serum GH and IGF-I levels during Sandostatin LAR
      treatment to assess whether the dose interval could be safely increased from 4 to
      6 weeks, without significant effect on serum GH concentrations or other
      biochemical and clinical markers of GH hypersecretion. PATIENTS AND METHODS:
      Fourteen patients (seven males) with GH concentrations below 5 mU/l during
      Sandostatin LAR treatment entered an 8-week withdrawal study following an
      injection. Subsequently, during an interval study patients received injections at
      6-week intervals (t = 0, 8, 14, 20, 26, 32, 38 and 44 weeks). Study parameters
      (fasting GH, average GH of eight plasma samples, IGF-I, and octreotide
      concentrations, symptoms score and quality-of-life score) were assessed 2, 4, 6
      and 8 weeks following the first injection (withdrawal) and at 26 and 44 weeks
      (interval study) before the next injection. RESULTS: During the withdrawal study,
      mean serum GH concentration increased significantly from 1.68 +/- 0.3 at 4 weeks
      to 2.57 +/- 0.5 mU/l at 6 weeks (P = 0.04, 4 vs. 6 weeks) and to 2.89 +/- 0.4
      mU/l at 8 weeks (P < 0.001, 4 vs. 8 weeks). Mean serum GH concentration was below
      5 mU/l in all patients at all time points, except for one patient at 8 weeks, and
      IGF-I levels remained normal in all patients. During withdrawal up to 8 weeks
      there was no significant change in serum IGF-I concentration, symptoms score or
      quality-of-life score. Mean serum octreotide decreased significantly from 1610 +/
      355 ng/l at 2 weeks to 1045 +/- 272 ng/l at 6 weeks (P = 0.002, 2 and 4 vs. 6
      weeks) and to 559 +/- 147 ng/l at 8 weeks. In the interval study, one patient had
      mean serum GH above 5 mU/l associated with an increase in symptoms at 26 weeks
      and she was withdrawn from the study. The remaining 13 patients completed the 6
      weekly injection study protocol and in the long term no significant changes in
      mean serum GH concentration, IGF-I concentration or symptom scores were observed
      (6 vs. 26 and 44 weeks). All patients had a mean serum GH concentration < 5 mU/l
      and serum IGF-I remained normal in 11 out of 14 patients at 26 weeks and nine out
      of 13 patients at 44 weeks. Moreover, the mean octreotide concentrations measured
      6 weeks after a Sandostatin LAR injection did not decrease in the long term.
      CONCLUSION: On the basis of serum GH concentrations, most patients with serum GH
      levels < 5 mU/l during Sandostatin LAR treatment using a 4-weekly schedule can be
      effectively treated with 6-weekly injections. However, during long-term treatment
      with 6-weekly injections, discordant IGF-I and GH results were observed in 30% of
      the patients and careful clinical monitoring is therefore required.

PMID- 12608934
TI  - Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated
      for cancer?
AB  - BACKGROUND AND OBJECTIVE: Chemotherapy treatment of childhood cancer may impair
      gonadal function, which may be manifested only in adulthood as permanent
      sterility. Detection of gonadal dysfunction in prepubertal children has been
      hampered by the absence of a sensitive marker. Inhibin B is secreted by small
      antral follicles and Sertoli cells in females and males, respectively, and may be
      a marker of gonadal function in prepubertal children. The aim of this pilot study
      was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins
      as markers of the early gonadotoxic effects of chemotherapy in prepubertal
      children treated for cancer. STUDY DESIGN AND SUBJECTS: Twenty-five prepubertal
      children (9 females), median age 4.5 years (range 1.2-12.8 years) with cancer (16
      solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied
      longitudinally. Blood samples were collected before and during chemotherapy
      (solid tumours) or immediately following induction and first intensification
      (ALL). Post-treatment (1-6 months) samples were collected in 12 of the patients
      (5 females). MEASUREMENTS: Dimeric inhibin B was measured by double antibody
      enzyme-linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive
      time-resolved immunofluorescence. RESULTS: Girls: Pretreatment inhibin B was
      slightly high in one girl but normal for age and sex in all others: median 16.1
      (range 9.4-186.2) ng/l, median SD score +0.2 (-1.3 to +2.6). Inhibin B decreased
      to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0.03), with
      no accompanying rise in FSH or LH. Post-treatment recovery of inhibin B was
      variable: median 16.1 (range < 8.0-44.2) ng/l, median SD score +0.1 (range < -2.4
      to +1.8). Sustained undetectable inhibin B levels were observed in 2/5 girls with
      correspondingly elevated FSH concentrations (11.8 and 10.9 U/l). Boys: Inhibin B
      was normal for age and sex in all boys before treatment with no significant
      change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores
      -0.3, -0.6 and -0.2, respectively). Inhibin B decreased to undetectable levels in
      one boy post-treatment with no accompanying increase in FSH or LH. CONCLUSIONS:
      In prepubertal girls with cancer, chemotherapy is associated with suppression of
      inhibin B, usually transient, which may indicate arrest of follicle development.
      Sustained suppression of inhibin B following treatment may be indicative of
      permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate
      effect on Sertoli cell production of inhibin B, although one boy showed a delayed
      effect. Inhibin B, together with sensitive measurements of FSH, may be a
      potential marker of the gonadotoxic effects of chemotherapy in prepubertal
      children with cancer.

PMID- 12608935
TI  - Effect of 2 years of cortisol normalization on the impaired bone mass and
      turnover in adolescent and adult patients with Cushing's disease: a prospective
      study.
AB  - BACKGROUND: Osteoporosis is a frequent, severe and often underestimated
      consequence of long-term hypercortisolism, often presenting as bone fracture.
      OBJECTIVE: This prospective study was designed to evaluate whether the
      abnormalities of bone mass and turnover can be similarly reversed in adolescent
      and adult patients with Cushing's disease, after correction of hypercortisolism.
      PATIENTS AND METHODS: Bone mineral density (BMD) at lumbar spine, serum
      osteocalcin (OC) and urinary cross-linked N-telopeptides of type I collagen (Ntx)
      levels were measured at diagnosis and 2 years after cure of Cushing's disease
      (CD) in six patients with childhood-onset and nine with adulthood-onset disease.
      Fifteen age-, sex- and body mass index (BMI)-matched healthy subjects served as
      controls. RESULTS: At diagnosis, BMD Z scores at lumbar spine and OC levels were
      lower (2.3 +/- 0.1 vs.-0.2 +/- 0.01; P < 0.01 and 1.6 +/- 0.1 vs. 9.6 +/- 1.2; P
      < 0.01 respectively) while urinary Ntx levels were significantly higher (139.9 +/
      6.1 vs. 82.0 +/- 1.6; P < 0.01) in CD patients than in controls. Among CD
      patients, similar values of Z scores (-2.4 +/- 0.3 vs.-2.2 +/- 0.1, P = 0.4) and
      OC levels (1.7 +/- 0.2 vs. 1.6 +/- 0.2, P = 0.6) were observed in adolescent and
      adults patients, whereas urinary Ntx levels were significantly higher (159.7 +/-
      7.9 vs. 125.9 +/- 3.3, P < 0.001) in the former than in the latter group. Two
      years after remission from hypercortisolism, OC levels (P < 0.001) and lumbar BMD
      Z scores (-2.2 +/- 0.3, P < 0.05; and -1.9 +/- 0.2; P < 0.01, respectively)
      increased significantly, while urinary Ntx levels reduced significantly (P <
      0.001) in both adolescent and adult patients. However, biochemical markers and Z
      scores of BMD remained significantly suppressed compared to controls.
      CONCLUSIONS: Bone impairment in childhood- and adulthood-onset Cushing's disease
      patients can be partly, but not completely, reversed 2 years after normalization
      of cortisol levels. Longer recovery times or additive therapeutic approaches are
      necessary to maximize peak bone mass in children and restore bone mass in adults
      with Cushing's disease.

PMID- 12608936
TI  - The effect of growth hormone (GH) replacement therapy in adult patients with type
      1 diabetes mellitus and GH deficiency.
AB  - OBJECTIVES: Specific problems in patients with insulin-dependent diabetes
      mellitus (IDDM) and GH deficiency are hypoglycaemic attacks, increased insulin
      sensitivity and loss of energy. These problems may be related to GH deficiency.
      PATIENTS: GH replacement was initiated in five patients with type 1 diabetes
      mellitus and GH deficiency for 6 months [four males and one female, mean age 41.6
      +/- 3.8 years, mean +/- standard error of the mean (SEM); body mass index (BMI)
      22.3 +/- 1.2 kg/m2]. METHODS: Body composition (bioimpedance), metabolic control
      [haemoglobin A1C (HbA1C)], insulin requirement and frequency of hypoglycaemia
      were measured, and quality of life was assessed using validated questionnaires.
      Monthly eye photographs were taken. RESULTS: IGF-I concentrations were below the
      age-adjusted range at baseline and increased significantly following GH
      replacement therapy [analysis of variance (ANOVA), P < 0.05]. Diabetes control as
      assessed by HbA1C remained stable (8.2 +/- 0.2 vs. 8.0 +/- 0.4), but needed a
      1.75-fold increase in insulin dose/day. Lean body mass tended to increase (P =
      0.07) and body fat mass decreased significantly (P > 0.01). Number of severe
      hypoglycaemic (< 3 mmol/l) attacks decreased significantly (P < 0.04) and quality
      of life assessed by validated questionnaires improved significantly in all
      patients [Psychological and General Well-Being Schedule (PGWBS), P < 0.04;
      Nottingham Health Profile (NHP), P < 0.05]. Monthly eye photographs revealed no
      changes in the retina in any patients. CONCLUSION: GH replacement therapy has a
      beneficial effect at the dose used. It restores body composition and decreases
      frequency and severity of hypoglycaemic episodes, thus improving quality of life.
      Long-term trials are needed to determine the safety of GH replacement therapy in
      these patients.

PMID- 12608937
TI  - Relationship between plasma insulin and left ventricular mass in normotensive
      participants of the Gubbio Study.
AB  - BACKGROUND: There is substantial but not conclusive evidence that insulin
      resistance is related to left ventricular mass (LVM) in hypertensive individuals.
      To what extent this association is mediated by the relationship between plasma
      insulin and body size and build is still debated, and is poorly explored in
      nonhypertensive people. OBJECTIVE: To explore the relationship between insulin or
      insulin resistance and LVM in a population-based sample of nonhypertensive
      participants of the Gubbio Study. METHOD: Echocardiographic LVM was determined in
      91 nondiabetic, nonhypertensive individuals aged 45-54 years, participating in a
      population-based screening. LVM normalized for height2.7 was used in the
      analyses; LV hypertrophy was defined as a value of > or = 50 g/m2.7 in men or >
      or = 47 g/m2.7 in women. Fasting plasma insulin and glucose were measured and the
      Homeostasis Model Assessment (HOMA) index was used as a measure of insulin
      resistance. RESULTS: LVM was positively and significantly correlated with body
      mass index (BMI) (P < 0.01), waist circumference (P < 0.01) and HOMA index (P <
      0.05), whereas correlations with plasma glucose and triglycerides did not reach
      statistical significance (P = 0.07 for both); all correlations were offset after
      adjusting for BMI. Fasting plasma insulin and HOMA index were not significantly
      different in subjects with or without LV hypertrophy (70.8 +/- 27.8 vs. 77.7 +/-
      29.6 pmol/l and 2.2 +/- 1.0 vs. 2.6 +/- 1.4, respectively). Bivariate analysis
      performed stratifying participants above or below the 75th percentile of the sex
      specific distribution for BMI (29.1 and 29.4 kg/m2 for males and females,
      respectively) and plasma insulin (84 pmol/l for either gender), did not result in
      appreciable differences in LVM due to insulin levels. Similar results were
      obtained replacing the HOMA index for insulin in the analysis. CONCLUSION: In
      nonhypertensive individuals left ventricular mass is not associated with plasma
      insulin independently of body mass index.

PMID- 12608938
TI  - Carriers for type II 3beta-hydroxysteroid dehydrogenase (HSD3B2) deficiency can
      only be identified by HSD3B2 genotype study and not by hormone test.
AB  - OBJECTIVE: We investigated adrenal steroidogenic function relevant to 3beta
      hydroxysteroid dehydrogenase (HSD3B2) activity in vivo and HSD3B2 genotype in
      clinically normal family members of patients with HSD3B2 genotype-proven HSD3B2
      deficiency congenital adrenal hyperplasia (CAH) to determine whether genotype
      proven carriers for HSD3B2 deficiency exhibit decreased enzyme activity analogous
      to the mildly decreased adrenal 21-hydroxylase activity in the carriers of CYP21
      gene mutation. DESIGN/PATIENTS: Nineteen adult family members (ages median/range:
      37/19-56 years) including 13 females and six males of six unrelated patients with
      HSD3B2 genotype-proven HSD3B2 deficiency were studied. MEASUREMENTS: All family
      members had HSD3B2 DNA analysis and an ACTH stimulation test (Cortrosyn 0.25 mg
      IV bolus) for determination of adrenal HSD3B activity. RESULTS: Ten of 13 females
      and five of six males were carriers of a proven or predictably deleterious
      mutation in one allele of the HSD3B2 gene, which was identified in the probands.
      ACTH-stimulated levels of 17-hydroxypregnenolone (delta5-17P), 17
      hydroxyprogesterone (17-OHP), cortisol (F), dehydroepiandrosterone (DHEA) and
      androstenedione (delta4-A) and ratios of delta5-17P to 17-OHP, delta5-17P to F
      and DHEA to delta4-A, as well as increments of delta5-17P and DHEA values (ACTH
      stimulated - baseline) in the genotype-proven female carriers (age, mean +/- SD:
      36 +/- 6.7 years) and male carriers (age, mean +/- SD: 37 +/- 6.7 years) did not
      differ significantly from age-matched normal females (35 +/- 5.4 years, n = 20)
      and normal males (35 +/- 6 years, n = 10), respectively. There were no
      significant differences in any of the ACTH-stimulated hormonal levels or ratios
      between the female carriers with a seriously deleterious genotype (n = 5) and the
      female carriers with mildly deleterious genotypes (n = 5). These hormonal levels
      and ratios in three genotype-normal females and one genotype-normal male
      overlapped with those of the carriers. CONCLUSION: These data suggest that normal
      adrenal HSD3B2 activity is maintained in the genotype-proven carriers because
      heterodimers of mutant and wild-type HSD3B2 enzymes may be stable and exhibit
      similar activity compared to homodimers of wild-type enzymes, possibly by a
      relatively rate-unlimited effect of haplo-wild-type enzyme activity. However, we
      cannot preclude entirely the possibility of a limited expression of another HSD3B
      activity under ACTH stimulation contributing to the normal adrenal HSD3B activity
      in vivo in the HSD3B2 genotype-proven heterozygotes. Which mechanism plays a role
      in maintaining normal enzyme activity in the heterozygotes remains to be
      elucidated. The hormone findings in the genotypic-proven carriers for HSD3B2
      deficiency also indicate that carriers for this disorder cannot be detected by a
      hormone test and can only be detected by HSD3B2 genotype study.

PMID- 12608939
TI  - The regulation of growth in glycogen storage disease type 1.
AB  - OBJECTIVE: To study endocrine and metabolic variables that affect growth in
      patients with glycogen storage disease type 1 (GSD-1) receiving standard dietary
      therapy. DESIGN: Observational study. PATIENTS AND MEASUREMENTS: Thirty-eight
      patients with GSD-1, age range 0.6-32.9 years, were investigated on their usual
      dietary regimens. Data on height, height velocity in prepubertal children,
      endocrine and metabolic responses to oral glucose load, 24-h serum cortisol and
      GH concentration profiles and serum IGF-1 concentrations were collected. RESULTS:
      The population studied was shorter than average, with a median height standard
      deviation score (SDS) of -1.60, but significantly taller than a historical
      population studied at the same institution that had not received dietary therapy
      at the time of study. A wide range of height SDS was encountered (-5.28 to 1.21)
      and a subset still exhibit marked growth failure. Median body mass index (BMI)
      SDS was 0.72 (range -1.34 to 3.96). Those patients with the greatest BMI SDS had
      the lowest serum GH concentrations but serum IGF-1 concentrations were within the
      normal range. Patients with the poorest growth exhibit low serum insulin
      concentration responses to glucose load, GH insensitivity and higher mean 24-h
      plasma cortisol levels when compared to those patients who were better grown.
      CONCLUSION: This study shows that overall the growth of this group of patients
      with glycogen storage disease type 1 has improved compared to that of a
      historical control group. There remains a subset of this population with poor
      growth despite therapy. The measured endocrine responses in this subset are
      similar to those reported for untreated patients. To improve the growth further
      in these individuals it will be necessary to understand whether this is failure
      of prescribed therapy or failure to comply with therapy.

PMID- 12608941
TI  - Forearm bone density in primary hyperparathyroidism: long-term follow-up with and
      without parathyroidectomy.
AB  - OBJECTIVE: The long-term effects of primary hyperparathyroidism (PHPT), whether
      treated or untreated, on cortical bone are unclear, but the balance of evidence
      suggests that fracture risk is modestly increased in this patient group. We
      therefore compared changes in forearm cortical bone mineral density (BMD), at the
      site most relevant for PTH-mediated bone loss, in two groups of patients with
      PHPT; one with and one without surgery. DESIGN AND PATIENTS: We followed the
      course of forearm bone mineral/bone width (BM/BW, g/cm2) measured by single
      energy photon absorptiometry at the standard proximal site, and Z-scores
      (deviations from the mean value expected for age, sex and race, calculated from a
      large local reference population) in 108 patients who underwent successful
      surgery (mean duration 47 months, range 12-120 months) and 108 who remained
      unoperated (mean duration 52 months, range 12-132 months). Criteria for
      recommending surgery had been formulated in 1975 and were generally similar to
      those of the NIH consensus conference published in 1991. At the time of diagnosis
      the Z-score was significantly reduced in both groups, indicating an earlier
      period of accelerated cortical bone loss. RESULTS: In the entire operated
      population there was no difference between the initial and final BM/BW. As the
      age-expected mean value declined, the Z-score became significantly less negative,
      and if the rate of change remained constant the values would have reached zero,
      indicating recovery of all bone lost as a result of the disease, after about 20
      years. In the unoperated patients BM/BW fell significantly but there was no
      change in Z-score, indicating that the rate of bone loss was the same as expected
      for normal ageing. CONCLUSIONS: It is reasonable to assume that cessation of
      further bone loss consequent on successful parathyroid surgery would eventually
      lead to abatement of the excess fracture risk, but the benefit to individual
      patients will depend mainly on their remaining life expectancy.

PMID- 12608940
TI  - Thyroid stimulating hormone (TSH) concentrations and menopausal status in women
      at the mid-life: SWAN.
AB  - OBJECTIVE: We evaluated menopausal symptoms, menstrual cycle bleeding
      characteristics and reproductive hormones for their associations with thyroid
      stimulating hormone (TSH) concentrations in women at the mid-life from five
      ethnic groups. METHODS: This report is from the baseline evaluation of the Study
      of Women's Health Across the Nation (SWAN), a community-based multiethnic study
      of the natural history of the menopausal transition. Enrollees were 42-52 years
      old (pre- and early perimenopausal) African American, Caucasian, Chinese,
      Hispanic and Japanese women (n = 3242). Enrollees were interviewed about self
      reported diagnosed hypo- and hyperthyroidism or thyroid treatment, menopausal
      symptoms and menstrual cycle bleeding characteristics. Serum was assayed for TSH,
      oestradiol, testosterone, FSH and SHBG. RESULTS: There were 6.2% of women with
      TSH > 5.0 mIU/ml and 3.2% with TSH < 0.5 IU/ml, cutpoints that have been used to
      encompass clinical and subclinical hypo- and hyperthyroidism, respectively.
      African American women had significantly lower mean TSH concentrations than
      Caucasian, Hispanic and Chinese women. Of the more than 15 menopause symptoms
      evaluated, only fearfulness was associated with having a TSH value > 5.0 mIU/ml
      (P < 0.008) or < 0.5 mIU/ml (P < 0.02). Women with TSH values outside the range
      of 0.5-5.0 mIU/ml were more likely to report shorter or longer menstrual periods
      (P = 0.004 for both) than women within that range. FSH, SHBG,
      dehydroepiandrosterone sulphate (DHEA-S), testosterone, and oestradiol
      concentrations were not associated with TSH concentrations. CONCLUSION: In mid
      aged women, there was a 9.6% prevalence of TSH values outside the euthyroid range
      of 0.5-5.0 mIU/ml. Although TSH was associated with bleeding length and self
      reported fearfulness, it was not associated with indicators of the menopausal
      transition, including menopausal stage defined by bleeding regularity, menopausal
      symptoms or reproductive hormone concentrations.

PMID- 12608942
TI  - The outcome in Australian children with hyperinsulinism of infancy: early
      extensive surgery in severe cases lowers risk of diabetes.
AB  - AIMS: Hyperinsulinism of infancy (HI) is characterized by unregulated insulin
      secretion in the presence of hypoglycaemia, often resulting in brain damage.
      Pancreatic resection for control of hypoglycaemia is frequently resisted because
      of the risk of diabetes mellitus (DM). We investigated retrospectively 62
      children with HI from nine Australian treatment centres born between 1972 and
      1998, comparing endocrine and neurological outcome in 28 patients receiving
      medical therapy alone with 34 who required pancreatic resection to control their
      hypoglycaemia. METHODS: History, treatment and clinical course were ascertained
      from file audit and interview. Risk of DM (hazard ratio) attributable to age at
      surgery (< vs. > or = 100 days at last pancreatectomy) and extent of resection (<
      vs. > or = 95%) were calculated using Cox proportional hazards regression and
      categorical variables compared by the chi2-test. Neurological outcome (normal,
      mild deficit or severe deficit) was derived from the most authoritative source.
      RESULTS: Surgically treated patients had a greater birthweight, earlier
      presentation and higher plasma insulin levels. Of 18 infants < 100 days and 16 >
      or = 100 days of age at surgery, four (all > or = 100 days) became diabetic as an
      immediate consequence of surgery and five (two < 100 days and three > or = 100
      days) became diabetic 7-18 years later. Surgery > or = 100 days and
      pancreatectomy > or = 95% were associated with development of diabetes (HR =
      12.61, CI 1.53-104.07 and HR = 7.03, CI 1.43-34.58, respectively).
      Neurodevelopmental outcome was no different between the surgical and medical
      groups with 44% overall with neurological deficits. Patients euglycaemic within
      35 days of the first symptom of hypoglycaemia (Group A) had a better
      neurodevelopmental outcome than those still hypoglycaemic > 35 days from first
      presentation (Group B) (P = 0.007). Prolonged hypoglycaemia in Group B was due
      either to delayed diagnosis or to need for repeat surgery because of continued
      hypoglycaemia. Within Group A, medically treated patients (who presented later
      with apparently milder disease) had a higher incidence of neurodevelopmental
      deficit (n = 15, four mild, three severe deficit) compared with surgically
      treated patients (n = 18, two mild, none severe deficit) (P < 0.025).
      CONCLUSIONS: Poor neurodevelopmental outcome remains a major problem in
      hyperinsulinism of infancy. Risk of diabetes mellitus with pancreatectomy varies
      according to age at surgery and extent of resection. Patients presenting early
      with severe disease have a better neurodevelopmental outcome and lower risk of
      diabetes if they are treated with early extensive surgery.

PMID- 12608943
TI  - Effectiveness of alendronate treatment in postmenopausal women with osteoporosis:
      relationship with BsmI vitamin D receptor genotypes.
AB  - OBJECTIVE: To assess whether there is a relationship between the effectiveness of
      alendronate treatment in postmenopausal women with osteoporosis and BsmI vitamin
      D receptor (VDR) genotypes. DESIGN: Prospective baseline-controlled clinical
      trial. PATIENTS: Sixty-eight Italian osteoporotic women were enrolled and treated
      with alendronate at a dose of 10 mg/day for 12 months. MEASUREMENTS: At entry and
      after treatment, lumbar bone mineral density (BMD) and serum osteocalcin (OC) and
      urinary deoxypyridinoline/creatinine ratio (DPD-Cr) levels were evaluated. DNA
      was extracted from blood and analysed for the BsmI polymorphism of the VDR gene.
      RESULTS: The mean percentage (% +/- SD) change from baseline in lumbar BMD was
      significantly higher (P < 0.01) in bb than in BB BsmI VDR genotypes (7.92 +/-
      4.31 vs. 3.40 +/- 1.81). No significant difference in lumbar BMD was observed in
      Bb VDR patients (6.01 +/- 3.89) in comparison with other groups. The mean
      percentage of change in serum OC and urinary DPD-Cr levels was significantly (P <
      0.01) lower in individuals with bb than in those with BB BsmI VDR genotypes (
      14.34 +/- 2.87 vs.-10.39 +/- 1.43 and -9.61 +/- 5.56 vs.-4.61 +/- 2.31). No
      significant difference in serum OC and urinary DPD-Cr levels was observed in Bb
      VDR patients (-12.31 +/- 2.11 and -6.52 +/- 2.65) in comparison with other
      groups. CONCLUSION: The different BsmI vitamin D receptor genotypes modify the
      pharmacological response to alendronate treatment in postmenopausal women with
      osteoporosis.

PMID- 12608944
TI  - Fat distribution in non-obese girls with and without precocious pubarche: central
      adiposity related to insulinaemia and androgenaemia from prepuberty to
      postmenarche.
AB  - OBJECTIVE: Precocious pubarche (PP) in girls is associated with hyperinsulinaemia
      and dyslipidaemia of prepubertal onset, and with ovarian hyperandrogenism and
      ovulatory dysfunction in adolescence, particularly if they also had prenatal
      growth restraint and postnatal growth acceleration. Hyperinsulinaemia may be the
      pathogenic key factor, possibly amplified by hyperandrogenaemia. While such PP
      girls do not have increased body mass index (BMI), we hypothesized that body fat
      mass and fat distribution may differ between PP girls and matched controls, and
      may relate to insulin and androgen levels. PATIENTS AND DESIGN: Sixty-seven PP
      girls (age range 6.0-18.0 years) and 65 control girls matched for age and
      pubertal stage (5.9-18.0 years) had height, weight, waist and hip circumferences
      measured, and dual-energy X-ray absorptiometry (DXA) assessment of total body fat
      mass, and fat mass in abdominal and truncal regions. All girls had fasting plasma
      glucose, serum insulin, lipids, testosterone and SHBG levels measured; PP girls
      also had a standard 2-h oral glucose tolerance test (oGTT). RESULTS: Despite no
      differences in BMI, PP girls had significantly larger waist circumference, waist
      to-hip ratio, total fat mass, percentage fat mass, abdominal fat mass, and
      truncal fat mass vs. controls in each pubertal stage. Overall, fasting insulin
      levels, free androgen index (FAI) and blood lipid levels were more closely
      related to central fat than to total body fat mass. In a multiple regression
      analysis, truncal fat mass was independently related to both fasting insulin (P =
      0.009) and FAI (P < 0.0001). Abdominal fat mass was inversely related to
      birthweight (r = -0.25, P = 0.001). In PP girls, central fat mass was positively
      related to insulin levels after oGTT (truncal fat vs. 30 min insulin; r = 0.46, P
      < 0.0005). CONCLUSIONS: Precocious pubarche girls had excess total body and
      central fat mass throughout all pubertal stages, and increased central fat was
      related to hyperinsulinaemia and hyperandrogenaemia. It remains to be verified
      whether body composition in PP girls can be normalized by insulin-sensitization
      and/or antiandrogen therapy.

PMID- 12608945
TI  - A relationship between serum ferritin and the insulin resistance syndrome is
      present in non-diabetic women but not in non-diabetic men.
AB  - BACKGROUND: Previous studies have suggested that serum ferritin is one of the
      components of the insulin resistance syndrome in Caucasians. Because serum
      ferritin levels differ significantly between men and women, variation in the role
      of ferritin in insulin resistance between the sexes, particularly in Asian
      populations, is still unknown. OBJECTIVE: To examine whether the association
      between serum ferritin and insulin resistance differs between men and women in
      randomly selected non-diabetic Chinese subjects. DESIGN: A retrospective study.
      PATIENTS: Four hundred and seventeen non-diabetic Chinese subjects (140 men and
      277 women) were studied. MEASUREMENTS: Fasting plasma glucose, insulin,
      lipoproteins and serum ferritin concentrations, as well as plasma glucose and
      insulin responses to a 75-g oral glucose test (n = 219), were determined.
      RESULTS: Fasting serum ferritin concentrations (mean +/- SEM) were significantly
      higher in men than in women (504 +/- 33 vs. 242 +/- 18 pmol/l, P < 0.001). In
      women, fasting serum ferritin concentrations correlated significantly with age,
      body mass index (BMI), amount of body fat, fasting plasma glucose, insulin,
      cholesterol, triglyceride concentrations, glucose response to an oral glucose
      load, and homeostasis model assessment (HOMA) of insulin resistance but not with
      blood pressure, high density lipoprotein (HDL) cholesterol levels and insulin
      response to oral glucose. On the contrary, none of the above anthropometric and
      metabolic variables was related to fasting serum ferritin levels in men. HOMA
      insulin resistance increased progressively across three different tertiles for
      measured serum ferritin concentrations in women (P < 0.003). In men, HOMA insulin
      resistance levels were not different among three differing measured serum
      ferritin levels (P = 0.424). Adjustment for age, BMI and menopause status did not
      change the significant relationship between HOMA insulin resistance and serum
      ferritin in women. CONCLUSIONS: We observed that a relationship between serum
      ferritin levels and insulin resistance exists in women but not in men. This
      sexual dimorphism merits further investigation.

PMID- 12608961
TI  - Acute septic arthritis of the hip in children in Northern Australia.

PMID- 12608963
TI  - Journal impact factors and research submission pressures.

PMID- 12608965
TI  - Fluoropolymer coated Dacron or polytetrafluoroethylene for femoropopliteal bypass
      grafting: a multicentre trial.
AB  - BACKGROUND: This trial was designed to compare graft patency between expanded
      polytetrafluoroethylene (PTFE) and fluoro-polymer coated Dacron for
      femoropopliteal bypass in patients in whom saphenous vein was unavailable.
      METHODS: A multicentre prospective trial randomized 129 patients (74 men, 55
      women) who underwent femoropopliteal bypass using either a PTFE or fluoropolymer
      coated Dacron graft. The indication for operation was disabling claudication in
      68 (52.7%) and critical limb ischaemia in 61 (47.3%) patients. Distal anastomosis
      was above the knee in 76 (58.9%) and below the knee in 53 (41.1%) patients.
      RESULTS: Primary patency at 6, 12 and 24 months was 71%, 56% and 47% for PTFE and
      50%, 36% and 36% for fluoropolymer coated Dacron (P = 0.002), respectively.
      Secondary patency at 6, 12 and 24 months was 77%, 60% and 48% for PTFE and 66%,
      49% and 46% for fluoropolymer coated Dacron (P = 0.13), respectively. The
      superior primary patency of PTFE over fluoropolymer coated Dacron was most
      evident in patients with poor prognostic indicators for graft survival: critical
      limb ischaemia (P = 0.001); below-knee anastomosis (P = 0.01); and smaller (6 mm)
      diameter grafts (P = 0.002). Graft thrombosis developed in the first month in 22
      of 61 (36%) patients receiving fluoropolymer coated grafts compared to six of 68
      (8.8%) patients receiving PTFE, which accounts for the difference in primary
      patency. Successful thrombectomy in 10 of the 22 fluoropolymer coated grafts
      resulted in similar secondary patency. CONCLUSION: Polytetrafluoroethylene has
      superior primary patency and similar secondary patency to fluoropolymer coated
      Dacron. These results support the preferential use of PTFE in patients with
      critical limb ischaemia, especially when a below-knee distal anastomosis and
      smaller diameter graft is required.

PMID- 12608967
TI  - Endoluminal stent grafts for aortic diseases: experience at a major teaching
      hospital in Hong Kong.
AB  - BACKGROUND: The purpose of the present paper was to review the initial experience
      of an endovascular aortic stent graft program at a major teaching hospital in
      Hong Kong. METHODS: Demographics, operative details, complications and follow-up
      data of all the patients receiving endovascular repair for aortic disease were
      recorded prospectively. RESULTS: Between July 1999 and December 2001,
      endovascular repairs were attempted in 39 patients with aortic disease. The
      procedural success rate was 97.4%. Thirty-three procedures were for abdominal
      aorto-iliac aneurysms. Graft configuration was bifurcated in 28 patients (85%)
      while an aorto-uni-iliac device with a femoro-femoral bypass was carried out in
      the remaining five patients. Thoracic procedures were carried out for one
      thoracic aortic aneurysm, two traumatic thoracic aortic injuries, one thoracic
      aortic dissection, and one thoracic aortic pseudoaneurysm with aorto-oesophageal
      fistula. There was one hospital mortality (2.6%) from a type A thoracic aortic
      dissection with cardiac tamponade. Postoperative complications were seen in seven
      patients (18%). With a mean follow-up of 11.6 +/- 8.1 months, there was no open
      conversion or rupture. The endoleak rate was 27% at discharge, 15% at 6 months
      and 5% at 12 months postoperatively. For aneurysm endografts, the aneurysm sac
      decreased in size in 21 patients (62%), and remained static in 13 patients (38%).
      CONCLUSIONS: The endoluminal stent graft appears to be a promising device that
      can be used safely in selected patients with aortic disease. Continued follow-up
      is required to monitor the presence of endoleak and the size of the aneurysm sac.

PMID- 12608969
TI  - Comparison of ankle-brachial pressure index measurements using an automated
      oscillometric device with the standard Doppler ultrasound technique.
AB  - BACKGROUND: The aim of the present study was to assess the accuracy of an
      automated oscillometric device (DINAMAP) in measuring ankle-brachial pressure
      index (ABPI) in the clinical setting. Results were then compared to those
      obtained using the standard Doppler technique. METHODS: A prospective comparative
      study of 50 healthy volunteers was carried out using a standard ward DINAMAP
      machine, hand-held Doppler and a 14 cm sphygmomanometer cuff. Three consecutive
      pressure readings were taken from all four limbs of the volunteers using both
      Doppler and DINAMAP techniques. The two techniques were carried out by different
      investigators who were blind to the findings of the other. The ABPI was
      calculated for each technique and the two techniques were compared. RESULTS:
      There was no significant agreement between the ABPI readings obtained by DINAMAP
      and those obtained by the standard Doppler technique. There was also a
      substantial variation in pressure readings produced by the DINAMAP for a given
      limb as measured by intraclass correlation of the three readings taken.
      CONCLUSIONS: There is no role for standard automated oscillometric devices in the
      calculation of ABPI in the vascular clinic.

PMID- 12608971
TI  - Laparoscopic placement of peritoneal dialysis catheters: 7 years experience.
AB  - BACKGROUND: Since 1994 we have placed all peritoneal dialysis (Tenckhoff)
      catheters at our hospital laparoscopically using a technique that incorporates
      suture fixation into the pelvis. The purpose of this study was to determine the
      long-term outcome of this approach. METHOD: Perioperative and follow-up data for
      all patients undergoing placement of a peritoneal dialysis catheter at the Royal
      Adelaide Hospital were collected prospectively and managed on unit specific and
      hospital wide computerized databases. A total of 148 procedures were carried out
      in 123 patients from March 1994 to November 2001. Follow-up ranged from 3 to 68
      months (median, 42 months). All procedures were undertaken or supervised by one
      surgeon, and catheters were routinely sutured into the pelvis at laparoscopy.
      RESULTS: There was no perioperative mortality in this series, and only one
      catheter could not be placed laparoscopically. This was in a patient with
      extensive intra-abdominal adhesions. Mean operative time was 27 min (range, 10
      100 min), and mean postoperative stay was 2.8 days (range, 1-12 days). Seven (5%)
      patients experienced peri/postoperative haemorrhage, and four of these underwent
      surgical re-exploration. Twenty-five (17%) catheters are still used for dialysis.
      Thirty-four (23%) catheters were removed when the recipient received a subsequent
      renal transplant, and 42 (28%) patients died during follow-up. Forty-six (31%)
      patients required catheter revision or removal because of technical problems; 26
      (18%) recurrent peritonitis or exit site infection; and 20 (14%) catheter
      blockage. Twenty-eight reinsertion procedures were carried out in 25 patients.
      Ten (7%) patients developed port site hernias at late follow-up, and required
      hernioplasty. Catheter migration leading to malfunction (poor drainage) occurred
      in eight (5%) patients only. CONCLUSIONS: Laparoscopic placement of peritoneal
      dialysis catheters is a safe and effective procedure. The majority of patients
      will dialyse successfully using this technique. Suturing the catheter tip into
      the pelvis is associated with a low rate of catheter migration.

PMID- 12608972
TI  - The Keystone Design Perforator Island Flap in reconstructive surgery.
AB  - BACKGROUND: A surgical technique for closing skin defects following skin cancer
      (particularly melanoma) removal is described in the present paper. Its use is
      illustrated in five patients. The technique has been used in 300 cases over the
      past 7 years and is suitable for all areas of the body from scalp to foot. We
      have coined the term Keystone Design Perforator Island Flap (KDPIF) because of
      its curvilinear shaped trapezoidal design borrowed from architectural
      terminology. It is essentially elliptical in shape with its long axis adjacent to
      the long axis of the defect. The flap is based on randomly located vascular
      perforators. The wound is closed directly, the mid-line area is the line of
      maximum tension and by V-Y advancement of each end of the flap, the 'islanded'
      flap fills the defect. This allows the secondary defect on the opposite side to
      be closed, exploiting the mobility of the adjacent surrounding tissue. The
      importance of blunt dissection is emphasized in raising these perforator island
      flaps as it preserves the vascular integrity of the musculocutaneous and
      fasciocutaneous perforators together with venous and neural connections. The
      keystone flap minimizes the need for skin grafting in the majority of cases and
      produces excellent aesthetic results. Four types of flaps are described: Type I
      (direct closure), Type II (with or without grafting), Type III (employs a double
      island flap technique), and Type IV (involves rotation and advancement with or
      without grafting). The patient is almost pain free in the postoperative phase.
      Early mobilization is possible, allowing this technique to be used in short stay
      patients. RESULTS: In a series of 300 patients with flaps situated over the
      extremities, trunk and facial region, primary wound healing was achieved in 99.6%
      with one out of 300 developing partial necrosis of the flap. CONCLUSIONS: The
      technique described in the present article offers a simple and effective method
      of wound closure in situations that would otherwise have required complex flap
      closure or skin grafting particularly for melanoma.

PMID- 12608973
TI  - Oesophagectomy for early adenocarcinoma and dysplasia arising in Barrett's
      oesophagus.
AB  - BACKGROUND: Oesophagectomy for high-grade dysplasia is controversial. METHODS: A
      prospective study was carried out on all patients who presented between 1993 and
      2001 with dysplasia or early adeno-carcinoma who were considered fit for surgery.
      Details of endoscopic biopsies, appearance, surveillance, operative pathology and
      outcome were recorded. RESULTS: Of 18 patients, one had low-grade dysplasia, six
      had high-grade dysplasia and 11 had early adenocarcinoma. No patient had their
      biopsy diagnosis down-staged following final pathology, but two patients with
      high-grade dysplasia on biopsy were upstaged to adenocarcinoma. Our only death
      from disease occurred in a 39-year-old man who had undergone yearly surveillance
      for 86 months until adenocarcinoma was confirmed. There was no operative
      mortality. CONCLUSION: Oesophagectomy for early adenocarcinoma and dysplasia in
      Barrett's oesophagus can be done with acceptable rates of mortality and
      morbidity. Surveillance until adenocarcinoma is confirmed does not guarantee
      curable disease.

PMID- 12608974
TI  - Acupuncture anaesthesia in inguinal hernia repair.
AB  - BACKGROUND: The present study was undertaken to evaluate the efficacy of
      acupuncture anaesthesia in inguinal hernia repair. METHODS: Twelve patients with
      non-recurrent inguinal hernia had Lichtenstein mesh repair under acupuncture
      anaesthesia. Selected acupuncture loci were stimulated with fine needles
      connected to low frequency current. Supplementary local anaesthetic was given
      when required. RESULTS: Four (33%) patients reported satisfactory analgesic
      effect throughout the operation without need for additional medication, eight
      (67%) patients experienced mild discomfort during the operation requiring 1-4 mL
      of 1% lignocaine injection. Blood pressure and heart rate were stable during the
      procedure. All patients were able to sit up and resume their diet immediately
      post-operatively. All but one patient were discharged on day one after the
      procedure, with no early or late complications reported. Most patients were
      satisfied with the analgesic effect of acupuncture anaesthesia. CONCLUSIONS:
      Acupuncture anaesthesia is a feasible anaesthetic option. It reduces the amount
      of local anaesthetic required, and thus the associated potential complications.
      It is effective in pain relief and inhibiting gastrointestinal upset.
      Postoperative recovery was rapid and complication free.

PMID- 12608975
TI  - Measuring the importance of attributes that influence consumer attitudes to
      colorectal cancer screening.
AB  - BACKGROUND: The aim of the present study was to rate the importance of attributes
      of screening for bowel cancer. METHOD: Randomly selected households in central
      Sydney were contacted to identify men and women aged 50-70 years who were then
      asked to complete a self-administered questionnaire about bowel cancer screening
      and related issues. Seven hundred and ninety-one residents (362 men and 429
      women) returned questionnaires. Respondents were asked to rate the extent to
      which each of 34 attributes would encourage them to participate in bowel cancer
      screening. RESULTS: The three most highly rated attributes were: if the test was
      recommended by their general practitioner (GP; 94% either 'strongly agreed' or
      'agreed'); if the test identified early cancers (92%); and if the test would
      avert a premature death due to bowel cancer (90%). Having a friend or relative
      with bowel cancer (61%), advertising (41%) or famous people promoting the program
      (62%) were less influential. Respondents who were unemployed or on a pension were
      less likely to participate in screening than those who were employed if there was
      an 'out of pocket' charge of 15.00 Australian dollars (chi 2 = 7.56, 2df, P =
      0.006). Respondents with higher levels of education were significantly more
      concerned than respondents with lower levels of education about test accuracy
      (chi 2 = 15.76, 2df, P < 0.001), its availability from their local chemist (chi 2
      = 16.96, 2df, P < 0.001), being able to return the test kit by post (chi 2 =
      21.9, 2df, P < 0.001) or deposit it with their local chemist (chi 2 = 10.0, 2df,
      P < 0.01). They were also less likely to be influenced by a famous person
      promoting bowel cancer screening (chi 2 = 18.87, 2df, P < 0.001). CONCLUSIONS:
      Our results endorse the role of the GP in bowel cancer screening. However, the
      study also has demonstrated that test accuracy, the convenience of the screening
      service and notification of test results are valued differently by subgroups in
      the community, according to their level of education.

PMID- 12608976
TI  - Transfer of one fascicle of ulnar nerve to functioning free gracilis muscle
      transplantation for elbow flexion.
AB  - BACKGROUND: In brachial plexus injury, elbow flexion is the first priority in
      reconstruction. Neglected cases need functioning free muscle transplantation that
      requires the donor nerve to supply the transplanted muscle. The purpose of this
      study was to investigate the effects and results of transferring one fascicle of
      the ulnar nerve to the transplanted gracilis muscle. METHODS: One woman and two
      men with neglected avulsions of the C5,C6 roots of the brachial plexus underwent
      free gracilis muscle transfer for elbow flexion. One fascicle of the ulnar nerve
      was used as the donor nerve. RESULTS: The mean period of follow-up was 33.3
      months. The average reinnervation time of gracilis muscle was 3.7 months. At the
      final examination, the mean strength of elbow flexion was 4.3 kgf. The grip
      strength, moving two-point discrimination and the strength of the wrist volar
      flexion on the affected side was not worse than before surgery in any patient at
      the last follow-up examination. CONCLUSIONS: A fascicle of the ulnar nerve can be
      one of the most effective options for functioning free muscle transplantation for
      elbow flexion.

PMID- 12608977
TI  - Acute septic arthritis of the hip in children in northern Australia.
AB  - BACKGROUND: The epidemiology, microbiology and clinical management of all
      children under 15 years of age presenting with acute septic arthritis of the hip
      to Royal Darwin Hospital from July 1994 to December 1999 were reviewed and the
      diagnostic value of various biological markers assessed. METHODS: Systematic
      review was undertaken of case notes of patients identified by searching the
      computerized hospital patient database and the admission records for the
      children's ward. RESULTS: Eleven cases were identified: 10 aboriginal and one
      caucasian. The mean temperature, white cell count, erythrocyte sedimentation rate
      (ESR), and C-reactive protein (CRP) at presentation were 39.2 degrees C,
      15,500/mL, 65 mm/h and 144 mg/L, respectively. All had ESR and/or CRP >20. Plain
      radiographs and ultrasonography were abnormal in 1/8 and 5/6 cases, respectively.
      Pathogens were isolated in nine cases: Staphylococcus aureus (n = 6),
      Streptococcus pyogenes (n = 2) and Streptococcus pneumoniae (n = 1). Patients
      received intravenous antibiotics for 8.6 days (range: 3-15 days) and subsequent
      oral antibiotics for 22 days (range: 0-42 days). The mean (range) time from
      hospital admission to arthrotomy; from hospital admission to antibiotic
      administration; and the overall hospital stay was 23 h (range: 3-48 h); 6 h
      (range: 0-48 h); and 41 days (range: 6-110 days), respectively. CONCLUSIONS:
      Elevation of temperature, white cell count, ESR and CRP were useful indicators of
      septic arthritis but initial diagnosis must be made on a clinical basis. Many
      patients had to be transferred from regional aboriginal communities and there was
      significant delay from onset of symptoms to arthrotomy.

PMID- 12608978
TI  - The mechanical and microbiological integrity of surgical gloves.
AB  - BACKGROUND: Several manufacturers supply surgical gloves that have been
      individually tested (IT) for leaks. Other manufacturers supply gloves in which
      sample gloves from each batch are tested for leaks (batch tested: BT). The latter
      brands may be rejected by surgeons because of presumed increased risk of wound
      infection and staff exposure to patient pathogens. The influence of differences
      between glove brands on performance in surgery has not been extensively studied.
      The aims of the present study were to test the mechanical and microbiological
      integrity of IT compared to BT gloves. METHODS: A total of 110 unused gloves from
      each of an IT and a BT brand were tested for leaks, first, by observation of
      water-jets from water-filled gloves and second, by measuring electrical
      resistance between inside and outside the glove surfaces, to give a baseline
      measure. A total of 304 IT and 280 BT gloves were then similarly leak-tested
      after 98 clean surgical procedures. The hands and gloves of scrub team members
      were cultured postsurgery. RESULTS: A total of 1/110 BT and 0/110 IT unused
      gloves contained leaks (NS, Fisher's exact test). Operative perforation rates
      were lower for BT compared with IT (8/280 cf. 22/304; P < 0.05 Fisher's exact
      test). There was no bias in types of operations or scrub team members to account
      for the difference. Growth of normal skin flora was found on virtually every
      wearer's hands post-operatively. Similar bacteria were frequently cultured from
      the outside of gloves at the conclusion of surgery (111/152 pairs IT cf. 122/140
      pairs BT; P < 0.01, Fisher's exact test). CONCLUSION: This study provides
      evidence that the clinical performance of BT gloves is no different to IT gloves.
      There was no significant difference in mechanical leak rates for unused gloves.
      Paradoxically, although IT gloves were more likely to show macro-perforations
      after surgery, the incidence of contamination on the surface of BT gloves was
      greater, possibly reflecting a qualitative difference in glove material. This
      study suggests that both types of gloves develop microporosity during use, which
      may allow transfer of bacteria from the surgeon's skin to the surface of the
      glove.

PMID- 12608979
TI  - Acute renal failure in the surgical setting.
AB  - Acute renal failure (ARF) is an unwelcome complication of major surgical
      procedures that contributes to surgical morbidity and mortality. Acute renal
      failure associated with surgery may account for 18-47% of all cases of hospital
      acquired ARF. The overall incidence of ARF in surgical patients has been
      estimated at 1.2%, although is higher in at-risk groups. Mortality of patients
      with ARF remains disturbingly high, ranging from 25% to 90%, despite advances in
      dialysis and intensive care support. Appreciation of at-risk surgical populations
      coupled with intensive perioperative care has the capacity to reduce the
      incidence of ARF and by implication mortality. Developments in understanding the
      pathophysiology of ARF may eventually result in newer therapeutic strategies to
      either prevent or accelerate recovery from ARF. At present the best form of
      treatment is prevention. In this review the epidemiology, pathophysiology,
      diagnosis, treatment and possible prevention of ARF will be discussed.

PMID- 12608980
TI  - The effect of indole-3-carbinol and sulforaphane on a prostate cancer cell line.
AB  - BACKGROUND: Cruciferous vegetable consumption is inversely related to the
      incidence of prostate cancer. We examined the effect of indole-3-carbinol (I3C)
      and of sulforaphane (constituents of cruciferous vegetables) on cell
      proliferation of a PC-3 prostate cancer cell line, in order to observe if an
      inhibitory effect might be detected in vitro. METHODS: PC-3 prostate cancer cells
      were cultured in 96-well microtitre plates. Indole-3-carbinol concentrations
      ranging from 0.1 mmol/L to 0.8 mmol/L or sulforaphane concentrations ranging from
      0.01 mmol/L to 0.06 mmol/L were added to the wells. Cell proliferation was
      measured by colorimetric assay and results were based on the mean value of
      triplicate experiments. Data are -presented as medians and interquartile ranges
      and were analysed using the Mann-Whitney U-test. RESULTS: Cell proliferation in
      PC-3 prostate cancer cells was significantly inhibited by I3C and sulforaphane at
      media concentrations of 0.2 mmol/L and 0.02 mmol/L, respectively. CONCLUSION:
      Both compounds inhibited the proliferation of prostate cancer cells in a dose
      dependent manner. These findings may help explain the observed protective effect
      of cruciferous vegetables in relation to prostate cancer.

PMID- 12608981
TI  - Minimal invasive surgery for hip replacement: a new technique using the NILNAV
      hip system.
AB  - BACKGROUND: Minimal invasive surgical techniques are used for cruciate ligament
      reconstructions, unicondylar knee replacements and, more recently, for fixation
      of fractures. This is a report of the first instrumented technique for hip
      replacement using a 5-cm incision without the need for a navigation system or X
      rays. METHODS: It uses the C.F.P stem (LINK) but is universal. It includes jigs
      for the osteotomy of the neck, a right-angled reamer and spacers (lollipops) to
      orientate the acetabular cup to the femoral stem. A case series of 14 patients
      using this new hip replacement technique (called NILNAV Hip System) is reported.
      RESULTS: The procedure was successfully performed on all seven patients, with
      reduced postoperative pain and stiffness, and increased quality of life and
      functional status. All patients were discharged on postoperative Days 1 and 2
      with minimal pain and blood loss. CONCLUSIONS: This new minimal access total hip
      replacement technique was successfully performed on seven patients. There are
      several advantages of using this system compared with the more traditional
      techniques. Such a technique should help reduce morbidity and mortality rates for
      those patients undergoing a total hip replacement.

PMID- 12608982
TI  - Improved design knot pusher for laparoscopic extracorporeal suturing.
AB  - BACKGROUND: Reliable instruments are essential for a hassle free laparoscopic
      operation. We describe a new knot pusher for improved extracorporeal suturing.
      METHODS: A new knot pusher was designed and tested in laparoscopic Nissen
      fundoplication. RESULTS: The instrument was used satisfactorily in 13
      laparoscopic Nissen fundoplications. There were no complications and the
      instrument was found, overall, to be superior to the commercially available knot
      pushers. CONCLUSION: The new knot pusher offers a tailored instrument for
      extracorporeal knot tying.

PMID- 12608983
TI  - Virtual reality simulators.

PMID- 12608984
TI  - Poisons and handwork: interactions between surgeons and medical oncologists.

PMID- 12608985
TI  - Interactions between surgeons and medical oncologists.

PMID- 12608986
TI  - Hip fractures and delay to surgery.

PMID- 12608987
TI  - Congenital absence of the vermiform appendix.

PMID- 12608988
TI  - The gist of it: Case reports of a gastrointestinal stromal tumour and a leiomyoma
      of the anorectum.

PMID- 12608992
TI  - Are pre-ganglionic neurones recruited in a set order?
AB  - AIM: The idea that, like somatic motor neurones, sympathetic pre-ganglionic
      neurones are engaged to fire in a pre-determined recruitment order, was
      investigated in chloralose-anaesthetized cats. METHOD: Ongoing pre-ganglionic
      spike activity was recorded from fine filaments of otherwise intact thoracic
      white rami, while post-ganglionic activity was recorded from the whole inferior
      cardiac nerve (ICN). Spikes of individual pre-ganglionic fibres were extracted
      from few-fibre recordings by spike shape analysis. Presumed cardiac pre
      ganglionic fibres were further selected by the spike-triggered average of ICN
      activity, which showed a clear peak when triggered by their spikes. RESULTS: To
      test whether particular pre-ganglionic neurones were recruited to fire in a set
      time sequence, the spontaneous spike trains of fibres in the same white ramus
      were compared by cross correlation. In all 24 cases the cross correlograms showed
      a central peak (width 163 +/- 15 ms), indicating that the two neurones tended to
      fire together. In 23 of the 24 cases that peak spanned the zero point on the time
      axis, showing that each neurone could fire either first or second. To test
      whether pre-ganglionic neurones were recruited in a set order with respect to
      burst amplitude, the firing of individual pre-ganglionic neurones was compared
      with the strength of the corresponding post-ganglionic burst discharge, on a
      heartbeat-by-heartbeat basis. Pre-ganglionic neurone firing was probabilistic:
      each neurone fired with only a minority of post-ganglionic bursts. Firing
      probability increased linearly with burst amplitude (30 of 30 cases). The slope
      of the relation varied between units, but its intercept was always close to the
      origin (zero pre-ganglionic firing probability at zero post-ganglionic burst
      size). CONCLUSION: The data indicate that, at least under these conditions,
      sympathetic pre-ganglionic neurones follow no set recruitment sequence in either
      their firing times or with respect to the strength of the autonomic motor output.

PMID- 12608991
TI  - Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone.
AB  - AIM: Neurons in the rostral ventrolateral medulla (RVLM) that project directly to
      sympathetic preganglionic neurons in the spinal cord play a critical role in
      maintaining tonic activity in sympathetic vasomotor nerves. Intracellular
      recordings in vivo from putative RVLM presympathetic neurons have demonstrated
      that under resting conditions these neurons display an irregular tonic firing
      rate, and also receive both excitatory and inhibitory synaptic inputs. This paper
      will briefly review some recent findings on the role of glutamate, GABA and
      angiotensin II (Ang II) receptors in maintaining the tonic activity of RVLM
      presympathetic neurons. RESULTS: Based on these findings, the following
      hypotheses will be discussed: (1) RVLM neurons receive tonic glutamatergic
      excitatory inputs, which originate from both medullary and supramedullary
      sources; (2) at least some neurons that project to and tonically inhibit RVLM
      presympathetic neurons are themselves tonically inhibited by GABAergic inputs
      originating from neurons in the caudalmost part of the ventrolateral medulla
      (caudal pressor area); (3) under normal conditions, Ang II receptors in the RVLM
      do not contribute significantly to the tonic activity of RVLM presympathetic
      neurons, but may do so in abnormal conditions such as heart failure or neurogenic
      hypertension; (4) RVLM presympathetic neurons maintain a significant level of
      tonic resting activity even when glutamate, GABA and Ang II receptors on the
      neurons are completely blocked. Under these conditions, the tonic activity is a
      consequence either of the intrinsic membrane properties of the neurons
      (autoactivity) or of synaptic inputs mediated by receptors other than glutamate,
      GABA or Ang II receptors. CONCLUSION: The current evidence indicates that the
      resting activity of RVLM presympathetic neurons is determined by the balance of
      powerful tonic excitatory and inhibitory synaptic inputs. Ang II receptors also
      contribute to the raised resting activity of these neurons in some pathological
      conditions.

PMID- 12608993
TI  - Transmission of signals through sympathetic ganglia--modulation, integration or
      simply distribution?
AB  - AIM: On structural grounds, synaptic transmission in sympathetic ganglia is
      potentially complex with extensive divergence and convergence between
      preganglionic and postganglionic neurones. In this review, the focus is on what
      constitutes a functional synapse in sympathetic ganglia and how intracellular
      recordings have enabled us to identify how the transmission process operates in
      vivo. RESULTS: Only one or two suprathreshold or 'strong' inputs are involved in
      activating each postganglionic neurone. The functional significance of the
      subthreshold or 'weak' inputs remains obscure. The strong inputs, and sometimes
      the weak ones as well, respond in the same way during reflexes. The expansion of
      ineffective weak connections enables the rapid restoration of functional control
      after lesions that damage preganglionic neurones. These novel connections may
      generate erroneous reflex responses after spinal injury. Postganglionic discharge
      in vivo consists of the summed firing of the strong preganglionic inputs limited,
      at high preganglionic discharge rates, by the properties of the
      afterhyperpolarization. CONCLUSION: Preganglionic signals are distributed widely
      through paravertebral ganglia with little modification.

PMID- 12608995
TI  - Why do human postganglionic neurones primarily only fire once during a
      sympathetic burst?
AB  - AIM: Single-unit recordings from muscle vasoconstrictor, cutaneous
      vasoconstrictor and sudomotor neurones in awake human subjects have shown that
      they tend to fire only once per sympathetic burst. We review the firing
      properties of human sympathetic neurones and examine the idea that the short
      duration of a sympathetic burst may limit the number of times a neurone can fire,
      using the human skeletomotor system as a model for the sympathetic nervous
      system. RESULTS: It is known that human alpha motor neurones usually fire in long
      trains during voluntary contractions, but what of their pattern when constrained
      by a brief burst? We recorded from single motor units in the tibialis anterior
      muscle while subjects generated brief electromyogram bursts in the intervals
      between heart beats, with a duration similar to that of muscle sympathetic
      bursts. Eight motor units fired mostly one spike per burst, with a pattern
      identical to that of sympathetic neurones. CONCLUSION: These results suggests
      that were it not for the constraint of the bursting pattern, individual
      sympathetic neurones would--like alpha motor neurones--tend to fire in long
      trains.

PMID- 12608994
TI  - Functional organization of peripheral vasomotor pathways.
AB  - AIM: In this article, we review the functional organization of the peripheral
      autonomic pathways regulating the vasculature. RESULTS: The final motor neurones
      in vasomotor pathways tend to be smaller than neurones in other autonomic
      pathways. This suggests that they have relatively smaller target territories and
      receive fewer pre-ganglionic inputs than non-vasomotor neurones. Nevertheless,
      single vasomotor neurones project to large areas of the vasculature separated by
      up to 7 mm. Different functional pools of vasomotor neurones project to specific
      segments of the vasculature, allowing for the selective neural control of
      resistance in vessels in proximal or distal regions of the vascular bed. In many
      cases, each functional pool of vasomotor neurones utilizes a characteristic
      combination of cotransmitters. The various pools of final motor neurones in
      vasomotor pathways receive convergent synaptic input from different pools of pre
      ganglionic neurones, many of which also contain neuropeptides which enhance the
      excitability of the final motor neurones. The excitability of vasomotor neurones
      regulating gastrointestinal and mesenteric blood flow, also can be increased by
      the actions of peptides such as substance P that are released from visceral
      nociceptors. CONCLUSIONS: We propose that autonomic pathways regulating the
      vasculature are organized into 'vasomotor units'. Each vasomotor unit consists of
      a pre-ganglionic neurone, the final motor neurones it innervates, and the blood
      vessels that they regulate. The vasomotor units are likely to be grouped into
      functional pools that can be recruited as necessary to provide highly specific,
      graded control of blood flow both within and between vascular beds.

PMID- 12608996
TI  - Neurophysiological analysis of target-related sympathetic pathways--from animal
      to human: similarities and differences.
AB  - The sympathetic nervous system regulates many different target tissues in the
      somatic and visceral domains of the body in a differentiated manner, indicating
      that there exist separate sympathetic pathways that are functionally defined by
      their target cells. Signals generated by central integration and channelled
      through the preganglionic neurons into the final sympathetic pathways are
      precisely transmitted through the para- and prevertebral ganglia and at the
      neuroeffector junctions to the effector cells. Neurophysiological recordings of
      activity in postganglionic neurons in skin and muscle nerves using
      microneurography in human subjects and in skin, muscle and visceral nerves, using
      conventional recording techniques in anaesthetized animals, clearly show that
      each type of sympathetic neuron exhibits a discharge pattern that is
      characteristic for its target cells and, therefore, its function. These findings
      justify labelling the neurons as muscle vasoconstrictor, cutaneous
      vasoconstrictor, sudomotor, lipomotor, cardiomotor, secretomotor neurons, etc.
      The discharge patterns monitor aspects of the central organization of the
      respective sympathetic system in the neuraxis and forebrain. They can be
      dissected into several distinct reflexes (initiated by peripheral and central
      afferent inputs) and reactions connected to central signals (related to
      respiration, circadian and other rhythms, command signals generated in the
      forebrain, etc). They are functional markers for the sympathetic final pathways.
      These neurophysiological recordings of the discharge patterns from functionally
      identified neurons of sympathetic pathways in the human and in animals are the
      ultimate reference for all experimental investigations that aim to unravel the
      central organization of the sympathetic systems. The similarities of the results
      obtained in the in vivo studies in the human and in animals justify concluding
      that the principles of the central organization of sympathetic systems are
      similar, if not identical, at least in the neuraxis, in both species. Future
      progress in the analysis of the central neuronal circuits that are associated
      with the different final sympathetic pathways will very much depend on whether we
      are able to align the human models and the animal models. Human models using
      microneurography have the advantage to work under awake conditions. The activity
      in the postganglionic neurons can be correlated with various other (afferent,
      centrally generated) signals, effector responses, perceptions, central changes
      monitored by imaging methods, etc. However, human models have considerable
      limitations. Animal models can be divided into in vivo models and various types
      of reduced in vitro models. Animal models allow using various methodological
      approaches (e.g., neurophysiological, pharmacological, modern anatomical tracing
      methods; behavioural animal models; transgenic animals), which cannot be used in
      the human. Interaction of the research performed in the human and animals will
      allow to design animal models that are relevant for diseases in which the
      sympathetic nervous systems is involved and to trace down the underlying
      pathophysiological mechanisms. The scientific questions to be asked are
      formulated on the basis of clinical observations resulting in testable hypotheses
      that are investigated in the in vivo human and animal models. Results obtained in
      the in vivo models lead to the formulation of hypotheses that are testable in
      reduced in vivo and particularly in vitro animal models. Microneurographic
      recordings from sympathetic postganglionic fibres in the human will keep its
      place in the analysis of the sympathetic nervous system in health and disease
      although only relatively few laboratories in the world will be able to keep the
      standards and expertise to use this approach. Experimental investigation of the
      organization of the sympathetic nervous system in animal models has changed
      dramatically in the last 15 years. The number of in vitro models and the
      methodological diversity have increased. In vivo experimentation on larger
      animals has almost disappeared and has been replaced by experimentation on rats,
      which became the species for practically all types of studies on the central
      organization of the sympathetic nervous system.

PMID- 12608997
TI  - Sympathetic nerve activity and neurotransmitter release in humans: translation
      from pathophysiology into clinical practice.
AB  - AIM: There has been a revolution in cardiovascular neuroscience in recent years
      with, in some cases, translation into clinical practice of the knowledge of
      pathophysiology gained through application of sympathetic nerve recording and
      catecholamine isotope dilution methodology. OBESITY-RELATED HYPERTENSION: An
      earlier hypothesis, based on findings in most models, was that weight gain in
      obesity is due in part to sympathetic nervous underactivity reducing
      thermogenesis. Microneurography and regional noradrenaline spillover measurements
      in human obesity have disproven this hypothesis, weakening the case for the use
      of beta3-adrenergic agonists to stimulate thermogenesis. Sympathetic nerve firing
      rates in post-ganglionic fibres directed to the skeletal muscle vasculature are
      increased, as is renal sympathetic tone, with a doubling of the spillover rate of
      noradrenaline from the kidneys. Given these findings, antiadrenergic
      antihypertensive drugs may be the preferred agents for obesity-related
      hypertension, but this has not been adequately tested. ESSENTIAL HYPERTENSION:
      Whether stress causes high blood pressure, previously hotly debated, has been
      under recent review by an Australian Government body, the Specialist Medical
      Review Council. Despite medicolegal implications, the ruling was that stress is
      one proven cause of hypertension. The judgment was reached after consideration of
      the epidemiological evidence, but in particular the described neural
      pathophysiology of essential hypertension: (a) persistent sympathetic nervous
      stimulation is commonly present, (b) suprabulbar projections of noradrenergic
      brainstem neurones are activated and (c) adrenaline is released as a
      cotransmitter in sympathetic nerves. These were taken to be biological markers of
      stress. CARDIAC FAILURE: At one time, the failing heart was thought to be
      sympathetically denervated. Longterm administration of inotropic adrenergic
      agonists, to provide the cardiac catecholamine stimulation thought to be lacking,
      increased mortality. Noradrenaline isotope dilution methodology subsequently
      demonstrated that the sympathetic outflow to the heart was preferentially
      activated, cardiac noradrenaline spillover being increased as much as 50-fold.
      The level of stimulation of the cardiac sympathetic nerves was the most powerful
      predictor of death. These observations provide the theoretical foundation for the
      very successful introduction of beta-adrenergic blockers for treatment of heart
      failure.

PMID- 12608998
TI  - Central angiotensin modulation of baroreflex control of renal sympathetic nerve
      activity in the rat: influence of dietary sodium.
AB  - AIM: Administration of angiotensin II (angII) into the cerebral ventricles or
      specific brain sites impairs arterial baroreflex regulation of renal sympathetic
      nerve activity (SNA). Further insight into this effect was derived from: (a)
      using specific non-peptide angII receptor antagonists to assess the role of
      endogenous angII acting on angII receptor subtypes, (b) microinjection of angII
      receptor antagonists into brain sites behind an intact blood-brain barrier to
      assess the role of endogenous angII of brain origin and (c) alterations in
      dietary sodium intake, a known physiological regulator of activity of the renin
      angiotensin system (RAS), to assess the ability to physiologically regulate the
      activity of the brain RAS. METHODS: In rats in balance on low, normal or dietary
      sodium intake, losartan or candesartan was injected into the lateral cerebral
      ventricle or the rostral ventrolateral medulla (RVLM) and the effects on basal
      renal SNA and the arterial baroreflex sigmoidal relationship between renal SNA
      and arterial pressure were determined. RESULTS: With both routes of
      administration, the effects were proportional to the activity of the RAS as
      indexed by plasma renin activity (PRA). The magnitude of both the decrease in
      basal renal SNA and the parallel resetting of arterial baroreflex regulation of
      renal SNA to a lower arterial pressure was greatest in low-sodium rats with
      highest PRA and least in high-sodium rats with lowest PRA. Disinhibition of the
      paraventricular nucleus (PVN) by injection of bicuculline causes pressor,
      tachycardic and renal sympathoexcitatory responses mediated via an
      angiotensinergic projection from PVN to RVLM. In comparison with responses in
      normal sodium rats, these responses were greatly diminished in high-sodium rats
      and greatly enhanced in low-sodium rats. CONCLUSION: Physiological changes in the
      activity of the RAS produced by alterations in dietary sodium intake regulate the
      contribution of endogenous angII of brain origin in the modulation of arterial
      baroreflex regulation of renal SNA.

PMID- 12608999
TI  - Arousal increases baroreflex inhibition of muscle sympathetic activity.
AB  - AIM: Surprising sensory stimuli causing arousal are known to evoke short-lasting
      activation of human sympathetic activity in skin but not in muscle nerves. In
      fact, anecdotal observations suggest that muscle sympathetic activity may be
      inhibited. To test this hypothesis, the effects of surprising somatosensory
      (electrical skin pulses) or visual (flash) stimuli on multiunit muscle
      sympathetic activity were studied in 36 healthy subjects, aged 19-71 years.
      METHODS: The stimuli were given either 200 or 400 ms after the R-wave of the
      electrocardiogram. Dummy stimuli, consisting of trigger pulses without sensory
      stimuli, served as controls. RESULTS: On a group basis, a single sensory stimulus
      of either type attenuated the amplitude of one or two sympathetic bursts, while
      no such effects occurred after dummy stimuli. Individually, the inhibition was
      evoked by at least one stimulus modality or delay in 16 subjects, whereas in
      three subjects no significant inhibition occurred. Electrodermal signs of skin
      sympathetic activation were present in all subjects. Compared with one, five
      repeated electrical skin pulses induced only minor additional inhibition of
      muscle sympathetic activity, indicating marked habituation of the neural
      response. In nine subjects, the experiments were repeated once and in three
      subjects twice (with intervals of 2-3 months); in 11 of the 12 subjects, the
      sympathetic effects were reproducible. In the group of subjects without
      significant sympathetic inhibition the stimuli induced a small, transient
      increase of mean blood pressure, which was not present in the group with
      sympathetic inhibition. CONCLUSION: The finding that different sensory stimuli
      induce similar effects that habituate markedly on repetition suggests that the
      inhibition of muscle sympathetic activity is because of arousal. The
      interindividual differences in sympathetic and blood pressure effects may be part
      of interindividual differences in behavioural responses to stress.

PMID- 12609000
TI  - Bursting into space: alterations of sympathetic control by space travel.
AB  - AIM: Astronauts return to Earth with reduced red cell masses and hypovolaemia.
      Not surprisingly, when they stand, their heart rates may speed inordinately,
      their blood pressures may fall, and some may experience frank syncope. We studied
      autonomic function in six male astronauts (average +/- SEM age: 40 +/- 2 years)
      before, during, and after the 16-day Neurolab space shuttle mission. METHOD: We
      recorded electrocardiograms, finger photoplethysmographic arterial pressures,
      respiration, peroneal nerve muscle sympathetic activity, plasma noradrenaline and
      noradrenaline kinetics, and cardiac output, and we calculated stroke volume and
      total peripheral resistance. We perturbed autonomic function before and during
      spaceflight with graded Valsalva manoeuvres and lower body suction, and before
      and after the mission with passive upright tilt. RESULTS: In-flight baseline
      sympathetic nerve activity was increased above pre-flight levels (by 10-33%) in
      three subjects, in whom noradrenaline spillover and clearance also were
      increased. Valsalva straining provoked greater reductions of arterial pressure,
      and proportionally greater sympathetic responses in space than on Earth. Lower
      body suction elicited greater increases of sympathetic nerve activity, plasma
      noradrenaline, and noradrenaline spillover in space than on Earth. After the
      Neurolab mission, left ventricular stroke volume was lower and heart rate was
      higher during tilt, than before spaceflight. No astronaut experienced orthostatic
      hypotension or pre-syncope during 10 min of post-flight tilting. CONCLUSION: We
      conclude that baseline sympathetic outflow, however measured, is higher in space
      than on earth, and that augmented sympathetic nerve responses to Valsalva
      straining, lower body suction, and post-flight upright tilt represent normal
      adjustments to greater haemodynamic stresses associated with hypovolaemia.

PMID- 12609001
TI  - Vestibular activation of sympathetic nerve activity.
AB  - AIM: The vestibulosympathetic reflex refers to sympathetic nerve activation by
      the vestibular system. Animal studies indicate that the vestibular system assists
      in blood pressure regulation during orthostasis. Although human studies clearly
      demonstrate activation of muscle sympathetic nerve activity (MSNA) during
      engagement of the otolith organs, the role of the vestibulosympathetic reflex in
      maintaining blood pressure during orthostasis is not well-established.
      Examination of the vestibulosympathetic reflex with other cardiovascular reflexes
      indicates that it is a powerful and independent reflex. Ageing, which is
      associated with an increased risk for orthostatic hypotension, attenuates the
      vestibulosympathetic reflex. The attenuated reflex is associated with a reduction
      in arterial pressure. CONCLUSION: These findings suggest that the
      vestibulosympathetic reflex assists in blood pressure regulation in humans, but
      future studies examining this reflex in other orthostatically intolerant
      populations are necessary to address this hypothesis.

PMID- 12609002
TI  - Effects of heat stress on baroreflex function in humans.
AB  - INTRODUCTION: Heat stress significantly reduces orthostatic tolerance in humans.
      The mechanism(s) causing this response remain unknown. The purpose of this review
      article is to present data pertaining to the hypothesis that reduced orthostatic
      tolerance in heat stressed individuals is a result of heat stress induced
      alterations in baroflex function. METHODS: In both normothermic and heat stressed
      conditions baroreflex responsiveness was assessed via pharmacological and non
      pharmacological methods. In addition, the effects of heat stress on post-synaptic
      vasoconstrictor responsiveness were assessed. RESULTS: Generally, whole body
      heating did not alter baroreflex sensitivity defined as the gain of the linear
      portion of the baroreflex curve around the operating point. However, whole body
      heating shifted the baroreflex curve to the prevailing (i.e. elevated) heart rate
      and muscle sympathetic nerve activity. Finally, the heat stress impaired
      vasoconstrictor responses to exogenous administration of adrenergic agonists.
      CONCLUSION: Current data do not support the hypothesis that reduced orthostatic
      tolerance associated with heat stress in humans is due to impaired baroreflex
      responsiveness. This phenomenon may be partially due to the effects of heat
      stress on reducing vasoconstrictor responsiveness.

PMID- 12609003
TI  - Sympathetic vasodilation in human muscle.
AB  - The idea that there might be sympathetic vasodilator nerves to skeletal muscle is
      an old concept that fits with the archaic 'fight or flight' model of the
      sympathetic nervous system. Clear evidence for vasodilator nerves to skeletal
      muscle began to emerge in animals during the 1930s, when stimulation of selected
      brainstem areas was shown to evoke hypertension, tachycardia and skeletal muscle
      vasodilation (i.e. the 'defense reaction'). By the 1940s and 1950s this idea was
      well established and it was shown in animals that the sympathetic dilator nerves
      to muscles were cholinergic. During this time, circumstantial evidence began to
      suggest the existence of sympathetic cholinergic vasodilator fibres in human
      skeletal muscle. In this context, the well- known forearm vasodilator response to
      mental stress was shown to be atropine-sensitive, and absent after surgical
      sympathectomy. However, while there was clear histological evidence for
      sympathetic cholinergic dilator fibres in animal muscle, such evidence was not
      seen in humans. Additionally, attempts to record from sympathetic dilator fibres
      human muscle have never demonstrated clear evidence for dilator nerve traffic,
      and many 'sympathetic dilator' responses are still present after local
      anaesthetic nerve block. More recently, the skeletal muscle dilator response to
      sympathoexcitatory manoeuvres in both humans and animals appears to be nitric
      oxide (NO)-dependent. While there are clearly atropine-sensitive and NO-dependent
      dilator nerves to skeletal muscles in animals, our current thinking is that most
      'sympathetic dilator' responses in human muscle are due to adrenaline or local
      cholinergic mechanisms acting to stimulate NO release from the vascular
      endothelium.

PMID- 12609004
TI  - Sympathetic nerve activity in metabolic control--some basic concepts.
AB  - A role for the sympathetic nervous system in hypertension has been looked for in
      relation to the 'metabolic syndrome' with associations between body weight,
      insulin sensitivity and hypertension. By use of microneurography human
      sympathetic responses to hypoglycaemia, normoglycaemic hyperinsulinaemia and food
      intake have been studied. A strong but differentiated influence of insulin
      induced hypoglycaemia comprises increase in muscle sympathetic nerve activity
      (MSNA) and the sudomotor part of skin sympathetic nerve activity (SSNA), whereas
      vasoconstrictor SSNA is inhibited. Responses to infusion of 2-deoxy-D-glucose are
      identical, suggesting central nervous system glucopenia and not insulin to be the
      causative factor. Insulin infusion during normoglycaemia evokes a moderate
      increase in MSNA; SSNA and blood pressure does not change. After glucose
      ingestion MSNA displays a sustained increase, which is only partly elicited by
      insulin. A significant albeit weaker increase occurs after pure protein or fat
      meals, and after glucose ingestion in C-peptide-negative diabetic patients, with
      no insulin secretion. In healthy elderly people the MSNA response to food intake
      is weak, because of a high outflow already at rest; this is suggested to explain
      postprandial hypotension in the elderly, a paradoxical mechanism behind clinical
      autonomic failure. A pathophysiological role of MSNA in the metabolic syndrome
      with hypertension has been speculated. An association between obesity and
      elevated level of MSNA at rest is established; observed relationships to chronic
      insulin levels and hypertension are less unanimous. The adipose tissue regulating
      hormone leptin has become one focus of interest in ongoing attempts to elucidate
      a possible role of the human sympathetic nervous system in the 'metabolic
      syndrome' and hypertension.

PMID- 12609006
TI  - Sympathetic control of white adipose tissue in lean and obese humans.
AB  - AIM: To induce lipolysis, catecholamines could reach the adipocyte via the blood
      stream after being released from the adrenal medulla or, alternatively, via
      neuronal release in the vicinity of the fat cell. Sympatho-neuronal effects on
      fat tissue lipolysis have been demonstrated in experimental animal models.
      However, the role of sympathetic nerves in the control of lipolysis in human
      white adipose tissue, which is sparsely innervated, has not been clarified.
      CONCLUSION: The present review summarizes evidence for a direct neuronal
      influence on lipolysis in humans.

PMID- 12609005
TI  - A leptin-sympathetic-leptin feedback loop: potential implications for regulation
      of arterial pressure and body fat.
AB  - AIM: This manuscript briefly reviews evidence and potential implications of a
      leptin-sympathetic-leptin feedback loop. RESULTS: Leptin increases sympathetic
      nerve activity to brown adipose tissue, kidney and other tissues. This action has
      implications for regulation of arterial pressure. In turn, there is evidence that
      sympathoadrenal stimulation inhibits leptin mRNA expression and secretion from
      white adipose tissue through beta adrenergic mechanisms. CONCLUSION: This
      sympathetic modulation of leptin expression has potential implications for
      regulation of body fat.

PMID- 12609007
TI  - Sympathetic nerve activity in hypotension and orthostatic intolerance.
AB  - AIM: The present paper reviews how changes in sympathetic nerve activity are
      related to hypotensive episodes and orthostatic intolerance in humans. RESULTS:
      It has been well documented that sympathetic neural traffic to skeletal muscles
      (muscle sympathetic nerve activity; MSNA) plays an essential role in maintaining
      blood pressure homeostasis mainly through baroreflex. The MSNA responded to
      gravitational loading from the head to the leg (+Gz) during passive head-up tilt
      (HUT). Patients who suffered from orthostatic hypotension with or without syncope
      were classified into at least two groups; low and high responders of MSNA to
      orthostatic loading. The typical examples belonging to the former group were
      patients of multiple system atrophy who had very low basal sympathetic outflow to
      muscle which responded extremely poorly to HUT. Patients of multiple system
      atrophy presented also postprandial hypotension in which muscle sympathetic
      response to oral glucose administration was absent. The latter group was
      represented by subjects who manifested vasovagal syncope with normal or even
      higher muscle sympathetic response to HUT, which was suddenly withdrawn
      concomitantly with bradycardia and hypotension. Similar withdrawal of sympathetic
      nerve traffic to muscle was encountered in a rare case of idiopathic non
      orthostatic episodic hypotension which accompanied bradycardia. The MSNA was
      suppressed by short-term exposure to microgravity but was enhanced after long
      term exposure to microgravity. Orthostatic intolerance after long-term exposure
      to microgravity was related to progressive reduction of muscle sympathetic
      response to orthostatic loading with impaired arterial baroreflex. CONCLUSION: It
      is concluded that hypotensive episodes are closely related to poor or lack of
      muscle sympathetic outflow, but may depend on various neural mechanisms to induce
      it.

PMID- 12609008
TI  - The activity of single vasoconstrictor nerve units in hypertension.
AB  - AIM: It has long been established from controlled experiments in anaesthetized
      animals that it is more accurate to quantify the mean frequency of efferent
      sympathetic nerve activity from single unit than from multi-unit bursts
      recordings. More recently, sympathetic nerve hyperactivity has been reported in
      patients with essential hypertension (EHT) when using microneurographic
      recordings from peripheral efferent nerves. This review will focus on the mean
      frequency of single unit of muscle sympathetic nerve activity (s-MSNA) in
      relation to that of multi-unit bursts (MSNA) as obtained by microneurography in
      EHT. RESULTS: We have shown that the resting levels of s-MSNA and MSNA were
      increased in uncomplicated EHT, white coat hypertension and in EHT complicated by
      left ventricular hypertrophy. There was a relatively greater increase in s-MSNA
      than in MSNA in mild hypertension and in complicated EHT. We also found that both
      s-MSNA and MSNA were increased to a similar extent in conditions known to affect
      reflexes emanating from the heart and influencing sympathetic output, such as
      acute myocardial infarction. In other preliminary studies, the increase of s-MSNA
      in response to the discomfort of cold pressor test was greater than that of MSNA
      and this difference was abolished by the centrally sympatholytic agent
      moxonidine. CONCLUSION: These results are consistent with the hypothesis that an
      increase in the mean frequency of central sympathetic discharge to the periphery
      (greater s-MSNA than MSNA) is involved in the pathogenesis and complications of
      EHT. Target organ damage may in turn lead to an increase in overall sympathetic
      output (excessive MSNA increase) through the operation of peripheral reflex
      mechanisms.

PMID- 12609009
TI  - Chemoreflexes--physiology and clinical implications.
AB  - The chemoreflexes are important modulators of sympathetic activation. The
      peripheral chemoreceptors located in the carotid bodies respond primarily to
      hypoxaemia. Central chemoreceptors located in the region of the brainstem respond
      to hypercapnia. Activation of either the hypoxic or hypercapnic chemoreflex
      elicits both hyperventilation and sympathetic activation. During apnoea, when the
      inhibitory influence of stretch of the pulmonary afferents is eliminated, there
      is a potentiation of the sympathetic response to both hypoxia and hypercapnia.
      This inhibitory influence of the pulmonary afferents is more marked on the
      sympathetic response to peripheral compared with central chemoreceptor
      activation. The arterial baroreflexes also have a powerful inhibitory influence
      on the chemoreflexes. This inhibition is again more marked with respect to the
      peripheral compared with central chemoreflexes. In patients with hypertension,
      there is a marked increase in the sympathetic and ventilatory response to
      hypoxaemia. During apnoea, with elimination of the inhibitory influence of
      breathing, the sympathetic response in untreated mild hypertensive patients is
      strikingly greater than that seen in matched normotensive controls. This
      potentiated peripheral chemoreflex sensitivity in hypertension may be explained
      in part by impaired baroreflex function in these patients. Enhanced peripheral
      chemoreflex sensitivity is also evident in patients with obstructive sleep
      apnoea. This peripheral chemoreflex enhancement is not explained by obesity, as
      obese individuals have a selective potentiation of the central chemoreceptors
      with peripheral chemoreflex responses similar to those seen in lean controls.
      Increased sensitivity to hypoxaemia has important implications in patients with
      obstructive sleep apnoea who experience repetitive and severe hypoxaemic stress.
      Tonic activation of the chemoreflex may also contribute to the high levels of
      sympathetic activity evident even during normoxic daytime wakefulness in sleep
      apnoea patients. Administration of 100% oxygen in patients with sleep apnoea
      results in reductions in heart rate, blood pressure and central sympathetic
      outflow. In patients with heart failure, the central chemoreflex response to
      hypercapnia is markedly and selectively enhanced. This increased central
      chemoreflex sensitivity may contribute to the development of central sleep apnoea
      in heart failure patients. Administration of 100% oxygen does not lower
      sympathetic activity in patients with heart failure, providing further evidence
      against any peripheral chemoreflex potentiation. The peripheral and central
      chemoreflexes have powerful effects on sympathetic activity in both health and
      disease and may contribute importantly to disease pathophysiology, particularly
      in conditions such as hypertension, obstructive sleep apnoea and heart failure.

PMID- 12609010
TI  - Sympathetic nerve activity in obstructive sleep apnoea.
AB  - The mechanisms underlying the link between obstructive sleep apnoea (OSA) and
      cardiovascular disease are not completely established. However, there is
      increasing evidence that autonomic mechanisms are implicated. A number of studies
      have consistently shown that patients with OSA have high levels of sympathetic
      nerve traffic. During sleep, repetitive episodes of hypoxia, hypercapnia and
      obstructive apnoea act through chemoreceptor reflexes and other mechanisms to
      increase sympathetic drive. Remarkably, the high sympathetic drive is present
      even during daytime wakefulness when subjects are breathing normally and no
      evidence of hypoxia or chemoreflex activation is apparent. Several neural and
      humoral mechanisms may contribute to maintenance of higher sympathetic activity
      and blood pressure. These mechanisms include chemoreflex and baroreflex
      dysfunction, altered cardiovascular variability, vasoconstrictor effects of
      nocturnal endothelin release and endothelial dysfunction. Long-term continuous
      positive airway pressure treatment decreases muscle sympathetic nerve activity in
      OSA patients. The vast majority of OSA patients remain undiagnosed. Unrecognized
      OSA may contribute, in part, to the metabolic and cardiovascular derangements
      that are thought to be linked to obesity, and to the association between obesity
      and cardiovascular risk. Furthermore, acting through sympathetic neural
      mechanisms, OSA may contribute to or augment elevated levels of blood pressure in
      a large proportion of the hypertensive patient population.

PMID- 12609011
TI  - Sympathetic activation in human heart failure: diverse mechanisms, therapeutic
      opportunities.
AB  - Plasma noradrenaline (NA) concentrations relate both to the severity of heart
      failure, and to its impact on survival, but have shortcomings that limit their
      usefulness as measures of sympathetic discharge. Neural recordings and the
      isotopic dilution method for determining organ-specific rates of NA spillover
      into plasma have enhanced our understanding of mechanisms responsible for
      sympathetic activation. Because the arterial baroreceptor reflex control of heart
      rate is impaired in heart failure, a parallel reduction in the reflex inhibition
      of sympathetic outflow has been assumed. However, human heart failure is
      characterized by rapidly responsive arterial baroreflex regulation of muscle
      sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation
      of MSNA, and activation of a cardiac-specific sympatho-excitatory reflex related
      to increased cardiopulmonary filling pressures. Together, these baroreceptor
      mediated mechanisms account only, in part, for the time course and magnitude of
      adrenergic activation in heart failure. Non-baroreflex sympatho-excitatory
      mechanisms include: a metaboreflex arising from exercising skeletal muscle,
      mediated, in part, by adenosine, co-existing sleep apnoea, and pre-junctional
      facilitation of NA release. Thus, sympathetic activation in the setting of
      impaired systolic function reflects the net balance and interaction between
      augmented excitatory and diminished inhibitory influences. Variation, between
      patients, in the dynamics, magnitude and progression of sympathetic activation
      mandates an individualized approach to investigation and therapy. Excessive
      sympathetic outflow to the heart and periphery can be addressed by several
      complimentary strategies: attenuating these sympatho-excitatory stimuli,
      modulating the neural regulation of NA release, and blocking the actions of
      catecholamines at post-junctional receptors.

PMID- 12609012
TI  - Behaviour of the adrenergic cardiovascular drive in atrial fibrillation and
      cardiac arrhythmias.
AB  - AIM: Animal studies have conclusively shown that the sympathetic nervous system
      plays a major role not only in regulating sinus node activity but also in
      promoting cardiac rhythm alterations. Less univocal and often circumstantial have
      been the evidences collected on this issue in humans. However, the introduction
      of the microneurographic technique in clinical research has allowed to gain new
      important insights on the role of neuroadrenergic factors in the pathophysiology
      of cardiac arrhythmias. METHODS: The present paper will review the results of
      microneurographic studies performed by our group and others in the field of
      cardiac rhythm disturbances by addressing three specific issues. First it will
      examine the relationships between heart rate and muscle sympathetic neural
      outflow in a variety of cardiovascular diseases characterized by sympathetic
      activation. This will be followed by an analysis of the behaviour of the
      sympathetic nerve traffic responses to paroxysmal atrial fibrillation. Finally,
      the sympathetic adjustments to spontaneously occurring or artificially induced
      pre-mature ventricular contractions will be highlighted.

PMID- 12609013
TI  - Pathological sympathoexcitation: how is it achieved?
AB  - AIM: Congestive heart failure (CHF) and obstructive sleep apnoea syndrome (OSAS)
      are both associated with an intense sympathoexcitation, including an increased
      muscle sympathetic nerve activity (MSNA). We have studied the firing
      characteristics of single vasoconstrictor fibres to the muscle vascular bed in
      CHF and OSAS patients, at rest and during transient sympathoexcitatory stimuli,
      to elucidate the mechanisms by which vasoconstrictor output is augmented in these
      conditions. RESULTS: The main alternatives for augmenting sympathetic output are
      an increased firing frequency of individual nerve fibres and an increased
      recruitment of nerve fibres. Starting with the frequency alternative, the
      inherent bursting character of MSNA provides two possibilities to increase the
      firing of individual fibres: (1) by increasing the proportion of neural bursts in
      which the fibre is active (increased firing probability) and (2) by increasing
      the number of spikes a fibre generates per burst (increased multiple within-burst
      firing). At rest and in cardiac sinus rhythm, an increased firing probability is
      seen in both CHF and OSAS patients, whereas increased multiple within-burst
      firing is found in OSAS but not in CHF. In response to transient
      sympathoexcitatory stimuli (such as pre-mature heart beats), both patient groups
      show marked shifts towards multiple within-burst firing. Thus, both mechanisms
      for augmenting discharge frequency are operating in these two pathological
      conditions, but the firing characteristics at rest differ significantly. During
      recording sessions in sympathoexcited patients, we have encountered
      vasoconstrictor fibres that are active almost exclusively during periods of
      transient sympathoexcitation, while being virtually silent at rest. This suggests
      that recruitment of previously inactive vasoconstrictor fibres, the second main
      alternative for increasing vasoconstrictor output, contributes to transient
      sympathoexcitatory responses in these patients. Although it seems reasonable to
      assume that recruitment may also contribute to the resting level of MSNA in CHF
      and OSAS, this issue is difficult to resolve in microneurographic studies.
      CONCLUSION: In conclusion, pathological sympathoexcitation appears to depend on
      both recruitment and increased firing frequency. A shift towards multiple within
      burst firing, at rest or in response to transient stimuli, may constitute a risk
      factor per se as it entails neural volleys with high instantaneous firing
      frequencies and consequently higher release of neurotransmitters.

PMID- 12609014
TI  - Prevalence of illicit drug use in plasmapheresis donors.
AB  - BACKGROUND AND OBJECTIVES: No data are presently available concerning the
      frequency of illicit drug use in plasmapheresis donors. We therefore examined
      source plasma units produced in the United States (US) and in Germany for
      evidence of illicit drug use among donors. MATERIALS AND METHODS: Seventy-five US
      plasma units from 10 different US states and 75 German plasma units that had been
      analysed principally for their protein composition were screened for drugs.
      Determinations were made, using automated immunoassays, of the presence of
      cannabis, cocaine, amphetamine, methamphetamine, methylenedioxymethamphetamine
      (MDMA), methylenedioxyethylamphetamine (MDE) and opiates. Positive results were
      confirmed by gas chromatography-mass spectrometry. RESULTS: Eleven US plasma
      units were found to be positive for cocaine (14.6%), whereas all German samples
      were cocaine negative (P = 0.0007). Fifteen US plasma units (20%) and one German
      unit (1.3%) were confirmed as positive for cannabis (P = 0.0003). Three out of 75
      US plasma units were positive for both cannabis and cocaine. In none of the 150
      samples were amphetamine, methamphetamine, MDMA, MDE or opiates detected.
      CONCLUSIONS: Our results strongly suggest differences in cocaine and cannabis
      consumption between US and German plasmapheresis donors. If these results are
      confirmed by larger-scale studies, random drug screening (including cocaine) of
      donors should be implemented in order to reduce the number of drug-containing
      plasma units, especially in the USA.

PMID- 12609015
TI  - Inactivation of pathogens in platelet concentrates by using a two-step procedure.
AB  - BACKGROUND AND OBJECTIVES: Platelet concentrates are contaminated with residual
      leucocytes and may also be infected with viruses and bacteria. We investigated
      whether these pathogens can be inactivated by a two-step procedure comprising
      photodynamic treatment in the presence of the phenothiazine dye, thionine,
      followed by irradiation with ultraviolet light (UV-B, wavelength range 290-330
      nm). MATERIALS AND METHODS: Platelet concentrates were prepared from buffy coats.
      The concentrates were spiked with different viruses, bacteria and leucocytes,
      then illuminated with yellow light in the presence of thionine at dye
      concentrations between 1 and 5 microm and with UV-B at doses up to 2.4 J/cm2. The
      infectivity of samples and the viability of leucocytes were assayed before and
      after treatment. The influence of treatment on in vitro platelet function was
      also examined. RESULTS: The inactivation of free viruses in platelet concentrates
      by photodynamic treatment with thionine/light was significantly enhanced when it
      was followed by irradiation with UV-B. The inactivation of leucocytes and of
      bacteria by UV-B was improved when it was preceded by thionine/light. Sterile
      platelet concentrates were prepared from buffy coats infected with Staphylococcus
      epidermidis. Platelet function and the storage stability of platelet concentrates
      were only moderately influenced by the two decontamination steps. CONCLUSIONS:
      Photodynamic treatment in the presence of the phenothiazine dye, thionine,
      followed by low-dose UVB, has the potential to inactivate viruses, leucocytes and
      bacteria, which might contaminate platelet concentrates. Both treatments
      complement each other.

PMID- 12609016
TI  - Hepatitis C virus-polymerase chain reaction minipool testing: 3 years in the
      largest Swiss blood transfusion service.
AB  - BACKGROUND AND OBJECTIVES: Hepatitis C virus-polymerase chain reaction (HCV-PCR)
      minipool testing can improve the safety of labile blood products owing to a
      reduction in the diagnostic preseroconversion window period. In Switzerland, HCV
      PCR minipool testing for the release of labile blood components became mandatory
      in September 1999. In the largest Swiss blood transfusion centre, HCV-PCR
      minipool testing began in January 1999. This report analyses the performance of
      the test during a 3-year period: 1 January 1999 to 31 December 2001. MATERIALS
      AND METHODS: EDTA-blood was collected in either standard tubes or plasma
      preparation (PPT) tubes from 10 blood transfusion services in Switzerland and
      then sent to the Blood Transfusion Service SRC Berne. Up to 48 donor samples were
      pooled overnight using Tecan Genesis RSP 200/8 pipettors. Viral RNA was extracted
      by using the Qiagen QIAamp 96 viral RNA BioRobot kit on a BioRobot 9604. For PCR
      amplification and detection of HCV or internal control (IC) sequences, the Roche
      Cobas Amplicor v2.0 test kit was used. Data management, pool resolution and
      identification of positive samples were performed using the PMS Software from
      Tecan. RESULTS: In the 3-year period from 1 January 1999 to 31 December 2001,
      839056 blood donor samples were tested in minipools of up to 48 samples. Thirty
      five HCV-PCR-positive donations were identified. Thirty-four samples had
      antibodies against HCV and were therefore also detected by screening for antibody
      to HCV (anti-HCV). In October 2001, one seronegative (but PCR-positive) donor was
      detected. CONCLUSIONS: HCV-PCR minipool testing was successfully introduced in
      the largest Swiss blood transfusion service. It was shown that the release of HCV
      PCR minipool results can be accomplished concurrently with the results of
      serological analysis. The challenge with a seronegative, but PCR-positive, donor
      demonstrates that the minipool testing strategy adds additional safety to blood
      products.

PMID- 12609017
TI  - Nanofiltration of single plasma donations: feasibility study.
AB  - BACKGROUND AND OBJECTIVES: Major technical developments have been made in recent
      years to improve the quality and safety of human plasma for transfusion and
      fractionation. The present study was performed to assess, for the first time, the
      feasibility of applying a nanofiltration process, using 75-nm and 35-nm mean pore
      size membranes (Planova) 75N and Planova 35N), to human plasma. MATERIALS AND
      METHODS: Ten apheresis plasma units were obtained from 10 plasma donors. Within 4
      h of collection, plasma was subjected to leucoreduction and filtration (using 75
      nm and 35-nm mean pore size membranes) at 35 degrees C, at less than 1 bar
      pressure. Aliquots of plasma were taken at all steps of the filtration procedure
      and numerous plasma quality parameters were measured. In addition, six hepatitis
      C virus (HCV)-positive plasma donations were experimentally subjected to the same
      filtration sequence and subsequently assessed by RNA polymerase chain reaction
      (PCR) and branched-chain DNA-quantification assays. RESULTS: Leucoreduced plasma
      can be reproducibly nanofiltered onto a sequence of 75-nm and 35-nm membranes, at
      a flow rate of 450 ml/h and a temperature of 35 +/- 0.5 degrees C. Some protein
      dilution, or loss, was found during filtration, but the plasma filtered through
      membranes with a mean pore size of 75 nm and 35 nm met in vitro specifications
      for use in transfusion or fractionation. There were no signs of activation of the
      coagulation system. HCV-positive plasma donations became negative, as judged by
      PCR and branched-chain DNA assay results, after filtration through the 35-nm
      membrane. CONCLUSIONS: It is possible to apply a 75 + 35-nm filtration process to
      leucoreduced human plasma. This technology may have important future benefits in
      improving the quality and safety of plasma, by removing blood cell debris and
      infectious agents.

PMID- 12609018
TI  - The blood-donation experience: perceived physical, psychological and social
      impact of blood donation on the donor.
AB  - BACKGROUND AND OBJECTIVES: This study aimed to investigate the impact and effects
      of blood donation on blood donors as perceived and reported by donors themselves.
      MATERIALS AND METHODS: A self-administered questionnaire was distributed to 600
      consecutive whole-blood donors (who had a history of at least one previous
      donation) consisting of an open-ended question asking whether the blood donation
      had any impact on the donor. The answers to this question were considered as
      descriptions of effects perceived by the donors to be evoked by whole-blood
      donation. RESULTS: In all, 528 subjects completed the questionnaire (88%; 319
      males and 209 females) and answered the question about the effects of blood
      donation. Altogether, 54% (287 out of 528) of the blood donors reported one or
      several effects. Exclusively positive effects were described by 29% (151) of
      blood donors, while exclusively negative effects and mixed effects (i.e.
      concomitant positive and negative effects in the same subject) were described by
      19% (103) and 6% (33), respectively, while no effect was reported by 46% (241) of
      the donors. A majority of the effects commenced within 1 h of blood donation. The
      positive effects lasted significantly longer (often for weeks, P < 0.0001) than
      negative effects (min/h/days). Among positive effects a feeling of satisfaction,
      of being more alert, and feeling generally better than before the blood donation
      predominated for both female and male donors. Among negative effects,
      vertigo/dizziness was reported more frequently by female donors (P < 0.0001).
      Logistic regression analysis revealed that the negative effects were less likely
      to occur with increasing age (P < 0.001) and that they were more likely to occur
      in female donors (P < 0.001) in comparison to male donors, irrespective of age.
      CONCLUSIONS: The majority of effects elicited by blood donation on blood donors
      were positive (i.e. feelings of satisfaction, greater alertness, increased
      wellbeing, etc.). The positive effects did not differ from the negative regarding
      time of onset, yet their duration was reported to be significantly longer. There
      was no association between frequency of occurrence of positive effects and the
      number of blood donations, indicating that there is no 'addictive' relationship
      between donors and blood donations. The findings in this study of high frequency
      of occurrence of positive long-lasting effects elicited in blood donors by blood
      donation may be of great importance for the recruitment of new blood donors as it
      may make blood donation less frightening and perhaps even attractive.

PMID- 12609019
TI  - Validation of flow cytometry to quantify the potency of anti-D immunoglobulin
      preparations.
AB  - BACKGROUND AND OBJECTIVES: Flow cytometry has been recommended as an alternative
      to that of autoanalyser methodology for estimation of anti-D potency. This
      investigation was performed to validate the flow cytometry method based on a
      quality assurance system. MATERIALS AND METHODS: A flow cytometry method based on
      indirect labelling of Rh(D)-positive red blood cells was validated using the
      parameters precision and accuracy and was compared to the autoanalyser data of
      manufacturers of anti-D immunoglobulin preparations. RESULTS: The experiment
      first investigated the possible differences between assays from single donors
      compared with a pooled assay. Red blood cells of four individual donors and their
      pooled red blood cells were interchangeable. There was no significant difference
      between donors, on one hand, and between the use of a single donation and the
      pooled red blood cells, on the other hand (P = 0.695). The two-sided 95%
      confidence intervals (CIs) of the difference between single donors and the pool
      ranged from -4.6% to 4.7%. The intermediate variability was determined by
      standard deviation (SD) = 48.4 IU/ml [coefficient of variation (CV) = 3.8%]; the
      repeatability was SD = 34.3 IU/ml (CV = 2.7%). Using a spiking experiment, the
      second part of the experiment investigated recovery of a known anti-D potency.
      The recovery of samples spiked with defined amounts of reference preparation was
      97.7-101%, with a mean bias of -1.3 (95% CI: -4.1 to 1.6). The results of the
      flow cytometry assay, as compared to those of the autoanalyser performed by the
      manufacturers of anti-D immunoglobulin preparations for those manufacturers who
      have their method validated in-house, ranged from 87 to 129%, indicating good
      correlation. CONCLUSIONS: Flow cytometry is a suitable quality control method for
      polyclonal anti-D immunoglobulins, which can be standardized in a quality control
      laboratory using a quality assurance system.

PMID- 12609021
TI  - Transfusion-related acute lung injury in North India from a donor related by
      marriage.

PMID- 12609020
TI  - A new antigen of the Er collection.

PMID- 12609022
TI  - A novel mutation in the RHD gene in Japanese individuals with weak D, encoding an
      amino acid change in the 11th transmembranous domain of the RhD protein.

PMID- 12609023
TI  - Prenatal management of alloimmune thrombocytopenia of the fetus.

PMID- 12609024
TI  - Re-organisation of the cytoskeleton during developmental programmed cell death in
      Picea abies embryos.
AB  - Cell and tissue patterning in plant embryo development is well documented.
      Moreover, it has recently been shown that successful embryogenesis is reliant on
      programmed cell death (PCD). The cytoskeleton governs cell morphogenesis.
      However, surprisingly little is known about the role of the cytoskeleton in plant
      embryogenesis and associated PCD. We have used the gymnosperm, Picea abies,
      somatic embryogenesis model system to address this question. Formation of the
      apical-basal embryonic pattern in P. abies proceeds through the establishment of
      three major cell types: the meristematic cells of the embryonal mass on one pole
      and the terminally differentiated suspensor cells on the other, separated by the
      embryonal tube cells. The organisation of microtubules and F-actin changes
      successively from the embryonal mass towards the distal end of the embryo
      suspensor. The microtubule arrays appear normal in the embryonal mass cells, but
      the microtubule network is partially disorganised in the embryonal tube cells and
      the microtubules disrupted in the suspensor cells. In the same embryos, the
      microtubule-associated protein, MAP-65, is bound only to organised microtubules.
      In contrast, in a developmentally arrested cell line, which is incapable of
      normal embryonic pattern formation, MAP-65 does not bind the cortical
      microtubules and we suggest that this is a criterion for proembryogenic masses
      (PEMs) to passage into early embryogeny. In embryos, the organisation of F-actin
      gradually changes from a fine network in the embryonal mass cells to thick cables
      in the suspensor cells in which the microtubule network is completely degraded. F
      actin de-polymerisation drugs abolish normal embryonic pattern formation and
      associated PCD in the suspensor, strongly suggesting that the actin network is
      vital in this PCD pathway.

PMID- 12609025
TI  - Interaction of NtCDPK1 calcium-dependent protein kinase with NtRpn3 regulatory
      subunit of the 26S proteasome in Nicotiana tabacum.
AB  - Using a yeast two-hybrid system, we identified NtRpn3, a regulatory subunit of
      26S proteasome, as an interacting protein of NtCDPK1 calcium-dependent protein
      kinase in Nicotiana tabacum. Rpn3 in yeast is an essential protein involved in
      proteolysis of cell cycle regulatory proteins, and the carrot homolog of Rpn3 was
      previously isolated as a nuclear antigen that is mainly expressed in the
      meristem. NtCDPK1 physically interacts with NtRpn3 in vitro in a Ca2+-independent
      manner and phosphorylates NtRpn3 in a Ca2+-dependent manner with Mg2+ as a
      cofactor. NtCDPK1 and NtRpn3 are co-localized in the nucleus, nuclear periphery,
      and around plasma membrane in vivo. Both NtCDPK1 and AtRpn3, an NtRpn3 homolog of
      Arabidopsis, are mainly expressed in the rapidly proliferating tissues including
      shoot and root meristems, and developing floral buds. Virus-induced gene
      silencing of either NtRpn3 or NtCDPK1 resulted in the phenotypes of abnormal cell
      morphology and premature cell death in newly emerged leaves. Finally, NtCDPK1
      interacts with NtRpn3 in vivo as shown by co-immunoprecipitation. Based on these
      results, we propose that NtCDPK1 and NtRpn3 are interacting in a common signal
      transduction pathway possibly for regulation of cell division, differentiation,
      and cell death in tobacco.

PMID- 12609026
TI  - Functional complementation in yeast reveals a protective role of chloroplast 2
      Cys peroxiredoxin against reactive nitrogen species.
AB  - The importance of nitric oxide (NO) as a signaling molecule to various plant
      physiological and pathophysiological processes is becoming increasingly evident.
      However, little is known about how plants protect themselves from nitrosative and
      oxidative damage mediated by NO and NO-derived reactive nitrogen species (RNS).
      Peroxynitrite, the product of the reaction between NO and superoxide anion, is
      considered to play a central role in RNS-induced cytotoxicity, as a result of its
      potent ability to oxidize diverse biomolecules. Employing heterologous expression
      in bacteria and yeast, we investigated peroxynitrite-scavenging activity in
      plants of 2-Cys peroxiredoxin (2CPRX), originally identified as a hydroperoxide
      reducing peroxidase that is ubiquitously distributed among organisms. The
      putative mature form of a chloroplast-localized 2CPRX from Arabidopsis thaliana
      was overproduced in Escherichia coli as an amino-terminally hexahistidine-tagged
      fusion protein. The purified recombinant 2CPRX, which was catalytically active as
      peroxidase, efficiently prevented the peroxynitrite-induced oxidation of a
      sensitive compound. We also examined in vivo the ability of the Arabidopsis 2CPRX
      to complement the 2CPRX deficiency of a Saccharomyces cerevisiae mutant.
      Functional expression in the mutant strain of the Arabidopsis 2CPRX not only
      increased cellular tolerance to hydrogen peroxide, but also complemented the
      hypersensitive growth defect induced by nitrite-mediated cytotoxicity. The
      complemented cells significantly enhanced the capacity to reduce RNS-mediated
      oxidative damages. The results presented here demonstrate a new role of plant
      2CPRX as a critical determinant of the resistance to RNS, and support the
      existence of a plant enzymatic basis for RNS metabolism.

PMID- 12609027
TI  - Module-specific regulation of the beta-phaseolin promoter during embryogenesis.
AB  - The phas promoter displays stringent spatial regulation, being very highly
      expressed during embryogenesis and completely silent during all phases of
      vegetative development in bean, Phaseolus vulgaris. This pattern is maintained in
      transgenic tobacco and, as shown here, Arabidopsis. Dimethyl sulphate in vivo
      footprinting analyses revealed that over 20 cis-elements within the proximal 295
      bp of the phas promoter are protected by factor binding in seed tissues whereas
      none are bound in leaves. The hypothesis that this complex profile represents a
      summation of several module (cotyledon, hypocotyl, and radicle)-specific factor
      DNA interactions has been explored by the incorporation of site-directed
      substitution mutations into 10 locations within the -295phas promoter. Only 2.6%
      of -295phas promoter activity remained after mutation of the G-box; the CCAAAT
      box, the E-box and the RY elements were also found to mediate high levels of
      expression in embryos. Whereas the CACA element has dual positive and negative
      regulatory roles, the vicilin box was identified as a strong negative regulatory
      element. The proximal (-70 to -64) RY motif was found to bestow expression in the
      hypocotyl while all the RY elements contribute to expression in cotyledons but
      not to vascular tissue expression during embryogenesis. RY elements at positions 
      277 to -271, -260 to -254, and -237 to -231 were found to orchestrate radicle
      specific repression. The G-box appears to be the functional abscisic acid
      responsive element and the E-site may be a coupling element. The results
      substantiate the concept that autarkical cis-element functions generate modular
      patterning during embryogenesis. They also reflect the existence of both
      redundancy and hierarchy in cis-element interactions. Importantly, the virtually
      identical expression patterns observed for the two distantly related plants
      studied argue strongly for the generality of function for the observed factor
      element interactions.

PMID- 12609028
TI  - AGL24 acts as a promoter of flowering in Arabidopsis and is positively regulated
      by vernalization.
AB  - MADS-domain-containing transcription factors comprise a large family of
      regulators that have diverse roles in plant development, including the regulation
      of flowering time. AGAMOUS-LIKE 20/SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1
      (SOC1) and FRUITFUL act to promote flowering, whereas FLOWERING LOCUS C (FLC),
      FLOWERING LOCUS M/MADS AFFECTING FLOWERING1, and SHORT VEGETATIVE PHASE are
      inhibitors of flowering. Here we report that AGAMOUS-LIKE 24 (AGL24) also plays a
      role in the regulation of flowering time. agl24 mutants are late flowering and
      overexpression of AGL24 causes early flowering in wild-type and late-flowering
      mutant backgrounds. The effect of AGL24 overexpression is most pronounced in
      autonomous-pathway-mutant and FRIGIDA-containing backgrounds. The behavior of
      AGL24 is most similar to that of SOC1. Like SOC1, AGL24 mRNA levels are
      upregulated by vernalization. Unlike SOC1, however, AGL24 mRNA levels are not
      affected by FLC, and therefore AGL24 may represent an FLC-independent target of
      the vernalization pathway. There is also evidence for cross-talk between AGL24
      and SOC1. When overexpressed, SOC1 and AGL24 are able to upregulate each other's
      expression. Thus, AGL24 represents another component in a network of MADS-domain
      containing transcription factors that regulate flowering time.

PMID- 12609029
TI  - Phytochrome control of flowering is temperature sensitive and correlates with
      expression of the floral integrator FT.
AB  - In Arabidopsis flowering is accelerated by reduced red:far-red (R:FR) ratio which
      signals the presence of neighbouring vegetation. Hastened flowering is one
      component of the shade-avoidance syndrome of responses, which alter many aspects
      of development in response to the threat of potential competition. Of the red/far
      red-absorbing photoreceptors it is phyB that plays the most prominent role in
      shade-avoidance, although other related phytochromes act redundantly with phyB.
      It is well established that the phyB mutant has a constitutively early flowering
      phenotype. However, we have shown that the early flowering phenotype of phyB is
      temperature-dependent. We have established that this temperature-sensitive
      flowering response defines a pathway that appears to be independent of the
      autonomous-FLC pathway. Furthermore, we have demonstrated that the phytochromes
      control the expression of the floral promoter FT. We have also shown that other
      phyB-controlled responses, including petiole elongation, are not sensitive to the
      same temperature change. This suggests that discrete pathways control flowering
      and petiole elongation, components of the shade-avoidance response. This work
      provides an insight into the phytochrome and temperature interactions that
      maintain flowering control.

PMID- 12609030
TI  - Brassinosteroid functions in a broad range of disease resistance in tobacco and
      rice.
AB  - Brassinolide (BL), considered to be the most important brassinosteroid (BR) and
      playing pivotal roles in the hormonal regulation of plant growth and development,
      was found to induce disease resistance in plants. To study the potentialities of
      BL activity on stress responding systems, we analyzed its ability to induce
      disease resistance in tobacco and rice plants. Wild-type tobacco treated with BL
      exhibited enhanced resistance to the viral pathogen tobacco mosaic virus (TMV),
      the bacterial pathogen Pseudomonas syringae pv. tabaci (Pst), and the fungal
      pathogen Oidium sp. The measurement of salicylic acid (SA) in wild-type plants
      treated with BL and the pathogen infection assays using NahG transgenic plants
      indicate that BL-induced resistance does not require SA biosynthesis. BL
      treatment did not induce either acidic or basic pathogenesis-related (PR) gene
      expression, suggesting that BL-induced resistance is distinct from systemic
      acquired resistance (SAR) and wound-inducible disease resistance. Analysis using
      brassinazole 2001, a specific inhibitor for BR biosynthesis, and the measurement
      of BRs in TMV-infected tobacco leaves indicate that steroid hormone-mediated
      disease resistance (BDR) plays part in defense response in tobacco. Simultaneous
      activation of SAR and BDR by SAR inducers and BL, respectively, exhibited
      additive protective effects against TMV and Pst, indicating that there is no
      cross-talk between SAR- and BDR-signaling pathway downstream of BL. In addition
      to the enhanced resistance to a broad range of diseases in tobacco, BL induced
      resistance in rice to rice blast and bacterial blight diseases caused by
      Magnaporthe grisea and Xanthomonas oryzae pv. oryzae, respectively. Our data
      suggest that BDR functions in the innate immunity system of higher plants
      including dicotyledonous and monocotyledonous species.

PMID- 12609031
TI  - Arabidopsis phosphatidylglycerophosphate synthase 1 is essential for chloroplast
      differentiation, but is dispensable for mitochondrial function.
AB  - Genetic dissection of the lipid bilayer composition provides essential in vivo
      evidence for the role of individual lipid species in membrane function. To
      understand the in vivo role of the anionic phospholipid, phosphatidylglycerol,
      the loss-of-function mutation was identified and characterized in the Arabidopsis
      thaliana gene coding for phosphatidylglycerophosphate synthase 1, PGP1. This
      mutation resulted in pigment-deficient plants of the xantha type in which the
      biogenesis of thylakoid membranes was severely compromised. The PGP1 gene coded
      for a precursor polypeptide that was targeted in vivo to both plastids and
      mitochondria. The activity of the plastidial PGP1 isoform was essential for the
      biosynthesis of phosphatidylglycerol in chloroplasts, whereas the mitochondrial
      PGP1 isoform was redundant for the accumulation of phosphatidylglycerol and its
      derivative cardiolipin in plant mitochondrial membranes. Together with findings
      in cyanobacteria, these data demonstrated that anionic phospholipids play an
      important, evolutionarily conserved role in the biogenesis and function of the
      photosynthetic machinery. In addition, mutant analysis suggested that in higher
      plants, mitochondria, unlike plastids, could import phosphatidylglycerol from the
      endoplasmic reticulum.

PMID- 12609032
TI  - Arabidopsis gene expression changes during cyst nematode parasitism revealed by
      statistical analyses of microarray expression profiles.
AB  - With the availability of microarray technology, the expression profiles of
      thousands of genes can be monitored simultaneously to help determine the
      mechanisms of these biological processes. We conducted Affymetrix GeneChip
      microarray analyses of the Arabidopsis-cyst nematode interaction and employed a
      statistical procedure to analyze the resultant data, which allowed us to identify
      significant gene expression changes. Quantitative real-time RT-PCR assays were
      used to confirm the microarray analyses. The results of the expression profiling
      revealed 128 genes with altered steady-state mRNA levels following infection by
      the sugar beet cyst nematode (Heterodera schachtii; BCN), in contrast to only 12
      genes that had altered expression following infection by the soybean cyst
      nematode (H. glycines; SCN). The expression of these 12 genes also changed
      following infection by BCN, i.e. we did not identify any genes regulated
      exclusively by SCN. The identification of 116 genes whose expression changes
      during successful cyst nematode parasitism by BCN suggests a potential
      involvement of these genes in the infection events starting with successful
      syncytium induction. Further characterization of these genes will permit the
      formulation of testable hypotheses to explain successful cyst nematode
      parasitism.

PMID- 12609033
TI  - CYP79F1 and CYP79F2 have distinct functions in the biosynthesis of aliphatic
      glucosinolates in Arabidopsis.
AB  - Cytochromes P450 of the CYP79 family catalyze the conversion of amino acids to
      oximes in the biosynthesis of glucosinolates, a group of natural plant products
      known to be involved in plant defense and as a source of flavor compounds, cancer
      preventing agents and bioherbicides. We report a detailed biochemical analysis of
      the substrate specificity and kinetics of CYP79F1 and CYP79F2, two cytochromes
      P450 involved in the biosynthesis of aliphatic glucosinolates in Arabidopsis
      thaliana. Using recombinant CYP79F1 and CYP79F2 expressed in Escherichia coli and
      Saccharomyces cerevisiae, respectively, we show that CYP79F1 metabolizes mono- to
      hexahomomethionine, resulting in both short- and long-chain aliphatic
      glucosinolates. In contrast, CYP79F2 exclusively metabolizes long-chain elongated
      penta- and hexahomomethionines. CYP79F1 and CYP79F2 are spatially and
      developmentally regulated, with different gene expression patterns. CYP79F2 is
      highly expressed in hypocotyl and roots, whereas CYP79F1 is strongly expressed in
      cotyledons, rosette leaves, stems, and siliques. A transposon-tagged CYP79F1
      knockout mutant completely lacks short-chain aliphatic glucosinolates, but has an
      increased level of long-chain aliphatic glucosinolates, especially in leaves and
      seeds. The level of long-chain aliphatic glucosinolates in a transposon-tagged
      CYP79F2 knockout mutant is substantially reduced, whereas the level of short
      chain aliphatic glucosinolates is not affected. Biochemical characterization of
      CYP79F1 and CYP79F2, and gene expression analysis, combined with glucosinolate
      profiling of knockout mutants demonstrate the functional role of these enzymes.
      This provides valuable insights into the metabolic network leading to the
      biosynthesis of aliphatic glucosinolates, and into metabolic engineering of
      altered aliphatic glucosinolate profiles to improve nutritional value and pest
      resistance.

PMID- 12609034
TI  - Cell cycle-dependent association of Arabidopsis actin-related proteins AtARP4 and
      AtARP7 with the nucleus.
AB  - Arabidopsis encodes at least eight actin-related proteins (ARPs) most of which
      have orthologs in other distant organisms. To gain insight into the role of ARPs
      in plants, we have examined the spatial expression and subcellular distribution
      of two highly divergent Arabidopsis ARPs, AtARP4 and AtARP7. AtARP4 is a homolog
      of human BAF53 and yeast Arp4, and AtARP7 is a novel, ancient and plant-specific
      actin-related protein that is not distinctly related to any known ARPs from other
      kingdoms. Analysis of both these proteins with AtARP4- and AtARP7-specific
      antibodies revealed that they were most abundant in young meristematic and floral
      tissues, but were expressed constitutively in all organs and cell types
      irrespective of their developmental stage. Immunofluorescence studies showed that
      both AtARP4 and AtARP7 were localized predominantly to the nucleus during
      interphase. In mitotic cells lacking a nuclear envelope (e.g. metaphase,
      anaphase, and early telophase stages), these ARPs were excluded from the
      condensed chromosomes and dispersed throughout the cytoplasm. In contrast, a
      putative Arabidopsis histone H2B protein remained associated with the interphase
      nuclei as well as chromosomes throughout the cell cycle. Based on our results and
      data on the yeast ortholog of AtARP4, these two nuclear plant ARPs may be
      involved in the modulation of chromatin structure and transcriptional regulation
      mainly in interphase cells.

PMID- 12609035
TI  - An enhanced transient expression system in plants based on suppression of gene
      silencing by the p19 protein of tomato bushy stunt virus.
AB  - Transient gene expression is a fast, flexible and reproducible approach to high
      level expression of useful proteins. In plants, recombinant strains of
      Agrobacterium tumefaciens can be used for transient expression of genes that have
      been inserted into the T-DNA region of the bacterial Ti plasmid. A bacterial
      culture is vacuum-infiltrated into leaves, and upon T-DNA transfer, there is
      ectopic expression of the gene of interest in the plant cells. However, the
      utility of the system is limited because the ectopic protein expression ceases
      after 2-3 days. Here, we show that post-transcriptional gene silencing (PTGS) is
      a major cause for this lack of efficiency. We describe a system based on co
      expression of a viral-encoded suppressor of gene silencing, the p19 protein of
      tomato bushy stunt virus (TBSV), that prevents the onset of PTGS in the
      infiltrated tissues and allows high level of transient expression. Expression of
      a range of proteins was enhanced 50-folds or more in the presence of p19 so that
      protein purification could be achieved from as little as 100 mg of infiltrated
      leaf material. The effect of p19 was not saturated in cells that had received up
      to four individual T-DNAs and persisted until leaf senescence. Because of its
      simplicity and rapidity, we anticipate that the p19-enhanced expression system
      will have value in industrial production as well as a research tool for isolation
      and biochemical characterisation of a broad range of proteins without the need
      for the time-consuming regeneration of stably transformed plants.

PMID- 12609036
TI  - Proliferating Floral Organs (Pfo), a Lotus japonicus gene required for specifying
      floral meristem determinacy and organ identity, encodes an F-box protein.
AB  - To study flower development in the model legume Lotus japonicus, a population of
      transgenic plants containing a maize transposable element (Ac) in their genome
      was screened for floral mutants. One mutation named proliferating floral organs
      (pfo) causes plants to produce a large number of sepal-like organs instead of
      normal flowers. It segregates as a single recessive Mendelian locus, and causes
      sterility. Scanning electron microscopy revealed that pfo affects the identity,
      number and arrangement of floral organs. Sepal-like organs form in the first
      whorl, and secondary floral meristems are produced in the next whorl. These in
      turn produce sepal-like organs in the first whorl and floral meristems in the
      second whorl, and the process is reiterated. Petals and stamens are absent while
      carpels are either absent or reduced. The pfo phenotype was correlated with the
      presence of an Ac insertion yielding a 1.6-kb HindIII restriction fragment on
      Southern blots. Both the mutant phenotype and this Ac element are unstable. Using
      the transposon as a tag, the Pfo gene was isolated. Conceptual translation of Pfo
      predicts a protein containing an F-box, with high overall similarity to the
      Antirrhinum FIMBRIATA, Arabidopsis UNUSUAL FLORAL ORGANS and Pisum sativum
      Stamina pistilloida proteins. This suggests that Pfo may regulate floral organ
      identity and meristem determinacy by targeting proteins for ubiquitination.

PMID- 12609037
TI  - Changes in hydrogen peroxide homeostasis trigger an active cell death process in
      tobacco.
AB  - In transgenic tobacco plants with reduced catalase activity, high levels of
      hydrogen peroxide (H2O2) can accumulate under photorespiratory conditions. Such a
      perturbation in H2O2 homeostasis induced cell death in clusters of palisade
      parenchyma cells, primarily along the veins. Ultrastructural alterations, such as
      chromatin condensation and disruption of mitochondrial integrity, took place
      before cell death. Furthermore, enhanced transcript levels of mitochondrial
      defense genes accompanied these mitochondrial changes. Pharmacological data
      indicated that the initiation and execution of cell death require de novo protein
      synthesis and that the signal transduction pathway leading to cell death involved
      changes in ion homeostasis, (de)phosphorylation events and an oxidative burst, as
      observed during hypersensitive responses. This oxidase-dependent oxidative burst
      is essential for cell death, but it is not required for the accumulation of
      defense proteins, suggesting a more prominent role for the oxidative burst in
      abiotic stress-induced cell death.

PMID- 12609038
TI  - Transcriptome analysis of sulfur depletion in Arabidopsis thaliana: interlacing
      of biosynthetic pathways provides response specificity.
AB  - Higher plants assimilate inorganic sulfate into cysteine, which is subsequently
      converted to methionine, and into a variety of other sulfur-containing organic
      compounds. To resist sulfur deficiency, plants must demonstrate physiological
      flexibility: the expression of an extensive set of genes and gene regulators that
      act in the affected pathways or signalling cascades must be delicately tuned in
      response to environmental challenges. To elucidate this network of interactions,
      we have applied an array hybridisation/transcript profiling method to Arabidopsis
      plants subjected to 6, 10 and 13 days of constitutive and induced sulfur
      starvation. The temporal expression behaviour of approximately 7200 non-redundant
      genes was analysed simultaneously. The experiment was designed in a way to
      identify statistically significant changes of gene expression based on sufficient
      numbers of repeated hybridisations performed with five uniform pools of plant
      material. The expression profiles were processed to select differentially
      expressed genes. Among the 1507 sulfur-responsive clones implicated in this way,
      632 genes responded specifically to sulfur deficiency by significant over
      expression. The sulfur-responsive genes were grouped according to functional
      categories or biosynthetic pathways. As expected, genes of the sulfur
      assimilation pathway were altered in expression. Furthermore, genes involved in
      flavonoid, auxin, and jasmonate biosynthesis pathways were upregulated in
      conditions of sulfur deficiency. Based on the correlative analysis of gene
      expression patterns, we suggest that a complex co-ordination of systematic
      responses to sulfur depletion is provided via integration of flavonoid, auxin and
      jasmonate pathway elements. Plait concept for transduction of specificity via the
      main non-specific signalling stream is proposed.

PMID- 12609039
TI  - Global expression profiling of sulfur-starved Arabidopsis by DNA macroarray
      reveals the role of O-acetyl-l-serine as a general regulator of gene expression
      in response to sulfur nutrition.
AB  - To investigate the changes in profiles of mRNA accumulation in response to sulfur
      deficiency, approximately 13 000 non-redundant Arabidopsis thaliana ESTs
      corresponding to approximately 9000 genes were analyzed using DNA macroarray.
      Three-week-old Arabidopsis plants grown on an agarose-solidified control medium
      were transferred to a sulfate-free medium and grown for 48 h for the analyses of
      sulfur-related metabolites and global gene expression profiles. Concentrations of
      sulfate, O-acetyl-l-serine (OAS), a positive regulator of sulfur deficiency
      responsive genes, cysteine and glutathione (GSH) were determined. Plants
      transferred to sulfate-free media had reduced concentrations of sulfate and GSH,
      and OAS concentrations increased. Macroarray analysis revealed a number of genes,
      including APR2 and Sultr1;2, whose mRNA accumulation was increased by sulfur
      deficiency. Profiling was also carried out with plants treated with OAS under
      sulfate-sufficient condition. Scatter plot analysis revealed a positive
      correlation between the changes of expression levels by sulfur deficiency and by
      OAS treatment among the clones tested, suggesting that mRNA accumulation of a
      number of genes under sulfur deficiency is mainly controlled by OAS
      concentrations in tissues. It was also revealed that the sets of genes regulated
      under sulfur deficiency in leaves and roots differ considerably.

PMID- 12609040
TI  - Expression profiling of the host response to bacterial infection: the transition
      from basal to induced defence responses in RPM1-mediated resistance.
AB  - Changes in transcription in leaves of Arabidopsis thaliana were characterised
      following challenge with strains of Pseudomonas syringae pv. tomato DC3000
      allowing differentiation of basal resistance (hrpA mutants), gene-specific
      resistance (RPM1-specified interactions) and susceptibility (wild-type pathogen).
      In planta avirulence gene induction, changes in host [Ca2+]cyt and leaf collapse
      were used to delineate the transition from infection to induced resistance. The
      plant responds rapidly, dynamically and discriminately to infection by
      phytopathogenic bacteria. Within the first 2 h host transcriptional changes are
      common to all challenges indicating that Type III effector function does not
      contribute to early events in host transcriptome re-programming. The timing of
      induction for specific transcripts was reproducible, hierarchical and modulated
      at least in part through EDS1 function. R gene-specific transcripts were not
      observed until 3 h after inoculation. Intriguingly, the R gene-specific response
      proteins are expected to localise to diverse cellular addresses indicative of a
      global impact on cellular homeostasis. The altered transcriptional response
      rapidly manifests into initial symptoms of leaf collapse within 2 h, although
      establishment of the full macroscopic HR occurs significantly later.

PMID- 12609041
TI  - AtBXL1, a novel higher plant (Arabidopsis thaliana) putative beta-xylosidase
      gene, is involved in secondary cell wall metabolism and plant development.
AB  - To investigate mechanisms involved in cell wall development, an Arabidopsis T-DNA
      insertion mutant collection was screened to identify mutants with beta
      glucuronidase fusion gene expression in tissues undergoing secondary cell wall
      thickening. This promoter-trapping strategy allowed the isolation of a
      transformant containing the GUS coding sequence inserted 700 bp upstream of the
      ATG of a putative beta-xylosidase gene. The transformant has no phenotype as the
      expression of the gene was not disrupted by the insertion. The analysis of the
      predicted protein, AtBXL1, suggests its targeting to the extracellular matrix and
      its involvement in cell wall metabolism through a putative activity towards
      xylans. The 2-kb promoter sequence of AtBXL1 was fused to the GUS coding sequence
      and introduced into wild-type Arabidopsis thaliana. GUS expression was shown to
      be restricted to tissues undergoing secondary cell wall formation. Beta
      xylosidase activity was associated with the cell wall-enriched fraction of
      different organs of wild-type plants. The level of activity correlates with
      transcript accumulation of AtBXL1 and other AtBXL1-related genes. Transgenic
      plants expressing the AtBXL1 cDNA in antisense orientation were generated. Lines
      exhibiting the highest decrease in AtBXL1 transcript accumulation and beta
      xylosidase activity had phenotypic alterations. This newly identified gene is
      proposed to be involved in secondary cell wall hemicellulose metabolism and plant
      development.

PMID- 12609042
TI  - Control of Ascorbate Peroxidase 2 expression by hydrogen peroxide and leaf water
      status during excess light stress reveals a functional organisation of
      Arabidopsis leaves.
AB  - In Arabidopsis leaves, high light stress induces rapid expression of a gene
      encoding a cytosolic ascorbate peroxidase (APX2), whose expression is restricted
      to bundle sheath cells of the vascular tissue. Imaging of chlorophyll
      fluorescence and the production of reactive oxygen species (ROS) indicated that
      APX2 expression followed a localised increase in hydrogen peroxide (H2O2)
      resulting from photosynthetic electron transport in the bundle sheath cells.
      Furthermore, leaf transpiration rate also increased prior to APX2 expression,
      suggesting that water status may also be involved in the signalling pathway.
      Abscisic acid stimulated APX2 expression. Exposure of ABA-insensitive mutants
      (abi1-1, abi2-1) to excess light resulted in reduced levels of APX2 expression
      and confirmed a role for ABA in the signalling pathway. ABA appears to augment
      the role of H2O2 in initiating APX2 expression. This regulation of APX2 may
      reflect a functional organisation of the leaf to resolve two conflicting
      physiological requirements of protecting the sites of primary photosynthesis from
      ROS and, at the same time, stimulating ROS accumulation to signal responses to
      changes in the light environment.

PMID- 12609043
TI  - A Mak-like kinase is a repressor of GAMYB in barley aleurone.
AB  - GAMYB is a gibberellin (GA)-regulated activator of hydrolase gene expression in
      the aleurone layer of germinating cereal grains. Although it is clear that GAMYB
      expression is regulated by GA, more remains to be understood about how this
      transcription factor operates within the GA-response pathway. In order to isolate
      new components from the GA-response pathway, barley aleurone libraries were
      screened for GAMYB-binding proteins using a recently developed yeast two-hybrid
      system, which is compatible with the use of transcription factors as baits. We
      isolated a new member of the emerging Mak-subgroup of cdc2- and MAP kinase
      related protein kinases. We have termed this GAMYB-binding protein KGM (for
      kinase associated with GAMYB). Transient expression of KGM specifically repressed
      alpha-amylase promoter activity at the level of GAMYB function but a mutation
      designed to de-stabilise the activation loop of KGM alleviated this repression.
      We propose that KGM is a negative regulator of GAMYB function in aleurone that
      may prevent precocious hydrolase gene expression.

PMID- 12609044
TI  - Function of a mitogen-activated protein kinase pathway in N gene-mediated
      resistance in tobacco.
AB  - The active defense of plants against pathogens often includes rapid and localized
      cell death known as hypersensitive response (HR). Protein phosphorylation and
      dephosphorylation are implicated in this event based on studies using protein
      kinase and phosphatase inhibitors. Recent transient gain-of-function studies
      demonstrated that the activation of salicylic acid-induced protein kinase (SIPK)
      and wounding-induced protein kinase (WIPK), two tobacco mitogen-activated protein
      kinases (MAPKs) by their upstream MAPK kinase (MAPKK), NtMEK2 leads to HR-like
      cell death. Here, we report that the conserved kinase interaction motif (KIM) in
      MAPKKs is required for NtMEK2 function. Mutation of the conserved basic amino
      acids in this motif, or the deletion of N-terminal 64 amino acids containing this
      motif significantly compromised or abolished the ability of NtMEK2DD to activate
      SIPK/WIPK in vivo. These mutants were also defective in interacting with SIPK and
      WIPK, suggesting protein-protein interaction is required for the functional
      integrity of this MAPK cascade. To eliminate Agrobacterium that is known to
      activate a number of defense responses in transient transformation experiments,
      we generated permanent transgenic plants. Induction of NtMEK2DD expression by
      dexamethasone induced HR-like cell death in both T1 and T2 plants. In addition,
      by using PVX-induced gene silencing, we demonstrated that the suppression of all
      three known components in the NtMEK2-SIPK/WIPK pathway attenuated N gene-mediated
      TMV resistance. Together with previous report that SIPK and WIPK are activated by
      TMV in a gene-for-gene-dependent manner, we conclude that NtMEK2-SIPK/WIPK
      pathway plays a positive role in N gene-mediated resistance, possibly through
      regulating HR cell death.

PMID- 12609045
TI  - Loss of non-host resistance of Arabidopsis NahG to Pseudomonas syringae pv.
      phaseolicola is due to degradation products of salicylic acid.
AB  - In plants carrying the NahG transgene, salicylate hydroxylase converts salicylic
      acid (SA) to catechol. Arabidopsis NahG plants are defective in non-host
      resistance to Pseudomonas syringae pv. phaseolicola strain 3121 (Psp), suggesting
      that resistance requires SA signaling. However, several mutants with defects in
      SA signaling, including eds1, pad4, eds5, sid2, and npr1, remain resistant to
      Psp, demonstrating that susceptibility of NahG plants is not due to absence of
      SA. SA synthesis is blocked in sid2NahG double mutants, but resistance to Psp is
      retained. Therefore, it must be the degradative action of NAHG on SA that causes
      the loss of resistance of NahG to Psp. Treatment of plants with catechol
      compromised Psp resistance suggesting that the effect of NahG on resistance
      results from catechol production. Application of catalase to NahG or catechol
      treated wild-type plants partially restored resistance to Psp, suggesting that
      the deleterious effect of catechol results from inappropriate production of
      hydrogen peroxide. These results indicate that conclusions about SA requirements
      based solely on phenotypes of NahG plants should be re-evaluated.

PMID- 12609046
TI  - Two means of transcriptional reactivation within heterochromatin.
AB  - DNA methylation levels and specific histone modifications of chromatin in
      interphase nuclei are taken as an indicator of transcriptional activity or
      silencing. Arabidopsis mutants impaired in maintenance of transcriptional gene
      silencing (TGS) alleviate TGS with or without affecting DNA methylation. Mutant
      ddm1, representing the first type, lacks a chromatin remodeling factor that
      regulates histone and DNA methylation. Mutant mom1, representing the second type,
      is affected in a different but still unknown silencing mechanism. Both classes of
      mutation have been studied mainly for their effects on specific loci. Here, we
      describe the cytological analysis of chromatin in ddm1 and mom1 mutants. The ddm1
      mutation causes a striking decondensation of centromeric heterochromatin, a re
      distribution of the remaining methylation of DNA, and a drastic change in the
      pattern of histone modification. A complex transgenic locus, which underwent
      stable inactivation and became heterochromatin-like, follows similar structural
      alterations. In contrast, nuclear organization in mom1 appears unaltered,
      demonstrating an involvement of MOM1 in transcriptional regulation within a
      heterochromatic environment.

PMID- 12609047
TI  - OsDREB genes in rice, Oryza sativa L., encode transcription activators that
      function in drought-, high-salt- and cold-responsive gene expression.
AB  - The transcription factors DREBs/CBFs specifically interact with the dehydration
      responsive element/C-repeat (DRE/CRT) cis-acting element (core motif: G/ACCGAC)
      and control the expression of many stress-inducible genes in Arabidopsis. In
      rice, we isolated five cDNAs for DREB homologs: OsDREB1A, OsDREB1B, OsDREB1C,
      OsDREB1D, and OsDREB2A. Expression of OsDREB1A and OsDREB1B was induced by cold,
      whereas expression of OsDREB2A was induced by dehydration and high-salt stresses.
      The OsDREB1A and OsDREB2A proteins specifically bound to DRE and activated the
      transcription of the GUS reporter gene driven by DRE in rice protoplasts. Over
      expression of OsDREB1A in transgenic Arabidopsis induced over-expression of
      target stress-inducible genes of Arabidopsis DREB1A resulting in plants with
      higher tolerance to drought, high-salt, and freezing stresses. This indicated
      that OsDREB1A has functional similarity to DREB1A. However, in microarray and RNA
      blot analyses, some stress-inducible target genes of the DREB1A proteins that
      have only ACCGAC as DRE were not over-expressed in the OsDREB1A transgenic
      Arabidopsis. The OsDREB1A protein bound to GCCGAC more preferentially than to
      ACCGAC whereas the DREB1A proteins bound to both GCCGAC and ACCGAC efficiently.
      The structures of DREB1-type ERF/AP2 domains in monocots are closely related to
      each other as compared with that in the dicots. OsDREB1A is potentially useful
      for producing transgenic monocots that are tolerant to drought, high-salt, and/or
      cold stresses.

PMID- 12609049
TI  - GFP-tagging of cell components reveals the dynamics of subcellular re
      organization in response to infection of Arabidopsis by oomycete pathogens.
AB  - Cytoplasmic aggregation, the rapid translocation of cytoplasm and subcellular
      components to the site of pathogen penetration, is one of the earliest reactions
      of plant cells against attack by microorganisms. We have investigated cytoplasmic
      aggregation during Arabidopsis-oomycete interactions. Infection by non-pathogenic
      Phytophthora sojae was prevented in the plant epidermal cell layer, whereas
      Peronospora parasitica isolates Cala2 (avirulent) and Noks1 (virulent) could both
      penetrate into the mesophyll cell layer. Epidermal cell responses to penetration
      by these oomycetes were examined cytologically with a range of transgenic
      Arabidopsis plants expressing Green Fluorescent Protein (GFP)-tagged cell
      components. These included plants containing GFP-TUA6 for visualizing
      microtubules, GFP-hTalin for actin microfilaments, GFP-tm-KKXX for endoplasmic
      reticulum (ER), and STtmd-GFP for the Golgi apparatus. In all interactions, actin
      microfilaments were actively re-arranged and formed large bundles in cytoplasmic
      strands focused on the penetration site. Aggregation of ER membrane and
      accumulation of Golgi bodies at the infection site were observed, suggesting that
      production and secretion of plant materials were activated around the penetration
      site. Microtubules did not become focused on the penetration site. No difference
      was evident between the responses of epidermal cells in the non-host,
      incompatible and compatible interactions. This result indicates that the
      induction of cytoplasmic aggregation in Arabidopsis epidermal cells was neither
      suppressed by the virulent strain of Peronospora, nor effective in stopping
      infection.

PMID- 12609048
TI  - Interactions between gene activity and cell layers during floral development.
AB  - The DEFICIENS (DEF) gene is required for establishing petal and stamen identity
      in Antirrhinum and is expressed in all three layers of the floral meristem in
      whorls 2 and 3. Expression of DEF in a subset of meristem layers gives rise to
      organs with characteristic shapes and cell types, reflecting altered patterns and
      levels of DEF gene activity. To determine how the contributions of layers and
      gene activity interact, we exploited a DEF allele which carries a transposon
      insertion in the MADS box region to generate periclinal chimeras expressing
      alleles with different activities. By comparing the phenotype, development and
      expression patterns of these chimeras we show that expression of DEF in L1 makes
      a major contribution to morphology in whorl 2, irrespective of the allele. By
      contrast L1 expression is largely unable to rescue whorl 3, possibly because of a
      non-autonomous inhibitor of DEF activity in this whorl.

PMID- 12609050
TI  - Inverted repeat of a heterologous 3'-untranslated region for high-efficiency,
      high-throughput gene silencing.
AB  - This report describes a method for the easy generation of inverted repeat
      constructs for the silencing of genes of unknown sequence which is applicable to
      high-throughput studies. This improved procedure for high-efficiency gene
      silencing is specific for a target gene, but does not require inverted repeat DNA
      of the target gene in the construct. The method employs an inverted repeat of the
      3'-untranslated region (3'-UTR) of a heterologous gene, and has been demonstrated
      using the 3'-UTR region of the nopaline synthase (nos) gene from Agrobacterium
      tumefaciens, which is often used as the 3'-UTR for transgene constructs. In a
      population of independent tomato primary transformants harboring a stably
      integrated polygalacturonase (PG) transgene driven by a constitutive promoter and
      linked to an inverted repeat of the nos 3'-UTR, 51 of 56 primary transformants
      (91% of the population) showed highly effective post-transcriptional silencing of
      the PG gene, with PG mRNA abundance in ripe fruit reduced by 98% or more. The
      method was also effective in Arabidopsis, where two different, relatively
      uncharacterized plant transcription factors were also targeted effectively. This
      method has the advantage of ease and rapidity in preparation of the constructs,
      since a gene of interest can be inserted into a binary vector already containing
      the promoter and the inverted nos domain in a single-cloning step, and does not
      require any knowledge of the DNA sequence. The approach is suitable for high
      throughput gene silencing studies, where it is necessary to investigate the
      function of hundreds to thousands of uncharacterized genes.

PMID- 12609051
TI  - A genome-wide identification of E2F-regulated genes in Arabidopsis.
AB  - The completion of the Arabidopsis genomic sequence offers the possibility to
      extract global information about regulatory mechanisms. Here, we describe a data
      mining strategy in combination with gene expression analysis to identify bona
      fide genes regulated by the E2F transcription factor. Starting with a genome-wide
      search of chromosomal sites containing E2F-binding sites, we studied in depth two
      of the most abundant E2F-binding sites within the Arabidopsis genome and
      identified over 180 potential E2F target genes. Among them and in addition to
      cell cycle-related genes, we have also identified genes belonging to other
      functional categories, e.g. transcription, stress and defense or signaling. We
      have determined the expression levels of genes selected from different categories
      under two experimental situations. Using cultured cells partially synchronized
      with aphidicolin, we found that most potential E2F targets identified in silico
      show a cell cycle-regulated expression pattern with a peak in early/mid S-phase.
      In addition, we used Arabidopsis transgenic plants expressing a DP gene
      containing a truncated DNA-binding domain, which likely has a dominant-negative
      effect on AtE2Fa, b and c (also named AtE2F3, 1 and 2, respectively), which
      require DP for efficient DNA binding. Contrary to the up-regulation observed in
      early/mid S-phase-cultured cells, the expression of a large number of potential
      E2F targets was decreased in the transgenic plants. Our results strongly support
      that the RBR/E2F pathway plays a crucial role in regulating the expression of the
      genes identified in this study.

PMID- 12609055
TI  - [Stress on research of nonalcoholic fatty liver disease].

PMID- 12609052
TI  - Retrofitting BACs with G418 resistance, luciferase, and oriP and EBNA-1 - new
      vectors for in vitro and in vivo delivery.
AB  - BACKGROUND: Bacterial artificial chromosomes (BACs) have been used extensively
      for sequencing the human and mouse genomes and are thus readily available for
      most genes. The large size of BACs means that they can generally carry intact
      genes with all the long range controlling elements that drive full levels of
      tissue-specific expression. For gene expression studies and gene therapy
      applications it is useful to be able to retrofit the BACs with selectable genes
      such as G418 resistance, reporter genes such as luciferase, and oriP/EBNA-1 from
      Epstein Barr virus which allows long term episomal maintenance in mammalian
      cells. RESULTS: We describe a series of retrofitting plasmids and a protocol for
      in vivo loxP/Cre recombination. The vector pRetroNeo carries a G418 resistance
      cassette, pRetroNeoLuc carries G418 resistance and a luciferase expression
      cassette, pRetroNeoLucOE carries G418 resistance, luciferase and an oriP/EBNA-1
      cassette and pRetroNeoOE carries G418 resistance and oriP/EBNA-1. These vectors
      can be efficiently retrofitted onto BACs without rearrangement of the BAC clone.
      The luciferase cassette is expressed efficiently from the retrofitting plasmids
      and from retrofitted BACs after transient transfection of B16F10 cells in tissue
      culture and after electroporation into muscles of BALB/c mice in vivo. We also
      show that a BAC carrying GFP, oriP and EBNA-1 can be transfected into B16F10
      cells with Lipofectamine 2000 and can be rescued intact after 5 weeks.
      CONCLUSION: The pRetro vectors allow efficient retrofitting of BACs with G418
      resistance, luciferase and/or oriP/EBNA-1 using in vivo expression of Cre. The
      luciferase reporter gene is expressed after transient transfection of retrofitted
      BACs into cells in tissue culture and after electroporation into mouse muscle in
      vivo. OriP/EBNA-1 allows stable maintenance of a 150-kb BAC without rearrangement
      for at least 5 weeks.

PMID- 12609056
TI  - [Selection of surgical procedure of combined kidney-pancreatic transplantation].
AB  - OBJECTIVE: To evaluate simultaneous kidney-pancreatic transplantation (SKPT) with
      bladder drainage and enteric drainage for its efficacy and safety. METHOD: SKPT
      was performed in 10 patients from Jan. 2000 to Feb. 2002. All patients had long
      standing insulin-dependent diabetes mellitus and subsequent renal failure.
      Bladder drainage (BD) of exocrine secretion was used in the first 2 cases and
      enteric drainage (ED) in last 8 patients. In BD, a two-layer hand sewn
      duodenocystostomy was performed. In ED, a two-layered side-to-side anastomosis
      was fashioned between the donor duodenal segment and the recipient jejunum. No
      Roux-en-Y limb was used. Quadruple immunosuppressive therapy with antithymocyte
      globulin, tacrolimus, mycophenolate mofetil and steroids was standard treatment
      in all patients. The patients were treated with quadruple therapy, which included
      antilymphocyte globulin (ALG) or anti-CD25 monoclonal antibody (Zenapax)
      induction therapy, prednisone, Cyclosporine A/tacrolimus, and mycophenolat
      mofetil (MMF). RESULTS: SPK was successfully applied to all cases without
      complication referable to the technique. All patients have achieved excellent
      renal function and euglycemia, and no further insulin treatment was needed
      between 1 and 5 days posttransplant. One patient with ED died due to sepsis and
      upper gastrointestinal hemorrhage 5 weeks after operation. The death occurred
      with functioning grafts. Until now no rejection episode and thrombosis were
      observed and all the grafts from nine patients are functioning well. The first 2
      patients with BD underwent slight metabolic complications and microscopic
      hematuria with entire follow-up time. Two episodes of reflux graft pancreatitis
      followed by macroscopic hematuria occurred in one patient with BD. CONCLUSION:
      Compared with SPK with BD, ED without Roux-en-Y anastomosis might be a more
      physiological and prior procedure for type I diabetes mellitus with uremia.

PMID- 12609057
TI  - [Mutation site of presenilin-1 gene in familial Alzheimer's disease].
AB  - OBJECTIVE: To explore the effect of mutation of presenilin-1 (PS-1) gene on the
      pathogenesis of familial Alzheimer disease (FAD). METHODS: Polymerase chain
      reaction-single strand conformation polymorphism (PCR-SSCP), denaturing high
      performance liquid chromatography (DHPLC), and DNA sequencing were used to detect
      the exons 4 and 5 of PS-1 gene of a 130-member family and a 50-member control
      group. RESULT: PCR-SSCP showed abnormality in PS-1 exon 5 among 5 AD patients and
      4 AD family members without AD symptoms. DHPLC further showed double peaks in the
      electrophoretic curves of the above nine persons, indicating the possibility of
      mutation. DNA sequencing revealed a missense mutation of GCT to GGT in code 136
      of PS-1 exon 5, leading to the substitution of Ala with Gly (Ala136Gly), in these
      9 persons. No mutation in exon 4 was found among these subjects. Mutation in exon
      4 and 5 was not found in other members of both this AD family and the control
      group. CONCLUSION: The mutation in exon 5 of PS-1 gene, found in this AD family,
      may be one of the responsible PS-1 gene mutations for familial Alzheimer disease
      in Chinese.

PMID- 12609059
TI  - [CT-guided percutaneous transthoracic aspiration biopsy of chest lesions: factors
      influencing the diagnostic accuracy].
AB  - OBJECTIVE: To investigate the factors influencing the diagnostic accuracy of CT
      guided percutaneous transthoracic aspiration biopsy of chest lesions. METHODS:
      Data of pathology and clinical follow-up of 224 patients who had undergone CT
      guided percutaneous transthoracic biopsy were collected. Univariate analysis and
      multivariate stepwise Logistic regression analysis were made to study the
      influence of the patient-related factors (sex, age, and presence of emphysema),
      lesion-related factors (histology, size, location, depth, and presence of cavity
      discovered by CT), and procedure factor (posture of patient during operation) on
      the diagnostic accuracy of CT-guided biopsy. RESULTS: (1) One hundred and sixty
      five lesions were diagnosed as malignant and 79 lesions as benign. The accuracy
      rate of CT-guided biopsy was 82.4% (201/244). Univariate analysis showed that the
      diagnostic accuracy rates of CT-guided biopsy for malignant and benign lesions
      were 88.5% and 69.6% respectively (chi(2) = 13.096, P < 0.01). The mean diameters
      of the lesions with correct diagnosis and of those misdiagnosed were 4.0 cm +/-
      1.8 cm and 3.1 cm +/- 1.4 cm respectively (F = 8.805, P < 0.01). (2) Multivariate
      stepwise Logistic regression analysis showed that among the various factors only
      histology (regression coefficient = 0.320, Wald chi(2) = 7.126, P < 0.01) and
      size (regression coefficient = 1.114, Wald chi(2) = 4.951, P < 0.05) were
      significantly associated with diagnostic accuracy. CONCLUSION: Histology and size
      of lesion are the determining factors for diagnostic accuracy of CT-guided
      transcutaneous thoracic needle aspiration biopsy.

PMID- 12609058
TI  - [The relationship between insulin resistance and postprandial abnormal serum
      triglyceride metabolism in essential hypertension].
AB  - OBJECTIVE: To investigate the relationship between insulin resistance (IR) and
      postprandial abnormal metabolism of serum triglyceride-rich lipoprotein in
      essential hypertension (EH). METHODS: In 44 patients with EH and 22 normal
      subjects (NS). Total cholesterol, HDL cholesterol, LDL cholesterol, apoliprotein
      AI and apoliprotein B in fasting serum and serum triglyceride before and 2, 4, 6,
      8 hours after a standardized fat loading were measured. Triglyceride peak
      response (TGPR) and the area under triglyceride curve (TG-AUC) over 8 hours were
      taken as the index of abnormal TG metabolism. Standardized 75 g oral glucose
      tolerance test was carried, the area under insulin curve (IS-AUC) over 3 hours
      and insulin sensitivity index were taken as the index of insulin sensitivity.
      RESULTS: TGPR and TG-AUC were higher in EH than those in NS (TGRP: 4.14 mmol/L +/
      3.0 mmol/L vs 2.06 mmol/L +/- 1.32 mmol/L, P < 0.01; TG-AUC: 20 mmol/L +/- 6
      mmol/L vs 10 mmol/L +/- 4 mmol/L, P < 0.05). 65.9% of EH had postprandial
      abnormal serum triglyceride metabolism. IS-AUC was higher in EH than that in NS,
      and ISI was lower in EH than that in NS. The incidence of IR in EH was 61%. 44 EH
      were categorized into 2 groups according to insulin sensitivity: EH with IR (n =
      27) and EH with normal insulin sensitivity (NIS, n = 17). TGPR and TG-AUC in EH
      with IR were significantly higher than those in EH with NIS (TGPR: 5.25 mmol/L +/
      3.03 mmol/L vs 3.16 mmol/L +/- 1.46 mmol/L, P < 0.05; TG-AUC: 25 +/- 13 mmol/L
      vs 13 +/- 7 mmol/L, P < 0.01). No significant difference was found between EH
      with NIS and NS (P > 0.05). TG-AUC and TRPG was positively related to IS-AUC and
      negatively related to ISI. CONCLUSION: Patients with EH had postprandial abnormal
      serum triglyceride metabolism, insulin resistance may aggravate postprandial
      triglyceride metabolism in EH.

PMID- 12609060
TI  - [Significance of tumor necrosis factor-alpha gene polymorphism in patients with
      acute severe pancreatitis].
AB  - OBJECTIVE: To investigate the relation of the frequency of TNF2 allele, a TNF
      alpha promoter polymorphism, and plasma concentrations of TNF-alpha and soluble
      tumor necrosis receptor (sTNF-R) to acute severe pancreatitis (ASP) and its
      severe complication--sepsis. METHODS: The DNA samples of peripheral white blood
      cells of 72 ASP patients, 16 of them being complicated by severe sepsis and the
      other 46 cases being without sepsis, and 89 healthy volunteers were extracted.
      PCR, NcoI digestion, and electrophoresis were used to examine the polymorphism of
      the TNF-alpha gene promoter region -308. Plasma concentrations of TNF-alpha, sTNF
      R I and sTNF-R II were measured by EASIA. RESULTS: The TNF2 allele frequency of
      ASP patients was 29.2% (21/72), not significantly different from that of healthy
      volunteers (25.7%, 25/89) (P > 0.05). The prevalence rate of TNF2 was 46.2% in
      patients with severe sepsis, significantly higher than that of the patients
      without asepsis (19.6%, P < 0.05). The plasma levels of TNF-alpha, sTNF-R I, and
      sTNF-R II were 36 +/- 30 ng/L, 5.4 +/- 3.5 micro g/L, and 11.2 +/- 7.9 micro g/L
      respectively in patients with ASP, not significantly different from those in the
      healthy controls (30 +/- 25 ng/L, 4.6 +/- 3.8 micro g/L, and 8.8 +/- 6.6 micro
      g/L respectively, P > 0.05). There was no significant difference in baseline TNF
      alpha levels between the TNF2 group and TNF1 group (37 +/- 31 ng/L vs. 31 +/- 25
      ng/L, P > 0.05). CONCLUSION: TNF-2 is not related to the pathogenesis of ASP, and
      is associated with the susceptibility to severe sepsis complicating ASP. The
      baseline TNF-alpha and sTNF-R levels have little value in predicting the
      development of severe sepsis.

PMID- 12609061
TI  - [Expression and significance of B-cell-specific activator protein of H/RS cell in
      classical Hodgkin's Lymphoma].
AB  - OBJECTIVE: To explore the expression of B-cell-specific activator protein (BSAP)
      of H/RS cell in classical Hodgkin's lymphoma (cHL). METHODS: Immunohistochemical
      method was used to detect the expression of BSAP in 33 samples of formalin-fixed,
      paraffin-embedded tissues of cHL. Nine samples of lymph node of reactive
      hyperplasia, 10 samples of B-cell lymphoma, and 10 samples of T-cell lymphoma
      were also detected as BSAP controls. Mouse-anti-human monoclonal antibodies CD20,
      CD30 and CD15 were detected among the cHL cases as routine comparison. RESULTS:
      30 of 33 (90.91%) cases of cHL were BSAP expression positive in H/RS cells, while
      all of the 33 (100%) cases of background B-lymphocytes were BSAP positive. Almost
      all B cells of lymph node reactive hyperplasia were BSAP positive. All malignant
      cells in B-cell lymphoma were BSAP positive, while all malignant cells in T-cell
      lymphoma were BSAP negative. Among the 33 cases of cHL there was a significant
      difference between the expression of BSAP and the expression of CD20 (30.30%) in
      H/RS cells (P = 0.000), and no significant difference between the expression of
      CD30 (93.94%) and CD15 (75.75%, P = 0.082). CONCLUSION: The frequent expression
      of BSAP in H/RS cells of classical Hodgkin's disease provides further evidence
      for its B-cell origin and helps to identify H/RS cells. The expression of BSAP in
      H/RS cells can be used to distinguish HL from anaplastic large cell lymphoma
      (ALCL).

PMID- 12609062
TI  - [Effects of antisense bcl-2 or survivin on the growth of human neuroblastoma cell
      line SK-N-MC].
AB  - OBJECTIVE: To study the effects of antisense bcl-2 and survivin (svv) mRNA on the
      growth of human neuroblastoma (NB) cell line SK-N-MC cells. METHODS: The
      recombinant vectors PBabe puro-Asbcl-2 and PBabe puro-Assvv. were constructed by
      directed cloning of the EcoRI-BamHI fragments of bcl-2 cDNA or svv cDNA into the
      retroviral vector PBabe puro Human NB cell line SK-N-MC cells were transfected
      with PBabe puro-Asbcl-2, PBabe puro-Assvv, or blank vector PBabe puro as control
      by lipofectamine trade mark. The transfected cells were selected in the medium
      containing puromycine. The stably transfected cells were further studied for
      inhibition of protein expression of endogenous bcl-2 and SVV by
      immunohistochemical staining and Western blotting. The effect of antisense bcl-2
      (Asbcl-2) and antisense svv (Assvv) mRNA on cell growth was determined by MTT
      method. The SK-N-MC cells transfected with the recombinant vectors were
      inoculated in nude mice to observe their carcinogenicity. RESULTS: Both the
      expression of bcl-2 and the expression of SVV significantly decreased in the
      antisense gene transfected cells in comparison to that in the original cells and
      cells transfected with blank vector. Seven days after the transfection, the MTT
      absorption (A(550)) was 0.374 +/- 0.001 5 in the cells transfected with Assvv,
      0.289 +/- 0.000 8 in the cells transfected with Asbcl-2, both significantly lower
      than those in the original cells and cells transfected with blank vector (1.102
      +/- 0.002 1 and 1.175 +/- 0.000 9 respectively). The induced tumors in the nude
      mice were smaller in the PBabe puro-Asbcl-2 transfected group and PBabe puro
      Assvv transfected group than in the original and control groups. CONCLUSION:
      Stably expression of antisense bcl-2 and of antisense svv mRNA can effectively
      inhibit the expression of endogenous bcl-2 and SVV proteins. Both of them may
      play a role in the neoplastic formation of NB cells.

PMID- 12609063
TI  - [Construction, bioactivity identification and structural characteristics analysis
      of a novel recombinant immunosuppression protein B7-2-L-PE40KDEL].
AB  - OBJECTIVE: To construct a novel recombinant B7-2-L- PE40KDEL fusion protein used
      to selectively kill T cells expressing high levels of CD28 so as to induce immune
      tolerance and prevent graft versus host disease (GVHD) and host versus graft
      disease (HVGD). METHODS: The cDNA encoding human B7-2 was ligated with cDNA
      encoding PE40KDEL by using sequence overlapping extension (SOE) techniques. The
      gene of interest was subcloned into a high output expression vector pRSETA and
      transformed into E. coli cells. Its molecular structural characteristics, such as
      flexibility, antigenicity, hydrophilicity, and epitope were analyzed. The
      purification protocol of expressed protein was established and its cytotoxicity
      to selectively kill T cells expressing high levels of CD28 was measured by MTT
      method. RESULTS: B7-2-L-PE40KDEL fusion protein was expressed at high levels in
      E. coli cells and the purified product attained over 95% of purity. The
      structural characteristics of B7-2-L-PE40KDEL were not significantly changed in
      comparison with B7-2 and PE40KDEL. In cytotoxicity assay, B7-2-L-PE40KDEL fusion
      protein specifically killed Jurkat cells which express high level CD28 receptor
      and was non-cytotoxic to CD28 receptor-negative cell line Raji. CONCLUSION: B7-2
      L-PE40KDEL novel fusion protein can selectively kill the T cells which express
      CD28 receptor and may become a kind of new effective drug for inducing T cell
      immune tolerance and preventing GVHD and HVGD.

PMID- 12609064
TI  - [The gene expression of nuclear transcriptional factor-kappa B and I kappa B in
      autogenous vein graft in rats].
AB  - OBJECTIVE: To investigate the gene expression of nuclear transcriptional factor
      kappa B (NF-kappa B) p65 and its inhibiting factor I kappa B in autogenous vein
      graft. METHODS: The right common jugular vein was transplanted to infrarenal
      abdominal aorta by microsurgical technique among 80 Wistar rats so as to
      establish an autogenous vein graft model. Ten vein graft samples were harvested 6
      hours, 24 hours, 3 days, 7 days, 2 weeks, 4 weeks, 6 weeks, and 8 weeks after
      surgery. NF kappa B p65 mRNA and I kappa B beta mRNA were measured by reverse
      transcription-PCR and in situ hybridization. Western blotting and
      immunohistochemistry were used to detect the protein expression of NF kappa B p65
      and I kappa B. RESULTS: The expressions of NF kappa B p65 mRNA and I kappa B beta
      mRNA 6 hours after the surgery were 16% +/- 4% and 31% +/- 9% respectively (P <
      0.01 vs. control vein). The expression of NF kappa B p65 mRNA reached in peak
      during the period 3 days to 7 days after the surgery (37% +/- 12% and 34% +/- 10%
      respectively, P< 0.01 vs. other teams), however, the I kappa B beta mRNA
      expression reached its peak during 1 to 2 weeks after the surgery (53% +/- 17%
      and 49% +/- 10% respectively, P < 0.01 vs. other teams). The expressions of NF
      kappa B p65 mRNA and I kappa B beta mRNA recovered to their baseline values 6
      weeks after surgery. The expression of p65 protein reached its peak 1 week after
      the surgery (32% +/- 13%) and then decreased gradually. The expressions of I
      kappa B alpha and I kappa B beta decreased to 1/3 to 1/2 of the normal vein 6
      hours to 24 hours after the surgery and then increased to 5 times that of the
      control vein 2 weeks after surgery (35% +/- 11% and 44% +/- 13% respectively).
      CONCLUSION: The NF-kappa B/I kappa B system is activated in autogenous vein
      graft. The NF kappa B may become a new target for the prevention and therapy of
      intimal hyperplasia and stenosis after vein graft.

PMID- 12609065
TI  - [Mechanism of intimal hyperplasia of venous grafts after coronary artery bypass
      grafting, an experimental study].
AB  - OBJECTIVE: To study the mechanism of intimal hyperplasia after coronary artery
      bypass grafting (CABG) and to find an effective way for preventing intimal
      hyperplasia. METHODS: Twenty-four male New Zealand rabbits were randomly divided
      into two groups of 12 rabbits: operation group and sham-operation (control)
      group. The external jugular vein was harvested and anastomosed end-to-side to the
      ipsilateral carotid artery in operation group or grafted in situ in the control
      group. Six rabbits in each group were killed and their grafted veins were taken 2
      weeks and 4 weeks after operation respectively. The mRNA expressions of
      transforming growth factor beta (TGF-beta), collagen I, collagen III, and
      angiotension 1 receptor (AT1R) were measured by RT-PCR and electrophoresis.
      RESULTS: The intimal hyperplasia was much more remarkable in the operation group
      than in the control group either 2 weeks or 4 weeks after operation. The mRNA
      expressions of TGF-beta, AT1R, collagen I, and collagen III were significantly
      higher in the operation group than in the control group, especially 2 weeks after
      (P < 0.01). Four weeks after the operation, the expressions of TGF-beta, AT1R,
      collagen I and collagen III were 4.05 +/- 0.49 vs 2.05 +/- 0.26, 18.23 +/- 1.32
      vs 4.61 +/- 0.53, 80 +/- 0.17 vs 0.90 +/- 0.18, and 7.05 +/- 0.68 vs 2.80 +/-
      0.17 respectively (all P < 0.05). CONCLUSION: TGF-beta and AT1R may have an
      important role in the intimal hyperplasia of venous graft in CABG. Continuous
      arterial pressure may be the main factor of increased expression of TGF-beta and
      AT1R that cause the enormous synthesis and deposit of collagen.

PMID- 12609066
TI  - [The expression and significance of heparanase and nm23-H1 in hepatocellular
      carcinoma].
AB  - OBJECTIVE: To explore the relation between heparanase (HPA) and nm23-H1 in
      hepatocellular carcinoma (HCC), and judge whether they may be used as valuable
      markers in predicting postoperative metastasis and recurrence of HCC. METHODS:
      Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry
      (S-P method) were used to measure the expressions of the HPA mRNA and nm23-H1
      protein in the primary tumor tissue and paracancer tissue of 33 cases of HCC. The
      paracancer tissues of 9 cases of benign liver tumor were used as normal controls.
      The results were analyzed in combination with the results of clinicopathological
      examination and follow-up. RESULTS: The expression of HPA gene was positive in 16
      cases of primary tumor tissues of HCC with a positive rate of 48.5%,
      significantly higher than those in paracancer tissues of HCC cases and in normal
      controls (P < 0.01). The HPA expression was not related with the size of tumor,
      envelope formation, AFP level, HBsAg state and cirrhosis of liver. The positive
      rates of HPA mRNA in the group with high tendency to metastasis or recurrence and
      the group with metastasis or recurrence during follow-up were significantly
      higher than that in the group with low tendency to metastasis or recurrence group
      (P < 0.05) and that in the group without metastasis or recurrence (P < 0.01). The
      poorly differentiated tumor and tumor of TNM stage III-IV had higher positive
      rates of HPA gene expression than the well-mediate differentiated tumor and tumor
      of TNM stage I-II (P < 0.05). The positive expression rates of nm23-Hl protein in
      HCC tissue was significantly lower than that in corresponding non-cancerous or
      normal liver tissue (P < 0.05). nm23-Hl expression was not related with the size
      of tumor, envelope formation, AFP level, HBsAg state, cirrhosis of liver,
      Edmondson grade, and TNM stage (P > 0.05). The positive rate of nm23-Hl in the
      group with high tendency to metastasis and recurrence and in patients with
      metastasis or recurrence during follow-up was obviously higher than that in the
      group with low tendency to metastasis and recurrence (P = 0.018) and that in the
      patients without metastasis and recurrence (P = 0.024), but no significant
      difference was found between HPA positive and negative groups (P = 0.082).
      According to the results of follow-up, the rates of accuracy in predicting
      metastasis of positive HPA, negative nm23-H1 and combination of positive HPA with
      negative nm23-H1 were 78.6% (11/14), 68.8% (11/16) and 88.9% (8/9) respectively.
      CONCLUSION: Expression of HPA and/or nm23-Hl are related with metastasis and
      recurrence of HCC. Combining the expression rate of HPA with the expression rate
      of nm23-H1 may increase the accuracy in predicting HCC postoperative metastasis
      and recurrence.

PMID- 12609067
TI  - [Culture and identification of nanobacteria in bile].
AB  - OBJECTIVE: To study the distribution and identification of nanobacteria in bile
      and to evaluate the identifying methods of nanobacteria. METHODS: RPMI1640
      culture or RPMI1640 culture with 10% heat-inactivated gamma-FBS was added into 75
      samples of cystic bile from gallbladders resected in operation. Nanobacteria were
      identified by immunohistochemical staining, transmission electron microscopy
      (TEM), and calcific staining. RESULTS: Nanobacteria were found in 45 bile samples
      with a positive rate of 61.3%. The positive rate of nanobacteria was 75.7% among
      37 bile samples with white precipitate adhering to the tube, and was 47.4% among
      the samples with flocculent precipitate or without precipitate (P < 0.05). The
      immunohistochemically confirmed presence of nanobacteria was re-confirmed by TEM
      in all the positive samples. The positive rate, sensitivity, specificity, false
      positive rate and false negative rate of calcific staining were 38.7%, 58.7%,
      93.1%, 6.9% and 41.3% respectively. CONCLUSION: Immunohistochemistry with
      monoclonal antibody of nanobacteria associated with TEM is useful in identifying
      nanobacteria. Calcific staining is of great value to identification of
      nanobacteria. Precipitation of white floccules adhering to the tube is an
      important microbiological characteristic of nanobacteria.

PMID- 12609068
TI  - [Effect of lipid protein complex on pulmonary vascular permeability in rats with
      severe burn].
AB  - OBJECTIVE: To investigate the effect of lipid protein complex (LPC) from burn
      wound on the pulmonary vascular permeability. METHODS: Fifty-two SD rats were
      made into 30%III degrees TBSA burn models. Six milliliters of peripheral blood
      were extracted from each rat 3 days after and LPC was isolated. Then 32 rats were
      killed. Their lungs and hearts were isolated to be made into experimental model
      of isolated perfused heart and lung and divided into 4 experimental groups
      perfused with different kinds of perfusion fluid containing LPC, serum from rats
      with burn, serum from normal rats, or perfusion fluid without above mentioned
      components (control group). Five minutes and 35 minutes after the perfusion, the
      lung weigh gain (LWG), fluid filtration coefficient (Kf) and pulmonary albumin
      permeability-surface area product (PS) were detected. RESULTS: Five minutes after
      perfusion the LWG was 0.08 +/- 0.04 g in the burn serum group, and 0.07 +/- 0.04
      g in the LPS group, both significantly higher than that in the control group
      (0.03 +/- 0.03, both P < 0.01). Thirty-five minutes after, the LWG was 0.56 +/-
      0.12 g in the burn serum group, and 0.40 +/- 0.10 g in the LPS group, both
      significantly higher than that in the control group (0.26 +/- 0.08 g, P < 0.01)
      and with a significant difference between the burn serum group and LPC group (P <
      0.05). PS was 7.6 +/- 1.3 x 10(-2) cm(3)/min x g DLW in the burn serum group,
      significantly higher than that in the control group (4.2 +/- 1.1 x 10(-2)
      cm(3)/min x g DLW, P < 0.01), and LPC group (4.6 +/- 1.2 2 x 10(-2) cm(3)/min x g
      DLW, P - 0.01), without a significant difference between the LPC and control
      group. Kf was 1.05 +/- 0.20 ml/min x kPa x g DLW in the burn serum group, and
      0.89 +/- 0.13 ml/min x kPa x g DLW in the LPC group, both significantly higher
      than that in control group (0.32 +/- 0.09 ml/min x kPa x g DLW, P < 0.01) and
      with a significant difference between the burn serum group and LPC group (P <
      0.05). No difference in LWG, PS, and Kf was found between normal serum group and
      control group. CONCLUSION: LPC from burn serum induces pneumonedema in severe
      burn animal and may play a role in increasing vascular permeability to small
      molecules.

PMID- 12609069
TI  - [Effects of ET-1 on isolated perfused rat liver and vascular rings at two stages
      of cirrhosis].
AB  - OBJECTIVE: To investigate the effects of ET-1 on isolated perfused rat liver and
      vascular rings at early and late stages of cirrhosis. METHODS: Liver cirrhosis
      was induced by an intraperitoneal injection of 50% CCl(4) (0.3 ml/100 g, twice a
      week). In the 9th and 14th weekend after injecting CCl(4), the isolated perfused
      liver and vascular rings were performed to evaluate effects of four
      concentrations of ET-1 on early and late stages of cirrhosis. RESULTS: The Ppv of
      L-HC group at baseline was higher than that of E-HC group, both were higher than
      that of the controls. However, there showed no differences on Phv in these
      groups. With the concentration of ET-1 increasing, PVP was elevated accordingly
      in E-HC and L-HC group. L-HC group showed higher PVP compared with E-HC group,
      both were higher than the controls. While in isolated vascular rings, with the
      deteriorating of cirrhosis, the cumulative response curves showed right-shift.
      0.1 nmol/L ET-1 showed mild relaxation on vascular rings in L-HC group.
      CONCLUSION: ET-1 can increase the PVP, especially with the deterioration of
      cirrhosis, there showed higher reaction compared with normal controls. The
      vascular rings showed low response on the contrary. So ET-1 plays an important
      role in the pathogenesis of portal hypertension. In view of its different roles
      on liver and vascular rings at early and late stages, administration of different
      selective antagonist of ET receptor at different stages of cirrhosis should be
      well considered.

PMID- 12609070
TI  - Evaluation of (99m)Tc-MIBI myocardial perfusion imaging with intravenous infusion
      of adenosine triphosphate in diagnosis of coronary artery disease.
AB  - OBJECTIVE: To evaluate the feasibility, safety and diagnostic accuracy of
      pharmacologic stress of (99m)Technetium-MIBI single-photon emission computed
      tomography (SPECT) with intravenous adenosine triphosphate (ATP) in patients with
      suspected coronary artery disease. METHODS: The study group included 263 patients
      who were suspected of having coronary artery disease. All patients underwent
      (99m)Tc-MIBI myocardial perfusion imaging with ATP infusion (0.16 mg/kg body
      weight per min for 5 min). 20 mCi of (99m)Tc-MIBI were injected 3 minutes after
      the start of ATP infusion. Myocardial SPECT images were obtained 60 minutes
      later. Then, two days later, 20 mCi of (99m)Tc-MIBI were administered at rest and
      myocardial SPECT was repeated. 51 patients also underwent coronary angiography
      within two weeks for evaluation of sensitivity and specificity of ATP-myocardial
      perfusion imaging in detection of coronary artery disease. The occurrence of
      cardiac and non-cardiac adverse effects was carefully monitored during and after
      intravenous ATP infusion. RESULTS: The ATP infusion protocol was completed in all
      patients. Although 59% of the patients had various kinds of adverse effects, most
      of them were mild. No patient required aminophyline. The most severe adverse
      effect was second degree type II atria-ventricular block (4/263), but all events
      were transient. The sensitivity and specificity of ATP-myocardial perfusion
      imaging were 97% and 82%, respectively. CONCLUSIONS: It is shown that
      (99m)Technetium-MIBI SPECT with intravenous ATP is a safe and feasible technique
      for detecting coronary artery disease in patients unable to perform the exercise
      test.

PMID- 12609071
TI  - Effect of arsenic trioxide on inhibition of restenosis after rabbit vascular
      injury and its mechanism.
AB  - OBJECTIVE: To investigate the effect and mechanism of arsenic trioxide
      (As(2)O(3)) on the prevention of restenosis after vascular injury. METHODS:
      Apoptosis induction of As(2)O(3) on cultured rabbit vascular smooth muscle cells
      (VSMCs) in vitro was observed. Thirty-two New Zealand white rabbits were randomly
      divided into 2- and 4-wk study groups, and their controls. 10% As(2)O(3) at 2.5
      mg x Kg(-1) x d(-1) or 0.9% sodium chloride was intraperitoneally infused for 3
      days before left common carotid arteries were denudated with a balloon. After
      denudation 2- and 4-wk animals were sacrificed for morphometry and
      immunohistochemical studies on carotid arteries, and for histopathology on liver
      and kidney. RESULTS: It was shown via cellular morphology and DNA fragments in
      electrophoresis that promotion of As(2)O(3) on cultured vascular smooth muscle
      cell apoptosis was dependent upon its concentration and duration. Compared with
      the control animals, the mean vascular intimal proliferation areas were reduced
      in 2-wk study animals (P < 0.05) and no difference was shown in 4-wk (P > 0.05),
      while the mean vascular luminal areas were all enlarged in both study groups (all
      P < 0.05). The downregulated bcl-2 expression (all P < 0.05 in 2- and 4-wk) and
      the upregulated bax expression (P < 0.01 in 2-wk; P < 0.05 in 4-wk) were detected
      by immunohistochemistry, in comparison with control groups. Gene bcl-2 and bax
      protein expression were consistent with the suppression of intimal proliferation
      and the enlargement of luminal areas in corresponding sections. CONCLUSION:
      As(2)O(3) induces apoptosis of VSMCs and inhibits experimental restenosis
      effectively after artery injury, via downregulation of bcl-2 and upregulation of
      bax expression.

PMID- 12609072
TI  - Expression of endoplasmic reticulum molecular chaperon GRP94 in human lung cancer
      tissues and its clinical significance.
AB  - OBJECTIVE: To investigate the relationship between the expression of glucose
      regulated protein 94 (GRP94) at the level of mRNA and protein in vivo and in
      human lung cancer. METHODS: RT-PCR, immunohistochemistry and/or Western blot were
      used in 54 cases of lung cancer tissues and corresponding normal lung tissues.
      RESULTS: There was a significant overexpression of GRP94 mRNA and protein in lung
      cancer tissues as compared with lung normal tissues. In lung cancer tissue, the
      relative level of GRP94 mRNA as evaluated by RT-PCR was 3.48 +/- 2.06, the level
      of GRP94 protein as evaluated by immunohistochemistry was + + to + + +, and by
      Western blot was 256.7 +/- 80.6. In lung normal tissue, the relative level of
      GRP94 mRNA was 2.01 +/- 1.83, the level of GRP94 protein was + to + + and 108.1
      +/- 42.3. The differences in expression of GRP94 between the two tissues were
      significant (P < 0.05). Furthermore, the over-expression of GRP94 in the lung
      cancer tissues was correlated to grade of differentiation and stage of tumors.
      There was stronger expression in poor-differentiated tumors than in mild-to-high
      differentiated tumors (P < 0.05). There was also a stronger expression in stage
      III than in stage I and II tumors (P < 0.05). No statistically significant
      difference was found among various pathological types of tumors. CONCLUSION:
      GRP94 was related with the occurrence, differentiation and progress of human lung
      cancer. Ascertaining the levels of GRP94 mRNA and protein may be valuable in
      evaluating the grade of differentiation and clinical stage of human lung cancer.

PMID- 12609073
TI  - Inhibiting effects of low-molecular weight heparin and adrenocortical hormone on
      hemolysis of red cells in patients with paroxysmal nocturnal hemoglobinuria in
      vitro.
AB  - OBJECTIVE: To study the effects of low-molecular weight heparin (LMWH) and
      adrenocortical hormone (dexamethasone) on the hemolysis of red cells of patients
      with paroxysmal nocturnal hemoglobinuria (PNH) in vitro. METHODS: Using Ham's
      test and micro-complement lysis sensitive test (mCLST), the changes in hemolysis
      of red cells from 6 typical PNH cases were examined after adding LMWH and
      dexamethasone in different concentrations into the test solution in vitro. The
      effects of LMWH and dexamethasone on the coagulation of the tested blood samples
      were also studied using the activated partial thromboplastin time (APTT) test.
      RESULTS: Both LMWH and dexamethasone inhibited the hemolysis of PNH red cells,
      and they also showed a synergistic effect. The inhibiting effects were dose
      dependent. Moreover, a tolerable dose of LMWH induced a limited prolongation of
      APTT. Dexamethasone showed two possible mechanisms in the inhibition of PNH red
      cells hemolysis through Ham's test and mCLST, respectively: (1) inhibiting both
      antibodies binding to red cells and (2) the initiation of the activation of
      complement 3 (C3). LMWH could inhibit hemolysis as determined by both Ham's test
      and mCLST, which indicated that LMWH could block the activation of complement
      cascade. CONCLUSIONS: Both LMWH and dexamethasone could inhibit hemolysis in PNH,
      and they showed a synergistic effect. Their mechanisms of inhibiting hemolysis
      differed from each other. Furthermore, a tolerable dose of LMWH induced a limited
      prolongation of APTT. LMWH might be useful for controlling acute hemolysis in
      patients with PNH and reducing the dose of adrenocortical hormone.

PMID- 12609074
TI  - Cloning and polymorphism analysis of IL-4 proximal promoter in asthmatic
      children.
AB  - OBJECTIVE: To clone and study the polymorphism within interleukin-4 (IL-4)
      proximal promoter of asthmatic children. METHODS: The IL-4 proximal promoter
      segments were amplified and selected by polymerase chain reaction (PCR) and
      single strand conformation polymorphism (SSCP) with genomic DNA from ten healthy
      children and forty patients with dominantly allergic familial histories as
      templates. The selected PCR segments were cloned into recombinant plasmids pIL-4
      Jx2. The PCR inserts were sequenced by dideoxy chain termination method. RESULTS:
      Seven aberrant bands were found in SSCP analysis from forty asthmatic patients.
      The sequencing results showed that four variant sites were found within or
      adjacent to the known IL-4 regulatory element. A C to A transversion located at 
      229 position was just within the positive regulatory element-I (PRE-I) in one
      patient. A C to T transition adjacent to the negative regulatory element-II (NRE
      II) and an extra G adjacent to TATA box were found in two patients. A five base
      nucleotide deletion was found near signal transducers and activators of
      transcription-6 responsive element (STAT-6 RE) in one patient. CONCLUSION: There
      were polymorphisms within the IL-4 proximal promoter of allergic asthmatic
      patients and these polymorphisms might result in aberrant expression of IL-4 gene
      and asthma.

PMID- 12609075
TI  - DNA analysis in a suspected individual with myotonic dystrophy family history and
      her abortus.
AB  - OBJECTIVE: To observe trinucleotide repeat number, (CTG)n in the 3'-untranslated
      region of the myotonic protein kinase (MTPK) gene in a clinically suspected woman
      with myotonic dystrophy (DM) family history and her abortus, in order to confirm
      the necessity of exerting antenatal examination in patients or suspected
      individuals with DM family history. METHODS: Long Expand Template polymerase
      chain reaction (PCR) system was used to analyze CTG trinucleotide repeat numbers
      located in the 3' untranslated region of MTPK on chromosome 19q13.2-3 in both
      peripheral white cells and muscles of the suspected mother and the other two DM
      patients in the family. The tissues of her abortus and blood of a health woman
      were detected, too. RESULTS: CTG repeats in both peripheral white cells and
      muscles of the suspected mother and the tissue of abortus were higher than normal
      range of CTG repeat number. There is no significant difference between blood and
      muscle samples. High CTG repeats were detected in blood and muscles of the
      typical DM members in the family, but in the blood sample of control, CTG repeats
      is normal. CONCLUSION: CTG trinucleotide analyses and antenatal examination
      should be done in pregnant with a DM family history, in order to reduce the birth
      rate of DM offspring.

PMID- 12609076
TI  - Detecting K-ras and p53 gene mutation from stool and pancreatic juice for
      diagnosis of early pancreatic cancer.
AB  - OBJECTIVE: To explore new methods for the early diagnosis of pancreatic cancer
      through detection of K-ras and p53 mutations in pancreatic juice and stool.
      METHODS: 201 patients in PUMC Hospital from 1994 - 2000 and 60 control
      individuals were enrolled in this study. K-ras point mutation was detected by PCR
      RFLP while p53 mutation was detected by PCR-SSCP. RESULTS: K-ras mutation was
      found in pancreatic juice in 87.8% (36/41) of pancreatic cancer patients and
      23.5% (4/17) of benign pancreatic disease patients. In 261 stool specimens,
      amplification found mutations successfully in 235 patients (90%). K-ras mutation
      was found in stool in 88% (66/75) of pancreatic cancer patients, 51.1% (24/47) of
      benign pancreatic disease patients and 19.6% (9/46) of normal individuals. p53
      mutation was found in pancreatic juice in 47.4% (18/38) of pancreatic cancer
      patients and 12.5% (2/16) of benign pancreatic disease patients. p53 mutation was
      found in stool in 37.1% (23/62) and 19.1% (4/21) of chronic pancreatitis
      patients. CONCLUSION: K-ras mutation in pancreatic juice has higher diagnosis
      sensitivity and specificity, and therefore may be used as a supplement in the
      diagnosis of pancreatic cancer. Detection of K-ras mutation combined with p53
      mutation in stool can aid in the screening of pancreatic cancer.

PMID- 12609077
TI  - Dynamic changes in the collagen metabolism of liver fibrosis at the transcription
      level in rabbits with Schistosomiasis japonica.
AB  - OBJECTIVE: To study the role of the synthesis and degradation of collagen at the
      transcription level during liver fibrogenesis due to schistosomiasis japonica in
      rabbits. METHODS: New Zealand rabbits challenged by cercariae of Schistosoma
      japonicum (S. japonicum) were served as animal models for liver fibrosis. Liver
      specimens were collected through operations at 4, 6, 8, 10, 12, 16, 20, 24 and 28
      wks after challenge. Type I collagen, type III collagen, type IV collagen, MMP-1
      and MMP-9 mRNA levels of liver tissue were detected by RT-PCR + Dot blot. The
      size of egg granulomas and the degree of liver fibrosis were measured by
      histopathological examinations. RESULTS: Type I collagen, type III collagen, type
      IV collagen, MMP-1 and MMP-9 mRNA levels increased simultaneously in the early
      stage after challenge. Most of them reached their peak at 10 weeks, and compared
      with normal controls, type I collagen, type III collagen, type IV collagen, MMP-1
      and MMP-9 mRNA levels increased by 12.0-, 11.0-, 6.6-, 10.0- and 11.0-fold,
      respectively, coinciding with the change of egg granulomas, i.e., the change in
      the inflammatory process. Then both collagen and collagenase mRNA levels
      decreased. Type I, III and IV collagen mRNA levels declined to 2-fold to 3-fold
      as compared with normal controls (P < 0.05), while MMP-1 and MMP-9 mRNA levels
      declined close to normal levels (P > 0.05) at 28 wks. This study shows that the
      synthesis and degradation of collagen keep a dynamic balance at the early stage
      of schistosomiasis japonica challenge, while at the later stages the quantity of
      collagen synthesis was higher than that of collagen degradation. CONCLUSIONS: It
      was confirmed at transcription level that when the quantity of collagen synthesis
      was higher than that of collagen degradation liver fibrogenesis may be resulted
      in.

PMID- 12609078
TI  - Expression of carbonic anhydrase IV in rabbit corneal endothelial cells.
AB  - OBJECTIVE: To demonstrate the molecular expression of carbonic anhydrase IV (CA
      IV) in rabbit corneal endothelium. METHODS: Reverse transcriptase polymerase
      chain reaction (RT-PCR) was performed using cultured and fresh rabbit corneal
      endothelial total RNA and specific primers for CA IV. The RT-PCR product was
      subcloned and sequenced. Immunoblotting and indirect immunofluorescence staining
      were performed to detect protein expression and distribution of CA IV using fresh
      and cultured rabbit corneal endothelium and rat anti-CA IV polyclonal antibody.
      RESULTS: RT-PCR screening gave positive bands at the predicted size for CA IV
      from fresh and cultured rabbit corneal endothelium. Sequencing further confirmed
      the identity of CA IV in corneal endothelium. Immunoblotting analysis showed a
      single band at 52 kDa for freshly isolated and cultured endothelial cells.
      Indirect immunofluorescence staining revealed an apparent positive staining in
      cultured endothelial cells. CONCLUSION: Carbonic anhydrase IV is expressed in
      rabbit corneal endothelium, which could contribute to the transendothelial
      HCO(3)(-) flux that is necessary to maintain corneal hydration and transparency.

PMID- 12609079
TI  - Experimental study on mechanism and rarity of metastases in skeletal muscle.
AB  - OBJECTIVE: To investigate the reasons for the rarity of metastases in skeletal
      muscle. METHODS: By injecting tumor cells (Walker256 rat carcinosarcoma) through
      the iliac artery (experimental group) and the tail vein (control group), animal
      models of blood-borne metastases were established. The quadriceps femoris muscle
      and lungs were observed grossly and microscopically. Immunohistochemistry was
      applied to investigate the expression of vascular cell adhesion molecule-1 (VCAM
      1) in the microvascular endothelium of these organs. Primary culture of rat
      skeletal muscle cells was established and conditioned medium (MCM) was collected.
      Effects of MCM on several tumor cell lines and the biochemical characteristics of
      skeletal muscle delivered tumor factor(s) were tested by MTT assay. Apoptosis and
      morphological examination were carried out to investigate the antitumor
      mechanisms of MCM. RESULTS: In the experimental group, there were no definite
      metastases observed in muscle cells. In the control group, lung metastases were
      present in the lungs of all rats that were sacrificed at the 14th day or died
      spontaneously (17 rats in all). There was no significant difference between the
      increase in VCAM-1 in quadriceps femoris muscle 7 days after iliac artery
      injection and that in lungs 7 days after tail vein injection (P > 0.05). In vitro
      studies showed that the proliferation of tumor cell lines of mouse SP2/0 myeloma,
      rat Walker256 carcinosarcoma or human chronic granulocytic leukemia K562, human
      acute lymphatic leukemia HL-60, LS-174-T colon adenocarcinoma, PC3-M prostatic
      carcinoma and lung giant cell carcinoma with different metastatic potency (PLA801
      C with low metastatic potency, PLA801-D with high metastatic potency) was
      significantly inhibited when cultured with MCM (P < 0.01 - 0.05). Proliferation
      of malignant cells showed a dose-dependent decrease, to a certain degree.
      Proliferation of normal rabbit joint epiphysial disk cells (RGP-2) were not
      affected by MCM. Proliferation of lung giant cell carcinoma cells with high
      metastatic potency showed a significant decrease even when cultured in highly
      diluted MCM (6.25% of primary MCM), when compared with the strain of low
      metastatic potency. Following ultrafiltration, boiling at 100 degrees C, and
      treatment with trypsin, skeletal muscle delivered tumor factor(s) were found to
      be a low molecular weight (MW <or= 10.0 KDa) component which was trypsin
      resistant but not heat resistant. The factor(s) did not induce apoptosis in K562
      cells but caused direct destruction of the cytoplasmic membrane. CONCLUSIONS: The
      rarity of metastases in skeletal muscles, generally accepted in the clinical
      setting, can be reproduced in an animal model. It does not seem to be related to
      VCAM-1 expression in the microvessels of these organs. Skeletal muscle delivered
      factor(s) play a key role in the mechanism of the rarity of metastases in
      skeletal muscle.

PMID- 12609080
TI  - Telomerase activity in urine in diagnosis and recurrence surveillance of
      urothelial carcinoma.
AB  - OBJECTIVE: To investigate the significance of telomerase activity in urine in the
      diagnosis and recurrence surveillance of urothelial carcinoma. METHODS:
      Telomerase activity in urine of 54 cases of urothelial carcinoma (urothelial
      carcinoma group) was estimated by polymerase chain reaction-enzyme-linked
      immunosorbent assay, and monitored continuously in 23 cases after tumor removal.
      46 patients with benign urological diseases were also included as the control
      group. RESULTS: The telomerase activity in urine of patients with urothelial
      carcinoma increased significantly as compared with the control group (P < 0.001),
      decreased into the normal range after tumor removal, and rose again upon
      intravesical tumor recurrence before the screening of recurrent tumors by
      cystoscopy. The higher the grade of tumor, the higher the telomerase activity; no
      correlation could be found between the preoperative level of telomerase activity
      in urine and recurrence. CONCLUSIONS: The examination of telomerase activity in
      urine is helpful in the diagnosis of urothelial carcinoma and may be related to
      the differentiation degree of tumors. Its sensitivity is higher than that of
      cystoscopic examination and may become an important ancillary method in the
      screening of urothelial carcinoma recurrence.

PMID- 12609082
TI  - Biomechanical study of human dura and its substitutes.
AB  - OBJECTIVE: To investigate the biomechanical characters of human dura and its
      substitutes and to establish guidelines for selection of optimal repair materials
      for reconstruction of skull base defects. METHODS: A measurement of creep
      properties of human dura and its substitutes were conducted using biomechanical
      tests. The dynamic changes of biomechanical properties of canine dura obtained
      from skull base defects were observed as well. RESULTS: The creep properties of
      human dura presented a linear-relationship between initial strain and stress, and
      the creep strain increased slowly with time. The creep compliance formula for
      human dura and its substitutes was as follows: J (t) = J(0) + Kf (t). The initial
      compliance of canine dura in skull base defects was reduced by 35%, 46% and 50%,
      respectively 1, 3 and 6 months after surgery. CONCLUSION: The optimal material
      for the repair of skull base defects can be estimated using creep compliance
      analysis. The less the compliance, the better the property of anti-protrusion.
      Fresh human dura is the least compliant and then in increasing order are
      lyophilized human dura, fresh human pericranium, Terylene and silicon membranes.
      The pattern of biomechanical characteristics of the dura mater at skull base
      defects shows that the strain ability of the dura mater decreases distinctly for
      1 - 3 months and then remains almost unchanged for 3 - 6 months after surgery.

PMID- 12609081
TI  - Urodynamic study of enhanced continent mechanism using tapered ileum as continent
      urinary reservoir.
AB  - OBJECTIVE: To investigate the effect of extramural support from the pouch and
      abdominal wall to enhance the continent mechanism of tapered ileum. METHODS: A
      total of 24 patients underwent a procedure in which an ileal segment was tapered
      into an efferent tube, of which a part was placed between the back surface of the
      rectus muscle and the ileal pouch wall. The internal orifice of the tapered ileum
      was anastomosed to the ileal pouch and its external orifice was anastomosed to
      the umbilicus. A urodynamic study of the efferent tubes and pouch was done 1.5 to
      3 months and 6 to 24 months postoperatively. RESULTS: One patient died of heart
      disease 55 days postoperatively, while 22 of the remaining 23 were completely
      continent day and night. At 1.5 to 3 months, the urodynamic study of the efferent
      tubes demonstrated that the maximum closure pressure with a full pouch was 46 -
      124 cmH(2)O (91.26 +/- 15.71 cmH(2)O) and with an empty pouch was 34 - 84 cmH(2)O
      (67 +/- 10.60 cmH(2)O). The difference in mean maximum closure pressure in the
      full and empty pouches was statistically significant (t = -11.78 and P =
      0.00001). At 6 to 24 months, a second urodynamic study was performed on 18 cases,
      demonstrating a reservoir capacity of 420 to 750 ml (481.67 +/- 78.83 ml).
      Reservoir pressure was 6 to 9 cmH(2)O (7.17 +/- 1.17 cmH(2)O) when the pouch was
      filled to 50 ml, and 16 to 35 cmH(2)O (24.12 +/- 5.61 cmH(2)O) when it was filled
      to maximum capacity. There was no contractive wave during the filling in any
      patient. Maximum closure pressure in the efferent tube was 80 to 194 cm H(2)O
      (98.89 +/- 26.34 cmH(2)O) when the pouch was filled with saline, and 64 to 128
      cmH(2)O (74.78 +/- 14.54 cmH(2)O) when the pouch was empty. The difference in
      mean maximum closure pressure in the full and empty pouches was statistically
      significant (t = -7.58 and P = 0.00003). CONCLUSIONS: This study indicates that
      the continent mechanism of tapered ileum may be greatly enhanced by extramural
      support from the abdominal and pouch walls.

PMID- 12609083
TI  - Psychological consequences derived during process of human hand allograft.
AB  - OBJECTIVE: To study the psychology and the treatment during the process of hand
      allograft. METHODS: The patients were interviewed to evaluate their states of
      mind and their abilities to manage stress during the selection of patients. The
      psychology of the two patients were trained before the operation and managed
      accordingly afterwards. RESULTS: One of 12 candidates was found to be unsuitable
      for the transplantation because of psychiatric problems. One week
      postoperatively, the two patients were anxious, lacked patience and were afraid
      of seeing the long-awaited grafted hand. After 1 week, the patients began to
      accept the new hand, with full acceptance of the hand 1 month later. With the
      recovery of hand sensation 4 to 5 months after the operation, the patients
      regarded the hand as their own. CONCLUSION: Psychological problems exist during
      preoperative selection of patients and postoperative rehabilitation, requiring
      psychologists in the hand transplantation team.

PMID- 12609084
TI  - Anti-tumor effect of human endostatin mediated by retroviral gene transfer in
      nude mice.
AB  - OBJECTIVE: To explore the inhibitory effect of human endostatin gene mediated by
      retroviral vector on the growth of human liver carcinoma. METHODS: A recombinant
      retroviral plasmid containing human endostatin gene and signal peptide was
      engineered and transferred into PA317 cells to produce retrovirus. Human liver
      carcinoma cells (SMMC7721) were infected with the above retrovirus to build a
      stable endostatin-transfected liver carcinoma cell line (SMMC-endo). The control
      liver carcinoma cell line (SMMC-pLncx) was developed in a similar way except that
      the plasmid was replaced by an empty retroviral vector. Immunohistochemistry and
      Western blot were used to test the expression and secretion of human endostatin.
      The biological activity of the expressed human endostatin was assessed by
      endothelial cell proliferation assay. The growth rates of SMMC-endo and control
      SMMC-pLncx cells in vivo and in vitro were also observed. RESULTS: The expression
      and secretion of human endostatin by endostatin-transfected SMMC-endo cells were
      confirmed by immunohistochemistry and Western blot. Compared with the control
      group, concentrated supernatant of SMMC-endo cells remarkably inhibited the
      proliferation of human umbilical vein endothelial cells by 48%, significantly
      higher than the inhibition by the control (10.2%; P < 0.01). The endostatin
      transfected SMMC-endo cells had similar in vitro growth rates to SMMC-pLncx
      cells. The in vivo experiment showed that the growth rate of SMMC-endo cells was
      slowed. Only in 3 out of 5 mice were tumors formed and flank tumors of SMMC-endo
      cells were 94.5% smaller than those of control cells 22 days after inoculation
      into nude mice (P < 0.001). CONCLUSIONS: Gene transfer of human endostatin
      mediated by retroviral vector is an effective form of cancer therapy.

PMID- 12609085
TI  - Infrared thermography display of cortical temperature in cats.
AB  - OBJECTIVE: To use infrared thermography to take cat cerebral cortical temperature
      in order to visualize the temperature of its entire cerebral cortex as an image.
      METHODS: After performing craniotomy for exposure of cerebral hemispheres in 52
      cats, their cortical temperatures were displayed and analyzed by computerized
      infrared thermovision. RESULTS: The temperature distribution of the cerebral
      cortex was uneven, with a maximum difference of 2.3 degrees C among different
      cortical areas. The temperature in the cortical anterior-inferior area (including
      the Ant. Ectosylvian, the lower section of Mid. Ectosylvian and the Ant. Sylvian)
      was higher compared to the temperature in the posterior-super-parts (Post.
      Suprasylvian, Mid. Suprasylvian, Post. Lateral and Ant. Lateral). Locations with
      higher or lower temperatures showed little change within three days after
      craniotomy, and the cortical temperature held steady. CONCLUSION: The use of
      cortical infrared thermo-images for display of cat cortical temperature is
      possible and has many advantages over traditional methods. This new neuroimaging
      method has a practical value in neurological research.

PMID- 12609086
TI  - Sensory evoked potentials in patients with affective disorders accompanying
      suicidal behavior.
AB  - OBJECTIVE: To investigate the variations of sensory evoked potentials (SEPs) in
      patients with affective disorders accompanying suicidal behavior. METHODS: 39
      depressive patients, 22 manic patients and 33 normal controls were included in
      the study. Visual, auditory and somatosensory evoked potentials (VEP, AEP & SSEP)
      were recorded from every subject using a Nicolet Spirit Instrument. RESULTS: Both
      the depressive and manic groups presented prolonged latencies and decreased
      amplitudes of major components of SEPs as compared to that of normal controls.
      Depressive patients with suicidal behavior had decreased P(3) amplitude of VEP (P
      < 0.05), while maniacs with suicidal behavior had decreased P(2) amplitudes of
      VEP & AEP (P < 0.05 or 0.01). Compared with patients without suicidal behavior,
      patients with suicidal behavior had significantly decreased P(3) amplitudes of
      VEP & SSEP. CONCLUSIONS: The variations of SEPs in patients with affective
      disorders is closely associated with a history of suicidal behavior. Their
      clinical significance and biological correlates with suicidal behavior need
      further study.

PMID- 12609087
TI  - Vascular and biliary complications after liver transplantation: interventional
      treatment.
AB  - OBJECTIVE: To evaluate the value of angiography and cholangiography on the
      diagnosis and interventional treatment of vascular and biliary complications
      after liver transplantation. METHODS: Sixteen of 46 patients (15 men and 1 woman,
      17 - 60 years old) after orthotopic liver transplantation received angiography
      due to abnormal ultrasonography or edema of lower limbs, or cholangiography due
      to progressing jaundice. Percutaneous transluminal angioplasty or drainage was
      performed in some patients. RESULTS: Fifteen patients experienced vascular
      complications and 4 patients had biliary complications. Three of them appeared to
      have both vascular and biliary complications. Hepatic artery complications were
      the most common complications (9/16), including hepatic artery thrombosis or
      stenosis (6/9), bleeding (2/9) and hepatic artery-dissecting aneurysm (1/9). One
      patient with hepatic artery thrombosis received transcatheter thrombolysis and
      two patients with bleeding received coil embolization. Inferior vena cava and
      portal vein stenosis were observed in 6 and 2 patients, respectively. After
      balloon angioplasty or stent placement, clinical symptoms were alleviated.
      Biliary complications, including biliary stricture and anastomotic bile leak,
      occurred in 4 patients. Jaundice decreased after percutaneous transhepatic
      cholangiography and drainage. CONCLUSIONS: Besides diagnosis, interventional
      methods include mini-invasive treatment for patients with vascular and biliary
      complications after liver transplantation. Balloon angiography and stent
      placement for venous stenosis are useful procedure for the treatment of these
      problems.

PMID- 12609088
TI  - Preoperative transarterial embolization of hypervascular vertebral tumor with
      permanent particles.
AB  - OBJECTIVE: To evaluate the safety and value of preoperative transarterial
      embolization of hypervascular vertebral tumors. METHODS: Sixteen patients with
      hypervascular vertebral tumors underwent transarterial embolization before
      surgery. The lesions were located between the middle cervical and lower lumbar
      spine. Forty-one arteries were embolized with permanent particles injected
      through a microcatheter, including polyvinyl alcohol (PVA) particles (150 - 500
      micro m) in 25 arteries and Dextran particles (150 - 350 micro m) in 16. Of
      these, 31 had pieces of gelatin sponge added for proximal pedicled embolization.
      The criteria for judging the effectiveness of embolization were completeness of
      tumor removal and estimated blood loss during surgery. RESULTS: The particles
      were injected into the tumor feeders through superselection in 17 arteries or
      flow control in 24. Tumor embolization was defined as "total" in five patients,
      "nearly total" in eight, "subtotal" in two, and "partial" in another. There were
      no symptomatic complications associated with embolization. Tumors were entirely
      removed in all patients. The average estimated blood loss during surgery was 1510
      ml (range of 200 - 6000 ml) for all 16 patients. CONCLUSION: Preoperative
      embolization of hypervascular vertebral tumors is safe and effective. It can make
      complete resection of a tumor possible and can make a previously unresectable
      tumor resectable. Superselection or flow control is necessary to achieve
      effective devascularization and to avoid complications.

PMID- 12609089
TI  - Cerebral angiography and MR perfusion images in patients with ischemic cerebral
      vascular disease.
AB  - OBJECTIVE: To evaluate the value of perfusion MR imaging and angiographic
      evidence of collateral circulation in symptomatic patients with ischemic
      cerebrovascular diseases (ICVD). METHODS: Cerebral angiography and perfusion MR
      were performed in 16 patients with symptoms of ICVD. Qualitative perfusion maps
      were calculated for regional cerebral blood volume (rCBV) and mean transit time
      (MTT). RESULTS: A total of 27 lesions were seen on the perfusion MR maps (6
      infarcts and 21 ischemic lesions) and most of them (26/27) showed a prolonged
      MTT. MTT is sensitive to the presence of ischemic lesions, but not sufficient in
      distinguishing infarct from ischemia. All of the infarcts showed a decreased
      rCBV, while most of the ischemic lesions showed a normal or increased rCBV. When
      collateral circulation was identified on angiography, most ischemic lesions were
      not infarcts and had a normal or increased rCBV. The absence of angiographically
      identifiable cerebral collaterals may not always result in an infarct; 50% had
      decreased rCBV. Despite the absence of angiographic collaterals, the other half
      had normal or increased rCBV. CONCLUSION: Cerebral angiographic evidence of
      collateral circulation is important in identifying a favorable outcome in
      patients with ICVD. However, a lesion with a normal or increased rCBV suggests a
      sufficient collateral circulation even without angiographic collaterals.
      Perfusion images may be a potentially useful adjunctive tool in the prediction of
      the outcome of ICVD, particularly where no apparent collateral macrocirculation
      is seen on CA.

PMID- 12609090
TI  - Selection of neuromuscular blocking agents in patients undergoing renal
      transplantation under general anesthesia.
AB  - OBJECTIVE: To study the pharmacodynamics of vecuronium,atracurium, mivacurium and
      rocuronium in patients with end-stage renal failure. METHODS: Forty-six patients
      with end-stage renal failure scheduled for renal transplantation and 53 patients
      with normal renal function were given either vecuronium, atracurium, mivacurium
      or rocuronium. The neuromuscular effects were monitored by the evoked response of
      the adductor pollicis to train-of-four stimulation of the ulnar nerve. RESULTS:
      Onset of vecuronium, atracurium and mivacurium occurred faster or tended to be
      faster in patients with end-stage renal failure, but there was no significant
      difference in onset by rocuronium between the control patients and renal failure
      patients. Furthermore, the no-response period, duration of action and recovery of
      atracurium did not differ between the two groups. There was no significant
      difference in duration of action or recovery of mivacurium between the two
      groups, whereas its no-response period was significantly prolonged in the
      patients with end-stage renal failure. There was no difference in no-response
      period or duration of action after the initial dose of vecuronium or rocuronium
      between the two groups. However, no-response period and duration of effect by
      vecuronium and rocuronium were prolonged with increasing incremental doses in
      patients with end-stage renal failure. CONCLUSIONS: All four muscle relaxants
      could be safely used in patients with end-stage renal failure. Onset of the
      relaxants were, in some cases, accelerated and no-response period of mivacurium
      was prolonged in patients with end-stage renal failure undergoing dialysis
      therapy. End-stage renal failure prolonged the no-response period and duration of
      action of vecuronium and rocuronium after repeated incremental doses, but did not
      alter those attributed to atracurium.

PMID- 12609091
TI  - pcDNAL1 genetic immunization can induce specific cell-mediated immune responses
      in C57BL/6 mice.
AB  - OBJECTIVE: To investigate the specific cell-mediated immune efficacy of the an
      HPV16 prophylactic vaccine. METHODS: C57BL/6 mice were randomly divided into 3
      groups: experimental group I (treated with pcDNA L1), control group II (treated
      with pcDNA3.1) and control group III (treated with PBS buffer). The mice were
      immunized three times during a three-week interval. Ten to fourteen days after
      the third inoculation, a footpad swelling test was used to detect delayed-type
      hypersensitivity (DTH) responses. Antigen-specific splenocyte proliferation assay
      and quantitation of IFN-gamma cells in splenocytes were performed by FACS assay.
      RESULTS: In the experimental group, splenocytes actively proliferated after
      stimulation with HPV16 VLP, and had developed a markedly larger amount of CD8(+)
      IFN-gamma(+) cells, which is an index for special CTL. Also, the footpad was
      significantly thickened upon inoculation with HPV16 VLP. CONCLUSION: Naked DNA
      vaccine of HPV16 L1 can induce specific cell-mediated immune responses in mice,
      which should be considered for evaluation of HPV16 DNA vaccine feasibility.

PMID- 12609092
TI  - A novel erythroid differentiation related gene EDRF1 upregulating globin gene
      expression in HEL cells.
AB  - OBJECTIVE: To further characterize the differentiation inducing properties of
      EDRF1 and demonstrate its functional pathway involved in regulation of globin
      gene expression. METHODS: By transfecting EDRF1 sense and antisense constructs
      into HEL cells, we identified the expression of globin and erythropoietin
      receptor genes by Northern blot analysis. RT-PCR and EMSA (electrophoresis
      mobility shift assay) were performed to monitor the expression and DNA-binding
      activity of erythroid specific transcription factors GATA-1 and NF-E2. RESULTS:
      It was shown that when EDRF1 was overexpressed, production of alpha-globin
      increased. In antisense EDRF1, overexpression of HEL cells, significant loss of
      alpha-, gamma-globin mRNA synthesis was observed. The transcription of endogenous
      GATA-1 and NF-E2 mRNA expression were maintained at the same levels compared with
      control experiments. However, the transcription activity of GATA-1 was severely
      impaired. Expression of erythropoietin receptor gene was not influenced by EDRF1
      gene overexpression. CONCLUSION: The results suggested that EDRF1 regulated alpha
      and gamma-globin gene synthesis by modulating DNA-binding activity of GATA-1
      transcription factor.

PMID- 12609094
TI  - Hospital management in China in a time of change.

PMID- 12609093
TI  - Primary angle closure glaucoma in Chinese and Western populations.
AB  - OBJECTIVE: To review the major progress in primary angle closure glaucoma (PACG).
      METHODS: Contents of this article were selected from the original papers or
      reviews related to primary angle closure glaucoma published in Chinese and
      foreign journals. A total of 76 articles were selected from several hundred
      original articles or reviews. The content of selected articles is in accordance
      with our purpose and the authors are authorized scientists in the study of
      glaucoma. RESULTS: Primary angle closure glaucoma is the most common type of
      glaucoma in the Sino-Mongoloid population. PACG in Chinese can be classified into
      three types depending on the mechanism of angle closure: 1. Multimechanism: 54.8%
      of Chinese PACG is caused by co-existing factors. The pattern of angle closure
      appears to mainly be creeping closure. After iridectomy, almost 40% of the cases
      still manifest a positive response to the darkroom provocative test and
      progressive synechial closure or recurrent angle closure may occur. Several
      mechanisms are involved in this form of PACG such as pupillary blocking
      component, iris crowding component and anterior positioned ciliary body. These
      factors can coexist in the follow patterns: pupillary blocking and iris crowding
      coexist; pupillary blocking and anterior positioned ciliary body coexist or three
      of them co-exist. 2. Pupillary block: (38.1% of Chinese PACG) is caused by iris
      bombe due to pupillary block with acute or subacute attack. It responds well to
      iridectomy or laser iridotomy. 3. Non-pupillary blocking: (7.8% of Chinese PACG).
      They usually have a deeper anterior chamber, and tend to be younger (below 40
      years of age). Angle closure in this form of PACG is caused by: iris crowding
      mechanism or/and anteriorly positioned ciliary body against iris root to angle.
      It is critical to distinguish multi-mechanism PACG from other types. The initial
      treatment for this type of PACG is also iridectomy, but after the pupillary block
      component is eliminated by iridectomy, the residual non-pupillary blocking
      components should be highlighted by a diagnostic treatment procedure or by a
      ultrasound biomicroscopy (UBM) provocative test. Finally, the role of UBM in the
      observation and evaluation of the mechanism of angle closure is discussed and
      future research directions on PACG in Asians are proposed. CONCLUSION: Chinese
      eyes have been recognized to be prone to the development of creeping angle
      closure. There is some direct evidence that creeping angle closure is caused by
      multiple mechanisms. Further study on this topic is needed.

PMID- 12609095
TI  - Consecutive allergen challenges resulted in decreased bronchial responsiveness.
AB  - OBJECTIVE: To investigate bronchial responsiveness to acetylcholine in allergic
      airway inflammation of SD rats. METHODS: SD rats were immunized and challenged by
      chicken ovalbumin (OVA). Airway responsiveness, acetylcholine (Ach) provocation
      concentration needed to increase baseline airway resistance by 200% (PC(200))
      were measured. RESULTS: The value of baseline airway resistance in asthma group
      was significantly higher than that in control group (2.282 +/- 0.128 vs 3.193 +/-
      0.239; P < 0.01). After multiple ovalbumin exposures, airway responsiveness to
      intravenous injection of acetylcholine decreased significantly (-LogPC(200):
      4.006 +/- 0.554 vs 2.059 +/- 0.262; P < 0.01). Bronchial alveolar lavage fluid
      (BALF) and lung tissue specimen analysis indicated that airway allergic
      inflammation was present. CONCLUSIONS: The study demonstrates a dissociation
      between the bronchoconstrictor response and bronchial hyper-responsiveness and
      indicates that multiple ovalbumin exposures induces persistent
      bronchoconstriction with airway hypo-responsiveness despite airway allergic
      inflammation.

PMID- 12609096
TI  - Sequential-release of anticancer drugs microcapsulated with ethylcellulose.
AB  - OBJECTIVE: To approach the sequential release of antitumor drugs and promote the
      effect of chemotherapy. METHODS: Adriamycin (ADM) and carboplatin (CBP) were
      respectively microcapsulated with ethylcellulose by organic phase separation. The
      morphology and sizes of the microcapsules were observed and measured with light
      microscope and scanning electromicroscope. The contents and the release rates of
      ADM and CBP in microcapsules were measured with fluorescence spectrophotometer
      and high-efficiency phantom chromatic (HPC) spectrum respectively. The antitumor
      sensitivity test in vitro was devised with MTT assay. RESULTS: The microcapsules
      of ADM and CBP were spherical in shape with diameters of 196 +/- 64 micro m and
      214 +/- 48 micro m respectively. The contents of one-layer and two-layer CBP and
      ADM microcapsules were 51.4%, 35.7% and 39.8% respectively, with the release
      rates in vitro of 62.4%/day, 54.8%/day and 48.2%/8 h. The results of drug
      sensitivity test in vitro demonstrated that the current preparation has never
      affected the stability and antitumor activity of CBP and ADM. CONCLUSION:
      Microcapsules with different drugs and different thickness of material have
      different release rate. Combined arterial chemoembolization with different
      microcapsules could approach the sequential release and promote the effect of
      chemotherapy.

PMID- 12609097
TI  - Familial Wolff-Parkinson-White syndrome is linked to the loci on chromosome 7q3.
AB  - OBJECTIVE: Wolff-Parkinson-White syndrome (WPW) is considered to be an autosomal
      dominant hereditary disease, but the gene is not identified. The objective of
      this study was to localize the genetic loci of Wolff-Parkinson-White syndrome.
      METHODS: Linkage analysis between the disease of Wolff-Parkinson-White syndrome
      and 3 STR (short tandem repeats) markers on 7q3 (D7S505, D7S688, and D7S483) was
      tested in 3 kindreds of the Wolff-Parkinson-White syndrome (101 numbers in total)
      by genotyping. RESULTS: Wolff-Parkinson-White syndrome was linked to the loci
      above. The maximum two-point Lod score detected at D7S505 was 6.4 at a
      recombination fraction (theta) of 0.1; the Lod score of D7S688, D7S483 was 5.3 vs
      2.5. CONCLUSION: The gene of Wolff-Parkinson-White syndrome is located at 7q3.

PMID- 12609099
TI  - Clinical application and effective assessment of cerinate porcelain laminate
      veneers.
AB  - OBJECTIVE: To study the esthetic and long-term effectiveness of cerinate
      porcelain laminate veneers. METHODS: A total of 736 front teeth were restored
      with cerinate porcelain laminate veneers, which were then tested at different
      time points by clinical tracking observation and appraisal. RESULTS: The short
      and long term rates of effectiveness were 96.6% and 96.2%, respectively. There
      was no relationship between clinical effectiveness and the length of restoration
      time. The failure rate was higher in 18 - 30 years old patients and those with
      discolored teeth. The major clinical performance was fold fissure and deciduous
      of porcelain laminate veneers. CONCLUSIONS: Cerinate porcelain laminate veneers
      are an ideal choice for dental esthetic restorations because they are
      unnoticeable, stable, strong and require no excessive dental preparation.

PMID- 12609098
TI  - The role of nuclear matrix protein 22 combined with bladder tumor antigen stat
      test in surveillance of recurring bladder cancer.
AB  - OBJECTIVE: To investigate a non-invasive, effective and rapid mode of detecting
      the recurrence of bladder cancer during follow-up. METHODS: Ninety patients
      following transurethral resection of bladder tumor (TURBt) surgery were recruited
      from January 1998 to March 2000. Standard ELISA was used to determine the
      quantity of nuclear matrix protein (NMP-22) in urine of all bladder cancer
      patients during their follow-up periods. Urine bladder tumor antigen (BTA) stat
      test was simultaneously performed and followed by cystoscopy. RESULTS: The total
      positive rates of urinary NMP-22 and BTA stat test were 76.7% (33/43) and 67.4%
      (29/43), respectively. Comparatively, this positive rate would increase to 93.0%
      (40/43) when the combination of both urine NMP-22 and BTA test were adopted.
      CONCLUSION: Examination of NMP-22 in urine is a rapid and effective way to detect
      the recurrence of bladder cancer. If combined with BTA test, NMP-22 may be used
      as a non-invasive method in surveillance of recurring of bladder cancer, which
      may reduce the frequency of patients needing to undergo conventional invasive
      cystoscopy.

PMID- 12609100
TI  - Deceleration injury of concomitant coronary artery and thoracic aorta: a case
      report.

PMID- 12609101
TI  - Successful resection of osteosarcoma pulmonary metastasis extending into left
      side of heart under cardiopulmonary bypass: a case report.

PMID- 12609102
TI  - [Evidence-based Primary Care Therapeutic Guidelines: an honest and practical
      task].

PMID- 12609103
TI  - [Attitudes and practices regarding physical activity: situation in Spain with
      respect to the rest of Europe].
AB  - AIM: To identify attitudes and practices in the Spanish population regarding
      physical activity, and to compare the situation in Spain with that of other
      member stages of the European Union (EU). DESIGN: Descriptive, cross-sectional
      study. SETTING: European Union (representative samples of all 15 member stages).
      Participants. From each member stage we obtained a representative sample of
      approximately 1000 subjects older than 15 years. A total of 15 239 individuals
      were asked to complete a questionnaire on attitudes regarding physical activity,
      body weight and health. Main measures. We classified participants into 6 possible
      stades of change toward physical activity, and subsequently regrouped them into
      static (precontemplation and relapse) and dynamic stages (contemplation,
      decision, action and maintenance). Multivariate analysis with unconditional
      logistic regression was used to determine which sociodemographic variables were
      related with static stages. RESULTS: Static stages of change were more prevalent
      in Spain than in the rest of the EU. Spanish participants of both sexes who had
      received primary education, were married, were smokers or were obese were more
      likely to be in a static stage with regard to physical activity. CONCLUSIONS: The
      proportion of Spaniards with a poor attitude toward changing their level of
      physical activity was higher than in the rest of the EU, and Spanish citizens
      were less perseverant in achieving positive changes.

PMID- 12609105
TI  - [Cryotherapy with nitrous oxide in primary care].
AB  - OBJECTIVE: To study the efficacy, tolerance and safety in primary care of the
      cryotherapy technique using nitrous oxide. Design. Descriptive, observational and
      transversal study. SETTING: Marinamansa-A Cuna Health Centre, Ourense.
      PARTICIPANTS: All the patients who consulted for cutaneous lesions caused by
      cryotherapy between March and April 2000 (n=130). MAIN MEASUREMENTS: Age, sex,
      diagnosis, location, size of lesion, duration of application of the cryogenic
      agent, previous treatment, side-effects observed, and evolution of the lesion.
      RESULTS: Mean age was 36.65 (95% CI, 32.57-40.74), of whom 53.8% (95% CI, 44.80
      62.50) were women. The most common lesions were common warts (68.5%), actinic
      Keratosis (12.3%) and plantar warts (7.7%). We found that most lesions were
      located on an upper limb (50.8%). The mean size of lesions was 8.65 mm2 (95% CI,
      4.50-12.80). 69.7% of warts were scraped prior to cryotherapy; and 16.2% received
      prior keratolysis. We found no side-effects in 32.3% of the patients; the
      commonest side-effect detected was blisters. Mean number of cryotherapy sessions
      was 2.82 (95% CI, 2.39-3.29). The technique was tolerated well in 83.8% of cases.
      We found total cure in 87.7%. Most of the cutaneous lesions that failed were
      common warts. CONCLUSIONS: Nitrous oxide is effective in most lesions caused by
      cryotherapy. The technique is tolerated well, can be handled easily and can be
      used in primary care.

PMID- 12609106
TI  - [Is the breath test reliable in primary care diagnosis of Helicobacter pylori
      infection?].
AB  - OBJECTIVE: To evaluate the reliability of the breath test urea 13C in the primary
      care for the diagnosis of Helicobacter pylori (Hp) infection. DESIGN:
      Descriptive, prospective and multicentric.Location. Urban area belonging to the
      Health Center Actur Sur of Zaragoza with participation of Miguel Servet Hospital.
      PARTICIPANTS: 87 patients with clinical diagnosis of functional dispepsia. In all
      of them was made a breath test with 13C urea as well as a gastroscopy with taking
      of samples for histology and ureasa fast test. MAIN MEASUREMENTS: Age, sex and
      the presence of positivity or negativity of infection by Hp were valued in the
      histology, ureasa test and in the breath test, considering the histology and the
      ureasa test like gold tests for this measurement, reason why it was demanded that
      the positive or outside negative result in both considering it nonambiguous.
      RESULTS: Two cases were excluded by ambiguous results. The 77.6% (66/85) were
      positive by histology and ureasa test, and these, 92.4% (61/66) were positives to
      the breath test. The sensitivity of this test was 92% and the specificity 100%.
      CONCLUSIONS: The breath test in primary care has a high value diagnosis of Hp
      infection, being able to avoid, in some cases, another invasives techniques like
      gastroscopy.

PMID- 12609107
TI  - [Prophylaxis of neural tube defects with folic acid in pregnant women from a
      health district].
AB  - OBJECTIVES: To evaluate the knowledge about the prophylaxis of neural tube
      defects (NTD) with supplements of folic acid and the correct therapeutic
      compliance. DESIGN: Observational, descriptive study. PARTICIPANTS: 346 pregnant
      women attending to deliver at the department of obstetrics and gynaecology,
      university hospital. MATERIAL AND METHODS: The following outcomes were gathered
      through a questionnaire: demographic variables, previous personal or family
      history of a pregnancy affected by a NTD, planning of pregnancy, knowledge about
      the value of the use of folic acid, health professional who prescribed it, and
      the beginning and duration of the prophylaxis. RESULTS: 95% of the participants
      used supplements of folic acid during their pregnancy. A 34% was able to describe
      folic acid as an efficacious method to diminish the incidence of NTD. The
      percentage of women who used correctly the prophylaxis was significantly greater
      when it was prescribed by a family physician (P=.003). CONCLUSIONS: A great
      proportion of women from our health district take folic acid during pregnancy,
      but just a small percent accomplishes the treatment correctly. The lack of
      awareness among women about the need for periconceptional folic acid supplements
      and how it should be taken following the recommendations to prevent NTD are the
      main reasons for not accomplishing a correct prophylaxis. Family physicians could
      play an important role as health educators.

PMID- 12609108
TI  - [Measurement of the legibility of written texts. Correlation between the Flesch
      manual method and computer methods].
AB  - OBJECTIVE: To compare, for the calculation of the Flesch legibility index, the
      original manual method and the computer programmes Word Perfect 7 and Microsoft
      Word 2000; and to correlate these with other computer measurements of legibility.
      DESIGN: Descriptive, observation study. SETTING: A Madrid Health Centre, within a
      study of the legibility of health education (HE) leaflets. MATERIAL: A sample of
      text from 100 HE leaflets and 11 general control texts. Main measurements. The 11
      texts were analysed through Flesch' s original manual method and the computer
      programmes mentioned, with which the number of words and sentences, the Flesch
      scores, the index of sentence complexity and the LEGIN index were calculated.
      Pearson's correlation coefficient was calculated for all the variables. RESULTS:
      There was very good correlation between the manual measurement of the Flesch
      index, the number of words and sentences, and their determination by means of
      computers (r>0.75); and excellent correlation between the two programmes (r>0.9).
      The results support the cut-off scores in other studies for legibility measured
      by computer. CONCLUSIONS: Measurement of legibility through the computer
      programmes used can reliably replace manual measurement of the Flesch index.

PMID- 12609109
TI  - [Optimising treatment of type-2 diabetes: adjusting the treatment to both patient
      and illness].

PMID- 12609110
TI  - [Semi-taught course specialising in family medicine (CuSEMF) in Mexico (1993
      1999)].

PMID- 12609111
TI  - [Prevalence, expression and impact of depressive disorders in primary care].
AB  - OBJECTIVE: To determine the prevalence and forms of clinical expression of
      depressive disorders in primary care patients. To analyse the under-detection of
      depression by primary care doctors. DESIGN: Descriptive and transversal study,
      with two-stage sampling. Setting. Primary care consultations in the Camp de
      Tarragona area. PARTICIPANTS: 1000 consecutive patients visiting their doctor for
      any reason will make up the first-stage sample. Of these 350 go on to the second
      stage (all the positive results in the screening for depression test plus a
      random one-seventh of the negative results). MAIN MEASUREMENTS: The first stage
      will consist of the screening of the sample for depressive disorders with Zung's
      Self-Rating Depression Scale. In the sub-sample that will go on to the second
      stage, the Structured Clinical Interview for DSM-IV Disorders will be used to
      establish diagnoses of depressive disorders and other co-morbid psychiatric
      disorders. There will also be a range of specific questionnaires to find reasons
      for consultation and the form of presentation of an eventual depressive disorder,
      medical co-morbidity, medication taken, use of health services, the functional
      and vital repercussions of depression. A questionnaire for the patient's G.P.
      will assess and detect depression. DISCUSSION: The study will enable us to check
      the validity for our patients of pre-suppositions on depression in primary care
      obtained from studies in other countries with different health structures and
      social and cultural conditioners, and to find diverse information extrapolated
      from specialist studies.

PMID- 12609112
TI  - [Quality of life evaluation for osteoporosis].

PMID- 12609113
TI  - [Q fever].

PMID- 12609114
TI  - [Giant hepatic hemangioma as cause of dyspepsia. Concerning a case].

PMID- 12609115
TI  - [Three cases of intestinal inflammatory disease caused by anti-depressant
      treatment with paroxetine].

PMID- 12609116
TI  - [Postgraduate assessment of family medicine residents].

PMID- 12609120
TI  - Message from the editor.

PMID- 12609117
TI  - [Meta-analyses do not show that pneumococcal vaccine is ineffective in preventing
      pneumococcal pneumonia in patients over 65].

PMID- 12609121
TI  - Nonepileptic seizures: time for progress.

PMID- 12609122
TI  - Cortical mapping of right hemisphere functions.
AB  - Right hemisphere functions were examined during cortical stimulation in six
      patients undergoing epilepsy surgery. Two patients showed mild hemispatial
      neglect and constructional disability with stimulation of several sites in the
      inferior parietal lobule and posterior temporal lobe. Two other patients showed
      no disruption of visuospatial functions with stimulation of similar parietal or
      posterior temporal sites. Nonverbal acoustic perception of environmental sounds
      was not disrupted with stimulation of right superior temporal cortex in one
      patient, and musical abilities were not affected by right superior temporal
      stimulation in another patient. Nondominant hemisphere functions may be more
      widely distributed and less localized than linguistic functions in the dominant
      hemisphere. 

PMID- 12609123
TI  - Impact of taking antiepileptic drugs at school in a group of children and
      adolescents.
AB  - The impact of epilepsy on the quality of life can be significant. Peer acceptance
      is important for the social adjustment of children. Even children with controlled
      seizures may appear different from their peers if they are required to leave the
      classroom to take antiepileptic drugs. The objective of this pilot study was to
      determine if there is a measurable effect on peer relationships in children
      having to leave the classroom or recess time to take antiepileptic medications in
      a school setting. Results of surveys mailed or distributed by a pharmacist were
      obtained from 47 children, aged 6 to 18 years. Children who reported poor seizure
      control were significantly more likely to have trouble making friends compared
      with those with seizures controlled (70% vs 27%, P = 0.02). Even though the
      majority reported good seizure control (7/8), the children who left the classroom
      to take medications reported that they had significantly more trouble making
      friends than those who did not leave the classroom (63% vs 21%, P = 0.03).
      Therefore, the effect of taking medication at school may be associated with a
      significant decrease in social and peer relationships, even in children with self
      reported good seizure control. 

PMID- 12609124
TI  - Anticonvulsant profile of ondansetron in rats.
AB  - Recent studies have shown the involvement of 5-hydroxytryptamine (5HT) in the
      pathogenesis of epilepsy. Hence it was decided to investigate the effect of the
      5HT3 receptor antagonist ondansetron against maximal electroshock (MES)-induced
      seizures in rats. Also, the anticonvulsant activity of ondansetron in combination
      with phenytoin and its effect on the cognitive deficits induced by phenytoin were
      studied. MES was induced through ear-clip electrodes using a current strength of
      150 mA for 0.2 second. The index of protection was taken as the inhibition of
      tonic hindlimb extension. The ED25 and ED16 doses of ondansetron were combined
      with subanticonvulsant doses of phenytion, i.e., 6 and 3 mg/kg. The retention
      latencies in the passive avoidance task (PAT) were assessed on Days 1 and 21 of
      chronic administration of ondansetron alone, phenytoin alone, and ondansetron in
      combination with phenytoin. The ED50 of ondansetron was found to be 1.05 (0.51
      2.2) mg/kg. The combination of ondansetron with phenytoin had a potentiating
      effect against MES. Also, the retention latencies in the PAT of ondansetron alone
      and ondansetron in combination with phenytoin were significantly higher than that
      of phenytoin alone. Thus, ondansetron has potent anticonvulsant activity in rats
      and further potentiates the anticonvulsant activity of phenytoin. Also, it
      attenuates the cognitive dysfunction induced by phenytoin and merits further
      research for its mechanisms. 

PMID- 12609125
TI  - Epilepsy and behavior: a brief history.
AB  - Behavioral changes-both real and imagined-have formed a halo around epilepsy
      since antiquity. The myth of epilepsy as a curse has been largely vanquished in
      modern cultures, but the disorder remains a social stigma for many patients. In
      ancient Rome people with epilepsy were avoided for fear of contagion, in the
      Middle Ages they were hunted as witches, and in the first half of our century
      they were labeled deviants and their marriage and reproduction were restricted by
      eugenistic medical doctors. Religious conversion experiences can occur in
      temporal relationship to changes in seizure frequency. Many religious leaders may
      have had epilepsy. However, changes in religious sentiment are not characteristic
      of epilepsy patients. Recognized since the late 19th century, postictal psychosis
      has stimulated theories regarding the mechanism of mania and psychosis.
      Understanding the pathophysiology of behavioral changes in epilepsy may offer
      insight into the psychopathology of other diseases. 

PMID- 12609126
TI  - Depression in epilepsy: a common but often unrecognized comorbid malady.
AB  - Depressive disorders (DDs) represent the most frequent psychiatric comorbidity in
      epilepsy (1-5). Despite their relatively high prevalence, DDs remain unrecognized
      and untreated in many patients with epilepsy. The purpose of this review is to
      examine the reasons behind the failure to recognize and treat DDs in epilepsy. We
      highlight the essential epidemiologic, etiopathogenic, and clinical aspects that
      need to be considered in the evaluation of every epileptic patient and dedicate
      the last section of this paper to the review of the most relevant treatment
      issues. If we are successful in our goals, the reader will be impressed by the
      significant impact of DDs on the quality of life of these patients, and by the
      need to investigate treatment modalities with the same scientific rigor used in
      the assessment of efficacy of antiepileptic drugs in the control of seizures. 

PMID- 12609127
TI  - The postictal state: a neglected entity in the management of epilepsy.
AB  - Some of the disability deriving from epilepsy derives from the postictal state
      (PS). The PS may be complicated by impaired cognition, headache, injuries, or
      secondary medical conditions. Postictal depression is common, postictal psychosis
      relatively rare, but both add to the morbidity of seizures. The mechanisms of the
      PS are poorly understood. Alteration of cerebral blood flow both results from and
      contributes to the PS. Many neurotransmitters or neuromodulators are involved in
      the physiology of the PS. Response to glutamate may partially desensitize after a
      seizure. Endogenous opiates and adenosine serve as natural antiepileptic
      medications in some circumstances. Nitric oxide has numerous effects on brain
      excitability, and may be particularly important in regulating postictal cerebral
      blood flow. Just as the pathophysiology of seizures is complicated, so is that of
      the PS multifactorial. As a practical issue, it would be very useful to have
      medications that reduce the morbidity of the PS. 

PMID- 12609130
TI  - "The spirit catches you and you fall down": epilepsy and the hmong.

PMID- 12609129
TI  - Foreword.

PMID- 12609128
TI  - Alternative medicine use by patients with epilepsy.
AB  - Purpose. The objectives of this study were, first, to determine the prevalence,
      characteristics, and demographic patterns of alternative medicine (AM) use in
      patients with epilepsy, and second, to ascertain the extent to which these
      patients inform the neurologist of AM use. Methods. Surveys were distributed
      randomly to patients attending a tertiary care epilepsy clinic. The survey
      assessed use of specific herbal medicine/dietary supplements, along with other
      forms of AM. Results. Of 150 surveys distributed, 92 were used for analysis.
      Twenty-two patients with epilepsy (24%) used AM, and only 31% of AM users
      reported such to their neurologists. Massage and herbs/supplements were used the
      most, and only two patients used AM specifically for treatment related to
      epilepsy. Conclusions. A sizable minority of patients with epilepsy who visit our
      tertiary care clinic use AM. Health professionals should actively monitor
      therapies to ensure safety and effectiveness with combined traditional medicine
      and AM use. 

PMID- 12609131
TI  - Impact of epilepsy in children.

PMID- 12609132
TI  - Epilepsy and the elderly.

PMID- 12609133
TI  - Epilepsy in my life.

PMID- 12609135
TI  - Quality of Life in Epilepsy: Time to Practice What We Preach.

PMID- 12609134
TI  - The meaning of quality of life to patients with epilepsy.

PMID- 12609136
TI  - The Human and Economic Burden of Epilepsy.

PMID- 12609137
TI  - A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation.
AB  - Context. Antiepileptic drugs (AEDs) are frequently used for their beneficial mood
      effects.Objective. We sought to determine if there was a quantifiable effect on
      mood of the vagus nerve stimulator (VNS) when used as an antiseizure
      treatment.Design. Mood was assessed before and 3 months after VNS implantation in
      adult epilepsy patients. A group of adult epilepsy patients on stable AED
      regimens were used as a comparison group. AED regimens were unchanged during the
      study. The change in mood scale scores across time was assessed by t test
      (intragroup) and two-factor repeated-measures ANOVA (intergroup).Setting. An
      epilepsy center in a university hospital was the setting.Subjects. Twenty
      consecutive adult epilepsy patients undergoing VNS implantation to improve
      seizure control and twenty adult seizure patients with no intervention were
      enrolled.Main outcome measures. The mood scales used were the Cornell Dysthymia
      Rating Scale (CDRS) and the Hamilton Depression (Ham-D), Hamilton Rating Scale
      for Anxiety (Ham-A), and Beck Depression Inventory (BDI) scales.Results. The VNS
      group showed a significant decrease in mood scale scores across time (t test CDRS
      P = 0.001, Ham-D P = 0.017, BDI P = 0.045), indicating a decrease in depressive
      symptoms. The Ham-A scores in the VNS group and the comparison group scores did
      not significantly change across time. There were no significant differences
      between groups across time, although the BDI approached significance at P = 0.07.
      The VNS group had a significant decrease in seizure frequency compared with the
      comparison group (P = 0.01). There was no difference in mood scales over time
      between the VNS treatment responders (defined by >50% decrease in seizure
      frequency) and nonresponders, suggesting dissociation between seizure frequency
      reduction and mood change.Conclusion. VNS treatment is associated with mood
      improvement as measured by multiple scales, but differences in mood scale scores
      over time between the VNS and a comparison group were not found.

PMID- 12609138
TI  - The Use of Sertraline in Patients with Epilepsy: Is It Safe?
AB  - Purpose. The purpose of this study was to assess the impact of the selective
      serotonin-reuptake inhibitor (SSRI) sertraline (SRT) on the severity and
      frequency of seizures of patients with epilepsy.Methods. We prospectively
      assessed the seizure frequency of 100 consecutive patients with partial (n = 95)
      and primary (n = 5) generalized epilepsy during a trial with SRT for the
      treatment of a depressive (n = 97) or obsessive-compulsive (n = 3) disorder. We
      compared the monthly seizure frequency recorded while on SRT with those logged
      during the 3 and 12 months preceding the start of SRT. A definite causality
      between seizure worsening and SRT was considered in the following circumstances:
      (1) occurrence of de novo generalized tonic-clonic seizure (GTC); (2) recurrence
      of a GTC following a period of at least 1 year without this seizure type; and (3)
      an increase in the monthly seizure frequency beyond the maximal recorded monthly
      frequency during both 3- and 12-month periods preceding SRT. A probable causality
      between SRT and seizure worsening was considered in the case of an increase in
      monthly seizures beyond the maximal frequency recorded during the 3-month, but
      not the 12-month, period preceding SRT.Results. Six patients (6%) experienced an
      increase in seizure frequency after starting SRT. One and five patients met
      criteria for definite and probable causality between SRT and seizure worsening,
      respectively. Adjustment of antiepileptic drug doses resulted in a return to
      baseline seizure frequency in the latter five patients; four patients were kept
      on SRT at the same doses. The SRT dose of these six patients was significantly
      lower (57.1 +/- 23.8 mg/day vs 111.8 +/- 56.8 mg/day; F = 6.35, P = 0.01) than
      that of the other 94 patients.Conclusion. SRT can be safely used in the vast
      majority of patients with epilepsy.

PMID- 12609139
TI  - Nonlinear Trends in Hippocampal Metabolic Function and Verbal Memory: Evidence of
      Cognitive Reserve in Temporal Lobe Epilepsy?
AB  - The present study explored the possibility of nonlinear trends in the
      relationship between verbal memory and hippocampal function in a series of 33
      patients with temporal lobe epilepsy (TLE). Right and left hippocampal metabolic
      function was quantified using levels of hippocampal creatine to N-acetylaspartate
      (Cr/NAA) derived from (1)H magnetic resonance spectroscopic imaging. An
      exploratory neural network analysis (multi-layer perceptron) suggested the
      possibility of either a quadratic or cubic trend in the relationship between left
      hippocampal Cr/NAA and verbal retention. Using regression-based curve estimation,
      the cubic function was found to optimally fit the data, explaining 41% of the
      variance in the relationship between verbal memory and hippocampal metabolic
      function. This was contrasted to the 28% variance explained by simple linear
      regression. These findings suggest that (1) the relationship between verbal
      retention and hippocampal function in patients with TLE is nonlinear, and (2)
      this could be explained in terms of a possible "cognitive reserve." Clinical
      implications are discussed.

PMID- 12609141
TI  - Epilepsy: Quality of Life and Cost of Care.
AB  - The primary goal of epilepsy management is to enable the patient to lead a
      lifestyle as free from the medical and psychosocial complications of seizures as
      possible. This approach benefits a patient's quality of life as well as his or
      her family and society (particularly from a cost-of-care perspective). Though
      treatment with antiepileptic drugs is the primary therapy for epilepsy, physical
      and psychosocial issues must also be addressed. The indirect costs of epilepsy
      are related to the patient's ability to function. Since quality of life in
      epilepsy patients is improved with successful management, the indirect (and
      possibly the total) costs of epilepsy may decrease as the medical and
      psychosocial aspects of the disease are successfully managed.

PMID- 12609140
TI  - Gender, Memory, and Hippocampal Volumes: Relationships in Temporal Lobe Epilepsy.
AB  - Previous research has suggested bilateral hippocampal support for verbal memory
      in women with early left-hemisphere injury and that women experience better
      verbal memory outcome following anterior temporal lobectomy (ATL). The present
      study investigated two issues: (1) Do women have better verbal memory outcome
      following ATL compared with men? (2) Are verbal memory abilities differentially
      supported by the right and left hippocampus in males and females? Verbal memory
      performance [Wechsler Memory Scale: Logical Memory (LM) savings score] was
      assessed in 70 patients who underwent ATL. MRI volumetric measurements of the
      left and right hippocampus were performed. No LM savings score difference was
      found between groups preoperatively although a statistically significant gender
      effect (P < 0.04) was found for postoperative LM savings scores. Females
      displayed better postoperative memory performance, regardless of side of surgery.
      Preoperative verbal memory performance was not associated with right or left
      hippocampal volumes in either left or right ATL females, although the right
      hippocampus was positively associated with memory performance for left ATL males.
      Hippocampal volumes were not associated with postoperative LM savings scores for
      any group. Results suggest that prose recall was only modestly influenced by
      gender and that bilateral hippocampal support for prose recall was not present in
      our female patients.

PMID- 12609142
TI  - Parkinsonism and Epilepsy: Case Report and Reappraisal of an Old Question.
AB  - Since Yakovlev's contribution in 1928, very few cases with parkinsonism and
      epilepsy have been reported in the literature. While antagonism has been claimed
      between the two conditions, little is hypothesized about the pathophysiological
      mechanisms involved. We report the case of a patient with both temporal lobe
      epilepsy and Parkinson's disease, who presented with a dramatic decrease in
      seizure frequency when the parkinsonian signs developed and disappearance of
      motor fluctuations following recurrence of seizures. On the basis of recent
      knowledge regarding both pathologies we propose new insights into this old
      question.

PMID- 12609143
TI  - To the Editor.

PMID- 12609144
TI  - Temporal Lobectomy and Dreams: An Insight into the Mechanism of Inhibition?. To
      the Editor.

PMID- 12609145
TI  - To the Editor.

PMID- 12609147
TI  - Epilepsy of the borderlands: seizure disorders in u.s. Latinos.

PMID- 12609146
TI  - Epilepsy and violence: when is the brain to blame?

PMID- 12609148
TI  - Side effect profiles and behavioral consequences of antiepileptic medications.
AB  - In 1991, Dodrill carefully reviewed the behavioral effects of antiepileptic drugs
      (AEDs) and concluded: "The area of behavioral effects of antiepileptic drugs is
      poorly defined, lacks recognized and validated methods of assessment, and has
      suffered from a number of methodological limitations, especially including the
      use of experimental designs which have led to the contamination of drug effects
      and subject effects" (1). He further observed that the best controlled study
      showed that the behavioral effects of AEDs were quite limited; the
      benzodiazepines had the most consistently favorable effect, but were of limited
      utility in epilepsy, because they were not typically administered on a long-term
      basis; carbamazepine was associated with a favorable behavior change, but this
      change was seen most consistently in nonepileptic subjects; relatively few
      studies of valproic acid had been conducted; phenytoin was not associated with
      either a consistently positive or consistently negative change; and the
      barbiturates were clearly associated with the most negative behavior change.
      Since Dodrill's review, eight new AEDs have been approved by the Food and Drug
      Administration (FDA) for use in the United States, thereby dramatically
      increasing the therapeutic options for patients with epilepsy. These new drugs
      also increase the complexity of choosing the ideal drug for any given patient.
      Certainly a critical component of the decision to initiate or continue a specific
      treatment is the side effect profile of the medication. In clinical practice,
      behavioral and cognitive side effects of the older AEDs are significant concerns.
      This paper reviews the clinically important behavioral and cognitive side effects
      of the more commonly used, established AEDs as well as the newer AEDs within the
      limits of currently available published peer-reviewed literature and clinical
      experience. Particular emphasis is given to subpopulations at risk.

PMID- 12609149
TI  - Aggression and violence in patients with epilepsy.
AB  - Violence has been associated with epilepsy. However, the links between violent
      behaviors and epilepsy involve multiple factors. These range from behaviors
      associated with underlying brain dysfunction to postictal delirious and psychotic
      states and rare cases of ictal aggression. This review describes the differential
      diagnosis of violent acts in epilepsy and the features that can be used to
      evaluate these behaviors.

PMID- 12609150
TI  - Epilepsy in our world: an ethnographic view.
AB  - This paper describes how epilepsy is viewed according to biomedicine and the
      scientific literature and argues that the subjective experience of people dealing
      with illness is often overlooked by focusing solely on this approach. A review of
      the pertinent literature from a social science perspective, mainly anthropology
      and sociology, illustrates the richness of the lived experience of epilepsy that
      can be uncovered by using ethnographic and other qualitative methods, including
      narrative studies, in the interest of informing medical practice and leading to a
      better understanding and treatment of people with this disorder.

PMID- 12609151
TI  - The effect of alcohol on convulsions and nitric oxide levels in seizure
      susceptible el mice.
AB  - To evaluate the influences of ethanol intake on convulsive seizures and brain
      nitric oxide (NO) production, EL mice, a strain highly susceptible to seizures,
      were given a 10% ethanol solution ad libitum. In mice consuming ethanol for 4, 8,
      and 12 weeks, seizures were not suppressed by zonisamide (75 mg/kg ip). Brain NO
      metabolite levels in mice after 12 weeks of consumption were significantly lower
      than those in control mice and those consuming ethanol for 4 weeks. Numbers of
      NADPH diaphorase-positive neurons in the hippocampal formation and parietal
      cortex of mice consuming for 4 and 12 weeks were significantly higher than in
      controls. These results suggested that increasing of numbers of NADPH diaphorase
      positive neurons in the hippocampal formation and parietal cortex were assumed to
      develop in compensation for reduction in whole-brain NO metabolite levels of EL
      mice exposed to ethanol.

PMID- 12609152
TI  - Comorbid psychiatric symptoms in temporal lobe epilepsy: association with
      chronicity of epilepsy and impact on quality of life.
AB  - Purpose. The goals of this work were to determine: (1) the nature and extent of
      differences in self-reported psychiatric symptoms between patients with temporal
      lobe epilepsy and matched healthy controls, (2) the relationship between
      chronicity (duration) of temporal lobe epilepsy and comorbid interictal
      psychiatric symptoms, and (3) the impact of comorbid psychiatric symptoms on self
      reported health-related quality of life. Methods. Patients with temporal lobe
      epilepsy (n = 54) and healthy controls (n = 38) were administered the Symptom
      Checklist-90-Revised (SCL-90-R) to assess the nature and severity of psychiatric
      symptomatology and epilepsy patients completed the Quality of Life in Epilepsy-89
      (QOLIE-89) to define health-related quality of life. Among epilepsy patients the
      SCL-90-R scales were examined in relation to chronicity of temporal lobe epilepsy
      as well as the impact of comorbid emotional-behavioral distress on health-related
      quality of life. Results. Compared with healthy controls, patients with epilepsy
      exhibited significantly higher (worse) scores across all but one of the 12 SCL-90
      R scales. Among patients with epilepsy, increasing chronicity was associated with
      significantly higher (worse) scores across all SCL-90-R scales and increased
      emotional-behavioral distress was associated with lower (worse) scores across all
      17 QOLIE-89 scales. Conclusion. Comorbid interictal psychiatric symptoms are
      elevated among patients with temporal lobe epilepsy compared with healthy
      controls and appear to be modestly associated with increasing chronicity
      (duration) of epilepsy. This comorbid emotional-behavioral distress is
      specifically associated with a significantly poorer health-related quality of
      life, and suggests that quality-of-life research should devote greater attention
      to the potential impact of comorbid psychiatric distress.

PMID- 12609153
TI  - Late-onset congenital adrenal hyperplasia: presentation as nonepileptic seizures.
AB  - This is a report of a woman with refractory nonepileptic seizures, anxiety
      disorder, and rapidly cycling mood changes in whom high levels of excitatory
      neuroactive steroids due to late-onset congenital adrenal hyperplasia origin may
      have played a role in pathogenesis and in whom endocrine treatment was the only
      efficacious therapeutic modality.

PMID- 12609154
TI  - Re: impact of taking antiepileptic drugs at school in a group of children and
      adolescents to the editor.

PMID- 12609155
TI  - Reply.

PMID- 12609156
TI  - Re: gender, memory, and hippocampal volumes: relationships in temporal lobe
      epilepsy to the editor.

PMID- 12609157
TI  - Reply.

PMID- 12609159
TI  - Reply.

PMID- 12609158
TI  - Re: parkinsonism and epilepsy: case report and reappraisal of an old question to
      the editor.

PMID- 12609160
TI  - Achieving best care for women with epilepsy.

PMID- 12609162
TI  - Psychoses in epilepsy: a review of Japanese studies.

PMID- 12609161
TI  - Presentation, evaluation, and treatment of nonconvulsive status epilepticus.
AB  - Nonconvulsive status epilepticus (NCSE) is much more common than is generally
      appreciated. It is certainly underdiagnosed, but its presentation is protean.
      Diagnostic criteria and treatment are controversial. Absence status is
      characterized by confusion or diminished responsiveness, with occasional blinking
      or twitching, lasting hours to days, with generalized spike and slow wave
      discharges on the EEG. Complex partial status consists of prolonged or repetitive
      complex partial seizures (with a presumed focal onset) and produces an "epileptic
      twilight state" with fluctuating lack of responsiveness or confusion. There is a
      clear overlapping of syndromes. Other confused, stuporous, or comatose patients
      with rapid, rhythmic, epileptiform discharges on the EEG may have
      "electrographic" status and should be considered in the same diagnostic category.
      NCSE typically occurs following supposedly controlled convulsions or other
      seizures, but with persistent neurologic dysfunction despite apparently adequate
      treatment. Confusion in the elderly or among emergency room patients is also a
      typical setting. The diagnosis of NCSE usually involves an abnormal mental status
      with diminished responsiveness, a supportive EEG, and often a response to
      anticonvulsant medication. All patients have clinical neurologic deficits, but
      the EEG findings and response to seizure medication are variable and are more
      controversial criteria. The response to drugs can be delayed for up to days.
      Experimental models and pathologic studies showing neuronal damage from status
      epilepticus pertain primarily to generalized convulsive status. Most morbidity
      from NCSE appears due to the underlying illness rather than to the NCSE itself.
      Some cases of prolonged NCSE or those with concomitant systemic illness, focal
      lesions, or very rapid epileptiform discharges may suffer more long-lasting
      damage. Although clinical studies show little evidence of permanent neurologic
      injury, the prolonged memory dysfunction in several cases and the similarities to
      convulsive status suggest that NCSE should be treated expeditiously. The
      diagnosis is important to make because NCSE impairs the patient's health
      significantly, and it is often a treatable and completely reversible condition.

PMID- 12609163
TI  - Predictors of Patient Inability to Cooperate during Intraoperative Language
      Mapping.
AB  - We examined the demographic, seizure history, personality, and intellectual
      variables in seizure surgery patients who underwent intraoperative language
      mapping to identify variables that may help predict inability to cooperate with
      intraoperative mapping. Of 26 patients who had intraoperative language testing
      during left hemisphere lobectomy, 9 were unable to cooperate with language
      mapping procedures. Mapping "failure" consisted of an inability to conform to
      task demands due to anxiety, inattention, immaturity, or confusion that
      necessitated changing from local to general endotracheal anesthesia. Patients who
      were unable to cooperate with intraoperative mapping had significantly lower IQs,
      lower educational attainment, and higher Depression scale scores on the Minnesota
      Multiphasic Personality Inventory (MMPI) relative to cooperative patients. There
      were no statistically significant differences between groups with respect to age,
      handedness, sex, age of onset of habitual seizures, seizure type, site of seizure
      focus, presence of a lesion, or previous psychiatric history.

PMID- 12609164
TI  - Absence of negative impact of levetiracetam on cognitive function and memory in
      normal and amygdala-kindled rats.
AB  - The effect of the new antiepileptic drug (AED) levetiracetam (LEV, Keppra) on
      cognitive function was studied in normal and amygdala-kindled rats by using the
      Morris water maze test. In addition, we investigated the effect of LEV on long
      term potentiation (LTP) in rat hippocampal slices. Sodium valproate (VPA) was
      used as comparator in all studies. Clonazepam (CZP) and carbamazepine (CBZ) were
      used in normal rats. The results indicated that doses of LEV known to suppress
      motor seizures did not alter cognitive performance. In contrast, similar doses of
      the classic AEDs all decreased learning performance of the rats. Likewise, VPA
      did alter LTP but LEV was inactive. Amygdala-kindled rats were more sensitive
      than normal rats to the effects of VPA. These results suggest that LEV may be
      devoid of negative impact on cognition in epileptic patients.

PMID- 12609165
TI  - Proposal for a new five-axis classification scheme for psychoses of epilepsy.
AB  - Based on an overview of the literature and a multicenter study in Japan, we
      propose a new five-axis classification scheme for psychoses of epilepsy: (1)
      epilepsy variables, (2) psychopathology variables, (3) ictus/EEG variables, (4)
      precipitating factors of psychoses, (5) organic background. A total of 128
      patients, 63 males and 65 females, with epilepsy and psychoses were recruited
      from five treatment centers. A wide heterogeneity of psychoses of epilepsy was
      demonstrated and categorization by a single axis was shown to be inadequate.
      Cluster analysis revealed four subgroups characterized by their psychopathology,
      temporal relationship to seizure occurrence, and EEG changes during psychoses. By
      comparing with the control epileptic group without psychoses, higher rates of
      mild intelligence disturbance and abnormal findings by brain imaging were proven
      among the psychotic group. The scheme involves a dimensional representation of
      individual patients to capture the complexity of their clinical background and to
      relay clinical information accurately and systematically. It is believed to hold
      direct therapeutic implications and to contribute to promoting research by
      enabling accumulation of a large number of patients on a multicenter basis.

PMID- 12609166
TI  - Characterization and health risk assessment of postmenopausal women with
      epilepsy.
AB  - Postmenopausal women with epilepsy represent an understudied patient population.
      The objectives of this cross-sectional study were to characterize the impact of
      menopause on seizure activity and to conduct a health risk assessment. We
      conducted telephone interviews of 40 postmenopausal women with epilepsy
      concerning the effect of menopause on seizure frequency. We surveyed use of
      hormone replacement therapy, postmenopausal bone fractures, use of vitamins, and
      frequency of exercise. The average age and mean seizure duration were 55.8 and
      27.6 years, respectively. Twenty-six women had onset of seizure activity before
      menopause. Of these 26, 3 reported fewer seizures after menopause, 7 reported
      more seizures, 11 reported no change, and 5 were unsure whether menopause
      affected their seizures. Only 30% of the 40 women were currently taking hormone
      replacement therapy. The impact of menopause on seizure activity was variable.
      Osteoporotic and cardiovascular preventive measures are underutilized. Patient
      education on these protective measures should be part of the comprehensive
      treatment approach in this "at-risk" patient population.

PMID- 12609168
TI  - Congenital adrenal hyperplasia presenting as nonepileptic seizures.

PMID- 12609167
TI  - Electrical cortical stimulation of the human prefrontal cortex evokes complex
      visual hallucinations.
AB  - Complex visual hallucinations are a well-known feature of electrical stimulation
      or epileptic discharge in the temporal lobe. It has been proposed that these
      visual hallucinations result from an electrical interference with the ventral
      visual processing stream in the lateral temporal lobe and the memory system in
      medial temporal structures, which explains their frequent visual and mnestic
      features. Even though recent studies have demonstrated visual and memory
      functions in the prefrontal cortex, up to now epileptic discharge or electrical
      stimulation of prefrontal structures has only rarely been reported to induce
      visual phenomena. We report on two patients undergoing invasive presurgical
      epilepsy evaluation in which electrical cortical stimulation of the left
      prefrontal cortex repeatedly induced complex visual hallucinations.
      Interestingly, the induced visual responses differed with respect to their
      spatial organization: whereas those evoked on the inferior frontal gyrus were
      perceived in the whole visual field, complex visual responses on the middle
      frontal gyrus were restricted to the contralateral hemispace. Based on the
      spatial organization of the visual experiences in our patients, animal work, and
      neuroimaging data it might be suggested that specific subregions of the human
      prefrontal cortex might contain separate visual and mnemonic processing
      mechanisms.

PMID- 12609169
TI  - Epilepsy and anxiety.

PMID- 12609170
TI  - Reply.

PMID- 12609171
TI  - Aggression and violence in patients with epilepsy.

PMID- 12609173
TI  - Message from the Editor.

PMID- 12609172
TI  - Reply.

PMID- 12609175
TI  - On Being Seizure-Free.

PMID- 12609174
TI  - Epilepsy and Insurance.

PMID- 12609176
TI  - The Behavioral Aspects of Epilepsy: An Overview of Controversial Issues.
AB  - The field of epilepsy and behavior is rich with controversial issues. In
      anticipation of an upcoming new feature of Epilepsy & Behavior called
      Controversial Issues in Epilepsy and Behavior, several highly debated issues are
      reviewed in this article. These include whether epilepsy is a neuropsychiatric
      disorder, the relationship between epilepsy and depression and the possible
      "bidirectional" interaction between the two disorders, and the differences in
      clinical expression of depression and psychotic disorders in epileptic and
      nonepileptic patients and the associated implications with respect to diagnosis
      and treatment. In addition, forced normalization and the very limited involvement
      of psychiatrists in the evaluation and management of patients with epilepsy are
      discussed.

PMID- 12609177
TI  - Predictors of Intelligence after Temporal Lobectomy in Children with Epilepsy.
AB  - Performance on standardized measures of intelligence was examined before and
      after temporal lobectomy in 50 children and adolescents. Group results showed
      small positive changes in Performance IQ (PIQ), but not Verbal IQ (VIQ). Analyses
      of individual patients showed that 28% had a significant change in VIQ after
      surgery, half of whom showed improvements. Increases in VIQ were associated with
      older age at time of surgery, lower VIQ before surgery, and positive seizure
      outcome after surgery, whereas longer follow-up time was predictive of smaller
      change. Increases in PIQ were seen in 25% of patients, and decreases occurred in
      8%. Predictors of postoperative change in PIQ were dual pathology and longer
      follow-up interval, both of which showed negative correlations. Enhanced
      intellectual function is not one of the benefits to be expected in the majority
      of children undergoing temporal lobectomy. Further studies are required to
      determine whether these conclusions may or may not be applied to other aspects of
      cognitive function.

PMID- 12609178
TI  - Verbal Memory in Newly Diagnosed Patients and Patients with Chronic Left Temporal
      Lobe Epilepsy.
AB  - The objective of this study was to evaluate verbal memory in newly diagnosed and
      chronic left temporal lobe epilepsy (LTLE). Verbal memory performance of 39 newly
      diagnosed, previously untreated adult patients with LTLE and 16 patients with
      chronic LTLE, as well as 46 healthy controls, was analyzed. The patients with
      newly diagnosed and chronic LTLE had impaired verbal memory performance compared
      with normal controls. Memory performance was more affected in chronic LTLE.
      However, preliminary data from 5-year follow-up of 20 newly diagnosed LTLE
      patients did not show any deterioration in verbal memory performance. The memory
      impairment was not associated with the etiology of epilepsy or the hippocampal
      volumes, but was associated with early onset of epilepsy in LTLE and with
      secondarily generalized seizure type in newly diagnosed LTLE. The results of this
      study show that verbal memory is impaired not only in chronic LTLE but also in
      newly diagnosed, untreated LTLE. This suggests that the memory problems observed
      in patients with chronic LTLE cannot be attributed solely to medication effects
      or the chronic effects of recurrent seizures.

PMID- 12609179
TI  - Lamotrigine Monotherapy Improves Depressive Symptoms in Epilepsy: A Double-Blind
      Comparison with Valproate.
AB  - Depressive symptoms are highly prevalent in patients with epilepsy. The
      antiepileptic drug lamotrigine has been shown to be an effective treatment for
      the depressive phase of bipolar disorder and to enhance mood and well-being in
      epilepsy patients. The effects of lamotrigine monotherapy on depressive symptoms
      in epilepsy have not been evaluated to date in a controlled clinical trial. A
      recently completed double-blind epilepsy trial comparing the effects of
      lamotrigine monotherapy and valproate monotherapy on weight change incorporated a
      battery of standard mood assessments. Mean screening Beck Depression Inventory
      scores showed that both lamotrigine and valproate groups suffered from mild
      depression at baseline. Lamotrigine monotherapy was reliably associated with
      earlier and larger improvements than valproate in mood assessed with the Beck
      Depression Inventory, the Cornell Dysthymia Rating Scale, and the Profile of Mood
      States. Considered in the context of other data showing lamotrigine's
      antidepressant efficacy in bipolar depression, these results suggest that
      lamotrigine improves mood in mildly depressed patients with epilepsy. Lamotrigine
      may be particularly useful in treating epilepsy patients with comorbid
      depression, the most common psychiatric illness in epilepsy.

PMID- 12609180
TI  - Single and Dual Pathologies of the Temporal Lobe: Effects on Cognitive Function
      in Children with Epilepsy.
AB  - The neuropathologies associated with temporal lobe epilepsy (TLE) are
      heterogeneous. The performance of 61 children with single pathology of
      hippocampal sclerosis (HS), temporal lobe tumor, or cortical dysplasia (CD) or
      dual pathology of HS + tumor or HS + CD was examined on measures of intelligence,
      language, memory, and executive function. Children with single pathologies
      performed significantly better than did children with HS + CD on all standardized
      measures of IQ. Children with tumors performed significantly better than children
      with dual pathology on receptive vocabulary. These results support prior research
      of an association between neuropathology and cognitive function in children with
      epilepsy and extend the findings to include additional neuropathologies and
      measures of cognitive functioning.

PMID- 12609181
TI  - Effects of Vagal Nerve Stimulation on Cognition and Quality of Life in Epilepsy.
AB  - To evaluate the cognitive and quality-of-life (QOL) impacts of vagal nerve
      stimulation (VNS), 160 patients with uncontrolled partial seizures from 20 sites
      were enrolled in a double-blind study. Patients were randomly assigned to low
      (minimal) stimulation (n = 82) or high (now clinically used) stimulation (n = 78)
      conditions and given a group of cognitive and QOL tests before implantation and
      after 12-16 weeks of VNS treatment. Results showed no clear cognitive changes.
      However, fewer emotional and physical problems were reported by the High Group
      than the Low Group at the end of the study. The 32 patients who had at least 50%
      seizure relief showed slightly more improvement in QOL variables than those
      patients who did not demonstrate this degree of seizure reduction. Overall, a
      small number of favorable QOL but no cognitive changes were associated with
      levels of VNS stimulation that are now typically used clinically.

PMID- 12609182
TI  - Frontal Localization of Absence Seizures Demonstrated by Ictal Positron Emission
      Tomography.
AB  - Generalized absence seizures are rarely reported to originate from one frontal
      lobe. We report an 8-year-old girl with atypical absence seizures demonstrated to
      be of right frontal origin by ictal positron emission tomography (PET). She had a
      congenital left hemiparesis and intractable seizures since age 3, and was
      referred for epilepsy surgery. During electroencephalography-video monitoring
      numerous episodes of atypical absence seizures were recorded in association with
      generalized 3- to 3.3-Hz spike-and-wave discharges by EEG. PET was performed with
      simultaneous EEG recording. Six typical seizures occurred during the
      fluorodeoxyglucose (FDG) uptake period. The PET scan demonstrated marked
      increased FDG uptake in right frontal region. Partial seizures of frontal lobe
      origin can manifest themselves as atypical absence seizures, with generalization
      based on secondary bilateral synchrony. In patients with frequent seizures the
      frontal seizure origin may be demonstrated noninvasively with functional imaging
      using PET or single-photon emission computed tomography.

PMID- 12609183
TI  - "Ictal" Alien Hand Syndrome.
AB  - The alien hand syndrome is rare, occurring with lesions in the mesial frontal
      lobe area and corpus callosum. We report an unusual presentation of seizures in a
      65-year-old woman with a presumed low-grade glioma involving the mesial frontal
      lobe region, with the "alien hand" seen only during a seizure. Neuropsychological
      evaluation revealed lateralized cognitive dysfunction consistent with the
      location of the lesion. There were no interictal indications of disconnection
      syndrome. The mechanism postulated is disruption of transcallosal motor
      connections due to the propagating seizure across nondominant motor regions.

PMID- 12609184
TI  - Aggression and Violence in Patients with Epilepsy. To the Editor.

PMID- 12609185
TI  - Reply.

PMID- 12609186
TI  - Reply.

PMID- 12609187
TI  - Message from the Editor.

PMID- 12609189
TI  - Is Epilepsy Progressive?

PMID- 12609188
TI  - From the Epilepsy Foundation.

PMID- 12609190
TI  - A Systematic Review of the Effects of Lamotrigine on Cognitive Function and
      Quality of Life.
AB  - Cognitive impairment associated with antiepileptic drug (AED) therapy represents
      a particular problem, especially in the young and elderly. Lamotrigine (LTG) is a
      new-generation AED that is effective and well tolerated in both the elderly and
      children. Existing data suggest that the cognitive deficits commonly associated
      with AED therapy are not commonly observed in patients receiving LTG as
      monotherapy, and, when LTG is used as an add-on therapy, any existing cognitive
      problems are not exacerbated and in some cases are clearly improved. Here we have
      reviewed previous studies that have examined the impact of LTG therapy on
      cognitive functioning. We have considered data from monotherapy and add-on
      clinical studies and also more indirect evidence from volunteer studies and from
      neurophysiological evaluations in epilepsy patients. These data suggest that the
      impact of LTG on cognition is at least equivalent to that of existing standard
      AEDs and, in many cases, the use of LTG is associated with improved cognitive
      functioning, which is not seen with standard AEDs. We have also considered the
      wider implications of patient quality of life, accepting that cognitive function
      may form an integral part of the patient's perceived quality of life.

PMID- 12609191
TI  - Drug Interactions between Psychoactive Agents and Antiepileptic Agents.

PMID- 12609192
TI  - Psychometric Properties of the German Translation of the QOLIE-31.
AB  - The purpose of this work was to assess the psychometric properties of the German
      Translation of the Quality of Life in Epilepsy Inventory, QOLIE-31. Internal
      consistency, construct and criterion validity, and responsiveness were tested in
      509 patients with epilepsy who were administered the questionnaires at
      application or at admittance to the epilepsy center Bethel. Construct validity
      was tested in patients with different seizure frequencies and different degrees
      of tolerability of antiepileptic drug (AED) therapy (adverse effects). The scales
      Epilepsy-Related Fears und Restrictions in Daily Life due to Epilepsy were used
      as criterion measures. Test-retest reliability (long-term stability) and
      responsiveness of the questionnaire were analyzed in subgroups of patients who
      responded to the questionnaires a second time (n = 256). Cronbach's alpha of the
      QOLIE-31 was 0.94 and varied between 0.76 and 0.90 for the seven subscales. The
      correlations of the QOLIE with Epilepsy-Related Fears and Restrictions in Daily
      Life revealed high correlations between Epilepsy-Related Fears and the QOLIE
      subscale Seizure Worry (r = 0.81, P < 0.01) and the total score (r = 0.62, P <
      0.01) and between Restrictions in Daily Life and the QOLIE subscale Social
      Functioning (r = 0.71) and the total score (r = 0.70, P < 0.01). Seizure
      frequency had a significant effect especially on the QOLIE subscales Social
      Functioning, Seizure Worry, and Overall QOL, whereas tolerability of AED therapy
      affected especially the subscales Medication Effects, Overall QOL, and Energy
      Fatigue. The test-retest reliability (intraclass correlation coefficient) was
      0.79 for the overall score and varied between 0.59 and 0.78 for the seven
      subscales. The German Translation of QOLIE-31 is a reliable and valid
      questionnaire with which to assess QOL in patients with epilepsy and is
      conceptually similar to the English version. It is a sensitive questionnaire with
      respect to seizure frequency and tolerability of antiepileptic drug treatment.

PMID- 12609193
TI  - The Electroencephalogram in Children with Developmental Dysphasia.
AB  - Speech and language delay is a common developmental or acquired disorder. It can
      be a feature of the autistic spectrum, and if regression of language coincides
      with epilepsy, the diagnosis of Landau-Kleffner syndrome is considered. Slow
      acquisition of language without regression is called developmental dysphasia. A
      retrospective review of clinical and electroencephalographic (including video
      electroencephalographic) data on 138 children with speech/language delay, seen in
      a year's time, is presented. The electroencephalogram (EEG) was abnormal in 61%
      of children with a history of language regression. The EEG was abnormal in only
      15% of children with developmental language disorder, most of whom also had
      clinical seizures. The difference between the two groups was highly significant
      (P = 0.004). Therefore obtaining an EEG in children with regression of language,
      especially if a history of clinical seizures is elicited, is indicated.

PMID- 12609194
TI  - Current Management of Epilepsy and Pregnancy: Fetal Outcome, Congenital
      Malformations, and Developmental Delay.
AB  - Purpose. Women with epilepsy (WWE) reportedly have increased rates of pregnancy
      complications and poor fetal outcomes related to both their epilepsy and
      antiepileptic drugs (AEDs). These results influence decisions about conceiving.
      Most published studies evaluate WWE treated before 1990. We sought to better
      define risks to pregnant WWE at a tertiary care center, which used current
      epilepsy guidelines.Methods. We retrospectively analyzed 100 consecutive
      pregnancies in WWE from 1990 to 2000. Maternal data: epilepsy syndrome, duration,
      AEDs used, seizure occurrence and frequency, delivery type and complications.
      Fetal outcomes: fetal birth weight (FBW), gestational age, incidence of
      prematurity, major and minor congenital malformations, developmental
      delay.Results. Maternal factors: 37% generalized and 63% partial epilepsies, 59%
      seizure-free throughout pregnancy, 30% increased and 22% decreased seizure
      frequency, 90% used AEDs, 21% required polytherapy, 98% took folate, and 48% with
      gestational seizures delivered by cesarean section, compared with 18% without
      seizures (P < 0.01). Fetal outcome: Mean FBW and gestational ages similar
      regardless of AED usage or exposure to maternal seizures, 3.9% prematurity, no
      cases of still birth or neonatal hemorrhagic disorder, 1.1% of children exposed
      to AEDs had major congenital malformations, and 6.2% of offspring had pervasive
      developmental delay (PDD).Conclusions. All fetal outcomes were similar to
      outcomes for the general population, with the exception of higher rates of PDD
      and cesarean section. In our small sample of WWE treated with current epilepsy
      management, the majority had excellent outcomes. Future large studies must
      confirm this.

PMID- 12609195
TI  - Measurement of Depression in Epilepsy.
AB  - The current study was designed to evaluate the accuracy of the Minnesota
      Multiphasic Personality Inventory-2 (MMPI-2) and the Beck Depression Inventory
      (BDI) in determining the presence of depression in epileptic patients. A
      psychiatric diagnostic interview was used as an external criterion for the
      presence of depression. The participants were 61 patients undergoing presurgical
      evaluation for treatment of epilepsy at the epilepsy treatment center of a
      research medical center. The results of the present study indicate that the
      accuracy of assessment of depression in epilepsy with psychological tests varies
      with the depression scale or subscale used. The BDI performed in general more
      effectively as a diagnostic instrument than the MMPI-2. The results suggest that
      the latter test was negatively impacted by somatic content present in some scales
      and subscales.

PMID- 12609196
TI  - Vagus Nerve Stimulation in the Developmentally Disabled.
AB  - Vagus nerve stimulation (VNS) with the neuro cybernetic prosthesis (NCP) is an
      approved treatment of partial seizures for patients 12 years and older.
      Developmentally disabled or mentally retarded patients with epilepsy may also
      benefit from VNS; however, their evaluation and management pose greater problems.
      A retrospective chart review was conducted on all patients diagnosed with mild to
      severe mental retardation who had an NCP implanted. Records of these 21 patients,
      ranging in age from 3 to 56 years, were reviewed regarding VNS efficacy, side
      effects, behavioral changes, and alterations in antiepileptic drugs (AEDs).
      Seizure types included partial onset and generalized. Sixteen patients had
      clearly evaluable seizures both pre- and postimplant, with a greater than 50%
      reduction in seizures noted in 68% (11/16) after 6 months of implant. There were
      no adverse events that prevented chronic stimulation. Institutional staff and
      family members were provided with both pre- and postoperative education on VNS
      and magnet use. VNS appeared to be an effective and well-tolerated therapy in
      this group of developmentally disabled patients with refractory epilepsy.

PMID- 12609197
TI  - Psychosocial and Neurobehavioral Factors Related to Surgical Treatment for
      Partial Epilepsy: A Multivariate Analysis.
AB  - Studies of temporal lobe surgery rarely include anatomical and neurobehavioral
      data in the analysis of outcome. We carried out a retrospective study on 50
      patients, using clinical data from case notes, resection volumes, and
      preoperative imaging data. Three main conclusions emerge from this study: (1)
      Psychosocial outcome is related to postoperative seizure control. (2) Late
      postoperative aggression and clinical depression are associated with bad
      psychosocial outcome. (3) Right-sided hippocampal sclerosis, as suggested by
      measurements with T2 relaxometry, correlates with interictal psychopathology, as
      measured with the Beck Depression Inventory, the Leyton Obsessional Inventory,
      and the Bear-Fedio personality inventory.

PMID- 12609198
TI  - Neuropsychological Outcome and the Extent of Resection in the Unilateral Temporal
      Lobectomy.
AB  - Thirty-eight patients who had undergone either a right (RTL, n = 19) or left
      (RTL, n = 19) en bloc unilateral temporal lobectomy were scanned using magnetic
      resonance imaging, and the extent of removal of the superior lateral (SL),
      inferolateral (IL), basal, parahippocampal, and hippocampal regions was rated
      using semiautomated analysis. Brain regional ratings were correlated against pre-
      versus postoperative changes in memory functioning. The results showed overall
      significant postoperative decline in verbal memory only in the LTL group. Despite
      this, in the RTL group basal and hippocampal region removal was correlated with
      visuospatial memory outcome. In the LTL group, IL and basal region removal was
      correlated with Performance Intelligence outcome. In each case, more resection
      was associated with worse functioning and vice versa. It was concluded that
      variability in neuropsychological outcome can be explained in part by variations
      in the extent of tissue removal within the en bloc operation.

PMID- 12609199
TI  - Assessment of Seizure Severity with Adjunctive Lamotrigine Therapy: Results from
      a U.S. Observational Study.
AB  - THE ADJUNCTIVE LAMICTAL (LAMOTRIGINE) IN EPILEPSY: Response to Treatment (ALERT)
      study was an observational study designed to assess the safety of lamotrigine in
      patients with refractory partial seizures when used in a general practice
      setting. We measured the impact of adjunctive lamotrigine therapy for 16 weeks on
      the severity of seizures using the Liverpool Seizure Severity Scale (LSSS). This
      questionnaire was scored using a revised scoring procedure that assesses the
      impact of treatment on the patients "most severe seizure." Data from the LSSS
      were also compared with physician-rated changes of seizure severity. Patients who
      completed 16 weeks of lamotrigine treatment showed a significant reduction in
      LSSS scores when compared with patients who discontinued lamotrigine (change
      scores: patient's taking lamotrigine at Week 16, 9.2 +/- 23.4; patients who
      discontinued lamotrigine by Week 16, 0.8 +/- 23.4, P < 0.05). These findings were
      supported by significant reductions in physician ratings of seizure severity in
      patients who completed 16 weeks of lamotrigine therapy. Seizure severity is an
      important outcome in the study of antiepileptic medication. Data from this
      observational study suggest that lamotrigine is effective in reducing seizure
      severity when used as an adjunctive therapy in patients with refractory partial
      seizures.

PMID- 12609200
TI  - The Case for Different Severity of Burns in "Contagious" versus "Possession"
      Seizures.
AB  - Serious seizure-related burns are reportedly common in cultures that use ground
      fire for cooking, heating, or ceremonial purposes. The seriousness of injuries in
      these cases has been ascribed to the reluctance of bystanders to assist
      individuals having a seizure either because of fear of contagion (Africa, New
      Guinea highlands) or because of fear of revenge by the occult (Haiti). We report
      four Haitian patients who fell into open fires during an epileptic seizure in
      religious gatherings. Patients were almost immediately rescued from the fire. In
      contrast to the African and New Guinean patients where upper body involvement was
      common, burns in these four patients were of moderate severity and involved
      primarily the lower body. The fear of contagion and belief in magic are
      interesting notions, but do not explain the different severity and distribution
      of injuries in these patients. A more likely explanation is that seizures in the
      African and New Guinean patients occurred while the patient and family were
      asleep, which probably delayed the rescue, whereas the Haitian patients were
      helped within moments of falling into the fire in their seizure. The position of
      the patient at the onset of the seizure is probably what determined the primary
      areas of thermal injury, and the time to rescue determined their severity and
      extension.

PMID- 12609201
TI  - Effects of Vagal Nerve Stimulation on Cognition and Quality of Life. To the
      Editor.

PMID- 12609202
TI  - Reply.

PMID- 12609203
TI  - Can we treat cognitive deficits in patients with epilepsy?

PMID- 12609204
TI  - From the epilepsy foundation.

PMID- 12609205
TI  - The etiology and diagnosis of status epilepticus.
AB  - Status epilepticus (SE) is a common, serious, potentially life-threatening,
      neurologic emergency characterized by prolonged seizure activity. Generalized
      convulsive status epilepticus (GCSE) is the most widely recognized form of SE.
      Direct consequences of convulsive movements from SE can result in injury to the
      body and brain. Nonconvulsive status epilepticus (NCSE) is underrecognized, with
      controversy surrounding the consequences and treatment. High mortality rates with
      GCSE have been noted in the past. New treatments for SE are emerging with new
      parenteral drug formulations as well as new agents for refractory SE, offering an
      opportunity to improve outcome. Special drug delivery systems, drug combinations,
      and neuroprotective agents that prevent the subsequent development of epilepsy
      may soon emerge as future options for treating SE.

PMID- 12609206
TI  - Stem cell grafting for epilepsy: clinical promise and ethical concerns.
AB  - The recent explosion of research on stem cells and neural grafting holds great
      promise for many neurological conditions, including epilepsy. Potential roles for
      cell grafting in epilepsy include remodeling of dysfunctional neuronal circuits
      and local delivery of neuromodulatory or neuroprotective factors. While many
      basic questions remain to be answered, initial human trials are underway in
      epilepsy as well as Parkinson's disease, Alzheimer's disease, stroke, and other
      conditions. It is not too early to begin ethical reflection on this dynamic
      field. Donor cells are often derived from human embryos, raising scarcity
      concerns as well as opposition from anti-abortion forces. Alternative donor
      sources are being actively developed. Safety concerns, adequate consent, and
      equitable access to care will also become important issues. Ethical issues most
      unique to neural grafting will revolve around redefining self-identity when
      personality and cognition may be altered by therapy. Views of selfhood and of
      being human have evolved in a historically contingent process, so that neural
      grafting and other consequences of the genetic revolution fall within a series of
      reductionist scientific developments that lead to an increasing instrumentation
      of our self-image. Neuroscientists and clinicians must interact with other
      cultural, religious, and academic groups to promote mutual understanding and
      richer, but scientifically accurate, views of what it means to be human. A good
      starting point may come by telling patients' stories, connecting scientific
      knowledge with the density of lived experience.

PMID- 12609207
TI  - Inpatient monotherapy studies in epilepsy: con.

PMID- 12609208
TI  - Inpatient monotherapy studies in epilepsy: pro.

PMID- 12609209
TI  - A pilot study of donepezil for memory problems in epilepsy.
AB  - We performed a pilot 3-month, open-label study of 5-10 mg donepezil, an
      anticholinesterase inhibitor, as treatment for memory problems in people with
      epilepsy. The Buschke Selective Reminding Test was administered at baseline and
      after 3 months of donepezil. In 18 completing patients, the total number of words
      recalled across learning trials was greater on donepezil (P = 0.4). No change was
      noted in attention, visual sequencing, mental flexibility, psychomotor speed, or
      reported quality-of-life scores. Mean 3-month seizure frequency at baseline was
      2.70 +/- 4.60, and during treatment, 3.06 +/- 4.52 (P = 0.19, not significant).
      Two patients experienced increased tonic-clonic seizures. Side effects included
      diarrhea, stomach cramps, insomnia, depression, and blurred vision. Cholinergic
      medication is worthy of investigation as treatment for memory problems in people
      with epilepsy, but attention must be paid to possible exacerbation of seizures.

PMID- 12609210
TI  - Self-Reported Mood Changes following 6 Months of Vagus Nerve Stimulation in
      Epilepsy Patients.
AB  - Vagus nerve stimulation (VNS) for treatment of drug-resistant epileptic seizures
      has been reported to have additional positive mood effects as obtained by
      psychiatric ratings. To avoid rater bias effects, this study used self-report
      questionnaires and examined changes in self-reported mood and health-related
      quality of life following 6 months of VNS treatment. From 40 adult patients
      treated with VNS since the beginning of the study, 28 patients (mean age: 35.4
      years) with unchanged medication were included. Repeated-measures MANOVA revealed
      a significant general mood improvement. Post hoc univariate tests obtained
      improvements of tenseness and dysphoria but not of depression, level of activity,
      or health-related quality of life. Mood and seizure outcome were correlated. VNS
      may improve unspecific states of indisposition and dysphoria. Absolute seizure
      reduction contributes to this antidysphoric effect. Since baseline depression
      scores were low, findings do not contradict but complement earlier reports of an
      antidepressive effect of VNS.

PMID- 12609212
TI  - No evidence for cognitive side effects after 6 months of vagus nerve stimulation
      in epilepsy patients.
AB  - Vagus nerve stimulation (VNS) can reduce seizure frequency in epilepsy patients
      and may affect central mechanisms of brain functioning. Experimental studies have
      provided evidence of cognitive alterations during VNS on phases. This single-arm
      follow-up study evaluates the potential of VNS to affect cognitive performance
      following long-term treatment. Thirty-six adult patients with medication
      resistant epilepsies enrolled. Cognition was assessed before and at least 6
      months after implantation of the stimulation device by a comprehensive
      neuropsychological assessment battery comprising tests on attention, motor
      functioning, short-term memory, learning and memory, and executive functions.
      Neither multiple testing of single score changes nor multivariate testing of
      cognitive domains revealed significant pre-post changes. Improvements in
      attentional performance were completely explained by practice effects as is
      usually expected. In particular, no negative side effects were revealed. These
      findings are in line with the clinical impression that VNS does not affect
      cognitive performance.

PMID- 12609211
TI  - Effects of 6 months of treatment with vagus nerve stimulation on behavior in
      children with lennox-gastaut syndrome in an open clinical and nonrandomized
      study.
AB  - The effect of vagus nerve stimulation (VNS) on behavior outcomes was studied in
      16 children with Lennox-Gastaut syndrome. We used the following stimulation
      parameters: output current, 11 2 to 2 mA; signal frequency, 30 Hz; signal pulse
      width, 500 microseconds; signal on and off times, 30 seconds on and 3 minutes
      off. The test battery consisted of cognitive tests measuring mental age,
      attention, language, psychomotor function, and cognitive style, and quality-of
      life measurements assessing independence, behavioral problems, symptoms of
      pervasive development disorders (PDDs) and mood. The results show relatively
      small changes in behavioral outcomes concurrently with modest effects on seizure
      frequency (an average of 26.9% seizure reduction). When baseline and endpoint
      measurements are compared none of the cognitive measures show any deterioration
      and three of five cognitive measures show slight positive changes. Among the
      quality-of-life measures, one measure showed a slight worsening of scores and
      three showed slight improvement. When the group is divided into subgroups on the
      basis of treatment effect the most prominent improvements are observed in the
      group without any effects of VNS on seizure frequency. These patients gained, on
      average, 9.5 months in mental age and showed more independent behavior, mood
      improvements and fewer PDD symptoms. This suggests an effect of VNS on behavioral
      function independent of changes in seizure frequency.

PMID- 12609213
TI  - A solvent used for antiepileptic drugs increases serum and brain zonisamide
      concentrations in seizure-susceptible el mice.
AB  - Effects of a solvent mixture commonly used to dissolve antiepileptic drugs on the
      anticonvulsive effect as well as serum and brain concentrations of zonisamide
      (ZNS), a sulfonamide derivative, were investigated. The solvent mixture consisted
      of propylene glycol (PG, 40%) and ethanol (10.5%) in saline (PES).
      Intraperitoneal administration of ZNS at 25, 50, and 75 mg/kg dissolved in PES
      suppressed seizures in the EL strain of mice more effectively than the same doses
      of ZNS in saline. Serum and brain concentrations of the drug were significantly
      higher with PES than with saline as the vehicle for administration. At a dose of
      75 mg/kg ip, both serum and brain ZNS concentrations in mice treated with ZNS in
      PES remained significantly higher than concentrations in mice treated with ZNS in
      saline from 1 to 6 hours after injection. PES mixtures including PG may not be
      suitable solvents for antiepileptic drugs in experiments investigating
      anticonvulsive effects.

PMID- 12609214
TI  - Postictal psychosis: resolution after electroconvulsive therapy.
AB  - The association between epilepsy and psychosis has generated considerable debate
      since the 19th century. Recently, diagnostic criteria for a distinct type of
      epileptic psychosis, postictal psychosis, have emerged. We present the case of a
      23-year-old woman who was admitted to the hospital with a catatonic-like
      psychosis after a cluster of partial complex seizures. She received a diagnosis
      of postictal psychosis, and fully recovered after electroconvulsive therapy. This
      article once again emphasizes the association between psychosis and epilepsy, a
      matter of great theoretical interest, as it provides a chance for developing an
      organic model for psychosis.

PMID- 12609215
TI  - Transcranial magnetic stimulation evidence of a potential role for progesterone
      in the modulation of premenstrual corticocortical inhibition in a woman with
      catamenial seizure exacerbation.
AB  - A transcranial magnetic stimulation paired-pulse paradigm was used to determine
      that cortical excitability was less during the late luteal phase than in the
      early follicular phase in a woman with epilepsy who had premenstrual seizure
      exacerbation. The data are consistent with the possibility that a reduction in
      GABA-mediated cortical inhibitory activity may be responsible. The administration
      of progesterone, a reproductive steroid with potent GABAergic metabolites, during
      the luteal phase restored cortical excitability to normal range.

PMID- 12609216
TI  - The sacred disease and its patron saint.
AB  - Although the Hippocratic natural theory of epilepsy as a brain disorder
      originated around 400 bc , it did not begin to take root until the 18th and 19th
      centuries, leaving the intervening centuries dominated by mostly supernatural
      concepts. This article provides historical insight into human behavior when
      afflicted with disease: supplication to a patron saint, Saint Valentine, a cult
      that spread throughout Europe.

PMID- 12609217
TI  - What Does ECS Stand for? Repetitive Transcranial Magnetic Stimulation in
      Depression. Volume 2, Number 3, Part 2 (June 1, 2001), pages S21-S29.

PMID- 12609218
TI  - Cognitive and behavioral effects of antiepileptic drugs.

PMID- 12609221
TI  - Adjunctive clinical trials in epilepsy: is a placebo arm necessary?

PMID- 12609220
TI  - From the Epilepsy Foundation.

PMID- 12609222
TI  - Epilepsy and multiple sclerosis.
AB  - A review of 29 published clinical series of adult patients who had epileptic
      seizures and multiple sclerosis (MS) yielded a prevalence of 2.3%, about three to
      six times that in the general adult population. The probable anatomic basis for
      the seizures is areas of inflammation, edema, and/or demyelination in the
      cerebral cortex and the juxtacortical white matter generated by a mechanism that
      is not completely understood; the fact that these plaques are very common
      suggests that other factors must operate in view of the rarity of seizures in MS.
      Seizures have been observed before and presumably marking the clinical onset of
      the disease, and during acute bouts. In some instances convulsions appear to be
      the only manifestations of an attack of MS, but there is no general acceptance of
      seizures as the first and only symptoms of the disease. The coincidental
      occurrence of both diseases, the nonspecific triggering effect of MS on latent
      epilepsy, and actual causation by MS are all possible explanations, but the last
      named is, in our opinion, extremely unusual.

PMID- 12609223
TI  - Psychopathologies in patients with nonepileptic seizures with and without
      comorbid epilepsy: how different are they?
AB  - The underlying psychopathology in patients with nonepileptic seizures (NES) is
      diverse and poorly understood. The prevalence of epilepsy in NES patients is
      higher than in the general population, so epilepsy can be understood as a risk
      factor for NES. The question emerges if psychopathology differs in NES patients
      with and without epilepsy. Retrospective data concerning psychopathology and
      personality in both groups show two differences: (1) somatoform disorders are
      more prevalent in NES-only patients and (2) personality disorders are more
      typical in NES patients with epilepsy and resemble the pattern of psychopathology
      found in epilepsy-only patients. If true, then NES in epilepsy patients may be
      associated with an epilepsy condition. Consequently, in studies of
      psychopathology in epilepsy patients, patients with comorbid nonepileptic
      seizures have to be included.

PMID- 12609224
TI  - Patient attitudes about treatments for intractable epilepsy.
AB  - OBJECTIVE: The goals of this study were to understand patient attitudes about the
      treatment of medically intractable epilepsy and to document potential barriers
      limiting patient access to the surgical treatment of epilepsy, highlighting the
      attitudes of adolescents and minorities. METHODS: Focus groups of adults with
      intractable epilepsy (n=10), adolescents with intractable epilepsy (n=4), parents
      of adolescents with intractable epilepsy (n=4), and African-Americans with
      intractable epilepsy (n=6) were conducted at UCLA, Los Angeles, California.
      RESULTS: Patients with intractable epilepsy communicated frustration with their
      continued disability despite trials of new medications. Their perceptions of the
      risks of the surgical treatment of epilepsy were exaggerated. Patients felt that
      their health care providers did not provide adequate information about epilepsy
      and portrayed epilepsy surgery negatively. CONCLUSIONS: This study illuminated
      several factors that could change patient attitudes and help improve patient
      access to the surgical treatment of epilepsy, especially among minorities and
      adolescents.

PMID- 12609225
TI  - A prospective study of teachers' ratings of behavior problems in children with
      new-onset seizures.
AB  - The purpose of this study was to explore the association between seizures and
      behavior problems in children with new-onset seizures using teachers' ratings of
      behavior. Subjects were 209 children with new-onset seizures and 93 children with
      asthma. Teacher ratings of behavior were collected prospectively over 24 months
      to determine differences between children with recurrent seizures, children
      without recurrent seizures, and children with asthma. During the 2-year period,
      155 (74%) children had at least one recurring seizure. Data were analyzed using
      repeated-measures analysis of variance both with and without covariates.
      Controlling for covariates, children experiencing recurrent seizures had higher
      Total (P=0.002) and Internalizing (P=0.018) Behavior Problems scores across all
      times than those not experiencing recurrent seizures. Children with asthma were
      similar to children not experiencing recurrent seizures. The association between
      seizures and behavioral problems was supported using behavioral ratings from
      teachers.

PMID- 12609226
TI  - Quality of life in pediatric epilepsy: demographic and disease-related predictors
      and comparison with healthy controls.
AB  - The purpose of the present study was to compare the health-related quality of
      life (HRQOL) of children with epilepsy with that of healthy controls and to
      examine predictors of HRQOL, including current treatment, seizure severity, and
      comorbid neurological impairments. The epilepsy group consisted of 41 children,
      aged 4-19 years. The control group consisted of 41 age-matched healthy children
      seen for well child care in a community pediatric practice. Results demonstrated
      that the HRQOL of the epilepsy group was significantly more limited than that of
      the control group. For children with epilepsy, comorbid neurological impairments
      and number of antiepileptic medications were associated with diminished HRQOL.
      Duration of illness, age of onset, seizure severity, and treatment type were not
      predictive of diminished HRQOL. The present findings suggest that presence of
      comorbid neurological impairments and number of medications are the best
      predictors of reduced HRQOL in children with epilepsy and may present a subgroup
      of patients with additional treatment needs.

PMID- 12609227
TI  - Seizure drawings: insight into the self-image of children with epilepsy.
AB  - Epilepsy is a chronic disorder that is associated with numerous psychological
      challenges, especially in children. Drawings have been underutilized as a method
      to obtain insight into psychological issues in children with epilepsy. We asked
      105 children with epilepsy, ages 5 to 18 years, to draw a picture of what it is
      like to have a seizure. Across ages and epilepsy syndromes, the drawings showed
      evidence of impaired self-concept, low self-esteem, and a sense of helplessness
      and vulnerability. Overall, the drawings of human figures were less developed
      than expected for chronological age. In some drawings, indicators of underlying
      depression were found. When considered by epilepsy syndrome or seizure type, some
      specific artistic features were noted. Children with simple partial (motor)
      seizures drew distorted body parts, especially limbs. Those with complex partial
      seizures depicted sensory symptoms and mental status changes such as confusion.
      Children with generalized tonic-clonic seizures showed shaking extremities.
      Drawings by children with absence seizures illustrated mainly staring. In
      conclusion, drawings are a powerful method to examine the self-concept of
      children with epilepsy and gain insight into their feelings about themselves and
      their world.

PMID- 12609228
TI  - Seizure-prone EL mice exhibit deficits in pup nursing and retrieval assessed
      using a novel method of maternal behavior phenotyping.
AB  - The selectively bred EL mouse strain exhibits hyperreactivity to environmental
      disturbance reflected by handling-induced seizures and motor hyperactivity in an
      exploratory task relative to a non-seizure-prone control strain. One possible
      mechanism for the nongenomic transmission of an adult seizure-prone/hyperactive
      phenotype is the quality of parenting provided to immature offspring. In
      particular, the quality of maternal behavior has been implicated as an
      environmental determinant in rodent biochemical and behavioral development. A
      complication in testing this hypothesis is that human handling for husbandry and
      testing itself triggers seizures in seizure-prone EL mice. Thus, the present
      study evaluated potential EL versus control strain differences in maternal
      behavior using a novel apparatus for passive observation of undisturbed mice.
      Nonmaternal behaviors were also measured to control for any nonspecific
      differences in activity or exploration. EL dams were slower than DDY controls to
      initiate pup retrieval and spent less time nursing/crouching over pups than DDY
      mice. EL dams also exhibited a profile of sustained exploration and grooming over
      time relative to the profile of DDY controls. These results suggest that EL
      mothers exhibit an overabundance of motor activities that compete with
      crouching/nursing and retrieval behaviors required for viability of the litter.

PMID- 12609229
TI  - Autonomic phenomena of temperature regulation in temporal lobe epilepsy.
AB  - Cold shiver and piloerection are rare ictal signs in focal epilepsies. They are
      often associated with an epileptic seizure focus within the temporal lobe. In
      rare cases the phenomenon of piloerection has been reported to be confined to
      body parts ipsilateral to the seizure focus. In this multicentric study epilepsy
      patients with ictal cold shiver and/or piloerection were retrospectively asked to
      describe exactly location and spreading patterns of these signs as well as their
      temporal sequence in relation to other ictal signs. Clinical data, etiology of
      epilepsy, and seizure focus location were also assessed. In our patient group
      there was a high relationship to an epileptic focus within the left temporal
      lobe. Distinct spreading patterns or unilateral piloerection was not indicative
      of a focus in the ipsilateral temporal lobe as described previously. Our results
      suggest that phenomena of temperature dysregulation during epileptic seizures may
      be of value in the presurgical evaluation as they may be indicative of a left
      temporal lobe seizure focus.

PMID- 12609230
TI  - Ketamine for refractory status epilepticus: a case of possible ketamine-induced
      neurotoxicity.
AB  - A 44-year-old man with treated neurosyphilis presented with subclinical status
      epilepticus (SE) refractory to intravenous high-dose lorazepam, phenytoin, and
      valproic acid over 4 days. Ketamine infusion was instituted after low-dose
      propofol sedation with gradual control of electrographic seizures over 72h.
      Reevaluation 3 months later revealed diffuse cerebellar and worsened cerebral
      atrophy, consistent with animal models of N-methyl-D-aspartate antagonist
      mediated neurotoxicity. Animal studies of prolonged ketamine therapy are required
      before widespread human use in SE.

PMID- 12609231
TI  - Religious experiences and epilepsy.

PMID- 12609232
TI  - Sudden religious conversions in temporal lobe epilepsy. 1970.

PMID- 12609233
TI  - Comparison of lamotrigine and valproate with respect to quality of life.

PMID- 12609236
TI  - Now you see it now you don't.

PMID- 12609235
TI  - Cognition of patients with partial epilepsy on carbamazepine.

PMID- 12609237
TI  - From the Epilepsy Foundation.

PMID- 12609239
TI  - Mood disorders are linked to health-related quality of life in epilepsy.

PMID- 12609240
TI  - Does P-glycoprotein play a role in pharmacoresistance to antiepileptic drugs?

PMID- 12609238
TI  - Understanding stigma.

PMID- 12609241
TI  - Cognition-induced epilepsy.
AB  - Cognition-induced epilepsy comprises a group of loosely tied syndromes
      characterized by seizures regularly precipitated by cognitive tasks. Linguistic
      operations (e.g., reading, writing) and decision making associated with
      visuospatial manipulation are the most frequent and best-characterized triggers.
      The syndromes reviewed have a high degree of overlap and clinical/EEG
      variability, suggesting that any of the neural networks subserving these complex
      tasks may promote seizures on either a topographic basis or a
      functional/connective basis. Treatment options include typical pharmacological
      and surgical interventions as well as stimulus alteration, threshold alteration,
      and avoidance conditioning. We postulate that more commonly encountered epilepsy
      syndromes also have complex triggers.

PMID- 12609243
TI  - Improvement in depression associated with partial epilepsy in patients treated
      with lamotrigine.
AB  - Interictal depression is common in patients with epilepsy and it significantly
      impacts quality of life. Previous studies indicate that lamotrigine may have
      antidepressant properties. Thirteen adults with uncontrolled partial seizures and
      concomitant depression were evaluated using measures of depression [Montgomery
      and Asberg Depression Rating Scale (MADRS) and the MMPI Depression Scale] and
      anxiety [Spielberger's State-Trait Anxiety Inventory (STAI)] to test the effects
      of lamotrigine on mood. Evaluations after 5 weeks and again after 3 months of
      lamotrigine treatment demonstrated significant improvement in depression and
      anxiety. Mean MADRS overall scores were significantly lower than pretreatment
      baseline at the 5-week and 3-month evaluations. The mean MMPI Depression score
      was significantly lower than baseline at the 3-month evaluation. State anxiety
      scores were significantly reduced from baseline after 5 weeks, but not at 3
      months, whereas Trait anxiety scores were reduced from baseline at the 5-week and
      3-month evaluations.

PMID- 12609242
TI  - Effect of war on the occurrence of epileptic seizures in children.
AB  - We studied the occurrence of epileptic seizures in 72 children from war-affected
      and 39 children from non-war-affected areas during and after the 1991-1992 war in
      Croatia. During the war, children from war-affected areas who had "stable"
      epilepsy before the war and regularly took antiepilepsy medications had epileptic
      seizures more often than children from areas not affected by the war. In 2002,
      all children (n=10) whose first epileptic seizure was related to a stressful
      event had a "stable" condition, whereas 4 of 10 children whose first epileptic
      seizure was not stress-related had an "unstable" condition. Typical absence
      seizures were observed in 6 of 10 children in the stress-related group and none
      in the non-stress-related patient group. Stressful life events can be provocative
      factors for the occurrence of epileptic seizures. Typical absence seizures are
      more likely to be provoked by stress then other types of epileptic seizures.

PMID- 12609244
TI  - The course of inattentive and hyperactive-impulsive symptoms in children with new
      onset seizures.
AB  - The purpose of the present study was to determine the prevalence of inattentive
      and hyperactive-impulsive symptoms in children with newly diagnosed epilepsy,
      explore the course of these symptoms over time, and examine factors associated
      with change in these symptoms. Parents of children (n=42) were administered the
      Attention Deficit Disorder Evaluation Scale-Home Version (ADDES-HV) at the time
      of diagnosis. The ADDES-HV was readministered after the child's seizures were
      controlled. Prior to initiation of anticonvulsant therapy, 31% of the children
      were rated as having clinically significant problems with inattention and 31%
      with hyperactivity-impulsivity. At follow-up, 27% had elevated symptoms of
      inattention and 24% had hyperactivity-impulsivity. Analysis of this change
      indicated that children with a normal MRI were more likely to have decreased
      hyperactive-impulsive behaviors following control of their seizures. Results
      suggest the need for assessment and monitoring of attention in children with
      epilepsy.

PMID- 12609245
TI  - Physicians underestimate the frequency of generic carbamazepine substitution:
      results of a survey and review of the problem.
AB  - Antiepileptic drugs (AEDs) possess a narrow therapeutic range, and generic
      substitution may lead to breakthrough seizures and adverse events. Prescribers of
      AEDs may be unaware how frequently generic substitution actually occurs. Surveys
      were administered to 845 physicians at the 2001 American Epilepsy Society (AES)
      meeting and the 2001 American Academy of Neurology (AAN) meeting. Two hundred
      fifty-eight physicians responded to the AES survey and 587 physicians to the AAN
      survey. Questions were multiple choice and displayed on a computer screen. Among
      other questions, physicians were asked: (1) What percentage of patients are
      substituted with a generic short-acting carbamazepine in the US annually? (2) Are
      you comfortable with patients receiving multiple formulations of generic
      carbamazepine? Responses to the first question were compared to the actual rate
      of generic substitution determined by an independent audit of 1,036,000 Tegretol
      prescriptions. In the AES survey, 10.9% of respondents estimated that 10% of
      patients had carbamazepine generic substitutions, 41.9% estimated a 30%
      substitution rate, 30.2% estimated a 50% rate, and 17.1% estimated a 70% rate.
      The AAN respondents had similar estimates: 17.5% guessed a 10% rate, 40.0% a 30%
      rate, 30.2% a 50% rate, and 12.3% a 70% rate. In the AES survey, 86.4% of
      respondents were not "comfortable with patients receiving multiple formulations
      of generic carbamazepine." Similarly, in the AAN survey, 80.3% of respondents did
      not endorse generic substitution of carbamazepine. An independent audit of
      generic substitutions revealed that of 766,000 prescriptions for 200mg of
      Tegretol, pharmacists substituted 551,000 (72%) with generic carbamazepine. Of
      199,000 prescriptions for 100mg of Tegretol, 140,000 (70%) were filled with a
      generic. Of 71,000 prescriptions for Tegretol 100mg/5ml suspension, 10,000 (14%)
      were filled with a generic. The overall substitution rate was 701,000/1,036,000
      (68%), much higher than estimated by the majority of surveyed attendees. In
      conclusion, most surveyed physicians at the 2001 AES and AAN meetings
      significantly underestimated the number of generic substitutions that occur for
      brand name short-acting carbamazepine. Given the potential for breakthrough
      seizures and adverse events related to generic substitution, physicians need to
      be more vigilant in their prescription-writing practices to prevent unwarranted
      generic substitution.

PMID- 12609246
TI  - Personality disorders as predictors of severe postsurgical psychiatric
      complications in epilepsy patients undergoing temporal lobe resections.
AB  - Purpose. Psychiatric disorders emerging after temporal lobe resections are a
      serious problem threatening the surgical success of patients with epilepsy. The
      present study aims to find psychiatric predictors that would indicate patients'
      risk to developing severe psychiatric complications after surgery.Methods. One
      hundred adult patients who had temporal lobe resections were followed
      prospectively over 2 years. Preoperative psychiatric diagnoses and postoperative
      development of the patients were documented. As a criterion of severe
      postoperative complication, admission to a psychiatric hospital was
      chosen.Results. Patients with personality disorders are at higher risk of
      suffering from postoperative psychiatric complications as compared with patients
      with other preoperative psychiatric conditions (such as depression) or with
      patients with no preoperative psychiatric diagnosis whatsoever.Conclusions.
      Personality disorders are caused by organic dispositions and negative
      environmental influence. They indicate a high mental vulnerability and compromise
      the brain's ability to combat stress. As a consequence patients with personality
      disorders are prone to suffer from severe psychiatric complications after
      epilepsy surgery. To minimize the negative influence of personality disorders in
      the process of surgical interventions, psychotherapeutic efforts are needed to
      reduce perisurgical stress factors and to strengthen the self-efficacy and social
      skills of these patients.

PMID- 12609247
TI  - Magnitude of the placebo effect in randomized trials of antiepileptic agents.
AB  - Placebo-controlled randomized trials ideally produce unbiased estimates of the
      treatment effect after accounting for nonpharmacological effects (regression to
      the mean, Hawthorne, and placebo effects). Recognizing that the magnitude of
      these effects may help understand why investigators need to control for them, we
      sought to measure this magnitude. We reviewed published meta-analyses of
      randomized, placebo-controlled add-on trials of antiepileptic medications versus
      placebo, included in the Cochrane Library. In randomized trials of antiepileptic
      agents for epilepsy, 9.3-16.6% of patients in the placebo arm had a >50%
      reduction in seizure frequency. This effect represents 20-50% of the effect
      observed with active agents. Because patients with epilepsy in the placebo arm of
      randomized trials experience a large clinical benefit due to nonpharmacological
      effects, randomized controlled trials are necessary to gauge the true magnitude
      of the treatment effect of new antiepileptic agents.

PMID- 12609248
TI  - Adult patient perceptions of emergency rectal medications for refractory
      seizures.
AB  - Background. Rectally administered benzodiazepine antiepilepsy drugs (AEDs) are a
      safe and effective therapy for acute repetitive seizures in patients on stable
      maintenance AEDs. Such medication provides an earlier treatment option for
      seizure control prior to emergency department (ED) visitation and may be
      administered outside of the hospital in carefully selected patients. The use of
      rectal medications, however, has a perceived association with fear and
      embarrassment. This study sought to address patient attitudes toward rectally
      delivered AEDs. Methods. A written, eight-question survey regarding adult patient
      attitudes toward rectal medication and ED visits was prospectively administered
      to 91 consecutive epilepsy patients in an epilepsy-based practice setting.
      Primary caretakers responded when patients were unable to do so. RESULTS: Forty
      eight female and thirty-two male survey responses were analyzed. The mean patient
      population was age 42.7 years with epilepsy for 23.7 years on 1.7 AEDs with a
      seizure frequency of 6.6/month. The majority had partial and generalized tonic
      clonic seizures and had obtained at least a high school education. Three patients
      (6%) had symptomatic generalized epilepsy and required caretaker responses.
      Eleven of ninety-one (12.1%) surveys were incomplete for analysis. Seventy-six of
      eighty (95%) respondents completed at least 50% of the survey questions. Forty
      three of sixty-four (67.2%) respondents were not embarrassed by rectal AEDs, and
      did not fear being teased by others. Additionally, most felt rectal AEDs were a
      good option in epilepsy management, yet would prefer a private setting for
      administration. Both seizures and rectal AED use appeared to be equally
      embarrassing to patients. While 53 of 76 (69.7%) reported ED visitation for
      seizures at some time, the vast majority (56/60, 93.3%) reported they would
      prefer treatment outside the hospital, as opposed to ED transport. Conclusions.
      The results from this adult patient survey suggest that individuals with epilepsy
      do not object to earlier administration of emergency rectal seizure medication
      relative to ED visitation. An undesirable perception of rectal medications in
      seizure emergencies does not appear to be limited by patient acceptance.

PMID- 12609249
TI  - Now you see it, now you don't: statistical and methodological considerations in
      fMRI.
AB  - We illustrate the effects of statistical threshold, spatial clustering, voxel
      size, and two approaches to multiple comparison correction on fMRI results. We
      first analyzed fMRI images obtained from a single subject during a noun-verb
      matching task. Data were analyzed with Statistical Parametric Mapping (SPM) using
      two different voxel sizes, and results were displayed at three different levels
      of statistical significance. At each statistical threshold, results were first
      uncorrected for multiple comparisons and spatial extent and then presented using
      a spatial extent cluster of 20 voxels. We then statistically controlled the Type
      I error rate associated with multiple comparisons by using the false discovery
      rate and by the random field adjustment for false-positive rate used by SPM. We
      also examined group results from language and graphesthesia paradigms at three
      levels of statistical significance. In all circumstances, apparent random
      activations decreased as more conservative statistical approaches were employed,
      but activation in areas considered to be functionally significant was also
      reduced. These issues are important in the choice of analytic approach and
      interpretation of fMRI results, with clear implications for the surgical
      management of individual patients when fMRI results are used to delineate
      specific areas of eloquent cortex.

PMID- 12609250
TI  - A recent classic on violence in epilepsy.

PMID- 12609251
TI  - The nature of aggression during epileptic seizures.

PMID- 12609254
TI  - Health-related quality of life of adults with epilepsy.

PMID- 12609255
TI  - Reply.

PMID- 12609253
TI  - Behavioral and emotional correlates of epilepsy in adolescence.

PMID- 12609256
TI  - Validity of the WADA test.

PMID- 12609257
TI  - Reply.

PMID- 12609258
TI  - Comorbidity of ictal fear and panic disorder.

PMID- 12609259
TI  - Letter to the Editor.

PMID- 12609260
TI  - Reply.

PMID- 12609261
TI  - From the Epilepsy Foundation. Saving money in state Medicaid programs: penny-wise
      and pound-foolish?

PMID- 12609262
TI  - Ictal aphasia.

PMID- 12609264
TI  - P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in
      mdr1a knockout mice.
AB  - Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a
      facilitatory role in refractory epilepsy by limiting the brain access of
      antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study
      of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood
      brain barrier. A parallel group of matched wild-type mice served as controls.
      AEDs were administered by subcutaneous injection and serum and brain drug
      concentrations determined at 30, 60, and 240min post-dosing. The brain-serum
      concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild
      type controls at all time points investigated. No consistent effects were
      observed with any other AED investigated. These findings suggest that topiramate
      may be a substrate for P-gp-mediated transport. Further studies employing a range
      of model systems are required to substantiate this observation and to address the
      potential role of drug transporters in refractory epilepsy.

PMID- 12609263
TI  - The effectiveness of psychological interventions for patients with relatively
      well-controlled epilepsy.
AB  - Previous reviews about psychological interventions focused on refractory epilepsy
      patients and were inconclusive; this review investigates what the contribution of
      the psychologist can be for the large group of patients with relatively well
      controlled epilepsy. This review was restricted to the literature reporting on
      adult patients with relatively well-controlled epilepsy. A literature search on
      the effect of psychological interventions was conducted using Medline and
      PsychInfo, including those studies published through March 2002. Applying strict
      inclusion criteria, a total of seven studies were identified. Four studies
      incorporated a waiting-list control group. Of these, one study addressing
      cognitive rehabilitation reported positive results on psychological outcome and
      one intervention based on comprehensive care led to seizure reduction, whereas
      all other studies were plagued too much by methodological inadequacies to allow
      firm conclusions to be drawn. Recommendations for future intervention studies,
      such as standardized interventions, controlling for positive attention, outcome
      measures without overlap with the intervention, and a follow-up measurement, are
      given. It is concluded that a concerted effort to assemble larger patient groups
      in randomized-controlled studies is a prerequisite to acquiring well-founded
      knowledge about psychological interventions in patients with relatively well
      controlled epilepsy.

PMID- 12609265
TI  - Partial seizure-like symptoms in borderline personality disorder.
AB  - The clinical presentation of borderline personality disorder (BPD) bears a
      striking resemblance to the behavioral alterations associated with temporal lobe
      epilepsy. Using the Limbic System Checklist-33, we found that BPD subjects
      reported more symptoms associated with partial seizures than did control
      subjects. BPD patients also exhibited deficits on immediate and delayed recall of
      the Rey-Osterrieth Complex Figure and produced distorted drawings of the Rey
      Figure. Their degree of impairment correlated with their report of temporolimbic
      symptoms. Results are consistent with the proposal that temporolimbic dysfunction
      underlies the behavioral dyscontrol and affective dysregulation present in BPD.

PMID- 12609266
TI  - Effect of Wada methodology in predicting lateralized memory impairment in
      pediatric epilepsy surgery candidates.
AB  - Because Wada evaluations are not standardized, it is impossible to know to what
      degree method variance accounts for reported differences in results. To examine
      this problem, three comprehensive epilepsy surgery centers compared the efficacy
      of two Wada memory methods to predict seizure onset laterality in 152 children
      being considered for epilepsy surgery. Wada memory asymmetries were evaluated
      using either real objects with no verbal response required or more mixed stimuli
      requiring a verbal response. When using real objects, Wada memory performance was
      significantly worse when relying on the side of seizure onset in both left and
      right seizure onset children. In contrast, Wada memory performance using mixed
      stimuli was worse on the side of seizure onset only among patients with seizures
      originating in the left-hemisphere. The superiority of real objects was most
      apparent in younger children with left side seizure onset. Results suggest the
      use of mixed stimuli is less sensitive to the effects of unilateral seizure
      onset, and thus, diminishes the capacity of the Wada test to predict lateralized
      seizure onset in children.

PMID- 12609267
TI  - Characteristics of patients initiated on the new antiepileptic drugs: a PADS
      study.
AB  - Whereas randomized controlled trials remain a standard for evaluating and
      comparing efficacy and safety of the new antiepileptic drugs (AEDs),
      postmarketing drug research offers a useful means of comparing efficacy and
      safety of new AEDs. However, differences in baseline characteristics of patients
      in different drug groups create the potential for bias in drug comparison
      studies. In this study, baseline demographic characteristics of 1,386 patients
      initiating lamotrigine (LTG), tiagabine (TGB), or topiramate (TPM) were compared
      to identify patient characteristics that may influence AED use in epilepsy
      patients. Data were collected at 14 epilepsy centers and included medications,
      seizure types and syndromes, and prior adverse events. There were 402 patients in
      the LTG group, 725 TPM, and 259 TGB. The groups differed both in their number of
      concurrent AEDs (p<0.001) and in their number of prior AEDs (p<0.01). There was
      no difference in proportion with partial versus generalized epilepsy syndromes.
      The groups differed in the proportions of patients with complex partial seizures
      (p=0.049), primary generalized tonic-clonic seizures (p=0.01), and myoclonic
      seizures (p=0.03). Baseline behavioral adverse event rate was lowest in patients
      initiating TPM (p<0.01); LTG patients had the lowest rate of prior AED-related
      rash (p=0.02). There was no relationship between AED assignment and patient age,
      age of epilepsy onset, epilepsy duration, institutionalization status, gender, or
      psychiatric history. Numerous epidemiological differences were identified among
      patients placed on the new AEDs, including current and prior AED profiles,
      seizure types, and prior adverse event history. Accounting for these differences
      is of crucial importance because they may bias conclusions of nonrandomized post
      marketing trials comparing the drugs.

PMID- 12609269
TI  - Clinical presentations of naturally occurring canine seizures: similarities to
      human seizures.
AB  - The clinical presentations of 119 canine seizures from 41 Standard Poodles and 11
      Dalmatians were classified according to a modified version of the International
      League Against Epilepsy (ILAE) seizure classification system. Standardized use of
      the ILAE system with dogs not only should facilitate research in veterinary
      medicine, which has no standard criteria for seizure classification, but also
      should facilitate comparisons between canine and human seizures. We found that
      for more than 80% of both breeds, at least some of their seizures had partial
      onsets. However, because it was common for partial seizures to secondarily
      generalize, the majority of Poodles (81%) and Dalmatians (91%) experienced at
      least some generalized seizures. Among partial seizures, complex partial were
      more frequent than simple partial. For both breeds, two thirds of those with
      partial onset seizures had exclusively complex partial. Among dogs with primary
      or secondarily generalized seizures, 80% of both breeds had tonic-clonic
      seizures.

PMID- 12609268
TI  - Quality of life outcome is associated with cessation rather than reduction of
      psychogenic nonepileptic seizures.
AB  - The outcome of psychogenic nonepileptic seizures (NES) is usually judged by
      recurrence of spells, but functional outcome or quality of life (QOL) is less
      well described. We tested the hypothesis that a decrease in NES recurrence yields
      corresponding improvement in QOL. Patients with NES were diagnosed with
      continuous video-EEG. We determined spell rate and QOL through a telephone
      interview at least six months after diagnosis. Thirty subjects consented to a
      follow-up interview (mean 17.4+/-1.5 months between diagnosis and interview). The
      rate of NES per week decreased significantly, and 10/30 (33%) had complete
      resolution. QOL, measured by the QOLIE-10 scale, did not improve proportionately
      with reduction in NES. However, subjects who reported a cessation of NES noted a
      significantly better total QOLIE-10 score (20.7+/-2.2) than those with continuing
      NES (27.4+/-1.6, P=0.02 by unpaired t test). Cessation rather than reduction of
      NES is associated with better QOL outcome.

PMID- 12609270
TI  - Levetiracetam monotherapy for adults with localization-related epilepsy.
AB  - We identified 37 patients with a history of partial seizures, with and without
      secondarily generalization, who received levetiracetam (LEV) (Keppra)
      monotherapy. Patients began LEV either as first line therapy (n=9) or were
      converted to LEV monotherapy (n=28) after failing prior antiepileptic medications
      (AEDs). Thirty-four patients continued on LEV for at least six months; of these,
      13 patients became seizure free and 15 patients had >50% reduction in their
      seizures. Three patients discontinued LEV because of adverse effects. LEV
      monotherapy can be effective and well tolerated in adults with new onset and
      difficult-to-control partial epilepsy. A prospective, large, double blind
      monotherapy study is needed to confirm this finding.

PMID- 12609271
TI  - Long-term effects of 24-month treatment with vagus nerve stimulation on behaviour
      in children with Lennox-Gastaut syndrome.
AB  - The long-term effects of vagus nerve stimulation (VNS) on behaviour were studied
      in 19 children with Lennox-Gastaut syndrome. We used the following stimulation
      parameters: output current: 112 to 2mA; signal frequency: 30Hz frequency; signal
      pulse width: 500&mgr;s; signal 'on and off' time: 30s 'on,' 3min 'off.' The test
      battery consisted of cognitive tests assessing mental age and quality of life
      measurements assessing independency, behavioural problems, and mood. The results
      show relatively small changes in the behavioural outcomes, concurrent with the
      modest effects of VNS on seizure frequency (an average of 20.6% seizure
      reduction). When baseline measurements are compared with the follow-up measures,
      neither the cognitive measure nor the quality of life measures show any
      deterioration and the cognitive measure (mental age) showed mild positive changes
      (gain of 4.2 months mental age during the follow-up period). None of the changes
      were statistically significant. Treatment effect was most prominent in the group
      with the highest mental age at baseline, which suggests that mental retardation
      is a negative prognostic factor for VNS treatment. Moreover, in this specific
      patient group, treatment effect did not increase with treatment duration. Some
      evidence during follow-up suggests a direct positive effect of VNS on behavioural
      function, independent of changes in seizure frequency. Long-term treatment with
      VNS is not associated with adverse behavioural effects. Mental retardation is a
      negative prognostic factor for the efficacy of VNS.

PMID- 12609273
TI  - To the Editor:

PMID- 12609272
TI  - Isolated unilateral cortical oedema and complex partial seizures in association
      with coxsackievirus B infection.
AB  - A unilateral cortical oedema in association with coxsackievirus B infection is
      reported. A 10-year-old girl presented with right hemiparesis and complex partial
      seizures. The cerebral MRI showed a unique pattern of isolated unilateral
      cortical oedema sparing the white matter with intravascular gadolinium
      enhancement of the left hemispheric sulcal veins. With anticonvulsant medication,
      the patient recovered within two weeks and MRI abnormalities were completely
      resolved after four weeks, whereas the EEG left hemispheric slowing showed
      delayed normalisation over the following five months.

PMID- 12609274
TI  - To the Editor:

PMID- 12609275
TI  - From the Epilepsy Foundation. Employment for People with Epilepsy: The Hardest
      Nut.

PMID- 12609276
TI  - Behavioral Aspects of Frontal Lobe Epilepsy.
AB  - There is growing interest in disorders of behavior, personality, and mood
      associated with focal epilepsies, though the neuropsychological and behavioral or
      psychiatric aspects of epilepsy have usually been treated separately. The causes
      of behavioral disorders in patients with focal epilepsies are multifactorial,
      though the positive effects of seizure control on behavior suggest that state
      dependency is a major contributing factor. Patients with temporal lobe epilepsy
      manifest depression, anxiety, neuroticism, and social limitations, as well as
      impaired memory. By contrast, studies of cognitive function in patients with
      frontal lobe epilepsy show executive dysfunctions in response
      selection/initiation and inhibition, as well as cognitive impairment,
      hyperactivity, conscientiousness, obsession, and addictive behaviors.

PMID- 12609277
TI  - The Mozart Effect.
AB  - This review deals with the Mozart Effect, an improvement of performance while
      listening to Mozart music. Previous studies have shown improved spatial temporal
      reasoning and improved IQ test results and neurophysiological changes, mainly
      increased coherence among different groups of subjects. This review emphasizes
      the effect on epileptiform patterns, both generalized and focal; provides an
      example of a chronic effect over a period of 1-2 days; addresses the distinctive
      aspects of the music to account for this phenomenon and shows that long-term
      periodicity in the power of the music is a special quality; and deals with the
      melodic line and shows that Mozart repeats the melodic line much more frequently
      than other well-known composers. It is likely that the superorganization of the
      cerebral cortex resonates with great organization found in Mozart music.

PMID- 12609278
TI  - Personality and Psychopathology in Nonepileptic Attack Disorder and Epilepsy: A
      Prospective Study.
AB  - To study the nature of personality and psychopathology in nonepileptic attack
      disorder (NEAD) and epilepsy, we prospectively assessed 45 consecutive attendees
      to a specialist assessment unit for epilepsy. Patients with NEAD were more likely
      to report clinically significant symptoms of anxiety, worry, disordered eating,
      and somatoform disorder. An ICD-10 diagnosis of anxiety or phobic disorder was
      significantly more common in NEAD patients. Together DSM-IV personality Clusters
      A and C were more common in epilepsy than NEAD. Hierarchical logistic regression
      with diagnosis as the target variable found anxiety, eating, and worry but not
      somatoform symptoms were reliably associated with NEAD. Together the Present
      State Examination (PSE) eating, PSE worrying/tension, PSE expansive mood, past
      psychiatric history, and gender variables allowed for correct classification of
      more than 88% of all cases. Personality and psychopathology variables seem to be
      valid clinical predictors of epilepsy and NEAD, and should be examined in
      epidemiological studies.

PMID- 12609279
TI  - Integration of Perceptual and Mnemonic Dysfunction: Sensory Auras Are Associated
      with Left Hemispheric Memory Impairment.
AB  - Memory function during the intracarotid amobarbital test was studied to test the
      hypothesis that left hemisphere memory impairment is associated with sensory
      auras. In a series of 37 patients undergoing preoperative evaluation for epilepsy
      surgery, the quantitative memory scores during amobarbital inactivation of right
      and left hemisphere were analyzed for correlation with habitual epileptic auras
      classified as either (a) experiential, forced emotion, or whole-body dysphoria or
      (b) sensory hallucinations and/or illusions or localized dysesthesias. The left
      hemispheric memory score impairment was significantly worse in association with
      auras classified as sensory hallucinations and/or illusions or localized
      dysesthesias compared with auras classified as experiential, forced emotion, or
      whole-body dysphoria (P < 0.05). This finding may assist in predicting left-sided
      hemispheric memory dysfunction in patients with seizures beginning as auras
      involving sensory material. The results suggest an integration of perceptual and
      mnemonic dysfunction in which sensory auras are associated with left hemispheric
      memory impairment.

PMID- 12609280
TI  - Effects of Long-Term Video-electroencephalographic Monitoring on Mood in Epilepsy
      Patients.
AB  - This study examines changes in mood of 79 epilepsy patients who completed the
      Profile of Mood States during long-term video-electroencephalographic monitoring
      (LTM). Statistical linear models included the effects of age, gender, increased
      seizure frequency, sleep deprivation, and taper of antiepileptic drugs (AEDs) on
      mood. Sleep deprivation increased fatigue and decreased vigor from baseline to
      Day 3, but not from baseline to Day 8 or the final day of the protocol. Taper of
      AEDs did not adversely affect mood, with removal of phenytoin improving mood.
      Subjects who had seizures during LTM also improved in mood, becoming less
      depressed and less fatigued than those who did not have seizures. Overall, our
      data indicate that LTM does not adversely affect mood. However, in the first few
      days of LTM, sleep deprivation may produce fatigue and lack of vigor, and should
      be used only as needed to provoke seizures.

PMID- 12609281
TI  - Prevalence of Psychopathology in Dutch Epilepsy Inpatients: A Comparative Study.
AB  - The purpose of this study was to determine the prevalence of psychiatric
      disorders in Dutch patients with epilepsy in comparison with epidemiological data
      on a representative sample of the Dutch population. The Composite International
      Diagnostic Interview (CIDI) was used to determine the prevalence of psychiatric
      disorders in 209 epilepsy patients and compared with findings in the general
      Dutch population. The prevalence in temporal lobe epilepsy (TLE) and extra
      temporal lobe epilepsy (extra-TLE) was also compared. Psychiatric disorders most
      frequently found in patients with epilepsy were anxiety and mood disorders. The
      last-year prevalence of these disorders was 25% for anxiety disorders and 19% for
      mood disorders. Compared with the general Dutch population, the prevalence of
      these disorders was significantly higher in epilepsy. No differences were found
      between patients with TLE and extra-TLE. It can be concluded that patients with
      epilepsy admitted to a tertiary epilepsy center suffer more often from mood and
      anxiety disorders than the general population.

PMID- 12609282
TI  - Decline in Verbal Memory Associated with Duration of Epilepsy: An Intracarotid
      Amobarbital Study.
AB  - Background. Many patients with mesial temporal sclerosis (MTS) observe that their
      memory has declined over time, but objective evidence for this is scant.Method.
      Verbal memory scores were obtained during amobarbital injection of the right
      carotid artery in 30 right-handed patients with right mesial temporal sclerosis
      and unilateral right temporal lobe seizures. These were compared with duration of
      epilepsy and seizure frequency. An estimate of the total number of lifetime
      seizures was formed by multiplying epilepsy duration by seizure
      frequency.Results. Verbal memory function in the left temporal lobe was
      negatively associated with longer duration of epilepsy (P < 0.05). There was a
      strong negative correlation between verbal memory and increased lifetime number
      of seizures (P < 0.01).Conclusion. This study provides evidence that seizures
      arising in the right temporal lobe lead to progressive dysfunction of memory
      functions in the contralateral side.

PMID- 12609283
TI  - Effect of the New Antiepileptic Drug Levetiracetam in an Animal Model of Mania.
AB  - The new antiepileptic drug levetiracetam (LEV, Keppra) was evaluated in a
      putative animal model for mania, namely, dexamphetamine-chlordiazepoxide mixture
      induced hyperactivity in rats submitted to a Y-shaped maze test. Lithium
      chloride, sodium valproate, and carbamazepine, all clinically effective drugs in
      the treatment of acute mania, were used as comparators. The results indicate that
      the clinical references significantly attenuated the mixture-induced
      hyperactivity, thus confirming the sensitivity and pharmacological validity of
      this model. LEV also significantly attenuated the mixture-induced hyperactivity
      at doses within the range of those reported to be active in epilepsy models. ucb
      L060, the R-enantiomer of LEV, was without effect, thus indicating that the
      "antimanic" activity of LEV is stereospecific. These results suggest a potential
      for LEV in the treatment of mania and possibly in the management of bipolar
      disorder.

PMID- 12609284
TI  - Exploration of Changes in Health-Related Quality of Life after 3 Months of Vagus
      Nerve Stimulation.
AB  - Purpose. The goal of this work was to explore changes in health-related quality
      of life (HRQOL) and reductions in seizure frequency among patients initiating
      vagus nerve stimulation (VNS) for medication-refractory epilepsy.Methods.
      Patients receiving VNS completed the Quality of Life in Epilepsy-10 (QOLIE-10) at
      baseline and after 3 months of stimulation. Patients were categorized as
      responders (>/=50% seizure reduction) and nonresponders (<50% seizure reduction).
      Data were analyzed for change from baseline to 3 months within each group and
      between groups.Results. Both groups reported improvements in almost all aspects
      of HRQOL. Statistically significant improvements were reported by responders in
      energy, memory, social aspects, mental effects, and fear of seizures; and by
      nonresponders in downheartedness and overall QOL. Responders improved
      significantly more than nonresponders in energy.Conclusions. These exploratory
      analyses showed little difference in HRQOL between responders and nonresponders,
      with both reporting improvements after 3 months of VNS. Follow-up may determine
      whether improvements are sustained or attributable to placebo effect.

PMID- 12609285
TI  - Major Psychiatric Disorders Subsequent to Treating Epilepsy by Vagus Nerve
      Stimulation.
AB  - Purpose. The goal of this work was documentation of incidence, phenomenology,
      pathogenesis, and treatment of psychiatric disorders occurring subsequent to
      treating epilepsy by vagus nerve stimulation (VNS).Methods. In a series of 81
      patients treated by VNS, all patients who developed major psychiatric
      complications underwent systematic psychiatric evaluation and treatment with
      psychotropic medication; VNS was modified if necessary.Results. After the seizure
      frequency was reduced by at least 75%, 7 of 81 patients (9%) developed major
      psychiatric disorders: Six became severely dysphoric (5 with catastrophic rage
      and 4 with psychotic symptoms), and one became psychotic. All 7 patients had
      experienced dysphoric disorders and 2 had experienced psychotic episodes prior to
      the VNS treatment. Five patients had frequent daily seizures prior to treatment.
      Remission or satisfactory improvement was achieved with psychotropic medication
      in 6 patients, aided by decreasing or interrupting VNS in two patients. One
      patient was noncompliant and suffered a fatal outcome.Conclusion. Severe
      interictal dysphoric disorders associated with catastrophic rage and psychotic
      episodes may develop on suppressing seizures by VNS in patients with previous
      epilepsy-related psychiatric disorders. Patients with multiple daily seizures may
      be more vulnerable to this occurrence. The phenomenon corresponds to the common
      finding of interictal dysphoric and psychotic symptoms emerging when inhibitory
      mechanisms predominate (alternative psychiatric disorders in the absence of
      seizures, or forced normalization of the EEG). The dysphoric symptom of
      catastrophic rage appears to occur more often on seizure suppression by VNS than
      by antiepileptic drugs. Psychiatric intervention, primarily with antidepressant
      medication, must be available to secure a good outcome; decrease of VNS may
      occasionally be required.

PMID- 12609286
TI  - Nonconvulsive Seizures Result in Behavioral but Not Electrophysiological Changes
      in Developing Rats.
AB  - It is not known if nonconvulsive seizures lead to functional or morphological
      changes in immature rats. Therefore we studied consequences of such seizures
      induced by kainic acid (KA) on Postnatal Day (PD) 12 (2 mg/kg ip). The animals
      were examined electrophysiologically (cortical epileptic afterdischarges (ADs)
      were elicited in rats with implanted electrodes on PD 14, 18 or 25) and
      behaviorally (open field was studied in another group of animals on PDs 18 and
      25). Hippocampal and cortical morphology was checked by light microscopy (Nissl
      staining) on PDs 18 and/or 25. Another group of rats was injected with a 6 mg/kg
      dose of KA on PD 18 and examined on PD 25. The dose of KA used induced only
      nonconvulsive seizures characterized by automatisms (scratching on PD 12, wet dog
      shakes on PD 18). Cortical ADs in animals stimulated on PD 14, 18, or 25 did not
      differ from those in control rats. KA-Treated rats exposed to open field two
      times (on PDs 18 and 25) exhibited more exploratory activities during the second
      exposure than control animals. A similar difference was noted in PD 25 rats
      injected with KA on PD 18. Qualitative histology did not reveal any obvious
      neuronal damage in hippocampus and cortex. These results demonstrate that
      nonconvulsive seizures induced at early developmental stages that do not result
      in observable electrophysiological and morphological changes may have delayed
      behavioral consequences.

PMID- 12609287
TI  - Depression and Anxiety in Patients with Epilepsy.
AB  - The aim of this investigation was to study the interaction between
      depression/anxiety and epilepsy. One hundred fifty individuals with partial
      epilepsy, 70 with idiopathic generalized epilepsy, and 100 controls were
      administered two self-rating mood questionnaires (Zung and Stai) for the
      evaluation of depression and anxiety, respectively. The group with epilepsy was
      much more severely impaired than the controls according to both mood
      questionnaires; the patients with partial epilepsy, especially those with
      temporal lobe epilepsy (TLE), were more depressed and anxious than the patients
      with generalized epilepsy. The group with left TLE appeared to have the highest
      levels of depression and anxiety. The final results of our study confirmed that
      some mood disorders are common throughout the epilepsy population, especially in
      patients with left TLE. No correlation was noted between the frequency of
      seizures and onset of epilepsy and the results of the mood questionnaires.
      Moreover, no differences were found in depression and anxiety between males and
      females among both left focus and right focus epilepsy patients.

PMID- 12609288
TI  - Employment Concerns of People with Epilepsy and the Question of Disclosure:
      Report of a Survey of the Epilepsy Foundation.
AB  - This article presents the results of a survey of the Epilepsy Foundation
      affiliates in the United States and Puerto Rico, regarding the employment-related
      questions and concerns of people with epilepsy. The survey also explored how
      Epilepsy Foundation affiliates advise people with epilepsy about disclosing
      epilepsy status in the employment-seeking process. Some of the major employment
      related questions and concerns reported by the affiliates included identifying
      resources to help in finding a job, questions about disclosure of epilepsy status
      in job applications, questions about job-related discrimination or Americans with
      Disabilities Act (ADA) violations, questions about the ADA, and questions about
      how to deal with co-workers or supervisors. Implications and design limitations
      are discussed.

PMID- 12609290
TI  - Psychopathology of Epilepsy. To the Editor:

PMID- 12609289
TI  - Psychopathology of Epilepsy. To the Editor:

PMID- 12609291
TI  - Psychopathology of Epilepsy. Reply.

PMID- 12609292
TI  - Psychopathology of Epilepsy. Reply.

PMID- 12609293
TI  - Psychopathology of Epilepsy. Reply.

PMID- 12609294
TI  - Psychopathology of Epilepsy. Reply.

PMID- 12609295
TI  - Animal Models for Human Seizure and Epileptic Activity. To the Editor:

PMID- 12609296
TI  - To the Editor.

PMID- 12609298
TI  - Animal Models for Human Seizure and Epileptic Activity. Reply.

PMID- 12609299
TI  - Introduction: stigma and epilepsy.

PMID- 12609297
TI  - To the Editor.

PMID- 12609300
TI  - The nature of stigma and medical conditions.
AB  - Stigma is society's negative evaluation of particular features or behavior.
      Cultural beliefs that define certain conditions negatively may create tainted and
      discounted identities for affected individuals and their families. Varied
      dimensions of stigmatized medical conditions include the nature of an illness,
      its history, and attributed characteristics; sources of the creation and
      perpetuation of stigma; the nature of the populations who are perceived to carry
      the illness; the kinds of treatments and practitioners sought for the condition;
      and how individuals with stigmatized medical conditions cope with societal
      insults that endanger their personal identity, social life, and economic
      opportunities. Individuals with stigmatized medical conditions, including
      epilepsy, may benefit from support groups that can help enhance their confidence.
      By focusing on the social and political resources and recourses available to
      them, such individuals can make substantial strides toward gaining their freedom
      from stigma.

PMID- 12609301
TI  - Stigma, epilepsy, and quality of life.
AB  - Despite advances in the understanding and treatment of epilepsy within the past
      several decades, people with this disorder continue to be stigmatized by it.
      Though attitudes toward people with epilepsy have improved over the years, for
      many people with epilepsy, stigma continues to adversely impact their
      psychological well-being and quality of life. The stigma of epilepsy can be
      linked to a number of factors, including underresourced medical services, poor
      seizure control, and inadequate knowledge of epilepsy. Neither informal stigma
      nor formal discrimination is inevitable for epilepsy patients; however, for many
      individuals, epilepsy remains a defining feature of their identity, and such
      issues are a source of considerable concern for a number of patients.

PMID- 12609302
TI  - Stigma and epilepsy.
AB  - For individuals with epilepsy in the United States and other countries, stigma
      can be one of the most distressing consequences of having seizures, along with
      the unpredictability of future seizures and the inability to drive. The impact of
      stigma on the lives of epilepsy patients is far reaching, frequently including
      effects on interpersonal relationships, general health, employment opportunities,
      and overall quality of life. Education about epilepsy directed at the broader
      community, as well as at the individual with epilepsy, is the most effective
      means of addressing misperceptions and fear. Epilepsy advocacy organizations,
      such as the Epilepsy Foundation, are important allies in this effort.

PMID- 12609303
TI  - People with epilepsy: what do they know and understand, and how does this
      contribute to their perceived level of stigma?
AB  - Understanding the factors that contribute to the process of stigmatization of
      those with epilepsy may be an important element in the management of this
      condition. This study was designed to determine the contribution of clinical,
      demographic, and psychosocial variables to the stigma of epilepsy in adults. More
      than 6000 adults from 10 European countries were surveyed. Almost half of
      respondents reported that they had difficulty accepting their illness, and 17%
      felt stigmatized by it. A number of factors were predictive of stigma, including
      seizure frequency, knowledge of epilepsy, duration of epilepsy, and seizure type.
      The relative contributions of these factors varied depending on the country of
      origin of those surveyed. Further research is warranted to determine societal
      influences on the process of stigmatization.

PMID- 12609304
TI  - ILAE/WHO "Out of the Shadows Campaign" Stigma: does the flag identify the cargo?
AB  - People with epilepsy around the globe are confronted with different levels and
      types of stigmatization, which may vary greatly among geographical regions and
      cultures. Furthermore, striking differences in social research into the stigma
      surrounding epilepsy can be seen across cultures. For instance, research projects
      taking place in Europe and North America place greater emphasis on perceived
      stigma (i.e., the type/amount of discrimination a person expects to encounter),
      whereas studies in the southern hemisphere (e.g., Africa south of the Sahara)
      emphasize enacted stigma (i.e., the type/amount of discrimination actually
      encountered). Cross-cultural research into the stigma of epilepsy may benefit
      from a multidisciplinary team from various cultural backgrounds, to develop a
      shared theoretical framework and shared research tools, which allow for
      contextual and cross-cultural adaptation.

PMID- 12609305
TI  - Evaluation and treatment of epilepsy in multiply handicapped individuals.
AB  - The evaluation and treatment of patients with seizures and multiple handicaps are
      challenging. An orderly approach to these patients, however, can be especially
      rewarding. As in other patient populations, evaluation rests on the clinical
      cornerstones of history, examination, imaging, and electroencephalography.
      Several disease entities are overrepresented in the multiply handicapped
      population. Here, we review the principles of evaluation and some of the most
      common etiologies of recurrent seizures afflicting handicapped individuals.
      Practical issues that arise in institutional settings are highlighted, and basic
      treatment principles are discussed.

PMID- 12609306
TI  - Psychiatric comorbidity in patients with developmental disorders and epilepsy: a
      practical approach to its diagnosis and treatment.
AB  - Psychiatric comorbidity in patients with developmental disorders and epilepsy
      (PDDEs) is relatively frequent. The majority of its pharmacological treatment has
      consisted of the use of neuroleptic drugs in an attempt to control behavioral
      disturbances, despite the fact that these symptoms may often mask underlying
      psychiatric disorders such as anxiety and depression, which require other types
      of psychotropic drugs. In this article, we review the pathogenic mechanisms that
      mediate the clinical manifestations of psychiatric disorders in PDDEs, highlight
      diagnostic strategies that may help in elucidating the correct psychiatric
      diagnosis, and review the psychopharmacological treatments available.

PMID- 12609307
TI  - Behavioral assessment in mentally retarded and developmentally disabled patients
      with epilepsy.
AB  - Behavioral disturbance is common in many individuals with mental retardation. Its
      presence in those with coexisting epilepsy provides a further challenge to the
      individual, caretakers, and family members. In particular, concerns that
      antiepileptic medication is causing such behavioral disturbances are often
      raised. For the clinician, assessment is crucial to minimize morbidity by
      appropriately identifying the cause of the behavioral disturbance. The assessment
      should aim to delineate whether the disturbance is due to a direct effect of
      epilepsy, its treatment, social impact, or factors unrelated to the epilepsy.
      However, before being able to make this differentiation, the clinician needs to
      understand the behavior itself. Assessing behavior in people with mental
      retardation requires a multifactorial approach. These factors include an
      objective and reliable description of the behavior and an assessment of its
      function. Detailed description requires a functional analysis of behavior. Such
      analysis may indicate the behavior is associated with epilepsy treatment or
      represents a seizure disorder in itself. In the majority of cases, though, it is
      likely that any disturbance seen is independent of epilepsy or its management.

PMID- 12609308
TI  - Treatment considerations: traditional antiepileptic drugs.
AB  - Selecting a specific antiepileptic drug for the treatment of seizures in those
      with mental retardation requires a balance of the drug's likely efficacy for both
      seizures and comorbid disorders versus adverse events. Phenobarbital is the most
      commonly used of the barbiturate drugs. Phenytoin is actually one of the best
      tolerated AEDs (side effects in most patients are signs of neurotoxicity).
      Carbamazepine is the drug of choice for many neurologists for the treatment of
      partial epilepsy, with a relative lack of sedation and low incidence of cosmetic,
      cognitive, and behavioral side effects. For more than 30 years, valproate has
      been available for treatment of generalized and partial seizures, convulsive or
      nonconvulsive. For this reason, it is used in the treatment of epilepsy in the
      multiply handicapped and mentally retarded. Benzodiazepines are the drug of
      choice for treatment of status epilepticus; however, good medical control
      requires early diagnosis and treatment.

PMID- 12609309
TI  - Antiepileptic drug treatment in the developmentally disabled: treatment
      considerations with the newer antiepileptic drugs.
AB  - Epilepsy is a common comorbidity among developmentally disabled (DD) patients,
      and special considerations apply to its treatment. In particular, clinicians
      should try to avoid antiepileptic drugs (AEDs) with sedating properties or
      adverse cognitive effects that might further diminish quality of life for DD
      patients. Behavioral changes due to medication and significant pharmacokinetic
      interactions with other medications are also concerns. The newer AEDs, approved
      in the 1990s, offer new options for the treatment of individuals with
      developmental disability and epilepsy. Gabapentin does not interact with the
      hepatic metabolism of other AEDs or psychotropic agents, results in a
      statistically significant reduction in seizure frequency in mentally retarded
      children, and is generally well tolerated. Felbamate is an effective broad
      spectrum AED, but has serious toxicity issues limiting its use. Lamotrigine has
      been extensively studied in the DD population, achieving seizure reduction rates
      of up to 50% in some trials. Although it is usually well tolerated in this
      population, its pharmacokinetic profile is influenced by concomitant medications.
      Levetiracetam has been found to be effective against kindled seizures and has
      been approved as adjunctive therapy for partial epilepsies. It does not cause any
      pharmacokinetic interactions, but may have behavioral side effects. Oxcarbazepine
      is a homologue of carbamazepine that has fewer drug interactions. It is approved
      for mono- or adjunctive therapy in patients with partial seizures, and its use in
      DD individuals appears to be worthwhile. Tiagabine is extensively bound to plasma
      proteins and is therefore subject to protein-binding displacement interactions by
      other highly protein-bound drugs, such as sodium valproate. While there are trial
      data showing its efficacy as adjunctive therapy in partial epilepsy in adults and
      children, there is a paucity of data specific to the DD population. Common side
      effects include sedation. Topiramate is a broad-spectrum AED approved as
      adjunctive therapy for partial and primary generalized tonic-clonic seizures. It
      appears to be particularly effective in patients with Lennox-Gastaut syndrome and
      those with cognitive disabilities. It appears to be better tolerated in the DD
      population than in the general population. Zonisamide has been effective in the
      DD population, yielding a seizure reduction of 50% in 41% of children in 1 trial.
      It has been associated with renal stone formation, sedation, and cognitive
      effects, however. The new AEDs have a role in treating seizures in the DD. Side
      effects that limit their use include anorexia, behavioral changes, and sedation.
      Seizure exacerbation can occur with the new AEDs and success is defined
      empirically and by improvements in quality of life.

PMID- 12609310
TI  - Treatment considerations: role of surgery.
AB  - Patients with developmental disabilities, including retardation and global
      developmental delay, are not ideal candidates for epilepsy surgery. Because they
      have an increased likelihood of diffuse brain dysfunction and multifocal or
      generalized epileptogenic zones, there is an increased chance that a focal
      cortical resection will not confer a major improvement in their seizure frequency
      and severity. There is also increased concern that cortical resection will lead
      to increase in the patient's disability. However, by applying the basic
      principles of epilepsy surgery selection (i.e., convergence of multiple lines of
      localizing evidence) to this population, patients with a reasonable likelihood of
      good seizure control can be identified. Various means of localizing seizure onset
      are reviewed, including history and examination, electroencephalography, magnetic
      resonance imaging, position emission tomography, single-photon-emission
      tomography, and magnetoencephalography.

PMID- 12609311
TI  - Treatment considerations: role of vagus nerve stimulator.
AB  - Epilepsy is considerably more common in individuals with mental retardation and
      developmental delays than in the general population. Compared with other groups
      with epilepsy, these individuals have higher seizure burdens, more often
      experience multiple seizure types, and more frequently have seizures that are
      medically refractory. The majority of these patients with refractory epilepsy
      will not have a surgically amenable epilepsy syndrome. For these individuals, the
      vagus nerve stimulator offers the potential for improved seizure control,
      abortive treatment of seizures, and medication reduction, which may lead to
      greater independence and other improvements in quality of life.

PMID- 12609312
TI  - Regulatory issues in the management of developmentally disabled patients.
AB  - Superimposed on the interplay of assessment and surgical and pharmacological
      treatment of epilepsy-intertwined with behavioral, psychiatric, and neurological
      conditions-are the fiduciary responsibilities and regulatory supervision
      necessary to protect the rights of developmentally disabled patients. Federal
      law, state regulations, interpretative material, and legal precedents contribute
      to a cumbersome, confusing, and frequently demoralizing guide to psychiatric care
      of mentally ill and developmentally disabled individuals. The Code of Federal
      Regulation governs people living in long-term residential facilities. Using
      examples from Wisconsin law, clinical and legal concepts are illustrated. Annual
      seizure graphs are used for frequent monitoring, better trend analysis, and
      reduced polypharmacy. An experienced board-certified psychiatrist ensures that an
      initial comprehensive psychiatric assessment, diagnosis, treatment plan, and
      quarterly treatment plan update-essential items for the Department of Justice's
      CRIPA review-are conducted. Most states have legislation designed to provide
      guidelines for the use of psychotropic medications to minimize abuse.

PMID- 12609313
TI  - Treatment of depressive disorders in epilepsy patients.
AB  - Epilepsy is a complex disorder that is associated with multiple adverse
      psychosocial effects. Depression appears to be the most prevalent psychiatric
      condition in epilepsy and has the greatest impact on subjective health status.
      Advances in neuroimaging indicate that depressive symptoms are predominantly
      associated with brain dysfunction, as opposed to social or vocational disability.
      These findings underscore the need to routinely screen persons with epilepsy for
      depression, using simple but accurate instruments, and to select the best
      treatment for each patient, based on adequate understanding of the available
      pharmacological and interpersonal therapies. This paper reviews epidemiological,
      health impact, screening and diagnosis, and treatment considerations in
      depressive disorders associated with epilepsy.

PMID- 12609314
TI  - Treatment of anxiety in epilepsy.
AB  - The association of anxiety with epilepsy has been noted for centuries. Anxiety
      can occur at different phases of a seizure event and present with diverse
      clinical symptoms similar to those seen in panic, obsessive-compulsive, or
      generalized anxiety disorders. Pharmacologic and nonpharmacologic treatments of
      anxiety in the context of epilepsy are discussed.

PMID- 12609315
TI  - Treatment of psychosis, aggression, and irritability in patients with epilepsy.
AB  - Psychosis, irritability, and aggression in persons with epilepsy are frequently
      the focus of clinical intervention. These neuropsychiatric symptoms may occur due
      to the bidirectional relationship between psychosis and epilepsy, in which the
      potential etiopathogenic mechanisms are believed to be closely related to the
      seizure disorder itself and also may result from underlying brain injury or
      behavioral intolerance of antiepileptic or other medication. Epileptic patients
      are at heightened risk for mood disorders, psychotic disorders, and delerium. The
      possible lowering of seizure threshold by psychotropic drugs should not
      contraindicate appropriate use of psychotropic agents, and risk may be minimized
      by the selection of agents not associated with a relatively high likelihood of
      altering seizure threshold. Behavioral toxicity of antiepileptic drugs (AEDs) is
      addressed by selection of alternative agents, and some AEDs appear to possess
      positive psychotropic effects. The use of antipsychotic, antidepressant, and
      other psychotropic agents in psychosis, irritability, and aggression in epilepsy
      is discussed, including dosage ranges, major side effects, and potential
      interactions between antieplieptic and psychotropic medication.

PMID- 12609316
TI  - Treatment of nonepileptic seizures.
AB  - Studies on nonepileptic seizures (NES) provide dichotomous data sets: extensive
      observational findings, but a paucity of controlled treatment data. Psychosocial
      stressors, whose full impact may lie outside a patient's awareness, often
      underlie NES. These stressors, along with patient's learned patterns of coping,
      may bring forth or potentiate comorbid psychiatric disorders. Patients with NES
      often have dysfunction in emotion regulation and family dynamics, as well as
      unemployment/disability. High percentages of comorbid disorders such as major
      depressive disorder, post-traumatic stress disorder, and cluster B personality
      with impulsivity (all disorders associated with serotonin system function) also
      exist in the NES population. The preliminary observational evidence suggests that
      specific psychotherapies and pharmacotherapy directed at comorbid conditions may
      be the most effective treatment for NES.

PMID- 12609317
TI  - Treatment strategies in Landau-Kleffner syndrome and paraictal psychiatric and
      cognitive disturbances.
AB  - Psychiatric and cognitive disturbances of the peri-ictal period (i.e., the
      seizure prodrome and the postictal period) can be considered paraictal
      disturbances, as they are directly related to the ictal event. There are also
      certain interictal psychiatric and cognitive disturbances that become apparent
      concomitantly with the onset of a seizure disorder and remit and/or significantly
      improve upon its remission. Such disorders also fall under the classification
      paraictal disorders, and are exemplified by Landau-Kleffner syndrome (LKS), a
      disorder in which language and psychiatric disturbances begin with the onset of
      epileptic activity and improve upon its disappearance. In this article, we review
      the treatment of paraictal cognitive and psychiatric disorders presenting as
      preictal and postictal psychiatric disturbances and LKS.

PMID- 12609318
TI  - Treatment of memory disorders in epilepsy.
AB  - Impaired memory is a common and often debilitating complaint in patients with
      epilepsy. Overlapping variables such as seizure control, attentional dysfunction,
      and mood disorders further complicate diagnosis and management. Direct therapy
      for memory deficits associated with epilepsy is rarely attempted. The varied
      pharmacological (AED selection, cholinesterase inhibitors, stimulants,
      antidepressants, and herbal supplements) and nonpharmacological approaches to
      cognitive remediation in epilepsy patients are reviewed.

PMID- 12609319
TI  - Treatment of sleep disorders in epilepsy.
AB  - The interrelationship of sleep and epilepsy is described. Seizures and their
      treatment, including antiepileptic medications, may affect sleep. In turn, sleep
      disorders may influence seizure control and contribute to daytime sleepiness in
      epilepsy patients. Parasomnias and other sleep-related disorders may mimic
      epileptic seizures, although the history and video-EEG polysomnography are often
      useful in distinguishing these events. The treatment of epilepsy patients with
      sleep disorders or sleep complaints, such as sleepiness or insomnia, is
      discussed. Diagnosis and treatment of coexisting sleep disorders may improve not
      only daytime sleepiness, but also seizure control. Sedating AEDs may benefit
      epilepsy patients with insomnia, and stimulating AEDs may benefit epilepsy
      patients with daytime sleepiness.

PMID- 12609320
TI  - Treatment of sexual disorders in people with epilepsy.
AB  - Sexual dysfunction is underreported in persons with epilepsy. The evaluation of
      sexual physiology in small samples of epilepsy patients shows abnormal sexual
      functioning, and points to low free testosterone levels as a contributing factor.
      Abnormal sexual physiology in epilepsy patients may be due to antiseizure
      medication-related altered testosterone metabolism and abnormal central
      gonadotropin secretion due to epileptic physiology in the brain. More information
      exists on the sexual side effects of "classic" antiseizure medications than the
      "new generation" of antiseizure medications; barbiturates appear to have the
      greatest risk. More active surveying for sexual dysfunction should be undertaken
      in epilepsy clinics; a simple, self-reported scale of sexual functioning is
      available. Testosterone replacement for men, dehydroepiandrosterone for women,
      and sildenafil for restoring sexual performance are appropriate.

PMID- 12609321
TI  - Treatment of attention-deficit disorder, cerebral palsy, and mental retardation
      in epilepsy.
AB  - Epilepsy in childhood is often associated with other neurologic disorders,
      including attention-deficit/hyperactivity disorder, cerebral palsy, and mental
      retardation. A single pathologic process may explain both epilepsy and these
      associated disorders. However, in some cases, distinct etiologies may be present.
      Recognition of these problems is essential, as is individualized treatment.
      Proper classroom placement; behavior modification, speech, occupational, and
      physical therapies; pharmacological agents; and even surgical procedures have a
      role in the management of these comorbid disorders. Diagnostic criteria and
      therapeutic modalities used in these syndromes will be discussed.

PMID- 12609322
TI  - Cognitive and behavioral effects of antiepileptic drugs.
AB  - Multiple factors contribute to the increased risk of cognitive and emotional
      deficits experienced by patients with epilepsy, including both the underlying
      disease state from which they suffer and the psychosocial disruption in their
      lifestyles that their seizures can produce. While antiepileptic drugs (AEDs) have
      the potential to reduce such risks by reducing seizure activity, they can also
      compound problems by dampening neuronal excitability throughout the brain and
      altering underlying neurochemical systems that impact thinking and mood.
      Therefore, for optimal treatment of epilepsy, one must achieve a balance between
      adequate seizure control and minimizing the potential side effects of the
      employed AEDs. This requires knowledge of the specific cognitive and behavioral
      effects of both established newer AEDs and an understanding of the general
      principles governing their delivery.

PMID- 12609324
TI  - Message from the Editor.

PMID- 12609323
TI  - Psychiatric uses of antiepileptic treatments.
AB  - Antiepileptic drugs (AEDs) possess potent negative or positive psychotropic
      effects. Clear evidence of benefit exists for valproate, carbamazepine, and
      lamotrigine in bipolar disorder. Reports of benefit from various AEDs in mood,
      anxiety, impulse control, and personality disorder are reviewed. Further research
      is needed to clarify which patients are likely to benefit. Clinicians must
      closely attend to the ongoing risk/benefit analysis and consider possible
      iatrogenic worsening of neuropsychiatric symptoms.

PMID- 12609325
TI  - From the Epilepsy Foundation.

PMID- 12609326
TI  - Forced normalization at the interface between epilepsy and psychiatry.
AB  - In 1953, Landolt described a group of patients with poorly controlled epilepsy
      who had psychotic episodes associated with remission of their seizures and
      disappearance of epileptiform activity on their EEGs. He called this phenomenon
      "forced normalization." Since then, neurologists and psychiatrists have been
      intrigued by this phenomenon, and although it has been also reported by others,
      its existence continues to be the source of much debate. In this article, we
      review the clinical characteristics and potential pathogenic mechanisms of forced
      normalization and illustrate the complexities inherent in reaching this
      diagnosis, as well as its differential diagnosis in two representative cases.

PMID- 12609327
TI  - The frontal lobe role in memory: a review of convergent evidence and implications
      for the Wada memory test.
AB  - Functional imaging studies have implicated the frontal lobe in many of the memory
      processes often thought to be the domain of medial temporal structures. Results
      from fMRI studies of normal subjects have suggested that some components of
      memory formation, including those components tested during the Wada memory test,
      may involve frontal lobe regions. Specific behavioral disruptions during carotid
      amytal injections support a model for frontal lobe anesthesia in explaining
      results of the Wada memory test. Cortical stimulation data suggest that frontal
      lobe disruption is sufficient to cause memory disturbances. The convergence of
      evidence suggests frontal lobe memory may limit the predictive value of the Wada
      memory test in defining the risk of memory loss following temporal lobectomy.

PMID- 12609328
TI  - Cognition and health-related quality of life in chronic well-controlled patients
      with partial epilepsy on carbamazepine monotherapy.
AB  - As a group, patients with epilepsy have reduced neuropsychological functioning
      and health-related quality of life (HRQOL), but the status of these factors is
      uncertain in seizure-free patients with seizure onset in adulthood on
      monotherapy. Nevertheless, some of these patients report neuropsychological
      problems. We hypothesized that subtle impairments in neuropsychological
      functioning and HRQOL may be underdiagnosed and related to these problems.
      Sixteen patients with localization-related epilepsy on monotherapy carbamazepine
      were compared with 16 age-, gender-, and education-matched healthy controls by
      means of a standardized neuropsychological screening battery, questionnaires
      about HRQOL (Short-Form Health Survey, SF-36), self-perceived neuropsychological
      functioning (Cognitive Failure Questionnaire), and mood (Profile of Mood States).
      No objective impairments in selective attention, memory, and executive
      functioning were found. However, a lower speed of information processing
      affecting everyday life functioning was found. Lower levels of self-perceived
      neuropsychological functioning were reported, whereas HRQOL was unimpaired
      relative to healthy controls. Physicians should not be reassured when patients
      receive adequate medication that prevents seizures; careful follow-up of speed of
      information processing and self-perceived neuropsychological functioning is
      needed.

PMID- 12609329
TI  - Parent-reported subjective complaints in children using antiepileptic drugs: what
      do they mean?
AB  - We used a parent-completed 20-item "side effect scale" quantifying complaints
      that parents perceive to be caused by antiepileptic drugs (AEDs) in 108 children
      with active epilepsy. We studied the associations between parent-reported
      complaints, severity of seizures, and restrictions due to epilepsy, and clinical
      data including number and AED load. In 85% of the children at least one complaint
      was reported, in less than 20% complaints were perceived as a substantial
      problem. In a multivariate analysis, there was no significant relationship
      between the "side effect scale" score and AED load, or the number of AEDs.
      However, complaints were associated with parent-reported frequency and severity
      of seizures. We conclude that the adverse effects of seizures or parental concern
      about the severity and intractability of seizures in their children may have
      influenced the reported complaints.

PMID- 12609330
TI  - Comorbidity of ictal fear and panic disorder.
AB  - Purpose. We sought to determine the prevalence of psychiatric conditions,
      particularly panic disorder, in epilepsy patients with ictal fear.Methods. A
      consecutive series of 12 patients with ictal fear underwent psychiatric
      evaluation, via either formal consultation with a psychiatrist or standardized
      interview using the Mini International Neuropsychiatric Interview; the latter was
      addended to create an instrument specifically for use in epilepsy patients (MINI
      Epi).Results. Four of the twelve patients (33%) with ictal fear had a comorbid
      diagnosis of panic disorder. One of these developed panic attacks only after
      epilepsy surgery, and another worsened after surgery, while in the other two
      panic attacks were not related to any surgical procedure. Two patients had other
      anxiety disorders. Eight patients (67%) had current or past depression; this did
      not appear to be related to the presence of panic disorder.Conclusion. A specific
      comorbidity exists between focal epilepsy with ictal fear and panic disorder.
      Involvement of the amygdala in both temporal lobe epilepsy and panic disorder may
      underlie this. The predisposition to panic disorder in these patients may be
      exacerbated by anterior temporal lobectomy.

PMID- 12609331
TI  - The relationship between poor medication compliance and seizures.
AB  - Predictors and consequences of inadequate compliance with seizure medications
      were assessed using a 10-item postal survey. Dose omissions were reported by 71%
      of the 661 respondents (2+/-2 doses of seizure medications), with 45% of patients
      reporting a seizure after a missed dose, at some time during treatment. Dose
      omission was more likely with longer use of seizure medications (more than 5
      years, P<0.01). Having seizures after missed doses was associated with number of
      seizure medication doses (P=0.04) and number of seizure medication
      tablets/capsules (P=0.01). Odds ratios showed that each increase in dose
      frequency (one, two, three, or four doses daily) increased the likelihood of a
      seizure after a missed dose by 36%. Taking larger numbers of tablets/capsules
      increased the odds of having a seizure after missed doses by 43%. These data
      provide evidence that medication compliance remains an important issue in
      epilepsy treatment.

PMID- 12609332
TI  - Psychological factors in the genesis and management of nonepileptic seizures:
      clinical observations.
AB  - Nonepileptic seizures (NES) are frequently thought to have a "psychogenic" basis.
      Two 6-month group psychotherapy programs were provided for patients diagnosed as
      having NES [eight patients were treated during the first program, seven during
      the second (N=15)] to explore the potential role of psychological factors in the
      genesis of NES and to determine if psychotherapeutic interventions reduced the
      frequency of NES. Of the 15 patients, 9 (60%) completed at least 58% of the
      treatment sessions. Of those 9 patients, 6 (66%) reported a decline in "seizure
      frequency." One reported an increase (11%). Self-reported frequency highly
      correlated with paranoid ideation. Dissociative phenomena were common as was a
      history of sexual abuse. Each patient reported being in an adult situation that
      they found unacceptable or intolerable. None perceived a solution to their
      situation. Reports by health care providers that their seizures were not "real"
      (i.e., true epilepsy) restimulated feelings associated with their not being
      believed when they reported being sexually abused as children. The psychological
      genesis of NES in this sample of patients appears rooted in the recurrent
      experience of being in abusive or exploited relationships for which they
      perceived no solution.

PMID- 12609333
TI  - Predicting the quality of life in Hong Kong Chinese adults with epilepsy.
AB  - Epilepsy is both a medical diagnosis and a social label. The traditional care of
      patients with epilepsy tends to focus on seizure control and drug treatment.
      There is a growing concern in the West about the importance of the influence of
      psychosocial factors on the quality of life. The main purpose of the present
      study is to explore and delineate the relationships between biomedical and
      psychosocial predictors and the health-related quality-of-life outcomes of
      Chinese patients in Hong Kong. Independent measures consisted of two types of
      predictors: biomedical and psychosocial variables. The biomedical variables
      included seizure frequency and the number of years since diagnosis. The
      psychosocial variables included locus of control, social support, and mood. The
      Quality of Life in Epilepsy Scale was used as the outcome measure. Correlation
      and hierarchical regression techniques were used. Results showed that
      psychosocial variables did make a significantly independent contribution to the
      prediction of the quality of life of patients with epilepsy. Furthermore, results
      suggested that mood could act as a mediator between seizure characteristics and
      psychosocial factors, on the one hand, and quality of life, on the other. The
      statistical significance of the health locus of control and the satisfaction with
      social support confirmed the importance of the influence of the subjective sense
      of mastery of condition on quality of life. The clinical implication was
      discussed in the context of developing psychological interventions in increasing
      the self-efficacy and resourcefulness of the patients.

PMID- 12609334
TI  - The behavioral and emotional correlates of epilepsy in adolescence: a 7-year
      follow-up study.
AB  - This 7-year follow-up study examined the behavioral and emotional adjustment of
      29 adolescents who experienced regular moderate seizures during middle childhood.
      Compared with national nonreferred norms on Achenbach checklists, both mothers
      and adolescents reported clinically significant difficulties in multiple areas
      regardless of current seizure status. Adolescents who currently experience
      regular seizures (N=10) reported no differences on psychological outcomes
      compared with nonseizing counterparts; in contrast, current seizure status was a
      strong predictor of mother-reported externalizing problems. Hierarchical
      regression analyses indicated that feelings about having or having had a seizure
      disorder and mother-adolescent relationship factors were significant predictors
      of current adjustment over and above current seizure status. Early mother-child
      relationship process variables and early medical risk were not associated with
      current adolescent outcomes. The findings are discussed in terms of the
      multidetermined nature of psychological adjustment to chronic medical illness and
      factors that may produce versus maintain behavioral and emotional problems in
      children and adolescents with seizure disorders.

PMID- 12609335
TI  - Epilepsy familiarity, knowledge, and perceptions of stigma: report from a survey
      of adolescents in the general population.
AB  - The Epilepsy Foundation surveyed general population adolescents concerning
      epilepsy. From March to July 2001, a 37-item questionnaire was distributed by 20
      Epilepsy Foundation affiliates to high school students. The final sample was
      19,441. Data were analyzed using descriptive statistics. Only about half (52%)
      remembered hearing about epilepsy. Most (67%) were not sure what to do if someone
      had a seizure. About three-fourths believed that youth with epilepsy were or
      might be more likely to get bullied or picked on than others. Less than a third
      (31%) would date a person with epilepsy. Results indicate that the social
      environment for adolescents with epilepsy is characterized by stigma and lack of
      familiarity and knowledge about epilepsy. Findings strongly support the need for
      public education for general population adolescents to increase knowledge and
      awareness to decrease the stigma associated with epilepsy.

PMID- 12609336
TI  - Lamotrigine monotherapy improves health-related quality of life in epilepsy: a
      double-blind comparison with valproate.
AB  - The effects of monotherapy with lamotrigine on health-related quality of life
      were compared with those of valproate monotherapy in a randomized, double-blind
      trial designed to evaluate treatment-emergent weight changes in patients with
      epilepsy. At the end of 8 months of treatment, significantly more patients using
      lamotrigine compared with valproate experienced quality-of-life improvements on
      the Health Perceptions (42% vs 15%), Energy/Fatigue (47% vs 28%), and Social
      Isolation (35% vs 16%) subscales of the Quality of Life in Epilepsy-89 (QOLIE-89)
      questionnaire (P<0.05). Compared with valproate-treated patients, lamotrigine
      treated patients were four times more likely to experience improvement in Health
      Perceptions, 2.3 times more likely to experience improvement in Energy/Fatigue,
      and 2.8 times more likely to experience improvement in Social Isolation (P<0.05).
      These quality-of-life improvements are consistent with the improvements in mood
      measured with the Beck Depression Inventory, the Cornell Dysthymia Rating Scale,
      and the Profile of Mood States among patients receiving lamotrigine. These data
      show that lamotrigine monotherapy provides benefits over valproate monotherapy in
      improving several aspects of health-related quality of life in patients with
      epilepsy. The observation that quality-of-life improvements during lamotrigine
      monotherapy occurred concurrently with improvements in mood suggests that the
      quality-of-life and mood changes may be causally related.

PMID- 12609337
TI  - Predictors of postoperative memory function after left anterior temporal
      lobectomy.
AB  - Patients who undergo left anterior temporal lobectomy (ATL) for intractable
      epilepsy are at risk of postoperative memory decline. This study attempts to
      identify the best predictors of memory after ATL using preoperative tests. Thirty
      two consecutive patients who underwent left ATL with preoperative and
      postoperative neuropsychological testing were retrospectively identified. The
      following independent variables were analyzed by multiple regression: age of
      onset of seizures, age of temporal lobe damage, gender, MRI results, preoperative
      memory testing, and intracarotid amytal procedure (IAP) results.
      Neuropsychological measures of verbal and nonverbal memory served as dependent
      variables. Male gender (P<0.005), failing the IAP with both left and right
      hemispheres (P<0.001), and higher logical memory (LM) scores preoperatively
      (P<0.001) were associated with greater declines in LM after surgery. Our data
      demonstrate that the IAP predicts postoperative memory independent of other
      factors known to affect memory after left ATL.

PMID- 12609339
TI  - The clinical applications of EEG: origins.

PMID- 12609338
TI  - Prospero Lambertini: miraculous cure of epilepsy and canonization of Vatican
      saints.

PMID- 12609340
TI  - Epilepsy: a paroxysmal cerebral dysrhythmia.

PMID- 12609343
TI  - Remacemide versus carbamazepine in newly diagnosed epilepsy.

PMID- 12609345
TI  - Metabolism of tricyclic anticonvulsant drugs.

PMID- 12609344
TI  - Introduction.

PMID- 12609346
TI  - Tricyclic anticonvulsants: mechanisms of action.

PMID- 12609347
TI  - Tricyclic anticonvulsants: efficacy in clinical trials.

PMID- 12609348
TI  - Tricyclic anticonvulsants: safety and adverse effects.

PMID- 12609349
TI  - Clinical use of tricyclic anticonvulsants in painful neuropathies and bipolar
      disorders.

PMID- 12609350
TI  - Message from the Editor.

PMID- 12609351
TI  - Depression and Mood Disorders.

PMID- 12609352
TI  - Peri-Ictal Behavioral and Cognitive Changes.
AB  - Peri-ictal behavioral and cognitive changes contribute substantially to
      disability and distress among people with epilepsy. Psychosis, depression, and
      suicide may all occur as complications of seizures. Greater appreciation and
      understanding of the peri-ictal period is clinically important and might open
      novel therapeutic windows. At the same time this period provides a model for
      understanding basic mechanisms underlying mood and thought disorders and the
      substrates of cognition, volition, emotion, and consciousness. This review will
      discuss behavioral and cognitive antecedents of seizures, including the preictal
      milieu, reflex seizures, and self-induced seizures. Behavioral and cognitive
      treatment approaches that have been undertaken are reviewed. Both acute and
      delayed postictal emotional, behavioral, and cognitive changes will be discussed.
      Finally, possible mechanisms by which epileptic brain activity and behavior may
      modify each other are considered.

PMID- 12609353
TI  - Neuropsychological Outcome in Children after Frontal Lobe Epilepsy Surgery.
AB  - We investigated the neuropsychological performance of children with frontal lobe
      epilepsy (FLE, n = 12) before and 1 year after surgery. Children with temporal
      lobe epilepsy (TLE, n = 12) were included as control group. Preoperatively,
      children with FLE had a significantly higher IQ than children with TLE, but were
      significantly more often impaired in manual motor coordination. Postoperatively,
      both groups improved in attention, short-term and long-term memory, and manual
      coordination, although the latter was not significant. Neuropsychological outcome
      in FLE patients was not better in seizure-free patients than in patients with
      continuing seizures. To avoid deterioration in language functions of patients in
      whom surgery involved left area 44, correspondence of results in cortical
      stimulation and intracarotid amytal test may be essential. All in all, our data
      indicate a favorable cognitive outcome in children 1 year after frontal lobe
      surgery.

PMID- 12609354
TI  - Recurrent Bicuculline-Induced Seizures in Rat Pups Cause Long-Term Motor Deficits
      and Increase Vulnerability to a Subsequent Insult.
AB  - Recurrent neonatal seizures are associated with a high risk of neurological
      sequelae. The major concern is whether recurrent neonatal seizures induce adverse
      effects on long-term cognition and/or motor performance. Rats were treated with
      intraperitoneal (ip) bicuculline for 3 consecutive days, starting from Postnatal
      Day 5 (P5). Kainic acid (KA, 4 mg/kg ip) was injected at P53 to investigate the
      susceptibility to a second insult, and then cognitive function was tested using
      the Morris water maze, and motor performance using the Rotarod test, in adulthood
      (P60). Finally, histological assessments of brains were performed. The rats
      treated with bicuculline had no deficits in cognition function and pathology
      findings, but had worse motor performance and increased susceptibility to later
      KA challenge. Our findings indicate that recurrent bicuculline-induced seizures
      in the developing brain result in long-term motor deficits and increase the risk
      of subsequent cognitive damage in response to a second insult.

PMID- 12609355
TI  - Nonorganic and Organic Psychiatric Disorders in Patients after Epilepsy Surgery.
AB  - This study aimed at describing preoperative psychiatric morbidity in a
      consecutive series of 70 epilepsy patients who were surgically treated and to
      analyze postoperative psychiatric morbidity and predisposing factors. Nonorganic
      (DSM-III-R) and organic (Lindqvist-Malmgren diagnostic system) psychiatric
      morbidity was prospectively assessed preoperatively and during the first two
      postoperative years. At presurgical evaluation 44.3% of the patients had a
      psychiatric diagnosis (nonorganic in 14.3%, organic in 38.6%). The most common
      nonorganic diagnosis was major depression; the most common organic diagnosis was
      Astheno-Emotional disorder (AE disorder). During the first two postoperative
      years 68.1% of the patients received some psychiatric diagnosis. The most common
      nonorganic diagnoses were anxiety and depressive disorders (AD disorders) in
      36.2%; the most common organic diagnosis was AE disorder in 52.2%. Patients with
      a preoperative history of AD disorders or AE disorder had a significantly higher
      risk of postoperative AD disorders (P < 0.01 and P < 0.001 respectively).
      Laterality, type of resection, histopathological diagnosis, or outcome were not
      significantly related to postoperative psychiatric morbidity. The importance of
      psychiatric assessment, including organic psychiatric disorders, is emphasized.

PMID- 12609356
TI  - Temporal Lobe Resections in Children with Epilepsy: Neuropsychiatric Status in
      Relation to Neuropathology and Seizure Outcome.
AB  - The purpose of this work was to relate clinical neuropsychiatric findings to
      histopathological diagnoses and seizure outcome in a retrospective study of 16
      children undergoing temporal lobe resections due to medically intractable
      epilepsy. These children constitute a heterogeneous group in which
      neuropsychiatric symptoms were common. The results of this study indicate a
      correlation between malformations of cortical development, less chance of seizure
      freedom, and neuropsychiatric problems in children with pharmacoresistant
      temporal lobe epilepsy. It is important to include neuropsychiatric assessments
      pre- and postoperatively and to inform parents that symptoms of autism spectrum
      disorders may or may not be improved after epilepsy surgery.

PMID- 12609357
TI  - Bilateral Memory Dysfunction in Epilepsy Surgery Candidates Detected by the
      Intracarotid Amobarbital Procedure (Wada Memory Test).
AB  - The intracarotid amobarbital procedure (IAP) is widely used in the evaluation of
      candidates for resective epilepsy surgery, in part to identify patients at risk
      for postoperative amnesia. Yet there is no widely accepted standardized protocol,
      and there is a paucity of quantitative data to assess the factors associated with
      poor IAP performance. This report summarizes our findings on 110 patients with
      intractable focal epilepsy who underwent IAP testing at our center. Ipsilateral
      IAP scores for patients with left-sided seizure foci were significantly lower
      than those for patients with right-sided seizure foci. Falsely and poorly
      lateralizing scores were also significantly more common in subjects with left
      sided seizure onsets. Twenty-four percent of subjects failed the IAP bilaterally,
      and patients who failed the IAP bilaterally had significantly lower scores on
      neuropsychologic measures. There was no difference between patients who passed
      and failed in the location, etiology, duration, or age of onset of epilepsy. We
      conclude that bilateral memory dysfunction is common in patients with intractable
      partial epilepsy. Whether memory dysfunction detected by IAP testing as performed
      at our center is predictive of functionally limiting postoperative amnesia
      remains to be determined.

PMID- 12609358
TI  - An Evaluation of the Effects of Methylphenidate on Outcomes in Adult Epilepsy
      Patients.
AB  - Purpose. To determine if methylphenidate (MPH) therapy can improve cognition in
      adult epilepsy patients on multiple antiepileptic drugs (AEDs), we assessed the
      impact of MPH on seizure activity, quality of life, cognition, and fatigue in
      patients with a primary diagnosis of localization-related epilepsy.Methods. This
      was an open-label, nonrandomized 3-month study. MPH (Ritalin) was added to
      patients' current antiepileptic drug regimens. Outcome measures included seizure
      activity, select AED serum concentrations, quality of life (via Quality of Life
      in Epilepsy-89 questions (QOLIE-89)), cognition (via Microcog), and fatigue (via
      a visual analog scale) at baseline and at monthly intervals for the treatment
      phase.Results. Eleven patients were enrolled and eight completed this pilot
      study. Of the eight completing the study, five were seizure-free at baseline and
      throughout the study. One patient had an increase, one a decrease, and one no
      change in seizure activity. No serious adverse events were observed. On average,
      serum AED concentrations changed <10% from baseline to the end of the study. Mean
      overall QOLIE-89 scores and select domains improved significantly from baseline.
      All Microcog domains improved from baseline. Fatigue also improved
      significantly.Conclusions. Adult epilepsy patients received relief from sedation
      with MPH and showed an improved quality of life, without significant alteration
      of seizure control.

PMID- 12609360
TI  - Message from the Editor.

PMID- 12609359
TI  - Chronically Impaired Frontal Lobe Function from Subclinical Epileptiform
      Discharges.
AB  - Subclinical epileptiform discharges (SEDs) are a common occurrence on
      electroencephalograms (EEGs). Their potential for acutely disrupting cognitive
      functions has been well documented, but detailed studies of cognitive performance
      by patients with chronic exposure to disruptive SEDs have been lacking and scant
      data have been available to guide treatment decisions or to assist in predicting
      recovery. We identified a patient with frequent frontotemporally (FT) predominant
      SEDs and monitored cognitive performance over time with periodic
      neuropsychological testing and EEGs. Over a 16-year period, Full Scale IQ rose 23
      points and Verbal IQ rose 30 as SEDs were suppressed. Severity of impairment,
      reflected by the marked increase in cognitive performance over time, was not
      predicted by his appearance and performance on routine tests of cognitive
      functions in the clinic. Quantitating total SED duration per EEG provided an
      objective marker to track severity over time. The cumulative effects of chronic
      exposure to disruptive SEDs may create a sustained "cognitive burden" or
      encephalopathic state that persists even in the absence of ongoing discharges.

PMID- 12609361
TI  - From the Epilepsy Foundation.

PMID- 12609362
TI  - Is the Psychopathology of Epilepsy Different from That of Nonepileptic Patients?

PMID- 12609363
TI  - Active-Control Comparative Equivalency Monotherapy Trials in Epilepsy: Are They
      Scientifically Valid?

PMID- 12609364
TI  - The Ethical and Scientific Shortcomings of Current Monotherapy Epilepsy Trials in
      Newly Diagnosed Patients.

PMID- 12609365
TI  - Overview of the Current Animal Models for Human Seizure and Epileptic Disorders.
AB  - A diversity of animal models are available for the study of epilepsy and these
      models have a proven history in advancing our understanding of basic mechanisms
      underlying epileptogenesis and have been instrumental in the screening of novel
      antiepileptic drugs. This review addresses the criteria that should be met in a
      valid animal model and provides an overview of current animal models that are
      relevant to human conditions. In addition, models not specific for any one human
      condition but rather exhibiting partial or generalized seizures are discussed.
      While most human disorders are without any animal model, those models that are
      clinically relevant have strengths and weaknesses. Finally, although few
      relevant, well-characterized animal models have been added to the list over
      recent years, major advancements in molecular genetics are contributing to the
      discovery of novel pathways involved in epileptogenesis.

PMID- 12609366
TI  - Factors Associated with Academic Achievement in Children with Controlled
      Epilepsy.
AB  - Children with epilepsy are at risk for academic underachievement. Multiple
      etiologies for this academic vulnerability have been suggested by past research
      including lower self-esteem, inattention, memory inefficiency, and lower
      socioeconomic status. The present study assessed 65 children (mean age = 10
      years, 5 months) with well-controlled epilepsy on the four primary factors, as
      well as academic achievement and intelligence. A stepwise regression analysis was
      employed with academic achievement as the dependent variable and measures of self
      esteem, attention, memory, and socioeconomic status as independent variables.
      When intelligence was controlled, attention was the only variable associated with
      achievement scores. Seizure variables including seizure type and duration of
      epilepsy were not associated with differences in academic performance. Findings
      support the importance of measuring attention skills in children with epilepsy
      and suggest that reduced auditory attention skills may be associated with
      decreased academic performance in these children.

PMID- 12609367
TI  - Severe Amnesia in Epilepsy: Causes, Anatomopsychological Considerations, and
      Treatment.
AB  - Severe amnesia in epileptic patients is a catastrophic condition that may be due
      to different etiologies. Because of the striking findings and thorough
      neuropsychological studies of Patient H.M., the literature has focused on
      postsurgical occurrence of such memory impairment, with much less emphasis on
      other causes. Here we summarize, for comparison, the history of H.M. We report
      five patients with pronounced memory loss who had extensive neuropsychological
      and electroencephalographic testing. MRI was also performed in four of the
      patients, MRI volumetric measurements of amygdala and hippocampal formation in
      three, and measurements of entorhinal cortex in two. The amnesia occurred after
      head trauma in one patient, following encephalitis in one, after partial status
      epilepticus in two, and after unilateral surgical resection in a woman with
      bilateral lesions. On the basis of these studies it was impossible to distinguish
      the role of recurrent temporal lobe epileptic seizures as distinct from
      underlying lesions in the genesis and course of the memory loss. We review here
      the anatomical substrate, neuropsychological, and other investigations and the
      etiological factors leading to the amnesia in these patients, together with
      current concepts regarding possible causes of such severe memory dysfunction. In
      patients with this degree of severity of memory deficit, temporal resection in an
      attempt to control seizures did not lead to a measurable increase in memory
      problems. It also, however, did not bring about worthwhile improvement in seizure
      control.

PMID- 12609368
TI  - The Development of a Method to Assess Patients' Cognitive Representations of
      Epilepsy.
AB  - Objective. The study describes the development of a new method for assessing
      cognitive representations of epilepsy.Methods. The study was a cross-sectional
      design contrasting the cognitive representations of three groups of epilepsy
      patients, varying in recency of onset (acute vs chronic) and the location of
      medical management (hospital vs community). A total of 94 patients were studied:
      21 recent onset, 47 patients with chronic epilepsy attending the clinic and 26
      patients with chronic epilepsy seen by general practitioners. An interview that
      combined open questions and structured questionnaire items was devised to assess
      six illness representation components; identity, beliefs about symptoms; causal
      beliefs; timeline, beliefs about temporal course; consequences, beliefs about the
      implications of epilepsy; control beliefs; and self-illness relationship, or the
      impact of epilepsy on patients' self perceptions.Results. The scales formed by
      the questionnaire items had satisfactory internal consistency. Further, the
      scales demonstrated logical interrelationships, and significant differences were
      found between the scales on group difference tests.Conclusions. Overall, the data
      provide support for the approach of administering quantitative illness
      representation scales within a brief structured interview format. The measure
      provides a way to elicit the health beliefs that determine patients' psychosocial
      reactions to epilepsy. Such insights are important in the development of
      effective psychological interventions.

PMID- 12609369
TI  - Treatment of Childhood Idiopathic Language Deterioration with Valproate.
AB  - Childhood idiopathic language deterioration is a rare condition in which children
      lose previously gained language skills. In some children this language
      deterioration occurs in association with behavioral seizures or EEG epileptiform
      activity. The effectiveness of antiepileptic drugs in this patient population is
      not known. Here we retrospectively reviewed records of 57 children with childhood
      idiopathic language deterioration associated with seizures or epileptiform
      activity on their EEG who received valproate for the purpose of treating their
      language impairment. In 22 of the children improvement in language skills was
      observed. In two children language returned to normal while in the other 20 the
      improvement was modest. Children who responded to valproate had an earlier age of
      onset of the aphasia than children who were nonresponders. Seizure type, EEG
      findings, developmental status, and presence or absence of a frequency-modulated
      auditory evoked potential were not related to response. This study demonstrates
      that valproate can be helpful in improving language function in some children
      with idiopathic language deterioration associated with seizures or epileptiform
      activity on the EEG.

PMID- 12609370
TI  - Psychological Treatment of Nonepileptic Events.
AB  - Nonepileptic events (NEEs) occur with and without true seizure disorders and vary
      greatly in clinical presentation. They are often associated with significant
      psychopathology. This paper proposes six categories of NEE patients based on
      psychosocial history, NEE etiology, and mechanisms of and response to
      psychotherapy. A series of 26 adult NEE patients were grouped according to six
      symptom patterns: (a) acute anxiety/panic, (b) impaired affect regulation and
      interpersonal skills, (c) somatization/conversion, (d) depression, (e)
      posttraumatic stress disorder, and (f) reinforced behavior pattern.
      Classification was made on the basis of the specific psychotherapeutic
      interventions found most effective with each patient group.

PMID- 12609371
TI  - Quality-of-Life Assessment in Patients Treated with Vagus Nerve Stimulation.
AB  - Vagus nerve stimulation (VNS) is a novel therapy used in patients with medically
      intractable epilepsy. We administered a Quality of Life in Epilepsy-10 (QOLIE-10)
      questionnaire consisting of questions designed to assess the patients' rating of
      their memory, level of physical and mental well-being, energy, depression,
      worries about seizures and work, social limitations, and overall quality of life
      on VNS treatment. The questionnaire was administered before and at 1-3 weeks, 5-7
      weeks, 3 months, 6 months, and 9-12 months after the initiation of VNS in 17
      patients. QOLIE-10 scores were significantly better after the initiation of the
      therapy as compared with baseline (P < 0.01). There was no correlation between
      the improvement in QOLIE-10 scores and the reduction in seizure frequency,
      decreased severity of seizures, or increased level of energy/alertness. We
      conclude that VNS therapy is associated with a significant improvement in
      subjective quality of life.

PMID- 12609372
TI  - Landau-Kleffner Syndrome: Localization of Epileptogenic Lesion Using Wavelet-
      Cross-Correlation Analysis.
AB  - Magnetoencephalographic findings in a 6-year-old patient suffering from acquired
      aphasia with convulsive disorder (Landau-Kleffner Syndrome, LKS) are presented.
      The data were analyzed using wavelet-cross-correlation analysis, a nonstationary
      analysis method developed to analyze the localization of an epileptogenic lesion
      and the propagation of epileptiform discharges. The results indicate that LKS
      might be a disorder of the primary temporal cortex, and that the auditory neural
      network may function as the circuit for the epileptic discharge propagation.

PMID- 12609373
TI  - Management of Epilepsy and Pregnancy.

PMID- 12609374
TI  - To the Editor.

PMID- 12609375
TI  - To the Editor.

PMID- 12609377
TI  - Reply.

PMID- 12609376
TI  - To the Editor.

PMID- 12609378
TI  - Pseudoseeing Is Pseudobelieving. To the Editor.

PMID- 12609380
TI  - To the Editor.

PMID- 12609379
TI  - To the Editor.

PMID- 12609381
TI  - To the Editor.

PMID- 12609382
TI  - Reply.

PMID- 12609383
TI  - Message from the Editor-in-Chief.

PMID- 12609384
TI  - From the Epilepsy Foundation: The Entitled to Respect Campaign.

PMID- 12609385
TI  - Seizure: A Reflection on the Recent Terrorism in America.

PMID- 12609386
TI  - Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects.
AB  - The widespread availability and use of herbal medicines raise the potential for
      adverse effects in the epilepsy population. Herbal sedatives (kava, valerian,
      chamomile, passionflower) may potentiate the effects of antiepileptic
      medications, increasing their sedative and cognitive effects. Despite some
      antiseizure effects in animal models, they should not be used in place of
      standard seizure medications because efficacy has not been established.
      Anecdotal, uncontrolled observations suggest that herbal stimulants containing
      ephedrine (ephedra or ma huang) and caffeine (cocoa, coffee, tea, mate, guarana,
      cola or kola) can exacerbate seizures in people with epilepsy, especially when
      taken in combination. Ginkgo and ginseng may also exacerbate seizures although
      the evidence for this is similarly anecdotal and uncertain. St. John's wort has
      the potential to alter medication pharmacokinetics and the seizure threshold. The
      essential oils of many plants contain epileptogenic compounds. There is mixed
      evidence for evening primrose and borage lowering the seizure threshold.
      Education of both health care providers and patients is the best way to avoid
      unintentional and unnecessary adverse reactions to herbal medicines.

PMID- 12609387
TI  - Psychosocial Adaptation to Epilepsy: The Role of Coping Strategies.
AB  - This article begins by reviewing the literature on the concept of psychosocial
      adaptation to impairment among persons with epilepsy. Particular attention is
      devoted to those roots reasoned to lie at the base of psychosocial problems
      manifested by people with epilepsy. The research literature on coping with
      epilepsy is then reviewed in two areas: (a) general coping styles and their
      relationship to psychosocial adaptation, and (b) specific coping strategies and
      their association with adaptation to epilepsy. Next, clinical implications of
      these findings are briefly outlined. The article concludes with a discussion of
      research limitations identified in the conceptualization and measurement of
      coping, followed by suggestions for future research on coping and adaptation to
      epilepsy.

PMID- 12609388
TI  - Intracranial Neurophysiological Correlates Related to the Processing of Faces.
AB  - Face perception and recognition is an intriguing ability, already present in
      neonates. Numerous studies in patients with brain lesions identified the temporo
      occipital cortex as the crucial structure for this capacity. Analysis of
      electrical signals (EEG) inside the brain of patients implanted with intracranial
      electrodes for diagnostic purposes allows researchers to describe the temporal
      and spatial organization of responses to various aspects of face processing in
      human subjects. Several findings have emerged and appear relevant for cerebral
      organization in general: (1) Selective face responses were obtained from the
      basal temporo-occipital cortex at around 200 ms (N200); however, other structures
      such as the lateral temporal lobe and frontal cortex also participate in face
      recognition and perception tasks. (2) Each structure has a distinct "response
      profile"; that is, with respect to a given task certain structures respond
      strongly, others less or not at all. This profile might change with a different
      task, although the physical parameters of the stimuli remain the same. (3) The
      right hemispheric predominance of face processing, as suggested by patient data
      and studies in healthy volunteers, seemed to be restricted to its early stages
      (i.e., before 100-150 ms). (4) Recognition of faces might be associated with
      differential intracranial responses, despite an incorrect overt response,
      reflecting neurophysiological correlates of implicit memory. (5) The more the
      stimulus resembled a complete human face, the earlier and larger the N200
      response was found, in particular over the basal temporobasal cortex. Analysis of
      electrical signals from intracranial electrodes might help to improve our
      understanding of the underlying physiological and anatomical constraints of
      cognitive processes.

PMID- 12609389
TI  - Cognitive Performance of Patients with Epilepsy and Calcified Neurocysticercotic
      Lesions: A Case-Control Study.
AB  - Neuropsychological tests were applied to 20 patients with focal epilepsy related
      to calcified neurocysticercosis (NCC) (mean: three lesions/patient; NCC group),
      22 patients with focal epilepsy without NCC (EPI group), and 29 healthy controls
      matched for age, sex, and educational level. The EPI and NCC groups were matched
      for age at onset of epilepsy, epilepsy duration, frequency of attacks, seizure
      semiology, interictal EEG findings, and antiepileptic drugs used. There were no
      differences in the digit span, word span, calculus, and Mini-Mental State
      examination among the three groups studied. The NCC and EPI groups showed lower
      scores than controls in immediate and delayed verbal memory, famous faces test,
      spatial recognition span, abstractions and judgment, and visuoconstructional
      abilities. The EPI group, but not the NCC group, also had lower scores in a
      praxis tests. There were no differences between the NCC and EPI groups in any of
      the tests applied (P > 15), except for the spatial recognition span, which was
      lower in the former. Cognitive impairment is a prevalent neuropsychological
      feature of patients with epilepsy and NCC.

PMID- 12609390
TI  - Vagus Nerve Stimulation for Patients in Residential Treatment Facilities.
AB  - THIS ANALYSIS COMPARED THE EFFECTIVENESS OF VAGUS NERVE STIMULATION (VNS) THERAPY
      AMONG PATIENTS WITH INTRACTABLE SEIZURES: a group living in residential treatment
      facilities (RTF) with a group not living in RTFs (non-RTF). Among a constant
      cohort of patients with baseline, 3-month, and 12-month data, the RTF group had
      significantly (P < 0.05) larger numbers of patients with generalized seizures,
      previous callosotomy, psychiatric disorders, behavioral problems, and Rett's
      syndrome. Median seizure reductions after 3 months were 33% in the RTF group and
      49% in the non-RTF group (P < 0.001); after 12 months, 50% (RTF) and 56% (non
      RTF). After both 3 and 12 months, alertness, mood, postictal recovery, and
      cluster seizures improved in more than a third of patients in both groups.
      Because VNS therapy does not interact with medications and is delivered
      automatically, it should be seriously considered for patients with intractable
      epilepsy who reside in RTFs.

PMID- 12609391
TI  - Evidence That Emotional Maladjustment Is Worse in Men Than in Women with
      Psychogenic Nonepileptic Seizures.
AB  - The purpose of this study is to examine the effects of gender on adjustment and
      cognition in patients with psychogenic nonepileptic seizures (NES) and on
      patients with epilepsy. We compared 57 women and 27 men, all at least 16 years
      old, with only NES as documented by long-term EEG-video monitor studies, to equal
      numbers of randomly selected women and men with only epileptic seizures.
      Variables examined included age, age of onset, education, scales from the MMPI,
      the WAIS-R, and the number of tests outside normal limits from the
      Neuropsychological Battery for Epilepsy. We found no significant differences in
      mean age, intelligence, or percentage of neuropsychological tests outside normal
      limits across the four groups. Women and men with NES had significantly later age
      of onset of attacks compared with subjects of either gender with epilepsy (26
      years vs 13 years, P < 0.001) and men with NES had greater educational
      achievement than women with NES or patients with epilepsy (P < 0.02). However,
      the most important findings were seen on the MMPI. Men with NES exhibited
      significantly greater elevations on multiple scales (especially Hysteria,
      Depression, Hypochondriasis, Psychoasthenia, Schizophrenia) compared with men
      with epilepsy or women with either epilepsy or NES. We conclude that men with NES
      have significantly worse patterns of emotional adjustment, as measured by the
      MMPI, than women with NES or subjects of either gender with epilepsy.

PMID- 12609392
TI  - Changing Physician Attitudes Toward the Ketogenic Diet: A "Parent-Centered"
      Approach to Physician Education about a Medication Alternative.
AB  - Alternative medical therapies such as the ketogenic diet are often dismissed by
      the medical community. We used a "parent-centered" approach to make physicians
      aware of the ketogenic diet, an alternative therapy for difficult-to control
      seizures in children. Parents became aware of the diet through national TV and
      film. Written and video information was made available to them and they were
      encouraged to ask their physicians about the potential usefulness of the
      ketogenic diet for their child. Between 1994 and 1999 we assessed the success of
      this approach with three surveys of all U.S. child neurologists. This "parent
      centered" approach increased physician knowledge about the diet, but had little
      effect on its use. Despite evidence of its effectiveness, physicians continued to
      reserve its use until children had failed most new anticonvulsants. Physicians
      say they would use it more often if "it worked better" and if they "had a
      dietitian with more experience."

PMID- 12609393
TI  - Language Disturbances as Side Effects of Topiramate and Zonisamide Therapy.
AB  - Reversible side effects of two sulfa-containing antiepileptic drugs (AEDs),
      topiramate (TPM) and zonisamide (ZNS), are reported. These effects differ from
      those of other AEDs in that language impairment was the predominant cognitive
      complaint. Information was available for 42 patients exposed to TPM. Twenty-two
      (52%) complained of adverse effects; 12, specifically of deficits in language
      related functions. Brief neuropsychological testing in four patients on TPM
      confirmed verbal deficits. These deficits could appear shortly after initiating
      TPM and disappear variably after drug withdrawal. Similar complaints were seen in
      a pilot study of ZNS monotherapy, administered in supratherapeutic doses,
      confirmed by neuropsychological testing. TPM and ZNS both contain a sulfa moiety,
      suggesting that verbal processing is especially sensitive to these sulfa
      containing AEDs.

PMID- 12609394
TI  - Ketamine Prevents Learning Impairment When Administered Immediately after Status
      Epilepticus Onset.
AB  - Permanent cognitive impairment is common following status epilepticus (SE) in
      both humans and animals. We examined the effect of the NMDA antagonist ketamine
      administered after SE onset on two forms of associative learning in the rat:
      conditioned taste aversion and fear-conditioned analgesia. Following the onset of
      lithium/pilocarpine-induced SE, rats were administered either ketamine (100
      mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked
      deficits in both learning measures at 1 month after SE. In contrast, ketamine
      treated and nonepileptic control animals did not differ in performance for either
      task. Although studies have shown that ketamine is ineffective at controlling
      electrographic seizures early in SE, these results are consistent with previous
      studies showing that ketamine can preserve learning proficiency if administered
      shortly after seizure onset. As a clinically available drug, ketamine may prove
      useful in the treatment of SE when combined with conventional antiepileptic
      strategies.

PMID- 12609396
TI  - Sexual Molestation and Psychogenic Seizures: The 1731 Trial of Marie Catherine
      Cadiere versus Father Jean-Baptiste Girard.

PMID- 12609395
TI  - A Prospective Evaluation of the Effects of a 12-Week Outpatient Exercise Program
      on Clinical and Behavioral Outcomes in Patients with Epilepsy.
AB  - Purpose. We hypothesized that patients randomized to an exercise program would
      demonstrate a measurable improvement in behavioral outcomes with no adverse
      clinical outcomes, as compared with control patients.Methods. This randomized,
      prospective, parallel, and controlled study spanned 12 weeks. Twenty-eight
      patients were randomized either to participate in a supervised exercise program
      (Exercise) or to continue their current level of activity with no planned
      intervention (Control). The Exercise group worked with an exercise physiologist
      three times per week. At specific intervals, behavioral (QOLIE-89, POMS, PSDQ,
      Self-Esteem) and clinical (seizure activity, antiepileptic drug (AED)
      concentrations) outcomes were measured.Results. Twenty-three patients completed
      the study (Exercise n = 14, Control n = 9). Of the four patients in the Exercise
      group with active seizures, two had no change, one had an increase, and one had a
      decrease in seizure activity. Of the three patients in the Control group with
      active seizures, one had no change, one had an increase, and one had a decrease
      in seizure activity. In all patients, there was <26% coefficient of variation in
      AED concentrations over the 12-week study, suggesting little or no impact of the
      exercise intervention. The overall quality of life and two domain scores improved
      from baseline to Week 12 in the Exercise group (P = 0.031), while the Control
      group score did not change (P = 0.943). In the Exercise group, there were several
      measures of physical self-concept and vigor that improved and total mood
      disturbance decreased from the beginning to the end of the program.Conclusion.
      This is the first randomized, controlled study of exercise in patients with
      epilepsy. Behavioral outcomes are positively influenced by moderate exercise and
      there is no impact on seizure frequency. This suggests that exercise should not
      be discouraged in the care of epilepsy patients. The ability to offer an exercise
      program adds a health promotion component to the current plan of care provided by
      our comprehensive epilepsy program.

PMID- 12609398
TI  - Psychopathology of Epilepsy. To the Editor.

PMID- 12609397
TI  - Topiramate Overdose: A Case Report and Literature Review.
AB  - Topiramate is a medication introduced in the United States in 1997 for the
      treatment of epilepsy. Studies are currently underway to determine its
      effectiveness in the treatment of multiple conditions including bipolar disorder.
      It is generally well tolerated at doses commonly used in the clinical setting,
      however, there is little information regarding its safety in overdose. We report
      the case of a 24-year-old woman who ingested 4000 mg of topiramate in a suicide
      attempt. She was asymptomatic following the overdose and did not develop any
      adverse sequelae. In this article we will discuss the commonly seen side effects
      of topiramate use and examine the available data concerning topiramate overdose.
      We will review recommendations for the management of such an overdose.

PMID- 12609399
TI  - Reply.

PMID- 12609400
TI  - Academic Achievement in Children with Controlled Epilepsy. To the Editor.

PMID- 12609401
TI  - Reply.

PMID- 12609403
TI  - Reply.

PMID- 12609402
TI  - To the Editor.

PMID- 12609405
TI  - Active-Control Comparative Equivalency Monotherapy Trials in Epilepsy. To the
      Editor.

PMID- 12609404
TI  - The Mozart Effect. To the Editor.

PMID- 12609406
TI  - Reply.

PMID- 12609408
TI  - To the Editor.

PMID- 12609409
TI  - Reply.

PMID- 12609407
TI  - To the Editor.

PMID- 12609410
TI  - No Laughing Matter.

PMID- 12609411
TI  - Sequential Design Studies for Antiepileptic Drugs.

PMID- 12609412
TI  - Active-Control Antiepileptic Drug Trials in the Newly Diagnosed Patient: Are We
      Getting Closer?

PMID- 12609413
TI  - Should Epilepsy Surgery Be Used in the Treatment of Autistic Regression?

PMID- 12609414
TI  - Behavioral Manifestations of Nonconvulsive Status Epilepticus.

PMID- 12609415
TI  - Efficacy and Safety of Remacemide versus Carbamazepine in Newly Diagnosed
      Epilepsy: Comparison by Sequential Analysis.
AB  - An international trial comparing remacemide hydrochloride with carbamazepine was
      undertaken in newly diagnosed epilepsy using a novel double-blind, parallel
      group, double triangular sequential design. Patients with two or more partial or
      generalized tonic-clonic seizures in the previous year were randomized to 600 mg
      daily of remacemide or carbamazepine. Subsequent dosage adjustments were allowed
      while maintaining the blind. The trial completed 20 months after initiation
      following the second interim analysis. Efficacy data on 449 patients showed
      carbamazepine to be significantly more effective than remacemide in preventing
      seizure recurrence (P = 0.003). Median time to first seizure after titration, the
      primary endpoint, was 112 days for remacemide and 306 days with carbamazepine.
      Time to second, third, and fourth seizures after randomization all significantly
      favored carbamazepine. Remacemide was shown unequivocally to be inferior to
      carbamazepine in this patient population. This study also establishes
      carbamazepine as a proven treatment for use in subsequent active control
      comparative trials.

PMID- 12609416
TI  - Psychosocial Well-Being of Carers of People with Epilepsy in Hong Kong.
AB  - The purpose of this study was to explore the factors associated with the quality
      of life and emotional states of the caregivers of people with epilepsy in Hong
      Kong. Sixty-five primary caregivers were administered rating scales of mood,
      quality of life, and intensity of various epileptic and psychosocial variables.
      Twenty-two percent of respondents were considered to have severe levels of
      anxiety, and 14%, severe levels of depression. Three-quarters of the caregivers
      interviewed had below-average scores on the quality-of-life measure, indicating
      that the carers' psychosocial adjustment was impaired. Contrary to the findings
      of previous studies, caregivers of patients with additional illnesses or learning
      disabilities were not more distressed than caregivers of patients with epilepsy
      only. Demographic characteristics and other medical and social factors associated
      with the psychosocial well-being of the carers of people with epilepsy were
      discussed. The findings of this study suggest the importance of including
      systematic measures of people's subjective experiences and perceptions in the
      study of social and psychological aspects of epilepsy.

PMID- 12609417
TI  - Ipsilateral Reorganization of Language in Early-Onset Left Temporal Lobe
      Epilepsy.
AB  - Purpose. Decline in confrontation naming ability occurs in a subset of temporal
      lobe epilepsy (TLE) patients following left (dominant) anterior temporal
      lobectomy (ATL). Patients with late age of onset of seizures are most vulnerable
      to such decline. In addition, object names typically acquired later in language
      development are the words most likely to be inaccessible after ATL. Early-onset
      left TLE patients may be at lower risk for post-ATL dysnomia either because they
      have a limited preoperative lexicon that does not include most late-age-of
      acquistion names or they undergo early ipsilateral language reorganization, which
      results in a lexicon similar to that of late-onset TLE patients but offers
      protection from post-ATL naming decline.Methods. Sixty-five left hemisphere
      speech dominant left TLE patients who had undergone ATL were assessed pre- and
      postoperatively on the Boston Naming Test (BNT).Results. The early- and late
      onset groups performed similarly across three BNT age-of-acquisition categories
      at the preoperative assessment. Words acquired relatively later in life were most
      likely to become inaccessible postoperatively for both groups, but the early
      onset patients showed significantly less overall postoperative decline in naming
      ability compared with the late-onset group.Conclusions. The more stable pre- to
      postoperative naming performance exhibited by early-onset patients cannot be
      attributed to lack of acquisition of the words shown to be most vulnerable to
      postoperative decline (i.e., late-age-of-acquisition words). Their object naming
      stability suggests that early-onset left TLE patients undergo intrahemispheric
      reorganization of language early in life that provides protective benefits.

PMID- 12609418
TI  - Memory Complaints in Medically Refractory Epilepsy: Relationship to Epilepsy
      Related Factors.
AB  - This study reports the results of a multicenter study on memory complaints in 252
      patients with epilepsy who presented with subjective complaints about memory
      problems in daily life. Memory complaints were measured with a standardized
      memory questionnaire (GKLE). The main purpose was to analyze the type of memory
      complaints and to examine the relationship between subjective complaints and
      several epilepsy-related factors. These include seizure type, lateralization and
      location of the focus, etiology, duration, age at onset, and antiepileptic
      medication. As expected patients experienced significantly more memory
      complaints. In particular, patients of older age and higher intelligence level
      complained more about their memory functioning. Although the clinical
      significance is marginal, neuroticism showed a significant relationship to the
      total complaint score. The total amount of subjective complaints is not related
      to the localization or lateralization of the epileptic disturbances. Patients
      with a longer duration of epilepsy complained significantly more about memory
      problems, especially about retrieving information from memory. All other epilepsy
      related factors showed no relationship to memory complaints.

PMID- 12609419
TI  - Hypersexuality after Temporal Lobe Resection.
AB  - Hypersexuality has occasionally been reported in patients with temporal lobe
      epilepsy following temporal lobe resection. The mechanism underlying this
      phenomenon is poorly understood. We describe seven patients who spontaneously
      reported dramatic postoperative changes in sexual behavior after unilateral
      temporal lobe resection. Five of the seven patients showed evidence of bilateral
      temporal lobe abnormalities. All of the patients had significant difficulties
      with postoperative psychosocial adjustment that preceded the onset of
      hypersexuality. Five of the patients were completely seizure-free and one
      reported postoperative auras. Recurrent complex partial seizures occurred at a
      reduced frequency in one patient after 6 months. In this patient, the period of
      seizure freedom did not directly correlate with the period of hypersexuality.
      These cases suggest that hypersexuality following unilateral temporal lobe
      resection is more likely to occur in the presence of psychosocial difficulties
      and contralateral temporal lobe abnormalities. Neurophysiological processes
      associated with seizure cessation alone do not appear to account for
      postoperative hypersexuality.

PMID- 12609420
TI  - The Mozart Effect: Additional Data.
AB  - After the review of the Mozart effect was published in this journal (Hughes JR.
      Epilepsy Behav 2001;2:369-417), additional data from the music of Haydn and Liszt
      have been analyzed that may account for the decrease in seizure activity
      originally reported during Mozart music. Even with these added data Mozart music
      continued to score significantly higher than the selections from the other six
      composers in one of the important characteristics of this music, namely, the
      repetition of the melody. However Haydn's values were second highest among
      Mozart, J. S. Bach, Wagner, Beethoven, Chopin, and Liszt.

PMID- 12609421
TI  - Topiramate Overdose: Clinical and Laboratory Features.
AB  - Limited data exist on overdose with new antiepileptic drugs. We reviewed the
      medical records of two patients who took a topiramate overdose as a suicide
      attempt. We recorded their medical and seizure histories, concomitant
      antiepileptic medications, neurologic examination, and laboratory findings at the
      time of presentation following the overdose. We also recorded their progress and
      the evolution of laboratory abnormalities. Both patients progressed to coma and
      had generalized convulsive status epilepticus, requiring intubation and treatment
      with benzodiazepines. Both patients recovered within 2 days but had a non-anion
      gap metabolic acidosis that persisted for 5-6 days. Physicians should carefully
      monitor patients treated with topiramate who develop signs of clinical
      depression. The non-anion-gap metabolic acidosis observed may be due to
      inhibition of renal cortical carbonic anhydrase.

PMID- 12609422
TI  - Tiagabine in the Management of Postencephalitic Epilepsy and Impulse Control
      Disorder.
AB  - Rationale. Anticonvulsants are used as primary or adjunctive agents in the
      treatment of psychiatric disorders. gamma-Aminobutyric acid (GABA) ergic
      modulation has been shown to be important in impulsive aggression. We
      investigated the treatment of impulse control disorders with aggressive features
      in two patients with post-encephalitic epilepsy using the anticonvulsant
      tiagabine, a novel GABA reuptake inhibitor.Methods. The cases of two patients who
      were previously treated with other anticonvulsants, had uncontrolled behaviors
      with intractable seizures and were placed on adjunctive tiagabine with control of
      both psychiatric and neurologic symptoms, were analyzed.Results. In case 1, 12 mg
      adjunctive tiagabine daily resulted in behavioral improvement that further
      improved with increased titration; however, when tiagabine was discontinued,
      abrupt behavioral decompensation occurred. In case 2, adjunctive tiagabine
      resulted in both seizure control and marked diminution of disinhibited behaviors
      with aggressive outbursts; however, when tiagabine was titrated from 20 mg daily
      to 24 mg daily increased irritability was noted that resolved with tiagabine
      reduction to 20 mg daily.Conclusion. In two cases, adjunctive tiagabine was
      effective in the management of both epilepsy and severe impulse control disorder.
      Optimal dosing to maximize anticonvulsant and psychotropic effects needs to be
      established. Further studies using tiagabine in the treatment of impulse control
      disorders are indicated.

PMID- 12609424
TI  - Effect of Ketamine on Learning Impairment. To the Editor.

PMID- 12609423
TI  - Epilepsy and Developmental Disabilities. Edited by Orrin Devinsky and Lauren E.
      Westbrook, with 56 contributing authors.

PMID- 12609425
TI  - Reply. To the Editor.

PMID- 12609426
TI  - Verbal Memory and Duration of Epilepsy. To the Editor.

PMID- 12609427
TI  - Herbal Medicines and Epilepsy. To the Editor.

PMID- 12609428
TI  - Reply. To the Editor.

PMID- 12609429
TI  - Herbal Medicines and Epilepsy. To the Editor.

PMID- 12609431
TI  - Herbal Medicines and Epilepsy. To the Editor.

PMID- 12609430
TI  - Employment for People with Epilepsy. To the Editor.

PMID- 12609432
TI  - Employment for People with Epilepsy. To the Editor.

PMID- 12609434
TI  - Message from the Editor.

PMID- 12609433
TI  - Employment for People with Epilepsy. To the Editor.

PMID- 12609436
TI  - What We Owe Our Seniors with Epilepsy-Thoughts on Quality of Life.

PMID- 12609435
TI  - Raising the Bar on Seizure Control.

PMID- 12609437
TI  - From the Epilepsy Foundation.

PMID- 12609438
TI  - Psychosis of Epilepsy: A Neurologist's Perspective.
AB  - Psychosis of epilepsy (POE) comprises a group of disorders that are closely
      associated with epileptic seizures. These include interictal POE, postictal
      psychosis, and alternative psychosis (also known as "forced normalization").
      Neurologists have, in general, played a limited role in the evaluation and
      management of patients with POE. Yet, as reviewed in this paper, a good
      understanding of electrophysiologic, neuroradiologic, and neuropathologic
      variables associated with POE can yield valuable data in the evaluation of the
      seizure disorder of these patients. The purpose of this review article is to
      highlight the clinical, neuroradiologic, neurophysiologic, and neuropathologic
      aspects of POE that can assist in the evaluation and management of the associated
      seizure disorder and to identify the circumstances in which a timely therapeutic
      intervention by neurologists can avert or minimize the occurrence of a psychotic
      episode. Specifically, the clinical characteristics of interictal POE and ictal,
      postictal, and alternative psychotic episodes are highlighted together with their
      potential pathogenic mechanisms and the associated treatment issues. Finally,
      discussions of psychotic disorders following epilepsy surgery and the
      pharmacotherapy of psychotic disorders in patients with epilepsy are presented.

PMID- 12609439
TI  - Epilepsy and Anxiety.
AB  - Although the affective and cognitive effects of seizures have long received
      attention, the anxiety spectrum of psychiatric complications of epilepsy has not
      been well-studied. Neither purely a mood, thought, or autonomic disorder, anxiety
      is a unique phenomenon in genesis and expression. Multidisciplinary efforts
      (neuroanatomy, neurochemistry, neuroendocrine, cognitive neuroscience, functional
      neuroimaging) are attempting to create a unified neuropsychiatric account of
      anxiety which, like epilepsy, can be regarded as a model phenomenon in the
      history of the relationship between neuroscience and mental illness. Comorbid
      anxiety and epilepsy offers a potentially rich nexus for theoretical and empiric
      investigation of the neurocircuitry and psychological mechanisms underlying each
      phenomenon.

PMID- 12609440
TI  - A New Scale to Assess Culture-Specific Beliefs and Attitudes about Epilepsy.
AB  - A new rating scale to assess cultural diversity in North American people's
      understanding of epilepsy was developed and its psychometric properties were
      evaluated. The content of the scale was based on the hypotheses that cultural
      diversity and experience with epilepsy would be associated with differences in
      people's beliefs and attitudes about epilepsy. The sample, 117 Caucasians, 71
      South Asians, and 40 East Asians, was drawn from a larger study. All participants
      had completed the newscale, Epilepsy Beliefs and Attitudes Scale (EBAS).
      Cronbach's coefficient alpha for the items in the scale was 0.85. A method of
      principal-axis factor analysis yielded three factors which were referred to as
      the Neurological, Enviro-psycho-physical, and Metaphysical subscales to emphasize
      the underlying themes of beliefs and attitudes they represented. A multivariate
      analysis of variance (MANOVA) revealed a significant main effect for culture (P <
      0.0001), epilepsy status (Caucasians only) (P < 0.007), and epilepsy familiarity
      group (P < 0.002). Further analysis was conducted between demographic variables,
      culture, and participants' subscale scores. Results indicated that age, gender,
      and education were not related to differential responses to the scale. However, a
      significant effect for the duration of stay in North America was found (P <
      0.02). An examination of the role of faith in higher power revealed that the
      participants may consider both the Neurological and Metaphysical beliefs
      concurrently. The results provided support for the EBAS as a reliable, valid, and
      culturally sensitive instrument.

PMID- 12609441
TI  - Consequences of Pentylenetetrazole Kindling on Spatial Memory and Emotional
      Responding in the Rat.
AB  - We investigated the consequences of pentylenetetrazole (PTZ) kindling on
      cognitive capacities of rats in a Morris water maze assessing spatial reference
      memory and in the spontaneous alternation test used as an index of working
      memory. The emotional consequences of PTZ kindling were also evaluated in an
      elevated plus maze test. Results indicated that PTZ kindled rats were not
      different from controls in mastering the water maze. However, PTZ kindled rats
      did not persist in searching the platform when evaluated at the end of learning.
      This suggests an altered place memory, although alternative explanations, like
      reduced anxiety, may be involved. Indeed, such anxiolytic activity was observed
      in a separate group of kindled rats evaluated in the plus maze test. No
      significant effect of PTZ kindling was noted in the spontaneous alternation test.
      These results question the generalization of previous results obtained in
      learning tests using electric shocks and illustrate the complexity of the PTZ
      model for the study of the behavioral consequences of kindling.

PMID- 12609442
TI  - Tolerance to and Withdrawal from Anticonvulsant Action of Diazepam: Role of
      Nitric Oxide.
AB  - Tolerance to the anticonvulsant action of diazepam as a result of central nervous
      system adaptation limits its use in epilepsy. In Wistar rats, diazepam 5 mg/kg ip
      twice daily produced tolerance to its anticonvulsant action in 6 days. Abrupt
      withdrawal caused hyperexcitability. Tolerance manifested as a decrease in
      seizure threshold to near-control values, while withdrawal hyperexcitability was
      evidenced by a significant decrease in seizure threshold below the control value.
      This effect was seen both in the "same group design" and "separate group design."
      L-Arginine (a donor of nitric oxide) and N(omega)-nitro-L-arginine (an inhibitor
      of nitric oxide synthase) were given in doses of 150 and 8 mg/kg, respectively,
      on Days 1, 3, and 6 along with diazepam in the same group design. Their role in
      preventing the development of tolerance to the anticonvulsant effect was seen on
      Days 1, 3, and 6. Withdrawal hyperexcitability was seen on Days 1, 2, and 4 after
      cessation of drug therapy. Both electroshock and pentylenetetrazole (PTZ)
      infusion were used as models of epilepsy, and seizure thresholds were determined.
      The up and down method of A. W. Kimball, W. T. Burnett, and G. D. Doherty (Radiat
      Res 1957;7:1-12) was used to determine the seizure threshold in cases of
      electroshock-induced seizures. L-Arginine, when administered with diazepam, was
      found to inhibit tolerance as well as withdrawal hyperexcitability. N(omega)
      nitro-L-arginine did not prevent the development of tolerance or withdrawal
      hyperexcitability in the electroshock model, while in the PTZ model inhibition of
      nitric synthesis prevented withdrawal hyperexcitability but had no effect on the
      development of tolerance.

PMID- 12609443
TI  - The Electroencephalogram in Attention Deficit-Hyperactivity Disorder: Emphasis on
      Epileptiform Discharges.
AB  - This study dealt with the electroencephalograms (EEGs) of 176 children with
      attention deficit-hyperactivity disorder (ADHD). Of special interest were the
      patients who had in their EEG some type of spike activity (spike group), in
      contrast with those without such activity (control group). In the entire group,
      27.8% were completely normal and an additional 18.8% had positive spikes as their
      only finding. Definite noncontroversial, epileptiform activity was seen in 30.1%,
      mainly focal (usually occipital or temporal), less often generalized, with
      bilaterally synchronous spike and waves complexes seen in 11 children. Extreme
      spindles or diffuse slow waves occurred only in the spike group (one exception in
      each) and slow wave abnormalities (mainly frontal or temporal), nearly always
      mild in degree, were seen mainly in the spike group. These different findings
      suggest that ADHD is a condition often with organic changes in the form of EEG
      abnormality, at times with epileptiform activity that could contribute to a
      deficit in attention or a plethora of movements.

PMID- 12609444
TI  - Postictal Depression following Subtle Seizures.
AB  - We describe a woman with stereotypic recurrent episodes of severe depression with
      suicidal ideation that follow series of simple partial seizures. Her seizures
      were not clinically recognized for many years. When her seizures are effectively
      treated with antiepileptic drug therapy, her depressive episodes remit.

PMID- 12609446
TI  - Seizure Disorders in U.S. Latinos. To the Editor.

PMID- 12609445
TI  - Right Hemisphere Language Dominance in a Right-Handed Patient with Late-Onset
      Seizures.
AB  - Right hemisphere language dominance is rare in right-handed individuals and
      usually the result of language transfer associated with early left hemisphere
      pathology. We studied a 33-year-old right-handed man, with a normal MRI scan, who
      developed left frontal lobe seizures at age 15 years. Language lateralization
      testing by intracarotid amobarbital injection and dichotic listening showed the
      patient to be strongly right hemisphere language dominant. The clinical features
      of this patient do not fit the profile of pathology-induced language transfer,
      but instead suggest that he was right hemisphere language dominant before
      developing seizures. This case underscores the importance of language
      lateralization testing in patients who are candidates for seizure surgery, even
      if they are strongly right-handed and have late-onset seizures, features usually
      associated with left hemisphere language dominance. One implication is that the
      incidence of right hemisphere language dominance in the right-handed population
      may be underestimated.

PMID- 12609447
TI  - Seizure Disorders in U.S. Latinos. To the Editor:

PMID- 12609448
TI  - Reply.

PMID- 12609449
TI  - Comorbid Psychiatric Symptoms in Temporal Lobe Epilepsy. To the Editor.

PMID- 12609451
TI  - Reply.

PMID- 12609450
TI  - Comorbid Psychiatric Symptoms in Temporal Lobe Epilepsy. To the Editor.

PMID- 12609452
TI  - Cry the Beloved Mind: A Voyage of Hope. By Vernon M. Neppe, M.D., Ph.D.

PMID- 12609454
TI  - Introduction.

PMID- 12609453
TI  - Epilepsy-I Can Live with That! Edited by Sue Goss.

PMID- 12609455
TI  - The ILAE/IBE/WHO Global Campaign against Epilepsy: Bringing Epilepsy "Out of the
      Shadows"
AB  - Epilepsy affects at least 100 million people worldwide at some time in their
      lives, especially in childhood and adolescence. It is a universal problem
      involving all ages, races, social classes, and nations. Nevertheless, it has been
      misunderstood, feared, and stigmatized for more than 3000 years. The psychosocial
      and economic consequences of epilepsy are considerable in developed nations but
      are even greater in developing nations, where the treatment gap may vary from 60
      to 98%. To address the long-standing worldwide neglect of this disease, a
      campaign titled Epilepsy: Out of the Shadows has been launched by an alliance of
      three global organizations: the International League against Epilepsy (ILAE), the
      International Bureau for Epilepsy (IBE), and the World Health Organization (WHO).
      Global, regional, and national initiatives are currently underway.

PMID- 12609456
TI  - Epilepsy from the Patient's Perspective: Review of Results of a Community-Based
      Survey.
AB  - A total of 1023 individuals with epilepsy responded to a community-based
      questionnaire survey. Relative to U.S. population norms, respondents had lower
      household incomes and lesser levels of educational and vocational attainment.
      Although 89% of respondents reported that their seizures were, in their
      estimation, at least somewhat controlled, 57% reported having suffered at least
      one seizure in the preceding year. Of the many concerns that accompanied life
      with epilepsy, fear (of a seizure, of embarrassment, even of death) was the issue
      most frequently reported. Eighty-eight percent of respondents reported having
      health insurance, and this insurance covered epilepsy treatment in 93% of cases.
      The majority of respondents said that they were satisfied with the medical care
      they were receiving but wished for more information about epilepsy. Despite
      advances in epilepsy therapy, freedom from seizures and optimal quality of life
      eludes many.

PMID- 12609457
TI  - Elements of Effective Chronic Care: A Model for Optimizing Outcomes for the
      Chronically Ill.
AB  - Current estimates are that there are 2.3 million individuals with epilepsy among
      99 million Americans suffering from chronic medical conditions. The healthcare
      system is designed to treat acutely ill patients and, as a result, often fails to
      meet the needs of the chronically ill. Care is provided in brief, problem-focused
      visits. Multiple studies have shown that this type of standard practice produces
      suboptimal care and outcomes, and is unsatisfactory to both patients and care
      providers. We developed the Chronic Care Model in an effort to synthesize system
      and practice changes associated with better outcomes. In patient care as
      described in this model, patient-provider interactions are planned in advance in
      accordance with evidence-based guidelines. A primary focus is on assisting
      patients and their families in becoming competent self-managers. The Chronic Care
      Model has been successfully implemented by more than 200 healthcare systems. In
      this paper, we explore the applicability of the Chronic Care Model in managing
      patients with epilepsy.

PMID- 12609458
TI  - Caring for People with Epilepsy: Resources for the Healthcare Provider.
AB  - Epilepsy, a condition that affects all age groups, can have life-altering
      effects. The psychosocial effects of epilepsy are often as detrimental as the
      seizures themselves. Unfortunately, healthcare professionals often find
      themselves providing more care in less time and may be unable to thoroughly
      address these psychosocial needs. Therefore, national organizations and
      electronic media resources are prepared to provide information and support. For
      example, the Epilepsy Foundation has a broad range of educational materials
      available on the Internet and provides patient-to-patient support through on-line
      chat rooms and through a new initiative entitled the HOPE (Helping Other People
      with Epilepsy) Mentor Program, a program that trains individuals with epilepsy
      and their family members to provide education and support. Directing patients
      toward available reliable resources can help the time-constrained professional
      ensure that patients' needs for education and psychosocial support are met.

PMID- 12609459
TI  - [3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with
      major depression before and after treatment with fluoxetine.
AB  - Serotonin has been involved in major depression and is also related to central
      and peripheral mechanisms of neuroimmunomodulation. Recently, the uptake of
      [3H]serotonin into human peripheral blood lymphocytes has been reported. We
      determined the density of serotonin uptake sites by the binding of [3H]paroxetine
      to blood peripheral lymphocyte membrane preparations of controls and of patients
      with major depression before and after treatment with fluoxetine for six weeks.
      The severity of depression was assessed by the use of Hamilton Rating Scale for
      Depression and of Beck Depression Inventory. There was a reduction in the number
      of sites for [3H]paroxetine in patients before administration of the
      antidepressant respecting controls, and a recovery after the treatment. Affinity
      was unchanged. No correlation was obtained between the severity of symptoms
      determined by Hamilton Rating Scale for Depression or by Beck Depression
      Inventory, and the number of binding sites for [3H]paroxetine. The levels of the
      plasma serotonin metabolite, 5-hydroxyindoleacetic acid, did not differ between
      the three groups of subjects, but serotonin was lower in patients after treatment
      respecting controls and in patients before treatment. The significant correlation
      between specific binding of [3H]paroxetine and plasma serotonin levels in
      controls was not present in the patients. Lymphocyte serotonin transporter is
      decreased in major depressed patients and is modulated by antidepressant
      treatment. In addition of counting with a peripheral marker in depression, the
      study of serotonin system in lymphocytes might contribute to understand the bi
      directional interaction between the nervous and the immune systems.

PMID- 12609460
TI  - Pharmacokinetic properties, induction of interferon, and efficacy of selected 5
      halo-6-phenyl pyrimidinones, bropirimine analogues, in a model of severe
      experimental autoimmune encephalomyelitis.
AB  - We showed previously that a 5-halo-6-phenyl-pyrimidinone, bropirimine (PNU
      54461), inhibited progression of severe experimental autoimmune encephalomyelitis
      (EAE), an animal model of human multiple sclerosis. In the work presented here,
      we examined the activity of a group of chemically-related bropirimine analogues.
      First, the pharmacokinetic properties of the bropirimine analogues were examined
      in normal mice following oral dosing. After equal oral doses, both PNU-56169 and
      PNU-63693 were found in the blood of normal mice at equal or higher
      concentrations than bropirimine, but PNU-54462 and PNU-56359 were present in
      blood only at very low concentrations. Next, we examined the bropirimine
      analogues for activity in our model of severe EAE. At a dose of 400 mg/kg
      administered orally every second day PNU-56169 nearly completely blocked EAE
      progression, but was ineffective at 100 mg/kg. PNU-63693 was effective in EAE at
      concentrations of 200 mg/kg, 100 mg/kg, 50 mg/kg, and as low as 25 mg/kg.
      Histopathology was examined by observing leukocyte infiltration into the lower
      spinal cords of the mice. Treatment with 400 mg/kg of PNU-56169 and doses of 25,
      50, 100, and 200 mg/kg of PNU-63693 significantly inhibited leukocyte
      infiltration into the lower spinal cord of treated mice in a dose-dependent
      manner. Orally administered PNU-56169 and PNU-63693 also stimulated significant
      concentrations of IFNalpha in the serum of treated mice, which may be related to
      the efficacy of the compounds in EAE. However, the correlation between IFNalpha
      in the blood and efficacy in treating EAE was not exact. Thus, PNU-56169 and PNU
      63693 were delivered to the blood following oral dosing, induced significant
      concentrations of IFNalpha in the blood, and were equally or more potent than PNU
      54461 in inhibiting clinical signs of EAE. The results suggest that 5-halo-6
      phenyl-pyrimidinones are an interesting class of compounds to investigate for
      development in the treatment of multiple sclerosis.

PMID- 12609461
TI  - Differential effect of a single high dose of the tricyclic antidepressant
      imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion
      following an in vivo lipopolysaccharide challenge in rats.
AB  - Tricyclic antidepressants (TCAs) of which imipramine is one, are commonly used in
      the treatment of depressive disorders and other forms of psychiatric illness.
      There have been many reports regarding the suppressive effects of TCAs on immune
      function. However, information is still limited regarding the effects of TCAs on
      the immune system, as many of the studies conducted to date have concentrated on
      in vitro exposure to such drugs, or ex vivo measures of immunity following drug
      administration. Thus in the present investigation, an in vivo challenge with
      bacterial lipopolysaccharide (LPS) (100 microg/kg; i.p.) was used to assess
      immunocompetence following administration of a single high dose of the TCA,
      imipramine (100 mg/kg, p.o.). The results demonstrated that imipramine
      pretreatment inhibits LPS-induced increases in serum concentrations of the
      proinflammatory cytokine, tumor necrosis factor (TNF)-alpha both 3 and 6 h,
      following administration. However, LPS-induced interleukin (IL)-1beta secretion
      was not significantly altered following imipramine treatment at either of the
      timepoints examined. In addition, serum concentrations of corticosterone and the
      antiinflammatory cytokine IL-10 were measured, and imipramine treatment failed to
      alter either basal, or LPS-induced increases in these immunosuppressive agents.
      In conclusion, although IL-1beta and TNF-alpha are both macrophage-derived
      proinflammatory cytokines, the present study demonstrates a differential
      sensitivity of these cytokines to the suppressive effects of the TCA imipramine.
      Furthermore, the suppressive effects of imipramine on LPS-induced TNF-alpha
      secretion could not be attributed to either increased glucocorticoid levels, or
      increased secretion of the antiinflammatory cytokine IL-10. The relevance of
      these findings to antidepressant-induced immunotoxicity are discussed.

PMID- 12609462
TI  - Skewed differentiation of bone marrow CD34+ cells of tumor bearers from dendritic
      toward monocytic cells, and the redirection of differentiation toward dendritic
      cells by 1alpha,25-dihydroxyvitamin D3.
AB  - Tumor presence is detrimental to the development of antigen-presenting dendritic
      cells. Since dendritic cells can arise from CD34+ precursor cells, the present
      study assessed the capacity of bone marrow CD34+ cells from tumor bearers to
      develop into dendritic cells when cultured in the absence of either tumor cells
      or their products. Culturing bone marrow CD34+ cells from mice bearing Lewis lung
      carcinomas yielded a lower number of dendritic cells than arose from CD34+ cells
      of normal mice. This reduced yield of dendritic cells was associated with a shift
      to development of monocytic cells and a reduced antigen presenting capability by
      the cultures. When the CD34+ cell cultures from tumor bearers were supplemented
      with the differentiation-inducing hormone 1alpha,25-dihydroxyvitamin D3, there
      was the restoration of dendritic cell development and antigen presenting ability.
      These results show that CD34+ cells from tumor bearers remain defective in their
      development into dendritic cells even when cultured outside the tumor
      environment, but development of dendritic cells can be restored with 1alpha,25
      dihydroxyvitamin D3.

PMID- 12609463
TI  - Induction of surface antigen CD69 expression in T-lymphocytes following exposure
      to actinomycin D.
AB  - The expression of surface antigen CD69 in immune response cells is typically
      associated with the early stage(s) of cell activation, with maximal expression
      levels within 4 h of appropriate antigenic or mitogenic stimulation, and
      maintenance of these high expression levels for 18-24 h. The expression profiles
      of CD69 in human peripheral blood mononuclear cells (PBMC) cultured with
      actinomycin D prior to mitogenic stimulation were evaluated by direct
      immunofluorescence using flow cytometry. Pretreatment of PBMC suspensions with
      low, non-toxic levels of actinomycin D stimulated CD3+ T-lymphocytes to express
      CD69 in a concentration-dependent manner. Furthermore, CD4+ T-lymphocytes were
      the primary cells responding in this fashion. Secondary mitogenic stimulation
      following antibiotic treatment potentiated cellular CD69 expression in these
      assays. CD69 expression was profoundly suppressed with in vitro actinomycin D
      concentrations >/=1-2 microg/ml, presumably by interference with cellular
      transcription/translation mechanisms. Parallel thymidine incorporation assays
      indicated that actinomycin D effectively inhibited thymidine uptake in a
      concentration-dependent manner, with complete inhibition at >/=0.1 microg/ml. The
      evaluation of cell cycling dynamics following antibiotic treatment, with and
      without secondary mitogen stimulation, indicated no substantial changes in DNA
      synthesis over controls. The diversity of these responses suggests that
      expression of CD69 may not solely reflect mitogenic activation status but may,
      under some conditions, result from induced cellular stress.

PMID- 12609464
TI  - A model appropriate to the transmission of a human food-borne pathogen in a
      multigroup managed herd.
AB  - We describe a model of microparasite transmission within a multigroup managed
      farming system. The model was formulated to represent transmission of Escherichia
      coli O157 within a typical UK dairy herd and was used to suggest possible on-farm
      control strategies. The model includes birth, death, maturation, the
      dry/lactating cycle and various types of transmission (i.e. direct,
      pseudovertical (representing direct faecal-oral transmission between dam and calf
      within the first 48 h) and indirect (via free-living infectious units in the
      environment)). A combination of numerical and analytical techniques was used to
      analyse the model. We found that pseudovertical transmission and indirect
      transmission via infectious units in the 'general' environment can lead to more
      groups being affected, but otherwise have relatively little effect on the
      invasion criteria. To reduce infection within the herd, we suggest that efforts
      be directed at reducing the opportunity for group-specific indirect transmission
      particularly within the weaned group.

PMID- 12609465
TI  - Seroprevalence of and risk factors for infectious bovine rhinotracheitis in beef
      cattle herds of Yucatan, Mexico.
AB  - The main objective of this cross-sectional study was to estimate the
      seroprevalence of infectious bovine rhinotracheitis (IBR) in a population of non
      vaccinated beef cattle in the livestock region of Yucatan, Mexico and to
      determine potential risk factors related to the seroprevalence. Also, we
      estimated the intraherd correlation (r(e)) and design effect (D) of IBR
      seropositivity. Cattle were selected by two-stage cluster sampling. Blood samples
      were collected from 564 animals from 35 herds. Sera were tested for antibodies
      against IBR using the serum-neutralisation test. Information regarding the herd
      and each animal sampled were recorded through a personal interview with the
      farmer or farm manager. The data were analysed using fixed-effects logistic
      multiple regression. Thirty-four of the 35 herds had at least one seropositive
      animal. The animal true seroprevalence was 54.4%. Animals in large herds or in
      production had higher odds of seropositivity than those in small herds or
      growing. The r(e) and D were 0.17 and 3.62, respectively.

PMID- 12609466
TI  - Factors related to the risk of neonatal mortality, birth-weight and serum
      immunoglobulin concentration in lambs in the UK.
AB  - Neonatal-lamb mortality represents an economic loss and welfare concern. Two
      factors often associated with the risk of mortality are birth-weight and serum
      immunoglobulin concentration. We used data from two studies to investigate risk
      factors for mortality between 2 and 14 days of age and factors affecting birth
      weight and serum immunoglobulin concentration at 48h of age. Dataset 1 included
      1339 lambs born on eight farms during the 1995 spring lambing season; dataset 2
      included 3172 lambs on seven farms during the 1991 spring lambing season. To
      account for some of the potential clustering within the data, multilevel models
      were used. Most (>75%) of the variation in the risk of mortality was at the lamb
      level. In dataset 1, factors significantly associated with increased odds of lamb
      mortality included low birth-weight and low serum immunoglobulin concentration.
      In dataset 2, significant risk factors for mortality included low birth-weight,
      ewe body-condition score, being born late in the season (relative to other lambs
      on the farm) and being born in multiple litters. There was a significant
      interaction between the effects of litter size and birth-weight. (Serum
      immunoglobulin concentration was not available for dataset 2.) More than half of
      the variation in birth-weight was at the ewe level, 27% at the lamb level, and
      18% at the farm level (dataset 1). Single birth and being male were associated
      with increased birth-weight in both datasets. In dataset 2 only, increasing ewe
      condition score and birth early in the study period were also associated with
      increased birth-weight. Fifty-six percent of the variation in immunoglobulin
      concentration was at the lamb level, 36% at the ewe level and only 7% at the farm
      level. Factors associated with reduced serum immunoglobulin concentration
      included early or late birth in the lambing season, being born later than 14 days
      after the first lamb born on the farm, multiple-birth litters and maternal
      mastitis.

PMID- 12609467
TI  - Seroincidence of porcine T. solium infection in the Peruvian highlands.
AB  - We performed repeated serological sampling of pigs in an endemic area of the
      Peruvian highlands (eight villages) to assess the feasibility of detecting
      incident cases of Taenia solium infection as indicators of ongoing transmission
      of the parasite. A total of 2245 samples corresponding to 1548 pigs were
      collected in three sampling rounds (n=716, 926, and 603, respectively). Village
      period specific seroprevalences of antibodies by enzyme-linked
      immunoelectrotransfer blot (EITB) assay varied from 39% (95% CI: 34, 44) to 76%
      (95% CI: 72, 79). The prevalence of cysticercosis increased with the age of the
      pigs (similarly for both sexes). Around 40% of pigs were re-sampled at the end of
      each 4-month period. Crude incidence risks were 48% (57/120, 95% CI: 43-52) and
      58% (111/192, 95% CI: 54-61) for each period. A proportion of seropositive
      animals became seronegative at the end of each period (23 and 15%). Incidence
      varied by the village, and the exposure period, and was higher in males than
      females (but did not differ by age).

PMID- 12609468
TI  - The relationship of alcohol outlet density to heavy and frequent drinking and
      drinking-related problems among college students at eight universities.
AB  - To determine whether alcohol outlet density was correlated with heavy and
      frequent drinking and drinking-related problems, we compared ecological measures
      of outlet density with survey measures of drinking using a geographic information
      system and the Harvard School of Public Health College Alcohol Study (n=3,421,
      site n=8). We identified 966 outlets within 8 2-mile study areas. Densities/site
      ranged from 32 to 185. Density was correlated with heavy drinking (r=0.82,
      p=0.01), frequent drinking (r=0.73, p=0.04) and drinking-related problems
      (r=0.79, p=0.02). Women, underage students and students who picked up binge
      drinking in college were affected. Implications for prevention and research are
      discussed.

PMID- 12609469
TI  - Communities, citizens, and the perceived importance of AIDS-related services in
      West Hollywood, California.
AB  - Successful strategies for prevention and treatment of human immuneodeficiency
      virus (HIV) and acquired immune deficiency syndrome (AIDS) in the developed world
      are commonly described in terms of community mobilisation and involvement. While
      a broadly defined 'gay community' has been regarded as central in mobilising
      responses to HIV and AIDS, other kinds of communities are also relevant,
      including place-based communities of citizens constituted by their shared
      residential location, and interest or affinity-based communities of individuals
      constituted by their relationship to AIDS (e.g. as HIV-positive, as care-giver,
      as activist). These overlapping communities are identified in West Hollywood, a
      city with a relatively large gay and lesbian population, and with high rates of
      HIV infection and AIDS. Results are presented from a 1993 survey of city
      residents (N=832), comparing perceptions of the relative importance of HIV and
      AIDS services. How does the perception of the importance of these services vary
      among individuals defined in terms of their potential membership of these three
      communities? The findings show that although household HIV-status and gay self
      identity were positively associated with relatively high ratings of importance
      for HIV and AIDS services, there was a strong consensus among all residents that
      AIDS was the top issue of concern for West Hollywood as a whole. In short, AIDS
      had emerged as a central issue for citizens of West Hollywood even though the
      majority of residents were not self-identified members of a gay community nor
      part of a narrowly-defined community of interest comprising households with a HIV
      positive member.

PMID- 12609470
TI  - Contacting your GP when the surgery is closed: issues of location and access.
AB  - This paper examines spatial variation in the delivery of out of hours care
      through general practice, in two Health Authorities in northwest England. It
      demonstrates considerable variations in the type of care provided to patients in
      different parts of the region. These differences are not due primarily to either
      the geographical or socio-economic characteristics of the areas. Rather, the type
      of out of hours care delivered depends much more on variations in the structure
      and organization of service delivery. These factors, in turn, largely reflect the
      history of service development in each area and the ethos of individual general
      practitioners instrumental in establishing the service.

PMID- 12609471
TI  - Neighborhood differences in social capital: a compositional artifact or a
      contextual construct?
AB  - Assessment of social capital at the neighborhood level is often based on
      aggregating individual perceptions of trust and reciprocity. Individual
      perceptions, meanwhile, are influenced through a range of individual attributes.
      This paper examines the socioeconomic and demographic attributes that
      systematically correlate with individual perception of social capital and
      determines the extent to which such attributes account for neighborhood
      differences in social capital. Using improved multilevel modeling procedures, we
      ascertain the extent to which differences in social capital perception can be
      ascribed to true neighborhood-level variations. The analysis is based on the 1994
      95 Community Survey of the Project on Human Development in Chicago Neighborhoods
      (PHDCN). The response measure is based on survey respondent's perceptions of
      whether people in their neighborhood can be trusted. The results suggest that
      even after accounting for individual demographic (age, sex, race, marital status)
      and socioeconomic characteristics (income, education), significant neighborhood
      differences remain in individual perceptions of trust, substantiating the notion
      of social capital as a true contextual construct.

PMID- 12609472
TI  - Urban primary health care in Africa: a comparative analysis of city-wide public
      sector projects in Lusaka and Dar es Salaam.
AB  - Since the 1980s, a number of health system interventions in Sub-Saharan Africa
      have targeted urban areas, reflecting increasing attention to the contextual
      contrasts between urban and rural health settings. This article compares attempts
      in two projects-in Zambia and Tanzania-to strengthen urban primary health care in
      the public sector and make it more inclusive in a dual sense: making quality
      services more accessible to the poor; and fostering community involvement in
      health care and health-related activity. The paper reveals that the projects have
      produced many similar outcomes (both positive and negative), despite differences
      in their managerial arrangements. After identifying issues that may need to be
      considered in other health initiatives, the discussion revisits the urban/rural
      dimension of health care in relation to three key aspects: the by-passing of
      primary services, community participation and inter-sectoral action.

PMID- 12609477
TI  - Pulmonary diffusing capacity in pregnancy at sea level and at high altitude.
AB  - The impact of pregnancy on respiratory function and whether this is influenced by
      living conditions, such as altitude of residence, must be determined if the
      management of pregnant women, particularly those with pulmonary disease is to be
      optimized. Pulmonary diffusing capacity, corrected for haemoglobin concentration
      (DL(COc)), therefore, was measured in 112 healthy Peruvian women with singleton
      pregnancies living at sea level and 192 living at 4300 m. At each location, 19
      non-pregnant women were studied. The mean DL(COc)s of the pregnant and non
      pregnant women studied at sea level were similar but lower than those of their
      high altitude counterparts (P<0.001, P<0.001). At high altitude, the mean
      DL(COc)s of women studied in the first and second trimester were similar to that
      of non-pregnant women, but the mean DL(COc) of pregnant women studied in the
      third trimester was lower than that of the non-pregnant women (P<0.01). Our
      results demonstrate that the effect of pregnancy on pulmonary diffusing capacity
      is influenced by altitude of residence.

PMID- 12609476
TI  - Measurement of dyspnea: word labeled visual analog scale vs. verbal ordinal
      scale.
AB  - We previously used a verbal ordinal rating scale to measure dyspnea. That scale
      was easy for subjects to use and the words provided consistency in ratings. We
      have recently developed a word labeled visual analog scale (LVAS) with labels
      placed by the subjects, retaining the advantages of a verbal scale while offering
      a continuous scale that generates parametric data. In a retrospective meta
      analysis of data from 43 subjects, individuals differed little in their placement
      of words on the 100 mm LVAS (mean+/-S.D. for slight=20+/-2.5 mm, moderate=50+/-5
      mm and severe=80+/-6 mm) and ratings were distributed uniformly along the scale.
      A significant stimulus-response correlation was obtained for both the LVAS
      (r(2)=0.98) and for the verbal ordinal scale (Spearman r=0.94). The resolution of
      the two scales differed only slightly. With meaningful verbal anchors, well
      defined end-points, and clear instructions about the specific sensation to be
      rated, both scales provide valid measures of dyspnea.

PMID- 12609478
TI  - A model of vertebrate resting metabolic rate: balancing energetics and O2
      transport in system design.
AB  - In vertebrates, maximal rates of oxygen consumption (V(O(2),max)) exceed resting
      rates (V(O(2),rest)) by an average factor of ten. This pattern of factorial scope
      has led to the hypothesis that V(O(2),rest) and V(O(2),max) are causally linked
      in vertebrates (aerobic capacity model, Bennett and Ruben, Science 206, 649-654,
      1979). We propose an alternate theory that vertebrate resting metabolic rates are
      regulated at levels to optimize metabolic performance during activity, by
      reducing cardiovascular response times for O(2) transport. First, we argue that
      circulatory convection has the potential to be rate-limiting to vertebrate
      aerobic adjustment. We then show mathematically that incremental changes in
      convection requirements exhibit a nonlinear dependence on initial values. From
      this, a cost-benefit model is constructed, using energetics and blood-convection
      requirements, to predict the optimal fractional allocation to V(O(2),rest) in
      vertebrates as 11% of V(O(2),max). The implications of our results to vertebrate
      metabolic design and the evolution of endothermy are discussed.

PMID- 12609479
TI  - Vasoreactions to acute hypoxia, whole lungs and isolated vessels compared:
      modulation by NO.
AB  - We aimed to explain diverse pulmonary vascular responses to hypoxia in different
      preparations and their modulation by NO. In rats we compared isolated perfused
      lungs (IPL), small vessels in vitro (PRVs) and in vivo preparations. In IPL and
      in vivo, acute and chronic nitric oxide synthase (NOS) blockade with L-NAME left
      normoxic pulmonary artery pressure unchanged but enhanced hypoxic
      vasoconstriction, hypoxia-induced pulmonary vasoconstriction (HPV). PRVs in
      vitro, precontracted with PGF(2alpha), showed four tension changes in acute
      hypoxia: dilatation, contraction, dilatation, contraction. Acute and chronic NOS
      blockade reduced the first two phases. In non-precontracted PRVs (from other
      laboratories), NOS inhibition enhanced HPV as in vivo and IPL; attenuation of HPV
      seems associated with precontraction. Thus reduced NOS activity does not cause
      pulmonary hypertension but exaggerates HPV. In IPL, prolonged severe hypoxia
      caused biphasic vasoconstriction separated by dilatation; the time course
      resembled that seen in PRVs. We suggest that the sequence of events during
      hypoxia in PRVs can be detected in whole lung preparations.

PMID- 12609480
TI  - Effect of medroxyprogesterone on inspiratory flow shapes during sleep in
      postmenopausal women.
AB  - We previously showed that medroxyprogesterone acetate (MPA) effectively decreases
      the arterial CO(2) levels in postmenopausal women with partial upper airway
      obstruction. The aim of the present study was to analyze the effects of MPA on
      the inspiratory flow shapes during sleep. Eight postmenopausal women with
      hypoxemia and partial upper airway obstruction during sleep (patients) received
      MPA 60 mg daily for 14 days. Four matched postmenopausal women without MPA
      treatment served as controls. Sleep and nasal pressure were recorded on each
      visit. Each breath was analyzed for duration, volume and inspiratory flow shape
      class. MPA shortened inspiration and prolonged expiration. The inspiratory
      volumes increased consistently in all flow shape classes. The inspiratory shapes
      with single late peak were transformed to those with double peak. MPA also
      decreased shapes with mid-peak or mid-plateau. MPA did not have an effect on
      sleep. Sleep modified the flow shape distribution only in patients but in a
      similar fashion in stages S2, SWS and REM. The results suggest that
      postmenopausal women present with a significant proportion breaths with poor
      initial inspiratory flow, which is reversed with MPA-induced respiratory
      stimulation.

PMID- 12609481
TI  - Arterial hypoxemia in exercising thoroughbreds is not affected by pre-exercise
      nedocromil sodium inhalation.
AB  - It has been reported that pulmonary injury (i.e. capillary stress failure) evoked
      histamine release from airway inflammatory/mast cells contributes to exercise
      induced arterial hypoxemia (EIAH) and that pre-exercise inhalation of nedocromil
      sodium mitigated EIAH in human subjects 'Med. Sci. Sports Exercise 29, (1997) 10
      16'. Because exercise-induced pulmonary hemorrhage due to capillary stress
      failure is routinely observed in racehorses, we examined whether nedocromil
      inhalation would similarly benefit EIAH and desaturation of hemoglobin in horses.
      Two sets of experiments, namely, placebo studies followed in 7 days by pre
      exercise nedocromil sodium (30 puffs=60 mg) inhalation experiments were carried
      out on 7 healthy, sound, exercise-trained thoroughbred horses. In both
      treatments, arterial and mixed-venous blood-gas/pH measurements were made at rest
      pre- and post-placebo/drug inhalation, as well as during incremental exercise
      leading to galloping at 14 m/sec on a 3.5% uphill grade-a workload that elicited
      maximal heart rate and caused pulmonary hemorrhage in all horses in both
      treatments, thereby indicating capillary stress failure had occurred. In both
      treatments, significant (P<0.0001) EIAH of a similar magnitude had developed by
      30 sec of maximal exertion, and further significant changes in arterial O(2)
      tension did not occur as exercise duration progressed to 120 sec. Thus, pre
      exercise inhalation of nedocromil sodium was ineffective in modifying the
      development and/or severity of EIAH in the present study. These findings argue
      against the airway inflammatory mediator(s) release hypothesis for causing
      arterial hypoxemia in racehorses.

PMID- 12609482
TI  - Effect of local shell conductance on the vascularisation of the chicken
      chorioallantoic membrane.
AB  - The vascularisation of the chorioallantoic membrane (CAM) of avian embryos is
      influenced by environmental oxygen partial pressure (P(O(2))) on a global level:
      incubation at high P(O(2)) reduces the density of pre- and post-capillary vessels
      of the CAM and decelerates the thinning of the blood-gas barrier, and vice versa.
      This study investigates the effects of local P(O(2)) on vascular development
      during the formative period of days ten to fifteen, by making half of the egg
      hypoxic and the other half hyperoxic. The densities of arterioles, venules and
      capillaries were reduced under the hypoxic side, compared to untreated eggs, but
      not significantly changed on the hyperoxic side. Harmonic mean thickness of the
      tissue barrier and total CAM blood volume were not affected by the treatments.
      Vascular development of the CAM was therefore only partly influenced by local
      P(O(2)).

PMID- 12609483
TI  - Arterial blood gas control in the upright versus recumbent Asian elephant.
AB  - In the elephant, there is concern that lateral recumbency (LR) impairs
      respiratory muscle and lung function resulting in clinically significant arterial
      hypoxemia. Using healthy adult female Asian elephants (Elephas maximus, n=6), the
      hypothesis was tested that, given the O(2) binding characteristics of elephant
      blood, substantial reductions in arterial O(2) pressure (Pa(O(2))) in LR could be
      tolerated without lowering arterial O(2) content appreciably. Fifteen minutes of
      LR decreased Pa(O(2)) from 103+/-2 (upright, U) to 77+/-4 mmHg (P<0.05) and
      hemoglobin O(2) saturation (U, 97.8+/-0.1, LR, 95.3+/-0.5%, P<0.05). However, due
      to a recumbency-induced hemoconcentration, arterial O(2) content was unchanged
      (U, 18.2+/-2.4, LR, 18.3+/-2.1 ml O(2) per 100 ml). In addition, there was a mild
      hyperventilation in LR that reduced arterial CO(2) pressure (P(CO(2))) from
      39.4+/-0.3 to 37.1+/-1.0 mmHg (P<0.05). These data indicate that the Asian
      elephant can endure at least short periods of LR without lowering arterial O(2)
      content.

PMID- 12609484
TI  - Vaccination stimulates retinal ganglion cell regeneration in the adult optic
      nerve.
AB  - We examined whether vaccination of adult rats with spinal cord homogenate (SCH)
      can promote regeneration of retinal ganglion cells (RGCs) after microcrush lesion
      of the optic nerve. Injured animals vaccinated with SCH showed axon growth into
      the optic nerve and such regeneration was not observed in animals vaccinated with
      liver homogenate (LH). Regeneration was not a consequence of neuroprotection
      since our vaccine did not protect RGCs from axotomy-induced cell death. Sera of
      vaccinated animals were tested for antibodies against myelin-associated
      glycoprotein, NogoA, Nogo-66 receptor, or chondroitin sulphate proteoglycans
      (CSPG), but no significant levels were detected. Antibodies to myelin basic
      protein were present in the serum of some SCH-vaccinated animals. In culture,
      serum from SCH-vaccinated animals promoted RGC growth on myelin but not on CSPG.
      Our results show that the effect of the pro-regenerative vaccine is mediated by
      antibodies to SCH. However, we were not able to detect a significant immune
      reaction to growth inhibitory proteins, suggesting alternative mechanisms for the
      success of vaccination to promote regeneration.

PMID- 12609485
TI  - TorsinA protein and neuropathology in early onset generalized dystonia with GAG
      deletion.
AB  - Familial, early onset, generalized torsion dystonia is the most common and severe
      primary dystonia. Most cases are caused by a 3-bp deletion (GAG) in the coding
      region of the TOR1A (DYT1) gene, which is widely expressed in human brain and
      encodes the protein torsinA. This study compares neuropathology and torsinA
      expression in the normal human brain with that in dystonia cases with and without
      the GAG deletion. TorsinA-like protein was expressed in neuronal cytoplasm
      throughout the human brain, including cerebellum, substantia nigra, hippocampus,
      and neostriatum, with higher levels in specific neurons. This immunostaining
      pattern was not discernibly different in dystonia and normal brains in midbrain
      and neostriatal regions. However, nigral dopaminergic neurons appeared to be
      larger in both GAG-deletion and non-GAG-deletion dystonia brains compared to
      normal, and may be more closely spaced in GAG-deletion brains. Beyond these
      apparent changes in neuronal size and spacing in dystonia brains, there was no
      indication of neuron loss, inflammation, DNA strand breaks, or altered
      distribution of torsin-like immunoreactivity, supporting a functional rather than
      degenerative etiology of early onset torsion dystonia.

PMID- 12609486
TI  - Transient forebrain ischemia induced phosphorylation of cAMP-responsive element
      binding protein is suppressed by hyperglycemia.
AB  - Hyperglycemia enhances brain damage due to transient cerebral ischemic stroke.
      The hyperglycemia-mediated detrimental effect is probably due to mitochondrial
      dysfunction and the resulting promotion of cell death pathways. In this study, we
      determined whether hyperglycemia suppresses cell survival signals that involve
      the cAMP-responsive element-binding protein (CREB) and activating transcription
      factor (ATF-2). Total and phosphorylated CREB and ATF-2 were measured in the
      cingulate cortex and dentate gyrus, two structures that are ischemia-resistant
      under normoglycemic conditions but become ischemia-vulnerable under hyperglycemic
      conditions, using immunocytochemistry and Western blot analysis. Samples were
      collected from normo-operated and hyperglycemic rats subjected to 15 min of
      ischemia followed by reperfusion. Transient ischemia induced a persistent
      phosphorylation of CREB in normoglycemic animals. Hyperglycemia suppressed
      phosphorylation of CREB in hyperglycemia-recruited areas. Ischemia also induced a
      transient increase of phospho-ATF-2 in the cingulated cortex that was suppressed
      by hyperglycmia. We conclude that suppression of neuronal survival signals by
      hyperglycemia may contribute to the mechanism of converting ischemia-resistant
      structures into vulnerable ones.

PMID- 12609487
TI  - Up-regulation of inducible nitric oxide synthase in the substantia nigra by
      lipopolysaccharide causes microglial activation and neurodegeneration.
AB  - The present study was designed to examine whether expression of iNOS was involved
      in LPS-induced neurodegeneration in rat substantia nigra (SN) and to study the
      role of NO in the loss of the SN dopaminergic neurons. In Western blot analysis,
      iNOS was induced in the SN after injection of LPS in a time- and dose-dependent
      manner. Immunofluorescence and immunohistochemical analyses revealed that the
      iNOS is located in a fully activated microglia with the characteristic amoeboid
      morphology. Furthermore, LPS-induced loss of dopaminergic neurons was
      significantly inhibited by the administration of L-N(G)-nitroarginine, a
      selective inhibitor of NOS, and the glucocorticoid dexamethasone. These
      inhibiting agents for iNOS reduced LPS-induced microglial activation, suggesting
      that NO has a role in inflammatory-mediated microglial activation. These results
      demonstrate that LPS induces the expression of iNOS in activated microglia in the
      SN, and that NO and/or its metabolites may play a crucial role in inflammation
      mediated degeneration of dopaminergic neurons.

PMID- 12609488
TI  - Tau and neurofilaments in a family with frontotemporal dementia unlinked to
      chromosome 17q21-22.
AB  - A Swiss frontotemporal dementia (FTD) kindred with extrapyramidal-like features
      and without motor neuron disease shows a brain pathology with ubiquitin-positive
      but tau-negative inclusions. Tau and neurofilament modifications are now studied
      here in three recently deceased family members. No major and specific decrease of
      tau was observed as described by others in, e.g., sporadic cases of FTD with
      absence of tau-positive inclusions. However, a slight decrease of tau,
      neurofilament, and synaptic proteins, resulting from frontal atrophy was
      detected. In parallel, polymorphic markers on chromosome 17q21-22, the
      centromeric region of chromosome 3 and chromosome 9, were tested. Haplotype
      analysis showed several recombination events for chromosomes 3 and 17, but
      patients shared a haplotype on chromosome 9q21-22. However as one of the patients
      exhibited Alzheimer and vascular dementia pathology with uncertain concomitant
      FTD, this locus is questionable. Altogether, these data indicate principally that
      the Swiss kindred is unlinked to locus 17q21-22, and that tau is not at the
      origin of FTD in this family.

PMID- 12609489
TI  - Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null
      mice.
AB  - The allele E4 of apolipoprotein E (apoE) is an important risk factor for
      Alzheimer's disease (AD) and the chronic brain inflammation which is associated
      with AD is more pronounced in subjects who carry this allele. In the present
      study, we employed mice transgenic for the human apoE isoforms apoE3 or apoE4 on
      a null mouse apoE background and intracerebroventricular injection of LPS to
      investigate the possibility that the regulation of brain inflammation is affected
      by the apoE genotype. LPS treatment of control mice resulted in activation of
      brain astrocytes and microglia whose extent decreased with age. LPS treatment of
      6-month-old apoE transgenic and control mice resulted in marked activation of
      brain astrocytes in the control and apoE3 transgenic mice but had no effect on
      astrogliosis of age-matched apoE-deficient and apoE4 transgenic mice. In
      contrast, there were no significant differences between the levels of activated
      microglia of the apoE3 and apoE4 transgenic mice following LPS treatment.
      Immunoblot assays revealed that the apoE4 and apoE3 transgenic mice had the same
      levels of brain apoE, which were similarly increased following LPS treatment.
      These results show that LPS-induced astrogliosis in apoE transgenic mice is
      regulated isoform-specifically by apoE3 and not by apoE4 and suggest that similar
      mechanisms may mediate the phenotypic expression of the apoE4 genotype in AD and
      in other neurodegenerative diseases.

PMID- 12609490
TI  - Complement-receptor-3 and scavenger-receptor-AI/II mediated myelin phagocytosis
      in microglia and macrophages.
AB  - Microglia and macrophages express the alpha(M)/beta(2) integrin complement
      receptor-3 (CR3/MAC-1; CD11b/CD18) and scavenger-receptor-AI/II (SRAI/II). Both
      can mediate myelin phagocytosis. We document that CR3/MAC-1 mediated myelin
      phagocytosis in microglia is modulated by complement and anti-CR3/MAC-1 mAbs.
      Complement augmented phagocytosis twofold. Anti-alpha(M) mAbs M1/70 and 5C6
      inhibited and anti-beta(2) mAb M18/2 augmented myelin phagocytosis in the
      presence and absence of active complement. Active complement modulated
      phagocytosis inhibition by M1/70 and 5C6 and phagocytosis augmentation by M18/2.
      CR3/MAC-1 mediated myelin phagocytosis may thus be, at least partially,
      independent of but modulated by complement. Anti-beta(2) mAb Game-46 did not
      affect phagocytosis. However, combining M18/2 with Game-46 resulted in
      phagocytosis augmentation that was larger in magnitude than that induced by M18/2
      alone. Thus, phagocytosis augmentation induced by one anti-beta(2) mAb was
      potentiated by another anti-beta(2) mAb. Combining M1/70 or 5C6 with M18/2
      inhibited M18/2-induced augmentation. Overall, mAbs-induced phagocytosis
      modulation ranged three- to sevenfold from inhibition to augmentation. Anti
      CR3/MAC-1 mAbs may reveal a mechanism by which native extracellular molecules
      bind to and modulate CR3/MAC-1 mediated myelin phagocytosis in microglia and
      macrophages. We further document SRAI/II mediated myelin phagocytosis in
      microglia and CR3/MAC-1 contributing to myelin phagocytosis two- to threefold
      more than SRAI/II when the two receptors function together.

PMID- 12609491
TI  - Exogenous soluble tumor necrosis factor receptor type I ameliorates murine
      experimental autoimmune neuritis.
AB  - Tumor necrosis factor (TNF) and its receptor (TNFR) have been strongly implicated
      in the pathogenesis of autoimmune disease. Soluble cytokine receptors may be shed
      naturally from cell membranes to inhibit cytokine activity. Experimental
      autoimmune neuritis (EAN) is a CD4 Th1 cell-mediated animal model of Guillain
      Barre syndrome (GBS) in humans. In the present study, we investigated the effects
      of soluble TNFR type I (sTNFR I) in EAN induced in mice by P0 peptide 180-199 and
      Freund's complete adjuvant. Our data from two different therapeutic regimens
      indicate that the administration of sTNFR I effectively ameliorated the clinical
      and pathological signs of EAN, i.e., decreased its severity, shortened its
      duration, and reduced inflammatory cell infiltration into the peripheral nervous
      system. The suppression of clinical EAN was accompanied in vitro by a marked
      reduction in antigen-specific T-cell proliferation and IFN-gamma synthesis by
      spleen cells from sTNFR I-treated mice, compared to control mice treated with
      PBS. These data directly demonstrate a pivotal role for TNF in the development of
      EAN and also suggest that sTNFR I may have therapeutic potential for alleviating
      GBS in humans.

PMID- 12609493
TI  - Different consequences of EGR2 mutants on the transactivation of human Cx32
      promoter.
AB  - The early growth response 2 (EGR2) transcription factor plays a crucial role in
      peripheral nerve myelination. Mutations of this gene are associated with a wide
      variety of demyelinating neuropathies differing from each other in the severity
      of nerve injury. Although the expression of EGR2 mutants inhibits the
      transactivation of myelin gene promoters, the exact molecular mechanism by which
      these mutations cause the alteration of the myelination process is still unknown.
      Recently, it was reported that EGR2 is directly involved in the transcriptional
      regulation of Connexin 32, a myelin gene frequently mutated in peripheral
      neuropathies. Here we describe the differential effect of two EGR2 mutants; while
      mutant D355V partially induces Cx32 promoter, mutant R381H does not. Furthermore,
      we show that a sequence located at -216, recognized by the wild-type and the
      mutant D355V recombinant proteins, is relevant for promoter transactivation.

PMID- 12609492
TI  - Ionotropic glutamate receptors: still a target for neuroprotection in brain
      ischemia? Insights from in vitro studies.
AB  - Although experimental studies have widely shown that the pharmacological blockade
      of ionotropic glutamate receptors reduces ischemic damage, clinical trials with
      classical AMPA and NMDA glutamate receptor antagonists have provided negative
      results. To address the involvement of ionotropic glutamate receptors in ischemic
      damage, corticostriatal brain slices were prepared from adult rats. Extracellular
      recordings were performed in the striatum after stimulation of the glutamatergic
      corticostriatal fibres. In vitro ischemia was induced for a 10-min period by
      omitting oxygen and glucose from the external medium. Under control conditions,
      ischemia produced an irreversible loss of the corticostriatal field potential
      amplitude, AP5, a competitive NMDA receptor antagonist, induced a slight rescue
      of the potential, while ifenprodil, a positive modulator of the proton sensor of
      the NMDA receptors, allowed a complete recovery from the ischemic insult. Similar
      neuroprotection was achieved by utilizing either CNQX, a broad spectrum AMPA
      receptors antagonist, or Joro spider toxin, a selective blocker of calcium
      permeable AMPA receptors. Interestingly, while CNZX also fully suppressed
      physiological excitatory transmission, Joro spider toxin was ineffective on this
      parameter. Finally, lamotrigine and remacemide, two antiepileptic drugs that
      differentially affect excitatory transmission, exerted neuroprotective effects
      against ischemia. Noticeably, a combination of low concentrations of these two
      drugs exerted a stronger neuroprotection than a single drug given in isolation.
      Thus, it might be possible to reach a neuroprotective action by utilizing doses
      of these compounds low enough to avoid side effects. Our experimental data still
      support the idea that a negative modulation of excitatory transmission can be
      neuroprotective against ischemia. In addition, our findings support the concept
      that it is possible to produce a significant neuroprotective action in the
      absence of a relevant interference with normal synaptic transmission.

PMID- 12609494
TI  - Word, nonword, and visual paired associate learning in Dutch dyslexic children.
AB  - Verbal and non-verbal learning were investigated in 21 8-11-year-old dyslexic
      children and chronological-age controls, and in 21 7-9-year-old reading-age
      controls. Tasks involved the paired associate learning of words, nonwords, or
      symbols with pictures. Both learning and retention of associations were examined.
      Results indicated that dyslexic children had difficulty with verbal learning of
      both words and nonwords. In addition, analysis of the errors made during nonword
      learning showed that both phonological errors and general learning errors were
      distributed similarly for the reading groups. This suggests that nonword learning
      in dyslexics is slower, but not qualitatively different from normal readers.
      Furthermore, no differences were found between the dyslexics and age-matched
      normal readers on non-verbal learning. Long-term retention of the learned visual
      verbal associations (both words and nonwords) was not impaired in dyslexic
      children as compared to normal readers. Finally, phonological awareness ability
      was assessed. Dyslexics performed worse than age-matched normal readers, but
      similar to reading-age controls.

PMID- 12609495
TI  - Genetic and environmental influences on individual differences in printed word
      recognition.
AB  - The genetic and environmental etiologies of individual differences in printed
      word recognition and related skills were explored in 440 identical and fraternal
      twin pairs between 8 and 18 years of age. A theoretically driven measurement
      model identified five latent variables: IQ, phoneme awareness, word recognition,
      phonological decoding, and orthographic coding. Cholesky decomposition models on
      these five latent constructs revealed the existence of both common and
      independent genetic effects, as well as non-shared environmental influences.
      There was evidence for moderate genetic influences common between IQ, phoneme
      awareness, and word-reading skills, and for stronger IQ-independent genetic
      influences that were common between phoneme awareness and word-reading skills,
      particularly phonological decoding. Phonological and orthographic coding skills
      in word recognition had both significant common and significant independent
      genetic influences, with implications for "dual-route" and "connectionist"
      reading models, subtypes of reading disabilities, and the remediation of reading
      disabilities.

PMID- 12609496
TI  - Dissociations between implicit and explicit memory in children: the role of
      strategic processing and the knowledge base.
AB  - A review of the literature shows that explicit memory develops substantially from
      three years of age to adulthood, while implicit memory remains stable across this
      age range. Previously, this developmental dissociation has been attributed to
      different memory systems, or to confounds with perceptual vs. conceptual
      processing. Prompted by an alternative developmental framework, the experiments
      reported here provide evidence against both interpretations. Instead, it will be
      argued that (a) the implicit-explicit developmental dissociation reflects
      differences in strategic processing (strategy use and metamemory) across
      childhood and (b) that implicit memory can show development if a child's
      knowledge base in the tested domain is developing with age.

PMID- 12609497
TI  - Insulin and leptin revisited: adiposity signals with overlapping physiological
      and intracellular signaling capabilities.
AB  - The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone
      insulin each function as afferent signals to the hypothalamus in an endocrine
      feedback loop that regulates body adiposity. Although these two hormones, and the
      receptors on which they act, are unrelated and structurally distinct, they exert
      overlapping effects in the arcuate nucleus, a key hypothalamic area involved in
      energy homeostasis. Defects in either insulin or leptin signaling in the brain
      result in hyperphagia, disordered glucose homeostasis, and reproductive
      dysfunction. To explain this striking physiological overlap, we hypothesize that
      hypothalamic insulin and leptin signaling converge upon a single intracellular
      signal transduction pathway, known as the insulin-receptor-substrate
      phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of
      model systems in which such "cross-talk" between insulin and leptin signal
      transduction has either been observed or can be inferred, discuss our own data
      demonstrating that insulin and leptin both activate hypothalamic
      phosphatidylinositol 3-kinase signaling, and discuss the significance of such
      convergence with respect to neuronal function in normal individuals and in
      pathological states such as obesity. Identification of the key early molecular
      events mediating the action of both insulin and leptin in hypothalamic neurons
      promises new insight into the regulation of these neurons in health and disease.

PMID- 12609498
TI  - Transgenic studies on the regulation of the anterior pituitary gland function by
      the hypothalamus.
AB  - The anterior pituitary gland is composed of five different cell types secreting
      hormones whose functions include the regulation of post-natal growth (growth
      hormone, GH), lactation (prolactin, PRL), reproduction (luteinising hormone, LH,
      and follicle stimulating hormone, FSH), metabolism (thyroid stimulating hormone,
      TSH), and stress (adrenocorticotrophic hormone, ACTH). The synthesis and
      secretion of the anterior pituitary hormones is under the control of
      neuropeptides released from the hypothalamus into a capillary portal plexus which
      flows through the external zone of the median eminence to the anterior lobe. This
      review describes the ways that gene transfer technologies have been applied to
      whole animals in order to study the regulation of anterior pituitary function by
      the hypothalamus. The extensive studies on these neuronal systems, within the
      context of the physiological integrity of the intact organism, not only exemplify
      the successful application of transgenic technologies to neuroendocrine systems,
      but also illustrate the problems that have been encountered, and the challenges
      that lie ahead.

PMID- 12609499
TI  - The magnocellular oxytocin system, the fount of maternity: adaptations in
      pregnancy.
AB  - Oxytocin secretion from the posterior pituitary gland is increased during
      parturition, stimulated by the uterine contractions that forcefully expel the
      fetuses. Since oxytocin stimulates further contractions of the uterus, which is
      exquisitely sensitive to oxytocin at the end of pregnancy, a positive feedback
      loop is activated. The neural pathway that drives oxytocin neurons via a
      brainstem relay has been partially characterised, and involves A2 noradrenergic
      cells in the brainstem. Until close to term the responsiveness of oxytocin
      neurons is restrained by neuroactive steroid metabolites of progesterone that
      potentiate GABA inhibitory mechanisms. As parturition approaches, and this
      inhibition fades as progesterone secretion collapses, a central opioid inhibitory
      mechanism is activated that restrains the excitation of oxytocin cells by
      brainstem inputs. This opioid restraint is the predominant damper of oxytocin
      cells before and during parturition, limiting stimulation by extraneous stimuli,
      and perhaps facilitating optimal spacing of births and economical use of the
      store of oxytocin accumulated during pregnancy. During parturition, oxytocin
      cells increase their basal activity, and hence oxytocin secretion increases. In
      addition, the oxytocin cells discharge a burst of action potentials as each fetus
      passes through the birth canal. Each burst causes the secretion of a pulse of
      oxytocin, which sharply increases uterine tone; these bursts depend upon auto
      stimulation by oxytocin released from the dendrites of the magnocellular neurons
      in the supraoptic and paraventricular nuclei. With the exception of the opioid
      mechanism that emerges to restrain oxytocin cell responsiveness, the behavior of
      oxytocin cells and their inputs in pregnancy and parturition is explicable from
      the effects of hormones of pregnancy (relaxin, estrogen, progesterone) on pre
      existing mechanisms, leading through relative quiescence at term inter alia to
      net increase in oxytocin storage, and reduced auto-inhibition by nitric oxide
      generation. Cyto-architectonic changes in parturition, involving evident
      retraction of glial processes between oxytocin cells so they get closer together,
      are probably a response to oxytocin neuron activation rather than being essential
      for their patterns of firing in parturition.

PMID- 12609500
TI  - Gene therapy for pituitary tumors: from preclinical models to clinical
      implementation.
AB  - Gene therapy, which entails the use of nucleic acids as drugs, is a new approach
      to treat disease. Gene therapy has been successfully implemented in several
      preclinical animal models, including several paradigms of experimental pituitary
      tumors. In spite of these successes, several critical issues need to be addressed
      before gene therapy can become a clinical reality for the treatment of pituitary
      tumors. These include the development of safer and more effective gene delivery
      vectors, the uncovering of novel therapeutic targets, the development of
      molecular switches which will allow turning therapeutic transgene expression "on"
      and "off" as and when it is needed, and the ability to scale up the vector
      preparations devoid of any putative contaminants. There are still many basic
      science developments that must take place in order to allow this new therapeutic
      technology to make its way successfully into the clinical arena to treat
      pituitary disease. We envisage these developments taking place within the next
      five years, gene therapy for pituitary tumors will then form part of the
      armamentarium available to better treat and manage pituitary tumors.

PMID- 12609501
TI  - Pathological analysis of muscle hypertrophy and degeneration in muscular
      dystrophy in gamma-sarcoglycan-deficient mice.
AB  - While calf muscle hypertrophy is a striking diagnostic finding in
      sarcoglycanopathy, as it is in Duchenne and Becker muscular dystrophies, its
      pathogenetic mechanism remains unknown. gamma-Sarcoglycan, one of the subunits of
      the sarcoglycan complex, is the protein responsible for gamma-sarcoglycanopathy.
      To elucidate the pathogenetic mechanisms of muscle hypertrophy and degeneration
      in muscular dystrophy, we utilized a mutant mouse as a model animal. In this
      study, we generated gamma-sarcoglycan-deficient (gsg-/-) mice by gene targeting.
      The gsg-/- mice described here, similar to the gsg-/- mice reported previously (J
      Cell Biol 142 (1998) 1279), demonstrated skeletal and cardiac muscle
      degeneration. The limb, shoulder, and pelvic muscles of the gsg-/- mice exhibited
      progressive muscle hypertrophy and weakness with age, and the findings were
      similar to those seen in other mouse models for limb-girdle and Duchenne muscular
      dystrophy. We found that the number of muscle fibers increased with age, and most
      of the fibers in the hypertrophic muscle were centrally nucleated regenerating
      fibers. Therefore, muscle hypertrophy of the gsg-/- mice may result from an
      increase of the number of muscle fibers and probable fiber branching and may not
      be due to the pseudohypertrophy caused by fibrous and fat tissue replacement, as
      has been long supposed in muscular dystrophy. The muscle pathology became more
      'dystrophic' in mice over 1 year of age when there was a marked variation in
      fiber size with interstitial fibrosis.

PMID- 12609502
TI  - Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation
      in mutant mice.
AB  - Deficiency of laminin alpha2 is the cause of one of the most severe muscular
      dystrophies in humans and other species. It is not yet clear how particular
      mutations in the laminin alpha2 chain gene affect protein expression, and how
      abnormal levels or structure of the protein affect disease. Animal models may be
      valuable for such genotype-phenotype analysis and for determining mechanism of
      disease as well as function of laminin. Here, we have analyzed protein expression
      in three lines of mice with mutations in the laminin alpha2 chain gene and in two
      lines of transgenic mice overexpressing the human laminin alpha2 chain gene in
      skeletal muscle. The dy(3K)/dy(3K) experimental mutant mice are completely
      deficient in laminin alpha2; the dy/dy spontaneous mutant mice have small amounts
      of apparently normal laminin; and the dy(W)/dy(W) mice express even smaller
      amounts of a truncated laminin alpha2, lacking domain VI. Interestingly, all
      mutants lack laminin alpha2 in peripheral nerve. We have demonstrated previously,
      that overexpression of the human laminin alpha2 in skeletal muscle in
      dy(2J)/dy(2J) and dy(W)/dy(W) mice under the control of a striated muscle
      specific creatine kinase promoter substantially prevented the muscular dystrophy
      in these mice. However, dy(W)/dy(W) mice, expressing the human laminin alpha2
      under the control of the striated muscle-specific portion of the desmin promoter,
      still developed muscular dystrophy. This failure to rescue is apparently because
      of insufficient production of laminin alpha2. This study provides additional
      evidence that the amount of laminin alpha2 is most critical for the prevention of
      muscular dystrophy. These data may thus be of significance for attempts to treat
      congenital muscular dystrophy in human patients.

PMID- 12609503
TI  - Spontaneous muscular dystrophy caused by a retrotransposal insertion in the mouse
      laminin alpha2 chain gene.
AB  - We identified a novel spontaneous mouse model of human congenital muscular
      dystrophy with laminin alpha2 chain deficiency, named dy(Pas)/dy(Pas). Homozygous
      animals rapidly developed a progressive muscular dystrophy leading to premature
      death. Immunohistological and biochemical analyses demonstrated the absence of
      laminin alpha2 chain expression in skeletal muscle. Analysis of the laminin
      alpha2 chain cDNA showed the insertion of the long terminal repeat of an
      intracisternal A-particle gene. In addition, a 6.1 kb insertion composed of
      retrotransposon elements was identified in the Lama2 sequence. The
      dy(Pas)/dy(Pas) mouse is thus the first spontaneous mutant with a complete
      laminin alpha2 chain deficiency in which the mutation has been identified.

PMID- 12609504
TI  - Persistent over-expression of specific CC class chemokines correlates with
      macrophage and T-cell recruitment in mdx skeletal muscle.
AB  - Prior studies and the efficacy of immunotherapies provide evidence that
      inflammation is mechanistic in pathogenesis of Duchenne muscular dystrophy. To
      identify putative pro-inflammatory mechanisms, we evaluated chemokine
      gene/protein expression patterns in skeletal muscle of mdx mice. By DNA
      microarray, reverse transcription-polymerase chain reaction, quantitative
      polymerase chain reaction, and immunoblotting, convergent evidence established
      the induction of six distinct CC class chemokine ligands in adult MDX: CCL2/MCP
      1, CCL5/RANTES, CCL6/mu C10, CCL7/MCP-3, CCL8/MCP-2, and CCL9/MIP-1gamma. CCL
      receptors, CCR2, CCR1, and CCR5, also showed increased expression in mdx muscle.
      CCL2 and CCL6 were localized to both monocular cells and muscle fibers,
      suggesting that dystrophic muscle may contribute toward chemotaxis. Temporal
      patterns of CCL2 and CCL6 showed early induction and maintained expression in mdx
      limb muscle. These data raise the possibility that chemokine signaling pathways
      coordinate a spatially and temporally discrete immune response that may
      contribute toward muscular dystrophy. The chemokine pro-inflammatory pathways
      described here in mdx may represent new targets for treatment of Duchenne
      muscular dystrophy.

PMID- 12609505
TI  - Two novel mutations in the COLQ gene cause endplate acetylcholinesterase
      deficiency.
AB  - Congenital myasthenic syndromes with endplate acetylcholinesterase deficiency are
      very rare autosomal recessive diseases, characterized by onset of the disease in
      childhood, general weakness increased by exertion, ophthalmoplegia and
      refractoriness to anticholinesterase drugs. To date, all reported cases are due
      to mutations within the gene encoding ColQ, a specific collagen that anchors
      acetylcholinesterase in the basal lamina at the neuromuscular junction. We
      identified two new cases of congenital myasthenic syndromes with endplate
      acetylcholinesterase deficiency. The two patients showed different phenotypes.
      The first patient had mild symptoms in childhood, which worsened at 46 years with
      severe respiratory insufficiency. The second patient had severe symptoms from
      birth but improved during adolescence. In both cases, the absence of
      acetylcholinesterase was demonstrated by morphological and biochemical analyses,
      and heteroallelic mutations in the COLQ gene were found. Both patients presented
      a novel splicing mutation (IVS1-1G-->A) affecting the exon encoding the proline
      rich attachment domain (PRAD), which interacts with acetylcholinesterase. This
      splicing mutation was associated with two different mutations, both of which
      cause truncation of the collagen domain (a known 788insC mutation belonging to
      one patient and a novel R236X to the other) and may impair its trimeric
      organization. The close similarity of the mutations of these two patients with
      different phenotypes suggests that other factors may modify the severity of this
      disease.

PMID- 12609507
TI  - Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated
      with desmin mutations.
AB  - Desmin myopathy is a familial or sporadic disorder characterized by the presence
      of desmin mutations that cause skeletal muscle weakness associated with cardiac
      conduction block, arrhythmia and heart failure. Distinctive histopathologic
      features include intracytoplasmic accumulation of desmin-reactive deposits and
      electron-dense granular aggregates in skeletal and cardiac muscle cells. We
      describe two families with features of adult-onset slowly progressive skeletal
      myopathy without cardiomyopathy. N342D point mutation was present in the desmin
      helical rod domain in patients of family 1, and I451M mutation was found in the
      non-helical tail domain in patients of family 2. Of interest, the same I451M
      mutation has previously been reported in patients with cardiomyopathy and no
      signs of skeletal myopathy. Some carriers of the I451M mutation did not develop
      any disease, suggesting incomplete penetrance. Expression studies demonstrated
      inability of the N342D mutant desmin to form cellular filamentous network,
      confirming the pathogenic role of this mutation, but the network was not affected
      by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare
      phenotypic variant of desmin myopathy allelic to the more frequent cardio
      skeletal form.

PMID- 12609506
TI  - Congenital myasthenic syndrome due to a novel missense mutation in the gene
      encoding choline acetyltransferase.
AB  - Congenital myasthenic syndromes are caused by different genetic defects affecting
      proteins expressed at the neuromuscular junction. Recently, the first molecular
      genetic defect resulting in a presynaptic congenital myasthenic syndrome has been
      reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline
      acetyltransferase, were described in five congenital myasthenic syndrome
      families. In this study, we investigated three patients from two independent
      Turkish kinships. Clinically, all patients presented with moderate myasthenic
      symptoms including ptosis and muscle weakness with increased fatigability.
      Multiple episodes of sudden apnea were reported for all patients. One child
      suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma,
      showed a severe myasthenic phenotype, requiring permanent ventilation.
      Genetically, we identified a novel missense mutation (I336T) in the CHAT gene
      homozygously in all three patients. Haplotype analysis revealed that the mutant
      allele cosegregates with the clinical phenotype in both families (maximum
      combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that
      CHAT mutations are responsible for a clinically distinct form of congenital
      myasthenic syndrome, characterized by episodic apnea. Infections and stress may
      lead to a life-threatening failure of neuromuscular transmission in congenital
      myasthenic syndrome with episodic apnea. The observation of the same mutation
      (I336T) in two independent Turkish kinships may suggest a common origin, i.e.
      founder.

PMID- 12609508
TI  - Increased mitochondrial processing intermediates associated with three
      tRNA(Leu(UUR)) gene mutations.
AB  - Accumulation of RNA 19 has been associated with mitochondrial myopathy,
      encephalopathy, lactic acidosis and stroke-like episodes. We analyzed total RNA
      in muscle specimens from six patients who had one of three pathogenetic point
      mutations in the mitochondrial tRNA(Leu(UUR)) gene, including A3243G, T3271C, and
      T3303C. Mitochondrial processing intermediates were identified and quantitated by
      Northern blotting. The percentage of DNA with the mutation also was determined in
      each patient. The intermediate (RNA 19) was significantly increased in all
      patients. The proportion of mutation-carrying RNA in processing intermediates was
      always higher than in the DNA fraction, suggesting that these mutations may have
      dominant-negative effects on mitochondrial RNA processing events at the
      tRNA(Leu(UUR)) gene boundary.

PMID- 12609513
TI  - Molecular characterization of Llchit1, a midgut chitinase cDNA from the
      leishmaniasis vector Lutzomyia longipalpis.
AB  - During development within the midgut of the sand fly vector, Leishmania parasites
      after undergoing differentiation and multiplication must escape the peritrophic
      matrix (PM). Although Leishmania chitinase is believed to take part in promoting
      the escape of the parasite from the PM by inducing degradation of chitin fibers,
      it is conceivable that a sand fly-derived chitinase can also have a role in such
      an event. Here we describe the molecular cloning and partial characterization of
      a complete cDNA from a putative gut-specific, blood-induced chitinase from the
      sand fly vector Lutzomyia longipalpis. Llchit1 has an ORF of 1425 bp that encodes
      a predicted 51.6 kDa mature protein showing high similarity with chitinases from
      several different organisms. Messenger RNA expression studies indicate that
      Llchit1 is detected only in the blood fed midgut and it seems to reach a peak at
      approximately 72 h post blood meal (PBM). To date, only one midgut-specific
      chitinase from an insect disease vector, AgChi-1 from Anopheles gambiae, has been
      characterized. As with its mosquito counterpart, Llchit1 can be a target for
      development of a transmission blocking vaccine.

PMID- 12609514
TI  - Identification of a gene overexpressed in aphids reared under short photoperiod.
AB  - Most aphids develop a cyclic parthenogenesis life-cycle. After several
      generations of viviparously produced parthenogenetic females, follows a single
      annual generation of sexual individuals, usually in autumn, that mate and lay the
      sexual eggs. Shortening of photoperiod at the end of the summer (together with
      temperature) is a key factor inducing the sexual response. Currently no genes
      involved in the cascade of events that lead to the appearance of sexual forms
      have been reported. After a Differential Display RT-PCR survey performed on
      Acyrthosiphon pisum aphids, we identified a gene that is overexpressed in aphids
      reared under short photoperiod conditions that induce sexuality in this species.
      This cDNA (called ApSDI-1) shows similarities with a protein involved in amino
      acid transport in GABAergic neurons. Since several studies implicate GABAergic
      transmission in the generation and modulation of circadian rhythmicity, we
      propose that ApSDI-1 could be involved in the transduction of the photoperiodic
      message and therefore be a candidate to participate at some point in processes
      that trigger the sexual response in aphids. This is the first gene identified in
      aphids whose expression is governed by the photoperiod.

PMID- 12609515
TI  - Toxicity to the pea aphid Acyrthosiphon pisum of anti-chymotrypsin isoforms and
      fragments of Bowman-Birk protease inhibitors from pea seeds.
AB  - Aphids feed on a protein-poor diet and are insensitive to several serine protease
      inhibitors. However, among the Bowman-Birk family of plant trypsin inhibitors
      (BBI), some members display significant toxicity to the pea aphid Acyrthosiphon
      pisum. A BBI isoform purified from pea seeds (PsTI-2) displays an IC50 of 41
      microM and a LC50 of 48 microM at 7 days. Our data show that the chymotrypsin
      directed active site from these bifunctional inhibitors is responsible for this
      activity, and that artificial cyclic peptides bearing the Bowman-Birk anti
      chymotrypsin head induce much greater toxicity and growth inhibition than their
      anti-trypsin counterparts. The toxic syndrome included a rapid behavioural
      response of aphids on diets containing the toxic peptides, with induced
      restlessness after only 1 h of exposure to the chymotrypsin inhibitor.
      Nevertheless, chymotrypsin activity was not detected in aphid guts, using two
      chromogenic chymotrypsin substrates, and the physiological target of the
      chymotrypsin inhibitor remains unknown. These data show for the first time that
      plant chymotrypsin inhibitors, still widely unexplored, may act as paradoxical
      toxicants to aphids and serve as defensive metabolites for phloem-feeding
      insects.

PMID- 12609516
TI  - Chymotrypsin genes in the malaria mosquitoes Anopheles aquasalis and Anopheles
      darlingi.
AB  - Four closely related chymotrypsin genes were identified in Anopheles aquasalis
      and Anopheles darlingi (Anachy1, Anachy2, Andchy1 and Andchy2). The deduced amino
      acid sequences were compared to other chymotrypsin sequences. These sequences
      were used to infer phylogenetic relationships among the different species.
      Genomic cloning revealed that, in contrast to An. aquasalis and A. gambiae, the
      chymotrypsin genomic locus in An. darlingi had a short intergenic region that
      accompanied the inverted position of the genes, suggesting inversion mechanisms
      in this species related to transposable elements. Alignments of the sequences
      upstream of the transcription start sites of Anachy1, Anachy2, Andchy1 and
      Andchy2 revealed areas with high similarity containing palindromic sequences.
      Northern analysis from An. aquasalis indicated that the transcription of chy 1
      and 2 are induced by blood feeding.

PMID- 12609517
TI  - In vitro expression and biochemical characterization of juvenile hormone esterase
      from Manduca sexta.
AB  - Juvenile hormone esterase (JHE) is a selective enzyme that hydrolyzes the methyl
      ester of juvenile hormone. This enzyme plays an important role in the regulation
      of metamorphosis in caterpillars, and is implicated in additional roles in
      development and reproduction in this and other orders of insect. The full length
      coding region of the JHE cDNA from Manduca sexta was subcloned into the
      baculovirus AcMNPV genome under the control of the p10 promoter. The recombinant
      virus demonstrated the expression of high levels of JHE activity when infected
      into Hi5 cells from Trichoplusia ni. The recombinant protein was partially
      purified by anion exchange chromatography and its biochemical characterization
      showed similar features to the wild type protein. The recombinant JHE has an
      estimated MW of 66500 Da. Some heterogeneity with the enzyme was observed when
      analyzed by isoelectric focusing, although the peak of JHE activity was observed
      at pI=6.0. It is highly sensitive to trifluoroketone inhibitors and certain
      phosphoramidothiolates, while relatively insensitive to other common esterase
      inhibitors. Incubating the enzyme with various organic solvents and detergents
      showed that the enzyme is activated at lower concentrations of
      solvents/detergents and remains significantly active even at high concentrations.
      The high tolerance of organic solvents may make this JHE enzyme useful in future
      applications as a synthetic catalyst.

PMID- 12609518
TI  - Characterization and cDNA cloning of three major proteins from pharate pupal
      cuticle of Manduca sexta.
AB  - Three proteins, MsCP20, MsCP27 and MsCP36, that are secreted in greatest quantity
      into the pharate pupal cuticle of Manduca sexta ( Hopkins et al., 2000) were
      purified and their amino acid sequences determined by mass spectrometry and Edman
      degradation. Although these proteins become sclerotized and insoluble in the
      pupal exoskeleton, their sequences contain features characteristic for proteins
      occurring in less sclerotized pliable cuticles, such as arthrodial membranes and
      soft larval cuticles. These proteins carry a secondary modification attached to a
      threonine residue, presumably an O-linked sugar moiety. cDNA clones of the genes
      for MsCP20, MsCP27 and MsCP36 were constructed from pharate pupal integument RNA.
      Close agreement was found between the amino acid sequences determined by Edman
      degradation and sequences deduced from the cDNA clones. The molecular masses
      determined by protein sequencing for MsCP20, MsCP27, and MsCP36 were 17713,
      17448, and 29582 Da, respectively, in close agreement with the masses deduced
      from the corresponding cDNA clones (17711, 17410, and 29638 Da). Temporal
      expression analysis indicates that MsCP20 and MsCP36 transcripts are present at
      low levels early in the fifth larval stadium, followed by a large increase in
      abundance prior to pupal ecdysis. MsCP27 was not detected during development of
      the fifth larval instar, but its transcript, like those of MsCP20 and MsCP36,
      increased to a peak level just before pupal ecdysis. Only the MsCP36 transcript
      was detected in adults. These results support the hypothesis that these proteins
      are synthesized by the epidermis and are subsequently deposited into the cuticle
      during the larval-pupal transformation of M. sexta where they become sclerotized
      in the formation of pupal exocuticle.

PMID- 12609519
TI  - A potential role for phenylalanine hydroxylase in mosquito immune responses.
AB  - In mosquitoes the melanotic encapsulation immune response is an important
      resistance mechanism against filarial worms and malaria parasites. The rate
      limiting substrate for melanin production is tyrosine that is hydroxylated by
      phenoloxidase (PO) to produce 3, 4-dihydroxyphenylalanine. The single pathway for
      endogenous production of tyrosine is by hydroxylation of phenylalanine by
      phenylalanine hydroxylase (PAH). In this study we describe a potential role for
      PAH in melanotic immune responses in the yellow fever mosquito, Aedes aegypti. A
      1.6 kb A. aegypti PAH cDNA, encoding a 51 kDa protein, was isolated and
      subsequently expressed in an Escherichia coli expression system. In developing
      mosquitoes, PAH transcript is present in all stages and it is differentially
      expressed in adult tissues. Following an immune-challenge with Dirofilaria
      immitis microfilariae (mf) or bacteria, PAH transcript is up-regulated in
      hemocytes. Likewise, western analysis of hemocytes collected from immune
      activated mosquitoes show an increase in gene product over control samples. Like
      PO, ultrastructure observations provide verification that PAH is located in
      oenocytoid and granulocyte hemocytes. Our results offer the first data that
      suggest PAH is used in mosquito melanin synthesis and defense responses.

PMID- 12609520
TI  - Mamestra configurata serpin-1 homologues: cloning, localization and developmental
      regulation.
AB  - A screen of a Mamestra configurata (bertha armyworm) midgut cDNA library
      identified three types of cDNA clones that resemble the Manduca sexta serpin-1
      gene family. Two serpins, 1b and 1c, possess a common conserved serpin amino
      terminal scaffold domain but bear no similarity to any members of the M. sexta
      gene family within the reactive centre loop. These serpins differ from one
      another by only two amino acids in the reactive centre loop (S(363)-->P) and
      serpin signature (M(369)-->T) regions. The other member, denoted serpin-1a, is
      closely related to the M. sexta serpin-1Z. M. configurata serpins as a group were
      expressed in all insect developmental stages including eggs, larvae and adult
      moths. Within larvae, serpin gene expression was restricted to the early to
      middle instar developmental phase and mainly in the fat body and hemocytes.
      Stress imposed by starvation strongly induced expression in fat body and to a
      lesser degree in alimentary organs, nervous system and Malphigian tubules.
      Conversely, starvation decreased expression in hemocytes. Wounding or inoculation
      with bacteria did not induce serpin gene transcription but did lead to the
      formation of higher and lower molecular weight forms, presumably serpin-protease
      complexes and resultant truncated serpin, respectively. Two dimensional PAGE and
      western blotting analysis revealed at least 12 distinct serpins consisting
      primarily of neutral, but also highly acidic and basic isoforms, as well as
      additional high and low molecular weight immuno-reactive species. Serpins-1b/1c
      are the more prominent serpin isoforms and are expressed predominantly in the fat
      body and subsequently exported to the hemolymph as revealed by western blotting
      and immunolocalization. The serpin-1b/1c isoform was found only as the fully
      glycosylated species within the hemolymph. Hemolymph protease activity was
      comprised mostly of serine proteases whose overall activity increased
      dramatically at the onset of the molt concomitant with a sharp decline in serpin
      gene expression.

PMID- 12609521
TI  - The identification of an age- and female-specific putative PBAN membrane-receptor
      protein in pheromone glands of Helicoverpa armigera: possible up-regulation by
      Juvenile Hormone.
AB  - The present study was designed to determine the age and female specificity of a
      membrane protein that binds to a pheromone biosynthesis activating neuropeptide
      (PBAN) ligand and to elucidate the effect of Juvenile Hormone (JH) on binding as
      well as pheromone activation. The precise age at which developing adult females
      of Helicoverpa armigera begin to respond to PBAN was determined. PBAN activates
      in vitro pheromone biosynthesis as well as its intracellular second messenger,
      cAMP, only in intersegments of newly emerged adult female pheromone glands (i.e.
      1-day-old females). An increase in response was observed in 2-day-old females.
      Intersegments of female pupae and the homologous tissues of adult males do not
      respond to PBAN. However, in the presence of Juvenile Hormone II (JH II) PBAN
      induced a response in females, 1 day before emergence (pharate females), but not
      in younger female pupae. This phenomenon was also observed after topical
      applications of the JH analog fenoxycarb (FX). In addition the response to PBAN
      by intersegments of FX-treated emerged adults increased significantly to the
      level of 2-day-old females. JH II also stimulated the level of incorporation of
      (35)S-labelled amino acids in female pupae into membrane proteins that are
      typical in adult intersegments. Using a photoaffinity-biotin labelled PBAN analog
      we demonstrate specific binding of a membrane protein (estimated MW: 50 kD) in
      adult females. This binding was not detected in female pupae 3 days before
      emergence. However, in such female pupae specific binding of the 50 kD protein by
      the photoaffinity-biotin labelled PBAN analog was induced after JH II or FX
      treatments thereby providing evidence that JH may up-regulate this putative
      receptor protein.

PMID- 12609522
TI  - Cytokines and the immune-testicular axis.
AB  - Cytokines are regulatory proteins involved in haematopoiesis, immune cell
      development, inflammation and immune responses. Several cytokines have direct
      effects on testicular cell functions, and a number of these are produced within
      the testis even in the absence of inflammation or immune activation events. There
      is compelling evidence that cytokines, in fact, play an important regulatory role
      in the development and normal function of the testis. Pro-inflammatory cytokines
      including interleukin-1 and interleukin-6 have direct effects on spermatogenic
      cell differentiation and testicular steroidogenesis. Stem cell factor and
      leukaemia inhibitory factor, cytokines normally involved in haematopoiesis, also
      play a role in spermatogenesis. Anti-inflammatory cytokines of the transforming
      growth factor-beta family are implicated in testicular development. Consequently,
      local or systemic up-regulation of cytokine expression during injury, illness or
      infection may contribute to the disruption of testicular function and fertility
      that frequently accompanies these conditions. The aim of this review is to
      provide a very brief summary of the extensive literature dealing with cytokines
      in testicular biology, and to follow this with some speculation concerning the
      significance of these molecules in interactions between the immune system and the
      testis.

PMID- 12609523
TI  - Pregnancy is associated with suppression of the nuclear factor kappaB/IkappaB
      activation pathway in peripheral blood mononuclear cells.
AB  - Modulations of maternal immune cell function are critical for successful growth
      and development of an antigenically distinct fetus. It has been proposed that
      pregnancy is associated both with suppression of the adaptive immune system and a
      generalised maternal inflammatory response with changes in immune function
      resembling those associated with septicemia, and these changes are more
      exaggerated when pregnancies are complicated with pre-eclampsia. The nuclear
      factor (NF)-kappaB family of transcription factors play a significant role in
      immune regulation. We hypothesised therefore that if pregnancy is associated with
      activation of the maternal immune system, this would be supported by the
      activation of NF-kappaB and degradation of IkappaBalpha and beta in peripheral
      blood mononuclear cells (PBMCs). We demonstrate the contrary: NF-kappaB activity
      is suppressed in PBMCs from pregnant females and more in pre-eclampsia. The
      inhibition of NF-kappaB activation in pregnancy is not attributed to over
      expression of IkappaBalpha or beta. In contrast, levels of IkappaBalpha and beta
      in cytoplasmic extracts from PBMCs in pregnancy are decreased compared with non
      pregnant controls, and IkappaBalpha levels are decreased more so in pre
      eclampsia. We have shown that activation of NF-kappaB in PBMCs from patients with
      septicemia follows the classical pathway. This pathway is differentially
      regulated in pregnancy. Alterations in NF-kappaB nuclear binding and IkappaBalpha
      levels were reproducible by culturing PBMCs in pooled pregnant serum. Taken
      together, these data indicate that pregnancy-specific factors exist to regulate
      expression of NF-kappaB/IkappaB in a pregnancy-specific manner, and may underlie
      one mechanism by which the fetus avoids maternal rejection throughout pregnancy.

PMID- 12609524
TI  - In-situ detection of both inflammatory and anti-inflammatory cytokines in resting
      peripheral blood mononuclear cells during pregnancy.
AB  - INTRODUCTION: Local and possibly systemic curtailment of the maternal immune
      response is important for a successful pregnancy. Although the local milieu at
      the utero-placental interface is likely to harbor the most prominent alterations,
      it is suggested, at least in mice, that systemic immunity is also tolerized
      during pregnancy. In the present study, we investigated mRNA expression of the
      key immunomodulatory cytokines; interleukin (IL)-4, IL-10, tumor necrosis factor
      (TNF)-alpha and interferon (IFN)-gamma during normal pregnancy. MATERIAL AND
      METHODS: In-situ hybridization (ISH) of cytokine mRNA in resting peripheral blood
      mononuclear cells (PBMCs) was used to detect the number of cells spontaneously
      expressing cytokines. Eleven women with normal gestations were followed during
      pregnancy as well as 8 weeks postpartum, and compared with 10 non-pregnant
      healthy controls. RESULTS: The numbers of IFN-gamma and IL-4 mRNA expressing
      cells were found to be significantly increased during pregnancy and postpartum
      compared with non-pregnant controls. Pregnant women and non-pregnant controls did
      not differ in their expression of TNF-alpha and IL-10. CONCLUSION: Our studies
      demonstrated increased numbers of both IFN-gamma and IL-4 mRNA expressing cells
      in blood suggesting that systemic immunomodulation, albeit partial, takes place
      during normal pregnancy. It is proposed that enhanced IL-4 expression, possibly
      in concert with other elevated anti-inflammatory immunomodulatory cytokines,
      curtail the potentially hazardous effects of IFN-gamma on systemic immunity
      during pregnancy.

PMID- 12609525
TI  - IL-1 receptor antagonist gene polymorphism in recurrent spontaneous abortion.
AB  - Genetic factors may contribute to the development of an aberrant pro-inflammatory
      immune response during pregnancy, thereby increasing the risk of some pregnancy
      related pathologies such as recurrent spontaneous abortion (RSA). Interleukin 1
      receptor antagonist is an important anti-inflammatory molecule encoded by the
      IL1RN gene, in which an intronic polymorphism has been described. Even though the
      molecular genetic mechanisms are not understood, this non-coding polymorphism,
      and especially IL1RN*2, has been associated with several chronic inflammatory and
      autoimmune diseases. IL1RN*2 is also associated with increased activity of IL
      1beta, which is an important pro-inflammatory cytokine. We investigated the
      genetic variants of IL1RN in 37 Finnish women with RSA and 800 randomly selected
      Finnish blood donors. The women with RSA showed a significantly increased
      frequency of genotypes bearing the rare allele IL1RN*3 compared to the blood
      donors (10.8 vs 2.1%, odds ratio 5.6, 95% CI: 1.5-19.0, P=0.006). Our results
      suggest that IL1RN polymorphisms may predispose to RSA in a small subgroup of
      patients.

PMID- 12609526
TI  - Associations between cytokine gene polymorphisms and recurrent pregnancy loss.
AB  - Since certain cytokines may play a role in unexplained recurrent pregnancy loss
      (RPL) and also some cytokine gene polymorphisms may affect the level of cytokine
      production, the aim of the present study was to investigate the relationship
      between RPL and polymorphisms of the genes coding for TNF-alpha (-308 G-->A), IL
      10 (-1082 G-->A), IL-6 (-174 G-->C), and IFN-gamma (+874 A-->T). Genotyping was
      performed in 48 RPL women and 108 ethnically matched healthy individuals. In
      addition, we performed a meta-analysis encompassing the present results and those
      from studies on the association of TNF-alpha, IL-10 and IFN-gamma polymorphisms
      with RPL published in the literature until December 2001. The results showed: (1)
      no evidence of association with IL-6 gene polymorphisms; (2) significant
      associations, revealed by the meta-analysis, with the high cytokine production
      genotypes of IFN-gamma (+874 T/T: odds ratio (OR)=1.92, P=0.04) and IL-10 (-1082
      G/G: OR=1.75, P=0.03), and a trend for association with the high TNF-alpha
      production genotypes -308 A/A and A/G (OR=1.61; P=0.18). We believe that the
      associations of these genotypes with RPL are interesting not only as risk factors
      but also because they represent another piece of evidence that these cytokines
      might be important in the pathogenesis of RPL.

PMID- 12609527
TI  - Repetitive and consistent cervicovaginal exposure to certain viral pathogens
      appears to protect against their sexual acquisition in some women: potential
      mechanisms.
AB  - Several groups have proposed that human female promiscuity or polyandry, with
      repetitive and consistent cervicovaginal exposure to human immunodeficiency virus
      type 1 (HIV-1), can lead to protection against sexual acquisition of HIV-1 in
      some of these women. The mechanism of this phenomenon, the highly exposed
      persistently HIV-seronegative (HEPS) state, is unknown. Thus far, it has been
      correlated with viral epitope-specific immune responses in only about half of the
      women evaluated. But when present, these responses decline rapidly following
      interruption of pathogen exposure, and correlate with prompt acquisition of HIV.
      I have extended the concept of HEPS to another sexually transmitted viral
      pathogen, human papillomavirus (HPV). Supporting clinical and immunological
      information were identified from a literature search using PubMed as well as
      several sets of epidemiological data, including longitudinal surveys of HIV-1
      incidence among female commercial sex workers (CSWs) in Africa and Thailand, and
      follow-up of a Danish cohort of CSWs and a large group of Brazilian women, both
      at high risk for HPV infection. These studies suggest that male-to-female penile
      vaginal transmission of at least two viruses, HIV-1 and HPV, is blocked by local
      mucosal responses, immunologic or otherwise, which require repetitive,
      uninterrupted exposure to pathogen. Exploration of the mechanisms underlying such
      ostensibly protective responses may facilitate development of STD vaccines.

PMID- 12609529
TI  - Detection of residual donor leucocytes in leucoreduced red blood cell components
      using a fluorescence microplate assay.
AB  - In November 1999, universal leucoreduction of blood components was introduced in
      the UK to minimise the risk of variant Creutzfeldt-Jakob Disease (vCJD)
      transmission by blood transfusion. The UK specifications for leucodepletion
      processes state that 99% of leucodepleted components should contain < 5 x 10(6)
      leucocytes/unit, within 95% confidence limits. However, this leucocyte
      concentration is below the detection limits of standard haematology analysers.
      The development of a fluorometric immunoassay to detect the residual donor
      leucocytes in leucoreduced blood components is described. Monoclonal antibodies
      to leucocyte-specific cell surface antigens, CD45 and CD15, were adsorbed to the
      well surface in 96-well microplates. Red blood cell samples containing low
      numbers of leucocytes were added to the wells and the cells of interest captured
      by the monoclonal antibodies. Since leucocytes are the only nucleated cells found
      in significant numbers in blood components they were quantified using PicoGreen,
      a fluorescent stain specific for dsDNA. In comparison to flow cytometry, the
      method currently used to detect low numbers of leucocytes, the microplate assay
      demonstrated excellent sensitivity (1.00) and acceptable specificity (0.81) when
      standard leucodepleted samples were tested. There was no significant difference
      between the two methods (p < or = 0.175). In conclusion, the fluorescence
      microplate assay represents a simple, high throughput alternative to flow
      cytometry for monitoring leucodepletion compliance in blood banks.

PMID- 12609528
TI  - Protein blotting: a review.

PMID- 12609530
TI  - Image analysis: a novel approach for the quantification of antineutrophil
      cytoplasmic antibody levels in patients with Wegener's granulomatosis.
AB  - Rises in antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase
      3 (PR3) have predictive potential for a relapse of Wegener's granulomatosis (WG).
      To assess the value of image analysis for monitoring ANCA levels, we measured PR3
      ANCA in a cohort of PR3-ANCA positive patients with WG that were prospectively
      followed in our clinic and compared findings with other techniques. ANCA levels
      were measured serially by quantitative image analysis, titration in indirect
      immunofluorescence (IIF), two different directly coated antigen-specific enzyme
      linked immunosorbent assays (ELISA), and a capture ELISA using a PR3-specific
      monoclonal antibody in 16 consecutive WG patients prior to a renal relapse, and
      in 16 age- and sex-matched patients with inactive WG. The positive predictive
      value (PPV) of an increase in ANCA titers by image analysis for relapse was 69%
      (11 of 16). The PPV of an increase in ANCA was 61% (11 of 18) by IIF, 71% (12 of
      17) by a commercial direct ELISA, 63% (12 of 19) by in-house direct ELISA, and
      75% (12 of 16) by capture ELISA. The negative predictive value (NPV) of the
      absence of an increase in ANCA titers by image analysis for relapse was 69% (11
      of 16). The NPV of the absence of an increase in ANCA was 64% (9 of 14) by IIF,
      73% (11 of 15) by a commercial direct ELISA, 63% (9 of 13) by in-house direct
      ELISA, and 75% (12 of 16) by capture ELISA. In conclusions, quantitative image
      analysis is a novel technique based on the principle of IIF to quantify ANCA
      levels in a single dilution in a patient sample. No major differences were
      observed between image analysis and the other techniques in their capacity to
      predict relapses of disease activity.

PMID- 12609532
TI  - Single step enrichment of blood dendritic cells by positive immunoselection.
AB  - Dendritic cells (DC) for cancer immunotherapy protocols are generated most
      commonly by in vitro differentiation of monocytes with exogenous cytokines (Mo
      DC). However, Mo-DC differ in their molecular phenotype and function from blood
      DC (BDC). Clinical isolation of BDC has been limited to the use of density
      gradients, which result in low yields of variable purity. We have developed a DC
      enrichment platform, which uses the CMRF-44 (IgM) or CMRF-56 (IgG) monoclonal
      antibodies (mAb) to select BDC that express these antigens after a short
      overnight incubation. After culture of peripheral blood mononuclear cells (PBMC)
      in autologous/AB serum, biotinylated CMRF-44 was used to select DC in a single
      step immuno-magnetic bead procedure; this produced populations containing up to
      99% CMRF-44(+) cells, including up to 67% CMRF-44(+) CD14(-) CD19(-) DC, from an
      initial starting population of approximately 0.5%. We observed consistent
      differences in the purities obtained from individual donors with a mean of 54%
      CMRF-44(+) cells (range 19-99%). Similar results were obtained using biotinylated
      CMRF-56 mAb, an antibody identifying a comparable population in cultured PBMC. We
      recovered an average of 54% and 66% of the available BDC in separations performed
      with the CMRF-44 and CMRF-56 mAb, respectively. The reproducibility of the
      procedure and the ability to perform it in a closed sterile system makes it
      suitable for clinical use. Larger scale preparations starting from apheresis
      derived PBMC will produce sufficient BDC for immunotherapy protocols. The
      purified BDC elicited strong allogeneic mixed leukocyte reactions and HLA classes
      II- and I-restricted antigen-specific primary immune responses.

PMID- 12609531
TI  - RBL cells expressing human Fc epsilon RI are a sensitive tool for exploring
      functional IgE-allergen interactions: studies with sera from peanut-sensitive
      patients.
AB  - Rat basophilic leukemia cells (RBL SX-38) express the alpha, beta, and gamma
      chains of human Fc epsilon RI. Following sensitization with IgE from a subset of
      allergic human donors, these cells can be triggered by exposure to anti-IgE or to
      very low concentrations of specific allergens. We examined 18 sera from patients
      who were highly sensitive to peanuts by history and had anti-peanut IgE by in
      vitro testing. The ability of these sera to sensitize the RBL SX-38 cells for
      degranulation with peanut allergens correlates very well with the absolute amount
      of anti-peanut IgE (r=0.95; p<0.001). The most effective sera contained at least
      50 kU/l of total IgE and at least 15 kU/l of peanut-specific IgE. RBL SX-38 cells
      sensitized with these sera degranulated optimally upon exposure to anti-IgE (net
      degranulation of 40+/-8%, means+/-S.D.; n=8) and to a 10(5)-10(6) dilution of
      crude peanut extract (CPE) (37+/-7% net degranulation; 93+/-13% of that seen with
      anti-IgE). This assay is quite sensitive. Cells sensitized with selected sera are
      activated by exposure to a 1:10(7) dilution of the CPE containing picogram
      amounts of peanut allergens. This assay is also quite specific. Cells sensitized
      with sera from patients with anti-peanut IgE and no detectable IgE against
      soybean, walnut or grass pollen did not degranulate following exposure to these
      latter antigens. The converse was also true; cells sensitized with sera from
      patients without anti-peanut IgE did not react to peanut. These data demonstrate
      that RBL cells expressing human Fc epsilon RI form the basis of a useful model
      system for the detection of allergens and for the study of IgE-allergen
      interactions.

PMID- 12609533
TI  - Monoclonal anti-idiotype antibodies recognizing the variable region of a high
      affinity antibody against 11-deoxycortisol. Production, characterization and
      application to a sensitive noncompetitive immunoassay.
AB  - Anti-idiotype antibodies recognizing the variable regions of a particular anti
      hapten antibody are valuable tools, which can be used in sensitive hapten
      immunoassays based on a noncompetitive format. Here, we describe the production
      and characterization of monoclonal anti-idiotype antibodies against idiotopes on
      the variable regions of an antibody showing high affinity and specificity to 11
      deoxycortisol (11-DC). 11-DC is the biosynthetic precursor of cortisol and a
      diagnostic index for the assessment of pituitary-adrenal function. BALB/c or A/J
      mice were repeatedly immunized with the anti-11-DC antibody conjugated with
      keyhole limpet hemocyanin and their spleen cells were then fused with P3/NS1/1
      Ag4-1 myeloma cells. Seven kinds of anti-idiotype antibodies were generated, one
      of which was a beta-type antibody recognizing the paratope and others which were
      alpha-type antibodies recognizing the framework region. A noncompetitive ELISA
      based on idiotype-anti-idiotype reactions was established using one of these
      alpha-type antibodies in combination with the beta-type antibody and with the
      anti-11-DC antibody. This noncompetitive assay system provided improved
      sensitivity (detection limit: 1.0 pg=2.9 fmol), which is approximately 10 times
      higher than the corresponding competitive enzyme immunoassay, and offered a
      practical specificity for clinical use. Appropriate serum 11-DC levels were
      obtained for normal subjects [0.16+/-0.09 (S.D.) microg/l (n=6), ranging from
      0.086 to 0.316 microg/l] using the present assay system.

PMID- 12609534
TI  - Chemiluminescence-based BrdU ELISA to measure DNA synthesis.
AB  - We describe a simple, sensitive, nonradioactive, relatively rapid and relatively
      inexpensive protocol to measure DNA synthesis in cultured cells by a
      chemiluminescent bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay
      (ELISA). We show that it exhibits similar sensitivity and activity as traditional
      3H-thymidine incorporation assays and a commercial chemiluminescent BrdU ELISA
      kit when tested in commonly used cell lines, such as NIH 3T3 cells, mink lung
      epithelial cells (Mv1LU), and baby hamster kidney (BHK-21) fibroblasts. This
      assay also exhibits a wider dynamic range than colorimetric BrdU ELISA methods.
      Besides being a viable, nonradioactive alternative to 3H-thymidine incorporation
      assays, our BrdU ELISA is less expensive than a commercial chemiluminescent BrdU
      ELISA kit.

PMID- 12609535
TI  - Single-cell analysis of the murine chemokines MIP-1alpha, MIP-1beta, RANTES and
      ATAC/lymphotactin by flow cytometry.
AB  - Upon stimulation, leukocytes secrete chemokines to attract distinct effector cell
      populations to the site of inflammation. Only a few data are available about the
      phenotype and the frequencies of cells expressing particular chemokines. To date,
      the expression of individual chemokines is mainly analyzed at the mRNA level or
      via ELISA. Both techniques do not allow the analysis of chemokines at the level
      of single cells. We have established the intracellular flow-cytometric detection
      of the murine chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP
      1beta, regulated on activation normal T cell expressed and secreted (RANTES) and
      activation-induced, T cell-derived and chemokine-related cytokine
      (ATAC)/lymphotactin. For detection of the nonclassical chemokine ATAC, we
      generated the novel mAb MTAC-2. Using this assay, we analyzed for the first time
      the frequency and kinetics of the expression of these murine chemokines in
      lymphocyte subpopulations. We show that these chemokines are differentially
      expressed by NK cells, naive and memory CD4(+) and CD8(+) T cells. Our results
      emphasize that the analysis of chemokine expression at the single-cell level is
      required to understand the functional role of specialized lymphocyte
      subpopulations in vivo.

PMID- 12609536
TI  - A rapid flow cytometric method for the detection of intracellular cyclooxygenases
      in human whole blood monocytes and a COX-2 inducible human cell line.
AB  - We have developed a flow cytometric method for the detection of intracellular
      cyclooxygenases (COX) in human whole blood monocytes and a COX-2 inducible human
      cell line. COX-2 is induced by endotoxin activation of whole blood monocytes or
      by the addition of fetal bovine serum (FBS) to a serum-deprived human
      fibroblastoid cell line, CCD-1070Sk. Cells are permeabilized with FACS Lysing
      Solution (FLS) containing saponin (Sap), stained intracellularly with COX-2 and
      COX-1 monoclonal antibodies (mAbs) and analyzed flow cytometrically.
      Intracellular COX-2 is specifically detected in endotoxin-stimulated CD14(+)
      monocytes in whole blood and in the inducible cell line. The specificity of COX-2
      and COX-1 binding is demonstrated by competitive inhibition studies in cells and
      binding studies on protein-conjugated beads. In addition, a two-color reagent
      combination is described which simultaneously detects COX-2 and COX-1. We
      conclude that specific, intracellular COX-1 and COX-2 expression can be readily
      identified by flow cytometry in whole blood monocytes and cultured cells. The
      relative rapidity, ease of use and small sample volume required by this assay
      makes it a suitable methodology for studying COX expression in both preclinical
      and clinical research settings.

PMID- 12609537
TI  - Western blot screening for monoclonal antibodies against human separase.
AB  - Separase is a cysteine protease that participates in separation of sister
      chromatids during mitosis. Human separase is a 230-kDa enzyme that is inhibited
      by binding to its protein inhibitor securin, specific phosphorylation, and
      subcellular localization. To further characterize human separase, we raised
      monoclonal antibodies specific against a C-terminal fragment of the protein. A
      critical step in monoclonal antibody production procedure is the primary
      screening of hybridoma supernatants. Here we report primary screening protocol
      utilizing Western blot analysis. The described screening protocol is carried out
      using fusion of a human separase fragment with two different purification tags,
      maltose-binding protein (MBP) and glutathione S-transferase (GST). Immunization
      by MBP-fusion was followed by primary screening with both MBP- and GST-separase
      fusions combined in the same preparation separated in SDS-PAGE. This highly
      sensitive screening approach reduced the number of positive signals by
      eliminating antibodies specific for the purification tag used in the immunization
      procedure. The described separase-specific antibodies were suitable for detection
      of endogenous separase in crude extracts, immunoprecipitation, and
      immunofluorescent cell staining experiments. The presented procedure is fast,
      reproducible and could be adopted as a primary screening scheme for a variety of
      protein antigens.

PMID- 12609538
TI  - Bispecific monoclonal antibodies against a viral and an enzyme: utilities in
      ultrasensitive virus ELISA and phage display technology.
AB  - A quadroma (hybrid-hybridoma) secreting bispecific antibodies with one paratope
      specific for M13 bacteriophage coat protein and another paratope specific for
      alkaline phosphatase (AP) was developed by electro-fusion of the two parental
      hybridomas and selected by a fluorescence activated cell sorter (FACS). The anti
      phage M13/anti-AP bsMAbs were purified from anti-phage M13 monospecific MAb by a
      novel affinity method using Mimetic Blue A6XL as immune complexes with AP. The
      purified bsMAbs with potentially every molecule uniformly bound with AP generated
      an immuno-probe with the theoretical highest specificity. An ultrasensitive
      sandwich ELISA for detecting viruses was developed by using this bsMAb coupled
      with an amplified ELISA procedure. The sensitivity of the assay was increased
      1000 times compared with conventional ELISA to achieve detection of 100 phage
      particles which is approximately 2.3 fg of phage coat protein. This type of bsMAb
      probe and ELISA format can be used to design new body fluid assays for viral load
      of HIV, hepatitis and other human pathogens as rapid and inexpensive alternatives
      to the PCR based method. This unique bispecific probe also allowed rapid and
      sensitive detection of bound M13/fd phage clones while panning for specific
      phages displaying peptide mimics against an antigen from a phage display peptide
      library. Furthermore, we demonstrate the principle virus purification using bsMAb
      as affinity ligand with a mild phosphate buffer elution. The results indicate
      that bsMAb could be used to develop affinity chromatography for purifying highly
      contagious and pathogenic viruses avoiding procedures employing prolonged high
      speed centrifugation.

PMID- 12609539
TI  - A simplified approach to determining P-glycoprotein expression in peripheral
      blood mononuclear cell subsets.
AB  - P-glycoprotein (P-gp), encoded by the MDR-1 (multidrug resistance) gene mediates
      the cellular efflux of several therapeutic agents with the potential of treatment
      failure. The differential expression of P-gp in many localised tissues and cells
      of the hematopoietic system implies diverse physiological and pharmacological
      roles. The exact function of P-gp involved in multidrug resistance remains
      unclear owing to the numerous discrepancies between different laboratories. The
      ability to characterise accurately P-gp expression has important clinical
      implications. However, a complete consensus recommendation regarding methods of P
      gp detection has been difficult to reach. With the advancement in immune
      technology and new commercially available antibodies, we describe a simplified
      direct immunofluorescent assay capable of detecting surface P-gp expression in
      peripheral blood mononuclear cells (PBMCs) and subpopulations of lymphocytes in
      vivo by dual colour flow cytometry. Results were expressed as mean increase in
      fluorescence (MI) compared to isotypically matched controls. Using this assay,
      differential basal P-gp expression was found to exist in the following
      significant hierarchy CD56+ (MI=0.684+/-0.273; n=15)>CD8+ (MI=0.312+/-0.117;
      n=15)>CD4+ (MI=0.194+/-0.086; n=15). This method is rapid and reproducible and
      has potential use for in vitro and in vivo application.

PMID- 12609540
TI  - Evaluation of antigen-specific responses using in vitro enriched T cells.
AB  - Antigen-specific lymphocytes are important in the immune response to viral
      infection. Peripheral blood mononuclear cells (PBMC) are traditionally used as a
      source of effector cells in most immunological studies. We described here the use
      of the bispecific monoclonal antibodies (BSMAB) anti CD3:CD8 (CD3,8) and anti
      CD3:CD4 (CD3,4B) to expand and selectively enrich CD4+ and CD8+ T cells
      populations, respectively. The expanded cells demonstrated >90% CD3+CD4+ or
      CD3+CD8+ by 14 days. We measured HIV- and CMV-specific responses of these subset
      enriched T cell and found that sensitivity and specificity is similar or higher
      when compared to PBMC in various cellular immunology assays (CMI). Vbeta analysis
      of BSMAB-enriched cells demonstrated comparable repertoire to the parent PBMC.
      Although both CD45RA(hi) and CD45RO(hi) cell populations were expanded with the
      BSMAB, selective subset depletion demonstrated that the antigen-specific T cell
      responses were restricted to the initial CD45RO(hi) memory effector subgroup. In
      conclusion, BSMAB in vitro enrichment of T cells allows significant expansion of
      the cell population without loss of specificity. This technique of cell expansion
      permits studies of T cell subset function in situations where the initial cell
      source is scarce, and presents an alternative for viable and functional T cells
      in immunological assays.

PMID- 12609541
TI  - How biotinylation can interfere with recognition: a surface plasmon resonance
      study of peptide-antibody interactions.
AB  - Biotinylation is one of the most frequently used labelling procedures in
      biochemistry and molecular biology. To study the influence of biotinylation on
      peptide antigenicity, we selected a peptide derived from the second extracellular
      loop of the beta(2)-adrenergic receptor. Interactions between different
      biotinylated and nonbiotinylated analogs and a monoclonal antibody directed
      against an epitope present within the N-terminal end of this peptide were studied
      in detail. Taking advantage of the BIACORE 3000 surface plasmon resonance
      equipment, we were able to compare antibody interactions with the immobilised
      peptides and with the same peptides in solution. While the nonbiotinylated
      peptide, immobilised by its N-terminus, was not recognised by the antibody, it
      was recognised either after immobilisation by means of the thiol group of the C
      terminal cysteine residue or as a free peptide tested as analyte with the
      monoclonal antibody immobilised on the chip. The N-terminal biotinylated forms
      were well recognised when immobilised on streptavidin but poorly (for the
      aminocaproyl-biotin derivative) or not at all (for the biotinylated derivative)
      when they were allowed to react with immobilised monoclonal antibody. These
      results indicate that the biotinyl moiety interacts with residues that are
      important for antibody recognition in solution but such interactions are
      abrogated when it is bound to the streptavidin. Molecular modeling confirmed that
      the N-terminus of the peptide mimicked to some extent the streptavidin binding
      site.

PMID- 12609542
TI  - Estimate of the total number of CD8+ clonal expansions in healthy adults using a
      new DNA heteroduplex-tracking assay for CDR3 repertoire analysis.
AB  - A T-cell receptor heteroduplex-tracking assay (TCR-HTA) was developed to analyze
      the sequence diversity of the TCR beta-chain mRNA of each of the 24 T-cell
      receptor beta-chain variable region (TRBV). TCR-HTA allowed an estimation of the
      number of expanded CD8 T-cell clones whose distinct CDR3 domain mRNA made up 2%
      or more of the transcript of each TRBV subfamily. An average of 40 CD8+ clonal
      expansions (range 34-49) was detected in three healthy adults. Correct sampling
      of the complex mRNA transcript populations was documented by the reproducible
      generation of TCR-HTA patterns using independently generated PCR amplicons. The
      CDR3 sequence of expanded T-cell clones could be rapidly determined by direct
      sequencing of DNA heteroduplex bands. CD4+ and CD8+ clonal expansions were found
      predominantly although not exclusively in CD45RO+ CD62L- effector/memory cells
      and the majority of expanded T-cell clones were stable over a period of at least
      6 months. Fewer CD4+ than CD8+ clonal expansions were detected in peripheral
      blood cells. By providing a high-resolution method for the detection of clonally
      expanded T-cell clones and by simplifying the pattern generated using traditional
      DNA heteroduplex analysis, TCR-HTA is shown to be a sensitive method for
      assessing levels of oligoclonality and changes in TRBV repertoires.

PMID- 12609543
TI  - Characterization of an interleukin-7-dependent thymic cell line derived from a
      p53(-/-) mouse.
AB  - In order to study the response of T cells to IL-7, we aimed to generate an IL-7
      dependent thymocyte line. CD4(-)CD8(-) thymocytes from a p53(-)/(-) mouse were
      continuously propagated in interleukin-7 (IL-7), and after 2 months there
      developed an immortal line termed "D1." The D1 line has retained a stable
      dependency on IL-7. Withdrawal of IL-7 from D1 cells induced arrest in G1 phase
      of the cell cycle, followed by apoptosis. In addition to IL-7, several other
      cytokines that employ gamma(c) as part of their receptor were also capable of
      stimulating D1 cell survival and proliferation. Gene induction by IL-7 was
      analyzed in D1 cells using RNase protection and array analysis and revealed a
      number of transcripts potentially involved in cell cycle, apoptosis and
      signaling.

PMID- 12609544
TI  - De novo identification of tumor-specific internalizing human antibody-receptor
      pairs by phage-display methods.
AB  - Three tumor-specific, internalizing human single-chain Fvs (scFvs) were obtained
      by direct selection against tumor cells from a large, nonimmune scFv-phage
      library pre-subtracted with various normal human cells. After scFv selection and
      characterization for cell binding and internalization, the scFvs were also
      employed in immunoprecipitations to identify putative receptors. In the case of a
      prostate tumor-cell specific scFv PR5, the receptor that mediated endocytosis was
      shown to be the transferrin receptor. For two pancreatic adenocarcinoma specific
      scFvs SW1 and PAN10, the alpha(3)beta(1) integrin was identified. The scFv SW1
      was studied in further detail and found to induce functional effects as a ligand
      mimetic by mediating cell adhesion and migration. The results demonstrated the
      feasibility of utilizing enhanced phage-display methods as a rapid and general
      approach for not only direct isolation of human internalizing scFvs, but also for
      identifying tumor cell-surface receptors from various classes. The use of scFv
      constructs that target tumor cells and undergo internalization could have
      significant impact on the future of cancer and gene therapy.

PMID- 12609545
TI  - Studies on interaction between hTNF-alpha and its two receptors with expressed
      hsTR55-preS1/hsTR75-preS1 fusion soluble receptors.
AB  - The gene encoding the N-terminal 2-50 amino acids of HBsAg-preS1 was amplified by
      PCR and fused to the 3'-end of two human soluble TNF receptor genes to form the
      hsTR55-preS1/hsTR75-preS1 fusion genes. The recombinant bicistronic expression
      vectors were further constructed, which contained one of the human soluble TNF
      receptor fusion genes and the encephalomyocarditis virus (EMCV) internal ribosome
      entry site (IRES), followed by the neomycin phosphotransferases as the selectable
      marker. BHK-21 cells transfected with those vectors by electroporation were
      selected with G-418, and the positive colonies expressing the protein of interest
      were obtained. All of the culture media of those transfects could fairly
      neutralize hTNFalpha-induced cytotoxicity to L929 cells. The expression of hsTR55
      preS1/hsTR75-preS1 in those cells has been further demonstrated by RT-PCR and
      indirect ELISA at RNA transcription and protein translation levels. Their K(d)
      (dissociation constant) value has also been assayed with BIOSENSOR method. The
      results showed that the fused HBsAg-preS1 peptide did not affect the dissociation
      constant of hsTR55 or hsTR75 with hTNFalpha and its muteins. Thus, a novel
      nonradioactive ELISA method was developed for studies on interaction between
      hTNFalpha and its two receptors using those expressed fusion receptors.

PMID- 12609546
TI  - A rapid 'one-plate' in vitro test for pyrogens.
AB  - A rapid, 'one-plate' monocyte-activation test is described for detecting
      endotoxin and non-endotoxin pyrogens in parenteral medicinal products. The one
      plate test offers useful gains over conventional 'two-plate' (cell culture
      plate+ELISA plate) tests in terms of its limit of detection, robustness, speed
      and cost. The 'one-plate' test is likely to be applicable to a wide range of
      products because it allows less time for product interference in the test. The
      'one-plate' test utilises pyrogen-free anti-cytokine (interleukin (IL)-6 or
      tumour necrosis factor alpha (TNFalpha)) antibodies (Ab), coated and stabilised
      onto (pyrogen-free) 96-well plates. Monocytes/monocytic cells, endotoxin
      (lipopolysaccharides, LPS) standard or sample and (pyrogen-free) second
      (labelled) Ab are cultured together (usually for 2-4 h) on the Ab-coated plate
      and then the plate is washed and the ELISA completed. There is no transfer from
      one plate to another and no (further) incubations of (released) cytokine with,
      first, coating Ab and, then, developing Ab since these steps have already taken
      place during the initial cell culture. The rapid, 'one-plate' test is readily
      automated. The preferred readout is IL-6, which gives a limit of detection of
      0.015 endotoxin units (EU)/ml with peripheral blood mononuclear cell (PBMNC),
      0.03 EU/ml with diluted whole blood and 0.05 EU/ml with a monocytic cell line
      (MONO MAC 6).

PMID- 12609547
TI  - Optimized determination of T cell epitope responses.
AB  - Pools of overlapping peptides corresponding to specific antigens are frequently
      used to identify T cell immune responses to vaccines or pathogens. While the
      response to the entire pool of peptides provides important information, it is
      often desirable to also know to which individual peptides within the pool the
      immune responses are directed. In this report, we analyzed various ways of
      deconvoluting an immune response to a pool of peptides to determine the number of
      different peptides to which the T cells are responding. We used a Monte Carlo
      simulation to optimize the construction of peptide pools that could identify
      responses to individual peptides using the fewest numbers of assays and patient
      material. We find that the number of assays required to deconvolute a pool
      increases by the logarithm of the number of peptides within the pool; however,
      the optimum configuration of pools changes dramatically according to the number
      of responses to individual peptides that are expected to be in the sample. Our
      simulation will help in the design of clinical trials in which the breadth of the
      response is being measured, by allowing a calculation for the minimum amount of
      blood that needs to be collected. In addition, our results guide the design and
      implementation of the experiments to deconvolute the responses to individual
      peptide epitopes.

PMID- 12609549
TI  - A new helper phage and phagemid vector system improves viral display of antibody
      Fab fragments and avoids propagation of insert-less virions.
AB  - Phage display technology (PDT) is a powerful method for isolating functional gene
      products such as antigen-specific monoclonal antibodies (mAbs). To improve the
      effectiveness of PDT, we sought to optimize display of Fab-g3p (antibody fragment
      fused with viral gene 3 protein) on phagemid virions and to optimize the yield of
      such phage. To do so, we constructed a novel helper phage, Phaberge, having a
      conditional deficiency in g3p production. Unlike most other published g3p
      deficient helper phage, Phaberge is produced at high levels, 10(11) PFU/ml. As
      compared to g3p-sufficient helper phage, Phaberge caused a 5-20-fold increase in
      display level. Another novel feature is that Phaberge only packages insert
      containing, not insert-less, phagemid into infectious virions. This should prove
      useful in preserving quality of phagemid libraries during propagation. In
      addition, other parameters were also found to affect production of phagemid
      virions. In particular, the choice of bacterial host cell, phagemid construct and
      growth temperature had a substantial impact on display levels, but generally no
      effect on number of phagemid virions produced. In short, we have established a
      set of parameters that improve production and quality of phagemid virions which
      we expect to facilitate the isolation of mAbs or other gene products by PDT.

PMID- 12609548
TI  - A sensitive bioassay for chicken interleukin-18 based on the inducible release of
      preformed interferon-gamma.
AB  - Conventional tests for measuring the biological activity of chicken interleukin
      (IL)-18 require primary chicken spleen cells. We now describe a sensitive
      bioassay that is based on interleukin-18-induced release of interferon (IFN)
      gamma by a permanent chicken cell line. In B19-2D8 cells, cytoplasmically stored
      interferon-gamma is quickly secreted in response to interleukin-18 exposure.

PMID- 12609550
TI  - Rapid and highly efficient gene transfer into natural killer cells by
      nucleofection.
AB  - Natural killer (NK) cells are important mediators of virus- and tumor-specific
      immune responses. The transfection of genes into NK cells has been proven
      difficult and so far requires infection with virus-based vectors. Here, the
      application of a novel nonviral, electroporation-based gene transfer method is
      described for the rapid and highly efficient transient transfection of NK cell
      lines as well as freshly isolated NK cells. In contrast to conventional methods,
      this technique, termed nucleofection, leads to direct transfer of DNA into the
      nucleus. Using reporter proteins H-2K(k), luciferase+, and enhanced yellow green
      fluorescent protein (EYFP) as independent read-out systems, transfection
      efficiencies of well over 50% were achieved in transient transfection assays. The
      highest luciferase activity could be measured only 4 h after transfection,
      whereas EYFP, when analyzed by flow cytometry, showed expression peaks after 28
      h. Interestingly, best transfection efficiencies were achieved with non-dividing
      NK cells. The novel nuclear gene transfer method presented here is highly useful
      for the analysis of NK cell-specific gene regulation and should facilitate the
      development of NK cell-based gene therapy approaches.

PMID- 12609552
TI  - DiscernArray technology: a cell-free method for the generation of protein arrays
      from PCR DNA.
AB  - Protein array technology offers a powerful tool to bridge genomics and
      proteomics. Currently, the bottleneck in the generation of protein arrays is the
      comprehensive production of functional proteins. We have developed a rapid cell
      free method, DiscernArray, which creates functional protein arrays directly from
      PCR DNA by in vitro synthesis of individual tagged proteins on tag-binding
      surfaces, such that the tagged proteins are immobilized on a surface as they are
      synthesised. DiscernArray is particularly useful for arraying proteins and
      domains which cannot be functionally produced in heterologous expression systems
      or for which the cloned DNA is not available.

PMID- 12609551
TI  - Spermine compaction is an efficient and economical method of producing
      vaccination-grade DNA.
AB  - Plasmid DNA inoculations can induce both humoral and cellular immunity, and this
      technique is now being employed in developing vaccination regimens for a large
      number of applications. DNA vaccination studies require the preparation of large
      amounts of purified plasmid DNA with low endotoxin contamination, and the cost
      burden for multiple injections, multiple animal or large animal studies is
      significant. We recently reported that selective compaction with spermine can be
      used to purify large quantities of DNA. We wanted to determine whether this
      method would produce DNA suitable for vaccination. Endotoxin levels for spermine
      compacted DNA were 0.3+/-0.01 endotoxin units (EU)/microg, well within the
      accepted range (less than 3 EU/microg) for in vivo use. When injected
      intramuscularly into mice, column-purified and spermine-compacted DNA induced an
      equivalent antigen-specific CD8+ T-cell response. The labor and time involved in
      purifying 5 mg of DNA by each method were similar, but the cost of spermine
      compacted DNA was only 20% of the cost of column-purified DNA. We conclude that
      spermine compaction is an efficient and economical method for preparing
      vaccination-grade DNA.

PMID- 12609553
TI  - Determination of intracellular heat shock protein 70 using a newly developed cell
      lysate immunometric assay.
AB  - Heat shock proteins (Hsp) have been associated to several clinical relevant
      conditions. Currently used methods to determine Hsp 70 possess certain drawbacks.
      Therefore, we developed a cell lysate immunometric assay (CLIA) for the
      quantification of intracellular Hsp 70. This CLIA uses a combination of two
      distinct monoclonal antibodies that recognize different epitopes on the Hsp 70
      molecule. A recombinant human Hsp 70 was used as the standard material. The
      detection range of the CLIA was 4-4000 ng/ml. The intra- and interassay
      coefficients of variation were, on average, 5% and 12%, respectively. The
      recovery varied between 81% and 116%. The Hsp 70 levels assayed after serial
      dilution of cell lysates varied linearly with dilution (between 97% and 120%).
      The reliability of the CLIA was assessed by comparison with the values determined
      by flow cytometric procedure; these two sets of values showed a highly
      significant correlation (r=0.896, p<0.0001), indicating that the two methods are
      comparable. We conclude that this assay represents a low-cost alternative of the
      flow cytometric technique.

PMID- 12609554
TI  - Cultivation of Cimicifuga racemosa (L.) nuttal and quality of CR extract BNO
      1055.
AB  - OBJECTIVES: For Cimicifuga racemosa, well-founded investigations concerning
      multiplication, germination of seeds and field cultivation have not yet been
      published. Defined origins or varieties with certain agronomic properties and a
      specific pattern of active compounds are not commercially available. Special
      challenges are found with regard to growing of young plantlets from seeds.
      Comprehensive investigations have been started to find optimal conditions for all
      steps of the whole process to establish cultivation for Cimicifuga. Aim is to get
      defined varieties or sources with desirable agronomic characteristics and
      specific reproducible compound patterns in order to reach homogeneous plant raw
      material. METHODS: For analytical tests, validated HPLC and TLC methods were
      used. RESULTS: Results from germination experiments with different temperature
      regimens show that the time for germination can be shortened from about 20 months
      to about 6 months. Gibberellic acid had positive influence on the development of
      the embryo. Content of triterpenglycosides and phenolic compounds was highest in
      May and June and decreased then from July until September. The quality of the
      ethanolic extract BNO 1055 (contained in Klimadynon(R) and Menofem(R)) differs
      from that of an isopropanolic extract. Comparison was carried out by means of TLC
      pattern of triterpenglycosides and phenolic compounds. CONCLUSION: Extensive
      systematic research on cultivation parameters with regard to all stages from the
      seeds to the herbal drug enables commercial field cultivation of Cimicifuga.
      Controlled cultivation (according to good agricultural practice or GAP) ensures
      the availability of homogenous standardized raw material. For pharmacological and
      clinical studies, standardized extracts and finished herbal medicinal products
      are required. Results of these studies are never transferable to other products
      and therefore valid only for the tested extracts/products.

PMID- 12609556
TI  - Soy isoflavones: hope or hype?
AB  - Approximately 50% of Americans use dietary supplements on a regular basis
      spending an estimated $20 billion on supplements in the year 2000. Soy contains
      genistein and daidzein, two phytoestrogens, which work through the estrogen
      receptor and cause alterations in serum lipids, bone metabolism, and possibly
      cognition. In this article, we review the issues regarding the interpretation
      with studies using soy-based isoflavones, discuss their mechanism of action, and
      review the literature on the effect of these bio-active compounds on lipid
      metabolism, osteoblasts and osteoclasts, bone markers, bone mineral density, and
      cognition.

PMID- 12609555
TI  - Phytoestrogens: endocrine disrupters or replacement for hormone replacement
      therapy?
AB  - OBJECTIVES: This review presents findings with clear statements from the
      literature as well as own results of effects of soy, red clover and their
      isoflavones as well as of the Cimicifuga racemosa extract BNO 1055. Experimental
      and clinical effects on climacteric complaints, osteoprotective effects, activity
      in the urogenital tract, and risks concerning cardiovascular diseases and mammary
      and endometrial tissue will be compared, also in comparison to classical hormone
      preparations. The question whether soy and red clover products and/or Cimicifuga
      racemosa (CR) preparations are endocrine disrupters or may fulfill the criteria
      of the so-called phyto-SERMs will be discussed. METHODS: Review of selected
      publications since 1980 and summary of unpublished own results of the authors.
      RESULTS: Experimental and clinical evidences suggest that soy/red clover and
      their isoflavones do not fulfill the criteria of an ideal SERM. They appear to
      have mild osteoprotective effects but do not improve climacteric complaints.
      Furthermore, they seem to stimulate uterine growth and mammary epithelial
      proliferation. In ovariectomized rats, the CR extract BNO 1055 showed many of the
      beneficial effects of 17beta-estradiol, including effects in the
      brain/hypothalamus to reduce serum LH levels, effects in the bone to prevent
      osteoporosis and estrogenic effects in the urinary bladder. The CR extract BNO
      1055 had no uterotrophic effect. CONCLUSION: If clinical studies confirm these
      results, the Cimicifuga racemosa preparation BNO 1055 would appear as an ideal
      SERM and may therefore be an alternative to hormone replacement therapy.

PMID- 12609557
TI  - In vitro effects of the Cimicifuga racemosa extract BNO 1055.
AB  - OBJECTIVES: Extracts of Black cohosh (Cimicifuga racemosa or CR) have been used
      for the treatment of climacteric complaints since decades. Efficacy, particularly
      concerning neurovegetative and psychic symptoms, has been proven in clinical
      trials. As active principle yet unknown substances with selective estrogen
      receptor modulator (SERM) activity are assumed. Recently, evidence arose that CR
      may also contain dopaminergic compounds, which may contribute to the therapeutic
      activity of the extract. METHODS: Two subtypes of the estrogen receptor (ERalpha
      and ERbeta) are known. To examine, whether active substances of CR extract BNO
      1055 (which is contained in Klimadynon and Menofem) bind to either of the two
      estrogen receptors, subtype-specific estrogen receptor ligand-binding assays with
      recombinant ERalpha or ERbeta were conducted. A ligand-binding assay with
      recombinant dopamine D(2)-receptor protein was employed to assess possible
      dopaminergic activity in the CR extract BNO 1055. RESULTS: While a displacement
      of radiolabeled estradiol from binding sites of a cytosol preparation from
      procine and human endometrium by CR extract BNO 1055 was shown no such
      displacement was achieved when either ERalpha or ERbeta protein was used as
      ligands for tracer. Dopaminergic activity in the CR extract BNO 1055 could be
      demonstrated with the D(2)-receptor assay. A countercurrent chromatography
      resulted in a separation of estrogenic and dopaminergic activity in two distinct
      fractions. CONCLUSIONS: It is suggested that not yet identified substances in the
      CR extract BNO 1055 bind to a yet unknown estrogen-binding site in the
      endometrium. Also, yet unknown dopaminergic compounds may contribute to the
      pharmacological profile of CR extract BNO 1055.

PMID- 12609558
TI  - Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and
      uterus.
AB  - OBJECTIVES: Hormone replacement therapy (HRT) has therapeutic effects on
      climacteric complaints and prevents osteoporosis. Owing to the increased risks of
      breast cancer and cardiovascular diseases, patients look for alternatives.
      Cimicifuga racemosa (CR) preparations might be an alternative, because they
      proved to reduce climacteric complaints as efficiently as conjugated estrogens
      without exerting estrogenic effects in the uterus. Whether CR has positive
      effects on bone and in fat tissue is currently unknown. Therefore,
      osteoprotective effects of the CR extract BNO 1055 and an influence on fat tissue
      were studied in ovariectomized rats. METHODS: Bone mineral density (BMD) of the
      tibia of ovariectomized (ovx) rats was determined by computer-assisted tomography
      (CT). CT scans of fat depots were perimetrically quantified. Bone turnover
      (osteocalcin, crosslaps) and lipocyte activity (leptin) were also determined.
      Uterine weights were measured and gene expression of estrogen-regulated uterine
      genes (IGF-1, ERbeta) was determined by RT-PCR. RESULTS: Treatment of the ovx
      rats over a period of 3 months with E(2) and the CR extract BNO 1055 showed
      osteoprotective effects; both significantly reduced the loss of BMD in tibia.
      Serum osteocalcin levels were significantly reduced by both treatments, whereas
      only E(2), but not BNO 1055, reduced serum crosslaps. A paratibial fat depot and
      serum leptin concentration were also significantly reduced. In contrast to E(2),
      the CR extract showed no effect on uterine weight and gene expression of E(2)
      regulated genes. CONCLUSION: The CR extract BNO 1055 exerted estrogenic effects
      in the bone (particularly in osteoblasts) and in fat tissue, but not in the
      uterus of ovx rats. The extract appears to contain rat organ-specific selective
      estrogen receptor modulators (SERMs), and if these findings can be approved in
      human it may be an alternative to HRT.

PMID- 12609559
TI  - Cimicifuga extract BNO 1055: reduction of hot flushes and hints on antidepressant
      activity.
AB  - Ethanolic- and isopropanolic-aqueous extracts of Cimicifuga racemosa are used for
      the treatment of climacteric complaints. As hot flushes and psychic complaints
      seem to be special targets for Cimicifuga extracts in clinical studies, these
      parameters were studied in experimental animals. Hot flush equivalents were
      measured in castrated rats as a quick increase in peripheral temperature with the
      aid of a transmitter implanted subcutaneously on the ventral side. The hot flush
      equivalents proved to respond to estrogen and the antidopaminergic drug
      veralipride but they were also reduced very effectively by Cimicifuga extract BNO
      1055 (which is contained in Klimadynon/Menofem). In addition, an ethanolic
      aqueous extract of C. racemosa was studied in the tail suspension test (TST), a
      behavioural test indicative for antidepressant activity. A significant decrease
      of the period of immobility was observed after treatment with 30 mg/kg body
      weight (bw) imipramine or with 50 or 100 mg/kg bw Cimicifuga extract. These
      findings in pharmacological tests-a reduction of the frequency of hot flush
      equivalents and hints on antidepressant activity of Cimicifuga extracts-are in
      good agreement with the therapeutical responses in climacteric women.

PMID- 12609560
TI  - Cimicifuga racemosa for the treatment of hot flushes in women surviving breast
      cancer.
AB  - OBJECTIVES: To examine the effect of Cimicifuga racemosa (CR BNO 1055) on hot
      flushes caused by tamoxifen adjuvant therapy in young premenopausal breast cancer
      survivors. This treatment presents an off-label use of CR BNO 1055. METHODS:
      Between May 1999 and December 2001, we accrued 136 breast cancer survivors aged
      35-52 years. After treatment with segmental or total mastectomy, radiation
      therapy and adjuvant chemotherapy, participants were in open-label randomly
      assigned (1-2) to receive tamoxifen 20 mg per day orally (usual-care group; n=46)
      or tamoxifen (same dose and posology) plus CR BNO 1055 (Menofem/Klimadynon,
      corresponding to 20 mg of herbal drug; intervention group n=90). Duration of
      treatment was 5 years for tamoxifen, according to international standards for
      adjuvant therapies, and 12 months for CR BNO 1055. Follow-up included clinical
      assessment every 2 months; the primary endpoint was to record the number and
      intensity of hot flushes. RESULTS: Comparing patients assigned to usual-care
      group with those assigned to intervention group, the number and severity of hot
      flushes were reduced after intervention. Almost half of the patients of the
      intervention group were free of hot flushes, while severe hot flushes were
      reported by 24.4% of patients of intervention group and 73.9% of the usual-care
      group (P<0.01). CONCLUSIONS: Hot flushes were the most frequent adverse reaction
      to tamoxifen adjuvant therapy in breast cancer survivors. The combined
      administration of tamoxifen plus CR BNO 1055 for a period of 12 months allowed
      satisfactory reduction in the number and severity of hot flushes.

PMID- 12609561
TI  - The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind
      placebo-controlled study: effects on menopause symptoms and bone markers.
AB  - OBJECTIVES: In the present study, therapeutic effects of the Cimicifuga racemosa
      preparation CR BNO 1055 (Klimadynon/Menofem) on climacteric complaints, bone
      metabolism and endometrium will be compared with those of conjugated estrogens
      (CE) and placebo. The question whether CR BNO 1055 contains substances with
      selective estrogen receptor modulator (SERM) activity will be investigated.
      METHODS: Sixty-two evaluable postmenopausal women were included in the double
      blind, randomized, multicentre study, and treated either with CR BNO 1055 (daily
      dose corresponding to 40 mg herbal drug), 0.6 mg CE, or matching placebo, for 3
      months. Menopausal symptoms were assessed by the menopause rating scale (MRS) and
      a diary. Levels of CrossLaps (marker of bone degradation) were determined by
      ELECSYS system and bone-specific alkaline phosphatase (marker of bone formation)
      by an enzymatic assay. Endometrial thickness was measured via transvaginal
      ultrasound; vaginal cytology was also studied. The primary efficacy criterion was
      the change from baseline to end point in the MRS. Change from baseline was
      analyzed for the secondary variables too. RESULTS: CR BNO 1055 proved to be
      equipotent to CE and superior to placebo in reducing climacteric complaints.
      Under both verum preparations, beneficial effects on bone metabolism have been
      observed in the serum. CR BNO 1055 had no effect on endometrial thickness, which
      was significantly increased by CE. Vaginal superficial cells were increased under
      CE and CR BNO 1055 treatment. CONCLUSION: The results concerning climacteric
      complaints and on bone metabolism indicate an equipotent effect of CR BNO 1055 in
      comparison to 0.6 mg CE per day. It is proposed that CR BNO 1055 contains
      substances with SERM activity, i.e. with desired effects in the
      brain/hypothalamus, in the bone and in the vagina, but without exerting
      uterotrophic effects.

PMID- 12609562
TI  - Treatment of lung cancer in the elderly. Part I: non-small cell lung cancer.
AB  - There is a general trend worldwide of an increasing incidence of elderly
      population. Age is the greatest risk factor for cancer; therefore, this
      demographic shift is the main reason for an increase of cancer incidence. Lung
      cancer is a typical disease of the elderly patients. This review summarizes the
      issues of treatment of non-small cell lung cancer (NSCLC) in the elderly. Early
      stage NSCLC is usually treated with radical surgery, locally advanced NSCLC with
      radiotherapy (RT) and/or chemotherapy (CHT) and metastatic disease with CHT, but
      the evidence for these approaches is based on studies which are usually performed
      with highly selected patients while elderly patients are under-represented. We
      used the data from studies addressing particularly elderly or providing subgroup
      information on age to analyse the feasibility of current standard approaches for
      elderly and discuss alternative approaches. Surgery is an effective method in
      elderly patients with early stage NSCLC although some approaches bear a somewhat
      higher risk of operative morbidity and mortality. RT for early stage may be an
      alternative with curative potential. For locally advanced stage RT alone, or
      combined radiochemotherapy in selected cases, is feasible for elderly patients
      with locally advanced NSCLC when a careful assessment of pre-therapeutic status
      is made and appropriate drugs are selected. Advanced age alone also should not
      preclude CHT, although the risk of adverse effect may be higher in certain cases.
      New generation drugs seem to be particularly feasible and efficient in elderly
      patients. In general, age itself does not seem to preclude patients from standard
      treatments although in some cases co-morbidity forces to alternative approaches.
      Currently, single-agent CHT should be considered as the standard treatment of
      advanced NSCLC elderly patients.

PMID- 12609563
TI  - Familial and second lung cancers: a nation-wide epidemiologic study from Sweden.
AB  - The role of hereditary factors in tumor development has been less well understood
      for lung cancer than for many other human neoplastic diseases. The nation-wide
      Swedish Family-Cancer Database was used on 10.2 million individuals and 4524 lung
      cancers to calculate standardized incidence ratios (SIRs) and 95% confidence
      intervals (CIs) for histological subtypes of lung cancer in 0-66-year-old
      offspring by cancers in family members. Additionally, SIRs for second lung
      cancers were analyzed. SIRs in offspring for all lung cancer were increased to
      1.87 (95% CI 1.66-2.10), adenocarcinoma to 2.15 (1.77-2.59) and squamous cell
      carcinoma to 1.86 (1.39-2.44) when a parent presented with lung cancer. The
      familial risk was not dependent on diagnostic age. Lung cancer associated with
      parental rectal, cervical, kidney, urinary bladder and endocrine gland cancer.
      The population attributable fraction of familial lung cancer was 2.97%. Risks for
      second lung cancers were increased in men and women after smoking and life style
      related sites, and after skin cancer, non-Hodgkin's lymphoma and Hodgkin's
      disease.

PMID- 12609564
TI  - Glutathione S-transferases and aromatic DNA adducts in smokers' bronchoalveolar
      macrophages.
AB  - Interindividual differences in the expression of carcinogen-metabolizing enzymes
      in the lung may modify the effective dose of tobacco carcinogens in this organ.
      We investigated the role of detoxifying glutathione S-transferases (GST) in the
      formation of aromatic DNA adducts in bronchoalveolar macrophages (BAM) of active
      smokers. The effect of GSTs on aromatic DNA adducts was studied separately and in
      combination with the PAH-metabolizing cytochrome P450 enzyme, CYP3A. GSTA, GSTM3,
      GSTP, and CYP3A protein levels were analyzed by Western blotting, GSTM1 and GSTP1
      genotypes were determined by polymerase chain reaction (PCR) based methods, and
      numbers of aromatic DNA adducts were measured by nuclease P1 enhanced 32P
      postlabeling method in BAM of 31 active smokers. No correlation was observed
      between GSTA or GSTP proteins or GSTM1 or GSTP1 genotypes and the level of
      aromatic DNA adducts. A high or medium expression level of GSTM3 was associated
      with a lower level of aromatic DNA adducts in the smokers who smoked less than 20
      cigarettes per day, when the effect of GSTM3 was analyzed in combination with
      CYP3A (regression analysis; F(6,24)=6.3, P<0.001). No protection by GSTM3 was
      observed in heavy smokers. High CYP3A levels, on the other hand, increased the
      number of DNA adducts regardless of the amount of smoking.

PMID- 12609565
TI  - Absence of mutations in the VHL gene but frequent loss of heterozygosity at 3p25
      26 in non-small cell lung carcinomas.
AB  - In this study we have examined 79 primary non-small cell lung tumours for the
      presence of mutations of the VHL gene as well as for allelic imbalance at the
      gene surrounding loci. While allelic imbalance was found in 83% of specimens,
      frequently affecting the whole 3p25-p26 region, no mutations were detected in the
      VHL coding region. The fractional regional loss (FRL) was significantly higher in
      squamous cell carcinomas (0.746) than adenocarcinomas (0.493) (Wilcoxon P=0.002).
      This is the first investigation of the VHL gene mutational status in primary lung
      tumours. Our results indicate that mutation is not a common means of VHL
      inactivation in NSCLC.

PMID- 12609566
TI  - CAI inhibits the growth of small cell lung cancer cells.
AB  - The effects of carboxyamido-triazole (CAI) on small cell lung cancer (SCLC) cells
      were investigated. Using SCLC cell lines NCI-H209 or H345, 20 micro M CAI had
      little effect on basal cytosolic Ca(2+) but inhibited the ability of 10 nM
      bombesin (BB) or 1 nM neurotensin (NT) to elevate cytosolic Ca(2+). Also, CAI,
      impaired the ability of BB or NT to cause tyrosine phosphorylation of focal
      adhesion kinase. In contrast, CAI did not affect the ability of (125I-Tyr(4))BB
      or 125I-NT to bind with high affinity to NCI-H345 cells. These results indicate
      that CAI impairs SCLC second messenger activation, but not neuropeptide receptor
      binding. Using a MTT growth assay, CAI inhibited the proliferation of NCI-H209 or
      H345 cells in a concentration-dependent manner with little proliferation
      occurring using 100 micro M CAI. Also, CAI inhibited colony formation of NCI-H209
      or H345 cells in a dose-dependent manner in vitro. In vivo, CAI (2 mg/day by
      gavage) inhibited significantly NCI-H209 xenograft proliferation in nude mice.
      Animals treated daily with CAI had significantly reduced CD31 immunostaining of
      microvessels in the tumor. Also, CAI inhibited the increase in vascular
      endothelial cell growth factor (VEGF) mRNA after addition of BB to SCLC cells.
      These results suggest that CAI inhibits the growth of SCLC cells as well as the
      angiogenesis of SCLC tumors in a VEGF-dependent manner.

PMID- 12609567
TI  - Correlation between apoptotic index and angiogenesis in non-small cell lung
      cancer: comparison between CD105 and CD34 as a marker of angiogenesis.
AB  - Only a few clinical studies have documented a significant correlation between
      intratumoral microvessel density (IMVD), a measurement of angiogenesis, and
      apoptotic index (AI), an incidence of apoptosis, although many experimental
      studies have confirmed that insufficient angiogenesis induces accelerated
      apoptotic cell death. In the present study, therefore, to assess AI in
      correlation with IMVD in resected non-small cell lung cancer, a total of 236
      patients with pathologic stage I to IIIa were reviewed. IMVDs were determined
      immunohistochemically with an antibody against a pan-endothelial marker, CD34
      (CD34-IMVD), and an antibody against a proliferation-related endothelial marker,
      CD105 (CD105-IMVD). AI was defined as the number of tumor cells positive for the
      terminal deoxynucleotidyl tranferase-mediated dUTP-biotin nick end-labeling
      staining per 1000 tumor cells. When CD34 was used as a marker of angiogenesis,
      the mean AIs for the lower-IMVD and the higher-IMVD patients were 20.1 and 17.5,
      respectively, demonstrating no significant difference between the lower- and the
      higher-IMVD patients. In contrast, when CD105 was used, the mean AI for the lower
      IMVD patients was significantly higher than that for the higher-IMVD patients
      (22.0 and 15.6, respectively; P=0.019). There was no significant correlation
      between proliferative activity and CD34-IMVD or CD105-IMVD. These results
      demonstrated that that decreased angiogenesis may induce enhanced apoptotic tumor
      cell death without affecting cell proliferation.

PMID- 12609568
TI  - Serum p53 antibodies in patients with lung cancer: correlation with
      clinicopathologic features and smoking.
AB  - Abnormalities of p53 gene can lead to the production of p53 antibodies (p53-Abs)
      in the serum of cancer patients. This study was designed to investigate the
      prevalence of p53-Abs in 133 lung cancer patients and the distribution of these
      antibodies to clinicopathologic features and smoking status. Twenty five (18.8%)
      lung cancer patients were found to have p53-Abs. The presence of p53-Abs did not
      correlate with sex or age but showed frequent association with tumors of squamous
      cell carcinoma (31%) in comparison with adenocarcinoma (13.6%) (P=0.052). There
      was a statistically significant difference in the incidence of p53-Abs between
      early disease group (stage I-II) and the advanced group (stage III-IV) (P=0.036),
      however, there was no relationship between the presence of p53-Abs and overall
      survival. Interestingly, the frequent of p53-Abs was higher in smokers (27.1%)
      than in non-smokers (13.6%), though the difference was of borderline of
      statistical significance (P=0.061). These findings suggested that p53-Abs could
      be a potential biomarker for the study of individual with lung cancer.

PMID- 12609569
TI  - The value of prognostic factors in small cell lung cancer: results from a
      randomised multicenter study with minimum 5 year follow-up.
AB  - We have evaluated the prognostic value of 22 pretreatment attributes in 436 small
      cell lung cancer (SCLC) patients included in a prospective multicenter study with
      a minimum 5-year follow-up. Pretreatment clinical and laboratory parameters were
      registered. Possible prognostic factors were evaluated by univariate analysis
      (log rank test) and by the Cox multivariate regression model. In the univariate
      analysis of all patients, only age, nodal metastasis, and skin metastasis were
      not associated with survival. The multivariate Cox model identified gender,
      extent of disease, performance status (PS), weight loss, platelet count, LDH, and
      NSE as independent prognostic factors. In subset multivariate analyses according
      to extent of disease, we found haemoglobin level, PS, NSE, and total WBC as
      significant prognostic indicators for survival in limited-stage disease (LD
      SCLC), while PS, weight loss, LDH, number of metastases, liver metastases, and
      brain metastases were identified as independent prognostic factors in extensive
      stage disease (ED-SCLC). There was a significant correlation between serum LDH
      and NSE levels. In conclusion, gender, extent of disease, PS, weight loss,
      haemoglobin, WBC count, platelet count, LDH, and NSE were all found to be
      independent prognostic factors for SCLC survival. However, the prognostic value
      of these factors depends highly on whether all or subsets of SCLC patients are
      studied.

PMID- 12609570
TI  - Psychological issues related to the use of spiral CT for lung cancer early
      detection.
AB  - Although the NCI is presently investigating whether enhanced detection of lung
      tumors via spiral CT reduces lung cancer mortality, use of this technology for
      lung cancer screening is already widespread in the US. Few data are available
      concerning level of interest in, or awareness of, spiral CT for lung cancer
      screening, correlates of participation in screening, or potential reactions to
      screening results (i.e. smoking cessation) among high-risk individuals. One
      hundred-and-seventy-two current or former smokers with no personal cancer history
      were queried about their awareness of spiral CT for lung cancer screening,
      received information about the procedure, and completed a survey that assessed
      interest in screening, correlates of screening interest (i.e. demographic,
      health, psychological), and expected effects of screening results on smoking.
      Seventy-seven percent of respondents were unaware of spiral CT for lung cancer
      screening and 62% expressed high interest in screening. Screening interest was
      positively related to screening self-efficacy, knowledge of asymptomatic illness,
      and perceived lung cancer risk. In the face of a positive scan, 52% of smokers
      said that they would quit, 43% said they would consider quitting, and 3% would
      continue smoking. If the scan was negative, 19% of smokers said that they would
      quit, 61% said they would consider quitting, and 20% would continue smoking.
      Finally, 59% of smokers were interested in smoking cessation counseling, with
      screening. These findings can help guide the design of psychological
      interventions to promote the utilization of spiral CT for early lung cancer
      detection as well as the development of protocols to promote behavior change
      within lung cancer screening programs, should future studies indicate that spiral
      CT screening can effectively reduce the overall lung cancer mortality rate.

PMID- 12609571
TI  - Small stage I cancers of the lung: genuineness and curability.
AB  - PURPOSE: To assess the genuineness and curability of diagnosed cases of Stage IA
      non-small-cell lung cancer of diameter 6-15 mm, with a view to screen-diagnosed
      asymptomatic cases. METHODS: We identified all cases of diagnosed Stage IA
      (T1N0M0) primary non-small-cell lung cancer documented in the Surveillance,
      Epidemiology, and End Results (SEER) registry in 1988-1994. There were 885 such
      cases of diameter 6-15 mm, 33 of them unresected, 1659 of diameter 16-25 mm, and
      782 of diameter 26-30 mm. We determined the 8-year cumulative lung-cancer death
      rates adjusted for competing causes of death, separately for untreated and fully
      resected cases. Given the relative underdetection of lymph node metastases of the
      untreated cases, we also documented the case-fatality rates for the resected with
      inclusion of those with detected intra-pulmonary, hilar or ipsilateral
      mediastinal lymph node metastases. RESULTS: The 8-year fatality rate for the
      diagnosed but untreated cases of lung cancer 6-15 mm in diameter was 87%, for 16
      25 mm it was 94%, and for 26-30 mm it was 88%. The corresponding estimates of
      cure rates with resection were 71, 67, and 55%, respectively. The cure rate
      estimate for the smallest cancers was 66% when adding those with detected lymph
      node metastases to the resected series, for those 16-25 mm in diameter it was
      65%, and for those 26-30 mm in diameter it was 51%. CONCLUSION: Almost all
      diagnosed cases of Stage IA lung cancer as small as 10 mm in diameter have a
      malignant natural course, fatal if not treated, thus representing genuine cancer.
      Most of these cases are curable by resection.

PMID- 12609572
TI  - Phase I/II trial of gemcitabine plus cisplatin and etoposide in patients with
      small-cell lung cancer.
AB  - OBJECTIVE: The objectives of this phase I/II study were to define the maximum
      tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and
      gemcitabine (PEG) in the treatment of previously untreated patients with small
      cell lung cancer (SCLC). PATIENTS AND METHODS: Chemonaive patients received fixed
      doses of gemcitabine (1000 mg/m(2) on days 1 and 8) and cisplatin (70 mg/m(2) on
      day 2) and escalating doses of etoposide (starting dose of 50 mg/m(2) on days 3,
      4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors
      were used. RESULTS: From September 1998 to April 2000, 56 patients with limited-
      or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two
      different etoposide doses were tested in eight patients. At the second level (75
      mg/m(2)), two out of two patients experienced dose-limiting toxicities
      (neutropenia and thrombocytopenia) and no further dose-escalation was attempted,
      thus an etoposide dose of 50 mg/m(2) was defined as the MTD. In the subsequent
      phase II evaluation, 48 additional patients were enrolled, for a total of 54
      patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred
      in 66.7 and 53.7% of patients, respectively. Non-hematologic toxicity was mild,
      with grade 3 diarrhea and fatigue as the main side effects. Two patients died of
      neutropenic sepsis (one at 75 mg/m(2) and the other at 50 mg/m(2) etoposide). Ten
      complete and 29 partial responses were reported, for an overall response rate of
      72.2% (95% confidence interval, 56.6-85.0%). The median duration of response and
      median survival were 8.0 and 10 months, respectively, with a 1-year survival
      probability of 37.5%. CONCLUSIONS: The combination of PEG is feasible and well
      tolerated as front-line chemotherapy in SCLC. A randomized comparison of this
      triplet is underway.

PMID- 12609574
TI  - Repeat mediastinoscopy after neoadjuvant therapy for non-small cell lung cancer.

PMID- 12609575
TI  - Multiple primary lung cancers: comment on current opinions.

PMID- 12609573
TI  - Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body
      hyperthermia for malignant pleural mesothelioma.
AB  - We performed a phase II study combining 41.8 degrees C whole body hyperthermia
      with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and
      etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients
      with malignant pleural mesothelioma. Of 27 chemonaive, non-metastatic patients
      enrolled, 25 patients were evaluable for response. Overall response rate was 20%
      (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start
      of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks).
      Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7
      weeks). One year overall survival was 68% and 2 year overall survival was 20%.
      Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in
      74 and 33% of treatment cycles, respectively. One patient died due to sepsis.
      These promising results are consistent with continued clinical investigation; a
      phase III clinical trial with whole body hyperthermia as the independent variable
      has been initiated.

PMID- 12609577
TI  - Effects of toy stimulation on the cognitive, communicative, and emotional
      functioning of adults in the middle stages of Alzheimer's disease.
AB  - Although several clinical reports describe the benefits of toy stimulation for
      dementia patients, there is little empirical support for this sensory stimulation
      approach. The purpose of this investigation was to examine the effects of toy
      stimulation on the language, cognition, and emotional state of patients in the
      middle stages of Alzheimer's disease (AD) during a formal testing situation.
      Eighteen patients completed a standardized test battery and picture description
      task twice, once with and once without a toy stimulus present. Three AD patients
      completed all tasks four times (twice with and twice without the toy) to examine
      performance consistency. Although some patients improved their performances in
      the presence of a toy, there were no significant group differences between the
      toy and no toy conditions for any experimental measure. Of the three patients who
      completed experimental tasks twice in the presence of a toy, two displayed some
      consistent improvements whereas the remaining patient's response pattern was
      variable. Caregiver feedback regarding toy stimulation was positive.
      Methodological limitations of the current study and suggestions for future
      research are discussed. LEARNING OUTCOMES: As a result of reading this article,
      the participant will be able to: (1) summarize the previous literature regarding
      sensory stimulation treatment approaches for patients with Alzheimer's disease or
      other dementing illnesses; and (2) describe the effects of toy stimulation on the
      linguistic and cognitive abilities, and emotional status of patients in the
      middle stages of Alzheimer's disease.

PMID- 12609579
TI  - Addressing generalization and maintenance of stuttering treatment in the schools:
      a critical look.
AB  - Generalization and maintenance are a widely recognized challenge for stuttering
      treatment. There are many reasons why this is the case. First, there is no
      accepted model of recovery, though self-efficacy may be a helpful construct and,
      secondly, the client's age, stuttering severity, and negative attitudes may be
      complicating factors. Three strategies for promoting generalization and
      maintenance in school settings are suggested based on current research evidence.
      They include probing and training for generalization, incorporating real-life
      elements into therapy, and training clients to self-regulate their behavior.
      These strategies appear to be viable and practical, but further research is
      needed to fully evaluate their effectiveness for school settings. LEARNING
      OUTCOMES: Readers will learn about (1) typical approaches to managing stuttering
      in the school setting, (2) barriers to generalization and maintenance of
      stuttering treatment gains, and (3) three strategies for promoting generalization
      and maintenance.

PMID- 12609578
TI  - Diagnostic accuracy and test-retest reliability of nonword repetition and digit
      span tasks administered to preschool children with specific language impairment.
AB  - To assess diagnostic accuracy and test-retest reliability, two forms of a nonword
      repetition task were administered to 22 preschool children with specific language
      impairment (SLI) and to 22 age- and gender-matched children with normal language
      (NL). Results were compared with performance on a digit span task and norm
      referenced test scores. Nonword repetition scores provided excellent sensitivity
      and specificity for discriminating between groups. Scores on both nonword
      repetition and digit span tasks improved significantly from first to second
      administrations for both groups, but remained relatively stable at the third
      administration. The SLI group appeared to benefit more from repetition than the
      NL group. Acceptable levels of test-retest reliability were achieved for the
      digit span task, but not for the NL group on the nonword repetition task. These
      preliminary findings suggest that with further refinement to improve test-retest
      reliability, nonword repetition holds promise as a diagnostic measure for SLI in
      preschool children. EDUCATIONAL OBJECTIVES: As a result of this activity, the
      participant will be able to (1) describe the content and administration of
      nonword repetition tasks; (2) explain why evidence of test-retest reliability is
      necessary before a measure may be considered reliable for diagnostic purposes;
      and (3) accurately compare the sensitivity and specificity of the nonword
      repetition task utilized in this study to standardized language test scores.

PMID- 12609580
TI  - Similarities in weak syllable omissions between children with specific language
      impairment and normally developing language: a preliminary report.
AB  - Two-year-olds with normally developing language (NL) and older children with
      specific language impairment (SLI) omit initial weak syllables from words (e.g.,
      "banana" approximately "nana"). Previous research revealed a phonetic "trace" of
      syllables omitted by children with NL (Carter, 1999; Carter & Gerken, submitted
      for publication). The present study asked whether similar evidence could be found
      for omissions by children with SLI. Fourteen children with SLI produced sentences
      containing reduced or unreduced disyllabic proper names (e.g., "Feed_cinda," from
      "Feed Lucinda" vs. "Feed Cindy"). Acoustic analyses revealed a significantly
      longer duration for verb-onset to name-onset of sentences containing the reduced
      name, indicating that although segmental material is omitted, an acoustic trace
      remains. In addition, a phonological examination showed similarities between
      groups regarding sentential and syllabic factors that affect omission rates, as
      well as an interesting difference that suggests different strategies the groups
      use in acquiring adult targets. LEARNING OUTCOMES: As a result of reading this
      article, participants should (1) have a better understanding of similarities and
      differences in the language production of children with specific language
      impairment and normally developing language, with regard to prosodic development,
      (2) be familiar with several models of the phenomenon of weak syllable omissions
      in children's developing language, and (3) recognize the importance of using a
      combination of linguistic analysis types when studying issues in child language
      production.

PMID- 12609581
TI  - Commentary: antimicrobials in dermatology.

PMID- 12609583
TI  - Sulfonamides in dermatology.

PMID- 12609584
TI  - Penicillin and semisynthetic penicillins in dermatology.

PMID- 12609582
TI  - Dyes in dermatology.

PMID- 12609585
TI  - Cephalosporins in dermatology.

PMID- 12609586
TI  - Tetracyclines in dermatology.

PMID- 12609588
TI  - Rifampin in dermatology.

PMID- 12609587
TI  - Macrolides in dermatology.

PMID- 12609589
TI  - Quinolones in dermatology.

PMID- 12609590
TI  - Linezolid, quinupristin/dalfopristin, and daptomycin in dermatology.

PMID- 12609591
TI  - Topical antimicrobial agents in dermatology.

PMID- 12609592
TI  - Drug interactions--fact or fiction?

PMID- 12609595
TI  - Expression of Drosophila neoplastic tumor suppressor genes discslarge, scribble,
      and lethal giant larvae in the mammalian ovary.
AB  - The similarities and differences in molecular mechanisms regulating invertebrate
      and mammalian folliculogenesis are starting to be deciphered. In Drosophila, the
      neoplastic tumor suppressor gene discslarge is crucial for suppressing
      proliferation and movement of follicle cells relative to the growing oocyte.
      Lethal giant larvae and scribble play similar roles and have been suggested to
      collaborate intimately with discslarge. We have identified and determined the
      expression pattern of murine homologs of these Drosophila genes. In situ data
      shows that murine discslarge-1, discslarge-3, discslarge-4, lethal giant larvae,
      and scribble are expressed in both overlapping and distinct patterns in oocytes
      and granulosa cells in maturing follicles. Disclarge-4 is expressed in the
      surface epithelium and is lost in mouse carcinogenic surface epithelial cells.
      All of these genes, as well as discslarge-2 and discslarge-5, are expressed in
      human ovaries. Our data suggests that as in Drosophila, these tumor suppressors
      may cooperate during mammalian folliculogenesis, but also have distinct
      functions.

PMID- 12609596
TI  - Slit and robo: expression patterns in lung development.
AB  - First described as an axonal guidance cue through its repulsive effect on neurons
      expressing its receptor Roundabout (Robo), the Slit ligand has effects on cell
      migration, axon branching and elongation. Indirect evidence implicates Slit and
      Robo in lung development. We now demonstrate that Slit-2 and Slit-3 are
      developmentally regulated in embryonic murine lung. Immunohistochemistry
      demonstrates Slit-2 and Slit-3 expression by the pulmonary mesenchyme and airway
      epithelium. Robo-1 and Robo-2 are also expressed by the developing mesenchyme and
      airway epithelium. As lung development progresses, Robo-1 and Robo-2 expression
      localizes to only the airway epithelium. We conclude Slit/Robo are expressed in
      temporo-spatially adjacent domains suggesting interactive roles in pulmonary
      bronchiolar development.

PMID- 12609597
TI  - The expression of planarian brain factor homologs, DjFoxG and DjFoxD.
AB  - Recent accumulating evidence revealed that planarian central nervous system (CNS)
      has numerous functional domains distinguished by a large number of neural
      markers, suggesting that primitive animals which developed CNS already had the
      framework of the brain development. It is of interest to investigate genes which
      have been acquired at an early stage of evolution for brain pattern formation.
      One such candidate is FoxG1 (BF-1), specifically expressed in the telencephalon
      and implicated in brain development. We identified a FoxG1 (BF-1) homolog gene in
      planarians (DjFoxG). We also identified a FoxD class gene, DjFoxD. DjFoxG is
      expressed in the body and brain, with strong expression in the mesenchyme
      surrounding the gut. During regeneration, an intense anterior signal is detected,
      but this is not restricted to the head. DjFoxD is expressed in the mid-apex of
      the head, between the two lobes of the brain. Strong expression was detected in
      the mid-anterior blastema. Thus, FoxG and FoxD homologs do exist in planarians,
      but are regulated differently than those in vertebrates.

PMID- 12609598
TI  - HMGB1, an architectural chromatin protein and extracellular signalling factor,
      has a spatially and temporally restricted expression pattern in mouse brain.
AB  - HMGB1 is an abundant chromatin component, so far considered ubiquitous. HMGB1
      also has an extracellular signalling role: when passively released by necrotic
      cells, it triggers inflammation; moreover, it can be actively secreted by myeloid
      cells, neurons and neuronal cancer cells. We show here that HMGB1 protein is
      undetectable in most cells in adult mouse brain, and is present in a subset of
      brain cells during development, with a very complex temporal, spatial and
      subcellular expression pattern. HMGB1 is expressed in the cortical plate of E14.5
      embryos, predominantly in the nucleus, although roughly 1% of cells show a
      cytoplasmic localization as well. In E16 embryos, HMGB1 is nuclearly expressed in
      scattered cells apparently moving from the ventricular zone to the cortical
      plate. HMGB1 expression is strongly down-regulated at later developmental stages;
      in adult mice significant expression is maintained only in areas of continuing
      neurogenesis. Finally, HMGB1 subcellular localization changes during retinoic
      acid induced differentiation of P19 neuroblastoma cells.

PMID- 12609599
TI  - The expression of a caudal homologue in a mollusc, Patella vulgata.
AB  - We cloned and analyzed the expression of a caudal homologue (PvuCdx) during the
      early development of the marine gastropod, Patella vulgata. PvuCdx is expressed
      at the onset of gastrulation in the ectodermal cells that constitute the
      posterior edge of the blastopore, as well as in the paired mesentoblasts, the
      stem cells that generate the posterior mesoderm of the trochophore larva. During
      larval stages, PvuCdx is expressed in the posterior neurectoderm of the larva, as
      well as in part of the mesoderm. This is the first report of the expression of a
      caudal gene in a lophotrochozoan species. The striking similarities with the
      expression of caudal in other organisms, such as chordates, suggest that a
      posterior expression of caudal is ancestral to Bilateria.

PMID- 12609601
TI  - The medaka midblastula transition as revealed by the expression of the paternal
      genome.
AB  - At midblastula transition (MBT), zygotic gene transcription is activated, cells
      become motile and cell division becomes asynchronous. The onset of the medaka
      (Oryzias latipes) MBT was examined using expressed sequence tag (EST) markers.
      Among 187 randomly chosen medaka EST markers, 33 EST markers and two genes (eIF
      4C and hsc70) showed polymorphisms in terms of insertion/deletions or restriction
      sites between the two parental inbred strains, one from the northern Japanese
      population and the other from the southern Japanese population. There was no
      evidence of zygotic expression of these EST markers before Stage 10 (early
      blastula stage), whereas expression of 12 genes was found from Stage 11 on. These
      results suggest that the medaka MBT in terms of first time transcription of
      paternal genes in the life of the embryo begins at Stage 11 (late blastula
      stage).

PMID- 12609600
TI  - Zfhx1a and Zfhx1b mRNAs have non-overlapping expression domains during chick and
      mouse midgestation limb development.
AB  - Smad-interacting protein 1 (Zfhx1b, Sip1) and Zfhx1a (deltaEF1) are
      transcriptional repressors belonging to the family of two-handed zinc
      finger/homeodomain proteins. Both of the proteins bind to a bipartite
      CACCT/CACCTG DNA sequence, but only Sip 1 can interact with activated SMAD
      proteins in vitro. To gain insight into their developmental roles, we
      investigated the mRNA expression patterns of both genes in developing mouse and
      chick limbs by in situ hybridization. To improve the resolution of the expression
      mapping we have used a dual in situ hybridization (DISH) technique allowing for a
      detection of expression of two different mRNAs on the same tissue section. Using
      DISH we could demonstrate that both genes were expressed in distinct non
      overlapping patterns in developing limbs of both species. Zfhx1a was expressed in
      a cell population immediately adjacent to cartilage anlagen as well as in
      developing tendons. Zfhx1b, in contrast, was present in a broad area around
      developing tendon and partially overlapping with the expression of genes
      associated with myogenic differentiation.

PMID- 12609602
TI  - Early expression of hypoxia-inducible factor 1alpha in the chicken embryo.
AB  - Hypoxia is known to regulate angiogenesis and tissue growth by the induction of
      the alpha subunit of the heterodimeric transcription factor, hypoxia-inducible
      factor 1. The expression pattern of HIF1alpha in both epithelial and mesenchymal
      structures of the chicken embryo through the first 7 days of development is
      reported here. HIF1alpha transcript is expressed diffusely throughout the
      neuroepithelium, limb, mesonephritic and cephalic mesenchyme, progressively
      becoming restricted to known proliferative zones of the central nervous system.
      Specific, strong expression is unexpectedly found in the endoderm of Sessel's
      pouch and in the ectoderm of both Rathke's pouch and the first branchial arch
      before the disappearance of the buccopharyngeal membrane.

PMID- 12609603
TI  - The expression patterns of c-kit and Sl in chicken embryos suggest unexpected
      roles for these genes in somite and limb development.
AB  - We have used whole-mount in situ hybridization to investigate the patterns of c
      kit and Sl expression in stage 11-22 chicken embryos. Our analysis shows that c
      kit and Sl are expressed quite differently in chicken embryos compared to the
      reported expression patterns of these genes in embryos of other taxa. Most
      notably, chicken c-kit is expressed in primordial germ cells as well as in the
      developing somite, the apical ectodermal ridge, and in the early foregut
      endoderm. Sl is expressed in the lateral and intermediate mesoderm and in
      extraembryonic membranes. These data suggest that chicken c-kit and Sl may play
      novel and unexpected roles in somitogenesis, limb development, and foregut
      development in avian embryos.

PMID- 12609604
TI  - Expression patterns of parathyroid hormone-related peptide (PTHrP) and
      parathyroid hormone receptor type 1 (PTHR1) during human development are
      suggestive of roles specific for each gene that are not mediated through the
      PTHrP/PTHR1 paracrine signaling pathway.
AB  - Close temporal and spatial relationships between Pthrp and Pthr1 gene expression
      are reported during fetal life in rats, suggestive of a developmental role via a
      paracrine signaling pathway. In agreement, disruption of this signaling pathway
      is associated with developmental defects, as documented in mice and humans.
      Surprisingly, however, only few organs are affected. We report here PTHrP and
      PTHR1 gene expression during human embryo-fetal development. We describe three
      patterns: in some organs, both genes are active ('hand-in-glove' fashion), while
      in others either PTHrP or PTHR1 transcripts are detected. In addition, in some
      tissues, expression of PTHrP or PTHR1 genes is transient. Abnormal development
      has been documented only for organs expressing both genes. The patterns that we
      observe are compatible with specific roles for each gene not mediated through the
      PTHrP/PTHR1 signaling pathway.

PMID- 12609605
TI  - Cloning and developmental expression of amphioxus Dachschund.
AB  - The nuclear factor dachshund (dac) is a key regulator of eye and leg development
      in Drosophila. We have cloned a Dachshund homologue from an invertebrate chordate
      amphioxus (Branchiostoma floridae). Sequence comparison reveals a high degree of
      similarity of amphioxus Dachshund (AmphiDach) to the known vertebrate and
      Drosophila dachshund genes. AmphiDach is first expressed in the prospective
      paraxial mesoderm at the gastrula stage. At the early neurula stage, expression
      is detected in developing somites and anterior endoderm, but in late neurula
      transcripts are present exclusively in the most posterior region of the cerebral
      vesicle and the anterior pharynx endoderm. Then, in larva, AmphiDach is localized
      in photoreceptive neurons of the frontal eye, infundibular organ, and endostyle
      as well as in Hesse organs and in nerve cells scattered along the nerve cord.
      Comparison of Dach expression in amphioxus and vertebrates suggests that such
      patterns are relatively similar (because they are expressed in somites,
      photoreceptor cells and CNS), even if expression of AmphiDach in the endostyle
      has no counterparts in its vertebrate homolog, the thyroid.

PMID- 12609606
TI  - Localization and expression pattern of type I postplasmic mRNAs in embryos of the
      ascidian Halocynthia roretzi.
AB  - The posterior-vegetal cytoplasm (PVC) of fertilized ascidian eggs plays important
      roles in embryo development. It has been reported that some maternal RNAs are
      localized to the PVC. We identified four novel type I postplasmic mRNAs that are
      localized to the PVC through the use of data from a cDNA project of maternal
      mRNAs in the eggs of Halocynthia roretzi (MAGEST database). The mRNAs are HrGLUT,
      HrPEN-1, and HrPEM-3, which show similarity to a glucose transporter, a g1
      related protein, and Ciona pem-3, respectively; and HrPEN-2, with no similarity.
      Maternal mRNAs of all four genes were identically localized to the PVC after
      ooplasmic segregation. During cleavage, they were concentrated in the centrosome
      attracting body (CAB) and were then segregated into the small blastomeres located
      at the posterior pole. This localization pattern is common to all known type I
      postplasmic mRNAs found so far. HrGLUT, HrPEN-1, and HrPEM-3 were expressed
      zygotically in various tissues later in embryogenesis: HrGLUT and HrPEM-3 in the
      mesenchyme and nervous system, and HrPEN-1 in the ectodermal cells.

PMID- 12609607
TI  - Sexually dimorphic expression of multiple doublesex-related genes in the
      embryonic mouse gonad.
AB  - The only molecular similarity shown so far for sexual regulatory genes among
      different phyla involves doublesex (dsx) of Drosophila, mab-3 and mab-23 of
      Caenorhabditis elegans, and Dmrt1 of vertebrates. These genes encode DM domain
      transcription factors (DM = dsx and mab-3) and are required for sexual
      differentiation. In the case of dsx and mab-3, the two genes control analogous
      aspects of sexual development, bind similar DNA sequences, and are capable of
      functional substitution in vivo. All three phyla have multiple DM domain genes,
      but it is unknown how many of these are involved in sexual development. Mammals,
      for example, have at least seven DM domain genes, but embryonic expression has
      only been examined in detail for Dmrt1(dsx- and mab-3 related transcription
      factor 1). We have identified additional murine DM domain genes and have examined
      their expression in the mouse embryo, with emphasis on the developing gonad. At
      least three murine DM domain genes in addition to Dmrt1 are expressed in the
      embryonic gonad: Dmrt4 is expressed at similar levels in gonads of both sexes;
      Dmrt3 is more highly expressed in males; and Dmrt7 is more highly expressed in
      females. Expression of three other genes is low or absent in the embryonic gonad.
      Two of these, Dmrt5 and Dmrt6, are expressed primarily in the brain, and the
      third, Dmrt2, is expressed in presomitic mesoderm and developing somites. Our
      data suggest that multiple DM domain genes may be involved in mammalian sexual
      development, and that they may function in both testis and ovary development.

PMID- 12609608
TI  - Up, down and up again is a signature global gene expression pattern at the
      beginning of gymnosperm embryogenesis.
AB  - Somatic embryogenesis of a gymnosperm, Picea abies, represents a sequence of
      specifically regulated developmental stages including proembryogenic mass (PEM),
      PEM-to-embryo transition, and early and late embryogeny. Here, we report cDNA
      array analysis of expression patterns of 373 genes in the beginning of P. abies
      embryo development. The analysis revealed a group of 107 genes (29% of arrayed
      cDNAs) which were upregulated upon PEM-to-embryo transition, then downregulated
      during early embryogeny and finally upregulated again at the beginning of late
      embryogeny. This major gene expression pattern was abrogated in a developmentally
      arrested cell line that is unable to pass through the PEM-to-embryo transition.
      Thirty-five genes (9.4% of arrayed cDNAs) were found to be differentially
      expressed during normal embryonic pattern formation. Among them, 22 genes (5.9%
      of arrayed cDNAs) were directly associated with embryo pattern formation and can
      be considered as marker genes for early stages of P. abies embryogenesis. The
      majority of the marker genes encode for proteins involved in translation and
      posttranslational modification. Among them, 18 genes displayed the major
      expression pattern.

PMID- 12609609
TI  - PCP4 is highly expressed in ectoderm and particularly in neuroectoderm
      derivatives during mouse embryogenesis.
AB  - PCP4 (PEP-19) belongs to a family of proteins involved in calcium transduction
      signals and binds calmodulin via an IQ motif, in a calcium independent manner.
      PCP4 gene maps to murine chromosome 16 and in human to chromosome 21. Murine PCP4
      expression in the brain has been detected by Northern blot analysis to be mainly
      post-natal and in the adult to have a neuronal pattern. To investigate if it
      might have a role earlier in development, we analyzed its expression during mouse
      embryogenesis by in situ hybridization from E7.5 post-coitum (p.c.) to E17.5
      p.c., and in P0 brain. Early, at E7.5, a high expression is restricted to the
      extra embryonic ectoderm. Embryonic expression starts at E9.5. At E10.5, PCP4
      shows a strong signal in the post-mitotic cells of the diencephalon, the
      metencephalon and the myelencephalon and in the dorsal and cranial ganglia. The
      floor plate is also densely labelled. At E17.5, PCP4 is expressed in the central
      nervous system, in the myenteric plexus, and in other ectoderm derivatives, for
      instance the lens, the hairy cells of the cochlea, the enamel organ and the hair
      follicles. Thus, during embryogenesis PCP4 is mainly expressed in ectoderm and
      neuroectoderm comprising neural crest derived cells.

PMID- 12609610
TI  - A novel NK-type homeobox gene, ENK (early embryo specific NK), preferentially
      expressed in embryonic stem cells.
AB  - In order to identify novel homeobox-containing genes involved in early embryonic
      development, we conducted a degenerate oligonucleotide polymerase chain reaction
      (PCR) screening of a murine embryonic stem (ES) cell cDNA library. ENK (early
      embryo specific expression NK family) was one of several genes isolated that was
      found to exhibit early embryo stage-specific expression. The full-length ENK cDNA
      was cloned and its genomic organization was characterized. Murine ENK spans 7.1
      kb, encodes four exons and maps to mouse chromosome 6F2. Reverse transcriptase
      PCR and Northern blot analyses show that ENK is preferentially expressed in pre
      implantation mouse embryos and a higher level in blastocysts. Whole-mount in situ
      hybridization analysis further demonstrates that ENK mRNA is present
      predominantly in the inner cell mass of blastocysts. The expression of ENK is
      markedly higher in undifferentiated ES cells than in retinoic acid differentiated
      ES cells and embryonic bodies. ENK expression slightly decreased in early
      primitive ectoderm-like (EPL) cells and was absent after the 9.5-day embryo
      stages. ENK is one of the few homeobox-encoding genes preferentially expressed in
      ES cells during mammalian embryogenesis.

PMID- 12609611
TI  - Expression of isotocin-neurophysin mRNA in developing zebrafish.
AB  - Neurohypophysial peptides are important regulators of homeostasis, reproduction
      and behavior. We have sequenced a zebrafish cDNA representing isotocin
      neurophysin (IT-NP) mRNA. The developmental expression pattern of zebrafish IT-NP
      mRNA was determined by whole-mount in situ hybridization histochemistry. At 32 h
      post fertilization (hpf) no IT-NP mRNA is detected. However, by 36 hpf, staining
      for IT-NP mRNA is detected in a tight bilateral cluster of cells located in the
      anterior hypothalamus. The IT-NP mRNA expression pattern remains remarkably
      stable throughout further development at least until 120 hpf.

PMID- 12609612
TI  - Expression of the Flk1 receptor and its ligand VEGF in the developing chick
      central nervous system.
AB  - The receptor tyrosine kinase Flk1 is known to mediate signals of vascular
      endothelial growth factor (VEGF) during vasculogenesis and hematopoiesis. We
      demonstrate by in situ hybridization that in addition to endothelial cells, chick
      Flk1 mRNA is also expressed in the notochord and in the neural epithelial cells
      of the ventral diencephalon, hindbrain, and spinal cord. During the development
      of the avascular chick retina, Flk1 mRNA is detected in the proliferative zone of
      the neural epithelium, whereas the VEGF ligand is expressed by differentiated
      retinal ganglion cells. Moreover, expression patterns of Flk1 in the retina are
      conserved among chick, quail and mouse, thus suggesting a distinct role of Flk1
      and VEGF in the development of the vertebrate central nervous system.

PMID- 12609613
TI  - Study on the complex site of L-tyrosine with rare-earth element Eu3+.
AB  - Amino acids are the primary units of proteins and play an important role in human
      life. The coordinate of L-tyrosine with rare-earth element Eu(3+) was
      investigated in solution by ultraviolet and was proved the molar ratio is 1:2.
      Then the solid complex was prepared by coprecipitation method. The complex was
      characterized by several analytical techniques, including Fourier Transform
      Infrared Spectroscopy, Differential Scanning Calorimetry, Scanning Electron
      Microscopy, 1H-NMR and 13C-NMR. Based on these data, we found that pentatomic
      ring was formed by binding with N atom in group of amino (-NH(2)) and O atom in
      group of carboxyl (-COOH).

PMID- 12609614
TI  - Ion-association method for the colorimetric determination of neomycin sulphate in
      pure and dosage forms.
AB  - A simple, fairly rapid, sensitive and accurate method is described for the
      colorimetric determination of neomycin sulphate (NMS), based on the measurement
      of the absorbance of the extracted organic soluble ion-association complex formed
      between neomycin dictation and a bulky counter anion. Different chromotropic acid
      azo dyes were examined as counter ions. The effect of pH, the counter ion
      concentration, sequence of addition and solvents for extraction were also
      illustrated. The most suitable system is based on reagent VIII (pH 7.5) with
      chloroform as the extraction solvent. The use of other counter ions, in
      conjunction with their respective solvents, was found to be less sensitive. The
      neomycin-reagent VIII system exhibits negligible or no interference when used for
      the determination of up to 58 microgml(-1) of NMS in the presence of several drug
      excipiences. The method has been used for the determination of up to 58 microgml(
      1) with a good recovery (99.8+/-1.5%), and the precision is supported by the low
      relative standard deviation </=1.35%. The sensitivity is discussed and the
      results are compared with the official method. The proposed method was applied
      successfully to the determination of NMS in pure and dosage forms, with a good
      precision and accuracy compared to the official one.

PMID- 12609615
TI  - Normal mode analyses of methyl palmitate all-trans and disordered forms in
      wagging progressive region.
AB  - Normal mode analyses are made for methyl palmitate molecule having all-trans or
      conformational disorders around the ester head group, in order to explain
      characteristic observed frequency shifts in the wagging progressive region
      between all-trans and disorder chains in triglyceride molecules. It was found
      that one gauche conformation at C(alpha)-C(beta) position and 90 degrees rotation
      of the ester head group in an alkyl chain produce frequency shifts for twisting
      mode as observed. For wagging modes, contamination of the disorders around the
      head group makes assignments change and apparent frequency shifts occur.

PMID- 12609616
TI  - Beta-alanine-oxalic acid (1:1) hemihydrate crystal: structure, 13C NMR and
      vibrational properties, protonation character.
AB  - The crystal structure of beta-alanine-oxalic acid (1:1) hemihydrate complex has
      been reinvestigated by X-ray diffraction method at 293 K. Formation of monoclinic
      crystal system belonging to C2/c space group and consisting of semi-oxalate
      chains, diprotonated beta-alanine dimers and water molecules bonded to both these
      units is confirmed. New results are obtained for distances in the carboxylic
      groups and hydrogen bonds. These structural observations are used for protonation
      degree monitoring on the carboxylic oxygen atoms. They are in accordance with our
      vibrational study. The 13C NMR spectra provide insights into the solid structure
      of this complex, character of its hydrogen bonds and the beta-alanine
      protonation.

PMID- 12609617
TI  - Utility of oxidation-reduction reaction for the determination of ranitidine
      hydrochloride in pure form, in dosage forms and in the presence of its oxidative
      degradates.
AB  - Three simple, accurate and sensitive colorimetric methods (A, B and C) for the
      determination of ranitidine HCl (RHCl) in bulk sample, in dosage forms and in the
      presence of its oxidative degradates are described. The first method A is based
      on the oxidation of the drug by N-bromosuccinimide (NBS) and determination of the
      unreacted NBS by measurement of the decrease in absorbance of amaranth dye (AM)
      at a suitable lambda(max)=520 nm. The methods B and C involve the addition of
      excess Ce(4+) and determination of the unreacted oxidant by decrease the red
      color of chromotrope 2R (C2R) at a suitable lambda(max)=528 nm for method B or
      decrease the orange pink color of rhodamine 6G (Rh6G) at a suitable
      lambda(max)=526 nm for method C. Regression analysis of Beer-Lambert plots showed
      good correlation in the concentration ranges 0.2-3.6, 0.1-2.8 and 0.1-2.6 microg
      ml(-1) for methods A, B and C, respectively. The apparent molar absorptivity.
      Sandell sensitivity, detection and quantitation limits were calculated. For more
      accurate results, Ringbom optimum concentration ranges were 0.3-3.4, 0.2-2.6 and
      0.2-2.4 microg ml(-1) for methods A, B and C, respectively. Analyzing pure and
      dosage forms containing RHCl tested the validity of the proposed methods. The
      relative standard deviations were </=1.38 with recoveries 98.9-101.0%.

PMID- 12609618
TI  - Preparation and study on the solid inclusion complex of sparfloxacin with HP-beta
      cyclodextrin.
AB  - The interaction of sparfloxacin with HP-beta-cyclodextrin (HP-beta-CD) has been
      studied by several analytical techniques, including 1H NMR, fluorescence
      spectroscopy, infrared spectroscopy, thermal analysis and scanning electron
      microscopy. In this paper, solid inclusion complex of sparfloxacin with HP-beta
      CD was synthesized by the coprecipitation method. In addition, the
      characterization of the inclusion complex has been proved by fluorimetry,
      infrared, differential scanning calorimetry and 1D, 2D NMR. The experimental
      results confirmed the existence of 1:1 inclusion complex of sparfloxacin with HP
      beta-CD. The formation constant of complex was determined by the fluorescence
      method and 1H NMR. Spacial configuration of complex has been proposed on 2D NMR
      technique.

PMID- 12609619
TI  - Magnetic, epr and SOD studies of some Cu(II)-Cu(II), Cu(II)-Ni(II) and Cu(II)
      Zn(II) imidazolate bridged complexes.
AB  - Magnetic, spectroscopic and superoxide dismutase activity of imidazolate bridged
      [(Salala)Cu-Im-Cu(Salala)]Na, [(Salala)Cu-Im-Zn(Salala)]Na and [(Salala)Cu-Im
      Ni(Salala)]Na (Salala=Salicyledenealiniate, Im=Imdiazolate) are described. The
      epr and electronic spectra of related mononuclear complexes, viz., [(Salala)Cu
      OH(2)] and [(Salala)Cu-ImH] also described. Appearance of a half-field signal in
      polycrystalline and decrease in mu(eff) per copper(II) ion indicate super
      exchange coupling between copper(II) ion in [(Salala)Cu-Im-Cu(Salala)]Na
      binuclear complex. A pH-dependent epr and UV-vis study of 50% aqueous DMSO
      solution of binuclear complexes suggest that the complexes are stable in narrow
      pH range.

PMID- 12609621
TI  - Luminescence of Tb3+ and Eu3+ doped amorphous zinc benzoates.
AB  - The Tb(3+) and Eu(3+) doped amorphous zinc benzoate were prepared. Their infrared
      absorption, emission and excitation spectra were measured. The luminescence
      mechanisms of Tb(3+) and Eu(3+) in the amorphous substrate were discussed. The
      bonding modes of OCO group to Zn(2+) ion have two of symmetric and asymmetric
      bridging bidentate. The energy of the S(1) pi,pi* excited state of benzene ring
      can be transferred to Tb(3+) and Eu(3+) ion, and results in characteristic
      emission from the 5D(4)-->(7)F(j) of Tb(3+) and 5D(0)-->(7)F(j) of Eu(3+),
      respectively.

PMID- 12609620
TI  - UV/Vis, IR and 1H NMR spectroscopic studies of bisazo-dianil compounds based on 5
      (2-carboxyphenyl azo)-salicylaldehyde and primary diamines.
AB  - The electronic absorption and emission spectra of the titled biazo-dianils are
      studied in organic solvents of different polarity as well as in aqueous buffer
      solutions of varying pH. The important bands in the IR spectra as well as the
      main signals of the 1H NMR spectra are assigned. The observed UV/Vis absorption
      bands are assigned to the corresponding electronic transitions. The fluorescence
      quantum yield and pK(a)(-) values in the ground and excited states are
      determined.

PMID- 12609622
TI  - On the stability of the hydrogen chloride complexes with ethylene and acetylene.
      A high resolution gas phase and ab initio study.
AB  - The temperature dependencies of the intensities of the HCl stretching bands of
      the hydrogen chloride complexes with acetylene and ethylene have been used to
      obtain estimates of the dissociation enthalpies of the two complexes. Quantum
      chemical calculations on the Hartree Fock and DFT/B3LYP levels of theory have
      been combined with experimental data to give estimates of the intensities of the
      HCl stretching vibration in the two complexes.

PMID- 12609623
TI  - Competitive interactions of adriamycin and ethidium bromide with DNA as studied
      by full rank parallel factor analysis of fluorescence three-way array data.
AB  - The competitive interactions of adriamycin (AMC) and a fluorescence probe of
      ethidium bromide (EB) with DNA have been studied by full rank parallel factor
      analysis (FRA-PARAFAC) of fluorescence excitation-emission three-way data array.
      The excitation and emission spectra as well as the equilibrium concentrations of
      co-existing species in different reaction mixtures can be directly obtained by
      the FRA-PARAFAC treatment. The concordance of the resolved excitation and
      emission spectra of AMC, EB and EB-DNA with the standard spectra of these species
      confirmed the reliability of the equilibrium concentrations of these components
      in the reaction mixtures studied. The results obtained are valuable for providing
      a deeper insight into the competitive interaction mechanism of AMC and EB with
      DNA. The conclusion was directly given out that the interaction of AMC with DNA
      is the intercalating model. The FRA-PARAFAC method as exemplified by the present
      study provides an useful approach for studying the interaction of clinical drugs
      with DNA in the presence of disturbance of drug assistants.

PMID- 12609624
TI  - Studies of the g factors and zero-field splitting for the trigonal Ti(2+)(Ga)
      S(p) defect center in GaP crystal.
AB  - The EPR g factors g(parallel), g(perpendicular) and zero-field splitting D
      suggested to be caused by a donor-acceptor nearest-neighbour pair defect
      [Ti(Ga)(2+)-Sp] in GaP:Ti(2+) co-doped with sulphur are calculated from the high
      order perturbation formulas based on a two spin-orbit coupling parameter model
      for the EPR parameters of 3d(2) ion in trigonal symmetry. The calculated results
      are close to the observed values. The suggestion of [Ti(Ga)(2+)-Sp] pair defect
      in GaP:Ti co-doped with sulphur is also confirmed from this calculation.

PMID- 12609625
TI  - Mossbauer and electronic spectral studies of iron(III) complexes of oximes.
AB  - The hydroxo-bridge complexes of the type [Fe(2)(ligand-H)(4)(OH)(2)] with
      bidentate nitrogen-oxygen donor ligands, viz. 2-hydroxynaphthaldehydeoxime
      [hnoH(2)], 2-hydroxyacetphenoneoxime [haoH(2)], salicylaldooxime [SalH(2)], 2
      hydroxypropiophenoneoxime [hnoH(2)] have been prepared. All the complexes have
      been characterized by elemental analysis, magnetic moments, electronic and
      Mossbauer spectral studies. Mossbauer parameters of the complexes clearly suggest
      high spin configuration of Fe(III) showing lower magnetic moment to that of the
      spin only value, i.e. 5.92 BM. It may be due to the antiferromagnetic interaction
      between Fe(III) centers.

PMID- 12609626
TI  - Interaction of nickel with 4-(2'-benzothiazolylazo) salicylic acid (BTAS) and
      simultaneous first-derivative spectrophotometric determination of nickel(II) and
      iron(III).
AB  - The solution properties of nickel complex with 4-(2'-benzo-thiazolylazo)
      salicylic acid (BTAS) have been studied by zero-order absorption
      spectrophotometry in 40% (v/v) ethanol at 20 degrees C and an ionic strength of
      0.1 mol dm(-3) (KNO(3)). The equilibria that exist in solution were established
      and the basic characteristics of complexes formed were determined. A new direct
      spectrophotometric method for the determination of trace amounts of the nickel is
      proposed based on the formation of the Ni (BTAS) complex at pH 7.0. The
      absorption maximum, molar absorbtivity, and Sandell's sensitivity of 1:1 (M:L)
      complex are 525 nm, 0.6 x 10(4) l mol(-1) cm(-1) and 2.824 x 10(-9) microg cm(
      2), respectively. The use of first-derivative spectrophotometry eliminates the
      interference of iron and enables the simultaneous determination of nickel and
      iron using BTAS. Quantitative determination of Ni(II) and Fe(III) is possible in
      the range (0.59-7.08) and (2.1-8.4) microg ml(-1), respectively with a relative
      standard deviation of 0.5%. The proposed method has been successfully applied to
      the simultaneous spectrophotometric determination of nickel and iron in steel
      alloys and aluminum alloys.

PMID- 12609627
TI  - Spectrophotometric determination of flucloxacillin in pharmaceutical preparations
      using some nitrophenols as a complexing agent.
AB  - Some nitrophenols are proposed as chromogenic reagents for the spectrophotometric
      determination of flucloxacillin. The reagent forms a greenish yellow 1:1 complex
      with flucloxacillin at pH 9.0. This complex is stable for at least 3.0 h after
      its formation. The greenish yellow charge transfer complex species has an
      absorption maximum at 446, 435, 442, 473 and 439 nm for p-nitrophenol (I), 2,4
      dinitrophenol (II), 3,5-dinitrosalycilic acid (III), picramic acid (IV) and
      picric acid (V), respectively, with a molar absorptivity between 1.43 x 10(4) and
      2.59 x 10(4) l mol(-1) cm(-1). Beer's low is valid over the concentration range
      2.0-40 microg ml(-1) of flucloxacillin. The detection and quantitation limits as
      well as relative standard deviation were also calculated. The reagents have been
      successfully used for the spectrophotometric determination of flucloxacillin in
      pure form and in pharmaceutical preparations.

PMID- 12609628
TI  - Alkyl halide charge transfer complexes with hard Lewis bases.
AB  - The unusual charge transfer complexes formed between alkyl halide acceptors and
      hard Lewis base donors (amines and alcohols) in low dielectric solvent were
      examined using ultraviolet spectroscopy. The lambda(max) of the complex decreases
      with increasing ionization potential of the donor. The complex formation
      equilibria were probed by thermodynamic analysis and concentration variation. At
      ambient temperatures complex formation is generally slightly exergonic with a
      negative complexation entropy. The complex extinction coefficients are much lower
      (<10 l mol(-1) cm(-1)) than for typical charge transfer complexes. These
      complexes are extraordinary within a classical context since the halide acceptors
      have a negative electron affinity. They exhibited an atypical hypsochromic shift
      with increasing solvent dielectric constant.

PMID- 12609630
TI  - Comparison of molecular orientation and phase transition behaviors in the two
      kinds of ordered ultrathin films of reversed duckweed polymer ES-3 studied by
      infrared grazing reflection-absorption spectroscopy.
AB  - A multilayer LB film and a casting film of reversed duckweed polymer ES-3 on Au
      evaporated glass slides were investigated by Fourier Transform infrared grazing
      reflection-absorption spectroscopy. It is found that the two kinds of ordered
      ultrathin films have different orientation of alkyl chains, nearly perpendicular
      to the substrate surface for the LB film while rather tilted for the casting
      film. The studies on their thermal transition behaviors indicate that both of the
      films have three phase transition processes, respectively, occurring near 65, 105
      and 140 degrees C for the former while near 80, 105 and 140 degrees C for the
      latter, but show different transition behavior in the each corresponding
      transition process. It is referred that at room temperature there are island-like
      domain structures formed in the LB film, but no ones in the casting film;
      however, the latter can form the domain structures between the first two
      transition points due to the desorption of solvents. The formation of domain
      structure seems to play two important roles, one of which is to make alkyl chains
      more perpendicular to the substrate surface, and the other to make alkyl chains
      more packed closely. Thermal cyclic experiments reveal that neither of the films
      could return to its original state after thermal cyclic treatment up to the
      temperature, which is above the third transition point, although its alkyl chain
      becomes highly ordered again.

PMID- 12609629
TI  - Perturbation of planarity as the possible mechanism of solvent-dependent
      variations of fluorescence quantum yield in 2-aryl-3-hydroxychromones.
AB  - In order to understand the unexpectedly low quantum yields of 3-hydroxyflavones
      (3-HFs) in certain solvents, such as acetonitrile or ethyl acetate, the
      comparative study of solvent-dependent properties of parent 3-HF, 2-furyl-3
      hydroxychromone and 2-benzofuryl-3-hydroxychromone derivatives have been
      performed. The results suggest that the formation of intermolecular hydrogen bond
      of 3-hydroxy group with the solvent favors non-planar conformations of phenyl
      group with respect to chromone system. This steric hindrance is not observed in
      the case of furan- and benzofuran-substituted 3-hydroxychromones (3-HCs). These
      results suggesting a new strategy for dramatic improvement of fluorescence
      properties of 3-HCs as two-wavelength ratiometric fluorescence probes.

PMID- 12609631
TI  - 1H NMR study of the inclusion of Costa-type organocobalt(III) complexes in
      cyclodextrins.
AB  - The inclusion behavior between Costa-type complexes and cyclodextrins (CDs) was
      studied by 1H NMR in aqueous solution. The results indicated that 1:1 inclusion
      complex was formed, in which the alkyl group of the guest was included in the
      cavity of CDs. The stability constants of the inclusion complexes were determined
      by the quantitative 1H NMR method. The effects on stability constants were
      discussed when various host and guest compounds were used.

PMID- 12609632
TI  - FT-Raman and photoacoustic infrared spectroscopy of Syncrude heavy gas oil
      distillation fractions.
AB  - FT-Raman and photoacoustic (PA) infrared spectra of six distillation fractions
      derived from Syncrude heavy gas oil (HGO), which has a boiling range from 343 to
      524 degrees C, were analyzed in detail in this study. Most of the information on
      the fingerprint region (200-1,800 cm(-1)) is provided by the FT-Raman spectra,
      which display approximately 30 bands that are assignable to functional groups in
      alkanes or aromatics. Monocyclic, bicyclic and tricyclic aromatics in the six
      fractions were also monitored using bands in this region. The C-H stretching
      region in both the FT-Raman and PA infrared spectra of the HGO distillation
      fractions was analyzed according to a curve-fitting algorithm used in previous
      investigations of samples with lower boiling points. The PA spectra of the HGO
      fractions were also analyzed by integration. The curve-fitting results show that
      the frequencies of the 11 Raman and 8 infrared bands used to model the aliphatic
      (approximately 2,775-3,000 cm(-1)) parts of the respective spectra are
      approximately constant across the entire HGO boiling range. These band positions
      are consistent with the results obtained in earlier studies of other distillation
      fractions obtained from Syncrude sweet blend. Both curve-fitting and integration
      show that the respective proportions of CH(2) and CH(3) groups do not vary
      significantly within the HGO region.

PMID- 12609633
TI  - Small interacting peptides. Part I. Interaction of cyclohexapeptides with an
      unspecific SiOH surface: comparison of infrared investigations and force field
      calculations.
AB  - The interaction of cyclohexapeptides c(X(1)(1)K(2)X(2)(3)K(4)X(3)(5)K(6)) in
      water with hydrolysed silicon surfaces were studied by attenuated total
      reflection Fourier transform infrared (ATR FTIR) spectroscopy and by force field
      calculations. The band sequences (1800-1500 cm(-1)) for dissolved and adsorbed
      cyclohexapeptides were recorded and compared with those obtained after flushing
      with distilled water in order to eliminate the background signal of the peptides
      in solution. Band analyses and principal component analyses were carried out for
      the characteristic peptide vibrations in order to evaluate the spectra. In
      addition, force field calculations were performed to study the binding energies
      to the surface and to illustrate the possible structures of the
      cyclohexapeptides. The positively charged lysine side chains of the
      cyclohexapeptides interact with the OH groups of the surface, as indicated by
      band shifts. This also was verified by the force field calculations. The bonding
      stability increases with the number of interacting sites (lysine side chains and
      other peptide residues) to the surface. These sites are determined by structure
      and polarity of the cyclohexapeptides.

PMID- 12609634
TI  - Vibrational characterization of the tertiary amide and thioamide group.
AB  - Force field calculations and vibrational spectra of (CH(3))(2)NCOCON(CH(3))(2)
      (TMO), (CH(3))(2)NCOCSN(CH(3))(2) (TMMTO) and (CH(3))(2)NCSCSN(CH(3))(2) (TMDTO)
      are discussed. The amide and thioamide fundamentals and those of other simple
      tertiary amides are compared. A characteristic pattern in infrared and Raman is
      proposed.

PMID- 12609635
TI  - Structure and vibrational study of the trimethylammonium hexafluorosilicate
      [(CH3)3NH]2SiF6 compound.
AB  - The X-ray powder diffraction pattern of [(CH(3))(3)NH](2)SiF(6) was obtained and
      indexed on the basis of a centred cubic unit cell with the P4(1)32 as the likely
      space group. The Infrared and Raman spectra of this compound have been recorded
      at room temperature and discussed in relation to the crystal structure. In this
      salt, the bands corresponding to the cation vibrational modes show that the
      symmetry of these cations is distorted from the free C(3v) one and that they are
      strongly hydrogen-bonded to the respective anions. However, the spectra of the
      anions can be interpreted in term of ordered groups as indicated by the splitting
      of the bands corresponding to some degenerate vibrational modes. The harmonic
      frequencies, corresponding to the (CH(3))(3)NH-SiF(6)-NH(CH(3))(3) optimised
      geometry, were calculated using the SCF semi-empirical MNDO-PM3 method.

PMID- 12609636
TI  - Synthesis and spectral characterization of some oxo-centered, trinuclear mixed
      valence iron thiocarboxylates.
AB  - Some mixed-valence Fe(II) Fe(III) complexes of thiocarboxylic acids and straight
      chain fatty acids with general formula [Fe(II)Fe(III)(2)O(SOCR)(6)(H(2)O)(3)] and
      [Fe(II)Fe(III)(2)O(SOCR)(3)(OOCR')(3)(CH(3)OH)(3)] (where, R=CH(3) or C(6)H(5)
      and R'=C(13)H(27), C(15)H(31) or C(17)H(35)) were synthesized and characterized
      by elemental analyses, spectral (infrared, electronic and Mossbauer) studies,
      molar conductance and magnetic susceptibility measurements. The infrared spectra
      suggested bridging nature of carboxylate and thiocarboxylate anions along with
      upsilon(asym)(Fe(3)O) vibrations in the complexes. Mossbauer studies revealed two
      resolved quadrupole doublets at 120-315 K confirming the presence of Fe(II) and
      Fe(III) moieties in the complexes. This was supported by the observed electronic
      spectral bands in the complexes at room temperature. The spectrum showed a band
      at around 13,800 cm(-1) which indicated an intervalence-transfer. Magnetic
      susceptibility measurements showed weak antiferromagnetic coupling related to
      mixed-valence pairs with S(2)=2, em leader S(1)=S(3)=5/2 spin exchange model.
      Conductance data indicated, the complexes were non-electrolytes in nitrobenzene.
      A structure has been established on the basis of these studies.

PMID- 12609637
TI  - Vibrational frequencies and structural determinations of di-vinyl sulfone.
AB  - We present a detailed analysis of the structure and infrared spectra of di-vinyl
      sulfone. The vibrational frequencies of the di-vinyl sulfone molecule were
      analyzed using standard quantum chemical techniques. Frequencies were calculated
      at the MP2 and DFT levels of theory using the standard 6-311G* basis set. The
      structural transformation of the chemical agent bis(2-chloroehtyl) sulfide (HD,
      mustard gas) and the related symmetry to a previously study compounds
      [Spectrochim. Acta Part A 55 (1999) 121; Spectrochim. Acta Part A 57 (2001) 2417]
      makes the symmetry of the di-vinyl sulfone molecule an interesting candidate for
      study. The molecule exists normally in a C(2) configuration. High-energy forms of
      di-vinyl sulfone with C(S) and C(1) symmetries also exist.

PMID- 12609638
TI  - Synthesis and spectroscopic investigations of iron(III) complexes with chlorides
      and dianionic, symmetrically halogen substituted phthalocyanines as ligands.
AB  - The synthesis of iron(III) complexes of general formula FeCl(R-pc), where R-pc
      are dianionic, symmetrically halogen substituted phthalocyanines at the positions
      2,9,16,23 or 1,8,15,22, from the corresponding amino substituted derivatives is
      described (R=Cl, Br, I). The complexes are characterized by UV-visible and
      infrared spectra, powder X-ray diffraction and magnetic susceptibility
      measurements. The effect of substituents at the periphery and the basicity of the
      solvents used on the electronic spectra are discussed. The Q band of the
      electronic spectra for symmetrically halogen substituted derivatives are
      redshifted and the substituents at 2,9,16,23- positions are more effective in
      redshifting the Q bands than those at 1,8,15,22-positions. Depending upon the
      basicity of the solvents, the ligand-to-metal charge transfer (LMCT) transitions
      on Q band envelop shift to the higher energy region in the order of
      pyridine>DMF>DMSO. The infrared absorption signals for C-H and metal-ligand
      vibrations appear to be sharper for 1,8,15,22 substituted derivatives than for
      2,9,16,23 substituted ones.

PMID- 12609639
TI  - A prospective study of the complication rate of use of patient restraint in the
      emergency department.
AB  - Patients are frequently involuntarily, physically restrained in the emergency
      department (ED). The purpose of this study was to determine the type and rate of
      complications experienced by patients physically restrained in the ED. A
      prospective, observational study was performed on consecutive patients who were
      restrained in a community, inner-city teaching hospital ED for a 1-year period.
      The ED nurses or physicians completed a restraint study checklist. The checklist
      included the reasons for restraints, restraint duration, method and number of
      restraints, use of chemical restraint, and complications resulting from the use
      of restraints. The 298 patients were accumulated during a 1-year period. The mean
      age was 36.5 years (range 14-89). Sixty-eight percent were men; 73% were African
      Americans, 16% Hispanic, and 11% Caucasian. One hundred six patients had more
      than one indication for patient restraint. Patients were restrained for a mean of
      4.8 h (range 0.2-25.0 h), with psychosis being the most frequent discharge
      diagnosis (33%). Patients were most frequently restrained on a cart with two
      restraints (59%), in the supine position (86%), and 27.5% had chemical restraint
      added. There were 20 complications (7%); getting out of restraints was the most
      common (10) and the remainder included vomiting (3), injured others (2), spitting
      (2), injured self (1), increased agitation (1), and other (1). These
      complications were not correlated with age, gender, race, number of restraints,
      use of chemical restraint, diagnosis, or duration of restraint. This study
      demonstrates a low rate of minor complications. We found that male patients were
      most often restrained for violent and disruptive behavior. Most commonly, two
      restraints were used in combination with chemical restraints for a duration of
      almost 5 h.

PMID- 12609640
TI  - A randomized study of electronic mail versus telephone follow-up after emergency
      department visit.
AB  - This study was conducted to determine whether electronic mail (e-mail) increases
      contact rates after patients are discharged from the emergency department (ED).
      Following discharge, patients were randomized to be contacted by telephone or e
      mail. The main outcome was success of contact. Secondary outcome was the median
      time of response. There were 1561 patients initially screened. Of these, 444 had
      e-mail and were included in the study. Half were contacted by telephone and the
      rest via e-mail. Our telephone contact rate was 58% (129/222) after two calls in
      a 48-h period and our e-mail contact was 41% (90/222). The telephone was nearly
      two times better than e-mail. The median time of response was 48 h for e-mail and
      18 h for telephone. It is concluded that the telephone is a better modality of
      contact than e-mail for patients discharged from the ED.

PMID- 12609641
TI  - Accuracy of the precordial V-Quick patch in persons with cardiac or pulmonary
      disease.
AB  - The aim of this study was to demonstrate the equivalence of 12-Lead
      Electrocardiograms (EKG) obtained with the new V-Quick patch and traditional tab
      style electrodes. Using a within-subject design, a convenience sample of 100
      subjects with either cardiac or pulmonary disease underwent two 12-lead EKGs, one
      with the traditional tab-style electrodes and one with the precordial patch.
      Computer-generated measurements of waveform axes and amplitude were obtained for
      both EKGs. Comparison of mean and 95% confidence intervals revealed no
      significant differences in Q, R or S wave amplitude across the six precordial
      leads. Furthermore, a four-factor ANOVA found no significant difference (p >
      0.05) in the Q, R and S wave amplitude between the type of electrode, gender and
      type of disease. A subset of 29 EKGs read by three experts found intra- (.90) and
      inter-rater (.84) reliability to be strong. In conclusion, the precordial V-Quick
      patch provided equivalent EKGs to those obtained using standard tab-style
      electrodes.

PMID- 12609642
TI  - Acute complications associated with shoulder dislocation at an academic Emergency
      Department.
AB  - Shoulder dislocation is the most frequent dislocation treated in the Emergency
      Department (ED). Orthopedic literature cites up to a 55% incidence of fracture,
      vascular or neurologic injury associated with this injury, but these studies
      suffer from referral bias. No large ED series has been reported. This
      retrospective chart review was conducted in an academic ED for patients with
      shoulder dislocation presenting July 1, 1995-June 30, 2000. There were 263 charts
      identified; 73 were miscoded and 5 were lost, leaving 190 for analysis. Mean age
      was 34.3 years. Fifty-five patients had at least one fracture (29%), 48 of which
      (76%) were of the Hill-Sachs type. Despite presence of a fracture, all shoulders
      underwent successful ED reduction. Sensory nerve deficits were found in 24
      (12.6%), which persisted after reduction in 25% of these patients. No vascular
      injuries were identified. The finding of fracture in 33% of patients with
      shoulder dislocation is in the range of rates reported in the orthopedic
      literature (15-55%). The finding that, despite the presence of a fracture, all
      underwent successful closed reduction is important, as one-third of these
      patients will have this condition. Neurologic deficits in 12% is significantly
      lower than the 21-65% reported in the orthopedic literature. Although
      complications associated with shoulder dislocation were relatively common, they
      did not significantly affect ED management.

PMID- 12609643
TI  - Ottawa Knee Rule: a comparison of physician and triage-nurse utilization of a
      decision rule for knee injury radiography.
AB  - The Ottawa Knee Rule (OKR) is a clinical decision rule for the ordering of knee
      radiographs by physicians in patients with blunt knee injuries. However, in many
      Emergency Departments, radiographs are also ordered by nurses during triage. This
      study was designed to compare application of the OKR by triage nurses and
      physicians. A consecutive sample of all patients presenting to the Emergency
      Department (ED) of a tertiary care military teaching hospital with blunt knee
      injuries that met OKR inclusion criteria were enrolled. Radiographs were ordered
      on all patients. Nurses and physicians were blinded to each other's examinations.
      Nurse-physician inter-reviewer reliability was compared using the kappa
      statistic. Of 172 enrolled subjects, 38 were excluded for incomplete data or
      multiple entries, leaving 134 study patients. Four fractures (3%) were detected.
      Fair inter-observer reliability was found on four of the five OKR components:
      patellar tenderness (PT, kappa = 0.31), proximal fibula tenderness (PFT, kappa =
      0.31), inability to flex > 90 degrees (FLEX, kappa = 0.24) and inability to walk
      four steps (WALK, kappa = 0.44). Nurses were more likely to overestimate the
      presence of individual components (PT 3.5x, PFT 6.6x, FLEX 1.9x and WALK 4.8x)
      and were 3.6 times more likely than Emergency Physicians (EP), overall, to order
      radiographs, representing a 21% vs. 37% reduced radiography rate, respectively.
      No fractures were missed by physicians or nurses. Triage nurses and EPs in this
      study had fair agreement in their application of the OKR. Triage nurses greatly
      overestimated knee injuries, while maintaining sensitivity, at the expense of
      specificity and cost savings.

PMID- 12609644
TI  - Cricothyrotomy: a 5-year experience at one institution.
AB  - We describe the prevalence, primary indications and immediate complications of
      emergency cricothyrotomy (cric) techniques, in a single institution's Emergency
      Department (ED) and associated air-medical transport service. This is a
      retrospective review at an academic, level-one trauma center with an annual ED
      census of 65,000 and an associated air-medical transport service (AMTS). All
      patients undergoing cric in the field or in the ED between July 1995 and June
      2000 were included. Expert reviewers from Emergency Medicine, Trauma Surgery and
      the AMTS prospectively defined the complication criteria. All charts with a
      possible complication underwent a blinded evaluation by reviewers representing
      each of the three clinical services. Descriptive statistics were used to
      summarize the data. Fifty crics were performed over 5 years. Seventy-six percent
      of crics were performed in trauma patients. The prevalence of cric in patients
      requiring airway management in the ED was 1.1% (95% CI, 0.7-1.6) and 10.9% (95%
      CI, 6.9-16.1) in the field by the AMTS. The prevalence of complications was 14%
      (95% CI, 4-32.6) in ED patients and 54.5% (95% CI, 32-75.6) for prehospital
      patients. The overall inter-rater agreement for complication rate was excellent
      (kappa =.87). Overall, 77% of crics were performed using the rapid four-step
      technique (RFST). There were no reports of complications associated with the RFST
      when performed in the ED. Non-RFST crics in the ED had an associated complication
      rate of 25% (95% CI, 2.8-60). Emergency cricothyrotomy was performed in
      approximately 1% of all emergency airway cases in the ED and at a higher rate by
      the AMTS. The most frequent indications were trauma related. Additionally, the
      RFST was the most commonly used technique for cric at this institution. The
      complication rate of cric was significantly higher in the prehospital environment
      than in the ED.

PMID- 12609645
TI  - The use of head computed tomography in elderly patients sustaining minor head
      trauma.
AB  - The study objectives were to ascertain historical and clinical criteria
      differentiating intracranial injury (ICI) in elderly patients with minor head
      trauma (MHT), and determine applicability of current head computed tomography
      (CT) scan indications in this population. A 12-month retrospective chart review
      was performed at a community teaching hospital with 34,000 annual Emergency
      Department (ED) visits. Included were patients > or = 65 years old sustaining MHT
      with a Glasgow Coma Scale (GCS) score of 13-15 who had a CT scan performed during
      their hospital stay. Data included: injury mechanism, symptoms, signs, GCS,
      anticoagulation use or studies, presence of alcohol or drug, CT scan result,
      diagnosis, and outcome and intervention(s). There were 133 patients, with 19
      (14.3%) suffering ICI. Four ICI patients required neurosurgical intervention. The
      mean age was 80.4 years and 66% were female. Four of 19 ICI patients (21%) had a
      GCS of 15, no neurologic symptoms, alcohol use or anticoagulation. Only 1 of 13
      signs and symptoms correlated with ICI. In this study, no useful clinical
      predictors of intracranial injury in elderly patients with MHT were found.
      Current protocols based on clinical findings may miss 30% of elderly ICI
      patients. Head CT scan is recommended on all elderly patients with MHT.

PMID- 12609646
TI  - Disruption of the extensor mechanism of the knee.
AB  - Ruptures of the extensor mechanism of the knee are rare, when compared with other
      knee injuries, and are frequently misdiagnosed. The outcome after surgical repair
      may be compromised if surgery is delayed. A case of quadriceps tendon rupture
      that was misdiagnosed for 2 months and a review of the literature are presented.
      Including extensor mechanism disruption in the differential diagnosis, and
      careful attention to key physical findings in the examination of all acutely
      injured knees, will ensure that this important injury is not overlooked.

PMID- 12609647
TI  - Anaphylaxis after low dose intravenous vitamin K.
AB  - Over-anticoagulation from warfarin is a common occurrence, and these patients are
      often referred to the Emergency Department for further treatment. Unfortunately,
      there is little guidance in the Emergency Medicine literature for the management
      of such patients. The American College of Chest Physicians (ACCP) issued
      guidelines in 1998 that address the use of vitamin K for patients with over
      anticoagulation. However, there is still debate as to the optimal dose and route
      of vitamin K administration. This case report describes a patient who was treated
      with intravenous vitamin K within the scope of these guidelines at a very low
      dose (1 mg) and had a fatal anaphylactic reaction. This article will further
      discuss this patient, the 1998 ACCP guidelines, and the data supporting the
      alternative of subcutaneously administered vitamin K for patients with over
      anticoagulation with no active bleeding.

PMID- 12609648
TI  - Prolonged QT syndrome in children: an uncommon but potentially fatal entity.
AB  - Prolonged QT syndrome may be either congenital, as in Jervell and Lange-Nielsen
      or Romano-Ward syndromes, or acquired in nature. Affected children are at risk
      for syncope, seizures, dysrhythmias and sudden death. Physicians should consider
      long QT syndrome (LQTS) in all patients who present with syncope. A thorough
      personal and family history should be documented, with particular attention to
      prior syncopal episodes, congenital deafness, and unexplained sudden death.
      Syncope that is either recurrent or induced by exercise or stress is concerning
      and also should be noted. An electrocardiogram with manual calculation of the QT
      interval should be performed on all patients with a suggestive history.
      Furthermore, the diagnosis of LQTS warrants evaluation of all other family
      members. With recognition and appropriate treatment of affected patients, the
      potentially fatal consequences of LQTS may be prevented.

PMID- 12609649
TI  - Flumazenil reversal of lorazepam-induced acute delirium.
AB  - We report the case of a 63-year-old man who presented to the Emergency Department
      (ED) with a 1-week history of sore throat, hoarseness and dysphagia. During his
      ED workup, the patient experienced an acute delirium 25 min after being given 2
      mg of Lorazepam. The patient's mentation returned to normal within 1-2 min of
      being given 1 mg of Flumazenil. We discuss the various behavioral side effects of
      benzodiazepines and the indications for the use of Flumazenil.

PMID- 12609650
TI  - Nebulized naloxone gently and effectively reverses methadone intoxication.
AB  - A 46-year-old woman presented to the Emergency Department with lethargy and
      respiratory depression after ingesting methadone. Initial oxygen saturation of
      61% on room air did not improve with supplemental oxygenation. As venous access
      was initially unobtainable, naloxone was administered by nebulizer. Within 5 min
      oxygen saturation was 100% and mental status was normal. The patient did not
      develop severe withdrawal symptoms. Naloxone hydrochloride has been administered
      by various routes to treat opioid toxicity. Our report describes the successful
      use of nebulized naloxone for methadone toxicity.

PMID- 12609651
TI  - Factors associated with mode of transport to acute care hospitals in rural
      communities.
AB  - This study identifies factors associated with mode of transport to rural
      hospitals. We evaluated 11,541 trauma patient visits that came by ground
      ambulance or private vehicle to the Emergency Department of one of six northwest
      Iowa rural hospitals. We performed univariate analyses and logistic regression
      analyses to identify factors associated with mode of transport for each severity
      level (fatal, major and minor). For major/fatal injuries, we found that those
      aged 65 years and over were 3.6 (95% CI = 2.7-4.9) times more likely to use
      ambulances than those under 15. Motor vehicle traffic injuries and hip fractures
      were also associated with ambulance usage, while arm fractures and farm-related
      injuries were not. We conclude that for major/fatal injuries, older persons,
      those injured from high velocity causes, and those with hip fractures are more
      likely to use an ambulance. Emergency Medical Services may improve the
      community's ambulance utilization by providing public education (e.g., proper use
      of 911 and injury severity recognition), and by collaborating with dispatch, the
      local community and health care providers. Further study of the community's and
      individuals' decision-making factors determining mode of transportation is
      needed.

PMID- 12609652
TI  - How far is that by air? The derivation of an air: ground coefficient.
AB  - The objective of this study was to derive a simple equation to convert distances
      between air miles traveled by a helicopter and ground miles traveled by an
      ambulance. We performed a retrospective analysis of a convenience sampling of 245
      "lights and sirens" ground ambulance transports between 1993 and 1997. Ground
      distances were recorded from odometer miles for each transport. Air miles were
      calculated using the Global Positioning System (GPS), measuring the distance in a
      straight line from the scene to the hospital. Air and ground distances were
      entered into a computerized spreadsheet, and the correlation coefficient and
      regression equation were derived. A simple approximation equation was developed
      and compared against the derived regression equation. There was a strong linear
      correlation between ground miles and air miles at virtually all distances studied
      (R = 0.932, R(2) = 0.869). Regression analysis revealed the following
      relationship: Ground miles = 0.94 + 1.25 (air miles). This was simplified to an
      approximation of: Ground miles = 1.3 (air miles). The approximation equation
      yielded an answer within 1 mile of the regression equation for distances up to 40
      air miles. It is concluded that in a mixed rural and urban EMS system, one may
      convert air and ground mileage estimates by using the simple relationship: Ground
      miles = 1.3 (air miles). This conversion coefficient may prove useful for EMS
      personnel in designing reasonable helicopter utilization policies, making
      accurate transport decisions and conducting research.

PMID- 12609653
TI  - Emergency medicine bedside ultrasound diagnosis of intussusception in a patient
      with chronic abdominal pain and unrecognized Peutz-Jeghers syndrome.
AB  - An adult patient presented to the Emergency Department (ED) with abdominal pain
      caused by intussusception. The diagnosis had not been made despite several prior
      evaluations for episodes of similar symptoms. The diagnosis was finally made by
      bedside ultrasound performed by the treating physicians in the ED. The patient's
      underlying condition of Peutz-Jeghers Syndrome with intestinal polyps was also
      previously undiagnosed. The discussion reviews and compares clinical aspects of
      intussusception in adults and children. Sonographic findings of intussusception
      and their pathological basis are described, and the accuracy of sonography in the
      diagnosis of intussusception is reviewed.

PMID- 12609654
TI  - Abdominal pain radiating to the back.

PMID- 12609655
TI  - Bicycle handlebar injury.

PMID- 12609656
TI  - Narrow-complex tachycardia in an elderly patient with presyncope.

PMID- 12609657
TI  - An elderly patient with intussusception.

PMID- 12609658
TI  - Cougar--The cab baby.

PMID- 12609659
TI  - Spontaneous rupture of arteriovenous fistula in a chronic dialysis patient.

PMID- 12609661
TI  - Development of a LC method for pharmaceutical quality control of the
      antimetastatic ruthenium complex NAMI-A.
AB  - Imidazolium trans-tetrachloro(dimethylsulfoxide)imidazoleruthenium(III) (NAMI-A)
      is a novel ruthenium complex with selective activity against metastases currently
      in Phase I clinical trials in the Netherlands. Pharmaceutical quality control of
      NAMI-A drug substance and lyophilized product warranted the development of an
      assay for determination and quantification of NAMI-A and degradation products. A
      high performance liquid chromatography (HPLC) method was developed, consisting of
      a C18 column with 0.50 mM sodium dodecylsulfate in 3% methanol at pH 2.5
      (acidified using trifluoromethanesulfonic acid) as the mobile phase and UV
      detection at 358 nm. The HPLC method was proven to be linear, accurate and
      precise. Stress testing showed that degradation products were separated from the
      parent compound. By combining results of nuclear magnetic resonance (NMR) and
      HPLC experiments, one degradation product was identified as the mono-hydroxy
      species of NAMI-A. HPLC analysis with off-line detection of the eluate with
      flameless atomic absorption spectrometry (F-AAS) showed that under most
      conditions, all ruthenium-containing compounds show a peak in the HPLC
      chromatogram and that all ruthenium applied to the column is recovered
      quantitatively. For completely degraded solutions of NAMI-A some ruthenium is
      retained on the column. Suitability of the HPLC method for the pharmaceutical
      quality control of NAMI-A lyophilized product was demonstrated.

PMID- 12609662
TI  - Spectrophotometric and chromatographic determination of rabeprazole in presence
      of its degradation products.
AB  - Three methods were presented for the determination of rabeprazole (RA) in
      presence of its degradation products. The first method was based on high
      performance liquid chromatographic (HPLC) separation of RA from its degradation
      products on a reversed phase, ODS column using a mobile phase of methanol-water
      (70:30, v/v) and UV detection at 284 nm. The second method was based on HPTLC
      separation followed by densitometric measurement of the spots at 284 nm. The
      separation was carried out on Merck HPTLC sheets of silica gel 60 F 254, using
      acetone-toluene-methanol (9:9:0.6 v/v) as mobile phase. The third method depends
      on first derivative of the ratio spectra (1DD) by measurement of the amplitudes
      at 310.2 nm. Moreover, the proposed HPLC method was utilized to investigate the
      kinetics of the oxidative and photo degradation processes. The pH-rate profile of
      degradation of RA in Britton-Robinson buffer solutions within the pH range 3-11
      was studied. In addition, the activation energy of RA degradation was calculated
      in Britton-Robinson buffer solution pH 7.

PMID- 12609663
TI  - Rapid quantification of the non-competitive NMDA antagonist MK-801 in canine
      cerebrospinal fluid and plasma by capillary gas chromatography-nitrogen
      phosphorus detection.
AB  - A facile and sensitive method utilizing solid-phase cartridge extraction and
      capillary gas chromatography (GC) with nitrogen phosphorus detection was
      validated for the determination of MK-801 [(+)-5-methyl-10,11-dihydro-5H
      dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a non-competitive NMDA receptor
      antagonist, in dog cerebrospinal fluid (CSF) and plasma. Clonidine hydrochloride
      was used as the internal standard (ISTD), after evaluation of several ISTD
      candidates. Separations were performed with an intermediate polarity fused silica
      capillary column, yielding typical retention times of 3.20 min for MK-801 and
      4.90 min for ISTD. Plasma and CSF samples were extracted with 100 mg Bond Elut
      C(18) TCA Copyright cartridges to yield methanolic eluates that were
      evaporatively enriched before reconstitution in anhydrous ethanol prior to
      injection. The standard curve was validated from 1 to 100,000 ng/ml for CSF, and
      from 0.1 to 1,000 ng/ml for plasma. Chromatograms from naive plasma and CSF
      exhibited no endogenous interfering peaks. The efficiency of extraction recovery
      was >94%, and the intra-assay and inter-assay precision was within 9% relative
      standard deviation (%R.S.D.) for both fluids. MK-801 and ISTD were stable in the
      injection solvent at 22 degrees C for at least 48 h. The assay was applied to the
      toxocologic study of intrathecal MK-801 administration in the dog.

PMID- 12609664
TI  - A simultaneous liquid chromatography/mass spectrometric assay of glutathione,
      cysteine, homocysteine and their disulfides in biological samples.
AB  - A liquid chromatography/mass spectrometric (LC/MS) method was developed for
      simultaneous detection and quantitation of glutathione (GSH), glutathione
      disulfide (GSSG), cysteine (CysSH), homocysteine (HCysSH) and homocystine in
      biological samples (rat brain, lung, liver, heart, kidneys, erythrocytes and
      plasma). Thiols were derivatized with a large excess of Ellman's reagent, a thiol
      specific reagent, to ensure an instantaneous and complete derivatization. The
      derivatization blocked the oxidation of the thiols to disulfides, preventing
      errors caused by thiol oxidation. The samples were then analyzed by LC/MS. The
      method provides a highly selective and sensitive assay for these endogenous
      thiols and their corresponding disulfides. The detection limits for GSH, GSSG,
      CysSH, HCysSH and homocystine were 3.3, 3.3, 16.5, 29.6 and 14.9 pmol,
      respectively. An attempt for cystine analysis was unsuccessful due to earlier
      elution of the compound and strong interferences caused by other endogenous
      compounds. This method will be a useful tool in the investigation of the roles of
      these important thiol-containing compounds and their corresponding disulfides in
      physiological and pathological processes.

PMID- 12609666
TI  - Structural studies on the impurities of troglitazone.
AB  - The impurity profile study of troglitazone has been carried out primarily by
      (liquid chromatography-mass spectrometry) LC-MS. Four process-related impurities
      have been detected by LC-MS and were confirmed by co-injection with authentic
      samples. Apart from the process-related impurities, two polar by-products were
      characterized by mass spectral data and comparison with reference samples, while
      one non-polar by-product and one degradation product have been isolated by means
      of preparative HPLC and characterized by 2D NMR and mass spectral study. Single
      crystal X-ray diffraction studies have been carried out on the degradation
      product. The formation and characterization of these by-products and degradation
      product are discussed.

PMID- 12609665
TI  - HPLC method for the analysis of harmol, harmalol, harmine and harmaline in the
      seeds of Peganum harmala L.
AB  - A simple and sensitive method for separation and determination of harmol,
      harmalol, harmine and harmaline has been developed and validated. Harmol,
      harmalol, harmine and harmaline were separated using a Metasil ODS column by
      isocratic elution with flow rate 1.5 ml/min. The mobile phase composition was
      Isopropyl alcohol-Acetonitrile-Water-Formic acid (100:100:300:0.3) (v/v/v/v) and
      pH adjusted 8.6 with triethylamine. Spectrophotometric detection was carried out
      at 330 nm. The linear range of detection for harmol, harmalol, harmine and
      harmaline were between 9.375-250, 30.750-246, 31.250-500 and 31.000-248
      microg/ml, respectively. The method described was suitable for the determination
      of harmol, harmalol, harmine and harmaline in the seeds of Peganum harmala L.

PMID- 12609667
TI  - Quantitation of paclitaxel in micro-sample rat plasma by a sensitive reversed
      phase HPLC assay.
AB  - A sensitive high-performance liquid chromatographic (HPLC) method was developed
      for the determination of paclitaxel in micro-samples of rat plasma in order to
      study the mechanism of enhanced systemic exposure of paclitaxel co-administered
      with P-glycoprotein inhibitors. The assay involved solid-phase extraction
      procedures using 2'-methylpaclitaxel as the internal standard. Chromatographic
      separations were achieved using a ZORBAX ODS C18 column and mobile phase
      consisting of acetonitrile, methanol and ammonium acetate buffer (10 mM, pH 5.0)
      (48.5:16.5:35) pumped at 0.8 ml/min. The effluents were measured for UV
      absorption at 227 nm, with retention times of 8.5 and 11.0 min for paclitaxel and
      2'-methylpaclitaxel, respectively. The chromatographic separation was excellent,
      with no endogenous interference. The standard curves showed a good linearity
      (r=0.9994) over the concentration ranges of 10-1,000 ng/ml. At 1,000 ng/ml, the
      absolute recoveries of paclitaxel and 2'-methylpaclitaxel are 89 and 90%,
      respectively. The intra- and inter-day variabilities of paclitaxel were both less
      than 15%. This validated method for the assay of paclitaxel in micro-sample rat
      plasma made it feasible to study the pharmacokinetics of the drug in a single
      rat.

PMID- 12609668
TI  - LC determination of salinomycin in fermentation broths and premixes.
AB  - A simple and rapid high performance liquid chromatography method for the
      determination of salinomycin in fermentation media of Streptomyces albus strains
      and in premixes has been developed. This method involves reverse-phase separation
      of the component analysed with UV detection at 210 nm using methanol and 0.2 M
      acetate buffer pH 5.8 (100:10, v/v) as the mobile phase. The reliability of the
      method was confirmed by validation. A linear relationship was obtained within
      range 0.2-2.0 mg ml(-1) (r=0.9999). The relative standard deviation of methods
      within-laboratory reproducibility was 1.6%. The estimated quantitation limit of
      assay was about 32.5 microg ml(-1). The method has been successfully used in the
      determination of salinomycin content in testing production processes and premixes
      of different commercial brands.

PMID- 12609669
TI  - Investigation of structure and enantioselectivity of BSA-encapsulated sol-gel
      columns prepared for capillary electrochromatography.
AB  - We have developed a protein-encapsulation technique using sol-gels for the
      preparation of monolithic capillary columns for capillary electrochromatography.
      Due to the silica-based matrix used, this hydrogel generates the appropriate
      electroosmotic flow. Electroosmotic mobility varied according to the gels
      fabricated under the different gelation conditions and using different starting
      materials. Using attenuated total reflectance (ATR)-FT-IR, the residual silanol
      groups in each hydrogels could be measured without drying procedures and it was
      found that electroosmotic mobility decreased with a reduction in the residual
      silanol groups. Enantiomeric separation of D,L-Trp was evaluated using bovine
      serum albumin (BSA)-encapsulated column. Preparatory conditions for BSA
      encapsulated columns also influenced the retention time and enantioselectivity of
      D,L-Trp. The gels composed of clusters with the diameter of around 1 microm.
      According to ATR-FT-IR study, BSA maintained its structure after encapsulation in
      the gel.

PMID- 12609670
TI  - Direct separation and quantitative determination of clenbuterol enantiomers by
      high performance liquid chromatography using an amide type chiral stationary
      phase.
AB  - Enantiomers of clenbuterol were directly separated by a new high performance
      chromatographic method on Chirex 3005 column. Several parameters such as mobile
      phase composition, column temperature and flow rate were studied. Baseline
      enantioseparation was achieved, using the optimized mobile phase of n-hexane-1,2
      dicholoethane-methanol (54:38:8, v/v/v) at 17 degrees C and 1.0 ml/min, with the
      separation factor (alpha) 1.43 and the resolution factor (R(S)) 1.81. The
      mechanism of separation was also discussed. Standard linear calibration cures
      were established for the R- and S-enantiomers, over the range of 26.1-1,045.8 and
      5.7-229.6 nmol/ml, with the correlation coefficient of 0.9999 for both. The
      limits of detection were 0.47 and 1.04 nmol/ml for R- and S-enantiomers,
      respectively. Recovery and precision of the method were also evaluated, which had
      been successfully used to monitor and identify quantitatively the profile of the
      clenbuterol enantiomers in human serum.

PMID- 12609671
TI  - HPLC for in-process control in the production of sultamicillin.
AB  - A high-performance liquid chromatographic assay coupled with UV detection (215
      nm) was developed for the determination of sultamicillin and its synthesis
      precursors. The separation of the analytes was performed on a Kromasil C(18)
      column (15 cm x 4.6 mm i.d., 5 microm) at 20 degrees C. The mobile phase (25 mM
      phosphate buffer, pH 7.0 and acetonitrile 48%) was pumped at a flow rate of 1.0
      ml min(-1). This method is sensitive (limits of detection ranged between 0.4 and
      1.2 mg l(-1)) and selective for the determination of sultamicillin and could be
      used for monitoring different synthetic routes.

PMID- 12609673
TI  - Sensitive determination of oxybutynin and desethyloxybutynin in dog plasma by LC
      ESI/MS/MS.
AB  - A sensitive and selective liquid chromatographic method coupled with tandem mass
      spectrometry (LC-MS/MS) was developed for the quantification of oxybutynin and
      desethyloxybutynin in dog plasma. Diazepam was used as internal standard, with
      plasma sample extracted using n-hexane and back-extracted using hydrochloric
      acid. A centrifuged lower layer (aqueous layer) was injected into a C(18) XTerra
      MS column (2.1 x 30 mm(2)) with 3.5 microm particle size. The analytical column
      lasted for at least 500 injections. The mobile phase was composed of 90%
      methanol, with flow rate at 200 microl/min. The mass spectrometer was operated in
      positive ion mode using electrospray ionization. Nitrogen was used as the
      nebulizer gas and argon was used as the collision gas. Using MS/MS with multiple
      reaction monitoring (MRM) mode, oxybutynin and desethyloxybutynin were detected
      without severe interferences from plasma matrix. Oxybutynin produced a protonated
      precursor ion ([M+H](+)) at m/z 358 and a corresponding product ion at m/z 142.
      Desethyloxybutynin produced a protonated precursor ion ([M+H](+)) at m/z 330 and
      a corresponding product ion at m/z 96. And internal standard (diazepam) produced
      a protonated precursor ion ([M+H](+)) at m/z 285 and a corresponding product ion
      at m/z 193. Detection of oxybutynin and desethyloxybutynin in dog plasma were
      accurate and precise, with detection limit at 0.1 ng/ml. This method has been
      successfully applied to a study of oxybutynin and desethyloxybutynin in dog
      plasma.

PMID- 12609672
TI  - Simultaneous determination of hydrochlorothiazide and several angiotensin-II
      receptor antagonists by capillary electrophoresis.
AB  - We have investigated the capability of the capillary zone electrophoretic (CZE)
      and micellar electrokinetic capillary chromatographic (MEKC) methods to
      simultaneously separate hydrochlorothiazide and six angiotensin-II-receptor
      antagonists (ARA-IIs): candesartan, eprosartan mesylate, irbesartan, losartan
      potassium, telmisartan, and valsartan. The CZE and MEKC methods are suitable for
      the qualitative and quantitative determination of combined HCT/ARA-IIs in
      pharmaceutical formulations. Depending on the ARA-II, at least one of the two
      methods can be used for each combination. The two methods have been validated in
      terms of their linearity of response, reproducibility, and accuracy.

PMID- 12609674
TI  - Potential of capillary electrophoresis for the monitoring of the stability of
      placental alkaline phosphatase.
AB  - Alkaline phosphatase (AP) is a potential therapeutic agent in the treatment of
      sepsis. In this paper the potential of capillary zone electrophoresis (CZE) for
      the monitoring of the degradation of placental alkaline phosphatase (PLAP) was
      investigated. To induce degradation PLAP samples were exposed to high
      temperatures, low and high pH and freeze-drying. The samples were then analyzed
      by CZE and enzymatic activity assay. Upon exposure to temperatures above 65
      degrees C, PLAP lost its activity exponentially over time, while CZE revealed
      both a linear decrease of the area of the main peak and a rise of degradation
      products. At acidic pH the enzyme appeared to lose its activity. CZE revealed a
      decrease of the area of the main peak, but no degradation products could be
      detected. At pH 12 the enzymatic activity and the area of the main peak both
      decreased linearly over time and, in addition, formation of degradation products
      could be detected by CZE. Activity and CZE profile of PLAP remained unchanged
      upon freeze-drying in the presence of inulin. Prolonged storage of freeze-dried
      samples at room temperature caused a slight decrease of enzymatic activity, while
      the potential formation of oligomers was revealed by CZE analysis. The examples
      in this study show that, in combination with activity assays, CZE can provide
      useful complementary information, especially on the status of the protein and the
      presence of degradation products.

PMID- 12609675
TI  - Simultaneous determination of montelukast and loratadine by HPLC and derivative
      spectrophotometric methods.
AB  - In this study, high performance liquid chromatography (HPLC) and second
      derivative spectrophotometry have been used and described for the simultaneous
      determination of montelukast and loratadine in pharmaceutical formulations. HPLC
      separation was achieved with a Symmetry C18 column and sodium phosphate buffer
      (pH adjusted to 3.7): acetonitrile (20:80, v/v) as eluent, at a flow rate of 1.0
      ml/min. UV detection was performed at 225 nm. The LC method is simple, rapid,
      selective and stability indicating for the determination of montelukast. 5-Methyl
      2-nitrophenol was used as internal standard for the purpose of quantification of
      both the drugs in HPLC. In the second-order derivative spectrophotometry, for the
      determination of loratadine the zero-crossing technique was applied at 276.1 nm,
      but for montelukast peak amplitude at 359.7 nm (tangent method) was used. Both
      methods were fully validated and a comparison was made for assay determination of
      selected drugs in formulations. The results confirm that the methods are highly
      suitable for its intended purpose.

PMID- 12609676
TI  - Effect of nicotinamide on the photolysis of cyanocobalamin in aqueous solution.
AB  - The photolysis of cyanocobalamin by visible light in the presence of nicotinamide
      at pH 1.0-7.0 has been studied. The second-order rate constants for the
      bimolecular interaction of these vitamins have been determined which vary from
      9.50 x 10(-3) (pH 1.0) to 1.25 x 10(-3) M(-1) min(-1) (pH 7.0). The rate-pH
      profile indicates a gradual slow decrease in rate in the pH range 1-3 followed by
      a relatively fast decrease in the pH range 3-7. The protonated form of
      cyanocobalamin appears to be more susceptible to photolysis than the non-ionised
      form. Cyanocobalamin photolysis leads to the formation of hydroxocobalamin at pH
      1.0-7.0.

PMID- 12609677
TI  - Evaluation of stability of enalapril maleate in solid phase.
AB  - The influence of temperature (from 383 to 348 K) and relative humidity (from 25.0
      to 76.4%) on the stability of enalapril maleate in the solid phase was
      investigated. Changes in the concentration enalapril maleate were followed by a
      HPLC method with UV detection. The kinetic and thermodynamic parameters [E(a) (kJ
      mol(-1))=168.5+/-27 for RH=0% and 149.1+/-48 for RH=76.4%; deltaH(not equal ) (kJ
      mol(-1))=166.1+/-30 for RH=0% and 146.6+/-50 for RH=76.4%; deltaS(not equal) (J
      (K(-1) mol(-1)))=120.3+/-169 for RH=0% and 82.1+/-110 for RH=76.4%) of the
      decomposition reaction were calculated.

PMID- 12609679
TI  - Method development and validation for the analysis of meloxicam in tablets by
      CZE.
AB  - A capillary zone electrophoresis assay for the analysis of meloxicam has been
      developed and validated. The influence of buffer concentration, buffer pH,
      methanol as organic modifier, capillary temperature, applied voltage and
      injection time was systemically investigated in a fused silica capillary (i.d. 50
      microm, total length 44 cm and effective length 35.5 cm). Optimum results were
      obtained with a 100 mM borate buffer (pH 8.5) containing 5% methanol, capillary
      temperature 25 degrees C, applied voltage 20 kV and injection time 3 s
      hydrodynamic injection. The detection wavelength was set to 205 nm. Diflunisal
      was used as internal standard. The method showed good selectivity, accuracy,
      precision, linearity and sensitivity according to the evaluation of the
      validation parameters. The method was applied to the determination of six
      pharmaceutical preparations including two dosage forms. The relative standard
      deviation of 7 replicate analyses for each sample was less than 0.66%. The
      results were compared with a spectrophotometric method reported in literature and
      no significant difference was found statistically.

PMID- 12609678
TI  - Validated spectrophotometric methods for the determination of amlodipine besylate
      in drug formulations using 2,3-dichloro 5,6-dicyano 1,4-benzoquinone and ascorbic
      acid.
AB  - Two simple and sensitive spectrophotometric methods have been proposed for the
      determination of amlodipine besylate either in pure form or in pharmaceutical
      formulations. The first method is based on the charge transfer complexation
      reaction of the drug with 2,3-dichloro 5,6-dicyano 1,4-benzoquinone (DDQ) to give
      coloured product having maximum absorbance at 580 nm. The second procedure
      depends on the measurement of purple red colour produced by the interaction of
      drug with ascorbic acid in N,N-dimethylformamide medium (DMF) which absorbed
      maximally at 530 nm. Under the optimized experimental conditions, Beer's law was
      obeyed in the concentration ranges of 1-125 and 10-140 microg ml(-1) with DDQ and
      ascorbic acid, respectively. Both the methods were applied successfully for the
      analysis of amlodipine besylate in dosage forms. Results of analyses were
      validated statistically and through recovery studies.

PMID- 12609680
TI  - Analysis of adulterants in a traditional herbal medicinal product using liquid
      chromatography-mass spectrometry-mass spectrometry.
AB  - Adulterations with synthetic drugs are common problems with herbal medicine and
      this can potentially cause serious adverse effects. It is therefore important to
      determine the presence of synthetic drugs in herbal medicine to ensure patients'
      safety. The objective of this study was to develop sensitive and specific methods
      to analyse phenylbutazone, caffeine and oxyphenbutazone present in a traditional
      Indonesian herbal product. Liquid chromatography-mass spectrometry-mass
      spectrometry (LC-MS-MS) methods in the selected reaction-monitoring (SRM) mode
      were developed. It was found that the sample contained 0.53% w/w (n=3, RSD=7.56%)
      phenylbutazone and 0.04% w/w (n=3, RSD=8.39%) caffeine. This corresponded to
      43.17 mg phenylbutazone and 3.23 mg caffeine in each sachet of powder. The
      methods were validated for linearity, precision, accuracy, LOD and LOQ. LOD and
      LOQ were found to be 3.69 and 12.29 ng/ml, respectively for phenylbutazone. For
      caffeine, the LOD and LOQ were 0.84 and 2.80 ng/ml, respectively. Oxyphenbutazone
      in the sample was found to be present at a level below the quantification level
      of 10.2 ng/ml. With better methods developed for analysis of adulterants in
      herbal medicine, the quality and safety of these medicines can be better
      controlled and regulated to ensure patients' safety.

PMID- 12609681
TI  - Development and evaluation of NucliSens basic kit NASBA for diagnosis of
      parainfluenza virus infection with 'end-point' and 'real-time' detection.
AB  - New methods for the detection of human parainfluenza viruses (HPIVs) were
      developed. These were based on nucleic acid sequence-based amplification (NASBA)
      and utilised the NucliSens Basic Kit. Primers and probes were selected from the
      haemagglutinin neuraminidase (HN) gene of HPIV1, HPIV2 and HPIV3, and from the
      phosphoprotein (P) of HPIV4a and -4b. Synthetic RNA, titrated control virus
      stocks and respiratory specimens (n=44) were utilised to evaluate performance of
      the assays. Detection of NASBA products was by probe hybridisation and
      electrochemiluminescence (ECL) ('end-point' detection) or using molecular beacons
      ('real-time' detection). The assays using ECL detection proved to be both
      sensitive and specific. Typically, less than or equal to 100 RNA copies or one
      TCID(50) input was detectable with no cross-reaction between the specific HPIV
      assays and other respiratory viruses. Results for clinical samples were
      concordant with those obtained by 'conventional' procedures by classical viral
      diagnostic methods. 'Real-time' detection utilised probes specific for either
      HPIV1 or HPIV3 with similar performance characteristics to the assays with 'end
      point' detection. The feasibility of multiplexing targets together was confirmed
      using a combined HPIV1 and HPIV3 assay with good results for ECL and molecular
      beacon detection on control material and clinical samples.

PMID- 12609682
TI  - Detection of type and subtypes of influenza virus by hybrid formation of FRET
      probe with amplified target DNA and melting temperature analysis.
AB  - Fluorescence resonance energy transfer probes were selected for three sets of
      reverse transcription -polymerase chain reaction (RT-PCR), each in duplex format
      to detect: (1). Influenza virus type A or B; (2). Neuraminidase subtypes N1 or
      N2; and (3). Hemagglutinin subtypes H1 or H3 using LightCycler Instrument. A pair
      of probes targeted a type or subtype specific RT-PCR amplified gene segment. The
      presence of a target in a set of amplification reaction was detected by increased
      fluorescence over background emitted from the appropriate reporter fluorophore on
      probe-target hybrid formation and by melting temperature (T(m)) analysis of probe
      target hybrid. The T(m) of a probe-target in a duplex amplification was
      distinctly different from the other, and thus T(m) value allowed specific
      detection of a target. Amplified product in each set of amplification was also
      examined by conventional agarose gel electrophoresis. The sensitivities of
      detection by fluorescence signal analysis were equal or ten times better than
      that detected by agarose gel electrophoresis.

PMID- 12609683
TI  - Comparative evaluation of four large-volume RNA extraction kits in the isolation
      of viral RNA from water samples.
AB  - The quality of the RNA extraction system plays a crucial role for the detection
      of viruses in water or environmental samples. In the present study we
      investigated the detection limit, the efficiency and the presence of eventually
      co-extracted inhibitors by comparing four commercially available large scale
      (>or=1 ml) viral RNA extraction methods (QIAamp Viral RNA Mini Kit in combination
      with preconcentration by Centricon YM-100 [Centricon-QIAamp], QIAamp UltraSens
      Virus Kit, NucliSens Isolation Kit and NucleoSpin RNA Virus F). A 1 ml 50 mM
      glycine (pH 8.0) containing 1% beef extract was spiked with different
      concentrations of poliovirus vaccine strains, extracted by the four methods and
      analysed by RT-nested PCR or RT-quantitative LightCycler PCR. Eight replicates
      were analysed for each concentration on different days. The positive cut-off
      point was determined to be at 0.25 CCID(50) per ml (Centricon-QIAamp), 1.46
      CCID(50) per ml (UltraSens), 0.4 CCID(50) per ml (NucliSens) and 3.03 CCID(50)
      per ml (NucleoSpin). Quantitative analysis (LightCycler) of a high-titer sample
      showed significant differences between the efficiencies of the four extraction
      methods examined. The efficiencies of the extraction methods were normalized to
      the NucliSens method as follows: (71% Centricon-QIAamp, 18% UltraSens, 100%
      NucliSens and 23% NucleoSpin). In addition, spiked negative controls did show
      significant differences, indicating a co-extraction of inhibitors. Compared with
      the non-inhibited positive control the inhibitions were 21, 37, 27 and 68% for
      the Centricon-QIAamp, UltraSens, NucliSens and NucleoSpin methods, respectively.
      Taken together, these findings indicate that of the four evaluated extraction
      methods both the NucliSens and Centricon-QIAamp are best suited to extract viral
      RNA from water samples previously concentrated and have shown to be very
      sensitive, efficient and robust methods.

PMID- 12609684
TI  - Enzyme-linked immunosorbent assay using recombinant antigens expressed in
      mammalian cells for serodiagnosis of tick-borne encephalitis.
AB  - A recombinant plasmid that expresses the tick-borne encephalitis (TBE) virus
      premembrane (prM) and envelope (E) proteins in mammalian cells was constructed.
      Recombinant proteins retained antigenic and conformational structures similar to
      those of native virus proteins, and transfected cells released virus-like
      particles (VLPs), which were 1.13-1.14 g/ml in density and 20-30 nm in diameter,
      into the culture medium. Recombinant E proteins were used for the development of
      an enzyme-linked immunosorbent assay (ELISA) to detect TBE virus-specific IgM and
      IgG antibodies in serum. The results of this ELISA correlated well with the
      results of commercial ELISA, when tested with 95 serum samples from clinically
      TBE-suspected patients. In addition, ELISA using recombinant antigens showed no
      cross-reactivity against serum from Japanese encephalitis (JE) patients, despite
      the cross-reactivity shown by commercial ELISA systems. These observations
      indicated that this newly developed ELISA system could distinguish tick-borne
      encephalitis from Japanese encephalitis infection, and that it constitutes a
      useful and safe alternative to conventional ELISA systems.

PMID- 12609685
TI  - Detection of potato viruses using microarray technology: towards a generic method
      for plant viral disease diagnosis.
AB  - Currently, most diagnostic methodology is geared towards detection of a very
      specific target species and often a number of assays need to be run in parallel
      to reach a result. The generic methods that are available for virus testing tends
      to give identification to the genus level only. The method described in this
      paper addresses this problem by exploiting a technology that has potential to
      test for a large number of targets in a single assay. Using the array
      constructed, the method was able to detect several common potato viruses (PVY,
      PVX, PVA, PVS) in single and mixed infections. The method was shown to be able to
      discriminate sequences with less than 80% sequence identity but was able to
      detect sequence variants with greater than 90% sequence identity. Thus the method
      should be useful for discriminating at the species level, but able to cope well
      with the intrinsic variability found within the genomes of RNA viruses. The
      sensitivity of the assay was found to be comparable with ELISA. The paper
      illustrates a significant step forward in the development of diagnostic
      methodologies by presenting for the first time a method that could theoretically
      be used not just for viruses, but for all the plant pathogens and pests that a
      modern diagnostic laboratory would want to test for, in a single completely
      generic and highly parallel format.

PMID- 12609686
TI  - Comparison of a microtiter plate system to Southern blot for detection of human
      herpesvirus 8 DNA amplified from blood and saliva.
AB  - The recent discovery of human herpesvirus 8 (HHV-8) as the etiologic agent of
      Kaposi's sarcoma (KS) has led to the interest in the development of PCR for this
      virus that is accurate, rapid, and convenient. We developed a sensitive PCR assay
      for HHV-8 with microtiter plate detection of amplimers. DNA was purified from
      white blood cells and saliva from HIV-infected men with and without Kaposi's
      sarcoma and one-step PCR was undertaken with primer sets specific for the N
      terminal region of the glycoprotein B gene and open reading frame (orf) 26 of HHV
      8. PCR was performed on 40 clinical specimens, followed by Southern blot and
      microtiter plate detection of amplimers. Results from the two methods of
      detection were nearly identical. Sensitivity for both methods based on serial
      dilution of a known standard was five to ten copies of HHV-8 per 400 ng of
      cellular DNA. In conclusion, microtiter plate detection of HHV-8 PCR amplimers is
      as sensitive and specific as Southern blot with much faster turnaround time at
      comparable cost, and utilizes common laboratory equipment.

PMID- 12609687
TI  - Establishment of an in vitro assay system mimicking human immunodeficiency virus
      type 1-induced neural cell death and evaluation of inhibitors thereof.
AB  - Human immunodeficiency virus type 1 (HIV-1)-associated central nervous system
      disorders, including encephalopathy, often occur in the late stage of HIV-1
      infection. Some inflammatory cytokines and HIV-1 antigens released from infected
      microglia or brain macrophages are considered to play an important role in
      neuropathogenesis. In this study, an in vitro assay system has been established
      for the evaluation of neural cell death, which would be predictive of the
      pathogenesis of neural cell death in vivo. The human neuroblastoma cell line SK-N
      SH was differentiated to a neural phenotype with retinoic acid, while the
      promyelocytic cell line HL-60 and its HIV-1-infected clone OM-10.1 were
      differentiated to macrophages with phorbol myristate acetate. When neural
      (differentiated SK-N-SH) cells were cocultured with either uninfected or HIV-1
      infected macrophages (differentiated HL-60 or OM-10.1 cells, respectively) for 3
      5 days, significant neural cell death was observed in the cells cocultured with
      infected macrophages. Direct contact with macrophages was not necessary for the
      induction of neural cell death, since indirect coculture or coculture
      supernatants could also induce neural cell death. Large amounts of cytokines and
      chemokines were released in the coculture supernatants. The CXCR4 antagonist
      AMD3100 and the HIV-1 transcription inhibitor K-37 partially inhibited neural
      cell death. These results indicate that this system seems to be a useful tool for
      the evaluation of compounds against HIV-1-induced neural cell death.

PMID- 12609688
TI  - Inactivation of classical swine fever virus: association of hydrostatic pressure
      and ultraviolet irradiation.
AB  - Reversible pressure-induced disassembly of several viruses has suggested the idea
      of using hydrostatic pressure to suppress virus infectivity. In this study, the
      effects of high hydrostatic pressure and ultraviolet (UV) irradiation were
      investigated on classical swine fever virus (CSFV) in an attempt to eliminate
      residual infectivity. The structural modifications were followed by intrinsic
      fluorescence and biological activity assays. The kinetics of CSFV inactivation
      showed that pressure-induced inactivation was not enough to eliminate viral
      infectivity. However, when pressure was applied in association with UV
      irradiation no infectious focus was observed. The application of these two
      methods against CSFV can be an attractive inactivation strategy for the
      development of a vaccine.

PMID- 12609689
TI  - A one-step RT-PCR and a flow cytometry method as two specific tools for direct
      evaluation of human herpesvirus-6 replication.
AB  - In order to confirm the occurrence of active Human herpesvirus-6 (HHV-6)
      infection, two optimal procedures were developed to detect directly replicating
      virus. MT4 cells and peripheral blood mononuclear cells (PBMCs) infected with two
      different strains (HST and a patient strain GUI) were used. The first method
      consisted of a one-step reverse transcription PCR amplifying a part of the late
      alternatively spliced U100 gene which encode the gp 82-105 viral glycoprotein.
      Two extraction methods and two RT-PCR kits were evaluated, leading to the
      selection of TaKaRa mRNA selective PCR kit. The second procedure consisted in a
      flow cytometry method to analyze the expression of two late viral HHV-6 antigens
      using 7C7 and 10G6 monoclonal antibodies. Four fixation permeabilization
      procedures were compared and the preparation of cells with paraformaldehyde (PFA)
      4% was found to be optimal. Evaluation of these methods was then realized during
      a sequential culture of HST strain on MT4 cells. This kinetic study confirmed
      that Mabs recognized late antigens and demonstrate that the U100 gene splicing
      starts at a late stage of multiplication whereas unspliced forms are detectable
      earlier in the cycle.

PMID- 12609690
TI  - Detection of rhinovirus and enterovirus in upper respiratory tract samples using
      a multiplex nested PCR.
AB  - Human enteroviruses and rhinoviruses are respiratory pathogens whose role in
      acute respiratory infection is underestimated due to the use of diagnostic
      procedures with poor sensitivity. To determine the prevalence of these two
      pathogens in the upper respiratory tract infections, a multiplex procedure was
      developed that both detect and differentiate rhinoviruses and enteroviruses. This
      sensitive procedure allowed the detection of both pathogens from archival
      material (nasal swabs) collected during the previous winters and differentiated
      rhinoviruses from enteroviruses. This procedure can be used to determine the role
      of these pathogens in mild or severe upper respiratory tract infections.

PMID- 12609691
TI  - Cell cycle independent infection and gene transfer by recombinant Sendai viruses.
AB  - A common problem for viral vectors in the field of somatic gene therapy is the
      dependence of an efficient cellular transduction on the cell cycle phase of
      target cells. An optimized viral vector system should therefore transduce cells
      in different cell cycle phases equally to improve transduction efficiencies.
      Recent observations that recombinant Sendai viruses (SeV) can infect a broad
      range of different tissues suggested SeV to be a good candidate for future gene
      therapeutic strategies in which dividing and non-dividing cells have to be
      reached. However, detailed data on the influence of distinct cell cycle phases on
      the infection of SeV or related viruses are missing. We report that
      synchronization of NIH 3T3 cells as well as contact inhibition of human
      fibroblast cells did not exhibit any negative influence on SeV infection rates.
      Furthermore, different attractive target tissues like human umbilical cord
      derived cells or primary human hepatocytes can be reached by SeV efficiently. As
      an important information for further cell cycle studies of paramyxoviruses we
      discovered surprisingly that the DNA polymerase inhibitor aphidicolin (induces a
      G(1)/M arrest) functions as an inhibitor of SeV but not of an adenoviral
      expression vector. In conclusion, the results demonstrate SeV based vector
      particles to be an ideal tool to reach equally cells coexisting in different cell
      cycle phases.

PMID- 12609692
TI  - Hallucinogen persisting perception disorder: what do we know after 50 years?
AB  - 'Flashbacks' following use of hallucinogenic drugs have been reported for
      decades; they are recognized in DSM-IV as 'Hallucinogen Persisting Perception
      Disorder (Flashbacks)', or HPPD. We located and analyzed 20 quantitative studies
      between 1955 and 2001 examining this phenomenon. However, many of these studies
      were performed before operational criteria for HPPD were published in DSM-III-R,
      so they are difficult to interpret in the light of current diagnostic criteria.
      Overall, current knowledge of HPPD remains very limited. In particular (1) the
      term 'flashbacks' is defined in so many ways that it is essentially valueless;
      (2) most studies provide too little information to judge how many cases could
      meet DSM-IV criteria for HPPD; and consequently (3) information about risk
      factors for HPPD, possible etiologic mechanisms, and potential treatment
      modalities must be interpreted with great caution. At present, HPPD appears to be
      a genuine but uncommon disorder, sometimes persisting for months or years after
      hallucinogen use and causing substantial morbidity. It is reported most commonly
      after illicit LSD use, but less commonly with LSD administered in research or
      treatment settings, or with use of other types of hallucinogens. There are case
      reports, but no randomized controlled trials, of successful treatment with
      neuroleptics, anticonvulsants, benzodiazepines, and clonidine. Although it may be
      difficult to collect large samples of HPPD cases, further studies are critically
      needed to augment the meager data presently available regarding the prevalence,
      etiology, and treatment of HPPD.

PMID- 12609693
TI  - Sensation seeking as a common factor in opioid dependent subjects and high risk
      sport practicing subjects. A cross sectional study.
AB  - OBJECTIVE: Animal research has outlined a vulnerability trait to drug dependence
      like behavior. The behavioral characteristic of this vulnerability is
      hyperactivity in response to a novel environment of which sensation seeking (SS)
      has been suggested as a possible equivalent in humans. If this is the case, SS
      should be more frequent in drug dependent and risky sports practicing subjects
      then controls. The objective of this study was to determine if opioid dependent
      subjects (ODS) and regular paragliders (RP) would be more SS then normal
      controls. DESIGN: Cross sectional study. PARTICIPANTS: Three groups of 34
      individuals (total 102) matched for age and sex were selected from ODS seeking
      treatment, a paragliding club, and a college staff. MAIN OUTCOME MEASURES: Global
      and sub-scores of the Zuckerman sensation seeking scale (SSS). RESULTS: Non
      parametric statistics (Kruskal Wallis and Wilcoxon 2-Sample Tests) were used
      given the non-normal distribution of SSS scores in the ODS and RP groups.
      Significant differences were found across the three groups for the Thrill and
      Adventure Seeking (TAS) (P = 0.001), dishinibition (Dis) (P = 0.0003) and total
      score (P = 0.001). ODS and RP scored significantly higher than controls on two
      (Dis and the TAS scales). RP also scored significantly higher on the Boredom
      Susceptibility (BS) scale (P = 0.04). CONCLUSION: Our results show that RP and
      ODS differ from controls and have some similarities based on the SSS. In this
      study, the ODS and the RP could express different forms of a general tendency to
      seek intense and abrupt sensations through various behaviors. Our results in
      humans are in favor of the hypothesis that the behavioral trait of vulnerability
      to drug dependence behavior is expressed through SS.

PMID- 12609694
TI  - Substance abuse treatment need among older adults in 2020: the impact of the
      aging baby-boom cohort.
AB  - BACKGROUND: There is concern that as the baby boom population ages in the US,
      there will be a substantial increase in the number of older adults needing
      treatment for substance abuse problems. To address this concern, projections of
      future treatment need for older adults (defined as age 50 and older) were made.
      METHODS: Using data from the National Household Survey on Drug Abuse, regression
      models including predictors of treatment need in 2000 and 2001 were developed.
      Treatment need was defined as having a DSM-IV alcohol or illicit drug use
      disorder in the past year. Regression parameters from these models were applied
      to the projected 2020 population to obtain estimates of the number of older
      adults needing treatment in 2020. RESULTS: The number of older adults in need of
      substance abuse treatment is estimated to increase from 1.7 million in 2000 and
      2001 to 4.4 million in 2020. This is due to a 50 percent increase in the number
      of older adults and a 70 percent increase in the rate of treatment need among
      older adults. CONCLUSIONS: The aging baby boom cohort will place increasing
      demands on the substance abuse treatment system in the next two decades,
      requiring a shift in focus to address the special needs of an older population of
      substance abusers. There is also a need to develop improved tools for measuring
      substance use and abuse among older adults.

PMID- 12609695
TI  - The Kreek-McHugh-Schluger-Kellogg scale: a new, rapid method for quantifying
      substance abuse and its possible applications.
AB  - The new Kreek-McHugh-Schluger-Kellogg scale ('KMSK scale') is designed to
      quantify self-exposure to opiates, cocaine, alcohol, and/or tobacco. Each section
      of the KMSK scale assesses the frequency, amount, and duration of use of a
      particular substance during the individual's period of greatest consumption. The
      scale also assesses the mode of use, whether the substance use is current or
      past, and whether each substance is the substance of choice. The administration
      time is under 5 min. In an initial validation study of this scale, 100 human
      subjects were administered the KMSK scale concurrently with the Structured
      Clinical Interview for DSM-IV (SCID-I DSM-IV version). The sensitivity and
      specificity were very good for opiates, cocaine, and alcohol use. In addition,
      the correlations between KMSK scores and the number of SCID-I criteria items met
      were excellent for opiates and cocaine and good for alcohol use. Nicotine
      dependence was not assessed in this study as there is no SCID-I nicotine
      criteria. These preliminary results show that the KMSK scale may have both
      construct validity similar to that of other established self-report measures and
      the potential to be an effective screening instrument for the assessment of a
      lifetime diagnosis of alcohol, opiate, or cocaine dependence.

PMID- 12609696
TI  - Genetic and environmental risk factors for the onset of drug use and problems in
      adoptees.
AB  - Applying survival analysis methodology to age-of-onset data from an adoption
      study (N = 196), we present evidence that risks for both drug use and drug
      problems (DSM abuse or dependence) are elevated when combined antisocial
      personality (ASP) and substance abuse is present in the same biological parent.
      It is increased not only in comparison to adoptees with no known biological risk,
      but also when compared to adoptees with a biological background for only
      substance problems or only ASP. Neither of these later groups showed a
      statistically higher risk when compared with controls. Among adoptees with
      recurrent drug use, adolescent aggressivity is also elevated when the combined
      substance abuse/ASP biological diathesis is present. Statistical control for
      aggressivity diminished but did not eliminate the predictive significance of the
      combined biological diathesis for drug problems. We also verify, using more
      refined methodology, our previous reports of gender and adverse adoptive
      environmental influences on drug-related outcomes in these subjects. We could not
      document a biology-environment interaction, but power to do so was rather low. We
      argue that the observed biological associations are broadly consistent with
      generalization to other substances of an alcoholism phenotype similar to
      Cloninger's Type II or Babor's Type B.

PMID- 12609697
TI  - Postmarketing surveillance of abuse liability of sibutramine.
AB  - The abuse liability of medications is a growing concern as the number of newly
      approved psychoactive medications increases. Postmarketing surveillance can
      assist in determining abuse liability, but strategies are not well-defined for
      medications believed to be at low abuse risk. Using a newly approved medication
      (sibutramine--an anorectic drug), a novel approach to postmarketing abuse
      surveillance was introduced. A one-page anonymous questionnaire covering
      sibutramine, a scheduled anorectic drug (phentermine), and a fabricated name was
      added to the intake process of 58 treatment programs. From the 8780 completed
      questionnaires, 8.8% had heard of sibutramine and phentermine. For continued use
      to get high (a proxy for abuse), the rate for sibutramine was lower than for
      phentermine (0.6 vs. 2.2%, McNemar's chi(2) = 110.45, P < 0.001) but was higher
      than for the fabricated name (0.6 vs. 0.3%, McNemar's chi(2) = 11.86, P < 0.001).
      These results suggest the risk of abuse associated with sibutramine was lower
      than that associated with a known abused drug, one that itself is considered low
      risk despite decades of population exposure. The relatively high rate of hearing
      of sibutramine may be due to the direct-to-consumer advertisement. This approach
      is only one indicator in a surveillance framework but appears promising and
      validates findings from laboratory-based abuse liability studies that also
      indicate low abuse liability for sibutramine.

PMID- 12609698
TI  - Intravenous use of prescribed sublingual buprenorphine tablets by drug users
      receiving maintenance therapy in France.
AB  - BACKGROUND: In 1996, sublingual buprenorphine was authorized for prescription in
      France for maintenance therapy (MT). MT should facilitate the rehabilitation of
      opioid-dependent drug users and reduce the risks associated with injection.
      However, misuse and side effects have been reported. OBJECTIVES: To assess the
      frequency of buprenorphine injection in 404 subjects on buprenorphine MT and to
      determine the factors associated with the injection of buprenorphine. METHODS: A
      cross-sectional survey was used to collect data from subjects on buprenorphine MT
      seeking treatment from health care networks, specialized structures, a prison and
      a hostel in three different regions of France (1998-1999). Information was
      collected by trained interviewers using a structured questionnaire. RESULTS:
      About half (46.5%) of the subjects on MT (188/404) had ever injected
      buprenorphine; 67.2% of this subgroup had since used both injected and sublingual
      buprenorphine. Variables associated with buprenorphine injection were having
      injected a substance other than buprenorphine (odds ratio (OR): 13.18; 95% CI:
      5.36-32.42), cannabis use (OR: 2.34; 95% CI: 1.51-3.63) and having a source of
      income other than a salary (OR: 1.58; 95% CI: 1.02-2.45) and heroin use (OR:
      0.23; 95% CI: 0.09-0.61). CONCLUSIONS: To decrease buprenorphine injection,
      prescribers of buprenorphine should participate in networks with specialized
      centers, and social and professional rehabilitation programs should be
      implemented for subjects on buprenorphine MT.

PMID- 12609699
TI  - Intravenous opiate maintenance in a cohort of injecting drug addicts.
AB  - BACKGROUND: Drug addiction is a major problem in many societies. The opiate
      maintenance program includes a prospective cohort of injecting drug addicts,
      treated with opiates such as heroin intravenously. An important aim of this
      program is to keep patients under medical supervision in order to reduce the
      health hazards associated with illicit drug consumption. In this paper we report
      the performance of this drug policy in terms of retention and analyse treatment
      withdrawals and hospitalisations. METHODS: Treatment retention was assessed using
      the Kaplan-Meier method (treatment withdrawals were defined as the event of
      interest). We analysed factors associated with treatment withdrawal using Cox
      regression analysis. In addition, we analysed hospitalisations occurring during
      the study period. RESULTS: Of 175 patients included in the study, 76 withdrew
      from the study. Of these, 29 were transferred to a substitution program. The 3
      year probability of remaining in the study was 61.7% (95%CI: 54.8-69.4%). Risk of
      treatment withdrawal was independently associated with age (hazard ratio 0.88
      [95%CI: 0.82-0.95]) and years of intravenous drug use (hazard ratio 1.11 [95%CI:
      1.04-1.18]). No association was found between risk of treatment withdrawal and
      HIV-, Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) serostatus. The
      percentages of HIV, HBV and HCV seroconversions observed during the study period
      were 0.7, 16.2 and 23.3%, respectively. A total of 84 hospitalisations were
      recorded in 49 patients, mainly due to infectious diseases. Hospitalised patients
      were not more likely to withdraw from the program. CONCLUSIONS: Retention is high
      in the intravenous opiate maintenance program and favours the continuation of
      this drug policy. Individuals with a shorter history of injecting drug use and of
      older age are more likely to continue intravenous opiate maintenance treatment.

PMID- 12609700
TI  - Alcohol high risk drinking, abuse and dependence among tobacco smoking medical
      care patients and the general population.
AB  - BACKGROUND: Little is known about the synergies of smoking and alcohol
      consumption in medical care patients. The objective, therefore, is to estimate
      the coincidence of hazardous and harmful alcohol consumption as well as alcohol
      abuse and dependence with tobacco smoking in a general hospital and general
      practices. METHODS: Three samples of 18-64 year olds include 510 consecutively
      admitted currently smoking in-patients of a general hospital, 271 patients of a
      randomized sample of general practices, and 1567 current smokers from a regional
      population in Germany. Data include the number of cigarettes and a diagnosis of
      alcohol dependence and abuse (DSM), harmful or hazardous alcohol use. RESULTS:
      The rates of current daily cigarette smokers with an alcohol dependence or abuse,
      harmful or hazardous alcohol consumption are 47.1% in the general hospital and
      32.1% in the general practice sample compared with 18.4% in the general
      population. The rates increase from nonsmokers to smokers and with the number of
      cigarettes. CONCLUSIONS: The findings fit into the evidence about alcohol and
      tobacco interactions in morbidity and mortality. General medical care settings
      are appropriate for the detection of alcohol dependence or abuse via smoking.

PMID- 12609701
TI  - Brief motivational feedback improves post-incarceration treatment contact among
      veterans with substance use disorders.
AB  - OBJECTIVES: To test the efficacy of providing brief motivational feedback to
      increase post-incarceration substance use disorders (SUD) treatment contact.
      DESIGN: Randomized clinical trial (feedback vs. control) with a 2-month post
      incarceration follow-up. PARTICIPANTS: Veterans (N = 73) incarcerated in a county
      jail system who met SUD diagnostic criteria. MEASURES: Baseline assessment
      included the Addiction Severity Index, the Form-90 assessment of recent alcohol
      use, and a DSM-IV SUD criteria checklist. The primary outcome was Veterans
      Administration (VA) appointments. Secondary outcomes were the Addiction Severity
      Index-Followup and the Treatment Services Review. INTERVENTION: All participants
      received baseline assessment. The feedback condition received personalized
      feedback and encouragement to explore ambivalence about change and treatment in a
      single interview. RESULTS: Participants receiving feedback were more likely to
      schedule appointments at a VA addictions clinic within 60 days of their jail
      release dates (67 vs. 41%; P < 0.03). Though differences were not statistically
      significant, more feedback participants attended addictions clinic appointments
      (47 vs. 32%; ns) and were retained in addictions treatment at 90 days (31 vs.
      14%; P < 0.08). Treatment appointments were more likely when intervention
      occurred close to release. Loss of participants to post-release follow-up
      interviews was >50%, limiting power to detect significant differences by self
      report. CONCLUSION: Brief motivational feedback shows promise as a way to link
      incarcerated individuals to SUD treatment services.

PMID- 12609702
TI  - Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and
      methadone doses.
AB  - We examined in vivo the influence of cytochrome P4503A4 (CYP3A4) activity,
      measured by the 30 min plasma 1'OH-midazolam/midazolam ratio after oral
      administration of 7.5 mg midazolam, on the methadone steady-state trough plasma
      concentrations in a group of 32 patients in methadone maintenance treatment.
      Patients were grouped as receiving 'low' (up to 99 mg/day, n = 10), 'high' (100
      199 mg/day, n = 11) and 'very high' (> or = 200 mg/day, n = 11) doses of
      methadone, and the CYP3A4 metabolic activity was compared between the three
      groups. (S)-methadone and (R,S)-methadone, but not (R)-methadone, concentrations
      to dose ratios significantly correlated with the midazolam ratios (r(2) = -0.17,
      P = 0.018; r(2) = -0.14, P = 0.032; r(2) = -0.10, P = 0.083, respectively), with
      a 76% higher CYP3A4 activity in the very high-dose group as compared with the low
      dose group. Significant differences in the CYP3A4 activity were calculated
      between the three groups (P = 0.0036), and group-to-group comparisons, using the
      Bonferroni correction, showed a significant difference between the low-dose and
      the very high-dose group (P = 0.0039), between the high-dose and the very high
      dose group (P = 0.0064), but not between the low-dose and the high-dose group (P
      = 0.070). The higher CYP3A4 activity measured in patients receiving very high
      methadone doses could contribute to the need for higher doses in some patients,
      due to an increased metabolic clearance. This, however, must be confirmed by a
      prospective study.

PMID- 12609703
TI  - Molecular pathogenesis of bilateral breast cancer.
AB  - Bilateral breast cancer (biBC) offers intriguing possibilities for molecular
      genetic investigations, however it is disproportionally less studied than its
      unilateral counterpart. By now, genetic research has succeeded to resolve at
      least two important aspects of biBC pathogenesis. First, it has been confirmed,
      that the vast majority if not all biBC arise due to clonally independent events
      but not due to contralateral metastatic spread. Second, unselected biBC cases
      have been shown to have a modest prevalence of BRCA germ-line mutations
      (approximately 5%), although a considerable frequency of BRCA defects (up to 20%)
      has been observed in early-onset and/or familial forms of the disease. Other data
      related to biBC appear to be at suggestive stage. Recent reports demonstrate,
      that the tumors forming biBC pair may show similarities of their molecular
      portraits, especially if they develop synchronously. This observations imply that
      the host factors may determine not only the level of breast cancer
      susceptibility, but also the molecular variant of the disease development. Apart
      from this, biBC may serve as a very demonstrative case group in the studies of
      breast cancer predisposing low-penetrance gene polymorphisms, because it is more
      likely to accumulate unfavorable allele combinations than the unilateral
      patients. The utility of this approach has been already exemplified by several
      scientific publications. Further research on the biBC molecular pathogenesis may
      significantly contribute to the general understanding of the process of malignant
      transformation.

PMID- 12609704
TI  - Suppression by iron chelator phenanthroline of sodium chloride-enhanced gastric
      carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.
AB  - The effect of prolonged administration of iron chelator phenanthroline on sodium
      chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N
      nitrosoguanidine, and the labeling and apoptotic indices in the gastric cancers
      was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats
      were given chow pellets containing 10% sodium chloride and intraperitoneal
      injections of phenanthroline at doses of 15 or 30 mg/kg body weight every other
      day. At week 52, feeding of sodium chloride significantly increased the incidence
      of gastric cancers, as compared with the control group. Prolonged injections of
      phenanthroline at both doses significantly reduced the incidence of gastric
      cancers, which was enhanced by oral supplementation with sodium chloride.
      Phenanthroline at both doses significantly decreased the labeling index of
      gastric cancers, which was enhanced by sodium chloride, and significantly
      increased the apoptotic index of gastric cancers, which was lowered by sodium
      chloride. In vitro examination using electron spin resonance revealed that sodium
      chloride promotes the production of hydroxyl radical during Fe(2+) oxidation by
      Fenton's reaction. These findings suggest that enhancement by sodium chloride of
      gastric carcinogenesis may be mediated by hydroxyl radicals.

PMID- 12609705
TI  - Multistage gene expression profiling in a differentially susceptible mouse colon
      cancer model.
AB  - The DNA alkylating agent, azoxymethane (AOM), induces tumor formation in the
      distal colon of susceptible mice. Differential susceptibility to this
      colonotropic carcinogen has been well characterized in A/J (sensitive) and AKR/J
      (resistant) mice. However, the reasons underlying the differential response to
      AOM and the molecular mechanisms involved in colon tumor progression remain
      unclear. To address these issues, we used a cDNA microarray approach to determine
      time-related changes in gene expression patterns in A/J and AKR/J colons
      following carcinogen treatment. In the present study, mice were injected
      intraperitoneally with either AOM (10mg/kg body weight once a week for 6 weeks)
      or 0.9% NaCl solution (vehicle controls). Total RNA was isolated from the distal
      colons at 1, 4, and 24 weeks post-AOM exposure. RNA was reverse transcribed and
      cDNA samples labeled with Cy3 and Cy5 were hybridized to a glass chip containing
      4608 mouse cDNA duplicate clones. The resulting mRNA expression levels were
      analyzed using GLEAMS 3.0, a Unix/Linux-based software program. Genes with more
      than twofold variations in expression levels were considered significant. Further
      clustering analysis was performed based on gene expression patterns at different
      time points using a novel adaptive centroid algorithm (ACA). Of the 4608 genes,
      118 clustered into 11 significant groups that displayed similar and distinct
      expression patterns between the strains following carcinogen treatment. Nine
      clusters were selected for further analysis based on their divergence in response
      between A/J and AKR/J and their potential role in tumorigenesis. Overall, our
      data indicate time- and strain-specific genetic alterations during different
      stages of colon tumorigenesis following AOM treatment.

PMID- 12609706
TI  - Differential roles of 2, 6, and 8 carbon ceramides on the modulation of gap
      junctional communication and apoptosis during carcinogenesis.
AB  - The inhibition of apoptosis and gap junctional intercellular communication (GJIC)
      has been implicated in tumor promotion. Ionizing radiation and oxidative
      toxicants activate sphingomyelinases resulting in the release of ceramides that
      control cell proliferation and apoptosis. A rat liver epithelial cell line
      treated with ceramides containing a 6 (C6) or 8 (C8) carbon acyl-group were
      potent inhibitors of GJIC and apoptosis, whereas a C2-ceramide was only a weak
      inhibitor of GJIC and strong inducer of apoptosis. Apoptosis induced by either
      serum deprivation or C2-ceramide was inhibited by the GJIC inhibitory C8
      ceramide. In conclusion, these results suggest that a chronic release of
      ceramides with acyl groups larger than C6 might act as tumor promoters.

PMID- 12609707
TI  - Lack of initiation activity in rat liver of low doses of 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline.
AB  - It has been generally accepted that genotoxic carcinogens have no threshold in
      exerting their potential for cancer induction. However, the non-threshold theory
      can be challenged for cancer risk assessment in humans. Here we examined low dose
      carcinogenicity of a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8
      dimethylimidazo[4,5-f]quinoxaline (MeIQx), using an in vivo medium-term bioassay
      to detect initiating activity for rat hepatocarcinogenesis. With MeIQx initiation
      at various doses followed by administration of phenobarbital, a well known
      hepatopromoter, no induction of glutathione S-transferase placental form-positive
      foci, assessed as preneoplastic lesions, was noted at doses of 0.001-1 ppm. The
      results imply a no-observed effect level for hepatocarcinogenicity with this
      genotoxic agent.

PMID- 12609708
TI  - Tumor initiating activity of Helicobacter pylori water extract on mouse skin
      carcinogenesis.
AB  - Helicobacter pylori (H. pylori) infection has been associated with gastric
      carcinogenesis, but responsible and detail mechanisms are insufficient by the
      absence of adequate data. To obtain direct evidence regarding the carcinogenicity
      of H. pylori, we investigated the initiating and promoting activity of H. pylori
      water extract (HPE) in two-stage mouse skin carcinogenesis model. HPE treatment,
      as an initiation, significantly enhanced tumor formation compared with control
      group. Moreover, HPE treatment increased production of 8-hydroxydeoxyguanosine in
      epidermal cells and HPE-initiated/TPA-promoted papillomas demonstrated a point
      mutation of the Ha-ras gene. These results suggest an initiating activity of HPE
      on two-stage mouse skin carcinogenesis.

PMID- 12609709
TI  - Chemoprevention of lung carcinogenesis by cacao liquor proanthocyanidins in a
      male rat multi-organ carcinogenesis model.
AB  - The effects of cacao liquor proanthocyanidins (CLPr) on tumorigenesis were
      investigated using a multi-organ carcinogenesis model in male F344 rats receiving
      combined treatment with a single i.p. injection of diethylnitrosamine (100 mg/kg
      body wt), four i.p. injections of N-methylnitrosourea (20 mg/kg body wt), four
      s.c. injections of dimethylhydrazine (40 mg/kg body wt), along with 0.05% N-butyl
      N-(4-hydroxybutyl)nitrosamine and then 0.1% 2,2'-dihydroxy-di-n
      propylnitrosamine, both in the drinking water, for 2 weeks each, during the
      initial 4-week period (DMBDD treatment). Starting 1 week thereafter, rats were
      administered CLPr at a dose of 0.025% or 0.25% and the experiment was terminated
      at week 36. The final survival rate for the DMBDD+0.25% CLPr group was
      significantly greater than for the DMBDD alone group. In the lung, significant
      reduction in the incidence and multiplicity of carcinomas was also observed, and
      in the thyroid, quantitative values for adenomas also tended to decrease in a
      CLPr dose-dependent manner. No significant modification in the small intestine,
      colon or kidney was evident. These results indicate that CLPr exerts
      chemopreventive effects in the lung without any promoting influence in other
      major organs.

PMID- 12609710
TI  - Prophylactic hyperbaric oxygen treatment and rat spinal cord re-irradiation.
AB  - Normal tissue injury may lead to severe, life threatening, late side effects
      after therapeutic use of irradiation. Neurological complications caused by
      radiation of the spinal cord are ascribed to progressive, irreversible damage to
      the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in
      irradiated tissue and has been proven to reduce late radiation injury in several
      normal tissues when applied during the latent period before complications become
      manifest. In the present study: (1). the prophylactic potential of HBO; (2).
      optimal timing of HBO therapy after spinal cord irradiation, i.e. during the
      latent period; and (3). effect of HBO on the re-irradiation tolerance of the
      spinal cord were investigated. The rat cervical spinal cord was locally X-ray
      irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10)
      included: irradiation alone and irradiation followed by 30 HBO treatments (100%
      oxygen at 240 kPa for 90 min) during latency, with HBO starting either
      immediately, 5, 10 or 15 weeks after the primary irradiation course. One year
      after the primary treatment, the same spinal cord volume was re-irradiated with
      20 Gy single dose. During life span, the animals were observed on the incidence
      of myelitis and the duration of the latent period. The actuarial analysis
      revealed no significant difference in neurological complications free survival
      between the irradiation alone and the irradiation+HBO treatment groups. A
      tendency towards radiosensitization was found in the group in which the primary
      irradiation course was immediately followed by the HBO treatment course. The data
      show that HBO applied during the latent period of progressively developing
      irradiation damage to the spinal cord does not increase the re-irradiation
      tolerance of this tissue.

PMID- 12609712
TI  - Metaplastic potential of p53 down-regulation in ovarian surface epithelial cells
      affected by ovulation.
AB  - That ovulation is a predisposing factor in common (surface) epithelial ovarian
      cancer is widely recognized; however, the molecular events which underscore early
      stage disease have not been elucidated. In vivo and in vitro studies using an
      ovine model system were designed to address a premise that oxidative distresses
      to DNA inflicted upon ovarian surface epithelial cells within a limited diffusion
      radius of the ovulatory site of follicular rupture, if gone uncorrected by p53
      dependent cycle arrest/repair pathways, could yield a progenitor of tumorigenic
      potential. Immunofluorescence image analysis was used to quantitate the DNA
      damage marker 8-oxoguanine, the tumor suppressor p53, the base-excision repair
      polymerase beta, and apoptotic internucleosomal DNA fragmentation in ovarian
      surface epithelial cells isolated from the perimeter of ovulated follicles. Up
      regulation of p53 coincided with accretion of 8-oxoguanine lesions. Oxidative
      disturbances to DNA were reconciled during the consequent luteal phase (before
      replicative repair of the ovarian rupture wound). Production of p53 was not
      related to apoptosis, but rather to induction of polymerase beta. Oxoguanine
      modifications persisted in cells affected by ovulation in which synthesis of p53
      was negated in culture by an antisense oligonucleotide. Inhibition of p53 was
      associated with discordant cellular growth rates and expression of the cancer
      antigen CA-125 - a phenotype of metaplastic transformation. It is suggested that
      the integrity of DNA of ovarian surface epithelial cells is compromised by
      reactive oxidants and inflammatory mediators generated during the ovulatory
      process and that malfunction in a damage-recognition and(or) repair mechanism is
      a determinant in the etiology of ovarian metaplasia and carcinogenesis.

PMID- 12609711
TI  - Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma
      (PPAR-gamma) gene and risk of prostate cancer among men in a large cancer
      prevention study.
AB  - The nuclear hormone receptor peroxisome proliferator-activated receptor-gamma
      (PPAR-gamma) may play a role in prostate carcinogenesis. We examined the
      association between the PPAR-gamma Pro12Ala polymorphism and prostate cancer risk
      in a cohort of Finnish male smokers. In a nested case-control analysis that
      included 193 prostate cancer cases and 188 matched controls, we found no
      significant association between this polymorphism and prostate cancer risk (odds
      ratio, OR=1.27, 95% confidence interval, CI: 0.83-1.94), or significant trend or
      association with tumor stage (OR=1.28, 95% CI: 0.54-3.04 for metastatic disease)
      or grade (OR=1.57, 95% CI: 0.63-3.91 for poorly differentiated disease). The
      Pro12Ala polymorphism does not appear to play a significant role in prostate
      cancer risk in this cohort of men.

PMID- 12609713
TI  - The effect of ursodeoxycholic acid on the survivin in thapsigargin-induced
      apoptosis.
AB  - Endoplasmic reticulum (ER) was recently suggested as a third subcellular
      compartment in apoptotic execution. Survivin is a member of inhibitors of
      apoptosis and ursodeoxycholic acid (UDCA) prevents apoptosis from various
      apoptotic stimuli. To assess the activity of survivin and the effect of UDCA on
      the survivin in ER stress-mediated apoptosis, we treated hepatoma cell lines with
      thapsigargin (TG). TG-induced apoptosis was assessed by morphological changes,
      DNA fragmentation, cleavages of poly(ADP-ribose)polymerase (PARP), and activation
      of calpain and caspase-12. The level of survivin was decreased after TG treatment
      in hepatoma cell lines indicating that survivin play an important role in ER
      stress-mediated apoptosis. UDCA prevented decrease in survivin levels and
      inhibited TG-induced apoptosis and caspase-12 activation suggesting an anti
      apoptotic effect of UDCA.

PMID- 12609714
TI  - The expression of mammaglobin mRNA in peripheral blood of metastatic breast
      cancer patients as an adjunct to serum tumor markers.
AB  - We conducted a study to compare the expression of human mammaglobin (hMAM) mRNA
      in breast cancer patients' peripheral blood with serum carcinoembryonic antigen
      (CEA) and CA 15.3. A total of 33 metastatic breast cancer patients were enrolled.
      The blood samples were used to test the expression of hMAM mRNA by reverse
      transcriptase polymerase chain reaction (RT-PCR) and CEA, CA 15.3 by
      radioimmunoassay. The serum CEA and CA 15.3 levels were elevated in 17 (51%) and
      23 (69%) of the patients, respectively. When combined CEA with CA 15.3, the
      sensitivity rate raised to 78%. hMAM mRNA was detected in 18 (54%) of the 33
      patients. When combined hMAM mRNA with CEA or CA 15.3, the sensitivity rate were
      81% and 90%, respectively (P=0.045). In conclusion, the hMAM mRNA RT-PCR can be
      an adjunct in detecting metastatic breast cancer.

PMID- 12609715
TI  - Caffeine diminishes cytotoxic effects of paclitaxel on a human lung
      adenocarcinoma cell line.
AB  - This study was performed to investigate how caffeine modifies the cytotoxic
      effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to
      5mM had less effect on clonogenic survival. The cell killing effect, due to
      paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined
      treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic
      effect of paclitaxel not only in dose-response but also in time-response curves.
      Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose
      dependent manner. In the cell cycle analysis, caffeine alone caused early G1
      accumulation, whereas paclitaxel alone caused an early increase in G2-M and a
      decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed
      the effect of paclitaxel on cell cycle distribution, where a dose-dependent early
      increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle
      modifying agents, such as caffeine, potentially diminish the cytotoxic activity
      of paclitaxel, and one should be careful when combining such agents.

PMID- 12609717
TI  - An adapted ImmunoMagnetic cell separation method for use in quantification of
      Escherichia coli O157:H7 from bovine faeces.
AB  - Detection of Escherichia coli O157:H7 organisms in food, clinical or
      environmental samples is necessary for diagnosis of infection and epidemiological
      investigations. However, this pathogen may be present in low numbers and
      difficult to identify among high numbers of other background bacteria. In order
      to increase the sensitivity of culture- and PCR detection, pre-enrichment of E.
      coli O157:H7 in broth culture combined with ImmunoMagnetic cell Separation (IMS)
      is routinely employed. These methods, although able to detect levels as low as 2
      cfu/g (from 10 to 25 g samples), are qualitative detection strategies only. If
      the actual numbers of E. coli O157:H7 are to be quantified, growth enrichment
      must be excluded and the organisms isolated directly from the sample of interest.
      Such quantification is necessary, for example, to determinate contamination
      levels on beef carcasses and for determination of bacterial numbers in in vivo
      gene expression studies. In the present study, it was not possible to recover
      organisms from bovine faecal suspensions using the customary IMS system and so a
      range of alternative buffers and other paramagnetic beads was tested. Combination
      of a 6.2-microm diameter bead with a detergent-based buffer gave optimal recovery
      of E. coli O157:H7 organisms from faecal suspensions. This system was validated
      for recovery of E. coli O157:H7 by comparing it with that obtained with the
      standard Dynabeads IMS protocol, using both the traditional broth enrichment
      method and a quantitative detection approach. We conclude that a 6.2-microm
      diameter Aureon bead can be used for quantitative isolation of E. coli O157:H7
      directly from bovine faeces and, for this purpose, is preferred to the 2.8-microm
      diameter Dynal bead.

PMID- 12609718
TI  - Enzymatic differentiation of Candida parapsilosis from other Candida spp. in a
      membrane filtration test.
AB  - A previously reported enzyme assay on a membrane filter using 4
      methylumbelliferyl (4-MU)-N-acetyl-beta-D-galactosaminide, -phosphate and 
      pyrophosphate as substrates for the differentiation of four Candida spp. has been
      extended to Candida parapsilosis. The substrate 4-MU-beta-D-glucoside was
      hydrolyzed by 28 test strains of this species but to a variable extent by seven
      other yeasts also. For a full enzymatic differentiation of C. parapsilosis from
      other medical yeasts, a battery of six reactions was required. Of 71 C.
      parapsilosis positive clinical samples, 4.2% gave a false negative result due to
      overgrowth by Candida albicans. The present assay is more rapid than a described
      spectrofluorometric determination of beta-D-glucosidase in a broth, i.e., 9-11 h
      versus up to >48 h.

PMID- 12609716
TI  - Introduction of wild-type p53 enhances thrombospondin-1 expression in human
      glioma cells.
AB  - Malignant gliomas are distinguished from low-grade gliomas by their intense
      angiogenesis. In gliomas, p53 is the most frequently altered gene and is involved
      in the early phase of glioma development. In contrast, homozygous p16 gene
      deletion is more common in high-grade gliomas. In order to understand the
      mechanism by which gliomas become more angiogenic during the malignant
      transformation, we examined the relationship between thrombospondin-1, a negative
      regulator in angiogenesis, and these tumor suppressor genes in malignant gliomas.
      Human glioma cell line U-251 MG, which has mutated p53 and deleted p16, was
      transduced with recombinant replication-defective adenovirus vectors containing
      the cDNA of wild-type p53, p16, and p21. Only the induction of wild-type p53
      enhanced expression of thrombospondin-1 mRNA and the protein in U-251 MG cells.
      Furthermore, thrombospondin-1 that was secreted in the culture medium was
      significantly increased (3.8-fold) as compared with that of the viral control 36
      h after infection with Ad5CMV-p53. In the presence of wild-type p53 plasmid DNA,
      the promoter activity was increased 7.4-fold as compared with an empty expression
      vector control. These studies may suggest that mutation of p53 gene endows
      gliomas with an angiogenic phenotype by reducing thrombospondin-1 production as
      well as enhancing the angiogenesis inducers in the early phase of malignant
      progression.

PMID- 12609720
TI  - Detection of Cyclospora cayetanensis using a quantitative real-time PCR assay.
AB  - Cyclospora cayetanensis, a coccidian parasite, with a fecal-oral life cycle, has
      become recognized worldwide as an emerging human pathogen. Clinical
      manifestations include prolonged gastroenteritis. While most cases of infection
      with C. cayetanensis in the United States have been associated with foodborne
      transmission, waterborne transmission has also been implicated. We report on the
      development and application of a real-time, quantitative polymerase chain
      reaction assay for the detection of C. cayetanensis oocysts, which is the first
      reported use of this technique for this organism. Both a species-specific primer
      set and dual fluorescent-labeled C. cayetanensis hybridization probe were
      designed using the inherent genetic uniqueness of the 18S ribosomal gene sequence
      of C. cayetanensis. The real-time polymerase chain reaction assay has been
      optimized to specifically detect the DNA from as few as 1 oocyst of C.
      cayetanensis per 5 microl reaction volume.

PMID- 12609719
TI  - Comparison of immunofluorescence assay and immunomagnetic
      electrochemiluminescence in detection of Cryptosporidium parvum oocysts in karst
      water samples.
AB  - Immunofluorescence assay (IFA) and immunomagnetic electrochemiluminescence (IM
      ECL) were used for comparison of the percent recovery of Cryptosporidium parvum
      in environmental water samples obtained from a spring draining a karst basin. The
      monoclonal antibodies to C. parvum, isotype IgG3 were used for optimization of
      the IM-ECL protocol. The combination of biotinylated and TAG-labeled anti-C.
      parvum antibodies with the streptavidin beads gave a linear regression slope for
      log ECL vs. log fresh oocysts of 0.79 (from 5 to 5,000 oocysts), which indicates
      a constant ECL signal per oocyst. Standard curves gave a dynamic range of 5 to
      5,000 oocysts/ml (fresh) and 10 to 100,000 cells/ml (4-month-old oocysts) with
      the maximum limit of linear detection higher than 100,000. The linear slope of 4
      month-old oocysts decreased to 0.62, which indicates that ECL signal is a
      function of oocyst age. The experiment associated with bead storage time shows
      that even after 4 months of storage of the biotinylated antibodies, the complex
      retains the ability for binding the oocysts and generating the ECL signal. Based
      on the IFA results in the experiment evaluating different protocols for oocysts
      recovery from karst water samples, the most efficient protocol involved
      dispersion, followed by flotation and immunomagnetic separation (IMS) (24%
      recovery). The ECL results obtained in that experiment were very similar to the
      results obtained in the IFA method, which indicates that the IM-ECL method is
      accurate. Results of the IFA in the study of the prevalence of C. parvum in the
      groundwater showed that oocysts were present in 78% of 1 L water samples with
      average number of oocysts of 6.4+/-5.5 and ranged from 0 (13 samples) to 23.3 (2
      samples). The ECL signal generated from these water samples ranged from 3,771 to
      622 (average 1,620+/-465). However, the background value estimated in groundwater
      samples with low number of oocysts detected by IFA was highly variable and
      elevated (from 3,702 to 272, average 1,503+/-475). The background value as a
      result of nonspecific binding to beads by unidentified organic components in the
      water can inhibit or even completely mask the signal generated by oocysts. Our
      investigations showed that the IM-ECL method appears to be promising for the
      qualitative and quantitative detection of C. parvum from the environmental water;
      however, the method requires further development to improve sensitivity and
      account for background signals.

PMID- 12609721
TI  - Surprisingly fast disappearance of beta-lactam selection pressure in cultivation
      as detected with novel biosensing approaches.
AB  - Tetracycline and beta-lactam resistances among others are used as selection
      markers in the production of recombinant proteins. The beta-lactam resistance is
      based on degradation, i.e. the selection pressure gradually disappears from the
      culture, whereas tetracycline resistance is based on active efflux. We have
      studied the kinetics of the stability of antibiotic selection pressure in culture
      using a simple model system (pBR322 in Escherichia coli). Concentrations of
      ampicillin, carbenicillin and tetracycline were measured with novel sensor cells
      developed in our lab. These cells are specifically induced to produce light in
      the presence of the drugs and here their performance was shown to be excellent in
      monitoring antibiotic concentrations in cell culture. The sensor cells are cheap
      to produce and use and a high number of samples can be analysed simultaneously.
      To our surprise, ampicillin and carbenicillin were completely degraded after 2.5
      3.0 h of culture, although it has been widely claimed that especially
      carbenicillin is a good selective agent, whereas tetracycline was stable in
      culture. beta-lactamase activity in culture was found to correlate with the
      kinetics of ampicillin degradation.

PMID- 12609722
TI  - Statistical analysis and biological interpretation of the flow cytometric
      heterogeneity observed in bacterial axenic cultures.
AB  - Histogram comparison and meaningful statistics in flow cytometry is probably the
      most widely encountered mathematical problem in flow cytometry. Ideally, a test
      for determining the statistical equality or difference of flow cytometric
      distributions will identify the significant differences or similarities of the
      obtained histograms. This situation is of particular interest when flow cytometry
      is used to study the heterogeneity of axenic bacterial populations. We have
      statistically measured the heterogeneity of successive cytometric measures, the
      modifications produced after 20 transfers from the same culture, and the
      differences between 20 subcultures of identical origin. The heterogeneity of the
      bacterial populations and the similarity of the obtained 360 histograms were
      analysed by standard statistical methods. We have studied bacterial axenic
      cultures in order to detect, quantify and interpret their cytometric
      heterogeneity, and to assess intrinsic differences and differences produced by
      laboratory manipulations. We concluded that the standard axenic cultures have a
      considerable intrinsic cellular and molecular heterogeneity. We suggest that the
      heterogeneity we have detected basically has two origins: cell size diversity and
      cell cycle variations.

PMID- 12609723
TI  - A rapid solid-phase fluorimetric assay for measuring bacterial adherence, using
      DNA-binding stains.
AB  - In this report, we describe the validation of a rapid, single-step, microtiter
      plate method for quantifying bacterial adherence, based on fluorescent labeling
      of microorganisms with cell-permeable fluorescent DNA-binding probes. We have
      tested the binding to saliva-coated microtiter plates of bacteria, including
      Helicobacter pylori and viridans streptococci (S. mitis, S. gordonii, S.
      sanguis), known to interact with salivary components. Furthermore, we tested the
      short-term and longer-term temporal stability of a saliva-mediated adherence of
      these bacteria in a healthy population (N=30). The assay exhibited excellent
      reliability statistics, yielding within-assay variability coefficients ranging
      from 4.9% to 11%. A range of approximately 5 x 10(4)-1 x 10(7) cells could be
      detected. This method may be generally applicable to study surface binding of
      virtually any microbial species, while obviating the need of radioactive
      materials or specific antibodies for quantification, thus providing a procedure
      that is useful to both basic and clinical research.

PMID- 12609724
TI  - Spectral imaging detection and counting of microbial cells in marine sediment.
AB  - Semiautomated detection and counting techniques for microbial cells in soil and
      marine sediment using microscopic-spectral-imaging analysis were developed.
      Microbial cells in microscopic fields were selectively detected from other
      fluorescent particles by their fluorescent spectrum, based on the spectral shift
      between the conjunction and nonconjunction of DNA fluorochrome (SYBR Green II)
      with nucleic acids. Using this technique, microbial cells could be easily
      detected in soil and 30-cm deep sediment samples from Tokyo Bay, both of which
      contain particles other than microbial cells. Total cell density was
      semiautomatically estimated at 1-6 x 10(9) cells cm(-3) of sediment sampled at
      different depths in Tokyo Bay, which corresponded to 65-106% (mean 88%) of visual
      direct counting. This technique may be useful for detecting microbial cells in
      soil and sediment samples from the deeper subsurface environment.

PMID- 12609725
TI  - Direct quantification of fungal DNA from soil substrate using real-time PCR.
AB  - Detection and quantification of genomic DNA from two ecologically different
      fungi, the plant pathogen Fusarium solani f. sp. phaseoli and the arbuscular
      mycorrhizal fungus Glomus intraradices, was achieved from soil substrate.
      Specific primers targeting a 362-bp fragment from the SSU rRNA gene region of G.
      intraradices and a 562-bp fragment from the F. solani f. sp. phaseoli translation
      elongation factor 1 alpha gene were used in real-time polymerase chain reaction
      (PCR) assays conjugated with the fluorescent SYBR(R) Green I dye. Standard curves
      showed a linear relation (r(2)=0.999) between log values of fungal genomic DNA of
      each species and real-time PCR threshold cycles and were quantitative over 4-5
      orders of magnitude. Real-time PCR assays were applied to in vitro-produced
      fungal structures and sterile and non-sterile soil substrate seeded with known
      propagule numbers of either fungi. Detection and genomic DNA quantification was
      obtained from the different treatments, while no amplicon was detected from non
      seeded non-sterile soil samples, confirming the absence of cross-reactivity with
      the soil microflora DNA. A significant correlation (P<0.0001) was obtained
      between the amount of genomic DNA of F. solani f. sp. phaseoli or G. intraradices
      detected and the number of fungal propagules present in seeded soil substrate.
      The DNA extraction protocol and real-time PCR quantification assay can be
      performed in less than 2 h and is adaptable to detect and quantify genomic DNA
      from other soilborne fungi.

PMID- 12609726
TI  - A simple micro-growth assay for enumerating bacteria.
AB  - A simple method for nonspecific determination of bacteria concentrations in a
      variety of liquid samples was developed. The assay was based on the time required
      for a sample grown in liquid media to reach a threshold turbidity. Samples were
      combined with media in a covered 96-well microwell plate and the turbidity was
      monitored in real time as the bacteria grew in a temperature-controlled plate
      reader. A significant problem with growth in microwells was condensation on the
      cover, which prevented accurate turbidity measurement. This problem was overcome
      by coating the cover with a small amount of surface-active agent. Salmonella and
      E. coli concentrations could be determined with a relative error of approximately
      20% at levels from 10 to 10(6) cells/ml (eight replicates). An assay of 10
      samples with standards required 10 min to set up and 20 min for data processing
      using a computer spreadsheet program. Growth time at 37 degrees C ranged from 4 h
      for samples at 10(7) cells/ml to 16 h for samples at 10 cells/ml.

PMID- 12609728
TI  - Assessing technician effects when extracting quantities from microscope images.
AB  - Consider an experiment where the response is based on an image; e.g., an image
      captured to a computer file by a digital camera mounted on a microscope. Suppose
      relevant quantitative measures are extracted from the images so that results can
      be analyzed by conventional statistical methods. The steps involved in extracting
      the measures may require that the technicians, who are processing the images,
      perform some subjective manipulations. In this case, it is important to determine
      the bias and variability, if any, attributable to the technicians' decisions.
      This paper describes the experimental design and statistical analyses that are
      useful for those determinations. The design and analysis are illustrated by
      application to two biofilm research projects that involved quantitative image
      analysis. In one investigation, the technician was required to choose a threshold
      level, then the image analysis program automatically extracted relevant measures
      from the resulting black and white image. In the other investigation, the
      technician was required to choose fiducial points in each of two images collected
      on different microscopes; then the image analysis program registered the images
      by stretching, rotating, and overlaying them, so that their quantitative features
      could be correlated. These investigations elucidated the effects of the
      technicians' decisions, thereby helping us to assess properly the statistical
      uncertainties in the conclusions for the primary experiments.

PMID- 12609727
TI  - Use of polyclonal antibodies to detect and quantify the NOR protein of nitrite
      oxidizers in complex environments.
AB  - In the approaches or models which aim to understand and/or predict how the
      functioning of ecosystems may be affected by perturbations or disturbances,
      little attention is generally given to microorganisms. Even when they are taken
      into account as indicators, variables which are poorly informative about the
      changes in the microbial functioning (microbial biomass or diversity or total
      number of microorganisms) are often used. To be able to estimate, in complex
      environments, the quantity of enzymes involved in key ecosystem processes may
      constitute a useful complementary tool. Here, we describe an immunological method
      for detecting and quantifying, in complex environments, the nitrite
      oxidoreductase (NOR), responsible for the oxidation of nitrite to nitrate. The
      alpha-catalytic subunit of the enzyme was purified from Nitrobacter hamburgensis
      and used for the production of polyclonal antibodies. These antibodies were used
      to detect and quantify the NOR by a chemifluorescence technique on Western blots
      after separation of total proteins from pure cultures and soil samples. They
      recognized the alpha-NOR of all the Nitrobacter species described to date, but no
      reaction was observed with members of other nitrite-oxidizing genera. The
      detection threshold and reproducibility of the proposed method were evaluated.
      The feasibility of its use to quantify NOR in a soil was tested.

PMID- 12609729
TI  - Development of a new antigen detection dot-ELISA for diagnosis of tubercular
      lymphadenitis in fine needle aspirates.
AB  - A sandwich dot enzyme-linked immunosorbent assay (ELISA) was standardized to
      detect mycobacterial antigen in fine needle aspirates of patients with tubercular
      lymphadenitis (TBLN). The assay was performed on nitrocellulose paper by using
      antibodies raised in mice and rabbits against crude soluble protein (CSP) of
      Mycobacterium tuberculosis. The test was able to detect as low as 5 ng
      protein/ml. A total of 225 suspected cases of tubercular lymphadenopathy were
      screened, out of which 96 were cytomorphologically confirmed as cases of
      tubercular lymphadenitis (50 acid-fast bacilli (AFB)-positive and 46 AFB
      negative). These were considered as positive controls. Only 28 cases were proven
      to be of nontubercular etiology and were considered as negative controls. In the
      remaining 101 (39 scanty) aspirates, tubercular etiology could neither be ruled
      out nor confirmed. Out of 50 AFB-positive confirmed cases of tubercular
      lymphadenitis, 46 were ELISA-positive. Out of 46 AFB-negative but
      cytomorphologically confirmed aspirates, antigen could be demonstrated in only 42
      aspirates. Four samples from patients with nontubercular etiology were also found
      to be ELISA-positive. Antigen was picked up in a total of 90.3% of aspirates with
      suspicion of tuberculosis and 79.5% of scanty aspirates. The assay was found to
      be 91.6% sensitive and 85.7% specific. The assay was found to be simple and
      rapid, and hence, could be performed in areas where health facilities are
      rudimentary.

PMID- 12609730
TI  - Use of green fluorescent protein to quantify the growth of Colletotrichum during
      infection of tobacco.
AB  - To develop a quantitative assay of fungal growth inside plant tissues, strains of
      Colletotrichum destructivum and Colletotrichum orbiculare were transformed with a
      modified green fluorescent protein (GFP) gene fused with a glyceraldehyde-3
      phosphate dehydrogenase promoter from Aspergillus nidulans. Transformants
      expressed GFP in culture and had the same growth rate and general appearance as
      the wild type. GFP was observed in all fungal structures during infection of
      leaves of Nicotiana benthamiana, except for the melanized appressoria and setae.
      The timing and appearance of the fungal structures in the host appeared to be
      identical to that of the wild type. GFP accumulation in inoculated leaves of N.
      benthamiana was quantified in leaf extracts using a fluorescence microplate
      reader, and the quantity of fluorescence was strongly correlated with the growth
      of the fungus as measured by the amount of fungal actin gene expression using
      Northern blot hybridizations. These results demonstrated that assaying green
      fluorescence levels from a GFP-transformed fungus is an accurate, fast and easy
      means of quantifying fungal growth inside host plant cells.

PMID- 12609731
TI  - A time-lapse capillary assay to study aerotaxis in the archaeon Halobacterium
      salinarum.
AB  - We have developed a method for time-lapse video photography and line scanning of
      optical densities for analysis of aerotactic responses of Halobacterium
      salinarum. This automated digital technique, along with line scan analysis of
      selected frames, gives a unique profile of the aerotactic migration of
      halobacterial cells.

PMID- 12609732
TI  - An inexpensive sample mold for pulsed-field electrophoresis.
AB  - Specimens for pulsed-field gel electrophoresis (PFGE) are formed using a plug
      mold. We report a technique which uses a disposable polyethylene pipette to
      prepare our specimen plug. We also report a convenient technique to handle
      portions of the plug used for the typical PFGE manipulations.

PMID- 12609733
TI  - Rapid differentiation between short-chain-length and medium-chain-length
      polyhydroxyalkanoate-accumulating bacteria with spectrofluorometry.
AB  - An approach for rapid differentiation between short-chain-length (scl) and medium
      chain-length (mcl) polyhydroxyalkanoate (PHA) producers was developed.
      Polyhydroxyalkanoate-accumulated bacterial cells stained with Nile red were
      suspended in water and subjected to fluorescence spectroscopy at a fixed
      excitation wavelength of 488 nm. The scl-PHA-accumulated bacteria revealed a
      maximum emission wavelength at 590 nm, and for mcl-PHA producers were seen at a
      wavelength of 575 nm. Combining Nile red staining and fluorescence spectroscopy,
      the accumulated PHA granules could be rapidly differentiated into scl-PHA and mcl
      PHA from the intact cells.

PMID- 12609734
TI  - Memory by modification: the influence of chromatin structure on gene expression
      during vertebrate development.
AB  - Multicellular development is programmed by regulated interactions between
      transcription factors and target genes. Target genes function as nucleosomal
      arrays whose higher order structure, composition and accessibility to
      transcription machinery are strictly and dynamically controlled. Several classes
      of chromatin-associated proteins generate or remove localized, covalent chromatin
      modifications that signify gene expression status, whereas others modulate
      nucleosome organization and so regulate template availability for transcription.
      In vertebrates, covalent modification of the DNA template itself also has
      dramatic impacts on gene expression and development. Here I review recent
      discoveries that improve our understanding of the influence of chromatin
      structure on gene expression and I discuss their relevance to mechanisms of
      vertebrate development.

PMID- 12609735
TI  - Translational machinery of channel catfish: II. Complementary DNA and expression
      of the complete set of 47 60S ribosomal proteins.
AB  - Ribosomal protein genes have become widely used as markers for phylogenetic
      studies and comparative genomics, but they have not been available in fish. We
      have cloned and sequenced a complete set of all 47 60S ribosomal protein cDNAs
      from channel catfish (Ictalurus punctatus), of which 43 included the complete
      protein encoding regions. Most ribosomal protein mRNAs in channel catfish are
      highly similar to their mammalian counterparts. However, L4, L14, and L29 are
      significantly shorter in channel catfish than in mammals due to deletions in the
      3' end of the gene. Two distantly related L5 cDNAs, L5a and L5b, were found in
      channel catfish. L5a is more similar to L5 in other vertebrates, while L5b showed
      significant levels of divergence, suggesting independent evolution of the two L5
      encoding genes. The 47 ribosomal protein genes are generally highly expressed and
      together account for 11-14% of overall gene expression, depending on the tissues.
      Expression levels were highly variable both within a single tissue among
      different ribosomal protein genes, and among tissues with regard to a single
      ribosomal protein gene. Strong tissue preference expression was also observed for
      some ribosomal proteins. This set of ribosomal protein gene sequences represents
      one of the most complete sets from any single organism and will aid in fish
      phylogenetic and comparative genomic studies.

PMID- 12609736
TI  - Overlapping gene structure of human VLCAD and DLG4.
AB  - Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a major enzyme catalysing the
      first step in mitochondrial beta-oxidation of long-chain fatty acids. During
      analysis of the VLCAD promoter, we discovered that another gene, discs-large
      related 4 (DLG4), overlaps VLCAD and is transcribed in the opposite direction.
      DLG4 encodes postsynaptic density-95 (PSD95) protein, which plays critical roles
      in the formation and maintenance of synaptic junctions. The transcription start
      site of the VLCAD gene was determined by primer extension analysis and the
      overlapping structure of VLCAD and DLG4 was clarified. VLCAD and DLG4 are
      arranged in a head-to-head orientation on chromosome 17p13, and share a 245 bp
      overlapping region that contains part of DLG4 exon 1 and the entire exon 1 of
      VLCAD including 62 bp of protein coding sequence. Despite the overlap of their 5'
      ends, DLG4 and VLCAD exhibit peak mRNA expression in different tissues,
      suggesting that they are independently regulated at the transcriptional level.
      Interestingly, VLCAD and DLG4 genes do not overlap in the mouse or Drosophila
      genomes.

PMID- 12609737
TI  - Amino acid substitutions in the human genome: evolutionary implications of single
      nucleotide polymorphisms.
AB  - Functional differences between amino acids have long been of interest in
      understanding protein evolution. Several indices exist for comparing residues on
      the basis of their physicochemical properties and frequencies of occurrence in
      conserved protein alignments. Here we present a residue dissimilarity index based
      on coding single nucleotide polymorphisms (SNPs) in the human genome. The index
      represents an average, organism-wide set of differences between residues and
      provides important insight into evolutionary restraints on residue substitutions
      in the human genome. Unlike previous models, it is not restricted to highly
      conserved protein structures, nor confounded by evolutionary differences between
      species. Our results confirm earlier observations regarding residue mutabilities
      but also suggest that in addition to the established key properties, such as size
      and polarity, charge conservation may be an important and currently
      underestimated factor in protein evolution. We also estimate that less than 51%
      of amino acid substitutions occurring in the human genome are evolutionarily
      neutral.

PMID- 12609738
TI  - Primary structure and compartmentalization of Drosophila melanogaster host cell
      factor.
AB  - Human host cell factor-1 (HCF-1) is a large, 2035-residue nuclear protein that
      interacts with cellular and viral transcription factors. It contains an N
      terminal kelch domain, C-terminal fibronectin type III (FnIII) domain, and a
      central region including tandem repeats which act as cleavage sites. A second
      human HCF-1 related gene encodes a protein with a high degree of homology in both
      the N-terminal kelch domain and C-terminal FnIII domain, but lacks the central
      portion and as a result is considerably smaller at 792 residues. A unique HCF
      orthologue has been found in Caenorhabditis elegans which is structurally more
      related to HCF-2 than HCF-1. Here we report the cloning and expression of the
      single Drosophila melanogaster host cell factor orthologue (dHCF). The dHCF is
      1500 residues in size, intermediate between HCF-1 and HCF-2 and contains an N
      terminal kelch domain, and C-terminal FnIII domain both of which show a very high
      degree of identity, and a central region of some 700 residues with more limited
      homology. Despite containing a central region no repeat-related motifs were
      apparent. The dHCF is expressed as a single unprocessed polypeptide consistent
      with the lack of the internal HCF-1 processing sites, and exhibits a
      predominantly nuclear localization. We show that this nuclear localization is
      dependent on a bipartite nuclear localization signal at the C-terminus of the
      protein, which contains a long spacer of 20 amino acids between two basic
      clusters. Finally, we also show that dHCF is unable to rescue the tsBN67 cell
      cycle arrest phenotype. These results indicate that dHCF is an orthologue of HCF
      1, although both proteins might not be functionally exchangeable.

PMID- 12609739
TI  - A chondrogenesis-related lipocalin cluster includes a third new gene, CALgamma.
AB  - We have previously reported the modulation, during chondrogenesis and/or
      inflammation, of two chicken genes laying in the same genomic locus and coding
      for two polypeptides of the lipocalin protein family, the extracellular fatty
      acid binding protein (ExFABP) and the chondrogenesis associated lipocalin beta
      (CALbeta). A third gene, located within the same cluster and coding for a new
      lipocalin, CALgamma, has been identified and is here characterized. Tissue
      distribution analyzed by real-time quantitative reverse transcriptase-polymerase
      chain reaction in chicken embryos shows a ubiquitous expression with predominant
      levels of mRNA transcripts in the liver and the brain. In the developing tibia, a
      high expression of CALgamma mRNA was evidenced by in situ hybridization within
      the pre-hypertrophic and the hypertrophic zones of the bone-forming cartilage. In
      agreement, dedifferentiated chondrocytes in vitro express the transcripts to the
      highest level when they re-differentiate reaching hypertrophy. Such peculiar
      developmental pattern of expression that is analogous to those already described
      for Ex-FABP and CALbeta suggests that all three proteins may act synergistically
      in the process of endochondral bone formation. Moreover, like Ex-FABP and
      CALbeta, CALgamma is also highly induced in dedifferentiated chondrocytes upon
      stimulation with lypopolysaccharides, indicating that the whole cluster quite
      possibly is transcriptionally activated not only in physiological morphogenic
      differentiation but also in pathological acute phase response.

PMID- 12609740
TI  - Organ-specific expressions and chromosomal locations of two mitochondrial
      aldehyde dehydrogenase genes from rice (Oryza sativa L.), ALDH2a and ALDH2b.
AB  - Recent studies have suggested that mitochondrial aldehyde dehydrogenase
      (aldehyde:NAD(P)(+) oxidoreductase, EC 1.2.1.3) (ALDH2) plays essential roles in
      pollen development in plants. Rice (Oryza sativa L.) ALDH2 is encoded by at least
      two ALDH2 genes, one of which (ALDH2a) was previously identified. In this study,
      to understand the roles of ALDH2 in rice, we isolated and characterized a cDNA
      clone encoding another rice ALDH2 (ALDH2b). An in vitro ALDH assay indicated that
      ALDH2b possesses an NAD(+)-linked activity for oxidation of acetaldehyde,
      glycolaldehyde and propionaldehyde. Northern blot and immunoblot analyses
      revealed that ALDH2b was constitutively present in all the organs examined,
      whereas ALDH2a was expressed in leaves of dark-grown seedlings and panicles. By
      RFLP linkage mapping, the ALDH2a and ALDH2b genes were mapped to the long arm of
      chromosome 2 and the short arm of chromosome 6, respectively. We suggest that the
      rice ALDH2a and ALDH2b genes are orthologues of maize mitochondrial ALDH genes,
      rf2b and rf2a, respectively.

PMID- 12609741
TI  - The Xenopus B2 factor involved in TFIIIA gene regulation is closely related to
      Sp1 and interacts in a complex with USF.
AB  - In the Xenopus laevis oocyte there is a million fold more transcription factor
      IIIA (TFIIIA) and its corresponding mRNA than in a somatic cell. These high
      levels of TFIIIA gene expression are achieved primarily by transcriptional
      regulation. The TATA box along with three positive cis-elements in the control
      region of the TFIIIA gene located at positions -269 to -264 (E1), -235 to -220
      (E2), and -669 to -636 (E3) are required for this high level of expression in
      oocytes. The proteins that bind E1 and E3 of the TFIIIA gene have been identified
      as Xenopus USF (Xl-USF) and B3 (homolog of Vg1 RBP/VERA). In this study the B2
      protein was found to bind E2 in a zinc-dependent fashion and anti-human Sp1 (but
      not Sp2, Sp3, nor Sp4) supershifted the B2:element 2 complex. The E2 binding
      protein was purified by DNA affinity chromatography. Based on supershift
      analysis, molecular weight estimation experiments, and purified human Sp1 DNA
      binding affinity tests the data strongly support the idea that the B2 protein is
      the Xenopus ortholog of Sp1, but not Sp2, Sp3, nor Sp4. Xl-USF binds to element 1
      of the TFIIIA gene which is immediately adjacent to element 2.
      Coimmunoprecipitation experiments using crude whole oocyte extracts revealed that
      Xenopus Sp1 and USF or closely related factors are present together in a high
      affinity complex. This structure contributes positively to the initiation of
      TFIIIA gene transcription in Xenopus oocytes.

PMID- 12609742
TI  - The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class
      IV POU-domain factor Pou4f2 (Brn-3b).
AB  - The Wilms' tumor gene Wt1 encodes a zinc finger protein, which is required for
      normal formation of the genitourinary system and mesothelial tissues. Our recent
      findings indicate that Wt1 also plays a critical role in the development of
      ganglion cells in the vertebrate retina. Here we show that the POU-domain factor
      Pou4f2 (formerly Brn-3b), which is necessary for retinal ganglion cell survival,
      is up-regulated in human embryonic kidney (HEK)293 cells with stable Wt1
      expression. Consistent with our previous observations of increased Pou4f2 mRNA in
      stably Wt1-transfeced HEK293 cells [EMBO J. 21 (2002) 1398], endogenous Pou4f2
      was also elevated at the protein level in the HEK293 transfectants as well as in
      U2OS osteosarcoma cells that expressed an inducible Wt1 isoform. Transient co
      transfection of a Wt1 expression construct activated a Pou4f2 promoter-reporter
      construct approximately 4-fold. Stimulation of the Pou4f2 promoter required a Wt1
      binding element that was similar to a degenerative consensus site previously
      identified in other Wt1 responsive genes. Double-immunofluorescent labeling
      revealed co-expression of Pou4f2 and Wt1 in glomerular podocytes of adult kidney
      and in developing retinal ganglion cells of mouse embryos. Pou4f2
      immunoreactivity was absent from the retinas of Wt1(-/-) embryos. In conclusion,
      we identified Pou4f2 as a novel downstream target gene of Wt1. Co-localization of
      both proteins in glomerular podocytes of the kidney and in developing retinal
      ganglion cells suggests a role for Wt1-Pou4f2 interaction in these tissues.

PMID- 12609743
TI  - Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development
      of obesity.
AB  - The hypothalamus integrates metabolic, neural and hormonal signals to evoke an
      intermittent appetitive drive in the daily management of energy homeostasis.
      Three major players identified recently in the feedback communication between the
      periphery and hypothalamus are leptin, ghrelin and neuropeptide Y (NPY). We
      propose that reciprocal circadian and ultradian rhythmicities in the afferent
      humoral signals, anorexigenic leptin from adipocytes and orexigenic ghrelin from
      stomach, encode a corresponding discharge pattern in the appetite-stimulating
      neuropeptide Y network in the hypothalamus. An exquisitely intricate temporal
      relationship among these signaling modalities with varied sites of origin is
      paramount in sustenance of weight control on a daily basis. Our model envisages
      that subtle and progressive derangements in temporal communication, imposed by
      environmental shifts in energy intake, impel a positive energy balance
      culminating in excessive weight gain and obesity. This conceptual advance
      provides a new target for designing pharmacologic or gene transfer therapies that
      would normalize the rhythmic patterns of afferent hormonal and efferent
      neurochemical messages.

PMID- 12609744
TI  - Shear stress attenuates endothelin and endothelin-converting enzyme expression
      through oxidative stress.
AB  - Shear stress is known to dilate blood vessels and exert an antiproliferative
      effect on vascular walls. These effects have partly been ascribed to shear stress
      induced regulation of the secretion of endothelium-derived vasoactive substances.
      In this study, to elucidate the role of shear stress in endothelin production by
      endothelial cells, we examined the effect of physiological shear stress on the
      mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1
      (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human
      umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow
      chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress
      in an intensity- and time-dependent manner within the physiological range (1.5 to
      15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA
      expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant
      increase in the intracellular peroxide concentration, and the down-regulation of
      ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely
      on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore,
      when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as
      well as ET-1 mRNA expression was attenuated in proportion to the concentration of
      H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative
      stress and transduce signal for the regulation of the gene expression of ECE as
      well as ET to attenuate vascular tone and inhibit the proliferation of vascular
      smooth muscle cells.

PMID- 12609745
TI  - Characterization of the NPGP receptor and identification of a novel short mRNA
      isoform in human hypothalamus.
AB  - Recently, an orphan G protein coupled receptor (GPCR) termed NPGPR was described.
      A shorter variant of this receptor lacking exon 1 was shown to have subnanomolar
      affinity for neuropeptide FF (NPFF), a pain modulatory peptide, and therefore was
      named NPFF(2) receptor. Here, we characterize the full-length cloned NPGPR and
      identify a novel short form lacking exon 2 with a differential pattern of mRNA
      abundance in several tissues and organs. The NPGPR is most similar to the
      recently cloned neuropeptide FF (NPFF) receptor which lacks exon 1, but also
      shows high homology to the orexin and neuropeptide Y (NPY) receptor families, two
      neuropeptides involved in food intake regulation. Therefore, we used binding
      studies to examine the interaction of NPFF, orexin and NPY with the NPGPR. [125I]
      NPFF was displaced by NPFF with an IC(50) of 14.7 +/- 8.8 nM, whereas [125I]
      Orexin B was displaced by Orexin B with an IC(50) of 415 +/- 195 nM. We conclude
      that orexins interact with the NPGPR and that the affinity of NPFF for NPGPR is
      approximately 100-fold lower than for the NPFF2 receptor. We postulate that NPGPR
      is a splice variant of the family of NPFF receptors and displays a binding
      profile different from the other members of the NPFF receptor family due to the
      presence of exon 1. In order to evaluate whether NPGPR levels are affected by the
      feeding status, we examined the mRNA level using real-time PCR in two feeding
      models, i.e. before and after diet-induced body weight increase as well as after
      chronic food restriction in rats. However, hypothalamic NPGPR mRNA was unchanged
      in both models. Therefore, our evidence does not support the hypothesis that
      NPGPR is involved in feeding regulation.

PMID- 12609746
TI  - EPYLRFamide-mediated reduction of acetylcholine-induced inward currents in Helix
      lucorum-identified neurones: role of NAADP-dependent and IP3-dependent Ca2+
      release from internal stores, calmodulin and Ca2+/calmodulin-dependent protein
      kinase II.
AB  - The effect of seven compounds intracellularly applied by spontaneous diffusion
      were investigated on the EPYLRFamide-induced reduction of acetylcholine-induced
      inward current (ACh-current) recorded from identified neurones from Helix
      lucorum. Inward currents were recorded from neurones LPa2, LPa3, RPa3 and RPa2 in
      isolated ganglia preparations using two-electrode voltage clamp technique. ACh
      was applied ionophoretically. Heparin, an antagonist of IP(3) receptors
      (IP(3)Rs), and IP(3), the agonist of IP(3)Rs, decreased the effect of
      EPYLRFamide. Thio-NADP, a blocker of NAADP-induced Ca(2+) release, beta-NAADP,
      Ca(2+) releaser, R24571, W-7 (both calmodulin antagonists), and KN-62, a
      selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase II, did not
      change the modulatory effect of EPYLRFamide. These data suggest that EPYLRFamide
      decreases ACh-current through elevation of the basal intracellular level of the
      putative endogenous agonist of IP(3)Rs which activates release of Ca(2+) from
      intracellular stores. It is concluded that intracellular free Ca(2+) acts on ACh
      receptor/ionic channel without activation of calmodulin and Ca(2+)/calmodulin
      dependent protein kinase II.

PMID- 12609747
TI  - Angiotensin II-induced release of oxytocin: interaction with norepinephrine and
      role in lactation.
AB  - These studies examined the receptors involved in angiotensin II (Ang II)
      stimulated secretion of systemic oxytocin (OT) and the role of this peptide in
      release of OT during suckling. Plasma OT concentrations were measured following
      intracerebroventricular (icv) injection of vehicle, Ang II, or Ang II following
      pretreatment with a selective AT1 (Losartan) or AT2 (PD 123319) receptor
      antagonist. Furthermore, we measured Ang II-induced OT release during central
      alpha-adrenergic receptor blockade (phentolamine). Finally, plasma OT
      concentrations before and during suckling were evaluated following central
      administration of Ang II receptor antagonists. The increase in systemic OT
      following central Ang II was abolished by AT1 receptor blockade and inhibited by
      the AT2 receptor antagonist. Furthermore, pretreatment with phentolamine
      significantly diminished systemic OT release in response to icv Ang II. Finally,
      central Ang II receptor blockade did not alter the increase in circulating OT
      during suckling. These data demonstrate that Ang II evoked OT release is mediated
      through activation of both AT1 and AT2 receptors and suggest that a component of
      Ang II-induced OT stimulation is due to norepinephrine release. Furthermore,
      central angiotensin systems do not have a direct role in stimulating OT release
      during suckling.

PMID- 12609748
TI  - Differential effects of saralasin and ramiprilat, the inhibitors of renin
      angiotensin system, on cerulein-induced acute pancreatitis.
AB  - Acute pancreatitis is an inflammatory disease characterized by pancreatic tissue
      edema, acinar cell necrosis, hemorrhage and inflammation of the damaged gland. It
      is believed that acinar cell injury is initiated by the activation of digestive
      zymogens inside the acinar cells, leading finally to the autodigestion of the
      pancreas. Previous study in our laboratory demonstrated that cerulein-induced
      acute pancreatitis was associated with an up-regulation of local renin
      angiotensin system (RAS) in rat pancreas. Therefore, the utilization of RAS
      inhibitors may provide a novel and alternative treatment for acute pancreatitis.
      By means of a rat model of cerulein-induced acute pancreatitis, results from the
      present study showed that an intravenous injection of saralasin, an antagonist
      for angiotensin II receptors, at a dose of 40 microg/kg 30 min before the
      induction of acute pancreatitis significantly attenuated pancreatic edema.
      Results from the biochemical measurements showed that pretreatment with saralasin
      at a dose of 20 microg/kg markedly reduced pancreatic injury, as evidenced by the
      decreased activities of alpha-amylase and lipase in plasma. However, the same
      recipe of ramiprilat, a specific inhibitor for angiotensin-converting enzyme, at
      a dose of 20 microg/kg did not provide any protective effect against acute
      pancreatitis. On the contrary, pretreatment with ramiprilat at a dose 40
      microg/kg enhanced cerulein-induced pancreatic injury. Results from
      histopathological analysis of these RAS inhibitors further confirmed with those
      results as obtained from biochemical analysis. These data indicate that
      administration of saralasin but not ramiprilat could be protective against acute
      pancreatitis and that activation of pancreatic RAS in acute pancreatitis may play
      a role in pancreatic tissue injury.

PMID- 12609750
TI  - Angiotensin II mediates catecholamine and neuropeptide Y secretion in human
      adrenal chromaffin cells through the AT1 receptor.
AB  - The aim of the present work was to study the effect of angiotensin II (Ang II) on
      catecholamines and neuropeptide Y (NPY) release in primary cultures of human
      adrenal chromaffin cells. Ang II stimulates norepinephrine (NE), epinephrine (EP)
      and NPY release from perifused chromaffin cells by 3-, 2- and 12-fold,
      respectively. The NPY release is more sustained than that of catecholamines. We
      found that the receptor-AT(2) agonist, T(2)-(Ang II 4-8)(2) has no effect on NE,
      EP and NPY release from chromaffin cells. We further showed that Ang II increases
      intracellular Ca(2+) concentration ([Ca(2+)](i)). The selective AT(1)-receptor
      antagonist Candesartan blocked [Ca(2+)](i) increase by Ang II, while T(2)-(Ang II
      4-8)(2) was ineffective. These findings demonstrate that AT(1) stimulation
      induces catecholamine secretion from human adrenal chromaffin cells probably by
      raising cytosolic calcium.

PMID- 12609749
TI  - Islet amyloid polypeptide inhibits glucagon release and exerts a dual action on
      insulin release from isolated islets.
AB  - We have studied the influence of a wide concentration range of islet amyloid
      polypeptide (IAPP) on both glucagon and insulin release stimulated by various
      types of secretagogues. In an islet incubation medium devoid of glucose, the rate
      of glucagon release being high, we observed a marked suppressive action by low
      concentrations of IAPP, 10(-10) and 10(-8) M, on glucagon release. Similarly,
      glucagon release stimulated by L-arginine, the cholinergic agonist carbachol, or
      the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX), an activator of
      the cyclic AMP system, was inhibited by IAPP in the 10(-10) and 10(-8) M
      concentration range. Moreover, basal glucagon release at 7 and 10 mM glucose was
      suppressed by IAPP. In contrast, IAPP exerted a dual action on insulin release.
      Hence, low concentrations of IAPP brought about a modest increase of basal
      insulin secretion at 7 mM glucose and also of insulin release stimulated by
      carbachol. High concentrations of IAPP, however, inhibited insulin release
      stimulated by glucose (10 and 16.7 mM), IBMX, carbachol and L-arginine. In
      conclusion, our data suggest that IAPP has complex effects on islet hormone
      secretion serving as an inhibitor of glucagon release and having a dual action on
      insulin secretion exerting mainly a negative feedback on stimulated and a
      positive feedback on basal insulin release.

PMID- 12609751
TI  - Somatostatin inhibits intestinal mucosal mast cell degranulation in normal
      conditions and during mast cell hyperplasia.
AB  - Several studies demonstrate that intestinal mucosal mast cells (IMMC) are
      modulated by nervous reflexes as well as by intraluminal content. We recently
      demonstrated that peptones, such as ovalbumin hydrolysate (OVH), induce the
      release of rat mast cell protease II (RMCP II), indicating IMMC degranulation.
      The response is due to complex neuroendocrine reflexes. Somatostatin (SS) and its
      analogues have been used as potential treatments for inflammation in other body
      systems with contradictory results. The aim of this study was to evaluate if
      somatostatin could contribute to the reduction of intestinal mucosal mast cell
      degranulation. Anesthetized rats were prepared for duodenal perfusion and mast
      cell activation was measured by analysis of RMCP II concentration in the duodenal
      perfusate. Somatostatin significantly decreased RMCP II concentration in both
      nonstimulated conditions and after ovalbumin hydrolysate perfusion. However, when
      somatostatin was given previously to OVH, the peptone still induced a slight
      increase of RMCP II. Similar effects were observed in animals previously treated
      with capsaicin. These protocols were repeated in animals infected with
      Trichinella spiralis, which induces mucosal mast cell hyperplasia. In these
      cases, somatostatin blocked the effect of OVH, thus, preventing an increase in
      RMCP II concentration. Fresh frozen tissue sections from the duodenum were
      processed in an attempt to demonstrate the presence of SS receptors in mast cells
      using immunofluorescence and Fluo-peptide labeling techniques. Confocal images
      from duodenum specimens demonstrate the existence of SS receptors in positive
      cells for RMCP II. Taken together, these results indicate that somatostatin
      diminishes mast cell activity and in consequence could prevent the intestinal
      responses to mast cell hyperplasia.

PMID- 12609752
TI  - Serum leptin activity in obese and lean patients.
AB  - Blood levels of the satiety hormone leptin are directly correlated to fat stores
      in obese and lean people. Therefore, leptin resistance is the logical explanation
      for the phenomenon of common obesity. However, the important question of whether
      or not the intrinsic leptin activity could differ between obese and lean people
      has not been examined before. In the present study, serum leptin activity was
      measured by an in vitro assay of leptin signaling in a modified culture of HEK
      293 cells. The system is based on activation of a luciferase reporter gene
      through a leptin receptor-dependent activation of the signal transducer and
      activator of transcription (STAT3). Serum samples from 20 obese and 20 non-obese
      individuals with leptin levels ranging from 3 to 75 ng/ml, as determined by
      radioimmunoassay (RIA), were used. A high correlation was observed for each serum
      sample between leptin RIA values and leptin activity in the bioassay. The results
      indicate that obesity in the 20 obese patients among the 40 individuals examined
      cannot be accounted for by alterations in leptin activity in our assay. The assay
      system provides a tool to screen for possible rare cases exhibiting alteration in
      leptin activity either due to a change in leptin itself or through interaction
      with other serum factors.

PMID- 12609754
TI  - Effects of lipopolysaccharide on neurokinin A content and release in the
      hypothalamic-pituitary axis.
AB  - The administration of bacterial lipopolysaccharide (LPS) markedly affects
      pituitary secretion, and its effects are probably mediated by cytokines produced
      by immune cells or by the hypothalamo-pituitary axis itself. Since neurokinin A
      (NKA) plays a role in inflammatory responses and is involved in the control of
      prolactin secretion, we examined the in vivo effect of LPS on the concentration
      of NKA in hypothalamus and pituitary (assessed by RIA) and serum prolactin levels
      in male rats. One hour after the intraperitoneal administration of LPS (250
      microg/rat), NKA content was decreased in the posterior pituitary but not in the
      hypothalamus or anterior pituitary. Three hours after injection, LPS decreased
      NKA concentration in the hypothalamus and anterior and posterior pituitary. In
      all the conditions tested, LPS significantly decreased serum prolactin. We also
      examined the in vitro effects of LPS (10 microg/ml), interleukin-6 (IL-6, 10
      ng/ml) and tumor necrosis factor alpha (TNF-alpha, 50 ng/ml) on hypothalamic NKA
      release. Interleukin-6 increased NKA release without modifying hypothalamic NKA
      concentration, whereas neither LPS nor TNF-alpha affected them. Our results
      suggest that IL-6 may be involved in the increase of hypothalamic NKA release
      induced by LPS. NKA could participate in neuroendocrine responses to endotoxin
      challenge.

PMID- 12609753
TI  - The role of hypothalamic histamine in leptin-induced suppression of short-term
      food intake in fasted rats.
AB  - OBJECTIVE: Leptin suppresses food intake; however, the precise mechanism is not
      fully understood. Histamine (HA), which acts as a neurotransmitter in the central
      nervous system, has also been shown to be involved in feeding and exerts an
      inhibitory effect through activation of H(1) receptors. Therefore, we studied the
      possible role of HA in short-term leptin-induced suppression of food intake.
      METHODS: We studied the 6-h feeding response of overnight-fasted adult (200 g)
      male Wistar rats to leptin and the HA synthesis inhibitor alpha
      fluoromethylhistidine (alpha-FMH). Levels of transcription for neuropeptide Y
      (NPY) and corticotropin-releasing hormone (CRH), as well as hypothalamic content
      of HA and the HA metabolite telemethyl-HA were investigated. RESULTS: Central
      administration of leptin (3, 5 and 10 microg at 09:00 h) in fasted rats caused a
      decrease in food intake. In contrast, central administration of alpha-FMH (11, 22
      and 112 microg at 09:00 h) increased food intake. Prior administration of alpha
      FMH prevented the leptin-induced decrease in food intake. Leptin decreased
      hypothalamic histamine content, while increasing the ratio between telemethyl-HA
      and HA, indicating that leptin reduces HA metabolism. Finally, alpha-FMH
      suppressed basal and leptin-induced CRH expression while stimulating NPY
      expression in fasted rats. CONCLUSION: Histamine is involved in leptin-induced
      inhibition of food intake. The role of histamine may be mediating, i.e. leptin
      may directly activate and/or change the metabolism of the histaminergic system.
      Alternatively, the histaminergic system may be involved in a permissive manner.

PMID- 12609755
TI  - The effect of endomorphins on the release of 3H-norepinephrine from rat nucleus
      tractus solitarii slices.
AB  - We used two, 3-min field stimulation cycles 30 min apart (S1, S2) in 3H
      norepinephrine-loaded, superfused rat nucleus tractus solitarii-dorsal motor
      vagal nucleus (NTS-DVN) slices. The stimulation-induced release was expressed as
      the area above the baseline. Drugs were introduced 12 min before S2 and drug
      actions were characterized in terms of alterations of S2/S1 ratios. The S2/S1
      ratio was 1.047 (0.946-1.159, n = 4, geometric mean and 95% confidence interval)
      in controls and 0.336 (0.230-0.490, n = 3), 0.726 (0.590-0.892, n = 4), 0.613
      (0.594-0.683, n = 4) and 0.665 (0.500-0.886, n = 4) in the presence of 10(-6) M
      clonidine, D-Ala(2),MePhe(4),Gly(5)-ol-enkephalin (DAMGO), endomorphin-1 (Tyr-Pro
      Trp-Phe-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) [the latter two in the
      presence of 10(-4) M diprotin A, an inhibitor of dipeptidyl-aminopeptidase IV
      (DAP-IV) enzyme]. The effect of DAMGO at 10(-5) M was significantly higher than
      at 10(-6) M, whereas the effect of endomorphins did not differ at the two
      concentration levels. Diprotin A potentiated only very modestly the action of
      endomorphins. These data (a) confirm the presence of functional mu-opioid
      receptors in the vagal complex, (b) render it likely that the enzymic degradation
      of endomorphins is not a highly effective process in brain slices and (c) may
      suggest that the apparent ceiling in the effect of endomorphins might be related
      to their partial agonist property.

PMID- 12609756
TI  - Presence and localization of CCK receptor subtypes in calf pancreas.
AB  - This study was undertaken to confirm the presence of CCK receptor subtypes in
      calf pancreas and establish their cellular localization. Using specific
      antibodies against CCKA and CCKB receptors, somatostatin, glucagon and insulin,
      we were able to confirm by Western blot the presence of both CCK receptor protein
      subtypes in the calf pancreas as a 80-85-kDa CCKA receptor and 40-45-kDa CCKB
      receptor. By immunofluorescence, the CCKB receptor colocalizes with the islets'
      somatostatin delta cells, confirming what was previously shown in other species,
      as well as on ductal cells. We could not reproduce in the calf its colocalization
      with glucagon alpha cells as observed in human and rat. Any specific localization
      of CCKA receptors with our multiple antibodies failed. Our observation that the
      CCKB receptor subtype is specifically localized on pancreatic delta cells as well
      as on ductal cells lets us support the hypothesis that in this species, CCK could
      be involved in somatostatin metabolism as well as hydrelatic secretion; its
      effect on enzyme secretion would be indirect.

PMID- 12609757
TI  - Proteolytic processing of chromogranin A by the prohormone convertase PC2.
AB  - The neuroendocrine secretory protein chromogranin A (CgA) is a precursor for
      various biologically active peptides. Several single and paired basic residues
      are present within its primary amino acid sequence comprising cleavage sites for
      prohormone convertases. In this study, SH-SY5Y human neuroblastoma cells were
      stably transfected with the prohormone convertase PC2 to analyse the proteolytic
      processing of endogenous chromogranin A and, in particular, the formation of the
      chromogranin-A-derived peptide GE-25. Our analyses revealed a significant change
      in the pattern of proteolytic conversion of chromogranin A in cells expressing
      PC2. Mock-transfected control cells contained mainly the intact chromogranin A
      molecule and hardly any shorter products were found. On the other hand, PC2
      transfected cells showed extensive processing of chromogranin A, resulting in
      significantly lower amounts of the intact precursor and especially high levels of
      the free peptide GE-25.

PMID- 12609758
TI  - Intracisternal administration of Angiotensin II AT1 receptor antisense
      oligodeoxynucleotides protects against cerebral ischemia in spontaneously
      hypertensive rats.
AB  - Pharmacological blockade of peripheral and brain Angiotensin II (Ang II) AT(1)
      receptors protects against brain ischemia. To clarify the protective role of
      brain AT(1) receptors, we examined the effects of specific antisense
      oligodeoxynucleotides (AS-ODN) targeted to AT(1) receptor mRNA administered
      intracisternally to spontaneously hypertensive rats (SHRs), 4 and 7 days before
      middle cerebral artery (MCA) occlusion, and we determined the infarct size and
      tissue swelling 24 h after surgery. A single intracisternal injection of AT(1)
      mRNA receptor antisense oligodeoxynucleotides reduced systemic blood pressure for
      5 days and AT(1) receptor binding for at least 4 days in the area postrema and
      the nucleus of the solitary tract. A similar injection of scrambled
      oligodeoxynucleotides (SC-ODN) was without effect. Both blood pressure and AT(1)
      receptor binding returned to normal 7 days after antisense receptor mRNA
      administration. Both the infarction size and the tissue swelling after middle
      cerebral artery occlusion were reduced when the antisense oligodeoxynucleotide
      was administered 7 days, but not 4 days, before the operation. We conclude that 4
      to 5 days of decrease in brain AT(1) receptor binding by a single administration
      of an AT(1) receptor mRNA oligodeoxynucleotide are sufficient to significantly
      protect the brain against ischemia resulting from total occlusion of a major
      cerebral vessel.

PMID- 12609759
TI  - Existence of ghrelin-immunopositive and -expressing cells in the proventriculus
      of the hatching and adult chicken.
AB  - Ghrelin was isolated from the rat stomach as an endogenous ligand for the growth
      hormone secretagogue receptor (GHS-R) and has been found in the gastrointestinal
      tract of many vertebrates. Although the sequence and structure of chicken ghrelin
      has recently been determined, morphological characteristics of ghrelin cells in
      the chicken gastrointestinal tract are still obscure. In this study, we
      investigated ghrelin expression and distribution of ghrelin-producing cells in
      the hatching and adult chicken gastrointestinal tract by RT-PCR,
      immunohistochemistry and in situ hybridization. Ghrelin mRNA expression was
      observed mainly in the proventriculus in the hatching chicken and in the
      proventriculus, pylorus and duodenum of the adult chicken by RT-PCR. Ghrelin
      immunopositive (ghrelin-ip) cells in the proventriculus were located at the
      mucosal layer but not in the myenteric plexus or smooth muscle layer. The number
      of ghrelin-ip cells in the adult chicken was greater than that in the hatching
      chicken. Interestingly, in the adult chicken, the number of ghrelin-ip cells were
      almost the same as that of ghrelin mRNA-expressing (ghrelin-ex) cells; however,
      in the hatching chicken, the number of ghrelin-ex cells was greater than that of
      ghrelin-ip cells. These results clearly demonstrate that ghrelin-producing cells
      exist in the chicken gastrointestinal tract, especially in the proventriculus,
      from hatching to adult stages of development, as well as in mammals.

PMID- 12609760
TI  - Early regulation of hypothalamic arcuate nucleus CART gene expression by short
      photoperiod in the Siberian hamster.
AB  - Cocaine- and amphetamine-regulated transcript (CART) mRNA is expressed in a
      number of hypothalamic nuclei including the arcuate nucleus (ARC). An increase in
      CART gene expression in the ARC of juvenile female Siberian hamsters (Phodopus
      sungorus) 14 days after transfer to short photoperiod at weaning and prior to
      major divergence of body weight trajectory in this seasonal mammal implicates
      CART in the induction of programmed weight change. In the current series of
      experiments, elevated CART mRNA in short photoperiod juvenile female animals
      relative to long photoperiod controls was apparent throughout the caudal-rostral
      extent of the ARC after 14 days, but was not observed when short photoperiod
      exposure was limited to 4-7 days. Elevated CART gene expression was also observed
      in juvenile males 14 days after transfer to short photoperiod at weaning, in
      adult female hamsters 14 days after transfer to short photoperiod and in adult
      male hamsters 21 days after transfer to short photoperiod. There were no
      consistent trends in expression levels of other energy balance-related genes with
      these relatively short duration photoperiod manipulations, suggesting that CART
      may be involved in short photoperiod-programmed body weight regulation.

PMID- 12609761
TI  - Different role of intracellular loops of glucagon-like peptide-1 receptor in G
      protein coupling.
AB  - Previous studies revealed the importance of the third intracellular loop of
      glucagon-like peptide-1 receptor (GLP-1R) in coupling to G(s) and G(i1) proteins.
      In order to further study the signaling mechanisms of GLP-1R, we tested three
      peptides, corresponding to the sequences of the first (IC(1)), the second
      (IC(2)), and the third (IC(3)) intracellular loop of GLP-1R, for their
      interactions with heterotrimeric G-proteins of different types (G(alphas),
      G(alphao), G(alphai1), and G(alpha11) plus G(beta1gamma2)) overexpressed in sf9
      cells. IC(3) peptide powerfully stimulates all types of tested G-proteins,
      whereas IC(1) and IC(2) peptides show differential effects on G-proteins. Both
      IC(1) and IC(2) peptides activate G(s) and cooperate with IC(3) peptide in its
      stimulation. G(o) is not affected by IC(1) and IC(2). G(i1) and G(11) are not
      affected by IC(1), but are activated by IC(2), which in activation cooperates
      with IC(3). We suggest that GLP-1R is not coupled only to G(s) and G(i1), as
      shown previously, but also to G(o) and G(11). IC(3) loop is the main switch that
      mediates signaling via GLP-1R to G-proteins, while IC(1) and IC(2) loops are
      important in discrimination between different types of G-proteins.

PMID- 12609762
TI  - Triple therapy with octreotide, galanin, and serotonin reduces the size and blood
      vessel density and increases apoptosis of a rat colon carcinoma.
AB  - A rat colonic adenocarcinoma was implanted subcutaneously in female nude
      (C57BL/6JBom-nu) mice. After 7 days, the animals were divided into different
      groups. One group received triple therapy with octreotide, galanin, and
      serotonin, 10 microg/kg body weight of each, twice daily. The second group served
      as controls and received only saline solution. Three groups received 10 microg/kg
      body weight twice daily of octreotide, galanin, or serotonin. The last group
      consisted of controls that received only saline solution. The treatment lasted
      for 5 days. The tumour volume, wet weight, and relative volume density of blood
      vessels were significantly decreased after the triple treatment, as compared to
      controls. Apoptotic index was significantly increased, but the proliferation
      index was not affected in the group of mice that received triple therapy. There
      was no significant difference between controls and mice treated with octreotide,
      galanin, or serotonin regarding tumour volume or weight. The relative volume
      density of blood vessels was decreased in tumours treated with galanin, but not
      with octreotide or serotonin. There was no statistical difference in the
      proliferation index between controls and animals treated with octreotide,
      galanin, or serotonin, as compared with controls. Tumour necrosis and increased
      apoptosis may be responsible for the reduction in the volume and weight of the
      tumour after triple therapy. Tumour necrosis may be caused by the induction of
      tumour ischemia due to a reduction in tumour blood flow, which is caused by
      decreased incidence of tumour-feeding blood vessels, and by constriction of
      tumour-feeding arterioles. These results are promising and may offer treatment
      for colon cancer.

PMID- 12609763
TI  - Xenin plasma concentrations during modified sham feeding and during meals of
      different composition demonstrated by radioimmunoassay and chromatography.
AB  - Xenin is a 25 amino acid peptide produced by specific endocrine cells of the
      duodenal mucosa. Xenin has multiple biological actions in the gastrointestinal
      tract. It modulates intestinal motility, affects exocrine pancreatic secretion,
      and gastric secretion of acid. In the present investigation, we studied plasma
      concentration of xenin in volunteers after modified sham feeding and after meals
      of different composition. Plasma xenin concentrations were determined by
      radioimmunoassay in unextracted plasmas and after acidic extraction using C-18
      Sep-Pak chromatography and after neutral extraction using affinity filtration.
      Both extraction methods were followed by C 18 r.p. HPLC chromatography. Xenin
      plasma concentrations in unextracted and in extracted plasma rose significantly
      after modified sham feeding when the food was brought to the volunteers from
      another room immediately before sham feeding started. When the volunteers had the
      opportunity to observe the preparation of the meal, xenin plasma concentrations
      during fasting were high and no further rise was observed after sham feeding.
      Isocaloric feeding resulted in elevated xenin concentrations in unextracted
      plasma and after high-pressure liquid chromatography. The methods of extraction,
      acidic or neutral, did not affect the results. CONCLUSION: Cephalic factors,
      investigated by modified sham feeding, stimulate release of xenin into the
      circulation. Xenin may participate in the central nervous regulation of
      gastrointestinal function.

PMID- 12609764
TI  - Endogenous ghrelin is an orexigenic peptide acting in the arcuate nucleus in
      response to fasting.
AB  - Ghrelin, a circulating growth-hormone releasing peptide derived from stomach,
      stimulates food intake through neuropeptide Y (NPY) neurons of the arcuate
      nucleus in the hypothalamus (ARC). We examined the effect of ghrelin
      microinjected into the ARC and the influence of intracerebroventricular (i.c.v.)
      pretreatment with a GHRH or NPY receptor antagonist on ghrelin-induced food
      intake in free-feeding male rats. Ghrelin (0.1-1 microg) stimulated food intake
      in a dose-dependent manner, and this effect was reduced by 55-60% by the Y(5) NPY
      receptor antagonist (10 microg i.c.v.), but not by the GHRH receptor antagonist
      MZ-4-71 (10 microg i.c.v.). We also evaluated the effects of passive ghrelin
      immunoneutralization by the microinjection of anti-ghrelin immunoglobulins (IgGs)
      intracerebroventricularly or directly into the ARC on food intake in free-feeding
      and fasted male rats. i.c.v. administration of anti-ghrelin IgGs decreased
      cumulative food intake over 24 h, whereas microinfusion of anti-ghrelin IgGs into
      the ARC induced only a short-lived (2 and 6 h) effect. Collectively, these data
      would indicate that centrally derived ghrelin has a major role in the control of
      food intake in rats and, in this context, blood-born ghrelin would be effective
      only in relation to its ability to reach the ARC, which is devoid of blood-brain
      barrier.

PMID- 12609765
TI  - Hematopoietic growth factor inducible neurokinin-1 type: a transmembrane protein
      that is similar to neurokinin 1 interacts with substance P.
AB  - Neurokinin 1 (NK-1) is a member of seven transmembrane G protein-coupled
      receptors. NK-1 interacts with peptides belonging to the tachykinin family and
      showed preference for substance P (SP). NK-1 is induced in bone marrow (BM)
      stroma. NK-1-SP interactions could lead to changes in the functions of
      lymphohematopoietic stem cell (LHSC). This report describes the cloning and
      characterization of a cDNA clone isolated after screening of three cDNA libraries
      with an NK-1-specific probe. Based on its expression, the cDNA clone was
      designated hematopoietic growth factor inducible neurokinin-1 type (HGFIN).
      Computational analyses predicted that HGFIN is transmembrane with the carboxyl
      terminal extracellular. Proteomic studies with purified HGFIN and SP showed
      noncovalent interactions. HGFIN-SP interactions were supported by transient
      expression of HGFIN in CHO cells. Transient expression of HGFIN in unstimulated
      BM fibroblasts led to the induction of endogenous NK-1. Since NK-1 expression in
      BM fibroblasts requires cell stimulation, these studies suggest that there might
      be intracellular crosstalk between NK-1 and HGFIN. Northern analyses with total
      RNA from different BM cell subsets showed that HGFIN was preferentially expressed
      in differentiated cells. This suggests that HGFIN might be involved in the
      maturation of LHSC. HGFIN was detected in several other tissues, but not in brain
      where NK-1 is constitutively expressed.

PMID- 12609766
TI  - Angiotensins in plasma of hypertensive rats and human.
AB  - The plasma levels of des-aspartate-angiotensin I (DAA-I) in three models of
      hypertensive rats and hypertensive subjects were determined and compared with
      their normotensive controls. The rationale for the study was based on our earlier
      findings showing that DAA-I is a physiological angiotensin peptide that is
      involved in the pathophysiology of the cardiovascular system. The determination
      was carried out by the technique of capillary electrophoresis. Plasma level of
      angiotensin I, angiotensin II, and angiotensin III was also determined as a
      measurement of the status of the renin-angiotensin system in the different models
      of hypertension. DAA-I was found to be significantly lower in the spontaneously
      hypertensive rats (SHR) (46.6 +/- 2.5 pmol/l compared to 66.1 +/- 3.4 pmol/l for
      the normotensive control Wistar Kyoto rats), renal hypertensive rats (54.2 +/-
      5.1 pmol/l compared to 72 +/- 2.5 pmol/l for the normotensive control Sprague
      Dawley rats), and essential human hypertensive subjects (15.2 +/- 0.9 pmol/l
      compared to 19.5 +/- 2.5 pmol/l for the normotensive adult), whilst plasma
      concentration of angiotensin I and angiotensin II is reflective of the state of
      the renin-angiotensin system in the particular model of hypertension. When the
      SHR and human hypertensive subjects were treated with an angiotensin converting
      enzyme (ACE) inhibitor, the plasma level of DAA-I increased significantly. These
      findings suggest that the low plasma level of DAA-I could be a characteristic
      defect of the renin-angiotensin system in the two genetic models of hypertension
      (SHR and human essential hypertensive subjects). The increase of the nonapeptide
      following ACE inhibitor treatment could be an important hitherto unrecorded
      contributory factor to the effectiveness of ACE inhibitors in combating heart
      pathology.

PMID- 12609768
TI  - The effects of sarmesin, an Angiotensin II analogue on seizure susceptibility,
      memory retention and nociception.
AB  - The present research studies the effects of sarmesin [Sar(1)Tyr(OMe)(4)]
      Angiotensin II (ANG II), an analogue of ANG II, on the seizure susceptibility,
      memory activity and nociception. It was found that this octapeptide, administered
      i.c.v., dose-dependently decreased the seizure intensity (pentylenetetrazol (PTZ)
      generalized seizure model and PTZ kindling) and augmented PTZ seizure threshold
      in mice. Sarmesin impaired the memory upon re-testing of rats 24 h later in the
      passive avoidance test. It decreased the pain threshold in a paw pressure
      nociceptive assay in rats. ANG II exerted pronociceptive effect as well. Taken
      together, these results reveal sarmesin as a behaviorally active peptide in the
      studied experimental animal models.

PMID- 12609767
TI  - Evidence on the presence of secretin cells in the gastric antral and oxyntic
      mucosa.
AB  - Secretin is released from upper small intestinal mucosa to drive pancreatic
      secretion of fluid and bicarbonate and inhibit gastric acid secretion. Recently,
      we found that, in isolated, vascularly perfused rat stomach model, the inhibition
      of acid secretion by pituitary adenylate cyclase activating polypeptide (PACAP)
      was mediated in part via local release of secretin. However, the presence of
      secretin-producing cells and mRNA in gastric mucosa, particularly in oxyntic
      mucosa, has not been established. The present study was carried out to establish
      the presence of secretin cells by immunohistochemical and mRNA by biochemical
      methods in gastric mucosa. Secretin cells were identified in antral mucosa (27.8
      +/- 2.0 cells/mm(2)) and corpus (4.7 +/- 0.5 cells/mm(2)). They were
      distinguishable, through double immunostaining, from gastrin and somatostatin
      cells in the antrum and from somatostatin cells in the corpus. The results of
      reverse transcription (RT)-PCR and Southern blot indicated that a secretin gene
      transcript of 454 bp was present in the mRNA extracts of both antral and corpus
      mucosae. The results indicated that secretin mRNA is present in gastric mucosa.
      In conclusion, secretin-producing cells and mRNA are present in gastric mucosa
      and the locally released secretin may exert a paracrine effect to inhibit acid
      secretion.

PMID- 12609769
TI  - Degradation of thymic humoral factor gamma2 by human plasma: involvement of
      angiotensin converting enzyme.
AB  - The degradation of thymic humoral factor-gamma2 (THF-gamma2), an immunoregulatory
      octapeptide important for T-lymphocyte regulation, by enzymes present in human
      plasma, was investigated. THF-gamma2 was metabolized through two steps that
      involved the detaching of N-terminal amino acid leucine followed by hydrolysis of
      the Lys(6)-Phe(7) bond. The THF-gamma2 cleavages were sensitive to aminopeptidase
      and metalloproteinase inhibitors. The degradation was completely blocked by
      amastatin and specific inhibitors of angiotensin converting enzyme (ACE). The
      cleavages occurred independently, with two different kinetics, faster for the N
      terminal hydrolysis than for that of the Lys(6)-Phe(7) bond. Purified human
      plasma ACE was used to characterize the hydrolysis of Lys(6)-Phe(7) bond. The
      K(m) and K(cat) values for THF-gamma2 hydrolysis were 0.273 mM and 107 s(-1),
      respectively. The optimum of chloride concentration was 300 mM, while that of pH
      was 7.6. The presence of ACE in circulating mononuclear cells raises the
      possibility that it may play a role in modulating the THF-gamma2 activity.

PMID- 12609770
TI  - Glucagon-like peptide-1 inhibits glucagon-induced glycogenolysis in perivenous
      hepatocytes specifically.
AB  - Hepatocytes form the hepatic acinus as a unit of microcirculation. Following the
      bloodstream, at least two different zones can be discerned: the periportal (PPH)
      and the perivenous (PVH) zones. Recently, we found that insulin inhibits glucagon
      induced glycogenolysis in PVH specifically. We therefore investigated the region
      specific functional effects of glucagon-like peptide-1 (GLP-1), which is known to
      have an insulin-like activity, on glucagon-induced glycogenolysis in isolated PPH
      and PVH prepared by the digitonin-collagenase method. GLP-1 inhibited 0.1 nM
      glucagon-induced increase in glucose release from the PVH of fed rats
      specifically (p < 0.01) and had an additive effect with insulin. Insulin binding
      did not differ between PPH and PVH of fed rats. GLP-1 did not displace [125I]
      glucagon binding to the purified hepatic cell membrane. Thus, it is directly
      confirmed that GLP-1 has an insulin-like activity in the liver.

PMID- 12609771
TI  - Differential effects of VIP and PACAP on survival of cultured adult rat myenteric
      neurons.
AB  - Our knowledge of neuroprotective factors important for the adult enteric nervous
      system is poor. Changes in expression of vasoactive intestinal peptide (VIP) and
      pituitary adenylate cyclase-activating peptide (PACAP) in enteric neurons in
      response to neuronal injury or colchicine treatment, as well as in intestinal
      adaptation, have been described. Cultured myenteric neurons increase their
      expression of VIP; furthermore, culturing myenteric neurons in the presence of
      VIP enhances neuronal survival. The aims of this study were to evaluate possible
      changes in PACAP expression in dissociated and cultured myenteric neurons from
      adult rat small intestine, and to determine the ability of PACAP-38 and PACAP-27
      to promote survival of cultured myenteric neurons, as compared with that of VIP.
      A marked decrease in the number of surviving neurons was noted during culturing.
      No difference in neuronal survival was found after culturing in the presence of
      PACAP-38 or PACAP-27, whereas VIP significantly increased neuronal survival. In
      contrast to the marked increase noted in the number of VIP-expressing neurons,
      culturing caused no change in the number of PACAP-expressing myenteric neurons.
      We were thus able to demonstrate that VIP, but not PACAP, promoted survival of
      myenteric neurons in culture. This suggests the presence of a VIP-specific
      receptor mediating neuroprotection in adult myenteric neurons.

PMID- 12609773
TI  - Xeroderma pigmentosum.
AB  - Xeroderma pigmentosum is a rare disorder transmitted in an autosomal recessive
      manner. Xeroderma pigmentosum is based on a genetic defect in the DNA repair
      system. This disease manifests in early childhood. Patients with xeroderma
      pigmentosum have a marked sensitivity to sunlight and develop serious sunburns
      with onset of poikilodermia in the light-exposed skin. Squamous cell carcinomas,
      basal cell carcinomas and malignant melanomas already appear in childhood. The
      majority of patients die before reaching adulthood because of metastases.
      Genetically, xeroderma pigmentosum is divided into 7 complementation groups (XP-A
      to XP-G) and the xeroderma pigmentosum variants (XP-V). Diagnostically,
      assignment to the specific complementation group is made according to the
      fusioning of xeroderma pigmentosum fibroblasts. Differential diagnosis must
      distinguish xeroderma pigmentosum from other so-called DNA-repair-deficiency
      syndromes like the Cockayne Syndrome and trichothiodystrophy. Currently, there
      are reports of successful application of a topical DNA Repair Enzyme. This is a
      recombinant liposomal encapsulated T4 endonuclease V, which repairs UV-induced
      cyclobutan-pyrimidine dimers. In future, causal therapy could be based on gene
      therapy. The introduction of an intact repair gene which specifically codes the
      repair protein, could open new possibilities in the treatment of xeroderma
      pigmentosum.

PMID- 12609774
TI  - Vaccine allergy and pseudo-allergy.
AB  - Allergic and pseudo-allergic reactions to vaccines frequently involve the skin,
      and can be generalized systemic symptoms (urticaria/angioedema, serum sickness,
      flares of eczema) or localized at the sites of vaccination (persistent nodules,
      abcesses, granulomas). Diagnosis of Arthus-type reactions is based on clinical
      history and specific IgM/IgG anti-toxoid determination. For other local
      reactions, diagnostic value of non-immediate responses in skin tests varies with
      clinical symptoms and substances involved. Immediate responses in skin tests and
      specific IgE determination have good diagnostic and/or predictive value in
      anaphylaxis and immediate/accelerated urticaria/angioedema to toxoid-,
      pneumococcus-, and egg- and gelatin-containing vaccines. Diagnosis of reactions
      to dextran in BCG is based on specific IgM/IgG determination. Most non-immediate
      generalized reactions result from non-specific inflammation, except for gelatin
      containing vaccines, but the diagnostic value of immuno-allergological tests with
      the vaccines and gelatin are controversial. Withholding booster injections is
      advised if specific IgM/IgG levels are high. If the levels are low, sequential
      injections of vaccines containing a single vaccinating agent are usually
      tolerated. However, injections of the vaccine should be performed using a "
      desensitization " procedure in patients reporting anaphylaxis and
      immediate/accelerated urticaria/angioedema.

PMID- 12609775
TI  - 47 patients in 14 families with the rare genodermatosis keratosis punctata
      palmoplantaris Buschke-Fischer-Brauer.
AB  - We summarize the clinical data of 47 patients with the rare genodermatosis
      keratosis punctata palmoplantaris Buschke-Fischer-Brauer. The pedigrees of 14
      German families were studied. In three families there was only one member
      affected, two or more affected members were found in the other families. These
      family pedigrees were consistent with autosomal dominant inheritance. Variable
      expression of the disease was noted in members within one family. Over pressure
      points punctate keratoses coalesced into hyperkeratotic plaques. There was
      palmoplantar hyperhidrosis in 3 families associated with keratosis. Continuous
      systemic retinoid treatment can clear symptoms. Future genetic classification on
      a molecular basis may reveal the existence of more than one entity of this
      clinically heterogeneous genodermatosis.

PMID- 12609776
TI  - Melorheostosis with ipsilateral nevus sebaceus (didymosis melorheosebacea).
AB  - We report an unusual case of unilateral melorheostosis and ipsilateral extensive
      sebaceous nevus. Because the two conditions affected the same side of the body,
      we hypothesize that they originated from a common genetic mechanism. The temporal
      and spatial co-occurrence may represent a further example of non-allelic
      didymosis (twin spotting). The embryo would carry two different recessive
      mutations at one gene locus or at linked loci on either of a pair of homologous
      chromosomes. Postzygotic recombination occurring during early embryonic
      development would result in two different populations of cells homozygous for
      either mutation. If this concept holds true, the present case may be described as
      " didymosis melorheosebacea ".

PMID- 12609777
TI  - The association of pityriasis rosea with cytomegalovirus, Epstein-Barr virus and
      parvovirus B19 infections - a prospective case control study by polymerase chain
      reaction and serology.
AB  - A viral aetiology is suspected for pityriasis rosea (PR). The objective was to
      investigate the association of PR with cytomegalovirus (CMV), Epstein Barr virus
      (EBV) and parvovirus B19 infections. Patients with PR were recruited in a primary
      care setting over 18 months. Blood was collected at initial presentation and four
      weeks later. Controls were the next age-and-sex-matched patients requiring blood
      collection for non-dermatological disease. Polymerase chain reaction was
      performed for EBV and parvovirus B19 DNA. Serology was done for CMV, EBV and
      parvovirus B19. 12 patients with PR and 12 control subjects were recruited. No
      patient had viral DNA or significant antibody rise against any of the viruses
      investigated. The seroprevalence of all three viruses and Ab titres in the
      patients with PR were insignificantly different from those of control subjects.
      Two patients had IgM detectable against CMV and EBV respectively. Based on other
      investigation results, we believe that both IgM results were caused by cross
      reactivity. PR is not associated with CMV, EBV or parvovirus B19 infections.

PMID- 12609779
TI  - Melanocyte transplantation for the treatment of vitiligo: effects of different
      surgical techniques.
AB  - This paper presents the results of a pilot clinical trial study, conducted on 11
      patients with stable vitiligo at the vitiligo outpatient clinic of The Unicamp
      University Hospital, between March 2000 and December 2001. This study was in
      accordance with the ethical standards of the Institutional Review Board. The
      patients were concomitantly treated with four different types of surgical
      techniques in 44 areas randomly chosen. There was a 90-day follow-up period. The
      following treatments were carried out: only cryotherapeutic treatment (OC);
      cryotherapy plus melanocyte culture medium (CM); cryotherapy plus transplantation
      of non-cultured melanocytes and keratinocytes (KM); and cryotherapy plus
      transplantation of cultured melanocytes (CC). The appearance of repigmentation
      and its evolution were followed all along the treatments. In the case of OC and
      CM no repigmentation occurred. Progressive repigmentation was observed over a
      period of 90 days in the case of KM and CC. In these two groups there was a
      significant reduction in the achromic areas during this time but no significant
      difference was found between the two treatments.

PMID- 12609778
TI  - Mitogen requirements of normal epidermal human melanocytes in a serum and tumor
      promoter free medium.
AB  - Normal human melanocytes were cultivated in a serum free medium and the
      proliferation rate and antigen expression in the absence of each supplement was
      assessed every 3 days for 3 weeks. Results showed that the proliferation rate was
      significantly decreased in the absence of basic fibroblast growth factor, insulin
      and bovine pituitary extract as assessed 3 and 6 days of incubation (< 0.01).
      From day 9 through day 21, absence of transferrin, hydrocortisone, calcium,
      cholera toxin and epidermal growth factor was associated with a significant
      decrease of proliferation (< 0.001). Cells incubated with plain medium were
      almost absent from culture plates on day 6 and afterwards (< 0.0001). No evidence
      of contamination by epidermal and dermal cells was detected as all cultivated
      cells were labeled with MAbs HMB-45 and K.1.2.58. Absence of each supplement did
      not substantially affect antigen expression. It is concluded that basic
      fibroblast growth factor, insulin, and bovine pituitary extract are significant
      mitogens for melanocytes grown in a serum free medium from the very early phases
      of their growth.

PMID- 12609780
TI  - Successful treatment of non-healing cases of cutaneous leishmaniasis, using a
      combination of meglumine antimoniate plus allopurinol.
AB  - Cutaneous leishmaniasis (CL) is endemic in many countries. It has been recognized
      as a major public health problem in Iran. The pentavalent antimonials are the
      first line drugs for the treatment of CL. Recently strains resistant to these
      drugs have been reported. Allopurinol (AL) has also been suggested for treatment
      of CL. The efficacy of combination of AL and meglumine antimoniate (MA) in
      treatment of non-healing cases of CL was evaluated. Non-healing cases of CL have
      been treated with combination of AL (20 mg/kg for 30 days) and meglumine
      antimoniate (60 mg/kg per day for 20 days). Twenty-six patients with lupoid
      leishmaniasis, 6 patients with chronic leishmaniasis and 5 patients who had
      unhealed leishmaniasis due to leishmanization were accepted for the study. All of
      the patients except two responded well to treatment, no side effects have been
      observed and a two year follow up showed no recurrence. A combination of AL and
      MA increase the antileishmanial effects of antimoniate. We suggest this
      combination therapy for non-healing and resistant cases of CL.

PMID- 12609781
TI  - The use of lymecycline in the treatment of moderate to severe acne vulgaris: a
      comparison of the efficacy and safety of two dosing regimens.
AB  - We compared the efficacy and safety of lymecycline 300 mg od vs lymecycline 150
      mg bid or placebo in the treatment of moderate to severe acne. 271 patients
      received either oral lymecycline 300 mg od + placebo od, lymecycline 150 mg bid,
      or placebo bid, for 12 weeks. Reduction in inflammatory lesion counts at week 12
      was the primary efficacy variable (global improvement was a primary efficacy
      parameter vs placebo) and safety was assessed by adverse events. Lymecycline 300
      mg od was non-inferior to lymecycline 150 mg bid at all time points and superior
      to placebo throughout the study. Drug-related adverse events were similar for all
      treatment groups. Lymecycline 300 mg od is as effective and safe as lymecycline
      150 mg bid in the treatment of moderate to severe acne. This new, once daily
      formulation could potentially contribute towards improved compliance rates with
      oral tetracyclines.

PMID- 12609782
TI  - Dermatologic radiotherapy of primary cutaneous follicle center cell lymphoma.
AB  - A retrospective study was performed to evaluate the results of dermatologic
      radiotherapy in a large series of patients affected by primary cutaneous B-cell
      lymphomas. The study included 104 patients with cutaneous follicle center cell
      lymphoma treated with orthovoltage radiotherapy from 1973 to 2000. The total
      doses ranged from 14 to 35 Gy (mean 23.55 Gy). Results regarded 102 patients
      (mean follow-up 65.08 months). Complete remission was observed in all cases; 76
      patients experienced a relapse after a mean interval of 22.03 months following
      radiotherapy, with a relapse-free rate of 22.82 % after 5 years. Extracutaneous
      progression was observed in 9 cases (8.82 %). An overall actuarial survival rate
      of 97.36 % was observed after 5 years. A salvage treatment of relapses brought 44
      cases to remission. Although we have observed a relapse-free rate lower than that
      reported by others, dermatologic radiotherapy was "curative" in 25.49 % of cases.
      Such treatment appears particularly useful in the cases with few lesions and in
      the management of new cutaneous localizations of follicular center cell lymphoma.

PMID- 12609783
TI  - Cinnarizine is a useful and well-tolerated drug in the treatment of acquired cold
      urticaria (ACU).
AB  - Old generation H1-type antihistamines are the standard therapeutic option for
      acquired cold urticaria (ACU), but adverse effects are common. New antihistamines
      are well tolerated but efficacy is often poor. The present study aims to evaluate
      efficacy and safety of cinnarizine in the treatment of ACU patients intolerant to
      old antihistamines and resistant to new drugs. We studied 14 patients (4 males
      and 10 females). Mean duration of the disease was 48.9 (range 7-102) months. Cold
      cube test was positive in 78.6 % of patients. Cold urticaria was idiopathic in 10
      (71.4 %) patients. Cryoglobulins were detected in the serum of 4 cases (28.6 %).
      Cinnarizine (25 mg t.i.d.) was administered for 3 months, and then it was gently
      tapered off and stopped within 2 months. A complete or good response was obtained
      in 8 (57.1 %) and 2 (14.3 %) patients, respectively. Only two patients were
      unresponsive (21.4 %). Tapering off or stopping cinnarizine was followed by the
      relapse of cold urticaria in 7 cases (50.0 %). These patients were amenable to a
      second treatment cycle. Six patients (42.9 %) had a persistent remission. A
      patient interrupted the therapy because of severe vertigo. Three patients
      reported mild and transitory adverse effects including epigastralgia, weight gain
      and drowsiness. In conclusion, cinnarizine at high doses may be considered as an
      effective and well-tolerated treatment for ACU.

PMID- 12609784
TI  - Laser therapy of giant congenital melanocytic nevi.
AB  - Giant congenital melanocytic nevi (GCMN) are rare disfiguring potentially
      malignant lesions present at birth. The approach of these patients is based on
      two main considerations: attempt to minimize the risk of malignancy, and obtain
      an acceptable cosmetic result. Sometimes they are too large to be removed by
      multiple surgical excision or by use of osmotic expander. The objective of
      treatment of giant congenital nevi is to obtain ablation without side effects or
      after-effects from aesthetics. But for the moment such treatment doesn't exist.
      The aim of this review was to access treatment of GCMN with lasers as an
      alternative to surgery. Lasers should only be regarded as a treatment option for
      GCMN that cannot be surgically excised. For the moment laser therapy of GCMN
      should be restricted to well controlled studies or to individual patients in whom
      surgical procedures are not possible or would result in unacceptable scarring.
      Today ultrashort high energy pulsed CO2 laser and the normal mode ruby laser are
      the two lasers available. But the results are too unforeseeable, and painful with
      these two lasers. The combined use of normal mode and Q-switched ruby lasers or
      ultrashort high energy pulsed CO2 laser and Q-switched ruby or Nd:YAG lasers can
      give us a solution. In the future perhaps new Q-switched laser could give us a
      better way of treatment, with less pain, and no scars. We need an improvement of
      the technology in this field and hopefully the picosecond systems will be
      available in the future.

PMID- 12609785
TI  - Comedolysis by a lipohydroxyacid formulation in acne-prone subjects.
AB  - Post-summertime exacerbation of acne is not a rare event. This study was
      conducted to assess the preventive effect of a proprietary formulation containing
      2-hydroxy-5-octanoyl benzoic acid on this environmental related disease. This
      compound is commonly called beta-lipohydroxyacid (LHA). Among a randomized group
      of 14 acne-prone women, 12 who developed cornified follicular plugs the end of
      summertime were treated by the LHA formulation twice daily for 2 weeks. Ten of 14
      other women who presented the same skin condition remained untreated as controls.
      The comedolytic effect was assessed using non-invasive ultraviolet-light video
      recording combined with computerized image analysis. The cornified follicular
      plugs were progressively cleared in 10/12 LHA-treated women and in 3/10 untreated
      volunteers. Analytical assessments showed a significant decrease in both the
      number and total size of microcomedones in the LHA-treated women. By contrast, no
      quantitative change was disclosed in the untreated group. It is concluded that
      the tested LHA formulation exerts comedolytic properties that might help in
      preventing post-summertime acne exacerbations.

PMID- 12609786
TI  - Efficacy and tolerability of natural synergised pyrethrins in a new thermo labile
      foam formulation in topical treatment of scabies: a prospective, randomised,
      investigator-blinded, comparative trial vs. permethrin cream.
AB  - We compared in a prospective, randomised, investigator-blinded trial, the
      efficacy and tolerability of a new synergised-pyrethrins thermo-labile foam (F)
      formulation with permethrin 5 % cream (P) in 40 patients with scabies. Clinical
      evolution of scabetic lesions (Clinical grading = CG) and itching intensity (IS)
      were assessed, using a 5-point semi-quantitative score, at baseline, at week 2
      and 4. F and P were equally effective in the clinical resolution of scabetic
      lesions. As compared to baseline, P reduced CG and IS from 3.4   0.7 and 3.1  
      0.4 to 0.2   0.6 and 1.4   1, at week 2, and to 0.0   0.0 and 0.1   0.3 at week
      4, respectively (P < 0.001). F reduced CG and IS from 3.3   0.5 and 3.2   0.4 to
      0.05   0.2 and 0.4   0.6 (week 2) and to 0.0   0.0 and 0.0   0.0 (week 4),
      respectively (P < 0.0001). As compared to P group, the IS in F group, at week 2,
      was significantly lower (0.4   0.6 vs. 1.4   1.1) (P < 0.0013). This foam
      formulation was at least as effective as permethrin 5 % cream in the treatment of
      scabies. In comparison with permethrin the foam induced a more rapid and complete
      resolution of itching.

PMID- 12609787
TI  - Changes from mid-1980s to late 1990s among clinical and demographic correlates of
      melanoma thickness.
AB  - Tumour thickness is the most relevant prognostic factor for cutaneous melanoma.
      Although the increasing incidence of melanoma is currently attributable to "thin"
      lesions, the incidence rates of "thick" melanomas have not declined. We want to
      identify the clinical and demographic characteristics of patients that are
      associated with diagnosis of thick (> 3 mm) cutaneous melanoma and whether they
      had changed from mid-1980s to late-1990s. Cutaneous malignant melanomas incidence
      in 1985-87 and in 1995-97 were retrieved from the Tuscany Cancer Registry,
      central Italy. Only cases with Breslow-thickness information (182/260 in 1985-87
      and 387/490 in 1995-97) were included. Thickness was categorised in < = 1 mm, 1-3
      mm and > 3 mm. Thickness was evaluated for each period of time according to
      gender, age, histological type, site and residence. For cases diagnosed in 1995
      97 the effect of such variables in predicting the risk of a thick tumour (vs. a
      thin one) was analysed in a logistic model. In 1985-87 patients with thick
      melanoma were more likely to be - with a statistically significant difference -
      males (38.1 % of thick tumours) than females (19.4 %), over 70 (57.7 % of thick
      tumour), with nodular melanoma (62.1 %) and residents far from the city of
      Florence (30.3 %); no differences were evidenced according to site. From 1985-87
      to 1995-97 there was a global shift towards thinner melanomas. In 1995-97 nodular
      type and old age were the only variables significantly associated with thick
      melanomas when other factors were taken into account in a multivariate analysis.
      According to most recent data, early detection activities should be focused on
      older patients and on nodular histotype. Male sex and residence was no longer
      found to be associated with late melanoma diagnosis.

PMID- 12609788
TI  - Skin cancer day in Italy: method of referral to open access clinics and tumor
      prevalence in the examined population.
AB  - Education campaigns to encourage self-examination coupled with rapid access to
      specialized dermatological clinics is considered the key strategy in the
      realization of early detection of cutaneous melanoma and non-melanoma skin cancer
      (NMSC). An alternative to an initial visit to the family doctor is open access to
      a skin cancer clinic at the decision of the individual. This approach has been
      followed mainly in countries with high melanoma incidence where the majority of
      the population is of northern European origin. However, the efficacy of this
      system has not been well established because there are few studies involving
      systematic follow up of individuals with positive screening through pathological
      confirmation of the diagnosis. We report the follow up data focussed on melanoma
      and NMSC detection rates in more than 1,000 subjects examined at numerous 1-day,
      open access clinics on the occasion of the Italian nation-wide "Skin Cancer Day"
      campaign promoted by the Federation of Italian Dermatological Societies. Total
      body skin examination was performed on all subjects, and surgical excision of a
      lesion was recommended in 41 of the 1042 subjects (3.9 %). Histologic diagnosis,
      available for 39/41 lesions, evidenced 3 superficial spreading melanomas (1 in
      situ, one "thin" lesion, ie. 0.30 mm in thickness, and one "thick" lesion, with a
      thickness of 4.53 mm) and 6 NMSC (5 BCC and 1 SCC). Thus, the prevalence of skin
      cancer (melanoma and NMSC) in this group was 0.8 % (9/1042), and the prevalence
      of melanoma was 3/1042, 0.2 %, rather similar to that found in populations of
      northern European origin. Open access to skin cancer clinics may represent an
      alternative approach to melanoma prevention also in southern European
      populations. Increased public awareness regarding skin cancer probably represents
      the main effect of this type of campaign.

PMID- 12609789
TI  - Topical treatment with imiquimod may induce regression of facial keratoacanthoma.
AB  - Keratoacanthoma (KA) is a rapidly growing tumour histologically resembling
      squamous cell carcinoma. Although it may regress spontaneously, KA is routinely
      treated by excision or radiation therapy. Here we report on the successful
      therapeutic use of imiquimod for the treatment of KA. Four patients with a one to
      six week history of facial KA were treated with imiquimod cream 5 % every second
      day for four to 12 weeks. In each patient, KA fully regressed under topical
      treatment with imiquimod. In three of the patients, KA had disappeared within
      four to six weeks. In two patients, disappearance was confirmed histologically.
      No recurrence occurred during a four- to six-month follow-up-period. Our
      observations indicate that topical immunostimulation with imiquimod may induce or
      promote immune defence mechanisms leading to KA regression. Imiquimod might
      therefore prove to be an effective non-invasive treatment modality for KA that
      warrants more extensive evaluation by clinical studies.

PMID- 12609790
TI  - Staging of classic Kaposi's sarcoma: a useful tool for therapeutic choices.
AB  - Three hundred patients with classic Kaposi's sarcoma (CKS) have attended our
      Department of Dermatology over a period of 20 years. Many of them have been
      treated by systemic chemotherapy with good responses. Due to the highly variable
      clinical evolution of the disease, it was, however, often difficult for us to
      decide whether or not to treat elderly patients. We therefore attempted to
      establish a new staging system based on objective criteria that more closely
      follow the clinical variability of CKS and make the therapeutic choices easier.
      The proposed staging system comprises 4 stages, each further divided according to
      the speed of disease evolution and presence of complications that can severely
      impair the quality of life. The application of this staging system to our
      patients has shown that evolution is prevalently slow in the maculo-nodular and
      infiltrative stages I and II and faster during the florid and disseminated stages
      III and IV. Complications are mainly present in the rapidly evolving florid and
      disseminated stages, with visceral involvement in the more aggressive forms.
      Based on these findings, we are employing systemic therapy in the florid and
      disseminated stages and in the infiltrative stage only in case of rapidly
      evolving or slowly evolving but complicated disease.

PMID- 12609791
TI  - Creeping eruption caused by a larva of the suborder Spirurina type X.
AB  - We report a case of creeping eruption caused by a larva of the suborder Spirurina
      type X, which developed in a 46-year-old Japanese male. The patient ate small raw
      squids (Watasenia scintillans) 5 days before the onset of symptoms. On
      examination, an approximately 25-cm-long serpiginous red track with vesicles was
      observed from the right to the upper left side of the abdomen of the patient.
      Histological examination revealed the transverse section of a larval worm in the
      upper to middle dermis.The patient serum was positive only for the antibody
      against larvae of the suborder Spirurina type X in ELISA, and negative for all
      other anti-parasite antibodies. Because a considerable number of people are fond
      of eating raw or nearly-raw fish and shellfish in Japan, opportunities for
      developing creeping eruption cause by parasites present in raw fish and shellfish
      are relatively high.

PMID- 12609792
TI  - Cutaneous manifestations as initial presentation of Waldenstrom's
      macroglobulinemia.
AB  - Waldenstr m's Macroglobulinemia is a rare chronic lymphoproliferative disease.
      Clinical manifestations include usually weakness, weight loss, lymphadenopathy.
      Lung, kidney, heart, nervous system or bone may be involved. Cutaneous
      manifestations are unusual and misunderstood. Two different types of cutaneous
      lesions are described: non-specific and specific. They may reveal the disease or
      appear during the course of it. We report a case of a Waldenstr m's
      Macroglobulinemia with cutaneous involvement.

PMID- 12609793
TI  - Rectal carcinoma associated with pagetoid phenomenon.
AB  - A 64-year-old woman was referred to our hospital with complaints of erosion in
      the anal region and rectal bleeding. The histopathological examination revealed
      Paget cells in an epidermis lesion of the skin and rectal carcinoma. The cells
      were positive for PAS, CEA, and CK20, and negative for GCDFP15 and CK7. Electron
      microscopic examination revealed the presence of many microvilli in the epidermal
      Paget cells as well as in the tumor cells and rectum itself. The results
      suggested that electron microscopy is a very useful technique to differentiate
      extramammary Paget's disease and pagetoid phenomenon. In the present case, the
      perianal skin lesion was proved to be due to intraepidermal spread of the rectal
      carcinoma, or so-called pagetoid phenomenon.

PMID- 12609794
TI  - Adult purpura fulminans associated with staphylococcal infection and
      administration of colony-stimulating factors.
AB  - Purpura fulminans (PF) is a rare syndrome of progressive haemorragic necrosis due
      to disseminated intravascular coagulation (DIC) and dermal vascular thrombosis
      leading to purpura and tissue necrosis. PF is more often associated with either a
      benign infection or a severe sepsis. Rarely, it has been related to drug intake.
      We report the case of a 24-year-old female patient who suffered from
      staphylococcal sepsis and pancytopenia, for which she was treated with
      antibiotics, granulocyte-colony stimulating factor (G-CSF) and
      granulocyte/macrophage CSF (GM-CSF). Two days after the last GM-CSF dose, she
      developed widespread necrotic plaques with erythematous borders and purpura in
      the breast, arms and legs. Coagulation tests indicated DIC and a skin biopsy
      showed fibrin thrombi in the superficial dermal vessels. The patient totally
      recovered after removal of the necrotic tissues and application of skin
      autografts. Although staphylococcal infection was most probably involved in the
      development of PF, a role of CSF cannot be excluded in this case.

PMID- 12609795
TI  - IFN-gamma -positive immunostaining in psoriatic lesional keratinocytes--reply to
      the comments of McKenzie et al.

PMID- 12609796
TI  - The presence of IFN-alpha immunostained cells in the psoriatic epidermis.

PMID- 12609797
TI  - Cutaneous aspergillosis in a patient with follicular lymphoma.

PMID- 12609799
TI  - [Current concepts on apoptotic signalling pathways: new targets for anticancer
      strategies].
AB  - Apoptosis is an essential physiological process that plays a critical role in
      development and cellular homeoastasis. This process is tightly regulated through
      multiple independent signalling pathways. Defects in apoptosis may contribute
      both to tumorigenesis and drug resistance. Understanding the molecular events
      that contribute to apoptosis enable a more rational approach to anticancer
      strategy development. These strategies will allow not only the development of new
      molecules targeting recently elucidated apoptotic signalling pathways, but also a
      better use of already kown drugs through new associations in so far as these
      target distinct signalling pathways.

PMID- 12609800
TI  - [Clinical development of anti-angiogenic agents in 2002].
AB  - In 2002, new developments in anti-angiogenic strategies encompassed two main
      aspects. Firstly, essential improvements were made in the field of methodology :
      novel techniques permitted to measure directly on patients the biological effects
      induced by anti-angiogenic treatments in the course of clinical trials. Secondly,
      results of the first phase I trials of endostatin, one of the most awaited anti
      angiogenic drugs, were published. These studies proved that endostatin was not
      toxic and that doses equivalent to the one effective in animals could safely be
      used in man, but efficacy results were not up to expectations. On the other hand,
      treatment targeting the VEGF pathway, and especially humanised anti-VEGF
      monoclonal antibody, had promising results. Further clinical trials are needed to
      gain clear insight into the precise role of those promising strategies for the
      management of solid tumours.

PMID- 12609801
TI  - [Perspectives on the oncologist pharmacopoeia].
AB  - MGI114, ET743, BBR3464, ZD0473, ZD9331, BN80915, J107088, F11782, XR11576,
      BMS247550, PS341, UCN01, ISIS 3521, STI571, ZD1839, IMC-C225, OSI774, SU5416, DNA
      minor and major grooves, chimeric proteins, ribonucleotide reductase,
      topoisomerases, tubuline, proteasome, protein kinase C, bcr-abl, EGF or VEGF
      tyrosine kinase receptors are code names (somewhat barbarian) and targets for new
      drugs which will complement the therapeutic arsenal of the twenty-first century
      oncologist. This review provides a survey their clinical advances.

PMID- 12609802
TI  - [Tissue microarrays a powerful tool in transfer and quality control in oncology].
AB  - The progress in the knowledge of molecular genetics and the availability of high
      throughput technologies offer the opportunity to identify new diagnostic and
      prognostic markers and new therapeutic targets in human cancer. The recently
      developed "tissue microarraysi (TMA) technology allows parallel molecular
      profiling of clinical samples. Using this technique and immunohistochemistry
      (IHC), fluorescence in situ hybridisation (FISH), or RNA in situ hybridisation
      (ISH), the pathologist is now able to perform unprecedented large-scale analyses.
      The advantages are significant: large number of cases assessed simultaneously for
      numerous markers, processing in identical conditions, reduced amount of archival
      tissues, excellent correlation with standard methods, reduction in cost and time.
      This article provides a short review of this technology, and points out several
      aspects of the TMA construction and its applications for clinical research.

PMID- 12609803
TI  - [Chemotherapy for patients with local-regional recurrent or metastatic carcinoma
      of the head and neck].
AB  - Chemotherapy has emerged to be a central component of curative strategies for
      patient with primary squamous cell carcinoma of the head and neck. The
      identification of agent active in head and neck cancer first occurred in patients
      with local regional recurrent and/or metastatic disease treated with palliative
      intent. The present paper reports the prognostic factors which based the
      understanding of these patients outcome. A review of the relevant results
      obtained by the standard chemotherapy in this recurrent population is performed.
      The current and future area of research were highlighted.

PMID- 12609805
TI  - [New advances in screening and treatment of ovarian cancer].
AB  - Advances were recently observed in the early diagnosis and treatment of
      epithelial ovarian cancer. Molecular biology, particularly proteomics, seems to
      offer interesting results concerning the screening of ovarian cancer. The
      treatment of this tumor is based on surgery and adjuvant chemotherapy. Several
      studies were recently published concerning the interest and results of para
      aortic lymphadenectomy and interval debulking surgery (after neo-adjuvant
      chemotherapy) in the surgical management of ovarian cancer. Advances in
      chemotherapy and new drugs will be also studied in this paper.

PMID- 12609804
TI  - [News in the medical treatment of breast cancer].
AB  - During the last decade, except for breast cancer, few "solid" tumours have
      benefited from significant progress in systemic treatment able to reduce the
      progression of metastases in advanced disease or to eradicate possible micro
      metastases in the adjuvant situation. This review aims to guide the reader along
      the paths of the progress made in hormonotherapy, chemotherapy and targeted
      molecular therapy. For each category, the authors will attempt to estimate the
      impact of the therapeutic advances upon day-to-day clinical practice.

PMID- 12609806
TI  - [Bladder cancer: realities and perspectives].
AB  - Bladder cancer is an urologic common tumor after prostatic carcinoma. Treatment
      of bladder cancer requires an interdisdisciplinary approach, including urologist,
      medical oncologist and radiation oncologist. Treatment of superficial tumors is
      based on endovesical instillations and sometimes on radical cystectomy for
      pejorative recurrences. For invasive tumor, radical cystectomy is needed. At
      present, ileal reconstructions could be largely proposed, in men as in women, for
      better quality of life. For selected patients, chemoradiotherapy is a valid
      alternative treatment to radical cystectomy, with similar survival rates and
      conservation rates of functional bladder about 50-60 %. In spite of the efficacy
      of local treatment, almost one half of patients develop metastasis. Recently, new
      drugs like paclitaxel, gemcitabine or Herceptin are available to improve the
      management of metastatic disease.

PMID- 12609807
TI  - [Gastro-intestinal stromal tumors: news and comments].
AB  - Gastrointestinal stromal tumors (GIST) are rare tumors occuring at all levels of
      the gastrointestinal tract, whose estimated incidence may be close to 2 new cases
      per 100 000 persons per year. GIST derive from the interstital cells of Cajal
      (ICC) responsible for the motility of the GI tract, or from a common precursor of
      ICC and of the smooth muscle cells of the digestive tract. GIST cells express the
      c-kit protoconcogene under an activated form, either mutated or constitutively
      activated, as well as the CD34 Ag. Mutations of the KIT gene is an early event in
      the process of transformation in these tumors. Until recently, GIST were not
      recognized as a distinct entity among soft tissue sarcoma. It is now clear that
      conventional chemotherapy is generally inactive in this tumor, surgery being the
      only efficient therapeutic modality even in patients with advanced disease.
      Rapidly accruing phase I, II and III trials in the USA and Europe (EORTC) have
      demonstrated since 2000 that imatinib mesylate (STI571) is an active agent in
      GIST with an initial response rate of 70 % and 10 % only of primary refractory
      tumors, yelding an improved overall survival as compared to historical series.
      Resistance are now being observed however. GIST has become the first model of a
      solid tumor treated efficiently by a treatment targetting the initial genetic
      alteration of the disease. Numerous question regarding the integration of this
      treatment with surgery and the long term outcome of these patients still remain
      to be answered however.

PMID- 12609809
TI  - [Chemoradiotherapy of solid tumours in the adult: current views and
      perspectives].
AB  - Clinical trials carried out during the last decade have given clear indication on
      the potential of concomitant association of radiotherapy and chemotherapy for
      improving local control and survival rates in the management of locally advanced
      solid tumours. In most trials, cisplatin was used alone or in combination with
      other drugs. Meta-analysis pointed to the potential of these combinations in head
      and neck, lung, cervical and oesophagus cancers. The interaction of radiotherapy
      with chemotherapy for these solid tumours appears to depend primarily on the time
      scheduling of radiation versus drug exposure and on radiation fractionation.
      Major improvements aiming at increasing therapeutic index, are expected from
      studies on the mode of action of drugs and on the mechanisms of acute toxicity of
      drugs and radiation.

PMID- 12609808
TI  - [Hepatic metastases from colorectal cancer].
AB  - Over the last 30 years, the benefits of surgical resection and systemic
      chemotherapy in the management of hepatic metastases from colorectal cancer have
      been established. Actually, surgical resections are feasible with a very low
      mortality and a 5-year survival that approaches 50 %, but only 10 % to 20 % of
      patients are candidate to surgery. The others gain benefit from chemotherapy with
      more and more active drugs. To improve this overall picture, efforts have been
      made to increase the number of patients that could be candidates for surgery and
      to decrease the risk of recurrence after surgical resection. Shrinkage of tumours
      after administration of preoperative chemotherapy and availability of ablative
      techniques (radiofrequency and cryotherapy) now permit to treat with curative
      intent metastases initially considered as non resectable. Chemotherapeutic
      regimens to decrease the risk of postoperative recurrence are actually tested in
      clinical trials.

PMID- 12609810
TI  - [Current views in geriatric oncology].
AB  - Geriatric oncology represents a novel specialty which can be defined as specific
      older cancer patients management. It includes a validated geriatric procedure,
      the comprehensive geriatric assessment, which is the best way of approaching the
      complex interacting medical problems of frail older patients. Geriatric
      assessment of elderly cancer patients is actually a subject for discussion among
      geriatric oncology community. Geriatric assessment may provide either guidelines
      for anti-cancer treatment in the elderly, or guidelines for the management of
      older patients with cancer. Two clinical research ways are now developed :
      firstly the definition of the most relevant geriatric variables allowing clinical
      trials in such a heterogeneous population; secondly, the determination and the
      validation of a specific tool to screen frail and vulnerable older patients, and
      the study of the geriatric assessment impact on the quality of life of older
      cancer people.

PMID- 12609811
TI  - [Economic assessment, a field between clinical research and observational
      studies].
AB  - Health technology assessments propose to study the differential impact of health
      interventions in a complex care system which is characterised by the multitude of
      individual behaviours and the diverse nature of the institutions involved.
      Current systems for data collection lend themselves poorly to this rigorous
      analysis of efficacy of treatments in the actual situations where they are used.
      Randomised trials endeavour to neutralise any parasitic interference which could
      compromise testing for a causal relationship between the treatment administered
      and the result obtained. Their methodology which establishes the term ceteris
      paribus in the principle of good practice lends itself poorly to an analysis of
      individual behaviour. Observational studies are start from actual treatment
      situations to describe them as reliably as possible. By definition, however,
      these assume that the natural course of events is not deviated by any
      intervention. The absence of an experimental plan increases the likelihood of
      bias and makes it more difficult to test for causal relationships. They lend
      themselves poorly to testing for incremental efficacy. The two instruments to be
      preferred are decisional analysis and quasi-experimental studies. Decisional
      analysis help to avoid the problems of external validity associated with
      randomised clinical trials by associating parameters which are extracted from
      data obtained from everyday practice. Quasi-experimental studies or pragmatic
      trials are based on the reality of behaviour of the prescriber and his/her
      patients; their impact on efficacy, quality of life social costs of the disease
      and of treatments may be identified under normal conditions of use.

PMID- 12609812
TI  - [Cancer and the law].
AB  - Health professionals are being impacted by a major reform in 2002. Indeed, after
      4 years of dialogues the French parliament has adopted a particularly innovative
      law of which title "Law in relation to patients rights and to the quality of the
      Health System" leads us to predict the dimension of the disruptions to come
      affecting the relation between physicians and patients in its legislative way.
      This law is directly descended from the "Huriet Law"--voted on December the 20th,
      1988--outlining the every day process of clinical research. This constitutes a
      significant challenge to rethink the medical informations we communicate to
      patients. The low number of oncologists in France is more than ever affected by
      this law, despite the will of the health professionals. More time spent with
      patients could only occur should there be increased human resources.

PMID- 12609814
TI  - Stimulation and blockade of GABA(A) receptors in the raphe pallidus: effects on
      body temperature, heart rate, and blood pressure in conscious rats.
AB  - Studies in anesthetized rats have implicated GABAA receptors in the region of the
      medullary raphe pallidus (RP) at the level of the facial nucleus in sympathetic
      nervous regulation of both heart rate and thermoregulatory mechanisms. Therefore,
      we examined the effect of microinjection of muscimol, a GABAA receptor agonist,
      and of bicuculline methiodide (BMI), a GABAA receptor antagonist, into the same
      region of the RP on heart rate, blood pressure, and core body temperature in
      conscious rats. Microinjection of BMI (40 pmol) into the RP evoked tachycardia
      that appeared within 1 min and was maximal within 10 min but had little or no
      effect on blood pressure or body temperature. Microinjection of muscimol (10-80
      pmol) at the same sites in the RP evoked marked dose-related decreases in body
      temperature that developed more slowly (i.e., maximum decreases appearing at 60
      75 min after 80 pmol) but had no effect on heart rate or blood pressure.
      Injection of either agent at sites outside the region had lesser or no effect on
      the measured parameters. These findings suggest that activity of neurons in the
      region of the RP plays an important role in the maintenance of body temperature
      but not heart rate under baseline conditions in conscious rats. Specifically,
      thermoregulatory neurons in this region appear to be tonically active and
      contribute to maintenance of body temperature under baseline conditions, while
      cardiac sympathetic premotor neurons in the RP are not active under these
      circumstances and thus do not support basal heart rate in conscious rats.

PMID- 12609815
TI  - Myogenic responses and compliance of mesenteric and splenic vasculature in the
      rat.
AB  - In the rat, the spleen is a major site of fluid efflux out of the blood. By
      contrast, the mesenteric vasculature serves as a blood reservoir. We proposed
      that the compliance and myogenic responses of these vascular beds would reflect
      their different functional demands. Mesenteric and splenic arterioles (
      approximately 150-200 microm) and venules (<250 microm) from rats anesthetized
      with pentobarbital sodium were mounted in a pressurized myograph. Mesenteric
      arterial diameter decreased from 146 +/- 6 to 133 +/- 6 microm on raising
      intraluminal pressures from 80 to 120 mmHg. This response was enhanced in the
      presence of N(omega)-nitro-l-arginine methyl ester (l-NAME; 139 +/- 6 to 112 +/-
      7 microm). There was no such myogenic response in the splenic arterioles, except
      in the presence of l-NAME (194 +/- 4 to 164 +/- 4.2 microm). We propose that,
      whereas mesenteric arterioles exhibit myogenic responses, this is normally masked
      by NO-mediated dilation in the splenic vessels. The mesenteric venules were
      highly distensible (active, 184 +/- 15 to 320 +/- 30.9 microm; passive in Ca(2+)
      free media, 209 +/- 31 to 344 +/- 27 microm; 4-8 mmHg) compared with the splenic
      vessels (active, 169 +/- 11 to 184 +/- 16 microm; passive, 187 +/- 12 to 207 +/-
      17 microm). We conclude that, in response to an increase in perfusion pressure,
      mesenteric arterial diameter would decrease to limit the changes in flow and
      microvascular pressure. In addition, mesenteric venous capacitance would
      increase. By contrast, splenic arterial diameter would increase, while there
      would be little change in venous diameter. This would enhance the increase in
      intrasplenic microvascular pressure and increase fluid extravasation.

PMID- 12609816
TI  - Effects of experimental weight perturbation on skeletal muscle work efficiency in
      human subjects.
AB  - Maintenance of reduced or elevated body weight results in respective decreases or
      increases in energy expended in physical activity, defined as 24-h energy
      expenditure excluding resting energy expenditure and the thermic effect of
      feeding, beyond those attributable to weight change. We examined skeletal muscle
      work efficiency by graded cycle ergometry and, in some subjects, rates of
      gastrocnemius muscle ATP flux during exercise by magnetic resonance spectroscopy
      (MRS), in 30 subjects (15 males, 15 females) at initial weight and 10% below
      initial weight and in 8 subjects (7 males, 1 female) at initial weight and 10%
      above initial weight to determine whether changes in skeletal muscle work
      efficiency at altered body weight were correlated with changes in the energy
      expended in physical activity. At reduced weight, muscle work efficiency was
      increased in both cycle ergometry [mean (SD) change = +26.5 (26.7)%, P < 0.001]
      and MRS [ATP flux change = -15.2 (23.2)%, P = 0.044] studies. Weight gain
      resulted in decreased muscle work efficiency by ergometry [mean (SD) change = 
      17.8 (20.5)%, P = 0.043]. Changes in muscle efficiency at altered body weight
      accounted for 35% of the change in daily energy expended in physical activity.

PMID- 12609817
TI  - Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH
      oxidase, and SOD expression.
AB  - Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG
      type 1 vs. type 2 receptors (AT1-R and AT2-R, respectively) is unknown. We
      infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin
      F2alpha (8-Iso) and malonyldialdehyde (MDA) were related to renal cortical mRNA
      abundance for subunits of NADPH oxidase and superoxide dismutases (SODs) using
      real-time PCR. Subsets of ANG II-infused rats were given the AT1-R antagonist
      candesartan cilexetil (Cand) or the AT2-R antagonist PD-123,319 (PD). Compared to
      vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh, 5.4 +/- 0.8 vs. ANG
      II, 7.6 +/- 0.5 pg/24 h; P < 0.05). This was prevented by Cand (5.6 +/- 0.5 pg/24
      h; P < 0.05) and increased by PD (15.8 +/- 2.0 pg/24 h; P < 0.005). There were
      similar changes in MDA excretion. Compared to Veh, ANG II significantly (P <
      0.005) increased the renal cortical mRNA expression of p22phox (twofold), Nox-1
      (2.6-fold), and Mn-SOD (1.5-fold) and decreased expression of Nox-4 (2.1-fold)
      and extracellular (EC)-SOD (2.1-fold). Cand prevented all of these changes except
      for the increase in Mn-SOD. PD accentuated changes in p22phox and Nox-1 and
      increased p67phox. We conclude that ANG II infusion stimulates oxidative stress
      via AT1-R, which increases the renal cortical mRNA expression of p22phox and Nox
      1 and reduces abundance of Nox-4 and EC-SOD. This is offset by strong protective
      effects of AT2-R, which are accompanied by decreased expression of p22phox, Nox
      1, and p67phox.

PMID- 12609818
TI  - The role of hypothalamic input on corticotroph maturation in fetal sheep.
AB  - Corticotropin-releasing hormone receptor type 1 (CRH-R1) expression and
      vasopressin type 1b (V1b) receptor protein decrease in late-gestation fetal
      sheep. Because hypothalamo-pituitary disconnection (HPD) has been demonstrated to
      prevent the morphological maturation of corticotrophs, we hypothesized that
      hypothalamic input is necessary for the maturational changes in CRH-R1 and V1b
      receptor levels. We measured CRH-R1 and V1b receptor expression in the anterior
      pituitaries of fetuses at 140 days gestational age (dGA) that underwent HPD or
      sham surgery at 120 dGA. CRH-R1 mRNA decreased similarly in HPD and sham-operated
      fetuses compared with 120 dGA naive fetuses. However, CRH-R1 protein levels were
      elevated in HPD fetuses compared with sham and were not different from 120 dGA
      values. V1b protein levels decreased similarly in HPD and sham-operated fetuses
      compared with 120 dGA naive fetuses. We conclude that hypothalamic input to the
      pituitary is necessary for the decrease in CRH-R1 receptor protein levels in late
      gestation fetal sheep. However, hypothalamic input is not necessary for the
      decrease in V1b receptor expression seen in late gestation.

PMID- 12609819
TI  - Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac
      contractile function in mice.
AB  - An increase in coronary perfusion pressure leads to increased cardiac
      contractility, a phenomenon known as the Gregg effect. Exogenous endothelin (ET)
      1 exerts a positive inotropic effect; however, the role of endogenous ET-1 in the
      contractile response to elevated load is unknown. We characterized here the role
      of ETA and ETB receptors in regulation of contractility in isolated, perfused
      mouse hearts subjected to increased coronary flow. Elevation of coronary flow
      from 2 to 5 ml/min resulted in 80 +/- 10% increase in contractile force (P <
      0.001). BQ-788 (ETB receptor antagonist) augmented the load-induced contractile
      response by 35% (P < 0.05), whereas bosentan (ETA/B receptor antagonist) and BQ
      123 (ETA receptor antagonist) attenuated it by 34% and 56%, respectively (P <
      0.05). CV-11974 (ANG II type 1 receptor antagonist) did not modify the increase
      in contractility. These results show that endogenous ET-1 is a key mediator of
      the Gregg effect in mouse hearts. Moreover, ET-1 has a dual role in the
      regulation of cardiac contractility: ETA receptor-mediated increase in
      contractile force is suppressed by ETB receptors.

PMID- 12609820
TI  - Modulation of mitochondrial nitric oxide synthase and energy expenditure in rats
      during cold acclimation.
AB  - To preserve thermoneutrality, cold exposure is followed by changes in energy
      expenditure and basal metabolic rate (BMR). Because nitric oxide (NO) modulates
      mitochondrial O(2) uptake and energy levels, we analyzed cold effects (30 days at
      4 degrees C) on rat liver and skeletal muscle mitochondrial NO synthases (mtNOS)
      and their putative impact on BMR. Cold exposure delimited two periods: A (days 1
      10), with high systemic O(2) uptake and weight loss, and B (days 10-30), with
      lower O(2) uptake and fat deposition. mtNOS activity and expression decreased in
      period A and then increased in period B by 60-100% in liver and skeletal muscle
      (P < 0.05). Conversely, mitochondrial O(2) uptake remained initially high in the
      presence of l-arginine and later fell by 30-50% (P < 0.05). On this basis, the
      estimated fractional contribution of liver plus muscle to total BMR varied from
      40% in period A to 25% in period B. The transitional modulation of mtNOS in rat
      cold acclimation could participate in adaptive responses that favor calorigenesis
      or conservative energy-saving mechanisms.

PMID- 12609821
TI  - Endothelial NO formation does not control myocardial O2 consumption in mouse
      heart.
AB  - To test whether endothelium-derived nitric oxide (NO) regulates mitochondrial
      respiration, NO was pharmacologically modulated in isolated mouse hearts, which
      were perfused at constant flow to sensitively detect small changes in myocardial
      O2 consumption (MVO2). Stimulation of NO formation by 10 microM bradykinin (BK)
      increased coronary venous nitrite release fivefold to 58 +/- 33 nM (n = 17).
      Vasodilatation by BK, adenosine (1 microM), or papaverine (10 microM) decreased
      perfusion pressure, left ventricular developed pressure (LVDP), and MVO2. In the
      presence of adenosine-induced vasodilatation, stimulation of endothelial NO
      synthesis by BK had no effect on LVDP and MVO2. Also, inhibition of NO formation
      by NG-monomethyl-l-arginine (l-NMMA, 100 microM) did not significantly alter LVDP
      and MVO2. Similarly, intracoronary infusion of authentic NO <or=2 microM did not
      influence LVDP or MVO2 (-1 +/- 1%). Only when NO was >2 microM were contractile
      dysfunction and MVO2 reduction observed. Because BK-induced stimulation of
      endothelial NO formation and basal NO are not sufficient to impair MVO2 in the
      saline-perfused mouse heart, a tonic control of the respiratory chain by
      endothelial NO is difficult to conceive.

PMID- 12609823
TI  - Triiodothyronine-mediated myosin heavy chain gene transcription in the heart.
AB  - We developed an RT-PCR assay to study both the time course and the mechanism for
      the triiodothyronine (T(3))-induced transcription of the alpha- and beta-myosin
      heavy chain (MHC) genes in vivo on the basis of the quantity of specific
      heterogeneous nuclear RNA (hnRNA). The temporal relationship of changes in
      transcriptional activity to the amount of alpha-MHC mRNA and the coordinated
      regulation of transcription of more than one gene in response to T(3) are
      demonstrated here for the first time. Quantitation of alpha-MHC hnRNA
      demonstrated that T(3) induced alpha-MHC transcription in hypothyroid rats within
      30 min of a single injection of T(3) (0.5 microg/100 g body wt). Maximal
      transcription rates (135% +/- 15.8 of euthyroid values) occurred 6 h after
      injection and subsequently declined in parallel with serum T(3) levels. The
      transcription of beta-MHC was reduced to 86% of peak hypothyroid levels 6 h after
      a single T(3) injection and reached a nadir of 59% of hypothyroid levels at 36 h.
      Analysis of the time course of T(3)-mediated induction of alpha-MHC hnRNA and
      repression of beta-MHC hnRNA indicates that separate molecular mechanisms are
      involved in the coordinated regulation of these genes.

PMID- 12609822
TI  - Differential effects of 5,6-EET on segmental pulmonary vasoactivity in the
      rabbit.
AB  - In the rabbit, 5,6-epoxyeicosatrienoic acid (EET) was reported both to dilate and
      to constrict pulmonary blood vessels. We propose that these seemingly
      contradictory results could be explained by differences in responses to 5,6-EET
      in large-conductance pulmonary arteries (PA) compared with smaller PA and
      resistance vessels. Thus we found that in rings of extralobar PA [>2-mm outside
      diameter (OD)], in which active tension had been increased with PGF(2alpha), 5,6
      EET produced relaxation in a concentration- and cyclooxygenase (COX)-dependent
      manner. In contrast, 5,6-EET increased tension in intralobar (1- to 2-mm OD) PA.
      Small extralobar PA (2- to 2.5-mm OD) exhibited intermediate responses. In the
      intact lung, the net effect of 5,6-EET (1 x 10(-8)-1 x 10(-5) M) was an increase
      in pulmonary vascular resistance (PVR) from 13.0 +/- 0.5 to 47.8 +/- 4.6 mmHg.
      100 ml(-1) x min(-1) (EC(50) 5.9 +/- 1.7 x 10(-7) M). The increase in PVR was
      accompanied by a 10-fold increase in perfusate thromboxane (TX)B(2)
      concentration. The 5,6-EET-induced increase in PVR was prevented with
      indomethacin (100 microM), a cyclooxygenase inhibitor, or ONO-3708 (20 microM), a
      TX/PGH(2) (TP) receptor antagonist, but not with OKY-046 (700 microM), a TX
      synthase inhibitor. These results demonstrate that although 5,6-EET dilates large
      extralobar PA segments in a COX-dependent manner, in the intact rabbit lung 5,6
      EET produces constriction that requires synthesis of a COX-dependent agonist of
      the TP receptor other than TX.

PMID- 12609824
TI  - Renal denervation chronically lowers arterial pressure independent of dietary
      sodium intake in normal rats.
AB  - The present study was designed to test the hypothesis that renal nerves
      chronically modulate arterial pressure (AP) under basal conditions and during
      changes in dietary salt intake. To test this hypothesis, continuous telemetric
      recording of AP in intact (sham) and renal denervated (RDNX) Sprague-Dawley rats
      was performed and the effect of increasing and decreasing dietary salt intake on
      AP was determined. In protocol 1, 24-h AP, sodium, and water balances were
      measured in RDNX (n = 11) and sham (n = 9) rats during 5 days of normal (0.4%
      NaCl) and 10 days of high (4.0% NaCl) salt intake, followed by a 3-day recovery
      period (0.4% NaCl). Protocol 2 was similar with the exception that salt intake
      was decreased to 0.04% NaCl for 10 days after the 5-day period of normal salt
      (0.04% NaCl) intake (RDNX; n = 6, sham; n = 5). In protocol 1, AP was lower in
      RDNX (91 +/- 1 mmHg) compared with sham (101 +/- 2 mmHg) rats during the 5-day
      0.4% NaCl control period. During the 10 days of high salt intake, AP increased <5
      mmHg in both groups so that the difference between sham and RDNX rats remained
      constant. In protocol 2, AP was also lower in RDNX (93 +/- 2 mmHg) compared with
      sham (105 +/- 4 mmHg) rats during the 5-day 0.4% NaCl control period, and AP did
      not change in response to 10 days of a low-salt diet in either group. Overall,
      there were no between-group differences in sodium or water balance in either
      protocol. We conclude that renal nerves support basal levels of AP, irrespective
      of dietary sodium intake in normal rats.

PMID- 12609825
TI  - Cardiac homeostasis is independent of calf venous compliance in subjects with
      paraplegia.
AB  - The purpose of this study was to examine cardiac hemodynamics during acute head
      up tilt (HUT) and calf venous function during acute head-down tilt (HDT) in
      subjects with paraplegia compared with sedentary nondisabled controls. Nineteen
      paraplegic males (below T6) and nine age-, height-, and weight-matched control
      subjects participated. Heart rate, stroke volume, and cardiac output were
      assessed using the noninvasive acetylene uptake method. Venous vascular function
      of the calf was assessed using venous occlusion plethysmography. After supine
      measurements were collected, the table was moved to 10 degrees HDT followed by
      the three levels of HUT (10, 35, and 75 degrees ) in random order. Cardiac
      hemodynamics were similar between the groups at all positions. Calf circumference
      was significantly reduced in the paraplegic group compared with the control group
      (P < 0.001). Venous capacitance and compliance were significantly reduced in the
      paraplegic compared with control group at supine and HDT. Neither venous
      capacitance (P = 0.37) nor compliance (P = 0.19) increased from supine with 10
      degrees HDT in the paraplegic group. A significant linear relationship was
      established between supine venous compliance and supine cardiac output in the
      control group (r = 0.80, P < 0.02) but not in the paraplegic group. The findings
      of reduced calf circumference and similar venous capacitance at supine rest and
      10 degrees HDT in the paraplegic group imply that structural changes may have
      limited venous dispensability in individuals with chronic paraplegia.
      Furthermore, the lack of a relationship between supine venous compliance and
      supine cardiac output suggests that cardiac homeostasis does not rely on venous
      compliance in subjects with paraplegia.

PMID- 12609826
TI  - Endopeptidases 3.4.24.15 and 24.16 in endothelial cells: potential role in
      vasoactive peptide metabolism.
AB  - The closely related metalloendopeptidases EC (EP24.15; thimet oligopeptidase) and
      24.16 (EP24.16; neurolysin) cleave a number of vasoactive peptides such as
      bradykinin and neurotensin in vitro. We have previously shown that hypotensive
      responses to bradykinin are potentiated by an inhibitor of EP24.15 and EP24.16
      (26), suggesting a role for one or both enzymes in bradykinin metabolism in vivo.
      In this study, we have used selective inhibitors that can distinguish between
      EP24.15 and EP24.16 to determine their activity in cultured endothelial cells
      (the transformed human umbilical vein endothelial hybrid cell line EA.hy926 or
      ovine aortic endothelial cells). Endopeptidase activity was assessed using a
      specific quenched fluorescent substrate [7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-d
      Lys(2,4-dinitrophenyl)], as well as the peptide substrates bradykinin and
      neurotensin (assessed by high-performance liquid chromatography with mass
      spectroscopic detection). Our results indicate that both peptidases are present
      in endothelial cells; however, EP24.16 contributes significantly more to
      substrate cleavage by both cytosolic and membrane preparations, as well as intact
      cells, than EP24.15. These findings, when coupled with previous observations in
      vivo, suggest that EP24.16 activity in vascular endothelial cells may play an
      important role in the degradation of bradykinin and/or other peptides in the
      circulation.

PMID- 12609827
TI  - Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma
      with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor
      biology.
AB  - The outcome of acquired immunodeficiency syndrome-related lymphomas (ARLs) has
      improved since the era of highly active antiretroviral therapy, but median
      survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone,
      vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral
      therapy in 39 newly diagnosed ARLs and examined protein expression profiles
      associated with drug resistance and histogenesis, patient immunity, and HIV
      dynamics and mutations. The expression profiles from a subset of ARL cases were
      also compared with a matched group of similarly treated HIV-negative cases.
      Complete remission was achieved in 74% of patients, and at 53 months median
      follow-up, disease-free and overall survival are 92% and 60%, respectively.
      Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+
      cells recovered by 12 months and the viral loads decreased below baseline by 3
      months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and
      higher CD10 expression, consistent with a germinal center origin and good
      prognosis, but were more likely to be highly proliferative and to express p53,
      adverse features with standard chemotherapy. Unlike HIV-negative cases, p53
      overexpression was not associated with a poor outcome, suggesting different
      pathogenesis. High tumor proliferation did not correlate with poor outcome and
      may partially explain the high activity of dose-adjusted EPOCH. The results
      suggest that the improved immune function associated with highly active
      antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from
      lymphomas of post-germinal center origin, which have a poor prognosis. These
      results suggest that tumor pathogenesis is responsible for the improved outcome
      of ARLs in the era of HAART.

PMID- 12609828
TI  - Involvement of a CD47-dependent pathway in platelet adhesion on inflamed vascular
      endothelium under flow.
AB  - Resting platelet adhesion to inflammatory vascular endothelium is thought to play
      a causal role in secondary thrombus formation or microcirculatory disturbance
      after vessel occlusion. However, though adhesion receptors involved in platelet
      matrix interactions have been extensively studied, the molecular mechanisms
      involved in platelet-endothelium interactions are incompletely characterized and
      have been mainly studied under static conditions. Using human platelets or
      platelets from wild-type and CD47-/- mice in whole blood, we demonstrated that at
      low shear rate, CD47 expressed on human and mouse platelets significantly
      contributes to platelet adhesion on tumor necrosis factor-alpha (TNF-alpha)
      stimulated vascular endothelial cells. Using the CD47 agonist peptide 4N1K and
      blocking monoclonal antibodies (mAbs), we showed that CD47 binds the cell-binding
      domain (CBD) of endothelial thrombospondin-1 (TSP-1), inducing activation of the
      platelet alphaIIbbeta3 integrin that in turn becomes able to link the endothelial
      receptors intercellular adhesion molecule 1 (ICAM-1) and alphavbeta3. Platelet
      CD36 and GPIbalpha are also involved because platelet incubation with blocking
      mAbs directed against each of these 2 receptors significantly decreased platelet
      arrest. Given that anti-CD47 treatment of platelets did not further decrease the
      adhesion of anti-CD36-treated platelets and CD36 is a TSP-1 receptor, it appears
      that CD36/TSP-1 interaction could trigger the CD47-dependent pathway. Overall,
      CD47 antagonists may be potentially useful to inhibit platelet adhesion on
      inflamed endothelium.

PMID- 12609829
TI  - CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant
      up-regulation of Cdc42 and Rac activities.
AB  - Although chemokines are well known to function in chemotaxis, additional roles
      for these molecules in the immune system are not well understood. Dendritic cells
      (DCs) developmentally regulate the expression of chemokine receptors to
      facilitate their migration from the peripheral tissues to regional lymph nodes.
      Expressions of CCR1 and CCR5 on immature DCs are down-regulated on maturation,
      whereas CCR7 is selectively expressed on mature DCs. In the present study, we
      examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of
      fluorescein isothiocyanate (FITC)-dextran by murine DCs. Both CCL19 and CCL21
      markedly induced rapid uptake of FITC-dextran by mature DCs but not immature DCs.
      In contrast, CCL3, a ligand of CCR1 and CCR5, induced rapid uptake of FITC
      dextran by immature DCs but not mature DCs. CCL19-induced endocytosis could be
      completely blocked by Clostridium difficile toxin B, which inhibits the Rho
      guanosine triphosphatase proteins, Rho, Rac, and Cdc42. This process was not
      abrogated by Y-27632, a specific inhibitor of Rho-associated kinase. In addition,
      CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs. These findings
      demonstrate that certain chemokines induce rapid endocytosis in each relevant DC
      population. It is suggested that CCR7 ligands activate Cdc42 and Rac, thereby
      inducing the endocytosis in mature DCs.

PMID- 12609830
TI  - A PAR domain transcription factor is involved in the expression from a
      hematopoietic-specific promoter for the human LMO2 gene.
AB  - The transcription factor LMO2 is believed to exert its effect through the
      formation of protein-protein interactions with other DNA-binding factors such as
      GATA-1 and TAL1. Although LMO2 has been shown to be critical for the formation of
      the erythroid cell lineage, the gene is also expressed in a number of
      nonerythroid tissues. In this report, we demonstrate that the more distal of the
      2 promoters for the LMO2 gene is highly restricted in its pattern of expression,
      directing the hematopoietic-specific expression of this gene. Deletion and
      mutation analyses have identified a critical cis element in the first
      untranslated exon of the gene. This element is a consensus-binding site for a
      small family of basic leucine zipper proteins containing a proline and acidic
      amino acid-rich (PAR) domain. Although all 3 members of this family are produced
      in erythroid cells, only 2 of these proteins, thyrotroph embryonic factor and
      hepatic leukemia factor, can activate transcription from this LMO2 promoter
      element. These findings represent a novel mechanism in erythroid gene regulation
      because PAR proteins have not previously been implicated in this process.

PMID- 12609831
TI  - Ligation of Siglec-8: a selective mechanism for induction of human eosinophil
      apoptosis.
AB  - Sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2
      isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only
      on human eosinophils, basophils, and mast cells. Until now, its function was
      unknown. Here we define a novel function of Siglec-8 on eosinophils. Siglec-8
      cross-linking with antibodies rapidly generated caspase-3-like activity and
      reduced eosinophil viability through induction of apoptosis. The pancaspase
      inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD
      FMK) completely blocked this response, implicating caspases in Siglec-8 cross
      linking-induced apoptosis. Eosinophil survival-promoting cytokines such as
      interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM
      CSF) failed to block apoptosis and instead enhanced the sensitivity of
      eosinophils to undergo apoptosis in response to Siglec-8 antibody. Siglec-8
      activation may provide a useful therapeutic approach to reduce numbers of
      eosinophils (and perhaps basophils and mast cells) in disease states where these
      cells are important.

PMID- 12609832
TI  - Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic
      trioxide-resistant HL-60 cells.
AB  - Recent reports indicate a broad spectrum of antileukemic activity for arsenic
      trioxide (As(2)O(3)) due to its ability to induce apoptosis via intracellular
      production of reactive oxygen species (ROS). Despite its potent apoptotic
      mechanism, As(2)O(3) is not equally effective in all leukemic cells, which has
      prompted a search for agents enhancing As(2)O(3) efficacy. Recently, evidence has
      been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may
      sensitize tumor cells to ROS-inducing anticancer agents. The aim of our
      investigation was to evaluate whether DHA enhances As(2)O(3)-mediated apoptosis
      in As(2)O(3)-resistant HL-60 cells. While 1 microM As(2)O(3) or 25 microM DHA
      reduced cell viability to 85.8% +/- 2.9% and 69.2% +/- 3.6%, combined treatment
      with As(2)O(3) and DHA reduced viability to 13.0% +/- 9.9% with a concomitant
      increase of apoptosis. Apoptotic cell death was preceded by collapse of the
      mitochondrial membrane potential, increased expression of proapoptotic B-cell
      lymphoma protein-2-associated X protein (Bax), and caspase-3 activation.
      Importantly, the combined effect of As(2)O(3) and DHA was associated with
      increased production of intracellular ROS and toxic lipid peroxidation products
      and was abolished by the antioxidant vitamin E or when oleic acid (a
      nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and
      toxic lipid peroxidation products most likely constitute the key mediators
      contributing to the combined effect of As(2)O(3) and DHA. Our data provide the
      first evidence that DHA may help to extend the therapeutic spectrum of As(2)O(3)
      and suggest that the combination of As(2)O(3) and DHA could be more broadly
      applied in leukemia therapy.

PMID- 12609833
TI  - Selective T-cell ablation with bismuth-213-labeled anti-TCRalphabeta as
      nonmyeloablative conditioning for allogeneic canine marrow transplantation.
AB  - Two major immunologic barriers, the host-versus-graft (HVG) and graft-versus-host
      (GVH) reactions, have to be overcome for successful allogeneic hematopoietic cell
      transplantation. T cells were shown to be primarily involved in these barriers in
      the major histocompatibility complex identical setting. We hypothesized that
      selective ablation of T cells using radioimmunotherapy together with postgrafting
      immunosuppression would suffice to ensure stable allogeneic engraftment. We had
      described a canine model of nonmyeloablative marrow transplantation in which host
      immune reactions were impaired by a single dose of 200 cGy total body irradiation
      (TBI), and both GVH and residual HVG reactions were controlled by postgrafting
      immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Here,
      we substituted the alpha-emitter bismuth-213 (213Bi) linked to a monoclonal
      antibody (mAb) against T-cell receptor (TCR) alphabeta, using the metal-binding
      chelate diethylenetriaminepentaacetic acid (DTPA) derivative cyclohexyl-(CHX)-A",
      for 200 cGy TBI. Biodistribution studies using a gamma-emitting indium-111
      labeled anti-TCRalphabeta mAb showed uptake primarily in blood, marrow, lymph
      nodes, spleen, and liver. Four dogs were treated with 0.13 to 0.46 mg/kg
      TCRalphabeta mAb labeled with 3.7 to 5.6 mCi/kg (137-207 MBq/kg) 213Bi. The
      treatment was administered in 6 injections on days -3 and -2 followed by
      transplantation of dog leukocyte antigen-identical marrow on day 0 and
      postgrafting immunosuppression with MMF/CSP. The therapy was well tolerated
      except for elevations of transaminases that were transient in all but one of the
      dogs. No other organ toxicities or signs of graft-versus-host disease were noted.
      The dogs had prompt allogeneic hematopoietic engraftment and achieved stable
      mixed donor-host hematopoietic chimerism with donor contributions ranging from 5%
      to 55% after more than 30 weeks of follow up.

PMID- 12609835
TI  - Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine
      nucleotide depletion.
AB  - Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that
      catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch
      point of purine nucleotide biosynthesis, leading to the generation of guanine
      nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides,
      prevents cell growth by G1 arrest, and induces cell differentiation in a cell
      type-specific manner. The molecular and sensing mechanisms underlying these
      effects are not clear. We have examined the induction of apoptosis by
      mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)
      dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant
      doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells
      in the ongoing presence of IL-3. Apoptosis was completely prevented by the
      addition of guanosine at time points up to 12 hours, after which caspase 3
      activity increased and apoptosis was not reversible. MPA treatment caused marked
      down-regulation of the MAP kinase kinase/extracellular regulatory kinase
      (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation
      of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of
      rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6
      kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase
      (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not
      induce apoptosis in IL-3-dependent cells, whereas inhibition of both pathways
      simulated the effects of MPA treatment. These results indicate that IMPDH
      inhibitors may be effective in modulating signal transduction pathways in
      hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for
      hematologic malignancies.

PMID- 12609836
TI  - Prognostic value of pretransplantation positron emission tomography using
      fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with
      high-dose chemotherapy and stem cell transplantation.
AB  - The study assessed the prognostic value of fluorine 18-fluorodeoxyglucose
      positron emission tomography ([18F]FDG-PET) after salvage chemotherapy before
      high-dose chemotherapy with stem cell transplantation (HDT/SCT) in patients with
      induction failure or relapsing chemosensitive lymphoma. Retrospective analysis of
      the clinical and conventional imaging data of 60 patients scheduled for HDT/SCT
      was performed in parallel with the analysis of the [18F]FDG-PET results. To
      determine the ability of [18F]FDG-PET to predict clinical outcome, PET images
      were reread without knowledge of conventional imaging and clinical history.
      Presence or absence of abnormal [18F]FDG uptake was related to progression-free
      survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis.
      Thirty patients showed a negative [18F]FDG-PET scan before HDT/SCT; 25 of those
      remained in complete remission, with a median follow-up of 1510 days. Two
      patients died due to a treatment-related mortality but without evidence of
      recurrent disease at that time (228-462 days). Only 3 patients had a relapse
      (median PFS, 1083 days) after a negative [18F]FDG-PET scan. Persistent abnormal
      [18F]FDG uptake was seen in 30 patients and 26 progressed (median PFS, 402 days);
      of these 26, 16 died from progressive disease (median OS, 408 days). Four
      patients are still in complete remission after a positive scan. Comparison
      between groups indicated a statistically significant association between [18F]FDG
      PET findings and PFS (P <.000001) and OS (P <.00002). [18F]FDG-PET has an
      important prognostic role in the pretransplantation evaluation of patients with
      lymphoma and enlarges the concept of chemosensitivity used to select patients for
      HDT/SCT.

PMID- 12609837
TI  - Adhesion of normal and Plasmodium falciparum ring-infected erythrocytes to
      endothelial cells and the placenta involves the rhoptry-derived ring surface
      protein-2.
AB  - Recent findings have challenged the current view of Plasmodium falciparum (P
      falciparum) blood-stage biology by demonstrating the cytoadhesion of early ring
      stage-infected erythrocytes (rIEs) to host endothelial cells and placental
      syncytiotrophoblasts. The adhesion of rIEs was observed only in parasites that
      bind to the placenta via chondroitin sulfate A (CSA). In this work, a panel of
      mouse monoclonal antibodies (mAbs) that specifically inhibit cytoadhesion of rIEs
      but not of mature IEs was generated The previously described ring surface protein
      2 (RSP-2), a 42-kDa protein, was identified as the target of the ring-stage
      specific mAbs. Time course surface fluorescence experiments revealed a short
      overlap (approximately 4 hours) of expression between RSP-2 and P falciparum
      erythrocyte membrane protein 1 (PfEMP1). Their consecutive expression enables IEs
      to adhere to endothelial cells during the entire blood-stage cycle. During this
      study, a new phenotype was detected in parasite cultures, the adhesion of normal
      erythrocytes (nEs) to endothelial cells. All adherent nEs were coated with RSP-2.
      Immunolocalization studies show that RSP-2 is a rhoptry-derived protein that is
      discharged onto the erythrocyte membrane during contact with merozoites. Our
      results identify RSP-2 as a key molecule in sequestration of young blood-stage
      forms and nEs to endothelial cells.

PMID- 12609834
TI  - IL-10 and TGF-beta induce alloreactive CD4+CD25- T cells to acquire regulatory
      cell function.
AB  - We previously reported that interleukin-10 (IL-10) and transforming growth factor
      (TGF)-beta treatment of primary mixed lymphocyte reaction (MLR) cultures resulted
      in secondary alloantigen-specific hyporesponsiveness and protection from graft
      versus-host disease (GVHD) lethality. Here, we report that CD4+ T cells recovered
      from the IL-10- and TGF-beta-treated primary MLR cultures have immunoregulatory
      function. Tolerized cells significantly inhibited proliferation of naive
      alloreactive CD4+ T cells in a primary MLR. Inhibition of the naive alloresponse
      was observed with as few as 1 tolerized cell to 10 naive responder cells.
      Tolerized cells were able to significantly reduce GVHD lethality when injected
      with naive alloreactive CD4+ T cells into major histocombatibility class (MHC) II
      disparate recipients. Rigorous CD25 depletion of the primary MLR had no effect on
      generation of a regulatory capacity, suggesting that the regulatory cells likely
      originated from CD4+CD25- T cells. Immune suppression was mediated independently
      of IL-10 and TGF-beta production, as neutralizing antibodies for IL-10, IL-10R,
      and TGF-beta were unable to revert suppression, and IL-10- deficient CD4+ T cells
      were able to mediate in vitro and in vivo suppression. The generation of
      immunoregulatory cells from a CD4+CD25- population during tolerization with IL-10
      and TGF-beta provides an additional mechanism to prevent GVHD lethality by T
      cells that may escape full tolerance induction.

PMID- 12609838
TI  - Platelet factor 4 enhances generation of activated protein C in vitro and in
      vivo.
AB  - Platelet factor 4 (PF4), an abundant platelet alpha-granule protein, accelerates
      in vitro generation of activated protein C (APC) by soluble
      thrombin/thrombomodulin (TM) complexes up to 25-fold. To test the hypothesis that
      PF4 similarly stimulates endothelium-associated TM, we assessed the influence of
      human PF4 on thrombin-dependent APC generation by cultured endothelial
      monolayers. APC generated in the presence of 1 to 100 microg PF4 was up to 5-fold
      higher than baseline for human umbilical vein endothelial cells, 10-fold higher
      for microvascular endothelial cells, and unaltered for blood outgrowth
      endothelial cells. In an in vivo model, cynomolgus monkeys (n = 6, each serving
      as its own control) were infused with either PF4 (7.5 mg/kg) or vehicle buffer,
      then with human thrombin (1.0 microg/kg/min) for 10 minutes. Circulating APC
      levels (baseline 3 ng/mL) peaked at 10 minutes, when PF4-treated and vehicle
      treated animals had APC levels of 67 +/- 5 ng/mL and 39 +/- 2 ng/mL, respectively
      (P <.001). The activated partial thromboplastin time (APTT; baseline, 28 seconds)
      increased maximally by 27 +/- 6 seconds in PF4-treated animals and by 9 +/- 1
      seconds in control animals at 30 minutes (P <.001). PF4-dependent increases in
      circulating APC and APTT persisted more than 2-fold greater than that of controls
      from 10 through 120 minutes (P < or =.04). All APTT prolongations were
      essentially reversed by monoclonal antibody C3, which blocks APC activity. Thus,
      physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC
      generation both in vitro by cultured endothelial cells and in vivo in a primate
      thrombin infusion model. These findings suggest that PF4 may play a previously
      unsuspected physiologic role in enhancing APC generation.

PMID- 12609839
TI  - Telomerase and telomere length in multiple myeloma: correlations with disease
      heterogeneity, cytogenetic status, and overall survival.
AB  - We have investigated the significance of telomerase activity (TA) and telomere
      length (TL) in multiple myeloma (MM). The analyses were undertaken on CD138+ MM
      cells isolated from the marrow of 183 patients either at diagnosis or in relapse.
      There was heterogeneity in telomerase expression; 36% of the patients had TA
      levels comparable to those detected in normal plasma cells, and 13% of patients
      had levels 1- to 4-fold greater than in a neuroblastoma cell line control. The TL
      of MM cells was significantly shorter than that of the patients' own leukocytes;
      in 25% of patients, the TL measured less than 4.0 kbp. Analysis of TL
      distribution indicated selective TA-mediated stabilization of shorter telomeres
      when mean TL fell below 5.5 kbp. Unusually long (10.8-15.0 kbp) telomeres were
      observed in 7 patients, and low TA was observed in 5 of 7 patients, suggesting
      the operation of a TA-independent pathway of telomere stabilization. A strong
      negative correlation existed between TA and TL or platelet count. TL negatively
      correlated with age and with interleukin-6 (IL-6) and beta2-microglobulin levels.
      Various cytogenetic abnormalities, including those associated with poor
      prognosis, strongly correlated with TA and, to a lesser extent, with short TL.
      High TA and short TL defined a subgroup of patients with poor prognosis. At 1
      year the survival rate in patients with TA levels lower than 25% of neuroblastoma
      control and TL greater than 5.5 kbp was 82%, whereas in patients with higher TA
      and shorter TL the survival rate was 63% (P =.004). The 2-year survival rate for
      patients with TA levels lower than 25% was 81%, and it was 52% in those with
      higher TA levels (P <.0001).

PMID- 12609840
TI  - Phosphatidylserine externalization in sickle red blood cells: associations with
      cell age, density, and hemoglobin F.
AB  - Phosphatidylserine (PS) is normally confined to the cytoplasmic leaflet of the
      red blood cell (RBC) membrane, but some sickle RBCs expose PS in the outer
      leaflet (PS+ cells). This study examined the relationships among PS
      externalization, fetal hemoglobin content, hydration state, and cell age. Sickle
      RBCs exhibit a wide range of PS externalization. Those with low-level exposure
      (type 1 PS+) include many young transferrin-receptor-positive (TfR+) cells. This
      is not specific for sickle cell disease because many nonsickle TfR+ cells are
      also PS+. RBCs with higher PS exposure (type 2 PS+) appear to be more specific
      for sickle cell disease. Their formation is most likely sickling dependent
      because type 2 PS+ dense sickle cells have a lower percentage of fetal hemoglobin
      (HbF) than PS- cells in the same density fraction (1.7 vs 2.9; n = 8; P <.01). In
      vivo experiments using biotin-labeled sickle cells showed a sharp decrease in the
      percentage of circulating, labeled PS+ cells in the first 24 hours after
      reinfusion. This decrease was confined to type 1 PS+ cells and was thus
      consistent with the reversal of PS exposure in very young cells. As the labeled
      cells aged in the circulation, the percentages of type 1 and type 2 PS+ cells
      increased. These studies indicate that PS externalization in sickle cells may be
      low level, as observed in many immature cells, or high level, which is associated
      with dehydration and appears to be more specific for sickle RBCs.

PMID- 12609841
TI  - Aggravation of endotoxin-induced disseminated intravascular coagulation and
      cytokine activation in heterozygous protein-C-deficient mice.
AB  - In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC),
      dysfunctional anticoagulant pathways are important. The function of the protein C
      system in DIC is impaired because of low levels of protein C and down-regulation
      of thrombomodulin. The administration of (activated) protein C results in an
      improved outcome in experimental and clinical studies of DIC. It is unknown
      whether congenital deficiencies in the protein C system are associated with more
      severe DIC. The aim of the present study was to investigate the effect of a
      heterozygous deficiency of protein C on experimental DIC in mice. Mice with
      single-allele targeted disruption of the protein C gene (PC+/-) mice and wild
      type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg)
      intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater
      decrease in fibrinogen level and a larger drop in platelet count. Histologic
      examination showed more fibrin deposition in lungs, kidneys, and liver in mice
      with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had
      significantly higher levels of proinflammatory cytokines, tumor necrosis factor
      alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction
      between the protein C system and the inflammatory response. Survival was lower at
      12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the
      important role of the protein C system in the coagulative-inflammatory response
      on endotoxemia and may suggest that congenital deficiencies in the protein C
      system are associated with more severe DIC and adverse outcome in sepsis.

PMID- 12609842
TI  - Generation of low-toxicity interleukin-2 fusion proteins devoid of
      vasopermeability activity.
AB  - Because of its key role in immunity, interleukin-2 (IL-2) has been studied
      extensively for the adoptive immunotherapy of cancer. Although systemic
      administration of IL-2 has been shown to stimulate antitumor responses in vivo,
      its efficacy in the clinic has been limited by the development of serious side
      effects, including the induction of vascular leak syndrome. Previously, we have
      identified a small peptide fragment of IL-2 that was found to contain the entire
      vasopermeability activity of the cytokine. The identification of the location of
      this potentially undesirable property of IL-2 enabled us to focus on the
      generation of mutant derivatives that might be lacking vasopermeability activity
      but that retain cytokine functionality. In addition to this discovery, our
      laboratory has constructed monoclonal antibody/IL-2 fusion proteins that can
      target this potent cytokine directly to tumor for the immunotherapy of both solid
      and lymphoid malignancies. Using this fusion protein technology, we have
      constructed a series of point mutations in the newly identified vasopermeability
      region of IL-2 for the purpose of deleting this activity. Fusion proteins showing
      reduced or deleted vasopermeability activity were then tested for their cytokine
      potency by several methods, including their binding to IL-2 receptors, T-cell
      proliferation assays, the induction of secondary cytokines, dose-escalating
      toxicity, and finally their ability to treat established solid tumors in
      syngeneic immunocompetent mice. The results of these studies clearly show that
      the vasopermeability activity of IL-2 can be substantially deleted by single
      point mutations such as Arg38Trp without grossly affecting the immune function of
      the cytokine.

PMID- 12609843
TI  - Evidence for a role for Galphai1 in mediating weak agonist-induced platelet
      aggregation in human platelets: reduced Galphai1 expression and defective Gi
      signaling in the platelets of a patient with a chronic bleeding disorder.
AB  - We have examined platelet functional responses and characterized a novel
      signaling defect in the platelets of a patient suffering from a chronic bleeding
      disorder. Platelet aggregation responses stimulated by weak agonists such as
      adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison,
      both aggregation and dense granule secretion were normal following activation
      with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA).
      ADP, thrombin, or thromboxane A2 (TxA2) signaling through their respective Gq
      coupled receptors was normal as assessed by measuring either mobilization of
      intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin
      phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin,
      ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in
      cyclic AMP (cAMP) was impaired, indicating dysfunctional Galphai signaling.
      Immunoblot analysis of platelet membranes with specific antiserum against
      different Galpha subunits indicated normal levels of Galphai2,Galphai3,Galphaz,
      and Galphaq in patient platelets. However, the Galphai1level was reduced to 25%
      of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no
      abnormality in either the Galphai1 or Galphai2 gene sequences. Our studies
      implicate the minor expressed Galphai subtype Galphai1 as having an important
      role in regulating signaling pathways associated with the activation of
      alphaIIbbeta3 and subsequent platelet aggregation by weak agonists.

PMID- 12609844
TI  - Major mutations in calf-1 and calf-2 domains of glycoprotein IIb in patients with
      Glanzmann thrombasthenia enable GPIIb/IIIa complex formation, but impair its
      transport from the endoplasmic reticulum to the Golgi apparatus.
AB  - The crystal structure of integrin alphavbeta3 comprises 3 regions of contact
      between alphav and beta3. The main contact on alphav is located in the beta
      propeller while calf-1 and calf-2 domains contribute minor interfaces. Whether or
      not contacts between calf-1 and calf-2 domains of glycoprotein (GP) IIb
      (alphaIIb) and GPIIIa (beta3) play a role in GPIIb/IIIa complex formation has not
      been established. In this study we analyzed the effects of 2 naturally occurring
      mutations in calf-1 and calf-2 domains on GPIIb/IIIa complex formation, its
      processing, and transport to the cell membrane. The mutations investigated were a
      deletion-insertion in exon 25 located in calf-2 and an in-frame skipping of exon
      20 located in calf-1. Mutated GPIIb cDNAs were cotransfected in baby hamster
      kidney cells with normal GPIIIa (beta3) cDNA. Analysis by flow cytometry failed
      to demonstrate detectable amounts of GPIIb or GPIIb/IIIa complex on the surface
      of cells transfected with each mutation, but immunohistochemical staining
      revealed their intracellular presence. GPIIb was mainly demonstrable as pro-GPIIb
      by immunoprecipitation of cell lysates expressing each mutation. Differential
      immunofluorescence staining of GPIIb and cellular organelles suggested that most
      altered complexes were located in the endoplasmic reticulum. Homology modeling of
      normal GPIIb based on the alphavbeta3 crystal structure revealed similar contacts
      between alphav and beta3 and between alphaIIb and beta3. Introduction of the
      mutations into the model yielded partial disruption of the normal contacts in the
      corresponding domains. These data suggest that despite partial disruption of calf
      1 or calf-2 domain, GPIIb/IIIa complex is formed but its transport from the
      endoplasmic reticulum is impaired.

PMID- 12609845
TI  - A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH
      genes and includes patients with good prognosis, nonnodal disease.
AB  - We analyzed lymphocyte morphology, histology, immunophenotype, immunoglobulin
      heavy chain (IgVH) gene mutations, and clinical course in 80 unselected patients
      presenting with circulating t(11;14) lymphocytes. Of the 80 patients, 43 had
      peripheral lymphadenopathy (nodal group), and histology confirmed mantle cell
      lymphoma (MCL) in all. There were 37 patients with no lymphadenopathy (nonnodal
      group); 13 of 37 had histology, all showing MCL. IgVH genes were unmutated in 28
      (90%) of 31 nodal and 15 (44%) of 34 nonnodal cases (P =.0001); CD38 was positive
      in 32 (94%) of 34 nodal and 16 (48%) of 33 nonnodal cases (P <.001); 41 (95%) of
      43 nodal patients required immediate treatment compared with 18 (49%) of 37
      nonnodal patients who had indolent disease (P <.0001). Median survival (95%
      confidence interval) was 30 months (10-50) in the nodal group and 79 months (22
      136) in the nonnodal group (P =.005). Mutation status did not statistically
      affect survival, but of 6 long-term survivors (> 90 months) all were nonnodal and
      5 of 5 had mutated IgVH genes. Lymphocyte morphology was heterogeneous in both
      groups: typical MCL in 56 cases (34 nodal, 22 nonnodal), blastoid MCL in 8 cases
      (3 nodal, 5 nonnodal), and small-cell MCL in 16 cases (6 nodal, 10 nonnodal, P
      =.12). Matutes immunophenotyping score was 1 in 65 cases and 2 in 15 (8 nodal, 7
      nonnodal). We find no evidence against a diagnosis of MCL in the nonnodal group
      and suggest that mutated IgVH genes may help identify patients with indolent
      disease.

PMID- 12609846
TI  - L-selectin stimulation enhances functional expression of surface CXCR4 in
      lymphocytes: implications for cellular activation during adhesion and migration.
AB  - L-selectin mediates leukocyte tethering and rolling, the first step in a
      sequential process of leukocyte adhesion and migration. Additionally, L-selectin
      has important signaling roles perhaps contributing to leukocyte activation and
      integrin-mediated adhesion. Because chemokines are critically involved in
      leukocyte activation, we questioned whether L-selectin signaling affects
      chemokine receptor expression and function. We observed that whereas only 5% to
      15% of freshly isolated lymphocytes expressed CXCR4 on the cell surface,
      intracellular CXCR4 was detectable in all cells. Engagement of L-selectin by
      antibody cross-linking or the L-selectin ligands fucoidan or sulfatide mobilized
      intracellular CXCR4 to significantly increase surface CXCR4 expression but did
      not affect CCR5, CCR7, or beta2-integrin expression. L-selectin stimulation also
      inhibited stromal-derived factor 1 (SDF-1)-induced CXCR4 internalization. The
      combined effects of L-selectin on CXCR4 trafficking are likely important in
      markedly enhancing cell activation by SDF-1. Blockade of SDF-1-induced CXCR4
      internalization resulted in enhanced actin polymerization on subsequent exposure
      to SDF-1. Physiologically more important, L-selectin stimulation increased SDF-1
      induced lymphocyte adhesion and transendothelial migration, which were inhibited
      by anti-leukocyte function-associated antigen 1 antibodies, tyrosine kinase
      inhibitors, and pertussis toxin. To further corroborate the additive stimulating
      effects, L-selectin signaling and SDF-1 increased beta2-integrin activation.
      Taken together, L-selectin-mediated signals specifically enhance CXCR4 expression
      and function, suggesting a novel mechanism for the modulation of lymphocyte
      activation during cell adhesion and transmigration.

PMID- 12609847
TI  - Human cytomegalovirus protein pp65 mediates accumulation of HLA-DR in lysosomes
      and destruction of the HLA-DR alpha-chain.
AB  - Human cytomegalovirus (HCMV) has developed multiple strategies to escape immune
      recognition. Here, we demonstrate that HCMV down-regulates HLA-DR expression in
      infected interferon gamma (IFN-gamma)-stimulated fibroblasts at 1 day after
      infection. Decreased HLA-DR expression was not observed on cells infected with an
      HCMV strain lacking the pp65 gene (RVAD65), but was observed on cells transfected
      with the pp65 gene. HLA-DR expression accumulated in vacuoles near the nucleus in
      HCMV-infected, but not in uninfected or RVAD65-infected cells. In addition, the
      HLA-DR alpha-chain, but not the beta-chain or HLA-DM, was degraded in HCMV
      infected but not in RVAD65-infected cells. Thus, the HCMV protein pp65 mediates
      decreased expression of HLA-DR, by mediating an accumulation of HLA class II
      molecules in lysosomes that results in degradation of the HLA-DR alpha-chain.

PMID- 12609848
TI  - A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor
      growth.
AB  - The goal of our study was to raise monoclonal antibodies (mAbs) against
      endothelial cell-surface proteins specific for tumor vasculature. Here, we
      describe the generation and intensive characterization of mAb AA98, including its
      functional properties and its antigen identification. In our study, an enhanced
      mAb AA98 immunoreactivity was observed on stimulated human umbilical vein
      endothelial cells (HUVECs). In addition, mAb AA98 showed remarkably restricted
      immunoreactivity against intratumoral neovasculature compared with blood vessels
      of normal tissues. We identified the AA98 antigen as human CD146, an adhesion
      molecule belonging to the immunoglobulin superfamily. Data from in vitro
      experiments imply structural and signaling functions for endothelial CD146;
      however, the role of CD146 in vivo is largely unknown. Here, we show that mAb
      AA98 displays antiangiogenic properties in vitro and in vivo. Proliferation and
      migration of HUVECs were inhibited by mAb AA98 as was angiogenesis in chicken
      chorioallantoic membrane (CAM) assays and tumor growth in 3 xenografted human
      tumor models in mice. Our data provide new insights into the function of CD146 on
      endothelial cells, validate CD146 as a novel target for antiangiogenic agents,
      and demonstrate that mAb AA98 has potential as a diagnostic and therapeutic agent
      in vascular and cancer biology.

PMID- 12609849
TI  - Homeodomain proteins MEIS1 and PBXs regulate the lineage-specific transcription
      of the platelet factor 4 gene.
AB  - Platelet factor 4 (PF4) is expressed during megakaryocytic differentiation. We
      previously reported that GATA-1 and ETS-1 regulate the rat PF4 promoter and
      transactivate the PF4 gene. For the present study, we investigated the regulatory
      elements and their transcription factors responsible for the lineage-specific
      expression of the PF4 gene. The promoter activities of deletion constructs were
      evaluated, and a novel regulatory element termed TME (tandem repeat of MEIS1
      binding element) (-219 to -182) was defined. Binding proteins to TME were
      strongly detected in HEL nuclear extracts by electrophoresis mobility shift assay
      (EMSA), and they were purified by DNA affinity chromatography. By performing
      Western blottings and supershift assays, the binding proteins were identified as
      homeodomain proteins, MEIS1, PBX1B, and PBX2. These factors are expressed in
      megakaryocytes differentiated from CD34+ cells in human cord blood. MEIS1 and
      PBXs bind to the TME as MEIS1/PBX complexes and activate the PF4 promoter. In
      nonmegakaryocytic HepG2 cells, GATA-1 and ETS-1 activate the PF4 promoter
      approximately 10-fold. Surprisingly, we found that additional expression of both
      MEIS1 and PBX2 multiplied this major activation another 2-fold. This activation
      was not observed when MEIS1 binding sites in the TME were disrupted. Furthermore,
      inhibition of the binding of endogenous MEIS1/PBX complexes to the TME decreased
      the promoter activity by almost one half, in megakaryocytic HEL cells. Thus,
      these studies demonstrate that the homeodomain proteins, MEIS1, PBX1B, and PBX2,
      play an important role in megakaryocytic gene expression.

PMID- 12609850
TI  - 19 A solution structure of the filarial nematode immunomodulatory protein, ES-62.

PMID- 12609851
TI  - DNA polymorphism: a comparison of force fields for nucleic acids.
AB  - The improvements of the force fields and the more accurate treatment of long
      range interactions are providing more reliable molecular dynamics simulations of
      nucleic acids. The abilities of certain nucleic acid force fields to represent
      the structural and conformational properties of nucleic acids in solution are
      compared. The force fields are AMBER 4.1, BMS, CHARMM22, and CHARMM27; the
      comparison of the latter two is the primary focus of this paper. The performance
      of each force field is evaluated first on its ability to reproduce the B-DNA
      decamer d(CGATTAATCG)(2) in solution with simulations in which the long-range
      electrostatics were treated by the particle mesh Ewald method; the crystal
      structure determined by Quintana et al. (1992) is used as the starting point for
      all simulations. A detailed analysis of the structural and solvation properties
      shows how well the different force fields can reproduce sequence-specific
      features. The results are compared with data from experimental and previous
      theoretical studies.

PMID- 12609853
TI  - Understanding pH-dependent selectivity of alamethicin K18 channels by computer
      simulation.
AB  - Alamethicin K18 is a covalently linked alamethicin dimer in which the glutamine
      residue at position 18 in each helix has been replaced by a lysine residue. As
      described in previous work, channels formed by this peptide show pH-dependent
      selectivity. The maximum anion selectivity of the putative octameric conducting
      state is obtained at pH 7 or lower. Inasmuch as no change in selectivity is seen
      between pH 7 and pH 3, and because protons are expected to be in equilibrium with
      the open state of the channel during a selectivity measurement, the channel is
      believed to be fully charged (i.e., all eight lysines protonated) at pH 7. In an
      effort to understand how such a highly charged channel structure is stable in
      membranes and why it is not more selective for anions, we have performed a number
      of computer simulations of the system. Molecular dynamics simulations of 10 ns
      each of the octameric bundle in a lipid bilayer environment are presented, with
      either zero, four, or eight lysines charged in the absence of salt, and with
      eight lysines charged in the presence of 0.5 M and 1 M KCl. When no salt is
      present and all lysines are charged, on average 1.9 Cl(-) ions are inside the
      channel and the channel significantly deforms. With 0.5 M KCl present, 2.9 Cl(-)
      ions are inside the channel. With 1 M KCl present, four Cl(-) ions are present
      and the channel maintains a regular structure. Poisson-Boltzmann calculations on
      models of the octameric channel also predict an average of 2-4 Cl(-) ions near
      the lysine residues as a function of ionic strength. These counterions lower the
      apparent charge of the channel, which may underlie the decrease in selectivity
      observed experimentally with increasing salt concentrations. We suggest that to
      increase the selectivity of Alm K18 channels, positive charges could be
      engineered in a narrower part of the channel.

PMID- 12609852
TI  - Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase
      complexed with the 5CITEP inhibitor: mechanism for inhibition and drug
      resistance.
AB  - The human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential
      enzyme in the life cycle of the virus and is an attractive target for the
      development of new drugs useful in acquired immunodeficiency syndrome multidrug
      therapy. Starting from the crystal structure of the 5CITEP inhibitor bound to the
      active site in the catalytic domain of the HIV-1 IN, two different molecular
      dynamics simulations in water have been carried out. In the first simulation the
      wild-type IN was used, whereas in the second one the double mutation T66I/M154I,
      described to lead to drug resistance, was introduced in the protein. Compelling
      differences have been observed in these two structures during analyses of the
      molecular dynamics trajectories, particularly in the inhibitor binding modes and
      in the conformational flexibility of the loop (residues 138-149) located near the
      three catalytic residues in the active site (Asp(64), Asp(116), Glu(152)).
      Because the conformational flexibility of this region is important for efficient
      biological activity and its behavior is quite different in the two models, we
      suggest a hypothetical mechanism for the inhibition and drug resistance of HIV-1
      IN. These results can be useful for the rational design of more potent and
      selective integrase inhibitors and may allow for the design of inhibitors that
      will be more robust against known resistance mutations.

PMID- 12609854
TI  - Integrated luminal and cytosolic aspects of the calcium release control.
AB  - We propose here a unitary approach to the luminal and cytosolic control of
      calcium release. A minimal number of model elements that realistically describe
      different data sets are combined and adapted to correctly respond to various
      physiological constraints. We couple the kinetic properties of the inositol 1,4,5
      trisphosphate receptor/calcium channel with the dynamics of Ca(2+) and K(+) in
      both the lumen and cytosol, and by using a detailed simulation approach, we
      propose that local (on a radial distance approximately 2 micro m) calcium
      oscillations in permeabilized cells are driven by the slow inactivation of
      channels organized in discrete clusters composed of between six and 15 channels.
      Moreover, the character of these oscillations is found to be extremely sensitive
      to K(+), so that the cytosolic and luminal calcium variations are in or out of
      phase if the store at equilibrium has tens or hundreds micro M Ca(2+),
      respectively, depending on the K(+) gradient across the reticulum membrane.
      Different patterns of calcium signals can be reproduced through variation of only
      a few parameters.

PMID- 12609855
TI  - Equilibrium shapes of erythrocytes in rouleau formation.
AB  - A well known physiological property of erythrocytes is that they can aggregate
      and form a rouleau. We present a theoretical analysis of erythrocyte shapes in a
      long rouleau composed of cells with identical sizes. The study is based on the
      area difference elasticity model of lipid membranes, and takes into consideration
      the adhesion of curved axisymmetric membranes. The analysis predicts that the
      erythrocytes in the rouleau can have either a discoid or a cup-like shape. These
      shapes are analogous to the discoid and stomatocyte shapes of free erythrocytes.
      The transitions between the discoid and cup-like shapes in the rouleau are
      characterized. The occurrence of these transitions depends on three model
      parameters: the cell relative volume, the preferred difference between the areas
      of the membrane bilayer leaflets, and the strength of the adhesion between the
      membranes. The cup-like shapes are favored at small relative volumes and small
      preferred area differences, and the discoid shapes are favored at large values of
      these parameters. Increased adhesion strength enlarges the contact area between
      the cells, flattens the cells, and consequently promotes the discoid shapes.

PMID- 12609857
TI  - Hydrogen-bonding propensities of sphingomyelin in solution and in a bilayer
      assembly: a molecular dynamics study.
AB  - Sphingomyelin is enriched within lipid microdomains of the cell membrane termed
      lipid rafts. These microdomains play a part in regulating a variety of cellular
      events. Computer simulations of the hydrogen-bonding properties of sphingolipids,
      believed to be central to the organization of these domains, can delineate the
      possible molecular interactions that underlie this lipid structure. We have
      therefore used molecular dynamics simulations to unravel the hydrogen-bonding
      behavior of palmitoylsphingomyelin (PSM). A series of eight simulations of 3 ns
      each of a single PSM molecule in water showed that the sphingosine OH and NH
      groups can form hydrogen bonds with the phosphate oxygens of their own polar
      head, in agreement with NMR data. Simulations of PSM in a bilayer assembly were
      carried out for 8 ns with three different force field parameterizations. The
      major physico-chemical parameters of the simulated bilayer agree with those
      established experimentally. The sphingosine OH group was mainly involved in
      intramolecular hydrogen bonds, in contrast to the almost exclusive intermolecular
      hydrogen bonds formed by the amide NH moiety. During the bilayer simulations the
      intermolecular hydrogen bonds among lipids formed a dynamic network characterized
      by the presence of hydrogen-bonded lipid clusters of up to nine PSM molecules.

PMID- 12609856
TI  - MD simulation of protein-ligand interaction: formation and dissociation of an
      insulin-phenol complex.
AB  - Complexes of proteins with small ligands are of utmost importance in
      biochemistry, and therefore equilibria, formation, and decay have been
      investigated extensively by means of biochemical and biophysical methods.
      Theoretical studies of the molecular dynamics of such systems in solution are
      restricted to 10 ns, i.e., to fast processes. Only recently new theoretical
      methods have been developed not to observe the process in real time, but to
      explore its pathway(s) through the energy landscape. From the profiles of free
      energy, equilibrium and kinetic quantities can be determined using transition
      state theory. This study is dedicated to the pharmacologically relevant insulin
      phenol complex. The distance of the center of mass chosen as a reaction
      coordinate allows a reasonable description over most of the pathway. The analysis
      is facilitated by analytical expressions we recently derived for distance-type
      reaction coordinates. Only the sudden onset of rotations at the very release of
      the ligand cannot be parameterized by a distance. They obviously require a
      particular treatment. Like a preliminary study on a peptide, the present case
      emphasizes the contribution of internal friction inside a protein, which can be
      computed from simulation data. The calculated equilibrium constant and the
      friction-corrected rates agree well with experimental data.

PMID- 12609858
TI  - A minimal physically realistic protein-like lattice model: designing an energy
      landscape that ensures all-or-none folding to a unique native state.
AB  - A simple protein model restricted to the face-centered cubic lattice has been
      studied. The model interaction scheme includes attractive interactions between
      hydrophobic (H) residues, repulsive interactions between hydrophobic and polar
      (P) residues, and orientation-dependent P-P interactions. Additionally, there is
      a potential that favors extended beta-type conformations. A sequence has been
      designed that adopts a native structure, consisting of an antiparallel, six
      member Greek-key beta-barrel with protein-like structural degeneracy. It has been
      shown that the proposed model is a minimal one, i.e., all the above listed types
      of interactions are necessary for cooperative (all-or-none) type folding to the
      native state. Simulations were performed via the Replica Exchange Monte Carlo
      method and the numerical data analyzed via a multihistogram method.

PMID- 12609859
TI  - Mechanical coupling via the membrane fusion SNARE protein syntaxin 1A: a
      molecular dynamics study.
AB  - SNARE trans complexes between membranes likely promote membrane fusion. For the t
      SNARE syntaxin 1A involved in synaptic transmission, the secondary structure and
      bending stiffness of the five-residue juxtamembrane linker is assumed to
      determine the required mechanical energy transfer from the cytosolic core complex
      to the membrane. These properties have here been studied by molecular dynamics
      and annealing simulations for the wild-type and a C-terminal-prolongated mutant
      within a neutral and an acidic bilayer, suggesting linker stiffnesses above 1.7
      but below 50 x 10(-3) kcal mol(-1) deg(-2). The transmembrane helix was found to
      be tilted by 15 degrees and tightly anchored within the membrane with a stiffness
      of 4-5 kcal mol(-1) A(-2). The linker turned out to be marginally helical and
      strongly influenced by its lipid environment. Charged lipids increased the
      helicity and H3 helix tilt stiffness. For the wild type, the linker was seen
      embedded deeply within the polar region of the bilayer, whereas the prolongation
      shifted the linker outward. This reduced its helicity and increased its average
      tilt, thereby presumably reducing fusion efficiency. Our results suggest that
      partially unstructured linkers provide considerable mechanical coupling; the
      energy transduced cooperatively by the linkers in a native fusion event is thus
      estimated to be 3-8 kcal/mol, implying a two-to-five orders of magnitude fusion
      rate increase.

PMID- 12609860
TI  - Folding of a highly conserved diverging turn motif from the SH3 domain.
AB  - Recent NMR structural characterization studies showed that a seven-residue
      segment (FKKGERL) from the src SH3 domain adopts the nativelike diverging type II
      beta-turn in aqueous solution in support of the prediction based on the I-sites
      library of sequence structural motifs. We study the conformational variability
      and folding/unfolding thermodynamics of this peptide in explicit solvent using
      replica-exchange molecular dynamics simulations, which greatly enhances the
      sampling of the conformational space. This peptide samples three main free energy
      basins (nativelike, intermediate, and unfolded) separated by small barriers. The
      nativelike basin is fractionally populated (DeltaG(300K) = 0.4 kcal/mol) with
      structures that satisfy a subset of the NMR-derived constraints. The intrinsic
      stability of the diverging turn is examined in relationship to the nature of
      three specific contacts: a turn-hydrogen bond, a mainchain-to-sidechain hydrogen
      bond, and an end-to-end hydrophobic contact. We have carried out simulations of
      mutants at the highly conserved GE positions in the sequence. The mutation E5D
      destabilizes the isolated diverging turn motif, contrary to the observation that
      this mutation stabilizes the fyn SH3 domain. The G4T mutation also destabilizes
      the isolated diverging turn; however, the extent of destabilization is smaller
      than that of the reverse mutation in the drk SH3.

PMID- 12609861
TI  - Heterogeneous presynaptic release probabilities: functional relevance for short
      term plasticity.
AB  - We discuss a model of presynaptic vesicle dynamics, which allows for
      heterogeneity in release probability among vesicles. Specifically, we explore the
      possibility that synaptic activity is carried by two types of vesicles; first, a
      readily releasable pool and, second, a reluctantly releasable pool. The pools
      differ regarding their probability of release and time scales on which released
      vesicles are replaced by new ones. Vesicles of both pools increase their release
      probability during repetitive stimulation according to the buildup of Ca(2+)
      concentration in the terminal. These properties are modeled to fit data from the
      calyx of Held, a giant synapse in the auditory pathway. We demonstrate that this
      arrangement of two pools of releasable vesicles can account for a variety of
      experimentally observed patterns of synaptic depression and facilitation at this
      synapse. We conclude that synaptic transmission cannot be accurately described
      unless heterogeneity of synaptic release probability is taken into account.

PMID- 12609862
TI  - Sperm initiate a Ca2+ wave in frog eggs that is more similar to Ca2+ waves
      initiated by IP3 than by Ca2+.
AB  - We have measured the initial propagation velocity of the sperm-induced Ca(2+)
      wave in the egg of Xenopus laevis and have compared it with the initial
      propagation velocities of the inositol triphosphate (IP(3))-induced and Ca(2+)
      induced Ca(2+) waves. The initial mean propagation velocity of the sperm-induced
      wave (13 microm/s) is very similar to that of the IP(3)-induced waves (12.3
      microm/s) and two times faster than the mean Ca(2+)-induced wave velocity (6.6
      microm/s). We have generated realistic simulations of the fertilization wave in
      the frog egg using a computational technique based on the finite difference
      method. Modeling refinements presented here include equations for the production,
      degradation, and diffusion of IP(3), a description for Ca(2+) dynamics in the
      endoplasmic reticulum, and a highly concentrated endoplasmic reticulum in the egg
      cortex. We conclude that models incorporating sperm-induced IP(3) generation fit
      the data best and those involving the influx of either Ca(2+) or a diffusible
      sperm factor fit the data poorly. This independence from Ca(2+) influx is also
      supported by electrophysiological data indicating that Ca(2+) influx is not
      needed to maintain open Cl(-) channels that generate the fertilization potential.

PMID- 12609863
TI  - Force generation by actin polymerization II: the elastic ratchet and tethered
      filaments.
AB  - The motion of many intracellular pathogens is driven by the polymerization of
      actin filaments. The propulsive force developed by the polymerization process is
      thought to arise from the thermal motions of the polymerizing filament tips.
      Recent experiments suggest that the nucleation of actin filaments involves a
      phase when the filaments are attached to the pathogen surface by a protein
      complex. Here we extend the "elastic ratchet model" of Mogilner and Oster to
      incorporate these new findings. We apply this "tethered ratchet" model to derive
      the force-velocity relation for Listeria and discuss relations of our theoretical
      predictions to experimental measurements. We also discuss "symmetry breaking"
      dynamics observed in ActA-coated bead experiments, and the implications of the
      model for lamellipodial protrusion in migrating cells.

PMID- 12609865
TI  - Forces and pressures in DNA packaging and release from viral capsids.
AB  - In a previous communication (Kindt et al., 2001) we reported preliminary results
      of Brownian dynamics simulation and analytical theory which address the packaging
      and ejection forces involving DNA in bacteriophage capsids. In the present work
      we provide a systematic formulation of the underlying theory, featuring the
      energetic and structural aspects of the strongly confined DNA. The free energy of
      the DNA chain is expressed as a sum of contributions from its encapsidated and
      released portions, each expressed as a sum of bending and interstrand energies
      but subjected to different boundary conditions. The equilibrium structure and
      energy of the capsid-confined and free chain portions are determined, for each
      ejected length, by variational minimization of the free energy with respect to
      their shape profiles and interaxial spacings. Numerical results are derived for a
      model system mimicking the lambda-phage. We find that the fully encapsidated
      genome is highly compressed and strongly bent, forming a spool-like condensate,
      storing enormous elastic energy. The elastic stress is rapidly released during
      the first stage of DNA injection, indicating the large force (tens of pico
      Newtons) needed to complete the (inverse) loading process. The second injection
      stage sets in when approximately 1/3 of the genome has been released, and the
      interaxial distance has nearly reached its equilibrium value (corresponding to
      that of a relaxed torus in solution); concomitantly the encapsidated genome
      begins a gradual morphological transformation from a spool to a torus. We also
      calculate the loading force, the average pressure on the capsid's walls, and the
      anisotropic pressure profile within the capsid. The results are interpreted in
      terms of the (competing) bending and interaction components of the packing
      energy, and are shown to be in good agreement with available experimental data.

PMID- 12609864
TI  - Fluctuations and slow variables in genetic networks.
AB  - Computer simulations of large genetic networks are often extremely time consuming
      because, in addition to the biologically interesting translation and
      transcription reactions, many less interesting reactions like DNA binding and
      dimerizations have to be simulated. It is desirable to use the fact that the
      latter occur on much faster timescales than the former to eliminate the fast and
      uninteresting reactions and to obtain effective models of the slow reactions
      only. We use three examples of self-regulatory networks to show that the usual
      reduction methods where one obtains a system of equations of the Hill type fail
      to capture the fluctuations that these networks exhibit due to the small number
      of molecules; moreover, they may even miss describing the behavior of the average
      number of proteins. We identify the inclusion of fast-varying variables in the
      effective description as the cause for the failure of the traditional schemes. We
      suggest a different effective description, which entails the introduction of an
      additional species, not present in the original networks, that is slowly varying.
      We show that this description allows for a very efficient simulation of the
      reduced system while retaining the correct fluctuations and behavior of the full
      system. This approach ought to be applicable to a wide range of genetic networks.

PMID- 12609866
TI  - Protein structure and dynamics in nonaqueous solvents: insights from molecular
      dynamics simulation studies.
AB  - Protein structure and dynamics in nonaqueous solvents are here investigated using
      molecular dynamics simulation studies, by considering two model proteins
      (ubiquitin and cutinase) in hexane, under varying hydration conditions.
      Ionization of the protein groups is treated assuming "pH memory," i.e., using the
      ionization states characteristic of aqueous solution. Neutralization of charged
      groups by counterions is done by considering a counterion for each charged group
      that cannot be made neutral by establishing a salt bridge with another charged
      group; this treatment is more physically reasonable for the nonaqueous situation,
      contrasting with the usual procedures. Our studies show that hydration has a
      profound effect on protein stability and flexibility in nonaqueous solvents. The
      structure becomes more nativelike with increasing values of hydration, up to a
      certain point, when further increases render it unstable and unfolding starts to
      occur. There is an optimal amount of water, approximately 10% (w/w), where the
      protein structure and flexibility are closer to the ones found in aqueous
      solution. This behavior can explain the experimentally known bell-shaped
      dependence of enzyme catalysis on hydration, and the molecular reasons for it are
      examined here. Water and counterions play a fundamental and dynamic role on
      protein stabilization, but they also seem to be important for protein unfolding
      at high percentages of bound water.

PMID- 12609867
TI  - A simple kinetic model describes the processivity of myosin-v.
AB  - Myosin-V is a motor protein responsible for organelle and vesicle transport in
      cells. Recent single-molecule experiments have shown that it is an efficient
      processive motor that walks along actin filaments taking steps of mean size close
      to 36 nm. A theoretical study of myosin-V motility is presented following an
      approach used successfully to analyze the dynamics of conventional kinesin but
      also taking some account of step-size variations. Much of the present
      experimental data for myosin-V can be well described by a two-state chemical
      kinetic model with three load-dependent rates. In addition, the analysis predicts
      the variation of the mean velocity and of the randomness-a quantitative measure
      of the stochastic deviations from uniform, constant-speed motion-with ATP
      concentration under both resisting and assisting loads, and indicates a substep
      of size d(0) approximately 13-14 nm (from the ATP-binding state) that appears to
      accord with independent observations.

PMID- 12609868
TI  - The citrate carrier CitS probed by single-molecule fluorescence spectroscopy.
AB  - A prominent region of the Na(+)-dependent citrate carrier (CitS) from Klebsiella
      pneumoniae is the highly conserved loop X-XI, which contains a putative citrate
      binding site. To monitor potential conformational changes within this region by
      single-molecule fluorescence spectroscopy, the target cysteines C398 and C414 of
      the single-Cys mutants (CitS-sC398, CitS-sC414) were selectively labeled with the
      thiol-reactive fluorophores AlexaFluor 546/568 C(5) maleimide (AF(546), AF(568)).
      While both single-cysteine mutants were catalytically active citrate carriers,
      labeling with the fluorophore was only tolerated at C398. Upon citrate addition
      to the functional protein fluorophore conjugate CitS-sC398-AF(546), complete
      fluorescence quenching of the majority of molecules was observed, indicating a
      citrate-induced conformational change of the fluorophore-containing domain of
      CitS. This quenching was specific for the physiological substrate citrate and
      therefore most likely reflecting a conformational change in the citrate transport
      mechanism. Single-molecule studies with dual-labeled CitS-sC398-AF(546/568) and
      dual-color detection provided strong evidence for a homodimeric association of
      CitS.

PMID- 12609871
TI  - Direct activation of gastric H,K-ATPase by N-terminal protein kinase C
      phosphorylation. Comparison of the acute regulation mechanisms of H,K-ATPase and
      Na,K-ATPase.
AB  - In this study we compared the protein kinase dependent regulation of gastric H,K
      ATPase and Na,K-ATPase. The protein kinase A/protein kinase C (PKA/PKC)
      phosphorylation profile of H,K-ATPase was very similar to the one found in the
      Na,K-ATPase. PKC phosphorylation was taking place in the N-terminal part of the
      alpha-subunit with a stoichiometry of approximately 0.6 mol Pi/mole alpha
      subunit. PKA phosphorylation was in the C-terminal part and required detergent,
      as is also found for the Na,K-ATPase. The stoichiometry of PKA-induced
      phosphorylation was approximately 0.7 mol Pi/mole alpha-subunit. Controlled
      proteolysis of the N-terminus abolished PKC phosphorylation of native H,K-ATPase.
      However, after detergent treatment additional C-terminal PKC sites became exposed
      located at the beginning of the M5M6 hairpin and at the cytoplasmic L89 loop
      close to the inner face of the plasma membrane. N-terminal PKC phosphorylation of
      native H,K-ATPase alpha-subunit was found to stimulate the maximal enzyme
      activity by 40-80% at saturating ATP, depending on pH. Thus, a direct modulation
      of enzyme activity by PKC phosphorylation could be demonstrated that may be
      additional to the well-known regulation of acid secretion by recruitment of H,K
      ATPase to the apical membranes of the parietal cells. Moreover, a distinct
      difference in the regulation of H,K-ATPase and Na,K-ATPase is the apparent
      absence of any small regulatory proteins associated with the H,K-ATPase.

PMID- 12609870
TI  - Regulation of the calcium release channel from skeletal muscle by suramin and the
      disulfonated stilbene derivatives DIDS, DBDS, and DNDS.
AB  - Activation of skeletal muscle ryanodine receptors (RyRs) by suramin and
      disulfonic stilbene derivatives (Diisothiocyanostilbene-2',2'-disulfonic acid
      (DIDS), 4,4'-dibenzamidostilbene-2,2'-disulfonic acid (DBDS),and 4,4'
      dinitrostilbene-2,2'-disulfonic acid (DNDS)) was investigated using planar
      bilayers. One reversible and two nonreversible mechanisms were identified. K(a)
      for reversible activation (approximately 100 micro M) depended on cytoplasmic
      [Ca(2+)] and the bilayer composition. Replacement of neutral lipids by negative
      phosphatidylserine increased K(a) fourfold, suggesting that reversible binding
      sites are near the bilayer surface. Suramin and the stilbene derivatives adsorbed
      to neutral bilayers with maximal mole fractions between 1-8% and with affinities
      approximately 100 micro M but did not adsorb to negative lipids. DIDS activated
      RyRs by two nonreversible mechanisms, distinguishable by their disparate DIDS
      binding rates (10(5) and 60 M(-1) s(-1)) and actions. Both mechanisms activated
      RyRs via several jumps in open probability, indicating several DIDS binding
      events. The fast and slow mechanisms are independent of each other, the
      reversible mechanism and ATP binding. The fast mechanism confers DIDS sensitivity
      approximately 1000-fold greater than previously reported, increases Ca(2+)
      activation and increases K(i) for Ca(2+)/Mg(2+) inhibition 10-fold. The slow
      mechanism activates RyRs in the absence of Ca(2+) and ATP, increases ATP
      activation without altering K(a), and slightly increases activity at pH < 6.5.
      These findings explain how different types of DIDS activation are observed under
      different conditions.

PMID- 12609869
TI  - Paracellular ion channel at the tight junction.
AB  - The tight junction of epithelial cells excludes macromolecules but allows
      permeation of ions. However, it is not clear whether this ion-conducting property
      is mediated by aqueous pores or by ion channels. To investigate the permeability
      properties of the tight junction, we have developed paracellular ion flux assays
      for four major extracellular ions, Na(+), Cl(-), Ca(2+), and Mg(2+). We found
      that the tight junction shares biophysical properties with conventional ion
      channels, including size and charge selectivity, dependency of permeability on
      ion concentration, competition between permeant molecules, anomalous mole
      fraction effects, and sensitivity to pH. Our results support the hypothesis that
      discrete ion channels are present at the tight junction. Unlike conventional ion
      channels, which mediate ion transport across lipid bilayers, the tight junction
      channels must orient parallel to the plane of the plasma membranes to support
      paracellular ion movements. This new class of paracellular-tight junction
      channels (PTJC) facilitates the transport of ions between separate extracellular
      compartments.

PMID- 12609872
TI  - Silence analysis of AMPA receptor mutated at the CaM-kinase II phosphorylation
      site.
AB  - Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by
      Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of
      the major contributors to the enhanced strength of glutamatergic synapses in CA1
      area of hippocampus during long-term potentiation. The molecular mechanism of
      AMPA receptor regulation by CaM-KII is examined here by a novel approach, silence
      analysis, which is independent of previously used variance analysis. I show that
      three fundamental channel properties-single-channel conductance, channel open
      probability, and the number of functional channels-can be measured in an
      alternative way, by analyzing the probability of channels to be simultaneously
      closed (silent). Validity of the approach was confirmed by modeling, and silence
      analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site
      phosphorylated by CaM-KII during long-term potentiation. Silence analysis
      indicates that a negative charge at S831 is a critical determinant for the
      enhanced channel function as a charge carrier. Silence and variance analyses,
      when applied to the same sets of data, were in agreement on the receptor
      regulation upon mutations. These results provide independent evidences for the
      mechanism of AMPA receptor regulation by CaM-KII and further strengthens the idea
      how calcium-dependent phosphorylation of AMPA receptors can contribute to the
      plasticity at central glutamatergic synapses.

PMID- 12609873
TI  - Control of ion conduction in L-type Ca2+ channels by the concerted action of S5-6
      regions.
AB  - Voltage-gated L-type Ca(2+) channels from cardiac (alpha(1C)) and skeletal
      (alpha(1S)) muscle differ from one another in ion selectivity and permeation
      properties, including unitary conductance. In 110 mM Ba(2+), unitary conductance
      of alpha(1S) is approximately half that of alpha(1C). As a step toward
      understanding the mechanism of rapid ion flux through these highly selective ion
      channels, we used chimeras constructed between alpha(1C) and alpha(1S) to
      identify structural features responsible for the difference in conductance.
      Combined replacement of the four pore-lining P-loops in alpha(1C) with P-loops
      from alpha(1S) reduced unitary conductance to a value intermediate between those
      of the two parent channels. Combined replacement of four larger regions that
      include sequences flanking the P-loops (S5 and S6 segments along with the P-loop
      containing linker between these segments (S5-6)) conferred alpha(1S)-like
      conductance on alpha(1C). Likewise, substitution of the four S5-6 regions of
      alpha(1C) into alpha(1S) conferred alpha(1C)-like conductance on alpha(1S). These
      results indicate that, comparing alpha(1C) with alpha(1S), the differences in
      structure that are responsible for the difference in ion conduction are housed
      within the S5-6 regions. Moreover, the pattern of unitary conductance values
      obtained for chimeras in which a single P-loop or single S5-6 region was replaced
      suggest a concerted action of pore-lining regions in the control of ion
      conduction.

PMID- 12609874
TI  - Co-expression of the 5-HT3B serotonin receptor subunit alters the biophysics of
      the 5-HT3 receptor.
AB  - Homomeric complexes of 5-HT(3A) receptor subunits form a ligand-gated ion
      channel. This assembly does not fully reproduce the biophysical and
      pharmacological properties of native 5-HT(3) receptors which might contain the
      recently cloned 5-HT(3B) receptor subunit. In the present study, heteromeric
      assemblies containing human 5-HT(3A) and 5-HT(3B) subunits were expressed in HEK
      293 cells to detail the functional diversity of 5-HT(3) receptors. We designed
      patch-clamp experiments with homomeric (5-HT(3A)) and heteromeric (5-HT(3AB))
      receptors to emphasize the kinetics of channel activation and desensitization. Co
      expression of the 5-HT(3B) receptor subunit reduced the sensitivity for 5-HT (5
      HT(3A) receptor: EC(50) 3 micro M, Hill coefficient 1.8; 5-HT(3AB) receptor:
      EC(50) 25 micro M, Hill coefficient 0.9) and markedly altered receptor
      desensitization. Kinetic modeling suggested that homomeric receptors, but not
      heteromeric receptors, desensitize via an agonist-induced open-channel block.
      Furthermore, heteromeric 5-HT(3AB) receptor assemblies recovered much faster from
      desensitization than homomeric 5-HT(3A) receptor assemblies. Unexpectedly, the
      specific 5-HT(3) receptor agonist mCPBG induced an open-channel block at both
      homomeric and heteromeric receptors. Because receptor desensitization and
      resensitization massively affect amplitude, duration, and frequency of synaptic
      signaling, these findings are evidence in favor of a pivotal role of subunit
      composition of 5-HT(3) receptors in serotonergic transmission.

PMID- 12609876
TI  - New cationic lipids form channel-like pores in phospholipid bilayers.
AB  - Two representatives of a new class of cationic lipids were found to have high
      pore-forming activity in planar bilayer membranes. These molecules, called BHHD
      TADC and BHTD-TADC, have qualitatively similar effects on phospholipid membranes.
      Addition of 2.5-5 micro M of either of them to the membrane bathing solutions
      resulted in formation of long-lived anion-selective pores with conductance in the
      range 0.1-2 nS in 0.1 M KCl. Pore formation was found to be dependent on the
      potential applied to the membrane. When negative potential was applied to
      membrane at the side of addition, the rate of pore formation was much lower
      compared to when the positive potential was applied. Dependence of pore formation
      on compound concentration was highly nonlinear, indicating that this process
      requires assembly of molecules in the membrane. Addition of any of these
      compounds on both sides of the membrane increased the efficiency of pore
      formation by one to two orders of magnitude. Pore formation was strongly pH
      dependent. Although pores were formed with high efficiency at pH 6.5, only
      occasional fluctuations of membrane conductance were observed at pH 7.5. Possible
      mechanisms of new compounds biological activity are discussed.

PMID- 12609875
TI  - Cascades of transient pores in giant vesicles: line tension and transport.
AB  - Under ordinary circumstances, the membrane tension of a giant unilamellar vesicle
      is essentially nil. Using visible light, we stretch the vesicles, increasing the
      membrane tension until the membrane responds by the sudden opening of a large
      pore (several micrometers in size). Only a single pore is observed at a time in a
      given vesicle. However, a cascade of transient pores appear, up to 30-40 in
      succession, in the same vesicle. These pores are transient: they reseal within a
      few seconds as the inner liquid leaks out. The membrane tension, which is the
      driving force for pore opening, is relaxed with the opening of a pore and the
      leakage of the inner liquid; the line tension of the pore's edge is then able to
      drive the closure of a pore. We use fluorescent membrane probes and real-time
      videomicroscopy to study the dynamics of the pores. These can be visualized only
      if the vesicles are prepared in a viscous solution to slow down the leakout of
      the internal liquid. From measurements of the closure velocity of the pores, we
      are able to infer the line tension,. We have studied the effect of the shape of
      inclusion molecules on. Cholesterol, which can be modeled as an inverted cone
      shaped molecule, increases the line tension when incorporated into the bilayers.
      Conversely, addition of cone-shaped detergents reduces. The effect of some
      detergents can be dramatic, reducing by two orders of magnitude, and increasing
      pore lifetimes up to several minutes. We give some examples of transport through
      transient pores and present a rough measurement of the leakout velocity of the
      inner liquid through a pore. We discuss how our results can be extended to less
      viscous aqueous solutions which are more relevant for biological systems and
      biotechnological applications.

PMID- 12609877
TI  - The lateral diffusion of selectively aggregated peptides in giant unilamellar
      vesicles.
AB  - We have systematically investigated the effect of aggregation of a transmembrane
      peptide on its diffusion in dimyristoylphosphatidylcholine and in
      palmitoyloleoylphosphatidylcholine model membranes. The hydrophobic segment of
      the b subunit from E. coli F(1)F(0)-ATP synthase was modified with a histidine
      tag at the carbonyl terminus and was aggregated selectively by using a series of
      multivalent, dendritic chelating agents with nitrilotriacetic acid functional
      groups. Peptide complexes ranging from monomers to hexamers were formed and
      studied in giant unilamellar vesicles. The rate of diffusion for the
      transmembrane peptide complexes were found to depend on the size of the complex.
      The results agree with predictions from the free area model for monomers and
      dimers, and the hydrodynamic continuum model for tetramers, pentamers, and
      hexamers. Comparisons with diffusion of lipids confirm that the diffusion of a
      transmembrane peptide is enhanced by coupling of density fluctuations between the
      two monolayers.

PMID- 12609878
TI  - Molecular basis for microbial adhesion to geochemical surfaces: computer
      simulation of Pseudomonas aeruginosa adhesion to goethite.
AB  - The adhesion of Pseudomonas aeruginosa to the goethite mineral is investigated
      using classical molecular simulation. A fragment model for goethite has been
      integrated into a fully atomistic membrane model. Properties for the resulting
      system are evaluated for a 1.5-ns simulation in the isothermal-isobaric ensemble.
      The response of the membrane to the presence of the mineral is investigated.
      Radial distribution functions are used to present an average picture of the
      hydrogen bonding. Orientational vectors, assigned to the saccharide groups,
      reveal the extent of the mineral's perturbations on the membrane. Significant
      structural changes were observed for the outermost saccharide groups, several of
      which rotate to form hydrogen bonds with the mineral surface. The structure of
      the inner core, and the corresponding integrity of the membrane, is maintained.
      The mineral surface dehydrates slightly in the presence of the membrane as
      saccharide hydroxyl groups compete with water molecules for hydrogen-bonding
      sites on its surface.

PMID- 12609879
TI  - Structural effects of covalent inhibition of phospholipase A2 suggest allosteric
      coupling between membrane binding and catalytic sites.
AB  - Phospholipase A(2) (PLA(2)) binds to membranes and catalyzes phospholipid
      hydrolysis, thus initiating the biosynthesis of lipid-derived mediators of
      inflammation. A snake-venom PLA(2) was completely inhibited by covalent
      modification of the catalytic histidine 48 by p-bromophenacyl bromide. Moreover,
      His(48) modification affected PLA(2) structure, its membrane-binding affinity,
      and the effects of PLA(2) on the membrane structure. The native PLA(2) increased
      the order parameter of fluid membranes, whereas the opposite effect was observed
      for gel-state membranes. The data suggest membrane dehydration by PLA(2) and the
      formation of PLA(2)-membrane hydrogen bonding. The inhibited PLA(2) had lower
      membrane-binding affinity and exerted weaker effects on membrane hydration and on
      the lipid-order parameter. Although membrane binding resulted in formation of
      more flexible alpha-helices in the native PLA(2), which corresponds to faster
      amide hydrogen exchange, the modified enzyme was more resistant to hydrogen
      exchange and experienced little structural change upon membrane binding. The data
      suggest that 1), modification of a catalytic residue of PLA(2) induces
      conformational changes that propagate to the membrane-binding surface through an
      allosteric mechanism; 2), the native PLA(2) acquires more dynamic properties
      during interfacial activation via membrane binding; and 3), the global
      conformation of the inhibited PLA(2), including the alpha-helices, is less stable
      and is not influenced by membrane binding. These findings provide further
      evidence for an allosteric coupling between the membrane-binding (regulatory)
      site and the catalytic center of PLA(2), which contributes to the interfacial
      activation of the enzyme.

PMID- 12609880
TI  - Mechanism of pH-triggered collapse of phosphatidylethanolamine liposomes
      stabilized by an ortho ester polyethyleneglycol lipid.
AB  - The mechanism of pH-triggered destabilization of liposomes composed of a
      polyethyleneglycol-orthoester-distearoylglycerol lipid (POD) and phosphatidyl
      ethanolamine (PE) has been studied using an ANTS/DPX leakage and a lipid-mixing
      assay. We developed a kinetic model that relates POD hydrolysis to liposome
      collapse. This minimum-surface-shielding model describes the kinetics of the pH
      triggered release of POD/PE liposomes. In the model, when acid-catalyzed
      hydrolysis lowers the mole percentage of POD on the liposome surface to a
      critical level, intervesicular lipid mixing is initiated, resulting in a burst of
      contents release. Two phases of content leakage are observed: a lag phase and a
      burst phase. During the lag phase, less than 20% of liposomal contents are
      released and the leakage begins to accelerate when approaching to the transition
      point. During the burst phase, the leakage rate is dependent on interbilayer
      contact. The burst phase occurs when the surface density of the PEG lipid is 2.3
      +/- 0.6 mol%, regardless of the pH. Vesicles containing 4 mol% of a pH
      insensitive PEG-lipid conjugate and 10% POD did not leak contents or collapse at
      any pH. These data are consistent with the stalk theory to describe the lamellar
      to-inverted hexagonal phase transition and set a lower bound of approximately 16
      PE lipids on the external monolayer as the contact site required for lipid mixing
      between two bilayers.

PMID- 12609881
TI  - Plasmon-waveguide resonance and impedance spectroscopy studies of the interaction
      between penetratin and supported lipid bilayer membranes.
AB  - The interaction between the cell-penetrating peptide, penetratin, and solid
      supported lipid bilayer membranes consisting of either egg phosphatidylcholine
      (PC) or a 75/25 mol% mixture of egg PC and palmitoyloleylphosphatidylglycerol has
      been studied by simultaneously measuring plasmon-waveguide resonance (PWR)
      spectra and impedance spectra of lipid-peptide mixtures. When penetratin was
      incorporated into an egg PC + palmitoyloleylphosphatidylglycerol bilayer, PWR
      measurements showed a hyperbolic increase in the average refractive index and the
      refractive index anisotropy, with no change in membrane thickness, over a
      concentration range between 0 and 2 micro M peptide. In the case of an egg PC
      bilayer, a biphasic dependence was observed, with a decrease in average
      refractive index and anisotropy and no thickness change occurring between 0 and 5
      micro M peptide, and an increase in membrane thickness occurring between 5 and 15
      micro M peptide with no further change in the refractive index parameters. For
      both membranes, the impedance spectroscopy measurements demonstrated that the
      electrical resistance was not altered by peptide incorporation, whereas a
      decrease in membrane capacitance occurred with the same concentration dependence
      as observed in the PWR experiments, although for the PC membrane no further
      changes in electrical properties were observed in the higher concentration range.
      A structural interpretation of these results is described, in which the peptide
      binds electrostatically within the headgroup region of the bilayer and influences
      the headgroup conformation, amount of bound water, and the lipid-packing density,
      without perturbing the hydrocarbon core of the bilayer.

PMID- 12609882
TI  - A rhombohedral phase of lipid containing a membrane fusion intermediate
      structure.
AB  - We constructed the electron density distribution from the x-ray diffraction of a
      phase of phospholipid that exhibited rhombohedral symmetry. To determine the
      phases of the diffraction amplitudes, we first extended the well-known one
      dimensional swelling method for planar bilayers to a three-dimensional method
      applicable to a layered system containing in-plane structures, such as
      rhombohedral structures. The complete phase determination was accomplished by a
      combination of the swelling method and Luzzati's pattern recognition method. The
      constructed electron density distribution showed that in each unit cell, two
      apposed monolayers merged across the water layer and developed into an hourglass
      structure consistent with a postulated membrane fusion intermediate state called
      a stalk. The observation of the stalk structure lends a strong support to the
      stalk hypothesis for membrane fusion and opens a way to measure the structural
      parameters in the fusion pathway.

PMID- 12609883
TI  - Effects of epicholesterol on the phosphatidylcholine bilayer: a molecular
      simulation study.
AB  - Epicholesterol (Echol) is an epimeric form of cholesterol (Chol). A molecular
      dynamics simulation of the fully hydrated dimyristoylphosphatidylcholine-Echol
      (DMPC-Echol) bilayer membrane containing approximately 22 mol % of Echol was
      carried out for 5 ns. A 3-ns trajectory generated between 2 and 5 ns of molecular
      dynamics simulation was used for analyses to determine the effects of Echol on
      the membrane properties. As reference systems, pure DMPC and mixed DMPC-Chol
      bilayers were used. The study shows that Echol, like Chol, changes the
      organization of the bilayer/water interface and increases membrane order and
      condensation, but to a lesser degree. Effects of both sterols are based on the
      same atomic level mechanisms; their different strength arises from different
      vertical localizations of Echol and Chol hydroxyl groups in the membrane/water
      interface.

PMID- 12609884
TI  - Real-time analysis of the effects of cholesterol on lipid raft behavior using
      atomic force microscopy.
AB  - Cholesterol plays a crucial role in cell membranes, and has been implicated in
      the assembly and maintenance of sphingolipid-rich rafts. We have examined the
      cholesterol-dependence of model rafts (sphingomyelin-rich domains) in supported
      lipid monolayers and bilayers using atomic force microscopy. Sphingomyelin-rich
      domains were observed in lipid monolayers in the absence and presence of
      cholesterol, except at high cholesterol concentrations, when separate domains
      were suppressed. The effect of manipulating cholesterol levels on the behavior of
      these sphingomyelin-rich domains in bilayers was observed in real time. Depletion
      of cholesterol resulted in dissolution of the model lipid rafts, whereas
      cholesterol addition resulted in an increased size of the sphingomyelin-rich
      domains and eventually the formation of a single raftlike lipid phase.
      Cholesterol colocalization with sphingomyelin-rich domains was confirmed using
      the sterol binding agent filipin.

PMID- 12609885
TI  - Single fungal kinesin motor molecules move processively along microtubules.
AB  - Conventional kinesins are two-headed molecular motors that move as single
      molecules micrometer-long distances on microtubules by using energy derived from
      ATP hydrolysis. The presence of two heads is a prerequisite for this processive
      motility, but other interacting domains, like the neck and K-loop, influence the
      processivity and are implicated in allowing some single-headed kinesins to move
      processively. Neurospora kinesin (NKin) is a phylogenetically distant, dimeric
      kinesin from Neurospora crassa with high gliding speed and an unusual neck
      domain. We quantified the processivity of NKin and compared it to human kinesin,
      HKin, using gliding and fluorescence-based processivity assays. Our data show
      that NKin is a processive motor. Single NKin molecules translocated microtubules
      in gliding assays on average 2.14 micro m (N = 46). When we tracked single,
      fluorescently labeled NKin motors, they moved on average 1.75 micro m (N = 182)
      before detaching from the microtubule, whereas HKin motors moved shorter
      distances (0.83 micro m, N = 229) under identical conditions. NKin is therefore
      at least twice as processive as HKin. These studies, together with biochemical
      work, provide a basis for experiments to dissect the molecular mechanisms of
      processive movement.

PMID- 12609886
TI  - Thermodynamic properties of the kinesin neck-region docking to the catalytic
      core.
AB  - Kinesin motors move on microtubules by a mechanism that involves a large, ATP
      triggered conformational change in which a mechanical element called the neck
      linker docks onto the catalytic core, making contacts with the core throughout
      its length. Here, we investigate the thermodynamic properties of this
      conformational change using electron paramagnetic resonance (EPR) spectroscopy.
      We placed spin probes at several locations on the human kinesin neck linker and
      recorded EPR spectra in the presence of microtubules and either 5'
      adenylylimidodiphosphate (AMPPNP) or ADP at temperatures of 4-30 degrees C. The
      free-energy change (DeltaG) associated with AMPPNP-induced docking of the neck
      linker onto the catalytic core is favorable but small, about 3 kJ/mol. In
      contrast, the favorable enthalpy change (DeltaH) and unfavorable entropy change
      (TDeltaS) are quite large, about 50 kJ/mol. A mutation in the neck linker,
      V331A/N332A, results in an unfavorable DeltaG for AMPPNP-induced zipping of the
      neck linker onto the core and causes motility defects. These results suggest that
      the kinesin neck linker folds onto the core from a more unstructured state,
      thereby paying a large entropic cost and gaining a large amount of enthalpy.

PMID- 12609887
TI  - Probing the electrostatic shielding of DNA with capillary electrophoresis.
AB  - The free solution mobility of a 20-bp double-stranded DNA oligomer has been
      measured in diethylmalonate (DM) and Tris-acetate buffers, with and without added
      NaCl or TrisCl. DM buffers have the advantage that the buffering ion is anionic,
      so the cation composition in the solution can be varied at will. The results
      indicate that the free solution mobility of DNA decreases linearly with the
      logarithm of ionic strength when the ionic strength is increased by increasing
      the buffer concentration. The mobility also decreases linearly with the logarithm
      of ionic strength when NaCl is added to NaDM buffer or TrisCl is added to TrisDM
      buffer. Nonlinear effects are observed if the counterion in the added salt
      differs from the counterion in the buffer. The dependence of the mobility on
      ionic strength cannot be predicted using the Henry, Debye-Huckel-Onsager, or
      Pitts equations for electrophoresis. However, the mobilities observed in all
      buffer and buffer/salt solutions can be predicted within approximately 20% by the
      Manning equation for electrophoresis, using no adjustable parameters. The results
      suggest that the electrostatic shielding of DNA is determined not only by the
      relative concentrations of the various ions in the solution, but also by their
      equivalent conductivities.

PMID- 12609888
TI  - Thermodynamic characterization of the folding coupled DNA binding by the
      monomeric transcription activator GCN4 peptide.
AB  - Dimerization is a widely believed critical requirement for the yeast
      transcriptional activator GCN4 specifically recognizing its DNA target sites.
      Nonetheless, the binding of the monomeric GCN4 to DNA target sites AP-1 and
      ATF/CREB was recently detected by kinetic studies. Here, for the first time, we
      present a detailed description of the thermodynamics of a monomeric peptide GCN4
      br, the basic region (226-252) of GCN4, binding to AP-1, and ATF/CREB. GCN4
      specifically binds to AP-1 and ATF/CREB in the monomeric form as shown by our
      circular dichroism thermal unfolding measurements. Isothermal titration
      calorimetry experiments indicate that the binding process of GCN4-br with DNA is
      enthalpically driven, accompanied by an unfavorable entropy change. The
      temperature dependence of DeltaH(0) reveals negative changes in heat capacity
      DeltaC(p): DeltaC(p) = -0.92 kJ. mol(-1) K(-1) and DeltaC(p) = -0.95 kJ. mol(-1)
      K(-1) for GCN4-br binding to AP-1 and ATF/CREB, respectively, which is a striking
      manifestation of GCN4-br specifically recognizing DNA target sites. These
      thermodynamic characteristics may give new insight into the mechanism by which
      GCN4 protein binds to DNA target sites for its transcriptional regulation.

PMID- 12609889
TI  - Selective excitation of native fluctuations during thermal unfolding simulations:
      horse heart cytochrome c as a case study.
AB  - The effect of temperature on the activation of native fluctuation motions during
      molecular dynamics unfolding simulations of horse heart cytochrome c has been
      studied. Essential dynamics analysis has been used to analyze the preferred
      directions of motion along the unfolding trajectories obtained by high
      temperature simulations. The results of this study have evidenced a clear
      correlation between the directions of the deformation motions that occur in the
      first stage of the unfolding process and few specific essential motions
      characterizing the 300 K dynamics of the protein. In particular, one of those
      collective motions, involved in the fluctuation of a loop region, is specifically
      excited in the thermal denaturation process, becoming progressively dominant
      during the first 500 ps of the unfolding simulations. As further evidence, the
      essential dynamics sampling performed along this collective motion has shown a
      tendency of the protein to promptly unfold. According to these results, the
      mechanism of thermal induced denaturation process involves the selective
      excitation of one or few specific equilibrium collective motions.

PMID- 12609890
TI  - Short peptide amyloid organization: stabilities and conformations of the islet
      amyloid peptide NFGAIL.
AB  - Experimentally, short peptides have been shown to form amyloids similar to those
      of their parent proteins. Consequently, they present useful systems for studies
      of amyloid conformation. Here we simulate extensively the NFGAIL peptide, derived
      from the human islet amyloid polypeptide (residues 22-27). We simulate different
      possible strand/sheet organizations, from dimers to nonamers. Our simulations
      indicate that the most stable conformation is an antiparallel strand orientation
      within the sheets and parallel between sheets. Consistent with the alanine
      mutagenesis, we find that the driving force is the hydrophobic effect. Whereas
      the NFGAIL forms stable oligomers, the NAGAIL oligomer is unstable, and
      disintegrates very quickly after the beginning of the simulation. The simulations
      further identify a minimal seed size. Combined with our previous simulations of
      the prion-derived AGAAAAGA peptide, AAAAAAAA, and the Alzheimer Abeta fragments
      16-22, 24-36, 16-35, and 10-35, and the solid-state NMR data for Abeta fragments
      16-22, 10-35, and 1-40, some insight into the length and the sequence matching
      effects may be obtained.

PMID- 12609891
TI  - Development of unified statistical potentials describing protein-protein
      interactions.
AB  - A residue-based and a heavy atom-based statistical pair potential are developed
      for use in assessing the strength of protein-protein interactions. To ensure the
      quality of the potentials, a nonredundant, high-quality dimer database is
      constructed. The protein complexes in this dataset are checked by a literature
      search to confirm that they form multimers, and the pairwise amino acid
      preference to interact across a protein-protein interface is analyzed and pair
      potentials constructed. The performance of the residue-based potentials is
      evaluated by using four jackknife tests and by assessing the potentials' ability
      to select true protein-protein interfaces from false ones. Compared to potentials
      developed for monomeric protein structure prediction, the interdomain potential
      performs much better at distinguishing protein-protein interactions. The
      potential developed from homodimer interfaces is almost the same as that
      developed from heterodimer interfaces with a correlation coefficient of 0.92. The
      residue-based potential is well suited for genomic scale protein interaction
      prediction and analysis, such as in a recently developed threading-based
      algorithm, MULTIPROSPECTOR. However, the more time-consuming atom-based potential
      performs better in identifying near-native structures from docking generated
      decoys.

PMID- 12609892
TI  - Computer simulations of membrane protein folding: structure and dynamics.
AB  - A lattice model of membrane proteins with a composite energy function is proposed
      to study their folding dynamics and native structures using Monte Carlo
      simulations. This model successfully predicts the seven helix bundle structure of
      sensory rhodopsin I by practicing a three-stage folding. Folding dynamics of a
      transmembrane segment into a helix is further investigated by varying the
      cooperativity in the formation of alpha helices for both random folding and
      assisted folding. The chain length dependence of the folding time of a
      hydrophobic segment to a helical state is studied for both free and anchored
      chains. An unusual length dependence in the folding time of anchored chains is
      observed.

PMID- 12609893
TI  - Primary folding dynamics of sperm whale apomyoglobin: core formation.
AB  - The structure, thermodynamics, and kinetics of heat-induced unfolding of sperm
      whale apomyoglobin core formation have been studied. The most rudimentary core is
      formed at pH(*) 3.0 and up to 60 mM NaCl. Steady state for ultraviolet circular
      dichroism and fluorescence melting studies indicate that the core in this acid
      destabilized state consists of a heterogeneous composition of structures of
      approximately 26 residues, two-thirds of the number involved for horse heart
      apomyoglobin under these conditions. Fluorescence temperature-jump relaxation
      studies show that there is only one process involved in Trp burial. This occurs
      in 20 micro s for a 7 degrees jump to 52 degrees C, which is close to the limits
      placed by diffusion on folding reactions. However, infrared temperature jump
      studies monitoring native helix burial are biexponential with times of 5 micro s
      and 56 micro s for a similar temperature jump. Both fluorescence and infrared
      fast phases are energetically favorable but the slow infrared absorbance phase is
      highly temperature-dependent, indicating a substantial enthalpic barrier for this
      process. The kinetics are best understood by a multiple-pathway kinetics model.
      The rapid phases likely represent direct burial of one or both of the Trp
      residues and parts of the G- and H-helices. We attribute the slow phase to burial
      and subsequent rearrangement of a misformed core or to a collapse having a high
      energy barrier wherein both Trps are solvent-exposed.

PMID- 12609894
TI  - Role of hydrophobic clusters and long-range contact networks in the folding of
      (alpha/beta)8 barrel proteins.
AB  - Analysis on the three dimensional structures of (alpha/beta)(8) barrel proteins
      provides ample light to understand the factors that are responsible for directing
      and maintaining their common fold. In this work, the hydrophobically enriched
      clusters are identified in 92% of the considered (alpha/beta)(8) barrel proteins.
      The residue segments with hydrophobic clusters have high thermal stability.
      Further, these clusters are formed and stabilized through long-range
      interactions. Specifically, a network of long-range contacts connects adjacent
      beta-strands of the (alpha/beta)(8) barrel domain and the hydrophobic clusters.
      The implications of hydrophobic clusters and long-range networks in providing a
      feasible common mechanism for the folding of (alpha/beta)(8) barrel proteins are
      proposed.

PMID- 12609895
TI  - Investigation of pathways for the low-pH conformational transition in influenza
      hemagglutinin.
AB  - Targeted molecular dynamics simulations were used to study the conformational
      transition of influenza hemagglutinin (HA) from the native conformation to
      putative fusogenic or postfusion conformations populated at low pH. Three
      pathways for this conformational change were considered. Complete dissociation of
      the globular domains of HA was observed in one pathway, whereas smaller
      rearrangements were observed in the other two. The fusion peptides became exposed
      and moved toward the target membrane, although occasional movement toward the
      viral membrane was also observed. The effective energy profiles along the paths
      show multiple barriers. The final low-pH structures, which are consistent with
      available experimental data, are comparable in effective energy to native HA. As
      a control, the uncleaved precursor HA0 was also forced along the same pathway. In
      this case both the final energy and the energy barrier were much higher than in
      the cleaved protein. This study suggests that 1) as proposed, the native
      conformation is the global minimum energy conformation for the uncleaved
      precursor but a metastable state for cleaved HA; 2) the spring-loaded
      conformational change is energetically plausible in full-length HA; and 3)
      complete globular domain dissociation is not necessary for extension of the
      coiled coil and fusion peptide exposure, but the model with complete dissociation
      has lower energy.

PMID- 12609896
TI  - Effects of oligomerization and secondary structure on the surface behavior of
      pulmonary surfactant proteins SP-B and SP-C.
AB  - The relationship among protein oligomerization, secondary structure at the
      interface, and the interfacial behavior was investigated for spread layers of
      native pulmonary surfactant associated proteins B and C. SP-B and SP-C were
      isolated either from butanol or chloroform/methanol lipid extracts that were
      obtained from sheep lung washings. The proteins were separated from other
      components by gel exclusion chromatography or by high performance liquid
      chromatography. SDS gel electrophoresis data indicate that the SP-B samples
      obtained using different solvents showed different oligomerization states of the
      protein. The CD and FTIR spectra of SP-B isolated from all extracts were
      consistent with a secondary structure dominated by alpha-helix. The CD and FTIR
      spectra of the first SP-C corresponded to an alpha-helical secondary structure
      and the spectra of the second SP-C corresponded to a mixture of alpha-helical and
      beta-sheet conformation. In contrast, the spectra of the third SP-C corresponded
      to antiparallel beta-sheets. The interfacial behavior was characterized by
      surface pressure/area (pi-A) isotherms. Differences in the oligomerization state
      of SP-B as well as in the secondary structure of SP-C all produce significant
      differences in the surface pressure/area isotherms. The molecular cross sections
      determined from the pi-A isotherms and from dynamic cycling experiments were 6
      nm(2)/dimer molecule for SP-B and 1.15 nm(2)/molecule for SP-C in alpha-helical
      conformation and 1.05 nm(2)/molecule for SP-C in beta-sheet conformation. Both
      the oligomer ratio of SP-B and the secondary structure of SP-C strongly influence
      organization and behavior of these proteins in monolayer assemblies. In addition,
      alpha-helix --> beta-sheet conversion of SP-C occurs simply by an increase of the
      summary protein/lipid concentration in solution.

PMID- 12609898
TI  - Monitoring of the formation and dissociation of polyethylenimine/DNA complexes by
      two photon fluorescence correlation spectroscopy.
AB  - Polyethylenimines (PEI) constitute efficient nonviral vectors for gene transfer.
      However, because free PEI shows some cytotoxicity and because intracellular
      dissociation of PEI/DNA complexes seems to be required for efficient
      transfection, it is important to monitor the concentrations of free and bound
      partners in the mixtures of DNA and PEI used for transfection. To reach this
      objective, we used fluorescence correlation spectroscopy with two-photon
      excitation to characterize the complexes formed with either rhodamine-labeled 25
      kDa PEI or DNA plasmid molecules. At the molar ratios of PEI nitrogen atoms to
      DNA phosphate usually used for transfection, we found that approximately 86% of
      the PEI molecules were in a free form. The PEI/DNA complexes are composed on the
      average by 3.5 (+/-1) DNA plasmids and approximately 30 PEI molecules. From this
      composition and the pK(a) of PEI, it could be inferred that in contrast to DNA
      condensation by small multivalent cations, only a limited neutralization of the
      DNA phosphate groups is required for DNA condensation by PEI. Moreover, DNA
      appears only poorly compacted in the PEI/DNA complexes. As an application,
      fluorescence correlation spectroscopy was used to monitor the purification of
      PEI/DNA complexes by ultrafiltration as well as the heparin-induced dissociation
      of the complexes.

PMID- 12609897
TI  - Nanotubules formed by highly hydrophobic amphiphilic alpha-helical peptides and
      natural phospholipids.
AB  - We previously reported that the 18-mer amphiphilic alpha-helical peptide, Hel 13
      5, consisting of 13 hydrophobic residues and five hydrophilic amino acid
      residues, can induce neutral liposomes (egg yolk phosphatidylcholine) to adopt
      long nanotubular structures and that the interaction of specific peptides with
      specific phospholipid mixtures induces the formation of membrane structures
      resembling cellular organelles such as the Golgi apparatus. In the present study
      we focused our attention on the effects of peptide sequence and chain length on
      the nanotubule formation occurring in mixture systems of Hel 13-5 and various
      neutral and acidic lipid species by means of turbidity measurements, dynamic
      light scattering measurements, and electron microscopy. We designed and
      synthesized two sets of Hel 13-5 related peptides: 1) Five peptides to examine
      the role of hydrophobic or hydrophilic residues in amphiphilic alpha-helical
      structures, and 2) Six peptides to examine the role of peptide length, having
      even number residues from 12 to 24. Conformational, solution, and morphological
      studies showed that the amphiphilic alpha-helical structure and the peptide chain
      length (especially 18 amino acid residues) are critical determinants of very long
      tubular structures. A mixture of alpha-helix and beta-structures determines the
      tubular shapes and assemblies. However, we found that the charged Lys residues
      comprising the hydrophilic regions of amphiphilic structures can be replaced by
      Arg or Glu residues without a loss of tubular structures. This suggests that the
      mechanism of microtubule formation does not involve the charge interaction. The
      immersion of the hydrophobic part of the amphiphilic peptides into liposomes
      initially forms elliptic-like structures due to the fusion of small liposomes,
      which is followed by a transformation into tubular structures of various sizes
      and shapes.

PMID- 12609899
TI  - Orientation and interactions of an essential tryptophan (Trp-38) in the capsid
      subunit of Pf3 filamentous virus.
AB  - The filamentous bacteriophage Pf3 consists of a covalently closed DNA single
      strand of 5833 nucleotides sheathed by approximately 2500 copies of a 44-residue
      capsid subunit. The capsid subunit contains a single tryptophan residue (Trp-38),
      which is located within the basic C-terminal sequence (-RWIKAQFF) and is
      essential for virion assembly in vivo. Polarized Raman microspectroscopy has been
      employed to determine the orientation of the Trp-38 side chain in the native
      virus structure. The polarized Raman measurements show that the plane of the
      indolyl ring is tilted by 17 degrees from the virion axis and that the indolyl
      pseudo-twofold axis is inclined at 46 degrees to the virion axis. Using the
      presently determined orientation of the indolyl ring and side-chain torsion
      angles, chi(1) (N-C(alpha)-C(beta)-C(gamma)) and chi(2,1) (C(alpha)-C(beta)
      C(gamma)-C(delta1)), we propose a detailed molecular model for the local
      structure of Trp-38 in the Pf3 virion. The present Pf3 model is consistent with
      previously reported Raman, ultraviolet-resonance Raman and fluorescence results
      suggesting an unusual environment for Trp-38 in the virion assembly, probably
      involving an intrasubunit cation-pi interaction between the guanidinium moiety of
      Arg-37 and the indolyl moiety of Trp-38. Such a C-terminal Trp-38/Arg-37
      interaction may be important for the stabilization of a subunit conformation that
      is required for binding to the single-stranded DNA genome during virion assembly.

PMID- 12609900
TI  - Measuring size distribution in highly heterogeneous systems with fluorescence
      correlation spectroscopy.
AB  - Fluorescence correlation spectroscopy (FCS) is a sensitive and widely used
      technique for measuring diffusion. FCS data are conventionally modeled with a
      finite number of diffusing components and fit with a least-square fitting
      algorithm. This approach is inadequate for analyzing data obtained from highly
      heterogeneous systems. We introduce a Maximum Entropy Method based fitting
      routine (MEMFCS) that analyzes FCS data in terms of a quasicontinuous
      distribution of diffusing components, and also guarantees a maximally wide
      distribution that is consistent with the data. We verify that for a homogeneous
      specimen (green fluorescent protein in dilute aqueous solution), both MEMFCS and
      conventional fitting yield similar results. Further, we incorporate an
      appropriate goodness of fit criterion in MEMFCS. We show that for errors
      estimated from a large number of repeated measurements, the reduced chi(2) value
      in MEMFCS analysis does approach unity. We find that the theoretical prediction
      for errors in FCS experiments overestimates the actual error, but can be
      empirically modified to serve as a guide for estimating the goodness of the fit
      where reliable error estimates are unavailable. Finally, we compare the
      performance of MEMFCS with that of a conventional fitting routine for analyzing
      simulated data describing a highly heterogeneous distribution containing 41
      diffusing species. Both methods fit the data well. However, the conventional fit
      fails to reproduce the essential features of the input distribution, whereas
      MEMFCS yields a distribution close to the actual input.

PMID- 12609901
TI  - Stability and Cu(II) binding of prion protein variants related to inherited human
      prion diseases.
AB  - All inherited forms of human prion diseases are linked with mutations in the
      prion protein (PrP) gene. Here we have investigated the stability and Cu(II)
      binding properties of three recombinant variants of murine full-length PrP(23
      231)-containing destabilizing point mutations that are associated with human
      Gerstmann-Straussler-Scheinker disease (F198S), Creutzfeld-Jakob disease (E200K),
      and fatal familial insomnia (D178N) by electron paramagnetic resonance and
      circular dichroism spectroscopy. Furthermore, we analyzed the variants H140S,
      H177S, and H187S of the isolated C-terminal domain of murine PrP, mPrP(121-231),
      to test a role of the histidine residues in Cu(II) binding. The F198S and E200K
      variants of PrP(23-231) differed in Cu(II) binding from the wild-type mPrP(23
      231). However, circular dichroism spectroscopy indicated that the variants and
      the wild type did not undergo conformational changes in the presence of Cu(II).
      The D178N variant showed a high tendency to aggregate at pH 7.4 both with and
      without Cu(II). At lower pH values, it showed the same Cu(II) binding behavior as
      the wild type. The analysis allowed for a better location of the Cu(II) binding
      sites in the C-terminal part of the protein. Our present data indicate that
      hereditary forms of prion diseases cannot be rationalized on the basis of altered
      Cu(II) binding or mutation-induced protein destabilization alone.

PMID- 12609902
TI  - Activation of hydrogen peroxide in horseradish peroxidase occurs within
      approximately 200 micro s observed by a new freeze-quench device.
AB  - To observe the formation process of compound I in horseradish peroxidase (HRP),
      we developed a new freeze-quench device with approximately 200 micro s of the
      mixing-to-freezing time interval and observed the reaction between HRP and
      hydrogen peroxide (H(2)O(2)). The developed device consists of a submillisecond
      solution mixer and rotating copper or silver plates cooled at 77 K; it freezes
      the small droplets of mixed solution on the surface of the rotating plates. The
      ultraviolet-visible spectra of the sample quenched at approximately 1 ms after
      the mixing of HRP and H(2)O(2) suggest the formation of compound I. The electron
      paramagnetic resonance spectra of the same reaction quenched at approximately 200
      micro s show a convex peak at g = 2.00, which is identified as compound I due to
      its microwave power and temperature dependencies. The absence of ferric signals
      in the electron paramagnetic resonance spectra of the quenched sample indicates
      that compound I is formed within approximately 200 micro s after mixing HRP and
      H(2)O(2). We conclude that the activation of H(2)O(2) in HRP at ambient
      temperature completes within approximately 200 micro s. The developed device can
      be generally applied to investigate the electronic structures of short-lived
      intermediates of metalloenzymes.

PMID- 12609903
TI  - Fluorescence correlation spectroscopy close to a fluctuating membrane.
AB  - Compartmentalization of the cytoplasm by membranes should have a strong influence
      on the diffusion of macromolecules inside a cell, and we have studied how this
      could be reflected in fluorescence correlation spectroscopy (FCS) experiments. We
      derived the autocorrelation function measured by FCS for fluorescent particles
      diffusing close to a soft membrane, and show it to be the sum of two
      contributions: short timescale correlations come from the diffusion of the
      particles (differing from free diffusion because of the presence of an obstacle),
      whereas long timescale correlations arise from fluctuations of the membrane
      itself (which create intensity fluctuations by modulating the number of detected
      particles). In the case of thermal fluctuations this second type of correlation
      depends on the elasticity of the membrane. To illustrate this calculation, we
      report the results of FCS experiments carried out close to a vesicle membrane.
      The measured autocorrelation functions display very distinctly the two expected
      contributions, and allow both to recover the diffusion coefficient of the
      fluorophore and to characterize the membrane fluctuations in term of a bending
      rigidity. Our results show that FCS measurements inside cells can lead to
      erroneous values of the diffusion coefficient if the influence of membranes is
      not recognized.

PMID- 12609904
TI  - Rietveld refinement on x-ray diffraction patterns of bioapatite in human fetal
      bones.
AB  - Bioapatite, the main constituent of mineralized tissue in mammalian bones, is a
      calcium-phosphate-based mineral that is similar in structure and composition to
      hydroxyapatite. In this work, the crystallographic structure of bioapatite in
      human fetuses was investigated by synchrotron radiation x-ray diffraction (XRD)
      and microdiffraction ( micro -XRD) techniques. Rietveld refinement analyses of
      XRD and micro -XRD data allow for quantitative probing of the structural
      modifications of bioapatite as functions of the mineralization process and
      gestational age.

PMID- 12609905
TI  - Statistical analysis of fluorescence correlation spectroscopy: the standard
      deviation and bias.
AB  - We present a detailed statistical analysis of fluorescence correlation
      spectroscopy for a wide range of timescales. The derivation is completely
      analytical and can provide an excellent tool for planning and analysis of FCS
      experiments. The dependence of the signal-to-noise ratio on different measurement
      conditions is extensively studied. We find that in addition to the shot noise and
      the noise associated with correlated molecular dynamics there is another source
      of noise that appears at very large lag times. We call this the "particle noise,"
      as its behavior is governed by the number of particles that have entered and left
      the laser beam sample volume during large dwell times. The standard deviations of
      all the points on the correlation function are calculated analytically and shown
      to be in good agreement with experiments. We have also investigated the bias
      associated with experimental correlation function measurements. A "phase diagram"
      for FCS experiments is constructed that demonstrates the significance of the bias
      for any given experiment. We demonstrate that the value of the bias can be
      calculated and added back as a first-order correction to the experimental
      correlation function.

PMID- 12609906
TI  - Phospholipid membrane interactions of saposin C: in situ atomic force microscopic
      study.
AB  - Saposin C (Sap C) is a small glycoprotein required for hydrolysis of
      glucosylceramidase in lysosomes. The full activity of glucosylceramidase requires
      the presence of both Sap C and acidic phospholipids. Interaction between Sap C
      and acidic phospholipid-containing membranes, a crucial step for enzyme
      activation, is not fully understood. In this study, the dynamic process of Sap C
      interaction with acidic phospholipid-containing membranes was investigated in
      aqueous buffer using atomic force microscopy. Sap C induced two types of membrane
      restructuring: formation of patch-like structural domains and the occurrence of
      membrane destabilization. The former caused thickness increase whereas the latter
      caused thickness reduction in the gel-phase membrane bilayer, possibly as a
      result of lipid loss or an interdigitating process. Patch-like domain formation
      was independent of acidic phospholipids, whereas membrane destabilization is
      dependent on the presence and concentration of acidic phospholipids. Sap C
      effects on membrane restructuring were further studied using synthetic peptides.
      Synthetic peptides corresponding to the amphipathic alpha-helical domains 1
      (designated "H1 peptide") and 2 (H2 peptide) of Sap C were used. Our results
      indicated that H2 contributed to domain formation but not to membrane
      destabilization, whereas H1 induced neither type of membrane restructuring.
      However, H1 was able to mimic Sap C's destabilization effect in conjunction with
      H2, but only when H1 was present first and H2 was added afterwards. This study
      provides an approach to investigate the structure-function aspects of Sap C
      interaction with phospholipid membranes, with insights into the mechanism(s) of
      Sap C-membrane interaction.

PMID- 12609907
TI  - Cell membrane alignment along adhesive surfaces: contribution of active and
      passive cell processes.
AB  - Cell adhesion requires nanometer scale membrane alignment to allow contact
      between adhesion receptors. Little quantitative information is presently
      available on this important biological process. Here we present an interference
      reflection microscopic study of the initial interaction between monocytic THP-1
      cells and adhesive surfaces, with concomitant determination of cell
      deformability, using micropipette aspiration, and adhesiveness, using a laminar
      flow assay. We report that 1), during the first few minutes after contact, cells
      form irregular-shaped interaction zones reaching approximately 100 micro m(2)
      with a margin extension velocity of 0.01-0.02 micro m/s. This happens before the
      overall cell deformations usually defined as spreading. 2), These interference
      reflection microscopic-detected zones represent bona fide adhesion inasmuch as
      cells are not released by hydrodynamic forces. 3), Alignment is markedly
      decreased but not abolished by microfilament blockade with cytochalasin or even
      cell fixation with paraformaldehyde. 4), In contrast, exposing cells to hypotonic
      medium increased the rate of contact extension. 5), Contacts formed in presence
      of cytochalasin, after paraformaldehyde fixation or in hypotonic medium, were
      much more regular-shaped than controls and their extension matched cell
      deformability. 6), None of the aforementioned treatments altered adhesiveness to
      the surface. It is concluded that adhesive forces and passive membrane
      deformations are sufficient to generate initial cell alignment to adhesive
      surfaces, and this process is accelerated by spontaneous cytoskeletally-driven
      membrane motion.

PMID- 12609908
TI  - Microrheology of human lung epithelial cells measured by atomic force microscopy.
AB  - Lung epithelial cells are subjected to large cyclic forces from breathing.
      However, their response to dynamic stresses is poorly defined. We measured the
      complex shear modulus (G(*)(omega)) of human alveolar (A549) and bronchial (BEAS
      2B) epithelial cells over three frequency decades (0.1-100 Hz) and at different
      loading forces (0.1-0.9 nN) with atomic force microscopy. G(*)(omega) was
      computed by correcting force-indentation oscillatory data for the tip-cell
      contact geometry and for the hydrodynamic viscous drag. Both cell types displayed
      similar viscoelastic properties. The storage modulus G'(omega) increased with
      frequency following a power law with exponent approximately 0.2. The loss modulus
      G"(omega) was approximately 2/3 lower and increased similarly to G'(omega) up to
      approximately 10 Hz, but exhibited a steeper rise at higher frequencies. The
      cells showed a weak force dependence of G'(omega) and G"(omega). G(*)(omega)
      conformed to the power-law model with a structural damping coefficient of
      approximately 0.3, indicating a coupling of elastic and dissipative processes
      within the cell. Power-law behavior implies a continuum distribution of stress
      relaxation time constants. This complex dynamics is consistent with the rheology
      of soft glassy materials close to a glass transition, thereby suggesting that
      structural disorder and metastability may be fundamental features of cell
      architecture.

PMID- 12609909
TI  - Cholesterol-induced protein sorting: an analysis of energetic feasibility.
AB  - The mechanism(s) underlying the sorting of integral membrane proteins between the
      Golgi complex and the plasma membrane remain uncertain because no specific Golgi
      retention signal has been found. Moreover one can alter a protein's eventual
      localization simply by altering the length of its transmembrane domain (TMD). M.
      S. Bretscher and S. Munro (SCIENCE: 261:1280-1281, 1993) therefore proposed a
      physical sorting mechanism based on the hydrophobic match between the proteins'
      TMD and the bilayer thickness, in which cholesterol would regulate protein
      sorting by increasing the lipid bilayer thickness. In this model, Golgi proteins
      with short TMDs would be excluded from cholesterol-enriched domains (lipid rafts)
      that are incorporated into transport vesicles destined for the plasma membrane.
      Although attractive, this model remains unproven. We therefore evaluated the
      energetic feasibility of a cholesterol-dependent sorting process using the theory
      of elastic liquid crystal deformations. We show that the distribution of proteins
      between cholesterol-enriched and cholesterol-poor bilayer domains can be
      regulated by cholesterol-induced changes in the bilayer physical properties.
      Changes in bilayer thickness per se, however, have only a modest effect on
      sorting; the major effect arises because cholesterol changes also the bilayer
      material properties, which augments the energetic penalty for incorporating short
      TMDs into cholesterol-enriched domains. We conclude that cholesterol-induced
      changes in the bilayer physical properties allow for effective and accurate
      sorting which will be important generally for protein partitioning between
      different membrane domains.

PMID- 12609910
TI  - The position of QB in the photosynthetic reaction center depends on pH: a
      theoretical analysis of the proton uptake upon QB reduction.
AB  - Electrostatics-based calculations have been performed to examine the proton
      uptake upon reduction of the terminal electron acceptor Q(B) in the
      photosynthetic reaction center of Rhodobacter sphaeroides as a function of pH and
      the associated conformational equilibrium. Two crystal structures of the reaction
      center were considered: one structure was determined in the dark and the other
      under illumination. In the two structures, the Q(B) was found in two different
      positions, proximal or distal to the nonheme iron. Because Q(B) was found mainly
      in the distal position in the dark and only in the proximal position under
      illumination, the two positions have been attributed mostly to the oxidized and
      the reduced forms of Q(B), respectively. We calculated the proton uptake upon
      Q(B) reduction by four different models. In the first model, Q(B) is allowed to
      equilibrate between the two positions with either oxidation state. This
      equilibrium was allowed to vary with pH. In the other three models the
      distribution of Q(B) between the proximal position and the distal position was pH
      independent, with Q(B) occupying only the distal position or only the proximal
      position or populating the two positions with a fixed ratio. Only the first
      model, which includes the pH-dependent conformational equilibrium, reproduces
      both the experimentally measured pH dependence of the proton uptake and the
      crystallographically observed conformational equilibrium at pH 8. From this
      model, we find that Q(B) occupies only the distal position below pH 6.5 and only
      the proximal position above pH 9.0 in both oxidation states. Between these pH
      values both positions are partially occupied. The reduced Q(B) has a higher
      occupancy in the proximal position than the oxidized Q(B). In summary, the
      present results indicate that the conformational equilibrium of Q(B) depends not
      only on the redox state of Q(B), but also on the pH value of the solution.

PMID- 12609911
TI  - Ionic mechanisms underlying spontaneous CA1 neuronal firing in Ca2+-free
      solution.
AB  - Hippocampal CA1 neurons exposed to zero-[Ca(2+)] solutions can generate periodic
      spontaneous synchronized activity in the absence of synaptic function.
      Experiments using hippocampal slices showed that, after exposure to zero
      [Ca(2+)](0) solution, CA1 pyramidal cells depolarized 5-10 mV and started firing
      spontaneous action potentials. Spontaneous single neuron activity appeared in
      singlets or was grouped into bursts of two or three action potentials. A 16
      compartment, 23-variable cable model of a CA1 pyramidal neuron was developed to
      study mechanisms of spontaneous neuronal bursting in a calcium-free extracellular
      solution. In the model, five active currents (a fast sodium current, a persistent
      sodium current, an A-type transient potassium current, a delayed rectifier
      potassium current, and a muscarinic potassium current) are included in the
      somatic compartment. The model simulates the spontaneous bursting behavior of
      neurons in calcium-free solutions. The mechanisms underlying several aspects of
      bursting are studied, including the generation of triplet bursts, spike duration,
      burst termination, after-depolarization behavior, and the prolonged inactive
      period between bursts. We show that the small persistent sodium current can play
      a key role in spontaneous CA1 activity in zero-calcium solutions. In particular,
      it is necessary for the generation of an after-depolarizing potential and
      prolongs both individual bursts and the interburst interval.

PMID- 12609914
TI  - New contract for general practitioners.

PMID- 12609912
TI  - Application of singular value decomposition to the analysis of time-resolved
      macromolecular x-ray data.
AB  - Singular value decomposition (SVD) is a technique commonly used in the analysis
      of spectroscopic data that both acts as a noise filter and reduces the
      dimensionality of subsequent least-squares fits. To establish the applicability
      of SVD to crystallographic data, we applied SVD to calculated difference Fourier
      maps simulating those to be obtained in a time-resolved crystallographic study of
      photoactive yellow protein. The atomic structures of one dark state and three
      intermediates were used in qualitatively different kinetic mechanisms to generate
      time-dependent difference maps at specific time points. Random noise of varying
      levels in the difference structure factor amplitudes, different extents of
      reaction initiation, and different numbers of time points were all employed to
      simulate a range of realistic experimental conditions. Our results show that SVD
      allows for an unbiased differentiation between signal and noise; a small subset
      of singular values and vectors represents the signal well, reducing the random
      noise in the data. Due to this, phase information of the difference structure
      factors can be obtained. After identifying and fitting a kinetic mechanism, the
      time-independent structures of the intermediates could be recovered. This
      demonstrates that SVD will be a powerful tool in the analysis of experimental
      time-resolved crystallographic data.

PMID- 12609915
TI  - Management of people who have been raped.

PMID- 12609916
TI  - Arms sales, health, and security.

PMID- 12609917
TI  - Mobile phones in hospitals.

PMID- 12609919
TI  - AIDS vaccine may offer hope only for some ethnic groups.

PMID- 12609922
TI  - Ephedra supplement may have contributed to sportsman's death.

PMID- 12609918
TI  - Fetal surgery.

PMID- 12609924
TI  - No deal in sight on cheap drugs for poor countries.

PMID- 12609925
TI  - Millions more at risk of arsenic poisoning than previously thought.

PMID- 12609930
TI  - Women too busy to exercise.

PMID- 12609935
TI  - Commissions start review of service framework for coronary heart disease.

PMID- 12609937
TI  - United States limits resident physicians to 80 hour working week.

PMID- 12609938
TI  - Rich countries pledge to help poor nations fight tobacco.

PMID- 12609939
TI  - Scientist or showman?

PMID- 12609940
TI  - Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on
      fractures and mortality in men and women living in the community: randomised
      double blind controlled trial.
AB  - OBJECTIVE: To determine the effect of four monthly vitamin D supplementation on
      the rate of fractures in men and women aged 65 years and over living in the
      community. DESIGN: Randomised double blind controlled trial of 100 000 IU oral
      vitamin D3 (cholecalciferol) supplementation or matching placebo every four
      months over five years. SETTING AND PARTICIPANTS: 2686 people (2037 men and 649
      women) aged 65-85 years living in the general community, recruited from the
      British doctors register and a general practice register in Suffolk. MAIN OUTCOME
      MEASURES: Fracture incidence and total mortality by cause. RESULTS: After five
      years 268 men and women had incident fractures, of whom 147 had fractures in
      common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks
      in the vitamin D group compared with the placebo group were 0.78 (95% confidence
      interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93,
      P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants
      died. The relative risk for total mortality in the vitamin D group compared with
      the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in
      men and women and in doctors and the general practice population. CONCLUSION:
      Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures
      without adverse effects in men and women living in the general community.

PMID- 12609942
TI  - Survey of claims of no effect in abstracts of Cochrane reviews.

PMID- 12609941
TI  - Validity of indirect comparison for estimating efficacy of competing
      interventions: empirical evidence from published meta-analyses.
AB  - OBJECTIVE: To determine the validity of adjusted indirect comparisons by using
      data from published meta-analyses of randomised trials. DESIGN: Direct comparison
      of different interventions in randomised trials and adjusted indirect comparison
      in which two interventions were compared through their relative effect versus a
      common comparator. The discrepancy between the direct and adjusted indirect
      comparison was measured by the difference between the two estimates. DATA
      SOURCES: Database of abstracts of reviews of effectiveness (1994-8), the Cochrane
      database of systematic reviews, Medline, and references of retrieved articles.
      RESULTS: 44 published meta-analyses (from 28 systematic reviews) provided
      sufficient data. In most cases, results of adjusted indirect comparisons were not
      significantly different from those of direct comparisons. A significant
      discrepancy (P<0.05) was observed in three of the 44 comparisons between the
      direct and the adjusted indirect estimates. There was a moderate agreement
      between the statistical conclusions from the direct and adjusted indirect
      comparisons (kappa 0.51). The direction of discrepancy between the two estimates
      was inconsistent. CONCLUSIONS: Adjusted indirect comparisons usually but not
      always agree with the results of head to head randomised trials. When there is no
      or insufficient direct evidence from randomised trials, the adjusted indirect
      comparison may provide useful or supplementary information on the relative
      efficacy of competing interventions. The validity of the adjusted indirect
      comparisons depends on the internal validity and similarity of the included
      trials.

PMID- 12609943
TI  - Risk of recurrence of prolonged pregnancy.

PMID- 12609944
TI  - Accessibility, acceptability, and effectiveness in primary care of routine
      telephone review of asthma: pragmatic, randomised controlled trial.
AB  - OBJECTIVE: To determine whether routine review by telephone of patients with
      asthma improves access and is a good alternative to face to face reviews in
      general practices. DESIGN: Pragmatic, randomised controlled trial. SETTING: Four
      general practices in England. PARTICIPANTS: 278 adults who had not been reviewed
      in the previous 11 months. INTERVENTION: Participants were randomised to either
      telephone review or face to face consultation with the asthma nurse. MAIN OUTCOME
      MEASURES: Primary outcome measures were the proportion of participants who were
      reviewed within three months of randomisation and disease specific quality of
      life, as measured by the Juniper mini asthma quality of life questionnaire.
      Secondary outcome measures included the validated "short Q" asthma morbidity
      score, nursing care satisfaction questionnaire score, and length of consultation.
      RESULTS: Of 137 people randomised to telephone consultation, 101 (74%) were
      reviewed, compared with 68 reviewed (48%) of the 141 people in the surgery group,
      a difference of 26% (95% confidence interval 14% to 37%; P<0.001; number needed
      to treat 3.8). Three months after randomisation the two groups did not differ in
      the Juniper score (risk difference -0.07 (95% confidence interval -0.40 to 0.27)
      or in satisfaction with the consultation (risk difference -0.07 (-0.27 to 0.13)).
      Telephone consultations were on average 10 minutes shorter than reviews held in
      the surgery (mean difference 10.7 minutes (12.6 to 8.8; P<0.001)). CONCLUSIONS:
      Compared with face to face consultations in the surgery, telephone consultations
      enable more people with asthma to be reviewed, without clinical disadvantage or
      loss of satisfaction. A shorter duration means that telephone consultations are
      likely to be an efficient option in primary care for routine review of asthma.

PMID- 12609945
TI  - Near patient testing for influenza in children in primary care: comparison with
      laboratory test.

PMID- 12609946
TI  - Achieving national service framework standards for cardiac rehabilitation and
      secondary prevention.
AB  - PROBLEM: Integrated care for patients who survive a myocardial infarction is
      lacking. Many patients are not offered cardiac rehabilitation, and secondary
      prevention is not optimal. DESIGN: 12 month audit of 106 patients who survived an
      acute myocardial infarction. BACKGROUND AND SETTING: Carrick Primary Care Trust
      in Cornwall (population 98 500) and one district general hospital. KEY MEASURES
      FOR IMPROVEMENT: Proportion of patients who complete a cardiac rehabilitation
      programme after a myocardial infarction. Proportion of patients with optimal
      secondary prevention, as measured by smoking status, body mass index, cholesterol
      <5.0 mmol/l, and blood pressure <140/85 mm Hg. STRATEGIES FOR CHANGE: We set up a
      novel, integrated, and seamless system for cardiac rehabilitation. We employed a
      cardiac liaison nurse to identify and assess in hospital all patients with
      suspected acute myocardial infarction. The nurse offered patients the choice of
      home based rehabilitation with the Heart Manual or hospital based rehabilitation.
      The nurse gave discharge details to the patient's general practice; these were to
      be included on a practice based register of coronary heart disease. EFFECTS OF
      CHANGE: All 106 eligible patients were offered cardiac rehabilitation and were
      included in a practice based register of coronary heart disease to facilitate
      long term follow up in primary care. 47 (44%) patients chose home based
      rehabilitation with the Heart Manual, and 41 (87%) of these completed the
      programme; 35 (33%) patients chose hospital based rehabilitation, and 17 (49%) of
      these completed the programme. The numbers of patients achieving secondary
      prevention targets improved significantly: those with serum cholesterol <5.0
      mmol/l at discharge increased from 28% at baseline to 75% at 12 months. Optimal
      care (at least 80-90% uptake of an intervention) was seen with antiplatelet and
      statin treatments and with smoking cessation. Significantly more patients were
      prescribed statins at follow up than at baseline (77/106 v 80/91, P=0.005).
      LESSONS LEARNT: National service framework targets for cardiac rehabilitation and
      secondary prevention can be achieved in patients who survive a myocardial
      infarction by integrating rehabilitation services (home and hospital) with
      secondary prevention clinics in primary care. Nurse led clinics in primary care
      facilitate long term structured care and optimal secondary prevention.

PMID- 12609947
TI  - Age related macular degeneration.

PMID- 12609949
TI  - Teaching small groups.

PMID- 12609948
TI  - Bilateral renovascular disease causing cardiorenal failure.

PMID- 12609950
TI  - The politics of AIDS in South Africa: beyond the controversies.

PMID- 12609951
TI  - Media influence on suicide. Television programme makers have an ethical
      responsibility.

PMID- 12609952
TI  - Death risk other than from suicide is raised in self harm.

PMID- 12609953
TI  - Low dosage tricyclic antidepressants in depression. Giving low dose tricyclics is
      not justified by evidence.

PMID- 12609954
TI  - Regulatory bodies can root out corruption.

PMID- 12609955
TI  - Mortality from methicillin resistant Staphylococcus aureus. Welsh surveillance
      data show plateau.

PMID- 12609956
TI  - Managing acute renal colic. Intramuscular diclofenac should be avoided.

PMID- 12609957
TI  - Establish reason why purulent rhinitis is persistent first.

PMID- 12609959
TI  - Who should pay for higher education?

PMID- 12609958
TI  - G7 countries are not to blame for Africa's brain drain.

PMID- 12609960
TI  - It's only money.

PMID- 12609962
TI  - MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell
      line models.
AB  - Inappropriate expression of the multidrug resistance (MDR1) gene encoding the P
      glycoprotein (Pgp) has been frequently implicated in resistance to different
      chemotherapeutic drugs. We have previously generated chronic myeloid leukemia
      (CML) cell lines resistant to the tyrosine kinase inhibitor imatinib mesylate
      (STI571), and one line (LAMA84-r) showed overexpression not only of the Bcr-Abl
      protein but also of Pgp. In the present study, we investigated this phenomenon in
      other cell lines overexpressing exclusively Pgp. Thus, cells from the K562/DOX
      line, described as resistant to doxorubicin due to MDR1 gene overexpression, grew
      continuously in the presence of 1 microM imatinib, but died in 4 to 5 days if the
      Pgp pump modulators verapamil or PSC833 were added to the imatinib-treated
      culture. Analysis of cell proliferation by the MTS (3-(4,5-dimethylthiazol-2-yl)
      5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay confirmed the
      differential sensitivity of K562/DOX to imatinib, which was also reversed by
      verapamil or PSC833. Flow cytometric analysis of the total phosphotyrosine
      content by intracytoplasmic staining after a 2-hour incubation with escalating
      doses of imatinib showed that the inhibitory concentrations of 50% (IC(50)) for
      inhibition of cellular protein tyrosine phosphorylation were 15, 10, and 5 microM
      for K562/DOX, K562/DOX plus verapamil, and K562, respectively. Retroviral
      mediated transfection of the BCR-ABL(+) AR230 cell line with the MDR1 gene
      decreased its sensitivity to imatinib, an effect that was also reversed by
      verapamil. The possible role of MDR overexpression in clinical resistance to
      imatinib remains to be defined. We therefore confirm that imatinib should be
      added to the extensive list of drugs that can be affected by the MDR phenomenon.

PMID- 12609963
TI  - Stroke risk in siblings with sickle cell anemia.
AB  - Cerebrovascular disease is a common cause of morbidity in sickle cell anemia
      (HbSS): approximately 10% of patients have a clinical stroke before 20 years of
      age, and another 22% have silent infarction on magnetic resonance imaging. The
      phenotypic variation among patients with HbSS suggests a role for modifier genes
      and/or environmental influences. To assess the familial component of clinical
      stroke in HbSS, we estimated the prevalence of clinical stroke among all patients
      and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425
      patients with sickle cell disease who were younger than 21 years, including 2353
      patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for
      patients with HbSS; 1.1% for patients with HbSbeta(o) thalassemia; 0.6% for
      patients with Sbeta(+) thalassemia; and 0% for patients with HbSC. In 207
      sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1
      sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation
      test indicated that the number of families in which 2 children had strokes was
      larger than the number expected if strokes were randomly distributed among
      children in sibships (P =.0012). There was no difference in stroke prevalence
      based on sex, nor was the mean age at stroke presentation significantly different
      between singletons and sibships with stroke. We conclude that there is a familial
      predisposition to stroke in HbSS. Attempts to identify genetic modifiers should
      be initiated with family-based studies.

PMID- 12609964
TI  - Severe skin reaction to imatinib in a case of Philadelphia-positive acute
      lymphoblastic leukemia.

PMID- 12609965
TI  - No effect of fasting plasma total homocysteine on protein C activity in vitro.

PMID- 12609966
TI  - The antiinflammatory endothelial tyrosine kinase Tie2 interacts with a novel
      nuclear factor-kappaB inhibitor ABIN-2.
AB  - Tie2 is a receptor tyrosine kinase expressed predominantly in endothelial cells
      and is essential for blood vessel formation and maintenance. The receptor has
      potent antiinflammatory effects on endothelial cells, suppressing vascular
      endothelial growth factor- and tumor necrosis factor-induced expression of
      leukocyte adhesion molecules and procoagulant tissue factor and inhibiting
      vascular leakage. To delineate the signaling pathways utilized by Tie2, we
      performed yeast two-hybrid screening of a human endothelial cell cDNA library and
      identified a novel protein interacting with the intracellular domain of the
      receptor. This protein was found to be human A20 binding inhibitor of NF-kappaB
      activation-2, ABIN-2, an inhibitor of NF-kappaB-mediated inflammatory gene
      expression. Coexpression of Tie2 and ABIN-2 in CHO cells confirmed the
      interaction occurs in mammalian cells. In contrast, Tie1 did not interact with
      ABIN-2 in the yeast two-hybrid system or mammalian cells. Deletion analysis
      identified the Tie2 binding motif to be encompassed between residues 171 and 272
      in ABIN-2. Interaction was dependent on Tie2 autophosphorylation but ABIN-2 was
      not tyrosine phosphorylated by Tie2. Furthermore, in endothelial cells the
      interaction was stimulated by the Tie2 ligand angiopoietin-1. Expression of ABIN
      2 deletion mutants in endothelial cells suppressed the ability of angiopoietin-1
      to inhibit phorbol ester-stimulated NF-kappaB-dependent reporter gene activity.
      These findings provide the first direct link between Tie2 and a key regulator of
      inflammatory responses in endothelial cells. Interaction between Tie2 and ABIN-2
      may be important in the vascular protective antiinflammatory actions of Tie2.

PMID- 12609967
TI  - Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and
      neointimal hyperplasia of rat carotid artery.
AB  - Neointimal proliferation occurring after vascular or endovascular procedures is a
      major complication leading to end-organ or limb ischemia. In experimental models,
      balloon injury has been shown to induce NAD(P)H oxidase to produce vascular
      superoxide anion (O2*-) production, which has been implicated in cell
      proliferation, but a direct link is still unclear. We postulated that inhibition
      of arterial NAD(P)H oxidase, resulting in decreased O2*-, would lessen the
      neointimal hyperplasia caused by balloon injury to the common carotid artery
      (CCA). Sprague-Dawley rats were implanted with osmotic minipumps containing
      either vehicle, a cell-permeant peptide that inhibits NAD(P)H oxidase (gp91ds
      tat, 10 mg/kg per day), or a scrambled peptide control (scrmb-tat). Two days
      after pump implantation, the left CCA was injured using an intravascular balloon
      embolectomy catheter (2F Fogarty). Systolic blood pressure was monitored by tail
      cuff. Fourteen days after injury, CCAs were harvested and analyzed by digital
      morphometry. Rats in both groups remained normotensive, with no significant
      differences in systolic blood pressure. Reactive oxygen species measurements
      after injury indicated a significant reduction in vascular O2*- in rats infused
      with gp91ds-tat, and the neointima/media area and thickness ratios were
      significantly lower in their arteries compared with control. On the contrary, no
      significant change in overall CCA diameter was observed in any group. Our data
      indicate that in response to balloon injury of the rat carotid artery, NAD(P)H
      oxidase activity contributes to neointimal hyperplasia and is involved in
      vascular cell proliferation and migration during restenosis.

PMID- 12609968
TI  - Increased superoxide generation is associated with pulmonary hypertension in
      fetal lambs: a role for NADPH oxidase.
AB  - Ligation of the ductus arteriosus in utero produces pulmonary hypertension and
      vascular remodeling in fetal and newborn lambs. However, the mechanisms producing
      these vascular changes are not well defined. Because reactive oxygen species
      (ROS) have been implicated as mediators of smooth muscle cell proliferation, we
      hypothesized that increased formation of ROS may be involved in the
      pathophysiology of pulmonary hypertension after in utero ductal ligation. Using
      ethidium fluorescence, we demonstrated an increase in superoxide levels after 9
      days of ductal ligation compared with control lungs (P<0.05) that was localized
      to the adventitia and smooth muscle cells of hypertensive vessels. SOD-1 and SOD
      2 protein levels and activities in lung, vein, and artery of hypertensive lambs
      were unchanged relative to controls after 2 days of ductal ligation. However,
      after 9 days, superoxide dismutase (SOD) activity was significantly decreased in
      arteries from ligated lambs without associated changes in SOD protein expression
      (P<0.05). Examination of NADPH oxidase expression as a potential source of the
      superoxide production indicated that the levels of p67phox, a subunit of the
      NADPH oxidase complex, were significantly increased in the pulmonary arteries,
      but not veins, from the ligated lung as early as 2 days (P<0.05). Functional
      analyses demonstrated that reducing superoxide levels significantly increased the
      NO-mediated relaxation of pulmonary arteries isolated after 9 days, but not 2
      days, of ductal ligation (P<0.05). These results suggest that increased NADPH
      oxidase expression may increase levels of superoxide in persistent pulmonary
      hypertension of the newborn lung tissue, and that increased superoxide blunts
      vascular relaxations to exogenous NO while stimulating smooth muscle cell growth.

PMID- 12609969
TI  - Intravenous administration of human bone marrow stromal cells induces
      angiogenesis in the ischemic boundary zone after stroke in rats.
AB  - We tested the hypothesis that intravenous infusion of human bone marrow stromal
      cells (hMSCs) promotes vascular endothelial growth factor (VEGF) secretion, VEGF
      receptor 2 (VEGFR2) expression and angiogenesis in the ischemic boundary zone
      (IBZ) after stroke. hMSCs (1x10(6)) were intravenously injected into rats 24
      hours after middle cerebral artery occlusion (MCAo). Laser scanning confocal
      microscopy (LSCM), immunohistochemistry and ELISA were performed to assay
      angiogenesis and levels of human and rat VEGF in the host brain, respectively. In
      addition, capillary-like tube formation was measured using mouse brain-derived
      endothelial cells (MBDECs). Morphological and three dimensional image analyses
      revealed significant (P<0.05) increases in numbers of enlarged and thin walled
      blood vessels and numbers of newly formed capillaries at the boundary of the
      ischemic lesion in rats (n=12) treated with hMSCs compared with numbers in rats
      (n=12) treated with PBS. ELISA measurements showed that treatment with hMSCs
      significantly (P<0.05) raised endogenous rat VEGF levels in the IBZ from 10.5+/
      1.7 ng/mL in the control group to 17.5+/-1.6 ng/mL in the hMSC-treated group. In
      addition, treatment with hMSCs increased endogenous VEGFR2 immunoreactivity. In
      vitro, when MBDECs were incubated with the supernatant obtained from cultured
      hMSCs, capillary-like tube formation was significantly (P<0.01) induced. However,
      hMSC-induced capillary-like tube formation was significantly (P<0.01) inhibited
      when the endothelial cells were incubated with the supernatant from hMSCs in the
      presence of a neutralizing anti-VEGFR2. These data suggest that treatment of
      stroke with hMSCs enhances angiogenesis in the host brain and hMSC-enhanced
      angiogenesis is mediated by increases in levels of endogenous rat VEGF and
      VEGFR2.

PMID- 12609970
TI  - Locus on chromosome 6p linked to elevated HDL cholesterol serum levels and to
      protection against premature atherosclerosis in a kindred with familial
      hypercholesterolemia.
AB  - Heterozygous familial hypercholesterolemia (FH) is a highly atherogenic genetic
      disorder leading to premature coronary heart disease (CHD), usually before 60
      years of age. We studied an extended multigenerational kindred with FH linked to
      chromosome 1p32 in which atherosclerotic complications were either delayed or
      prevented in individuals with elevated HDL cholesterol (HDL-C) levels or
      hyperalphalipoproteinemia (HA). Premature CHD was observed in FH individuals
      without HA. The study of this family established that the HA trait in the family
      also followed an autosomal dominant mode of inheritance with a pattern of
      segregation independent from FH. We identified a locus on chromosome 6 linked to
      elevated HDL-C levels (HA) in this family. Haplotype analysis refined the
      localization to a 7.32-cM interval (73 to 80 cM from pter) flanked by markers
      D6S1280 and D6S1275. Parametric 2-point and multipoint analyses yielded maximum
      LOD scores of 3.05 and 3.17, respectively. This finding was confirmed with a
      nonparametric multipoint score of 3.78 (P=0.0009). We propose that this locus,
      linked to elevated HDL-C levels, confers protection against premature CHD within
      an FH context.

PMID- 12609971
TI  - Ca2+ sparks in rabbit ventricular myocytes evoked by action potentials:
      involvement of clusters of L-type Ca2+ channels.
AB  - It is not clear how many L-type Ca2+ channels (LCCs) are required to ensure that
      a Ca2+ spark is triggered during a normal mammalian action potential (AP). We
      investigated this in rabbit ventricular myocytes by examining both the properties
      of sparks evoked by APs and the activity of LCCs. We measured Ca2+ sparks evoked
      by repeated APs with pipettes containing 2 mmol/L EGTA and single LCC activity in
      cell-attached patches depolarized to +50 mV using pipettes containing 110 mmol/L
      Ba2+. With 2 mmol/L Ca2+ in the external solution, we observed sparks at the
      beginning of every evoked AP at numerous locations. Each spark was observed
      repeatedly at a fixed location and began during a limited interval after the AP
      peak. These sparks occurred with a probability of approximately unity. However,
      the chance that an LCC does not open during the interval when a spark is
      triggered is quite high ( approximately 0.13). Therefore, because single channels
      open with a probability significantly lower than 1, more than one LCC must be
      available to ensure that sparks are triggered with a probability of approximately
      unity. We conclude that it is likely that a cluster of LCCs is involved in gating
      a cluster of ryanodine receptors at the beginning of an AP.

PMID- 12609972
TI  - Endothelial cells secrete triglyceride lipase and phospholipase activities in
      response to cytokines as a result of endothelial lipase.
AB  - The endothelium interacts extensively with lipids and lipoproteins, but there are
      very few data regarding the ability of endothelial cells to secrete lipases. In
      this study, we investigated the ability of endothelial cells to secrete the
      triglyceride lipase and phospholipase activities characteristic of endothelial
      lipase (EL), a recently described member of the triglyceride lipase gene family.
      No lipase activities were detected under basal conditions, but treatment with
      cytokines significantly stimulated the expression of both activities. Using
      antibodies to EL, we determined that both activities were primarily a result of
      this enzyme. In addition to the increase in lipolytic activity, cytokine
      treatment was demonstrated to substantially upregulate EL protein and EL mRNA in
      a dose-dependent manner. Cytokines did not change EL mRNA stability. Both new
      protein synthesis and activation of NF-kappaB influenced the induction of EL by
      cytokines, suggesting that multiple pathways contribute to this process. The
      upregulation of EL by cytokines is in sharp contrast to the downregulation by
      cytokines of the other two major members of this gene family, lipoprotein lipase
      and hepatic lipase, and has implications for the physiological role of EL in
      inflammatory conditions and its potential role in the modulation of lipoprotein
      metabolism during inflammatory conditions, including atherosclerosis.

PMID- 12609973
TI  - Calmodulin regulation of excitation-contraction coupling in cardiac myocytes.
AB  - Calmodulin (CaM) as a ubiquitous Ca2+ sensor interacts with multiple key
      molecules involved in excitation-contraction (EC) coupling. In the present study,
      we report that adenoviral expression of a mutant CaM lacking all of its four Ca2+
      binding sites, CaM(1-4), at a level 6.5-fold over endogenous CaM markedly
      increases the amplitude and abbreviates the decay time of Ca2+ transients and
      contraction in cultured rat ventricular myocytes. To determine the underlying
      mechanisms, we examined the properties of L-type Ca2+ channels, Ca2+/CaM
      dependent protein kinase II (CaMKII), and phospholamban (PLB) in the sarcoplasmic
      reticulum (SR). We found that CaM(1-4) expression markedly augmented L-type Ca2+
      current amplitude and slowed its inactivation. Surprisingly, overexpression of
      CaM(1-4) increased CaMKII activity and phosphorylation of PLB-Thr-17. Moreover,
      CaM(1-4) elevated diastolic Ca2+ and caffeine-labile Ca2+ content of the SR.
      Inhibition of CaMKII by KN-93 or a myristoylated autocamtide-2 related inhibitory
      peptide prevented the aforementioned PLB phosphorylation and reversed the
      positive inotropic and relaxant effects, indicating that CaMKII is essential to
      CaM(1-4) actions. These results demonstrate that CaM modulates Ca2+ influx, SR
      Ca2+ release, and Ca2+ recycling during cardiac EC coupling. A novel finding of
      this study is that expression of a Ca2+-insensitive CaM mutant can lead to
      activation of CaMKII in cardiac myocytes.

PMID- 12609975
TI  - DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus
      glycoprotein E2.
AB  - The hepatitis C virus (HCV) genome codes for highly mannosylated envelope
      proteins, which are naturally retained in the endoplasmic reticulum. We found
      that the HCV envelope glycoprotein E2 binds the dendritic cell-specific
      intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and the related
      liver endothelial cell lectin L-SIGN through high-mannose N-glycans. Competing
      ligands such as mannan and an antibody directed against the carbohydrate
      recognition domains (CRD) abrogated binding. While no E2 interaction with distant
      monomeric CRDs on biosensor chips could be detected, binding is observed if CRDs
      are closely seeded (Kd = 48 nm) and if the CRD is part of the oligomeric-soluble
      extracellular domain of DC-SIGN (Kd = 30 nm). The highest affinity is seen for
      plasma membrane-expressed DC-SIGN and L-SIGN (Kd = 3 and 6 nm, respectively).
      These results indicate that several high-mannose N-glycans in a structurally
      defined cluster on E2 bind to several subunits of the oligomeric lectin CRD. High
      affinity interaction of viral glycoproteins with oligomeric lectins might
      represent a strategy by which HCV targets to and concentrates in the liver and
      infects dendritic cells.

PMID- 12609974
TI  - Interferon-gamma stimulates the expression of the inducible cAMP early repressor
      in macrophages through the activation of casein kinase 2. A potentially novel
      pathway for interferon-gamma-mediated inhibition of gene transcription.
AB  - Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates the immune
      function, cell proliferation, apoptosis, macrophage activation, and numerous
      other cellular responses. These biological actions of IFN-gamma are characterized
      by both the activation and the inhibition of gene transcription. Unfortunately,
      in contrast to gene activation, the mechanisms through which the cytokine
      suppresses gene transcription remain largely unclear. We show here for the first
      time that exposure of macrophages to IFN-gamma leads to a dramatic induction in
      the expression of the inducible cAMP early repressor (ICER), a potent inhibitor
      of gene transcription. In addition, a synergistic action of IFN-gamma and calcium
      in the activation of ICER expression was identified. The IFN-gamma-mediated
      activation of ICER expression was not blocked by H89, bisindoylmaleimide,
      SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase
      C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase,
      calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In
      contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to
      inhibit response. Consistent with this finding, IFN-gamma stimulated CK2 activity
      and the level of phosphorylated cAMP response element-binding protein, which is
      known to induce ICER gene transcription, and this response was inhibited in the
      presence of apigenin. These studies, therefore, identify a previously
      uncharacterized pathway, involving the IFN-gamma-mediated stimulation of CK2
      activity, activation of cAMP response element-binding protein, and increased
      production of ICER, which may then play an important role in the inhibition of
      macrophage gene transcription by this cytokine.

PMID- 12609976
TI  - The cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1 cooperate to restrict
      proliferative life span in differentiating ovarian cells.
AB  - The timing of cellular exit from the cell cycle during differentiation is
      specific for each cell type or lineage. Granulosa cells in the ovary establish
      quiescence within several hours after the ovulation-inducing luteinizing hormone
      surge, whereas they undergo differentiation into corpora lutea. The expression of
      Cdk inhibitors p21(Cip1/Waf1) and p27(Kip1) is up-regulated during this process,
      suggesting that these cell cycle inhibitors are involved in restricting
      proliferative capacity of differentiating granulosa cells. Here we demonstrate
      that the lack of p27(Kip1) and p21(Cip1) synergistically renders granulosa cells
      extended an proliferative life span. Immunohistochemical analyses demonstrated
      that corpora lutea of p27(Kip1), p21(Cip1) double-null mice showed large numbers
      of cells with bromodeoxyuridine incorporation and high proliferative cell nuclear
      antigen expression, which were more remarkable than those in p27(Kip1) single
      deficient mice showing modest hyperproliferation. In contrast, differentiating
      granulosa cells in p21(Cip1)-deficient mice ceased proliferation similarly to
      those in wild-type mice. Interestingly, granulosa cells isolated from p27(Kip1),
      p21(Cip1) double-null mice exhibited markedly prolonged proliferative life span
      in culture, unlike cells with other genotypes. Cultured p27(Kip1), p21(Cip1)
      double-null granulosa cells maintained expression of steroidogenic enzymes and
      gonadotropin receptors through 8-10 passages and could undergo further
      differentiation in responses to cAMP accumulation. Thus, the cooperation of
      p27(Kip1) and p21(Cip1) is critical for withdrawal of granulosa cells from the
      cell cycle, in concert with luteal differentiation and possibly culture-induced
      senescence.

PMID- 12609977
TI  - Redox regulation of cAMP-responsive element-binding protein and induction of
      manganous superoxide dismutase in nerve growth factor-dependent cell survival.
AB  - Reactive oxygen species (ROS) act as both signaling molecules and mediators of
      cell damage in the nervous system and are implicated in the pathogenesis of
      neurodegenerative diseases. Neurotrophic factors such as the nerve-derived growth
      factor (NGF) support neuronal survival during development and promote
      regeneration after neuronal injury through the activation of intracellular
      signals whose molecular effectors and downstream targets are still largely
      unknown. Here we present evidence that early oxidative signals initiated by NGF
      in PC12 cells, an NGF-responsive cell line, play a critical role in preventing
      apoptosis induced by serum deprivation. This redox-signaling cascade involves
      phosphatidylinositol 3-kinase, the small GTPase Rac-1, and the transcription
      factor cAMP-responsive element-binding protein (CREB), a molecule essential to
      promote NGF-dependent survival. We found that ROS are necessary for NGF-dependent
      phosphorylation of CREB, an event directly correlated with CREB activity, whereas
      hydrogen peroxide induces a robust CREB phosphorylation. Cells exposed to NGF
      show a late decrease in the intracellular content of ROS when compared with
      untreated cells and increased expression of the mitochondrial antioxidant enzyme
      manganese superoxide dismutase, a general inhibitor of cell death. Accordingly,
      serum deprivation-induced apoptosis was selectively inhibited by low
      concentrations of the mitochondrially targeted antioxidant Mito Q
      (mitoquinol/mitoquinone). Taken together, these data demonstrate that the oxidant
      dependent activation of CREB is a component of NGF survival signaling in PC12
      cells and outline an intriguing circuitry by which a cytosolic redox cascade
      promotes cell survival at least in part by increasing mitochondrial resistance to
      oxidative stress.

PMID- 12609978
TI  - Mechanism of mitosis-specific activation of MEK1.
AB  - Activation of cyclin B-Cdc2 is an absolute requirement for entry into mitosis,
      but other protein kinase pathways that also have mitotic functions are activated
      during G(2)/M progression. The MAPK cascade has well established roles in entry
      and exit from mitosis in Xenopus, but relatively little is known about the
      regulation and function of this pathway in mammalian mitosis. Here we report a
      detailed analysis of the activity of all components of the Ras/Raf/MEK/ERK
      pathway in HeLa cells during normal G(2)/M. The focus of this pathway is the
      dramatic activation of an endomembrane-associated MEK1 without the corresponding
      activation of the MEK substrate ERK. This is because of the uncoupling of MEK1
      activation from ERK activation. The mechanism of this uncoupling involves the
      cyclin B-Cdc2-dependent proteolytic cleavage of the N-terminal ERK-binding domain
      of MEK1 and the phosphorylation of Thr(286). These results demonstrate that
      cyclin B-Cdc2 activity regulates signaling through the MAPK pathway in mitosis.

PMID- 12609979
TI  - Expression of the pro-apoptotic gene gadd153/chop is elevated in liver with aging
      and sensitizes cells to oxidant injury.
AB  - Aging is generally accompanied by reduced tolerance to oxidative stress and
      altered responsiveness to proliferative signals. We have shown that hepatocytes
      derived from aged rats (24-26 months) exhibit greater sensitivity to H(2)O(2)
      treatment and reduced proliferation following epidermal growth factor (EGF)
      treatment than cells of young adult rats (5-6 months). Here we examined the
      effects of aging and calorie restriction (CR) on expression of the oxidative
      stress-inducible and pro-apoptotic gene gadd153 (chop) in these hepatocytes, and
      we investigated its influence on sensitivity to oxidants. We show that aging was
      associated with elevated expression of gadd153, both basally and in response to
      H(2)O(2) treatment. CR, which attenuates age-associated declines in stress
      tolerance, prevented the age-related increase in gadd153 expression. EGF
      treatment also resulted in gadd153 induction in old cells. This effect was absent
      in young cells and in old cells of CR rats. gadd153 induction by EGF was reactive
      oxygen species-dependent and correlated with heightened sensitivity to subsequent
      H(2)O(2) treatment, suggesting that elevated Gadd153 contributes to the greater
      sensitivity of EGF-pretreated old cells to oxidative stress. Additional support
      for this hypothesis was provided by experiments with Rat1 fibroblasts in which
      conditional expression of Gadd153 conferred increased sensitivity to H(2)O(2). We
      propose a model whereby the diminished ability of old hepatocytes to overcome an
      EGF-triggered reactive oxygen species load leads to induction of the proapoptotic
      gene gadd153, which, in turn, sensitizes the cells to oxidant injury. Our
      findings point to gadd153 expression levels as an important factor in liver
      aging.

PMID- 12609980
TI  - Poly(I-C)-induced Toll-like receptor 3 (TLR3)-mediated activation of NFkappa B
      and MAP kinase is through an interleukin-1 receptor-associated kinase (IRAK)
      independent pathway employing the signaling components TLR3-TRAF6-TAK1-TAB2-PKR .
AB  - Recent studies show that a member of the interleukin-1 (IL-1)/Toll receptor
      superfamily, Toll-like receptor 3 (TLR3), recognizes double-stranded RNA (dsRNA).
      Because of the similarity in their cytoplasmic domains, IL-1/Toll receptors share
      signaling components that associate with the IL-1 receptor, including IL-1
      receptor-associated kinase (IRAK), MyD88, and TRAF6. However, we find that, in
      response to dsRNA, TLR3 can mediate the activation of both NFkappaB and mitogen
      activated protein (MAP) kinases in IL-1-unresponsive mutant cell lines, including
      IRAK-deficient I1A and I3A cells, which are defective in a component that is
      downstream of IL-1R but upstream of IRAK. These results clearly indicate that
      TLR3 does not simply share the signaling components employed by the IL-1
      receptor. Through biochemical analyses we have identified an IRAK-independent
      TLR3-mediated pathway. Upon binding of dsRNA to TLR3, TRAF6, TAK1, and TAB2 are
      recruited to the receptor to form a complex, which then translocates to the
      cytosol where TAK1 is phosphorylated and activated. The dsRNA-dependent protein
      kinase (PKR) is also detected in this signal-induced TAK1 complex. Kinase
      inactive mutants of TAK1 (TAK1DN) and PKR (PKRDN) inhibit poly(dI.dC)-induced
      TLR3-mediated NFkappaB activation, suggesting that both of these kinases play
      important roles in this pathway.

PMID- 12609981
TI  - Mnd2 and Swm1 are core subunits of the Saccharomyces cerevisiae anaphase
      promoting complex.
AB  - The anaphase-promoting complex (APC) is a multisubunit E3 ubiquitin ligase that
      regulates the metaphase-anaphase transition and exit from mitosis in eukaryotic
      cells. Eleven subunits have been previously identified in APC from budding yeast.
      We have identified two additional subunits, Mnd2 and Swm1, by mass spectrometry.
      Both Mnd2 and Swm1 were found specifically associated with a highly purified
      preparation of APC from haploid yeast whole cell extract. Moreover, the APC co
      purified with epitope-tagged Mnd2 and Swm1. Both proteins were present in APC
      preparations from haploid cells arrested in G(1), S, and M phases and from
      meiotic diploid cells, indicating that they are constitutive components of the
      complex throughout the yeast cell cycle. Mnd2 interacted strongly with Cdc23,
      Apc5, and Apc1 when coexpressed in an in vitro transcription/translation
      reaction. Swm1 also interacted with Cdc23 and Apc5 in this system. Previous
      studies described meiotic defects for mutations in MND2 and SWM1. Here, we show
      that mnd2delta and swm1delta haploid strains exhibit slow growth and accumulation
      of G(2)/M cells comparable with that seen in apc9delta or apc10Delta strains and
      consistent with an APC defect. Taken together, these results demonstrate that
      Swm1 and Mnd2 are functional components of the yeast APC.

PMID- 12609982
TI  - TIP120A associates with cullins and modulates ubiquitin ligase activity.
AB  - The cullin-containing ubiquitin-protein isopeptide ligases (E3s) play an
      important role in regulating the abundance of key proteins involved in cellular
      processes such as cell cycle and cytokine signaling. They have multisubunit
      modular structures in which substrate recognition and the catalysis of
      ubiquitination are carried out by distinct polypeptides. In a search for proteins
      involved in regulation of cullin-containing E3 ubiquitin ligases we
      immunopurified CUL4B-containing complex from HeLa cells and identified TIP120A as
      an associated protein by mass spectrometry. Immunoprecipitation of cullins
      revealed that all cullins tested specifically interacted with TIP120A. Reciprocal
      immunoaffinity purification of TIP120A confirmed the stable interaction of
      TIP120A with cullin family proteins. TIP120A formed a complex with CUL1 and Rbx1,
      but interfered with the binding of Skp1 and F-box proteins to CUL1. TIP120A
      greatly reduced the ubiquitination of phosphorylated IkappaBalpha by SCF(beta
      TrCP) ubiquitin ligase. These results suggest that TIP120A functions as a
      negative regulator of SCF E3 ubiquitin ligases and may modulate other cullin
      ligases in a similar fashion.

PMID- 12609983
TI  - A rational approach to Re-engineer cytochrome P450 2B1 regioselectivity based on
      the crystal structure of cytochrome P450 2C5.
AB  - The regioselectivity for progesterone hydroxylation by cytochrome P450 2B1 was re
      engineered based on the x-ray crystal structure of cytochrome P450 2C5. 2B1 is a
      high K(m) progesterone 16alpha-hydroxylase, whereas 2C5 is a low K(m)
      progesterone 21-hydroxylase. Initially, nine individual 2B1 active-site residues
      were changed to the corresponding 2C5 residues, and the mutants were purified
      from an Escherichia coli expression system and assayed for progesterone
      hydroxylation. At 150 microm progesterone, I114A, F297G, and V363L showed 5-15%
      of the 21-hydroxylase activity of 2C5, whereas F206V showed high activity for an
      unknown product and a 13-fold decrease in K(m). Therefore, a quadruple mutant,
      I114A/F206V/F297G/V363L (Q), was constructed that showed 60% of 2C5 progesterone
      21-hydroxylase activity and 57% regioselectivity. Based on their 2C5-like
      testosterone hydroxylation profiles, S294D and I477F alone and in combination
      were added to the quadruple mutant. All three mutants showed enhanced
      regioselectivity (70%) for progesterone 21-hydroxylation, whereas only Q/I477F
      had a higher k(cat). Finally, the remaining three single mutants, V103I, V367L,
      and G478V, were added to Q/I477F and Q/S294D/I477F, yielding seven additional
      multiple mutants. Among these, Q/V103I/S294D/I477F showed the highest k(cat) (3
      fold higher than that of 2C5) and 80% regioselectivity for progesterone 21
      hydroxylation. Docking of progesterone into a three-dimensional model of this
      mutant indicated that 21-hydroxylation is favored. In conclusion, a systematic
      approach to convert P450 regioselectivity across subfamilies suggests that active
      site residues are mainly responsible for regioselectivity differences between 2B1
      and 2C5 and validates the reliability of 2B1 models based on the crystal
      structure of 2C5.

PMID- 12609985
TI  - Surface expression of inward rectifier potassium channels is controlled by
      selective Golgi export.
AB  - Traffic of integral membrane proteins along the secretory pathway is not simply a
      default process but can be selective. Such selectivity is achieved by sequence
      information within the cargo protein that recruits coat protein complexes to
      drive the formation of transport vesicles. A number of sequence motifs have been
      identified in the cytoplasmic domains of ion channels that regulate early
      trafficking events between the endoplasmic reticulum and the Golgi complex. Here,
      we demonstrate that the following trafficking step from the Golgi compartment to
      the plasma membrane can also be selective. The N-terminal domain of the inward
      rectifier potassium channel Kir2.1 contains specific sequence information that is
      necessary for its efficient export from the Golgi complex. Lack of this
      information results in accumulation of the protein within the Golgi and a
      significant decrease in cell surface expression. As similar results were obtained
      for the N terminus of another Kir channel subfamily member, Kir4.1, which could
      functionally substitute for the Kir2.1 N terminus, we propose a more general role
      of the identified N-terminal domains for post-Golgi trafficking of Kir channels.

PMID- 12609984
TI  - Cytokine suppression of dopamine-beta-hydroxylase by extracellular signal
      regulated kinase-dependent and -independent pathways.
AB  - Cholinergic differentiation factors (CDFs) suppress noradrenergic properties and
      induce cholinergic properties in sympathetic neurons. The CDFs leukemia
      inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) bind to a
      LIFR.gp130 receptor complex to activate Jak/signal transducers and activators of
      transcription and Ras/mitogen-activated protein kinases signaling pathways.
      Little is known about how these differentiation factors suppress noradrenergic
      properties. We used sympathetic neurons and SK-N-BE(2)M17 neuroblastoma cells to
      investigate CDF down-regulation of the norepinephrine synthetic enzyme dopamine
      beta-hydroxylase (DBH). LIF and CNTF activated extracellular signal-regulated
      kinases (ERKs) 1 and 2 but not p38 or Jun N-terminal kinases in both cell types.
      Preventing ERK activation with PD98059 blocked CNTF suppression of DBH protein in
      sympathetic neurons but did not prevent the loss of DBH mRNA. CNTF decreased
      transcription of a DBH promoter-luciferase reporter construct in SK-N-BE(2)M17
      cells, and this was also ERK-independent. Cytokine inhibition of DBH promoter
      activity did not require a silencer element but was prevented by overexpression
      of the transcriptional activator Phox2a. Inhibiting ERK activation increased
      basal DBH transcription in SK-N-BE(2)M17 cells, and DBH mRNA in sympathetic
      neurons. Transfection of Phox2a into PD98059-treated M17 cells resulted in a
      synergistic increase in DBH promoter activity compared with Phox2a or PD98059
      alone. These data suggest that CDFs down-regulate DBH protein via an ERK
      dependent pathway but inhibit DBH gene expression through an ERK-independent
      pathway. They further suggest that ERK activity inhibits basal DBH gene
      expression.

PMID- 12609986
TI  - ERK activation is required for double-stranded RNA- and virus-induced interleukin
      1 expression by macrophages.
AB  - Double-stranded (ds) RNA, which accumulates during viral replication, activates
      the antiviral response of infected cells. In this study, we have identified a
      requirement for extracellular signal-regulated kinase (ERK) in the regulation of
      interleukin 1 (IL-1) expression by macrophages in response to dsRNA and viral
      infection. Treatment of RAW 264.7 cells or mouse macrophages with dsRNA
      stimulates ERK phosphorylation that is first apparent following a 15-min
      incubation and persists for up to 60 min, the accumulation of iNOS and IL-1 mRNA
      following a 6-h incubation, and the expression of iNOS and IL-1 at the protein
      level following a 24-h incubation. Inhibitors of ERK activation prevent dsRNA
      induced ERK phosphorylation and IL-1 expression by macrophages. The regulation of
      macrophage activation by ERK appears to be selective for IL-1, as ERK inhibition
      does not attenuate dsRNA-induced iNOS expression by macrophages. dsRNA stimulates
      both ERK activation and IL-1 expression by macrophages isolated from dsRNA
      dependent protein kinase (PKR)-deficient mice, indicating that PKR does not
      participate in this antiviral response. These findings support a novel PKR
      independent role for ERK in the regulation of the antiviral response of IL-1
      expression and release by macrophages.

PMID- 12609987
TI  - Involvement of histone acetylation in ovarian steroid-induced decidualization of
      human endometrial stromal cells.
AB  - Histone acetyltransferases and histone deacetylases (HDACs) determine the
      acetylation status of histones, regulating gene transcription. Decidualization is
      the progestin-induced differentiation of estrogen-primed endometrial stromal
      cells (ESCs), which is crucial for implantation and maintenance of pregnancy. We
      here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up
      regulation of decidualization markers such as insulin-like growth factor binding
      protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by
      17beta-estradiol (E(2)) plus progesterone (P(4)) in cultured ESCs, but not
      glandular cells, both isolated from human endometrium. Morphological changes
      resembling decidual transformation were also augmented by co-addition of TSA.
      Acid urea triton gel analysis and immunoblot using acetylated histone type
      specific antibodies demonstrated that treatment with E(2) plus P(4) significantly
      increased the levels of acetylated H3 and H4 whose increment was augmented by co
      treatment with TSA. Chromatin immunoprecipitation assay revealed that treatment
      with E(2) plus P(4) increased the amount of proximal progesterone-responsive
      region of IGFBP-1 promoter associated with acetylated H4, which was dramatically
      enhanced by co-addition of TSA. Taken together, our results suggest that histone
      acetylation is deeply involved in differentiation of human ESCs and that TSA has
      a potential as an enhancer of decidualization through promotion of progesterone
      action.

PMID- 12609988
TI  - Profile-based data base scanning for animal L-type lectins and characterization
      of VIPL, a novel VIP36-like endoplasmic reticulum protein.
AB  - Consensus profiles were established to screen data bases for novel animal L-type
      lectins. The profiles were generated from linear sequence motifs of the human L
      type lectin-like membrane proteins ERGIC-53, ERGL, and VIP36 and by optimal
      alignment of the entire carbohydrate recognition domain of these proteins. The
      search revealed numerous orthologous and homologous L-type lectin-like proteins
      in animals, protozoans, and yeast, as well as the sequence of a novel family
      member related to VIP36, named VIPL for VIP36-like. Sequence analysis suggests
      that VIPL is a ubiquitously expressed protein and appeared earlier in evolution
      than VIP36. The cDNA of VIPL was cloned and expressed in cell culture. VIPL is a
      high-mannose type I membrane glycoprotein with similar domain organization as
      VIP36. Unlike VIP36 and ERGIC-53 that are predominantly associated with
      postendoplasmic reticulum (ER) membranes and cycle in the early secretory
      pathway, VIPL is a non-cycling resident protein of the ER. Mutagenesis
      experiments indicate that ER retention of VIPL involves a RKR di-arginine signal.
      Overexpression of VIPL redistributed ERGIC-53 to the ER without affecting the
      cycling of the KDEL-receptor and the overall morphology of the early secretory
      pathway. The results suggest that VIPL may function as a regulator of ERGIC-53.

PMID- 12609989
TI  - Amino acids interfere with the ERK1/2-dependent control of macroautophagy by
      controlling the activation of Raf-1 in human colon cancer HT-29 cells.
AB  - Activation of ERK1/2 stimulates macroautophagy in the human colon cancer cell
      line HT-29 by favoring the phosphorylation of the Galpha-interacting protein
      (GAIP) in an amino acid-dependent manner (Ogier-Denis, E., Pattingre, S., El
      Benna, J., and Codogno, P. (2000) J. Biol. Chem. 275, 39090-39095). Here we show
      that ERK1/2 activation by aurintricarboxylic acid (ATA) treatment induces the
      phosphorylation of GAIP in an amino acid-dependent manner. Accordingly, ATA
      challenge increased the rate of macroautophagy, whereas epidermal growth factor
      did not significantly affect macroautophagy and GAIP phosphorylation status. In
      fact, ATA activated the ERK1/2 signaling pathway, whereas epidermal growth factor
      stimulated both the ERK1/2 pathway and the class I phosphoinositide 3-kinase
      pathway, known to decrease the rate of macroautophagy. Amino acids interfered
      with the ATA-induced macroautophagy by inhibiting the activation of the kinase
      Raf-1. The role of the Ras/Raf-1/ERK1/2 signaling pathway in the GAIP- and amino
      acid-dependent control of macroautophagy was confirmed in HT-29 cells expressing
      the Ras(G12V,T35S) mutant. Similar to the protein phosphatase 2A inhibitor
      okadaic acid, amino acids sustained the phosphorylation of Ser(259), which is
      involved in the negative regulation of Raf-1. In conclusion, these results add a
      novel target to the amino acid signaling-dependent control of macroautophagy in
      intestinal cells.

PMID- 12609990
TI  - Substrate-induced conformational changes in the transmembrane segments of human P
      glycoprotein. Direct evidence for the substrate-induced fit mechanism for drug
      binding.
AB  - The human multidrug resistance P-glycoprotein (P-gp, ABCB1) is quite promiscuous
      in that it can transport a broad range of structurally diverse compounds out of
      the cell. We hypothesized that the transmembrane (TM) segments that constitute
      the drug-binding site are quite mobile such that drug binding occurs through a
      "substrate-induced fit" mechanism. Here, we used cysteine-scanning mutagenesis
      and oxidative cross-linking to test for substrate-induced changes in the TM
      segments. Pairs of cysteines were introduced into a Cys-less P-gp and the mutants
      treated with oxidant (copper phenanthroline) in the presence or absence of
      various drug substrates. We show that cyclosporin A promoted cross-linking
      between residues P350C(TM6)/G939C(TM11), while colchicine and demecolcine
      promoted cross-linking between residues P350C(TM6)/V991C(TM12). Progesterone
      promoted cross-linking between residues P350C(TM6)/A935C(TM11),
      P350C(TM6)/G939C(TM11), as well as between residues P350C(TM6)/V991C(TM12). Other
      substrates such as vinblastine, verapamil, cis-(Z)-flupenthixol or trans-(E)
      flupenthixol did not induce cross-linking at these sites. These results provide
      direct evidence that the packing of the TM segments in the drug-binding site is
      changed when P-gp binds to a particular substrate. The induced-fit mechanism
      explains how P-gp can accommodate a broad range of compounds.

PMID- 12609991
TI  - Activation of p38 plays a pivotal role in the inhibitory effect of
      lipopolysaccharide and interleukin-1 beta on long term potentiation in rat
      dentate gyrus.
AB  - Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria,
      has been shown to induce profound changes both peripherally and centrally. It has
      recently been reported that intraperitoneal injection of LPS inhibited long term
      potentiation (LTP) in perforant path-granule cell synapses and that this effect
      was coupled with an increase in the concentration of the proinflammatory
      cytokine, interleukin-1 beta (IL-1 beta). The LPS-induced effects were abrogated
      by inhibition of caspase-1, suggesting that IL-1 beta may mediate the effects of
      LPS. Here we report that the inhibition of LTP induced by LPS and IL-1 beta was
      coupled with stimulation of the stress-activated protein kinase p38 in
      hippocampus and entorhinal cortex and that this effect was abrogated by the p38
      inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL
      1RI-/- mice. The data also indicate that activation of the transcription factor,
      nuclear factor kappa B (NF kappa B), may play a role, since the inhibitory effect
      of LPS and IL-1 beta on LTP was attenuated by the NF kappa B inhibitor, SN50;
      consistently, LPS and IL-1 beta led to activation of NF kappa B in entorhinal
      cortex. We suggest that one consequence of these LPS and IL-1 beta-induced
      changes is a compromise in glutamate release in dentate gyrus, which was coupled
      with the inhibition of LTP. The evidence is consistent with the idea that the LPS
      induced impairment in LTP is mediated by IL-1 beta and is a consequence of
      activation of p38.

PMID- 12609992
TI  - Modulation of Rac1 and ARF6 activation during epithelial cell scattering.
AB  - Epithelial cell scattering encompasses the dissolution of intercellular
      junctions, cell-cell dissociation, cell spreading, and motility. The Rac1 and
      ARF6 GTPases have been shown to regulate one or more of these aforementioned
      processes. In fact, activated Rac1 has been shown to promote cell-cell adhesion
      as well as to enhance cell motility, leading to conflicting reports on the effect
      of Rac1 activation on epithelial cell motility. In this study, we have examined
      the activation profiles of endogenous Rac1 and ARF6 during the sequential stages
      of epithelial cell scattering. Using Madin-Darby canine kidney cells treated with
      hepatocyte growth factor/scatter factor or cell lines stably expressing activated
      v-Src, we show that Rac1 and ARF6 exhibit distinct activation profiles during
      cell scattering. We have found that an initial ARF6-dependent decrease in the
      levels of Rac1-GTP is necessary to induce cell-cell dissociation. This is
      followed by a steady increase in Rac1 and ARF6 activation and cell migration. In
      sum, this study documents the progression of ARF6 and Rac1 activities during
      epithelial cell scattering.

PMID- 12609993
TI  - Mechanisms for the formation of isoprostane endoperoxides from arachidonic acid.
      "Dioxetane" intermediate versus beta-fragmentation of peroxyl radicals.
AB  - The isoprostanes are a class of autoxidation products generated from arachidonic
      acid (or its esters) by a free radical initiated process. The potent biological
      activity of these compounds has been attracting intense research interest since
      they were detected in humans as well as animal models in the early 1990s. The
      measurement of these compounds has been regarded as one of the most useful non
      invasive biomarkers for oxidative stress status. Two mechanisms for the formation
      of these compounds have been proposed. In the first mechanism, a peroxyl radical
      undergoes successive 5-exo cyclizations analogous to the enzymatic mechanism
      proposed for prostaglandin biosynthesis. The second mechanism starts with a 4-exo
      cyclization of a peroxyl radical leading to an intermediate dioxetane, a
      mechanism that has also been proposed for prostaglandin biosynthesis as well as
      for the formation of 4-hydroxy nonenal (HNE). Autoxidation of cholesteryl-15
      HpETE under free radical conditions provides Type IV isoprostanes. The
      "dioxetane" mechanism for isoprostane generation from 15-HpETE requires that
      optically pure products are formed from an optically pure reactant, whereas an
      alternate mechanism for the process involving beta-fragmentation of the 15
      peroxyl would give racemic isoprostane products. We have carried out a test of
      the mechanism based upon these stereochemical requirements. The results of
      analysis of the product mixture derived from autoxidation of optically pure Ch-15
      HpETE by atmospheric pressure chemical ionization-mass spectrometry coupled with
      chiral high performance liquid chromatography indicate that the major isoprostane
      diastereomers are formed as a racemic mixture. These experimental results are
      consistent with a mechanism for isoprostane formation involving beta
      fragmentation of the 15-peroxyl radical followed by re-addition of oxygen to form
      the 11-HPETE peroxyl, and they exclude a mechanism proceeding through the
      formation of a dioxetane intermediate.

PMID- 12609994
TI  - Identification and characterization of adenosine 5'-tetraphosphate in human
      myocardial tissue.
AB  - Endocrine functions of the human heart have been studied extensively. Only
      recently, nucleotidergic mechanisms have been studied in detail. Therefore, an
      isolation strategy was developed to isolate novel nucleotide compounds from human
      myocardium. The human myocardial tissue was fractionated by several
      chromatographic studies. A substance purified to homogeneity was identified as
      adenosine 5'-tetraphosphate (Ap(4)) by matrix-assisted laser
      desorption/ionization mass spectrometry (MALDI MS), post-source decay MALDI MS,
      and enzymatic cleavage analysis. Furthermore, Ap(4) was also identified in
      ventricular specific granules. In the isolated perfused rat heart, Ap(4) elicited
      dose-dependent vasodilations. Vasodilator responses were abolished in the
      presence of the P(2Y1) receptor antagonist MRS 2179 (1 microm) or the NO synthase
      inhibitor N(G)-nitro-l-arginine methyl ester (50 microm). After removal of the
      endothelium by Triton X-100, Ap(4) induced dose-dependent vasoconstrictions.
      Inhibition of P(2X) receptors by pyridoxal phosphate-6-azophenyl-2',4'-disulfonic
      acid (30 microm) or desensitization of P(2X) receptors by alpha,beta-methylene
      ATP (alpha,beta-meATP, 1 microm) diminished these vasoconstrictor responses
      completely. In the present study Ap(4) has been isolated from human tissue. Ap(4)
      was shown to exist in human myocardial tissue and was identified in ventricular
      specific granules. In coronary vasculature the nucleotide exerted vasodilation
      via endothelial P(2Y1) receptors and vasoconstriction via P(2X) receptors on
      vascular smooth muscle cells. Ap(4) acts as an endogenous extracellular mediator
      and might contribute to the regulation of coronary perfusion.

PMID- 12609995
TI  - Activation of cGMP-dependent protein kinase by protein kinase C.
AB  - The cGMP-dependent protein kinases (PKG) are emerging as important components of
      mainstream signal transduction pathways. Nitric oxide-induced cGMP formation by
      stimulation of soluble guanylate cyclase is generally accepted as being the most
      widespread mechanism underlying PKG activation. In the present study, PKG was
      found to be a target for phorbol 12-myristate 13-acetate (PMA)-responsive protein
      kinase C (PKC). PKG1alpha became phosphorylated in HEK-293 cells stimulated with
      PMA and also in vitro using purified components. PKC-dependent phosphorylation
      was found to activate PKG as measured by phosphorylation of vasodilator
      stimulated phosphoprotein, and by in vitro kinase assays. Although there are 11
      potential PKC substrate recognition sites in PKG1alpha, threonine 58 was examined
      due to its proximity to the pseudosubstrate domain. Antibodies generated against
      the phosphorylated form of this region were used to demonstrate phosphorylation
      in response to PMA treatment of the cells with kinetics similar to vasodilator
      stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this
      site (T58E) generated a partially activated PKG that was more sensitive to cGMP
      levels. A phospho-null mutation (T58A) revealed that this residue is important
      but not sufficient for PKG activation by PKC. Taken together, these findings
      outline a novel signal transduction pathway that links PKC stimulation with
      cyclic nucleotide-independent activation of PKG.

PMID- 12609996
TI  - Heterotrimer formation, together with isoprenylation, is required for plasma
      membrane targeting of Gbetagamma.
AB  - Nascent beta and gamma subunits of heterotrimeric G proteins need to be targeted
      to the cytoplasmic face of the plasma membrane (PM) in order to transmit signals.
      We show that beta(1)gamma(2) is poorly targeted to the PM and predominantly
      localized to endoplasmic reticulum (ER) membranes when expressed in HEK293 cells,
      but co-expression of a G protein alpha subunit allows strong PM localization of
      the beta(1)gamma(2). Furthermore, C-terminal isoprenylation of the gamma subunit
      is necessary but not sufficient for PM localization of beta(1)gamma(2).
      Isoprenylation of gamma(2) and localization of beta(1)gamma(2) to the ER occurs
      independently of alpha expression. Efficient PM localization of beta(1)gamma(2)
      in the absence of co-expressed alpha is observed when a site for palmitoylation,
      a putative second membrane targeting signal, is introduced into gamma(2). When a
      mutant of alpha(s) is targeted to mitochondria, beta(1)gamma(2) follows,
      consistent with an important role for alpha in promoting subcellular localization
      of betagamma. Furthermore, we directly demonstrate the requirement for alpha by
      showing that disruption of heterotrimer formation by the introduction of alpha
      binding mutations into beta(1) impedes PM targeting of beta(1)gamma(2). The
      results indicate that two membrane targeting signals, lipid modification and
      alpha binding, make concerted contributions to PM localization of betagamma.

PMID- 12609997
TI  - Molecular localization of the inhibitory arachidonic acid binding site to the
      pore of hIK1.
AB  - We previously demonstrated that the endogenously expressed human intermediate
      conductance, Ca(2+)-activated K(+) channel (hIK1) was inhibited by arachidonic
      acid (AA) (Devor, D. C., and Frizzell, R. A. (1998) Am. J. Physiol. 274, C138
      C148). Here we demonstrate, using the excised, inside-out patch-clamp technique,
      that hIK1, heterologously expressed in HEK293 cells, is inhibited 82 +/- 2% (n =
      16) with 3 microm AA, being half-maximally inhibited (IC(50)) at 1.4 +/- 0.7
      microm. In contrast, AA does not inhibit the Ca(2+)-dependent, small conductance
      K(+) channel, rSK2, another member of the KCNN gene family. Therefore, we
      utilized chimeric hIK1/rSK2 channels to define the AA binding domain on hIK1 to
      the S5-Pore-S6 region of the channel. Subsequent site-directed mutagenesis
      revealed that mutation of Thr(250) to Ser (T250S) resulted in a channel with
      limited sensitivity to block by AA (8 +/- 2%, n = 8), demonstrating that Thr(250)
      is a key molecular determinant for the inhibition of hIK1 by AA. Likewise, when
      Val(275) in S6 was mutated to Ala (V275A) AA inhibited only 43 +/- 11% (n = 9) of
      current flow. The double mutation T250S/V275A eliminated the AA sensitivity of
      hIK1. Introducing the complimentary single amino acid substitutions into rSK2
      (S359T and A384V) conferred partial AA sensitivity to rSK2, 21 +/- 3% and 31 +/-
      3%, respectively. Further, introducing the double mutation S359T/A384V into rSK2
      resulted in a 63 +/- 8% (n = 9) inhibition by AA, thereby demonstrating the
      ability to introduce this inhibitory AA binding site into another member of the
      KCNN gene family. These results demonstrate that AA interacts with the pore
      lining amino acids, Thr(250) and Val(275) in hIK1, conferring inhibition of hIK1
      by AA and that AA and clotrimazole share similar, if not identical, molecular
      sites of interaction.

PMID- 12609999
TI  - The activation domains, the proline-rich domain, and the C-terminal basic domain
      in p53 are necessary for acetylation of histones on the proximal p21 promoter and
      interaction with p300/CREB-binding protein.
AB  - The p53 transcription factor contains two separate tandem activation domains (AD1
      and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD).
      Previously, we have shown that these domains are necessary for transcriptional
      activity. To further characterize the role of these domains in transactivation,
      we analyzed the regulation of p21, a well characterized p53 target gene, by
      various p53 mutants deficient in one or more of these domains. We found that the
      induction of endogenous p21 is compromised by AD1-deficient p53 (p53(AD1(-))),
      AD2-deficient p53 (p53(AD2(-))), both AD1- and AD2-deficient p53 (p53(AD1(-)AD2(
      ))), p53(deltaPRD), which lacks PRD, and p53(deltaBD), which lacks BD. However,
      p53(AD2(-)), p53(deltaPRD), and p53(deltaBD) are still capable of activating
      exogenous p21 promoter to an extent comparable with that by wild-type p53. Thus,
      we performed chromatin immunoprecipitation assay to measure the DNA binding
      ability of various p53 mutants in vivo. We found that like wild-type p53, these
      p53 mutants are capable of binding to the p53 response elements in the p21
      promoter. In contrast, we found that the extent of acetylated histones on the p21
      promoter, especially the proximal promoter, and the amount of interaction with
      p300/CREB-binding protein, which contain histone acetyltransferase activity,
      directly correlate with the activity of p53 to induce endogenous p21.
      Furthermore, we showed that down-regulation of p300/CBP by short interference RNA
      markedly decreases the ability of p53 to induce endogenous p21. These data lead
      us to hypothesize that when p53 binds to the responsive element(s) of a target
      gene, its ability to interact with histone acetyltransferase-containing proteins
      and subsequently the acetylation of histones bound to the proximal promoter
      dictate the induction level of a target gene.

PMID- 12609998
TI  - Kinetic properties of "soluble" adenylyl cyclase. Synergism between calcium and
      bicarbonate.
AB  - "Soluble" adenylyl cyclase (sAC) is a widely expressed source of cAMP in
      mammalian cells that is evolutionarily, structurally, and biochemically distinct
      from the G protein-responsive transmembrane adenylyl cyclases. In contrast to
      transmembrane adenylyl cyclases, sAC is insensitive to heterotrimeric G protein
      regulation and forskolin stimulation and is uniquely modulated by bicarbonate
      ions. Here we present the first report detailing kinetic analysis and biochemical
      properties of purified recombinant sAC. We confirm that bicarbonate regulation is
      conserved among mammalian sAC orthologs and demonstrate that bicarbonate
      stimulation is consistent with an increase in the V(max) of the enzyme with
      little effect on the apparent K(m) for substrate, ATP-Mg(2+). Bicarbonate can
      further increase sAC activity by relieving substrate inhibition. We also identify
      calcium as a direct modulator of sAC activity. In contrast to bicarbonate,
      calcium stimulates sAC activity by decreasing its apparent K(m) for ATP-Mg(2+).
      Because of their different mechanisms, calcium and bicarbonate synergistically
      activate sAC; therefore, small changes of either calcium or bicarbonate will lead
      to significant changes in cellular cAMP levels.

PMID- 12610000
TI  - Parkinson's disease-associated alpha-synuclein is a calmodulin substrate.
AB  - Alpha-synuclein is a neuronal protein thought to be central in the pathogenesis
      of Parkinson's disease (PD) because it comprises the fibrillar core of Lewy
      bodies, one of the histologically defining lesions of PD, and because mutations
      in alpha-synuclein cause autosomal dominant PD. Although its physiologic role is
      uncertain, alpha-synuclein is a synaptic protein that may contribute to
      plasticity. We produced synuclein with incorporated photoprobes to identify and
      purify novel synuclein-interacting proteins both to begin to clarify the
      physiology of synuclein and to identify factors that may regulate synuclein
      conformation. We detected several cross-links and purified and identified one as
      calmodulin (CaM). CaM binds to both wild type and PD-associated mutant alpha
      synucleins in a calcium-dependent manner. We further demonstrate that CaM and
      alpha-synuclein interact in intact cells in a calcium-dependent manner and that
      activated CaM accelerates the formation of synuclein fibrils in vitro. We
      hypothesize that the known calcium control of synuclein function is mediated
      through CaM interaction and that CaM potentially alters synuclein conformation.

PMID- 12610002
TI  - Quality of care for diabetic patients in a large urban public hospital.
AB  - OBJECTIVE: We compared diabetes quality-of-care indicators for patients receiving
      medical treatment in three practice settings of the same hospital. RESEARCH
      DESIGN AND METHODS: A cross-sectional medical record review for patients
      receiving care between 1 July 2000 and 30 June 2001 was conducted. Records were
      abstracted from three practice settings: the Diabetes Clinic (DIABETES), a
      general medicine clinic staffed by internal medicine residents (RESIDENT), and a
      general medicine clinic whose providers were medical school faculty physicians
      (FACULTY). Record review (n = 791) yielded data on diabetes indicators that were
      derived primarily from the Diabetes Quality Improvement Project. RESULTS: There
      were significant differences between the DIABETES, RESIDENT, and FACULTY clinics
      for the percentages of patients with HbA(1c) testing (94 vs. 92 vs. 76%, P <
      0.001), HbA(1c) >9.5% (31 vs. 36 vs. 43%, P < 0.05), nephropathy assessment (79
      vs. 67 vs. 58%, P < 0.001), lipid assessment (86 vs. 79 vs. 76%, P < 0.050), LDL
      <130 mg/dl (54 vs. 44 vs. 43%, P < 0.05), blood pressure <140/90 mmHg (63 vs. 55
      vs. 49%, P < 0.025), eye examinations (64 vs. 50 vs. 31%, P < 0.001), foot
      examinations (97 vs. 55 vs. 24%, P < 0.001), ACE inhibitor treatment (66 vs. 69
      vs. 35%, P < 0.001), and aspirin treatment (71 vs. 59 vs. 15%, P < 0.001).
      CONCLUSIONS: There is considerable variation in diabetes management in different
      primary care settings of the same hospital. Although management in all settings
      was suboptimal, the results attained by the patients in the Diabetes Clinic
      represent minimal achievable goals for all diabetic patients in this hospital.

PMID- 12610001
TI  - Exercise training, without weight loss, increases insulin sensitivity and
      postheparin plasma lipase activity in previously sedentary adults.
AB  - OBJECTIVE: To determine the effects of exercise, without weight loss, on insulin
      sensitivity (S(I)), postheparin plasma lipase activity (PHPL), intravenous fat
      clearance rate (K(2)), and fasting lipids in sedentary adults. RESEARCH DESIGN
      AND METHODS: At baseline and after 6 months of walk training (intensity 45-55 or
      65-75% heart rate reserve, frequency 3-4 or 5-7 days/week, duration 30
      min/session), anthropometric indexes, S(I), PHPL, K(2), and fasting lipids were
      measured in 18 sedentary adults (12 women, 6 men; 51.9 +/- 5.8 years of age, BMI
      28.9 +/- 4.6 kg/m(2)). RESULTS: Exercise increased S(I) (2.54 +/- 2.74 vs. 4.41
      +/- 3.30 microU ml(-1) x min(-1), P < 0.005) and both lipoprotein lipase (LPL)
      (1890 +/- 1380 vs. 4926 +/- 1858 nEq free fatty acid [FFA]. ml(-1). h(-1)) and
      hepatic lipase (HL) activities (3326 +/- 1605 vs. 4636 +/- 1636 nEq FFA. ml(-1) x
      h(-1)) (both P < 0.001), without altering BMI, waist circumference, K(2), or
      fasting lipids. Correlations between changes in LPL and the total:HDL cholesterol
      ratio (r = -0.54) and changes in the LPL:HL ratio and waist circumference (r = 
      0.50) were significant (P < 0.05). CONCLUSIONS: Exercise, without weight loss,
      increases S(I) and PHPL activity in previously sedentary adults, without changing
      K(2) or fasting lipid levels. Furthermore, increased LPL is associated with a
      decreased total:HDL ratio, and an increased LPL:HL ratio is associated with a
      decreased waist circumference. Therefore, even modest amounts of exercise in the
      absence of weight loss positively affect markers of glucose and fat metabolism in
      previously sedentary, middle-aged adults.

PMID- 12610003
TI  - Comparative effects of Irbesartan on ambulatory and office blood pressure: a
      substudy of ambulatory blood pressure from the Irbesartan in Patients with Type 2
      Diabetes and Microalbuminuria study.
AB  - OBJECTIVE: Irbesartan was renoprotective independently of its blood pressure
      lowering effect in the Irbesartan in Patients With Type 2 Diabetes and
      Microalbuminuria (IRMA2) study. However, blood pressure was evaluated by trough
      office blood pressure (OBP), which may underestimate reductions in 24-h
      ambulatory blood pressure (ABP). In the present study, we evaluated 24-h blood
      pressure patterns in a subpopulation of the IRMA2 trial. RESEARCH DESIGN AND
      METHODS: Type 2 diabetic patients (n = 43) with persistent microalbuminuria (as
      determined by repeated overnight measurements of urinary albumin excretion [UAE])
      and hypertension who were included in the IRMA2 study at the Steno Diabetes
      Center were subjected to 24-h ABP (Takeda, TM2420) measurements before and 2
      years after randomization to placebo (n = 15), irbesartan 150 mg daily (Irb150; n
      = 13), or irbesartan 300 mg daily (Irb300; n = 15). RESULTS: At baseline, the
      placebo, Irb150, and Irb300 groups were comparable: OBP: 157 +/- 15/89 +/- 7, 156
      +/-15/91 +/- 11, and 159 +/- 16/90 +/- 9 mmHg (NS); 24-h ABP: 148 +/- 13/83 +/-
      11, 148 +/- 16/82 +/- 7 and 147 +/- 16/81 +/- 10 mmHg (NS); and UAE (geometric
      mean with 95% CI): 43 (32-57), 46 (30-70), and 59 (42-85) micro g/min (NS),
      respectively. We found that 2 years after randomization, OBP was significantly
      reduced in all three groups (by 11/7, 13/8, and 13/8 mmHg in the placebo, Irb150,
      and Irb300 groups, respectively), but that there were no significant differences
      among groups. Reductions in 24-h ABP were similar in the three groups (11/10,
      5/7, and 7/8 mmHg, respectively; NS), as were reductions in day ABP (11/9, 7/7,
      and 8/9 mmHg, respectively; NS) and night ABP (4/11, 7/7, and 3/3 mmHg,
      respectively; NS). The reduction in UAE at the end of the study was 0% (-86 to
      42), 38% (-14 to 66), and 73% (59 to 82), respectively (overall, P < 0.01).
      CONCLUSION: Irbesartan is renoprotective independently of its beneficial effect
      in lowering 24-h blood pressure in patients with type 2 diabetes and persistent
      microalbuminuria.

PMID- 12610004
TI  - A comparison of the prevalence of the metabolic syndrome using two proposed
      definitions.
AB  - OBJECTIVE: To compare the prevalence of the metabolic syndrome using two
      definitions: one proposed by the Third Report of the National Cholesterol
      Education Program Expert Panel on Detection, Evaluation, and Treatment of High
      Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) and one by the
      World Health Organization (WHO). RESEARCH DESIGN AND METHODS: We used data from a
      nationally representative sample of the noninstitutionalized civilian population
      of the U.S. from the Third National Health and Nutrition Examination Survey, a
      cross-sectional health examination survey (1988-1994). RESULTS: Among 8608
      participants aged >or=20 years, the age-adjusted prevalence was 23.9% using the
      ATP III definition and 25.1% using the WHO definition. Among all participants,
      86.2% were classified as either having or not having the metabolic syndrome under
      both definitions. Estimates differed substantially for some subgroups, however.
      For example, in African-American men, the WHO estimate was 24.9%, compared with
      the ATP III estimate of 16.5%. CONCLUSIONS: A universally accepted definition of
      the metabolic syndrome is needed.

PMID- 12610005
TI  - Clinical performance of CGMS in type 1 diabetic patients treated by continuous
      subcutaneous insulin infusion using insulin analogs.
AB  - OBJECTIVE: Performance criteria have been established for in vitro blood glucose
      monitoring, particularly for the self-monitoring of blood glucose using glucose
      meters. Devices intended for use in the future, such as the continuous glucose
      monitoring system (CGMS), should satisfy similar criteria, particularly in
      diabetic patients under intensive therapy. RESEARCH DESIGN AND METHODS: The
      analysis was conducted on 18 type 1 diabetic patients (not controlled, HbA(1c)
      >7.5%) treated by external pump using insulin analogs. Each patient received a
      glucose sensor for 3 days during his/her hospitalization and was instructed in
      its operation. Medtronic criteria were used to determine the accuracy of the
      CGMS. In addition, the data were analyzed according to American Diabetes
      Association (ADA) criteria, Clarke Error Grid analysis, and method of residuals,
      with the glucose oxidase method using a Beckman analyzer used as the reference
      method. Specificity and sensitivity were evaluated from the viewpoint of accuracy
      in the detection of hypoglycemia. For nine patients, two glucose sensors were
      simultaneously inserted into an abdominal site to determine the reproducibility
      of the system. RESULTS-Among the 33 glucose sensors inserted, 6 (18%) were
      nonfunctional. The mean duration of CGMS recording was 63 +/- 12 h. From all of
      the 692 sets of data that paired glucose readings and CGMS, the coefficients of
      correlation ranged from 0.87 to 0.92 and the mean absolute error ranged from 12.8
      to 15.7%. The time experienced in hypoglycemia (<55 mg/dl) was reported at 86 +/-
      62 min/day. Only 39% of the CGMS values satisfied the ADA precision criteria to
      within +/-10%, and 19% of these values satisfied the future ADA precision
      criteria of accuracy to within +/-5%. The means of difference method showed that
      the CGMS slightly underestimated the plasma glucose values (mean = -12 mg/dl).
      Error grid analysis showed only 77% of the glucose sensor values were in zone A,
      and 98.9% were in zones A and B. Two values fell in zone C and a single value
      fell in zone D. The sensitivity and specificity of the CGMS to detect
      hypoglycemia were 33 and 96%, respectively. A total of 6666 paired sensor values
      were recorded with a coefficient of correlation of 0.84 with a coefficient of
      variation of 8.25%. CONCLUSIONS: CGMS could be useful in routine clinical
      practice to provide much more information on the glucose profile than
      intermittent self-monitoring of blood glucose (SMBG). However, CGMS cannot be
      used as a replacement for glucose meters because it does not satisfy the
      conventional performance goals set down for in vitro glucose measurements and
      could therefore lead to clinically incorrect treatment decisions.

PMID- 12610006
TI  - Insulin detemir is associated with more predictable glycemic control and reduced
      risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal
      bolus regimen with premeal insulin aspart.
AB  - OBJECTIVE: Insulin detemir is a soluble basal insulin analog with a unique
      mechanism of protracted action designed to reduce the variability associated with
      conventional basal insulins. This trial compared the glycemic control, risk of
      hypoglycemia, and effect on body weight of insulin detemir and NPH insulin in
      patients with type 1 diabetes treated with rapid-acting insulin aspart at meals.
      RESEARCH DESIGN AND METHODS: This study was a 6-month multinational open parallel
      group comparison conducted at 46 centers in five countries and included 448
      patients with type 1 diabetes randomized 2:1 to insulin detemir or NPH insulin,
      respectively. RESULTS: After 6 months, comparable HbA(1c) levels were found
      between the two treatment groups. Fasting plasma glucose tended to be lower in
      patients treated with insulin detemir, but this difference was not statistically
      significant (-0.76 mmol/l, P = 0.097). Within-subject variation in self-measured
      fasting blood glucose was lower with insulin detemir than with NPH insulin (SD
      3.37 vs. 3.78 mmol/l, P < 0.001). Risk of hypoglycemia was 22% lower with insulin
      detemir than with NPH insulin (P < 0.05) and 34% lower for nocturnal (2300-0600)
      hypoglycemia (P < 0.005). Nightly plasma glucose profiles were smoother and more
      stable with insulin detemir (P = 0.05). Body weight was significantly lower with
      insulin detemir at the end of the trial (P < 0.001). CONCLUSIONS: Treatment with
      insulin detemir resulted in more predictable glycemic control, with smoother
      plasma glucose profiles than NPH insulin and a significant reduction in the risk
      of hypoglycemia. The reduction in body weight with insulin detemir is a potential
      additional advantage. Regimens optimized for insulin detemir may be able to
      improve glycemic control beyond that possible with NPH insulin.

PMID- 12610007
TI  - Trends in the diabetes quality improvement project measures in Maine from 1994 to
      1999.
AB  - OBJECTIVE: To examine changes in the management of patients with diabetes from
      1994 to 1999 using the claims-based Diabetes Quality Improvement Project (DQIP)
      accountability measures. RESEARCH DESIGN AND METHODS: Administrative claims from
      an employer-based health insurance cohort in Maine were used to describe the
      prevalence of claims-based DQIP accountability measures-HbA(1c) testing, dilated
      eye examination, lipid profile, and monitoring for diabetic nephropathy-from 1994
      (n = 1151) to 1999 (n = 2221) in a 100% sample of adults (18-64 years of age)
      with diabetes. The Mantel-Haenszel chi(2) test for trend was performed on each
      measure. Prevalence estimates were also stratified by three insurance products:
      health maintenance organization (HMO), point of service, and indemnity. RESULTS:
      There was a positive trend for all outcome measures (P < 0.001). The baseline and
      final frequencies (percent increase) for lipid testing, HbA(1c), dilated eye
      examination, and screening for diabetic nephropathy were as follows: 13-50%
      (257%), 37-69% (92%), 30-46% (53%), and 37-50% (36%), respectively. Individuals
      with diabetes and indemnity insurance were much less likely to receive these
      measures than individuals with other types of insurance, whereas people in HMOs
      were more likely to receive HbA(1c) testing and lipid profiles. CONCLUSIONS: The
      proportion of patients with diabetes receiving DQIP accountability measures
      significantly increased from 1994 to 1999. There is large variation in prevalence
      among these measures and insurance products. It is urgent to identify effective
      mechanisms for delivering consistent preventive care that are congruent with
      defined standards of benefit.

PMID- 12610008
TI  - Lifestyle modification to improve blood pressure control in individuals with
      diabetes: is physician advice effective?
AB  - OBJECTIVE: To determine the effectiveness of physician advice on hypertension
      related lifestyle modification in individuals with diabetes. RESEARCH DESIGN AND
      METHODS: Data on adults with one or more physician visit in the 1998 National
      Health Interview Survey (NHIS) were analyzed (diabetes, n = 1609; no diabetes, n
      = 19672). The proportion with hypertension who received physician advice to lose
      weight, increase physical activity, or take antihypertensive medications and the
      proportion who reported adhering to advice were compared by diabetes status.
      Logistic regression was used to identify factors associated with receipt of
      physician advice and adherence to advice by diabetes status controlling for
      covariates. Then, logistic regression was also used to determine the extent to
      which patient adherence among people with diabetes differed by age, sex, and
      race/ethnicity, controlling for other covariates. STATA statistical software was
      used for all analyses to account for the complex survey design of NHIS. RESULTS:
      Controlling for covariates, individuals with diabetes were more likely to receive
      advice (odds ratio [OR] 1.94 for weight loss, 1.99 for exercise, and 2.16 for
      medications). Adherence was more likely in individuals with diabetes (OR 1.40 for
      losing weight and 2.16 for taking medications). Adherence in people with diabetes
      did not differ by sex or race/ethnicity. Subjects 18-44 years old were least
      likely to report losing weight (OR 0.15) or taking medications (0.31) compared
      with subjects >or=65 years old. CONCLUSIONS: Physician advice appears effective
      at changing hypertension-related lifestyles in people with diabetes regardless of
      sex or race/ethnicity. However, advice on increasing physical activity does not
      seem as effective.

PMID- 12610009
TI  - The effect of alcohol intake on insulin sensitivity in men: a randomized
      controlled trial.
AB  - OBJECTIVE: Population data suggest that alcohol consumption may influence the
      risk of diabetes in a biphasic manner, but this has not been tested by any
      controlled interventions. The object of this study was to determine whether
      reducing alcohol intake in moderate-to-heavy drinkers (40-110 g/day) results in
      improvement in insulin sensitivity. RESEARCH DESIGN AND METHODS: A 4-week run-in
      period where subjects maintained their usual drinking pattern was followed by
      randomization to a two-way cross-over intervention study. In each of two 4-week
      treatment interventions, subjects either substituted their usual alcohol intake
      with a 0.9% alcohol beer or maintained their usual alcohol intake. At the end of
      each 4-week period, insulin sensitivity as determined by the low-dose insulin
      glucose infusion test and the homeostasis model assessment (HOMA) score, and
      biomarkers of alcohol consumption (gamma-glutamyl transpeptidase [gamma-GT] and
      HDL cholesterol) were measured. RESULTS: A total of 16 healthy men aged 51.0 +/-
      2.7 (mean +/- SEM) years with a BMI of 26.4 +/- 0.61 kg/m(2) completed the study.
      There was a large reduction in alcohol intake (72.4 +/- 5.0 vs. 7.9 +/- 1.6
      g/day, P < 0.001) and significant reductions in gamma-GT (geometric mean 24.4
      units/l [95% CI 19.7-30.2] vs. 18.6 units/l [15.5-22.2], P < 0.01) and HDL
      cholesterol (1.36 +/- 0.07 vs. 1.13 +/- 0.07 mmol/l, P < 0.001). There was no
      effect of alcohol on insulin sensitivity index (ISI), fasting insulin, glucose,
      or HOMA score. CONCLUSIONS: A substantial reduction in alcohol intake from 7.2 to
      0.8 standard drinks per day in healthy men did not change insulin sensitivity as
      measured by ISI or HOMA score.

PMID- 12610010
TI  - Fatty acid composition of serum lipid fractions in type 2 diabetic patients with
      microalbuminuria.
AB  - OBJECTIVE: To determine the fatty acid composition of serum phospholipid,
      triglyceride, and cholesterol ester fractions and to analyze the lipid profile of
      microalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A case
      control study was conducted with 72 patients: 37 were normoalbuminuric (urinary
      albumin excretion rate [UAER] <20 microg/min), and 35 were microalbuminuric (UAER
      20-200 microg/min). After 4 weeks of a standardized diet, the fatty acid
      composition of phospholipid, triglyceride, and cholesterol ester fractions was
      determined by gas chromatography. Total cholesterol and triglycerides were
      measured by enzymatic-colorimetric methods; cholesterol HDL by double
      precipitation with heparin, MnCl(2), and dextran sulfate; and apolipoprotein B by
      immunoturbidimetry. RESULTS: Microalbuminuric patients showed a lower proportion
      of polyunsaturated fatty acids (24.8 +/- 11.0%), especially of the n-6 family
      (21.7 +/- 10.5%), in triglyceride fraction than normoalbuminuric patients (34.1
      +/- 11.3%, P = 0.001 and 31.4 +/- 11.5%, P < 0.001, respectively). Patients with
      microalbuminuria also presented higher levels of saturated fatty acids in
      triglyceride fraction (43.4 +/- 18.0% vs. 34.7 +/- 13.1%, P = 0.022). In the
      logistic regression analysis, only the proportion of polyunsaturated fatty acids
      in triglyceride fraction remained significantly associated with microalbuminuria
      (odds ratio [OR] 0.92, 95% CI 0.85-0.98, P = 0.019). Total cholesterol, HDL
      cholesterol, triglyceride, and apolipoprotein B levels were similar in normo- and
      microalbuminuric patients. CONCLUSION: Microalbuminuria in type 2 diabetic
      patients is associated with low polyunsaturated fatty acid contents in serum
      triglyceride fraction. This association may represent a risk factor for
      cardiovascular disease and may contribute to the progression of renal disease.

PMID- 12610011
TI  - Dietary fat predicts coronary heart disease events in subjects with type 2
      diabetes.
AB  - OBJECTIVE: To investigate whether quantity or quality of dietary fat predicts
      coronary heart disease (CHD) events in middle-aged type 2 diabetic subjects.
      RESEARCH DESIGN AND METHODS: The dietary habits of 366 type 2 diabetic men and
      295 women, aged 45-64 years and free from CHD, were assessed with a 53-item food
      frequency questionnaire. They were followed up for 7 years. RESULTS: Men in the
      highest tertile of the polyunsaturated/saturated fat (P/S) ratio (>0.28) had a
      significantly lower risk for CHD death than men in the two lowest tertiles (5.0
      vs. 14.2%, P = 0.009). The risk for all CHD events was 14.2 vs. 23.2%,
      respectively (P = 0.044). P/S ratio did not predict CHD events in women. In Cox
      multiple regression analyses taking into account other cardiovascular risk
      factors, the highest P/S ratio tertile was associated with the lowest rate of CHD
      death in men (P = 0.048). CONCLUSIONS: Low P/S ratio in men predicted future CHD
      events in type 2 diabetic subjects independently of conventional CHD risk
      factors.

PMID- 12610012
TI  - Amino acid ingestion strongly enhances insulin secretion in patients with long
      term type 2 diabetes.
AB  - OBJECTIVE: Insulin secretion in response to carbohydrate intake is blunted in
      type 2 diabetic patients. However, it is not clear whether the insulin response
      to other stimuli, such as amino acids, is also diminished. Recently, we defined
      an optimal insulinoptropic mixture containing free leucine, phenylalanine, and a
      protein hydrolysate that substantially enhances the insulin response in healthy
      young subjects when coingested with carbohydrate. In this study, we aimed to
      investigate the insulinotropic capacity of this mixture in long-term type 2
      diabetic patients. RESEARCH DESIGN AND METHODS: Ten type 2 diabetic patients
      (aged 59.1 +/- 2.0 years, BMI 26.5 +/- 0.7 kg/m(2)) and 10 healthy control
      subjects (58.8 +/- 2.1 years, 26.5 +/- 0.7 kg/m(2)) visited our lab twice, during
      which insulin responses were determined following ingestion of carbohydrate only
      (CHO) or carbohydrate with the free amino acid/protein mixture (CHO+PRO). All
      subjects received 0.7 g x kg(-1) x h(-1) carbohydrate with or without 0.35 g x
      kg(-1) x h(-1) of the amino acid/protein mixture. RESULTS: Insulin responses were
      dramatically increased in the CHO+PRO trial in both the type 2 diabetic and
      control groups (189 and 114%, respectively) compared with the CHO trial (P <
      0.01). Plasma glucose, glucagon, growth hormone, cortisol, IGF-I, and IGF binding
      protein 3 responses were not different between trials within the 2-h time frame.
      CONCLUSIONS: The insulin secretory capacity in long-term type 2 diabetic patients
      is substantially underestimated, as the insulin response following carbohydrate
      intake can be nearly tripled by coingestion of a free amino acid/protein mixture.
      Future research should be performed to investigate whether such nutritional
      interventions can improve postprandial glucose disposal.

PMID- 12610013
TI  - The PedsQL in type 1 and type 2 diabetes: reliability and validity of the
      Pediatric Quality of Life Inventory Generic Core Scales and type 1 Diabetes
      Module.
AB  - OBJECTIVE: The Pediatric Quality of Life Inventory (PedsQL) is a modular
      instrument designed to measure health-related quality of life (HRQOL) in children
      and adolescents aged 2-18 years. The PedsQL 4.0 Generic Core Scales are child
      self-report and parent proxy-report scales developed as the generic core measure
      to be integrated with the PedsQL disease-specific modules. The PedsQL 3.0 Type 1
      Diabetes Module was designed to measure diabetes-specific HRQOL. RESEARCH DESIGN
      AND METHODS: The PedsQL Generic Core Scales and Diabetes Module were administered
      to 300 pediatric patients with type 1 or type 2 diabetes and 308 parents.
      RESULTS: Internal consistency reliability for the PedsQL Generic Core Total Scale
      score (alpha = 0.88 child, 0.89 parent-report) and most Diabetes Module scales
      (average alpha = 0.71 child, 0.77 parent-report) was acceptable for group
      comparisons. The PedsQL 4.0 distinguished between healthy children and children
      with diabetes. The Diabetes Module demonstrated intercorrelations with dimensions
      of generic and diabetes-specific HRQOL. CONCLUSIONS: The results demonstrate the
      reliability and validity of the PedsQL in diabetes. The PedsQL may be used as an
      outcome measure for diabetes clinical trials and research.

PMID- 12610014
TI  - Prospective analysis of mortality, morbidity, and risk factors in elderly
      diabetic subjects: Nagano study.
AB  - OBJECTIVE: To clarify mortality and morbidity of intensively managed elderly
      diabetic individuals and to explore factors predicting mortality and diabetes
      related end points. RESEARCH DESIGN AND METHODS: A total of 390 elderly (>or=65
      years of age) outpatients with type 2 diabetes ( 173 men and 217 women, mean age
      73.0 years) were analyzed. The mean HbA(1c) upon entry was 6.8% (332 receiving
      oral hypoglycemics and/or insulin) and blood pressure upon entry was 136/74 mmHg
      (219 receiving antihypertensive drugs). The patients have been followed-up for 3
      years with HbA(1c) <7.0% and blood pressure <145/80 mmHg as targets, with
      mortality and an aggregate of fatal and nonfatal diabetes-related events as end
      points. Mortality rate and causes of mortality, as well as risk factors for
      mortality and morbidity, were determined. RESULTS: The mortality rate, 2.9% per
      year, was comparable to that of the age- and sex-matched general population.
      Stroke was a leading cause of mortality after malignancy. By the univariate Cox
      proportional hazards model, only high serum creatinine and prior stroke were
      highly significant and strong risks for both end points. In those without prior
      stroke and receiving antihypertensive agents, the incidence of the diabetes
      related end point based on their systolic blood pressure (SBP) quartile was U
      shaped, with the nadir at the 3rd (SBP, 137-147 mmHg) and the peak at the 1st
      (SBP <or= 125 mmHg) quartile. CONCLUSIONS: In well-controlled elderly diabetic
      subjects, there was no excessive mortality compared to the age- and sex-matched
      general population. Renal dysfunction and prior stroke were independent risks for
      mortality and morbidity. In those without prior stroke, a risk of too much
      lowering of blood pressure was suggested.

PMID- 12610015
TI  - Estimated number of adults with prediabetes in the US in 2000: opportunities for
      prevention.
AB  - OBJECTIVE: To estimate the percent and number of overweight adults in the U.S.
      with prediabetes who would be potential candidates for diabetes prevention as per
      the American Diabetes Association Position Statement (12). RESEARCH DESIGN AND
      METHODS: We analyzed data from the Third National Health and Nutrition
      Examination Survey (NHANES III; 1988-1994) and projected our estimates to the
      year 2000. We defined impaired glucose tolerance (IGT; 2-h glucose 140-199
      mg/dl), impaired fasting glucose (IFG; fasting glucose 110-125 mg/dl), and
      prediabetes (IGT or IFG) per American Diabetes Association (ADA) criteria. The
      ADA recently recommended that all overweight people (BMI >or=25 kg/m(2)) who are
      >or=45 years of age with prediabetes could be potential candidates for diabetes
      prevention, as could prediabetic people aged >25 years with risk factors. In
      NHANES III, 2-h postload glucose concentrations were done only among subjects
      aged 40-74 years. Because we were interested in overweight people who had both
      the 2-h glucose and fasting glucose tests, we limited our estimates of IGT, IFG,
      and prediabetes to those aged 45-74 years. RESULTS-Overall, 17.1% of overweight
      adults aged 45-74 years had IGT, 11.9% had IFG, 22.6% had prediabetes, and 5.6%
      had both IGT and IFG. Based on those data, we estimated that in the year 2000,
      9.1 million overweight adults aged 45-74 had IGT, 5.8 million had IFG, 11.9
      million had prediabetes, and 3.0 million had IGT and IFG. CONCLUSIONS: Almost 12
      million overweight individuals aged 45-74 years in the U.S. may benefit from
      diabetes prevention interventions. The number will be substantially higher if
      estimation is extended to individuals aged >75 and 25-44 years.

PMID- 12610017
TI  - The association between impaired glucose tolerance and birth weight among black
      and white women in central North Carolina.
AB  - OBJECTIVE: This study examines the relationship of glucose intolerance during
      pregnancy to birth weight among black and white participants of the Pregnancy,
      Infection, and Nutrition Study. RESEARCH DESIGN AND METHODS: This prospective
      cohort study recruited women from prenatal clinics in central North Carolina at
      24-29 weeks' gestation. A 1-h 50-g glucose challenge test (GCT) and 100-g oral
      glucose tolerance test (OGTT) were conducted. Impaired glucose tolerance (IGT)
      was defined as one high value on the OGTT, gestational diabetes mellitus (GDM) as
      two or more high values, and normal glucose tolerance (NGT) was defined as a low
      or high value on the GCT screen but no high values on the OGTT. Women with known
      glucose status and birth outcome information were included in this analysis (n =
      2055). RESULTS: Black women with IGT had higher rates of both macrosomia (38.5%)
      and large for gestational age (LGA) (53.9%) compared with white women (10.0% and
      13.2%). Black infants' birth weights (3800 g) and prevalence of macrosomia and
      LGA were significantly higher among mothers with IGT compared with NGT women
      (birth weight, 3184 g; macrosomia, 7.0%; LGA, 11.6%). In contrast, among white
      infants, there was no significant increase in birth weight, macrosomia, or LGA
      associated with the mother's glucose tolerance status. In addition, there was no
      effect of GDM on birth weight in either group. CONCLUSIONS: This study suggests
      that, independent of maternal prepregnant weight, there may be significant
      increased risk of macrosomia among black IGT women but not among white IGT women.
      Further investigations into factors that may contribute to the observed results
      are needed.

PMID- 12610016
TI  - Visceral adiposity and the risk of impaired glucose tolerance: a prospective
      study among Japanese Americans.
AB  - OBJECTIVE: Greater visceral adiposity, higher insulin resistance, and impaired
      insulin secretion increase the risk of type 2 diabetes. Whether visceral
      adiposity increases risk of impaired glucose tolerance (IGT) independent of other
      adipose depots, insulin resistance, and insulin secretion is not known. RESEARCH
      DESIGN AND METHODS: Study subjects included 128 Japanese Americans with normal
      glucose tolerance at entry. Baseline variables included plasma glucose and
      insulin measured after an overnight fast and during a 75-g oral glucose tolerance
      test, fat areas by computed tomography, insulin secretion (incremental insulin
      response [IIR] [30 min insulin - fasting insulin]/30 min glucose), and insulin
      resistance index (homeostasis model assessment for insulin resistance [HOMA-IR]).
      RESULTS: During the 10- to 11-year follow-up period, we confirmed 57 cases of
      IGT. Significant predictors of IGT included intra-abdominal fat area (IAFA) (odds
      ratio [OR] for a 1 SD increase 3.82, 95% CI 1.63-8.94 at a fasting plasma glucose
      [FPG] level of 4.5 mmol/l), HOMA-IR (2.41, 1.15-5.04), IIR (0.30, 0.13-0.69 at an
      FPG level of 4.5 mmol/l), the interactions of IAFA by FPG (P = 0.003), and IIR by
      FPG (P = 0.030) after adjusting for age, sex, FPG, and BMI. The multiple-adjusted
      OR of IAFA increased and that of IIR decreased as FPG level decreased because of
      these interactions. Even after adjustment for total fat area, total subcutaneous
      fat area, or abdominal subcutaneous fat area, all of these associations remained
      a significant predictor of IGT incidence. CONCLUSIONS: Greater visceral adiposity
      increases the risk of IGT independent of insulin resistance, insulin secretion,
      and other adipose depots in Japanese Americans.

PMID- 12610018
TI  - Hypoglycemia prevalence in prepubertal children with type 1 diabetes on standard
      insulin regimen: use of continuous glucose monitoring system.
AB  - OBJECTIVE: To determine hypoglycemia prevalence in prepubertal children on thrice
      (TID) and twice (BID) daily insulin regimens, using the Medtronic Minimed
      Continuous Glucose Monitoring System. RESEARCH DESIGN AND METHODS: Twenty-eight
      children aged <12 years (median 9.8, range 6.9-11.8) wore the sensor for three
      consecutive days and nights. Hypoglycemia was defined as glucose <60 mg/dl for
      >15 min. Data are expressed as the percentage of time period spent hypoglycemic.
      RESULTS: Hypoglycemia prevalence was 10.1% (mean 2.6 h. subject(-1) x day(-1)).
      Hypoglycemia was more common at night compared with daytime (18.81 vs. 4.4%, P <
      0.001); 78 and 43% of subjects showed hypoglycemia on at least one night and two
      or more nights, respectively. Nocturnal episodes were prolonged (median 3.3 h)
      and asymptomatic (91% of episodes). Prevalence was greater between 0400 and 0730
      h than between 2200 and 0400 h (25.5 vs. 15.4%, P < 0.001). On a TID compared
      with a BID regimen, nocturnal hypoglycemia prevalence was reduced, particularly
      between 0400-0730 h (22.9 vs. 27.4%, P = 0.005), whereas hypoglycemia the
      following morning (0730-1200 h) was greater (7.8 vs. 2.8%, P < 0.001). Nocturnal
      hypoglycemia risk was associated with decreasing age (by a factor of 0.6 for a
      year less in age), increased insulin dose (by 1.6 for an increase of 0.1 units.
      kg(-1) x day(-1)), insulin regimen (by 0.2 on a BID compared with a TID regimen),
      and increased weight standard deviation score (SDS) (by 2.7 for a one SDS rise).
      CONCLUSIONS: Use of standard insulin regimens results in high prevalence and
      large intraindividual variation in hypoglycemia, particularly at night.
      Independent risk factors for nocturnal hypoglycemia were younger age, greater
      daily insulin dose, insulin regimen, and increasing weight.

PMID- 12610019
TI  - Community-based screening for diabetes in Michigan.
AB  - OBJECTIVE: To describe and evaluate a community-based diabetes screening program
      supported by the Michigan Department of Community Health. RESEARCH DESIGN AND
      METHODS: Between 1 June 1999 and 31 December 1999, community screening for
      diabetes was conducted by voluntary organizations using a standard protocol,
      American Diabetes Association (ADA) questionnaires, and ADA capillary plasma
      glucose criteria. RESULTS: A total of 3506 individuals were screened, 14% of whom
      did not meet criteria for screening. Of the 3031 individuals appropriately
      screened, 57% were classified as being at high risk based on the ADA
      questionnaire and 5% had positive screening tests based on ADA capillary plasma
      glucose criteria. Despite systematic follow-up, the screening program's yield of
      individuals with undiagnosed diabetes was <1%. CONCLUSIONS: Community screening
      for diabetes conducted according to ADA recommendations was extremely inefficient
      at identifying individuals with undiagnosed diabetes. The ADA diabetes screening
      questionnaire resulted in many false positive tests, and the ADA criteria for
      positive plasma glucose tests likely missed a substantial portion of individuals
      with undiagnosed diabetes. Relying on biochemical tests such as random plasma
      glucose, changing the criteria for a positive plasma glucose test, targeting
      racial and ethnic minority groups, and targeting medically underserved
      individuals might improve the yield of community-based diabetes screening.

PMID- 12610020
TI  - Incidence of type 1 diabetes in Lithuanians aged 0-39 years varies by the urban
      rural setting, and the time change differs for men and women during 1991-2000.
AB  - OBJECTIVE: Type 1 diabetes has been associated with factors related to welfare
      and social class. During the past decade, Lithuania has experienced a transition
      period, leading to dramatic changes in the socioeconomic structure of the
      society. RESEARCH DESIGN AND METHODS: Incidence in the group aged 0-39 years by
      urban-rural setting (cities >100000 inhabitants, towns, and rural areas), period
      (1991-1995 and 1996-2000), age, and sex were studied using Poisson regression.
      RESULTS: The age- and sex-standardized incidence per 100000 inhabitants per year
      was higher in men aged 0-39 years than in women (9.5 and 6.9, respectively,
      incidence rate ratio [IRR] = 1.39, P < 0.001). Incidence was lower in rural areas
      than in towns and cities (7.1, 9.0, and 8.8, respectively, P < 0.001). The urban
      rural differences in incidence were most marked among children aged 0-9 years.
      From 1991-1995 to 1996-2000, the overall incidence increased from 8.7 to 10.5
      (IRR = 1.22, P = 0.001) in men and from 6.2 to 7.8 (IRR = 1.25, P = 0.002) in
      women. For men, the increase over time occurred predominantly in the cities, from
      8.4 to 11.8 (IRR = 1.40, P < 0.001), and in the older age-groups. In contrast,
      for women, the incidence increased more in small towns and rural areas, from 5.8
      to 7.7 (IRR = 1.33, P = 0.003), and in the younger age-groups. CONCLUSIONS: The
      incidence of type 1 diabetes in Lithuania differs depending on the urban-rural
      setting, and the pattern of change over time differs between the sexes, both by
      urban-rural setting and age-group. The findings support the theory that lifestyle
      related factors connected to socioeconomic status are important for the
      occurrence of type 1 diabetes.

PMID- 12610021
TI  - The impact of smoking on inhaled insulin.
AB  - OBJECTIVE: This study, one of the first to address issues of pulmonary insulin
      delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via
      the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette
      smokers and nonsmokers. RESEARCH DESIGN AND METHODS: In this randomized two
      period crossover efficacy and safety trial in 27 nondiabetic smokers and 16
      nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects
      received single doses of inhaled insulin (33.8 IU) following overnight fasting on
      consecutive dosing days. On one dosing day, smokers smoked three cigarettes
      immediately before insulin administration ("acute smoking"); on the other dosing
      day, smokers had not smoked since midnight ("nonacute smoking"). After
      inhalation, 6-h serum insulin and serum glucose profiles were determined.
      RESULTS: Pharmacokinetic results for evaluable subjects were derived from serum
      insulin profiles. The amount of insulin absorbed during the first 6 h after
      dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6
      h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P =
      0.0017); peak concentration was both higher and earlier in the smokers (maximal
      serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to
      maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003).
      The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for
      nonsmokers and smokers, respectively. No safety issues arose. CONCLUSIONS:
      Absorption of inhaled insulin via the AERx iDMS was significantly greater in
      smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject
      variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These
      data prompt more extensive investigation of inhaled insulin in diabetic smokers.

PMID- 12610022
TI  - Losartan reduces the costs associated with diabetic end-stage renal disease: the
      RENAAL study economic evaluation.
AB  - OBJECTIVE: To evaluate the within-trial effect of losartan and conventional
      antihypertensive therapy (CT) compared with placebo and CT on the economic cost
      associated with end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: The
      Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist
      Losartan (RENAAL) study was a multinational double-blind randomized placebo
      controlled clinical trial designed to evaluate the renal protective effects of
      losartan on a background of CT (excluding ACE inhibitors and angiotensin II
      receptor agonists [AIIAs]) in patients with type 2 diabetes and nephropathy. The
      primary composite end point was doubling of serum creatinine, ESRD, or death.
      Data on the duration of ESRD were used to estimate the economic benefits of
      slowing the progression of nephropathy. The cost associated with ESRD was
      estimated by combining the days each patient experienced ESRD with the cost of
      ESRD over time. The cost of ESRD for individuals with diabetes was estimated
      using data from the U.S. Renal Data System. Total cost was estimated as the sum
      of the cost associated with ESRD and the cost of study therapy. RESULTS-We
      estimated that losartan and CT compared with placebo and CT reduced the number of
      days with ESRD by 33.6 per patient over 3.5 years (P = 0.004, 95% CI 10.9-56.3).
      This reduction in ESRD days resulted in a decrease in cost associated with ESRD
      of 5144 US dollars per patient (P = 0.003, 95% CI 1701 to 8587 US dollars). After
      accounting for the cost of losartan, the reduction in ESRD days resulted in a net
      savings of 3522 US dollars per patient over 3.5 years (P = 0.041, 143 to 6900 US
      dollars). CONCLUSIONS: Treatment with losartan in patients with type 2 diabetes
      and nephropathy not only reduced the incidence of ESRD, but also resulted in
      substantial cost savings.

PMID- 12610023
TI  - Is the current definition for diabetes relevant to mortality risk from all causes
      and cardiovascular and noncardiovascular diseases?
AB  - OBJECTIVE: To assess the relation between fasting plasma glucose (FPG) or 2-h
      plasma glucose (2hPG) and mortality from all causes, cardiovascular disease
      (CVD), and non-CVD and to determine whether the relationship is graded or
      threshold. RESEARCH DESIGN AND METHODS: Diabetes Epidemiology: Collaborative
      Analysis Of Diagnostic Criteria in Europe (DECODE) is a collaborative prospective
      study of 22 cohorts in Europe with baseline glucose measurements for 29714
      subjects aged 30-89 years who were followed-up for 11 years (329050 person
      years). Hazard ratio (HR) for death was estimated using Cox regression analysis.
      RESULTS: High glucose concentrations as well as very low glucose levels were
      associated with increased risk of death. Compared with an FPG of 4.50-6.09
      mmol/l, the multivariate-adjusted HR (95% CI) for FPG <4.50 mmol/l was 1.2 (1.0
      1.4) for all-cause, 1.3 (1.0-1.8) for CVD, and 1.1 (0.9-1.4) for non-CVD
      mortality; the corresponding HRs for diabetes (FPG >or=7.0 mmol/l) were 1.6 (1.4
      1.8), 1.6 (1.3-1.9), and 1.6 (1.4-1.9), respectively. For a 2hPG of 3.01-4.50
      mmol/l, as compared with a 2hPG of 4.51-5.50 mmol/l, the HRs were 1.1 (1.0-1.2),
      1.1 (0.9-1.3), and 1.1 (1.0-1.3), respectively; the corresponding HRs for
      diabetes (2hPG >or=11.1 mmol/l) were 2.0 (1.7-2.3), 1.9 (1.5-2.4), and 2.1 (1.7
      2.5), respectively. The HR for previously undetected diabetes defined by 2hPG was
      not significantly different from that for known diabetes, which was significantly
      higher than that for undetected diabetes based on FPG. Subjects with a 2hPG of
      10.01-11.09 mmol/l had mortality risks similar to those diabetic subjects defined
      by an FPG >or=7.0 mmol/l. CONCLUSIONS: The relation between mortality and glucose
      was J shaped rather than showing threshold effect at high glucose levels, except
      for CVD mortality and 2hPG, where the relation was graded and increasing.

PMID- 12610024
TI  - Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy
      symptom and diabetic neuropathy examination scores.
AB  - OBJECTIVE: To evaluate the discriminative power of the Diabetic Neuropathy
      Symptom (DNS) and Diabetic Neuropathy Examination (DNE) scores for diagnosing
      diabetic polyneuropathy (PNP), as well as their relation with cardiovascular
      autonomic function testing (cAFT) and electro-diagnostic studies (EDS). RESEARCH
      DESIGN AND METHODS: Three groups (matched for age and sex) were selected: 24
      diabetic patients with neuropathic foot ulcers (DU), 24 diabetic patients without
      clinical neuropathy or ulcers (DC), and 21 control subjects without diabetes (C).
      In all participants, the DNS and DNE scores were assessed and cAFT (heart rate
      variability [HRV], baroreflex sensitivity [BRS]), and EDS were performed (Nerve
      Conduction Sum [NCS] score; muscle fiber conduction velocity: fastest/slowest
      ratio [F/S ratio]). RESULTS: Both the DNS and the DNE scores discriminated
      between the DU and DC groups significantly (P < 0.001). The DNE score even
      discriminated between DC and C (P < 0.05). Spearman's correlation coefficients
      between both DNS and DNE scores and cAFT (HRV -0.42 and -0.44; BRS -0.30 and 
      0.29, respectively) and EDS (NCS 0.51 and 0.62; F/S ratio 0.44 and 0.62,
      respectively) were high. Odds ratios were calculated for both DNS and DNE scores
      with cAFT (HRV 4.4 and 5.7; BRS 20.7 and 14.2, respectively) and EDS (NCS 5.6 and
      16.8; F/S ratio 7.2 and 18.8, respectively). CONCLUSIONS: The DNS and DNE scores
      are able to discriminate between patients with and without PNP and are strongly
      related to cAFT and EDS. This further confirms the strength of the DNS and DNE
      scores in diagnosing diabetic PNP in daily clinical practice.

PMID- 12610025
TI  - Diabetes and sleep disturbances: findings from the Sleep Heart Health Study.
AB  - OBJECTIVE: To test the hypothesis that diabetes is independently associated with
      sleep-disordered breathing (SDB), and in particular that diabetes is associated
      with sleep abnormalities of a central, rather than obstructive, nature. RESEARCH
      DESIGN AND METHODS: Using baseline data from the Sleep Heart Health Study (SHHS),
      we related diabetes to 1). the respiratory disturbance index (RDI; number of
      apneas plus hypopneas per h of sleep); 2). obstructive apnea index (OAI; >or=3
      apneas/h of sleep associated with obstruction of the upper airway); 3). percent
      of sleep time < 90% O(2) saturation; 4). central apnea index (CAI; >or=3 apneas
      [without respiratory effort]/h sleep); 5). occurrence of a periodic breathing
      (Cheyne Stokes) pattern; and 6) sleep stages. Initial analyses excluding persons
      with prevalent cardiovascular disease (CVD) were repeated including these
      participants. RESULTS: Of the 5874 participants included in this report, 692
      (11.8%) reported diabetes or were taking oral hypoglycemic medications or insulin
      and 1002 had prevalent CVD. Among the 4872 persons without CVD, 470 (9.6%) had
      diabetes. Diabetic participants had worse CVD risk factor profiles than their
      nondiabetic counterparts, including higher BMI, waist and neck circumferences,
      triglycerides, higher prevalence of hypertension, and lower HDL cholesterol (P <
      0.001, all). Descriptive analyses indicated differences between diabetic and
      nondiabetic participants in RDI, sleep stages, sleep time <90% O(2) saturation,
      CAI, and periodic breathing (P < 0.05, all). However, multivariable regression
      analyses that adjusted for age, sex, BMI, race, and neck circumference eliminated
      these differences for all sleep measures except percent time in rapid eye
      movement (REM) sleep (19.0% among diabetic vs. 20.1% among nondiabetic subjects,
      P < 0.001) and prevalence of periodic breathing (odds ratio [OR] for diabetic
      subjects versus nondiabetic subjects 1.80, 95% CI 1.02-3.15). Additionally,
      adjusted analyses showed diabetes was associated with nonstatistically
      significant elevations in the odds of an increased central breathing index (OR
      1.42, 95% CI 0.80-2.55). Addition to the analysis of the 1002 persons with
      prevalent CVD (including 222 people with diabetes) did not materially change
      these results. CONCLUSIONS: These data suggest that diabetes is associated with
      periodic breathing, a respiratory abnormality associated with abnormalities in
      the central control of ventilation. Some sleep disturbances may result from
      diabetes through the deleterious effects of diabetes on central control of
      respiration. The high prevalence of SDB in diabetes, although largely explained
      by obesity and other confounders, suggests the presence of a potentially
      treatable risk factor for CVD in the diabetic population.

PMID- 12610026
TI  - Are spouses of patients with type 2 diabetes at increased risk of developing
      diabetes?
AB  - OBJECTIVE: To determine whether spouses of patients with type 2 diabetes have an
      increased risk of diabetes compared with spouses of subjects with normal glucose
      tolerance. RESEARCH DESIGN AND METHODS: A random sample of spouses of patients
      with type 2 diabetes (group 1S) attending a general practice diabetes clinic was
      compared with spouses of nondiabetic subjects (as determined by oral glucose
      tolerance test [OGTT]) (group 2S). Spouses in both groups underwent OGTT, fasting
      lipid profile, and blood pressure (BP) measurements. RESULTS: A total of 245
      subjects in group 1S and 234 subjects in group 2S underwent OGTT. Group 1S had a
      significantly higher incidence of fasting glucose, impaired glucose tolerance, or
      type 2 diabetes (19.1 vs. 9.4%). Group 1S also had higher fasting glucose and
      triglyceride levels, higher BMI, and a trend toward higher BP. Multivariate
      logistic regression analysis, adjusted for BMI and age, showed the risk of
      diabetes in the spouse of a patient with diabetes was 2.11 (95% CI 1.74-5.1), as
      compared with the spouse of a subject with normal glucose tolerance. Similarly,
      the risk of any degree of glucose intolerance in a spouse of a patient with type
      2 diabetes was 2.32 (1.87-3.98), as compared with a spouse of a subject with
      normal glucose tolerance. CONCLUSIONS: Spouses of patients with type 2 diabetes
      have a significantly increased risk of glucose intolerance and type 2 diabetes,
      and they should be classified as high risk for diabetes. This finding has
      implications for screening programs, which should include spouses of subjects
      with diabetes.

PMID- 12610027
TI  - The confidence in diabetes self-care scale: psychometric properties of a new
      measure of diabetes-specific self-efficacy in Dutch and US patients with type 1
      diabetes.
AB  - OBJECTIVE: To examine psychometric properties of the Confidence in Diabetes Self
      Care (CIDS) scale, a newly developed instrument assessing diabetes-specific self
      efficacy in Dutch and U.S. patients with type 1 diabetes. RESEARCH DESIGN AND
      METHODS: Reliability and validity of the CIDS scale were evaluated in Dutch (n =
      151) and U.S. (n = 190) outpatients with type 1 diabetes. In addition to the CIDS
      scale, assessment included HbA(1c), emotional distress, fear of hypoglycemia,
      self-esteem, anxiety, depression, and self-care behavior. The Dutch sample
      completed additional measures on perceived burden and importance of self-care.
      Test-retest reliability was established in a second Dutch sample (n = 62).
      RESULTS: Internal consistency (Cronbach's alpha = 0.86 for Dutch patients and
      0.90 U.S. patients) and test-retest reliability (Spearman's r = 0.85, P < 0.0001)
      of the CIDS scale were high. Exploratory factor analysis showed one strong
      general factor. Spearman's correlations between the CIDS scale and other measures
      were moderate and in the expected directions, and high HbA(1c) levels were
      associated with low CIDS scores in the U.S. sample only. Low CIDS scores were
      positively associated with self-care but not with glycemic control in the
      original samples. CIDS scores in the U.S. and Dutch samples did not show any
      statistically significant differences. U.S. men had higher CIDS scores than U.S.
      women. CONCLUSIONS: The CIDS scale is a reliable and valid measure of diabetes
      specific self-efficacy for use in patients with type 1 diabetes. High
      psychometric similarity allows for cross-cultural comparisons.

PMID- 12610028
TI  - Work stress and low sense of coherence is associated with type 2 diabetes in
      middle-aged Swedish women.
AB  - OBJECTIVE: The risk of type 2 diabetes is suggested to be increased for
      individuals exposed to stress. We analyzed the association of work stress by high
      demands, low decision latitude, and job strain (combination of high demands and
      low decision latitude) with type 2 diabetes. We also studied low sense of
      coherence (SOC) (a factor for successful coping with stressors) in association
      with type 2 diabetes. Finally, we investigated the combination of SOC and demands
      or SOC and decision latitude in association with the disease. RESEARCH DESIGN AND
      METHODS: This cross-sectional study recruited 4821 healthy Swedish women (aged 35
      56 years) residing in five municipalities in the Stockholm area. An oral glucose
      tolerance test identified 52 women with type 2 diabetes. Relative risks (RRs)
      with 95% CIs were estimated in a logistic multiple regression analysis. RESULTS:
      No association was found between high demands and type 2 diabetes (RR 1.1 [CI 0.5
      2.2]). Low decision latitude was associated with type 2 diabetes with a RR of 2.2
      (1.0-4.8). The RR of type 2 diabetes with low SOC was 3.7 (1.2-11.2). The
      combination of low SOC and low decision latitude was associated with type 2
      diabetes with a RR of 2.6 (1.2-5.7). Homeostasis model assessment revealed an
      association of 4.2 (1.2-15.0) between low SOC and insulin resistance.
      CONCLUSIONS: This study provided new evidence that stress factors such as low
      decision latitude at work and low SOC were associated with type 2 diabetes in
      middle-aged Swedish women.

PMID- 12610029
TI  - The diabetes risk score: a practical tool to predict type 2 diabetes risk.
AB  - OBJECTIVE: Interventions to prevent type 2 diabetes should be directed toward
      individuals at increased risk for the disease. To identify such individuals
      without laboratory tests, we developed the Diabetes Risk Score. RESEARCH DESIGN
      AND METHODS: A random population sample of 35- to 64-year-old men and women with
      no antidiabetic drug treatment at baseline were followed for 10 years. New cases
      of drug-treated type 2 diabetes were ascertained from the National Drug Registry.
      Multivariate logistic regression model coefficients were used to assign each
      variable category a score. The Diabetes Risk Score was composed as the sum of
      these individual scores. The validity of the score was tested in an independent
      population survey performed in 1992 with prospective follow-up for 5 years.
      RESULTS: Age, BMI, waist circumference, history of antihypertensive drug
      treatment and high blood glucose, physical activity, and daily consumption of
      fruits, berries, or vegetables were selected as categorical variables. Complete
      baseline risk data were found in 4435 subjects with 182 incident cases of
      diabetes. The Diabetes Risk Score value varied from 0 to 20. To predict drug
      treated diabetes, the score value >or=9 had sensitivity of 0.78 and 0.81,
      specificity of 0.77 and 0.76, and positive predictive value of 0.13 and 0.05 in
      the 1987 and 1992 cohorts, respectively. CONCLUSIONS: The Diabetes Risk Score is
      a simple, fast, inexpensive, noninvasive, and reliable tool to identify
      individuals at high risk for type 2 diabetes.

PMID- 12610030
TI  - Changes in diabetes self-care behaviors make a difference in glycemic control:
      the Diabetes Stages of Change (DiSC) study.
AB  - OBJECTIVE: This study compared diabetes Treatment As Usual (TAU) with Pathways To
      Change (PTC), an intervention developed from the Transtheoretical Model of Change
      (TTM), to determine whether the PTC intervention would result in greater
      readiness to change, greater increases in self-care, and improved diabetes
      control. RESEARCH DESIGN AND METHODS: Participants were stratified by diabetes
      treatment and randomized to treatment with PTC or TAU as well as being randomized
      regarding receipt of free blood testing strips. The PTC consisted of stage
      matched personalized assessment reports, self-help manuals, newsletters, and
      individual phone counseling designed to improve readiness for self-monitoring of
      blood glucose (SMBG), healthy eating, and/or smoking cessation. A total of 1029
      individuals with type 1 and type 2 diabetes who were in one of three pre-action
      stages for either SMBG, healthy eating, or smoking were recruited. RESULTS: For
      the SMBG intervention, 43.4% of those receiving PTC plus strips moved to an
      action stage, as well as 30.5% of those receiving PTC alone, 27.0% of those
      receiving TAU plus strips, and 18.4% of those receiving TAU alone (P < 0.001).
      For the healthy eating intervention, more participants who received PTC than TAU
      (32.5 vs. 25.8%) moved to action or maintenance (P < 0.001). For the smoking
      intervention, more participants receiving PTC (24.3%) than TAU (13.4%) moved to
      an action stage (P < 0.03). In intention-to-treat (ITT) analysis of those
      receiving the SMBG intervention, PTC resulted in a greater reduction of HbA(1c)
      than TAU, but this did not reach statistical significance. However, in those who
      moved to an action stage for the SMBG and healthy eating interventions, HbA(1c)
      was significantly reduced (P < 0 0.001). Individuals who received the healthy
      eating intervention decreased their percentage of calories from fat to a greater
      extent (35.2 vs. 36.1%, P = 0.004), increased servings of fruit per day (1.89 vs.
      1.68, P = 0.016), and increased vegetable servings (2.24 vs. 2.06, P = 0.011) but
      did not decrease weight. However, weight loss for individuals who received the
      healthy eating intervention and who increased SMBG frequency as recommended was
      significantly greater, with a 0.26-kg loss in those who remained in a pre-action
      SMBG stage but a 1.78-kg loss in those performed SMBG as recommended (P <or= 0.
      01). CONCLUSIONS: This study demonstrates that this intervention has the
      potential of positively impacting the health of broad populations of individuals
      with diabetes, not just the minority who are ready for change.

PMID- 12610031
TI  - How well do patients' assessments of their diabetes self-management correlate
      with actual glycemic control and receipt of recommended diabetes services?
AB  - OBJECTIVE: Although patient diabetes self-management is a key determinant of
      health outcomes, there is little evidence on whether patients' own assessments of
      their self-management correlates with glycemic control and key aspects of high
      quality diabetes care. We explored these associations in a nationwide sample of
      Veterans' Affairs (VA) patients with diabetes. RESEARCH DESIGN AND METHODS: We
      abstracted information on achieved level of glycemic control (HbA(1c)) and
      diabetes processes of care (receipt of HbA(1c) test, eye examination, and
      nephropathy screen) from medical records of 1032 diabetic patients who received
      care from 21 VA facilities and had answered the Diabetes Quality Improvement
      Program survey in 2000. The survey included sociodemographic measures and a five
      item scale assessing the patients' diabetes self-management (medication use,
      blood glucose monitoring, diet, exercise, and foot care [alpha = 0.68]). Using
      multivariable regression, we examined the associations of patients' reported self
      management with HbA(1c) level and receipt of each diabetes process of care. We
      adjusted for diabetes severity and comorbidities, insulin use, age, ethnicity,
      income, education, use of VA services, and clustering at the facility level.
      RESULTS: Higher patient evaluations of their diabetes self-management were
      significantly associated with lower HbA(1c) levels (P < 0.01) and receipt of
      diabetes services. Those in the 95th percentile for self-management had a mean
      HbA(1c) level of 7.3 (95% CI 6.4-8.3), whereas those in the 5th percentile had
      mean levels of 8.3 (7.4-9.2). For every 10-point increase in patients' ratings of
      their diabetes self-management, even after adjusting for number of outpatient
      visits, the odds of receiving an HbA(1c) test in the past year increased by 15%
      (4-27%), of receiving an eye examination increased by 16% (7-27%), and of
      receiving a nephropathy screen increased by 13% (2-26%). CONCLUSIONS: In this
      sample, patients' assessments of their diabetes self-care using a simple five
      question instrument were significantly associated both with actual HbA(1c)
      control and with receiving recommended diabetes services. These findings
      reinforce the usefulness of patient evaluations of their own self-management for
      understanding and improving glycemic control. The mechanisms by which those
      patients who are more actively engaged in their diabetes self-care are also more
      likely to receive necessary services warrant further study.

PMID- 12610032
TI  - Unadjusted and adjusted prevalence of diagnosed depression in type 2 diabetes.
AB  - OBJECTIVE: To estimate the prevalence of diagnosed depression in a large
      population of individuals with type 2 diabetes, compared to a matched control
      group, and to estimate the extent of depression that is independently associated
      with diabetes. RESEARCH DESIGN AND METHODS: We compared the prevalence of
      diagnosed depression in all 16180 full-year health maintenance organization
      members in 1999 who had been diagnosed with type 2 diabetes and in 16180
      comparison members without diabetes matched for age and sex. We ascertained
      diagnoses from the Kaiser Permanente Northwest Region's electronic medical
      record. Using multiple logistic regression, we adjusted the prevalence estimates
      for the presence of cardiovascular disease, age, sex, and body weight. RESULTS:
      Depression was more common in individuals with type 2 diabetes than among matched
      control subjects (17.9 vs. 11.2%; P < 0.001). Women in both groups were nearly
      twice as likely to be depressed as men; however, the relative difference in
      depression prevalence between subjects with and without diabetes was greater in
      men. In the multivariate model for women, body weight was a much stronger
      predictor of depression than diabetes status. CONCLUSIONS: This study further
      documents the association between depression and diabetes, providing unadjusted
      population-based estimates in a large sample. Depression remained associated with
      diabetes after adjustment for several other possible causes. The association
      among diabetes, cardiovascular disease, depression, and obesity are multifaceted
      and differ for men and women.

PMID- 12610033
TI  - A controlled trial of web-based diabetes disease management: the MGH diabetes
      primary care improvement project.
AB  - OBJECTIVE: To test effects of a web-based decision support tool, the diabetes
      Disease Management Application (DMA), developed to improve evidence-based
      management of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a group
      randomized controlled trial of 12 intervention and 14 control staff providers and
      307 intervention and 291 control patients with type 2 diabetes in a hospital
      based internal medicine clinic. Providers were randomly assigned from May 1998
      through April 1999 to have access to the DMA (intervention) or not to have access
      (control). The DMA displays interactive patient-specific clinical data, treatment
      advice, and links to other web-based care resources. We compared patients in the
      intervention and control groups for changes in processes and outcomes of care
      from the year preceding the study through the year of the study by intention-to
      treat analysis. RESULTS: The DMA was used for 42% of scheduled patient visits.
      The number of HbA(1c) tests obtained per year increased significantly in the
      intervention group (+0.3 tests/year) compared with the control group (-0.04
      tests/year, P = 0.008), as did the number of LDL cholesterol tests (intervention,
      +0.2 tests/year; control, +0.01 tests/year; P = 0.02) and the proportions of
      patients undergoing at least one foot examination per year (intervention, +9.8%;
      control, -0.7%; P = 0.003). Levels of HbA(1c) decreased by 0.2 in the
      intervention group and increased by 0.1 in the control group (P = 0.09);
      proportions of patients with LDL cholesterol levels <130 mg/dl increased by 20.3%
      in the intervention group and 10.5% in the control group (P = 0.5). CONCLUSIONS:
      Web-based patient-specific decision support has the potential to improve evidence
      based parameters of diabetes care.

PMID- 12610035
TI  - Inhaled insulin using the AERx Insulin Diabetes Management System in healthy and
      asthmatic subjects.
AB  - OBJECTIVE: The AERx insulin Diabetes Management System (AERx iDMS) (Aradigm,
      Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for
      systemic absorption. This study examined the effects on pulmonary function,
      pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and
      nonasthmatic subjects without diabetes. RESEARCH DESIGN AND METHODS: A total of
      28 healthy and 17 asthmatic (forced expiratory volume during the first second [
      FEV(1)] 50-80% of predicted value) subjects were enrolled in a two-part, open
      label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single
      inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part
      1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects
      on pulmonary function. RESULTS: Inhaled insulin showed area under the curve
      (AUC)((0-360 min)) values that were significantly greater for healthy subjects
      than for asthmatic subjects (P = 0.013), whereas no difference was observed for
      maximum concentration (C(max)) in the two groups. A greater reduction of serum
      glucose as indicated by area over the curve (AOC)((0-360 min)) was observed in
      healthy subjects (P = 0.007). Asthmatic subjects had greater intrasubject
      variations in insulin AUC((0-360 min)) and C(max) values than healthy subjects,
      but similar variations in glucose AOC((0-360 min)). No significant changes in
      FEV(1), forced vital capacity (FVC), and FEV(1)/FVC were observed from pre- to
      postdose times, and there were no observed safety issues. CONCLUSIONS: After
      inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin
      than healthy subjects, resulting in less reduction of serum glucose. No effects
      on airway reactivity were observed. Diabetic patients with asthma may need to
      inhale more insulin than patients with normal respiratory function in order to
      achieve similar glycemic control.

PMID- 12610034
TI  - Comparison of a clinical model, the oral glucose tolerance test, and fasting
      glucose for prediction of type 2 diabetes risk in Japanese Americans.
AB  - OBJECTIVE: To test the validity of a published clinical model for predicting
      incident diabetes in Japanese Americans. RESEARCH DESIGN AND METHODS: A total of
      465 nondiabetic Japanese Americans (243 men, 222 women), aged 34-75 years, were
      studied at baseline and at 5-6 years. A total of 412 subjects were studied at 10
      years. The clinical model included age, sex, ethnicity, BMI, systolic blood
      pressure, fasting plasma glucose (FPG), HDL cholesterol, and family history of
      diabetes at baseline. Diabetes status at 5-6 and 10 years was determined by 75-g
      oral glucose tolerance test. The clinical model, 2-h glucose, and FPG were
      compared using receiver-operating characteristic (ROC) curves. RESULTS-The
      diabetes risk associated with BMI, sex, and HDL cholesterol differed by age (P
      <or= 0.011). At 5-6 years, the clinical model ROC curve area (0.896) was higher
      than that for FPG (0.776, P = 0.008), but not for 2-h glucose (0.851, P = 0.341),
      for subjects aged <or=55 years. For older subjects, the clinical model ROC curve
      area (0.599) was lower than that for 2-h glucose (0.792, P <or= 0.001), but not
      for FPG (0.627, P = 0.467). At 10 years, there were no significant differences
      between the clinical model, FPG, and 2-h glucose ROC curve areas in either age
      group. CONCLUSIONS: In Japanese Americans aged <or=55 years, a clinical model was
      better than FPG for predicting diabetes after 5-6 years but not after 10 years.
      The model was not useful in older Japanese Americans, whereas 2-h glucose was
      useful for predicting diabetes risk regardless of age.

PMID- 12610036
TI  - The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic
      acid: the SYDNEY trial.
AB  - OBJECTIVE: Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or
      improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+)
      K(+) ATPase activity in experimental diabetes and in humans and may improve
      positive neuropathic sensory symptoms, in this report we further assess the
      safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of
      positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS: Metabolically
      stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor
      polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA
      (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week
      for 14 treatments. The primary end point was change of the sum score of daily
      assessments of severity and duration of TSS. Secondary end points were sum scores
      of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction,
      quantitative sensation tests (QSTs), and an autonomic test. RESULTS: At
      randomization, the groups were not significantly different by the criteria of
      metabolic control or neuropathic end points. After 14 treatments, the TSS of the
      ALA group had improved from baseline by an average of 5.7 points and the placebo
      group by an average of 1.8 points (P < 0.001). Statistically significant
      improvement from baseline of the ALA, as compared with the placebo group, was
      also found for each item of the TSS (lancinating and burning pain, asleep
      numbness and prickling), NIS, one attribute of nerve conduction, and global
      assessment of efficacy. CONCLUSIONS: Intravenous racemic ALA, a potent
      antioxidant, rapidly and to a significant and meaningful degree, improved such
      positive neuropathic sensory symptoms as pain and several other neuropathic end
      points. This improvement of symptoms was attributed to improved nerve
      pathophysiology, not to increased nerve fiber degeneration. Because of its safety
      profile and its effect on positive neuropathic sensory symptoms and other
      neuropathic end points, this drug appears to be a useful ancillary treatment for
      the symptoms of diabetic polyneuropathy.

PMID- 12610038
TI  - Pramlintide as an adjunct to insulin therapy improves long-term glycemic and
      weight control in patients with type 2 diabetes: a 1-year randomized controlled
      trial.
AB  - OBJECTIVE: Mealtime amylin replacement with the human amylin analog pramlintide,
      as an adjunct to mealtime insulin replacement, reduces postprandial glucose
      excursions in patients with type 2 diabetes. The aim of the present study was to
      assess the long-term efficacy and safety of pramlintide in this patient
      population. RESEARCH DESIGN AND METHODS: In a 52-week, double-blind, placebo
      controlled, parallel-group, multicenter study, 656 patients with type 2 diabetes
      (age 57 +/- 10 years, diabetes duration 12 +/- 7 years, BMI 34.0 +/- 7.0 kg/m(2),
      HbA(1c) 9.1 +/- 1.2%, mean +/- SD) treated with insulin (alone or in combination
      with sulfonylureas and/or metformin) were randomized to receive additional
      preprandial subcutaneous injections of either placebo or pramlintide (60 micro g
      TID, 90 microg BID, or 120 microg BID). RESULTS: Treatment with pramlintide 120
      micro g BID led to a sustained reduction from baseline in HbA(1c) (-0.68 and 
      0.62% at weeks 26 and 52, respectively), which was significantly greater than
      that seen with placebo (P < 0.05). The proportion of patients achieving an
      HbA(1c) <8% was approximately twofold greater with pramlintide (120 microg BID)
      than with placebo (46 vs. 28%, P < 0.05). The glycemic improvement with
      pramlintide 120 micro g BID was accompanied by a mean weight loss (-1.4 kg vs.
      +0.7 kg with placebo at week 52, P < 0.05) and occurred without an overall
      increase in the severe hypoglycemia event rate. The most common adverse event
      associated with pramlintide use was transient, mild-to-moderate nausea.
      CONCLUSIONS: Mealtime amylin replacement with pramlintide 120 microg BID, as an
      adjunct to insulin therapy, improves long-term glycemic and weight control in
      patients with type 2 diabetes.

PMID- 12610037
TI  - Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of
      erectile dysfunction in men with diabetes: a multicenter double-blind placebo
      controlled fixed-dose study.
AB  - OBJECTIVE: This study evaluated the efficacy and safety of vardenafil treatment
      for erectile dysfunction (ED) in men with diabetes. RESEARCH DESIGN AND METHODS:
      In this prospective multicenter double-blind placebo-controlled fixed-dose
      parallel-group phase III trial, 452 patients with diabetes (type 1 or type 2) and
      ED were randomized to take 10 or 20 mg vardenafil or placebo as needed for 12
      weeks. Efficacy responses were assessed by International Index of Erectile
      Function domain scores, rates of vaginal penetration and successful intercourse,
      and a global assessment question (GAQ) about erection improvement during the
      previous 4 weeks. RESULTS: After 12 weeks of treatment, a dose-dependent (P =
      0.02) improvement in erections was noted for the GAQ, with 57 and 72% of men
      taking 10 mg or 20 mg vardenafil, respectively, reporting improved erections, in
      contrast to 13% after taking placebo (P < 0.0001). For the erectile function
      domain, dose-dependent (P = 0.03) final scores for the 10- and 20-mg dose were
      17.1 and 19.0 compared with 12.6 for placebo (P < 0.0001). Both vardenafil doses
      significantly enhanced the rates of successful penetration (P < 0.0001) and
      successful intercourse (P < 0.0001) compared with placebo. Vardenafil treatment
      was effective in increasing intercourse success rates at all levels of baseline
      ED severity, at each level of plasma HbA(1c), and for type 1 and 2 diabetes.
      Treatment-emergent adverse events were primarily mild to moderate headache
      (<or=13%), flushing (<or=10%), and rhinitis (<or=10%). CONCLUSIONS: Vardenafil
      statistically improved erectile function and was generally well tolerated in
      these diabetic patients with ED.

PMID- 12610039
TI  - Differential effects of acute and extended infusions of glucagon-like peptide-1
      on first- and second-phase insulin secretion in diabetic and nondiabetic humans.
AB  - OBJECTIVE: The purpose of this study was to determine whether an extended
      infusion of the incretin hormone glucagon-like peptide 1 (GLP-1) has a greater
      effect to promote insulin secretion in type 2 diabetic subjects than acute
      administration of the peptide. RESEARCH DESIGN AND METHODS: Nine diabetic
      subjects and nine nondiabetic volunteers of similar age and weight were studied
      in identical protocols. First-phase insulin release (FPIR; the incremental
      insulin response in the first 10 min after the intravenous glucose bolus) and
      second-phase insulin release (SPIR; the incremental insulin response from 10-60
      min after intravenous glucose) were measured during three separate intravenous
      glucose tolerance tests (IVGTTs): 1). without GLP-1 (control); 2). with acute
      administration of GLP-1 as a square wave starting just before glucose
      administration; and 3). with an extended infusion of GLP-1 for 3 h before and
      during the IVGTT. RESULTS: In the subjects with diabetes, FPIR was severely
      impaired-a defect that was only modestly improved by acute administration of GLP
      1 (197 +/- 97 vs. 539 +/- 218 pmol/l. min, P < 0.05), while SPIR was
      substantially increased (1952 +/- 512 vs. 8072 +/- 1664 pmol/l. min, P < 0.05).
      In contrast, the 3-h preinfusion of GLP-1 normalized fasting hyperglycemia (7.9
      +/- 0.5 vs. 5.2 +/- 0.6, P < 0.05), increased FPIR by 5- to 6-fold (197 +/- 97
      vs. 1141 +/- 409 pmol/l. min, P < 0.05), and augmented SPIR significantly (1952
      +/- 512 vs. 4026 +/- 851 pmol/l. min, P < 0.05), but to a lesser degree than the
      acute administration of GLP-1. In addition, only the 3-h GLP-1 preinfusion
      significantly improved intravenous glucose tolerance (K(g) control 0.61 +/- 0.04,
      acute infusion 0.71 +/- 0.04, P = NS; 3-h infusion 0.92 +/- 0.08%/min, P < 0.05).
      These findings were also noted in the nondiabetic subjects in whom acute
      administration of GLP-1 significantly increased SPIR relative to the control
      IVGTT (9439 +/- 2885 vs. 31553 +/- 11660 pmol/l. min, P < 0.001) with less effect
      on FPIR (3221 +/- 918 vs. 4917 +/- 1614 pmol/l. min, P = 0.075), while the 3-h
      preinfusion of GLP-1 significantly increased both FPIR (3221 +/- 918 vs. 7948 +/-
      2647 pmol/l. min, P < 0.01) and SPIR (9439 +/- 2885 vs. 21997 +/- 9849 pmol/l.
      min, P < 0.03). CONCLUSIONS: Extended administration of GLP-1 not only augments
      glucose-stimulated insulin secretion, but also shifts the dynamics of the insulin
      response to earlier release in both diabetic and nondiabetic humans. The
      restitution of some FPIR in subjects with type 2 diabetes is associated with
      significantly improved glucose tolerance. These findings demonstrate the benefits
      of a 3-h infusion of GLP-1 on beta-cell function beyond those of an acute insulin
      secretagogue, and support the development of strategies using continuous or
      prolonged GLP-1 receptor agonism for treating diabetic patients.

PMID- 12610041
TI  - Insulin sensitivity and the risk of incident hypertension: insights from the
      Insulin Resistance Atherosclerosis Study.
AB  - OBJECTIVE: The insulin resistance syndrome has been described as including
      hypertension. Previous studies have documented cross-sectional associations
      between insulin sensitivity (S(I)) and blood pressure or prevalent hypertension.
      Prospective data have been sparse. RESEARCH DESIGN AND METHODS: The Insulin
      Resistance Atherosclerosis Study (IRAS) is a prospective study of the
      associations of S(I) with atherosclerosis and other risk factors for
      cardiovascular disease. We examined the association between S(I), measured using
      the frequently sampled intravenous glucose tolerance test with minimal model
      analysis, and incident hypertension (defined as per the Joint National
      Committee), at the 5-year examination in 840 IRAS participants who were free of
      hypertension at the baseline examination. RESULTS: Adjusted for age, sex,
      ethnicity, and smoking status, for each unit greater S(I), the risk of
      hypertension was 10% lower (95% CI 2-19, P < 0.05). CONCLUSIONS: These findings,
      from a prospective study, support the presence of a modest protective association
      between greater S(I) and lower risk of hypertension. These findings support the
      contention that interventions that improve S(I) may be beneficial with respect to
      the development of hypertension and cardiovascular disease. This contention
      should be tested in randomized clinical trials.

PMID- 12610040
TI  - Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus
      regular human insulin in adolescents with type 1 diabetes on intensive insulin
      regimens.
AB  - OBJECTIVE: To compare blood glucose control and incidence of nocturnal
      hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens
      managed with either an insulin analog combination or NPH insulin plus regular
      human insulin. RESEARCH DESIGN AND METHODS: In a randomized cross-over study, 28
      adolescents with type 1 diabetes on multiple injection therapy received either
      insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin
      prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week
      treatment arm, subjects completed home blood glucose profiles, and at the end of
      each treatment arm, they were admitted for an overnight metabolic profile. A
      total of 25 subjects completed the study. RESULTS: Compared with R/NPH therapy,
      LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus
      R/NPH): fasting (8.0 vs. 9.2 mmol/l, P < 0.0001), 2 h postbreakfast (8.1 vs. 10.7
      mmol/l, P < 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P < 0.01), and 2 h postlunch
      (8.0 vs. 9.5 mmol/l, P < 0.002). However, there was no difference in mean blood
      glucose levels before or after the evening meal. Incidence of nocturnal
      hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH
      therapy; however, there was no difference in rates of self-reported symptomatic
      hypoglycemia. Total insulin dose required to achieve target blood glucose control
      was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P <
      0.005), but there was no significant difference in HbA(1c) levels (LIS/GLAR
      versus R/NPH: 8.7 vs. 9.1%, P = 0.13). CONCLUSIONS: Combination therapy with
      insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and
      was at least as effective as R/NPH insulin therapy in maintaining glycemic
      control in adolescents on multiple injection regimens.

PMID- 12610042
TI  - Serum lipoproteins in the diabetes control and complications trial/epidemiology
      of diabetes intervention and complications cohort: associations with gender and
      glycemia.
AB  - OBJECTIVE: To relate the nuclear magnetic resonance (NMR)-determined lipoprotein
      profile, conventional lipid and apolipoprotein measures, and in vitro
      oxidizibility of LDL with gender and glycemia in type 1 diabetes. RESEARCH DESIGN
      AND METHODS: In the 1997-1999 Diabetes Control and Complications
      Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort,
      serum from 428 women and 540 men were characterized by conventional lipids, NMR,
      apolipoprotein levels, and LDL susceptibility to in vitro oxidation. Simple and
      partial correlation coefficients were calculated for each lipoprotein-related
      parameter versus gender, with and without covariates (age, diabetes duration,
      concurrent HbA(1c), DCCT randomization, hypertension, BMI, waist-to-hip ratio,
      and albuminuria). For concurrent HbA(1c), data were analyzed as above, exchanging
      gender for HbA(1c). Associations were significant if P < 0.05. RESULTS: Although
      men and women had similar total and LDL cholesterol and triglycerides, men
      exhibited the following significant percent differences in NMR profiles versus
      women: small VLDL 41; IDL -30; medium LDL 39; small LDL 21; large HDL -32; small
      HDL 35; LDL particle concentration 4; VLDL and HDL diameters -8 and -4,
      respectively. Small VLDL, small HDL, medium LDL (women only), small LDL (men
      only), and LDL particle concentration were positively correlated, and HDL size
      was inversely correlated, with concurrent HbA(1c). NMR profile was unrelated to
      prior DCCT randomization. Susceptibility of LDL to oxidation was unrelated to
      gender and glycemia. CONCLUSIONS: Male gender and poor glycemia are associated
      with a potentially more atherogenic NMR lipoprotein profile. Neither gender nor
      glycemia influence LDL oxidation in vitro.

PMID- 12610043
TI  - First-trimester C-reactive protein and subsequent gestational diabetes.
AB  - OBJECTIVE: Systemic inflammation is associated with the development of type 2
      diabetes. We tested the hypothesis that increased inflammation, measured early in
      pregnancy, is associated with the subsequent development of gestational diabetes
      mellitus (GDM), a precursor of type 2 diabetes. RESEARCH DESIGN AND METHODS: We
      conducted a prospective nested case-control study in a pregnancy cohort. First
      trimester C-reactive protein (CRP) levels were measured using a high-resolution
      assay in 43 women who subsequently developed GDM and in a random sample of 94
      women who remained euglycemic throughout pregnancy. Median CRP levels were
      compared using Wilcoxon's rank-sum test. Logistic regression was used to compute
      unadjusted and multivariable-adjusted odds ratios for developing GDM among CRP
      tertiles. RESULTS: First-trimester CRP levels were significantly increased among
      women who subsequently developed GDM compared with control subjects (3.1 vs. 2.1
      mg/l, P < 0.01). The risk of developing GDM among women in the highest CRP
      tertile compared with the lowest tertile was 3.2 (95% CI 1.2-8.8). After
      adjusting for age, race/ethnicity, smoking, parity, blood pressure, and
      gestational age at CRP sampling, the risk of developing GDM among women in the
      highest compared with the lowest tertile was 3.6 (95% CI 1.2-11.4). When BMI was
      included in the model, however, the association between increased CRP and GDM was
      attenuated (odds ratio for the highest compared with lowest tertile 1.5 [95% CI
      0.4-5.5]). CONCLUSIONS: In women who develop GDM, there is evidence of increased
      inflammation during the first trimester. This association is mediated in part by
      increased BMI. Larger studies are needed to verify these results.

PMID- 12610044
TI  - Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene
      and the response rate to therapy with pioglitazone in patients with type 2
      diabetes.
AB  - OBJECTIVE: To investigate the influence of peroxisome proliferator-activated
      receptor-gamma (PPAR-gamma) gene variants on the response rate to therapy with
      the thiazolidinedione (TZD) pioglitazone, because in vitro studies have suggested
      that genetic variants of the PPAR-gamma gene may influence the drug efficacy of
      TZD. RESEARCH DESIGN AND METHODS: A total of 131 patients were treated in an open
      label, randomized, multicenter study with pioglitazone (45 mg o.d.) during a
      course of >or=26 weeks. Response to the pioglitazone therapy was defined by
      either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA(1c)
      values after 26 weeks of pioglitazone treatment. We evaluated the association
      between the PPAR-gamma genotype and the response rate to pioglitazone treatment.
      RESULTS: The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not
      associated with the response rate to pioglitazone treatment in patients with type
      2 diabetes. However, we identified initial fasting plasma glucose level >11.0
      mmol/l, HbA(1c) value >9.0%, BMI >32 kg/m(2), and fasting C-peptide
      concentrations at baseline >2.5 pmol/l as predominant confounding factors for the
      responder frequency to pioglitazone treatment. CONCLUSIONS: The Pro12Ala variant
      in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone,
      suggesting that the drug-treatment response is independent from pharmacogenetic
      effects between PPAR-gamma and its ligand pioglitazone. Whether the Ala12Ala
      genotype plays a role in the response rate to TZD therapy remains to be
      determined.

PMID- 12610045
TI  - Beta-cell function and the development of diabetes-related complications in the
      diabetes control and complications trial.
AB  - In patients with type 1 diabetes, measurement of connecting peptide (C-peptide),
      cosecreted with insulin from the islets of Langerhans, permits estimation of
      remaining beta-cell secretion of insulin. In this retrospective analysis to
      distinguish the incremental benefits of residual beta-cell activity in type 1
      diabetes, stimulated (90 min following ingestion of a mixed meal) C-peptide
      levels at entry in the Diabetes Control and Complications Trial (DCCT) were
      related to measures of diabetic retinopathy and nephropathy and to incidents of
      severe hypoglycemia. Based on the analytical sensitivity of the assay (0.03
      nmol/l) and study entry criteria, the DCCT subjects were divided into four groups
      of stimulated C-peptide responses: <or=0.03, 0.04-0.20, 0.21-0.50 nmol/l at
      entry, and 0.21-0.50 nmol/l at entry and at least 1 year later (sustained C
      peptide secretion). Uniformly in the intensive and partially in the conventional
      DCCT treatment groups, any C-peptide secretion, but especially at higher and
      sustained levels of stimulated C-peptide, was associated with reduced incidences
      of retinopathy (both a single three-step change and a repeated three-step change
      on the Early Treatment of Diabetic Retinopathy Study [ETDRS] scale at the next 6
      month visit) and nephropathy (both albuminuria >40 mg/24 h once and repeated at
      the next annual visit). There were also differences in severe hypoglycemia across
      C-peptide levels in both treatment groups. In the intensively treated cohort
      there were essentially identical prevalences of severe hypoglycemia (
      approximately 65% of participants) in the first three groups; however, those
      subjects with mixed-meal stimulated C-peptide level >0.20 nmol/l for at least
      baseline and the first annual visit in the DCCT experienced a reduced prevalence
      of approximately 30%. Therefore, even modest levels of beta-cell activity at
      entry in the DCCT were associated with reduced incidences of retinopathy and
      nephropathy. Also, continuing C-peptide (insulin) secretion is important in
      avoiding hypoglycemia (the major complication of intensive diabetic therapy).

PMID- 12610046
TI  - Effect of glucagon-like peptide 1 (7-36 amide) on insulin-mediated glucose uptake
      in patients with type 1 diabetes.
AB  - OBJECTIVE: To examine the insulinomimetic insulin-independent effects of glucagon
      like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients. RESEARCH
      DESIGN AND METHODS: We used the hyperinsulinemic-euglycemic clamp (480 pmol. m(
      2) x min(-1)) in paired randomized studies of six women and five men with type 1
      diabetes. In the course of one of the paired studies, the subjects also received
      GLP-1 at a dose of 1.5 pmol. kg(-1) x min(-1). The patients were 41 +/- 3 years
      old with a BMI of 25 +/- 1 kg/m(2). The mean duration of diabetes was 23 +/- 3
      years. RESULTS: Plasma glucose was allowed to fall from a fasting level of
      approximately 11 mmol/l to 5.3 mmol/l in each study and thereafter was held
      stable at that level. Plasma insulin levels during both studies were
      approximately 900 pmol/l. Plasma C-peptide levels did not change during the
      studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the
      fasting level of 31 +/- 3 to 150 +/- 17 pmol/l. Plasma glucagon levels fell from
      the fasting levels of approximately 14 pmol/l to 9 pmol/l during both paired
      studies. Hepatic glucose production was suppressed during the glucose clamps in
      all studies. Glucose uptake was not different between the two studies (
      approximately 40 micromol. kg(-1) x min(-1)). CONCLUSIONS: GLP-1 does not augment
      insulin-mediated glucose uptake in lean type 1 diabetic patients.

PMID- 12610047
TI  - Association of the CTLA-4 gene 49 A/G polymorphism with type 1 diabetes and
      autoimmune thyroid disease in Japanese children.
AB  - OBJECTIVE: To clarify the role of the T-lymphocyte-associated-4 (CTLA-4)
      polymorphism in the susceptibility to child-onset type 1 diabetes with regard to
      its clinical characteristics and complications with autoimmune thyroid disease
      (AITD) in the Japanese population. RESEARCH DESIGN AND METHODS: The CTLA-4 49 A/G
      polymorphism was detected by the PCR-restriction fragment-length polymorphism
      (RFLP) method in 97 type 1 diabetic subjects and 20 patients with Graves'
      disease, a cohort which included 4 patients who also had type 1 diabetes.
      RESULTS: The genotypes and allele frequencies of this polymorphism did not differ
      between the type 1 diabetic subjects and the control subjects. The G allele
      frequency was 63.9% in the type 1 diabetic subjects. The G allele frequency in
      the subgroup of patients with a high titer of autoantibodies to the GAD antibody
      (Ab) was 72.9% (P = 0.0499 vs. control subjects); in the subgroup of patients
      without HLA DRB1*0405, it was 72.6% (P = 0.0271 vs. control subjects); and in the
      subgroup of patients with a residual beta-cell function, it was 78.6% (P = 0.0391
      vs. control subjects). The G allele frequency in the patients with Graves'
      disease was also significantly higher at 78.1% (P = 0.0405 vs. control subjects).
      Furthermore, the frequency in our diabetic subjects complicated with Graves'
      disease was even higher (87.5%). CONCLUSIONS: We have demonstrated that a
      distinct association exists between the G allele of CTLA-4 and high values of GAD
      Ab, residual beta-cell function, and the absence of HLA-DRB1*0405.

PMID- 12610048
TI  - Impact of incident diabetes and incident nonfatal cardiovascular disease on 18
      year mortality: the multiple risk factor intervention trial experience.
AB  - OBJECTIVE: To report long-term risks for total, cardiovascular disease (CVD), and
      coronary heart disease (CHD) mortality associated with incident diabetes (using
      current diagnostic criteria) and with incident nonfatal CVD (NF-CVD). RESEARCH
      DESIGN AND METHODS: A total of 11645 participants without diabetes or CVD at
      baseline from the Multiple Risk Factor Intervention Trial who survived to the end
      of the trial were grouped by during-trial incident diabetes and/or NF-CVD events:
      neither diabetes nor NF-CVD, diabetes only, NF-CVD only, or both diabetes and NF
      CVD. Incident diabetes was defined by use of hypoglycemic agents or fasting
      glucose >or=126 mg/dl at any time over the 6 trial years. Proportional hazards
      models tested group differences in mortality over 18 post-trial years. RESULTS:
      Among 3859 total deaths were 1846 from CVD and 1277 from CHD, with death rates
      per 10000 person-years of 203, 97, and 67, respectively. Multivariate-adjusted
      hazard ratios (HRs) for total mortality were 2.75 (P < 0.0001) for those with NF
      CVD and diabetes both, 1.92 (P < 0.0001) for those with NF-CVD only, and 1.49 (P
      < 0.0001) for those with diabetes only, relative to neither diabetes nor NF-CVD.
      NF-CVD was associated with a higher hazard of death than diabetes for total (HR
      1.29, P = 0.0004), CVD (HR 1.76, P < 0.0001), and CHD (HR 1.88, P < 0.0001)
      mortality. Only the subgroup of participants on hypoglycemic agents showed an
      equivalent risk of total mortality relative to participants with NF-CVD (HR 0.93,
      P = 0.54). CONCLUSIONS: Current diabetes diagnostic criteria conferred
      significantly increased total, CVD, and CHD mortality risks independent of the
      impact of NF-CVD. NF-CVD was more strongly predictive of mortality.

PMID- 12610049
TI  - Development of congestive heart failure in type 2 diabetic patients with
      microalbuminuria or proteinuria: observations from the DIABHYCAR (type 2
      DIABetes, Hypertension, CArdiovascular Events and Ramipril) study.
AB  - OBJECTIVE: The DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events
      and Ramipril) study allowed investigators to analyze factors leading to the
      development of congestive heart failure (CHF) in type 2 diabetic patients with
      abnormal urinary albumin concentration. RESEARCH DESIGN AND METHODS: Type 2
      diabetic subjects of both sexes aged >or=50 years who had a urinary albumin
      concentration >or=20 mg/l were randomly allocated to 1.25 mg/day ramipril or
      placebo in addition to their usual treatment and treated for 3-6 years in a
      double-blind fashion. Major outcomes including hospitalization for CHF were
      recorded during the follow-up. RESULTS: Of the 4912 included patients, 187
      developed CHF during the study. There was no significant difference in the
      incidence of CHF between the two treatment groups. Using a multivariate analysis,
      independent risk factors for the occurrence of CHF were age, history of
      cardiovascular disease, baseline urinary albumin concentration, baseline HbA(1c),
      and smoking habits. A total of 68 of the 187 patients (36.4%) died during the 12
      +/- 11-month period after the first hospitalization for CHF, whereas the annual
      mortality rate of the population who did not develop CHF was 3.2%. CONCLUSIONS:
      Presence of atherosclerotic disease, baseline urinary albumin concentration, and
      HbA(1c) level were indicators for further development of CHF. Occurrence of CHF
      is a major prognostic turn in a diabetic patient's life.

PMID- 12610050
TI  - Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular
      disease in nondiabetic american indians: the Strong Heart Study.
AB  - OBJECTIVE: Insulin resistance (IR) and the metabolic syndrome (MS) are associated
      with type 2 diabetes and adverse cardiovascular disease (CVD) risk factor
      profiles. Whether IR and MS predict CVD independently of diabetes and other CVD
      risk factors is not known. This study examines whether IR and/or presence of MS
      are independently associated with CVD in nondiabetic American Indians (AI).
      RESEARCH DESIGN AND METHODS: We examined 2283 nondiabetic AI who were free of CVD
      at the baseline examination of the Strong Heart Study (SHS). CVD risk factors
      were measured, IR was quantified using the homeostasis model assessment (HOMA),
      and MS as defined by the National Cholesterol Education Program Adult Treatment
      Panel (ATP III) was assessed for each participant. Incident CVD and diabetes were
      ascertained during follow-up. RESULTS: MS was present in 798 individuals (35%),
      and 181 participants (7.9%) developed CVD over 7.6 +/- 1.8 years of follow-up.
      Age, BMI, waist circumference, and triglyceride levels increased and HDL
      cholesterol decreased across tertiles of HOMA-IR. Risk of diabetes increased as a
      function of baseline HOMA-IR (6.3, 14.6, and 30.1%; P < 0.001) and MS (12.8 vs.
      24.5%). In Cox models adjusted for CVD risk factors, risk of CVD did not increase
      either as a function of baseline HOMA-IR or MS, but individual CVD risk factors
      predicted subsequent CVD. CONCLUSIONS: Among nondiabetic AI in the SHS, HOMA-IR
      and MS both predict diabetes, but neither predicts CVD independently of other
      established CVD risk factors.

PMID- 12610051
TI  - Insulin secretion and insulin sensitivity pattern is different in isolated
      impaired glucose tolerance and impaired fasting glucose: the risk factor in
      Impaired Glucose Tolerance for Atherosclerosis and Diabetes study.
AB  - OBJECTIVE: Isolated impaired fasting glucose (IFG) and impaired glucose tolerance
      (IGT) are two risk categories for type 2 diabetes. This study compared both
      categories with respect to the degree of insulin secretion abnormalities and
      insulin resistance. RESEARCH DESIGN AND METHODS: This is a crossover comparison
      of a population at high risk for type 2 diabetes. The subjects were recruited
      from the Risk Factor in Impaired Glucose Tolerance for Atherosclerosis and
      Diabetes (RIAD) study. They underwent a 75-g oral glucose tolerance test, with
      measurement of specific insulin, C-peptide, proinsulin, and free fatty acids at
      baseline and every 30 min after load for 2 h. Factor analysis was performed to
      evaluate the importance of insulin resistance and secretion abnormalities in both
      categories. RESULTS: All categories of prediabetic hyperglycemia had a higher
      cardiovascular risk factor level when adjusted for sex, age, and BMI compared to
      control subjects with normal glucose tolerance. Subjects with isolated IFG were
      more insulin resistant than those with IGT. By contrast, subjects with isolated
      IGT exhibited a more severe deficit in early- and late-phase insulin secretion
      versus IFG subjects. As shown with factor analysis, in IFG the insulin resistance
      factor explained 28.4% of the variance, whereas in IGT the insulin secretion
      factor was dominant, explaining 31.1% of the total variance. CONCLUSIONS: Our
      cross-sectional data from the RIAD study demonstrate that isolated IFG and
      isolated IGT are different with respect to the degree of insulin resistance and
      anomalies in insulin secretion, and that subjects with IGT exhibit a deficit in
      the early and late phases of insulin secretion. This finding may be important for
      a differential approach in primary prevention of type 2 diabetes.

PMID- 12610053
TI  - Contributions of fasting and postprandial plasma glucose increments to the
      overall diurnal hyperglycemia of type 2 diabetic patients: variations with
      increasing levels of HbA(1c).
AB  - OBJECTIVE: The exact contributions of postprandial and fasting glucose increments
      to overall hyperglycemia remain controversial. The discrepancies between the data
      published previously might be caused by the interference of several factors. To
      test the effect of overall glycemic control itself, we analyzed the diurnal
      glycemic profiles of type 2 diabetic patients investigated at different levels of
      HbA(1c). RESEARCH DESIGN AND METHODS: In 290 non-insulin- and non-acarbose-using
      patients with type 2 diabetes, plasma glucose (PG) concentrations were determined
      at fasting (8:00 A.M.) and during postprandial and postabsorptive periods (at
      11:00 A.M., 2:00 P.M., and 5:00 P.M.). The areas under the curve above fasting PG
      concentrations (AUC(1)) and >6.1 mmol/l (AUC(2)) were calculated for further
      evaluation of the relative contributions of postprandial (AUC(1)/AUC(2), %) and
      fasting [(AUC(2) - AUC(1))/AUC(2), %] PG increments to the overall diurnal
      hyperglycemia. The data were compared over quintiles of HbA(1c). RESULTS: The
      relative contribution of postprandial glucose decreased progressively from the
      lowest (69.7%) to the highest quintile of HbA(1c) (30.5%, P < 0.001), whereas the
      relative contribution of fasting glucose increased gradually with increasing
      levels of HbA(1c): 30.3% in the lowest vs. 69.5% in the highest quintile (P <
      0.001). CONCLUSIONS: The relative contribution of postprandial glucose excursions
      is predominant in fairly controlled patients, whereas the contribution of fasting
      hyperglycemia increases gradually with diabetes worsening. These results could
      therefore provide a unifying explanation for the discrepancies as observed in
      previous studies.

PMID- 12610052
TI  - Soluble tumor necrosis factor-alpha receptors in young obese subjects with normal
      and impaired glucose tolerance.
AB  - OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is a possible link between
      obesity and impaired glucose tolerance (IGT) and type 2 diabetes. Data about TNF
      alpha and soluble forms of its receptors (sTNFR1 and sTNFR2) in IGT are
      controversial. The aim of the present study was to assess plasma TNF-alpha,
      sTNFR1, and sTNFR2 levels and to evaluate the relationships with insulin
      resistance in obese subjects with IGT. RESEARCH DESIGN AND METHODS: A total of
      104 subjects participated in the present study: 30 obese subjects with IGT (obese
      IGT), 32 obese subjects with normal glucose tolerance (obese-NGT), and 42 lean
      healthy control subjects (control-NGT). Anthropometry and blood biochemical
      parameters were measured and euglycemic-hyperinsulinemic clamp was performed.
      RESULTS: Obese-IGT subjects were more insulin resistant in comparison with obese
      NGT and control-NGT groups; obese-NGT subjects were more insulin resistant than
      control-NGT. Plasma sTNFR1 and sTNFR2 were markedly higher in both groups of
      obese subjects in comparison with control-NGT and in the obese-IGT versus obese
      NGT group. Plasma sTNFR1 and sTNFR2 were inversely related to insulin
      sensitivity. Both relationships remained significant after adjustment for age,
      BMI, waist girth, percent body fat, plasma glucose, insulin, nonesterified fatty
      acids, cholesterol, and triglycerides. Correlation between sTNFR2 and insulin
      sensitivity was also present in all the groups analyzed separately, but the
      correlation between sTNFR1 and insulin sensitivity was present only in the obese
      NGT group. CONCLUSIONS: Our data suggest that TNF-alpha receptors are increased
      in obese-IGT subjects and are related to insulin resistance. These findings
      indicate that the TNF-alpha system might contribute to the development of insulin
      resistance in glucose-intolerant subjects.

PMID- 12610054
TI  - Safety and efficacy of repaglinide in type 2 diabetic patients with and without
      impaired renal function.
AB  - OBJECTIVE: To evaluate the influence of renal impairment on the safety and
      efficacy of repaglinide in type 2 diabetic patients. RESEARCH DESIGN AND METHODS:
      This multinational, open-label study comprised a 6-week run-in period, continuing
      prestudy antidiabetic medication, followed by a titration period (1-4 weeks) and
      a 3-month maintenance period. Patients with normal renal function (n = 151) and
      various degrees of renal impairment (n = 130) were treated with repaglinide
      (maximal dose of 4 mg, three times daily). Safety and efficacy assessments were
      performed at baseline (end of run-in) and at the end of study treatment. RESULTS:
      The type and severity of adverse events during repaglinide treatment were similar
      to the run-in period. The number of patients with adverse events was not
      significantly related to renal function during run-in or repaglinide treatment.
      Percentage of patients with hypoglycemic episodes increased significantly (P =
      0.007) with increasing severity of renal impairment during run-in but not during
      repaglinide treatment (P = 0.074). Metabolic control (HbA(1c) and fasting blood
      glucose) with repaglinide was unchanged from that on previous antidiabetic
      medication. Final repaglinide dose tended to be lower for patients with severe
      and extreme renal impairment than for patients with less severe renal impairment
      or normal renal function (P = 0.032). CONCLUSIONS: Repaglinide has a good safety
      and efficacy profile in type 2 diabetic patients complicated by renal impairment
      and is an appropriate treatment choice, even for individuals with more severe
      degrees of renal impairment.

PMID- 12610055
TI  - RANTES promoter genotype is associated with diabetic nephropathy in type 2
      diabetic subjects.
AB  - OBJECTIVE: To evaluate the effect of RANTES gene promoter polymorphism and RANTES
      receptor (CCR5 gene) promoter polymorphism on diabetic nephropathy in Japanese
      type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: A total 616 Japanese
      subjects with type 2 diabetes were recruited. Polymorphisms of -28 C/G and -403
      G/A in the RANTES gene promoter region, and of 59029 G/A in the CCR5 gene
      promoter region were detected by PCR-RFLP (restriction fragment length
      polymorphism). The association of these genotypes with nephropathy was analyzed.
      RESULTS: While the RANTES -403 genotype showed no association with nephropathy,
      the frequency of the -28G allele was significantly higher in the DN2 group
      (urinary albuminuria-to-creatinine ratio [ACR] >or=300 mg/g creatinine, serum
      creatinine <2.0 mg/dl) than in the DN0 (ACR <30 mg/g creatinine) and DN1 (ACR
      >or=30 mg/g creatinine and <300 mg/g creatinine) groups. The frequency of a
      RANTES -28G-positive genotype (C/G or G/G) was higher in the DN2 group than in
      the DN0 and DN1 groups (34% vs. 25 and 20%, P = 0.0268, chi(2) = 4.905), and the
      frequency of a CCR5 59029 A-positive genotype (G/A or A/A) was higher in the DN1
      and DN2 groups than in the DN0 group (84 and 85% vs. 76%, P = 0.0123, chi(2) =
      6.269). Discriminant analysis showed that the RANTES -28G-positive genotype and
      CCR5 59029A-positive genotype were independently associated with nephropathy. The
      percentage of macroalbuminuria was twofold higher in the subjects having -28G or
      59029A and threefold higher in the subjects having -28G and 59029A than in the
      subjects without -28G and 59029A. CONCLUSIONS: The RANTES promoter -28G genotype
      and CCR5 promoter 59029A genotype may be independent risk factors for diabetic
      nephropathy in patients with type 2 diabetes and may have an additive effect on
      nephropathy.

PMID- 12610056
TI  - Type 2 diabetic individuals have impaired leg blood flow responses to exercise:
      role of endothelium-dependent vasodilation.
AB  - OBJECTIVE: Diabetic individuals have impaired endothelium-dependent forearm
      vasodilatory responses to ischemia, acetylcholine, and other endothelium
      dependent agonists. The functional significance of impaired endothelium-dependent
      dilation in diabetic individuals is uncertain but is most likely to be manifest
      during leg muscle exercise and may have relevance to peripheral vascular disease
      and leg ischemia, which is prevalent in diabetic individuals. The current study
      aimed to determine the relationship between leg blood flow (LBF) responses to
      endothelium-dependent vasodilation and dynamic large muscle exercise. RESEARCH
      DESIGN AND METHODS: LBF responses (thermodilution) to intrafemoral arterial
      infusions of an endothelium-dependent (acetylcholine) and endothelium-independent
      (sodium nitroprusside) vasodilator and a standardized 25-min cycling bout at 60%
      VO(2peak) were compared in nine male type 2 diabetic subjects and nine age-, sex
      , VO(2peak)-, and weight-matched control subjects. RESULTS: LBF responses to
      acetylcholine and exercise but not sodium nitroprusside were significantly (P <
      0.05) attenuated in patients with diabetes compared with healthy control
      subjects. The percentage increase in LBF in response to exercise and
      acetylcholine were significantly correlated (r = 0.54, P = 0.02). Furthermore,
      resting plasma glucose was significantly related to the LBF response to exercise
      (r = -0.66, P = 0.003) independently of insulin, HbA(1c), lipids, BMI, and blood
      pressure. CONCLUSIONS: The increase in LBF during exercise is substantially
      attenuated in type 2 diabetic compared with matched control subjects. Impaired
      endothelium-dependent vasodilation secondary to elevated plasma glucose may
      underlie this observation. This mechanism may be of importance in determining the
      leg ischemic threshold in diabetic individuals with peripheral vascular disease.

PMID- 12610057
TI  - Value of coronary artery calcium scanning by computed tomography for predicting
      coronary heart disease in diabetic subjects.
AB  - OBJECTIVE: The South Bay Heart Watch is a cohort study designed to determine the
      significance of coronary calcium in high-risk asymptomatic patients. This is a
      report of the relative risk (RR) for outcomes of coronary artery calcium in
      diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS: A total of 1312
      diabetic and nondiabetic subjects underwent risk factor screening and computed
      tomography testing for coronary calcium at baseline and were followed clinically
      for 6.3 +/- 1.4 years. End points were either 1). hard events of nonfatal
      myocardial infarction (MI) or coronary death or 2). any cardiovascular event
      (nonfatal MI, coronary death, coronary revascularization, or stroke). RESULTS:
      The incidence rates of a hard event and any cardiovascular event for diabetic and
      nondiabetic subjects were 14.5 and 6.1% and 23.8 and 12.2%, respectively (P <
      0.001). Cox regression analyses of the combined risk relationship of diabetes
      status and calcium score demonstrated that relative to nondiabetic subjects with
      low calcium scores (<2.8), diabetic subjects with calcium scores >or=2.8
      exhibited at least a fourfold increase in the risk of either a hard or any
      cardiovascular event (P < 0.001). Cox regression analyses conducted separately
      for nondiabetic and diabetic subjects revealed that coronary calcium score risk
      groups were significantly associated with events in nondiabetic subjects (RR >or=
      2.6, P <or= 0.01), but not in diabetic subjects (RR <or= 1.7, P > 0.05).
      CONCLUSIONS: The risk of coronary heart disease increases with increasing calcium
      scores and diabetes status. Calcium scores have less prognostic value in diabetic
      subjects.

PMID- 12610058
TI  - Smoking and progression of diabetic nephropathy in type 1 diabetes.
AB  - OBJECTIVE: Cigarette smoking contributes to development of diabetic nephropathy.
      However, long-term studies on the effect of smoking on decline in kidney function
      in diabetic nephropathy are lacking. We assessed the impact of smoking on
      progression of diabetic nephropathy in type 1 diabetic patients enrolled in a
      prospective observational cohort study started in 1983. RESEARCH DESIGN AND
      METHODS: We identified all albuminuric type 1 diabetic patients (n = 301)
      followed for at least 3 years, median (range) 7 years (3-14), who underwent at
      least yearly measurement of glomerular filtration rate (GFR) by the (51)Cr-EDTA
      plasma clearance technique (n = 8, range 3-24). In total, 192 men and 109 women
      were included (age [mean +/- SD] 36 +/- 11 years, duration of diabetes 22 +/- 8
      years); 271 patients were treated with antihypertensive drugs, predominantly ACE
      inhibitors in 179 patients. Patients were classified as smokers if they smoked
      more than one cigarette per day during a portion of or the entire observation
      period. Blood pressure, albuminuria, HbA(1c), and serum cholesterol were measured
      every 3-4 months during the study. RESULTS: In all 301 patients, the mean (SE)
      rate of decline in GFR (deltaGFR) was 4.0 (0.2) mlx min(-1) x year(-1) during the
      investigation period. No difference in Delta GFR was demonstrated between
      nonsmokers (n = 94), deltaGFR 4.5 (0.4), ex-smokers (n = 31), deltaGFR 3.1 (0.7),
      and smokers (n = 176), deltaGFR 3.9 (0.3) ml x min(-1) x year(-1), respectively
      (NS). Adjustment for other risk factors for progression of diabetic nephropathy
      did not alter the results: smoking was not associated with deltaGFR, whereas
      blood pressure, albuminuria, HbA(1c), and serum cholesterol were demonstrated to
      be independent progression promoters. CONCLUSIONS: In our study, smoking was not
      associated with decline in kidney function in type 1 diabetic patients with
      diabetic nephropathy.

PMID- 12610059
TI  - Economic costs of diabetes in the US in 2002.
AB  - OBJECTIVE: Diabetes is the fifth leading cause of death by disease in the U.S.
      Diabetes also contributes to higher rates of morbidity-people with diabetes are
      at higher risk for heart disease, blindness, kidney failure, extremity
      amputations, and other chronic conditions. The objectives of this study were 1).
      to estimate the direct medical and indirect productivity-related costs
      attributable to diabetes and 2). to calculate and compare the total and per
      capita medical expenditures for people with and without diabetes. RESEARCH DESIGN
      AND METHODS: Medical expenditures were estimated for the U.S. population with and
      without diabetes in 2002 by sex, age, race/ethnicity, type of medical condition,
      and health care setting. Health care use and total health care expenditures
      attributable to diabetes were estimated using etiological fractions, calculated
      based on national health care survey data. The value of lost productivity
      attributable to diabetes was also estimated based on estimates of lost workdays,
      restricted activity days, prevalence of permanent disability, and mortality
      attributable to diabetes. RESULTS-Direct medical and indirect expenditures
      attributable to diabetes in 2002 were estimated at 132 billion US dollars. Direct
      medical expenditures alone totaled 91.8 billion US dollars and comprised 23.2
      billion US dollars for diabetes care, 24.6 billion US dollars for chronic
      complications attributable to diabetes, and 44.1 billion US dollars for excess
      prevalence of general medical conditions. Inpatient days (43.9%), nursing home
      care (15.1%), and office visits (10.9%) constituted the major expenditure groups
      by service settings. In addition, 51.8% of direct medical expenditures were
      incurred by people >65 years old. Attributable indirect expenditures resulting
      from lost workdays, restricted activity days, mortality, and permanent disability
      due to diabetes totaled 39.8 billion US dollars. U.S. health expenditures for the
      health care components included in the study totaled 865 billion US dollars, of
      which 160 billion US dollars was incurred by people with diabetes. Per capita
      medical expenditures totaled 13243 US dollars for people with diabetes and 2560
      US dollars for people without diabetes. When adjusting for differences in age,
      sex, and race/ethnicity between the population with and without diabetes, people
      with diabetes had medical expenditures that were approximately 2.4 times higher
      than expenditures that would be incurred by the same group in the absence of
      diabetes. CONCLUSIONS: The estimated 132 billion US dollars cost likely
      underestimates the true burden of diabetes because it omits intangibles, such as
      pain and suffering, care provided by nonpaid caregivers, and several areas of
      health care spending where people with diabetes probably use services at higher
      rates than people without diabetes (e.g., dental care, optometry care, and the
      use of licensed dietitians). In addition, the cost estimate excludes undiagnosed
      cases of diabetes. Health care spending in 2002 for people with diabetes is more
      than double what spending would be without diabetes. Diabetes imposes a
      substantial cost burden to society and, in particular, to those individuals with
      diabetes and their families. Eliminating or reducing the health problems caused
      by diabetes through factors such as better access to preventive care, more
      widespread diagnosis, more intensive disease management, and the advent of new
      medical technologies could significantly improve the quality of life for people
      with diabetes and their families while at the same time potentially reducing
      national expenditures for health care services and increasing productivity in the
      U.S. economy.

PMID- 12610060
TI  - American Association of Clinical Endocrinologists (AACE) consensus conference on
      the insulin resistance syndrome: 25-26 August 2002, Washington, DC.

PMID- 12610061
TI  - Do we need the oral glucose tolerance test to identify future cases of type 2
      diabetes?

PMID- 12610062
TI  - Electronic medical records and diabetes care improvement: are we waiting for
      Godot?

PMID- 12610063
TI  - Does exercise without weight loss improve insulin sensitivity?

PMID- 12610064
TI  - Point: yes, it is necessary to rely entirely on glycemic values for the insulin
      treatment of all gestational diabetic women.

PMID- 12610066
TI  - Impact of an intramural competition on outcome of diabetes care.

PMID- 12610065
TI  - Counterpoint: glucose monitoring in gestational diabetes: lots of heat, not much
      light.

PMID- 12610067
TI  - U-shaped association between white blood cell count and fasting plasma glucose
      level.

PMID- 12610068
TI  - Diabetes, nitric oxide, and heat shock proteins.

PMID- 12610069
TI  - Heteroplasmic mitochondrial DNA 3310 mutation in NADH dehydrogenase subunit 1
      associated with type 2 diabetes, hypertrophic cardiomyopathy, and mental
      retardation in a single patient.

PMID- 12610070
TI  - A new case of lipoatrophy with lispro insulin in insulin pump therapy: is there
      any insulin preparation free of complications?

PMID- 12610071
TI  - Intensive insulin treatment and QT-interval.

PMID- 12610072
TI  - Austronesian-speaking people in Papua New Guinea have susceptibility to obesity
      and type 2 diabetes.

PMID- 12610073
TI  - Pitfalls in the laboratory diagnosis of diabetic ketoacidosis in Gitelman's
      syndrome.

PMID- 12610074
TI  - Metformin-induced hemolytic anemia in a patient with glucose-6- phosphate
      dehydrogenase deficiency.

PMID- 12610075
TI  - No delay in glucose change at antecubital skin in hypoglycemia of normal
      subjects.

PMID- 12610076
TI  - Pregnancy complicated by diabetic ketoacidosis: maternal and fetal outcomes.

PMID- 12610077
TI  - Prediction of wound radius reductions and healing times in neuropathic diabetic
      foot ulcers.

PMID- 12610078
TI  - Cost effectiveness of the direct measurement of 3-beta-hydroxybutyrate in the
      management of diabetic ketoacidosis in children.

PMID- 12610079
TI  - Evidence for associated cutaneous microangiopathy in diabetic patients with
      neuropathic foot ulceration.

PMID- 12610081
TI  - Coronary artery disease and carotid artery intima-media thickness in Japanese
      type 2 diabetic patients.

PMID- 12610082
TI  - Acute and prolonged effects of sildenafil on brachial artery flow-mediated
      dilatation in type 2 diabetes.

PMID- 12610083
TI  - Digital retinal images and teleophthalmology for detecting and grading diabetic
      retinography.

PMID- 12610086
TI  - Technical issues in retinopathy screening.

PMID- 12610089
TI  - To pump or not to pump?

PMID- 12610090
TI  - Risk management in pathology.

PMID- 12610091
TI  - Endocervical glandular lesions: controversial aspects and ancillary techniques.
AB  - The incidence of malignant and premalignant endocervical glandular lesions is
      increasing. This review covers controversial and difficult aspects regarding the
      categorisation and diagnosis of these lesions. The terminology of premalignant
      endocervical glandular lesions is discussed because of the differences between
      the UK terminology and the widely used World Health Organisation classification.
      The morphology and histological subtypes of premalignant endocervical glandular
      lesions are described. Early invasive adenocarcinoma and difficulties in the
      diagnosis and recognition of this entity are covered, as is the measurement of
      early invasion within cervical adenocarcinoma. Several benign endocervical
      glandular lesions can mimic malignant and premalignant endocervical glandular
      lesions, and the distinction of these benign mimics from premalignant and
      malignant lesions using ancillary immunohistochemical studies is also covered.
      Antibodies used to distinguish between endometrial and endocervical
      adenocarcinoma, in the diagnosis of cervical minimal deviation adenocarcinoma of
      mucinous type (adenoma malignum), and in the diagnosis of cervical mesonephric
      lesions are also reviewed.

PMID- 12610093
TI  - Bacillus anthracis.
AB  - The events of 11 September 2001 and the subsequent anthrax outbreaks have shown
      that the West needs to be prepared for an increasing number of terrorist attacks,
      which may include the use of biological warfare. Bacillus anthracis has long been
      considered a potential biological warfare agent, and this review will discuss the
      history of its use as such. It will also cover the biology of this organism and
      the clinical features of the three disease forms that it can produce: cutaneous,
      gastrointestinal, and inhalation anthrax. In addition, treatment and vaccination
      strategies will be reviewed.

PMID- 12610096
TI  - Immunohistochemical classification of B cell neoplasms.

PMID- 12610092
TI  - HPV infections in benign and malignant sinonasal lesions.
AB  - This review updates the evidence that the human papillomavirus (HPV) is involved
      in the development of benign and malignant sinonasal lesions. Since the early
      1980s, when evidence was provided on the possible involvement of HPV in the
      aetiology of both benign respiratory papillomas and squamous cell carcinomas, a
      substantial number of studies have explored this issue. To date, 33.3% of
      sinonasal papillomas and 21.7% of sinonasal carcinomas analysed have been shown
      to be positive for HPV. Many elements of the data parallel the observations made
      in HPV lesions at other mucosal sites, such as malignant transformation and
      frequent recurrence after radical treatment; the fact that low risk HPV types 6
      and 11 are usually confined to benign lesions, whereas the reverse is true for
      the oncogenic HPV types 16 and 18; and the presence of squamo-columnar junctions
      and squamous cell metaplasia in the sinonasal system. The discrepancies reported
      by several studies might result in part from technical reasons, but it is also
      possible that sinonasal lesions have a heterogeneous aetiology (HPV related and
      non-related) and/or that some novel (yet unidentified) HPV types exist in these
      lesions, which are detected by some studies but not by others.

PMID- 12610094
TI  - Burkitt's lymphoma: new insights into molecular pathogenesis.
AB  - The World Health Organisation classification reports three subcategories of
      Burkitt's lymphoma (BL)--endemic, non-endemic, and immunodeficiency associated-
      proposed to reflect the major clinical and genetic subtypes of this disease.
      These different types of BL have been reviewed and studied by
      immunohistochemistry and molecular methods. The results point out the
      heterogeneity of BL and suggest that AIDS related BL may have a different
      pathogenesis from that of classic BL.

PMID- 12610097
TI  - Increased Nox2 expression in human cardiomyocytes after acute myocardial
      infarction.
AB  - BACKGROUND/AIMS: Recent studies indicate the presence of reactive oxygen species
      (ROS) producing homologues of the enzymatic subunit (Nox2) of phagocytic NADPH
      oxidase in non-phagocytic cells. Interestingly, in these cells, ROS produced by
      the Nox2 homologue(s) was shown to play a role in various regulatory processes,
      including cell death, proliferation, and aging. The purpose of this study was to
      investigate whether human cardiomyocytes express Nox2. METHODS: The expression of
      Nox2 was studied in human cardiomyocytes using western blot and
      immunohistochemical analysis. To analyse the putative expression of Nox2 in human
      heart disease, cardiac samples from patients who had died subsequent to acute
      myocardial infarction (AMI) were studied. RESULTS: Both in western blot and
      immunohistochemical studies, Nox2 expression was found in normal human
      cardiomyocytes. In patients with AMI, a significant increase in Nox2 expression
      was found both in viable and in jeopardised cardiomyocytes in the infarcted area.
      In addition, in the "remote from infarction" area, Nox2 expression was present in
      cardiomyocytes, but was not increased. CONCLUSIONS: Nox2 or its homologue(s) is
      expressed in normal and jeopardised human cardiomyocytes. This expression is
      increased in patients with AMI, suggesting a role for this ROS producing Nox2
      homologue(s) in the human heart after AMI.

PMID- 12610098
TI  - Expression of Ki-67 and cytokeratin 20 in hyperplastic polyps of the colorectum.
AB  - AIMS: To study the expression of Ki-67 and cytokeratin 20 (CK20) in a group of
      hyperplastic polyps (including a group with "atypical" features) with the aim of
      determining whether upper crypt Ki-67 staining and lower crypt CK20 staining
      correlated with these atypical features, as assessed by light microscopy.
      METHODS: Fifty seven formalin fixed, paraffin wax embedded hyperplastic
      colorectal polyps from 53 patients were selected on histological grounds; these
      comprised 26 typical polyps and 31 with atypical features, which included nuclear
      hyperchromatism, basal crowding, and increased mitotic activity. These polyps
      were examined using a standard immunohistochemical method with antibodies against
      CK20 and Ki-67. Comparisons were made with normal mucosa, adenomatous polyps, and
      carcinomas. RESULTS: Of the 26 typical polyps, 17 showed the usual pattern of
      lower crypt Ki-67 and upper crypt CK20 staining; one with upper crypt Ki-67
      staining but normal surface CK20 staining; seven with Ki-67 confined to the lower
      half of crypts but with scattered lower crypt CK20; and one with both upper crypt
      Ki-67 staining, together with scattered CK20 basal staining. Of the 31 polyps
      with atypical features, 11 showed the usual staining pattern of lower crypt Ki-67
      staining and surface staining with CK20; two showed Ki-67 staining extending into
      the upper half of crypts, but with a normal surface staining with CK20; 14 showed
      Ki-67 confined to the lower half of crypts, but scattered lower crypt staining
      with CK20; and four showed upper crypt Ki-67 staining together with scattered
      CK20 lower crypt staining. CONCLUSIONS: The normal pattern of lower crypt Ki-67
      and upper crypt CK20 was seen in 28 of the 57 hyperplastic polyps and, in
      general, this corresponded with standard light microscopic appearances. Twenty
      one of the 57 polyps showed lower crypt mosaic CK20 staining, which in general
      corresponded with basal abnormalities on light microscopy, although seven
      specimens had normal appearances. Two smaller subsets emerged, one showing upper
      crypt Ki-67 staining in the presence of normal CK20 expression (three cases) and
      another in which a combination of lower crypt CK20 and upper crypt Ki-67
      expression was seen (five cases). This last pattern was similar to that of
      neoplastic polyps and raises the possibility that a subgroup of hyperplastic
      polyps exists that may be a variant with malignant potential. Further studies
      with markers of mismatch repair genes and K-ras mutations may help to clarify
      this issue.

PMID- 12610100
TI  - Histological changes in the oesophageal squamous mucosa: correlation with
      ambulatory 24 hour pH monitoring.
AB  - AIMS: To determine the value of squamous mucosal histology in the assessment of
      patients with gastro-oesophageal reflux symptoms. METHODS: Sixty six patients
      with reflux symptoms underwent endoscopy with oesophageal biopsy, manometry, and
      24 hour oesophageal pH testing. The following histological features were assessed
      in squamous mucosa: the degree of basal cell hyperplasia, the degree of papillary
      zone elongation, and the density of neutrophil and eosinophil infiltration.
      Comparisons were made between the histological findings and the oesophageal
      function tests. RESULTS: The correlation between the traditionally accepted
      histological markers of gastro-oesophageal reflux disease in squamous mucosa and
      24 hour pH testing was predominantly negative, with the exception of neutrophil
      inflammation in the squamous mucosa of patients with complicated reflux disease.
      CONCLUSIONS: This study was unable to confirm the value of the Ismail-Beigi
      criteria as histological markers of acid reflux. By inference, biopsy of the
      oesophageal squamous mucosa is of limited value in the assessment of patients
      with reflux symptoms.

PMID- 12610101
TI  - Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel
      disease.
AB  - AIMS: Hypoxia inducible factors 1alpha and 2alpha (HIF1alpha and HIF2alpha) are
      hypoxia regulated transcriptional factors, which control the expression of a
      variety of genes responsible for angiogenesis, glycolysis, and the inhibition of
      apoptosis. Because angiogenesis and tissue regeneration are integral components
      of the inflammatory process, this study was designed to investigate the role of
      HIFalpha molecules in inflammatory bowel disease. METHODS: Surgical specimens
      from patients with active ulcerative colitis (UC) and Crohn's disease (CD) were
      assessed immunohistochemically for HIF1alpha and HIF2alpha reactivity, and the
      expression of these molecules was compared with the expression of the angiogenic
      factors thymidine phosphorylase (TP), vascular endothelial growth factor (VEGF),
      and VEGF-KDR activated vasculature. The vascular density of the lesions was also
      assessed using anti-CD31 immunostaining. RESULTS: HIF1alpha was expressed focally
      (epithelial cells, stromal fibroblasts, and myocytes) in both UC and CD, whereas
      HIF2alpha was expressed focally in UC and diffusely in CD. TP expression was
      uniformly positive in both diseases. VEGF expression was absent in CD, and weakly
      positive in UC. The VEGF-KDR reactivity of the submucosal vasculature was only
      slightly increased in UC and CD compared with normal tissue. The inflammatory
      cells stained with HIF2alpha and TP in all cases, but the reactivity was
      generalised in CD and focal in UC. In both diseases, vascular density was
      significantly higher than that seen in normal tissue. CONCLUSIONS: The discordant
      expression of HIF2alpha and VEGF in CD suggests an inherent deficiency of the
      intestine to respond to various stresses by the induction of VEGF. This finding
      should be investigated further.

PMID- 12610103
TI  - Inhibin is more specific than calretinin as an immunohistochemical marker for
      differentiating sarcomatoid granulosa cell tumour of the ovary from other spindle
      cell neoplasms.
AB  - AIMS: To describe a case of recurrent sarcomatoid adult granulosa cell tumour
      (AGCT) of the ovary and to evaluate the usefulness of two ovarian sex cord
      stromal markers (inhibin and calretinin) in separating sarcomatoid AGCT from true
      sarcomas. METHODS: A 72 year old woman presented with a recurrent sarcomatoid
      AGCT in the sigmoid colon mesentery, which histologically mimicked a malignant
      gastrointestinal stromal tumour (GIST). This index case and 79 sarcomas (32
      GISTs, 28 leiomyosarcomas, 15 endometrial stromal sarcomas (ESSs), including one
      with sex cord-like areas, and four undifferentiated uterine sarcomas) were
      immunostained using antibodies to inhibin and calretinin. RESULTS: The recurrent
      sarcomatoid AGCT expressed diffuse, strong cytoplasmic immunoreactivity with
      inhibin and focal but strong nuclear and cytoplasmic positivity with calretinin.
      Focal, weak cytoplasmic inhibin expression limited to sex cord-like areas was
      present in one ESS. None of the other sarcomas expressed inhibin. Focal, strong
      calretinin immunoreactivity was identified in 11 leiomyosarcomas and one GIST.
      The case of ESS with sex cord-like areas showed strong immunoreactivity for
      calretinin limited to the sex cord-like areas. CONCLUSIONS: Inhibin is a useful
      immunomarker to distinguish sarcomatoid AGCT from other spindle cell neoplasms
      that may enter into the differential diagnosis. Calretinin appears to be less
      specific than inhibin.

PMID- 12610102
TI  - p21WAF1 expression in invasive breast cancer and its association with p53, AP-2,
      cell proliferation, and prognosis.
AB  - AIMS: To evaluate the expression and prognostic relevance of p21(WAF1) in breast
      cancer and to investigate its association with p53, activator protein 2 (AP-2),
      and cell proliferation (as assessed by Ki-67 expression). METHODS: p21(WAF1)
      expression was analysed immunohistochemically in a large prospective, consecutive
      series of 420 patients with breast cancer diagnosed and treated between 1990 and
      1995 at Kuopio University Hospital, Kuopio, Finland. Inter-relations between
      p21(WAF1) expression and p53, AP-2, and Ki-67 were evaluated. The expression of
      p21(WAF1) was also compared with clinicopathological parameters and the patients'
      survival. RESULTS: In general, nuclear p21(WAF1) expression was low in carcinomas
      (median, 2.5%; range, 0-70%). Expression was lowest in lobular carcinomas (chi(2)
      = 7.4; p = 0.025). p21(WAF1) positive tumours were more often p53 positive
      (chi(2) = 4.2; p = 0.041) but expression of p21(WAF1) did not correlate with AP-2
      expression or Ki-67 in the whole patient group. In addition, the combined
      expression of p21 and p53 was not associated with AP-2 expression. High nuclear
      p21(WAF1) positivity (n = 160; 38%) was associated with poor differentiation
      (chi(2) = 8.1; p = 0.017). In the univariate analyses, p21(WAF1) expression had
      no prognostic value for predicting breast cancer related survival (BCRS) or
      recurrence free survival (RFS) in the whole patient group or in the subgroups
      investigated. However, in postmenopausal patients with lymph node metastases, and
      oestrogen receptor (ER) and/or progesterone receptor (PR) positive tumours, high
      p21(WAF1) expression predicted response to adjuvant hormonal treatment with
      antioestrogens. In the univariate analysis, the significant factors for
      predicting BCRS were Ki-67 expression, stage, lymph node status, histological
      grade, ER and PR status, and those for RFS were Ki-67 expression, stage, and
      lymph node status. In the multivariate analysis, the independent predictors of
      shorter BCRS were high cell proliferation activity measured by Ki-67 expression
      (p < 0.001), advanced stage (p < 0.001), and poor differentiation (p = 0.048).
      Shorter RFS was independently predicted by high cell proliferative activity (p <
      0.001) and advanced stage (p < 0.001). CONCLUSIONS: The regulation of p21(WAF1)
      seems to occur independently of p53 or AP-2 and analysing p21(WAF1) expression
      provided no prognostic information for patients with breast cancer.

PMID- 12610104
TI  - Measurement of IgG antibodies to Chlamydia trachomatis by commercial enzyme
      immunoassays and immunofluorescence in sera from pregnant women and patients with
      infertility, pelvic inflammatory disease, ectopic pregnancy, and laboratory
      diagnosed Chlamydia psittaci/Chlamydia pneumoniae infection.
AB  - BACKGROUND: Screening for Chlamydia trachomatis specific antibodies is valuable
      in diagnosing asymptomatic pelvic inflammatory disease (PID) and tubal damage
      following repeated episodes of PID. The assays in current use are unsuitable for
      screening large numbers of samples so there is a need to develop more suitable
      assays. AIMS: To compare the performance of several commercial C trachomatis
      enzyme immunoassays (EIAs) (SeroCT, C tracho(pep), Medac p-EIA, Vircell and
      Labsystems C trachomatis IgG EIAs) using major outer membrane protein (MOMP), an
      inactivated organism EIA (Genzyme Virotech EIA), and a genus specific EIA
      (Platelia Chlamydia IgG) with the whole cell inclusion immunofluorescence (WIF)
      assay. In addition, to adapt, using time resolved fluorescence technology, the
      assay showing the highest correlation with WIF. METHODS: Ninety sera from
      patients presenting with ectopic pregnancies, 187 sera from those with a variety
      of types of infertility, 33 sera from cases of PID where a fourfold rise in WIF
      titre occurred, and 90 sera from antenatal clinic attenders were tested. A panel
      of 36 sera from laboratory diagnosed cases of Chlamydia psittaci/Chlamydia
      pneumoniae infection was also tested. RESULTS: The Genzyme Virotech EIA showed
      the highest rank correlation coefficient (0.82) with WIF, particularly at high
      WIF titres. The MOMP specific assays varied in their correlation with WIF, with
      rank correlation coefficients ranging from 0.70 (Medac p-EIA) to 0.80 (Vircell
      EIA). The Genzyme Virotech assay showed poor specificity (5.6%; 95% confidence
      interval (CI), 0.68% to 18.7%)--it was reactive with 34 of the panel of 36 C
      psittaci/C pneumoniae positive sera. The MOMP based EIAs showed high specificity,
      particularly the Medac p-ELISA (97.2%; 95% CI, 85.5% to 99.9%)--only one serum
      was reactive. In view of the good correlation between WIF and the Genzyme
      Virotech EIA, a time resolved fluorescence immunoassay (TRFIA) was developed
      using the Genzyme Virotech antigen. Using an appropriate cut off the TRFIA assay
      showed excellent correlation with WIF. CONCLUSIONS: The TRFIA assay may be useful
      as a screening assay, possibly in conjunction with one of the highly specific
      EIAs studied (for example, Medac p-EIA) to confirm the antibody specificity of
      sera selected by the screening assay.

PMID- 12610105
TI  - Minimal focus of adenocarcinoma on prostate biopsy: clinicopathological
      correlations.
AB  - AIMS: To establish the clinicopathological features of minimal volume prostate
      adenocarcinoma on prostate biopsy. METHODS: Twenty four cases of minimal
      adenocarcinoma diagnosed on prostate biopsy and treated by radical prostatectomy
      were reviewed. RESULTS: The major microscopic criteria were nuclear enlargement
      (22 of 24), infiltrative pattern (19 of 24), prominent nucleoli (19 of 24),
      intraluminal eosinophilic secretions (15 of 24), and high grade intraepithelial
      neoplasia associated (11 of 24). Sixteen of 24 cases were assigned a Gleason
      score 6 on biopsy. When the whole gland was assessed, 22 of these tumours were
      localised to the prostate (stage pT2), and only two cases were stage pT3.
      CONCLUSIONS: Minimal focus of adenocarcinoma on prostate biopsy is not an
      uncommon finding. It is usually an intermediate grade and localised stage
      neoplasm.

PMID- 12610106
TI  - Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm
      following hereditary retinoblastoma.
AB  - This report describes two patients who developed leiomyosarcomas, one involving
      the subcutaneous tissue of the thigh and the pelvic soft tissues and the other
      the urinary bladder, following hereditary retinoblastoma 36 and 38 years earlier,
      respectively. There is an increased risk of the development of sarcoma, most
      commonly osteosarcoma, as a second malignancy following hereditary
      retinoblastoma. Leiomyosarcoma developing as a second malignancy has rarely been
      reported and most have occurred in the field of previous radiotherapy. The
      literature on leiomyosarcoma occurring as a second neoplasm following
      retinoblastoma is reviewed.

PMID- 12610107
TI  - Chronic osteomyelitis mimicking sarcoma.
AB  - This report describes a rare case of chronic osteomyelitis in a 60 year old man
      mimicking a soft tissue sarcoma. Chronic osteomyelitis is an infrequent cause of
      a soft tissue mass and is usually diagnosed clinically by a combination of
      radiology and microbiology. Rarely, COM can mimic a primary bony neoplasm, but
      this is the first reported case where it mimicked a soft tissue sarcoma. The
      clinical, radiological, and histological appearances of this case will be
      discussed.

PMID- 12610108
TI  - Invasive lobular carcinoma and cytokeratin immunohistochemistry: an audit.

PMID- 12610109
TI  - Role of the LXXLL-motif and activation function 2 domain in subcellular
      localization of Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita
      critical region on the X chromosome, gene 1).
AB  - Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the
      X chromosome, gene 1 (Dax-1, NR0B1) is an orphan nuclear receptor that represses
      transcription by Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1, NR5A1).
      Observations on human diseases and the phenotypes of mice, in which the
      corresponding genes have been disrupted, have elucidated essential roles of these
      two nuclear receptors in differentiation of steroidogenic tissues. However,
      little is known about how the functions of these factors are regulated. Here we
      have examined their subcellular localization and have clarified the molecular
      mechanisms regulating subcellular localization of Dax-1. Prompted by the finding
      that nuclear localization of Dax-1 correlates with the presence of Ad4BP/SF-1 in
      the early stages of pituitary development, we have tested the possibility that
      interaction between the two factors is essential for the nuclear localization of
      Dax-1. In vitro studies with cultured cells demonstrated that an interaction
      involving the LXXLL motifs in the N-terminal repeat region of Dax-1 plays a key
      role in its subcellular localization. In addition, we found that a mutant form of
      DAX-1 (L466R), from a patient with adrenal hypoplasia congenita, was defective in
      nuclear localization in spite of having an intact N terminus. Taken together, the
      results reveal that the subcellular localization of Dax-1 is influenced by the
      presence of Ad4BP/SF-1, and that two regions of Dax-1 have important roles for
      this process.

PMID- 12610110
TI  - Unr is required in vivo for efficient initiation of translation from the internal
      ribosome entry sites of both rhinovirus and poliovirus.
AB  - Translation of picornavirus RNAs is mediated by internal ribosomal entry site
      (IRES) elements and requires both standard eukaryotic translation initiation
      factors (eIFs) and IRES-specific cellular trans-acting factors (ITAFs). Unr, a
      cytoplasmic RNA-binding protein that contains five cold-shock domains and is
      encoded by the gene upstream of N-ras, stimulates translation directed by the
      human rhinovirus (HRV) IRES in vitro. To examine the role of Unr in translation
      of picornavirus RNAs in vivo, we derived murine embryonic stem (ES) cells in
      which either one (-/+) or both (-/-) copies of the unr gene were disrupted by
      homologous recombination. The activity of picornaviral IRES elements was analyzed
      in unr(+/+), unr(+/-), and unr(-/-) cell lines. Translation directed by the HRV
      IRES was severely impaired in unr(-/-) cells, as was that directed by the
      poliovirus IRES, revealing a requirement for Unr not previously observed in
      vitro. Transient expression of Unr in unr(-/-) cells efficiently restored the HRV
      and poliovirus IRES activities. In contrast, the IRES elements of
      encephalomyocarditis virus and foot-and-mouth-disease virus are not Unr
      dependent. Thus, Unr is a specific regulator of HRV and poliovirus translation in
      vivo and may represent a cell-specific determinant limiting replication of these
      viruses.

PMID- 12610111
TI  - The STAT2 activation process is a crucial target of Sendai virus C protein for
      the blockade of alpha interferon signaling.
AB  - Sendai virus (SeV) C protein functions as an interferon (IFN) antagonist and
      renders cells unresponsive to both alpha/beta IFN (IFN-alpha/beta) and IFN-gamma.
      We have recently found the physical association of the C protein with signal
      transducer and activator of transcription 1 (STAT1) in infected cells. However,
      involvement of the C-STAT1 interaction in the blockade of IFN signaling has
      remained unclear. We generated here a series of C mutant proteins that retained
      or lost the STAT1-binding capacity and examined their effects on IFN-alpha
      signaling. All of the C mutant proteins with no STAT1-binding capacity lost the
      ability to inhibit the IFN-alpha response. In contrast, the C mutant proteins
      retaining the STAT1-binding capacity suppressed IFN-alpha-stimulated tyrosine
      phosphorylation of both STAT2 and STAT1 to various degrees. Remarkably, their
      anti-IFN-alpha capacities correlated well with the inhibitory effect on
      phosphorylation of STAT2 rather than STAT1. In infected cells, the levels of
      tyrosine-phosphorylated (pY) STAT2 were below the detection level irrespective of
      duration of IFN-alpha stimulation, whereas the levels of pY-STAT1 strikingly
      increased after long-term IFN-alpha stimulation. These results suggest that the
      STAT2 activation process is a crucial target for the blockade of IFN-alpha
      signaling. An in vitro binding assay with extracts from (STAT1-deficient) U3A and
      (STAT1-expressing) U3A-ST1 cells suggested the requirement of STAT1 for the C
      STAT2 interaction. Furthermore, expression of STAT1 enhanced the inhibitory
      effect of the C protein on STAT2 activation in U3A cells. The C protein thus
      appears to participate in the inhibitory process for STAT2 activation through the
      STAT1 interaction.

PMID- 12610112
TI  - Induction of apoptosis by paramyxovirus simian virus 5 lacking a small
      hydrophobic gene.
AB  - Simian virus 5 (SV5) is a member of the paramyxovirus family, which includes
      emerging viruses such as Hendra virus and Nipah virus as well as many important
      human and animal pathogens that have been known for years. SV5 encodes eight
      known viral proteins, including a small hydrophobic integral membrane protein
      (SH) of 44 amino acids. SV5 without the SH gene (rSV5deltaSH) is viable, and
      growth of rSV5deltaSH in tissue culture cells and viral protein and mRNA
      production in rSV5deltaSH-infected cells are indistinguishable from those of the
      wild-type SV5 virus. However, rSV5deltaSH causes increased cytopathic effect
      (CPE) and apoptosis in MDBK cells and is attenuated in vivo, suggesting the SH
      protein plays an important role in SV5 pathogenesis. How rSV5deltaSH induces
      apoptosis in infected cells has been examined in this report. Tumor necrosis
      factor alpha (TNF-alpha), a proinflammatory cytokine, was detected in culture
      media of rSV5deltaSH-infected cells. Apoptosis induced by rSV5deltaSH was
      inhibited by neutralizing antibodies against TNF-alpha and TNF-alpha receptor 1
      (TNF-R1), suggesting that TNF-alpha played an essential role in rSV5deltaSH
      induced apoptosis in a TNF-R1-dependent manner. Examination of important proteins
      in the TNF-alpha signaling pathway showed that p65, a major NF-kappaB subunit
      whose activation can lead to transcription of TNF-alpha, was first translocated
      to the nucleus and was capable of binding to DNA and then was targeted for
      degradation in rSV5deltaSH-infected cells while expression levels of TNF-R1
      remained relatively constant. Thus, rSV5deltaSH induced cell death by activating
      TNF-alpha expression, possibly through activation of the NF-kappaB subunit p65
      and then targeting p65 for degradation, leading to apoptosis.

PMID- 12610113
TI  - Retroviruses have differing requirements for proteasome function in the budding
      process.
AB  - Proteasome inhibitors reduce the budding of human immunodeficiency virus types 1
      (HIV-1) and 2, simian immunodeficiency virus, and Rous sarcoma virus. To
      investigate this effect further, we examined the budding of other retroviruses
      from proteasome inhibitor-treated cells. The viruses tested differed in their Gag
      organization, late (L) domain usage, or assembly site from those previously
      examined. We found that proteasome inhibition decreased the budding of murine
      leukemia virus (plasma membrane assembly, PPPY L domain) and Mason-Pfizer monkey
      virus (cytoplasmic assembly, PPPY L domain), similar to the reduction observed
      for HIV-1. Thus, proteasome inhibitors can affect the budding of a virus that
      assembles within the cytoplasm. However, the budding of mouse mammary tumor virus
      (MMTV; cytoplasmic assembly, unknown L domain) was unaffected by proteasome
      inhibitors, similar to the proteasome-independent budding previously observed for
      equine infectious anemia virus (plasma membrane assembly, YPDL L domain).
      Examination of MMTV particles detected Gag-ubiquitin conjugates, demonstrating
      that an interaction with the ubiquitination system occurs during assembly, as
      previously found for other retroviruses. For all of the cell lines tested, the
      inhibitor treatment effectively inactivated proteasomes, as measured by the
      accumulation of polyubiquitinated proteins. The ubiquitination system was also
      inhibited, as evidenced by the loss of monoubiquitinated histones from treated
      cells. These results and those from other viruses show that proteasome inhibitors
      reduce the budding of viruses that utilize either a PPPY- or PTAP-based L domain
      and that this effect does not depend on the assembly site or the presence of
      monoubiquitinated Gag in the virion.

PMID- 12610114
TI  - Glial cell-specific regulation of the JC virus early promoter by histone
      deacetylase inhibitors.
AB  - The human polyomavirus JC virus is the etiologic agent of the fatal disease
      demyelinating progressive multifocal leukoencephalopathy. Although multiple
      transcription factors have been shown to interact with the JC virus promoter and
      regulate transcriptional activity, their relevance to cell specificity remains
      elusive. To investigate whether chromatin structure controls glial cell-specific
      expression of JC virus early genes, glial and nonglial cells were transfected
      with a reporter plasmid containing the JC virus early promoter and then treated
      with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium
      butyrate. TSA and butyrate induced 20- to 30-fold activation of the JC virus
      promoter in nonglial cells, whereas less than 2-fold induction was observed in
      glial cells. These results indicate that the JC virus early promoter might be
      highly suppressed in nonglial cells by hypoacetylated chromatin and activated by
      hyperacetylation. In support of this, chromatin immunoprecipitation assays
      demonstrated acetylation of the JC virus promoter region in U87MG cells but no
      acetylation in HeLa cells. In addition, treatment of HeLa cells with TSA induced
      hyperacetylation of the JC virus promoter, whereas minimal induction was seen in
      U87MG cells. Deletional and site-directed mutational analyses revealed that the
      enhancer region and Sp1 binding site upstream of the TATA box were important for
      TSA-mediated activation. We confirmed TSA-mediated activation of the JC virus
      promoter in the context of natural chromatin structure in stable cell lines.
      Thus, it appears that chromatin structure may control JC virus transcription in a
      cell-specific manner.

PMID- 12610115
TI  - Loss of the perforin cytotoxic pathway predisposes mice to experimental
      cytomegalovirus retinitis.
AB  - AIDS-related human cytomegalovirus (HCMV) retinitis continues to be a chronic
      ophthalmologic problem among human immunodeficiency virus type 1 (HIV-1)-infected
      patients who do not respond to highly active antiretroviral therapy. Although
      HCMV retinitis occurs during HIV-1-induced immunosuppression, the precise
      effector mechanism(s) that fails during the immunopathogenesis of AIDS to allow
      onset and progression of HCMV retinal disease remains unclear. We therefore
      performed a series of experiments to explore the relative roles of distinct
      pathways of lymphocyte-mediated cytotoxicity in either resistance or
      susceptibility to experimental murine cytomegalovirus (MCMV) retinitis in mice.
      Whereas mutant C57BL/6 mice deficient in the Fas/FasL cytotoxic pathway (gld
      mice) were identical to normal C57BL/6 mice and exhibited absolute resistance to
      retinal necrosis following subretinal MCMV inoculation, knockout C57BL/6 mice
      deficient in the perforin cytotoxic pathway (PKO mice) were susceptible to MCMV
      retinitis. Susceptibility of PKO mice to MCMV retinitis correlated with increased
      ocular MCMV titers when compared with ocular MCMV titers of gld and normal mice.
      Since mice with retrovirus-induced immunodeficiency syndrome (MAIDS) exhibited a
      frequency and severity of MCMV retinitis that were equivalent to those observed
      in PKO mice, we hypothesized that susceptibility to MCMV retinitis during MAIDS
      correlates with a decrease in the perforin cytotoxic pathway. To test this
      hypothesis, we developed a quantitative competitive reverse transcription-PCR
      assay to measure mouse perforin mRNA levels in the splenic T lymphocytes and MCMV
      inoculated eyes of normal mice or mice with MAIDS. Perforin mRNA levels in
      splenic T lymphocytes were significantly decreased during MAIDS, by approximately
      100-fold, from perforin mRNA levels in normal mice. Moreover, MCMV-inoculated
      eyes destined to develop retinitis during MAIDS also showed a significant
      decrease in perforin mRNA levels from the perforin mRNA levels of MCMV-inoculated
      eyes of normal mice destined to be resistant to retinitis. As expected, perforin
      mRNA could not be detected in unmanipulated and uninfected eyes of normal mice.
      These results provide the first evidence that the perforin cytotoxic pathway is
      more important than the Fas/FasL cytotoxic pathway in providing resistance to
      experimental MCMV retinitis and that loss of the perforin cytotoxic pathway
      predisposes to MCMV retinitis.

PMID- 12610116
TI  - Strain-dependent structural variants of herpes simplex virus type 1 ICP34.5
      determine viral plaque size, efficiency of glycoprotein processing, and viral
      release and neuroinvasive disease potential.
AB  - The ability of certain strains of herpes simplex virus type 1 (HSV-1) to cause
      encephalitis or neuroinvasive disease in the mouse upon peripheral infection is
      dependent on a combination of activities of specific forms of viral proteins. The
      importance of specific variants of ICP34.5 to neuroinvasive disease potential and
      its correlation with small-plaque production, inefficient glycoprotein
      processing, and virus release were suggested by comparison of ICP34.5 from the
      SP7 virus, originally obtained from the brain of a neonate with disseminated
      disease, and the tissue culture-passaged progeny of SP7 (SLP5 and SLP10) and the
      KOS321 virus. SLP5, SLP10, and KOS321 are attenuated and exhibit a large-plaque
      phenotype, including efficient glycoprotein processing and viral release. We show
      that expression of the KOS321 ICP34.5 protein in cells infected with SP7 or
      ICP34.5 deletion mutants promotes large plaque formation and efficient viral
      glycoprotein processing, while expression of the SP7 ICP34.5 protein decreases
      efficiency of viral glycoprotein processing. In addition, a recombinant virus,
      4hS1, with the SP7 ICP34.5 gene replacing the KOS321-like ICP34.5 gene in the
      SLP10a background, rescues the small-plaque phenotype and neuroinvasive disease.
      The major difference in the ICP34.5 gene product is the number of Pro-Ala-Thr
      repeats in the middle region of the protein, with 18 for SP7 and 3 for KOS321.
      Strain-dependent differences in the ICP34.5 protein can therefore alter the
      tissue culture behavior and the virulence of HSV-1.

PMID- 12610117
TI  - Vaccinia virus G7L protein Interacts with the A30L protein and is required for
      association of viral membranes with dense viroplasm to form immature virions.
AB  - The vaccinia virus A30L protein is required for the association of electron
      dense, granular, proteinaceous material with the concave surfaces of crescent
      membranes, an early step in viral morphogenesis. For the identification of
      additional proteins involved in this process, we used an antibody to the A30L
      protein, or to an epitope appended to its C terminus, to capture complexes from
      infected cells. A prominent 42-kDa protein was resolved and identified by mass
      spectrometry as the vaccinia virus G7L protein. This previously uncharacterized
      protein was expressed late in infection and was associated with immature virions
      and the cores of mature particles. In order to study the role of the G7L protein,
      a conditional lethal mutant was made by replacing the G7L gene with an inducible
      copy. Expression of G7L and formation of infectious virus was dependent on the
      addition of inducer. Under nonpermissive conditions, morphogenesis was blocked
      and viral crescent membranes and immature virions containing tubular elements
      were separated from the electron-dense granular viroplasm, which accumulated in
      large spherical masses. This phenotype was identical to that previously obtained
      with an inducible, conditional lethal A30L mutant. Additional in vivo and in
      vitro experiments provided evidence for the direct interaction of the A30L and
      G7L proteins and demonstrated that the stability of each one was dependent on its
      association with the other.

PMID- 12610118
TI  - Autographa californica nucleopolyhedrovirus orf69 encodes an RNA cap (nucleoside
      2'-O)-methyltransferase.
AB  - The AcNPV orf69 gene encodes a protein that contains an S-adenosylmethionine
      (AdoMet)-dependent methyltransferase signature motif. More significantly, ORF69
      shows high conservation at residues diagnostic for (nucleoside 2'-O)
      methyltransferase activity. To analyze the function of this protein, which was
      renamed MTase1, it was overexpressed in Escherichia coli and purified to
      homogeneity. Photo cross-linking experiments showed that MTase1 bound AdoMet, and
      functional assays demonstrated cap 0-dependent methyltransferase activity. In
      vivo expression assays in insect cells showed that MTase1 was synthesized during
      the late phase of infection and that its expression was dependent on viral DNA
      replication. Primer extension analysis identified a late promoter motif, ATAAG,
      at the transcription start site. A mutant virus was constructed by inserting the
      lacZ gene into the coding region of mtase1. Immunoblot analysis confirmed that
      MTase1 was not synthesized in these cells, and single-step growth curves revealed
      that the rate of virus replication in tissue culture was not affected by the
      absence of MTase1.

PMID- 12610119
TI  - Interactions between the transmembrane segments of the alphavirus E1 and E2
      proteins play a role in virus budding and fusion.
AB  - The alphavirus envelope is built by heterodimers of the membrane proteins E1 and
      E2. The complex is formed as a p62E1 precursor in the endoplasmic reticulum.
      During transit to the plasma membrane (PM), it is cleaved into mature E1-E2
      heterodimers, which are oligomerized into trimeric complexes, so-called spikes
      that bind both to each other and, at the PM, also to nucleocapsid (NC) structures
      under the membrane. These interactions drive the budding of new virus particles
      from the cell surface. The virus enters new cells by a low-pH-induced membrane
      fusion event where both inter- and intraheterodimer interactions are reorganized
      to establish a fusion-active membrane protein complex. There are no intact
      heterodimers left after fusion activation; instead, an E1 homotrimer remains in
      the cellular (or viral) membrane. We analyzed whether these transitions depend on
      interactions in the transmembrane (TM) region of the heterodimer. We observed a
      pattern of conserved glycines in the TM region of E1 and made two mutants where
      either the glycines only (SFV/E1(4L)) or the whole segment around the glycines
      (SFV/E1(11L)) was replaced by leucines. We found that both mutations decreased
      the stability of the heterodimer and increased the formation of the E1 homotrimer
      at a suboptimal fusion pH, while the fusion activity was decreased. This
      suggested that TM interactions play a role in virus assembly and entry and that
      anomalous or uncoordinated protein reorganizations take place in the mutants. In
      addition, the SFV/E1(11L) mutant was completely deficient in budding, which may
      reflect an inability to form multivalent NC interactions at the PM.

PMID- 12610120
TI  - The human cytomegalovirus UL82 gene product (pp71) accelerates progression
      through the G1 phase of the cell cycle.
AB  - As viruses are reliant upon their host cell to serve as proper environments for
      their replication, many have evolved mechanisms to alter intracellular conditions
      to suit their own needs. For example, human cytomegalovirus induces quiescent
      cells to enter the cell cycle and then arrests them in late G(1), before they
      enter the S phase, a cell cycle compartment that is presumably favorable for
      viral replication. Here we show that the protein product of the human
      cytomegalovirus UL82 gene, pp71, can accelerate the movement of cells through the
      G(1) phase of the cell cycle. This activity would help infected cells reach the
      late G(1) arrest point sooner and thus may stimulate the infectious cycle. pp71
      also induces DNA synthesis in quiescent cells, but a pp71 mutant protein that is
      unable to induce quiescent cells to enter the cell cycle still retains the
      ability to accelerate the G(1) phase. Thus, the mechanism through which pp71
      accelerates G(1) cell cycle progression appears to be distinct from the one that
      it employs to induce quiescent cells to exit G(0) and subsequently enter the S
      phase.

PMID- 12610121
TI  - A virus-virus interaction circumvents the virus receptor requirement for
      infection by pathogenic retroviruses.
AB  - During ongoing C-type retrovirus infection, the probability of leukemia caused by
      insertional gene activation is markedly increased by the emergence of recombinant
      retroviruses that repeatedly infect host cells. The murine mink cell focus
      inducing (MCF) viruses with this property have acquired characteristic changes in
      the N-terminal domain of their envelope glycoprotein that specify binding to a
      different receptor than the parental ecotropic virus. In this report, we show
      that MCF virus infection occurs through binding to this receptor (termed Syg1)
      and, remarkably, by a second mechanism that does not utilize the Syg1 receptor.
      By the latter route, the N-terminal domain of the ecotropic virus glycoprotein
      expressed on the cell surface in a complex with its receptor activates the fusion
      mechanism of the MCF virus in trans. The rate of MCF virus spread through a
      population of permissive human cells was increased by establishment of trans
      activation, indicating that Syg1 receptor-dependent and -independent pathways
      function in parallel. Also, trans activation shortened the interval between
      initial infection and onset of cell-cell fusion associated with repeated
      infection of the same cell. Our findings indicate that pathogenic retrovirus
      infection may be initiated by virus binding to cell receptors or to the virus
      envelope glycoprotein of other viruses expressed on the cell surface. Also, they
      support a broader principle: that cooperative virus-virus interactions, as well
      as virus-host interactions, shape the composition and properties of the
      retrovirus quasispecies.

PMID- 12610122
TI  - Human immunodeficiency virus type 1 infection and replication in normal human
      oral keratinocytes.
AB  - Recent epidemiologic studies show increasing human immunodeficiency virus type 1
      (HIV-1) transmission through oral-genital contact. This paper examines the
      possibility that normal human oral keratinocytes (NHOKs) might be directly
      infected by HIV or might convey infectious HIV virions to adjacent leukocytes.
      PCR analysis of proviral DNA constructs showed that NHOKs can be infected by
      CXCR4-tropic (NL4-3 and ELI) and dualtropic (89.6) strains of HIV-1 to generate a
      weak but productive infection. CCR5-tropic strain Ba-L sustained minimal viral
      replication. Antibody inhibition studies showed that infection by CXCR4-tropic
      viral strains is mediated by the galactosylceramide receptor and the CXCR4
      chemokine coreceptor. Coculture studies showed that infectious HIV-1 virions can
      also be conveyed from NHOKs to activated peripheral blood lymphocytes, suggesting
      a potential role of oral epithelial cells in the transmission of HIV infection.

PMID- 12610123
TI  - Cellular mobile genetic elements in the regulatory region of the pneumotropic
      mouse polyomavirus genome: structure and function in viral gene expression and
      DNA replication.
AB  - DNA from the murine pneumotropic virus was extracted from virus in lung tissue of
      infected mice, and the regulatory region of the genome was amplified by PCR. The
      regulatory region of individual plasmid cloned DNA molecules appeared to have
      heterogeneous enhancer segments, whereas the protein-coding part of the genome
      had a uniform length. Nucleotide sequence analysis revealed that the majority of
      the DNA molecules had a structure differing from the standard type. A 220-bp
      insertion at nucleotide position 142 with a concomitant deletion of nucleotides
      143 to 148 was prominent. There were two variants of the 220-bp insertion,
      differing at two nucleotide positions at one of the termini. Other DNA molecules
      had complete or partial deletions of these structures and surrounding sequences
      in the viral enhancer. However, the end of the insertion at nucleotide 142 was
      frequently preserved. The viral early and late promoter activity of the variant
      regulatory regions was tested in a luciferase reporter assay by using transfected
      NIH 3T3 cells. In relation to the standard-type DNA, all variants, including a
      G272T mutant, had much stronger late promoters. In contrast, the early promoter
      activity was influenced in a positive or negative direction by individual
      mutations. Also, the activity of the viral origin of DNA replication was affected
      by the sequence variation of the regulatory region, although the effects were
      smaller than for the late promoter. Analysis by Southern blotting and
      quantification using dot blots showed that approximately 10(3) copies of material
      related to the 220-bp insert in murine pneumotropic virus DNA was present in
      mouse and human DNA but not in Escherichia coli DNA. Moreover, analysis by PCR
      indicated that there were multiple copies in the mouse genome of sequences that
      were identical or closely related to the 220-bp viral DNA segment. These data
      together with the nucleotide sequence analysis suggest that the 220-bp insertion
      is related to a transposable element of a novel type.

PMID- 12610124
TI  - A Japanese encephalitis virus peptide present on Johnson grass mosaic virus-like
      particles induces virus-neutralizing antibodies and protects mice against lethal
      challenge.
AB  - Protection against Japanese encephalitis virus (JEV) is antibody dependent, and
      neutralizing antibodies alone are sufficient to impart protection. Thus, we are
      aiming to develop a peptide-based vaccine against JEV by identifying JEV peptide
      sequences that could induce virus-neutralizing antibodies. Previously, we have
      synthesized large amounts of Johnson grass mosaic virus (JGMV) coat protein (CP)
      in Escherichia coli and have shown that it autoassembled to form virus-like
      particles (VLPs). The envelope (E) protein of JEV contains the virus
      neutralization epitopes. Four peptides from different locations within JEV E
      protein were chosen, and these were fused to JGMV CP by recombinant DNA methods.
      The fusion protein autoassembled to form VLPs that could be purified by sucrose
      gradient centrifugation. Immunization of mice with the recombinant VLPs
      containing JEV peptide sequences induced anti-peptide and anti-JEV antibodies. A
      27-amino-acid peptide containing amino acids 373 to 399 from JEV E protein,
      present on JGMV VLPs, induced virus-neutralizing antibodies. Importantly, these
      antibodies were obtained without the use of an adjuvant. The immunized mice
      showed significant protection against a lethal JEV challenge.

PMID- 12610125
TI  - Genetic fate of recombinant adeno-associated virus vector genomes in muscle.
AB  - Recombinant adeno-associated virus (rAAV) vectors are promising human gene
      transfer vectors, because they mediate long-term gene expression in vivo. The
      vector DNA form responsible for sustained gene expression has not been clearly
      defined, but it has been presumed that the vector integrates to some degree and
      persists in this manner. Using two independent methods, we were unable to
      identify rAAV integrants in mouse muscle. In the first approach, we were unable
      to recover host cell-vector DNA junctions from a lambda phage library generated
      using transduced mouse muscle DNA that contained a high vector copy number.
      Following this result, we devised a PCR assay based on the principle that
      integrated rAAV vector sequences could be amplified using primers specific for
      mouse interspersed repetitive sequences (B1 elements). Using this assay, we
      analyzed transduced mouse muscle DNA isolated from 6 to 57 weeks after injection
      and did not detect amplification above background levels. Based on the
      demonstrated sensitivity of the assay, these results suggested that >99.5% of
      vector DNA was not integrated. Additional analyses using a novel DNA exonuclease
      showed that the majority of the rAAV vector DNA in muscle persisted over time as
      transcriptionally active monomeric and concatameric episomes.

PMID- 12610126
TI  - Measles virus infects and suppresses proliferation of T lymphocytes from
      transgenic mice bearing human signaling lymphocytic activation molecule.
AB  - Humans are the only natural reservoir of measles virus (MV), one of the most
      contagious viruses known. MV infection and the profound immunosuppression it
      causes are currently responsible for nearly one million deaths annually. Human
      signaling lymphocytic activation molecule (hSLAM) was identified as a receptor
      for wild-type MV as well as for MV strains prepared as vaccines. To better
      evaluate the role of hSLAM in MV pathogenesis and MV-induced immunosuppression,
      we created transgenic (tg) mice that expressed the hSLAM molecule under the
      control of the lck proximal promoter. hSLAM was expressed on CD4(+) and CD8(+) T
      cells in the blood and spleen and also on CD4(+), CD8(+), CD4(+) CD8(+), and CD4(
      ) CD8(-) thymocytes. Wild-type MV, after limited passage on B95-8 marmoset B
      cells, and the Edmonston laboratory strain of MV infected hSLAM-expressing cells.
      There was a direct correlation between the amount of hSLAM expressed on the
      cells' surface and the degree of viral infection. Additionally, MV infection
      induced downregulation of receptor hSLAM and inhibited cell division and
      proliferation of hSLAM(+) but not hSLAM(-) T cells. Therefore, these tg mice
      provide the opportunity for analyzing and comparing MV-T cell interactions and MV
      pathogenesis in cells expressing only the hSLAM MV receptor with those of tg mice
      whose T cells selectively express another MV receptor, CD46.

PMID- 12610127
TI  - The stable 2.0-kilobase intron of the herpes simplex virus type 1 latency
      associated transcript does not function as an antisense repressor of ICP0 in
      nonneuronal cells.
AB  - During latency, herpes simplex virus expresses a unique set of latency-associated
      transcripts (LATs). As the 2.0-kb LAT intron is complementary to, and overlaps,
      the 3' end of the ICP0 transcript, it has been suggested that the stable LAT
      intron might function as an antisense repressor of ICP0 expression. We tested
      this hypothesis in cell culture by dissociating cis- and trans-acting effects of
      the 2.0-kb LAT, using a series of complementary strategies. Initially, we
      constructed 293T cell lines that stably express the nuclear 2.0-kb LAT intron to
      determine whether LAT accumulation in trans affects ICP0 expression. ICP0 mRNA
      and protein expression profiles were studied (i) following infections with a
      viral mutant containing wild-type LAT and ICP0 sequences but having deletions of
      other immediate-early (IE) genes, thus preventing the progression of viral early
      gene expression, (ii) at early time points after infection with wild-type virus,
      before viral LAT expression, and (iii) by plasmid transfections. Northern and
      Western blot analysis showed that trans expression of the 2.0-kb LAT intron does
      not affect ICP0 mRNA expression, stability, accumulation, splicing, or
      translation. In addition, suppression of viral replication by overexpression of
      the 2.0-kb LAT, which has been detected previously in neuronal cell lines, was
      not found in these nonneuronal cell lines. However, deletion of the latency
      active promoter (LAP) region of the virus resulted in overexpression of IE genes,
      which occurred soon after infection, before viral LAT expression had commenced.
      This was not complemented by the expression of LAT in trans, suggesting that the
      LAP deletion affected transcriptional regulation of the IE genes in cis. We
      conclude that the function of the highly conserved LAT intron is unlikely to
      involve a direct-acting anti-ICP0 antisense mechanism but that the LAT region
      could affect ICP0 mRNA expression from the viral genome.

PMID- 12610128
TI  - Cell surface-binding motifs of L2 that facilitate papillomavirus infection.
AB  - Human papillomavirus type 16 (HPV16) is the primary etiologic agent of cervical
      carcinoma, whereas bovine papillomavirus type 1 (BPV1) causes benign
      fibropapillomas. However, the capsid proteins, L1 and L2, of these divergent
      papillomaviruses exhibit functional conservation. A peptide comprising residues 1
      to 88 of BPV1 L2 binds to a variety of cell lines, but not to the monocyte
      derived cell line D32, and blocks BPV1 infection of mouse C127 cells. Residues 13
      to 31 of HPV16 L2 and BPV1 L2 residues 1 to 88 compete for binding to the cell
      surface, and their binding, unlike that of HPV16 L1/L2 virus-like particles, is
      unaffected by heparinase or trypsin pretreatment of HeLa cells. A fusion of HPV16
      L2 peptide 13-31 and GFP binds (K(d), approximately 1 nM) to approximately 45,000
      receptors per HeLa cell. Furthermore, mutation of L2 residues 18 and 19 or 21 and
      22 significantly reduces both the ability of the HPV16 L2 13-31-GFP fusion
      protein to bind to SiHa cells and the infectivity of HPV16 pseudovirions.
      Antibody to BPV1 L2 peptides comprising residues 115 to 135 binds to intact BPV1
      virions, but fails to neutralize at a 1:10 dilution. However, deletion of
      residues 91 to 129 from L2 abolishes the infectivity of BPV1, but not their
      binding to the cell surface. In summary, L2 residues 91 to 129 contain epitopes
      displayed on the virion surface and are required for infection, but not virion
      binding to the cell surface. Upon the binding of papillomavirus to the cell
      surface, residues 13 to 31 of L2 interact with a widely expressed, trypsin- and
      heparinase-resistant cell surface molecule and facilitate infection.

PMID- 12610129
TI  - The 5'-end sequence of the genome of Aichi virus, a picornavirus, contains an
      element critical for viral RNA encapsidation.
AB  - Picornavirus positive-strand RNAs are selectively encapsidated despite the
      coexistence of viral negative-strand RNAs and cellular RNAs in infected cells.
      However, the precise mechanism of the RNA encapsidation process in picornaviruses
      remains unclear. Here we report the first identification of an RNA element
      critical for encapsidation in picornaviruses. The 5' end of the genome of Aichi
      virus, a member of the family Picornaviridae, folds into three stem-loop
      structures (SL-A, SL-B, and SL-C, from the most 5' end). In the previous study,
      we constructed a mutant, termed mut6, by exchanging the seven-nucleotide
      stretches of the middle part of the stem in SL-A with each other to maintain the
      base pairings of the stem. mut6 exhibited efficient RNA replication and
      translation but formed no plaques. The present study showed that in cells
      transfected with mut6 RNA, empty capsids were accumulated, but few virions
      containing RNA were formed. This means that mut6 has a severe defect in RNA
      encapsidation. Site-directed mutational analysis indicated that as the mutated
      region was narrowed, the encapsidation was improved. As a result, the mutation of
      the 7 bp of the middle part of the stem in SL-A was required for abolishing the
      plaque-forming ability. Thus, the 5'-end sequence of the Aichi virus genome was
      shown to play an important role in encapsidation.

PMID- 12610130
TI  - Oligomerization and activity of the helicase domain of the tobacco mosaic virus
      126- and 183-kilodalton replicase proteins.
AB  - A protein-protein interaction within the helicase domain of the Tobacco mosaic
      virus (TMV) 126- and 183-kDa replicase proteins was previously implicated in
      virus replication (S. Goregaoker, D. Lewandowski, and J. Culver, Virology 282:320
      328, 2001). To further characterize the interaction, polypeptides covering the
      interacting portions of the TMV helicase domain were expressed and purified.
      Biochemical characterizations demonstrated that the helicase domain polypeptides
      hydrolyzed ATP and bound both single-stranded and duplexed RNA in an ATP
      controlled fashion. A TMV helicase polypeptide also was capable of unwinding
      duplexed RNA, confirming the predicted helicase function of the domain.
      Biochemically active helicase polypeptides were shown by gel filtration to form
      high-molecular-weight complexes. Electron microscopy studies revealed the
      presence of ring-like oligomers that displayed six-sided symmetry. Taken
      together, these data demonstrate that the TMV helicase domain interacts with
      itself to produce hexamer-like oligomers. Within the context of the full-length
      126- and 183-kDa proteins, these findings suggest that the TMV replicase may form
      a similar oligomer.

PMID- 12610131
TI  - 3' nontranslated RNA signals required for replication of hepatitis C virus RNA.
AB  - We describe a mutational analysis of the 3' nontranslated RNA (3'NTR) signals
      required for replication of subgenomic hepatitis C virus (HCV) RNAs. A series of
      deletion mutants was constructed within the background of an HCV-N replicon that
      induces the expression of secreted alkaline phosphatase in order to examine the
      requirements for each of the three domains comprising the 3'NTR, namely, the
      highly conserved 3' terminal 98-nucleotide (nt) segment (3'X), an upstream
      poly(U)-poly(UC) [poly(U/UC)] tract, and the variable region (VR) located at the
      5' end of the 3'NTR. Each of these domains was found to contribute to efficient
      replication of the viral RNA in transiently transfected hepatoma cells.
      Replication was not detected when any of the three putative stem-loop structures
      within the 3'X region were deleted. Similarly, complete deletion of the
      poly(U/UC) tract abolished replication. Replacement of a minimum of 50 to 62 nt
      of poly(U/UC) sequence was required for detectable RNA replication when the
      native sequence was restored in a stepwise fashion from its 3' end. Lengthier
      poly(U/UC) sequences, and possibly pure homopolymeric poly(U) tracts, were
      associated with more efficient RNA amplification. Finally, while multiple
      deletion mutations were tolerated within VR, each led to a partial loss of
      replication capacity. The impaired replication capacity of the deletion mutants
      could not be explained by reduced translational activity or by decreased
      stability of the RNA, suggesting that each of these mutations may impair
      recognition of the RNA by the viral replicase during an early step in negative
      strand RNA synthesis. The results indicate that the 3'-most 150 nt of the HCV-N
      genome [the 3'X region and the 3' 52 nt of the poly(U/UC) tract] contain RNA
      signals that are essential for replication, while the remainder of the 3'NTR
      plays a facilitating role in replication but is not absolutely required.

PMID- 12610133
TI  - Protein synthesis and endoplasmic reticulum stress can be modulated by the
      hepatitis C virus envelope protein E2 through the eukaryotic initiation factor
      2alpha kinase PERK.
AB  - The hepatitis C virus envelope protein, E2, is an endoplasmic reticulum (ER)
      bound protein that contains a region of sequence homology with the double
      stranded RNA-activated protein kinase PKR and its substrate, the eukaryotic
      translation initiation factor 2 (eIF2). We previously reported that E2 modulates
      global translation through inhibition of the interferon-induced antiviral protein
      PKR through its PKR-eIF2alpha phosphorylation site homology domain (PePHD). Here
      we show that the PKR-like ER-resident kinase (PERK) binds to and is also
      inhibited by E2. At low expression levels, E2 induced ER stress, but at high
      expression levels, and in vitro, E2 inhibited PERK kinase activity. Mammalian
      cells that stably express E2 were refractory to the translation-inhibitory
      effects of ER stress inducers, and E2 relieved general translation inhibition
      induced by PERK. The PePHD of E2 was required for the rescue of translation that
      was inhibited by activated PERK, similar to our previous findings with PKR. Here
      we report the inhibition of a second eIF2alpha kinase by E2, and these results
      are consistent with a pseudosubstrate mechanism of inhibition of eIF2alpha
      kinases. These findings may also explain how the virus promotes persistent
      infection by overcoming the cellular ER stress response.

PMID- 12610132
TI  - Two nonoverlapping domains on the Norwalk virus open reading frame 3 (ORF3)
      protein are involved in the formation of the phosphorylated 35K protein and in
      ORF3-capsid protein interactions.
AB  - Expression of the Norwalk virus open reading frame 3 (ORF3) in Spodoptera
      frugiperda (Sf9) cells yields two major forms, the predicted 23,000-molecular
      weight (23K) form and a larger 35K form. The 23K form is able to interact with
      the ORF2 capsid protein and be incorporated into virus-like particles. In this
      paper, we provide mass spectrometry evidence that both the 23K and 35K forms are
      composed only of the ORF3 protein. Two-dimensional gel electrophoresis and
      phosphatase treatment showed that the 35K form results solely from
      phosphorylation and that the 35K band is composed of several different
      phosphorylated forms with distinct isoelectric points. Furthermore, we analyzed
      deletion and point mutants of the ORF3 protein. Mutants that lacked the C
      terminal 33 amino acids (ORF3(1-179), ORF3(1-152), and ORF3(1-107)) no longer
      produced the 35K form. An N-terminal truncation mutant (ORF3(51-212)) and a site
      directed mutant (ORF3(T201V)) were capable of producing the larger form, which
      was converted to the smaller form by treatment with protein phosphatase. These
      data suggest that the region between amino acids 180 and 212 is phosphorylated,
      and mass spectrometry showed that amino acids Arg196 to Arg211 are not
      phosphorylated; thus, phosphorylation of the serine-threonine-rich region from
      Thr181 to Ser193 must be involved in the generation of the 35K form. Studies of
      the interaction between the ORF2 protein and full-length and mutated ORF3
      proteins showed that the full-length ORF3 protein (ORF3(FL)), ORF3(1-179), ORF3(1
      152), and ORF3(51-212) interacted with the ORF2 protein, while an ORF3(1-107)
      protein did not. These results indicate that the region of the ORF3 protein
      between amino acids 108 and 152 is responsible for interaction with the ORF2
      protein.

PMID- 12610134
TI  - Requirement of the adenovirus IVa2 protein for virus assembly.
AB  - The adenovirus L1 52/55-kDa protein is required for viral DNA packaging and
      interacts with the viral IVa2 protein, which binds to the viral packaging
      sequence. Previous reports suggest that the IVa2 protein plays a role in viral
      DNA packaging and that this function of the IVa2 protein is serotype specific. To
      further examine the function of the IVa2 protein in viral DNA packaging, a mutant
      virus that does not express the IVa2 protein was constructed by introducing two
      stop codons at the beginning of the IVa2 open reading frame in a full-length
      bacterial clone of adenovirus type 5. The mutant virus, pm8002, was defective for
      growth in 293 cells, although it replicated its DNA and produced early and late
      viral proteins. Electron microscopic and gradient analyses revealed that the
      mutant virus did not assemble any viral particles in 293 cells. In 293-IVa2
      cells, which express the IVa2 protein, infectious viruses were produced, although
      the titer of the mutant virus was lower than that of the wild-type virus,
      indicating that these cells may not fully complement the mutation. The mutant
      viral particles produced in 293-IVa2 cells were heterogeneous in size and shape,
      less stable, and did not traffic efficiently to the nucleus. Marker rescue
      experiments with a wild-type IVa2 DNA fragment confirmed that the only mutations
      present in pm8002 were in the IVa2 gene. The results indicate that the IVa2
      protein is required for adenovirus assembly and suggest that virus particles may
      be assembled around the DNA rather than DNA being packaged into preformed
      capsids.

PMID- 12610135
TI  - A zinc ion controls assembly and stability of the major capsid protein of
      rotavirus.
AB  - The recent determination of the crystal structure of VP6, the major capsid
      protein of rotavirus, revealed a trimer containing a central zinc ion coordinated
      by histidine 153 from each of the three subunits. The role of the zinc ion in the
      functions of VP6 was investigated by site-directed mutagenesis. The mutation of
      histidine 153 into a serine (H153S and H153S/S339H) did not prevent the formation
      of VP6 trimers. At pH <7.0, about the pK of histidine, wild-type and mutated VP6
      proteins display similar properties, giving rise to identical tubular and
      spherical assemblies. However, at pH >7.0, histidine 153 mutant proteins did not
      assemble into the characteristic 45-nm-diameter tubes, in contrast to wild-type
      VP6. These observations showed that under conditions in which histidine residues
      are not charged, the properties of VP6 depended on the presence of the centrally
      coordinated zinc atom in the trimer. Indeed, wild-type VP6 depleted of the zinc
      ion by a high concentration (100 mM) of a metal-chelating agent behaved like the
      H153 mutant proteins. The susceptibility of wild-type VP6 to proteases is greatly
      increased in the absence of zinc. NH(2)-terminal sequencing of the proteolytic
      fragments showed that they all contained the beta-sheet-rich VP6 head domain,
      which appeared to be less sensitive to protease activity than the alpha-helical
      basal domain. Finally, the mutant proteins assembled well on cores, as
      demonstrated by both electron microscopy and rescue of transcriptase activity.
      Zinc is thus not necessary for the transcription activity. All of these
      observations suggest that, in solution, VP6 trimers present a structural
      flexibility that is controlled by the presence of a zinc ion.

PMID- 12610136
TI  - The human cytomegalovirus major immediate-early enhancer determines the
      efficiency of immediate-early gene transcription and viral replication in
      permissive cells at low multiplicity of infection.
AB  - To determine the effect of the human cytomegalovirus (CMV) major immediate-early
      (MIE) enhancer or promoter on the efficiency of viral replication in permissive
      human cells, we constructed recombinant viruses with their human MIE promoter,
      enhancer, and promoter plus enhancer replaced with the murine CMV components.
      After a low multiplicity of infection (MOI) (0.01 PFU/cell), recombinant human
      CMV with the murine CMV promoter replicated like the wild type but recombinant
      virus with the murine enhancer replicated less efficiently. Immediate-early (IE)
      viral protein pIE72 (UL123), early viral protein (UL44), and viral DNA synthesis
      were significantly decreased. The effect of the human CMV enhancer substitution
      with the murine CMV enhancer was also demonstrated in different cell types by
      using recombinant virus with the UL127 promoter, driving the expression of green
      fluorescent protein (GFP). After an MOI of 1, GFP expression was high with the
      human CMV enhancer and significantly lower with the murine CMV enhancer. Even
      though at a high MOI (10 PFU/cell), the murine CMV enhancer was as efficient as
      the human CMV enhancer for the transcription of IE genes in human foreskin
      fibroblast cells, at lower MOIs, the murine CMV enhancer was less efficient.
      Proximal and distal chimeras of the human and murine enhancers also replicated
      less efficiently at a low MOI and expressed lower levels of GFP from the UL127
      promoter. These experiments demonstrate that the entire human CMV enhancer has
      evolved for the efficient expression of the viral IE and early genes in human
      cells. Possible functions of the human CMV enhancer and promoter at a low MOI are
      discussed.

PMID- 12610137
TI  - Enhancement of mucosal immunization with virus-like particles of simian
      immunodeficiency virus.
AB  - Cholera toxin (CT) is the most potent known mucosal adjuvant, but its toxicity
      precludes its use in humans. Here, in an attempt to develop safe and effective
      mucosal adjuvants, we compared immune responses to simian immunodeficiency virus
      (SIV) virus-like particles (VLPs) after intranasal coimmunization with RANTES,
      CpG oligodeoxynucleotides (ODN), or CT. Antibody analysis demonstrated that
      RANTES and CpG ODN had capacities for mucosal adjuvanticity, i.e., for enhancing
      serum and vaginal antibodies specific to SIV Env, similar to those for CT. RANTES
      and CpG ODN skewed serum antibodies predominantly to the immunoglobulin G2a
      isotype. Most importantly, RANTES and CpG ODN were more effective than CT in
      increasing neutralizing titers of both serum and vaginal antibodies. After
      intranasal coadministration with VLPs, RANTES or CpG ODN also induced increased
      levels of gamma interferon (IFN-gamma)-producing lymphocyte and cytotoxic T
      lymphocyte activities in both spleen and lymph nodes but did not increase the
      levels of interleukin-4-producing lymphocytes. The results suggest that RANTES
      and CpG ODN enhance immune responses in a T-helper-cell-type-1 (Th1)-oriented
      manner and that they can be used as effective mucosal adjuvants for enhancing
      both humoral and cellular immune responses in the context of VLPs, which are
      particulate antigens.

PMID- 12610139
TI  - Rational site-directed mutations of the LLP-1 and LLP-2 lentivirus lytic peptide
      domains in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41
      indicate common functions in cell-cell fusion but distinct roles in virion
      envelope incorporation.
AB  - Two highly conserved cationic amphipathic alpha-helical motifs, designated
      lentivirus lytic peptides 1 and 2 (LLP-1 and LLP-2), have been characterized in
      the carboxyl terminus of the transmembrane (TM) envelope glycoprotein (Env) of
      lentiviruses. Although various properties have been attributed to these domains,
      their structural and functional significance is not clearly understood. To
      determine the specific contributions of the Env LLP domains to Env expression,
      processing, and incorporation and to viral replication and syncytium induction,
      site-directed LLP mutants of a primary dualtropic infectious human
      immunodeficiency virus type 1 (HIV-1) isolate (ME46) were examined. Substitutions
      were made for highly conserved arginine residues in either the LLP-1 or LLP-2
      domain (MX1 or MX2, respectively) or in both domains (MX4). The HIV-1 mutants
      with altered LLP domains demonstrated distinct phenotypes. The LLP-1 mutants (MX1
      and MX4) were replication defective and showed an average of 85% decrease in
      infectivity, which was associated with an evident decrease in gp41 incorporation
      into virions without a significant decrease in Env expression or processing in
      transfected 293T cells. In contrast, MX2 virus was replication competent and
      incorporated a full complement of Env into its virions, indicating a differential
      role for the LLP-1 domain in Env incorporation. Interestingly, the replication
      competent MX2 virus was impaired in its ability to induce syncytia in T-cell
      lines. This defect in cell-cell fusion did not correlate with apparent defects in
      the levels of cell surface Env expression, oligomerization, or conformation. The
      lack of syncytium formation, however, correlated with a decrease of about 90% in
      MX2 Env fusogenicity compared to that of wild-type Env in quantitative luciferase
      based cell-cell fusion assays. The LLP-1 mutant MX1 and MX4 Envs also exhibited
      an average of 80% decrease in fusogenicity. Altogether, these results demonstrate
      for the first time that the highly conserved LLP domains perform critical but
      distinct functions in Env incorporation and fusogenicity.

PMID- 12610140
TI  - Triggering of human parainfluenza virus 3 fusion protein (F) by the hemagglutinin
      neuraminidase (HN) protein: an HN mutation diminishes the rate of F activation
      and fusion.
AB  - For human parainfluenza virus type 3 and many other paramyxoviruses, membrane
      fusion mediated by the fusion protein (F) has a stringent requirement for the
      presence of the homotypic hemagglutinin-neuraminidase protein (HN). With the goal
      of gaining further insight into the role of HN in the fusion process, we
      developed a simple method for quantitative comparison of the ability of wild-type
      and variant HNs to activate F. In this method, HN/F-coexpressing cells with red
      blood cells (RBC) bound to them at 4 degrees C are transferred to 22 degrees C,
      and at different times after transfer 4-guanidino-neu5Ac2en (4-GU-DANA) is added;
      this inhibitor of the HN-receptor interaction then releases all reversibly bound
      RBC but not those in which F insertion in the target membrane or fusion has
      occurred. Thus, the amount of irreversibly bound (nonreleased) RBC provides a
      measure of F activation, and the use of fluorescently labeled RBC permits
      microscopic assessment of the extent to which F insertion has progressed to
      fusion. We studied two neuraminidase-deficient HN variants, C28a, which has two
      mutations, P111S and D216N, and C28, which possesses the D216N mutation only.
      C28a but not C28 exhibits a slow fusion phenotype, although determination of the
      HNs' receptor-binding avidity (with our sensitive method, employing RBC with
      different degrees of receptor depletion) showed that the receptor-binding avidity
      of C28a or C28 HN was not lower than that of the wild type. The F activation
      assay, however, revealed fusion-triggering defects in C28a HN. After 10 and also
      20 min at 22 degrees C, irreversible RBC binding was significantly less for cells
      coexpressing wild-type F with C28a HN than for cells coexpressing wild-type F
      with wild-type HN. In addition, F insertion progressed to fusion more slowly in
      the case of C28a HN-expressing cells than of wild-type HN-expressing cells.
      Identical defects were found for P111S HN, whereas for C28 HN, representing the
      216 mutation of C28a, F activation and fusion were as rapid as for wild-type HN.
      The diminished fusion promotion capacity of C28a HN is therefore attributable to
      P111S, a mutation in the stalk region of the molecule that causes no decrease in
      receptor-binding avidity. C28a HN is the first parainfluenza virus variant found
      so far to be specifically defective in HN's F-triggering and fusion promotion
      functions and may contribute to our understanding of transmission of the
      activating signal from HN to F.

PMID- 12610138
TI  - Potential role for CD63 in CCR5-mediated human immunodeficiency virus type 1
      infection of macrophages.
AB  - Macrophages and CD4(+) lymphocytes are the principal target cells for human
      immunodeficiency virus type 1 (HIV-1) infection, but the molecular details of
      infection may differ between these cell types. During studies to identify
      cellular molecules that could be involved in macrophage infection, we observed
      inhibition of HIV-1 infection of macrophages by monoclonal antibody (MAb) to the
      tetraspan transmembrane glycoprotein CD63. Pretreatment of primary macrophages
      with anti-CD63 MAb, but not MAbs to other macrophage cell surface tetraspanins
      (CD9, CD81, and CD82), was shown to inhibit infection by several R5 and
      dualtropic strains, but not by X4 isolates. The block to productive infection was
      postfusion, as assessed by macrophage cell-cell fusion assays, but was prior to
      reverse transcription, as determined by quantitative PCR assay for new viral DNA
      formation. The inhibitory effects of anti-CD63 in primary macrophages could not
      be explained by changes in the levels of CD4, CCR5, or beta-chemokines.
      Infections of peripheral blood lymphocytes and certain cell lines were unaffected
      by treatment with anti-CD63, suggesting that the role of CD63 in HIV-1 infection
      may be specific for macrophages.

PMID- 12610141
TI  - Yellow fever virus/dengue-2 virus and yellow fever virus/dengue-4 virus chimeras:
      biological characterization, immunogenicity, and protection against dengue
      encephalitis in the mouse model.
AB  - Two yellow fever virus (YFV)/dengue virus chimeras which encode the prM and E
      proteins of either dengue virus serotype 2 (dengue-2 virus) or dengue-4 virus
      within the genome of the YFV 17D strain (YF5.2iv infectious clone) were
      constructed and characterized for their properties in cell culture and as
      experimental vaccines in mice. The prM and E proteins appeared to be properly
      processed and glycosylated, and in plaque reduction neutralization tests and
      other assays of antigenic specificity, the E proteins exhibited profiles which
      resembled those of the homologous dengue virus serotypes. Both chimeric viruses
      replicated in cell lines of vertebrate and mosquito origin to levels comparable
      to those of homologous dengue viruses but less efficiently than the YF5.2iv
      parent. YFV/dengue-4 virus, but not YFV/dengue-2 virus, was neurovirulent for 3
      week-old mice by intracerebral inoculation; however, both viruses were attenuated
      when administered by the intraperitoneal route in mice of that age. Single-dose
      inoculation of either chimeric virus at a dose of 10(5) PFU by the
      intraperitoneal route induced detectable levels of neutralizing antibodies
      against the homologous dengue virus strains. Mice which had been immunized in
      this manner were fully protected from challenge with homologous neurovirulent
      dengue viruses by intracerebral inoculation compared to unimmunized mice.
      Protection was associated with significant increases in geometric mean titers of
      neutralizing antibody compared to those for unimmunized mice. These data indicate
      that YFV/dengue virus chimeras elicit antibodies which represent protective
      memory responses in the mouse model of dengue encephalitis. The levels of
      neurovirulence and immunogenicity of the chimeric viruses in mice correlate with
      the degree of adaptation of the dengue virus strain to mice. This study supports
      ongoing investigations concerning the use of this technology for development of a
      live attenuated viral vaccine against dengue viruses.

PMID- 12610142
TI  - In vitro selection and characterization of hepatitis C virus serine protease
      variants resistant to an active-site peptide inhibitor.
AB  - The hepatitis C virus (HCV) serine protease is necessary for viral replication
      and represents a valid target for developing new therapies for HCV infection.
      Potent and selective inhibitors of this enzyme have been identified and shown to
      inhibit HCV replication in tissue culture. The optimization of these inhibitors
      for clinical development would greatly benefit from in vitro systems for the
      identification and the study of resistant variants. We report the use HCV
      subgenomic replicons to isolate and characterize mutants resistant to a protease
      inhibitor. Taking advantage of the replicons' ability to transduce resistance to
      neomycin, we selected replicons with decreased sensitivity to the inhibitor by
      culturing the host cells in the presence of the inhibitor and neomycin. The
      selected replicons replicated to the same extent as those in parental cells.
      Sequence analysis followed by transfection of replicons containing isolated
      mutations revealed that resistance was mediated by amino acid substitutions in
      the protease. These results were confirmed by in vitro experiments with mutant
      enzymes and by modeling the inhibitor in the three-dimensional structure of the
      protease.

PMID- 12610143
TI  - Recruitment of herpes simplex virus type 1 transcriptional regulatory protein
      ICP4 into foci juxtaposed to ND10 in live, infected cells.
AB  - At the early stages of herpes simplex virus type 1 (HSV-1) infection, parental
      viral genomes have a tendency to become juxtaposed to cellular nuclear structures
      known as PML (promyelocytic leukemia) nuclear bodies or ND10, while the immediate
      early (IE) protein ICP0 precisely colocalizes with these structures. Previous
      indirect-immunofluorescence studies observed that the HSV-1 transcriptional
      regulator ICP4 has a mainly diffuse nuclear distribution early in infection and
      is later recruited into viral replication compartments. We have constructed HSV-1
      variants expressing ICP4 and ICP0 linked to ECFP and EYFP, respectively, both
      singly and in combination. Coupled with an efficient method of expressing
      autofluorescent PML in ND10, we have studied the dynamics of ICP0, ICP4, and ND10
      in live, infected cells. The greater sensitivity and lower background signals in
      live cells revealed that early in infection, ICP4 forms discrete foci, some of
      which are juxtaposed to ND10, while ICP0 was found to colocalize precisely with
      PML. As expected from these results, using a double-labeled virus, we observed
      that foci of ICP0 and ICP4 were also juxtaposed but not colocalized early in
      infection. Some of the ICP4 foci must have contained parental viral genomes,
      because they developed into replication compartments. We propose that a
      proportion of the ND10-associated ICP4 foci represent ICP4 molecules being
      recruited onto parental viral genomes, a process likely to be a critical step
      early in lytic infection. These results may be analogous to the localization of
      IE1 and IE2 during human cytomegalovirus infection, suggesting a principle common
      to the alpha- and betaherpesviruses.

PMID- 12610145
TI  - Generation of an infectious clone of VR-2332, a highly virulent North American
      type isolate of porcine reproductive and respiratory syndrome virus.
AB  - A full-length cDNA clone of the prototypical North American porcine reproductive
      and respiratory syndrome virus (PRRSV) isolate VR-2332 was assembled in the
      plasmid vector pOK(12). To rescue infectious virus, capped RNA was transcribed in
      vitro from the pOK(12) clone and transfected into BHK-21C cells. The supernatant
      from transfected monolayers were serially passaged on Marc-145 cells and porcine
      pulmonary alveolar macrophages. Infectious PRRSV was recovered on Marc-145 cells
      as well as porcine pulmonary macrophages; thus, the cloned virus exhibited the
      same cell tropism as the parental VR-2332 strain. However, the cloned virus was
      clearly distinguishable from the parental VR-2332 strain by an engineered marker,
      a BstZ17I restriction site. The full-length cDNA clone had 11 nucleotide changes,
      2 of which affected coding, compared to the parental VR-2332 strain.
      Additionally, the transcribed RNA had an extra G at the 5' end. To examine
      whether these changes influenced viral replication, we examined the growth
      kinetics of the cloned virus in vitro. In Marc-145 cells, the growth kinetics of
      the cloned virus reflected those of the parental isolate, even though the titers
      of the cloned virus were consistently slightly lower. In experimentally infected
      5.5-week-old pigs, the cloned virus produced blue discoloration of the ears, a
      classical clinical symptom of PRRSV. Also, the seroconversion kinetics of pigs
      infected with the cloned virus and VR-2332 were very similar. Hence, virus
      derived from the full-length cDNA clone appeared to recapitulate the biological
      properties of the highly virulent parental VR-2332 strain. This is the first
      report of an infectious cDNA clone based on American-type PRRSV. The availability
      of this cDNA clone will allow examination of the molecular mechanisms behind
      PRRSV virulence and attenuation, which might in turn allow the production of
      second-generation, genetically engineered PRRSV vaccines.

PMID- 12610144
TI  - The Epstein-Barr virus SM protein induces STAT1 and interferon-stimulated gene
      expression.
AB  - Viruses utilize numerous mechanisms to counteract the host's immune response.
      Interferon production is a major component of the host antiviral response. Many
      viruses, therefore, produce proteins or RNA molecules that inhibit interferon
      induced signal transduction pathways and their associated antiviral effects.
      Surprisingly, some viruses directly induce expression of interferon-induced
      genes. SM, an early lytic Epstein-Barr virus (EBV) nuclear protein, was found to
      specifically increase the expression of several genes (interferon-stimulated
      genes) that are known to be strongly induced by alpha/beta interferons. SM does
      not directly stimulate alpha/beta interferon secretion but instead induces STAT1,
      an intermediate step in the interferon signaling pathway. SM is a
      posttranscriptional activator of gene expression and increases STAT1 mRNA
      accumulation, particularly that of the functionally distinct STAT1beta splice
      variant. SM expression in B lymphocytes is associated with decreased cell
      proliferation but does not decrease cell viability or induce cell cycle arrest.
      These results indicate that EBV can specifically induce cellular genes that are
      normally physiological targets of interferon by inducing components of cytokine
      signaling pathways. Our findings therefore suggest that some aspects of the
      interferon response may be positively modulated by infecting viruses.

PMID- 12610146
TI  - The interaction between the fiber knob domain and the cellular attachment
      receptor determines the intracellular trafficking route of adenoviruses.
AB  - Most of the presently used adenovirus (Ad) vectors are based on serotype 5.
      However, the application of these vectors is limited by the native tropism of
      Ad5. To address this problem, a series of fiber chimeric vectors were produced to
      take advantage of the different cellular receptors used by Ad of different
      subgroups. In this study we utilize an Ad5-based chimeric vector containing
      sequences encoding the Ad35 fiber knob domain instead of the Ad5 knob (Ad5/35L)
      to analyze factors responsible for selection of intracellular trafficking routes
      by Ads. By competition analysis with recombinant Ad5 and Ad35 knobs we showed
      that the Ad5/35L vector infected cells through a receptor different from the Ad5
      receptor. Intracellular trafficking of Ad5 and Ad5/35L viruses was analyzed in
      HeLa cells by tracking fluorophore-conjugated Ad particles, by immunostaining for
      capsid hexon protein, by electron microscopy, and by Southern blotting for viral
      DNA. These studies showed that the interaction with the Ad35 receptor(s)
      predestines Ad5/35L vector to intracellular trafficking pathways different from
      those of Ad5. Ad5 efficiently escaped from the endosomes early after infection.
      In contrast, Ad5/35L remained longer in late endosomal/lysosomal compartments and
      used them to achieve localization to the nucleus. However, a significant portion
      of Ad5/35L particles appeared to be recycled back to the cell surface. This
      phenomenon resulted in significantly less efficient Ad5/35L-mediated gene
      transfer compared to that of Ad5. We also demonstrated that the selection of
      intracellular trafficking routes was determined by the fiber knob domain and did
      not depend on the length of the fiber shaft. This study contributes to a better
      understanding of the mechanisms that govern the infection of retargeted, capsid
      modified vectors which have potential application for hematopoietic stem cell and
      tumor gene therapy.

PMID- 12610148
TI  - A nonconventional nuclear localization signal within the UL84 protein of human
      cytomegalovirus mediates nuclear import via the importin alpha/beta pathway.
AB  - The open reading frame UL84 of human cytomegalovirus encodes a multifunctional
      regulatory protein which is required for viral DNA replication and binds with
      high affinity to the immediate-early transactivator IE2-p86. Although the exact
      role of pUL84 in DNA replication is unknown, the nuclear localization of this
      protein is a prerequisite for this function. To investigate whether the
      activities of pUL84 are modulated by cellular proteins we used the Saccharomyces
      cerevisiae two-hybrid system to screen a cDNA-library for interacting proteins.
      Strong interactions were found between pUL84 and four members of the importin
      alpha protein family. These interactions could be confirmed in vitro by pull down
      experiments and in vivo by coimmunoprecipitation analysis from transfected cells.
      Using in vitro transport assays we showed that the pUL84 nuclear import required
      importin alpha, importin beta, and Ran, thus following the classical importin
      mediated import pathway. Deletion mutagenesis of pUL84 revealed a domain of 282
      amino acids which is required for binding to the importin alpha proteins. Its
      function as a nuclear localization signal (NLS) was confirmed by fusion to
      heterologous proteins. Although containing a cluster of basic amino acids similar
      to classical NLSs, this cluster did not contain the NLS activity. Thus, a complex
      structure appears to be essential for importin alpha binding and import activity.

PMID- 12610149
TI  - Transmembrane domains 1 and 2 of the latent membrane protein 1 of Epstein-Barr
      virus contain a lipid raft targeting signal and play a critical role in
      cytostasis.
AB  - The latent membrane protein 1 (LMP-1) oncoprotein of Epstein-Barr virus (EBV) is
      a constitutively active, CD40-like cell surface signaling protein essential for
      EBV-mediated human B-cell immortalization. Like ligand-activated CD40, LMP-1
      activates NF-kappaB and Jun kinase signaling pathways via binding, as a
      constitutive oligomer, to tumor necrosis factor receptor-associated factors
      (TRAFs). LMP-1's lipid raft association and oligomerization have been linked to
      its activation of cell signaling pathways. Both oligomerization and lipid raft
      association require the function of LMP-1's polytopic multispanning transmembrane
      domain, a domain that is indispensable for LMP-1's growth-regulatory signaling
      activities. We have begun to address the sequence requirements of the polytopic
      hydrophobic transmembrane domain for LMP-1's signaling and biochemical
      activities. Here we report that transmembrane domains 1 and 2 are sufficient for
      LMP-1's lipid raft association and cytostatic activity. Transmembrane domains 1
      and 2 support NF-kappaB activation, albeit less potently than does the entire
      polytopic transmembrane domain. Interestingly, LMP-1's first two transmembrane
      domains are not sufficient for oligomerization or TRAF binding. These results
      suggest that lipid raft association and oligomerization are mediated by distinct
      and separable activities of LMP-1's polytopic transmembrane domain. Additionally,
      lipid raft association, mediated by transmembrane domains 1 and 2, plays a
      significant role in LMP-1 activation, and LMP-1 can activate NF-kappaB via an
      oligomerization/TRAF binding-independent mechanism. To our knowledge, this is the
      first demonstration of an activity's being linked to individual membrane-spanning
      domains within LMP-1's polytopic transmembrane domain.

PMID- 12610147
TI  - Antiviral activity and conformational features of an octapeptide derived from the
      membrane-proximal ectodomain of the feline immunodeficiency virus transmembrane
      glycoprotein.
AB  - Feline immunodeficiency virus (FIV) provides a valuable animal model by which
      criteria for lentivirus control strategies can be tested. Previous studies have
      shown that a 20-mer synthetic peptide of the membrane-proximal ectodomain of FIV
      transmembrane glycoprotein, designated peptide 59, potently inhibited the growth
      of tissue culture-adapted FIV in feline fibroblastoid CrFK cells. In the present
      report we describe the potential of this peptide to inhibit the replication of
      primary FIV isolates in lymphoid cells. Because antiviral activity of peptide 59
      was found to map to a short segment containing three conserved Trp residues,
      further analyses focused on a derivative of eight amino acids ((770)W-I(777)),
      designated C8. Peptide C8 activity was found to be dependent on conservation of
      the Trp motif, to be removed from solution by FIV absorbed onto substrate cells,
      and to be blocked by a peptide derived from the N-terminal portion of FIV
      transmembrane glycoprotein. Structural studies showed that peptide C8 possesses a
      conformational propensity highly uncommon for peptides of its size, which may
      account for its considerable antiviral potency in spite of small size.

PMID- 12610150
TI  - The domains of glycoprotein D required to block apoptosis induced by herpes
      simplex virus 1 are largely distinct from those involved in cell-cell fusion and
      binding to nectin1.
AB  - Glycoprotein D (gD) interacts with two alternative protein receptors, nectin1 and
      HveA, to mediate herpes simplex virus (HSV) entry into cells. Fusion of the
      envelope with the plasma membrane requires, in addition to gD, glycoproteins gB,
      gH, and gL. Coexpression of the four glycoproteins (gD, gB, gH, and gL) promotes
      cell-cell fusion. gD delivered in trans is also capable of blocking the apoptosis
      induced by gD deletion viruses grown either in noncomplementing cells (gD(-/-))
      or in complementing cells (gD(-/+)). While ectopic expression of cation
      independent mannose-6 phosphate receptor blocks apoptosis induced by both stocks,
      other requirements differ. Thus, apoptosis induced by gD(-/-) virus is blocked by
      full-length gD (or two gD fragments reconstituting a full-length molecule),
      whereas ectopic expression of the gD ectodomain is sufficient to block apoptosis
      induced by gD(-/+) virus. In this report we took advantage of a set of gD
      insertion-deletion mutants to map the domains of gD required to block apoptosis
      by gD(-/-) and gD(-/+) viruses and those involved in cell-cell fusion. The
      mutations that resulted in failure to block apoptosis were the same for gD(-/-)
      and gD(-/+) viruses and were located in three sites, one within the
      immunoglobulin-type core region (residues 125, 126, and 151), one in the upstream
      connector region (residues 34 and 43), and one in the C-terminal portion of the
      ectodomain (residue 277). A mutant that carried amino acid substitutions at the
      three glycosylation sites failed to block apoptosis but behaved like wild-type gD
      in all other assays. The mutations that inhibited polykaryocyte formation were
      located in the upstream connector region (residues 34 and 43), at the alpha1
      helix (residue 77), in the immunoglobulin core and downstream regions (residue
      151 and 187), and at the alpha3 helix (residues 243 and 246). Binding of soluble
      nectin1-Fc to cells expressing the mutant gDs was generally affected by the same
      mutations that affected fusion, with one notable exception (Delta277-310), which
      affected fusion without hampering nectin1 binding. This deletion likely
      identifies a region of gD involved in fusion activity at a post-nectin1-binding
      step. We conclude that whereas mutations that affected all functions (e.g.,
      upstream connector region and residue 151) may be detrimental to overall gD
      structure, the mutations that affect specific activities identify domains of gD
      involved in the interactions with entry receptors and fusogenic glycoproteins and
      with cellular proteins required to block apoptosis. The evidence that
      glycosylation of gD is required for blocking apoptosis supports the conclusion
      that the interacting protein is the mannose-6 phosphate receptor.

PMID- 12610151
TI  - Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV)
      relieves the viral block to dendritic cell activation: potential of vhs- HSV
      vectors for dendritic cell-mediated immunotherapy.
AB  - Herpes simplex virus (HSV) infects dendritic cells (DC) efficiently but with
      minimal replication. HSV, therefore, appears to have evolved the ability to enter
      DC even though they are nonpermissive for virus growth. This provides a potential
      utility for HSV in delivering genes to DC for vaccination purposes and also
      suggests that the life cycle of HSV usually includes the infection of DC.
      However, DC infected with HSV usually lose the ability to become activated
      following infection (M. Salio, M. Cella, M. Suter, and A. Lanzavecchia, Eur. J.
      Immunol. 29:3245-3253, 1999; M. Kruse, O. Rosorius, F. Kratzer, G. Stelz, C.
      Kuhnt, G. Schuler, J. Hauber, and A. Steinkasserer, J. Virol. 74:7127-7136,
      2000). We report that for DC to retain the ability to become activated following
      HSV infection, the virion host shutoff protein (vhs) must be deleted. vhs usually
      functions to destabilize mRNA in favor of the production of HSV proteins in
      permissive cells. We have found that it also plays a key role in the inactivation
      of DC and is therefore likely to be important for immune evasion by the virus.
      Here, vhs would be anticipated to prevent DC activation in the early stages of
      infection of an individual with HSV, reducing the induction of cellular immune
      responses and thus preventing virus clearance during repeated cycles of virus
      latency and reactivation. Based on this information, replication-incompetent HSV
      vectors with vhs deleted which allow activation of DC and the induction of
      specific T-cell responses to delivered antigens have been constructed. These
      responses are greater than if DC are loaded with antigen by incubation with
      recombinant protein.

PMID- 12610152
TI  - Natural alpha interferon-producing cells respond to human immunodeficiency virus
      type 1 with alpha interferon production and maturation into dendritic cells.
AB  - Natural alpha interferon (IFN-alpha)-producing cells (IPCs) are now recognized as
      identical to plasmacytoid dendritic cell (DC) precursors in human blood and are
      thought to play an important role in antiviral immunity. In the present study, we
      examined the susceptibility as well as the cellular responses of IPCs to human
      immunodeficiency virus type 1 (HIV-1) infection. HLA-DR(+) CD11c(-) lineage
      negative cells (IPCs) were purified from peripheral blood mononuclear cells by
      magnetic-bead separation and cell sorting. We substantiated that IPCs expressing
      the major HIV-1 coreceptors, CXCR4 and CCR5, are susceptible to infection of both
      T-cell-line-tropic NL4-3 and macrophage-tropic JR-CSF HIV-1 by quantification of
      HIV-1 p24 in the culture supernatants and by provirus integration assay using
      human conserved Alu-HIV-1 long terminal repeat PCR. To evaluate the cellular
      response of IPCs to HIV-1, we examined IFN-alpha production and their
      differentiation into DCs. After incubation with either NL4-3 or JR-CSF, IPCs
      produced a large amount of IFN-alpha and at the same time underwent morphological
      differentiation into DCs with upregulation of CD80 and CD86. Heat inactivation of
      the supernatants containing HIV-1 did not affect the IFN-alpha production and
      maturation, whereas removal of virions by ultracentrifugation completely
      nullified both biological effects, indicating that these cellular responses do
      not require actual HIV-1 infection but are elicited by interaction with HIV-1
      virions or certain viral components. In conclusion, these data strongly suggest
      that IPC can directly recognize and respond to HIV-1 with IFN-alpha production,
      which is crucial for preventing progress of HIV-1 infection and occurrence of
      opportunistic infection.

PMID- 12610154
TI  - T cells infiltrate the brain in murine and human transmissible spongiform
      encephalopathies.
AB  - CD4 and CD8 T lymphocytes infiltrate the parenchyma of mouse brains several weeks
      after intracerebral, intraperitoneal, or oral inoculation with the Chandler
      strain of mouse scrapie, a pattern not seen with inoculation of prion protein
      knockout (PrP(-/-)) mice. Associated with this cellular infiltration are
      expression of MHC class I and II molecules and elevation in levels of the T-cell
      chemokines, especially macrophage inflammatory protein 1beta, IFN-gamma-inducible
      protein 10, and RANTES. T cells were also found in the central nervous system
      (CNS) in five of six patients with Creutzfeldt-Jakob disease. T cells harvested
      from brains and spleens of scrapie-infected mice were analyzed using a newly
      identified mouse PrP (mPrP) peptide bearing the canonical binding motifs to major
      histocompatibility complex (MHC) class I H-2(b) or H-2(d) molecules, appropriate
      MHC class I tetramers made to include these peptides, and CD4 and CD8 T cells
      stimulated with 15-mer overlapping peptides covering the whole mPrP. Minimal to
      modest K(b) tetramer binding of mPrP amino acids (aa) 2 to 9, aa 152 to 160, and
      aa 232 to 241 was observed, but such tetramer-binding lymphocytes as well as CD4
      and CD8 lymphocytes incubated with the full repertoire of mPrP peptides failed to
      synthesize intracellular gamma interferon (IFN-gamma) or tumor necrosis factor
      alpha (TNF-alpha) cytokines and were unable to lyse PrP(-/-) embryo fibroblasts
      or macrophages coated with (51)Cr-labeled mPrP peptide. These results suggest
      that the expression of PrP(sc) in the CNS is associated with release of
      chemokines and, as shown previously, cytokines that attract and retain PrP
      activated T cells and, quite likely, bystander activated T cells that have
      migrated from the periphery into the CNS. However, these CD4 and CD8 T cells are
      defective in such an effector function(s) as IFN-gamma and TNF-alpha expression
      or release or lytic activity.

PMID- 12610153
TI  - Infectivity of a human respiratory syncytial virus lacking the SH, G, and F
      proteins is efficiently mediated by the vesicular stomatitis virus G protein.
AB  - To examine the requirements of the human respiratory syncytial virus (HRSV) SH
      (small hydrophobic), G (attachment), and F (fusion) proteins for virus
      infectivity and morphology, we used the prototype A2 strain of HRSV to generate a
      series of cDNAs from which (i) the SH open reading frame (ORF), (ii) the SH and G
      ORFs, or (iii) the SH, G, and F ORFs were deleted. Each deleted ORF was replaced
      as follows: the SH ORF was replaced with that of green fluorescent protein; the G
      ORF was replaced with that of G(vsv), a chimeric glycoprotein consisting of the
      vesicular stomatitis Indiana virus (VSIV) G protein ecto- and transmembrane
      domains coupled to the HRSV F cytoplasmic tail; and the F ORF was replaced with
      that of marker protein beta-glucuronidase. The number of genes and the intergenic
      junctions in the constructs were kept as found in A2 virus in order to maintain
      authentic levels of transcription. Infectious viruses were recovered from all
      three engineered cDNAs and designated RSdeltash, RSdeltash,g/G(vsv), and
      RSdeltash,g,f/G(vsv), respectively. Low-pH-induced syncytium formation was
      observed in cells infected with viruses RSdeltaSH,G/G(vsv) and
      RSdeltaSH,G,F/G(vsv), indicating that G(vsv) was expressed and functional.
      Neutralization of infectivity by anti-VSIV G antibodies and inhibition of entry
      by ammonium chloride showed that RSdeltaSH,G,F/G(vsv) infectivity was mediated by
      G(vsv) and that an acidification step was required for entry into the host cell,
      similar to VSIV virions. All three engineered viruses displayed growth kinetics
      and virus yields similar to a wild-type A2 virus, both in Vero and HEp-2 cells.
      Abundant virus-induced filaments were observed at the surface of cells infected
      with each of the three engineered viruses or with virus A2, indicating that
      neither the SH and G proteins nor the F protein ecto- and transmembrane domains
      were required for the formation of these structures. This is the first report of
      the recovery of an infectious HRSV lacking a fusion protein of the
      Paramyxoviridae family and of manipulation of the HRSV entry pathway via
      incorporation of a nonparamyxoviral transmembrane glycoprotein.

PMID- 12610155
TI  - K-bZIP of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV
      8) binds KSHV/HHV-8 Rta and represses Rta-mediated transactivation.
AB  - The regulatory circuit for Kaposi's sarcoma-associated herpesvirus/human
      herpesvirus 8 (KSHV/HHV-8) gene expression bears resemblance to that of Epstein
      Barr virus (EBV), but with interesting differences. Based on protein sequence
      similarities and synteny to their EBV counterparts, two KSHV/HHV-8 viral
      regulatory factors, HHV-8 Rta and K-bZIP, encoded by open reading frame (ORF) 50
      and ORF K8, respectively, have been identified. Rta is an immediate early
      transcriptional activator that activates lytic viral replication and mediates
      viral reactivation from latency, while ORF K8 is an early gene activated by Rta.
      Extensive splicing of ORF K8 mRNA leads to the production of K-bZIP, a protein of
      the basic domain-leucine zipper (bZIP) family. The role of K-bZIP in viral
      replication, however, remains unresolved. Here, we report that K-bZIP is a
      nuclear protein that binds Rta directly both in vivo and in vitro and represses
      Rta-mediated transactivation of the K-bZIP promoter. We further demonstrate that
      the leucine zipper domain of K-bZIP is required for Rta binding and a K-bZIP
      mutant lacking the leucine zipper does not repress Rta activity. Finally, the K
      bZIP-mediated repression of Rta transactivation cannot be restored by
      overexpression of the transcriptional coactivator p300 or the p300-CBP-associated
      factor, P/CAF. Our results suggest that K-bZIP is involved in a feedback circuit
      to turn off its own expression and possibly the expression of other early genes
      activated by Rta.

PMID- 12610156
TI  - Neurovirulence in mice of H5N1 influenza virus genotypes isolated from Hong Kong
      poultry in 2001.
AB  - We studied the pathogenicity of five different genotypes (A to E) of highly
      pathogenic avian H5N1 viruses, which contained HA genes similar to those of the
      H5N1 virus A/goose/Guangdong/1/96 and five different combinations of "internal"
      genes, in a mouse model. Highly pathogenic, neurotropic variants of genotypes A,
      C, D, and E were isolated from the brain after a single intranasal passage in
      mice. Genotype B virus was isolated from lungs only. The mouse brain variants had
      amino acid changes in all gene products except PB1, NP, and NS1 proteins but no
      common sets of mutations. We conclude that the original H5N1/01 isolates of
      genotypes A, C, D, and E were heterogeneous and that highly pathogenic
      neurotropic variants can be rapidly selected in mice.

PMID- 12610158
TI  - Effect of amino acid substitution of the V3 and bridging sheet residues in human
      immunodeficiency virus type 1 subtype C gp120 on CCR5 utilization.
AB  - The V3 loop and the bridging sheet domain of human immunodeficiency virus type 1
      (HIV-1) subtype B envelope glycoprotein gp120 have been implicated in CCR5
      coreceptor utilization. In this study, mutant envelope glycoproteins of a subtype
      C isolate containing substitutions in the V3 or C4 region were generated to
      determine which are required for efficient CCR5-dependent cell fusion and viral
      entry. We found that the V3 crown and C4 residues are relatively dispensable for
      cell-cell fusion, although some residues may be involved in the regulation of
      early postentry steps in viral replication. In contrast, seven highly conserved
      residues located in the V3 stem are critical for CCR5 utilization, which can
      explain the apparent paradox that the functional convergence in CCR5 usage by
      genetically divergent HIV-1 strains involves a variable region. The finding that
      C4 residues do not have a critical role may appear to contradict the current
      model that bridging sheet residues are involved in the gp120-CCR5 interaction.
      However, a plausible interpretation is that these C4 residues may have a distinct
      role in the binding and fusion steps of the gp120-CCR5 interaction.

PMID- 12610157
TI  - Epstein-Barr virus (EBV) nuclear antigen 1 colocalizes with cellular replication
      foci in the absence of EBV plasmids.
AB  - Epstein-Barr virus (EBV) EBNA-1 is the only EBV-encoded protein that is essential
      for the once-per-cell-cycle replication and maintenance of EBV plasmids in
      latently infected cells. EBNA-1 binds to the oriP region of latent EBV plasmids
      and cellular metaphase chromosomes. In the absence of oriP-containing plasmids,
      EBNA-1 was highly colocalized with cellular DNA replication foci that were
      identified by immunostaining S-phase cells for proliferating cell nuclear antigen
      and replication protein A (RP-A) in combination with DNA short pulse-labeling.
      For the association of EBNA-1 with the cellular replication focus areas, the EBNA
      1 regions of amino acids (aa) 8 to 94 and/or aa 315 to 410, but not the RP-A
      interacting carboxy-terminal region, were necessary. These results suggest a new
      aspect of latent virus-cell interactions.

PMID- 12610159
TI  - An amino acid in the central catalytic domain of three retroviral integrases that
      affects target site selection in nonviral DNA.
AB  - Integrase can insert retroviral DNA into almost any site in cellular DNA;
      however, target site preferences are noted in vitro and in vivo. We recently
      demonstrated that amino acid 119, in the alpha2 helix of the central domain of
      the human immunodeficiency virus type 1 integrase, affected the choice of
      nonviral target DNA sites. We have now extended these findings to the integrases
      of a nonprimate lentivirus and a more distantly related alpharetrovirus. We found
      that substitutions at the analogous positions in visna virus integrase and Rous
      sarcoma virus integrase changed the target site preferences in five assays that
      monitor insertion into nonviral DNA. Thus, the importance of this protein residue
      in the selection of nonviral target DNA sites is likely to be a general property
      of retroviral integrases. Moreover, this amino acid might be part of the cellular
      DNA binding site on integrase proteins.

PMID- 12610160
TI  - Human papillomavirus types 16, 31, and 58 use different endocytosis pathways to
      enter cells.
AB  - The early steps of the intracellular trafficking of human papillomavirus type 16
      (HPV-16), -31, and -58 pseudovirions were studied by investigating the effects of
      drugs acting at defined points of endocytosis pathways on virus-like particle
      mediated pseudoinfection by overexpression of a dominant-negative form of the
      Eps15 protein to inhibit clathrin-mediated endocytosis and by electron
      microscopy. The results obtained suggested the involvement of clathrin-mediated
      endocytosis in HPV-16 and HPV-58 entry and caveola-mediated endocytosis in HPV-31
      entry.

PMID- 12610161
TI  - Chimeric and pseudotyped parvoviruses minimize the contamination of recombinant
      stocks with replication-competent viruses and identify a DNA sequence that
      restricts parvovirus H-1 in mouse cells.
AB  - Recent studies demonstrated the ability of the recombinant autonomous
      parvoviruses MVMp (fibrotropic variant of the minute virus of mice) and H-1 to
      transduce therapeutic genes in tumor cells. However, recombinant vector stocks
      are contaminated by replication-competent viruses (RCVs) generated during the
      production procedure. To reduce the levels of RCVs, chimeric recombinant vector
      genomes were designed by replacing the right-hand region of H-1 virus DNA with
      that of the closely related MVMp virus DNA and conversely. Recombinant H-1 and
      MVMp virus pseudotypes were also produced with this aim. In both cases, the
      levels of RCVs contaminating the virus stocks were considerably reduced (virus
      was not detected in pseudotyped virus stocks, even after two amplification
      steps), while the yields of vector viruses produced were not affected. H-1 virus
      could be distinguished from MVMp virus by its restriction in mouse cells at an
      early stage of infection prior to detectable viral DNA replication and gene
      expression. The analysis of the composite viruses showed that this restriction
      could be assigned to a specific genomic determinant(s). Unlike MVMp virus, H-1
      virus capsids were found to be a major determinant of the greater permissiveness
      of various human cell lines for this virus.

PMID- 12610162
TI  - Malignant transformation of Epstein-Barr virus-negative Akata cells by
      introduction of the BARF1 gene carried by Epstein-Barr virus.
AB  - Spontaneous loss of the Epstein-Barr virus (EBV) genome in the BL cell line Akata
      led to loss of tumorigenicity in SCID mice, suggesting an important oncogenic
      activity of EBV in B cells. We previously showed that introduction of the BARF1
      gene into the human B-cell line Louckes induced a malignant transformation in
      newborn rats (M. X. Wei, J. C. Moulin, G. Decaussin, F. Berger, and T. Ooka,
      Cancer Res. 54:1843-1848, 1994). Since 1 to 2% of Akata cells expressed lytic
      antigens and expressed the BARF1 gene, we investigated whether introduction of
      the BARF1 gene into EBV-negative Akata cells can induce malignant transformation.
      Here we show that BARF1-transfected, EBV-negative Akata cells activated Bcl2
      expression and induced tumor formation when they were injected into SCID mice. In
      addition, when EBV-positive Akata cells expressing a low level of BARF1 protein
      were injected into SCID mice, the expression of BARF1, as well as several lytic
      proteins, such as EA-D, ZEBRA, and a 135-kDa DNA binding protein, increased in
      tumor cells while no latent LMP1 and late gp220-320 expression was observed in
      tumor cells. These observations suggest that the BARF1 gene may be involved in
      the conferral of tumorigenicity by EBV.

PMID- 12610163
TI  - The type B leukemogenic virus truncated superantigen is dispensable for T-cell
      lymphomagenesis.
AB  - Type B leukemogenic virus (TBLV) is a variant of mouse mammary tumor virus (MMTV)
      that causes T-cell lymphomas in mice. We have constructed a TBLV-MMTV hybrid,
      pHYB-TBLV, in which 756 bp of the C3H MMTV long terminal repeat (LTR) was
      replaced with 438 bp of the TBLV LTR. Intraperitoneal injection of pHYB-TBLV
      transfectants consistently resulted in T-cell lymphomas in 50% of injected
      weanling BALB/c mice with an average latency period of 5.7 (+/- 1.5) months.
      Transfectants of pHYB-TBLV containing a double-frameshift mutation in the
      truncated superantigen gene (sag) induced T-cell lymphomas with similar
      incidences, latency periods, and phenotypes, suggesting that cis-acting elements
      in the TBLV LTR determine disease specificity.

PMID- 12610165
TI  - Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) open reading frame
      4 protein (kaposica) is a functional homolog of complement control proteins.
AB  - The genome analysis of Kaposi's sarcoma-associated herpesvirus (KSHV) has
      revealed the presence of an open reading frame (ORF 4) with sequence homology to
      complement control proteins. To assign a function to this protein, we have now
      expressed this ORF using the Pichia expression system and shown that the purified
      protein inhibited human complement-mediated lysis of erythrocytes, blocked cell
      surface deposition of C3b (the proteolytically activated form of C3), and served
      as a cofactor for factor I-mediated inactivation of complement proteins C3b and
      C4b (the subunits of C3 convertases). Thus, our data indicate that this KSHV
      inhibitor of complement activation (kaposica) provides a mechanism by which KSHV
      can subvert complement attack by the host.

PMID- 12610164
TI  - Effects of dipeptide insertions between codons 69 and 70 of human
      immunodeficiency virus type 1 reverse transcriptase on primer unblocking,
      deoxynucleoside triphosphate inhibition, and DNA chain elongation.
AB  - Finger insertion mutations of human immunodeficiency virus type 1 (HIV-1) reverse
      transcriptase (RT) (T69S mutations followed by various dipeptide insertions) have
      a multinucleoside resistance phenotype that can be explained by decreased
      sensitivity to deoxynucleoside triphosphate (dNTP) inhibition of the nucleotide
      dependent unblocking activity of RT. We show that RTs with SG or AG (but not SS)
      insertions have three- to fourfold-increased unblocking activity and that all
      three finger insertion mutations have threefold-decreased sensitivity to dNTP
      inhibition. The additional presence of M41L and T215Y mutations increased
      unblocking activity for all three insertions, greatly reduced the sensitivity to
      dNTP inhibition, and resulted in defects in in vitro DNA chain elongation. The
      DNA chain elongation defects were partially repaired by additional mutations at
      positions 210, 211, and 214. These results suggest that structural communication
      between the regions of RT defined by these mutations plays a role in the
      multinucleoside resistance phenotype.

PMID- 12610166
TI  - Role of the virus nucleoprotein in the regulation of lymphocytic choriomeningitis
      virus transcription and RNA replication.
AB  - The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) has a
      bisegmented negative-strand RNA genome. Each segment carries two viral genes in
      opposite orientation and separated by an intergenic region (IGR). The RNA
      dependent RNA polymerase (RdRp) L of LCMV produces subgenomic mRNA and full
      length genomic and antigenomic RNA species in two different processes termed
      transcription and replication, respectively. It is widely accepted that
      intracellular nucleoprotein (NP) levels regulate these two processes.
      Intracellular NP levels increase during the course of the infection, resulting in
      the unfolding of secondary RNA structures within the IGR. Structure-dependent
      transcription termination at the IGR is thereby attenuated, promoting replication
      of genome and antigenome RNA species. To test this hypothesis, we established a
      helper-virus-free minigenome (MG) system where intracellular synthesis of an S
      segment analogue from a plasmid is driven by RNA polymerase I. Cotransfection
      with two additional plasmids expressing the minimal viral trans-acting factors L
      and NP under control of RNA polymerase II allowed for RNA synthesis mediated by
      the intracellularly reconstituted LCMV polymerase. Both processes, transcription
      and replication, were strictly dependent on NP. However, both were equally
      enhanced by incrementally increasing amounts of NP up to levels in the range of
      those in LCMV-infected cells. Our data are consistent with a central role for NP
      in transcription and replication of the LCMV genome, but they do not support the
      participation of NP levels in balancing the two processes.

PMID- 12610168
TI  - The prognostic role of detection of circulating melanoma cells in the blood.

PMID- 12610167
TI  - Endogenous virus and hepatitis C virus-like particle budding in BHK-21 cells.

PMID- 12610169
TI  - Differences in outcome in adolescents with acute lymphoblastic leukemia: a
      consequence of better regimens? Better doctors? Both?

PMID- 12610170
TI  - Carcinomatosis--is cure an option?

PMID- 12610171
TI  - Clinical trials: time for action.

PMID- 12610172
TI  - Prognostic value of circulating melanoma cells detected by reverse transcriptase
      polymerase chain reaction.
AB  - PURPOSE: Factors that are predictive of prognosis in patients who are diagnosed
      with malignant melanoma (MM) are widely awaited. Detection of circulating
      melanoma cells (CMCs) by reverse transcriptase-polymerase chain reaction (RT-PCR)
      has recently been postulated as a possible negative prognostic factor. Two main
      questions were addressed: first, whether the presence of CMCs, defined as the
      patient being positive for any of the three markers, had a prognostic role; and
      second, what the predictive value of each individual marker was. PATIENTS AND
      METHODS: A consecutive series of 200 melanoma patients observed between January
      1997 and December 1997, with stage of disease ranging from I to IV, was analyzed
      by semiquantitative RT-PCR. Tyrosinase, p97, and MelanA/MART1 were used as
      markers to CMCs on baseline peripheral blood samples. Progression-free survival
      (PFS) was used as a unique end point and was described by the product limit
      method. Multivariable analysis was applied to verify whether the auspicated
      prognostic value of these markers was independent of the stage of disease, and a
      subgroup analysis was performed that excluded patients with stage IV disease.
      RESULTS: Overall, 32% (64 of 200) of patients progressed, and a median PFS of 52
      months in the whole series was observed. The presence of CMCs and the markers
      individually or combined was predictive of prognosis in the univariate analysis
      but did not provide additional prognostic information to the stage of disease in
      multivariable models. In the subgroup analysis of stage (ie, I-III subgroup),
      similar results were observed. CONCLUSION: Detection of CMCs in peripheral blood
      samples at the time of MM diagnosis by semiquantitative RT-PCR does not add any
      significant predictive value to the stage of disease. Thus, this approach should
      not be used in clinical practice, and further studies are required to determine
      its usefulness.

PMID- 12610173
TI  - Should adolescents with acute lymphoblastic leukemia be treated as old children
      or young adults? Comparison of the French FRALLE-93 and LALA-94 trials.
AB  - PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of
      acute lymphoblastic leukemia (ALL) in adolescents. PATIENTS AND METHODS: From
      June 1993 to September 1994, 77 and 100 adolescents (15 to 20 years of age) were
      enrolled in the pediatric FRALLE-93 and adult LALA-94 protocols, respectively.
      Among the different prognostic factors, we retrospectively analyzed the effect of
      the trial on achieving complete remission (CR) and event-free survival (EFS).
      RESULTS: Patients were younger in the FRALLE-93 than in the LALA-94 protocol
      (median age, 15.9 v 17.9 years, respectively), but other characteristics were
      similar, including median WBC count (18 x 10(9) cells/L v 16 x 10(9) cells/L),
      B/T-lineage (54 of 23 v 72 of 28 patients), CD10-negative ALL (13% v 15%), and
      poor-risk cytogenetics (t(9;22), t(4;11), or hypodiploidy less than 45
      chromosomes: 6% v 5%). The CR rate depended on WBC count (P =.005) and trial (94%
      v 83% in FRALLE-93 and LALA-94, respectively; P =.04). Univariate analysis showed
      that unfavorable prognostic factors for EFS were as follows: the trial (estimated
      5-year EFS, 67% v 41% for FRALLE-93 and LALA-94, respectively; P <.0001), an
      increasing WBC count (P <.0001), poor-risk cytogenetics (P =.005), and T-lineage
      (P =.01). The trial and WBC count remained significant parameters for EFS in
      multivariate analysis (P <.0001 and P =.0004). Lineage subgroup analysis showed
      an advantage for the FRALLE-93 trial for CR achievement (98% v 81%; P =.002) and
      EFS (P =.0002) in B-lineage ALL and for EFS (P =.05) in T-lineage ALL. Age was
      not a significant prognostic factor in this population of adolescents.
      CONCLUSION: This study's findings indicate that adolescents should be included in
      intensive pediatric protocols and that new trials should be designed, inspired by
      pediatric protocols, for the treatment of young adults with ALL.

PMID- 12610174
TI  - Prognostic value of tumor size, metastases, extension into bone, and increased
      tumor marker in children with malignant sacrococcygeal germ cell tumors: a
      prospective evaluation of 71 patients treated in the German cooperative protocols
      Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89.
AB  - PURPOSE: To evaluate the prognostic value of metastases, extension into bone, and
      alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ
      cell tumors (GCTs) prospectively collected in two cooperative Maligne
      Keimzelltumoren (MAKEI) protocols (83/86 and 89). PATIENTS AND METHODS: Between
      October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal
      primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or
      yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1
      and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients
      had metastases, and 35 children presented with extension into bone. At diagnosis,
      22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children
      showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values
      of greater than 100,000 ng/mL. Five patients died of complication during
      treatment and were excluded from further evaluation. Seventy-one patients could
      be analyzed. RESULTS: The 5-year relapse-free survival rate (RFS, Kaplan-Meier)
      was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after
      diagnosis). The RFS of patients with and without metastases was different, but
      not significantly so (0.71 v 0.82). The outcome of patients with extension into
      bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5
      years). Above-normal AFP level had no prognostic significance (P =.52).
      CONCLUSION: In children with malignant sacrococcygeal GCTs treated with an
      intensive, short-interval, platinum-based regimen, the stage, extent of
      metastases, extension into bone, and AFP level had no prognostic significance.

PMID- 12610175
TI  - Utility of routine psychological screening in the childhood cancer survivor
      clinic.
AB  - PURPOSE: This study examined the utility of routine psychologic screening in a
      childhood cancer survivor clinic by evaluating patient acceptance, comparing
      subjects' symptoms to normative data, examining the utility of specific tests,
      and identifying risk factors associated with psychological distress. METHODS:
      During their annual clinic visit, 101 adult survivors of childhood cancer (median
      age, 25 years) completed the Symptom Checklist 90 Revised (SCL-90), as well as
      the Short Form 36 (SF-36), Beck Depression Inventory (BDI), and one additional
      suicide question. Psychological distress was operationally defined according to
      the published SCL-90 clinical case rule, classifying subjects with a consistent
      pattern of symptom elevations as clinical cases. RESULTS: The majority of
      subjects (80%) completed the screening in less than 30 minutes and reported
      little (15%) or no (84%) distress. Sixty-four percent believed it would help
      "very much" or "moderately" in getting to know them, and 35% thought it would
      help "slightly." On the SCL-90, 32 subjects (31.7%) had a positive screen,
      indicating significant psychological distress. All subjects with clinically
      significant symptoms on the BDI and SF-36 Mental Health Scale were cases on the
      SCL-90 (case-positive). Suicidal symptoms were reported in 13.9% of the sample,
      all of whom were SCL-90 cases. In a logistic regression model, subjects'
      dissatisfaction with physical appearance, poor physical health, and treatment
      with cranial radiation were associated with psychological distress. CONCLUSION:
      Results demonstrate that routine psychological screening can be successfully
      integrated into the cancer survivor clinic and may be effective in identifying
      those survivors with significant distress who require further evaluation.

PMID- 12610176
TI  - Treatment of children with nonmetastatic paratesticular rhabdomyosarcoma: results
      of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) of the
      International Society of Pediatric Oncology.
AB  - PURPOSE: To report the results of the Malignant Mesenchymal Tumors studies (MMT
      84 and 89) of the International Society of Pediatric Oncology (SIOP) in males
      with nonmetastatic paratesticular rhabdomyosarcoma. PATIENTS AND METHODS: From
      1984 to 1994, 96 males were treated in SIOP protocols. Radical inguinal
      orchidectomy was recommended, but initial retroperitoneal lymph node dissection
      was not performed. Disease was staged according to the SIOP tumor-node-metastasis
      staging system. Treatment was stratified by stage. In the MMT 89 study, males
      with completely resected tumors at diagnosis received less chemotherapy
      (vincristine and dactinomycin) than patients in the MMT 84 study (ifosfamide,
      vincristine, and dactinomycin). RESULTS: Median age at diagnosis was 65 months.
      Thirty-one tumors were larger than 5 cm, and 13 males were older than 10 years
      with a tumor larger than 5 cm. At a median follow-up of 7 years, 87 patients were
      alive; 79 were in first complete remission and eight were in second complete
      remission. Relapse occurred in 16 patients (17%). At 5 years, the overall
      survival (OS) rate was 92%, with an event-free survival (EFS) rate of 82%. OS and
      EFS were significantly worse for males with tumors greater than 5 cm and for
      males older than 10 years at diagnosis. CONCLUSION: Males with paratesticular RMS
      have an excellent prognosis except for a selected group of patients older than 10
      years or with tumor greater than 5 cm. Intensified chemotherapy incorporating
      alkylating agents for this subgroup may be preferred to the use of systematic
      lymphadenectomy to improve survival while minimizing the burden of therapy.

PMID- 12610177
TI  - Surgery combined with peritonectomy procedures and intraperitoneal
      chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II
      study.
AB  - PURPOSE: To evaluate the tolerance of peritonectomy procedures (PP) combined with
      intraperitoneal chemohyperthermia (IPCH) in patients with peritoneal
      carcinomatosis (PC), a phase II study was carried out from January 1998 to
      September 2001. PATIENTS AND METHODS: Fifty-six patients (35 females, mean age
      49.3) were included for PC from colorectal cancer (26 patients), ovarian cancer
      (seven patients), gastric cancer (six patients), peritoneal mesothelioma (five
      patients), pseudomyxoma peritonei (seven patients), and miscellaneous reasons
      (five patients). Surgeries were performed mainly on advanced patients (40
      patients stages 3 and 4 and 16 patients stages 2 and 1) and were synchronous in
      36 patients. All patients underwent surgical resection of their primary tumor
      with PP and IPCH (with mitomycin C, cisplatinum, or both) with a closed sterile
      circuit and inflow temperatures ranging from 46 degrees to 48 degrees C. Three
      patients were included twice. RESULTS: A macroscopic complete resection was
      performed in 27 cases. The mortality and morbidity rates were one of 56 and 16 of
      56, respectively. The 2-year survival rate was 79.0% for patients with
      macroscopic complete resection and 44.7% for patients without macroscopic
      complete resection (P =.001). For the patients included twice, two are alive
      without evidence of disease, 54 and 47 months after the first procedure.
      CONCLUSION: IPCH and PP are able to achieve unexpected long-term survival in
      patients with bulky PC. However, one must be careful when selecting the patients
      for such an aggressive treatment, as morbidity rate remains high even for an
      experienced team.

PMID- 12610178
TI  - Phase III comparison of two irinotecan dosing regimens in second-line therapy of
      metastatic colorectal cancer.
AB  - PURPOSE: Randomized trials in fluorouracil (FU)-refractory colorectal cancer
      demonstrate significant survival advantages for patients receiving irinotecan. We
      prospectively compared the efficacy and tolerability of two irinotecan regimens
      (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3
      weeks) in such patients. PATIENTS AND METHODS: This multicenter, open-label,
      phase III study randomly assigned patients in a 1:2 ratio to irinotecan given
      either weekly (125 mg/m(2)) or once every 3 weeks (350 mg/m(2), or 300 mg/m(2) in
      patients who were >/= 70 years of age, who had Eastern Cooperative Oncology Group
      performance status equal to 2, or who had prior pelvic irradiation). RESULTS:
      With median follow-up of 15.8 months, there was no significant difference in 1
      year survival (46% v 41%, respectively; P =.42), median survival (9.9 v 9.9
      months, respectively; P =.43), or median time to progression (4.0 v 3.0 months,
      respectively; P =.54) between the two regimens. Grade 3/4 diarrhea occurred in
      36% of patients treated weekly and in 19% of those treated once every 3 weeks (P
      =.002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34%
      of those treated once every 3 weeks (P =.35). Treatment-related mortality
      occurred in five patients (5.3%) receiving irinotecan weekly and three patients
      (1.6%) given therapy once every 3 weeks (P =.12). Global quality of life was not
      statistically different between treatment groups. CONCLUSION: Irinotecan
      schedules of weekly and of once every 3 weeks demonstrated similar efficacy and
      quality of life in patients with FU-refractory, metastatic colorectal cancer. The
      regimen of once every 3 weeks was associated with a significantly lower incidence
      of severe diarrhea.

PMID- 12610179
TI  - Thymidylate synthase protein expression in primary colorectal cancer: lack of
      correlation with outcome and response to fluorouracil in metastatic disease
      sites.
AB  - PURPOSE: The aim of this study was to investigate the utility of quantitating
      thymidylate synthase (TS) in the primary tumor as a surrogate for metastatic
      disease sites to predict the likelihood of response and outcome to fluorouracil
      (FU) treatment in patients with metastatic colorectal cancer. METHODS: TS protein
      expression was evaluated using the TS 106 antibody and the avidin biotin labeling
      immunohistochemical technique in primary tumor samples from 219 patients with
      metastatic colorectal cancer. The patients were a representative sample of those
      patients enrolled into the Eastern Cooperative Oncology Group E2290 protocol that
      evaluated five separate FU-containing regimens in patients with metastatic
      residual or recurrent colorectal carcinoma. RESULTS: Our retrospective analysis
      found that the level and extent of TS protein expression in the primary tumor did
      not correlate with overall survival in patients with metastatic or recurrent
      colorectal cancer. A trend toward a direct correlation between the level of TS
      protein expression and response was noted in tumors that expressed high TS
      levels. This response advantage for patients expressing high TS levels in the
      primary tumor was apparent regardless of what FU-based treatment the patient
      received but was most apparent in the subgroup treated with leucovorin, in which
      the level of TS expression and response to FU and leucovorin reached statistical
      significance (P =.034). No significant interaction could be detected between the
      addition of leucovorin to FU and the level of TS expression in the primary tumor.
      CONCLUSION: This study demonstrated that measurement of TS protein levels in the
      primary tumor tissue does not aid in predicting outcome or response to FU in a
      metastatic disease site. These assays must be performed on biopsy tissue from the
      metastatic disease site that is used to radiologically assess response and
      outcome to treatment.

PMID- 12610180
TI  - Genetic tumor markers with prognostic impact in Dukes' stages B and C colorectal
      cancer patients.
AB  - PURPOSE: To examine several genetic changes in primary colorectal carcinomas
      (CRCs) from patients with 10 years of follow-up and associate the findings with
      clinicopathologic variables. MATERIAL AND METHODS: DNA from 220 CRCs were
      analyzed for allelic imbalances at 12 loci on chromosome arms 1p, 14q, 17p, 18q,
      and 20q, and the microsatellite instability (MSI) status was determined. The
      clinical significance of the tumor protein 53 (TP53) mutations was re-evaluated.
      RESULTS: Patients with tumors containing 17p or 18q deletions had shorter
      survival than those without these alterations (P =.021, P =.008, respectively).
      This was also significant for the Dukes' B group (P =.025, P =.010,
      respectively). Furthermore, patients with tumors showing losses of both
      chromosome arms revealed an even poorer disease outcome than those with either
      17p or 18q loss. Patients with low increase in 20q copy number in their tumors
      had longer survival compared with those without changes (P =.009) or those with a
      high increase of copy number (P =.037). This was also evident for the Dukes' C
      group (P =.018, P =.030, respectively). MSI was seemingly a beneficial marker for
      survival (P =.071). A significant association between mutations affecting the L3
      zinc-binding domain of TP53 and survival was confirmed in this cohort after 10
      years of follow-up, and also was found to apply for patients in the Dukes' B
      group. Several associations were found among genetic and pathologic data.
      CONCLUSION: The present study indicates that 17p, 18q, and 20q genotypes, and
      TP53 mutation status add information in the subclassification of Dukes' B and C
      patients and may have impact on the choice of treatment.

PMID- 12610181
TI  - Public attitudes toward participation in cancer clinical trials.
AB  - PURPOSE: The objective of this study is to understand the attitudes of American
      adults toward participation in cancer clinical trials. METHODS: A national
      probability sample of 1,000 adults aged 18 and older living in noninstitutional
      settings was interviewed by telephone by Harris Interactive during March and
      April 2000. One participant was selected from each household selected for the
      study. The resulting data were weighted to reflect the full adult population of
      the United States as reported in Current Population Reports. An Index of
      Participation in a Cancer Clinical Trial was computed, using a confirmatory
      factor analysis and converting the factor scores into a 0-to-100 scale. RESULTS:
      Approximately 32% of American adults (64 million individuals) indicate that they
      would be very willing to participate in a cancer clinical trial if asked to do
      so. An additional 38% of adults (76 million individuals) scored in a range that
      indicates that they are inclined to participate in a cancer clinical trial if
      asked, but hold some questions or reservations about participation. Projected
      rates of diagnosis, eligibility, and recruitment indicate that substantially more
      patients are willing to participate than are actually accrued. CONCLUSION: These
      results indicate that the primary problem with accrual is not the attitudes of
      patients, but rather that the loss of potential participants is the result of the
      unavailability of an appropriate clinical trial and the disqualification of large
      numbers of patients. The pool of willing patients is further reduced by the
      reluctance of some physicians to engage in accrual.

PMID- 12610182
TI  - Randomized, controlled trial of an easy-to-read informed consent statement for
      clinical trial participation: a study of the Eastern Cooperative Oncology Group.
AB  - PURPOSE: Studies have documented that the majority of consent documents for
      medical diagnosis and treatment are written at a reading level above that of the
      majority of the U.S. population. This study hypothesized that use of an easy-to
      read consent statement, when compared with a standard consent statement, will
      result in higher patient comprehension of the clinical treatment protocol, lower
      patient anxiety, higher patient satisfaction, and higher patient accrual.
      METHODS: A randomized controlled trial was conducted in 44 institutions that were
      members or affiliates of three cooperative oncology groups. Institutions were
      randomly assigned to administer either an easy-to-read consent statement or the
      standard consent statement to patients being recruited to participate in selected
      cancer treatment trials. Telephone interviews were conducted with a total of 207
      patients to assess study outcomes. RESULTS: Patients in the intervention arm
      demonstrated significantly lower consent anxiety and higher satisfaction compared
      with patients in the control arm. Patient comprehension and state anxiety were
      not affected by the intervention. Accrual rates into the parent studies also did
      not differ significantly between the two study groups. CONCLUSION: Clinical trial
      informed consent statements can be modified to be easier to read without omitting
      critical information. Patient anxiety and satisfaction can be affected by the
      consent document. The generalizability of these study results is limited by the
      characteristics of the patient sample. Ninety percent of the sample were white
      women, and the mean Rapid Estimate of Adult Literacy in Medicine score was
      approximately 64, indicating a literacy level at or above the ninth grade.

PMID- 12610183
TI  - Final results of a randomized phase III trial comparing cyclophosphamide,
      epirubicin, and fluorouracil with a dose-intensified epirubicin and
      cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast
      cancer: an EORTC-NCIC-SAKK multicenter study.
AB  - PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a
      dose-intensified anthracycline regimen in locally advanced breast cancer.
      PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly
      assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to
      14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil
      (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV
      day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor
      (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14
      days. The study was designed to detect a 15% improvement; that is, from 50% to
      65% in median progression-free survival (PFS) in favor of the dose-intensified
      regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years.
      The median dose intensity delivered for C and E reached, respectively, 85% and
      87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm.
      The dose-intensified arm was slightly more emetogenic and generated more grade 3
      to 4 anemia but less febrile neutropenia episodes. After a median follow-up of
      5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months
      for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and
      51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does
      not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy
      for unselected locally advanced breast cancer patients.

PMID- 12610184
TI  - Long-term survival of patients with supraclavicular metastases at diagnosis of
      breast cancer.
AB  - BACKGROUND: Patients with supraclavicular metastases at diagnosis of breast
      cancer were classified between 1987 and 2002 as having stage M(1) breast cancer
      according to the tumor-node-metastasis (TNM) system. The 2003 edition of the TNM
      staging guidelines has classified such patients as having stage IIIC disease. To
      determine relative prognosis, we compared long-term survival in a population
      based cohort of patients with isolated supraclavicular metastases (nodal-M(1)) to
      outcomes of patients with stage IIIB or M(1) (other) disease at presentation.
      MATERIALS AND METHODS: Among patients with breast cancer and known tumor stage
      referred to the British Columbia Cancer Agency from 1976 to 1985, 336 IIIB, 233
      M(1), and 51 nodal-M(1) patients were identified. Actuarial overall and breast
      cancer-specific survival rates were determined to 20 years. RESULTS: Overall
      survival at 20 years was 13.2% for nodal-M(1) cases (95% confidence interval
      [CI], 5% to 26%), 9.4% for IIIB cases (95% CI, 6% to 14%), and 1.3% for M(1)
      (other) cases (95% CI, 0.4% to 3.5%; log-rank P <.0005). Overall survival was
      similar between nodal-M(1) and IIIB cases (P =.27). Breast cancer-specific
      survival at 20 years was 24.1% for nodal-M(1) cases (95% CI, 13% to 37%), 30.2%
      for IIIB cases (95% CI, 23% to 38%), and 3.9% for M(1) (other) cases (95% CI, 2%
      to 8%; log-rank P <.0005). Breast cancer-specific survival was significantly
      different for nodal-M(1) cases compared with either IIIB or M(1) (other) cases (P
      =.008 for both). CONCLUSION: Patients with supraclavicular metastases at
      diagnosis have significantly better outcomes than patients with M(1) (other)
      disease and overall survival similar to patients with IIIB disease.
      Reclassification as stage IIIC is appropriate for patients with breast cancer who
      present with supraclavicular nodal metastases alone.

PMID- 12610185
TI  - Predictors of long-term outcomes in older breast cancer survivors: perceptions
      versus patterns of care.
AB  - PURPOSE: There are few data on sequelae of breast cancer treatments in older
      women. We evaluated posttreatment quality of life and satisfaction in a national
      population. PATIENTS AND METHODS: Telephone surveys were conducted with a random
      cross-sectional sample of 1,812 Medicare beneficiaries 67 years of age and older
      who were 3, 4, and 5 years posttreatment for stage I and II breast cancer.
      Regression models were used to estimate the adjusted risk of decrements in
      physical and mental health functioning by treatment. In a subset of women (n =
      732), additional data were used to examine arm problems, impact of cancer, and
      satisfaction, controlling for baseline health, perceptions of ageism and racism,
      demographic and clinical factors, region, and surgery year. RESULTS: Use of
      axillary dissection was the only surgical treatment that affected outcomes,
      increasing the risk of arm problems four-fold (95% confidence interval, 1.56 to
      10.51), controlling for other factors. Having arm problems, in turn, exerted a
      consistently negative independent effect on all outcomes (P </=.001). Processes
      of care were also associated with quality of life and satisfaction. For example,
      women who perceived high levels of ageism or felt that they had no choice of
      treatment reported significantly more bodily pain, lower mental health scores,
      and less general satisfaction. These same factors, as well as high perceived
      racism, were significantly associated with diminished satisfaction with the
      medical care system. CONCLUSION: With the exception of axillary dissection, the
      processes of care, and not the therapy itself, are the most important
      determinants of long-term quality of life in older women.

PMID- 12610186
TI  - Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed
      by surgery and postoperative doxorubicin-based chemotherapy in locally advanced
      breast cancer: a phase I/II trial.
AB  - PURPOSE: Preoperative chemotherapy is the conventional primary treatment in
      locally advanced breast cancer (LABC). We investigated the safety and efficacy of
      primary twice-weekly paclitaxel and concurrent radiation (RT) before modified
      radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS
      AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary
      chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1
      hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8
      Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after
      completion of chemoradiation or on recovery of skin toxicity. Postoperatively,
      patients who responded to paclitaxel and RT received four cycles of
      doxorubicin/paclitaxel, whereas patients who did not respond received
      doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from
      paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and
      stomatitis (2%). Postsurgery complications occurred in six patients (14%). The
      only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade
      3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%),
      arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and
      nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was
      91%. Thirty-four percent of patients achieved a pathologic response in the
      mastectomy specimen: 16% pathologic complete responses (clearance of invasive
      cancer in the breast and axillary contents) and 18% pathologic partial responses
      (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice
      weekly paclitaxel with concurrent RT is a feasible and effective primary
      treatment for LABC. Future studies should compare primary chemoradiation to
      chemotherapy in LABC.

PMID- 12610187
TI  - Intensive induction chemotherapy with CBOP/BEP in patients with poor prognosis
      germ cell tumors.
AB  - PURPOSE: Despite a high cure rate in patients with testicular cancer, there
      remain patients in the poor prognosis group who have a less favorable outcome.
      Intensive induction chemotherapy using a regimen consisting of carboplatin,
      bleomycin, vincristine, and cisplatin, followed by bleomycin, etoposide, and
      cisplatin (CBOP/BEP), developed at the Royal Marsden Hospital, is designed to
      overcome the rapid proliferation seen in germ cell tumors. This study assesses
      the outcome of patients with poor-prognosis nonseminomatous germ cell tumors
      (NSGCT) treated with CBOP/BEP. PATIENTS AND METHODS: Patients with NSGCT from
      three centers, classified as poor prognosis according to International Germ Cell
      Classification Consensus Group criteria, were treated with CBOP/BEP regimen
      during the period from 1989 to 2000. Data on treatment toxicity, relapse-free
      survival (RFS), and overall survival (OS) were collected prospectively on a
      hospital database. RESULTS: Fifty-four male patients with poor prognosis NSGCT
      were treated with CBOP/BEP. The RFS at 3 and 5 years for all patients was 83.2%
      (95% confidence interval [CI], 68.8% to 91.3%). After a median follow-up of 4
      years, the OS of the 54 patients was 91.5% (95% CI, 78.6% to 96.8%) at 3 years
      and 87.6% (95% CI, 71.3% to 94.9%) at 5 years. Three-year OS in patients with a
      primary mediastinal germ cell tumor was 77.1% (95% CI, 34.5% to 93.9%) compared
      with 95.4% (95% CI, 82.8% to 98.8%) in patients with a testicular primary tumor
      (P =.24). CONCLUSION: The results reported here compare favorably with the
      historical results of alternative regimens used in the management of poor
      prognosis NSGCT. We suggest a phase III trial to confirm our findings.

PMID- 12610189
TI  - Phase II trial of autologous tumor vaccination, anti-CD3-activated vaccine-primed
      lymphocytes, and interleukin-2 in stage IV renal cell cancer.
AB  - PURPOSE: Previous preclinical and clinical studies have demonstrated that
      autologous tumor vaccines can induce relatively specific tumor-reactive T cells
      in draining lymph nodes. The adoptive transfer of these cells can result in tumor
      regression. PATIENTS AND METHODS: Patients with stage IV renal cell cancer (RCC)
      were vaccinated with irradiated autologous tumor cells admixed with Calmette
      Guerin bacillus. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs)
      were harvested and the lymphoid cells secondarily activated with anti-CD3
      monoclonal antibody and expanded in interleukin 2 (IL-2). The activated cells
      were subsequently infused intravenously along with the concomitant administration
      of bolus IL-2 (360,000 U/kg intravenously x 15 doses). RESULTS: Thirty-nine
      patients were entered onto the study, of whom 34 completed an initial course of
      cell therapy consisting of a mean (SEM) number of 4.3 (2.2) x 10(10) VPLN cells.
      Among subjects who received cell therapy, there were nine responses (four
      complete responses [CRs] and five partial responses [PRs]), for an overall
      response rate of 27%. The durations of the CRs were > 48, 45, > 35, and 12
      months, and the durations of the PRs were > 63, 48, 15, 12, and 4 months.
      Cultured tumor cells were available to assess in vitro cytokine release of VPLN
      cells in 24 subjects. The median cytokine release ratio of interferon gamma
      (IFNgamma) to IL-10 for responders and nonresponders was 992 and 5, respectively,
      which was significantly different (P =.047). CONCLUSION: The treatment protocol
      resulted in durable tumor responses in patients with advanced RCC. The ratio of
      IFNgamma and IL-10 cytokines released in response to tumor by the VPLN cells was
      a significant correlate with tumor response.

PMID- 12610188
TI  - Randomized, multicenter, phase II trial of two multicomponent regimens in
      androgen-independent prostate cancer.
AB  - PURPOSE: Several multicomponent regimens have been reported to be useful in
      advanced androgen-independent prostate cancer. We used a randomized phase II
      design to evaluate and compare two such regimens. Patients were accrued primarily
      in the community setting. PATIENTS AND METHODS: Patients with progressive,
      androgen-independent prostate cancer were randomly assigned to one of two
      treatments: either ketoconazole/doxorubicin alternating with
      vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide
      (TEE). Patients were prospectively stratified on the basis of disease volume. The
      primary end points were response and overall survival time. RESULTS: A total of
      75 patients were registered; 71 are included in the analysis. By the criterion of
      an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11
      (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to
      KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI],
      10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months)
      for patients treated with KA/VE. Many patients (24%) failed to complete at least
      6 weeks of therapy, including five (8%) treatment-related early deaths.
      CONCLUSION: Each of these regimens produced clinically significant responses, and
      the observed median survival (18.9 months for all 71 patients) compares favorably
      with previously published results, especially in the community setting.
      Nonetheless, it is apparent that these first-generation regimens must be applied
      judiciously, and thus we view efforts at better patient selection and the
      development of more tolerable therapies as higher priorities than carrying either
      of these regimens to phase III evaluation in the cooperative group setting.

PMID- 12610191
TI  - Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma
      patients.
AB  - PURPOSE: Standard therapies for non-Hodgkin's lymphoma (NHL) are associated with
      an increased risk of developing treatment-related myelodysplastic syndrome or
      acute myelogenous leukemia (tMDS/AML). However, there is considerable debate over
      the incidence or risk of tMDS/AML in NHL patients treated with any particular
      modality and the factors that contribute to malignant transformation. DESIGN:
      Conclusions were based on thorough analysis of data reported in the peer-reviewed
      literature and careful examination of the statistical methodology and methods for
      identifying cases of tMDS/AML. Unless noted, data are reported only for NHL
      patients, excluding Hodgkin's disease patients. RESULTS: Despite differences in
      methods used to identify cases and to estimate the cumulative incidence over time
      (actuarial v cumulative calculations), up to 10% of NHL patients treated with
      either conventional-dose chemotherapy or high-dose therapy and autologous stem
      cell transplantation may develop tMDS/AML within 10 years of primary therapy.
      Kaplan-Meier estimates of the actuarial incidence, which are based on censoring
      of patients who died without developing tMDS/AML, can lead to artificially high
      estimates with large confidence intervals at later time points. Although there is
      much debate about the cause(s) of tMDS/AML, there is compelling evidence that
      alkylating agents, certain other leukemogenic agents, and total-body irradiation
      (TBI) cause chromosomal damage that can lead to tMDS/AML. CONCLUSION: Limiting
      exposure to alkylating agents and eliminating TBI from transplantation
      conditioning regimens may reduce the relative risk of tMDS/AML.

PMID- 12610190
TI  - Extended follow-up of patients with hairy cell leukemia after treatment with
      cladribine.
AB  - PURPOSE: Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell
      lymphoproliferative disorder involving the marrow and spleen. Therapy for HCL
      includes splenectomy, interferon alfa-2a and alfa-2b, pentostatin, and
      cladribine. The purpose of this article was to report the extended follow-up of
      HCL patients treated with cladribine. PATIENTS AND METHODS: Two hundred nine
      patients with HCL who were treated with cladribine had at least 7 years of follow
      up. A course of cladribine constituted a 7-day continuous intravenous infusion at
      a dose of 0.1 mg/kg/d. RESULTS: Of the 207 assessable patients who had at least 7
      years of follow-up, 196 (95%) achieved a complete response (CR) and 11 (5%)
      achieved a partial response (PR) after a single course of cladribine (overall
      response rate, 100%). The median first-response duration for all responders was
      98 months. Seventy-six patients (37%) experienced relapse after their first
      course of cladribine. The median time to first relapse for all responders was 42
      months. Time to treatment failure of CRs compared with PRs was statistically
      significant (P <.0005). The overall survival rate was 97% recorded at 108 months.
      Forty-seven patients developed 58 second malignancies. The observed-to-expected
      ratio for second malignancies was 2.03 (95% confidence interval, 1.49 to 2.71).
      CONCLUSION: These results confirm previous observations that single courses of
      cladribine administered to patients with HCL induce high response rates, the
      majority of which are CRs. Most patients enjoy long-lasting complete remissions,
      and those patients who experience relapse can be successfully re-treated with
      cladribine.

PMID- 12610192
TI  - Impact of smoking on cancer stage at diagnosis.
AB  - BACKGROUND: Studies evaluating the relationship between smoking and cancer spread
      are limited. METHODS: We studied the relationship between cancer stage at
      diagnosis (local, regional, or metastatic) and smoking history (current,
      previous, or nonsmoker). For lung cancer, patterns of spread were also studied.
      RESULTS: In a tumor registry for eastern North Dakota, northwestern Minnesota,
      and northern South Dakota, 11,716 cases were identified from 1986 to 2001.
      Current smokers (relative risk [RR], 2.11; 95% confidence interval, 1.93 to 2.32;
      P <.001) and previous smokers (RR, 1.56; 95% confidence interval, 1.42 to 1.72; P
      <.001) had an increased risk of metastatic disease at diagnosis. Current smokers
      (RR, 1.39; 95% confidence interval, 1.29 to 1.51; P <.001), but not previous
      smokers, also had an increased risk of regional disease. An increase in
      metastatic disease was most evident for prostate cancer (RR, 1.53; P =.003). An
      increase in regional disease was most evident for head and neck (RR, 3.53; P
      <.001), prostate (RR, 1.83; P =.030), and breast cancer (RR, 1.22; P =.005).
      Compared with previous smokers, current smokers with metastatic lung cancer were
      more likely to have involvement of the brain (33.6% v 23.0%; P =.004), bone
      marrow, adrenal gland, and pericardium (24.7% v 15.9%; P =.004). CONCLUSION:
      Previous or current smoking is a risk factor for increased cancer stage in a wide
      range of malignancies. Further study is required to determine whether this
      association is causal.

PMID- 12610194
TI  - Lung cancer risk reduction after smoking cessation: observations from a
      prospective cohort of women.
AB  - PURPOSE: We conducted this study because the duration of excess lung cancer risk
      among former smokers has been inconsistently reported, doubt has been raised
      regarding the population impact of smoking cessation, and differential risk
      reduction by histologic cell type after smoking cessation needs to be confirmed.
      METHODS: The Iowa Women's Health Study is a prospective cohort study of 41,836
      Iowa women aged 55 to 69 years. In 1986, mailed questionnaires were used to
      collect detailed smoking history. Age-adjusted lung cancer incidence through 1999
      was analyzed according to years of smoking abstinence. Relative risks were
      estimated using Cox regression analysis. RESULTS: There were 37,078 women in the
      analytic cohort. Compared with the never smokers, former smokers had an elevated
      lung cancer risk (relative risk, 6.6; 95% confidence interval, 5.0 to 8.7) up to
      30 years after smoking cessation for all former smokers. However, a beneficial
      effect of smoking cessation was observed among recent and distant former smokers.
      The risk of adenocarcinoma remained elevated up to 30 years for both former
      heavier and former lighter smokers. CONCLUSION: The risk for lung cancer is
      increased for both current and former smokers compared with never smokers and
      declines for former smokers with increasing duration of abstinence. The decline
      in excess lung cancer risk among former smokers is prolonged compared with other
      studies, especially for adenocarcinoma and for heavy smokers, suggesting that
      more emphasis should be placed on smoking prevention and lung cancer
      chemoprevention.

PMID- 12610193
TI  - Nicotine patch therapy based on smoking rate followed by bupropion for prevention
      of relapse to smoking.
AB  - PURPOSE: To determine whether (1) tailored nicotine patch therapy that is based
      on smoking rate can be carried out in a multisite oncology investigative group
      practice setting, (2) long-term use of bupropion reduces the rate of relapse to
      smoking in smokers who stop smoking with nicotine patch therapy, and (3)
      bupropion can initiate smoking abstinence among smokers who have failed to stop
      smoking after nicotine patch therapy. PARTICIPANTS AND METHODS: Fourteen North
      Central Cancer Treatment Group sites recruited generally healthy adult smokers
      from the general population for nicotine patch therapy and based the patch dosage
      on smoking rates. At completion of nicotine patch therapy, nonsmoking
      participants were eligible to be assigned to bupropion or placebo for 6 months
      (for relapse prevention). and smoking participants were eligible to be assigned
      to bupropion or placebo for 8 weeks of treatment. RESULTS: Of 578 subjects, 31%
      were abstinent from smoking at the end of nicotine patch therapy. Of those
      subjects not smoking at the end of nicotine patch therapy who entered the relapse
      prevention phase, 28% and 25% were not smoking at 6 months (the end of the
      medication phase) for bupropion and placebo, respectively (P =.73). For those
      still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking
      with bupropion or placebo, respectively (P =.12). CONCLUSION: Tailored nicotine
      patch therapy for the general population of smokers can be provided in a
      multisite oncology investigative group setting. Bupropion did not reduce relapse
      to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion
      did not initiate abstinence among smokers who failed to stop smoking with
      nicotine patch therapy.

PMID- 12610195
TI  - Neuroprotective effect of vitamin E supplementation in patients treated with
      cisplatin chemotherapy.
AB  - PURPOSE: The aim of this study is to evaluate the neuroprotective effect of
      antioxidant supplementation with vitamin E in patients treated with cisplatin
      chemotherapy. METHODS: Between April 1999 and October 2000, forty-seven patients
      were randomly assigned to either group one, which received vitamin E
      supplementation during cisplatin chemotherapy, or to group two, which received
      cisplatin chemotherapy alone. Alpha-tocopherol (vitamin E; 300 mg/d) was
      administered orally before cisplatin chemotherapy and continued for 3 months
      after the suspension of treatment. For preclinical studies, nude mice carrying
      the human melanoma tumor were treated with cisplatin alone or in combination with
      vitamin E. RESULTS: Twenty-seven patients completed six cycles of cisplatin
      chemotherapy: 13 patients in group one and 14 patients in group two. The
      incidence of neurotoxicity was significantly lower in group one (30.7%) than it
      was in group two (85.7%; P <.01). The severity of neurotoxicity, measured with a
      comprehensive neurotoxicity score based on clinical and neurophysiological
      parameters, was significantly lower in patients who were supplemented with
      vitamin E than in patients who were not supplemented with vitamin E (2 v 4.7, P
      <.01). The results of the preclinical studies showed that when cisplatin was
      combined with vitamin E, no differences were observed in tumor weight inhibition,
      tumor growth delay, or life span as compared with treatment with cisplatin alone.
      CONCLUSION: Supplementation of patients receiving cisplatin chemotherapy with
      vitamin E decreases the incidence and severity of peripheral neurotoxicity.

PMID- 12610196
TI  - Shared treatment decision making: what does it mean to physicians?
AB  - PURPOSE: Physicians are urged to practice shared treatment decision making
      (STDM), yet this concept is poorly understood. We developed a conceptual
      framework describing essential characteristics of a shared approach. This study
      assessed the degree of congruence in the meanings of STDM as described in the
      framework and as perceived by practicing physicians. METHODS: A cross-sectional
      survey questionnaire was mailed to eligible Ontario medical and radiation
      oncologists and surgeons treating women with early-stage breast cancer. Open
      ended and structured questions elicited physicians' perceptions of shared
      decision making. RESULTS: Most study physicians spontaneously described STDM
      using characteristics identified in the framework as essential to this concept.
      When presented with clinical examples in which the decision-making roles of
      physicians and patients were systematically varied, study physicians
      overwhelmingly identified example 4 as illustrating a shared approach. This
      example was deliberately constructed to depict STDM as defined in the framework.
      In addition, more than 85.0% of physicians identified as important to STDM
      specific patient and physician roles derived from the framework. These included
      the following: the physician gives information to the patient on treatment
      benefits and risks; the patient gives information to the physician about her
      values; the patient and physician discuss treatment options; both agree on the
      treatment to implement. CONCLUSION: Substantial congruence was found between the
      meaning of STDM as described in the framework and as perceived by study
      physicians. This supports use of the framework as a conceptual tool to guide
      research, compare different treatment decision-making approaches, clarify the
      meaning of STDM, and enhance its translation into practice.

PMID- 12610197
TI  - Perspectives on the value of American Society of Clinical Oncology clinical
      guidelines as reported by oncologists and health maintenance organizations.
AB  - PURPOSE: Although the American Society of Clinical Onoclogy's (ASCO) Health
      Services Research (HSR) committee activities have primarily focused on clinical
      guideline development, little is known about the value placed on these guidelines
      by the desired end users. ASCO members and Health Maintenance Organizations
      (HMOs) were surveyed on the value and implementation of ASCO guidelines. In this
      article, we summarize our findings. METHODS: ASCO members (n = 1500) were queried
      about whether they had read ASCO's first four clinical guidelines and technology
      assessment; whether they agreed with the recommendations; whether they used
      guidelines in clinical practice; and how guidelines had affected reimbursement.
      HMOs (n = 131) were queried on how they identify, implement, and value the first
      four ASCO clinical guidelines. RESULTS: The membership survey indicated that ASCO
      guidelines were read more often by physicians in private healthcare settings
      compared with physicians in academic practices (P <.02). Disagreement rates were
      low for all guidelines (range, 1% to 7%). One quarter of respondents reported
      that the guidelines were difficult to find and difficult to apply to the practice
      setting, and approximately one tenth of respondents indicated that the guidelines
      were difficult to evaluate, interpret, or read. The HMO survey indicated that one
      third of HMOs reported use of ASCO guidelines, with higher rates of usage by
      larger HMOs and by those with higher National Committee on Quality Assurance
      (NCQA) ratings. Respondent HMOs valued guidelines for various purposes and used
      multiple methods of guideline identification and implementation. CONCLUSION: ASCO
      guidelines are generally highly supported by physicians and HMOs. Additional
      studies are needed to identify implementation barriers and to see whether
      guidelines have resulted in improvements in healthcare.

PMID- 12610199
TI  - Communicating the value of adjuvant chemotherapy.

PMID- 12610198
TI  - American oncologists' views of internet use by cancer patients: a mail survey of
      American Society of Clinical Oncology members.
AB  - PURPOSE: Americans are turning more and more frequently to the Internet to obtain
      health information. The specific effects on patients, doctors, and the clinical
      encounter are not well known. METHODS: A brief mail survey was sent to a
      systematic sample of 5% of medical oncologists and hematologist/oncologists
      listed in the membership directory of the American Society of Clinical Oncology.
      RESULTS: Response rate to this mail survey was 46.2%. Oncologists' median
      estimate of the proportion of their patients using the Internet to obtain cancer
      information was 30%. Subjects responded that, on average, 10 minutes were added
      to each patient encounter in which Internet information was discussed. Responding
      oncologists reported that use of the Internet had the ability to simultaneously
      make patients more hopeful, confused, anxious, and knowledgeable. Forty-four
      percent of responding oncologists reported that they sometimes or rarely had
      difficulty discussing Internet information, and only 9% of subjects reported that
      they sometimes or always felt threatened when patients brought Internet
      information to discuss. In narrative responses, oncologists reported both
      positive and negative effects of Internet use by patients. CONCLUSION: In this
      brief mail survey to a systematic sample of American oncologists in academic and
      community practice, respondents reported that a significant proportion of their
      patients use the Internet to obtain cancer information. Oncologists viewed
      Internet information as having both positive and negative effects on the clinical
      encounter. Further research is needed on the effects of patients' use of the
      Internet to obtain cancer information involving both patients and oncologists.

PMID- 12610200
TI  - Unusual abdominal tumors: case 1. Small bowel carcinoid presenting as an acute
      abdomen.

PMID- 12610201
TI  - Unusual abdominal tumors: case 2. Intra-abdominal desmoplastic small round cell
      tumor.

PMID- 12610202
TI  - Unusual abdominal tumors: case 3. Multiple lymphomatous polyposis in lymphoma of
      colon.

PMID- 12610203
TI  - Unusual abdominal tumors: case 4. Multiple lymphomatous polyposis in mantle cell
      lymphoma.

PMID- 12610205
TI  - Intraperitoneal chemotherapy for stage III ovarian cancer.

PMID- 12610206
TI  - Regarding "Sweet time unafflicted".

PMID- 12610207
TI  - X-inactivation patch size in human female tissue confounds the assessment of
      tumor clonality.
AB  - Most models of tumorigenesis assume that tumors are monoclonal in origin. This
      conclusion is based largely on studies using X chromosome-linked markers in
      females. One important factor, often ignored in such studies, is the distribution
      of X-inactivated cells in tissues. Because lyonization occurs early in
      development, many of the progeny of a single embryonic stem cell are grouped
      together in the adult, forming patches. As polyclonality can be demonstrated only
      at the borders of X-inactivation patches, the patch size is crucial in
      determining the chance of demonstrating polyclonality and hence the number of
      tumors that need to be examined to exclude polyclonality. Previously studies
      using X-linked genes such as glucose-6-phosphate dehydrogenase have been
      handicapped by the need to destroy the tissues to study the haplotypes of glucose
      6-phosphate dehydrogenase [Fialkow, P.-J. (1976) Biochim. Biophys. Acta 458, 283
      321] or to determine the restriction fragment length polymorphisms of X
      chromosome-linked genes [Vogelstein, B., Fearon, E. R., Hamilton, S. R. &
      Feinberg, A. P. (1985) Science 227, 642-645]. Here we visualize X-inactivation
      patches in human females directly. Results show that the patch size is relatively
      large in both the human colon and breast, confounding assessment of tumor
      clonality with traditional X-inactivation studies.

PMID- 12610208
TI  - Molecular classification of familial non-BRCA1/BRCA2 breast cancer.
AB  - In the decade since their discovery, the two major breast cancer susceptibility
      genes BRCA1 and BRCA2, have been shown conclusively to be involved in a
      significant fraction of families segregating breast and ovarian cancer. However,
      it has become equally clear that a large proportion of families segregating
      breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately,
      despite intensive effort, the identification of additional breast cancer
      predisposition genes has so far been unsuccessful, presumably because of genetic
      heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non
      BRCA1/2 breast cancer families (termed BRCAx families) comprise a
      histopathologically heterogeneous group, further supporting their origin from
      multiple genetic events. Accordingly, the identification of a method to
      successfully subdivide BRCAx families into recognizable groups could be of
      considerable value to further genetic analysis. We have previously shown that
      global gene expression analysis can identify unique and distinct expression
      profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show
      that gene expression profiling can discover novel classes among BRCAx tumors, and
      differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based
      comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic
      genetic alterations within the BRCAx subgroups. These findings illustrate that,
      when gene expression-based classifications are used, BRCAx families can be
      grouped into homogeneous subsets, thereby potentially increasing the power of
      conventional genetic analysis.

PMID- 12610209
TI  - A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition.
AB  - A rhodium(III) complex, rac-[Rh(bpy)(2)phzi](3+) (bpy, 2,2'-bipyridine; phzi,
      benzo[a]phenazine-5,6-quinone diimine) has been designed as a sterically
      demanding intercalator targeted to destabilized mismatched sites in double
      helical DNA. The complex is readily synthesized by condensation of the phenazine
      quinone with the corresponding diammine complex. Upon photoactivation, the
      complex promotes direct strand scission at single-base mismatch sites within the
      DNA duplex. As with the parent mismatch-specific reagent,
      [Rh(bpy)(2)(chrysi)](3+) [chrysene-5,6-quinone diimine (chrysi)], mismatch
      selectivity depends on the helix destabilization associated with mispairing.
      Unlike the parent chrysi complex, the phzi analogue binds and cleaves with high
      affinity and efficiency. The specific binding constants for CA, CC, and CT
      mismatches within a 31-mer oligonucleotide duplex are 0.3, 1, and 6 x 10(7) M(
      1), respectively; site-specific photocleavage is evident at nanomolar
      concentrations. Moreover, the specificity, defined as the ratio in binding
      affinities for mispaired vs. well paired sites, is maintained. The increase in
      affinity is attributed to greater stability in the mismatched site associated
      with stacking by the heterocyclic aromatic ligand. The high-affinity complex is
      also applied in the differential cleavage of DNA obtained from cell lines
      deficient in mismatch repair vs. those proficient in mismatch repair. Agreement
      is found between photocleavage by the mismatch-specific probes and deficiency in
      mismatch repair. This mismatch-specific targeting, therefore, offers a potential
      strategy for new chemotherapeutic design.

PMID- 12610210
TI  - Comparison of formation of reactive conformers for the SN2 displacements by
      CH3CO2- in water and by Asp124-CO2- in a haloalkane dehalogenase.
AB  - The S(N)2 displacement of Cl(-) from 1,2-dichloroethane by acetate (CH(3)CO(2)(
      )) in water and by the carboxylate of the active site aspartate in the haloalkane
      dehalogenase of Xanthobacter autothropicus have been compared by using molecular
      dynamics simulations. In aqueous solution, six families of contact-pair
      structures (I-VI) were identified, and their relative concentrations and
      dissociation rate constants were determined. The near attack conformers (NACs)
      required for the S(N)2 displacement reaction are members of the IV (CH(3)COO(
      )...CH(2)(Cl)CH(2)Cl) family and are formed in the sequence II-->III-->IV-->NAC.
      The NAC subclass is defined by the COO(-)...CCl contact distance of < or = 3.41 A
      and the COO(-)...CCl angle of 157-180 degrees. The mole percentage of NACs is
      0.16%, based on the 1 M standard state. This result may be compared with 13.4
      mole percentage of NACs in the Michaelis complex in the enzyme. It follows that
      NAC formation in the enzyme is favored by 2.6 kcal/mol. Because reaction
      coordinates from S to TS, both in water and in the enzyme, pass via NAC (i.e., S 
      -> NAC --> TS), the reduction in the S --> NAC barrier by 2.6 kcal/mol accounts
      for approximately 25% of the reduction of total barrier in the S --> TS (10.7
      kcal/mol). The remaining 75% of the advantage of the enzymatic reaction revolves
      around the efficiency of NAC --> TS step. This process, based on previous
      studies, is discussed briefly.

PMID- 12610211
TI  - Is the olfactory receptor a metalloprotein?
AB  - The sense of smell is arguably our most primal faculty and also the least
      understood. Even our own olfactorily impaired species is capable of detecting
      approximately 10,000 distinct scents [Buck, L. & Axel, R. (1991) Cell 65, 175
      187]. To achieve that amazing diversity, mammals have approximately 1,000
      olfactory genes, which accounts for approximately 3% of their entire genome
      [Mombaerts, P. (1999) Science 286, 707-711]. The olfactory receptors (ORs) are
      believed to be seven-helix transmembrane proteins, with an odorant-binding site
      on the periplasmic domain and a G protein-binding site on the cytoplasmic domain.
      Odorants first bind to an OR, which then undergoes some structural change that
      triggers the G protein activation and the following cascade of events leading to
      nerve cell activity. The structural details of ORs, however, remain to be
      determined. In this paper, we will describe a hypothesis in which metal ions play
      an important role for odorant recognition. We analyze the predicted structure and
      consensus sequence of the ORs and propose a metal-binding site in the loop
      between fourth and fifth helix (4-5 loop). We have prepared synthetically a
      pentapeptide that contains this putative binding site and find that it not only
      has high affinity for binding Cu(II) and Zn(II) ions, but that it also undergoes
      a dramatic transition to an alpha-helical structure upon metal ion binding. Based
      on these observations, we propose a "shuttlecock" mechanism for the possible
      structural change in ORs upon odorant binding. This mechanism involves membrane
      penetration of the 4-5 loop after residue charge neutralization by metal ion
      binding.

PMID- 12610212
TI  - cDNA cloning and biochemical characterization of S-adenosyl-L-methionine: 2,7,4'
      trihydroxyisoflavanone 4'-O-methyltransferase, a critical enzyme of the legume
      isoflavonoid phytoalexin pathway.
AB  - Formononetin (7-hydroxy-4'-methoxyisoflavone, also known as 4'-O-methyldaidzein)
      is an essential intermediate of ecophysiologically active leguminous
      isoflavonoids. The biosynthetic pathway to produce 4'-methoxyl of formononetin
      has been unknown because the methyl transfer from S-adenosyl-L-methionine (SAM)
      to 4'-hydroxyl of daidzein has never been detected in any plants. A hypothesis
      that SAM: daidzein 7-O-methyltransferase (D7OMT), an enzyme with a different
      regiospecificity, is involved in formononetin biosynthesis through its
      intracellular compartmentation with other enzymes recently prevails, but no
      direct evidence has been presented. We proposed a new scheme of formononetin
      biosynthesis involving 2,7,4'-trihydroxyisoflavanone as the methyl acceptor and
      subsequent dehydration. We now cloned a cDNA encoding SAM: 2,7,4'
      trihydroxyisoflavanone 4'-O-methyltransferase (HI4'OMT) through the screening of
      functionally expressed Glycyrrhiza echinata (Fabaceae) cDNAs. The reaction
      product, 2,7-dihydroxy-4'-methoxyisoflavanone, was unambiguously identified.
      Recombinant G. echinata D7OMT did not show HI4'OMT activity, and G. echinata
      HI4'OMT protein free from D7OMT was partially purified. HI4'OMT is thus concluded
      to be distinct from D7OMT, and their distant phylogenetic relationship was
      further presented. HI4'OMT may be functionally identical to (+)-6a
      hydroxymaackiain 3-OMT of pea. Homologous cDNAs were found in several legumes,
      and the catalytic function of the Lotus japonicus HI4'OMT was verified,
      indicating that HI4'OMT is the enzyme of formononetin biosynthesis in general
      legumes.

PMID- 12610213
TI  - The CUP-SHAPED COTYLEDON genes promote adventitious shoot formation on calli.
AB  - In Arabidopsis, shoots regenerate on calli derived from hypocotyl explants.
      Mutations in CUC1 and CUC2 (CUP-SHAPED COTYLEDON) reduce the induction of
      adventitious shoots on calli. To elucidate the function of CUC1 and CUC2 during
      this process, these genes were overexpressed in calli. Our results indicate that
      CUC1 and CUC2 promote adventitious shoot formation on calli. To clarify their
      functions, the concentrations of auxin and cytokinin in the shoot-inducing medium
      were changed. Calli of the single and double mutants of cuc1 and cuc2, as well as
      calli overexpressing either of the CUC genes, responded similarly. This suggests
      that neither of the genes are involved in synthesis or sensitivity of these
      hormones. During embryogenesis, CUC1 and CUC2 induce shoot apical meristem
      formation through activation of STM (SHOOT MERISTEMLESS). Our analyses using the
      stm mutant and an STM::GUS construct suggest that CUC1 and CUC2 also function
      upstream of STM even in calli.

PMID- 12610214
TI  - In vivo and in vitro characterization of the ARR11 response regulator implicated
      in the His-to-Asp phosphorelay signal transduction in Arabidopsis thaliana.
AB  - In Arabidopsis thaliana, Histidine-to-Aspartate (His--> Asp) phosphorelay is a
      paradigm of a signaling system that is considered to be involved in response to
      plant hormones, including ethylene and cytokinin. In the current framework of His
      ->Asp phosphorelay in this higher plant, the type-B ARR (response regulator)
      family members appear to act as DNA-binding transcriptional regulators. Although
      Arabidopsis thaliana has 11 type-B ARR family members, except for ARR1 and ARR2,
      no biological information is available with regard to others. As the main
      objective of this study, we characterized another example, ARR11, in terms of not
      only its in vitro biochemical properties, but also its biological activity in
      plants. In plants, the ARR11 gene was expressed predominantly in roots. In vitro,
      ARR11 showed the ability to acquire a phosphoryl group from a histidine
      containing phosphotransfer intermediate (AHP), and also it showed the ability to
      recognize a specific nucleotide sequence, GGATT. These in vitro results supported
      the view that ARR11 is indeed a DNA-binding transcription factor, the ability of
      which is most likely modulated by phosphorylation in its receiver domain. In
      vivo, when a C-terminal DNA-binding domain lacking the N-terminal phospho
      accepting (or receiver) domain was aberrantly expressed, the resulting transgenic
      plants showed characteristic anomalies during development of apical parts. The
      observed anomalies included "unusual proliferation of tissues in cotyledons" and
      "outgrowth of adventitious shoots near cotyledons". These results with regard to
      the functions of ARR11 are mainly discussed in comparison with those of the
      previously characterized type-B response regulators.

PMID- 12610215
TI  - Changes in alpha-xylosidase during intact and auxin-induced growth of pine
      hypocotyls.
AB  - A complete cDNA from Pinus pinaster Aiton, potentially coding for an alpha
      xylosidase able to remove the xylose residue from xyloglucan oligosaccharides,
      has been cloned. Its sequence was homologous to previously published alpha
      xylosidase genes from Arabidopsis and nasturtium. The protein also showed the two
      signature regions of family 31 of glycosyl hydrolases. The gene expression level
      was quantified by competitive RT-PCR, under different growth conditions,
      throughout seedling development, in different regions along the hypocotyls and in
      auxin-treated hypocotyl segments, and related with growth capacity and alpha
      xylosidase activity. A role of alpha-xylosidase in regulating the level of
      xyloglucan oligosaccharides within the apoplast is proposed. The action of an
      alpha-xylosidase removing the xylose residue, would make possible the action of a
      beta-glucosidase deblocking the xyloglucan oligosaccharide degradation and it
      could serve as a control point for the regulation of the apoplastic levels of
      xyloglucan oligosaccharides.

PMID- 12610216
TI  - Characterization and expression of a novel member (JBURE-II) of the urease gene
      family from jackbean [Canavalia ensiformis (L.) DC].
AB  - Canavalia ensiformis (jackbean) seeds contain the proteins urease and canatoxin,
      a variant form of the jackbean urease. Here we have cloned a cDNA encoding
      another isoform of urease, called JBURE-II. This cDNA was obtained by RT-PCR
      using as template total RNA extracted from C. ensiformis tissues. Nucleotide
      sequence analysis showed that JBURE-II clones share 86% similarity with known
      jackbean urease. The presence in C. ensiformis of a family of urease-related
      genes with at least three members was demonstrated by Southern blot analysis. In
      order to understand the pattern of expression of the JBURE-II gene, we collected
      tissue samples from different stages of flower and embryo development. The
      results of RT-PCR show that JBURE-II is expressed from flower buds throughout
      seed maturation. Semi-quantitative RT-PCR indicates that expression of urease and
      JBURE-II genes is induced in seedlings and in leaves treated with abscisic acid,
      a phytohormone involved in seed maturation and wound response. This work
      constitutes the first report on the presence of a family of urease genes in
      jackbean, and provides characterization of a cDNA encoding a new member of this
      gene family.

PMID- 12610217
TI  - Effects of extracellular pH on the metabolic pathways in sulfur-deprived, H2
      producing Chlamydomonas reinhardtii cultures.
AB  - Sustained photoproduction of H(2) by the green alga, Chlamydomonas reinhardtii,
      can be obtained by incubating cells in sulfur-deprived medium [Ghirardi et al.
      (2000b) Trends Biotechnol. 18: 506; Melis et al. (2000) Plant Physiol. 122: 127].
      The current work focuses on (a) the effects of different initial extracellular
      pHs on the inactivation of photosystem II (PSII) and O(2)-sensitive H(2)
      production activity in sulfur-deprived algal cells and (b) the relationships
      among H(2)-production, photosynthetic, aerobic and anaerobic metabolisms under
      different pH regimens. The maximum rate and yield of H(2) production occur when
      the pH at the start of the sulfur deprivation period is 7.7 and decrease when the
      initial pH is lowered to 6.5 or increased to 8.2. The pH profile of hydrogen
      photoproduction correlates with that of the residual PSII activity (optimum pH
      7.3-7.9), but not with the pH profiles of photosynthetic electron transport
      through photosystem I or of starch and protein degradation. In vitro hydrogenase
      activity over this pH range is much higher than the actual in situ rates of H(2)
      production, indicating that hydrogenase activity per se is not limiting. Starch
      and protein catabolisms generate formate, acetate and ethanol; contribute some
      reductant for H(2) photoproduction, as indicated by 3-(3,4-dichlorophenyl)-1,1
      dimethylurea and 2,5-dibromo-6-isopropyl-3-methyl-1,4-benzoquinone inhibition
      results; and are the primary sources of reductant for respiratory processes that
      remove photosynthetically generated O(2). Carbon balances demonstrate that
      alternative metabolic pathways predominate at different pHs, and these depend on
      whether residual photosynthetic activity is present or not.

PMID- 12610218
TI  - Characterization of citrate transport through the plasma membrane in a carrot
      mutant cell line with enhanced citrate excretion.
AB  - The superior ability of citrate excretion in a carrot (Daucus carota L.) mutant
      cell line, namely IPG (insoluble phosphate grower) [Takita et al. (1999a) Plant
      Cell Physiol. 40: 489] cells has been characterized in terms of citrate transport
      at the plasma membrane. IPG cells released about a 20-fold increase in citrate in
      comparison with malate, while the concentration of malate was only 35% lower than
      that of citrate in the cell sap. Citrate excretion was sensitive to anion channel
      blockers, such as niflumic acid and anthracene-9-carboxylic acid. These results
      indicate that IPG cells release citrate through the plasma membrane using citrate
      specific anion channels. The rate of citrate release from IPG cells was not
      affected by the concentration of aluminum (0 and 50 micro M), soluble P(i) (0 or
      2 mM) and the pH (4.5-5.6) of the medium, suggesting that anion channels would
      not be regulated by such external conditions. Citrate excretion correlated with
      the H(+) efflux, possibly from the action of H(+)-ATPase on the plasma membrane.
      The activity of plasma membrane H(+)-ATPase was about three times higher in IPG
      cells than in wild-type cells, and might be involved in the high citrate
      excretion ability.

PMID- 12610219
TI  - Sugar retrieval by coats of developing seeds of Phaseolus vulgaris L. and Vicia
      faba L.
AB  - Influxes of glucose, fructose and sucrose were characterised for coat cells of
      developing seeds of Phaseolus vulgaris L. and Vicia faba L. by monitoring uptake
      of [(14)C]sugars into excised seed-coat halves and two different protoplast
      populations derived from seed coats. Sugar influxes by the two populations of
      protoplasts were similar for each sugar species [sucrose > (fructose
      approximately glucose)] and hexoses competed with sucrose. Concentration
      dependent influxes of all three sugars by excised seed coats could be described
      by a simple directly proportional relationship between concentration ([S]) and
      uptake rate (v) in the physiological range of sugar concentrations (v
      approximately A.[S]). Alternatively, with the exception of fructose influx by
      Vicia, all could be fitted to a Michaelis-Menten relationship, as could sucrose
      uptake by Vicia protoplasts. Apparent K(m) values were high ( approximately 100
      500 mM) compared with those reported for other systems. Sucrose transport was
      distinct from glucose and fructose transport in both species. Sugar influx was
      decreased by p-chloromercuribenzenesulfonic acid, carbonylcyanide m
      chlorophenylhydrazone and erythrosin B. These responses are consistent with
      sugar/H(+) symport acting to retrieve photoassimilates leaked to the apoplasm
      during post-sieve element transport within seed coats.

PMID- 12610220
TI  - Fusion with HDEL protects cell wall invertase from early degradation when N
      glycosylation is inhibited.
AB  - Previous data obtained in different suspension-cultured plant cells have clearly
      illustrated that N-glycans are absolutely required for transport of glycoproteins
      to the extracellular compartment, regardless of their oligosaccharide structure
      [see Lerouge et al. (1998) Plant Mol. Biol. 38: 31 for review]. In the present
      study the role of N-glycosylation in the transport of glycoproteins to the cell
      surface was studied in BY2 tobacco cells using both endogenous and recombinant
      cell wall invertases as markers. When synthesized without their N-glycans, both
      invertases were very rapidly degraded. This degradation did not occur in an
      acidic compartment and was brefeldin A-insensitive. Therefore, it most probably
      represents a pre-Golgi event. However, the low efficiency of specific inhibitors
      did not favor a strong contribution of proteasomes in this proteolysis. In
      contrast, addition of a C-terminal His-Asp-Glu-Leu (HDEL) extension prevented
      arrival of these non-glycosylated glycoproteins in the compartment where they are
      degraded. These results argue for the presence of an endoplasmic reticulum (ER)
      domain specialized in protein degradation. Consistent with our results and the
      well-known stabilization of recombinant proteins retained in the ER, the addition
      of an ER retention signal to a protein would prevent its targeting to an ER
      domain devoted to degradation.

PMID- 12610221
TI  - Inhibition of plastid division by ampicillin in the pteridophyte Selaginella
      nipponica Fr. et Sav.
AB  - We investigated the effect of the beta-lactam antibiotic, ampicillin, on plastid
      division in the pteridophyte Selaginella nipponica. Guard cells of plantlets
      treated with 1 mM ampicillin only often had one plastid, whereas guard cells of
      untreated plantlets had two to four plastids. We generated a S. nipponica cell
      culture system and used it to investigate the effects of ampicillin. Treatment
      with 1 mM ampicillin had no effect on cell division in culture. We classified
      cultured cells into four types based on the number of plastids they contained:
      one (Type I), two (Type II), three or four (Type III) and more than five (Type
      IV). After 3 d in culture, the percentage of each cell type (I-IV) was 29.5,
      46.7, 20.9, and 1.9%, respectively. Subsequently, the percentage of Types III and
      IV increased gradually, reaching 61.9 and 11.4%, respectively, after 15 d in
      culture in the absence of ampicillin. When 1 mM ampicillin was added, there was a
      minimal increase in the number of Type III and IV cells, with high percentages of
      Type I and II cells (32.4 and 45.7%, respectively) after 15 d. These results
      suggest that ampicillin inhibits plastid division in S. nipponica.

PMID- 12610222
TI  - Analysis of the feed-forward effects of sink activity on the photosynthetic
      source-sink balance in single-rooted sweet potato leaves. I. Activation of
      RuBPcase through the development of sinks.
AB  - Single-rooted sweet potato leaves having a petiole with a fragment of stem
      allocated exceptionally large amounts of photosynthates to tuberous roots, the
      only major storage organ, throughout an experimental period of 50 d. The increase
      in photosynthetic activity for CO(2) fixation depended exclusively on the
      development of sink activity due to the growth of tuberous roots. Thus this model
      expressed a remarkable feed-forward effect on the photosynthetic source-sink
      balance. The level of ribulose-1,5-bisphosphate carboxylase (RuBPcase) protein in
      the leaves increased continuously during the period. The lowered initial as well
      as total activity of RuBPcase observed at the start of the experiment was raised
      with the cancellation of the sink-limited state due to the development of
      tuberous roots. The maximum activity determined after removing some inhibitor(s)
      from the enzyme by treating the leaf extract with SO(4)(2-) was much greater than
      the total activity and remained approximately constant throughout the
      experimental period. The clear decrease in the difference between maximum and
      total activities with the development of tuberous roots might reflect the
      reactivation of RuBPcase due to the removal of some inhibitor(s) from the enzyme
      through the cancellation of the sink-limited state.

PMID- 12610223
TI  - Application of vanadate-induced nucleotide trapping to plant cells for detection
      of ABC proteins.
AB  - The vanadate-induced nucleotide trapping technique, which has been conventionally
      used to characterize mammalian ATP-binding cassette (ABC) proteins, was applied
      to berberine-producing plant cell cultures, Thalictrum minus and Coptis japonica.
      One membrane protein at ca. 180 kDa was photoaffinity-labeled with 8-azido-[alpha
      (32)P]ATP in the T. minus cells in the presence of vanadate, which was
      specifically induced by the addition of benzyladenine in a similar manner as the
      induction of berberine biosynthesis in these cell cultures, whereas three bands
      were observed in the C. japonica cells in the size region between 120 and 150 kDa
      corresponding to full-sized ABC protein. The benzyladenine-induced band in T.
      minus showed properties similar to those of human MDR1, including the recognition
      of berberine, which suggests that the ABC protein detected in T. minus takes this
      endogenous alkaloid as a putative substrate for transport. This is the first
      application of this technique to plant cells.

PMID- 12610224
TI  - Susceptibility of Chara myosin to SH reagents.
AB  - Cellular and intracellular motile events in plants are susceptible to SH reagents
      such as N-ethylmaleimide (NEM). It has long been believed that the target of the
      reagent is myosin. We compared the effect of NEM on the motile and ATPase
      activities of skeletal muscle myosin with that on plant myosin using characean
      algal myosin. It was found that the motile activity of myosin prepared from NEM
      treated C. corallina decreased to a level accountable for the decrease in the
      velocity of cytoplasmic streaming but it was also found that Chara myosin was far
      less susceptible to NEM than skeletal muscle myosin.

PMID- 12610225
TI  - Constitutive expression of a novel-type ammonium transporter OsAMT2 in rice
      plants.
AB  - To characterize ammonium transport pathways in rice, two cDNAs with high homology
      to MEP/AMT2-type ammonium transporters, OsAMT2;1 and OsAMT3;1, were isolated.
      Expression of OsAMT2;1 in an ammonium-uptake-defective yeast mutant showed that
      this gene encodes functional ammonium transporters. OsAMT2;1 was constitutively
      expressed in both roots and shoots irrespective of the supply of inorganic
      nitrogen to the medium, whereas OsAMT3;1 expression was relatively weak. A
      database search with the amino acid sequence of OsAMT2;1 showed that there are 10
      putative OsAMT genes in rice, i.e. three each for OsAMT1, OsAMT2 and OsAMT3,
      respectively, and one for OsAMT4.

PMID- 12610226
TI  - An abundant periplasmic protein of the denitrifying phototroph Rhodobacter
      sphaeroides f. sp. denitrificans is PstS, a component of an ABC phosphate
      transport system.
AB  - To understand a physiological role of an abundant 34-kDa periplasmic protein in
      the denitrifying phototroph Rhodobacter sphaeroides f. sp. denitrificans grown in
      a medium containing malate as the carbon source, the gene for the protein was
      isolated. The deduced amino acid sequence of the protein had a sequence
      similarity of 66.2% to that of PstS from Sinorhizobium meliloti. The downstream
      sequence of the Rhodobacter pstS contained five genes similar to pstCAB and
      phoUB, and its upstream sequence contained a putative regulatory sequence that is
      analogous to the Pho box involved in phosphate-limitation-induced gene expression
      in Escherichia coli. Both the amount of the PstS and the pstS promoter-driven
      expression of lacZ activity increased about two-fold in response to phosphate
      limitation. This is the first isolation of pst genes encoding proteins of an ABC
      phosphate transporter system from phototrophic bacteria.

PMID- 12610227
TI  - Evolution of chloroplast vesicle transport.
AB  - Vesicle traffic plays a central role in eukaryotic transport. The presence of a
      vesicle transport system inside chloroplasts of spermatophytes raises the
      question of its phylogenetic origin. To elucidate the evolution of this transport
      system we analyzed organisms belonging to different lineages that arose from the
      first photosynthetic eukaryote, i.e. glaucocystophytes, chlorophytes,
      rhodophytes, and charophytes/embryophytes. Intriguingly, vesicle transport is not
      apparent in any group other than embryophytes. The transfer of this eukaryotic
      type vesicle transport system from the cytosol into the chloroplast thus seems a
      late evolutionary development that was acquired by land plants in order to adapt
      to new environmental challenges.

PMID- 12610228
TI  - Asymmetric inheritance of oxidatively damaged proteins during cytokinesis.
AB  - Carbonylated proteins were visualized in single cells of the budding yeast
      Saccharomyces cerevisiae, revealing that they accumulate with replicative age.
      Furthermore, carbonylated proteins were not inherited by daughter cells during
      cytokinesis. Mother cells of a yeast strain lacking the sir2 gene, a life-span
      determinant, failed to retain oxidatively damaged proteins during cytokinesis.
      These findings suggest that a genetically determined, Sir2p-dependent asymmetric
      inheritance of oxidatively damaged proteins may contribute to free-radical
      defense and the fitness of newborn cells.

PMID- 12610229
TI  - Samples of stars beyond the solar system: silicate grains in interplanetary dust.
AB  - We have identified six circumstellar silicate grains within interplanetary dust
      particles (IDPs). Their extrasolar origins are demonstrated by their extremely
      anomalous oxygen isotopic compositions. Three 17O-rich grains appear to originate
      from red giant or asymptotic giant branch stars. One 16O-rich grain may be from a
      metal-poor star. Two 16O-poor grains have unknown stellar sources. One of the
      grains is forsterite, and two are amorphous silicate "GEMS" (glass with embedded
      metal and sulfides), which is consistent with astronomical identifications of
      crystalline and amorphous silicates in the outflows of evolved stars. These
      observations suggest cometary origins of these IDPs and underscore the perplexing
      absence of silicates among circumstellar dust grains from meteorites.

PMID- 12610230
TI  - Swimming in spacetime: motion by cyclic changes in body shape.
AB  - Cyclic changes in the shape of a quasi-rigid body on a curved manifold can lead
      to net translation and/or rotation of the body. The amount of translation depends
      on the intrinsic curvature of the manifold. Presuming spacetime is a curved
      manifold as portrayed by general relativity, translation in space can be
      accomplished simply by cyclic changes in the shape of a body, without any
      external forces.

PMID- 12610231
TI  - The missing link between science and service.

PMID- 12610233
TI  - State Mental Health Policy: New Mexico's Medicaid managed care waiver: organizing
      input from mental health consumers and advocates.

PMID- 12610235
TI  - Datapoints: use of nonpsychiatric inpatient care by medicaid mental health
      service users.

PMID- 12610234
TI  - Practical geriatrics: clinically significant nonmajor geriatric depression.

PMID- 12610236
TI  - Rehab rounds: use of the Americans with Disabilities Act by young adults with
      schizophrenia.
AB  - Introduction by the column editors: People with mental illness have consistently
      identified employment as a strong unmet need, yet only one in five people with
      schizophrenia has been able to work in full-time competitive employment and less
      than 50 percent work at all, despite the advent of evidence-based services, such
      as supported employment (1,2). However, there are compelling developmental,
      clinical, and economic reasons for people with mental illnesses to pursue
      competitive employment as they attempt to normalize and reconstruct their lives
      (3). Even with a mainstreaming ideology that encourages everyone who wants work
      to seek it, the real challenges are to organize supportive employment services,
      match people to jobs, and sustain clients in a continuum of work rehabilitation
      (4). Several Rehab Rounds columns have focused on programs aimed at enhancing the
      work functioning of people with serious mental disorders by using supported
      employment (5), increasing work readiness (6), and teaching fundamental workplace
      skills (7). In this month's column, Deborah Gioia and John S. Brekke describe the
      impact of the Americans With Disabilities Act on the work experience of young
      adults with schizophrenia.

PMID- 12610237
TI  - Multimedia reviews: multimedia overload produces "symplexity".
AB  - We humans "know" from information mediated through our "natural senses." All
      outside signals come to us through some medium-sound waves, pressure and touch,
      light waves, radio and television waves, and so forth. McLuhan's famous mantra
      "The medium is the message" paradoxically highlighted the critical transformation
      of meaning when each type of medium-radio, television, drums, hand signals-by its
      very nature modifies the message it is transmitting. In this month's column Dr.
      Zingrone brings challenging new ideas to the field of human communication and
      vividly describes the communication distortions that occur when the overload of
      increasingly complex modern media results in a paradoxical diminution of meaning
      itself. He has coined a term for this unintended consequence and given it to his
      exciting new book, The Media Symplex: At the Edge of Meaning in the Age of Chaos
      (1). Many of us may recognize the effect created by this accelerating phenomenon
      our stupefaction as we experience the onslaught of sound and visual signals
      produced by a television news screen, where an avalanche of rapidly changing,
      overlapping, and distorted visual images flash at our eyes while screeching,
      undulating synthetic "music" crashes about our ears. And in that chaos we
      struggle to find meaning,Dr. Zingrone, who worked with McLuhan and who has
      written extensively about his work (2,3), has succeeded in his new book to move
      the pioneering work of human communication scientists forward and thereby help us
      all to understand the developing paradox and danger of more communication yet
      less meaning.

PMID- 12610238
TI  - Emergency psychiatry: rapid screening for cognitive impairment in the psychiatric
      emergency service: II. A flexible test strategy.

PMID- 12610239
TI  - Moving treatment research from clinical trials to the real world.
AB  - Recently the National Institutes of Health has been emphasizing research that
      takes findings generated by clinical research and translates them into treatments
      for patients who are seen in day-to-day nonresearch settings. This translational
      process requires a series of steps in which elements of both efficacy and
      effectiveness research are combined into successively more complex designs.
      However, there has been little discussion of exactly how to develop and
      operationalize these designs. This article describes an approach to the
      development of these hybrid designs. Their operationalization is illustrated by
      using the design of an ongoing effectiveness treatment study of panic disorder in
      primary care. Experts in both efficacy and effectiveness research collaborated to
      address the methodologic and data collection issues that need to be considered in
      designing a first-generation effectiveness study. Elements of the overall study
      design, setting or service delivery context, inclusion and exclusion criteria,
      recruitment and screening, assessment tools, and intervention modification are
      discussed to illustrate the thinking behind and rationale for decisions about
      these different design components. Although the series of decisions for this
      study were partly influenced by considerations specific to the diagnosis of panic
      disorder and the context of the primary care setting, the general stepwise
      approach to designing treatment interventions using an effectiveness model is
      relevant for the development of similar designs for other mental disorders and
      other settings.

PMID- 12610240
TI  - Bridging the gap: a hybrid model to link efficacy and effectiveness research in
      substance abuse treatment.
AB  - Many behavioral and pharmacologic treatments for which there is strong empirical
      support are rarely used in clinical practice in the treatment of substance
      dependence. In an effort to facilitate greater emphasis on issues such as
      utility, practicality, and cost earlier in the evaluation of promising therapies,
      the authors propose a hybrid model to link efficacy and effectiveness research. A
      hybrid model may foster broader use of empirically validated treatments in
      substance abuse treatment programs and enhance the scientific yield of
      effectiveness research. The hybrid model retains essential features of efficacy
      research (randomization, use of control conditions, independent assessment of
      outcome, and monitoring of treatment delivery) while expanding the research
      questions to also address issues of importance in effectiveness studies. Such
      issues include diversity in settings, clinicians, and patients; cost
      effectiveness of treatment; training issues; and patient and clinician
      satisfaction.

PMID- 12610242
TI  - Managing sexual behavior on adult acute care inpatient psychiatric units.
AB  - OBJECTIVE: Protecting and safeguarding persons with impaired decisional capacity
      are among the critical functions of a psychiatric hospital. The objective of this
      study was to investigate the elements of these functions as they relate to sexual
      behavior on an adult acute care inpatient psychiatric unit and to develop a
      policy to prevent or at least manage such behavior. METHODS: The authors
      undertook an extensive literature review of articles and legal cases. The review
      was presented at numerous meetings of staff and interdisciplinary teams on the
      adult teaching unit at Bellevue Hospital in New York City. The findings from the
      review and the results of staff discussions were used in creating the policy.
      RESULTS AND CONCLUSIONS: In the acute care setting, it may be both reasonable and
      prudent to prevent all sexual interactions between patients, especially given the
      potential risks of such behavior. Concerns include the transmission of sexually
      transmitted disease, reproductive issues, and the legal implications of
      nonconsensual activity. Despite these concerns, adult psychiatric inpatients
      should be granted as many rights as are possible without having an adverse effect
      on their treatment or recovery. There is currently no standard for a sexual
      behavior policy for psychiatric inpatients. Thus ward staff are left with minimal
      guidance and potential confusion in the event that sexual incidents do occur, and
      there is a greater likelihood of arbitrary responses. The policy developed
      through this study is an example of how individual institutions can enforce a
      structured protocol when dealing with an ambiguous and difficult issue.

PMID- 12610241
TI  - Willingness to pay for depression treatment in primary care.
AB  - OBJECTIVE: The authors analyzed data from 615 depressed primary care patients to
      determine their willingness to pay for depression treatment. METHODS: A sample of
      615 adult patients from four primary care clinics participated in a randomized
      controlled trial of a disease management program for depression in primary care.
      Participants were asked at baseline interviews and six-month follow-up interviews
      how much they would be willing to pay per month for a six-month treatment that
      would eliminate their symptoms of depression. Multiple regression analyses were
      used to estimate the association between demographic and clinical factors and
      willingness to pay for depression treatment and to examine changes. RESULTS: The
      mean amount that participants were willing to pay for depression treatment at
      baseline was $270+/-187 per month, or about 9 percent of the participants'
      household income. Willingness to pay was significantly associated with household
      income and with the severity of depressive symptoms. Over six months, the amount
      that participants were willing to pay decreased along with their severity of
      depressive symptoms. CONCLUSIONS: The amount that participants were willing to
      pay was comparable to that reported for the treatment of other chronic medical
      disorders and higher than the actual cost of depression treatment. Measurements
      of willingness to pay may be a promising method for assessing the value of
      treatments for common mental disorders.

PMID- 12610243
TI  - Psychiatric emergency services and the system of care.
AB  - OBJECTIVE: Admissions to psychiatric emergency services have frequently been
      cited as a gauge of how well a mental health system manages behavioral disorders.
      However, few measurements of the longitudinal association between psychiatric
      emergencies and characteristics of a mental health system have been described.
      The purpose of this study was to assess whether weekly admissions to psychiatric
      emergency services would increase when outpatient services were reduced, whether
      weekly admissions would increase when greater effort was made to identify and
      treat persons with acute mental illness, and whether weekly admissions would
      decrease when emergency services were enhanced to include postrelease case
      management. METHODS: Time-series methods were applied to approximately 29,010
      admissions to three psychiatric emergency services of the San Francisco
      Department of Public Health over a 180-week period. RESULTS: Reduced outpatient
      services, efforts to identify acutely ill persons, and changes in emergency
      services themselves were found to affect admissions to emergency services.
      However, community events such as extreme weather, holidays, job loss, and the
      scheduling of receipt of income also affected the workload of the emergency
      service. CONCLUSIONS: The causes and course of mental illness inextricably tie a
      psychiatric emergency service to the overall mental health system and to events
      in the community it serves. These connections make it possible for managers to
      anticipate the use of emergency services and to detect disruptions in the
      remainder of the mental health services systems.

PMID- 12610244
TI  - Factors related to psychiatric hospital readmission among children and
      adolescents in state custody.
AB  - OBJECTIVE: This study examined factors related to psychiatric hospital
      readmission among children and adolescents who were wards of the Illinois
      Department of Children and Family Services. METHODS: The authors analyzed service
      reports and clinical ratings on the Childhood Severity of Psychiatric Illness
      (CSPI) for 500 randomly selected children and adolescents who underwent
      psychiatric hospitalization. Children who were readmitted to the hospital within
      three months of discharge from the index hospitalization were compared with those
      who were not readmitted in terms of preadmission factors, clinical
      characteristics at the index hospitalization, services in the hospital, and
      posthospital services. RESULTS: The children who were readmitted were rated as
      more learning disabled or developmentally delayed and had received fewer
      posthospital service hours than the children who were not readmitted. The highest
      rates of readmission were found among children who lived in congregate care
      settings before the index hospitalization and those who lived in a rural region.
      CONCLUSIONS: The findings of this study highlight the significance of enabling
      factors, notably living arrangement, geographic region, and posthospital
      services, for children and adolescents in the child welfare system. Prevention of
      readmission among these children must focus on community-based services.

PMID- 12610245
TI  - Use of substance abuse treatment services by persons with mental health and
      substance use problems.
AB  - OBJECTIVES: This study provided population estimates of mental syndromes and
      substance use problems and examined whether the co-occurrence of mental health
      and substance use problems was associated with the use of substance abuse
      treatment services. METHODS: Study data were drawn from the 1997 National
      Household Survey on Drug Abuse. RESULTS: Of the total sample of 16,661 adults, 2
      percent reported using services for alcohol or drug use problems in the previous
      year. Among the 3,474 (17 percent) who reported at least one alcohol or drug use
      problem, 6 percent used substance abuse services. Only 4 percent of persons who
      reported substance use problems alone received any substance abuse treatment
      service in the previous year. Only 3 percent of persons who reported alcohol use
      problems alone received such services. Among persons with one or more substance
      use problems, the prevalence of service use was 11 percent among persons who
      reported one co-occurring mental syndrome and 18 percent among those who reported
      two or more mental syndromes. Multiple logistic regression analyses identified a
      number of subgroups who might have needed substance abuse services but did not
      receive them, including women, Asians and Pacific Islanders, college graduates,
      persons employed full-time, persons who abused alcohol only, and persons with
      substance use problems who reported no coexisting mental syndromes. CONCLUSIONS:
      The rate of help seeking among persons with alcohol use problems is low, which is
      a public health concern.

PMID- 12610247
TI  - Clinical utility and policy implications of a statewide mental health screening
      process for juvenile offenders.
AB  - OBJECTIVES: This study examined the utility of screening adjudicated juvenile
      offenders for mental health symptoms at intake to the State of Washington
      Juvenile Rehabilitation Administration. The authors assessed the ability of a
      screening measure, the Massachusetts Youth Screening Inventory, second edition
      (MAYSI-2), to identify youths with mental health problems and co-occurring
      substance use problems. This study also examined the relationship of these
      symptoms to treatment utilization both before and after intake to the juvenile
      justice system. Ethnic and gender differences in the screening results were
      studied. METHODS: The MAYSI-2 was administered to 1,840 youths consecutively
      admitted to state custody. Cluster analysis was used to group the youths by
      mental health symptom status, and the relationship between symptoms and treatment
      utilization was tested in the groups identified in the cluster analysis. RESULTS:
      Youths who reported a high level of mental health symptoms, with or without co
      occurring substance use problems, were more likely to have received previous
      mental health treatment than youths with a low level of mental health symptoms.
      Youths with a high level of mental health symptoms were more likely to receive
      extraordinary sentences and were thus less likely to be eligible for community
      transition programs than youths with a low level of mental health symptoms.
      Significant gender and ethnic differences in mental health symptom reporting on
      the screening inventory were found. Female offenders were significantly more
      likely than male offenders to report a high level of symptoms, and Hispanic
      youths were significantly less likely than youths in other ethnic groups to
      report a high level of symptoms. CONCLUSIONS: The MAYSI-2 has utility in
      identifying youths in the juvenile justice system who have mental health
      problems, and MAYSI-2 results are related to use of treatment services both
      before and after intake to the juvenile justice system. Ethnic and gender
      differences in MAYSI-2 reporting must be considered in interpreting mental health
      screening data.

PMID- 12610246
TI  - Case managers' perspectives on critical ingredients of assertive community
      treatment and on its implementation.
AB  - OBJECTIVE: The authors sought to identify case managers' perspectives on the
      critical ingredients, therapeutic mechanisms of action, and gaps in
      implementation of the critical ingredients of assertive community treatment.
      METHODS: Seventy-three assertive community treatment teams that attended the 1997
      National Assertive Community Treatment Conference rated the degree to which 16
      clinical activities were beneficial to clients and rated the importance of 27
      possible critical ingredients of the ideal team as well as the extent to which
      each ingredient characterized their team. RESULTS: At least 50 percent of the
      teams rated 24 of the 27 critical ingredients as "very important." Having a full
      time nurse on the team was rated as the most important ingredient, and medication
      management was rated as the most beneficial clinical activity. The ratings of
      teams from urban and rural settings were highly correlated. Critical elements
      that the teams reported as being the most underimplemented included the presence
      of a full-time substance abuse specialist, a psychiatrist's involvement on the
      team, team involvement with hospital discharge, and working with a client support
      system. CONCLUSIONS: Case managers strongly endorsed the team approach as well as
      medical aspects of assertive community treatment. Despite broad consensus on the
      critical ingredients of the ideal assertive community treatment team, several
      important ingredients appear to be consistently underimplemented.

PMID- 12610249
TI  - Differences between patient and staff perceptions of aggression in mental health
      units.
AB  - OBJECTIVE: This study examined the views of patients and staff involved in
      incidents of aggression to help understand emotions experienced, perceptions of
      causes, and recommendations for ways of reducing the frequency of aggression.
      METHODS: A total of 29 staff and 29 patients from four psychiatric inpatient
      units who were involved in 47 incidents of aggression over a four-month period
      were interviewed shortly after the incidents. RESULTS: Significant differences
      were found between staff and patient perceptions of the causes of aggression and
      recommendations for reducing it. Many staff members perceived the patient's
      illness as the cause of the aggression and believed that, to manage aggression,
      changes in medication were largely indicated. In contrast, patients perceived
      illness, interpersonal factors, and environmental factors as being almost equally
      responsible for their aggression, and nearly all patients emphasized the need for
      improved staff-patient communication and more flexible unit rules in helping
      reduce aggression. Patients and staff were generally satisfied with the way the
      aggressive incidents were managed, but more staff than patients had an
      opportunity to debrief. CONCLUSIONS: Staff and patients had different perceptions
      of causes of aggression and ways to reduce it. Staff supervision and training
      should highlight the need for understanding patients' perspectives.

PMID- 12610248
TI  - Use of VA aftercare following military discharge among patients with serious
      mental disorders.
AB  - OBJECTIVE: This study examined the use of Department of Veterans Affairs (VA)
      aftercare services among patients with serious mental disorders who were
      discharged from the military after a first admission to a Department of Defense
      (DoD) hospital. METHODS: Administrative data from the DoD and VA health systems
      were linked to identify active-duty servicemen and -women who were hospitalized
      in a military hospital with a diagnosis of major depression, bipolar disorder, or
      schizophrenia between 1993 and 1996 and who were subsequently discharged from the
      military. Split population survival analysis was used to examine separately the
      correlates of contact with VA outpatient mental health services and, among those
      who had contact, the time to contact after military discharge. RESULTS: Fifty-two
      percent of 2,861 identified individuals had received outpatient care from VA
      mental health clinics by the end of September 1998. The rate of contact was lower
      than in virtually all studies of aftercare following hospital discharge. Women,
      older persons, and persons with schizophrenia or bipolar disorder were more
      likely to contact VA outpatient mental health services than men, younger persons,
      and those with major depression. Among those who made contact, older persons had
      a longer time to contact. CONCLUSIONS: Many people who leave the military because
      of serious mental illness do not receive aftercare from the VA. The reasons for
      such low rates of contact are not clear. Identifying patients who need aftercare
      but do not receive it and ensuring that they have access to needed services
      remains an important challenge for the DoD and the VA.

PMID- 12610250
TI  - An automated treatment for jet lag delivered through the internet.
AB  - Seventy percent of persons who suffer from psychiatric illness do not receive
      treatment. Cost-effective, automated treatment can be delivered through the
      Internet but can be complicated by the lack of professional supervision. This
      open study piloted a fully automated, publicly available treatment for jet lag as
      a means of highlighting some of the issues involved in delivering treatment over
      the Internet. Twenty study participants rated the severity of their jet lag
      symptoms and their adherence to a light-exposure schedule calculated to
      accelerate adaptation to a new time zone. A significant negative correlation was
      observed between how closely participants followed the light-exposure schedules
      and the severity of their jet lag symptoms.

PMID- 12610251
TI  - Prevention of depressive symptoms through the use of distance technologies.
AB  - Psychoeducational materials can be disseminated at minimal expense through the
      use of distance technologies, offering an opportunity for prevention. The
      objective of this project was to develop and evaluate a psychoeducational
      computer program designed to prevent depressive symptoms. The program was
      accessible through the Internet or by touch-tone telephone. A total of 786
      participants were randomly assigned either to the preventive intervention or to
      an information-only control condition. Over a three-month follow-up period, no
      differences between the groups were observed. However, three of the target
      variables (cognitive style, activity level, and sleep quality) were found to be
      strong predictors of whether a participant had an episode of major depression
      during the follow-up period.

PMID- 12610252
TI  - Perceived coercion and treatment adherence in an outpatient commitment program.
AB  - The authors investigated whether mental health inpatients' perceptions of
      coercion were associated with postdischarge treatment adherence. Patients
      eligible for New York's outpatient commitment program were interviewed and their
      perceptions of coercion measured during hospitalization and at one, five, and 11
      months after discharge. Medication and clinical treatment adherence were measured
      at the three postdischarge interviews. Among the 117 participants who completed
      at least one follow-up interview, higher perceived coercion scores were
      correlated with greater self-reported adherence to clinical treatment at the one
      month follow-up but not with participants' greater self-reported adherence at
      subsequent follow-ups or with providers' ratings of participants' adherence.
      Perceived coercion scores were positively correlated with participants' self
      reported adherence to injected medications.

PMID- 12610253
TI  - Process, not practice.

PMID- 12610255
TI  - Psychiatric services for people with mental retardation.

PMID- 12610256
TI  - Cultural competence and corporate culture.

PMID- 12610259
TI  - Inspection science.

PMID- 12610261
TI  - Energy. Britain to cut CO2 without relying on nuclear power.

PMID- 12610260
TI  - Public health. AIDS vaccine trial produces disappointment and confusion.

PMID- 12610262
TI  - Paleoanthropology. Java skull offers new view of Homo erectus.

PMID- 12610263
TI  - Planetary science. New front-runner for carving Martian gullies.

PMID- 12610265
TI  - Spacetime. Recipe for rocket-free space travel: dive in and paddle, patiently.

PMID- 12610264
TI  - Labor unrest. Yale grad students prepare to strike.

PMID- 12610266
TI  - War on cancer. NCI goal aims for cancer victory by 2015.

PMID- 12610267
TI  - Columbia disaster. Smaller station crew would put more pressure on research.

PMID- 12610268
TI  - Canadian budget. Graduate training, research councils are big winners.

PMID- 12610269
TI  - Fusion research. ITER negotiations heat up as all sites pass muster.

PMID- 12610270
TI  - Aging. The wisdom of the wizened.

PMID- 12610271
TI  - Drug development. Biotech thinking comes to academic medical centers.

PMID- 12610272
TI  - American Association for the Advancement of Science meeting. Bitter news for
      tender tongues.

PMID- 12610273
TI  - American Association for the Advancement of Science meeting. False memories, true
      pain.

PMID- 12610274
TI  - American Association for the Advancement of Science meeting. Nuclear-powered
      bugs.

PMID- 12610275
TI  - American Association for the Advancement of Science meeting. Behind the wheel of
      an expanding axon.

PMID- 12610276
TI  - American Association for the Advancement of Science meeting. Record donation to
      AAAS for innovation.

PMID- 12610277
TI  - More on science and politics.

PMID- 12610278
TI  - Of mice and their environments.

PMID- 12610279
TI  - On making science freely available.

PMID- 12610280
TI  - India's "lost" generation?

PMID- 12610281
TI  - FDA: status quo or changes needed?

PMID- 12610282
TI  - Comment on "Little evidence for developmental plasticity of adult hematopoietic
      stem cells".

PMID- 12610284
TI  - Aging. Antiaging research and the need for public dialogue.

PMID- 12610285
TI  - Counterterrorism. Making the world a safer place.

PMID- 12610286
TI  - Immunology. Isomeric antibodies.

PMID- 12610287
TI  - Botany. Leaf development takes shape.

PMID- 12610288
TI  - Chemistry. Building solutions--one molecule at a time.

PMID- 12610289
TI  - Cell biology. Protein degradation unlocked.

PMID- 12610291
TI  - Astronomy. A preposterous universe.

PMID- 12610290
TI  - Human genetics. Primate shadow play.

PMID- 12610292
TI  - Research on aging: the end of the beginning.

PMID- 12610293
TI  - Evolutionary medicine: from dwarf model systems to healthy centenarians?
AB  - Restriction of the number of calories consumed extends longevity in many
      organisms. In rodents, caloric restriction decreases the levels of plasma glucose
      and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer,
      immunosenescence, and inflammation without irreversible side effects. In
      organisms ranging from yeast to mice, mutations in glucose or IGF-I-like
      signaling pathways extend life-span but also cause glycogen or fat accumulation
      and dwarfism. This information suggests a new category of drugs that could
      prevent or postpone diseases of aging with few adverse effects.

PMID- 12610294
TI  - The endocrine regulation of aging by insulin-like signals.
AB  - Reduced signaling of insulin-like peptides increases the life-span of nematodes,
      flies, and rodents. In the nematode and the fly, secondary hormones downstream of
      insulin-like signaling appear to regulate aging. In mammals, the order in which
      the hormones act is unresolved because insulin, insulin-like growth factor-1,
      growth hormone, and thyroid hormones are interdependent. In all species examined
      to date, endocrine manipulations can slow aging without concurrent costs in
      reproduction, but with inevitable increases in stress resistance. Despite the
      similarities among mammals and invertebrates in insulin-like peptides and their
      signal cascade, more research is needed to determine whether these signals
      control aging in the same way in all the species by the same mechanism.

PMID- 12610295
TI  - Genetics and the specificity of the aging process.
AB  - The identification and study of long-lived mutant animals has provided valuable
      insights into the mechanisms that limit the life-span of organisms. Findings with
      the gene SIR2 suggest that the rate of aging can be regulated under certain
      conditions. Indeed, increased expression of SIR2 lengthens life-span by acting on
      biological processes that promote survival under conditions of scarcity. In
      addition, studies of mutant strains of Caenorhabditis elegans, in particular daf
      2, clk-1, and isp-1 mutants, suggest that the biology of reactive oxygen species
      in the mitochondria and elsewhere might be the main determinant of life-span in
      this organism. Thus, the aging process may be more specific than previously
      anticipated on evolutionary grounds.

PMID- 12610296
TI  - Aging and genome maintenance: lessons from the mouse?
AB  - Recent progress in the science of aging is driven largely by the use of model
      systems, ranging from yeast and nematodes to mice. These models have revealed
      conservation in genetic pathways that balance energy production and its damaging
      by-products with pathways that preserve somatic maintenance. Maintaining genome
      integrity has emerged as a major factor in longevity and cell viability. Here we
      discuss the use of mouse models with defects in genome maintenance for
      understanding the molecular basis of aging in humans.

PMID- 12610297
TI  - A chemical route to carbon nanoscrolls.

PMID- 12610299
TI  - An x-ray nebula associated with the millisecond pulsar B1957+20.
AB  - We have detected an x-ray nebula around the binary millisecond pulsar B1957+20. A
      narrow tail, corresponding to the shocked pulsar wind, is seen interior to the
      known Halpha bow shock and proves the long-held assumption that the rotational
      energy of millisecond pulsars is dissipated through relativistic winds.
      Unresolved x-ray emission likely represents the shock where the winds of the
      pulsar and its companion collide. This emission indicates that the efficiency
      with which relativistic particles are accelerated in the postshock flow is
      similar to that for young pulsars, despite the shock proximity and much weaker
      surface magnetic field of this millisecond pulsar.

PMID- 12610298
TI  - Antibody multispecificity mediated by conformational diversity.
AB  - A single antibody was shown to adopt different binding-site conformations and
      thereby bind unrelated antigens. Analysis by both x-ray crystallography and pre
      steady-state kinetics revealed an equilibrium between different preexisting
      isomers, one of which possessed a promiscuous, low-affinity binding site for
      aromatic ligands, including the immunizing hapten. A subsequent induced-fit
      isomerization led to high-affinity complexes with a deep and narrow binding site.
      A protein antigen identified by repertoire selection made use of an unrelated
      antibody isomer with a wide, shallow binding site. Conformational diversity,
      whereby one sequence adopts multiple structures and multiple functions, can
      increase the effective size of the antibody repertoire but may also lead to
      autoimmunity and allergy.

PMID- 12610300
TI  - Transformation of a simple plastic into a superhydrophobic surface.
AB  - Superhydrophobic surfaces are generally made by controlling the surface chemistry
      and surface roughness of various expensive materials, which are then applied by
      means of complex time-consuming processes. We describe a simple and inexpensive
      method for forming a superhydrophobic coating using polypropylene (a simple
      polymer) and a suitable selection of solvents and temperature to control the
      surface roughness. The resulting gel-like porous coating has a water contact
      angle of 160 degrees. The method can be applied to a variety of surfaces as long
      as the solvent mixture does not dissolve the underlying material.

PMID- 12610301
TI  - A new species of yunnanozoan with implications for deuterostome evolution.
AB  - Yunnanozoans are a distinctive clade of Lower Cambrian metazoans. Although widely
      accepted as deuterostomes, their exact placement within this superphylum is
      controversial. Here we describe a new species of Haikouella (H. jianshanensis)
      from the Chengjiang Lagerstatte (Yunnan, China) with exceptional preservation of
      a number of features. These include external gills, which suggest that the origin
      of the pharyngeal clefts was independent of the gills. The diagnostic branchial
      arches of chordates may, therefore, be composite structures. No evidence was
      found for the chordate-like structures that have been described in other
      yunnanozoans. We propose that yunnanozoans are stem-group deuterostomes, allied
      to the vetulicolians.

PMID- 12610302
TI  - Homo erectus calvarium from the Pleistocene of Java.
AB  - A Homo erectus calvarium [Sambungmacan 4 (Sm 4)] was recovered from Pleistocene
      sediments at Sambungmacan in central Java. Micro-computed tomography analysis
      shows a modern human-like cranial base flexion associated with a low
      platycephalic vault, implying that the evolution of human cranial globularity was
      independent of cranial base flexion. The overall morphology of Sm 4 is
      intermediate between that of earlier and later Javanese Homo erectus; apparent
      morphological specializations are more strongly expressed in the latter. This
      supports the hypothesis that later Pleistocene Javanese populations were
      substantially isolated and made minimal contributions to the ancestry of modern
      humans.

PMID- 12610303
TI  - Foraging adaptation and the relationship between food-web complexity and
      stability.
AB  - Ecological theory suggests that complex food webs should not persist because of
      their inherent instability. "Real" ecosystems often support a large number of
      interacting species. A mathematical model shows that fluctuating short-term
      selection on trophic links, arising from a consumer's adaptive food choice, is a
      key to the long-term stability of complex communities. Without adaptive foragers,
      food-web complexity destabilizes community composition; whereas in their
      presence, complexity may enhance community persistence through facilitation of
      dynamical food-web reconstruction that buffers environmental fluctuations. The
      model predicts a linkage pattern consistent with field observations.

PMID- 12610304
TI  - Phylogenetic shadowing of primate sequences to find functional regions of the
      human genome.
AB  - Nonhuman primates represent the most relevant model organisms to understand the
      biology of Homo sapiens. The recent divergence and associated overall sequence
      conservation between individual members of this taxon have nonetheless largely
      precluded the use of primates in comparative sequence studies. We used sequence
      comparisons of an extensive set of Old World and New World monkeys and hominoids
      to identify functional regions in the human genome. Analysis of these data
      enabled the discovery of primate-specific gene regulatory elements and the
      demarcation of the exons of multiple genes. Much of the information content of
      the comprehensive primate sequence comparisons could be captured with a small
      subset of phylogenetically close primates. These results demonstrate the utility
      of intraprimate sequence comparisons to discover common mammalian as well as
      primate-specific functional elements in the human genome, which are unattainable
      through the evaluation of more evolutionarily distant species.

PMID- 12610305
TI  - EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin.
AB  - Terminally misfolded proteins in the endoplasmic reticulum (ER) are
      retrotranslocated to the cytoplasm and degraded by proteasomes through a
      mechanism known as ER-associated degradation (ERAD). EDEM, a postulated Man8B
      binding protein, accelerates the degradation of misfolded proteins in the ER.
      Here, EDEM was shown to interact with calnexin, but not with calreticulin,
      through its transmembrane region. Both binding of substrates to calnexin and
      their release from calnexin were required for ERAD to occur. Overexpression of
      EDEM accelerated ERAD by promoting the release of terminally misfolded proteins
      from calnexin. Thus, EDEM appeared to function in the ERAD pathway by accepting
      substrates from calnexin.

PMID- 12610306
TI  - Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.
AB  - The mechanisms that determine how folding attempts are interrupted to target
      folding-incompetent proteins for endoplasmic reticulum-associated degradation
      (ERAD) are poorly defined. Here the alpha-mannosidase I-like protein EDEM was
      shown to extract misfolded glycoproteins, but not glycoproteins undergoing
      productive folding, from the calnexin cycle. EDEM overexpression resulted in
      faster release of folding-incompetent proteins from the calnexin cycle and
      earlier onset of degradation, whereas EDEM down-regulation prolonged folding
      attempts and delayed ERAD. Up-regulation of EDEM during ER stress may promote
      cell recovery by clearing the calnexin cycle and by accelerating ERAD of
      terminally misfolded polypeptides.

PMID- 12610307
TI  - Activation of lysosomal function during dendritic cell maturation.
AB  - In response to a variety of stimuli, dendritic cells (DCs) transform from
      immature cells specialized for antigen capture into mature cells specialized for
      T cell stimulation. During maturation, the DCs acquire an enhanced capacity to
      form and accumulate peptide-MHC (major histocompatibility complex) class II
      complexes. Here we show that a key mechanism responsible for this alteration was
      the generalized activation of lysosomal function. In immature DCs, internalized
      antigens were slowly degraded and inefficiently used for peptide loading.
      Maturation induced activation of the vacuolar proton pump that enhanced lysosomal
      acidification and antigen proteolysis, facilitating efficient formation of
      peptide-MHC class II complexes. Lysosomal function in DCs thus appears to be
      specialized for the developmentally regulated processing of internalized
      antigens.

PMID- 12610308
TI  - Genetic control of surface curvature.
AB  - Although curvature of biological surfaces has been considered from mathematical
      and biophysical perspectives, its molecular and developmental basis is unclear.
      We have studied the cin mutant of Antirrhinum, which has crinkly rather than flat
      leaves. Leaves of cin display excess growth in marginal regions, resulting in a
      gradual introduction of negative curvature during development. This reflects a
      change in the shape and the progression of a cell-cycle arrest front moving from
      the leaf tip toward the base. CIN encodes a TCP protein and is expressed
      downstream of the arrest front. We propose that CIN promotes zero curvature
      (flatness) by making cells more sensitive to an arrest signal, particularly in
      marginal regions.

PMID- 12610309
TI  - Steroid control of longevity in Drosophila melanogaster.
AB  - Ecdysone, the major steroid hormone of Drosophila melanogaster, is known for its
      role in development and reproduction. Flies that are heterozygous for mutations
      of the ecdysone receptor exhibit increases in life-span and resistance to various
      stresses, with no apparent deficit in fertility or activity. A mutant involved in
      the biosynthesis of ecdysone displays similar effects, which are suppressed by
      feeding ecdysone to the flies. These observations demonstrate the importance of
      the ecdysone hormonal pathway, a new player in regulating longevity.

PMID- 12610310
TI  - Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
AB  - Molecular etiologies of heart failure, an emerging cardiovascular epidemic
      affecting 4.7 million Americans and costing 17.8 billion health-care dollars
      annually, remain poorly understood. Here we report that an inherited human
      dilated cardiomyopathy with refractory congestive heart failure is caused by a
      dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN),
      a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular
      Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice
      recapitulated human heart failure with premature death. Cellular and biochemical
      studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit
      SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA
      mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium
      transients in myocytes. These results indicate that myocellular calcium
      dysregulation can initiate human heart failure-a finding that may lead to
      therapeutic opportunities.

PMID- 12610313
TI  - Recent advances in immunomodulation in the treatment of inflammatory bowel
      disease.
AB  - This review in depth considers the thiopurines azathioprine, 6-mercaptopurine and
      6-thioguanine, methotrexate, ciclosporin, infliximab and less well-established
      immunomodulators (including thalidomide, mycophenolate, tacrolimus and
      natalizumab among others) in their role of modifying the course of ulcerative
      colitis and Crohn's disease. The five papers are preceded by an overview on the
      therapeutic order of precedence, the indications and duration of therapy, as well
      as future concepts.

PMID- 12610314
TI  - Thiopurine therapy: when to start and when to stop.
AB  - The thiopurines azathioprine and 6-mercaptopurine are effective both for active
      disease and for maintaining remission in both Crohn's disease and ulcerative
      colitis. This review describes criteria for starting thiopurines (two or more
      courses of steroids in a calendar year, relapse as prednisolone is reduced below
      15 mg/day, within 6 weeks of stopping steroids) and the benefits of continuing
      treatment for up to 5 years. Challenging issues, such as thiopurine intolerance,
      relative merits of azathioprine, 6-mercaptopurine, monitoring therapy and
      thiopurines in pregnancy are addressed.

PMID- 12610315
TI  - Methotrexate: first-line or second-line immunomodulator?
AB  - Methotrexate is established as an effective treatment for inducing remission or
      preventing relapse in Crohn's disease. This review discusses the mechanisms of
      action, pharmacokinetics and clinical trials as well as considering the
      comparative efficacy between thiopurines and methotrexate. Comparisons are made
      with the treatment of rheumatoid arthritis. Its role in ulcerative colitis and
      potential toxicity are addressed. At present, the role of methotrexate is in the
      treatment of active or relapsing Crohn's disease for patients who are refractory
      to, or intolerant of, azathioprine or 6-mercaptopurine.

PMID- 12610317
TI  - Ciclosporin and refractory colitis.
AB  - Intravenous ciclosporin 4 mg/kg daily is rapidly effective as a salvage therapy
      for patients with refractory colitis, who would otherwise face colectomy, but its
      use is controversial because of risk of toxicity, and long-term failure rate.
      Opportunistic infections remain a serious concern, with a number of reports of
      death related to ciclosporin. Renal and neurotoxicity are also well-recognized.
      The drug should not be continued for more than 3-6 months and its main role is as
      a bridge to azathioprine or 6-mercaptopurine. Risks of toxicity can be reduced by
      using lower doses (2 mg/kg/day intravenously), by oral microemulsion ciclosporin,
      or by monotherapy without corticosteroids. Preliminary evidence shows good
      response rates, but further studies are needed to confirm optimal use of this
      potent, but hazardous, therapy.

PMID- 12610316
TI  - Infliximab as disease-modifying therapy.
AB  - Recent insights in the pathophysiology of Crohn's disease have revealed that
      tumour necrosis factor (TNF) plays a pivotal role in mucosal inflammation.
      Infliximab is a chimeric anti-TNF monoclonal antibody with potent anti
      inflammatory effects, probably based on apoptosis of inflammatory cells. Numerous
      controlled trials have demonstrated efficacy in both active and fistulating
      Crohn's disease. Appropriate indications for using infliximab and growing
      experience with safety aspects have made this treatment a highly valuable tool in
      the management of Crohn's disease.

PMID- 12610318
TI  - Alternative immunomodulators.
AB  - There is now a large number of potential immunomodulatory agents that may be of
      value in inflammatory bowel disease. The newer immunosuppressants, such as
      tacrolimus and mycophenolate, probably offer little more than providing
      comparable alternatives to more established agents, and fish oil and other
      eicosanoid modulators are probably not especially potent if effective. The
      biological agents, however, bring a more novel and potentially powerful approach.
      Natalizumab, and targeted mucosal delivery of interleukin-10 already show
      considerable promise.

PMID- 12610319
TI  - The use of contrast-enhanced power Doppler ultrasound in the diagnosis and follow
      up of inflammatory abdominal masses associated with Crohn's disease.
AB  - 1. Contrast-enhanced power Doppler ultrasound has a high sensitivity and
      specificity in the detection and evaluation of inflammatory abdominal masses
      associated with Crohn's disease. 2. The spatial resolution and sensitivity of
      this technique allows the detection of small inflammatory abdominal masses of 1
      cm or above. 3. The absence of any associated X-ray radiation allows repeated
      examinations to be undertaken. This facilitates assessment of disease progression
      and response to treatment 4. The early detection of the complications of Crohn's
      disease may facilitate treatment by medical means rather than necessitating
      surgical intervention. Clinical and biochemical assessment of the complications
      of Crohn's disease such as abscess, stricture and fistula formation is extremely
      difficult. Radiological imaging is therefore widely utilized. This includes
      barium studies, ultrasound, computed tomography and nuclear medicine techniques.
      Contrast-enhanced power Doppler ultrasound has high sensitivity and specificity
      in the detection and evaluation of inflammatory abdominal masses associated with
      Crohn's disease, and compares favourably with computed tomography. The spatial
      resolution and sensitivity of contrast-enhanced power Doppler ultrasound enables
      the detection of small inflammatory abdominal masses. The absence of radiation
      dose to the patient allows multiple and serial examinations to be undertaken.
      This facilitates assessment of disease progression and response to treatment. The
      early detection of the extra-mural complications of Crohn's disease and the close
      monitoring of response to medical treatment may obviate the need for surgical
      intervention.

PMID- 12610322
TI  - Ca2+ response in neutrophils after exposure to bacterial N-formyl-methionyl
      leucyl-phenylalanine: delayed response in ulcerative colitis.
AB  - OBJECTIVE: In acute stages of ulcerative colitis (UC), neutrophils migrate from
      the circulation into inflamed colonic tissue, initiated by yet unknown stimuli.
      The bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a
      component of the surface membrane of colonic bacteria such as Escherichia coli
      and stimulates Ca2+ influx into neutrophils, reflecting the fact that ionized
      calcium is an important secondary messenger for several neutrophil functions,
      including locomotion, phagocytosis and free oxygen radical production. Recent
      studies have revealed that Ca2+ dependent ICAM-1/beta 2-integrin mediated
      neutrophil migration is impaired in UC patients. The aim of the present work was
      to study the influx of Ca2+ into peripheral blood neutrophils of UC patients
      after exposure to FMLP and after binding of either beta 2-integrins or
      intercellular adhesion molecule-1 (ICAM-1). METHODS: The relative intracellular
      Ca2+ levels ([Ca2+]i ) were measured spectrofluorometrically in neutrophils
      isolated from eight UC patients and eight controls. The cells were exposed to 1
      nm FMLP, 5 pm free ICAM-1, or antibodies binding ICAM-1 or the beta 2-integrins
      CD11a, CD11b, CD11c and CD18. RESULTS: A pronounced increase in [Ca2+]i was
      observed by exposure of cells to FMLP, and neutrophils from UC patients showed a
      consistent and significant delayed response as compared to cells from control
      subjects (P < 0.01). Antibody mediated cross-linking of CD18 triggered a small
      but detectable increase in [Ca2+]i, which did not differ between patients and
      controls. CONCLUSION: A delayed response to bacterial peptides appears to be a
      phenotypic trait for neutrophils of UC patients. A connection between FMLP
      stimulated Ca2+ influx and CD11/CD18 upregulation is discussed.

PMID- 12610321
TI  - Fecal alpha 1-antitrypsin clearance as a marker of clinical relapse in patients
      with Crohn's disease of the distal ileum.
AB  - BACKGROUND: Crohn's disease (CD) shows a chronic relapsing course but no marker
      of relapse is currently available. However, fecal alpha 1-antitrypsin (alpha 1
      AT) clearance (alpha 1-ATCl) is an indicator of protein loss and increases during
      active inflammation. We assessed the usefulness of fecal alpha 1-ATCl in
      predicting clinical relapse in patients with inactive ileal CD. DESIGN: In a
      prospective longitudinal study, 26 patients with inactive ileal CD (Crohn's
      disease activity index (CDAI) < 150) (18 males, mean age 43 +/- 10, range 23-58)
      were enrolled. Fecal alpha 1-ATCl and concentration, daily stool weight and serum
      alpha 1-AT were measured at baseline (visit 1), after 1 week (visit 2) and 3
      weeks (visit 3) in 24/26 patients (two drop-outs) (short-term study). In six of
      these 26 patients, fecal alpha 1-ATCl was also measured every 3 months for 1 year
      (long-term study). All patients were clinically assessed every 3 months for 1
      year and every 6 months for 2 years. Ten healthy volunteers were tested as
      controls. METHODS: Serum and fecal alpha 1-AT concentration was quantified by
      radial immunodiffusion. RESULTS: The median fecal alpha 1-ATCl value at baseline
      was higher in inactive patients undergoing clinical relapse (CDAI > 200) in the
      next 6 months than in those remaining in remission at 6 months (P = 0.03). Fecal
      alpha 1-ATCl showed a 75% sensitivity, 85% specificity, 50% positive predictive
      value and 94% negative predictive value in predicting CD relapse in the next 6
      months. In the long-term follow-up, fecal alpha 1-ATCl values increased at 12
      months compared with both baseline and 6 month values (P = 0.005; P = 0.009).
      Fecal alpha 1-ATCl was higher in patients with raised C-reactive protein (P =
      0.039). CONCLUSIONS: Results from our study suggest that fecal alpha 1-ATCl is an
      indicator of clinical relapse in patients with CD of the distal ileum under
      regular surveillance.

PMID- 12610320
TI  - Contrast-enhanced power Doppler ultrasound in the diagnosis and follow-up of
      inflammatory abdominal masses in Crohn's disease.
AB  - OBJECTIVE: The purpose of this study was to evaluate the potential usefulness of
      contrast-enhanced power Doppler ultrasound in the detection and follow-up of
      local complications (phlegmon and abscess) in Crohn's disease. METHODS: With this
      aim, 28 patients with suspected abdominal inflammatory mass were examined with
      power Doppler ultrasound before and after intravenous administration of the
      ultrasound contrast agent Levovist, with evaluation of vascularity within and/or
      around the inflammatory mass. Colour Doppler flow was characterized as clearly
      visible, minimally visible or absent. All the patients underwent a post-contrast
      computed tomography exam. RESULTS: Power Doppler ultrasound, after administration
      of contrast medium, allows the detection of small inflammatory masses in Crohn's
      disease, particularly those under 2 cm in diameter, when compared with computed
      tomography. CONCLUSIONS: We conclude that contrast-enhanced power Doppler
      ultrasound is a sensitive method for the detection of small abdominal
      inflammatory masses and for differential diagnosis between phlegmon and abscess.

PMID- 12610323
TI  - Differential expression of toll-like receptors 2 and 4 in patients with liver
      cirrhosis.
AB  - OBJECTIVE: Toll-like receptors (TLR) 2 and 4 were shown recently to mediate
      lipopolysaccharide (LPS)/endotoxin effects in vivo. Absence of clinical features,
      such as fever and leucocytosis, frequent infections, and up-regulation of anti
      inflammatory cytokines suggest systemic differential regulation of LPS effects in
      patients with chronic endotoxinaemia due to liver cirrhosis. DESIGN: Regulation
      of TLR2 and TLR4 represents a possible pathway to control LPS-induced immune
      responses in liver cirrhosis. METHODS: We compared the expression of TLR2 and
      TLR4 in peripheral blood mononuclear cells (PBMC) (n = 28) and in liver biopsies
      (n = 20) of controls and of patients with liver cirrhosis by applying the reverse
      transcriptase polymerase chain reaction technique. The data were correlated to
      serum levels of LPS and CD14. RESULTS: Expression of TLR2 was up-regulated (P <
      0.01 to P < 0.05) in the PBMC of patients with high serum endotoxin levels, while
      TLR4 expression in patients at Child-Pugh stage A was down-regulated,
      irrespective of the origin (alcoholic or viral) of cirrhosis. A strong and
      significant correlation between expression of TLR2 and serum LPS (r = 0.638, P <
      0.01) and soluble CD14 (r = 0.550, P < 0.05) was observed. Intrahepatic
      expression of TLR2/4 was not altered significantly in patients with liver
      cirrhosis. CONCLUSION: Our data indicate LPS-driven regulation of TLR2/4 in
      patients with liver cirrhosis, suggesting involvement in mechanisms of systemic
      LPS hyporesponsiveness.

PMID- 12610324
TI  - The effect of hypothermia on primary porcine hepatocyte metabolism monitored by
      (1H) nuclear magnetic resonance spectroscopy.
AB  - OBJECTIVE: The aim of our study was to use (1H) nuclear magnetic resonance (NMR)
      spectroscopy as a tool to assess metabolic functions of hepatocytes and to
      monitor major metabolic pathways of these cells during culture following
      hypothermic preservation. METHODS: After isolation, 2 x 10(7) primary porcine
      hepatocytes were preserved at 4 degrees C in supplemented Leibovitz L-15 medium
      for 48 h. Viability was assessed at isolation, 24 and 48 h. At isolation and at
      48 h cells were plated and cultured with serum free supplemented Williams E
      medium. 1H NMR spectroscopy was used to assess indices of glucose metabolism,
      ammonia clearance indices and ketone bodies precursors at 48 h post-plating. Peak
      integration was applied with sodium 3-(trimethylsilyl-2,2,3,3-2H4)-1-propionate
      as an internal standard to obtain quantitative results. RESULTS: Results were
      obtained from six isolations. Viability was 78.1 +/- 1.2% at isolation, 69 +/-
      3.4% at 24 h and 58.9 +/- 3.8% at 48 h of hypothermia. Plating efficiency was 87
      +/- 4% for freshly isolated cells and 33.6 +/- 7.6% for hypothermically preserved
      cells. Glucose consumption was comparable in both groups. Hypothermically
      preserved cells consumed more threonine, produced more pyruvate and alanine but
      less lactate. They also produced less acetate and consumed less tyrosine.
      Glutamate and glutamine concentrations were similar under both conditions.
      CONCLUSION: 1H NMR spectroscopy is a valid method for assessing metabolic
      pathways of cultured primary porcine hepatocytes. Although hypothermically
      preserved cells had a reduced plating efficiency, they were still metabolically
      active. Thus, hypothermia can be used as a temporary preservation technique for
      primary porcine hepatocytes.

PMID- 12610325
TI  - From clinical evidence to everyday practice: implementing findings from a cost
      effectiveness analysis for endoscopic injection therapy for upper
      gastrointestinal bleeding.
AB  - BACKGROUND: A previous upper-gastrointestinal bleeding trial showed that patients
      treated with repeated fibrin glue injection for upper-gastrointestinal bleeding
      have significantly less rebleeding than those treated with polidocanol.
      OBJECTIVE: To analyse the cost and effectiveness of repeated fibrin glue
      injection and to investigate whether these results change physicians' attitudes.
      DESIGN: A retrospective random sample of five hospitals from the previous study,
      collection of cost identification, and follow-up data on 320 patients (155 in the
      polidocanol group, 165 in the fibrin glue group). METHODS: An incremental cost
      effectiveness analysis and comparison of outcomes was performed using chi-squared
      tests and Kaplan-Meier survival analysis. A survey was carried out using a
      questionnaire in the five hospitals on local guidelines for management of ulcer
      bleeding, and its results were analysed qualitatively. The measure of
      effectiveness is the number of prevented rebleedings. Further variables were
      length of hospital stay and length of intensive care unit (ICU) stay. RESULTS:
      The cost for the prevention of one additional rebleeding by repeated fibrin glue
      treatment amounts to 14,316 +/- 4981 euros (incremental cost-effectiveness
      ratio). There were no significant differences in length of stays in ICU or in
      hospital. The physicians did not change their management plans for patients with
      upper-gastrointestinal bleeding. In a survey, it was seen that other factors,
      such as local guidelines, attitudes towards new treatment options, and ease of
      handling of drugs, are more important than a result of a single study for a
      behavioural change of the doctors. CONCLUSIONS: The study was not designed
      prospectively to address a pharmacoeconomic question. As relevant variables (e.g.
      length of ICU stay) could not be reliably ascertained retrospectively, this may
      lead to biased estimates of the incremental cost-effectiveness ratio.

PMID- 12610326
TI  - Does the addition of a prokinetic to proton pump inhibitor therapy help reduce
      duodenogastro-oesophageal reflux in patients with Barrett's oesophagus?
AB  - OBJECTIVE: The metaplastic change of Barrett's oesophagus is linked to both acid
      and duodenal reflux together with impaired motility. Proton pump inhibitors (PPI)
      reduce acid reflux, but no treatment is available that reduces duodenogastro
      oesophageal reflux (DGOR). The aim of this study was to investigate whether
      adding a prokinetic to PPI treatment could improve oesophageal motility and
      subsequently reduce reflux. METHODS: Two groups of patients with Barrett's
      oesophagus on PPI therapy (prokinetic, n = 12; placebo, n = 11) were
      investigated. At visit 1, ambulatory oesophageal manometry was performed, and
      peristaltic and simultaneous wave percentage and characteristics were measured.
      DGOR and pH measurements were also performed. After treatment with either the
      prokinetic cisapride or placebo, all investigations were repeated (visit 2).
      Analysis of covariance and Spearman's correlation coefficients of changes from
      visit 1 to visit 2 were used to compare data. RESULTS: There was no significant
      difference between the two groups with respect to DGOR, DGOR characteristics, or
      the percentage of peristalsis and simultaneous waves and their characteristics.
      There was no correlation between DGOR and motility changes. Although no
      significant differences existed between acid reflux in the two groups, five
      patients with high supine acid reflux showed a significant reduction after
      treatment with cisapride. CONCLUSIONS: Addition of cisapride to PPI treatment
      does not appear to improve oesophageal motility or reduce DGOR in patients with
      Barrett's oesophagus.

PMID- 12610327
TI  - The effect of non-pathogenic Escherichia coli in symptomatic uncomplicated
      diverticular disease of the colon.
AB  - BACKGROUND: The effect of probiotics in symptomatic uncomplicated diverticular
      disease of the colon has not been followed. DESIGN: Treatment (T1) with an
      intestinal antimicrobial (dichlorchinolinol) and absorbent (active coal tablets)
      was compared with the same set-up supplemented with non-pathogenic Escherichia
      coli(T2) in a prospective open trial. SETTING: The study was performed at the
      outpatient department of a tertiary centre. PARTICIPANTS: Fifteen subjects (5
      males, 10 females) aged 68-91 years (average 74.8 years) presented with abdominal
      pain, irregular defecation, bloating and excessive flatulence. Diagnosis was
      established with colonoscopy, double-contrast barium enema, or both.
      INTERVENTIONS: The T1 regimen was administered for 1 week. In the T2 regimen, the
      application of E. coli strain Nissle (Mutaflor capsules, 2.5 x 10(10) viable
      bacteria/capsule) followed immediately after T1 for an average of 5.2 weeks. MAIN
      OUTCOME MEASURES: The lengths of two successive remissions with the T1 set-up
      were compared with the length of remission after T2. The intensity of symptoms
      before and after administration of the probiotic was also evaluated. RESULTS The
      lengths of two successive remissions after T1 amounted to 2.66 and 2.20 months
      (average 2.43 months). The average length of remission after T2 was 14.1 months
      (P < 0.001). All symptoms after T2 decreased significantly (P < 0.001).
      CONCLUSIONS: Non-pathogenic strain Nissle significantly prolonged the remission
      period and improved the abdominal syndrome in symptomatic uncomplicated
      diverticular disease. A randomized, placebo-controlled study is recommended.

PMID- 12610328
TI  - Bile acid stress in the mother and baby unit.
AB  - Intrahepatic cholestasis of pregnancy (ICP) affects about 0.7% of deliveries in
      Britain. It is regarded as a benign condition for the mother but is associated
      with increased fetal mortality in late pregnancy and early delivery is advised.
      Ursodeoxycholic acid (UDCA) treatment is beneficial to the mother and does not
      appear to harm the fetus. ICP is often regarded as a disease of the maternal
      liver already made 'cholestatic' by high levels of circulating progesterone. We
      propose that ICP should be considered as a feto-maternal disease involving
      complex interactions between maternal and fetal bile acid metabolism across the
      placenta. During the late stages of gestation, when there is a rise in fetal and
      maternal bile acid levels, the placenta may fail to render potentially
      hepatotoxic bile acids water soluble and hence excretable. This might cause a
      vicious cycle leading to further cholestasis in the maternal liver already
      challenged by progesterone.

PMID- 12610329
TI  - Complete remission of a metastatic gastrointestinal stromal tumour with the
      tyrosine kinase inhibitor imatinib (STI 571): effect of low dosage in an advanced
      tumour with exon 11 mutation.
AB  - We report a 51-year-old man with an advanced malignant metastatic
      gastrointestinal stromal tumour, who showed a complete response after 5 months of
      treatment with imatinib at a dose of 400 mg per day. An early treatment response
      was demonstrated in an 18fluorodeoxyglucose positron emission tomography scan
      after 1 month of therapy. Complete remission was documented histologically by
      negative serial biopsies of residual tumour nodes after 5 months of therapy. No
      serious side effects were seen with imatinib. A 21 bp, exon 11, in-frame mutation
      of the c-kit gene was found by DNA sequence analysis of tumour tissue.

PMID- 12610330
TI  - Primary squamous cell carcinoma of the stomach: a case report and review of the
      literature.
AB  - Primary squamous cell carcinoma of the stomach is extremely rare. To date, only
      80 cases have been reported. A 65-year-old man with complaints of epigastric pain
      and cachexia for the past year is presented. He had a tumour with infiltration of
      the corpus and antrum of the stomach. The tumour was unresectable, and the
      patient died within 3 months.

PMID- 12610331
TI  - Advanced intrahepatic cholangiocarcinoma in hepatitis C virus-related
      decompensated cirrhosis: case report and review of the literature.
AB  - A 75-year-old man with no known previous liver disease was admitted to our
      institution because of right pleural effusion, backache, and pain in the upper
      right quadrant. Physical and laboratory work-up revealed decompensated liver
      cirrhosis. Spiral computed tomography (CT) showed a 6-cm tumour in the right
      liver lobe. Serum levels of aminotransferases, prothrombin time, total bilirubin,
      alphafetoprotein and carcinoembryonic antigen were within normal limits. However,
      the patient had elevated cholestatic enzymes, diffuse hypergammaglobulinaemia, a
      six-fold increase in carbohydrate antigen 19-9 (CA 19-9), cryoglobulinaemia, and
      reactivity against hepatitis C virus (anti-HCV). Although hepatocellular
      carcinoma is the most common cancer in a cirrhotic patient with chronic viral
      hepatitis, the investigation revealed the presence of intrahepatic
      cholangiocarcinoma (ICC). This is a less frequently occurring primary liver
      tumour, the aetiology and pathogenesis of which remain unclear in the majority of
      cases. The coexistence of HCV liver disease and ICC might be an incidental
      finding, but recently some reports have shown a relatively high incidence of this
      tumour in patients with HCV-related cirrhosis. The current aspects regarding ICC
      prevalence in HCV patients, the possible aetiopathogenetic links between this
      tumour and HCV, and the importance for ICC detection and characterization using
      the enhancement patterns with quadruple-phase spiral CT scan are also discussed.

PMID- 12610349
TI  - Novel and classic myoepithelial/stem cell markers in metaplastic carcinomas of
      the breast.
AB  - Metaplastic carcinomas of the breast (MCBs) are unusual neoplasms characterized
      by an admixture of glandular epithelial components, which frequently exhibit
      features of squamous differentiation, and mesenchymal malignant components.
      Regardless of the presence of myoepithelial features in MCB, no consensus
      concerning their putative histogenesis has yet been achieved. Recently, novel
      putative myoepithelial markers have been developed, including p63, maspin, and P
      cadherin. We assessed the expression of these myoepithelial markers in MCBs and
      compared their expression with classic myoepithelial markers.
      Immunohistochemistry using the streptavidin-biotin-peroxidase complex technique
      with antibodies raised against p63, maspin, P-cadherin, actin (clones CGA7, 1A4
      and HHF35), cytokeratin 14 (Ck14), and vimentin was performed on 16 MCBs (7
      matrix-producing MCBs, 6 adenosquamous MCBs, and 3 MCBs with heterologous
      elements). In healthy breast lobules and ducts adjacent to the tumors,
      myoepithelial cells showed distinctive and consistent immunoreactivity for p63,
      maspin, P-cadherin, actin, S-100 protein, and Ck14. Matrix-producing MCBs were
      positive for maspin in all cases, for p63 in 4 of 7 cases, and for P-cadherin in
      4 of 7 cases. Adenosquamous MCB showed immunoreactivity for p63, maspin, and P
      cadherin in 5 of 6 cases. All novel myoepithelial markers and Ck14 decorated
      squamous cell islands. MCBs with heterologous elements were positive for p63 in 1
      case, for maspin in all 3 cases, and for P-cadherin in 2 cases. All cases showed
      at least one of the novel myoepithelial markers. Eleven of 16 cases were positive
      for actin. Eleven of 14 cases reacted with Ck14, and all cases that stained for S
      100 protein (9 of 9) and vimentin (13 of 13) were also positive. Based on our
      findings, the balance of probabilities favors that MCBs may have a basal or
      myoepithelial cell histogenesis and differentiation.

PMID- 12610350
TI  - Prognostic significance of cyclin a expression in meningiomas.
AB  - Unconstrained cell proliferation is characteristic of tumors. It is caused by the
      functional disorders of proteins that constitute the cell cycle mechanism. The
      cell cycle is controlled by cyclins, cyclin-dependent kinases, and cyclin
      dependent kinase inhibitors. Many reports have proved, in cancers, that cyclins,
      cyclin-dependent kinases, and cyclin-dependent kinase inhibitors are out of
      control. Cyclin A is a protein that regulates critical transition of the cell
      cycle. The expression of cyclin A in meningiomas by immunohistochemical method
      was investigated. Furthermore, the correlation among cyclin A expression,
      clinical course, and proliferative potential were also evaluated. Seventy-seven
      meningiomas were studied. The mean cyclin A labeling indices were as follows:
      benign meningiomas, 1.01% +/- 0.62%; atypical meningiomas, 4.23% +/- 1.82%; and
      anaplastic meningiomas, 7.72% +/- 0.88%. Analyses of variance showed that
      significant differences existed between tumor grades for cyclin A labeling
      indices. A linear positive correlation between the cyclin A labeling index and
      bromodeoxyuridine labeling index was observed. The multivariate analysis using
      Cox's hazards model showed a high cyclin A labeling index (>3%) was a significant
      risk factor for recurrence. A high Ki-67 labeling index (>5%) and high tumor
      grade (World Health Organization grade II, III) were also significant risk
      factors for recurrence. These results suggested that the evaluation of cyclin A
      expression in meningiomas provides significant clinical information, especially
      as an independent prognostic indicator.

PMID- 12610351
TI  - Pathogenesis and significance of collagenous micronodules of the prostate.
AB  - Collagenous micronodules, also known as mucinous fibroplasia, are microscopic
      structures characterized by the presence of small eosinophilic nodules in areas
      immediately adjacent to prostatic glandular epithelium. The pathogenesis of
      collagenous micronodules is unknown, although their relation with mucin has been
      suggested. The objective of our study was to analyze the structural
      characteristics of collagenous micronodules by using histochemistry,
      immunohistochemistry, and electron microscopy to elucidate the pathogenesis of
      this lesion. We analyzed 15 cases of prostate adenocarcinoma (12 prostatectomy
      specimens and 3 biopsy specimens) with collagenous micronodules. The collagenous
      micronodules were closely associated with well-formed malignant glands, where
      tumor cells exhibited basophilic to amphophilic cytoplasm. Occasionally,
      intraluminal collagen fragments were observed within malignant but not benign
      glands. Collagenous micronodules were not associated with mucin, confirmed by
      negative stainings of mucicarmin or alcian blue in all the collagenous
      micronodules analyzed in this study. Therefore, the term "mucinous fibroplasia"
      may not be accurate. Collagenous micronodules stained weakly positive for
      periodic acid-Schiff. Trichrome stain highlighted the presence of collagenous
      micronodules as distinct blue structures. Collagen IV and laminin immunostaining
      performed in 12 cases outlined the micronodules with minimal staining in the
      center. These findings indicated that collagenous micronodules consisted of
      predominantly collagen fragments admixed with basement membrane material.
      Ultrastructurally, they were composed of fragmented banded collagen fibrils
      surrounded by the basement membrane material. Collagenous micronodules are formed
      by subepithelial accumulations of fragmented collagen fibers, possibly related to
      the digestion by collagenase produced by prostatic adenocarcinoma cells.

PMID- 12610352
TI  - The phenotype of Hurthle and Warthin-like papillary thyroid carcinomas is
      distinct from classic papillary carcinoma as to the expression of retinoblastoma
      protein and E2F-1 transcription factor.
AB  - Retinoblastoma protein plays an important role in controlling cell cycle
      progression. The active form of retinoblastoma protein binds to E2F-1 and
      inhibits transcription of S phase genes. Overexpression of E2F-1 has been
      suggested as an important factor in carcinogenesis. The Hurthle cell (HPCA) and
      Warthin-like (WLPCA) variants of papillary carcinoma are two closely related
      entities that arise in association with Hashimoto's thyroiditis and share the
      presence of oxyphilic changes in the lining of epithelial cells and the presence
      of papillary nuclear features. The current study included formalin-fixed,
      paraffin-embedded tissues from 58 cases of thyroid papillary carcinoma: 20 HPCA,
      6 WLPCA, 22 conventional papillary carcinomas (PCA), and 10 follicular variants
      of papillary carcinoma (FVPCA). The immunohistochemical studies were performed
      for retinoblastoma (Rb-1) and E2F-1, (KH95) after heat-induced epitope retrieval.
      None of the PCA or FVPCA cases were in the positive range for Rb-1. All cases of
      HPCA and WLPCA of the thyroid showed reactivity in 50% or more of the nuclei in
      the neoplastic cell population. As for E2F-1, all cases of HPCA and WLPCA showed
      positive reactivity, whereas none of the PCA or FVPCA cases were in the positive
      range. In conclusion, HPCA and WLPCA are Rb-positive and E2F-1-positive; PCA and
      FVPCA are Rb-negative and E2F1-negative. Hurthle metaplastic epithelium in
      Hashimoto's thyroiditis is Rb-positive and E2F-1-negative. This phenotypic
      difference is also helpful in distinguishing hyperplastic Hurthle cell
      proliferation in Hashimoto's thyroiditis from HPCA or WLPCA.

PMID- 12610353
TI  - MUC-1 mucin protein expression in B-cell lymphomas.
AB  - We have recently shown that MUC1, mapped to the chromosomal band 1q21, is
      rearranged or amplified in 15% of B-cell lymphomas and that rearrangement led to
      over-expression of MUC-1 mucin in a case of diffuse large B-cell lymphoma
      (DLBCL). To determine the incidence of MUC-1 mucin expression and its clinical
      significance in B-cell lymphomas, we investigated a panel of 113 cases by
      immunohistochemistry (IHC). MUC-1 mucin expression was detected in the majority
      of cases (92.9%), with moderate to high levels noted in 50.4% of all histologic
      subsets comprising DLBCL (82 cases), follicular lymphoma (FL) (15 cases), FL with
      transformation to DLBCL (4 cases), and other B-cell lymphomas (12 cases). No
      statistically significant correlation was found between MUC-1 mucin expression
      and MUC1 genomic status (amplification/rearrangement) evaluated by Southern blot
      analysis, and 1q21 abnormality by karyotypic analysis. For all cases, MUC-1 mucin
      expression correlated with a previous history of lymphoma (p=0.003).

PMID- 12610354
TI  - 8q24 amplification in transitional cell carcinoma of bladder.
AB  - Genomic amplifications of the long arm of chromosome 8q are frequently detected
      in a number of tumor types, including neoplasias of the urothelium. DNA level
      amplification and increased expression of at 8q24 is commonly associated with
      chromosomal gains in this region. Using a urothelial cancer tissue microarray,
      the authors investigated the 8q24 amplification on bladder tumors and metastases.
      High-copy 8q24 amplification was detected in 9% (12 of 131) of primary tumors and
      33% (6 of 18) of distant metastases. Additionally, the authors investigated the
      expression profiles of two frequently used biomarkers, p53 and Ki67, on the same
      arrays that had been analyzed for the 8q24 amplification. 8q24 amplification was
      positively correlated with Ki67 protein expression ( < 0.005), whereas a similar
      correlation with p53 did not reach statistical significance ( = 0.19). The
      authors conclude that 8q24 amplification occurs in a small subgroup of primary
      bladder tumors and in a more significant group of distant metastases.

PMID- 12610355
TI  - Morphometrical quantification of spermatogonial germ cells with the 57B anti-MAGE
      A4 antibody in the evaluation of testicular biopsies for azoospermia.
AB  - The melanoma-associated antigen (MAGE) gene family of cancer-testis antigens is
      expressed in certain malignant neoplasms and the testis, but not in other healthy
      tissues. The aim of this study was to determine the usefulness of
      immunohistochemical staining with the 57B anti-MAGE-A4 mouse monoclonal antibody
      (MAb) in testicular biopsy specimens from patients with nonobstructive
      azoospermia and obstructive azoospermia (OA). Fifty-four cases of Sertoli cell
      only (SCO), 30 cases of spermatocytic arrest, 15 cases of hypospermatogenesis,
      and 10 testicular biopsy specimens with OA (normal spermatogenesis) were
      evaluated. Immunohistochemistry was performed using the 57B MAb, which primarily
      recognizes the MAGE-A4 antigen in paraffinized tissues. The cells were
      quantitated by a computerized image analysis system. Testicular biopsy specimens
      with normal spermatogenesis exhibited strong nuclear and cytoplasmic MAGE-A4
      staining of spermatogonia and weak staining of spermatocytes, but not spermatids
      or Sertoli or Leydig cells. No staining was detected in SCO cases. In five cases
      of SCO with focal spermatogenesis, spermatogonial cells that were initially
      missed by hematoxylin and eosin staining were detected by MAGE-A4
      immunohistochemistry. Immunostaining with the 57B MAb greatly enhanced
      identification of spermatogonia in cases of spermatocytic arrest and
      hypospermatogenesis. The number of MAGE-A4-positive spermatogonia was
      significantly decreased in hypospermatogenesis, as opposed to the OA group (12.1
      +/- 4.3 and 30.3 +/- 10.0, respectively). The number of MAGE-A4-positive primary
      spermatocytes was significantly increased in early maturation arrest, as compared
      with the OA group (48.2 +/- 10.8 and 16.9 +/- 9.8, respectively). The 57B anti
      MAGE-A4 MAb is a useful marker for the detection and quantitation of
      spermatogonial germ cells. It also facilitates automated image analysis and
      provides greater accuracy in the histopathologic evaluation of testicular biopsy
      specimens.

PMID- 12610356
TI  - Rapid immunohistochemistry for cytokeratin in the intraoperative evaluation of
      sentinel lymph nodes for metastatic breast carcinoma.
AB  - The sensitivity and specificity of detecting metastatic breast carcinoma in
      sentinel lymph nodes using a rapid immunohistochemistry technique was determined
      and compared with methods currently used at the authors' institution. At the time
      of intraoperative consultation, after routine diagnostic touch preparations and
      frozen sections were prepared, 6-microm frozen sections of 72 sentinel lymph
      nodes from 32 patients with breast carcinoma were placed on plus slides, fixed in
      cold acetone for 2 or 3 minutes, and stored at -70 degrees C. These sections were
      immunostained with a prediluted broad-spectrum anticytokeratin monoclonal
      antibody coupled to an inert polymer with horseradish peroxidase (DAKO EPOS).
      Slides were ready for interpretation within 16 minutes and were scored as
      positive, negative, or equivocal for metastatic carcinoma. Results were compared
      with those of the intraoperative touch preparations and frozen sections and with
      paraffin-embedded, hematoxylin and eosin-stained, and AE1/AE3 immunostained
      permanent sections. Fourteen (19%) sentinel lymph nodes were positive for
      metastatic carcinoma in 13 patients. All methods tested were 100% specific. The
      rapid immunohistochemistry method was the least sensitive (57% sensitivity) of
      all methods used to detect metastasis. Routine diagnostic touch preparations,
      frozen sections, and permanent sections had sensitivities of 69%, 86%, and 100%
      respectively. In conclusion, this rapid immunohistochemistry method would not be
      helpful in intraoperative assessment of sentinel lymph nodes in breast cancer
      patients due to its low sensitivity.

PMID- 12610357
TI  - Immunohistochemistry frequently detects c-Kit expression in pulmonary small cell
      carcinoma and may help select clinical subsets for a novel form of chemotherapy.
AB  - The presence of c-Kit immunoreactivity in gastrointestinal stromal tumor (GIST),
      currently guides treatment with the selective c-Kit inhibitor STI571 (or Gleevec)
      in clinical trials and establishes a precedent of immunohistochemistry-guided
      treatment decisions. Thus, the optimization of detection conditions for c-Kit and
      the determination of its incidence in other malignancies have clinical bearing.
      Aims of our study were: 1) to determine the incidence of c-Kit expression in
      formalin-fixed paraffin-embedded tissue (FFPE) in pulmonary small cell carcinoma
      (SCC) and non small cell carcinoma (NSCC), pulmonary carcinoid, and malignant
      mesothelioma (MM); and 2) to test the feasibility of c-Kit determination using
      commercially available antibodies and routine immunohistochemical settings,
      comparing the performance of two commercially available antibodies, Dako and
      Santa Cruz. The Dako antibody detected positive stain in 10/22 SCC, 3/8
      carcinoids, 1/57 NSCC (1/30 adenocarcinomas, 0/24 squamous cell carcinomas, 0/3
      large cell undifferentiated carcinomas), and 7/33 MM. The Santa Cruz antibody
      detected c-kit in 8/22 SCC, 0/57 NSCC, 1/8 carcinoids, and 0/33 MM. HIER
      increased the performance of both antibodies. We conclude that c-Kit can
      routinely be detected in FFPE tissue with commercially available antibodies, and
      that the Dako anti-c-Kit has a higher sensitivity than the Santa Cruz antibody. C
      Kit expression is common in SCC and carcinoids, very rare in NSCC, and infrequent
      in MM. The frequent c-Kit expression in SCC highlights that this molecule plays
      an important role in the biology of this malignancy, and that it could be
      targeted in subsets of patients for therapy with c-Kit inhibitors.

PMID- 12610358
TI  - The problem with KIT: clinical implications and practical difficulties with CD117
      immunostaining.
AB  - Immunohistochemical staining for KIT (CD117) was performed on 144 cases of soft
      tissue sarcoma and 11 cases of gastrointestinal stromal tumor (GIST). Diffuse
      global staining in almost all neoplastic cells was a consistent feature of GIST
      but was also seen in some types of soft tissue sarcoma that resemble GISTs
      morphologically, such as synovial sarcoma and leiomyosarcoma. This finding is of
      diagnostic importance because some of these sarcoma types may involve the
      intestinal wall and simulate primary GIST. Most other positive cases showed focal
      staining. Although focal positivity may not be a problem in resected specimens,
      it has the potential to be misleading in biopsy material. Our results are
      concordant with some reports of CD117 expression in soft tissue tumors, but they
      differ from those reported by other laboratories. This discrepancy in the
      literature may be the result of variation in antibodies used or variation in
      immunohistochemical staining protocol. Regardless of the technical or scientific
      explanation, an understanding of the difficulties with KIT immunostaining is
      critical. Not only is KIT positivity used as a prerequisite for the diagnosis of
      GISTs, but treatment eligibility for STI571 in patients with GIST, and
      increasingly with other tumors, relies on positive KIT immunostaining.

PMID- 12610359
TI  - Immunohistochemical evaluation of hormone receptor for routine practice of breast
      cancer: highly sensitive procedures significantly contribute to the correlation
      with biochemical assays.
AB  - Immunohistochemical evaluation of hormone receptors for breast cancer has been
      performed parallel to biochemical assays. Recently, immunohistochemistry has
      tended to substitute the biochemical method in Japan. To clarify the factors
      concerned and problems to be resolved, we reviewed our evaluation system for
      hormone receptors by immunohistochemistry from 1990. A total of 861 breast cancer
      samples were examined by immunohistochemistry and biochemistry. In 3 main
      periods, phase 1 (1990-1993), phase 2 (1995-1998), and phase 3 (1999-2001),
      increasing sensitivity of the immunohistochemical method was provided by
      commercially available staining systems and shown to range from 83.6% (phase 1)
      to 92.0% (phase 3). The highly sensitive procedures of the antigen retrieval and
      peroxidase-conjugated polymer method are main contributing factors. The authors
      examined how these procedures influenced the distribution of positive cell
      population; concordance rate, including sensitivity and specificity; cutoff
      points; and evaluation categories. The correlation between biochemistry and
      immunohistochemistry was extensively studied in the 1980s and 1990s. In reference
      to the progress achieved in the United States and United Kingdom to control the
      current situation in Japan, it should be recognized that recently developed,
      highly sensitive procedures boost the immunoreactivity, which will affect the
      basic factors for technical validation.

PMID- 12610360
TI  - The immunohistochemical detection of mismatch repair gene proteins (MLH1, MSH2,
      MSH6, and PMS2): practical aspects in antigen retrieval and biotin blocking
      protocols.
AB  - The immunohistochemical detection of the mismatch repair (MMR) proteins is used
      as a screening test with microsatellite instability for the detection of
      hereditary nonpolyposis colon cancer (HNPCC). The authors describe a simple and
      cost-effective method using a pressure cooker and microwave oven for antigen
      retrieval and a modified method for applying a commercial biotin blocking kit.
      Colorectal tumors of 20 patients of the HNPCC spectrum were included in this
      study. Eighty paraffin sections were cut and submitted for immunohistochemical
      analysis using a routine protocol and a pressure cooker protocol. Parallel
      sections for biotin blocking were also run, including the modified biotin block
      for each protocol. The sections were incubated with the following antibodies:
      MLH1, MSH2, MSH6, and PMS2. All cases examined exhibited a normal expression of
      the MMR proteins in the nucleus and adjacent nonneoplastic tissue elements and
      consequently defined as having a normal expression of these proteins. Cases with
      tumor that exhibited a loss of the nuclear staining with the MMR proteins with a
      concurrent staining of the adjacent nonneoplastic cells were classified as
      abnormal MMR expression. The series of 20 cases using pressure cooker antigen
      retrieval produced superior results to the routine immunohistochemical protocol
      used previously in our laboratory. The modified biotin block also gave consistent
      results. The reproducibility and consistency of this procedure has resulted it in
      being used routinely for suspected HNPCC cases, both current and archival.

PMID- 12610362
TI  - Comparison of quantification of histochemical staining by hue-saturation
      intensity (HSI) transformation and color-deconvolution.
AB  - We tested a recently developed flexible method of separation and quantification
      of immunohistochemical staining by means of color image analysis. An algorithm
      was recently developed to deconvolve the color information acquired with RGB
      cameras, to calculate the contribution of each of the applied stains, based on
      the stain-specific RGB absorption. The algorithm was tested using a set of lung
      tumor samples labeled for the detection of Ki-67, an antigen expressed in
      proliferating cells, covering a wide range of staining levels. Quantification of
      the labeling was compared with HSI-based segmentation and manual analysis of the
      same samples. The recently developed deconvolution method performed significantly
      better than the HSI based system when compared to manual counting as gold
      standard. The deconvolution system showed significantly reduced variability in
      the LI determination, especially of highly labeled control samples. This resulted
      in significant increase in sensitivity of classification of samples with
      increased KI-67 labeling without changing the specificity, when compared to the
      HSI based method.

PMID- 12610361
TI  - Vascular tissue fragility assessed by a new double stain method.
AB  - Although matrix metalloproteinases (MMPs) are known to be involved in the
      development of atherosclerosis and the instability of atheromatous plaques, much
      remains to be learned about their roles at the tissue level. To help clarify this
      area, we established a new double staining method using film in situ zymography
      and immunohistochemistry. Using this technique, a comprehensive analysis of the
      gelatinolytic activity in human vessel tissue demonstrated that gelatinolytic
      activity is enhanced in the shoulder region and fibrous cap at superficial areas
      of the atheromatous plaque in the presence of thrombolysis. Enzyme assay
      clarified high activity in the superficial area (7.50 +/- 5.04 U/mg weight; P <
      0.001). Gelatin zymography also indicated that addition of the antiplatelet
      agent, trapidil, alters the amount of secretion of MMP-2 and MMP-9 and their
      activation ratio. This novel approach to detect the activity of gelatinases in
      resected tissues may aid in the selection of optimal treatment of individual
      patients.

PMID- 12610363
TI  - Removal of mercuric chloride deposits from B5-fixed tissue will affect the
      performance of immunoperoxidase staining of selected antibodies.
AB  - B5 clearing is a step used before immunoperoxidase staining to remove the
      precipitated mercuric chloride deposits caused by B5 fixation of tissue. In the
      B5 clearing procedure, the slides are treated with Lugol's iodine and 5% sodium
      thiosulfate before antigen retrieval and the application of the primary antibody.
      The goal of this project was to study the effect of the B5 clearing protocol on
      immunoperoxidase staining on paraffin-embedded tissue, which has not been
      previously reported in a series of antibodies. We evaluated 75 antibodies using
      the 2-step clearing protocol and performed paired immunoperoxidase staining on
      the Ventana ES instrument, with and without the clearing protocol. We found that
      among 75 antibodies studied, 3 (CD5, CD30, and synaptophysin) showed total
      obliteration of reactivity, and 3 (ALK, Ulex, and GFAP) showed partial reduction
      of the staining compared with the controls. Pathologists must be aware of the
      possible false-negative staining effect caused by the routinely used B5 clearing
      protocol. Control tissues must receive the same clearing protocol (i.e., placed
      on case slides) to ensure detection of this effect.

PMID- 12610364
TI  - Immunohistochemical assessment of a testicular tumor in a 63-year-old patient:
      proposal for an integrated clinicopathologic approach.
AB  - A 63-year-old man was admitted to our hospital for complaints of a painless knot
      in his right testicle. The patient underwent orchiectomy for suspicion of
      malignancy. Pathologic examination detected a firm, circumscribed mass that
      consisted histologically of noncohesive, large, undifferentiated tumor cells
      diffusely infiltrating the testicular interstice. Because of the patient's
      advanced age and the structure of the neoplastic cells, the differential
      diagnosis favored a lymphoma over a malignant germ cell tumor but also included a
      dedifferentiated metastatic neoplasm. Immunohistochemistry was tailored
      accordingly and was completed using three successive panels of antibodies.
      Immunostaining with the first panel of antibodies directed against leukocyte
      epitopes (CD45, CD20, and CD3) remained negative and made a lymphoma unlikely.
      The subsequent panel (cytokeratin AE1/3, cytokeratin 18, and HMB-45) helped to
      rule out a malignant melanoma and aided to settle the diagnosis of a metastatic
      carcinoma. The reaction pattern of the last panel of antibodies pointed to a
      pulmonary origin of the putative primary tumor (PSA-negative, TTF-1-positive, and
      CK20-negative). The diagnosis of a metastasized poorly differentiated
      adenocarcinoma of the lung was confirmed by autopsy 5 months later. This case
      represents the extremely rare occurrence of a testicular metastasis as a primary
      manifestation of an occult neoplasm and shows the usefulness of an integrated
      site-specific clinicomorphologic approach that should precede and guide the
      choice of diagnostic immunoreagents.

PMID- 12610365
TI  - Laboratory pressure cooker safety management.

PMID- 12610366
TI  - People should not have to resort to assisted suicide.

PMID- 12610367
TI  - Lessons to be learnt from the Victoria Climbie inquiry.

PMID- 12610368
TI  - Nurse manager who did not take any action over 'bad' nurse.

PMID- 12610369
TI  - Sickle cell disease patients and patient-controlled analgesia.
AB  - Sickle cell disease (SCD) is one of the world's commonest hereditary disorders.
      Painful episodes are the overriding manifestation. SCD pain is largely opioid
      sensitive and, in severe cases, adult patients warranting hospitalization often
      need parenteral opioids. Pain is essentially subjective and is often best
      controlled by patients themselves. This study looks at SCD patients' perceptions
      of self-administering parenteral opioids. Using a mainly multiple-choice
      questionnaire and a focus group interview, data were gathered from 40 adult SCD
      patients during hospitalization over a 4-month period. The study was approved by
      the local research ethics committee and the lead clinicians in both the pain and
      haematology departments. All patients had past opioid-experience for acute pain.
      The majority (65%) had previously used PCA diamorphine in addition to other
      opioids. The findings demonstrate that SCD patients perceive the main benefit of
      PCA to lie in its potential to restore their control over pain relief while in
      hospital. Other perceived advantages over nurse-administered analgesia included
      better analgesia accessibility, quick pain relief and relative independence from
      staff. Patients identified that realization of PCA's full potential is being
      limited by ineffective analgesic regimens, analgesic side effects and technical
      shortcomings. Patients found the main disadvantages of PCA to relate to nursing
      care issues including restrictions placed upon patients' ability to exercise
      choice and much reduced direct nurse contact. The implications for nursing
      practice and management involve addressing these patients' concerns through staff
      training, improving patient-staff communication, inputting resources and further
      research.

PMID- 12610370
TI  - Legal remedies for employees if they are injured in the workplace.

PMID- 12610372
TI  - Physical examination and history-taking skills in a prostate clinic.
AB  - The proliferation of nurse-led initiatives arising from nurse
      specialist/practitioner posts in urology is reflected in areas such as the
      management of bladder cancer, erectile dysfunction, stoma care, and prostate
      disease. The establishment of the role of urology specialist nurse in one North
      Oxfordshire hospital led to the development of a nurse-led prostate assessment
      clinic for male patients with lower urinary tract symptoms arising from benign
      prostatic hyperplasia. A description of how training was conducted, and the
      subsequent reappraisal of competency, is given in relation to physical
      examination and history-taking skills necessary for the development of this
      initiative.

PMID- 12610371
TI  - Autonomy, privacy and informed consent 3: elderly care perspective.
AB  - Despite the growing interest in clinical healthcare ethics, there is a dearth of
      empirical studies investigating the ethical elements of day-to-day clinical
      practice from the perspective of either patients or staff. This article, the
      third in a four-part series, reports the results of a Scottish Study that formed
      part of a multi-site comparative study funded by the European Commission. It
      explores patient autonomy, privacy and informed consent in the care of elderly
      people in long-stay care facilities (i.e. nursing homes and continuing care
      units). A convenience sample of 101 elderly residents and their nurses (n = 160)
      participated in the study. Data were collected by means of a self-completion
      questionnaire for staff and a structured interview schedule for elderly
      residents. Results indicate marked differences between staff's and residents'
      responses on three of the four dimensions explored: information-giving, and
      opportunity to participate in decision-making about care and consent. There was
      much closer agreement between staff's and residents' responses regarding
      protection of patient privacy. From the results of this study there is indication
      of a clear need for further empirical studies exploring issues of patient
      autonomy, privacy and informed consent in the day-to-day nursing care of older
      people. Findings to date suggest there is still a significant need to educate
      staff concerning ethical awareness and sensitivity to the dignity and rights of
      patients.

PMID- 12610374
TI  - Transcultural nursing: how do nurses respond to cultural needs?
AB  - The aim of the study was to explore how nurses responded to the cultural needs of
      their clients. From the transcultural point of view, healthcare providers must
      deliver a service that is culturally sensitive and appropriate. However, for a
      variety of reasons, there is growing concern that the cultural healthcare needs
      of minority ethnic groups are not met adequately. This study was done to outline
      nurses' activity in transcultural care. Empirical data were obtained from a
      sample of registered nurses (n = 126) who were invited to complete questionnaires
      pertaining to cultural care. As a result of data analysis, the quantitative
      findings are presented as tables and the qualitative data as categories and
      themes. The findings suggest that most respondents felt that patients' cultural
      needs should be given consideration. Cultural aspects of care seem to be a
      feature of the overall nursing picture within a multicultural context of health
      care. Many participants claimed that they responded to the cultural needs of
      patients. Some felt that patients' cultural needs are adequately met; such needs
      are perceived as religious practices, diets, communication, dying, prayer and
      culture. Furthermore, a significant number of respondents suggested that they
      would like further education in meeting the cultural needs of their patients.
      This study offers some insights into transcultural healthcare practice, and, in
      accordance with the findings, identifies strategies for improving these practices
      for nursing and nurse education.

PMID- 12610375
TI  - School nurse advisers have an important role.

PMID- 12610376
TI  - [Can one avoid a hepatic biopsy in the management of diffuse diseases of the
      liver?].

PMID- 12610373
TI  - Measured improvement in rate of healing of venous ulceration.
AB  - This case study describes a pivotal intervention associated with improved wound
      appearance and healing rate in a young, active woman with extensive venous stasis
      ulcers. These extensive ulcerations were heavily exudative and covered by a layer
      of yellow eschar. Yellow eschar and drainage were successfully managed with a
      capillary dressing (Vacutex), which promoted therapeutic compression as applied
      by standard dressings. This case provides data in favour of wound care protocols
      featuring Vacutex, specifically designed to address the consequences that wound
      drainage and eschar have in dramatically large venous stasis ulcers.

PMID- 12610377
TI  - [Psychosurgery, a different approach to psychiatric disease].

PMID- 12610378
TI  - [Twenty euros...so what?].

PMID- 12610379
TI  - [Adverse drug reactions (ADRs) to antimalarial drugs. Analysis of spontaneous
      report from the French pharmacovigilance database (1996-2000)].
AB  - OBJECTIVE: Although the benefit/risk ratio of older antimalarial drugs (quinine,
      chloroquine) is well established less is known concerning the data about newer
      drugs. This article assesses and analyses the antimalarial-induced ADRs reported
      to the French pharmacovigilance system. METHODS: All cases of ADR(s) reported to
      the French pharmacovigilance database over a period of 5 years, from January 1,
      1996 to December 31, 2000. Our study included the antimalarials (excluding
      doxycycline) used in France for the cure and prophylaxis of malaria. For each
      notification we noted the data relative to the patient (gender, age), the
      antimalarial drug (prevention or cure), the associated drugs and the adverse
      events (imputability, delay before onset, severity and evolution). RESULTS:
      Between 1996 and 2000, a total of 508 reports were collected, representing 0.6%
      of the notifications reported to the French pharmacovigilance database over the
      same period. For chemoprophylaxis, the chloroquine-proguanil combination
      predominated (n=230, i.e. 54%), followed by mefloquine (n=163, i.e. 38%) and
      chloroquine (n=36, i.e. 8%). Women predominated (53%). The mean age of the
      patients was of 40.6+/-16.1 years (range: 0-77 years). The majority of cases
      (67%) were aged 26 to 60 years (n=337). For curative treatment, halofantrine was
      the first line drug (n=30, i.e. 38%), followed by mefloquine (n=20, i.e. 26%),
      quinine (n=18, i.e. 24%) and chloroquine (n=9, i.e. 12%). Whatever the
      indication, the chloroquine-proguanil combination (n=230) and mefloquine (n=183)
      represented 81% of the reports (45 and 36% respectively). We noted 1 040 adverse
      events corresponding to 508 observations. The adverse events were classified as
      severe in 41.4% of cases. However, the percentage was highest for the curative
      (64%) than for the prophylactic treatments (37.5%) (p<0.01). For halofantrine and
      quinine, the adverse events were classified as severe in respectively 76 and 67%
      of cases. We studied the profile of adverse events of each antimalarial drug.
      CONCLUSION: Our study underlined several elements: the considerable number of
      psychiatric problems related to the use of chloroquine-proguanil and the hepatic
      disorders due to halofantrine, the profile of the adverse events of each drug and
      the unexpected adverse events which should not be neglected in some cases.

PMID- 12610381
TI  - [Acute psychosis following treatment with chloroquine for a primo-invasion of
      Plasmodium vivax malaria].

PMID- 12610380
TI  - [Localized amyloidosis of the cavum].
AB  - INTRODUCTION: Amyloidosis is characterized by extracellular deposits of proteins.
      OBSERVATION: A 66 year-old patient presented with a pseudo-tumoral amyloidosis of
      the cavum. Clinical and biological examinations confirmed the localized aspect of
      the disease and immunohistochemical exploration identified a type AL amyloidosis.
      COMMENTS: The disease may be diffuse involving many organs and leading to various
      clinical manifestations. It can also be localized and take on a pseudo-tumoral
      aspect. Localised amyloidosis is a rare lesion of the upper aero-digestive tract,
      predominating in the larynx. Nasopharyngeal involvement is exceptional.

PMID- 12610382
TI  - [Late diagnosis of a Di George syndrome].

PMID- 12610383
TI  - [The limits of screening for breast cancer have some advantages].

PMID- 12610385
TI  - [Breast imaging and biopsy procedures in the diagnosis of breast cancer].
AB  - THE INTEREST OF IMAGING: Mammography permits diagnosis of infra-clinical breast
      lesions with a sensitivity of around 80%. Moreover, with the improvement of the
      apparatuses and films, the latter permit analysis of the breast areas in most
      cases. Sonography, indisputable support for the study of dense breasts, is a
      complement to mammography and clinical examination. Magnetic resonance imaging is
      the most sensitive technique, but cannot be used in routine controls. The
      principle images are essentially opacities characterised by enhanced density in
      the glandular parenchyma (circular or round, asymmetrical opacities of
      architectural density and disorganisation, stellar and epiculated opacities) and
      micro-calcifications without specific appearance, revealing when isolated in situ
      intra-ductal or micro-invasive lesions. THE INTEREST OF BIOPSY PROCEDURES: For
      non-palpable tumours discovered on imaging, stereo or radio-guided cytological
      aspirations are proposed so long as the image is not too small. In the presence
      of infra-clinical images inaccessible to guided cytology, stereotaxy micro
      biopsies can be performed. The relative insufficiency of results obtained has led
      to the proposal of needles of larger calibre used in an apparatus called a
      mammotome or in the ABBI system, the latter permitting radio-guided surgical
      excision. PRIORITY GIVEN TO CLINICAL CONTROLS: The technical progress must not
      lead one to neglect the clinical examination, which, in 5 to 30% of cases,
      reveals a cancer when the mammography or sonography does not.

PMID- 12610384
TI  - [Mass screening for breast cancer].
AB  - A CONTROVERSIAL SUBJECT: Several large randomised studies have demonstrated a
      reduction in mortality due to breast cancer of around 30% in women aged over 50,
      with the development of systematic mammography. There are data also suggesting an
      identical benefit in women aged 40 to 49, when screening is intensified. A recent
      meta-analysis has contradicted the results of randomised studies on screening,
      but this study is clearly debatable. THE SITUATION IN FRANCE: No randomised study
      has been organised. A national program is aimed at screening 7 400 000 women aged
      50 to 74. THE KEY TO SUCCESS: The active participation of women, health
      professionals and public authorities is the fundamental condition for a well
      organised mass screening.

PMID- 12610387
TI  - [Action must be taken within 3 hours following a cerebrovascular accident].

PMID- 12610386
TI  - [Ductal carcinomas in situ].
AB  - EPIDEMIOLOGY: Presently representing 15 to 30% of new cases of breast cancer,
      ductal carcinomas in situ do not have specific epidemiological characteristics.
      The age at which they occur is between 49 and 54 years. DIAGNOSTIC METHODS: The
      diagnosis is evoked primarily when confronted with an area of micro
      calcifications discovered on a mammography. Needle aspiration cytology, useful in
      cases of palpable abnormalities or infra-clinical masses, is of no interest in
      isolated micro-calcifications for which surgical biopsy following radiological
      localisation is the technique of choice. Needle micro-biopsy permits collecting
      analysable tissue for histological but not cytological examination. Macro
      biopsies combine stereotaxic localisation of micro-calcification areas and their
      excision when isolated. The choice of the method varies depending on the case.
      FROM AN ANATOMOPATHOLOGICAL POINT OF VIEW: Ductal or intra-galactophoric
      carcinomas are carcinomas of the glactophores that do not infiltrate the
      connective tissue. They are defined histologically by architectural and
      cytological characteristics, which differentiate them from lobular carcinomas in
      situ. They constitute a group of heterogenic lesions not only morphologically but
      also histologically and with regard to their progression. THERAPEUTIC MODALITIES:
      The aim of treatment is to ensure that the patients have a maximum of chances of
      cure at the cost of the least possible therapeutic consequences. Mastectomy,
      treatment of choice for many years, is still recommended in certain situations.
      In other cases, conservative treatment is possible so long as excision of the
      micro-calcifications is complete on the post-surgical mammography and, in the
      case of biopsy excision, that healthy margins of at least 10 millimetres exist.
      Following surgery, there is no sufficient consensus to propose essential
      recommendations concerning the place of monitoring alone, irradiation or
      tamoxifen.

PMID- 12610388
TI  - [Medicine should be evidence-based, surgery too].
AB  - SURGERY TOO: The concept of evidence-based medicine, in vogue for several years,
      must also apply to surgery, even if the latter has specific characteristics.
      ADVANTAGES OF EVIDENCE-BASED SURGERY: The advantages are related to the expansion
      of surgeons' critical eye and their questioning of the scientifically unfounded
      dogmas. CONSTRAINTS OF EVIDENCE-BASED SURGERY: The constraints are not only
      basically material with the need to have access to data banks, which often costs
      money, but also methodological with the need to assess the scientific quality of
      the articles found in the literature. LIMITS OF EVIDENCE-BASED SURGERY: These are
      related to the rarity of randomized trials and meta-analyses in the surgical
      literature and therefore, regarding surgery as opposed to other medical domains,
      to the reduced level of evidence. Hence,to develop good quality, so-called
      "pragmatic" and prospective trials is needed. DANGERS OF EVIDENCE-BASED SURGERY:
      The greatest danger is the fact that the evidence-based approach is either
      misunderstood or misconstrued, particularly since it integrates in the scientific
      data the surgeons' decision, the clinical context or even the patients'
      preference. CONCLUSION: Evidence-based surgery is not a fleeting fancy. Today, it
      is a well-established fact, the aim of which is to treat the patients according
      to the most fitting scientific data.

PMID- 12610389
TI  - [The place of natriuretic peptide in the diagnosis of heart failure].

PMID- 12610390
TI  - [Depression and associated organic pathologies, a still under-estimated
      comorbidity. Results of the DIALOGUE study].
AB  - INTRODUCTION: The field of comorbidity between organic pathologies and mood
      disorders remains insufficiently explored, whereas such comorbidities predict a
      more unfavorable outcome of both mood disorders and organic pathologies
      themselves. OBJECTIVE: The purpose of the Depression and organic diseases study
      (DIALOGUE) was to obtain in France a set of quantitative data on the prevalence
      of comorbidities between major depressive episodes (MDE) and associated chronic
      organic pathologies (ACOP), as well as on the diagnostic and therapeutic
      difficulties encountered in the management of such comorbidities in daily medical
      practice. METHODS: General practitioners (GP) and private or hospital
      psychiatrists were invited to collect several socio-demographic, clinical and
      therapeutic data on five consecutive patients corresponding to the inclusion
      criteria. Four groups of patients were set up: 2 082 patients followed up in
      primary care by their GP for a chronic somatic pathology (GPS group), as well as
      2 017, 1 335 and 522 patients respectively followed up in primary care (PPD
      group), private (GPD group) or hospital psychiatry (HPD group) for a depression
      not already treated, or requiring modification of its pharmacological treatment
      (GPD, PPD and HPD group). RESULTS: Among the patients of the GPS group, 41%
      presented with an associated MDE and, among the depressed patients of the three
      other groups, respectively 47, 55 and 63% presented with an ACOP. MDE were rather
      old (more than six months of duration) and severe. However, only 20% of the MDE
      in the GPS group had a treatment in progress, while in 74% of these same cases
      the onset of MDE was retrospectively dated more than 2 months before the day of
      the inclusion in the study. The ACOP, whose functional impact was judged as more
      severe (cancer, HIV, neurological diseases, renal insufficiency, osteo-articular
      diseases, insulino-dependent diabetes and coronary heart disease) were more often
      considered as responsible for the concomitant MDE and more often followed up in
      psychiatric settings than the other pathologies. Among the overlap signs between
      the ACOP and the MDE, fatigue was cited first and embarrassed psychiatrists more
      than GPs, contrary to sleep disorders. In spite of the diagnostic difficulties
      related to the comorbidity and recognized by all the physicians, GPs seldom asked
      for the opinion of a psychiatrist (5%) and appealed less often than psychiatrists
      to the cognitive and affective signs specific of the depression (low self-esteem,
      anhedonia). CONCLUSION: The unrecognized frequency in the association between
      depression and organic pathologies pleads for closer cooperation between GPs and
      psychiatrists, as for continuous training not only of the GPs, but also the
      psychiatrists, in order to limit the observational biases and the therapeutic
      hesitations induced by these comorbidities.

PMID- 12610391
TI  - [Sterilization for women using a hysteroscopy technique under local anaesthesia].
AB  - OBJECTIVES: and methods The July 2001 law allows capable and consenting adult
      women to be sterilized after a period of reflection of 4 months and signature of
      an informed consent formula. The first French study on hysteroscopic tubular
      sterilization under local anaesthesia using expanding titanium, steel and nickel
      implants, is reported. RESULTS: From February to October 2002, 25 women, with a
      mean age of 40 years, having conceived 2 or more children, benefited from this
      technique. The duration of the surgical procedure was a mean of 26 minutes
      (range: 16 to 57 minutes). In 2 women presenting with uterus retroversion,
      catheterisation of the fallopian tubes was impossible. Local anaesthesia was only
      used in 15 women, and led to the reduction in the number of days of
      hospitalisation. CONCLUSION: This pilot study confirms the feasibility of trans
      cervical sterilization of women under local anaesthesia.

PMID- 12610393
TI  - [The curse of the black spot].

PMID- 12610392
TI  - [The association of polyarteritis nodosa and familial Mediterranean fever].
AB  - INTRODUCTION: Some necrotizing vasculitis may be associated with familial
      Mediterranean fever (FMF). We report a new case of polyarteritis nodosa (PAN)
      that preceded the diagnosis of FMF. OBSERVATION: A young woman of Turkish origin
      had a long childhood history of inflammatory arthralgia and myalgia, leading to
      the provisional diagnosis of chronic juvenile arthritis, then, after a
      confirmative muscle biopsy, to the diagnosis of PAN, whose outcome remained
      benign. At the age of 19, she was diagnosed as having FMF on clinical and genetic
      grounds, and colchicine led to the regression of most symptoms. DISCUSSION: As
      with Henoch-Schonlein's purpura, PAN seems significantly associated with FMF. Its
      characteristics are a younger age at onset, more frequent peri-renal hematoma,
      overlap between classical PAN and micropolyangeitis, and overall better
      prognosis. In its muscular form, PAN is difficult to distinguish from protracted
      febrile myalgia, a recently described manifestation of FMF, in which pathological
      findings are poorly documented.

PMID- 12610395
TI  - [The clinical diagnosis of melanoma].
AB  - EARLY DIAGNOSIS FOR EFFICIENT MANAGEMENT: The melanoma is a cutaneous tumour of
      poor prognosis and its incidence is increasing. Some risk factors are now well
      established ( field, phototype, family history) and its early discovery is
      clinically possible since the lesions are visible to the eye. When diagnosed
      early, the prognosis is clearly improved. CLINICAL FORMS OF VARYING PROGNOSIS:
      Depending on the clinical, histopathological and progressive differences, it is
      possible to distinguish a Superficial Spreading Melanoma (60 to 70%), nodular
      melanoma (10 to 15%), Dubreuilh's melanoma (5 to 10%) and acrolentigenous
      melanoma (5%). Apart from these 4 major clinical forms, there is also the sub
      ungual melanoma and the mucosal melanoma. Particular situations may also exist:
      the discovery of metastasis without identification of cutaneous tumour, a
      melanoma in a pregnant woman or a child, a familial melanoma or multiple
      melanomas. THE ELEMENTS OF DIAGNOSIS: The semiological analysis of an often
      pigmented lesion of the skin, relying on the ABCDE rule and the notion of rapid
      progression, is the first stage in the diagnostic approach. It is completed,
      following complete exeresis, by anatomopathological exploration (Breslow's index,
      existence of ulceration, signs of regression, Clark's classification,
      histological type and mitotic activity). Two further elements should also be
      taken into account: the results of a dermatoscopy and the analysis of the
      sentinel nodes.

PMID- 12610394
TI  - [Epidemiology of melanoma].
AB  - A WORRYING INCIDENCE: In frequency, the melanoma, is placed just after breast,
      colic and pulmonary cancer with around 6 000 new cases per year in France.
      Moreover, it is the tumour that is increasing the most and its frequency has
      doubled over the past 10 years. It is presently estimated as 7 to 9/100 000 in
      France. THE IMPACT OF PREVENTIVE MEASURES: Primary and secondary prevention is
      therefore crucial, as is the identification of patients at risk. However, till
      now, the impact of educational and preventive campaigns with regard to sun
      exposure, which plays a major role in the development of a melanoma, are still
      insufficient

PMID- 12610404
TI  - [Facial anesthetic blocks in the treatment of acute pain during ophthalmic
      zoster].
AB  - BACKGROUND: Ophthalmic zoster is frequently accompanied by severe pain in the
      frontal and nasal divisions of the ophthalmic nerve. Treating this pain is often
      difficult, particularly in elderly patients, owing to iatrogenic effects and to
      interactions with the pre-existing diseases and treatments frequently present in
      this age group. The aim of our study was to consider the efficacy and toxicity of
      the frontal and nasal nerve blocks in the treatment of severe pain during acute
      ophthalmic zoster in the elderly. MATERIAL AND METHODS: A prospective study was
      conducted on 20 patients (mean age, 76 +/-7 years; range, 63-88) presenting with
      acute ophthalmic zoster with severe pain (less than 1 month since onset), which
      had resisted analgesic medication. All patients had a visual analogue score for
      pain (VAS) of 4 or more and received one or more anesthetic blocks of a compound
      of bupivacaine with adrenaline associated with clonidine at the frontal branch
      and sometimes the nasal branch levels of the ophthalmic nerve. Pain was measured
      daily by VAS for 5 days, and the blocks were repeated if the VAS was still 4 or
      higher. Patients were checked for local or systemic side effects. RESULTS: The
      number of anesthetic blocks per patient ranged from one to four (mean: 2.3 +/
      0.7). All patients experienced less pain after the first injection. The mean
      preinjection VAS was 7.4 +/-1 and fell to 4.8 +/-1.0, 4.1 +/-1.1, 3.5 +/-1.0, 3.2
      +/-0.6 and 2.8 +/-0.9 at day 1, day 2, day 3, day 4 and day 5, respectively
      (p<0.001). It was possible to reduce analgesic medication permanently in all
      patients. No local or systemic side effect was observed. CONCLUSION: Anesthetic
      blocks of the frontal and nasal branches, repeated if necessary, give fast and
      effective relief from the severe pain of acute ophthalmic zoster. They are fully
      tolerated and simple to administer, making them an excellent indication in the
      complementary treatment of the pain of hyperalgic acute zoster in the elderly.

PMID- 12610396
TI  - [Treatment of melanoma].
AB  - At the stage of primary tumour and lymph node extension, the treatment of
      melanoma is mainly surgical. Interferon alpha has obtained marketing
      authorisation to be used as adjuvant therapy at different doses in the treatment
      of these two stages of the disease and must therefore be discussed with the
      patient. At the metastatic stage, no real progress in chemotherapy has been noted
      for more than 20 years. Combined therapy with chemotherapy and cytokines
      (interferon alpha or interleukine 2) increases the percentage of response but
      without increasing the overall survival. THREE IMMUNOTHERAPY TECHNIQUES: Cellular
      immunotherapy represents the main hope of these future years in the treatment of
      melanoma, with the injection of in vitro expanded cytotoxic T cells, vaccination
      and dendritic cells. Although clinical results are starting to be published,
      cellular immunotherapy remains in the field of clinical research, within the
      framework of clinical trials.

PMID- 12610405
TI  - [Molteno implant and refractory glaucoma. Evaluation of postoperative IOP control
      and complications with a modified surgical procedure].
AB  - BACKGROUND: Management of refractory glaucoma is difficult because classic
      medical and surgical treatments are ineffective in controlling highly elevated
      intraocular pressure (IOP). Drainage implants are an alternative to
      cyclodestructive procedures in refractory glaucoma. The double-plate Molteno
      implant, a tube linked to two polypropylene plates, allows aqueous humor drainage
      from the anterior chamber towards the posterior subconjunctival spaces. The main
      postoperative complication is severe hypotony, potentially responsible for a
      decrease in visual acuity in cases of advanced glaucoma. Surgical modifications
      such as external tube occlusion can reduce postoperative hypotony. However, tube
      occlusion may lead to transient postoperative hypertony. Our retrospective study
      reports on double-plate Molteno implantation with intraoperative external tube
      occlusion associated with trabeculectomy in some cases. MATERIAL AND METHODS:
      Thirteen eyes of 13 patients with refractory glaucoma were included in the study
      (5 cases of open angle glaucoma, 7 cases of secondary glaucoma, one case of
      primary congenital glaucoma). All had ocular hypertony despite maximal tolerable
      medical treatment; 84.5% had previously undergone trabeculectomy with mitomycin
      (1-5 procedures) and 61% had undergone cyclophotocoagulation (1-4 sessions). All
      underwent double-plate Molteno implantation with external tube occlusion between
      1993 and 2001. In three cases, intraoperative trabeculectomy was also performed.
      Visual acuity, IOP, relevant medical treatment and potential complications were
      reported at each follow-up visit. Complete success was defined as IOP less than
      21 mmHg without treatment, while IOP control with medical treatment was
      considered as relative success. RESULTS: Mean (+/-SD) follow-up was 2.9+/-2.1
      years (range, 9 months to 8 years). Mean (+/-SD) initial and final IOPs were
      35.2+/-7 mmHg and 17.1+/-5 mmHg, respectively, i.e., a 50% IOP decrease. Mean (+/
      SD) initial and final medical treatments were, respectively, 4.3+/-1.5 (61% with
      systemic acetazolamide) and 1.3+/-1.4 (without acetazolamide). The complete
      success rate was 38.5% and relative success 92.3%. Immediate postoperative
      hypertony occurred in 60% of the cases with external tube occlusion alone (10
      cases). This hypertony was controlled with medical treatment in 2/3 of the cases
      but required surgical reintervention in 1/3 of the cases. For patients with
      intraoperative trabeculectomy (3 cases), postoperative immediate IOP without
      medical treatment was 2, 5 and 8 mmHg respectively. Complications reported were
      flat anterior chamber (1 case), visual acuity decrease (4 cases), lens
      opacification (1 case), macular edema (1 case), corneal edema (2 cases: 1
      transient, 1 corneal decompensation) and long-term refractory hypertony (1 case).
      CONCLUSION: The double-plate Molteno implant is effective in controlling IOP in
      refractory glaucoma. External tube occlusion prevents complications related to
      excessive filtration; however, it may lead to transient postoperative hypertony.
      This hypertony can be avoided when simultaneous trabeculectomy is performed.
      Corneal decompensation remains the major complication of this surgical procedure.

PMID- 12610406
TI  - [Progression of subjective refraction after artificial divergence surgery and its
      relation to a possible myopic spasm].
AB  - PURPOSE: To study the effect on subjective refraction of artificial divergence
      surgery in congenital nystagmus with blocking convergence. METHODS: Retrospective
      study on 139 cases, with a study of visual acuity and optical correction with
      habitual glasses 1-5 years after operation, according to age and ocular alignment
      (orthophoria or exophoria). RESULTS: Increased myopia with glasses of
      approximatively 1 diopter, but likely to be due to eye growth in this young
      population (mean age, 14 years). This myopic shift is higher in the exophoric
      population, but there is a tendency to prescribe a stronger correction to help
      control the phoria. A few rare cases of true myopic spasm were noted. CONCLUSION:
      After artificial divergence surgery, true cases of increased myopia were rare.
      Tonic vergence is stronger than accommodative vergence.

PMID- 12610407
TI  - [Iris melanomas. A retrospective study of 11 patients treated by surgical
      excision].
AB  - INTRODUCTION: Iris melanoma, even when a malignant tumor, has a slow progressive
      course. Surgical treatment is easy because of localization of the tumor but can
      be accompanied by a range of complications, from photophobia to cosmetic
      problems. MATERIALS AND METHODS: We reviewed the records of 11 patients with iris
      melanoma treated by surgical excision with posterior limbus incision.
      Conventional iridectomy was performed in nine cases and iridocyclectomy in two
      cases. RESULTS: There were seven females and four males ranging in age from 27 to
      76 years. Histologically, 10 tumors were composed of B spindle cells and one was
      mixed. For all patients, followed up for 1-5 years, final visual acuity was more
      than 6/10. One patient complained of photophobia and cataract developed in one 76
      year-old woman at the end of follow-up. CONCLUSION: Because of the good prognosis
      of iris melanoma, conservative treatment can be given in most of cases (without
      local complications). Surgical resection confirms diagnosis after
      histopathological examination, with good final functional result thanks to
      scleral tunnel incision, which induces less astigmatism than corneal incisions.
      In the future, these findings will have to be confirmed by a corneal topography
      study before and after surgery.

PMID- 12610408
TI  - [Diabetic cystoid macular edema and vitrectomy. Preliminary results: about 19
      cases].
AB  - INTRODUCTION: Vitrectomy can be performed to release the anteroposterior and
      tangential vitreoretinal tractions that sometimes create diabetic macular edema.
      The present study evaluates the efficacy of this treatment. MATERIAL AND METHODS:
      We retrospectively studied 19 operated eyes in 15 patients with diabetes over 17
      months. The group's mean age was 61.4 years. There were 11 men and 4 women, with
      13 cases of noninsulinodependent and two cases of insulinodependent diabetes. A
      vitrectomy was done by the same surgeon to detach posterior hyaloidal and inner
      limiting membranes. Two groups were defined and compared, one including patients
      whose visual acuity had improved and the other, patients with no improvement. We
      used Student's t test and Leven's test from SPSS. RESULTS: Improvement in visual
      acuity was observed in 57.8% of the eyes studied, stabilization was achieved in
      26.3%, and regression was noted in 15.7%. Cystoid macular edema resolved in
      68.42% of eyes. Furthermore, inner limiting membrane colored by indocyanine green
      was removed. An angiographic improvement was noted in 68.42% of eyes. There was
      no significant difference between the two groups allowing a definition of success
      criteria. CONCLUSION: Vitrectomy for diabetic cystoid macular edema is currently
      under study and seems effective given its encouraging results.

PMID- 12610410
TI  - [Steinert myotonic dystrophy and blepharoptosis surgery: 9 case reports].
AB  - Steinert myopathic dystrophy is a generalized, hereditary disease with bone,
      muscular, heart and ocular involvement. PATIENTS AND METHODS: This is a
      retrospective study of nine patients with significant blepharoptosis due to
      Steinert disease, who were treated at the Adolphe de Rothschild Ophthalmology
      Foundation over a period of 5 years. Ptosis was symmetric and major in all cases
      with poor levator excursion. Severity criteria were an absence of the Bell
      phenomenon and diminished orbicularis tone. A frontalis suspension was performed
      in eight cases with intentional undercorrection. The outcome was favorable in all
      cases, 2 with a slight overcorrection underwent a second operation DISCUSSION:
      conclusion: Surgical treatment of ptosis in Steinert disease is difficult because
      of a risk of lagophthalmic, keratopathy due to the severity of the disease, an
      absence of the Bell phenomenon and ophthalmoplegia. This surgery must be
      undertaken with caution, most often using a frontalis suspension. Undercorrection
      must be systematic, with the single goal of freeing the pupil in the primary
      position.

PMID- 12610411
TI  - [Leber's idiopathic stellate neuroretinitis: about two cases].
AB  - BACKGROUND: Described by Theodore Leber in 1916, this syndrome is characterized
      by unilateral visual loss, optic disc swelling and a stellate pattern of
      exudative deposits in the macula. MATERIAL AND METHODS: Two young adults were
      examined for sudden unilateral visual loss preceded by a flu-like syndrome.
      Fundus examination revealed a swollen optic disc and a macular star, visualized
      on fluorescein angiography. Visual field, laboratory tests and cranial and
      orbital tomodensitometry were performed. RESULTS: Visual field examination showed
      a centrocecal scotoma. Laboratory tests showed inflammatory syndrome in one case.
      Serology testing (leptospirosis, cat scratch disease, toxoplasmosis and syphilis,
      etc.) were negative. Tomodensitometry of the brain and orbits gave normal
      results. One of the patients was treated with intravenous steroid boluses; the
      other received no treatment. A few weeks after the beginning of symptoms, the
      swelling of the optic disc seemed to have declined, leaving the macular star
      unchanged. CONCLUSION: These two cases typically describe Leber's idiopathic
      stellate neuroretinitis. The prognosis for visual recovery is usually reported to
      be excellent, but visual sequelae have been described.

PMID- 12610412
TI  - [Atypical Cogan syndrome].
AB  - Atypical Cogan syndrome is a systemic vascular disease close to Cogan syndrome.
      It is characterized by different ocular manifestations associated with Meniere
      like audiovestibulatory dysfunction with symptoms arising more than 2 years
      before or after the ocular abnormalities. We report the case of a 63-year-old
      woman whose ocular manifestations involved alternating scleritis, myositis and
      uveitis associated with audiovestibulatory signs, and the onset of ocular muscle
      and nerve palsies. In the light of this observation, we discuss the clinical
      characteristics, diagnostic means, differential diagnoses and therapeutic
      modalities of this syndrome.

PMID- 12610409
TI  - [Should associated intraoperative and/or postoperative photocoagulation be
      systematic during or after vitrectomy for proliferative diabetic
      vitreoretinopathy?].
AB  - PURPOSE: To analyze the results of vitrectomy in proliferative diabetic
      vitreoretinopathy and to check whether systematic intra- and/or postoperative
      photocoagulation is necessary in most cases. PATIENTS AND METHODS: We
      retrospectively reviewed 108 patient records (137 eyes) of vitrectomy performed
      for complications of proliferative diabetic vitreoretinopathy between 1982 and
      2000. Fifty-eight percent of the patients were women. The average age was 44
      years. Sixty percent of the patients presented with diabetes type 1. Only 39% of
      the eyes had complete preoperative panretinal photocoagulation. Preoperative
      visual acuity was lower than 2/200 in 81% of eyes, 27% presenting initially with
      traction retinal detachment involving the macula. The surgical technique used was
      segmentation-delamination. Endodiathermy was necessary in 45% of the eyes and
      intraoperative photocoagulation was not performed. Postoperative complementary
      photocoagulation was carried out in only 9% of the eyes. RESULTS: Results were
      analyzed with an average follow-up of 66 months. Anatomical success was obtained
      in 69% of the eyes, with 55% visual improvement. These results were unchanging at
      long-term follow-up in 95% of the eyes studied. Iatrogenic retinal breaks were
      observed in 8% of the eyes. Postoperative complications were dominated by single
      (8%) or recurrent vitreous hemorrhage (8%). The rate of postoperative neovascular
      glaucoma was approximately 5%. These results are similar to the rates reported by
      other authors using intraoperative endophotocoagulation. CONCLUSION: Intra-
      and/or postoperative photocoagulation should not be systematic but reserved for
      management of iatrogenic retinal breaks and also for extensive panretinal
      photocoagulation in recurrent vitreous hemorrhage.

PMID- 12610414
TI  - [Palpebral tumors: clinical and diagnostic considerations].
AB  - The vast majority of palpebral tumors are benign and, when complete,
      straightforward excision is curative. In some cases, laser ablation can be
      appropriate. These tumors originate from the pilosebaceous adnexa of the skin and
      are mainly composed of cysts. For carcinomas, the extent of the tumoral expansion
      must be assessed on pathological examination of a specimen. In case of
      recurrence, the tumor may extend beyond the clinically visible borders. This is
      particularly true in the sclerodermiform type of basal cell carcinoma, which
      invades tissues deeply, in spindle cell carcinoma, which spreads within the
      thickness of the epidermis or the conjunctival epithelium, and in sebaceous gland
      carcinoma, which can present in a masquerade fashion.

PMID- 12610415
TI  - [Pathology in the diagnosis and treatment of palpebral tumors].
AB  - The authors stress the role and place of pathology in the diagnosis and treatment
      of eyelid tumors. After a brief report on the main histological characteristics
      of eyelid tumors and their classification, the pathological methods are
      described, with particular attention paid to the technical aspects of frozen
      sections in palpebral surgery. AIM: This study reports the main pathological
      techniques available for use in eyelid tumor surgery. The advantages of frozen
      sections are reported from a retrospective study of basal-cell carcinomas of the
      eyelid. MATERIAL AND METHODS: All basal-cell carcinomas treated at the Reims
      Hospital from 1985 to 1999 were retrospectively studied. The pathological aspects
      are reported. Most of the tumors (155/193) were examined with frozen sections.
      Recurrences are considered. CONCLUSION: Pathology in eyelid tumor surgery must be
      taken into consideration. Frozen section examination may eliminate recurrences
      and limit healthy tissue taken at resection. This method is a very useful tool in
      this type of surgery. The benefits of the classic Mohs technique can be completed
      by a technique that is more precisely adapted to the control of the lateral
      limits of the excision in reconstructions which are often complex.

PMID- 12610416
TI  - [Radiotherapy in the treatment of eyelid tumors].
AB  - We describe the different radiation therapy techniques for malignant tumors of
      the eyelid, their results in squamous-cell and basal-cell carcinoma, their side
      effects, and the advantages and disadvantages compared to surgery. The most
      frequent indications for radiation in the management of these tumors are also
      reviewed.

PMID- 12610417
TI  - [Treatment of benign eyelid conditions with Argon laser].
AB  - Eyelid surgery is not always uneventful. Complications (punctal ectropion,
      retractile scars) can sometimes occur. Argon laser treatment is an interesting
      alternative technique, particularly in cases with cosmetic indications. The
      advantages of the procedure, compared to surgery are numerous: magnified view of
      tissue removal, enhancing complete excision; good hemostasis, avoiding wound
      sutures and bandage; fast and painless technique; outpatient office procedure
      with little post-operative care; good acceptance of the technique by most of the
      patients. The technique and the main indications are described in this paper.

PMID- 12610418
TI  - [Surgical treatment of eyelid tumors].
AB  - After reviewing the general principles of eyelid reconstruction, the authors
      present reconstruction techniques with regard to the location and size of the
      eyelid defect. When the defect is less than one-quarter of lid length, direct
      suture is possible. When the defect is larger, reconstruction techniques differ
      for the upper and lower lid.

PMID- 12610420
TI  - [Nonpenetrating deep sclerectomy (NPDS) in ultrasound biomicroscopy (UBM)].

PMID- 12610421
TI  - [Multilocular eyelid hidrocystoma: an anatomical and clinical observation].
AB  - A cystic cutaneous mass was observed on the lateral canthus of the left eyelid in
      a 25-year-old woman, 2 years after being operated on for a lesion that had
      existed in the same area several years before, but the patient could not identify
      its nature. The present mass appeared as a well-circumscribed bluish cystic
      lesion. A surgical resection was performed; pathological analysis disclosed a
      cystic sweat tumor composed of several contiguous cysts. One year of follow-up
      has revealed no complications.

PMID- 12610422
TI  - [Contribution of magnetic resonance spectrometry to the diagnosis of intracranial
      tumors].
AB  - Magnetic resonance spectroscopy (MRS) is a method enabling the analysis of the
      tissue metabolic content. It may offer a more accurate diagnosis of the
      intracranial tumors than conventional MRI sequences. MRS of normal brain
      parenchyma displays 4 main metabolites: N-acetyl aspartate (neuronal marker),
      creatine (cellular density marker), choline (membrane activity marker) and
      myoinositol (glial marker); pathological processes lead to variations of the
      level of these metabolites and/or the appearance of abnormal metabolites
      (lactate), following different patterns according to pathological process
      involved: glioma, meningioma, metastasis, bacterial or toxoplasmic abscess,
      radionecrosis. The potential clinical use of this method includes positive,
      differential and etiological diagnosis of tumors, determination of the level of
      malignancy of gliomas, screening for tumor recurrence following treatment. Our
      laboratory has been performing MR spectroscopic explorations of brain tumors for
      many years. Based on this experience, we show how MRS can be routinely performed
      in the clinical setting, what are its limitations and potential, and what kind of
      information can be supplied to the clinician.

PMID- 12610423
TI  - [Clinical features and psychopathology of factitious disorders].
AB  - Factitious disorders are characterized by self-produced symptoms and a chronic
      course, sometimes with severe complications. Pathomimia occurs more often in
      women, even though the Munchausen syndrome is found especially in men. Among the
      various clinical features of pathomimia, the most frequent are factitious fevers
      and cutaneous pathomimia. Factitious psychiatric disorders are not rare, such as
      factitious psychotic symptoms, mournings or post-traumatic stress disorders. The
      main elements of diagnostic orientation are the odd expression of the reported
      symptoms, a capricious and disconcerting course, as well as the multiplicity of
      the previous history, with many imprecise diagnoses. Concerning the
      psychopathology, and contrary to the simple simulation, immediate utility of the
      alleged symptoms is not the expected goal, one of the essential psychological
      motivations being to challenge the physician. Among comorbid pathological
      personalities, there seems to be some close relations between pathomimia and
      hysterical personality, whereas the Munchausen syndrome shares common features
      with antisocial personality.

PMID- 12610424
TI  - [B-cell anomalies in systemic lupus erythematosus].
AB  - Systemic lupus erythematosus is a non-organ-specific autoimmune disease
      characterized biologically by B lymphocyte hyperactivity and the production of
      autoantibodies directed against various cellular components, in particular
      nuclear antigens. Different strains of mice spontaneously develop a lupus-like
      disease and constitute a guidelight for human SLE. Both polyclonal B cell
      stimulation and clonal expansion induced by self-antigens participate in B cell
      hyperactivity observed in human and mouse SLE. B cells are hyperactive to various
      stimuli, in particular those delivered by T cells through surface molecules or
      cytokines. The consequences are an increased production of immunoglobulins and
      the development of autoantibodies thought to induce the major part of tissue
      lesions. B cells also participate in the pathological process as antigen
      presenting and cytokine-secreting cells. An intrinsic defect of B cells is
      suspected to be responsible for B cell anomalies as illustrated by certain
      spontaneous murine models of SLE (motheaten mice) and by lupus-like syndromes
      observed in mice rendered deficient for genes controlling the B-cell receptor
      (BCR) signaling pathway. Genome wide scan analysis of various lupus strains
      allowed to identify several loci predisposing to lupus among which certain are
      associated with B cell hyperactivity suggesting that the intrinsic defect is
      inherited.

PMID- 12610425
TI  - Anti-nucleosome antibodies and T-cell response in systemic lupus erythematosus.
AB  - Evidence accumulated in recent years suggests that nucleosomes play a pivotal
      role in the induction phase and pathogenesis of systemic lupus erythematosus
      (SLE). Apoptotic cells are an important source of nucleosomes and apoptosis
      defects have been described in patients with SLE as well as in lupus mice.
      Moreover, it has been demonstrated that the intravenous injection of apoptotic
      cells in normal mice generated the production of anti-nuclear antibodies and led
      to the development of symptoms associated with lupus disease. In this review, we
      briefly summarize these results and describe recent findings on the
      characterization of histone T-cell epitopes recognized by CD4(+) cells from
      different strains of lupus mice. We have tested a panel of overlapping peptides
      spanning the whole sequences of H4 and H3 histones for recognition by CD4(+) T
      cells from unprimed (NZBxNZW) F1 and MRL/lpr lupus mice. We have also immunized
      naive BALB/c mice with nucleosomes or syngeneic apoptotic and non-apoptotic
      spleen cells, and tested the activation of Th cells reacting ex vivo with H4 and
      H3 peptides. Our results suggest that nucleosomes and apoptotic cells may
      effectively act as initiator of autoreactive Th cell development in lupus mice.
      In the BW lupus model, the region 53-85 of H3, which also contains B-cell
      epitopes recognized by antibodies from (NZBxNZW) F1 mice and lupus patients,
      might be important.

PMID- 12610426
TI  - [Anti-SSA/Ro and anti-SSB/La antibodies. What's new?].
AB  - Anti-SSA/Ro and anti-SSB/La autoantibodies recognize different epitopes on
      polypeptides associated with small RNAs called scYRNA situated mostly in the
      cytoplasmic compartment (70%) and few in the nuclear compartment (30%). These
      hYRNPs (h=human) can be found on the cytoplasmic membrane or in small blebs
      during apoptosis after various stimuli such as UVB, 17-beta-estradiol, viral
      infection, TNF alpha and other cellular apoptosis inducing molecules. At least
      two major different proteins are called SSA/Ro: a 52 kDa Ro (with two subtypes
      alpha and beta) and a 60 kDa Ro. There is only one SSB/La protein of 48 kDa. In
      some circumstances, other proteins such as calreticuline (MW 57 kDa) join Ro/SSA
      proteins on some YRNAs. Anti-SSA/Ro antibodies are detected in the sera of 30% of
      patients with SLE, even during preclinical setting; anti-Ro/SSA are strongly
      associated (90%) with some subtypes of SLE such as old-onset (>50 y) SLE,
      subacute lupus erythematosus, drug-induced subacute lupus erythematosus and in
      patients with hereditary C2 or C4 or C1q deficiency with lupus or lupus-like
      disease. Anti-SSA/Ro are also associated with primary Sjogren syndrome (50% to
      60%) and with undifferenciated connective tissue disease (UCTD). Anti-SSA/Ro
      antibodies are almost always present in sera of mothers with babies with neonatal
      lupus syndrome (NNL) and with complete congenital heart block (CCHB). This last
      event is very unusual in pregnant patients with anti-Ro/SSA antibodies (1% to 2%
      of primigeste women). Some good evidences such as experimental models in vitro or
      ex-vivo, argue for the responsibility of maternal anti-Ro/SSA 52 kDa and/or anti
      La/SSB antibodies (or associated IgG antibodies) as major etiologic factor of
      CCHB and NNL. IgG anti-Ro 52 beta kDa has been shown able to interrupt the
      atrioventricular conduction as well as the L calcium channel influx of fetal
      cardiocytes. Other factors must be taken into account to explain discordant twins
      (with and without CCHB). More recently anti-Ro/SSA antibodies were associated
      with QT interval prolongation in newborns without CCHB.

PMID- 12610429
TI  - Giardia lamblia infection in a patient with myotonic dystrophy.
AB  - Myotonic dystrophy is an autosomal dominant muscle disorder characterized by
      muscle wasting and weakness and a number of other systemic abnormalities. Some
      patients have hypo-IgG that is asymptomatic in most of them. We report the case
      of a 42-year-old woman with myotonic dystrophy and hypo-IgG who experienced
      asthenia and weight loss secondary to Giardia lamblia bowel infection.

PMID- 12610428
TI  - [Cutaneous and osteoarticular Scedosporium apiospermum infection].
AB  - Scedosporium apiospermum is a widely distributed fungus that can be found in the
      soil, manure and decaying vegetation. Human infection with this fungus is
      facilited by immunodepression. A 65-year-old man, who was taking oral
      methylprednisolone for rheumatoid polyarthritis had for a few months ulcerated or
      suppurative nodules whose incision discharged a thick honey-colored exudate. An
      ulceration over the first right metatarsophalangian articulation had left the
      bone exposed. The treatment for Pseudomonas aeruginosa, initially isolated in the
      exudate was unsuccessful. Other microbiology samples exhibited Scedosporium
      apiospermum, without bacteria. The pathogenic nature of the infection was proven
      on a skin and bone (head of the first metatarsian) biopsy showing numerous
      branching and septate hyphae. The patient was successfully treated by
      itraconazole. Scedosporium apiospermum is the cause of a growing number of human
      infections due to widespread use of immunosuppressors. Skin and lung
      localizations predominate. Osteoarticular infection is relatively rare, which
      contributes to the originality of this observation. Treatment is not well defined
      and essentially combines surgical drainage with antifungals like itraconazole.
      This emergent fungal infection, which has non specific clinical manifestations,
      must be considered in immunocompromised patients.

PMID- 12610430
TI  - [Ankylosing spondylitis and amyloidosis. A case report].

PMID- 12610427
TI  - Lessons from the "Euro-Lupus Cohort".
AB  - The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus
      erythematosus (SLE) that have been followed prospectively since 1991. These
      patients have been gathered by a European consortium - the "Euro-Lupus Project
      Group". This consortium was originated as part of the network promoted by the
      "European Working Party on SLE", a working group created in 1990 in order to
      promote research in Europe on the different problems related to this disease. The
      "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and
      mortality characteristics in the present decade as well as defines several
      clinical and immunological prognostic factors.

PMID- 12610431
TI  - [Shoulder arthroplasty for non-operated anterior shoulder instability with
      secondary osteoarthritis].
AB  - PURPOSE OF THE STUDY: The purpose of this study was to analyze the natural
      history of osteoarthritis of the shoulder joint secondary to non-operated
      anterior instability, to evaluate the clinical and radiological outcome after
      arthroplasty for this indication, and to compare results with data reported in
      the literature. MATERIAL AND METHODS: Twenty-eight Aequalis shoulder
      arthroplasties were performed for osteoarthritis secondary to anterior shoulder
      instability in patients who had not undergone any prior stabilizing surgical
      procedure. This multicentric series was reviewed retrospectively at a mean follow
      up of 44 months (range 24-87 month). Preoperative and last follow-up clinical
      status was compared using the Constant score. Standard operative technique was
      used and anatomic position of the implants was achieved in 27 patients. Total
      shoulder arthroplasty was performed in eighteen patients and simple humeral
      implantation in ten. Patients were divided into two sub-groups for analysis of
      outcome (age at first dislocation > or < 40 years). RESULTS: There were four
      complications including one early loosening that required revision arthroplasty.
      Outcome was excellent or good in 54% of the cases. Group 1 (age at first
      dislocation < 40 years) included 17 patients and exhibited male predominance
      (13/17), young age at first dislocation (mean 28.5 years), high number of
      dislocations (mean 13), and a long natural history of osteoarthritis (mean 28
      years). In this sub-group, imaging disclosed constructive osteoarthritis
      reflecting a long history. There was one case with a full-thickness tear of the
      supraspinatus. Outcome was excellent or good in 64% of these 17 patients (14
      underwent total shoulder arthroplasty). The sub-group of 11 patients whose first
      dislocation occurred after the age of 40 years exhibited female predominance
      (9/11), a small number of dislocations (mean 1.3), and a short natural history of
      osteoarthritis (mean 6 years). In this sub-group, imaging disclosed six cases of
      basically chondrolytic osteoarthritis reflecting a short evolution. There were
      seven cases of full-thickness tears of the supraspinatus. Outcome was excellent
      or good in 36% of these 11 patients (4 underwent total shoulder arthroplasty).
      DISCUSSION: The forty-year age cutoff allowed us to distinguish two populations.
      The first population of patients whose first dislocation had occurred before the
      age of 40 years was predominantly male, with a long history of constructive
      osteoarthritis without rotator cuff tears. Most of these patients were treated
      with total shoulder arthroplasty which gave results similar to those obtained
      with arthroplasty for primary centered osteoarthritis. The second sub-group of
      patients aged over 40 years at the time of the first dislocation were
      predominantly female with a short history of minimally constructive
      osteoarthritis and frequent rotator cuff tears. Humeral implants were used for
      most of these patients and gave less favorable results than in the former sub
      group, probably due to the high rate of rotator cuff tears.

PMID- 12610432
TI  - [Chronic anterior shoulder dislocation treated by open reduction sparing the
      humeral head].
AB  - PURPOSE OF THE STUDY: Treatment options for unreduced anterior dislocation of the
      shoulder have varied from nonoperative treatment to different surgical options.
      Little has been written in the literature on the management of unreduced anterior
      dislocation or on the results of the different procedures. We report our
      experience and present the outcome after an open reduction joint-saving procedure
      used in five patients. MATERIAL AND METHODS: Five patients, mean age 39 years
      (range 17-69 years) underwent the joint-saving procedure for chronic anterior
      shoulder dislocation. Pain was predominant for two patients and functional
      impairment for three. The shoulder had been anteriorly dislocated for six weeks
      to up to 36 months (average 14 months). Open reduction was performed in all cases
      with reinsertion of the capsulo-labral complex onto the anterior glenoid rim. A
      bone graft was used in one patient to reconstruct an anterior glenoid bone defect
      involving more than half of the joint surface. No graft was used to fill the
      humeral head defect. RESULTS: At an average follow-up of 25 months (range 12-36
      months), outcome was excellent in one patient, good in three, and poor in one
      (Rowe and Zarins score). Postoperatively, the overall score averaged 75 points
      (range 40-90). Pain score improved from 12 to 27 points. Three shoulders were
      totally pain free and two had mild to moderate pain. Motion improved from 12 to
      28 points. Anterior active elevation averaged 126 degrees, external active
      rotation 17 degrees, and internal active rotation to the level of the first
      lumbar vertebral body. Functional score improved from 9 to 20 points. All the
      patients were able to perform daily living activities. The radiographic
      evaluation showed anterior subluxation of one shoulder one year after surgery.
      Osteoarthritis was also noted in one patient. No peroperative or postoperative
      complication was seen. DISCUSSION: Unreduced anterior shoulder dislocation should
      be treated with an open reduction and reconstruction of the specific lesions,
      unless the patient is old or debilitated. This operation can however be difficult
      and requires extensive soft tissue release, and occasionally use of a bone graft
      to reconstruct the anterior defect of the glenoid. The long-term results remain
      modest. When the humeral head cannot be saved because of extensive osteochondral
      lesions, shoulder arthroplasty must be the treatment of choice.

PMID- 12610433
TI  - [Management of stiffness after total knee arthroplasty: indication for different
      mobility management in 62 cases].
AB  - PURPOSE OF THE STUDY: Stiffness of the knee is a common reason for revision of
      total knee arthroplasty. Three methods are currently used to mobilize the knee:
      manipulation under general anesthesia, arthroscopic release, open surgical
      release. The purpose of the present work was to determine the respective
      indications of these three procedures in a large single-center study. MATERIAL
      AND METHODS: We retrospectively assessed all revision procedures without
      component exchange in patients with a stiff total knee prosthesis. Sixty-two
      procedures were performed in our institution between 1989 and 2001. All patients
      were followed for at least one year. There were 34 manipulations under general
      anesthesia, 18 arthroscopic release procedures, and 10 open surgical release
      procedures. The three groups were not different for all parameters studied except
      time interval between implantation of the prosthesis and the mobilization
      procedure: 17 weeks for manipulation under general anesthesia, 46 weeks for
      arthroscopic release, 97 weeks for surgical release. A comparable postoperative
      analgesia and rehabilitation program was instituted for all patients. RESULTS:
      Range of flexion improved after all 62 procedures: mean 58.4 degrees before the
      procedure, mean 94.6 degrees at one-year follow-up. Flexion deformity also
      improved from 7.6 degrees to 2.5 degrees at one year (p=0.001). From surgery to
      one-year follow-up, there was a decrease in flexion (104.6 degrees to 94.6
      degrees ) and an increase in flexion deformity (1.3 degrees to 2.5 degrees )
      (NS). The worst postoperative ranges of motion were observed at six weeks after
      the procedure. Improvement was then observed up to six months but was not
      significant. There was no improvement in flexion beyond six months after the
      mobilization procedure. The results of the three techniques were not
      significantly different. Failures were however more frequent when manipulation
      under anesthesia was performed more than eight weeks after prosthetic insertion,
      and when arthroscopic release was performed more than six months after prosthetic
      insertion (p<0.01). DISCUSSION AND CONCLUSION: We recommend treatment of stiff
      total knee prosthesis by manipulation under general anesthesis if the procedure
      is performed less than eight weeks after implantation; a delay of six weeks is
      even better because intraoperative complications were observed for patients
      treated between six and eight weeks. Between eight weeks and six months,
      arthroscopic release should be advised, surgical release thereafter. Whatever the
      delay, this protocol is appropriate for stiff knee prostheses without infection
      and without component malposition. Whatever procedure is applied, the definite
      range of motion is reached six months after the intervention.

PMID- 12610434
TI  - [Biodegradable meniscus fixations: a comparative biomechanical study].
AB  - PURPOSE: Numerous new all inside meniscus repair techniques using biodegradable
      fixation devices have become available in the last years. Few studies have dealt
      with the biomechanical properties of these implants so far. The aim of this study
      was to analyze meniscus repairs under cyclic loading conditions for different
      fixation devices (Meniscus Arrow, Clearfix Meniscal Screw, Meniscal Dart,
      BioStinger) and to compare them to standard suture techniques. MATERIAL AND
      METHODS: Eighty meniscus repairs on 27 medial porcine menisci were performed. For
      biomechanical testing loosening, number of failures, failure modes and failure
      loads were evaluated under cyclic and maximum loading conditions. Testing was
      performed on a materials testing machine. RESULTS: During cyclic loading 10 out
      of 40 (25%) fixation devices failed. A gap appeared between the 2 parts of the
      meniscus within the first loading cycles. The failure strengths obtained with the
      4 meniscus fixation devices did not differ significantly (Meniscus Arrow: 44 N;
      Clearfix Meniscal Screw: 35 N; Meniscal Dart: 33 N; BioStinger: 54 N). Besides
      for the BioStinger, the values of the sutures were significantly higher. The use
      of a stronger suture material (PDS 0) increased the failure load significantly.
      During maximum loading the fixation devices failed by both pull-out of the head
      or the tip of the device, except for the BioStinger showing only pull-out of the
      head. All sutures failed by breakage, except for the PDS 0 horizontal sutures in
      which 50% of complete tissue failures could be noted. CONCLUSION: This study
      shows that meniscal fixation devices may fail under repetitive loading
      conditions. A gap appeared between the meniscal margins within the first loading
      cycles irrespective of the suture type and fixation device used. Both gapping and
      failure modes of the fixation devices may be design-specific. The maximum failure
      loads differed significantly between the bioabsorbable devices and the sutures.
      Stronger suture materials increased the failure loads significantly. To allow a
      complete evaluation of new meniscus fixation devices not only biomechanical, but
      also biological and clinical parameters need to be analyzed in forthcoming
      studies.

PMID- 12610435
TI  - [Cellular culture of osteoblasts and fibroblasts on porous calcium-phosphate bone
      substitutes].
AB  - PURPOSE OF THE STUDY: Calcium phosphate ceramics are synthetic bone substitutes
      able to fill in bone destruction as a support of the bone growth. This work
      consisted in an in vitro assessment of osteoblasts and fibroblasts cultures on
      macroporous calcium-phosphate bone substitutes to analyze the interaction between
      cells and bone substitute. MATERIALS AND METHODS: The macroporous ceramic was
      composed of 70% hydroxyapatite and 30% tri-calcium phosphate with known
      mechanical and physico-chemical properties. Three compounds were processed with
      different size of macropore and with or without microporosity on their surface.
      Cells were seeded on discs measuring 10 mm in diameter and 2 mm in thickness.
      Cellular viability was evaluated by the MTT test for every stage of observation.
      An histological study to observe the invasion in the depth of discs was
      performed. Scanning electron microscopy was used to analyze the cellular
      comportment in contact with the surface of substitutes. RESULTS: An exponential
      cellular growth was effective on each substitute with the two cellular types.
      Cells spread on the surface of the compounds covering macropores and colonized
      the depth of the discs. A size of macropore of 300 microm or more seemed to
      support this invasion. 15 microm sized interconnections appeared to be effective
      to allow cell migration between macropores. The cell proliferation was similar on
      substitutes with or without microporosity. CONCLUSION: Biomaterials currently
      used as bone substitute are more or less osteoconductive but they have no
      osteoinductive property. A hybrid association of calcium-phosphate ceramic with
      osteogenic cells should promote the development of a calcium phosphate compound
      with osteoinductive capacity.

PMID- 12610436
TI  - [Contribution of the Gigli saw for ablation of non-loosened surface-treated
      femoral stems inserted without cement: six cases].
AB  - The purpose of this work was to present a technique using the Gigli saw through a
      transfemoral approach in removal of surface-treated femoral implants without
      cement. Results from six cases are reported. For five patients, ablation of the
      implant was achieved easily and rapidly with the Gigli saw, taking a mean nine
      minutes once the cortical window had been achieved. The technique failed in one
      patient. We had one fracture of the cortical window at its removal and one
      transverse shaft fracture in the lower part of the femorotomy related to
      movements of the Gigli saw. A standard length stem was implanted in four of the
      five successful cases. Complete weight bearing was authorized between the 3(rd)
      and 7(th) month. Bony healing of the cortical window was achieved in 4 out of 5
      cases before the end of the first year.

PMID- 12610437
TI  - [Intraspinal rib penetration in four patients in neurofibromatosis vertebral
      deformities].
AB  - We describe the clinical and radiological features observed in four patients with
      neurofibromatosis-related scoliosis or kyphoscoliosis who developed rib
      penetration into the intervertebral foraminae. Rib penetration should be searched
      for on standard and elective x-rays in patients with moderate curvatures. The
      diagnosis can be confirmed by computed tomography or magnetic resonance imaging
      of the spine. In case of major deviation, x-rays must be carefully examined, with
      an accurate search for spinal cord compression to avoid missing the diagnosis.
      Surgical treatment must consist in ablation of the posterior ends of the
      dislocated ribs associated with anterior and posterior fusion. It should be
      performed early to avoid the development of spinal cord compression.

PMID- 12610438
TI  - [Voluntary bilateral dislocation of the hip in children: a case report and review
      of the literature].
AB  - Voluntary bilateral dislocation of the hip was discovered in a three-year-old
      girl. Dislocation was documented by arthrography and computed tomography. After
      failure of a capsuloraphy, successful treatment was achieved with bilateral
      femoral varus oseotomy. Stability has been good after six years follow-up.
      Clinical and radiological signs as well as the underlying causes and treatment
      are discussed in light of this case and fifteen others reported in the
      literature.

PMID- 12610439
TI  - [Spontaneous shoulder dislocation by posterior primary humeral notch: two case
      reports].
AB  - We report two cases of spontaneous anterior dislocation of the shoulder. Although
      the underlying etiology was different, both patients presented a posterior bone
      defect as the causal mechanism. Shoulder dislocation is explained by
      constitutional factors, which should include posterior bone defect.

PMID- 12610440
TI  - [Digital tuberculous revealed by trauma].
AB  - Tuberculous dactylitis is an uncommon condition which is particularly difficult
      to differentiate from other lesions, particularly tumors. Diagnosis must be
      confirmed by histology and/or bacteriology studies. We report the case of a 64
      year-old diabetic woman who consulted for a painful tumefaction on her fourth
      finger of the left hand which had developed after minimal trauma. The x-ray of
      the hand visualized multiple bony defects involving the second phalanx of the
      fourth finger and a fracture. Pathology examination of a biopsy specimen revealed
      granulomatous osteitis with typical caseous necrosis. The clinical signs and
      radiographic images resolved after anti-tuberculosis treatment.

PMID- 12610441
TI  - [Coverage of heel tissue loss by two pediculated flaps in a single procedure].
AB  - We report the case of a traffic accident victim who suffered major tissue loss of
      the heal. We used two pediculated flaps to close the gap in a single procedure.
      The remaining tissue presented zones of necrosis from the plantar aspect to the
      posterior half of the calcaneum, up to the insertion of the calcaneus tendon,
      extending 5 cm on the posterior aspect of the heal. We decided to combine a
      medial plantar flap with a lateral supramalleolar flap. The thick medial plantar
      flap allowed cover of the calcaneum and sensitivity. The calcaneus tendon was
      covered with the lateral supramalleolar flap. The thickness of the flap was
      adapted to match the tissue defect. At six months, the patient had recovered
      walking function with satisfactory weight bearing on the heal. Flap sensitivity
      was satisfactory with no slipping phenomenon.

PMID- 12610442
TI  - [Is there currently a place for euthanasia in the presence of intolerable
      physical pain?].

PMID- 12610443
TI  - [Is sentinel gland biopsy in breast cancer an alternative to axillary
      curettage?].

PMID- 12610444
TI  - [The installation of the National Academy of Medicine in rue Bonaparte in Paris
      101 years ago].

PMID- 12610445
TI  - [NADIS 2000, development of an electronic medical record for patients infected by
      HIV, HBV and HCV].
AB  - OBJECTIVE: to develop an electronic medical record for patients living with HIV,
      HBV or HCV in order to improve their management, facilitate communication between
      all the caregivers, and to create a useful medical database for research and
      assessments. This project (NADIS 2000) involved 6 centres of Infectious Diseases
      in France in partnership with Fedialis Medica (subsidiary of the GSK group in
      France). METHODS: A specifications sheets was drawn-up by a piloting Committee
      regrouping the various correspondents in each centre and a computer expert
      representing Fedialis Medica. A Scientific and Development committee regrouped
      the heads of departments of each centre and the representatives from Fedialis
      Medica and GSK and was charged with defining the general concept of the project
      and guaranteeing the scientific and clinical aspects. RESULTS: NADIS 2000 version
      1.0 was activated in the departments of infectious diseases in Nice and Toulouse
      in November 2000 and in others Units at the end of 2001. NADIS 2000 permitted
      real-time use by the physicians in the Outpatients and Day-care Units and was
      easily handled by all the practitioners. Its use was eased by the principles
      clearly defined before its application (department project, progressive but
      exhaustive use), an intuitive interface simulating a consultation, and functions
      proposing direct benefits for the physicians (graphical visualization of the
      biological variables, printing of prescriptions and letters). CONCLUSION: The
      activation and input methods of NADIS 2000 are user friendly and the physicians
      find it rapidly easy to use. New functional aspects are being developed as well
      as its use in other hospital departments.

PMID- 12610446
TI  - [The French experience with preimplantation genetic diagnosis (PGD)].
AB  - CONTEXT: Context Preimplantation genetic diagnosis (PGD) consists in the genetic
      analysis of one or two embryo cells obtained following embryo biopsy on the third
      day of culture. This diagnostic technique is reserved for couples with an
      identified risk of transmitting a serious and incurable disease and hence avoids
      the distress of having to revert to an abortion. METHOD: Since the publication
      ten years ago of the first preimplantation genetic diagnosis by the team in the
      UK, the number of PGD centres has progressed, but slowly. This is due to the need
      to associate the efforts of an in vitro fertility laboratory and a genetic
      laboratory capable of providing a diagnosis only on one or two embryo cells. This
      technique, controlled by the 1994 bio-ethical laws, first appeared in France in
      the year 2000. RESULTS: The indications, the techniques used and the first 12
      births obtained in the first year of activity in the first two official centres
      in France are reported. In particular, no error in diagnosis following the PGD
      was noted with the systematic blood sample taken from the umbilical cord at
      birth. CONCLUSION: This diagnosis is of interest for couples who present risk of
      genetic transmission. The advantages and inconveniences of this method must be
      weighed against the prenatal diagnosis.

PMID- 12610447
TI  - [Bilateral pneumothorax and tamponade after acupuncture].
AB  - INTRODUCTION: The "target" of acupuncture is usually the muscle, but it
      occasionally approaches other anatomical structures such as the pleura, which may
      subsequently suffer damage. OBSERVATION: During a session of acupuncture, a 25
      year-old woman had a malaise with shock and neurological disorders. The initial
      examinations revealed a bilateral pneumothorax associated with pericardial and
      peritoneal effusions. Symptomatic reanimation combining dopamine, left pleural
      draining and pericardial puncture led to rapid haemodynamic improvement. The
      etiological exploration, having eliminated an underlying pathology, concluded in
      the diagnosis of tamponade and bilateral pneumothorax following a session of
      acupuncture. COMMENTS: Our patient presented the association of two traumatic
      complications of acupuncture: cardiac tamponade due to haemopericardium and
      bilateral pneumothorax. Although these complications are rare, they must be
      known.

PMID- 12610448
TI  - [The interest of radiotherapy in cancer of the rectum].
AB  - CONTEXT: Surgery remains the standard treatment of rectal cancer. The risk of
      local recurrence is still a serious problem with an incidence of between 15 and
      45%. This depends on the initial TNM stage and the surgical technique. In order
      to optimally improve local control and survival of the patients, radiotherapy has
      become an unavoidable adjuvant treatment in specific situations. ISOLATED
      RADIOTHERAPY: For locally advanced cancers (T3 or T4), pre-surgical radiotherapy
      followed by curative surgery is the standard treatment because of the improvement
      in global survival and good local control that has recently been confirmed. With
      radiotherapy it is also possible to schedule conservative sphincter surgery in
      the case of low rectal lesions and permit surgery of initially inoperable
      lesions. THE CONCOMITANT ASSOCIATION OF RADIOTHERAPY AND CHEMOTHERAPY DURING THE
      PRE-SURGICAL PERIOD: In rare cases in which the tumour stage was underestimated
      in the pre-surgical controls, post-surgical concomitant radio-chemotherapy is
      required. In cases in which surgery was performed first line, in the presence of
      histological factors of poor prognosis, post-surgical radio-chemotherapy is
      warranted. In the United States, the reference chemotherapy used in this
      association is 5 FU in continuous intravenous infusion. In the rare cases of
      contraindication for surgery, exclusive concomitant radio-chemotherapy is an
      appropriate solution, even if no treatment has been validated in this indication.
      Palliative surgery can be proposed in supplement: usually a colostomy or, more
      rarely excision using the endorectal route. MEDICAL TREATMENT: Exclusive radio
      chemotherapy has only demonstrated interest in the palliative treatment of
      inoperable loco-regional relapses that have already undergone radiation or in
      metastatic stages as in colon cancers. Currently post-surgical chemotherapy is
      recommended in stage III cancer of the rectum as in colon cancers at the same
      stage.

PMID- 12610449
TI  - [Measures to be taken in adults with bronchiolitis].
AB  - The majority of bronchial and interstitial diseases of the adult are accompanied
      by bronchiolar inflammation, but over time the use of the term "bronchiolitis"
      has been limited to a few specific affections. Bronchiolitis with predominantly
      alveolar involvement Some "bronchiolites" emphasize the problem of an
      interstitial pneumopathy, since the disease predominantly involves the alveolar
      spaces. Only a few bronchiolites are severely damaging: bronchiolitis obliterans
      with organizing pneumonia and interstitial pneumopathy with respiratory
      bronchiolitis. These predominantly alveolar affections reveal the clinical
      (crepitant rales), radiographic (multiple or even diffuse opacities), and
      functional aspects (restrictive ventilation problems). Brochiolitis with
      obstructive airway problems In this case the disease predominantly involves the
      bronchioles and spares the alveolar tissue. The term "bronchiolitis" is in this
      case perfectly justified. The clinical picture is evocative with obstructed
      airway and a clear pulmonary parenchyma on the thoracic x-ray. These affections
      belong to the obstructive broncho-pneumopathy group. The prototype is
      brochiolitis obliterans, the anatomic correlation of which is generally
      constrictive bronchiolitis obliterans. Occasionally primitive, it frequently
      complicates the progression of many morbid states (transplants, collagenosis,
      inhaled or ingested toxic substances.). Diffuse panbronchiolitis Other
      "bronchiolites" deviate from this framework and are accompanied by marked lesions
      of other respiratory tracts (membrane bronchioles, cartilage bronchi, mucosa, ear
      nose and throat). The prototype is panbronchiolitis, described in the Far East.
      It is exceptional in Europe, where similar but nosologically different clinical
      aspects are observed during various diseases: cystic fibrosis, Young's syndrome,
      hypogammaglobulinemia, bone marrow transplant, context of HIV or haemorrhagic
      recto-colitis.

PMID- 12610450
TI  - [Gluten-induced ataxia].

PMID- 12610451
TI  - [Medicine must continue to be considered as an art and not a science. Interview
      with Louis Hollender by Marie Solignac].

PMID- 12610452
TI  - [Acute renal failure following ingestion of Cortinarius orellanus in 12 patients.
      Initial presentation and progress over a period of 13 years].
AB  - INTRODUCTION: This study reports the largest series of acute renal failure
      following collective poisoning by Cortinarius orellanus since 1957. PATIENTS:
      Twelve men, in whom altered renal function appeared following ingestion of
      mushroom soup (Cortinarius orellanus) when they were 20 to 23 year-old, were
      followed up for 13 years. RESULTS: After a period of latency of between 2 to 5
      days, the patients complained of asthenia, intense thirst and digestive and
      neurological disorders. On admission, 4 were anuretic and two exhibited polyuria.
      Leukocyturia was detected in all patients but without proteinuria. Renal biopsy
      was performed on day 14 in seven patients. It revealed severe tubulo-interstitial
      lesions with polymorphous cell infiltration, oedema, loose fibrosis and
      epithelial necrosis. Eight patients required haemodialysis. Nine patients
      received corticosteroids for less than 6 months. Over a follow-up period of 13
      years, seven patients recovered normal renal function, four underwent
      transplantation and one was still under haemodialysis and died, victim of a car
      accident. CONCLUSION: The incidence of acute renal failure varies from 30 to 46%.
      It depends on individual sensitivity, pre-existing nephropathy and the cumulated
      dose of toxin ingested. Early and severe interstitial fibrosis, marked
      interstitial oedema and tubular epithelial necrosis are the most characteristics
      renal lesions. Renal failure regresses progressively over several months in 60%
      of cases. In the other patients, terminal renal failure appears immediately or
      after several years. The evolution is not influenced by corticosteroid therapy.

PMID- 12610453
TI  - [The major trends of the French accreditation process. A review of the first 182
      reports published].
AB  - OBJECTIVES: To reply to the following questions: what is the status of the
      accreditation process and what are the general trends pointed out by the experts
      visitors ? METHODS: A study was conducted on the 182 accreditation reports
      regarding health centres, published by the Anaes from June 2000 to July 2002. A
      reading scale was developed and data was registered in the database. Statistical
      analysis first described the hospitals (legal status, location, size, number of
      sites, presence or lack of technical devices, emergency units, and consultations)
      and then matched them with the specific parameters of the accreditation process
      (date of involvement, date of audit, date of the accreditation deliberation,
      number of experts and visitors and number and type of decisions. RESULTS: The
      results underlined the most frequent decisions among the 10 referentials of the
      accreditation process. The patients' case reports and the management of quality
      and prevention predominated. Recent French laws and the decision of the Anaes to
      apply these themes in their strategic orientation can explain this. COMMENTS: The
      large hospital size and multi-sites organisation appeared to be negative elements
      and justify the apprehension felt by the 'major hospitals'.

PMID- 12610454
TI  - [Acute haemorrhagic pericarditis following influenza vaccination].
AB  - INTRODUCTION: Pericarditis following influenza vaccination is a rare
      complication. The few cases reported in the literature were all benign.
      OBSERVATION: An 87 year-old man developed a haemorrhagic pericarditis following
      an influenza vaccination. The outcome was rapidly favourable after surgical
      pericardiectomy followed by treatment with colchicine. In the absence of
      etiology, the hypothesis of post-vaccination pericarditis was proposed. COMMENTS:
      Despite its low incidence, the hypothesis of post-vaccination pericarditis must
      be evoked. Diagnosis therefore relies on various arguments. Although usually
      benign, medical and surgical treatments were required in our patient.

PMID- 12610455
TI  - [Homocysteine and alcohol consumption. An ambiguous relationship and a new
      paradox].
AB  - HOMOCYSTEINEMIA AND ITS VARIATIONS: The increase in plasma concentrations of
      homocysteine (Hcy) is a factor of cardiovascular risk. Its determinants are
      multifactorial, genetic and environmental. Out of the ingestion of dietary
      supplements containing vitamin B6, folates and B12, other substances such as
      coffee or alcohol contribute in the increase in Hcy. THE EFFECTS OF ALCOHOL: The
      alcohol-Hcy interaction is complex and ambiguous. Although chronic alcoholism
      clearly increases Hcy concentration, the effects of moderate and regular
      consumption of alcohol are debated in epidemiological studies. Following
      adjustment of various parameters, it is now admitted that alcohol moderately
      increases Hcy levels. This is paradoxical since the coronary protective effects
      of alcoholic beverages has been well established. THE PARTICULAR CASE OF BEER:
      However, a negative correlation between Hcy and alcoholic beverages has been
      described in some studies, more especially in beer-drinkers. The hypothesis of a
      reduction in Hcy induced by the beer contents has been described in an
      interventional study. The vitamins contained in beer, particularly B6, may well
      be at the origin of this beneficial effect.

PMID- 12610456
TI  - [The problems in France created by the HIV/AIDS epidemic at the onset of the
      third millenium].
AB  - UNANSWERED QUESTIONS: The HIV/AIDS epidemic represented a medical, social and
      political challenge to our society. It raises numerous questions, to which some
      replies have been partially proposed. In the context of less attention paid to
      AIDS, the epidemic continues to create problems in France and has led to the
      debates on medical and sanitary questions and other political, social and
      economical issues. FROM A THERAPEUTIC POINT OF VIEW: Among the issues concerning
      health management, those related to treatment are first-line: progress in
      therapeutic indications, choice of antiretroviral molecules and their
      combinations, particular aspects of treatments delivered in certain circumstances
      (pregnant women or primary-infection), difficulties in the assessment of the
      benefit/risk progress. The problems of compliance that occasionally induce severe
      side effects, provoke therapeutic failure in some patients and for whom rapid
      access to new antiretroviral molecules and new therapeutic strategies is
      mandated. THE CROSS-LINK WITH POLITICAL, SOCIAL AND ECONOMIC PROBLEMS: The
      resulting debates partly depend on the progress made in therapeutics. The latter
      have led to expectations of HIV-infected patients, who would like to benefit
      fully from the promise of a return to normal life (access to insurance and
      medically-assisted procreation). HIV/AIDS has led to new ethical debates on the
      rights of patients, such as those related to screening, clinical research or
      confidential access of under-aged patients to treatment. Some of these aspects
      involve political decisions: prevention measures to be taken against the
      possibility of a new epidemic, the risks and damages related to the use of drugs
      and the guarantee of access to treatment of patients living in under-developed
      countries.

PMID- 12610457
TI  - [Positron emission tomography in clinical oncology].
AB  - A NEW FORM OF MEDICAL IMAGING: Positron emission tomography (PET) is used for the
      non-invasive in vivo visualisation of biochemical cell processes. It reveals the
      metabolic characteristics of neoplastic lesions and hence their identification by
      compensating the lack of lesion specificity of radiological techniques. VARIOUS
      INDICATIONS: Using the current oncology marker, 18F-fluorodeoxyglucose (FDG),
      excellent results with PET have been established at all stages of neoplasia,
      notably for the diagnosis of initial malignancy and the identification of
      residual lesions and early detection of relapses. Moreover, the fact that the
      whole of the body can be explored makes PET the tool of choice in the control of
      the extension and operability of cancers. With the close correlation between
      imaging and the metabolism of the lesions, PET is the earliest and most precise
      for assessing the effects of treatment. LIMITS AND PERSPECTIVES: The existence of
      benign inflammatory FDG binding should lead to the development of markers of
      other metabolisms directly linked to cell proliferation. The lack of anatomical
      reference points characteristic of PET does not permit the precise localisation
      of the lesions detected and could be corrected by combining, in a single
      apparatus, the PET camera and an X scan, the anatomical resolution of which is
      irreplaceable. This type of equipment represents the development of a new branch
      of medical imaging, oncological imaging.

PMID- 12610458
TI  - [Violence within the family].

PMID- 12610459
TI  - [Factors associated with organ and tissue donation refusal. Prospective study in
      the West of France].
AB  - OBJECTIVE: The refusal to permit organ sampling is of around 30% and is one of
      the principle causes for the lack of sampling. This study was aimed at
      establishing the frequency of decisions taken with regard to donations and the
      factors associated with refusal. METHOD: A prospective study was conducted
      between April 2, 2000 and March 31, 2001 in hospitals authorised to perform organ
      sampling in the Western area of France. For each potential donor identified, a
      questionnaire was filled in after each interview. A logistical model was used in
      order to identify the independent and statistical factors associated with the
      refusal to allow sampling of an organ or tissue. RESULTS: Among the potentials
      donors, 265 brain dead donors, and 868 donors with ceased heart beats for tissue
      sampling, were included. The refusal rate was of respectively 32.8 and 45 %. Only
      2.4% of potential donors carried cards identifying them as such. While living,
      the rate of refusal expressed by the two types of potential donors was similar
      (9%). The brain dead potential donors had more frequently expressed their consent
      for donation (20.7 vs. 9%). In the organ donors, the interviews were conducted by
      two persons in only 37.9% of cases, and in 2.4% of cases of potential tissue
      donors. In the potential organ donors, only those with a card identifying them as
      such and the hesitations of the family at the start of the interview were
      significantly associated with a lesser frequency of refusal. In potential tissue
      donors, the hesitations of the family reduced the refusal rate but age, religious
      beliefs, death etiology and the person conducting the interview increased it.
      CONCLUSION: The encouraging efforts made for the awareness of donation during a
      person's lifetime must continue and the use of a donor card extended. The
      development of co-ordination posters in the hospitals would enhance the
      development of binomial interviews with the families.

PMID- 12610460
TI  - [Patients hospitalized in advanced or terminal phase of a serious life
      threatening disease].
AB  - OBJECTIVE: The end-point of this survey was to evaluate the number of patients in
      advanced or terminal phase of a life-threatening disease and hospitalised in the
      university hospital in Grenoble on a given day. The secondary end-points were
      determination of the profile of patients undergoing palliative care and the
      therapeutic charge they represented for the hospital in order to develop optimal
      medico-psycho-social responses adapted to the needs of this population, their
      family and friends and the teams of health professionals who treat them. METHODS:
      The survey was based on a questionnaire including 106 items and one open
      question, filled-in by a physician and the nurses of the hospital, together with
      the interviewer. RESULTS: Out of the 1495 patients hospitalised in the hospital
      centre (84% occupation), 114 patients were included in the study, i.e., 8% of the
      total number of patients present. Patients' mean age was of 70 (21<x<98); 40%
      were aged over 75. The principle motivation for hospitalisation was an acute
      medical problem (54%) followed by the impossibility of remaining at home (42%);
      32% of the patients were hospitalised for a scheduled follow-up or treatment. The
      pathologies most frequently observed were cancer (61%) and neuro-degenerative
      disorders (28%). In our study, this category of patient exhibited a complex and
      heavy medico-psycho-social profile. It also revealed, when compared with a
      similar study conducted in 1996 at the Pitie-Salpetriere hospital, that the
      identification of an advanced or terminal phase of a disease was generally late
      and probably prohibited the patients, their families and the nursing staff from
      access to specific accompaniment. COMMENTS: Our results demonstrate the need for
      palliative care unit (with beds) in large establishments such as the university
      hospital in Grenoble, in the centre of large towns. Although not all terminally
      ill patients require a specialised palliative care unit, we feel that the
      creation of such units will be mandatory in the years to come, if only because of
      public pressure or necessity.

PMID- 12610461
TI  - [Frequency of anaemia and indications for treatment with epoetin in chronic renal
      failure at the pre-dialysis stage].
AB  - OBJECTIVES: To determine the degree of anaemia corresponding to the decreasing
      levels of renal function in patients with chronic renal failure (CRF) and not yet
      on dialysis, and to assess the indications for treatment with recombinant
      erythropoeitin (epoetin). METHODS: We studied the relationship between
      haemoglobin (Hb) concentration and creatinine clearance (Ccr) in 403 consecutive
      patients with CRF regularly monitored in nephrology consultations between January
      1 and June 30, 1999, and who received appropriate iron and vitamin
      supplementation. These patients were then followed-up until June 30, 2000 or
      until maintenance dialysis was initiated. RESULTS: There was a significant and
      close correlation between the degree of anaemia and renal dysfunction. An Hb
      value<11 g/dl (corresponding to the present threshold for the indication of
      epoetin) was observed in 62% of patients with creatinine levels>400 micromol/l
      and in 58% when Ccr was<20 ml/mn/1.73 m2. Whatever the level of CRF, the degree
      of anaemia was higher in the women than in the men. Among the 123 patients who
      had to start maintenance dialysis during the observation period, 85 (69%) were
      treated with epoetin before dialysis was started. CONCLUSION: In patients with
      CRF, clinically symptomatic anaemia is more frequent than imagined, and early
      treatment is required. Regular monitoring of Hb and iron levels is mandatory in
      order to allow patients to benefit from timely initiation of epoetin and thus
      prevent the development of disabling asthenia and other deleterious consequences
      of anaemia.

PMID- 12610463
TI  - [Benign granular cell anal tumor].
AB  - INTRODUCTION: Granular cell tumors (GCT) are rarely located in the perianal area.
      OBSERVATION: Over the past 3 years, a 56 year-old man presented a papule of the
      right margin of the anus that had progressively increased in size (1.5 cm). Cell
      proliferation was located in the dermis and strongly expressed the S100 protein.
      It was covered by a pseudo-epitheliomatous hyperplasia of the overlying
      epidermis. Forty months after local surgical excision, there was no sign of
      recurrence. COMMENTS: Granular cell tumors are rare and usually benign. When
      cutaneous or mucosal, the pseudo-epitheliomatous hyperplasia of the overlying
      epithelium may, on superficial samples, be mistakenly diagnosed as squamous cell
      carcinomas. Malignant GCT may, histologically, appear identical to a benign GCT
      and only the appearance of metastases (generally after local recurrence) permits
      the subsequent diagnosis of malignancy.

PMID- 12610462
TI  - [Staphylococcus aureus meningitis with intermediate sensitivity to glycopeptides.
      Therapeutic indications].
AB  - INTRODUCTION: Since 1997, several observations of glycopeptide intermediate
      Staphylococcus aureus (GISA) infections have been described. We report the case
      of meningitis. OBSERVATION: A 46 year-old man was treated surgically on several
      occasions for a meningioma of the back cranial fossa. Intracranial hypertension
      required the placing of a cerebrospinal leading-catheter. He developed a GISA
      meningitis. Antibiotics and removal of the catheter cured the infection.
      DISCUSSION: To our knowledge, this is the first observation of GISA meningitis.
      Such infections are rare and are probably underestimated due to the lack of
      standardized detection methods. They occur in fragile, surgical, immunodeficient
      patients, often living with prostheses. Prior treatment with vancomycine is often
      reported. The emergence of these infections is a serious therapeutic problem,
      since vancomycine is a major antibiotic used in the treatment of meticillin
      resistant S. aureus (MRSA) infections.

PMID- 12610464
TI  - [Upper gastrointestinal hemorrhage, a topical subject].

PMID- 12610465
TI  - [The aims of endoscopy in upper gastrointestinal hemorrhage].
AB  - FOR DIAGNOSIS AND FOR TREATMENT: Endoscopy for upper gastrointestinal haemorrhage
      has a double objective. It is difficult and to be optimal, it must be conducted
      at the right time and in the best technical conditions as possible. Depending on
      the etiology, identification of the cause of bleeding precedes the choice of the
      haemostatic method to be used, preferentially injections of adrenaline in the
      case of bleeding ulcers and elastic ligature in the case of ruptured oesophageal
      varicose veins. In general the aim of endoscopic treatment is to stop the
      haemorrhage and to reduce as far as possible the risk of recurrent haemorrhage,
      which represents a factor of high deathrate.

PMID- 12610466
TI  - [The place of endoscopic treatment in hemorrhagic ulcers].
AB  - INJECTIONS OF ADRENALINE: More than one third of upper gastrointestinal
      haemorrhages are still of ulcerous origin. In the case of active bleeding ulcers
      or ulcers with non-haemorrhagic visible vessels, endoscopy should be performed to
      stop bleeding. Injections of adrenaline, which combine efficacy, simplicity and
      absence of morbidity represent the treatment of choice for many. THE USE OF
      THERMAL METHODS: Spurting haemorrhages are probably the only haemorrhages that
      would benefit from injections of adrenaline combined with another haemostatic
      method, notably thermal. THE NEED FOR ASSOCIATED MEDICAL TREATMENT: Whatever the
      haemostatic method used, a powerful anti-secretory treatment administered
      intravenously must be associated since it will enhance the effects of endoscopic
      treatment.

PMID- 12610467
TI  - [The place of endoscopic treatment in portal hypertension].
AB  - A POTENTIALLY SEVERE EVENT: Upper gastrointestinal haemorrhage in a cirrhotic
      patient is always extremely serious, particularly in the case of rupture of the
      oesophageal varices, which is the most frequent cause. THE TWO POLES OF
      TREATMENT: Early vasoactive treatment permits elastic ligature in optimal
      conditions using an endoscope. The prevention of other complications of cirrhosis
      is an essential element in the management of these patients.

PMID- 12610468
TI  - [The place of endoscopic treatment in other causes of upper gastrointestinal
      haemorrhage].
AB  - IN MALLORY-WEISS SYNDROME: With fissuring of the cardial area, probably
      subsequent to a rapid increase in intra-gastric pressure, hemorrhagic Mallory
      Weiss syndrome may justify haemostatic endoscopic treatment. However, one should
      not forget that the majority of these syndromes usually regress spontaneously. IN
      DIEULAFOY'S ULCERS: Loss of substance destroying the muscle mucosa, Dieulafoy's
      ulcer would be at the origin of around 2% of upper gastrointestinal haemorrhages.
      Initial haemostasis can be obtained using endoscopic treatment in 85% of cases.
      The mechanical methods (clips, elastic ligature) are probably more effective than
      injections, but they are still under assessment.

PMID- 12610469
TI  - [Phase I clinical trials in oncology: a moral dilemma for the investigators].

PMID- 12610470
TI  - [An overview on palliative care and the end of life. Results of a survey
      conducted in a sample of the French population].
AB  - OBJECTIVE: To have an overview of the French population concerning palliative
      care. METHOD: French opinion poll, based on a questionnaire submitted to 302
      persons recruited at random in the street, in several regions of France. It
      included questions concerning the representation of pain, the sick body, death,
      the end of life and palliative care. RESULTS: Regarding the management of pain,
      the majority of persons surveyed (59.6%) felt that the general practitioner was
      the appropriate referent to treat pain. The population's experience with regard
      to the death of a close relative revealed that death had occurred in hospital in
      58.3% of cases. Nevertheless, the majority (57%) of the population wished to die
      in their own home. The concept of palliative care centres is increasing in the
      public's mind, but remains vague in its practical aspects for 60.9% of the
      population surveyed. For 29.5% of the population surveyed, information and
      training of health professionals in palliative care was considered as a priority.
      CONCLUSION: The end of life and death is a source of fear for most of the
      population. This motivates a transfer towards the medical corps for the
      professional and technical management of this period of life, and the health
      professionals must be prepared to respond appropriately to this specific demand.

PMID- 12610471
TI  - [Association between the A2 allele of the HLA system and age at onset of
      Alzheimer's disease].
AB  - OBJECTIVE: Alzheimer is a multifactor disease occurring in a sensitive genetic
      territory. The e4 allele of the apolipoprotein E (APO E) is a recognised factor
      of risk. Some studies have suggested an association between the A2 allele of the
      HLA system and an earlier onset of the disease notably when it appears before the
      age of 64 or after the age of 75. The aim of our study was to explore this
      hypothesis in an independent sample of patients. METHODS: We compared the
      influence of the A2 allele of the HLA system on the age at onset of the disease
      in two groups of Caucasian patients presenting with Alzheimer's disease: early
      onset if the disease appeared before the age of 60 (n= 31) and late onset if it
      had appeared after the age of 75 (n= 44). The influence of the e4 allele of APO E
      was also taken into account. RESULTS: The comparison of the patients depending on
      the presence or not of at least one HLA-A2 allele revealed no significant
      difference, whatever the group of patients studied, in the age at onset of the
      disease. CONCLUSION: The age at onset of Alzheimer's disease was not influenced
      in our study by the presence of the HLA-A2 allele.

PMID- 12610472
TI  - [Progressive multifocal leukoencephalitis complicating polymyositis].
AB  - INTRODUCTION: Progressive multifocal leukoencephalitis (PML) must be evoked in
      patients presenting with a systemic disease during which multiple neurological
      deficiencies rapidly worsen. OBSERVATION: A 17 year-old girl suffering from
      histologically confirmed polymyositis was treated with corticosteroids. Two years
      after the diagnosis she exhibited global signs of cerebral damage with fever and
      magnetic resonance imaging evoked leukoencephalitis. COMMENTS: An affection of
      the central nervous system, PML is characterised by the existence of multiple
      areas of demyelination in the hemispheric white substance of the cerebral trunk
      and sometimes the cerebellum, whereas the grey substance is usually spared. This
      entity occurs more frequently in HIV-infected patients, but also in patients in
      whom the immunodeficiency may have other causes, such as the treatment for a
      systemic disease for example.

PMID- 12610473
TI  - [Anthrax in the era of biowarfare].
AB  - THE CONDITIONS OF INFECTION: Anthrax is a zoonosis due to Bacillus anthracis.
      Human contamination usually results from contact with an infected animal or
      product, or direct exposure to the bacteria. The latter represents one of the
      principle agents that can be used in biowarfare by spraying the spores. VARIOUS
      POSSIBILITIES: The inhaled form of the disease, characterised by hemorrhagic
      necrosis of the mediastinum adenopathies and septic shock, is the form that would
      probably be observed during a terrorist attack. The cutaneous and digestive forms
      are also possible. EVOLUTION: The clinical diagnosis, easy in the cutaneous form,
      is difficult in the other, rapidly progressive forms. Many guidelines have been
      published with recommendations for the treatment and prophylaxis of anthrax.
      Prognosis remains poor in the systemic form of the disease.

PMID- 12610474
TI  - [Cervical smears: towards an optimal screening for cervical cancer].
AB  - THE INTEREST OF CERVICO-UTERINE CYTOLOGY: Cytology is the most appropriate means
      of screening for cancers and pre-cancerous states of the cervix. It permits the
      prevention of invasive cancers by identifying the precursor lesions, which exist
      more than 10 years before the invasion, and their effective excision or
      destruction. The absence of screening represents the greatest risk factor for
      invasive cancer and explains its higher frequency in developing countries. The
      Bethesda system is a language shared by cytologists and clinicians for spotting
      situations at risk Histology is essential before any therapeutic decision. It is
      provided by biopsies during colposcopy or by diagnostic coning in ambiguous
      situations. The cytological diagnosis of a low grade lesion and atypia of
      undetermined significance sometimes corresponds, histologically, to a high grade
      lesion. ENHANCING THE RESULTS OF SCREENING: The invasive cervical cancers still
      observed in France can be attributed to the lack of screening, lack of management
      and cytological false negatives. Conditions for optimising screening are wide
      coverage of women, good quality smears, competent cytologists and the appropriate
      follow-up of abnormal smears.

PMID- 12610475
TI  - [B-type natriuretic peptide for the diagnostic and prognostic assessment in
      cardiology. Its interest and perspectives of application].
AB  - A HORMONE REVEALING VENTRICULAR DYSFUNCTION: B-type natriuretic peptide or Brain
      natriuretic peptide (BNP) is a neurohormone secreted by the ventricular myocytes
      in response to volume expansion and pressure overload. It is a sensitive marker
      of ventricular dysfunction in symptomatic and asymptomatic patients, and its
      dosage is correlated with the severity of the dysfunction. INDICATION FOR ITS
      DOSAGE IN HEART FAILURE: Since the results of recent studies, many authors
      recommend its routine use in heart failure, in order to confirm the diagnosis in
      difficult cases, assess severity, prognosis and the efficacy of treatment. Such
      use requires that the results of these studies be known and that the threshold
      value be adapted according to the age, concomitant diseases and indication of the
      dosage. OTHER AFFECTIONS: Its diagnostic and prognostic interest in acute
      coronary syndromes and hypertension is presently being studied.

PMID- 12610476
TI  - [Acute streptococcal sore throats in children, state of the present situation.
      Interview with Pr. E Bingen by Marie Solignac].

PMID- 12610477
TI  - Pectoralis major transfer for anterior-superior subluxation in massive rotator
      cuff insufficiency.
AB  - The purpose of this study was to evaluate the outcome after subcoracoid
      pectoralis major transfer for anterior-superior shoulder instability in massive
      rotator cuff insufficiency. Fourteen patients underwent subcoracoid pectoralis
      major transfer for this debilitating surgical complication. At a mean 17.5-month
      follow-up, there were 11 satisfactory and 3 unsatisfactory results. Nine of the
      patients were satisfied with the procedure and would repeat the operation under
      similar circumstances. Pain scores, as measured on a visual analog scale,
      decreased from 6.9 to 3.2 postoperatively. Mean forward flexion increased from
      24.4 degrees to 60.8 degrees. American Shoulder and Elbow Society functional
      outcome score increased from 27.2 preoperatively to 47.7 postoperatively.
      Thirteen of the fourteen patients had improved humeral head containment and
      improved ability to perform activities of daily living at waist level. A
      subcoracoid pectoralis major muscle transfer has a low complication rate and is a
      viable option in this difficult patient population, with better results than
      those previously reported.

PMID- 12610478
TI  - Relationship between os acromiale and acromioclavicular joint anatomic position.
AB  - Most of the orthopaedic literature on os acromiale is focused on the clinical
      implications, such as impingement and rotator cuff tears; although os acromiale
      is present in 8% of subjects, scarce information is reported on the causes that
      may predispose patients to it. Our aim is to investigate whether the origin of os
      acromiale is related to the position of the acromioclavicular (AC) joint. The
      acromions of 211 volunteers (control group) and 33 subjects without or with os
      acromiale were radiographically (axillary view) classified by the Edelson and
      Taitz method. The method distinguishes the acromion into three types on the basis
      of the distance between the anterior aspect of the acromion and the AC joint. Of
      33 subjects with os acromiale, 11 were without pain. We have compared the
      frequency of the three types of acromion observed in the two investigated
      cohorts. Half of the acromions of the control group (52.1%) had the articular
      facet of the AC joint on the acromion tip, whereas in 45.4% the facet tip was
      located distally. On the other hand, of 33 subjects with os acromiale, 18.1% and
      81.1%, respectively, had the AC joint lying on or distal to the acromion tip. Our
      data suggest that the greater the distance of the AC joint from the anterior edge
      of the acromion, the higher the likelihood of an os acromiale.

PMID- 12610479
TI  - Open anterior acromioplasty with preservation of the coracoacromial ligament: A
      modified surgical technique.
AB  - The importance of the preservation of the subacromial arch has been stressed
      recently, especially in irreparable lesions of the rotator cuff to prevent
      anterosuperior migration of the humeral head. The purpose of this article is to
      describe the surgical technique of a modified open anterior acromioplasty
      performed through an intra-acromial osteotomy that increases the subacromial
      space and preserves the insertion of the coracoacromial ligament on the
      undersurface of the acromion. To compare this new technique with classical
      acromioplasty, a prospective but nonrandomized study was performed including 20
      patients undergoing open anterior acromioplasty and 22 patients undergoing a
      modified open anterior acromioplasty. At a mean follow-up of 18 months, no
      differences related to shoulder function as evaluated by the Constant score were
      found between these two groups. This modified acromioplasty increases the
      subacromial space, preserving the anatomy of the subacromial arch, and provides
      functional results as good as those obtained with classical open acromioplasty.

PMID- 12610480
TI  - Long-term clinical and radiologic results after Eden-Hybbinette operation for
      anterior instability of the shoulder.
AB  - A retrospective study was done to assess long-term results after surgery with the
      Eden-Hybbinette technique for unidirectional anterior glenohumeral instability.
      Between 1962 and 1976, 118 patients (119 shoulders) were treated. Eighty-seven
      patients answered a questionnaire. Of 119 shoulders, 77 were examined clinically
      and 74 radiographically a mean of 29 years after surgery. Forty-two were lost to
      follow-up. For 74% of shoulders, patients were satisfied, and for 26%, patients
      had some remaining discomfort. The most common reason for discomfort was
      persistent instability. The recurrence rate was 20%, although only 8 patients
      required reoperation. The mean time from surgery until redislocation was 15
      months (range, 1-60 months). The mean Rowe shoulder score was 84 +/- 15 (range,
      45-100), with 48 of 77 shoulders rated as excellent, 16 of 77 as good, 9 of 77 as
      fair, and 4 of 77 as poor. The Constant-Murley score averaged 85 +/- 14 (range,
      20-100). Glenohumeral arthrosis was seen in 35 of 74 shoulders (47%). There was
      no significant difference between those with arthrosis and those without as far
      as age at first dislocation, age at surgery, or follow-up. Shoulders with
      arthrosis had a tendency to have reduced external rotation (P =.056) when
      compared with shoulders without radiologic changes. This study showed that most
      patients were satisfied with their shoulders. There was a high rate of radiologic
      arthrosis, but in most patients it caused limited restriction of movement as the
      only symptom.

PMID- 12610482
TI  - Simple, minimally invasive surgical technique for treatment of type 2 fractures
      of the distal clavicle.
AB  - Neer type 2 fractures of the distal clavicle have a high rate of nonunion and
      delayed union. A simple, minimally invasive surgical technique using suture
      fixation is introduced. In this series 12 patients were treated with suture
      fixation of this fracture with absorbable suture material, resulting in union of
      all fractures. There was a rapid return to function and no complications. This
      technique allows simple, minimally invasive fixation with good fracture healing
      and early return to work and sports.

PMID- 12610481
TI  - Glenohumeral articular cartilage changes in rotator cuff disease.
AB  - This study aims to clarify the natural history of glenohumeral articular
      cartilage changes in rotator cuff disease. We assessed 33 cadaveric shoulder
      joints, examining the rotator cuffs for macroscopic tears and the articular
      surfaces for degenerative changes. Ten specimens had tears of the rotator cuff.
      Articular degenerative changes were noted in 23 joints. Articular cartilage
      degeneration was almost twice as frequent in the group with rotator cuff tears
      (10/10 shoulders) as in those without tears (13/23 shoulders). This difference
      was statistically significant. This strong correlation between tears of the
      rotator cuff and articular degeneration has not been documented previously, other
      than in the extreme situation of massive cuff tears and cuff-tear arthropathy.
      This is deserving of further study because it may have implications for surgical
      management.

PMID- 12610483
TI  - Loss of subscapularis function after total shoulder replacement: A seldom
      recognized problem.
AB  - Little attention has focused on subscapularis integrity after total shoulder
      replacement (TSR). We have noted that several patients have loss of internal
      rotation and subscapularis function on follow-up, leading to our review of
      success in restoring subscapularis function after TSR. A retrospective review was
      done of the records of 41 patients after TSR performed between 1995 and 2000.
      Mean follow-up was 1.9 years. Terminal internal rotation was evaluated by the
      lift-off and belly-press examinations. Subscapularis function was assessed by the
      patients' ability to tuck in a shirt. The subscapularis was repaired anatomically
      in 9 cases and through bone tunnels in 32 patients. Abnormal results were found
      for 25 of 37 lift-off examinations (67.5%) and 24 of 36 belly-press examinations
      (66.6%). Of 25 patients with an abnormal lift-off finding, 92% reported reduced
      subscapularis function (Fisher exact test, P <.01). Despite meticulous attention
      to subscapularis repair, suboptimal return of function was found on clinical
      examination and assessment of activities of daily living.

PMID- 12610484
TI  - Stress shielding and bone resorption in shoulder arthroplasty.
AB  - The radiographs of 64 patients with 70 humeral head replacements were reviewed
      for signs of stress shielding. Of these, 49 were implanted for rheumatoid
      arthritis and 21 for osteoarthritis. The radiographic follow-up averaged 5.3
      years. Measurements of cortex thickness were performed in 4 regions along the
      stem of the implant, and the differences between the postoperative radiograph and
      the radiograph at follow-up were calculated. The size of the stem in relation to
      the diameter of the humerus was calculated with the use of validated measures,
      resulting in the relative stem size. In 6 patients (9%) a significant reduction
      in cortical thickness was observed in the proximal-lateral region of the humeral
      stem, 5 in rheumatoid patients and 1 in an osteoarthritic patient. In the stress
      shielding group, the relative stem size was found to be significantly higher than
      that in the non-stress shielding group (0.58 vs 0.48). Osteoporosis, especially
      present in rheumatoid arthritis, could well be a risk factor. It was concluded
      that stress shielding is a long-term complication of shoulder arthroplasty and
      that the relative stem size is an important factor in its genesis.

PMID- 12610485
TI  - Age-related changes of the glenoid labrum in normal shoulders.
AB  - A growing number of labral changes are described in the literature. The purpose
      of this study was to evaluate the glenoid and labrum of normal shoulders at
      different ages and characterize any apparent age-dependent changes. We analyzed
      32 normal cadaveric shoulders with a mean age of 57 years (range, 18-89 years).
      There were 22 male and 10 female cadavers, with 14 right and 18 left specimens.
      The shoulders were studied macroscopically, histologically, and radiologically.
      The radiologic evaluation consisted of an analysis of the subchondral
      mineralization of the glenoid with the use of computed tomographic
      osteoabsorptiometry. Macroscopically, there were no statistically significant
      differences among the age groups. Histopathologically, the labrum showed a
      significant qualitative and quantitative increase (P <.01) in lesions across all
      regions with increasing age. In younger individuals, lesions at the 12-o'clock
      position were the most prevalent, with the incidence increasing with age. The
      anterosuperior position was the region with the next highest prevalence. This was
      also the area of the highest stress distribution on the glenoid. Our studies
      demonstrated clear histopathologic changes of the glenoid labrum that are
      significantly age-related at specific sites. The earliest changes are seen close
      to the area of highest stress distribution of the glenoid, which could explain
      the progressive labral changes with increasing age. Arthroscopically detected
      changes of the glenoid labrum should be evaluated in the context of age-related
      changes in normal shoulders.

PMID- 12610486
TI  - The anteroinferior labrum helps center the humeral head on the glenoid.
AB  - Previous work suggests that the labrum helps center the humeral head. We
      hypothesized that detachment of the labrum alone would shift the head from its
      centered position toward the detachment, and repair would restore its centered
      position. Five young shoulders were used, and glenoids were potted with the
      articular surfaces oriented horizontally. Unconstrained humeral heads were
      subjected to 30-N compressive loads and no displacing force. Using a technique
      with 10-micrometer resolution, we quantified head and glenoid positions before
      and after anteroinferior labral detachment and after three types of repair.
      Detachment was associated with humeral head shift toward the labral lesion in all
      specimens, averaging 0.74 mm (range, 0.51-1.00 mm) (P <.005). Repair to the lip
      restored the labrum's centering effect variably. Repair with suture anchors on
      the glenoid face over-reduced the humeral head, shifting it posterosuperiorly by
      a mean of 3.47 mm (range, 0.71-6.7 mm) (P <.05). The labrum is important for
      humeral head centering, even without displacing loads.

PMID- 12610487
TI  - Persistence of the olecranon physis in baseball players: Results following
      operative management.
AB  - The purpose of this study is to report the results of operative management for
      pain associated with persistence of the olecranon physis in baseball players.
      Five maturing adolescent baseball players (4 male and 1 female) with pain
      associated with persistence of the olecranon physis underwent operative
      stabilization and autogenous bone grafting with second-stage hardware removal.
      All 5 patients remained symptomatic after a variable length of conservative
      management. At a mean follow-up of 32 months (range, 7-84 months), all 5 were
      satisfied with their results. All returned to or surpassed their previous level
      of performance. Operative management is recommended for a symptomatic, persistent
      olecranon physis in the high-demand, skeletally mature overhead athlete in whom
      conservative management has failed. Operative stabilization with internal
      fixation and autogenous iliac crest bone grafting results in the resolution of
      symptoms and a high rate of return to previous throwing performance.

PMID- 12610488
TI  - The kinematic elbow axis as a parameter to evaluate total elbow replacement: A
      cadaver study of the iBP elbow system.
AB  - Malpositioning of prosthetic implants leads to biomechanical changes, often
      resulting in deteriorating functional outcome. This emphasizes the relevance of
      evaluating the surgical process of inserting the prostheses. This study tested to
      what extent the iBP elbow prosthesis and its alignment tools enabled a surgeon to
      reconstruct normal joint kinematics. It demonstrates the use of the kinematic
      elbow axis as an evaluation tool. An electromagnetic tracking device registered
      controlled passive elbow flexion of 10 embalmed upper extremities. The position
      and direction of the preoperative and postoperative kinematic elbow axes were
      established with the use of helical axes and compared. The postoperative position
      of the elbow axis differed from the preoperative axis because of limitations of
      the alignment tools. Suggestions for adjustment of the alignment tools are made.
      The direction of the imposed resection plane was correct; therefore, the
      direction of the postoperative elbow axis corresponded with the direction of the
      preoperative axis.

PMID- 12610489
TI  - Techniques in managing proximal humeral malunions.

PMID- 12610491
TI  - Endoscopic removal of a bullet from the scapulothoracic space.

PMID- 12610490
TI  - Atraumatic conditions of the sternoclavicular joint.

PMID- 12610492
TI  - Subacromial infection following corticosteroid injection.

PMID- 12610493
TI  - Intraarticular osteoid osteoma of the proximal humerus: A case report.

PMID- 12610494
TI  - Proximal translation of the radius following arthroplasty of the distal
      radioulnar joint in Hajdu-Cheney syndrome.

PMID- 12610495
TI  - Delayed repair of a pectoralis major tendon rupture with allograft: A case
      report.

PMID- 12610496
TI  - Prognostic significance of positive peritoneal cytology in endometrial carcinoma
      confined to the uterus.
AB  - A retrospective analysis was performed to evaluate the prognostic significance of
      peritoneal cytology in patients with endometrial carcinoma limited to the uterus.
      A total of 280 patients with surgically staged endometrial carcinoma that was
      histologically confined to the uterus were examined clinicopathologically. The
      median length of follow-up was 62 (range, 12-135) months. All patients underwent
      hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only
      three patients received adjuvant postoperative therapy. No preoperative adjuvant
      therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology.
      The 5-year survival rate among patients with positive or negative peritoneal
      cytology was 91 or 95%, respectively, showing no significant difference (log
      rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients
      with positive cytology, compared with that of 94% among patients with negative
      cytology, and the difference was not significant (log-rank, P=0.52). Multivariate
      proportional hazards model revealed only histologic grade to be an independent
      prognostic factor of survival (P=0.0003, 95% CI 3.02 - 40.27) among the factors
      analysed (age, peritoneal cytology, and depth of myometrial invasion).
      Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21-9.92)
      was also the only independent prognostic factor of disease-free survival. We
      concluded that the presence of positive peritoneal cytology is not an independent
      prognostic factor in patients with endometrial carcinoma confined to the uterus,
      and adjuvant therapy does not appear to be beneficial in these patients.

PMID- 12610497
TI  - Endothelin-1: a multifunctional molecule in cancer.
AB  - Endothelin-1 is a small vasoconstrictor peptide that was first identified in
      1988. Here we review the evidence implicating ET-1 in tumorigenesis. In
      particular, we concentrate on the role of ET-1 in mitogenesis, apoptosis,
      angiogenesis, tumour invasion and metastasis, and discuss the potential for
      endothelin-system modulation as an adjuvant therapeutic strategy.

PMID- 12610498
TI  - Chemotherapy for malignant pleural mesothelioma: past results and recent
      developments.
AB  - This review summarises the results of previously conducted clinical trials, and
      subsequently presents data arising from all phase II-III studies on chemotherapy
      of malignant pleural mesothelioma (MPM) published since the last relevant
      overview. While response rates exceeding 30% have barely been achieved with
      established cytotoxic drugs in MPM therapy, novel chemotherapeutic agents and
      their combinations appear more promising. This applies especially to the
      antimetabolites, and in particular to pemetrexed that produced response rates of
      up to 45% in combination with platinum compounds. Raltitrexed combined with
      oxaliplatin has also been shown to be effective, and gemcitabine-applied as a
      single agent or in combination with cisplatin-as well as vinorelbine appear to
      improve the quality of life in patients presenting with MPM. Data can now be more
      precisely analysed by increasingly implemented randomised studies, applying a
      standardised staging system, and distinguishing prognostic groups. While
      chemotherapy for MPM remains a challenging task, important steps have clearly
      been made in the past years to combat this aggressive disease. The publication of
      pemetrexed with cisplatin phase III results in a peer-reviewed journal may soon
      establish a standard of care.

PMID- 12610500
TI  - Baseline and early lymphopenia predict for the risk of febrile neutropenia after
      chemotherapy.
AB  - A risk model for febrile neutropenia (FN) after conventional cytotoxic
      chemotherapy, based on early (day 5) lymphopenia and the dose of chemotherapy,
      has been described. A risk index based on parameters available at day 1 would be
      easier in daily practice. The objectives of this work were (1) to investigate a
      risk model for FN using only day 1 blood cell count and (2) to compare the day 1
      and day 5 risk models. Three series of patients were used for the delineation
      and/or validation of these two risk models: (1) the exhaustive cohort of 950
      patients treated in the Department of Medicine of the CLB in 1996 (CLB-1996
      series), (2) the Elypse 1 series, a prospective series of 321 patients treated in
      community hospitals and regional cancer centres, and (3) a previously reported
      Elypse 0 series of 329 patients. Day 1 blood cell count was available in all
      three series, while day 5 blood cell count was available only in the Elypse 0 and
      1 series. In the CLB-1996 series, 92 (9.7%) patients experienced FN; only
      chemotherapy dose and day 1 lymphopenia < or =700 microl(-1) had an independent
      prognostic value for FN in multivariate analysis. In patients with both risk
      factors ('high-risk group'), the incidence of FN was 44, 50 and 61% in the CLB
      1996. Elypse 1 and 0 series, respectively, indicating that the 'day 1' risk model
      enables one to identify patients at high-risk for FN. Besides, the observed
      incidence of FN in the high-risk group of the 'day 5' model (i.e. patients with
      day 5 lymphopenia < or =700 microl(-1) and receiving high-risk CT) was 45 and 69%
      in the Elypse 0 and 1 series, respectively. In the Elypse 1 and 0 series, 15 and
      12% of all patients who experienced FN were in the high-risk group of the 'day 1'
      risk model as compared to 25 and 62% for the high-risk group of the 'day 5' risk
      model. Both day 1 and day 5 lymphopenia are associated with an increased risk of
      FN in patients treated with chemotherapy. The 'day 1' model identifies a small
      population of patients at high risk for FN, but has a lower sensitivity than the
      day 5 model.

PMID- 12610499
TI  - Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN
      alpha in patients with metastatic melanoma.
AB  - The purpose of this study is to determine the toxicity and efficacy of
      temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2
      (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon
      alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74
      evaluable patients received, in four separate cohorts, escalating doses of TMZ
      (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5
      microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical
      treatment was scheduled on day 22 and cycles were repeated in stable or
      responding patients following evaluation. Data were analysed after a median
      follow-up of 20 months (12-30 months). The overall objective response rate was
      31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred
      in all disease sites including the central nervous system (CNS). Of the 36
      patients with responding or stable disease, none developed CNS metastasis as the
      first or concurrent site of progressive disease. Median survival was 252 days
      (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of
      TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred
      in 48.5% (34 out of 70) fully monitored patients following TMZ and was present
      after immunotherapy in two patients. The main toxicity of combined immunotherapy
      was the flu-like syndrome (grade 3) and transient liver function disturbances
      (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined
      immunotherapy demonstrates efficacy in patients with stage IV melanoma and is
      associated with toxicity that is manageable on an outpatient basis.

PMID- 12610501
TI  - Outpatient weekly neoadjuvant chemotherapy followed by radiotherapy for advanced
      nasopharyngeal carcinoma: high complete response and low toxicity rates.
AB  - Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumour. The
      aim of this prospective study is to evaluate the toxicity and efficacy of an
      outpatient weekly neoadjuvant chemotherapy (NeoCT) plus radiotherapy for advanced
      NPC. From November 1998 to August 2001, 90 NPC patients meeting the following
      criteria were treated: (1) neck node >6 cm; (2) supraclavicular node metastasis;
      (3) skull base destruction/intracranial invasion plus multiple nodes metastasis;
      (4) multiple neck nodes metastasis with one of nodal size >4 cm; or (5) elevated
      serum LDH level. The NeoCT consists of cisplatin 60 mg m(-2), alternating with 5
      fluorouracil 2500 mg m(-2) plus leucovorin 250 mg m(-2) (P-FL) by an outpatient
      weekly schedule for a total of 10 weeks. Local radiotherapy > or =70 Gy by
      conventional fractionation was delivered within 1 week after NeoCT. Patient
      compliance was rather good. Grade 3-4 toxicity of NeoCT included leucopaenia
      (7.8%), anaemia (18.9%), thrombocytopaenia (3.3%), nausea/vomiting (4.4%), and
      weight loss (1.1%). Response evaluated after NeoCT showed 73.3% complete response
      (CR) rate of primary tumour, 71.1% CR rate of neck nodes, and an overall CR rate
      of 57.8%. In all, 88 out of 90 patients received rebiopsy of primary tumour and
      55 patients (62.5%) revealed pathological CR. After a median follow-up time of 24
      months, one persistent disease and 18 relapses were noted. The 2-year nasopharynx
      disease-free, neck disease-free, distant disease-free, overall, and progression
      free survival rates are 98.9, 95.9, 80.0, 92.1, and 77.5%, respectively.
      Preliminary data of the current study show that P-FL NeoCT plus radiotherapy is a
      low-toxic regimen with promising results on very advanced NPC patients and merits
      to be investigated in phase III trials.

PMID- 12610502
TI  - Percentage of the positive area of bone metastasis is an independent predictor of
      disease death in advanced prostate cancer.
AB  - We addressed in this study whether quantifying the extent of disease on bone
      scans can predict the disease death of patients with advanced prostate cancer
      using computer-assisted image analysis. Pretreatment radionuclide bone scans were
      reviewed in 56 patients with bone metastases from prostate cancer, and the
      percentage of the positive area on a bone scan (%PABS) was quantified
      automatically using a personal computer with the NIH Image program for estimation
      of the accurate extent of metastatic bone lesions on a bone scan. The
      significance of the %PABS as well as the other known prognostic factors was
      evaluated using univariate and multivariate Cox proportional hazards analysis. In
      univariate regression analysis, the %PABS (P=0.0155), serum alkaline phosphatase
      (P=0.0272), the tumour grade based on biopsy (P=0.044) and the number of bone
      lesions on bone scans (P=0.0388) were well associated with disease-specific
      survival. In multivariate analysis, the %PABS (P=0.0155, relative risk ratio
      2.603), but not the other factors, was the independent predictor of the disease
      death. These results suggest that the %PABS is a novel parameter for predicting
      the prognosis of patients with advanced prostatic cancer.

PMID- 12610503
TI  - Interaction between Ku80 protein and a widely used antibody to adenomatous
      polyposis coli.
AB  - The adenomatous polyposis coli (APC) gene and its expressed product are highly
      studied because of its role as a tumour-suppressor protein. Inherited mutations
      in APC lead to the condition known as familial adenomatous polyposis (FAP), which
      predisposes the affected individuals to colorectal cancer. Furthermore, mutations
      in APC are found in the majority of sporadic cases of colon cancer. There have
      been many published studies concerning the cellular localisation of APC, this
      being fundamental to our understanding of its function, but there has also been
      much concern over the specificity of certain commercially available antibodies to
      APC. Here we report that the widely used antibody APC(N15) demonstrates a strong
      interaction with the Ku80 subunit of the Ku heterodimer under defined
      experimental conditions. Based on the data presented here, we suggest that
      APC(N15) is not suitable for many applications used for the study of APC.

PMID- 12610504
TI  - Transcriptional impairment of beta-catenin/E-cadherin complex is not associated
      with beta-catenin mutations in colorectal carcinomas.
AB  - We report the absence of beta-catenin mutations in 63 sporadic colorectal
      carcinomas (SCRCs) with demonstrated decreased beta-catenin and E-cadherin mRNA
      expression and E-cadherin protein expression in a subset of carcinomas examined,
      suggesting that beta-catenin mutations are an extremely rare phenomenon in SCRCs
      and are not responsible for the transcriptional impairment of the beta-catenin/E
      cadherin adhesion complex observed in these tumours.

PMID- 12610505
TI  - Aberrant caspase-activated DNase (CAD) transcripts in human hepatoma cells.
AB  - The gene of caspase-activated DNase (CAD), the key enzyme for nucleosome cleavage
      during apoptosis, is mapped at chromosome 1p36, a region usually associated with
      hemizygous deletions in human cancers, particularly in hepatoma (HCC). It is
      tempting to speculate that CAD plays a tumour-suppressive role in
      hepatocarcinogenesis. To address this, we examined the CAD transcripts in six
      human HCC cell lines, one liver tissue from a non-HCC subject, and peripheral
      blood leukocytes (PBL) from three healthy individuals. Alternatively spliced CAD
      transcripts with fusion of exon 1 to exon 7 were isolated in most of the examined
      samples including HCC cells and normal controls. However, relatively abundant
      alternatively spliced CAD transcripts with fusion of exon 2 to exon 6 or 7, in
      which the corresponding domain directing CAD interaction with ICAD was preserved,
      were found only in poorly differentiated Mahlavu and SK-Hep1 cells.
      Interestingly, an abnormal CAD transcript with its exon 3 replaced by a truncated
      transposable Alu repeat was isolated in Hep3B cells, indicative of the
      implication of an Alu-mediated genomic mutation. Moreover, mis-sense mutations in
      the CAD genes were identified in all six HCC cell lines. Upon UV-induced
      apoptosis, DNA fragmentation efficiency was found to be intact, partially reduced
      and remarkably reduced in Huh7 and J328, Hep3B and HepG2, and Mahlavu cells,
      respectively. That mutations and aberrantly spliced transcripts for the CAD gene
      are frequently present in human HCC cells, especially in poorly differentiated
      HCC cells, suggests a significant role of CAD in human hepatocarcinogenesis.

PMID- 12610506
TI  - Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions.
AB  - The clinical management of pancreatic disease is often hampered by a lack of
      tissue diagnosis. Endoscopic pancreatography offers the opportunity to
      investigate exfoliated cells. However, the significance of mere cytological
      investigation is compromised by an insufficient sensitivity. The evaluation of
      the molecular background of carcinogenesis hopefully is capable of providing more
      sensitive diagnostic markers. The p16INK4a-/retinoblastoma tumour-suppressive
      pathway has been shown to be involved in the development of near to all
      pancreatic neoplasms. p14ARF is another tumour suppressor located in the
      immediate neighbourhood of p16INK4a. Promoter methylation has been demonstrated
      to be a major inactivating mechanism of both genes. We sought to further evaluate
      the role of the gene locus INK4a methylation status in the endoscopic
      differentiation of chronic inflammatory and neoplastic pancreatic disease.
      Pancreatic fluid specimens of 61 patients with either pancreatic carcinoma (PCA:
      39), chronic pancreatitis (CP: 16) or a normal pancreatogram (NAD: 6) were
      retrieved. In order to detect methylation of either the p14ARF or the p16INK4a
      promoter a methylation-specific PCR protocol was applied. While 19 out of 39
      patients with PCA showed p16 promoter methylation (49%), none of the 16 patients
      with CP revealed p16 promoter methylation. p14ARF methylation was found in a
      lower percentage of PCA specimens and in none of the samples of patients with CP.
      These results suggest a specific significance of INK4a for the development of
      malignant pancreatic disease. Our data further indicate a potential role for
      INK4a methylation as a diagnostic marker in the endoscopic differentiation of
      benign and malignant pancreatic disease.

PMID- 12610507
TI  - Effector CD8+CD45RO-CD27-T cells have signalling defects in patients with
      squamous cell carcinoma of the head and neck.
AB  - A subset of circulating T cells (CD8(+)CD45RO(-)CD27(-)) with a naive phenotype,
      but mediating effector function, is considered to play an important role in host
      antitumour defence. To investigate the attributes of these effector T cells in
      patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous
      blood was obtained from 39 individuals with cancer and 45 normal controls (NC).
      Peripheral blood mononuclear cells were isolated, stained with labelled
      monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-zeta as
      well as isotype controls and examined by multicolour flow cytometry. Annexin V
      binding to CD8(+) T cells and PMA/ionomycin-induced IFN-gamma expression were
      also evaluated in patients and NC. The proportions of CD45RA(+)CD45RO(-) (naive)
      and CD45RA(-)CD45RO(+) (memory) cells were found to be comparable within the
      CD8(+) T-cell subset. However, relative to NC, the frequency of effector
      CD8(+)CD45RO(-)CD27(-) cells was strikingly increased in all SCC patients
      regardless of the disease status (P=0.0003). The proportion of these cells was
      found to increase with age in both patients and NC. In NC, stimulated IFN-gamma
      expression was largely restricted to CD8(+)CD45RO(-)CD27(+) cells, while in
      patients CD8(+)CD45RO(-)CD27(-) expressed IFN-gamma after ex vivo stimulation.
      Expression of the TCR-associated zeta chain was decreased or absent in freshly
      isolated CD8(+)CD45RO(-)CD27(-) T cells in patients (P<0.0001). Annexin V was
      found to bind to a higher proportion of circulating CD8(+) T cells in patients
      than NC (P<0.006), and significantly more Annexin V(+) T cells were present in
      the effector (P<0.0059) than the naive subset within the CD8(+)CD45RO(-)
      compartment. The data indicate that the expanded CD8(+)CD45RO(-)CD27(-) T cells,
      which contain precursors of IFN-gamma-producing T cells, are zeta-negative and
      sensitive to apoptosis in the circulation of patients with HNC.

PMID- 12610508
TI  - CD24 is an independent prognostic marker of survival in nonsmall cell lung cancer
      patients.
AB  - Originally identified as a B-cell marker, expression of the cell surface molecule
      CD24 has meanwhile been observed in a variety of human malignancies. It appears
      to function as a ligand of P-Selectin, an adhesion molecule that is present in
      activated platelets and endothelial cells. We aimed to determine the rate of CD24
      expression in our nonsmall cell lung cancer (NSCLC) collection and to clarify its
      correlation with clinicopathological parameters including patients' survival. A
      total of 89 NSCLC were analysed immunohistochemically using a monoclonal CD24
      antibody (clone 24C02) and a standard detection system (LSAB, DAKO) on NSCLC
      tissue microarrays (TMA). The staining was semiquantitatively scored (0, 1+, 2+,
      3+) and grouped into high (2+, 3+)- and low (0, 1+)-level expression for
      statistical analysis. A high level of CD24 expression was observed in 45% of the
      cases, preferentially adenocarcinomas. Patients whose tumours had a high CD24
      expression showed a significantly shorter median survival time of 23 months vs 38
      months (P=0.033, log-rank test). Similarly tumour, grading, nodal status and
      clinical stage were significant prognostic markers in univariate survival
      analysis. Importantly, in the Cox regression-based multivariate analysis, CD24
      expression (P=0.025) together with tumour stage (P=0.006) and grade (P=0.011)
      proved to be independent prognostic parameters. We hypothesise that the decreased
      survival of NSCLC patients with strongly CD24-positive tumours is related to an
      enhanced propensity of haematogenous metastasis formation, which might be P
      Selectin mediated.

PMID- 12610509
TI  - Vascular endothelial growth factor-D is an independent prognostic factor in
      epithelial ovarian carcinoma.
AB  - We assessed the presence of vascular endothelial growth factor (VEGF)-C, VEGF-D
      and their receptor VEGFR-3 by immunohistochemistry in 59 epithelial ovarian
      carcinomas, 11 borderline tumours and 20 benign cystadenomas. VEGF-C and VEGF-D
      were generally expressed in tumour cells and also in endothelia adjacent to
      tumour nests which showed a strong staining for them. VEGFR-3 was expressed in
      lymphatic and vascular endothelial cells adjacent to tumour nests.
      Immunoreactivity was significantly more frequent as lesions progressed from a
      benign tumour to advanced carcinoma. A strong correlation was found between VEGF
      C and VEGF-D detected in carcinoma and VEGFR-3 detected in neighbouring
      endothelial cells. Increased expression of VEGF-C, VEGF-D and VEGFR-3 was
      significantly associated with lymph node metastasis and peritoneal metastasis
      outside the pelvis. There was a significant correlation between the high levels
      of VEGF-C and VEGF-D proteins, and poor survival. The presence of VEGF-D was an
      independent prognostic indicator by multivariate analysis. We conclude that VEGF
      C, VEGF-D and VEGFR-3 play an important role in lymphatic spread and
      intraperitoneal tumour development in ovarian carcinoma. Since VEGF-D was found
      to be an independent predictor of poor outcome, its measurement, together with
      other prognostic markers may improve prospective identification of patients with
      a poor prognosis.

PMID- 12610510
TI  - Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and
      vulval squamous cell carcinoma.
AB  - Human papillomavirus (HPV) is thought to cause some vulval squamous cell
      carcinomas (VSCC) by degrading p53 product. Evidence on whether HPV-negative VSCC
      results from p53 mutation is conflicting. We performed immunohistochemistry for
      p53 product on 52 cases of lone vulval intraepithelial neoplasia (VIN), 21 cases
      of VIN with concurrent VSCC and 67 cases of VSCC. We had previously performed HPV
      detection and loss of heterozygosity (LOH) analyses on these samples. Abnormal
      p53 immunoreactivity (p53-positive) rates in HPV-positive VSCC and HPV-negative
      VSCC were 22% (12/54) and 31% (4/13), respectively (P<0.74). p53 immunoreactivity
      was associated with LOH at the p53 locus (P<0.004), but neither technique
      differentiated between HPV-positive and HPV-negative VSCC. p53 immunoreactivity
      was associated with overall LOH rates (p53-positive VSCC vs p53-negative VSCC
      mean fractional regional allelic loss 0.41 vs 0.24, respectively, P<0.027). LOH
      at 3p25 was more frequent in p53-positive VSCC cf p53-negative VSCC (70 vs 21%,
      respectively, P<0.007). There was a trend in p53 disruption associated with
      invasive disease; HPV-positive VSCC demonstrated more disruption than VIN
      associated with VSCC, which had more disruption than lone VIN III (22 vs 10 vs
      0%, respectively, P<0.005). In all, three out of 73 cases of VIN were p53
      positive. All three were associated with concurrent or previous VSCC. Meta
      analysis of previous studies revealed significantly more p53 disruption in HPV
      negative VSCC cf HPV-positive VSCC (58 vs 33%, respectively; P<0.0001). p53
      immunoreactivity/mutation in VIN only appeared in association with VSCC. These
      data suggest that HPV-independent vulval carcinogenesis does not exclusively
      require disruption of p53, p53 disruption may work synergistically with LOH at
      specific loci and p53-positive VIN should be checked carefully for the presence
      of occult invasion.

PMID- 12610511
TI  - Minichromosome maintenance (Mcm) proteins, cyclin B1 and D1, phosphohistone H3
      and in situ DNA replication for functional analysis of vulval intraepithelial
      neoplasia.
AB  - Vulval intraepithelial neoplasia (VIN) is defined histopathologically by
      distinctive abnormalities of cellular maturation and differentiation. To
      investigate the functional properties of VIN, the expression of several proteins
      involved in the regulation of the cell cycle as well as in situ DNA replication
      competence was analysed by immunohistochemistry. Snap-frozen vulval biopsies were
      graded as normal squamous epithelium (n=6), undifferentiated HPV positive VIN 1
      (n=3), VIN 2 (n=8) and VIN 3 (n=20). Immunohistochemistry was performed using the
      following markers: cyclin D1 (expressed in middle/late G1), cyclin B1 (expressed
      in G2/early M), phosphorylated histone H3 (expressed during mitosis) and
      minichromosome maintenance (Mcm) proteins 2 and 5 (expressed during the cell
      cycle, but not in differentiated or quiescent cells). In situ DNA replication
      competence was used to identify S-phase cells. The percentage of positively
      stained nuclei in three representative microscopic fields was calculated per
      biopsy. In normal vulva, the expression of all markers was restricted to the
      proliferative compartment of the basal layer of the epithelium. In contrast in
      high-grade VIN, the majority of epithelial cells expressed the Mcm proteins from
      basal to superficial layer. The detection of cyclins B1 and D1, phospho-histone
      H3 and in situ DNA replication was also found through the full thickness of these
      lesions but by a lower proportion of the cells. This is consistent with these
      markers providing a series of 'snapshots' of the cell cycle status of individual
      cells. The low-grade VIN showed reduced expression of the cell cycle markers in
      relation to the level of dysplasia. The combination of these analyses establishes
      that the majority of VIN cells remain in a functional replicative or
      prereplicative state of the cell cycle. Clinical application of these analyses
      may provide a basis for improved diagnosis of VIN.

PMID- 12610512
TI  - Polymorphism of the insulin gene is associated with increased prostate cancer
      risk.
AB  - High insulin levels are linked with increased cancer risk, including prostate
      cancer. We examined the associations between prostate cancer with polymorphisms
      of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and
      IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race,
      and countries of origin were genotyped for +1127 INS-PstI in INS, -4217 TH-PstI
      in TH, and +3580 IGF2-MspI in IGF2. The homozygous CC genotype of +1127 INS-PstI
      occurred in over 60% of the population. It was associated with an increased risk
      of prostate cancer in nondiabetic Blacks and Caucasians (OR=3.14, P=0.008). The
      CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022)
      and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes
      of INS showed only null to modest associations with prostate cancer. The
      polymorphism of INS may play a role in the aetiology of prostate cancer. Given
      the high prevalence of the CC genotype and its association with late age of onset
      of low-grade tumours, this polymorphism may contribute to the unique
      characteristics of prostate cancer, namely a high prevalence of indolent cancers
      and the dramatic increase in incidence with age.

PMID- 12610513
TI  - Analysis of the candidate 8p21 tumour suppressor, BNIP3L, in breast and ovarian
      cancer.
AB  - Loss of heterozygosity (LOH) on the short arm of chromosome 8, at 8p12-p23, is
      one of the most frequent genetic events in both breast and ovarian cancer,
      suggesting the location of a shared tumour suppressor gene. Microcell-mediated
      chromosome transfer of chromosome 8 suppresses tumorigenicity and growth of
      colorectal and prostate cancer cell lines, further supporting the presence of a
      tumour suppressor gene on 8p. We have taken a candidate gene approach to try to
      identify this tumour suppressor gene at 8p12-p23. BNIP3L, which has sequence
      homology to pro-apoptotic proteins and the ability to suppress colony formation
      in soft agar, is located at 8p21, within a region of ovarian cancer LOH, breast
      cancer LOH and prostate cancer metastasis suppression. BNIP3L expression was
      assessed by both RT-PCR and Northern blot analysis in breast and ovarian cancer
      cell lines and found to be expressed at similar levels relative to expression in
      their respective normal epithelial cell lines. Genetic analysis of BNIP3L in 40
      primary ovarian and 25 primary breast tumours identified one somatic, intronic
      mutation in one ovarian tumour, as well as several polymorphisms, including one
      resulting in an amino-acid substitution. These data suggest that BNIP3L is
      unlikely to be the target of 8p LOH in ovarian or breast cancer.

PMID- 12610514
TI  - IGF1 genotype, mean plasma level and breast cancer risk in the Hawaii/Los Angeles
      multiethnic cohort.
AB  - The insulin-like growth factor 1 gene (IGF1) is a strong candidate gene for a
      breast cancer susceptibility model. We investigated a dinucleotide repeat 969 bp
      upstream from the transcription start site of the IGF1 gene for possible
      associations with plasma IGF1 levels and breast cancer risk in a multiethnic
      group of postmenopausal women. Furthermore, we investigated the relation between
      race/ethnicity, mean plasma IGF1 levels and breast cancer rates in the Hawaii/Los
      Angeles Multiethnic Cohort. The mean age-adjusted IGF1 level among Latino
      American women, 116 ng ml(-1), was statistically significantly lower than the
      mean age-adjusted IGF1 levels for each of the three other racial/ethnic groups,
      African-American, Japanese-American and Non-Latino White women (146, 144 and 145
      ng ml(-1), respectively) (P<0.0001). Latino-American women have the lowest breast
      cancer rates of any racial/ethnic group in the cohort. These results support the
      investigation of an expansion of the hypothesis for an important role of IGF1 in
      breast cancer tumorigenesis to different racial/ethnic groups and to
      postmenopausal women. It is unlikely that any involvement of IGF1 in breast
      cancer aetiology is mediated by the IGF1 dinucleotide repeat polymorphism, which
      was not significantly associated with circulating IGF1 levels nor breast cancer
      risk in this study. Research into relevant determinants of IGF1 levels in the
      blood must continue.

PMID- 12610516
TI  - Intratumour heterogeneity in the uptake of macromolecular therapeutic agents in
      human melanoma xenografts.
AB  - Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human
      serum albumin ((99m)Tc-HSA) was studied in human melanoma xenografts in an
      attempt to identify transport barriers leading to inadequate and heterogeneous
      uptake of macromolecular therapeutic agents in tumours. The Bioscope imaging
      system, which can detect the distribution of (99m)Tc in 10-microm-thick tissue
      sections with a spatial resolution of just above 50 microm, was used to image the
      (99m)Tc-HSA uptake. Xenografted tumours of four human melanoma cell lines were
      included in the study. Significant intratumour heterogeneity in the uptake of
      (99m)Tc-HSA was detected. The heterogeneity had two distinctly different
      components, one random and one radial component. The uptake was lowest in the
      centre of the tumours and increased towards the tumour periphery. This radial
      heterogeneity was superimposed by a random heterogeneity, that is, spots with
      high uptake colocalised with spots with high vascular density and regions without
      significant uptake colocalised with necrotic regions. The magnitude of the
      heterogeneity did not change significantly with time after the administration of
      (99m)Tc-HSA. The tumours showed a random and a radial heterogeneity in blood
      perfusion similar to that in the uptake of (99m)Tc-HSA. The observations reported
      here suggest that the intratumour heterogeneity in the distribution of (99m)Tc
      HSA was initiated primarily because of heterogeneity in the supply of (99m)Tc-HSA
      through the microvasculature, and that the presence of severe transport barriers
      in the tumour interstitium prevented significant equalisation of the initial
      heterogeneity with time. Consequently, strategies for improving the delivery of
      macromolecular therapeutic agents to tumours should focus on increasing the
      tumour blood perfusion to increase the total uptake and improving the diffusion
      conditions in the tumour interstitium to diminish the heterogeneity in the
      uptake.

PMID- 12610515
TI  - Foscan uptake and tissue distribution in relation to photodynamic efficacy.
AB  - Clinical photodynamic therapy (PDT) schedules are based on the assumption that
      optimum drug-light intervals are times at which there is a maximum differential
      between photosensitiser retention in the tumour and surrounding normal tissue.
      However, vascular-mediated effects contribute to tumour destruction by PDT;
      therefore, plasma sensitiser levels and endothelial cell drug exposure could also
      be important determinants of PDT response. The purpose of this study was to
      investigate the influence of tumour, tissue and plasma concentrations of the
      photosensitiser Foscan (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response.
      Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were
      injected (i.v.) with a single dose of (14)C-labelled mTHPC, or with two doses,
      separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured
      at 5 min to 120 h after drug administration. The PDT tumour and skin responses
      were evaluated by illuminating separate groups mice at intervals of 5 min to 120
      h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin
      increased during the first 24 h after a single injection, and remained almost
      constant for at least 120 h. The second injection produced a further, rapid
      increase in mTHPC levels in tumours and skin, with steady state being maintained
      from 20 min to 120 h. By contrast, PDT response of both tumours and skin were
      maximal for illumination at 1-3 h after drug, with very little response when
      illumination was given 48-120 h after drug. There was no significant correlation
      between tumour or skin drug level and PDT response. There was, however, a
      significant correlation between plasma drug levels and tumour or skin response,
      excluding an initial distribution time of 20 min. These studies demonstrate a
      pronounced disassociation between tumour drug levels and optimum drug-light
      intervals for PDT response with Foscan. We suggest that the PDT effect, in both
      tumours and normal tissues, is largely mediated via vascular damage and that the
      selectivity of PDT is not based on differential tumour drug uptake.

PMID- 12610517
TI  - A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established
      glioma cell line and sensitisation to TRAIL by genotoxic agents.
AB  - Most tumour cells are sensitive to TRAIL-induced apoptosis, but not normal cells;
      thus, cancer therapy using TRAIL is expected clinically. Several tumour cells are
      resistant to TRAIL-induced apoptosis, and various mechanisms of such resistance
      were reported in individual cases. In this study, we established a TRAIL
      resistant glioma cell line, which completely lacked TRAIL receptors. In addition,
      this tumour cell line had wild-type p53 tumour-suppressive gene, suggesting new
      mechanisms for tumour cells to expand and escape from immune surveillance. The
      present study further explored the mechanisms that determine the sensitivity to
      TRAIL. We show that genotoxic agents such as cisplatin, doxorubicin and
      camptothecin, in addition to UV radiation, can induce TRAIL-R2 on the cell
      surface of TRAIL receptor-negative tumour cells. Newly synthesised TRAIL-R2 is
      functional, so apoptosis is effectively induced by TRAIL, but it is significantly
      inhibited by constitutive expression of dominant-negative p53. In addition,
      apoptosis induced by pretreatment of genotoxic agents and additional stimulation
      of TRAIL is efficiently inhibited by either antagonistic anti-TRAIL-R2 antibody
      or pan-caspase inhibitor z-VAD-FMK. Taken together, these findings suggest that
      resistance to TRAIL by lack of TRAIL receptors on glioma is restored by genotoxic
      agents, which support the new strategies for tumour killing by TRAIL-bearing
      cytotoxic cells in combination with genotoxic treatment.

PMID- 12610518
TI  - A novel hypoxia-dependent 2-nitroimidazole KIN-841 inhibits tumour-specific
      angiogenesis by blocking production of angiogenic factors.
AB  - Tumour angiogenesis is initiated by angiogenic factors that are produced in large
      amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour
      specific antiangiogenesis because normal tissues are not usually hypoxic. On the
      other hand, blocking a biological function of endothelial cells is known to
      result in angiogenic inhibition. To produce a tumour-specific and powerful
      antiangiogenesis, we determined whether potent angiogenic inhibition could be
      achieved by inhibiting the production of angiogenic factors by hypoxic tumour
      cells and simultaneously blocking certain angiogenic steps in endothelial cells
      under normoxia. We focused on the 2-nitroimidazole moiety, which is easily
      incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic
      cytotoxin. We designed and synthesised 2-nitroimidazole derivatives designated as
      KIN compounds, and investigated their antiangiogenic activities under normoxia
      using a chick embryo chorioallantoic membrane. KIN-841 (2-nitroimidazole 1
      acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent
      manner. This compound inhibited the proliferation of bovine pulmonary arterial
      endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis
      lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation
      by KIN-841 under hypoxia increased about five-fold compared to that under
      normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive
      production of vascular endothelial cell growth factors induced by 3LL cells as
      determined by tritium-labelled thymidine ([(3)H]thymidine) incorporation into
      BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL
      cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These
      results indicate that the regulation of the production of angiogenic factors by
      hypoxic tumour cells is a useful target for tumour-specific angiogenesis
      inhibition, and that KIN-841, which causes simultaneous direct inhibition of
      endothelial cell function and production of angiogenic factors by hypoxic tumour
      cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the
      potential for clinical use of KIN-841 as an antitumour drug is very high.

PMID- 12610519
TI  - Degree of tumour vascularity correlates with drug accumulation and tumour
      response upon TNF-alpha-based isolated hepatic perfusion.
AB  - Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis
      factor alpha (TNF-alpha) is currently performed in clinical trials in patients
      with hepatic metastases. Previous studies led to the hypothesis that the use of
      TNF-alpha in isolated limb perfusion causes specific destruction of tumour
      endothelial cells and thereby induces an increased permeability of tumour
      vasculature. However, whether TNF-alpha contributes to the therapeutic efficacy
      in IHP still remains unclear. In an in vivo rat liver metastases model we studied
      three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175
      soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was
      performed with melphalan with or without the addition of TNF-alpha. IHP with
      melphalan alone resulted, in all tumour types, in a decreased growth rate.
      However in the BN-175 tumour addition of TNF-alpha resulted in a strong
      synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete
      response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531
      and BN-175) or only minor sensitivity (ROS-1) to TNF-alpha, ruling out a direct
      interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour
      bearing rats when TNF-alpha was coadministrated with melphalan was strongly
      correlated with drug accumulation in tumour tissue, as only in these rats a five
      fold increased melphalan concentration was observed. Secondly,
      immunohistochemical analysis of microvascular density (MVD) of the tumour showed
      a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These
      results indicate a direct relation between vascularity of the tumour and TNF
      alpha mediated effects. Assessment of the tumour vasculature of liver metastases
      would be a way of establishing an indication for the utility of TNF-alpha in this
      setting.

PMID- 12610520
TI  - Restored T-cell activation mechanisms in human tumour-infiltrating lymphocytes
      from melanomas and colorectal carcinomas after exposure to interleukin-2.
AB  - We investigated the effects of interleukin-2 (IL-2) exposure on T-cell signal
      transduction molecules and apoptosis markers in tumour-infiltrating lymphocytes
      (TIL) isolated from 20 melanoma and 16 colorectal carcinoma metastases and
      expanded in vitro for therapeutic reinfusion. Before IL-2 culture, TIL showed
      undetectable or very low levels of T-cell receptor (TCR) epsilon chain, p56(lck),
      Fas ligand (FasL) and Bax expression, while Bcl-2 values were elevated. Cancer
      cells were characterised by low or absent Fas and Bcl-2 and high Bax expression.
      Notably, they also expressed FasL. After 41-48 days of IL-2 culture, TCR epsilon
      chain and p56(lck) expression of TIL rose to median values of approximately 80
      and 30% positive cells, respectively (P<0.001), FasL expression was detected in
      45% cells from melanomas (P<0.001) and in 3% from colorectal carcinomas (P=0.09),
      and Bax-positive cells increased from 17.5 to 70% (P=0.005). Moreover, TCR zeta
      chain-positive cells were significantly increased from baseline (P=0.001), Bcl-2
      positive cells dropped from 50 to 1% (P=0.007) and perforin content was high,
      while Fas expression was not significantly modified by IL-2 culture. In
      conclusion, our data suggest that the degree of immunosuppression in TIL from
      melanomas and colorectal carcinomas is very high, and the apoptosis markers'
      repertoire of cancer cells resembles that of immune-privileged tissue.
      Interleukin-2 culture appears to restore lymphocyte activation mechanisms,
      resulting in consistent FasL expression and perforin production.

PMID- 12610521
TI  - Expression level of integrin alpha 5 on tumour cells affects the rate of
      metastasis to the kidney.
AB  - Tumour metastasis is known clinically to have organ specificity. We hypothesised
      that integrins might be involved in determining the organ specificity of tumour
      metastasis. Here, we report the results of spontaneous metastasis tested in nude
      mice that were inoculated with Chinese hamster ovary (CHO) cells expressing
      integrin alpha 5 beta 1 at various levels. The growth of the primary tumour
      inversely correlated with the alpha 5 expression level on CHO cells, which is
      consistent with a previous report (Schreiner et al, 1991). The rates of
      pulmonary, lymph node, and adrenal metastases that developed in nude mice were
      not related to changes of the alpha 5 expression level on CHO cells. Kidney
      metastasis developed in 40% of nude mice inoculated with alpha 5B2 cells (CHO
      cells overexpressing alpha 5) and in 20% of mice with CHO-K1 cells (CHO cells
      expressing native alpha 5), whereas inoculation with CHO-B2 cells (alpha 5
      defective mutants) and alpha 5CHO cells with the highest expression of alpha 5
      did not lead to development of kidney metastasis. Furthermore, alpha 5CHO, which
      shows the slowest growth of these cell types, did not lead to primary tumours in
      nude mice. These findings suggest that there is an appropriate level of alpha 5
      expression on tumour cells that leads to metastasis. Microscopic observations
      revealed that micrometastasis in the kidney was formed in glomeruli. An adhesion
      assay using frozen sections of the kidney demonstrated that alpha 5B2 cells, but
      not CHO-B2 cells, effectively adhered to glomeruli. Kidney metastasis in vivo and
      the adhesion of alpha 5B2 to glomeruli shown ex vivo were significantly
      suppressed by the administration of GRGDS peptide. Finally, we conclude that the
      interaction of alpha 5 beta 1 on tumour cells with fibronectin in kidney
      glomeruli is involved in kidney metastasis and that the tumour has appropriate
      levels of integrins crucial for metastasis.

PMID- 12610522
TI  - Comparative plant development: the time of the leaf?
AB  - A key problem in developmental biology is understanding the origin of
      morphological innovations. Comparative studies in plants with different leaf
      morphologies indicate that the developmental pathway defined by KNOTTED1-type
      homeodomain proteins could be involved in generating different leaf forms. The
      differential expression of regulatory proteins has emerged as an important factor
      in driving morphological innovations in the plant kingdom--an idea that is well
      supported by quantitative trait locus analyses.

PMID- 12610523
TI  - Dying for a cause: invertebrate genetics takes on human neurodegeneration.
AB  - If invertebrate neurons are injured by hostile environments or aberrant proteins
      they die much like human neurons, indicating that the powerful advantages of
      invertebrate molecular genetics might be successfully used for testing specific
      hypotheses about human neurological diseases, for drug discovery and for non
      biased screens for suppressors and enhancers of neurodegeneration. Recent
      molecular dissection of the genetic requirements for hypoxia, excitotoxicity and
      death in models of Alzheimer disease, polyglutamine-expansion disorders,
      Parkinson disease and more, is providing mechanistic insights into neurotoxicity
      and suggesting new therapeutic interventions. An emerging theme is that neuronal
      crises of distinct origins might converge to disrupt common cellular functions,
      such as protein folding and turnover.

PMID- 12610524
TI  - Mice, microbes and models of infection.
AB  - We urgently need animal models to study infectious disease. Mice are susceptible
      to a similar range of microbial infections as humans. Marked differences between
      inbred strains of mice in their response to pathogen infection can be exploited
      to analyse the genetic basis of infections. In addition, the genetic tools that
      are available in the laboratory mouse, and new techniques to monitor the
      expression of bacterial genes in vivo, make it the principal experimental animal
      model for studying mechanisms of infection and immunity.

PMID- 12610525
TI  - Tracing floral adaptations from ecology to molecules.
AB  - Flowers have long fascinated humans. The scientific study of floral biology
      unifies many diverse areas of research, ranging from systematics to ecology, and
      from genetics to molecular biology. Despite this unity, few plant species offer
      the experimental versatility to encompass all levels of biological investigation
      in a single system. An exception is the morning glory genus Ipomoea, in which a
      broad picture of floral evolution, ranging from ecology to molecular biology, is
      emerging.

PMID- 12610526
TI  - The modern molecular clock.
AB  - The discovery of the molecular clock--a relatively constant rate of molecular
      evolution--provided an insight into the mechanisms of molecular evolution, and
      created one of the most useful new tools in biology. The unexpected constancy of
      rate was explained by assuming that most changes to genes are effectively
      neutral. Theory predicts several sources of variation in the rate of molecular
      evolution. However, even an approximate clock allows time estimates of events in
      evolutionary history, which provides a method for testing a wide range of
      biological hypotheses ranging from the origins of the animal kingdom to the
      emergence of new viral epidemics.

PMID- 12610527
TI  - Innovations: applications of insect transgenesis.
AB  - The recent establishment of broadly applicable genetic transformation systems
      will allow the analysis of gene function in diverse insect species. This will
      increase our understanding of developmental and evolutionary biology.
      Furthermore, insect transgenesis will provide new strategies for insect pest
      management and methods to impair the transmission of pathogens by human disease
      vectors. However, these powerful techniques must be applied with great care to
      avoid harm to our environment.

PMID- 12610528
TI  - China's struggle for practical regulations in medical ethics.
AB  - The introduction of ethical regulations in medicine in China might seem at odds
      with the country's social and moral reality. Chinese bioethicists find themselves
      torn between the necessity to re-create a fully-fledged modern health-care system
      and aspirations to become global players in the biomedical sciences. The result
      is a top-down approach in medical ethics, created on behalf of the people.
      Despite its introduction, there are concerns about whether China is prepared to
      embrace the standards it claims to have adopted.

PMID- 12610531
TI  - Massive parallelism, randomness and genomic advances.
AB  - In reviewing the past decade, it is clear that genomics was, and still is, driven
      by innovative technologies, perhaps more so than any other scientific area in
      recent memory. From the outset, computing, mathematics and new automated
      laboratory techniques have been key components in allowing the field to move
      forward rapidly. We highlight some key innovations that have come together to
      nurture the explosive growth that makes a new era of genomics a reality. We also
      document how these new approaches have fueled further innovations and
      discoveries.

PMID- 12610532
TI  - Discovering genotypes underlying human phenotypes: past successes for mendelian
      disease, future approaches for complex disease.
AB  - The past two decades have witnessed an explosion in the identification, largely
      by positional cloning, of genes associated with mendelian diseases. The roughly
      1,200 genes that have been characterized have clarified our understanding of the
      molecular basis of human genetic disease. The principles derived from these
      successes should be applied now to strategies aimed at finding the considerably
      more elusive genes that underlie complex disease phenotypes. The distribution of
      types of mutation in mendelian disease genes argues for serious consideration of
      the early application of a genomic-scale sequence-based approach to association
      studies and against complete reliance on a positional cloning approach based on a
      map of anonymous single nucleotide polymorphism haplotypes.

PMID- 12610533
TI  - The genetics and genomics of cancer.
AB  - The past decade has seen great strides in our understanding of the genetic basis
      of human disease. Arguably, the most profound impact has been in the area of
      cancer genetics, where the explosion of genomic sequence and molecular profiling
      data has illustrated the complexity of human malignancies. In a tumor cell,
      dozens of different genes may be aberrant in structure or copy number, and
      hundreds or thousands of genes may be differentially expressed. A number of
      familial cancer genes with high-penetrance mutations have been identified, but
      the contribution of low-penetrance genetic variants or polymorphisms to the risk
      of sporadic cancer development remains unclear. Studies of the complex somatic
      genetic events that take place in the emerging cancer cell may aid the search for
      the more elusive germline variants that confer increased susceptibility. Insights
      into the molecular pathogenesis of cancer have provided new strategies for
      treatment, but a deeper understanding of this disease will require new
      statistical and computational approaches for analysis of the genetic and
      signaling networks that orchestrate individual cancer susceptibility and tumor
      behavior.

PMID- 12610534
TI  - Epigenetic regulation of gene expression: how the genome integrates intrinsic and
      environmental signals.
AB  - Cells of a multicellular organism are genetically homogeneous but structurally
      and functionally heterogeneous owing to the differential expression of genes.
      Many of these differences in gene expression arise during development and are
      subsequently retained through mitosis. Stable alterations of this kind are said
      to be 'epigenetic', because they are heritable in the short term but do not
      involve mutations of the DNA itself. Research over the past few years has focused
      on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation
      and histone modifications. Here, we review advances in the understanding of the
      mechanism and role of DNA methylation in biological processes. Epigenetic effects
      by means of DNA methylation have an important role in development but can also
      arise stochastically as animals age. Identification of proteins that mediate
      these effects has provided insight into this complex process and diseases that
      occur when it is perturbed. External influences on epigenetic processes are seen
      in the effects of diet on long-term diseases such as cancer. Thus, epigenetic
      mechanisms seem to allow an organism to respond to the environment through
      changes in gene expression. The extent to which environmental effects can provoke
      epigenetic responses represents an exciting area of future research.

PMID- 12610535
TI  - Molecular evolution meets the genomics revolution.
AB  - Changes in technology in the past decade have had such an impact on the way that
      molecular evolution research is done that it is difficult now to imagine working
      in a world without genomics or the Internet. In 1992, GenBank was less than a
      hundredth of its current size and was updated every three months on a huge spool
      of tape. Homology searches took 30 minutes and rarely found a hit. Now it is
      difficult to find sequences with only a few homologs to use as examples for
      teaching bioinformatics. For molecular evolution researchers, the genomics
      revolution has showered us with raw data and the information revolution has given
      us the wherewithal to analyze it. In broad terms, the most significant outcome
      from these changes has been our newfound ability to examine the evolution of
      genomes as a whole, enabling us to infer genome-wide evolutionary patterns and to
      identify subsets of genes whose evolution has been in some way atypical.

PMID- 12610537
TI  - Tailoring the genome: the power of genetic approaches.
AB  - In the last century, genetics has developed into one of the most powerful tools
      for addressing basic questions concerning inheritance, development, individual
      and social operations and death. Here we summarize the current approaches to
      these questions in four of the most advanced models organisms: Saccharomyces
      cerevisiae (yeast), Caenorhabditis elegans (worm), Drosophila melanogaster (fly)
      and Mus musculus (mouse). The genomes of each of these four models have been
      sequenced, and all have well developed methods of efficient genetic
      manipulations.

PMID- 12610536
TI  - The application of molecular genetic approaches to the study of human evolution.
AB  - The past decade of advances in molecular genetic technology has heralded a new
      era for all evolutionary studies, but especially the science of human evolution.
      Data on various kinds of DNA variation in human populations have rapidly
      accumulated. There is increasing recognition of the importance of this variation
      for medicine and developmental biology and for understanding the history of our
      species. Haploid markers from mitochondrial DNA and the Y chromosome have proven
      invaluable for generating a standard model for evolution of modern humans.
      Conclusions from earlier research on protein polymorphisms have been generally
      supported by more sophisticated DNA analysis. Co-evolution of genes with language
      and some slowly evolving cultural traits, together with the genetic evolution of
      commensals and parasites that have accompanied modern humans in their expansion
      from Africa to the other continents, supports and supplements the standard model
      of genetic evolution. The advances in our understanding of the evolutionary
      history of humans attests to the advantages of multidisciplinary research.

PMID- 12610538
TI  - The transformation of the model organism: a decade of developmental genetics.
AB  - The past decade has seen the development of powerful techniques to dissect the
      molecular processes that regulate development. New tools have been used to reveal
      the basis of cell polarity, morphogen gradients and regulation of signaling in
      developing animals. Cell biology and developmental biology have become closely
      intertwined, and many genes that had been thought of as regulators of general
      cell biological (housekeeping) functions have been shown to act as specific
      developmental regulators. Vertebrate developmental genetics is now flourishing,
      with forward and reverse genetics in both zebrafish and the mouse providing new
      dimensions to our understanding of development.

PMID- 12610539
TI  - Plant genetics: a decade of integration.
AB  - The last decade provided the plant science community with the complete genome
      sequence of Arabidopsis thaliana and rice, tools to investigate the function of
      potentially every plant gene, methods to dissect virtually any aspect of the
      plant life cycle, and a wealth of information on gene expression and protein
      function. Focusing on Arabidopsis as a model system has led to an integration of
      the plant sciences that triggered the development of new technologies and
      concepts benefiting plant research in general. These enormous changes led to an
      unprecedented increase in our understanding of the genetic basis and molecular
      mechanisms of developmental, physiological and biochemical processes, some of
      which will be discussed in this article.

PMID- 12610540
TI  - Bioinformatics in the post-sequence era.
AB  - In the past decade, bioinformatics has become an integral part of research and
      development in the biomedical sciences. Bioinformatics now has an essential role
      both in deciphering genomic, transcriptomic and proteomic data generated by high
      throughput experimental technologies and in organizing information gathered from
      traditional biology. Sequence-based methods of analyzing individual genes or
      proteins have been elaborated and expanded, and methods have been developed for
      analyzing large numbers of genes or proteins simultaneously, such as in the
      identification of clusters of related genes and networks of interacting proteins.
      With the complete genome sequences for an increasing number of organisms at hand,
      bioinformatics is beginning to provide both conceptual bases and practical
      methods for detecting systemic functional behaviors of the cell and the organism.

PMID- 12610541
TI  - Proteomics: the first decade and beyond.
AB  - Proteomics is the systematic study of the many and diverse properties of proteins
      in a parallel manner with the aim of providing detailed descriptions of the
      structure, function and control of biological systems in health and disease.
      Advances in methods and technologies have catalyzed an expansion of the scope of
      biological studies from the reductionist biochemical analysis of single proteins
      to proteome-wide measurements. Proteomics and other complementary analysis
      methods are essential components of the emerging 'systems biology' approach that
      seeks to comprehensively describe biological systems through integration of
      diverse types of data and, in the future, to ultimately allow computational
      simulations of complex biological systems.

PMID- 12610542
TI  - Bankable assets?

PMID- 12610543
TI  - Myelin: not just a conduit for conduction.

PMID- 12610544
TI  - Intoxicated cells and stomach ulcers.

PMID- 12610545
TI  - Fibrillin controls TGF-beta activation.

PMID- 12610546
TI  - Connecting the dots.

PMID- 12610550
TI  - Is Tsix repression of Xist specific to mouse?

PMID- 12610552
TI  - A cast of thousands.

PMID- 12610553
TI  - UK industry consolidation is slow despite big merger.

PMID- 12610554
TI  - US budget/Bioshield initiative emphasizes bioterrorism countermeasures.

PMID- 12610555
TI  - US authorities uphold suspension of SCID gene therapy.

PMID- 12610556
TI  - Japan launches new life-science initiatives.

PMID- 12610558
TI  - Data analysis--the Achilles heel of proteomics.

PMID- 12610559
TI  - Recombinant antibody microarrays--a viable option?

PMID- 12610560
TI  - Encoding technical information in GM organisms.

PMID- 12610561
TI  - Transgenic organisms--time for conceptual diversification?

PMID- 12610562
TI  - Why reinvent risk?

PMID- 12610563
TI  - Telomere-driven replicative senescence is a stress response.

PMID- 12610564
TI  - Choosing CCR5 or Rev siRNA in HIV-1.

PMID- 12610565
TI  - In the pursuit of industrial proteomics.

PMID- 12610566
TI  - 'Omics' of the mitochondrion.

PMID- 12610567
TI  - Bringing diabetes therapeutics to the big screen.

PMID- 12610568
TI  - Fingers reach for the genome.

PMID- 12610569
TI  - Harnessing microbial appetites for remediation.

PMID- 12610571
TI  - A systematic approach to modeling, capturing, and disseminating proteomics
      experimental data.
AB  - Both the generation and the analysis of proteome data are becoming increasingly
      widespread, and the field of proteomics is moving incrementally toward high
      throughput approaches. Techniques are also increasing in complexity as the
      relevant technologies evolve. A standard representation of both the methods used
      and the data generated in proteomics experiments, analogous to that of the MIAME
      (minimum information about a microarray experiment) guidelines for
      transcriptomics, and the associated MAGE (microarray gene expression) object
      model and XML (extensible markup language) implementation, has yet to emerge.
      This hinders the handling, exchange, and dissemination of proteomics data. Here,
      we present a UML (unified modeling language) approach to proteomics experimental
      data, describe XML and SQL (structured query language) implementations of that
      model, and discuss capture, storage, and dissemination strategies. These make
      explicit what data might be most usefully captured about proteomics experiments
      and provide complementary routes toward the implementation of a proteome
      repository.

PMID- 12610572
TI  - Proteomic analysis of post-translational modifications.
AB  - Post-translational modifications modulate the activity of most eukaryote
      proteins. Analysis of these modifications presents formidable challenges but
      their determination generates indispensable insight into biological function.
      Strategies developed to characterize individual proteins are now systematically
      applied to protein populations. The combination of function- or structure-based
      purification of modified 'subproteomes', such as phosphorylated proteins or
      modified membrane proteins, with mass spectrometry is proving particularly
      successful. To map modification sites in molecular detail, novel mass
      spectrometric peptide sequencing and analysis technologies hold tremendous
      potential. Finally, stable isotope labeling strategies in combination with mass
      spectrometry have been applied successfully to study the dynamics of
      modifications.

PMID- 12610573
TI  - The application of mass spectrometry to membrane proteomics.
AB  - Membrane proteins perform some of the most important functions in the cell,
      including the regulation of cell signaling through surface receptors, cell-cell
      interactions, and the intracellular compartmentalization of organelles. Recent
      developments in proteomic strategies have focused on the inclusion of membrane
      proteins in high-throughput analyses. While slow and steady progress continues to
      be made in gel-based technologies, significant advances have been reported in non
      gel shotgun methods using liquid chromatography coupled to mass spectrometry
      (LC/MS). These latter strategies facilitate the identification of large numbers
      of membrane proteins and modifications, and have the potential to provide
      insights into protein topology and orientation in membranes.

PMID- 12610574
TI  - Equivalents in biotechnology patents.

PMID- 12610578
TI  - Bioveterinary science: development of a discipline.

PMID- 12610579
TI  - Missing the big picture.

PMID- 12610580
TI  - Shuttle inquiry to piece disaster together from the ground up.

PMID- 12610581
TI  - Biologists wary that cash up front could mean cuts later.

PMID- 12610582
TI  - DNA study deepens rift over Iceland's genetic heritage.

PMID- 12610583
TI  - Cancer fears cast doubts on future of gene therapy.

PMID- 12610585
TI  - Long-lost wave report sinks asteroid impact theory.

PMID- 12610584
TI  - London gears up for road congestion charge.

PMID- 12610587
TI  - Hints of age bias spur calls for grant reforms.

PMID- 12610588
TI  - India debates results of its first transgenic cotton crop.

PMID- 12610586
TI  - Civil war leaves Ivory Coast research in tatters.

PMID- 12610591
TI  - Replacing the Space shuttle: On wings and a prayer.

PMID- 12610589
TI  - Social scientists call for abolition of dishonesty committee.

PMID- 12610593
TI  - Flying into history.

PMID- 12610592
TI  - Epigenetics and disease: Altered states.

PMID- 12610594
TI  - Concern about Japan's unclear biotech regulations.

PMID- 12610595
TI  - Reviewing should be shown in publication list.

PMID- 12610602
TI  - Thermohaline circulation: The current climate.

PMID- 12610596
TI  - Toxicology rethinks its central belief.

PMID- 12610603
TI  - Molecular motors: A magnificent machine.

PMID- 12610604
TI  - Quantum gravity: The quantum of area?

PMID- 12610605
TI  - Inflammation: Border crossings.

PMID- 12610606
TI  - Global change: Dishing the dirt on coral reefs.

PMID- 12610607
TI  - Autoimmunity: A case of mistaken identity.

PMID- 12610609
TI  - Astronomy: Hot gas around the Galaxy.

PMID- 12610611
TI  - Human behaviour: Adult persistence of head-turning asymmetry.

PMID- 12610612
TI  - Planetary science: Volcanism or aqueous alteration on Mars?

PMID- 12610614
TI  - Physiology: Why does metabolic rate scale with body size?

PMID- 12610615
TI  - Physiology: Allometric cascades.

PMID- 12610618
TI  - The far-ultraviolet signature of the 'missing' baryons in the Local Group of
      galaxies.
AB  - The number of baryons detected in the low-redshift (z < 1) Universe is far
      smaller than the number detected in corresponding volumes at higher redshifts.
      Simulations of the formation of structure in the Universe show that up to two
      thirds of the 'missing' baryons may have escaped detection because of their high
      temperature and low density. One of the few ways to detect this matter directly
      is to look for its signature in the form of ultraviolet absorption lines in the
      spectra of background sources such as quasars. Here we show that the amplitude of
      the average velocity vector of 'high velocity' O vi (O5+) absorption clouds
      detected in a survey of ultraviolet emission from active galactic nuclei
      decreases significantly when the vector is transformed to the frames of the
      Galactic Standard of Rest and the Local Group of galaxies. At least 82 per cent
      of these absorbers are not associated with any 'high velocity' atomic hydrogen
      complex in our Galaxy, and are therefore likely to result from a primordial warm
      hot intergalactic medium pervading an extended corona around the Milky Way or the
      Local Group. The total mass of baryons in this medium is estimated to be up to
      approximately 10(12) solar masses, which is of the order of the mass required to
      dynamically stabilize the Local Group.

PMID- 12610617
TI  - Dynein structure and power stroke.
AB  - Dynein ATPases are microtubule motors that are critical to diverse processes such
      as vesicle transport and the beating of sperm tails; however, their mechanism of
      force generation is unknown. Each dynein comprises a head, from which a stalk and
      a stem emerge. Here we use electron microscopy and image processing to reveal new
      structural details of dynein c, an isoform from Chlamydomonas reinhardtii
      flagella, at the start and end of its power stroke. Both stem and stalk are
      flexible, and the stem connects to the head by means of a linker approximately 10
      nm long that we propose lies across the head. With both ADP and vanadate bound,
      the stem and stalk emerge from the head 10 nm apart. However, without nucleotide
      they emerge much closer together owing to a change in linker orientation, and the
      coiled-coil stalk becomes stiffer. The net result is a shortening of the molecule
      coupled to an approximately 15-nm displacement of the tip of the stalk. These
      changes indicate a mechanism for the dynein power stroke.

PMID- 12610619
TI  - Experimental realization of freely propagating teleported qubits.
AB  - Quantum teleportation is central to quantum communication, and plays an important
      role in a number of quantum computation protocols. Most information-processing
      applications of quantum teleportation include the subsequent manipulation of the
      qubit (the teleported photon), so it is highly desirable to have a teleportation
      procedure resulting in high-quality, freely flying qubits. In our previous
      teleportation experiment, the teleported qubit had to be detected (and thus
      destroyed) to verify the success of the procedure. Here we report a teleportation
      experiment that results in freely propagating individual qubits. The basic idea
      is to suppress unwanted coincidence detection events by providing the photon to
      be teleported much less frequently than the auxiliary entangled pair. Therefore,
      a case of successful teleportation can be identified with high probability
      without the need actually to detect the teleported photon. The experimental
      fidelity of our procedure surpasses the theoretical limit required for the
      implementation of quantum repeaters.

PMID- 12610620
TI  - A stable silicon-based allene analogue with a formally sp-hybridized silicon
      atom.
AB  - Carbon chemistry exhibits a rich variety in bonding patterns, with homo- or
      heteronuclear multiple bonds involving sp-hybridized carbon atoms as found in
      molecules such as acetylenes, nitriles, allenes and carbon dioxide. Carbon's
      heavier homologues in group 14 of the periodic table--including silicon,
      germanium and tin--were long thought incapable of forming multiple bonds because
      of the less effective p(pi)-p(pi) orbital overlap involved in the multiple bonds.
      However, bulky substituents can protect unsaturated bonds and stabilize compounds
      with formally sp-hybridized heavy group-14 atoms: stable germanium, tin and lead
      analogues of acetylene derivatives and a marginally stable tristannaallene have
      now been reported. However, no stable silicon compounds with formal sp-silicon
      atoms have been isolated. Evidence for the existence of a persistent
      disilaacetylene and trapping of transient 2-silaallenes and other X = Si = X'
      type compounds (X, X' = O, CR2, NR, and so on) are also known, but stable silicon
      compounds with formally sp-hybridized silicon atoms have not yet been isolated.
      Here we report the synthesis of a thermally stable, crystalline trisilaallene
      derivative containing a formally sp-hybridized silicon atom. We find that, in
      contrast to linear carbon allenes, the trisilaallene is significantly bent. The
      central silicon in the molecule is dynamically disordered, which we ascribe to
      ready rotation of the central silicon atom around the molecular axis.

PMID- 12610621
TI  - Coral record of increased sediment flux to the inner Great Barrier Reef since
      European settlement.
AB  - The effect of European settlement on water quality in the Great Barrier Reef of
      Australia is a long-standing and controversial issue. Erosion and sediment
      transport in river catchments in this region have increased substantially since
      European settlement, but the magnitude of these changes remains uncertain. Here
      we report analyses of Ba/Ca ratios in long-lived Porites coral from Havannah Reef
      -a site on the inner Great Barrier Reef that is influenced by flood plumes from
      the Burdekin river--to establish a record of sediment fluxes from about 1750 to
      1998. We find that, in the early part of the record, suspended sediment from
      river floods reached the inner reef area only occasionally, whereas after about
      1870--following the beginning of European settlement--a five- to tenfold increase
      in the delivery of sediments is recorded with the highest fluxes occurring during
      the drought-breaking floods. We conclude that, since European settlement, land
      use practices such as clearing and overstocking have led to major degradation of
      the semi-arid river catchments, resulting in substantially increased sediment
      loads entering the inner Great Barrier Reef.

PMID- 12610622
TI  - A discontinuity in mantle composition beneath the southwest Indian ridge.
AB  - The composition of mid-ocean-ridge basalt is known to correlate with attributes
      such as ridge topography and seismic velocity in the underlying mantle, and these
      correlations have been interpreted to reflect variations in the average extent
      and mean pressures of melting during mantle upwelling. In this respect, the
      eastern extremity of the southwest Indian ridge is of special interest, as its
      mean depth of 4.7 km (ref. 4), high upper-mantle seismic wave velocities and thin
      oceanic crust of 4-5 km (ref. 6) suggest the presence of unusually cold mantle
      beneath the region. Here we show that basaltic glasses dredged in this zone, when
      compared to other sections of the global mid-ocean-ridge system, have higher
      Na(8.0), Sr and Al2O3 compositions, very low CaO/Al2O3 ratios relative to TiO2
      and depleted heavy rare-earth element distributions. This signature cannot simply
      be ascribed to low-degree melting of a typical mid-ocean-ridge source mantle, as
      different geochemical indicators of the extent of melting are mutually
      inconsistent. Instead, we propose that the mantle beneath approximately 1,000 km
      of the southwest Indian ridge axis has a complex history involving extensive
      earlier melting events and interaction with partial melts of a more fertile
      source.

PMID- 12610623
TI  - Single origin of Malagasy Carnivora from an African ancestor.
AB  - The Carnivora are one of only four orders of terrestrial mammals living in
      Madagascar today. All four (carnivorans, primates, rodents and lipotyphlan
      insectivores) are placental mammals with limited means for dispersal, yet they
      occur on a large island that has been surrounded by a formidable oceanic barrier
      for at least 88 million years, predating the age of origin for any of these
      groups. Even so, as many as four colonizations of Madagascar have been proposed
      for the Carnivora alone. The mystery of the island's mammalian origins is
      confounded by its poor Tertiary fossil record, which leaves us with no direct
      means for estimating dates of initial diversification. Here we use a multi-gene
      phylogenetic analysis to show that Malagasy carnivorans are monophyletic and thus
      the product of a single colonization of Madagascar by an African ancestor.
      Furthermore, a bayesian analysis of divergence ages for Malagasy carnivorans and
      lemuriforms indicates that their respective colonizations were temporally
      separated by tens of millions of years. We therefore conclude that a single
      event, such as vicariance or common dispersal, cannot explain the presence of
      both groups in Madagascar.

PMID- 12610624
TI  - The effect of aggressiveness on the population dynamics of a territorial bird.
AB  - A central issue in ecology lies in identifying the importance of resources,
      natural enemies and behaviour in the regulation of animal populations. Much of
      the debate on this subject has focused on animals that show cyclic fluctuations
      in abundance. However, there is still disagreement about the role of extrinsic
      (food, parasites or predators) and intrinsic (behaviour) factors in causing
      cycles. Recent studies have examined the impact of natural enemies, although
      spatial patterns resulting from restricted dispersal or recruitment are
      increasingly recognized as having the potential to influence unstable population
      dynamics. We tested the hypothesis that population cycles in a territorial bird,
      red grouse Lagopus lagopus scoticus, are caused by delayed density-dependent
      changes in the aggressiveness and spacing behaviour of males. Here we show that
      increasing aggressiveness experimentally for a short period in autumn reduced
      recruitment and subsequent breeding density by 50%, and changed population
      trajectories from increasing to declining. Intrinsic processes can therefore have
      fundamental effects on population dynamics.

PMID- 12610625
TI  - Auxin promotes Arabidopsis root growth by modulating gibberellin response.
AB  - The growth of plant organs is influenced by a stream of the phytohormone auxin
      that flows from the shoot apex to the tip of the root. However, until now it has
      not been known how auxin regulates the cell proliferation and enlargement that
      characterizes organ growth. Here we show that auxin controls the growth of roots
      by modulating cellular responses to the phytohormone gibberellin (GA). GA
      promotes the growth of plants by opposing the effects of nuclear DELLA protein
      growth repressors, one of which is Arabidopsis RGA (for repressor of gal-3). GA
      opposes the action of several DELLA proteins by destabilizing them, reducing both
      the concentration of detectable DELLA proteins and their growth-restraining
      effects. We also show that auxin is necessary for GA-mediated control of root
      growth, and that attenuation of auxin transport or signalling delays the GA
      induced disappearance of RGA from root cell nuclei. Our observations indicate
      that the shoot apex exerts long-distance control on the growth of plant organs
      through the effect of auxin on GA-mediated DELLA protein destabilization.

PMID- 12610626
TI  - Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune
      inflammation of the brain.
AB  - Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40
      subunits. Analyses in vitro have defined IL-12 as an important factor for the
      differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting
      interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL
      12 is essential for T-cell-dependent immune and inflammatory responses in vivo,
      primarily through the use of IL-12 p40 gene-targeted mice and neutralizing
      antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL
      12 but a different p19 subunit, is produced predominantly by macrophages and
      dendritic cells, and shows activity on memory T cells. Evidence from studies of
      IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest,
      however, that IL-23 may also affect macrophage function directly. Here we show,
      by using gene-targeted mice lacking only IL-23 and cytokine replacement studies,
      that the perceived central role for IL-12 in autoimmune inflammation,
      specifically in the brain, has been misinterpreted and that IL-23, and not IL-12,
      is the critical factor in this response. In addition, we show that IL-23, unlike
      IL-12, acts more broadly as an end-stage effector cytokine through direct actions
      on macrophages.

PMID- 12610627
TI  - Targeted recycling of PECAM from endothelial surface-connected compartments
      during diapedesis.
AB  - Leukocytes enter sites of inflammation by squeezing through the borders between
      endothelial cells that line postcapillary venules at that site. This rapid
      process, called transendothelial migration (TEM) or diapedesis, is completed
      within 90 s after a leukocyte arrests on the endothelial surface. In this time,
      the leukocyte moves in ameboid fashion across the endothelial borders, which
      remain tightly apposed to it during transit. It is not known how the endothelial
      cell changes its borders rapidly and reversibly to accommodate the migrating
      leukocyte. Here we show that there is a membrane network just below the
      plasmalemma at the cell borders that is connected at intervals to the junctional
      surface. PECAM-1, an integral membrane protein with an essential role in TEM, is
      found in this compartment and constitutively recycles evenly along endothelial
      cell borders. During TEM, however, recycling PECAM is targeted to segments of the
      junction across which monocytes are in the act of migration. In addition,
      blockade of TEM with antibodies against PECAM specifically blocks the recruitment
      of this membrane to the zones of leukocyte migration, without affecting the
      constitutive membrane trafficking.

PMID- 12610628
TI  - Cdc42 regulates GSK-3beta and adenomatous polyposis coli to control cell
      polarity.
AB  - Cell polarity is a fundamental property of all cells. In higher eukaryotes, the
      small GTPase Cdc42, acting through a Par6-atypical protein kinase C (aPKC)
      complex, is required to establish cellular asymmetry during epithelial
      morphogenesis, asymmetric cell division and directed cell migration. However,
      little is known about what lies downstream of this complex. Here we show, through
      the use of primary rat astrocytes in a cell migration assay, that Par6-PKCzeta
      interacts directly with and regulates glycogen synthase kinase-3beta (GSK-3beta)
      to promote polarization of the centrosome and to control the direction of cell
      protrusion. Cdc42-dependent phosphorylation of GSK-3beta occurs specifically at
      the leading edge of migrating cells, and induces the interaction of adenomatous
      polyposis coli (Apc) protein with the plus ends of microtubules. The association
      of Apc with microtubules is essential for cell polarization. We conclude that
      Cdc42 regulates cell polarity through the spatial regulation of GSK-3beta and
      Apc. This role for Apc may contribute to its tumour-suppressor activity.

PMID- 12610629
TI  - Structure of the extracellular region of HER2 alone and in complex with the
      Herceptin Fab.
AB  - HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor
      receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in
      humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4). ErbB
      receptors are essential mediators of cell proliferation and differentiation in
      the developing embryo and in adult tissues, and their inappropriate activation is
      associated with the development and severity of many cancers. Overexpression of
      HER2 is found in 20-30% of human breast cancers, and correlates with more
      aggressive tumours and a poorer prognosis. Anticancer therapies targeting ErbB
      receptors have shown promise, and a monoclonal antibody against HER2, Herceptin
      (also known as trastuzumab), is currently in use as a treatment for breast
      cancer. Here we report crystal structures of the entire extracellular regions of
      rat HER2 at 2.4 A and human HER2 complexed with the Herceptin antigen-binding
      fragment (Fab) at 2.5 A. These structures reveal a fixed conformation for HER2
      that resembles a ligand-activated state, and show HER2 poised to interact with
      other ErbB receptors in the absence of direct ligand binding. Herceptin binds to
      the juxtamembrane region of HER2, identifying this site as a target for
      anticancer therapies.

PMID- 12610630
TI  - Crystal structure of the specificity domain of ribonuclease P.
AB  - RNase P is the only endonuclease responsible for processing the 5' end of
      transfer RNA by cleaving a precursor and leading to tRNA maturation. It contains
      an RNA component and a protein component and has been identified in all
      organisms. It was one of the first catalytic RNAs identified and the first that
      acts as a multiple-turnover enzyme in vivo. RNase P and the ribosome are so far
      the only two ribozymes known to be conserved in all kingdoms of life. The RNA
      component of bacterial RNase P can catalyse pre-tRNA cleavage in the absence of
      the RNase P protein in vitro and consists of two domains: a specificity domain
      and a catalytic domain. Here we report a 3.15-A resolution crystal structure of
      the 154-nucleotide specificity domain of Bacillus subtilis RNase P. The structure
      reveals the architecture of this domain, the interactions that maintain the
      overall fold of the molecule, a large non-helical but well-structured module that
      is conserved in all RNase P RNA, and the regions that are involved in
      interactions with the substrate.

PMID- 12610631
TI  - Metal-insulator transition in chains with correlated disorder.

PMID- 12610632
TI  - A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and
      clk-1 mutants.

PMID- 12610634
TI  - A moving story.

PMID- 12610635
TI  - Location, location, location.

PMID- 12610641
TI  - The fate of neural crest stem cells: nature vs nurture.

PMID- 12610642
TI  - Anger is a wind that blows out the light of the mind (old proverb).

PMID- 12610643
TI  - MMR and autistic enterocolitis: consistent epidemiological failure to find an
      association.

PMID- 12610644
TI  - Molecular basis of lithium action: integration of lithium-responsive signaling
      and gene expression networks.
AB  - The clinical efficacy of lithium in the prophylaxis of recurrent affective
      episodes in bipolar disorder is characterized by a lag in onset and remains for
      weeks to months after discontinuation. Thus, the long-term therapeutic effect of
      lithium likely requires reprogramming of gene expression. Protein kinase C and
      glycogen synthase kinase-3 signal transduction pathways are perturbed by chronic
      lithium at therapeutically relevant concentrations and have been implicated in
      modulating synaptic function in nerve terminals. These signaling pathways offer
      an opportunity to model critical signals for altering gene expression programs
      that underlie adaptive responses of neurons to long-term lithium exposure. While
      the precise physiological events critical for the clinical efficacy of lithium
      remain unknown, we propose that linking lithium-responsive genes as a regulatory
      network will provide a strategy to identify signature gene expression patterns
      that distinguish between therapeutic and nontherapeutic actions of lithium.

PMID- 12610645
TI  - Recombination in a schizophrenic proband fails to exclude CHRNA7 at chromosome
      15q14.

PMID- 12610646
TI  - Association between the BDNF gene and schizophrenia.

PMID- 12610647
TI  - The axonal chemorepellant semaphorin 3A is increased in the cerebellum in
      schizophrenia and may contribute to its synaptic pathology.
AB  - The neuropathological features of schizophrenia are suggestive of a
      developmentally induced impairment of synaptic connectivity. Semaphorin 3A
      (sema3A) might contribute to this process because it is a secreted chemorepellant
      which regulates axonal guidance. We have investigated sema3A in the cerebellum
      (an area in which expression persists in adulthood), and measured its abundance
      in 16 patients with schizophrenia and 16 controls. In adults, sema3A was
      predominantly localized to the inner part of the molecular layer neuropil,
      whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A
      was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay
      (+28%; P<0.05) and immunohistochemistry (+45%; P<0.01). We also measured reelin
      mRNA, since reelin is involved in related developmental processes and is
      decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend
      reduction in the subjects with schizophrenia (-26%; P=0.07) and, notably, was
      negatively correlated with sema3A. Sema3A also correlated negatively with
      synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in
      schizophrenia, and is associated with downregulation of genes involved in
      synaptic formation and maintenance. In this respect, sema3A appears to contribute
      to the synaptic pathology of schizophrenia, perhaps via ongoing effects of
      persistent sema3A elevation on synaptic plasticity. The findings are consistent
      with an early neurodevelopmental origin for the disorder, and the reciprocal
      changes in sema3A and reelin may be indicative of a pathogenic mechanism that
      affects the balance between trophic and inhibitory factors regulating
      synaptogenesis.

PMID- 12610649
TI  - Differences in neuroanatomical sites of apoD elevation discriminate between
      schizophrenia and bipolar disorder.
AB  - We previously demonstrated that apolipoprotein D (apoD) levels are elevated in
      the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects
      with schizophrenia and bipolar disorder compared to controls, suggesting a focal
      compensatory response to neuropathology associated with psychiatric disorders. We
      have now extended those studies by measuring apoD protein levels in additional
      brain regions from post-mortem samples of schizophrenic and bipolar disorder
      subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were
      observed in the lateral prefrontal cortex (Brodmann Area 46) in both
      schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex
      (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder,
      respectively). However, differences between the disease groups were observed in
      other brain regions. In subjects with schizophrenia, but not bipolar disorder,
      apoD levels were significantly elevated in the amygdala (42.8%) and thalamus
      (31.7%), while in bipolar disorder, but not schizophrenia, additional increases
      were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate
      cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical
      overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well
      as areas of pathology that distinguish the two disorders.

PMID- 12610648
TI  - Identification of candidate genes for psychosis in rat models, and possible
      association between schizophrenia and the 14-3-3eta gene.
AB  - Although the genetic contribution to schizophrenia is substantial, positive
      findings in whole-genome linkage scans have not been consistently replicated. We
      analyzed gene expression in various rat conditions to identify novel candidate
      genes for schizophrenia. Suppression subtraction hybridization (SSH), with polyA
      mRNA from temporal and frontal cortex of rats, was used to identify
      differentially expressed genes. Expression of mRNA was compared between adult
      Lewis and Fischer 344 (F344) rats, adult and postnatal day 6 (d6) F344, and adult
      F344 treated with haloperidol or control vehicle. These groups were chosen
      because each highlights a particular aspect of schizophrenia: differences in
      strain vulnerability to behavioral analogs of psychosis; factors that may relate
      to disease onset in relation to CNS development; and improvement of symptoms by
      haloperidol. The 14-3-3 gene family, as represented by 14-3-3gamma and 14-3-3zeta
      isoforms in the SSH study, and SNAP-25 were among the candidate genes. Genetic
      association between schizophrenia and the 14-3-3eta gene, positioned close to a
      genomic locus implicated in schizophrenia, and SNAP-25 genes was analyzed in 168
      schizophrenia probands and their families. These findings address three different
      genes in the 14-3-3 family. We find a significant association with schizophrenia
      for two polymorphisms in the 14-3-3eta gene: a 7 bp variable number of tandem
      repeats in the 5' noncoding region (P=0.036, 1 df), and a 3' untranslated region
      SNP (753G/A) that is an RFLP visualized with Ava II (P=0.028). There was no
      significant genetic association with SNAP-25. The candidate genes identified may
      be of functional importance in the etiology, pathophysiology or treatment
      response of schizophrenia or psychotic symptoms. This is to our knowledge the
      first report of a significant association between the 14-3-3eta-chain gene and
      schizophrenia in a family-based sample, strengthening prior association reports
      in case-control studies and microarray gene expression studies.

PMID- 12610650
TI  - Linkage disequilibrium mapping provides further evidence of a gene for reading
      disability on chromosome 6p21.3-22.
AB  - Linkage disequilibrium (LD) mapping was used to follow up reports of linkage
      between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22.
      Using a two-stage approach, we tested for association between RD and 22
      microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage
      2) parent/proband trios in which RD was rigorously defined. The most significant
      replicated associations were observed between combinations of markers
      D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2,
      P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001).
      The only two-marker association observed in both samples was with D6S422/1665
      (P=0.01, 0.04). No single marker showed replicated association but D6S506
      produced values of P=0.01 and 0.08 which were significant when combined (P=0.02).
      We observed weaker and less consistent evidence of association in a region of
      confirmed linkage to RD in previous studies. The most consistently significant
      haplotypic association D6S109/422/1665, showed association with single-word
      reading, spelling, phonological awareness, phonological decoding, orthographic
      accuracy and random automised naming, but not with vocabulary or Attention
      Deficit Hyperactivity Disorder. Our findings strongly support the presence of a
      gene contributing to RD in a region of chromosome 6 between markers D6S109 and
      D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.

PMID- 12610651
TI  - Sodium channels SCN1A, SCN2A and SCN3A in familial autism.
AB  - Autism is a psychiatric disorder with estimated heritability of 90%. One-third of
      autistic individuals experience seizures. A susceptibility locus for autism was
      mapped near a cluster of voltage-gated sodium channel genes on chromosome 2.
      Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder
      GEFS+. To evaluate these sodium channel genes as candidates for the autism
      susceptibility locus, we screened for variation in coding exons and splice sites
      in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of
      intron sequence were screened. Only six families carried variants with potential
      effects on sodium channel function. Five coding variants and one lariat
      branchpoint mutation were each observed in a single family, but were not present
      in controls. The variant R1902C in SCN2A is located in the calmodulin binding
      site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q
      in SCN1A was observed in one autism family and had previously been identified in
      a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint
      mutation was tested in cultured lymphoblasts. Additional population studies and
      functional tests will be required to evaluate pathogenicity of the coding and
      lariat site variants. SNP density was 1/kb in the genomic sequence screened. We
      report 38 sodium channel SNPs that will be useful in future association and
      linkage studies.

PMID- 12610652
TI  - Activation of Wnt signaling rescues neurodegeneration and behavioral impairments
      induced by beta-amyloid fibrils.
AB  - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is
      probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We
      report here molecular changes induced by Abeta, both in neuronal cells in culture
      and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as
      an in vivo model of the disease. Results indicate that in both systems, Abeta
      neurotoxicity resulted in the destabilization of endogenous levels of beta
      catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which
      mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the
      survival of post-mitotic neurons against Abeta neurotoxicity and recovered
      cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of
      Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and
      reversed with conditioned medium containing the Wnt-3a ligand. We also examined
      the spatial memory performance of rats injected with preformed Abeta fibrils in
      the Morris water maze paradigm, and found that chronic lithium treatment
      protected neurodegeneration by rescuing beta-catenin levels and improved the
      deficit in spatial learning induced by Abeta. Our results are consistent with the
      idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt
      signaling components and indicate that lithium or compounds that mimic this
      signaling cascade may be putative candidates for therapeutic intervention in
      Alzheimer's patients.

PMID- 12610653
TI  - Role of protein kinase Calpha in the regulated secretion of the amyloid precursor
      protein.
AB  - Protein kinase C (PKC) has a key role in the signal transduction machinery
      involved in the regulation of amyloid precursor protein (APP) metabolism. Direct
      and indirect receptor-mediated activation of PKC has been shown to increase the
      release of soluble APP (sAPPalpha) and reduce the secretion of beta-amyloid
      peptides. Experimental evidence suggests that specific isoforms of PKC, such as
      PKCalpha and PKC epsilon, are involved in the regulation of APP metabolism. In
      this study, we characterized the role of PKCalpha in the regulated secretion of
      APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a
      plasmid expressing PKCalpha antisense cDNA. Cells expressing antisense PKCalpha
      secrete less sAPPalpha in response to phorbol esters. In contrast, carbachol
      increases the secretion of sAPPalpha to similar levels in wild-type cells and in
      cells transfected with antisense PKCalpha by acting on APP metabolism through an
      indirect pathway partially involving the activation of PKC. These results suggest
      that the direct PKC-dependent activation of the APP secretory pathway is
      compromised by reduced PKCalpha expression and a specific role of this isoform in
      these mechanisms. On the other hand, indirect pathways that are also partially
      dependent on the mitogen-activated protein kinase signal transduction mechanism
      remain unaffected and constitute a redundant, compensatory mechanism within the
      APP secretory pathway.

PMID- 12610654
TI  - Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory
      formation.
AB  - Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic
      plasticity such as long-term potentiation (LTP), a form of synaptic correlate of
      learning and memory. BDNF is also implicated in learning and memory. We have
      demonstrated that radial arm maze training in rats for spatial learning and
      memory results in a significant increase in the BDNF mRNA expression in the
      hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only
      acquisition, but also maintenance and/or recall of spatial memory in the maze.
      Although these results suggest a role of BDNF for spatial memory processes, the
      signal transduction mechanisms that mediate the actions of BDNF remain unknown.
      Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB),
      phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the
      hippocampus increased in parallel with spatial memory formation. Moreover, an
      activation of translational processes was suggested in the hippocampus after the
      maze training. When spatial learning was inhibited by antisense BDNF
      oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K
      inhibitor wortmannin impaired spatial learning. Our findings suggested that
      activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the
      hippocampus is important for spatial memory.

PMID- 12610655
TI  - Disruption of nicotine conditioning by dopamine D(3) receptor ligands.
AB  - Tobacco smoking is the first cause of preventable death in modern countries.
      Nicotine replacement therapy or sustained release bupropion helps smoking
      cessation, but relapse rates are still very high. Nicotine, like other drugs of
      abuse, activates the dopamine mesolimbic system, which originates in the ventral
      tegmental area and projects notably to the nucleus accumbens. Situations or
      environmental stimuli previously associated with cigarette smoking, for example,
      smell of cigarette smoke, can elicit craving in abstinent smokers and promote
      relapse. Reducing the effects of nicotine-associated cues might therefore have
      potential therapeutic utility for smoking cessation. Such an approach has been
      validated for cocaine in animals, by using the dopamine D(3) receptor-selective
      partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior.
      Here we show that rats repeatedly injected with nicotine in a particular
      environment develop nicotine-conditioned locomotor responses, accompanied by an
      increase in D(3) receptor expression in the nucleus accumbens. This conditioned
      behavior was inhibited by BP 897 or a selective D(3) receptor antagonist,
      suggesting that antagonizing dopamine selectively at the D(3) receptor disrupts
      nicotine-conditioned effects and might represent a novel therapeutic approach for
      smoking cessation.

PMID- 12610656
TI  - Serotonin transporter availability correlates with alcohol intake in non-human
      primates.
AB  - A low level of alcohol intoxication upon initial exposure and impulsive
      aggressiveness predispose humans to alcoholism. In non-human primates, central
      serotonin transporter availability and turnover rate were associated with
      aggressive behavior and a low response to initial alcohol exposure. We assessed
      the respective effects of these factors on alcohol intake in a free choice
      paradigm. Serotonin transporter availability in the raphe area, the origin of
      central serotonergic projections, was measured with single-photon emission
      computed tomography and the radioligand [(123)I]beta-CIT in 11 rhesus monkeys
      with low and high central serotonin turnover. The amount of alcohol intake in the
      3-month observation period was positively correlated with serotonin transporter
      availability (R=0.76, P=0.006), but not with aggressiveness (R=0.19, P=0.6) or
      alcohol response upon first exposure (R=-0.48, P=0.2). In a linear multiple
      regression analysis with serotonin transporter availability, alcohol response,
      and aggressiveness as independent variables, 82% of the variance of alcohol
      intake was explained and serotonin transporter availability emerged as the only
      statistically significant factor (beta=7.81, P=0.006). These observations
      indicate that there may be a direct relationship between serotonin transporter
      availability and alcohol intake after controlling for aggression and alcohol
      response on first exposure.

PMID- 12610657
TI  - Agouti-related protein prevents self-starvation.
AB  - Food restriction leads to a paradoxical increase in physical activity and further
      suppression of food intake, such as observed in anorexia nervosa.(1,2) To
      understand this pathophysiological process, we induced physical hyperactivity and
      self-starvation in rats by restricting food in the presence of running wheels.
      Normally, decreased melanocortin receptor activity will prevent starvation.(3,4)
      However, we found that self-starvation increased melanocortin receptors in the
      ventral medial hypothalamus, a brain region involved in eating behavior.(5)
      Suppression of melanocortin receptor activity, via central infusion of Agouti
      related protein (AgRP), increased survival rate in these rats by counteracting
      physical hyperactivity, food intake suppression as well as deregulated body
      temperature. We conclude that self-starvation may result from insufficient
      suppression of central melanocortin receptor activity.

PMID- 12610658
TI  - Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers
      susceptibility to bipolar disorder.
AB  - There is evidence for the involvement of glutamatergic transmission in the
      pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie
      lithium and valproate) have been found to act via the N-methyl-D-aspartate
      receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of
      bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is
      coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence
      of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C
      polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or
      schizoaffective disorder, manic type, probands with their living parents were
      studied. In all, 73 triads had heterozygous parents for the 1001-G/C
      polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were
      suitable for the final analyses, that is, the transmission disequilibrium test
      (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we
      found a preferential transmission of the G allele to the affected individuals
      (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The
      1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest
      association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are
      replicated there could be important implications for the involvement of the GRIN1
      in the pathogenesis of BP. The role of the gene variants in predicting the
      response to mood stabilizers in BP should also be investigated.

PMID- 12610661
TI  - Florence Sabin and the mechanism of blood vessel lumenization during
      vasculogenesis.
AB  - The notion that blood vessel lumina and primordial blood plasma are linked by a
      single mechanism, intracellular vacuolation of angioblasts, has, for the most
      part, been overlooked since it was first described in the early decades of the
      last century. That vacuolation may play a major role in blood vessel formation
      during vasculogenesis is revisited from the perspective of Florence Sabin's
      seminal studies in the nascent mesoderm of living chick blastoderms.

PMID- 12610662
TI  - An integrin and Rho GTPase-dependent pinocytic vacuole mechanism controls
      capillary lumen formation in collagen and fibrin matrices.
AB  - A major question that remains unanswered concerning endothelial cell (EC)
      morphogenesis is how lumens are formed in three-dimensional extracellular
      matrices (ECMs). Studies from many laboratories have revealed a critical role for
      an ECM-integrin-cytoskeletal signaling axis during EC morphogenesis. We have
      discovered a mechanism involving intracellular vacuole formation and coalescence
      that is required for lumen formation in several in vitro models of morphogenesis.
      In addition, a series of studies have observed vacuoles in vivo during angiogenic
      events. These vacuoles form through an integrin-dependent pinocytic mechanism in
      either collagen or fibrin matrices. In addition, we have shown that the Cdc42 and
      Rac1 guanosine triphosphatases (GTPases), which control actin and microtubule
      cytoskeletal networks, are required for vacuole and lumen formation. These
      GTPases are also known to regulate integrin signaling and are activated after
      integrin-matrix interactions. Furthermore, the expression of green fluorescent
      protein-Rac1 or -Cdc42 chimeric proteins in ECs results in the targeting of these
      fusion proteins to intracellular vacuole membranes during lumen formation. Thus,
      a matrix-integrin-cytoskeletal signaling axis involving both the Cdc42 and Rac1
      GTPases regulates the process of EC lumen formation in three-dimensional collagen
      or fibrin matrices.

PMID- 12610663
TI  - Lumen formation: in vivo versus in vitro observations.
AB  - Lumen formation must accompany the de novo growth of blood vessels during
      embryological development, the production of new vessels (vasculogenesis), and
      the expansion or remodeling of the microcirculation in differentiated tissue
      (angiogenesis). The debate over lumen origin centers on whether this is an
      intracellular or intercellular phenomenon, entailing vesicle accretion or loss of
      endothelial cell (EC) contact, and whether this represents an intrinsic property
      of ECs or relies on extrinsic signals. In addition, recent in vivo data suggest
      that a third mechanism, that of longitudinal division, may be used to expand
      existing capillary networks. Importantly, more than one mechanism of lumen
      formation may be found in response to a given angiogenic signal. Tubule formation
      by ECs in a matrix is an increasingly popular form of in vitro angiogenesis
      assay, and it may offer insights into the mechanisms involved during growth in
      embryos or under pathological conditions in adults. Crucial to the validity of in
      vitro preparations is the extent to which tubule assembly and lumen formation
      mirrors that observed in vivo, although these data cannot elucidate the controls
      operative during adaptive remodeling of the vascular bed. Similar structures may
      be observed in vivo and in vitro, and may represent the situation found during
      angiogenesis and vasculogenesis, respectively. Lumen formation during
      angiogenesis, and tubule formation during EC culture, require the existence of
      cell polarity. As tubule formation is not a unique property of ECs, how this is
      developed is a key area where in vitro studies may extend our understanding of EC
      biology.

PMID- 12610664
TI  - Branching out: a molecular fingerprint of endothelial differentiation into tube
      like structures generated by Affymetrix oligonucleotide arrays.
AB  - The process of endothelial differentiation into a network of tube-like structures
      with patent lumens requires an integrated program of gene expression. To identify
      genes upregulated in endothelial cells during the process of tube formation, RNA
      was prepared from several different time points (0, 4, 8, 24, 40, and 48 hours)
      and from three different experimental models of human endothelial tube formation:
      in collagen gels and fibrin gels driven by the combination of PMA (80), bFGF (40
      ng/ml) and bFGF (40 ng/ml) or in collagen gels driven by the combination of HGF
      (40 ng/ml) and VEGF (40 ng/ml). Gene expression was evaluated using Affymetrix
      Gene Chip oligonucleotide arrays. Over 1000 common genes were upregulated greater
      than twofold over baseline at one or more time points in the three different
      models. In the present study, we discuss the identified genes that could be
      assigned to major functional classes: apoptosis, cytoskeleton, proteases, matrix,
      and matrix turnover, pumps and transporters, membrane lipid turnover, and
      junctional molecules or adhesion proteins.

PMID- 12610665
TI  - Arteriogenesis: the development and growth of collateral arteries.
AB  - In patients with atherosclerotic vascular diseases, collateral vessels bypassing
      major arterial obstructions have frequently been observed. This may explain why
      some patients remain without symptoms or signs of ischemia. The term
      "arteriogenesis" was introduced to differentiate the formation of collateral
      arteries from angiogenesis, which mainly occurs in the ischemic, collateral flow
      dependent tissue. Many observations in various animal models and humans support
      that the remodeling of preexisting collateral vessels is the mechanism of
      collateral artery formation. This remodeling process seems to be mainly flow
      mediated. It involves endothelial cell activation, basal membrane degradation,
      leukocyte invasion, proliferation of vascular cells, neointima formation (in most
      species studied), and changes of the extracellular matrix. The contribution of
      ischemia to arteriogenesis is still unclear, but arteriogenesis clearly can occur
      in the absence of any significant ischemia. It is questionable, whether
      collateral arteries also form de novo in ischemic vascular diseases. A better
      understanding of the mechanisms of arteriogenesis will be important for the
      design of more effective strategies for the treatment of patients with ischemic
      vascular diseases.

PMID- 12610667
TI  - Hysterectomy: the right to choose.

PMID- 12610666
TI  - Microvascular remodeling: a complex continuum spanning angiogenesis to
      arteriogenesis.
AB  - Angiogenesis, the arterialization of capillaries, and arteriogenesis are specific
      manifestations of the complex continuum of blood vessel-remodeling processes that
      are produced by environmental stimuli. Together, they determine the integrative
      control of vascular assembly and pattern formation. Vascular assembly and pattern
      formation are critical elements of therapeutic vascular collateralization of
      progressively ischemic organs and in the tissue engineering or organogenesis of
      various tissue substitutes. An integrative systems approach is useful to measure
      the dynamics of vascular assembly in vivo across time scales from the embryo to
      the adult, and spanning spatial scales from cells to whole networks, to
      understand the complex interplay of multiple interacting cells and signal
      molecules. This requires in vivo observations, multiscale computer simulations,
      and tools for the genetic regulation of cell interactions. The new view of
      vascular remodeling as a continuum that can be manipulated in various tissues and
      in different size blood vessels, using appropriately coordinated multisignal
      stimuli, should open new therapeutic avenues.

PMID- 12610668
TI  - The management of nausea and vomiting of pregnancy.

PMID- 12610670
TI  - Reliability Study of the Laparoscopic Skills Index (LSI): a new measure of
      gynaecologic laparoscopic surgical skills.
AB  - OBJECTIVE: To construct and test the reliability of the Laparoscopic Skills Index
      (LSI) as a new, multi-item, objective measure of laparoscopic skills in
      gynaecology. METHODS: Construction of the LSI involved (1). item selection, (2).
      choosing a method to scale responses, (3). design, and (4). choosing a scoring
      method. Internal consistency and rater reliability were tested. One community
      based gynaecologist (rater A) and 3 teaching faculty gynaecologists (raters B, C,
      and D) reviewed 20 videotaped gynaecologic laparoscopy operations and scored
      operator (subject) performance. RESULTS: Cronbach's a was 0.95, indicating a high
      level of internal consistency. The intraclass correlation coefficient (ICC) for
      all 4 raters was 0.51 (95% confidence interval [CI], 0.20-0.76), indicative of
      moderate interrater reliability. A systematic observer bias was seen wherein
      rater A's scores closely paralleled, but were consistently higher than, those of
      raters B, C, and D. The ICC for raters B, C, and D only was 0.77 (95% CI, 0.56
      0.90), which is consistent with very good rater agreement. CONCLUSION: The LSI
      appears to have the properties of a reliable, unidimensional index, in which the
      item variables are true components of the overall attribute, that is,
      laparoscopic skill.

PMID- 12610671
TI  - Uterine compression sutures as an alternative to hysterectomy for severe
      postpartum hemorrhage.
AB  - OBJECTIVE: To assess the use of B-Lynch type uterine compression sutures as an
      alternative to hysterectomy for severe postpartum hemorrhage (PPH) due to uterine
      atony. METHODS: The use of uterine compression sutures for severe postpartum
      hemorrhage was reviewed over a 30-month period (January 2000 June 2002) in a
      tertiary obstetric unit. RESULTS: In 7 cases of uterine atony at the time of
      Caesarean section, which were unresponsive to all oxytocic agents, a B-Lynch type
      compression suture was used before resorting to hysterectomy. In 6 of the 7
      women, the bleeding was controlled with the suture, while the other required
      hysterectomy. CONCLUSION: At the time of writing there were 6 reports in the
      literature involving a total of 20 women who were successfully treated with this
      type of compression suture for severe atonic PPH. Our review adds 7 cases and
      found that the B-Lynch compression suture is easy to apply and should be
      considered in cases of severe atonic PPH when oxytocic agents fail, and before
      resorting to hysterectomy.

PMID- 12610672
TI  - Sublingual nitroglycerine as a tocolytic in external cephalic version: a
      comparative study.
AB  - OBJECTIVE: To study the effect of sublingual nitroglycerine as a tocolytic on the
      success rate of external cephalic version (ECV) in nulliparous and parous women.
      METHODS: A retrospective case-controlled study of all ECV cases from February
      1996 to February 2000 in a single centre. The rates of successful ECV were
      compared between women who had their ECV before February 1998 (control group),
      those who had their ECV after February 1998 and received 0.8 mg sublingual
      nitroglycerine spray as a tocolytic agent, and those who had their ECV after
      February 1998 and received no tocolytic agents. Nulliparous and parous women were
      studied separately. Data were collected for parity, gestational age, maternal
      age, placental localization, and side effects. Chi-square and Kruskal-Wallis
      tests were performed for statistical comparison. RESULTS: Of 150 women who had
      their ECV after February 1998, 120 (80%) received sublingual nitroglycerine
      (group 1: cases using 0.8 mg sublingual nitroglycerine spray as a tocolytic
      agent) and were compared to the 30 patients who did not receive sublingual
      nitroglycerine or other tocolytics after February 1998 (group 2) and to 137
      patients who had their ECV before February 1998 (control group). Of the women who
      received sublingual nitroglycerine, 5 (4%) had hypotension and 7 (6%) had
      headaches and/or nausea. The rate of successful ECV was 27% in group 1 versus 30%
      in group 2 (p = 0.86) versus 28% in the control group (p = 0.88) for nulliparous
      patients, and 67% versus 80% (p = 0.30) versus 51% (p = 0.09) respectively for
      parous women. However, the success rate was increased overall in parous women
      after the introduction of nitroglycerine as a tocolytic for ECV in February 1998
      (71% vs. 51%, p = 0.02). CONCLUSION: Although the success rate of ECV has
      increased in recent years, the use of sublingual nitroglycerine as a tocolytic
      was not associated with this higher success rate. A randomized, controlled trial
      is needed.

PMID- 12610673
TI  - Impact of participation in the Halifax County Preterm Birth Prevention Project.
AB  - OBJECTIVES: (1). To determine if participation in the Halifax County Preterm
      Birth Prevention Project (HCPBPP) reduced the risk of preterm birth; (2). to
      evaluate the degree to which specific components of the HCPBPP contributed to
      preterm-birth risk reduction. METHODS: A nested case-control study was conducted
      among women residing in Halifax County who gave birth at the IWK Grace Health
      Centre during the final year of the HCPBPP. Cases, defined as women who delivered
      preterm (<37 weeks), and controls, defined as women who delivered at full term,
      were recruited to complete interviewer-administered questionnaires. Three
      controls per case were sequentially selected. The exposures of interest were
      overall participation and compliance with specific components of the program.
      Univariate and multivariate statistical methods were employed to evaluate the
      effect of exposure to the preterm-birth prevention program. RESULTS: Seventy
      cases and 210 controls were enrolled in the study. Although 82% of subjects
      participated in some aspect of the HCPBPP, only 8% of high-risk and 6% of low
      risk women complied fully with program recommendations. Exposure to project
      educational strategies or pelvic examinations provided no protective benefit for
      preterm birth in low-risk or high-risk women. However, compliance with prenatal
      care providers recommendations to restrict activity or monitor for uterine
      contractions by self-palpation was associated with a marked reduction in the risk
      of preterm birth among low-risk women (odds ratio, 0.20; 95% confidence interval,
      0.08 0.50). CONCLUSION: Although full participation in the HCPBPP protocol was
      limited, the findings of this case-control study suggest that activity
      restriction and uterine activity monitoring by self-palpation may reduce the
      likelihood of preterm birth in women with no identifiable risk factors for
      prematurity.

PMID- 12610674
TI  - Economic evaluation in obstetrics and gynaecology: principles and practice.
AB  - Greater attention in health care over the last 2 decades has been placed on
      determining how best to spend the resources available. Economic evaluation is a
      commonly used tool to compare health-care services and treatments on the basis of
      costs and benefits. However, the principles on which economic evaluations are
      based are not well understood, and guidelines for conducting such evaluations in
      practice are often not followed. This paper describes the overarching principle
      of opportunity cost, and highlights the implication that decision-making in
      health care should necessarily be based on both costs and benefits. Two notions
      of efficiency, technical and allocative, are also presented, and the important
      point is made that the specific type of economic evaluation chosen must be based
      not on the unit of benefit in the given study, as is commonly done, but rather on
      the type of efficiency being addressed. The 3 primary types of economic
      evaluation are outlined, and a common pitfall in economic evaluation, the
      incremental cost-effectiveness ratio, is critiqued. Finally, a number of
      methodological considerations when conducting economic evaluations in practice
      are presented.

PMID- 12610675
TI  - Ruptured uterus: a seven-year review of cases from Accra, Ghana.
AB  - OBJECTIVE: To determine the incidence, causes, management, and the means of
      prevention of uterine rupture, as well as the characteristics of women with the
      condition, recorded in the Department of Obstetrics and Gynaecology at Korle-Bu
      Teaching Hospital in Accra, Ghana. DESIGN: A retrospective study between January
      1, 1995, and December 31, 2001. RESULTS: During the study period, of 82061
      deliveries at the Korle-Bu Teaching Hospital, 193 women developed uterine
      rupture, an incidence of 2.4 per 1000 deliveries. Of these 193 women, 24.6% had
      had a previous Caesarean section. The most frequent associated factor of uterine
      rupture was prolonged labour (33.6%). The perinatal mortality rate was 74.3%.
      Almost 70% (66.9%) of women underwent a total abdominal hysterectomy as
      management. The case fatality rate was 1.0%. CONCLUSION: A more vigilant approach
      to preventing prolonged and obstructed labour in delivery units within and around
      Accra, Ghana, is required to reduce the incidence of this condition.

PMID- 12610676
TI  - Statins.
AB  - Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors, otherwise known
      as statins, are the most common class of lipid lowering medications prescribed
      today. Although this class of medications is contraindicated in pregnant women
      and those trying to conceive, there are many individuals who would benefit from
      these medications. Multiple randomized controlled trials have demonstrated that
      statins are effective in both primary and secondary prevention of coronary artery
      disease. Simple risk stratification tools can identify the women who would
      benefit.

PMID- 12610677
TI  - Mifepristone.

PMID- 12610678
TI  - The presence of a third party during breast and pelvic examinations.

PMID- 12610679
TI  - Midwifery.

PMID- 12610680
TI  - Hemiparetic stroke impairs anticipatory control of arm movement.
AB  - Internal models are sensory motor mappings used by the nervous system to
      anticipate the force requirements of movement tasks. The ability to use internal
      models likely underlies the development of skillful control of the arm throughout
      life. It is currently unknown to what extent individuals with hemiparetic stroke
      can form and implement such internal models. To examine this issue, we measured
      whether such individuals could learn to anticipate forces applied to their arms
      by a lightweight robotic device as they practiced reaching to a target. Thirteen
      subjects with post-stroke hemiparesis were tested. Forces were applied to the
      arm, which curved the hand path in either the medial or lateral direction, as the
      subjects reached repeatedly towards a target located in front of them at their
      workspace boundary. The subjects exhibited a decreased ability to adapt to the
      perturbing forces with their hemiparetic arms. That is, they did not straighten
      their reaching path as well, compared to their ipsilesional arms, and they
      exhibited smaller aftereffects when the perturbing force was unexpectedly
      removed. The ability to adapt to the force improved significantly with decreasing
      impairment severity, as quantified using both clinical scales and quantitative
      strength measurements. Some subjects with strength reductions as severe as 60%
      were able to adapt to the fields, generating significant aftereffects. We
      conclude that hemiparetic stroke impairs the ability to implement internal models
      used for anticipatory control of arm movement, although even some severely
      weakened subjects retain at least a partial ability to form and use internal
      models. Finding ways to fully restore this adaptive ability, or to make use of
      what adaptive ability remains during rehabilitation, is an important goal for
      improving functional motor recovery.

PMID- 12610681
TI  - Matching different levels of isometric torque in elbow flexor muscles after
      eccentric exercise.
AB  - Human subjects generated a specified level of isometric torque with elbow flexor
      muscles of one arm, the reference arm, under visual feedback. They were then
      asked to generate what they perceived to be the same level, with the other arm,
      the indicator, but with no visual feedback. A number of torque levels, between 2%
      and 30% of maximum were used in the matching trials. Elbow flexors of one arm
      were then exercised eccentrically on a dynamometer. Immediately after the
      exercise, there was a large (40%) drop in maximum voluntary torque, as well as
      some soreness and swelling 24 h later, indicative of muscle damage. When the
      torque-matching experiment was repeated after the indicator arm had been
      exercised, the indicator signalled torque levels significantly below the
      reference level (P<0.05). When the reference arm was exercised, errors were in
      the opposite direction. Over the 4 days of testing post-exercise, errors became
      less as torque levels returned to normal. When errors were expressed in terms of
      maximum torque post-exercise, they were significantly reduced. This suggested
      that subjects were using as a matching cue the perceived effort required to
      generate a given level of torque rather than the level of torque itself.
      Persisting matching errors, from 24 h onwards after the eccentric contractions,
      were proposed to include a component attributable to the muscle soreness. Changes
      in electromyogram recorded after eccentric exercise were consistent with the
      effort-matching hypothesis. The muscle's torque-angle relationship was used to
      estimate matching ability in the absence of fatigue. One forearm was placed at
      various angles and its reference torque was matched by the other, the indicator,
      always at 90 degrees. Again, matching errors were consistent with an
      interpretation based on a match of effort rather than torque.

PMID- 12610682
TI  - Postnatal growth and column spacing in cat primary visual cortex.
AB  - The primary visual cortex (area 17) of cats continues to grow substantially
      during early postnatal development. To assess the implications of this growth for
      the organization of visual cortical maps, we analysed both postnatal growth of
      area 17 and the spacing of ocular dominance columns in the same animals using 2
      deoxyglucose autoradiography to label cortical activation patterns. Quantitative
      analyses of area size and column spacing were performed on flat-mount sections of
      the cortical hemispheres. Our analysis of the surface area revealed an average
      increase of the size of area 17 between the third and tenth postnatal weeks by
      about 51%. About 75% of this increase occurred during the third and sixth
      postnatal weeks (size increase of 37%). However, the distance between adjacent
      columns did not exhibit a similar increase but rather remained constant during
      the same postnatal period. Since cortical growth is not accompanied by an
      increased spacing of ocular dominance columns, new functional modules must
      somehow be added during the first postnatal weeks to occupy the enlarging
      cortical sheet. Possible mechanisms underlying the formation of new modules are
      discussed.

PMID- 12610683
TI  - Inhibition of midbrain-evoked tonic and rhythmic motor activity by cutaneous
      stimulation in decerebrate cats.
AB  - The effect of mechanical and electrical stimulation of cervical cutaneous
      afferents was analysed on both the centrally induced tonic and rhythmic
      activities in hindlimb antagonist muscle nerves of 16 decerebrate paralysed cats.
      Electrical stimulation of dorsal midbrain evoked in the nerve to the tibialis
      anterior muscle (TAn) either rhythmic discharges (n=14), associated with tonic
      discharges in ten cats, or only tonic discharges (n=4). Centrally induced
      activity in the ipsilateral nerve to gastrocnemius medialis (GMn) occurred in
      fewer cats (n=12) and displayed similar patterns as in TAn. Manual traction of
      the scruff of the neck reduced the TAn tonic and rhythmic discharges (n=6) by 73%
      (P<0.05) and 71% (P<0.05), respectively, and reduced only the tonic component of
      GMn discharges (by 41%, n=3). Electrical stimulation (impulses 0.1-0.5 ms, 50 Hz)
      of cervical nerves belonging to C5 or C6 dermatomes, the intensity (0.4-4 mA) of
      which induced minimal inhibition of both TAn and GMn discharges, reduced
      significantly the tonic component of TAn discharges (by 39%, n=4). At higher
      intensities of electrical cervical nerve stimulation (2-6 mA) inducing maximal
      inhibitory effect, both tonic and rhythmic activities in TAn and GMn were both
      significantly reduced by, respectively, 81% and 94% in TAn (n=7), and by 49% and
      43% in GMn (n=7). Electrical cervical nerve stimulation consistently reduced the
      isolated tonic discharge in TAn by 66% (n=4, P<0.05) and in GMn by 23% (n=3) when
      present. Thus the tonic component was more sensitive to inhibition than the
      rhythmic component of hindlimb muscle nerve activity.

PMID- 12610684
TI  - Timing of low frequency responses of anterior and posterior canal vestibulo
      ocular neurons in alert cats.
AB  - The pitch vertical vestibulo-ocular reflex (VOR) is accurate and symmetrical when
      tested in the normal upright posture, where otolith organ and central velocity
      storage signals supplement the basic VOR mediated by the semicircular canals.
      However, when the animal and rotation axis are together repositioned by rolling
      90 degrees to one side, head forward pitch rotations that excite the anterior
      semicircular canals elicit a more accurately timed VOR than do oppositely
      directed rotations that excite the posterior canals. This suggests that velocity
      storage of posterior canal signals is lost when the head is placed on its side.
      We recorded from 47 VOR relay neurons, second-order vestibulo-ocular neurons, of
      alert cats to test whether asymmetries are evident in the responses of neurons in
      the medial and superior vestibular nuclei during earth-horizontal axis rotations
      in the normal upright posture. Neurons were identified by antidromic responses to
      oculomotor nucleus stimulation and orthodromic responses to labyrinth
      stimulation, and were classified as having primarily anterior, posterior, or
      horizontal canal input based on response directionality. Neuronal response gains
      and phases were recorded during 0.5 Hz and 0.05 Hz sinusoidal oscillations in
      darkness. During 0.5 Hz rotations, anterior canal second-order vestibulo-ocular
      neurons responded approximately in phase with head velocity (mean phase re head
      position, +/- SE, 80 degrees +/- 3 degrees, n=18), as did posterior canal second
      order vestibulo-ocular neurons (mean phase 81 degrees +/- 1 degree, n=25).
      Lowering the rotation frequency to 0.05 Hz resulted in only slight advances in
      response phases of individual anterior canal second-order vestibulo-ocular
      neurons (mean phase 86 degrees +/- 6 degrees, mean advance 7 degrees +/- 5
      degrees, n=12). In contrast, posterior canal second-order vestibulo-ocular
      neurons behaved more like semicircular canal afferents, with responses markedly
      phase-advanced (mean advance 28 degrees +/- 5 degrees, n=14) by lowering rotation
      frequency to 0.05 Hz (mean phase 111 degrees +/- 5 degrees, n=14). In summary,
      low frequency responses of anterior and posterior canal second-order vestibulo
      ocular neurons recorded during horizontal axis pitch correspond to the VOR they
      excite during vertical axis pitch. These results show that velocity storage is
      evident at anterior but not posterior canal second-order vestibulo-ocular
      neurons. We conclude that responses of posterior canal second-order vestibulo
      ocular neurons are insufficient to explain the accurate low frequency VOR phase
      observed during backward head pitch in the upright posture, and that velocity
      storage or otolith signals required for VOR accuracy are carried by other
      neurons.

PMID- 12610686
TI  - Impaired regulation of stride variability in Parkinson's disease subjects with
      freezing of gait.
AB  - Patients with Parkinson's disease (PD) often experience freezing of gait, a
      debilitating phenomenon during which the subject suddenly becomes unable to start
      walking or to continue to move forward. Little is known about the gait of those
      subjects with PD who experience freezing of gait or the pathophysiology of
      freezing. One possibility is that freezing of gait is a truly paroxysmal
      phenomenon and that the usual walking pattern of subjects who experience freezing
      of gait is not different than that of other patients with PD who do not
      experience these transient episodes of freezing of gait. On the other hand, a
      recent study noted gait changes just prior to freezing and concluded that
      dyscontrol of the cadence of walking contributes to freezing. To address this
      question, we compared the gait of PD subjects with freezing of gait to PD
      subjects without freezing of gait. Given the potential importance of the
      dyscontrol of the cadence of walking in freezing, we focused on two aspects of
      gait dynamics: the average stride time (the inverse of cadence, a measure of the
      walking pace or rate) and the variability of the stride time (a measure of
      "dyscontrol," arrhythmicity and unsteadiness). We found that although the average
      stride time was similar in subjects with and without freezing, stride-to-stride
      variability was markedly increased among PD subjects with freezing of gait
      compared to those without freezing of gait, both while "on" (P<0.020) and "off"
      (P<0.002) anti-parkinsonian medications. Further, we found that increased gait
      variability was not related to other measures of motor control (while off
      medications) and levodopa apparently reduced gait variability, both in subjects
      with and without freezing. These results suggest that a paradigm shift should
      take place in our view of freezing of gait. PD subjects with freezing of gait
      have a continuous gait disturbance: the ability to regulate the stride-to-stride
      variations in gait timing and maintain a stable walking rhythm is markedly
      impaired in subjects with freezing of gait. In addition, these findings suggest
      that the inability to control cadence might play an important role in this
      debilitating phenomenon and highlight the key role of dopamine-mediated pathways
      in the stride-to-stride regulation of walking.

PMID- 12610685
TI  - Serotonin receptors 5-HT1A and 5-HT3 reduce hyperexcitability of dorsal horn
      neurons after chronic spinal cord hemisection injury in rat.
AB  - Spinal cord injury (SCI) results in abnormal pain syndromes in humans. In a
      rodent model of SCI, T13 spinal hemisection results in allodynia and hyperalgesia
      due in part to interruption of descending pathways, including serotonergic (5-HT)
      systems, that leads to hyperexcitability of dorsal horn neurons. To characterize
      further the role of 5-HT and 5-HT receptor subtypes 5-HT(1A) and 5-HT(3) in
      neuronal activation after hemisection, we have examined the responsiveness of
      dorsal horn neurons to a variety of innocuous and noxious peripheral stimuli.
      Male Sprague-Dawley rats, 150-175 g, were spinally hemisected (n=40) at T13 and
      allowed 4 weeks for development of mechanical allodynia and thermal hyperalgesia.
      Animals then underwent electrophysiologic recording and the results were compared
      with those from sham controls (n=15). Evoked responses of convergent dorsal horn
      neurons (n=224 total) at L3-L5 to innocuous and noxious peripheral stimuli were
      characterized after administration of vehicle, 5-HT (25, 50, 100, and 200
      microg), 5-HT (100 microg) in conjunction with the selective 5-HT(1A) antagonist
      WAY 100135 (100 microg), the 5-HT(3) antagonist MDL 72222 (100 microg), the
      selective 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 150
      microg), or the 5-HT(3) agonist 2-Me-5HT (75 microg), with or without
      pretreatment with antagonists; all treatments were delivered topically onto the
      cord adjacent to the recording electrode. In hemisected animals, increased
      responsiveness of convergent cells to all peripheral stimuli was observed
      bilaterally when compared to controls. No changes in ongoing background activity
      were present. In control animals, only the highest dose of 5-HT (200 microg) was
      sufficient to reduce evoked activity, whereas in hemisected animals a
      concentration-dependent decrease in response was observed. In hemisected animals,
      both 5-HT(1A) and 5-HT(3) receptor antagonism reduced the effectiveness of 5-HT,
      restoring elevated evoked activity by up to 70% at the doses tested.
      Administration of 5-HT(1A) and 5-HT(3) receptor agonists also decreased
      hyperexcitability, effects prevented by pretreatment with corresponding
      antagonists. These results demonstrate the development of denervation
      supersensitivity to 5-HT following SCI, corroborate behavioral studies showing
      the effectiveness of 5-HT in reducing allodynia and hyperalgesia after SCI, and
      contribute to a mechanistic understanding of the role of 5-HT receptor subtypes
      in chronic central pain.

PMID- 12610687
TI  - Increased hippocampal uptake of tumor necrosis factor alpha and behavioral
      changes in mice.
AB  - Brain trauma may alter the function of the blood-brain barrier (BBB) and affect
      psychomotor activity. We have shown that the transport system for tumor necrosis
      factor alpha (TNF alpha) at the BBB undergoes regulatory changes after spinal
      cord injury. In this study, we show in CD1 mice that mild trauma by weight-drop
      to the right temporal region specifically increases the uptake of blood-borne TNF
      alpha. This increase, measured by use of radiolabeled murine TNF alpha, occurred
      only in the right hippocampus 24 h after injury and returned to normal at 1 week.
      There was no increase in the uptake of the vascular marker albumin at 1 h, 24 h,
      or 1 week postinjury, indicating that the BBB remained relatively intact. Human
      interleukin-1 beta, which does not cross the BBB by saturable transport, showed
      no significant changes in brain uptake after trauma. Therefore, the selective
      entry of TNF alpha in the injured right hippocampus may be explained by enhanced
      transport across the BBB. To explore the functional relevance of this transport
      regulation, we measured mouse behavior by the staircase test. The number of
      rearings, mainly reflective of exploratory behavior, decreased at 1 h and 1 day
      after injury but increased at 1 week after a 30-g weight-drop injury. The number
      of stairs ascended, mainly indicative of locomotor activity, was unchanged at all
      times tested. We conclude that mild, blunt brain trauma involving the hippocampus
      causes specific upregulation of TNF alpha transport and a selective change in
      exploratory behavior. Although no causal relationship can be established at this
      time, the behavioral changes might be related to the increased TNF alpha
      transport after trauma.

PMID- 12610688
TI  - Effect of cadmium on 24-h variations in hypothalamic dopamine and serotonin
      metabolism in adult male rats.
AB  - This study was designed to analyze the possible cadmium effects on time-of-day
      variations of anterior, mediobasal, and posterior hypothalamic contents of
      dopamine (DA), serotonin (5-HT), and norepinephrine (NE) content in adult male
      rats. Also DA and 5-HT metabolism, as expressed by the ratio 3,4-dihydroxyphenyl
      acetic acid (DOPAC) to DA and 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT,
      respectively, were studied. Adult male rats were given cadmium at a dose of 25
      ppm of cadmium chloride in drinking water for 1 month. Age-matched rats having
      access to cadmium-free water were used as controls. Weight gain for the whole
      period was not changed by cadmium exposure. The metal accumulated in the
      hypothalamus of rats. In the three hypothalamic regions, significant 24-h
      variations of NE and 5-HT concentration were found in controls, while DA content
      changed rhythmically in mediobasal hypothalamus only. Mean content of NE, 5-HT,
      and DA of anterior, mediobasal, and posterior hypothalamus decreased after
      cadmium exposure. After cadmium the 24-h pattern of NE changed only in mediobasal
      hypothalamus, whereas the metal changed significantly the pattern of 5-HT in all
      regions. DOPAC to DA and 5-HIAA to 5-HT ratios decreased and were differentially
      changed in all hypothalamic regions analyzed in cadmium-treated rats. There was a
      statistically significant relationship between time of administration of metal
      and time that the change took place in biogenic amines in the hypothalamus. These
      results indicate that cadmium may depress hypothalamic biogenic amine release.

PMID- 12610689
TI  - Influence of terminal action requirements on action-centered distractor effects.
AB  - Tipper (1985; Q J Exp Psychol A 37:571-590) has suggested that competing
      responses programmed to distracting stimuli are inhibited based on their
      relationship to the action being performed. The present paper reports two
      experiments designed to examine the influence of the terminal action of a task on
      the allocation of visual attention. Taken together the results suggest that when
      engaging targets in an environment, which includes distracting stimuli, competing
      responses are likely to be programmed in parallel and that the relationship
      between competing responses can include both spatial position and action
      characteristics.

PMID- 12610690
TI  - Influence of the supplementary motor area on primary motor cortex excitability
      during movements triggered by neutral or emotionally unpleasant visual cues.
AB  - The stronger anatomo-functional connections of the supplementary motor area
      (SMA), as compared with premotor area (PM), with regions of the limbic system,
      suggest that SMA could play a role in the control of movements triggered by
      visual stimuli with emotional content. We addressed this issue by analysing the
      modifications of the excitability of the primary motor area (M1) in a group of
      seven healthy subjects, studied with transcranial magnetic stimulation (TMS),
      after conditioning TMS of SMA, during emotional and non-emotional visually cued
      movements. Conditioning TMS of the PM or of contralateral primary motor cortex
      (cM1) were tested as control conditions. Single-pulse TMS over the left M1 was
      randomly intermingled with paired TMS, in which a conditioning stimulation of the
      left SMA, left PM or right M1 preceded test stimulation over the left M1. The
      subjects carried out movements in response to computerised visual cues (neutral
      pictures and pictures with negative emotional content). The amplitudes of motor
      evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle
      after paired TMS were measured and compared with those obtained after single
      pulse TMS of the left M1 under the various experimental conditions. Conditioning
      TMS of the SMA in the paired-pulse paradigm selectively enhanced MEP amplitudes
      in the visual-emotional triggered movement condition, compared with single-pulse
      TMS of M1 alone or with paired TMS during presentation of neutral visual cues. On
      the other hand, conditioning TMS of the PM or cM1 did not differentially
      influence MEP amplitudes under visual-emotional triggered movement conditions.
      This pattern of effects was related to the intensity of the conditioning TMS over
      the SMA, being most evident with intensities ranging from 110% to 80% of motor
      threshold. These results suggest that the SMA in humans could interface the
      limbic and the motor systems in the transformation of emotional experiences into
      motor actions.

PMID- 12610693
TI  - Sex differences in lateralisation of fine manual skills in children.
AB  - One hundred and twelve children (55 boys and 57 girls) were tested using two
      tasks taken from the Movement Assessment Battery for Children. The girls had a
      larger between-hands asymmetry than boys on the threading nuts on bolt task, thus
      indicating they were more lateralised. On the other task, placing pegs, no such
      sex differences were found. We present our findings as a warning to others that
      even though two tasks are assumed to measure the same, in this case unimanual
      performance, differences in task constraints will exist. Such differences may
      constitute a confounding factor when trying to infer about lateralisation based
      on behavioural tasks.

PMID- 12610691
TI  - Clonus after human spinal cord injury cannot be attributed solely to recurrent
      muscle-tendon stretch.
AB  - Clonus, presented behaviorally as rhythmic distal joint oscillation, is a common
      pathology that occurs secondary to spinal cord injury (SCI) and other
      neurological disabilities. There are two predominant theories as to the
      underlying mechanism of clonus. The prevailing one is that clonus results from
      recurrent activation of stretch reflexes. An alternative hypothesis is that
      clonus results from the action of a central oscillator. We present evidence that
      the mechanism underlying clonus in individuals with SCI is not solely related to
      muscle stretch. We studied electromyography (EMG) of the soleus (SOL), medial
      gastrocnemius (MG), tibialis anterior (TA), medial and lateral hamstrings, vastus
      medialis, vastus lateralis, and rectus femoris from subjects with clinically
      complete and clinically incomplete SCI during stretch-induced ankle clonus,
      stepping, and non-weight-bearing standing. Clonic EMG of the SOL, MG, and TA
      occurred synchronously and were not consistently related to muscle-tendon stretch
      in any of the conditions studied. Further, EMG activity during stretch-induced
      ankle clonus, stepping, and non-weight-bearing standing had similar burst
      frequency, burst duration, silent period duration, and coactivation among
      muscles, indicating that clonic EMG patterns occurred over a wide range of
      kinematic and kinetic conditions, and thus proprioceptive inputs. These results
      suggest that the repetitive clonic bursts could not be attributable solely to
      immediate afferent feedback such as recurrent muscle stretch. However, these
      results support the theory that the interaction of central mechanisms and
      peripheral events may be responsible for clonus.

PMID- 12610694
TI  - Oculomotor consequences of feeble image size inequality at near reading distance.
AB  - Reading and working with a computer screen are activities of everyday life that
      take place at near vision. This study examines whether at such a near distance,
      normal subjects are capable of modifying the natural conjugacy of their saccades
      when exposed to a feeble image size inequality of 2%; similar inequality exists
      for persons who wear spectacles of slightly different power for the two eyes.
      Subjects were seated at 40 cm in front of a screen where a random dot pattern was
      projected. They were asked to make saccades of 7.5 degrees and 15 degrees along
      the horizontal and vertical principal meridians and horizontal saccades between
      secondary and tertiary positions in the upper and lower field. Five subjects
      performed the experiment with a 2% overall reduction lens inserted over their
      dominant eye; three subjects participated in a second experiment with an overall
      magnification lens of 2% also inserted in front of the dominant eye. The results
      showed a persistent decrease or increase in the size of the saccade of the
      dominant eye that was subject dependent for horizontal saccades, but consistent
      over subjects for vertical saccades. Persistent disconjugacy, at least for
      vertical saccades, is interpreted as evidence of learning.

PMID- 12610695
TI  - Modulation of cutaneous reflexes in arm muscles during walking: further evidence
      of similar control mechanisms for rhythmic human arm and leg movements.
AB  - Stimulation of cutaneous nerves innervating the hand evokes prominent reflexes in
      many arm muscles during arm cycling. We hypothesized that the mechanisms
      controlling reflex modulation during the rhythmic arm swing of walking would be
      similar to that documented during arm cycling. Thus, we expected cutaneous
      reflexes to be modulated by position in the walking cycle (phase dependence) and
      be different when walking compared to contraction while standing (task
      dependence). Subjects performed static postures similar to those occurring during
      walking and also walked on a treadmill while the superficial radial nerve was
      electrically stimulated pseudorandomly throughout the step cycle. EMG was
      recorded bilaterally from upper limb muscles and kinematic recordings were
      obtained from the elbow and shoulder joints. Step cycle information was obtained
      from force-sensing insoles. Analysis was conducted after averaging contingent
      upon the occurrence of stimulation in the step cycle. Phase-dependent modulation
      of cutaneous reflexes at early (approximately 50-80 ms) and middle (approximately
      80-120 ms) latencies was observed. Coordinated bilateral reflexes were seen in
      posterior deltoid and triceps brachii muscles. Task dependency was seen in that
      reflex amplitude was only correlated with background EMG during static
      contraction (75% of comparisons for both early and middle latency reflexes).
      During walking, no significant relationship between reflex amplitude and
      background EMG level was found. The results show that cutaneous reflex modulation
      during rhythmic upper limb movement is similar to that seen during arm cycling
      and to that observed in leg muscles during locomotion. These results add to the
      evidence that, during cyclical movements of the arms and legs, similar neural
      mechanisms observed only during movement (e.g. central pattern generators)
      control reflex output.

PMID- 12610696
TI  - Analysis of aqueous 2,4,6-trinitrotoluene (TNT) using a fluorescent displacement
      immunoassay.
AB  - We report a rapid, simple, and sensitive assay that is potentially amenable to
      high throughput screening for analysis of 2,4,6-trinitrotoluene (TNT) present in
      aqueous solutions. The assay is based on the change in fluorescence emission
      intensity of a fluorescently labeled TNT analogue pre-bound to an anti-TNT
      antibody that occurs upon its competitive displacement by TNT. The assay can be
      performed in both cuvette- and 96-well plate-based formats. TNT at a level of 0.5
      micro g L(-1) (0.5 ppb) was detected in phosphate buffered saline; detection
      improved to 0.05 micro g L(-1) (0.05 ppb) for TNT dissolved in artificial
      seawater.

PMID- 12610692
TI  - The response of vestibulo-ocular reflex pathways to electrical stimulation after
      canal plugging.
AB  - The vestibulo-ocular reflex (VOR) allows clear vision during head movements by
      generating compensatory eye movements. Its response to horizontal rotation is
      reduced after one horizontal semicircular canal is plugged, but recovers
      partially over time. The majority of VOR interneurons contribute to the shortest
      VOR pathway, the so-called three-neuron arc, which includes only two synapses in
      the brainstem. After a semicircular canal is plugged, transmission of signals by
      the three-neuron arc originating from the undamaged side may be altered during
      recovery. We measured the oculomotor response to single current pulses delivered
      to the vestibular labyrinth of alert cats between 9 h and 1 month after plugging
      the contralateral horizontal canal. The same response was also measured after
      motor learning induced by continuously-worn telescopes (optically induced motor
      learning). Optically induced learning did not change the peak velocity of the
      evoked eye movement (PEEV) significantly but, after a canal plug, the PEEV
      increased significantly, reaching a maximum during the first few post-plug days
      and then decreasing. VOR gain also showed transient changes during recovery.
      Because the PEEV occurred early in the eye movement evoked by a current pulse, we
      think the observed increase in PEEV represented changes in transmission by the
      three-neuron arc. Sham surgery did not result in significant changes in the
      response to electrical stimulation or in VOR gain. Our data suggest that
      different pathways and processes may underlie optically induced motor learning
      and recovery from plugging of the semicircular canals.

PMID- 12610698
TI  - Combined micro-droplet and thin-film-assisted pre-concentration of lead traces
      for on-line monitoring using anodic stripping voltammetry.
AB  - An improved analytical method for airborne lead traces is reported. It is based
      on using a Venturi scrubber sampling device for simultaneous thin-film stripping
      and droplet entrapment of aerosol influxes. At least threefold enhancement of the
      lead-trace pre-concentration is achieved. The sampled traces are analyzed by
      square-wave anodic stripping voltammetry. The method was tested by a series of
      pilot experiments. These were performed using contaminant-controlled air intakes.
      Reproducible calibration plots were obtained. The data were validated by
      traditional analysis using filter sampling. LODs are comparable with the
      conventional techniques. The method was successfully applied to on-line and in
      situ environmental monitoring of lead.

PMID- 12610697
TI  - The homogeneity of heavy metal deposition on glass fibre filters collected using
      a high-volume sampler in the vicinity of an opencast chrome mine complex at Kemi,
      Northern Finland.
AB  - The homogeneity of heavy metal (Cr, Ni, Cu, Fe and Cd) distribution on glass
      fibre filters (Munktell MG 160, 203 x 254 mm, 75 g m(-2)) collected using a high
      volume sampler (Wedding & Associates) at an opencast chrome mine complex at Kemi,
      Northern Finland was studied. The heavy metals in the total suspended particulate
      (TSP) material were analysed by inductively coupled plasma atomic emission
      spectrometry (ICP-AES) or graphite furnace atomic absorption spectrometry
      (GFAAS). The glass fibre filters were digested in a microwave oven using a
      mixture of aqua regia+HF acids. There was significant non-uniform distribution of
      heavy metals on glass fibre filters. The TSP material containing chromite was
      very difficult to dissolve by acid digestion. The results from X-ray fluorescence
      spectrometry (XRF), and from energy filtering transmission electron microscope
      (EFTEM) equipped with energy dispersive X-ray spectrometer (EDS), showed that
      insoluble residue left after microwave oven digestion with aqua regia+HF acids
      was probably partly due to chemical reactions occurring during microwave heating.

PMID- 12610699
TI  - Size analysis of industrial carbon blacks by sedimentation and flow field-flow
      fractionation.
AB  - Carbon black is one of the most useful particulate materials in the industrial
      field. Among the various physical properties of carbon black, size and size
      distribution are the most important properties to affect the quality of a final
      product. However, it is difficult to measure the exact particle size of carbon
      black since it suffers unavoidable interference from flocculation. In this study,
      the effects of various factors on the dispersion of industrial carbon blacks were
      investigated for the determination of size and size distribution of carbon black
      particles. Sedimentation and flow field-flow fractionations (FIFFF) were used to
      determine the size of carbon black, and their optimum analytical conditions were
      tested by changing surfactant, pH, ionic strength, and method of dispersion. The
      results showed that surfactant structure and its concentration played significant
      roles in dispersion stability. Carbon black was dispersed well with a nonionic
      surfactant with a pH of around 8 and an ionic strength of 0.003 M. The mean
      diameters measured from two types of FFF and photon correlation spectroscopy are
      in good agreement. This study demonstrates the potential of sedimentation and
      flow FFF for analyzing highly adsorptive industrial particles and guides for
      sample preparation.

PMID- 12610700
TI  - Homogeneity check of agricultural and food industries samples using near infrared
      spectroscopy.
AB  - Samples distributed in proficiency testing schemes (PTS) need to be homogeneous
      in order to be sure that if a laboratory has a result different from the other
      laboratories, its error can be attributed to its analysis method and not to its
      sample. This control must be done according to the ISO 13528 draft standard
      before sending the samples to the laboratories. It can be done by determining
      homogeneity targets by sub-contracting to accredited laboratories using reference
      methods, but this engenders logistic and financial problems. That is why a
      homogeneity check using Near Infrared Spectroscopy (NIR) has been developed for
      agricultural and food industries samples prepared for PTS at Bipea (Bureau
      Interprofessionnel d'Etudes Analytiques). To evaluate the homogeneity among
      samples, this procedure involves a comparison of NIR spectra, the determination
      of global homogeneity criteria and the use of control charts. The method of
      control developed and carried out at Bipea allows the rapid and easy monitoring
      of the performance of the sample preparation.

PMID- 12610701
TI  - Effect of humic acid on the bioavailability of radionuclides to rice plants.
AB  - We investigated the effect of humic acid and solution pH on the uptake of the
      radionuclides, (83)Rb, (137)Cs, (54)Mn, (65)Zn, (88)Y, (102)Rh, and (75)Se in
      rice plants by the multitracer technique. The addition of humic acid to a culture
      medium containing SiO(2) increased the uptake of Mn and Zn at pH 4.3, whereas
      their uptake was decreased at pH 5.3. Humic acid depressed the uptake of Y at
      both pHs. The uptake of Se, which does not interact with humic acid, was not
      affected by its presence. These results suggest that uptake of the radionuclides
      by the rice plant is regulated by the affinity of radioactive nuclides for humic
      acid, as well as by the soil solution's pH.

PMID- 12610702
TI  - Ion-selective electrodes based on metalloporphyrins for gibberellic acid
      determination in agricultural products.
AB  - This work describes the construction, evaluation and analytical application of
      electrodes selective to the gibberellate anion for the determination of
      gibberellic acid in agricultural products. Several types of PVC membrane
      electrodes without internal reference solution were prepared using the
      manganese(III) complex of meso-tetraphenylporphyrin (TPP) as ionophore and
      dibutyl phthalate (DBP), as plasticizer. The incorporation of lipophilic chemical
      species as additives, was also carried out aiming the evaluation of the response
      characteristics of the electrodes. To accomplish the analysis of commercial
      agricultural products a selective membrane composed of 28.0% (w/w) of PVC, 66.0%
      (w/w) of plasticizer and 6% (w/w) of ionophore was used, with no additive. This
      potentiometric unit presented a linear response between 10(-4) and 10(-1) mol L(
      1) in gibberellate, a slope of about -69 mV dec(-1) and a reproducibility of
      about +/-1 mV day(-1). The potentiometric analysis of gibberellic acid in
      commercial products was carried out by direct potentiometry and the results
      obtained were compared with those provided by HPLC.

PMID- 12610703
TI  - Quantitative analysis of geraniol, nerol, linalool, and alpha-terpineol in wine.
AB  - A mixture of [(2)H(7)]-geraniol, [(2)H(7)]-nerol, [(2)H(7)]-linalool and
      [(2)H(7)]-alpha-terpineol was prepared for use as internal standards in a rapid
      and accurate analytical method, employing gas chromatography-mass spectrometry
      (GC/MS), to determine the concentration of geraniol, nerol, linalool and alpha
      terpineol in wine. The method avoids the possible formation, degradation and
      interconversion of these compounds during their analysis.

PMID- 12610704
TI  - Study of the acid-base properties of fulvic acid-like substances extracted from
      senescent leaves of eucalyptus and oak.
AB  - The acid-base properties of two fulvic acids (FA) extracted from senescent leaves
      of eucalyptus and oak were characterized by carrying out potentiometric
      titrations at two FA concentrations and four ionic strengths (0.005 M <[KNO(3)]
      <1.0 M). Experimental data were analyzed by means of the master curve approach,
      which includes an electrostatic spherical double layer model, and the Langmuir
      Freundlich isotherm was used to fit the data. The contribution of the
      electrostatic effect to the proton binding reaction was lower than that observed
      for soil fulvic acids. The chemical heterogeneity of both samples was described
      by two acid sites with p Ks of about 4 and 7.5, the most abundant being the
      carboxylic site of p K = 4.

PMID- 12610705
TI  - Column-switching high-performance liquid chromatography electrospray mass
      spectrometry coupled with on-line of extraction for the determination of mono-
      and di-(2-ethylhexyl) phthalate in blood samples.
AB  - A novel method based on column-switching high-performance liquid chromatography
      electrospray mass spectrometry (LC-MS) coupled with an on-line extraction column
      containing conjugated avidin has been developed for direct injection analysis of
      di(2-ethylhexyl) phthalate (DEHP) and its metabolite, mono(2-ethylhexyl)
      phthalate (MEHP), in blood samples. The sample preparation for on-line extraction
      involved the mixing of blood samples with internal standards, DEHP-d(4) and MEHP
      d(4), in LC glass vials. A linear response was found for column-switching LC-MS
      when tests were conducted within the validated range of 25 to 1000 ng mL(-1) for
      DEHP and 5 to 1000 ng mL(-1) for MEHP, with correlation coefficients (r) greater
      than 0.999. In addition, the recoveries of DEHP and MEHP from human plasma were
      calculated by using this method with on-line extraction, yielding recoveries of
      up to 91.2% (RSD<5%). We measured the background levels of DEHP and MEHP in six
      human plasma samples from healthy volunteers and three fetal bovine serum samples
      for cell-line culture. DEHP and MEHP were not detected in all human plasma
      samples (N.D. is <25 ng mL(-1) for DEHP, and N.D. is <5.0 ng mL(-1) for MEHP). In
      contrast, high DEHP contamination of commercially available fetal bovine serum
      samples was found by this method.

PMID- 12610706
TI  - High-performance liquid chromatographic determination of cocaine and
      benzoylecgonine by direct injection of human blood plasma sample into an alkyl
      diol-silica (ADS) precolumn.
AB  - A column-switching high-performance liquid chromatographic method with UV
      detection for the determination of cocaine (COC) and benzoylecgonine (BZE) in
      human blood plasma samples is described. The method uses an alkyl-diol-silica ADS
      C18 extraction precolumn. A 50- micro L plasma sample was introduced to the ADS
      precolumn in order to separate the analytes from proteins and endogenous
      compounds. The fraction containing COC and BZE was back-flushed and transferred
      to an Alltech mixed-mode C(18)/cation-exchange analytical column for final
      separation. The validation of the method revealed quantitative recoveries from
      95.0 to 99.0% for COC at three different concentrations (0.5, 1.0 and 2.0 micro g
      mL(-1)), and from 96.0 to 99.0% for BZE at the same concentration levels with
      coefficients of variation <4.00% (n=5). The detection limit (signal to noise
      ratio (S/N)>3) was 0.03 micro g mL(-1) for all the compounds with an injection
      volume of 50 micro L. However, it was possible to enhance the sensitivity further
      by injecting larger plasma volumes, up to 200 micro L, at the same optimal
      conditions. The overlap of sample preparation, analysis and reconditioning of the
      extraction column, increase the overall sample throughput to 5 samples h(-1). The
      developed method has been applied to human blood plasma samples from subjects
      suspected of cocaine abuse.

PMID- 12610707
TI  - Application of a gold electrode, modified by a self-assembled monolayer of 2
      mercaptodecylhydroquinone, to the electroanalysis of hemoglobin.
AB  - A gold electrode modified by a self-assembled monolayer of 2
      mercaptodecylhydroquinone (H(2)Q(CH(2))(10)SH) was applied to investigate the
      electrochemical response of hemoglobin in aerated buffer solutions. Compared with
      a bare gold electrode, the monolayer of H(2)Q(CH(2))(10)SH could suppress the
      reduction wave of dissolved oxygen in the buffer while effectively promoting the
      rate of electron transfer between hemoglobin and the electrode. Thus, a
      convenient way for electroanalysis of hemoglobin in air was achieved at the
      H(2)Q(CH(2))(10)SH/Au electrode. A linear relationship existed between peak
      current and concentration of hemoglobin in the range 1 x 10(-7)-1 x 10(-6) mol L(
      1).

PMID- 12610708
TI  - Simultaneous electrochemical determination of xanthine and uric acid at a
      nanoparticle film electrode.
AB  - A sensitive electrochemical method was developed for simultaneous determination
      of uric acid (UA) and xanthine (XA) at a glassy carbon electrode modified with
      multi-wall carbon nanotubes (MWNTs) film. The oxidation peak currents of UA and
      XA were increased at the MWNTs film electrode significantly. The experimental
      parameters, which influence the peak currents of UA and XA, such as the amount of
      MWNTs on the glassy carbon electrode, the pH of the solution, accumulation time,
      and scan rate, were optimized. Under optimum conditions, the peak currents were
      linear to the concentration of UA over the wide range from 1 x 10(-7) mol L(-1)
      to 1 x 10(-4) mol L(-1) and to that of XA over the wide range from 2 x 10(-8) mol
      L(-1) to 2 x 10(-5) mol L(-1). The interferences studies showed that the MWNTs
      modified electrode exhibited excellent selectivity in the presence of ascorbic
      acid, dopamine, and hypoxanthine. The proposed procedure was successfully applied
      to detect UA and XA in human serum without any preliminary treatment.

PMID- 12610710
TI  - Spectrophotometric methods for determination of enalapril and timolol in bulk and
      in drug formulations.
AB  - Two simple and accurate spectrophotometric methods for determination of timolol
      and enalapril maleate are described. The first method is based on chelate
      formation with palladium(II) chloride in buffered medium. The second method is
      based on the formation of the colored complex between palladium(II), eosin, and
      the two cited drugs using methylcellulose as surfactant to increase the
      solubility and intensity of the formed complexes. Under optimum conditions the
      complexes showed maximum absorption at 369.4 nm and 362.8 nm for timolol and
      enalapril maleate, respectively, in the first method and 552.2 and 550.6 nm for
      the second method. Apparent molar absorptivities were 1.8 x 10(3) and 1.3 x 10(3)
      and Sandell's sensitivities were 5.9 x 10(-4) and 2.7 x 10(-4) for timolol and
      enalapril maleate in the first method; in the second method molar absorptivities
      were 2.8 x 10(4) and 1.1 x 10(4) while Sandell's constants were 9.1 x 10(-3) and
      2.3 x 10(-3) for timolol and enalapril maleate. The solutions of the complexes
      obeyed Beer's law in the concentration ranges 20-200 micro g mL(-1) and 50-300
      micro g mL(-1) for timolol and enalapril maleate, respectively. In the second
      method, because the reaction was more sensitive the ranges were reduced to 1.6-16
      micro g mL(-1) for timolol 8-56 micro g mL(-1) for enalapril maleate. The
      proposed methods were applied to the determination of the two drugs in their
      pharmaceutical formulation.

PMID- 12610709
TI  - Unilamellar liposomes covalently coupled on silica gel for liquid chromatography.
AB  - Silica gel was used as a support for the covalent coupling of liposomes, which
      could overcome drawbacks of soft gel beads in column efficiency and separation
      speed. The influences of the concentration of added dimethylaminopyridine and
      reaction time on the chloroformate activation reaction of silica gel were
      investigated. Temperature and pH for covalent coupling of liposomes on the
      activated silica gel were also optimized. Experimental results indicated that the
      stability of the covalently coupled liposome columns was obviously superior to
      that of the noncovalently coated liposome columns but the selectivity of both
      columns was basically identical. Separation and analysis of a crude extract of a
      traditional Chinese medicine Ligusticum Wallichii and a mixture of small peptides
      on both columns further support this conclusion.

PMID- 12610711
TI  - Determination of phosphorus in small amounts of protein samples by ICP-MS.
AB  - Inductively coupled plasma mass spectrometry (ICP-MS) is used for phosphorus
      determination in protein samples. A small amount of solid protein sample (down to
      1 micro g) or digest (1-10 micro L) protein solution was denatured in nitric acid
      and hydrogen peroxide by closed-microvessel microwave digestion. Phosphorus
      determination was performed with an optimized analytical method using a double
      focusing sector field inductively coupled plasma mass spectrometer (ICP-SFMS) and
      quadrupole-based ICP-MS (ICP-QMS). For quality control of phosphorus
      determination a certified reference material (CRM), single cell proteins (BCR
      273) with a high phosphorus content of 26.8+/-0.4 mg g(-1), was analyzed. For
      studies on phosphorus determination in proteins while reducing the sample amount
      as low as possible the homogeneity of CRM BCR 273 was investigated. Relative
      standard deviation and measurement accuracy in ICP-QMS was within 2%, 3.5%, 11%
      and 12% when using CRM BCR 273 sample weights of 40 mg, 5 mg, 1 mg and 0.3 mg,
      respectively. The lowest possible sample weight for an accurate phosphorus
      analysis in protein samples by ICP-MS is discussed. The analytical method
      developed was applied for the analysis of homogeneous protein samples in very low
      amounts [1-100 micro g of solid protein sample, e.g. beta-casein or down to 1
      micro L of protein or digest in solution (e.g., tau protein)]. A further
      reduction of the diluted protein solution volume was achieved by the application
      of flow injection in ICP-SFMS, which is discussed with reference to real protein
      digests after protein separation using 2D gel electrophoresis.The detection
      limits for phosphorus in biological samples were determined by ICP-SFMS down to
      the ng g(-1) level. The present work discusses the figure of merit for the
      determination of phosphorus in a small amount of protein sample with ICP-SFMS in
      comparison to ICP-QMS.

PMID- 12610712
TI  - Figures of merit of pneumatic and ultrasonic sample introduction systems in
      inductively coupled plasma-multichannel-based emission spectrometry in an ultra
      clean environment.
AB  - Conventional figures of merit such as limits of detection, signal to background
      ratio or repeatability, are used to determine the performance of pneumatic and
      ultrasonic sample introduction systems in an ultra-clean environment with an
      axially viewed inductively coupled plasma-atomic emission spectrometry and
      multichannel detection. We observed that the ultrasonic nebuliser offered a large
      improvement of signal intensity (10-133 greater) compared to a cyclone chamber
      coupled with a pneumatic Meinhard nebuliser. This improvement is associated with
      an average increase of signal to background ratio by a factor 86 and an average
      decrease of detection limits by a factor 6. The improvement factors generally
      depend on the element and for the same element on spectral lines. Typically, the
      observed values of detection limits in this work are lower than those published
      and obtained in non-ultra-clean conditions. The results emphasize that the
      environmental conditions of cleaning and analysis are essential to avoid and
      control cross contamination of the samples and hence to obtain low detection
      limits.

PMID- 12610713
TI  - Determination of Cu, Ni, and Zn in fuel ethanol by FAAS after enrichment in
      column packed with 2-aminothiazole-modified silica gel.
AB  - This work describes the synthesis and characterization of 2-aminothiazole
      modified silica gel (SiAT), as well as its application for preconcentration (in
      batch and column technique) of Cu(II), Ni(II) and Zn(II) in ethanol medium. The
      adsorption capacities of SiAT determined for each metal ion were (mmol g(-1)):
      Cu(II)=1.20, Ni(II)=1.10 and Zn(II)=0.90. In addition, results obtained in flow
      experiments, showed a recovery of ca. 100% of the metal ions adsorbed in a column
      packed with 500 mg of SiAT. The eluent was 2.0 mol L(-1) HCl. The sorption
      desorption of the studied metal ions made possible the development of a
      preconcentration method for metal ions at trace level in fuel ethanol using flame
      AAS for their quantification.

PMID- 12610714
TI  - Mercury determination in solid phases from application of the modified BCR
      sequential extraction procedure: a valuable tool for assessing its mobility in
      sediments.
AB  - The present paper presents a feasibility study for the evaluation of mercury
      mobility in sediments by application of the modified BCR three-step sequential
      extraction procedure (BCR-SEP). The aim of the study was to evaluate the effect
      of acidification, reduction and oxidation processes on mercury mobility from
      sediments, once the SEP was validated with other trace metals. As extractable
      mercury amounts were mostly found below detection limits of the advanced mercury
      analyser (AMA-254) used for measuring the extracts (L.D.<0.5 ng), the use of a
      solid sampling atomic absorption spectrometer with a specially designed furnace
      for Hg atomisation was found to be an optimal technique to quantify Hg in the
      solid residues coming from the SEP. With this approach, mercury was found to be
      hardly mobile and only for one of the moderately polluted sediments (BCR CRM
      320), extractable mercury (exchangeable fraction, BCR procedure step 1) has been
      found. An oxidation step with H(2)O(2) was required to obtain extractability up
      to 64% of the total content in a highly polluted lagoon sediment.

PMID- 12610715
TI  - Microwave-assisted steam distillation with simultaneous liquid/liquid extraction
      of pentachlorophenol from organic wastes and soils.
AB  - An efficient method for extracting pentachlorophenol (PCP) from organic solid
      matrices and soils using direct excitation of the fresh samples by microwave
      energy is presented. Steam-volatile PCP partitioned into the organic solvent n
      hexane within the closed extraction vessel, resulting in recovery rates of 85-92%
      from aged samples. Condensed water provided a boundary layer between extract and
      sample thus preventing any contact of PCP with and re-partitioning into the
      sample. Duration of the microwave-assisted process was 35 min. Crude extracts
      were derivatized by heptafluorobutyric anhydride (HFBA) to improve selectivity
      and sensitivity resulting in detection limits of 1-2 micro g kg(-1). GC-MS/MS
      analyses proved that suitable extracts with only minor impurities were obtained.
      Common sample treatment steps like drying, thorough grinding, frequent
      transferring, and tedious clean-up, and concentration procedures which all can
      cause certain losses of analyte were minimized. The efficiency of the method was
      verified by comparison with an established ultrasonic extraction procedure. This
      microwave-assisted pressurized steam distillation with simultaneous partition
      into an organic phase thus provides a streamlined and efficient strategy which
      requires no additional investment in standard equipment for microwave-assisted
      extractions (MAE). Degradation of analytes at longer extraction times must be
      taken into account.

PMID- 12610716
TI  - Evaluation of the efficiency of extraction of PAHs from diesel particulate matter
      with pressurized solvents.
AB  - Pressurized Fluid Extraction (PFE) was evaluated for the extraction of polycyclic
      aromatic hydrocarbons (PAHs) and nitro-derivatives from diesel particulate
      matter. Extraction conditions were set up by performing several tests in which
      temperature, solvent strength, pressure, and static time were gradually
      increased. The results obtained on a laboratory test material made of a "lean"
      (low content of soluble fraction) Diesel particulate matter indicate that very
      severe conditions were needed in order to obtain better recoveries of the higher
      molecular weight molecules. Moreover, extraction efficiency seems to be
      influenced by the amount of soluble matter in the particulate, so that a "lean"
      particulate appears more difficult to extract. Recoveries of the deuterated
      standards of certain PAHs (i.e. indeno[1,2,3- cd]pyrene) were incomplete even
      with the toughest conditions tested. Experiments carried out on a certified
      material (SRM 1650 from NIST) also indicate that PFE can perform a better
      extraction of some of the PAHs than the method used for certification, but still
      incomplete. Comparison of results obtained on the SRM with different extraction
      techniques suggests that the composition of the extract varies considerably with
      the extraction technique and conditions. It is relevant to notice that recent
      Diesel engines produce leaner particulate: for future materials more drastic
      extraction conditions will be required.

PMID- 12610717
TI  - Dopamine agonists disrupt visual latent inhibition in normal males using a within
      subject paradigm.
AB  - Latent inhibition (LI) is the delayed learning of an association when the
      conditioned stimulus has previously been experienced out of the context of that
      association. LI can be measured across species and has been used to understand
      the neurobiology of schizophrenia, since some reports suggest that schizophrenia
      patients exhibit LI deficits. One challenge of LI studies in humans has resulted
      from the fact that LI paradigms have almost uniformly involved between-subject
      comparisons. We now report a new within-subject paradigm that detected LI in
      normal adult male subjects after ingestion of a placebo. After amphetamine (20 mg
      p.o.) or bromocriptine (1.25 mg p.o.), LI was not evident, suggesting that the LI
      detected by this paradigm is sensitive to disruption by dopamine agonists. The
      apparent advantages and limitations of this paradigm are discussed with regard to
      its future use in understanding the neural basis of reported LI deficits in
      schizophrenia.

PMID- 12610718
TI  - Switching patients to aripiprazole from other antipsychotic agents: a multicenter
      randomized study.
AB  - RATIONALE: Switching patients from one antipsychotic to another can lead to
      tolerability problems or transient symptom exacerbations. It is important to
      compare switching strategies to determine which methods produce the best possible
      patient outcomes. OBJECTIVE: To investigate the efficacy, safety and tolerability
      of three dosing strategies for switching chronic, stable patients with
      schizophrenia from current oral antipsychotic monotherapy to once-daily oral
      aripiprazole monotherapy. METHOD: Patients in this 8-week, open-label, outpatient
      study were randomized to: 1). immediate initiation of 30 mg/day aripiprazole with
      simultaneous immediate discontinuation of current antipsychotic; 2). immediate
      initiation of 30 mg/day aripiprazole while tapering off current antipsychotic
      over 2 weeks; or 3). up-titrating aripiprazole to 30 mg/day over 2 weeks, while
      simultaneously tapering off current antipsychotic. Efficacy assessments included
      PANSS, CGI-S, and CGI-I scores. Safety assessments included: adverse events (AEs)
      recording, evaluation of extrapyramidal symptoms (EPS), vital signs, ECG, and
      clinical laboratory tests. RESULTS: Efficacy with aripiprazole was maintained
      during the study with numerical improvements compared with baseline in all three
      groups. The overall incidence of AEs was broadly comparable across all groups,
      and AEs were generally mild to moderate in severity and time-limited.
      Discontinuations due to AEs were comparable across the groups. No deterioration
      in EPS occurred in any group. The reduction in body weight and plasma prolactin
      levels following switch to aripiprazole were comparable across the three groups.
      CONCLUSION: Any of the three strategies evaluated can be used safely for
      switching patients to aripiprazole from antipsychotic monotherapy. Furthermore,
      patients' symptoms may continue to improve after switching to aripiprazole.

PMID- 12610719
TI  - Laccases and their occurrence in prokaryotes.
AB  - Laccases are copper-containing proteins that require O(2) to oxidize phenols,
      polyphenols, aromatic amines, and different non-phenolic substrates by one
      electron transfer, resulting in the formation of reactive radicals. Although
      their specific physiological functions are not completely understood, there are
      several indications that laccases are involved in the morphogenesis of
      microorganisms (e.g., fungal spore development, melanization) and in the
      formation and/or degradation of complex organic substances such as lignin or
      humic matter. Owing to their high relative non-specific oxidation capacity,
      laccases are useful biocatalysts for diverse biotechnological applications. To
      date, laccases have been found only in eukaryotes (fungi, plants); however,
      databank searches and experimental data now provide evidence for their
      distribution in prokaryotes. This survey shows that laccase-like enzymes occur in
      many gram-negative and gram-positive bacteria. Corresponding genes have been
      found in prokaryotes that are thought to have branched off early during
      evolution, e.g., the extremely thermophilic Aquifex aeolicus and the archaeon
      Pyrobaculum aerophilum. Phylogenetically, the enzymes are members of the multi
      copper protein family that have developed from small-sized prokaryotic azurins to
      eukaryotic plasma proteins.

PMID- 12610720
TI  - Utilization of acidic amino acids and their amides by pseudomonads: role of
      periplasmic glutaminase-asparaginase.
AB  - The acidic amino acids (Asp, Glu) and their amides (Asn, Gln) support rapid
      growth of a variety of Pseudomonas strains when provided as the sole source of
      carbon and nitrogen. All key enzymes of glutamate metabolism were detected in P.
      fluorescence, with glutaminase and asparaginase showing the highest specific
      activities. A periplasmic glutaminase/asparaginase activity (PGA) was found in
      all pseudomonads examined, including a number of root-colonizing biocontrol
      strains. The enzyme was purified and shown to be identical with the ansB gene
      product described previously. In addition to PGA, P. fluorescens contains a
      cytoplasmic asparaginase with marked specificity for Asn. PGA is strongly and
      specifically induced by its substrates (Asn, Gln) but also by the reaction
      products (Asp, Glu). In addition, PGA is subject to efficient carbon catabolite
      repression by glucose and by citrate cycle metabolites. A mutant of P. putida
      KT2440 with a disrupted ansB gene was unable to utilize Gln, whereas growth of
      the mutant on other amino acids was normal.

PMID- 12610721
TI  - Autotrophic CO2 fixation pathways in archaea (Crenarchaeota).
AB  - Representative autotrophic and thermophilic archaeal species of different
      families of Crenarchaeota were examined for key enzymes of the known autotrophic
      CO(2) fixation pathways. Pyrobaculum islandicum ( Thermoproteaceae) contained key
      enzymes of the reductive citric acid cycle. This finding is consistent with the
      operation of this pathway in the related Thermoproteus neutrophilus. Pyrodictium
      abyssi and Pyrodictium occultum ( Pyrodictiaceae) contained ribulose 1,5
      bisphosphate carboxylase, which was active in boiling water. Yet,
      phosphoribulokinase activity was not detectable. Operation of the Calvin cycle
      remains to be demonstrated. Ignicoccus islandicus and Ignicoccus pacificus (
      Desulfurococcaceae) contained pyruvate oxidoreductase as potential carboxylating
      enzyme, but apparently lacked key enzymes of known pathways; their mode of
      autotrophic CO(2) fixation is at issue. Metallosphaera sedula, Acidianus
      ambivalens and Sulfolobus sp. strain VE6 ( Sulfolobaceae) contained key enzymes
      of a 3-hydroxypropionate cycle. This finding is in line with the demonstration of
      acetyl-coenzyme A (CoA) and propionyl-CoA carboxylase activities in the related
      Acidianus brierleyi and Sulfolobus metallicus. Enzymes of central carbon
      metabolism in Metallosphaera sedula were studied in more detail. Enzyme
      activities of the 3-hydroxypropionate cycle were strongly up-regulated during
      autotrophic growth, supporting their role in CO(2) fixation. However, formation
      of acetyl-CoA from succinyl-CoA could not be demonstrated, suggesting a modified
      pathway of acetyl-CoA regeneration. We conclude that Crenarchaeota exhibit a
      mosaic of three or possibly four autotrophic pathways. The distribution of the
      pathways so far correlates with the 16S-rRNA-based taxa of the Crenarchaeota.

PMID- 12610722
TI  - A new purple sulfur bacterium isolated from a littoral microbial mat,
      Thiorhodococcus drewsii sp. nov.
AB  - A new strain of purple sulfur bacterium was isolated from a marine microbial mat
      sampled in Great Sippewissett Salt Marsh at the Atlantic coast (Woods Hole,
      Mass., USA). Single cells of strain AZ1 were coccus-shaped, highly motile by
      means of a single flagellum, and did not contain gas vesicles. Intracellular
      membranes were of the vesicular type. However, additional concentric membrane
      structures were present. The photosynthetic pigments were bacteriochlorophyll a
      and carotenoids of the normal spirilloxanthin series, with rhodopin as the
      dominant carotenoid. Hydrogen sulfide (up to 11 mM), sulfur, thiosulfate, and
      molecular hydrogen were used as electron donors during anaerobic phototrophic
      growth. During growth on sulfide, elemental sulfur globules were transiently
      stored inside the cells. Strain AZ1 is much more versatile than most other
      Chromatiaceae with respect to electron donor and organic substrates. In the
      presence of CO(2), it is capable of assimilating C(1)-C(5) fatty acids, alcohols,
      and intermediates of the tricarboxylic acid cycle. Strain AZ1 could also grow
      photoorganotrophically with acetate as the sole photosynthetic electron donor.
      Chemotrophic growth in the dark under microoxic conditions was not detected.
      Optimum growth occurred at pH 6.5-6.7, 30-35 degrees C, > or =50 micro mol quanta
      m(-2) s(-1), and 2.4-2.6% NaCl. The DNA base composition was 64.5 mol% G+C.
      Comparative sequence analysis of the 16S rRNA gene confirmed that the isolate is
      a member of the family Chromatiaceae. Sequence similarity to the most closely
      related species, Thiorhodococcus minor DSMZ 11518(T), was 97.8%; however, the
      value for DNA-DNA hybridization between both strains was only 20%. Because of the
      low genetic similarity and since strain AZ1 physiologically differs considerably
      from all other members of the Chromatiaceae, including Trc. minor, the new
      isolate is described as a new species of the genus Thiorhodococcus,
      Thiorhodococcus drewsii sp. nov.

PMID- 12610723
TI  - Characterization of the gene encoding glutamate dehydrogenase ( gdhA) from the
      ruminal bacterium Ruminococcus flavefaciens FD-1.
AB  - The gene encoding glutamate dehydrogenase ( gdhA) in the ruminal bacterium
      Ruminococcus flavefaciens FD-1 was cloned. A degenerate primer based on the N
      terminal amino acid sequence of the purified protein was used in conjunction with
      genome walking to obtain the complete ORF of 1,365 bp, capable of encoding a
      polypeptide of 455 amino acid residues. The translated ORF contained the amino
      acid motifs characteristic of the subfamily GDH S_50(I) small glutamate
      dehydrogenases, including the catalytic site, and matched the originally deduced
      N-terminal amino acid sequence. BLAST search yielded high scores with other GdhA
      sequences from a variety of organisms, the closest match being with the GdhA
      sequence of Corynebacterium glutamicum (63% amino acid identity). Classification
      of the GdhA enzyme from R. flavefaciens FD-1 as a GDH S_50(I) subfamily member
      was further supported by phylogenetic analysis. The transcript size determined by
      Northern blot analysis was in good agreement with the putative regulatory region
      of the gene and confirmed its monocistronic structure. R. flavefaciens GdhA
      activity appears to be regulated primarily at the level of transcription. Brief
      exposure to 20 mM NH(4)Cl prior to extraction did not alter the level of
      activity. Transcriptional regulation, studied with quantitative real-time RT-PCR,
      demonstrated a three-fold increase of the gdhA transcript concentration in
      ammonia-limited cells in comparison with an excess of ammonia in the medium. This
      is in agreement with the enzyme activity data obtained under ammonia- and carbon
      limited growth conditions.

PMID- 12610724
TI  - Saccharin as a sole source of carbon and energy for Sphingomonas xenophaga SKN.
AB  - A bacterium, strain SKN, that was able to utilize saccharin as the sole source of
      carbon and energy for aerobic growth, was enriched and isolated from communal
      sewage. The isolate was identified as a strain of Sphingomonas xenophaga.
      Saccharin was quantitatively converted to cell material, sulfate, ammonium and,
      presumably, CO(2). The specific rate of saccharin-dependent oxygen uptake during
      growth reached a maximum before the culture entered the stationary phase and then
      fell to undetectable levels. Saccharin was degraded only in the presence of
      molecular oxygen. Catechol was detected as an intermediate during degradation of
      saccharin in whole cells and catechol 1,2-dioxygenase was expressed inducibly
      during growth with saccharin. There was an apparent requirement of 2 mol O(2)/mol
      saccharin to remove the substituents on the ring and to cleave the ring. We
      presume that S. xenophaga SKN synthesizes a multi-component saccharin dioxygenase
      that simultaneously cleaves off both vicinal substituents from the aromatic ring
      to yield catechol and the undefined precursor of CO(2) as well as sulfate and
      ammonium ions.

PMID- 12610725
TI  - A two [4Fe-4S]-cluster-containing ferredoxin as an alternative electron donor for
      2-hydroxyglutaryl-CoA dehydratase from Acidaminococcus fermentans.
AB  - The key step in the fermentation of glutamate by Acidaminococcus fermentans is a
      reversible syn-elimination of water from ( R)-2-hydroxyglutaryl-CoA to ( E)
      glutaconyl-CoA catalyzed by 2-hydroxyglutaryl-CoA dehydratase, a two-component
      enzyme system. The actual dehydration is mediated by component D, which contains
      1.0 [4Fe-4S](2+) cluster, 1.0 reduced riboflavin-5'-phosphate and about 0.1
      molybdenum (VI) per heterodimer. The enzyme has to be activated by the extremely
      oxygen-sensitive [4Fe-4S](1+/2+)-cluster-containing homodimeric component A,
      which generates Mo(V) by an ATP/Mg(2+)-induced one-electron transfer. Previous
      experiments established that the hydroquinone state of a flavodoxin (m=14.6 kDa)
      isolated from A. fermentans served as one-electron donor of component A, whereby
      the blue semiquinone is formed. Here we describe the isolation and
      characterization of an alternative electron donor from the same organism, a two
      [4Fe-4S](1+/2+)-cluster-containing ferredoxin (m=5.6 kDa) closely related to that
      from Clostridium acidiurici. The protein was purified to homogeneity and almost
      completely sequenced; the magnetically interacting [4Fe-4S] clusters were
      characterized by EPR and Mossbauer spectroscopy. The redox potentials of the
      ferredoxin were determined as -405 mV and -340 mV. Growth experiments with A.
      fermentans in the presence of different iron concentrations in the medium (7-45
      microM) showed that flavodoxin is the dominant electron donor protein under iron
      limiting conditions. Its concentration continuously decreased from 3.5 micromol/g
      protein at 7 microM Fe to 0.02 micromol/g at 45 microM Fe. In contrast, the
      concentration of ferredoxin increased stepwise from about 0.2 micromol/g at 7-13
      microM Fe to 1.1+/-0.1 micromol/g at 17-45 microM Fe.

PMID- 12610726
TI  - Molecular characterization of HPr and related enzymes, and regulation of HPr
      phosphorylation in the ruminal bacterium Streptococcus bovis.
AB  - Molecular properties of HPr, enzyme I, and HPr kinase in Streptococcus bovis, and
      the regulation of HPr phosphorylation were examined. The genes encoding HPr
      (ptsH) and enzyme I (ptsI) were found to be cotranscribed. Two transcriptional
      start sites were detected in a region upstream of the HPr kinase gene (hprK). HPr
      kinase had both HPr-phosphorylating and HPr-dephosphorylating activities. The
      importance of phosphorylation of Ser-46 in HPr was shown by using a mutant HPr in
      which Ser-46 was replaced by Ala. When S. bovis was grown in glucose-limited
      medium, the amount of seryl-phosphorylated HPr (HPr-[Ser-P]) decreased
      drastically as the growth rate decreased. In contrast, the amount of histidyl
      phosphorylated HPr (HPr-[His-P]) increased gradually as the growth rate
      decreased. The amount of HPr kinase did not greatly change with the growth phase,
      whereas the intracellular P(i) concentration increased as the growth rate
      decreased. HPr-[Ser-P] decreased as the intracellular P(i) increased as a
      consequence of inhibition of HPr kinase activity by P(i) and simultaneous
      enhancement of HPr-[Ser-P] phosphatase activity by P(i). Thus, it is conceivable
      that the ratio of HPr-[Ser-P] to HPr-[His-P] is regulated by the bifunctional
      activity of HPr kinase in response to intracellular P(i) concentration.

PMID- 12610727
TI  - Suppression-subtractive hybridisation reveals variations in gene distribution
      amongst the Burkholderia cepacia complex, including the presence in some strains
      of a genomic island containing putative polysaccharide production genes.
AB  - Some strains of the Burkholderia cepacia complex, including the ET12 lineage,
      have been implicated in epidemic spread amongst cystic fibrosis (CF) patients.
      Suppression-subtractive hybridisation was used to identify genomic regions within
      strain J2315 (ET12 lineage; genomovar IIIA) that were absent from a non
      transmissible genomovar IIIB strain. Sequence data from 15 subtracted clones were
      used to interrogate the genome sequence of strain J2315 and identify genomic
      regions incorporating the subtracted sequences. Many of the genomic regions
      displayed abnormally low GC content and similarity to sequences implicated in
      gene transfer. The distribution of three subtracted regions amongst members of
      the B. cepacia complex varied. A large cluster of genes with strong sequence
      similarity to capsular production genes from Burkholderia mallei and other
      bacterial pathogens was identified. This genomic island was detected in some but
      not all representatives of genomovar IIIA, two out of four genomovar I strains,
      and one of two strains of Burkholderia multivorans, but was not detected in
      Burkholderia stabilis, Burkholderia vietnamiensis, genomovar VI or Burkholderia.
      ambifaria. The polysaccharide production gene cluster of strain J2315 carries an
      IS 407-like sequence within the gene similar to B. mallei wcbO that is lacking in
      other ET12 isolates. Genes from this cluster are expressed during exponential
      growth in broth.

PMID- 12610728
TI  - The alternative use of exons 2 and 3 in cathepsin B mRNA controls enzyme
      trafficking and triggers nuclear fragmentation in human cells.
AB  - Pathological overexpression and trafficking of the cysteine peptidase cathepsin B
      depend in part on the composition of its mRNA. To investigate the roles of the
      alternatively spliced exons 2 and 3 in the 5'-untranslated region of cathepsin B
      mRNA we produced constructs of cathepsin B fused to green fluorescent protein.
      Expression and trafficking of the fluorescent chimeric products was followed in
      living human immortalized chondrocytes and HeLa cells. Although synthesized at
      different rates, proteins encoded by the full transcript and by that missing exon
      2 followed a classic route, with the endosomal-lysosomal compartment as the final
      target. The point-mutated variant missing the glycosylation site for lysosomal
      targeting followed the secretory pathway. A truncated form of cathepsin B lacking
      the signal peptide and part of the propeptide, and encoded by the construct
      missing exons 2 and 3, was neither found in the Golgi apparatus nor in vesicles,
      but rather in the cytoplasm as patches associated with membranous and short
      fibrillar elements. This particular form of truncated cathepsin B produced
      nuclear damage and shrinking of the trans Golgi network and of the acidic
      compartment. The C-terminal, six-amino acid-long propeptide of cathepsin B did
      not exhibit a discernible role in protein trafficking.

PMID- 12610729
TI  - Toll-like receptor 2 is expressed by alveolar epithelial cells type II and
      macrophages in the human lung.
AB  - The ability of the host to recognize pulmonary invasion by pathogenic organisms
      and establish an appropriate host response to infection requires innate immune
      defense mechanisms. Early bacterial clearance in the lung is mediated by alveolar
      macrophages (AM) and polymorphonuclear neutrophils. Additionally alveolar
      epithelial cells type II (AEC-II) may act as immunoregulatory cells. The toll
      like receptors (TLR) are part of this innate immune defense, recognizing
      conserved patterns on microorganisms. Toll-like receptor 2 (TLR2) is crucial in
      detecting components of gram-positive bacteria and mycobacteria. Signals
      initiated by the interaction of TLR2 with bacterial components direct the
      subsequent inflammatory response. The detection of TLR2 mRNA in human lung tissue
      prompted us to localize the expression of mRNA and protein at the cellular level
      using a novel method for tissue fixation. We utilized HOPE-fixed lung specimen
      sections for targeting mRNA by in situ hybridization and protein by
      immunohistochemistry using the monoclonal antibody TL2.1. In normal lung areas
      the expression of TLR2 mRNA and protein was found to be located in cells
      resembling AEC-II and AM. Expression of mRNA was verified by RT-PCR and DNA
      sequencing. These results indicate a potential mechanism of increased
      immunosurveillance at the alveolar level controlling the localized infection.

PMID- 12610732
TI  - Expression and distribution of phocein and members of the striatin family in
      neurones of rat peripheral ganglia.
AB  - Phocein and members of the striatin family (striatin, SG2NA and zinedin) are
      intracellular proteins, mainly expressed in neurones of the mammalian central
      nervous system where they are thought to be involved in vesicular traffic and
      Ca(2+) signalling. Here, we have investigated whether these proteins are also
      present in the peripheral nervous system, by analysing their expression and
      distribution within sensory neurones of the vagal (nodose and jugular) ganglia,
      the petrosal ganglion, the dorsal root ganglion, and also in the sympathetic
      neurones of the superior cervical ganglion. RT-PCR experiments showed that mRNAs
      of phocein, striatin, SG2NA and zinedin are present in all studied peripheral
      ganglia. Immunocytochemical detections demonstrate that phocein, striatin and
      SG2NA are expressed in neurones of vagal, petrosal and dorsal root ganglia.
      Immunoblotting experiments confirm these data and in addition demonstrate that:
      (1) the proteins phocein, striatin and SG2NA are also present in the superior
      cervical ganglion and (2) zinedin is detected in all studied ganglia. The
      distribution appears to differ: immunoreactivity for striatin and SG2NA is found
      only in soma of sensory neurons, whereas immunoreactivity for phocein is observed
      in both soma and processes. Our study thus demonstrates that phocein and the
      members of the striatin family are expressed not only in central nervous system
      but also in the peripheral nervous system and, in particular, in afferent sensory
      neurones.

PMID- 12610730
TI  - Plectin tethers desmin intermediate filaments onto subsarcolemmal dense plaques
      containing dystrophin and vinculin.
AB  - Plectin is a versatile cytoskeletal linker protein that preferentially localizes
      at interfaces between intermediate filaments and the plasma membrane in muscle,
      epithelial cells, and other tissues. Its deficiency causes muscular dystrophy
      with epidermolysis bullosa simplex. To better understand the functional roles of
      plectin beneath the sarcolemma of skeletal muscles and to gain some insights into
      the underlying mechanism of plectin-deficient muscular dystrophy, we studied in
      vivo structural and molecular relationships of plectin to subsarcolemmal
      cytoskeletal components, such as desmin, dystrophin, and vinculin, in rat
      skeletal muscles. Immunogold electron microscopy revealed that plectin fine
      threads tethered desmin intermediate filaments onto subsarcolemmal dense plaques
      overlying Z-lines and I-bands. These dense plaques were found to contain
      dystrophin and vinculin, and thus may be the structural basis of costameres. The
      in vivo association of plectin with desmin, (meta-)vinculin, dystrophin, and
      actin was demonstrated by immunoprecipitation experiments. Treatment of plectin
      immunoprecipitates with gelsolin reduced actin, dystrophin, and (meta-)vinculin
      but not desmin, implicating that subsarcolemmal actin could partly mediate the
      interaction between plectin and dystrophin or (meta-)vinculin. Altogether, our
      data suggest that plectin, along with desmin intermediate filaments, might serve
      a vital structural role in the stabilization of the subsarcolemmal cytoskeleton.

PMID- 12610731
TI  - Paracrine role of soluble guanylate cyclase and type III nitric oxide synthase in
      ovine fetal pulmonary circulation: a double labeling immunohistochemical study.
AB  - Endothelial nitric oxide synthase (eNOS) or NOS-III in the endothelium catalyzes
      production of nitric oxide (NO). Nitric oxide diffuses freely into vascular
      smooth muscle, where it activates soluble guanylate cyclase (sGC) to produce
      guanosine 3',5'-cyclic monophosphate (cGMP) and causes vasorelaxation. The
      NO/cGMP pathway is an important signaling pathway in the control of perinatal
      pulmonary circulation. An exact colocalization of NOS-III in the pulmonary
      endothelium and sGC in the vascular smooth muscle was demonstrated using a double
      immunolabeling technique. The sGC immunoreactivity was higher in resistant
      pulmonary vessels and veins than in conduit arteries, whereas NOS-III
      immunoreactivity was higher in conduit arteries than in veins. These results
      demonstrated anatomically in situ a paracrine role of NOS-III and sGC in the
      regulation of fetal pulmonary circulation and suggested a heterogeneous
      distribution of NOS-III and sGC within fetal ovine pulmonary vasculature. Our
      results provided an anatomic basis that supported previous functional studies on
      perinatal control of pulmonary circulation.

PMID- 12610733
TI  - Expression of connexin 37, 40 and 43 in rat mesenteric arterioles and resistance
      arteries.
AB  - Connexins are the protein constituents of gap junctions which mediate
      intercellular communication in most tissues. In arterioles gap junctions appear
      to be important for conduction of vasomotor responses along the vessel. Studies
      of the expression pattern of connexin isoforms in the microcirculation are
      sparse. We investigated the expression of the three major vascular connexins in
      mesenteric arterioles (diameter <50 micro m) from male Sprague-Dawley rats, since
      conducted vasomotor responses have been described in these vessels. The findings
      were compared with those obtained from upstream small resistance arteries.
      Indirect immunofluorescence techniques were used on whole mounts of mesenteric
      arterioles and on frozen sections of resistance arteries (diameter approximately
      300 micro m). Mesenteric arterioles expressed Cx40 and Cx43 in the endothelial
      layer, and Cx37 was found in most but not all vessels. Connexins were not
      demonstrated in the media. In resistance arteries endothelial cells expressed
      Cx37, Cx40 and Cx43. Ultrastructural studies of mesenteric arterioles confirmed
      that gap junction plaques between endothelial cells are present, whereas
      myoendothelial, or smooth muscle cell gap junctions could not be demonstrated.
      The findings suggest that smooth muscle cells in mesenteric arterioles may not be
      well coupled and favour that conducted vasomotor responses in these vessels are
      propagated through the endothelial cell layer.

PMID- 12610734
TI  - Serum response factor plays an important role in the mechanically overloaded
      plantaris muscle of rats.
AB  - Molecular signaling pathways linking the hypertrophy after mechanical overloading
      in vivo have not been identified. Using western blot analysis,
      immunoprecipitation, and immunohistochemistry, we investigated the effect of the
      mechanical overloading state on RhoA, serum response factor (SRF), and MyoD in
      the rat plantaris muscle. Adult male rats (10 weeks of age) were used in this
      experiment. Compensatory enlargement of the plantaris muscle was induced in one
      leg of each rat by surgical removal of the ipsilateral soleus and gastrocnemius
      muscles. In the normal plantaris muscle of rats, slight expression of RhoA and
      SRF was observed in the quiescent satellite cells possessing CD34 and c-Met.
      Western blotting using the homogenate of whole muscle clearly showed that
      mechanical overloading of the plantaris muscle significantly increased the amount
      of RhoA during 3-6 days postsurgery. Threonine phosphorylation of SRF occurred at
      2-4 h after mechanical overloading. The most marked increase in SRF protein was
      observed in the hypertrophied muscle at 6 days postsurgery. At 2 days
      postoperation, SRF immunoreactivity was not detected in the proliferating
      satellite cells possessing bromodeoxyuridine and in the infiltrating macrophages
      expressing ED1 in the overloaded muscle by surgical removal. The SRF protein was
      colocalized with RhoA, FAK, and myogenin but not Myf-5 in many mononuclear cells
      at 6 days of functional overload. At this time, MyoD immunoreactivity was
      detected in the cytoplasm of mononuclear cells (possibly satellite cell-derived
      myoblasts) possessing SRF protein at the nucleus. These results suggest that the
      signaling pathway through RhoA-FAK-SRF is important to the differentiation of
      satellite cells by interacting MyoD and myogenin in the hypertrophied muscle of
      rats.

PMID- 12610735
TI  - Postmortem alterations in the pH range of myofibrillar ATPase
      activation/inactivation.
AB  - A histochemical assay for myofibrillar adenosine triphosphatase (mATPase)
      activity is routinely utilized in the delineation of fiber types in healthy human
      skeletal muscle. Each fiber type has a specific pH range of mATPase stability
      (activation). Outside of this pH range, mATPase activity is labile (inactivated),
      no reaction product is formed, and the fibers remain unstained. The aim of the
      present study was to carefully investigate the pH stability/lability of mATPase
      in postmortem muscles. To this end, vastus lateralis muscle samples were obtained
      approximately 0.5, 1, 2, 3, and 4 days after death, as well as control samples
      from a healthy young man and woman. Serial cross sections of the muscle samples
      were assayed for mATPase activity throughout preincubation pH ranges of 4.15-4.7
      and 10.2-10.5 in increments of 0.05 pH units. Myosin heavy chain analysis (as
      well as a regression analysis comparing fiber type area and relative myosin heavy
      chain content) verified the mATPase-based fiber types. The pH ranges of mATPase
      stability/lability for the control samples were as previously reported, and
      support the use of preincubation pH values of 4.3, 4.6, and 10.4 for the
      delineation of fiber types in normal human muscle. For the postmortem samples,
      both quantitative and qualitative changes altered the pH ranges of mATPase
      activation/inactivation. Quantitative changes consisted of a time-dependent loss
      of mATPase activity that was inhibited in all fibers outside the pH range of 4.15
      10.50. In addition, qualitative changes caused "shifts to the left" in mATPase
      stability within the fast fiber types (IIA and IIB). As such, complete inhibition
      of mATPase activity did not occur until preincubation at pH 4.45 and pH 4.30 for
      fiber types IIA and IIB, respectively. For the postmortem vastus lateralis muscle
      samples, optimal preincubation pH values for mATPase-based fiber type delineation
      were pH 4.30, 4.45, and 10.35. The reason for these qualitative changes in
      mATPase stability is not known. However, postmortem changes such as increased
      lactate production and marked acidification may play a role.

PMID- 12610736
TI  - The so-called "testis-specific aldehyde dehydrogenase" corresponds to type 2
      retinaldehyde dehydrogenase in the mouse.
AB  - The distribution pattern of "testis-specific aldehyde dehydrogenase" in mouse
      tissues was investigated. Because of the broad substrate specificity and the high
      degree of sequence identity of the large aldehyde dehydrogenase family a specific
      detection of single isoforms is not possible by histochemical means. Therefore,
      the technique of native isoelectric focusing was used. Thus, the expression of
      four to five banded "testis-specific aldehyde dehydrogenase" in the mouse testis
      was confirmed. However, the activity of this enzyme with the same pattern of
      multiplicity was found not only in the testis but also in the uterus and in
      embryonic tissues. At 9.5 and 10.5 days of embryonic development the enzyme
      activity was restricted to tissues of the embryonic trunk and absent in extracts
      from cranial tissues. The tissue distribution as well as substrate specificity
      and isoelectric points indicate that the "testis-specific aldehyde dehydrogenase"
      corresponds to mouse type 2 retinaldehyde dehydrogenase.

PMID- 12610739
TI  - Intrarectal pharmacokinetics of two formulations of quinine in children with
      falciparum malaria.
AB  - OBJECTIVE: To compare the intrarectal bioavailabilities of two parenteral
      formulations of quinine most available in French- (Cinchona alkaloid mixture) and
      English (hydrochloride salt) -speaking areas of Africa. METHODS: The
      pharmacokinetics of quinine was investigated in four groups of 12 children with
      acute Plasmodium falciparum malaria receiving 8 mg/kg quinine base every 8 h
      either as hydrochloride salt or Cinchona alkaloid mixture by a slow 4-h
      intravenous infusion or intrarectal administration. Body temperature and
      parasitaemia were monitored, and blood quinine concentrations were measured by
      means of high-performance liquid chromatography. RESULTS: At 72 h, all the
      children were aparasitaemic and apyretic. Quinine C(max) values were higher after
      intravenous infusion of the hydrochloride salt and Cinchona alkaloid mixture
      (6.9+/-1.9 micro g/ml and 5.2+/-1.3 micro g/ml) than after intrarectal
      administration (3.5+/-1.4 micro g/ml and 3.1+/-1.6 micro g/ml), but t(max) values
      were similar (3.6+/-1.5, 4.2+/-1.0, 4.0+/-1.9, and 4.7+/-2.0 h, respectively).
      Intrarectal relative bioavailabilities of hydrochloride salt solution (57%) and
      Cinchona alkaloid mixture (62%) were similar. CONCLUSION: Whatever the parenteral
      formulation of quinine, the blood concentration-time profiles of quinine were
      similar after intrarectal administration. Intrarectal administration of
      hydrochloride salt solution is a possible mode of quinine delivery in remote
      rural areas of Africa.

PMID- 12610738
TI  - The skin vasoconstrictor assay does not correlate significantly to airway or
      systemic responsiveness to inhaled budesonide in asthmatic patients.
AB  - OBJECTIVE: The responsiveness to inhaled corticosteroid varies among individual
      asthmatic patients. It is not known, however, whether the effects of
      corticosteroids on one bodily tissue reflect the response in another in a given
      individual. The aim was to a assess whether skin vasoconstrictor assay might
      predict airway and systemic tissue responsiveness to inhaled budesonide in
      patients with asthma. METHODS: Twenty-two patients with mild to moderate
      persistent asthma previously enrolled in a dose-response study assessing the
      effects of inhaled budesonide on airway bronchial challenge testing, exhaled
      nitric oxide and blood cortisol and eosinophil count were recalled for assessment
      of vasoconstrictor response to topical budesonide. The MacKenzie vasoconstrictor
      assay was performed by applying tenfold dilutions from 10(-2) g/ml to 10(-8) g/ml
      budesonide and visually assessing the degree of skin blanching after 18 h at each
      concentration. RESULTS: There was a significant overall dose-response effect for
      the degree of skin blanching at each concentration. There was no significant
      correlation between the effects on the skin and measures of anti-asthmatic
      efficacy or systemic effect after 3 weeks of 400 microg/day inhaled budesonide.
      There was a significant correlation with the overall dose-cutaneous response
      effect versus the overall dose-response effect with adenosine monophosphate (r=
      0.53) but not methacholine bronchial challenge testing or serum cortisol.
      CONCLUSION: It may not be possible to use the McKenzie vasoconstrictor assay to
      predict which patients are most or least susceptible to inhaled corticosteroids
      for anti-asthmatic efficacy or systemic adverse effects.

PMID- 12610740
TI  - Effect of ciprofloxacin on the pharmacokinetics of ropivacaine.
AB  - OBJECTIVE: To assess the effect of ciprofloxacin on the pharmacokinetics of
      ropivacaine. METHODS. In a double-blind, randomised, cross-over study, nine
      healthy volunteers were treated for 2.5 days with 500 mg oral ciprofloxacin or
      placebo twice daily. On day 3, they received a single dose of 0.6 mg/kg
      ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine (3-OH
      ropivacaine), and (S)-2',6'-pipecoloxylidide (PPX) in venous plasma and urine
      were measured for up to 12 h and 24 h, respectively. RESULTS: Ciprofloxacin
      decreased the mean clearance (CL) of ropivacaine by 31% (P<0.05), with a
      considerable inter-individual variation (range from -52% to +39%). It also
      decreased the area under the plasma concentration-time curve (AUC) of 3-OH
      ropivacaine by 38% (P<0.05) and urinary excretion of 3-OH-ropivacaine by 27%
      (P<0.05). Ciprofloxacin increased the AUC of PPX by 71% (P<0.01) and urinary
      excretion of PPX by 97% (P<0.01). CONCLUSION: Ciprofloxacin modestly decreased
      the mean ropivacaine CL by inhibiting the CYP1A2-mediated formation of 3-OH
      ropivacaine. At the same time, the CYP3A4-mediated formation of PPX was
      increased. There was a marked inter-individual variation in the extent of the
      interaction, and, for some individuals, the concomitant use of ciprofloxacin with
      ropivacaine might produce toxic symptoms.

PMID- 12610741
TI  - CYP2D6*10 alleles do not determine plasma fluvoxamine concentration/dose ratio in
      Japanese subjects.
AB  - OBJECTIVE: The purpose of the present study was to investigate whether plasma
      fluvoxamine (FV) concentration is associated with CYP2D6*10 allele polymorphisms.
      METHODS: Subjects were 46 Japanese patients (21 males) carrying neither *3, *4
      nor *5 alleles and treated orally using FV. Venous blood was obtained from each
      patient for determination of FV concentration/dose (C/D) ratio (plasma
      concentration of FV divided by daily dose of FV per body weight) and CYP2D6
      genotyping. RESULTS: No significant differences in FV C/D ratio were found
      between subjects with no (n=13), one (n=18) or two (n=15) *10 alleles.
      CONCLUSION: Our results indicate that CYP2D6*10 genotypes do not exert
      significant effects on FV C/D ratio. As CYP2D6 genotypes differ with ethnic
      background, further studies should be conducted in different populations.

PMID- 12610742
TI  - Identification of epoxybergamottin as a CYP3A4 inhibitor in grapefruit peel.
AB  - OBJECTIVE: The oral availability of many drugs metabolised by the enzyme
      cytochrome P(450) 3A4 (CYP3A4) is increased if co-administered with grapefruit
      juice. Extracts from grapefruit peel have also demonstrated inhibitory activity
      and, during commercial manufacturing of grapefruit juice, inhibitory components
      might be squeezed into the juice from the peel. Thus, the aim of this in vitro
      study was to identify CYP3A4 inhibitors in grapefruit peel. METHODS: Grapefruit
      peel was extracted with diethyl ether, and the extract was further fractionated
      by normal-phase chromatography. Fractions demonstrating significant CYP3A4
      inhibitory activity, as measured by the relative reduction in N-demethylation of
      diltiazem in transfected human liver epithelial cells, were subsequently
      separated by preparative thin-layer chromatography. Constituents of the fractions
      and isolated compounds were identified by nuclear magnetic resonance
      spectroscopy. Analysis of diltiazem and N-demethyl-diltiazem was performed using
      high-performance liquid chromatography. RESULTS: Of the identified components in
      grapefruit peel, only epoxybergamottin demonstrated a concentration-dependent
      inhibition of the CYP3A4-mediated N-demethylation of diltiazem. The IC(50) value
      was calculated to be 4.2+/-1.1 micro M. Coumarins without the furan ring and
      flavonoids isolated from grapefruit peel did not interfere with the metabolism of
      diltiazem. The results indicated the presence of other CYP3A4 inhibitors in
      grapefruit peel, but these agents were lost during the purification process
      excluding their identification. CONCLUSION: The furanocoumarin epoxybergamottin,
      present in grapefruit peel, is an inhibitor of CYP3A4. In commercial
      manufacturing of grapefruit juice, epoxybergamottin is possibly distributed into
      the juice. During manufacturing, however, epoxybergamottin may be hydrolysed to
      6',7'-dihydroxybergamottin, which has been suggested as an important CYP3A4
      inhibitor in grapefruit juice.

PMID- 12610743
TI  - Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic
      impairment.
AB  - OBJECTIVE: To assess the effect of chronic hepatic impairment on rosuvastatin
      disposition, pharmacodynamic activity and tolerability. METHODS: This was an open
      label, non-randomised, parallel-group trial. Six subjects were enrolled in each
      of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment),
      Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the
      latter two strata were age, weight, race, sex and smoking history matched. All
      subjects were given rosuvastatin 10 mg for 14 days. RESULTS: In subjects with CP
      A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and
      C(max) were similar to subjects with normal hepatic function (geometric mean
      values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B
      who had the highest CP scores (i.e. the highest degrees of hepatic impairment)
      had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml
      and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased
      in all strata, but the response was more variable in the CP-B group. Rosuvastatin
      was well tolerated, and the safety profile was similar in subjects with hepatic
      impairment and normal hepatic function. CONCLUSION: In most subjects with mild-to
      moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin
      were similar to subjects with normal hepatic function (more extensive hepatic
      impairment may increase systemic exposure to rosuvastatin), and most had LDL-C
      reductions similar to subjects with normal hepatic function.

PMID- 12610744
TI  - Transplacental passage of lamotrigine in a human placental perfusion system in
      vitro and in maternal and cord blood in vivo.
AB  - OBJECTIVE: We studied transplacental passage of lamotrigine (3,5-diamino-6-[2,3
      dichlorophenyl]-1,2,4-triazine; LTG) using an ex vivo human placental perfusion
      method and in in vivo samples. METHODS: Term placentas from healthy mothers
      without medications were perfused in a recirculating dual perfusion system. LTG
      (2.5 microg/ml, n=4; 10 microg/ml, n=4) and reference compound antipyrine (100
      microg/ml) were added into the maternal circulation. The disappearance of drugs
      from the maternal circulation and appearance into the foetal circulation was
      followed every 15 min up to 2 h. Drug concentrations were analysed using high
      performance liquid chromatography. In addition to human placental perfusions, we
      analysed LTG concentrations in maternal vein and cord blood samples after
      delivery from two epileptic mothers receiving LTG therapy during pregnancy.
      RESULTS: LTG was detectable in the foetal circulation at 15 min in all of the
      perfusions, indicating rapid transfer. Maternal and foetal concentrations reached
      equilibrium at 60 min with both concentrations used. The feto-maternal ratio was
      1.26+/-0.20 with 10 microg/ml LTG and 0.83+/-0.41 with 2.5 microg/ml LTG at the
      end of the perfusion. The transfer of LTG from the maternal to the foetal
      compartment at 120 min was 28.9+/-10.7% with 2.5 microg/ml LTG and 37.8+/-3.2%
      with 10 microg/ml LTG (p>0.05). In the serum samples from epileptic mothers, the
      cord blood maternal concentration ratio was 1.02 in one pair and 1.55 in the
      other. CONCLUSIONS: LTG crossed the placenta easily and rapidly, indicating that
      the maternal treatment leads to a considerable foetal exposure.

PMID- 12610745
TI  - A clinical study investigating the pharmacokinetic interaction between NN703
      (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4
      substrate.
AB  - OBJECTIVE: NN703 (tabimorelin) is an orally active growth hormone (GH)
      secretagogue intended for use as an alternative to daily injections of GH. In
      vitro studies in human liver microsomes have indicated that NN703 is a mechanism
      based inhibitor of CYP3A4. The aim of the present study was to investigate in man
      the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4.
      METHODS: Seventeen adult male subjects were enrolled in the study, and each
      received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day
      1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day
      9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam
      and its main metabolite, alpha-hydroxymidazolam, were investigated. RESULTS:
      Following a single dose of NN703 (day 3), the AUC of both midazolam and alpha
      hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both).
      After repeated NN703 dosing (day 9), NN703 levels reached steady state, and
      midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas
      alpha-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline
      (n.s.). Following the washout period (day 16), midazolam AUC decreased to values
      lower than those on day 3 and day 9, but still significantly (45%) higher than
      baseline levels (P=0.0001). The C(max) values of midazolam and alpha
      hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect
      following repeated NN703 dosing was more pronounced. The t(1/2) of midazolam
      increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady
      state on day 9. CONCLUSION: This study shows that administration of NN703 and
      midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of
      midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.

PMID- 12610746
TI  - Initial 3-month usage characteristics predict long-term use of benzodiazepines:
      an 8-year follow-up.
AB  - OBJECTIVE: The aim of the study was to identify initial usage predictors for
      prolonged benzodiazepine use. METHODS: An 8-year pharmacy data-based study (1983
      1992) was carried out on a retrospective cohort of 425 initial benzodiazepine
      users. The setting was the only pharmacy in a community of 13,500 people.
      RESULTS: Among the 425 initial users, 36% had a single initial exposure year, 50%
      had two to seven exposure years, and 14% had benzodiazepine use during all 8
      years of follow-up. Prolonged use over more years was associated with an initial
      high number of prescriptions, elderly patients and initial use of hypnotics. Two
      patterns of irregular prolonged use were investigated: increase in use was
      associated with a shorter length of the first usage period and switching to
      another benodiazepine during the first 90 days; relapses of use were associated
      with a shorter length of first usage period and initial use of an anxiolytic.
      Gender and initial dosage were not associated with prolonged use at all.
      CONCLUSION: During the first 90 days after initiation of benzodiazepine use, a
      number of determinants of prolonged benzodiazepine use were visible. The
      prescribers of these drugs and the pharmacists should advise rational use not
      only at the start but also at the moment of the first repeat prescription in
      order to prevent needless prolonged use and dependence.

PMID- 12610747
TI  - Use of calcium antagonists and worsening renal function in patients receiving
      angiotensin-converting-enzyme inhibitors.
AB  - OBJECTIVE: The objective of this study was to assess whether calcium antagonists,
      which have been proven to dilate the afferent glomerular arteriole, might prevent
      increases in serum creatinine levels among older subjects who started treatment
      with angiotensin-converting enzyme (ACE) inhibitors. METHODS: We explored the
      association between use of calcium antagonists and incident increases in serum
      creatinine in 780 elderly patients with baseline creatinine levels <1.2 mg/dL
      (106.19 micromol/L), who were enrolled in a multicenter pharmacoepidemiology
      study, and who started using ACE inhibitors during their hospital stay. Among
      these participants, 279 also started using calcium antagonists. Demographic
      variables, comorbid conditions, medications, and objective tests, which were
      associated with increasing serum creatinine levels in separate regression models,
      were examined as potential confounders in a summary model. RESULTS: Among
      patients receiving ACE inhibitors, serum creatinine levels increased in 22% of
      participants who were dispensed calcium antagonists, and in 31% of other patients
      (P=0.005). In the summary regression model, use of calcium antagonists was
      associated with a decreased risk of worsening renal function (RR 0.56, 95% CI
      0.37-0.84). The adjusted risk of increasing serum creatinine was lower (RR 0.25,
      95% CI 0.05-0.95) in participants receiving higher calcium antagonists dosages
      than in those taking lower dosages. This protective effect of calcium antagonists
      was not detected in patients not dispensed ACE inhibitors. CONCLUSION: ACE
      inhibitors are underused in older subjects, mainly because of the higher
      incidence of renal damage among geriatric populations. Our results indicate that
      among elderly patients receiving ACE inhibitors, the use of calcium antagonists
      is associated with a reduced risk of worsening renal function. Thus, these
      results warrant trials aiming at establishing whether combined treatment with
      calcium antagonists might allow the use of ACE inhibitors in clinical practice to
      be expanded to the elderly population.

PMID- 12610749
TI  - Reporting adverse drug reactions on a geriatric ward: a pilot project.
AB  - OBJECTIVE: To test a method for registration of adverse drug reactions (ADRs)
      resulting in hospital admission and of ADRs occurring during hospital stay.
      Spontaneous reporting was compared with data from patient interview. METHODS:
      Spontaneous reporting of ADRs by nurses and physicians, as well as patient
      interviews by pharmacists. This pilot project was carried out in the geriatric
      ward of the Ghent University Hospital over a period of 8 months in order to
      develop suitable registration forms and to test feasibility. Causality, severity,
      type and level of intervention of the reported ADRs were analysed. Reports from
      physicians and nurses were compared with the data obtained by patient interviews.
      RESULTS: During the 8 months, for 168 patients, 12 spontaneous reports were
      received from physicians and nurses. Fifty-six of these patients were interviewed
      and 32 ADRs were reported. Only 2 ADRs detected by patient interview were also
      reported spontaneously. The interviews of the 56 geriatric patients indicated
      that 20% of them were admitted to the hospital because of an ADR. ADRs occurred
      during hospital stay in another 20% of those patients. CONCLUSION: Spontaneous
      reporting by physicians and nurses revealed considerably fewer ADRs than patient
      interview by pharmacists. Physicians and nurses reported the more serious ADRs
      that occurred during hospital stay, whereas the interviews revealed more ADRs
      that caused hospital admission. Our data confirm that ADRs are an important cause
      of hospital admission of geriatric patients and occur frequently during their
      hospital stay.

PMID- 12610748
TI  - Determinants for drug prescribing to children below the minimum licensed age.
AB  - OBJECTIVES: In the light of the undesired effects that unlicensed and off-label
      drug use might have, it is necessary to study the determinants affecting the
      prescribing of such drugs. Prescription of drugs to children younger than the
      minimum licensed age may carry the highest risk of adverse reactions. To obtain
      insight into the factors that affect prescription of drugs to children below the
      minimum licensed age, we conducted a population-based case-control study.
      METHODS: The case-control study was nested in a cohort of 13,426 children aged 0
      16 years, who were registered in the Integrated Primary Care Information (IPCI)
      project, a longitudinal observational general practitioners' database in the
      Netherlands. "Cases" were children who received a drug prescription for which
      they were below the minimum licensed age. To each case we matched up to four
      controls based on GP practice and patient age. As potential risk factors we
      evaluated the use of health care resources, and acute and chronic morbidity.
      RESULTS: We identified 447 cases who were matched to 1355 controls. The cases
      consulted their GPs significantly more often during the preceding half year, had
      more drug prescriptions, and had more specialist referrals than the controls.
      Respiratory diseases were the most important determinants for the prescription of
      drugs to children below the minimum licensed age. In adolescents, migraine and
      other headaches were the most important reasons. CONCLUSIONS: This study showed
      that children suffering from respiratory disease or migraine have the highest
      risk of receiving a drug prescription for which the patient is below the minimum
      licensed age. Regulatory authorities and the pharmaceutical industry should be
      stimulated to improve the evaluation of drug efficacy and safety in children.

PMID- 12610750
TI  - Low plasma cefaclor levels in cystectomized bladder cancer patients with various
      types of urinary diversion.

PMID- 12610751
TI  - Raynaud's phenomenon induced by drugs acting on neurotransmission: two cases
      under reboxetine and one under tegaserod.

PMID- 12610752
TI  - [Pathophysiology of neuronal injury in bacterial meningitis: concepts and
      implications].

PMID- 12610753
TI  - The association of myasthenia gravis and connective tissue diseases. Effects of
      thymectomy in six cases with rheumatoid arthritis and one case with systemic
      lupus erythematosus.
AB  - OBJECTIVES: To describe the effects of thymectomy in a group of patients with
      myasthenia gravis (MG) with associated connective tissue diseases (CTD). PATIENTS
      AND METHODS: We analyzed six patients with CTD and myasthenia. They were followed
      up for at least 3 years. RESULTS: Records of a cohort of 132 patients with
      established diagnosis of MG undergoing thymectomy in our institution between 1987
      1999 were reviewed. The percentage of patients with CTD was 5 % (6/132). Five
      patients had rheumatoid arthritis (RA) and one patient systemic lupus
      erythematosus (SLE). All patients were women, and the mean age was 38.5 years old
      (SD 13.7). Mean time of MG diagnosis to operation was 16 months (range from 1 to
      144 months). Preoperative Osserman classification was the following: stage IIb,
      four patients; stage III, one patient; and stage IV, one patient. Before surgery
      all patients were on anticholinesterase agent (pyridostigmine), and four patients
      were on corticosteroids. An extended transsternal thymectomy was practiced on
      five patients and a transcervical thymectomy was performed in the remaining
      patient. Pathologic findings were as follows: thymic hyperplasia in four patients
      and thymic atrophy in the other two. Good response (remission or improvement) was
      present in three patients (50 %) and poor response (no change or worse) in the
      other three (50 %). CONCLUSIONS: A low response to the thymectomy is observed in
      patients with MG and associated CTD (RA and an SLE).

PMID- 12610754
TI  - [Primary focal dystonia: descriptive study of 205 patients].
AB  - OBJECTIVES: To describe the clinical and epidemiologic aspects of different types
      of focal dystonia. PATIENTS AND METHODS: A total of 205 patients with primary
      focal dystonia were studied retrospectively and the following variables were
      analyzed: gender, age of onset, age at examination, evolution time, history of
      trauma, association with other movement disorders, fluctuations of dystonic
      symptoms as well as a family history of dystonia, Parkinson's disease, tremor,
      and lefthandedness or stuttering. We compared these variables among the different
      clinical categories of focal dystonia. RESULTS: Those patients with cranial and
      laryngeal dystonia were significantly older at the onset of symptoms compared
      with patients with writer's cramp. Males were more prevalent than females in all
      categories of focal dystonia except for cranial dystonia. Prior history of trauma
      and association with tremor were more frequent in patients with cervical dystonia
      than in those with others dystonic categories. Most patients with cranial,
      cervical and laryngeal dystonia had fluctuations in the intensity of dystonic
      symptoms, unlike the patients with writer's cramp. CONCLUSIONS: There is a caudo
      cranial gradient in age of onset and the age of onset increases as the cranial
      presentation becomes greater. Females are more prevalent in cranial dystonia and
      there is a preponderance of males in the dystonias with a lower location. The
      dystonias with cranial distribution frequently present fluctuations of symptoms
      during the day. Association with other movement disorders, such as tremor, and
      prior history of trauma, is common in patients with cervical dystonia.

PMID- 12610755
TI  - [Parkinson's disease of Adolf Hitler and its influence in the development of
      World War Second].
AB  - Adolf Hitler very probably suffered from Parkinson's disease. The first symptoms
      of it began to appear in 1937/1938. It is likely that its appearance, and the
      fear that it caused regarding his survival, lead Hitler to advance his initial
      projects of military expansion of the great Germany beginning in 1943. Thus, the
      Second World War broke out in 1939, perhaps quite before the time in which
      Germany would be prepared. Chronic treatment carried out with opiates, cocaine,
      amphetamines, and strychnine may very well be related with a very abnormal
      judgement of the problems and absence of trust in the advice of his team. With
      this, he would make military decisions that would end up being ill-fated for his
      interests and which, after 1942, would lead to a change in the course of the war.

PMID- 12610756
TI  - [Clinical decision-making: systematic reviews and meta-analysis].
AB  - Randomized clinical trials and mainly meta-analysis, have become the gold
      standard in the assessment of drug efficacy. A meta-analysis is a systematic
      review that uses statistical techniques to combine and summarize results of
      previous studies. Thereby, their design helps to identify and explain
      inconsistencies in the results of previous studies. One of the most complex and
      valid designs consists in obtaining the original database for each study
      (published or not) performing a <<pooled analysis>> or meta-analysis of
      individualized patient data. This type of meta-analysis avoids the partiality
      which may originate from the non-publication of nonsignificant studies. The
      future tendency would recommend that investigators, clinicians, reviewers,
      journal editors and sponsors agree on publication criteria other than positive p
      values such as clinical validity and clinical relevance.

PMID- 12610757
TI  - [Stem cells: solution to the problem of transplants in Parkinson's disease?].
AB  - The use of neural transplantation or cellular therapies for Parkinson's disease
      (PD) is based on the idea of substituting nigral dopaminergic neurons lost as a
      consequence of the degenerative process. More than 400 people with PD have
      received a transplant with highly variable results. Success of cellular therapy
      depends on the survival of a sufficient number of trasplanted dopaminergic cells
      and on the restoration of normal striatal circuitry, disrupted by the disease
      process. None of the currently used cellular sources can generate an unlimited
      number of dopaminergic cells. Stem cells (SC) are pluripotent cells which may be
      obtained from embryonic, fetal or adult tissues. SC can be isolated, expanded in
      culture during long periods of time and induced to differentiate into
      dopaminergic cells. Cellular lines can be created and can be stored. Therefore, a
      large amount of dopaminergic cells can be obtained from a single SC and they can
      be used when necessary. Embryonic SC seems to be more plastic than adult SC;
      however, the plasticity of adult SC may be higher than initially thought due to a
      phenomenon called transdifferentiation. Several studies carried out in
      experimental models have shown that SC therapy is viable. SC may be also the
      ideal vehicle for gene therapy. However, much work remains to be done before SC
      can be applied to human beings. Different aspects of neural development should be
      elucidated and important practical problems should be overcome, particularly
      those related to the development of germinal tumors and immunological rejection.
      Finally, ethical controversies should be carefully managed. Neurologia
      2003;18(2):74-100

PMID- 12610758
TI  - [Chiari malformation type I and reversible syringomyelia].

PMID- 12610759
TI  - [Extracranial and intracranial vascular abnormalities and nevus of Ota in the
      same family].
AB  - We present a 17 year old patient suffering from hemangioma on the left side of
      his face and neck. The evolution of his disease has been followed-up since he was
      8 1/2 months old. His mother has nevus of Ota in the sclera and adjacent zones in
      both sides. At the age of 8 1/2 months, the patient had an ischemic stroke in the
      territory of the left middle cerebral artery during the surgical correction of
      the aortic arch coarctation. The conventional arteriogram performed at 10 months
      of life showed several malformations of the intracranial and extracranial
      arteries. At the age of 16 years the cutaneous hemangioma was atrophic and a new
      angiographic study by magnetic resonance arteriography (MRA) showed all the
      vascular anomalies with higher objectivity than the conventional arteriography,
      especially the absence of some arteries and the abnormal position of some others.
      Moreover it could detect the decrease of the caliber of the intracranial arteries
      and the disappearance of hemangiomatous malformations even though the patient had
      not received any treatment for the cutaneous hemangioma. We think that this
      syndrome, which still has no definite name, has a parallel spontaneous biological
      process with progressing vascular size during the first months or years of life
      and, later, the vessels regress slowly but progressively, leading to a small
      caliber or even the occlusion of the vessels of the cutaneous hemangioma and of
      the abnormal extracranial and intracranial arteries. At the same time, there is a
      slow but progressive presence of transdural collateral vascularization of the
      brain. We do not find any relationship between the hemangiomatous syndrome of the
      patient and the nevus of Ota of his mother.

PMID- 12610760
TI  - [Malignant catatonia as paradigm of neuropsychiatric disease].
AB  - Catatonia is a large neuropsychiatric syndrome with multiple etiologies
      (psychiatric disorder, cerebral structural lesion, systemic disease, secondary to
      drugs and toxic agents) and varied clinical manifestations (cognitive and
      behavioral disorders, motor and speech disorders and vegetative disorders). The
      presence of disautonomy means a situation having vital risk, that requires
      immediate therapeutic intervention. A 22 year old woman was admitted due to a
      picture of stupor, fever, maintained postures, rigidity, seizures and tachycardia
      and hypertension episodes; this picture initiated four weeks earlier, with
      psychotic and affective symptoms and she slowly developed speech and motor
      activity impairment. Initially, she had been treated with neuroleptics,
      anticholinergics and antidepressants. The CT, MRI and CSF studies were normal.
      The EEG revealed diffuse slow waves and right frontotemporal paroxystic activity
      Laboratory determinations showed elevation of CK, coinciding with the vegetative
      disorder phase. The picture resolved progressively in two months, after receiving
      19 sessions of electroshock therapy. In all the patients, and above all in those
      who receive neuroleptics, with symptoms suggesting catatonia, the presence of
      disautonomy should be considered as an alarm situation, which would make it
      necessary to discontinue the neuroleptics and to adopt special control.
      Electroshock therapy is the most effective therapeutic option in the situation of
      malignant catatonia.

PMID- 12610761
TI  - [Progressive cranial neuropathy due to perineural spread of a facial squamous
      cell carcinoma].
AB  - The paper aims to present the case of a progressive and unilateral cranial
      polyneuropathy due to perineural spread of cutaneous squamous cell carcinoma.
      This is a case of a 73 year old man with a history of squamous cell carcinoma in
      the right temporal region that was removed in 1992. In May 2000 he first
      presented pain and numbness in the distribution of the first branch of right
      trigeminal nerve and weakness of the ipsilateral frontal muscle. Later on he
      presented right ophthalmoplegia, and damage of lower cranial nerves, leading to
      dysphagia and respiratory distress. He was admitted in March 2001 for a
      gastrostomy for feeding, when ataxia and recurrence of the right temporal lesion
      ensued. After three examinations with MRI, the fourth study showed meningeal
      carcinomatous and a metastatic lesion in the brainstem. Histopathologic
      examination demonstrated dermal and perineural invasion by squamous cell
      carcinoma. The necropsy also showed meningeal, perineural and endoneural
      infiltration of atypical epidermal cells and a pons mass composed of the same
      cells. We conclude that the perineural spread of the cutaneous carcinoma is an
      exceptional cause of cranial neuropathy, however it must be ruled out in patients
      with progressive and unilateral cranial neuropathy. In these cases, when no
      radiological abnormalities are noted, a biopsy may be performed on the peripheral
      branches of the cranial nerve to confirm the diagnosis.

PMID- 12610762
TI  - [Normalization of the Parkinsonian voice during sleep].

PMID- 12610764
TI  - Endoscopic removal of periorbital lesions - where next?

PMID- 12610763
TI  - [Ischemic infarction in the territory of the posteroinferior cerebellar artery
      with spinal cord involvement (Opalski syndrome)].

PMID- 12610765
TI  - Endoscopic removal of periorbital lesions.
AB  - In this article, the authors describe the technique, indications and contra
      indications for removing various periorbital lesions with an endoscope. The
      principal reason for using this technique is the excellent postoperative
      cosmesis. Seven patients in total had lesions removed in this manner. The only
      complication noted was some leakage of the contents of a dermoid cyst
      intraoperatively. Cosmesis postoperatively was excellent in all cases. None of
      the cases had to be converted to an 'open' procedure.

PMID- 12610766
TI  - Pterional orbital decompression in diseases with acute increase of intraorbital
      pressure.
AB  - BACKGROUND: Orbital cellulitis as well as traumatic or spontaneous intraorbital
      hemorrhages can lead to an acute rise of intraorbital pressure, threatening the
      function of orbital vascular, muscular and neural structures. The treatment of
      this rare entity with extended pterional orbital decompression is described in
      comparison with other methods of orbital decompression. PATIENTS AND METHODS:
      Between 1991 and 2000 the authors treated 16 patients with sight-threatening
      acute elevations of intraorbital pressure due to orbital cellulitis (3 patients)
      and spontaneous (3 patients), postoperative (1 patient) or traumatic diffuse or
      localized intraorbital hemorrhage (9 patients) with extended pterional orbital
      decompression. Pre- and postoperative parameters, like visual acuity,
      exophthalmos, restrictions of extraocular motility and pupillary disturbances,
      were retrospectively analyzed. RESULTS: In all patients, a distinct improvement
      of preoperative symptoms, like complete reduction of proptosis in all cases,
      improvement of visual acuity in 12 patients, improvement of eye motility
      disturbances in 14 patients and of afferent pupillary disturbances in 6 patients,
      was achieved by decompressing the orbital contents within a mean of 30.5 hours
      after onset of symptoms. Severe, operation-related complications were not seen.
      CONCLUSION: Extended pterional orbital decompression represents an effective
      treatment alternative and supplement in cases of severe, ocular function
      threatening cases of acute elevated orbital pressure, due, for example, to
      orbital cellulitis or diffuse or localized spontaneous and traumatic intraorbital
      hemorrhage, where immediate reduction of pressure on orbital neural, muscular and
      vascular structures is intended.

PMID- 12610767
TI  - Treatment of post-blepharoplasty lower lid retraction by free tarsoconjunctival
      grafting.
AB  - BACKGROUND: Blepharoplasty is probably the most commonly performed facial
      cosmetic procedure. Despite attempts to prevent its occurrence, post
      blepharoplasty lower eyelid malposition with inferior scleral show and corneal
      exposure can occur, particularly with non-ophthalmologist surgeons. Since a
      repair must oppose the force of gravity and recurrent scarring, it is often
      difficult to achieve functional and esthetically pleasing surgical correction. A
      variety of authors have documented methods to correct post-blepharoplasty lower
      eyelid malposition. A review of such methods is presented. This is the first
      paper to analyze results from free tarsoconjunctival grafting specifically in
      cases of post-blepharoplasty lower lid retraction. METHODS: The present case
      series report attempts to examine the efficacy of free tarsoconjuctival grafting
      in patients with post-blepharoplasty lower lid malposition. Ten patients, ranging
      in age from 48-75 years (mean = 58.7 years), presented with varied amounts of
      inferior scleral show and ocular symptoms, including epiphora, dry eye and ocular
      irritation. Varied amounts of lagophthalmos and superficial punctate keratitis
      were detected in five eyes and ten eyes, respectively. As described, each patient
      (20 eyes) underwent bilateral free conjunctival grafting from upper to lower
      eyelids. RESULTS: After a follow-up interval of 3-32 months (mean = 15 months),
      all patients experienced a decrease in inferior scleral show and symptomatology.
      The decrease in inferior scleral show ranged from 0.75 to 3 mm, with an average
      decrease of 1.61 mm; symptoms of epiphora, dry eye or discomfort persisted in
      only four eyes. The amount of lagophthalmos and superficial punctate keratitis
      also decreased postoperatively. Side effects were minimal. INTERPRETATION: We
      conclude that in the specific case of post-blepharoplasty lower lid retraction,
      free tarsoconjunctival grafting is both safe and effective.

PMID- 12610768
TI  - A review of the outcome of upper lid lowering for eyelid retraction and
      complications of spacers at a single unit over five years.
AB  - AIM: To review the outcome of upper lid lowering for eyelid retraction at a
      single unit over five years and to report the high complication rate with
      mersilene mesh as a spacer material. METHODS: We retrospectively reviewed the
      case records of 48 patients who underwent upper lid lowering for lid retraction
      between January 1995 and January 2000. RESULTS: The indication for surgery was
      eyelid retraction secondary to dysthyroid disease in 41 patients, seventh nerve
      palsy in 3 cases, overcorrection of ptosis elsewhere in 3 cases and previously
      treated orbital lymphoma in one patient. A good result was achieved in 80% with a
      single procedure. Undercorrection occurred in 10% and overcorrection occurred in
      8%. Spacer material, either mersilene mesh or more recently vicryl, was used in
      42% of lids. Late extrusion of mersilene mesh occurred in 20% of lids that had a
      spacer inserted an average of 18 months postoperatively. CONCLUSIONS: The high
      extrusion rate with mersilene was unacceptable and the alternative spacer
      material vicryl is now used. The possibility of revisional surgery because of
      under- or overcorrection should be explained to patients.

PMID- 12610769
TI  - Huge corneal dermoid in a well-formed eye: a case report and review of the
      literature.
AB  - A 25-day-old boy presented with a left corneal mass and left nasal obstruction.
      The mass involved the entire cornea with a skin-like surface and protruded
      outside the palpebral fissure. CT of the orbits disclosed a large cyst coating
      the entire left cornea, in an eye with a well-formed anterior chamber and a
      clearly evident lens. CT also revealed left nasal meningo-encephalocele. The eye
      with the mass was excised. The histopathologic report confirmed the diagnosis of
      corneal dermoid in an otherwise normally developed eye. This report of a huge
      dermoid involving the entire corneal diameter and extending into the sclera
      without ocular alteration posterior to Descemet's membrane is the first such
      report in the literature. The literature on corneal dermoids is also reviewed.

PMID- 12610770
TI  - Cystadenoma of the lacrimal gland.
AB  - Cystadenoma is a benign cystic tumor predominantly affecting the major and minor
      salivary glands. We present a case of bilateral cystadenoma of the lacrimal
      gland, which to the best of our knowledge has never been reported earlier. The
      patient had slowly increasing, painless, bilateral upper eyelid swelling. On
      examination, the tumors were multilobulated, mobile and transilluminant.
      Ultrasonography and CT-scan revealed cystic lesions with multiple septations in
      the region of both lacrimal fossae. Complete excision of the tumors was performed
      because of their potential for malignant transformation. The histopathological
      findings confirmed the diagnosis.

PMID- 12610771
TI  - Enophthalmos associated with primary breast carcinoma.
AB  - BACKGROUND AND OBJECTIVE: The most common source of metastases to the orbit is
      from breast carcinoma. The orbital presentation can be the presenting sign of the
      cancer. Proptosis or exophthalmos is the more usual way metastases present,
      associated with ocular motility problems or diplopia. We present a case of
      enophthalmos associated with breast carcinoma whereby there is as yet no
      radiological evidence of an actual orbital metastatic lesion. PATIENTS AND
      METHODS: A 51-year-old Caucasian woman with a known history of breast cancer
      presented with a 10-month history of vertical diplopia, particularly on upgaze.
      She noted that her left eye was becoming more "sunken" and examination confirmed
      an 8-mm enophthalmos on that side with restricted vertical eye movements and
      abduction. RESULTS: A provisional diagnosis of metastatic breast cancer was made.
      CT and MRI scans were performed. The main feature noted was that of orbital fat
      atrophy with no evidence of an orbital mass. She has been followed up for a
      period of 2(1/2) years with 6-monthly scans. There has been no progression of her
      clinical signs and no orbital lesion found so far. We are continuing to review
      her. CONCLUSION: Although no actual orbital mass has been found yet, we are
      treating her case as enophthalmos associated with scirrhosing breast carcinoma;
      she may, however, have spontaneous orbital fat atrophy, triggered by the cancer.

PMID- 12610772
TI  - Visual agnosia and prosopagnosia in childhood: a prospective case study.
AB  - Selective impairments in visual processing are well documented in adults but
      rarely reported in children. The few childhood cases reported are mostly
      retrospective accounts with little attention paid to developmental, assessment or
      management issues. We report a prospective case study of a boy with prosopagnosia
      and visual processing deficits of presumed developmental origin. At the age of 4
      years, AL presented with a range of cognitive and visual recognition deficits.
      Subsequent assessments revealed an evolving pattern in visual recognition and
      dissociations between developing skills. At the age of 7 AL has impairments in
      early perceptual analysis, visual organisation and in complex visual processing.
      Although he can identify facial features and match faces he is unable to
      recognise familiar faces. His reading and spelling are developing normally. The
      nature of his deficits and his progress are discussed within a cognitive
      neuropsychological framework.

PMID- 12610773
TI  - Learning and recall of story content and spatial location after unilateral
      temporal-lobe excision in children and adolescents.
AB  - The present study examined verbal and spatial learning and memory in children and
      adolescents who had undergone unilateral temporal lobectomy versus controls. All
      participants were trained to criterion before a delay to assess learning
      efficiency. There were no significant differences between the groups in rate of
      learning the verbal task. The right temporal-lobe group, but not the left, had
      difficulty learning spatial information. These findings indicate a specific
      effect of early right temporal-lobe lesions on spatial learning. As material
      specificity is more often found in adults for verbal information, the present
      results highlight the unique role of the temporal-lobe in development.

PMID- 12610774
TI  - Neuropsychological findings in two children diagnosed with hamartoses: evidence
      of a NLD phenotypic profile.
AB  - Hamartoses (HM) are defined as disorders involving nonneoplastic tissue
      overgrowth. Studies have examined the neuropsychological profiles of children
      with common HM, such as neurofibromatosis type 1. Limited information is known
      regarding neuropsychological profiles of rare HM such as Osteochondromatosis
      Syndrome (OS) and Klippel-Trenaunay Syndrome (KTS). The current investigation is,
      to our knowledge, the first attempt to define the cognitive phenotypes in two
      boys with OS and KTS. Results revealed significantly greater impairments
      involving sensorimotor and visuospatial skills, while verbal memory and language
      skills appeared relatively preserved. Significant neurobehavioral problems and
      marked social difficulties were evident. These findings suggest that these
      syndromes are on a Nonverbal Learning Disorder (NLD) continuum, with varying
      degrees of severity.

PMID- 12610775
TI  - Two sets of twins with selective mutism: neuropsychological findings.
AB  - Neuropsychological data are reviewed from two sets of dizygotic twins presenting
      with selective mutism characterized by situation specific anxiety, extreme
      passive behavior, lack of responsivity, lack of peer interaction, and a chronic
      course of selective mutism. Both sets of twins had a history of prematurity and
      delayed speech development. One set of twins presented with normal intelligence
      and normal receptive language skills but with expressive language and oral motor
      sequencing difficulties. The second set of twins presented with Verbal IQ
      deficits and significant receptive and expressive language deficits. A summary of
      current conceptualizations regarding etiology and treatment of selective mutism
      is provided.

PMID- 12610776
TI  - Effects of IQ on executive function measures in children with ADHD.
AB  - The present study compared children with Attention-Deficit Hyperactivity Disorder
      (ADHD) and controls on a selected set of clinical measures of executive function
      (EF). A total of 92 children (51 ADHD, 41 control), ages 6-16, completed measures
      chosen from a larger neuropsychological battery to illustrate diverse components
      of the EF construct (planning, inhibitory control, response preparation, memory
      search). The selected measures were moderately correlated with one another, and
      moderately correlated with IQ. After controlling for age, sex, presence of
      learning disability (LD), ADHD, and IQ test version, Full Scale IQ was
      significantly related to four of the five selected EF measures. A second analysis
      showed group differences on the EF measures at different IQ levels. After
      covarying for age, there was a significant multivariate effect for IQ level
      (average, high average, superior) and a significant multivariate interaction
      between group (ADHD vs. control) and IQ level. Three of the five selected EF
      measures showed significant univariate group effects (controls performing better
      than ADHD) at the average IQ level; however, there were no significant group
      differences between children with ADHD and controls at high average or superior
      IQ levels. These results suggest that clinical measures of EF may differ among
      children with ADHD and controls at average IQ levels, but there is poorer
      discriminatory power for these measures among children with above average IQ.

PMID- 12610778
TI  - On the identification of disease mutations by the analysis of haplotype
      similarity and goodness of fit.
AB  - The observation that haplotypes from a particular region of the genome differ
      between affected and unaffected individuals or between chromosomes transmitted to
      affected individuals versus those not transmitted is sound evidence for a disease
      liability mutation in the region. Tests for differentiation of haplotype
      distributions often take the form of either Pearson's chi(2) statistic or tests
      based on the similarity among haplotypes in the different populations. In this
      article, we show that many measures of haplotype similarity can be expressed in
      the same quadratic form, and we give the general form of the variance. As we
      describe, these methods can be applied to either phase-known or phase-unknown
      data. We investigate the performance of Pearson's chi(2) statistic and haplotype
      similarity tests through use of evolutionary simulations. We show that both
      approaches can be powerful, but under quite different conditions. Moreover, we
      show that the power of both approaches can be enhanced by clustering rare
      haplotypes from the distributions before performing a test.

PMID- 12610781
TI  - Vanishing pediatric nursing faculty.

PMID- 12610779
TI  - Germline p53 mutations in a cohort with childhood sarcoma: sex differences in
      cancer risk.
AB  - To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed
      cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from
      107 kindreds ascertained through patients with childhood soft-tissue sarcoma who
      were treated at the University of Texas M. D. Anderson Cancer Center. We
      systematically followed members in these kindreds for cancer incidence for >20
      years and evaluated their p53 gene status. We found seven kindreds with germline
      p53 mutations that include both missense and truncation mutation types. Kaplan
      Meier analysis showed similar cancer risks between 21 missense and 35 truncation
      p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly
      higher cancer risk in female carriers than in male carriers (log-rank
      chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific
      cancer. The calculated standardized incidence ratio (SIR) showed that mutation
      carriers had a risk for all types of cancer that was much higher than that for
      the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0)
      whereas noncarriers had a risk for all types of cancer that was similar to that
      in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed
      a >100-fold higher risk of sarcoma, female breast cancer, and hematologic
      malignancies for the p53 mutation carriers and agreed with the findings of an
      earlier segregation analysis based on the same cohort. These results
      quantitatively illustrated the spectrum of cancer risk in germline p53 mutation
      carriers and will provide valuable reference for the evaluation and treatment of
      patients with cancer.

PMID- 12610780
TI  - Variants in CHEK2 other than 1100delC do not make a major contribution to breast
      cancer susceptibility.
AB  - We recently reported that a sequence variant in the cell-cycle-checkpoint kinase
      CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in
      noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2
      variants confer susceptibility to breast cancer, we screened the full CHEK2
      coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with
      three or more cases of breast cancer. We identified one novel germline variant,
      R117G, in two separate families. To evaluate the possible association of R117G
      and two germline variants reported elsewhere, R145W and I157T with breast cancer,
      we screened 737 BRCA1/2-negative familial breast cancer cases from 605 families,
      459 BRCA1/2-positive cases from 335 families, and 723 controls from the United
      Kingdom, the Netherlands, and North America. All three variants were rare in all
      groups, and none occurred at significantly elevated frequency in familial breast
      cancer cases compared with controls. These results indicate that 1100delC may be
      the only CHEK2 allele that makes an appreciable contribution to breast cancer
      susceptibility.

PMID- 12610782
TI  - Urban American Indian family caregivers' perceptions of barriers to management of
      childhood asthma.
AB  - American Indian family caregivers of children with asthma face numerous barriers
      to effective management of the illness. The purpose of this qualitative,
      community-based study is to identify those barriers as perceived by family
      caregivers in a large Midwestern city. An ecological perspective and principles
      of family-centered care provided the theoretical orientation for the study.
      Interviews were conducted with 16 urban Ojibwe family caregivers of children with
      asthma. Five categories of barriers characterize the families' experiences:
      provider (individual and system), condition-related, family caregiver,
      socioeconomic, and environmental. Examination of these findings suggests
      directions for improving care to American Indian children with asthma and their
      families.

PMID- 12610783
TI  - Infants with colic: their childhood characteristics.
AB  - The purpose of this study was to compare 40 six- to eight-year-old children, 20
      with prospectively ascertained infantile colic and a matched sample of 20 without
      colic, on characteristics of emotional regulation and on parent stress. Children
      completed tests of cognitive ability, and mothers completed childhood behavioral
      questionnaires and a parenting stress assessment. Children with colic had
      maternal ratings suggestive of more difficulty with emotional regulation than
      their noncolic matches and displayed a more impulsive cognitive style. However,
      the mean scores of both groups were in the normal range.

PMID- 12610784
TI  - Constant vigilance: mothers' work parenting young children with type 1 diabetes.
AB  - Little is known about the experiences of mothers raising young children with type
      1 diabetes. The purpose of this study was to describe the day-to-day experiences
      of mothers (N = 28) raising young children under 4 years of age with type 1
      diabetes. Descriptive, naturalistic inquiry principles were used to interview
      subjects, as well as to manage and analyze the data. The mothers reported using
      the management behavior of constant vigilance. Their concerns about hypoglycemia
      and providing competent care reflected the interplay between their fears and
      profound sense of responsibility for managing the disease. Mothers reported
      having to learn the management behaviors and to occasionally adjust the day-to
      day management when either severe hypoglycemia or developmental milestones
      occurred. Although mothers initially had feelings of incompetence with the care
      they provided, with time, they became very skilled. There were also reports of
      limited access to babysitting, child care, or respite services. The intensity of
      their constant vigilance associated with their concerns, responsibility, and lack
      of supports resulted in some mothers having physical and/or emotional problems.
      The findings of the study highlight the importance of identifying family and/or
      community resources that may provide mothers with support that could reduce some
      of the tremendous stress and burden of responsibility experienced after diagnosis
      of diabetes.

PMID- 12610785
TI  - The utility of Cox's Interaction Model to direct the assessment and prevention of
      adolescent aggression.
AB  - The current study of violence prevention is hampered by a lack of consensus on
      the definition of violence. There is, however, some agreement about the
      behavioral cues that may predict violent behavior such as aggression. Although it
      has been shown that individual-level variables (e.g., race, gender, and
      ethnicity) are correlated with aggressive behavior, it is clear that they alone
      are not explanatory of aggressive behavior. This article demonstrates how the
      Interaction Model of Client Health Behavior is an important health behavior
      framework for the assessment of aggression in adolescents, offering insight into
      the contextual nature of adolescent aggression. Victimization and witnessing of
      violence, frequently identified to be precursors of adolescent aggression in
      current epidemiologic studies, are examined within this framework. On the basis
      of the interactional nature of the phenomenon, necessary components for
      successful prevention programs are suggested. Finally, future research
      implications calling for a well-designed study that integrates individual and
      contextual variables with the use of this theory-driven explanatory framework are
      proposed.

PMID- 12610786
TI  - Stage-based interventions for low-fat diet with middle school students.
AB  - Preventing obesity and cardiovascular disease at early ages is important;
      however, few effective interventions for early adolescents have been reported. In
      this study, low-income, culturally diverse students from an urban middle school
      (n = 60) received four classroom interventions with the use of a combined Health
      Promotion/Transtheoretical Model to control fat in diet and increase physical
      activity. A control group (n = 57) received the usual classroom education.
      Pretest percentage fat in diet was regressed on demographics, access to low-fat
      foods, perceived self-efficacy, benefits/barriers, and stage of change with
      results as proposed by the model [F(9,64) = 5.77; p =.000; adjusted R(2) = 0.35].
      Posttest percentage fat in food was significantly less for the intervention group
      as compared with the control group (t = 2.06; df, 115; p =.04).

PMID- 12610788
TI  - Selection of growth parameters to define failure to thrive.
AB  - Failure to thrive (FTT) is a syndrome of growth failure due to undernutrition.
      Determining whether an infant has FTT is based on the use of an anthropometric
      indicator and a selected cutoff value for that indicator. These anthropometric
      indicators include weight for age, weight for length, and length for age, and the
      cutoff values include the 10th, 5th, and 3rd percentiles. Each indicator and
      selected cutoff value provide unique information about an infant's growth.
      However, these parameters are often used interchangeably to explain the same
      growth phenomenon. The sensitivity and specificity of each anthropometric
      indicator are a function of the cutoff value selected and dictate which infants
      will be classified as having FTT and which infants will be classified as healthy.
      Depending on the sensitivity and specificity of the indicator, some infants with
      FTT will be classified as healthy, and some healthy infants will be classified as
      having FTT. A clear rationale for the selection of an anthropometric indicator
      and a cutoff value for defining FTT are important for increasing the
      generalizability of research findings and thereby expanding the current knowledge
      base related to FTT.

PMID- 12610787
TI  - Father-child teaching interactions: the relationship to father involvement in
      caregiving.
AB  - This study examined whether the amount of caregiving is related to the behavior
      of a father and his child during a structured teaching interaction. Healthy
      infants and toddlers (51 girls and 59 boys) and their fathers were observed in
      their homes. Fathers reported the frequency of involvement in caregiving during
      the previous week. Although fathers in higher and lower involvement groups were
      equally sensitive to the child's cues and responsive to the child's distress,
      fathers who were more involved in caregiving had higher scores in cognitive
      growth fostering as measured by the Nursing Child Assessment Teaching Scale.

PMID- 12610789
TI  - Welfare reform at the crossroads: pediatric nurses bridging the gap between self
      sufficiency and health.

PMID- 12610790
TI  - Teaching holistic child health promotion using Watson's theory of human science
      and human care.
AB  - "Preservation and advancement of human care is a critical issue for nursing today
      in our increasingly depersonalized society. The mandate for nursing within
      science as well as within society is a demand for cherishing of the wholeness of
      human personality" (Watson, 1999, p. 29). Children today are being faced with
      having to deal with this societal "depersonalization." How children grow up to
      perceive themselves and others is crucial in developing future adults who
      genuinely care about themselves and humankind in its totality. Watson's (1999)
      human science and human care theory was incorporated into teaching health
      promotion to a group of preadolescent children.

PMID- 12610791
TI  - An assessment of the mental health of physicians specializing in the field of
      child neurology.
AB  - We assessed physicians working in the field of child neurology with the aim of
      improving the physicians' mental health. Our questionnaire included a burnout
      inventory and a general health questionnaire. We analyzed 29 responses from
      physicians in a variety of countries obtained through the Internet. According to
      their responses, 8 (27.5%) of the respondents had attained a burnout status, and
      27 respondents (93.1%) had neurotic conditions. We found a greater percentage of
      physicians in poor mental health than we had found previously in assessments made
      in Japan. However, the respondents in the present survey had more positive styles
      for coping with stress. The length of time working as a physician affected
      respondents in Japan and internationally, whereas nationality or working
      environment (workplace, night shifts, and so on) did not. Consultants or mentors
      on work and assertive stress coping would be effective.

PMID- 12610792
TI  - An evidence-based eating disorder program.
AB  - The Children's Hospital of Denver has an internationally renowned outpatient
      inpatient treatment program for children, adolescents, and young adults with
      eating disorders (EDs). A unique feature of this ED program is its inpatient
      location on a medical unit. The nurses are medically trained, yet their patients
      with EDs have complex emotional and psychological problems. To address the
      special needs of these patients, a child life specialist worked in collaboration
      with other members of an ED health care team to create a program better serving
      ED pediatric patients. An evidence-based approach was used to drive this program.
      The child life specialist queried other health care facilities for best practice
      ideas, searched the literature, and analyzed unit-based ED data to design a
      program matching the needs of the patients.

PMID- 12610794
TI  - Should infection still be considered as the most likely triggering factor for
      rheumatoid arthritis?

PMID- 12610795
TI  - Bisphosphonates for arthritis--a confusing rationale.

PMID- 12610796
TI  - Lack of association between -384 and 114 IL-2 gene polymorphisms and rheumatoid
      arthritis.
AB  - OBJECTIVE: To investigate the association of 2 single nucleotide polymorphisms
      (SNP) at positions -384 and 114 in the human interleukin 2 (IL-2) gene with
      susceptibility to and severity of rheumatoid arthritis (RA). METHODS: Genotyping
      for these IL-2 variants was performed by a polymerase chain reaction restriction
      fragment length polymorphism method in 174 RA patients and 153 control
      individuals. RESULTS: No statistically significant differences were observed when
      the -384 and 114 IL-2 genotype distributions between RA patients and healthy
      controls were compared. In addition, no association was found between the IL-2
      genotypes with any demographic and clinical variables tested. CONCLUSION: Our
      results provide no evidence for genetic association conferred by the -384 and 114
      IL-2 SNP with respect to susceptibility and severity of RA.

PMID- 12610797
TI  - Tumor necrosis factor receptor 2 microsatellite and exon 6 polymorphisms in
      rheumatoid arthritis in Taiwan.
AB  - OBJECTIVE: To investigate the role of tumor necrosis factor receptor 2
      microsatellite allele (TNFR2ms) and TNFR2 exon 6 polymorphisms in the
      pathogenesis of rheumatoid arthritis (RA) in Taiwan. Methods. TNFR2ms was
      determined in 114 patients with RA and 75 healthy controls by polymerase chain
      reaction (PCR) method and electrophoresis with sequencing gel. The TNFR2 exon 6
      polymorphisms were also simultaneously measured by PCR restriction fragment
      length polymorphism method. RESULTS: The phenotypic and allelic frequencies of
      TNFR2ms 18 were significantly lower in patients with RA than in controls. The
      genotype frequency of TNFR2ms 16/18 was also significantly decreased in patients.
      In contrast, the phenotypic and allelic frequencies of TNFR2ms 15 showed a trend
      to be increased in patients with RA. There were no significant differences in the
      frequencies of various TNFR2ms and exon 6 polymorphisms concerning presence and
      absence of rheumatoid factor, bone erosion, rheumatoid nodules, or Sjogren's
      syndrome manifestation. Conclusion. TNFR2ms 18 may have a protective effect on
      the development of RA in Taiwanese, while TNFR2ms 15 tends to have a
      precipitating effect. TNFR2 exon 6 polymorphisms are not related to
      susceptibility for RA. TNFR2ms and exon 6 polymorphisms were not associated with
      the clinical manifestations of RA in Taiwanese. A synergistic effect for
      susceptibility to RA was found between TNFR2ms 15 and HLA-DR4.

PMID- 12610798
TI  - Risk communication in rheumatoid arthritis.
AB  - OBJECTIVE: Some people believe that certain issues should be protected from all
      trade-offs. These issues are referred to as "protected values." We investigated
      whether some patients with rheumatoid arthritis (RA) treat the risk of adverse
      effects (AE) as "protected values," i.e., as unacceptable regardless of how small
      the risk. METHODS: Patients with RA rated willingness to risk 17 different AE on
      a visual analog scale, where 0 = not willing under any circumstances and 100 =
      definitely willing. Participants then rated willingness to take medication as the
      risk of each AE was progressively decreased by 2 levels from its actual risk,
      using a 5 level scale ranging from 10 in 100 to 1 in 100,000. RESULTS: Between
      32% and 39% of participants were not more willing to accept a risk of AE causing
      reversible cosmetic changes (e.g., acne), between 35% and 47% were not more
      willing to accept a risk of AE causing reversible discomfort (e.g., rash), and
      between 41% and 45% were not more willing to accept a risk of AE causing
      potential irreversible damage (e.g., pneumonitis) as the probability of each of
      these AE was substantially decreased. Unwillingness to accept risk of toxicity
      was especially evident for cancer, where 66% of patients refused to accept a risk
      of cancer occurring in 1 in 100,000 persons. CONCLUSION: Among patients
      particularly concerned with the risk of drug toxicity, many remain unwilling to
      accept the risk of AE even when their probability is decreased to levels far
      below their actual risk. These results suggest that patients may treat
      particularly worrisome AE as protected values, which may lead to poor decision
      making in clinical practice.

PMID- 12610799
TI  - Allele and antigen-specific treatment of rheumatoid arthritis: a double blind,
      placebo controlled phase 1 trial.
AB  - OBJECTIVE: Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant
      autoantigen in patients with rheumatoid arthritis (RA). Administration of major
      histocompatibility complex (MHC) Class II complexed antigens without requisite
      costimulatory signals can induce immunologic tolerance. We evaluated the safety,
      pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263
      is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13
      mer peptide derived from HC gp-39 (also referred to as CDP263). METHODS: Thirty
      one HLA-DRB1*0401 positive patients with persistent RA disease activity despite
      concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or
      placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in
      subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included
      recording of adverse events and measurement of CD4/CD8 counts, reactivity to
      recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed
      using the Paulus 20 criteria. RESULTS: Treatment was well tolerated, with
      injection site reaction the most common adverse event. There was no loss of
      reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR.
      The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was
      seen; responses were more common among patients receiving the highest doses of
      AG4263 and among those with baseline T cell reactivity to CDP263. CONCLUSION:
      AG4263 was safe, well tolerated, and without evidence of generalized immune
      suppression. Along with the observed trend toward clinical efficacy, the results
      suggest that this therapeutic approach warrants further investigation in patients
      with RA.

PMID- 12610800
TI  - Prevalence of rheumatoid arthritis and hepatitis C in those age 60 and older in a
      US population based study.
AB  - OBJECTIVE: A positive association between rheumatoid arthritis (RA) and hepatitis
      C virus (HCV) infection has been reported in clinic based cross sectional
      studies. We investigated if RA and HCV are associated in a population based
      survey. METHODS: Using data from the National Health and Nutrition Examination
      Survey III, hepatitis C and RA status were determined for subjects > or = 60
      years of age. RA was defined to be present when 3 of 6 American College of
      Rheumatology (ACR) criteria were met. RESULTS: Of 6596 subjects, 1827 (27.7%)
      were excluded due to missing data. Of the remaining 4769, 196 subjects (4.1%) met
      our modified ACR criteria for probable RA: 63 tested positive for anti-HCV
      antibodies (1.3%) while 35 were HCV RNA positive (0.7%). Two subjects had both
      HCV antibodies and RA, while one subject was both HCV RNA positive and had RA.
      HCV antibody positivity was not associated with RA (OR 0.44, 95% CI 0.07-2.80).
      Similarly, HCV positivity by polymerase chain reaction was not associated with RA
      (OR 0.77, 95% CI 0.10-6.19). CONCLUSION: These results argue against a potential
      role for HCV in the etiology of RA in the US population aged 60 years and over.

PMID- 12610801
TI  - Infections preceding early arthritis in southern Sweden: a prospective population
      based study.
AB  - OBJECTIVE: To detect evidence of infections preceding early arthritis in Southern
      Sweden and to compare the clinical outcome of remission during a 6-month followup
      for patients with and without signs of prior infection. METHODS: Adult patients
      with arthritis of less than 3 months' duration were referred from primary health
      care centers to rheumatologists. All patients were systematically screened for
      infections caused by Salmonella typhimurium and Salmonella enteritidis, Yersinia
      enterocolitica, Campylobacter jejuni, Borrelia burgdorferi, Chlamydia
      trachomatis, Chlamydia pneumoniae, and parvovirus B19. RESULTS: Seventy-one
      patients were included in this study. Twenty-seven (38%) patients had reactive
      arthritis (ReA), 17 (24%) undifferentiated arthritis, 15 (21%) rheumatoid
      arthritis (RA), 4 (6%) psoriatic arthritis, and the rest (11%) other diagnoses.
      Of all the patients, 45% had evidence of a recent infection preceding the
      arthritis, as indicated by laboratory tests and/or disease history. C. jejuni
      dominated the ReA group. The occurrence of recent C. trachomatis, B. burgdorferi,
      C. pneumoniae, and parvovirus B19 infections was low. Overall, 58% of the
      patients went into remission during the 6-month followup. Of the patients with a
      preceding infection, 69% went into remission as compared to 38% of the patients
      without a preceding infection (p = 0.011). Thirty-three percent of the patients
      with RA were in remission after 6 months. CONCLUSION: In this population-based
      cohort, 45% of the patients presenting with a new-onset arthritis had had a prior
      infection. Campylobacter ReA dominated the ReA group. There were only a few cases
      preceded by infections by C. trachomatis, B. burgdorferi, C. pneumoniae, and
      parvovirus B19 infections. Remission during the first 6 months was especially
      frequent in the group of patients with a prior infection, but the remission rate
      was relatively high even for arthritis without prior infection.

PMID- 12610802
TI  - A randomized double blind, placebo controlled trial of topical Tripterygium
      wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis.
AB  - OBJECTIVE: To assess the efficacy of topical Tripterygium wilfordii (TW), a
      Chinese herbal therapy, in rheumatoid arthritis (RA). METHODS: A 6 week
      randomized double blind placebo controlled study of 61 patients with RA meeting
      American College of Rheumatology (ACR) criteria was conducted in China. The
      primary outcome was a modified ACR-20 response rate, analyzed by logistic
      regression analysis. RESULTS: The modified ACR-20 response rate differed
      significantly (topical TW 58% vs placebo 20%; p = 0.002). There was an 8.1-fold
      (95% CI 1.9-35.4) increase in the modified ACR-20 response for the TW compared to
      the placebo group, adjusted for age and erythrocyte sedimentation rate.
      CONCLUSION: Topical TW appears efficacious for the treatment of RA, but larger
      studies are needed.

PMID- 12610803
TI  - Two year randomized controlled trial of etidronate in rheumatoid arthritis:
      changes in serum aminoterminal telopeptides correlate with radiographic
      progression of disease.
AB  - OBJECTIVE: To investigate the effect of intermittent cyclical etidronate
      treatment on radiographic progression, bone collagen markers, and clinical
      disease activity in patients with rheumatoid arthritis (RA). METHODS: Forty
      patients with RA of less than 5 years' duration were randomized to receive
      intermittent cyclical etidronate therapy in conjunction with antirheumatic
      therapy or antirheumatic therapy alone (without etidronate) in a 2 year open
      label protocol. Radiographs of hands and feet and serum samples for determination
      of aminoterminal propeptide (PINP), crosslinked C-telopeptide (ICTP), and
      aminoterminal telopeptides (NTx) of type I collagen were obtained at baseline and
      at 24 months. RESULTS: There was significant and similar worsening of the
      radiologic scores in both treatment groups. Both PINP, a marker of bone
      formation, and ICTP, an indicator of collagen degradation, declined in the
      etidronate group compared to the control group (p = 0.001 and p = 0.042,
      respectively). The groups did not differ for the change in serum NTx, a specific
      systemic marker of osteoclastic bone resorption. However, the change in serum NTx
      correlated significantly with the increase in erosion score in the total study
      population and in the control group (r = 0.41, p = 0.01 and r = 0.48, p = 0.034,
      respectively). CONCLUSION: Etidronate therapy did not prevent radiologic
      progression in patients with RA, but the decline in serum PINP and ICTP
      concentrations suggests a favorable effect on general bone metabolism.
      Correlation between the change in serum NTx and worsening of the erosion score
      provides biochemical evidence that osteoclast is the principal cell type
      responsible for focal bone resorption in RA.

PMID- 12610804
TI  - Bone resorption and inflammatory inhibition efficacy of intermittent cyclical
      etidronate therapy in rheumatoid arthritis.
AB  - OBJECTIVE: Osteoclast activation or cartilage and bone destruction are developed
      in patients with rheumatoid arthritis (RA). The efficacy of etidronate with
      respect to osteoporosis, inhibition of bone resorption and destruction, and
      antiinflammation in RA was examined for 72 weeks. METHODS: Sixty-three patients
      with RA (56 women, 7 men) were divided into a group that received intermittent
      cyclical etidronate therapy (ICET) (31 patients) and a non-ICET group (32
      patients). Over a 72 week followup period, the urinary deoxypyridinoline (DPD),
      serum bone alkaline phosphatase (BAP), bone mineral density (BMD), Larsen damage
      score, Lansbury activity index, and concentrations of serum C-reactive protein
      (CRP) and serum interleukin 6 (IL-6) of the 2 groups were compared. RESULTS: In
      the non-ICET group, a significant decrease in BMD and a significant increase in
      the Larsen damage score were observed. In the ICET group, the level of DPD
      started to decrease 12 weeks after etidronate administration and progression of
      the Larsen damage score was significantly inhibited. IL-6 concentration was
      significantly decreased 72 weeks after etidronate administration. Concentrations
      of BAP and CRP and the Lansbury activity index were not significantly different
      between the ICET and the non-ICET groups. A significant correlation between the
      IL-6 and DPD concentrations was observed. CONCLUSION: Etidronate was effective at
      inhibiting bone resorption and destruction in study patients with RA, while not
      increasing BAP concentrations; and a correlation was observed between the
      concentration of DPD and IL-6, indicating the antiinflammatory effect of
      etidronate.

PMID- 12610805
TI  - Frequency of adverse drug reactions in patients with systemic lupus
      erythematosus.
AB  - OBJECTIVE: The literature suggests that patients with systemic lupus
      erythematosus (SLE) have a higher frequency of adverse drug reactions (ADR). We
      performed this case control study to compare the prevalence of ADR in patients
      with SLE and controls with inflammatory arthritis. METHODS: We surveyed 249
      patients, 145 with SLE and 104 age and sex matched controls with other types of
      inflammatory arthritis, such as rheumatoid arthritis (RA), probable RA, and
      psoriatic arthritis. We asked about exposure and ADR to the following classes of
      drugs: (1) beta-lactam antibiotics, (2) sulfonamides, (3) other antibiotics, (4)
      disease modifying antirheumatic drugs (DMARD), and (5) nonsteroidal
      antiinflammatory drugs (NSAID). Personal and family atopic histories were
      obtained. The 2 groups were obtained from a single rheumatologic practice and had
      similar characteristics and drug exposures. RESULTS: The response rate was 63% in
      the SLE patients and 64% in the control group. The mean age was 47.8 +/- 1.5
      years in patients with SLE and 46.1 +/- 1.7 years in controls (p < 0.51). Ninety
      two percent of SLE patients and 88% of controls were female (p < 0.42). Both
      groups had been exposed similarly to all antibiotics, as there were no
      significant differences between groups (exposure to sulfa antibiotics 53% in SLE
      patients vs 46% in controls), and to NSAID (84% SLE group vs 93% controls). Few
      patients from the SLE group had DMARD exposure, with the exception of plaquenil
      (65% SLE group vs 30% controls; p < 0.0001) and azathioprine (18% SLE group vs 4%
      controls; p < 0.006). There were between-groups differences with respect to total
      number of ADR with sulfa antibiotics (exposed had 25/48 reactions in SLE group vs
      6/31 in controls; p < 0.003), but not with other drugs. Most ADR to sulfa
      antibiotics were cutaneous (rash). Subjects with an allergic or atopic history
      had more ADR (p < 0.0005). There were no differences between SLE patients and
      controls in having an allergic history (p < 0.88). Subjects with a positive
      family history of allergies were more likely to have ADR (p < 0.0043). SLE
      patients and controls with a personal versus family history of environmental
      allergies did not differ in having ADR (p < 0.16 and p < 0.83, respectively).
      CONCLUSION: Both intolerances and true allergic reactions were not dissimilar in
      patients with SLE compared to controls with inflammatory arthritis, with the
      exception of cutaneous reactions to sulfa antibiotics in SLE patients. This has
      not been the experience of other investigators (with increased ADR with several
      antibiotics in SLE groups) who used healthy, best friend, and relative controls
      with dissimilar frequencies of drug exposures. Perhaps differences observed in
      the past (where SLE patients have more ADR than healthy controls) are true of
      other inflammatory arthritis subjects (who have different drug exposures than
      healthy individuals) rather than just SLE. Differences could also exist in the
      pharmacogenetics, as our sample population was mostly Caucasian.

PMID- 12610806
TI  - Kinins and cytokines in plasma and cerebrospinal fluid of patients with
      neuropsychiatric lupus.
AB  - OBJECTIVE: To evaluate the kinin system components and selected cytokines in
      plasma and cerebrospinal fluid (CSF) of patients with neuropsychiatric lupus
      (NPL). METHODS: We studied 29 women with active NPL and 29 healthy women matched
      to patients for age. Low (LKg) and high molecular weight kininogen (HKg) and
      cytokine concentrations [interleukin 1beta (IL-1beta), IL-6, IL-8, IL-10, and
      tumor necrosis factor-a (TNF-a)] were determined by ELISA. The activities of
      tissue kallikrein, plasma prekallikrein, and kininase II were assayed by their
      action on selective substrates. RESULTS: Compared to controls, patients with NPL
      presented increased plasma and CSF levels of LKg, HKg, and prekallikrein,
      increased activity of tissue kallikrein and kininase II, and increased levels of
      IL-6, IL-10, and TNF-a (p < 0.001 each comparison). IL-1beta levels were
      increased in patient plasma (p < 0.001), whereas plasma IL-8 levels did not
      differ from controls. IL-1beta and IL-8 were not detected in CSF of patients or
      controls. CONCLUSION: The increased levels of kininogen fractions, kallikreins,
      and kininase II in patient plasma and CSF indicate overactivity of the kinin
      system, suggesting intense kinin production. Since kinins may induce the
      production of proinflammatory cytokines including IL-1beta, IL-6, and TNF-a,
      these findings support the participation of kinins and cytokines in the acute
      manifestations of NPL. Most of the variables evaluated in patients' CSF increased
      proportionally in relation to plasma levels. In contrast, the activity of tissue
      kallikrein in patient CSF increased out of proportion to plasma levels, appearing
      to be locally synthesized in response to brain involvement.

PMID- 12610807
TI  - Cardiovascular risk factor screening in systemic lupus erythematosus.
AB  - OBJECTIVE: To evaluate the frequency of cardiovascular (CV) disease risk factor
      screening in systemic lupus erythematosus (SLE). METHODS: Medical records of
      patients from a lupus clinic and 5 private practices were assessed for CV disease
      risk factors, including hyperlipidemia, hypertension, diabetes mellitus, smoking,
      family history of CV disease, antiphospholipid antibodies, hyperhomocysteinemia,
      postmenopausal status, obesity, and nephrotic syndrome. RESULTS: A total of 183
      records were included: 60 (33%) from the lupus clinic and 123 (67%) from private
      practices. Serum lipid profiles were measured in 56/183 (31%): 37/60 (62%) in the
      lupus clinic vs 19/123 (15%) private practice. Of the 56 with lipids measured,
      the individual tests obtained were as follows: total cholesterol in 56 (100%),
      HDL in 50 (89%), triglycerides in 49 (88%), LDL in 48 (86%), and VLDL in 33
      (59%). Thirty-one of 56 patients (55%) had elevated lipids. Only 9/25 (36%) with
      hyperlipidemia who had a subsequent visit had a response to the hyperlipidemia
      charted. Of 9 nonlipid risk factors, a median of 8 were assessed in the lupus
      clinic vs 3 in private practices. The most frequent risk factors screened were
      nephrotic syndrome (91%), hypertension (74%), and smoking (59%). CONCLUSION:
      Despite an inordinately high risk of CV disease in SLE, assessment of CV risk
      factors was surprisingly uncommon among the practices assessed. Greater attention
      needs to be paid to CV disease risk factor screening in patients with lupus.

PMID- 12610808
TI  - Cyclophosphamide adjuvant arthritis in Trypanosoma cruzi infected rats with
      inflammatory cytokine effects.
AB  - OBJECTIVE: To analyze whether the cyclophosphamide (CYC) induced reestablishment
      of adjuvant arthritis (AA) in chronically Trypanosoma cruzi infected rats
      correlates with changes in the secretion of pro- and antiinflammatory cytokines
      by popliteal lymph node cells. METHODS: Inbred "l" rats infected with T. cruzi 90
      days earlier and age matched controls were given CYC (25 mg/kg body weight) or
      physiologic saline 48 h before arthritis induction. Popliteal lymph node cells
      were collected at the time of AA induction (48 h after CYC treatment) or during
      the peak response, to study the concanavalin-A (ConA) or Mycobacterium
      tuberculosis-driven in vitro proliferation of several cytokines in their culture
      supernatants. Results. Infected rats given CYC were recovered from the otherwise
      decreased ConA induced proliferation seen at the time of peak AA. The CYC
      mediated reestablishment of AA in T. cruzi infected rats coexisted with an
      increased presence of tumor necrosis factor-a in supernatants from either antigen
      or ConA stimulated cultures as well as interleukin 12 (IL-12) in the latter case.
      CYC also lowered to normal the increased IL-10 levels from ConA stimulated
      cultures that the T. cruzi group displayed at the time of inducing AA.
      Conclusion. The process by which CYC restores the clinical expression of AA
      affects the balance between cytokines that influence the regulation of arthritis
      in favor of the inflammatory component.

PMID- 12610809
TI  - HLA antigens may influence the age of onset of psoriasis and psoriatic arthritis.
AB  - OBJECTIVE: To analyze whether HLA antigens may influence the age of onset of both
      psoriasis and psoriatic arthritis (PsA). METHODS: One hundred thirty-five
      patients with PsA (77 men, 58 women, mean age 47 +/- 12 yrs) were analyzed. All
      were studied with a standard protocol and consecutively recruited to evaluate the
      relative contribution of HLA-Cw and HLA-B27 alleles to PsA susceptibility. Fifty
      patients with psoriasis alone were also recruited to analyze the role of HLA-Cw
      genes on disease susceptibility. HLA-Cw antigens were investigated by DNA based
      methods (PCR-SSOP), while HLA-B27 antigen was studied using serological methods,
      and their frequencies were compared to 177 healthy controls. RESULTS: In PsA Cw6+
      patients, the mean age at psoriasis onset was 23 +/- 12 years compared to 32 +/-
      12 years in Cw6- patients (p = 0.012). Age of arthritis onset was 35 +/- 13 years
      in Cw6+ patients versus 38 +/- 12 years in Cw6- patients (p = NS). In patients
      with psoriasis alone, the age at onset was 18 +/- 10 years in Cw6+ versus 30 +/-
      11 years in Cw6- patients (p < 0.01). Cw6 correlated well with a positive family
      history of psoriasis among first-degree relatives (64% of patients with family
      history were Cw6+, whereas only 30% of those without family history had this
      allele (p < 0.05). The onset age of psoriasis in HLA-B27+ patients was 24 +/- 8
      years vs 32 +/- 14 years in B27- patients (p = 0.026), whereas onset age of
      arthritis was 30 +/- 10 years in B27+ compared to an age of onset of 40 +/- 12 in
      B27- patients (p = 0.0056). CONCLUSION: Our results confirm the known association
      between Cw6, early onset psoriasis and positive family history (type I
      psoriasis). The association between HLA-B27 and earlier onset ages for both
      psoriasis and arthritis in PsA had not previously been emphasized. The HLA
      antigens may determine not only disease susceptibility, but also the age of
      disease onset in psoriasis and PsA.

PMID- 12610810
TI  - The structure and histopathology of the "enthesis organ" at the navicular
      insertion of the tendon of tibialis posterior.
AB  - OBJECTIVE: To investigate the structure, histopathology, and molecular
      composition of tissue specializations of the tibialis posterior enthesis. They
      collectively reduce stress concentration at the insertion site and are part of an
      "enthesis organ." This has implications for understanding the basis of
      enthesopathy. METHODS: Fifty-two specimens of tibialis posterior and the
      associated superomedial part of the calcaneonavicular ligament taken from
      cadavers were sectioned longitudinally and examined by routine histology (42
      samples) or immunohistochemistry (10 samples). Serial sections of formalin fixed
      material were stained with Masson's trichrome, toluidine blue, or hematoxylin,
      eosin and alcian blue. A panel of antibodies against collagens,
      glycosaminoglycans, and proteoglycans was used to immunolabel methanol fixed
      material. RESULTS: The enthesis organ consists of the enthesis itself, the
      superomedial part of the calcaneonavicular ligament (which may fuse with the
      tendon), the tendon sheath, and associated accessory bones. The accessory bones
      lay in a region of fibrocartilage that was present even in specimens where the
      bones themselves were absent. Degenerative changes were seen at the enthesis,
      around the accessory bones, and in the walls of the tendon sheath. The navicular
      and accessory bone entheses, together with the calcaneonavicular ligament, were
      all rich in fibrocartilage. This immunolabeled for aggrecan, link protein, type
      II collagen, and versican. CONCLUSION: The complexity of the enthesis organ, and
      the diversity of sites showing histopathological changes, suggest that
      enthesopathy may not be located precisely at the osteotendinous junction. It
      could target a number of adjacent locations, in accord with what happens at other
      entheses; e.g., in patients with spondyloarthropathy. The prominence of
      fibrocartilage in the enthesis organ, and the degenerative changes to which it is
      subject, support the view that spondyloarthropathy has an underlying
      biomechanical basis.

PMID- 12610811
TI  - Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn's
      disease.
AB  - OBJECTIVE: To determine the prevalence of sacroiliitis in patients who have back
      pain in Crohn's disease (CD) using computed tomography (CT); and to reassess the
      association of sacroiliitis in CD with HLA-B27. METHODS: A total of 134
      consecutive patients with CD completed a questionnaire about musculoskeletal
      symptoms. Those reporting low back pain were assessed, including plain
      radiographs and CT of the sacroiliac joints. HLA-B27 status was determined in
      patients with and without back pain. RESULTS: There were 70 (52%) patients with
      low back pain, of whom 31 (45%) had CT evidence of sacroiliitis. These were
      characterized by more frequent morning spinal stiffness and positive sacroiliac
      compression tests even when sacroiliitis was not suspected. Nine had previously
      recognized radiological and clinical ankylosing spondylitis (AS), and of these
      78% were HLA-B27 positive. Of those with newly identified sacroiliitis, 14% were
      HLA-B27 positive. This frequency was not statistically dissimilar to the 9% HLA
      B27 positivity of those without back pain. CONCLUSION: Sacroiliitis defined by CT
      is a common cause of low back pain in CD. A relationship of sacroiliitis and HLA
      B27 could be confirmed only for those with classical AS. Our results accord with
      the possibility that sacroiliitis in CD is an isolated phenomenon, which is
      unrelated to HLA-B27 and which may evolve into classical spinal ankylosis in
      genetically susceptible subjects.

PMID- 12610812
TI  - A randomized, double blind, placebo controlled trial of a topical cream
      containing glucosamine sulfate, chondroitin sulfate, and camphor for
      osteoarthritis of the knee.
AB  - OBJECTIVE: To assess the ability of a topical preparation of glucosamine sulfate
      and chondroitin sulfate to reduce pain related to osteoarthritis (OA) of the
      knee. METHODS: Sixty-three patients were randomized to receive either a topical
      glucosamine and chondroitin preparation or placebo to be used as required over an
      8 week period. Efficacy was assessed using a visual analog scale (VAS) for pain
      as well as the Western Ontario and McMaster Universities Osteoarthritis Index
      (WOMAC), and the SF-36 questionnaire. RESULTS: VAS scores indicated a greater
      mean reduction in pain for the glucosamine/chondroitin preparation group (mean
      change -3.4 cm, SD 2.6 cm) compared to the placebo group (mean change -1.6 cm, SD
      2.7 cm) after 8 weeks. After 4 weeks the difference between active and placebo
      groups in their mean reduction from baseline was 1.2 (95% CI 0.1 to 2.4, p =
      0.03) and after 8 weeks was 1.8 (95% CI for difference between groups, 0.6 to 2.9
      cm; p = 0.002). CONCLUSION: Topical application of glucosamine and chondroitin
      sulfate is effective in relieving the pain from OA of the knee and improvement is
      evident within 4 weeks.

PMID- 12610813
TI  - Men's shoes and knee joint torques relevant to the development and progression of
      knee osteoarthritis.
AB  - OBJECTIVE: To determine if men's dress shoes and sneakers increase knee joint
      torques and play the same role in the development and/or progression of knee
      osteoarthritis (OA) as women's high-heeled dress shoes. METHODS: Three
      dimensional data regarding lower extremity torques and motion were collected
      during walking in 22 healthy men while (1) wearing dress shoes, (2) wearing
      sneakers, and (3) barefoot. Data were plotted and qualitatively compared; major
      peak values were statistically compared between conditions. RESULTS: The external
      knee varus torque in early stance was slightly greater with the dress shoes and
      sneakers, but this slight increase can be explained by the faster walking speed
      with shoes. No significant increases were found in any other of the sagittal,
      coronal, or transverse knee torques when walking with dress shoes and sneakers
      compared to barefoot. CONCLUSION: Men's dress shoes and sneakers do not
      significantly affect knee joint torques that may have relevance to the
      development and/or progression of knee OA.

PMID- 12610814
TI  - Joint-specific multidimensional assessment of pain (J-MAP): factor structure,
      reliability, validity, and responsiveness in patients with knee osteoarthritis.
AB  - OBJECTIVE: To develop a reliable and valid instrument for measuring and
      monitoring joint-specific pain. METHODS: Developed using patient interviews,
      reviews of pain literature, and expert input from orthopedic surgeons, the final
      Joint-Specific Multidimensional Assessment of Pain (J-MAP) includes the 6-item
      Pain Sensory and the 4-item Pain Affect subscales. Scores on the J-MAP Pain
      Sensory and Affect subscales range from 0 to 100, with higher scores indicating
      more pain intensity and worse pain distastefulness, respectively. Following the
      assessment of the factor structure, patients' scores (n = 180) on the J-MAP
      subscales were converted to equal interval scores using Rasch analyses. A
      psychometric evaluation of the items and Rasch-calibrated scores was conducted
      and included an assessment of reliability, validity, and responsiveness for use
      with patients with radiographic knee osteoarthritis. RESULTS: Evidence from the
      factor analyses showed that the J-MAP Pain Sensory and Affect items made up 2
      distinct factors. Internal consistency estimates for the J-MAP subscales exceeded
      0.85. The J-MAP subscales showed evidence for validity and were shown to be
      internally and externally responsive, demonstrating greater responsiveness than
      the Arthritis Impact Measurement Scale or the Medical Outcome Study Short Form-36
      pain subscales. Finally, evidence was found supporting the J-MAP subscales'
      ability to distinguish target joint pain from pain emanating from other
      musculoskeletal conditions. CONCLUSION: The J-MAP is a reliable, valid, and
      responsive measure for assessing joint-specific pain at a single time point, or
      changes over time for one or a group of patients with knee osteoarthritis. With
      this initial evidence of its psychometric rigor, further testing of the
      measurement properties of the J-MAP in other joints and in other populations
      should be undertaken.

PMID- 12610815
TI  - Molecular changes in human osteoarthritic cartilage after 3 weeks of oral
      administration of BAY 12-9566, a matrix metalloproteinase inhibitor.
AB  - OBJECTIVE: To determine the effect of BAY 12-9566, a matrix metalloproteinase
      inhibitor, on articular cartilage metabolism in patients with osteoarthritis
      (OA). METHODS: Thirty-five patients with OA were randomized to receive oral daily
      dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee
      surgery. Cartilage samples were obtained at surgery and examined for markers of
      proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and
      keratan sulfate epitope content) and type II collagen synthesis (C-propeptide
      content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content
      (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum,
      synovial fluid, and cartilage. RESULTS: Comparisons between study drug and
      placebo treatments revealed that at the 100 mg dose there was a significant
      increase in the 846 epitope (p = 0.012). Total type II collagen content was also
      higher at this dosage (p = 0.012). Alterations in collagen degradation and
      synthesis were not detected. CONCLUSION: BAY 12-9566 at daily doses of 100 mg
      significantly altered proteoglycan turnover, resulting in a cartilage composition
      reflected by the content of the 846 epitope that is more characteristic of a
      young growing individual. The increase in this epitope may signify increased
      matrix synthesis. The increase in type II collagen content was unexpected, since
      there was no other evidence for altered collagen turnover. However, increased
      matrix assembly would also be indicated by this increased content.

PMID- 12610816
TI  - Facilitation of fas mediated apoptosis of human chondrocytes by the proteasome
      inhibitor and actinomycin D.
AB  - OBJECTIVE: We investigated the susceptibility of chondrocytes to apoptosis
      induced by anti-Fas and various potentiators, and the relevant signaling pathway.
      METHODS: Chondrocytes were cultured from cartilages obtained at the time of joint
      replacement surgery for knee osteoarthritis (OA) or femur neck fracture. Fas
      receptor ligation was performed with agonistic anti-Fas antibody (clone CH-11) at
      concentrations ranging from 0.5 to 1.0 micro g/ml. Mitogen activated protein
      kinase inhibitors SB203580 and PD98059, cycloheximide, bisindolylmaleimide,
      actinomycin D, or MG132 were added with anti-Fas to facilitate cell death.
      Chondrocyte surface expression of Fas was analyzed by FACS, and the expression of
      apoptosis related proteins analyzed by Western blot. RESULTS: Cell death
      increased upon coculture with 0.5 micro g/ml of anti-Fas and 0.2 micro g/ml of
      actinomycin D or 20 micro M MG132. Apoptosis potentiated by actinomycin D or
      MG132 was effectively inhibited by caspase inhibitors, implicating the
      involvement of the caspase cascade in chondrocyte apoptosis. Compared with
      untreated cells or actinomycin D treated cells, cells treated with MG132 showed
      distinct shifts in the distribution of surface Fas fluorescence. Although
      concentrations of Bcl-2, Bax, FLICE inhibitory protein (FLIP), and Fas ligand
      were unaffected by MG132 or actinomycin D, both treatments led to a significant
      increase of p53. The expression of the p53 response proteins, MDM2 and p21, was
      elevated in MG132 treated chondrocytes. CONCLUSION: Our results suggest that
      chondrocytes can be rendered sensitive to anti-Fas mediated apoptosis by the
      proteasome inhibitor MG132 and the transcription inhibitor actinomycin D. MG132
      and actinomycin D show different characteristics in terms of apoptosis signaling.

PMID- 12610817
TI  - Apoptosis and p53 expression in chondrocytes relate to degeneration in articular
      cartilage of immobilized knee joints.
AB  - OBJECTIVE: We have reported that articular cartilage showed early stage
      degeneration at 7 and 14 days after immobilization, moderate degeneration at 28
      days, and severe degeneration at 42 days in rabbits. To test whether apoptosis
      occurs in association with p53 expression in chondrocytes during the process of
      articular cartilage degeneration, we investigated the degree of cartilage
      degeneration, the frequency of apoptotic cells, and the levels of p53 mRNA in
      rabbits and mice after knee immobilization. METHODS: Right knees of male Japanese
      white rabbits were immobilized in full extension with fiberglass casts for up to
      42 days. Similarly, right knees of male p53 wild-type [p53 (+/+)] and p53 null
      [p53 (-/-)] mice were immobilized in full extension with bandage tape for up to
      84 days. Apoptotic cells were confirmed by TUNEL staining on the sections of knee
      joints. Total RNA of articular chondrocytes obtained from Day 0 or immobilized
      knees was analyzed semiquantitatively by RT-PCR using specific primers for p53.
      RESULTS: Articular cartilage degenerated after immobilization of p53 (+/+) mouse
      knees, but not after immobilization of p53 (-/-) knees. Apoptotic cells were
      observed in articular cartilage in the femur and tibia of rabbits and p53 (+/+)
      mice after immobilization. However, only a few apoptotic cells were observed at
      the same sites in p53 (-/-) mice. In RT-PCR analysis, the levels of p53 mRNA
      obtained from immobilized groups were significantly higher than those of Day 0
      groups in rabbit and p53 (+/+) mouse knees. CONCLUSION: Apoptosis and p53
      expression in chondrocytes relate to degeneration in articular cartilage of
      immobilized knee joints.

PMID- 12610818
TI  - What do tender points measure? Influence of distress on 4 measures of tenderness.
AB  - OBJECTIVE: To examine the relationship between current pain, distress, and
      ascending and random measures of tenderness. METHODS: Manual tender point counts
      and dolorimeter measures of the pressure pain threshold were determined in a
      sample of 47 women representative of the general population with respect to
      tenderness. In addition, discrete pressure stimuli of varying intensities to the
      left thumb were applied in random fashion. Distress was measured with the Brief
      Symptom Inventory and the Beck Depression Inventory, and pain was evaluated with
      the Short Form McGill Pain Questionnaire. RESULTS: Only the random measure of
      tenderness was relatively independent of an individual's current psychological
      state. The respective correlation coefficients between measures of tenderness and
      psychological state were generally greatest for the manual tender point count and
      also significant for the dolorimeter measures. In contrast, all measures were
      highly correlated with ratings of spontaneous pain, again with the manual tender
      point count showing the strongest, and the random method the weakest,
      correlations. Linear regression analysis replicated the results of the
      correlational analysis. CONCLUSION: As a measure of tenderness, the number of
      positive tender points is clearly influenced by an individual's distress. Other
      more sophisticated measures of tenderness that randomly present stimuli in an
      unpredictable fashion appear to be relatively immune to these biasing effects,
      although our results obtained in a research setting have yet to be replicated in
      clinical practice.

PMID- 12610819
TI  - Workshop report: knowledge translation of musculoskeletal health research.

PMID- 12610820
TI  - Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases
      with a mean 10 year followup.
AB  - OBJECTIVE: As continuity of care in our institution allows longterm followup
      studies, we reviewed the files of all consecutive patients with juvenile chronic
      (idiopathic) arthritis (JCA) followed since 1970 to establish the frequency of
      remission. METHODS: Charts of all patients with JCA were reviewed. Relevant
      variables were entered into a customized database. The presence of remission
      (lack of signs of disease activity in the absence of antirheumatic therapy for at
      least 6 mo) during the disease course and at the last visit was assessed.
      RESULTS: The cohort included 683 patients, 463 females and 220 males. According
      to the disease onset, 420 had oligoarticular, 108 polyarticular (23 rheumatoid
      factor positive), and 88 systemic disease; 67 had a juvenile spondyloarthropathy
      (SpA). For all 4 categories the mean followup period was about 10 years. At the
      last visit 224 cases were in remission (32.8%). Remission rate was scarcely
      influenced by age at disease onset, but differed in the different disease
      categories. Of the total group of 683 patients, 153 (22.4%) were lost to followup
      (no control for at least 2 years). For all 4 categories the remission rate at the
      last visit was higher in patients who had been lost to followup: 42.3% versus
      29.0% for systemic onset JCA, 20.8% versus 16.5% for polyarticular onset JCA,
      44.7% versus 33.6% for pauciarticular onset JCA, and 66.7% versus 26.8% for
      juvenile SpA. The probability of attaining remission decreased in proportion to
      delay in entering the tertiary care center (from 35.7% to 22.8%). The rate of
      remission reached its peak after 5-10 years of followup, after which the trend
      reversed. CONCLUSION: Childhood arthritis achieved remission in only about one
      third of our cases, with differences among disease categories based on the
      diagnosis.

PMID- 12610821
TI  - Early predictors of longterm outcome in patients with juvenile rheumatoid
      arthritis: subset-specific correlations.
AB  - OBJECTIVE: To determine early predictors of longterm outcome in juvenile
      rheumatoid arthritis (JRA) in a multicenter cohort. METHODS: Patients were
      selected if they were > or = 8 years of age; the onset of arthritis occurred > or
      = 5 years before study; and a diagnosis of JRA was made at a participating
      center. Outcome variables were scores on self-administered Childhood Health
      Assessment Questionnaires (CHAQ) and active disease duration. Possible
      explanatory variables assessed included characteristics present at onset, HLA
      alleles, in particular the rheumatoid arthritis associated shared epitope (RASE),
      and radiographic indicators of joint damage within 2 years of onset. Data for 393
      patients were available. Multivariate analyses were performed for the total group
      and for each onset subtype. RESULTS: Male sex correlated with worse disability in
      systemic onset JRA but less disability in RF negative, and a shorter active
      disease duration in RF positive polyarticular onset JRA. Positive antinuclear
      antibody correlated with a longer active disease duration in patients with
      pauciarticular onset JRA. Younger age at onset predicted longer active disease
      duration in pauciarticular and RF negative polyarticular, and a shorter active
      disease duration in systemic onset JRA. Residence on a reserve, rather than
      native North American race, correlated with worse disability. The RASE correlated
      with less disability in systemic JRA; but no correlation with outcome was evident
      for patients with rheumatoid factor positive polyarticular JRA. CONCLUSION:
      Variables predictive of longterm outcome in JRA are specific for each onset
      subtype. The most important early predictors were age at onset and sex of the
      patient. Place of residence may have a greater effect on disability than race.
      RASE may associate with a more favorable outcome in systemic onset disease.

PMID- 12610822
TI  - Evaluation of eutectic lidocaine/prilocaine cream (EMLA) for steroid joint
      injection in children with juvenile rheumatoid arthritis: a double blind,
      randomized, placebo controlled trial.
AB  - OBJECTIVE: To evaluate the efficacy of eutectic lidocaine/prilocaine cream (EMLA)
      in reducing the pain associated with steroid joint injection in children with
      juvenile arthritis. METHODS: A randomized, double blind, placebo controlled
      parallel group trial. Thirty-one children (ages 8-18 yrs) scheduled for steroid
      injection into a knee were randomized into groups having either 2.5 g
      lidocaine/prilocaine cream or placebo cream applied to the injection site 60-90
      min before the procedure. Patients assessed the pain associated with initial
      needle insertion and subsequent steroid injection using a 10 cm visual analog
      scale. RESULTS: No significant difference was found in the pain reported after
      needle insertion or steroid injection between the lidocaine/prilocaine cream
      group (n = 17) and the placebo group (n = 14). There was a trend toward an
      association of lower median scores with the pain of steroid injection in the
      lidocaine/prilocaine group (6 mm) compared with the placebo group (22 mm).
      CONCLUSION: Application of 2.5 g lidocaine/prilocaine cream for 60-90 min had no
      statistically significant analgesic effect on pain associated with injections of
      steroids into the knees of children with juvenile arthritis.

PMID- 12610823
TI  - The publication rate of abstracts from the 4th Park City Pediatric Rheumatology
      meeting in peer-reviewed journals: what factors influenced publication?
AB  - OBJECTIVE: To measure the impact of a rheumatology scientific meeting by
      examining publication rates of the abstracts in peer-reviewed journals and to
      investigate factors that influenced publication. METHODS: We examined the outcome
      of 257 abstracts submitted to the 1998 4th Park City Pediatric Rheumatology
      meeting, all of which were published in The Journal of Rheumatology (April 2000).
      A MEDLINE search of all abstracts, by authors, topics, and keywords was
      performed. A mail questionnaire regarding publication and factors influencing
      submission was sent to authors of abstracts not found in this search. Factors
      analyzed for influence on publication included author geography, disease studied,
      study topic, study design, positive or negative results, and the novelty of the
      study. RESULTS: Ninety-two abstracts (36%) were published as of January 2002 in
      peer-reviewed journals, most frequently in The Journal of Rheumatology (32
      abstracts). Factors with a positive influence on publication included abstracts
      from the Middle East, analytical studies, positive results, and novel studies.
      Factors negatively associated with publication include origin from South and
      Central America, studies of physical therapy, education and psychosocial issues,
      and studies with negative results. The main causes cited by authors for not
      submitting abstracts for publication included a lack of time or low priority to
      write a full paper, or a desire to further expand the study. CONCLUSION: The 4th
      Park City meeting had an important clinical scientific impact measured by
      abstracts published in peer-reviewed journals. In future meetings, abstracts that
      will eventually be published are likely to have an analytical design, positive
      results, and a novel topic.

PMID- 12610824
TI  - Defining Clinical Improvement in Adult and Juvenile Myositis.
AB  - The lack of consensus regarding outcome measures and trial design issues in the
      idiopathic inflammatory myopathies (IIM) is inhibiting the conduct and
      interpretation of clinical trials. To begin to address these problems, a
      multispecialty group of over 70 adult and pediatric neurologists,
      rheumatologists, rehabilitation medicine physicians, statisticians, and patient
      support group leaders, called the International Myositis Outcome Assessment
      Collaborative Study Group (IMACS), is engaged in developing consensus on the
      assessment of disease activity and damage for myositis clinical trials. As part
      of this ongoing international effort, members of this group met in November 2001
      at a work-shop entitled "Defining Clinical Improvement in Adult and Juvenile
      Myositis." A goal of the work-shop was to review current data on the validity and
      responsiveness of the recently published proposed preliminary core set measures
      for disease outcome assessment in clinical trials for myositis and to define the
      degree of change in each core set measure that is clinically meaningful. Despite
      differences in the clinical presentations, natural history and responses to
      therapy between adult onset and juvenile onset myositis, expert specialists in
      these diseases came to a consensus that the amount of improvement that is
      clinically meaningful in each core measure is the same for adult and juvenile
      myositis. For the domains of muscle strength and physical function, a minimum of
      15% improvement is clinically significant, whereas for the physician and patient
      global assessments, as well as the extramuscular assessment, a minimum of 20%
      improvement is considered clinically meaningful, and for serum levels of muscle
      associated enzymes, at least 30% improvement is needed to be clinically
      important. This workshop is the first of several planned to develop
      multidisciplinary, international consensus on the conduct and reporting of IIM
      clinical trials.

PMID- 12610825
TI  - Familial vasculitides: Churg-Strauss syndrome and Wegener's granulomatosis in 2
      first-degree relatives.
AB  - Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG) are uncommon
      primary vasculitides, characterized by the involvement of the small to medium
      size vessels and by the frequent presence of serum antineutrophil cytoplasmic
      antibodies (ANCA). The pathogenesis of ANCA associated vasculitides is unclear,
      but roles for both genetic and environmental factors have been suggested.
      Familial cases of WG, but not CSS, have been reported. We describe the occurrence
      of CSS in a man and, 5 years later, WG in his son. These patients live together
      in an urban area of Northern Italy and share the HLA haplotype A*03; B*07; C*w07;
      DRB 1*0404, DQB 1*0302. To our knowledge, this is the first report of the
      familial clustering of CSS and WG in first-degree relatives.

PMID- 12610826
TI  - Kaposi's sarcoma following immune suppressive therapy for Wegener's
      granulomatosis.
AB  - The association between Kaposi's sarcoma and infection with human herpesvirus 8
      is now well recognized. Immunologic impairment is associated with 2 forms of
      Kaposi's sarcoma, epidemic [associated with human immunodeficiency virus (HIV)
      infection] and iatrogenic (associated with immunosuppressive treatment); both
      forms have become more common during the last decade. We describe an HIV negative
      54-year-old man who developed Kaposi's sarcoma 2 months after the beginning of
      immuno-suppressive therapy for Wegener's granulomatosis (WG). With tapering of
      medication, complete remission of Kaposi's sarcoma was achieved in one year. To
      our knowledge, this is the second reported case of iatrogenic Kaposi's sarcoma in
      a patient with WG.

PMID- 12610827
TI  - Bilateral optic nerve sheath enhancement from giant cell arteritis.
AB  - An 83-year-old man presented with acute bilateral visual loss to no light
      perception (NLP) OD and 20/50 OS. His fundus examination showed moderate
      bilateral pallid disc edema. A sedimentation rate was 60 mm/h. Magnetic resonance
      imaging of the brain and orbits with gadolinium revealed marked bilateral
      enhancement of the optic nerve sheaths and adjacent orbital fat. He underwent
      biopsies of the optic sheath OD and bilateral temporal arteries. Histopathology
      of the optic nerve sheath area revealed fibroadipose tissue containing numerous
      arteries with intimal thickening, and mild mural inflammation consisting
      predominantly of lymphocyte with occasional giant cells. The bilateral temporal
      artery biopsies revealed focal disruption of the elastic lamina with rare giant
      cells. His vision had since stabilized on IV methypdnisolone therapy. The
      biopsies of the nerve sheath suggest that the radiologic finding of optic nerve
      sheath enhancement in giant cell arteritis is caused by tbe same pathophysiology,
      and therefore may be a manifestation of this systemic disease.

PMID- 12610828
TI  - Non-L-tryptophan related eosinophilia-myalgia syndrome with hypoproteinemia and
      hypoalbuminemia.

PMID- 12610829
TI  - Ankylosing tarsitis.

PMID- 12610830
TI  - Septic discitis as a complication of infective endocarditis caused by
      Streptococcus oralis.

PMID- 12610831
TI  - An unusual cause of loin pain in a patient with systemic lupus erythematosus.

PMID- 12610832
TI  - Why "spondylodiscitis," why "SAPHO syndrome"?

PMID- 12610834
TI  - [Regeneration of ocular tissues].

PMID- 12610833
TI  - Mycobacterium tuberculosis infection of a tophaceous pseudogout nodule.

PMID- 12610835
TI  - [Establishment of the concept of new clinical entities--complete and incomplete
      form of congenital stationary night blindness].
AB  - I summarized our long-term study to prove that the complete and incomplete types
      of congenital stationary night blindness (CSNB) are different clinical entities
      and that the latter is a newly identified disease which has never been reported
      in the past. CSNB with normal fundi and negative electroretinogram (ERG) showing
      selective reduction of the b-wave was previously known as the "Schubert
      Bornschein type". For the sake of convenience, we classified the disease into two
      types according to the absence or the presence of rod function: complete CSNB and
      incomplete CSNB. The hereditary mode of the former is X-linked recessive and
      autosomal recessive, while that of the latter is X-linked recessive. They are
      never found together in a single family. We found several additional differences
      between the two types, including ERG oscillatory potentials, cone mediated ERG,
      and refractive errors, all leading us to hypothesize that the two types are not
      variants of a single disease but are the sum of two different clinical entities.
      Our hypothesis has recently been proven true by molecular genetical analysis.
      Namely, the mutated gene in X-linked recessive complete CSNB was found in the
      nyctalopin (NYX) gene, while that in incomplete CSNB was found in the calcium
      channel (CANCA1F) gene which encodes the retina-specific calcium channel alpha 1
      subunit. These results proved that complete and incomplete CSNB are different
      clinical entities and that the latter is the first disease of the eye which
      discloses mutation of this region. We classified 90 patients to include 49
      complete and 41 incomplete types. Fifteen incomplete CSNB patients underwent gene
      analysis and they all showed mutation of the CACNA1F gene. We also examined for
      gene mutation in several patients who had progressive retinal disease and
      negative ERG and found two siblings with CANA1F gene mutation. This finding
      indicates that the mutation of the CACNA1F gene can also cause progressive
      retinal disease in addition to incomplete CSNB. Gene analysis of 11 patients with
      complete CSNB was performed and 6 revealed mutation of the NYX gene. The
      remaining 5 patients showed neither NYX nor CACNA1F gene mutation, suggesting
      they are of autosomal recessive complete CSNB where gene mutation has not been
      identified. The comparison of our phenotype and genotype diagnosis indicated that
      a precise ERG analysis can provide correct differentiation between complete and
      incomplete types. Other clinical findings include moderately low visual acuity in
      both types, high or moderate myopia in complete CSNB, and wide distribution from
      myopia to hyperopia in incomplete CSNB. Pathophysiology studies using clinical
      patients and animal models suggested that complete CSNB has a complete defect of
      the ON-bipolar cells or their synapses in the rod and cone visual pathways,
      leaving the OFF pathway intact (OFF-retina). On the other hand, the incomplete
      CSNB has an incomplete defect of the ON and OFF bipolar cells or their synapses
      in the rod and cone visual pathways. The macular function is relatively well
      preserved in both types, which was shown by focal macular ERG. The incomplete
      CSNB patients seldom complain of night blindness, which causes us to overlook
      this disease because we then tend not to perform ERG testing. This disease is not
      so rare and clinicians should be more aware of its existence. The incomplete CSNB
      is a new hereditary retinal disease detected by Japanese investigators just like
      the Oguchi disease, and it has much unknown pathophysiology which needs to be
      identified in the future. Since the namings of complete and incomplete CSNB may
      be misunderstood as indicating functional classification of one disease, it has
      been proposed internationally to change the name "complete type" to CSNB1 and
      that of "incomplete type" to CSNB2.

PMID- 12610836
TI  - [The pathogenesis and treatment of corneal disorders].
AB  - In this 21 st century, it is predicted that blindness caused by corneal disorders
      which are difficult to prevent or treat will increase. It is important to study
      the pathogenesis, prevention, and treatment of these corneal disorders. Two
      corneal disorders, keratoconus and corneal dystrophy, were investigated to
      elucidate the pathogenesis by using molecular biological or molecular genetic
      techniques. Corneal transplantation is performed to restore vision of patients
      with corneal disorders, but the condition of the donor corneal endothelium is the
      key to maintaining transparency of the grafted cornea. We investigated the
      function or cell cycle mechanism of corneal endothelium at the level of the gene,
      and we also studied induced genes of endothelial cells during preservation of
      donor corneas. 1. Keratoconus: We searched for keratoconus patients with
      questionnaires sent to 141 hospitals in the 23 Wards of Tokyo. The incidence of
      patients was estimated to be 12.4 x 10(-5) for males and 6.7 x 10(-5) for
      females. The male/female ratio was 1.7: 1.0. The number of male patients was low
      when compared with studies reported 17 years ago. Rupture of Descemet's membrane
      in males was significantly higher than in females. Genesis of incidence:
      Apoptosis-related gene expression in thinning of the cornea was analyzed with
      cDNA microarrays, using mRNA isolated from cultured keratocytes of normal human
      corneas and keratoconus corneas. The expression of tumor necrosis factor alpha
      induced protein 6(TNFAIP 6) was more enhanced, while insulin growth factor
      binding protein 5(IGFBP 5) was less expressed in keratoconus patients. 2. Corneal
      dystrophy: In corneal dystrophy related to four candidate genes such as
      transforming growth factor beta-induced(TGFBI) gene, membrane component 1 surface
      maker 1(M 1 S 1) gene, carbohydrate sulfotransferase gene 6(CHST 6), and collagen
      type VIII alpha-2(COL8 A 2) gene, 208 Japanese and 42 Vietnamese families were
      analyzed for the gene mutation and studied for the frequency of gene mutation and
      differences of clinical features. About 80% of Japanese with corneal dystrophies
      had mutation of the TGFBI gene and about 70% of them had Avellino corneal
      dystrophy. However, in Vietnamese patients, mutations were found in both the
      TGFBI gene (lattice corneal dystrophy; the phenotype gene was His 626 Arg) and in
      the CHST gene. The difference in frequency in gene mutations was significant
      between the two nationalities. Moreover, a novel corneal dystrophy associated
      with Asp 123 His mutation in TGFBI gene was found in one Vietnamese family. 3.
      Corneal endothelial cell: 1) gene expression: We performed random sequence and
      homology research analysis of 1,000 clones from a rabbit corneal endothelial cDNA
      library. Forty-five genes, including collagen type VIII alpha-1, were listed for
      the frequently observed cDNA in the library. 2) gene transfection: One of the
      causes of a growth-arrested state in human corneal endothelium was thought to be
      the presence of transforming growth factor-beta (TGF-beta) in aqueous humor. The
      transfection of Smad 7 gene, which blocks the signal, showed proliferation of the
      endothelial cells in the presence of aqueous humor. This suggests that there may
      be a possible practical application for using gene transfection with a non-viral
      DNA vector or with an adenovirus vector.

PMID- 12610837
TI  - [Regeneration of the retina using pigment epithelial cell transplantation].
AB  - At has been reported that transplantation of appropriate cells, growth factors,
      and/or extracellular matrix may help the regeneration of damaged tissues or
      organs. Some growth factors, such as basic fibroblast growth factor(bFGF), have
      been successfully transferred to patients with ischemic heart disease. Embryonic
      dopamine neurons were also transplanted into the brains of patients with
      Parkinson's disease successfully. We have also performed cultured auto iris
      pigment epithelial cell (IPE) transplantation into the subretinal space after
      removal of choroidal neovascularization in patients with age-related macular
      degeneration (AMD). Here, we report the results of auto IPE transplantation in 35
      patients, who could be followed for more than 6 months. We also tried to apply
      cell transplantation to other retinal diseases by managing the transplanted cells
      as introduced growth factor genes. Auto IPE transplantation was performed after
      removal of choroidal neovascular membranes (CNV). Visual acuity wes improved by
      more than 0.2 log MAR in 18 of 35 patients (51.5%), it was unchanged in 11
      patients (31.5%), and it was worsened in 6 patients (17%). No significant
      difference was observed in comparison to patients who underwent CNV removal only.
      However, unlike the previous reports, we found no patients showing rejection. We
      also found that the cultured transplanted cells never showed proliferation under
      the retina or in the vitreous cavity and concluded that cultured auto IPE
      transplantation can be performed safely without complications. Next, we examined
      whether cell transplantation can be expanded to other degenerative retinal
      diseases. One of our results showed that host RPE may play an important role
      against the transplanted cells in the subretinal regions. When we introduced bFGF
      gene into the cells, we found synexpression cluster of the genes in the cells.
      One of the most prominent movements among the genes was lysyl oxidase like-1
      gene, which plays an important role in the maturation of the extracellular
      collagen and in cell attachment. However, when we examined the cell attachment on
      the culture plates after 12 hours of culture, no significant difference was
      observed between the cells with or without bFGF. Further, when we examined the
      area of the cells transplanted into the subretinal space of rats during
      successive follow-up using fluorescein marker (EGFP), no statistical significance
      was observed. The gene expression pattern may be different when we introduce
      different growth factor gene. No antibody production was generated against the
      growth factor gene introduced cells after cell transplantation. Further, when we
      made transgenic mice expressing bFGF or Axokine cDNA in the RPE of rd mice, no
      photoreceptor degeneration was observed. One of the reasons was suspected to be
      that bFGF was expressed systemically by the promoter of tyrosinase related
      protein 1 gene and may lead to lethality. Another reason was suspected to be
      suppression of the function of Axokine by the down-regulation of the ciliary
      neurotrophic factor or its receptor gene. Conversely, when we produced
      photoreceptor degeneration by constant light damage in the rats, we found partial
      photoreceptor rescue by transplantation of the growth factor gene introduced RPE.
      We show here the possibility that growth factor gene introduced cell
      transplantation may be applied to retinal diseases, if we select appropriate
      cells and genes.

PMID- 12610838
TI  - [Transplantation of corneal endothelial cells].
AB  - Though conventional corneal transplantation has achieved great success, it still
      has several drawbacks including limited availability of donor corneas, recurrent
      allograft rejection, and subsequent graft failure in certain cases.
      Reconstructing clinically usable corneas by applying the technology of
      regenerative medicine can offer a solution to these problems, as well as making
      corneal transplantation a non-emergency surgery and enabling the usage of banked
      corneal cells. In the present study, we focused on corneal endothelium that is
      critical for corneal transparency and investigated the reconstruction of cornea
      utilizing cultured human corneal endothelial cells (HCECs). We succeeded in
      steadily culturing HCECs by using culture dishes pre-coated with extracellular
      matrix produced by calf corneal endothelial cells and culture media that
      contained basic fibroblast growth factor and fetal bovine serum. We performed the
      following analysis utilizing these cultured HCECs. The older the donor was, the
      more frequently large senescent cells appeared in the passaged HCECs. The
      telomeres of HCECs were measured as terminal restriction fragments (TRF) by
      Southern blotting. HCECs, in vivo from donors in their seventies had a long TRFs
      of over 12 kilobases. Passaging shortened the TRFs but there was no difference in
      TRFs among donors of various ages. These results indicated that shortening of
      telomere length is not related to senescence of HCECs. We investigated the role
      of advanced glycation end products (AGEs) in the senescence of in vivo HCECs. The
      results indicated that AGE-protein in the aqueous humor is endocytosed into HCECs
      via AGE receptors expressed on the surface of HCECs and damages HCECs by
      producing reactive oxygen species and inducing apoptosis, suggesting that AGEs,
      at least partly, cause the senescence of HECEs. HCECs were cultured using adult
      human serum instead of bovine serum to get rid of bovine material that can be
      infected with prions. Primary and passage culture of HCECs was possible using
      adult human serum. We reconstructed the cornea using cultured HCECs and human
      corneal stroma. The corneal stroma, on which the cell suspension of HCECs was
      poured, was mildly centrifuged to enhance the HCECs attachment to the stroma. The
      cell density of HCECs on the reconstructed cornea reached 2,500 cells/mm2. The
      pump function of the reconstructed cornea was measured with an Ussing chamber.
      The potential difference in the reconstructed cornea and normal cornea was 0.30
      mV and 0.40 mV, respectively; indicating that the pump function of the
      reconstructed cornea is 75% of that of the normal cornea. The reconstructed
      cornea was transplanted to a rabbit eye and stayed transparent for 6 months after
      the operation. Fluorescein labeled cultured HCECs remained on the graft 1 month
      after the transplantation, indicating that transplanted HCECs contributed to the
      transparency of the graft. The possibility of using artificial stroma or porcine
      corneal stroma as a carrier of cultured HCECs was investigated. The artificial
      stroma made of alkaline-treated collagen could not be sutured but showed good
      transparency, biocompatibility, and cell-attachability. Porcine corneal stroma,
      expressing little xeno-sugar antigen alpha-gal epitope, induced no super acute
      rejection but mild cellular rejection when transplanted in the cornea of animals
      possessing natural antibody to alpha-gal epitope. The cornea reconstructed with
      porcine corneal stroma and HCECs had an average cell density of 1721/mm2 and had
      approximately 60% of the pump function of a normal cornea. As new technologies in
      corneal transplantation, the application of self immature cells and the direct
      delivery of cultured HCECs into the anterior chamber were investigated. Part of
      rat mononuclear cells that were obtained from the bone marrow and injected into
      the rat anterior chamber transformed into corneal endothelium-like cells,
      suggesting that self immature cells can transform into corneal endothelial cells.
      Cultured rabbit corneal endothelial cells that endocytosed iron were injected
      into the anterior chamber of rabbits whose corneal endothelium was cryo-injured,
      and were pulled to Descemet's membrane by putting a magnet on the eyelid. In
      these rabbits, corneal edema decreased more quickly than in the control group and
      no intraocular pressure rise was observed during 8 weeks after the operation,
      suggesting that the direct delivery of cultured HCECs into the anterior chamber
      can be an alternative method of choice. The following obstacles should be
      addressed to make the transplantation of cultured corneal endothelial cells
      clinically applicable. 1. To reconstruct a cornea that is the same as or superior
      to the normal cornea, more innovation is necessary in the method of culturing and
      seeding HCECs. We should consider utilizing HCECs obtained from fetuses after
      clearing ethical issues. Moreover, we need to develop a method to enhance the
      cell density and the cell functions. 2. Porcine corneal stroma is promising as a
      carrier of HCECs instead of human corneal stroma, which is in very limited
      supply. The usefulness of porcine corneal stroma acellularized to prevent
      retrovirus infection should be evaluated. 3. To make the self immature cells
      applicable to corneal transplantation, we should elucidate the corneal
      endothelial cell specific markers and the factors that are necessary to induce
      self immature cells to become corneal endothelial cells. 4. The direct delivery
      of cultured HCECs into the anterior chamber can be an alternative method of
      choice when its long-term safety is confirmed.

PMID- 12610840
TI  - Neurorehabilitation and brain plasticity.

PMID- 12610839
TI  - [Ocular surface reconstruction by tissue engineering].
AB  - Ocular surface reconstruction by tissue engineering using somatic stem cells is a
      second-generation modality. In order to treat bilaterally affected, severe ocular
      surface disorders, we investigated the transplantation of two types of cultivated
      mucosal epithelia: allogenic corneal epithelial stem cells, and autologous oral
      mucosal epithelial cells. For this, first, we summarized the clinical results of
      allogenic keratoepithelioplasty and limbal transplantation. In addition, we
      showed that the immunological shift from Th1 to Th2 by using keyhole limpet
      hemocyanin was effective in suppressing the incidence of immunological rejection.
      Second, we investigated the transplantation of cultivated human corneal
      epithelial stem cells onto amniotic membrane. The cultivated sheet was created by
      co-culture with 3T3 fibroblasts, using the air-lift method, in cultivating the
      corneal epithelial stem cell on the amniotic membrane. These cultivated cells
      demonstrated positive keratin 3 and 12 specific to in vivo corneal epithelium,
      tight junction related proteins, and telomerase activity. The transplanted
      allogenic human corneal epithelial sheet survived on the corneal surface in all
      cases, and was quite effective for achieving ocular surface stability in the
      acute phase of Stevens-Johnson syndrome, ocular cicatricial pemphigoid, or
      chemical injury. However, a few cases developed immunological rejection or
      opportunistic infection. Third, to establish the transplantation of the
      autologous cultivated oral mucosal epithelial sheet, we performed animal
      experiments using rabbits. In vitro oral mucosal epithelial sheet showed
      histology similar to that of in vivo corneal epithelial sheet. It expressed
      positive keratin 3 as well. Since the autologous transplantation of this sheet
      survived on the ocular surface with the recovery of corneal transparency, a
      cultivated oral mucosal epithelium may become a substitute for corneal
      epithelium. Fourth, we created a cultivated human corneal endothelial cell sheet
      on amniotic membrane using a similar technique, and transplanted it to a rabbit
      eye as a xenograft. The transplanted corneal endothelial cell density was over
      3,000 cells/mm2, and it was actively functioning even after the transplantation.
      Lastly, to explore cell markers for corneal epithelial stem cells, we established
      a technique using laser micro-capture, and introduced amplified fragment length
      polymorphism (AFLP), identifying several candidate molecules as stem cell
      markers.

PMID- 12610841
TI  - Physiotherapy based on the Bobath concept for adults with post-stroke hemiplegia:
      a review of effectiveness studies.
AB  - The Bobath concept, also known as neurodevelopmental treatment, is a widely used
      approach in the rehabilitation of hemiparetic subjects in many countries. Despite
      50 years of clinical use its effectiveness is questionable. This paper aims to
      examine whether there is evidence to accept neurodevelopmental treatment as an
      effective approach. A systematic literature search was undertaken. Fifteen trials
      have been selected and classified according to a 5-level hierarchic scale of
      evidence for clinical interventions. Results show no evidence proving the
      effectiveness of neurodevelopmental treatment or supporting neurodevelopmental
      treatment as the optimal type of treatment, but neither do methodological
      limitations allow for conclusions of non-efficacy. Methodological aspects of
      selected studies are discussed and requirements for further research are
      suggested.

PMID- 12610842
TI  - Comparison of clinical gait analysis strategies by French neurologists,
      physiatrists and physiotherapists.
AB  - Clinical and functional gait analysis is used widely by different professionals
      dealing with patients with hemiplegia. The aim of this study was to examine the
      gait analysis strategies of neurologists, specialists in physical and
      rehabilitation medicine (physiatrists) and physiotherapists. Differences in
      global analysis strategy and choice of indicators between different clinicians
      have not previously been studied precisely, and we believe that a standardized
      approach would enhance the training of young practitioners. The knowledge
      acquisition phase (specialists' expertise identification) was completed by an
      identified expert with a subject groups of 5 neurologists, 5 specialists in
      physical and rehabilitation medicine and 5 physiotherapists, who were asked to
      comment on a videotape of patients with hemiplegia walking, followed by a semi
      directed interview. The results show that specialists use a wide variety of gait
      indicators. The total number of different medical vocabulary and expressions used
      to describe gait was 396, semantically grouped as 60 general indicators.
      Specialists highlighted an analysis strategy (order, type and number of
      indicators) typical to each professional specialty. The neurologists tried to
      identify the elements allowing localization of lesions and characterized the
      hemiplegia globally,while the specialists in physical and rehabilitation medicine
      conducted a bio-mechanical analysis and the physiotherapists were highly
      descriptive. The differences in strategies adopted by each specialty contribute
      to an enrichment of gait analysis. This should be taken into account in teaching
      and determining gait assessment scales.

PMID- 12610843
TI  - Analgesic effects of transcutaneous electrical nerve stimulation and
      interferential currents on heat pain in healthy subjects.
AB  - This study examined whether transcutaneous electrical nerve stimulation or
      interferential current was more effective in reducing experimentally induced heat
      pain. Forty-eight young healthy subjects were randomly divided into the following
      groups: (i) transcutaneous electrical nerve stimulation; (ii) interferential
      current; and (iii) no stimulation. A multi-function electrical stimulator was
      used to generate the transcutaneous electrical nerve stimulation or
      interferential current. A thermal sensory analyser was used to record the heat
      pain threshold. The stimulation lasted for 30 minutes and the heat pain
      thresholds were measured before, during and after the stimulation. Transcutaneous
      electrical nerve stimulation (p = 0.003) and interferential current (p = 0.004)
      significantly elevated the heat pain threshold, but "no stimulation" did not. The
      thresholds of the transcutaneous electrical nerve stimulation and interferential
      current groups were significantly higher than that of the control group 30
      minutes into the stimulation (p = 0.017). Both transcutaneous electrical nerve
      stimulation and interferential current increased the heat pain threshold to a
      similar extent during stimulation. However, the post-stimulation effect of
      interferential current lasted longer than that of transcutaneous electrical nerve
      stimulation.

PMID- 12610844
TI  - Rehabilitation problems after acute disseminated encephalomyelitis: four cases.
AB  - The aim of this study is to describe rehabilitation problems in patients with
      acute disseminated encephalomyelitis. The study examines retrospective clinical
      data. Data are reported from 4 patients, who were consecutively admitted and
      examined with the Functional Independence Measure and magnetic resonance imaging.
      It was found that the lesions in the brains affected by acute disseminated
      encephalomyelitis are widespread, but become smaller with time. Motor symptoms
      dominate at first, but recovery is quite good. Social and cognitive functions are
      also affected, however, and require a much longer recovery time. These symptoms
      are, thus, the dominating problem in the rehabilitation ward. At clinical follow
      up after 3 years the cognitive problems still influenced the lives of the
      patients. It is concluded that social and cognitive problems seem to be common in
      patients with acute disseminated encephalomyelitis. Recovery in these areas takes
      a long time and this is the main rehabilitation problem, since it affects the
      capability of the person to reintegrate into society.

PMID- 12610845
TI  - Does the functional reach test reflect stability limits in elderly people?
AB  - OBJECTIVE: To explore how the Functional Reach test correlates with the
      displacement of the centre of pressure and whether the test is a measure of the
      stability limits in healthy elderly people. Also to explore the performance
      parameters during the Functional Reach test. DESIGN: Method comparison study.
      SUBJECTS: Twenty-seven healthy elderly subjects. METHODS: Whole body kinematics
      (ELITE systems), ground reaction forces (AMTI) and muscle activity (EMG) parallel
      with clinical yardstick measure while performing the Functional Reach test.
      RESULTS: This study showed a low correlation (r = 0.38) between reach distance
      and displacement of centre of pressure and a moderate correlation (r = 0.68)
      between forward rotation of the trunk and reach distance. The movement during the
      Functional Reach test was characterized by a large forward rotation of the trunk
      and a small extension in the ankle. The latter constraining centre of pressure
      forward displacement. CONCLUSIONS: The results suggest that the Functional Reach
      test is a weak measure of the stability limits. Movement of the trunk seems to
      influence the test more than the displacement of the centre of pressure. When
      using the Functional Reach test for assessing balance, compensatory mechanisms
      should be taken into account.

PMID- 12610846
TI  - Sporadic inclusion body myositis: pilot study on the effects of a home exercise
      program on muscle function, histopathology and inflammatory reaction.
AB  - OBJECTIVE: To evaluate the safety and effect of a home training program on muscle
      function in 7 patients with sporadic inclusion body myositis. DESIGN: The
      patients performed exercise 5 days a week over a 12-week period. METHODS: Safety
      was assessed by clinical examination, repeated muscle biopsies and serum levels
      of creatine kinase. Muscle strength was evaluated by clinical examination,
      dynamic dynamometer and by a functional index in myositis. RESULTS: Strength was
      not significantly improved after the exercise, however none of the patients
      deteriorated concerning muscle function. The histopathology was unchanged and
      there were no signs of increased muscle inflammation or of expression of
      cytokines and adhesion molecules in the muscle biopsies. Creatine kinase levels
      were unchanged. A significant decrease was found in the areas that were
      positively stained for EN-4 (a marker for endothelial cells) in the muscle
      biopsies after training. CONCLUSION: The home exercise program was considered as
      not harmful to the muscles regarding muscle inflammation and function. Exercise
      may prevent loss of muscle strength due to disease and/or inactivity.

PMID- 12610847
TI  - Dizziness and unsteadiness following whiplash injury: characteristic features and
      relationship with cervical joint position error.
AB  - Dizziness and/or unsteadiness are common symptoms of chronic whiplash-associated
      disorders. This study aimed to report the characteristics of these symptoms and
      determine whether there was any relationship to cervical joint position error.
      Joint position error, the accuracy to return to the natural head posture
      following extension and rotation, was measured in 102 subjects with persistent
      whiplash-associated disorder and 44 control subjects. Whiplash subjects completed
      a neck pain index and answered questions about the characteristics of dizziness.
      The results indicated that subjects with whiplash-associated disorders had
      significantly greater joint position errors than control subjects. Within the
      whiplash group, those with dizziness had greater joint position errors than those
      without dizziness following rotation (rotation (R) 4.5 degrees (0.3) vs 2.9
      degrees (0.4); rotation (L) 3.9 degrees (0.3) vs 2.8 degrees (0.4) respectively)
      and a higher neck pain index (55.3% (1.4) vs 43.1% (1.8)). Characteristics of the
      dizziness were consistent for those reported for a cervical cause but no
      characteristics could predict the magnitude of joint position error. Cervical
      mechanoreceptor dysfunction is a likely cause of dizziness in whiplash-associated
      disorder.

PMID- 12610848
TI  - Hydrotherapy for Rett syndrome.
AB  - OBJECTIVE: The effects of hydrotherapy on an 11-year-old girl with stage III Rett
      syndrome were investigated. METHODS: The Halliwick method was used to apply
      hydrotherapy in a swimming pool twice a week for 8 weeks. The girl's physical
      abilities were assessed 3 times: before and 5 minutes after a single hydrotherapy
      session and after 8 weeks of hydrotherapy. The tests included analysis of
      stereotypical movements, functional hand use, hand skills, gait and balance,
      hyperactive behaviour, communication and social interaction. RESULTS: Immediately
      after hydrotherapy, stereotypical movements decreased and this decrease continued
      during the following 8 weeks. The girl's feeding activities and hand skills
      increased markedly. After 8 weeks of hydrotherapy, her walking balance was
      improved, interaction with her environment increased and hyperactive behaviour
      and anxiety decreased. CONCLUSION: In conclusion, after the application of
      hydrotherapy, stereotypical hand movements had decreased and purposeful hand
      functions and feeding skills increased in this case. Whether hydrotherapy has a
      positive effect on the functional use of the hand in Rett syndrome should be
      investigated using more subjects.

PMID- 12610849
TI  - Critical care nutrition: reducing the risk of aspiration.
AB  - While aspiration is a fairly common event for critically ill patients on enteral
      tube feeding, progression to aspiration pneumonia is difficult to predict due to
      variation in host factors and characteristics of the aspirate material.
      Aspiration of oropharyngeal secretions is of equal if not greater importance than
      aspiration of gastric contents. Monitors for aspiration such as glucose oxidase,
      blue food coloring, and gastric residual volumes are insensitive and unreliable.
      A number of clinical risk factors can be identified at the bedside. A variety of
      management strategies may be used in the intensive care unit to reduce risk of
      aspiration, while efforts continue to provide sufficient volume of enteral
      nutrients.

PMID- 12610850
TI  - Prevention and treatment of stress ulcers in critically ill patients.
AB  - Critically ill patients are at increased risk of developing stress-related
      mucosal lesions. The pathogenesis of stress-related mucosal disease is not
      entirely clear, but probably is associated with impairment of mucosal protective
      mechanisms due to compromised gastric mucosal microcirculation. Acid also plays
      an integral role. The incidence of gastrointestinal bleeding among intensive care
      unit patients has been declining over the past 30 years. Only a small proportion
      of patients with stress-related mucosal lesions develop clinically overt
      bleeding, and the majority of the overt bleedings do not lead to hemodynamic
      instability. However, the presence of gastrointestinal bleeding in a critically
      ill patient predicts markedly increased mortality. Prolonged mechanical
      ventilation and coagulopathy are the most important predictors of stress ulcer
      related bleeding. Critically ill patients with stress ulcer related bleeding
      should be managed in the acute setting just as patients presenting with upper
      gastrointestinal bleeding. Available evidence supports the use of stress ulcer
      prophylaxis in patients with risk factors for bleeding. Both histamine 2 receptor
      antagonists and sucralfate are effective forms of stress ulcer bleeding
      prophylaxis. More potent acid suppression by proton pump inhibitors may offer
      additional benefit in the prevention of stress ulcer bleeding.

PMID- 12610851
TI  - Colonic pseudo-obstruction: the dilated colon in the ICU.
AB  - Acute colonic pseudo-obstruction is a syndrome of massive dilation of the colon
      without mechanical obstruction that develops in hospitalized patients with
      serious underlying medical and surgical conditions. Increasing age, cecal
      diameter, delay in decompression, and status of the bowel significantly influence
      mortality, which is approximately 40% when ischemia or perforation is present.
      Evaluation of the markedly distended colon in the intensive care unit setting
      involves excluding mechanical obstruction and other causes of toxic megacolon
      such as Clostridium difficile infection, and assessing for signs of ischemia and
      perforation. The risk of colonic perforation in acute colonic pseudo-obstruction
      increases when cecal diameter exceeds 12 cm and when the distention has been
      present for greater than 6 days. Appropriate management includes supportive
      therapy and selective use of neostigmine and colonoscopy for decompression. Early
      recognition and management are critical in minimizing complications.

PMID- 12610852
TI  - Gallbladder and biliary tract disease in the intensive care unit.
AB  - Intensive care unit patients present a difficult challenge in the diagnosis and
      treatment of complications related to the biliary tract. Altered mental status
      interferes with the patient's ability to communicate symptoms and give a reliable
      physical examination. Laboratory data are often nonspecific in diagnosing
      complications of biliary tract disease because of the high incidence of
      cholestasis in intensive care unit patients. Likewise, routine radiographic
      evaluation has a marked decreased sensitivity and specificity in evaluating
      biliary tract disorders. Taken together, these factors often lead to a delay in
      diagnosis of biliary tract problems in the intensive care unit patient.
      Intervention in these patients is associated with high morbidity and mortality
      when compared to the ambulatory setting. This article reviews the clinical
      presentation, differential diagnosis, and management options of biliary tract
      complications in this complex patient population.

PMID- 12610854
TI  - The critically ill liver patient: fulminant hepatic failure.
AB  - Fulminant hepatic failure is a challenging medical condition that requires
      intensive care management to prevent-major complications (cerebral edema,
      infections, and multi-system organ failure) and assistance from a liver
      transplant team when it is believed that liver regeneration is unlikely.
      Unfortunately, there are no specific medical therapies or devices to correct all
      of the functions of a liver. N-acetylcysteine is used for the treatment of
      acetaminophen overdose, but for most other causes of fulminant hepatic failure
      therapy is supportive care. This case illustrates many of the problems that are
      encountered during medical management of fulminant hepatic failure.

PMID- 12610855
TI  - Commission on Cancer Liaison Report.

PMID- 12610853
TI  - The critically ill liver patient: the variceal bleeder.
AB  - Esophageal varices develop in patients with cirrhosis once portal pressure,
      measured by hepatic venous pressure gradient, and exceeds 10 mm Hg. At a portal
      pressure of 12 mm Hg, variceal bleeding may develop that is associated with a
      mortality of 30% to 50% per episode. In addition to an elevated portal pressure,
      other risk factors for the development of variceal hemorrhage include: variceal
      size, endoscopic features on the variceal wall (i.e., red wales), and Child-Pugh
      class. In patients with suspected variceal hemorrhage, the treatment of the acute
      episode includes intravascular volume expansion, hemostasis through the use of
      pharmacological agents and endoscopy, and the prevention and treatment of
      potential complications associated with variceal hemorrhage such as aspiration
      pneumonia, spontaneous bacterial peritonitis and hepatic encephalopathy. Given a
      high rate of rebleeding, long-term prevention through secondary prophylaxis
      should be instituted in all patients who have survived an episode of variceal
      bleeding. Current prophylactic options include: non-selective beta-blockers alone
      (first line) or in combination with long-acting nitrates (isosorbide mononitrate)
      and/or endoscopic variceal obliteration achieved through sclerotherapy or
      preferably, band ligation.

PMID- 12610856
TI  - Radiation oncology practice mergers: bigger is better!

PMID- 12610857
TI  - Every breath you take--the image-guided motion management story.

PMID- 12610858
TI  - Medical technology companies broaden role to support the financial success of
      clinics.
AB  - Market challenges continue to mount for hospitals and clinics, causing an
      unparalleled focus on profitability and return on investment for services. To
      support these challenges, technology suppliers that were once content to deliver
      and install equipment have become partners with the institutions they serve.
      Savvy technology companies are offering an extensive array of services that
      assist facilities in the planning, cost justification, implementation and ongoing
      support of their technology. The result is a marriage of progress and profit,
      resulting in solutions that enhance both the quality of care and the bottom line.

PMID- 12610859
TI  - Community communications: hospital uses its own report card to tell public how
      it's providing quality care.
AB  - Over the years, many types of healthcare report cards have emerged to give
      consumers comparative quality information right at their fingertips. One
      organization, though, Licking Memorial Health Systems of Newark, OH, has created
      a report card over the past 3 years to tell the community how it is doing-
      keeping in mind healthcare issues that affect every member of the community.
      Getting these data at the hospital level required a new approach at the
      departmental levels.

PMID- 12610860
TI  - Humana looks to ISO registration to address quality improvement and customer
      satisfaction.
AB  - Seeking new ways to improve standardization of clinical operations and customer
      focus, Louisville, KY-based Humana, Inc. announced in November that it has become
      the first healthcare company to be registered in the U.S. under ISO 9001:2000, a
      quality management standard published by the International Organization for
      Standardization (ISO).

PMID- 12610861
TI  - New report card compares end-of-life care initiatives across the country.
AB  - A report card from Last Acts and the Robert Wood Johnson Foundation takes a first
      look on a state-by-state basis at how end-of-life care and related issues are
      approached by healthcare organizations across the country.

PMID- 12610862
TI  - [Current status and future perspectives in chemotherapy for testicular cancer].
AB  - Approximately eighty percent of patients with disseminated testicular cancer can
      currently be cured because of the progress in cisplatin-based chemotherapy. For
      good risk disseminated disease, three courses of bleomycin, etoposide and
      cisplatin (BEP) is the most reliable induction chemotherapy. Cisplatin,
      ifostamide and either etoposide or vinblastine (VIP or VeIP) is effective
      standard-dose salvage chemotherapy, especially for relapsed patients with good
      prognosis features. However, remission is of short duration in many cases,
      resulting in an overall long-term disease-free survival rate of 10% to 25%. One
      possible approach to improve outcome is drug-dose increment. In recent years,
      high-dose chemotherapy (HDCT) with autologous stem-cell rescue has been used with
      some success in the first relapse cases and refractory cases. Although these non
      randomized data are promising, the clinical benefit of HDCT remains to be
      confirmed in an ongoing randomized study. Another strategy is to include a new
      active drug in the chemotherapy regimen. Recent studies combining new active
      agents such as paclitaxel, gemcitabine and irinotecan have showed promising
      results in patients with poor prognostic disease or as salvage therapy.

PMID- 12610863
TI  - [Chemoprevention of lung cancer].
AB  - Since a high concentration of beta-carotene in blood reduces the risk of lung
      cancer, a large-scale intervention examination containing beta-carotene was
      conducted, mainly by the National Cancer Institute. The results showed that the
      risk of lung cancer increased with administration of beta-carotene. This result
      demonstrates that continuation of smoking is an important factor in the increased
      risk, and not smoking is confirmed to be the most important prevention method.
      The authors examined the treatment effect of raising the concentration of folic
      acid and vitamin B12 in blood on bronchial dysplasia as a pre-cancerous lesion. A
      significant medical treatment effect was see in the folic acid and vitamin B12
      medication groups, which seems promising for the chemoprevention of lung cancer.

PMID- 12610864
TI  - [Diagnostic imaging--recent progress].
AB  - Current advances in the diagnostic imaging for lung cancer includes multidetector
      row CT (MDCT), lung cancer screening using low-dose MDCT and fluorodeoxyglucose
      positron emission tomography (FDG-PET) imaging. There is no question about the
      clinical usefulness of MDCT, and the further development of the hardware and the
      software of MDCT will open new horizons for CT diagnosis. PET is not an
      alternative modality to CT but a supplementary one, which adds metabolic
      information to the morphology. Recently, experimental research on the refraction
      imaging of human lung specimens has been performed with synchrotron radiation.
      With progressive refinement, this technique may come to have some practical
      purpose in diagnosing lung cancer in vivo.

PMID- 12610866
TI  - [Molecular-targeted therapy].
AB  - This article reviews the concept of molecular-targeted therapy and the current
      development status of molecular-targeted agents for lung cancer. Epidermal growth
      factor receptor inhibitors have shown promising antitumor activity against
      cisplatin-resistant non-small cell lung cancer in phase II trials. Appropriate
      clinical evaluation of these agents and collaboration with basic researchers are
      essential for further development.

PMID- 12610865
TI  - [Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung
      cancer in Japan].
AB  - The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and
      novel treatment modalities are urgently needed for advanced NSCLC. Backed by
      advances in the understanding of cancer biology, gene therapy has been developed
      in recent years. The p53 gene is altered in over 50% of cancers and has been
      extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene
      transfer is currently under clinical evaluation worldwide for the treatment of
      cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC
      patients in Japan. As an interim report, we provide a brief summary of the
      current status of this study, highlighting the safety and clinical efficacy of Ad
      p53. As of September 2002, 13 patients were enrolled to this study, and safety
      and antitumor effects have been noted.

PMID- 12610867
TI  - [Current status of the neo-adjuvant and adjuvant therapy for the resectable non
      small cell lung cancer].
AB  - Generally, the surgical resection has been considered to be the standard therapy
      for the clinical Stage I-IIIA non-small cell lung cancer (NSCLC). However, the 5
      year-survival rate has been reached approximately less than 20%. To improve the
      prognosis, especially for the Stage IIIA NSCLC, many clinical trials have been
      performed to assess the availability of the chemotherapy or radiation therapy in
      the preoperative or postoperative period. Although some clinical trials
      concerning about the neo-adjuvant therapy have reported the improvement of the
      postoperative survival rate, the availability of both neo-adjuvant and adjuvant
      therapy is still controversial. Further assessment for the well designed phase
      III clinical trials will be necessary to establish the availability of such
      modalities for the treatment of respectable NSCLC.

PMID- 12610868
TI  - [Heavy ion therapy for non-small cell lung cancer--new, radical radiotherapy for
      advanced-age patients as an alternative to surgery].
AB  - Clinical trials of carbon beam radiotherapy for stage I non-small cell lung
      cancer (NSCLL), and their results, are briefly described. The local control rate,
      cause-specific and overall survival rates of 146 patients with clinical stage I
      NSCLC were 82.0%, 59.0% and 59.0%, respectively. Radiation pneumonia was not
      serious and infrequent (2.1%). In the phase II clinical study, the local control
      rate of 50 patients was 100% without radiation pneumonia, resulting in a 74.0%
      overall survival rate. Carbon beam therapy could be an alternative to surgery,
      especially for lung cancer patients of advanced age and/or with complications.
      For locally advanced lung cancer treated with carbon beams, excellent local
      control as in stage I NSCLC has been demonstrated, providing hopeful prospects
      for the treatment of lung cancer.

PMID- 12610869
TI  - [Idiopathic pulmonary fibrosis and lung cancer].
AB  - It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are
      frequently associated with lung cancer. Although a complication with lung cancer
      is an important prognostic factor for IPF, standard treatments for lung cancer
      cannot be given because of IPF. Especially, the administration of many anticancer
      agents is limited by a complication with IPF, which is recognized as a risk
      factor for the development of fatal lung injury in cancer chemotherapy.
      Epidemiological studies reveal that cigarette smoking and occupational and
      environmental exposure to toxic substances are common risk factors for both IPF
      and lung cancer. It has been assumed that metaplasia in fibrous lesions is
      pathologically a precancerous lesion, but it is necessary to prove several
      genetic abnormalities in the process of carcinogenesis in order to clarify that.
      Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT
      and transforming growth factor (TGF)-beta 1 type II receptor, have been reported.

PMID- 12610870
TI  - [Optimal dosing schedule in combination therapy with irinotecan and doxifluridine
      in a human colorectal cancer xenograft model].
AB  - A combination therapy with CPT-11 and 5-FU/LV has been recently established as a
      first-line therapy for metastatic colorectal cancer. However, severe adverse
      effects have also been reported from this combination therapy, and a modality to
      reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less
      myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT
      11. However, since each drug has the possibility of inducing diarrhea, there is
      concern about their use in combination therapy. Therefore, in the present study,
      our aim was to establish an optimal schedule in murine models, which shows no
      increase in diarrhea but maintains potent antitumor activity. In non-tumor
      bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was
      given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused
      diarrhea in the single treatment. CPT-11 was administered simultaneously or
      sequentially with 5'-DFUR. With the simultaneously administered schedule, the
      diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR
      single treatment groups. On the other hand, with the sequentially administered
      schedule the diarrhea was not much stronger than that found in the single agent
      treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three
      day intervals, the diarrhea was not augmented at all. In mice bearing human
      colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination
      with 5'-DFUR was additive in all of the examined schedules. The efficacy in the
      sequential schedule was the same as in the simultaneous schedule. These results
      suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be
      more tolerable than and equally efficacious to the simultaneous administration
      schedule. Clinical study of this sequential administration in combination therapy
      is warranted.

PMID- 12610871
TI  - [Histoculture drug response assay (HDRA) guided induction concurrent
      chemoradiotherapy for mediastinal node-positive non-small cell lung cancer].
AB  - To improve the response to chemotherapy for non-small cell lung cancer (NSCLC),
      effective drugs should be selected for each patient. In 1994 we introduced
      histoculture drug response assay (HDRA) for NSCLC patients. For clinical N2
      patients, biopsy of mediastinal lymph node is performed both for histological
      diagnosis and for HDRA. Induction concurrent chemoradiotherapy is then performed
      using HDRA positive chemotherapy agents. We have treated three patients with this
      strategy. HDRA could be performed using mediastinal lymph node biopsy specimens.
      Tumor reduction rates of these patients were 80.4%, 85.3%, and 57.1%. Their
      histological responses were Ef.3, Ef.2, and Ef.1b, respectively. Complete
      resection was done in all patients. This strategy appeared to be useful in NSCLC
      patients with mediastinal lymph node metastasis.

PMID- 12610872
TI  - [A phase I study of gemcitabine and irinotecan as second line treatment for
      advanced non-small cell lung cancer].
AB  - A phase I study was conducted to determine the maximum tolerated dose (MTD) and
      the dose limiting toxicity (DLT) of gemcitabine and irinotecan combination
      therapy as second line treatment in patients with advanced non-small cell lung
      cancer (NSCLC). Twelve patients with measurable NSCLC (age range 46-74 years; 7
      males, 5 females; performance status 0 = 4, 1 = 8) who progressed or failed first
      line chemotherapy were enrolled. Prior chemotherapy was platinum-based without
      gemcitabine or irinotecan. Gemcitabine was administered at a fixed dose of 1,000
      mg/m2 after irinotecan administration, and irinotecan was administered at doses
      from 50 to 125 mg/m2 with an increment of 25 mg/m2, both on day 1 and 8.
      Chemotherapy was repeated every 3 weeks. Grade 3/4 leukopenia occurred in three
      patients (25%), neutropenia in four (33%), anemia in one (8%), and
      thrombocytopenia in one (8%). Grade 3 nausea and vomiting was observed in three
      (25%), grade 2 diarrhea in one (8%), and liver dysfunction in one (8%). Other
      toxicities were mild. Two of the three patients at level 4 (irinotecan 125 mg/m2)
      experienced dose limiting toxicity: one patient experienced grade 4 leukopenia
      and neutropenia, and the other experienced treatment delay of more than 2 weeks.
      The objective response rate was 16.6% (2/12). The maximum tolerated dose in this
      combination therapy was gemcitabine 1,000 mg/m2 and irinotecan 125 mg/m2. The
      dose level of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 on day 1 and 8 of
      a 3-week cycle is recommended for a phase II study.

PMID- 12610873
TI  - [Paclitaxel and carboplatin with or without pirarubicin (THP-ADR) as first line
      chemotherapy in elderly patients].
AB  - To evaluate the validity of administration of paclitaxel and carboplatin with or
      without pirarubicin (THP-ADR) as first line chemotherapy in elderly patients with
      gynecologic cancer, we explored the efficacy and safety of these regimens. From
      October 1, 1998 to September 30, 2001, we administered paclitaxel and carboplatin
      with or without THP-ADR pursuant to the chart we prepared originally as first
      line chemotherapy in patients with gynecologic cancer. Eleven elderly patients
      (age > 70 years) and 62 younger patients (age < 70 years) were entered into the
      present study. Paclitaxel was administered as a 3-hour intravenous (i.v.)
      infusion at dosages of 135 to 180 mg/m2 immediately followed by carboplatin over
      60 minutes at dosages of area under the curve (AUC) 3 to 5, administered
      intravenously or intraperitoneally. We observed grade 3/4 anemia more frequently
      in elderly patients receiving the regimen including paclitaxel and carboplatin
      without THP-ADR (9% v.s. 47%, p < 0.0001). Grade 3/4 anemia (10% v.s. 22%, p =
      0.02) and grade 3/4 thrombocytopenia (7% v.s. 22%, p = 0.007), febrile
      neutropenia (14% v.s. 44%, p = 0.02) also occurred more frequently in elderly
      patients receiving the regimen including paclitaxel and carboplatin with THP-ADR.
      The overall response rates were equivalent among elderly and younger patients
      (69% and 78%), respectively. The regimen consisting of paclitaxel and carboplatin
      without THP-ADR was applied safely to elderly patients.

PMID- 12610874
TI  - [High-dose chemotherapy with autologous peripheral blood stem cell
      transplantation for the treatment of multiple myeloma refractory to conventional
      chemotherapy].
AB  - High-dose chemotherapy with autologous peripheral blood stem cell transplantation
      was administered to five patients with refractory myeloma. To collect peripheral
      blood stem cells, apheresis was done by administering doxorubicin 40 mg/m2 on the
      first day, and etoposide 60 mg/m2 on the first, second, and third days, followed
      by G-CSF administration to harvest cells. The high-dose chemotherapy consisted of
      melphalan 60 mg/m2 administered for 4 days and infusion of mononuclear cells. No
      serious side effects were observed during the clinical course. After
      transplantation, complete or partial responses were achieved. APBSCT is
      considered to be a useful method because it had an antitumor effect against
      multiple myeloma that is refractory to conventional chemotherapy, as well as
      against multiple myeloma that is sensitive to chemotherapy, and it can be safely
      performed.

PMID- 12610875
TI  - [Effective transarterial neoadjuvant chemotherapy with paclitaxel (TXL) in a case
      of locally advanced breast cancer].
AB  - The patient was a 49-year-old woman who had locally advanced breast cancer with
      skin invasion. She was placed on neoadjuvant weekly systemic chemotherapy of TXL
      (65 mg/m2) and ADM (20 mg/m2). After systemic chemotherapy, she underwent 2
      courses of transarterial neoadjuvant chemotherapy of TXL (day 1, 8, 15). We
      administered TXL (45 mg/m2) into the subclavian artery and TXL (20 mg/m2) into
      the internal thoracic artery. Although she experienced grade 3 leukopenia during
      systemic chemotherapy, she experienced only grade 2 alopecia and grade 1 nausea
      during transarterial chemotherapy. After chemotherapy, she underwent radical
      mastectomy. We report herein a case in which transarterial neoadjuvant
      chemotherapy with TXL was effective.

PMID- 12610876
TI  - [A case of advanced recurrent breast cancer responding to treatment with weekly
      docetaxel combined with doxorubicin].
AB  - The patient was a 60-year-old women who had undergone left modified radical
      mastectomy on April 7, 1999, and was treated with chemo- and hormonal therapy of
      UFT and TAM. Two years and 6 months later, she showed multiple lung metastases.
      Because 5'-DFUR + MPA therapy was not effective, weekly docetaxel (TXT) +
      adriamycin (ADM) was carried out, and definite improvement in the lung and lymph
      nodes metastases was observed. It is suggested that this combination therapy may
      be useful for advanced recurrent breast cancer patients with multiple lung
      metastases.

PMID- 12610877
TI  - [Complete remission of esophageal undifferentiated carcinoma with nedaplatin and
      5-FU chemotherapy and endoesophageal brachytherapy].
AB  - The patient was a 74-year-old female. Type 1 undifferentiated carcinoma (non
      small cell type) was detected in the middle of the thoracic esophagus in August
      1999. Although the lesion was diagnosed as T2, N0, and Stage II, the patient was
      judged to be a poor risk, inoperable case because of a complex past history of
      renal and respiratory dysfunctions, and dysbasia. Intravenous administration of
      nedaplatin at 15.8 mg/m2 and 5-FU 590.6 mg/m2 were carried out for 5 consecutive
      days as chemotherapy. The second cycle of chemotherapy was performed with
      nedaplatin reduced to 11.8 mg/m2 on the basis of the adverse reactions observed
      after the first cycle, and PR was attained. As for radiotherapy, additional
      extracorporeal irradiation was judged to be too dangerous from her history, so
      endoesophageal brachytherapy alone was added, and CR was obtained. The patient
      has maintained a CR for more than 2 years after discharge. In this poor risk case
      with a highly malignant undifferentiated carcinoma, an "individualization
      strategy" was effective.

PMID- 12610878
TI  - [A patient with stage IVb small cell carcinoma of the esophagus who survived 23
      months after systemic cancer chemotherapy].
AB  - A 59-year-old male visited our hospital with complaints of difficulty in
      swallowing. X-ray barium studies and upper gastrointestinal endoscopic
      examination revealed an irregular ulcerated lesion in the lower portion of the
      esophagus, which was diagnosed based on pathology tests as small cell carcinoma.
      A computed tomography scan showed para-aortic lymph node swelling and multiple
      liver metastases. Treatment with chemotherapy of CDDP and 5-FU showed clinical
      complete remission. However, the patient died of paraaortic lymph node
      metastasis, recurrence of the original lesion, multiple liver metastasis and
      brain metastasis 23 months after diagnosis. The prognosis of small cell carcinoma
      of the esophagus is quite unfavorable because of the highly aggressive biological
      behavior. However, if remission is achieved by chemotherapy as in this case, a
      better prognosis is possible.

PMID- 12610879
TI  - [A case of type 4 gastric cancer, diagnosed after operation for Krukenberg's
      tumor, treated by TS-1 plus low-dose cisplatinum].
AB  - Survival of patients with advanced gastric cancer with Krukenberg's tumor is
      poor. We report the case of a good response in a 37-year-old woman who had type 4
      gastric cancer, diagnosed after the operation of Krukenberg's tumor, and then was
      treated with TS-1, a DPD inhibitory fluoropyrimidine, in combination with a low
      dose cisplatinum (CDDP). Endoscopic gastric biopsy showed signet-ring cell
      adenocarcinoma and moderately differentiated tubular adenocarcinoma, and computed
      tomography (CT) showed the para-aortic lymph node metastasis before the
      chemotherapy. The patient was treated with two courses of TS-1 (100 mg/day, day 1
      21) plus CDDP (10 mg/m2, day 1-5, 8-12, 15-19) with two-week interval. After the
      first course, gastric biopsy did not show any cancer cells and lymph node
      metastasis had disappeared. Serum CA19-9 decreased gradually week by week during
      the chemotherapy, even during the washout period after the first course, and was
      normalized after two courses. This case suggests that the combination of TS-1 and
      low-dose CDDP is effective against type 4 advanced gastric cancer.

PMID- 12610881
TI  - [A case of advanced colon cancer responding to treatment with levofolinate
      combined with 5-fluorouracil].
AB  - The patient was a 70-year-old man who had sigmoid colon cancer with multiple lung
      and paraaortic lymph node metastases. Sigmoidectomy was performed on August 3,
      2001. After the operation, combined l-Leucovorin (LV) + 5-fluorouracil (5-FU) was
      carried out. As a result, lung and lymph node metastases were reduced markedly
      and CEA level decreased. It is suggested that this combination therapy may be
      useful for advanced colon cancer patients.

PMID- 12610880
TI  - [A case report--TS-1/CDDP combined chemotherapy found effective for metastatic
      recurrence after operation for colon cancer].
AB  - A 68-year-old male with a history of gastric resection for gastric cancer
      underwent resection of the sigmoid colon for a sigmoid colon cancer in February,
      2000. The cancer was classified as stage III b. After operation, l-LV + 5-FU
      therapy was administered, but metastases to the abdominal wall, right inguinal
      lymph node and spleen developed in succession, and resection was repeated. In
      October 2001, 1 year and 8 months after sigmoidectomy, however, multiple
      metastasis to the intraperitoneal lymph node had developed. As surgery was not
      indicated, TS-1/CDDP combined chemotherapy was started. TS-1 80 mg/day was
      administered for 4 weeks, the drug was withdrawn for 2 weeks and CDDP 80 mg was
      injected by intravenous drip at the 8th day of TS-1 administration, which was
      used as one course. From the second course after inception of the administration,
      CA19-9 decreased, and after the third course the upper intraperitoneal metastatic
      lesion disappeared on CT. CR has been continued for 4 months up to the present.
      Our results suggest a possibility that this therapy is effective not only for
      gastric cancer but also for colon cancer. This therapy can be administered at
      home. It is considered to be a useful therapy from the viewpoint of QOL as well.
      The high DPD activity of the tumor may have been one reason this treatment was
      effective. This case also seems significant from the viewpoint of attaining
      individualization of the drug selection in chemotherapy.

PMID- 12610882
TI  - [A case of advanced pancreatic cancer with multiple liver metastasis that
      improved remarkably with use of low-dose cisplatin and TS-1].
AB  - The prognosis and QOL of unresectable pancreatic cancer are very poor. A
      symptomless 60-year-old male was admitted for examination of a high serum CA19-9
      level. Following ultrasound and abdominal CT, we diagnosed unresectable advanced
      pancreatic cancer with multiple liver metastasis. After we obtained his informed
      consent, we administered continuous infusion of 5-FU and low-dose cisplatin
      (CDDP) infusion (low-dose FP therapy) for 3 weeks. He then underwent combination
      chemotherapy with low-dose CDDP and TS-1 on an outpatient basis. During the
      chemotherapy, he did not experience any major adverse event and his QOL was
      relatively good. On follow-up CT 3 months later, the primary tumor in the
      pancreas was found to be stable. However, the size and number of liver tumors
      were remarkably reduced. The serum CA19-9 level had also remarkably decreased
      from 48,300 U/ml to 1,480 U/ml. In conclusion, the combination chemotherapy using
      low-dose CDDP and TS-1 can be effective in cases of unresectable pancreatic
      cancer with multiple liver metastasis.

PMID- 12610884
TI  - [Single nucleotide polymorphism and novel drug discovery].
AB  - The finding of genetic polymorphisms and clarification of the influences of their
      functions will be a possible way to obtain the therapeutic target moleculars for
      diseases. In clinical trial of new drug, which is targeted the therapeutic
      molecular, the gene examination will be needed to classify possible responder and
      unresponder patients. On the other hand, it is important to make effort on the
      elimination of candidate drugs, their pharmacokientic and metabolism, clinical
      efficacy and toxicity will be markedly influenced by genetic polymorphism.

PMID- 12610883
TI  - [A case of liver metastasis of pancreatic duct carcinoma successfully treated
      with gemcitabine].
AB  - We report a patient in whom systemic chemotherapy using gemcitabine was effective
      against liver metastases of pancreatic cancer. A 72-year-old woman underwent
      pancreatoduodenectomy with lymphadenectomy and partial resection of the portal
      vein following a diagnosis of pancreatic cancer, and her postoperative course was
      uneventful. The diagnosis was stage III anaplastic ductal carcinoma (t2n1P0H0M0).
      One year and 3 months after the operation, however, her serum level of
      carbohydrate antigen 19-9 (CA19-9) was found to be elevated, and CT examination
      revealed a mass in the liver that was diagnosed as liver that was metastases.
      Systemic chemotherapy was performed with a regimen of gemcitabine 600 mg/m2/week
      for 3 weeks, followed by a week rest, for the first three courses. On and after
      fourth course, gemcitabine 1,000 mg/m2/week was administered. The serum CA19-9
      level was down from 882 U/ml to normal after 5 courses of chemotherapy and CT
      examination revealed that liver metastases had completely vanished. Although no
      evidence of deterioration was observed, the patient died of infectious pneumonia
      10 months after recurrence. The prognosis of liver metastases of pancreatic
      cancer is quite unfavorable. However, if remission is achieved with gemcitabine,
      the patient has the possibility to obtain a better outcome.

PMID- 12610885
TI  - [Cladribine].
AB  - Cladribine (2-chlorodeoxyadenosine: 2-CdA) is a chlorinated purine analogue that
      is resistant to degradation by adenosine deaminase. Phosphorylated derivatives of
      2-CdA accumulate in lymphocytes with high deoxycytidine kinase activity,
      resulting in DNA strand breaks and cell death. Since the cytotoxic properties of
      2-CdA are independent of cell division, 2-CdA is expected to be an effective
      agent in the treatment of indolent lymphoid malignancy with low-growth fraction.
      The agent was synthesized and has been investigated extensively by researchers at
      the Scripps Clinic and Research Foundation in the United States. The FDA approved
      cladribine for use against hairy cell leukemia, in 1993, and it was approved
      against hairy cell leukemia and indolent B-cell lymphoma in Japan in 2002 as
      Leustatin (Janssen Pharma Co. Ltd., Tokyo, Japan). The efficacy, toxicity and
      clinical usefulness of this agent against indolent lymphoid malignancies will be
      described according to the data from several clinical trials conducted in the
      United States, European countries and Japan.

PMID- 12610886
TI  - Characteristics of systemic and topical agents implicated in toxicity of the
      middle and inner ear.

PMID- 12610887
TI  - Topical aminoglycosides? No. The case against using these agents in chronic ear
      disease.

PMID- 12610888
TI  - Topical aminoglycosides? Yes. The case for using these agents in chronic ear
      disease.

PMID- 12610889
TI  - Other topical agents are safer and just as effective.

PMID- 12610890
TI  - Benefits of aminoglycoside drops still outweigh the risks.

PMID- 12610891
TI  - Medicare: all or nothing.

PMID- 12610892
TI  - Long-term ventilating tube with tympanosclerosis.

PMID- 12610893
TI  - Maxillary sinus mucocele.

PMID- 12610894
TI  - The effects of yelling in loud, smoky bars.

PMID- 12610896
TI  - Ameloblastoma.

PMID- 12610895
TI  - ENG in a woman with Meniere's syndrome who had a previous endolymphatic sac
      decompression.

PMID- 12610897
TI  - Parotid gland lymphoepithelial cysts in HIV infection.

PMID- 12610898
TI  - Cervical esophageal foreign body.

PMID- 12610899
TI  - Reducing billing errors at the point of service.

PMID- 12610900
TI  - Direct application of dexamethasone for the treatment of chronic eustachian tube
      dysfunction.
AB  - We undertook a prospective study to determine the safety and effectiveness of the
      direct administration of a steroid to the eustachian tube via the Silverstein
      MicroWick in 11 patients with chronic eustachian tube dysfunction, including two
      who had Samter's triad. All patients had previously been treated with medical
      therapy and surgical middle ear ventilation without resolution. The MicroWick was
      placed directly in the eustachian tube orifice through a pressure-equalization
      tube. Patients received 3 drops of dexamethasone 4 mg/ml three times a day. The
      drops were discontinued after 4 weeks, and the MicroWick and ventilation tube
      were removed after 3 months. At study's end, eight patients (72.7%) reported
      subjective improvement in terms of a reduction in aural pressure and fullness.
      Audiometric testing demonstrated a 55% reduction in the mean air-bone gap and a
      3% increase in the mean speech discrimination score. Bone pure-tone averages
      remained stable. Tympanometry showed that five patients (45.5%) converted from
      type B or C tympanograms to type A. Four patients (36.4%) had persistent
      perforations. Both patients with Samter's triad improved with therapy. These
      preliminary results suggest that direct dexamethasone administration to the
      eustachian tube is safe and effective for the treatment of chronic eustachian
      tube dysfunction. Long-term studies to confirm these findings are under way.

PMID- 12610901
TI  - Is same-day discharge suitable following rigid esophagoscopy? Findings in a
      series of 655 cases.
AB  - It has been suggested that more otolaryngologic procedures should be performed on
      an outpatient basis, and that rigid upper aerodigestive tract endoscopy might be
      a particularly suitable procedure in this regard. To determine if this is indeed
      the case, we retrospectively reviewed the records of 563 patients who had
      undergone 655 rigid esophagoscopies in our unit between Jan 1, 1991, and July 31,
      1998. We ascertained the rate of complications (primarily esophageal perforation)
      following such procedures and, when they did occur, we determined the length of
      time between surgery and the onset of the complications' signs and symptoms. Our
      aims were to establish the minimum duration of postoperative observation that is
      required following esophagoscopy and to propose criteria for safe same-day
      discharge. We found that perforation rates were 4.5% following therapeutic
      procedures (dilation, biopsy, and foreign-body removal) and 1.2% following
      diagnostic procedures. In 40% of the patients who experienced perforations, no
      such signs or symptoms were noted within the first 8 hours following surgery.
      This finding has important implications for surgeons who wish to perform rigid
      esophagoscopy on an outpatient basis.

PMID- 12610902
TI  - A rare case of a sebaceous nevus in the external auditory canal.
AB  - We report the case of a patient who came to us for evaluation of a progressive
      unilateral hearing loss and who was found to have a sebaceous nevus in an unusual
      location: the external auditory canal. A sebaceous nevus is a congenital organoid
      mass that occurs primarily on the face, scalp, and periauricular regions. Despite
      the predilection of sebaceous nevi for the head and neck, reports of this lesion
      rarely appear in the otolaryngology literature. Left untreated, the lesion can
      progress through three stages of gross and histopathologic development; a
      sebaceous nevus begins as a small benign papule, grows into an enlarging mass
      with different characteristics, and ultimately becomes a secondary neoplasm. The
      lesion's potential for malignant transformation and its association with
      syndromes underscores the importance of prompt recognition and appropriate
      management. This case report adds the sebaceous nevus to the differential
      diagnosis of external auditory canal lesions and provides essential information
      about this rare mass.

PMID- 12610903
TI  - Visual-field loss caused by sinusitis: a case report.
AB  - The author reports a case of visual-field loss that was not characterized by any
      direct compression or external signs of sinus disease. The patient's hemianopia
      was found to be associated with severe sinusitis, which had not been clinically
      apparent and which had not extended beyond the bony walls of the sinuses.
      Following surgical drainage of the affected sinuses, the hemianopia resolved
      immediately and completely.

PMID- 12610904
TI  - Hysterical stridor: a report of two cases.
AB  - Stridor as an initial symptom of a conversion reaction (hysteria) is rare. We
      report cases of hysterical stridor in two older women, unrelated and
      unacquainted, from the same rural community in Oman. Once the diagnosis was made,
      both patients were successfully treated with a single dose of an anxiolytic. We
      also review the literature on hysterical stridor and discuss the diagnostic
      dilemmas and therapeutic options.

PMID- 12610906
TI  - Adult supraglottitis subsequent to smoking crack cocaine.
AB  - Supraglottitis is one possible complication of smoking crack cocaine. From 1992
      through 2001, our institution treated nine patients for thermal supraglottitis
      secondary to crack cocaine inhalation. In this article, we describe two of these
      cases, and we briefly review what is known about this entity and the mechanism of
      injury. We also provide our recommendations for management.

PMID- 12610905
TI  - Giant frontoethmoid mucocele with intracranial extension: case report.
AB  - We report the case of a 31-year-old woman who came to us with a giant
      frontoethmoid mass that had extended into the intracranial region and invaded the
      left orbit. We removed the lesion in its entirety via a combined intranasal and
      transcranial approach. We discuss the advantages and disadvantages of different
      surgical approaches, and we explain why we recommend a combined approach for the
      type of giant lesion that we encountered.

PMID- 12610907
TI  - Avoiding perils and pitfalls in velocardiofacial syndrome: an otolaryngologist's
      perspective.
AB  - Velocardiofacial syndrome is classically characterized by clefting of the
      secondary palate, cardiac defects, learning disabilities, and facial dysmorphism.
      Knowledge of this syndrome is of significant importance to otolaryngologists
      because a failure to recognize it prior to head and neck surgery can result in
      serious iatrogenic injury, including velopalatal insufficiency and damage to
      anomalous carotid arteries. To illustrate these issues, we describe the case of a
      5-year-old boy with velocardiofacial syndrome. We also review the literature on
      velocardiofacial syndrome, which is not very extensive, perhaps because it is
      often difficult to recognize.

PMID- 12610908
TI  - Iatrogenic maxillary sinus recirculation and beyond.
AB  - Recirculation of nasal mucus occurs when secretions that have been transported
      out of the natural maxillary ostium return to the sinus via a surgically created
      or accessory ostium. Recirculation increases the risk of persistent sinus
      infection. In this article, we describe a case of mucus recirculation in a
      patient who had not responded to two previous sinus surgeries for recurrent
      rhinosinusitis. We also postulate the possibility of ethmoid recirculation.

PMID- 12610911
TI  - [Mother and Newborn, Present and Future. Proceedings and abstracts of the 1st
      International Meeting. Milan, Italy, 11-13 December 2002].

PMID- 12610909
TI  - Plasma cell granuloma of the thyroid with Hashimoto's thyroiditis: report of a
      rare case.
AB  - As only eight cases have been previously reported in the literature, plasma cell
      granuloma of the thyroid gland is a rare entity. This condition can be confused
      with a benign or malignant neoplastic thyroid process. In this article, we
      describe a new case of plasma cell granuloma of the thyroid gland that occurred
      in a 46-year-old man who also had Hashimoto's thyroiditis. This case represents
      only the second documented instance of a plasma cell granuloma of the thyroid
      occurring in the setting of Hashimoto's thyroiditis. Moreover, it is only the
      second case of a plasma cell granuloma that has been reported in a male.

PMID- 12610912
TI  - [Near infrared spectroscopy: what applications?].

PMID- 12610914
TI  - [Chorioamnionitis and preterm labor].

PMID- 12610913
TI  - [Timing and method of delivery in premature labor].

PMID- 12610915
TI  - [Chorioamnionitis and brain damage].

PMID- 12610918
TI  - The role of ultrasound.

PMID- 12610916
TI  - [Perinatal steroids between evidence based medicine and clinical reality].

PMID- 12610919
TI  - [Traditional nuclear magnetic resonance].

PMID- 12610921
TI  - [Can ultrasonography predict prognosis?].

PMID- 12610922
TI  - [Early assessment of mobility and posture as prognosis indicators].

PMID- 12610923
TI  - [Follow up and rehabilitation].

PMID- 12610924
TI  - [Nutrition after discharge in VLBW babies: effects on growth].

PMID- 12610925
TI  - The newborn baby with intrauterine growth retardation (IUGR): medical treatment
      and choice of the follow-up.

PMID- 12610926
TI  - Intrapartum surveillance and diagnosis of asphyxia.

PMID- 12610927
TI  - [What is new in neonatal resuscitation and in the use of oxygen].

PMID- 12610930
TI  - [Hypothermia: clinical application].

PMID- 12610931
TI  - [Role of EEG].

PMID- 12610932
TI  - The role of evoked potentials.

PMID- 12610933
TI  - The role of imaging.

PMID- 12610935
TI  - [Who should be treated with resuscitation, when it should be used and when it
      should be ceased: the point of view of the neonatologist].

PMID- 12610936
TI  - [The point of view of the obstetrician].

PMID- 12610937
TI  - [Evidence based medicine and neonatal care].

PMID- 12610938
TI  - [How to train nurses in "care"].

PMID- 12610940
TI  - [Support for the newborn and his/her family: how to do it].

PMID- 12610939
TI  - The experience in a Canadian NICU (Montreal).

PMID- 12610942
TI  - Twenty-five years of conducting polymers.

PMID- 12610943
TI  - Quadruple hydrogen bonded systems.
AB  - In this feature article, the development of linear quadruple hydrogen bonded
      systems is discussed, emphasizing applications in supramolecular chemistry and
      self-assembly.

PMID- 12610944
TI  - Novel, stereoselective tricyclization of a dienyne by titanium aryloxide centers.
AB  - Titanium centers supported by aryloxide ligation mediate the tricyclization of a
      dienyne via intramolecular insertion of an olefin into the titanium-vinyl bond of
      a titanacyclopent-2-ene.

PMID- 12610945
TI  - Nonlinear amplification of circular dichroism activity upon cyclodimerization of
      a chiral saddle-shaped porphyrin.
AB  - A cyclic dimer of chiral saddle-shaped porphyrin with p-xylylene linkers, upon
      interaction with mandelic acid, showed an enhanced circular dichroism activity,
      which was more than 7 times as large as that of a monomeric reference.

PMID- 12610946
TI  - Computational evidence that the inverse kinetic isotope effect for reductive
      elimination of methane from a tungstenocene methyl-hydride complex is associated
      with the inverse equilibrium isotope effect for formation of a sigma-complex
      intermediate.
AB  - Calculations on [H2Si(C5H4)2]W(Me)H demonstrate that the interconversion between
      [H2Si(C5H4)2]W(Me)H and the sigma-complex [H2Si(C5H4)2]W(sigma-HMe) is
      characterized by normal kinetic isotope effects for both reductive coupling and
      oxidative cleavage; the equilibrium isotope effect, however, is inverse and is
      the origin of the inverse kinetic isotope effect for the overall reductive
      elimination of methane.

PMID- 12610948
TI  - Synthesis of a nonionic water soluble semiconductive polymer.
AB  - A new nonionic water-soluble fluorescent conjugated polymer is reported with
      hydroxyl and amide side chains surrounding an aromatic polymer backbone.

PMID- 12610947
TI  - A new entry to N-heterocyclic carbene chemistry: synthesis and characterisation
      of a triscarbene complex of thallium(I).
AB  - The synthesis and characterisation of a thallium(I) triscarbene complex of the
      chelating, tripodal carbene ligand 1,3,5-[tris(3-tert-butylimidazol-2
      ylideno)methyl]-2,4,6-trimethylbenzene is reported, in which the thallium ion is
      coordinated by three N-heterocyclic carbene donors in a distorted trigonal planar
      environment.

PMID- 12610949
TI  - 1,3-dimethylimidazolium-2-carboxylate: the unexpected synthesis of an ionic
      liquid precursor and carbene-CO2 adduct.
AB  - 1,3-Dimethylimidazolium-2-carboxylate is formed in good yield, rather than the
      anticipated organic salt, 1,3-dimethylimidazolium methyl carbonate, as the
      reaction product resulting from both N-alkylation and C-carboxylation of 1
      methylimidazole with dimethyl carbonate; the crystal structure of the zwitterion
      exhibits pi-stacked rings and two-dimensional sheets constructed by hydrogen
      bonds from imidazolium-ring hydrogens to the carboxylate group.

PMID- 12610950
TI  - Ni(II) complexes containing chiral tridentate phosphines as new catalysts for the
      hydroamination of activated olefins.
AB  - Ni(II) complexes containing chiral tridentate ferrocenyl phosphines(Ni(PPP)) have
      been found to efficiently catalyse the hydroamination of activated olefins with
      both anilines and aliphatic amines at r.t. (TON up to 71, TOF up to ca. 3 h-1,
      and enantioselectivities up to 69% ee).

PMID- 12610951
TI  - Studies on the performance stability of mixed conducting BSCFO membranes in
      medium temperature oxygen permeation.
AB  - A permeation study using bare Ba0.5Sr0.5Co0.8Fe0.2Ox membranes shows that stable
      oxygen fluxes are only achieved when operating the membrane at temperatures
      higher than 1023 K and indicates therefore that short contact time membrane
      reactors will be most suitable for future upgrading of light hydrocarbons.

PMID- 12610952
TI  - The elusive aldol reaction of enolates with aldolates--a highly stereoselective
      process using three different carbonyl components.
AB  - Three different carbonyl components are assembled to tetrahydropyran-2,4-diols by
      two successive diastereoselective aldol reactions.

PMID- 12610953
TI  - Site-specific cleavage of human telomerase RNA using PNA-neocuproine.Zn(II)
      derivatives.
AB  - Here we report the synthesis of a novel PNA based neocuproine.Zn RNA cleaving
      agent; we demonstrate that such agents sequence specifically cleave a synthetic
      RNA target and in particular the RNA component of human telomerase.

PMID- 12610954
TI  - Dendrimers as scaffolds for the synthesis of spherical porphyrin arrays.
AB  - This communication describes a self assembled porphyrin sphere. The globular
      macromolecular assembly contains 12 terminal porphyrins and has a molecular mass
      in excess of 15,000 g mol-1.

PMID- 12610955
TI  - A novel preparation of nano-Cu/ZnO by photo-reduction of Cu(OCH(Me)CH2NMe2)2 on
      ZnO at room temperature.
AB  - Room-temperature preparation of nano-Cu on ZnO by UV light induced photo
      reduction of Cu(OCH(Me)CH2NMe2)2 precursor was achieved, indicating a novel
      method of nano-Cu/ZnO synthesis from an organometallic copper precursor in non
      aqueous media without further chemical reduction.

PMID- 12610956
TI  - Mechanism of direct oxidation of cyclohexene to cyclohexanone with nitrous oxide.
      Theoretical analysis by DFT method.
AB  - New very effective results on the liquid-phase oxidation of cyclohexene to
      cyclohexanone by nitrous oxide are analyzed using the B3LYP/6-31G* approximation
      to predict a two-step reaction mechanism correlated with the experimental data.

PMID- 12610957
TI  - Improvement of the hydrothermal stability of SAPO-34.
AB  - Hydrothermal stability of SAPO-34 is greatly improved by the treatment of the
      acidic form of the SAPO-34 with NH3.

PMID- 12610958
TI  - Unprecedented stabilisation of the Ag2(2+)-ion by two hydrido-iridium(III)
      complexes.
AB  - The complex [[(eta 5-C5Me5)(Ph3P)Ir(mu-H)2]2Ag2(OSO2CF3)2], containing the
      Ag2(2+)-ion, has been synthesized; crystallographic and spectroscopic data are
      described.

PMID- 12610959
TI  - Lactide polymerization by well-defined calcium coordination complexes:
      comparisons with related magnesium and zinc chemistry.
AB  - Amide and alkoxide coordination complexes of calcium supported by beta-diiminato
      and bulky trispyrazolylborate complexes are reported together with their activity
      in lactide ring-opening polymerization; some are amongst the most active systems
      discovered to date.

PMID- 12610960
TI  - Meso-tetrakis[o-(N-methyl)pyridinium]porphyrin ensembles with axially coordinated
      cyclodextrin-penetrating phenethylimidazole: reversible dioxygen-binding in
      aqueous DMF solution.
AB  - alpha-Cyclodextrin (alpha CD)-penetrating 2-methyl-1-phenethylimidazole
      coordinates to the zinc(II) and iron(II) complexes of meso-tetrakis[o-(N
      methyl)pyridinium] porphyrinate, giving non-covalently linked alpha CD-porphyrin
      ensembles; the iron(II) complex can reversibly bind and release dioxygen in
      aqueous DMF solution.

PMID- 12610961
TI  - The use of 4-substituted pyridines to afford amphiphilic, pegylated cadmium
      selenide nanoparticles.
AB  - Amphiphilic cadmium selenide (CdSe) nanoparticles were prepared by surface
      functionalization with novel ligands 1 and 2, composed of pyridine moieties
      substituted in the 4-position with polyethylene glycol (PEG) chains.

PMID- 12610962
TI  - B(C6F5)3-catalyzed formation of B-P bonds by dehydrocoupling of phosphine
      boranes.
AB  - Tris(pentafluorophenyl)borane was used as a new catalyst in the formation of P-B
      bonds by dehydrocoupling of phosphine-boranes.

PMID- 12610964
TI  - Novel addition reactions of titanacycle phosphonates by tuning of Ti(O-i-Pr)4/2i
      PrMgCl.
AB  - Di- or tri-substituted vinylphosphonates, 2-5, can be obtained in a highly regio-
      and stereoselective manner from 1-alkynylphosphonates, by manipulation of Ti(O-i
      Pr)4/2i-PrMgCl.

PMID- 12610963
TI  - A new strategy for folding oligo(m-phenylene ethynylenes).
AB  - Backbone-rigidified oligo(m-phenylene ethynylenes) fold into crescent or helical
      conformations in non-polar organic solvents.

PMID- 12610965
TI  - Crystal engineering toward intersecting channels in a interpenetrated diamondoid
      network based on a net-to-net H-bonding interaction.
AB  - A thermally stable, four-fold interpenetrating diamondoid coordination network,
      Cd(imidazole-4-acrylate)2, with open intersecting channels within the interwoven
      nets, is strategically designed and synthesized on the basis of a spring-like net
      to-net hydrogen-bonding interaction.

PMID- 12610966
TI  - 1,4-dibutoxy-2,3-di(4-pyridyl)-8,11,15,18,22,25-hexakis(hexyl)- phthalocyaninato
      zinc, a self-assembled coordination polymer in the solid state.
AB  - The title compound forms intermolecular zinc-nitrogen coordinated species in
      solution and self-assembles to form a coordination polymer in the solid state,
      the X-ray structure for which shows that the unit cell contains eight macrocycle
      units in two chains comprising both enantiomeric forms as ABBA/BAAB sequences.

PMID- 12610967
TI  - A ditopic ferrocene receptor for anions and cations that functions as a
      chromogenic molecular switch.
AB  - A ferrocene-based ditopic receptor containing a urea and a benzocrown ether unit
      shows a remarkable colour switching (ON-and-OFF) function induced by anion and
      cation recognition.

PMID- 12610968
TI  - Chirality of photopolymerized organized supramolecular polydiacetylene films.
AB  - Photopolymerized organized molecular films of polydiacetylene showed chirality
      although the monomeric amphiphilic diacetylene was achiral.

PMID- 12610969
TI  - First example of a taxane-derived propellane in Taxus canadensis needles.
AB  - The first example of a propellane isolated from the needles of a yew is reported;
      the biogenesis from a putative taxane precursor is proposed.

PMID- 12610970
TI  - Novel solvent properties of choline chloride/urea mixtures.
AB  - Eutectic mixtures of urea and a range of quaternary ammonium salts are liquid at
      ambient temperatures and have interesting solvent properties.

PMID- 12610971
TI  - Novel gas-phase ion-molecule aromatic nucleophilic substitution in beta
      carbolines.
AB  - We report a novel gas-phase ion-molecule aromatic-nucleophilic substitution
      reaction between beta-carbolines and water vapour, that accounts for the
      observation of ions with higher masses than the precursor ion in the MS/MS
      spectra.

PMID- 12610972
TI  - Tris(2,4,6-trichloro-3,5-dinitrophenyl)methyl radical: a new stable coloured
      magnetic species as a chemosensor for natural polyphenols.
AB  - We report the synthesis, electron paramagnetic resonance and electrochemical
      properties of a novel stable radical of the TTM series. Its strong electron
      acceptor ability has been tested with (-)-epicatechin, a natural polyphenolic
      antioxidant.

PMID- 12610973
TI  - Alkoxy/siloxy group exchange in the system vinyltrialkoxysilane-iridium(I)
      siloxide complex.
AB  - A study of reactions of dimeric siloxide iridium complex, [[(cod)Ir(mu-OSiMe3)]2]
      (1) with vinyltriethoxysilane and vinyltrimethoxysilane has revealed a new type
      of the reation--alkoxy group transfer from silicon to iridium with a simultaneous
      transfer of a siloxy group from iridium to silicon--as a result of which
      vinyldialkoxytrimethyldisiloxane and dimeric alkoxide iridium complex
      [[(cod)Ir(mu-OR)]2] (3) are formed. The structure of [[(cod)Ir(mu-OEt)]2] (3a)
      has been solved by X-ray diffraction.

PMID- 12610974
TI  - eta 6-Arene complexes of Ni(II), efficient catalysts for 1,3-butadiene and
      styrene polymerization.
AB  - A simple procedure for the preparation of cationic arene complexes of Ni(II) of
      composition [Ni(eta 6-ArX)(eta 3-C3H5)]+[BAr'4]- (X = OH, H) is reported. These
      compounds are shown to behave as highly active catalysts for the polymerization
      of 1,3-butadiene and styrene.

PMID- 12610975
TI  - Efficient degradation of organic pollutants mediated by immobilized iron
      tetrasulfophthalocyanine under visible light irradiation.
AB  - Supported iron tetrasulfophthalocyanine can efficiently catalyze the degradation
      of organic pollutants by H2O2 under visible light irradiation in an aqueous
      solution, and the catalyst can be easily recycled without apparent loss of
      activity.

PMID- 12610976
TI  - Infrared response of multiwalled boron nitride nanotubes.
AB  - We report the infrared (IR) response of bulk samples of multiwalled boron nitride
      nanotubes, produced by a substitution reaction from single walled carbon
      nanotubes, which is dominated by two characteristic BN-vibrations at 800 and 1372
      cm-1.

PMID- 12610977
TI  - Scintillation-based potassium signalling using 2,5-diphenyloxazole-tagged aza-18
      crown-6.
AB  - In the presence of ionising radiation, an aza-18-crown-6 molecule covalently
      attached to a 2,5-diphenyloxazole (PPO) moiety scintillates weakly, addition of
      potassium ions results in enhanced levels of scintillation, the degree of
      scintillation reflecting the concentration of the potassium ions.

PMID- 12610978
TI  - Highly stable performance of catalytic methane dehydrocondensation towards
      benzene on Mo/HZSM-5 by a periodic switching treatment with H2 and CO2.
AB  - Excellent stability and high catalytic activity of methane dehydrocondensation
      towards benzene and naphthalene on Mo/HZSM-5 were achieved at 1023-1073 K by a
      periodic H2 or CO2 switching operation, owing to the efficient removal of coke
      deposition.

PMID- 12610979
TI  - Enantioselective molecularly imprinted polymers via ring-opening metathesis
      polymerisation.
AB  - Enantioselective molecularly imprinted polymers (MIPs) have been synthesised via
      ROMP for the first time.

PMID- 12610980
TI  - The unique nucleophilic reactivity of arylaminochlorocarbenes.
AB  - 4-Methyl and 4-methoxyphenylaminochlorocarbene (readily formed by deprotonation
      of the Vilsmeier reagent derived from the corresponding N-methylformanilide with
      Hunig's base) reacted with diethyl acetylenedicarboxylate to give 1:2 quinoline
      adducts, while p-halophenylaminochlorocarbenes yielded benzoazepine derivatives
      from 2:1 interaction of the carbene with oxalyl chloride under the same reaction
      conditions.

PMID- 12610982
TI  - Water-soluble stilbene dendrimers.
AB  - The third generation of novel photo-responsive water-soluble stilbene dendrimer
      (trans- and cis-G3 WSD) undergoes unusual one-way trans-to-cis isomerization to
      give 100% of cis isomer at the photostationary state on UV irradiation in water.

PMID- 12610981
TI  - Transparent thin films and monoliths synthesized from fullerene doped mesoporous
      silica: evidence for embedded monodispersed C60.
AB  - Thin films and monoliths of mesostructured silica containing embedded
      monodispersed molecules of C60 may be prepared via a sol-gel route in which the
      C60 is added during the synthesis or via post-synthesis adsorption; evidence from
      diffuse reflectance spectroscopy suggests that the embedded C60 exist
      predominantly in monomeric form.

PMID- 12610983
TI  - A chiral metallacyclophane for asymmetric catalysis.
AB  - Chiral metallacyclophanes were self-assembled from cis-(PEt3)2PtCl2 and
      enantiopure atropisomeric 1,1'-bina-phthyl-6,6'-bis(acetylenes) and used in
      highly enantioselective catalytic diethylzinc additions to aldehydes to afford
      chiral secondary alcohols.

PMID- 12610984
TI  - Preparation of three-dimensional chromium oxide porous single crystals templated
      by SBA-15.
AB  - Three-dimensional porous chromium oxide single crystals have been prepared by
      aminosilylation of the surface silanols of the template, SBA-15, anchoring of
      dichromic acid to the grafted amine groups, thermal decomposition of inorganic
      and organic compounds, and removal of the silica framework with HF.

PMID- 12610986
TI  - The radical anions and the electron affinities of perfluorinated benzene,
      naphthalene and anthracene.
AB  - Although benzene and naphthalene do not have electron affinities in the
      conventional sense, perfluorobenzene and perfluoronaphthalene have nonzero
      electron affinities. Theoretical methods extensively calibrated with experiment
      for the prediction of electron affinities (EAs) predict the EAs of
      perfluorobenzene, perfluoronaphthalene and perfluoroanthracene as 0.69, 1.02 and
      1.84 eV, respectively. A rough estimate of 2.39 eV is made for the electron
      affinity of perfluorotetracene. Thus the perfluoro polycyclic aromatic
      hydrocarbons (PAHs) are predicted to be effective electron acceptors.

PMID- 12610985
TI  - Synthesis of 6'-sulfodisaccharides by beta-N-acetylhexosaminidase-catalyzed
      transglycosylation.
AB  - Presulfated N-acetylglucosaminyl donor (pNP beta-D-6-SO3-GlcNAc) was applied for
      the synthesis of sulfosugars using the beta-N-acetylhexosaminidase-catalyzed
      transglycosylation, to afford the critically stereocontrolled sulfodisaccharides
      carrying the 6-sulfo GlcNAc residue at the non-reducing sides in one step.

PMID- 12610987
TI  - Capture and detection of a quencher labeled oligonucleotide by poly(phenylene
      ethynylene) particles.
AB  - Fluorescence quenching of poly(phenylene ethynylene) (PPE) particles by a Cy-5
      labeled oligonucleotide is 2 orders of magnitude more sensitive than direct
      excitation of the Cy-5 fluorophore.

PMID- 12610989
TI  - Haptenylated mercaptodextran-coated gold nanoparticles for biomolecular assays.
AB  - Gold nanoparticles coated with haptenylated mercaptodextrans bind specifically to
      paramagnetic beads coated with the corresponding antibody.

PMID- 12610988
TI  - Biodegradable thermoresponsive poly(amino acid)s.
AB  - Reaction of poly(succinimide) with a mixture of 5-aminopentanol and 6
      aminohexanol produced new thermoresponsive polymers based on biodegradable
      poly(amino acids)s, poly(N-substituted alpha/beta-asparagine)s, showing a clear
      LCST in water.

PMID- 12610990
TI  - Synthesis and structural features of the first thallium(I) selenoether
      derivatives.
AB  - The first evidence for thallium(I) complexes involving selenoether ligands is
      presented, together with the structure determinations for the 1D chain species
      [T1[MeSe(CH2)3SeMe]]PF6 and the 3D network species [T1[MeSe(CH2)2SeMe]]PF6.

PMID- 12610992
TI  - Asymmetric electrochemical lactonization of diols on a chiral 1
      azaspiro[5.5]undecane N-oxyl radical mediator-modified graphite felt electrode.
AB  - A graphite felt electrode modified with (6S,7R,10R)-4-amino-2,2,7-trimethyl-10
      isopropyl-1-azaspiro[5.5]undecane N-oxyl was prepared for electrocatalytic
      oxidation of diols; electrolysis of diols on the modified electrode yielded
      optically active lactones (92.0-96.4%), with an enantiopurity of 82-99% ee.

PMID- 12610991
TI  - On the kinetics and energetics of one-electron oxidation of 1,3,5-triazines.
AB  - One-electron oxidation of 1,3,5-triazines is observed with both excited uranyl
      ion (*UO2(2+)) and sulfate radical anion (SO4.-) in aqueous solution, but not
      with Tl2+, indicating that the standard reduction potentials E degree of 1,3,5
      triazine radical cations are = 2.3 +/- 0.1 V vs. NHE, consistent with theoretical
      calculations; this suggests that if triazines inhibit electron transfer during
      photosynthesis, they would need to act on the reductive part of the electron
      transport chain.

PMID- 12610993
TI  - Cation-pi interactions as a tool to enhance the power of a chiral auxiliary
      during asymmetric photoreactions within zeolites.
AB  - Owing to the existence of cation-pi interactions, aryl chiral auxiliaries perform
      far better than alkyl chiral auxiliaries during asymmetric photoreaction.

PMID- 12610994
TI  - Solvatochromic response imposed by environmental changes in matrix/chromophore
      entities: luminescent cyclometalated platinum (II) complex in Nafion and silica
      materials.
AB  - Luminescent cyclometalated complex [Pt(L)py]+ (1) immobilised in Nafion film
      exhibits a solvatochromic shift in emission maximum from 530 to 650 nm upon
      immersion in ethanol but no effect is detected with aprotic organic solvents,
      whereas the emission of the [Pt(L)]+ luminophore anchored in silica materials
      shows a blue shift from approximately 665 to 550 nm upon exposure to pentane
      vapour but no shift is observed for ethanol vapour.

PMID- 12610995
TI  - On-line gas chromatographic monitoring of catalyst processes in a microfabricated
      chemical reactor.
AB  - A microfabricated catalyst reactor, prepared from glass and polydimethylsiloxane,
      has been directly interfaced to a gas chromatograph permitting real time reaction
      monitoring allowing rapid catalyst characterisation.

PMID- 12610997
TI  - First linear alignment of five C-Se...O...Se-C atoms in anthraquinone and 9
      (methoxy)anthracene bearing phenylselanyl groups at 1,8-positions.
AB  - Five Ci-Se...O...Se-Ci atoms in anthraquinone and 9-(methoxy)anthracene bearing
      phenylselanyl groups at 1,8-positions align linearly, the origin of which is
      shown to be a nonbonded 5c-6e interaction of the five atoms.

PMID- 12610998
TI  - Nitrogen atom exchange between molybdenum, tungsten and carbon. A convenient
      method for N-15 labeling.
AB  - The compound (ButO)3W identical to N serves to exchange the nitrogen atoms
      between nitriles (MeC identical to N and PhC identical to N), itself and
      (ButO)3Mo identical to N in solution at room temperature.

PMID- 12610996
TI  - The nature of the DNA template (single- versus double-stranded) affects the rate
      of aquation of a dinuclear Pt anticancer drug.
AB  - The rate of aquation of a dinuclear platinum anticancer agent is altered in the
      presence of template DNA with enhancement of hydrolysis in the presence of single
      stranded over double-stranded DNA, emphasising how the alteration of chemical
      properties of small molecules in the presence of large host interactions is also
      dependent on the conformation and nature of that host.

PMID- 12610999
TI  - Deactivation processes of homogeneous Pd catalysts using in situ time resolved
      spectroscopic techniques.
AB  - UV-Vis, combined with ED-XAFS shows, for the first time, the evolution of
      inactive Pd dimers and trimers, that are a possible first stage in the
      deactivation process of important palladium catalysed reactions, leading to
      larger palladium clusters and eventually palladium black.

PMID- 12611000
TI  - Synthesis of poly(aryleneethynylene)s bearing glucose units as substituents.
AB  - A series of poly(aryleneethynylene)s functionalized with acetylated
      glucopyranosyl units were synthesized by the Pd-catalyzed reaction of
      trimethylsilylethynyl derivatives with aromatic halides in the presence of silver
      oxide.

PMID- 12611001
TI  - Mechanistic aspects of acetone addition to metalloaromatic complexes of iridium:
      a DFT investigation.
AB  - DFT calculations were used to reveal the unexpected reactivity and mechanism of
      the addition of acetone to metallabenzene, metallapyrylium and metallathiabenzene
      complexes of iridium.

PMID- 12611002
TI  - Reaction of ADP with amino acid methyl esters mediated by trimethylsilyl
      chloride.
AB  - Reaction of ADP with amino acid methyl esters mediated by trimethylsilyl chloride
      in pyridine produced adenosine 5'-phosphoramidates in good yields under mild
      conditions, it is interesting that nucleophilic attack of amino acid methyl
      esters only occurred on alpha-phosphorus of ADP.

PMID- 12611003
TI  - Chiral quantification of D-, L-, and meso-tartaric acid mixtures using a mass
      spectrometric kinetic method.
AB  - Accurate quantification of the optical isomers in a ternary mixture of D-, L-,
      and meso-tartaric acids is achieved using electrospray ionization tandem mass
      spectrometry for in-situ metal complex formation and a three-point calibration
      method to quantify the dissociation kinetics.

PMID- 12611004
TI  - Synthesis and fluorescence enhancement of oligophenylene-substituted
      calix[4]arene assemblies.
AB  - Tetra-oligophenylene substituted calix[4]arene assemblies containing up to three
      phenylene units have been synthesized by a convergent approach using Suzuki cross
      coupling and their optical properties were investigated and compared with the
      corresponding monomer.

PMID- 12611005
TI  - Stabilization of the previously unknown tautomer HP(OH)2 of hypophosphorous acid
      as ligand; preparation of [W3(Ni(HP(OH)2))Q4(H2O)9]4+ (Q = S, Se) complexes.
AB  - Bis(hydroxy)phosphine, the isomer of hypophosphorous acid which remained elusive
      for a long time, coordinates to the Ni site of heterometallic clusters with a
      W3NiQ4 core (Q = S, Se) to give [W3(Ni(HP(OH)2))Q4(H2O)9]4+ (Q = S, Se).

PMID- 12611006
TI  - Highly efficient chiral metal cluster systems derived from Ru3(CO)12 and chiral
      diiminodiphosphines for the asymmetric transfer hydrogenation of ketones.
AB  - The chiral Ru cluster-based catalyst systems generated in situ from Ru3(CO)12 and
      chiral diiminodiphosphine tetradentate ligands effected asymmetric transfer
      hydrogenation of propiophenone in 2-propanol, leading to 1-phenyl-1-propanol in
      94% yield and with 96% ee.

PMID- 12611007
TI  - Employing the simple monosilylcopper reagent, Li[PhMe2SiCuI], in 1,4-addition
      reactions.
AB  - Conjugate addition reactions using the simple Li[PhMe2SiCuI] reagent to a variety
      of alpha,beta-unsaturated carbonyl compounds is described; dimethyl sulfide from
      the purification of CuI plays a key role for very high yields as well as high
      stereoselectivities in the formation of beta-silyl carbonyl compounds.

PMID- 12611008
TI  - Definitive identification of cysteine and glutathione complexes of bismuth by
      mass spectrometry: assessing the biochemical fate of bismuth pharmaceutical
      agents.
AB  - Solutions containing BiCl3, bismuth subsalicylate or Bi(NO3)3 with L-cysteine, DL
      homocysteine, D-methionine or glutathione have been examined by electrospray mass
      spectrometry. Prominent peaks are assigned to bismuth complexes of these
      biomolecules and provide insight towards understanding the bioactivity of bismuth
      compounds.

PMID- 12611009
TI  - A light-harvesting fluorinated fullerene donor-acceptor ensemble; long-lived
      charge separation.
AB  - In a first example of a trannulene-based donor-acceptor dyad visible light
      photoexcitation generates a long-lived (870 ns) charge-separated state.

PMID- 12611010
TI  - High acid catalytic activity of aluminosilicate molecular sieves with MCM-41
      structure synthesized from precursors of colloidal faujasite.
AB  - The synthesis of micro/mesoporous aluminosilicate with a hexagonal arrangement of
      pores has been achieved by cationic surfactant-templating in a
      tetramethylammonium-containing solution precursor of colloidal faujasite; this
      material is zeolite nanocrystal-free and exhibits high catalytic activity in m
      xylene conversion.

PMID- 12611011
TI  - Formation and structural observation of cesium encapsulated single-walled carbon
      nanotubes.
AB  - Cesium encapsulation inside single-walled carbon nanotubes (SWNTs) is for the
      first time realized by ion irradiation of SWNTs immersed in a magnetized alkali
      metal plasma, the configuration of which is confirmed to comprise three varieties
      by field emission type transmission electron microscopy (FE-TEM) and scanning TEM
      (STEM) observation.

PMID- 12611012
TI  - Configuration assignment in small organic molecules via residual dipolar
      couplings.
AB  - Here we propose a new method to assign relative configurations of stereocenters
      in small organic molecules by using residual dipolar couplings; the main
      advantage of this method is that spatial proximity of the stereocenters is not
      required.

PMID- 12611013
TI  - Formation and observation of dimers of a metal complex with long alkyl side
      chains aligned on a graphite surface.
AB  - Scanning tunnelling microscope was successfully applied to observe self-assembled
      molecular images of (bis(5-dodecylsalicylidene)ethylenediaminato)nickel(II) in
      the form of dimers on highly oriented pyrolytic graphite.

PMID- 12611014
TI  - Light induced excited high spin-state trapping in [FeL2](BF4)2 (L = 2,6
      di(pyrazol-1-yl)pyridine).
AB  - The spin-crossover complex [FeL2](BF4)2 undergoes a LIESST transition at 30 K on
      irradiation; the structures of the low-spin ground and high-spin metastable
      states at this temperature are presented.

PMID- 12611015
TI  - Chiral information transfer by solid-solid interaction: application for absolute
      configuration assignment.
AB  - Host-guest complexes of calix[4]resorcarene with chiral molecules were
      efficiently formed by solid-solid grinding and exhibited CD Cotton effects
      reflecting the absolute configuration of the guest.

PMID- 12611016
TI  - Chirality transfer during alkylation of chiral amides.
AB  - Chiral amides derived from O-methyl mandelic acid and achiral amines underwent
      enantioselective alpha-methylation on treatment with LTMP followed by addition of
      methyl iodide; chirality transfer from an undeprotonated chiral amide into an
      achiral enolate in a mixed aggregate is supposed to be responsible for the
      asymmetric induction.

PMID- 12611017
TI  - A novel layered oxysulfide intergrowth compound Sr4Mn2Cu5O4S5 containing a
      fragment of the alpha-Cu2S antifluorite structure.
AB  - Sr4Mn2Cu5O4S5 contains manganese oxide sheets separated by unusual antifluorite
      type Cu3S3 layers in which copper(I) ions are distributed over three- and four
      coordinates sites in a similar fashion to in alpha-Cu2-xS and suggestive of high
      two-dimensional copper ion mobility.

PMID- 12611018
TI  - Chemometric analysis of comprehensive two-dimensional separations.

PMID- 12611019
TI  - Column technology for capillary electrochromatography.

PMID- 12611020
TI  - Gas chromatography with inductively coupled plasma mass spectrometric detection
      (GC-ICP MS).

PMID- 12611021
TI  - GC-MS analysis of halocarbons in the environment.

PMID- 12611022
TI  - Microfluidics for ultrasmall-volume biological analysis.

PMID- 12611023
TI  - Recent trends in proteome analysis.

PMID- 12611024
TI  - Improving our understanding of reversed-phase separations for the 21st century.

PMID- 12611025
TI  - Clinical applications of high-performance affinity chromatography.

PMID- 12611027
TI  - Views of laypersons on the role employers play in return to work when sick
      listed.
AB  - Sickness absenteeism is an increasing public health problem, but few studies have
      examined the views of laypersons regarding factors that promote return to work.
      The present investigation concerns the opinions of such individuals on the role
      employers play in this context. Data from five focus-group interviews of
      laypersons with experience of long-term sickness absence were subjected to
      grounded theory analysis. When asked about factors that hinder or promote return
      to work, the laypersons spontaneously emphasized the importance of the employer.
      Specifically, they stressed the need for a structured back-to-work program at
      each workplace, which should include contacting absent employees and informing
      fellow workers of possible changes in task assignments upon return of the absent
      person. Reported hindering factors included lack of such information, leading to
      envy and harassment. Respondents also asserted the importance of work supervisors
      in creating a positive emotional atmosphere.

PMID- 12611026
TI  - Treatment- and cost-effectiveness of early intervention for acute low-back pain
      patients: a one-year prospective study.
AB  - In an attempt to prevent acute low-back pain from becoming a chronic disability
      problem, an earlier study developed a statistical algorithm which accurately
      identified those acute low-back pain patients who were at high risk for
      developing such chronicity. The major goal of the present study was to evaluate
      the clinical effectiveness of employing an early intervention program with these
      high-risk patients in order to prevent the development of chronic disability at a
      1-year follow-up. Approximately 700 acute low-back pain patients were screened
      for their high-risk versus low-risk status. On the basis of this screening, high
      risk patients were then randomly assigned to one of two groups: a functional
      restoration early intervention group (n = 22), or a nonintervention group (n =
      48). A group of low-risk subjects (n = 54) who did not receive any early
      intervention was also evaluated. All these subjects were prospectively tracked at
      3-month intervals starting from the date of their initial evaluation, culminating
      in a 12-month follow-up. During these follow-up evaluations, pain disability and
      socioeconomic outcomes (such as return-to-work and healthcare utilization) were
      assessed. Results clearly indicated that the high-risk subjects who received
      early intervention displayed statistically significant fewer indices of chronic
      pain disability on a wide range of work, healthcare utilization, medication use,
      and self-report pain variables, relative to the high-risk subjects who do not
      receive such early intervention. In addition, the high-risk nonintervention group
      displayed significantly more symptoms of chronic pain disability on these
      variables relative to the initially low-risk subjects. Cost-comparison savings
      data were also evaluated. These data revealed that there were greater cost
      savings associated with the early intervention group versus the no early
      intervention group. The overall results of this study clearly demonstrate the
      treatment- and cost-effectiveness of an early intervention program for acute low
      back pain patients.

PMID- 12611028
TI  - Methodological challenges in studying recurrence of low back pain.
AB  - Recurrences of low back pain (LBP) have been shown to be both frequent and
      costly, with reported recurrence rates ranging from 5 to 82%. Numerous
      methodological approaches have been developed to identify recurrence but there
      has been no standardized definition of LBP recurrence or required follow-up time.
      The objective of this study was to compare the methodological approaches used to
      analyze LBP recurrence in seminal contributions and to describe the differences
      in definitions of LBP recurrence and follow-up structure. Twelve seminal articles
      were identified for review during which four types of LBP recurrence definition
      and two types of follow-up structure were recognized. Definitional and follow-up
      differences considerably contributed to variations in computed recurrence rates
      due either to measurement or other methodological shortcomings, such as loss to
      follow-up and sick person effect. The results suggest that there is a need to
      develop a standardized definition of LBP recurrence and a standardized approach
      to follow-up to allow direct comparisons of published research findings. The use
      of alternative definitions is also likely to impact analyses of risk factors
      contributing to LBP recurrence and direct and indirect costs associated with
      treating LBP.

PMID- 12611029
TI  - Balance abilities of different-aged workers in physically demanding jobs.
AB  - The postural and functional balance abilities of workers in physically demanding
      jobs were assessed in relation to age and occupation. Postural balance was tested
      with a force platform, and functional balance was measured during walking on a
      wooden plank. The subjects, 23-61 years of age, were fire fighters (men, n = 69),
      construction workers (men, n = 52), nursing staff (women, n = 51), and home care
      workers (women, n = 66). In the older (> or = 50 years) groups the time used for
      the functional balance test was 3-5 s longer and the velocity moment of the
      postural balance was 16-30 mm2/s higher than in the groups aged < or = 39 years.
      Construction workers performed better than fire fighters, and both groups had
      better functional balance than home care workers and nursing staff. The balance
      demands of work and deterioration with age should be taken into account when work
      ability is promoted, especially among older workers in physically demanding jobs.

PMID- 12611030
TI  - Negative feelings exacerbate hostile attributions of intent in highly aggressive
      boys.
AB  - Tested the hypothesis that aggressive boys' tendency to attribute hostile
      intentions to peers is exacerbated in a negative emotional state. Twenty-nine
      highly aggressive boys in special education, 12 moderately aggressive boys in
      regular education, and 16 nonaggressive boys in regular education inferred peers'
      intentions in 8 vignettes concerning ambiguous provocation by peers. Mild
      negative emotions were induced by unjust loss of a manipulated computer game.
      Half the vignettes were completed in this negative emotional state. After
      completion of all vignettes, the game was played again and won to reinduce
      positive feelings. Self-ratings of feelings obtained throughout the study showed
      the manipulations consecutively induced negative and positive feelings. Negative
      feelings increased hostile attribution of intent in the highly aggressive group.
      Highly and moderately aggressive boys responded more aggressively than
      nonaggressive boys.

PMID- 12611031
TI  - Social skills training in children with attention deficit hyperactivity disorder:
      a randomized-controlled clinical trial.
AB  - Evaluated efficacy of social skills training (SST) on children with 2 subtypes of
      attention deficit hyperactivity disorder (ADHD). Participants were 120 children
      (30 girls, 90 boys), ages 8 to 12 with ADHD-Inattentive type (ADHD-I; n = 59) or
      Combined type (ADHD-C; n = 61). The children were randomly assigned within
      diagnosis subtype to the treatment condition (8 weeks of SST) or the no
      intervention control condition. SST led to greater improvements in both parent-
      and child-perceived assertion skills in the children with ADHD, yet did not
      affect the other domains of social competence. Diagnostically heterogeneous
      groups led to greater improvements on parent-report of their child's cooperation
      and assertion abilities as well as children's report of their own empathy skills.
      Diagnostically homogeneous groups led to greater decreases in externalizing
      behaviors at posttreatment but not at follow-up. Children with comorbid
      oppositional defiant disorder (ODD) did not benefit as much from the
      intervention. Children with ADHD-I improved in assertion skills more than
      children with ADHD-C, yet the 2 diagnostic entities did not differ in improvement
      levels across all other social skills.

PMID- 12611032
TI  - [Heart transplantation: equality of access?].

PMID- 12611033
TI  - [Geographic variations in access to heart transplantation in France].
AB  - This study was undertaken to determine whether there were regional variations in
      the access to the national waiting list for cardiac transplantation and in access
      to cardiac transplantation itself in France. The incidence of inscription on the
      waiting list for transplantation was calculated for new candidates living in each
      region between 1998 and 2000, indicating the level of access to the waiting list.
      The average interval before transplantation between 1995 and 2000 was calculated
      by the Kaplan-Meier method. The regional lack of transplant organs was estimated
      by the ratio of the difference between patients inscribed on the waiting list and
      those operated, over the number of patients operated. The overall national
      incidence of inscription of the waiting list for cardiac transplantation was 8
      new patients per year per million inhabitants with a range of 1.7 in Corsica to
      12.1 in Lorraine. The regional incidence was lower than the national reference in
      5 regions in higher in 4 regions. There was a strong attraction of patients to
      the Ile-de-France, Pays de la Loire and Rhone-Alpes regions. The average waiting
      time for transplantation in France was 3.7 months and ranged from 1.2 months in
      Brittany to 15.4 months in Aquitaine (p < 0.001). The degree of regional lack of
      transplant organs was significantly and positively correlated with the average
      waiting time for transplantation. The results of this study show that there are
      regional differences in the incidence of inscription on the waiting list for
      cardiac transplantation in France and a significant variation in waiting times
      for cardiac transplantation, and therefore, in access to cardiac transplantation.

PMID- 12611034
TI  - [Changes in left ventricular torsion during ischemia-reperfusion].
AB  - We aimed to characterise the alterations of left ventricular twist during
      ischaemia-reperfusion and to study their relationship to global left ventricular
      function. Systolic left ventricular twist was measured at the mid-papillary
      muscle level by colour tissue Doppler echocardiography in 7 anaesthetised open
      chest dogs at baseline, 90 min-occlusion of the left anterior descending, and 180
      min after reflow. Tissue Doppler was also performed in 34 patients after anterior
      infarct and in 20 controls. In controls, rotation occurred counterclockwise when
      viewed from the base. In a random subset of subjects, the assessment of
      ventricular twist by tissue Doppler was validated against magnetic resonance
      myocardial tagging. Myocardial ischaemia led to a decrease in ventricular twist
      in dogs and infarct patients (p < 0.01). This decrease was correlated with the
      extent of the asynergic area and global left ventricular function (p < 0.001). In
      dogs, cardiac twist was higher after reflow relative to ischaemia (p < 0.01).
      Thus, acute myocardial ischaemia is responsible for a decrease in left
      ventricular twist that is related to global ventricular function. Colour tissue
      Doppler echocardiography provides straightforward assessment of left ventricular
      twist in humans.

PMID- 12611035
TI  - [Patient information and the cardiologist].
AB  - AIM OF THE STUDY: The patient's information prior to paraclinical testings is a
      part of the medical deontology and takes on increasing legal importance since new
      laws. METHODS: From December 2001 to January 2002, we administered to
      cardiologists through the website of the French Society of Cardiology a
      questionnaire in order to determine the way the information is dispensed to
      patients and to compare the results to the survey performed in 2000. RESULTS:
      Among the 293 answers obtained, 243 were utilizable. The answers were obtained
      from cardiologists working on private medicine (27.5%), public medicine (52.8%)
      or mixed (19.7%). Information was more frequently dispensed for invasive
      procedures: coronary angiography (92.2%), cardiac pacing (76.8%) than non
      invasive assessments: transesophageal echocardiography (47.6%) and treadmill test
      (44.7%). The most frequent information document given to patients was the one
      edited by the French Society of Cardiology (71.6%). In the great majority of
      cases, there is the prescribing cardiologist (35.9%) and/or the one performing
      the assessment who dispenses the information, generally the day prior the
      examination (73.5%) with additive explanations (91.4%). Few patients refuse the
      examination after information. The situation where the assessment is performed on
      a patient without the faculty of understanding modalities and the necessity of
      that examination is in emergency (45%). In 63.4% of cases, the cardiologist
      requires the patients signature on the information document. CONCLUSION:
      Information dispensation prior to an examination is generally well done by
      cardiologists. The evidence of the information's dispensation is not at ease and
      most of cardiologists require written document from their patients, which is not
      legally necessary.

PMID- 12611036
TI  - [Remodelling the aortic root by resection of the ascending aorta and non-coronary
      sinus in annular dilatation of the aorta and acute dissection of the descending
      aorta. 29 observations].
AB  - The first conservative surgical procedures of the native aortic valve in annular
      dilatation were performed by Yacoub and David [1, 2]. These so-called remodelling
      and inclusion procedures provided hope for a normal life without long-term
      anticoagulant therapy for patients with Marfan's syndrome, with protection from
      the complication of an acute dissection of the ascending aorta. The authors
      reported their experience in the Archives des Maladies du Coeur et des Vaisseaux
      in 1999, with excellent results [3]. However, a certain number of cases are
      encountered in which the Yacoub and David procedures cannot be performed because
      of the presence of a pseudo-bicuspid valve, isolated asymmetrical dilatation of
      the non-coronary sinus or acute dissection of the aorta without dilatation of the
      aortic root. In these forms, the authors have developed a technique of
      remodelling the aortic root with conservation of the native valve by resecting
      the ascending aorta and non-coronary sinus, rather than carrying out a Bentall
      procedure. Twenty-nine cases of this type have been treated in this way for three
      different indications: aneurysm of the ascending aorta with bicuspid aortic
      valve, aneurysm of the ascending aorta with aortic insufficiency and extension to
      the posterior sinus, and type A acute dissection of the aorta.

PMID- 12611037
TI  - [Femoro-popliteal emboli: treatment by manual thrombo-aspiration].
AB  - Acute arterial thrombo-embolic pathology constitutes a common pathology in the
      elderly population, principally in cases of cardiac arrhythmia. Out study allowed
      analysis of the results of percutaneous manual thrombo-aspiration as a primary
      procedure in a series of 25 patients (average age: 73.3 +/- 11.3 years)
      presenting with a picture of acute femoro-popliteal ischaemia, of supposed
      cardiac origin. Most of the patients had an arrhythmia with atrial fibrillation
      (68%), and 88% had grade II ischaemia. The site of proximal occlusion most
      frequently found was the popliteal axis (22 patients). Thrombo-aspiration was
      performed in all cases via the common femoral route homo-lateral with the
      ischaemia, by anterograde approach, after having obtained a diagnostic angiograph
      of the opposite side. The procedure, with an average duration of 39 minutes,
      allowed restoration of good quality flow in at least 2 axes subjacent to the
      occlusion in 23 patients (92%). Besides two failures, two complications (8%) were
      counted (one Scarpa haematoma and one early re-thrombosis). This good result was
      sustained long term, with 94% of patients reviewed on average 3 years after the
      procedure remaining asymptomatic. Manual thrombo-aspiration thus constitutes a
      technique of choice in the framework of the management of acute infra-inguinal
      emboli due to its angiographic and functional results on the one hand, and its
      low morbidity on the other, in a population particularly exposed to the risk of
      spontaneous and post-operative vascular complications.

PMID- 12611039
TI  - [Evolution of interventional cardiology in France during the last decade (1991
      2000)].
AB  - The annual inquiry by the "Angiography and Interventional Cardiology Group" of
      the French Society of Cardiology has allowed the evolution of interventional
      cardiology in France between 1991 and 2000 to be monitored. The results of the
      2000 inquiry have been analysed in particular. The number of coronarography
      centres has increased by 27% in 10 years, growing from 173 in 1991 to stabilise
      at 220, and the number of centres performing percutaneous coronary angioplasty
      grew from 128 to 175 (+27%) at the same time. The number of coronarographies
      increased by 79% (131,636 to 236,111), and angioplasties increased by 197%
      (30,885 to 91,901). In the year 2000, angiographic procedures represented 39% of
      coronarographies, against 23% in 1991. Endoprosthesis implantation constitutes
      the principal revolution of this decade, the number of procedures growing from
      393 to 77,388 between 1991 and 2000, some 84.2% of angioplasties, and a total
      number of endoprostheses of 107,869 (1.39 stents per procedure). The other
      revascularisation techniques remain anecdotal, representing only 1.9% of
      procedures. In 2000, at the 135 centres supplying detailed information, direct
      stenting represented 38.5% of procedures, and the indications for restenosis were
      9.9%. The number of interventions performed in the public or private sector is
      almost identical for each category, only morphological or functional explorations
      remain the privilege of the public sector in the university setting. The activity
      of the University Hospitals Centres has noticeably and regularly decreased since
      1991, falling from 39.2% to 28.7% of coronarographies and from 41.8% to 31.1% of
      angioplasties in 2000.

PMID- 12611038
TI  - [Atrial flutter with 1/1 nodo-ventricular conduction with amiodarone. From
      physiopathology to diagnosis].
AB  - Atrial flutter with 1/1 nodo-ventricular conduction is a classical complication
      of Vaughan-Williams's Class I antiarrhythmic drugs. The increase of the flutter
      cycle and weak action of the antiarrhythmic on the atrioventricular node leads to
      1/1 conduction of atrial depolarisation to the ventricles. In view of their
      marked action on the atrioventricular node, this type of pro-arrhythmic effect is
      very unexpected with Class III antiarrhythmics. The authors report 7 cases of 1/1
      atrial flutter with oral amiodarone observed between 1994 and 2001. The patients
      were 6 men and 1 woman with an average age of 58 +/- 14 years. Four of them had
      underlying cardiac disease; none were hyperthyroid. The initial arrhythmia was
      2/1 atrial flutter (n = 4), 1/1 atrial flutter (n = 2) and atrial fibrillation (n
      = 1). Treatment was preventive with doses of 400 mg/day associated with
      carvedilol in one patient and 200 mg/day in another. The other five patients all
      received loading doses of 9200 +/- 2400 mg over 10 +/- 4 days. The symptoms were
      palpitations (n = 2) associated in one patient with hypotension, one syncope, one
      near syncope and one cardiogenic shock. The ventricular cycle of the 1/1 flutter
      was 287 +/- 33 ms. The QRS duration was 136 +/- 35 ms with ventricular
      tachycardia-like appearances in 3 cases. An adrenergic trigger factor was noted
      in 5 patients. One patient required emergency cardioversion. The authors discuss
      the physiopathology of 1/1 flutter and theoretical diagnostic methods are
      proposed. In conclusion, amiodarone does not always prevent the occurrence of 1/1
      nodo-ventricular conduction in atrial flutter.

PMID- 12611040
TI  - [Aortic dissections: recent endovascular therapeutic advances and current
      indications].
AB  - Dissection is one of the most serious diseases of the aorta if only because of
      its potential for rupture, but also for other complications which may be fatal.
      Replacement with a prosthesis remains the treatment of reference as an emergency
      for proximal dissection and as an elective procedure for selected cases of distal
      dissection with complications. Despite steady progress in ancillary management
      (distal perfusion, circulatory arrest, cardiac, neurological and visceral
      protection) the operation remains a very invasive procedure. Aortic
      endoprostheses represent the therapeutic innovation of the decade for the
      treatment of aortic aneurysms and their use could be extended to dissections, at
      least for the most distal forms and to patients at very high surgical risk.

PMID- 12611041
TI  - [Can stress echocardiography by quantified?].
AB  - Stress echocardiography has been validated for the evaluation of myocardial
      ischaemia and viability despite a semi-quantitative interpretation based on
      visual analysis of segmental myocardial thickening. The technique remains,
      therefore, partially subjective, which probably affects its diagnostic value and
      reproducibility, especially during the learning period of a non-expert operator.
      A first step towards better reproducibility was made possible by Second Harmonic
      imaging and standardised interpretation according to the recommendations of the
      American Society of Echocardiography. The quantification is based on the analysis
      of numerical data obtained by Doppler tissue imaging or color kinesis. Doppler
      Tissular Imaging in the pulsed mode with analysis of transparietal velocity
      gradients or regional deformation is currently under evaluation. However, the use
      of threshold values for myocardial velocities has been of little diagnostic value
      and the use of algorithms adjusted for age, heart rate and gender are necessary.
      Another approach is that of colour coding of endocardial displacement (Color
      Kinesis) with automatic contour detection. This relatively easy technique
      requires a shorter post-processing and the initial results are encouraging.

PMID- 12611042
TI  - [The vulnerable plaque: a necessary concept in the management of
      atherothrombosis].
AB  - The advance of cardiology has improved the prognosis of atherothrombosis through
      direct diagnosis and early management, but the global incidence of
      atherothrombotic events has been modified only slightly. Currently, although the
      stenosing effect of atherosclerosis is well known and if treated hardly poses a
      problem, the unpredictable risk of arterial thrombosis continues to cause the
      seriousness of the disease in as much as it is not linked to the degree of
      stenosis. The initiation of thrombosis progresses via destabilisation phenomena
      of atherosclerotic plaques with rupture or erosion of the capsule. The
      identification of plaques "at risk" of instability, so-called "vulnerable"
      plaques, is thus now a fundamental concept. Thanks to anatomo-pathology, certain
      morphological and functional criteria of these vulnerable plaques are better
      understood and are starting to find a clinical resonance. An inflammatory
      syndrome scenario, thin capsule, and a large lipidic heart associated with an as
      yet quiescent atherosclerotic plaque are predictive elements of acute coronary
      syndrome. These elements show promise and an already combined biological and
      morphological approach will certainly be at the heart of clinical research for
      years to come.

PMID- 12611043
TI  - Aortic pulse wave velocity, an independent marker of cardiovascular risk.
AB  - Aortic pulse wave velocity (PWV), a classical index of aortic stiffness, may be
      easily measured in humans using non invasive ultrasound methods of high
      reproducibility. Recent epidemiological studies have shown that, independently of
      confounding factors as age, blood pressure and cardiac mass, aortic PWV is a
      predictor of cardiovascular (CV) mortality in populations of hypertensive
      subjects, whether they have or not end-stage renal disease. Since aortic PWV is
      dominantly influenced by age, this finding may be of major importance for the
      evaluation of CV risk in geriatric populations.

PMID- 12611044
TI  - Cell transplantation for post-ischemic heart failure.
AB  - Post-ischemic heart failure is becoming a major issue for public health in
      occidental countries and therapeutical options are limited. Therefore cell
      transplantation was developed as an alternative strategy to improve cardiac
      structure and function. This review describes the multiple cell types and
      clinical trials considered for use in this indication. The transplantation of
      fetal or neonatal cardiomyocytes has proven to be functionally successful, but
      ethical as well as technical reasons make their clinical use limited. Recent
      reports, however, suggested that adult autologous cardiomyocytes could be
      prepared from stem cells present in various mesenchymal tissues. Alternatively,
      endothelial progenitors originating from bone marrow or peripheral blood could
      promote the neoangiogenesis within the scar tissue. Finally, the transplantation
      of skeletal muscle cells (SMC) in the infarcted area improved myocardial
      function, in correlation with the development of skeletal muscle tissue in
      various animal models. The latter results paved the way for the development of a
      first phase I clinical trial of SMC transplantation in patients with severe
      ischemic heart failure. It required the scale-up of human cell production
      according to Good Manufacturing Procedures, it started in June 2000 in Paris and
      was terminated in November 2001, and it was followed by several others. The
      results were encouraging and prompted the onset of a blinded, multicentric phase
      II clinical trial for SMC transplantation. Meanwhile, clinical trials also
      evaluate the safety and efficacy of various cells types originating from the bone
      marrow.

PMID- 12611045
TI  - Extracellular matrix and cardiac remodelling.
AB  - Cardiac remodelling associated with primitive and secondary cardiomyopathy is
      generally associated with changes in the expression in extracellular matrix (ECM)
      proteins as well as their transmembrane receptors, the integrins. It emerges now
      that the ECM provides a structural, chemical, and mechanical substrate that is
      essential in cardiac function and responses to pathophysiological signals. This
      review will describe the various elements of the ECM, its modifications that are
      associated with cardiac hypertrophy and heart failure, and the molecular basis
      bringing a better insight into the dynamics of the ECM.

PMID- 12611047
TI  - [Treatment with lepirudin in heparin-induced thrombocytopenia. A case report].
AB  - We report the case of a 71 old woman presenting a bilateral massive pulmonary
      embolism with intraventricular right thrombus complicating heparin induced
      thrombocytopenia (HIT) persistent after one month of conventional anticoagulant
      processing. We underline the effectiveness of lepirudin (Refludan) in the
      curative processing of pulmonary embolism allowing here to avoid a complex
      surgical thromboembolectomy. We evoke the place of this molecule in the curative
      therapeutic strategy of HIT with thrombotic phenomena.

PMID- 12611046
TI  - [Anaphylactic shock and myocytic necrosis after treatment with Artotec].
AB  - Treatment with non-steroid anti-inflammatory drugs associated with a
      prostaglandin analogue is common, but the potential cardiovascular effects are
      largely unknown. The authors report a case of myocardial necrosis and
      anaphylactic shock due to treatment with diclofenac and misoprostol. The
      reintroduction of the treatment in hospital led to the recurrence of the initial
      cutaneous and cardiac symptoms in this patient.

PMID- 12611048
TI  - [Roses for Archie Cochrane].

PMID- 12611049
TI  - [Evidence-based medicine and everyday practice of clinical obstetrics--a
      contradiction?].
AB  - Evidence-based medicine and clinical routine in obstetrics often display
      discrepancies. Three examples--cerclage, tocolysis and management of over-term
      pregnancies--are given to describe the state of the art. The translation of
      science-based data into practice will then be discussed.

PMID- 12611050
TI  - [Guidelines for obstetrics in Germany].
AB  - In a more broader sense guidelines are generally available recommendations for
      physicians. Ideally, they describe treatment and decision pathways. Most
      guidelines for obstetrics published by the Association of the Scientific Medical
      Societies in Germany (AWMF, http://leitlinien.net) do not fulfill the quality
      requirements of the Agency for Quality in Medicine (AQuMed, http://www.aezq.de)
      in either their goals or their formal presentation. Currently, clinical practice
      is guided by a consensus of existing expert opinions. Obstetric guidelines are
      poorly developed at level 1. It is uncertain whether additional scientific
      evidence can improve already published guidelines. Nonetheless, existing
      guidelines should be re-evaluated and revised regularly--as has been done in some
      instances.

PMID- 12611051
TI  - [Ultrasound screening in pregnancy: evidence and maternity care reality].
AB  - Since 1980 maternity care in Germany has included ultrasound screening. The aim
      of this review is (1) to assess the benefit of ultrasound screening on the basis
      of randomised, controlled trials in accordance with the criteria of evidence
      based medicine, (2) to examine current screening practice and the quality of
      German maternity care in everyday clinical practice, and (3) to indicate
      priorities for further screening developments. We reviewed Cochrane reviews,
      health technology assessment reports and relevant individual studies. The three
      essential effects that may be achieved by ultrasound screening include: (1)
      earlier detection of multiple pregnancies, (2) better dating of pregnancy and
      reduction in induced labour by 40%, and (3) more frequent and earlier detection
      of foetal malformations including the option for an abortion. Yet, early
      detection does not increase the rate of successful pregnancies. The effects
      mentioned are only incompletely achieved with standard maternity care in Germany.
      For example, there is no evidence for an essential reduction of the frequency
      with which labour is induced. Detection rates in routine preventive care are
      markedly lower than described for trial conditions. Only multiple pregnancies can
      be identified more or less completely; detecting other target diagnoses remains
      unsatisfactory: placenta praevia 57% (without signs of bleeding 14%),
      postmaturity 46%, malformations 30-40% and intrauterine growth retardation 30%.
      Also, high rates of false positive findings can be observed that might lead to
      follow-up examinations and unnecessary treatment procedures. Quality of maternity
      screening is low and is not subjected to substantial quality assurance. We
      suggest the following priority measures: (1) to improve the quality of screening
      by modifying the previous three-step concept with the aim of promoting
      accessibility of highly qualified examiners for all pregnant women, (2) to
      strengthen quality assurance, (3) to assist the pregnant woman with her informed
      decision by offering independent and non-directional counselling concerning the
      advantages and disadvantages of screening and (4) to focus maternity care on
      effective interventions according to the criteria of evidence-based medicine.

PMID- 12611052
TI  - [Gestational diabetes: a controversial issue in obstetrics].
AB  - The diagnosis and therapy of gestational diabetes (GDM) remains a controversial
      issue. What is known from the pathophysiological and clinical facts, risks exist
      for both mother and foetus. In individual cases these risks cannot be estimated
      exactly. Until the results are available from large randomised controlled and
      prospective studies, women with GDM should be treated individually, considering
      the different treatment recommendations.

PMID- 12611053
TI  - [The clinical onset of spontaneous labor in obstetrical research].
AB  - The onset of labour is a cornerstone in the process of childbirth, albeit
      difficult to define. When a woman's subjective assessment that labour has started
      is not accompanied by cervical changes, discrepancies can arise between her and
      her caregivers' perceptions of what labour and childbirth is all about. In this
      review we examine how definitions and operational terms for the onset of labour
      evolved and varied with the prevailing paradigms in the clinical research agenda.
      In the 1950's, the relatively simple concept of labour, divided in a first stage
      of dilatation and a second stage of expulsion, changed to encompass a latent and
      active phase of dilatation, based on the work of Friedman and Sachtleben. Later
      on, the resulting wide variation in the total duration of labour shrank
      drastically with the emergence of "active management of labour", which required a
      different operational definition. Subsequently, the transition from observational
      to controlled clinical research required firmer starting points. Thus, more
      readily defined starting points, such as admission to hospital or even time of
      randomisation, replaced the nebulously vague and erratic "onset of labour" in the
      clinical research agenda. As the paradigms shifted from labour itself to the
      outcome of labour, the onset of labour and its vagaries became an embarrassment
      that needed to be overcome. Yet, within the goal of effective care during labour
      and childbirth, the onset of labour remains as much of a cornerstone as it has
      been for a long time. Thence outcome-centred thinking may need to take a step
      back and also embrace process evaluation, if clinical research in maternity care
      is to achieve its ultimate aim: optimal care for both mother and baby.

PMID- 12611054
TI  - [Early post-partum discharge of mother and child: a literature review].
AB  - This review summarises data on the relationship between the duration of postnatal
      hospital stay and neonatal outcome for term and preterm infants. Almost all of
      the data available derive from observational studies and should thus be
      interpreted with caution. For term infants, several studies found an increase in
      readmission rates in infants discharged early; in one of these studies, hospital
      discharge at less than 30 hours post partum was associated with an increase of
      neonatal mortality by almost four times. These risks may be reduced by
      establishing a rigorous follow-up program including home visits, for example, by
      a midwife. Disadvantages concerning mother-infant interaction or breast feeding
      success have not yet been demonstrated. For preterm infants, two randomised
      studies showed substantial cost savings due to an early discharge program
      involving home visits and telephone contacts, while there was no increase in the
      rate of readmissions or other complications. Translated into the German setting,
      these data suggest a way of reducing the length of hospital stay for both term
      and preterm neonates and their mothers without compromising their outcome, a goal
      that may become even more relevant with the imminent introduction of a
      reimbursement system based on diagnosis-related groups (DRGs).

PMID- 12611055
TI  - [Evidence-based midwifery practice in Scotland: a discussion of the problems].
AB  - In recent years there has been a drive to base all health care provision upon the
      most recent, appropriate scientific evidence. This has prompted an interest in
      research by midwives in clinical practice who want to ensure that they are
      providing the best possible care. Those midwives who do not use evidenced based
      practice but instead teach, support and demonstrate ritualistic practices without
      reference to the substantial research available, are limiting women's choice in
      maternity care. In a recent trial investigating whether routine suturing of
      perineal lacerations is required, the trial's outcome was jeopardised because of
      midwives' beliefs about suturing. The rationale for such ritualistic behaviour is
      not always easy to understand and using a framework of power and it is examined
      in this article to determine what concepts are influencing these practices. The
      article concludes by suggesting that some midwives appear to ignore the results
      of this trial and other research and demonstrate a paternalistic attitude towards
      their clients.

PMID- 12611056
TI  - [Childbirth: a comprehensive perspective. Approaches in health technology
      assessment].
AB  - Are the routine interventions provided during a normal birth process in a
      hospital setting evidence-based? The World Health Organisation has developed
      evidence-based interventions especially for low risk women world-wide. The
      trained midwife is the most appropriate and cost effective caregiver in normal
      pregnancy and birth. Obstetrics in the area of conflict between technology,
      economy and law can turn a normal physiological event into a medical procedure.
      It leads to unnecessary interventions and to a concentration of large numbers of
      labouring women in technically well equipped units with concomitant
      complications. Technological advances create a desire for perfectionism.
      Different interests must be safeguarded in both medical and legal risk-benefit
      assessments. The differences in the reimbursement of normal vaginal delivery and
      sectio are contradictory. Our ways of caring for pregnant and birthing women
      reflect their societal value. Health Technology Assessment adds to decision
      making by pointing out and analysing different aspects.

PMID- 12611058
TI  - [Drug therapy in postmenopausal osteoporosis. An analysis of healty service
      delivery].
AB  - The current care and management of menopausal women diagnosed with osteoporosis
      was analysed by using two different data sets. We investigated prescriptions for
      drugs approved for the treatment of osteoporosis (vitamin D, calcium, fluoride,
      calcitonin, oestrogen/gestagen combinations, oral bisphosphonates) that were
      issued by general practitioners and primary care internists between February 1999
      and February 2000 to women over 50 years of age diagnosed with osteoporosis
      (MediPlus database). For orientation purposes these data were compared to
      treatment data from the core documentation of regional collaborative rheumatology
      centres for patients with inflammatory rheumatic diseases as their primary
      diagnosis and osteoporosis as secondary diagnosis. According to the MediPlus
      database, 64.5% of the patients diagnosed with osteoporosis received some kind of
      osteoporosis-specific therapy, which in most cases consisted of monotherapy with
      calcium (34.7%) or a bisphosphonate (8.9%). The number of prescriptions issued
      per year was between 2.1 and 3.3, depending on the drug class used. This means
      that a maximum of 108 to 207 days per year was covered by therapy. 1.4% of the
      patients received combination therapy consisting of calcium plus bisphosphonate
      and 3% were treated with calcium plus hormone replacement therapy in accordance
      with the recommendations of the German Osteoporosis Working Group (DAGO). 71% of
      the female patients over 50 years of age with osteoporosis as a secondary
      diagnosis received such a therapy in the rheumatology centres. Among this high
      risk group of patients, 29% who presented to a rheumatologist for the first time
      had been administered osteoporosis-specific medication during the previous 12
      months as compared to 77% who had previously been given rheumatologic treatment.
      CONCLUSION: The data reveal significant deficits in the primary care treatment of
      postmenopausal osteoporosis.

PMID- 12611057
TI  - [Critical appraisal of a meta-analysis on the effects of hormone replacement
      therapy on non-vertebral fractures and suggestions to increase the transparency
      of meta-analyses].
AB  - The present article discusses the difficulties in using data from a meta-analysis
      of the effects of hormone replacement therapy on non-vertebral fractures.
      Comparison between the fracture data extracted from the primary studies and the
      data included in the meta-analysis showed discrepancies for the primary endpoint
      in three out of 14 studies. Since the complex decision processes behind meta
      analyses are often not transparent to the reader it is recommended to provide
      further details on decision processes for data collection, selection and
      inclusion criteria for unpublished data. This information could be made available
      on the website of the publishing journal.

PMID- 12611059
TI  - Autologous or allogeneic hematopoietic cell transplantation for non-Hodgkin's
      lymphoma?

PMID- 12611060
TI  - Non-infectious lung complications after transplantation.

PMID- 12611061
TI  - Allogeneic hematopoietic cell transplantation for inborn metabolic diseases.
AB  - Clinical experience for more than two decades has shown that allogeneic HCT may
      benefit some but not all patients with inherited metabolic diseases. The HCT
      procedure is most effective in presymptomatic patients and those with indolent
      forms of storage diseases but is ineffective in those with overt neurological
      symptoms or aggressive neonatal or infantile forms. HCT alone does not correct
      skeletal dysplasia in MPSs and may not prevent development or progression of the
      peripheral neuropathy in sphingolipidoses and ALD. Decisions regarding HCT in
      patients with storage diseases should be made by investigators knowledgeable
      about these diseases, with judicious use of laboratory and clinical resources
      necessary to reach the best therapeutic decision for the individual patient.

PMID- 12611063
TI  - Myocardial neovascularization by adult bone marrow-derived angioblasts:
      strategies for improvement of cardiomyocyte function.
AB  - In the pre-natal period, hemangioblasts derived from the human ventral aorta give
      rise to cellular elements involved in both hematopoiesis and vasculogenesis,
      resulting in formation of the primitive capillary network. Endothelial precursors
      with phenotypic and functional characteristics of embryonic hemangioblasts are
      also present in human adult bone marrow, and can be used to induce infarct bed
      vasculogenesis and angiogenesis after experimental myocardial infarction. The
      neovascularization results in decreased apoptosis of hypertrophied myocytes in
      the peri-infarct region, long-term salvage and survival of viable myocardium,
      reduction in collagen deposition, and sustained improvement in cardiac function.
      Autologous angioblasts may also be useful in cellular therapy strategies aiming
      to regenerate myocardial tissue after established heart failure. It is likely
      that protocols using cardiomyocyte/mesenchymal stem cells will require balanced
      co-administration of angioblasts to provide vascular structures for supply of
      oxygen and nutrients to both the chronically ischemic, endogenous myocardium and
      to the newly-implanted cardiomyocytes. Future studies will need to address the
      timing, relative concentrations, source and route of delivery of each of these
      cellular populations in animal models of acute and chronic myocardial ischemia.

PMID- 12611062
TI  - Developmental potentials of hematopoietic and neural stem cells following
      injection into pre-implantation blastocysts.
AB  - Pluripotent embryonic stem (ES) cells are able to differentiate in vivo into all
      cell types of the fetal and adult organism and in vitro they can differentiate
      into a variety of cell types. In contrast, multipotent somatic stem cells (SSCs)
      isolated from fetal and adult tissues differentiate into mature effector cells of
      their tissue. However, recent studies imply that SSCs can also generate cell
      types of heterologous tissues indicating unexpected broad differentiation
      potentials. In order to examine and compare the developmental potentials of SSCs,
      we exposed hematopoietic stem cells (HSCs) and neural stem cells (NSCs) to an
      environment that is permissive for the development of all cell types of the
      embryo, namely the mouse preimplantation blastocyst. Using this approach we were
      able to detect progeny of HSCs and NSCs frequently in developing chimeric
      animals. Analysis of 18 different adult tissues revealed minor preferences of
      HSCs for hematopoietic tissues, while progeny of NSCs were mostly detected in
      neural tissues. Furthermore we observe that human cord blood-derived CD34+ and
      CD34+/CD38- HSCs also engraft murine embryos and that human donor contribution
      persists into adulthood. Our studies show the existence of tissue specific
      engraftment preferences of HSCs and NSCs and that both stem cell types are non-ES
      cell-like.

PMID- 12611064
TI  - Monitoring of donor cell chimerism for the detection of relapse and early
      immunotherapeutic intervention in acute lymphoblastic leukemias.

PMID- 12611065
TI  - Detection of relapse by sequential monitoring of chimerism in circulating CD34+
      cells.
AB  - Relapse of the underlying malignant disease represents one of the major causes of
      treatment failure in patients treated with stem cell transplantation, especially
      in patients with acute leukemia. Detection of minimal residual disease (MRD)
      after allogenic stem cell transplantation (SCT) is important to schedule
      therapeutic intervention, e.g. donor lymphocyte infusion. We asked, whether
      chimerism analysis in circulating CD34+ cells might be a feasible method to
      monitor MRD in patients after allogeneic SCT. Eighty-seven patients undergoing
      allogeneic SCT were prospectively analyzed. CD34+ cells were prepared from
      peripheral blood samples and sorted after immunomagnetic preenrichment. Results
      were correlated to overall chimerism and results of nested RT-PCR for the bcr-abl
      rearrangement in Ph1-cases. In the 87 patients a median of 8 analyses (range 2
      22) covering a median period of 295 days (range 28-1152) were performed. A
      hematological relapse was observed in 22/84 engrafting patients (26%). In twenty
      patients, the relapse was detected in the CD34+ fraction, in 14 of these
      patients, donor chimerism in CD34+ cells decreased 12-97 days (median 52 days)
      before the clinical diagnosis. In two cases, CD34+ chimerism failed to
      demonstrate the relapse. In patients with relapsing CML, the decrease of donor
      CD34+ cells was associated with reappearance of bcr-abl transcripts. Treatment
      (reduction of immunosuppression, DLI or STI571) was associated with an increase
      of donor derived CD34+ cells and clearance of bcr-abl positive cells. Sequential
      chimerism analysis in CD34+ cells is feasible and sensitive, allowing early
      detection of relapse and monitoring of therapeutic intervention. This method
      appears especially useful in patients with high risk leukemia lacking other
      markers for detection of MRD.

PMID- 12611066
TI  - Monitoring of minimal residual disease after allografting: a requirement to guide
      DLI treatment?

PMID- 12611067
TI  - Cytoreduction, DLI, or mobilized peripheral blood progenitors.

PMID- 12611068
TI  - DLI or second transplant.
AB  - We analyzed toxicity and efficacy of second allogeneic hematopoietic stem cell
      transplantation (HSCT) or donor lymphocyte infusions (DLI) in 66 patients
      relapsing with acute myeloid leukemia (n = 15), acute lymphoblastic leukemia (n =
      5), chronic myeloid leukemia (n = 14), non-Hodgkin's lymphoma (n = 14), myeloma
      (n = 8), myelodysplastic syndrome (n = 8), and metastatic renal cell carcinoma (n
      = 2). Forty-one patients were given second HSCT and 25 DLI. Sixteen patients
      (39%) are alive and disease-free after a second HSCT including 13 who had
      received nonmyeloablative conditioning. Thirteen patients (52%) are alive after
      DLI with mainly chronic myeloid leukemia patients in continuous complete
      remission. Relapse after HSCT is still a challenging situation and further
      studies to improve outcome of these patients are warranted.

PMID- 12611070
TI  - Targeting alloreactive T cells to hematopoietic system specific minor
      histocompatibility antigens for cellular immunotherapy of hematological
      malignancies after stem cell transplantation.

PMID- 12611069
TI  - Imatinib for relapsed BCR/ABL positive leukemias.

PMID- 12611071
TI  - Immunotherapy for Hodgkin's disease.
AB  - EBV proteins present in the malignant Hodgkin Reed-Sternberg (HR-S) cells of
      about 40% of patients with Hodgkin's Disease (HD) provide targets for
      immunotherapy with virus-specific cytotoxic T lymphocytes (CTL). However, Hodgkin
      tumors use multiple strategies to avoid CTL, including down-regulation of
      immunodominant EBV antigens, and secretion of cytokines and chemokines such as
      TGF-beta, that inhibit the activation of CTL and professional antigen-presenting
      cells (APC). To be effective against this tumor, CTL must resist some or all of
      these strategies. Thirteen patients with multiply-relapsed HD received EBV
      specific CTL, generated ex vivo using the autologous EBV-transformed B cells
      (LCL) as stimulator cells. After CTL infusion, EBV-specific immunity increased,
      virus load decreased, CTL homed to sites of malignancy and persisted for up to
      ten months. Clinically, CTL produced resolution of B symptoms and mixed tumor
      responses including one complete remission of residual disease remaining after
      autologous bone marrow transplant. However, no complete remission of bulky
      disease was achieved. Although LMP2-specific CTL activity could be detected in
      some of the infused CTL lines, they were present in low frequency. In pre
      clinical studies, LMP1 and LMP2-specific CTL could be produced by stimulating
      PBMC from patients and normal donors with autologous dendritic cells expressing
      LMP1 or LMP2 from adenoviral vectors. Further, CTL could be rendered resistant to
      the devastating effects of TGF-beta by transduction with a retrovirus vector
      expressing a dominant-negative TGF-beta receptor, while transgenic IL-12 could
      increase the expression of Th1 and decrease that of Th2 cytokines. Future
      clinical studies will test the efficacy of CTL with improved antigen-specificity
      and resistance to Hodgkin immune evasion strategies.

PMID- 12611072
TI  - Targeting CD19 with genetically modified EBV-specific human T lymphocytes.
AB  - Human Epstein-Barr virus-specific T cells were genetically modified to express
      chimeric receptors specific for human CD19, which is expressed on the cell
      surface of most B cell malignancies. The receptor-modified EBV-specific T cells
      can be expanded and maintained long term in the presence of EBV-infected B cells.
      They recognize autologous EBV-infected targets through their conventional T cell
      receptor, and allogeneic EBV-infected targets and tumor targets through their
      chimeric receptor. They efficiently lyse both EBV and CD19-positive tumor targets
      in the absence of background cytotoxicity against CD19-negative targets. Donor
      derived EBV-specific T cells expressing chimeric anti-tumor receptors may
      represent a source of effector cells that could be safely administered to
      leukemia patients to eradicate minimal residual disease after allogeneic bone
      marrow transplantation.

PMID- 12611073
TI  - Visualization of tumor growth and response to NK-T cell based immunotherapy using
      bioluminescence.

PMID- 12611074
TI  - Allogeneic stem cell transplants in chronic myeloid leukemia.
AB  - Indisputable advances in the conventional therapy of chronic myeloid leukemia
      (CML), like the establishment of interferon-alfa as the standard treatment for
      first chronic phase patients and the introduction of imatinib-mesylate as a
      highly active compound in patients failing interferon-alfa treatment or with more
      advanced disease are challenging allogeneic stem cell transplantation (SCT) as
      the single treatment modality, which currently offers long-term remissions below
      the threshold of sensitive molecular methods for the detection of BCR-ABL
      transcripts. Since stable molecular remissions are thought to be a prerequisite
      for cure of CML, allogeneic SCT remains the only curative treatment option for
      younger patients (i.e. beyond the age of 55 years), who have an HLA-matched
      related or unrelated donor. Nowadays, suitable HLA-matched unrelated donors can
      be identified for 70% to 75% of caucasian patients lacking an HLA-identical
      sibling donor, which substantially has promoted the broader application of
      allogeneic SCT.

PMID- 12611076
TI  - Allogeneic stem cell transplantation in chronic lymphocytic leukemia: the con's.

PMID- 12611075
TI  - Reduced non-relapse mortality after reduced intensity conditioning in advanced
      chronic lymphocytic leukemia.
AB  - We studied in 30 patients with progressive or relapsing chronic lymphocytic
      leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after
      conditioning with fludarabine, busulfan and ATG is effective and if treatment
      related mortality can be reduced compared to myeloablative conditioning regimens.
      Patients had 15 matched related and 15 matched unrelated donors. Graft-versus
      host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination
      with "short course" methotrexate or mycophenolate mofetil. The median follow-up
      is 24 months. At last follow up 11 patients were in complete and 13 in partial
      remission. Six patients had stable or progressive disease. Late complete
      remissions occurred up to one year after transplantation and the number of
      patients with CR is still increasing. Four patients died due to treatment related
      complications resulting in a probability of treatment-related mortality of 15%
      (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and
      progression free survival at two years was 79% and 61%, respectively. In
      conclusion, HSCT after reduced conditioning may lower the treatment-related
      toxicity and has the capacity to induce complete remissions.

PMID- 12611077
TI  - Pharmacological aspects of the new triazole voriconazole.

PMID- 12611078
TI  - Improving the outcome of invasive aspergillosis: new diagnostic tools and new
      therapeutic strategies.

PMID- 12611079
TI  - Rituximab as in vivo purging agent in autologous stem cell transplantation for
      relapsed B-NHL.
AB  - In vivo purging may avoid relapse after high dose therapy (HDT) for relapsed
      lymphoma. Therefore, we have evaluated feasibility and efficacy of Rituximab as
      in vivo purging agent included into a sequential salvage protocol for CD20+ B-NHL
      in chemosensitive relapse or induction failure. Thirty seven patients were
      treated within this protocol and in 36/37 a stem cell product could be acquired
      with rare NHL contamination. Overall, due to the intensity of treatment there has
      been a substantial morbidity, including high rates of viral reactivation.
      However, only one patient died during treatment due to sepsis. Response rates
      were favourable with an overall response rate of 97% (with 30/35CR). With a
      maximum follow up of 3.5 years, 15 patients relapsed. Overall, the treatment
      protocol has proven feasible with high purging efficiency and encouraging
      remission rates in this unfavourable patient group.

PMID- 12611080
TI  - VEGFs, angiopoietins, Ephrins and their receptors: putative targets for tumor
      therapy?

PMID- 12611081
TI  - Translation of vascular diversity into targeted therapeutics.

PMID- 12611082
TI  - Quantitating angiogenesis and assessing the causal relationship between
      angiogenesis and tumorigenesis: problems and progress.

PMID- 12611083
TI  - Matrix metalloproteinase/integrin interactions as target for anti-angiogenic
      treatment strategies.
AB  - Modulation of the balance between pro- and antiangiogenic factors holds great
      promise for the treatment of a broad spectrum of human disease ranging from
      ischemic heart disease to cancer. This requires both the identification of
      angiogenic regulators and their efficient delivery to target organs. Here, we
      demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2
      (termed PEX) delivered by lentiviral vectors in different angiogenesis models.
      Transduction of human endothelial cells with PEX virus suppressed endothelial
      invasion and formation of capillary-like structures without affecting chemotaxis
      in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor
      induced matrix metalloproteinase 2 activation and angiogenesis on chicken
      chorioallantoic membranes. PEX expression also inhibited tumor-induced
      angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that
      lentiviral vectors can deliver sufficient quantities of antiangiogenic substances
      to achieve therapeutic effects in vivo.

PMID- 12611084
TI  - Regulators of angiogenesis as targets for anti-angiogenic tumor therapy.

PMID- 12611085
TI  - Angiogenesis in hematologic malignancies.

PMID- 12611086
TI  - Role of neuropilins and semaphorins in angiogenesis and cancer.

PMID- 12611087
TI  - Using history and colposcopy to select women for endocervical curettage. Results
      from 2,287 cases.
AB  - OBJECTIVE: To enhance the yield of endocervical curettage (ECC) by defining risks
      for abnormality. STUDY DESIGN: Demographic and medical information collected at
      colposcopy and subsequent histology were reviewed retrospectively. Statistical
      analysis was by t and chi 2 tests. RESULTS: Among 2,287 women undergoing ECC at
      colposcopy, in only 105 (5%) did positive ECC require excisional therapy that
      would not otherwise have been recommended. Women with positive ECC were older
      (mean, 39.0 vs. 33.2 years; P < .001) and of higher parity (mean, 3.0 vs. 2.0
      births; P < .001), with earlier first intercourse (at 16.6 vs. 17.2 years, P =
      .006), more unsatisfactory colposcopy (148 [27%] of 545 women with unsatisfactory
      colposcopy vs. 183 [12%] of 1,523 women with satisfactory colposcopy; P < .001)
      and more colposcopic impressions of cervical intraepithelial neoplasia (CIN) 2-3
      (163 [51%] of 323 vs. 443 [25.6%] of 1,730 women with low grade or a negative
      impression; P < .001). The likelihood of missed CIN 2-3 was 0.4%, with no missed
      cancers among women with satisfactory colposcopy and either a normal colposcopic
      impression (1/254) or nulliparity (2/474). CONCLUSION: ECC identifies otherwise
      undetected preinvasive and invasive lesions but may be avoided in women with
      satisfactory colposcopy who are nulliparous or have no colposcopic lesions.

PMID- 12611088
TI  - Deepest vertical amniotic fluid pocket at term. Normal values and clinical
      application.
AB  - OBJECTIVE: To determine the normal values of the deepest vertical amniotic fluid
      pocket (DVP) in term pregnancies and whether a similar relationship to birth
      weight (BW) exists. STUDY DESIGN: Two hundred thirty-one term patients (37-42
      weeks) with intact membranes and a normal amniotic fluid index (AFI) were
      included. DVP was identified and compared to BW, BW > 4,000 g (large for
      gestational age [LGA]) and BW < 2,500 g (small for gestational age [SGA]).
      Statistical comparisons and linear regression models were made. RESULTS: The mean
      gestational age was 39.6 weeks, and mean BW 3,284 g. Mean DVP was 4.5 cm. This
      did not vary significantly by gestational age. A positive linear correlation was
      observed between DVP and BW. DVP was greater for pregnancies with LGA (5.2 vs.
      4.3 cm [P < .003]). No difference was observed for SGA. The relative risk for a
      fetus > 4,000 g when the DVP was > 6 was 4.0 (1.6-9.5) and 15.8 (1.6-157.6) if
      maternal diabetes was also present. No difference was determined for SGA using a
      DVP < 2. CONCLUSION: Higher DVP is associated with delivery of an LGA infant,
      particularly in diabetic women.

PMID- 12611089
TI  - Ultrasonic prediction of term birth weight in Hispanic women. Accuracy in an
      outpatient clinic.
AB  - OBJECTIVE: To investigate the accuracy of ultrasonic fetal biometric algorithms
      for estimating term fetal weight. STUDY DESIGN: Ultrasonographic fetal biometric
      assessments were made in 74 Hispanic women who delivered at 37-42 weeks of
      gestation. Measurements were taken of the fetal biparietal diameter, head
      circumference, abdominal circumference and femur length. Twenty-seven standard
      fetal biometric algorithms were assessed for their accuracy in predicting fetal
      weight. Results were compared to those obtained by merely guessing the mean term
      birth weight in each case. RESULTS: The correlation between ultrasonically
      predicted and actual birth weights ranged from 0.52 to 0.79. The different
      ultrasonic algorithms estimated fetal weight to within +/- 8.6-15.0% (+/- 295-520
      g) of actual birth weight as compared with +/- 13.6% (+/- 449 g) for guessing the
      mean birth weight in each case (mean +/- SD). The mean absolute prediction errors
      for 17 of the ultrasonic equations (63%) were superior to those obtained by
      guessing the mean birth weight by 3.2-5.0% (96-154 g) (P < .05). Fourteen
      algorithms (52%) were more accurate for predicting fetal weight to within +/-
      15%, and 20 algorithms (74%) were more accurate for predicting fetal weight to
      within +/- 10% of actual birth weight than simply guessing the mean birth weight
      (P < .05). Ten ultrasonic equations (37%) showed significant utility for
      predicting fetal weight > 4,000 g (likelihood ratio > 5.0). CONCLUSION: Term
      fetal weight predictions using the majority of sonographic fetal biometric
      equations are more accurate, by up to 154 g and 5%, than simply guessing the
      population-specific mean birth weight.

PMID- 12611090
TI  - Necessity of endometrial biopsy in women with enlarged uteri and a preoperative
      diagnosis of uterine leiomyomata.
AB  - OBJECTIVE: To determine the necessity of a preoperative endometrial biopsy when
      evaluating a patient with symptomatic uterine fibroids. STUDY DESIGN: This was a
      retrospective study of 182 cases of hysterectomy for symptomatic uterine
      fibroids. The patients were stratified into 2 groups: those with uteri weighing
      between 280 and 500 g and with uteri weighing > 500 g. Charts were reviewed for
      all patients who did not have an endometrial biopsy and for all cases of
      malignancy. RESULTS: Of the patients with menorrhagia, 21-30% did not undergo a
      preoperative biopsy. In those who did, biopsy failed to detect 2.75% of
      malignancies. All patients diagnosed postoperatively with malignancy had
      presented with complaints of bleeding. CONCLUSION: With complaints other than
      bleeding, a preoperative endometrial biopsy may be omitted. However, any
      menstrual complaints warrant an investigation of the endometrium even though the
      incidence of endometrial carcinoma in these larger uteri is only 1.1%.

PMID- 12611091
TI  - Urolithiasis in pregnancy. Diagnosis, management and pregnancy outcome.
AB  - OBJECTIVE: To review our experiences with ureterolithiasis and nephrolithiasis in
      pregnancy and compare their outcomes with those in the rest of the obstetric
      population. STUDY DESIGN: A database of obstetric deliveries was used to identify
      patients with (cases) and without (controls) urolithiasis and to compare
      demographics and pregnancy complications between the groups. Furthermore,
      retrospective chart review of the cases group was utilized to obtain additional
      pertinent information. RESULTS: Over a 3-year period, there were 21,010
      deliveries, 86 of which had symptomatic urolithiasis, for an incidence of 1 in
      244 pregnancies. Renal calculi occurred more commonly in Caucasians than African
      Americans. Patients were more likely to become symptomatic in the second or third
      trimester, and most stones passed spontaneously. Pregnancy complications were
      similar between the groups; however, there was a higher percentage of preterm
      premature rupture of membranes in the nephrolithiasis cases (7.0% vs. 2.9%, P <
      .05). CONCLUSION: Nephrolithiasis and ureterolithiasis occurred more commonly in
      Caucasians during pregnancy. The majority of patients became symptomatic in the
      last two-thirds of pregnancy and usually passed the calculus spontaneously. A
      higher incidence of preterm premature rupture of membranes was noted in
      pregnancies complicated by urolithiasis.

PMID- 12611092
TI  - Evaluation of contact sensitization in vulvar lichen simplex chronicus. A
      proposal for a battery of selected allergens.
AB  - OBJECTIVE: To determine the role of contact sensitization in vulvar lichen
      simplex chronicus and to select appropriate batteries of allergens to test. STUDY
      DESIGN: Between 1993 and 2000, 61 women affected by vulvar lichen simplex
      chronicus were enrolled to evaluate the role of contact hypersensitivity. All the
      patients underwent patch tests with the Italian standard series and with a wide
      battery of allergens (preservatives, perfumes, emulsifiers, medicaments) and
      products they used routinely. RESULTS: Of the women, 47.5% had at least one
      positive patch test, and relevant positivities were observed in 26%. The relevant
      allergens were usually medicaments and preservatives. CONCLUSION: It would be
      acceptable to reduce the number of allergens tested, in particular omitting the
      perfume series. Patch tests are a helpful diagnostic tool in vulvar lichen
      simplex chronicus and improve prescribing practice.

PMID- 12611093
TI  - Clinical significance of the floating fetal head in nulliparous women in labor.
AB  - OBJECTIVE: To examine the course of labor in nulliparous women in active labor
      with a floating fetal head. STUDY DESIGN: A prospective, cohort study of
      nulliparous women presenting in active labor at term with a floating fetal head
      (station > or = -3, n = 108) or engaged fetal head (n = 241). All patients were
      examined by a senior physician. Assignment to the study or control group was
      noted in the investigator's records. However, management of labor was at the
      discretion of the labor ward team on duty. RESULTS: Cesarean section rates for
      failure to progress were significantly higher in the study group (17.1% versus
      4.2%, P < .0001), and the second stage of labor was prolonged (65.3 +/- 27.1
      versus 54.9 +/- 30.2 minutes, P < .03). None of the women who had a persistently
      floating fetal head at 7 cm of cervical dilation delivered vaginally. Birth
      weights were larger (P < .03) and Apgar scores lower (P < .0001) in the study
      group. The lengths of the active phase and instrumental delivery rates were
      similar in the two groups. CONCLUSION: Nulliparous women presenting in active
      labor at term with a floating head are at substantially increased risk of
      cesarean section for abnormal progress of labor. However, the majority of
      patients will still deliver vaginally. A persistently floating head with advanced
      cervical dilation (7 cm) should prompt consideration of cesarean section since
      little is to be gained by waiting.

PMID- 12611094
TI  - Endometrial brush biopsy. An accurate outpatient method of detecting endometrial
      malignancy.
AB  - OBJECTIVE: To describe 633 cases using the Tao Brush for endometrial biopsy (EBB)
      in an outpatient setting. STUDY DESIGN: Histologic follow-up specimens within six
      months of EBB in an outpatient setting were evaluated over a two-year period.
      Diagnosis by EBB relied mainly on histologic evaluation of hematoxylin and eosin
      stained tissue sections and was complemented by additional cytologic smear
      examination in our laboratory. Diagnostic categories included the following:
      nondiagnostic (ND), benign endometrium (BE), hyperplasia without atypia (H),
      atypia (AT) and atypical hyperplasia (AH)/carcinoma (CA). The correlation between
      EBB and follow-up histology was analyzed. RESULTS: A total of 633 EBBs were
      evaluated. Diagnoses were rendered in 569 cases, with a diagnostic rate of 90%.
      Histologic follow-up was evailable for 156 patients. Twelve AH/CA diagnosed by
      EBB were confirmed by histologic follow-up as CA. However, there was one false
      positive case, in which EBB showed AH/CA and dilatation and curettage (D&C)
      revealed disordered, weakly proliferative endometrium. Nine of 10 EBBs with AT
      diagnoses were 3 CA, 1 AH and 5 BE on follow-up. Two of eight H had D&C follow-up
      that also showed H. Histologic follow-up was available in 114 of 538 benign EBBs
      and showed benign correlation in 112 cases. There were two false negative cases;
      the EBB diagnoses were atrophic endometrium and weakly proliferative endometrium,
      while D&C showed focal AH in both cases. Among the ND cases, 18 of 64 had tissue
      follow-up and disclosed 4 CA, 1 H, 12 BE and 1 ND. CONCLUSION: EBB is a reliable
      diagnostic tool for endometrial sampling in an outpatient setting. The
      sensitivity and specificity in identifying CA among satisfactory specimens is
      100% and 96%, respectively, when AT or a more severe diagnosis is made by EBB.
      Assessment of specimen adequacy is important for pathologists interpreting EBB.
      In our study, four cases of adenocarcinoma were identified in the follow-up D&C
      in patients with nondiagnostic EBB.

PMID- 12611095
TI  - Successful pregnancy resulting from cryopreserved pronuclear and cleaved embryos
      thawed and cultured to blastocysts, refrozen and transferred. A case report.
AB  - BACKGROUND: Twice-frozen, thawed embryos may have utilization in vitro
      fertilization (IVF) cycles. CASE: A 37-year-old woman with endometriosis and
      infertility returned five years after a fresh IVF cycle. Seven cryopreserved
      embryos (2 pronuclear [pn] and cleaved) were thawed, and five developed to the
      blastocyst stage. One blastocyst was transferred, and the remaining four were
      recryopreserved. This transfer did not result in pregnancy. The remaining four
      blastocysts were thawed, and two were transferred resulting in a live, singleton
      delivery. CONCLUSION: Pregnancy can result from cryopreserved 2-pn and cleaved
      embryos cultured to blastocysts, refrozen and then transferred at the blastocyst
      stage.

PMID- 12611096
TI  - Bowel injury occurring during an outpatient LLETZ procedure. A case report.
AB  - BACKGROUND: Large loop excision of the transformation zone (LLETZ) of the cervix
      has almost entirely replaced cold knife conization for the treatment of
      dysplasia. CASE: A 17-year-old woman, gravida 0, underwent LLETZ of the cervix
      for treatment of cervical intraepithelial neoplasia 2. A bowel injury occurred
      during the procedure. The bowel was repaired in the operating room, and no long
      term complications resulted. CONCLUSION: While LLETZ is a minor outpatient
      procedure, serious complications can occur.

PMID- 12611097
TI  - Cystic struma ovarii presenting with ascites and an elevated CA-125 level. A case
      report.
AB  - BACKGROUND: Struma ovarii is a monodermal teratoma that usually presents as a
      solid pelvic mass. Occasionally the lesions are cystic. Rare cases present with
      ascites or pseudo-Meigs' syndrome. The association of a cystic struma ovarii with
      ascites and an elevated CA-125 level is exceptionally rare. CASE: A 51-year-old
      woman presented with ascites and a cystic pelvic mass. There was marked elevation
      of her CA-125 level. The clinical impression was ovarian carcinoma. Frozen
      section revealed a multicystic struma ovarii. CONCLUSION: Struma ovarii can mimic
      ovarian carcinoma clinically, particularly if cystic and associated with ascites
      and an elevated CA-125 level.

PMID- 12611098
TI  - Omental trophoblastic implants and hemoperitoneum after laparoscopic
      salpingostomy for ectopic pregnancy. A case report.
AB  - BACKGROUND: In this era of cost containment, laparoscopic management of ectopic
      pregnancy has become the mainstay of dealing with this common gynecologic
      emergency. The aim of surgical intervention remains conservation of the fallopian
      tube, if possible; salpingectomy is reserved for cases of tubal rupture and/or
      recurrent ectopic pregnancy, where little hope exists of salvaging tubal
      function. CASE: A 28-year-old woman, para 2, underwent laparoscopic salpingostomy
      for ectopic pregnancy. She experienced intraabdominal bleeding within the initial
      12 hours of the postoperative period. On exploratory laparotomy, there was active
      bleeding from the site of the salpingostomy, and a salpingectomy was performed.
      The patient was lost to follow-up and on postoperative day 21 presented with
      signs of intraabdominal bleeding; repeat laparotomy revealed active bleeding from
      trophoblastic implants within the greater omentum. The omentum was adherent to
      the anterior abdominal wall at the site of umbilical trocar placement. An
      infracolic omentectomy was performed, with a subsequent uneventful postoperative
      course; the patient was followed until resolution of the serum beta-hCG.
      CONCLUSION: Postoperative surveillance is important. Positive intraabdominal
      pressure during laparoscopic surgery and the Trendelenburg position may be
      contributory to cephalad migration of trophoblast remnants, with the scavenging
      action of the omentum and adherence to the site of umbilical trocar placement
      theoretically providing a mechanism for neovascularization and sustenance of the
      parasitic trophoblast.

PMID- 12611099
TI  - Large uterine defect found at cesarean section. A case report.
AB  - BACKGROUND: Uncomplicated uterine perforation has been considered a benign event.
      Since the advent of operative hysteroscopy, there have been several reports of
      uterine rupture during pregnancy in patients who have undergone that procedure
      when complicated by known or unsuspected uterine perforation. Large fundal
      defects without rupture have also been reported. CASE: A 23-year-old, white woman
      was admitted for labor induction at 42 weeks' gestation. After an unsuccessful
      attempt at labor induction, a cesarean section (C/S) was performed. At that time
      a large (5-cm) fundal defect was noted. A thorough history suggested that the
      defect was probably the result of unsuspected perforation of the uterus during
      dilatation and currettage for a late first-trimester fetal death. A follow-up
      hysterosalpingogram was done and consultation obtained regarding future
      management. A course of expectant management with C/S prior to the onset of labor
      was advised. Three years later, after an uncomplicated pregnancy, a repeat C/S
      was done at 38 weeks' gestation. CONCLUSION: Patients with a history of operative
      hysteroscopy or difficult curettage may have sustained known or unsuspected
      perforations of the uterus with subsequent scarring or defect, placing them at
      some risk of uterine rupture during pregnancy. Patients should be counseled
      regarding these risks, and assessment by hysterography might be helpful.

PMID- 12611100
TI  - The role of religion/spirituality in the medical curriculum.

PMID- 12611101
TI  - Hormones for menopause: what might the east teach the west?

PMID- 12611102
TI  - Backstage practice.

PMID- 12611103
TI  - The perils of trumpeting.

PMID- 12611104
TI  - Upbeat downtime.

PMID- 12611106
TI  - Keeping fiddlers fit.

PMID- 12611108
TI  - Soothing sounds.

PMID- 12611107
TI  - Keeping dancers on their feet.

PMID- 12611109
TI  - Closing the gap. Funding clinical medical education in Minnesota.
AB  - In recent years, decreasing funding for graduate medical education (GME) from
      private payers, combined with increasing competition between teaching and
      nonteaching hospitals for managed care contracts and cuts in federal aid to
      teaching hospitals, have led to a worsening financial crisis for the nation's
      teaching facilities. For more than a decade, Minnesota's teaching hospitals have
      been dealing with the same issues, and recent articles have discussed the impact
      that declining funding and a market increasingly dominated by managed care have
      had on graduate medical education. Although there is agreement that teaching
      hospitals have higher costs for patient care than nonteaching hospitals,
      relatively little research has been done to determine the magnitude of the costs
      of GME or to isolate their components. Using data from the Minnesota Department
      of Health's Medical Education and Research Costs (MERC) Fund, the author analyzes
      the costs to teaching facilities of providing clinical training to resident
      physicians and students and examines the sources of funding that are available to
      offset these costs.

PMID- 12611110
TI  - The medical education funding gap. One hospital's perspective.
AB  - Graduate medical education (GME) is a complex and expensive enterprise in which
      costs are borne by the teaching institution. With teaching hospitals under
      increasing financial stress due to an expansion of managed care and shrinking
      governmental support of medical education, there is a growing gap between GME
      costs and funding. This article describes GME costs and revenues at Hennepin
      County Medical Center, a teaching hospital in Minneapolis, where in the calendar
      year 2000, GME costs exceeded GME funds by $21 million.

PMID- 12611111
TI  - When to refer patients to a nephrologist?

PMID- 12611112
TI  - Waiting for healthcare. Physician offices can dramatically reduce how long
      patients wait for appointments.

PMID- 12611113
TI  - Comprehensive breast cancer screening. Programs now include individual risk
      assessment.
AB  - A comprehensive breast cancer screening program needs to include risk assessment
      in addition to clinical breast examination and mammography. Women identified as
      being at increased risk should have an individualized schedule of screening
      mammography and a proven prevention program tailored to their level of risk. In
      this article, Drs Cardenas and Frisch review risk factors, screening methods, and
      individual risk assessment, then explain how to use them in conjunction to
      identify tumors at an earlier, more curable stage.

PMID- 12611114
TI  - Screening for colorectal cancer. Guidelines for choosing the appropriate test for
      each patient.
AB  - The importance of screening for colorectal cancer has been established, but the
      decision about which test to use for each patient may seem less clear. In this
      article, Dr Wineman discusses assessment of colorectal cancer risk and the
      advantages and disadvantages of the fecal occult blood test, flexible
      sigmoidoscopy, double-contrast barium enema, and colonoscopy. Potential screening
      methods that could make regular colon examination more acceptable to patients
      also are presented.

PMID- 12611115
TI  - Update on cervical cancer screening. Current diagnostic and evidence-based
      management protocols.
AB  - Pap smear screening for cervical cancer has been a preventive health success.
      Although improved technology is increasing the accuracy of this technique, more
      women who have never been tested will need to undergo screening in order to
      further decrease the incidence of cervical cancer in the United States. The
      establishment of infection with high-risk genital HPV types as a causative factor
      in cervical cancer is a major breakthrough in understanding of this disease.
      Testing for the presence of high-risk HPV DNA should increase the ability to
      identify women who are truly at risk for cancer and true cancer precursors and to
      more efficiently plan further diagnostic evaluation. The 2001 revisions in TBS
      reflect our improved understanding of the epidemiology and natural history of
      cervical epithelial abnormalities and cervical cancer. These revisions are
      designed to facilitate communication between the clinician and the laboratory and
      to improve the clinician's ability to accurately interpret the cytology report
      and plan initial management of any abnormalities.

PMID- 12611116
TI  - Renal manifestations of hepatitis C virus infection. Extrahepatic complications
      often are silent--and thus overlooked.
AB  - Renal involvement often occurs in HCV infection. The most common renal
      manifestation is MPGN with or without cryoglobulinemia. Patients with
      glomerulonephritis may have no clinical evidence of systemic or liver
      involvement. Pathogenesis of HCV-associated MPGN is mediated by glomerular
      deposition of circulating immune complexes containing HCV and anti-HCV. The
      treatment of choice for MPGN is IFN-alpha. However, success is limited, and many
      patients fail to respond or experience relapse on discontinuation of therapy.
      Newer treatment modalities, such as high-dose IFN-alpha and recombinant IFN alpha
      2b and ribavirin combination therapy, have led to improved suppression of HCV RNA
      levels.

PMID- 12611117
TI  - Patient notes: obsessive-compulsive disorder.

PMID- 12611118
TI  - Postmenopausal hormone replacement therapy and prevention: no chance for
      celebration? What should doctors do? A personal opinion.

PMID- 12611119
TI  - Clinical relevance of apoptosis in early and late post-infarction left
      ventricular remodeling.
AB  - Apoptosis may represent an important pathophysiological mechanism causing
      progressive myocardiocyte loss and left ventricular dilation, even late after
      acute myocardial infarction (AMI). This review discusses the role of myocardial
      apoptosis on the basis of findings from experimental studies in animals and from
      observational studies in humans with the purpose of assessing the clinical
      relevance, determinants and mechanisms of myocardial apoptosis and the potential
      therapeutic implications. A more profound understanding of the impact of
      myocardiocyte loss on prognosis and of the mechanisms involved may lead to an
      improved understanding of cardiac remodeling and possibly to an improved patient
      care. In fact, among the potential modulators of myocardial apoptosis,
      angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers
      have already been shown to improve the prognosis and symptoms in patients with
      post-infarction heart failure, and a reduction in myocardial apoptosis could
      partly contribute to such a beneficial effect. Several other putative factors
      could also modulate myocardial apoptosis after AMI, and many are currently under
      intense investigation. In particular, the infarct-related artery patency late
      after AMI may be a major clinical determinant of myocardial apoptosis and
      clinical benefits deriving from an open artery (the "open-artery hypothesis"),
      such as a slowing down of the remodeling process and a reduced arrhythmic risk,
      could be due, at least in part, to a reduced apoptotic myocardiocyte loss.

PMID- 12611120
TI  - Mitral regurgitation of degenerative etiology: should the timing of surgery be
      changed in the mitral valve repair era?
AB  - The timing of surgery in patients with chronic mitral regurgitation is a
      controversial issue. Left ventricular dysfunction progresses silently and is
      partly predictable; depressed left ventricular contractility sometimes
      accompanies a normal ejection fraction. Severe symptoms remain a clear
      recommendation for surgery. However several factors suggest that surgery should
      not be delayed until severe symptoms appear: impact on survival of ejection
      fraction < 60%, preoperative symptoms, and atrial fibrillation. Early surgery is
      justified in patients with degenerative mitral regurgitation independently of the
      type of lesion (prolapse of posterior, anterior or both the leaflets), because
      the addition of new techniques to the surgical armamentarium has neutralized
      prolapse of the anterior leaflet as an incremental risk factor for reoperation.
      In conclusion, early surgery is a reasonable treatment for low-risk patients with
      repairable valves and should be considered in asymptomatic patients with ejection
      fraction approaching the lower limit of normal, history of paroxysmal atrial
      fibrillation or pulmonary hypertension during exercise.

PMID- 12611121
TI  - Normal distribution of an intravascular ultrasound index of vessel remodeling.
AB  - BACKGROUND: As a consequence of plaque accumulation, coronary arteries may
      undergo both compensatory enlargement and paradoxical constriction. The aim of
      this study was to address the distribution of the different remodeling patterns
      in patients with obstructive coronary atherosclerosis. METHODS: Eighty-seven non
      branching segments of native coronary arteries with de novo, focal, non-ostial
      lesions were imaged at intravascular ultrasound (IVUS). Images were acquired with
      a motorized pull-back at a speed of 0.5 mm/s. The cross-sectional area (CSA)
      circumscribed by the external elastic membrane (EEM), the plaque + media complex
      and the lumen area were measured at its narrowest site (CSA with the minimal
      lumen area) and in the reference segment (average of proximal and distal
      reference cross-sections, defined as the most normal looking sites). The IVUS
      index of vessel remodeling (VRI) was calculated using the following formula:
      (narrowest site EEM CSA--reference EEM CSA)/reference EEM CSA*100. The index was
      tested for normality using the Kolmogorov-Smirnov goodness-of-fit test. RESULTS:
      The frequency distribution of VRI was found to have a normal unimodal
      distribution (p = 0.60). VRI ranged from -60 to +164, with a mean of 9.3 +/- 28.0
      and a median of 3.6. Frequency distribution of VRI slightly skewed towards right
      (skewness index 1.69). None of the analyzed clinical and morphological variables
      predicted the presence of compensatory enlargement as opposed to paradoxical
      constriction. CONCLUSIONS: The frequency distribution of the vascular remodeling
      of de novo coronary lesions is unimodal. Therefore, compensatory enlargement and
      paradoxical constriction represent the extremes of a continuous spectrum.

PMID- 12611123
TI  - Out-of-hospital early defibrillation successfully challenges sudden cardiac
      arrest: the Piacenza Progetto Vita project.
AB  - BACKGROUND: Early defibrillation is the most important intervention influencing
      survival following sudden cardiac arrest (SCA). In order to improve public access
      to early defibrillation, in North America several experiences of out-of-hospital
      early defibrillation by non-medical volunteers have been successfully implemented
      and demonstrated to improve survival. METHODS: Since 1999, in Piacenza, we have
      established "Progetto Vita", the first experience of out-of-hospital early
      defibrillation by non-medical volunteers in a medium-size European city. Thirty
      nine semiautomatic external defibrillators were placed in Piacenza, Italy
      (266,531 inhabitants) and distributed in 12 high-risk locations, 12 lay-staffed
      ambulances and 15 police-cars. A total of 1285 lay volunteers were trained by the
      emergency medical system to intervene in all cases of suspected SCA. RESULTS:
      During the first 15 months, 203 codes for suspected SCA were dispatched; 197 were
      confirmed SCA. The overall survival was 5.6% (11/197): survival improved from
      2.9% (4/134) with emergency medical system intervention to 11.1% (7/63) when the
      "Progetto Vita" was activated (p < 0.05). The survival rate on "shockable" rhythm
      was 43.7% in the group of patients treated by volunteers vs 16.6% in those
      treated by emergency medical system aid (p = 0.05). CONCLUSIONS: The widespread
      use of semiautomatic external defibrillators allows early defibrillation by non
      medical volunteers and more than triples the survival rate following out-of
      hospital SCA.

PMID- 12611122
TI  - Radiofrequency ablation of atrioventricular nodal reentrant tachycardia: the risk
      of intraprocedural, late and long-term atrioventricular block. The Veneto Region
      multicenter experience.
AB  - BACKGROUND: Radiofrequency ablation of either the fast or the slow pathway in
      atrioventricular nodal reentrant tachycardia (AVNRT) can be complicated by
      transient or permanent atrioventricular (AV) block. Little is known about the
      possibility of AV block occurring during the first weeks after the procedure and
      nothing about the risk of AV block during the long-term follow-up. METHODS: To
      clarify these latter points, from February 1990 to December 2000 we enrolled 510
      consecutive patients (56 males, 454 females, mean age 55 +/- 16 years) with
      AVNRT. The target of ablation was the fast pathway in 29 patients (group A) and
      the slow pathway in 474 (group B), while in 7 (group C) the slow pathway was
      targeted after unsuccessful fast pathway ablation. Follow-up was available for
      488/510 (95.6%). The length of follow-up was 8.2 +/- 2.4 years in group A, 3.4 +/
      2.4 years in group B (83 group B patients had a follow-up > 6 years: 7.3 +/- 0.8
      years), and 7.3 +/- 2.4 years in group C. RESULTS: The success rates were 93, 99
      and 100% in the three groups respectively. Intraprocedural II-III degree AV block
      occurred in 6/29 patients (20%) of group A, in 11/474 patients (2.3%) of group B
      and in 3/7 patients (42%) of group C. In all patients of groups A and C, the II
      III degree AV block was transient. In contrast, in 6/474 patients of group B
      (1.2%, 2 II degree and 4 III degree AV block) the block still persisted at the
      end of the procedure. Within 7 days of the procedure, a late persistent II-III
      degree AV block developed in 1/29 patients (3.4%, 1 III degree) of group A, in
      1/474 patients (0.2%, 1 II degree) of group B and in 0/7 patients of group C. In
      1 out of 6 patients of group B who developed an intraprocedural persistent AV
      block, 1:1 conduction resumed within the first week. A definitive pacemaker was
      implanted for permanent III degree AV block in 1/29 patients of group A (3.4%),
      in 4/474 patients (0.8%) of group B and in 0/7 patients of group C. In the
      remaining 2/474 group B patients with permanent II degree AV block, a pacemaker
      was not implanted. During follow-up, no patient presented with a II-III degree AV
      block related to the ablation. In group B, 2 patients received a pacemaker
      implant for reasons unrelated to the ablation (1 sick sinus syndrome, 1
      progressive intraventricular conduction disease). CONCLUSIONS: The risk of
      permanent AV block in patients who undergo fast or slow pathway ablation is low
      and limited to the procedure or to the days immediately after the procedure, and
      there is no risk of II-III degree AV block during long-term follow-up.

PMID- 12611124
TI  - Safety and diagnostic accuracy of intravenous accelerated high-dose dipyridamole
      atropine stress echocardiography.
AB  - BACKGROUND: In the present study, the safety and diagnostic accuracy of a
      modified protocol with accelerated high-dose dipyridamole-atropine stress
      echocardiography, utilized in an attempt to significantly shorten the test
      imaging time with respect to the standard protocol, were evaluated. METHODS:
      Three hundred and thirty-seven patients (231 men, 106 women, mean age 63 +/- 9
      years) with known or suspected coronary artery disease underwent 404 tests. The
      ECG and blood pressure were continuously monitored during constant infusion of
      0.21 mg/kg/min of dipyridamole over 4 min; atropine (0.50 mg at 5 and 6 min) was
      given in order to reach > or = 85% of the age-predicated heart rate. The wall
      motion score index and the 16-segment model were used to evaluate contractility.
      Eighty-nine patients underwent selective coronary angiography. Coronary artery
      stenosis was considered significant if the vessel diameter was < 50% of the
      normal value. RESULTS: Eight-eight out of 404 tests were positive: 72 for
      echocardiographic criteria, 11 for ECG criteria, 2 for clinical symptoms, and 3
      for combined criteria. Three hundred and sixteen tests were negative. In 303
      tests atropine was administered and 380 tests were performed in pharmacological
      wash-out. The maximal heart rate was 105.8 +/- 9 b/min and the maximal blood
      pressure was 128 +/- 19/78 +/- 9 mmHg. No major side effects nor life-threatening
      complications were observed. In 24 tests (5.9%) only minor side effects occurred
      and in no case did these effects cause premature suspension of the test. The
      sensitivity, specificity and diagnostic accuracy of angiographically assessed
      coronary artery disease were 56, 86 and 73% respectively. CONCLUSIONS:
      Accelerated high-dose dipyridamole echocardiography is practical, feasible and
      safe and allows for a significant reduction in the imaging time, with an
      increased cost-effectiveness and tolerance of the patients. In our experience the
      diagnostic accuracy of this new protocol was quite good and similar to that of
      the standard test.

PMID- 12611125
TI  - Improving practice patterns in heart failure through a national cardiological
      network: the case of ACE-inhibitors.
AB  - BACKGROUND: Despite the well-established benefits of ACE-inhibitors in chronic
      heart failure (CHF), current treatment rates and prescribed doses are lower than
      those proven to improve survival. We evaluated whether participation in a
      specialist network and the use of a common database would impact on the
      compliance with CHF guidelines. METHODS: We analyzed the rate and determinants of
      ACE-inhibitor use and prescribed doses among 8102 patients with CHF enrolled at
      133 cardiology centers participating in a national network. RESULTS: 6625
      patients (82%) took ACE-inhibitors, most commonly enalapril (41%, mean dose 16 +/
      9 mg), captopril (25%, mean dose 74 +/- 44 mg) and lisinopril (14%, mean dose 13
      +/- 8 mg). The predictors of the non-prescription of ACE-inhibitors were: female
      gender (odds ratio--OR 1.46, 95% confidence interval-CI 1.28-1.67), older age (OR
      1.01, 95% CI 1.01-1.02), valvular etiology (OR 1.87, 95% CI 1.60-2.20), NYHA
      class III-IV (OR 1.25, 95% CI 1.09-1.42) and creatinine levels > 2.5 mg/dl (OR
      5.19, 95% CI 3.36-8.02). Conversely a left ventricular ejection fraction < 30%
      (OR 0.78, 95% CI 0.65-0.94) and a hypertensive (OR 0.69, 95% CI 0.55-0.86) or
      idiopathic (OR 0.67, 95% CI 0.57-0.78) etiology increased the rate of ACE
      inhibitor prescription. Low ACE-inhibitor doses were prescribed to 26.4% of
      cases. CONCLUSIONS: The IN-CHF database, an educational and organizational effort
      led by a national cardiology society, demonstrates that high rates of ACE
      inhibitor treatment may be achieved in routine clinical practice in a cardiology
      setting.

PMID- 12611126
TI  - Is an individualized treatment possible in patients with paroxysmal
      supraventricular reentrant tachycardia?

PMID- 12611127
TI  - Effect of renal artery stenting on the progression of renovascular renal failure:
      a case of intravascular ultrasound-confirmed renovascular disease.
AB  - We report the case of a 71-year-old male, submitted to percutaneous transluminal
      renal angioplasty (PTA) plus stent implantation following the confirmation, at
      intravascular ultrasound, of severe unilateral renal artery stenosis in the
      setting of a single functional kidney and of evidence of renal insufficiency
      (serum creatinine value 300 mumol/l). At 6 months of follow-up the serum
      creatinine levels had returned to normal (98 mumol/l). This case shows the role
      of direct PTA on the overall renal function in a case of global renal ischemia.

PMID- 12611128
TI  - Spontaneous coronary dissection of all three coronary arteries: a case
      description with medium-term angiographic follow-up.
AB  - Spontaneous coronary artery dissection is a rare cause of ischemic heart disease,
      often related with a poor prognosis. We report the case of a 38-year-old woman
      without cardiovascular risk factors, admitted to our coronary care unit for
      unstable angina with ECG findings of inferior ischemia. The day after, an acute
      anterior myocardial infarction occurred and was treated with intravenous
      thrombolysis. Again, there were ECG signs of transient inferior ischemia.
      Coronary angiography showed widespread spontaneous coronary dissection involving
      the terminal left main stem, both the left anterior descending and circumflex
      artery, and the right coronary artery even peripherally, rendering any type of
      revascularization procedure inappropriate. The patient was placed on beta
      blockers, acetylsalicylic acid and nitrates and her symptoms resolved; the 17
      month angiographic follow-up showed almost complete healing of spontaneous
      coronary artery dissection. The peculiarities of the case are discussed and a
      review of the literature is provided.

PMID- 12611129
TI  - Painless acute aortic dissection presenting as echocardiographically diagnosed
      left ventricular outflow tract obstruction.
AB  - We present an unusual case of painless acute aortic dissection with an atypical
      echocardiographic presentation that could be confused with an aortic stenosis.
      Transesophageal echocardiography excluded the presence of aortic stenosis and
      disclosed a systolic anterior movement of the mitral valve as the cause of left
      ventricular outflow tract obstruction. It also revealed a type A aortic
      dissection.

PMID- 12611130
TI  - Left ventricular free wall rupture: off-pump sutureless patch and glue technique.
AB  - Left ventricular free wall rupture is a well-recognized complication of
      myocardial infarction and is a frequent cause of death. Immediate surgical repair
      is the treatment of choice and many different surgical approaches have been
      reported. We describe an off-pump sutureless technique with the use of a
      glutaraldehyde-treated bovine pericardial patch and biological glue (N-butyl-2
      cyanoacrylate) in a 60-year-old male patient with echocardiographic evidence of
      cardiac tamponade and a free wall rupture site on the lateral wall. The recovery
      was uneventful and the patient was discharged from the hospital on the eleventh
      postoperative day. At 3 months, he remained well and without any symptoms.

PMID- 12611132
TI  - [Long-term outcome of conservative surgery for kidney cancer: survival, blood
      pressure, and renal function].
AB  - PURPOSE: Nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) remains
      controversial for elective indications (low stage RCC in the presence of a normal
      contralateral kidney). In this single center study survival rate and, as novel
      aspects, the frequency of postoperative arterial hypertension and renal function
      parameters were investigated to evaluate safety and efficacy of NSS. PATIENTS AND
      METHODS: The complete data of 248 patients operated nephron-sparing for RCC
      between 1975 and 1995 were evaluated. One hundred and seventy-five patients were
      treated for elective indication (95% with tumor stage T1 or T2), 73 patients for
      mandatory indication (bilateral tumors, solitary kidney, renal insufficiency).
      The mean follow-up was 75 months (maximum 23 years). RESULTS: Mean tumor-size was
      lower under elective (3.8 cm) than under mandatory (4.7 cm) indication. Overall
      tumor-specific survival after 5 years for both indications was 88%. Comparing
      preoperative vs. follow-up values, arterial blood pressure and serum-creatinine
      values remained unchanged for both indications. The incidence of postoperative
      proteinuria (19% imperative, 11% elective indication) was strongly related to
      hypertension. CONCLUSIONS: NSS for RCC under elective indication achieves patient
      survival comparable to the results of radical nephrectomy. The presented data do
      not indicate significant longterm complications such as arterial hypertension,
      proteinuria or deterioration of renal function as a result of glomerulosclerosis
      or hyperfiltration. This gives further argument for the concept of NSS in RCC as
      an alternative to radical nephrectomy in the presence of a healthy contralateral
      kidney.

PMID- 12611131
TI  - Large infero-posterior wall pseudoaneurysm of the left ventricle: an unusual
      presentation.
AB  - Post-myocardial infarction left ventricular pseudoaneurysm resulting from free
      wall rupture is a rare finding and its recognition during life is uncommon. The
      diagnosis is difficult since symptoms, clinical evaluation and
      electrocardiographic and X-ray findings are usually non-specific. We herein
      present a case of a pseudoaneurysm manifesting after a silent myocardial
      infarction and diagnosed at echocardiography in a patient who, at the time of
      hospitalization, had a history and clinical and laboratory findings suggestive of
      pulmonary embolism. The patient was successfully operated. The present report
      underlines the diagnostic and prognostic value of two-dimensional transthoracic
      echocardiography. The clinical and laboratory findings are also discussed in the
      light of the recent literature.

PMID- 12611133
TI  - [Microcatheterization with gadolinium and glue embolization for post-biopsy
      arteriovenous fistula in a patient with renal failure].
AB  - Percutaneous renal biopsy is frequently used in diagnosis of renal dysfunction.
      Nevertheless, complications, mostly vascular, may occur. Treatment must be
      minimally invasive with nephron preservation, especially in kidney failure. We
      present an interesting therapeutic approach with highly selective catheterization
      under gadolinium and glue embolization, leading to total cure of iatrogenic
      fistula without renal deterioration.

PMID- 12611134
TI  - [Spontaneous subcapsular hematoma of the kidney. Report of 6 cases].
AB  - Spontaneous subcapsular haematoma (SCH) of the kidney is a rare condition,
      secondary to kidney tumors in more than 50% of cases. Diagnosis is suggested by
      sonography and confirmed by CT-scan. Renal angiography, performed in
      haemodynamically stable patients, shows the origin of bleeding and allows
      embolization. The authors report 6 cases of SCH of the kidney, one of which
      occurred after extra-corporeal shock-wave lithotripsy.

PMID- 12611135
TI  - [Cutaneo-reno-colonic fistula in tubercular kidney with staghorn calculus: report
      of a case].
AB  - We report a rare case of colorenocutaneous fistula, in a patient with a stone of
      the left kidney. The fistula was successfully managed by single stage surgery
      (nephrectomy, fistulectomy and suture of colon). Histopathological examination
      revealed renal tuberculosis. Surgery was completed by an anti-tubercular
      treatment.

PMID- 12611136
TI  - ["Cystic incidentaloma" of the adrenal gland: report of a case].
AB  - Cystic tumors of the adrenal gland are uncommon, but are being increasingly more
      frequently diagnosed during routine radiological evaluation. The management of
      these "incidentalomas" remains to be defined. Adrenal cysts have been
      traditionally managed by excision or aspiration to rule out malignancy. Actually,
      for some authors, in the cases of incidentally found cysts, if the suspicion of
      malignancy is low, and the lesion is non-functional, observation of the patients
      with regular follow-up may be an alternative. We report a case of a non-aspirated
      incidental adrenal cyst with a follow-up of four years.

PMID- 12611137
TI  - [Right ovarian vein syndrome: report of a case and review of the literature].
AB  - Ovarian vein syndrome corresponds to ureteral compression by a dilated ovarian
      vein. The pathogeny of this syndrome is discussed. It seems to be multifactorial,
      comprising an anatomical and hormonal factors. Ovarian vein syndrome is
      classically described on the right side. Patients present with lumbar pain or
      renal colic. Diagnosis is mainly urographic. The surgery constitutes radical
      treatment of the entity. However, this disorder can be successfully treated
      laparoscopically. Transcatheter embolisation provides excellent result which may
      replace or complement the traditional surgical approaches of this disease. On the
      basis of one case and other recent series, the authors review its different
      aspects, including some considerations on this rarely reorganized and poorly
      understood disease.

PMID- 12611138
TI  - [Giant retroperitoneal liposarcoma: report of a case].
AB  - Liposarcoma is a rare and primary malignancy developed from mesenchymal tissue.
      We report the case of a 32-year-old woman who had a complete exeresis of a 15 cm
      retroperitoneal myxoid liposarcoma. Three months later, a 9 cm local recurrence
      was excised and radiotherapy was performed. In 2000, a local recurrence and an
      intestinal localisation of the liposarcoma were observed. The retroperitoneal
      tumor could not be removed and she had an intestinal resection followed by
      chemotherapy. With the literature data, we review the pathological, therapeutic
      and prognostic aspects of this tumor.

PMID- 12611139
TI  - [Vesico-uterine fistula of obstetrical origin. Report of 3 cases].
AB  - Vesico-uterine fistulae (VUF) lead to an abnormal breech between the bladder and
      the womb. They are responsible for urinary incontinence and/or cyclic hematuria.
      They are rare and, in most cases, lead to complications following caesarean
      deliveries. We report observations of 3 vesico-uterine fistulae treated over a 5
      years period at university maternity based at Casablanca, Morocco; they all
      occurred following caesarean deliveries. These patients were consulted for
      urinary leakage occurring few weeks up to many years following surgical
      traumatism. Diagnosis was evoked clinically in all cases and confirmed by
      intravenous urography and/or hysterography. These VUF were successfully treated
      by simple breech suture at laparotomy. Treatment is very simple and efficient
      when the diagnosis is made early and fistula simple. Surgery is recommended after
      medical treatment failure aiming at fistula drainage.

PMID- 12611141
TI  - [Epididymal tuberculosis: report of a case with particular color Doppler
      ultrasonography finding].
AB  - Isolated tuberculous epididymitis is a rare entity. Because of the increase of
      this pathology, tuberculosis should be considered in the differential diagnosis
      of a scrotal swelling even in the absence of a history of previous tuberculosis.
      We report a case of isolated tuberculous epididymitis, diagnosed in an early
      stage, with color Doppler ultrasound findings.

PMID- 12611140
TI  - [Seminal vesicle cyst associated with renal agenesis and ipsilateral ectopic
      ureter. Report of a case].
AB  - The authors report one case of a seminal vesicle cyst. They discuss this
      pathology and its relation to ureteral ectopy, as well as the therapeutic options
      for these entities. They present their experience in the resolution of this case.

PMID- 12611143
TI  - Prevention of allergy to acrylates and latex in dental personnel.
AB  - Contact allergy to acrylate monomers and immediate hypersensitivity to latex
      gloves in dental personnel calls for preventive measures to reduce the risks. The
      aim of the study was to evaluate the preventive effect of an information campaign
      after a 3-year follow-up. The campaign included instructions and training
      according to an ordinance, both in writing and orally, e.g. concerning the choice
      of products and protection devices and the proper handling of the materials. The
      follow-up was carried out through 1997-2000 and included all eligible 513
      subjects. Information on new cases was ascertained by a questionnaire and reports
      from the occupational health service and the department of dermatology. The
      number of expected new cases was based on the incidence rate, derived from a
      preceding prevalence study in the same county, and the exposed years at risk in
      the follow-up period. No new case of allergy to acrylates or latex rubber was
      found in the follow-up period as against 4.91 expected (p = 0.007). In
      conclusion, this study indicates that occupational allergies can be prevented
      successfully, but requires vigorous measures to influence the behaviour and the
      routines of daily work in dental practice.

PMID- 12611142
TI  - [Genito-urinary malacoplakia. Report of 10 cases and review of the literature].
AB  - The malakoplakia is a rare and benign disease. Its urinary localisation is
      commonly known. It has no clinical particularity. The diagnosis is histological.
      The physiopathology is infectious associated with a local macrophage function
      failure. The treatment associates antibiotic and colinergic drugs. Surgical
      removal is necessary only when the organ is destroyed. We report 10 cases of
      urinary malakoplakia with 4 renal localisation's causing pyonephrosis in the
      majority of cases, 3 prostatic localisation's that were wrongly considered as
      prostatic adenocarcinoma after a rectal examination and finally 3 testicular
      localisation's causing a necrotic destruction of the testis. The urinalysis was
      positive in 4 cases. We did 4 kidney removals, 3 endoscopic prostatic resections
      and 3 testis removals. The diagnosis was made by the histological examination of
      the surgical products.

PMID- 12611144
TI  - Long-term follow-up of intra-articular injections into the temporomandibular
      joint in patients with rheumatoid arthritis.
AB  - A long-term (12 years) follow-up of treatment with intra-articular injections
      into the temporomandibular joint (TMJ) of steroid or non-steroid agents was
      performed in 21 patients with rheumatoid arthritis (RA) and symptomatic TMJs. The
      aim of the study was to compare symptoms, signs and radiological appearance of
      the TMJ initially and at the follow-up in this group of patients. Eleven patients
      were assigned to a steroid group and 10 patients to a non-steroid group. Initial
      and follow-up clinical and radiological examination procedures were the same. The
      radiological evaluation was based on a grading system using standard reference
      films. At follow-up, 14 patients reported no pain from the TMJ and positive
      changes in most clinical variables were found in both groups. Radiographic follow
      up examination was performed on 12 patients. Initially, all but 4 of the 24
      joints had structural bone changes. At follow-up, 2 joints had lower, 11 joints
      had unchanged and 11 joints had higher radiological grades. Two out of 5 and 3
      out of 10 joints in the steroid and non-steroid group, respectively, showed
      progression of structural bone changes. Among 9 untreated joints, 6 had higher
      radiological grades and 3 were unchanged. In the 11 TMJs with higher radiological
      grades at follow-up, there was in most cases moderate progression of erosive
      changes. The results suggest that the long-term development of symptoms and signs
      from the TMJ in patients previously treated was good and the long-term
      progression of joint destruction was low for both steroid and non-steroid agents
      in this patient group with RA.

PMID- 12611145
TI  - Do intact collagen fibers increase dentin bond strength?
AB  - The purpose of the present study was to evaluate surface morphology and shear
      bond strength of All Bond 2 bonded to dentin surfaces, that were treated
      progressively to remove collagen fibers. For the study of surface morphology,
      fifteen teeth were divided in to five groups. Dentin surfaces in groups 1-4 were
      etched either with 24% EDTA for 30 seconds or 32% phosphoric acid for 15 seconds
      with and without subsequent treatment with 10% NaOCl for 60 seconds. Group 5
      received no treatment and served as control. Evaluation was performed using
      scanning electron microscopy. Thirty teeth were used for the shear bond strength
      test. Two experimental surfaces were prepared on each tooth and cylindrical
      copper matrixes were attached to the surfaces. Experimental surfaces were divided
      into four groups and treated in the same way as group 1-4 in the morphology part
      of the study. Dentin was bonded with All Bond 2, after which a flowable composite
      was inserted and light cured. Shear strength test was performed at a crosshead
      speed of 1 mm/minute until the composite debonded. Results showed that etching
      followed by treatment with NaOCl removed all collagen fibers from the dentin
      surfaces, while treatment with EDTA alone denuded the fiber structures. Shear
      strength was significantly decreased when surfaces were treated with NaOCl. The
      highest shear strength values were obtained in the EDTA etched group. The results
      from the present study indicate that exposed dentin associated collagen fibers
      increases adhesion of All Bond 2 to dentin.

PMID- 12611147
TI  - [Acute hemorrhage. View on the problem].
AB  - Acute hemorrhage is a main cause of reduction of blood oxygen capacity. The main
      aim of correction of sequels of acute hemorrhage is to maintain effective gas
      exchange by restoring central circulation and microcirculation, the rate of
      diuresis, by normalizing water-salt exchange, to eliminate anemia,
      hypoproteinemia, and acute blood coagulability disorders. The values of oxygen
      budget with calculated oxygen delivery and consumption and those of hemoglobin
      and hematocrit which are of great value only after recovery of circulating blood
      volume are considered to be major indications for hemotransfusion. A relationship
      is established between the extraction and uptake of oxygen and its delivery. The
      concept of the critical level of oxygen delivery is considered, ways of
      correcting oxygen indebtedness are presented. Alternatives to the use of
      hemotransfusions by employing the solutions of modified hemoglobulin and
      perfluorocarbon-containing emulsions are under consideration. A possible
      algorithm of aid rendering in acute hemorrhage is given.

PMID- 12611146
TI  - Caries prevalence in 3-year-old children living in a low socio-economic
      multicultural urban area in southern Sweden.
AB  - The aim of this study was to investigate the prevalence of dental caries in 3
      year-old children living in a multi-cultural low socio-economic urban area of
      Malmo, Sweden, and to establish its relationship to some medical, oral and
      behavioural factors associated with caries risk. All 238 children that became 3
      years of age between July and December 2000 were invited to participate and 94%
      showed up for examination. The parents completed a structured questionnaire
      concerning social and ethnic background, medical history and oral health
      behaviour and a clinical examination of the child was performed in optimal light
      with a mirror and probe. Visible plaque, gingival health and occurrence of
      initial and manifest caries lesions, extractions and fillings (defs) were scored.
      The prevalence of caries was 85% with a mean defs value of 4.4 +/- 4.3. Of those
      with caries, 55% had manifest lesions while 45% exhibited lesions that were
      limited within the enamel. The variables significantly associated with caries
      were frequent intake of meals (odds ratio, OR = 6.0), gingivitis (OR = 3.7),
      presence of visible plaque (OR = 3.2) and compromising medical conditions (OR =
      2.7). Children without fluoride supplements or fluoridated toothpaste had
      significantly (p < 0.05) more caries that those with a daily intake of fluoride
      (mean defs 7.2 +/- 5.3 vs 4.0 +/- 4.0). In conclusion, a high prevalence of
      caries was found in a low socio-economic multi-cultural population in an urban
      area of Malmo, Sweden. Thus, early childhood caries may still be a public health
      problem in certain groups, which calls for collective preventive measures to be
      re-instituted.

PMID- 12611148
TI  - [Acute and massive hemorrhage: mechanisms of compensation and damage].
AB  - To evaluate the body's compensatory reserves, experiments were made on
      anesthetized (with heparine) mongrel dogs of both sexes weighing 8-25 kg. The
      experiments have indicated that early monitoring of physiological parameters
      (external respiration, cardiovascular performance, hemostasis, red blood cell
      morphometry) in the first 5-10 minutes of acute massive hemorrhage is of high
      informative value. The generalization of vasoconstriction resulting in higher
      overall blood volume, the maintenance of venous return, tachypnea, active
      spontaneous hemodilution, and increased heart rate are the leading mechanisms of
      perfusion pressure maintenance in early acute hemorrhage. The severity of acute
      damage to the membranes of red blood cells and endotheliocytes and hence changes
      occurring in the suspension structure of blood, which drastically impairs its
      rheological parameters and fluidity, can play the key role in the pathogenesis of
      decompensatory cardiovascular and visceral functions in prolonged arterial
      hypotension. The findings open up new possibilities for early evaluation and
      prediction of the ensurina course of delayed massive hemorrhage.

PMID- 12611149
TI  - [Cardioprotective effect of exogenous creatine phosphate in acute hemorrhage].
AB  - Experiments on noninbred albino male rats under the conditions of the whole body
      and the isolated isovolumically contracting heart have shown that a substantial
      contribution to postresuscitative cardiac damages is made by energy deficiency
      that triggers a group of mechanisms of damaging cardiomyocytic membranes.
      Exogenous creatine phosphate (CP) reduces postresuscitative mortality rates,
      improves bioenergy, contractile and rhythmical functions of the heart, decreases
      the rate of myocardial lipid peroxidation, by showing as a whole a
      cardioprotective action. The latter is realized by directly protecting the
      cardiomyocytic sarcolemma and the improvement of energy metabolism is secondary.
      Despite the likely mediation of this effect, improved energy metabolism is
      undoubtedly a key point of the protective action of exogenous CP if the heart is
      postresuscitatively damaged.

PMID- 12611150
TI  - [Permeability of the blood-brain barrier in severe craniocerebral trauma].
AB  - Permeability of the blood-brain barrier was studied by comparing the molar
      concentrations of albumin and alpha 2-macroglobulin in the spinal fluid and blood
      of patients with severe brain injury. If the outcome was good, the selective
      permeability of the barrier was shown to be fully retained, which meant that its
      regulatory and protective functions remained normal. If the outcome was poor, the
      selective permeability changed to a greater extent and the alterations found
      suggested that the regulatory function of the barrier was preserved with
      simultaneous loss of its protective properties. More marked changes in the
      function of blood-brain barrier and in the protein composition of spinal fluid
      occurred with simultaneously elevated intracranial pressure.

PMID- 12611152
TI  - [Laser radiation to correct disorders of blood albumin transport in severe
      mechanical trauma].
AB  - The paper provides evidence for that it is expedient to perform multi-stage
      intravascular low-intensity laser blood radiation in patients with severe
      mechanical trauma and massive blood loss in the early posttraumatic period. The
      use of laser radiation at a wavelength of 632.0 nm by inserting a disposable
      light guide (its end power was 1.5-2.0 mW, and the duration of a session--30 min)
      as part of complex therapy in this group of patients romotes the increase of
      plasma albumin transport ability and the general stimulation of natural
      detoxifixation mechanisms.

PMID- 12611151
TI  - [Spectrum of plasma lipoproteids in patients with severe mechanical trauma].
AB  - Changes in the plasma lipoprotein spectrum were studied in patients with severe
      mechanical trauma. These changes were shown to be associated with the severity of
      injury and with the age of patients. The steady-state reduction in the plasma
      concentrations of cholesterol in patients aged under 55 years who have a serious
      mechanical trauma may be considered to be a poor predictor. In patients above 55
      years, the severity of their condition may be judged from the changes in the
      concentration of high density lipoproteins: the positive changes in this
      parameter are indicative of a good clinical outcome.

PMID- 12611153
TI  - [Role of autoPEEP in the optimization of the respiratory pattern in patients with
      acute parenchymatous lung diseases].
AB  - The paper presents the results of a study of the impact of autoPEEP (positive end
      expiratory pressure) on gas exchange in the lungs, their biomechanical
      characteristics, the transport and consumption of oxygen by inverting the
      inspiration/expiration ratio under the volume-controlled mechanical ventilation
      of the lung (VCMVL) in patients with acute parenchymatous lung lesion, as well as
      how to choose the optimum inspiration/expiration ratio in VCMVL by analyzing the
      pattern of total PEEP (the sum of positioning and autoPEEP) in this group of
      patients.

PMID- 12611154
TI  - [Effects of perftoran on experimental acute intestinal ischemia].
AB  - The studies were carried out on 76 albino noninbred male rats weighing 210-420 g.
      Ischemia of a jejunal segment was induced by applying a tourniquet to the base of
      a loop with the mesentery until the circulation fully stopped. Nonoxygenated
      perfluorane (an experimental group) or saline solution (a control group) was
      injected in a dose of 0.8-1.0 ml/100 g intraarterially 15 minutes before the
      termination of ischemia. During 90 min of reperfusion, there was a progressive
      decline of blood pressure (BP) with reference to the ischemic period by 39.8 +/-
      20.9 and 20.8 +/- 14.6% in an experimental and control groups, respectively (p >
      0.05). Biomicroscopy indicated that by min 5 of reperfusion, a relative reduction
      in the diameter (50-400 microns) of nutrient mesenteric arteries was half as
      large as that in the control group (24.0 +/- 5.5 and 45.1 +/- 3.6%; p < 0.05); by
      min 90, differences decreased (41.5 +/- 4.2 and 50.3 +/- 2.8%, respectively; p >
      or = 0.05). In the experimental group, perfluorane prevents the development of
      irreversible structural changes in the reperfusion period: the remaining cryptal
      epithelium is a source of regeneration of the integumentary epithelium of forming
      villi of the small intestinal mucosa.

PMID- 12611155
TI  - [Perftoran infusion in acute myocardial infarction].
AB  - Fifty patients with acute myocardial infarction were examined after infusion of
      perfluorane. Microcirculatory status was evaluated by biomicroscopy of the eye
      conjunctival capillaries. Changes in the capillaries were evaluated by B-Ditcel
      classification. Myocardial status was studied by ECG and EchoCG. Myocardial
      contractility was assessed by the degree of shortening of the anteroposterior
      size and ejection fraction. Changes in coagulogram were studied. After the
      infusion of perfluorane, the number of functioning capillaries increased, venous
      congestion decreased, arteriolar and venular diameters increased, and
      hypercoagulation was corrected.

PMID- 12611156
TI  - [Role of multimodal evoked potentials in evaluations of persistent vegetative
      state of nontraumatic origin].
AB  - Persistent vegetative state (PVS) is a kind of release from coma, manifesting by
      absence of any signs of cognitive activity. Progress in reanimatology leads to an
      increase in the number of patients with PVS, thus creating a new medical and
      social problem. Study of atraumatic PVS acquires special importance because of a
      drastic increase in its incidence, necessitating definition of criteria of this
      state formation and its prognostic signs. Multimodal evoked potentials (MEP) now
      play an important role in diagnosis and prediction of PVS. The impact of acoustic
      stem (ASEP), visual (VEP), somatosensory (SSEP), and cognitive (CEP) evoked
      potentials is analyzed and early diagnostic and prognostic neurophysiological
      criteria are defined. Results of dynamic examinations of 23 patients (9 men and
      14 women) aged 10-67 years with atraumatic PVS are presented. According to
      neurophysiological data, PVS in the majority of patients is characterized by
      absence of cognitive responses to a significant stimulus (wave P300) during
      examinations of CEP and of cortical response during examination of SSEP. VEP and
      long latent acoustic evoked potentials are as rule intact in atraumatic PVS.
      According to ASEP, stem functions were intact or slightly changed in the examined
      patients with PVS. Prognostically unfavorable and relatively favorable signs in
      the time course of MEP are defined.

PMID- 12611157
TI  - [Relationship of immune imbalance with the development of multiple organ failure
      in patients with complicated postoperative period after the cardiac surgery].
AB  - A relationship of the functional status of the viscera with the immune system was
      studied in 38 cardiac surgical patients with septic complications and multi-organ
      failure in the postoperative period. In deceased patients (n = 13), the total
      functional organ compensation index was lower whereas the total functional
      decompensation index was higher than those in survivors (n = 25). In the deceased
      patients, each vital organ was more commonly decompensated than that in the
      survivors, but a definite discrepancy was ascertained only in the immune system
      (92% versus 16%, p < 0.0001). The average number of decompensated organs was
      found to increase with the severity of immunological disorders. Therefore, there
      is a rather high correlation between the functional status of vital organs and
      the degree of immunological imbalance. The authors show it necessary to use
      immunity-corrective drugs (splenopid) to enhance the efficiency of treatment
      organ failure.

PMID- 12611158
TI  - [Therapy of arterial hypertension with verapamil hydrochloride in patients after
      myocardial revascularization].
AB  - Verapamil hydrochloride, a calcium blocker from a group of phenyl alkylamines,
      was tested for its effect on central hemodynamics (CH) and blood oxygen
      transporting function (BOTF) in 14 patients with arterial hypertension after
      surgical myocardial revascularization. CH and BOTF were studied by using a Swan
      Hanz catheter and directly measuring blood pressure (BP). There was a significant
      reduction in BPmean, total peripheral vascular resistance index, left ventricular
      stroke outcome index, and oxygen delivery index. Verapamil in an average dose of
      80.4 +/- 18.02 mg at the injection rate of 24.6 +/- 3.9 micrograms/kg/min was
      shown to make BPmean normal 16.8 +/- 6.35 min later. The agent is comparable with
      other calcium blockers, such as nifedipine and isradipine in its action on CH and
      BOTF, as well as in its efficiency and safety.

PMID- 12611159
TI  - [Kinetic modeling during continuous hemodiafiltration in patients with sepsis and
      multiorgan failure].
AB  - Kinetic simulation in terms of urea and creatinine is the best way of prescribing
      a dialysis dose and assessing its quality as it considers differences in a
      patient's body weight, the level of catabolism, the rate of equilibration,
      including the recirculation phenomenon noticeably observed under shock. A 2-pool
      model of distribution of urea and creatinine was employed in the study. The
      latter was carried out in 31 patients (17 males and 14 females) with sepsis and
      multi-organ failure receiving 50 sessions of continuous hemodiafiltration (CHDF).
      The mean duration of CHDF was 73.8 +/- 7.0 (4.0-207.0) hours, the daily volumes
      of a substitute, a dialysate, and an effluent (filtrate + dialysate) were 33 +/-
      1.0 (5.0-60.0), 43.9 +/- 0.8 (2.6-62.0), and 80.4 +/- 1.6 (12.0-122.3) liters a
      day, respectively. An analysis confirmed the high efficiency of CHDF close to
      that of the daily volume-body weight ratio and showed that such conditions of the
      procedure are optimal in maintaining azotemia at the subnormal level irrespective
      of the degree of cababolism.

PMID- 12611160
TI  - [Therapeutical potentialities of rapid opioid detoxification].
AB  - The influences of rapid detoxification (RD) versus the routine approach to
      abolishing the withdrawal syndrome on the clinical manifestations of opioid
      dependence were evaluated. The use of RD revealed a therapeutical dissociation:
      its effective influence on somatoneurological manifestations of the withdrawal
      syndrome and its very insignificant impact on mental disorders, including drug
      addiction. It is concluded that RS is a modern and promising method to arrest the
      opioid withdrawal syndrome, which is alternative to other therapeutical
      approaches, but inadequate to treat drug addiction.

PMID- 12611161
TI  - [Complex therapy of pancreatitis in patients with chronic alcoholism].

PMID- 12611162
TI  - [The shape of high-voltage impulse and the effect of defibrillation].
AB  - The paper discusses how to choose the optimum shape of a pulse for electric
      defibrillation of the heart. The authors' data are given on the values of an
      induced field in the contracting myocardial structure when a defibrillator evokes
      pulses. Mono- and bipolar pulse-induced changes of the transmembranous potential
      on the hyper- and depolarized sides of a cell are calculated. Mechanisms of
      defibrillation in the use of pulses of different shapes are considered.

PMID- 12611163
TI  - [Therapy of postresuscitation behavioral disorders with mexidol and kyotorphin].
AB  - A complex of behavioral tests revealed diminished anxiety, increased locomotor
      and exploratory activities, and changes in different learning tests in
      resuscitated animals. Mexidol alone and in combination with kyotorphin exhibited
      antistressogenic and nootropic activities, and led to a compensation of ischemic
      lesions in rats. It can be stated that a the injection of mexidol in combination
      with kyotorphin yielded better results due to its neuroprotective effect in the
      CA1 and CA4 fields of the hippocampus.

PMID- 12611164
TI  - [Glutamine metabolism in the brain and in the liver in critical conditions].
AB  - Experiments on cats and rats have established that critical conditions caused by
      acute hemorrhage, hepatotoxin, and hepatectomy lead to ammonia accumulation in
      the brain and liver due to the predominance of decay of glutamine over its
      formation in these organs. With this, the depressed formation of glutamine is a
      universal cell response to a pathogenic agent whereas a change in glutamine
      deamination in disease depends on both the nature of a pathogenic agent and the
      organ wherein this reaction occurs.

PMID- 12611165
TI  - [Development of individual hyperbaric oxygenation regimens].

PMID- 12611166
TI  - [Non-steroidal antiinflammatory agents in therapy of postoperative pain].

PMID- 12611167
TI  - [The role of forces "vis a fronte" in the formation of venous return of blood to
      the heart].
AB  - Changes in venous return compared with changes in negative intrathoracic pressure
      at deep breathing and in right atrial pressure after the administration of
      pressure stimuli on the cardiovascular system were studied in acute experiments
      with anesthetized cats. No correlation was found between the value of negative
      intrathoracic pressure and the mean value of venous return or between the mean
      value of right atrial pressure and the mean value of venous return in the intact
      cardiovascular system provided the animal body is placed horizontally. It was
      concluded that both the negative intrathoracic pressure and the right atrial
      pressure are not the main factors influencing the venous return volume.

PMID- 12611168
TI  - [Current views on the pathogenesis of atherosclerosis from the position of
      infectious pathology].
AB  - The role of immune inflammation at atherogenesis is studied in the paper. Two
      etiological factors of atherosclerosis pathogeny are under examination: the role
      of modified low density lipoproteins (mLDL) and essential parasites (Chlamydia
      pneumoniae and Cytomegaloviruses). Generality of immune response during
      persistent infection into a blood vessel wall and deposit or formation of mLDL
      are discussed. The point of view is substantiated that the development of
      atherosclerotic damages of blood vessels is speeded up by a combination of the
      two mentioned etiological factors.

PMID- 12611169
TI  - [Achievements and problems in studies of antibiotic peptides of an organic
      origin].
AB  - The paper contains the original data of the authors and literature survey in the
      field of studies of the structure and functions of antibiotic peptides. Physical
      and-chemical as well as structural properties of a new subfamily of defensins,
      i.e. minidefensins (theta-defensins), are described in detail. Mechanisms of the
      antibiotic action of defensins and bactenecins as well as their role in
      regulating the body immune reactions are discussed.

PMID- 12611170
TI  - [Therapeutic potential of protein kinase CK2 modulators].
AB  - Data on the nuclear cascade of signal transduction, including protein kinase CK2
      (PKCK2), transcription factor HMG14 and chromatin myosin-like proteins, are
      generalized with regard for the modern understanding of mechanisms of synaptic
      plasticity. The role of the neurospecific isoform and subunit structure of PKCK2,
      of the individual subunit autophosphorylation of PKCK2, of phosphorylation of
      substrate-proteins in the enzyme activity and of conformation transformations of
      chromatin is examined. Data on changes in the CK2-induced cascade and synaptic
      plasticity in learning, on age-related amnesia and on cognitive deficits induced
      by ethanol and chloridine in rat embryos are presented. The prospects for using
      modulators PKCK2, 4,5-di(N-methylcarbamoyl)-l-alkyl-imidazoles, as potential
      nootropics are discussed.

PMID- 12611171
TI  - [Immune response to live influenza vaccine].
AB  - Priority data on the induction, by using a Russian live cold-adapted reassortant
      influenza vaccine (LIV), of the cellular and humoral immunity with regard for
      attenuation and genetic reassortment of vaccine stains as well as with regard for
      the age of vaccinated persons and the production of Th1 (IFNY, IL-2) and Th2 (IL
      4) cytokine markers in vitro are presented. It was demonstrated in vivo that a
      pathogenic virus of the A group by far more actively induced the lymphocyte
      apoptosis as compared with attenuated genetically reassorted stains. Unlike the
      influenza pathogenic virus, the genetically attenuated and reassorted strain did
      not produce any negative effects on the induction of cellular immunity. A
      comparative study of the LIV immunogenic properties in vaccinated persons showed
      an advantage of LIV over inactivated influenza vaccine (IIV) in stimulating the
      cellular and local immunity in the elderly. Unlike IIV, LIV induced an active and
      balanced immune response developing due to Th1 and Th2 activation. LIV was found
      to stimulate well enough the production of IFN and IL-2 in both young and old
      persons.

PMID- 12611172
TI  - [Neuropeptide induction of compensatory processes at aphasias].
AB  - Dynamic changes of speech function were studied in patients with persistence
      aphatic disorders after stroke under the conditions of application of V2
      vasopressin receptor agonist (1-desamino-8-D-arginin-vasopressin). A course of
      intranasal administration of the medical drug by using the double blind control
      showed a reliable reduction of frustration severity of expressive and impressive
      speech in patients with aphasias of different forms and degrees. A correlation of
      positive influence of vasopressin on speech, verbal memory and attention was
      found at efferent motor aphasias. The achieved effects preserved during a two
      year catamnestic observation period. A repeated course of therapy resulted in an
      additional improvement of speech. Neuropeptide restored initially, in patients
      with aphasias, relatively simple forms of speech and later--complicated ones.
      This resulted in an improvement of speech functions which are regulated by both
      cerebral hemispheres. Supposedly, neuropeptide optimized the activity of both the
      right and left cerebral hemispheres. The stability of the obtained effects is
      explained by induction, due to vasopressin, of compensatory processes leading to
      reorganization of intercentral connections.

PMID- 12611173
TI  - [Damaging impacts at the critical time periods of prenatal ontogenesis as a
      factor modifying the cerebral structural development and postnatal behavior
      reactions].
AB  - Results of a study of the nature of changes in the rat neocortex, which were
      observed during an early postnatal period (postnatal days 1 to 10) and which were
      induced by a single prenatal hypoxia on the 16th or 19th embrionic day (E16,
      E19), are presented in the paper. Acute hypoxia, administered on E16, was shown
      to result in an underdevelopment of cortical layers as well in damage to cell
      orientation and differentiation, i.e. it disturbed the histogenic processes
      (proliferation, migration and differentiation), which are most active at this
      time period. An immunohistochemical examination of the brain made during the
      postnatal period after an intrauterine hypoxia suggests that damage to
      proliferation and differentiation occurred in glial cells. Hypoxia administered
      on E19, when the level of proliferation in the brain was lower, had a less
      pronounced damaging effect. Deviations in the neocortical structure and in the
      animal's behavior found during the postnatal period could be caused by the
      heterochromic and heteromorphous development of brain regions in the fetus.

PMID- 12611174
TI  - [Study of IS-elements aimed at establishing a degree of the relationship of
      multiple-serotype Streptococcal strains of group B].
AB  - The presence and restriction fragment length polymorphism of IS 861 and IS 1548
      were analyzed among 113 streptococcal strains of group B. 13 strains were found
      to possess both IS 861 and IS 1548, 54 strains were found to possess only IS 861,
      and 46 strains had neither IS 861 nor IS 1548. 9 HindIII and 6 EcoRI restriction
      patterns, hybridizing correspondingly with IS 861 and IS 1548, were discovered. A
      certain correlation between IS 1548 and IS 861 hybridizing patterns, on the one
      hand, and restriction patterns, found by pulse-electrophoresis, on the other
      hand, was established. It was demonstrated that restriction fragment length
      polymorphism of IS 1548 and 861 can be used to evaluate the degree of
      relationship between the strains.

PMID- 12611175
TI  - [Protein of Escherichia coli interacting specifically with human low density
      lipoproteins].
AB  - Escherichia coli 48 kDa protein interacting specifically with human low-density
      lipoproteins is described. The dissociation constant of this highly specific
      interaction was found to be equal to 4 mkg LDL per 1 ml or 7.3 x 10 M, which is
      comparable with the dissociation constant of the complex formed by LDL and human
      LDL receptor. A protocol for purifying the E. Coli binding protein was developed
      and antibodies against this purified protein were raised. The absence of
      sequences with homology to the ligand-binding repeats of the human LDL receptor
      in E. Coli proteome was shown by computer analysis of E. Coli genome. A
      conclusion was made that binding of the human LDL with specific E. Coli protein
      is thus mediated by other sequences and by another mechanism different from that,
      which occurs in human cells during the interaction of lipoproteins with their
      specific receptor. The establishment of specific interaction between E. Coli
      protein and human LDL can turn out to be useful in the future for purifying
      lipoproteins of a specific class and for administering plasmapheresis in patients
      with severe hyperlipoproteinemia.

PMID- 12611177
TI  - [Geriatric psychiatry in Russia: the state-of-the-art and prospects of
      development].

PMID- 12611176
TI  - [Neurogenic heart injuries and their pharmacological correction by a new taurine
      derivative].
AB  - An antiischemic effect of a new n-phenylalkyl derivative of taurine was shown in
      experiments with rats. The effect is predetermined by an improvement of energetic
      metabolism in the myocardium, by the restoration of the activity of energetic
      exchange enzymes and by a reduction of the lipid peroxidation intensity. Besides,
      it was found that the drug can inhibit the activity of cytokines (IL-l gamma, and
      TNF gamma), which can be of significant practical importance in the treatment of
      myocardial ischemia and chronic heart insufficiency.

PMID- 12611178
TI  - [Autoimmune myocarditis: current aspects of immune pathogenesis].

PMID- 12611181
TI  - [Youths who do not consult ... how to improve adolescent health care access?].
AB  - Several studies have shown that a substantial part of teenagers suffer from light
      to severe health problems but that many of them feel embarrassed to consult or
      have difficulties in accessing to proper health care. This situation is linked
      with two main factors: On one hand, adolescents live a transitional period of
      their life during which they no longer depend on their parents to decide when and
      where to consult and do not know how to use the health care system. On the other
      hand, as they are struggling for their autonomy, they usually want to solve their
      problems themselves and any form of help may be felt as a menace to their growing
      independence. This paper discusses several opportunities to solve the problem of
      the discrepancy between teenagers' health needs and health care. One first avenue
      is to improve the health professionals' knowledge and skills and to encourage a
      physician-patient relationship based on empathy, confidentiality and mutual
      confidence, as well as the professional's ability to focus not only on problems
      but also on the adolescent's resources. A second mean is to enhance the
      accessibility and attractiveness of the health care facilities and services. A
      third way is to develop a network approach, a close collaboration with the
      professionals who work closely with young people and who can thus encourage them
      to seek help when needed (low-threshold approach).

PMID- 12611180
TI  - [Vaccines against poverty].
AB  - In spite of major technological advances during the past ten years, the gap
      between rich and poor countries remains considerable. Among the 10.5 million
      children deaths in 1995, 99% occurred in developing countries and 1% in
      industrialised ones. Only 5 diseases (pneumonia, diarrhoea, measles, malaria and
      AIDS), as well as malnutrition, are responsible for more than 60% of the deaths.
      Most of them could be averted by an equitable access to health care and
      efficacious prevention programmes in the community. Every year, 3 million
      children are saved thanks to routine vaccinations, but also 4 millions die
      because they are not immunised, and this almost exclusively in developing
      countries. It is therefore urgent to develop strategies aimed at reaching the
      poorest of the poor, in order to reduce the burden of disease in these population
      and contribute thus to the well-being of families and to a sustainable economical
      development.

PMID- 12611182
TI  - [Children and scuba diving. How to start?].
AB  - Contra-indications to scuba diving are now well defined. The number of children
      practicising this sport is increasing. However, no consensus nor prospective
      study exists that allows to determine an age under which physicians should advise
      against scuba diving. This paper reviews many different approaches and,
      considering physiopathology and intellecual development, suggests a practical
      attitude.

PMID- 12611183
TI  - [Community-acquired pneumonia in children: applications of the WHO decision trees
      in Switzerland].

PMID- 12611184
TI  - [My child bleeds easily: clinical and paraclinical approach].
AB  - The aim of this review article is to provide a clinical guideline for the child
      presenting with easy bruising, distinguishing among the different etiologic
      groups associated with this symptom what is normal and what is not, allowing then
      to establish an algorithm for work-up and follow-up. We also precise in which
      concrete situation it would be necessary to refer the child to a pediatric
      hematologist.

PMID- 12611185
TI  - [Chronic arthroses in children: practical approach and epidemiological data].
AB  - Osteo-articular symptoms are frequent in pediatrics, but chronic arthritis is
      rare in childhood. Arthritis may be difficult to recognize in children and there
      is a large differential diagnosis including infectious and neoplastic diseases.
      Even if juvenile arthritis has often a favourable course, significant functional
      damage may occur. The diagnosis and the follow-up of chronic arthritis should be
      performed in collaboration with a specialized consultation in pediatric
      rheumatology, in order to allow access to multidisciplinary medical care and help
      to increase the clinical and epidemiological knowledge in these rare diseases. A
      study is starting this fall aimed at collecting epidemiological datas on
      childhood arthritis in the french part of Switzerland.

PMID- 12611186
TI  - [Ambulatory parenteral antibiotics in the treatment of severe pediatric
      infections].
AB  - The indications to parenteral antibiotic treatment in paediatrics are frequent.
      Antibiotic agents with antimicrobial spectrums and pharmacodynamic properties
      allowing effective and secure outpatient parenteral therapy are now widely
      available. Outpatient treatment has a number of advantages including important
      economic benefits. The physician responsible for conducting such treatment should
      select patients according to strict criteria and never neglect security and
      quality issues. In this article, the authors discuss different aspects (general,
      medical, psychosocial, economic and practical) related to outpatient parenteral
      antibiotic treatment of severe paediatric infections.

PMID- 12611187
TI  - [Hemolytic-uremic syndrome: varieties and particulars in the pneumococcal form; a
      case report].

PMID- 12611188
TI  - [Diagnosis and management of urinary tract dilatations detected in utero].
AB  - About 1% of the newborns show abnormalities of the urinary tract, representing
      25% of the antenatally detected malformations. Most of these urinary
      abnormalities are detected by prenatal ultrasound between the 14th and the 22nd
      week of gestation. Their outcome is determined during the first weeks of
      pregnancy and depends on the degree of renal impairment and the presence of
      associated extrarenal malformations. Establishing the outcome is often difficult,
      however it can be predicted by ultrasound and biochemistry of fetal urine.
      Prenatal management should consist in follow-up and careful organisation of the
      postnatal management of congenital uropathies. Every antenatally dilated urinary
      tract requires postnatal investigation. Postnatal ultrasound on the 3rd to 4th
      day of life is recommended for confirming or excluding urinary abnormalities. In
      case of persistence, ultrasound has to be completed by other radiologic methods.
      Voiding cystourethrography and/or nuclear renography allow to identify the origin
      of the observed abnormalities. Apart from a few situations needing immediate
      correction, surgical treatment is rarely indicated. The principal of postnatal
      management is prevention of urinary tract infections by antibiotic prophylaxis
      and a close follow-up until adulthood.

PMID- 12611189
TI  - [Glomerular filtration markers in pediatrics].
AB  - The assessment of glomerular filtration rate (GFR) is critical for the diagnosis
      and management of renal diseases in pediatric nephrology. Ideally, it requires
      the measurement of the renal clearance of a filtration marker. Inulin, an
      exogenous marker, is the only compound the excretion of which occurs exclusively
      by glomerular filtration, with no tubular handling. Therefore, inulin clearance
      provides the most accurate method to measure GFR and is considered as the "gold
      standard", at all ages including very premature neonates. However, inulin
      dearance is cumbersome and alternative methods are used in clinical practice. If
      urine is available, endogenous creatinine clearance is the most reliable method.
      When urine collection is difficult to obtain, GFR can be estimated by the plasma
      concentration of endogenous markers mainly eliminated by glomerular filtration,
      such as creatinine, or the more recently described cystatin C and beta 2
      microglobulin. When the endogenous production of these markers is constant, their
      plasma concentration reflects glomerular filtration; it increases with decreasing
      renal function. However, in pediatric patients creatinine production depends on
      muscle mass, which significantly increases with linear growth, as well as age and
      gender. Mathematical formulas taking these parameters into account have thus been
      developed. Among these, the so-called "Schwartz formula" is often used and is a
      reliable estimate of GFR in children. Finally, radionuclide renal scans can be
      used to evaluate the separate glomerular function of each kidney.

PMID- 12611190
TI  - [Normal values in pediatric nephrology].
AB  - The presence of renal disease can be excluded on the basis of a few simple tests:
      some of them are performed at the bed side: the assessment of miction frequency
      and urine flow rate, urine analysis by dipstick, urine specific gravity and
      osmolality. All these simples tests provide valuable information. When suspected,
      a functional defect can be confirmed by analyzing the urinary excretion of urine
      solutes, such as proteins, glucose and electrolytes. Imaging studies such as
      ultrasonography and radioisotopic scintigraphy can define the size and the
      separate function of the kidneys. The assessment of blood pressure is mandatory
      in childhood, the more so when renal disease is suspected. Normal values for all
      these parameters vary as a function of age, body weight and body surface area.
      They are briefly described here.

PMID- 12611192
TI  - [Ketotic hypoglycemia in children].
AB  - Idiopathic ketotic hypoglycemia is the most frequent cause of hypoglycemia in
      children between 1 and 5 years of age. The symptoms and signs of hypoglycemia are
      often overlooked because they mimic signs of other common diseases like
      psychiatric disorders, migraine, gastro-enterological dysfunction, or visual
      disturbances. Glycemia and ketone bodies in the urine should be systematically
      investigated in such cases. Because hypoglycemia is a life-threatening event and
      can lead to severe neurological sequelae, intravenous administration of glucose
      is mandatory. These children respond promptly to glucose. Infants with normal
      growth and psychomotor development, normal physical examination who present with
      a first episode of symptomatic fasting hypoglycemia and elevated ketonuria, and
      who improve quickly after intravenous glucose administration, do not need a
      comprehensive metabolic and endocrine workup. Recurrence of hypoglycemic attacks
      can be prevented by supplying frequent snacks containing complex carbohydrates,
      so called "slow sugars", particularly at bed-time. Other causes of ketotic
      hypoglycemia are briefly presented.

PMID- 12611191
TI  - [Heliox in pediatrics].
AB  - Heliox is composed of oxygen and helium and its low specific gravity allows a
      modification of the gas flow within the airway. Breathing heliox favors a laminar
      flow and therefore decreases the work of breathing. Its usefulness in the child
      is established in croup or in post-extubation stridor. It can be considered if
      conventional treatment fails to improve the child's breathing pattern. Its major
      goal is to avoid invasive manoeuvers as much as possible.

PMID- 12611193
TI  - [The pediatrician, his laboratory and its uncertainty].
AB  - Four aspects of uncertainty linked to the laboratory of medical analysis are
      discussed. 1) Uncertainty and the laboratory test: the post-test probability of a
      diagnostic is intimately linked to the ability to establish clinically the pre
      test probability. 2) Uncertainty and the patient: reference values are most often
      chosen from the literature. The analytical methodology as well as the population
      of reference should be carefully checked. 3) Uncertainty and the laboratory
      result: this uncertainty will diminish if preanalytical conditions are
      standardized and if analytical imprecision is known. The analytical imprecision
      is given by the coefficient of variation (CV) of the internal quality control.
      The CV is used to calculate the critical difference. 4) Uncertainty and the
      practitioner: to efficiently diminish this uncertainty in the case of unusual
      questions of the medical practice, a network should be established between the
      practitioner, the medical specialists and the scientific specialists of the
      laboratory.

PMID- 12611194
TI  - [Local resources in management of adult victims of violence and abuse: a method
      of presentation and diffusion].
AB  - Always more health problems require integrated care. So professionals needs to be
      aware of local and regional network resources (social, legal, home care, etc.)
      and specific offers of each individual institution. This article present a method
      used for creating a register of institutions involved in adults violence and
      elder abuse, for health professionals. Dates collected by interviewing
      professionals permitted to class institutions by intervention domain and offer.
      Five utility indicators (POUCE method) were selected for the register. A score
      has been attributed to each institution according to their problematic-related
      offers. Professional in charge of each institution validated information. This
      map, available in paper or CDrom, affords general practitioneer a quick and
      targeted access to a large number of dates, according to patient needs. This
      method could be useful for other health problems requiring exhaustive and
      targeted information about local and regional community resources (alcoholism,
      addiction, palliatives care, etc.)

PMID- 12611195
TI  - [Social pharmacology: a new topic in clinical pharmacology].
AB  - Social Pharmacology, a new field in Clinical Pharmacology, describes the
      relationships between Society and Drugs. Topics of Social Pharmacology are first,
      the social consequences of populations' exposure to drugs and, secondly, the
      social factors explaining drug use behind clinical or rational explanations.
      Social Pharmacology also investigates the reasons for prescription, delivery,
      consumption and self-medication of drugs (behind clinical or rational factors).
      The paper discusses the role of the different players of Social Pharmacology in
      the field of drug development, evaluation, prescription and consumption. For
      example, the pharmaceutical industry should play an important role in the
      discovery of new medically and socially "desirable" drugs. Drug companies are
      also involved in this field for drug information to doctors but also patients.
      Regulatory agencies are concerned by social factors involved in drug approval,
      regulation of the maximal level of drug use, application and transferability of
      clinical trials to daily clinical practice. Social Pharmacologists also
      investigate the factors (others than clinical or rational) regulating drug use.
      Drug consumption varies according to social characteristics of physicians (sub
      speciality, medical education, cultural origin, etc) or patients (gender, age,
      education, country, kind of work, social status etc). Relationships between drugs
      and religion make up a large chapter of Social Pharmacology. Other topics in
      Social Pharmacology involving other health professionals (pharmacists), lawyers
      and the media are also discussed. Finally, drugs should be considered as
      important social markers of population behaviour. The role of the Social
      Pharmacologist is to identify these social and irrational factors governing drug
      use in order to adapt and rationalize drug utilization in daily clinical
      practice.

PMID- 12611196
TI  - [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism].
AB  - Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several
      compounds relevant in pharmacology or toxicology, with diverse clinical
      consequences. Inter-ethnic variations in distribution of the acetylation
      phenotype are significant. The caffeine test is most often used to assess the
      acetylation phenotype and to identify rapid and slow acetylators. The NAT2
      phenotype could account for the increased risk of certain side effects in slow
      acetylators treated with isoniazid (particularly peripheral neuropathies and
      lupus erythematosus), although therapeutic efficacy seems to be independent of
      the acetylation status. Hypersensibility reactions with sulfonamides (including
      Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who
      also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity
      induced by amonafide is more frequent in rapid acetylators, probably because of
      increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2
      may play a protective role against bladder cancer, although studies have shown
      contradictory results. Slow acetylators may have a risk of developing primitive
      liver cancer. For lung cancer, data are not conclusive, but slow acetylation
      status may predispose to mesothelioma in subjects exposed to asbestos. No
      relation has been found between acetylation phenotype and breast cancer.
      Contradictory results were reported on its role in colorectal cancer. Non-smoking
      type 1 diabetics may be at increased risk of nephropathy if they are rapid
      acetylators. Parkinson's disease may be more frequent among slow acetylators, but
      again, data have shown contradictory results. Finally, a poor acetylator
      phenotype may predispose to atopic diseases.

PMID- 12611197
TI  - [Grapefruit juice and drugs: a hazardous combination?].
AB  - A single glass of grapefruit juice can improve the oral bioavailability of a drug
      thus either increasing its efficacy or enhancing its adverse effects particularly
      if the therapeutic index is narrow. Grapefruit juice acts by inhibiting
      presystemic drug metabolism mediated by CYP P450 3A4 in the small bowel and this
      interaction would appear to be more relevant if the CYP 3A4 content is high and
      the drug has a strong first pass degradation. Intestinal P-glycoprotein may also
      be affected by grapefruit juice. The compounds responsible for this food-drug
      interaction have not as yet been identified but this phenomenon could result from
      a complex synergy between flavonoids (naringin, naringenin), furanocoumarins
      (6',7'-dihydroxybergamottin, bergamottin) and sesquiterpen (nootkatone). In our
      study, we report the mechanisms of action of grapefruit juice and the
      interactions between grapefruit juice and 42 drugs; to date, only 12 drugs showed
      no interaction. Taking these results into consideration, patients should be
      educated about grapefruit juice intake with medication.

PMID- 12611198
TI  - [Preventive therapy for nausea and vomiting in patients on opioid therapy for non
      malignant pain in rheumatology].
AB  - OBJECTIVE: To determine if systematic use of metoclopramide associated with
      opioids (Morphine sulfate SR) decreases the incidence of nausea and vomiting
      (N&V), established adverse effects of opioids. METHOD: Open randomised study with
      132 patients treated for non malignant pain (71 women, 61 men, mean age 53.4
      years). One group (n = 76) was treated with morphine alone; the other (n = 56)
      with morphine plus metoclopramide. Mean duration of therapy: 6 days; mean dosage:
      60 mg/d RESULTS: In the 2 groups, N&V were present in the first 72 hours. The
      frequency of N&V in the morphine group was 38.1% (conform with the literature).
      The systematic use of metoclopramide decreases the frequency of N&V: p < 0.005.
      However the use of morphine > 60 mg/d decreases N&V: p = 0.036. High dosages of
      morphine can have an antiemetic effect by interaction with the mu receptors in
      the antiemetic center and not in the trigger zone which has an emetic effect.
      CONCLUSION: The systematic use of metoclopramide with opioid therapy for non
      malignant pain in rheumatology decreases the risk of nausea and vomiting.

PMID- 12611199
TI  - [Prevention of thrombosis during pregnancy: from recommendations to practice from
      26 cases].
AB  - Recommendations have recently been published regarding the prescription of low
      molecular-weight heparin (LMWH) during pregnancy in women at risk of
      thromboembolism. To assess how well these recommendations are followed, we
      retrospectively recorded all pregnancy consultations in a thrombosis unit for two
      years. Of the 26 women included (mean age 30 +/- 4.8 years), 81% presented with a
      history of thromboembolism, 35% thrombophilia, and 15% a history of pregnancy
      termination for medical reasons. Clinical follow-up concerned 17% of the women;
      8% were given aspirin, 63% LMWH at prophylactic dosages, 4% combination of
      aspirin and prophylactic LMWH, and 8% were on curative LMWH. Neither
      thromboembolic nor neonatal events were observed. One case of termination of
      pregnancy for medical reasons was observed at the 5th month. Although we also
      took into account the gravity of previous thromboembolism, our prescriptions were
      globally in compliance with the recommendations. This approach has still to be
      validated with a decision-making tree.

PMID- 12611200
TI  - [Comparative study of two antitussive drugs in the treatment of acute dry cough
      of infectious origin (prospective, randomized, single blind study)].
AB  - The objective was to compare, during a 5-day therapy, the efficacy and
      tolerability of an antihistaminic antitussive syrup, oxomemazine, combining a
      small quantity of guaifenesine (T), with a centrally acting antitussive,
      clobutinol (S), in adult patients aged from 18 to 70 years and presenting with a
      dry cough of infectious origin. This study was performed by 22 general
      practitioners and 130 ambulatory patients were enrolled. The primary criterion of
      this multicenter, randomized, single blind study was to compare the evolution of
      cough intensity using a Visual Analog Squale (VAS) graduated from 0 to 10 cm.
      Nine secondary criteria including tolerability were also assessed. With regard to
      cough intensity, the treatments were not equivalent. A greater reduction was
      observed with T (-5.2 +/- 2.3 versus -4.3 +/- 2.3). This result was confirmed by
      a further reduction in cough intensity at days: 2 (p = 0.04), 4 (p = 0.05), and 5
      (p = 0.02). The frequency of cough disappearance before the end of the study was
      significantly greater for T than for S: 46% versus 29% (p = 0.05). The time
      before disappearance of the cough was 4.0 + 1.1 days for both medicines.
      Induction of sleep and the frequency of nocturnal wakening were significantly
      better for T from day 4 (p = 0.02). The drowsiness induced by T meant that
      diurnal quality of life was better with S on days 1 (p = 0.002) and 2 (p = 0.01).
      Tolerability was similar for both medicines. In conclusion, as a symptomatic
      treatment of dry cough, T is efficient and well tolerated. Moreover, we have
      observed a tendency towards superior efficacy of T than S. T is therefore a
      useful alternative in the therapeutic armamentarium available to the general
      practitioner.

PMID- 12611201
TI  - [Dextropropoxyphene hepatotoxicity: four cases and literature review].
AB  - We report 4 cases of hepatic injury in patients treated with a dextropropoxyphene
      paracetamol combination in which the causal relationship with dextropropoxyphene
      can be suspected. These four cases show similarities with the 29 cases found in
      international publications. Hepatotoxicity occurs more frequently among old
      patients and women. Clinically, this condition can mimic a biliary tract disease
      with sometimes few or no symptoms. Biochemical criteria can show cholestatic,
      mixed or cytolytic hepatitis. Intrahepatic cholestasis may be found in liver
      biopsies sometimes suggesting cholangitis. Outcome is favourable on withdrawal of
      the drug. The mechanism of action of dextropropoxyphene is discussed.

PMID- 12611202
TI  - [Benign prostatic hyperplasia: patients' perception of medical treatment and
      their expectations. Results of a french survey involving patients treated with
      finasteride].
AB  - Benign prostatic hyperplasia (BPH) is increasingly common in medical practice, as
      a result of the inevitable aging of the population. The current therapeutic
      strategy includes three alternatives: watchful waiting, medical treatment and
      invasive therapy. Finasteride is one of the pharmacological options available.
      Many clinical studies have demonstrated its efficacy and good safety profile in
      patients with BPH. The survey we report provides new insights into what has to
      date been a purely therapeutic approach by taking into consideration patients'
      expectations and their perception of finasteride treatment. Results indicate that
      the main preoccupation for patients with BPH is that the pharmacological
      treatment will reduce the risk of major urological complications and the need for
      surgery (treatment characteristics considered as very or extremely important by
      88 and 93% of patients, respectively). Decreasing symptoms and improving quality
      of life take second place after these primary concerns. Patient perception of
      finasteride is excellent. Nearly all patients are satisfied by the efficacy of
      the treatment, 89% of them reporting good to extremely good improvement of
      symptoms, the rapid onset of relief being particularly important. The efficacy of
      finasteride is not hindered by any tolerability issues and is further
      strengthened by its ease of use. Although this novel survey includes a number of
      biases, it nevertheless demonstrates that treatment of BPH with finasteride is
      well accepted by patients and satisfies their expectations. In addition, it
      provides a mass of general epidemiological data on patients with BPH, as well as
      on current medical practice regarding this condition.

PMID- 12611203
TI  - [Sudden hypertension in adults: blood pressure increase without immediate
      visceral damage and emergency cases].

PMID- 12611204
TI  - [Prescription of antibiotics in odontology and stomatology].

PMID- 12611205
TI  - [Management of cutaneous mucosal herpes in immunocompetent subjects].

PMID- 12611206
TI  - [Nalbuphine (Nubain) dependence: 2 cases].

PMID- 12611207
TI  - [Acute encephalopathy and polyneuropathy from disulfiram: toxicity and
      interactions].

PMID- 12611208
TI  - [Electron beam computed tomography as a method to study coronary
      atherosclerosis].
AB  - Coronary artery disease is very prevalent in western countries and it represents
      the most frequent cause of death for both men and women. In the United States
      over 7 million people suffer from this ailment and about 500,000 die each year
      from its complications. Often the presenting event is an acute myocardial
      infarction or sudden death and the cost for society both financial and in terms
      of human lives lost is excessive. Despite the emphasis on prevention of
      atherosclerosis, unheralded events continue to occur in the general population in
      the absence of established risk factors. Indeed, risk factors justify only 60-70%
      of the risk of events for an individual patient. The focus of research has
      therefore turned to the application of non-invasive modalities for the imaging of
      the atherosclerotic plaque in its pre-clinical stages. The aim is to apply this
      information to guide a physician in choosing the patient in need of more
      aggressive preventive measures. One such imaging modality, electron beam
      tomography, is employed to visualize the calcified component of the
      atherosclerotic plaque. Calcium deposition in the wall of the coronary arteries
      is a highly sensitive and specific marker of atherosclerotic disease. This
      article summarizes the extensive amount of research published during the past 15
      years on the use of calcium imaging as a tool to predict events.

PMID- 12611209
TI  - [Autologous cellular cardiomyoplasty in humans: can we hit the mark?].
AB  - Myocardial cell therapy is a new promising therapeutic option for patients with
      heart failure. In this paper, we review the main experimental evidences and the
      first clinical researches in this field. Moreover, a comment on the theoretical
      and practical aspects for a pilot clinical use and a glance to the future are
      also provided.

PMID- 12611211
TI  - [Quality management in cardiovascular echography].
AB  - The quality management of an organization can be defined as the ability to
      identify, plan and implement programs of measure, analysis, verification and
      control that allow to monitor management, resources, activities, processes and
      output/outcome of the same organization, including the satisfaction of the
      customers. Whatever the model used, it is demonstrated that the management
      quality system, either for professional quality or for organization, turns out to
      be effective even in the health organizations within and to any level of
      organizational-structural complexity. The present paper concerns the experience
      of the Italian Society of Cardiovascular Echography (SIEC) on quality
      certification, both as a scientific society compared to other health
      organizations and to cardiovascular echo laboratories, and the definition of
      minimum requirements for the accreditation of the same laboratories. The model
      most frequently used for quality management is represented by the ISO 9000:
      Vision 2000, that is a management model with specific reference to the
      organization and the customer satisfaction. The model applied to the health
      structure needs a rapid change in mentality that addresses the operators to
      define, share and achieve objectives to be brought on by means of an active
      collaboration, group activity and deep sense of belonging necessary to the
      attainment of expected objectives. When the model is applied by a scientific
      society, it is necessary to take into account the different structural and
      functional organization, the constitution and the operators differing on the
      point of view of origin, experiences, mentality, and roles. The ISO 9000: Vision
      2000 model can be applied also to the cardiovascular echo laboratory which may be
      compared to a simple organization; for its corrected functioning, SIEC has
      defined minimal requirements for the accreditation, realization and modalities to
      carry out and manage quality. The quality system represents a new way of
      operating of an organization that enhances capability and performance of the
      operators, stimulates their creativity and facilitates the activities of all, to
      guarantee both the quality of the product and the satisfaction of operators and
      customers at the same time.

PMID- 12611210
TI  - [Quality system Vision 2000].
AB  - A recent document of the Italian Ministry of Health points out that all
      structures which provide services to the National Health System should implement
      a Quality System according to the ISO 9000 standards. Vision 2000 is the new
      version of the ISO standard. Vision 2000 is less bureaucratic than the old
      version. The specific requests of the Vision 2000 are: a) to identify, to monitor
      and to analyze the processes of the structure, b) to measure the results of the
      processes so as to ensure that they are effective, d) to implement actions
      necessary to achieve the planned results and the continual improvement of these
      processes, e) to identify customer requests and to measure customer satisfaction.
      Specific attention should be also dedicated to the competence and training of the
      personnel involved in the processes. The principles of the Vision 2000 agree with
      the principles of total quality management. The present article illustrates the
      Vision 2000 standard and provides practical examples of the implementation of
      this standard in cardiological departments.

PMID- 12611213
TI  - [The ethics of communication in medicine].
AB  - The present situation of the information related to the new therapeutical and
      diagnostic possibilities in all fields of medicine is at risk, because it is
      undermined by a series of promoting elements which influence its ethicality. Some
      of the causes to be mentioned refer to the changes occurred in the society and in
      the economy of western countries, as well as the evolution of the scientific
      thought, both in terms of research and of applied philosophy. The advent of the
      welfare state, of consumerism, the enormous successes in all fields of medicine,
      the diffusion of communication together with the inevitable, uncontrollable
      personalization, are certainly concomitant causes. The conclusions we can draw
      cannot be optimistic. Those who practice medicine, therefore, should pay
      particular attention to the scientific aspects. Applied science, the ethics of
      the message but above all the relationship doctor-patient, which should be lived
      as a vocation, represent a useful filter to curb the risk of a decadent and
      consumeristic practice, where the patient becomes an object rather than an
      individual.

PMID- 12611212
TI  - [Ministernotomy improves the postoperative course in aortic valve replacement].
AB  - BACKGROUND: The advantages and the safety aspects of ministernotomy, in aortic
      valve replacement, are presently under investigation. The aim of this study was
      to compare the postoperative results between ministernotomy access and standard
      total sternotomy access. METHODS: Between January 1997 and July 2002, 98 patients
      underwent elective aortic valve replacement. They were divided into two groups:
      group Gm (49 patients) undergoing a ministernotomy approach ("reversed C" or
      "reversed L") and group Gs (49 patients) undergoing conventional total
      sternotomy. RESULTS: The length of the skin incision was significantly shorter in
      group Gm (p < 0.001). The total operative time was significantly longer in group
      Gm (p = 0.02), but no significant differences were found in the cardiopulmonary
      bypass and aortic cross-clamping times. Mean mediastinal drainage, incidence of
      bleeding > 800 ml, mechanical ventilation time, intensive care unit stay and
      hospital stay were significantly greater in group Gs. Five days after the
      surgical procedure, spirometric analysis demonstrated a significant reduction in
      total lung capacity, and in maximum expiratory and inspiratory pressures in group
      Gs compared with group Gm (p = 0.003, p = 0.001, p = 0.01, respectively).
      CONCLUSIONS: Our results showed that in addition to cosmetic advantages,
      ministernotomy is also associated with a better outcome in terms of sternal
      stability, blood loss and transfusions, and postoperative pain. Ministernotomy
      also improved the recovery of respiratory function, with a shorter mechanical
      ventilation time and allowed an earlier hospital discharge.

PMID- 12611215
TI  - [Teaching in endourology and simulators].

PMID- 12611214
TI  - [Cardiogenic shock following mantlefield radiotherapy for Hodgkin's lymphoma:
      emergency treatment with coronary stent and follow-up at 6 months. Report of a
      case and review of the literature].
AB  - Radiation therapy is an effective and common treatment modality for Hodgkin's
      lymphoma, with proven long-term high survival rates and freedom from recurrences.
      However, the development of radiation-induced coronary artery disease,
      characterized by severe and widespread coronary involvement and by a high
      mortality secondary to acute ischemic events, is one of the most feared
      complications of this treatment modality. Furthermore, in such patients the
      optimal approach to revascularization remains to be determined, owing to some
      specific technical surgical difficulties and, as reported in the literature, to
      the limited experience available to date with percutaneous intervention,
      especially in case of acute ischemic syndromes. We report on a case of acute
      anterior myocardial infarction with cardiogenic shock in a 29-year-old male who
      had undergone radiation therapy to the chest for Hodgkin's lymphoma 10 years
      previously. He was immediately transferred to the catheterization laboratory:
      intra-aortic balloon counterpulsation was followed by coronary angiography which
      revealed severe, widespread triple-vessel disease and an acutely suboccluded very
      large left anterior descending coronary artery providing collaterals to large
      segments of the right and circumflex coronary territories. Primary angioplasty
      and stenting of the left anterior descending coronary artery was performed
      successfully, with a gradual amelioration of the hemodynamic and clinical
      parameters. Angiographic follow-up at 6 months demonstrated a widely patent
      stent, with minimal neointimal hyperplasia but no evidence of restenosis. The
      patient remained asymptomatic. We discuss our therapeutic strategy and review the
      relevant literature on the subject.

PMID- 12611216
TI  - [Excision of large masses in urologic surgery].
AB  - OBJECTIVES: To analyze a series of big masses excised in urologic surgery
      detailing the reasons after which the indications for surgery were set up,
      evaluating technical difficulties appeared during the procedures and balancing
      them with the aimed benefits. METHODS/RESULTS: 10.581 Operative reports from 1980
      were retrospectively reviewed and 8 cases were selected as fit with the concept
      of giant mass, being of more or less weight depending on the organ they arose
      from. They vary in weight from a 350 gr. prostate with benign prostatic
      hyperplasia to a 5.150 gr. renal carcinoma. All masses diagnosed but not excised
      are excluded from the analysis. CONCLUSIONS: Various difficulties appearing
      during excision were recorded depending on size, location, and etiology of each
      mass which resulted in operative time, transfusions, complications and outcomes.
      Only specific clinical cases seem to justify an, almost always, very aggressive
      approach.

PMID- 12611217
TI  - [NMP-22 test. Is it useful in the follow-up of patients with superficial bladder
      tumor?].
AB  - OBJECTIVES: 1.--To evaluate the efficacy of the NMP-22 as a diagnostic test for
      bladder tumor recidives; 2.--To compare the efficacy of NMP-22 vs. urine
      cytology. METHODS: 90 Patients with superficial bladder tumors were included in
      the study, undergoing cytologic, cystoscopic and NMP-22 marker controls. NMP 22
      test was considered positive when the marker signal was higher than 10 U/ml.
      Cistoscopy was the reference test. RESULTS: Patients in the study had an average
      age of 69 years, ranging from 45 to 91. 88% were males and 12% females. 61.2% of
      the tumors were Ta, 37.6% T1 and 1.2% Cis, being 17.8% grade I, 63.4% grade II
      and 18.8% grade III. NMP-22 showed a global sensitivity of 32.1%, and a
      specificity of 5.1%. Positive predictive value (PPV) was 75% and negative
      predictive value (NPV) 75.3% for a relapse rate of 27.7%. Urine cytology showed
      an overall sensitivity of 28.6%, 95.2% specificity, PPV 72.7% and NPV 74.7%. When
      both tests were used altogether sensitivity was 46.4%, specificity 90.3%, PPV
      68.43% and NPV 78.9%. CONCLUSIONS: The NMP-22 marker has shown low sensitivity so
      that control by cystoscopy may not be avoided. The combination of NMP-22 and
      urine cytology increases sensitivity minimally. It is not possible to replace
      cystoscopy in the follow-up of patients with superficial bladder tumors.

PMID- 12611218
TI  - [Urinary endometrioma].
AB  - OBJECTIVES: To analyze the series of cases of endometriosis with urologic
      involvement reported in our country. METHODS/RESULTS: We found a total of 26
      cases of endometriosis including our case, 15 affected bladder and 11 ureter.
      Independently of ureteral or bladder location, the treatment performed varied,
      from transurethral resection and laser to cystectomy in cases involving bladder,
      from segmental ureterectomy with ureteral reimplantation to nephrectomy in
      ureteral cases. CONCLUSIONS: Surgery is the definitive solution for urinary tract
      endometriomas. The definitive treatment of endometriosis must be done by
      gynecologists, by means of hormonal and surgical treatment depending on age,
      severity and location of the lesions, patient's wishes for future pregnancies,
      and tolerance to hormone therapy.

PMID- 12611219
TI  - [Technique of intraoperative planning in prostatic brachytherapy with permanent
      implants of 125I or 103Pd].
AB  - OBJECTIVES: Prostatic brachytherapy with permanent 125I or 123Pd seeds
      implantation is a therapeutic option for organ-confined prostate cancer. We
      analyze the technique based on previous planning, our current intraoperative
      planning procedure and the reasons that moved us to introduce this change.
      METHODS: Changes in prostate volume and spatial localization observed between
      previous planning and intraoperative images, and possible difficulties for seed
      implantation due to pubic arch interference are some of the reasons that induce
      us to change technique. RESULTS: Before the operation, we calculate the prostatic
      volume by transrectal ultrasound; with this information we determine the total
      implant activity following Wu's nomogram, and per-seed activity; therefore, it is
      an individual process for each patient. We perform a peripheral implant, placing
      75-80% of the seeds within the peripheral prostatic zone, generally through 12-15
      needles, the rest of the seeds are placed in the central prostatic zone using a
      maximum of 3-4 needles in high volume prostates. The day of intervention, after
      positioning and catheter insertion, volumetry is re-checked. Ultrasound images
      (from base to apex every 5 mm) are transferred to the planner were a suitable
      seed distribution is determined. Implantation is then performed placing all
      needles unloaded, and then intraoperative post-planning to allow us to check
      implant precision is performed after cistoscopically check that there is no
      urethral or bladder penetration by any needle. We finish with the insertion of
      seeds into the prostate. Total time for the procedure is around 90 minutes.
      CONCLUSIONS: Intraoperative planning is an additional step for the treatment of
      prostate cancer with permanent seeds brachytherapy, which avoids the
      disadvantages of previous planning and improves tumor inclusion in the ideal
      irradiation dose area, which will translate into better local disease control.

PMID- 12611220
TI  - [Can indexes based on PSA determine which patients should undergo repeated
      ultrasound-guided transrectal prostatic biopsy? Study on 546 patients who
      underwent repeated biopsy].
AB  - OBJECTIVES: Ultrasound guided prostate biopsy is the most effective test for
      prostate cancer diagnosis, but its sensitivity is not higher than 80% so that
      biopsy repetition must be considered in patients with persistent diagnostic
      doubts after a previous negative one. However, the majority will be negative as
      it happened in the first biopsy and the percentage of normal biopsies increases
      successively. Various indexes based on PSA are proposed to determine which
      patients have a higher risk of cancer detection by biopsy. We evaluate the
      efficacy of PSA density (PSAD), free/total PSA ratio (F/T PSA) and PSA velocity
      (PSAV) to select patients with high PSA and previous negative biopsy. METHODS:
      546 patients who underwent more than one prostate biopsy were included in the
      study. 121 patients underwent 3 biopsies, 25 underwent 4 biopsies and 7 five
      biopsies, for a total of 1245 biopsies. Patients already diagnosed of prostate
      cancer who had received treatment, and postoperative urethrovesical anastomosis
      biopsies were excluded. Between 4 and 6 samples were obtained; transitional zone
      was included if previous biopsy was negative; sextant biopsy was repeated in high
      grade PIN, and 4 or 5 cores were taken from the affected side in cases with non
      conclusive glandular atypia. The relationship between PSAD, PSAV and F/T PSA and
      the diagnosis of cancer was evaluated, as well as its sensitivity, specificity,
      positive and negative predictive values. RESULTS: 21.2% patients presented cancer
      on 2nd biopsy and 26% overall. Mean age was 68.3 years (51-84). Patients with
      cancer and negative biopsy showed significant differences in F/T PSA and PSAD,
      but not in PSAV. Sensitivities for PSAD higher than 0.15 ng/ml/ml, F/T PSA lower
      than 0.18 and PSAV higher than 0.75 ng/ml/year were 0.89, 0.9 and 0.49
      respectively and specificities were 0.28, 0.2 and 0.4 respectively. ROC curve
      areas were calculated for these indexes being 0.63 for F/T PSA, and 0.47 for
      PSAV. CONCLUSIONS: Although their specificity is low, free to total PSA ratio and
      PSA density showed the highest sensitivity; PSAV is almost non valid to
      discriminate the result in the biopsy. Although we could slightly diminish the
      number of repeat biopsies loosing a few tumors, only the urologist can determine
      when biopsies should be repeated in patients with elevated PSA, taking into
      consideration all concurrent factors (Baseline status, age, risk-benefit ratio of
      new biopsies...).

PMID- 12611221
TI  - [Intradiverticular bladder tumor: C.T. assessment].
AB  - OBJECTIVES: To review the role of computerized tomography on the diagnosis of
      intradiverticulum bladder cancer. We present images of various cases and perform
      a bibliographic review. METHODS: 5 cases of intra-diverticulum bladder cancer
      were identified after a retrospective review. All cases had pathological
      confirmation. Radiological findings are reviewed for this technique and compared
      with those obtained by other diagnostic tests. RESULTS: CT scan allowed the
      diagnosis of the disease and its extension. Lateral wall was the most frequent
      diverticulum location and intra-diverticulum mass was the most frequent clinical
      presentation. Two patients showed tumor calcification, one in the peripheral
      area, the other allover the tumor area. Vascular behavior of these tumors is
      similar to the rest of non intra-diverticulum bladder neoplasms. Two cases showed
      main lumen involvement as well. All tumors were transitional cell carcinomas.
      CONCLUSIONS: CT scan is an efficient diagnostic method for the intra-diverticulum
      carcinoma as well as for extension determination, and it is essential for
      surgical planning.

PMID- 12611222
TI  - [Urodynamics foundations: contractile potency and urethral doppler].
AB  - OBJECTIVES: To calculate the bladder softening factor, elastic constant and
      contractile potency. METHODS: For the analysis we considered bladder behavior
      like that of a spring. See articles 1 and 2 published in this issue. Using
      flowmetry, Doppler ultrasound and abdominal pressure (Transrectal pressure
      register catheter) an analytical solution that permits calculation of factors
      defining bladder behavior was looked for. Doppler ultrasound allows us to know
      urine velocity through the prostatic urethra and, therefore, to calculate bladder
      contractile potency. RESULTS: Equations are solved reaching an analytical
      solution that allows calculating those factors that define bladder behavior:
      Bladder contractile potency, detrusor elastic constant, considering it behaves
      like a spring, and calculation of muscle resistance to movement. All thanks to
      Doppler ultrasound that allows to know urine speed. CONCLUSIONS: The bladder
      voiding phase is defined with the aforementioned factors; storage phase behavior
      can be indirectly inferred. Only uroflowmetry curves, Doppler ultrasound and
      abdominal pressure value are used. We comply with the so called non invasive
      urodynamics although for us it is just another phase in the biomechanical study
      of the detrusor muscle. Main conclusion is the addition of Doppler ultrasound to
      the urodynamist armamentarium as an essential instrument for the comprehension of
      bladder dynamics and calculation of bladder behavior defining factors. It is not
      a change in the focus but in the methods, gaining knowledge and diminishing
      invasion.

PMID- 12611223
TI  - [New master arm for transurethral resection with a robot].
AB  - OBJECTIVE: In 1998, we designed a robot for transurethral resection that
      consisted of a master arm and a slave arm that reproduced the movements of the
      master. We describe the innovative master arm developed in two university
      departments that supersedes the mere "joystick" concept to become a true,
      operative surgical instrument. METHODS: The new master arm was developed from a
      conventional resectoscope working element integrated into a robotic manipulative
      device and fitted with angular displacement sensors. Each sensor, part of a
      computer-controlled feed back system commands the position and movements of the
      slave arm which, in turn, move the resectoscope. The surgeon freely chooses and
      manages precisely within a three-dimensional surgical field four basic
      resectoscope maneuvers; horizontal and vertical displacement, penetration
      withdrawal, and rotation; he also controls the movements and operation of the
      resectoscope cutting loop. Additional computer-programs provide the surgeon with
      an error-free, fail-safe surgical instrument that denies any movements outside
      the planned surgical field. RESULTS: The fact that the new easily used instrument
      is similar in shape and works like conventional resectoscopes greatly helps
      familiarization and training. Advanced technology reduces the number of errors
      usually associated with fatigue or inexperience of the surgeon. CONCLUSIONS: The
      new surgical instrument handles just like conventional instruments so surgeons do
      not need to change their usual operating procedures. In addition, an early
      warning program detects instantly and denies inappropriate maneuvers. This
      facility confers peace of mind to the surgeon and ensures patient satisfaction.

PMID- 12611224
TI  - [Extracorporeal lithotripsy in lumbar ureteral lithiasis. Is the ureteral
      catheter necessary?].
AB  - OBJECTIVES: To evaluate the efficacy of JJ catheter as urinary diversion in the
      treatment of lumbar ureteral lithiasis by ESWL. METHODS: Results obtained in our
      ESWL unit between january 1990 and October 2000 are compared. 680 cases of
      lithiasis are divided into 5 groups for analysis: Group A: Lumbar ureter non
      obstructive lithiasis. 200 cases. Group B: Lumbar ureter obstructive lithiasis
      without urinary diversion. 307 cases. Group C: Lumbar ureter obstructive
      lithiasis with JJ catheter. 90 cases. Group D: Lumbar ureter lithiasis with
      percutaneous nephrostomy. 32 cases. Group E: Lumbar ureter lithiasis pushed up to
      renal cavities by JJ catheter. 51 cases. RESULTS: Groups are compared for stone
      size, number of ESWL sessions and average number of shock waves. Repeated ESWL,
      complications and success rates are also analyzed. Statistical analysis of these
      results and its comparison by 2 proportion comparison tests show that groups B
      and C are homogeneous in size. We analyze these groups for complete success rate,
      partial success, and fragmentation index; it is derived from this analysis that
      Group C maintains the same level of fragmentation but not fragment expulsion,
      being this due to the only difference between groups B and C, which is the JJ
      catheter. CONCLUSIONS: In our series JJ catheter makes fragment expulsion
      difficult after treatment of the lumbar ureter lithiasis although it minimises
      the incidence of renal colic, the most frequent post-ESWL complication.

PMID- 12611225
TI  - [Perirenal involvement in Waldenstrom disease].
AB  - OBJECTIVE: To describe radiological, histological findings and cytometric
      features of perirenal masses: an unusual involvement pattern of the kidney by
      Waldenstrom disease. This pattern, not associated with nodal regional disease
      should be considered in the differential diagnosis of perirenal pathology
      (extramedullary hematopoiesis, liposarcoma, haematoma...). METHODS/RESULTS: A 68
      year-old man, with Waldenstrom macroglobulinemia presented in ultrasound
      exploration bilateral perirenal hypoecogenic mass. Histopathological examination
      and cytometric determination of fine-needle aspiration biopsy showed a monoclonal
      lymphoplasmocitoid proliferation of B-cells arranged in a diffuse pattern.
      CONCLUSION: Although perirenal involvement of the kidney by non Hodgkin
      lymphoplasmocitoid lymphoma is a rare phenomenon, this disease should be
      considered in differential diagnosis of perirenal pathology. Histological and
      cytometric examination are essential for diagnostic evaluation.

PMID- 12611226
TI  - [Epithelioid angiosarcoma of the adrenal gland. Report of a case].
AB  - OBJECTIVES: We report one case of adrenal epithelioid angiosarcoma. METHODS: We
      review the clinical and histopathological features of this rare adrenal sarcoma
      and perform a bibliographic review. RESULTS: A 60 year old male without past
      medical history presented with a six week flank pain. CT scan and MRI showed a
      big adrenal tumor without renal involvement. Definitive diagnosis was obtained by
      histopathological study and immunohistochemical techniques. CONCLUSIONS: Although
      adrenal sarcomas are rare, angiosarcoma must be considered in the differential
      diagnosis of every adrenal tumor. Surgery is the treatment of choice with or
      without adjuvant chemotherapy/radiotherapy, depending on pathological stage and
      prognostic factors derived from the histopathological study.

PMID- 12611227
TI  - [Urine ascites in renal transplantation].
AB  - OBJECTIVE: To report a case of urinary ascites secondary to an urinoma produced
      by a pielic and proximal ureter fistula after kidney transplantation in a 21 year
      old male patient. METHODS: Diagnosis was established by biochemical analysis of
      the perirenal fluid collection and ascitic fluid, and conservative management of
      the urinary tract by percutaneous nephrostomy was undertaken. RESULTS: Surgical
      repair of the fistulae solved the case. CONCLUSIONS: Urinary ascites is an
      unusual complication after kidney transplantation. Urinary tract fistula is the
      etiology in most of the cases although it can be idiopathic. In the case of
      urinary tract fistulae, conservative management can solve the case and surgical
      repair is the option when conservative treatment fails.

PMID- 12611228
TI  - [Cacchi Ricci disease associated with congenital hemihypertrophy].
AB  - OBJECTIVE: An uncommon case of medullary sponge kidney with congenital
      hemihypertrophy complicated by nephrocalcinosis and nephrolithiasis is reported
      here. METHODS/RESULTS: A 29 year old female patient with multiple episodes of
      renal colic is presented. Clinical features, radiological findings and
      differential diagnosis in a patient with Cacchi-Ricci disease are discussed. At
      least twenty-nine cases associated with congenital hemihypertrophy have been
      reported previously. CONCLUSIONS: A significant number of patients with medullary
      sponge kidney are asymptomatic. In many cases the diagnosis is made when a
      patient is evaluated by intravenous urography for some unrelated problem.
      However, medullary sponge kidney has been reported in association with rare
      congenital anomalies (Beckwith-Widemann syndrome and congenital hemihypertrophy)
      and these patients appear to be at risk of malignant neoplasms of the adrenal
      gland, kidney and liver, therefore they must be followed closely.

PMID- 12611229
TI  - [Simultaneous leiomyoma and transitional carcinoma of the bladder. Report of a
      case].
AB  - OBJECTIVES: To report this case of bladder leiomyoma, benign tumor of the
      bladder, due to its low frequency (0.43%) and to perform a bibliographic review.
      METHODS AND RESULTS: Case of a 46 year old female who refers a history of voiding
      symptoms, macroscopic haematuria with clots, asthenia, anorexia and right flank
      pain for 15 days prior to consultation. After blood tests, X ray tests,
      ultrasound and CT scan she underwent hysterectomy, anexectomy, radical cystectomy
      and ureteral reimplantation to a Mainz II sigmoid pouch. Currently, 44 months
      after surgery her outcome has been satisfactory. CONCLUSION: Bladder leiomyoma, a
      disease without specific symptoms, is occasionally found in pathological
      evaluation; biopsy is the confirmative diagnostic test. They are rarely found
      outside the uterus and gastrointestinal tract.

PMID- 12611230
TI  - [Renal artery embolism].
AB  - OBJECTIVES: To report a case of renal artery embolism. To review the clinical,
      diagnostic and therapeutic features of this disease interesting for the
      urologist. METHODS/RESULTS: Case of a 47 year old male with history of
      cardiovascular disease who presents in the emergency room with left flank pain.
      Radiological studies (Intravenous pyelogram (IVP) and ultrasound) ruled out
      urinary tract obstruction and oriented to renal vascular disease. Arteriography
      was performed showing left renal artery embolism. Fibrinolytic therapy was
      successful. CONCLUSIONS: Renal artery embolism is an unusual non traumatic
      vascular urologic emergency. Generally, it appears in patients with emboligenous
      heart diseases, mainly auricular fibrillation associated with mitral stenosis.
      More than half the cases are asymptomatic; if they have symptoms, the most common
      presentation is sudden onset of intense flank pain, resistive to analgesia.
      Laboratory tests show hematuria, pyuria, proteinuria, leucocytosis, increased
      LDH, GOT and alkaline phosphatase, and variable renal function impairment. An
      ultrasound showing no signs of obstructive uropathy and absent function in the
      IVP lead to diagnosis. In the case of early diagnosis, intra-arterial fibinolysis
      is the treatment of choice, leaving surgery for cases where renal function is in
      danger. Main complications are vasculorenal hypertension and renal failure.

PMID- 12611231
TI  - [Bladder metastasis of malignant melanoma: report of a case].
AB  - OBJECTIVES: To report one case of malignant melanoma metastasis into the urinary
      tract, diagnosed after excision of the primary lesion. METHODS: Case of a 75 year
      old male with history of malignant melanoma in the scapular region excised 7
      years before who presents with lower urinary tract symptoms (LUTS), hematuria and
      a hypogastric mass, 12 cm in diameter, located superficially and anterior to the
      bladder. He underwent partial cystectomy for excision of the mass, prostate
      adenomectomy and lithiasis extraction. RESULTS: Pathological study showed
      neoplasic cell proliferation with tendency to form sparse round nests or sheaths;
      cells had wide, polygonal cytoplasms and occasionally melanocitic pigment.
      Protein S-100 detection by Immunohistochemical tests was positive, being the
      final diagnosis malignant melanoma metastasis. CONCLUSIONS: Bladder metastatic
      disease is unusual and rarely clinically evident. Nevertheless, it is frequent
      for bladder metastases to be caused by melanoma. Bladder metastatic lesions are
      rarely symptomatic, although approximately 15% of the cases are symptomatic,
      being hematuria the most common presentation. Although radical cystectomy seems
      to be the treatment of choice in potentially curable patients with solitary
      metastasis, to date no patient has survived more than three years, demonstrating
      the aggressive natural history and ominous prognosis of this disease.

PMID- 12611232
TI  - Urinary tract infections in adult and adolescent males of a developing community:
      pattern, bacteriology and genito-urinary predisposing factors.
AB  - OBJECTIVES: Analysis of 95 consecutive adult and adolescent males with urinary
      tract infections to determine the pattern, bacteriology and the predisposing
      causes. METHODS: The period was 12 months, and the number of patients was 95
      consecutive cases. They were adult and adolescent males with urinary tract
      infection. Their age ranged from 13-100 years, (median 55, mean 53.3 years).
      RESULTS: Hospital and community acquired urinary tract infections occurred in 40%
      and 60% of patients respectively. E. coli was isolated from 66.7% of community
      acquired infections, which was well below the reported literature of 80-90%.
      CONCLUSIONS: Enterococci and Enterobacter spp. Appear to be emerging as important
      hospital and community acquired urinary tract pathogens in males. Bladder outflow
      obstruction accounted for over 50% of all genito urinary causes of urinary tract
      infections, while genitourinary malignancy occurred in nearly 20% of patients.
      The implications of these findings are discussed.

PMID- 12611233
TI  - [Endogenous ethanol production in patients with liver cirrhosis, motor alteration
      and bacterial overgrowth].
AB  - BACKGROUND: Small intestinal bacterial overgrowth generates endogenous ethanol
      production both in experimental animals and humans. Patients with cirrhosis have
      small intestinal bacterial overgrowth, but endogenous ethanol production has not
      been studied in them. AIM: To investigate endogenous ethanol production in
      patients with cirrhosis, altered intestinal motility and small intestinal
      bacterial overgrowth. PATIENTS AND METHODS: Eight patients with cirrhosis of
      different etiologies and altered gastrointestinal motility, consisting in changes
      in the migrating motor complex, were studied. All had also small intestinal
      bacterial overgrowth, measured by means of the H2 breath test with lactulose.
      Plasma ethanol levels were measured by gas liquid chromatography in fasting
      conditions and 120 min after a carbohydrate rich meal. RESULTS: In fasting
      conditions, no patient had endogenous ethanol production. Alter the meal, ethanol
      in concentrations of 11.3 and 8.2 mg/del were detected in two patients.
      Negligible amounts of ethanol were detected in 4 patients and two patients had
      undetectable alcohol levels. CONCLUSIONS: A low endogenous production of ethanol
      was demonstrated in six of eight patients with cirrhosis.

PMID- 12611234
TI  - [Laparoscopic and classic cholecystectomy in patients with liver cirrhosis].
AB  - BACKGROUND: The prevalence of gallstones is increased in patients with cirrhosis.
      However the presence of cirrhosis has been generally considered a relative
      contraindication to cholecystectomy. AIM: To investigate the complications and
      the outcomes of laparoscopic and open cholecystectomy in patients with cirrhosis.
      PATIENTS AND METHODS: Sixty seven patients with gallstones with well-documented
      cirrhosis undergoing cholecystectomy (laparoscopic cholecystectomy (LC) in 35 and
      open cholecystectomy (OC) in 32), were studied. The mean age was 57.7 + 10.3
      years for LC and 58.9 + 11.6 years for OC. In the LC group, 26 were classified as
      Child-Pugh class A, 8 as Child's B class and 1 as Child's class C. In the OC
      group, 12 were classified as Child's class A, 15 as Child's B and 5 as Child's C.
      RESULTS: Complications occurred in 4 of 35 (12.3%) LC patients (1 patients was
      Child A and 3 were B). In the OC group 14 of 32 patients had complications (4
      Child A, 7 B and 3 C, 43.7% p < 0.05 as compared with LC group). Three patients
      in the OC group died (9.4%). Mean hospital stay was 2.8 + 1.9 and 13 + 12 days in
      LC and OC patients, respectively (p < 0.05). CONCLUSIONS: LC has a lower rate of
      complications than OC and is a reasonable option for Child's class A and B
      patients with cirrhosis and gallstones.

PMID- 12611235
TI  - [Subserous gallbladder carcinoma: expression of cadherine-catenine complex].
AB  - BACKGROUND: Subserous gallbladder carcinoma is difficult to diagnose and treat.
      There are no tissue markers with prognostic value in this type of tumor. AIM: To
      study the immunohistochemical expression of E-cadherin alpha and beta catenin in
      subserous gallbladder carcinoma. PATIENTS AND METHODS: One hundred seventeen
      subjects (103 women and 14 men aged 62 and 69 years as a mean, respectively),
      were studied. Thirty five gallbladder samples without evidence of cancer were
      used as controls. Expression of markers was studied with standard
      immunohistochemical techniques for formalin fixed and paraffin embedded tissue.
      RESULTS: Ninety seven percent of tumors were adenocarcinoma. A lower or absent
      expression of E-cadherin, alpha catenin and beta catenin was observed in 26, 33
      and 29% of tumors, respectively. Actuarial five years survival was 37%. No
      association between macroscopic features of the tumor and survival was observed.
      Well differentiated tumors had a 73% survival, whereas less differentiated tumors
      had a 30% survival. Tumors with a normal expression of the markers had a slightly
      better survival, although not significant (p = 0.06). CONCLUSIONS: Approximately
      30% of subserous gallbladder carcinoma have an abnormal expression of E-cadherin,
      alpha catenin and beta catenin. This abnormal expression has no relationship with
      prognosis and is probably secondary to the aberrant genic expression of the
      tumor.

PMID- 12611236
TI  - [Immunodiagnosis of Strongyloides stercoralis infections in Chile using ELISA
      test].
AB  - BACKGROUND: Strongyloides stercoralis is a world wide distributed small
      intestinal nematode parasite. In immunocompetent individuals S stercoralis can
      produce asymptomatic infections or a moderate clinical picture of diarrhea, some
      cases become chronic. In immunocompromised patients, a disseminated disease may
      appear, sometimes fatal. In Chile, there is little epidemiological information
      about S stercoralis infections and appropriate diagnostic techniques are usually
      not used. AIM: To evaluate the yield of an ELISA test for the diagnosis of
      strongyloidiasis in Chilean patients. MATERIAL AND METHODS: Ten serum samples
      from patients with S stercoralis infections confirmed by a positive stool
      examination, 66 samples from individuals with other infections by tissue
      helminthes (24 toxocariasis, 15 trichinellosis, 11 hydatidosis, 12 fascioliasis
      and 4 cysticercosis), 13 samples from subjects with autoimmune diseases and 49
      samples from apparently healthy individuals with a normal eosinophil count, were
      studied. ELISA antigen was prepared using a filariform larval extract obtained
      from a murine species of Strongyloides, maintained in laboratory animals.
      RESULTS: Using 0.33 optical density units as a cut off value, 9 of 10 sera of S
      stercoralis infected individuals, had a positive ELISA test. No cross reactions
      were observed with sera of patients with other helminthic infections, autoimmune
      diseases or in healthy individuals. Thus, specificity, positive and negative
      predictive values were 100%. CONCLUSIONS: The results obtained are similar with
      those found by other investigators. ELISA test for strongyloidiasis is a useful
      tool for the diagnosis of clinical cases and for seroepidemiological studies of
      this nematode infection in Chile.

PMID- 12611237
TI  - [High prevalence of osteoporosis in asymptomatic postmenopausal Mapuche women].
AB  - BACKGROUND: Genetic and environmental factors are responsible for variations in
      the frequency of osteoporosis. Prevalence of osteoporosis in Mapuche women
      (native Chileans) is unknown. AIM: To assess the prevalence and risk factors for
      osteoporosis in Mapuche women. MATERIAL AND METHOD: A random sample of 95
      asymptomatic postmenopausal Mapuche females, stratified by age, was studied.
      Women with diseases or medications that could interfere with calcium metabolism
      were excluded. Spine and femoral neck bone mass density was determined using a
      Lunar DPX Alpha densitometer. RESULTS: Seventeen percent of women had normal bone
      mineral density in both spine and femoral neck. In the spine, 25.3% had a normal
      bone mineral density, 17.9% had osteopenia and 56.8% had osteoporosis. In the
      femoral neck, 34.7% had a normal bone mineral density, 57.9% had osteopenia, and
      7.4% had osteoporosis. There was a positive correlation between bone mineral
      density and body mass index. Women with more than one hour per day of physical
      activity, had a significantly lower proportion of osteopenia or osteoporosis. No
      association between bone mineral density and parity or calcium intake, was
      observed. CONCLUSIONS: There is a high prevalence of osteopenia and osteoporosis
      among Mapuche women. Osteoporosis was associated with low body mass index.

PMID- 12611238
TI  - [Community-acquired pneumonia in hospitalized adult patients. Clinical
      presentation and prognostic factors].
AB  - BACKGROUND: Community-acquired pneumonia (CAP) is a serious health problem in
      Chile. AIM: To study prognostic factors on admission and outcome of CAP, in
      immune competent adult patients, hospitalized in the Catholic University Clinical
      Hospital. PATIENTS AND METHODS: All adult patients admitted with a CAP in a
      period of 2 years were prospectively studied. Patients with immunodeficiency,
      solid tumors or receiving oral adrenal steroids were excluded from the study.
      RESULTS: In the study period, 463 patients (69 +/- 19 years, 55% male) were
      evaluated. Ninety four percent were treated with 2nd or 3rd generation
      cephalosporins. Mean hospital length of stay was 10 days. Mortality during
      hospital stay was 8% and in the ensuing 30 days, it was 12%. Bacterial etiology
      was established in 25% of cases. The most frequent pathogens isolated were
      Streptococcus pneumoniae (10.2%), Haemophilus influenzae (3.7%), Staphylococcus
      aureus (2.8%) and Gram negative bacilli (5.2%). Admission prognostic factors
      associated with hospital mortality were an age over 65 years, presence of
      comorbidity, chronic neurological and hepatic disease, suspicion of aspiration,
      duration of symptoms for less than 3 days, presence of dyspnea and altered mental
      status, absence of cough, fever and chills; low blood pressure, tachypnea,
      metabolic acidosis, hypoxemia, high blood urea nitrogen, hypernatremia,
      hyperkalemia, hyperphosphatemia, hypoalbuminemia, multilobar radiographic
      pulmonary infiltrates, bacteremia, high risk categories of the Fine Index (IV and
      V), and admission to Intermediate Care Unit or ICU. CONCLUSIONS: The features of
      community acquired pneumonia of these patients are similar to those reported
      abroad.

PMID- 12611240
TI  - [An analysis of authorship in articles published in Revista Medica de Chile].
AB  - BACKGROUND: Multiauthorship and unjustified authorship have been documented in
      journals with wide international circulation but this has not been thoroughly
      studied in journals from developing countries. Revista Medica de Chile is
      published in Spanish and it contains about 40% of the clinical and biomedical
      manuscripts generated by Chilean authors. OBJECTIVES: To evaluate temporal trends
      in the number of authors per article in Rev Med Chile and authors' compliance
      with the International Committee of Medical Journal Editors (ICMJE) criteria of
      authorship (updated 2001). DESIGN: A retrospective analysis of the number of
      authors per article between 1969 and 2000; and a prospective survey applying a
      contribution checklist to authors of manuscripts published in the year 2000.
      "Justified authorship" was assigned to whom self-declared contributions to: 1)
      conception and design of the study, or acquisition of data, or analysis and
      interpretation of data; 2) drafting the article, or critically reviewed it; and
      3) approved the final version. "Partial authorship" to whom lacked one of those 3
      criteria. "Unjustified authorship" was assigned to whom participated only in data
      collection, or in diagnostic/therapeutic procedures, or in the statistical
      analysis, or in combinations lacking the main descriptors required for justified
      authorship. RESULTS: The number of authors in research articles increased in the
      last decade: From 3.9 +/- 1.6 (mean +/- SD) in 1969 and 4.9 +/- 2.0 in 1989 to
      5.7 +/- 2.5* in 1994, 5.2 +/- 2.6* in 1999 and 5.4 +/- 2.2* in 2000 (*p < 0.05
      compared to previous years). In contrast, it remained stable in case reports (4.1
      +/- 1.9) and in reviews, public health or medical education articles (3.3 +/-
      1.8). Among 921 authors surveyed (90% of authors in the year 2000), 51.2%
      qualified for "justified authorship", 42.3% for "partial authorship" and only
      6.4% for "unjustified authorship". CONCLUSIONS: In a medical journal from a
      developing country, multiauthorship has increased mildly in research articles.
      Most participants complied fully or partially with the ICMJE criteria of
      authorship. Creditable authorship can be improved by continuous education and a
      critical attitude by the authors, readers, reviewers and editors.

PMID- 12611239
TI  - [Neuropsychological and neurophysiological features of Fahr's disease].
AB  - BACKGROUND: Fahr's disease (basal ganglia calcification) is characterized by bi
      hemispherical calcium deposition in basal ganglia, dentate nucleus and semioval
      center. Its clinical manifestations are a rigid hypokinetic syndrome, mood
      disorders and cognitive impairment. AIM: To report to the results of a
      neurological assessment of three siblings with Fahr disease. PATIENTS AND
      METHODS: Three sisters, aged 55, 56 and 58 years, were studied. All had a rigid
      hypokinetic clinical picture associated with cerebellar involvement and a
      cognitive impairment that progressed in 8, 6 and 10 years respectively. Brain CAT
      scans showed symmetric and extensive calcifications of cerebellar white matter
      and dentate nuclei, pons, mesencephalon, lenticular nuclei, thalami and semioval
      centers. Hypoparathyroidism was ruled out. Cognition was assessed with WAIS and
      Benton tests and Weschler memory scale. The time of reaction to visual stimuli
      was studied. The processing speed of visual information and the interhemispheric
      conduction time of such information, were calculated. Cognitive evoked potentials
      (P 300) were also studied. RESULTS: Cognitive impairment involved verbal and
      visual-spatial memory, planning, attention and concentration capacities and
      visual constructive skills. There was a prolongation of reaction time latencies
      and loss of the normal asymmetry of interhemispheric transmission (without right
      to left facilitation). P 300 evoked potentials were absent. CONCLUSIONS: These
      observations suggest that the pathogenesis of cognitive and motor changes in
      Fahr's disease is based in a dysfunction of cortico basal connections and their
      interhemispheric relations. This defines a subcortical dementia secondary to
      mineral deposits in subcortical structures.

PMID- 12611241
TI  - [Primary aldosteronism and pregnancy: report of 2 cases].
AB  - Based on two patients, we discuss the difficulties in diagnosing and managing
      primary aldosteronism in pregnancy, which derive from changes of the renin
      angiotensin-aldosterone axis, from the uncertainty regarding blood pressure
      control along gestation and postpartum, and from the contraindication to the use
      of spironolactone. The first case is a 27 years old woman with a long standing
      refractory hypertension, a hemorrhagic stroke with left brachial hemiplegia and
      crural hemiparesia, two miscarriages, one stillbirth and one offspring with
      intrauterine growth retardation. Due to hypokalemia, a plasma aldosterone/renin
      activity ratio of 91, and a negative genetic screening for glucocorticoid
      remediable aldosteronism (GRA), a primary hyperaldosteronism with normal adrenals
      in CT scan was diagnosed, and good blood pressure control was attained with
      spironolactone. After two and a half years of normotension, a fifth pregnancy,
      managed with methyldopa evolved with satisfactory blood pressures, plasma
      potassium, fetal growth, uterine and umbilical arterial resistance indexes, and
      maternal endothelial function. At 37 1/2 weeks of pregnancy the patient delivered
      a healthy newborn weighing 2,960 g. Blood pressure rose during the 48 hours of
      postpartum in the absence of proteinuria and required i.v. hydralazine. The
      second patient is a 37 years old woman, with known refractory hypertension for 7
      years, hypokalemia, plasma aldosterone/renin activity ratio greater than 40,
      normal adrenals in the CAT scan, and a negative genetic screening for GRA. She
      had normotensive pregnancies 5 and 3 years prior to the detection of
      hypertension, with hypertensive crisis in both postpartum periods,
      retrospectively considered as expressions of primary hyperaldosteronism.

PMID- 12611243
TI  - [Contribution of psychosocial factors in chronic low-back pain].
AB  - Low back pain (LBP) is a highly prevalent and costly cause of disability. In
      spite of a large amount of research in this field, there is still controversy
      about which factors are more important to determine chronicity in low back pain.
      Recent results have shown that LBP becomes a chronic condition mainly because of
      the relationship between psychosocial factors and pain. This relationship would
      explain the resistance of chronic LBP to classical medical treatment, which
      results in absenteeism and high economical costs. In this study we review recent
      results, including our own, that elucidate the contribution of psychosocial
      factors to chronic LBP. A biopsychosocial approach to these patients is highly
      recommended.

PMID- 12611244
TI  - [Hemodynamic impact of positive end expiratory pressure (PEEP) during severe
      respiratory failure: present view].
AB  - Bedside evaluation of pulmonary mechanics and thoracic computed axial tomography
      have changed the ventilatory management of patients suffering an acute
      respiratory failure caused by adult respiratory distress syndrome (ARDS).
      Mortality has been reduced limiting tidal volumes, which avoids alveolar
      overdistention and by the use of positive end expiratory pressure (PEEP), that
      reduces the damage caused by cyclical alveolar collapse-reopening. Nowadays, it
      is well known that inappropriate mechanical ventilation enhances lung damage
      caused by the underlying disease. However, the optimal adjustment of PEEP is not
      yet established. Usually, it is not easy to achieve an equilibrium between an
      optimal lung recruitment without producing alveolar overdistention and
      hemodynamic adverse effects such as hypotension and reduction of cardiac output.
      This paper reviews the interactions between heart and lung.

PMID- 12611242
TI  - [Herbal medicines and severe adverse effects: uvular angioedema caused by
      Echballium elaterium].
AB  - Herbal medicine is a growing alternative for established medicine. Many plants
      and herbs are currently in use for a myriad of diseases and symptoms. However,
      there are many reports in the literature of life-threatening adverse effects of
      these drugs. We report a 39 years old male, that consulted for pain in the
      nostrils and severe nasal obstruction, that appeared two hours after instilling
      Ecballium elaterirum in the nostrils. On physical examination, uvular edema was
      observed. The patient was successfully managed with intravenous betametasone and
      chlorphenamine.

PMID- 12611246
TI  - [Two cases of empyema caused by Peptostreptococcus].

PMID- 12611245
TI  - [Reflections about the historical development of biomedical sciences in Chile and
      the role of Revista Medica de Chile: an homage on 130-years old].
AB  - When Revista Medica de Chile turns to be 130 years old, the author reflects about
      the difficulties that scientific and technological creativity faces in Chile,
      considering that there was a 70 years gap between its historical origin in Chile
      compared to developed countries. The scientific progress erases the boundaries
      between Biomedicine and science and technology. This progress has resulted in an
      improvement in the quality of scientific publications in Revista Medica de Chile.
      The editorial work has also contributed to this improvement. Revista Medica de
      Chile has obtained international recognition and stands in a good position as a
      medical journal in Latin America and Chile.

PMID- 12611247
TI  - A new focus for health care debates in Congress.

PMID- 12611249
TI  - Genomics in medicine: hype or real promise? Interview by Ed Rabinowitz.

PMID- 12611250
TI  - HIPAA security requirements.

PMID- 12611248
TI  - Beauty, for a fee.

PMID- 12611251
TI  - Is new better? Assessing new medical technologies.

PMID- 12611252
TI  - Managing obesity.

PMID- 12611253
TI  - Identifying quality care for arthritis.

PMID- 12611254
TI  - E-solutions to HIPAA compliance challenges.

PMID- 12611255
TI  - [Gastrointestinal stromal tumors: open problems].

PMID- 12611256
TI  - [Radical surgical treatment of gastric cancer. Personal experience].
AB  - After surgical therapy the survival outcome of gastric cancer is still poor.
      Early diagnosis and radical surgery are the two most important means to improve
      the prognosis. Radical surgery must include all lymph nodes embryologically
      related to stomach. The aim of this study was to verify whether an aggressive
      surgical strategy can increase postoperative survival rate. In the period 1990
      1994 eighty two patients with gastric cancer were operated on. The M:F ratio was
      1.6:1 and the mean age was 65.3 years (range 23-89). Palliative operations (6
      gastroenterostomy) were performed in 7.3% of cases. In the other patients, 36
      total gastrectomies (43.9%), 8 total gastrectomies extended to spleen, pancreas
      and colon (9.7%), 32 distal subtotal gastrectomies (39.1%) were performed.
      Gastric exeresis was always associated with lymph node dissection extended to
      level I and II (R2). In some cases level III and IV lymphadenectomy (R3) was
      performed according to Maruyama-Mishima technique. There were no intraoperative
      deaths. The operative mortality was 13.6% for total gastrectomies and 3.1% for
      subtotal gastrectomies. Postoperative complications occurred in 15.9% of total
      gastrectomies (3 anastomotic fistula, 2 wound infection, 1 subphrenic abscess, 1
      melena) and in 3.1% of subtotal gastrectomies (1 sepsis). Stage III and IV
      cancers represented 74.4% of all cases (stage IIIA 19.6%, IIIB 21.9%, IV 32.9%).
      Metastatic lymph node involvement (N2+) affected 53.1% of T3 and 88.2% of T4
      cancers. The mean survival rate of patients subjected to gastroenterostomy was 6
      months. The 2-year survival for total gastrectomies was 42%, for subtotal
      gastrectomies 28.1%. In our experience, wide removal of lymph nodes and total or
      extended gastrectomies were performed without any increase of mortality and
      morbidity. In advanced stages, a wider exeresis increased survival and prevented
      local recurrence.

PMID- 12611257
TI  - [Spigelio hernia: 5-year experience].
AB  - Spigelian hernia is a rare condition of the abdominal wall; 13 cases occurred in
      the last five years are here reported. These patients were treated surgically,
      using direct reconstruction of the abdominal wall in eight cases, while a tension
      free hernioplasty was utilized in five cases.

PMID- 12611258
TI  - [Hyperhomocysteinemia and thrombosis: clinical case and literature's review].
AB  - Patients with homocystinuria have an increased risk for both venous and artherial
      thrombosis but it has been found that even moderate increase in homocysteine
      levels are associated with heightened risk of thromboembolism. The Authors report
      a case of juvenile vasculopathy in a patient with hyperomocysteinemia. In this
      case the patient presented both venous and artherial thromboembolism in the
      absence of the most important risk factors. The opportunity is stressed to
      perform clinical tests for the correct diagnosis of hyperhomocysteinemia because
      it is possible, with the use of folic acid and vitamin B12, to correct the
      elevated levels of homocysteine.

PMID- 12611259
TI  - [Management of groin hernias: long term results].
AB  - The Authors report their experience in the treatment of groin hernias. Over the
      years, hospital stay and anaesthetic procedure were modified without compromising
      the quality of results. The Authors conclude that groin hernia may be treated in
      a outpatient or day surgery regimen saving money.

PMID- 12611260
TI  - [Peritoneal papillary serous carcinoma: clinical report].
AB  - Peritoneal papillary serous carcinoma (PPSC) is a rare tumour that involves the
      surface of the peritoneum, with prevalence in female patients and can originate
      from a single or multicentric focus is here described. A primary peritoneal
      serous carcinoma is here described. The patient has been treated with paclitaxel
      175 mg/m2 and carboplatinum AUC 6.

PMID- 12611261
TI  - [Extended lymphadenectomy for carcinoma of pancreatic head. Personal experience].
AB  - Long-term survival in patients with cancer of the pancreatic head is
      disappointing. Surgery is the only curative therapy. Unfortunately the prognosis
      of patients resected (10-15%) is extremely poor due to loco-regional cancer
      recurrence (50%). Lymphatic and perineural invasion might account for local
      recurrence. Japanese studies reported the importance of an extended
      lymphadenectomy during the classic Whipple exeresis (40% of patients present
      lymph node metastases). During the period 1996-2000 at our Institution 20
      patients (14 M, 6 F, mean age 62.4 years) with pancreatic head cancer (17
      adenocarcinoma, 1 lymphoma, 2 carcinoma) underwent Whipple's exeresis with a
      regional (peripancreatic or R1) and juxta-regional (para-aortic or R2)
      lymphadenectomy according to Ishikawa technique. R1 nodes consisted of lymph
      nodes at the pylorus, superior head, common bile duct, anterior
      pancreaticoduodenal region, inferior head and superior mesenteric vessels. R2
      nodes consisted of lymph nodes at the superior body, inferior body, mid colic
      region, common hepatic duct, coeliac truncus and para-aortic region. This wide
      dissection was quite easy also in patients with a serious cholestatic disease.
      Intraoperative mortality was 0%. Operative mortality was 5%. Postoperative
      complications (20%) were 1 sepsis, 1 hepato-renal syndrome with hepatic coma, 1
      mechanical intestinal obstruction, 1 wound infection. Eight patients (40%) died
      in 6 months in average (neoplastic recurrence 40%). Notwithstanding the advanced
      disease (stage III 50%; N1+ 50%), twelve patients (60%) have a mean postoperative
      survival rate of 18.5 (range 1-48) months without neoplastic recurrence. Tumour
      diameter was less than 4 cm in 83.3% of cases. An earlier diagnosis (with tumour
      diameter < 4 cm) can improve pancreatic head cancer prognosis. A wide surgical
      exeresis with a R2 lymph nodes clearance together with surrounding connective and
      nervous tissue can remove micrometastases with a better control local recurrence.

PMID- 12611262
TI  - Use of mesh to repair the submuscolar pocket in breast reconstruction: a new
      possible technique.
AB  - The reconstruction of the female breast after mastectomy has become a crucial
      part of primary breast cancer therapy. Setting of an implant is possible only in
      case of locally abounding soft tissue coverage and when no radiation has before
      performed. It is necessary a complete integrity of the submuscolar pocket and
      good blood supply of the skin to avoid failure of the procedure. In Author's
      experience, started since 1994, an immediate breast reconstruction after
      mastectomy is performed using gel-silicon implants directly when it was possible
      or setting first an expander. In six cases the condition of major pectoralis
      muscle after mastectomy was so foul that an immediate breast reconstruction with
      prosthesis was not realizable. However, the Authors tried a new technique using
      polypropylene mesh sutured on the major pectoralis muscle to cover the muscle
      partially destroyed. Preliminary data from the 6 pts seems to be encouraging.

PMID- 12611263
TI  - [Esophageal perforations and fistulas: clinical management].
AB  - Aim of this study was the literature review regarding esophageal perforations and
      fistulas. We examined the most common causes, clinical findings (symptoms and
      signs), laboratory and imaging studies for differential diagnosis and
      complications. Finally, we examined the surgical or endoscopic treatment and the
      prognosis.

PMID- 12611264
TI  - Cloning, DNA sequence, and expression of Aeromonas caviae WS7b chitinase gene.
AB  - A chitinase-producing bacterium, designated WS7b, was isolated from a soil sample
      obtained from a black-pepper plantation on Bangka Island, Indonesia. Fatty-acid
      methyl-ester analysis indicated that the isolate was Aeromonas caviae. A
      chitinase gene from WS7b was cloned in a pUC19-based plasmid vector, but without
      its natural promoter. The complete nucleotide sequence of the gene was
      determined, and the structural gene consisted of a 2748-bp region encoding 864
      amino acids. DNA sequence analysis indicated that the gene had been cloned
      without its promoter, and this was confirmed by chitinase-plate assay of the
      truncated version of the gene in Escherichia coli. The chitinase gene product
      showed amino-acid sequence similarity to chiA from A. caviae. Chitinase enzyme
      activity was determined spectrophotometrically, using colloidal chitin azure as
      substrate for extracellular and intracellular fractions. The ability of the
      chitinase cloned in E. coli to hydrolyze chitin was less than that of the enzyme
      in its indigenous host.

PMID- 12611265
TI  - Immunocytolocalization of tryptophan decarboxylase in Catharanthus roseus hairy
      roots.
AB  - We investigated the intracellular distribution of tryptophan decarboxylase (TDC)
      (EC 4.1.1.28) in Catharanthus roseus hairy roots using immunofluorescence and
      immunogold techniques. TDC was detected by immunofluorescence localization in the
      cytosol and in the apoplastic region of the meristematic cells of the roots, with
      a slight enrichment in the epidermal cells of the root cap and in the
      meristematic region. In the enlargement zone, TDC was localized only in the first
      three layers of the cortex. In the maturation zone, the enzyme was not present.
      Immunogold studies confirmed that the enzyme was localized in the cytosol of the
      meristematic region, and intense gold labeling was found in the apoplastic zone.
      A protein fraction isolated from the apoplastic zone and assayed for TDC activity
      showed high activity.

PMID- 12611266
TI  - Problems associated with determining protein concentration: a comparison of
      techniques for protein estimations.
AB  - Although a range of methods are available for determining protein concentration,
      many scientists encounter problems when quantifying proteins in the laboratory.
      The most commonly used methods for determining protein concentration in a modern
      biochemistry laboratory would probably be the Lowry and/or the Bradford protein
      assays. Other techniques, including direct spectrophotometric analysis and
      densitometry of stained protein gels, are applied, but perhaps to a lesser
      extent. However, the reliability of all of the above techniques is questionable
      and dependent to some extent on the protein to be assayed. In this paper we
      describe problems we encountered when using some of the foregoing techniques to
      quantify the concentration of poly(adenosine diphosphate-ribose) polymerase-1
      (PARP-1), a nuclear enzyme found in most eukaryotes. We also describe how, by
      using a fluorescence-based assay and amino acid analysis, we overcame the
      problems we encountered.

PMID- 12611267
TI  - Insertion of modifications in the beta-globin locus using GET recombination with
      single-stranded oligonucleotides and denatured PCR fragments.
AB  - We describe the use of the GET recombination system with oligonucleotides or
      single-stranded polymerase chain reaction (PCR) fragments to insert modifications
      in the human beta-globin locus without counterselection. The method involves
      recombination between oligonucleotides or denatured PCR fragments and homologous
      sequences in the beta-globin gene in a clone of 205-kb bacterial artificial
      chromosome (BAC), based on the inducible expression of the recE, recT, and gam
      genes. In this method, oligonucleotides or denatured PCR fragments are
      electroporated directly into cells carrying both the globin BAC and the pGETrec
      plasmid, after induction of the GET recombination system. Recombinant BAC clones
      are identified by PCR, using allele-specific amplification for the mutated
      sequences. We have used this approach to insert a unique restriction site as well
      as a common thalassemia mutation (stop codon 39, C-->T) into the human beta
      globin locus. We have observed the frequency of recombinant clones to be as high
      as 1 in 100-200 clones. Therefore, this approach provides a simple and efficient
      method for introducing point mutations and other fine modifications into BACs,
      and should greatly facilitate the use of BACs for functional studies and
      therapeutic applications.

PMID- 12611268
TI  - A simple, high-yield method for obtaining multipotential mesenchymal progenitor
      cells from trabecular bone.
AB  - In vitro cultures of primary, human trabecular bone-derived cells represent a
      useful system for investigation of the biology of osteoblasts. Our recent
      discovery of the multilineage mesenchymal differentiation potential of trabecular
      bone-derived cells suggests the potential application of these cells as
      mesenchymal progenitors for tissue repair and regeneration. Such applications are
      crucially dependent on efficient cell-isolation protocols to yield cells that
      optimally proliferate and differentiate. In this study, we describe a simple,
      high-yield procedure, requiring minimal culture expansion, for the isolation of
      mesenchymal progenitor cells from human trabecular bone. Moreover, these cells
      retain their ability to differentiate along multiple mesenchymal lineages through
      successive subculturing. Cell populations isolated and cultured as described here
      allow the efficient acquisition of a clinically significant number of cells,
      which may be used as the cell source for tissue-engineering applications.

PMID- 12611269
TI  - Aerosol gene therapy.
AB  - Gene therapy is a novel field of medicine that holds tremendous therapeutic
      potential for a variety of human diseases. Targeting of therapeutic gene delivery
      vectors to the lungs can be beneficial for treatment of various pulmonary
      diseases such as lung cancer, cystic fibrosis, pulmonary hypertension, alpha-1
      antitrypsin deficiency, and asthma. Inhalation therapy using formulations
      delivered as aerosols targets the lungs through the pulmonary airways. The
      instant access and the high ratio of the drug deposited within the lungs
      noninvasively are the major advantages of aerosol delivery over other routes of
      administration. Delivery of gene formulations via aerosols is a relatively new
      field, which is less than a decade old. However, in this short period of time
      significant developments in aerosol delivery systems and vectors have resulted in
      major advances toward potential applications for various pulmonary diseases. This
      article will review these advances and the potential future applications of
      aerosol gene therapy technology.

PMID- 12611270
TI  - Detecting mycotoxins in agricultural commodities.
AB  - It is difficult to obtain precise and accurate estimates of the true mycotoxin
      concentration of a bulk lot when using a mycotoxin-sampling plan that measures
      the concentration in a small portion of the bulk lot. A mycotoxin-sampling plan
      is defined by a mycotoxin test procedure and a defined accept/reject limit. A
      mycotoxin test procedure is a complicated process and generally consists of
      several steps: (a) a sample is taken from the lot, (b) the sample is ground
      (comminuted) in a mill to reduce particle size, (c) a subsample is removed from
      the comminuted sample, and (d) the mycotoxin is extracted from the comminuted
      subsample and quantified. Even when using accepted test procedures, there is
      variability associated with each step of the mycotoxin test procedure. Because of
      this variability, the true mycotoxin concentration in the lot cannot be
      determined with 100% certainty by measuring the mycotoxin concentration in a
      sample taken from the lot. The variability for each step of the mycotoxin test
      procedure, as measured by the variance statistic, is shown to increase with
      mycotoxin concentration. Sampling is usually the largest source of variability
      associated with the mycotoxin test procedure. Sampling variability is large
      because a small percentage of kernels are contaminated and the level of
      contamination on a single seed can be very large. Methods to reduce sampling,
      sample preparation, and analytical variability are discussed.

PMID- 12611271
TI  - The use of resolvases T4 endonuclease VII and T7 endonuclease I in mutation
      detection.
AB  - Mutation and polymorphism detection is of increasing importance in the field of
      molecular genetics. This is reflected by the plethora of chemical, enzymatic, and
      physically based methods of mutation detection. The ideal method would detect
      mutations in large fragments of DNA and position them to single base-pair (bp)
      accuracy. Few methods are able to quickly screen kilobase lengths of DNA and
      position the mutation at the same time. The Enzyme Mismatch Cleavage (EMC) method
      of mutation detection is able to reliably detect nearly 100% of mutations in DNA
      fragments as large as 2 kb and position them to within 6 bp. This method exploits
      the activity of a resolvase enzyme from T4, T4 endonuclease VII, and, more
      recently, a second bacteriophage resolvase, T7 endonuclease I. The technique uses
      these enzymes to digest heteroduplex DNA formed by annealing wild-type and mutant
      DNA. Digestion fragments indicate the presence, and the position, of any
      mutations. The method is robust and reliable and much faster and cheaper than
      sequencing. These attributes have resulted in its increasing use in the field of
      mutation detection.

PMID- 12611273
TI  - The necessity to develop drugs against parasitic diseases.
AB  - This review focuses on the most significant trends in the development of drugs
      for the treatment of malaria, African sleeping sickness and toxoplasmosis. In the
      case of malaria, those include new fixed-dose artemisinin combinations,
      antifolates and new targets in the apicoplast of Plasmodium falciparum. Targets
      in the treatment of trypanosomiasis are the biosynthesis of
      glycosylphosphatidylinositol and enzymes involved in the biosynthesis of
      trypanothione. Efforts to develop a vaccine against toxoplasmosis are discussed
      as well.

PMID- 12611272
TI  - Universal primers for the PCR-mediated amplification of DNA 1: a satellite-like
      molecule associated with begomovirus-DNA beta complexes.
AB  - DNA 1 is a single-stranded DNA molecule of approximately 1370 nucleotides. It is
      associated with monopartite geminiviruses of the genus Begomovirus, which require
      a DNA beta component for symptomatic infection. The DNA 1 molecule requires the
      helper begomovirus for movement in plants, but is capable of self-replication. We
      designed two abutting primer pairs (DNA101/DNA102 and UN101/UN102) to conserved
      sequences of DNA 1. This allowed polymerase chain reaction-mediated amplification
      of the full-length molecule from total nucleic acid extracts produced from
      various host plants from geographically distinct, worldwide locations. These
      primers are useful both as diagnostic probes and for producing full-length
      infectious clones for in planta studies.

PMID- 12611274
TI  - Cyanopeptide analogues: new lead structures for the design and synthesis of new
      thrombin inhibitors.
AB  - This contribution deals with the structure-based design and syntheses of the new
      serine protease inhibitors RA-1001 and RA-1002, which are analogues of the blue
      green algae derived cyanopeptide aeruginosin 98-B. Both compounds inhibit
      thrombin with Ki values of 5.6 microM and 8.7 microM, respectively.

PMID- 12611275
TI  - New propargyl thioquinolines--synthesis, antiproliferative activity in vitro and
      structure-activity relationships.
AB  - The series of the propargyl thioquinolines has been prepared on the basis of the
      reaction of thioquinanthrene (1) (1,4-dithiino[2,3-c:5,6-c']-diquinoline) with
      sodium alkoxides. Some of these compounds have revealed good antiproliferative
      activity in vitro against the cells of human and murine cancer lines. 13C NMR
      spectra were measured for the studied compounds to examine the electronic
      properties-activity relationships. A regression study on 10 compounds showed a
      linear correlation of antiproliferative activity with electronic properties,
      expressed as the 13C NMR chemical shift for C-4 carbon atom (R2 = 0.97). It was
      found that compounds with chemical shift for C-4 value falling in the range of
      135-140 ppm exhibited significant antiproliferative activity, while compounds
      which possess moderate or low activity are located in the range 140-165 ppm. This
      finding leads to the expectation that the antiproliferative activity of propargyl
      thioquinolines can be predicted using the 13C NMR chemical shift value of their C
      4 carbon atom.

PMID- 12611276
TI  - Formulating and stability of benzodiazepines in a new lipid emulsion formulation.
AB  - The objective of the current study was to evaluate the novelty of a new lipid
      emulsion formulation containing 30% oil phase as a drug delivery system.
      Therefore different benzodiazepines (BZs), namely diazepam, tetrazepam,
      clonazepam and lorazepam, were incorporated into this emulsion formulation. This
      lipid emulsion formulation showed enhanced solubilization capacity as 10 mg/ml,
      10 mg/ml, 0.9 mg/ml, and 1.8 mg/ml formulations for diazepam, tetrazepam,
      clonazepam, and lorazepam were achieved, respectively. Incorporating the drugs
      into the lipid emulsion did not alter its physicochemical properties. Also the
      free and the drug emulsion formulations displayed good physical stability after
      autoclaving and after around one year of storage at shelf, as no changes in the
      physicochemical properties were observed. Most drugs also showed stable behavior
      after autoclaving and after approximately 1 year of storage at shelf. The only
      exception was lorazepam, as only around 50% of the drug was still intact after
      autoclaving.

PMID- 12611277
TI  - Study of the prolonged release of theopylline from polymeric matrices based on
      grafted chitosan with acrylamide.
AB  - The aim of this work was to study the performance of chitosan (CB) grafted with
      acrylamide (CB-g-A) as prolonged drug release matrix as compared with unmodified
      chitosan. A non-pH dependent swelling behaviour for the matrix tablets based on
      grafted chitosan was observed. The overlaping between degree of swelling measured
      by weighing (DSw) and measured by increase of diameter (DSd) up to 240 minutes
      showed that the swelling process could be isotropic. The non-pH dependent
      swelling behaviour of these matrices could be explained by the partial
      substitution of amine groups of the chitosan chain by acrylamide. The grafting
      reaction provides an ionizable amine group by a neutral amide group which make
      the matrix non pH-dependent. On the contrary, the matrix tablet based on chitosan
      showed a pH dependent swelling behaviour where the swelling process could be
      anisotropic. The higher degree of erosion and swelling of the formulation based
      on CB-g-A600 (%G = 600) compared with the formulation based on chitosan and CB-g
      A418 (%G = 418) could explain the higher fraction of theopylline released. For
      all formulations studied in this work, the amount of theopylline released from
      the matrix tablets was found to be controlled by a combination of the diffusion
      process and relaxation of the polymeric structure. These results match with the
      controlled swelling behaviour and low degree of erosion observed for these
      systems.

PMID- 12611278
TI  - Vehicle effects on in vitro skin permeation of thiocolchicoside.
AB  - Thiocolchicoside, a semi-synthetic derivative of colchicoside, is used in topical
      formulations for its anti-inflammatory and muscle-relaxant properties. The
      objective of this study was to evaluate the effect of a (propylene glycol
      diperlagonate) DPPG and (propylene glycol) PG mixture present in an innovative
      foam formulation (Miotens) on the flux of thiocolchicoside through excised human
      skin. Furthermore, the in vitro permeation behaviour of this new formulation
      (Miotens foam) was compared to another commercial product (Muscoril ointment) and
      to a control gel formulation (thiogel), both enhancer free. The best permeation
      profile was obtained from the foam formulation (Miotens) which was able to
      increase the thiocolchicoside flux about three fold compared to control
      formulation (thiogel) and about two fold compared to the commercial formulation
      Muscoril ointment.

PMID- 12611279
TI  - Ascorbic acid induces redifferentiation and growth inhibition in human hepatoma
      cells by increasing endogenous hydrogen peroxide.
AB  - The mechanisms of redifferentiation and growth inhibition induced in human
      hepatoma cells by ascorbic acid (AA) were studied. After treatment with AA, the
      content of hydrogen peroxide (H2O2) and the activity of superoxide dismutase
      (SOD) increased in a concentration- and time-dependent manner, while the activity
      of catalase (CAT) decreased in a concentration- and time-dependent manner. Using
      6 mM AA as a positive control, after treatment by 50 microM hydrogen peroxide,
      the malignant characteristics of human hepatoma cells were alleviated; for
      example as cell surface charge markedly decreased, the electrophoresis rate
      dropped from 1.68 microns.s-1.V-1.cm-1 to 0.97, the average of alpha-fetoprotein
      content decreased from 327 micrograms.g-1 protein to 193, and gamma-glutamyl
      transpeptidase activity fell from 0.84 U.g-1 protein to 0.30. The indexes related
      to cell differentiation were promoted, such as tyrosine-alpha-ketoglutarate
      transaminase activity increased from 17.1 mumol.g-1 protein to 33.1, and the
      colonogenic potential decreased by 79.3%. SOD and 3-amino-1,2,4-triazole (AT)
      exhibited some effects, but there were statistically significant differences
      between the SOD, AT and H2O2 or AA groups. AA induced growth inhibition and
      redifferentiation of human hepatoma cells through the production of hydrogen
      peroxide, since addition of SOD (200 units/ml), an enzyme that dismutates
      superoxide and generates hydrogen peroxide, and AT (1.5 mM), a CAT inhibitor that
      inhibits the activity of CAT and leads to an increase in H2O2 content, showed
      some inducing changes emphasizing the involvement of reactive oxygen species
      (ROS) in redifferentiation of hepatoma cells. AA can cause the content of H2O2 to
      increase, and the factor H2O2 showed a similar effect to AA on growth and
      redifferentiation suggests that H2O2 is involved in hepatoma cell
      redifferentiation. In conclusion, these results suggest that AA inhibits tumor
      growth and induces tumor redifferentiation by virtue of producing H2O2.

PMID- 12611280
TI  - Antihyperglycaemic effect of Casearia esculenta root extracts in streptozotocin
      induced diabetic rats.
AB  - The present study was carried out to evaluate the antihyperglycaemic effect of
      Casearia esculenta root extract and to study the activities of liver hexokinase
      and gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6
      bisphosphatase in liver and kidney of normal and streptozotocin-induced diabetic
      rats. Oral administration of aqueous extract of root (300 mg/kg body weight) for
      45 days resulted in a significant reduction in blood glucose from 250.79 +/-
      12.65 to 135.70 +/- 8.90 and in a decrease in the activities of glucose-6
      phosphatase and fructose-1,6-bishosphatase and an increase in the activity of
      liver hexokinase. However, in the case of 200 mg/kg body weight of extract, less
      activity was observed. The study clearly shows that the root extract of C.
      esculenta possesses potent antihyperglycaemic activity but weaker than that of
      glibenclamide.

PMID- 12611282
TI  - [Georg Dragendorff and his students--the M. Sc. dissertations in pharmacy at
      Tartu University (1864-1894)].
AB  - The present paper deals with the M.Sc. dissertations on pharmacy at the
      University of Tartu/Dorpat (nowadays in Estonia) in 1864-1894. While Professor G.
      Dragendorff worked in Tartu, 89 persons defended their M.Sc. degrees in pharmacy
      and 88 persons their M. D. theses in the same field, a total of 177 dissertations
      for the Institute of Pharmacy, which comprises one third of the M.Sc. degrees in
      Pharmacy in the whole of Russia. This was the most fruitful era in the activity
      of Dragendorff and the most successful period in the history of pharmacy in Tartu
      University.

PMID- 12611281
TI  - Willipelletierine, a new diterpenoid alkaloid from Consolida scleroclada (Boiss.)
      Schrod.
AB  - From the aerial parts of Consolida scleroclada (Boiss.) Schrod. collected in
      Turkey, a new diterpenoid alkaloid named willipelletierine has been isolated
      along with the known diterpenoid alkaloids aconitine, lapaconidine, and
      delcosine. The structure for willipelletierine was established on the basis 1H,
      13C, DEPT, homonuclear 1H COSY, HETCOR and NOESY NMR studies.

PMID- 12611283
TI  - Comparative study of some additives for the improvement of terfenadine
      performance.

PMID- 12611284
TI  - The nature of interaction of 4'-[(N-benzoyl) aminomethanocarboxy]-2,4
      dihydroxybenzcarbothioamide with blood lymphocytes.

PMID- 12611285
TI  - New illudane sesquiterpenes from the basidiomycete Clitocybe rivulosa HKI 0273.

PMID- 12611286
TI  - [Elderly persons with a small pension. Poignant neglect by administrative and
      political attention in case of insecure investments].

PMID- 12611287
TI  - [Ethical aspects of anti-Alzheimer drugs: experiences of caregivers].
AB  - The development and use of acetylcholinesterase inhibitors raise ethical issues.
      Ethical issues concern the consequences of an early diagnosis, the creation of
      unreasonable hope, possible negative effects of rivastigmine use, problems
      concerning stopping with rivastigmine, the patient role in decision-making and
      the possibility of conflicting interests. Within the ethical literature,
      hypotheses about the meaning of this drug for the patients have been formulated.
      This research aimed to investigate the experiences of caregivers of patients who
      used rivastigmine. The data have been collected by semi-structured interviews.
      The study included 12 caregivers of rivastigmine users. The--preliminary--results
      seem to indicate that theoretical considerations should be modified in the light
      of the experiences of caregivers. For example, problematic consequences of an
      early diagnosis and the creation of unreasonable hope did not appear in this
      study. Also problems concerning the rising awareness of cognitive decline were
      not found. In the interest of a further ethical debate concerning the development
      and use of antidementia drugs it is important to modify these theoretical
      considerations.

PMID- 12611288
TI  - ["Natural cause of death or not?" How do nursing home physicians act when in
      doubt of natural cause of death?].
AB  - The objective of the study was to explore if nursing home physicians act by law,
      when they doubt the natural cause of death. In May 1999, a questionnaire was sent
      to 153 nursing home physicians in the region of Utrecht and Nijmegen. They were
      asked if they consult the coroner when they have doubts about the natural cause
      of death. Eighty-six percent (104) returned the questionnaire. Thirty-two percent
      of the nursing home physicians always consult the coroner and 52% does so most of
      the time. Only 12% does not consult the coroner most of the time and 2% never
      does. The main reasons for not consulting the coroner were that nursing home
      physicians judge a death after a fall as an incident that fits in the descending
      lifeline of patients and that some nursing home physicians had bad experiences
      consulting the coroner. We conclude that this policy may lead to
      underregistration of unnatural deaths. Changing the definition or changing the
      law may reduce this problem. Education and information can also contribute to
      change in physician's attitudes.

PMID- 12611289
TI  - [Measuring discomfort in patients with dementia. Validity of a Dutch version of
      the Discomfort Scale--dementia of Alzheimer type (DS-DAT)].
AB  - The Discomfort Scale--Dementia of Alzheimer Type (DS-DAT) is an instrument to
      assess discomfort in patients with severe dementia by observing patients'
      behaviour during five minutes. Trained nursing home physicians collected data of
      662 pneumonia patients with dementia. The data were used to test the validity of
      a Dutch translation of the DS-DAT as a measure of discomfort. Internal
      consistency of the nine-item instrument was favourable (Cronbach's alpha ranged
      between 0.82 and 0.84 for different times during and following the pneumonia),
      and factor analyses indicated measurement of a single concept. Furthermore, as
      hypothesised, discomfort appeared moderately associated with acute illness.
      Nursing home physicians' assessment of DS-DAT scores therefore appeared a
      suitable method to assess discomfort in severely demented psychogeriatric nursing
      home patients for research purposes. For use in individual patients, results are
      probably too strongly affected by the chosen time fluctuations of assessment. For
      this purpose, the current rater assessment instructions should be adapted and
      tested.

PMID- 12611290
TI  - [Does education influence the results of the Amsterdam Dementia-Screening Test
      (ADS)?].
AB  - The goal of this study was to explore the correlation between education and the
      results of five dementia screening tests. In a study of 551 consecutively
      enrolled psychogeriatric day care attendants individual differences in education
      explained only very small portions of variance (< or = 0.63%) in four tests
      (visual recognition memory, orientation, category fluency and alternating
      sequences) of the Amsterdam Dementia Screening Test, a standard
      neuropsychological battery. The only exception was graphical copying of two- or
      three-dimensional geometric designs, where education explained 6.25% of the
      variance in copying accuracy. The more education participants had (from
      incomplete or complete primary education, through extended primary education,
      lower technical and vocational training, and secondary to higher education), the
      better their copying performance was. There was however one exception, in that
      participants with secondary education copied designs significantly less
      accurately than participants with lower technical and vocational training.
      Differences in copying accuracy of subjects with higher versus lower educational
      attainment were largest for participants matched for high levels of cognitive
      function. More severe cognitive impairment attenuated education effects. Higher
      education did not protect against decline of copying performance as a consequence
      of increasing cognitive impairment. For each of three educational levels,
      premorbid copying performance was estimated by constructing a regression equation
      using an independent measure of cognitive functioning (in terms of visual
      recognition memory, orientation and category fluency) as the predictor variable.
      The results support the clinical utility of controlling for educational level
      when interpreting individual copying performance.

PMID- 12611291
TI  - [Anesthesia in surgical treatment of the ascending aorta-arch aneurysms].
AB  - The paper analyzes anesthesiological maintenance of infusion therapy, optimal
      criteria for effective brain protection, complications and mortality in 42
      patients during operations on the ascending portion and arch of the aorta under
      deep hypothermic circulatory arrest. For this purpose, the patients were divided
      into 2 groups: Group 1 comprised 20 patients operated on before 1998; Group 2
      included 22 patients operated on in 1998 to 2001. In both groups, circulatory
      arrest lasted 44 +/- 7 min. The patients were cooled to a temperature of 13.5 +/-
      0.5 degrees C, to 15 +/- 0.6 degrees C in the nasopharynx. The duration of
      cooling was 58 +/- 5 and 73 +/- 6 min, respectively; that of warming-up was 70 +/
      8 and 83 +/- 6 min. Investigations have indicated that determination of the
      optimum brain cooling requires a complex assessment of central temperature
      values, electroencephalographic monitoring (visual estimation of a curve and
      quantitative characteristics), SjbO2 and cerebral metabolism. The investigations
      have shown that the procedure for anesthesiological maintenance and cerebral
      metabolism is safe and effective even in patients with arrested circulation
      lasting longer than 60 min. The operative mortality does not depend on the use of
      circulatory arrest under deep hypothermia and on its duration. Hemodynamic
      instability due to bleeding, as well as myocardial infarction, marked
      hemodilution during extracorporeal circulation are major factors that cause an
      increase in the rates of incidence of complications and mortality. The procedure
      used for anesthesiological maintenance and infusion therapy, decreased blood
      loss, and a reduction in the incidence of myocardial infarction could
      significantly reduce operative mortality. The fact that there were no
      neurological complications even during prolonged (80-min) circulatory arrest has
      shown that the brain-protective procedure including both general and regional
      cooling is reliable and to the extent of the indicated criteria. So is
      pharmacological protection.

PMID- 12611292
TI  - [Implementation of modern principles of blood saving methods at cardiac surgery
      under extracorporeal circulation].
AB  - The introduction of principles of bloodless surgery into different areas of
      practical medicine is favoured by not only risks from donor blood transfusion,
      but also by the results of the researches dealing with the body's adaptation to
      acute anemia, with the determination of its allowable limits, and with much
      experience with bloodless operations used in Jehovah's Witnesses. The present
      study was undertaken to make a scientific-and-practical assessment of actual own
      blood funds and their introduction in order to decrease or refuse to use donor
      blood at cardiac surgery under extracorporeal circulation (EC). A retrospective
      analysis of hemotransfusion policy in 1993-2001 was conducted in over 2000
      patients operated on under EC for coronary heart disease, acquired and congenital
      cardiac diseases at the Open Cardiac Surgery Department, Russian Surgery Research
      Center, Russian Academy of Medical Sciences. Own blood saving methods, such as
      intraoperative autohemotransfusion as two modalities, washed autoerythrocytic
      reinfusion, autoplasma reinfusion, as well as the use of different
      pharmaceuticals effective in reducing hemorrhage after EC were evaluated. The
      introduction of the above own blood saving methods may decrease the use of donor
      erythrocytes and freshly frozen plasma by 2.6 and 1.8 times, respectively, may
      completely refuse transfusing thromboplasma, assure adequate hemostasis, reduce
      the incidence of adverse reactions associated with donor blood transfusion in
      cardiac surgical patients. A complex use of the developed saving donor blood
      methods and pharmaceuticals aimed at improving hemostasis allowed donor blood
      transfusion to be completely refused in more than 70% of patients at
      aortocoronary bypass surgery under EC.

PMID- 12611293
TI  - [Anesthesiological aspects of early activation of patients after aortocoronary
      bypass surgery].
AB  - The specific features of the course of anesthesia and the time of extubation were
      studied in 142 patients suffering from coronary heart disease who had undergone
      myocardial revascularization. All the patients were divided into 3 groups in
      accordance with the type of anesthesia. Group 1 patients (n = 48) received
      routine anesthesia with ketamine, benzodiazepines, and large-dose fentanyl. Group
      2 (n = 45) had combined anesthesia with inhalational and intravenous anesthetics
      having their better pharmacodynamics (such as isoflurane, diprivan, tracrium). In
      Group 3 (n = 49), the authors employed another developed modality of anesthesia
      using high thoracic (TII-TIV) epidural anesthesia as a basic component of
      anesthesiological maintenance. The two developed modalities of anesthesia almost
      halved the use of total dose opioids, which promoted patients' early
      postoperative recovery of consciousness and respiration. The time before
      extubation was 9.9 +/- 2.1, 4.5 +/- 1.1, and 1.5 +/- 1.2 hours in Groups 1, 2,
      and 3, respectively (p < 0.05). The developed anesthesia procedure using
      isoflurane, midazolam, propofol, and small-dose fentanyl ensures safe and early
      (up to 6-hour) extubation in 73% of the patients undergone aortocoronary bypass
      surgery. The developed anesthesiological protocol based on thoracic epidural
      anesthesia enables extubation to be carried out on the operating table within an
      hour in 75% of patients after aortocoronary bypass surgery. A comparative
      intraoperative analysis of hemodynamics, the incidence of myocardial ischemia,
      arrhythmias, glucose levels has indicated that the anesthesia techniques aimed at
      a patient's early activation are not inferior in the degree of protection to
      routine anesthesia using large doses of opioids, ketamine, and diazepam. When
      used in combination with thoracic epidural block, the methods are superior to the
      latter.

PMID- 12611294
TI  - [Postoperative period in early activated patients after myocardial
      revascularization].
AB  - The specific features of an early postoperative period were studied in 115
      patients undergone myocardial revascularization who were divided into 3 groups
      according to the time of postoperative activation. Group 1 comprised 35 patients
      in whom tracheal extubation was made in the operating room 30-60 min after the
      end of the operation. Group 2 included 32 patients extubated 2-8 hours after
      admission to the resuscitation and intensive care unit (RICU); Group 3 consisted
      of 48 patients undergone tracheal intubation for more than 8 hours. The patients
      of this group received traditional anesthesia using ketamine, benzodiazepines,
      and large-dose fentanyl. The developed combined anesthesia with inhalational and
      intravenous anesthetics having their better pharmacodynamics, such as isoflurane,
      diprivan, tracrium, was used in 60.3% of the patients in Groups 1 and 2. The
      developed type of anesthesia using a high thoracic (T2-T4) epidural blockade as a
      basic component of anesthesiological maintenance was studied. In Group 2, the
      preextubation time was twice less than that in a control group (5.2 +/- 0.3 and
      10.8 +/- 0.4 hours, respectively, p < 0.05). In groups with early extubation, the
      incidence of clinically significant cardiovascular disorders was less than that
      in the controls, which is indicative of better performance of the cardiovascular
      system. In Group 1, the frequency of reintubations for arterial hypoxemias was
      2.8% and that of pneumonias and pulmonary microatelectasis was 2.5 times less as
      that in Group 3 (9%, p < 0.05). Chills occurred in 6, 4, and 15% of cases in
      Groups 1, 2, and 3, respectively (p < 0.05). A programme on early activation
      after aortocoronary bypass surgery could reduce the patients' stay at the RICU on
      an average by 24 hours without increasing the risk for postoperative
      complications.

PMID- 12611295
TI  - [Cerebral oximetry during cardiac surgery under extracorporeal circulation].
AB  - The time course of changes in rSO2 were studied in 58 patients during the
      uncomplicated course of cardiac operations under extracorporeal circulation (EC)
      and moderate hypothermia. rSO2 was also compared with central hemodynamic
      parameters, bioelectrical cerebral activity, and hemoglobin oxygen saturation of
      the bulb of the internal jugular vein (jbSO2). In the pre- and postperfusion
      period there was a significant correlation of rSO2 and jbSO2 (p = 0.01), yet with
      a low correlation coefficient (r = 0.348). During EC, no correlation was found
      between rSO2 and jbSO2 (p = 0.09, r = 0.386). Changes in rSO2, blood pressure,
      EEC, body temperature were analyzed in 2 groups of patients at the stages of an
      operation under EC. Group 1 comprised patients with cardiac valvular apparatus
      lesions and Group 2 included those with coronary heart disease who differed not
      only in age, but also in the history of mainly cerebrovascular atherosclerotic
      lesions, hypertensive disease, myocardial infarction, etc. In patients from both
      groups, a reduction in rSO2 occurred at the beginning of EC and at the maximum of
      cooling. But if in Group 1 patients, the significant reductions in rSO2 at the
      beginning of EC coincided both with that in mean blood pressure (BPmean), as
      compared to the baseline values (from 75.55 +/- 10.68 to 66.5 +/- 11.73 mm Hg, p
      = 0.01), and with the change in the frequency spectrum of EEC (a decrease in the
      frequency of the right edge, as compared to the baseline values, from 20.77 +/-
      1.44 to 19.58 +/- 1.14 Hz, p = 0.01), in Group 2 patients, all significant
      decreases in rSO2 were accompanied only by a significant reduction in BPmean, but
      without changes in the frequency spectrum of EEG. It should be noted that over
      the uncomplicated course of an operation all changes in rSO2 were in the normal
      range of age-related values.

PMID- 12611297
TI  - [Rocuronium (esmerone) in anesthesia during surgery under extracorporeal
      circulation].
AB  - The study was undertaken to examine the myoplegic, hemodynamic, and histamine
      releasing effects of the new aminosteroidal myorelaxant Rocuronium (esmerone,
      Organon firm) used to maintain anesthesia in cardiac surgical patients by
      orienting to early tracheal extubation. Twenty two patients aged 50 +/- 3 years
      operated on under extracorporeal circulation were examined. At the initial stage
      of maintenance, the agent in a dose of 0.6 mg/kg failed to affect cardiac pump
      function and to elevate plasma histamine levels. A moderate vagolytic effect was
      shown in 45% of cases. The incidence of myoplegia reduced in patients with
      significant circulatory insufficiency. In the preperfusion period, Rocuronium in
      a dose of 10.2 +/- 0.9 micrograms/kg/min blocked neuromuscular conduction (NMC)
      at a level of 5.1 +/- 1.8 to 19.2 +/- 3.5%. During hypothermic extracorporeal
      circulation and postperfusion period, the dosage of the myorelaxant substantially
      decreased. After termination of Rocuronium infusion, the time of up to 95%
      recovery of NMC was 63 +/- 6 min. Early tracheal extubation was conducted in 68%
      of the patients 69 +/- 7.6 min after the end of the operation. Residual myoplegia
      was absent. The predictable recovery of NMC following the use of Rocuronium
      creates conditions for early activation of patients operated on under
      extracorporeal circulation.

PMID- 12611296
TI  - [Modern nondepolarizing myorelaxants in cardiac surgery].
AB  - The electromyographic and hemodynamic profile and side effects of the new
      nondepolarizing myorelaxants Mivacurium chloride (Mivacron), Cisathracurium
      besilate (Nimbex), Rocuronium bromide (Esmerone) were studied in 117 adult
      patients. All the test myorelaxants as bolus or infusion in a dose of 3.ED95 were
      found to be effective in creating adequate conditions for tracheal intubation and
      neuromuscular block (NMB) maintenance during operations on the coronary arteries
      and cardiac vales under extracorporeal circulation. In terms of the onset rate of
      NMB, Esmerone is the drug of choice for tracheal intubation. Esmerone and Nimbex
      in a dose of 3.ED95 did not produce a noticeable hemodynamic effect. The former
      was found to have a slight vagolytic effect. When rapidly injected as bolus,
      Mivacron caused a significant decrease in blood pressure and heart rate by 10
      12%. Based on a comprehensive study, the authors have scientifically
      substantiated principles in the choice of nondepolarizing myorelaxants in cardiac
      surgical patients in relation to the baseline hemodynamic values, the stage of an
      operation, and the duration of artificial pulmonary ventilation.

PMID- 12611298
TI  - [Temperature regimen of extracorporeal circulation during aortocoronary bypass
      surgery].
AB  - The purpose of the study is to comparatively evaluate the impact of normo- and
      hypothermic perfusion on acid-base balance (ABB), gas blood composition,
      metabolic parameters, and hemostasis. Fifty patients undergone multiple
      aortocoronary bypass under extracorporeal circulation (EC) were examined. Twenty
      four patients and 26 (Groups 1 and 2, respectively) had been operated on under
      normo- and hypothermia. The groups did not differ in age, body weight, the
      duration of an operation, the number of shunts, the time of EC, and myocardial
      ischemia. ABB, gas blood composition, the concentrations of hemoglobin, lactate,
      fibrinogen, prothrombin time, thrombin time, activated partial thromboplastin
      time, activated coagulation time, blood coagulation time as described by Leigh
      White, the count of platelets, and ADP-induced platelet aggregation in the early
      postperfusion and postoperative periods, following 24 and 48 hours after surgery.
      There were no significant differences in the values of ABB, gas blood
      composition, blood lactate levels in patients from both groups. However,
      metabolic acidosis, elevated blood lactate concentrations were more frequently
      encountered in Group 2 patients, which suggests that hypothermia prduces a more
      aggressive effect on systemic homeostasis. Impact of normo- and hypothermia on
      the coagulative link of homeostasis was not revealed. Nevertheless, hypothermic
      EC halved the functional activity of platelets, which has a substantial effect on
      the size of postoperative blood loss.

PMID- 12611299
TI  - [Anesthesia in obese patients].
AB  - Anesthesiological aids were analyzed in 70 obese patients undergone a total of 88
      surgical interventions (in 1992 to 2002). This category of patients presented
      difficulties with tracheal intubation and gas exchange management at all stages
      of anesthesia and medication, which is associated with high chest rigidity, large
      distribution volume due to excess fatty tissue and serious comorbidity. The
      authors propose basic ways of solving the problems occurring with the use of
      fibrooptic equipment for tracheal intubation and suggest that short-acting agents
      with extraorgan elimination for induction and maintenance of anesthesia and
      special methods of artificial pulmonary ventilation (traditional volume-cyclic
      and jetwise high-frequency pulmonary ventilation) should be used to maintain
      effective gas exchange.

PMID- 12611300
TI  - [Anesthesia during liver transplantation].
AB  - Different methods and components of anesthesia during operations in donors and
      recipients were studied by using the experience in maintaining anesthesia during
      39 relative and 7 cadaveric hepatic transplantations. The experience in using
      epidural anesthesia and total intravenous anesthesia at the donor stage of
      hepatic lobar transplantation was comparatively analyzed. Combined epidural
      anesthesia (CEA) may be used during long-term and traumatic operations dealing
      with hepatic lobectomy in a relative donor since it is noted for low
      hepatotoxicity and no drastic hemodynamic exposures. CEA can substantially reduce
      pharmacological loading with opioids or myorelaxants, which is particularly
      important in taking the lobe of the liver. This reduces the recovery period of
      adequate own respiration, activates a patient more rapidly, substantially reduces
      the risk for postoperative iatrogenic complications. Balanced general anesthesia
      whose major component is inhalational anesthesia with isoflurane is the method of
      choice in performing an operation in the recipient. The use of isoflurane in the
      minimal-flow mode is cost-effective and safe. When anesthesia is performed in the
      recipient, it is necessary to take in account drastic hemodynamic pattern changes
      at the liverless stage during vein-venous bypass surgery, including the liver
      into systemic circulation, and the likelihood of development of significant
      reperfusion and concomitant metabolic and coagulative disorders.

PMID- 12611301
TI  - [Anesthesia during radical surgery for esophageal cancer].
AB  - The paper summarizes the experience with 245 anesthesias made in 1983 to 2002
      during operations for malignant esophageal neoplasms and cardioesophageal cancer.
      The specific features of the perioperative period, monitoring of the function of
      vital viscera, the technical features of transhiatal esophagectomy, risk factors
      of postoperative complications and principles of their prevention are considered.
      The ways of optimizing anesthesiological protection during radical esophageal
      operations are discussed.

PMID- 12611302
TI  - [Optimization of anesthesiological maintenance of x-ray surgical interventions in
      children].
AB  - Two procedures for intravenous anesthesia during X-ray surgical interventions
      were evaluated in 38 children aged 3 to 13 years. Initial anesthesia (with
      intramuscular midazole and ketamine), followed by the fractional use of the
      latter agents in Group 1 and propofol in Group 2, in order to maintain
      anesthesia. Blood pressure (BP) (noninvasively), heart rate (HR), SpO2, and
      respiratory rate (RR) were monitored. After the initial anesthesia, mean BP
      (BPmean) increased by 40 and 24% in Groups 1 and 2, respectively. So did HR by 23
      and 31%, respectively. In Group these changes retained throughout the basic stage
      of intervention. In Group 2 on propofol infusion, BPmean and HR returned to
      normal values and remained at this level till the end of the intervention, SpO2
      and RR did not differ from the baseline values in both groups. Thus, a
      combination of intravenous ketamine and intramuscular propofol provides steady
      state values of BP and HR at the basic state of X-ray surgical intervention in
      children, which increases the reliability of studies and surgical safety in
      patients.

PMID- 12611303
TI  - [Prevention of postoperative nausea and vomiting with highly selective 5-HT3
      serotonin receptors antagonists during different types of surgery].
AB  - A prospective study was conducted to examine the efficacy of highly selective, 5
      HT3 serotonin receptor antagonists (Zofran, 4 mg; Latran, 4 and 8 mg; Navoban, 2
      and 5 mg) during plastic and abdominal (endoscopic and routine) interventions in
      165 patients aged 14 to 77 years who had ASA Classes I-III. The drugs caused no
      adverse reactions and were effective in controlling postoperative nausea and
      vomiting (PONV) after surgery under total intravenous anesthesia. In plastic
      surgery, Navoban, Zofran, and Latran controlled PONV in 94, 81, and 70% of cases,
      respectively. In abdominal surgery, Zofran (4 mg) and Latran (4 mg and 8 mg) did
      this in 87, 80, and 90% of cases, respectively. Risk factors for PONV are
      analyzed. The pathophysiological aspects of PONV and practical approaches to
      making an antiemetic strategy are discussed.

PMID- 12611304
TI  - [Sleep and sedation: clinical and electrophysiological parallels].
AB  - Clinical and electrophysiological studies were performed in 10 volunteers and 45
      patients with Classes I and II, as stated by the American Society of
      Anesthesiologists, to evaluate consciousness during sedation. Prior studies on
      volunteers showed that there was a clear correlation between N-REM sleep and SEF
      in 90% of cases. Based on these findings, the authors propose a modified
      suppressed consciousness scale whose rating was adjusted to the levels of N-REM
      sleep. Irrespective of the type and technique of sedation (infusion of thiopental
      and propofol; PCS, midazolam), changes in the levels of drug-depressed
      consciousness were found to be the same.

PMID- 12611305
TI  - [Sandostatin (octreotide)--drug and neurotransmitter (experimental study)].
AB  - Sandostatin (octreotide), a synthetic analogue of somatostatin that is a hormone
      and neurotransmitter of pain conduction, has been developed. The drug has been
      widely used in gastroenterological care; however, its role as a neurotransmitter
      has been little studied. The authors performed experimental studies to evaluate
      the effects of octreotide on the nociceptive sensitivity of animals (the
      intravenous dose being 1 mg/kg) and on the actinociceptive activity of fentanyl
      (the intraperitoneal doses, 125 and 250 micrograms/kg). The study has
      demonstrated that octreotide in a dose of 1 mg/kg causes a steady-state
      hyperalgesic effect. A combination of octreotide and fentanyl in the above
      diseases substantially reduces the analgesic activity of the latter just 15 min
      after injection, which should be borne in mind in applying the above agents in
      clinical practice.

PMID- 12611306
TI  - [Carboxyperitoneum and clinical efficacy of nondepolarizing relaxants with
      different types of metabolism].
AB  - A total of 108 patients operated on the abdominal cavity were examined with
      laparoscopic equipment or via laparotomic assess. The recovery time of
      neuromuscular conduction was defined for a myorelaxant with organ-depended
      metabolism (pipecuronium) and, predominantly, nonorgan-depended metabolism
      (athracurium and cisathracurium) in relation to the type of surgical technique
      (laparoscopy and laparotomy). It is concluded that carboxyperitoneum prolongs the
      recovery of neuromuscular conduction for pipecuronium without affecting this
      parameter in athracurium and cisathracurium. It is more expedient to use these
      myorelaxants during laparoscopic operations than pipecuronium, a myorelaxant
      having organ-dependent metabolism.

PMID- 12611307
TI  - [Prevention of clot formation and improvement of blood rheological properties
      during microsurgical operations. Part II. Comparative studies of small doses of
      acelysin and low molecular weight heparin enoxaparine (clexane)].

PMID- 12611308
TI  - [Diabetes mellitus, chronic kidney failure, hemodialysis--strategy and tactics of
      anesthesiologist].

PMID- 12611309
TI  - [Modern computer and telecommunication technologies in anesthesiology].

PMID- 12611310
TI  - [Anesthesiology and pharmacoeconomy].

PMID- 12611311
TI  - Amalgam under attack.

PMID- 12611312
TI  - New York State health profile.
AB  - The CDC publications on state health profiles provide an opportunity to compare
      the general health of New York State residents with that of the rest of the
      country. While many areas of improvement and favorable state rankings are
      reported, limitations, particularly for minority populations, are highlighted. A
      summary of many of these findings is provided.

PMID- 12611313
TI  - An unusual symptom of lidocaine allergy. Report of a case.
AB  - The incidence of lidocaine allergy is rare. A confirmed case of antigen/antibody
      reaction is presented here. It is further distinguished by the unusual presence
      of blurred vision in the patient.

PMID- 12611314
TI  - Herbal supplements. Any relevancy to dental practice?
AB  - The increasing popularity of herbal supplements demands that dentists be more
      knowledgeable about the effects these supplements have on oral health and
      treatments. Based on the medical literature, at least some of the popular
      products appear to have the potential to elicit oral manifestations and adverse
      interactions with dental drugs. These effects seem to be associated primarily
      with antiplatelet, sedative and hepatotoxic properties of the herbs. An
      understanding of the effects of herbal supplements would allow dentists to
      provide improved dental care and to educate patients taking these products.

PMID- 12611315
TI  - Delirium in advanced cancer: a psychoeducational intervention for family
      caregivers.
AB  - Delirium, a global brain dysfunction, develops frequently in advanced cancer. It
      is a leading source of distress for family caregivers. Following recommendations
      from palliative care professionals and caregivers for terminally ill cancer
      patients, a psychoeducational intervention was implemented in a palliative care
      hospice to help family caregivers cope with delirium and, eventually, to
      contribute to early detection. Prior to receiving information on delirium, the
      majority of the family caregivers did not know what it was or that it could be
      treated. Few knew that patients in terminal care could become delirious. For
      caregivers, receiving the intervention increased their confidence they were
      making good decisions, and the majority felt that all family caregivers should be
      informed on the risk of delirium (p < 0.009). A specific intervention on
      delirium, tailored to the needs of the family caregivers, seems beneficial for
      caregivers and for patients.

PMID- 12611316
TI  - Developing palliative care surveillance in Canada: results of a pilot study.
AB  - OBJECTIVE: A pilot study compiled data from six palliative care centres across
      Canada to assess the feasibility of developing a national surveillance system.
      METHODS: Data provided for the three-year period between 1993-1997 were combined
      into a comparative minimum data set. Analyses included 6,369 care episodes from
      five centres, plus 948 patients from one centre. RESULTS: Care was provided in
      various settings including acute care wards, dedicated palliative care units,
      tertiary care, chronic care, and at home. Palliative care patients comprised
      equal numbers of men and women, with a median age of 69 years; 92% had cancer
      diagnoses. Median length of stay (LOS) for each care episode was 13 days,
      increasing to 40-43 days for a patient's entire time in care. LOS varied greatly,
      by care setting, from seven days (dedicated unit), to 19 days (tertiary unit), 37
      days (home), and 54 days (chronic care). Our findings are similar to those
      reported from national surveys in Australia and the United Kingdom. SUMMARY: This
      study generated useful baseline data and identified key issues requiring
      resolution before establishing a national surveillance system, including the need
      to track patients across care settings.

PMID- 12611317
TI  - Nurse specialist assessment and management of palliative care patients who are
      depressed--a study of perceptions and attitudes.
AB  - Depression is a frequent symptom in palliative care patients but is often not
      diagnosed. In the U.K., the majority of patients with advanced cancer are
      referred to a clinical nurse specialist (CNS) whose remit includes the assessment
      of psychological symptoms and depression. Clinical nurse specialists have a key
      role in the diagnosis and management of patients with depression and it is
      important that they have the skills to do so. A postal questionnaire of all U.K.
      hospital, hospice, and community palliative care clinical nurse specialist teams
      was carried out to determine how they assessed depression in their patients. The
      response rate was 40%. Seventy-nine percent of all clinical nurse specialists
      believed their skills were poor in this area, and 92% felt they required further
      training. These beliefs were substantiated by the difficulties nurses encountered
      in assessing depression and by their beliefs regarding antidepressant medication.
      Clinical nurse specialists have a pivotal role in improving the detection and
      management of depression in palliative care patients, and require further
      training in this area.

PMID- 12611318
TI  - A multi-professional short-term group intervention for informal caregivers of
      patients using a home palliative care service.
AB  - Informal carers of home palliative care patients have high unmet needs. However,
      interventions for carers are few. This research-based short-term group
      intervention addresses the information and support needs of carers.
      Multiprofessional informal teaching is combined with peer support. The
      intervention was designed by integrating the findings from a qualitative study
      and the evidence on needs and interventions, in order to address the key issues
      of feasibility, acceptability, and accessibility. Qualitative data from attendees
      showed that identifying with other carers and validating feelings, asking
      questions of professionals, and providing each other with support and
      encouragement were valuable outcomes from the group.

PMID- 12611320
TI  - The role of the pharmacist in palliative care: results of a survey conducted in
      Australia and Canada.
AB  - A survey was conducted to determine what pharmaceutical services are provided to
      palliative care sites in Australia and Canada, and the pharmacist's role on the
      interdisciplinary team. Questionnaires were sent to 100 selected sites in each
      country. Questions pertained to demographics and the level of duties performed.
      Australian 42/76 (55.3%) and Canadian 59/69 (85.5%) sites employed palliative
      care pharmacists. Most Australians (83.3%) and Canadians (69.8%) worked under 20
      hours/week on the palliative care service. Administrative duties and basic drug
      supply functions were more common in Australia, whilst Canadians had greater
      participation in team meetings and rounds. Medication review was the most common
      clinical duty; approximately 70% of respondents in each country provided specific
      advice on pharmacotherapy, administration, treatment, adverse effects, and
      incompatibilities. Education was universally important, but active participation
      in conferences, publication, and research was infrequent. Pharmacists in both
      Australia and Canada are important members of the palliative care team, and
      provide a similar high level of unique and valuable services to patients and
      their families.

PMID- 12611319
TI  - Factors that promote success in home palliative care: a study of a large suburban
      palliative care practice.
AB  - It has been repeatedly shown that most people would prefer to die in their own
      homes. However, many factors affect the feasibility of this choice. This study
      retrospectively examined the medical and nursing charts of 402 cancer patients
      who wished to die at home and had been referred to a palliative care service. Of
      those reviewed, 223 (55%) died at home, while 179 died in hospitals. The presence
      of more than one caregiver, an increased length of time between diagnosis and
      referral to a palliative care physician, an increased length of time under that
      physician's care, older age at referral, home ownership, and race were all
      significantly associated with home death, as were certain cancer diagnoses. The
      most compelling of these predictive factors have formed the basis for an
      evaluation tool, soon to be validated, to help palliative health professionals
      assess the viability of home-based palliative care culminating in a home death.

PMID- 12611321
TI  - Practical wisdom: competencies required in alleviating suffering in palliative
      care.
AB  - The aim of this article is to reflect upon the competencies required to alleviate
      suffering in palliative care. The knowledge to prudently and wisely act in a
      situation involving human relationships can be defined in terms of practical
      abilities and contextual skills. In the setting of the care of the very ill and
      dying, practical wisdom such as the carer's ability to meet the suffering person
      and to act with sensitivity and openness, becomes important. From this, learning
      to alleviate suffering emerges as receiving insight and wisdom from the suffering
      person's experience of suffering. This means that the testimony of suffering
      persons--what they have endured, given up and experienced--becomes as significant
      as theoretical and practical knowledge of suffering. The professional carer needs
      to learn how to be open to and interpret what the suffering person, living with
      suffering and death in the midst of life, can teach.

PMID- 12611322
TI  - Communication in cancer care: recent developments.

PMID- 12611323
TI  - An evaluation of the use of and satisfaction with the Palliative Care Pain and
      Symptom Pocket Card.

PMID- 12611324
TI  - [Organizational and methodological approaches to improving the microbiological
      diagnosis of tuberculosis in Russia].
AB  - The practice of the researchers of the Central Research Institute of Tuberculosis
      in Russia's experimental areas yielded approaches to improving the
      microbiological diagnosis of tuberculosis in both specialized and general health
      care facilities. A decisive role in enhancing the efficiency of microbiological
      identification of patients with tuberculosis is played by the following factors:
      laboratory staff training, provision of laboratories with qualitative equipment
      and reagents, introduction of unified methods and those approved by the Ministry
      of Health of the Russian Federation, regular supervision of jurisdictional
      laboratories, and outside test quality control. The efficiency of microbiological
      diagnosis of bacillary patients primarily depends on the expediency of formation
      of groups of patients under study, the observance of the frequency of
      examinations, and the assurance of the quality of collected materials. With this,
      the centralization of microbiological tests for tuberculosis at the most trained,
      certified, and licensed large laboratories that exercise a centralized control
      over the quality of microbiological tests.

PMID- 12611325
TI  - [Comparative clinical, X-ray, and immunogenetic characteristics of respiratory
      tuberculosis actively detected in risk groups and in individuals turning for
      medical help].
AB  - Clinical, X-ray, and immunogenetic parameters were comparatively assessed in two
      groups of first identified patients diagnosed at annual fluorographic studies in
      groups at risk for tuberculosis and in individuals visiting general health care
      facilities for symptoms of inflammatory bronchopulmonary disease. Great
      differences were established in the clinical and X-ray manifestations, the course
      of the disease, and the patients' immunogenetic status in these groups.
      Tuberculosis in the patients identified on their referral to general health care
      facilities is characterized by more severe clinical manifestations, a greater
      spread of inflammatory and destructive changes in the lung, and massive bacterial
      isolation. There were certain associations of the HLA antigens A2 and A 11 as
      markers indicative of tuberculosis resistance with the antigens B35 and Cw4
      suggestive of predisposition to tuberculosis in patients with chronic bronchitis.

PMID- 12611326
TI  - [Analyzing the drug resistance of Mycobacterium tuberculosis in Russia's
      experimental areas introducing the WHO tuberculosis control programme].
AB  - The authentic data on the drug resistance of Mycobacterium tuberculosis can be
      obtained only provided that standard laboratory procedures and the unified
      standardized method for determining the resistance are used along with a
      compulsory outside quality control over the performance of this test. The
      supervisory activities of the researchers of the Central Research Institute of
      Tuberculosis (CRIT), Russian Academy of Medical Sciences, made in some regions of
      Russia included standardization of methods and their implementation quality
      control allowed them to reveal and to correct main errors in drug resistance
      testing. In this connection, this made it to record the true level of M.
      tuberculosis resistance to essential antituberculous agents in the areas
      investigated by the researchers of CRIT. Analyzing the data on the drug
      resistance of M. tuberculosis in the above areas leads to the conclusion that
      2000 was marked by rather high rates of primary drug resistance; nearly a fourth
      of all new and prior cases of pulmonary tuberculosis studied for its drug
      resistance were carriers of a M. tuberculosis resistant to at least one
      antituberculous agent.

PMID- 12611327
TI  - [Examining the distribution of HLA antigens in patients with tuberculosis and in
      healthy individuals in the Erza District, Republic of Tyva].
AB  - The paper presents the results of typing by HLA classes I and II antigens in 55
      patients with tuberculosis and 85 healthy Tyvians in the Erza District. Republic
      of Tyva. HLA I and II antigens were determined serologically and polymerase chain
      reaction, respectively. Tyvian patients with pulmonary tuberculosis had HLA B7
      antigen more frequently and HLA B12 antigen less frequently than the controls.
      The findings suggest that pulmonary tuberculosis is associated with HLA-DRB1
      14(6) specificity in this district of the Republic of Tyva. These data may be
      useful in forming groups at risk for pulmonary tuberculosis in the district under
      study.

PMID- 12611328
TI  - [Value of enzyme immunoassay in the diagnosis and differential diagnosis of
      abacillary tuberculosis in children and teenagers ].
AB  - Positive enzyme immunoassay (EIA) was found in 59.6% of patients of tuberculosis.
      Positive responses were significantly more frequently detected in patients with
      pulmonary tuberculosis than in those with intrathoracic lymph nodal tuberculosis
      (ITLNT) (62.2 +/- 7.4 versus 38.9 +/- 11.8%, respectively; p < 0.05. There was no
      significance difference in the rate of positive responses in patients with ITLNT
      (38.9 +/- 11.8%) and healthy individuals inoculated with Mycobacterium
      tuberculosis (17.6 +/- 9.5%). Sixteen (61.5%) patients with pneumonia showed a
      positive response, which amounted to 38.5% specificity of the method. The
      findings suggest that EIA may not be used as a screening test for early diagnosis
      of tuberculosis in children and teenagers and for differential diagnosis of
      pulmonary tuberculosis and nonspecific pneumonia. EIA data may be assessed only
      in combination with other diagnostic criteria.

PMID- 12611329
TI  - [Efficacy of treatment for pulmonary tuberculosis with multidrug mycobacterial
      resistance].
AB  - The efficiency of treatment was studied in 149 patients with pulmonary
      tuberculosis who isolated multidrug resistance of Mycobacteria tuberculosis
      (MBT). The multidrug resistance of MTB, to at least isoniazid and rifampicin can
      be associated with both the resistance to other essential (streptomycin,
      ethambutol) and that to reserve drugs. With this, patients with MBT resistance to
      a combination of essential and reserve drugs more frequently showed a chronic
      course of the disease with severe clinical manifestations and more disseminated
      infiltrative-and-destructive lesions in the lung. Drug treatment regimens using a
      combination of reserve drug were effective only in patients with MBT resistance
      to essential drugs while they were little effective in those with resistance to
      essential and reserve agents. The use of artificial pneumothorax in patients with
      MBT resistance to essential and reserve agents could cease bacterial isolation in
      77.8% of the patients even by ingesting a small number of the drugs. Clinically,
      the occurrence of MBT resistance to reserve drugs is justified to determine a
      radically new status in patients in the context of chemotherapy and the whole
      further treatment in this group of patients. A clinical classification of MBT
      multidrug resistance is proposed, which identifies two categories of patients
      with pulmonary tuberculosis: those resistant to essential drugs and those
      resistant to a combination of essential and reserve drugs.

PMID- 12611330
TI  - [Pulmonary tuberculosis in adolescents in relation to different degree of drug
      resistance].
AB  - Ninety adolescents with bacterial isolates of active forms of pulmonary
      tuberculosis were followed up. Drug resistance of Mycobacteria tuberculosis was
      revealed in 57 (63.3%) patients. Primary resistance was determined in 43 (47.7%)
      patients. The patients had not received antituberculous agents. Complete or
      partial coincidence of MBT resistance and sensitivity with the data of an
      infection focus. The course of tuberculosis during adequate treatment by using
      essential and reserve agents in the adolescents with varying MBT resistance was
      different. In patients (n = 18) resistant to 1-2 agents, the course of the
      disease little differed from that in those patients with drug-responding
      tuberculosis, except for later closure of decay cavities. In patients resistant
      to 3 drugs or more showed a slow course of the disease with significant residual
      changes in most patients.

PMID- 12611331
TI  - [Plasmapheresis in the complex treatment of patients with acutely progressive
      pulmonary tuberculosis].
AB  - The efficiency of plasmapheresis versus routine methods of detoxification in the
      complex treatment was compared in 100 patients with acutely progressive pulmonary
      tuberculosis. After 2 and 4 months, plasmapheresis was found to arrest the
      intoxication syndrome in 56 and 100% of the patients, respectively. This
      treatment in these patients resulted in ceased bacterial isolation in 52% of the
      patients following 2 months and lung cavern closure in 36% of cases after 6
      months. This ultimately reduced the time of hospital stay on the average of 2
      months, its duration being not longer than 7-8 months.

PMID- 12611332
TI  - [Dynamics of changes in lung function in patients with recurrent tuberculosis and
      ineffective primary treatment in intensive phase of controlled chemotherapy].
AB  - In 51 patients with recurrent tuberculosis and ineffective primary treatment in
      intensive controlled chemotherapy, VC, FVC, FEV1, FEV1/VC%, PEF, MEF25, MEF50,
      MEF75, Pa02, PaCO2 were measured before, during, and after intensive controlled
      chemotherapy. Lung function improved in 51.0% of the patients and deteriorated in
      19.6%. There was a combination of better and worse lung function in 9.8% of the
      examinees. The improvement of lung function was observed only during effective
      chemotherapy, its deterioration was seen mainly during ineffective chemotherapy,
      rarely during successful chemotherapy. The main cause of better lung function was
      the resolution of fresh inflammatory changes and that of worse lung function is
      the cicatricial transformation of lung tissue.

PMID- 12611333
TI  - [Dynamics in microcirculation and regional ventilation of the lung during
      treatment in patients with destructive tuberculosis].
AB  - Studies of the time course of changes in regional blood flow and regional
      ventilation of the lung in patients with destructive pulmonary tuberculosis (DPT)
      suggest that there may be different shifts in radionuclide indices after
      antibacterial therapy. Full recovery of regional blood flow and regional
      ventilation of the lung sometimes is accounted for by the resolution of
      inflammatory changes, by the healing of destruction frequently attended by a
      significant improvement, but there is a more regular change in the areas of the
      underlying process in particular, through evolving pneumosclerosis. A
      comprehensive radionuclide study in patients with destructive pulmonary
      tuberculosis in combination with clinical and X-ray studies allows clinicians to
      investigate the extent and site of a pathological process and thereby to define
      the functional status of capillary blood flow and pulmonary alveoles.
      Radionuclide studies enable a trend of a pathological process in the lung to be
      defined during treatment since alterations in the lung reflect the time course of
      changes in a specific process and the efficiency of treatment.

PMID- 12611334
TI  - [Specific features of the diagnosis and course of tuberculosis of peripheral
      lymph nodes in adults].

PMID- 12611335
TI  - [Treatment of patients with contaminant HIV infection and tuberculosis].

PMID- 12611336
TI  - [Acute toxic encephalopathy in patients with tuberculosis].
AB  - A hundred and thirty five patients admitted to Moscow Tuberculosis Hospital No. 7
      for disseminated and progressive forms of tuberculosis were examined. Among
      neurological disorders in tuberculosis, acute toxic encephalopathy (ATE) should
      be placed in the first place in terms of their severity, problems of diagnosis
      and treatment. In patients with acutely progressive forms of tuberculosis, the
      development of ATE is brought about by two factors: 1) significant tuberculous
      toxemia concurrent, in 37% of cases, with severe alcoholic intoxication that
      leads to generalized toxic and allergic vasculitis and as a result DIC syndrome;
      2) cerebral hypoxia with dyscirculatory disorders due to progressive
      cardiopulmonary failure. The status of patients with tuberculosis and ATE is
      generally critical or extremely critical. These are actually resuscitative
      patients. Most patients have disseminated bilateral lung lesions with multiple
      decay cavities, with massive bacterial isolation found at sputum bacterioscopy.
      With this, mycobacterial resistance to at least one antituberculous drug was
      found in 83% of cases. Primary multidrug resistance was detected in 29.6% of
      patients. The diagnosis of ATE in patients with tuberculosis is difficult and
      requires that tuberculous meningitis shall be excluded. Acute progression, no
      spinal fluid changes, significant signs of cooagulopathy and thrombcytopathy with
      multiorgan failure and progressive DIC syndrome may diagnose ATE in patients with
      acutely progressive tuberculosis. The specific features of treatment in patients
      with tuberculosis and ATE are intensive antituberculous therapy with
      predominantly parenteral administration of drugs and intensive therapy for the
      DIC syndrome. Despite the treatment, 48 (35.6%) patients died from progressive
      tuberculosis and ATE, in 40 (29.6%), therapeutic efficiency was low due to
      multidrug myobacterial resistance.

PMID- 12611337
TI  - [Enhancing the effectiveness of chemotherapy for pulmonary tuberculosis by
      phytotherapy in patients with different genetic markers].

PMID- 12611338
TI  - [Iron metabolism in patients with different variants of pulmonary tuberculosis].
AB  - Prior to treatment, 48 patients with different forms of pulmonary tuberculosis
      were examined. Serum iron concentrations, total iron-binding capacity of the
      serum (STIBC), its unsaturated iron-binding capacity (SUSIB), serum transferrin
      iron saturation coefficient (SC), total protein in the serum, red blood cells,
      hemoglobin, colour index were determined. All the parameters under study were in
      the normal range in patients with a favourable involutional course of pulmonary
      tuberculosis. In patients with acutely progressive pulmonary tuberculosis, serum
      iron levels, STIBC, SC were drastically decreased, while SUSIB was in the normal
      range. All this was attended by phenomena of hypochromic anemia. The pattern of
      the found changes leads to the conclusion that patients with acutely progressive
      tuberculosis develop iron-redistributing anemia caused by the changes in the
      amount and quality of transferrin, iron binding during free radical processes and
      mobilization of the antioxidant defense system rather than true iron deficiency.

PMID- 12611339
TI  - [Characterization of an experimental model of endogenously reactivated
      tuberculosis: detection of Mycobacterial DNA during chemotherapy].
AB  - The study was undertaken to determine the value of detection of DNA of
      Mycobacterium tuberculosis (MBT) during chemotherapy on an experimental model of
      an endogenously reactivated tuberculous process. A hundred and fifty BALB/C mice
      were intravenously inoculated by MBT strain H37Rv and received antituberculous
      chemotherapy (isoniazid and large-dose pyrazinamide) during 4 and 6 months. Solid
      medium inoculation, bacterioscopy, cytology, polymerase chain reaction were used
      to show the value of detection of MBT DNA in the viscera and blood in confirming
      the development of tuberculosis and testifying the preservation of MBT in the
      body if the treatment regimen was incomplete, which can lead to endogenous
      reactivation of the process under certain conditions. Gene typing of MBT, as
      described in?? of the Russian Federation under IS6110 provided evidence for the
      endogenous pattern of reactivation.

PMID- 12611340
TI  - [Action of ultraviolet laser radiation on extracellular and phagocytic
      Mycobacteria tuberculosis in vitro].
AB  - Ultraviolet laser radiation (a wavelength of 248 nm) was examined in vitro for
      its bacteriostatic and bactericidal actions on M. tuberculosis H37Rv.
      Sterilization was achieved when a dose of 10 m/J/cm2 was applied. This indicates
      that this type of radiation suppresses both the formation of colonies upon
      exposure of free Mycobacteria in the suspension and the incorporation of 3H
      uracil by the mycobacteria phagocytized with peritoneal macrophages.

PMID- 12611341
TI  - [Differential diagnosis of disseminated pulmonary diseases of nontumor nature].

PMID- 12611342
TI  - [History of the setting up of the research museum of the Central Research
      Institute of Tuberculosis, Russian Academy of Medical Sciences].

PMID- 12611343
TI  - [The status of hormone therapy in breast cancer in 2001?].
AB  - Cancer of the breast represents in Tunisia and the most frequent female cancer in
      the world. Hormonotherapy is one of the main weapons of the medical treatment
      based on the blockage of hormonal action on the cellular growth. Endocrine
      therapy remains an essential part of treatment in both adjuvant and metastatic
      settings and is guided by the presence and degree of expression of estrogen
      receptor (ER) and progesterone receptor (PgR). Adjuvant 5-years tamoxifen (TAM)
      is still the standard therapy for postmenopausal ER and/or PgR positive women. In
      premenopausal women and in adjuvant setting, medical castration by LH-RH
      analogues plus Tamoxifen in addition to chemotherapy improve the prognosis. All
      these data arose from the successive meta-analyses done showing a benefit from
      hormonotherapy for patients with positive HR in term of survival, disease-free
      survival, loco-regional and distant relapse rate. In metastatic disease, the
      position of tamoxifen is presently in competition with the third generation
      antiaromatases that seems to be equally active as tamoxifen opening the way for
      its use for the future in adjuvant situations.

PMID- 12611344
TI  - [Radiologically guided lumbar injections].
AB  - Lumbar injections of corticosteroids are an established part of sciatica
      nonsurgical treatment; that's to their anti-inflammatory properties.
      Fluoroscopically monitored injections are more likely to place medication at the
      exact target site and with higher concentration; then they maximize therapeutic
      results. Lumbar steroid injections are efficient at short and middle term, and
      they precipitate relief.

PMID- 12611345
TI  - [Brucellosis zoonoses in Tunisia: critical study of sanitary legislation].
AB  - The author presents a critical study of the sanitary legal texts of zoonotic
      brucellosis control. The tunisian legal texts are sometimes incomplete and old.
      The review of these texts, in order to improve the legal frame of control, is now
      necessary.

PMID- 12611346
TI  - [Uterine adenomyosis. Clinical and therapeutic study. Report of 87 cases].
AB  - STUDY OBJECTIVE: The aim of our study is the analysis of Pound epidemiological,
      clinical, paraclinical and therapeutic aspects of adenomyosis. METHODS: A
      retrospective analysis was carried out on 87 patients who underwent hysterectomy
      for a variety of reasons (except for prolapse) between January 1, 1990, and
      December 31, 1997; and whose Histologic analysis of hysterectomy specimen
      revealed adenomyosis. RESULTS: 586 hysterectomy (except prolapse) was performed
      during the study period: frequency of adenomyosis in hysterectomy specimen is of
      14.85%. The mean age of our patients is 43.97 years (Range: 26-64 years). 29.88%
      of them are postmenopausal and 41.37% had a past history of uterine trauma. Main
      symptoms were pelvic pain (71.22%) and abnormal uterine bleeding (82.77%).
      Preoperative diagnosis has been suspected on hysteroscopy in 63.22% of cases,
      hysterography in 58.46% and transvaginal sonography in 40.5%. A radical surgery
      first has been indicated in 57 cases, after failure of medical treatment in 16
      cases and after failure of endometrial resection in 14 cases. Histologic analysis
      of the hysterectomy specimen shows associated myoma in 32.18% of cases,
      hyperplasia in 13.79%, polyps in 5.74% and atrophy in 3.44%. CONCLUSION:
      Adenomyosis, enigmatic disease, escapes always to a well-codified therapeutic
      strategy and bound closely related to hysterectomy. Earliest diagnosis could
      avoid the systematic evolution toward the radical treatments.

PMID- 12611347
TI  - [Prevalence of degenerative complications of diabetes in an outpatient
      population].
AB  - The aim of this study was to evaluate the frequency of micro and macro vascular
      complications among a cohort of diabetic out-patients without proteinuria.
      PATIENTS AND METHODS: It is a cross sectional study of 249 diabetic patients (126
      mean and 123 women) 166 with type 2 diabetes and 83 with type 1 diabetes.
      Patients were recruited according to sex, age and diabetic duration
      stratification. Mean age was 45.2 +/- 6.6 years and mean duration of diabetic was
      8.9 +/- 7 years. Diabetic complications were investigated through a
      questionnaire, physical examination, ECG eyes fundoscopy and microalbuminuria
      measured in overnight urine collection. RESULTS: Prevalence of diabetic micro
      angiopathy in our population was one of the most frequent in the world. Diabetic
      peripheral neuropathy and retinopathy were the most frequent complications found
      in our patients. It was 63.5% for peripheral neuropathy, 43.8% for retinopathy
      and 25.3% for microalbuminuria. Macro angiopathy, as defined by hypertension,
      coronary heart diseases (CHD), lower limb arteritis (LLA) or stroke, was found in
      24.5% of patients. CHD rate was equal to 14.5% and LLA in 12.4%. Prevalence rates
      of vascular complications of diabetes were correlated with age, duration and type
      of diabetes. CONCLUSION: Prevention of diabetes complications needs early
      screening of glucose tolerance abnormalities, better glycemic control, reduction
      of associated vascular risk factors and identification of genetic factors
      predisposing to a higher cardiovascular risk.

PMID- 12611348
TI  - [Knowledge, treatment and control of hypertension. Results of a multicenter study
      of patients hospitalized for cardiac ischemia].
AB  - The study objective was to assess the prevalence, level of treatment, and control
      of hypertension in CHDs patients. We conducted a cross-sectional survey on 1109
      patients hospitalised for a first episode of MI in the main hospitals of the
      District of Tunis during the period 1999-2000. Hypertension and control level are
      defined according to the JNC recommendations. HBP is defined as SBP > = 140 and
      or DBP > = 90 mm Hg and the use of blood pressure-lowering medication for the
      indication of hypertension. Hypertension is controlled by medication if SBP < 140
      and DBP < 90 mm Hg. We conduct analysis by socio demographic variables, medical
      history and CHDs risk factors. 54.9% men and 72.1% women were hypertensive. The
      prevalence of hypertension increases with age in both genders. The logistic
      regression have shown that the age-adjusted odds ratios were statically
      significant for diabetes, obesity, high cholestrolemia and cigarettes smoking.
      Only 68.9% of the hypertensive were aware of having hypertension, women were more
      aware than men (84.6% versus 61.7%, p < 0.001). Awareness increase with age and
      education level. Among hypertensive, 94.4% were treated but only 41.3% were
      controlled. The study highlights the problem of the hypertension, and contributes
      to identify the iceberg of this CHDs risk factor. An effort must be done to
      involve the health personnel for educating patients, the population for changing
      their life style and manager for enhancing the availability of drugs. The
      question is how much will be the cost of HBP and CVDs control for a country which
      has a limited resources.

PMID- 12611349
TI  - [Malignant hyperthermia].
AB  - Malignant hyperthermia is a potentially fatal pharmacogenetic disease triggered
      by volatile anesthetics and/or succinylcholine. Dysregulation of intracellular
      calcium homeostasis is the trigger of the acute crisis. Malignant hyperthermia
      crisis correspond to an hypermetabolic state, which occurred acutely and
      interesting skeletal muscular cell. Early manifestations grouped tachycardia,
      tachypnea, masseter spasm, mixed acidosis and raise of the end expiratory CO2
      pressure. Hyperthermia is a late sign, rhabdomyolysis is a sign of the severity
      of the malignant hyperthermia. The successful treatment is based on an early
      diagnosis, immediately interruption of triggering agents, intravenous
      administration of Dantrolene in sufficient dosage and starting of adequate
      symptomatic treatment. Prevention of this complication is based on asking the
      patient about genetic predisposition to malignant hyperthermia. Confirmation of
      the susceptibility to malignant hyperthermia can be provided by in vitro
      contracture test with halothane or caffeine after muscle biopsy.

PMID- 12611350
TI  - [AIDS in Tunisian women. Study of 92 cases].
AB  - The authors report a retrospective study about 92 cases of HIV-1 infections among
      adult tunisian women hospitalised or consulting in the department of infectious
      diseases at Rabta hospital over a period of 15 years and 6 months. The middle age
      is 33.2 years. 64.1% of patients are married, and the conjoint is HIV-1 positive
      in 84.1% of cases. The route of transmission is sexual in 75%, parenteral in
      22.8% and unknown in 2.2%. According to CD4 level and clinical symptoms, patients
      are at AIDS stage in 75.5%. The main clinical symptoms are: oral candidiasis in
      92.4%, diarrhea in 54.3%, pneumocystis carinii pneumoniae in 11.9%, cerebral
      toxoplasmosis in 10.9%, septicemia caused particularly by salmonella in 9.7%,
      tuberculosis in 6.7%, cryptococcal meningitis in 4.3% an Kaposi's sarcoma in
      3.2%. Mother to child HIV transmission is found in 33.3%, and the mortality is
      noted in 43.5% of cases.

PMID- 12611351
TI  - [Permanent ventricular tachycardia: prognostic and therapeutic problems: three
      case reports].
AB  - The permanent ventricular tachycardia (PVT) represent a rare and dangerous
      arrhythmia that causes prognostic and therapeutic difficulties. Three patients
      admitted during last year for PVT complicating ischemic cardiomyopathy in two
      cases and idiopathic cardiomyopathy in the last case. These patients were
      admitted from emergency department for sustained monomorphic ventricular
      tachycardia. The ECG showed wide QRS tachycardia of ventricular origin. The
      direct current shock (DCS) has revealed ECG criteria of old myocardial infarction
      in two cases. The transthoracic echocardiography displayed dilated left
      ventricule (LV) with 35% mean ejection fraction. It also showed the presence of
      LV aneurysm in one case. The cardiac catheterization showed proximal left
      anterior descending artery obstruction in one patient and left circomflex artery
      stenosis in other patient. There was no indication of revascularization because
      of the age of myocardial infarction. The follow-up of these patients demonstrated
      the persistence of the VT for at least 6 days with recurrence after the DCS and
      resistant to Lidocaine-Amiodarone association. The sinus rhythm was established
      by the propranolol-Amiodarone in one patient, Amiodarone added to treatment of
      congestive heart failure for the patient with ventricular aneurysm. The third
      patient died after one week of PVT complicated by cardiogenic shock just before a
      trial of radiofrequency ablation (RFA). We concluded through these cases that PVT
      is a troublesome arrhythmia for more than one reason. It appears of tewly in
      patients with advanced cardiomyopathy worsening the hemodynamic conditions
      oftenly the pharmacological treatment is mostly always difficult. The treatment
      of choice is RFA for those resistant to medical treatment.

PMID- 12611352
TI  - [School failure and epilepsy: a case-control study].
AB  - School difficulties and educational inadequacy usually correlate with the child's
      epilepsy. The target of our study is to discover the most precocious possible the
      epilepsy and to prevent educational failure in the population of children from 6
      to 15 years old. We have carried out a retrospective study on 162 children of an
      educational age. This population was made up of 100 epileptic children followed
      over a period of 3 years (1995-1997) and a witness group made up of 62 children
      selected from brothers and sisters of the study group, with the same sex in
      default of the opposed sex who are educated. We have noted that at the same age
      between children from the group of study and children from the witness group. The
      class of study was significantly inferior in the group of study: the educational
      average class is 4th against 5th in the witness group P = 0.11. The difference
      was about one year. The difference of educational results was significant. For
      the last educational year, the educational mark was 8.99/20 in the group of study
      against 12/20 in the witness one. P < 10-5. For the last educational semester,
      the educational mark was 9.5/20 in the group of study against 11.9/20 in the
      witness group. (P = 3 x 10(-4)).

PMID- 12611353
TI  - [False left ventricular aneurysm: report of 5 cases].
AB  - Between 1972 and 2000, left ventricular false aneurysm was diagnosed in 5
      patients. These patients consisted of three man and 2 women, aged between 58 and
      70 years. Clinical presentation was characterized by severe heart failure,
      complicating a posterior myocardial infarction, in 4 patients. Left ventricular
      angiography, has confirmed the false aneurysm in all patients. Three patients
      underwent surgical management, with good result in 2 cases (follow-up of 9 and 13
      years), and an early postoperative death in one case. Two patients refused
      surgery and died suddenly. Ischemic myocardial disease, represent the most
      frequent etiology. Left ventricular false aneurysm prognosis should be improved
      by emergent surgical management, preventing fatal rupture.

PMID- 12611354
TI  - [Hypertrophic cardiomyopathy: a rare cause of vascular dementia. A case report].
AB  - Herein, we report a case of a 51 year old man who experienced three ischemic
      cerebral infarcts in a time of few months. The patient consulted after the third
      accident. Neurological presentation included pseudobulbar syndrome with a mild
      cognitive deficit, aphasia, left hemiparesia, hemiasomatognosia and homonymous
      lateral hemianopsia. Cerebral tomodensitometry and magnetic resonance imaging
      evidenced large infarcts images involving right middle cerebral artery territory
      and bilateral borderline zones in the junction of the territories of the middle
      and posterior cerebral arteries. Ambulatory 24 hours ECG recording (Holter)
      revealed two hits of non-sustained ventricular tachycardia. Transoesophageal
      echocardiography conveyed to the diagnosis of hypertrophic cardiomyopathy and
      displayed the presence of a left auricular thrombus. Anticoagulant therapy and
      rehabilitation allowed a substantial recovering of the patient's cognitive
      functions and wasting of the intracardiac thrombus. The clinical features
      observed in our patient meet the recommended DSM IV diagnosis criteria of
      vascular dementia, an exceptional complication of HCM. The clinical findings,
      neuroimagery investigation results, and the chronological link between cerebral
      attacks and cognitive function deterioration argue for a demential syndrome of
      vascular origin resulting from multiple embolic infarcts involving medium sized
      arteries (multi-infarct dementia). The authors emphasize the rarity of such
      observation. HCM must be considered as a potential cause of embolic stroke and
      likewise a multi-infarct dementia.

PMID- 12611355
TI  - [Lupus hepatitis].
AB  - We report the case of 42 year-old man who presents an acute polyarthritis
      associated with systemic manifestation and immunologic disorders related to
      systemic lupus erythematosus. Hepatic tests show cholostase and cytolysis.
      Hepatic involvement is linked with systemic lupus erythematosus after exclusion
      of hepatotoxic drugs, viral hepatitis and absence of anti mitochondrial and anti
      muscle antibodies. Lupus hepatitis seems to be correlated with autoantibodies to
      ribosomal P protein. Its treatment remains to be defined.

PMID- 12611356
TI  - Drugs for disruptive features in dementia.
AB  - It is estimated that around 750,000 people in the UK have dementia and, of these,
      60% will have behavioural changes or psychological symptoms. These features tend
      to occur in clusters, of which the five most readily recognised are characterised
      by aggression, apathy, depression, psychomotor agitation or psychosis. Here, we
      review the place of drug therapy in the management of patients in whom these
      features are disruptive.

PMID- 12611357
TI  - Topical steroids for atopic dermatitis in primary care.
AB  - Atopic dermatitis is very common. In most instances, the condition is relatively
      mild and can be managed in primary care. Topical corticosteroids are the standard
      therapy for controlling acute 'flares' of dermatitis. However, poor communication
      between doctors and patients often results in suboptimal use of such therapy.
      Here, we review the efficacy and safety of topical corticosteroids for the
      treatment of atopic dermatitis. We discuss their optimal use in primary care, and
      the advice and information that patients or parents of children need when using
      such treatment.

PMID- 12611358
TI  - System for assisted mobility using eye movements based on electrooculography.
AB  - This paper describes an eye-control method based on electrooculography (EOG) to
      develop a system for assisted mobility. One of its most important features is its
      modularity, making it adaptable to the particular needs of each user according to
      the type and degree of handicap involved. An eye model based on
      electroculographic signal is proposed and its validity is studied. Several human
      machine interfaces (HMI) based on EOG are commented, focusing our study on
      guiding and controlling a wheelchair for disabled people, where the control is
      actually effected by eye movements within the socket. Different techniques and
      guidance strategies are then shown with comments on the advantages and
      disadvantages of each one. The system consists of a standard electric wheelchair
      with an on-board computer, sensors and a graphic user interface run by the
      computer. On the other hand, this eye-control method can be applied to handle
      graphical interfaces, where the eye is used as a mouse computer. Results obtained
      show that this control technique could be useful in multiple applications, such
      as mobility and communication aid for handicapped persons.

PMID- 12611359
TI  - Initial on-line evaluations of the LF-ASD brain-computer interface with able
      bodied and spinal-cord subjects using imagined voluntary motor potentials.
AB  - Previous research has focused on developing a brain-controlled switch named the
      low frequency asynchronous switch design (LF-ASD) that is suitable for
      intermittent control of devices such as environmental control systems, computers,
      and neural prostheses. On-line implementations of the LF-ASD have shown promising
      results in response to actual index finger flexions with able-bodied subjects.
      This paper reports the results of initial on-line evaluations of the LF-ASD brain
      controlled switch with both able-bodied subjects and subjects with high-level
      spinal-cord injuries. This paper has demonstrated that users can activate the LF
      ASD switch by imaging movement. In this paper, two able-bodied subjects were able
      to control the LF-ASD with imagined voluntary movements with hit (true positive)
      rates above 70% and false positive rates below 3% while two subjects with high
      level spinal-cord injuries demonstrated hit rates ranging from 45-48% and false
      positive rates below 1%.

PMID- 12611360
TI  - Full-screen magnification for windows using DirectX Overlays.
AB  - This paper presents the basic features of software-based magnifiers used by some
      visually impaired people to read information from a computer screen. The paper
      briefly presents two major approaches to full-screen magnification for modern
      multiple window systems (the paper focuses on Microsoft Windows). This paper
      describes in detail the architecture and operation of a full-screen magnifier
      that uses Microsoft DirectX Overlays. This approach leads to a robust magnifier
      that has a low computational overhead. The magnifier has problems with video
      cards that use a YUV color model but these problems may be addressed by RGB to
      YUV translation software--an issue that is still to be investigated. The
      magnifier also has problems when the generic device driver, rather than the
      manufacturer's device driver, is installed on the system. The paper presents two
      further strategies for full screen magnification, namely, using multimonitor
      support and true type fonts for text enlargement.

PMID- 12611361
TI  - The instantaneous axis of rotation (IAOR) of the foot and ankle: a self
      determining system with implications for rehabilitation medicine application.
AB  - A noninvasive method for determining the instantaneous axis of rotation (IAOR) of
      the foot and ankle during human ambulation has been developed. The algorithm uses
      three-dimensional (3-D) external marker trajectories to describe the IAOR of the
      calcaneus with respect to the tibia. Multiple optimization techniques were used
      to fit a plane and a sphere to the marker trajectories, with the constraint that
      the center of the sphere lie on the plane. The IAOR was defined perpendicular to
      the plane and passed through the center of the sphere. The results from
      validation procedures have demonstrated the applicability of the method.
      Experimental IAOR data acquired from normal adult subjects indicated the ability
      to track the IAOR during gait. This self-determining system for locating a
      patient's foot and ankle IAOR during gait may benefit rehabilitation applications
      in pedorthic and prosthetic design, surgical and nonsurgical treatment, and
      rehabilitative approaches to suprasegmental functional accommodation.

PMID- 12611362
TI  - Paraplegic standing supported by FES-controlled ankle stiffness.
AB  - The objective of this paper was to investigate whether a paraplegic subject is
      able to maintain balance during standing by means of voluntary and reflex
      activity of the upper body while being supported by closed loop controlled ankle
      stiffness using FES. The knees and hips of the subject were held in extended
      positions by a mechanical apparatus, which restricted movement to the sagittal
      plane. The subject underwent several training sessions where the appropriate
      level of stiffness around the ankles was maintained by the mechanical apparatus.
      This enabled the subject to learn how to use the upper body for balancing. After
      the subject gained adequate skills closed-loop FES was employed to regulate ankle
      stiffness, replacing the stiffness provided by the apparatus. A method to control
      antagonist muscle moment was implemented. In subsequent standing sessions, the
      subject had no difficulties in maintaining balance. When the FES support was
      withheld, the ability to balance was lost.

PMID- 12611363
TI  - Stability analysis for postural control in a two-joint limb system.
AB  - The stability behavior of a multi-joint limb with electrically activated muscles
      provides important clues for postural control of motor tasks. The stability
      property of the musculoskeletal system can be characterized with its eigenvalues
      evaluated at operating postures in the workspace. A planar arm model with
      shoulder and elbow joints and three pairs of antagonistic muscles was constructed
      in ADAMS. Stability behavior of shoulder and elbow joints was analyzed using the
      loci of eigenvalues in the s-plane. In the analysis of open-loop cocontraction of
      antagonist muscles with increasing activation from 5% to 100%, the eigenvalues of
      the shoulder and elbow joints were confined within the left half of the s-plane
      in a stripe of +/- j 0.5, and moved toward left onto the real axis. The shoulder
      eigenvalues were generally nearer to the imaginary axis than the elbow ones,
      indicating a more oscillatory behavior at the shoulder joint than that at the
      elbow joint. The effects of joint configuration evaluated within the workspace
      from 40 degrees to 110 degrees for the elbow and from 40 degrees to 120 degrees
      for the shoulder showed that the elbow eigenvalues were more prone to
      configuration changes, particularly elbow angles. We also developed a simulation
      paradigm for sampled data FES control systems that contain a mixture of
      continuous time components and sampling and hold effects. This simulation
      paradigm is useful for realistic simulation of local feedback controller
      performance.

PMID- 12611364
TI  - A review of portable FES-based neural orthoses for the correction of drop foot.
AB  - This paper reviews the technological developments in neural orthoses for the
      correction of upper motor neurone drop foot since 1961, when the technique was
      first proposed by Liberson and his co-workers. Drop foot stimulator (DFS)
      developments are reviewed starting with hard-wired single-channel and
      multichannel surface functional electrical stimulation (FES) systems, followed by
      implanted drop foot stimulators, and then continuing with microprocessor-based
      surface and implanted drop foot stimulators. The review examines the role of
      artificial and "natural" sensors as replacements for the foot-switch as the
      primary control sensor in drop foot stimulators. DFS systems incorporating real
      time control of FES and completely implanted DFS systems finish the review.

PMID- 12611365
TI  - The effects of long-term FES-assisted walking on intrinsic and reflex dynamic
      stiffness in spastic spinal-cord-injured subjects.
AB  - The effects of long-term functional electrical stimulation (FES)-assisted walking
      on ankle dynamic stiffness were examined in spinal cord-injured (SCI) subjects
      with incomplete motor function loss. A parallel-cascade system identification
      method was used to identify intrinsic and reflex contributions to dynamic ankle
      stiffness at different ankle positions while subjects remained relaxed. Intrinsic
      stiffness dynamics were well modeled by a linear second-order model relating
      intrinsic torque to joint position. Reflex stiffness dynamics were accurately
      described by a linear third-order model relating halfwave rectified velocity to
      reflex torque. We examined four SCI subjects before and after long-term FES
      assisted walking (> 16 mo). Another SCI subject, who used FES for only five
      months was examined 12 mo latter to serve as a non-FES, SCI control. Reflex
      stiffness decreased in FES subjects by an average of 53% following FES-assisted
      walking, intrinsic stiffness also dropped by 45%. In contrast, both reflex and
      intrinsic stiffness increased in the non-FES, SCI control. These findings suggest
      that FES-assisted walking may have therapeutic effects, helping to reduce
      abnormal joint stiffness.

PMID- 12611366
TI  - Classification of finger activation for use in a robotic prosthesis arm.
AB  - Hand amputees would highly benefit from a robotic prosthesis, which would allow
      the movement of a number of fingers. In this paper we propose using the
      electromyographic signals recorded by two pairs of electrodes placed over the arm
      for operating such prosthesis. Multiple features from these signals are extracted
      whence the most relevant features are selected by a genetic algorithm as inputs
      for a simple classifier. This method results in a probability of error of less
      than 2%.

PMID- 12611368
TI  - 'A first' for Canadian harm reduction.

PMID- 12611369
TI  - Provision of HIV-related services to people who inject drugs. A public health
      crisis.

PMID- 12611367
TI  - Functionally selective peripheral nerve stimulation with a flat interface nerve
      electrode.
AB  - One of the important goals of peripheral nerve electrode development is to design
      an electrode for selective recruitment of the different functions of a common
      nerve trunk. A challenging task is gaining selective access to central axon
      populations. In this paper, a simple electrode that takes advantage of the neural
      plasticity to reshape the nerve is presented. The flat interface nerve electrode
      (FINE) reshapes the nerve into a flat geometry to increase the surface area and
      move central axon populations close to the surface. The electrode was implanted
      acutely on the sciatic nerve of eight cats. The FINE can significantly reshape
      the nerve and fascicles (p < 0.0001) while maintaining the same total nerve cross
      sectional area. The stimulation thresholds were 2.89 nC for pulse amplitude
      modulation and 10.2 nC for pulse-width modulation. Monopolar, square-pulse
      stimulation with single contacts on the FINE selectively recruited each of the
      four main branches of the sciatic nerve. Simultaneous stimulation with two
      contacts produced moments about the ankle joint that were a combination of the
      moments produced by the individual contacts when stimulated separately.

PMID- 12611371
TI  - [The modern hospice movement in Germany--II: Euthanasia--a concept in
      transition].

PMID- 12611370
TI  - Amantadine-induced multiple spike waves on an electroencephalogram of a
      schizophrenic patient.
AB  - Although amantadine is relatively free of side effects compared with levodopa,
      the incidence and severity of unwanted effects, such as hallucinations, insomnia
      and dizziness, markedly increase when the daily dose exceeds 200 mg. A 63-year
      old schizophrenic female developed the Pisa syndrome following neuroleptic
      medication. She was started on a regimen of amantadine, 200 mg per day, on
      September 4, and the electroencephalogram (EEG) on September 11 was within normal
      limits. The dosage was increased to 300 mg on September 18 because there was no
      improvement and no side effects. Two days later a generalised convulsion occurred
      and an EEG revealed frequent multiple spikes or sharp waves with slow waves. No
      epileptic seizure has been observed since the amantadine was discontinued. The
      EEG on September 27 was again within normal limits. To our knowledge, the EEG of
      a patient with convulsion induced by amantadine has not been described
      previously. The epileptic mechanisms of amantadine have not been elucidated;
      however, it may be related to a modulating role of dopamine in the central
      nervous system.

PMID- 12611372
TI  - CTSU provides tools that link research and practice.

PMID- 12611373
TI  - [Cannabis and Nifluril: reply].

PMID- 12611374
TI  - [Update of the non-chemotherapy drug-induced agranulocytosis].

PMID- 12611375
TI  - Induced sputum for diagnosing Pneumocystis carinii pneumonia in HIV patients: new
      data, new issues.
AB  - The complexity of bronchoalveolar lavage (BAL) has motivated the search for
      noninvasive methodology to retrieve specimens for detecting the presence of
      various pulmonary diseases. Induced sputum (IS) has been shown to be a reliable
      tool in terms of sensitivity and specificity comparable to BAL. Investigators
      from institutions worldwide have published several reports providing evidence in
      support of one or the other or a combination of both approaches. Among them are
      studies demonstrating the sensitivity and specificity of IS in diagnosing
      Pneumocystis carinii pneumonia (PCP) in patients with acquired immunodeficiency
      syndrome (AIDS). In 1996, highly active antiretroviral therapy was introduced for
      routine use and the morbidity from opportunistic infections decreased sharply. An
      earlier study showed that cost-effectiveness depends on the prevalence of a given
      condition in the population. More recent studies have confirmed that prophylaxis
      against PCP can be stopped after increasing the CD4 cell count, thus reducing the
      attractiveness of IS as a preferred method for monitoring the course of disease.
      This review presents a brief description of the evolution of the bronchoalveolar
      lavage versus induced sputum controversy and reconsiders the strengths and
      weaknesses of the earlier arguments in light of newer data that have emerged with
      regard to Pneumocystis carinii pneumonia in acquired immunodeficiency syndrome.

PMID- 12611376
TI  - Seronegative spondyloarthropathy of familial Mediterranean fever.
AB  - Familial Mediterranean fever (FMF) is characterized by an autosomal inheritance
      pattern, Mediterranean ancestry, and history of recurrent fever. We present a 30
      year-old Turkish man with FMF and accompanying seronegative spondyloarthropathy.
      His diagnose depended on the clinical course of his disease: recurrent fever
      accompanied by abdominal pain attacks together with a positive family history and
      his ethnic origin and sacroiliitis. We review the common manifestations of FMF
      and remind physicians that sacroiliac joint involvement must be kept in mind in
      presence of articular symptoms in a FMF patient.

PMID- 12611377
TI  - [New international recommendations for the determination of enzyme activities at
      37 degrees C ].

PMID- 12611378
TI  - [From legal consultation. Key word: numbers 21-1 and 2106 EBM].

PMID- 12611379
TI  - [Fee regulation for physicians: standard charges expanded].

PMID- 12611383
TI  - [General H1-H2-blockade for anesthesia induction. Commentary on an article in Der
      Anasthesist (2002) 51:420-421].

PMID- 12611384
TI  - [Endotracheal intubation in pediatrics. With or without the cuff?].

PMID- 12611385
TI  - [Sepsis therapy. A dilemma in times of limited financial resources].

PMID- 12611386
TI  - Health of the Iraqi people hangs in the balance.

PMID- 12611387
TI  - The people of Iraq face a grim future with or without a war.

PMID- 12611388
TI  - US military prepares for Iraq to use chemical and biological weapons.

PMID- 12611389
TI  - US military plans to lead relief efforts in Iraq.

PMID- 12611390
TI  - Iraq's refugees and internally displaced people will face hardship wherever they
      go.

PMID- 12611391
TI  - Cytokine mediation of experimental heart failure-induced anhedonia.
AB  - Immune system dysfunction is hypothesized to influence several disease states,
      including cardiovascular disease and psychological depression. The comorbidity of
      depression and coronary artery disease may be influenced by immune system-brain
      interactions involving proinflammatory cytokines. The present studies evaluated
      an index of depression in a rodent model of heart failure by measuring responses
      to rewarding electrical brain stimulation, which provides an experimental
      procedure to operationally define anhedonia in rats. Heart failure led to a
      rightward shift in the current-response relationship in the brain stimulation
      paradigm, indicative of reduced rewarding properties of the brain stimulation
      (i.e., anhedonia). Acute treatment with a tumor necrosis factor antagonist,
      etanercept, reduced circulating tumor necrosis factor- levels in rats with heart
      failure and restored responding for electrical brain stimulation. The current
      findings have implications for the study of pathophysiological mechanisms
      underlying the association of cardiovascular disease and depression.

PMID- 12611392
TI  - Unique endothelin receptor binding in kidneys of ETB receptor deficient rats.
AB  - Gariepy and colleagues (Gariepy CE, Williams SC, Richardson JA, Hammer RE, and
      Yanagisawa M. J Clin Invest 102: 1092-1101, 1998.) developed rescued spotting
      lethal rats that carry a naturally occurring deletion of the endothelin (ET) type
      B receptor gene resulting in a lack of functional renal ETB receptor expression.
      It has been shown that rats homozygous (sl/sl) for the deletion have elevated
      plasma ET-1 levels; thus, the purpose of this study was to determine whether this
      deletion would result in a downregulation of ETA receptors in renal tissue. ET-1
      and ET-3 binding experiments were performed with cortex, outer medullary, and
      inner medullary membranes of heterozygous (sl/+) and sl/sl ETB receptor-deficient
      rats. 125I-labeled ET-1 binding in sl/sl cortex and outer medulla was
      significantly lower than cortex and outer medulla from sl/+ rats. In contrast to
      sl/+ rats, [125I]ET-3 binding was not detected in the cortex and outer medulla of
      sl/sl rats, indicating a lack of ETB receptor expression. The inner medulla of
      sl/+ rats also demonstrated an abundance of ETB receptors. Surprisingly, however,
      we also observed significant [125I]ET-3 binding in the sl/sl inner medulla.
      Furthermore, ET-3 binding in the inner medulla could be blocked with an ETA
      receptor antagonist in sl/sl rats but not in tissue from sl/+ rats. These studies
      indicate that rats deficient in ETB receptors have decreased renal cortical and
      outer medullary ETA receptor number, most likely in response to elevated plasma
      ET-1 levels. In addition, homozygous ETB-deficient rats express a novel inner
      medullary ET-3 binding site.

PMID- 12611393
TI  - Erectile dysfunction in spontaneously hypertensive rats: pathophysiological
      mechanisms.
AB  - Hypertensive men have a higher prevalence of erectile dysfunction (ED) than the
      general population. Experimental evidence of ED in hypertensive animals is
      scarce. This study evaluates the erectile function of spontaneously hypertensive
      rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) in vivo by the
      increase in intracavernosal pressure after electrical stimulation of the
      cavernous nerve (CN) and by isometric tension studies on corporal strips.
      Frequency-dependent erectile responses to CN stimulations were reduced in SHR.
      Phenylephrine induced lower corporal contractions in SHR although pD2 values were
      similar to WKY. Endothelium-dependent relaxations to ACh were impaired
      significantly in SHR, and indomethacin improved these relaxations in both WKY and
      SHR, the latter thus reaching values similar to WKY. Corporal relaxations to
      sodium nitroprusside were enhanced in SHR. Thus a dysfunctional alpha-adrenergic
      contraction of the corporal smooth muscle, an increased cyclooxygenase-dependent
      constrictor tone, and/or a defect in endothelium-dependent reactivity are
      associated with the altered erectile mechanisms in SHR. Drugs targeting
      endothelial dysfunction may delay the occurrence of ED as a complication of
      hypertension.

PMID- 12611394
TI  - Are large clinical trials in rapidly lethal diseases usually unethical?

PMID- 12611395
TI  - 5-HT1A receptor agonist 8-OH-DPAT acts in the hindbrain to reverse the
      sympatholytic response to severe hemorrhage.
AB  - Central administration of serotonergic 5-HT1A receptor agonists delays the reflex
      sympatholytic response to severe hemorrhage in conscious rats. To determine the
      region where 5-HT1A receptor agonists act to mediate this response, recovery of
      mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve
      activity (RSNA) was compared in hemorrhaged rats after injection of the selective
      5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in
      various regions of the cerebroventricular system or the systemic circulation.
      Three minutes after injection of 8-OH-DPAT (48 nmol/kg), MAP and RSNA were higher
      in hemorrhaged rats given drug in the fourth ventricle (94 +/- 5 mmHg, 82 +/- 18%
      of baseline) or the systemic circulation (90 +/- 4 mmHg, 113 +/- 15% of baseline)
      than in rats given drug in the Aqueduct of Sylvius (63 +/- 4 mmHg, 27 +/- 11% of
      baseline), the lateral ventricle (42 +/- 3 mmHg, -8 +/- 18% of baseline), or in
      rats given saline in various brain regions (47 +/- 5 mmHg, -42 +/- 10% of
      baseline). A lower-dose injection of 8-OH-DPAT (10 nmol/kg) also accelerated the
      recovery of MAP and RSNA in hemorrhaged rats when given in the fourth ventricle
      (94 +/- 26 mmHg, 72 +/- 33% of baseline 3 min after injection) but not the
      systemic circulation (46 +/- 4 mmHg, -25 +/- 30% of baseline). These data
      indicate that 8-OH-DPAT acts on receptors in the hindbrain to reverse the
      sympatholytic response to hemorrhage in conscious rats.

PMID- 12611397
TI  - A nonlinear compartmental model of Sr metabolism. II. Its physiological relevance
      for Ca metabolism.
AB  - We have studied the peculiarities of the nonlinear compartmental model for human
      Sr metabolism (Staub JF, Foos E, Courtin B, Jochemsen R, and Perault-Staub AM. Am
      J Physiol Regul Integr Comp Physiol 284: R819-R834, 2003), including its
      physiological reliability in the context of Sr-Ca similarity-dissimilarity. We
      found it to be relevant to Ca metabolism, except for discrimination against Sr
      relative to Ca at urinary and intestinal levels. The main findings are as
      follows: 1) the saturable part of intestinal absorption, shared by Sr and Ca,
      does not seem to be responsible for the discrimination of the transcellular
      pathway; 2) although there is little discrimination in bone, the physicochemical
      behaviors of Sr and Ca at the bone surface differ, at least quantitatively; and
      3) Sr behaves as a "tracer" for Ca metabolic pathways and, under non-steady-state
      conditions, can also reveal self-regulatory processes. It is suggested that they
      depend on Ca2+ (cationic)-sensing receptors that are apparently more sensitive to
      Sr than to Ca. Acting on gastrointestinal and osteoblast lineage cells, these
      slow processes might contribute to adaptive, rather than homeostatic, regulation
      of Ca metabolism. Understanding these features could help clarify the
      pharmacological and therapeutic effects of oral Sr.

PMID- 12611396
TI  - A nonlinear compartmental model of Sr metabolism. I. Non-steady-state kinetics
      and model building.
AB  - A model of Sr metabolism was developed by using plasma and urinary Sr kinetic
      data obtained in groups of postmenopausal women who received four different oral
      doses of Sr and collected during the Sr administration period (25 days) and for
      28 days after cessation of treatment. A nonlinear compartmental formalism that is
      appropriate for study of non-steady-state kinetics and allows dissociation of
      variables pertaining to Sr metabolism (system 1) from those indirectly operating
      on it (system 2) was used. At each stage of model development, the dose-dependent
      model response was fitted to the four sets of data considered simultaneously (1
      set per dose). A seven-compartment model with internal Sr distribution and
      intestinal, urinary, and bone metabolic pathways was selected. It includes two
      kinds of nonlinearities: those accounting for saturable intestinal and bone
      processes, which behave as intrinsic nonlinearities because they are directly
      dependent on Sr, and extrinsic nonlinearities (dependent on system 2), which
      suggest the cooperative involvement of plasma Sr changes in modulating some
      intestinal and bone mineral metabolic pathways. With the set of identified
      parameter values, the initial steady-state model predictions are relevant to
      known physiology, and some peculiarities of model behavior for long-term Sr
      administration were simulated.

PMID- 12611398
TI  - Early pregnancy care. Part 2.

PMID- 12611399
TI  - Transcriptional regulation of inflammatory genes before transplantation: a role
      for hypoxia inducible factor-1alpha?

PMID- 12611400
TI  - From philosophy to practice: selected issues in financing and coordinating long
      term care.

PMID- 12611401
TI  - Funding long-term care: applications of the trade-off principle in both public
      and private sectors.
AB  - The uncertain need for long-term care services is a risk best protected by
      insurance. However, the current funding relies heavily on personal payment and
      public welfare, and only lightly on social and private insurances. This method,
      akin to sitting on a two-legged stool, is unlikely to be sustainable. To
      incorporate insurance as a key component of funding and to mobilize public and
      private resources more effectively, we propose a three-legged-stool funding model
      under which social insurance would provide a basic protection, to be supplemented
      by private insurance and personal payment. When these sources do not provide
      sufficient protection for some individuals, Medicaid as public welfare would
      serve as a safety net. This article (a) discusses how to implement this funding
      model by using the trade-off principle in both the public and private sectors
      when resources for long-term care are scarce, and (b) analyzes several objections
      to this model from cognitive psychology/behavioral economics

PMID- 12611402
TI  - Policy implications of an annuity approach to integrating long-term care
      financing and retirement income.
AB  - The authors consider an integrated income and disability annuity as an
      alternative framework for long-term care financing, show that pooling disability
      and mortality risks can reduce the need for medical underwriting, and discuss
      private and public implications. Data from the National Mortality Followback
      Survey of 1986 were used to simulate current underwriting and minimal
      underwriting, excluding only those already eligible for benefits. Remaining
      disability, life expectancy, and premiums are compared under both underwriting
      assumptions. Under minimal underwriting, 98% of persons age 65 would be eligible
      to purchase disability protection through an integrated annuity, versus 77% under
      current underwriting. Premiums for both the income and disability components were
      lower with minimal underwriting. Combining income and disability protection may
      be able to expand private markets for long-term care financing beyond what
      appears possible in the long-term care insurance market. Public policy should
      avoid the distortion of choices created by focusing exclusively on an insurance
      model.

PMID- 12611403
TI  - Examining disputes over ownership rights to frozen embryos: will prior consent
      documents survive if challenged by state law and/or constitutional principles?

PMID- 12611404
TI  - Redefining parenthood.

PMID- 12611405
TI  - Obtaining informed consent from continuing care residents: issues and
      recommendations.
AB  - As the number of older adults residing in continuing care facilities increases,
      mental health professionals will provide more services and conduct more research
      in this setting. Mental health professionals working with continuing care
      residents will find themselves regularly challenged by ethical issues,
      particularly obtaining informed consent. Characteristics of the continuing care
      setting and residents make obtaining informed consent especially challenging.
      Mental health professionals must overcome these challenges in order to fulfill
      the following three requirements of informed consent: (1) the client is
      competent, (2) the client is provided with sufficient information, and (3) the
      client has not been coerced and/or the consent is voluntary. This article will
      examine the issues surrounding the fulfillment of these requirements in a
      continuing care facility, and will provide suggestions and guidelines that mental
      health professionals can utilize during the informed consent process.

PMID- 12611406
TI  - Bringing your DNA to work: employers' use of genetic testing under the Americans
      with Disabilities Act.

PMID- 12611407
TI  - "Loving infertile couple seeks woman age 18-31 to help have baby. $6,500 plus
      expenses and a gift": should we regulate the use of assisted reproductive
      technologies by older women?

PMID- 12611408
TI  - Clones, controversy, and criminal law: a comment on the proposal for legislation
      governing assisted human reproduction.
AB  - In the past few years there has been a tremendous amount of regulatory conflict
      and social controversy in the area of reproductive genetics. The Canadian
      government has recently released a proposal for legislating in this complex
      arena. Although the proposed Bill contains many positive elements, it is argued
      that the use of the criminal law as a regulatory mechanism is neither warranted
      nor appropriate. The author suggests a more flexible and responsive system of
      moratoriums and licenses that would enable review and adjustment to the realities
      of emerging reproductive technologies is a better approach.

PMID- 12611409
TI  - Private long-term care insurance: a look ahead.
AB  - The author's objective is to summarize and synthesize what is known about the
      private long-term care insurance market and its impact on public expenditures,
      policyholders, their families, and providers. Primary data were compiled from
      national studies and published and nonpublished information from the long-term
      care insurance industry. The study design was the review and analysis of
      empirical data. Data were collected from in-person, mail, and telephone
      interviews, as well as from a review of the literature. The market is growing
      rapidly in part due to the vast improvements in product design and to federal and
      state public policies. Growth in the market should result in modest reductions in
      public long-term care expenditures. Most claimants are satisfied with their
      policy, but many still do not feel that their needs are being met. Service
      delivery and provider issues are critical to making money work for disabled
      persons and insurers will be increasingly called on to help address this issue.
      The market for long-term care insurance will continue to grow. Over time, this
      insurance will likely play a more meaningful role in meeting the needs of
      disabled elders and their families.

PMID- 12611410
TI  - Euthanasia and assisted suicide in the post-Rodriguez era: lessons from foreign
      jurisdictions.
AB  - Euthanasia and assisted suicide are highly controversial subjects that have drawn
      much attention in Canada over the last two decades. This paper outlines how the
      Netherlands, the United States, Australia, and Canada have approached the
      practices. Jurisprudence, public opinion polls, legislative developments, and the
      positions of medical organizations and their members are included in the
      analysis. A number of arguments for and against the continued prohibition of the
      practices in Canada are evaluated. As well, information regarding the extent to
      which euthanasia and assisted suicide are performed in these countries is
      assessed. It will be shown that Canadians currently enjoy significant control
      over decisions concerning end of life. The principles of autonomy and beneficence
      provide the foundation necessary to justify lifting the prohibition of voluntary
      euthanasia and assisted suicide in Canada. With regard to the development of
      safeguards, the way in which foreign jurisdictions have dealt with both
      procedures is highly instructive. A qualified system of pre-authorization, unlike
      those adopted elsewhere, would prevent abuses from occurring and maintaining the
      prohibition of non-voluntary and involuntary euthanasia. Since legislators are in
      the best position to deal with the issues, change in the law should be made by
      the government, not the judiciary. Practical legislation is feasible and a
      proposal of what this should entail is presented.

PMID- 12611411
TI  - Titrating versus targeting home care services to frail elderly clients: an
      application of agency theory and cost-benefit analysis to home care policy.
AB  - The article summarizes the shortcomings of current home care targeting policy,
      provides a conceptual framework for understanding the sources of its problems,
      and proposes an alternative resource allocation method. Methods required for
      different aspects of the study included synthesis of the published literature,
      regression analysis of risk predictors, and comparison of actual resource
      allocations with simulated budgets. Problems of imperfect agency ranging from
      unclear goals and inappropriate incentives to lack of information about the
      marginal effectiveness of home care could be mitigated with an improved budgeting
      method that combines client selection and resource allocation. No program can
      produce its best outcome performance when its goals are unclear and its
      technology is unstandardized. Titration of care would reallocate resources to
      maximize marginal benefit for marginal cost.

PMID- 12611412
TI  - Effective coordination of medical and supportive services.
AB  - For at least the past quarter century, tension between "medical/allied health"
      and "social" models of care have characterized much of the home-care policy
      debate. There has also emerged a growing body of research and boundary-bending
      care models based on a holistic view of care recipients and caregiving. Such
      models coordinate between medical care and expanded supportive community services
      (SCS) that range from assistance with lifestyle modification, self-care, and
      informal care to adult-day services and home-health care. This article presents a
      new rationale for these models based on disablement theory and recent accounts of
      fairness in health policy. This approach is contrasted with the efficiency and
      efficacy policy perspectives that have received the most attention. The
      implications of an equal-opportunity approach to home-care policy for performance
      indicators are explored. Six basic models of coordination and current evidence on
      their impacts are described from this new perspective. Using qualitative data
      from two recent projects, five dimensions of care recipient and caregiver
      experiences that may be relevant to performance measurement are described.
      Suggestions for further service innovations and research are offered.

PMID- 12611413
TI  - Coordinating services across the continuum of health, housing, and supportive
      services.
AB  - This article describes trends in three areas of state long-term care policy for
      elderly low-income Medicaid beneficiaries--providing home care services to
      residents in subsidized housing and assisted living; offering nursing home
      residents opportunities to relocate to community settings; and integrating acute
      and long-term care services for beneficiaries who are dually eligible for
      Medicare and Medicaid. The information was obtained from reports and studies on
      state policy, site visits, and interviews with state officials. Multiple
      initiatives responding to consumer preferences and fragmentation of the delivery
      systems were identified. Key components were consumer demand; the availability of
      nursing facility alternatives; and state priorities for controlling expenditure
      growth. States use Medicaid to develop broad service menus that include in-home,
      community, residential, and institutional services. Several states are conducting
      demonstration programs that improve coordinating or integration of long-term care
      with the acute care system.

PMID- 12611414
TI  - Considerations re: infection control procedures. Canadian Dental Association.

PMID- 12611415
TI  - A comparison of current practice in school-based substance use prevention
      programs with meta-analysis findings.
AB  - The series of seminal meta-analytic studies of school-based substance use
      prevention program studies conducted by the late Nancy S. Tobler and colleagues
      concluded that programs with content focused on social influences' knowledge,
      drug refusal skills, and generic competency skills and that use participatory or
      interactive teaching strategies were more effective than programs focused on
      knowledge and attitudes and favoring traditional didactic instruction. The
      present study compared current school practice against evidence-based standards
      for "effective content" and "effective delivery," derived from the Tobler
      findings. Respondents were the lead staff who taught substance use prevention in
      the 1998-1999 school year in a national sample of public and private schools that
      included middle school grades (N = 1,795). Results indicate that most providers
      (62.25%) taught effective content, but few used effective delivery (17.44%), and
      fewer still used both effective content and delivery (14.23%). Those who taught
      an evidence-based program (e.g., Life Skills Training, Project ALERT), however,
      were more likely to implement both effective content and delivery, as were those
      teachers who were recently trained in substance use prevention and were
      comfortable using interactive teaching methods. The findings indicate that the
      transfer to practice of research knowledge about school-based substance use
      prevention programming has been limited.

PMID- 12611416
TI  - Alcohol use among adolescent mothers: heterogeneity in growth curves, predictors,
      and outcomes of alcohol use over time.
AB  - This paper examines patterns of alcohol use over a 10-year period in a sample of
      adolescent mothers and includes both predictors and outcomes of young mothers'
      alcohol use patterns over time. This study used mixture modeling to identify
      latent trajectory classes based on alcohol consumption over 10 years. Results
      indicate that there is significant heterogeneity in alcohol use trajectories of
      adolescent mothers during the transition from adolescence to adulthood as well as
      significant predictors and outcomes that vary by latent class trajectory.
      Specifically, measures of the consumption of alcohol by both quantity and
      frequency yielded multiple latent trajectory classes. Alcohol quantity measures
      yielded a two-class model with higher and lower quantity users. Age at first
      drink significantly differentiated between the two classes indicating that the
      younger the respondent was, the more likely she belonged to the higher quantity
      user class. In addition, members of the higher quantity class had significantly
      more negative outcomes in adulthood. The second measure of alcohol consumption,
      alcohol frequency, yielded a four-class solution consisting of low-level users,
      early decliners, late decliners, and increasers. As with alcohol quantity, age at
      first drink significantly differentiated between classes, as did age at first
      birth, in the expected direction. Similarly, two classes with the greatest growth
      and patterns of use over time, late decliners and increasers, had significantly
      worse outcomes in adulthood. The results suggest that identifying underlying
      heterogeneity in alcohol use can be informative with regard to both predictors
      and outcomes for young women who were adolescent mothers. Results suggest that
      there are possible higher order factors that can account for the results of this
      study.

PMID- 12611417
TI  - Characteristics of effective school-based substance abuse prevention.
AB  - This study summarizes, using meta-analytic techniques, results from 94 studies of
      school-based prevention activities that examined alcohol or other drug use
      outcomes. It set out to determine what features of school-based substance abuse
      prevention programs are related to variability in the size of program effects, It
      asked (1) Which populations (e.g., high risk vs. general population) should be
      targeted for prevention services? (2) What is the best age or developmental stage
      for prevention programming? (3) Does program duration matter? and (4) Does the
      role of the person delivering the service (e.g., teacher, law enforcement
      officer, peer) matter? The results suggest that targeting middle school aged
      children and designing programs that can be delivered primarily by peer leaders
      will increase the effectiveness of school-based substance use prevention
      programs. The results also imply that such programs need not be lengthy. The
      evidence related to the targeting issue is sparse, but suggests that, at least
      for programs teaching social competency skills, targeting higher risk youths may
      yield stronger effects than targeting the general population. Suggestions for
      future research are offered.

PMID- 12611418
TI  - Feelings about risk and the epidemic diffusion of adolescent sexual behavior.
AB  - Rapid initiation of sexual risk behavior in adolescents can be explained by
      diffusion processes similar to those used to model epidemics. These models
      suggest that novel behavior can spread to all individuals exposed to the
      behavior. An alternative interpretation places greater emphasis on developmental
      changes in feelings toward risk behavior that can explain or limit the diffusion
      process. This research examined the initiation of sexual behavior in adolescents
      living in high-poverty urban environments. A cross-section of African American
      youth (N = 355) ages 9-17 living in public housing were interviewed using privacy
      enhancing "talking computers." Sexual risk behavior (unprotected sexual
      intercourse) was assessed along with perceived sexual behavior of friends and
      personal feelings about sexual intercourse and condom use. Age trends in both
      peer-group perceptions and personal feelings displayed increasing attraction
      toward risky sex. Diffusion processes were strongly related to sexual initiation
      and condom use even after controlling for changes in personal feelings.
      Nevertheless, feelings toward sexual risk behavior moderated the diffusion
      process. Adolescents with less favorable feelings toward sex were less
      susceptible to the diffusion of sexual initiation and those with more favorable
      feelings toward condoms were more likely to use them consistently. Interventions
      that focus on adolescents' feelings toward risk behavior can help to limit the
      diffusion of risk behavior in high-risk urban environments.

PMID- 12611419
TI  - Examining the role of implementation quality in school-based prevention using the
      PATHS curriculum. Promoting Alternative THinking Skills Curriculum.
AB  - In order for empirically validated school-based prevention programs to "go to
      scale," it is important to understand the processes underlying program
      dissemination. Data collected in effectiveness trials, especially those measuring
      the quality of program implementation and administrative support, are valuable in
      explicating important factors influencing implementation. This study describes
      findings regarding quality of implementation in a recent effectiveness trial
      conducted in a high-risk, American urban community. This delinquency prevention
      trial is a locally owned intervention, which used the Promoting Alternative
      THinking Skills Curriculum as its major program component. The intervention
      involved 350 first graders in 6 inner-city public schools. Three schools
      implemented the intervention and the other 3 were comparison schools from the
      same school district. Although intervention effects were not found for all the
      intervention schools, the intervention was effective in improving children's
      emotional competence and reducing their aggression in schools which effectively
      supported the intervention. This study, utilizing data from the 3 intervention
      schools (13 classrooms and 164 students), suggested that 2 factors contributed to
      the success of the intervention: (a) adequate support from school principals and
      (b) high degree of classroom implementation by teachers. These findings are
      discussed in light of the theory-driven models in program evaluation that
      emphasized the importance of the multiple factors influencing the implementation
      of school-based interventions.

PMID- 12611421
TI  - Social stress increases blood pressure and cardiovascular pathology in a
      normotensive rat model.
AB  - Territorial stress (TS) elevates blood pressure (BP) in several mammalian
      species. However, cardiovascular pathology following chronic stress has not been
      consistently shown in a non-genetic hypertension model. Therefore, the hypothesis
      tested was that social stress would directly increase: BP, collagen deposition in
      coronary and mesenteric arteries, and myocardial fibrosis. Wistar-Kyoto (WKY)
      male rats, four weeks of age, were divided into one of three groups: controls (n
      = 9), territorial stress (TS, n = 12), and social isolation followed by
      territorial stress (SITS, n = 11). Blood pressure was measured biweekly, and
      blood samples biweekly for serum testosterone, corticosterone, epinephrine and
      norepinephrine. Blood pressure significantly increased in the TS (130 mmHg, p <
      0.05) and SITS (150 mmHg, p < 0.05) groups, compared to controls (120 mmHg,
      ANOVA, F = 6.7, p < 0.001). Coronary collagen was increased 47% in the TS group
      and 90% in the SITS group compared to controls (p < 0.05). The coronary
      wall/lumen ratio increased significantly (45%, p < 0.05) in the SITS group
      compared to the controls. Myocardial fibrosis was increased 27% in the TS group
      and 74% in the SITS group compared to controls (p < 0.05). In conclusion, stress
      treatments increased BP and cardiac pathology in a normotensive rat strain.

PMID- 12611420
TI  - Hypertension associated with reduced plasma thrombomodulin levels and a
      hypercoagulable state in rats.
AB  - The plasma thrombomodulin (TM) level, an indicator of systemic endothelial cell
      damage, was measured in spontaneously hypertensive rats (SHR), deoxycorticosteron
      acetate (DOCA)-induced hypertensive rats and normotensive Wistar-Kyoto (WKY) rats
      to clarify its changes in hypertension. Plasma TM levels, measured by enzyme
      linked immuno-sorbent assay, decreased with aging (5-20-weeks-old) in both SHR
      and WKY, and they were lower in SHR than age-matched WKY in all ages examined.
      Deoxycorticosteron acetate-induced hypertensive WKY also showed decreased TM
      levels compared with normotensive WKY. Accelerated coagulation and fibrinolysis
      shown by the increases in thrombin-antithrombin complex (TAT) and D-dimer levels
      were observed in both groups of hypertensive rats. These results suggest that
      hypertension may decrease plasma TM levels and induce a hypercoagulable state in
      rats.

PMID- 12611422
TI  - Increased dietary potassium and magnesium attenuate experimental volume dependent
      hypertension possibly through endogenous sodium-potassium pump inhibitor.
AB  - We and others have shown that inhibition of cardiovascular muscle (CVM) cell
      Na+,K-ATPase activity (NKPTA) due to increased level of endogenous sodium
      potassium pump inhibitor (SPI) is involved in the mechanism of volume expanded
      (VE) experimental and human essential hypertension (HT). Since diets fortified
      with very high potassium (K) or very high magnesium (Mg) decrease blood pressure
      (BP), we have examined the effect of a moderate increase in dietary K alone and a
      moderate increase in dietary K and Mg on plasma levels of SPI, CVM cell NKPTA,
      and BP in reduced renal mass (RRM)-salt HT rats, a classical model of VE HT.
      Seventy Percent-RRM rats were divided in four dietary groups, (1) Na free and
      normal K and Mg (0Na-K-Mg); (2) normal Na, K and Mg (Na-K-Mg); (3) normal Na and
      high K (2 x normal), and normal Mg (Na-2K-Mg); and (4) normal Na and high K (2 x
      normal), and high Mg (2 x normal) (Na-2K-2Mg). As expected, compared to control
      0Na-K-Mg rats, Na-K-Mg rats developed HT. Blood pressure increased significantly
      less in Na-2K-Mg rats whereas, BP did not increase in Na-2K-2Mg rats.
      Hypertension in NA-K-Mg rats was associated with an increase in plasma SPI and
      digitalis like factor (DIF) and a decrease in renal and myocardial NKPTA.
      However, doubling the Mg along with K in the diet (Na-2K-2Mg) normalized SPI and
      DIF and increased myocardial and renal NKPTA, compared to control 0Na-K-Mg rats.
      Also, compared to 0Na-K-Mg rats, water consumption, urine excretion, urinary
      sodium excretion urinary potassium excretion (U(Na)V), and (U(K)V) increased in
      the other three groups, more so in Na-2K-2Mg rats. These data show that K and Mg
      have additive effects in preventing an increase in SPI, thus probably preventing
      the BP increase in RRM rats.

PMID- 12611423
TI  - Renin-angiotensin-aldosterone system loci and multilocus interactions in young
      onset essential hypertension.
AB  - OBJECTIVE: Renin-angiotensin-aldosterone system component genes have been
      associated to essential hypertension. Thus, we studied the association of singe
      locus or multilocus interactions with young-onset essential hypertension. SETTING
      AND DESIGN: This is a case-control study based on a population sample of
      adolescent at an inner city. PARTICIPANTS: We studied 54 adolescents with
      hypertension and 121 age-matched normotensives, recruited from a high-school
      student population of 934 interviewed individuals. METHODS: Resting blood
      pressure was measured on three different days and normalized (Z-score) by sex and
      age. Genotypes of ACE (I/D) angiotensinogen (T174M and M235T), ATIR (A1166C), and
      CYP11B2 (C-344T) were determined by PCR/RFLP or ASO. RESULTS: Although genotype
      frequencies were not different in both groups, we found a significant dominant
      effect of ACE D and angiotensinogen 235T alleles on normalized systolic arterial
      blood pressure in males. This effect was confirmed by sib-pair linkage analysis
      taking normalized blood pressure as a quantitative trait. We independently
      analyzed multilocus interactions in normotensive and hypertensive adolescents
      searching for multiple locus deviation from Hardy-Weinberg or linkage
      equilibrium. We found that from 63 multilocus combinations, 4 deviated
      significantly from equilibrium in hypertensive adolescents but none in the
      normotensives. Deviations from equilibrium may indicate that the combination of
      alleles at different loci affects susceptibility or resistance to the disease.
      CONCLUSION: In addition to the angiotensin-converting enzyme (ACE) and
      angiotensinogen (AGT) gene variants, gene-gene interactions may be important
      causative factors in a complex disease such as young-onset essential
      hypertension.

PMID- 12611424
TI  - Insulin mediated hemodynamic responses in spontaneous hypertensive rats (SHRs):
      effect of chromosome 4 gene transfer.
AB  - The spontaneous hypertensive rat (SHR) is a widely studied model of essential
      hypertension and has been reported to exhibit alterations in carbohydrate and
      lipid metabolism. Genetic linkage studies implicated that SHR carries deletion
      variant of Cd36 gene of chromosome 4, the gene that encodes fatty acid
      transporter. Thus it could be possible that primary genetic defect in SHR is
      compromised tissue utilization of fatty acid that would form the basis for the
      pathogenesis of hyperinsulinemia, insulin resistance and insulin-mediated
      responses. We measured both the hemodynamic and metabolic responses to insulin in
      SHR in comparison with the chromosome congenic spontaneous hypertensive rats
      (cSHRs) (rats in which piece of chromosome 4 containing wild type Cd36 was
      integrated into the SHR genome). A bolus infusion of insulin increased iliac
      conductance and decreased blood pressure in Wistar Kyoto (WKY) rats. However, in
      SHR insulin did not reduce blood pressure as in WKY but after about 15 min it
      significantly enhanced blood pressure and reduced iliac conductance. Whereas in
      cSHR insulin did not reduce blood pressure as in WKY rats. However, pressor
      responses to insulin were eliminated by chromosome 4 gene transfer. Glucose
      clearance was significantly slower in both SHR and cSHR. Glucose tolerance test
      revealed that SHR are hyperinsulinemic and insulin resistant. These findings
      indicate that transfer of segment of chromosome 4 from Brown Norway rats onto
      spontaneous hypertensive background eliminates hyperinsulinemia and pressor
      effects of insulin.

PMID- 12611425
TI  - Toward a praxis theory of suffering.

PMID- 12611426
TI  - Social and cultural considerations in recovery from anorexia nervosa: a critical
      poststructuralist analysis.
AB  - New directives in health care research challenge researchers to move analysis
      beyond that of the individual and focus on social, cultural, and historical
      processes as interrelated determinants of health and illness. Adhering to a
      poststructuralist methodology, this article moves the analytic focus beyond
      individualistic narratives and into social and cultural discourses concerning
      recovery from anorexia nervosa. This study focused on social and cultural
      assumptions identified, seemingly as a paradox, through accounts articulated by
      young women who are in recovery or have recovered from anorexia nervosa. By
      theorizing outside of an individualized framework, it is possible to foreground
      the relationships between individualism, health, self-surveillance, women, the
      body, and the notion of recovery from anorexia.

PMID- 12611427
TI  - "Race" and the difficulties of language.
AB  - "Race," a construct created by scientists, is deeply ingrained in everyday
      discourses. Using postmodern theories to help us think through the complexities
      of language in relation to race, we come to understand that truths about race are
      changing, contingent, and contested products of cultural construction. It is
      impossible to understand or represent race as an object of study such that it can
      be known, yet untouched, by language. Health effects are one important
      consequence of race, particularly related to quality, access, marginalization,
      and privilege. Analyzing the effects of race bring it visibly into being, and
      makes evident how language shapes our understandings of the world and its human
      inhabitants.

PMID- 12611428
TI  - Grounded theory, feminist theory, critical theory: toward theoretical
      triangulation.
AB  - Nursing and social science scholars have examined the compatibility between
      feminist and grounded theory traditions in scientific knowledge generation,
      concluding that they are complementary, yet not without certain tensions. This
      line of inquiry is extended to propose a critical feminist grounded theory
      methodology. The construction of symbolic interactionist, feminist, and critical
      feminist variants of grounded theory methodology is examined in terms of the
      presuppositions of each tradition and their interplay as a process of theoretical
      triangulation.

PMID- 12611429
TI  - An emerging discourse: toward epistemic diversity in nursing.
AB  - Grounded in a postmodern feminist methodology, this article undertakes an initial
      analysis of a newly emerging discourse in contemporary nursing academia in the
      United States. Two currently prominent discourses in nursing, a dominant
      discourse informed by the processes and values of "science" in the Enlightenment
      sense and a concurrent marginalized discourse informed by postmodernism, are
      described as a context for the emerging discourse. A genealogy informed by the
      work of Foucault is presented as a basis for an analysis of the power effects
      resulting from the conflict between these 2 discourses. Finally, 3 recent texts
      in nursing are analyzed and common themes identified as indicative of a new
      intertextual discourse, termed "epistemic diversity," emerging from this
      discursive conflict.

PMID- 12611431
TI  - Poststructuralist musings on the mind/body question in health care.
AB  - Consideration of mind/body phenomena in health care has been grounded in the
      constraints of overt and covert paradigmatic assumptions and the mechanisms of
      power/knowledge that poststructuralists pose as characteristic of empiricism.
      This article examines the development and conceptualization of mind/body
      phenomena within the context of evidence considered fitting in health care, that
      is, within the disciplinary matrix of empiricism. Discussion focuses particularly
      on inference, probability, and cause and effect, significant components of
      empiricism, as they have influenced the direction of the mind/body debate in
      health care during the 20th and early 21st centuries. A focus on disciplinary
      structure and rules of force subtly grounding empiricism may be the best we have
      for grasping the place of a phenomenon like mind/body within nursing and the
      health care disciplines, if such grasping is warranted at all.

PMID- 12611430
TI  - An essay on an authentic meaning of medicalization: the patient's perspective.
AB  - In this essay, the experiences of the author serve as a key to a critical
      understanding of medicalization in the treatment of cancer in American society.
      Forms of medicalization described are (a) giving useless treatments to keep the
      patient under medical care; (b) demeaning and undermining efforts at self
      determination and self-care; and (c) keeping the patient's life suspended by
      continual reminders that death is just around the corner, and that all time and
      energy left must be devoted to ferreting out and killing the disease.

PMID- 12611432
TI  - The Quality-Caring Model: blending dual paradigms.
AB  - Evidence supports associations between professional nursing and quality health
      outcomes. Yet, what specifically accounts for those linkages remains buried in
      the daily practice of nursing. The Quality-Caring Model exposes and demonstrates
      the value of nursing within the evidence-based practice milieu of modern health
      care. It favors a process, or way of being, that challenges modernist conventions
      and highlights the power of relationships. By reaffirming the nature of nursing's
      work as relationship-centered, the blended model describes the 2 dominant
      relationships that comprise professional encounters. Relationships characterized
      by caring are theorized to influence positive outcomes for patients/families,
      health care providers, and health care systems. Model components are clarified,
      assumptions described, and propositions stated. Conceptual-theoretical linkages
      in the model are identified and ties to empirical indicators provide the logical
      consistency necessary for validation. Clinical practice and research applications
      of the model are offered. The Quality-Caring Model helps to translate the hidden
      work of nursing into objective terms that can be tested. Scientifically
      demonstrating its worth will advance professional nursing while simultaneously
      improving the quality of health care.

PMID- 12611433
TI  - Molecular mechanisms of TRS instability.
AB  - To date several neurodegenerative disorders including myotonic dystrophy,
      Huntington's disease, Kennedy's disease, fragile X syndrome, spinocerebellar
      ataxias or Friedreich's ataxia have been linked to the expanding trinucleotide
      sequences. Although phenotypic features vary among these debilitating diseases,
      the structural abnormalities of the triplet repeat containing DNA sequences is
      the primary cause for all of these disorders. Expansions of the CAG repeat within
      coding regions of miscellaneous genes result in the synthesis of aberrant
      proteins containing enormously long polyglutamine stretches. Such proteins
      acquire toxic functions and/or may direct cells into the apoptotic cycle. On the
      other hand, massive expansions of various triplet repeats (i.e., CTG/CAG,
      CGG/CCG/, GAA/TTC) inside the noncoding regions lead to the silencing of
      transcription and therefore affect expression of the adjacent genes. The
      repetitive character of TRS allows stretches of such tracts to form slipped
      stranded structures, self-complementary hairpins, triplexes or more complex
      configurations called "sticky DNA", which are not equally processed by some
      cellular mechanisms, as compared to random DNA. It is likely that the instability
      of the short TRS (below the threshold level) occurs due to the SILC pathway,
      which is driven by the DNA slippage. Accumulation of the short expansions leads
      to the disease premutation state where the MLC pathway becomes predominant.
      Independent of which mechanism is involved in the MLC pathway (replication,
      transcription, repair or recombination) the process of complementary strand
      synthesis is crucial for the TRS instability. Generally, dependent on the
      location of the tract which has higher potential to form secondary DNA structure,
      further processing of such tract may result in expansions (secondary structure
      formed at the newly synthesized strand) or deletions (structure present on the
      template strand). Analyses of molecular mechanisms of the TRS genetic instability
      using bacteria, yeast, cell lines and transgenic animals as models allowed the
      scientists to better understand the role of some major cellular processes in the
      development of neurodegenerative disorders in humans. However, it is necessary to
      remember that most of these investigations were focused on the involvement of
      each particular process separately. Much less of this work though was dedicated
      to the search for the interactions between such cellular systems that in effect
      could result in different rate of TRS expansions. Thus, more intensive studies
      are necessary in order to fully understand the phenomenon ofthe dynamic mutations
      leading to the human hereditary neurodegenerative diseases.

PMID- 12611434
TI  - Myotonic dystrophy: discussion of molecular basis.

PMID- 12611435
TI  - Spinocerebellar ataxias caused by polyglutamine expansions.

PMID- 12611436
TI  - Spinocerebellar ataxia type 10: a disease caused by a large ATTCT repeat
      expansion.

PMID- 12611437
TI  - The molecular basis of Friedreich ataxia.

PMID- 12611439
TI  - IFSHT--what does it mean to you? International Federation of Societies for Hand
      Therapy.

PMID- 12611438
TI  - "Back to the future".

PMID- 12611440
TI  - Electromyographic activity in stiff and normal elbows during elbow flexion and
      extension.
AB  - This prospective, controlled pilot study investigated electromyographic activity
      in elbow muscles during active elbow flexion and extension and during prolonged
      elbow extension with and without resistance. Biceps brachii, brachialis,
      brachioradialis, and triceps activity was measured in 10 subjects with elbow
      motion deficits after injury and in 10 controls. Surface electromyography was
      recorded during active elbow flexion, extension, and passively positioned elbow
      extension with and without 3 lb on the distal forearm. All muscles of the stiff
      elbow group had greater activity compared with controls during active elbow
      flexion and extension. Biceps brachii of the stiff group showed antagonist
      activity equivalent to agonist. For all other flexors in both groups, agonist
      activity was greater than antagonist. During prolonged extension, biceps brachii,
      unweighted, showed greater activity in the stiff group than in controls. Both
      groups showed greater flexor activity when weighted. Across time, activity was
      sustained or increased in all muscles in both groups.

PMID- 12611441
TI  - Development of the Functional Dexterity Test (FDT): construction, validity,
      reliability, and normative data.
AB  - Dexterity tests take time to administer; however, the information obtained is an
      important component of a comprehensive examination of the hand. This article
      introduces a dexterity test suitable for use as part of routine examination of
      the hand. The Functional Dexterity Test (FDT) was developed as a measure of
      dexterity that takes a minimum amount of time to administer, yet provides
      information regarding the patient's ability to use the hand for daily tasks
      requiring a 3-jaw chuck prehension between the fingers and the thumb. The test
      was developed over 20 years. Interrater and intrarater reliability ranges between
      good and excellent. Construct validity was confirmed in 2 clinical studies.
      Preliminary normative data were obtained in 6 samples of convenience. Along with
      statistical data, this article provides equipment standards and instructions.

PMID- 12611442
TI  - Measuring normal hand dexterity values in normal 3-, 4-, and 5-year-old children
      and their relationship with grip and pinch strength.
AB  - After surgery for trauma or correction of congenital anomaly, hand function is
      difficult to evaluate in children because there are no reference norms on
      children 3 to 5 years old. The purpose of this study was to determine whether
      reproducible normative values for hand dexterity and grip and pinch strength
      could be obtained in young children using simple tests that could be administered
      quickly within the attention span of a 3- to 5-year-old. The Functional Dexterity
      Test (FDT), a pegboard test validated for adults and older children, seemed to
      meet our requirements for dexterity. The FDT was administered to a convenience
      sample of normal children in a prekindergarten school who were grouped according
      to age: 3-year-olds (n = 17), 4-year-olds (n = 24), and 5-year-olds (n = 22).
      Hand dominance was determined. The task was demonstrated by 1 of the 2 testers.
      The child was asked to turn the pegs over in the pegboard without using the free
      hand or balancing the peg against the chest. Both hands were tested. Grip and
      pinch strengths were measured in both hands in a consistent manner. All the
      children were tested with the arm at the side and the elbow at 90 degrees. A
      dynamometer was used for grip strength and a pinch meter was used to measure key
      (lateral) and tripod pinch strengths. Means and SDs were calculated for each age
      group, and the dependent values of dexterity, strength, and dominance were
      correlated. Dexterity and strength scores were significantly different by age
      group. A good FDT score in the dominant hand was predictive of a good score in
      the nondominant hand. Grip and pinch strength correlated poorly with functional
      dexterity. The normative values established in this study for children in the 3-
      to 5-year-old range can be referenced for disability estimates and establishing
      goals for children after surgery or hand injury.

PMID- 12611443
TI  - Changes in postural risk and general health associated with a participatory
      ergonomics education program used by heavy video display terminal users: a pilot
      study.
AB  - To determine if a brief, participatory ergonomics education program was
      associated with changes in work posture and general health of heavy video display
      terminal (VDT) users, 23 full-time VDT users participated in an on-site, small
      group, 60-minute ergonomics education session and 1 week later an individual 15
      minute follow-up session at their workstation. Posture was assessed by a blinded
      tester who scored videotape records to complete the Postural and Repetitiveness
      Risk Factors Index (PRRI), and general health status was assessed via self
      administered Short-Form 36 Health Survey (SF-36) questionnaire before the
      intervention and again 5 weeks later. Five weeks after the 60-minute session,
      PRRI scores were 19% lower than were preintervention scores (p < 0.01),
      indicating lower postural risk. SF-36 physical (2% higher) and mental (4% higher)
      component scores were not statistically different, however, before and after
      intervention (p > 0.05). Although the participatory ergonomics education program
      was associated with improved work posture (PRRI scores) after 5 weeks, general
      physical and mental health (SF-36 scores) did not change within this time period.
      These results suggest that a participatory ergonomics program, which is of short
      duration and minimally disruptive to the normal workplace routine, may have a
      rapid effect on improving work posture. Although awkward posture is thought to be
      a risk factor for work-related musculoskeletal disorders, multigroup and long
      term randomized trials are required to establish the effectiveness of
      participatory ergonomics programs in reducing the incidence and severity of
      musculoskeletal disorders associated with heavy VDT use.

PMID- 12611444
TI  - Reliability and validity of the BTE-Primus grip tool.
AB  - This study was designed to examine the reliability and validity of the newly
      designed grip tool of the Baltimore Therapeutic Equipment (BTE)-Primus and to
      investigate the effects of body position (sit versus stand), handedness, and
      fatigue on grip strength. The subjects performed maximal grip strength tests
      using the Jamar dynamometer and the BTE-Primus. Intraclass correlation
      coefficients were calculated for test-retest reliability and criterion-related
      validity. A repeated measures analysis of covariance was conducted to reveal
      differences in grip strength between instruments, body positions, hands, and
      sessions. The BTE-Primus grip tool was found to be reliable (r = 0.97 to 0.98)
      and valid (r = 0.95 to 0.96). There were no significant differences in grip
      strength scores between the Jamar and the BTE-Primus or between sitting and
      standing. Grip strength scores of the right hand were significantly greater than
      those of the left hand, and grip strength scores in the first session were
      significantly greater than those in the second session. The results of this study
      indicate that clinicians can use the BTE-Primus grip attachment at the second
      handle setting and know that is reliable, valid, and comparable to the second
      handle setting of the Jamar dynamometer.

PMID- 12611445
TI  - Effects of forearm venous drainage on responses to the volume provocation test.
AB  - The volume provocation test (VPT) has been shown to induce a transitory increase
      of forearm and hand volume. Although these changes have been quantified in
      previous studies, the postulated mechanism underlying the VPT required further
      investigation. This study used a test-retest design in which the VPT was applied
      to 20 subjects before and during blood donation. During the standard VPT, the
      experimental arm was cuffed for 4 minutes at 15 mm Hg less than diastolic blood
      pressure, but a cannula siphoned blood from a superficial forearm vein during
      blood donation. Subjects rated the level of discomfort for each protocol, and
      reported data regarding symptom quality and location. Discomfort data during the
      VPT (1.95/10) was higher (p(1-tailed) < 0.005) than during blood donation
      (1.1/10), and subjects reported fewer volume-related symptoms during blood
      donation. These findings support the hypothesis that the VPT operates through a
      vascular mechanism, which is milder during blood donation.

PMID- 12611446
TI  - Competencies in hand therapy.
AB  - The Hand Therapy Certification Commission, Inc., in consultation with the
      Professional Examination Service, completed a practice analysis of hand therapy
      in 2001. One goal was to obtain information about the competencies shown by
      therapists at specific points of experience. Six competency areas were identified
      and included in the final survey: scientific knowledge, clinical
      judgment/clinical reasoning, technical skills, interpersonal and communication
      skills, professionalism, and resource management. Certified Hand Therapists
      (CHTs) in the United States and Canada participated in the survey. All six
      competencies were rated moderately or highly critical to professional
      effectiveness. Thirty hypothesized behavioral progressions (from novice to
      expert) were included; 27 were validated by the results, indicating that CHTs
      show competence that is unique and increases over time. Potential uses of these
      results by CHTs and hand therapy organizations are proposed, especially in regard
      to candidate eligibility, self-assessment by CHTs, and planning for continuing
      education.

PMID- 12611447
TI  - A full-contact proximal forearm brace.
AB  - Patients who use this full-contact brace seem to have fewer complaints of pain,
      resulting in increased ability to complete functional tasks, work, and play
      sports. The brace is easy and inexpensive to fabricate.

PMID- 12611448
TI  - Distal radius fractures: therapy practice patterns.

PMID- 12611449
TI  - American Society of Hand Therapists (ASHT) Presidential Address from the Ottawa
      meeting, September 2002. Reaching for excellence.

PMID- 12611450
TI  - Seventeenth Nathalie Barr Lecture 2002. The value of perspective/the power of
      partnership.

PMID- 12611451
TI  - Estradiol promotes growth and angiogenesis in polyoma middle T transgenic mouse
      mammary tumor explants.
AB  - Estrogen is important for breast carcinogenesis and the majority of breast
      cancers maintain hormone dependency. Estrogen has the ability to stimulate both
      breast epithelial cell growth and angiogenesis, and a well-characterized in vivo
      cancer model where these functional interactions can be studied is lacking. We
      demonstrate estrogen dependent angiogenesis, growth in vivo, and proliferation in
      vitro, in explants from polyoma middle T transgenic mouse mammary tumors. Thus,
      in addition to genetic similarities, this model also exerts a sex hormone, and
      angiogenic phenotype similar to human breast cancer. This immune-competent animal
      model offers the opportunity to study molecular events in estrogen dependent
      breast cancer.

PMID- 12611452
TI  - Family history of breast and ovarian cancer and the risk of breast carcinoma in
      situ.
AB  - A family history of breast cancer is an important risk factor for breast
      carcinoma in situ (BCIS), however, there are no detailed analyses of its
      variation in effect by number, type, laterality or age at onset of affected
      relatives nor by association with ovarian cancer. In addition, the role of the
      breast cancer susceptibility genes, BRCA1 and BRCA2, in the development of BCIS
      is unclear. OBJECTIVE: To better define the role of: (1) a family history of
      breast and ovarian cancer and (2) the cancer susceptibility genes, BRCA1 and
      BRCA2, in the development of BCIS. METHODS: The data are 875 ductal carcinoma in
      situ (DCIS) and 123 lobular carcinoma in situ (LCIS) cases diagnosed among
      residents of the state of Connecticut from September 15, 1994 to March 14, 1998
      and between the age of 20 and 79 years. Controls (n = 999) are female Connecticut
      residents collected via random-digit-dial and frequency matched to the cases by 5
      year age intervals. Telephone interviews were used to collect information on risk
      factors and cancer screening history. Logistic regression was used to provide
      maximum likelihood estimates of the odds ratios (OR) with 95% confidence
      intervals (95% CI). The probability of being a BRCA1 and/or BRCA2 gene carrier
      was calculated for each case and control, using family history of breast and
      ovarian cancer, age/age at diagnosis for relatives, prevalence and penetrance
      data for BRCA1/BRCA2, and self-report of Jewish heritage. RESULTS: Cases with
      DCIS or LCIS were significantly more likely to report a first degree family
      history of breast cancer (OR: 1.6, 95% CI: 1.3, 2.1 and 1.8, 95% CI: 1.2, 2.9,
      respectively) than were controls. In addition, DCIS cases were 2.4 (95% Cl: 0.8,
      7.2) times more likely than controls to report both an affected mother and
      sister. An inverse association was suggested between age at onset and DCIS risk
      with cases aged 49 years or younger at 2.1 (95% CI: 1.3, 3.4) times the risk of
      controls (95% CI) versus 1.5 (95% CI: 1.1, 2.0) for cases older than 49 years. An
      elevated risk of DCIS was associated with a family history of ovarian cancer but
      did not reach statistical significance (OR: 1.3, 95% CI: 0.7, 2.5). Approximately
      3.7% and 1.9% of DCIS cases were predicted to carry a mutation in BRCA1 and
      BRCA2, respectively. CONCLUSIONS: A family history of breast cancer is associated
      with an increased risk of DCIS and LCIS, particularly among women with multiple
      relatives affected at early ages. Statistical risk models predict a low
      prevalence rate of BRCA1 and BRCA2 in DCIS; these estimates await confirmation
      through laboratory testing.

PMID- 12611453
TI  - Membrane disrupting lytic peptide conjugates destroy hormone dependent and
      independent breast cancer cells in vitro and in vivo.
AB  - We have prepared conjugates of a membrane disrupting lytic peptide (hecate) and a
      15-amino acid segment of the beta-chain of CG and hecate and the decapeptide,
      luteinizing hormone releasing hormone (LHRH). We have tested the concept that
      these conjugates will target breast cancer cells expressing LH/CG or LHRH
      receptors. In previous studies, we were able to destroy prostate cancers in vitro
      and in vivo with lytic peptide conjugates. Hecate, hecate-betaCG and LHRH-hecate
      were added to cultures of the human breast cancer cell lines MCF-7 and MDA-MB
      435S. Hecate and its conjugates showed concentration dependent toxicity to both
      cell lines. The lytic peptide alone showed similar EC50 values for both cell
      lines; however, there was a significant difference between the EC50 values when
      the conjugates were tested. The hormone dependent MCF-7 cell line was less
      sensitive to the betaCG conjugate than to the LHRH conjugate; the reverse was
      found for the hormone independent MDA-MB-435S cells. Removal of steroids
      decreased the sensitivity of MCF-7 cells to both lytic peptide conjugates and
      this sensitivity could be restored by adding estradiol. Activation of protein
      kinase C further increased the sensitivity to the drug. MDA-MB-435S xenografts
      were established in intact female athymic nude mice, which were treated once a
      week for 3 weeks with hecate-betaCG via the lateral tail vein. The ability of
      hecate-betaCG to destroy xenografts of human breast cancer cells (MDA-MB-435S) in
      nude mice was demonstrated for the first time. We conclude that hecate-betaCG and
      LHRH-hecate conjugates could serve as useful drugs for the treatment of breast
      cancer.

PMID- 12611454
TI  - The combination of gemcitabine and vinorelbine is an active regimen as second
      line therapy in patients with metastatic breast cancer pretreated with taxanes
      and/or anthracyclines: a phase I-II study.
AB  - PURPOSE: To evaluate the activity and toxicity of gemcitabine and vinorelbine
      (GemVin), in patients with advanced breast cancer, previously treated with
      anthracyclines alone or with taxanes. Patients and methods. Nine patients were
      entered into the phase I and 50 patients were entered into the phase II study.
      Gemcitabine was administered beginning with the dose of 800 mg/m2 and vinorelbine
      was given at the fixed dose of 25 mg/m2, both on days 1 and 8, every 21 days.
      Escalated dose levels of gemcitabine were planned by increments of 200 mg/m2 per
      level. The median age of the 50 assessable patients for the phase II study was
      56.5 years (range 30-70) and median performance status (PS, ECOG score), 1 (range
      0-2). The dominant sites of metastases were viscera in 40, bone in five and soft
      tissue in five patients. First-line chemotherapy for metastatic disease with
      taxanes and anthracyclines or with anthracyclines alone was administered in 36
      and 14 patients, respectively. RESULTS: The optimal schedule for the combination
      was gemcitabine 800 mg/m2 and vinorelbine 25 mg/m2. The maximum tolerated dose of
      gemcitabine was 1000 mg/m2, with grade 4 neutropenia occurring in two cases at
      this dose level. Overall, 267 cycles were given to the 50 patients enrolled into
      the phase II (mean 5.3; range 3-9). The schedule was well tolerated: three
      patients experienced grade 4 neutropenia and another four patients experienced
      grade 3 anemia. Non-hematological toxicities were moderate. A major objective
      response was observed in 42% of patients (95% confidence interval (CI), 28-57%),
      with complete remission in four (8%) and partial response in 17 (34%) patients.
      The median time to progression was 6 months. Activity as well as toxicity were
      similar in the subgroups of the patients pretreated either with combinations of
      taxanes and anthracyclines or anthracyclines alone. CONCLUSIONS: The optimal
      GemVin schedule is an effective and well tolerated second-line therapy in
      patients with metastatic breast cancer pre-treated with anthracycline-based
      schedules or with combinations of anthracyclines and taxanes.

PMID- 12611455
TI  - A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer
      independently from the cathepsin D gene.
AB  - Tumor cell invasion requires expression of degradative enzymes such as
      plasminogen activator, collagenase, and cathepsins. Cathepsin D, a lysosomal
      aspartic protease produced constitutively in human breast cancer cell lines, also
      has mitogenic activity in breast cancer cells. Additionally, high cathepsin D
      expression is associated with increased risk of metastasis in patients with node
      negative breast cancer. Recently, a novel aspartic protease gene, ALP56 (aspartic
      like protease 56kDa), has been identified. To examine possible interrelationships
      we quantitated ALP56 mRNA and cathepsin D mRNA in breast cancers using reverse
      transcription polymerase chain reaction. ALP56 mRNA expression was greater in
      cancers than in noncancerous tissues (p < 0.0001), as was expression of cathepsin
      D mRNA. ALP56 gene expression was dose-dependently down-regulated in T-47D breast
      cancer cells treated with estradiol, while cathepsin D was up-regulated.
      Expression of ALP56 mRNA in estrogen receptor (ER)-positive breast cancers was
      less than that in ER-negative cancers, and mRNA expression for ALP56 and
      cathepsin D did not correlate with one another. Thus ALP56 as well as cathepsin D
      may be a useful target molecule in breast cancer treatment.

PMID- 12611456
TI  - Increased expression of BRCA1 mRNA predicts favorable response to anthracycline
      containing chemotherapy in breast cancers.
AB  - Clinical significance of BRCA1 and BRCA2 mRNA levels in tumor tissues as
      predictors of response to anthracycline-containing chemotherapy was studied in
      breast cancer patients. Fifty-one patients with locally advanced breast tumors (n
      = 43) or locally recurrent tumors (n = 8) underwent tumor biopsy and were treated
      with CE (cyclophosphamide (600 mg/m2) plus epirubicin (60 mg/m2), q3w). BRCA1 and
      BRCA2 mRNA levels in the tumors were determined by a real-time PCR assay, and the
      expression of p53 and erbB2 in tumors was determined by immunohistochemistry.
      BRCA1 mRNA levels (1.317 +/- 0.277, mean +/- S.E.) of responders were
      significantly (p < 0.05) higher than those (0.609 +/- 0.097) of non-responders
      but there was no significant difference in BRCA2 mRNA levels between responders
      (1.590 +/- 0.326) and non-responders (1.586 +/- 0.410). Tumors were dichotomized
      into the BRCA1 mRNA levels high and low group according to the cut-off value of
      0.55. Response rate (65%) of tumors with high BRCA1 mRNA levels was significantly
      (p < 0.05) higher than that (32%) of tumors with low BRCA1 mRNA levels. There was
      no significant association between response to CE and the expression of p53 or
      erbB2. Positive predictive value, negative predictive value, and diagnostic
      accuracy of BRCA1 mRNA determination in the prediction of response to CE were 65,
      68, and 67%, respectively. These results suggest a possibility that BRCA1 mRNA
      levels in tumor tissues might be useful in the prediction of response to CE
      treatment in breast cancer patients.

PMID- 12611457
TI  - Monitoring the size and response of locally advanced breast cancers to
      neoadjuvant chemotherapy (weekly paclitaxel and epirubicin) with serial enhanced
      MRI.
AB  - PURPOSE: To determine if early cancer size reduction seen on enhanced magnetic
      resonance imaging (MRI) can serve as a response predictor and to correlate final
      tumor sizes on MRI and excised gross tumor size to microscopic findings in
      patients with locally advanced breast cancers treated with preoperative
      neoadjuvant chemotherapy. METHODS AND MATERIALS: Thirty-three patients with
      advanced breast cancer entered this prospective chemotherapeutic study. Serial,
      dynamic, enhanced MRI was performed before chemotherapy induction, after the
      first course of chemotherapy and after the third course of chemotherapy prior to
      surgery. Responses were measured by image subtraction of tumor size on subsequent
      axial MRIs using the response evaluation criteria in solid tumors (RECIST). Early
      tumor size reduction, percentage of relative early tumor size reduction and final
      tumor size response were calculated and analyzed statistically. Sizes of residual
      tumors measured on MRI and gross tumors in excised breasts were correlated with
      microscopic findings. RESULTS: Based on tumor sizes measured with enhanced MRI,
      four complete responders (CR), 19 partial responders (PR) and 10 non-responder
      were documented. Twelve (52%) of the 23 responders (CR and PR)had reached the
      criteria for PR (> or = 30% size reduction) after the first course of
      chemotherapy. All CR had a marked early size reduction (ESR) of more than 45%.
      Using the receiver operating characteristic (ROC) curve, a good cutoff point for
      early tumor size reduction was 7.4 cm, with a false positive rate of 0.1 and a
      false negative rate of 0.13. The percentage of ESR was 8.8%, with a false
      positive rate of 0.1 and a false negative rate of 0.09. Residual tumor size on
      MRI correlated well with microscopic findings (r = 0.982, p < 0.001) and gross
      tumor size in excised breasts correlated moderately with microscopic findings (r
      = 0.640, p < 0.001). CONCLUSION: Serial, dynamic, enhanced MRI monitoring of
      chemotherapeutic response in patients with locally advanced breast cancer can be
      used to assess early response to chemotherapy and post-chemotherapy tumor size
      change. Although the residual tumor size on MRI correlated well with the
      microscopic findings, surgical determination of residual cancer load is still
      recommended to avoid underestimation.

PMID- 12611458
TI  - Tamoxifen and the farnesyl transferase inhibitor FTI-277 synergize to inhibit
      growth in estrogen receptor-positive breast tumor cell lines.
AB  - Farnesyl transferase inhibitors (FTIs) serve to specifically inhibit farnesyl
      isoprenoid lipid modification of proteins. Although originally developed as anti
      Ras oncoprotein drugs, it now appears that these compounds function independently
      of Ras. FTIs have been shown to inhibit transformation by a variety of
      mechanisms, including apoptosis involving cytochrome c release from mitochondria.
      Tamoxifen exhibits both anti-estrogenic and estrogenic properties and is widely
      used as an estrogen antagonist for the treatment of estrogen receptor (ER)
      positive human breast tumors. Tamoxifen can induce ER-dependent apoptosis in
      human breast tumor cells by a mechanism involving the Bcl2/mitochondrial arm of
      the apoptotic machinery. Since tamoxifen and FTIs may stimulate distinct
      components of the mitochondrial-based apoptotic machinery, we reasoned that their
      effects might be synergistic. Here we show that anti-estrogens and an FTI (FTI
      277) synergize to inhibit cell growth and enhance cell death in ER positive,
      human breast tumor cell lines. However, the drugs exhibited only additive effects
      on an ER negative cell line. Analysis of treated ER positive T-47D cells
      demonstrated that a synergistic increase in apoptosis was induced, as measured by
      increased caspase 3 activity. Thus, tamoxifen and FTIs may synergize to promote
      apoptotic cell death in ER positive human breast tumor cells.

PMID- 12611459
TI  - Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation.
AB  - Previous results indicated that lymphoblastoid cell lines (LCL) with a BRCA1
      mutation are hypersensitive to the chromosome-damaging effects of gamma
      irradiation or hydrogen peroxide as revealed by the micronucleus test. We now
      investigated six LCL (three with and three without a BRCA1 mutation) in more
      detail, to see whether LCL represent a useful model for the investigation of
      mechanisms responsible for the known mutagen sensitivity of lymphocytes from
      women carrying a BRCA1 mutation. Our results show that there is no systematic
      difference in radiation sensitivity between LCL with and without a BRCA1
      mutation. Spontaneous and gamma radiation-induced micronucleus frequencies were
      in same range. Furthermore, cytotoxic effects (reduced cell proliferation,
      reduced viability) induced by gamma radiation were not different. The only
      difference found was an induction of micronuclei by 10 microM hydrogen peroxide
      in BRCA1 cell lines while a concentration of 20 microM hydrogen peroxide was
      necessary to induce micronuclei in control cells. Comet assay experiments did not
      reveal differences with regard to the induction and removal of primary DNA
      damage. Furthermore, expression of BRCA1 mRNA after gamma irradiation showed
      considerable variability and there was no clear difference between cell lines
      with and without BRCA mutation. These results indicate that LCL with a BRCA1
      mutation do not generally show the same mutagen sensitivity as lymphocytes with
      the same BRCA1 mutation. Therefore, the use of LCL to study the mechanisms
      underlying mutagen sensitivity due to a heterozygous BRCA1 mutation seems to be
      limited.

PMID- 12611460
TI  - Retrospective analysis of breast cancer among young African American females.
AB  - PURPOSE: To evaluate the patterns of failure, relapse-free survival and overall
      survival among African American breast cancer patients younger than 40 years.
      PATIENTS AND METHODS: We retrospectively reviewed the records of 124 African
      American breast cancer patients younger than 40 years who were registered with
      the Howard University Cancer Center Database between 1990 and 1999. One hundred
      and six patients were found eligible and subsequently included in this analysis.
      Ninety-eight percent of these patients were pre-menopausal and 30% had a
      documented family history of breast cancer. Patient distribution per stage is as
      follows: 19%, stage I; 61%, stage II; 16%, stage III and 4%, stage IV. Surgery
      was a component of treatment for 98% of the patients. Forty-six percent underwent
      mastectomy, 47% had breast-conserving surgery and 5% underwent biopsy only. Fifty
      nine percent of the patients received adjuvant radiation and 56% were also
      treated with adjuvant chemotherapy. Median follow-up was 35 months (range of 4
      126 months). RESULTS: Locoregional only first failure rate was 6% while systemic
      failure occurred in 20% of these patients. Among 17 stage III patients, 50%
      developed distant metastasis. The 5-year overall survival for these patients was
      73%, with relapse-free survival being numerically similar. Patients with early
      stage disease, stages I and II, were noted to have 5-year overall survival rates
      of 100 and 78-83%, respectively. Those who presented with stage III or stage IV
      disease had dismal 5-year overall survival rates of 25-29 and 0%, respectively.
      Multivariate analysis using the Cox proportional hazard model identified the
      presence of metastasis as a factor that significantly affects survival in these
      young African American females. CONCLUSION: These results show that African
      American females younger than 40 years with early stage breast cancer have local
      control and survival rates comparable to that of the general population. In
      contrast, young African American females in this study, with stages III and IV
      disease, appear to suffer a worse prognosis despite standard therapy. A larger
      series of young African American females with breast cancer, followed for a
      longer period of time, will be required to confirm a negative trend in survival.

PMID- 12611461
TI  - Reproductive factors, glutathione S-transferase M1 and T1 genetic polymorphism
      and breast cancer risk.
AB  - We conducted a hospital-based case-control study to evaluate the interactive
      effect of reproductive factors and glutathione S-transferase (GST) M1 and T1
      genetic polymorphisms in individual susceptibility to breast cancer. The study
      population consisted of 189 incident breast cancer cases and 189 age-matched
      controls with no known malignant diseases. GSTM1/T1 genotypes were determined by
      a multiplex polymerase chain reaction (PCR) method, and odds ratios (ORs) and 95%
      confidence intervals (CIs) were calculated by conditional logistic regression
      model. The parity factors were grouped as (1) high-risk status defined as
      nullipara or para with experience of first full-term pregnancy (FFTP) at or over
      30 years, and (2) low-risk status defined as para with experience of FFTP under
      30 years. A significant multiplicative interaction was observed between GSTM1 and
      GSTT1 null genotypes and high-risk status of parity factor in all women and in
      premenopausal women (P < or = 0.01), but not in postmenopausal women (P > 0.05).
      The interaction between the combined genotypes of GSTM1 and GSTT1 and status of
      parity factor was also significant in all women and in premenopausal women (P <
      0.01). Our findings suggest that genetic polymorphisms GSTM1/T1 could modify
      estrogen-related breast cancer risk.

PMID- 12611462
TI  - Expression of cell cycle regulatory proteins in breast carcinomas before and
      after preoperative chemotherapy.
AB  - Molecular markers predicting response to preoperative chemotherapy would be of
      major clinical relevance in breast cancer. Therefore, we studied the relationship
      between the expression of cell cycle regulatory proteins and clinical outcome in
      breast cancer patients receiving preoperative chemotherapy. Expression of
      p2lWaf1, p27KiP1, p53, cyclin D3 and Ki-67 was determined in breast carcinomas by
      means of immunohistochemistry both prior and after preoperative chemotherapy.
      Expression data were compared with both clinical parameters and response to
      preoperative chemotherapy with either cyclophosphamide/methotrexate/5
      fluorouracil (CMF, n = 29) or epirubicin/docetaxel (ED, n = 36). In paired
      samples before and after preoperative chemotherapy, the percentage of p21Waf1,
      p27Kip1, p53 and cyclin D3 positive nuclei of tumor cells in postchemotherapy
      specimens was significantly higher than the percentage in prechemotherapy samples
      but no change in Ki-67 expression was observed. High Ki-67 expression (p = 0.02),
      negative estrogen receptor status (p = 0.01) and negative progesterone receptor
      status (p = 0.04) were associated with complete pathologic response to
      chemotherapy, whereas the other markers did not predict response. In conclusion,
      expression levels of p21Waf1, p27Kip1, p53 and cyclin D3 significantly increased
      after preoperative chemotherapy in breast carcinomas but only high Ki-67
      expression, negative estrogen receptor status and negative progesterone receptor
      status were associated with complete pathologic response to preoperative
      chemotherapy.

PMID- 12611463
TI  - Estrogen receptors and distinct patterns of breast cancer relapse.
AB  - BACKGROUND: We conducted an analysis of prospectively collected data to compare
      the clinical behavior of ER-negative versus ER-positive tumors with respect to
      rates and sites of recurrence. METHODS: A total of 647 patients with operable
      stage II or III breast cancer were enrolled in two consecutive adjuvant therapy
      protocols conducted between 1980 and 1986. The correlations between ER status and
      time to first recurrence, site of first recurrence, and time to breast cancer
      death were assessed on 558 (86%) patients with available ER status data using
      hazard function and hazard ratio function analysis. RESULTS: The rates of
      recurrence were significantly higher in patients with ER-negative status for the
      first two years of follow-up, but not thereafter. Similar results were observed
      for breast cancer death, and these results held up after adjustment for
      differences in treatment, age, menopausal status, and tumor burden. When the site
      of first recurrence was studied, ER-negative status was associated with a
      significantly higher rate of tumor recurrence in the viscera and soft tissues,
      while ER-positive status was associated with significantly higher rates of tumor
      recurrence involving bone. CONCLUSIONS: The clinical behavior of ER-positive
      tumors is different from ER-negative cancer. ER status had a pronounced effect on
      the rates and sites of recurrence. Furthermore, this apparent association
      diminished over the follow-up period. Recurrence rates were significantly higher
      in patients with ER-negative status for the first two years of follow-up, but not
      thereafter.

PMID- 12611464
TI  - The modified firefly luciferase reporter gene (luc+) but not Renilla luciferase
      is induced by all-trans retinoic acid in MCF-7 breast cancer cells.
AB  - Luciferase genes are widely used as reporters to analyze promoter and regulatory
      elements. We found that a luciferase reporter gene vector with a modified firefly
      luciferase gene (luc+), but not Renilla luciferase (Rluc), was induced by all
      trans retinoic acid (tRA) in the MCF-7 breast cancer cell line. tRA (5 x 10(-6)
      M) increased luciferase activity of the pGL3 promoter vector (containing luc+) up
      to approximately 3.8-fold in MCF-7 cells, but not in LNCaP prostate cancer cells
      or JEG-3 choriocarcinoma cells. Chimeric plasmids were constructed and showed
      that tRA-induction required the luc+ gene, but not any specific promoter or
      vector sequence. Time course and dose-response studies of tRA-induction indicated
      that longer treatment (> 24h) and higher tRA dose (> 10(-6) M) were required for
      luc+ induction compared with those for a positive retinoic acid response element
      (maximum induction at 6 h and 10(-8) M tRA). Studies with the translation
      inhibitor, cycloheximide, indicated the half-life of the luc+ protein was
      increased from 9.7 +/- 1.5 to 22.1 +/- 3.1 h with tRA treatment. Other retinoids,
      TTNPB, a retinoic acid receptor beta/gamma-specific ligand, and a retinoid X
      receptor ligand, did not significantly increase luc+ expression. Caution is
      needed in analysis of retinoid responsive gene regulation with the luciferase
      reporter system in MCF-7 cells, especially at high retinoid concentrations.

PMID- 12611465
TI  - Consensus statement: Expedition Inspiration fund for breast cancer research
      meeting 2002.

PMID- 12611466
TI  - Mutational analysis of estrogen receptor-beta gene in human breast cancers.

PMID- 12611467
TI  - Environmental endocrine disrupting chemicals.

PMID- 12611468
TI  - Environmental estrogens: roles in male reproductive tract problems and in breast
      cancer.
AB  - It has been hypothesized that endocrine disruptors and particularly synthetic
      estrogenic environmental contaminants (xenoestrogens) are etiologic factors in
      the global decrease of sperm counts and other problems of the male reproductive
      tract, including cryptorchidism, hypospadias, and testicular cancer.
      Xenoestrogens might also be linked to an increased incidence of breast cancer in
      women. These hypotheses have stimulated research addressing the current incidence
      rates and time-dependent changes in these human health problems, and the results
      do not support the hypotheses. With the exception of testicular cancer, the
      evidence does not indicate that sperm counts and other male reproductive tract
      problems are increasing, and correlations with xenoestrogen exposure have not
      been made. Moreover, initial observations that the level of certain
      organochlorine pollutants is higher in breast cancer patients vs. controls have
      not been duplicated in more recent studies. The results do not preclude an
      environmental eitology to some of these health problems or to susceptible
      subpopulations, and these areas require further research and critical scrutiny.

PMID- 12611469
TI  - Environmental exposure to polychlorinated biphenyls and breast cancer risk.
AB  - Breast cancer is a major public health problem in the United States and in most
      industrialized countries. Although epidemiologic studies have identified a number
      of established risk factors for this disease, these factors explain only a small
      proportion of breast cancer incidence. Environmental exposure has been implicated
      in breast cancer etiology because of the vast geographic variation in breast
      cancer incidence rates across countries and regions within countries. Further,
      the steady increase in breast cancer rates over the past decades points to a
      potential role of environmental exposure in its development. One suspected
      environmental factor is the polychlorinated biphenyls (PCBs), which were
      manufactured commercially for a variety of industrial applications from the 1930s
      until the 1970s. PCBs have been associated with estrogenic, tumor promoting, and
      immunosuppressive activities, all of which are relevant in the development of
      breast cancer. The purpose of this review is to summarize the growing body of
      epidemiological evidence on the association between environmental PCB exposure
      and breast cancer risk. Three major types of study design have been used to
      investigate such a relation: clinic-based case-control studies, retrospective
      case-control studies, and nested case-control studies. Although findings from
      clinic-based case-control studies tend to point to an adverse effect of high PCB
      body burden on risk, the results from the more methodologically sound
      retrospective and nested studies do not provide strong support for a role of PCBs
      in breast cancer development. The association between PCB exposure and risk among
      racially and genetically susceptible subgroups may warrant further investigation.
      Methodological challenges in the design and analysis of epidemiologic studies on
      PCBs and breast cancer risk are discussed.

PMID- 12611470
TI  - 1,4-Dichlorobenzene-Induced liver tumors in the mouse: evaluation of the role of
      chlorohydroquinones.
AB  - 1,4-Dichlorobenzene (1,4-DCB) is a wide-spread environmental contaminant and well
      described hepatotoxicant for rats and mice. The prolonged oral or inhalation
      exposure to 1,4-DCB is associated with an increased frequency of hepatic tumors
      in mice, but not in rats. Evidence is lacking of direct genotoxicity with 1,4-DCB
      or its metabolites, and no generally accepted mechanism has been found to account
      for the increased numbers of 1,4-DCB-induced hepatic tumors in mice. No
      information is available on the carcinogenic effects of 1,4-DCB in humans. Here
      we consider evidence that the biotransformation of 1,4-DCB to substituted
      hydroquinone species contributes to hepatic adenoma and carcinoma formation in
      mouse liver. This phenomenon has implications for human carcinogenesis.

PMID- 12611471
TI  - Phytoremediation of selenium-contaminated soils and waters: fundamentals and
      future prospects.
AB  - Interest in selenium pollution and remediation technology has escalated during
      the past two decades. Although not known to be essential for plants, selenium is
      an essential micronutrient for humans and animals, having important benefits for
      their nutrition. At high concentrations, however, selenium becomes toxic to
      animals and humans. A major selenium controversy in the 1980s emerged in
      California at the Kesterson National Wildlife Refuge; hence, scientists,
      environmental regulators, politicians, and the general public in the United
      States became aware of selenium's potential as an environmental contaminant.
      Consequently, extensive research has been conducted in the western United States,
      and a vast amount of financial resources have been allocated to develop
      management strategies and remediation technologies for reducing the impact of
      naturally occurring selenium on the biological environment. A plant-based
      technology, defined as 'phytoremediation', has received increasing recognition as
      a low-cost, environmentally friendly approach for managing the toxic effects of
      selenium. Plants have the ability to absorb and sequester selenium and to convert
      inorganic selenium to volatile forms of organic compounds that are released
      harmlessly into the atmosphere. The present review summarizes recent research
      findings and information about strategies on using phytoremediation systems to
      detoxify selenium-contaminated soils and waters in natural and agricultural
      ecosystems.

PMID- 12611472
TI  - Environmental risk factors for rheumatoid arthritis.
AB  - In this review we examine the association between rheumatoid arthritis (RA) and
      exposure to silica and other environmental toxicants. We performed a series of
      meta-analyses of peer-reviewed studies, using 10 studies for silica, and 5
      studies for other exposures published between 1986 and 2001. Before the meta
      analyses, all studies were reviewed and evaluated for heterogeneity and
      publication bias. We detected a significant heterogeneity among studies on silica
      and calculated a combined estimator of relative risk (RR), using the random
      effect model. Most studies reported consistent elevation in the risk of RA with
      exposure to silica. The combined RR for silica exposure was 3.43 195% confidence
      interval (95% CI) 2.25-5.22] for all studies, and 4.45 (95% CI 2.24-8.86) for
      male cohorts. The combined RR for male farmers was 1.40 [95% CI 1.18-1.66] and
      was 1.29 [95% CI 0.84-1.97] for pesticide exposure. The combined RR for hair
      dressers was 1.52 [95% CI 1.04-2.20]. The findings of this study suggest a
      significant elevation in the risk of RA from exposure to silica. Further studies
      assessing the dose-response effect would greatly aid in determining whether the
      observed association is causal.

PMID- 12611473
TI  - Echocardiography and Doppler sonography in the evaluation of cardiac structure
      and function.
AB  - Physical activity increases the work load of the heart. The adjustments of the
      heart depend on the quality and quantity of the work performed. These adjustments
      concern the function and the morphology of the cardiovascular system. It is
      important to underline that these adjustments are not permanent and can disappear
      when physical activity is stopped. In young subjects the risks are very few while
      the benefits may be shown on a better and more armonic body structure. In the
      elderly the benefits can be achieved with a lesser cost for submaximal
      activities, but the risks are of course more frequent due the possible onset of
      cardiovascular disease. It is important to correctly recognize the limits whitin
      which the physical activity can be allowed because beneficial. Echocardiography
      has given an important contribution to evaluate the morpho-functional adaptions
      of the athlete's heart. Similarly, it has proven useful in the detection of
      pathological cardiovascular modifications, asymptomatic or pausymptomatic, that
      do not allow certification to practise sport at agonistic levels.

PMID- 12611474
TI  - Anthropometrical analysis of the hand as a Repetitive Strain Injury (RSI)
      predictive method in pianists.
AB  - In the present work we have studied the anthropometrical characteristics of the
      pianists hands to predict their potential vulnerability to suffer from Repetitive
      Strain Injury (RSI). To get this goal we studied the size and morphotype of the
      hands of pianists affected by RSI. Firstly we observed that 222 individuals from
      341 studied pianists (65.1% of the total) presented RSI. Secondly we appreciated
      that affected hands were mostly small sized (60% of the affected hands) and
      classifiable in a distinct morphotype named B (68% of the affected hands). This
      fact suggest they both were the most vulnerable to RSI. Finally we may conclude
      anthropometrical analysis of pianists hands may be used to reduce the high
      incidence of this illness given that it may predict performers potential
      vulnerability to RSI. It also has to be remarked that further studies in this
      knowledge field are required to reduce the incidence of playing-related medical
      problems in general, and RSI in particular, in pianist population.

PMID- 12611475
TI  - Histomorphometrical and comparative analysis of three muscles of buffalo (Bubalus
      bubalis L.).
AB  - Three muscles were analyzed, Longissimus dorsi, Semimembranosus and Caput longum
      Tricipitis brachii taken from nine cow buffaloes, by examining the histochemical
      and morphometrical characteristics of different muscle fibres types and their
      distribution inside the examined muscles. Cross sectional area, perimeter,
      maximum and minimum diameter of about 200 fibres were measured for each muscle,
      and fast-twitch glycolytic fibres (FG), fast-twitch oxidative-glycolytic fibres
      (FOG), slow-twitch oxidative fibres (SO) were histochemically differentiated. The
      data have been elaborated with the SPSS software. The variance analysis indicates
      that there are not significant differences about dimensions between FG and FOG
      fibres, while the average values of transversal section area and perimeter are
      greater than the oxidative fibres in all examined muscles. The Semimembranosus
      muscle in comparison to the Longissimus dorsi and to the Caput longum Tricipitis
      brachii muscles has muscle fibres with the smallest value of transversal section
      area and perimeter. The balanced distribution and intense myofibrillar adenosine
      triphosphatose and succinic dehydrogenase activities of the three fibres types in
      Caput longum Tricipitis brachii muscle can be justified by the function performed
      by this muscle which, together with the other heads of the Triceps brachii acts
      essentially as extensor of the forearm in fact, differences in the dimensions of
      the different fibre types inside the three examined muscles have been underlined;
      this fact can be justified for every muscle performs different motor functions.

PMID- 12611477
TI  - Human mucosal epithelium involvement in prenatal growth of maxillary sinuses.
AB  - The mechanism of formation of the maxillary sinuses is not elucidated as yet,
      although their morphology during embryogenesis is well described. In the prenatal
      period, the pneumatization hypothesis is not valid. As the molecular approach to
      this problem is difficult to apply to human samples, we decided to apply
      immunohistochemical reactions to analyse the synthesis of selected molecules
      involved in the rebuilding of tissues. Hematoxylin-eosin staining and
      immunohistochemical reactions for the detection of MMPs (matrix
      metalloproteinases), one of their inhibitor TIMP 1 (tissue inhibitor of MMPs),
      BMP 6 (bone morphogenetic protein 6) and TGF-beta (transforming growth factor
      beta) were performed in the epithelium the mucosa of the maxillary sinuses of
      several human foetuses from the collection of the Anatomical Institute. The age
      of the foetuses was 8, 11, 15, 16, 17, 18 and 22 weeks. An intense positive
      reaction for MMPs 1, 2 and 3 was found in the mucosal epithehum of developing
      sinuses in the whole series of foetuses was found. The reaction was more intense
      in advanced stages of foetal development. Tissue derived inhibitor TIMP was
      hardly detectable, regardless of the age of samples. However, the intensity of
      the reaction for TGFbeta was strong in both young and more mature sinus
      epithelium. The presence of BMP 6, a member of the superfamily of TGFbeta, was
      detected although the intensity of this reaction in the epithelium was rather
      weak. Both TGFbeta and BMP 6 are well known as regulators of differentiation in
      the course of organogenesis. Results of the histochemical analysis suggest the
      possible involvement of the epithelium in the growth and formation of the
      maxillary sinuses. The main argument for this is intense reaction for MMP
      proteases which, as in bone, regulate the turnover and rebuilding processes of
      the extracellular matrix (ECM).

PMID- 12611476
TI  - Early events of experimental exposure to amorphous and crystalline silica in the
      rat: time course of surfactant protein D.
AB  - Pneumoconioses determined by chronic inhalation of different kinds of silica
      present with peculiar clinical and histopathological features. Silicosis, caused
      by crystalline silica, is characterized by typical fibrous parenchymal nodules.
      Less defined are pneumoconioses due to amorphous silica. Aim of current
      experimental research on silicosis is to investigate the early events that lead
      to nodular fibrosis of the lung. A secretory component of the pulmonary
      environment, surfactant, seems to be involved in silica toxicity; surfactant
      protein D is a protein constituent, apparently involved in the homeostasis of the
      phospholipid component. We studied the behaviour of SP-D 2, 12 and 24 hours after
      treatment with 200 mg/kg crystalline silica or pumice powder suspended in 400
      microl/kg saline solution and instiled intratracheally to rats. Both
      immunohistochemical localization and immunoblotting quantification demonstrated a
      sensible increase in intracellular SP-D, localized in alveolar type II cells and
      some bronchiolar epithelial cells, 2 hours after treatment. Increment appears
      less marked 12 hours after administration, reaching again levels comparable to
      control at 24 hours. The behaviour of SP-D after pumice instilation is similar,
      but with a significantly minor increment at 2 hours. These results indicate
      crystalline silica as responsible for a stronger acute injury of pulmonary
      tissue.

PMID- 12611479
TI  - Alternative views of tissue stem cell plasticity.
AB  - Stem cells have traditionally been characterized as either embryonic
      (pluripotent) or tissue-specific (multipotent). Thus, tissue-specific stem cells
      generate the cell types comprising a particular tissue in embryos and, in some
      cases, adults. A recent series of studies, however, has challenged the notion of
      lineage restriction in multipotent stem cells. These experiments have been
      interpreted as evidence that stem cells from one tissue can be induced to
      differentiate into cells of other organs, either in vitro or after
      transplantation in vivo. This paper reviews the current evidence for stem cell
      plasticity. Some of the potential caveats to the current work are also discussed
      and, finally, the potential underlying mechanisms of stem cell plasticity are
      examined.

PMID- 12611478
TI  - Gait analysis in young sedentary and sports subjects.

PMID- 12611480
TI  - Functional significance of genetic abnormalities in multiple myeloma.
AB  - Multiple myeloma (MM) is a B-cell neoplasm characterized by infiltration of the
      bone marrow with malignant plasma cells, synthesizing and secreting monoclonal
      immunoglobulin fragments. The malignant transformation of this terminally
      differentiated plasma cell is the result of a multistep transformation process.
      In spite of recent advances in this field, the cause and the exact molecular
      genetic basis of MM remain obscure. In this review, an attempt has been made to
      summarize the genetic alterations having functional significance in the
      generation and progression of MM, and also the existing relationship between
      genetic abnormalities and chemosensitivity, as well as the typical genetic
      alterations in various MM subgroups. Factors known to have a role in the
      conversion of monoclonal gammopathy of unknown significance (MGUS) to MM are also
      reviewed.

PMID- 12611481
TI  - The prognostic role of CD5 negativity in B-cell chronic lymphocytic leukaemia: a
      case-control study.
AB  - B cells in chronic lymphocytic leukaemia (CLL) usually express the CD5 antigen,
      which appears to participate in the pathogenesis of autoimmune phenomena.
      However, 7-20% of B-CLL patients are CD5-. The aim of this study was to assess
      whether CD5 expression could be used as a discriminating factor for two subgroups
      of B-CLL. Twenty-nine CD5- B-CLL patients were compared in terms of clinico
      biological characteristics and survival with a control group of 29 sex- and age
      matched, consecutive CD5+ B-CLL subjects. B-CLL was considered to be CD5- when
      less than 5% of mononuclear cells expressed CD5 after subtraction of the number
      of T cells. Splenomegaly, lymph node involvement, and haemolytic anemia were
      found in CD5+ patients in a significantly higher proportion than in their CD5-
      counterparts, who presented with an earlier stage of disease. CD5- patients had a
      median survival of 97.2 (22-130) months, exceeding CD5+ subjects significantly
      [84.0 (19-120) months, p = 0.0025]. CD5- patients seemingly present with milder
      disease and have a favourable prognosis compared with the vast majority of B-CLL
      patients who express CD5.

PMID- 12611482
TI  - Serum homocysteine level in Behcet's disease.
AB  - Recent studies of the prevalence of hyperhomocysteinemia in Behcet's disease have
      shown contradicting results. The aim of the present study was to investigate the
      serum homocysteine level in patients diagnosed as having Behcet's disease. Venous
      blood was taken from 27 patients with Behcet's disease and 21 healthy controls.
      Serum homocysteine levels were measured using fluorescence polarization
      immunoassay. In addition, serum vitamin B12 and folic acid levels were measured
      by chemiluminescent enzyme immunoassay. The mean levels of vitamin B12, folic
      acid, and homocysteine were not significantly different in patients with Behcet's
      disease when compared with the healthy controls (p = 0.17, p = 0.13, and p =
      0.05, respectively). The results of this study confirmed that homocysteine levels
      were not elevated in Behcet's disease when compared with the control group.
      Further studies in a subset of Behcet patients with a history of thrombosis are
      needed to determine the prevalence of hyperhomocysteinemia in the thrombotic form
      of the disease.

PMID- 12611483
TI  - Diagnostic significance of serum soluble transferrin receptors in various anemic
      diseases: the first multi-institutional joint study in Japan.
AB  - Serum soluble transferrin receptor (sTfR) has been reported to be higher in
      patients with iron deficiency or with elevated erythropoiesis. In the present
      study, serum sTfR was measured in various anemic diseases and their clinical
      significance was examined in a multi-institutional joint study. Serum sTfRs in
      patients with the following anemic diseases were markedly higher than those in
      normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04
      mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l,
      n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p <
      0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p <
      0.0001). There were significant differences between IDA and ACD (p < 0.0001),
      between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001),
      and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n =
      9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels
      and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two
      classified groups according to Muirhead's criteria, as IDA and non-IDA groups
      with or without recombinant human erythropoietin (rHuEPO) treatment.
      Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p
      < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with
      rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p <
      0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy
      of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration
      is a useful diagnostic tool for discrimination between IDA and ACD, and between
      AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the
      Japanese population.

PMID- 12611484
TI  - The involvement of the Na(+)/H(+) exchanger in the formation of microvesicles by
      porcine platelets.
AB  - Activated platelets release microvesicles, which express procoagulant activity.
      The mechanism by which vesicles are formed is not entirely clear. This study was
      undertaken to determine whether a link exists between the operation of the plasma
      membrane Na(+)/H(+) exchanger (NHE) and vesiculation. It was found, that
      platelets treated with NHE-simulating monensin and the sodium influx-inducing
      gramicidin (without concomitant H+ efflux) produced vesicles demonstrating
      procoagulant activity. Alkalinization of platelet cytosol by NH4Cl failed to
      evoke vesicle release. Collagen and phorbol ester (PMA)-evoked vesiculation was
      diminished in the presence of 5-(N-ethyl-N-isopropyl amiloride) (EIPA, inhibitor
      of NHE) or GF 109203X (inhibitor of protein kinase C). Vesicle formation induced
      by collagen, PMA, and the calcium ionophore A23187 was less pronounced in the
      absence of external Na+. In comparison with collagen, thrombin was a stronger
      inducer of vesiculation. Platelets stimulated by thrombin, collagen, and PMA
      accumulated 22Na+, a phenomenon inhibited in the presence of EIPA. Collagen
      evoked vesicle formation started with aggregation but culminated after its
      completion. The data indicate a significant contribution of the Na(+)/H(+)
      exchanger in the formation of microvesicles by porcine platelets.

PMID- 12611486
TI  - Telomere length analysis on cord blood cells by the flow-FISH method.
AB  - Telomerase is the enzyme responsible for synthesizing telomeric repeats at the
      ends of chromosomes to maintain telomere length. Recent studies have suggested
      that telomere shortening may serve as a surrogate marker of the progression of
      malignant disorders and seems to be accelerated in allogeneic bone marrow
      transplant recipients. In this study, the results of the telomere length of nine
      cord blood mononuclear cell samples are presented. Telomere length was measured
      by the flow-FISH method, using a peptide nucleic acid probe. The proportion of
      cord blood cell subsets (CD19/CD34/CD3) was also evaluated. The telomere length
      of the internal control 1301 cell line was estimated to be 100%. The mean
      telomere length of cord blood cells was 18.5 +/- 3.9%, compared with the internal
      control. The progenitor CD34+ cells were detected as 2.6 +/- 0.7% in the lymphoid
      gate measured. Linear correlation analysis did not find any connection between
      the cell subsets (CD3+, CD34+, CD19+) and the telomere length. The findings
      confirm that the telomere flow-FISH method is sufficient for estimation of the
      telomere length. Assessment of the current procedures of collection,
      manipulation, and ex vivo expansion of cord blood cells in terms of their effect
      on telomere shortening might be important.

PMID- 12611485
TI  - Changes in immunological recovery in patients who received post-transplant G-CSF
      or GM-CSF after autologous peripheral blood stem cell transplantation (PBSCT).
AB  - In this prospective study, the effects of granulocyte colony-stimulating factor
      (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on
      immunological reconstitution after autologous peripheral blood stem cell
      transplantation (PBSCT) were investigated for 6 months. Thirty-five patients
      received G-CSF 5 microg/kg per day and 26 patients received GM-CSF SC 5 microg/kg
      per day from day 1 to leukocyte engraftment (>1000 per mm3). Peripheral blood
      samples were obtained on 14, 28, 100, and 180 days after transplantation for
      immunological evaluation. CD3+, CD4+, CD8+, CD19+, and CD56+ cells were analysed
      by flow cytometry. Immunoglobulin levels (IgG, IgA, and IgM) and complement
      levels (C3c and C4) were measured by nephelometry. Both G-CSF and GM-CSF groups
      were comparable with respect to age, sex, the period from diagnosis to
      transplantation, total nucleated cells infused, the number of CD34+ cells,
      conditioning regimens (TBI and non-TBI), and post-transplant infection. CD3+ and
      CD8+ cells on day 14 following autologous PBSCT + G-CSF were significantly higher
      than following autologous PBSCT + GM-CSF (p = 0.008 and p = 0.021, respectively).
      The number of CD4 cells and the CD4/CD8 ratio were not different at several time
      points between the two groups. CD19+, CD56+ cells and immunoglobulin levels
      showed a faster recovery pattern in the autologous PBSCT + G-CSF group. The
      effect of G-CSF on immune reconstitution after autologous PBSCT is more prominent
      than that of GM-CSF. The possible role of haematopoietic growth factor on immune
      recovery and its clinical importance should be investigated in further studies.

PMID- 12611487
TI  - Gaucher disease type I complicated with Parkinson's syndrome.
AB  - Gaucher disease type I is the so-called non-neuronal adult form of the
      autosomally inherited lysosomal storage disease. The simultaneous occurrence of
      Gaucher disease with Parkinson's syndrome has been reported to aggravate both
      disorders, leading to an unusually early onset and therapy resistance.
      Neurological alterations in Gaucher disease type I are mostly related to CNS
      bleeding and skeletal complications. The patient presented here was sensitive to
      combination therapy for 5 years.

PMID- 12611488
TI  - Severe thrombocytopenia as a presenting symptom of hepatitis C virus infection.

PMID- 12611489
TI  - High-dose verapamil + trandolapril-induced thrombotic microangiopathy.
AB  - Thrombotic microangiopathy (TMA) is a syndrome characterized by microangiopathic
      haemolytic anaemia, thrombocytopenia, and several variable signs of organ damage
      due to the platelet thrombi in the microcirculation. This article reports a case
      with TMA which developed after ingestion of a high-dose combination of verapamil
      and trandolapril. To the authors' knowledge, no prior cases of TMA induced by
      trandolapril (an angiotensin-converting enzyme inhibitor) and verapamil (a
      calcium channel blocker) have been reported in the literature.

PMID- 12611490
TI  - Facial paresis after fludarabine treatment for advanced chronic lymphocytic
      leukaemia.
AB  - This case report discusses a case with advanced-stage chronic lymphocytic
      leukaemia (CLL) that presented with facial paresis after fludarabine treatment. A
      68-year old patient with CLL (Rai classification, stage IV) was admitted to
      Gulhane Military Medical Academy for treatment. Fludarabine, 30 mg/m2 daily for 5
      days, was given. Right facial paresis was observed at day 8 after administration
      of fludarabine. The general and psychiatric condition of the patient in
      myelosuppression did not permit aetiological investigation for paresis.
      Thereafter, the patient died due to septic shock. Possible aetiological reasons
      why the patient being treated for advanced-stage CLL had facial paresis after the
      administration of fludarabine ended are discussed.

PMID- 12611491
TI  - Effect of prostaglandin F2alpha on gonadal carbohydrate metabolism of silkworm,
      Bombyx mori L.
AB  - Effect of prostaglandin F2alpha (PGF2alpha) on carbohydrate accumulation in
      gonads of the multivoltine silkworm (hybrid: Xinhang x Keming) has been studied
      by means of topical application to larvae of the silkworm. Increased weights of
      larvae and reproduction organs, as well as carbohydrate metabolism in gonads of
      the silkworm, Bombyx mori L. was found after treatment with prostaglandin
      F2alpha. The increase in weight (larvae 21.9%, testis 28.9%, and ovary 33.3%) was
      associated with increases in the biomolecules (20-30%) and LDH and aldolase
      activity (18-25%). The results suggest that the accumulation of carbohydrates
      denotes a higher extent of utility of the energy sources in function of the
      testes and ovaries, and the routine application of prostaglandin F2alpha would be
      helpful in improving the reproductivity and egg quality of the silkworm.

PMID- 12611492
TI  - Prostaglandin D2 synthase enzymes and PPARgamma are co-expressed in mouse 3T3-L1
      adipocytes and human tissues.
AB  - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a critical
      regulator of adipocyte differentiation. Whilst 15-deoxy-delta(12,14)
      prostaglandin J2 (15-d-PGJ2) has been identified as a putative endogenous ligand
      for this transcription factor, it is unclear whether the enzymes necessary for 15
      d-PGJ2 biosynthesis are co-expressed with PPARgamma. Prostaglandin D2 synthase
      (PGDS) enzymes represent the terminal enzymatic components responsible for 15-d
      PGJ2 production. Both glutathione (GSH)-dependent and GSH-independent PGDS
      isoenzymes exist. We have, therefore, examined the expression of PGDS isoenzymes
      in mouse 3T3-L1 adipocytes, and various human tissues. The GSH-independent PGDS
      was found to be expressed in 3T3-L1 cells both before and after their
      differentiation into adipocytes. By contrast, we were unable to detect expression
      of the GSH-dependent PGDS at any stage during the adipose conversion of 3T3-L1
      cells. Quantitative analysis of mRNA levels for PPARgamma and each PGDS isoenzyme
      revealed their co-expression in a number of human tissues and cell types,
      including adipose tissue, placenta, prostate, and macrophages. These data reveal
      the potential for de novo 15-d-PGJ2 synthesis in the context of PPARgamma
      expression, suggesting that this prostaglandin may contribute to PPARgamma
      signalling in vivo.

PMID- 12611493
TI  - Concentrations of endogenous prostaglandin F2alpha in boar semen and effect of a
      72-h incubation period on exogenous prostaglandin F2alpha concentration in
      extended boar semen.
AB  - PGF2alpha in semen has been shown to induce uterine contractions, thereby,
      facilitating sperm transport during fertilization. Previously, we demonstrated
      that extended boar semen used in artificial insemination does not increase
      myometrial contractility, but PGF2alpha supplementation did. In this study, we
      determined the concentrations of endogenous PGF2alpha in pre-sperm and sperm-rich
      fractions of the boar ejaculate and examined whether changes in the concentration
      of exogenous PGF2alpha occurred when added to extended boar semen after 72-h
      incubation at a 17 degrees C storage temperature. Concentrations of endogenous
      PGF2alpha (n = 10 boars) in pre-sperm and sperm-rich fractions were 69.6 +/- 7.6
      and 58.9 +/- 4.4 pg/ml, respectively. No differences were observed in the
      concentrations of exogenous PGF2alpha in the extended boar semen at 0 h (59.3 +/-
      3.3 microg/ml) and after a 72-h incubation period (52.0 +/- 2.1 microg/ml). These
      results suggest that the concentration of endogenous PGF2alpha in boar semen used
      for artificial insemination is < 100 pg/ml. The concentration of exogenous
      PGF2alpha in the extended boar semen did not differ after 72 h, which indicates
      that it is not metabolized during this period of time.

PMID- 12611494
TI  - Effect of hCG injection on prostaglandin E concentrations in ram seminal plasma.
AB  - Ram and bull seminal plasma, respectively, contain 0.5-20 microg PGE/ml and 5-10
      ng PGE/ml. To demonstrate that PGE concentrations in the seminal plasma are
      related to sperm quality and could be affected by hormonal stimulation in vivo,
      four rams were injected with 500 IU hCG, in and out of season. The rams responded
      1 week after hCG with a 1.5- to 4-fold increase in seminal plasma PGE. The PGE
      peak was temporally separate from the hCG-induced rise in seminal plasma
      testosterone which was observed after 1 day. Using a simulated cryptochid ram,
      peaks in seminal fluid PGE were found to be associated with increased sperm
      velocity and sperm counts. In bulls, PGE concentrations in the seminal plasma of
      good bulls were significantly higher than that found in poor and cryptorchid
      bulls.

PMID- 12611496
TI  - In vitro response of prostaglandin E2 receptor (EP3) in the term pregnant rat
      uterus and cervix to misoprostol.
AB  - We examined and compared the in vitro effects of misoprostol (synthetic
      prostaglandin E1 (PGE1) analogue) on prostaglandin E2 (PGE2) secretion and EP3
      receptor mRNA expression in the pregnant rat myometrium and cervix at 19 days
      gestation. Myometrial and cervical tissue samples were exposed to media with or
      without misoprostol (50 or 100 pg/ml) and incubated for 15 and 30 min, and 1, 3,
      6, 12, and 24 h. Media and tissue samples were collected for quantification of
      PGE2 and mRNA expression of rEP3alpha and rEP3beta receptor, respectively. PGE2
      secretion increased (P < or = 0.05) in the myometrium exposed to 50 and 100 pg/ml
      misoprostol. Cervical PGE2 secretion increased following exposure to the 100
      pg/ml dose only. In the myometrium, 50 and 100 pg/ml misoprostol induced
      elevations in rEP3alpha and rEP3beta receptor mRNA expression. rEP3alpha and
      rEP3beta receptor mRNA expression in the cervix was not different from controls.
      These data demonstrate that the EP3 receptor is differentially expressed in the
      myometrium and cervix in response to misoprostol. This may account for the
      ability of misoprostol to stimulate the myometrium when administered for cervical
      ripening.

PMID- 12611495
TI  - Antenatal administration of celecoxib, a selective cyclooxygenase (COX)-2
      inhibitor, appears to improve placental perfusion in the pregnant rabbit.
AB  - To investigate the effects of celecoxib on fetal growth, and placental prostanoid
      and nitric oxide (NO) production in fetal rabbits, pregnant rabbits received
      celecoxib (30 mg/kg per day) from 13 to 20 days (Cel-A), from 13 to 28 days (Cel
      B), or vehicle from 13 to 28 days gestation. Fetal body and organ weights, and
      measurements of linear growth were recorded. The placentas were weighed and
      analyzed for prostaglandins (PGs), NO oxidation products (NOx), and total
      cellular protein levels. Placental prostaglandin E2 (PGE2) and NOx levels
      increased (P < or = 0.05), while thromboxane B2 levels were suppressed (P < or =
      0.01) in Cel-B group. Tail length and brain weight were greater, while lung
      weights were lower in the Cel-B group (P < or = 0.05). Maternal administration of
      celecoxib appears to preferentially increase placental vasodilators and decrease
      placental TxA2, suggesting that the drug may increase uteroplacental perfusion
      without adverse fetal outcome.

PMID- 12611497
TI  - Changes in growth and lipid profiles of silk gland, mid-gut biochemical
      composition of silkworm, Bombyx mori L. on exposure to prostaglandin F2alpha.
AB  - The growth of the silkworm is influenced by the outside and inside environment.
      Among them, the category of various endocrine hormone of inside is the main
      factors that adjust the characters such as growth and propagate. In this
      experiment, we applied different dosage of prostaglandin to the fourth and fifth
      instar silkworm to observe the effects of prostaglandin F2alpha (PGF2alpha) on
      silk gland growth, mid-gut biochemical constituents and the lipid profiles of
      silkworm larva, Bombyx mori L. The weight of the posterior silk gland increased
      significantly (P < 0.001) by 20-24% after treatment with PGF2alpha. The increase
      in the lipid profiles except lipase activity suggests that the silk gland had
      more synthetic activity that might reflect in active spinning of silkworm larva.
      The changes of total proteins, free amino acids and alkaline phosphatase in mid
      gut of control and PGF2alpha treated silkworm, B. mori L. indicate that PGF2alpha
      favored stimulatory effect on physiology of digestion, absorption and
      transportation of nutrients which might influence on the growth and development
      of larva.

PMID- 12611498
TI  - Changes in prostaglandin secretion by the regressing bovine corpus luteum.
AB  - Secretion of prostaglandins (PGs) by the regressing corpus luteum (CL) was
      investigated in the cow. Six cows were implanted with microcapillary dialysis
      membranes of a microdialysis system (MDS) into the CL during Days 8-9 (Day 0 =
      estrus), and a prostaglandin (PG) F2alpha analogue (Estrumate) was injected
      intramuscularly (i.m.) to induce luteolysis. Acute increases in intraluteal
      release of PGF2alpha and PGE2 were observed during the first 4 h, followed by
      decreases over the next 8 h. Intraluteal release of both PGs gradually increased
      again during the period 48-72 h. Concentrations of PGF2alpha in ovarian venous
      plasma (OVP) were 4-13 times higher than those of jugular venous plasma (JVP) (P
      < 0.001) during the period of the experiment, and increased from 24 h after
      treatment with Estrumate (P < 0.05). Cyclooxygenase (COX)-2 mRNA expression
      increased (P < 0.05) at 2 and 24 h after treatment with Estrumate. The results
      indicated that local release of PGF2alpha and PGE2, and COX-2 mRNA expression
      were increased by Estrumate in the regressing CL at the later stages of
      luteolysis. Thus, luteal secretion of PGs may be involved in the local mechanism
      for structural rather than functional luteolysis.

PMID- 12611499
TI  - Role of prostaglandin E2 in basal and noradrenaline-induced progesterone
      secretion by the bovine corpus luteum.
AB  - The role of prostaglandin E2 (PGE2) in basal and noradrenaline (NA)-stimulated
      utilization of high density lipoprotein (HDL) as a source of cholesterol for
      progesterone synthesis was examined. In Experiment 1, a cannula was inserted into
      the aorta abdominalis through the coccygeal artery (cranial to the origin of the
      ovarian artery) in mature heifers, to facilitate infusion of NA (4 mg/30 min; n =
      3) on day 10 of the estrous cycle. Three other heifers were similarly cannulated
      to serve as control. Before, during, and after NA or saline infusion, blood
      samples from the vena cava were collected every 5-15 min for analysis of PGE2,
      progesterone, and cholesterol. Each NA infusion stimulated (P < 0.01) secretion
      of both hormones in heifers. Short-duration increases (P < 0.05) in progesterone
      were observed due to the infusion of NA while cholesterol was not altered
      significantly. In addition, increases in PGE2 concentrations (P < 0.05) compared
      to controls were seen after NA infusion. Therefore, we used an in vitro model to
      verify the effect of PGE2 on HDL utilization by luteal cells from day 5 to 10 of
      the estrous cycle. In the preliminary experiment, 10(-6) M of PGE2 out of four
      different doses examined was selected for further studies, since it evoked the
      highest release of progesterone. In the next experiment, it was found that HDL
      increases progesterone secretion by luteal cells and both PGE2 and LH increased
      (P < 0.05) the response to HDL while NA did not. In the last in vitro experiment,
      progesterone stimulated PGE2 secretion by luteal cells. In conclusion, PGE2 may
      be directly involved in the utilization of cholesterol from HDL for progesterone
      synthesis. Furthermore, PGE2 may influence NA-stimulated progesterone secretion
      by the corpus luteum (CL). It is concluded that there is a positive feedback loop
      between progesterone and luteal PGE2 during days 5-10 of the estrous cycle.

PMID- 12611500
TI  - Applications of high-field (W-band) EPR to M-M bonded units (M = Cr, Mo): the
      first confirmed oxidation of a Cr2 4+ paddlewheel complex to a stable
      isostructural Cr2 5+ product.
AB  - The EPR spectra of [Cr(2)[(PhN)(2)CN(CH(2))(4)](4)]PF(6) and
      [Mo(2)(TiPB)(4)]PF(6) (TiPB = anion of 2,4,6-triisopropylbenzoic acid) at W-band
      are shown to have g values significantly lower than 2.00 and exhibit parallel and
      perpendicular components (not resolved at X-band). Therefore the unpaired
      electrons of the M(2)(5+) units must reside on metal-based (not ligand-based)
      orbitals. Thus, the chromium compound must be considered as the first confirmed
      oxidation product of a Cr(2)(4+) paddlewheel complex comparable to the Mo(2)(5+)
      compounds.

PMID- 12611501
TI  - A monomeric imidazol-2-ylidene-silver(I) chloride complex: synthesis, structure,
      and solid state 109Ag and 13C CP/MAS NMR characterization.
AB  - The structure of 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene-silver(I)
      chloride, 1, has been determined to be a monomer with weak head-to-tail H...Cl
      interactions in the solid state. A multinuclear NMR study using a (13)C(carbene)
      labeled derivative, 1((13)C), exhibits (13)C-(107,109)Ag coupling in solution.
      Further, the solid state CP/MAS NMR parameters, including the principal
      components of the chemical shift tensors for both the (13)C and (109)Ag centers,
      have been determined. With the aid of DFT calculations, the orientation of the
      chemical shift tensors have been assigned.

PMID- 12611502
TI  - Room temperature phosphorescence from a platinum(II) diimine
      bis(pyrenylacetylide) complex.
AB  - Room temperature phosphorescence has been observed in a synthetically facile
      Pt(II) complex, Pt(dbbpy)(CtriplebondC-pyrene)(2) (dbbpy = 4,4'-di(tert-butyl)
      2,2'-bipyridine; CtriplebondC-pyrene = 1-ethynylpyrene), in fluid solution. The
      static and time-resolved absorption and luminescence data are consistent with
      phosphorescence emerging from the appended CtriplebondC-pyrenyl units following
      excitation into the low energy dpi Pt --> pi* dbbpy metal-to-ligand charge
      transfer absorption bands.

PMID- 12611503
TI  - Anion receptors: a new class of amide/quaternized amine macrocycles and the
      chelate effect.
AB  - A new class of tetraamide macrocyclic receptors for anions with two quaternized
      amine functionalities exhibited higher affinities for anions compared with the
      corresponding neutral amides. In two crystal structures of halide complexes of
      the prototypes with phenyl and pyridine spacers, the anions are held by hydrogen
      bonding with the amide hydrogens. The pyridine analogues display higher
      affinities in general than the phenyl systems, a phenomenon which is attributed
      to the anion version of the chelate effect.

PMID- 12611504
TI  - [(CH3)3NCH2CH2NH3]SnI4: a layered perovskite with quaternary/primary ammonium
      dications and short interlayer iodine-iodine contacts.
AB  - The organic-inorganic hybrid [(CH(3))(3)NCH(2)CH(2)NH(3)]SnI(4) presents a
      layered perovskite structure, templated by an organic dication containing both a
      primary and a quaternary ammonium group. Due to the high charge density and small
      size of the organic cation, the separation of the perovskite layers is small and
      short iodine-iodine contacts of 4.19 A are formed between the layers. Optical
      thin-film measurements on this compound indicate a significant red shift of the
      exciton peak (630 nm) associated with the band gap, as compared with other
      SnI(4)(2)(-)-based layered perovskite structures.

PMID- 12611505
TI  - High-nuclearity metal-cyanide clusters: synthesis, magnetic properties, and
      inclusion behavior of open-cage species incorporating [(tach)M(CN)3] (M = Cr, Fe,
      Co) complexes.
AB  - The use of 1,3,5-triaminocyclohexane (tach) as a capping ligand in generating
      metal-cyanide cage clusters with accessible cavities is demonstrated. The
      precursor complexes [(tach)M(CN)(3)] (M = Cr, Fe, Co) are synthesized by methods
      similar to those employed in preparing the analogous 1,4,7-triazacyclononane
      (tacn) complexes. Along with [(tach)Fe(CN)(3)](1)(-), the latter two species are
      found to adopt low-spin electron configurations. Assembly reactions between
      [(tach)M(CN)(3)] (M = Fe, Co) and [M'(H(2)O)(6)](2+) (M' = Ni, Co) in aqueous
      solution afford the clusters [(tach)(4)(H(2)O)(12)Ni(4)Co(4)(CN)(12)](8+),
      [(tach)(4)(H(2)O)(12)Co(8)(CN)(12)](8+), and
      [(tach)(4)(H(2)O)(12)Ni(4)Fe(4)(CN)(12)](8+), each possessing a cubic arrangement
      of eight metal ions linked through edge-spanning cyanide bridges. This geometry
      is stabilized by hydrogen-bonding interactions between tach and water ligands
      through an intervening solvate water molecule or bromide counteranion. The
      magnetic behavior of the Ni(4)Fe(4) cluster indicates weak ferromagnetic coupling
      (J = 5.5 cm(-)(1)) between the Ni(II) and Fe(III) centers, leading to an S = 6
      ground state. Solutions containing [(tach)Fe(CN)(3)] and a large excess of
      [Ni(H(2)O)(6)](2+) instead yield a trigonal pyramidal
      [(tach)(H(2)O)(15)Ni(3)Fe(CN)(3)](6+) cluster, in which even weaker ferromagnetic
      coupling (J = 1.2 cm(-)(1)) gives rise to an S = (7)/(2) ground state.
      Paralleling reactions previously performed with [(Me(3)tacn)Cr(CN)(3)],
      [(tach)Cr(CN)(3)] reacts with [Ni(H(2)O)(6)](2+) in aqueous solution to produce
      [(tach)(8)Cr(8)Ni(6)(CN)(24)](12+), featuring a structure based on a cube of
      Cr(III) ions with each face centered by a square planar [Ni(CN)(4)](2)(-) unit.
      The metal-cyanide cage differs somewhat from that of the analogous Me(3)tacn
      ligated cluster, however, in that it is distorted via compression along a body
      diagonal of the cube. Additionally, the compact tach capping ligands do not
      hinder access to the sizable interior cavity of the molecule, permitting host
      guest chemistry. Mass spectrometry experiments indicate a 1:1 association of the
      intact cluster with tetrahydrofuran (THF) in aqueous solution, and a crystal
      structure shows the THF molecule to be suspended in the middle of the cluster
      cavity. Addition of THF to an aqueous solution containing [(tach)Co(CN)(3)] and
      [Cu(H(2)O)(6)](2+) templates the formation of a closely related cluster,
      [(tach)(8)(H(2)O)(6)Cu(6)Co(8)(CN)(24) superset THF](12+), in which paramagnetic
      Cu(II) ions with square pyramidal coordination are situated on the face-centering
      sites. Reactions intended to produce the cubic
      [(tach)(4)(H(2)O)(12)Co(8)(CN)(12)](8+) cluster frequently led to an isomeric two
      dimensional framework, [(tach)(H(2)O)(3)Co(2)(CN)(3)](2+), exhibiting mer rather
      than fac stereochemistry at the [Co(H(2)O)(3)](2+) subunits. Attempts to assemble
      larger edge-bridged cubic clusters by reacting [(tach)Cr(CN)(3)] with
      [Ni(cyclam)](2+) (cyclam = 1,4,8,11-tetraazacyclotetradecane) complexes instead
      generated extended one- or two-dimensional solids. The magnetic properties of one
      of these solids, two-dimensional [(tach)(2)(cyclam)(3)Ni(3)Cr(2)(CN)(6)]I(2),
      suggest metamagnetic behavior, with ferromagnetic intralayer coupling and weak
      antiferromagnetic interactions between layers.

PMID- 12611506
TI  - Solution chemistry of copper(II)-gentamicin complexes: relevance to metal-related
      aminoglycoside toxicity.
AB  - The adverse effect to the inner ear of aminoglycosides, drugs widely administered
      for the treatment of serious infections, appears to result from the interaction
      of these drugs with Cu(II) or Fe(II)/Fe(III) ions. To understand more completely
      the metal-induced side effects of one such antibiotic, gentamicin, we studied
      copper(II) coordination to gentamicin C1a by potentiometry, UV-vis, CD, and EPR
      spectroscopies, and ESI mass spectrometry. Only monomeric complexes of the
      CuH(n)L stoichiometry, with n ranging from 3 to -2, were detected over the pH
      range of 4-12. CuH(3)L and CuH(2)L complexes exhibit the same coordination mode,
      binding copper(II) through the amino nitrogen atom and a deprotonated alcoholic
      oxygen atom of the garosamine ring. In the CuHL and CuL complexes a second amino
      nitrogen atom of the purpurosamine ring participates in central ion coordination.
      Finally, the additional axial binding of the deprotonated oxygen of the hydroxyl
      group of the 2-deoxystreptamine moiety occurs in the CuH(-)(1)L and CuH(-)(2)L
      complexes. Interactions of the Cu(II)-gentamicin-H(2)O(2) system at pH 7.4 with
      N,N-dimethyl-p-nitrosoaniline, arachidonic acid, and plasmid DNA confirmed that
      gentamicin complexes facilitate oxidative reactions leading to peroxidation of
      arachidonic acid and scission of double-stranded DNA mediated by copper-bound
      reactive oxygen species. However, the stability constants of Cu(II)-gentamicin
      complexes are inferior to the binding constants of copper(II) complexes with
      other components of human serum or cells. Computer simulations of copper(II)
      distribution in the human blood plasma showed that the concentration of
      gentamicin would have to be at impossible levels (100 M) before a significant
      fraction of Cu(II) ions would be bound to gentamicin. Further, once introduced
      into aqueous solution, histidine replaces gentamicin in Cu(II)-gentamicin
      complexes. Therefore, Cu(II)-gentamicin complexes might not exist under
      physiological conditions.

PMID- 12611507
TI  - Syntheses and characterization of two dioxygen-reactive dinuclear macrocyclic
      schiff-base copper(I) complexes.
AB  - The dinuclear copper(I) complex [Cu(2)L(1)(CH(3)CN)(2)](ClO(4))(2) (1, L(1) =
      3,6,9,17,20,23-hexaazatricyclo[23.3.1.1]triaconta
      1(29),2,9,11(30),12(13),14,16,23,25,27-decaene) has been structurally
      characterized. As previously described, intramolecular ligand hydroxylation (at
      the aromatic ring) was observed when 1 was reacted with dioxygen. A stopped-flow
      analysis of the reaction of 1 with dioxygen under different conditions did not
      allow a "dioxygen intermediate" to be spectroscopically detected. Detailed NMR
      and electrochemical data on 1 are also presented and evaluated for the first
      time. No copper(II) complexes of L(1) could be characterized due to hydrolysis of
      the compounds. In contrast, complex 2-differing from 1 only in an increase in the
      size of the chelate rings-did not undergo intramolecular hydroxylation when it
      was oxidized. The crystal structure of 2 is also described.

PMID- 12611508
TI  - Titanium alkoxides as initiators for the controlled polymerization of lactide.
AB  - Fourteen titanium alkoxides were synthesized for comparison of their catalytic
      properties in the bulk and solution polymerization of lactide (LA). In bulk
      polymerizations, they are effective catalysts in terms of polymer yield and
      molecular weight. Titanatranes gave polylactides with significantly increased
      molecular weight over more extended polymerization times, and those with five
      membered rings afforded polymers in higher yields and with larger molecular
      weights than their six-membered ring counterparts. Steric hindrance of the rings
      was found to significantly affect polymer yields. Increased heterotactic-biased
      poly(rac-LA) was formed as the number of chlorine atoms increased in TiCl(x)(O-i
      Pr)(4)(-)(x). In solution polymerizations, titanium alkoxides catalyzed
      controlled polymerizations of LA, and end group analysis demonstrated that an
      alkoxide substituent on the titanium atom acted as the initiator. That
      polymerization is controlled under our conditions was shown by the linearity of
      molecular weight versus conversion. A tendency toward formation of heterotactic
      biased poly(rac-LA) was observed in the solution polymerizations. The rate of
      ring-opening polymerization (ROP) and the molecular weight of the polymers are
      greatly influenced by the substituents on the catalyst, as well as by factors
      such as the polymerization temperature, polymerization time, and concentration of
      monomer and catalyst.

PMID- 12611509
TI  - Photophysics and redox behavior of chiral transition metal polymers.
AB  - The absorption and emission spectra, excited-state lifetimes, quantum yields, and
      electrochemical measurements have been obtained for a new series of chiral
      complexes based on three different chiral 2,2':6',2' '-terpyridine ligands, (-)
      ctpy, (-)-[ctpy-x-ctpy], and (-)-[ctpy-b-ctpy], with one, two, or multiple Ru
      metal centers. The room-temperature absorption and emission maxima of [[((-)
      ctpy)Ru]-(-)-[ctpy-b-ctpy]-[Ru((-)-ctpy)]](PF(6))(4) and ((-)-[ctpy-b-ctpy])
      [[Ru((-)-[ctpy-b-ctpy])](PF(6))(2)](n) were shifted to lower energies and also
      exhibited significantly longer luminescence lifetimes when compared to [Ru((-)
      ctpy)(2)](PF(6))(2), [[((-)-ctpy)Ru]-(-)-[ctpy-x-ctpy]-[Ru((-)-ctpy)]](PF(6))(4),
      and ((-)-[ctpy-x-ctpy])-[[Ru((-)-[ctpy-x-ctpy])](PF(6))(2)](n). In terms of their
      electrochemical behavior, all of the complexes studied exhibited one Ru-centered
      and two ligand-centered redox waves and the [[((-)-ctpy)Ru]-(-)-[ctpy-x-ctpy]
      [Ru((-)-ctpy)]](PF(6))(4), ((-)-[ctpy-x-ctpy])-[[Ru((-)-[ctpy-x
      ctpy])](PF(6))(2)](n), and ((-)-[ctpy-b-ctpy])-[[Ru((-)-[ctpy-b
      ctpy])](PF(6))(2)](n)() complexes were found to electrodeposit upon ligand-based
      reduction. The difference between the formal potentials of the Ru-centered and
      the first ligand-centered (least negative) waves corresponded linearly with the
      changes in the observed emission energies. The shifts in energy are discussed
      using a particle-in-a-box model, and the luminescence lifetimes are discussed in
      terms of the structure of the excited-state manifold.

PMID- 12611510
TI  - Iron hemiporphycene as a functional prosthetic group for myoglobin.
AB  - The iron complex of hemiporphycene, a molecular hybrid of porphyrin with
      porphycene, was incorporated into the apomyoglobin pocket to examine ligand
      binding ability of the iron atom in the novel porphyrinoid. Apomyoglobin was
      successfully coupled with a stoichiometric amount of ferric hemiporphycene to
      afford the reconstituted myoglobin equipped with the iron coordination structure
      of native protein. Cyanide, imidazole, and fluoride coordinated to the ferric
      protein with affinities comparable with those for native myoglobin. The ferrous
      myoglobin was functionally active to bind O(2) and CO reversibly at pH 7.4 and 20
      degrees C. The O(2) affinity is 12-fold higher than that of native myoglobin
      while the CO affinity is slightly lower, suggesting decreased discrimination
      between O(2) and CO in the heme pocket. The functional anomaly was interpreted to
      reflect increased sigma-bonding character in the Fe(II)-O(2) bond. In contrast
      with 6-coordinate native NO protein, the NO myoglobin containing ferrous
      hemiporphycene is in a mixed 5- and 6-coordinate state. This observation suggests
      that the in-plane configuration of the iron atom in hemiporphycene is
      destabilized by NO. Influence of the core deformation was also detected with both
      the infrared absorption for the ferrous CO derivative and electron paramagnetic
      resonance for ferric imidazole complex. Anomalies in the ferric and ferrous
      derivatives were ascribed to the modified iron-N(pyrrole) interactions in the
      asymmetric metallo core of hemiporphycene.

PMID- 12611512
TI  - Laves-phase structural changes in the system CaAl2-xMgx.
AB  - Compounds CaAl(2)(-)(x)Mg(x) (0 < or = x < or = 2) were synthesized and
      structurally characterized by X-ray diffraction experiments. With increasing Mg
      content x the sequence of Laves phase structures MgCu(2) --> MgNi(2) --> MgZn(2)
      is revealed. The homogeneity ranges of the underlying phases were determined to
      be 0 < or = x < 0.24(1) (MgCu(2) type), 0.66(2) < x < 1.07(3) (MgNi(2) type), and
      1.51(5) < x < or = 2.0 (MgZn(2) type). Mg/Al site occupancies in
      CaAl(1.34)Mg(0.66) and in CaAl(0.44)Mg(1.56) were refined from neutron powder
      diffraction experiments and exposed a pronounced segregation of Al and Mg in
      MgNi(2)-type CaAl(1.34)Mg(0.66) where Al atoms preferentially occupy the
      positions corresponding to trigonal bipyramids. In MgZn(2)-type
      CaAl(0.44)Mg(1.56), however, the Mg/Al distribution was found to be nearly
      uniform. Structural stability in the quasi-binary system CaAl(2)(-)(x)Mg(x) was
      investigated by first-principles calculations in which random occupational
      disorder of Mg and Al was modeled with the virtual crystal approximation. The
      theoretical calculations reproduced the experimental compositional stability
      ranges of the three different Laves phase structures very well. Structural
      changes in the quasi-binary system CaAl(2)(-)(x)Mg(x) are induced by the electron
      concentration, which decreases with increasing x. The stability of the different
      Laves phase structures as a function of electron concentration was analyzed by
      the method of moments.

PMID- 12611511
TI  - A ferromagnetically coupled CrCu3 tetramer and GdCu4 pentamer with a [15]N4
      macrocylic ligand incorporating an oxamido bridge.
AB  - The synthesis and structural and magnetic properties of heteropolynuclear
      complexes [(L(3)Cu)(3)Cr](CH(3)CN)(3)(ClO(4))(3) (2) and
      [(L(3)Cu)(4)Gd.H(2)O](CH(3)OH)(H(2)O)(ClO(4))(3) (3) (H(2)L(3) ligand is 2,3
      dioxo-5,6:14,15-dibenzo-1,4,8,12-tetraazacyclo-pentadeca-7,12-diene) and their
      precursor L(3)Cu (1) are presented. Complex 2 crystallizes in space group P2(1)/n
      with cell parameters a = 20.828(6) A, b = 18.321(5) A, c = 7.578(5) A, alpha = 90
      degrees, beta = 91.990(8) degrees, gamma = 90 degrees, and Z = 4. The Cr(III)
      center is coordinated by six oxygen atoms from three Cu(II) precursors. The Cr-O
      bonds range over 1.948-1.982 A. The coordination environments of all the terminal
      Cu(II) ions change in comparison with their Cu(II) precursor. The ferromagnetic
      coupling (J = 16.48(1) cm(-)(1)) observed for 2 can be rationalized by symmetry
      considerations. For any pair of interacting magnetic orbitals, strict
      orthogonality is obeyed and the interaction is ferromagnetic. Complex 3
      crystallizes in space group P1 with cell parameters a = 14.805(4) A, b =
      16.882(5) A, c = 17.877(5) A, alpha = 75.403(5) degrees, beta = 83.317(6)
      degrees, gamma = 70.600(5) degrees, and Z = 2. The central Gd(III) assumes an 8 +
      1 coordination environment, namely eight oxygen atoms from four Cu(II) precursors
      and one oxygen atom from H(2)O. The fit of the experimental data gives J =
      0.27(2) cm(-)(1), g(Gd) = 1.98(1), and g(Cu) = 2.05(1). This small and positive J
      value shows weak ferromagnetic interaction between metal ions.

PMID- 12611513
TI  - Flux synthesis of the noncentrosymmetric cluster compounds Cs2SnAs2Q9 (Q = S, Se)
      containing two different polychalcoarsenite beta-[AsQ4]3- and [AsQ5]3- ligands.
AB  - Two noncentrosymmetric quaternary tin chalcoarsenates, Cs(2)SnAs(2)S(9) (1) and
      Cs(2)SnAs(2)Se(9) (2), were synthesized by the polychalcoarsenate flux method.
      Compound 1 crystallizes in the orthorhombic space group Pmc2(1) with a = 7.386(3)
      A, b = 14.614(5) A, c = 14.417(5) A, and Z = 4. Compound 2 crystallizes in the
      monoclinic space group P2(1) with a = 7.715(5) A, b = 17.56(1) A, c = 7.663(5) A,
      beta = 115.86(1) degrees, and Z = 2. Both structures contain the same tin
      centered molecular cluster anions [Sn[AsQ(2)(Q(2))][AsQ(Q(2))(2)]](2)(-) (Q = S,
      Se) separated by Cs cations. The Sn(4+) ion is in a distorted octahedral
      environment coordinated by two different pyramidal-shaped tridentate ligands,
      [AsQ(2)(Q(2))](3)(-) and [AsQ(Q(2))(2)](3)(-). These compounds absorb visible
      light at energies above 1.98 and 1.45 eV for 1 and 2, respectively. Differential
      thermal analysis revealed that 1 melts at 350 degrees C and on cooling gives a
      glass. The glass recrystallizes at 268 degrees C upon subsequent heating.
      Compound 2 melts at 258 degrees C.

PMID- 12611515
TI  - New framework connectivity patterns in templated networks: the creatinine zinc
      phosphites C4N3OH7.ZnHPO3, C4N3OH7.Zn(H2O)HPO3, and (C4N3OH7)2.ZnHPO3.H2O.
AB  - The syntheses, crystal structures, and properties of C(4)N(3)OH(7).ZnHPO(3),
      C(4)N(3)OH(7).Zn(H(2)O)HPO(3), and (C(4)N(3)OH(7))(2).ZnHPO(3).H(2)O are
      reported. These new creatinine zinc phosphites are built up from networks of
      vertex-sharing HPO(3) pseudopyramids and various types of ZnO(2)N(2), ZnO(3)N,
      and ZnO(2)N(H(2)O) tetrahedra, resulting in extended structures of different
      dimensionalities (as sheets, clusters, and chains, respectively). They
      demonstrate the structural effect of incorporating "terminal" (nonnetworking) Zn
      N and Zn-OH(2) moieties into zinc centers. Crystal data: C(4)N(3)OH(7).ZnHPO(3),
      triclinic, P1 (No. 2), a = 8.9351(4) A, b = 9.5011(4) A, c = 9.9806(4) A, alpha =
      87.451(1) degrees, beta = 85.686(1) degrees, gamma = 89.551(1) degrees, Z = 4;
      C(4)N(3)OH(7).Zn(H(2)O)HPO(3), monoclinic, P2(1)/c (No. 14), a = 10.1198(7) A, b
      = 7.2996(5) A, c = 13.7421(9) A, beta = 107.522(1) degrees, Z = 4;
      (C(4)N(3)OH(7))(2).ZnHPO(3).H(2)O, triclinic, P1 (No. 2), a = 10.7289(6) A, b =
      10.9051(6)A, c = 13.9881(8) A, alpha = 89.508(1) degrees, beta = 74.995(1)
      degrees, gamma = 74.932(1) degrees, Z = 4.

PMID- 12611514
TI  - Symmetric and asymmetric dinuclear manganese(IV) complexes possessing a [MnIV2(mu
      O)2(muO2CMe)]3+ core and terminal Cl- ligands.
AB  - The synthesis of new dinuclear manganese(IV) complexes possessing the
      [Mn(IV)(2)(mu-O)(2)(mu-O(2)CMe)](3+) core and containing halide ions as terminal
      ligands is reported. [Mn(2)O(2)(O(2)CMe)Cl(2)(bpy)(2)](2)[MnCl(4)] (1; bpy = 2,2'
      bipyridine) was prepared by sequential addition of [MnCl(3)(bpy)(H(2)O)] and
      (NBzEt(3))(2)[MnCl(4)] to a CH(2)Cl(2) solution of
      [Mn(3)O(4)(O(2)CMe)(4)(bpy)(2)]. The complex
      [Mn(IV)(2)O(2)(O(2)CMe)Cl(bpy)(2)(H(2)O)](NO(3))(2) (2) was obtained from a
      water/acetic acid solution of MnCl(2).4H(2)O, bpy, and (NH(4))(2)[Ce(NO(3))(6)],
      whereas the [Mn(IV)(2)O(2)(O(2)CR)X(bpy)(2)(H(2)O)](ClO(4))(2) [X = Cl(-) and R =
      Me (3), Et (5), or C(2)H(4)Cl (6); and X = F(-), R = Me (4)] were prepared by a
      slightly modified procedure that includes the addition of HClO(4). For the
      preparation of 4, MnF(2) was employed instead of MnCl(2).4H(2)O.
      [Mn(2)O(2)(O(2)CMe)Cl(2)(bpy)(2)](2)[MnCl(4)].2CH(2)Cl(2) (1.2CH(2)Cl(2))
      crystallizes in the monoclinic space group C2/c with a = 21.756(2) A, b =
      12.0587(7) A, c = 26.192(2) A, alpha = 90 degrees, beta = 111.443(2) degrees,
      gamma = 90 degrees, V = 6395.8(6) A(3), and Z = 4.
      [Mn(2)O(2)(O(2)CMe)Cl(H(2)O)(bpy)(2)](NO(3))(2).H(2)O (2.H(2)O) crystallizes in
      the triclinic space group Ponemacr; with a = 11.907(2) A, b = 12.376(2) A, c =
      10.986(2) A, alpha = 108.24(1) degrees, beta = 105.85(2) degrees, gamma =
      106.57(1) degrees, V = 1351.98(2) A(3), and Z = 2.
      [Mn(2)O(2)(O(2)CMe)Cl(H(2)O)(bpy)(2)](ClO(4))(2).MeCN (3.MeCN) crystallizes in
      the triclinic space group Ponemacr; with a = 11.7817(7) A, b = 12.2400(7) A, c =
      13.1672(7) A, alpha = 65.537(2) degrees, beta = 67.407(2) degrees, gamma =
      88.638(2) degrees, V = 1574.9(2) A(3), and Z = 2. The cyclic voltammogram (CV) of
      1 exhibits two processes, an irreversible oxidation of the [MnCl(4)](2)(-) at
      E(1/2) approximately 0.69 V vs ferrocene and a reversible reduction at E(1/2) =
      0.30 V assigned to the [Mn(2)O(2)(O(2)CMe)Cl(2)(bpy)(2)](+/0) couple (2Mn(IV) to
      Mn(IV)Mn(III)). In contrast, the CVs of 2 and 3 show only irreversible reduction
      features. Solid-state magnetic susceptibility (chi(M)) data were collected for
      complexes 1.1.5H(2)O, 2.H(2)O, and 3.H(2)O in the temperature range 2.00-300 K.
      The resulting data were fit to the theoretical chi(M)T vs T expression for a
      Mn(IV)(2) complex derived by use of the isotropic Heisenberg spin Hamiltonian (H
      = -2JS(1)S(2)) and the Van Vleck equation. The obtained fit parameters were (in
      the format J/g) -45.0(4) cm(-)(1)/2.00(2), -36.6(4) cm(-)(1)/1.97(1), and 
      39.3(4) cm(-)(1)/1.92(1), respectively, where J is the exchange interaction
      parameter between the two Mn(IV) ions. Thus, all three complexes are
      antiferromagnetically coupled.

PMID- 12611516
TI  - Crystal and molecular structures of alkali oxalates: first proof of a staggered
      oxalate anion in the solid state.
AB  - The molecular and crystal structures of solvent-free potassium, rubidium, and
      cesium oxalates have been determined ab initio from high-resolution synchrotron
      and X-ray laboratory powder patterns. In the case of potassium oxalate
      K(2)C(2)O(4) (a = 10.91176(7) A, b = 6.11592(4) A, c = 3.44003(2) A,
      orthorhombic, Pbam, Z = 2), the oxalate anion is planar, whereas in cesium
      oxalate Cs(2)C(2)O(4) (a = 6.62146(5) A, b = 11.00379(9) A, c = 8.61253(7) A,
      beta = 97.1388(4) degrees, monoclinic, P2(1)/c, Z = 4) it exhibits a staggered
      conformation. For rubidium oxalate at room temperature, two polymorphs exist, one
      (beta-Rb(2)C(2)O(4)) isotypic to potassium oxalate (a = 11.28797(7) A, b =
      6.29475(4) A, c = 3.62210(2) A, orthorhombic, Pbam, Z = 2) and the other (alpha
      Rb(2)C(2)O(4)) isotypic to cesium oxalate (a = 6.3276(1) A, b = 10.4548(2) A, c =
      8.2174(2) A, beta = 98.016(1) degrees, monoclinic, P2(1)/c, Z = 4). The potassium
      oxalate structure can be deduced from the AlB(2) type, and the cesium oxalate
      structure from the Hg(99)As type, respectively. The relation between the two
      types of crystal structures and the reason for the different conformations of the
      oxalate anion are discussed.

PMID- 12611517
TI  - Oxovanadium(IV) and -(V) complexes of dithiocarbazate-based tridentate Schiff
      base ligands: syntheses, structure, and photochemical reactivity of compounds
      involving imidazole derivatives as coligands.
AB  - The tridentate dithiocarbazate-based Schiff base ligands H(2)L (S-methyl-3-((5-R
      2-hydroxyphenyl)methyl)dithiocarbazate, R = NO(2), L = L(2); R = Br, L = L(3))
      react with [VO(acac)(2)] in the presence of imidazole derivatives as coligands to
      form oxovanadium(IV) and cis-dioxovanadium(V) complexes. With benzimidazole and N
      methylimidazole, the products are oxovanadium(IV) complexes, viz.
      [VOL(3)(BzIm)].0.5CH(3)CN (1a) and [VOL(N-MeIm)(2)] (L = L(3), 1b; L = L(2), 1c),
      respectively. In both 1a,b, the O and S donor atoms of the tridentate ligand are
      cis to the terminal oxo group (in the "equatorial" plane) and mutually trans, but
      the N donor atom is respectively cis and trans to the oxo atom, as revealed from
      X-ray crystallography. When imidazole or 4-methylimidazole is used as the
      ancillary ligand, the products obtained are water-soluble cis-dioxovanadium(V)
      complexes [VO(2)L(R'-ImH)] (L = L(3) and L(2), R' = H and Me, 2a-d). These
      compounds have zigzag chain structures in the solid state as confirmed by X-ray
      crystallographic investigations of 2a,d, involving an alternating array of
      LVO(2)(-) species and the imidazolium counterions held together by Coulombic
      interactions and strong hydrogen bonding. Complexes 2a-d are stable in water or
      methanol. In aprotic solvents, viz. CH(3)CN, DMF, or DMSO, however, they undergo
      photochemical transformation when exposed to visible light. The putative product
      is a mixed-oxidation divanadium(IV/V) species obtained by photoinduced reduction
      as established by EPR, electronic spectroscopy, and dynamic (1)H NMR experiments.

PMID- 12611518
TI  - Photoinduced chemical reactions on natural single crystals and synthesized
      crystallites of mercury(II) sulfide in aqueous solution containing naturally
      occurring amino acids.
AB  - Photoirradiation at >300 nm of aqueous suspensions of several natural crystal
      specimens and synthesized crystallites of mercury(II) sulfide (HgS) induced
      deaminocyclization of optically active or racemic lysine into pipecolinic acid
      (PCA) under deaerated conditions. This is the first example, to the best of our
      knowledge, of photoinduced chemical reactions of natural biological compounds
      over natural minerals. It was found that the natural HgS crystals had activity
      higher than those of synthesized ones but lower than those of other sulfides of
      transition metals, e.g., CdS and ZnS, belonging to the same II-IV chalcogenides.
      In almost all of the photoreactions, decompostion of HgS occurred to liberate
      hydrogen sulfide (H(2)S) and Hg(2+), and the latter seemed to have undergone in
      situ reductive deposition on HgS as Hg(0) after a certain induction period (24-70
      h) during the photoirradiation, as indicated by the darkened color of the
      suspensions. The formation of PCA, presumably through combination of oxidation of
      lysine and reduction of an intermediate, cyclic Schiff base, could also be seen
      after a certain induction time of the Hg(0) formation. This was supported by the
      fact that the addition of small amount of Hg(2+) (0.5 wt % of HgS) increased the
      PCA yield by almost 2-fold. We also tried to elucidate certain aspects of the
      plausible stereochemical reactions in relation to the chiral crystal structure of
      HgS. Although, in some experiments, slight enantiomeric excess of the product PCA
      was observed, the excess was below or equal to the experimental error and no
      other supporting analytical data could not be obtained; we cannot conclude the
      enantiomeric photoproduction of PCA by the natural chiral HgS specimen.

PMID- 12611519
TI  - Synthesis, characterization, and photophysical studies of new bichromophoric
      ruthenium(II) complexes.
AB  - The photophysical properties of a series of prepared ruthenium tris(bipyridine)
      complexes, covalently linked to aromatic species, of type [Ru(bpy)(2)-(4-methyl
      4'-(arylaminocarbonyl)-2,2'-bipyridine)](2+) ([Ru(bpy)(2)(mbpy-L)](2+), where bpy
      = 2,2'-bipyridine; mbpy = 4-methyl-4'-carbonyl-2,2'-bipyridine; and L = 2
      aminonaphthyl (naph), 9-aminoanthryl (anth), 1-aminopyrenyl (pyr), or 9
      aminoacridinyl (acrd)) were studied by electronic absorption spectroscopy and
      steady state and time resolved luminescence spectroscopies. The absorption
      spectra of the MLCT electronic transition of the complexes are similar, which is
      in agreement with a practically constant redox potential of Ru(III/II) close to
      1.28 V versus Ag/AgCl. However, the luminescence spectra of the new complexes are
      red shifted compared to Ru(bpy)(3)(2+), and this effect is ascribed to solvation
      and inductive effects of the amide group which enhance the symmetry breakdown
      among the three bipyridyl ligands. The energy stabilization of the (3)MLCT state
      is in the range 2.1-8.4 kJ/mol. The triplet-triplet energy transfer between the
      Ru complex and the aromatic species linked by an amide spacer is a slow process
      with rate constants of 2.6 x 10(4), 3.6 x 10(4), and 4.9 x 10(4) s(-)(1) for
      anthracene, acridine, and pyrene as acceptors in methanol, respectively. The
      energy transfer rate constant increases with decreasing polarity of the solvent.
      In dichloromethane, the rate constants for anthracene, acridine, and pyrene
      acceptors are 2.6 x 10(5), 1.5 x 10(5), and 2.9 x 10(5) s(-)(1), respectively.
      The low efficiency of energy transfer is due to the small difference in triplet
      energy between donor and acceptor species, weak electronic coupling, and
      unfavorable Franck-Condon factors, despite the short separation distance between
      donor and acceptor species in an amide bridge.

PMID- 12611520
TI  - Characterization of the low-energy electronic excited States of benzoyl
      substituted ferrocenes.
AB  - Resonance Raman spectroscopy has been employed to probe the excited-state
      distortions associated with the low-energy electronic transition of
      benzoylferrocene and 1,1'-dibenzoylferrocene. Resonance intensity enhancement of
      in-plane ligand modes, in general, and the carbonyl stretching mode, in
      particular, supports the proposal that the excited state populated by this
      transition contains appreciable metal-to-ligand charge transfer character. The
      redistribution of charge that occurs upon populating this state weakens the metal
      ring bonding and facilitates the loss of a benzoylcyclopentadienide anion. This
      photochemical reaction has been investigated by an on-line electrospray
      ionization mass spectrometry technique that allows direct detection of primary
      and secondary products with solution lifetimes down to the millisecond range.

PMID- 12611522
TI  - Lanthanum gallium bismuthide, LaGaBi2.
AB  - The ternary rare-earth gallium bismuthide LaGaBi(2) has been prepared through
      reaction of the elements. Its structure (Pearson symbol hP24, hexagonal, space
      group P6/mmm, Z = 6, a = 13.5483(4) A, c = 4.3937(1) A) contains columns of La(6)
      trigonal prisms centered by Bi atoms. These columns are surrounded by a framework
      consisting of three-atom-wide Bi ribbons and Ga(6) rings. Additional Bi atoms are
      sandwiched between pairs of Ga(6) rings. LaGaBi(2) is structurally closely
      related to La(13)Ga(8)Sb(21). A retrotheoretical analysis of the structure
      through extended Huckel band structure calculations suggests an interesting
      electronic situation in which strong multiple bonding in the Ga-Ga network
      coexists with weak hypervalent bonding in the Bi-Bi network and confirms the
      metallic behavior seen in electrical resistivity measurements.

PMID- 12611521
TI  - The arrangement of first- and second-shell water molecules in trivalent aluminum
      complexes: results from density functional theory and structural crystallography.
AB  - The structural and energetic features of a variety of gas-phase aluminum ion
      hydrates containing up to 18 water molecules have been studied computationally
      using density functional theory. Comparisons are made with experimental data from
      neutron diffraction studies of aluminum-containing crystal structures listed in
      the Cambridge Structural Database. Computational studies indicate that the
      hexahydrated structure Al[H(2)O](6)(3+) (with symmetry T(h)()), in which all six
      water molecules are located in the innermost coordination shell, is lower in
      energy than that of Al[H(2)O](5)(3+).[H(2)O], where only five water molecules are
      in the inner shell and one water molecule is in the second shell. The analogous
      complex with four water molecules in the inner shell and two in the outer shell
      undergoes spontaneous proton transfer during the optimization to give
      [Al[H(2)O](2)[OH](2)](+).[H(3)O(+)](2), which is lower in energy than
      Al[H(2)O](6)(3+); this finding of H(3)O(+) is consistent with the acidity of
      concentrated Al(3+) solutions. Since, however, Al[H(2)O](6)(3+) is detected in
      solutions of Al(3+), additional water molecules are presumed to stabilize the
      hexa-aquo Al(3+) cation. Three models of a trivalent aluminum ion complex
      surrounded by a total of 18 water molecules arranged in a first shell containing
      6 water molecules and a second shell of 12 water molecules are discussed. We find
      that a model with S(6) symmetry for which the Al[H(2)O](6)(3+) unit remains
      essentially octahedral and participates in an integrated hydrogen bonded network
      with the 12 outer-shell water molecules is lowest in energy. Interactions between
      the 12 second-shell water molecules and the trivalent aluminum ion in
      Al[H(2)O](6)(3+) do not appear to be sufficiently strong to orient the dipole
      moments of these second-shell water molecules toward the Al(3+) ion.

PMID- 12611523
TI  - Syntheses of a Cp'Re=S derivative and more complex products.
AB  - The reaction of Cp'ReCl(2)S(3) (Cp' = Me(4)EtC(5)) with slightly less than 2
      equiv of a phosphine reagent results in the formation of [Cp'Re(Cl)(2)(mu-S)](2),
      2, which has been characterized by an X-ray diffraction study. Reactions of 2
      with nucleophiles did not lead to monomeric derivatives of the type
      Cp'ReS(Cl)(2)(Nuc). The reaction of Cp'ReCl(2)(SC(2)H(4)S) with (Me(3)Si)(2)S
      resulted in the formation of three new products: Cp'ReS(SC(2)H(4)S), 4;
      Cp'Re(S(3))(SC(2)H(4)S), 5; and a tetranuclear derivative, [(Cp'Re)(2)(mu
      S)(mu,eta(2)-SC(2)H(4)S)(mu,eta(1)-SC(2)H(4)S](2)Cl(2), 6. Complexes 4 and 6 have
      been characterized by X-ray diffraction studies. The electrochemical properties
      of the mononuclear Re=S derivative, 4, are compared with those of Re=O and Re=NR
      analogues.

PMID- 12611524
TI  - Chiral direction and interconnection of helical three-connected networks in metal
      organic frameworks.
AB  - The control of the interpenetration and chirality of a family of metal-organic
      frameworks is discussed. These systems contain two- (A) and four-fold (B)
      interpenetration of helical three-connected networks generated by binding the
      1,3,5-benzenetricarboxylate (btc) ligand to a metal center. These frameworks have
      the general formula Ni(3)(btc)(2)X(m)Y(n).solvent (where X = pyridine or 4
      picoline, Y = ethylene glycol, 1,2-propanediol, 1,4-butanediol, meso-2,3
      butanediol, 1,2,6-hexanetriol, glycerol). The structural and chemical effects of
      modifying the alcohol and aromatic amine ligands bound to the metal center
      include controlling the thermal stability and the degree of interpenetration.
      Covalent linking of the four interpenetrating networks in the A family and the
      switching of diol binding from mono- to bidentate are demonstrated. Recognition
      of chiral diols by the hand of the network helices is investigated by binding an
      alcohol ligand with two chiral centers of opposite sense to the same helix. This
      reveals the subtle nature of the helix-ligand interaction.

PMID- 12611525
TI  - Dlf complexes with uniform coordination geometry: structural and magnetic
      properties of an LnNi2 core supported by a heptadentate amine phenol ligand.
AB  - The synthesis and physical characterization of a series of lanthanide (Ln(III))
      and nickel (Ni(II)) mixed trimetallic complexes with the heptadentate (N(4)O(3))
      amine phenol ligand H(3)trn [tris(2'-hydroxybenzylaminoethyl)amine] has been
      accomplished in order to extend our understanding of how amine phenol ligands can
      be used to coaggregate d- and f-block metal ions and to investigate further the
      magnetic interaction between these ions. The one-pot reaction in methanol of
      stoichiometric amounts of H(3)trn with NiX(2).6H(2)O (X = ClO(4), NO(3)) followed
      by addition of the corresponding LnX(3).6H(2)O salt, and then base, produces
      complexes of the general formula [LnNi(2)(trn)(2)]X.nH(2)O. The complexes were
      characterized by a variety of analytical techniques. Crystals of five of the
      complexes were grown from methanol solutions and their structures were determined
      by X-ray analysis: [PrNi(2)(trn)(2)(CH(3)OH)]ClO(4).4CH(3)OH.H(2)O,
      [SmNi(2)(trn)(2)(CH(3)OH)]NO(3).4CH(3)OH.2H(2)O,
      [TbNi(2)(trn)(2)(CH(3)OH)]NO(3).4CH(3)OH.3H(2)O,
      [ErNi(2)(trn)(2)(CH(3)OH)]NO(3).6CH(3)OH, and
      [LuNi(2)(trn)(2)(CH(3)OH)]NO(3).4.5CH(3)OH.1.5H(2)O. The
      [LnNi(2)(trn)(2)(CH(3)OH)](+) complex cation consists of two octahedral Ni(II)
      ions, each of which is encapsulated by the ligand trn(3)(-) in an N(4)O(2)
      coordination sphere with one phenolate O atom not bound to Ni(II). Each
      [Ni(trn)](-) unit acts as a tridentate ligand toward the Ln(III) ion via two
      bridging and one nonbridging phenolate donors. Remarkably, in all of the
      structurally characterized complexes, Ln(III) is seven-coordinate and has a
      flattened pentagonal bipyramidal geometry. Such uniform coordination behavior
      along the whole lanthanide series is rare and can perhaps be attributed to a
      mismatch between the geometric requirements of the bridging and nonbridging
      phenolate donors. Magnetic studies indicate that ferromagnetic exchange occurs in
      the Ni(II)/Ln(II) complexes where Ln = Gd, Tb, Dy, Ho, or Er.

PMID- 12611526
TI  - Syntheses, crystal engineering, and magnetic property of a dicyanamide bridged
      three-dimensional manganese(II)-nitronyl nitroxide coordination polymer derived
      from a new radical.
AB  - Syntheses, structural characterization, crystal engineering, and variable
      temperature magnetic study at fixed field strength of a novel dicyanamide bridged
      three-dimensional manganese(II)-nitronyl nitroxide compound, [Mn(II)(NIT
      tz)(dca)(2)] (1), (NIT-tz = 2-(2-thiazole)-4,4,5,5-tetramethyl-4,5-dihydro-1H
      imidazolyl-1-oxy-3-oxide, a new Ullman type radical) have been described. The
      compound crystallizes in the orthorhombic P2(1)2(1)2(1) space group with the
      following unit cell parameters: a = 11.015(2) A, b = 12.6134(14) A, c =
      13.7652(9) A, and Z = 4. In this complex, the radical behaves as a bidentate
      chelating ligand, while four single end-to-end dicyanamide (dca) units construct
      the three-dimensional structure. Inside the structure, there exist diamond-shaped
      channels, spiral networks, and helical chains. Variable-temperature (5-300 K, 1
      T) magnetic susceptibility data reveal the existence of antiferromagnetic
      interaction in this molecule. The magnetic behavior is explained by considering
      the exchange-coupled manganese(II)-radical system, which is subjected to the
      Mn(II)-dca-Mn(II) intermolecular interactions (H = -2JS(1).S(2) - 2zJ'<S>S). The
      least-squares fitting of the data results J = -73 cm(-)(1), g = 1.99, and J' = 
      0.17 cm(-)(1) (z = 4).

PMID- 12611527
TI  - H-bonding dependent structures of (NH4+)3H+(SO4 2-)2. Mechanisms of phase
      transitions.
AB  - The role of different H-bonds in phases II, III, IV, and V of triammonium
      hydrogen disulfate, (NH(4)(+))(3)H(+)(SO(4)(2)(-))(2), has been studied by X-ray
      diffraction and (1)H solid-state MAS NMR. The proper space group for phase II is
      C2/c, for phases III and IV is P2/n, and for phase V is P onemacr;. The
      structures of phases III and IV seem to be the same. The hydrogen atom
      participating in the O(-)-H(+).O(-) H-bond in phase II of
      (NH(4)(+))(3)H(+)(SO(4)(2)(-))(2) at room temperature is split at two positions
      around the center of the crucial O(-)-H(+).O(-) H-bonding, joining two SO(4)(2)(
      ) tetrahedra. With decreasing temperature, it becomes localized at one of the
      oxygen atoms. Further cooling causes additional differentiation of possibly
      equivalent sulfate dimers. The NH(4)(+) ions participate mainly in bifurcated H
      bonds with two oxygen atoms from sulfate anions. On cooling, the major
      contribution of the bifurcated H-bond becomes stronger, whereas the minor one
      becomes weaker. This is coupled with rotation of sulfate ions. In all the phases
      of (NH(4)(+))(3)H(+)(SO(4)(2)(-))(2), some additional, weak but significant,
      reflections are observed. They are located between the layers of the reciprocal
      lattice, suggesting possible modulation of the host (NH(4)(+))(3)H(+)(SO(4)(2)(
      ))(2) structure(s). According to (1)H MAS NMR obtained for phases II and III, the
      nature of the acidic proton disorder is dynamic, and localization of the proton
      takes place in a broader range of temperatures, as can be expected from the X-ray
      diffraction data.

PMID- 12611528
TI  - The electronic spectrum of Re2Cl8 2-: a theoretical study.
AB  - One of the prototype compounds for metal-metal multiple bonding, the
      Re(2)Cl(8)(2)(-) ion, has been studied theoretically using multiconfigurational
      quantum chemical methods. The molecular structure of the ground state has been
      determined. It is shown that the effective bond order of the Re-Re bond is close
      to three, due to the weakness of, in particular, the delta bond. The electronic
      spectrum has been calculated with the inclusion of spin-orbit coupling. Observed
      spectral features have been reproduced with good accuracy, and a number of new
      assignments are suggested.

PMID- 12611529
TI  - Zinc-bound thiolate-disulfide exchange: a strategy for inhibiting metallo-beta
      lactamases.
AB  - The mononuclear zinc thiolate complexes [(Tp(PhMe))Zn(S-R)], where Tp(PhMe) is
      hydrotris((3-methyl-5-phenyl)pyrazolyl)borate and (S-R) is benzyl thiolate, 4
      nitrophenylthiolate, 4-trifluoromethylphenylthiolate, 4-chlorophenylthiolate,
      phenylthiolate, 2-methylphenylthiolate, 4-methylphenylthiolate, 4
      methoxyphenylthiolate, or 4-hydroxyphenylthiolate, were synthesized.
      Representative members of the class were also characterized structurally. The
      benzyl thiolate complex undergoes a thiolate-disulfide exchange reaction with a
      variety of diphenyl and dipyridyl disulfides. Kinetic studies revealed that the
      reaction shows saturation behavior in both complex and disulfide for most of the
      disulfides studied. Combined with studies of the lability of the coordinated
      thiolate, a mechanism is proposed where the reactive species is the zinc
      coordinated thiolate. When the free benzyl thiol was allowed to react with the
      same disulfides, the reaction was slower by a factor of 20-200 than that for the
      zinc-thiolate complex, depending on the particular disulfide employed. Since most
      metallo-beta-lactamases contain one or more cysteine residues, the one in the
      active site being coordinated to zinc, the present study was extended to examine
      whether disulfides can be used as inhibitors of these enzymes by selective
      oxidation of the metal-bound cysteine. Several disulfides allowed to react with
      metallo-beta-lactamase CcrA from Bacteroides fragilis were moderate to potent
      irreversible inhibitors of the enzyme.

PMID- 12611530
TI  - First anionic 1,10-phenanthroline-2,9-dicarboxylate containing metal complex
      obtained from a novel 1:1 proton-transfer compound: synthesis, characterization,
      crystal structure, and solution studies.
AB  - The new 1,10-phenanthroline containing 1:1 proton-transfer compound LH(2),
      [pyda.H(2)](2+)[phendc](2-), was synthesized from the reaction of 2,6
      pyridinediamine, pyda, and 1,10-phenanthroline-2,9-dicarboxylic acid,
      phendc.H(2), and characterized by elemental analysis, ES-Ms, IR, (1)H, (13)C NMR,
      and UV/vis spectroscopies. Subsequently, the first example of [phendc](2)(-)
      containing anionic complex [pyda.H](2)[Co(phendc)(2)].10H(2)O, was prepared,
      using the above novel proton-transfer compound, and structurally characterized by
      single-crystal X-ray diffraction. The complex crystallizes in the space group
      P2(1)/n of the monoclinic system with four molecules in a unit cell of dimensions
      a = 11.877(3) A, b = 31.473(9) A, c = 12.915(4) A, and beta = 116.223(5) degrees.
      The structure has been refined to a final value for the crystallographic R factor
      of 0.0524 based on 9021 observed independent reflections. The complexation
      reactions of pyda, phendc.H(2), and LH(2) with H(+) as well as LH(2) with Co(II)
      in aqueous solution were investigated by potentiometric pH titrations, and the
      equilibrium constants for all major complexes formed are described. The results
      are presented in the form of distribution diagrams revealing the concentrations
      of individual complex species as a function of pH. The results revealed that, at
      a pH range of 5.2-6.2, the major complex species is [(pyda.H)](2)[Co(phendc)(2)],
      similar to the isolated crystalline complex.

PMID- 12611531
TI  - Substantial increase of the ordering temperature for [MnII/MoIII(CN)7]-based
      magnets as a function of the 3d ion site geometry: example of two supramolecular
      materials with Tc = 75 and 106 K.
AB  - Two molecule-based magnets, [Mn(2)(tea)Mo(CN)(7)].H(2)O, 1, and
      [Mn(2)(tea)Mo(CN)(7)], 2 (tea stands for triethanolamine), formed with the 4d ion
      building block, [Mo(CN)(7)](4)(-), Mn(II) ions, and an additional ligand, tea,
      have been prepared and structurally characterized by single-crystal X-ray
      analyses. Whereas 1 is obtained by a self-assembling process in solution,
      compound 2 is quantitatively formed through a smooth thermal treatment of 1.
      Their magnetic properties revealed that these compounds exhibit magnetic ordering
      at T(c) = 75 and 106 K respectively for compounds 1 and 2. The difference for
      their critical temperature is attributed to the geometry of the coordination
      sphere of a Mn(II) site found to be square-pyramidal for 1 and tetrahedral for 2.

PMID- 12611532
TI  - Monitoring the redox-driven assembly/disassembly of a dicopper(I) helicate with
      an auxiliary fluorescent probe.
AB  - The assembly/disassembly of a dicopper(I) helicate with a bis-bidentate imine
      quinoline ligand is driven by the Cu(II)/Cu(I) redox change and is signaled by a
      fluorescent probe bearing a -COO(-) group (coumarine 343). The probe coordinates
      the Cu(II) center of the monomeric complex, which quenches its emission
      (fluorescence off), and is released upon reduction and formation of the Cu(I)
      helicate (fluorescence on).

PMID- 12611533
TI  - Assembly of discrete, one-, two-, and three-dimensional silver(I) supramolecular
      complexes containing encapsulated acetylide dianion with nitrogen-donor spacers.
AB  - The first successful attempt to construct supramolecular entities via
      incorporation of bifunctional exodentate ligands into the silver acetylide system
      is reported. Coordination assembly with nitrogen-donor spacers led to the
      formation of five distinct supramolecular complexes, namely
      [(Ag(2)C(2))(AgCF(3)CO(2))(4)(pyz)(2)](n) (1),
      [(Ag(2)C(2))(2)(AgCF(3)CO(2))(10)(CF(3)CO(2))(4)(DabcoH)(4)(H(2)O)(1.5)].H(2)O
      (2), [(Ag(2)C(2))(AgCF(3)CO(2))(4)(CF(3)CO(2))(bpaH)](n)() (3),
      [(Ag(2)C(2))(AgCF(3)CO(2))(8)(bpa)(4)](n) (4), and
      [(Ag(2)C(2))(2)(AgCF(3)CO(2))(10)(bppz)(2)(H(2)O)](n) (5) (pyz = pyrazine; Dabco
      = 1,4-diazabicyclo[2.2.2]octane; bpa = 1,2-bis(4-pyridyl)ethane; bppz = 2,3-bis(2
      pyridyl)pyrazine). Complex 1 is a three-dimensional framework composed of silver
      columns cross-linked by pyrazine bridges, whereas 2 contains a discrete
      supermolecule whose core is a Ag(14) double cage that is completely surrounded by
      trifluoroacetate, aqua, and terminal monoprotonated Dabco ligands. Complex 3 has
      a branched-tree architecture with one terminal of the bpa ligand attached to the
      silver backbone and the other exposed and protonated. In 4, neutral decanuclear
      [(Ag(2)C(2))(AgCF(3)CO(2))(8)] units are interlinked by bpa spacers adopting both
      gauche and anti conformations to generate a layer structure. Another two
      dimensional network was formed with bppz serving as an angular bridging ligand in
      5, in which the building unit is a silver quadruple cage containing 24 silver
      atoms.

PMID- 12611534
TI  - Electronic structure of iron chlorins: characterization of bis(l-valine methyl
      ester)(meso-tetraphenylchlorin)iron(III)triflate and bis(l-valine methyl
      ester)(meso-tetraphenylchlorin)iron(II).
AB  - The synthesis and characterization of the two iron chlorin complexes
      [Fe(III)(TPC)(NH(2)CH(CO(2)CH(3))(CH(CH(3))(2)))(2)]CF(3)SO(3) (1) and
      Fe(II)(TPC)[(NH(2)CH(CO(2)CH(3))(CH(CH(3))(2))](2) (2) are reported. The crystal
      structure of complex 1 has been determined. The X-ray structure shows that the
      porphyrinate rings are weakly distorted. The metal-nitrogen distances to the
      reduced pyrrole N(4), 2.034(4) A, and to the pyrrole trans to it N(2), 2.012(4)
      A, are longer than the distances to the two remaining nitrogens [N(1), 1.996(4)
      A, and N(3), 1.984(4) A], leading to a core-hole expansion of the macrocycle due
      to the reduced pyrrole. The (1)H NMR isotropic shifts at 20 degrees C of the
      different pyrrole protons of 1 varied from -0.8 to -48.3 ppm according to bis
      ligated complexes of low-spin ferric chlorins. The EPR spectrum of
      [Fe(TPC)(NH(2)CH(CO(2)CH(3))(CH(CH(3))(2)))(2)]CF(3)SO(3) (1) in solution is
      rhombic and gives the principal g values g(1) = 2.70, g(2) = 2.33, and g(3) =
      1.61 (Sigmag(2) = 15.3). These spectroscopic observations are indicative of a
      metal-based electron in the d(pi) orbital for the
      [Fe(TPC)(NH(2)CH(CO(2)CH(3))(CH(CH(3))(2)))(2)]CF(3)SO(3) (1) complex with a
      (d(xy))(2)(d(xz)d(yz))(3) ground state at any temperature. The X-ray structure of
      the ferrous complex 2 also shows that the porphyrinate rings are weakly
      distorted. The metal-nitrogen distances to the reduced pyrrole N(4), 1.991(5) A,
      and to the pyrrole trans to it N(2), 2.005(6) A, are slightly different from the
      distances to the two remaining nitrogens [N(1), 1.988(5) A, and N(3), 2.015(5)
      A], leading to a core-hole expansion of the macrocycle due to the reduced
      pyrrole.

PMID- 12611535
TI  - [Mo5VMo7VIO30(BPO4)2(O3P-Ph)6]5-: a phenyl-substituted molybdenum(V/VI) boro
      phosphate polyoxometalate.
AB  - The title polyanion is the first hybrid borophosphate-phenylphosphonate
      polyoxometalate. It was structurally characterized as its imidazolium salt,
      (C(3)N(2)H(5))(5)[Mo(12)O(30)(BPO(4))(2)(O(3)P-Ph)(6)].H(2)O (monoclinic,
      P2(1)/c, a = 22.120(3) A, b = 13.042(2) A, and c = 32.632(4) A, beta = 101.293(3)
      degrees ), which was synthesized hydrothermally from imidazole, molybdenum oxide
      and metal, and boric, phosphoric, and phenylphosphonic acids. The anion is the
      second example of a new class of polyoxometalates that resemble Dawson anions but
      where the two pole caps of three edge-sharing MoO(6) octahedra in the latter are
      replaced by other units, in this case tetrahedral borate sharing corners with
      three phenylphosphonic groups, [(OB)(O(3)P-Ph)(3)]. The 12 molybdenum atoms
      forming the two equatorial belts of the cluster are of mixed-valence, five are
      Mo(V) and seven are Mo(VI), and the resulting five electrons are delocalized.
      Four of these electrons are paired according to the temperature dependence of the
      magnetic susceptibility. The new compound is soluble in a mixture of water and
      pyridine (in equal volumes) as well as in nitromethane, and the anions are intact
      in these solutions.

PMID- 12611536
TI  - Hydrogen-bonded extended arrays of the [Re6(mu3-Se)8]2+ core-containing clusters.
AB  - Site-differentiated solvated clusters of the general formula [Re(6)(mu(3)
      Se)(8)(PEt(3))(n)(MeCN)(6)(-)(n)](SbF(6))(2) (n = 4, cis and trans; n = 5)
      undergo ligand substitution reaction with isonicotinamide to afford the
      corresponding amide derivatives, [Re(6)(mu(3)
      Se)(8)(PEt(3))(n)(isonicotinamide)(6)(-)(n)](2+) [1 (n = 5); 2 (n = 4, trans); 3
      (n = 4, cis)]. Retention of stereochemistry in each case was confirmed by (1)H
      and (31)P NMR. The solid-state structures of all three compounds were established
      crystallographically, which revealed self-complementary hydrogen-bonding
      interactions between adjacent cluster units. While complex 1 exists as hydrogen
      bonded dimers in the solid state, compounds 2 and 3 form one-dimensional chains
      of clusters bridged by paired hydrogen bonds. It is the rigid stereochemistry of
      the cluster, combined with the classic crystal engineering motif of complementary
      N-H.O amide hydrogen bonding, that affords the predictable solid-state structures
      and dimensionality.

PMID- 12611537
TI  - Photothermally induced Bergman cyclization of metalloenediynes via near-infrared
      ligand-to-metal charge-transfer excitation.
AB  - Reaction of 1,2-bis(tert-butyldimethylsilyloxy)-4,5-diiodobenzene with 2 equiv of
      phenylacetylene followed by deprotection with KF/HBr yields the catechol-enediyne
      ligand 4,5-bis(phenylethynyl)benzene-1,2-diol (CatED, 1). Metathesis of
      VO(SALIMH)ACAC.CH(3)OH (2) with 1 and subsequent air oxidation yields (4,5
      bis(phenylethynyl)-1,2-dihydroxyphenyl)[4-(2
      (salicylideneamino)ethyl)imidazolyl]oxovanadium(V).CH(3)OH [VO(SALIMH)CatED],
      (3), in 85%. The thermal Bergman cyclization temperature for 3 is very high (246
      degrees C), which is expected for a rigid, benzannulated enediyne motif. The
      electronic spectrum of 3 exhibits two strong ligand-to-metal charge transfer
      (LMCT) transitions centered at 584 nm (epsilon = 6063 M(-)(1) cm(-)(1)) and 1028
      nm (epsilon = 8098 M(-)(1) cm(-)(1)). These transitions derive from CatED-to-V(V)
      ligand-to-metal charge transfer, the assignment of which is verified by resonance
      enhancement of several CatED vibrational modes in the Raman spectra obtained with
      lambda = 785 vs lambda = 457.9 nm under low power and/or temperature conditions.
      At elevated temperatures (113-323 K) and powers (2-5 mW), excitation of 3 in the
      solid state with lambda = 785 nm leads to generation of a black, sparingly
      soluble, fluorescent product that exhibits weak vibrational features in the 580
      600, 1200-1350, and 1450-1600 cm(-)(1) regions, indicative of V-O (CatED) and
      aromatic ring units. The C=C ring modes correspond well with the vibrational
      characteristics of poly(p-phenylene) and derivatives thereof. Additionally,
      materials generated in both the solid-state thermal and photothermal reactions of
      3 demonstrate the formation of high molecular weight species ranging from 5000 to
      274 000. On the basis of these data and the literature precedent for formation of
      poly(p-phenylene) via thermolysis of simple enediynes, the reaction poses a
      unique approach for photoinitiating Bergman cyclization with long-wavelength
      excitation, as well as the generation of polymeric products.

PMID- 12611538
TI  - Synthesis and atructure of [meso-triarylcorrolato]silver(III).
AB  - An efficient meso-triarylcorrole synthesis is detailed, and the formation and
      spectroscopic properties of their diamagnetic square-planar d(8) Ag(III)
      complexes are described. The spectroscopic properties of the [corrolato]Ag(III)
      complexes are contrasted with those of the corresponding [porphyrinato]Ag(II)
      complexes. The oxidation state of the central metal in the corrolato complexes
      was inferred from their diamagnetic NMR spectra, from X-ray photoelectron
      spectroscopy measurements, and by single-crystal X-ray diffractometry of the
      [meso-tetra-p-tolylcorrolato]silver(III) complex TTCAg(III), as its toluene
      solvate (crystal data for C(40)H(29)N(4)Ag.C(7)H(8): monoclinic space group C2/c
      with a = 21.4679(19) A, b = 20.7606(19) A, c = 16.0122(11) A, beta = 93.700(4)
      degrees, V = 7121.5(10) A(3), Z = 8, R = 0.0453, and R(w) = 0.1131). The
      conformation of the corrolato ligand in the complex is slightly saddled. The
      Ag(III) complexes are without precedent in the coordination chemistry of
      corroles. The Ag(III) complexes underline the ability of meso-triarylcorroles to
      stabilize higher oxidation states as compared to the corresponding meso
      tetraarylporphyrinato complexes.

PMID- 12611539
TI  - Reaction of (mu-oxo)diiron(III) core with CO2 in N-methylimidazole: formation of
      mono(mu-carboxylato)(mu-oxo)diiron(III) complexes with N-methylimidazole as
      ligands.
AB  - Several iron(III) complexes with N-methylimidazole (N-MeIm) as the ligand have
      been synthesized by using N-MeIm as the solvent. Under anaerobic conditions,
      [Fe(N-MeIm)(6)](ClO(4))(3) (1) reacts with stoichiometric amounts of water in N
      MeIm to afford the (mu-oxo)diiron(III) complex, [Fe(2)(mu-O)(N
      MeIm)(10)](ClO(4))(4) (3). Exposure of a solution of 3 in N-MeIm to
      stoichiometric and excess CO(2) gives rise to the (mu-oxo)(mu
      carboxylato)diiron(III) species [Fe(2)(mu-O)(mu-HCO(2))(N-MeIm)(8)](ClO(4))(3)
      (4) and the methyl carbonate complex [Fe(2)(mu-O)(mu-CH(3)OCO(2))(N
      MeIm)(8)](ClO(4))(3) (5), respectively. Formation of the formato-bridged complex
      4 upon fixation of CO(2) by 3 in N-MeIm is unprecedentated. Methyl transfer from
      N-MeIm to a bicarbonato-bridged (mu-oxo)diiron(III) intermediate appears to give
      rise to 5. Complex 3 is a good starting material for the synthesis of (mu
      oxo)mono(mu-carboxylato)diiron(III) species [Fe(2)(mu-O)(mu-RCO(2))(N
      MeIm)(8)](ClO(4))(3) (where R = H (4), CH(3) (6), or C(6)H(5) (7)); addition of
      the respective carboxylate ligand in stoichiometric amount to a solution of 3 in
      N-MeIm affords these complexes in high yields. Attempts to add a third bridge to
      complexes 4, 6, and 7 to form the (mu-oxo)bis(mu-carboxylato)diiron(III) species
      result in the isolation of the previously known triiron(III) mu-eta(3)-oxo
      clusters [[Fe(mu-RCO(2))(2)(N-MeIm)](3)O](ClO(4)) (8). The structures of 3, 4, 6,
      and 7 allow one, for the first time, to inspect the various features of the
      [Fe(2)(mu-O)(mu-RCO(2))](3+) moiety with no strain from the ligand framework.

PMID- 12611540
TI  - Electronic tuning of the lability of Pt(II) complexes through pi-acceptor
      effects. Correlations between thermodynamic, kinetic, and theoretical parameters.
AB  - pi-Acceptor effects are often used to account for the unusual high lability of
      [Pt(terpy)L]((2)(-)(n)+) (terpy = 2,2':6',2' '-terpyridine) complexes. To gain
      further insight into this phenomenon, the pi-acceptor effect was varied
      systematically by studying the lability of [Pt(diethylenetriamine)OH(2)](2+)
      (aaa), [Pt(2,6-bis-aminomethylpyridine)OH(2)](2+) (apa), [Pt(N-(pyridyl-2-methyl)
      1,2-diamino-ethane)OH(2)](2+) (aap), [Pt(bis(2-pyridylmethyl)amine)OH(2)](2+)
      (pap), [Pt(2,2'-bipyridine)(NH(3))(OH(2))](2+) (app), and [Pt(terpy)OH(2)](2+)
      (ppp). The crystal structure of the apa precursor [Pt(2,6-bis
      aminomethylpyridine)Cl]Cl.H(2)O was determined. The substitution of water by a
      series of nucleophiles, viz. thiourea, N,N-dimethylthiourea, N,N,N',N'
      tetramethylthiourea, I(-), and SCN(-), was studied under pseudo-first-order
      conditions as a function of concentration, pH, temperature, and pressure, using
      stopped-flow techniques. The data enable an overall comparison of the
      substitution behavior of these complexes, emphasizing the role played by the
      kinetic cis and trans pi-acceptor effects. The results indicate that the cis pi
      acceptor effect is larger than the trans pi-acceptor effect, and that the pi
      acceptor effects are multiplicative. DFT calculations at the B3LYP/LACVP level of
      theory show that, by the addition of pi-acceptor ligands to the metal, the
      positive charge on the metal center increases, and the energy separation of the
      frontier molecular orbitals (E(LUMO) - E(HOMO)) of the ground state Pt(II)
      complexes decreases. The calculations collectively support the experimentally
      observed additional increase in reactivity when two pi-accepting rings are
      adjacent to each other (app and ppp), which is ascribed to "electronic
      communication" between the pyridine rings. The results furthermore indicate that
      the pK(a) value of the platinum bound water molecule is controlled by the pi
      accepting nature of the chelate system and reflects the electron density around
      the metal center. This in turn controls the rate of the associative substitution
      reaction and was analyzed using the Hammett equation.

PMID- 12611541
TI  - Bonding coordination requirements induce antiferromagnetic coupling between m
      phenylene bridged o-iminosemiquinonato diradicals.
AB  - Triply bridged bis-iminodioxolene dinuclear metal complexes of general formula
      M(2)(diox-diox)(3), with M = Co, Fe, have been synthesized using the bis
      bidentate ligand N,N'-bis(3,5-di-tert-butyl-2-hydroxyphenyl)-1,3
      phenylenediamine. These complexes were characterized by means of X-ray, HF-EPR,
      and magnetic measurements. X-ray structures clearly show that both complexes can
      be described as containing three bis-iminosemiquinonato ligands acting in a bis
      bidentate manner toward tripositive metal ions. The magnetic data show that both
      of these complexes have singlet ground states. The observed experimental behavior
      indicates the existence of intraligand antiferromagnetic interactions between the
      three pairs of m-phenylene units linked iminosemiquinonato radicals (J = 21 cm(
      )(1) for the cobalt complex and J = 11 cm(-)(1) for the iron one). It is here
      suggested that the conditions for the ferromagnetic coupling that is expected to
      characterize the free diradical ligand are no longer satisfied because of the
      severe torsional distortion induced by the metal coordination.

PMID- 12611542
TI  - Dinitrogen formation by oxidative intramolecular N---N coupling in cis,cis
      [(bpy)2(NH3)RuORu(NH3)(bpy)2]4+.
AB  - The (15)N-labeled diammine(mu-oxo)ruthenium complex cis,cis
      [(bpy)(2)(H(3)(15)N)Ru(III)ORu(III)((15)NH(3))(bpy)(2)](4+) ((2-(15)N)(4+)) was
      synthesized from cis,cis-[(bpy)(2)(H(2)O)Ru(III)ORu(III)(H(2)O)(bpy)(2)](4+) by
      using ((15)NH(4))(2)SO(4) and isolated as its perchlorate salt in 17% yield. A
      1:1 mixture of (2-(15)N)(4+) and nonlabeled cis,cis
      [(bpy)(2)(H(3)(14)N)Ru(III)ORu(III)((14)NH(3))(bpy)(2)](4+) were
      electrochemically oxidized in aqueous solution. The gaseous products (14)N(2) and
      (15)N(2) were formed in equimolar amounts with only a small amount of (14)N(15)N
      detected. This demonstrates that dinitrogen formation by oxidation of the
      diammine complex proceeds by intramolecular N---N coupling.

PMID- 12611543
TI  - Encapsulation of cobalt phthalocyanine in zeolite-y: evidence for nonplanar
      geometry.
AB  - Cobalt (II) phthalocyanine (CoPc) molecules have been encapsulated within the
      supercage of zeolite-Y. The square-planar complex, being larger than the almost
      spherical cage, is forced to adopt a distorted geometry on encapsulation. A
      comparative spectroscopic and magnetic investigation of CoPc encapsulated in
      zeolite-Y and in the unencapsulated state is reported. These results supported by
      molecular modeling have been used to understand the nature and extent of the loss
      of planarity of CoPc on encapsulation. The encapsulated molecule is shown to be
      the trans-diprotonated species in which the center of inversion is lost due to
      distortions required to accommodate the square complex within the zeolite.
      Encapsulation also leads to an enhancement of the magnetic moment of the CoPc.
      This is shown to be a consequence of the nonplanar geometry of the encapsulated
      molecule resulting in an excited high-spin state being thermally accessible.

PMID- 12611544
TI  - Nickel complexes of a bulky beta-diketiminate ligand.
AB  - Nickel(II) chloride forms a complex with tetrahydrofuran, NiCl(2)(THF)(1.5), that
      can be used to prepare nickel chloride complexes of a bulky beta-diketiminate
      ligand L(Me). [L(Me)NiCl](2) and L(Me)NiCl(2)LiTHF(2), which have tetrahedral
      geometries in the solid state, are in equilibrium with three-coordinate
      L(Me)NiCl. Thermodynamic parameters for the equilibrium between [L(Me)NiCl](2)
      and L(Me)NiCl are DeltaH = 51(5) kJ/mol and DeltaS = 116(11) J/(mol.K). L(Me)NiCl
      forms a tetrahydrofuran complex with a binding constant of 1.2(2) M(-)(1) at 21
      degrees C. The chloride complexes were used to generate a three-coordinate
      nickel(II)-amido complex. This amido complex, L(Me)NiN(SiMe(3))(2), is compared
      with L(Me)MN(SiMe(3))(2) (M = Mn, Fe, Co) (Panda, A.; Stender, M.; Wright, R. J.;
      Olmstead, M. M.; Klavins, P.; Power, P. P. Inorg. Chem. 2002, 41, 3909-3916).
      Trends in the metrical parameters of the three-coordinate L(Me)M(II) amido
      compounds are similar to the trends in three-coordinate L(tBu)M(II) chloride
      compounds (Holland, P. L.; Cundari, T. R.; Perez, L. L.; Eckert, N. A.;
      Lachicotte, R. J. J. Am. Chem. Soc. 2002, 124, 14416-14424).

PMID- 12611545
TI  - Stability of divalent europium in an ionic liquid: spectroscopic investigations
      in 1-methyl-3-butylimidazolium hexafluorophosphate.
AB  - In this work, devoted to 1-methyl-3-butylimidazolium hexafluorophosphate ionic
      liquid (BumimPF(6)), the importance of the purity of the solvent for
      spectroscopic investigations is highlighted. Results from small angle X-ray
      scattering indicate that the pure solvent exhibits a local organization.
      Europium(II), which appears to be unusually stable in BumimPF(6), is
      characterized by spectroscopic techniques (absorption, luminescence). Solvation
      of Eu(II) in BumimPF(6) and complexation effects in the presence of the crown
      ether 15C5 solubilized in the ionic liquid are discussed.

PMID- 12611546
TI  - Mn(approximately)2.4Mo6O9: first example of empty twin chains of edge-sharing M6
      octahedra in transition metal cluster chemistry.
AB  - The novel ternary reduced molybdenum oxide Mn(approximately)(2.4)Mo(6)O(9) has
      been synthesized by solid-state reaction at 1400 degrees C for 96 h in sealed
      molybdenum crucibles. Electron diffraction studies showed that
      Mn(approximately)(2.4)Mo(6)O(9) presents a complex crystal structure with a 3d
      incommensurate modulation. The average crystal structure was determined on a
      single-crystal by X-ray diffraction in the orthorhombic space group Pnma with the
      following lattice parameters: a = 16.4824(2) A, b = 2.8273(2) A, c = 17.3283(2)
      A, Z = 4. The Mo network consists of empty twin chains of trans-edge-sharing
      octahedra that occur for the first time in a solid-state compound. The Mo-Mo
      distances within the chains range from 2.62 to 2.92 A, and the Mo-O distances
      from 1.99 to 2.17 A as usually observed in the reduced molybdenum oxides. Single
      crystal resistivity measurements show that Mn(approximately)(2.4)Mo(6)O(9) is
      metallic between 4.2 and 300 K. The magnetic susceptibility data indicate
      paramagnetic behavior due to the Mn(2+) moment at high temperatures with a weak
      ferromagnetic behavior below 80 K.

PMID- 12611548
TI  - Generation of a peroxynitrato metal complex from nitrogen dioxide and coordinated
      superoxide.
AB  - The reaction between photogenerated NO(2) radicals and a superoxochromium(III)
      complex, Cr(aq)OO(2+), occurs with rate constants k(Cr)(20) = (2.8 +/- 0.2) x
      10(8) M(-)(1) s(-)(1) (20 vol % acetonitrile in water) and k(Cr)(40) = (2.6 +/-
      0.5) x 10(8) M(-)(1) s(-)(1) (40 vol % acetonitrile) in aerated acidic solutions
      and ambient temperature. The product was deduced to be a peroxynitrato complex,
      Cr(aq)OONO(2)(2+), which undergoes homolytic cleavage of an N-O bond to return to
      the starting materials, the rate constants in the two solvent mixtures being
      k(H)(20) = 172 +/- 4 s(-)(1) and k(H)(40) = 197 +/- 7 s(-)(1). NO(2) reacts
      rapidly with 10-methyl-9,10-dihydroacridine, k(A)(20) = 2.2 x 10(7) M(-)(1) s(
      )(1), k(A)(40) = (9.4 +/- 0.2) x 10(6) M(-)(1) s(-)(1), and with N,N,N',N'
      tetramethylphenylenediamine, k(T)(40) = (1.84 +/- 0.03) x 10(8) M(-)(1) s(-)(1).

PMID- 12611547
TI  - Synthesis, structure, and magnetic properties of two new vanadocarboxylates with
      three-dimensional hybrid frameworks.
AB  - (V(III)(OH))(2)[C(6)H(2)(CO(2))(4)].4H(2)O (labeled MIL-60) and
      V(III)(OH)[(2)(O(2)C)C(6)H(2)(COOH)(2)].H(2)O (labeled MIL-61) were
      hydrothermally synthesized from mixtures of VCl(3), 1,2,4,5
      benzenetetracarboxylic acid, and water heated for 3 days at 473 K. The structure
      of MIL-60 was solved from single-crystal X-ray diffraction data in the triclinic
      centrosymmetric P1 (No. 2) space group with lattice parameters a = 6.3758(5) A, b
      = 6.8840(5) A, c = 9.0254(5) A, alpha = 69.010(2) degrees, beta = 85.197(2)
      degrees, gamma = 79.452(2) degrees, V = 363.53(5) A(3), and Z = 1. The structure
      of MIL-61 was ab initio determined from an X-ray powder diffraction pattern. MIL
      61 crystallizes in the Pnma (No. 62) orthorhombic space group with lattice
      parameters a = 14.8860(1) A, b = 6.9164(1) A, c = 10.6669(2) A, V = 1098.23(3)
      A(3), and Z = 4. Both structures contain the same inorganic building block that
      consists of trans chains of V(III)O(4)(OH)(2) octahedra. The three-dimensional
      frameworks of MIL-60 and MIL-61 are constituted by the linkage of these chains
      via the organic molecules so delimiting the channels or cages where the water
      molecules are encapsulated. The magnetic behavior of these two phases is
      presented: MIL-60 is paramagnetic, and MIL-61 antiferromagnetically orders below
      T(N) = 55(5) K.

PMID- 12611549
TI  - Syntheses, structures, and dynamic behavior of chiral racemic organoantimony and 
      bismuth compounds RR'SbCl, RR'BiCl, and RR'SbM [R = 2-(Me2NCH2)C6H4, R' =
      CH(Me3Si)2, M = H, Li, Na].
AB  - RR'SbCl (1) and RR'BiCl (2) [R = 2-(Me(2)NCH(2))C(6)H(4), R' = CH(Me(3)Si)(2)]
      form by the reaction of R'ECl(2) (E = Sb, Bi) with RLi. The reaction of 1 with
      LiAlH(4) and metalation with n-BuLi gives RR'SbH (3) and RR'SbLi.2THF (4) (THF =
      tetrahydrofuran). Transmetalation of 4 with sodium tert-butoxide in the presence
      of TMEDA (TMEDA = tetramethylethylenediamine) leads to RR'SbNa.TMEDA (5).
      Structural analyses by (1)H NMR in C(6)D(6), C(6)D(5)CD(3), or (CD(3))(2)SO with
      a variation of the temperature (1, 2, 4, and 5) and by single-crystal X-ray
      diffraction (1, 2, 4, and 5) revealed the intramolecular coordination of the
      pendant Me(2)N group on the pnicogen centers in 1 and 2 and on Li or Na in 4 or
      5. The variable-temperature (1)H NMR spectra of the hydride 3 in C(6)D(6),
      C(6)D(5)CD(3), or (CD(3))(2)SO show that the pyramidal configuration on antimony
      is stable up to 100 degrees C, whereas inversion at the nitrogen is not prevented
      by internal coordination even at -80 degrees C. The crystals of 1, 2, 4, and 5
      consist of discrete molecules with the Sb and Bi atoms in an approximately Psi
      trigonal-bipyramidal environment in the cases of 1 and 2 and in a pyramidal
      environment in the cases of 4 and 5. Crystal data for 1: triclinic, space group
      Ponemacr;, a = 7.243(4) A, b = 10.373(3) A, c = 15.396(5) A, alpha = 79.88
      degrees, beta = 78.27 degrees, gamma = 71.480(10) degrees, V = 1066.2(7) A(3), Z
      = 2, R = 0.0614. 2: monoclinic, space group P2(1)/n, a = 10.665(2) A, b =
      14.241(2) A, c = 14.058(2) A, beta = 90.100(10) degrees, V = 2135.1(6) A(3), Z =
      4, R = 0.049. 4: monoclinic, space group P2(1)/n, a = 11.552(2) A, b = 16.518(3)
      A, c = 15.971(5) A, beta = 96.11(2) degrees, V = 3030.2(12) A(3), Z = 4, R =
      0.0595. 5: monoclinic, space group P2(1)/n, a = 9.797(2) A, b = 24.991(5) A, c =
      14.348(3) A, beta = 94.98(3) degrees, V = 3499.66(12) A(3), Z = 4, R = 0.0571.
      The dissociation of the intramolecular N-pnicogen bond and inversion at the
      nitrogen occurs when solutions of 1 or 2 in C(6)D(6) or C(6)D(5)CD(3) are heated
      above 25 or 30 degrees C. 1 and 3-5 are stable with respect to inversion of the
      configuration at the antimony in C(6)D(6), C(6)D(5)CD(3), or (CD(3))(2)SO up to
      160 degrees C. Bismuth inversion, probably via the edge mechanism, is observed in
      solutions of 2 in (CD(3))(2)SO at 45 degrees C but not in C(6)D(5)CD(3) below 125
      degrees C.

PMID- 12611550
TI  - Syntheses and structures of metallocene methyltrihydroborate derivativies:
      Cp2ZrCl[(mu-H)2BHCH3], Cp2Zr[(mu-H)2BHCH3]2, and Cp2Ti[(mu-H)2BHCH3].
AB  - In reactions of zirconocene dichloride, Cp(2)ZrCl(2), with 1 equiv and an excess
      amount of LiBH(3)CH(3), the methyltrihydroborate complexes, Cp(2)ZrCl[(mu
      H)(2)BHCH(3)], 1, and Cp(2)Zr[(mu-H)(2)BHCH(3)](2), 2, were isolated. The
      reaction of titanocene dichloride, Cp(2)TiCl(2), with an excess amount of
      LiBH(3)CH(3) produced the monosubstituted methyltrihydroborate complex,
      Cp(2)Ti[(mu-H)(2)BHCH(3)], 3. The titanium was reduced from Ti(IV) to Ti(III),
      producing a 17-electron, paramagnetic titanocene complex. Under a dynamic vacuum
      at room temperature, compound 2 decomposed and produced the zirconium hydride
      compound Cp(2)ZrH[(mu-H)(2)BHCH(3)]. Single crystal X-ray structures of 1, 2, and
      3 were determined. Crystal data for 1: space group P2(1)/c, a = 13.7921(3) A, b =
      13.4227(3) A, c = 13.0868(3) A, beta = 91.6448(12) degrees, Z = 8. Crystal data
      for 2: space group Pna2(1), a = 15.2949(4) A, b = 9.3417(2) A, c = 9.3211(2) A, Z
      = 4. Crystal data for 3: space group Fmm2, a = 9.1795(3) A, b = 13.0993(5) A, c =
      8.8520(3) A, Z = 4.

PMID- 12611551
TI  - New low-temperature preparations of some simple and mixed co and ni dispersed
      sulfides and their chemical behavior in reducing atmosphere.
AB  - A series of simple (CoS(2), Co(9)S(8), NiS(2), NiS, Ni(3)S(2)) and mixed sulfides
      (NiCo(2)S(4), Ni(0.33)Co(0.67)S(2), Ni(3)Co(6)S(8), CuCo(2)S(4),
      Cu(0.33)Co(0.67)S(2)) was prepared using low-temperature procedures. To obtain
      the mixed sulfides, the mixtures of the solutions of the corresponding salts were
      precipitated by Na(2)S and then heated in a sulfiding atmosphere at 300 degrees
      C. It has been found that the product phase composition depends on the sulfiding
      atmosphere. Using a H(2)S/Ar mixture leads to pyrite type sulfides, whereas
      treatment in H(2)S/H(2) flow allowed the preparation of Ni-Co and Cu-Co
      thiospinels. The as prepared highly dispersed single-phase materials were
      characterized by X-ray powder diffraction, scanning electron microscopy,
      temperature-programmed reduction (TPR), elemental analysis, and BET surface area
      measurements.

PMID- 12611552
TI  - Synthesis and molecular structure of the dihydrobis(thioxotriazolinyl)borato
      complexes of zinc(II), bismuth(III), and nickel(II). M...H-B interaction studied
      by Ab initio calculations.
AB  - Reacting the heterocycle 5-thioxo-1,4-dihydro-4-ethyl-3-methyl-1,2,4-triazole
      (thioxotriazoline) with sodium tetrahydroborate in the molar ratio of
      approximately 2:1 at 130 degrees C provides the new ligand
      dihydrobis(thioxotriazolinyl)borato, [Bt(Et,Me)](-), as its sodium salt. The
      neutral complexes of this anionic ligand with zinc(II), bismuth(III), and
      nickel(II) have been synthesized and characterized by X-ray crystallography. In
      every complex, the ligand is coordinated to the metal in the S(2) mode,
      generating eight-membered chelate rings. The bismuth and nickel complexes exhibit
      two M.H-B interactions responsible for the dodecahedral and octahedral
      geometries, respectively. For the zinc complex, the trigonal-bipyramidal
      coordination is achieved with an apical Zn.H-B interaction. The crystal
      structures for the three complexes are described, and ab initio calculations on
      Bi(III), Ni(II), and Zn(II) compounds have been performed in order to assess the
      nature of the M.H-B interaction and its role for the definition of the molecular
      geometries.

PMID- 12611553
TI  - Synthesis and structure of Sr3GaN3 and Sr6GaN5: strontium gallium nitrides with
      isolated planar [GaN3]6- anions.
AB  - Two new strontium gallium nitrides were obtained as single crystals by reaction
      in molten Na. Black Sr(3)GaN(3) is isostructural with its transition metal
      analogues, Sr(3)MnN(3), Ba(3)MnN(3), Sr(3)CrN(3), Ba(3)CrN(3), and Ba(3)FeN(3),
      and is the first example of a 313-ternary nitride containing only main group
      metals. It crystallizes in space group P6(3)/m (No. 176) with a = 7.584(2) A, c =
      5.410(3) A, and Z = 2. Black Sr(6)GaN(5) is isostructural with Ca(6)GaN(5) and
      also with its transition metal analogues, Ca(6)MnN(5) and Ca(6)FeN(5). It
      crystallizes in space group P6(3)/mcm (No. 193) with a = 6.6667(6) A, c =
      12.9999(17) A, and Z = 2. Both Ga compounds contain isolated planar [GaN(3)](6)(
      ) nitridometallate anions of D(3)(h)() symmetry.

PMID- 12611555
TI  - Treatment with enteric-coated peppermint oil reduced small-intestinal bacterial
      overgrowth in a patient with irritable bowel syndrome.

PMID- 12611557
TI  - The methionine-homocysteine cycle and its effects on cognitive diseases.
AB  - Homocysteine, a sulfur-containing amino acid, is a metabolite of the essential
      amino acid methionine, and exists at a critical biochemical intersection in the
      methionine cycle - between S-adenosylmethionine, the indispensable ubiquitous
      methyl donor, and vitamins B12 and folic acid. High blood levels of homocysteine
      signal a breakdown in this vital process, resulting in far-reaching biochemical
      and life consequences. The link between homocysteine and cardiovascular disease
      is well established, and decreasing plasma total homocysteine by providing
      nutritional cofactors for its metabolism has been shown to reduce the risk of
      cardiovascular events. Information has been emerging regarding a connection
      between homocysteine metabolism and cognitive function, from mild cognitive
      decline (age-related memory loss) to vascular dementia and Alzheimer's disease.
      Significant deficiencies in the homocysteine re-methylation cofactors cobalamin
      (B12) and folate, as well as the trans-sulfuration cofactor vitamin B6, are
      commonly seen in the elderly population, with a resultant increase in
      homocysteine with advancing age. Hyperhomocysteinemia has been shown to be an
      independent risk factor for cognitive dysfunction. Indirect and direct vascular
      damage can be caused by homocysteine, which has been implicated in vascular
      dementia, with an increased risk of multiple brain infarcts and dementia as
      homocysteine levels rise. A significant correlation has been found between risk
      of Alzheimer's disease and high plasma levels of homocysteine, as well as low
      levels of folic acid, and vitamins B6 and B12. All of these disease associations
      are thought to be interrelated via increased homocysteine and S
      adenosylhomocysteine and subsequent hypomethylation of numerous substances,
      including DNA and proteins, that render vascular structures and neurons more
      susceptible to damage and apoptosis. Providing the nutritional cofactors for
      proper functioning of the methionine cycle may improve methylation and protect
      the brain from damage. Further studies need to be performed to assess whether
      this will also reduce the risk of cognitive diseases and/or improve cognitive
      functioning.

PMID- 12611558
TI  - Therapeutic applications of fenugreek.
AB  - Fenugreek has a long history of medical uses in Ayurvedic and Chinese medicine,
      and has been used for numerous indications, including labor induction, aiding
      digestion, and as a general tonic to improve metabolism and health. Preliminary
      animal and human trials suggest possible hypoglycemic and antihyperlipidemic
      properties of oral fenugreek seed powder.

PMID- 12611559
TI  - Can CAM therapies help reduce antibiotic resistance?
AB  - The Centers for Disease Control and Prevention (CDC) reported the consumption of
      235 million doses of antibiotics in 2001. It is estimated that 20-50 percent of
      these were unnecessarily prescribed for viral infections. Bacteria that
      antibiotics have controlled in the past are increasingly developing resistance to
      these drugs. Today, virtually all important bacterial infections in the United
      States and throughout the world are becoming resistant. For this reason,
      antibiotic resistance is among the CDC's top concerns. A large portion of
      antibiotics are dispensed by pediatricians treating common outpatient infectious
      diseases. The overuse of antimicrobials is beginning to be discouraged as
      scientific evidence is emerging to support the use of other therapies. In
      pediatric practice an emphasis on accurate diagnoses, control of environmental
      risk factors, and utilization of complementary and alternative medicine (CAM)
      therapies could reduce antibiotic prescribing. Antibiotic resistance poses a
      growing threat to health. CAM therapies may provide a safer, more effective
      treatment for many acute infections of childhood.

PMID- 12611560
TI  - The interaction of cigarette smoking and antioxidants. Part III: ascorbic acid.
AB  - The requirement for antioxidant nutrients depends on a person's exposure to
      endogenous and exogenous reactive oxygen species. Since cigarette smoking results
      in an increased cumulative exposure to reactive oxygen species from both sources,
      it would seem cigarette smokers might have an increased requirement for
      antioxidant nutrients. This review examines available evidence of ascorbic acid
      supplementation and combinations of antioxidants as interventions in smokers and
      their effect on functional biomarkers of nicotine metabolism, oxidative stress,
      DNA damage, and endothelial function.

PMID- 12611561
TI  - A case of early renal functional impairment resolved with nutrients and
      botanicals.
AB  - The use of three herbal/nutritional products over a period of two months
      normalized blood urea nitrogen (BUN), serum creatinine, and creatinine clearance
      in a case of early functional kidney impairment. Although previous use of
      intravenous EDTA resolved Raynaud's syndrome symptoms, it provided little
      improvement to abnormal creatinine clearance.

PMID- 12611562
TI  - Thiamine. Monograph.

PMID- 12611564
TI  - Astragalus membranaceus. Monograph.

PMID- 12611563
TI  - Selenium. Monograph.

PMID- 12611565
TI  - Department of surgery, The Johns Hopkins Medical Institutions.

PMID- 12611566
TI  - Factors affecting esophageal motility in gastroesophageal reflux disease.
AB  - BACKGROUND: There are conflicting data concerning the effect of gastroesophageal
      reflux disease (GERD) on esophageal motor function. HYPOTHESIS: Duration of GERD
      might affect severity of symptoms, grade of esophageal mucosal injury, and
      esophageal motor behavior. DESIGN: Retrospective study of a defined cohort.
      SETTINGS: Two referral centers, one of them academic, for esophageal
      gastrointestinal motility disorders. PATIENTS: One hundred forty-seven patients
      with documented GERD. MAIN OUTCOME MEASURES: Symptoms, grade of mucosal injury on
      esophagoscopy, esophageal manometry, ambulatory esophageal pH monitoring, and
      esophagogram. RESULTS: Patients with GERD had significantly decreased lower
      esophageal sphincter resting pressure (P =.02), lower amplitude of esophageal
      peristalsis at all levels of measurement (P<.001), and more delayed esophageal
      transit (P =.007) compared with control subjects. Patients with dysphagia, severe
      esophagitis, and Barrett esophagus presented with a longer history of the
      disease, significantly worse esophageal motor function (P<.01), and more
      prolonged esophageal transit than patients without the above features of the
      disease. Impairment of esophageal peristalsis and lower esophageal sphincter
      resting pressure were significantly inversely related to the duration of the
      disease (P<.001). Also, delay of esophageal transit was significantly related to
      the duration of the disease (P =.002) and inversely related to the amplitude of
      esophageal peristalsis (P<.001). Unlike the manometric variables, the extent of
      reflux, as assessed by ambulatory 24-hour esophageal pH monitoring, was not
      related to the duration of the disease. CONCLUSION: A long history of GERD is
      more commonly associated with presence of dysphagia, delayed esophageal transit,
      severe esophagitis, presence of Barrett esophagus, and impaired esophageal
      motility.

PMID- 12611567
TI  - Retroperitoneal sarcomas: grade and survival.
AB  - BACKGROUND: The survival of patients with retroperitoneal sarcomas depends on the
      feasibility of complete resection and the grade of the tumor. HYPOTHESIS: A high
      rate of complete resection, wide rather than local excision when feasible, and a
      policy of prompt reoperation for local recurrence all improve survival. METHODS:
      A review of 130 consecutive patients with retroperitoneal soft tissue sarcomas
      (1977-2001). RESULTS: The complete resectability rate was 95%, being 99% (78/79)
      for the primary tumors and 90% (46/51) for tumors referred with local recurrence.
      Local recurrence after complete resection occurred in 41% (32/79) of those with
      primary tumors and in 61% (31/51) of those referred with local recurrence (P
      =.06). The local recurrence rate was 63% after local excision and 39% after wide
      resection (P =.02). Of 83 patients with relapse, 37 (45%) were rendered
      surgically disease free. The estimated 5-year (10-year in parentheses) survival
      from the first surgery at our center was 65% (56%) for patients with primary
      tumors and 53% (34%) for patients referred with local recurrence (P =.23). For
      the primary tumors, the 5- and 10-year survival rates were 70% and 60%,
      respectively, after wide resection and 47% and 39%, respectively, after local
      excision (P =.04). For the primary tumors, the 5-year survival was 92%, 54%, and
      48% for grades I, II, and III, respectively (P =.02). For those referred with
      local recurrence, the figures were 76%, 45%, and 19% for grades I, II, and III,
      respectively (P<.001). CONCLUSIONS: A high resectability rate (95%) is possible
      in retroperitoneal sarcomas. The survival estimates are similar to those
      following resection of extremity soft tissue sarcomas given an effective
      reoperation policy for local recurrences. Wide resection lowers the local
      recurrence and improves survival significantly. Survival varies significantly
      according to the grade of the tumor.

PMID- 12611568
TI  - Advantages of laparoscopic colectomy in older patients.
AB  - HYPOTHESIS: Few data describe the relative benefits of an expedited recovery
      program and laparoscopic technique in older vs younger patients undergoing
      colectomy. We compared short-term outcomes in age-matched cohorts of patients
      undergoing laparoscopic vs open segmental colectomy managed with the Controlled
      Rehabilitation With Early Ambulation and Diet program. DESIGN: Four age-matched
      cohorts of patients were compared: (1). patients 70 years or older undergoing
      laparoscopic colectomy (group 1), (2). those 70 or older undergoing open
      colectomy (group 2), (3). those younger than 60 undergoing laparoscopic colectomy
      (group 3), and (4). those younger than 60 undergoing open colectomy (group 4).
      METHODS: Data collected included age, sex, body mass index, Physiologic and
      Operative Severity Score for the Enumeration of Morbidity and Mortality, American
      Society of Anesthesiologists' score, estimated blood loss, operative duration in
      minutes, pathologic findings, type of segmental colectomy, complications,
      mortality, length of hospital stay, and 30-day readmission rate. RESULTS: Four
      hundred seventy-six patients fulfilled the inclusion criteria and had complete
      data available for collection (group 1, 50 patients; group 2, 123 patients; group
      3, 181 patients; and group 4, 122 patients). Demographic data, operative
      procedures, and pathologic findings were similar among the cohorts. The mean +/-
      SEM length of hospital stay was significantly shorter with laparoscopic surgery
      in both age cohorts (group 1, 4.2 +/- 3.0 days; group 2, 9.3 +/- 7.6 days; group
      3, 3.9 +/- 5.9 days; and group 4, 6.1 +/- 3.0 days). The mean +/- SEM direct
      hospital costs were significantly lower only with laparoscopic colectomy in the
      older cohorts. Using the Physiologic and Operative Severity Score for the
      Enumeration of Morbidity and Mortality, it was noted that group 2 experienced an
      observed rate of morbidity similar to that predicted. Conversely, groups 1, 3,
      and 4 had rates that were significantly lower than expected. Mean +/- SEM
      readmission rates were comparable in the older cohorts (group 1, 6.0%, and group
      2, 6.5%) but significantly different in the younger cohorts (group 3, 9.4%, and
      group 4, 4.1%). CONCLUSIONS: The Controlled Rehabilitation With Early Ambulation
      and Diet program in combination with laparoscopic segmental colectomy can be
      safely performed in all age groups. The technique offers particular advantages to
      older patients because of reductions in length of hospital stay, morbidity and
      mortality rates, and direct cost of care.

PMID- 12611569
TI  - Impact of neoadjuvant chemoradiation on anal sphincter function in patients with
      carcinoma of the midrectum and low rectum.
AB  - HYPOTHESIS: Preoperative chemoradiation for patients with stage II and III
      midrectal and low rectal cancer may improve survival and decrease local
      recurrence rate. We evaluated the long-term impact of neoadjuvant chemoradiation
      on anal sphincter function. DESIGN: Prospective analysis. SETTING: Tertiary
      referral center. PATIENTS: From March 1, 1996, to January 31, 2002, 50 patients
      with midrectal and low rectal cancer who underwent total mesorectal excision were
      prospectively enrolled. INTERVENTIONS: Patients received either surgical therapy
      alone (group 1, n = 22) or preoperative, combined chemoradiation (group 2, n =
      28). Group 2 was divided into patients with midrectal (group 2A, n = 14) and low
      rectal (group 2B, n = 14) cancer. Anorectal manometry was performed
      preoperatively and a median of 384 days postoperatively. MAIN OUTCOME MEASURES:
      Anal resting pressure, squeeze pressure, anal sphincter vector volumes, length of
      the high-pressure zone, sensory threshold of the pouch, and rectal capacity.
      RESULTS: Preoperative manometric values were comparable between the groups. No
      statistically significant manometric differences occurred in group 1
      postoperatively. Mean resting pressure (preoperative and postoperative,
      respectively: 89 +/- 35 mm Hg, 53 +/- 17 mm Hg), resting vector volume (605 +/-
      324 cm( 3), 142 +/- 88 cm(3)), and maximal tolerable volume (144 +/- 29 mL, 82 +/
      44 mL) decreased significantly in chemoradiated patients postoperatively
      (P<.05). Manometric values of group 2B patients remained stable postoperatively,
      while mean resting pressure (73 +/- 22 mm Hg vs 52 +/- 14 mm Hg) and resting
      vector volume (631 +/- 288 cm(3) vs 145 +/- 78 cm(3)) decreased significantly in
      group 2A patients (P<.001). CONCLUSIONS: Total mesorectal excision does not
      influence anal sphincter function during long-term follow-up. Neoadjuvant
      chemoradiation results in disordered anal sphincter function in patients with
      midrectal cancer. Low and rectoanal anastomosis seems to obtain better anal
      sphincter function than higher anastomosis in chemoradiated patients.

PMID- 12611570
TI  - Professionalism: lifelong commitment for surgeons.
AB  - Presently, there is a major initiative to rekindle the humanistic qualities in
      the practice of medicine. Although there have been many suggestions on ways to
      rejuvenate this initiative, it has not been a primary focus of graduate medical
      education until recently. Surgery residents are expected to maintain a high
      standard of ethical behavior; demonstrate a commitment to continuity of patient
      care; and demonstrate sensitivity to the age, gender, and culture of patients and
      fellow health care professionals. We in surgical education must accept the
      responsibility for the renewal in teaching and evaluating the professional and
      ethical principles of surgery residents. This change will not happen quickly, but
      it should be done skillfully because future generations will look back on this
      time of renewal in medicine and critique us on our ability or inability to
      achieve this goal.

PMID- 12611572
TI  - Value of live donor liver transplantation experience in major hepatectomy for
      hepatocellular carcinoma.
AB  - BACKGROUND: Live donor liver transplantation (LDLT) mandates conversance in liver
      anatomy and major hepatectomy. Hepatocellular carcinoma is most reliably treated
      by hepatectomy. HYPOTHESIS: The outcomes of major hepatectomy for hepatocellular
      carcinoma are influenced by the surgeon's LDLT experience. DESIGN: We collected
      prospective cohort study data on patient and disease characteristics. SETTING:
      Tertiary referral center. PATIENTS: A retrospective study was performed on 250
      patients who underwent major hepatectomy for hepatocellular carcinoma from
      January 16, 1996, through December 28, 2001. MAIN OUTCOME MEASURES: Overall and
      disease-free survival and outcomes including blood loss, blood transfusion, and
      complications. RESULTS: The 3 liver transplantation surgeons (LTSs) performed 102
      major hepatectomies; the 4 hepatobiliary and pancreatic surgeons (HBPSs), 148
      major hepatectomies. Patients in both groups had similar baseline
      characteristics. The mean +/- SD blood loss in the LTS and HBPS groups was 1.36
      +/- 1.37 and 2.21 +/- 2.40 L, respectively (P<.001). The mean +/- SD blood
      transfusion in the LTS and HBPS groups was 0.27 +/- 0.82 and 0.51 +/- 0.94 L,
      respectively (P =.001). Fewer patients in the LTS group required blood
      transfusion (17/102 [16.7%]; HBPS group, 57/148 [38.5%]; P<.001). We found no
      difference in overall and disease-free survival between the groups. The median
      overall survival was 55.8 months for the nontransfused group, and 34.3 months for
      the transfused group (P =.06). Median disease-free survival was 16.1 months for
      the nontransfused group compared with 12.4 months for the transfused group (P
      =.25). Cox regression multivariate analysis showed that transfusion, cirrhosis,
      and venous invasion worsened overall survival. Venous invasion, cirrhosis, and
      tumor size adversely affected disease-free survival. CONCLUSIONS: The LTS group
      lost less blood and required less blood transfusions than the HBPS group. Blood
      transfusion worsened overall survival. The significantly lower blood transfusion
      requirement of the LTS group contributes to a potential advantage in their
      overall survival.

PMID- 12611573
TI  - Hyperbaric oxygen for treating wounds: a systematic review of the literature.
AB  - OBJECTIVE: To determine whether hyperbaric oxygen (HBO) therapy is an effective
      adjunct treatment for hypoxic wounds. METHODS: We identified studies from
      technology assessment reports on HBO and a MEDLINE search from mid-1998 to August
      2001. We accepted randomized controlled trials (RCTs), cohorts, and case series
      that reported original data, included at least 5 patients, evaluated the use of
      HBO for wound care, and reported clinical outcomes. Demographics, wound
      conditions, HBO regimen, adverse events, and major clinical outcomes were
      extracted from each study. RESULTS: Fifty-seven studies, 7 RCTs, 16 nonrandomized
      studies, and 34 case series involving more than 2000 patients are included in
      this review. None of the studies used wound tissue hypoxia as a patient inclusion
      criterion. The study results suggest that HBO may be beneficial as an adjunctive
      therapy for chronic nonhealing diabetic wounds, compromised skin grafts,
      osteoradionecrosis, soft tissue radionecrosis, and gas gangrene compared with
      standard wound care alone. Serious adverse events associated with HBO include
      seizures and pressure-related traumas, such as pneumothorax. A few deaths in the
      studies were associated with these adverse events. CONCLUSIONS: The overall study
      quality is poor, with inadequate or no controls in most studies. The studies
      suggest that HBO may be helpful for some wounds, but there is insufficient
      evidence to ascertain the appropriate time to initiate therapy and to establish
      criteria that determine whether patients will benefit. Serious adverse events may
      occur. High-quality RCTs that evaluate the short- and long-term risks and
      benefits of HBO are necessary to better inform clinical decisions.

PMID- 12611575
TI  - Adult soft tissue Ewing sarcoma or primitive neuroectodermal tumors: predictors
      of survival?
AB  - BACKGROUND: Ewing sarcoma (ES) is the second most common primary osseous
      malignancy in childhood and adolescence. The improvement in survival is primarily
      associated with the combination of surgery and chemotherapy. HYPOTHESIS: Little
      is known about the outcome of adults with soft tissue ES or primitive
      neuroectodermal tumors (PNET). Certain prognostic factors from soft tissue
      sarcomas (tumor size, tumor location, margin status, and initial presentation) in
      adults (>16 years) with ES/PNET will help to identify factors associated with
      outcome. METHODS: Between July 1, 1982, and June 30, 2000, we identified 59 adult
      patients with primary soft tissue ES/PNET. Clinicopathologic factors were
      correlated with the end points studied: patient factors, tumor factors,
      pathologic factors, status of surgical margins, adjuvant chemotherapy, and
      radiation therapy. RESULTS: There were 41 male and 18 female patients, with a
      median age of 27 years (range, 16-72 years). Median tumor size was 8 cm, with all
      lesions being high grade. The most common site was the trunk (n = 22), with an
      even distribution of retroperitoneal, pelvis, buttock, and lower extremity (all n
      = 5). The median follow-up was 29 months (range, 6-222 months), with local
      recurrence identified in 13 patients (22%), with a median time to recurrence of
      15 months (range, 5-200 months). Overall 5-year survival was 60%. Initial
      presentation was the only predictor of long-term survival, with primary tumor
      only presentation having a 5-year survival of 60% (median not reached) compared
      with primary tumor plus metastatic disease having a 5-year survival of 33%
      (median, 17 months) (P =.02). CONCLUSION: Initial presentation of disease
      represents the only predictor of survival identified in this small group of adult
      patients with ES/PNET.

PMID- 12611576
TI  - Effect of intraperitoneal antiadhesive fluids in a rat peritonitis model.
AB  - HYPOTHESIS: Phospholipids and icodextrin reduce peritoneal adhesions resulting
      from general peritonitis without promoting abscess formation. DESIGN: Evaluation
      of adhesion reduction fluids in a randomized animal study using a standardized
      peritonitis model. SETTING: Experimental animal model in a university laboratory.
      INTERVENTIONS: In 60 rats, experimental peritonitis was induced using the cecal
      ligation and puncture model. On day 1, the abdominal cavity was rinsed with 10 mL
      of isotonic sodium chloride solution and the cecum was resected. Animals were
      randomly assigned to 3 groups: the RL group, which received Ringer lactate
      intraperitoneally; the PL group, which received phospholipids intraperitoneally;
      and the ID group, which received icodextrin intraperitoneally. In each group, 50%
      of the animals were humanely killed at day 11 and 50% at day 21. MAIN OUTCOME
      MEASURES: The areas of adhesions were measured and the abscess formation was
      scored according to location and size. Abscesses, abdominal fluid, and blood were
      sampled for microbiologic workup. RESULTS: The median area of adhesions was
      significantly lower in the PL groups (PL(11), 43.7 mm(2); PL(21), 20.4 mm( 2))
      than in the RL groups (RL(11), 163.8 mm(2); RL( 21), 120.9 mm(2)) and ID groups
      (ID(11), 418.5 mm( 2); ID(21), 218.6 mm(2)). Abscess formation was increased by
      icodextrin but not influenced by phospholipids, whereas microbiologic
      investigations did not reveal any differences among these 3 groups. CONCLUSIONS:
      In this model of general peritonitis, phospholipids significantly reduced
      adhesion formation without promoting septic complications. Icodextrin enhanced
      adhesion and abscess formation in this peritonitis model. Phospholipids may be
      beneficial for adhesion control in general peritonitis.

PMID- 12611577
TI  - Comparative analysis of molecular alterations in fibroadenomas associated or not
      with breast cancer.
AB  - HYPOTHESIS: The cause of breast cancer is linked to many macroscopic events,
      including benign breast disease. In this study we asked whether molecular changes
      could discriminate fibroadenoma, which is one of the most common benign breast
      disease lesions associated or not with breast cancer. DESIGN: Retrospective
      cohort study. SETTING: Anticancer medical center. SUBJECTS: Archival tissues in
      32 cases of fibroadenoma, diagnosed in the same breast as a breast carcinoma, are
      compared with a control group of 26 cases of fibroadenomas unaffected by breast
      cancer. MAIN OUTCOME MEASURES: Histological features are characterized in all
      samples. The epithelial and stromal components are analyzed for a loss of
      heterozygosity and a microsatellite instability using a polymerase chain reaction
      based method with 11 polymorphic microsatellite markers at 7 chromosomal regions
      frequently altered in breast cancer. The p53 gene mutations were also determined
      at exons 5 to 9. RESULTS: The frequency of complex fibroadenomas was similar in
      both groups (P =.42). Only in the case group did we observe proliferative lesions
      confined in fibroadenomas, including atypical ductal hyperplasia (2 cases),
      lobular neoplasia (3 cases), or low-grade ductal carcinoma in situ (2 cases).
      There is no significant morphological difference between the 2 groups. Neither
      microsatellite alterations nor p53 gene mutations are present in the fibroadenoma
      components. Loss of heterozygosity is found only in the epithelial component of
      the 2 ductal carcinomas in situ confined in fibroadenomas. CONCLUSIONS: Genetic
      alterations, which are most frequently involved in malignant breast carcinomas,
      are not present in fibroadenomas, regardless of their association with breast
      cancer or their histological complexity. These findings suggest that
      fibroadenomas are not associated with breast carcinogenesis.

PMID- 12611578
TI  - Computer-aided diagnosis for 3-dimensional breast ultrasonography.
AB  - HYPOTHESIS: Using 3-dimensional (3-D) over 2-dimensional (2-D) ultrasonographic
      (US) images of the breast represents a potentially significant advantage for
      computer-aided diagnosis (CAD). BACKGROUND: Although conventional 2-D US images
      of the breast are increasingly used in surgical clinical practice, 3-D US imaging
      of the breast, a newly introduced technique, can offer more information than 2-D
      US images do. DESIGN: This study deals with a CAD method for use with the
      proposed 3-D US images of the breast and compares its performance with
      conventional 2-D US versions. METHODS: The test databases included 3-D US images
      of 107 benign and 54 malignant breast tumors for a total of 161 US images. All
      solid nodules at US belong to categories above C3 (ie, probably benign). The 3-D
      US imaging was performed using a scanner (Voluson 530; Kretz Technik, Zipf,
      Austria). New 3-D autocorrelation coefficients extended from the traditional 2-D
      autocorrelations were developed to extract the texture characteristics of the 3-D
      US images. The extracted texture features of the 3-D US images were used to
      classify the tumor as benign or malignant using the neural network. RESULTS: At
      the receiver operating characteristic analysis, 3-D and 2-D autocorrelation
      calculating schemes yielded Az values (ie, area under the receiver operating
      characteristic curve) of 0.97 and 0.85 in distinguishing between benign and
      malignant lesions, respectively. Accuracy, sensitivity, specificity, positive
      predictive value, and negative predictive value are statistically significantly
      improved using 3-D instead of 2-D US images for CAD. CONCLUSIONS: The proposed
      system (for 3-D and 2-D CAD) is expected to be a useful computer-aided diagnostic
      tool for classifying benign and malignant tumors on ultrasonograms and can
      provide a second reading to help reduce misdiagnosis. Findings from this study
      suggest that using 3-D over 2-D US images for CAD represents a potentially
      significant advantage.

PMID- 12611579
TI  - Colonic interposition after esophagectomy for cancer.
AB  - HYPOTHESIS: The use of colonic interposition in esophageal replacement after
      esophagectomy for cancer results in similar morbidity, mortality, and long-term
      outcome compared with gastric transposition. DESIGN: Prospectively collected
      database on patients with esophageal cancer from January 1, 1982, through
      December 31, 2000. SETTING: Academic university hospital department of surgery.
      PATIENTS: We compared 42 patients who underwent colonic interposition (colon
      group) with 959 patients who underwent gastric transposition (stomach group)
      after esophagectomy. MAIN OUTCOME MEASURES: Morbidity, mortality, and long-term
      survival. RESULTS: Greater blood loss (median, 1000 vs 700 mL; P<.001) and longer
      operation duration (median, 270 vs 225 minutes; P<.001) were encountered in the
      colon group. We found no difference in cardiopulmonary complications, but we
      found significantly greater incidences of anastomotic leakage (14.3% vs 3.9%; P
      =.007) and intra-abdominal septic complications (9.5% vs 0.2%; P<.001) in the
      colon group. Conduit ischemia developed in 5 patients (0.5%) in the stomach
      group, 3 of whom underwent successful staged reconstruction with colon. One
      patient (2.4%) in the colon group was found to have conduit ischemia and died.
      Hospital mortality rates included 7 patients (16.7%) from the colon group and 102
      (10.6%) from the stomach group (P =.21). These figures improved to 0 and 27
      (5.5%), respectively, in the second half of the study period (P>.99). Median
      survival was 12.8 and 10.4 months in the stomach and colon groups, respectively
      (P =.4). CONCLUSIONS: Colonic interposition is a more complex procedure with
      increased morbidity, compared with gastric transposition. Overall mortality and
      survival, however, were similar to those for gastric transposition.

PMID- 12611580
TI  - Axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in
      situ of the breast.
AB  - HYPOTHESIS: A sentinel lymph node (SLN) biopsy should not be considered a
      standard procedure in the treatment of all patients with ductal carcinoma in situ
      (DCIS) of the breast if the lesion is completely excised by radical surgery and
      there are free margins of resection. DESIGN: Prospective case series. SETTING:
      Department of breast surgery of a comprehensive cancer center. PATIENTS: From
      January 1, 1998, to December 1, 2001, 223 unselected consecutive patients
      affected by pure DCIS of the breast underwent an SLN biopsy. RESULTS: Metastases
      in the SLN were detected in 7 (3.1%) of the 223 patients, and complete axillary
      dissection was subsequently performed in all these patients but 1. Of these 7
      patients, 5 had only micrometastases in the SLNs; and in the 6 patients treated
      with complete axillary dissection, the SLN was the only positive node.
      CONCLUSIONS: Because of the low prevalence of metastases, an SLN biopsy should
      not be considered a standard procedure in all patients with DCIS. In patients
      with pure DCIS in whom the lesion is completely excised by radical surgery, an
      SLN biopsy could be avoided. It could be considered in patients with DCIS
      undergoing mastectomy, in whom there exists a higher risk of harboring an
      invasive component using definitive histologic features, like large solid tumors
      or diffuse or multicentric microcalcifications; in these patients, an SLN biopsy
      cannot be performed at a later operation. Complete axillary dissection may not be
      mandatory if the SLN is micrometastatic.

PMID- 12611581
TI  - Risk factors for postoperative infectious complications in noncolorectal
      abdominal surgery: a multivariate analysis based on a prospective multicenter
      study of 4718 patients.
AB  - HYPOTHESIS: Infectious complications are the main causes of postoperative
      morbidity in abdominal surgery. Identification of risk factors, which could be
      avoided in the perioperative period, may reduce the rate of postoperative
      infectious complications. DESIGN: A database was established from 3 prospective,
      randomized, multicenter studies. Multivariate analysis was performed using
      nonconditional logistic regression expressed as an odds ratio (OR). SETTING:
      Multicenter studies (ie, private medical centers, institutional hospitals, and
      university hospitals). PATIENTS: From June 1982 to September 1996, a database was
      established containing the information of 4718 patients who underwent
      noncolorectal abdominal surgery. MAIN OUTCOME MEASURES: The dependent variables
      studied included surgical site infection (SSI) (divided into parietal and deep
      infectious complications with or without fistulas) and global infectious
      complications (SSI and extraparietal and abdominal infectious complications).
      RESULTS: The rate of global infectious complications was 13.3%; SSI, 4.05%;
      parietal infectious complications, 2.2%; deep infectious complications with
      fistulas, 2.18%; and deep infectious complications without fistulas, 1.38%. In
      multivariate analysis, the following 7 independent risk factors for global
      infectious complications have been identified: age (60-74 years, OR, 1.64; >or=75
      years, OR, 1.45); being underweight (OR, 1.51); having cirrhosis (OR, 2.45),
      having a vertical abdominal incision (OR, 1.66); having a suture placed or an
      anastomis of the bowel (OR, 1.48) in the digestive tract; having a prolonged
      operative time (61-120 minutes, OR, 1.66; 121 minutes, OR, 2.72); and being
      categorized as having a class 4 surgical site (ie, obese patients or having a
      risk factor of a healing defect) (OR, 1.66). Ceftriaxone sodium therapy was
      identified as a protective factor (OR, 0.43). In multivariate analysis, the
      following 5 independent risk factors for SSI have been identified: the existence
      of a preoperative cutaneous abscess or cutaneous necrosis (OR, 4.75), having a
      suture placed or an anastomosis of the bowel (OR, 1.82) in the digestive tract,
      having postoperative abdominal drainage (OR, 2.15), undergoing a surgical
      procedure for the treatment of cancer (OR, 1.74), and receiving curative
      anticoagulant therapy (OR, 3.33) postoperatively. CONCLUSIONS: Our data show that
      risk factors for SSI and for global infectious complications are disparate.
      Indeed, only the placement of a suture or having an anastomosis of the bowel in
      the digestive tract is a risk factor for both SSI and global infections. Some of
      these factors may be modifiable before or during the surgical procedure to reduce
      the infection rate or to prevent postoperative complications.

PMID- 12611582
TI  - Percutaneous isolated hepatic perfusion for chemotherapy: a phase 1 study.
AB  - BACKGROUND: Increasing the drug concentration in tumors may produce massive
      tumoral response. By using a variety of hepatic vascular isolation techniques,
      high concentrations of chemotherapeutic drugs may be achieved in the hepatic
      vascular bed. HYPOTHESIS: Complete percutaneous isolated hepatic perfusion (IHP)
      is feasible and safe. DESIGN: Case series. SETTING: The hepatobiliary unit of a
      university hospital. PATIENTS: Ten patients with irresectable and chemoresistant
      hepatic tumors were eligible for study participation; 4 patients with hepatic
      metastases of breast cancer, gastric cancer, colorectal cancer, and
      cholangiocarcinoma were included. INTERVENTION: Patients received 3 successive
      courses of chemotherapy by IHP. The first course was given at laparotomy, and the
      next 2 courses were given percutaneously. The interval between courses was 3 to 6
      weeks. Each course involved IHP of the liver for 15 to 30 minutes, without
      oxygenation, with 1 to 3 boluses of melphalan (15 mg). MAIN OUTCOME MEASURES:
      Morbidity and mortality. RESULTS: Ten IHPs were performed (4 at laparotomy and 6
      percutaneously). Concentrations of melphalan in the extracorporeal circulation
      were 10 times higher than those in the systemic circulation. Percutaneous IHPs
      had more leakage than those at laparotomy. However, hepatotoxicity was minimized.
      One patient experienced hepatic artery thrombosis, and 3 had severe neutropenia.
      Minor complications included ascites and pleural effusion. No deaths were
      observed 2 months after the last IHP. One partial response was observed (hepatic
      metastases of breast cancer). CONCLUSION: Percutaneous IHP for intensive
      chemotherapy is less aggressive and less hepatotoxic than IHP at laparotomy and
      may be iterative.

PMID- 12611583
TI  - Management dilemmas with choledochal cysts.
AB  - CONTEXT: Choledochal cysts are rare and of unknown cause. Their presentation is
      protean, with the classical triad of pain, jaundice, and mass rarely seen. The
      potential complications are serious, including pancreatitis, cholangitis, and
      cholangiocarcinoma. OBJECTIVE: To present the current experience and evidence
      relating to all aspects of choledochal cysts to derive appropriate management
      recommendations. METHODS: Review of relevant literature in the English language
      indexed on MEDLINE. RESULTS: The elaboration of the classification of choledochal
      cysts. We describe the modes of presentation and optimal investigation and
      summarize the current theories on etiology and malignant transformation. The
      results of different management strategies are presented. CONCLUSIONS:
      Choledochal cysts are often detected during the investigation of nonspecific
      symptoms, or even incidentally detected. Magnetic resonance imaging is the best
      imaging modality for the diagnosis and characterization of these cysts. Complete
      excision and hepaticojejenostomy is the management of choice.

PMID- 12611584
TI  - Image of the month. Thoracic neurilemoma.

PMID- 12611585
TI  - Incidental appendectomy in the symptomatic patient.

PMID- 12611586
TI  - Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5
      trisphosphate receptor type 1.
AB  - The inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) is an intracellular
      IP(3)-gated Ca(2+) channel that is located on intracellular Ca(2+) stores and
      modulates Ca(2+) signalling. Using the yeast two-hybrid system, we screened a
      mouse brain cDNA library with bait constructs for mouse IP(3)R type 1 (IP(3)R1)
      to identify IP(3)R1-associated proteins. In this way, we found that carbonic
      anhydrase-related protein (CARP) is a novel IP(3)R1-binding protein. Western blot
      analysis revealed that CARP is expressed exclusively in Purkinje cells of the
      cerebellum, in which IP(3)R1 is abundantly expressed. Immunohistochemical
      analysis showed that the subcellular localization of CARP in Purkinje cells is
      coincident with that of IP(3)R1. Biochemical analysis also showed that CARP is co
      precipitated with IP(3)R1. Using deletion mutagenesis, we established that amino
      acids 45-291 of CARP are essential for its association with IP(3)R1, and that the
      CARP-binding site is located within the modulatory domain of IP(3)R1 amino acids
      1387-1647. CARP inhibits IP(3) binding to IP(3)R1 by reducing the affinity of the
      receptor for IP(3). As reported previously, sensitivity to IP(3) for IP(3)
      induced Ca(2+) release in Purkinje cells is low compared with that in other
      tissues. This could be due to co-expression of CARP with IP(3)R in Purkinje cells
      and its inhibitory effects on IP(3) binding.

PMID- 12611587
TI  - Arachidonate release and prostaglandin production by group IVC phospholipase A2
      (cytosolic phospholipase A2gamma).
AB  - While the role of the group IVA Ca(2+)-dependent cytosolic phospholipase
      A(2)alpha (cPLA(2)alpha) in arachidonic acid (AA) metabolism has been well
      documented, that of its paralogue, Ca(2+)-independent group IVC PLA(2)
      (cPLA(2)gamma), has remained uncertain. Here we show, using a transfection
      strategy, that cPLA(2)gamma has the ability to increase the spontaneous and
      stimulus-induced release of cellular fatty acids. The AA released by cPLA(2)gamma
      was metabolized further to prostaglandin E(2) via cyclo-oxygenase-1 (COX-1) in
      the immediate response, and via COX-2 in the delayed response. Mutation of the
      putative catalytic-centre residue Ser(82) abrogated the AA-releasing function of
      cPLA(2)gamma both in vitro and in vivo. Confocal microscopy revealed that
      cPLA(2)gamma was distributed in the perinuclear endoplasmic reticulum membranes.
      Mutating the C-terminal prenylation site of cPLA(2)gamma abrogated its
      intracellular membrane localization and cellular AA-releasing function, without
      reducing its enzyme activity in vitro. Our results indicate that cPLA(2)gamma is
      the second cPLA(2) enzyme that contributes to cellular AA metabolism and
      phospholipid remodelling under appropriate conditions.

PMID- 12611588
TI  - Leucine-zipper-mediated homo- and hetero-dimerization of GIT family p95-ARF
      GTPase-activating protein, PIX-, paxillin-interacting proteins 1 and 2.
AB  - ADP-ribosylation factor GTPase-activating proteins (ARFGAPs) of the G-protein
      coupled receptor kinase interactor 1/p95 paxillin kinase linker/p95-ARFGAP Pak
      interacting exchange factor paxillin-binding protein (APP)-1 family are
      multidomain proteins, which interact functionally with both ARF and Rac GTPases.
      These proteins are involved in the dynamic reorganization of adhesion and the
      cytoskeleton during cell motility. Our previous work [Di Cesare, Paris,
      Albertinazzi, Dariozzi, Andersen, Mann, Longhi and de Curtis (2000) Nat. Cell
      Biol. 2, 521-530] has pointed out a role for p95-APP1 in the regulation of ARF6
      mediated membrane recycling. These proteins include different domains, and are
      capable of interacting stably with proteins that are supposed to play a role in
      the regulation of actin dynamics and adhesion. They contain a coiled-coil region
      comprising a putative leucine zipper, predicted to be involved in dimerization.
      In the present study, we have investigated the possibility that these proteins
      form dimers. Our results show that p95-APP1 forms homodimers and may also form
      heterodimers with the other member of the family, p95 paxillin kinase linker/p95
      APP2. Both homo- and heterodimerization are disrupted by mutation of two leucine
      residues in the coiled-coil region of p95-APP1. The N-terminal portion of p95
      APP1, including the ARFGAP domain, three ankyrin repeats and the Pak-interacting
      exchange factor-binding region, are not required for dimerization. Evidence is
      presented for the existence of endogenous oligomeric complexes. The implication
      of dimerization/oligomerization in the functioning of these proteins is
      discussed.

PMID- 12611589
TI  - Polymorphic glutathione S-transferase subunit 3 of rat liver exhibits different
      susceptibilities to carbon tetrachloride: differences in their interactions with
      heat-shock protein 90.
AB  - Rat glutathione S-transferase (GST) subunit 3 gene has polymorphism, one type
      encoding Asn(198)-Cys(199) (NC type) and another encoding Lys(198)-Ser(199) (KS
      type). To examine whether the two types of GST 3-3 exhibit different
      susceptibilities to oxidative stress in vivo, rats were administered with CCl(4),
      a hepatotoxin causing severe oxidative stress, and its effect on liver GST 3-3
      was compared. Decrease in GST activities in liver due to CCl(4) administration
      was more evident in NC type rats than in KS type rats, and most GST activities of
      KS type rats were confined to S-hexylglutathione-Sepharose, whereas those of NC
      type rats were not. Decreases in GST subunits 1 and 3 were more marked in NC type
      rats and glutathiolated NC type GST 3-3 was also detected. These results
      indicated that KS and NC type GST 3-3 of rat livers exhibited different
      susceptibilities to CCl(4) in vivo. A protein consisting of a subunit with
      molecular mass of 90 kDa was shown to bind to KS type GST 3-3 but not to NC type.
      This protein was identified as heat-shock protein (HSP) 90beta by N-terminal
      amino acid sequencing and immunoblotting. A specific HSP90 inhibitor geldanamycin
      released their binding. There was no difference in the binding of apoptosis
      signal-regulating kinase 1 to GST 3-3 between NC and KS type rats. These findings
      suggest that HSP90 interacts with KS type GST 3-3 and thereby protects it from
      inactivation due to CCl(4).

PMID- 12611590
TI  - Substrate specificities of mouse heparan sulphate glucosaminyl 6-O
      sulphotransferases.
AB  - Glycosaminoglycan heparan sulphate interacts with a variety of proteins, such as
      growth factors, cytokines, enzymes and inhibitors and, thus, influences cellular
      functions, including adhesion, motility, differentiation and morphogenesis. The
      interactions generally involve saccharide domains in heparan sulphate chains,
      with precisely located O-sulphate groups. The 6-O-sulphate groups on glucosamine
      units, supposed to be involved in various interactions of functional importance,
      occur in different structural contexts. Three isoforms of the glucosaminyl 6-O
      sulphotransferase (6-OST) have been cloned and characterized [H. Habuchi, M.
      Tanaka, O. Habuchi, K. Yoshida, H. Suzuki, K. Ban and K. Kimata (2000) J. Biol.
      Chem. 275, 2859-2868]. We have studied the substrate specificities of the
      recombinant enzymes using various O-desulphated poly- and oligo-saccharides as
      substrates, and using adenosine 3'-phosphate 5'-phospho[(35)S]sulphate as
      sulphate donor. All three enzymes catalyse 6-O-sulphation of both -GlcA-GlcNS-
      and -IdoA-GlcNS- (where GlcA represents D-glucuronic acid, NS the N-sulphate
      group and IdoA the L-iduronic acid) sequences, with preference for IdoA
      containing targets, with or without 2-O-sulphate substituents. 6-OST1 showed
      relatively higher activity towards target sequences lacking 2-O-sulphate, e.g.
      the -GlcA-GlcNS- disaccharide unit. Sulphation of such non-O-sulphated acceptor
      sequences was generally favoured at low acceptor polysaccharide concentrations.
      Experiments using partially O-desulphated antithrombin-binding oligosaccharide as
      the acceptor revealed 6-O-sulphation of N-acetylated as well as 3-O-sulphated
      glucosamine residues with each of the three 6-OSTs. We conclude that the three 6
      OSTs have qualitatively similar substrate specificities, with minor differences
      in target preference.

PMID- 12611591
TI  - Engineered allosteric mutants of the integrin alphaMbeta2 I domain: structural
      and functional studies.
AB  - The alpha-I domain, found in the alpha-subunit of the leucocyte integrins such as
      alphaMbeta2 and alphaLbeta2, switches between the open and closed tertiary
      conformations, reflecting the high- and low-affinity ligand-binding states of the
      integrin that are required for regulated cell adhesion and migration. In the
      present study we show, by using point mutations and engineered disulphide bonds,
      that ligand affinity can be reduced or increased allosterically by altering the
      equilibrium between the closed and open states. We determined equilibrium
      constants for the binding of two ligands, fibrinogen and intercellular cell
      adhesion molecule 1, to the alphaM-I domain by surface plasmon resonance, and
      determined crystal structures of a low-affinity mutant. Locking the domain in the
      open conformation increases affinity by a factor of no greater than 10,
      consistent with a closely balanced equilibrium between the two conformations in
      the absence of ligand. This behaviour contrasts with that of the unliganded
      alphaL-I domain, for which the equilibrium lies strongly in favour of the closed
      conformation. These results suggest significant differences in the way the parent
      integrins regulate I domain conformation and hence ligand affinity.

PMID- 12611593
TI  - Optimizing alkaline lysis for DNA plasmid recovery.
AB  - Optimization of the alkaline lysis (P2) and neutralization (N3) steps in the
      recovery of DNA plasmids was pursued. Experiments were conducted at the test-tube
      and 5-litre scales with 3 kb (pUC18) and 20 kb (pQR150) plasmids. The scale and
      degree of mixing/shear did not affect the optimum yield of supercoiled plasmid
      during the P2 step, but did effect the time required for the optimum to be
      achieved. This optimum time for P2 at the large scale was longer (8-9 min),
      especially when a low-shear impeller was used. Also, when the yield of
      supercoiled plasmid reached a maximum during the P2 step, the purity (percentage
      of plasmids in the supercoiled form) simultaneously reached a minimum. As the
      duration of the N3 step increased from 1 to 6 min, the yield of the supercoiled
      plasmids remained fairly constant, provided that a lowshear impeller was used.
      The neutralized (post-N3) plasmid solution was shear-sensitive; however, mixing
      with a Rushton turbine in a tank (maximum energy dissipation rate in the mixing
      tank, epsilon (max), 12 m(2)/s(3); mixing-tank power consumption/volume of mixing
      tank, 2.0 W/m(3)) for 5-10 min resulted in a slight decrease in supercoiled
      plasmid and a notable increase in genomic DNA concentrations. The loss of the
      larger 20 kb plasmid (20%) was more than for the 3 kb plasmid. Finally, preparing
      the cells for alkaline lysis with lysozyme or low-pressure homogenization did not
      increase the plasmid yield. Furthermore, the homogenizer broke up the genomic DNA
      into fragments that followed through the entire Qiagen prep with the plasmids as
      impurities.

PMID- 12611594
TI  - Tissue injury and repair in the female human reproductive tract.
AB  - The female reproductive tract is unique in its capacity to remodel constantly
      throughout adult life. Some of the remodelling events that occur naturally in the
      uterus, specifically menstruation, parturition, endometrial regeneration and
      uterine involution, have features in common with events of tissue injury and
      repair in other tissues, where they may occur after injury or in association with
      various pathologies. This review draws comparisons between the normally occurring
      tissue 'injury' and repair in the reproductive tract and that occurring
      elsewhere.

PMID- 12611595
TI  - The impact of endocrine disruptors on oocyte competence.
AB  - To date, approximately 60 chemicals have been identified as endocrine disruptors:
      exogenous agents that interfere with various aspects of natural hormone
      physiology. The potential reproductive and health hazards of these environmental
      chemicals have recently generated concern among the scientific community, policy
      makers and general public. The present review presents and discusses the
      available evidence that environmental chemicals are causing ovarian toxicity in
      various species, with particular attention to farm animals. The impact of chronic
      exposure to endocrine disruptors via food and drinking water cannot be neglected
      when studying fertility problems in these species. This review focuses attention
      on the superfamily of organochlorine chemicals, persistent organic pollutants
      (POPs), because of their persistence in the environment, ability to concentrate
      up the food chain, continued detection in environmental matrices and ability to
      be stored in the adipose tissue of animals and humans. Published data clearly
      indicate that POPs disrupt mammalian oocyte maturation and follicle physiology in
      every species studied so far, including farm animals. However, as most of the
      data available still derive from experiments performed on laboratory species or
      in vitro models, great care should be taken when extrapolations to other species
      or environmental situations are attempted.

PMID- 12611592
TI  - Regulation of targets of mTOR (mammalian target of rapamycin) signalling by
      intracellular amino acid availability.
AB  - In mammalian cells, amino acids affect the phosphorylation state and function of
      several proteins involved in mRNA translation that are regulated via the
      rapamycin-sensitive mTOR (mammalian target of rapamycin) pathway. These include
      ribosomal protein S6 kinase, S6K1, and eukaryotic initiation factor 4E-binding
      protein, 4E-BP1. Amino acids, especially branched-chain amino acids, such as
      leucine, promote phosphorylation of 4E-BP1 and S6K1, and permit insulin to
      further increase their phosphorylation. However, it is not clear whether these
      effects are exerted by extracellular or intracellular amino acids. Inhibition of
      protein synthesis is expected to increase the intracellular level of amino acids,
      whereas inhibiting proteolysis has the opposite effect. We show in the present
      study that inhibition of protein synthesis by any of several protein synthesis
      inhibitors tested allows insulin to regulate 4E-BP1 or S6K1 in amino-acid
      deprived cells, as does the addition of amino acids to the medium. In particular,
      insulin activates S6K1 and promotes initiation factor complex assembly in amino
      acid-deprived cells treated with protein synthesis inhibitors, but cannot do so
      in the absence of these compounds. Their effects occur at concentrations
      commensurate with their inhibition of protein synthesis and are not due to
      activation of stress-activated kinase cascades. Inhibition of protein breakdown
      (autophagy) impairs the ability of insulin to regulate 4E-BP1 or S6K1 under such
      conditions. These and other data presented in the current study are consistent
      with the idea that it is intracellular amino acid levels that regulate mTOR
      signalling.

PMID- 12611596
TI  - Growth hormone, insulin-like growth factor I and cell proliferation in the mouse
      blastocyst.
AB  - The role of growth hormone (GH) in embryonic growth is controversial, yet
      preimplantation embryos express GH, insulin-like growth factor I (IGF-I) and
      their receptors. In this study, addition of bovine GH doubled the proportion of
      two-cell embryos forming blastocysts and increased by about 25% the number of
      cells in those blastocysts with a concentration-response curve showing maximal
      activity at 1 pg bovine GH ml(-1), with decreasing activity at higher and lower
      concentrations. GH increased the number of cells in the trophectoderm by 25%, but
      did not affect the inner cell mass of blastocysts. Inhibition of cell
      proliferation by anti-GH antiserum indicated that GH is a potent autocrine or
      paracrine regulator of the number of trophectoderm cells in vivo. Type 1 IGF
      receptors (IGF1R) were localized to cytoplasmic vesicles and plasma membrane in
      the apical domains of uncompacted and compacted eight-cell embryos, but were
      predominantly apparent in cytoplasmic vesicles of the trophectoderm cells of the
      blastocyst, similar to GH receptors. Studies using alpha IR3 antiserum which
      blocks ligand activation of IGF1R, showed that IGF1R participate in the autocrine
      or paracrine regulation of the number of cells in the inner cell mass by an
      endogenous IGF-I-IGF1R pathway. However, alpha IR3 did not affect GH stimulation
      of the number of trophectoderm cells. Therefore, GH does not use secondary
      actions via embryonic IGF-I to modify the number of blastocyst cells. This result
      indicates that GH and IGF-I act independently. GH may selectively regulate the
      number of trophectoderm cells and thus implantation and placental growth.
      Embryonic GH may act in concert with IGF-I, which stimulates proliferation in the
      inner cell mass, to optimize blastocyst development.

PMID- 12611597
TI  - Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial
      cell proliferation in the ovariectomized mouse.
AB  - It has been suggested that endometrial angiogenesis in response to the sex
      steroids oestrogen and progesterone is mediated at a local level via compounds
      such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)
      and platelet-derived growth factor (PDGF), acting through their respective
      tyrosine kinase receptors. The aim of the present study was to use SUGEN tyrosine
      kinase receptor angiogenic inhibitor compounds SU5416, SU5402, SU11652 and
      SU11685, to determine whether VEGF, FGF or PDGF play a role in mediating
      endometrial endothelial cell proliferation after administration of oestrogen and
      progesterone. Endometrial endothelial cell proliferation was induced in adult
      ovariectomized mice by either oestrogen alone for 24 h (E1), or a regimen using
      oestrogen alone, then progesterone with low dose oestrogen, followed by
      progesterone with high-dose oestrogen (PE) over a total of 7 days. Each
      angiogenesis inhibitor compound was injected daily for 4 days (100 mg kg(-1) day(
      1), s.c.) before endometrial tissue collection at either the E1 or PE stage. This
      study also evaluated the effect of VEGF antiserum (0.2 ml, i.p.) on endothelial
      cell proliferation at the E1 stage. All four angiogenic inhibitor compounds
      significantly reduced endothelial cell proliferation activity at the E1 and PE
      stages. The greatest reduction in the endothelial cell proliferative index was at
      the E1 stage in the group treated with the VEGF receptor inhibitor SU5416 (2.5 +/
      0.7% versus 27.9 +/- 1.1%, P < 0.001), with a reduction of similar magnitude in
      the group treated with anti-VEGF antibody. At the PE stage, all four inhibitors
      significantly reduced endothelial cell proliferation to a similar extent,
      indicating that VEGF, FGF and PDGF are all involved. These results demonstrate
      that endometrial angiogenesis after acute oestrogen treatment is primarily
      mediated by VEGF, but that under the influence of combined oestrogen and
      progesterone, FGF and PDGF are also probably involved.

PMID- 12611598
TI  - Effects of pregnancy on pulsatile secretion of LH and gonadotrophin-releasing
      hormone-induced LH release in sheep: a longitudinal study.
AB  - Pulsatile LH secretion and its control throughout pregnancy have not been fully
      determined in sheep. Expt 1 determined the patterns of LH secretion in five ewes
      on days 10, 20, 60 and 120 of pregnancy and on day 10 postpartum, compared with
      those on day 10 of the oestrous cycle. Mean (+/- SEM) concentrations of LH
      declined steadily throughout pregnancy (ANOVA, P < 0.01) and were lower (P <
      0.01) on day 60 (0.19 +/- 0.3 ng ml(-1)) and on day 120 (0.18 +/- 0.4 ng ml(-1))
      of pregnancy than on day 10 of the oestrous cycle (0.55 +/- 0.04 ng ml(-1)). This
      decrease was due to a significant reduction in the number and the amplitude of LH
      pulses. Only on day 120 of pregnancy were progesterone concentrations higher (P <
      0.01) than on day 10 of the oestrous cycle. Although concentrations of
      progesterone on day 10 postpartum were barely detectable, mean LH concentration
      (0.45 +/- 0.09 ng ml(-1)) was not different from that on day 10 of the oestrous
      cycle. Expt 2 examined the LH responses in a separate group of four ewes to a
      physiological dose of GnRH (0.2 microg) on days 10, 20, 60 and 120 of pregnancy
      and on day 10 postpartum, compared with those on day 10 of the oestrous cycle.
      The area under the LH response curve and the maximum LH concentrations induced by
      GnRH declined steadily throughout pregnancy (ANOVA, P < 0.01) and were lower (P <
      0.01) on days 60 and 120 of pregnancy than on day 10 of the oestrous cycle, but
      these parameters were not different between day 10 postpartum and day 10 of the
      oestrous cycle. Expt 3 examined the LH responses in a separate group of four ewes
      to a potent GnRH agonist, buserelin (0.5 microg), on days 10, 60 and 120 of
      pregnancy. The area under the LH response curve and the maximum LH concentrations
      induced by GnRH were lower (P < 0.01) on days 60 and 120 than on day 10 of
      pregnancy, but were not different between days 60 and 120. This longitudinal
      study demonstrates that the pulsatile LH release and pituitary responsiveness to
      GnRH decreases progressively as pregnancy advances, but does not support the
      hypothesis that high concentrations of progesterone are solely responsible for
      the inhibition of pulsatile LH secretion and GnRH-induced LH release during
      pregnancy in sheep.

PMID- 12611599
TI  - Neutrophil recruitment and phagocytosis of boar spermatozoa after artificial
      insemination of sows, and the effects of inseminate volume, sperm dose and
      specific additives in the extender.
AB  - In this study the recruitment of leucocytes and phagocytosis of spermatozoa after
      artificial insemination of multiparous sows was investigated. In Expt 1, groups
      of sows received either no inseminate (n = 6) or inseminates with various
      concentrations of spermatozoa and seminal plasma or different inseminate volumes
      (n = 9 per group). In Expt 2, groups of sows received inseminates containing no
      addition, caffeine + CaCl(2), or excess EDTA (n = 6 per group). Leucocytes and
      spermatozoa were counted in the collected backflow from the vulva, and in the PBS
      flushings of the genital tract of sows killed at 4 h after insemination. Tissue
      homogenates were checked for remaining spermatozoa. Leucocyte recruitment did not
      depend on the presence of seminal plasma or spermatozoa. In the control groups
      about 43% of the inseminated spermatozoa were found in the backflow and 5% in the
      genital tract. Many spermatozoa could be recognized inside polymorphonuclear
      leucocytes. With an inseminate volume of 20 ml instead of 80 ml, fewer
      spermatozoa were found in the backflow and more (non-phagocytosed) spermatozoa
      were recovered in the uterus (P < or = 0.05). With a sperm dose of 0.24 x 10(9)
      instead of 2.4 x 10(9), a higher percentage of the inseminated spermatozoa was
      recovered in the oviducts (P < or = 0.05). The use of caffeine + CaCl(2) resulted
      in lower recruitment of leucocytes (P < or = 0.05) and a higher number of non
      phagocytosed spermatozoa in the uterus (P < or = 0.01) compared with controls.
      The numbers of spermatozoa in the oviducts were not different. Insemination with
      excess EDTA had no positive effects on the number of spermatozoa in the genital
      tract.

PMID- 12611600
TI  - Apoptosis in cumulus cells during in vitro maturation of bovine cumulus-enclosed
      oocytes.
AB  - The aim of this study was to investigate whether apoptosis occurs in cumulus
      cells during in vitro maturation (IVM) of bovine cumulus-enclosed oocytes (CEOs).
      The bovine CEOs obtained from ovaries from an abattoir were cultured for 24 h in
      IVM medium in the presence or absence of 10% (v/v) fetal bovine serum. The
      developmental competence of enclosed oocytes, as assessed by the development of
      the blastocyst after IVF, was significantly higher in the serum-treated group
      than in the control group. The morphological features of apoptosis that were
      analysed by orcein staining were hardly detectable in the cumulus cells at the
      start (0 h) of IVM, but were evident at the end (24 h) of IVM both in the control
      and serum-treated groups. Genomic DNA was extracted from CEOs at 0, 6, 12, 18 and
      24 h of IVM and subjected to ligation-mediated PCR (LM-PCR) to detect apoptotic
      internucleosomal DNA fragmentation. DNA fragmentation was hardly detectable at
      the start of IVM, but increased in a time-dependent manner as the IVM culture
      proceeded. DNA fragmentation was not observed in the oocytes, indicating that
      fragmentation occurs in cumulus cells. The degree of fragmentation was lower in
      the serum-treated group compared with the control group. The LM-PCR analysis of
      DNA extracted from CEOs at 24 h of IVM, in which the DNA had been pretreated with
      Klenow enzyme or T4 DNA polymerase, revealed that the characteristic forms of the
      DNA ends generated during cumulus cell apoptosis were mainly 3'-overhangs and
      blunt ends. In conclusion, the results of the present study demonstrate that
      cumulus cells in bovine CEOs spontaneously undergo apoptosis during IVM. The
      degree of apoptosis may be correlated with the developmental competence of the
      enclosed oocytes.

PMID- 12611601
TI  - Fate of lactadherin P47 during post-testicular maturation and capacitation of
      boar spermatozoa.
AB  - Polyclonal avian antibody was used partially to characterize the pig sperm
      lactadherin P47. P47 is a mosaic protein, composed of two epidermal growth factor
      (EGF)-like domains and two C1/C2 domains. P47 is homologous to the bovine mammary
      gland protein MGP 53/57 and mouse milk fat globule protein. Expression of P47
      along the male genital tract and its localization on spermatozoa during post
      testicular maturation and capacitation were studied. P47 was detected in the
      testis and in all parts of the epididymis by immunohistochemistry and by western
      blots of tissue extracts. By indirect immunocytochemistry, P47 was localized at
      the apical ridge of the sperm head in testicular, epididymal and ejaculated
      spermatozoa. The fluorescence intensity progressed during sperm transit from
      caput to cauda epididymis, probably caused by the ongoing expression and
      subsequent accumulation of P47 on the sperm surface. During the time course of
      capacitation, P47 appears to be unmasked by the release of coating proteins and
      appears to migrate from the apical ridge onto the entire acrosomal region,
      showing an intensive fluorescence pattern after 3 h capacitation in vitro. The
      kinetics of signal changes during in vitro capacitation were different in
      epididymal and ejaculated spermatozoa, indicating accelerated capacitational
      plasma membrane destabilization in epididymal spermatozoa.

PMID- 12611602
TI  - Progesterone production in bovine luteal cells treated with drugs that modulate
      nitric oxide production.
AB  - The aim of this study was to investigate the influence of nitric oxide (NO)
      donors (S-nitroso-L-acetyl penicillamine, spermine-NO complex and sodium
      nitroprusside) and NO synthase inhibitors (N(omega)-nitro-L-arginine methyl
      ester, N(omega)-nitro-l-arginine, and (+/-)-2-amino-5,6-dihydro-6-methyl-4H-1,3
      thiazine) on progesterone production by dispersed bovine luteal cells cultured
      for 24 h. All NO donors inhibited progesterone production and increased nitrite
      or nitrate concentration in the medium in a dose-dependent manner. Secretion of
      progesterone was reduced to 75% (P < 0.01), 56% (P < 0.001) and 37% (P < 0.001)
      by S-nitroso-L-acetyl penicillamine; to 65% (P < 0.001), 45% (P < 0.001) and 33%
      (P < 0.001) by spermine-NO complex and to 77% (P < 0.05), 74% (P < 0.01) and 54%
      (P < 0.001) by sodium nitroprusside treatments at concentrations of 10(-5), 10(
      4) and 10(-3) mol l(-1), respectively, compared with the concentration of this
      hormone measured in cells cultured in medium alone. NO synthase inhibitors
      decreased significantly (P < 0.05) nitrite or nitrate concentration and increased
      progesterone secretion with different potency at different doses. Significant
      increases in progesterone production were observed after N(omega)-nitro-L
      arginine methyl ester treatment at a concentration of 10(-5) mol l(-1) and 10(-4)
      mol l(-1), and after N(omega)-nitro-l-arginine administration at a concentration
      of 10(-6) mol l(-1) (P < 0.01) and 10(-5) mol l(-1) (P < 0.05), compared with the
      concentration of this hormone measured in control cells. The results indicate
      that both NO donors and NO synthase inhibitors regulate steroidogenesis in
      cultured bovine luteal cells from days 10 to 14 of the oestrous cycle; however,
      the degree of progesterone inhibition by NO donors and stimulation by NO synthase
      inhibitors was dependent on the drug used.

PMID- 12611603
TI  - Seasonal control of penile development of Siberian hamsters (Phodopus sungorus)
      by daylength and testicular hormones.
AB  - Seasonal variation in prepubertal penile growth has not previously been studied.
      The present study assessed the influence of daylength and androgens on penile
      development in the Siberian hamster (Phodopus sungorus). Adult penile masses were
      achieved at 18 and 8 weeks of age in hamsters maintained from birth under short
      (10 h light:14 h dark) versus long (14 h light:10 h dark) daylengths,
      respectively. Insulin-like growth factor I concentrations, previously implicated
      in penile growth, did not differ between hamsters maintained in short versus long
      daylengths. Gonadectomized juvenile males maintained in short and long daylengths
      and administered testosterone attained adult penile masses well in advance of
      untreated gonad-intact males maintained in short daylengths. Hamsters from both
      photoperiods, castrated as juveniles and first treated with testosterone in
      adulthood, also achieved adult penile masses. The photoinhibited gonad is
      insufficient to promote penile growth, and prepubertal gonadal secretions during
      short daylengths are not necessary for eventual penile development. Among young
      born near the end of the mating season, onset of neuroendocrine refractoriness to
      short daylengths at about 100 days of age and subsequent gonadal development
      induces growth in all reproductive tissues. Timing of puberty and increased
      androgen secretion controlled by daylength are the primary determinants of
      postnatal penile growth, which may also be affected by prenatal and early
      postnatal organizational actions of androgens.

PMID- 12611604
TI  - Pregnancies and improved early embryonic development with bovine oocytes matured
      in vitro with 9-cis-retinoic acid.
AB  - Retinoids have an important role in cell growth, morphogenesis and
      differentiation. In the present study the developmental potential of bovine
      oocytes was examined after in vitro maturation in the presence of 9-cis-retinoic
      acid, a vitamin A metabolite, at 5 nmol l(-1) in chemically defined conditions.
      Experiments studied early in vitro development, blastocyst differential cell
      counts and the capacity of embryos to establish pregnancy after transfer to
      recipients. After in vitro fertilization and culture in simple medium, blastocyst
      development and hatching rates increased in oocytes matured with 9-cis-retinoic
      acid. Addition of ethanol (used as a solvent for 9-cis-retinoic acid) resulted in
      higher cell counts and proportions of cells in the inner mass of day 7
      blastocysts. Day 8 blastocysts represented most differences observed in the
      number of cells. In these embryos, ethanol and 9-cis-retinoic acid increased both
      the number of cells and proportions in the inner mass. However, while ethanol
      treatment reduced the number of cells in the trophectoderm, 9-cis-retinoic acid
      did not. The total number of cells was unaffected by treatment within 1 day,
      although untreated oocytes lead to day 8 blastocysts with reduced total cell
      counts. Once transferred to recipients, both fresh and vitrified-warmed
      blastocysts derived from oocytes matured with 9-cis-retinoic acid yielded more
      pregnancies at day 60. Modifications of retinoid metabolism affect development
      and trophectoderm differentiation, and in vitro maturation with 9-cis-retinoic
      acid increased the developmental competence of the oocyte.

PMID- 12611605
TI  - Analysis of atresia in equine follicles using histology, fresh granulosa cell
      morphology and detection of DNA fragmentation.
AB  - Follicular atresia has been examined previously by various biochemical and
      histological methods. The aim of this study was to compare, for the first time,
      detection of granulosa cell apoptosis by biochemical DNA analysis and microscopic
      examination of fresh granulosa cell morphology with the established method of
      detecting atresia by histology in equine follicles. DNA extracted from granulosa
      cells was examined by staining with ethidium bromide and end-labelling with
      [(32)P]dideoxy-ATP, which labels the free 3'-end of DNA fragments. In 25 of 26
      follicles (96%) there was agreement between end-labelling and staining of DNA
      with ethidium bromide (P < 0.001). Granulosa cell apoptosis was distinguished
      more easily in the end-labelled samples than by staining with ethidium bromide.
      Histological atresia and apoptosis as detected by biochemical DNA analysis were
      significantly correlated (P < 0.02) with 20 of 22 follicles (91%) receiving
      corresponding classifications with the two methods. No follicles with granulosa
      cell apoptosis as detected by biochemical DNA analysis were histologically
      viable, but some of the histologically early atretic follicles did not display
      DNA laddering. Stereomicroscopic evaluation of morphology of the fresh granulosa
      cells was significantly correlated (P < 0.001) with the histological findings,
      with 29 of 33 follicles (88%) receiving corresponding classifications. There was
      a potential error in determining follicle health by biochemical DNA analysis
      only, as both histologically early and late atretic follicles in some cases did
      not show DNA laddering. Thus, if relying solely on biochemical detection of
      apoptosis, severely atretic follicles could wrongly be classified as healthy
      follicles.

PMID- 12611606
TI  - Role of the angiotensin II system in regulation of ovulation and blood flow in
      the rat ovary.
AB  - The aim of the present study was to examine the roles of the angiotensin II
      receptor subtypes, AT(1) and AT(2), in ovulation, and to evaluate the
      contribution of angiotensin II-mediated pathways in regulation of ovarian blood
      flow. The AT(1)-specific antagonist, losartan, was administered alone or in
      combination with the AT(2)-specific antagonist, PD123319, to preovulatory rat
      ovaries perfused in vitro. Losartan (100 micromol l(-1)) did not affect the
      number of ovulations, whereas the combination of losartan (100 micromol l(-1))
      and PD123319 (10 micromol l(-1)) inhibited ovulation. The angiotensin II
      antagonists did not affect the ovarian production of oestradiol, progesterone,
      prostaglandin E(2) (PGE(2)), PGF(2 alpha) or plasminogen activator activity.
      Ovarian nitric oxide production was inhibited by losartan. Ovarian blood flow was
      measured by laser Doppler flowmetry in vivo in preovulatory rat ovaries.
      Intrabursal injection of angiotensin II reduced ovarian blood flow of
      gonadotrophin-stimulated rats. Losartan had no effect on basal ovarian blood flow
      but completely blocked the angiotensin II-induced reduction. In contrast,
      treatment with PD123319 increased basal ovarian blood flow and failed to reverse
      the effect of exogenously administered angiotensin II, indicating that under
      physiological conditions, ovarian blood flow of the rat is negatively regulated
      by angiotensin II mainly through the action of AT(2). Taken together, these
      results indicate that two different types of angiotensin II receptor facilitate
      ovulation by cooperative mechanisms and that they regulate ovarian blood flow in
      a different manner.

PMID- 12611607
TI  - Presence of LH receptor mRNA in granulosa cells as a potential marker of oocyte
      developmental competence and characterization of the bovine splicing isoforms.
AB  - As the expression of the LH receptor (LH-R) in granulosa cells is thought to be
      associated with later stages of folliculogenesis, this study was undertaken to
      evaluate the presence of LH-R mRNA as a suitable marker for developmental
      competence of oocytes. Granulosa cells and cumulus-oocyte complexes (COCs) were
      recovered from cows that had received ovarian stimulation. The COCs were
      subjected to embryo production procedures in vitro to assess the embryonic
      potential of the oocyte, and the corresponding granulosa cells were used to
      evaluate the presence of LH-R mRNA by RT-PCR. The presence of LH-R transcripts in
      granulosa cells is not a key characteristic of a follicle bearing a competent
      oocyte, although a higher proportion of oocytes reach the blastocyst stage when
      LH-R mRNA is detected in the granulosa cells. Different LH-R isoforms were cloned
      and sequence discrepancies among six of the isoforms enabled the design of
      specific oligonucleotides to study the presence of the isoforms in different
      follicular cells. All LH-R transcripts studied and the 80 kDa protein product
      corresponding to the full length receptor were found in granulosa cells of small
      (< 4 mm) and large (> 5 mm) follicles. When the granulosa cells were cultured,
      the transcripts were downregulated by the culture conditions; downregulation was
      more acute in granulosa cells from small follicles. The addition of LH to the
      culture media enhanced LH-R mRNA downregulation. The presence of several LH-R
      transcript isoforms was tissue specific and in the theca cells LH-R mRNA was
      restricted mainly to cells from larger follicles. This finding indicates that the
      expression and the splicing of LH-R mRNA are regulated in a cell-specific and
      follicular size-specific manner.

PMID- 12611609
TI  - The role of the novel adipocyte-derived hormone adiponectin in human disease.
AB  - Adiponectin, also called GBP-28, apM1, AdipoQ and Acrp30, is a novel adipose
      tIssue-specific protein that has structural homology to collagen VIII and X and
      complement factor C1q, and that circulates in human plasma at high levels. It is
      one of the physiologically active polypeptides secreted by adipose tIssue, whose
      multiple functions have started to be understood in the last few Years.A
      reduction in adiponectin expression is associated with insulin resistance in some
      animal models. Administration of adiponectin has been accompanied by a reduction
      in plasma glucose and an increase in insulin sensitivity. In addition,
      thiazolidinediones, drugs that enhance insulin sensitivity through stimulation of
      the peroxisome proliferator-activated receptor-gamma, increase plasma adiponectin
      and mRNA levels in mice. On the other hand, this adipocyte protein seems to play
      a protective role in experimental models of vascular injury. In humans,
      adiponectin levels are inversely related to the degree of adiposity and
      positively associated with insulin sensitivity both in healthy subjects and in
      diabetic patients. Plasma adiponectin levels have been reported to be decreased
      in some insulin-resistant states, such as obesity and type 2 diabetes mellitus,
      and also in patients with coronary artery disease. On the contrary, chronic renal
      failure, type 1 diabetes and anorexia nervosa are associated with increased
      plasma adiponectin levels. Concentrations of plasma adiponectin have been shown
      to correlate negatively with glucose, insulin, triglyceride levels and body mass
      index, and positively with high-density lipoprotein-cholesterol levels and
      insulin-stimulated glucose disposal. Weight loss and therapy with
      thiazolidinediones increased endogenous adiponectin production in humans.
      Adiponectin increases insulin sensitivity by increasing tIssue fat oxidation,
      resulting in reduced circulating fatty acid levels and reduced intracellular
      triglyceride contents in liver and muscle. This protein also suppresses the
      expression of adhesion molecules in vascular endothelial cells and cytokine
      production from macrophages, thus inhibiting the inflammatory processes that
      occur during the early phases of atherosclerosis. In view of these data, it is
      possible that hypoadiponectinemia may play a role in the development of
      atherosclerotic vascular disease. In summary, the ability of adiponectin to
      increase insulin sensitivity in conjunction with its anti-inflammatory and anti
      atherogenic properties have made this novel adipocytokine a promising therapeutic
      tool for the future, with potential applications in states associated with low
      plasma adiponectin levels.

PMID- 12611608
TI  - Non-genomic actions of sex steroid hormones.
AB  - Steroid hormone receptors have been traditionally considered to act via the
      regulation of transcriptional processes, involving nuclear translocation and
      binding to specific response elements, and ultimately leading to regulation of
      gene expression. However, novel non-transcriptional mechanisms of signal
      transduction through steroid hormone receptors have been identified. These so
      called 'non-genomic' effects do not depend on gene transcription or protein
      synthesis and involve steroid-induced modulation of cytoplasmic or cell membrane
      bound regulatory proteins. Several relevant biological actions of steroids have
      been associated with this kind of signaling. Ubiquitous regulatory cascades such
      as mitogen-activated protein kinases, the phosphatidylinositol 3-OH kinase and
      tyrosine kinases are modulated through non-transcriptional mechanisms by steroid
      hormones. Furthermore, steroid hormone receptor modulation of cell membrane
      associated molecules such as ion channels and G-protein-coupled receptors has
      been shown. TIssues traditionally considered as 'non-targets' for classical
      steroid actions are instead found to be vividly regulated by non-genomic
      mechanisms. To this aim, the cardiovascular and the central nervous system
      provide excellent examples, where steroid hormones induce rapid vasodilatation
      and neuronal survival via non-genomic mechanisms, leading to relevant
      pathophysiological consequences. The evidence collected in the past Years
      indicates that target cells and organs are regulated by a complex interplay of
      genomic and non-genomic signaling mechanisms of steroid hormones, and the
      integrated action of these machineries has important functional roles in a
      variety of pathophysiological processes. The understanding of the molecular basis
      of the rapid effects of steroids is therefore important, and may in the future
      turn out to be of relevance for clinical purposes.

PMID- 12611610
TI  - The prevalence of anti-thyroid peroxidase antibodies and autoimmune thyroiditis
      in children and adolescents in an iodine replete area.
AB  - BACKGROUND: The iodine supply of the population in Berlin has normalized during
      the last 5 Years. Therefore autoimmune thyroiditis has become the most important
      differential diagnosis in children and adolescents with goiter. OBJECTIVE: The
      aim of the present study was to define the prevalence of anti-thyroid peroxidase
      (TPO) antibodies and autoimmune thyroiditis in children and adolescents with a
      normalized iodine intake. DESIGN: To enable the measurement of antibodies to
      thyroid peroxidase (anti-TPO-Ab) in a large cohort, a method to determine anti
      TPO-Ab in dried filter paper blood spots was established. In co-operation with
      pediatricians the antibody prevalence was assessed and data regarding thyroid
      size, echostructure and the medical history concerning iodine intake and familial
      thyroid diseases were collected. METHODS: 660 children and adolescents
      participated in the study; urinary iodine, TSH and TPO-Ab were measured and an
      ultrasound of the thyroid gland was performed. RESULTS: The sensitivity of the
      newly established filter paper assay was 91.8% and specificity was 100%. The
      results confirmed the improved iodine supply, with a median urinary iodine
      concentration of 139 microg iodine/g creatinine. The prevalence of anti-TPO-Ab
      was 3.4% with a female to male ratio of 2.7:1. CONCLUSION: The prevalence of anti
      TPO-Ab is lower or equal to data reported from other iodine sufficient areas.
      Data from a moderate iodine deficiency in schoolchildren range from 0.0 to 7.3%.
      Using the new filter paper method field studies can be implemented to monitor the
      effect of changes in iodine nutrition on thyroid autoimmunity. Furthermore, this
      study on the prevalence of anti-TPO-Ab in a cohort of healthy children and
      adolescents in an iodine replete area can serve as reference data for future
      investigations and for the comparison with other groups of patients with
      increased risks for thyroid autoimmunity.

PMID- 12611611
TI  - Association of selenium with thyroid volume and echostructure in 35- to 60-year
      old French adults.
AB  - OBJECTIVE: To investigate the relationship between selenium status, thyroid
      Volume and gland echostructure. DESIGN: Cross-sectional. METHODS: In 792 men (45
      60 Years) and 1108 women (35-60 Years) from the SU.VI.MAX study, thyroid Volume
      and gland echostructure were determined ultrasonographically. At baseline,
      thyrotropin, free thyroxine, selenium, zinc, alpha-tocopherol, beta-carotene,
      retinol, urinary iodine and thiocyanate concentrations were measured. Alcohol
      consumption, smoking, and menopausal status were assessed by a questionnaire. A
      stepwise linear and a logistic regression model were used, adjusting for
      antioxidant vitamins, trace elements status and age. RESULTS: In women, there was
      an inverse association between selenium status and thyroid Volume (P=0.003). A
      protective effect of selenium against goiter (odds ratio (OR)=0.07, 95%
      confidence interval (CI)=0.008-0.6) and thyroid tIssue damage (OR=0.2, 95%
      CI=0.06-0.7) was observed. There was no evidence of an association between
      menopausal status and other antioxidant elements, thyroid Volume or thyroid
      hypoechogenicity. Smoking, but not alcohol consumption, was associated with an
      increased risk of thyroid enlargement in women (OR=3.94, 95% CI=1.64-9.48). No
      association between thyroid Volume, thyroid structure or selenium was found in
      men. CONCLUSION: Our findings suggest that selenium may protect against goiter.
      Selenium was related to thyroid echostructure, suggesting it may also protect
      against autoimmune thyroid disease.

PMID- 12611612
TI  - Association between the GH receptor/exon 3 genotype and the level of exon 3
      positive GH-binding protein in human serum.
AB  - OBJECTIVE: The human GH-binding protein (GHBP) is derived from the GH receptor
      (GHR) through proteolytic cleavage of its extracellular domain. Two isoforms of
      the GHBP exist, differing in the retention or exclusion of exon 3: E3(+)GHBP and
      E3(-)GHBP. Our study aimed to answer the questions whether the level of E3(+)GHBP
      in the serum correlates with the GHR exon 3 expression and whether or not the E3
      genotype matches the mRNA expression pattern. METHODS: Since exon 3
      retention/deletion can be detected at the protein level using epitope-specific
      antibodies, we were able to quantify the two isoforms by means of specific
      immunoassays in a total of 37 individuals. Additionally, these persons were also
      genotyped for exon 3 by genomic PCR and tested for GHR exon 3 mRNA expression by
      RT-PCR. RESULTS: We found a significant correlation between GHR exon 3 genotype
      and the ratio of E3(+)GHBP and E3(-)GHBP in the serum. Moreover, the genotype
      matched exactly the mRNA expression in fibroblasts and/or blood leukocytes in all
      samples investigated. The levels of E3(+)GHBP are more strongly correlated with
      body mass index, proinsulin and C-peptide than the levels of the E3(-) isoform.
      CONCLUSIONS: Our results show that the GHR exon 3 genotype is in accord with the
      type of GHBP isoforms found in the serum. Our data thus support the idea that the
      presence of exon 3-retaining and -excluding GHR/GHBP isoforms results from a
      genomic deletion rather than from alternative splicing.

PMID- 12611613
TI  - Gender differences in the prevalence, clinical features and response to
      cabergoline in hyperprolactinemia.
AB  - BACKGROUND: Gender differences in tumor size are supposed to exist in
      hyperprolactinemia since microadenomas are more commonly found in women and
      macroadenomas in men. Whether this reflects only a delay in diagnosis in men or a
      true gender difference in tumor pathogenesis is still unclear. OBJECTIVE: To
      prospectively analyze gender differences in the presentation and response to
      cabergoline treatment in 219 consecutive newly diagnosed patients with
      hyperprolactinemia. DESIGN: An open prospective design. SUBJECTS: Of the 219
      patients of which 145 were women; 107 patients had macroprolactinoma, 97 had
      microprolactinoma, and 15 had non-tumoral hyperprolactinemia. METHODS: Presenting
      clinical symptoms, prolactin levels and tumor size at magnetic resonance imaging
      were measured before and 3-6 Months after cabergoline therapy. RESULTS:
      Prevalence of microprolactinomas (56% vs 22%, P=<0.0001) and non-tumoral
      hyperprolactinemia (10% vs 0%, P=0.01) was higher in women than in men. Men and
      women were of similar age (median 32 vs 29 Years; P=0.2) and a similar number had
      gonadal/sexual dysfunction (85 vs 83%, P=0.6); weight gain (70 vs 46%; P=<0.0001)
      and galactorrhea (52 vs 19%; P=<0.0001) were more common in women. Prolactin
      levels were higher in men than in women, whether exhibiting macro- (2848+/-2954
      vs 1132+/-2351 microg/l, P=<0.0001) or microadenomas (187.8+/-51.8 vs 135.4+/
      60.5 microg/l, P=0.009) and the size of the adenoma was larger in men than in
      women irrespective of macro- (25.8+/-12.4 vs 17.2+/-7.2 mm, P=<0.0001) or
      microadenoma diagnosis (8.0+/-1.4 vs 7.1+/-1.6 mm, P=0.04). After treatment,
      prolactin levels decreased by 89.2-96.4% in all groups, and normalized more
      frequently in micro- than in macroadenoma patients (86 vs 64%, P<0.0001),
      regardless of gender (70% vs 69%, P=0.9). Menses resumed in 82% of women, libido
      disturbances improved in 57% of men. Tumor size was reduced by 45+/-25% and 52+/
      24% in macroprolactinoma patients and by 44+/-31 and 38+/-29% in
      microprolactinoma patients in women and men respectively. Visual field defects
      disappeared in 61% of women and in 71% of men (P=0.6). CONCLUSIONS: Prevalence of
      macroprolactinomas was similar in men and women; microprolactinomas and non
      tumoral hyperprolactinemia were more frequent in women. Clinical symptoms at
      presentation differed according to gender, with galactorrhea and weight gain more
      frequent in women. The successful response to cabergoline treatment for 6 Months
      was higher in micro- than in macroprolactinoma patients and was similar in women
      and men.

PMID- 12611615
TI  - Pituitary size in patients with Laron syndrome (primary GH insensitivity).
AB  - OBJECTIVE: The purpose of the present study was to investigate whether lifelong
      secretion of high levels of GH, characteristic of Laron syndrome, leads to an
      increase in the size of the pituitary gland. METHODS: Eleven patients (six
      females, five males) with Laron syndrome underwent magnetic resonance imaging of
      the pituitary region with a system operating at 0.5 T. There were nine adults
      aged 36-68 Years and two children, a 4-Year-old boy and a 9-Year-old girl. The
      latter patient had been treated with IGF-I (150-180 mg/kg per day) since the age
      of 3 Years; all the other patients were untreated. The height of the
      adenohypophysis was measured on the sagittal images and compared with reference
      values for age and sex. RESULTS: The height of the adenohypophysis was within the
      normal range for age and gender in all patients, except for one male, who had a
      small gland. No congenital anomalies of the pituitary-hypothalamic region were
      detected. CONCLUSION: Despite the lifelong high levels of GH, no pituitary
      hypertrophy was detected. The anatomy of the pituitary-hypothalamic region in
      Laron syndrome is normal.

PMID- 12611614
TI  - A study of carotid intima-media thickness in GH-deficient Japanese adults during
      onset among adults and children.
AB  - OBJECTIVES: Increased carotid intima-media thickness (IMT) has been reported
      among Caucasian adult GH-deficient (AGHD) patients, but not Japanese. Also, it is
      known that the clinical and biochemical characteristics of AGHD patients are
      somewhat different based on the onset of the disease in either childhood or adult
      life. Nevertheless, there has been no study comparing the magnitude of the
      deviation of their IMT from normal subjects between child-onset (CO) and adult
      onset (AO) patients in terms of Z score. The aim of this study, therefore, was
      first to examine whether Japanese AGHD patients have a risk of early development
      of atherosclerosis similar to Caucasian patients and secondly to assess the
      difference in the onset and in progression of atherosclerosis. DESIGN AND
      SUBJECTS: Thirty-four patients (17 CO-AGHD, age 29+/-7 Years, body mass index
      (BMI) 24+/-3.8 kg/m(2) and 17 AO-AGHD, age 48+/-12 Years, BMI 23+/-3.6 kg/m(2))
      and 34 age- and sex-matched healthy controls (17 CO controls and 17 AO controls)
      were enrolled in the present study. Blood samples were taken for measurements of
      lipids, lipoproteins and IGF-I. Subsequently, patients underwent IMT assessment.
      RESULTS: CO patients were significantly younger than AO patients. The duration of
      GH-deficiency in CO patients was significantly longer than that in AO patients.
      Serum triglyceride (TG) was significantly higher in CO patients than in CO
      controls (P<0.05). Serum total cholesterol and TG were significantly higher in AO
      patients than in AO controls (P<0.01). The IMT was significantly greater in CO
      and AO patients (0.82+/-0.08 and 0.79+/-0.03 mm) than in CO and AO controls
      (0.59+/-0.02 and 0.68+/-0.03 mm, P<0.01 and P<0.01 respectively). There was no
      significant difference in raw values of IMT between CO and AO patients. However,
      the Z score of IMT calculated using normal Japanese IMT values was significantly
      higher in CO than in AO patients (2.07+/-0.68 vs 0.35+/-0.48, P<0.05).
      CONCLUSIONS: These findings suggest that GH deficiency appears to increase an
      atherosclerotic risk in Japanese AGHD patients, as with Caucasians, and to cause
      more extensive IMT thickening in CO-AGHD than AO-AGHD patients.

PMID- 12611616
TI  - Decreased plasma adiponectin concentrations in nondiabetic women with elevated
      homeostasis model assessment ratios.
AB  - OBJECTIVE: Whether the adipocyte-derived protein adiponectin is associated with
      insulin resistance independently of the effects of adiposity and the diabetic
      state is an important question. We explored, in a cross-sectional study of 486
      Japanese nondiabetic women, the relationship between the calculated insulin
      resistance (homeostasis model assessment ratio (HOMA-R)) and adiponectin levels
      determined using a validated sandwich ELISA. DESIGN AND METHODS: All participants
      were stratified into tertiles for HOMA-R (approximately <1.5, 1.5< or =
      approximately <3.0, 3.0< or = approximately ) and the differences across tertiles
      of continuous variables were tested with ANOVA. Two-way ANOVA was used to
      determine possible relationships for plasma adiponectin between tertiles of HOMA
      R and several stratified parameters. Multiple regression analyses were performed
      with HOMA-R or fasting serum insulin as dependent variable, and diastolic blood
      pressure (BP), body mass index (BMI), serum triglyceride (TG), leptin and
      adiponectin as independent determinants. RESULTS: Mean plasma adiponectin in the
      high HOMA-R group decreased compared with that in the low HOMA-R group both
      before (mean+/-s.e.m. 6.2+/-0.6 vs 9.2+/-0.3 microg/ml, P<0.001) and after
      adjustment for body fat mass (BFM) as kg or percent (0.31+/-0.04 vs 0.69+/-0.03,
      0.18+/-0.02 vs 0.34+/-0.01, both P<0.001). HOMA-R was inversely associated with
      adiponectin levels both before (r=-0.37, P<0.001) and after adjustment for BFM
      (r=-0.49, -0.46, both P<0.001). After covariate adjustment for age, diastolic BP,
      BMI and serum TG, HOMA-R retained a significant correlation with adiponectin/BFM
      (kg). Both adiponectin and leptin were the significant determinants of HOMA-R or
      fasting insulin in multiple regression models. CONCLUSIONS: Adiponectin was
      inversely associated with insulin resistance in nondiabetic subjects,
      independently from age, BP, adiposity and serum lipids. Because adiponectin is
      thought to have an anti-atherogenic action, the presence of hypoadiponectinemia
      may predispose subjects to atherosclerosis, and may progress the atherogenesis in
      insulin resistance.

PMID- 12611617
TI  - Hypercalcemia due to sun exposure in a patient with multiple myeloma and elevated
      parathyroid hormone-related protein.
AB  - A patient with multiple myeloma who developed hypercalcemia during three
      different stages of his disease, with a different hypercalcemic agent elevated in
      his serum on each occasion, is described. The initial episode of hypercalcemia
      was associated with high serum interleukin-6 (IL-6). After treatment for myeloma
      normocalcemia was achieved. Subsequently, a relapse of hypercalcemia occurred,
      this time characterized by frankly elevated plasma parathyroid hormone-related
      protein (PTHrP) but normal IL-6. Monotherapy with pamidronate infusions resulted
      in remission of the hypercalcemia and a significant fall in PTHrP levels. A third
      spell of hypercalcemia characterized by an acute rise in serum 25-hydroxyvitamin
      D and 1,25-dihydroxyvitamin D to abnormally high levels occurred during the
      summer season after prolonged and intense exposure to the sun.

PMID- 12611618
TI  - Pharyngeal pituitary non-functioning adenoma with normal intra-sellar gland:
      massive tumor shrinkage on octreotide therapy.
AB  - OBJECTIVE: Functioning or non-functioning ectopic tumors may develop from
      pharyngeal pituitary remnants. They constitute <1% of all obstructive pharyngeal
      masses and they have a strong tendency to bleed. We report a case of a non
      functioning ectopic pituitary adenoma of the rhino-pharynx studied over a long
      term somatostatin analog treatment. PATIENT AND TREATMENT: A 60-Year-old woman
      presented with severe posterior epistaxis. She had complained of nasal
      obstruction for the past 2 Years. Magnetic resonance imaging (MRI) and endoscopic
      examination revealed a 2 cm exophytic, bleeding mass in the cavum, which was
      judged inoperable, and a biopsy was performed. On immunostaining, tumor cells
      were positive for pancytokeratins MNF 116 and C11, epithelial membrane antigen,
      chromogranin and neuron-specific enolase (NSE), and negative for synaptophysin,
      desmin, actin, estrogen and progesterone receptors, all anterior pituitary
      hormones and human chorionic gonadotropin. Blood levels of the above hormones and
      tumor markers were normal, except for a moderate elevation of NSE (33.8 microg/l,
      normal value <12 microg/l). It was concluded that this was a non-functioning
      pituitary adenoma of the rhino-pharynx. MRI showed a normal intra-sellar
      pituitary gland, including the normal bright signal of the posterior lobe.
      Somatostatin receptor scintigraphy (SRS) disclosed intense tracer uptake in the
      tumor, indicating high somatostatin receptor content. There was also an intense
      uptake in the intra-sellar pituitary. Therapy with long-acting octreotide was
      started, 20 mg per Month i.m. RESULTS: The patient has been on octreotide for the
      last 12 Months. Nasal obstruction rapidly subsided and bleeding did not recur.
      Repeated endoscopic examinations showed rapid tumor reduction, the mass shrinkage
      being almost complete at 3 Months. This was confirmed by MRI, while SRS showed
      markedly decreased uptake in the residual tumor and the intra-sellar pituitary,
      and NSE became normal. CONCLUSION: Pharyngeal pituitary remnant adenomas are
      rare, but they must be considered in the differential diagnosis of bleeding or
      obstructive masses of the rhino-pharynx. In this case, the positive SRS
      influenced the choice of octreotide, as an alternative to surgery. As we show for
      the first time in this location, octreotide can exert prolonged and marked anti
      tumoral effects in non-functioning adenoma.

PMID- 12611619
TI  - The extracellular portion of the insulin receptor beta-subunit regulates the
      cellular trafficking of the insulin-insulin receptor complex. Studies on Chinese
      hamster ovary cells carrying the Cys 860-->Ser insulin receptor mutation.
AB  - OBJECTIVE: Chinese hamster ovary (CHO) cells transfected with human engineered
      insulin receptor (IR) cDNA to mutate Cys 860 to Ser (CHO-IR(C860S)) showed a
      defective insulin internalization without affecting insulin binding and IR
      autophosphorylation. Moreover, this mutation reduces insulin receptor substrate
      (IRS)-1 tyrosine phosphorylation and insulin-induced metabolic and mitogenic
      effects. Altogether, these observations support a role of the extracellular
      domain of IR beta-subunit in insulin and receptor intracellular targeting as well
      as in insulin signaling. DESIGN AND METHODS: This study assesses in more details
      the effect of IR(C860S) mutation on the trafficking of the insulin-IR complex. In
      particular, IR internalization, phosphorylation, dissociation and recycling, as
      well as insulin degradation and retroendocytosis have been investigated in CHO
      cells overexpressing either wild type (CHO-IR(WT)) or mutated IRs. RESULTS: the
      C860S mutation significantly decreases IR internalization both insulin stimulated
      and constitutive. In spite of a similar dissociation of internalized insulin-IR
      complex, recycling of internalized IR was significantly faster (half life
      (t(1/2)): 21 min vs 40 min, P<0.001) and more extensive (P<0.01) for IR(C860S)
      than for IR(WT). On the other hand, insulin degradation and retroendocytosis were
      superimposable in both cell lines. As expected, insulin-induced phosphorylation
      was similar in both IRs, however dephosphorylation was much more rapid and was
      greater (P<0.01) in CHO-IR(WT) as compared with CHO-IR(C860S) cells. CONCLUSIONS:
      Transmembrane and intracellular domain of IR seem to be determinants for IR
      internalization. Now we report that Cys 860 in the IR beta-subunit ectodomain may
      be of relevance in ensuring a proper internalization and intracellular
      trafficking of the insulin-IR complex.

PMID- 12611620
TI  - A psycho-endocrinological overview of transsexualism.

PMID- 12611622
TI  - Lifetime follow-up care is necessary for all patients with treated thyroid
      nodules.

PMID- 12611624
TI  - Peptomics, identification of novel cationic Arabidopsis peptides with conserved
      sequence motifs.
AB  - Few plant peptides involved in intercellular communication have been
      experimentally isolated. Sequence analysis of the Arabidopsis thaliana genome has
      revealed numerous transmembrane receptors predicted to bind proteinacious
      ligands, emphasizing the importance of identifying peptides with signaling
      function. Annotation of the Arabidopsis genome sequence has made it possible to
      identify peptide-encoding genes. However, such annotational identification is
      impeded because small genes are poorly predicted by gene-prediction algorithms,
      thus prompting the alternative approaches described here. We initially performed
      a systematic analysis of short polypeptides encoded by annotated genes on two
      Arabidopsis chromosomes using SignalP to identify potentially secreted peptides.
      Subsequent homology searches with selected, putatively secreted peptides, led to
      the identification of a potential, large Arabidopsis family of 34 genes. The
      predicted peptides are characterized by a conserved C-terminal sequence motif and
      additional primary structure conservation in a core region. The majority of these
      genes had not previously been annotated. A subset of the predicted peptides show
      high overall sequence similarity to Rapid Alkalinization Factor (RALF), a peptide
      isolated from tobacco. We therefore refer to this peptide family as RALFL for
      RALF-Like. RT-PCR analysis confirmed that several of the Arabidopsis genes are
      expressed and that their expression patterns vary. The identification of a large
      gene family in the genome of the model organism Arabidopsis thaliana demonstrates
      that a combination of systematic analysis and homology searching can contribute
      to peptide discovery.

PMID- 12611625
TI  - The application of abstract topology to RAS-related signal transduction pathways.
AB  - Ras is a protein related to cancer development. It is a convergence point for
      different signal transduction pathways that allow the cell to respond to external
      stimuli with different cell functions like growth, division, death, etc. In this
      paper, we analyze the signal pathways generated by different Ras effectors (Raf,
      RalGDS and PI3K), and the pathway relating Ras to the cell cycle control. We show
      that the interaction among different elements of these pathways induces a
      topologic structure in the set of elements. We discuss properties of this
      topology and give an algorithm to build it. The application of topological
      concepts makes easier the interaction analysis. Using a computational algorithm,
      we can create isolated, independently manageable sub-groups. Then we construct
      their hierarchical structure. The procedure allows us to visualize groups of
      elements related to the Ras effectors involved in cell growth, the elements
      involved in the cytoskeleton regulation, and the elements related to the cell
      cycle control. Thus the division in sub-groups does not only make easier the
      analysis, but it also provides a biologically meaningful subdivision.

PMID- 12611626
TI  - Information and sequence extraction around the 5'-end and translation initiation
      site of human genes.
AB  - FIE (5'-end Information Extraction) is a web-based program designed primarily to
      extract the sequence of the regions around the 5'-end and around the translation
      initiation sites for a particular gene, based on information provided by
      LocusLink.

PMID- 12611627
TI  - MMT--a pathway modeling tool for data from rapid sampling experiments.
AB  - The identification of metabolic regulation is a major concern in metabolic
      engineering. Metabolic regulation phenomena depend on intracellular compounds
      such as enzymes, metabolites and cofactors. A complete understanding of metabolic
      regulation requires quantitative information about these compounds under in vivo
      conditions. This quantitative knowledge in combination with the known network of
      metabolic pathways allows the construction of mathematical models that describe
      the dynamic changes in metabolite concentrations over time. Rapid sampling
      combined with pulse experiments is a useful tool for the identification of
      metabolic regulation owing to the transient data they provide. Enzymatic tests in
      combination with ESI-LC-MS (Electrospray Ionization Liquid Chromatographic Tandem
      Mass Spectrometry) and HPLC measurements have been used to identify up to 30
      metabolites and nucleotides from rapid sampling experiments. A metabolic modeling
      tool (MMT) that is built on a relational database was developed specifically for
      analysis of rapid sampling experiments. The tool allows to construct complex
      pathway models with information stored in the relational database. Parameter
      fitting and simulation algorithms for the resulting system of Ordinary
      Differential Equations (ODEs) are part of MMT. Additionally explicit sensitivity
      functions are calculated. The integration of all necessary algorithms in one tool
      allows fast model analysis and comparison. Complex models have been developed to
      describe the central metabolic pathways of Escherichia coli during a glucose
      pulse experiment.

PMID- 12611628
TI  - Evaluating transmembrane topology prediction methods for the effect of signal
      peptide in topology prediction.
AB  - Reported performance of existing transmembrane (TM) topology prediction methods
      were often based on evaluations which neglected the risk of signal peptides (SP)
      being predicted as putative TM as well. Here, we evaluated 12 selected TM
      topology prediction methods (TMpred, TopPred II, DAS, TMAP, MEMSAT 2, SOSUI, PRED
      TMR2, TMHMM 2.0, HMMTOP 2.0, SPLIT 3.5, TM Finder, and MPEx) for the effect of SP
      in prediction performance considering three SP treatments, namely: "remain"
      (untreated), "removed first", and "removed later". The results showed that the
      presence of SP significantly affected the prediction performance of the 12
      selected TM topology prediction methods for all three predicted attributes (the
      number of transmembrane segments (TMSs), the number of TMSs plus position, and
      the N-tail location) and for the predicted topology (combined predictions of
      three attributes) by causing a reduction in prediction accuracy. In particular,
      lower prediction accuracies were obtained if SP is left untreated (remain) while
      significant increases were observed if SP is removed either first or later.
      However, between "removed first" and "removed later" SP treatments, the
      difference was statistically insignificant. In addition, we found that machine
      learning-based prediction methods were less affected by the presence of SP than
      hydropathy-based methods, but still the potential risk of degrading the
      prediction performance is there however to a lesser degree. Thus, when performing
      genome-wide analysis, the SP issue should be addressed during TM topology
      prediction.

PMID- 12611629
TI  - PESI--an intelligent system for prediction of enzyme-substrate interactions based
      on experimental constraints.
AB  - We present a system for predicting protein-protein modifications, and demonstrate
      its usefulness in the field of signal transduction research. Signal transduction
      is one of the most important areas of investigation in biological research. One
      of the major mechanisms frequently employed by cells to regulate signal
      transduction processes involves protein phosphorylation by various kinases. As
      many as 1,000 protein kinases and 500 protein phosphatases in the human genome
      are thought to be involved in phosphorylation processes which regulate all
      aspects of cell function. The complexity of such interactions stems from the
      enormous number of factors and interactions, which makes the identification of
      putative substrates for any given enzyme by straightforward experimentation
      increasingly difficult. We present here a data mining algorithm, based on the
      similarity between the modifier proteins and between the modified proteins, and
      on experimental constraints. The application presented here (PESI) focuses on
      substrate phosphorylation by various enzymes. This algorithm reduces the number
      of substrate candidates for experimental study by about two orders of magnitude.
      Moreover, this algorithm has already yielded predictions for previously unknown
      substrates of the enzymes PKCdelta and PKCeta, which we have confirmed
      experimentally.

PMID- 12611630
TI  - 2D gels and bioinformatics--an eye to the future.
AB  - 2-D Gel Technology has had profound impact on proteomic research over the years.
      Informatics support brought a new dimension to 2D gels and associated
      technologies. But with advent of new and emerging technologies, it will be
      interesting to observe the trends of 2D gel technology in the years to come. Here
      we review 2D gel technology and its applications besides looking at the future
      scope of 2D gels in the post genome era.

PMID- 12611631
TI  - How well do we understand the clusters found in microarray data?
AB  - We wished to quantify the state-of-the-art of our understanding of clusters in
      microarray data. To do this we systematically compared the clusters produced on
      sets of microarray data using a representative set of clustering algorithms
      (hierarchical, k-means, and a modified version of QT_CLUST) with the annotation
      schemes MIPS, GeneOntology and GenProtEC. We assumed that if a cluster reflected
      known biology its members would share related ontological annotations. This
      assumption is the basis of "guilt-by-association" and is commonly used to assign
      the putative function of proteins. To statistically measure the relationship
      between cluster and annotation we developed a new predictive discriminatory
      measure. We found that the clusters found in microarray data do not in general
      agree with functional annotation classes. Although many statistically significant
      relationships can be found, the majority of clusters are not related to known
      biology (as described in annotation ontologies). This implies that use of guilt
      by-association is not supported by annotation ontologies. Depending on the
      estimate of the amount of noise in the data, our results suggest that
      bioinformatics has only codified a small proportion of the biological knowledge
      required to understand microarray data.

PMID- 12611632
TI  - Prediction of food protein allergenicity: a bioinformatic learning systems
      approach.
AB  - Food hypersensitivity is constantly increasing in Western societies with a
      prevalence of about 1-2% in Europe and in the USA. Among children, the incidence
      is even higher. Because of the introduction of foods derived from genetically
      modified crops on the marketplace, the scientific community, regulatory bodies
      and international associations have intensified discussions on risk assessment
      procedures to identify potential food allergenicity of the newly introduced
      proteins. In this work, we present a novel biocomputational methodology for the
      classification of amino acid sequences with regard to food allergenicity and non
      allergenicity. This method relies on a computerised learning system trained using
      selected excerpts of amino acid sequences. One example of such a successful
      learning system is presented which consists of feature extraction from sequence
      alignments performed with the FASTA3 algorithm (employing the BLOSUM50
      substitution matrix) combined with the k-Nearest-Neighbour (kNN) classification
      algorithm. Briefly, the two features extracted are the alignment score and the
      alignment length and the kNN algorithm assigns the pair of extracted features
      from an unknown sequence to the prevalent class among its k nearest neighbours in
      the training (prototype) set available. 91 food allergens from several
      specialised public repositories of food allergy and the SWALL database were
      identified, pre-processed, and stored, yielding one of the most extensively
      characterised repositories of allergenic sequences known today. All allergenic
      sequences were classified using a standard one-leave-out cross validation
      procedure yielding about 81% correctly classified allergens and the
      classification of 367 non-allergens in an independent test set resulted in about
      98% correct classifications. The biocomputational approach presented should be
      regarded as a significant extension and refinement of earlier attempts suggested
      for in silico food safety assessment. Our results show that the framework
      described here is powerful enough to become useful as part of a multiple
      procedure test scheme that also depicts other evaluation approaches such as solid
      phase immunoassay and tests for stability to digestions.

PMID- 12611634
TI  - Alive another day.

PMID- 12611635
TI  - Sarcolemmal and mitochondrial K(ATP) channels and myocardial ischemic
      preconditioning.
AB  - Ischemic preconditioning (IPC) is the phenomenon whereby brief periods of
      ischemia have been shown to protect the myocardium against a sustained ischemic
      insult. The result of IPC may be manifest as a marked reduction in infarct size,
      myocardial stunning, or incidence of arrhythmias. While many substances and
      pathways have been proposed to play a role in the signal transduction mediating
      the cardioprotective effect of IPC, overwhelming evidence indicates an intimate
      involvement of the ATP-sensitive potassium channel (K(ATP) channel) in this
      process. Initial hypotheses suggested that the surface or sarcolemmal K(ATP)
      (sarcK(ATP)) channel mediated the cardioprotective effects of IPC. However, much
      research has subsequently supported a major role for the mitochondrial K(ATP)
      channel (mitoK(ATP)) as the one involved in IPC-mediated cardioprotection. This
      review presents evidence to support a role for the sarcK(ATP) or the mitoK(ATP)
      channel as either triggers and/or downstream mediators in the phenomenon of IPC.

PMID- 12611633
TI  - Development of a porcine skeletal muscle cDNA microarray: analysis of
      differential transcript expression in phenotypically distinct muscles.
AB  - BACKGROUND: Microarray profiling has the potential to illuminate the molecular
      processes that govern the phenotypic characteristics of porcine skeletal muscles,
      such as hypertrophy or atrophy, and the expression of specific fibre types. This
      information is not only important for understanding basic muscle biology but also
      provides underpinning knowledge for enhancing the efficiency of livestock
      production. RESULTS: We report on the de novo development of a composite skeletal
      muscle cDNA microarray, comprising 5500 clones from two developmentally distinct
      cDNA libraries (longissimus dorsi of a 50-day porcine foetus and the
      gastrocnemius of a 3-day-old pig). Clones selected for the microarray assembly
      were of low to moderate abundance, as indicated by colony hybridisation. We
      profiled the differential expression of genes between the psoas (red muscle) and
      the longissimus dorsi (white muscle), by co-hybridisation of Cy3 and Cy5 labelled
      cDNA derived from these two muscles. Results from seven microarray slides
      (replicates) correctly identified genes that were expected to be differentially
      expressed, as well as a number of novel candidate regulatory genes. Quantitative
      real-time RT-PCR on selected genes was used to confirm the results from the
      microarray. CONCLUSION: We have developed a porcine skeletal muscle cDNA
      microarray and have identified a number of candidate genes that could be involved
      in muscle phenotype determination, including several members of the casein kinase
      2 signalling pathway.

PMID- 12611636
TI  - Designing of 'intelligent' liposomes for efficient delivery of drugs.
AB  - The liposome- vesicles made by a double phospholipid layers which may encapsulate
      aqueous solutions- have been introduced as drug delivery vehicles due to their
      structural flexibility in size, composition and bilayer fluidity as well as their
      ability to incorporate a large variety of both hydrophilic and hydrophobic
      compounds. With time the liposome formulations have been perfected so as to serve
      certain purposes and this lead to the design of "intelligent" liposomes which can
      stand specifically induced modifications of the bilayers or can be surfaced with
      different ligands that guide them to the specific target sites. We present here a
      brief overview of the current strategies in the design of liposomes as drug
      delivery carriers and the medical applications of liposomes in humans.

PMID- 12611637
TI  - Neural stem cells in aging and disease.
AB  - Aging in the central nervous system is associated with progressive loss of
      function which is exacerbated by neurodegenerative disorders such as Alzheimer's
      and Parkinson's diseases. The two primary cell replacement strategies involve
      transplantation of exogenous tissue, and activation of proliferation of
      endogenous cells. Transplanted tissue is used to either directly replace lost
      tissue, or to implant genetically engineered cells that secrete factors which
      promote survival and/or proliferation. However, successful application of any
      cell replacement therapy requires knowledge of the complex relationships between
      neural stem cells and the more restricted neural and glial progenitor cells. This
      review focuses on recent advances in the field of stem cell biology of the
      central nervous system, with an emphasis on cellular and molecular approaches to
      replacing cells lost in neurodegenerative disorders.

PMID- 12611638
TI  - Megamitochondria formation - physiology and pathology.
AB  - Mitochondria undergo structural changes simultaneously with their functional
      changes in both physiological and pathological conditions. These structural
      changes of mitochondria are classified into two categories: simple swelling and
      the formation of megamitochondria (MG). Data have been accumulated to indicate
      that free radicals play a crucial role in the mechanism of the MG formation
      induced by various experimental conditions which are apparently various. These
      include ethanol-, chloramphenicol- and hydrazine-induced MG formation.
      Involvement of free radicals in the mechanism of MG formation is showed by the
      fact that MG formation is successfully suppressed by free radical scavengers such
      as alpha-tocopherol, coenzyme Q(10), and 4-OH-TEMPO. Detailed mechanisms and
      pathophysiological meanings of MG formation still remain to be investigated.
      However, a body of evidence strongly suggests that enormous changes in
      physicochemical and biochemical properties of the mitochondrial membranes during
      MG formation take place and these changes are favorable for membrane fusion. A
      recent report showed that continous exposure of cells with MG to free radicals
      induces apoptosis, finding which suggests that MG formation is an adaptative
      process to unfavorable environments at the level of intracellular organelles.
      Mitochondria try to decrease intracellular reactive oxygen species (ROS) levels
      by decreasing the consume of oxygen via MG formation. If mitochondria succeed to
      suppress intracellular ROS levels, MG return to normal both structurally and
      functionally, and they restore the ability to actively synthesize ATP. If cells
      are additionally exposed to excess amounts of free radicals, MG become swollen,
      membrane potential of mitochondria (DeltaPsim) decreases, cytochrome c is
      released from mitochondria, leading to activation of caspases and apoptosis is
      induced.

PMID- 12611639
TI  - Activated c-Met signals through PI3K with dramatic effects on cytoskeletal
      functions in small cell lung cancer.
AB  - Small cell lung cancer (SCLC) is an aggressive illness with early metastases.
      There are several receptor tyrosine kinases (RTKs) overexpressed in SCLC,
      including c-Met. c-Met contains an external semaphorin-like domain, a cytoplasmic
      juxtamembrane domain, tyrosine kinase domain and multiple tyrosines that bind to
      adapter molecules. We have previously reported that c-Met is abundantly expressed
      in the NCI-H69 SCLC cell line and now have determined the downstream effects of
      stimulating c-Met via its ligand hepatocyte growth factor (HGF). Utilizing unique
      phospho-specific antibodies generated against various tyrosines of c-Met, we show
      that Y1003 (binding site for c-Cbl and a negative regulatory site), Y1313
      (binding site for PI3K), Y1230/Y1234/Y1235 (autophosphorylation site), Y1349
      (binding site for Grb2), Y1365 (important in cell morphogenesis) are
      phosphorylated in response to HGF (40 ng/ml, 7.5 min) in H69 cells. Since
      multiple biological and biochemical effects are transduced through the PI3K
      pathway, we determine the role of PI3K in the c-Met/HGF stimulation pathway. We
      initially determined that by inhibiting PI3K with LY294002 (50 microM over 72
      hours), there was at least a 55% decrease in viability of H69 cells. Since H69
      SCLC cells form clusters in cell culture, we determined the effects of HGF and
      LY294002 on cell motility of the clusters by time-lapse video microscopy. In
      response to HGF, SCLC moved much faster and formed more clusters, and this was
      inhibited by LY294002. Finally, we determined the downstream signal transduction
      of HGF stimulation of c-Met with and without inhibition of c-Met (with
      geldanamycin, an anisamycin antibiotic that inhibits c-Met in SCLC) or PI3K (with
      LY294002). We show that association of c-Met with PI3K and GAB2 is diminished by
      inhibiting c-Met. In summary, activation of the c-Met pathway targets the PI3K
      pathway in SCLC and this may be an important therapeutic target.

PMID- 12611640
TI  - Dantrolene protects neurons against kainic acid induced apoptosis in vitro and in
      vivo.
AB  - Apoptotic cell death induced by kainic acid (KA) in cultures of rat cerebellar
      granule cells (CGC) and in different brain regions of Wistar rat pups on
      postnatal day 21 (P21) was studied. In vitro, KA (100-500 microM) induced a
      concentration-dependent loss of cell viability in MTT assay and cell death had
      apoptotic morphology as studied by chromatin staining with propidium iodide (PI).
      In vivo, twenty-four hours after induction of status epilepticus (SE) by an
      intraperitoneal KA injection (5 mg/kg) we quantified apoptotic cells in
      hippocampus (CA1 and CA3), parietal cortex and cerebellum using PI staining and
      terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)
      technique. We report that dantrolene, a specific ryanodine receptor antagonist,
      was able to significantly reduce the apoptotic cell death in CGC cultures and in
      hyppocampal CA1 and parietal cortex regions. Our finding can be valuable for
      neuroprotective therapy strategies in patients with repeated generalized seizures
      or status epilepticus.

PMID- 12611642
TI  - Blood histamine is associated with coronary artery disease, cardiac events and
      severity of inflammation and atherosclerosis.
AB  - BACKGROUND: Mast cells are prevalent in the shoulder of unstable atheromas;
      cardiac mast cells secrete proteases capable of activating matrix
      metalloproteinases. Histamine is essential in the inflammatory cascade of the
      unstable plaque. Ascorbate depletion has been correlated with histaminemia which
      has been shown to impair endothelial-dependent vasodilation. This study evaluates
      whether oxidative stress as measured by isoprostanes (PGF(2alpha)) coupled with
      an inflammatory state characterized by histaminemia predisposes patients to acute
      coronary syndrome (ACS). METHODS: Whole blood histamine, serum vitamin C, and
      serum PGF(2alpha) levels were drawn on 50 patients with ACS as determined by
      standard diagnostic criteria, 50 patients with stable coronary artery disease
      (SCAD), and 50 age and sex matched normal controls (C). RESULTS: Data were
      analyzed by stepwise discriminant and Spearman's rank correlation coefficient. A
      significant relationship exists between histamine and PGF(2alpha). As PGF(2alpha)
      rises above 60 pg/mL, an increase in histamine occurs in both the ACS and SCAD
      groups. A significant inverse relationship exists between ascorbate and histamine
      in the ACS versus C groups (P < 0.01) and the SCAD versus C groups (P < 0.01).
      CONCLUSION: Histamine and isoprostane levels increase in SCAD and ACS patients.
      Mast cell activation and lipid oxidation generated during atherosclerosis
      manifest this inflammatory response. Accelerated isoprostane formation and
      depleted ascorbate paired with histaminemia is active in CAD and predispose
      patients to acute coronary syndrome. Blood histamine alone may be a better risk
      factor for coronary events, and a better prognostic indicator than CRP even when
      combined with lipid indexes.

PMID- 12611641
TI  - Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in
      cancer patients: impact of an antioxidant treatment.
AB  - OBJECTIVE: So far, it is not well established whether oxidative stress found in
      cancer patients results from an increased production of oxidants in the body or
      from a failure of physiological antioxidant systems. To further investigate this
      question we have assessed the blood levels of reactive oxygen species as a marker
      of free radicals producing oxidative stress and the most relevant of the
      physiological body enzymes counteracting reactive oxygen species, namely
      glutathione peroxidase and superoxide dismutase. Serum levels of proinflammatory
      cytokines and IL-2 were also investigated. All these parameters were studied in
      relation to the clinically most important index of disease progression, namely
      Performance Status (ECOG PS). We also tested the reducing ability of different
      antioxidant agents on reactive oxygen species levels by measuring the increase in
      glutathione peroxidase activity, and the reduction of serum levels of IL-6 and
      TNF. DESIGN, SETTING AND SUBJECTS: We carried out an open non randomized study on
      28 advanced stage cancer patients (stage III, 10.7%, and stage IV, 89.3%) with
      tumours at different (8) sites: all were hospitalized in the Medical Oncology
      Dept, University of Cagliari Interventions. The patients were divided into 5
      groups and a different antioxidant treatment was administered to each group. The
      selected antioxidants were: alpha lipoic acid 200 mg/day orally, N-acetylcysteine
      1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally, amifostine 375
      mg/day i.v., reduced glutathione 600 mg/day i.v., vitamin A 30000 IU/day orally
      plus vitamin E 70 mg/day orally plus Vitamin C 500 mg/day orally. The antioxidant
      treatment was administered for 10 consecutive days. RESULTS: Our results show
      that all but one of the antioxidants tested were effective in reducing reactive
      oxygen species levels and 2 of them (cysteine-containing compounds and
      amifostine) had the additional effect of increasing glutathione peroxidase
      activity. Comprehensively, the "antioxidant treatment" was found to have an
      effect both on reactive oxygen species levels and glutathione peroxidase
      activity. The antioxidant treatment also reduced serum levels of IL-6 and TNF.
      Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.

PMID- 12611643
TI  - Stem cells (p63(+)) in keratinocyte cultures from human adult skin.
AB  - Epidermal stem cells (ESC) are responsible for maintaining skin cellular
      homeostasis, as they give rise to fast-dividing transit amplifying cells
      committed to terminal differentiation, while retaining their self-renewal
      capacity. However, no pure ESC cultures are available and no highly specific
      cytochemical marker was identified. We report here the experimental conditions
      allowing the selective enrichment in ESC, using cultured adult human
      keratinocytes. The main step was the selection of cells able to rapidly adhere to
      human collagen type IV in vitro. Thus, an increased proportion of putative ESC of
      about 65% was obtained, as demonstrated by p63 expression.

PMID- 12611644
TI  - Beneficial effect of enalapril in spontaneously hypertensive rats cardiac
      remodeling with nitric oxide synthesis blockade.
AB  - AIMS: To study the efficiency of an angiotensin converting enzyme inhibitor on
      the blood pressure (BP) and the myocardium remodeling when spontaneously
      hypertensive rats (SHRs) are submitted to nitric oxide synthesis (NOs) blockade
      (with L-NAME) and simultaneously treated. METHODS: Young adult male SHRs were
      separated in four groups (n = 5) and treated for 20 days: Control, L-NAME, L
      NAME+Enalapril, and Enalapril. The alterations of the BP, heart mass/body mass
      ratio and stereological parameters for myocytes, connective tissue and
      intramyocardial vessels were studied among the groups. RESULTS: The SHRs with NOs
      blockade showed a great modification of the myocardium with extensive areas of
      reparative and interstitial fibrosis and accentuated hypertrophy of the cardiac
      myocytes (cross sectional area 60% higher in animals taking L-NAME than in
      Control SHRs). Comparing the SHRs with NO deficiency (L-NAME group), the Control
      SHRs and the Enalapril treated SHRs significant differences were found in the BP
      and in all stereological parameters. The NO deficiency caused an important BP
      increment in SHRs that was partially attenuated by Enalapril. This Enalapril
      effect was more pronounced in Control SHRs. A significant increment of the
      intramyocardial vessels was observed in NO deficient SHRs and Control SHRs
      treated with Enalapril demonstrated by the stereology (greater microvascular
      densities in treated SHRs). CONCLUSION: Enalapril administration showed a
      beneficial effect on vascular remodeling and myocardial hypertrophy in SHRs. In
      SHRs with NO blockade, however, the beneficial effect of Enalapril occurred only
      in vascular remodeling.

PMID- 12611645
TI  - Ex vivo differentiation of umbilical cord blood progenitor cells in the presence
      of placental conditioned medium.
AB  - Hematopoetic stem cells (HSC) are the progenitors for the lympho-hematopoietic
      system, with long lifespan and high proliferation potential. Transplantation of
      HSC from bone marrow or peripheral blood represents a standard therapy in severe
      hematological conditions. A possible alternative source of HSC is the umbilical
      cord blood, prepared by various separation procedures followed by expansion in
      cultures supplemented with hematopoietic growth factors. In order to check the
      effects of placental conditioned medium (PCM) from placental cells culture upon
      viability of HSC, we added plasma, PCM, dimetil sulfoxyde or hemin in HSC
      cultures. Flow cytometry or direct scoring of solid cultures using CD45+, CD34+,
      CD71+ and CD14+ fluorescent-labeled monoclonal antibodies evaluated the effects
      upon cell proliferation and colony forming ability of HSC cultures, versus
      controls. PCM produced the highest proliferation, followed by plasma, DMSO and
      hemin. PCM improved the survival time and maintained a higher proportion of
      immature cells. PCM stimulates the differentiation towards myeloid lineage
      progenitor cells (>90% being CD45+), increasing the percentage of CD14+,
      granulocites /monocytes precursors. It is highly suggestive that PCM contains
      growth factors or cytokines, which regulate the development of HSC.
      Characterization of these factors is in progress.

PMID- 12611646
TI  - Effect of ischemia-reperfusion on the post-rest inotropy of isolated perfused rat
      heart.
AB  - This paper aims to study the effect of ischemia-reperfusion on the post-rest
      inotropy and to characterize post-rest B1:B2 ratio as an index of intracellular
      Ca(2+) overload. When the rest interval between the cardiac beats is increased,
      the magnitude of the post-rest beats is increased. First beat (B1) is maximally
      potentiated with exponential decline of the second (B2) and subsequent beats,
      thereby establishing a normal B1:B2 ratio of post- rest inotropy of the cardiac
      muscle. The rest potentiation of B1 and subsequent decay in the magnitude B2 is
      thought to develop from the time-dependent changes in the Ca(2+)-uptake and
      release from the sarcoplasmic reticulum (SR). Ca(2+)-kinetics of SR can be
      modulated by a variety of interventions which produce Ca(2+) loading of the SR.
      METHODS: Isolated perfused (K-H buffer, 34 degrees C) rat hearts were paced at 1
      Hz (steady state frequency). Interbeat intervals between 1s and 10s were
      introduced and the recovery in the left ventricular contractile force (Pmax) of
      post-rest B1 and B2 for each interval was recorded. Their relative relationship
      was computed and compared under control and experimental conditions. RESULTS:
      High extracellular Ca(2+) (2.50 to 7.0 mM) or low extracellular Na(+) (50% of
      control), and ischemia (60 min, 34 degrees C) - reperfusion (30 min, 34 degrees
      C) caused the reversal of the control relationship of the B1 to B2, with B2 being
      more potentiated than B1, accompanied by the appearance of after-contractions
      during the rest intervals of 4s or more. The mean (+/- SE) control B1:B2 ratio
      (at 4s interval) of 1.12 +/- 0.05 was significantly (P<0.001) reduced to 0.93 +/-
      0.07; 0.89 +/- 0.01; and 0.96 +/- 0.02 after high Ca(2+) (6 mM) perfusion, low
      Na(+)(50%) perfusion and ischemia-reperfusion respectively. Simultaneous
      perfusion with ryanodine (1 microM) abolished the after-contractions and
      significantly increased the reduced ratios. The time course of changes in B1:B2
      ratio after graded ischemia-reperfusion showed a significant fall in the ratio
      between 30 and 60 min of ischemia. A parallel change in Pmax and a significant
      rise in the left ventricular end-diastolic pressure, indicating an irreversible
      phase of the injury was recorded. No significant changes in B1:B2 ratio were
      detected during the reversible phase (<30 min) of the ischemia-reperfusion
      injury. CONCLUSIONS: Ischemia-reperfusion induces significant alterations in the
      relative ratio of the post-rest contractions of the left ventricle in isolated
      perfused rat heart. The altered ratios were characterized to predict the
      irreversibility of the reperfusion injury and to index the extent of Ca(2+)
      loading of the sarcoplasmic reticulum.

PMID- 12611647
TI  - Highly effective techniques in computerized dental tissue morphometry.
AB  - The effectiveness of computer-aided morphometry is greatly dependent on the
      capabilities of the software platforms, but the literature provides only
      information about the measurement methods and their medical interpretation. The
      purpose of our work is to create a link between the technical algorithm and the
      medical significance, by a detailed description of measurement procedures,
      accompanied by the interpretation of their results. The developed techniques
      operate at a pixel level, by deriving a full benefit from the computational
      resources available in the modern software environments for image processing. The
      approach is built on three illustrative cases, formulated in a large sense, so as
      to cover classes of general problems, referring to cellular entities and tubular
      structures in cross and longitudinal section. Specimens belonging to the dentin
      pulp complex were chosen, because they permit a quantitative analysis for each
      morphological element, as well as comparative discussion. With appropriate
      adaptations of the procedures, the measurements of other types of normal and
      pathological tissues can be analogously addressed. The design, implementation and
      exploitation of our procedures are supported by specific references to the use of
      an image analysis system (Zeiss KS400). The algorithmic background remains valid
      (except for some possible minor changes) when similar software is used.
      Consequently, the results and their interpretations, prove the importance of the
      numerical analysis in automating the quantitative evaluation of the structural
      features.

PMID- 12611648
TI  - Significance of platelet-activating factor acetylhydrolase in patients with non
      insulin-dependent (type 2) diabetes mellitus.
AB  - BACKGROUND: Non-insulin dependent diabetes mellitus (NIDDM) represents an
      independent risk factor for cardiovascular diseases (CVD), being characterized by
      a continuous low-grade inflammation and endothelial activation state. Plasma
      platelet - activating factor - acetylhydrolases (PAF-AHs) are a subgroup of
      Ca(2+)-independent phospholipase A(2) family (also known as lipoprotein
      associated phospholipases A(2)) that hydrolyze and inactivate the lipid mediator
      platelet-activating factor (PAF) and/or oxidized phospholipids. This enzyme is
      considered to play an important role in inflammatory diseases and
      atherosclerosis. The present study aims to investigate the relations between the
      levels of PAF-AH activity and LDL-cholesterol / HDL-cholesterol (LDL-ch / HDL-ch)
      ratio in NIDDM patients as compared to controls. METHODS: serum PAF-AH activity
      was measured in 50 patients with dyslipidemia, in 50 NIDDM patients and in 50
      controls (normal lipid and glucose levels). Total cholesterol, LDL-ch, HDL-ch,
      triglyceride and blood glucose were determined in all subjects. RESULTS: All
      NIDDM patients display hiperlipidemia, with increased LDL-ch and triglyceride
      levels. There is a significant correlation between LDL-ch levels (especially LDL
      ch / HDL-ch ratio) and PAF-AH activity in dyslipidemic and NIDDM patients.
      CONCLUSION: Diabetic and dyslipidemic patients have an increased plasma PAF-AH
      activity correlated with their LDL-ch levels and mainly with LDL-ch / HDL-ch
      ratio. Plasma PAF-AH high levels appear to be important as a risk marker for
      endothelial dysfunction in patients with NIDDM.

PMID- 12611649
TI  - From molecular genetics to functional genomics and physiome.

PMID- 12611650
TI  - Multiorgan dysfunction syndrome: how water might contribute to its progression.
AB  - Multiorgan dysfunction syndrome (MODS) is one of the most frequent conditions
      encountered in intensive-care medicine. MODS is defined as total or partial loss
      of two or more organs with vital functions. The development of acute renal
      failure (ARF) in MODS leads to an additional aggravation with considerably higher
      hospital mortality than in other ICU patients with MODS. Whereas dissolved
      substances involved in the regulation of regional blood flow, endothelial cell
      injury, microvascular permeability, oxygenation, and nutrition of cells are at
      the focus of interest in MODS, hardly any scientific attention is paid to their
      main solvent water. An impaired renal water excretion and an increased metabolic
      water volume requiring excretion interfere with diffusive and convective oxygen
      transport through the different fluid compartments. It will be shown first that
      the ratio of U(osm)/ P(osm) appears to be a reliable tool to assess overhydration
      in ARF. Secondly, the limits of urinary output in response to water intake will
      be considered. Furthermore, the metabolic water formation by an enhanced
      degradation of endogenous protein and fat will be discussed. Finally, the daily
      caloric intake is questioned with respect to energy expenditure and metabolic
      water formation.

PMID- 12611651
TI  - Real cells - virtual computers.
AB  - Now it is quite usual to use real computers to simulate virtual cells. I suggest
      that real cells (e.g. cells cultured in vitro) might be considered and used as
      molecular automata. As an imaginary experience, a molecular automata can be
      built, using real cells and a chemical inert molecule. I suggest that one could
      be able to test statistical properties of a 2D gas trapped in a box using this
      sort of automata. Moreover, I would conjecture that any possible algorithm can be
      implemented in such molecular automata.

PMID- 12611653
TI  - Nuclear waste transportation: case studies of identifying stakeholder risk
      information needs.
AB  - The U.S. Department of Energy (DOE) is responsible for the cleanup of our
      nation's nuclear legacy, involving complex decisions about how and where to
      dispose of nuclear waste and how to transport it to its ultimate disposal site.
      It is widely recognized that a broad range of stakeholders and tribes should be
      involved in this kind of decision. All too frequently, however, stakeholders and
      tribes are only invited to participate by commenting on processes and activities
      that are near completion; they are not included in the problem formulation
      stages. Moreover, it is often assumed that high levels of complexity and
      uncertainty prevent meaningful participation by these groups. Considering the
      types of information that stakeholders and tribes need to be able to participate
      in the full life cycle of decision making is critical for improving participation
      and transparency of decision making. Toward this objective, the Consortium for
      Risk Evaluation with Stakeholder Participation (CRESP) participated in three
      public processes relating to nuclear waste transportation and disposal in 1997
      1998. First, CRESP organized focus groups to identify concerns about nuclear
      waste transportation. Second, CRESP conducted exit surveys at regional public
      workshops held by DOE to get input from stakeholders on intersite waste transfer
      issues. Third, CRESP developed visual tools to synthesize technical information
      and allow stakeholders and tribes with varying levels of knowledge about nuclear
      waste to participate in meaningful discussion. In this article we share the
      results of the CRESP findings, discuss common themes arising from these
      interactions, and comment on special considerations needed to facilitate
      stakeholder and tribal participation in similar decision-making processes.

PMID- 12611654
TI  - Histopathologic and histochemical biomarker responses of Baltic clam, Macoma
      balthica, to contaminated Sydney Harbour sediment, Nova Scotia, Canada.
AB  - Sediments in Sydney Harbour, Nova Scotia, are highly contaminated by polynuclear
      aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and heavy metals.
      Histopathologic and histochemical evaluations were made on the Baltic clam,
      Macoma balthica, exposed to 11 Sydney Harbour sediment samples. Histologic
      lesions in digestive gland (tubular dilation or atrophy, macrophage aggregates,
      tubular cell necrosis, and tissue inflammation) and gonads (macrophage
      aggregates, supporting cell, germ cell, and ovarian cell necroses) were
      frequently detected in clams exposed to the most contaminated sediments from the
      harbor. Clams exposed to these contaminated sediments also had the highest acid
      phosphatase activity. The average scores of tubular dilation or atrophy, ovarian
      cell necrosis, and the sums of mean digestive gland lesions correlated
      significantly with sediment PCBs, and the activities of acid phosphatase
      correlated significantly with sediment heavy metals, PAHs, and PCBs. Among the
      lesions, digestive gland tubular dilation or atrophy, tubular cell, germ cell,
      and ovarian cell necroses, and the activity of acid phosphatase are the best
      sublethal effect indicators in Macoma exposed to Sydney Harbour sediments. Key
      words: biomarkers, chronic biologic effects, clams, histology, histochemistry,
      Macoma balthica, marine sediment, polynuclear aromatic hydrocarbons,
      polychlorinated biphenyls.

PMID- 12611652
TI  - Azole fungicides affect mammalian steroidogenesis by inhibiting sterol 14 alpha
      demethylase and aromatase.
AB  - Azole compounds play a key role as antifungals in agriculture and in human
      mycoses and as non-steroidal antiestrogens in the treatment of estrogen
      responsive breast tumors in postmenopausal women. This broad use of azoles is
      based on their inhibition of certain pathways of steroidogenesis by high-affinity
      binding to the enzymes sterol 14-alpha-demethylase and aromatase. Sterol 14-alpha
      demethylase is crucial for the production of meiosis-activating sterols, which
      recently were shown to modulate germ cell development in both sexes of mammals.
      Aromatase is responsible for the physiologic balance of androgens and estrogens.
      At high doses, azole fungicides and other azole compounds affect reproductive
      organs, fertility, and development in several species. These effects may be
      explained by inhibition of sterol 14-alpha-demethylase and/or aromatase. In fact,
      several azole compounds were shown to inhibit these enzymes in vitro, and there
      is also strong evidence for inhibiting activity in vivo. Furthermore, the
      specificity of the enzyme inhibition of several of these compounds is poor, both
      with respect to fungal versus nonfungal sterol 14-alpha-demethylases and versus
      other P450 enzymes including aromatase. To our knowledge, this is the first
      review on sterol 14-alpha-demethylase and aromatase as common targets of azole
      compounds and the consequence for steroidogenesis. We conclude that many azole
      compounds developed as inhibitors of fungal sterol 14-alpha-demethylase are
      inhibitors also of mammalian sterol 14-alpha-demethylase and mammalian aromatase
      with unknown potencies. For human health risk assessment, data on comparative
      potencies of azole fungicides to fungal and human enzymes are needed.

PMID- 12611655
TI  - Power-line frequency electromagnetic fields do not induce changes in
      phosphorylation, localization, or expression of the 27-kilodalton heat shock
      protein in human keratinocytes.
AB  - The linkage of the exposure to the power-line frequency (50-60 Hz)
      electromagnetic fields (EMF) with human cancers remains controversial after more
      than 10 years of study. The in vitro studies on the adverse effects of EMF on
      human cells have not yielded a clear conclusion. In this study, we investigated
      whether power-line frequency EMF could act as an environmental insult to invoke
      stress responses in human keratinocytes using the 27-kDa heat shock protein
      (HSP27) as a stress marker. After exposure to 1 gauss (100 micro T) EMF from 20
      min to 24 hr, the isoform pattern of HSP27 in keratinocytes remained unchanged,
      suggesting that EMF did not induce the phosphorylation of this stress protein.
      EMF exposure also failed to induce the translocation of HSP27 from the cytoplasm
      to the nucleus. Moreover, EMF exposure did not increase the abundance of HSP27 in
      keratinocytes. In addition, we found no evidence that EMF exposure enhanced the
      level of the 70-kDa heat shock protein (HSP70) in breast or leukemia cells as
      reported previously. Therefore, in this study we did not detect any of a number
      of stress responses in human keratinocytes exposed to power-line frequency EMF.

PMID- 12611656
TI  - Threshold of trichloroethylene contamination in maternal drinking waters
      affecting fetal heart development in the rat.
AB  - Halogenated hydrocarbons such as trichloroethylene (TCE) are among the most
      common water supply contaminants in the United States and abroad. Epidemiologic
      studies have found an association but not a cause-and-effect relation between
      halogenated hydrocarbon contamination and increased incidence of congenital
      cardiac malformations or other defective birth outcomes. Avian and rat studies
      demonstrated statistically significant increases in the number of congenital
      cardiac malformations in those treated with high doses of TCE, either via
      intrauterine pump or in maternal drinking water, compared with controls. This
      study attempts to determine if there is a threshold dose exposure to TCE above
      which the developing heart is more likely to be affected. Sprague-Dawley rats
      were randomly placed in test groups and exposed to various concentrations of TCE
      (2.5 ppb, 250 ppb, 1.5 ppm, 1,100 ppm) in drinking water or distilled water
      (control group) throughout pregnancy. The percentage of abnormal hearts in the
      treated groups ranged from 0 to 10.48%, with controls having 2.1% abnormal
      hearts, and the number of litters with fetuses with abnormal hearts ranged from 0
      to 66.7%, and the control percentage was 16.4%. The data from this study indicate
      not only that there is a statistically significant probability overall of a dose
      response to increasing levels of TCE exposure, but also that this trend begins to
      manifest at relatively low levels of exposure (i.e., < 250 ppb). Maternal rats
      exposed to more than this level of TCE during pregnancy showed an associated
      increased incidence of cardiac malformations in their developing rat fetuses.

PMID- 12611657
TI  - Development and application of a robust speciation method for determination of
      six arsenic compounds present in human urine.
AB  - Six arsenic species [arsenate, arsenite, arsenocholine, arsenobetaine, monomethyl
      arsonic acid, and dimethyl arsinic acid] present in human urine were determined
      using ion-exchange chromatography combined with inductively coupled plasma mass
      spectrometry (IC-ICP-MS). Baseline separation was achieved for all six species as
      well as for the internal standard (potassium hexahydroxy antimonate V) in a
      single chromatographic run of less than 30 min, using an ammonium carbonate
      buffer gradient (between 10 and 50 mM) at ambient temperature, in conjunction
      with cation- and anion-exchange columns in series. The performance of the method
      was evaluated with respect to linearity, precision, accuracy, and detection
      limits. This method was applied to determine the concentration of these six
      arsenic species in human urine samples (n = 251) collected from a population
      based exposure assessment survey. Method precision was demonstrated by the
      analysis of duplicate samples that were prepared over a 2-year analysis period.
      Total arsenic was also determined for the urine samples using flow injection
      analysis coupled to ICP-MS. The summed concentration of the arsenic species was
      compared with the measured arsenic total to demonstrate mass balance.

PMID- 12611659
TI  - Fenitrothion: toxicokinetics and toxicologic evaluation in human volunteers.
AB  - An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the
      acceptable daily intake (ADI)] and 0.36 mg/kg/day (72 X ADI) administered as two
      daily divided doses for 4 days in 12 human volunteers was designed and undertaken
      after results from a pilot study. On days 1 and 4, blood and urine samples were
      collected for analysis of fenitrothion and its major metabolites, as well as
      plasma and red blood cell cholinesterase activities, and biochemistry and
      hematology examination. Pharmacokinetic parameters could only be determined at
      the higher dosage, as there were insufficient measurable fenitrothion blood
      levels at the lower dosage and the fenitrooxone metabolite could not be measured.
      There was a wide range of interindividual variability in blood levels, with peak
      levels achieved between 1 and 4 hr and a half-life for fenitrothion of 0.8-4.5
      hr. Although based on the half-life, steady-state levels should have been
      achieved; the area under the curve (AUC)(0-12 hr) to AUC(0-(infinity) )ratio of
      1:3 suggested accumulation of fenitrothion. There was no significant change in
      plasma or red blood cell cholinesterase activity with repeated dosing at either
      dosage level of fenitrothion, and there were no significant abnormalities
      detected on biochemical or hematologic monitoring.

PMID- 12611658
TI  - Developmental neurotoxicity elicited by prenatal or postnatal chlorpyrifos
      exposure: effects on neurospecific proteins indicate changing vulnerabilities.
AB  - The developmental neurotoxicity of the organophosphate pesticide chlorpyrifos
      (CPF) is thought to involve both neurons and glia, thus producing a prolonged
      window of vulnerability. To characterize the cell types and brain regions
      involved in these effects, we administered CPF to developing rats and examined
      neuroprotein markers for oligodendrocytes (myelin basic protein, MBP), for
      neuronal cell bodies (neurofilament 68 kDa, NF68), and for developing axons
      (neurofilament 200 kDa, NF200). Prenatal CPF administration on gestational days
      (GDs) 17-20 elicited an immediate (GD21) enhancement of MBP and NF68; by
      postnatal day (PN) 30, however, there were deficits in all three biomarkers, with
      the effect restricted to females. Exposure in the early postnatal period, PN1-4,
      did not evoke significant short-term or long-term changes in the neuroproteins.
      However, with treatment on PN11-14, we found reductions in MBP in the immediate
      posttreatment period (PN15, PN20) throughout the brain, and deficiencies across
      all three proteins emerged by PN30. With this regimen, males were targeted
      preferentially. The sex-selective effects seen here for the GD17-20 and PN11-14
      regimens match those reported earlier for subsequent behavioral performance.
      These results indicate a shift in the populations of neural cells targeted by
      CPF, dependent upon the period of exposure. Similarly, developmental differences
      in the sex selectivity of the biochemical mechanisms underlying neurotoxicant
      actions are likely to contribute to discrete behavioral outcomes.

PMID- 12611660
TI  - Biotransformations of bisphenol A in a mammalian model: answers and new questions
      raised by low-dose metabolic fate studies in pregnant CD1 mice.
AB  - We investigated the metabolic fate of a low dose (25 micro g/kg) of bisphenol A
      [2,2-bis(4-hydroxy-phenyl)propane] (BPA) injected subcutaneously in CD1 pregnant
      mice using a tritium-labeled molecule. Analytic methods were developed to allow a
      radio-chromatographic profiling of BPA residues in excreta and tissues, as well
      as in mothers' reproductive tracts and fetuses, that contained more than 4% of
      the administered radioactivity. BPA was extensively metabolized by CD1 mice.
      Identified metabolite structures included the glucuronic acid conjugate of BPA,
      several double conjugates, and conjugated methoxylated compounds, demonstrating
      the formation of potentially reactive intermediates. Fetal radioactivity was
      associated with unchanged BPA, BPA glucuronide, and a disaccharide conjugate. The
      latter structure, as well as that of a dehydrated glucuronide conjugate of BPA (a
      major metabolite isolated from the digestive tract), showed that BPA metabolic
      routes were far more complex than previously thought. The estrogenicity of the
      metabolites that were identified but not tested for hormonal activity cannot be
      ruled out; however, in general, conjugated BPA metabolites have significantly
      lower potency than that of the parent compound. Thus, these data suggest the
      parental compound is responsible for the estrogenic effects observed in fetuses
      exposed to BPA during gestation in this mammalian model.

PMID- 12611661
TI  - A geographic information system for characterizing exposure to Agent Orange and
      other herbicides in Vietnam.
AB  - Between 1961 and 1971, U.S. military forces dispersed more than 19 million
      gallons of phenoxy and other herbicidal agents in the Republic of Vietnam,
      including more than 12 million gallons of dioxin-contaminated Agent Orange, yet
      only comparatively limited epidemiologic and environmental research has been
      carried out on the distribution and health effects of this contamination. As part
      of a response to a National Academy of Sciences' request for development of
      exposure methodologies for carrying out epidemiologic research, a conceptual
      framework for estimating exposure opportunity to herbicides and a geographic
      information system (GIS) have been developed. The GIS is based on a relational
      database system that integrates extensive data resources on dispersal of
      herbicides (e.g., HERBS records of Ranch Hand aircraft flight paths, gallonage,
      and chemical agent), locations of military units and bases, dynamic movement of
      combat troops in Vietnam, and locations of civilian population centers. The GIS
      can provide a variety of proximity counts for exposure to 9,141 herbicide
      application missions. In addition, the GIS can be used to generate a quantitative
      exposure opportunity index that accounts for quantity of herbicide sprayed,
      distance, and environmental decay of a toxic factor such as dioxin, and is
      flexible enough to permit substitution of other mathematical exposure models by
      the user. The GIS thus provides a basis for estimation of herbicide exposure for
      use in large-scale epidemiologic studies. To facilitate widespread use of the
      GIS, a user-friendly software package was developed to permit researchers to
      assign exposure opportunity indexes to troops, locations, or individuals.

PMID- 12611662
TI  - Estrogenic activity of styrene oligomers after metabolic activation by rat liver
      microsomes.
AB  - In this study we examined estrogenic activity of styrene oligomers after
      metabolic activation by rat liver microsomes. Trans-1,2-diphenylcyclobutane
      (TCB), cis-1,2-diphenylcyclobutane (CCB), 1,3-diphenylpropane, 2,4-diphenyl-1
      butene, 2,4,6-triphenyl-1-hexene, and 1-alpha-phenyl-4ss-(1 -phenylethyl)tetralin
      were negative in the yeast estrogen screening assay and estrogen reporter assay
      using estrogen-responsive human breast cancer cell line MCF-7. However, TCB
      exhibited estrogenic activity after incubation with liver microsomes of
      phenobarbital-treated rats in the presence of reduced nicotinamide adenine
      dinucleotide phosphate (NADPH). Minor activity was observed when liver microsomes
      of untreated or 3-methylcholanthrene-treated rats were used instead of those from
      phenobarbital-treated rats. CCB, 1,3-diphenylpropane, and 2,4-diphenyl-1-butene
      also exhibited estrogenic activity after metabolic activation by liver
      microsomes, but the activity was lower than that of TCB. 2,4,6-Triphenyl-1-hexene
      and 1-alpha-phenyl-4ss-(1 -phenylethyl)tetralin did not show estrogenic activity
      after such incubation. When TCB was incubated with liver microsomes of
      phenobarbital-treated rats in the presence of NADPH, three metabolites were
      detected by high-performance liquid chromatography (HPLC). One metabolite
      isolated by HPLC exhibited a significant estrogenic activity. The active
      metabolite was identified as trans-1-(4-hydroxyphenyl)-2-phenylcyclobutane by
      mass and nuclear magnetic resonance spectral analysis. These results suggest that
      the estrogenic activity of TCB was caused by the formation of the 4-hydroxylated
      metabolite.

PMID- 12611663
TI  - A delta-aminolevulinic acid dehydratase (ALAD) polymorphism may modify the
      relationship of low-level lead exposure to uricemia and renal function: the
      normative aging study.
AB  - In this study we investigated whether a known delta-aminolevulinic acid
      dehydratase (ALAD) exon 4 polymorphism has a modifying effect on the association
      of blood or bone lead level with uricemia and indices of renal function among
      middle-aged and elderly men. We performed a cross-sectional study of subjects who
      participated between 1991 and 1995 in the Department of Veterans Affairs
      Normative Aging Study. Information on blood lead levels, bone lead levels
      (measured by K-shell X-ray fluorescence), serum uric acid, serum creatinine,
      estimated creatinine clearance, and ALAD polymorphism status was available in 709
      subjects. Regression models were constructed to examine the relationships of
      serum uric acid, serum creatinine, and estimated creatinine clearance to blood or
      bone lead level, stratified by genotype. We also adjusted for age, body mass
      index, blood pressure, smoking, alcohol consumption, and ingestion of analgesic
      medications (n = 638). Of the 709 subjects, 7 (1%) and 107 (15%) were homozygous
      and heterozygous for the variant (ALAD-2) allele, respectively. The mean (range)
      serum uric acid and creatinine levels were 6.5 (2.9-10.6) and 1.2 (0.6-2.5)
      mg/dL. No significant differences were found in serum uric acid, serum
      creatinine, or estimated creatinine clearance by ALAD genotype. However, after
      adjusting for other potential confounders, we found a significant linear
      relationship between serum uric acid and patella bone lead (p = 0.040) among the
      ALAD 1-2/2-2 genotype individuals above a threshold patellar lead level of 15
      micro g/g. In contrast, among the wild-type (ALAD 1-1) individuals, there was a
      suggestion of a significant linear relationship of serum uric acid with patella
      bone lead (p = 0.141), but only after a threshold of 101 micro g/g. There was
      evidence of a significant (p = 0.025) interaction of tibia lead with genotype
      (ALAD 1-1 vs. ALAD 1-2/2-2) regarding serum creatinine as an outcome, but in the
      same linear regression model tibia lead alone was not a significant predictor of
      serum creatinine. Conversely, for estimated creatinine clearance, patella lead,
      but not the interaction of patella lead with genotype, was a significantly
      independent predictor (p = 0.026). Our findings suggest that ALAD genotype may
      modify the effect of lead on the renal excretion of uric acid as well as overall
      renal function among middle-aged and elderly men who had community
      (nonoccupational) exposures to lead. Additional research is needed to ascertain
      whether this constitutes a true gene-environment interaction and, if so, its
      clinical impact.

PMID- 12611664
TI  - Long-term follow-up of the residents of the Three Mile Island accident area: 1979
      1998.
AB  - The Three Mile Island (TMI) nuclear power plant accident (1979) prompted the
      Pennsylvania Department of Health to initiate a cohort mortality study in the TMI
      accident area. This study is significant because of the long follow-up (1979
      1998), large cohort size (32,135), and evidence from earlier reports indicating
      increased cancer risks. Standardized mortality ratios (SMRs) were calculated to
      assess the mortality experience of the cohort compared with a local population.
      Relative risk (RR) regression modeling was performed to assess cause-specific
      mortality associated with radiation-related exposure variables after adjustment
      for individual smoking and lifestyle factors. Overall cancer mortality in this
      cohort was similar to the local population [SMRs = 103.7 (male); 99.8 (female)].
      RR modeling showed neither maximum gamma nor likely gamma exposure was a
      significant predictor of all malignant neoplasms; bronchus, trachea, and lung; or
      heart disease mortality after adjusting for known confounders. The RR estimates
      for maximum gamma exposure (less than or equal to 8, 8-19, 20-34, greater than or
      equal to 35 mrem) in relation to all lymphatic and hematopoietic tissue (LHT) are
      significantly elevated (RRs = 1.00, 1.16, 2.54, 2.45, respectively) for males and
      are suggestive of a potential dose-response relationship, although the test for
      trend was not significant. An upward trend of RRs and SMRs for levels of maximum
      gamma exposure in relation to breast cancer in females (RRs = 1.00, 1.08, 1.13,
      1.31; SMRs = 104.2, 113.2, 117.9) was also noted. Although the surveillance
      within the TMI cohort provides no consistent evidence that radioactivity released
      during the nuclear accident has had a significant impact on the overall mortality
      experience of these residents, several elevations persist, and certain potential
      dose-response relationships cannot be definitively excluded.

PMID- 12611665
TI  - Organochlorines in Swedish women: determinants of serum concentrations.
AB  - We studied associations between lifestyle/medical factors and lipid-adjusted
      serum concentrations of seven polychlorinated biphenyl (PCB) congeners and five
      chlorinated pesticides/metabolites among 205 Swedish women (54-75 years old).
      Serum concentrations were significantly associated with age, body mass index,
      body weight change, diabetes mellitus, consumption of fatty fish, and place of
      residence. The findings suggest that lifestyle/medical factors may confound
      results in epidemiologic studies when they are related to both serum
      concentrations and disease. Moreover, disease itself may influence serum
      concentrations of some organochlorines, as indicated by the negative associations
      between recent weight change and serum concentrations of some PCB congeners, p,p 
      dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) and the
      positive association between diabetes mellitus and HCB concentrations. Age was
      the only determinant that showed a consistent association with all compounds
      studied (positive); otherwise associations with single determinants varied among
      compounds even within the PCB group. This shows that the studied organochlorines
      should not be treated as a homogeneous group of compounds in epidemiologic
      studies.

PMID- 12611666
TI  - Effects of PCB exposure on neuropsychological function in children.
AB  - In the last decade advances in the analytic methods for quantification of
      polychlorinated biphenyls (PCBs) have resulted in widespread availability of
      congener-specific analysis procedures, and large amounts of data on PCB congener
      profiles in soil, air, water, sediments, foodstuffs, and human tissues have
      become available. These data have revealed that the PCB residues in environmental
      media and human tissues may not closely resemble any of the commercial PCB
      mixtures, depending on source of exposure, bioaccumulation through the food
      chain, and weathering of PCBs in the environment. At the same time, toxicological
      research has led to a growing awareness that different classes of PCB congeners
      have different profiles of toxicity. These advances in analytic techniques and
      toxicological knowledge are beginning to influence the risk assessment process.
      As the data from ongoing PCB studies assessing the mediators of neurobehavioral
      outcomes in children are published, the weight of evidence for PCB effects on
      neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA),
      Holland, Germany, and the Faroe Islands have all reported negative associations
      between prenatal PCB exposure and measures of cognitive functioning in infancy or
      childhood. The German study also reported a negative association between
      postnatal PCB exposure and cognitive function in early childhood--a result that
      had not been found in previous studies. Only one published study in North
      Carolina (USA) has failed to find an association between PCB exposure and
      cognitive outcomes. Despite the fact that several more recent studies have used
      congener-specific analytic techniques, there have been only limited attempts to
      assess the role of specific PCB congeners or classes of congeners in mediating
      neurodevelopmental outcomes. From a statistical standpoint, attempts to determine
      the role of individual congeners in mediating outcomes are hampered by the fact
      that concentrations of most individual congeners are highly correlated with each
      other and with total PCBs. From a toxicological standpoint, these efforts are
      hampered by the fact that many of the PCB congeners present in human tissues have
      never been studied in the laboratory, and their relative potency to produce
      nervous system effects is unknown. More complete information on the health
      effects of various congeners or congener classes would allow more informed
      scientific and risk assessment decisions.

PMID- 12611667
TI  - Organophosphorus pesticide exposure of urban and suburban preschool children with
      organic and conventional diets.
AB  - We assessed organophosphorus (OP) pesticide exposure from diet by biological
      monitoring among Seattle, Washington, preschool children. Parents kept food
      diaries for 3 days before urine collection, and they distinguished organic and
      conventional foods based on label information. Children were then classified as
      having consumed either organic or conventional diets based on analysis of the
      diary data. Residential pesticide use was also recorded for each home. We
      collected 24-hr urine samples from 18 children with organic diets and 21 children
      with conventional diets and analyzed them for five OP pesticide metabolites. We
      found significantly higher median concentrations of total dimethyl alkylphosphate
      metabolites than total diethyl alkylphosphate metabolites (0.06 and 0.02 micro
      mol/L, respectively; p = 0.0001). The median total dimethyl metabolite
      concentration was approximately six times higher for children with conventional
      diets than for children with organic diets (0.17 and 0.03 micro mol/L; p =
      0.0003); mean concentrations differed by a factor of nine (0.34 and 0.04 micro
      mol/L). We calculated dose estimates from urinary dimethyl metabolites and from
      agricultural pesticide use data, assuming that all exposure came from a single
      pesticide. The dose estimates suggest that consumption of organic fruits,
      vegetables, and juice can reduce children's exposure levels from above to below
      the U.S. Environmental Protection Agency's current guidelines, thereby shifting
      exposures from a range of uncertain risk to a range of negligible risk.
      Consumption of organic produce appears to provide a relatively simple way for
      parents to reduce their children's exposure to OP pesticides.

PMID- 12611668
TI  - Association of lung function with declining ambient air pollution.
AB  - Recent studies have found a declining prevalence of respiratory infections in
      East German children, along with a tremendous improvement of air pollution since
      1990. The present study evaluates the effects of improved air quality on lung
      function. Three consecutive cross-sectional surveys of schoolchildren ages 11-14
      years from three communities in East Germany were performed in 1992-1993, 1995
      1996, and 1998-1999. Lung function tests were available from 2,493 children. The
      annual mean of total suspended particulates (TSP) declined from 79 to 25 micro
      g/m(3), whereas levels for sulfur dioxide declined from 113 to 6 micro g/m(3).
      Mean forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV(1))
      of the children increased from 1992-1993 to 1998-1999. The adjusted percent
      change of the geometric mean of FVC was 4.7% for a 50 micro g/m(3) decrease of
      TSP (p = 0.043) and 4.9% for a decrement of 100 micro g/m(3) SO(2) (p = 0.029).
      Effects on FEV(1) were smaller and not statistically significant. Our study
      indicates that a reduction of air pollution in a short time period may improve
      children's lung function.

PMID- 12611669
TI  - Superfund basic research program: a model for contemporary research programs.

PMID- 12611670
TI  - Importance of the Great Lakes.

PMID- 12611671
TI  - Appreciation for "Remembering Alice Stewart".

PMID- 12611672
TI  - Nitrate and methemoglobinemia.

PMID- 12611674
TI  - Estimating costs of environmental disease.

PMID- 12611675
TI  - Addressing global warming.

PMID- 12611677
TI  - PCB's legacy: fewer boys.

PMID- 12611678
TI  - From the lab to the land.

PMID- 12611679
TI  - The earth's open wounds: abandoned and orphaned mines.

PMID- 12611680
TI  - Not-so-superfund: growing needs vs. declining dollars.

PMID- 12611726
TI  - Experimental evidence of regional myocardial ischemia during beating heart
      coronary bypass: prevention with temporary intraluminal shunts.
AB  - BACKGROUND: Our center has been performing beating heart coronary artery bypass
      grafting with a temporary intraluminal shunt since 1983. Based on our clinical
      observations of more than 846 surgical cases, we believe that a temporary
      intraluminal shunt (TIS) greatly reduces the risk of the patient developing
      regional myocardial ischemia during clamping of the coronary artery. To seek
      evidence in support of our clinical observations, we evaluated the effects of
      coronary clamping with and without TIS in a porcine experimental model. METHODS:
      We compared 2 groups of healthy Landrace pigs that underwent the same period of
      coronary occlusion but differed only in whether a TIS was used. The shunt device
      was a straight flow-through silicone tube that has been described in detail in
      previous publications. Ischemic changes during the test period were detected via
      analysis of monophasic action potential (MAP) recordings. MAPs were recorded with
      the contact electrode technique, which has been shown to be specific for
      ischemia. In group I (no shunt) animals (n = 25), MAPs were monitored during a
      single 15-minute occlusion of the left anterior descending (LAD) coronary artery
      without any form of distal perfusion. In group II (shunted) animals (n = 15),
      MAPs were sampled over the same intervals after the LAD was snared and opened and
      the TIS was introduced within the first 2 minutes. Infarct analysis using
      biochemical end points (serum lactate dehydrogenase [LDH] and creatine
      phosphokinase-myocardial band [CPK-MB]) was performed with standard serologic
      assays. RESULTS: Confirming the presence of regional ischemia in group I (no
      shunt) were significant changes from baseline in measurements of mean action
      potential duration, upstroke velocity (dV/dt), and total MAP area (millivolts
      milliseconds). The presence of ischemia in group I was also confirmed by
      significant elevations in serum LDH and CPK-MB levels. Furthermore, the use of
      lidocaine was greater in group I (no shunt) animals than in group II (shunted)
      animals because of the greater frequency of ventricular arrhythmias in group I (P
      =.001). Six animals (24%) in group I and no animals in group II developed
      ventricular fibrillation during the 15 minutes of occlusion (P =.046). Ischemic
      changes in the MAP were found only prior to shunt insertion in Group II animals,
      and the MAP then promptly returned to normal a few minutes after TIS flow was
      established. Statistical analysis revealed significant differences between group
      I and group II in MAP duration, dV/dt, total area, lidocaine requirements,
      incidence of ventricular fibrillation, and serum LDH levels. CONCLUSIONS: There
      has been controversy about the relative effectiveness of temporary intraluminal
      shunting for reducing the risk of regional myocardial ischemia during beating
      heart coronary artery bypass grafting. At least in this porcine model, we could
      demonstrate a positive effect of shunting, which parallels our clinical
      experience using TIS in hundreds of patients for the past 2 decades. In the
      animal model, we demonstrated preservation of the MAP, as well as a reduction in
      both the incidence of ventricular arrhythmias and the serum levels of ischemic by
      products, when temporary intraluminal shunting was used. It is our conclusion
      that intraluminal shunts do protect the vulnerable myocardium from regional
      ischemia during the period of temporary coronary occlusion necessary for
      construction of a bypass graft on the beating heart. Temporary intraluminal
      shunting is a costeffective adjunct that can increase safety and reliability in
      offpump coronary artery bypass grafting.

PMID- 12611727
TI  - Beating heart revascularization with minimal extracorporeal circulation in
      patients with a poor ejection fraction.
AB  - BACKGROUND: Coronary artery bypass grafting with cardioplegia in patients with a
      low ejection fraction carries a risk of myocardial ischemia. Beating heart
      surgery is associated with hemodynamic changes when the heart is manipulated. We
      assessed an alternative: minimal extracorporeal circulation for coronary artery
      bypass grafting on a beating heart in patients with a poor ejection fraction.
      METHODS: From January 2000 to January 2002, 50 patients with an ejection fraction
      of less than 35%, who represented 10% of all patients undergoing coronary artery
      procedures, underwent revascularization on a beating heart with assistance. We
      used a closed cardiopulmonary bypass system with a centrifugal pump without
      reservoir, and the surgical strategy was modified to avoid aortic cross-clamping
      and to decrease bypass time. RESULTS: The main preoperative characteristics were:
      age (mean +/- SD) of 64 +/- 11.2 years (range, 41-87 years), 35 male patients
      (70%), mean left ejection fraction of 24.8% +/- 11.2%, and a mean EuroSCORE of
      5.8 +/- 2.7. Revascularizations of 146 distal anastomoses (2.9 +/- 0.7
      grafts/patient) were completed. Twelve percent were double bypass, 86% were
      triple bypasses, and 2% were quadruple bypasses; the mean bypass time was 64.2 +/
      26.2 minutes. The mean graft number was 2.9, and the hospital mortality was 2%.
      Perioperative hematocrit levels were 30.1%, and 26% of patients received
      transfusions. Postoperative data showed a median extubation time of 9 hours, a
      median intensive care unit stay of 48 hours, and a hospital stay of 8 +/- 2 days.
      Postoperative complications included inotropic support (14%), cerebrovascular
      events (2%), reoperation for homeostasis (4%), delayed sternal closure (2%), and
      mediastinitis (2%). Peak troponin Ic level remained a low 2.4 +/- 1.9  g/mL.
      Follow-up at 6 months was complete with 1 late mortality and with a mean ejection
      fraction of 30.5% +/- 10.8% for the survivors. CONCLUSIONS: Coronary
      revascularization on a beating heart with extracorporeal assistance can be done
      in patients with a low ejection fraction. It avoids the myocardial injury
      associated with aortic cross-clamping and allows safe and complete coronary
      revascularization.

PMID- 12611728
TI  - NextStitch: double-stranded suture chain, a tool to optimize approximation of
      sutures in valve surgery with echocardiographic correlation.
AB  - Suture technique for valve replacement surgery has often focused on decreasing
      the soft tissue injury that leads to pseudoaneurysm formation and associated
      latent infection. There is universal recognition that precise suture placement is
      essential for avoiding adverse sequelae while allowing flexibility during the
      implantation of the prosthesis. The use of a continuous chain of linked
      horizontal mattress sutures (NextStitch) has allowed maximal precision in the
      approximation of sutures within the valve annulus. The product was used in a
      series of consecutive mitral and aortic valve replacements, and typical
      echocardiographic images from each type of implantation are presented.
      Postoperative echocardiography images revealed that no perivalvular leaks
      occurred and that NextStitch did not obscure detailed interrogation or assessment
      of the valve prosthesis.

PMID- 12611729
TI  - Total arterial off-pump coronary revascularization with only internal thoracic
      artery and composite radial artery grafts.
AB  - OBJECTIVE: Total arterial off-pump coronary artery bypass (OPCAB) grafting with
      only internal thoracic artery (ITA) and composite radial artery (RA) grafts has
      been applied extensively to avoid cerebral complications and late vein graft
      failure. We evaluated the initial experience with this method by clinical and
      angiographic study. METHODS: Between April 2000 and May 2002, 257 patients
      underwent OPCAB grafting with this technique. The range of ages at operation was
      42 to 86 years (mean, 66.1 +/- 8.6 years). On average, 3.28 +/- 0.86 grafts per
      patient were completed. More than 4 distal anastomoses were performed in 88
      patients (34%). For coronary revascularization, 289 ITA and 555 RA grafts were
      used. The RA was used as a Y graft in 211 patients, as an I graft (for ITA
      extension) in 52 patients, and as a K graft (the side of the RA attached to the
      side of the left ITA) in 28 patients. Sequential bypass grafting was performed
      with 190 RA and 7 ITA grafts. The sites of distal anastomoses were 256 left
      anterior descending arteries (30%), 236 posterolateral branches (28%), 144
      posterior descending arteries (17%), 106 diagonal branches (13%), 82 obtuse
      marginal branches (10%), and 19 right coronary arteries (2%). RESULTS: There were
      1 operative death (0.4%) due to cerebral hemorrhage and 2 episodes of stroke
      (0.8%) during postoperative angiography. There were no clinical underperfusion
      syndromes or new intra-aortic balloon pump insertions. Perioperative myocardial
      infarction occurred in 12 patients (4.7%), sternal dehiscence in 5 (1.9%), and
      early coronary intervention in 4 (1.6%). There was no deep wound infection,
      reexploration for bleeding, or hand ischemia. The actuarial survival rate and the
      cardiac event-free rate at 2 years were 98.6% +/- 2.4% and 94.2% +/- 0.8%,
      respectively. Early postoperative angiography revealed a 97.8% (264/270) graft
      patency of ITAs and 97.9% (512/523) graft patency of RAs in 238 patients. Flow
      competition of the RA graft was recognized in 22 patients and, as indicated by
      follow-up angiographic study, did not cause late graft occlusion. CONCLUSIONS:
      OPCAB grafting with ITAs and composite RAs provides excellent early and
      intermediate clinical results and graft patency.

PMID- 12611730
TI  - Robotic-assisted endoscopic thoracic aortic anastomosis in juvenile lambs.
AB  - BACKGROUND: Advances in robotic technology have enabled a wider range of
      applications for minimally invasive techniques in cardiac surgery, including
      mitral valve repair and coronary artery bypass grafting. With increased technical
      sophistication, robotic-assisted techniques can be developed for the endoscopic
      repair of certain congenital cardiac lesions. OBJECTIVE: The purpose of this
      study was to assess the feasibility of closed chest thoracic aortic anastomosis
      in a juvenile ovine model. METHODS: Lambs, aged 45 to 55 days, underwent surgery
      that was performed using the da Vinci robotic surgical system. Using 3 ports, the
      surgeon dissected the descending thoracic aorta and mobilized it free from
      attachments, using single-lung ventilation and CO2 insufflation. Snares were
      introduced through 2 stab wounds for aortic occlusion proximally and distally. In
      4 lambs, the aorta was completely transected and reanastomosed using interrupted
      nitinol sutures. One lamb underwent longitudinal aortotomy, and patch aortoplasty
      was performed with the placement of a Gore-Tex patch. Snares were released and
      the animals were recovered once hemodynamically stable. Animals were sacrificed
      at 6 to 12 hours after surgery and the descending aorta was harvested. Burst
      pressure testing was performed on the anastomoses. RESULTS: All 5 lambs survived
      the procedure with stabilization of hemodynamic parameters following surgery. The
      mean aortic clamp time was 47 +/- 17 minutes, and the anastomosis was completed
      in 26 +/- 5 minutes. The mean burst pressure was 163 +/- 9 mm Hg. CONCLUSIONS:
      Endoscopic thoracic aortic anastomosis can be performed safely and with adequate
      exposure in a juvenile large-animal model using computer-assisted surgical
      techniques. With further refinements, these approaches could be applied to the
      repair of congenital anomalies of the aorta, including interrupted aortic arch
      and aortic coarctation.

PMID- 12611731
TI  - Repair of acute ascending aorta-arch dissection with continuous body perfusion: a
      case report.
AB  - An approach for the replacement of the distal ascending aorta-proximal arch and
      acute dissection is described. During the operation, the patient's entire body
      was continuously perfused, the aortic arch was excluded from the arterial
      circulation, and the aorta was not clamped at any time. To achieve continuous
      body perfusion, we independently cannulated the right axillary and the left
      femoral arteries. The right atrium was cannulated for systemic venous return, and
      the right radial artery was used for arterial blood pressure monitoring. The
      myocardium was protected with retrograde cardioplegia, and the body was protected
      with moderate hypothermia. Vascular clamps were placed to the proximal
      innominate, left carotid, and left subclavian arteries without discontinuing
      perfusion of the right axillary artery. A temporary clamp was applied to the
      femoral line, the aorta was transected, and a large Foley catheter was inserted
      through the true aortic lumen. The Foley bulb was positioned in the proximal
      descending thoracic aorta and distended with saline until the aortic blood return
      ceased. The femoral line clamp was removed from the cannula, and the entire body
      was perfused during the completion of the distal aortic anastomosis. At the
      completion of the anastomosis, the Foley bulb was slightly deflated. Once the
      inserted graft was filled with blood, a large vascular clamp was applied to the
      graft, and the previously placed clamps were removed from the arch branches. The
      femoral line was removed, and the body was perfused and rewarmed via the axillary
      cannulation. Following completion of the proximal graft-aortic anastomosis, the
      heart was reperfused, and all cannulas were removed in the usual fashion. Rapid
      recovery characterized the patient's initial postoperative course; however,
      multiple organ failure secondary to pump-induced inflammatory response followed.
      Aggressive medical management resulted in complete patient recovery. No
      neurologic deficits were observed, and the patient regained full cognitive
      function. This report describes a simple approach to facilitate repair of the
      aortic arch and minimize postoperative organ failure.

PMID- 12611733
TI  - A simple method of creating LVAD outflow tract aortic anastomosis.
AB  - Left ventricular assist device (LVAD) implantation is frequently complicated by
      intraoperative and postoperative bleeding, particularly at the aortic anastomosis
      site. Many modifications of the anastomosis have been attempted. We describe a
      simple method to anastomose the LVAD outflow tract to the ascending aorta with
      minimal bleeding and a short anastomosis time.

PMID- 12611732
TI  - Effects of phospholipid-coated extracorporeal circuits on clinical outcome
      parameters and systemic inflammatory response in coronary artery bypass graft
      patients.
AB  - INTRODUCTION: The use of extracorporeal circulation (ECC) during coronary artery
      bypass graft (CABG) surgery is associated with a systemic inflammatory response
      due to the contact of blood with artificial surfaces. The clinical relevance of
      ECC-related systemic inflammation varies with the patient, and such inflammation
      may be accompanied by intermittent organ dysfunction and an increased
      catecholamine requirement. We investigated the effects of a new phospholipid
      coating system of ECC on systemic inflammatory response and clinical outcome
      following CABG. METHODS: Patients scheduled for CABG surgery were prospectively
      divided randomly into 2 patient groups: patients using noncoated ECC materials
      and patients using phospholipid-coated ECC materials. Clinical data measured
      perioperatively included hemodynamics, aortic clamp time, duration of bypass,
      time to extubation, catecholamine requirement, length of intensive care unit
      (ICU) stay, postoperative blood loss, and amount of blood transfused. In
      addition, blood samples were collected before cannulation and at 2, 24, and 48
      hours postoperative. Cytokines (tumor necrosis factor alpha [TNF-alpha] and
      interleukin 10 [IL-10]) and P-selectin were measured with an enzyme-linked
      immunosorbent assay. Plasma nitrate/nitrite levels (NOx) were determined by the
      Griess reaction. RESULTS: A significant increase of TNF-a level was noted in the
      uncoated control group only. In the uncoated group, IL-10 levels significantly
      increased at 2 hours postoperative, whereas levels remained unchanged in the
      phospholipid coating group. P-selectin increased 2 hours postoperative in the
      uncoated group, and no significant changes were noted in the phospholipid coating
      group. At 24 hours postoperative, total plasma NOx production significantly
      increased in the phospholipid coating group but remained constant in the control
      group. No significant differences with respect to postoperative parameters (time
      to extubation, ICU stay, amount of bleeding, blood transfused, and catecholamine
      requirement) were observed. CONCLUSIONS: Phospholipid coating significantly
      reduces the systemic increase in proinflammatory and anti-inflammatory cytokines
      and P-selectin. Despite the comparable clinical outcomes in this study, the
      observed significant reduction in systemic inflammatory parameter values suggests
      an improved biocompatibility of ECC materials when they are coated with
      phospholipids.

PMID- 12611737
TI  - Biventricular pacing for congestive heart failure: early experience in surgical
      epicardial versus coronary sinus lead placement.
AB  - OBJECTIVE: Biventricular pacing (BVP) has recently been introduced for the
      treatment of refractory congestive heart failure. Coronary sinus lead placement
      for left ventricular pacing is technically difficult, has a risk of lead
      dislodgement, and has long procedure times. Surgical epicardial lead placement
      has the potential advantage of the visual selection of an optimal pacing site,
      does not need exposure to ionic radiation, and allows lead multiplicity, but it
      does require a thoracotomy and general anesthesia. We report our early experience
      of BVP with both modalities. METHODS: BVP was performed in 12 patients with New
      York Heart Association (NYHA) class IV congestive heart failure (10 men, 2
      women). Mean patient age was 68.7 years (range, 41-83 years). Surgical epicardial
      leads were placed through a 2- to 3-inch incision via a left fourth or fifth
      intercostal thoracotomy in 4 patients with single lung ventilation under general
      anesthesia. The other 8 patients underwent transvenous coronary sinus lead
      placement under conscious sedation. RESULTS: Postoperative NYHA class status
      improved from class IV to class II in 8 patients and to class III in 3 patients.
      In 5 of the 8 patients who had undergone follow-up echocardiography with mitral
      regurgitation, the severity of the mitral regurgitation improved. The mean left
      ventricular ejection fractions before and after BVP were 18.3% +/- 8.3% and 20.5%
      +/- 8.0%, respectively (P =.16). Mean fluoroscopy and total procedure times for
      transvenous lead placement were 77 +/- 19 minutes and 266 +/- 117 minutes,
      respectively. The mean surgery time for epicardial lead placement was 122 +/- 13
      minutes. There were no differences between the 2 methods in pacing threshold or
      in lead dislodgement. There were no complications related to the surgery or the
      laboratory procedure. CONCLUSION: In patients with NYHA class IV congestive heart
      failure, epicardial lead placement through a minithoracotomy for BVP was
      performed safely with benefits equivalent to those of coronary sinus lead
      placement and with a shorter procedure time.

PMID- 12611734
TI  - Increased incidence of proximal aortic atherosclerotic disease in patients with
      internal carotid occlusion.
AB  - BACKGROUND: Atherosclerotic involvement of the proximal aorta is a major cause of
      embolic operative stroke in cardiac surgery. Its incidence is less well known in
      patients with severe carotid disease. METHODS: We reviewed the incidence of
      proximal atherosclerotic aortic disease in patients with internal carotid
      occlusion (group 1) and then compared it to a group of patients with normal
      carotids undergoing cardiac surgery (group 2). Both groups had preoperative
      carotid Doppler and epiaortic ultrasound analysis at the time of surgery.
      RESULTS: Epiaortic ultrasound results showed that the degree of atherosclerosis
      in group 1 was normal in 9 patients (10.2%), mild in 34 (38.6%), moderate in 29
      (33%), and severe in 16 (18.2%). In group 2, the degree of atherosclerosis was
      normal in 70 patients (9.3%), mild in 466 (61.8%), moderate in 150 (19.9%), and
      severe in 68 (9.0%). Stroke rate was higher in group 1 at 4.5% versus 1.1% for
      group 2 (P =.029). No difference in surgical mortality was found. CONCLUSIONS:
      Patients with internal carotid occlusions undergoing heart surgery have a higher
      incidence of proximal aortic atherosclerotic disease. Epiaortic ultrasound
      examination is strongly recommended.

PMID- 12611738
TI  - Pregnancy and valvular heart disease.
AB  - Heart disease can affect anyone at any time, and pregnant women are not
      exceptions. Some type of cardiac pathologic disease can be seen in 1% to 2% of
      all pregnant women. Because of the high fetal mortality rate and the high
      relative rate of maternal mortality in surgery, medical management is the first
      line of treatment. Nevertheless, when medical treatment fails, cardiac surgery
      may be necessary. Here we present such a case of cardiac valvular disease
      complicated by pregnancy. Current decision-making, treatment, and trends are
      reviewed.

PMID- 12611739
TI  - Off-pump myocardial revascularization. The single-suture technique: how to avoid
      any complication.
AB  - INTRODUCTION: Coronary artery bypass grafting without cardiopulmonary bypass
      (CPB) is now an accepted technique of complete myocardial revascularization. The
      technique was originally described by Kolesov [Kolesov 1967] and later abandoned
      when the CPB became the gold standard for cardiac operations on the arrested
      heart. In the late 1980s off-pump coronary grafting was reintroduced by Benetti
      and Buffolo with very encouraging results, especially for high-risk patients
      [Benetti 1985, Buffolo 1996]. This technique was limited to the grafting of left
      anterior descending (LAD) coronary artery and sometimes to the right coronary
      artery (RCA) [Benetti 1985, Buffolo 1996]. In recent years, technical advantages
      in coronary exposure and mechanical stabilization have come from the industry,
      leading to the possibility of a complete off-pump myocardial revascularization.
      The exposure of coronary arteries in the circumflex territory has been described
      by Ricardo Lima from Brazil. He described a series of four sutures on the
      pericardium, which allowed a good exposure of such surgically difficult
      territory. Tomas Salerno simplified the "Lima sutures" with a technique using a
      single suture placed in the oblique sinus of the posterior pericardium, which
      allowed a good exposure of the circumflex territory and less heart manipulation.
      [Bergsland 1997, Salerno 1999, Ricci 2000]. This deep pericardial suture may
      injure the organs situated just behind the pericardium, such as the esophagus and
      thoracic aorta [Ricci 2000], and several complications have been reported in
      literature: injury of the left lower pulmonary vein has resulted in post
      operative bleeding and dangerous hematoma behind the left atrium [Fukui 2002];
      and subcutaneous emphasema has been detected in several cases in our experience.
      We report a different way to pose the single lima suture in order to avoid any
      damage to the structures behind the posterior pericardium.

PMID- 12611741
TI  - Interventions for mild cognitive impairment and Alzheimer disease: new
      strategies, new hope.

PMID- 12611742
TI  - Drug development and Alzheimer disease.

PMID- 12611743
TI  - Use of cholinesterase inhibitors in clinical practice: evidence-based
      recommendations.
AB  - Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of
      patients with Alzheimer disease (AD) and are the only class of drugs approved by
      the Food and Drug Administration (FDA) for treatment of this condition. This
      review provides evidenced-based recommendations for use of ChE-Is in clinical
      practice. The author searched computerized literature databases of the approved
      ChE-Is widely used in clinical practice (donepezil, rivastigmine, and
      galantamine), and extended the review with bibliographies from identified
      articles and package inserts of information reviewed by the FDA. Double-blind,
      placebo-controlled trials providing Class I evidence were used as data sources
      whenever possible. Articles with Class II and Class III data were used when Class
      I data were unavailable. In general, ChE-Is exert modest reproducible effects in
      patients with mild-to-moderate AD. Drug-placebo differences are evident on global
      and cognitive measures. Secondary outcomes, including measures of activities of
      daily living and behavior, also typically demonstrate drug-placebo differences in
      favor of the active agent. Head-to-head trials of ChE-Is are limited; existing
      trials suggest no major differences in efficacy. Observations from clinical
      trials imply that early initiation of therapy is associated with greater long
      term benefits. Clinical trials with withdrawal periods indicate that withdrawal
      and re-initiation of treatment may result in loss of benefit. Open-label
      extensions of double-blind trials show that differences in level of functioning
      between treated populations and extrapolated for untreated populations continue
      for several years. Side effects of ChE-Is include nausea, vomiting, diarrhea, and
      anorexia, and are more frequent during dose escalation than maintenance therapy.
      Clinical-trial populations differ substantially from unselected populations of AD
      patients, and these selection biases demand that efficacy data from clinical
      trials be generalized with caution.

PMID- 12611744
TI  - Imaging-based measures of disease progression in clinical trials of disease
      modifying drugs for Alzheimer disease.
AB  - The authors review and assess imaging-based strategies for measuring the rate of
      progression of Alzheimer disease (AD). Such techniques may be useful in addition
      to the behavioral instruments typically used in these studies and may be more
      sensitive to treatment-related change. MEDLINE searches obtained relevant
      published literature. Articles were reviewed with particular attention to
      assessments of rate of disease progression and the effects of investigational
      drugs. Authors studied a variety of techniques, including volumetric magnetic
      resonance imaging, functional MRI, fluorodeoxyglucose positron emission
      tomography, and several target-specific radiopharmaceuticals. In cross-sectional
      as well as small longitudinal trials, many of these show promise not only in
      diagnosis, but also as measures of disease progression. The effects of drugs that
      provide symptomatic relief on these measures have not been fully characterized.
      Even less is known about the effects of investigational drugs that may slow
      disease progression. Several neuroimaging techniques have been studied that could
      improve the ability of clinical trials to quantify the rate of progression of AD.
      Clinical trials of investigational drugs would benefit from more systematic
      validation of image-based outcome measures. Several choices of imaging techniques
      are available. An understanding of the relationship between a statistically
      significant effect size in an imaging marker and a clinically significant change
      in rate of disease progression will require additional studies.

PMID- 12611745
TI  - Impact of study design and patient population on outcomes from cholinesterase
      inhibitor trials.
AB  - The authors conducted a comparative review of study designs and patient
      populations used in pivotal trials investigating various cholinesterase
      inhibitors (tacrine, donepezil, rivastigmine, galantamine, controlled-release
      physostigmine, and metrifionate) and their impact on outcomes reported. Study
      design parameters that were investigated included patient selection, definitions
      of adverse dropouts and serious adverse events, effective doses used, dosing
      flexibility (fixed versus flexible), forced titration, and titration rate.
      Population characteristics included medical comorbidity and disease severity.
      Data suggest that differences in study designs and patient populations affect
      outcomes. Therefore, caution should be taken before making decisions on relative
      efficacy, safety, and tolerability, because clinical studies are not always
      directly comparable.

PMID- 12611747
TI  - Non-steroidal anti-inflammatory drug (NSAID) use and Alzheimer disease in
      community-dwelling elderly patients.
AB  - OBJECTIVE: Recently, greater attention has been paid to the role of inflammatory
      processes in the pathophysiology of Alzheimer disease (AD). However, the
      mechanism by which anti-inflammatory agents (NSAIDs) might slow the progression
      of AD is not completely known. The aim of the present study was to examine the
      relationship between NSAIDs use and AD in a large sample of community-dwelling
      elderly people. METHODS: In a cross-sectional retrospective study, the authors
      analyzed data on patients admitted to home care programs. A total of 12 home
      health agencies participated in the project, with a total of 2,708 patients
      enrolled in the present study. The main outcome measures were the prevalence of
      AD and use of NSAIDs treatment. RESULTS: Compared with all non-users, NSAID users
      had a nearly 50% lower risk of being affected by AD. Separate multivariate
      analyses of subjects receiving different types of NSAIDs found a significantly
      decreased risk of cognitive impairment associated with non-aspirin NSAID use,
      whereas, among subjects taking aspirin, the difference in estimated risk did not
      reach statistical significance. CONCLUSION: The results of this population-based
      cross-sectional study are consistent with the notion that long-term NSAIDs use
      has a protective effect against AD. However, after possible confounding effects
      of age and several other variables potentially associated with cognitive
      impairment were controlled, this association was statistically significant only
      for non-aspirin NSAIDs use.

PMID- 12611746
TI  - Donepezil HCl (E2020) maintains functional brain activity in patients with
      Alzheimer disease: results of a 24-week, double-blind, placebo-controlled study.
AB  - OBJECTIVE: The authors evaluated the effects of donepezil (10 mg/day) versus
      placebo on brain glucose metabolism. METHODS: This was a randomized, double
      blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate
      Alzheimer disease (AD). Functional brain activity was quantified by measuring
      average glucose metabolism in an axial brain slice and regional brain glucose
      metabolism using positron emission tomography. RESULTS: At Week 24, relative to
      the pons metabolic rate, mean brain glucose metabolism in an axial slice at the
      level of the striatum was maintained within 0.5% of mean baseline levels for
      donepezil-treated patients, whereas it declined by an average of 10.4% in placebo
      treated patients. This observation was confirmed by an analysis of differences in
      the mean slopes of glucose metabolism in the striatal slice in donepezil- and
      placebo-treated patients during the 24-week period. Significant treatment
      differences at Week 24 favoring donepezil for the mean percentage change from
      baseline in regional brain glucose metabolism were observed in four predefined
      regions of interest: the right parietal lobe 1, left temporal lobe 2, right
      frontal lobe 2, and left frontal lobe 2. CONCLUSION: Placebo-treated patients
      with AD show a decline in functional brain activity, relative to the pons, in
      several regions, and treatment with donepezil may slow this decline.

PMID- 12611748
TI  - Usefulness of plasma haloperidol levels for monitoring clinical efficacy and side
      effects in Alzheimer patients with psychosis and behavioral dyscontrol.
AB  - OBJECTIVE: This study investigated whether measurement of plasma levels may be
      useful in monitoring clinical efficacy and side effects during oral haloperidol
      (HL) treatment of psychosis and behavioral dyscontrol in patients with Alzheimer
      disease (AD). METHODS: After a single-blind placebo period of 1 week, 71
      outpatients with AD were randomized to a 6-week, double-blind, placebo-controlled
      trial of HL 2 mg-3 mg/day (standard dose), HL 0.5 mg-0.75 mg/day (low dose), or
      placebo, with plasma levels for HL drawn at the end of 6 weeks. RESULTS: Of the
      40 patients who received active HL for 6 weeks, 35 had plasma levels drawn.
      Plasma levels were all below the lower limit of the postulated therapeutic range
      in schizophrenia. Nonetheless, HL plasma level significantly correlated with
      clinical efficacy as measured by reduction in Brief Psychiatric Rating Scale
      Total score, Psychosis factor, and Hostile-Suspiciousness factor, the Behavioral
      Syndromes Scale for Dementia Psychomotor Agitation scale, and with the severity
      of extrapyramidal side effects (EPS). Oral dose did not significantly correlate
      with any of these efficacy or side-effect measures. Plasma levels significantly
      correlated with HL dose. When both HL dose and HL plasma level were included as
      independent variables in linear-regression analyses, only HL plasma level was a
      significant predictor of efficacy and EPS. CONCLUSION: Measurement of HL plasma
      levels may have potential usefulness as an adjunct in monitoring treatment
      response to oral HL in AD patients with psychosis or disruptive behavior.

PMID- 12611749
TI  - Effect of light on agitation in institutionalized patients with severe Alzheimer
      disease.
AB  - OBJECTIVE: Preliminary data suggest that morning bright light might improve
      symptoms of agitation, a serious problem in patients with dementia. The authors
      expand on an earlier pilot study by evaluating the effect of bright light therapy
      on agitated behavior in a large sample of patients with severe dementia. METHODS:
      Ninety-two patients were randomly assigned to morning bright light, morning dim
      red light, or evening bright light. Agitation was rated by research staff who
      observed the patients every 15 minutes throughout the treatment period and by
      caregivers at one time-point before and one time-point after treatment. RESULTS:
      Morning bright light delayed the acrophase of the agitation rhythm by over 1.5
      hours. Bright light was associated with improved caregivers' ratings but had
      little effect on observational ratings of agitation. CONCLUSION: Although the
      result that light shifted the peak of the agitated behavior might be
      generalizable to patients with milder forms of AD, the fact that agitation was
      not ameliorated might not be. Because the suprachiasmatic nucleus (SCN) of
      patients with severe AD is likely to be more degenerated, and the circadian
      activity rhythms deteriorate as the disease progresses, it is still possible that
      patients with more intact SCNs, that is, patients with mild or moderate AD, might
      benefit from light treatment even more than those with severe AD.

PMID- 12611750
TI  - Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based
      cohort: effects on cognition.
AB  - OBJECTIVE: The authors sought to identify patterns and associations of
      prescription and over-the-counter sedative-hypnotic use in an older, rural, blue
      collar, community-based cohort in southwestern Pennsylvania over 10 years.
      METHODS: A group of 1,627 individuals age 65 and over were recruited and assessed
      during 1987-1989 and re-assessed during approximately biennial waves. Data
      included sleep medications, demographics, depressive symptoms, sleep complaints,
      and cognitive functioning (Mini-Mental State Exam [MMSE]). RESULTS: At Waves 1
      through 5, the mean age of the cohort increased from 73.4 to 80.5 years. Use of
      prescription sedative-hypnotics (primarily benzodiazepines) increased from 1.8%
      to 3.1%, and over-the-counter sedative-hypnotic use (primarily diphenhydramine)
      increased from 0.4% to 7.6%. At Wave 5 (1996-1998), 8.17% of the sample reported
      using diphenhydramine as a sleep aid. After adjusting for age and sex,
      diphenhydramine use was associated with higher education and more depressive
      symptoms, the latter becoming nonsignificant after controlling for initial
      insomnia. MMSE became significantly associated with diphenhydramine use when 143
      subjects with dementia were excluded from the analysis. CONCLUSION: As the cohort
      aged, prescription sedative-hypnotic use remained relatively stable, whereas over
      the-counter sedative use, principally diphenhydramine, increased substantially.
      The association of this drug with cognitive impairment in persons without
      dementia highlights its potential for causing adverse reactions in older adults.

PMID- 12611752
TI  - Apathy and executive dysfunction in mild cognitive impairment and Alzheimer
      disease.
AB  - OBJECTIVE: The authors assessed and contrasted frontally mediated behavior
      changes in patients diagnosed with Mild Cognitive Impairment (MCI) and Alzheimer
      disease (AD). Apathy, executive dysfunction, and disinhibition are common in AD,
      but these behaviors have not been studied in MCI. METHODS: Participants were
      patients diagnosed with AD (n=25) or MCI (n=20). Current behavior and behavior
      before the onset of cognitive impairment was rated by knowledgeable informants on
      the Frontal Systems Behavior Scale (FrSBe). RESULTS: Apathy and executive
      dysfunction exhibited the greatest increase in both MCI and AD, and both
      increased significantly over baseline scores. No significant differences in
      behavior change were found between the two groups. Behavior change was moderately
      correlated with a measure of dementia severity, indicating that greater disease
      severity was associated with more abnormal behavior. CONCLUSION: Changes in
      frontally-mediated behaviors are common in very early and mild stages of
      cognitive impairment, even before functional decline in daily living is evident.
      These behaviors deserve more study in MCI because they may have implications for
      prognosis, treatment adherence, family distress, and patient quality of life.

PMID- 12611751
TI  - Executive dysfunction and apathy predict functional impairment in Alzheimer
      disease.
AB  - OBJECTIVE: The purpose of this study was to examine the extent to which executive
      cognitive dysfunction and frontally-mediated behavioral disturbances are
      associated with functional impairment in patients with mild-to-moderate Alzheimer
      disease (AD). METHODS: Patients with AD (N=45) completed the Mattis Dementia
      Rating Scale, and patients' caregivers completed the Frontal Systems Behavioral
      Inventory and a modified form of the Lawton and Brody Activities of Daily Living
      (ADLs) Questionnaire. RESULTS: Multiple-regression analyses revealed that
      executive cognitive dysfunction and apathy scores accounted for 44% of the
      variance in instrumental activities of daily living; executive cognitive
      dysfunction alone explained 17% of the variance in instrumental ADLs, and apathy
      scores explained an additional 27%. Executive dysfunction and frontal-behavioral
      impairment explained 28% of the variance in basic ADLs (BADLs), and, after
      accounting for executive dysfunction, apathy was the only symptom found to
      explain additional unique variance in BADLs. CONCLUSION: These findings suggest
      that specific cognitive and behavioral symptoms are associated with functional
      impairment in patients with AD.

PMID- 12611753
TI  - Agitation and depression in frail nursing home elderly patients with dementia:
      treatment characteristics and service use.
AB  - OBJECTIVE: The authors describe characteristics, treatment, and acute service use
      associated with agitation and depression in dementia. METHODS: Authors used
      retrospective chart review of symptoms, physician-level prescribing, and acute
      service use over 3 months for 2,487 physically frail older residents, including
      1,836 with dementia, (mean age: 79.8 years) in 109 long-term care facilities,
      describing differences between uncomplicated dementia and three mutually
      exclusive subgroups of complicated dementia, including dementia with agitation
      only, dementia with depression-only, and dementia with mixed agitation and
      depression. RESULTS: Compared with the other subgroups, frail elderly patients
      with dementia complicated by mixed agitation and depression have the highest rate
      of hospitalization, the greatest number of medical diagnoses, and the greatest
      medical severity, and they receive the greatest number of psychiatric
      medications. Depression in dementia (either alone or mixed with agitation) was
      associated with greater prevalence of pain. CONCLUSIONS: Dementia complicated by
      mixed agitation and depression accounts for over one-third of complicated
      dementia and is associated with multiple psychiatric and medical needs, intensive
      pharmacological treatment, and use of high-cost services. Research should target
      this complex, high-risk group to develop appropriate diagnostic criteria and
      effective treatment interventions.

PMID- 12611754
TI  - 17beta-estradiol reduces plasma Abeta40 for HRT-naive postmenopausal women with
      Alzheimer disease: a preliminary study.
AB  - OBJECTIVE: One mechanism to support the potentially beneficial effects of
      estrogen in the brain for postmenopausal women potentially involves the hormone's
      ability to favorably alter the processing of amyloid-precursor protein (APP),
      believed to play an important role in the pathobiology of Alzheimer disease (AD).
      The authors evaluated the effects of estrogen administration on plasma
      concentration of one by-product of APP processing, Abeta40, for postmenopausal
      women with AD. METHODS: In a placebo-controlled, double blind, parallel-group
      design study, 20 women were randomized to receive either 0.10 mg/day of
      transdermal 17beta-estradiol or a placebo for 8 weeks and were retrospectively
      evaluated as to whether basal levels of Abeta40 were affected by pre-study use of
      hormone replacement therapy (HRT). Blood samples were collected and cognitive
      tests were administered at baseline; at Weeks 3, 5, and 8 during treatment; and
      again 8 weeks after treatment termination. RESULTS: For the group as a whole,
      plasma Abeta40 was not reliably reduced in response to short-term estradiol
      administration. For HRT-naive subjects, baseline Abeta40 concentrations were
      higher than those of previous HRT users, and controlled estradiol administration
      significantly reduced plasma Abeta40 by the end of the 8-week treatment period.
      CONCLUSIONS: These results provide preliminary clinical evidence to support an
      effect of estradiol on Abeta-processing for AD women who are HRT-naive. This
      finding suggests that the hormone may serve as an Abeta-lowering agent for HRT
      naive AD women, which may, in turn, have ultimate ramifications for the
      progression of AD pathology.

PMID- 12611756
TI  - Semantic interference in mild Alzheimer disease: preliminary findings.
AB  - OBJECTIVE: The authors evaluated the usefulness and psychometric properties of
      the Semantic Interference Test (SIT) in patients with mild Alzheimer disease
      (AD). METHODS: Subjects were first presented with 10 common objects to be learned
      over three trials. Proactive interference was assessed by having subjects recall
      10 new objects that were semantically related to the previous ones. Retroactive
      interference was assessed by having subjects recall the original 10 objects.
      RESULTS: Controlling for overall memory impairment, very mildly impaired AD
      patients demonstrated significantly greater proactive and retroactive
      interference effects than the normal, community-dwelling comparison group. The
      proactive score alone and the combined proactive-plus-retroactive score index
      were more effective than traditional neuropsychological measures of delayed
      recall in distinguishing between the very mildly impaired AD group and the normal
      comparison group. CONCLUSION: The authors discuss the potential usefulness of the
      SIT in identifying vulnerability to semantic interference in early AD.

PMID- 12611755
TI  - A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer
      disease.
AB  - OBJECTIVE: Authors determined the impact of high-dose vitamin supplements on
      plasma homocysteine levels in patients with Alzheimer disease (AD). METHODS:
      Authors used an open-label trial of folic acid, vitamin B(12), and vitamin B(6),
      in combination for 8 weeks, with measurement of plasma homocysteine levels in the
      fasting state and after methionine-loading. A total of 69 subjects with AD were
      enrolled, including 33 who were taking standard multivitamin supplements; 66 were
      available at 8-week follow-up. RESULTS: The high-dose vitamin regimen was
      associated with a significant reduction in fasting and post-methionine-loading
      homocysteine. Reductions were greater in the subgroup not using multivitamins,
      but were also significant in the multivitamin users. CONCLUSION: High-dose
      vitamin supplementation reduces homocysteine levels in patients with AD. The
      effect of supplementation on rate of cognitive decline will be assessed later in
      a randomized, double-blind study.

PMID- 12611757
TI  - A structured, open trial of risperidone therapy for delusions of theft in
      Alzheimer disease.

PMID- 12611758
TI  - Treatment-related decisional capacity.

PMID- 12611760
TI  - Focal CO2/H+ alters phrenic motor output response to chemical stimulation of cat
      pre-Botzinger complex in vivo.
AB  - Microinjection of dl-homocysteic acid (DLH), a glutamate analog, into the pre
      Botzinger complex (pre-BotC) can produce tonic excitation of phrenic nerve
      discharge. Although this DLH-induced tonic excitation can be modified by systemic
      hypercapnia, the role of focal increases in pre-BotC CO(2)/H(+) in this
      modulation of the DLH-induced response remains to be determined. Therefore, we
      examined the effects of unilateral microinjection of DLH (10 mM; 10-20 nl) into
      the pre-BotC before and during increased focal pre-BotC CO(2)/H(+) (i.e., focal
      tissue acidosis) in chloralose-anesthetized, vagotomized, mechanically ventilated
      cats. Focal tissue acidosis was produced by blockade of carbonic anhydrase with
      either focal acetazolamide (AZ) or methazolamide (MZ) microinjection. For these
      experiments, sites were selected in which unilateral microinjection of DLH into
      the pre-BotC produced a nonphasic tonic excitation of phrenic nerve discharge (n
      = 10). Microinjection of 10-20 nl AZ (50 microM) or MZ (50 microM) into these 10
      sites in the pre-BotC increased the amplitude and/or frequency of eupneic phrenic
      bursts, as previously reported. Subsequent microinjection of DLH produced
      excitation in which phasic respiratory bursts were superimposed on tonic
      discharge. These DLH-induced phasic respiratory bursts had an increased frequency
      compared with the preinjection baseline frequency (P < 0.05). These findings
      demonstrate that modulation of phrenic motor activity evoked by DLH-induced
      activation of the pre-BotC is influenced by focal CO(2)/H(+) chemosensitivity in
      this region. Furthermore, these findings suggest that focal increases in pre-BotC
      CO(2)/H(+) may have contributed to the modulation of the DLH-induced responses
      previously observed during systemic hypercapnia.

PMID- 12611761
TI  - Hormone-sensitive lipase activity and fatty acyl-CoA content in human skeletal
      muscle during prolonged exercise.
AB  - Hormone-sensitive lipase (HSL) catalyzes the hydrolysis of intramuscular
      triacylglycerols (IMTGs), but HSL regulation is poorly understood in skeletal
      muscle. The present study measured human skeletal muscle HSL activity at rest and
      during 120 min of cycling at 60% of peak O2 uptake. Several putative HSL
      regulators were also measured, including muscle long-chain fatty acyl-CoA (LCFA
      CoA) and free AMP contents and plasma epinephrine and insulin concentrations. HSL
      activity increased from resting levels by 10 min of exercise (from 2.09 +/- 0.19
      to 2.56 +/- 0.22 mmol. min-1x kg dry mass-1, P < 0.05), increased further by 60
      min (to 3.12 +/- 0.27 mmol x min-1x kg dry mass-1, P < 0.05), and decreased to
      near-resting rates after 120 min of cycling. Skeletal muscle LCFA CoA increased
      (P < 0.05) above rest by 60 min (from 15.9 +/- 3.0 to 50.4 +/- 7.9 micromol/kg
      dry mass) and increased further by 120 min. Estimated free AMP increased (P <
      0.05) from rest to 60 min and was approximately 20-fold greater than that at rest
      by 120 min. Epinephrine was increased above rest (P < 0.05) at 60 (1.47 +/- 0.15
      nM) and 120 min (4.87 +/- 0.76 nM) of exercise. Insulin concentrations decreased
      rapidly and were lower than resting levels by 10 min and continued to decrease
      throughout exercise. In summary, HSL activity was increased from resting levels
      by 10 min, increased further by 60 min, and decreased to near-resting values by
      120 min. The increased HSL activity at 60 min was associated with the stimulating
      effect of increased epinephrine and decreased insulin levels. After 120 min, the
      decreased HSL activity was associated with the proposed inhibitory effects of
      increased free AMP. The accumulation of LCFA CoA in the 2nd h of exercise may
      also have reduced the flux through HSL and accounted for the reduction in IMTG
      utilization previously observed late in prolonged exercise.

PMID- 12611762
TI  - Muscle creatine uptake and creatine transporter expression in response to
      creatine supplementation and depletion.
AB  - The total creatine pool size [Cr(total); creatine (Cr) + phosphocreatine (PCr)]
      is crucial for optimal energy utilization in skeletal muscle, especially at the
      onset of exercise and during intense contractions. The Cr(total) likely is
      controlled by long-term modulation of Cr uptake via the sodium-dependent Cr
      transporter (CrT). To test this hypothesis, adult male Sprague-Dawley rats were
      fed 1% Cr, their muscle Cr(total) was reduced by approximately 85% [1% beta
      guanidinoproprionic acid (beta-GPA)], or their muscle Cr(total) was repleted (1%
      Cr after beta-GPA depletion). Cr uptake was assessed by skeletal muscle (14)C-Cr
      accumulation to Cr and PCr by using hindlimb perfusion, and CrT protein content
      was assessed by Western blot. Cr uptake rate decreased with dietary Cr
      supplementation in the white gastrocnemius (WG; 45%) only. Depletion of muscle
      Cr(total) to approximately 15% of normal increased Cr uptake in the soleus (21%)
      and red gastrocnemius (22%), corresponding to 70-150% increases in muscle CrT
      content. In contrast, the inherently lower Cr uptake rate in the WG was unchanged
      with depletion of muscle Cr(total) even though CrT band density was increased by
      230%. Thus there was no direct relationship between apparent muscle CrT abundance
      and Cr uptake rates. However, Cr uptake rates scaled inversely with decreases in
      muscle Cr(total) in the high-oxidative muscle types but not in the WG. This
      implies that factors controlling Cr uptake are different among fiber types. These
      observations may help explain the influence of initial muscle Cr(total), time
      dependency, and variations in muscle Cr(total) accumulation during Cr
      supplementation.

PMID- 12611763
TI  - Exercise training alleviates MCT1 and MCT4 reductions in heart and skeletal
      muscles of STZ-induced diabetic rats.
AB  - We compared the changes in monocarboxylate transporter 1 (MCT1) and 4 (MCT4)
      proteins in heart and skeletal muscles in sedentary control and streptozotocin
      (STZ)-induced diabetic rats (3 wk) and in trained (3 wk) control and STZ-induced
      diabetic animals. In nondiabetic animals, training increased MCT1 in the
      plantaris (+51%; P < 0.01) but not in the soleus (+9%) or the heart (+14%). MCT4
      was increased in the plantaris (+48%; P < 0.01) but not in the soleus muscles of
      trained nondiabetic animals. In sedentary diabetic animals, MCT1 was reduced in
      the heart (-30%), and in the plantaris (-31%; P < 0.01) and soleus (-26%)
      muscles. MCT4 content was also reduced in sedentary diabetic animals in the
      plantaris (-52%; P < 0.01) and soleus (-25%) muscles. In contrast, in trained
      diabetic animals, MCT1 and MCT4 in heart and/or muscle were similar to those of
      sedentary, nondiabetic animals (P > 0.05) but were markedly greater than in the
      sedentary diabetic animals [MCT1: plantaris +63%, soleus +51%, heart +51% (P >
      0.05); MCT4: plantaris +107%, soleus +17% (P > 0.05)]. These studies have shown
      that 1) with STZ-induced diabetes, MCT1 and MCT4 are reduced in skeletal muscle
      and/or the heart and 2) exercise training alleviated these diabetes-induced
      reductions.

PMID- 12611764
TI  - Effects of different exercise modes on mineralization, structure, and
      biomechanical properties of growing bone.
AB  - Weight bearing during exercise plays an important role in improving the
      mechanical properties of bone. The effect on bone of non-weight-bearing exercise
      such as swimming remains controversial. To investigate the effects of exercise
      mode on growing bone, 29 male Wistar rats (7 wk old) were randomly assigned to a
      running exercise group (Run, n = 9), a swimming exercise group (Swim, n = 10), or
      a nonexercise control group (Con, n = 10). During an 8-wk training session (20-60
      min/day, 5 days/wk), the Run rats were trained at progressively increasing
      running speeds (12-22 m/min), and weights attached to the tail of the Swim rats
      were progressively increased from 0 to 2% of their body weight. The bone mineral
      density of the proximal tibiae of the Run rats was significantly higher than in
      the Swim (P < 0.05). Femoral wet weights of the two exercise groups were
      significantly higher than in the control group (P < 0.05). Interestingly, the
      percent difference between the tissue wet weight and dry weight (water content
      ratio), which is related to bone mechanical properties, was significantly higher
      in the tibiae of the Swim rats and the femora of both exercise groups compared
      with controls (P < 0.05). Extrinsic as well as intrinsic biomechanical material
      properties were measured in a three-point bending test. Bone mechanical
      properties of the tibiae and femora of rats in the Swim and Run groups were
      significantly greater than those in the control group (P < 0.05). In summary,
      different modes of exercise may benefit bone mechanical properties in different
      ways. The specific effects of swimming exercise (non-weight-bearing exercise) on
      bone require further study.

PMID- 12611765
TI  - Aerobic exercise training reduces plasma endothelin-1 concentration in older
      women.
AB  - Endothelial function deteriorates with aging. On the other hand, exercise
      training improves the function of vascular endothelial cells. Endothelin-1 (ET
      1), which is produced by vascular endothelial cells, has potent constrictor and
      proliferative activity in vascular smooth muscle cells and, therefore, has been
      implicated in regulation of vascular tonus and progression of atherosclerosis. We
      previously reported significantly higher plasma ET-1 concentration in middle-aged
      than in young humans, and recently we showed that plasma ET-1 concentration was
      significantly decreased by aerobic exercise training in healthy young humans. We
      hypothesized that plasma ET-1 concentration increases with age, even in healthy
      adults, and that lifestyle modification (i.e., exercise) can reduce plasma ET-1
      concentration in previously sedentary older adults. We measured plasma ET-1
      concentration in healthy young women (21-28 yr old), healthy middle-aged women
      (31-47 yr old), and healthy older women (61-69 yr old). The plasma level of ET-1
      significantly increased with aging (1.02 +/- 0.08, 1.33 +/- 0.11, and 2.90 +/-
      0.20 pg/ml in young, middle-aged, and older women, respectively). Thus plasma ET
      1 concentration was markedly higher in healthy older women than in healthy young
      or middle-aged women (by approximately 3- and 2-fold, respectively). In healthy
      older women, we also measured plasma ET-1 concentration after 3 mo of aerobic
      exercise (cycling on a leg ergometer at 80% of ventilatory threshold for 30 min,
      5 days/wk). Regular exercise significantly decreased plasma ET-1 concentration in
      the healthy older women (2.22 +/- 0.16 pg/ml, P < 0.01) and also significantly
      reduced their blood pressure. The present study suggests that regular aerobic
      endurance exercise reduces plasma ET-1 concentration in older humans, and this
      reduction in plasma ET-1 concentration may have beneficial effects on the
      cardiovascular system (i.e., prevention of progression of hypertension and/or
      atherosclerosis by endogenous ET-1).

PMID- 12611766
TI  - Upright LBPP application attenuates elevated postexercise resting thresholds for
      cutaneous vasodilation and sweating.
AB  - We evaluated postexercise venous pooling as a factor leading to previously
      reported increases in the postexercise esophageal temperature threshold for
      cutaneous vasodilation (ThVD) and sweating (ThSW). Six subjects were randomly
      exposed to lower body positive pressure (LBPP) and to no LBPP after an exercise
      and no-exercise treatment protocol. The exercise treatment consisted of 15 min of
      upright cycling at 65% of peak oxygen consumption, and the no-exercise treatment
      consisted of 15 min upright seated rest. Immediately after either treatment,
      subjects donned a liquid-conditioned suit used to regulate mean skin temperature
      and then were positioned within an upright LBPP chamber. The suit was first
      perfused with 20 degrees C water to control and stabilize skin and core
      temperature before whole body heating. Subsequently the skin was heated (
      approximately 4.0 degrees C/h) until cutaneous vasodilation and sweating
      occurred. Forearm skin blood flow and arterial blood pressure were measured
      noninvasively and were used to calculate cutaneous vascular conductance during
      whole body heating. Sweat rate response was estimated from a 5.0-cm2 ventilated
      capsule placed on the upper back. Postexercise ThVD and ThSW were both
      significantly elevated (0.27 +/- 0.04 degrees C and 0.25 +/- 0.04 degrees C,
      respectively) compared with the no-exercise trial without LBPP (P < 0.05).
      However, the postexercise increases in both ThVD and ThSW were reversed with the
      application of LBPP. Our results support the hypothesis that the postexercise
      warm thermal responses of cutaneous vasodilation and sweating are attenuated by
      baroreceptor modulation via lower body venous pooling.

PMID- 12611767
TI  - Stretch-activated ion channels and c-fos expression remain active after repeated
      eccentric bouts.
AB  - This study was undertaken to measure the response of stretch-activated ion
      channels (SAC) and transcript levels of the oncogene c-fos to separate bouts of
      eccentric contractions (EC). It was hypothesized that SAC in rat skeletal muscle
      would contribute to resting membrane potential depolarization after separate
      repeated bouts of EC. Blockage of SAC during an EC training regime also tested
      the necessity of SAC for a training response. It was also hypothesized that
      transcript levels of c-fos would be maximally elevated after the first exposure
      to EC and diminish with repeated exposures. The results indicate less
      depolarization after multiple bouts of EC, which could be reversed by blocking
      the SAC. Transcript levels of c-fos were elevated to a similar degree after
      either a single or multiple exposures to EC. EC training resulted in significant
      increases in contractile force and muscle wet and dry weights in nontreated
      animals. Training in the presence of the SAC-blocker streptomycin produced
      similar changes in contractile force without changes in muscle weight. SAC and c
      fos are activated after several exposures to EC and therefore remain as possible
      signals in EC training responses.

PMID- 12611768
TI  - Peripheral opioidergic regulation of the tracheobronchial mucociliary transport
      system.
AB  - We hypothesized that, in the airway mucosa, opioids are inhibitory neural
      modulators that cause an increase in net water absorption in the airway mucosa
      (as in the gut). Changes in bidirectional water fluxes across ovine tracheal
      mucosa in response to basolateral application of the opioid peptides beta
      endorphin, dynorphin A-(1-8), and [d-Ala(2), d-Leu(5)]-enkephalin (DADLE) were
      measured. beta-Endorphin and dynorphin A-(1-8) decreased luminal-to-basolateral
      water fluxes, and dynorphin A-(1-8) and DADLE increased basolateral-to-luminal
      water flux. These responses were electroneutral. In seven beagle dogs,
      administration of aerosolized beta-endorphin (1 mg) to the tracheobronchial
      airways decreased the clearance of radiotagged particles from the bronchi in 1 h
      from 34.7 to 22.0% (P < 0.001). Naloxone abrogated the beta-endorphin-induced
      changes in vitro and in vivo. Contrary to our hypothesis, the opioid-induced
      changes in water fluxes would all lead to a predictable increase in airway
      surface fluid. The beta-endorphin-induced increases in airway fluid together with
      reduced bronchial mucociliary clearance may produce procongestive responses when
      opioids are administered as antitussives.

PMID- 12611769
TI  - Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on
      transitions in humans.
AB  - Near-infrared spectroscopy (NIRS) was utilized to gain insights into the kinetics
      of oxidative metabolism during exercise transitions. Ten untrained young men were
      tested on a cycle ergometer during transitions from unloaded pedaling to 5 min of
      constant-load exercise below (<VT) or above (>VT) the ventilatory threshold.
      Vastus lateralis oxygenation was determined by NIRS, and pulmonary O2 uptake (Vo 
      -> Vo2) was determined breath-by-breath. Changes in deoxygenated hemoglobin +
      myoglobin concentration Delta[deoxy(Hb + Mb)] were taken as a muscle oxygenation
      index. At the transition, [Delta[deoxy(Hb + Mb)]] was unmodified [time delay
      (TD)] for 8.9 +/- 0.5 s at <VT or 6.4 +/- 0.9 s at >VT (both significantly
      different from 0) and then increased, following a monoexponential function [time
      constant (tau) = 8.5 +/- 0.9 s for <VT and 7.2 +/- 0.7 s for >VT]. For >VT a slow
      component of Delta[deoxy(Hb + Mb)] on-kinetics was observed in 9 of 10 subjects
      after 75.0 +/- 14.0 s of exercise. A significant correlation was described
      between the mean response time (MRT = TD + tau) of the primary component of
      Delta[deoxy(Hb + Mb)] on-kinetics and the tau of the primary component of the
      pulmonary Vo2 on-kinetics. The constant muscle oxygenation during the initial
      phase of the on-transition indicates a tight coupling between increases in O2
      delivery and O2 utilization. The lack of a drop in muscle oxygenation at the
      transition suggests adequacy of O2 availability in relation to needs.

PMID- 12611770
TI  - Local blood circulation among knee extensor synergists in relation to alternate
      muscle activity during low-level sustained contraction.
AB  - The relation between local circulation and alternate muscle activity among knee
      extensor synergists was determined during low-level sustained knee extension at
      2.5% of maximal voluntary contraction for 60 min in seven subjects. Blood volume
      of rectus femoris (RF) and vastus lateralis (VL) was assessed by using near
      infrared spectroscopy. Surface electromyogram (EMG) was recorded from RF, VL, and
      vastus medialis (VM). Alternate muscle activity was observed between RF and
      either VL or VM. Cross-correlation analysis was used to investigate the relation
      between blood volume and integrated EMG (iEMG) sequences throughout the task. One
      negative peak in the cross-correlation function was seen between the iEMG and
      blood volume with time lag of 30-60 s, indicating that muscle activity increases
      (or decreases) with the decrease (or increase) in local circulation with the
      corresponding time lag. Two cases in the emergence of alternate muscle
      activities, i.e., an increase in the EMG of RF accompanied by a decline of EMG in
      VL (case I) and vice versa (case II) were further analyzed. The time lag between
      iEMG and blood volume was longer in case I than that in case II. These results
      were statistically significant in the RF but not in the VL. It is concluded that
      even during low-level sustained contraction, local circulation is modulated by
      the alternate muscle activity of knee extensor synergists, and a negative
      correlation between the muscle activity and blood volume sequences was found in
      only RF but not in VL.

PMID- 12611771
TI  - ATP synthesis and proton handling in muscle during short periods of exercise and
      subsequent recovery.
AB  - We used (31)P-magnetic resonance spectroscopy to study proton buffering in finger
      flexor muscles of eight healthy men (25-45 yr), during brief (18-s) voluntary
      finger flexion exercise (0.67-Hz contraction at 10% maximum voluntary
      contraction; 50/50 duty cycle) and 180-s recovery. Phosphocreatine (PCr)
      concentration fell 19 +/- 2% during exercise and then recovered with half time =
      0.24 +/- 0.01 min. Cell pH rose by 0.058 +/- 0.003 units during exercise as a
      result of H(+) consumption by PCr splitting, which (assuming no lactate
      production or H(+) efflux) implies a plausible non-P(i) buffer capacity of 20 +/-
      3 mmol. l intracellular water(-1). pH unit(-1). There was thus no evidence of
      significant glycogenolysis to lactate during exercise. Analysis of PCr kinetics
      as a classic linear response suggests that oxidative ATP synthesis reached 48 +/-
      2% of ATP demand by the end of exercise; the rest was met by PCr splitting.
      Postexercise pH recovery was faster than predicted, suggesting "excess proton"
      production, with a peak value of 0.6 +/- 0.2 mmol/l intracellular water at 0.45
      min of recovery, which might be due to, e.g., proton influx driven by cellular
      alkalinization, or a small glycolytic contribution to PCr resynthesis in
      recovery.

PMID- 12611772
TI  - Glutamine supplementation further enhances exercise-induced plasma IL-6.
AB  - Exercise stimulates the production and release of interleukin-6 (IL-6) from
      skeletal muscle. Glutamine is also synthesized in skeletal muscle and is involved
      in protein synthesis within this tissue. During exercise, plasma levels of
      glutamine decline, and this may affect the concentration of plasma IL-6 via a
      decrease in IL-6 synthesis and release from muscle. We hypothesized that
      glutamine supplementation would attenuate the exercise-induced decrease in plasma
      glutamine concentration and, thus, further enhance levels of plasma IL-6. Eight
      healthy men participated in a randomized, double-blind, crossover study in which
      they performed 2 h of cycle ergometry at 75% of peak O2 uptake. They received
      glutamine, glutamine-rich protein, or placebo supplementation at intervals during
      and 2 h after exercise. Exercise induced an 11-fold increase in plasma IL-6,
      which was further enhanced by glutamine (18-fold) and glutamine-rich protein (14
      fold) supplementation, administered at doses that attenuated the exercise-induced
      decrease in plasma glutamine concentration.

PMID- 12611773
TI  - Prior exercise increases basal and insulin-induced p38 mitogen-activated protein
      kinase phosphorylation in human skeletal muscle.
AB  - We have examined the effects of insulin on p38 mitogen-activated protein kinase
      (MAPK) phosphorylation in human skeletal muscle and the effects of prior exercise
      hereon. Seven men performed 1-h one-legged knee extensor exercise 3 h before the
      initiation of a 100-min euglycemic-hyperinsulinemic (600 pmol/l) clamp. Glucose
      uptake across the legs was measured with the leg balance technique, and muscle
      biopsies were obtained from the rested and exercised vastus lateralis before and
      during insulin infusion. Net glucose uptake during the clamp was approximately
      50% higher (P < 0.05) in the exercised leg than in the rested leg. Insulin
      induced a modest sustained 1.2- and 1.3-fold increase (P < 0.05) in p38 MAPK
      phosphorylation in the rested and exercised legs, respectively. However, p38
      phosphorylation was approximately 50% higher (P < 0.05) in the exercised compared
      with the rested leg before and during insulin infusion. We conclude that a
      physiological concentration of insulin causes modest but sustained activation of
      the p38 MAPK pathway in human skeletal muscle. Furthermore, the stimulatory
      effect of exercise on p38 phosphorylation is persistent for at least 3 h after
      exercise and remains evident during subsequent insulin stimulation. Because p38
      MAPK has been suggested to play a necessary role in activation of GLUT-4 at the
      cell surface, the present data may suggest a putative role of p38 MAPK in the
      increased insulin sensitivity of skeletal muscle after exercise.

PMID- 12611774
TI  - Acute molecular responses of skeletal muscle to resistance exercise in able
      bodied and spinal cord-injured subjects.
AB  - Spinal cord injury (SCI) results in muscle atrophy, which contributes to a number
      of health problems, such as cardiovascular deconditioning, metabolic derangement,
      and osteoporosis. Electromyostimulation (EMS) holds the promise of ameliorating
      SCI-related muscle atrophy and, therefore, improving general health. To date, EMS
      training of long-term SCI subjects has resulted in some muscle hypertrophy but
      has fallen short of normalizing muscle mass. The aim of this study was to compare
      the molecular responses of vastus lateralis muscles from able-bodied (AB) and SCI
      subjects after acute bouts of EMS-induced resistance exercise to determine
      whether SCI muscles displayed some impairment in response. Analysis included mRNA
      markers known to be responsive to increased loading in rodent muscles. Muscles of
      AB and SCI subjects were subjected to EMS-stimulated exercise in two 30-min
      bouts, separated by a 48-h rest. Needle biopsy samples were obtained 24 h after
      the second exercise bout. In both the AB and SCI muscles, significant changes
      were seen in insulin-like growth factor binding proteins 4 and 5, cyclin
      dependent kinase inhibitor p21, and myogenin mRNA levels. In AB subjects, the
      mRNA for mechano-growth factor was also increased. Before exercise, the total RNA
      concentration of the SCI muscles was less than that of the AB subjects but not
      different postexercise. The results of this study indicate that acute bouts of
      resistance exercise stimulate molecular responses in the skeletal muscles of both
      AB and SCI subjects. The responses seen in the SCI muscles indicate that the
      systems that regulate these molecular responses are intact, even after extended
      periods of muscle unloading.

PMID- 12611775
TI  - Exercise-induced changes to in vitro T-lymphocyte mitogen responses using CFSE.
AB  - Carboxyfluorescein diacetate succinamidyl ester (CFSE) labeling of lymphocyte
      populations can provide unique insights into cell function at rest and with
      exercise, due to its ability to quantify cell division on an individual cell
      basis. This study aimed to characterize the effect of acute, intense exercise on
      T-lymphocyte function. Well-trained endurance runners completed 60 min of
      treadmill running at 95% of individual anaerobic threshold. Blood samples were
      collected before exercise; after 30 and 60 min of exercise; and after 30, 60, and
      90 min of recovery. Isolated peripheral blood mononuclear cells were labeled with
      CFSE and cultured with or without mitogen (phytohemagglutinin). After culture,
      cell suspensions were labeled with CD3 (allophycocyanin) and CD8 (phycoerythrin),
      and expansion rates and cell death rates were calculated for each sample, as well
      as mitosis rates for each cell generation. Exercise was associated with a 60%
      decrease in cell expansion in both CD4 and CD8 cell types from before exercise to
      midexercise (P < 0.05). The significant decrease in expansion rate in the
      midexercise samples for both cell types was mirrored by a 65% increase in cell
      death (P < 0.05) in both cell types at that sample point. Exercise had no effect
      on the mitosis rate of either CD4 or CD8 cells in any cell generation
      (generations 0-3). This study indicates that 1 h of intense exercise affects in
      vitro T-lymphocyte function. These data suggest, for the first time, that
      exercise decreases cell expansion rate via an increase in cell death of both CD4
      and CD8 T lymphocytes, rather than a decrease in mitosis.

PMID- 12611777
TI  - Collaborating with developing countries in psychiatric research.

PMID- 12611776
TI  - Conducting psychiatric research in the developing world: challenges and rewards.

PMID- 12611778
TI  - Understanding the neurobiology of emotion perception: implications for
      psychiatry.

PMID- 12611779
TI  - Between ourselves: psychodynamics and the interpersonal domain.

PMID- 12611780
TI  - Is early intervention for psychosis a waste of valuable resources?

PMID- 12611781
TI  - Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and
      consequences. Selective literature review.
AB  - BACKGROUND: Hyperprolactinaemia has for decades been an inevitable and neglected
      side-effect of antipsychotic medication. The recent introduction of prolactin
      sparing antipsychotic agents makes a re-examination of this problem timely. AIMS:
      To review the literature on antipsychotic-induced hyperprolactinaemia and its
      consequences. METHOD: A search was made of the Medline database (1966-2002) for
      key articles, supplemented by cross-referencing. RESULTS: During antipsychotic
      treatment prolactin concentrations can rise to ten times normal levels or above,
      and existing data indicate that 17-78% of female patients have amenorrhoea with
      or without galactorrhoea. Survey data, however, suggest that clinicians
      underestimate the prevalence of these conditions. Long-term consequences of
      antipsychotic-related hypo-oestrogenism require further research but are likely
      to include premature bone loss. CONCLUSIONS: Antipsychotic-induced
      hyperprolactinaemia should become a focus of interest in the drug treatment of
      psychiatric patients.

PMID- 12611782
TI  - Cross-cultural differences in the epidemiology of unexplained fatigue syndromes
      in primary care.
AB  - BACKGROUND: Unexplained fatigue has been extensively studied but most of the
      samples used were from Western countries. AIMS: To present international data on
      the prevalence of unexplained fatigue and fatigue as a presenting complaint in
      primary care. Method Secondary analysis of the World Health Organization study of
      psychological problems in general health care. A total of 5438 primary care
      attenders from 14 countries were assessed with the Composite International
      Diagnostic Interview. RESULTS: The prevalence of unexplained fatigue of 1-month
      duration differed across centres, with a range between 2.26 (95% CI 1.17-4.33)
      and 15.05 (95% CI 10.85-20.49). Subjects from more-developed countries were more
      likely to report unexplained fatigue but less likely to present with fatigue to
      physicians compared with subjects from less developed countries. CONCLUSIONS: In
      less-developed countries fatigue might be an indicator of unmet psychiatric need,
      but in more-developed countries it is probably a symbol of psychosocial distress.

PMID- 12611783
TI  - Effects of a branched-chain amino acid drink in mania.
AB  - BACKGROUND: Administration of a complex tyrosine-free amino acid drink acutely
      decreases manic symptoms. Although a nutrient-based approach to illness
      management is attractive, complex amino acid drinks are too unpalatable for
      repeated administration. AIMS: To assess whether a simple, branched-chain amino
      acid (BCAA) drink diminishes manic symptoms acutely and following repeated
      administration. METHOD: Twenty-five patients with mania were randomly and blindly
      allocated to treatment with BCAA (60 g) or placebo daily for 7 days. RESULTS:
      Relative to placebo, the BCAA drink lowered mania ratings acutely over the first
      6 h of treatment. In protocol completers there was a persistent advantage to the
      BCAA group 1 week after the end of treatment. CONCLUSIONS: A nutritional
      intervention that decreases tyrosine availability to the brain acutely
      ameliorates manic symptoms. Further studies are required to assess whether this
      approach has longer-term efficacy.

PMID- 12611784
TI  - Neurocognitive impairment in drug-free patients with major depressive disorder.
AB  - BACKGROUND: Although neurocognitive impairment has been widely reported in major
      depressive disorder (MDD), confounding factors, such as the effects of
      psychotropic medication, have rarely been controlled for. AIMS: To examine
      neurocognitive function in medication-free patients with MDD and healthy
      controls. METHOD: Forty-four patients meeting DSM-IV criteria for MDD, all
      psychotropic-medication-free for at least 6 weeks, and 44 demographically
      matched, healthy comparison subjects completed a comprehensive neurocognitive
      battery. RESULTS: Patients with depression were impaired significantly in a range
      of cognitive domains, including attention and executive function and visuospatial
      learning and memory, compared with controls. Motor and psychomotor functions were
      intact. Severity of depression correlated with learning and memory performance,
      but not executive function. CONCLUSIONS: Pronounced neurocognitive impairment was
      found in this sample of young adult out-patients with MDD. This is not
      attributable to the confounding effects of psychotropic medication and could
      therefore provide an objective marker of brain dysfunction in depression.

PMID- 12611785
TI  - Use of cognitive therapy for relapse prevention in chronic depression. Cost
      effectiveness study.
AB  - BACKGROUND: There is a lack of data on the cost-effectiveness of relapse
      prevention in depression. METHOD: A total of 158 subjects with partially remitted
      major depression despite adequate clinical treatment were randomly allocated to
      cognitive therapy in addition to antidepressants and clinical management v.
      antidepressants and clinical management alone. Relapse rates and health care
      resource utilisation were measured prospectively over 17 months. RESULTS:
      Cumulative relapse rates in the cognitive therapy group were significantly lower
      than in the control group (29% v. 47%). The incremental cost incurred in subjects
      receiving cognitive therapy over 17 months (pound sterling 779; 95% CI pound
      sterling 387- pound sterling 1170) was significantly lower than the overall mean
      costs of cognitive therapy (pound sterling 1164; 95% CI pound sterling 1084-
      pound sterling 1244). The incremental cost-effectiveness ratio ranged from pound
      sterling 4328 to pound sterling 5027 per additional relapse prevented.
      CONCLUSIONS: In individuals with depressive symptoms that are resistant to
      standard treatment, adjunctive cognitive therapy is more costly but more
      effective than intensive clinical treatment alone.

PMID- 12611786
TI  - Paracingulate sulcus morphology in men with early-onset schizophrenia.
AB  - BACKGROUND: Cingulate dysfunction has been reported in schizophrenia. Although
      the paracingulate sulcus (PCS) is known to be asymmetric in healthy people,
      little information is available about its morphology in schizophrenia. AIMS: To
      search for morphological anomalies of the PCS in men with early-onset
      schizophrenia. METHOD: The PCS was examined in magnetic resonance images of the
      brains of men with schizophrenia and 100 healthy men. RESULTS: A significant
      asymmetry was found in the brains of healthy volunteers, whose sulci were more
      frequent and more marked in the left hemisphere. In contrast, the sulcus was as
      frequent in the right as in the left hemisphere in the patient group. Moreover,
      patients displayed significantly more rightward asymmetry, and overall less
      asymmetrical patterns than the comparison group. CONCLUSIONS: Since the PCS has
      developed at 36 weeks of gestation, these findings suggest an impaired maturation
      of the cingulate region during the third trimester.

PMID- 12611787
TI  - Disintegration of the components of language as the path to a revision of
      Bleuler's and Schneider's concepts of schizophrenia. Linguistic disturbances
      compared with first-rank symptoms in acute psychosis.
AB  - BACKGROUND: The 20th century ended without a resolution of the debate about the
      supremacy of Schneider's psychopathological conceptualisation of schizophrenia
      (the first-rank symptoms) over Bleuler's 'four As' (disorders of association and
      affect, ambivalence and autism). AIMS: To examine the relationships between
      linguistic deviations and symptoms in patients with acute psychosis. METHOD: We
      assessed language disturbances and first-rank symptoms with the Clinical Language
      Disorder Rating Scale (CLANG) in 30 consecutive patients with acute psychosis,
      selected for the presence of at least one active first-rank symptom, and 15
      control participants with depression but no psychotic symptoms. RESULTS: Strong
      positive correlations were found between the CLANG factor 'poverty' and first
      rank delusions of control and between semantic/phonemic paraphasias and verbal
      auditory hallucinations [corrected]. Language disturbances were superior to
      nuclear symptoms in discriminating ICD-10 schizophrenia from other psychoses.
      CONCLUSIONS: Evaluating the features of psychosis as deviations in the cerebral
      organisation of language paves the way to a concept of psychosis that supersedes
      these traditional but competing categorical concepts.

PMID- 12611788
TI  - Care needs of elderly people with schizophrenia. Assessment of an
      epidemiologically defined cohort in Scotland.
AB  - BACKGROUND: Little is known of the needs of elderly patients with psychotic
      illnesses. AIMS: To measure the care needs of an epidemiologically based group of
      patients over the age of 65 years suffering from psychotic illness, using a
      standardised assessment. METHOD: All patients aged 65 years and over with a
      diagnosis of schizophrenia and related disorders from a defined catchment area
      were identified. Their health and social care needs were investigated using the
      Cardinal Needs Schedule. RESULTS: The 1-year prevalence of schizophrenia and
      related disorders was 4.44 per 1000 of the population at risk. There were high
      levels of unmet need for many patients, including those in National Health
      Service (NHS) continuing-care beds. CONCLUSIONS: Many needs were identified, all
      of which could be addressed using the existing skills of local health and social
      care professionals. The investigation raises serious concerns about standards of
      hospital and community care for elderly patients with schizophrenia. The findings
      may be unique, reflecting long-standing problems within a particularly hard
      pressed part of the NHS. However, it is not known whether a similar situation
      exists in other parts of the UK.

PMID- 12611789
TI  - Assertive community treatment across the Atlantic: comparison of model fidelity
      in the UK and USA.
AB  - BACKGROUND: The significant reductions in hospital admission demonstrated in US
      assertive community treatment (ACT) studies have not been replicated in the UK.
      Explanations cite poor UK 'model fidelity' and/or better UK standard care. No
      international model-fidelity comparisons exist. AIMS: To compare high-fidelity US
      ACT teams with a UK team. METHOD: The UK 700's ACT team (n=97) was compared with
      high-fidelity US ACT teams (n=73) by using two measures: a forerunner of the
      Dartmouth Assertive Community Treatment schedule (to assess adherence to ACT
      principles) and 2-year prospective activity data. RESULTS: The UK and US teams
      had similar high-fidelity scores. Although significant differences were found in
      the amount and type of activity, practice differences in areas central to ACT
      were not great. CONCLUSIONS: The failure of UK ACT studies to demonstrate the
      outcome differences of early US studies cannot be attributed entirely to the lack
      of ACT fidelity.

PMID- 12611790
TI  - Objectivity in psychoanalytic assessment of couple relationships.
AB  - BACKGROUND: Clinicians claim that partners in a couple can be understood to share
      a mode of relating, at an unconscious level. Assessment of this depends on
      inference from observable data. This study tests the viability and reliability of
      a modification of the Personal Relatedness Profile (PRP) for this purpose. AIMS:
      To test the interrater reliability and construct validity of a joint PRP score
      for couples. METHOD: Seven therapists independently rated couples' interactions
      using the 30-item PRP and segments of videotaped interviews with 19 couples.
      RESULTS: Interrater reliability was good and correlations between items clearly
      supported the underlying Kleinian bipolar model used (paranoid-schizoid/
      depressive positions). CONCLUSIONS: Psychoanalytic couple psychotherapists agree
      in independent judgements of the nature of couple functioning, these judgements
      being based on envisaging couples in terms of an unconsciously shared state of
      mind.

PMID- 12611791
TI  - Suicide prevention: a study of patients' views.
AB  - BACKGROUND: Suicide prevention strategies are usually formulated without seeking
      the views of people with psychiatric illnesses. AIMS: To establish what helped
      patients with severe psychiatric illness when they felt suicidal. METHOD: A semi
      structured interview was constructed following transcribed interviews with 12
      patients. This was administered to 59 out-patients with serious and enduring
      mental illness, focusing on factors they found helpful or unhelpful when at their
      most despairing. RESULTS: Three-quarters of patients were in contact with
      psychiatric services when feeling at their lowest, and this contact was generally
      deemed to be helpful. Social networks were considered just as helpful as
      psychiatric services by the half of patients who discussed their feelings with
      friends or relatives. Religious beliefs and affiliations were helpful. Negative
      influences included the media and the stigma of psychiatric illness. CONCLUSIONS:
      Efforts at suicide prevention might usefully focus on enhancing patients' social
      networks, increasing the likelihood of early contact with psychiatric services
      and decreasing the stigma attached to psychiatric illness. Larger studies of
      patients exposed to different service models would be informative.

PMID- 12611792
TI  - Telephone support and suicide prevention.

PMID- 12611793
TI  - Qigong and suicide prevention.

PMID- 12611794
TI  - Success of community care?

PMID- 12611795
TI  - Olanzapine toxicity in unconjugated hyperbilirubinaemia (Gilbert's syndrome).

PMID- 12611796
TI  - The treatment of hypochondriasis by hypnosis.

PMID- 12611798
TI  - Can transcriptome size be estimated from SAGE catalogs?
AB  - MOTIVATION: SAGE (Serial Analysis of Gene Expression) can be used to estimate the
      number of unique transcripts in a transcriptome. A simple estimator that corrects
      for sequencing and sampling errors was applied to a SAGE library (137 832 tags)
      obtained from mouse embryonic stem cells, and also to Monte Carlo simulated
      libraries generated using assumed distributions of 'true' expression levels
      consistent with the data. RESULTS: When the corrected data themselves were taken
      as the underlying model of 'ground truth', the estimator converged to the 'true'
      value (53 535) only after counting 300 000 simulated tags, more than twice the
      number in the experiment. The SAGE data could also be well fit by a Monte Carlo
      model based on a truncated inverse-square distribution of expression levels, with
      130 000 'true' transcripts and 10(6) samples needed for convergence. We conclude
      that the size of a transcriptome is ill-determined from SAGE libraries of even
      moderately large size. In order to obtain a valid estimate, one must sample a
      number of tags inversely proportional to the lowest abundance level, which is not
      known a priori. This constrains the design of SAGE experiments intended to
      determine biological complexity. AVAILABILITY: The 'homemade' software used for
      this analysis was not designed for general or 'production' use, but the authors
      will be happy to share Fortran sourcecode with interested parties. CONTACT:
      sternm@grc.nia.nih.gov

PMID- 12611799
TI  - An information theoretic approach for analyzing temporal patterns of gene
      expression.
AB  - MOTIVATION: Arrays allow measurements of the expression levels of thousands of
      mRNAs to be made simultaneously. The resulting data sets are information rich but
      require extensive mining to enhance their usefulness. Information theoretic
      methods are capable of assessing similarities and dissimilarities between data
      distributions and may be suited to the analysis of gene expression experiments.
      The purpose of this study was to investigate information theoretic data mining
      approaches to discover temporal patterns of gene expression from array-derived
      gene expression data. RESULTS: The Kullback-Leibler divergence, an information
      theoretic distance that measures the relative dissimilarity between two data
      distribution profiles, was used in conjunction with an unsupervised self
      organizing map algorithm. Two published, array-derived gene expression data sets
      were analyzed. The patterns obtained with the KL clustering method were found to
      be superior to those obtained with the hierarchical clustering algorithm using
      the Pearson correlation distance measure. The biological significance of the
      results was also examined. AVAILABILITY: Software code is available by request
      from the authors. All programs were written in ANSI C and Matlab (Mathworks Inc.,
      Natick, MA).

PMID- 12611800
TI  - Comparisons and validation of statistical clustering techniques for microarray
      gene expression data.
AB  - MOTIVATION: With the advent of microarray chip technology, large data sets are
      emerging containing the simultaneous expression levels of thousands of genes at
      various time points during a biological process. Biologists are attempting to
      group genes based on the temporal pattern of their expression levels. While the
      use of hierarchical clustering (UPGMA) with correlation 'distance' has been the
      most common in the microarray studies, there are many more choices of clustering
      algorithms in pattern recognition and statistics literature. At the moment there
      do not seem to be any clear-cut guidelines regarding the choice of a clustering
      algorithm to be used for grouping genes based on their expression profiles.
      RESULTS: In this paper, we consider six clustering algorithms (of various
      flavors!) and evaluate their performances on a well-known publicly available
      microarray data set on sporulation of budding yeast and on two simulated data
      sets. Among other things, we formulate three reasonable validation strategies
      that can be used with any clustering algorithm when temporal observations or
      replications are present. We evaluate each of these six clustering methods with
      these validation measures. While the 'best' method is dependent on the exact
      validation strategy and the number of clusters to be used, overall Diana appears
      to be a solid performer. Interestingly, the performance of correlation-based
      hierarchical clustering and model-based clustering (another method that has been
      advocated by a number of researchers) appear to be on opposite extremes,
      depending on what validation measure one employs. Next it is shown that the group
      means produced by Diana are the closest and those produced by UPGMA are the
      farthest from a model profile based on a set of hand-picked genes. AVAILABILITY:
      S+ codes for the partial least squares based clustering are available from the
      authors upon request. All other clustering methods considered have S+
      implementation in the library MASS. S+ codes for calculating the validation
      measures are available from the authors upon request. The sporulation data set is
      publicly available at http://cmgm.stanford.edu/pbrown/sporulation

PMID- 12611801
TI  - A multivariate approach applied to microarray data for identification of genes
      with cell cycle-coupled transcription.
AB  - We have analyzed microarray data using a modeling approach based on the
      multivariate statistical method partial least squares (PLS) regression to
      identify genes with periodic fluctuations in expression levels coupled to the
      cell cycle in the budding yeast, Saccharomyces cerevisiae. PLS has major
      advantages for analyzing microarray data since it can model data sets with large
      numbers of variables and with few observations. A response model was derived
      describing the expression profile over time expected for periodically transcribed
      genes, and was used to identify budding yeast transcripts with similar profiles.
      PLS was then used to interpret the importance of the variables (genes) for the
      model, yielding a ranking list of how well the genes fitted the generated model.
      Application of an appropriate cutoff value, calculated from randomized data,
      allows the identification of genes whose expression appears to be synchronized
      with cell cycling. Our approach also provides information about the stage in the
      cell cycle where their transcription peaks. Three synchronized yeast cell
      microarray data sets were analyzed, both separately and combined. Cell cycle
      coupled periodicity was suggested for 455 of the 6,178 transcripts monitored in
      the combined data set, at a significance level of 0.5%. Among the candidates, 85%
      of the known periodic transcripts were included. Analysis of the three data sets
      separately yielded similar ranking lists, showing that the method is robust.

PMID- 12611802
TI  - Clustering of time-course gene expression data using a mixed-effects model with B
      splines.
AB  - MOTIVATION: Time-course gene expression data are often measured to study dynamic
      biological systems and gene regulatory networks. To account for time dependency
      of the gene expression measurements over time and the noisy nature of the
      microarray data, the mixed-effects model using B-splines was introduced. This
      paper further explores such mixed-effects model in analyzing the time-course gene
      expression data and in performing clustering of genes in a mixture model
      framework. RESULTS: After fitting the mixture model in the framework of the mixed
      effects model using an EM algorithm, we obtained the smooth mean gene expression
      curve for each cluster. For each gene, we obtained the best linear unbiased
      smooth estimate of its gene expression trajectory over time, combining data from
      that gene and other genes in the same cluster. Simulated data indicate that the
      methods can effectively cluster noisy curves into clusters differing in either
      the shapes of the curves or the times to the peaks of the curves. We further
      demonstrate the proposed method by clustering the yeast genes based on their cell
      cycle gene expression data and the human genes based on the temporal
      transcriptional response of fibroblasts to serum. Clear periodic patterns and
      varying times to peaks are observed for different clusters of the cell-cycle
      regulated genes. Results of the analysis of the human fibroblasts data show seven
      distinct transcriptional response profiles with biological relevance.
      AVAILABILITY: Matlab programs are available on request from the authors.

PMID- 12611803
TI  - Estimating the diversity of peptide populations from limited sequence data.
AB  - MOTIVATION: Combinatorial libraries of peptides such as those displayed on the
      surface of a bacteriophage particle have become widely used tools for
      characterizing protein-protein and protein-small molecule interactions. The
      quality of a library frequently depends on its completeness, or diversity-the
      proportion of possible sequences actually present in the library. The diversity
      of these libraries is frequently quoted on the basis of phage titers that provide
      little information about their completeness. RESULTS: Here, an analytical
      expression for diversity is introduced and a method for estimating the diversity
      of a peptide library from the sequences of a limited number of the members of the
      library is demonstrated. The diversities of a number of computationally
      constructed and actual peptide libraries are estimated using this method.

PMID- 12611804
TI  - Statistical alignment based on fragment insertion and deletion models.
AB  - MOTIVATION: The topic of this paper is the estimation of alignments and mutation
      rates based on stochastic sequence-evolution models that allow insertions and
      deletions of subsequences ('fragments') and not just single bases. The model we
      propose is a variant of a model introduced by Thorne et al., (J. Mol. Evol., 34,
      3-16, 1992). The computational tractability of the model depends on certain
      restrictions in the insertion/deletion process; possible effects we discuss.
      RESULTS: The process of fragment insertion and deletion in the sequence-evolution
      model induces a hidden Markov structure at the level of alignments and thus makes
      possible efficient statistical alignment algorithms. As an example we apply a
      sampling procedure to assess the variability in alignment and mutation parameter
      estimates for HVR1 sequences of human and orangutan, improving results of
      previous work. Simulation studies give evidence that estimation methods based on
      the proposed model also give satisfactory results when applied to data for which
      the restrictions in the insertion/deletion process do not hold. AVAILABILITY: The
      source code of the software for sampling alignments and mutation rates for a pair
      of DNA sequences according to the fragment insertion and deletion model is freely
      available from http://www.math.uni-frankfurt.de/~stoch/software/mcmcsalut under
      the terms of the GNU public license (GPL, 2000).

PMID- 12611805
TI  - MaxSubSeq: an algorithm for segment-length optimization. The case study of the
      transmembrane spanning segments.
AB  - MOTIVATION: A problem in predicting the topography of transmembrane proteins is
      the optimal localization of the transmembrane segments along the protein
      sequences, provided that each residue is associated with a propensity of being or
      not being included in the transmembrane protein region. From previous work it is
      known that post-processing of propensity signals with suited algorithms can
      greatly improve the quality and the accuracy of the predictions. In this paper we
      describe a general dynamic programming-like algorithm (MaxSubSeq, Maximal
      SubSequence) specifically designed to optimize the number and length of segments
      with constrained length in a given protein sequence. Previous application of our
      algorithm, has proved its effectiveness in the optimization task of both neural
      network and hidden Markov models output, and in this paper we present the
      detailed description of MaxSubSeq. RESULTS: We describe the application of
      MaxSubSeq to the location of both helical and beta strand transmembrane segments,
      optimizing the outputs derived with different predictive algorithms. For all
      alpha transmembrane proteins we use both the standard Kyte-Doolittle (KD)
      hydropathy scale and the TMHMM predictor (http://www.cbs.dtu.dk/). Using a set of
      188 well characterized membrane proteins, MaxSubSeq nearly doubles the correct
      location of transmembrane segments as compared to the standard KD hydrophobicity
      plot, reaching 51% accuracy. If MaxSubSeq is used to optimize the TMHMM method
      the accuracy increases from 68 to 72%. When used to regularize the prediction of
      beta transmembrane strands, obtained using both a neural network and a HMM based
      predictors, MaxSubSeq increases the accuracy per protein up to 72 and 73%
      respectively. AVAILABILITY: The program is available upon request to the authors,
      or it is accessible through our web server
      (http://gpcr.biocomp.unibo.it/predictors/)

PMID- 12611806
TI  - Detection of unrelated proteins in sequences multiple alignments by using
      predicted secondary structures.
AB  - MOTIVATION: Multiple sequence alignments are essential tools for establishing the
      homology relations between proteins. Essential amino acids for the function
      and/or the structure are generally conserved, thus providing key arguments to
      help in protein characterization. However for distant proteins, it is more
      difficult to establish, in a reliable way, the homology relations that may exist
      between them. In this article, we show that secondary structure prediction is a
      valuable way to validate protein families at low identity rate. RESULTS: We show
      that the analysis of the secondary structures compatibility is a reliable way to
      discard non-related proteins in low identity multiple alignment. AVAILABILITY:
      This validation is possible through our NPS@ server (http://npsa-pbil.ibcp.fr)

PMID- 12611807
TI  - Alignment-free sequence comparison-a review.
AB  - MOTIVATION: Genetic recombination and, in particular, genetic shuffling are at
      odds with sequence comparison by alignment, which assumes conservation of
      contiguity between homologous segments. A variety of theoretical foundations are
      being used to derive alignment-free methods that overcome this limitation. The
      formulation of alternative metrics for dissimilarity between sequences and their
      algorithmic implementations are reviewed. RESULTS: The overwhelming majority of
      work on alignment-free sequence has taken place in the past two decades, with
      most reports published in the past 5 years. Two main categories of methods have
      been proposed-methods based on word (oligomer) frequency, and methods that do not
      require resolving the sequence with fixed word length segments. The first
      category is based on the statistics of word frequency, on the distances defined
      in a Cartesian space defined by the frequency vectors, and on the information
      content of frequency distribution. The second category includes the use of
      Kolmogorov complexity and Chaos Theory. Despite their low visibility, alignment
      free metrics are in fact already widely used as pre-selection filters for
      alignment-based querying of large applications. Recent work is furthering their
      usage as a scale-independent methodology that is capable of recognizing homology
      when loss of contiguity is beyond the possibility of alignment. AVAILABILITY:
      Most of the alignment-free algorithms reviewed were implemented in MATLAB code
      and are available at http://bioinformatics.musc.edu/resources.html

PMID- 12611809
TI  - Subnetwork hierarchies of biochemical pathways.
AB  - MOTIVATION: The vastness and complexity of the biochemical networks that have
      been mapped out by modern genomics calls for decomposition into subnetworks. Such
      networks can have inherent non-local features that require the global structure
      to be taken into account in the decomposition procedure. Furthermore, basic
      questions such as to what extent the network (graph theoretically) can be said to
      be built by distinct subnetworks are little studied. RESULTS: We present a method
      to decompose biochemical networks into subnetworks based on the global geometry
      of the network. This method enables us to analyze the full hierarchical
      organization of biochemical networks and is applied to 43 organisms from the WIT
      database. Two types of biochemical networks are considered: metabolic networks
      and whole-cellular networks (also including for example information processes).
      Conceptual and quantitative ways of describing the hierarchical ordering are
      discussed. The general picture of the metabolic networks arising from our study
      is that of a few core-clusters centred around the most highly connected
      substances enclosed by other substances in outer shells, and a few other well
      defined subnetworks. AVAILABILITY: An implementation of our algorithm and other
      programs for analyzing the data is available from
      http://www.tp.umu.se/forskning/networks/meta/ SUPPLEMENTARY INFORMATION:
      Supplementary material is available at
      http://www.tp.umu.se/forskning/networks/meta/

PMID- 12611810
TI  - PopHist: inferring population history from the spectrum of allele frequencies.
AB  - SUMMARY: PopHist is a computer program that uses the frequency spectrum of
      alleles to: (a) estimate maximum likelihood parameters describing a population's
      history; and (b) compare alternative hypotheses about population history using
      likelihood ratio tests. The program uses the matrix coalescent, a method for
      calculating theoretical frequency spectra that can be applied to sets of unlinked
      sites. AVAILABILITY: Source code and documentation are available at
      http://mombasa.anthro.utah.edu/wooding/PopHist

PMID- 12611808
TI  - The systems biology markup language (SBML): a medium for representation and
      exchange of biochemical network models.
AB  - MOTIVATION: Molecular biotechnology now makes it possible to build elaborate
      systems models, but the systems biology community needs information standards if
      models are to be shared, evaluated and developed cooperatively. RESULTS: We
      summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML
      based format for representing biochemical reaction networks. SBML is a software
      independent language for describing models common to research in many areas of
      computational biology, including cell signaling pathways, metabolic pathways,
      gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is
      freely available from http://www.sbml.org/

PMID- 12611812
TI  - IS: a web-site for intron statistics.
AB  - SUMMARY: A web server has been established for the statistical evaluation of
      introns in various taxonomic groups and the comparison of taxonomic groups in
      terms of intron type, length, base composition, etc. The options include the
      graphic analysis of splice sites and a probability test for exon-shuffling within
      the selected group. AVAILABILITY: introns.abc.hu,
      http://www.icgeb.trieste.it/introns

PMID- 12611811
TI  - 3MOTIF: visualizing conserved protein sequence motifs in the protein structure
      database.
AB  - SUMMARY: 3MOTIF is a web application that visually maps conserved sequence motifs
      onto three-dimensional protein structures in the Protein Data Bank (PDB; Berman
      et al., Nucleic Acids Res., 28, 235-242, 2000). Important properties of motifs
      such as conservation strength and solvent accessible surface area at each
      position are visually represented on the structure using a variety of color
      shading schemes. Users can manipulate the displayed motifs using the freely
      available Chime plugin. AVAILABILITY: http://motif.stanford.edu/3motif/

PMID- 12611813
TI  - Protein family annotation in a multiple alignment viewer.
AB  - SUMMARY: The Pfaat protein family alignment annotation tool is a Java-based
      multiple sequence alignment editor and viewer designed for protein family
      analysis. The application merges display features such as dendrograms, secondary
      and tertiary protein structure with SRS retrieval, subgroup comparison, and
      extensive user-annotation capabilities. AVAILABILITY: The program and source code
      are freely available from the authors under the GNU General Public License at
      http://www.pfizerdtc.com

PMID- 12611814
TI  - The European Bioinformatics Institute web site: a new view.
AB  - SUMMARY: The European Bioinformatics Institute (EBI), and outstation of the
      European Molecular Biology laboratory, has revamped its web site for the second
      time since 1997 in order to address increased user demand as well as establishing
      better uniformity and easier accessibility for the ever growing number of users
      and services it offers to the community. A GRID-like hardware infrastructure has
      been put in place to provide round the clock services in a redundant and reliable
      fashion. AVAILABILITY: http://www.ebi.ac.uk/

PMID- 12611815
TI  - Methacholine-induced airway hyperresponsiveness is dependent on Galphaq
      signaling.
AB  - Airway function in health and disease as well as in response to bronchospastic
      stimuli (i.e., irritants, allergens, and inflammatory mediators) is controlled,
      in part, by cholinergic muscarinic receptor regulation of smooth muscle. In
      particular, the dependence of airway smooth muscle contraction/relaxation on
      heterotrimeric G protein-coupled receptor signaling suggests that these events
      underlie the responses regulating airway function. Galphaq-containing G proteins
      are proposed to be a prominent signaling pathway, and the availability of
      knockout mice deficient of this subunit has allowed for an investigation of its
      potential role in airway function. Airway responses in Galphaq-deficient mice
      (activities assessed by both tracheal tension and in vivo lung function
      measurements) were attenuated relative to wild-type controls. Moreover, ovalbumin
      sensitization/aerosol challenge of Galphaq-deficient mice also failed to elicit
      an allergen-induced increase in airway reactivity to methacholine. These findings
      indicate that cholinergic receptor-mediated responses are dependent on Galphaq
      mediated signaling events and identify Galphaq as a potential target of
      preventative/intervening therapies for lung dysfunction.

PMID- 12611816
TI  - Role of clathrin- and actin-dependent endocytotic pathways in lung phospholipid
      uptake.
AB  - We evaluated the contribution of endocytotic pathways to pulmonary uptake of
      surfactant lipids from the alveolar space. Resting and stimulated 8
      bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) uptake of unilamellar
      liposomes labeled with either [(3)H]dipalmitoylphosphatidylcholine ([(3)H]DPPC)
      or 1-palmitoyl-2-[12-(7-nitro-2-1,3-benzoxadiazol-4-yl) amino] dodecanoyl
      phosphatidylcholine (NBD-PC) was studied in isolated perfused rat lungs and
      isolated type II cells. Amantadine and phenylarsine oxide, inhibitors of clathrin
      mediated endocytosis, each decreased [(3)H]DPPC uptake under resting conditions
      by approximately 40%; their combination had no additional effect. Cytochalasin D,
      an inhibitor of actin-dependent processes, reduced liposome uptake by 55% and
      potentiated the effect of either clathrin inhibitor alone. Relative inhibition
      for all agents was higher in the presence of 8-Br-cAMP. The effect of inhibitors
      was similar for liposomes labeled with [(3)H]DPPC or NBD-PC. By fluorescence
      microscopy, NBD-PC taken up by lungs was localized primarily to alveolar type II
      cells and was localized to lamellar bodies in both lungs and isolated cells.
      These studies indicate that both clathrin-mediated and actin-mediated pathways
      are responsible for endocytosis of DPPC-labeled liposomes by alveolar type II
      cells in the intact lung.

PMID- 12611817
TI  - Minimal lung and systemic responses to TNF-alpha in preterm sheep.
AB  - TNF-alpha has been associated with chorioamnionitis and the subsequent
      development of bronchopulmonary dysplasia in preterm infants. We asked whether
      bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung
      inflammation, lung maturation, and systemic effects in fetal sheep. We compared
      the responses to IL-1alpha, a cytokine known to induce these responses in preterm
      sheep. Intra-amniotic TNF-alpha caused no chorioamnionitis, no lung maturation,
      and a very small increase in inflammatory cells in the fetal lung after 5 h, 2
      days (d), and 7 d. In contrast, IL-1alpha induced inflammation and lung
      maturation. TNF-alpha given into the airways at birth increased granulocytes in
      the bronchoalveolar lavage fluid of ventilated preterm lungs and decreased the
      mRNA for surfactant protein C but did not adversely effect postnatal lung
      function. An intravascular injection of IL-1alpha caused a systemic inflammatory
      response in fetal sheep, whereas there was no fetal response to intravascular TNF
      alpha. Fetal and newborn preterm sheep are minimally responsive to TNF-alpha.
      Therefore, the presence of a mediator such as TNF-alpha in a developing animal
      does not necessarily mean that it is causing the responses anticipated from
      previous results in adult animals.

PMID- 12611818
TI  - Stem cell antigen-1 expression in the pulmonary vascular endothelium.
AB  - Although the function of the cell surface protein stem cell antigen-1 (Sca-1) has
      not been identified, expression of this molecule is a characteristic of bone
      marrow-derived hematopoietic stem cell populations. Expression of Sca-1, however,
      is not restricted to hematopoietic tissue. By RT-PCR and Western analysis, we
      found that Sca-1 is expressed in the adult mouse lung. Sca-1 immunohistochemistry
      revealed a linear staining pattern on the endothelial surface of large and small
      pulmonary arteries and veins and alveolar capillaries. Expression of Sca-1 in the
      pulmonary endothelium was confirmed by dual fluorescent microscopy on lung
      sections and by fluorescence-activated cell sorting analysis of digested lung
      tissue; each of these methods showed colocalization with the endothelial marker
      platelet/endothelial cell adhesion molecule-1. In the kidney, Sca-1 expression
      was also noted in large vessels, but, in contrast to the lung, was not observed
      in capillaries. Overall, our data indicate that Sca-1 expression helps define the
      surface phenotype of endothelial cells throughout the pulmonary vasculature.

PMID- 12611819
TI  - Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is
      endothelium dependent.
AB  - The main aim of this study was to determine the effects of endothelium removal on
      tension and intracellular Ca(2+) ([Ca(2+)](i)) during hypoxic pulmonary
      vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and
      mesenteric arteries (MA) were mounted on myographs and loaded with the Ca(2+)
      sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin
      F(2alpha), and the effects of hypoxia were examined. HPV in isolated IPA
      consisted of a transient constriction superimposed on a second sustained phase.
      Only the latter phase was abolished by endothelial denudation. However, removal
      of the endothelium had no effect on [Ca(2+)](i) at any point during HPV. The
      endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although
      constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced
      an initial transient rise in tension and [Ca(2+)](i), followed by vasodilatation
      and a fall in [Ca(2+)](i) to (but not below) prehypoxic levels. These results are
      consistent with sustained HPV being mediated by an endothelium-derived
      constrictor factor that is distinct from endothelin-1 and that elicits
      vasoconstriction via Ca(2+) sensitization.

PMID- 12611820
TI  - Genetic epidemiology of schizophrenia: phenotypes, risk factors, and reproductive
      behavior.

PMID- 12611821
TI  - Defining clinical phenotypes of juvenile mania.
AB  - OBJECTIVE: The authors suggest criteria for a range of narrow to broad phenotypes
      of bipolar disorder in children, differentiated according to the characteristics
      of the manic or hypomanic episodes, and present methods for validation of the
      criteria. METHOD: Relevant literature describing bipolar disorder in both
      children and adults was reviewed critically, and the input of experts was sought.
      RESULTS: Areas of controversy include whether the diagnosis of bipolar disorder
      should require clearly demarcated affective episodes and, if so, of what
      duration, and whether specific hallmark symptoms of mania should be required for
      the diagnosis. The authors suggest a phenotypic system of juvenile mania
      consisting of a narrow phenotype, two intermediate phenotypes, and a broad
      phenotype. The narrow phenotype is exhibited by patients who meet the full DSM-IV
      diagnostic criteria for hypomania or mania, including the duration criterion, and
      also have hallmark symptoms of elevated mood or grandiosity. The intermediate
      phenotypes include 1) hypomania or mania not otherwise specified, in which the
      patient has clear episodes and hallmark symptoms, but the episodes are between 1
      and 3 days in duration, and 2) irritable hypomania or mania, in which the patient
      has demarcated episodes with irritable, but not elevated, mood. The broad
      phenotype is exhibited by patients who have a chronic, nonepisodic illness that
      does not include the hallmark symptoms of mania but shares with the narrower
      phenotypes the symptoms of severe irritability and hyperarousal. CONCLUSIONS: The
      presence of distinct episodes and hallmark symptoms can be used to differentiate
      clinical phenotypes of juvenile mania. The utility and validity of this system
      can be tested in subsequent research.

PMID- 12611822
TI  - Concomitant psychotropic medication for youths.
AB  - OBJECTIVE: This study reviewed the clinical research and practice literature
      relating to the prevalence and patterns of concomitant psychotropic medication
      given to youths with emotional and behavioral disorders. METHOD: A MEDLINE search
      from 1996 through spring 2002, including a review of references from relevant
      published articles and reports, was undertaken to identify available information
      on concomitant psychotropic medication for youths. RESULTS: The data supporting
      concomitant psychotropic medication for youths are almost exclusively based on
      case reports and small-scale, nonblind assessments. In the mid-1990s, over 20% of
      outpatient youths treated in community mental health centers and over 40% of
      youths treated in inpatient psychiatric facilities were given concomitant
      psychotropic medication. The rate has since increased. Psychiatrists more than
      primary care physicians prescribe concomitant psychotropic medication, and they
      show great variability in their prescribing habits. Youths with aggressive
      behavior, male gender, severe emotional illness, and disabling social
      maladjustment are most likely to receive concomitant psychotropic medication.
      CONCLUSIONS: Substantive systematic evidence is needed to clarify this
      increasingly common, inadequately researched child psychopharmacologic practice.

PMID- 12611823
TI  - Acute porphyrias: a case report and review.

PMID- 12611825
TI  - Fertility of patients with schizophrenia, their siblings, and the general
      population: a cohort study from 1950 to 1959 in Finland.
AB  - OBJECTIVE: Genetic factors are the most important risk factors for schizophrenia.
      However, despite the fact that patients with schizophrenia have significantly
      fewer offspring than the general population, schizophrenia persists. The authors
      investigated whether the siblings of patients with schizophrenia produce more
      offspring, thereby compensating for the low fertility of the affected
      individuals. METHOD: From all 870,093 individuals born in Finland from 1950 to
      1959, the authors determined how many had schizophrenia or were siblings of
      schizophrenia patients and how many offspring they had. The population data were
      obtained from the Population Register Center of Finland, and the National
      Hospital Discharge Register was used to identify all persons who had been
      hospitalized because of schizophrenia. Appropriate regression models were used to
      model age at the birth of the first child, number of children, and proportion of
      males among offspring. RESULTS: Of the total population, 1.3% were patients with
      schizophrenia, and 2.8% were their siblings. The mean number of offspring among
      female siblings was slightly but significantly higher than among women in the
      general population (1.89 versus 1.83), while the opposite was true for the male
      siblings (1.57 versus 1.65 among men in the general population). The mean number
      of offspring among patients with schizophrenia was 0.83 for women and 0.44 for
      men. CONCLUSIONS: Lower than average fertility among patients with schizophrenia
      is not compensated for by higher fertility among their siblings. Thus, the
      persistence of schizophrenia in the general population is not explained by this
      simple evolutionary mechanism.

PMID- 12611826
TI  - Do hypertension and diuretic treatment in pregnancy increase the risk of
      schizophrenia in offspring?
AB  - OBJECTIVE: Diuretics prescribed after the first trimester for treatment of
      hypertension in pregnant women may interfere with normal plasma volume expansion
      and cause volume depletion. The authors hypothesized that prenatal exposure to
      diuretics and maternal hypertension might disrupt fetal neurodevelopment and
      increase the risk of schizophrenia in offspring. METHOD: Using data from the
      Copenhagen Perinatal Cohort of individuals born between 1959 and 1961, the
      authors studied the relationship of maternal hypertension and diuretic treatment
      during pregnancy with the risk of schizophrenia (ICD-8 code 295) in the
      offspring. Prenatal medical information was linked to the Danish National
      Psychiatric Register. The effects of maternal hypertension and diuretic treatment
      were adjusted for the maternal history of schizophrenia, social status of the
      family breadwinner, mother's age, and concomitant drug treatment during
      pregnancy. RESULTS: In a risk set of 7,866 individuals, 84 cases of schizophrenia
      were found (1.1% prevalence). Logistic multiple regression analysis identified
      the following independent risk factors: maternal hypertension (odds ratio=1.69
      [95% CI=1.02-2.80]), diuretic treatment in the third trimester (odds ratio=2.55
      [95% CI=1.21-5.37]), and maternal schizophrenia (odds ratio=11.12 [95% CI=4.60
      29.91]). Prenatal exposure to both hypertension and diuretic treatment in the
      third trimester conferred a 4.01-fold (95% CI=1.41-11.40) elevated risk.
      CONCLUSIONS: Children of mothers with hypertension in pregnancy plus diuretic
      treatment in the third trimester were at significantly increased risk of
      developing schizophrenia. In pregnancies complicated by hypertension, diuretics
      may interfere with aspects of fetal neurodevelopment and thus increase the
      vulnerability of offspring to the development of schizophrenia later in life.

PMID- 12611827
TI  - Association between a functional catechol O-methyltransferase gene polymorphism
      and schizophrenia: meta-analysis of case-control and family-based studies.
AB  - OBJECTIVE: There is strong evidence for a genetic contribution to schizophrenia,
      but efforts to identify susceptibility genes have been largely unsuccessful
      because of the low power of individual studies. The authors' goal was to evaluate
      the collective evidence for an association between the Val158/108Met polymorphism
      of the catechol O-methyltransferase (COMT) gene and schizophrenia. METHOD: They
      performed separate meta-analyses of existing case-control and family-based
      association studies. RESULTS: Overall, case-control studies showed no indication
      of an association between either allele and schizophrenia, and family-based
      studies found modest evidence implicating the Val allele in schizophrenia risk.
      The pooled analyses of studies from diverse geographical regions may have
      obscured ethnic differences in patterns of genetic risk for schizophrenia.
      Stratification of the studies by ethnicity of the subjects yielded evidence for
      an association with the Val allele in case-control studies of European samples
      and, especially, in family-based studies of European samples. Case-control and
      family-based studies of Asian samples produced mixed results and, overall, little
      evidence for association. CONCLUSIONS: The results of the two types of
      association studies diverged somewhat, but the evidence from the family-based
      studies, although based on fewer reports, may be more accurate. The Val allele
      may be a small but reliable risk factor for schizophrenia for people of European
      ancestry, but the influence of this polymorphism on risk in Asian populations
      remains unclear. These results call for more family-based studies to confirm the
      association between COMT and schizophrenia in European samples and to clarify its
      contribution to risk in Asian samples. They also suggest that case-control
      studies should use methods of genomic control to avoid being confounded by
      population stratification.

PMID- 12611828
TI  - Do urbanicity and familial liability coparticipate in causing psychosis?
AB  - OBJECTIVE: The urban environment and familial liability are risk factors for
      psychotic illness, but it is not known whether a biological synergism exists
      between these two proxy causes. METHOD: The amount of biological synergism
      between familial liability (defined as a family history of delusions and/or
      hallucinations necessitating psychiatric treatment) and a five-level rating of
      population density of place of residence was estimated from the additive
      statistical interaction in a general population risk set of 5,550 individuals.
      RESULTS: Both the level of urbanicity (adjusted summary odds ratio=1.57, 95%
      CI=1.30-1.89) and familial liability (adjusted odds ratio=4.59, 95% CI=2.41-8.74)
      increased the risk for psychotic disorder, independently of each other. However,
      the effect of urbanicity on the additive scale was much larger for individuals
      with evidence of familial liability (risk difference=2.58%) than in those without
      familial liability (risk difference=0.40%). An estimated 60%-70% of the
      individuals exposed to both urbanicity and familial liability had developed
      psychotic disorder because of the synergistic action of the two proxy causes.
      CONCLUSIONS: Given that familial clustering of psychosis is thought to reflect
      the effect of shared genes, the findings support a mechanism of gene-environment
      interaction in the causation of psychosis.

PMID- 12611829
TI  - Working memory deficits and levels of N-acetylaspartate in patients with
      schizophreniform disorder.
AB  - OBJECTIVE: The authors used proton magnetic resonance spectroscopic imaging ((1)H
      MRSI) to assess potential reductions of N-acetylaspartate (a marker of neuronal
      integrity) in the hippocampal area and dorsolateral prefrontal cortex of patients
      with schizophreniform disorder. In addition, they assessed the relationship
      between N-acetylaspartate levels and working memory deficits. METHOD: Twenty-four
      patients with DSM-IV schizophreniform disorder and 24 healthy subjects were
      studied. Subjects underwent (1)H-MRSI and were given the N-back working memory
      test. RESULTS: The schizophreniform disorder patients had selective reductions of
      N-acetylaspartate ratios in the hippocampal area and the dorsolateral prefrontal
      cortex, and a positive correlation was seen between N-acetylaspartate ratios in
      the dorsolateral prefrontal cortex and performance during the 2-back working
      memory condition. CONCLUSIONS: Similar to findings reported in schizophrenia
      studies, N-acetylaspartate reductions in the hippocampal area and the
      dorsolateral prefrontal cortex were seen in patients with schizophreniform
      disorder. Moreover, the results support other evidence that neuronal pathology in
      the dorsolateral prefrontal cortex accounts for a proportion of working memory
      deficits already present at illness outset.

PMID- 12611830
TI  - Parental schizophrenia spectrum disorders in childhood-onset and adult-onset
      schizophrenia.
AB  - OBJECTIVE: Childhood onset of "adult" psychiatric disorders may be caused, in
      part, by more salient genetic risk. In this study, the rates of schizophrenia
      spectrum disorders among parents of patients with childhood-onset and adult-onset
      schizophrenia and parents of community comparison subjects were compared. METHOD:
      To assess the presence of axis I and axis II disorders associated with
      schizophrenia, parents of patients with childhood-onset schizophrenia (95
      parents), patients with adult-onset schizophrenia (86 parents), and community
      comparison subjects (123 parents) were interviewed directly by using
      semistructured instruments. Information on 19 additional parents (parents of
      childhood-onset patients, N=2; parents of adult-onset patients, N=11; parents of
      community comparison subjects, N=6) was obtained by using a family history
      interview with the same instruments. Transcribed interviews were scored by a
      rater blind to group membership, and the morbid risks for schizophrenia spectrum
      disorders in the three groups were compared. RESULTS: Parents of patients with
      childhood-onset schizophrenia had a significantly higher morbid risk of
      schizophrenia spectrum disorders (24.74%) than parents of patients with adult
      onset schizophrenia (11.35%), and parents of both patient groups had a greater
      risk of schizophrenia spectrum disorders than did parents of comparison subjects
      (1.55%). CONCLUSIONS: Parents of patients with childhood-onset schizophrenia have
      a higher rate of schizophrenia spectrum disorders than parents of patients with
      adult-onset illness. This is consistent with the hypothesis that a childhood
      onset of schizophrenia is due, at least in part, to a greater familial diathesis
      for the disorder.

PMID- 12611831
TI  - Dimensions of religiosity and their relationship to lifetime psychiatric and
      substance use disorders.
AB  - OBJECTIVE: The role of religion in mental illness remains understudied. Most
      prior investigations of this relationship have used measures of religiosity that
      do not reflect its complexity and/or have examined a small number of psychiatric
      outcomes. This study used data from a general population sample to clarify the
      dimensions of religiosity and the relationships of these dimensions to risk for
      lifetime psychiatric and substance use disorders. METHOD: Responses to 78 items
      assessing various aspects of broadly defined religiosity were obtained from 2,616
      male and female twins from a general population registry. The association between
      the resulting religiosity dimensions and the lifetime risk for nine disorders
      assessed at personal interview was evaluated by logistic regression. Of these
      disorders, five were "internalizing" (major depression, phobias, generalized
      anxiety disorder, panic disorder, and bulimia nervosa), and four were
      "externalizing" (nicotine dependence, alcohol dependence, drug abuse or
      dependence, and adult antisocial behavior). RESULTS: Seven factors were
      identified: general religiosity, social religiosity, involved God, forgiveness,
      God as judge, unvengefulness, and thankfulness. Two factors were associated with
      reduced risk for both internalizing and externalizing disorders (social
      religiosity and thankfulness), four factors with reduced risk for externalizing
      disorders only (general religiosity, involved God, forgiveness, and God as
      judge), and one factor with reduced risk for internalizing disorders only
      (unvengefulness). CONCLUSIONS: Religiosity is a complex, multidimensional
      construct with substantial associations with lifetime psychopathology. Some
      dimensions of religiosity are related to reduced risk specifically for
      internalizing disorders, and others to reduced risk specifically for
      externalizing disorders, while still others are less specific in their
      associations. These results do not address the nature of the causal link between
      religiosity and risk for illness.

PMID- 12611832
TI  - Generalized anxiety disorder in patients with major depression: is DSM-IV's
      hierarchy correct?
AB  - OBJECTIVE: DSM-III imposed a hierarchical relationship in the diagnosis of
      anxiety disorders in depressed patients, stipulating that anxiety disorders could
      not be diagnosed if their occurrence was limited to the course of a mood
      disorder. In the subsequent versions of the DSM this hierarchy was eliminated for
      all anxiety disorders except generalized anxiety disorder. The authors examined
      the validity of this remaining hierarchical relationship between mood and anxiety
      disorders. METHOD: Psychiatric outpatients with major depressive disorder (N=332)
      were evaluated with a semistructured diagnostic interview and completed paper-and
      pencil questionnaires on presentation for treatment. To study the validity of the
      DSM-IV hierarchical relationship between generalized anxiety disorder and mood
      disorders, the authors made a diagnosis of modified generalized anxiety disorder
      for patients with major depressive disorder who met all the criteria for
      generalized anxiety disorder except for the exclusion criterion. The analyses
      compared the characteristics of three nonoverlapping groups of patients with DSM
      IV major depressive disorder: 1) those with coexisting DSM-IV generalized anxiety
      disorder, 2) those with coexisting modified generalized anxiety disorder, and 3)
      those with neither DSM-IV nor modified generalized anxiety disorder. RESULTS:
      Compared to the depressed patients without generalized anxiety disorder, the
      depressed patients with DSM-IV and modified generalized anxiety disorder had
      higher levels of suicidal ideation; poorer social functioning; a greater
      frequency of other anxiety disorders, eating disorders, and somatoform disorders;
      higher scores on most subscales of a multidimensional self-report measure of DSM
      IV axis I disorders; a greater level of pathological worry; and a higher morbid
      risk for generalized anxiety disorder in first-degree family members. The two
      generalized anxiety disorder groups did not differ from each other. CONCLUSIONS:
      The findings question the validity of the DSM-IV hierarchical relationship
      between major depressive disorder and generalized anxiety disorder and suggest
      that the exclusion criterion should be eliminated.

PMID- 12611833
TI  - Capsulotomy for refractory anxiety disorders: long-term follow-up of 26 patients.
AB  - OBJECTIVE: The objective of the present study was to evaluate the long-term
      efficacy and safety of capsulotomy in patients with anxiety disorders. METHOD:
      Twenty-six patients who had undergone bilateral thermocapsulotomy were followed
      up 1 year after the procedure and after a mean of 13 years. Primary diagnoses
      were generalized anxiety disorder (N=13), panic disorder (N=8), and social phobia
      (N=5). Measures of psychiatric status included symptom rating scales and
      neuropsychological testing. Ratings were done by psychiatrists not involved in
      patient selection or postoperative treatment. A quantitative magnetic resonance
      imaging (MRI) evaluation was conducted to search for common anatomic
      denominators. Seventeen of the 23 patients who were alive at long-term follow-up
      were followed up in person, and one was interviewed by telephone; the relatives
      of these 18 patients were interviewed. RESULTS: The reduction in anxiety ratings
      was significant both at 1-year and long-term follow-up. Seven patients, however,
      were rated as having substantial adverse symptoms; the most prominent adverse
      symptoms were apathy and dysexecutive behavior. Neuropsychological performance
      was significantly worse in the patients with adverse symptoms. No common anatomic
      denominator could be found in responders in the analysis of MRI scans.
      CONCLUSIONS: Thermocapsulotomy is an effective treatment for selected cases of
      nonobsessive anxiety but may carry a significant risk of adverse symptoms
      indicating impairment of frontal lobe functioning. These findings underscore the
      importance of face-to-face assessments of adverse symptoms.

PMID- 12611834
TI  - Differential brain metabolic predictors of response to paroxetine in obsessive
      compulsive disorder versus major depression.
AB  - OBJECTIVE: Serotonin reuptake inhibitor (SRI) medications are effective in the
      treatment of both major depressive disorder and obsessive-compulsive disorder
      (OCD), but it is unknown whether the neural substrates of treatment response for
      the two disorders are the same or different. The authors sought to identify
      pretreatment cerebral glucose metabolic markers of responsiveness to SRI
      treatment in patients with OCD versus major depressive disorder and to determine
      whether the pretreatment patterns associated with improvement of OCD symptoms
      were the same as or different from those associated with improvement of major
      depressive disorder symptoms. METHOD: [(18)F]Fluorodeoxyglucose positron emission
      tomography was used to measure cerebral glucose metabolism in 27 patients with
      OCD alone, 27 with major depressive disorder alone, and 17 with concurrent OCD
      and major depressive disorder, who were all then treated with 30-60 mg/day of
      paroxetine for 8-12 weeks. Correlations were calculated between pretreatment
      regional metabolism and pre- to posttreatment changes in the severity of OCD
      symptoms, depressive symptoms, and overall functioning. RESULTS: While
      improvement of OCD symptoms was significantly correlated with higher pretreatment
      glucose metabolism in the right caudate nucleus (partial r=-0.53), improvement of
      major depressive disorder symptoms was significantly correlated with lower
      pretreatment metabolism in the amygdala (partial r=0.71) and thalamus (partial
      r=0.34) and with higher pretreatment metabolism in the medial prefrontal cortex
      and rostral anterior cingulate gyrus (Talairach coordinates: x=0, y=62, z=10)
      (z=2.91). CONCLUSIONS: These findings suggest that, although both OCD and major
      depressive disorder respond to SRIs, the two syndromes have different
      neurobiological substrates for response. Elevated activity in the right caudate
      may be a marker of responsiveness to antiobsessional treatment, while lower right
      amygdala activity and higher midline prefrontal activity may be required for
      response of depressive symptoms to treatment.

PMID- 12611835
TI  - Pregabalin in generalized anxiety disorder: a placebo-controlled trial.
AB  - OBJECTIVE: Current drug therapies for generalized anxiety disorder have
      limitations. In a controlled trial, the novel agent pregabalin was studied for
      the treatment of patients with generalized anxiety disorder. METHOD: In this
      double-blind study, patients with DSM-IV generalized anxiety disorder were
      randomly assigned to receive pregabalin (150 mg/day or 600 mg/day), lorazepam (6
      mg/day), or placebo. A 1-week placebo lead-in was followed by 4 weeks of
      treatment and then a 1-week dose taper. The primary efficacy measure was the
      Hamilton Anxiety Rating Scale score at endpoint. RESULTS: A total of 276 patients
      were randomly assigned to a treatment group and received at least one dose of
      their assigned medication. Fewer patients given lorazepam (59%, N=40 of 68)
      completed the trial than did those given placebo (73%, N=50 of 69), 600 mg/day of
      pregabalin (71%, N=50 of 70), or 150 mg/day or pregabalin (90%, N=62 of 69). The
      mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the
      patients given 150 mg/day of pregabalin (-9.2), 600 mg/day of pregabalin (-10.3),
      and lorazepam (-12.0) were significantly greater than the decrease in those given
      placebo (-6.8). As early as the week 1 observation, pregabalin significantly
      reduced the total Hamilton anxiety scale score compared with placebo. The most
      frequent adverse events reported for pregabalin and lorazepam were somnolence and
      dizziness. There were no serious adverse events reported by patients given
      pregabalin, and no withdrawal syndrome was associated with pregabalin treatment.
      CONCLUSIONS: These results indicate that pregabalin is an effective, rapidly
      acting, and safe treatment for generalized anxiety disorder. In short-term
      treatment, pregabalin does not appear to have the withdrawal symptoms associated
      with the benzodiazepines.

PMID- 12611836
TI  - Sexual orientation and self-harm in men and women.
AB  - OBJECTIVE: Recent studies of homosexual people have found higher rates of
      nonfatal suicidal behavior than among heterosexuals. The purpose of this study
      was to determine associations between self-harm and sexual orientation for men
      and women separately, defining sexual orientation by sexual attraction rather
      than by behavior. METHOD: In a birth cohort of 1,019 New Zealand young adults
      eligible to be interviewed at age 26 years, 946 participated in assessments of
      both sexual attraction and self-harm. RESULTS: Both women and men who had
      experienced same-sex attraction had higher risks of self-harm. The odds ratios
      for suicidal ideation in the past year were 3.1 for men and 2.9 for women. Odds
      ratios for ever having deliberately self-harmed were 5.5 for men and 1.9 for
      women. Men with same-sex attraction were also significantly more likely to report
      having attempted suicide. In both sexes, a greater degree of same-sex attraction
      predicted increasing likelihood of self-harm, with over one-third of men and
      women with persistent major same-sex attraction reporting this. Men with even a
      minor degree of same-sex attraction had high rates of self-harm and resulting
      physical injury. One-quarter of deliberate self-harm among men and one-sixth
      among women was potentially attributable to same-sex attraction. CONCLUSIONS:
      This study provides evidence of a link between increasing degrees of same-sex
      attraction and self-harm in both men and women, with the possibility of some
      difference between the sexes that needs to be explored further.

PMID- 12611837
TI  - Use of psychotropic medications among HIV-infected patients in the United States.
AB  - OBJECTIVE: This study describes the prevalence and pattern of use of psychotropic
      medications by HIV-positive patients receiving medical care in the United States
      and the search for possible predictors of use. METHOD: The HIV Cost and Services
      Utilization Study database was analyzed. From the estimated 231,400 HIV-positive
      patients in medical care in the contiguous United States, a probability sample of
      2,864 adults who had paid at least one visit to their medical provider in early
      1996 was selected. A representative group of 1,561 received the long form of the
      Composite International Diagnostic Interview and a questionnaire on psychotropic
      medications used during the previous 6 months; 1,489 patients (95.4%) completed
      the assessments. RESULTS: An estimated 27.2% of HIV-positive patients took
      psychotropic medications in 1996. Antidepressants were the most commonly
      prescribed drug class (20.9% of patients), followed by anxiolytics (16.7%),
      antipsychotics (4.7%), and psychostimulants (3.0%). Among patients with major
      depression or dysthymia, 43.2% reported receiving antidepressants, and 34.3%
      reported receiving anxiolytics. Psychiatric comorbidity was associated with
      greater use of psychotropics. Use of psychotropics in general, and
      antidepressants in particular, was significantly lower among African Americans
      than whites or Hispanics. Among patients with mood disorders, 61.0% of whites,
      51.4% of African Americans, and 66.7% of Hispanics reported use of antidepressant
      medications or some type of psychosocial intervention. CONCLUSIONS: Psychotropics
      were commonly used by HIV-positive patients in medical care. About half of the
      patients suffering from depressive disorders did not receive antidepressants.
      Psychotropic drug use was lower among African Americans than other ethnic groups.

PMID- 12611838
TI  - Controlled clinical trial of interpersonal psychotherapy versus parenting
      education program for depressed pregnant women.
AB  - OBJECTIVE: Antenatal depression is a significant risk factor for postpartum
      depression, with a 10%-12% prevalence in all pregnancies. Rates of depression are
      higher for pregnant women with chronic stressors, financial and housing problems,
      and inadequate social support. Despite the prevalence and associated family and
      infant morbidity, there are no controlled clinical treatment trials regarding
      this topic, to the authors' knowledge. APA has identified treatment of depression
      during pregnancy as a priority for clinical guidelines. METHOD: A 16-week
      bilingual controlled clinical trial compared a group receiving interpersonal
      psychotherapy for antepartum depression to a parenting education control program.
      Fifty outpatient antepartum women who met DSM-IV criteria for major depressive
      disorder were randomly assigned to interpersonal psychotherapy or a didactic
      parenting education program. Thirty-eight women remained in the study and were
      included in the data analysis. Depressed mood was measured with the Edinburgh
      Postnatal Depression Scale, the Beck Depression Inventory, and the Hamilton
      Depression Rating Scale. The Clinical Global Impression (CGI) and the Hamilton
      depression scale measured recovery. RESULTS: The interpersonal psychotherapy
      treatment group showed significant improvement compared to the parenting
      education control program on all three measures of mood at termination. Recovery
      criteria were met in 60% of the women treated with interpersonal psychotherapy,
      according to a CGI score of < or = 2. In addition, there was a significant
      correlation between maternal mood and mother-infant interaction. CONCLUSIONS:
      Interpersonal psychotherapy is an effective method of antidepressant treatment
      during pregnancy and should be a first-line treatment in the hierarchy of
      treatment for antepartum depression.

PMID- 12611839
TI  - Achieving board certification in psychiatry: a cohort study.
AB  - OBJECTIVE: The purpose of this study was to track the progress of a cohort of
      graduates of psychiatry residency training programs in achieving certification by
      the American Board of Psychiatry and Neurology (ABPN). These data provide a
      detailed picture of how recent graduates perform on the ABPN's examinations.
      METHOD: The subjects for this study were the 739 new candidates who sat for the
      part I examination in fall 1994. The cohort's performance on the part I and part
      II examinations was analyzed, as was the relationship between performance on the
      two examinations. RESULTS: Approximately 8 years after their first attempt at the
      part I examination, 85% of the cohort were certified, and 15% were not. The
      majority passed both the part I and part II examinations on the first attempt.
      Those who passed part I on the first attempt were more likely than those who
      failed to pass part II on the first attempt. Of the 627 who were certified at
      follow-up, 199 (32%) were also certified in one subspecialty, and 29 (5%) were
      certified in two, for a total of 257 subspecialty certificates. CONCLUSIONS: The
      results of this study suggest that most recent graduates of residency training
      programs who attempt the ABPN process are likely to become board certified, and
      the majority will do so by passing both components on the first attempt.

PMID- 12611840
TI  - Parahippocampal gray matter density in panic disorder: a voxel-based morphometric
      study.
AB  - OBJECTIVE: The authors examined possible cerebral gray matter abnormalities in
      patients with panic disorder. METHOD: Gray matter concentration in 18 panic
      disorder outpatients and 18 healthy subjects was compared by using a voxel-based
      morphometry approach. RESULTS: Gray matter density of the left parahippocampal
      gyrus was significantly lower in patients with panic disorder compared with
      healthy subjects. CONCLUSIONS: This result provides further support for the
      involvement of the parahippocampal area in the pathophysiology of panic disorder.

PMID- 12611841
TI  - Structural brain MRI abnormalities in healthy siblings of patients with childhood
      onset schizophrenia.
AB  - OBJECTIVE: Childhood-onset schizophrenia shows progressive brain magnetic
      resonance imaging (MRI) changes during adolescence, which follow a back-to-front
      "wave." The authors' goal was to examine whether healthy siblings of patients
      with childhood-onset schizophrenia show structural brain abnormalities and the
      age-related pattern of abnormalities seen in patients with childhood-onset
      schizophrenia. METHOD: Anatomic brain MRI scans were obtained from 15
      psychiatrically healthy full siblings of 15 patients with childhood-onset
      schizophrenia and from 32 matched community volunteers. Automated measures were
      used to compare total and regional brain volumes of the siblings and volunteers.
      RESULTS: Siblings of patients with childhood-onset schizophrenia had smaller
      total cerebral volume and total, frontal, and parietal gray matter volumes than
      volunteers. When divided into younger and older groups, younger siblings had
      smaller parietal gray matter volumes and older siblings showed trends for smaller
      total and frontal gray matter volumes. CONCLUSIONS: Healthy siblings of patients
      with childhood-onset schizophrenia share brain MRI abnormalities with the
      patients that may follow a similar pattern of progression. Developmental brain
      abnormalities in childhood-onset schizophrenia may thus be genetic trait markers.

PMID- 12611842
TI  - Inferior frontal white matter anisotropy and negative symptoms of schizophrenia:
      a diffusion tensor imaging study.
AB  - OBJECTIVE: The purpose of this study was test the hypothesis that abnormalities
      of inferior frontal white matter are related to the negative symptoms of
      schizophrenia. METHOD: Fractional anisotropy of white matter tracts in the
      prefrontal area of 10 schizophrenic patients was determined by diffusion tensor
      imaging. Patients were also assessed for severity of negative symptoms by using
      the Schedule for the Assessment of Negative Symptoms (SANS). RESULTS: Inferior
      frontal white matter fractional anisotropy was significantly inversely correlated
      with the SANS global ratings of negative symptoms. CONCLUSIONS: These data, while
      preliminary, suggest that impaired white matter integrity in the inferior frontal
      region may be associated with the severity of negative symptoms in schizophrenia.

PMID- 12611843
TI  - Psychotic depression and mortality.
AB  - OBJECTIVE: Major depressive disorder is associated with elevated mortality rates
      that increase with the severity of depression. The authors hypothesized that
      patients with psychotic depression would have higher mortality rates than
      patients with nonpsychotic depression. METHOD: Survival analytic techniques were
      used to compare the vital status of 61 patients with psychotic major depression
      with that of 59 patients with nonpsychotic major depression up to 15 years after
      hospital admission. Medical status was assessed with the Cumulative Illness
      Rating Scale. Dexamethasone suppression test (DST) data were available for 101
      patients. RESULTS: The mortality rate for subjects with psychotic depression was
      significantly greater than that for those with nonpsychotic depression, with 41%
      versus 20%, respectively, dying within 15 years after hospital admission. A
      proportional hazards model with age and medical status entered as covariates
      confirmed a significantly higher mortality rate in patients with psychotic
      depression (hazards ratio=2.31). A positive DST result was associated with
      psychotic depression but was not related to vital status. CONCLUSIONS: Patients
      with psychotic depression have a two-fold greater risk of death than do patients
      with severe, nonpsychotic major depression.

PMID- 12611844
TI  - Increased cortical GABA concentrations in depressed patients receiving ECT.
AB  - OBJECTIVE: Reduced gamma-aminobutyric acid (GABA) concentrations have been
      reported in the plasma, CSF, and cortex of depressed subjects. Of interest is
      that ECT, one of the most effective treatments for severe refractory depression,
      produces considerable anticonvulsant effects that may be related to increased
      GABAergic transmission. The purpose of this study was to determine if cortical
      GABA concentrations increase following a course of ECT. METHOD: Occipital cortex
      GABA concentrations in eight depressed patients were measured by using proton
      magnetic resonance spectroscopy before and after a course of ECT. RESULTS: A
      significant increase in occipital cortex GABA concentrations was seen following
      ECT treatment of depression. CONCLUSIONS: Occipital cortex GABA concentrations
      increase two-fold following ECT. This suggests possible GABAergic involvement in
      ECT's mechanism of anticonvulsant and antidepressant actions.

PMID- 12611845
TI  - Association of comorbid posttraumatic stress disorder and major depression with
      greater risk for suicidal behavior.
AB  - OBJECTIVE: Posttraumatic stress disorder (PTSD) increases the risk of suicidal
      behavior; a major depressive episode also increases the risk for suicidal
      behavior. The authors' goal was to examine the effect of comorbid PTSD and major
      depressive episode on suicidal behavior. METHOD: Inpatients with a diagnosis of
      major depressive episode (N=156) were assessed for PTSD, suicidal behavior, and
      clinical risk factors for suicidal acts. RESULTS: Patients with comorbid major
      depressive episode and PTSD were more likely to have attempted suicide, and women
      with both disorders were more likely to have attempted suicide than men with both
      disorders. Cluster B personality disorder and PTSD were independently related to
      history of suicide attempts. CONCLUSIONS: The greater rate of suicide attempts
      among patients with comorbid PTSD and major depressive episode was not due to
      differences in substance use, childhood abuse, or cluster B personality
      disorders.

PMID- 12611846
TI  - The influence of cognitive impairment and behavioral dysregulation on daily
      functioning in the nursing home setting.
AB  - OBJECTIVE: The influence of psychiatric symptoms and cognitive impairment on
      daily living skills was explored in a series of nursing home residents. Three
      categories of symptoms were examined: behavioral disturbances, depression, and
      delusions. METHOD: Nursing home residents (N=69) underwent comprehensive
      psychiatric evaluations. Relationships among psychiatric symptoms, cognitive
      function, and daily living skills were assessed by using regression and
      correlation analyses. RESULTS: Cognitive decline had the greatest effect on
      functional impairment in a standard least squares model, followed by behavioral
      disturbances. Psychiatric symptoms correlated positively with each other and with
      functional impairment, and correlated inversely with cognitive functioning.
      CONCLUSIONS: Cognitive decline appears to confer the greatest burden of
      functional disability in the nursing home setting. After cognitive effects were
      accounted for, behavioral dysregulation was also associated with functional
      impairment. In conclusion, interventions to enhance cognition and ameliorate
      behavioral disturbances are important areas for future studies in long-term care.

PMID- 12611847
TI  - Treating acute stress disorder following mild traumatic brain injury.
AB  - OBJECTIVE: Acute stress disorder permits early identification of trauma survivors
      who are at risk of developing chronic posttraumatic stress disorder (PTSD). This
      study aimed to prevent PTSD in people who developed acute stress disorder after a
      mild brain injury by early provision of cognitive behavior therapy. METHOD:
      Twenty-four civilian trauma survivors with acute stress disorder were given five
      individually administered sessions of either cognitive behavior therapy or
      supportive counseling within 2 weeks of their trauma. RESULTS: Fewer patients
      receiving cognitive behavior therapy than supportive counseling met criteria for
      PTSD at a posttreatment evaluation (8% versus 58%, respectively). There were also
      fewer cases of PTSD at a 6-month follow-up evaluation among those receiving
      cognitive behavior therapy (17%) than among those receiving supportive counseling
      (58%). Patients in the cognitive behavior therapy condition displayed less
      reexperiencing and avoidance symptoms at the follow-up evaluation than patients
      receiving supportive counseling. CONCLUSIONS: These findings suggest that PTSD
      following mild brain injury can be effectively prevented with early provision of
      cognitive behavior therapy.

PMID- 12611848
TI  - Safety of quetiapine during pregnancy.

PMID- 12611849
TI  - Clozapine and tardive dyskinesia.

PMID- 12611850
TI  - Quetiapine and falsely elevated nortriptyline level.

PMID- 12611851
TI  - Comparative effectiveness of antipsychotic drugs.

PMID- 12611852
TI  - Comparative effectiveness of antipsychotic drugs.

PMID- 12611853
TI  - Comparative effectiveness of antipsychotic drugs.

PMID- 12611855
TI  - Comparative effectiveness of antipsychotic drugs.

PMID- 12611854
TI  - Comparative effectiveness of antipsychotic drugs.

PMID- 12611857
TI  - Neuroactive steroid levels in patients with panic disorder.

PMID- 12611859
TI  - Summer birth and deficit schizophrenia.

PMID- 12611861
TI  - Psychiatry and neurology.

PMID- 12611863
TI  - Psychiatry and neurology.

PMID- 12611864
TI  - Genetic linkage in schizophrenia.

PMID- 12611865
TI  - Genetic linkage in schizophrenia.

PMID- 12611866
TI  - Genetic linkage in schizophrenia.

PMID- 12611880
TI  - Molecular analysis of collagen binding by the human discoidin domain receptors,
      DDR1 and DDR2. Identification of collagen binding sites in DDR2.
AB  - The widely expressed mammalian discoidin domain receptors (DDRs), DDR1 and DDR2,
      are unique among receptor tyrosine kinases in that they are activated by the
      extracellular matrix protein collagen. Various collagen types bind to and
      activate the DDRs, but the molecular details of collagen recognition have not
      been well defined. In this study, recombinant extracellular domains of DDR1 and
      DDR2 were produced to explore DDR-collagen binding in detail. In solid phase
      assays, both DDRs bound collagen I with high affinity. DDR1 recognized collagen I
      only as a dimeric and not as a monomeric construct, indicating a requirement for
      receptor dimerization in the DDR1-collagen interaction. The DDRs contain a
      discoidin homology domain in their extracellular domains, and the isolated
      discoidin domain of DDR2 bound collagen I with high affinity. Furthermore, the
      discoidin domain of DDR2, but not of DDR1, was sufficient for transmembrane
      receptor signaling. To map the collagen binding site within the discoidin domain
      of DDR2, mutant constructs were created, in which potential surface-exposed loops
      in DDR2 were exchanged for the corresponding loops of functionally unrelated
      discoidin domains. Three spatially adjacent surface loops within the DDR2
      discoidin domain were found to be critically involved in collagen binding of the
      isolated DDR2 extracellular domain. In addition, the same loops were required for
      collagen-dependent receptor activation. It is concluded that the loop region
      opposite to the polypeptide chain termini of the DDR2 discoidin domain
      constitutes the collagen recognition site.

PMID- 12611881
TI  - Activating transcription factor 4 overexpression inhibits proliferation and
      differentiation of mammary epithelium resulting in impaired lactation and
      accelerated involution.
AB  - The basic leucine zipper containing activating transcription factors (ATFs)
      modulates the expression of growth-regulating genes. In this study, we sought to
      determine specifically the consequences of ATF4 expression on mammary gland
      development in transgenic mice. Overexpression of ATF4 severely impaired normal
      development of the mammary gland, which was associated with reduced proliferation
      and differentiation of mammary alveolar epithelium and up-regulation of p21(WAF1)
      and p27(Kip1). In addition, there was also impaired lactation accompanied by
      decreased expression of alpha-lactoalbumin, whey acidic protein, and beta-casein,
      possibly because of the down-regulation of STAT5a tyrosine phosphorylation.
      Mammary gland involution in ATF4-transgenic mice was accelerated, compared with
      wild type littermates by whole mount analysis. In addition, day 18 of lactation
      in transgenic mice was phenotypically equivalent to day 3 of involution in wild
      type mice, as determined by the TUNEL assay and expression of Bax. The
      concentration of the proapoptotic molecule caspase-3 was increased during
      lactation in ATF4-transgenic animal. Mammary glands from ATF4-transgenic mice
      also showed significant nuclear translocation of activated STAT3 and up
      regulation of one of its target genes, insulin-like growth factor-binding protein
      5, which is thought to facilitate apoptosis by sequestering insulin-like growth
      factor. Together, these findings suggest that ATF4 may play a role during mammary
      gland development and that down-regulation of ATF4 may be important for the onset
      of involution in the mammary gland.

PMID- 12611882
TI  - Mitochondrially localized active caspase-9 and caspase-3 result mostly from
      translocation from the cytosol and partly from caspase-mediated activation in the
      organelle. Lack of evidence for Apaf-1-mediated procaspase-9 activation in the
      mitochondria.
AB  - Active caspase-9 and caspase-3 have been observed in the mitochondria, but their
      origins are unclear. Theoretically, procaspase-9 might be activated in the
      mitochondria in a cytochrome c/Apaf-1-dependent manner, or activated caspase-9
      and -3 may translocate to the mitochondria, or the mitochondrially localized
      procaspases may be activated by the translocated active caspases. Here we present
      evidence that the mitochondrially localized active caspase-9 and -3 result mostly
      from translocation from the cytosol (into the intermembrane space) and partly
      from caspase-mediated activation in the organelle rather than from the Apaf-1
      mediated activation. Apaf-1 localizes exclusively in the cytosol and, upon
      apoptotic stimulation, translocates to the perinuclear area but not to the
      mitochondria. In most cases, the mitochondrially localized procaspase-9 and -3
      are released early during apoptosis and translocate to the cytosol and/or
      perinuclear area. Cytochrome c and the mitochondrial matrix protein Hsp60 are
      also rapidly released to the cytosol early during apoptosis. Both the early
      release of proteins like cytochrome c and Hsp60 from the mitochondria as well as
      the later translocation of the active caspase-9/-3 are partially inhibited by
      cyclosporin A, an inhibitor of mitochondrial membrane permeabilization. The
      mitochondrial active caspases may function as a positive feedback mechanism to
      further activate other or residual mitochondrial procaspases, degrade
      mitochondrial constituents, and disintegrate mitochondrial functions.

PMID- 12611883
TI  - Structure of the Alzheimer's disease amyloid precursor protein copper binding
      domain. A regulator of neuronal copper homeostasis.
AB  - A major source of free radical production in the brain derives from copper. To
      prevent metal-mediated oxidative stress, cells have evolved complex metal
      transport systems. The Alzheimer's disease amyloid precursor protein (APP) is a
      major regulator of neuronal copper homeostasis. APP knockout mice have elevated
      copper levels in the cerebral cortex, whereas APP-overexpressing transgenic mice
      have reduced brain copper levels. Importantly, copper binding to APP can greatly
      reduce amyloid beta production in vitro. To understand this interaction at the
      molecular level we solved the structure of the APP copper binding domain (CuBD)
      and found that it contains a novel copper binding site that favors Cu(I)
      coordination. The surface location of this site, structural homology of CuBD to
      copper chaperones, and the role of APP in neuronal copper homeostasis are
      consistent with the CuBD acting as a neuronal metallotransporter.

PMID- 12611884
TI  - Heat shock suppresses the permeability transition in rat liver mitochondria.
AB  - Heat shock proteins inhibit apoptotic and necrotic cell death in various cell
      types. However, the specific mechanism underlying protection by heat shock
      proteins remains unclear. To test the hypothesis that heat shock proteins inhibit
      cell death by blocking opening of mitochondrial permeability transition (MPT)
      pores, mitochondria from heat-preconditioned rat livers were isolated by
      differential centrifugation. Heat shock inhibited MPT pore opening induced by 50
      microm CaCl(2) plus 5 microm HgCl(2) or 1 microm mastoparan and by 200 microm
      CaCl(2) alone. Half-maximal swelling was delayed 15 min or more after heat shock
      compared with control. Heat shock also increased the threshold of unregulated
      (Ca(2+)-independent and cyclosporin A-insensitive) MPT pore opening induced by
      higher doses of HgCl(2) and mastoparan. Heat shock treatment decreased
      mitochondrial reactive oxygen species formation by 27% but did not change
      mitochondrial respiration, membrane potential, Ca(2+) uptake, or total
      glutathione in mitochondrial and cytosolic extracts of liver. Western blot
      analysis showed that mitochondrial Hsp25 increased, whereas Hsp10, Hsp60, Hsp70,
      Hsp75, cyclophilin D, and voltage-dependent anion channel did not change after
      heat shock. These results indicate that heat shock causes resistance to opening
      of MPT pores, which may contribute to heat shock protection against cellular
      injury.

PMID- 12611885
TI  - A basic cluster determines topology of the cytoplasmic M3-M4 loop of the glycine
      receptor alpha1 subunit.
AB  - The inhibitory glycine receptor is a member of the ligand-gated ion channel
      superfamily of neurotransmitter receptors, which are composed of homologous
      subunits with four transmembrane segments (M1-M4), each. Here, we demonstrate
      that the correct topology of the glycine receptor alpha1 subunit depends
      critically on six positively charged residues within a basic cluster, RFRRKRR,
      located in the large cytoplasmic loop (designated M3-M4 loop) following the C
      terminal end of M3. Neutralization of one or more charges of this cluster, but
      not of other charged residues in the M3-M4 loop, led to an aberrant translocation
      into the endoplasmic reticulum lumen of the M3-M4 loop. However, when two of the
      three basic charges located in the ectodomain linking M2 and M3 were neutralized,
      in addition to two charges of the basic cluster, endoplasmic reticulum
      disposition of the M3-M4 loop was prevented. We conclude that a high density of
      basic residues C-terminal to M3 is required to compensate for the presence of
      positively charged residues in the M2-M3 ectodomain, which otherwise impair
      correct membrane integration of the M3 segment.

PMID- 12611886
TI  - Crystal structure of carbapenem synthase (CarC).
AB  - The proposed biosynthetic pathway to the carbapenem antibiotics proceeds via
      epimerization/desaturation of a carbapenam in an unusual process catalyzed by an
      iron- and 2-oxoglutarate-dependent oxygenase, CarC. Crystal structures of CarC
      complexed with Fe(II) and 2-oxoglutarate reveal it to be hexameric (space group
      C2221), consistent with solution studies. CarC monomers contain a double-stranded
      beta-helix core that supports ligands binding a single Fe(II) to which 2
      oxoglutarate complexes in a bi-dentate manner. A structure was obtained with l-N
      acetylproline acting as a substrate analogue. Quantum mechanical/molecular
      mechanical modeling studies with stereoisomers of carbapenams and carbapenems
      were used to investigate substrate binding. The combined work will stimulate
      further mechanistic studies and aid in the engineering of carbapenem
      biosynthesis.

PMID- 12611887
TI  - Regulation of the cyclin D3 promoter by E2F1.
AB  - We have previously demonstrated that ectopic expression of E2F1 is sufficient to
      drive quiescent cells into S phase and that E2F1 expression can contribute to
      oncogenic transformation. Key target genes in this process include master
      regulators of the cell cycle, such as cyclin E, which regulates G(1) progression,
      and cyclin A, which is required for the initiation of DNA synthesis. In the
      present work, we present novel evidence that a second G(1) cyclin, cyclin D3, is
      also potently activated by E2F1. First, an estrogen receptor-E2F1 fusion protein
      (ER-E2F1) potently activates the endogenous cyclin D3 mRNA upon treatment with 4
      hydroxytamoxifen, which induces nuclear accumulation of the otherwise cytosolic
      fusion protein. Furthermore, trans-activation of cyclin D3 by ER-E2F1 occurs even
      in the presence of the protein synthesis inhibitor cycloheximide and thus appears
      direct. Second, all of the growth-stimulatory members of the E2F family (E2F1, 
      2, and -3A) potently activate a cyclin D3 promoter reporter, whereas growth
      restraining members of the family (E2F4, -5, and -6) have little effect. Third,
      recombinant E2F1 binds with high affinity to the cyclin D3 promoter in vitro.
      Fourth, chromatin immunoprecipitation assays demonstrate that endogenous E2F1 is
      associated with the cyclin D3 promoter in vivo. Finally, mapping experiments
      localize the essential E2F regulatory element of the cyclin D3 promoter to a
      noncanonical E2F site in the promoter between nucleotides -143 and -135 relative
      to the initiating methionine codon. We conclude that in addition to cyclins E and
      A, E2F family members can also activate one member of the D-type cyclins, further
      contributing to the ability of the stimulatory E2F family members to drive
      cellular proliferation.

PMID- 12611888
TI  - The stress- and inflammatory cytokine-induced ectodomain shedding of heparin
      binding epidermal growth factor-like growth factor is mediated by p38 MAPK,
      distinct from the 12-O-tetradecanoylphorbol-13-acetate- and lysophosphatidic acid
      induced signaling cascades.
AB  - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a critical
      growth factor for a number of physiological and pathological processes. HB-EGF is
      synthesized as a membrane-anchored form (pro-HB-EGF), and pro-HB-EGF is cleaved
      at the cell surface to yield soluble HB-EGF by a mechanism called "ectodomain
      shedding." We show here that the ectodomain shedding of pro-HB-EGF in Vero cells
      is induced by various stress-inducing stimuli, including UV light, osmotic
      pressure, hyperoxidation, and translation inhibitors. The pro-inflammatory
      cytokine interleukin-1beta also stimulated the ectodomain shedding of pro-HB-EGF.
      An inhibitor of p38 MAPK (SB203580) or the expression of a dominant-negative (dn)
      form of p38 MAPK inhibited the stress-induced ectodomain shedding of pro-HB-EGF,
      whereas an inhibitor of JNK (SP600125) or the expression of dnJNK1 did not. 12-O
      Tetradecanoylphorbol-13-acetate (TPA) and lysophosphatidic acid (LPA) are also
      potent inducers of pro-HB-EGF shedding in Vero cells. Stress-induced pro-HB-EGF
      shedding was not inhibited by the inhibitors of TPA- or LPA-induced pro-HB-EGF
      shedding or by dn forms of molecules involved in the TPA- or LPA-induced pro-HB
      EGF shedding pathway. Reciprocally, SB203580 or dnp38 MAPK did not inhibit TPA-
      or LPA-induced pro-HB-EGF shedding. These results indicate that stress-induced
      pro-HB-EGF shedding is mediated by p38 MAPK and that the signaling pathway
      induced by stress is distinct from the TPA- or LPA-induced pro-HB-EGF shedding
      pathway.

PMID- 12611889
TI  - Calorimetric determination of thermodynamic parameters of reaction reveals
      different enthalpic compensations of the yeast hexokinase isozymes.
AB  - The change in enthalpy and rate constants for the reactions of yeast hexokinase
      isozymes, PI (Hxk1) and PII (Hxk2), was determined at pH 7.6 and 25 degrees C by
      isothermal titration calorimetry. The reactions were done in five buffer systems
      with enthalpy of protonation varying from -1.22 kcal/mol (phosphate) to -11.51
      kcal/mol (Tris), allowing the determination of the number of protons released
      during glucose phosphorylation. The reaction is exothermic for both isozymes with
      a small, but significant (p < 0.0001), difference in the enthalpy of reaction
      (Delta HR), with an Delta HR of -5.1 +/- 0.2 (mean +/- S.D.) kcal/mol for Hxk1,
      and an Delta HR of -3.3 +/- 0.3 (mean +/- S.D.) kcal/mol for Hxk2. The Km for ATP
      determined by ITC was very similar to those reported in the literature for both
      isozymes. The effect of NaCl and KCl, from 0 to 200 mM, showed that although the
      rate of reaction decreases with increasing ionic strength, no change in the Delta
      HR was observed suggesting an entropic nature for the ionic strength. The
      differences in Delta HR obtained here for both isozymes strongly suggest that,
      besides glucose phosphorylation, another side reaction such as ATP hydrolysis
      and/or enzyme phosphorylation is taking place.

PMID- 12611890
TI  - Spatial clustering of isozyme-specific residues reveals unlikely determinants of
      isozyme specificity in fructose-1,6-bisphosphate aldolase.
AB  - Vertebrate fructose-1,6-bisphosphate aldolase exists as three isozymes (A, B, and
      C) that demonstrate kinetic properties that are consistent with their
      physiological role and tissue-specific expression. The isozymes demonstrate
      specific substrate cleavage efficiencies along with differences in the ability to
      interact with other proteins; however, it is unknown how these differences are
      conferred. An alignment of 21 known vertebrate aldolase sequences was used to
      identify all of the amino acids that are specific to each isozyme, or isozyme
      specific residues (ISRs). The location of ISRs on the tertiary and quaternary
      structures of aldolase reveals that ISRs are found largely on the surface (24 out
      of 27) and are all outside of hydrogen bonding distance to any active site
      residue. Moreover, ISRs cluster into two patches on the surface of aldolase with
      one of these patches, the terminal surface patch, overlapping with the actin
      binding site of aldolase A and overlapping an area of higher than average
      temperature factors derived from the x-ray crystal structures of the isozymes.
      The other patch, the distal surface patch, comprises an area with a different
      electrostatic surface potential when comparing isozymes. Despite their location
      distal to the active site, swapping ISRs between aldolase A and B by multiple
      site mutagenesis on recombinant expression plasmids is sufficient to convert the
      kinetic properties of aldolase A to those of aldolase B. This implies that ISRs
      influence catalysis via changes that alter the structure of the active site from
      a distance or via changes that alter the interaction of the mobile C-terminal
      portion with the active site. The methods used in the identification and analysis
      of ISRs discussed here can be applied to other protein families to reveal
      functionally relevant residue clusters not accessible by conventional primary
      sequence alignment methods.

PMID- 12611891
TI  - The subunit composition of the human NADH dehydrogenase obtained by rapid one
      step immunopurification.
AB  - Defects of the NADH dehydrogenase complex are predominantly manifested in
      mitochondrial diseases and are significantly associated with the development of
      many late onset neurological disorders such as Parkinson's disease. Here we
      describe an immunocapture procedure for isolating this multisubunit membrane
      bound complex from human tissue. Using small amounts of immunoisolated protein,
      one-dimensional and two-dimensional gel electrophoresis, matrix-assisted laser
      desorption ionization time-of-flight (MALDI-TOF) peptide mass finger printing
      (PMF), and nanoflow liquid chromatography mass spectrometry/mass spectrometry (LC
      MS/MS), we can resolve and identify the human homologues of 42 polypeptides
      detected so far in the more extensively studied beef heart complex I. These
      polypeptides include the GRIM-19 protein, which is claimed to be involved in
      apoptosis, a polypeptide first identified by gene screening as a neuronal
      protein, as well as a protein thought to be in differentiation linked processes.
      The concordance of data from human and bovine complex I isolated by different
      procedures adds to the certainty that these novel proteins of seemingly diverse
      function are a part of complex I.

PMID- 12611893
TI  - CpG oligodeoxynucleotides modulate the osteoclastogenic activity of osteoblasts
      via Toll-like receptor 9.
AB  - Regulation of osteoclastogenesis by lipopolysaccharide (LPS) is mediated via its
      interactions with toll-like receptor 4 (TLR4) on both osteoclast- and osteoblast
      lineage cells. We have recently demonstrated that CpG oligodeoxynucleotides (CpG
      ODNs), known to mimic bacterial DNA, modulate osteoclastogenesis via interactions
      with osteoclast precursors. In the present study we characterize the interactions
      of CpG ODNs with osteoblasts, in comparison with LPS. We find that, similar to
      LPS, CpG ODNs modulate osteoclastogenesis in bone marrow cell/osteoblast co
      cultures, although in a somewhat different pattern. Osteoblasts express receptors
      for both LPS and CpG ODN (TLR4 and TLR9, respectively). The osteoblastic TLR9
      transmits signals into the cell as demonstrated by NFkappaB activation as well as
      by extracellular-regulated kinase (ERK) and p38 phosphorylation. Similar to LPS,
      CpG ODN increases in osteoblasts the expression of tumor necrosis factor (TNF)
      alpha and macrophage-colony stimulating factor (M-CSF). The two TLR ligands do
      not affect osteoprotegerin expression in osteoblasts. CpG ODN does not
      significantly affect receptor activator of NFkappaB ligand (RANKL) expression, in
      contrast to LPS, which induces the expression of this molecule. In the co
      cultures CpG ODN induces RANKL expression in osteoblasts as a result of the more
      efficient TNF-alpha induction. CpG ODN activity (modulation of
      osteoclastogenesis, gene expression, ERK and p38 phosphorylation, and nuclear
      translocation of NFkappaB) is specific, because the control oligodeoxynucleotide,
      not containing CpG, is inactive. Furthermore, these effects (unlike the LPS
      effects) are inhibited by chloroquine, suggesting a requirement for endosomal
      maturation/acidification, the classic CpG ODN mode of action. We conclude that
      CpG ODN, upon TLR9 ligation, induces osteoblasts osteoclastogenic activity.

PMID- 12611892
TI  - hsp72 inhibits focal adhesion kinase degradation in ATP-depleted renal epithelial
      cells.
AB  - Prior heat stress (HS) or the selective overexpression of hsp72 prevents
      apoptosis caused by exposure to metabolic inhibitors by protecting the
      mitochondrial membrane and partially reducing caspase-3 activation. Focal
      adhesion kinase (FAK), a tyrosine kinase, exhibits anti-apoptotic properties and
      is a potential target for degradation by caspase-3. This study tested the
      hypothesis that hsp72 interacts with FAK, preventing caspase-3-mediated
      degradation during ATP depletion. ATP depletion (5 mm NaCN and 5 mm 2-deoxy-d
      glucose in the absence of medium glucose) caused FAK degradation within 15 min.
      FAK degradation was completely prevented by a caspase-3-specific inhibitor. HS
      induced the accumulation of hsp72, increased the interaction between hsp72 and
      FAK, and significantly inhibited FAK degradation during ATP depletion. Selective
      overexpression of wild-type hsp72 (but not hsp72DeltaEEVD) reproduced the
      protective effects of HS on FAK cleavage. Purified hsp72 prevented the
      degradation of FAK by caspase-3 in vitro in a dose-dependent manner without
      affecting caspase-3 activity. Interaction between hsp72 and FAK is critical
      because both exogenous ATP and deletion of the substrate-binding site decreased
      protection of FAK by hsp72. These data indicate that FAK is an early target of
      injury in cells exposed to metabolic inhibitors and demonstrate that hsp72
      reduces caspase-3-mediated proteolysis of FAK, an anti-apoptotic protein.

PMID- 12611894
TI  - Upstream stimulatory factor represses the induction of carnitine
      palmitoyltransferase-Ibeta expression by PGC-1.
AB  - Transcriptional regulation of carnitine palmitoyltransferase-1beta (CPT-1beta) is
      coordinated with contractile gene expression through cardiac-enriched
      transcription factors, GATA4 and SRF. Metabolic modulation of CPT-1beta promoter
      activity has been described with the stimulation of gene expression by oleate
      that is mediated through the peroxisome proliferator-activated receptor (PPAR)
      pathway. The coactivator, peroxisomal proliferator-activated receptor gamma
      coactivator (PGC-1), enhances gene expression through interactions with nuclear
      hormone receptors and the myocyte enhancer factor 2 (MEF2) family. PGC-1 and
      MEF2A synergistically activate CPT-1beta promoter activity. This stimulation is
      enhanced by mutation of the E-box sequences that flank the MEF2A binding site.
      These elements bind the upstream stimulatory factors (USF1 and USF2), which
      activate transcription in CV-1 fibroblasts. However, overexpression of the USF
      proteins in myocytes depresses CPT-1beta activity and significantly reduces MEF2A
      and PGC-1 synergy. Co-immunoprecipitation studies demonstrate that PGC-1 and USF2
      proteins can physically interact. Our studies demonstrate that PGC-1 stimulates
      CPT-1beta gene expression through MEF2A. USF proteins have a novel role in
      repressing the expression of the CPT-1beta gene and modulating the induction by
      the coactivator, PGC-1.

PMID- 12611895
TI  - A soluble form of the first extracellular domain of mouse type 2beta
      corticotropin-releasing factor receptor reveals differential ligand specificity.
AB  - The heptahelical receptors for corticotropin-releasing factor (CRF), CRFR1 and
      CRFR2, display different specificities for CRF family ligands: CRF and urocortin
      I bind to CRFR1 with high affinity, whereas urocortin II and III bind to this
      receptor with very low affinities. In contrast, all the urocortins bind with high
      affinities, and CRF binds with lower affinity to CRFR2. The first extracellular
      domain (ECD1) of CRFR1 is important for ligand recognition. Here, we characterize
      a bacterially expressed soluble protein, ECD1-CRFR2beta, corresponding to the
      ECD1 of mouse CRFR2beta. The K(i) values for binding to ECD1-CRFR2beta are:
      astressin = 10.7 (5.4-21.1) nm, urocortin I = 6.4 (4.7-8.7) nm, urocortin II =
      6.9 (5.8-8.3) nm, CRF = 97 (22-430) nm, urocortin III = sauvagine >200 nm. These
      affinities are similar to those for binding to a chimeric receptor in which the
      ECD1 of CRFR2beta replaces the ECD of the type 1B activin receptor (ALK4). The
      ECD1-CRFR2beta possesses a disulfide arrangement identical to that of the ECD1 of
      CRFR1, namely Cys(45)-Cys(70), Cys(60)-Cys(103), and Cys(84)-Cys(118). As
      determined by circular dichroism, ECD1-CRFR2beta undergoes conformational changes
      upon binding astressin. These data reinforce the importance of the ECD1 of CRF
      receptors for ligand recognition and raise the interesting possibility that
      different ligands having similar affinity for the full-length receptor may,
      nevertheless, have different affinities for microdomains of the receptor.

PMID- 12611896
TI  - Evidence for a relief of repression mechanism for activation of the human
      telomerase reverse transcriptase promoter.
AB  - The transcriptional activation of human telomerase reverse transcriptase (hTERT)
      is an important step during cellular immortalization and tumorigenesis. To study
      how this activation occurs during immortalization, we have established a set of
      genetically related pre-crisis cells and their immortal progeny. As expected,
      hTERT mRNA was detected in our telomerase-positive immortal cells but not in pre
      crisis cells or telomerase-negative immortal cells. However, transiently
      transfected luciferase reporters controlled by hTERT promoter sequences exhibited
      similar levels of luciferase activity in both telomerase-positive and -negative
      cells, suggesting that the endogenous chromatin context is likely required for
      hTERT regulation. Analysis of chromatin susceptibility to DNase I digestion
      consistently identified a DNase I hypersensitivity site (DHS) near the hTERT
      transcription initiation site in telomerase-positive cells. In addition, the
      histone deacetylase inhibitor trichostatin A (TSA) induced hTERT transcription
      and also a general increase in chromatin sensitivity to DNase treatment in
      telomerase-negative cells. The TSA-induced hTERT transcription in pre-crisis
      cells was accompanied by the formation of a DHS at the hTERT promoter.
      Furthermore, the TSA-induced hTERT transcription and chromatin alterations were
      not blocked by cycloheximide, suggesting that this induction does not require de
      novo protein synthesis and that TSA induces hTERT expression through the
      inhibition of histone deacetylation at the hTERT promoter. Taken together, our
      results suggest that the endogenous chromatin environment plays a critical role
      in the regulation of hTERT expression during cellular immortalization.

PMID- 12611897
TI  - Identification of the ricin lipase site and implication in cytotoxicity.
AB  - Ricin is a heterodimeric plant toxin and the prototype of type II ribosome
      inactivating proteins. Its B-chain is a lectin that enables cell binding. After
      endocytosis, the A-chain translocates through the membrane of intracellular
      compartments to reach the cytosol where its N-glycosidase activity inactivates
      ribosomes, thereby arresting protein synthesis. We here show that ricin possesses
      a functional lipase active site at the interface between the two subunits. It
      involves residues from both chains. Mutation to alanine of catalytic serine 221
      on the A-chain abolished ricin lipase activity. Moreover, this mutation slowed
      down the A-chain translocation rate and inhibited toxicity by 35%. Lipase
      activity is therefore required for efficient ricin A-chain translocation and
      cytotoxicity. This conclusion was further supported by structural examination of
      type II ribosome-inactivating proteins that showed that this lipase site is
      present in toxic (ricin and abrin) but is altered in nontoxic (ebulin 1 and
      mistletoe lectin I) members of this family.

PMID- 12611898
TI  - C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and
      FKBP52 cause differential binding to Hsp90.
AB  - Hsp90 assembles with steroid receptors and other client proteins in association
      with one or more Hsp90-binding cochaperones, some of which contain a common
      tetratricopeptide repeat (TPR) domain. Included in the TPR cochaperones are the
      Hsp70-Hsp90-organizing protein Hop, the FK506-binding immunophilins FKBP52 and
      FKBP51, the cyclosporin A-binding immunophilin CyP40, and protein phosphatase
      PP5. The TPR domains from these proteins have similar x-ray crystallographic
      structures and target cochaperone binding to the MEEVD sequence that terminates
      Hsp90. However, despite these similarities, the TPR cochaperones have distinctive
      properties for binding Hsp90 and assembling with Hsp90.steroid receptor
      complexes. To identify structural features that differentiate binding of FKBP51
      and FKBP52 to Hsp90, we generated an assortment of truncation mutants and
      chimeras that were compared for coimmunoprecipitation with Hsp90. Although the
      core TPR domain (approximately amino acids 260-400) of FKBP51 and FKBP52 is
      required for Hsp90 binding, the C-terminal 60 amino acids (approximately 400-end)
      also influence Hsp90 binding. More specifically, we find that amino acids 400-420
      play a critical role for Hsp90 binding by either FKBP. Within this 20-amino acid
      region, we have identified a consensus sequence motif that is also present in
      some other TPR cochaperones. Additionally, the final 30 amino acids of FKBP51
      enhance binding to Hsp90, whereas the corresponding region of FKBP52 moderates
      binding to Hsp90. Taking into account the x-ray crystal structure for FKBP51, we
      conclude that the C-terminal regions of FKBP51 and FKBP52 outside the core TPR
      domains are likely to assume alternative conformations that significantly impact
      Hsp90 binding.

PMID- 12611899
TI  - Structure-function analysis of T4 RNA ligase 2.
AB  - Bacteriophage T4 RNA ligase 2 (Rnl2) exemplifies a polynucleotide ligase family
      that includes the trypanosome RNA-editing ligases and putative RNA ligases
      encoded by eukaryotic viruses and archaea. Here we analyzed 12 individual amino
      acids of Rnl2 that were identified by alanine scanning as essential for strand
      joining. We determined structure-activity relationships via conservative
      substitutions and examined mutational effects on the isolated steps of ligase
      adenylylation and phosphodiester bond formation. The essential residues of Rnl2
      are located within conserved motifs that define a superfamily of nucleotidyl
      transferases that act via enzyme-(lysyl-N)-NMP intermediates. Our mutagenesis
      results underscore a shared active site architecture in Rnl2-like ligases, DNA
      ligases, and mRNA capping enzymes. They also highlight two essential signature
      residues, Glu(34) and Asn(40), that flank the active site lysine nucleophile
      (Lys(35)) and are unique to the Rnl2-like ligase family.

PMID- 12611900
TI  - Identification of a novel human constitutive androstane receptor (CAR) agonist
      and its use in the identification of CAR target genes.
AB  - The orphan nuclear constitutive androstane receptor (CAR) is proposed to play a
      central role in the response to xenochemical stress. Identification of CAR target
      genes in humans has been limited by the lack of a selective CAR agonist. We
      report the identification of 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5
      carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) as a novel human CAR agonist
      with the following characteristics: (a) potent activity in an in vitro
      fluorescence-based CAR activation assay; (b) selectivity for CAR over other
      nuclear receptors, including the xenobiotic pregnane X receptor (PXR); (c) the
      ability to induce human CAR nuclear translocation; and (d) the ability to induce
      the prototypical CAR target gene CYP2B6 in primary human hepatocytes. Using
      primary cultures of human hepatocytes, the effects of CITCO on gene expression
      were compared with those of the PXR ligand rifampicin. The relative expression of
      a number of genes encoding proteins involved in various aspects of steroid and
      xenobiotic metabolism was analyzed. Notably, CAR and PXR activators
      differentially regulated the expression of several genes, demonstrating that
      these two nuclear receptors subserve overlapping but distinct biological
      functions in human hepatocytes.

PMID- 12611901
TI  - The K+ channel KZM1 mediates potassium uptake into the phloem and guard cells of
      the C4 grass Zea mays.
AB  - In search of K(+) channel genes expressed in the leaf of the C(4) plant Zea mays,
      we isolated the cDNA of KZM1 (for K(+) channel Zea mays 1). KZM1 showed highest
      similarity to the Arabidopsis K(+) channels KAT1 and KAT2, which are localized in
      guard cells and phloem. When expressed in Xenopus oocytes, KZM1 exhibited the
      characteristic features of an inward-rectifying, potassium-selective channel. In
      contrast to KAT1- and KAT2-type K(+) channels, however, KZM1 currents were
      insensitive to external pH changes. Northern blot analyses identified the leaf,
      nodes, and silks as sites of KZM1 expression. Following the separation of maize
      leaves into epidermal, mesophyll, and vascular fractions, quantitative real-time
      reverse transcriptase-PCR allowed us to localize KZM1 transcripts predominantly
      in vascular strands and the epidermis. Cell tissue separation and KZM1
      localization were followed with marker genes such as the bundle sheath-specific
      ribulose-1,5-bisphosphate carboxylase, the phloem K(+) channel ZMK2, and the
      putative sucrose transporter ZmSUT1. When expressed in Xenopus oocytes, ZmSUT1
      mediated proton-coupled sucrose symport. Coexpression of ZmSUT1 with the phloem
      K(+) channels KZM1 and ZMK2 revealed that ZMK2 is able to stabilize the membrane
      potential during phloem loading/unloading processes and KZM1 to mediate K(+)
      uptake. During leaf development, sink-source transitions, and diurnal changes,
      KZM1 is constitutively expressed, pointing to a housekeeping function of this
      channel in K(+) homeostasis of the maize leaf. Therefore, the voltage-dependent
      K(+)-uptake channel KZM1 seems to mediate K(+) retrieval and K(+) loading into
      the phloem as well as K(+)-dependent stomatal opening.

PMID- 12611902
TI  - Regulation of the SHP-2 tyrosine phosphatase by a novel cholesterol- and cell
      confluence-dependent mechanism.
AB  - Endothelial cells approaching confluence exhibit marked decreases in tyrosine
      phosphorylation of receptor tyrosine kinases and adherens junctions proteins,
      required for cell cycle arrest and adherens junctions stability. Recently, we
      demonstrated a close correlation in endothelial cells between membrane
      cholesterol and tyrosine phosphorylation of adherens junctions proteins. Here, we
      probe the mechanistic basis for this correlation. We find that as endothelial
      cells reach confluence, the tyrosine phosphatase SHP-2 is recruited to a low
      density membrane fraction in a cholesterol-dependent manner. Binding of SHP-2 to
      this fraction was not abolished by phenyl phosphate, strongly suggesting that
      this binding was mediated by other regions of SHP-2 beside its SH2 domains.
      Annexin II, previously implicated in cholesterol trafficking, was associated in a
      complex with SHP-2, and both proteins localized to adhesion bands in confluent
      endothelial monolayers. These studies reveal a novel, cholesterol-dependent
      mechanism for the recruitment of signaling proteins to specific plasma membrane
      domains via their interactions with annexin II.

PMID- 12611903
TI  - Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and
      phosphorylation in DNA damage checkpoint control.
AB  - BRCA1 is a tumor suppressor involved in DNA repair and damage-induced checkpoint
      controls. In response to DNA damage, BRCA1 relocalizes to nuclear foci at the
      sites of DNA lesions. However, little is known about the regulation of BRCA1
      relocalization following DNA damage. Here we show that mediator of DNA damage
      checkpoint protein 1 (MDC1), previously named NFBD1 or Kiaa0170, is a proximate
      mediator of DNA damage responses that regulates BRCA1 function. MDC1 regulates
      ataxia-telangiectasia-mutated (ATM)-dependent phosphorylation events at the site
      of DNA damage. Importantly down-regulation of MDC1 abolishes the relocalization
      and hyperphosphorylation of BRCA1 following DNA damage, which coincides with
      defective G(2)/M checkpoint control in response to DNA damage. Taken together
      these data suggest that MDC1 regulates BRCA1 function in DNA damage checkpoint
      control.

PMID- 12611904
TI  - Structural and functional properties of human plasma high density-sized
      lipoprotein containing only apoE particles.
AB  - To investigate the metabolism of HDL-apolipoprotein E (apoE) particles in human
      plasma, we isolated a fraction of plasma HDL-apoEs that lack apoA-I (HDL-LpE)
      from subjects with apoE3/3 phenotype by immunoaffinity. Plasma HDL-LpE had a
      particle size ranging from 9 nm to 18.5 nm in diameter and was characterized by
      two-dimensional nondenaturing gradient gel electrophoresis as having either gamma
      , prebeta1-, prebeta2-, or alpha-electrophoretic mobility. HDL-LpE was also
      present in the medium of cultured human hepatoma cell lines and monocyte-derived
      macrophages. The majority of apoE3 was found as a monomeric form in HDL-LpE and
      floated at density d > 1.21 g/ml. Plasma levels of HDL-LpE in normolipidemic,
      CETP-deficient, and ABCA1-deficient subjects were 0.72 +/- 0.15 mg/dl (n = 12),
      1.77 +/- 0.75 mg/dl (n = 3), and 0.55 +/- 0.11 mg/dl (n = 3), respectively. The
      ratio of HDL-apoE containing apoA-I to HDL-LpE was significantly higher 4 h after
      a fat load, representing a 35 +/- 9% increase (n = 3). Isolated plasma HDL-LpE3
      was as effective as apoE3, reconstituted HDL particles, or apoA-I in promoting
      cellular cholesterol efflux. These results demonstrate that 1) plasma HDL-LpE may
      have hepatogenous and macrophagic origins; 2) HDL-LpE was preserved even with
      large reductions in apoA-I-containing lipoproteins; 3) HDL-LpE was active in the
      transfer of apoE to triglyceride-rich lipoproteins, and 4) HDL-LpEs efficiently
      take up cell-derived cholesterol.

PMID- 12611905
TI  - Characterization of the long pentraxin PTX3 as a TNFalpha-induced secreted
      protein of adipose cells.
AB  - Exposure of preadipocytes to long-chain fatty acids induces the expression of
      several markers of adipocyte differentiation. In an attempt to identify novel
      genes and proteins that are regulated by fatty acids in preadipocytes, we
      performed a substractive hybridization screening and identified PTX3, a protein
      of the pentraxin family. PTX3 mRNA expression is transient during adipocyte
      differentiation of clonal cell lines and is absent in fully differentiated cells.
      Stable overexpression of PTX3 in preadipocytes has no effect on adipocyte
      differentiation. In line with this, PTX3 mRNA is expressed in the stromal
      vascular fraction of adipose tissue, but not in the adipocyte fraction; however,
      in 3T3-F442A adipocytes, the PTX3 gene can be reinduced by tumor necrosis factor
      alpha (TNFalpha) in a dose-dependent manner. This effect is accompanied by PTX3
      protein secretion from both 3T3-F442A adipocytes and explants of mouse adipose
      tissue. PTX3 mRNA levels are found to be higher in adipose tissue of genetically
      obese mice versus control mice, consistent with their increased TNFalpha levels.
      In conclusion, PTX3 appears as a TNFalpha-induced protein that provides a new
      link between chronic low-level inflammatory state and obesity.

PMID- 12611906
TI  - A missense mutation in the Abcg5 gene causes phytosterolemia in SHR, stroke-prone
      SHR, and WKY rats.
AB  - Sitosterolemia is an autosomal recessive disorder caused by mutations in the
      ABCG5 or ABCG8 half-transporter genes. These mutations disrupt the mechanism that
      distinguishes between absorbed sterols and is most prominently characterized by
      hyperabsorption and impaired biliary elimination of dietary plant sterols.
      Sitosterolemia patients retain 15-20% of dietary plant sterols, whereas normal
      individuals absorb less than 1-5%. Normotensive Wistar Kyoto inbred (WKY inbred),
      spontaneously hypertensive rat (SHR), and stroke-prone spontaneously hypertensive
      rat (SHRSP) strains also display increased absorption and decreased elimination
      of dietary plant sterols. To determine if the genes responsible for
      sitosterolemia in humans are also responsible for phytosterolemia in rats, we
      sequenced the Abcg5 and Abcg8 genes in WKY inbred, SHR, and SHRSP rat strains.
      All three strains possessed a homozygous guanine-to-thymine transversion in exon
      12 of the Abcg5 gene that results in the substitution of a conserved glycine
      residue for a cysteine amino acid in the extracellular loop between the fifth and
      sixth membrane-spanning domains of the ATP binding cassette half-transporter,
      sterolin-1. The identification of this naturally occurring mutation confirms that
      these rat strains are important animal models of sitosterolemia in which to study
      the mechanisms of sterol trafficking.

PMID- 12611907
TI  - Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity
      associated with apoB-containing lipoproteins.
AB  - Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme
      associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and
      primarily with LDL. A small proportion of enzymatic activity is also associated
      with HDL. Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with
      HDL. The effect of fenofibrate on PAF-AH and PON1 activities in patients with
      dyslipidemias of Types IIA, IIB, and IV were studied. Fenofibrate reduced plasma
      PAF-AH activity in all patient groups. In Type IIA patients, this reduction was
      mainly due to a fall in enzyme activity associated with the dense LDL subspecies,
      whereas in Type IIB and Type IV patients, it was due to the decrease in PAF-AH
      activity associated with both the VLDL+IDL and dense LDL subspecies. Drug therapy
      in Type IIB and Type IV patients significantly increased the HDL-associated PAF
      AH activity due to the increase in enzyme activity associated with the HDL-3c
      subfraction. Fenofibrate did not affect serum PON1 activities toward paraoxon and
      phenylacetate in either patient group. The fenofibrate-induced elevation of HDL
      associated PAF-AH activity in dyslipidemic patients of Type IIB and Type IV, as
      well as the reduction in enzyme activity associated with atherogenic apoB
      containing lipoproteins in all patient groups, may represent a new and important
      antiatherogenic effect of this potent lipid-modulating agent.

PMID- 12611908
TI  - Effect of ursodeoxycholic acid on cholesterol absorption and metabolism in
      humans.
AB  - Qualitative and quantitative changes in intraluminal bile acid composition may
      alter cholesterol absorption and synthesis and LDL receptor expression. In a
      randomized crossover design outpatient study, 12 adults aged 24-36 years took 15
      mg/kg/day ursodeoxycholic acid (UDCA) or no bile acid supplement (control) for 20
      days while being fed a controlled diet (AHA Step II). A liquid meal of defined
      composition was then given and luminal samples collected. Cholesterol absorption
      and cholesterol fractional synthetic rate (FSR) were assessed by stable isotopic
      methods. With UDCA treatment, bile was enriched significantly (P < 0.0001) to
      40.6 +/- 2.6% (mean +/- SEM) compared with 2.2 +/- 2.6% for controls. Regardless,
      plasma total, HDL, and LDL cholesterol were unchanged with UDCA treatment.
      Intraluminal cholesterol solubilized in the aqueous phase during the entire
      collection was decreased (P = 0.012) in UDCA-treated subjects (101.0 +/- 7.2
      mg/ml/120 min) compared with controls (132.5 +/- 7.2 mg/ml/120 min.). Percent
      micellar cholesterol was increased in UDCA-treated versus controls after meal
      ingestion. No changes were found in cholesterol absorption, FSR, or LDL receptor
      mRNA with UDCA treatment compared with controls. Thus, despite marked enrichment
      in luminal bile with UDCA and decreased cholesterol solubilization, no
      differences in cholesterol absorption or metabolism are found when diet and
      genetic differences in absorption are carefully controlled.

PMID- 12611909
TI  - Trafficking defects in endogenously synthesized cholesterol in fibroblasts,
      macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice.
AB  - Niemann-Pick type C1 disease (NPC1) is an inherited neurovisceral lipid storage
      disorder, hallmarked by the intracellular accumulation of unesterified
      cholesterol and glycolipids in endocytic organelles. Cells acquire cholesterol
      through exogenous uptake and endogenous biosynthesis. NPC1 participation in the
      trafficking of LDL-derived cholesterol has been well studied; however, its role
      in the trafficking of endogenously synthesized cholesterol (endoCHOL) has
      received much less attention. Previously, using mutant Chinese hamster ovary
      cells, we showed that endoCHOL moves from the endoplasmic reticulum (ER) to the
      plasma membrane (PM) independent of NPC1. After arriving at the PM, it moves
      between the PM and internal compartments. The movement of endoCHOL from internal
      membranes back to the PM and the ER for esterification was shown to be defective
      in NPC1 cells. To test the generality of these findings, we have examined the
      trafficking of endoCHOL in four different physiologically relevant cell types
      isolated from wild-type, heterozygous, and homozygous BALB/c NPC1NIH mice. The
      results show that all NPC1 homozygous cell types (embryonic fibroblasts,
      peritoneal macrophages, hepatocytes, and cerebellar glial cells) exhibit partial
      trafficking defects, with macrophages and glial cells most prominently affected.
      Our findings suggest that endoCHOL may contribute significantly to the overall
      cholesterol accumulation observed in selective tissues affected by Niemann-Pick
      type C disease.

PMID- 12611910
TI  - ZNF202 is inversely regulated with its target genes ABCA1 and apoE during
      macrophage differentiation and foam cell formation.
AB  - The zinc finger protein ZNF202 is a transcriptional repressor that binds to
      promoter elements predominantly found in genes involved in lipid metabolism. Here
      we demonstrate that ZNF202 mRNA expression is inversely correlated with ATP
      binding cassette A1 (ABCA1), ABCG1, and apolipoprotein E (apoE) in human
      monocytes. Upregulation of ABCA1, ABCG1, and apoE expression during monocyte
      differentiation and foam cell formation was accompanied by a simultaneous
      downregulation of both ZNF202 mRNA isoforms m1 and m3. Conversely, deloading of
      macrophage foam cells with HDL3 caused upregulation of ZNF202 mRNA. To further
      characterize the transcriptional regulation of the ZNF202 gene, comparative
      genomic sequence analysis and reporter gene assays were performed. The ZNF202
      core promoter region resides within 247 bp upstream of the transcription
      initiation site and is highly active in THP-1 monocytes, yet downregulated upon
      macrophage differentiation. Using site-directed mutagenesis, we show that two
      highly conserved transcription factor binding sites, a GC-box and an Ets-binding
      motif, are required for ZNF202 gene expression. Furthermore, electrophoretic
      mobility shift assays demonstrate in vitro binding of PU.1 and GC-box binding
      proteins to the ZNF202 proximal promoter. We conclude that the inversely
      correlated transcriptional activity of ZNF202 and its target genes during
      macrophage differentiation may reflect a direct regulatory interdependence and
      thus provide further evidence for ZNF202 as an important gatekeeper of lipid
      efflux.

PMID- 12611911
TI  - Hepatic lipase mediates an increase in selective uptake of HDL-associated
      cholesteryl esters by cells in culture independent from SR-BI.
AB  - Scavenger receptor class B type I (SR-BI) mediates the selective uptake of HDL
      cholesteryl esters (CEs) by the liver. Hepatic lipase (HL) promotes this lipid
      uptake independent from lipolysis. The role of SR-BI in this HL-mediated increase
      in selective CE uptake was explored. Baby hamster kidney (BHK) cells were
      transfected with the SR-BI cDNA yielding cells with SR-BI expression, whereas no
      SR-BI was detected in control cells. These cells were incubated in medium
      containing 125I [3H]cholesteryl oleyl ether-labeled HDL3 (d = 1.125-1.21 g/ml)
      and HL was absent or present. Tetrahydrolipstatin (THL) blocked lipolysis. In
      control BHK cells and in BHK cells with SR-BI, HDL3 selective CE uptake (3H-125I)
      was detectable and SR-BI promoted this uptake. In both cell types, HL mediated an
      increase in selective CE uptake from HDL3. Quantitatively, this HL effect was
      similar in control BHK cells and in BHK cells with SR-BI. These results suggest
      that HL promotes selective uptake independent from SR-BI. To investigate the role
      of cell surface proteoglycans on the HL-mediated HDL3 uptake, proteoglycan
      deficiency was induced by heparinase digestion. Proteoglycan deficiency decreased
      the HL-mediated promotion of selective CE uptake. In summary, the stimulating HL
      effect on HDL selective CE uptake is independent from SR-BI and lipolysis.
      Proteoglycans are a requisite for the HL action on selective uptake. Results
      suggest that (a) pathway(s) distinct from SR-BI mediate(s) selective CE uptake
      from HDL.

PMID- 12611912
TI  - Acute hypoxia occludes hTREK-1 modulation: re-evaluation of the potential role of
      tandem P domain K+ channels in central neuroprotection.
AB  - The human tandem P domain K+ channel hTREK-1 (KCNK2) is distributed widely
      through the CNS. Here, whole-cell patch clamp recordings were employed to
      investigate the effects of hypoxia on hTREK-1 channels stably expressed in human
      embryonic kidney cells. Acute hypoxia caused a rapid and reversible inhibition of
      whole-cell K+ current amplitudes; this was PO2 dependent with a maximal
      inhibition achieved at 60 mmHg and below. In accordance with previous studies,
      hTREK-1 current amplitudes were enhanced by arachidonic acid. This effect was
      concentration dependent, with maximal enhancement observed at a concentration of
      10 microM. Membrane deformation by the crenator trinitrophenol (to mimic cell
      swelling) or the cup former chlorpromazine (to mimic cell shrinkage) caused
      robust activation and inhibition of currents, respectively. However, current
      augmentation by either arachidonic acid or trinitrophenol was completely
      prevented during hypoxia; conversely, hypoxia blunted the inhibitory action of
      chlorpromazine. The abilities of arachidonic acid to augment currents and of
      hypoxia to completely abrogate this effect were also observed in cell-attached
      patches. Our data indicate that hypoxia interacts with hTREK-1, and occludes its
      modulation by arachidonic acid and membrane deformation. These findings also
      suggest that the potential neuroprotective role of TREK channels, which has
      recently been proposed, requires reconsideration since hTREK-1 activation is
      unlikely when ambient PO2 is below 60 mmHg - a situation which normally pertains
      in the CNS even during systemic normoxia.

PMID- 12611913
TI  - Separate mechanical processes underlie fast and slow effects of medial
      olivocochlear efferent activity.
AB  - Sound-evoked vibrations of the basilar membrane (BM) in anaesthetised guinea-pigs
      are shown to be affected over two distinct time scales by electrical stimulation
      of the medial olivocochlear efferent system: one is fast (10-100 ms), the other
      much slower (10-100 s). For low and moderate level tones near the BM's
      characteristic frequency, both fast and slow effects inhibited BM motion.
      However, fast inhibition was accompanied by phase leads, while slow inhibition
      was accompanied by phase lags. These findings are consistent with a hypothesis
      that both fast and slow effects decrease sound amplification in the cochlea.
      However, the opposing directions of the phase changes indicate that separate
      mechanical processes must underlie fast and slow effects. One plausible
      interpretation of these findings is that efferent slow effects are caused by
      outer-hair-cell stiffness decreases, while efferent fast effects are caused by
      reductions in 'negative damping'.

PMID- 12611914
TI  - Control of glutamatergic neurotransmission in the rat spinal dorsal horn by the
      nucleoside transporter ENT1.
AB  - Adenosine modulates nociceptive processing in the superficial dorsal horn of the
      spinal cord. In other tissues, membrane transporters influence profoundly the
      extracellular levels of adenosine. To investigate the putative role of nucleoside
      transporters in the regulation of excitatory synaptic transmission in the dorsal
      horn, we employed immunohistochemistry and whole-cell patch-clamp recording of
      substantia gelatinosa neurons in slices of rat spinal cord in vitro. The rat
      equilibrative nucleoside transporter (rENT1) was revealed by antibody staining to
      be abundant in neonatal and mature dorsal horn, especially within laminae I-III.
      This was confirmed by immunoblots of dorsal horn homogenate.
      Nitrobenzylthioinosine (NBMPR), a potent non-transportable inhibitor of rENT1,
      attenuated synaptically evoked EPSCs onto lamina II neurons in a concentration
      dependent manner. Application of an adenosine A1 antagonist 1,3-dipropyl-8
      cyclopentylxanthine produced a parallel rightward shift in the NBMPR
      concentration-effect curve. The effects of NBMPR were partially reversed by
      adenosine deaminase, which facilitates the metabolic degradation of adenosine.
      The modulation by NBMPR of evoked EPSCs was mimicked by exogenous adenosine or
      the selective A1 receptor agonist, 2-chloro-N6-cyclopentyl adenosine. NBMPR
      reduced the frequency but not the amplitude of spontaneous miniature EPSCs and
      increased the paired-pulse ratio of evoked currents, an effect that is consistent
      with presynaptic modulation. These data provide the first direct evidence that
      nucleoside transporters are able to critically modulate glutamatergic synaptic
      transmission.

PMID- 12611915
TI  - Force generation induced by rapid temperature jumps in intact mammalian (rat)
      skeletal muscle fibres.
AB  - We examined the tension (force) responses induced by rapid temperature jumps (T
      jumps) in electrically stimulated, intact fibre bundles (5-10 fibres, fibre
      length approximately 2 mm) isolated from a foot muscle (flexor hallucis brevis)
      of the rat; the muscle contains approximately 90 % type 2 fast fibres. In steady
      state experiments, the temperature dependence of the twitch tension was basically
      similar to that previously described from other fast muscles; the tetanic tension
      increased 3- to 4-fold in raising the temperature from approximately 2 to 35
      degrees C and the relation between the tetanic tension and the reciprocal
      absolute temperature was sigmoidal with half-maximal tension at 9.5 degrees C. A
      rapid T-jump of 3-5 degrees C was induced during a contraction by applying an
      infrared laser pulse (lambda = 1.32 micro, 0.2 ms) to the 50 microl trough
      containing the fibre bundle immersed in physiological saline. At approximately 10
      degrees C, a T-jump induced a large transient tension rise when applied during
      the rising phase of a twitch contraction, the amplitude of which decreased when
      the T-jump was delayed with respect to the stimulus; a T-jump probably perturbs
      an early step in excitation-contraction coupling. No transient increase was seen
      when a T-jump was applied during twitch relaxation. When applied during the
      plateau of a tetanic contraction a T-jump induced a tension rise to a higher
      steady tension level; the tension rise after a T-jump was 2-3 times faster than
      the corresponding phase of the initial tension rise in a tetanus. The approach to
      a new steady tension level after a T-jump was biphasic with a fast (phase 2b,
      approximately 35 s-1 at 10 degrees C) and a slow component (phase 3, < 10 s-1).
      The rates of both components increased (Q10 approximately 3) but their amplitudes
      decreased with increase of the steady temperature. These results from tetanized
      intact fibres are consistent with the thesis previously proposed from studies on
      Ca2+-activated skinned fibres, that the elementary force generation step in
      muscle is enhanced by increased temperature; the findings indicate that an
      endothermic molecular step underlies muscle force generation.

PMID- 12611916
TI  - D-Serine differently modulates NMDA receptor function in rat CA1 hippocampal
      pyramidal cells and interneurons.
AB  - The organization of the neuronal hippocampal network depends on the tightly
      regulated interaction between pyramidal cells (PCs) and interneurons (Ints). NMDA
      receptor (NMDAR) activation requires the binding of glutamate and co-activation
      of the 'glycine site'. It has been reported that D-serine is a more potent
      endogenous agonist than glycine for that site. While many studies have focused on
      NMDAR function in PCs, little is known regarding the modulation of NMDARs in
      Ints. We studied the modulatory effect of D-serine on NMDAR EPSCs in PCs and in
      stratum radiatum Ints using whole-cell patch-clamp recording in rat acute
      hippocampal slices. We found that D-serine enhances NMDAR function and
      differently modulates NMDAR currents in both cell types. The augmentation of
      NMDAR currents by D-serine was significantly larger in PCs compared with Ints.
      Moreover, we found differences in the kinetics of NMDAR currents in PCs and Ints.
      Our findings indicate that regulation of NMDAR through the 'glycine site' depends
      on the cell types. We speculate that the observed differences arise from
      assemblies of diverse NMDAR subunits. Overall, our data suggest that D-serine may
      be involved in regulation of the excitation-inhibition balance in the CA1
      hippocampal region.

PMID- 12611917
TI  - A novel signalling pathway originating in mitochondria modulates rat skeletal
      muscle membrane excitability.
AB  - Single skeletal muscle fibres from rat and cane toad were mechanically skinned
      and stimulated either electrically by initiating action potentials in the sealed
      transverse (t-) tubular system or by ion substitution causing depolarisation of
      the t-system to pre-determined levels. Depression of mitochondrial ATP-producing
      function with three diverse mitochondrial function antagonists (azide: 1-10 mM;
      oligomycin 1 microg ml-1 and carbonyl cyanide 4-trifluoromethoxyphenylhydrazone
      (FCCP) 1 microM), under conditions in which the cytosolic ATP was maintained high
      and constant, invariably reduced the excitability of rat fibres but had no
      obvious effect on the excitability of toad fibres, where mitochondria are less
      abundant and differently located. The reduction in excitability linked to
      mitochondria in rat fibres appears to be caused by depolarisation of the sealed t
      system membrane. These observations suggest that mitochondria can regulate the
      functional state of mammalian muscle cells and have important implications for
      understanding how the balance between ATP utilisation and ATP production is
      regulated at the cellular level in general and in mammalian skeletal muscle
      fibres in particular.

PMID- 12611918
TI  - Skeletal muscle dictates the fibrinolytic state after exercise training in
      overweight men with characteristics of metabolic syndrome.
AB  - While there is indisputable evidence supporting the beneficial role of aerobic
      exercise in reducing cardiovascular risk factors, there are few dose-response
      studies of this relationship. Increasingly, it is thought that the cardiovascular
      benefits of exercise are significantly influenced by adaptations within skeletal
      muscle and its vasculature. However, little is known about the molecular
      mechanisms underlying these adaptations. To address this need, we initiated a
      study utilizing longitudinal, microarray-based gene expression profiling of
      serial skeletal muscle biopsies obtained from the study of targeted risk
      reduction intervention through defined exercise (STRRIDE). STRRIDE participants
      were overweight and exhibited symptoms characteristic of the metabolic syndrome
      that typically precedes type II diabetes such as insulin resistance, abnormal
      lipids and glucose intolerance. Expression data were statistically filtered and
      sorted into exercise training-responsive clusters based on gene product
      knowledge. One such cluster included genes that promote the degradation of fibrin
      clots such as tissue plasminogen activator (t-PA), connective tissue activation
      peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein
      levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were
      subsequently shown to change significantly in both skeletal muscle and serum in
      response to exercise training. Our data show that the rigors of exercise directly
      induce fibrinolytic genes and protein cascades, both within muscle, and in the
      systemic circulation. This finding is particularly significant given that the
      metabolic syndrome is an independent risk factor for peripheral vascular disease
      and thrombotic events within the heart and brain. We conclude that aerobic
      exercise training induces both local and systemic changes in fibrinolysis and
      vascular homeostasis that are probably protective against cardiovascular disease.

PMID- 12611919
TI  - Differential structural adaptation to haemodynamics along single rat cremaster
      arterioles.
AB  - We tested the hypothesis that under physiological conditions, arterioles match
      their diameter to the level of shear stress. Haemodynamic and anatomical data
      were obtained in segments of the first-order arteriole of the rat cremaster
      muscle. Along this segment of ~10 mm in length, local blood pressure decreased
      from 68 +/- 4 mmHg upstream to 54 +/- 3 mmHg downstream (n = 5). Pulse pressure
      decreased from 8.2 +/- 1.3 mmHg upstream to 4.1 +/- 0.6 mmHg downstream. At the
      same locations, an increase in arteriolar diameter was measured in vivo, from 179
      +/- 4 microm upstream to 203 +/- 4 microm downstream (n = 10). In vitro pressure
      diameter relations of maximally dilated vessels showed that the passive diameter
      was larger in downstream than upstream segments over a 15-125 mmHg pressure range
      (n = 18). The wall stress was similar for the upstream vs. downstream location:
      266 +/- 16 vs. 260 +/- 14 mN mm-2. However, shear stress decreased from 30 +/- 5
      to 21 +/- 5 dyn cm-2 (3.0 +/- 0.5 to 2.1 +/- 0.5 N m-2; n = 4) along the artery.
      In conclusion, these results demonstrate that shear stress is not the only factor
      in determining vascular calibre. We suggest that arteriolar calibre may rather
      depend on an interplay between shear stress and the local pressure profile.

PMID- 12611920
TI  - Human skeletal muscle and erythrocyte proteins involved in acid-base homeostasis:
      adaptations to chronic hypoxia.
AB  - Chronic hypoxia is accompanied by changes in blood and skeletal muscle acid-base
      control. We hypothesized that the underlying mechanisms include altered protein
      expression of transport systems and the enzymes involved in lactate, HCO3- and H+
      fluxes in skeletal muscle and erythrocytes. Immunoblotting was used to quantify
      densities of the transport systems and enzymes. Muscle and erythrocyte samples
      were obtained from eight Danish lowlanders at sea level and after 2 and 8 weeks
      at 4100 m (Bolivia). For comparison, samples were obtained from eight Bolivian
      natives. In muscle membranes there were no changes in fibre-type distribution,
      lactate dehydrogenase isoforms, Na+,K+-pump subunits or in the lactate-H+ co
      transporters MCT1 and MCT4. The Na+-H+ exchanger protein NHE1 was elevated by 39
      % in natives compared to lowlanders. The Na+-HCO3- co-transporter density in
      muscle was elevated by 47-69 % after 2 and 8 weeks at altitude. The membrane
      bound carbonic anhydrase (CA) IV in muscle increased in the lowlanders by 39 %,
      whereas CA XIV decreased by 23-47 %. Levels of cytosolic CA II and III in muscle
      and CA I and II in erythrocytes were unchanged. The erythrocyte lactate-H+ co
      transporter MCT1 increased by 230-405 % in lowlanders and was 324 % higher in
      natives. The erythrocyte inorganic anion exchanger (Cl--HCO3- exchanger AE1) was
      increased by 149-228 %. In conclusion, chronic hypoxia induces dramatic changes
      in erythrocyte proteins, but only moderate changes in muscle proteins involved in
      acid-base control. Together, these changes suggest a hypoxia-induced increase in
      the capacity for lactate, HCO3- and H+ fluxes from muscle to blood and from blood
      to erythrocytes.

PMID- 12611921
TI  - Anaplerosis of the muscle tricarboxylic acid cycle pool during contraction: does
      size matter?

PMID- 12611923
TI  - Relative rates of anaplerotic flux in rested and contracted rat skeletal muscle
      measured by 13C NMR spectroscopy.
AB  - Flux through anaplerotic pathways in skeletal muscle has not been evaluated
      quantitatively during both rest and contraction, nor have fibre type-specific
      rates of anaplerotic flux been studied. Steady-state analysis using 13C NMR
      spectroscopy enables calculation of Y (flux rate through anaplerotic pathways
      relative to tricarboxylic acid (TCA) cycle flux). Under inhalation anaesthesia,
      [2,4,6,8-13C4]octanoate was infused into the jugular vein of the intact rat (n =
      10) and the sciatic nerve of one limb was stimulated at the voltage required to
      elicit maximal force output at 0.5 Hz. In resting muscle, Y was higher in soleus
      (0.41 +/- 0.22) versus white gastrocnemius (WG) (0.18 +/- 0.11). Y was 0.29 +/-
      0.06 in the predominantly red portion of the gastrocnemius (RG) during rest.
      During contraction, Y was similar to the resting value in soleus (0.34 +/- 0.14),
      RG (0.20 +/- 0.04) and WG (0.15 +/- 0.08); Y was higher in soleus versus both RG
      and WG during contraction. These results demonstrate: (1) relative flux through
      anaplerotic pathways is 15-41 % of TCA cycle flux at rest and during muscle
      contraction, (2) higher relative anaplerotic flux in oxidative (soleus) versus
      glycolytic muscle (WG) during rest and in slow-twitch (soleus) versus fast-twitch
      (RG and WG) muscle during contraction, and (3) relative flux through anaplerotic
      pathways is maintained in all muscle fibre types during contraction, which
      indicates that absolute rates of anaplerotic flux rise in proportion to increased
      oxidation rates during contraction. These results are consistent with a sustained
      increase in substrate entry into and exit from the TCA cycle through anaplerotic
      pathways during contraction.

PMID- 12611922
TI  - Hyperexcitability and reduced low threshold potassium currents in auditory
      neurons of mice lacking the channel subunit Kv1.1.
AB  - A low voltage-activated potassium current, IKL, is found in auditory neuron types
      that have low excitability and precisely preserve the temporal pattern of
      activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1
      potassium channel subunits, which combine in expression systems to produce
      channel tetramers with properties similar to those of IKL, including sensitivity
      to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including
      auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore
      decided to investigate how the absence of Kv1.1 affected channel properties and
      function in MNTB neurons from mice lacking Kcna1. We used the whole cell version
      of the patch clamp technique to record from MNTB neurons in brainstem slices from
      Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-)
      littermates. There was an IKL in voltage-clamped -/- MNTB neurons, but it was
      about half the amplitude of the IKL in +/+ neurons, with otherwise similar
      properties. Consistent with this, -/- MNTB neurons were more excitable than their
      +/+ counterparts; they fired more than twice as many action potentials (APs)
      during current steps, and the threshold current amplitude required to generate an
      AP was roughly halved. +/- MNTB neurons had excitability and IKL amplitudes
      identical to the +/+ neurons. The IKL remaining in -/- neurons was blocked by
      DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6
      (also DTX-sensitive). DTX increased excitability further in the already
      hyperexcitable -/- MNTB neurons, suggesting that -/- IKL limited excitability
      despite its reduced amplitude in the absence of Kv1.1 subunits.

PMID- 12611924
TI  - GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus
      muscle activity in NREM but not REM sleep.
AB  - The pharyngeal muscles, such as the genioglossus (GG) muscle of the tongue, are
      important for effective lung ventilation since they maintain an open airspace.
      Rapid-eye-movement (REM) sleep, however, recruits powerful neural mechanisms that
      can abolish GG activity, even during strong reflex respiratory stimulation by
      elevated CO2. In vitro studies have demonstrated the presence of GABAA receptors
      on hypoglossal motoneurons, and these and other data have led to the speculation
      that GABAA mechanisms may contribute to the suppression of hypoglossal motor
      outflow to the GG muscle in REM sleep. We have developed an animal model that
      allows us to chronically manipulate neurotransmission at the hypoglossal motor
      nucleus using microdialysis across natural sleep-wake states in rats. The present
      study tests the hypothesis that microdialysis perfusion of the GABAA receptor
      antagonist bicuculline into the hypoglossal motor nucleus will prevent the
      suppression of GG muscle activity in REM sleep during both room-air and CO2
      stimulated breathing. Ten rats were implanted with electroencephalogram and neck
      muscle electrodes to record sleep-wake states, and GG and diaphragm electrodes
      for respiratory muscle recording. Microdialysis probes were implanted into the
      hypoglossal motor nucleus for perfusion of artificial cerebrospinal fluid (ACSF)
      or 100 microM bicuculline during room-air and CO2-stimulated breathing (7 %
      inspired CO2). GABAA receptor antagonism at the hypoglossal motor nucleus
      increased respiratory-related GG activity during both room-air (P = 0.01) and CO2
      stimulated breathing (P = 0.007), indicating a background inhibitory GABA tone.
      However, the effects of bicuculline on GG activity depended on the prevailing
      sleep-wake state (P < 0.005), with bicuculline increasing GG activity in non-REM
      (NREM) sleep and wakefulness both in room air and hypercapnia (P < 0.01), but GG
      activity was effectively abolished in those REM periods without phasic twitches
      in the GG muscle. This abolition of GG activity in REM sleep occurred regardless
      of ACSF or bicuculline at the hypoglossal motor nucleus, or room-air or CO2
      stimulated breathing (P > 0.63). We conclude that these data in freely behaving
      rats confirm previous in vitro studies that GABAA receptor mechanisms are present
      at the hypoglossal motor nucleus and are tonically active, but the data also show
      that GABAA receptor antagonism at the hypoglossal motor nucleus does not increase
      GG muscle activity in natural REM sleep.

PMID- 12611928
TI  - Congenital abnormalities of the central nervous system.

PMID- 12611925
TI  - The coding of uniform colour figures in monkey visual cortex.
AB  - Psychophysical studies indicate that perception of the colour and brightness of a
      surface depends on neural signals evoked by the borders of the surface rather
      than its interior. The visual cortex emphasizes contrast borders, but it is
      unclear whether colour surface signals also exist, whether colour border signals
      are orientation selective or mainly non-oriented, and whether cortical processing
      tends to separate colour and form information. To address these questions we
      examined the representation of uniform colour figures by recording single neuron
      activity from areas V1 and V2 in alert macaque monkeys during behaviourally
      induced fixation. Three aspects of coding were quantified: colour, orientation
      and edge selectivity. The occurrence of colour selectivity was not correlated
      with orientation or edge selectivity. The fraction of colour-selective cells was
      the same (64 % in layers 2 and 3 of V1, 45 % in V2) for oriented and non-oriented
      cells, and for edge-selective and surface-responsive cells. Oriented cells were
      often highly selective in colour space, and about 40 % of them were selective for
      edge polarity or border ownership. Thus, contrary to the idea of feature maps,
      colour, orientation and edge polarity are multiplexed in cortical signals. The
      results from V2 were similar to those from upper-layer V1, indicating that
      cortical processing does not strive to separate form and colour information.
      Oriented cells were five times more frequent than non-oriented cells. Thus, the
      vast majority of colour-coded cells are orientation tuned. Based on response
      profiles across a 4 deg square figure, and the relative frequency of oriented and
      non-oriented cells, we estimate that the cortical colour signal is 5-6 times
      stronger for the edges than for the surface of the figure. The frequency of
      oriented colour cells and their ability to code edge polarity indicate that these
      cells play a major role in the representation of surface colour.

PMID- 12611929
TI  - Neurological and cognitive decline in adolescence.

PMID- 12611926
TI  - Pharmacologically induced enhancement of recurrent inhibition in humans: effects
      on motoneurone discharge patterns.
AB  - The aim of the present study was to investigate the effects of spinal recurrent
      inhibition on human motoneurone discharge patterns. The tonic discharge activity
      of motor unit pairs was recorded in the extensor carpi radialis (ECR) and
      abductor digiti minimi (ADM) muscles during voluntary isometric contraction.
      While undergoing continuous intravenous saline (NaCl 0.9 %) perfusion, the
      subjects were given a short lasting injection of L-acetylcarnitine (L-Ac), which
      has been found to potentiate recurrent inhibition in humans. The variability,
      synchronization and coherence of the motor unit discharges were analysed during
      four successive test periods (lasting 2-3 min each). A significant decrease in
      the inter-spike interval (ISI) coefficient of variation was observed in the
      discharge patterns of the motor units tested in the ECR and not in the ADM, which
      were not accompanied by any consistent changes in the mean ISIs of the motor unit
      activity in either muscle. The L-Ac injection also led to a significant increase
      in the synchronization in half of the motor unit pairs tested in the ECR muscle
      (n = 29), whereas no consistent changes were observed with the ADM motor units (n
      = 25). However, coherence analysis failed to reveal any consistent differences in
      the incidence of significant values of coherence spectrum between the pre
      injection and injection periods among the motor unit pairs tested with either
      saline or L-Ac injections, in either the ECR or ADM muscles. The contrasting
      effects on the variability and the synchronization of the motor unit discharges
      observed with ECR motoneurones known to undergo recurrent inhibition and with ADM
      motoneurones known to lack recurrent inhibition suggest that the drug may have
      specific effects which are mediated by an enhancement of the Renshaw cell
      activity. The decrease in the ISI variability is in line with the hypothesis that
      recurrent inhibition may contribute along with the post-spike after
      hyperpolarization to limiting the influence of the synaptic noise on the firing
      times of steadily discharging motoneurones. The present data, which suggest that
      recurrent inhibition plays a synchronizing rather than a desynchronizing role,
      are in keeping with the fact that the Renshaw cells may provide an important
      source of common inhibitory inputs.

PMID- 12611930
TI  - Interface between neurology and psychiatry in childhood.

PMID- 12611931
TI  - The cerebral palsies: a physiological approach.

PMID- 12611932
TI  - Learning difficulties: what the neurologist needs to know.

PMID- 12611933
TI  - Taking over epilepsy from the paediatric neurologist.

PMID- 12611934
TI  - Vein of galen malformations.

PMID- 12611935
TI  - Role of cocontraction in arm movement accuracy.
AB  - Cocontraction (the simultaneous activation of antagonist muscles around a joint)
      provides the nervous system with a way to adapt the mechanical properties of the
      limb to changing task requirements-both in statics and during movement. However,
      relatively little is known about the conditions under which the motor system
      modulates limb impedance through cocontraction. The goal of this study was to
      test for a possible relationship between cocontraction and movement accuracy in
      multi-joint limb movements. The electromyographic activity of seven single- and
      double-joint shoulder and elbow muscles was recorded using surface electrodes
      while subjects performed a pointing task in a horizontal plane to targets that
      varied randomly in size. Movement speed was controlled by providing subjects with
      feedback on a trial-to-trial basis. Measures of cocontraction were estimated both
      during movement and during a 200-ms window immediately following movement end. We
      observed an inverse relationship between target size and cocontraction: as target
      size was reduced, cocontraction activity increased. In addition, trajectory
      variability decreased and endpoint accuracy improved. This suggests that,
      although energetically expensive, cocontraction may be a strategy used by the
      motor system to facilitate multi-joint arm movement accuracy. We also observed a
      general trend for cocontraction levels to decrease over time, supporting the idea
      that cocontraction and associated limb stiffness are reduced over the course of
      practice.

PMID- 12611936
TI  - Dynamics of orientation tuning in macaque V1: the role of global and tuned
      suppression.
AB  - The temporal development of neural selectivity to physical attributes of a visual
      stimulus, such as its orientation and spatial frequency, can provide important
      clues about mechanisms of cortical tuning. We measured the dynamics of
      orientation tuning in macaque primary visual cortex (V1) and found several
      dynamical features in the data: changes in global enhancement and suppression,
      narrowing of orientation bandwidth, small but significant shifts in preferred
      orientation, and "Mexican-hat" tuning curves. The dynamics data were analyzed
      with a model that sums two fixed, tuned components (enhancement and suppression)
      and one global (untuned) component. The analysis suggests that there is early
      global enhancement followed by global and tuned suppression. Tuned suppression
      accounts for the dynamical reduction of orientation bandwidth and for the
      generation of Mexican-hat tuning profiles. Our findings imply that global and
      tuned suppression are important factors that determine the selectivity and
      dynamics of V1 responses to orientation.

PMID- 12611937
TI  - Effects of expectations for different reward magnitudes on neuronal activity in
      primate striatum.
AB  - In behavioral science, it is well known that humans and nonhuman animals are
      highly sensitive to differences in reward magnitude when choosing an outcome from
      a set of alternatives. We know that a realm of behavioral reactions is altered
      when animals begin to expect different levels of reward outcome. Our present aim
      was to investigate how the expectation for different magnitudes of reward
      influences behavior-related neurophysiology in the anterior striatum. In a
      spatial delayed response task, different instruction pictures are presented to
      the monkey. Each image represents a different magnitude of juice. By reaching to
      the spatial location where an instruction picture was presented, animals could
      receive the particular liquid amount designated by the stimulus. Reliable
      preferences in reward choice trials and differences in anticipatory licks,
      performance errors, and reaction times indicated that animals differentially
      expected the various reward amounts predicted by the instruction cues. A total of
      374 of 2,000 neurons in the anterior parts of the caudate nucleus, putamen, and
      ventral striatum showed five forms of task-related activation during the
      preparation or execution of movement and activations preceding or following the
      liquid drop delivery. Approximately one-half of these striatal neurons showed
      differing response levels dependent on the magnitude of liquid to be received.
      Results of a linear regression analysis showed that reward magnitude and single
      cell discharge rate were related in a subset of neurons by a monotonic positive
      or negative relationship. Overall, these data support the idea that the striatum
      utilizes expectancies that contain precise information concerning the predicted,
      forthcoming level of reward in directing general behavioral reactions.

PMID- 12611938
TI  - Projections from primary somatosensory cortex to the neostriatum: the role of
      somatotopic continuity in corticostriatal convergence.
AB  - We characterized the organization of corticostriatal projections from rodent
      primary somatosensory cortex (SI), testing the hypothesis that projections from
      SI areas representing subcomponents of the forelimb exhibit greater neostriatal
      overlap than projections from areas representing separate body parts. The
      anterograde tracers Fluoro-Ruby (FR), Alexa Fluor (AF), and biotinylated dextran
      amine (BDA) were injected into physiologically identified regions of rat SI.
      Injection locations were confirmed by examining the SI barrel fields and limb
      representations in tangential sections processed for cytochrome oxidase (CO).
      Experimental animals were divided into two groups: one group received multiple
      tracer injections in neighboring SI regions that represent separate body parts
      (whiskers, forepaw, and hindpaw); the other group received injections in SI areas
      that represent different components of the forelimb (forepaw, antebrachium, and
      brachium). The distribution of labeled terminals and their varicosities in the
      neostriatum and in the thalamus were plotted and quantitatively analyzed. For
      most animals, tracer overlap in the thalamus was either minimal or completely
      absent. In the neostriatum, projections from the whisker, forelimb, and hindlimb
      representations terminated in regions that rarely overlap with each other, while
      those originating from different parts of the forelimb representation were more
      likely to terminate in overlapping parts of the neostriatum. To the extent that
      neostriatal activation depends on corticostriatal convergence, the
      corticostriatal projections in the sensorimotor channel appeared to be organized
      so that neostriatal neurons may signal when multiple components of the same body
      part are activated simultaneously.

PMID- 12611939
TI  - Pharmacological characterization of an adenylyl cyclase-coupled 5-HT receptor in
      aplysia: comparison with mammalian 5-HT receptors.
AB  - We attempted to identify compounds that are effective in blocking the serotonin
      (5-hydroxytryptamine, 5-HT) receptor(s) that activate adenylyl cyclase (AC) in
      Aplysia CNS. We call this class of receptor 5-HT(apAC). Eight of the 14
      antagonists tested were effective against 5-HT(apAC) in CNS membranes with the
      following rank order of potency: methiothepin > metergoline approximately
      fluphenazine > clozapine > cyproheptadine approximately risperidone approximately
      ritanserin > NAN-190. GR-113808, olanzapine, Ro-04-6790, RS-102221, SB-204070,
      and spiperone were inactive. Methiothepin completely blocked 5-HT stimulation of
      AC with a K(b) of 18 nM. Comparison of the pharmacological profile of the 5
      HT(apAC) receptor with those of mammalian 5-HT receptor subtypes suggested it
      most closely resembles the 5-HT(6) receptor. AC stimulation in Aplysia sensory
      neuron (SN) membranes was also blocked by methiothepin. Methiothepin
      substantially inhibited two effects of 5-HT on SN firing properties that are
      mediated by a cAMP-dependent reduction in S-K(+) current: spike broadening in
      tetraethylammonium/nifedipine and increased excitability. Consistent with
      cyproheptadine blocking 5-HT stimulation of AC, cyproheptadine also blocked the 5
      HT-induced increase in SN excitability. Methiothepin was less effective in
      blocking AC-mediated modulatory effects of 5-HT in electrophysiological
      experiments on SNs than in blocking AC stimulation in CNS or SN membranes. This
      reduction in potency appears to be due to effects of the high ionic strength of
      physiological saline on the binding of this antagonist to the receptor.
      Methiothepin also antagonized AC-coupled dopamine receptors but not AC-coupled
      small cardioactive peptide receptors. In conjunction with other pharmacological
      probes, this antagonist should be useful in analyzing the role of 5-HT in various
      forms of neuromodulation in Aplysia.

PMID- 12611940
TI  - Fatigue of paralyzed and control thenar muscles induced by variable or constant
      frequency stimulation.
AB  - Muscles paralyzed by chronic (>1 yr) spinal cord injury fatigue readily. Our aim
      was to evaluate whether the fatigability of paralyzed thenar muscles (n = 10)
      could be reduced by the repeated delivery of variable versus constant frequency
      pulse trains. Fatigue was induced in four ways. Intermittent supramaximal median
      nerve stimulation (300-ms-duration trains) was delivered at 1) constant high
      frequency (13 pulses at 40 Hz each second for 2 min); 2) variable high frequency
      (each second for 2 min). The first two intervals of each variable frequency train
      were 5 and 20 ms. The remaining pulses were evenly distributed in time across 275
      ms. The number of pulses varied for each subject such that the force time
      integral in the unfatigued state matched that evoked by a constant 40-Hz train;
      3) constant low frequency (7 pulses at 20 Hz each second for 4 min); and 4)
      variable low frequency (each second for 4 min). The pulse pattern was the same as
      that for variable high frequency except that the force-time integral was matched
      to that produced by the constant low-frequency stimulation. These same
      experiments were performed on the thenar muscles of five able-bodied control
      subjects. The variable high-frequency trains used to fatigue paralyzed and
      control muscles had an average (+/- SE) of 12 +/- 2 and 10 +/- 1 pulses,
      respectively. Variable low-frequency trains had 7 +/- 1 and 6 +/- 1 pulses,
      respectively. Significant mean force declines of comparable magnitude (to 20-25%
      initial fatigue force or to 13-21% initial 50 Hz force) were seen in paralyzed
      muscles with all four stimulation protocols. The force reductions in paralyzed
      muscles were always accompanied by significant increases in half-relaxation time
      and decreases in force-time integral, irrespective of the stimulation protocol.
      Significant force decreases also occurred in control muscles during each fatigue
      test. Again, these force declines were similar whether constant or variable pulse
      patterns were used at high or low frequencies (to 40-60% initial fatigue force or
      to 29-36% initial 50 Hz force). The force reductions in control muscles were
      significantly less than those seen in paralyzed muscles, except when constant
      high-frequency stimulation was used. The variations in stimulation frequency,
      pulse pattern, and pulse number used in this study therefore had little influence
      on thenar muscle fatigue in control subjects or in spinal cord-injured subjects
      with chronic paralysis.

PMID- 12611941
TI  - Nicotine enhances the depressive actions of A beta 1-40 on long-term potentiation
      in the rat hippocampal CA1 region in vivo.
AB  - Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as
      a cellular model of memory. Beta amyloid (A beta) is involved in Alzheimer's
      disease (AD), a neurode-generative disorder leading to cognitive deficits.
      Nicotine is also claimed to act as a cognitive enhancer. A beta is known to bind
      with high affinity to the alpha 7-nicotinic acetylcholine receptor (nAChR). Here
      we have investigated the effect of intracerebroventricular (i.c.v.) injection of
      the endogenous peptide A beta 1-40 on LTP in area CA1 of urethananesthetized
      rats. We also examined the effect of A beta 12-28 (i.c.v.), which binds with high
      affinity to the alpha 7-nAChR and the specific alpha 7-nAChR antagonist
      methyllycaconitine (MLA) on LTP. We found that A beta 12-28 had no effect on LTP,
      whereas MLA depressed significantly LTP, suggesting that activation of the alpha
      7-nAChR is a requirement for LTP. Within the in vivo environment, where other
      factors may compete with A beta 12-28 for binding to alpha 7-nAChR, it does not
      appear to modulate LTP. To determine if the depressive action of A beta 1-40 on
      LTP could be modulated by nicotine, these agents were also co-applied. Injection
      of 1 or 10 nmol A beta 1-40 caused a significant depression of LTP, whereas
      nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with A
      beta 1-40 1 h prior to LTP induction caused a further significant depression of
      LTP compared with A beta 1-40 alone. These results demonstrate that nicotine
      enhances the deficit in LTP produced by A beta 1-40. This then suggests that
      nicotine may exacerbate the depressive actions of A beta on synaptic plasticity
      in AD.

PMID- 12611944
TI  - Neural basis of visually guided head movements studied with fMRI.
AB  - We used event-related fMRI to measure brain activity while subjects performed
      saccadic eye, head, and gaze movements to visually presented targets. Two
      distinct patterns of response were observed. One set of areas was equally active
      during eye, head, and gaze movements and consisted of the superior and inferior
      subdivisions of the frontal eye fields, the supplementary eye field, the
      intraparietal sulcus, the precuneus, area MT in the lateral occipital sulcus and
      subcortically in basal ganglia, thalamus, and the superior colliculus. These
      areas have been previously observed in functional imaging studies of human eye
      movements, suggesting that a common set of brain areas subserves both oculomotor
      and head movement control in humans, consistent with data from single-unit
      recording and microstimulation studies in nonhuman primates that have described
      overlapping eye- and head-movement representations in oculomotor control areas. A
      second set of areas was active during head and gaze movements but not during eye
      movements. This set of areas included the posterior part of the planum temporale
      and the cortex at the temporoparietal junction, known as the parieto-insular
      vestibular cortex (PIVC). Activity in PIVC has been observed during imaging
      studies of invasive vestibular stimulation, and we confirm its role in processing
      the vestibular cues accompanying natural head movements. Our findings demonstrate
      that fMRI can be used to study the neural basis of head movements and show that
      areas that control eye movements also control head movements. In addition, we
      provide the first evidence for brain activity associated with vestibular input
      produced by natural head movements as opposed to invasive caloric or galvanic
      vestibular stimulation.

PMID- 12611943
TI  - A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and
      in vitro is attenuated by verapamil.
AB  - The effect of intracerebroventricular (icv) injection of A beta 25-35 and/or
      intraperitoneal (ip) application of the L-type calcium channel (VDCC) blockers
      verapamil or diltiazem were examined in vivo. To by-pass possible systemic
      actions of these agents, their effects on long-term potentiation (LTP) in the CA1
      region of the in vitro hippocampal slice preparation were also examined.
      Application of A beta 25-35 (10 nmol in 5 microl, i.c.v.) significantly impaired
      LTP in vivo, as did IP injection of verapamil (1 or 10 mg/kg) or diltiazem (1 or
      10 mg/kg). In the in vitro slice preparation, LTP was also depressed by prior
      application of A beta 25-35 (500 nmol), verapamil (20 microM), or diltiazem (50
      microM). Combined application of A beta 25-35 and verapamil in either the in vivo
      or in vitro preparation resulted in a significant reversal of the LTP depression
      observed in the presence of either agent alone. However, co-application of
      diltiazem and A beta 25-35 failed to attenuate the depression of LTP observed in
      the presence of either agent alone in vivo or in vitro. Since LTP is a cellular
      correlate of memory and A beta is known to be involved in Alzheimer's disease
      (AD), these results indicate that verapamil, a phenylalkylamine, may be useful in
      the treatment of cognitive deficits associated with AD.

PMID- 12611946
TI  - Spatial sensitivity in field PAF of cat auditory cortex.
AB  - We compared the spatial tuning properties of neurons in two fields [primary
      auditory cortex (A1) and posterior auditory field (PAF)] of cat auditory cortex.
      Broadband noise bursts of 80-ms duration were presented from loudspeakers
      throughout 360 degrees in the horizontal plane (azimuth) or 260 degrees in the
      vertical median plane (elevation). Sound levels varied from 20 to 40 dB above
      units' thresholds. We recorded neural spike activity simultaneously from 16 sites
      in field PAF and/or A1 of alpha-chloralose-anesthetized cats. We assessed spatial
      sensitivity by examining the dependence of spike count and response latency on
      stimulus location. In addition, we used an artificial neural network (ANN) to
      assess the information about stimulus location carried by spike patterns of
      single units and of ensembles of 2-32 units. The results indicate increased
      spatial sensitivity, more uniform distributions of preferred locations, and
      greater tolerance to changes in stimulus intensity among PAF units relative to A1
      units. Compared to A1 units, PAF units responded at significantly longer
      latencies, and latencies varied more strongly with stimulus location. ANN
      analysis revealed significantly greater information transmission by spike
      patterns of PAF than A1 units, primarily reflecting the information transmitted
      by latency variation in PAF. Finally, information rates grew more rapidly with
      the number of units included in neural ensembles for PAF than A1. The latter
      finding suggests more accurate population coding of space in PAF, made possible
      by a more diverse population of neural response types.

PMID- 12611945
TI  - Activity-dependent induction of multitransmitter signaling onto pyramidal cells
      and interneurons of hippocampal area CA3.
AB  - The granule cells of the dentate gyrus (DG) are considered to be glutamatergic,
      but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA),
      and the vesicular GABA transporter mRNA. Their expression is regulated in an
      activity-dependent manner and coincides with the appearance of GABAergic
      transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These
      data support the hypothesis that MF are able to release glutamate and GABA.
      Following the principle that a given neuron releases the same neurotransmitter(s)
      onto all its targets, we here demonstrate the emergence, after a generalized
      convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III
      onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides
      inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of
      GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is
      also revealed in both targets, which postsynaptically modulates the glutamatergic
      and GABAergic fast neurotransmission. The emergence of these nonglutamatergic
      signals depends on protein synthesis. In contrast to cholinergic responses evoked
      by associational/commissural fibers activation, cholinergic transmission evoked
      by DG stimulation is only observed after seizures and is strongly depressed by
      the activation of mGluR-II, whereas both are depressed by M2-AChR activation.
      With immunohistological experiments, we show that this cholinergic pathway runs
      parallel to the MF. Thus seizures compromise a delicate balance of excitation and
      inhibition, on which a complex interaction of different neurotransmitters emerges
      to counteract excitation at pre- and postsynaptic sites. Particularly, MF
      GABAergic inhibition emerges to exert an overall inhibitory action on CA3.

PMID- 12611947
TI  - Nonspiking and spiking proprioceptors in the crab: nonlinear analysis of
      nonspiking TCMRO afferents.
AB  - The proprioceptor that signals the position and movement of the first joint of
      crustacean legs provides an excellent system for investigating information
      processing and transmission in neurons that function in a graded (nonspiking)
      manner in the context of a simple motor system. The thoracic-coxal muscle
      receptor organ (TCMRO) spans the thoracic-coxal joint and transmits graded
      signals to the CNS via two large nonspiking axons. The response characteristics
      and nonlinear models of the input-output relationship for the two nonspiking
      TCMRO afferents (S and T fibers) were determined using white noise analysis
      (Wiener kernel) methods. The best-fitting linear responses of these neurons was
      similar, as were their second-order kernels. The gains of the afferents slowly
      increased with increasing frequency and reached a maximum at approximately 40-60
      Hz for the S fiber and 60-80 Hz for the T fiber. Above this corner frequency, the
      gains of both afferents decreased at approximately 20 dB/decade for the remainder
      of the 220-Hz stimulus bandwidth. The shape of the first-order kernels, and hence
      the corresponding (linear) gain functions, of both afferents were similar when
      driven with different amplitudes of noise, covering a 40-fold amplitude range.
      Predictions of the S fiber response based on the first two Wiener kernels were
      accurate, with the second-order model producing a mean square error of 6-8%.
      Second-order Wiener models for the T fiber were less accurate with a mean square
      error of approximately 22-26%, but this accuracy improved to 10-16% with the
      incorporation of the third-order term in the Wiener expansion. The effect of
      cable properties on the transmission of the sensory potentials to the CNS was
      evaluated by determining the system characteristics using membrane potentials 5-7
      mm distal to the transduction site. The major change after transmission along the
      axon was a low-pass filtering of the sensory signals and consequent reduction in
      signal bandwidth.

PMID- 12611948
TI  - Nonspiking and spiking proprioceptors in the crab: white noise analysis of
      spiking CB-chordotonal organ afferents.
AB  - The proprioceptors that signal the position and movement of the first two joints
      of crustacean legs provide an excellent system for comparison of spiking and
      nonspiking (graded) information transfer and processing in a simple motor system.
      The position, velocity, and acceleration of the first two joints of the crab leg
      are monitored by both nonspiking and spiking proprioceptors. The nonspiking
      thoracic-coxal muscle receptor organ (TCMRO) spans the TC joint, while the coxo
      basal (CB) joint is monitored by the spiking CB chordotonal organ (CBCTO) and by
      nonspiking afferents arising from levator and depressor elastic strands. The
      response characteristics and nonlinear models of the input-output relationship
      for CB chordotonal afferents were determined using white noise analysis (Wiener
      kernel) methods. The first- and second-order Wiener kernels for each of the four
      response classes of CB chordotonal afferents (position, position-velocity,
      velocity, and acceleration) were calculated and the gain function for each
      receptor determined by taking the Fourier transform of the first-order kernel. In
      all cases, there was a good correspondence between the response of an afferent to
      deterministic stimulation (trapezoidal movement) and the best-fitting linear
      transfer function calculated from the first-order kernel. All afferents also had
      a nonlinear response component and second-order Wiener kernels were calculated
      for afferents of each response type. Models of afferent responses based on the
      first- and second-order kernels were able to predict the response of the
      afferents with an average accuracy of 86%.

PMID- 12611949
TI  - Role of myelination in the development of a uniform olivocerebellar conduction
      time.
AB  - Purkinje cells generate simultaneous complex spikes as a result of
      olivocerebellar activity. This synchronization (to within 1 ms) is thought to
      result from electrotonic coupling of inferior olivary neurons. However, the
      distance from the inferior olive (IO) varies across the cerebellar cortex. Thus
      signals generated simultaneously at the IO should arrive asynchronously across
      the cerebellar cortex, unless the length differences are compensated for.
      Previously, it was shown that the conduction time from the IO to the cerebellar
      cortex remains nearly constant at approximately 4 ms in the rat, implying the
      existence of such compensatory mechanisms. Here, we examined the role of
      myelination in generating a constant olivocerebellar conduction time by
      investigating the latency of complex spikes evoked by IO stimulation during
      development in normal rats and myelin-deficient mutants. In normal rats,
      myelination not only reduced overall olivocerebellar conduction time, but also
      disproportionately reduced the conduction time to vermal lobules, which had the
      longest response latencies prior to myelination. The net result was a nearly
      uniform conduction time. In contrast, in myelin-deficient rats, conduction time
      differences to different parts of the cerebellum remained during the same
      developmental period. Thus myelination is the primary factor in generating a
      uniform olivocerebellar conduction time. To test the importance of a uniform
      conduction time for generating synchronous complex spike activity, multiple
      electrode recordings were obtained from normal and myelin-deficient rats. Average
      synchrony levels were higher in normal rats than mutants. Thus the uniform
      conduction time achieved through myelination of olivocerebellar fibers appears to
      be essential for the normal expression of complex spike synchrony.

PMID- 12611950
TI  - Role of intracortical inhibition in selective hand muscle activation.
AB  - Previous studies have shown that intracortical inhibition (ICI) plays an
      important role in shaping the output from primary motor cortex (M1). This study
      explored the muscle specificity and temporal modulation of ICI during the
      performance of a phasic index finger flexion task. Fifteen subjects were asked to
      rest their dominant hand on a computer mouse and depress the mouse button using
      their index finger in time with a 1-Hz auditory metronome, while keeping the rest
      of their hand as relaxed as possible. Responses to single- and paired-pulse
      transcranial magnetic stimulation were recorded from the first dorsal
      interosseous (FDI) and abductor pollicis brevis (APB) muscles while subjects were
      at rest and during "on" and "off" phases of the task. For FDI during the on
      phase, motor evoked potential (MEP) amplitude and pretrigger EMG increased and
      ICI decreased, as expected. This pattern of modulation was also observed for APB
      in seven subjects. The remaining eight subjects demonstrated a decrease in MEP
      amplitude and increase in ICI for APB during the on phase. This was associated
      with significantly less APB activation during the on phase. These findings
      suggest that an increase in ICI and decrease in corticospinal excitability can
      prevent unwanted muscle activation in a muscle-specific, temporally modulated
      manner.

PMID- 12611951
TI  - Endogenous acetylcholine and nicotine activation enhances GABAergic and
      glycinergic inputs to cardiac vagal neurons.
AB  - The heart slows during expiration and heart rate increases during inspiration.
      This cardiorespiratory interaction is thought to occur by increased inhibitory
      synaptic events to cardiac vagal neurons during inspiration. Since cholinergic
      receptors have been suggested to be involved in this cardiorespiratory
      interaction, we tested whether endogenous cholinergic activity modulates
      GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the
      nucleus ambiguus, whether nicotine can mimic this facilitation, and we examined
      the nicotinic receptors involved. Cardiac vagal neurons in the rat were labeled
      with a retrograde fluorescent tracer and studied in an in vitro slice using patch
      clamp techniques. Application of neostigmine (10 microM), an acetylcholinerase
      inhibitor, significantly increased the frequency of both GABAergic and
      glycinergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons.
      Exogenous application of nicotine increased the frequency and amplitude of both
      GABAergic and glycinergic IPSCs. The nicotinic facilitation of both GABAergic and
      glycinergic IPSCs were insensitive to 100 nM alpha-bungarotoxin but were
      abolished by dihydro-beta-erythrodine (DHbetaE) at a concentration (3 microM)
      specific for alpha4beta2 nicotinic receptors. In the presence of TTX, nicotine
      increased the frequency of GABAergic and glycinergic miniature synaptic events,
      which were also abolished by DHbetaE (3 microM). This work demonstrates that
      there is endogenous cholinergic facilitation of GABAergic and glycinergic
      synaptic inputs to cardiac vagal neurons, and activation of alpha4beta2 nicotinic
      receptors at presynaptic terminals facilitates GABAergic and glycinergic
      neurotransmission to cardiac vagal neurons. Nicotinic facilitation of inhibitory
      neurotransmission to premotor cardiac parasympathetic neurons may be involved in
      generating respiratory sinus arrhythmia.

PMID- 12611953
TI  - Regulation of neuronal function by choline and 4OH-GTS-21 through alpha 7
      nicotinic receptors.
AB  - A unique feature of alpha7 nicotinic acetylcholine receptor physiology is that,
      under normal physiological conditions, alpha7 receptors are constantly perfused
      with their natural selective agonist, choline. Studying neurons of hypothalamic
      tuberomammillary (TM) nucleus, we show that choline and the selective alpha7
      receptor agonist 4OH-GTS-21 can regulate neuronal functions directly, via
      activation of the native alpha7 receptors, and indirectly, via desensitizing
      those receptors or transferring them into a state "primed" for desensitization.
      The direct action produces depolarization and thereby increases the TM neuron
      spontaneous firing (SF) rate. The regulation of the spontaneous firing rate is
      robust in a nonphysiological range of choline concentrations >200 microM.
      However, modest effects persist at concentrations of choline that are likely to
      be attained perineuronally under some conditions (20-100 microM). At high
      physiological concentration levels, the indirect choline action reduces or even
      eliminates the responsiveness of alpha7 receptors and their availability to other
      strong cholinergic inputs. Similarly to choline, 4OH-GTS-21 increases the TM
      neuron spontaneous firing rate via activation of alpha7 receptors, and this
      regulation is robust in the range of clinically relevant concentrations of 4OH
      GTS-21. We conclude that factors that regulate choline accumulation in the brain
      and in experimental slices such as choline uptake, hydrolysis of ACh, membrane
      phosphatidylcholine catabolism, and solution perfusion rate influence alpha7
      nAChR neuronal and synaptic functions, especially under pathological conditions
      such as stroke, seizures, Alzheimer's disease, and head trauma, when the choline
      concentration in the CSF is expected to rise.

PMID- 12611954
TI  - Ca2+ ions block and permeate serotonin 5-HT3 receptor channels in rat hippocampal
      interneurons.
AB  - The serotonin 5-HT(3) receptor native to rat hippocampal CA1 stratum radiatum
      interneurons is blocked by Ca(2+) ions in a dose- and voltage-dependent manner,
      which is reflected by a region of negative slope conductance in the I-V curve.
      The steep dependence on the extracellular Ca(2+) concentration suggests that the
      channel contains more than one binding site for Ca(2+). A three barrier-two site
      model, based on Eyring rate theory, was used to describe the I-V curves. When
      extra- and intracellular K(+) and Cs(+) were substituted with Na(+), the I-V
      curves were accurately fit by the model, unlike the I-V curves recorded under
      standard ionic conditions. This suggests that the K(+) and Cs(+) permeabilities
      are small compared with that of Na(+). The distribution of the energy barriers
      and binding sites for Ca(2+) and Na(+) showed that the binding sites are located
      at approximately the 13' and the -4' position in the ion channel. The model
      predicts that at large hyperpolarized membrane potentials (more negative than 
      120 mV), the fractional Ca(2+) current amounts to approximately 1% of the total
      ion current. However, at physiologically relevant membrane potentials, the
      fractional Ca(2+) current is smaller (<0.1%) and the relative Ca(2+) permeability
      (P(Ca)/P(Na)) is estimated to be 0.10 at -60 mV.

PMID- 12611955
TI  - Organization of ipsilateral excitatory and inhibitory pathways in the human motor
      cortex.
AB  - Motor cortex stimulation has both excitatory and inhibitory effects on
      ipsilateral muscles. Excitatory effects can be assessed by ipsilateral motor
      evoked potentials (iMEPs). Inhibitory effects include an interruption of
      ipsilateral voluntary muscle activity known as the silent period (iSP) and a
      reduction in corticospinal excitability evoked by conditioning stimulation of the
      contralateral motor cortex (interhemispheric inhibition, IHI). Both iSP and IHI
      may be mediated by transcallosal pathways. Their relationship to the
      contralateral corticospinal projection and whether iSP and IHI represent the same
      phenomenon remain unclear. The neuronal population activated by transcranial
      magnetic stimulation (TMS) is highly dependent on the direction of the induced
      current in the brain. We examined the relationship among iMEP, iSP, IHI, and the
      contralateral corticospinal system by examining the effects of different stimulus
      intensities and current directions. Surface electromyography (EMG) was recorded
      from both first dorsal interosseous (FDI) muscles. The iSP in the right FDI
      muscle was obtained by right motor cortex stimulation during voluntary muscle
      contraction. IHI was examined by conditioning stimulation of the right motor
      cortex followed by test stimulation of the left motor cortex at interstimulus
      intervals (ISIs) of 2-80 ms. The induced current directions tested in the right
      motor cortex were anterior medial (AM), posterior medial (PM), posterior lateral,
      and anterior lateral (AL). Contralateral MEPs (cMEPs) had the lowest threshold
      with the AM direction and the shortest latency with the PM direction. iMEPs were
      present in 8 of 10 subjects. Both iMEP and IHI did not show significant
      directional preference. iSP was observed in all subjects with the highest
      threshold for the AL direction and the longest duration for the AM direction.
      cMEP, iSP, and IHI all increased with stimulus intensity up to approximately 75%
      stimulator output. Target muscle activation decreased IHI at 8-ms ISI but had
      little effect on IHI at 40-ms ISI. iSP and IHI at 8-ms ISI did not correlate at
      any stimulus intensities and current directions tested, and factor analysis
      showed that they are explained by different factors. However, active IHI at 40-ms
      ISI was explained by the same factor as iSP. The different directional preference
      for cMEP compared with iMEP and IHI suggests that these ipsilateral effects are
      mediated by populations of cortical neurons that are different from those
      activating the corticospinal neurons. iSP and IHI do not represent the same
      phenomenon and should be considered complementary measures of ipsilateral
      inhibition.

PMID- 12611956
TI  - Oblique effect: a neural basis in the visual cortex.
AB  - The details of oriented visual stimuli are better resolved when they are
      horizontal or vertical rather than oblique. This "oblique effect" has been
      confirmed in numerous behavioral studies in humans and to some extent in animals.
      However, investigations of its neural basis have produced mixed and inconclusive
      results, presumably due in part to limited sample sizes. We have used a database
      to analyze a population of 4,418 cells in the cat's striate cortex to determine
      possible differences as a function of orientation. We find that both the numbers
      of cells and the widths of orientation tuning vary as a function of preferred
      orientation. Specifically, more cells prefer horizontal and vertical orientations
      compared with oblique angles. The largest population of cells is activated by
      orientations close to horizontal. In addition, orientation tuning widths are most
      narrow for cells preferring horizontal orientations. These findings are most
      prominent for simple cells tuned to high spatial frequencies. Complex cells and
      simple cells tuned to low spatial frequencies do not exhibit these anisotropies.
      For a subset of simple cells from our population (n = 104), we examined the
      relative contributions of linear and nonlinear mechanisms in shaping orientation
      tuning curves. We find that linear contributions alone do not account for the
      narrower tuning widths at horizontal orientations. By modeling simple cells as
      linear filters followed by static expansive nonlinearities, our analysis
      indicates that horizontally tuned cells have a greater nonlinear component than
      those tuned to other orientations. This suggests that intracortical mechanisms
      play a major role in shaping the oblique effect.

PMID- 12611957
TI  - From subthreshold to firing-rate resonance.
AB  - Many types of neurons exhibit subthreshold resonance. However, little is known
      about whether this frequency preference influences spike emission. Here, the link
      between subthreshold resonance and firing rate is examined in the framework of
      conductance-based models. A classification of the subthreshold properties of a
      general class of neurons is first provided. In particular, a class of neurons is
      identified in which the input impedance exhibits a suppression at a nonzero low
      frequency as well as a peak at higher frequency. The analysis is then extended to
      the effect of subthreshold resonance on the dynamics of the firing rate. The
      considered input current comprises a background noise term, mimicking the massive
      synaptic bombardment in vivo. Of interest is the modulatory effect an additional
      weak oscillating current has on the instantaneous firing rate. When the noise is
      weak and firing regular, the frequency most preferentially modulated is the
      firing rate itself. Conversely, when the noise is strong and firing irregular,
      the modulation is strongest at the subthreshold resonance frequency. These
      results are demonstrated for two specific conductance-based models and for a
      generalization of the integrate-and-fire model that captures subthreshold
      resonance. They suggest that resonant neurons are able to communicate their
      frequency preference to postsynaptic targets when the level of noise is
      comparable to that prevailing in vivo.

PMID- 12611958
TI  - Effect of neuritic cables on conductance estimates for remote electrical
      synapses.
AB  - The conductance of electrical synapses is usually estimated from voltage
      recordings at the neuronal somata under the assumption that each cell is
      isopotential. This approach neglects effects of intervening neurites. For a cell
      pair with unbranched neurites and an electrical synapse at their ends, we used
      cable theory to derive an analytical expression that relates the synaptic
      conductance to voltage recordings at the cell bodies and to the neurite
      properties. The equation implies that the conventional method significantly
      underestimates the actual synapse conductance if the neurite length is comparable
      to the electrotonic length constant and if the synaptic conductance is similar to
      the serial neurite conductance. For an experimental test, we cultured pairs of
      snail neurons on protein patterns, resulting in a geometry that matched the
      theoretical model. Using the isopotential theory, we estimated the synapse
      conductances and found them to be rather weak. To obtain the cable properties, we
      recorded spatiotemporal maps of signal propagation in the neurites using a
      voltage-sensitive dye. Fits of these maps to a passive cable model showed that
      the snail neurons are electrotonically rather compact. Given these features of
      our experimental system, the synaptic conductances derived with the
      nonisopotential model deviated from the estimates of the isopotential theory by
      about 13%. This discrepancy, although small, shows that even in electrotonically
      compact neurons coupled by weak synapses the impact of the neuritic cables on
      conductance estimates cannot be neglected. When applied to less compact and more
      strongly coupled cell pairs in vivo, our approach can supply the realistic
      estimates of synaptic conductances that are necessary for a better understanding
      of the role of electrical coupling in neural systems.

PMID- 12611959
TI  - Interplay between activation of GIRK current and deactivation of Ih modifies
      temporal integration of excitatory input in CA1 pyramidal cells.
AB  - Trains of brief iontophoretic glutamate pulses were delivered onto the apical
      dendrites of CA1 pyramidal cells at variable frequencies (3-100 Hz) to examine
      how the activation of a G protein-activated, inwardly rectifying K(+) (GIRK)
      conductance alters the postsynaptic processing of repetitive excitatory input.
      Application of the GIRK channel agonist baclofen (20 microM) reduced the
      amplitude of individual glutamate-evoked postsynaptic potentials (GPSPs) and
      attenuated summation of GPSPs so that higher stimulus intensities were required
      to fire the cell. Notably, GIRK channel activation not only decreased GPSPs, but
      also suppressed the subsequent afterhyperpolarization (AHP), which arises from a
      transient deactivation of the hyperpolarization-activated cation current (I(h)).
      Voltage-clamp recordings ruled out a direct modulatory action of baclofen on
      I(h). GIRK channel activation alone accounts for AHP suppression, firstly
      because, with smaller GPSP amplitudes, fewer I(h) channels are deactivated,
      resulting in a diminished AHP, and secondly because, owing to its progressive
      increase in the hyperpolarizing direction, the GIRK conductance shunts a large
      portion of the remaining AHP. We provide experimental evidence that the
      suppression of the I(h)-dependent AHP by GIRK channel activation bears particular
      significance on the processing of repetitive excitatory inputs at frequencies at
      which the deactivation kinetics of I(h) exert a prominent depressing effect. In
      functional terms, activation of GIRK current not only produces a time-independent
      mitigation of incoming excitatory input, which results directly from the opening
      of an instantaneous K(+) conductance, but might also cause a time-dependent
      redistribution of synaptic weight within a stimulus train, which we link to an
      interplay with the deactivation of I(h).

PMID- 12611960
TI  - Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are
      reversed by NMDA antagonism.
AB  - Hypocretin-1 and -2 (Hcrt-1 and -2, also called orexin-A and -B) are newly
      identified neuropeptides synthesized by hypothalamic neurons. Defects in the Hcrt
      system underlie the sleep disorder narcolepsy, which is characterized by sleep
      fragmentation and the involuntary loss of muscle tone called cataplexy. Hcrt
      neurons project to multiple brain regions including cranial and spinal motor
      nuclei. In vitro studies suggest that Hcrt application can modulate presynaptic
      glutamate release. Together these observations suggest that Hcrt can affect motor
      output and that glutamatergic processes may be involved. We addressed these
      issues in decerebrate cats by applying Hcrt-1 and -2 into the trigeminal motor
      nucleus to determine whether these ligands alter masseter muscle activity and by
      pretreating the trigeminal motor nucleus with a N-methyl-d-aspartate (NMDA)
      antagonist to determine if glutamatergic pathways are involved in the
      transduction of the Hcrt signal. We found that Hcrt-1 and -2 microinjections into
      the trigeminal motor nucleus increased ipsilateral masseter muscle tone in a dose
      dependent manner. We also found that Hcrt application into the hypoglossal motor
      nucleus increases genioglossus muscle activity. Pretreatment with a NMDA
      antagonist (d-(-)-2-amino-phosphonovaleric acid) abolished the excitatory
      response of the masseter muscle to Hcrt-1 application; however, pretreatment with
      methysergide, a serotonin antagonist had no effect. These studies are the first
      to demonstrate that Hcrt causes the excitation of motoneurons and that functional
      NMDA receptors are required for this response. We suggest that Hcrt regulates
      motor control processes and that this regulation is mediated by glutamate release
      in the trigeminal motor nucleus.

PMID- 12611961
TI  - Learning and adaptation in a recurrent model of V1 orientation selectivity.
AB  - Learning and adaptation in the domain of orientation processing are among the
      most studied topics in the literature. However, little effort has been devoted to
      explaining the diverse array of experimental findings via a physiologically based
      model. We have started to address this issue in the framework of the recurrent
      model of V1 orientation selectivity and found that reported changes in V1
      orientation tuning curves after learning and adaptation can both be explained
      with the model. Specifically, the sharpening of orientation tuning curves near
      the trained orientation after learning can be accounted for by slightly reducing
      net excitatory connections to cells around the trained orientation, while the
      broadening and peak shift of the tuning curves after adaptation can be reproduced
      by appropriately scaling down both excitation and inhibition around the adapted
      orientation. In addition, we investigated the perceptual consequences of the
      tuning curve changes induced by learning and adaptation using signal detection
      theory. We found that in the case of learning, the physiological changes can
      account for the psychophysical data well. In the case of adaptation, however,
      there is a clear discrepancy between the psychophysical data from alert human
      subjects and the physiological data from anesthetized animals. Instead, human
      adaptation studies can be better accounted for by the learning data from behaving
      animals. Our work suggests that adaptation in behaving subjects may be viewed as
      a short-term form of learning.

PMID- 12611962
TI  - Early development of voltage-gated ion currents and firing properties in neurons
      of the mouse cerebral cortex.
AB  - Voltage- and current-clamp recordings were made from acute slices of mouse
      cerebral cortex from embryonic day 14 to postnatal day 17. We targeted cells in
      the migratory population of the embryonic intermediate zone (IZ) and in deep
      layers of embryonic and postnatal cortical plate (CP). IZ neurons maintain fairly
      consistent properties through the embryonic period, all expressing high-input
      resistance, inward Na(+) currents and outward K(+) currents, and none showing any
      hyperpolarization-activated currents. In CP neurons, several changes in
      physiological properties occur in the late embryonic and early postnatal period:
      inward Na(+) current density is strongly upregulated while outward K(+) current
      density remains almost unchanged, input resistance drops dramatically, and a
      hyperpolarization-activated current resembling I(h) appears. As a result of these
      changes, the action potential becomes larger, shorter in duration, and its
      threshold shifts to more negative potentials. In addition, CP cells become
      capable of firing repetitively and an increasing fraction show spontaneous action
      potentials. This coordinated development of ion channel properties may help to
      time the occurrence of developmentally relevant spontaneous activity in the
      immature cortex.

PMID- 12611963
TI  - NMDA receptor blockade in the superior colliculus increases receptive field size
      without altering velocity and size tuning.
AB  - Neonatal brain injury triggers compensatory processes that can be adaptive or
      detrimental, but little is known about the mechanisms of compensation or how they
      might affect the response properties of neurons within the injured region. We
      have studied this issue in a rodent model. Partial ablation of the hamster
      superior colliculus (SC) at birth results in a compressed but complete visual
      field map in the remaining SC and a compensatory conservation of receptive field
      (RF) size and stimulus velocity and size tuning. The circuit underlying stimulus
      tuning in this system or its preservation after brain lesions is not known. Our
      previous work has shown that N-methyl-d-aspartate (NMDA) receptors are necessary
      for the development and conservation of RF size after partial SC ablation. In
      this study, we examined whether NMDA receptor function is also necessary for the
      development and conservation of stimulus velocity and size tuning. We found that
      velocity and size tuning were unaffected by chronic postnatal blockade of NMDA
      receptors and the resulting increases in RF size. Thus NMDA receptors in the SC
      are not necessary for the development of stimulus velocity and size tuning or in
      the compensatory maintenance of these properties following brain damage. These
      results suggest that stimulus velocity and size tuning may arise in the retina or
      from NMDA receptor-independent circuitry intrinsic to SC. The lack of conflict
      between NMDA receptor activity-dependent and -independent processes may allow
      conservation of some RF properties while others change during injury-induced or
      evolutionary changes in afferent/target convergence.

PMID- 12611964
TI  - Mutation and activation of Galpha s similarly alters pre- and postsynaptic
      mechanisms modulating neurotransmission.
AB  - Constitutive activation of Galphas in the Drosophila brain abolishes associative
      learning, a behavioral disruption far worse than that observed in any single cAMP
      metabolic mutant, suggesting that Galphas is essential for synaptic plasticity.
      The intent of this study was to examine the role of Galphas in regulating
      synaptic function by targeting constitutively active Galphas to either pre- or
      postsynaptic cells and by examining loss-of-function Galphas mutants (dgs) at the
      glutamatergic neuromuscular junction (NMJ) model synapse. Surprisingly, both loss
      of Galphas and activation of Galphas in either pre- or postsynaptic compartment
      similarly increased basal neurotransmission, decreased short-term plasticity
      (facilitation and augmentation), and abolished posttetanic potentiation. Elevated
      synaptic function was specific to an evoked neurotransmission pathway because
      both spontaneous synaptic vesicle fusion frequency and amplitude were unaltered
      in all mutants. In the postsynaptic cell, the glutamate receptor field was
      regulated by Galphas activity; based on immunocytochemical studies, GluRIIA
      receptor subunits were dramatically downregulated (>75% decrease) in both loss
      and constitutive active Galphas genotypes. In the presynaptic cell, the synaptic
      vesicle cycle was regulated by Galphas activity; based on FM1-43 dye imaging
      studies, evoked vesicle fusion rate was increased in both loss and constitutively
      active Galphas genotypes. An important conclusion of this study is that both
      increased and decreased Galphas activity very similarly alters pre- and
      postsynaptic mechanisms. A second important conclusion is that Galphas activity
      induces transynaptic signaling; targeted Galphas activation in the presynapse
      downregulates postsynaptic GluRIIA receptors, whereas targeted Galphas activation
      in the postsynapse enhances presynaptic vesicle cycling.

PMID- 12611965
TI  - Nature of variability in saccades.
AB  - We studied the variability in saccades by comparing the peak velocities of
      saccades with the same target amplitude made with different actual amplitudes. We
      tested three hypotheses: the pulse-height noise hypothesis (peak velocity and
      amplitude vary proportionally), the localization noise hypothesis (variability in
      amplitude and peak velocity lie along the main sequence), and the independent
      noise hypothesis (variability in amplitude and peak velocity are independent). We
      measured eye orientation in two experiments by a scleral coil and a video system.
      Surprisingly, the main source of variability of saccades depended on the
      measurement system used. A combination of localization noise and independent
      noise best describes the data obtained by the video system. The independent noise
      (e.g., measurement inaccuracy) was the main source of variability. For the
      scleral coils, the variability was considerably larger than for the less accurate
      video system. The pulse-height noise hypothesis best describes this additional
      variability. Therefore we conclude that pulse-height noise is the main source of
      variability in saccades measured with scleral coils. We discuss the influence of
      scleral coils on saccade generation and suggest that a change in motor strategy
      due to the discomfort of wearing the coils might be the cause of the increased
      variability.

PMID- 12611966
TI  - Relation between bicarbonate concentration and voltage dependence of sodium
      currents in freshly isolated CA1 neurons of the rat.
AB  - It recently has been shown that whole cell calcium and sodium currents are
      modulated by CO(2)/HCO(3)(-)-buffered saline. While the bicarbonate ion, but not
      CO(2), has been proven to modulate calcium currents, this information is lacking
      for sodium currents. Furthermore, it is not known whether the strength of
      modulation dependents on the bicarbonate concentration or whether it is an all-or
      nothing phenomenon. To answer these questions, we used the whole cell voltage
      clamp technique on freshly isolated hippocampal CA1 neurons from the rat. A
      voltage step from -130 to -20 mV elicited a sodium current with an amplitude of 
      5.1 +/- 0.5 nA (mean +/- SE, n = 17) when cells were superfused with HEPES
      buffered saline. The amplitude of this current increased during a subsequent
      superfusion with solutions containing increasing amounts of bicarbonate and CO(2)
      (%CO(2)/mM HCO(3)(-): 2.5/5.6; 5.0/18; 10/37), with a maximal increment in 10%
      CO(2)/37 mM HCO(3)(-) of -6.9 +/- 0.8 nA. The increase in amplitude was
      associated with a linear negative shift (slope: -0.7 mV/mM HCO(3)(-)) of the
      potential of half-maximal activation (DeltaV(h,a): -19.4 +/- 1.8 mV in 10% CO(2))
      but not with an alteration in the maximal conductance (g(max): HEPES: 203.1 +/-
      21.0 nS and 10% CO(2)/37 mM HCO(3)(-): 207.3 +/- 21.3 nS). In addition, the
      potential of half-maximal inactivation (V(h,i)) shifted to more negative
      potentials (slope: -0.6 mV/mM HCO(3)(-)) with increasing amounts of bicarbonate
      and CO(2) (HEPES: -53.6 +/- 11.8 mV; 10% CO(2)/37 mM HCO(3)(-): -69.8 +/- 2.1
      mV), making the amplitude of the current highly sensitive for small potential
      changes at resting membrane potential. The same negative shift in voltage
      dependence arose when cells were exposed to solutions with different amounts of
      bicarbonate (5.6; 18; 26 mM) but constant CO(2) (5%) with slope rates of -0.5
      mV/mM HCO(3)(-) for V(h,a) and -0.5 mV/mM HCO(3)(-) for V(h,i). Again, there was
      no correlation between bicarbonate concentration and the size of g(max). When
      currents were evoked in solutions containing a constant concentration (18 mM) of
      bicarbonate but different amounts of CO(2) (2.5; 5.0 10%), no significant changes
      have been observed. The present data demonstrate that bicarbonate ions, and not
      CO(2), modulate voltage-gated sodium currents in a concentration-dependent
      manner. Because the amplitude of the sodium current becomes highly sensitive to
      membrane potential changes concomitant with increased bicarbonate amounts, this
      may be critical for the excitability of the neuronal network in situations (like
      metabolic acidosis, respiratoric alkalosis and hypercapnia) in which the
      concentration of this ion can alter.

PMID- 12611967
TI  - New corticocuneate cellular mechanisms underlying the modulation of cutaneous
      ascending transmission in anesthetized cats.
AB  - The ascending cutaneous transmission through the middle cuneate nucleus is
      subject to cortico-feedback modulation. This work studied the intracuneate
      cellular mechanisms underlying the corticocuneate influence. Single unit
      extracellular records combined with iontophoresis showed that the corticocuneate
      input activates cuneo-lemniscal (CL) and noncuneo-lemniscal (nCL) cells via N
      methyl-D-aspartate (NMDA) and non-NMDA receptors as shown by the decrease of the
      cortical-induced activation on ejection of CNQX and APV, either alone or in
      combination. These results were confirmed by in vivo intracellular recordings.
      Two subgroups of nCL cells were distinguished according to their sensitivity to
      iontophoretic ejection of glycine and its antagonist, strychnine. Finally, the
      corticalevoked activation of CL cells was decreased by GABA and increased by
      glycine acting at a strychnine-sensitive site, indicating that glycine indirectly
      affects the cuneo-lemniscal transmission. A model is proposed whereby the cortex
      influences CL cells through three different mechanisms, producing 1) activation
      via non-NMDA and NMDA receptors, 2) inhibition through GABAergic nCLs, and 3)
      disinhibition via serial glycinergic-GABAergic nCL cells. These corticocuneate
      feedback effects serve to potentiate the activity of CL cells topographically
      aligned through direct activation and disinhibition, while inhibiting, via
      GABAergic cells, other CL neurons not topographically aligned.

PMID- 12611968
TI  - Orexin-A depolarizes nucleus tractus solitarius neurons through effects on
      nonselective cationic and K+ conductances.
AB  - The nucleus tractus solitarius (NTS) plays central roles in a number of autonomic
      functions including cardiovascular control. Orexin (ORX)-A is a 33-amino-acid
      peptide implicated in the central regulation of energy metabolism, sleep, and the
      cardiovascular system. Studies demonstrate the presence of ORX-immunoreactive
      axons and both OX(1)R (orexin receptor) and OX(2)R mRNA within NTS. In this
      study, whole cell patch-clamp recordings were obtained from NTS neurons in rat
      medullary slices. Current-clamp studies showed that bath application of various
      concentrations of ORX-A depolarized 90.7% (78 of 86) of neurons tested while the
      remaining cells were either unaffected or showed small hyperpolarizations in
      response to peptide administration. Depolarizing effects were maintained in the
      presence of 5 microM TTX, and were concentration dependent. Using voltage-clamp
      techniques, we also identified modulatory actions of ORX-A on specific ion
      channels. Our results demonstrate that not only does ORX-A inhibit a specific
      potassium conductance (the sustained K(+) current) in NTS neurons, but it also
      activates a nonselective cationic conductance (NSCC). These data suggest that ORX
      A effects on central cardiovascular control may result from direct actions on NTS
      neurons and also highlight the ability of this peptide to influence neuronal
      excitability as a consequence of concurrent modulation of multiple ion channels.

PMID- 12611969
TI  - What determines the frequency of fast network oscillations with irregular neural
      discharges? I. Synaptic dynamics and excitation-inhibition balance.
AB  - When the local field potential of a cortical network displays coherent fast
      oscillations ( approximately 40-Hz gamma or approximately 200-Hz sharp-wave
      ripples), the spike trains of constituent neurons are typically irregular and
      sparse. The dichotomy between rhythmic local field and stochastic spike trains
      presents a challenge to the theory of brain rhythms in the framework of coupled
      oscillators. Previous studies have shown that when noise is large and recurrent
      inhibition is strong, a coherent network rhythm can be generated while single
      neurons fire intermittently at low rates compared to the frequency of the
      oscillation. However, these studies used too simplified synaptic kinetics to
      allow quantitative predictions of the population rhythmic frequency. Here we show
      how to derive quantitatively the coherent oscillation frequency for a randomly
      connected network of leaky integrate-and-fire neurons with realistic synaptic
      parameters. In a noise-dominated interneuronal network, the oscillation frequency
      depends much more on the shortest synaptic time constants (delay and rise time)
      than on the longer synaptic decay time, and approximately 200-Hz frequency can be
      realized with synaptic time constants taken from slice data. In a network
      composed of both interneurons and excitatory cells, the rhythmogenesis is a
      compromise between two scenarios: the fast purely interneuronal mechanism, and
      the slower feedback mechanism (relying on the excitatory-inhibitory loop). The
      properties of the rhythm are determined essentially by the ratio of time scales
      of excitatory and inhibitory currents and by the balance between the mean
      recurrent excitation and inhibition. Faster excitation than inhibition, or a
      higher excitation/inhibition ratio, favors the feedback loop and a much slower
      oscillation (typically in the gamma range).

PMID- 12611970
TI  - Effects of ventrobasal lesion and cortical cooling on fast oscillations (>200 Hz)
      in rat somatosensory cortex.
AB  - High-frequency oscillatory activity (>200 Hz) termed "fast oscillations" (FO)
      have been recorded in the rodent somatosensory cortex and may reflect very rapid
      integration of vibrissal information in sensory cortex. Yet, while
      electrophysiological correlates suggest that FO is generated within intracortical
      networks, contributions of subcortical structures along the trigeminal pathway
      remain uncertain. Using surface and laminar electrode arrays, in vivo recordings
      of vibrissal and electrically evoked FO were made within somatosensory cortex of
      anesthetized rodents before and after ablation of the ventrobasal thalamus (VB)
      or during reversible cortical cooling. In VB-lesioned animals, vibrissal
      stimulation failed to evoke FO, while epicortical stimulation in lesioned animals
      remained effective in generating FO. In nonlesioned animals, cortical cooling
      eliminated vibrissal-evoked FO despite the persistence of thalamocortical input.
      Vibrissal-evoked FO returned with the return to physiological temperatures.
      Results from this study indicate that somatosensory cortex alone is able to
      initiate and sustain FO. Moreover, these data suggest that cortical network
      interactions are solely responsible for the generation of FO, while synchronized
      thalamocortical input serves as the afferent trigger.

PMID- 12611971
TI  - Fast and slow locomotor burst generation in the hemispinal cord of the lamprey.
AB  - A fundamental question in vertebrate locomotion is whether distinct spinal
      networks exist that are capable of generating rhythmic output for each group of
      muscle synergists. In many vertebrates including the lamprey, it has been claimed
      that burst activity depends on reciprocal inhibition between antagonists. This
      question was addressed in the isolated lamprey spinal cord in which the left and
      right sides of each myotome display rhythmic alternating activity. We sectioned
      the spinal cord along the midline and tested whether rhythmic motor activity
      could be induced in the hemicord with bath-applied D-glutamate or N-methyl-D
      aspartate (NMDA) as in the intact spinal cord or by brief trains of electrical
      stimuli. Fast rhythmic bursting (2-12 Hz), coordinated across ventral roots, was
      observed with all three methods. Furthermore, to diminish gradually the crossed
      glycinergic inhibition, a progressive surgical lesioning of axons crossing the
      midline was implemented. This resulted in a gradual increase in burst frequency,
      linking firmly the fast hemicord rhythm [6.6 +/- 1.7 (SD) Hz] to fictive swimming
      in the intact cord (2.4 +/- 0.7 Hz). Ipsilateral glycinergic inhibition was not
      required for the hemicord burst pattern generation, suggesting that an
      interaction between excitatory glutamatergic neurons suffices to produce the
      unilateral burst pattern. In NMDA, burst activity at a much lower rate (0.1-0.4
      Hz) was also encountered, which required the voltage-dependent properties of NMDA
      receptors in contrast to the fast rhythm. Swimming is thus produced by pairs of
      unilateral burst generating networks with reciprocal inhibitory connections that
      not only ensure left/right alternation but also downregulate frequency.

PMID- 12611972
TI  - Primate pupillary light reflex: receptive field characteristics of pretectal
      luminance neurons.
AB  - This study examined the response properties of luminance neurons found within the
      pretectal olivary nucleus (PON), which is the pretectal nucleus that mediates the
      primate pupillary light reflex. We recorded the activity of 121 single units in
      alert, behaving rhesus monkeys trained to fixate a back-projected laser spot
      while a luminance stimulus was presented. The change in the firing rate of
      luminance neurons was measured as a function of changes in the size, retinal
      illuminance, and position of the stimulus. We found that these neurons possessed
      large receptive fields, which were sufficiently distinct that they could be
      placed into three classes. Approximately 40% of the PON luminance neurons
      responded well to stimuli presented in either the contralateral or ipsilateral
      hemifield. These neurons were classified as "bilateral" neurons. In the primate,
      retinal projections to the pretectum and other retinorecipient nuclei are
      organized such that direct retinal input can only account for the contralateral
      hemifield responses of these neurons. Thus the representation of the ipsilateral
      hemifield in "bilateral" PON cells must result from input from a nonretinal
      source. Approximately 30% of PON neurons responded only to stimuli presented in
      the contralateral hemifield. These neurons were classified as "contralateral"
      neurons. Finally, approximately 30% of PON neurons responded to stimuli presented
      at or near the animal's fixation point. These neurons were classified as
      "macular" neurons. The mean firing rates of all classes of neurons increased with
      increases in stimulus size and luminance within their receptive fields. The
      thresholds and magnitude of these responses closely matched those that would be
      appropriate for mediating the pupillary light reflex. In summary, these results
      suggest that all three classes of PON neurons contribute to the behaviorally
      observed pupillomotor field characteristics in which stimuli at the macular
      produce substantially larger pupillary responses than more peripheral stimuli.
      The contributions of "bilateral" and "contralateral" cells account for pupillary
      responses evoked by peripheral changes in luminance, whereas the contributions of
      all three cell classes account for the larger pupillary responses evoked by
      stimuli in the central visual field.

PMID- 12611973
TI  - Characteristics of the pupillary light reflex in the alert rhesus monkey.
AB  - This study investigated the static and dynamic characteristics of the pupillary
      light reflex (PLR) in the alert rhesus monkey. Temporal characteristics of the
      PLR were investigated with Maxwellian viewing during sinusoidal changes in
      illumination of a 36 degrees stimulus in both monkeys and humans. Bode plots of
      the PLR response were fitted by a linear model composed of a delay combined with
      a cascaded first- and second-order filter. The Bode magnitude plots conformed to
      this model with a sharp roll-off above 1.3 Hz for the human PLR and 1.9 Hz for
      the monkey PLR. Bode phase angle plots were fitted by this model with a delay of
      280 ms for humans and 160 ms for monkeys. To investigate the influence of the
      sympathetic innervation of the iris on steady-state pupil diameter, dynamics of
      pupillary responses, and the latency of the PLR, we blocked this innervation
      pharmacologically with a selective alpha-1 adrenoreceptor antagonist. Although
      there was a resultant miosis (decrease in pupil diameter) from the relaxation of
      the pupil dilator muscle, no other measures of the PLR, including the dynamics
      and latency, were significantly affected by this treatment. We examined the
      pupillary responses evoked by visual stimuli presented either binocularly or
      monocularly at various locations on a 80 x 60 degrees tangent screen. These
      pupillomotor fields revealed that, as has been reported for humans, stimuli at
      the fovea and surrounding macular region of monkeys produce substantially larger
      pupillary responses than more peripheral stimuli and that binocular responses are
      substantially greater than can be accounted for by the linear summation of
      binocular retinal illuminance. In conclusion, we found that the spatial
      characteristics of the PLR of the rhesus monkey are very similar, in all
      important aspects, to those reported for humans and that the temporal responses
      of the PLR are comparable between the two species. The rhesus monkey thus
      provides an excellent model for experimental studies of the neural control of the
      pupil.

PMID- 12611974
TI  - Human amylin actions on rat cholinergic basal forebrain neurons: antagonism of
      beta-amyloid effects.
AB  - Human amylin (hAmylin), a 37-amino acid pancreatic peptide, and amyloid beta
      protein (A beta), a 39-43 amino acid peptide, abundantly deposited in the brains
      of Alzheimer's patients, induce neurotoxicity in hippocampal and cortical
      cultures. Although the mechanism of this neurotoxicity is unknown, both peptides
      are capable of modulating ion channel function that may result in a disruption of
      cellular homeostasis. In this study, we examined the effects of hAmylin on whole
      cell currents in chemically identified neurons from the rat basal forebrain and
      the interactions of hAmylin-induced responses with those of A beta. Whole cell
      patch-clamp recordings were performed on enzymatically dissociated neurons of the
      diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. Bath
      application of hAmylin (1 nM to 5 microM) resulted in a dose-dependent reduction
      in whole cell currents in a voltage range between -30 and +30 mV. Single-cell RT
      PCR analysis reveal that all DBB neurons responding to hAmylin or A beta were
      cholinergic. Using specific ion channel blockers, we identified hAmylin and A
      beta effects on whole cell currents to be mediated, in part, by calcium-dependent
      conductances. Human amylin also depressed the transient outward (IA) and the
      delayed rectifier (IK) potassium currents. The hAmylin effects on whole cell
      currents could be occluded by A beta and vice versa. Human amylin and A beta
      responses could be blocked with AC187 (50 nM to 1 microM), a specific antagonist
      for the amylin receptor. The present study indicates that hAmylin, like A beta,
      is capable of modulating ion channel function in cholinergic basal forebrain
      neurons. Furthermore, the two peptides may share a common mechanism of action.
      The ability of an amylin antagonist to block the responses evoked by hAmylin and
      A beta may provide a novel therapeutic approach for Alzheimer's disease.

PMID- 12611975
TI  - Chemical response pattern of different classes of C-nociceptors to pruritogens
      and algogens.
AB  - Vasoneuroactive substances were applied through intradermal microdialysis
      membranes and characterized as itch- or pain-inducing in psychophysical
      experiments. Histamine always provoked itching and rarely pain, capsaicin always
      pain but never itching. Prostaglandin E(2) (PGE(2)) led preferentially to
      moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more
      often than itching. Subsequently the same substances were used in
      microneurography experiments to characterize the sensitivity profile of human
      cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal
      nociceptors), 52 mechanoinsensitive, histamine-negative (CMi(His-)), and 24
      mechanoinsensitive, histamine-positive (CMi(His+)) units were compared. CMi(His+)
      units were most responsive to histamine and to PGE(2) and less to serotonin, ACh,
      bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi(His-) units
      showed significantly weaker responses to histamine, PGE(2), and acetylcholine.
      Capsaicin and bradykinin responses were not significantly different in the two
      classes of mechano-insensitive units. We conclude that CMi(His+) units are
      "selective," but not "specific" for pruritogenic substances and that the pruritic
      potency of a mediator increases with its ability to activate CMi(His+) units but
      decreases with activation of CMH and CMi(His-) units.

PMID- 12611976
TI  - Contribution of BK Ca2+-activated K+ channels to auditory neurotransmission in
      the Guinea pig cochlea.
AB  - Large-conductance calcium-activated potassium (BK) channels are known to play a
      prominent role in the hair cell function of lower vertebrates where these
      channels determine electrical tuning and regulation of neurotransmitter release.
      Very little is known, by contrast, about the role of BK channels in the mammalian
      cochlea. In the current study, we perfused specific toxins in the guinea pig
      cochlea to characterize the role of BK channels in cochlear neurotransmission.
      Intracochlear perfusion of charybdotoxin (ChTX) or iberiotoxin (IbTX) reversibly
      reduced the compound action potential (CAP) of the auditory nerve within minutes.
      The cochlear microphonics (CM at f1 = 8 kHz and f2 = 9.68 kHz) and their
      distortion product (DPCM at 2f1-f2) were essentially not affected, suggesting
      that the BK specific toxins do not alter the active cochlear amplification at the
      outer hair cells (OHCs). We also tested the effects of these toxins on the whole
      cell voltage-dependent membrane current of isolated guinea pig inner hair cells
      (IHCs). ChTX and IbTX reversibly reduced a fast outward current (activating above
      -40 mV, peaking at 0 mV with a mean activation time constant tau ranging between
      0.5 and 1 ms). A similar block of a fast outward current was also observed with
      the extracellular application of barium ions, which we believe permeate through
      Ca2+ channels and block BK channels. In situ hybridization of Slo antisense
      riboprobes and immunocytochemistry demonstrated a strong expression of BK
      channels in IHCs and spiral ganglion and to a lesser extent in OHCs. Overall, our
      results clearly revealed the importance of BK channels in mammalian cochlear
      neurotransmission and demonstrated that at the presynaptic level, fast BK
      channels are a significant component of the repolarizing current of IHCs.

PMID- 12611977
TI  - Unitary EPSCs of corticogeniculate fibers in the rat dorsal lateral geniculate
      nucleus in vitro.
AB  - To investigate unitary corticogeniculate excitatory postsynaptic currents
      (EPSCs), whole cell patch-clamp recordings were obtained from 20 principal cells
      in slices of the dorsal lateral geniculate nucleus (dLGN) of DA-HAN rats. EPSCs,
      evoked by electrical stimulation of corticogeniculate axons, had size
      distributions with one or more quantal peaks. Gaussian curves fitted to such
      distributions gave a mean quantal size (q) of -5.0 +/- 0.7 (SD) pA for the EPSCs.
      Paired-pulse ratio (EPSC2/EPSC1) was 3.3 +/- 0.9 for stimuli separated by 40 ms.
      The mean quantal size was similar for facilitated EPSCs (-5.2 +/- 0.8 pA),
      implying an increase in mean quantal content (m). Most corticogeniculate axons
      were capable of releasing only one or two quanta onto individual principal cells.
      Mean resting release probability (p) was low, 0.09 +/- 0.04. Binomial models,
      with the same n but increased p, could account for both the basal and facilitated
      EPSC size distributions in 6/8 cells. It is suggested that the low resting
      efficacy of corticogeniculate synapses serves to stabilize this excitatory
      feedback system. The pronounced facilitation in conjunction with large
      convergence from many corticogeniculate cells would provide a transient, potent
      excitation of dLGN cells, compliant with the idea of a visually driven neuronal
      amplifier.

PMID- 12611978
TI  - An information theoretic approach to the contributions of the firing rates and
      the correlations between the firing of neurons.
AB  - To analyze the extent to which populations of neurons encode information in the
      numbers of spikes each neuron emits or in the relative time of firing of the
      different neurons that might reflect synchronization, we developed and analyzed
      the performance of an information theoretic approach. The formula quantifies the
      corrections to the instantaneous information rate that result from correlations
      in spike emission between pairs of neurons. We showed how these cross-cell terms
      can be separated from the correlations that occur between the spikes emitted by
      each neuron, the auto-cell terms in the information rate expansion. We also
      described a method to test whether the estimate of the amount of information
      contributed by stimulus-dependent synchronization is significant. With simulated
      data, we show that the approach can separate information arising from the number
      of spikes emitted by each neuron from the redundancy that can arise if neurons
      have common inputs and from the synergy that can arise if cells have stimulus
      dependent synchronization. The usefulness of the approach is also demonstrated by
      showing how it helps to interpret the encoding shown by neurons in the primate
      inferior temporal visual cortex. When applied to a sample dataset of
      simultaneously recorded inferior temporal cortex neurons, the algorithm showed
      that most of the information is available in the number of spikes emitted by each
      cell; that there is typically just a small degree (approximately 12%) of
      redundancy between simultaneously recorded inferior temporal cortex (IT) neurons;
      and that there is very little gain of information that arises from stimulus
      dependent synchronization effects in these neurons.

PMID- 12611979
TI  - How do infants adapt to loading of the limb during the swing phase of stepping?
AB  - Previous results from this laboratory have shown that human infants (<12 mo old)
      respond appropriately to transient changes in sensory input during stepping. We
      examined how infants adapted to a more enduring change in sensory input by
      applying load to one limb during stepping. A small weight (500-900 g) was
      strapped around the lower leg of infants aged 3-11 mo. Stepping with the weight
      on was recorded on the treadmill for a period of 0.5-3 min. The weight was then
      quickly detached during stepping, and the immediate response to unexpected loss
      of the weight recorded. Three-segment dynamic analysis of leg motion was used to
      estimate hip, knee, and ankle torques during swing in the sagittal plane. All
      infants adapted to the additional load on the leg by immediately increasing the
      generation of hip and knee flexor muscle torques. When the weight was removed, 7
      of the 22 infants tested exhibited an after-effect (high stepping) in the first
      step after removal of the weight. The after-effect was manifested as an increase
      in toe trajectory height and hip flexion and coincided with higher hip flexor
      muscle torque in early swing. In an additional series of control experiments
      using seven infants, after-effects were shown to be unrelated to a sudden change
      in cutaneous input with removal of the weight. The presence of an after-effect
      indicates that some infants made an enduring adaptation to their stepping pattern
      that is revealed with the unexpected removal of the weight.

PMID- 12611980
TI  - PKA and PKC enhance excitatory synaptic transmission in human dentate gyrus.
AB  - cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) are two major
      modulators of synaptic transmission in the CNS but little is known about how they
      affect synaptic transmission in the human CNS. In this study, we used forskolin,
      a PKA activator, and phorbol ester, a PKC activator, to examine the effects of
      these kinases on synaptic transmission in granule cells of the dentate gyrus in
      human hippocampal slices using whole-cell recording methods. We found that both
      forskolin and phorbol ester increased the frequency of spontaneous and miniature
      excitatory postsynaptic currents (sEPSCs and mEPSCs) but left the amplitude
      unaffected. Inactive forskolin and phorbol ester had no effect on sEPSCs in human
      dentate granule cells. Prior application of forskolin occluded the effects of
      phorbol ester on mEPSC frequency. Tetanic stimulation applied to the perforant
      path induced short-term depression in dentate gyrus granule cells. Both forskolin
      and phorbol ester significantly enhanced this short-term depression. Taken
      together, these results demonstrate that PKA and PKC are involved in up
      regulation of excitatory synaptic transmission in human dentate granule cells,
      primarily by presynaptic mechanisms. In addition, the occlusion experiments
      suggest that the two kinases may share a common signal pathway.

PMID- 12611981
TI  - Amygdala input promotes spread of excitatory neural activity from perirhinal
      cortex to the entorhinal-hippocampal circuit.
AB  - A number of sensory modalities most likely converge in the rat perirhinal cortex.
      The perirhinal cortex also interconnects with the amygdala, which plays an
      important role in various motivational and emotional behaviors. The neural
      pathway from the perirhinal cortex to the entorhinal cortex is considered one of
      the main paths into the entorhinal-hippocampal network, which has a crucial role
      in memory processes. To investigate the potential associative function of the
      perirhinal cortex with respect to sensory and motivational stimuli and the
      influence of the association on the perirhinal-entorhinal-hippocampal
      neurocircuit, we prepared rat brain slices including the perirhinal cortex,
      entorhinal cortex, hippocampal formation, and amygdala. We used an optical
      imaging technique with a voltage-sensitive dye to analyze 1) the spatial and
      functional distribution of inputs from the lateral nucleus of the amygdala to the
      perirhinal cortex; 2) the spread of neural activity in the perirhinal cortex
      after layers II/III stimulation, which mimics sensory input to the perirhinal
      cortex; and 3) the effect of associative inputs to the perirhinal cortex from
      both the lateral amygdaloid nucleus and layers II/III of the perirhinal cortex on
      the perirhinal-entorhinal-hippocampal neurocircuit. Following stimulation in the
      superficial layers of the perirhinal cortex, electrical activity only propagated
      into the entorhinal cortex when sufficient activation occurred in the deep layers
      of perirhinal area 35. We observed that single stimulation of either the
      perirhinal cortex or amygdala did not result in sufficient neural activation of
      the deep layers of areas 35 to provoke activity propagation into the entorhinal
      cortex. However, the deep layers of area 35 were depolarized much more strongly
      when the two stimuli were applied simultaneously, resulting in spreading
      activation in the entorhinal cortex. Our observations suggest that a functional
      neural basis for the association of higher-order sensory inputs and emotion
      related inputs exists in the perirhinal cortex and that transfer of sensory
      information to the entorhinal-hippocampal circuitry might be affected by the
      association of that information with incoming information from the amygdala.

PMID- 12611982
TI  - Nicotinic receptors on local circuit neurons in dentate gyrus: a potential role
      in regulation of granule cell excitability.
AB  - Although the dentate gyrus is one of the primary targets of septo-hippocampal
      cholinergic afferents, relatively little is known about the cholinergic
      physiology of neurons in the area. By combining whole cell patch-clamp recording
      with brief local application of exogenous agonists in horizontal slices, we found
      that there is robust expression of functional somatic alpha 7-containing
      nicotinic acetylcholine receptors (nAChRs) on molecular layer interneurons, hilar
      interneurons, and the glutamatergic mossy cells of the dentate hilus. In
      contrast, the principal neurons of the dentate gyrus, the granule cells, are
      generally unresponsive to focal somatic or dendritic application of ACh in the
      presence of atropine. We also demonstrate that cholinergic activation of alpha 7
      containing nAChRs on the subgranular interneurons of the hilus can produce
      methyllycaconitine-sensitive GABAergic inhibitory postsynaptic currents (IPSCs)
      in nearby granule cells and enhance the amplitude of an electrically evoked
      monosynaptic IPSC. Further, activation of alpha 7-containing nAChRs on
      subgranular interneurons that is timed to coincide with synaptic release of
      glutamate onto these cells will enhance the functional inhibition of granule
      cells. These findings suggest that a complex interplay between glutamatergic
      afferents from the entorhinal cortex and cholinergic afferents from the medial
      septum could be involved in the normal regulation of granule cell function. Such
      a relationship between these two afferent pathways could be highly relevant to
      the study of both age-related memory dysfunction and disorders involving
      regulation of excitability, such as temporal lobe epilepsy.

PMID- 12611983
TI  - A slow fraction of Mg2+ unblock of NMDA receptors limits their contribution to
      spike generation in cortical pyramidal neurons.
AB  - The timing of voltage-dependent removal of Mg(2+) block of N-methyl-d-aspartate
      receptors (NMDARs) is potentially critical for determining their nonlinear
      contribution to excitability. Here, we measure the kinetics of NMDAR unblock in
      nucleated patch and whole cell recordings of rat cortical pyramidal neurons
      during depolarizing voltage steps. At room temperature, the unblock showed a very
      fast component (tau < 1 ms) and a slower component (tau = 14-23 ms in nucleated
      patches). The slow component accounted for half of the current at +40 mV and its
      amplitude and time constant showed some voltage dependence. Blocking with
      hyperpolarization was very fast (tau < 200 micros). Voltage-clamp with action
      potential waveforms, at both room temperature and at 33 degrees C, showed that
      the rising phase of single fast action potentials unblocks far less NMDAR current
      than expected from the stationary voltage dependence, while a large amplitude of
      current is uncovered during the upstroke of slow calcium action potentials. The
      repolarization of fast sodium action potentials uncovers an NMDAR tail current,
      much bigger than the stationary level of current.

PMID- 12611984
TI  - Effects of partial lidocaine inactivation of the paramedian pontine reticular
      formation on saccades of macaques.
AB  - To investigate the brain stem control of saccadic eye movements, the paramedian
      pontine reticular formation (PPRF) in rhesus monkeys was temporarily and
      partially inactivated with the local anesthetic lidocaine. The influence on
      ipsilesional, contralesional, and upward saccades was examined. While the effects
      of the inactivation on contralesional and upward saccades were inconsistent and
      small, consistent and marked modifications were observed for ipsilesional
      movements. For ipsilesional, horizontal saccades, all lidocaine injections caused
      a decrease in peak velocity and a proportional increase in duration, which
      substantially altered the shape of the velocity profile. The rise in duration
      usually fell short of preventing hypometric saccades at the peak of the effect.
      However, as the lidocaine effect dissipated, the amplitude often returned to
      control, even though the velocity and duration remained compromised. For
      ipsilesional, oblique saccades, the effect of lidocaine on the horizontal
      component was similar to that for horizontal saccades. The vertical component of
      oblique saccades was also influenced, albeit to a much lesser extent: the
      duration of the vertical component typically increased, while the vertical peak
      velocity either decreased or exhibited no significant change. These results were
      compared with simulations of three prominent models for cross-coupling oblique
      saccades. In general, these results of the temporary inactivation of PPRF are
      consistent with the predictions of local feedback models for saccadic control.

PMID- 12611985
TI  - Contrast threshold of a brisk-transient ganglion cell in vitro.
AB  - We measured the contrast threshold for mammalian brisk-transient ganglion cells
      in vitro. Spikes were recorded extracellularly in the intact retina (guinea pig)
      in response to a spot with sharp onset, flashed for 100 ms over the receptive
      field center. Probability density functions were constructed from spike responses
      to stimulus contrasts that bracketed threshold. Then an "ideal observer" (IO)
      compared additional trials to these probability distributions and decided, using
      a single-interval, two-alternative forced-choice procedure, which contrasts had
      most likely been presented. From these decisions we constructed neurometric
      functions that yielded the threshold contrast by linear interpolation. Based on
      the number of spikes in a response, the IO detected contrasts as low as 1% [4.2
      +/- 0.4% (SE); n = 35]; based on the temporal pattern of spikes, the IO detected
      contrasts as low as 0.8% (2.8 +/- 0.2%). Contrast increments above a very low
      "basal contrast" were discriminated with greater sensitivity than they were
      detected against the background. Performance was optimal near 37 degrees C and
      declined with a Q(10) of about 2, similar to that of retinal metabolism. By the
      method used by previous in vivo studies of brisk-transient cells, our most
      sensitive cells had similar thresholds. The in vitro measurements thus provide an
      important benchmark for comparing sensitivity of neurons upstream (cone and
      bipolar cell) and downstream to assess efficiency of retinal and central
      circuits.

PMID- 12611986
TI  - Differentiation of visceral and cutaneous pain in the human brain.
AB  - The widespread convergence of information from visceral, cutaneous, and muscle
      tissues onto CNS neurons invites the question of how to identify pain as being
      from the viscera. Despite referral of visceral pain to cutaneous areas,
      individuals regularly distinguish cutaneous and visceral pain and commonly have
      contrasting behavioral reactions to each. Our study addresses this dilemma by
      directly comparing human neural processing of intensity-equated visceral and
      cutaneous pain. Seven subjects underwent fMRI scanning during visceral and
      cutaneous pain produced by balloon distention of the distal esophagus and contact
      heat on the midline chest. Stimulus intensities producing nonpainful and painful
      sensations, interleaved with rest periods, were presented in each functional run.
      Analyses compared painful to nonpainful conditions. A similar neural network,
      including secondary somatosensory and parietal cortices, thalamus, basal ganglia,
      and cerebellum, was activated by visceral and cutaneous painful stimuli. However,
      cutaneous pain evoked higher activation bilaterally in the anterior insular
      cortex. Further, cutaneous but not esophageal pain activated ventrolateral
      prefrontal cortex, despite higher affective scores for visceral pain. Visceral
      but not cutaneous pain activated bilateral inferior primary somatosensory cortex,
      bilateral primary motor cortex, and a more anterior locus within anterior
      cingulate cortex. Our results reveal a common cortical network subserving
      cutaneous and visceral pain that could underlie similarities in the pain
      experience. However, we also observed differential activation patterns within
      insular, primary somatosensory, motor, and prefrontal cortices that may account
      for the ability to distinguish visceral and cutaneous pain as well as the
      differential emotional, autonomic and motor responses associated with these
      different sensations.

PMID- 12611987
TI  - Vagal input to lateral area 3a in cat cortex.
AB  - Penfield's sensory homunculus included visceral organs at its lateral extreme,
      and vagal input was recently identified lateral to the intraoral representation
      in primary somatosensory cortex (S1) of rats. We tested whether vagal input is
      similarly located in cats where area 3b (equivalent to S1) is clearly
      distinguishable from adjacent regions. Field potentials were recorded from the
      intact dura over the left hemisphere using electrical stimulation of the left or
      right cervical vagus nerve in seven cats. A surface positive-negative potential
      was evoked from either side in the lateral part of the sigmoid gyrus. Finer
      mapping made at the pial surface with a microelectrode identified a focal site
      anteromedial to the anterior tip of the coronal sulcus. Depth recordings
      demonstrated polarity reversals and multi-unit vagal responses, indicating that
      the potentials were generated by an afferent activation focus in the middle
      layers of the cortex. The S1 mechanoreceptive representation was localized by
      mapping multi-unit somatosensory receptive fields in the middle cortical layers
      near the coronal sulcus. The vagal-evoked potential site was distinctly anterior
      to the intraoral S1 representation and adjacent to the masseteric-nerve-evoked
      potential focus. Lesions made at the focal site revealed that this site is
      cytoarchitectonically located in area 3a not area 3b. Thus vagal input to the
      sensorimotor cortex in cats resembles deep rather than cutaneous somatic input,
      similar to the localization of nociceptive-specific input to area 3a in monkeys.
      The possibilities are considered that this vagal input is involved in motor
      control and in the sensory experience of visceral afferent activity.

PMID- 12611988
TI  - Putaminal activity for simple reactions or self-timed movements.
AB  - To examine the role of basal ganglia-cortical circuits in movement initiation, we
      trained monkeys to make the same arm movements in two ways-in immediate reaction
      to a randomly timed external cue (cued movements) and also following a variable
      delay without an explicit initiation signal (self-timed movements). The two
      movement types were interleaved and balanced in overall timing to allow a direct
      comparison of activity before and during the movement. Posterior putaminal
      neurons generally had phasic, movement-related discharges that were comparable
      for cued and self-timed movements. On cued movements, neuronal activity increased
      sharply following cue onset. However, for self-timed movements, there was a slow
      build-up in activity that preceded the phasic discharge. This slow build-up was
      time-locked to movement and restricted to a narrow time window hundreds of
      milliseconds before movement. The difference in premovement activity between cued
      and self-timed trials was present before the earliest cue-onset times and was not
      related to any differences in the overall time-to-move between the two types of
      trials. These features suggest that activity evolving in the basal ganglia
      cortical circuitry may drive the initiation of movements by increasing until an
      activity threshold is exceeded. The activity may increase abruptly in response to
      an external cue or gradually when the timing of movements is determined by the
      animals themselves rather than an external cue. In this view, small changes in
      activity that occur in advance of the much larger perimovement neuronal activity
      may be an important determinant of when movement occurs. In support of this
      hypothesis, we found that even for cued movements, faster reaction times were
      associated with slightly higher levels of activity hundreds of milliseconds
      before movement.

PMID- 12611989
TI  - Dopamine modulates synaptic transmission between rat olfactory bulb neurons in
      culture.
AB  - The glomerular layer of the olfactory bulb (OB) contains synaptic connections
      between olfactory sensory neurons and OB neurons as well as connections among OB
      neurons. A subpopulation of external tufted cells and periglomerular cells
      (juxtaglomerular neurons) expresses dopamine, and recent reports suggest that
      dopamine can inhibit olfactory sensory neuron activation of OB neurons. In this
      study, whole cell electrophysiological and primary culture techniques were
      employed to characterize the neuromodulatory properties of dopamine on
      glutamatergic transmission between rat OB mitral/tufted (M/T) cells and
      interneurons. Immunocytochemical analysis confirmed the expression of tyrosine
      hydroxylase, the rate-limiting enzyme for dopamine synthesis, in a subpopulation
      of cultured neurons. D2 receptor immunoreactivity was also observed in cultured
      M/T cells. Dopamine reduced spontaneous excitatory synaptic events recorded in
      interneurons. Although the D1 receptor agonist SKF38393 and the D2 receptor
      agonist bromocriptine mesylate mimicked this effect, evoked excitatory
      postsynaptic potentials (EPSPs) recorded from monosynaptically coupled neuron
      pairs were attenuated by dopamine and bromocriptine but not by SKF38393. Neither
      glutamate-evoked currents nor the membrane resistance of the postsynaptic
      interneuron were affected by dopamine. However, evoked calcium channel currents
      in the presynaptic M/T cell were diminished during the application of either
      dopamine or bromocriptine, but not SKF38393. Dopamine suppressed calcium channel
      currents even after nifedipine blockade of L-type channels, suggesting that
      inhibition of the dihydropyridine-resistant high-voltage activated calcium
      channels implicated in transmitter release may mediate dopamine's effects on
      spontaneous and evoked synaptic transmission. Together, these data suggest that
      dopamine inhibits excitatory neurotransmission between M/T cells and interneurons
      via a presynaptic mechanism.

PMID- 12611990
TI  - Drawing sequences of segments in 3D: kinetic influences on arm configuration.
AB  - Complex movements are generally thought to consist of a series of simpler
      elements. If this is so, how does the sensorimotor system assemble the pieces?
      This study recorded and evaluated sequences of arm movements to various targets
      placed in three-dimensional (3D) space. Subjects performed sequences consisting
      of single, double, or triple segments with the same first target but with
      different second targets. The data analysis focused on the first movement segment
      and evaluated hand path curvature, the hand's final approach to the first target,
      and the whole arm postures at the beginning and end. Although some idiosyncratic
      differences in approach were observed, only the final arm posture depended, in a
      consistent way, on which particular movement was to follow as the second segment.
      This provided evidence for "coarticulation" of the two segments, only at the
      level of arm posture, and simulations revealed that this anticipatory
      modification improved the energetic efficiency of the second segment. Data from
      movements through five consecutive triple segments (i.e., 5 triangles) were
      assessed to determine whether kinematic constraints, such as Donders' law, apply
      to repetitive drawing movements. Although such constraints could prevent the
      accumulation of changes in arm posture, this was not observed. Instead, in most
      cases, the elbow was a little bit higher at the end of each triangle than at the
      beginning. Taken together, the results suggest that coarticulation may facilitate
      the joining of two segments and the efficiency of the second movement, but does
      not extend over the drawing of several segments.

PMID- 12611991
TI  - Electrical stimulation of the supplementary eye fields in the head-free macaque
      evokes kinematically normal gaze shifts.
AB  - The supplementary eye fields (SEFs), located on the dorsomedial surface of the
      frontal cortex, are involved in high-level aspects of saccade generation. Some
      reports suggest that the same area could also be involved in the generation of
      motor commands for the head. If so, it is important to establish whether this
      structure encodes eye and head commands separately or gaze commands that give
      rise to coordinated eye-head movements. Here we systematically stimulated (50
      microA, 300 Hz, 200 ms) the SEF of two head-free (head unrestrained) macaques
      while recording three-dimensional eye and head rotations. A total of 55 sites
      were found to consistently elicit saccade-like gaze movements, always in the
      contralateral direction with variable vertical components, and ranging in average
      amplitude from 5 to 60 degrees. These movements were always a combination of eye
      in-head saccades and head-in-space movements. We then performed a comparison
      between these movements and natural gaze shifts. The kinematics of the elicited
      movements (i.e., their temporal structure, their velocity-amplitude
      relationships, and the relative contributions of the eye and the head as a
      function of movement amplitude) were indistinguishable from those of natural gaze
      shifts. Additionally, they obeyed the same three-dimensional constraints as
      natural gaze shifts (i.e., eye-in-head movements obeyed Listing's law, whereas
      head- and eye-in-space movements obeyed Donders' law). In summary, gaze movements
      evoked by stimulating the SEF were indistinguishable from natural coordinated eye
      head gaze shifts. Based on this we conclude that the SEF explicitly encodes gaze
      and that the kinematics aspects of eye-head coordination are implicitly specified
      by mechanisms downstream from the SEF.

PMID- 12611992
TI  - Activity in the parabigeminal nucleus during eye movements directed at moving and
      stationary targets.
AB  - The parabigeminal nucleus (PBN) is a small satellite of the superior colliculus
      located on the edge of the midbrain. To identify activity related to visuomotor
      behavior, we recorded from PBN cells in cats trained to fixate moving and
      stationary targets. Cats tracked moving targets primarily with small catch-up
      saccades, and for target speeds of 2-6 degrees /s, they did so with sufficient
      accuracy to keep targets within 2.5 degrees of the visual axis most of the time.
      During intersaccade intervals of such close-order tracking, PBN cells fired at
      rates related to retinal position error (RPE), the distance between the center of
      the retina and the saccade target. Each cell was characterized by a best
      direction of RPE. Most commonly, activity rose rapidly with increasing RPE,
      peaked at a small RPE within the area centralis, and dropped off gradually with
      increasing target distance. For some cells, the range over which activity was
      monotonically related to RPE was considerably larger, but because the PBN was not
      systematically sampled, the maximum range of RPE encoded is presently unknown.
      During saccades, activity began to change at about peak saccade velocity and then
      rapidly reached a level appropriate to the RPE achieved at saccade end. Most
      response fields were large, and stationary saccade targets presented anywhere
      within them evoked brisk responses that terminated abruptly on saccade offset.
      Spontaneous saccades in the dark had little effect on PBN activity. These data
      suggest that the PBN is an integral part of a midbrain circuit generating target
      location information.

PMID- 12611993
TI  - Spike-dependent GABA inputs to bipolar cell axon terminals contribute to lateral
      inhibition of retinal ganglion cells.
AB  - The inhibitory surround signal in retinal ganglion cells is usually attributed to
      lateral horizontal cell signaling in the outer plexiform layer (OPL). However,
      recent evidence suggests that lateral inhibition at the inner plexiform layer
      (IPL) also contributes to the ganglion cell receptive field surround. Although
      amacrine cell input to ganglion cells mediates a component of this lateral
      inhibition, it is not known if presynaptic inhibition to bipolar cell terminals
      also contributes to surround signaling. We investigated the role of presynaptic
      inhibition by recording from bipolar cells in the salamander retinal slice. TTX
      reduced light-evoked GABAergic inhibitory postsynaptic currents (IPSCs) in
      bipolar cells, indicating that presynaptic pathways mediate lateral inhibition in
      the IPL. Photoreceptor and bipolar cell synaptic transmission were unaffected by
      TTX, indicating that its main effect was in the IPL. To rule out indirect actions
      of TTX, we bypassed lateral signaling in the outer retina by either electrically
      stimulating bipolar cells or by puffing kainate (KA) directly onto amacrine cell
      processes lateral to the recorded cell. In bipolar and ganglion cells, TTX
      suppressed laterally evoked IPSCs, demonstrating that both pre- and postsynaptic
      lateral signaling in the IPL depended on action potentials. By contrast, locally
      evoked IPSCs in both cell types were only weakly suppressed by TTX, indicating
      that local inhibition was not as dependent on action potentials. Our results show
      a TTX-sensitive lateral inhibitory input to bipolar cell terminals, which acts in
      concert with direct lateral inhibition to give rise to the GABAergic surround in
      ganglion cells.

PMID- 12611994
TI  - The accessory optic system contributes to the spatio-temporal tuning of motion
      sensitive pretectal neurons.
AB  - The nucleus of the basal optic root (nBOR) of the accessory optic system (AOS)
      and the pretectal nucleus lentiformis mesencephali (LM) are involved in the
      analysis of optic flow that results from self-motion and are important for
      oculomotor control. These neurons have large receptive fields and exhibit
      direction selectivity to large moving stimuli. In response to drifting sine wave
      gratings, LM and nBOR neurons are tuned to either low spatial/high temporal
      frequencies (SF, TF) or high SF/low TF stimuli. Given that velocity = TF/SF,
      these are referred to as "fast" and "slow" neurons, respectively. There is a
      heavy projection from the AOS to the pretectum, although its function is unknown.
      We recorded the directional and spatio-temporal tuning of LM units in pigeons
      before and after nBOR was inactivated by tetrodotoxin injection. After nBOR
      inactivation, changes in direction preference were observed for only one of 18 LM
      units. In contrast, the spatio-temporal tuning of LM units was dramatically
      altered by nBOR inactivation. Two major effects were observed. First, in response
      to motion in the preferred direction, most (82%) neurons showed a substantially
      reduced (mu = -67%) excitation to low SF/high TF gratings. Second, in response to
      motion in the anti-preferred direction, most (63%) neurons showed a dramatically
      reduced (mu = -78%) inhibition to high SF/low TF gratings. Thus the projection
      from the nBOR contributes to the spatio-temporal tuning rather than the
      directional tuning of LM neurons. We propose a descriptive model whereby LM
      receives inhibitory and excitatory input from "slow" and "fast" nBOR neurons,
      respectively.

PMID- 12611995
TI  - Competition between saccade goals in the superior colliculus produces saccade
      curvature.
AB  - When saccadic eye movements are made in a search task that requires selecting a
      target from distractors, the movements show greater curvature in their
      trajectories than similar saccades made to single stimuli. To test the hypothesis
      that this increase in curvature arises from competitive interactions between
      saccade goals occurring near the time of movement onset, we performed single-unit
      recording and microstimulation experiments in the superior colliculus (SC). We
      found that saccades that ended near the target but curved toward a distractor
      were accompanied by increased presaccadic activity of SC neurons coding the
      distractor site. This increased activity occurred approximately 30 ms before
      saccade onset and was abruptly quenched on saccade initiation. The magnitude of
      increased activity at the distractor site was correlated with the amount of
      curvature toward the distractor. In contrast, neurons coding the target location
      did not show any significant difference in discharge for curved versus straight
      saccades. To determine whether this pattern of SC discharge is causally related
      to saccade curvature, we performed a second series of experiments using
      electrical microstimulation. Monkeys made saccades to single visual stimuli
      presented without distractors, and we stimulated sites in the SC that would have
      corresponded to distractor sites in the search task. The stimulation was
      subthreshold for evoking saccades, but when its temporal structure mimicked the
      activity recorded for curved saccades in search, the subsequent saccades to the
      visual target showed curvature toward the location coded by the stimulation site.
      The effect was larger for higher stimulation frequencies and when the stimulation
      site was in the same colliculus as the representation of the visual target. These
      results support the hypothesis that the increased saccade curvature observed in
      search arises from rivalry between target and distractor goals and are consistent
      with the idea that the SC is involved in the competitive neural interactions
      underlying saccade target selection.

PMID- 12611996
TI  - Utilization and compensation of interaction torques during ball-throwing
      movements.
AB  - The manner in which the CNS deals with interaction torques at each joint in ball
      throwing was investigated by instructing subjects to throw a ball at three
      different speeds, using two (elbow and wrist) or three joints (shoulder, elbow,
      and wrist). The results indicated that the role of the muscle torque at the most
      proximal joint was to accelerate the most proximal joint and to produce the
      effect of interjoint interaction on the distal joints. In the three-joint
      throwing, shoulder muscle torque produced the assistive interaction torque for
      the elbow, which was effectively utilized to generate large elbow angular
      velocity when throwing fast. However, at the wrist, the muscle torque always
      counteracted the interaction torque. By this kinetic mechanism, the wrist angular
      velocity at the ball-release time was kept relatively constant irrespective of
      ball speed, which would lead to an accurate ball release. Thus it was concluded
      that humans can adjust the speed and accuracy of ball-throwing by utilizing
      interaction torque or compensating for it.

PMID- 12611997
TI  - Interaction between smooth anticipation and saccades during ocular orientation in
      darkness.
AB  - A saccade triggered during sustained smooth pursuit is programmed using retinal
      information about the relative position and velocity of the target with respect
      to the eye. Thus the smooth pursuit and saccadic systems are coordinated by using
      common retinal inputs. Yet, in the absence of retinal information about the
      relative motion of the eye with respect to the target, the question arises
      whether the smooth and saccadic systems are still able to be coordinated possibly
      by using extraretinal information to account for the saccadic and smooth eye
      movements. To address this question, we flashed a target during smooth
      anticipatory eye movements in darkness, and the subjects were asked to orient
      their visual axis to the remembered location of the flash. We observed multiple
      orientation saccades (typically 2-3) toward the memorized location of the flash.
      The first orienting saccade was programmed using only the position error at the
      moment of the flash, and the smooth eye movement was ignored. However, subsequent
      saccades executed in darkness compensated gradually for the smooth eye
      displacement (mean compensation congruent with 70%). This behavior revealed a 400
      ms delay in the time course of orientation for the compensation of the ongoing
      smooth eye displacement. We conclude that extraretinal information about the
      smooth motor command is available to the saccadic system in the absence of visual
      input. There is a 400-ms delay for smooth movement integration, saccade
      programming and execution.

PMID- 12611998
TI  - Role of the unperturbed limb and arms in the reactive recovery response to an
      unexpected slip during locomotion.
AB  - Understanding reactive recovery responses to slipping is fundamental in falls
      research and prevention. The primary purpose of this study was to investigate the
      role of the unperturbed limb and arms in the reactive recovery response to an
      unexpected slip. Ten healthy, young adults participated in this experiment in
      which an unexpected slip was induced by a set of steel free-wheeling rollers.
      Surface electromyography (EMG) data were collected from the unperturbed limb
      (i.e., the swing limb) rectus femoris, biceps femoris, tibialis anterior, and the
      medial head of gastrocnemius, and bilateral gluteus medius, erector spinae, and
      deltoids. Kinematic data were also collected by an optical imaging system to
      monitor limb trajectories. The first slip response was significantly different
      from the subsequent recovery responses to the unexpected slips, with an
      identifiable reactive recovery response and no proactive changes in EMG patterns.
      The muscles of the unperturbed limb, upper body, and arms were recruited at the
      same latency as those previously found for the perturbed limb. The arm elevation
      strategies assisted in shifting the center of mass forward after it was
      posteriorly displaced with the slip, while the unperturbed limb musculature
      demonstrated an extensor strategy supporting the observed lowering of the limb to
      briefly touch the ground to widen the base of support and to increase stability.
      Evidently a dynamic multilimb coordinated strategy is employed by the CNS to
      control and coordinate the upper and lower limbs in reactive recovery responses
      to unexpected slips during locomotion.

PMID- 12611999
TI  - Follower neurons in lobster (Panulirus interruptus) pyloric network regulate
      pacemaker period in complementary ways.
AB  - Distributed neural networks (ones characterized by high levels of
      interconnectivity among network neurons) are not well understood. Increased
      insight into these systems can be obtained by perturbing network activity so as
      to study the functions of specific neurons not only in the network's "baseline"
      activity but across a range of network activities. We applied this technique to
      study cycle period control in the rhythmic pyloric network of the lobster,
      Panulirus interruptus. Pyloric rhythmicity is driven by an endogenous oscillator,
      the Anterior Burster (AB) neuron. Two network neurons feed back onto the
      pacemaker, the Lateral Pyloric (LP) neuron by inhibition and the Ventricular
      Dilator (VD) neuron by electrical coupling. LP and VD neuron effects on pyloric
      cycle period can be studied across a range of periods by altering period by
      injecting current into the AB neuron and functionally removing (by
      hyperpolarization) the LP and VD neurons from the network at each period. Within
      a range of pacemaker periods, the LP and VD neurons regulate period in
      complementary ways. LP neuron removal speeds the network and VD neuron removal
      slows it. Outside this range, network activity is disrupted because the LP neuron
      cannot follow slow periods, and the VD neuron cannot follow fast periods. These
      neurons thus also limit, in complementary ways, normal pyloric activity to a
      certain period range. These data show that follower neurons in pacemaker networks
      can play central roles in controlling pacemaker period and suggest that in some
      cases specific functions can be assigned to individual network neurons.

PMID- 12612000
TI  - ASIC3 and ASIC1 mediate FMRFamide-related peptide enhancement of H+-gated
      currents in cultured dorsal root ganglion neurons.
AB  - The acid-sensing ion channels (ASICs) form cation channels that are transiently
      activated by extracellular protons. They are expressed in dorsal root ganglia
      (DRG) neurons and in the periphery where they play a function in nociception and
      mechanosensation. Previous studies showed that FMRFamide and related peptides
      potentiate H(+)-gated currents. To better understand this potentiation, we
      examined the effect of FMRFamide-related peptides on DRG neurons from wild-type
      mice and animals missing individual ASIC subunits. We found that FMRFamide and
      FRRFamide potentiated H(+)-gated currents of wild-type DRG in a dose-dependent
      manner. They increased current amplitude and slowed desensitization following a
      proton stimulus. Deletion of ASIC3 attenuated the response to FMRFamide-related
      peptides, whereas the loss of ASIC1 increased the response. The loss of ASIC2 had
      no effect on FMRFamide-dependent enhancement of H(+)-gated currents. These data
      suggest that FMRFamide-related peptides modulate DRG H(+)-gated currents through
      an effect on both ASIC1 and ASIC3 and that ASIC3 plays the major role. The recent
      discovery of RFamide-related peptides (RFRP) in mammals suggested that they might
      also modulate H(+)-gated current. We found that RFRP-1 slowed desensitization of
      H(+)-gated DRG currents, whereas RFRP-2 increased the peak amplitude. COS-7 cells
      heterologously expressing ASIC1 or ASIC3 showed similar effects. These results
      suggest that FMRFamide-related peptides, including the newly identified RFRPs,
      modulate H(+)-gated DRG currents through ASIC1 and ASIC3. The presence of several
      ASIC subunits, the diversity of FMRFamide-related peptides, and the distinct
      effects on H(+)-gated currents suggest the possibility of substantial complexity
      in modulation of current in DRG sensory neurons.

PMID- 12612001
TI  - Dendritic Ca2+ transients evoked by action potentials in rat dorsal cochlear
      nucleus pyramidal and cartwheel neurons.
AB  - Simultaneous fluorescence imaging and electrophysiologic recordings were used to
      investigate the Ca(2+) influx initiated by action potentials (APs) into dorsal
      cochlear nucleus (DCN) pyramidal cell (PC) and cartwheel cell (CWC) dendrites.
      Local application of Cd(2+) blocked Ca(2+) transients in PC and CWC dendrites,
      demonstrating that the Ca(2+) influx was initiated by dendritic Ca(2+) channels.
      In PCs, TTX eliminated the dendritic Ca(2+) transients when APs were completely
      blocked. However, the Ca(2+) influx could be partially recovered during an
      incomplete block of APs or when a large depolarization was substituted for the
      blocked APs. In CWCs, dendritic Ca(2+) transients evoked by individual APs, or
      simple spikes, were blocked by TTX and could be recovered during an incomplete
      block of APs or by a large depolarization. In contrast, dendritic Ca(2+)
      transients evoked by complex spikes, a burst of APs superimposed on a slow
      depolarization, were not blocked by TTX, despite eliminating the APs superimposed
      on the slow depolarization. These results suggest two different mechanisms for
      the retrograde activation of dendritic Ca(2+) channels: the first requires fast
      Na(+) channel-mediated APs or a large somatic depolarization, whereas the second
      is independent of Na(+) channel activation, requiring only the slow
      depolarization underlying complex spikes.

PMID- 12612002
TI  - NMDA receptor-dependent long-term synaptic depression in the entorhinal cortex in
      vitro.
AB  - The entorhinal cortex receives a large projection from the piriform (primary
      olfactory) cortex and, in turn, provides the hippocampal formation with most of
      its cortical sensory input. Synaptic plasticity in this pathway may therefore
      affect the processing of olfactory information and memory encoding. We have
      recently found that long-term synaptic depression (LTD) can be induced in this
      pathway in vivo by repetitive paired-pulse stimulation but not by low-frequency
      (1 Hz) stimulation with single pulses. Here, we have used field potential
      recordings to investigate the stimulation parameters and transmitter receptors
      required for the induction of LTD in the rat entorhinal cortex in vitro. The
      effectiveness of low-frequency stimulation (900 pulses at 1 or 5 Hz) and repeated
      delivery of pairs of stimulation pulses (30-ms interpulse interval) was assessed.
      Only repeated paired-pulse stimulation resulted in lasting LTD, and a low
      intensity paired-pulse stimulation protocol that induces LTD in vivo was only
      effective in the presence of the GABA(A) receptor antagonist bicuculline (50
      microM). LTD could also be induced in normal ACSF, however, by increasing the
      number of pulse-pairs delivered and by increasing the stimulation intensity
      during LTD induction. The induction of LTD was blocked by constant bath
      application of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2
      amino-5-phosphonovalerate (50 microM), indicating that LTD is dependent on NMDA
      receptor activation. However, LTD was not blocked by the group I/II mGluR
      antagonist (RS)-alpha-ethyl-4-carboxyphenylglycine (500 microM) or by bicuculline
      (50 microM). The induction of LTD in the entorhinal cortex in vitro is therefore
      dependent on intense stimulation that recruits activation of NMDA receptors, but
      does not require concurrent activation of mGluRs or inhibitory synaptic inputs.

PMID- 12612003
TI  - Propagating wave and irregular dynamics: spatiotemporal patterns of cholinergic
      theta oscillations in neocortex in vitro.
AB  - Neocortical "theta" oscillation (5-12 Hz) has been observed in animals and human
      subjects but little is known about how the oscillation is organized in the
      cortical intrinsic networks. Here we use voltage-sensitive dye and optical
      imaging to study a carbachol/bicuculline induced theta ( approximately 8 Hz)
      oscillation in rat neocortical slices. The imaging has large signal-to-noise
      ratio, allowing us to map the phase distribution over the neocortical tissue
      during the oscillation. The oscillation was organized as spontaneous epochs and
      each epoch was composed of a "first spike," a "regular" period (with relatively
      stable frequency and amplitude), and an "irregular" period (with variable
      frequency and amplitude) of oscillations. During each cycle of the regular
      oscillation, one wave of activation propagated horizontally (parallel to the
      cortical lamina) across the cortical section at a velocity of approximately 50
      mm/s. Vertically the activity was synchronized through all cortical layers. This
      pattern of one propagating wave associated with one oscillation cycle was seen
      during all the regular cycles. The oscillation frequency varied noticeably at two
      neighboring horizontal locations (330 microm apart), suggesting that the
      oscillation is locally organized and each local oscillator is about </=300 microm
      wide horizontally. During irregular oscillations, the spatiotemporal patterns
      were complex and sometimes the vertical synchronization decomposed, suggesting a
      de-coupling among local oscillators. Our data suggested that neocortical theta
      oscillation is sustained by multiple local oscillators. The coupling regime among
      the oscillators may determine the spatiotemporal pattern and switching between
      propagating waves and irregular patterns.

PMID- 12612004
TI  - Induction of NMDA and GABAA receptor-mediated Ca2+ oscillations with KCC2 mRNA
      downregulation in injured facial motoneurons.
AB  - To clarify the changes that occur in gamma-aminobutyric acid type A (GABA(A))
      receptor-mediated effects and contribute to alterations in the network activities
      after neuronal injury, we studied intracellular Ca(2+) concentration
      ([Ca(2+)](i)) dynamics in a rat facial-nerve-transection model. In facial
      motoneurons, an elevation of the resting [Ca(2+)](i), GABA-mediated [Ca(2+)](i)
      transients, enhancement of the glutamate-evoked [Ca(2+)](i) increases, and
      spontaneous [Ca(2+)](i) oscillations were induced by axotomy. All these axotomy
      induced modifications were abolished by the GABA(A)-receptor antagonist
      bicuculline and N-methyl-d-aspartate (NMDA)-receptor antagonist d(-)-2-amino-5
      phosphonopentanoic acid. A downregulation of K(+)-Cl(-) cotransporter (KCC2)
      mRNA, an increase in intracellular Cl(-) concentration ([Cl(-)](i)), and
      transformation of GABAergic hyperpolarization to depolarization were also induced
      by axotomy. We suggest that in axotomized neurons KCC2 downregulation impairs Cl(
      ) homeostasis and makes GABA act depolarizing, resulting in endogenous GABA
      inducing [Ca(2+)](i) oscillations via facilitation of NMDA-receptor activation.
      Such GABA(A)-receptor-mediated [Ca(2+)](i) oscillations may play a role in neural
      survival and regeneration.

PMID- 12612005
TI  - Baro-activated neurons with pulse-modulated activity in the rat caudal
      ventrolateral medulla express GAD67 mRNA.
AB  - GABAergic neurons in the caudal ventrolateral medulla (CVLM) are believed to
      mediate the sympathetic baroreceptor reflex by inhibiting presympathetic neurons
      in the rostral ventrolateral medulla (RVLM). Accordingly, some CVLM neurons are
      activated by increased arterial pressure (AP; baro-activated), have activity
      strongly modulated by the AP pulse (pulse-modulated), and can be antidromically
      activated from the RVLM. This study examined whether baro-activated, pulse
      modulated CVLM neurons are indeed GABAergic and examined their structures. We
      recorded extracellularly from 19 baro-activated, pulse-modulated CVLM neurons in
      chloralose-anesthetized rats. Most of these cells (13/19) were silenced by
      decreasing AP with nitroprusside, but some (6/19) remained active at low AP
      levels. They were also excited by phenyl biguanide (17/17) but inhibited by
      noxious tail pinch (8/11). Twelve baro-activated cells were filled with
      biotinamide and examined for expression of GAD67 mRNA. Because adjacent vagal
      motor neurons are also activated by increased AP, we examined choline
      acetyltransferase (ChAT) immunoreactivity. Most baro-activated cells (9/12)
      expressed high levels of GAD67 mRNA, the rest (3/12) displayed lower levels of
      GAD67 mRNA, but none showed ChAT immunoreactivity. In contrast, adjacent baro
      inhibited CVLM cells had no GAD67 mRNA (n = 5) but were instead tyrosine
      hydroxylase immunoreactive (n = 7). Reconstruction of baro-activated CVLM neurons
      revealed axons that projected dorsomedially and rostrally with several axon
      collaterals. These data demonstrate the existence of GABAergic CVLM neurons with
      the physiological characteristics expected of interneurons that mediate the
      sympathetic baroreceptor reflex. In addition, baro-activated GABAergic CVLM
      neurons appear to integrate several types of inputs and provide inhibition to
      multiple targets.

PMID- 12612006
TI  - Kinematics and kinetics of multijoint reaching in nonhuman primates.
AB  - The present study identifies the mechanics of planar reaching movements performed
      by monkeys (Macaca mulatta) wearing a robotic exoskeleton. This device maintained
      the limb in the horizontal plane such that hand motion was generated only by
      flexor and extensor motions at the shoulder and elbow. The study describes the
      kinematic and kinetic features of the shoulder, elbow, and hand during reaching
      movements from a central target to peripheral targets located on the
      circumference of a circle: the center-out task. While subjects made reaching
      movements with relatively straight smooth hand paths and little variation in peak
      hand velocity, there were large variations in joint motion, torque, and power for
      movements in different spatial directions. Unlike single-joint movements, joint
      kinematics and kinetics were not tightly coupled for these multijoint movements.
      For most movements, power generation was predominantly generated at only one of
      the two joints. The present analysis illustrates the complexities inherent in
      multijoint movements and forms the basis for understanding strategies used by the
      motor system to control reaching movements and for interpreting the response of
      neurons in different brain regions during this task.

PMID- 12612007
TI  - Response of the respiratory network of mice to hyperthermia.
AB  - Most mammals modulate respiratory frequency (RF) to dissipate heat (i.e.,
      panting) and avoid heat stroke during hyperthermic conditions. During
      hyperthermia, the RF of intact mammals increases and then declines or ceases
      (apnea). It has been proposed that this RF modulation depends on the presence of
      higher brain structures such as the hypothalamus. However, the direct effects of
      hyperthermia on the respiratory neural network have not been examined. To address
      this issue, the respiratory neural network [i.e., ventral respiratory group
      (VRG)] was isolated in a brain stem preparation taken from the medulla of mice
      (P0 -P6). Integrated population activity, predominated by inspiratory neurons,
      was recorded extracellularly from VRG neurons. The bath temperature was then
      heated from 30 to 40 degrees C, resulting in a biphasic frequency response in VRG
      activity. Following an initial six- to sevenfold increase and subsequent decline,
      fictive RF was maintained at a frequency that was higher than baseline frequency;
      at 40 degrees C, the RF was maintained at about two to four times that at 30
      degrees C. The inspiratory burst amplitude and duration were significantly
      reduced during hyperthermic conditions. An increase in RF and decrease in VRG
      burst amplitude and duration also occurred when heating from 37 to 40 degrees C.
      Fictive apnea typically occurred during cooling to the control temperature.
      Furthermore, changes in hypoglossal motor nucleus activity paralleled those of
      the VRG, suggesting that temperature modulation of the VRG is likely to have a
      behaviorally relevant impact on respiration. We conclude that the VRG activity
      itself is modulated during hyperthermia and the respiratory network is
      particularly sensitive to temperature changes.

PMID- 12612008
TI  - Computational diversity in the cochlear nucleus angularis of the barn owl.
AB  - The cochlear nucleus angularis (NA) is widely assumed to form the starting point
      of a brain stem pathway for processing sound intensity in birds. Details of its
      function are unclear, however, and its evolutionary origin and relationship to
      the mammalian cochlear-nucleus complex are obscure. We have carried out
      extracellular single-unit recordings in the NA of ketamine-anesthetized barn
      owls. The aim was to re-evaluate the extent of heterogeneity in NA physiology
      because recent studies of cellular morphology had established several distinct
      types. Extensive characterization, using tuning curves, phase locking,
      peristimulus time histograms and rate-level functions for pure tones and noise,
      revealed five major response types. The most common one was a primary-like
      pattern that was distinguished from auditory-nerve fibers by showing lower vector
      strengths of phase locking and/or lower spontaneous rates. Two types of chopper
      responses were found (chopper-transient and a rare chopper-sustained), as well as
      onset units. Finally, we routinely encountered a complex response type with a
      pronounced inhibitory component, similar to the mammalian typeIV. Evidence is
      presented that this range of response types is representative for birds and that
      earlier conflicting reports may be due to methodological differences. All five
      response types defined were similar to well-known types in the mammalian cochlear
      nucleus. This suggests convergent evolution of neurons specialized for encoding
      different behaviorally relevant features of the auditory stimulus. It remains to
      be investigated whether the different response types correlate with morphological
      types and whether they establish different processing streams in the auditory
      brain stem of birds.

PMID- 12612010
TI  - Coincidence detection in pyramidal neurons is tuned by their dendritic branching
      pattern.
AB  - Neurons display a variety of complex dendritic morphologies even within the same
      class. We examined the relationship between dendritic arborization and the
      coupling between somatic and dendritic action potential (AP) initiation sites in
      layer 5 (L5) neocortical pyramidal neurons. Coupling was defined as the relative
      reduction in threshold for initiation of a dendritic calcium AP due to a
      coincident back-propagating AP. Simulations based on reconstructions of biocytin
      filled cells showed that addition of oblique branches of the main apical dendrite
      in close proximity to the soma (d < 140 microm) increases the coupling between
      the apical and axosomatic AP initiation zones, whereas incorporation of distal
      branches decreases coupling. Experimental studies on L5 pyramids in acute brain
      slices revealed a highly significant (n = 28, r = 0.63, P < 0.0005) correlation:
      increasing the fraction of proximal oblique dendrites (d < 140 microm), e.g.,
      from 30 to 60% resulted on average in an increase of the coupling from
      approximately 35% to almost 60%. We conclude that variation in dendritic
      arborization may be a key determinant of variability in coupling (49 +/- 17%;
      range 19-83%; n = 37) and is likely to outweigh the contribution made by
      variations in active membrane properties. Thus coincidence detection of inputs
      arriving from different cortical layers is strongly regulated by differences in
      dendritic arborization.

PMID- 12612009
TI  - PRQFVamide, a novel pentapeptide identified from the CNS and gut of Aplysia.
AB  - We have purified a novel pentapeptide from the Aplysia nervous system using
      bioassay on gut contractions. The structure of the peptide is Pro-Arg-Gln-Phe-Val
      amide (PRQFVa). The precursor for PRQFVa was found to code for 33 copies of
      PRQFVamide and four related pentapeptides. Peaks corresponding to the predicted
      masses of all five pentapeptides were detected in Aplysia neurons by matrix
      assisted laser desorption/ionization time-of-flight mass spectrometry. Northern
      analysis revealed that expression of the precursor is abundant in the abdominal
      ganglion, much less in the pedal and cerebral ganglia, and rarely seen in the
      buccal and pleural ganglia. PRQFVa-positive neurons, mapped by
      immunohistochemistry and in situ hybridization, were present in all the central
      ganglia. PRQFVa immunopositive processes were observed in the gut, particularly
      in association with the vasculature. Some arteries and other highly vascularized
      tissues, such as the gill and the kidney, also contain numerous PRQFVa
      immunopositive processes. Application of synthetic PRQFVa suppresses not only
      contractions of the gut but also contractions of vasculature. PRQFVa is expressed
      in some of the neurons within the feeding circuitry and application of synthetic
      PRQFVa was found to decrease the excitability of some (B4/5 and B31/32) but not
      all (B8) neurons of the buccal feeding circuit. Our findings suggest that PRQFVa
      may act as a modulator within the feeding system as well as in other systems of
      Aplysia.

PMID- 12612012
TI  - Motor unit firing during and after voluntary contractions of human thenar muscles
      weakened by spinal cord injury.
AB  - Spinal cord injury may change both the distribution and the strength of the
      synaptic input within a motoneuron pool and therefore alter force gradation.
      Here, we have studied the relative contributions of motor unit recruitment and
      rate modulation to force gradation during voluntary contractions of thenar
      muscles performed by five individuals with chronic (>1 yr) cervical spinal cord
      injury. Mean +/- SD thenar unit firing rates were low during both steady-level
      25% (8.3 +/- 2.2 Hz, n = 27 units) and 100% maximal voluntary contractions (MVCs,
      9.2 +/- 3.1 Hz, n = 23 units). Thus modest rate modulation, or a lack of it in
      some units, was seen despite an average fourfold increase in integrated surface
      electromyographic activity and force. During ramp contractions, units were
      recruited at 5.7 +/- 2.5 Hz, but still only reached maximal firing rates of 12.8
      +/- 4.9 Hz. Motor units were recruited up to 85% of the maximal force achieved
      (14.6 +/- 5.6 N). In contrast, unit recruitment in control hand muscles is
      largely complete by 30% MVC. Thus, during voluntary contractions of thenar
      muscles weakened by cervical spinal cord injury, motor unit rate modulation was
      limited and recruitment occurred over a wider than usual force range. Those motor
      units that were stopped voluntarily had significantly lower derecruitment versus
      recruitment thresholds. However, 8 units (24%) continued to fire long after the
      signal to end the voluntary contraction at a mean frequency of 5.9 +/- 0.8 Hz.
      The forces generated by this prolonged unit activity ranged from 0.3 to 7.2%
      maximum. Subjects were unable to stop this involuntary unit activity even with
      the help of feedback. The mechanisms that underlie this prolonged motor unit
      firing need to be explored further.

PMID- 12612011
TI  - Insulin-like growth factor I modifies electrophysiological properties of rat
      brain stem neurons.
AB  - On systemic injection, insulin-like growth factor I (IGF-I) elicits a prolonged
      increase in the excitability of dorsal column nuclei (DCN) cells in the brain
      stem as well as other target neurons within the brain. We have explored the
      cellular mechanisms involved in the stimulatory effects of IGF-I as well as its
      functional consequences. In a rat slice preparation, IGF-I induced a sustained
      depolarization of 2-5 mV in 81% of DCN neurons. Depolarization was accompanied
      with an increase in the input resistance (15%). Voltage-clamp recordings
      displayed that IGF-I decreased a K+-mediated A current (60%). Furthermore, IGF-I
      increased, in 78% of cells, the peak amplitude (25%), and rising slope (32%) of
      the excitatory postsynaptic potential evoked by dorsal column stimulation; in
      this case, a presynaptic facilitatory process appears to be involved. When
      anesthetized adult rats are injected in the carotid artery with IGF-I,
      extracellularly recorded propioceptive DCN neurons not only show increased spike
      activity but also an expansion of their cutaneous receptive field in 83% of DCN
      cells. Significantly, the increased excitability evoked by IGF-I in the DCN cells
      depends both in vivo and in vitro, on activation of p38 mitogen-activated protein
      kinase (MAPK), a Ser-kinase known to modulate K+ channel activity. We concluded
      that systemic IGF-I modulated the electrophysiological properties of target
      neurons within the brain. In turn, these changes probably contribute to
      functional reorganization processes such as expansion of neuronal receptive
      fields.

PMID- 12612013
TI  - Pursuit subregion of the frontal eye field projects to the caudate nucleus in
      monkeys.
AB  - It has been well established by recording, inactivation, and neuroanatomical
      studies that the caudate nucleus is important for the control of saccadic eye
      movements. However, until now, there has been little evidence that the caudate
      nucleus plays a role in smooth pursuit eye movements. In the present study, we
      physiologically identified the smooth pursuit subregion of the frontal eye field
      (FEFsem) and the saccadic subregion of the frontal eye field (FEFsac) in four
      Cebus monkeys. Anterogradely transported tracers (biotinylated dextran amines and
      wheat germ aglutinin conjugated to horseradish peroxidase) were then used to
      determine the efferent connections of the FEFsem to the caudate nucleus and to
      compare those connections with projections arising in the FEFsac. We observed
      dense projections from the FEFsem to the head and body of the caudate. The FEFsem
      and FEFsac terminal fields were of approximately equal density and total area.
      The region of FEFsem-labeled axon terminals overlapped only slightly with the
      region of FEFsac-labeled terminals. These results suggest that the caudate
      nucleus may play an important role in the control of smooth pursuit eye movements
      via feedback loops involving the basal ganglia and thalamus. Our results further
      suggest that the basal ganglia circuitry concerned with controlling visual
      pursuit is physically segregated from that concerned with controlling saccadic
      eye movements.

PMID- 12612014
TI  - A role for myotonic dystrophy protein kinase in synaptic plasticity.
AB  - Myotonic dystrophy (DM) is associated with an expanded triplet repeat in the 3'
      untranslated region of the gene for myotonic dystrophy protein kinase (DMPK),
      which may reduce DMPK expression. It is unclear how reduced DMPK expression might
      contribute to the symptoms of DM because the normal function of DMPK is not yet
      understood. Thus we investigated the function of DMPK to gain insight into how
      reduced DMPK expression might lead to cognitive dysfunction in DM. We recently
      demonstrated a role for DMPK in modifying the cytoskeleton, and remodeling of the
      cytoskeleton is thought to be important for cognitive function. Therefore we
      hypothesized that DMPK might normally contribute to synaptic plasticity and
      cognitive function via an effect on actin cytoskeletal rearrangements. To test
      for involvement of DMPK in synaptic plasticity, we utilized the DMPK null mouse.
      This mouse showed no changes in baseline synaptic transmission in hippocampal
      area CA1, nor any changes in long-term synaptic potentiation (LTP) measured 3 h
      after induction. There was a significant decrease, however, in the decremental
      potentiation with a duration of 30-180 min that accompanies LTP. These results
      suggest a role for DMPK in synaptic plasticity that could be relevant to the
      cognitive dysfunction associated with DM.

PMID- 12612015
TI  - The time course of perisaccadic receptive field shifts in the lateral
      intraparietal area of the monkey.
AB  - Neurons in the lateral intraparietal area of the monkey (LIP) have visual
      receptive fields in retinotopic coordinates when studied in a fixation task.
      However, in the period immediately surrounding a saccade these receptive fields
      often shift, so that a briefly flashed stimulus outside the receptive field will
      drive the neurons if the eye movement will bring the spatial location of that
      vanished stimulus into the receptive field. This is equivalent to a transient
      shift of the retinal receptive field. The process enables the monkey brain to
      process a stimulus in a spatially accurate manner after a saccade, even though
      the stimulus appeared only before the saccade. We studied the time course of this
      receptive field shift by flashing a task-irrelevant stimulus for 100 ms before,
      during, or after a saccade. The stimulus could appear in receptive field as
      defined by the fixation before the saccade (the current receptive field) or the
      receptive field as defined by the fixation after the saccade (the future
      receptive field). We recorded the activity of 48 visually responsive neurons in
      LIP of three hemispheres of two rhesus monkeys. We studied 45 neurons in the
      current receptive field task, in which the saccade removed the stimulus from the
      receptive field. Of these neurons 29/45 (64%) showed a significant decrement of
      response when the stimulus appeared 250 ms or less before the saccade, as
      compared with their activity during fixation. The average response decrement was
      38% for those cells showing a significant (P < 0.05 by t-test) decrement. We
      studied 39 neurons in the future receptive field task, in which the saccade
      brought the spatial location of a recently vanished stimulus into the receptive
      field. Of these 32/39 (82%) had a significant response to stimuli flashed for 100
      ms in the future receptive field, even 400 ms before the saccade. Neurons never
      responded to stimuli moved by the saccade from a point outside the receptive
      field to another point outside the receptive field. Neurons did not necessarily
      show any saccadic suppression for stimuli moved from one part of the receptive
      field to another by the saccade. Stimuli flashed <250 ms before the saccade
      evoked responses in both the presaccadic and the postsaccadic receptive fields,
      resulting in an increase in the effective receptive field size, an effect that we
      suggest is responsible for perisaccadic perceptual inaccuracies.

PMID- 12612016
TI  - Physiological response properties of neurons in the superior paraolivary nucleus
      of the rat.
AB  - The superior paraolivary nucleus (SPON) is a prominent nucleus of the superior
      olivary complex. In rats, this nucleus is composed of a morphologically
      homogeneous population of GABAergic neurons that receive excitatory input from
      the contralateral cochlear nucleus and inhibitory input from the ipsilateral
      medial nucleus of the trapezoid body. SPON neurons provide a dense projection to
      the ipsilateral inferior colliculus and are thereby capable of exerting profound
      modulatory influence on collicular neurons. Despite recent interest in the
      structural and connectional features of SPON, little is presently known
      concerning the physiological response properties of this cell group or its
      functional role in auditory processing. We utilized extracellular, in vivo
      recording methods to study responses of SPON neurons to broad band noise, pure
      tone, and amplitude-modulated pure tone stimuli. Localization of recording sites
      within the SPON provides evidence for a medial (high frequency) to lateral (low
      frequency) tonotopic representation of frequencies within the nucleus. Best
      frequencies of SPON neurons spanned the audible range of the rat and receptive
      fields were narrow with V-shaped regions near threshold. Nearly all SPON neurons
      responded at the offset of broad band noise and pure tone stimuli. The vast
      majority of SPON neurons displayed very low rates of spontaneous activity and
      only responded to stimuli presented to the contralateral ear, although a small
      population showed binaural facilitation. Most SPON neurons also generated spike
      activity that was synchronized to sinusoidally amplitude-modulated tones. Taken
      together, these data suggest that SPON neurons may serve to encode temporal
      features of complex sounds, such as those contained in species-specific
      vocalizations.

PMID- 12612018
TI  - Eyelid movements: behavioral studies of blinking in humans under different
      stimulus conditions.
AB  - The kinematics and neurophysiological aspects of eyelid movements were examined
      during spontaneous, voluntary, air puff, and electrically induced blinking in
      healthy human subjects, using the direct magnetic search coil technique
      simultaneously with electromyographic recording of the orbicularis oculi muscles
      (OO-EMG). For OO-EMG recordings, surface electrodes were attached to the lower
      eyelids. To measure the vertical lid displacement, a search coil with a diameter
      of 3 mm was placed 1 mm from the rim on the upper eyelid on a marked position.
      Blink registrations were performed from the zero position and from 28 randomly
      chosen positions. Blinks elicited by electrical stimulation of the supraorbital
      nerve had shortest duration and were least variable. In contrast, spontaneous
      blinks had longer duration and greater variability. Blinks induced by air puff
      had a slightly longer duration and similar variability as electrically induced
      blinks. There was a correlation between the maximal down phase amplitude and the
      integrated OO-EMG. Blink duration and maximal down phase amplitude were affected
      by eye position. Eyes positioned 30 degrees above horizontal displayed the
      shortest down phase duration and the largest maximal down phase amplitude and
      velocity. At 30 degrees below horizontal, blinks had the longest total duration,
      the longest down phase duration, and the lowest maximal down phase amplitude and
      velocity. The simultaneously recorded integrated OO-EMG was largest in the 30
      degrees downward position. In four subjects, the average blinking data showed a
      linear relation between eye position and OO-EMG, maximal down phase amplitude,
      and maximal downward velocity.

PMID- 12612019
TI  - Local field potentials and the encoding of whisker deflections by population
      firing synchrony in thalamic barreloids.
AB  - In layer IV of rat somatosensory cortex, barrel circuitry is highly sensitive to
      thalamic population firing rates during the first few milliseconds of the whisker
      evoked response. This sensitivity of barrel neurons to thalamic firing synchrony
      was inferred previously from analysis of simulated barrel circuitry and from
      single-unit recordings performed one at a time. In this study, we investigate
      stimulus-dependent synchronous activity in the thalamic ventral posteromedial
      nucleus (VPm) using the more direct approach of local field potential (LFP)
      recording. We report that thalamic barreloid neurons generate larger magnitude
      LFP responses to principal versus adjacent whiskers, to preferred versus
      nonpreferred movement directions, and to high- versus low-velocity/acceleration
      deflections. Responses were better predicted by acceleration than velocity, and
      they were insensitive to the final amplitude of whisker deflection. Importantly,
      reliable and robust stimulus/response relationships were found only for the
      initial 1.2-7.5 ms of the thalamic LFP response, reflecting arrival of afferent
      information from the brain stem. Later components of the thalamic response, which
      are likely to coincide with arrival of inhibitory inputs from the thalamic
      reticular nucleus and excitatory inputs from the barrel cortex itself, are
      variable and poorly predicted by stimulus parameters. Together with previous
      results, these findings underscore a critical role for thalamic firing synchrony
      in the encoding of small but rapidly changing perturbations of specific whiskers
      in particular directions.

PMID- 12612020
TI  - Temporal and spatial profiles of pontine-evoked monoamine release in the rat's
      spinal cord.
AB  - In the spinal cord, the monoamine neurotransmitter norepinephrine, which is
      released mainly from fibers descending from the dorsal pons, has major modulatory
      effects on nociception and locomotor rhythms. To map the spatial and temporal
      patterns of this release, changes in monoamine level were examined in laminae I
      VIII of lumbar segments L3-L6 of halothane-anesthetized rats during pontine
      stimulation. The changes were measured through a carbon fiber microelectrode at
      0.5-s intervals by fast cyclic voltammetry, which presently is the method of best
      spatiotemporal resolution. When different pontine sites were tested with 20-s
      pulse trains (50-to 200-microA amplitude, 0.5-ms pulse width, and 50-Hz
      frequency) during measurement in the dorsal horn (lamina IV), the largest
      consistent increases were produced by the locus ceruleus, although effective
      pontine sites extended 1.5 mm dorsally and ventral from the locus ceruleus. When
      the locus ceruleus stimulus was used to map the spinal cord, increased levels
      were always seen in lamina I and laminae IV-VIII, whereas 50% of sites in laminae
      II and III showed substantial decreases and the rest showed increases. These
      increases typically had short latencies [4.5 +/- 0.4 (SE) s] and variable decay
      times (5-200 s), with peaks occurring during the stimulus train (mean rise-time:
      12.0 +/- 0.6 s). The mean peak level was 544 +/- 82 nM as estimated from
      postexperimental calibration with norepinephrine. Other significant laminar
      differences included higher mean peak concentrations (805 nM) and rise times
      (14.9 s) in lamina I and shorter latencies in lamina VI (3.2 s). Peak
      concentrations were inversely correlated with latency. When stimulation frequency
      was varied, increases were disproportionately larger with faster frequencies (>
      or =50 Hz), hence extrajunctional overflow probably contributed most of the
      signal. We conclude, generally, that pontine noradrenergic control is exerted on
      widespread spinal laminae with a significant component of paracrine transmission
      after several seconds of sustained activity. Relatively stronger effects prevail
      where nociceptive transmission (lamina I) and locomotor rhythm generation (lamina
      VI) occur.

PMID- 12612021
TI  - Sensory-motor interaction in the primate auditory cortex during self-initiated
      vocalizations.
AB  - Little is known about sensory-motor interaction in the auditory cortex of
      primates at the level of single neurons and its role in supporting vocal
      communication. The present study investigated single-unit activities in the
      auditory cortex of a vocal primate, the common marmoset (Callithrix jacchus),
      during self-initiated vocalizations. We found that 1) self-initiated
      vocalizations resulted in suppression of neural discharges in a majority of
      auditory cortical neurons. The vocalization-induced inhibition suppressed both
      spontaneous and stimulus-driven discharges. Suppressed units responded poorly to
      external acoustic stimuli during vocalization. 2) Vocalization-induced
      suppression began several hundred milliseconds prior to the onset of
      vocalization. 3) The suppression of cortical discharges reduced neural firings to
      below the rates expected from a unit's rate-level function, adjusted for known
      subcortical attenuation, and therefore was likely not entirely caused by
      subcortical attenuation mechanisms. 4) A smaller population of auditory cortical
      neurons showed increased discharges during self-initiated vocalizations. This
      vocalization-related excitation began after the onset of vocalization and is
      likely the result of acoustic feedback. Units showing this excitation responded
      nearly normally to external stimuli during vocalization. Based on these findings,
      we propose that the suppression of auditory cortical neurons, possibly
      originating from cortical vocal production centers, acts to increase the dynamic
      range of cortical responses to vocalization feedback for self monitoring. The
      excitatory responses, on the other hand, likely play a role in maintaining
      hearing sensitivity to the external acoustic environment during vocalization.

PMID- 12612022
TI  - Prediction of muscle activity by populations of sequentially recorded primary
      motor cortex neurons.
AB  - We have adopted an analysis that produces a post hoc prediction of the time
      course of electromyogram (EMG) activity from the discharge of ensembles of
      neurons recorded sequentially from the primary motor cortex (M1) of a monkey.
      Over several recording sessions, we collected data from 50 M1 neurons and several
      distal forelimb muscles during a stereotyped precision grip task. Ensemble
      averages were constructed from 5 to 10 trials for each neuron and EMG signal. We
      used multiple linear regression on randomly chosen subsets of these neurons to
      find the best fit between the neuronal and EMG data. The fixed delay between
      neuronal and EMG signals that yielded the largest coefficient of determination
      (R(2)) between predicted and actual EMG was 50 ms. R(2) averaged 0.83 for
      ensembles composed of 15 neurons. If, instead, each neuronal signal was delayed
      by the time of its peak cross-correlation with the EMG signal, R(2) increased to
      0.88. Using all 50 neurons, R(2) under these conditions averaged nearly 0.97. A
      similar analysis was conducted with signals recorded during both a power grip and
      a precision grip task. Quality of the fit dropped dramatically when parameters
      from the precision grip for a given set of neurons were used to fit data recorded
      during the power grip. However, when a single set of regression parameters was
      used to fit a combination of the two tasks, the quality of the fits decreased by
      <10% from that of a single task.

PMID- 12612023
TI  - Correspondence between odorant-evoked patterns of receptor neuron input and
      intrinsic optical signals in the mouse olfactory bulb.
AB  - We compared odorant-evoked patterns of receptor neuron input to the mouse
      olfactory bulb, imaged with a calcium-sensitive dye, with those of intrinsic
      optical signals imaged from the same preparations. Both methods yielded patterns
      of glomerular activity that showed a strong concentration dependence, a loosely
      organized chemotopy, and involved widely distributed glomeruli. Presynaptic
      calcium and intrinsic signals showed similar odorant concentration thresholds.
      Intrinsic signal foci were larger than their corresponding calcium signals, and
      input to multiple adjacent glomeruli often appeared as a single intrinsic focus.
      Nonetheless, at near-threshold concentrations, the correspondence between the
      glomerular calcium and intrinsic signals averaged 75%, with a 71% correspondence
      between the most strongly activated glomeruli. The correspondence between
      strongly activated glomeruli decreased as odorant concentration increased,
      dropping to 51% at 5- to 15-fold higher concentrations. Intrinsic signal foci
      often saturated at lower concentrations than the calcium signal, implying a
      smaller dynamic range, and suprathreshold concentrations could recruit strong
      intrinsic signals in areas showing little or no calcium signal. These differences
      were such that, at suprathreshold concentrations, the chemotopy of calcium and
      intrinsic signal response maps often differed. These results suggest that
      intrinsic optical signals closely reflect receptor neuron input to glomeruli at
      low odorant concentrations but reflect additional processes at higher
      concentrations (activation of second-order neurons, centrifugal input, or
      constraints on the coupling between neuronal activity and hemodynamic changes).
      Intrinsic signals that are not associated with receptor neuron input have the
      potential to impact the interpretation of spatial coding strategies in the
      olfactory bulb.

PMID- 12612024
TI  - Similar electrophysiological changes in axotomized and neighboring intact dorsal
      root ganglion neurons.
AB  - We investigated electrophysiological changes in chronically axotomized and
      neighboring intact dorsal root ganglion (DRG) neurons in rats after either a
      peripheral axotomy consisting of an L5 spinal nerve ligation (SNL) or a central
      axotomy produced by an L5 partial rhizotomy (PR). SNL produced lasting
      hyperalgesia to punctate indentation and tactile allodynia to innocuous stroking
      of the foot ipsilateral to the injury. PR produced ipsilateral hyperalgesia
      without allodynia with recovery by day 10. Intracellular recordings were obtained
      in vivo from the cell bodies (somata) of axotomized and intact DRG neurons, some
      with functionally identified peripheral receptive fields. PR produced only minor
      electrophysiological changes in both axotomized and intact somata in L5 DRG. In
      contrast, extensive changes were observed after SNL in large- and medium-sized,
      but not small-sized, somata of intact (L4) as well as axotomized (L5) DRG
      neurons. These changes included (in relation to sham values) higher input
      resistance, lower current and voltage thresholds, and action potentials with
      longer durations and slower rising and falling rates. The incidence of
      spontaneous activity, recorded extracellularly from dorsal root fibers in vitro,
      was significantly higher (in relation to sham) after SNL but not after PR, and
      occurred in myelinated but not unmyelinated fibers from both L4 (9.1%) and L5
      (16.7%) DRGs. We hypothesize that the changes in the electrophysiological
      properties of axotomized and intact DRG neurons after SNL are produced by a
      mechanism associated with Wallerian degeneration and that the hyperexcitability
      of intact neurons may contribute to SNL-induced hyperalgesia and allodynia.

PMID- 12612025
TI  - Vigabatrin induces tonic inhibition via GABA transporter reversal without
      increasing vesicular GABA release.
AB  - Two forms of GABAergic inhibition coexist: fast synaptic neurotransmission and
      tonic activation of GABA receptors due to ambient GABA. The mechanisms regulating
      ambient GABA have not been well defined. Here we examined the role of the GABA
      transporter in the increase in ambient [GABA] induced by the anticonvulsant
      vigabatrin. Pretreatment of cultured rat hippocampal neurons with vigabatrin (100
      microM) for 2-5 days led to a large increase in ambient [GABA] that was measured
      as the change in holding current induced by bicuculline during patch-clamp
      recordings. In contrast, there was a decrease in the frequency of spontaneous
      miniature inhibitory postsynaptic currents mIPSCs with no change in their
      amplitude distribution, and a decrease in the magnitude of IPSCs evoked by
      presynaptic stimulation during paired recordings. The increase in ambient [GABA]
      was not prevented by blockade of vesicular GABA release with tetanus toxin or
      removal of extracellular calcium. During perforated patch recordings, the
      increase in ambient [GABA] was prevented by blocking the GABA transporter,
      indicating that the GABA transporter was continuously operating in reverse and
      releasing GABA. In contrast, blocking the GABA transporter increased ambient
      [GABA] during whole cell patch-clamp recordings unless GABA and Na(+) were added
      to the recording electrode solution, indicating that whole cell recordings can
      lead to erroneous conclusions about the role of the GABA transporter in control
      of ambient GABA. We conclude that the equilibrium for the GABA transporter is a
      major determinant of ambient [GABA] and tonic GABAergic inhibition. We propose
      that fast GABAergic neurotransmission and tonic inhibition can be independently
      modified and play complementary roles in control of neuronal excitability.

PMID- 12612027
TI  - Effects of hypodynamia-hypokinesia on the muscle spindle discharges of rat soleus
      muscle.
AB  - The aim of this study was to determine whether Ia and II fiber discharges of
      soleus muscle spindles were modified after a 14-day period of hypodynamia
      (absence of weight bearing) and hypokinesia (reduction of motor activity). Fifty
      one and 38 afferent fibers were studied, respectively, in control and hypodynamia
      hypokinesia (HH) groups. Under deep anesthesia (pentobarbital, 30 mg/kg), a L3-L6
      laminectomy was performed. Unitary potentials from the L5 dorsal root were
      recorded in response to ramp-and-hold stretches applied at two stretch amplitudes
      (3 and 4 mm) and four stretch velocities (6, 10, 15, and 30 mm/s) and to
      sinusoidal stretches applied at four stretch amplitudes (0.12, 0.25, 0.5, and 1
      mm) and six stretch frequencies (0.5, 1, 2, 3, 6, and 10 Hz). In both animal
      groups, the Ia fibers showed higher dynamic index values, smaller linear range,
      and higher vibration sensitivity than the II fibers. They also exhibited a pause
      in their discharges during the stretch release contrary to II fibers, which
      displayed no pause in their responses. After HH, our results showed that for both
      fiber types all parameters measured under ramp-and-hold stretches (except the
      static sensitivity) were significantly increased and under sinusoidal stretches,
      the vibration sensitivity increased, and the response amplitude only increased at
      0.12-mm stretch amplitude. The linear range of Ia afferents was limited to 0.12
      mm, whereas it was unchanged for the II fibers. After HH, the stretches could be
      better transmitted to the muscle spindles, probably resulting from changes in
      passive mechanical properties of the soleus.

PMID- 12612026
TI  - Quantitative comparison between functional imaging and single-unit spiking in rat
      somatosensory cortex.
AB  - The profile of activity across rat somatosensory cortex on stimulation of a
      single whisker was examined using both intrinsic signal imaging and
      electrophysiological recording. In the same animals, under sodium pentobarbital
      anesthesia, the intrinsic signal response to a 5-Hz stimulation of whisker C2 was
      recorded through a thinned skull. Subsequently, the thinned skull was removed,
      and individual cortical neurons were recorded at multiple locations and in all
      cortical layers in response to the same whisker stimulation paradigm. The
      amplitude of the evoked response obtained with both techniques was quantified
      across the cortical surface with respect to distance (<or=1.6 mm) from the peak
      intrinsic signal activity. Cortical neurons were rated as having a significant or
      nonsignificant whisker-evoked response as compared with a baseline period of
      spontaneous firing; a minority of neurons exhibited a small but significant
      increase in neuronal spiking even at long distances (>1.6 mm) from the optically
      determined peak of activity. Overall, this analysis shows a significant
      correlation between the two techniques in terms of the profile of evoked activity
      across the cortical surface. Furthermore, this data set affords a detailed and
      quantitative comparison between the two activity-dependent techniques-one
      measuring an intrinsic decrease in light reflectance based largely on metabolic
      changes and one measuring neuronal firing patterns. Studies such as this,
      comparing directly between imaging and detailed electrophysiology, may influence
      the interpretation of the extent of the activated area as assessed with in vivo
      functional imaging techniques.

PMID- 12612028
TI  - Target selection for reaching and saccades share a similar behavioral reference
      frame in the macaque.
AB  - The selection of one of two visual stimuli as a target for a motor action may
      depend on external as well as internal variables. We examined whether the
      preference to select a leftward or rightward target depends on the action that is
      performed (eye or arm movement) and to what extent the choice is influenced by
      the target location. Two targets were presented at the same distance to the left
      and right of a fixation position and the stimulus onset asynchrony (SOA) was
      adjusted until both targets were selected equally often. This balanced SOA time
      is then a quantitative measure of selection preference. In two macaque monkeys
      tested, we found the balanced SOA shifted to the left side for left-arm movements
      and to the right side for right-arm movements. Target selection strongly depended
      on the horizontal target location. By varying eye, head, and trunk position, we
      found this dependency embedded in a head-centered behavioral reference frame for
      saccade targets and, somewhat counter-intuitively, for reach targets as well.
      Target selection for reach movements was influenced by the eye position, while
      saccade target selection was unaffected by the arm position. These findings
      suggest that the neural processes underlying target selection for a reaching
      movement are to a large extent independent of the coordinate frame ultimately
      used to make the limb movement, but are instead closely linked to the coordinate
      frame used to plan a saccade to that target. This similarity may be indicative of
      a common spatial framework for hand-eye coordination.

PMID- 12612029
TI  - Sodium imaging of climbing fiber innervation fields in developing mouse Purkinje
      cells.
AB  - Maturation of specific neuronal connections in the mature nervous system includes
      elimination of redundant synapses formed earlier during development. In the
      cerebellum of adult animals, each Purkinje cell (PC) is innervated by a single
      climbing fiber (CF). In early postnatal development each PC is innervated by
      multiple CFs and elimination of synapses formed by supernumerary CFs occurs until
      monoinnervation is established at around postnatal day 20 (P20) in mice. It is
      not clear whether multiple CFs, or only a single CF, translocate from the cell
      body of immature PCs to the developing dendrite and, in case several CFs
      translocate, whether they share or segregate their innervation fields. To
      localize CF innervation fields, we imaged changes in postsynaptic sodium
      concentration resulting from CF-mediated postsynaptic currents. We found that
      more than one CF translocates from an innervation field on the cell body of the
      PC to the developing dendrite and that these CFs share rather than segregate
      their innervation fields. We concluded that both the soma and the proximal
      dendrite of the PC are territories of competition for the developing CFs and that
      the overlapping of their termination fields may be the prerequisite for a local
      process of elimination of all but one CF, as previously demonstrated in the
      developing neuromuscular junction.

PMID- 12612031
TI  - Synapse formation between isolated axons requires presynaptic soma and
      redistribution of postsynaptic AChRs.
AB  - The involvement of neuronal protein synthetic machinery and extrinsic trophic
      factors during synapse formation is poorly understood. Here we determine the
      roles of these processes by reconstructing synapses between the axons severed
      from identified Lymnaea neurons in cell culture, either in the presence or
      absence of trophic factors. We demonstrate that, although synapses are maintained
      between isolated pre- and postsynaptic axons for several days, the presynaptic,
      but not the postsynaptic, cell body, however, is required for new synapse
      formation between soma-axon pairs. The formation of cholinergic synapses between
      presynaptic soma and postsynaptic axon requires gene transcription and protein
      synthesis solely in the presynaptic neuron. We show that this synaptogenesis is
      contingent on extrinsic trophic factors present in brain conditioned medium (CM).
      The CM-induced excitatory synapse formation is mediated through receptor tyrosine
      kinases. We further demonstrate that, although the postsynaptic axon does not
      require new protein synthesis for synapse formation, its contact with the
      presynaptic cell in CM, but not in defined medium (no trophic factors),
      differentially alters its responsiveness to exogenously applied acetylcholine at
      synaptic compared with extrasynaptic sites. Together, these data suggest a
      synergetic action of cell-cell signaling and trophic factors to bring about
      specific changes in both pre- and postsynaptic neurons during synapse formation.

PMID- 12612033
TI  - A temporally asymmetric Hebbian rule governing plasticity in the human motor
      cortex.
AB  - Synaptic plasticity is conspicuously dependent on the temporal order of the pre-
      and postsynaptic activity. Human motor cortical excitability can be increased by
      a paired associative stimulation (PAS) protocol. Here we show that it can also be
      decreased by minimally changing the interval between the two associative stimuli.
      Corticomotor excitability of the abductor pollicis brevis (APB) representation
      was tested before and after repetitively pairing of single right median nerve
      simulation with single pulse transcranial magnetic stimulation (TMS) delivered
      over the optimal site for activation of the contralateral APB. Following PAS,
      depression of TMS-evoked motor-evoked potentials (MEPs) was induced only when the
      median nerve stimulation preceded the TMS pulse by 10 ms, while enhancement of
      cortical excitability was induced using an interstimulus interval of 25 ms,
      suggesting an important role of the sequence of cortical events triggered by the
      two stimulation modalities. Experiments using F-wave studies and electrical brain
      stem stimulation indicated that the site of the plastic changes underlying the
      decrease of MEP amplitudes following PAS (10 ms) was within the motor cortex. MEP
      amplitudes remained depressed for approximately 90 min. The decrease of MEP
      amplitudes was blocked when PAS(10 ms) was performed under the influence of
      dextromethorphan, an N-methyl-d-aspartate-receptor antagonist, or nimodipine, an
      L-type voltage-gated calcium-channel antagonist. The physiological profile of the
      depression of human motor cortical excitability following PAS(10 ms) suggests
      long-term depression of synaptic efficacy to be involved. Together with earlier
      findings, this study suggests that strict temporal Hebbian rules govern the
      induction of long-term potentiation/long-term depression-like phenomena in vivo
      in the human primary motor cortex.

PMID- 12612034
TI  - Strychnine-sensitive glycine receptors depress hyperexcitability in rat dentate
      gyrus.
AB  - Previously we have shown that strychnine-sensitive glycine-gated chloride
      channels (GlyRs) are functionally expressed by CA1 pyramidal cells and GABAergic
      interneurons in mature rat hippocampal slices. We now report that glycine
      application to dentate granule cells and hilar interneurons recorded in acute
      slices from adolescent rats elicits a strychnine-sensitive current similar to
      glycine-mediated currents recorded in area CA1, indicating that GlyRs are also
      present on neurons in the dentate gyrus. This finding suggests that GlyRs have a
      widespread distribution in the hippocampal region. The physiological role of
      GlyRs in forebrain is unclear, but it is possible that these receptors mediate
      neuronal inhibition, similar to gamma-aminobutyric acid-A (GABA(A)) receptors and
      thus could be a novel target for antiepileptic therapy. Therefore we tested the
      hypothesis that activation of inhibitory GlyRs could suppress neuronal
      hyperexcitability in dentate, a brain region vulnerable to epileptic activity. In
      whole-cell current-clamp recordings of granule cells, we observed a membrane
      potential hyperpolarization followed by cessation of the action potential firing
      pattern in hyperexcitable slices induced by elevated extracellular K(+) or by
      blocking GABA(A) receptors with bicuculline. The GlyR antagonist, strychnine,
      prevented the antiepileptic effect of glycine. These results demonstrate that
      glycine, acting at GlyRs, elicits neuronal inhibition in dentate. Further, our
      findings suggest the possibility that these receptors could be a therapeutic
      target for the treatment of epilepsy.

PMID- 12612035
TI  - Stretch responses of cutaneous RA afferent neurons in mouse hairy skin.
AB  - Rapidly adapting (RA), stretch-sensitive neurons were recorded in vitro, using an
      isolated preparation of skin and nerve from mouse hindlimb. The skin was
      stretched uniaxially using a pseudo-Gaussian noise stimulus. Loads and
      displacements were recorded as were spike responses of single RA afferent
      neurons. The goal was to determine what components of the mechanical stimulus
      were associated with spike responses. The association between stimuli and spike
      responses was measured using multiple logistic regression. Spike responses were
      strongly associated with the rate of change of stress and weakly associated with
      the rate of change of strain and with stress. There was no association between
      spike responses and strain. There were significant memory effects associated with
      each variable, and memory effects differed for each variable. The maximal effect
      of the rate of change of stress was observed 8-12 ms prior to a spike.

PMID- 12612037
TI  - Millivolt-scale DC shifts in the human scalp EEG: evidence for a nonneuronal
      generator.
AB  - Slow shifts in the human scalp-recorded EEG, including those related to changes
      in brain CO(2) levels, have been generally assumed to result from changes in the
      level of tonic excitation of apical dendrites of cortical pyramidal neurons. We
      readdressed this issue using DC-EEG shifts elicited in healthy adult subjects by
      hypo- or hypercapnia. A 3-min period of hyperventilation resulted in a prompt
      negative shift with a rate of up to 10 microV/s at the vertex (Cz) and an
      extremely steep dependence (up to 100 microV/mmHg) on the end-tidal Pco(2). This
      shift had a maximum of up to -2 mV at Cz versus the temporal derivations (T3/T4).
      Hyperventilation-like breathing of 5% CO(2)-95% O(2), which does not lead to a
      significant hypocapnia, resulted in a near-complete block of the negative DC
      shift at Cz. Hypoventilation, or breathing 5% CO(2) in air at normal respiratory
      rate, induced a positive shift. The high amplitude of the voltage gradients on
      the scalp induced by hyperventilation is not consistent with a neuronal origin.
      Instead, the present data suggest that they are generated by extracortical volume
      currents driven by a Pco(2)-dependent potential difference across epithelia
      separating the cerebrospinal fluid and blood. Since changes in respiratory
      patterns and, hence, in the level of brain Pco(2), are likely to occur under a
      number of experimental conditions in which slow EEG responses have been reported
      (e.g., attention shifts, preparatory states, epileptic seizures, and hypoxic
      episodes), the present results call for a thorough reexamination of the
      mechanisms underlying scalp-recorded DC-EEG responses.

PMID- 12612036
TI  - Angiotensin II activates a nitric-oxide-driven inhibitory feedback in the rat
      paraventricular nucleus.
AB  - The hypothalamic paraventricular nucleus (PVN) has been shown to play major
      obligatory roles in autonomic and neuroendocrine regulation. Angiotensin II (ANG)
      acts as a neurotransmitter regulating the excitability of magnocellular neurons
      in this nucleus. We report here that ANG also activates a nitric-oxide-mediated
      negative feedback loop in the PVN that acts to regulate the functional output of
      magnocellular neurons. Thus in addition to its depolarizing actions on
      magnocellular neurons, ANG application results in an increase in the frequency of
      inhibitory postsynaptic potentials in a population of these neurons without
      effect on the amplitude of these events. ANG was also without significant effect
      on the mean frequency or amplitude of mini synaptic currents analyzed in voltage
      clamp experiments. This increase in inhibitory input after ANG can be abolished
      by the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methylester,
      demonstrating a requisite role for nitric oxide in the activation of this
      pathway. The depolarization of magnocellular neurons that show increased
      inhibitory postsynaptic potential (IPSP) frequency in response to ANG is
      significantly smaller than that observed in neurons in which IPSPs frequency was
      unaffected (3.2 +/- 1.1 vs. 8.0 +/- 0.5 mV, P < 0.05). Correspondingly, after
      nitric oxide synthase inhibition, the depolarizing effects of ANG on
      magnocellular neurons are augmented (2.0 +/- 0.7 vs. 6.7 +/- 0.7 mV, P < 0.05).
      The depolarization was also enhanced in the presence of the GABAergic antagonist
      bicuculline (1.9 +/- 1.2 vs. 11.9 +/- 2.3, P < 0.001). These data demonstrate
      that there exists within the PVN an intrinsic negative feedback loop that
      modulates neuronal excitability in response to peptidergic excitation.

PMID- 12612038
TI  - Altered triggering of a prepared movement by a startling stimulus.
AB  - An experiment is reported that investigated the effects of an auditory startling
      stimulus on a compound movement task. Previous findings have shown that, in a
      targeting task, a secondary movement can be initiated based on the proprioceptive
      information provided by a primary movement. Studies involving the presentation of
      a startling stimulus have shown that in reaction time (RT) tasks, prepared
      ballistic movements could be released early when participants are startled. In
      the present study we sought to determine whether the secondary component in an
      ongoing movement task, once prepared, could also be triggered by a startling
      stimulus. Participants performed a slow active elbow extension (22 degrees /s),
      opening their hand when the arm passed 55 degrees of extension from the starting
      point. An unexpected 124 dB startle stimulus was presented 5, 25, or 45 degrees
      into the movement. Findings showed that, when participants were startled, the
      secondary component was triggered despite incongruent kinesthetic information.
      However, this only occurred when the startle was presented late in the primary
      movement. This suggests that the secondary movement was not prepared prior to
      task initiation, but was "loaded" into lower brain structures at some point
      during the movement in preparation to be triggered by the CNS. This occurred late
      in the movement sequence, but >/=400 ms prior to reaching the target. These
      findings indicate that, in addition to ballistic RT tasks, a startle can be used
      to probe response preparation in ongoing compound movement tasks.

PMID- 12612039
TI  - Ca2+ transient evoked by chemical stimulation is enhanced by PGE2 in vagal
      sensory neurons: role of cAMP/PKA signaling pathway.
AB  - The effect of prostaglandin E(2) (PGE(2)) on chemical stimulation-evoked calcium
      (Ca(2+)) transient was investigated in isolated vagal sensory neurons of the rat
      using fura-2-based ratiometric Ca(2+) imaging. Application of capsaicin (3 x 10(
      8) to 10(-7) M; 15 s) caused a rapid surge of intracellular Ca(2+) concentration
      in small- and medium-size neurons; the response was reproducible when >10 min
      elapsed between two challenges and was absent in nominally Ca(2+)-free solution.
      After pretreatment with PGE(2) (3 x 10(-7) M; 5 min), the peak of this capsaicin
      evoked Ca(2+) transient was increased by almost fourfold, and its duration was
      also prolonged. This augmented response to capsaicin induced by PGE(2) gradually
      declined but remained higher than control after 15-min washout. Similarly, PGE(2)
      pretreatment also markedly enhanced the Ca(2+) transients induced by other
      chemical stimulants to C neurons, such as phenylbiguanide (PBG), adenosine 5'
      triphosphate (ATP), and KCl. The Ca(2+) transients evoked by PBG, ATP, and KCl
      were potentiated after the pretreatment with PGE(2) to 242, 204, and 163% of
      their control, respectively. This potentiating effect of PGE(2) could be mimicked
      by forskolin (10(-6) M; 5 min), an activator of adenylyl cyclase, and 8-(4
      chlorophenylthio)adenosine-3'-5'-cyclic monophosphate (CPT-cAMP; 3 x 10(-6) M, 10
      min), a membrane-permeable cAMP analogue. Furthermore, the potentiating effects
      of PGE(2), forskolin, and CPT-cAMP were abolished by N-[2-(p
      bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89; 10(-5) M; 15-20 min), a
      protein kinase A (PKA) inhibitor. In summary, these results show that PGE(2)
      reversibly potentiates the chemical stimuli-evoked Ca(2+) transients in cultured
      rat vagal sensory neurons, and this potentiating effect is mediated through the
      cyclic AMP/PKA transduction cascade.

PMID- 12612041
TI  - Relative contributions of balance and voluntary leg-coordination deficits to
      cerebellar gait ataxia.
AB  - Different cerebellar regions participate in balance control and voluntary limb
      coordination, both of which might be important for normal bipedal walking. We
      wanted to determine the relative contributions of balance versus leg-coordination
      deficits to cerebellar gait ataxia in humans. We studied 20 subjects with
      cerebellar damage and 20 control subjects performing three tasks: a lateral
      weight-shifting task to measure balance, a visually guided stepping task to
      measure leg- coordination, and walking. We recorded three-dimensional joint
      position data during all tasks and center of pressure coordinates during weight
      shifting. Each cerebellar subject was categorized as having no detectable
      deficits, a balance deficit only, a leg-placement deficit only, or both deficits.
      We then determined the walking abnormalities associated with each of these
      categories. Five of 10 measures of gait ataxia were abnormal in cerebellar
      subjects with a balance deficit, but only 1 was abnormal in cerebellar subjects
      with a leg-placement deficit. Furthermore, subjects with a balance deficit
      performed worse than subjects with a leg-placement deficit on 9 of the 10 gait
      measures. Finally, performance on the balance task, but not the leg-placement
      task, explained a significant proportion of the variance in walking speed for the
      entire cerebellar group. We conclude that balance deficits are more closely
      related to cerebellar gait ataxia than leg-placement deficits. Our findings are
      consistent with animal literature, which has suggested that cerebellar control of
      balance and gait are interrelated, and dissociable from cerebellar control of
      voluntary, visually guided limb movements.

PMID- 12612042
TI  - Model of song selectivity and sequence generation in area HVc of the songbird.
AB  - In songbirds, nucleus HVc plays a key role in the generation of the syllable
      sequences that make up a song. Auditory responses of neurons in HVc are selective
      for single syllables and for combinations of syllables occurring in temporal
      sequences corresponding to those in the bird's own song. We present a model of
      HVc that produces syllable- and temporal-combination-selective responses on the
      basis of input from recorded bird songs filtered through spectral temporal
      receptive fields similar to those measured in field L, a primary auditory area.
      Normalization of the field L outputs, similar to that proposed in models of
      visual processing, plays an important role in the generation of syllable
      selective responses in the model. For temporal-combination-selective responses, N
      methyl-d-aspartate (NMDA) conductances provide a memory that allows inhibitory
      neurons to gate responses to a final syllable in a sequence on the basis of
      responses to earlier syllables. When the same network that produces temporal
      combination-selective responses is excited by a nonspecific timing signal, it
      generates a similar pattern of output as it does in response to auditory song
      input. Thus the same model network can perform both sensory and motor functions.

PMID- 12612043
TI  - Hyperalgesia and neural excitability following injuries to central and peripheral
      branches of axons and somata of dorsal root ganglion neurons.
AB  - We examined thermal hyperalgesia, excitability of dorsal root ganglion (DRG)
      neurons, and antinociceptive effects of N-methyl-d-aspartate (NMDA) receptor
      antagonists in rats with injury to different regions of DRG neurons. The central
      or peripheral branches of axons of DRG neurons were injured by partial dorsal
      rhizotomy (PDR) and chronic constriction injury of sciatic nerve (CCI),
      respectively, or the somata injured by chronic compression of DRG (CCD). Thermal
      hyperalgesia was evidenced by significantly shortened latencies of foot
      withdrawal to radiant heat stimulation of the plantar surface. Intracellular
      recordings were obtained in vitro from L(4) and/or L(5) ganglia. There are four
      principle findings: 1) PDR as well as CCD and CCI induced thermal hyperalgesia;
      2) PDR produced significantly less severe and shorter duration hyperalgesia than
      CCD and CCI; 3) intrathecal administration of NMDA receptor antagonists d-2-amino
      5-phosphonovaleric acid (APV) and dizocilpine maleate (MK-801) inhibited thermal
      hyperalgesia in PDR, CCD, and CCI rats. Pretreatment of APV and MK-801 delayed
      the emergence of hyperalgesia for 48-72 h, while posttreatment inhibited
      hyperalgesia for 24-36 h; and 4) CCD and CCI increased excitability of DRG
      neurons as judged by the significantly lowered threshold currents and action
      potential voltage thresholds and increased incidence of repetitive discharges.
      However, PDR did not alter the excitability of DRG neurons. These findings
      indicate that injury to the dorsal root, compared with injury to the peripheral
      nerve or DRG somata has different effects on the development of hyperalgesia.
      These contributions involve different changes in DRG membrane excitability, but
      each involves pathways (presumably in the spinal cord) that depend on NMDA
      receptors.

PMID- 12612040
TI  - Neurosteroid effects on GABAergic synaptic plasticity in hippocampus.
AB  - We have previously reported that short-term (48-72 h) exposure to the GABA
      modulatory steroid 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) increases
      expression of the alpha4 subunit of the GABA(A) receptor (GABAR) in the
      hippocampus of adult rats. This change in subunit composition was accompanied by
      altered pharmacology and an increase in general excitability associated with
      acceleration of the decay time constant (tau) for GABA-gated current of pyramidal
      cells acutely isolated from CA1 hippocampus similar to what we have reported
      following withdrawal from the steroid after chronic long-term administration.
      Because GABAR can be localized to either synaptic or extrasynaptic sites, we
      tested the hypothesis that this change in receptor kinetics is mediated by
      synaptic GABAR. To this end, we evaluated the decay kinetics of TTX-resistant
      miniature inhibitory postsynaptic currents (mIPSCs) recorded from CA1 pyramidal
      cells in hippocampal slices following 48-h treatment with 3alpha,5alpha/beta-THP
      (10 mg/kg, ip). Hormone treatment produced a marked acceleration in the fast
      decay time constant (tau(fast)) of GABAergic mIPSCs. This effect was prevented by
      suppression of alpha4-subunit expression with antisense (AS) oligonucleotide,
      suggesting that hormone treatment increases alpha4-containing GABAR
      subsynaptically. This conclusion was further supported by pharmacological data
      from 3alpha,5beta-THP-treated animals, demonstrating a bimodal distribution of
      taus for individual mIPSCs following bath application of the alpha4-selective
      benzodiazepine RO15-4513, with a shift to slower values. Because 40-50% of the
      individual taus were also shifted to slower values following bath application of
      the non-alpha4-selective benzodiazepine agonist lorazepam (LZM), we suggest that
      the number of GABAR synapses containing alpha4 subunits is equivalent to those
      that do not following 48-h administration of 3alpha,5beta-THP. The decrease in
      GABAR-mediated charge transfer resulting from accelerated current decay may then
      result in increased excitability of the hippocampal circuitry, an effect
      consistent with the increased behavioral excitability we have previously
      demonstrated.

PMID- 12612044
TI  - Neuronal activity related to the visual representation of arm movements in the
      lateral cerebellar cortex.
AB  - Testing the hypothesis that the lateral cerebellum forms a sensory representation
      of arm movements, we investigated cortical neuronal activity in two monkeys
      performing visually guided step-tracking movements with a manipulandum. A virtual
      target and cursor image were viewed co-planar with the manipulandum. In the
      normal task, manipulandum and cursor moved in the same direction; in the mirror
      task, the cursor was left-right reversed. In one monkey, 70- and 200-ms time
      delays were introduced on cursor movement. Significant task-related activity was
      recorded in 31 cells in one animal and 142 cells in the second: 10.2% increased
      activity before arm movements onset, 77.1% during arm movement, and 12.7% after
      the new position was reached. To test for neural representation of the visual
      outcome of movement, firing rate modulation was compared in normal and mirror
      step-tracking. Most task-related neurons (68%) showed no significant directional
      modulation. Of 70 directionally sensitive cells, almost one-half (n = 34, 48%)
      modulated firing with a consistent cursor movement direction, many fewer
      responding to the manipulandum direction (n = 9, 13%). For those "cursor-related"
      cells tested with delayed cursor movement, increased activity onset was time
      locked to arm movement and not cursor movement, but activation duration was
      extended by an amount similar to the applied delay. Hence, activity returned to
      baseline about when the delayed cursor reached the target. We conclude that many
      cells in the lateral cerebellar cortex signaled the direction of cursor movement
      during active step-tracking. Such a predictive representation of the arm movement
      could be used in the guidance of visuo-motor actions.

PMID- 12612045
TI  - Neuromagnetic correlates of perceived contrast in primary visual cortex.
AB  - When a target grating is flashed into a larger, surrounding grating, its contrast
      is perceived to be lower when both gratings are oriented collinearly rather than
      orthogonally. This effect can be used to dissociate the perceived contrast from
      the physical contrast of a target grating. We recorded the transient electric
      potentials and magnetic fields evoked by flashed target gratings and compared
      them with psychophysical judgments of perceived contrast. Both early (100 ms) and
      late (150 ms) transients were reduced in amplitude when targets were flashed into
      a collinear rather than orthogonal surround, thus paralleling the reduction in
      perceived contrast. Although targets in orthogonal backgrounds required 40% lower
      physical contrast to match the perceived contrast of collinear targets, the
      amplitudes of electrophysiological transients of matching stimuli were almost
      identical. Thus the responses correlated better with perceived than with physical
      target contrast. This holds especially for the late transient response. Source
      localization indicated that the transients in question may originate in primary
      visual cortex. Our results therefore identify the activity of primary visual
      cortex as one possible neural correlate of perceived contrast.

PMID- 12612047
TI  - Raphe magnus neurons respond to noxious colorectal distension.
AB  - Physiological studies of neurons in raphe magnus (RM) and the adjacent nucleus
      reticularis magnocellularis (NRMC) have demonstrated that the response to noxious
      cutaneous stimulation predicts the response to opioid administration and
      therefore a cell's functional role in nociceptive modulation. Although visceral
      stimulation, like opioids, elicits antinociception, little is known about how RM
      and NRMC cells respond to visceral stimulation. Therefore RM and NRMC cells were
      tested for their responses to both colorectal distension (CRD) and noxious
      cutaneous heat in halothane-anesthetized rats. Less than a third of serotonergic
      cells responded to CRD with small increases or decreases in discharge rate. In
      contrast, almost two-thirds of nonserotonergic cells responded to CRD stimulation
      with either excitatory (35%) or inhibitory (30%) responses to CRD. The response
      to heat did not predict the response to CRD with nearly equal proportions of heat
      excited, -inhibited, and -unaffected cells being excited, inhibited, or
      unaffected by CRD. The dissociation between the responses to cutaneous heat and
      CRD demonstrates that cell classes based on the response to noxious heat are not
      homogeneous and may play multiple functional roles.

PMID- 12612048
TI  - Neural coding of spatial phase in V1 of the macaque monkey.
AB  - We examine the responses of single neurons and pairs of neurons, simultaneously
      recorded with a single tetrode in the primary visual cortex of the anesthetized
      macaque monkey, to transient presentations of stationary gratings of varying
      spatial phase. Such simultaneously recorded neurons tended to have similar tuning
      to the phase of the grating. To determine the response features that reliably
      discriminate these stimuli, we use the metric-space approach extended to pairs of
      neurons. We find that paying attention to the times of individual spikes, at a
      resolution of approximately 30 ms, and keeping track of which neuron fires which
      spike rather than just the summed local activity contribute substantially to
      phase coding. The contribution is both quantitative (increasing the fidelity of
      phase coding) and qualitative (enabling a 2-dimensional "response space" that
      corresponds to the spatial phase cycle). We use a novel approach, the extraction
      of "temporal profiles" from the metric space analysis, to interpret and compare
      temporal coding across neurons. Temporal profiles were remarkably consistent
      across a large subset of neurons. This consistency indicates that simple
      mechanisms (e.g., comparing the size of the transient and sustained components of
      the response) allow the temporal contribution to phase coding to be decoded.

PMID- 12612049
TI  - Automatic sorting for multi-neuronal activity recorded with tetrodes in the
      presence of overlapping spikes.
AB  - Multi-neuronal recording is a powerful electrophysiological technique that has
      revealed much of what is known about the neuronal interactions in the brain.
      However, it is difficult to detect precise spike timings, especially synchronized
      simultaneous firings, among closely neighboring neurons recorded by one common
      electrode because spike waveforms overlap on the electrode when two or more
      neurons fire simultaneously. In addition, the non-Gaussian variability
      (nonstationarity) of spike waveforms, typically seen in the presence of so-called
      complex spikes, limits the ability to sort multi-neuronal activities into their
      single-neuron components. Because of these problems, the ordinary spike-sorting
      techniques often give inaccurate results. Our previous study has shown that
      independent component analysis (ICA) can solve these problems and separate single
      neuron components from multi-neuronal recordings. The ICA has, however, one
      serious limitation that the number of separated neurons must be less than the
      number of electrodes. The present study combines the ICA and the efficiency of
      the ordinary spike-sorting technique (k-means clustering) to solve the spike
      overlapping and the nonstationarity problems with no limitation on the number of
      single neurons to be separated. First, multi-neuronal activities are sorted into
      an overly large number of clusters by k-means clustering. Second, the sorted
      clusters are decomposed by ICA. Third, the decomposed clusters are progressively
      aggregated into a minimal set of putative single neurons based on similarities of
      basis vectors estimated by ICA. We applied the present procedure to multi
      neuronal waveforms recorded with tetrodes composed of four microwires in the
      prefrontal cortex of awake behaving monkeys. The results demonstrate that there
      are functional connections among neighboring pyramidal neurons, some of which
      fire in a precise simultaneous manner and that precisely time-locked monosynaptic
      connections are working between neighboring pyramidal neurons and interneurons.
      Detection of these phenomena suggests that the present procedure can sort multi
      neuronal activities, which include overlapping spikes and realistic non-Gaussian
      variability of spike waveforms, into their single-neuron components. We processed
      several types of synthesized data sets in this procedure and confirmed that the
      procedure was highly reliable and stable. The present method provides insights
      into the local circuit bases of excitatory and inhibitory interactions among
      neighboring neurons.

PMID- 12612050
TI  - KChIP1 and frequenin modify shal-evoked potassium currents in pyloric neurons in
      the lobster stomatogastric ganglion.
AB  - The transient potassium current (I(A)) plays an important role in shaping the
      firing properties of pyloric neurons in the stomatogastric ganglion (STG) of the
      spiny lobster, Panulirus interruptus. The shal gene encodes I(A) in pyloric
      neurons. However, when we over-expressed the lobster Shal protein by shal RNA
      injection into the pyloric dilator (PD) neuron, the increased I(A) had somewhat
      different properties from the endogenous I(A). The recently cloned K-channel
      interacting proteins (KChIPs) can modify vertebrate Kv4 channels in cloned cell
      lines. When we co-expressed hKChIP1 with lobster shal in Xenopus oocytes or
      lobster PD neurons, they produced A-currents resembling the endogenous I(A) in PD
      neurons; compared with currents evoked by shal alone, their voltage for half
      inactivation was depolarized, their kinetics of inactivation were slowed, and
      their recovery from inactivation was accelerated. We also co-expressed shal in PD
      neurons with lobster frequenin, which encodes a protein belonging to the same EF
      hand family of Ca(2+) sensing proteins as hKChIP. Frequenin also restored most of
      properties of the shal-evoked currents to those of the endogenous A-currents, but
      the time course of recovery from inactivation was not corrected. These results
      suggest that lobster shal proteins normally interact with proteins in the
      KChIP/frequenin family to produce the transient potassium current in pyloric
      neurons.

PMID- 12612051
TI  - Cellular and network mechanisms of slow oscillatory activity (<1 Hz) and wave
      propagations in a cortical network model.
AB  - Slow oscillatory activity (<1 Hz) is observed in vivo in the cortex during slow
      wave sleep or under anesthesia and in vitro when the bath solution is chosen to
      more closely mimic cerebrospinal fluid. Here we present a biophysical network
      model for the slow oscillations observed in vitro that reproduces the single
      neuron behaviors and collective network firing patterns in control as well as
      under pharmacological manipulations. The membrane potential of a neuron
      oscillates slowly (at <1 Hz) between a down state and an up state; the up state
      is maintained by strong recurrent excitation balanced by inhibition, and the
      transition to the down state is due to a slow adaptation current (Na(+)-dependent
      K(+) current). Consistent with in vivo data, the input resistance of a model
      neuron, on average, is the largest at the end of the down state and the smallest
      during the initial phase of the up state. An activity wave is initiated by
      spontaneous spike discharges in a minority of neurons, and propagates across the
      network at a speed of 3-8 mm/s in control and 20-50 mm/s with inhibition block.
      Our work suggests that long-range excitatory patchy connections contribute
      significantly to this wave propagation. Finally, we show with this model that
      various known physiological effects of neuromodulation can switch the network to
      tonic firing, thus simulating a transition to the waking state.

PMID- 12612052
TI  - Development of inward rectification and control of membrane excitability in
      mesencephalic v neurons.
AB  - The present study was performed to assess the postnatal development and
      functional roles of inward rectifying currents in rat mesencephalic trigeminal
      (Mes V) neurons, which are involved in the genesis and control of oral-motor
      activities. Whole cell voltage-clamp recordings obtained from Mes V neurons in
      brain stem slices identified fast (I(KIR)) and slow (I(h)) inward rectifying
      currents, which were specifically blocked by BaCl(2) (300-500 microM) or 4-(N
      ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD 7288,
      10 microM), respectively. The whole cell current density for these channels
      increased between postnatal days 2 to 12 (P2-P12), and the time courses for I(h)
      activation and deactivation were each well described by two time constants.
      Application of ZD 7288 produced membrane hyperpolarization in the majority of
      cells and prolonged afterhyperpolarization repolarization. Additionally, in the
      presence of ZD 7288, spike frequency was decreased and adaptation was more
      pronounced. Interestingly, these neurons exhibited a voltage-dependent membrane
      resonance (<10 Hz) that was prominent around resting potential and more negative
      to rest and was blocked by ZD 7288. These results suggest that I(h) contributes
      to stabilizing resting membrane potential and controlling cell excitability. The
      presence of I(h) imparts the neuron with the unique property of low-frequency
      membrane resonance; the ability to discriminate between synaptic inputs based on
      frequency content.

PMID- 12612053
TI  - DJBP: a novel DJ-1-binding protein, negatively regulates the androgen receptor by
      recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by
      abrogation of this complex.
AB  - DJ-1 was identified by us as a novel oncogene that transforms mouse NIH3T3 cells
      in cooperation with ras. We later identified PIAS (protein inhibitor of activated
      STAT)xalpha as a DJ-1-binding protein, and found that DJ-1 restored androgen
      receptor (AR) transcription activity that was repressed by PIASxalpha. To further
      characterize the function of DJ-1, we cloned cDNA encoding a novel DJ-1-binding
      protein, DJBP, by a yeast two-hybrid system. DJBP mRNA was found to be
      specifically expressed in the testis. In addition to the binding of DJBP to the
      COOH-terminal region of DJ-1, DJBP was also found to bind in vitro and in vivo to
      the DNA-binding domain of the AR in a testosterone-dependent manner and to be
      colocalized with DJ-1 or AR in the nucleus. Furthermore, a co-immunoprecipitation
      assay showed that the formation of a ternary complex between DJ-1, DJBP, and AR
      occurred in cells in which DJ-1 bound to the AR via DJBP. It was found that DJBP
      repressed a testosterone-dependent AR transactivation activity in monkey Cos1
      cells by recruiting histone deacetylase (HDAC) complex, including HDAC1 and
      mSin3, and that DJ-1 partially restored its repressed activity by abrogating DJBP
      HDAC complex. These results suggest that AR is positively regulated by DJ-1,
      which antagonizes the function of negative regulators, including DJBP.

PMID- 12612054
TI  - NF-kappaB-mediated induction of p21(Cip1/Waf1) by tumor necrosis factor alpha
      induces growth arrest and cytoprotection in normal human keratinocytes.
AB  - Cellular stressors such as UV irradiation, chemical irritants, or an immune
      system challenge in an otherwise healthy host induce the production and release
      of cytokines, such as tumor necrosis factor (TNF) alpha, which are powerful
      regulators of tissue homeostasis. TNFalpha, an important mediator of inflammation
      in the skin and mucosa, often represents the first physiological response to such
      noxious stimuli. TNFalpha not only acts systemically to promote inflammation, but
      also locally at the site of the stimulus to modulate cell growth and survival. It
      has been demonstrated previously that epithelial cells undergo growth arrest and
      differentiation in the presence of TNFalpha. However, the mechanism of this
      response is not well understood. Here we show that in primary cultures of human
      foreskin keratinocytes, TNFalpha mediates cellular growth arrest through
      activation of the transcription factor NF-kappaB. The cdk inhibitor
      p21(Cip1/Waf1) is activated through NF-kappaB and is an important mediator of
      this growth arrest response. In addition, TNFalpha-treated cell populations are
      markedly less susceptible to apoptosis by UV irradiation and this cytoprotective
      effect is at least in part mediated by p21(Cip1/Waf1) as well.

PMID- 12612055
TI  - repp86: A human protein associated in the progression of mitosis.
AB  - Human repp86 becomes detectable in the nucleoplasm of cycling cells at the G(1)-S
      boundary, condenses at the centrosomes with the onset of mitosis, during which it
      progressively locates to the mitotic spindle and to the midbody, and vanishes at
      the completion of cytokinesis. The repp86 cDNA was cloned and sequenced. Full
      length repp86 and its COOH-terminal domain cosediment with polymerized
      microtubules, linking repp86 to the family of microtubule-associated proteins.
      During prophase and metaphase, repp86 interacts on the mitotic spindle with the
      putative motor protein Hklp2. Thus, repp86 may function in targeting Hklp2 to the
      microtubule minus ends, its activity being regulated by phosphorylation of
      serine/threonine residues. Exogenous overexpression of repp86 provokes
      accumulation of cells in G(2)-M phase and subsequent polyploidization, suggesting
      that excess repp86 may interfere with correct nuclear division.

PMID- 12612056
TI  - Phosphorylation of the cyclin b1 cytoplasmic retention sequence by mitogen
      activated protein kinase and Plx.
AB  - The cyclin B1/Cdc2 complex regulates many of the dramatic cellular rearrangements
      observed at mitosis. Although predominantly cytoplasmic during interphase, this
      kinase complex translocates precipitously to the nucleus at the G(2)-M
      transition. The interphase cytoplasmic location of cyclin B1/Cdc2 reflects
      continuous, albeit slow, nuclear import and much more rapid nuclear export. In
      contrast, the sudden nuclear accumulation of the complex before entry into
      mitosis reflects a marked increase in the import rate, with a concomitant
      inhibition of cyclin B1 nuclear export. These dynamic changes in cyclin B1/Cdc2
      localization are regulated by phosphorylation of four serines within a region of
      cyclin B1 known as the cytoplasmic retention sequence (CRS). Phosphorylation of
      all four serines is required for rapid nuclear entry, whereas phosphorylation of
      only the last in the series (Ser 113) is required to prevent nuclear export by
      CRM1. As these residues represent key loci of regulation, it is important to
      identify the kinases acting on these sites. Here we report that Xenopus cyclin B1
      is regulated by both Erk and Plx kinases, and that Cdc2, counter to previous
      speculation, is not required for CRS phosphorylation. Phosphorylation of the
      first two of the CRS serines (Ser 94 and Ser 96) is catalyzed by Erk in the
      Xenopus system. Although it was previously reported that Ser 113 is a Plx
      substrate, we were unable to observe phosphorylation of this residue in isolation
      by purified Plx. Rather, in contrast to previously published data, we have found
      that the penultimate CRS serine (Ser 101) is a Plx substrate. Collectively, these
      data demonstrate a new role for Erk in mitotic regulation, identify the Ser 101
      directed kinase, and provide a picture of cyclin B1/Cdc2 regulation by the
      combinatorial action of distinct kinases.

PMID- 12612058
TI  - Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes
      in breast cancer cells.
AB  - Tamoxifen is a widely used breast cancer therapeutic and preventative agent.
      Although functioning as an estrogen antagonist at the cellular level,
      transcriptional profiling revealed that at the molecular level, tamoxifen
      functions largely as an agonist, virtually recapitulating the gene expression
      profile induced in breast cancer cells by estrogen. Remarkably, tamoxifen induces
      transcription factors and genes involved in promoting cell cycle progression
      including fos, myc, myb, cdc25a, cyclins E and A2, and stk15 with kinetics that
      paralleled that of cells cycling in response to estrogen, even though tamoxifen
      treated cells are not transiting through the cell cycle. Induction of cell cycle
      associated genes was specific for tamoxifen, and did not occur with raloxifene.
      However, cyclin D1 was a key estrogen-induced gene not expressed in response to
      tamoxifen or raloxifene but constitutively expressed in tamoxifen-resistant
      cells.

PMID- 12612057
TI  - 8-hydroxydeoxyguanosine causes death of human leukemia cells deficient in 8
      oxoguanine glycosylase 1 activity by inducing apoptosis.
AB  - Our previous study showed that KG-1, a human acute leukemia cell line, has
      mutational loss of 8-oxoguanine (8-hydroxyguanine; oh(8)Gua) glycosylase 1 (OGG1)
      activity and that its viability is severely affected by 8-hydroxydeoxyguanosine
      (8-oxodeoxyguanosine; oh(8)dG). In the present study, the nature of the killing
      action of oh(8)dG on KG-1 was investigated. Signs observed in oh(8)dG-treated KG
      1 cells indicated that death was due to apoptosis, as demonstrated by: increased
      sub-G(1) hypodiploid (apoptotic) cells, DNA fragmentation, and apoptotic body
      formation; loss of mitochondrial transmembrane potential, the release of
      cytochrome c from mitochondria into the cytosol, and the down-regulation of bcl
      2; and the activation of caspases 8, 9, and 3, and the efficient inhibition of
      the apoptotic process by caspases inhibitors. This apoptosis appears not to be
      associated with Fas/Fas ligand because the expressions of these proteins were
      unchanged. Apoptotic KG-1 cells showed a high concentration of oh(8)Gua in DNA.
      Moreover, the increased concentration of oh(8)Gua in DNA, and the apoptotic
      process were not suppressed by the antioxidant, N-acetylcysteine, and thus the
      process is independent of reactive oxygen species. Of the 18 cancer cell lines
      treated with oh(8)dG, 3 cell lines (H9, CEM-CM3, and Molt-4) were found to be
      committed to apoptosis, and all of these showed very low OGG1 activity and a
      marked increase in the concentration of oh(8)Gua in DNA. These observations
      indicate that in addition to its mutagenic action, oh(8)Gua in DNA disturbs cell
      viability by inducing apoptosis.

PMID- 12612059
TI  - Phosphatidylinositol 3-kinase and mek1/2 are necessary for insulin-like growth
      factor-I-induced vascular endothelial growth factor synthesis in prostate
      epithelial cells: a role for hypoxia-inducible factor-1?
AB  - Due to the importance of vascular endothelial growth factor (VEGF) in the
      neovascularization of solid tumors, a clear understanding of how VEGF is
      regulated in normal and tumor cells is warranted. We investigated insulin-like
      growth factor (IGF)-I-stimulated signaling pathways that increase the rate of
      VEGF synthesis in primary cultures of normal prostate epithelial cells (PrEC).
      IGF-I increased the secretion of VEGF(165) into PrEC growth medium and stimulated
      transcription of a reporter gene driven by a 1.5-kb region of the VEGF promoter.
      Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling
      pathways completely abrogated the IGF-I-induced increase in VEGF secretion and
      promoter activity, indicating a dependence on coordinate signaling from both
      pathways to produce this effect. Levels of the transcription factors hypoxia
      inducible factor (HIF)-1 and Fos were elevated in response to IGF-I in a PI3-K
      dependent and Mek1/2-dependent manner, respectively. The expression of an
      activator protein (AP)-1 dominant negative in an immortalized prostate epithelial
      cell line PZ-HPV-7 suppressed the IGF-I-induced increase in VEGF promoter
      activity. Mutation of the hypoxia response element (HRE), which mediates hypoxic
      stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the
      VEGF promoter, despite the fact that this mutation inhibited PI3-K-stimulated
      VEGF promoter activity in prostate cancer cells. These data indicate that PI3-K
      signaling does not increase VEGF transcription through transactivation by HIF-1
      at the HRE in normal PrEC. This work also suggests that an additional signal, not
      stimulated by IGF-I in PrEC, is needed for HIF-1 to stimulate transcription from
      the VEGF HRE.

PMID- 12612060
TI  - The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha
      through activation of proteasomes.
AB  - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon receptor
      (AhR) ligands suppress 17beta-estradiol (E)-induced responses in the rodent
      uterus and mammary tumors and in human breast cancer cells. Treatment of ZR-75,
      T47D, and MCF-7 human breast cancer cells with TCDD induces proteasome-dependent
      degradation of endogenous estrogen receptor alpha (ERalpha). The proteasome
      inhibitors MG132, PSI, and PSII inhibit the proteasome-dependent effects induced
      by TCDD, whereas the protease inhibitors EST, calpain inhibitor II, and
      chloroquine do not affect this response. ERalpha levels in the mouse uterus and
      breast cancer cells were significantly lower after cotreatment with E plus TCDD
      than after treatment with E or TCDD alone, and our results indicate that AhR
      mediated inhibition of E-induced transactivation is mainly due to limiting levels
      of ERalpha in cells cotreated with E plus TCDD. TCDD alone or in combination with
      E increases formation of ubiquitinated forms of ERalpha, and both
      coimmunoprecipitation and mammalian two-hybrid assays demonstrate that TCDD
      induces interaction of the AhR with ERalpha in the presence or absence of E. In
      contrast, E does not induce AhR-ERalpha interactions. Thus, inhibitory AhR
      ERalpha cross talk is linked to a novel pathway for degradation of ERalpha in
      which TCDD initially induces formation of a nuclear AhR complex which
      coordinately recruits ERalpha and the proteasome complex, resulting in
      degradation of both receptors.

PMID- 12612061
TI  - Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult
      ventricular myocytes and elicits episodes of abrupt sinus bradycardia.
AB  - The ERG1 gene encodes a family of potassium channels. Mutations in human ERG1
      lead to defects in cardiac repolarization, referred to as the long QT syndrome.
      Through homologous recombination in mouse embryonic stem cells the ERG1 B
      potassium channel transcript was eliminated while the ERG1 A transcript was
      maintained. Heterologous expression of ERG1 isoforms had previously indicated
      that the deactivation time course of ERG1 B is 10-fold more rapid than that of
      ERG1 A. In day-18 fetal +/+ myocytes, I(Kr) exhibited two time constants of
      deactivation (3,933 +/- 404 and 350 +/- 19 ms at -50 mV), whereas in age-matched
      ERG1 B(-/-) mice the rapid component was absent. Biexponential deactivation rates
      (2,039 +/- 268 and 163 +/- 43 ms at -50 mV) were also observed in adult +/+
      myocytes. In adult ERG1 B(-/-) myocytes no I(Kr) was detected. Electrocardiogram
      intervals were similar in +/+ and -/- mice. However, adult -/- mice manifested
      abrupt spontaneous episodes of sinus bradycardia (>100 ms of slowing) in 6 out of
      21 mice. This phenomenon was never observed in +/+ mice (0 out of 16). We
      conclude that ERG1 B is necessary for I(Kr) expression in the surface membrane of
      adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus
      bradycardia.

PMID- 12612062
TI  - Human transcription elongation factor NELF: identification of novel subunits and
      reconstitution of the functionally active complex.
AB  - The multisubunit transcription elongation factor NELF (for negative elongation
      factor) acts together with DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole)
      sensitivity-inducing factor (DSIF)/human Spt4-Spt5 to cause transcriptional
      pausing of RNA polymerase II (RNAPII). NELF activity is associated with five
      polypeptides, A to E. NELF-A has sequence similarity to hepatitis delta antigen
      (HDAg), the viral protein that binds to and activates RNAPII, whereas NELF-E is
      an RNA-binding protein whose RNA-binding activity is critical for NELF function.
      To understand the interactions of DSIF, NELF, and RNAPII at a molecular level, we
      identified the B, C, and D proteins of human NELF. NELF-B is identical to COBRA1,
      recently reported to associate with the product of breast cancer susceptibility
      gene BRCA1. NELF-C and NELF-D are highly related or identical to the protein
      called TH1, of unknown function. NELF-B and NELF-C or NELF-D are integral
      subunits that bring NELF-A and NELF-E together, and coexpression of these four
      proteins in insect cells resulted in the reconstitution of functionally active
      NELF. Detailed analyses using mutated recombinant complexes indicated that the
      small region of NELF-A with similarity to HDAg is critical for RNAPII binding and
      for transcriptional pausing. This study defines several important protein-protein
      interactions and opens the way for understanding the mechanism of DSIF- and NELF
      induced transcriptional pausing.

PMID- 12612063
TI  - Roles for SR proteins and hnRNP A1 in the regulation of c-src exon N1.
AB  - The splicing of the c-src exon N1 is controlled by an intricate combination of
      positive and negative RNA elements. Most previous work on these sequences focused
      on intronic elements found upstream and downstream of exon N1. However, it was
      demonstrated that the 5' half of the N1 exon itself acts as a splicing enhancer
      in vivo. Here we examine the function of this regulatory element in vitro. We
      show that a mutation in this sequence decreases splicing of the N1 exon in vitro.
      Proteins binding to this element were identified as hnRNP A1, hnRNP H, hnRNP F,
      and SF2/ASF by site-specific cross-linking and immunoprecipitation. The binding
      of these proteins to the RNA was eliminated by a mutation in the exonic element.
      The activities of hnRNP A1 and SF2/ASF on N1 splicing were examined by adding
      purified protein to in vitro splicing reactions. SF2/ASF and another SR protein,
      SC35, are both able to stimulate splicing of c-src pre-mRNA. However, splicing
      activation by SF2/ASF is dependent on the N1 exon enhancer element whereas
      activation by SC35 is not. In contrast to SF2/ASF and in agreement with other
      systems, hnRNP A1 repressed c-src splicing in vitro. The negative activity of
      hnRNP A1 on splicing was compared with that of PTB, a protein previously
      demonstrated to repress splicing in this system. Both proteins repress exon N1
      splicing, and both counteract the enhancing activity of the SR proteins. Removal
      of the PTB binding sites upstream of N1 prevents PTB-mediated repression but does
      not affect A1-mediated repression. Thus, hnRNP A1 and PTB use different
      mechanisms to repress c-src splicing. Our results link the activity of these well
      known exonic splicing regulators, SF2/ASF and hnRNP A1, to the splicing of an
      exon primarily controlled by intronic factors.

PMID- 12612064
TI  - Human cytomegalovirus pp71 stimulates cell cycle progression by inducing the
      proteasome-dependent degradation of the retinoblastoma family of tumor
      suppressors.
AB  - The oncoproteins of the DNA tumor viruses, adenovirus E1A, simian virus 40 T
      antigen, and papillomavirus E7, each interact with the retinoblastoma family of
      tumor suppressors, leading to cell cycle stimulation, apoptosis induction, and
      cellular transformation. These proteins utilize a conserved LXCXE motif, which is
      also found in cellular proteins, to target the retinoblastoma family. Here, we
      describe a herpesvirus protein that shares a subset of the properties of the DNA
      tumor virus oncoproteins but maintains important differences as well. The human
      cytomegalovirus pp71 protein employs an LXCXD motif to attack the retinoblastoma
      family members and induce DNA synthesis in quiescent cells. pp71 binds to and
      induces the degradation of the hypophosphorylated forms of the retinoblastoma
      protein and its family members p107 and p130 in a proteasome-dependent manner.
      However, pp71 does not induce apoptosis and fails to transform cells. Thus, the
      similarities and differences in comparison to E1A, T antigen, and E7 make pp71 an
      interesting new tool with which to further dissect the role of the
      retinoblastoma/E2F pathway in cellular growth control and carcinogenesis.

PMID- 12612065
TI  - Interleukin-3 stimulation of mcl-1 gene transcription involves activation of the
      PU.1 transcription factor through a p38 mitogen-activated protein kinase
      dependent pathway.
AB  - We have previously demonstrated that the antiapoptotic gene mcl-1 is activated by
      interleukin-3 (IL-3) in Ba/F3 pro-B cells through two promoter elements
      designated the CRE-2 and SIE motifs. While the CRE-2-binding complex contains the
      CREB protein and is activated by IL-3 through the phosphatidylinositol 3
      kinase/Akt-dependent pathway, the identity and cytokine activation pathway of the
      SIE-binding complex remains unclear. In this report, we demonstrated that PU.1 is
      one component of the SIE-binding complex. A chromatin immunoprecipitation assay
      further confirmed that PU.1 binds to the mcl-1 promoter region containing the SIE
      motif in vivo. While IL-3 stimulation does not significantly alter the SIE
      binding activity of PU.1, it markedly increases PU.1's transactivation activity.
      The latter effect coincides with the increased phosphorylation of PU.1 following
      IL-3 activation of a p38 mitogen-activated protein kinase (p38(MAPK))-dependent
      pathway. A serine-to-alanine substitution at position 142 significantly weakens
      PU.1's ability to be phosphorylated by the p38(MAPK) immunocomplex. Furthermore,
      this S142A mutant is impaired in the ability to be further stimulated by IL-3 to
      transactivate the mcl-1 reporter through the SIE motif. Taken together, our
      results demonstrate that IL-3 stimulation of mcl-1 gene transcription through the
      SIE motif involves phosphorylation of PU.1 at serine 142 by a p38(MAPK)-dependent
      pathway.

PMID- 12612066
TI  - Regulation of TATA-binding protein binding by the SAGA complex and the Nhp6 high
      mobility group protein.
AB  - Transcriptional activation of the yeast HO gene involves the sequential action of
      DNA-binding and chromatin-modifying factors. Here we examine the role of the SAGA
      complex and the Nhp6 architectural transcription factor in HO regulation. Our
      data suggest that these factors regulate binding of the TATA-binding protein
      (TBP) to the promoter. A gcn5 mutation, eliminating the histone acetyltransferase
      present in SAGA, reduces the transcription of HO, but expression is restored in a
      gcn5 spt3 double mutant. We conclude that the major role of Gcn5 in HO activation
      is to overcome repression by Spt3. Spt3 is also part of SAGA, and thus two
      proteins in the same regulatory complex can have opposing roles in
      transcriptional regulation. Chromatin immunoprecipitation experiments show that
      TBP binding to HO is very weak in wild-type cells but markedly increased in an
      spt3 mutant, indicating that Spt3 reduces HO expression by inhibiting TBP
      binding. In contrast, it has been shown previously that Spt3 stimulates TBP
      binding to the GAL1 promoter as well as GAL1 expression, and thus, Spt3 regulates
      these promoters differently. We also find genetic interactions between TBP and
      either Gcn5 or the high-mobility-group protein Nhp6, including multicopy
      suppression and synthetic lethality. These results suggest that, while Spt3 acts
      to inhibit TBP interaction with the HO promoter, Gcn5 and Nhp6 act to promote TBP
      binding. The result of these interactions is to limit TBP binding and HO
      expression to a short period within the cell cycle. Furthermore, the synthetic
      lethality resulting from combining a gcn5 mutation with specific TBP point
      mutations can be suppressed by the overexpression of transcription factor IIA
      (TFIIA), suggesting that histone acetylation by Gcn5 can stimulate transcription
      by promoting the formation of a TBP/TFIIA complex.

PMID- 12612067
TI  - Molecular determinants of glucocorticoid receptor mobility in living cells: the
      importance of ligand affinity.
AB  - The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR),
      which is activated upon ligand binding, and can alter the expression of target
      genes either by transrepression or transactivation. We have applied FRAP
      (fluorescence recovery after photobleaching) to quantitatively assess the
      mobility of the yellow fluorescent protein (YFP)-tagged human GR alpha-isoform
      (hGRalpha) in the nucleus of transiently transfected COS-1 cells and to elucidate
      determinants of its mobility. Addition of the high-affinity agonist dexamethasone
      markedly decreases the mobility of the receptor in a concentration-dependent
      manner, whereas low-affinity ligands like corticosterone decrease the mobility to
      a much lesser extent. Analysis of other hGRalpha ligands differing in affinity
      suggests that it is the affinity of the ligand that is a major determinant of the
      decrease in mobility. Similar results were observed for two hGRalpha antagonists,
      the low-affinity antagonist ZK98299 and the high-affinity antagonist RU486. The
      effect of ligand affinity on mobility was confirmed with the hGRalpha mutant
      Q642V, which has an altered affinity for triamcinolone acetonide, dexamethasone,
      and corticosterone. Analysis of hGRalpha deletion mutants indicates that both the
      DNA-binding domain and the ligand-binding domain of the receptor are required for
      a maximal ligand-induced decrease in receptor mobility. Interestingly, the
      mobility of transfected hGRalpha differs among cell types. Finally, the
      proteasome inhibitor MG132 immobilizes a subpopulation of unliganded receptors,
      via a mechanism requiring the DNA-binding domain and the N-terminal part of the
      ligand-binding domain. Ligand binding makes the GR resistant to the immobilizing
      effect of MG132, and this effect depends on the affinity of the ligand. Our data
      suggest that ligand binding induces a conformational change of the receptor which
      is dependent on the affinity of the ligand. This altered conformation decreases
      the mobility of the receptor, probably by targeting the receptor to relatively
      immobile nuclear domains with which it transiently associates. In addition, this
      conformational change blocks immobilization of the receptor by MG132.

PMID- 12612068
TI  - Evidence for DNA translocation by the ISWI chromatin-remodeling enzyme.
AB  - The ISWI proteins form the catalytic core of a subset of ATP-dependent chromatin
      remodeling activities. Here, we studied the interaction of the ISWI protein with
      nucleosomal substrates. We found that the ability of nucleic acids to bind and
      stimulate the ATPase activity of ISWI depends on length. We also found that ISWI
      is able to displace triplex-forming oligonucleotides efficiently when they are
      introduced at sites close to a nucleosome but successively less efficiently 30 to
      60 bp from its edge. The ability of ISWI to direct triplex displacement was
      specifically impeded by the introduction of 5- or 10-bp gaps in the 3'-5' strand
      between the triplex and the nucleosome. In combination, these observations
      suggest that ISWI is a 3'-5'-strand-specific, ATP-dependent DNA translocase that
      may be capable of forcing DNA over the surface of nucleosomes.

PMID- 12612070
TI  - RNA polymerase II accumulation in the promoter-proximal region of the
      dihydrofolate reductase and gamma-actin genes.
AB  - The carboxyl-terminal domain (CTD) of RNA polymerase II (Pol II) can be
      phosphorylated at serine 2 (Ser-2) and serine 5 (Ser-5) of the CTD heptad repeat
      YSPTSPS, and this phosphorylation is important in coupling transcription to RNA
      processing, including 5' capping, splicing, and polyadenylation. The mammalian
      endogenous dihydrofolate reductase and gamma-actin genes have been used to study
      the association of Pol II with different regions of transcribed genes (promoter
      proximal compared to distal regions) and the phosphorylation status of its CTD.
      For both genes, Pol II is more concentrated in the promoter-proximal regions than
      in the interior regions. Moreover, different phosphorylation forms of Pol II are
      associated with distinct regions. Ser-5 phosphorylation of Pol II is concentrated
      near the promoter, while Ser-2 phosphorylation is observed throughout the gene.
      These results suggest that the accumulation of paused Pol II in promoter-proximal
      regions may be a common feature of gene regulation in mammalian cells.

PMID- 12612069
TI  - Activation of the early B-cell-specific mb-1 (Ig-alpha) gene by Pax-5 is
      dependent on an unmethylated Ets binding site.
AB  - Methylation of cytosine in CpG dinucleotides promotes transcriptional repression
      in mammals by blocking transcription factor binding and recruiting methyl-binding
      proteins that initiate chromatin remodeling. Here, we use a novel cell-based
      system to show that retrovirally expressed Pax-5 protein activates endogenous
      early B-cell-specific mb-1 genes in plasmacytoma cells, but only when the
      promoter is hypomethylated. CpG methylation does not directly affect binding of
      the promoter by Pax-5. Instead, methylation of an adjacent CpG interferes with
      assembly of ternary complexes comprising Pax-5 and Ets proteins. In
      electrophoretic mobility shift assays, recruitment of Ets-1 is blocked by
      methylation of the Ets site (5'CCGGAG) on the antisense strand. In transfection
      assays, selective methylation of a single CpG within the Pax-5-dependent Ets site
      greatly reduces mb-1 promoter activity. Prior demethylation of the endogenous mb
      1 promoter is required for its activation by Pax-5 in transduced cells. Although
      B-lineage cells have only unmethylated mb-1 genes and do not modulate methylation
      of the mb-1 promoter during development, other tissues feature high percentages
      of methylated alleles. Together, these studies demonstrate a novel DNA
      methylation-dependent mechanism for regulating transcriptional activity through
      the inhibition of DNA-dependent protein-protein interactions.

PMID- 12612071
TI  - Dominant negative dimerization of a mutant homeodomain protein in Axenfeld-Rieger
      syndrome.
AB  - Axenfeld-Rieger syndrome is an autosomal-dominant disorder caused by mutations in
      the PITX2 homeodomain protein. We have studied the mechanism underlying the
      dominant negative K88E mutation, which occurs at position 50 of the homeodomain.
      By using yeast two-hybrid and in vitro pulldown assays, we have documented that
      PITX2a can form homodimers in the absence of DNA. Moreover, the K88E mutant had
      even stronger dimerization ability, primarily due to interactions involving the C
      terminal region. Dimerization allowed cooperative binding of wild-type (WT)
      PITX2a to DNA containing tandem bicoid sites in a head-to-tail orientation (Hill
      coefficient, 1.73). In contrast, the WT-K88E heterodimer bound the tandem sites
      with greatly reduced cooperativity and decreased transactivation activity. To
      further explore the role of position 50 in PITX2a dimerization, we introduced a
      charge-conservative mutation of lysine to arginine (K88R). The K88R protein had
      greatly reduced binding to a TAATCC element and did not specifically bind any
      other TAATNN motif. Like K88E, K88R formed relatively stronger dimers with WT. As
      predicted by our model, the K88R protein acted in a dominant negative manner to
      suppress WT PITX2a activity. These results suggest that the position 50 residue
      in the PITX2 homeodomain plays an important role in both DNA binding and
      dimerization activities.

PMID- 12612072
TI  - A Raf-1 mutant that dissociates MEK/extracellular signal-regulated kinase
      activation from malignant transformation and differentiation but not
      proliferation.
AB  - It is widely thought that the biological outcomes of Raf-1 activation are solely
      attributable to the activation of the MEK/extracellular signal-regulated kinase
      (ERK) pathway. However, an increasing number of reports suggest that some Raf-1
      functions are independent of this pathway. In this report we show that mutation
      of the amino-terminal 14-3-3 binding site of Raf-1 uncouples its ability to
      activate the MEK/ERK pathway from the induction of cell transformation and
      differentiation. In NIH 3T3 fibroblasts and COS-1 cells, mutation of serine 259
      resulted in Raf-1 proteins which activated the MEK/ERK pathway as efficiently as
      v-Raf. However, in contrast to v-Raf, RafS259 mutants failed to transform. They
      induced morphological alterations and slightly accelerated proliferation in NIH
      3T3 fibroblasts but were not tumorigenic in mice and behaved like wild-type Raf-1
      in transformation assays measuring loss of contact inhibition or anchorage
      independent growth. Curiously, the RafS259 mutants inhibited focus induction by
      an activated MEK allele, suggesting that they can hyperactivate negative-feedback
      pathways. In primary cultures of postmitotic chicken neuroretina cells, RafS259A
      was able to sustain proliferation to a level comparable to that sustained by the
      membrane-targeted transforming Raf-1 protein, RafCAAX. In contrast, RafS259A was
      only a poor inducer of neurite formation in PC12 cells in comparison to RafCAAX.
      Thus, RafS259 mutants genetically separate MEK/ERK activation from the ability of
      Raf-1 to induce transformation and differentiation. The results further suggest
      that RafS259 mutants inhibit signaling pathways required to promote these
      biological processes.

PMID- 12612073
TI  - Two domains of the progesterone receptor interact with the estrogen receptor and
      are required for progesterone activation of the c-Src/Erk pathway in mammalian
      cells.
AB  - In breast cancer cells, estrogens activate the Src/Erk pathway through an
      interaction of the estrogen receptor alpha (ERalpha) with the SH2 domain of c
      Src. Progestins have been reported to activate also this pathway either via an
      interaction of the progesterone receptor isoform B (PRB) with ERalpha, which
      itself activates c-Src, or by direct interaction of PRB with the SH3 domain of c
      Src. Here we identify two domains of PRB, ERID-I and -II, mediating a direct
      interaction with the ligand-binding domain of ERalpha. ERID-I and ERID-II flank a
      proline cluster responsible for binding of PRB to c-Src. In mammalian cells, the
      interaction of PRB with ERalpha and the progestin activation of the Src/Erk
      cascade are abolished by deletion of either ERID-I or ERID-II. These regions are
      not required for transactivation of a progesterone-responsive reporter gene.
      Mutations in the proline cluster of PRB that prevent a direct interaction with c
      Src do not affect the strong activation of c-Src by progestins in the presence of
      ERalpha. Thus, in cells with ERalpha, ERID-I and ERID-II are necessary and
      sufficient for progestin activation of the endogenous Src/Erk pathway.

PMID- 12612074
TI  - Rfm1, a novel tethering factor required to recruit the Hst1 histone deacetylase
      for repression of middle sporulation genes.
AB  - Transcriptional repression is often correlated with the alteration of chromatin
      structure through modifications of the nucleosomes in the promoter region, such
      as by deacetylation of the N-terminal histone tails. This is presumed to make the
      promoter region inaccessible to other regulatory factors and the general
      transcription machinery. To accomplish this, histone deacetylases are recruited
      to specific promoters via DNA-binding proteins and tethering factors. We have
      previously reported the requirement for the NAD(+)-dependent histone deacetylase
      Hst1 and the DNA-binding protein Sum1 for vegetative repression of many middle
      sporulation genes in Saccharomyces cerevisiae. Here we report the identification
      of a novel tethering factor, Rfm1, that is required for Hst1-mediated repression.
      Rfm1 interacts with both Sum1 and Hst1 and is required for the Sum1-Hst1
      interaction. DNA microarray and Northern blot analyses showed that Rfm1 is
      required for repression of the same subset of Sum1-repressed genes that require
      Hst1. These results suggest that Rfm1 is a specificity factor that targets the
      Hst1 deacetylase to a subset of Sum1-regulated genes.

PMID- 12612075
TI  - Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid
      raft-associated transmembrane adaptor.
AB  - PAG/Cbp (hereafter named PAG) is a transmembrane adaptor molecule found in lipid
      rafts. In resting human T cells, PAG is tyrosine phosphorylated and associated
      with Csk, an inhibitor of Src-related protein tyrosine kinases. These
      modifications are rapidly lost in response to T-cell receptor (TCR) stimulation.
      Overexpression of PAG was reported to inhibit TCR-mediated responses in Jurkat T
      cells. Herein, we have examined the physiological relevance and the mechanism of
      PAG-mediated inhibition in T cells. Our studies showed that PAG tyrosine
      phosphorylation and association with Csk are suppressed in response to activation
      of normal mouse T cells. By expressing wild-type and phosphorylation-defective
      (dominant-negative) PAG polypeptides in these cells, we found that the inhibitory
      effect of PAG is dependent on its capacity to be tyrosine phosphorylated and to
      associate with Csk. PAG-mediated inhibition was accompanied by a repression of
      proximal TCR signaling and was rescued by expression of a constitutively
      activated Src-related kinase, implying that it is due to an inactivation of Src
      kinases by PAG-associated Csk. We also attempted to identify the protein tyrosine
      phosphatases (PTPs) responsible for dephosphorylating PAG in T cells. Through
      cell fractionation studies and analyses of genetically modified mice, we
      established that PTPs such as PEP and SHP-1 are unlikely to be involved in the
      dephosphorylation of PAG in T cells. However, the transmembrane PTP CD45 seems to
      play an important role in this process. Taken together, these data provide firm
      evidence that PAG is a bona fide negative regulator of T-cell activation as a
      result of its capacity to recruit Csk. They also suggest that the inhibitory
      function of PAG in T cells is suppressed by CD45. Lastly, they support the idea
      that dephosphorylation of proteins on tyrosine residues is critical for the
      initiation of T-cell activation.

PMID- 12612076
TI  - Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for
      IKK complex activity and NF-kappaB activation.
AB  - The IkappaB kinase (IKK) complex mediates activation of transcription factor NF
      kappaB by phosphorylation of IkappaB proteins. Its catalytic subunits, IKKalpha
      and IKKbeta, require association with the regulatory IKKgamma (NEMO) component to
      gain full basal and inducible kinase activity. However, the oligomeric
      composition of the IKK complex and its regulation by IKKgamma are poorly
      understood. We show here that IKKgamma predominantly forms tetramers and
      interacts with IKKalpha or IKKbeta in this state. We propose that tetramerization
      is accomplished by a prerequisite dimerization through a C-terminal coiled-coil
      minimal oligomerization domain (MOD). This is followed by dimerization of the
      dimers with their N-terminal sequences. Tetrameric IKKgamma sequesters four
      kinase molecules, yielding a gamma(4)(alpha/beta)(4) stoichiometry. Deletion of
      the MOD leads to loss of tetramerization and of phosphorylation of IKKbeta and
      IKKgamma, although the kinase can still interact with the resultant IKKgamma
      monomers and dimers. Likewise, MOD-mediated IKKgamma tetramerization is required
      to enhance IKKbeta kinase activity when overexpressed in 293 cells and to
      reconstitute a lipopolysaccharide-responsive IKK complex in pre-B cells. These
      data thus suggest that IKKgamma tetramerization enforces a spatial positioning of
      two kinase dimers to facilitate transautophosphorylation and activation.

PMID- 12612077
TI  - Intersection of the Kap123p-mediated nuclear import and ribosome export pathways.
AB  - Kap123p is a yeast beta-karyopherin that imports ribosomal proteins into the
      nucleus prior to their assembly into preribosomal particles. Surprisingly,
      Kap123p is not essential for growth, under normal conditions. To further explore
      the role of Kap123p in nucleocytoplasmic transport and ribosome biogenesis, we
      performed a synthetic fitness screen designed to identify genes that interact
      with KAP123. Through this analysis we have identified three other karyopherins,
      Pse1p/Kap121p, Sxm1p/Kap108p, and Nmd5p/Kap119p. We propose that, in the absence
      of Kap123p, these karyopherins are able to supplant Kap123p's role in import. In
      addition to the karyopherins, we identified Rai1p, a protein previously
      implicated in rRNA processing. Rai1p is also not essential, but deletion of the
      RAI1 gene is deleterious to cell growth and causes defects in rRNA processing,
      which leads to an imbalance of the 60S/40S ratio and the accumulation of
      halfmers, 40S subunits assembled on polysomes that are unable to form functional
      ribosomes. Rai1p localizes predominantly to the nucleus, where it physically
      interacts with Rat1p and pre-60S ribosomal subunits. Analysis of the rai1/kap123
      double mutant strain suggests that the observed genetic interaction results from
      an inability to efficiently export pre-60S subunits from the nucleus, which
      arises from a combination of compromised Kap123p-mediated nuclear import of the
      essential 60S ribosomal subunit export factor, Nmd3p, and a DeltaRAI1-induced
      decrease in the overall biogenesis efficiency.

PMID- 12612078
TI  - Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi's sarcoma
      associated herpesvirus RTA-mediated lytic reactivation.
AB  - An important step in the herpesvirus life cycle is the switch from latency to
      lytic reactivation. The RTA transcription activator of Kaposi's sarcoma
      associated herpesvirus (KSHV) acts as a molecular switch for lytic reactivation.
      Here we demonstrate that KSHV RTA recruits CBP, the SWI/SNF chromatin remodeling
      complex, and the TRAP/Mediator coactivator into viral promoters through
      interactions with a short acidic sequence in the carboxyl region and that this
      recruitment is essential for RTA-dependent viral gene expression. The Brg1
      subunit of SWI/SNF and the TRAP230 subunit of TRAP/Mediator were shown to
      interact directly with RTA. Consequently, genetic ablation of these interactions
      abolished KSHV lytic replication. These results demonstrate that the recruitment
      of CBP, SWI/SNF, and TRAP/Mediator complexes by RTA is the principal mechanism to
      direct well-controlled viral gene expression and thereby viral lytic
      reactivation.

PMID- 12612079
TI  - The STE20 kinase HGK is broadly expressed in human tumor cells and can modulate
      cellular transformation, invasion, and adhesion.
AB  - HGK (hepatocyte progenitor kinase-like/germinal center kinase-like kinase) is a
      member of the human STE20/mitogen-activated protein kinase kinase kinase kinase
      family of serine/threonine kinases and is the ortholog of mouse NIK (Nck
      interacting kinase). We have cloned a novel splice variant of HGK from a human
      tumor line and have further identified a complex family of HGK splice variants.
      We showed HGK to be highly expressed in most tumor cell lines relative to normal
      tissue. An active role for this kinase in transformation was suggested by an
      inhibition of H-Ras(V12)-induced focus formation by expression of inactive,
      dominant-negative mutants of HGK in both fibroblast and epithelial cell lines.
      Expression of an inactive mutant of HGK also inhibited the anchorage-independent
      growth of cells yet had no effect on proliferation in monolayer culture.
      Expression of HGK mutants modulated integrin receptor expression and had a
      striking effect on hepatocyte growth factor-stimulated epithelial cell invasion.
      Together, these results suggest an important role for HGK in cell transformation
      and invasiveness.

PMID- 12612080
TI  - Late cytoplasmic maturation of the small ribosomal subunit requires RIO proteins
      in Saccharomyces cerevisiae.
AB  - Numerous nonribosomal trans-acting factors involved in pre-rRNA processing have
      been characterized, but few of them are specifically required for the last
      cytoplasmic steps of 18S rRNA maturation. We have recently demonstrated that
      Rrp10p/Rio1p is such a factor. By BLAST analysis, we identified the product of a
      previously uncharacterized essential gene, YNL207W/RIO2, called Rio2p, that
      shares 43% sequence similarity with Rrp10p/Rio1p. Rio2p homologues were
      identified throughout the Archaea and metazoan species. We show that Rio2p is a
      cytoplasmic-nuclear protein and that its depletion blocks 18S rRNA production,
      leading to 20S pre-rRNA accumulation. In situ hybridization reveals that in Rio2p
      depleted cells, 20S pre-rRNA localizes in the cytoplasm, demonstrating that its
      accumulation is not due to an export defect. We also show that both Rio1p and
      Rio2p accumulate in the nucleus of crm1-1 cells at the nonpermissive temperature.
      Nuclear as well as cytoplasmic Rio2p and Rio1p cosediment with pre-40S particles.
      These results strongly suggest that Rio2p and Rrp10p/Rio1p are shuttling proteins
      which associate with pre-40S particles in the nucleus and they are not necessary
      for export of the pre-40S complexes but are absolutely required for the
      cytoplasmic maturation of 20S pre-rRNA at site D, leading to mature 40S ribosomal
      subunits.

PMID- 12612081
TI  - Regulation of insulin receptor signaling by the protein tyrosine phosphatase
      TCPTP.
AB  - The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic
      reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although
      targeted to the nucleus, TC45 can exit in response to specific stimuli to
      dephosphorylate cytoplasmic substrates. In this study, we investigated the
      downregulation of insulin receptor (IR) signaling by TCPTP. In response to
      insulin stimulation, the TC48-D182A and TC45-D182A "substrate-trapping" mutants
      formed stable complexes with the endogenous tyrosine-phosphorylated IR beta
      subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45
      D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in
      part colocalized with the IR beta-subunit at the cell periphery. These results
      indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In
      immortalized TCPTP(-/-) murine embryo fibroblasts, insulin-induced IR beta
      subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were
      enhanced relative to the values in TCPTP(+/+) cells. Importantly, the expression
      of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced
      signaling in TCPTP(-/-) cells. These results indicate that the differentially
      localized variants of TCPTP may dephosphorylate the IR and downregulate insulin
      induced signaling in vivo.

PMID- 12612082
TI  - A novel RING finger protein, human enhancer of invasion 10, alters mitotic
      progression through regulation of cyclin B levels.
AB  - The process of cellular morphogenesis is highly conserved in eukaryotes and is
      dependent upon the function of proteins that are centrally involved in
      specification of the cell cycle. The human enhancer of invasion clone 10 (HEI10)
      protein was identified from a HeLa cell library based on its ability to promote
      yeast agar invasion and filamentation. Through two-hybrid screening, the mitotic
      cyclin B1 and an E2 ubiquitin-conjugating enzyme were isolated as HEI10
      interacting proteins. Mutation of the HEI10 divergent RING finger motif
      (characteristic of E3 ubiquitin ligases) and Cdc2/cyclin binding and
      phosphorylation sites alter HEI10-dependent yeast phenotypes, including delay in
      G(2)/M transition. In vertebrates, the addition of HEI10 inhibits nuclear
      envelope breakdown and mitotic entry in Xenopus egg extracts. Mechanistically,
      HEI10 expression reduces cyclin B levels in cycling Xenopus eggs and reduces
      levels of the cyclin B ortholog Clb2p in yeast. HEI10 is itself a specific in
      vitro substrate of purified cyclin B/cdc2, with a TPVR motif as primary
      phosphorylation site. Finally, HEI10 is itself ubiquitinated in egg extracts and
      is also autoubiquitinated in vitro. These and other points lead to a model in
      which HEI10 defines a divergent class of E3 ubiquitin ligase, functioning in
      progression through G(2)/M.

PMID- 12612083
TI  - Transcriptional repressor functions of Drosophila E2F1 and E2F2 cooperate to
      inhibit genomic DNA synthesis in ovarian follicle cells.
AB  - Individual members of the E2F/DP protein family control cell cycle progression by
      acting predominantly as an activator or repressor of transcription. In Drosophila
      melanogaster the E2f1, E2f2, Dp, and Rbf1 genes all contribute to replication
      control in ovarian follicle cells, which become 16C polyploid and subsequently
      undergo chorion gene amplification late in oogenesis. Mutation of E2f2, Dp, or
      Rbf1 causes ectopic DNA replication throughout the follicle cell genome during
      gene amplification cycles. Here we show by both reverse transcription-PCR and DNA
      microarray analysis that the transcripts of prereplication complex (pre-RC) genes
      are elevated compared to the wild type in E2f2, Dp, and Rbf1 mutant follicle
      cells. For some genes the magnitude of this transcriptional derepression is
      greater in Rbf1 than in E2f2 mutants. These differences correlate with
      differences in the magnitude of the replication defects in follicle cells, which
      attain an inappropriate 32C DNA content in both Rbf1 and Dp mutants but not in
      E2f2 mutants. The ectopic genomic replication of E2f2 mutant follicle cells can
      be suppressed by reducing the Orc2, Orc5, or Mcm2 gene dose by half, indicating
      that small changes in pre-RC gene expression can affect DNA synthesis in these
      cells. We conclude that RBF1 forms complexes with both E2F1/DP and E2F2/DP that
      cooperate to repress the expression of pre-RC genes, which helps confine DNA
      synthesis to sites of gene amplification. In contrast, E2F1 and E2F2 repressors
      function redundantly for some genes in the embryo. Thus, the relative functional
      contributions of E2F1 and E2F2 to gene expression and cell cycle control depends
      on the developmental context.

PMID- 12612084
TI  - Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF
      motifs.
AB  - Coactivator recruitment by activation function 2 (AF2) in the steroid receptor
      ligand binding domain takes place through binding of an LXXLL amphipathic alpha
      helical motif at the AF2 hydrophobic surface. The androgen receptor (AR) and
      certain AR coregulators are distinguished by an FXXLF motif that interacts
      selectively with the AR AF2 site. Here we show that LXXLL and FXXLF motif
      interactions with steroid receptors are modulated by oppositely charged residues
      flanking the motifs and charge clusters bordering AF2 in the ligand binding
      domain. An increased number of charged residues flanking AF2 in the ligand
      binding domain complement the two previously characterized charge clamp residues
      in coactivator recruitment. The data suggest a model whereby coactivator
      recruitment to the receptor AF2 surface is initiated by complementary charge
      interactions that reflect a reversal of the acidic activation domain-coactivator
      interaction model.

PMID- 12612085
TI  - The TRE17 oncogene encodes a component of a novel effector pathway for Rho
      GTPases Cdc42 and Rac1 and stimulates actin remodeling.
AB  - The Rho family GTPases Cdc42 and Rac1 play fundamental roles in transformation
      and actin remodeling. Here, we demonstrate that the TRE17 oncogene encodes a
      component of a novel effector pathway for these GTPases. TRE17 coprecipitated
      specifically with the active forms of Cdc42 and Rac1 in vivo. Furthermore, the
      subcellular localization of TRE17 was dramatically regulated by these GTPases and
      mitogens. Under serum-starved conditions, TRE17 localized predominantly to
      filamentous structures within the cell. Epidermal growth factor (EGF) induced
      relocalization of TRE17 to the plasma membrane in a Cdc42-/Rac1-dependent manner.
      Coexpression of activated alleles of Cdc42 or Rac1 also caused complete
      redistribution of TRE17 to the plasma membrane, where it partially colocalized
      with the GTPases in filopodia and ruffles, respectively. Membrane recruitment of
      TRE17 by EGF or the GTPases was dependent on actin polymerization. Finally, we
      found that a C-terminal truncation mutant of TRE17 induced the accumulation of
      cortical actin, mimicking the effects of activated Cdc42. Together, these results
      identify TRE17 as part of a novel effector complex for Cdc42 and Rac1,
      potentially contributing to their effects on actin remodeling. The present study
      provides insights into the regulation and cellular function of this previously
      uncharacterized oncogene.

PMID- 12612086
TI  - Cortactin is a component of clathrin-coated pits and participates in receptor
      mediated endocytosis.
AB  - The actin cytoskeleton is believed to contribute to the formation of clathrin
      coated pits, although the specific components that connect actin filaments with
      the endocytic machinery are unclear. Cortactin is an F-actin-associated protein,
      localizes within membrane ruffles in cultured cells, and is a direct binding
      partner of the large GTPase dynamin. This direct interaction with a component of
      the endocytic machinery suggests that cortactin may participate in one or several
      endocytic processes. Therefore, the goal of this study was to test whether
      cortactin associates with clathrin-coated pits and participates in receptor
      mediated endocytosis. Morphological experiments with either anti-cortactin
      antibodies or expressed red fluorescence protein-tagged cortactin revealed a
      striking colocalization of cortactin and clathrin puncta at the ventral plasma
      membrane. Consistent with these observations, cells microinjected with these
      antibodies exhibited a marked decrease in the uptake of labeled transferrin and
      low-density lipoprotein while internalization of the fluid marker dextran was
      unchanged. Cells expressing the cortactin Src homology three domain also
      exhibited markedly reduced endocytosis. These findings suggest that cortactin is
      an important component of the receptor-mediated endocytic machinery, where,
      together with actin and dynamin, it regulates the scission of clathrin pits from
      the plasma membrane. Thus, cortactin provides a direct link between the dynamic
      actin cytoskeleton and the membrane pinchase dynamin that supports vesicle
      formation during receptor-mediated endocytosis.

PMID- 12612087
TI  - Stabilization of p53 by CP-31398 inhibits ubiquitination without altering
      phosphorylation at serine 15 or 20 or MDM2 binding.
AB  - CP-31398, a styrylquinazoline, emerged from a high throughput screen for
      therapeutic agents that restore a wild-type-associated epitope (monoclonal
      antibody 1620) on the DNA-binding domain of the p53 protein. We found that CP
      31398 can not only restore p53 function in mutant p53-expressing cells but also
      significantly increase the protein level and promote the activity of wild-type
      p53 in multiple human cell lines, including ATM-null cells. Cells treated with CP
      31398 undergo either cell cycle arrest or apoptosis. Further investigation showed
      that CP-31398 blocks the ubiquitination and degradation of p53 but not in human
      papillomavirus E6-expressing cells. Of note, CP-31398 does not block the physical
      association between p53 and MDM2 in vivo. Moreover, unlike the DNA-damaging agent
      adriamycin, which induces strong phosphorylation of p53 on serines 15 and 20, CP
      31398 exposure leads to no measurable phosphorylation on these sites. We found
      that CP-31398 could also stabilize exogenous p53 in p53 mutant, wild-type, and
      p53-null human cells, even in MDM2-null p53(-/-) mouse embryonic fibroblasts. Our
      results suggest a model wherein CP-31398-mediated stabilization of p53 may result
      from reduced ubiquitination, leading to high levels of transcriptionally active
      p53. Further understanding of this mechanism may lead to novel strategies for p53
      stabilization and tumor suppression in cancers, even those with absent ARF or
      high MDM2 expression.

PMID- 12612088
TI  - The phospholipid transfer protein gene is a liver X receptor target expressed by
      macrophages in atherosclerotic lesions.
AB  - The liver X receptors (LXRs) are members of the nuclear receptor superfamily that
      are activated by oxysterols. In response to ligand binding, LXRs regulate a
      variety of genes involved in the catabolism, transport, and uptake of cholesterol
      and its metabolites. Here we demonstrate that LXRs also regulate plasma
      lipoprotein metabolism through control of the phospholipid transfer protein
      (PLTP) gene. LXR ligands induce the expression of PLTP in cultured HepG2 cells
      and mouse liver in vivo in a coordinate manner with known LXR target genes.
      Moreover, plasma phospholipid transfer activity is increased in mice treated with
      the synthetic LXR ligand GW3965. Unexpectedly, PLTP expression was also highly
      inducible by LXR in macrophages, a cell type not previously recognized to express
      this enzyme. The ability of synthetic and oxysterol ligands to regulate PLTP mRNA
      in macrophages and liver is lost in animals lacking both LXRalpha and LXRbeta,
      confirming the critical role of these receptors. We further demonstrate that the
      PLTP promoter contains a high-affinity LXR response element that is bound by
      LXR/RXR heterodimers in vitro and is activated by LXR/RXR in transient
      transfection studies. Finally, immunohistochemistry studies reveal that PLTP is
      highly expressed by macrophages within human atherosclerotic lesions, suggesting
      a potential role for this enzyme in lipid-loaded macrophages. These studies
      outline a novel pathway whereby LXR and its ligands may modulate lipoprotein
      metabolism.

PMID- 12612089
TI  - Genetic diversity: frameshift mechanisms alter coding of a gene (Epstein-Barr
      virus LF3 gene) that contains multiple 102-base-pair direct sequence repeats.
AB  - Frameshift mutations provide recognized mechanisms for changing the coding
      potential of an organism. Here, multiple frameshifts are identified in repetitive
      sequences within an Epstein-Barr virus unspliced early gene, LF3, which is
      associated with the viral replicative cycle and also transcriptionally expressed
      in many virally associated tumors. On the DNA strand encoding LF3, there are
      three open reading frames, only one of which contains an initiation codon. Most
      (>95%) of the gene consists of numerous (>20, varying with cell source) GC-rich
      copies of a 102-bp direct repeat (called IR 4) flanked by small unique sequences.
      LF3 may express a protein if its initiation and termination codons reside in the
      same reading frame, but this is not always the case. Frameshifting events,
      occurring in short runs of pyrimidines (mainly C residues) in the repeats, give
      rise to mutations which may provide a mechanism for escape of an LF3 function
      from host surveillance. Sequence studies link these frameshifts to DNA
      replication errors. Notably, the number of sites in LF3 at which such mutations
      can occur permits a very large amount of diversity in this gene. Our data also
      suggest a second degeneracy mechanism within the protein itself, which influences
      its stability and may reflect a host defense mechanism. LF3 thus provides a
      potentially important model for studying the quest for supremacy between a virus
      and its host.

PMID- 12612092
TI  - Structure for community participation.

PMID- 12612093
TI  - Courage in politics and urban health: a cautionary tale.

PMID- 12612090
TI  - mRNA instability in the nucleus due to a novel open reading frame element is a
      major determinant of the narrow tissue specificity of folate receptor alpha.
AB  - The folate receptor type alpha (FR-alpha) is a promising tumor marker and target.
      Here, we investigate the mechanistic basis for the tumor specificity and vast
      overexpression of FR-alpha. Among representative FR-alpha-positive (HeLa and JAR)
      and FR-alpha-negative (MG63, Caki1, and HT3) cell lines, the transcription rates
      of the endogenous FR-alpha gene, as well as the FR-alpha promoter activity, were
      relatively weak and comparable, but the FR-alpha transcript was abundant only in
      total RNA and nuclear RNA from the FR-alpha-positive cells. Rous sarcoma virus
      (RSV) promoter-driven expression of the FR-alpha gene was 7 to 30 times greater
      in the FR-alpha-positive than in FR-alpha-negative cells, both at the protein and
      mRNA levels, independently of intron sequences. Through the use of chimeric FR
      alpha/FR-beta cDNAs, the above pattern of FR-alpha expression was attributed to a
      60-bp sequence in the FR-alpha open reading frame. This sequence element, when
      placed in the 5' untranslated region of RSV promoter-luciferase, decreased the
      reporter expression approximately 7- to 20-fold in FR-alpha-negative cells (MG63,
      Caki1, HT3, BG1, and MCF7) relative to FR-alpha-positive cells (HeLa, JAR, and
      JEG3). Substitution of this FR-alpha element in FR-beta increased the in vivo
      degradation rate of the transcript in the nuclei of MG63 cells but not in the
      nuclei of HeLa cells or in the cytosol of MG63 or HeLa cells. The results reveal
      an efficient mechanism by which a novel sequence element causes differential
      transcript degradation in the nucleus to ensure narrow tissue specificity for a
      gene (e.g., that for FR-alpha) whose transcription is weak and relatively
      nonselective. FR-alpha exhibited constitutive mRNA and protein synthesis during
      the cell cycle and a slow protein turnover, presumably ensuring a high steady
      state level of the receptor in cells that could override the nuclear mRNA
      instability determinant.

PMID- 12612091
TI  - Brain lipid binding protein in axon-Schwann cell interactions and peripheral
      nerve tumorigenesis.
AB  - Loss of axonal contact characterizes Schwann cells in benign and malignant
      peripheral nerve sheath tumors (MPNST) from neurofibromatosis type 1 (NF1)
      patients. Tumor Schwann cells demonstrate NF1 mutations, elevated Ras activity,
      and aberrant epidermal growth factor receptor (EGFR) expression. Using cDNA
      microarrays, we found that brain lipid binding protein (BLBP) is elevated in an
      EGFR-positive subpopulation of Nf1 mutant mouse Schwann cells (Nf1(-/-) TXF) that
      grows away from axons; BLBP expression was not affected by farnesyltransferase
      inhibitor, an inhibitor of H-Ras. BLBP was also detected in EGFR-positive cell
      lines derived from Nf1:p53 double mutant mice and human MPNST. BLBP expression
      was induced in normal Schwann cells following transfection with EGFR but not H
      Ras12V. Furthermore, EGFR-mediated BLBP expression was not inhibited by dominant
      negative H-Ras, indicating that BLBP expression is downstream of Ras-independent
      EGFR signaling. BLBP-blocking antibodies enabled process outgrowth from Nf1(-/-)
      TXF cells and restored interaction with axons, without affecting cell
      proliferation or migration. Following injury, BLBP expression was induced in
      normal sciatic nerves when nonmyelinating Schwann cells remodeled their
      processes. These data suggest that BLBP, stimulated by Ras-independent pathways,
      regulates Schwann cell-axon interactions in normal peripheral nerve and
      peripheral nerve tumors.

PMID- 12612094
TI  - Getting to know you: forging relationships between public health and the press.

PMID- 12612096
TI  - Broadening participation in community problem solving: a multidisciplinary model
      to support collaborative practice and research.
AB  - Over the last 40 years, thousands of communities-in the United States and
      internationally-have been working to broaden the involvement of people and
      organizations in addressing community-level problems related to health and other
      areas. Yet, in spite of this experience, many communities are having substantial
      difficulty achieving their collaborative objective, and many funders of community
      partnerships and participation initiatives are looking for ways to get more out
      of their investment. One of the reasons we are in this predicament is that the
      practitioners and researchers who are interested in community collaboration come
      from a variety of contexts, initiatives, and academic disciplines, and few of
      them have integrated their work with experiences or literatures beyond their own
      domain. In this article, we seek to overcome some of this fragmentation of effort
      by presenting a multidisciplinary model that lays out the pathways by which
      broadly participatory processes lead to more effective community problem solving
      and to improvements in community health. The model, which builds on a broad array
      of practical experience as well as conceptual and empirical work in multiple
      fields, is an outgrowth of a joint-learning work group that was organized to
      support nine communities in the Turning Point initiative. Following a detailed
      explication of the model, the article focuses on the implications of the model
      for research, practice, and policy. It describes how the model can help
      researchers answer the fundamental effectiveness and "how-to" questions related
      to community collaboration. In addition, the article explores differences between
      the model and current practice, suggesting strategies that can help the
      participants in, and funders of, community collaborations strengthen their
      efforts.

PMID- 12612097
TI  - Community participation in a multisectoral intervention to address health
      determinants in an inner-city community in central Havana.
AB  - It is increasingly acknowledged that the process of community involvement is
      critical to the successful implementation of community-based health
      interventions. Between 1995 and 1999, a multisectoral intervention called Plan
      Cayo Hueso was launched in the inner-city community of Cayo Hueso in Havana,
      Cuba, to address a variety of health determinants. To provide a better
      understanding of the political structures and processes involved, the Cuban
      context is described briefly. The interventions included improvements in housing,
      municipal infrastructure, and social and cultural activities. A qualitative
      study, consisting of interviews of key informants as well as community members,
      was conducted to evaluate the community participatory process. Questions from an
      extensive household survey pre- and postintervention that had been conducted in
      Cayo Hueso and a comparison community to assess the effectiveness of the
      intervention also informed the analysis of community participation, as did three
      community workshops held to choose indicators for evaluating effectiveness and to
      discuss findings. It was found that formal leaders led the interventions,
      providing the institutional driving force behind the plan. However, extensive
      community involvement occurred as the project took advantage of the existing
      community-based organizations, which played an active role in mobilizing
      community members and enhanced linkage systems critical to the project's success.
      Women played fairly traditional roles in interventions outside their households,
      but had equivalent roles to men in interventions within their household units.
      Most impressive about this project was the extent of mobilization to participate
      and the multidimensional ecosystem approach adopted. Indeed, Plan Cayo Hueso
      involved a massive mobilization of international, national, and community
      resources to address the needs of this community. This, as well as the
      involvement of community residents in the evaluation process, was seen as
      resulting in improved social interactions and community well-being and enhanced
      capacity for future action. While Cuba is unique in many respects, the lessons
      learned about enhancing community participation in urban health intervention
      projects, as well as in their evaluation, are applicable worldwide.

PMID- 12612098
TI  - Barriers to breast cancer screening for low-income Mexican and Dominican women in
      New York City.
AB  - The proportion of Mexican and Dominican women has increased rapidly in New York
      City and in other urban areas, and breast cancer screening rates continue to be
      lower for Latina women as a whole, but particularly for some nationality
      subgroups. The current analysis explored the reasons why Mexican and Dominican
      women from medically underserved communities in New York City do not seek breast
      cancer screening. Data were collected through interviews with 298 Mexican and
      Dominican women aged 40-88 years; the interviews included an open-ended question
      on the barriers women face in seeking screening. The three most commonly cited
      barriers were not taking care of oneself (descuido) (52.3%), lack of information
      (49.3%), and fear (44.6%). Women who had been screened cited fear, pain, or other
      personal barriers more often, but women who had never had a mammogram cited cost
      or other logistical barriers. Responses from Dominican and Mexican women were
      significantly different, with Mexican women more often citing shame or
      embarrassment and Dominican women more often citing fear. The dependent variable,
      barriers to screening, was grouped into major categories. When sociodemographic
      factors were controlled for, the effect of ethnicity disappeared. Multivariate
      logistic regression revealed that women with a source of health care were less
      likely to cite any logistical barriers, but significantly more likely to report
      only personal barriers (such as fear or descuido). The analysis indicated that
      personal barriers were very prevalent in the communities studied. It may not be
      sufficient merely to increase access to breast cancer screening services for low
      income Latinas: even when women have a source of health care, personal barriers
      may prevent many women from seeking screening. Outreach programs need to be
      tailored to the target communities as there are significant differences among
      groups of Latinas. Targeted outreach programs must work in tandem with programs
      to increase access to ensure that both personal and logistical barriers to
      screening are addressed.

PMID- 12612100
TI  - Estimation of the number of injecting drug users attending an outreach syringe
      exchange program and infection with human immunodeficiency virus (HIV) and
      hepatitis C virus: the AjUDE-Brasil project.
AB  - This study estimated the number of street injecting drug user (IDU) clients of a
      syringe-exchange program (SEP) who were infected with human immunodeficiency
      virus (HIV) and hepatitis C virus (HCV). A two-sample capture-recapture method
      was carried out. The first capture listed all interviewed IDUs outreached for
      syringe exchange from April 1 to May 1, 1998; the second capture involved those
      outreached from May 2 to June 6, 1998. Blood spots were collected for HIV and HCV
      serologies. Analysis used captured probability model varying with time. We
      interviewed 55 IDUs in the first capture and 99 in the second; 17 participated in
      both samples. An estimate of 317 IDUs attending the SEP was obtained (95%
      confidence interval [CI] 235-467). Based on the overall seroprevalence rates for
      HIV (47.7%) and HCV (53.1%), it was estimated that 151 IDUs were HIV infected
      (95% CI 112-223) and 168 (95% CI 125-248) were HCV infected. Enumeration of IDUs
      associated with estimates of the total number of HIV and HCV seropositives
      provide a powerful tool for SEPs to help monitor the number of IDUs, to plan for
      provisions, and to organize the new demands on existing health facilities for HIV
      and HCV care.

PMID- 12612099
TI  - Drug injection among street youths in Montreal: predictors of initiation.
AB  - In North America, street youths are generally considered at very high risk of
      injection drug use. To estimate the incidence rate of injection drug use in this
      population and to identify predictors of injection drug use, we conducted the
      present analysis. Among participants to a cohort study initiated in January 1995,
      we selected subjects who had never injected at study entry and had completed at
      least one follow-up questionnaire. Predictors of initiation were identified using
      Cox proportional hazard regression models. Among the 415 never injectors (mean
      age at entry 19.5 years), 74 had initiated injection by January 2000 (incidence
      rate 8.2 per 100 person-years). Independent predictors of initiation were recent
      episode of homelessness; age younger than 18 years; being tattooed; recently
      using hallucinogens, heroin, and cocaine/crack/freebase; having a friend who
      injects drugs; and having ever experienced extrafamilial sexual abuse. This study
      showed that injection drug use is frequent among street youths, but prevention
      appears possible.

PMID- 12612101
TI  - Preliminary estimates of human immunodeficiency virus prevalence and incidence
      among cocaine abusers of Porto Alegre, Brazil.
AB  - A sample of 193 southern Brazilian inner-city cocaine abusers was studied to
      assess the prevalence of human immunodeficiency virus (HIV) infection. Following
      the exclusion of those who were seropositive from the intake sample, a cohort of
      138 HIV-negative cocaine abusers was followed for 18 months to assess
      seroincidence rates and the associated characteristics. HIV status, drug use,
      sexual risk behaviors, and presence and severity of medical and psychiatric
      symptoms were collected at intake using a Brazilian version of the Risk
      Assessment Battery, the Addiction Severity Index (ASI), Symptom Check List-90
      (SCL-90), and Beck Depression Inventory (BDI); this was repeated at 6-, 12-, and
      18-month intervals. The overall seroprevalence was 28.5%, and the variables
      associated with HIV seropositivity were age older than 25 years, being single,
      having less than 8 years of education, and having injected cocaine at least once.
      Although follow-up procedures were difficult to implement due to sample
      characteristics, we obtained data from 82.6% of the participants for at least one
      follow-up and for 57% at all follow-up windows. Most participants showed high
      scores on the Beck Depression Inventory (mean of 20.6 +/- 13.9) and Symptom Check
      List-90 (mean of 106.4 +/- 91.9). There were 8 seroconversions in the 18-month
      period, yielding an incidence rate of 5.03/100 (confidence interval [CI] 2.2-9.7)
      person-years at risk. None of the seroconverters reported recent cocaine
      injection, and only 14.5% of the overall sample reported ever injecting cocaine,
      which suggests that another significant mode of transmission via sexual behavior
      should be considered as well. Each of these findings has important implications
      for the design of preventive interventions.

PMID- 12612102
TI  - Type and location of injection drug use-related soft tissue infections predict
      hospitalization.
AB  - The prevalence of soft tissue infections (abscesses, cellulitides, infected
      ulcers) among injection drug users (IDUs) is estimated to be between 21% and 32%.
      Little is known regarding the health care utilization associated with these
      infections. This study describes IDUs seeking emergency department (ED) care for
      soft tissue infections, their inpatient health care utilization, including
      operating room procedures, and the types and locations of infections associated
      with increased inpatient health care utilization. This study used a medical
      record case series of all IDUs seeking initial care for soft tissue infections at
      an urban, public emergency department from November 1999 through April 2000.
      Initial care for IDU-related soft tissue infections was sought by 242 patients.
      Most were male (63.6%), Caucasian (69.4%) and without health insurance (52.0%),
      and most had abscesses (72.3%). All patients with only cellulitis had arm or leg
      infections, while most abscesses were arm, deltoid, or buttock infections
      (81.1%). Forty percent of the patients were hospitalized, and 44.3% of the
      hospitalizations were for 3 or more days. Patients with only cellulitis were more
      likely to be hospitalized compared to those with abscesses. Among those with
      abscesses, deltoid abscesses were 5.2 times more likely to receive an operating
      room procedure compared to other abscess locations. IDUs with cellulitis and
      deltoid abscesses commonly required inpatient care and operating room procedures.
      The morbidity associated with such infections and the intensive use of hospital
      services needed to treat these infections provide strong rationale for the
      development of preventive interventions and improved care for this neglected
      clinical problem.

PMID- 12612103
TI  - Gender differences in sexual and injection risk behavior among active young
      injection drug users in San Francisco (the UFO Study).
AB  - Female injection drug users (IDUs) represent a large proportion of persons
      infected with HIV in the United States, and women who inject drugs have a high
      incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
      Therefore, it is important to understand the role of gender in injection risk
      behavior and the transmission of blood-borne virus. In 2000-2002, 844 young (<30
      years old) IDUs were surveyed in San Francisco. We compared self-reported risk
      behavior between 584 males and 260 female participants from cross-sectional
      baseline data. We used logistic regression to determine whether demographic,
      structural, and relationship variables explained increased needle borrowing, drug
      preparation equipment sharing, and being injected by another IDU among females
      compared to males. Females were significantly younger than males and were more
      likely to engage in needle borrowing, ancillary equipment sharing, and being
      injected by someone else. Females were more likely than males to report recent
      sexual intercourse and to have IDU sex partners. Females and males were not
      different with respect to education, race/ethnicity, or housing status. In
      logistic regression models for borrowing a used needle and sharing drug
      preparation equipment, increased risk in females was explained by having an
      injection partner who was also a sexual partner. Injecting risk was greater in
      the young female compared to male IDUs despite equivalent frequency of injecting.
      Overlapping sexual and injection partnerships were a key factor in explaining
      increased injection risk in females. Females were more likely to be injected by
      another IDU even after adjusting for years injecting, being in a relationship
      with another IDU, and other potential confounders. Interventions to reduce sexual
      and injection practices that put women at risk of contracting hepatitis and HIV
      are needed.

PMID- 12612104
TI  - Intention to use condoms among three low-income, urban African American
      subgroups: cocaine users, noncocaine drug users, and non-drug users.
AB  - Cocaine use, marijuana use, alcohol use, and polysubstance use (e.g., alcohol and
      cocaine, alcohol and marijuana) are associated with high-risk sexual behavior and
      higher rates of sexually transmitted diseases (STDs) and human immunodeficiency
      virus (HIV). The purpose of this study was to examine readiness for using condoms
      among three groups (cocaine users, noncocaine drug users, and non-drug users) of
      African Americans living in low-income urban settings. African Americans in this
      sample differed in sex risk behaviors according to their drug use status.
      Noncocaine drug users reported higher levels of sex risk behaviors than non-drug
      users, and cocaine users reported the highest levels of risk. Cocaine users also
      reported lower levels of condom use with their main and nonmain sexual partners
      than both other groups. Results of multivariate analyses indicate that, compared
      to the other two groups, cocaine users are at earlier stages of readiness for
      condom use with main partners. Cocaine users have accurate perceptions of their
      HIV risk, but are more likely to factor into their decisions for using condoms
      cost and the trouble that it takes to get condoms. Different approaches to
      sexually transmitted disease and human immunodeficiency virus prevention will be
      necessary to meet the needs of these three different subgroups.

PMID- 12612105
TI  - Adherence to HIV medications in a cohort of men who have sex with men: impact of
      September 11th.
AB  - Adherence to highly active antiretroviral therapy (HAART) regimens remains a
      challenge for people living with human immunodeficiency virus (HIV). Severe
      traumas like that of September 11, 2001, can exacerbate the difficulties already
      associated with adherence. A community-based sample of 68 HIV-seropositive men
      who have sex with men (MSM) living in New York City who were on protease
      inhibitor HAART regimens completed quantitative assessments to examine adherence
      in the aftermath of September 11th. Data were drawn from a larger study of drug
      use and HIV medication adherence. Assessments conducted from September 24, 2001
      to October 24, 2001 were compared to assessments taken 2-4 months prior to
      September 11th. Repeated measures analyses of variance were used to analyze the
      number of missed and suboptimal doses (doses taken outside the prescribed time by
      +/-4 hours) reported in the 2 weeks prior to each respective assessment. The
      results indicated a significant increase in the number of missed doses and the
      number of suboptimal doses immediately after the events of September 11th.
      Differences in adherence were not influenced, however, by sociodemographic
      characteristics. These results suggest that the events of September 11th had an
      impact on adherence to HIV medications among MSM in New York City and provide
      further support for the notion that the events of September 11th may have
      adversely impacted the lives of seropositive individuals. Attention should be
      paid by clinicians working with HIV-positive individuals on how this event has
      been incorporated into lives of individuals already burdened by a chronic and
      demanding disease.

PMID- 12612106
TI  - Re: "Named reporting and mandatory partner notification in New York State: the
      effect on consent for perinatal HIV testing".

PMID- 12612108
TI  - The case of Sally Clark.

PMID- 12612109
TI  - Foundation hospitals: a new direction for NHS reform?

PMID- 12612111
TI  - Five steps to conducting a systematic review.

PMID- 12612110
TI  - Xenotransplantation: where are we today?

PMID- 12612113
TI  - Severe refractory hypercalcaemia in HTLV-1 infection.

PMID- 12612112
TI  - Cause and outcome of atypical chest pain in patients admitted to hospital.
AB  - In patients with acute chest pain the prime need, usually, is to diagnose and
      treat myocardial infarction or ischaemia. When a cardiac origin for the pain has
      been excluded, patients are commonly discharged without either a diagnosis or a
      plan for follow-up. We studied a group of such patients to see how far causation
      was pursued and how their mortality compared with that of patients with a proven
      cardiac cause for their symptoms. The study population was 250 patients admitted
      over five weeks with chest pain suspected of being cardiac in origin. Initial
      assessment included an electrocardiogram and measurement of troponin T. If
      neither of these indicated a cardiac event, the patient was deemed to have
      'atypical' chest pain and the cause, where defined, was recorded. Outcomes at one
      year were determined by questionnaire and by assessment of medical notes. Of the
      250 patients, 142 had cardiac pain (mean age 79 years, 58% male) and 108 atypical
      chest pain (mean age 60 years, 55% male). Of those with atypical pain, 40 were
      discharged without a diagnosis; in the remaining 68 the pain was thought to be
      musculoskeletal (25), cardiac (21), gastrointestinal (12) or respiratory (10) in
      origin. 41 patients were given a follow-up appointment on discharge. At one year,
      data were available on 103 (96%) patients. The mortality rate was 2.9% (3
      patients) compared with 18.3% in those with an original cardiac event. Half of
      the patients with atypical pain had undergone further investigations and 14% had
      been readmitted. The yield of investigative procedures was generally low (20%)
      but at the end of the year only 27 patients remained undiagnosed. Patients with
      atypical chest pain form a substantial proportion of emergency admissions. The
      symptoms often persist or recur. The commonest causation is musculoskeletal, but
      a sizeable minority remain undiagnosed even after follow-up.

PMID- 12612114
TI  - Pathergy in non-Hodgkin lymphoma.

PMID- 12612115
TI  - Three cases of atypical mycobacterial cervical adenitis.

PMID- 12612116
TI  - Cardiac memory mimicking myocardial ischaemia.

PMID- 12612117
TI  - Legal considerations of clinical guidelines: will NICE make a difference?

PMID- 12612118
TI  - Thomas Willis and the background to Cerebri Anatome.

PMID- 12612119
TI  - Myths and mandrakes.

PMID- 12612120
TI  - A glass of water.

PMID- 12612122
TI  - Outpatient clinic: where is the delay?

PMID- 12612121
TI  - The health of Gulf War veterans.

PMID- 12612123
TI  - How objective are systematic reviews?

PMID- 12612124
TI  - Asperger's syndrome.

PMID- 12612125
TI  - Capacity and consent.

PMID- 12612126
TI  - The philosophy of science.

PMID- 12612128
TI  - Noise exposure in motorcyclists.

PMID- 12612130
TI  - A short history of nutritional science: part 1 (1785-1885).

PMID- 12612131
TI  - The American Society for Nutritional Sciences (1979-2003): years of action and
      change.

PMID- 12612133
TI  - Commentary on the paper of Damon et al. (December 2002).

PMID- 12612132
TI  - Fish oil consumption and reduction of arterial disease.
AB  - Fish oil consumption may help to normalize the prethrombotic state and reduce
      arterial disease. This antithrombotic potential of fish oil, rich in (n-3)
      polyunsaturated fatty acids (PUFA), has been attributed to a reduction in
      platelet activation, a lowering of plasma triglycerides and (vitamin K-dependent)
      coagulation factors and/or a decrease in vascular tone. Most intervention studies
      have shown only moderate effects of (n-3) PUFA on these hemostatic variables. On
      the other hand, the usually small prolongation in bleeding time with fish oil
      does not appear to lead to bruising or hemorrhage, at least in healthy subjects.
      This contrasts with the increased bleeding risk accompanying the more prominent
      antihemostatic effects of antiplatelet and anticoagulant drugs. Here we propose
      that the beneficial effect of (n-3) PUFA diet is related to down-regulation of
      the mutually positive interactions of platelet activation and coagulation. In
      addition, we consider the possibility that the dietary effect on hemostatic and
      lipid factors involves transcription regulation of multiple genes, perhaps in a
      subject-dependent manner.

PMID- 12612134
TI  - Short-term intake of conjugated linoleic acid inhibits lipoprotein lipase and
      glucose metabolism but does not enhance lipolysis in mouse adipose tissue.
AB  - Feeding diets supplemented with t10c12 conjugated linoleic acid (CLA) to growing
      mice reduces body fat mass. The effects are evident after 1 wk and maximal by 3
      wk and are accompanied by reductions in fat cell size. This may complicate direct
      comparisons with adipocytes from control mice. Accordingly, we investigated the
      early biochemical events that occur within adipocytes during the first week of
      CLA feeding, before changes in the size of adipocytes have occurred. Female ICR
      mice were fed a control diet or a diet supplemented with 0.5 g/100 g of CLA for 4
      d, at which time there were no differences in body weight, fat mass or adipocyte
      size (except that CLA-fed mice had fewer adipocytes >90 micro m in diameter).
      Parametrial adipose tissue from the CLA-fed mice had significantly reduced
      heparin-releasable lipoprotein lipase (LPL) and intracellular LPL activities and
      significantly reduced glucose incorporation into CO(2), fatty acid and glycerol.
      There were no differences between adipose tissues from CLA-fed or control mice in
      the ratios of 16:0 to 16:1 and 18:0 to 18:1 fatty acids or in norepinephrine
      stimulated lipolysis. Serum insulin levels in food-deprived mice, measured at 4 d
      and 7 wk, did not differ between groups nor did the concentration of free fatty
      acids in serum of food-deprived or fed mice measured at the same time points. In
      mice, CLA-induced inhibition of heparin-releasable LPL and glucose metabolism may
      be the most important early steps leading to subsequent body fat reduction. In
      addition, CLA does not appear to enhance lipolysis in mouse adipose tissue in
      vivo.

PMID- 12612135
TI  - Oxidative folding of interleukin-2 is impaired in flavin-deficient jurkat cells,
      causing intracellular accumulation of interleukin-2 and increased expression of
      stress response genes.
AB  - Secretory proteins such as interleukin (IL)-2 undergo oxidative folding
      (disulfide formation) in the endoplasmic reticulum (ER) before secretion. Studies
      in yeast have suggested that oxidative folding depends on the flavoprotein Ero1p;
      unfolded proteins accumulate in the ER, triggering cellular stress response.
      Here, human lymphoid cells (Jurkat cells) were used to model effects of cellular
      flavin supply on secretion of IL-2 (containing one disulfide bond) and cellular
      stress response. Cells were cultured in media containing 0.85, 3.1, 12.6 or 300.6
      nmol/L riboflavin for 5 wk, representing severely deficient, moderately
      deficient, physiologic and pharmacologic plasma concentrations in humans,
      respectively. Transport rates of riboflavin were increased in severely and
      moderately deficient cells compared with cells cultured in physiologic medium;
      this increase was not sufficient to prevent intracellular depletion of
      riboflavin, as judged by glutathione reductase activity and intracellular
      concentrations of glutathione. Intracellular accumulation of IL-2 was greater in
      severely deficient cells than in other groups. Nevertheless, severely deficient
      cells secreted normal amounts of IL-2 into the extracellular space, mediated by
      increased transcriptional activity of the IL-2 gene. Riboflavin-deficient cells
      responded to intracellular accumulation of IL-2 with increased expression of
      genes encoding ubiquitin-activating enzyme E1 and X box-binding protein,
      consistent with cellular stress. These findings are consistent with the
      hypothesis that flavin deficiency may cause cellular stress by accumulation of
      unfolded proteins in human cells.

PMID- 12612136
TI  - Altering dietary protein type and quantity reduces urinary albumin excretion
      without affecting plasma glucose concentrations in BKS.cg-m +Lepr db/+Lepr db
      (db/db) mice.
AB  - Protein restriction is used conventionally in the prevention and treatment of
      diabetic nephropathy. Recently, the use of soy protein instead of animal protein
      has been postulated as a new preventive and treatment option. The aim of this
      study was to determine the qualitative and quantitative effects of dietary
      protein on biomarkers of diabetic nephropathy in a Type 2 diabetes mellitus mouse
      model (BKS.cg-m +Lepr(db)/+Lepr(db) mice). Diabetic (+Lepr(db)/+Lepr(db)) and
      control (m+/m+) mice (n = 24/group) consumed one of four different diets ad
      libitum [20% casein, 20% soy protein, 12% casein or 12% soy protein (energy-based
      percentages)] from 35 +/- 4 d of age until termination (184-217 d of age). Blood
      and urine were collected throughout the study to measure biomarkers of diabetes
      and diabetic nephropathy. Kidney tissue was collected at the end of the study for
      weight. In diabetic mice, a 20% casein diet increased urinary albumin excretion
      to macroalbuminuric levels, whereas a 20% soy protein diet led to no major
      changes in urinary albumin excretion. Low protein diets (12%), independently of
      protein type, decreased urinary albumin excretion to low microalbuminuric levels.
      There were no significant differences in plasma glucose concentrations. These
      findings show lower urinary albumin excretion when a soy protein diet or a low
      casein diet is fed, suggesting a delay in the progression of diabetic
      nephropathy.

PMID- 12612137
TI  - Dietary (n-3) fat and cholesterol alter tissue antioxidant enzymes and
      susceptibility to oxidation in SHR and WKY rats.
AB  - Previously, 8% fish oil blend diets, compared to butter and soybean oil blend
      diets, reduced specific antioxidant enzyme activities and tissue susceptibility
      to in vitro oxidative stress in spontaneously hypertensive (SHR) and Wistar Kyoto
      (WKY) rats. Moreover, high cholesterol (5.0 g/kg diet) diets protected against in
      vitro tissue lipid oxidation. In this study, we hypothesized that 160 g fat/kg
      diet as blends of (n-6) or (n-3) oils and cholesterol would alter antioxidant
      enzyme activities and thus increase tissue susceptibility to oxidation. The
      effects of diet blends of saturated (butter, B), (n-6) (soybean oil, SBO) or (n
      3) (menhaden oil, MO) oils with cholesterol (0.5 or 5.0 g/kg) on systolic blood
      pressure (SBP), plasma lipids, antioxidant enzymes and susceptibility to
      oxidation were examined in SHR and WKY rats. SBP at 13 wk of age was greater (P <
      0.001) in SHR than in WKY rats, but was not affected by diets. Plasma cholesterol
      and triacylglycerols were decreased (P < 0.001) by MO diets. Hepatic glutathione
      reductase activities were reduced (P < 0.001) in SBO-fed SHR and enhanced in SBO-
      and MO-fed WKY rats. Glutathione levels were reduced (P < 0.001) in RBC and
      enhanced (P < 0.001) in livers of MO-fed rats. Lipid oxidation was enhanced (P <
      0.001) in red blood cells (RBC) from SBO groups, and hearts and livers of MO
      groups. High cholesterol diets reduced (P < or = 0.001) susceptibility to lipid
      peroxidation in RBC and liver of SHR and WKY rats. Greater amounts of dietary (n
      3) fat enhance tissue susceptibility to oxidation, which can be modulated by
      increased dietary cholesterol in SHR and WKY rats.

PMID- 12612138
TI  - Dietary fats differentially modulate the expression of lecithin:cholesterol
      acyltransferase, apoprotein-A1 and scavenger receptor b1 in rats.
AB  - In the present study the effects of dietary fat with defined fatty acids on
      lecithin:cholesterol acyltransferase (LCAT) and apoA-1, the two components of HDL
      that play a major role in reverse cholesterol transport (RCT), were examined. In
      addition, the expression of scavenger receptor B1 (SR-B1), the receptor involved
      in the uptake of HDL core lipids, was also determined under the same conditions
      in rats fed semisynthetic diets supplemented with triolein (TO), tripalmitin (TP)
      or menhaden oil (MO). Serum LCAT activity [ micro mol CE/(L.h)] was significantly
      (P < 0.05) higher in rats fed TO (33 +/- 4) compared with those fed TP (23 +/- 3)
      or MO (21 +/- 1). The levels of hepatic LCAT mRNA and hepatic SR-B1 receptor
      protein did not differ between rats fed TP and MO. The triolein diet, on the
      other hand, increased the induction of hepatic LCAT mRNA and hepatic SR-B1
      receptor protein 1.5- to 2-fold. Serum HDL cholesterol concentrations differed
      among all groups and were 1.30 +/- 0.08, 1.17 +/- 0.10 and 0.91 +/- 0.06 mmol/L
      for TO-, TP- and MO-fed rats, respectively. Serum apoA-1 levels were
      significantly higher in TO-fed rats than in the other two groups. The data
      indicate that TO increases the secretion of HDL and its components (apoA-1 and
      LCAT), and stimulates the production of hepatic SR-B1 receptor protein. Overall,
      these results suggest that triolein may promote RCT and thus retard the
      development of atherosclerosis.

PMID- 12612139
TI  - Decreased cholinergic stimulation of insulin secretion by islets from rats fed a
      low protein diet is associated with reduced protein kinase calpha expression.
AB  - Undernutrition has been shown to affect the autonomic nervous system, leading to
      permanent alterations in insulin secretion. To understand these interactions
      better, we investigated the effects of carbamylcholine (CCh) and phorbol 12
      myristate 13-acetate (PMA) on insulin secretion in pancreatic islets from rats
      fed a normal (17%; NP) or low (6%; LP) protein diet for 8 wk. Isolated islets
      were incubated for 1 h in Krebs-bicarbonate solution containing 8.3 mmol
      glucose/L, with or without PMA (400 nmol/L) and CCh. Increasing concentrations of
      CCh (0.1-1000 micro mol/L) dose dependently increased insulin secretion by islets
      from both groups of rats. However, insulin secretion by islets from rats fed the
      NP diet was significantly higher than that of rats fed the LP diet, and the dose
      response curve to CCh was shifted to the right in islets from rats fed LP with a
      50% effective concentration (EC(50)) of 2.15 +/- 0.7 and 4.64 +/- 0.1 micro mol
      CCh/L in islets of rats fed NP and LP diets, respectively (P < 0.05). PMA-induced
      insulin secretion was higher in islets of rats fed NP compared with those fed LP.
      Western blotting revealed that the protein kinase (PK)Calpha and phospholipase
      (PL)Cbeta(1) contents of islets of rats fed LP were 30% lower than those of
      islets of rats fed NP (P < 0.05). In addition, PKCalpha mRNA expression was
      reduced by 50% in islets from rats fed LP. In conclusion, a reduced expression of
      PKCalpha and PLCbeta(1) may be involved in the decreased insulin secretion by
      islets from LP rats after stimulation with CCh and PMA.

PMID- 12612140
TI  - Red wine polyphenolics increase LDL receptor expression and activity and suppress
      the secretion of ApoB100 from human HepG2 cells.
AB  - Epidemiologic studies suggest that the consumption of red wine may lower the risk
      of cardiovascular disease. The cardioprotective effect of red wine has been
      attributed to the polyphenols present in red wine, particularly resveratrol (a
      stilbene, with estrogen-like activity), and the flavonoids, catechin,
      epicatechin, quercetin and phenolic acids such as gallic acid. At present, very
      little is known about the mechanisms by which red wine phenolic compounds benefit
      the cardiovascular system. Therefore, the aim of this study was to elucidate
      whether red wine polyphenolics reduce lipoprotein production and clearance by the
      liver. Cultured HepG2 cells were incubated in the presence of dealcoholized red
      wine, alcohol-containing red wine and atorvastatin for 24 h. The apolipoprotien
      B100 (apoB100) protein (marker of hepatic lipoproteins) was quantified on Western
      blots with an anti-apoB100 antibody and the enhanced chemiluminescence detection
      system. Apolipoprotein B100 levels in the cells and that secreted into the media
      were significantly reduced by 50% in liver cells incubated with alcohol-stripped
      red wine compared with control cells. This effect of dealcoholized red wine on
      apoB100 production in HepG2 cells was similar to the effect of atorvastatin. Apo
      B100 production was significantly attenuated by 30% in cells incubated with
      alcoholized red wine, suggesting that the alcohol was masking the effect of red
      wine polyphenolics. Apo B100 production was significantly attenuated by 45% with
      the polyphenolic compounds resveratrol and quercertin. In addition, dealcoholized
      and alcoholized red wine and atorvastatin significantly increased 3-hydroxy-3
      methylglutaryl coenzyme A (HMG-CoA) reductase mRNA and LDL receptor binding
      activity relative to controls. Dealcoholized red wine also increased LDL receptor
      gene expression. Collectively, this study suggests that red wine polyphenolics
      regulate major pathways involved in lipoprotein metabolism.

PMID- 12612142
TI  - Biotin supplementation increases expression of genes encoding interferon-gamma,
      interleukin-1beta, and 3-methylcrotonyl-CoA carboxylase, and decreases expression
      of the gene encoding interleukin-4 in human peripheral blood mononuclear cells.
AB  - Stimulation of immune cells by antigens triggers changes in the transcription of
      genes encoding cytokines and other proteins; these changes in gene expression are
      part of the normal immune response. Previous studies have provided evidence that
      biotin status may affect secretion of cytokines by immune cells. Here we
      determined whether biotin supplementation affects gene expression in human immune
      cells. Peripheral blood mononuclear cells were isolated from healthy adults
      before and after supplementation with 8.8 micro mol biotin/d for 21 d. Cells were
      cultured ex vivo with concanavalin A for 21 h to simulate stimulation with
      antigens. Expression of genes that play roles in cytokine metabolism, cell
      proliferation, signal transduction, stress response, apoptosis and biotin
      homeostasis was quantified by using DNA microarrays and reverse transcriptase
      polymerase chain reaction. The abundance of mRNA encoding interferon-gamma,
      interleukin-1beta, and 3-methylcrotonyl-CoA carboxylase was 4.3, 5.6 and 8.9
      times greater, respectively, after supplementation with biotin compared with
      before supplementation. In contrast, the abundance of mRNA encoding interleukin-4
      was 6.8 times greater before supplementation than after supplementation. These
      data suggest that biotin supplementation affects gene expression in human immune
      cells. Effects of biotin on gene expression are likely to modulate the response
      of immune cells to antigens.

PMID- 12612141
TI  - Feed restriction significantly alters lipogenic gene expression in broiler
      breeder chickens.
AB  - Broiler breeder pullets were divided into two groups at 21 wk of age. One group
      was given free access to feed (ad libitum) and the other fed a limited amount of
      feed (restricted). At 22 wk, all birds were photostimulated and maintained
      throughout an egg-laying cycle ending at 36 wk. Samples of liver and abdominal
      fat pad were collected just before photostimulation (prelight), after
      photostimulation at first egg and at peak egg production (plateau). Hepatic
      expression of sterol regulatory element binding protein-1, ATP-citrate lyase,
      fatty acid synthase, malic enzyme, acetyl-CoA carboxylase and stearoyl-CoA
      (Delta9) desaturase 1 genes in ad libitum birds declined from their highest
      levels just before photostimulation as the birds came into and maintained egg
      production. In contrast, the restricted birds had significant (P < 0.05)
      increases in the expression of these genes after photostimulation at first egg
      with a subsequent decline as they reached peak egg production. Hepatic expression
      of fatty acid binding protein, VLDL apolipoprotein (apoVLDL-II) and apoB genes
      increased significantly (P < 0.05) in both ad libitum and restricted breeders
      after photostimulation, whereas apoA1 gene expression declined during this time.
      Abdominal fat pad weights were significantly (P < 0.05) higher in the ad libitum
      compared with restricted birds after photostimulation. Lipoprotein lipase in this
      tissue showed a pattern of expression similar to that observed for the hepatic
      lipogenic enzyme genes. In conclusion, feed restriction during the pullet-to
      breeder transition period significantly (P < 0.05) altered hepatic lipogenic gene
      expression in broiler breeders.

PMID- 12612143
TI  - Decreased carotenoid concentrations due to dietary sucrose polyesters do not
      affect possible markers of disease risk in humans.
AB  - Excessive consumption of energy and fat increases the risk for obesity. Snacks
      containing sucrose polyesters (SPE) as a dietary fat replacer are on the market
      in the United States. SPE products have been shown to lower concentrations of
      serum carotenoids in short-term studies. Experimental studies on the longer-term
      effects on health of decreased carotenoid concentrations are lacking. A 1-y
      randomized, double-blind, placebo-controlled parallel trial was performed.
      Subjects (n = 380) with a habitual low or high fruit and vegetable intake were
      assigned to the treatments (0, 7, 10 or 17 g/d SPE). SPE was given in the form of
      spreads, chips or both. The groups were compared for serum carotenoids, vitamins
      and markers of oxidative damage, eye health, cardiovascular health and immune
      status. After 1 y, serum lipid-adjusted carotenoids showed the largest decrease
      in the SPE chips and spread group (17 g/d) compared with the control group [alpha
      carotene 33%; beta-carotene 31%, lycopene 24%, beta-cryptoxanthin 18%, lutein 18%
      (all P < 0.001) and zeaxanthin 13% (P < 0.05)]. Consumption of SPE spread (10 g/d
      SPE) decreased carotenoid concentrations by 11-29% (all P < 0.05). SPE chips (7
      g/d SPE) decreased zeaxanthin (11%), beta-carotene (12%) and alpha-carotene (21%;
      all P < 0.05). Serum lipid adjusted alpha-tocopherol decreased significantly by 6
      8% (all P < 0.001) in all SPE groups. No negative effects were observed on
      markers of oxidation, eye health, cardiovascular health or immune status. This
      study shows that decreases in serum carotenoid concentrations do not affect
      possible markers of disease risk.

PMID- 12612144
TI  - The consumption of processed tomato products enhances plasma lycopene
      concentrations in association with a reduced lipoprotein sensitivity to oxidative
      damage.
AB  - Lycopene, the predominant carotenoid in tomatoes, is hypothesized to mediate the
      health benefits of tomato products. We designed a study to examine the change in
      plasma lycopene and resistance of lipoproteins to ex vivo oxidative stress.
      Healthy individuals (n = 60; age >40 y; 30 men/30 women) consumed a lycopene-free
      diet for 1 wk and were subsequently randomized to receive 35 +/- 1, 23 +/- 1 or
      25 +/- 1 mg lycopene/d from Campbell's Condensed Tomato Soup (CS), Campbell's
      Ready To Serve Tomato Soup (RTS) or V8 Vegetable Juice (V8), respectively, for 15
      d. Total plasma lycopene concentrations decreased from 0.499 +/- 0.044 to 0.322
      +/- 0.027 (35%, P < 0.0001) micro mol/L for the 60 participants during the 7-d
      washout period. After intervention, total lycopene concentrations increased for
      those consuming CS, RTS and V8 (compared with the washout period for each group)
      to 0.784 +/- 0.083 (123%, P < 0.0001), 0.545 +/- 0.061 (57%, P < 0.01) and 0.569
      +/- 0.061 (112%, P < 0.0001) micro mol/L, respectively. The concentrations of all
      lycopene isomers decreased during the washout period. As a percentage of plasma
      total lycopene isomers for the 60 subjects, all-trans-lycopene decreased from
      44.4 +/- 1.2 to 39.6 +/- 1.2 (P < 0.0001), whereas total cis-lycopene isomers
      increased from 55.6 +/- 1.2 to 60.4 +/- 1.2 (P < 0.0001) during the washout
      period, a shift that was reversed by consumption of tomato products for 15 d. The
      ex vivo lipoprotein oxidation lag period, used as a measure of antioxidant
      capacity, increased significantly from 64.7 +/- 2.4 min at the end of the washout
      period (all groups) to 70.1 +/- 4.0 (P < 0.05), 68.3 +/- 2.4 (P < 0.05) and 71.7
      +/- 4.0 min (P < 0.01) after treatment for the CS, RTS and V8 groups,
      respectively. This study shows that lycopene concentrations and isomer patterns
      change rapidly with variation in dietary intake. In addition, 15 d of tomato
      product consumption significantly enhanced the protection of lipoproteins to ex
      vivo oxidative stress.

PMID- 12612145
TI  - Regulation of sulfur amino acid metabolism in men in response to changes in
      sulfur amino acid intakes.
AB  - We showed previously that 64% of the total dietary sulfur amino acid (SAA)
      requirement could be supported by dietary cysteine (Cys). However, the
      observation of such a sparing effect may be affected by the dietary intakes of
      SAA provided. The aim of this study was to compare methionine (Met) metabolism
      and transsulfuration (TS) in five healthy men fed three different diets (in
      random order) for 3 d each, with varying combinations of Met and Cys: 24 mg
      Met/(kg. d) and no Cys (diet A); 13 mg Met/(kg. d) and 11 mg Cys/(kg. d) (diet
      B); and 5 mg Met/(kg. d) and 19 mg Cys/(kg. d) (diet C). On d 3, Met kinetics and
      TS were assessed using orally administered L-[1-(13)C, methyl-(2)H(3)]methionine.
      Met demethylation (transmethylation, TM) significantly decreased as the dietary
      Met to Cys ratio decreased. Met TS was significantly lower during diets B [2.8 +/
      0.4 micro mol/(kg. h)] and C [1.5 +/- 0.5 micro mol/(kg. h)] than during diet A
      [7.8 +/- 2.9 micro mol/(kg. h)] (P < 0.05). The results of the present study
      indicate that when the ratio of Met to Cys fed is typical of that found in major
      food proteins and total SAA are sufficient to meet requirements, TS is
      significantly reduced compared with the case in which SAA needs are supplied by
      Met alone. We conclude that Cys sparing occurs through an increase in the
      fraction of the homocysteine pool destined for RM relative to TS (RM:TS).

PMID- 12612146
TI  - Moderate antioxidant supplementation has no effect on biomarkers of oxidant
      damage in healthy men with low fruit and vegetable intakes.
AB  - The link between high fruit/vegetable intake and reduced chronic disease may be
      partly explained by antioxidant protection. To determine the effect of moderate
      antioxidant intake on biomarkers of oxidant damage, we assessed in vivo lipid and
      protein oxidation in 77 healthy men whose typical diet contained few fruits and
      vegetables (mean of 2.6 servings/d). The 39 nonsmokers and 38 smokers, age 20- 51
      y, were given a daily supplement (272 mg vitamin C, 31 mg all-rac-alpha
      tocopherol, and 400 micro g folic acid), or placebo, for 90 d with their usual
      diet. Blood and urine were taken at baseline and the end of the study for
      determination of lipid peroxidation products, including F(2)-total and 8
      isoprostanes, and protein carbonyls. Urine thiobarbituric acid reactive
      substances (TBARS) was the only oxidant damage marker that was significantly
      higher in smokers compared to nonsmokers (P < 0.05). Supplementation increased
      plasma ascorbate and tocopherol, but had no effect on the oxidant biomarkers. In
      healthy young men, the endogenous antioxidant defense system and a modest intake
      of dietary antioxidants are adequate to minimize levels of in vivo oxidant damage
      such that they cannot be differentiated by current methods.

PMID- 12612147
TI  - Supplementation of diets with the black rice pigment fraction attenuates
      atherosclerotic plaque formation in apolipoprotein e deficient mice.
AB  - Apolipoprotein (apo)E-deficient mice were used to study the antiatherogenic
      effect of black rice pigment fraction (BRF) and the possible mechanisms by which
      it inhibits atherogenesis. The apoE-deficient mice (n = 45) were randomly divided
      into three groups and received AIN-93G diet (positive group), AIN-93G with 5 g of
      black rice pigment fraction/100 g (BRF group) and AIN-93G with 5 g of white rice
      outer layer fraction/100 g (WRF group) for 16 wk. C57BL/6J mice (n = 15) received
      AIN-93G and were used as a control group. Blood samples were collected for
      measurement of lipid concentration, antioxidized LDL antibody and nitric oxide
      concentration. Livers were extracted for determination of cholesterol
      concentrations, and aortas were used to determine cholesterol concentrations and
      inducible nitric oxide synthase protein and mRNA expression. Hearts were used to
      assess atherosclerotic plaque formation. The apoE-deficient mice fed the black
      rice pigment fraction diet had 48% (P < 0.01) less atherosclerotic lesion area
      compared with apoE-deficient mice fed only the AIN-93G diet and 46% (P < 0.01)
      less lesion area compared with mice fed the white rice outer layer fraction diet.
      This observation corresponded with significantly (P < 0.05) lower total serum
      cholesterol, lower liver and aorta cholesterol (P < 0.01) and higher HDL
      cholesterol (P < 0.05) concentrations and lower (P < 0.05) antioxidized LDL
      antibody titer in apoE-deficient mice fed the black rice pigment fraction diet
      compared with positive and WRF groups. Notwithstanding this, mice fed the black
      rice pigment fraction diet also had lower CD4(+) T lymphocyte expression (P <
      0.05) and weaker inducible nitric oxide synthase expression (P < 0.05) compared
      with mice fed the AIN-93G diet and the white rice outer layer fraction diet,
      respectively. We concluded that the inhibition of atherosclerotic lesions of the
      black rice pigment fraction is attributed to the improvement in cholesterol
      accumulation and reduction in oxidative stress and inflammation.

PMID- 12612148
TI  - A soybean peptide isolate diet promotes postprandial carbohydrate oxidation and
      energy expenditure in type II diabetic mice.
AB  - The aim of the present study was to determine the effects of dietary proteins on
      the oxidation of dietary carbohydrate and lipids in type II diabetic mice. KK
      A(y) strain mice were provided free access to a high fat diet (30% of energy as
      fat) for an initial 4-wk period to induce diabetes. To reduce body weight gain,
      the mice were subsequently fed restrictive isoenergetic and isonitrogenous diets
      (35% of energy as protein and 5% as fat) based on either casein or soy protein
      isolate hydrolysate (SPI-H) for 4 wk. To measure exogenous carbohydrate and lipid
      oxidation, the mice were fed a diet containing (13)C-glucose or (13)C-triolein
      while they were in a respiratory chamber for 72 h. Postprandial energy
      expenditure was higher in the SPI-H than in the casein group; this difference was
      due to an increase in postprandial exogenous and endogenous carbohydrate
      oxidation. There were no differences in 24-h energy expenditure between dietary
      groups. Oxidation of exogenous carbohydrate tended to be higher (P = 0.054) in
      the SPI-H group during the 24 h of measurement. Fecal excretion of (13)C-glucose
      was lower but the excretion of lipid was higher in mice fed the SPI-H diet than
      in casein-fed mice. These results indicate that in type II diabetic mice, dietary
      SPI-H not only inhibits the absorption of dietary lipids and increases the
      absorption of dietary carbohydrates but also augments postprandial energy
      expenditure, which is accompanied by a postprandial increase in oxidation of
      dietary carbohydrates.

PMID- 12612150
TI  - Urinary sulfur excretion and the nitrogen/sulfur balance ratio reveal nonprotein
      sulfur amino acid retention in piglets.
AB  - We evaluated the use of urinary sulfur (S) excretion as a measure of sulfur amino
      acid (SAA) catabolism and the nitrogen/sulfur (N/S) molar balance ratio as an
      indicator of nonprotein SAA storage in growing piglets. After confirming that an
      intravenous dose of sulfate is fully recovered in urinary sulfate, we measured
      urinary S recovery after an intravenous dose of methionine in 6 piglets fed an
      adequate protein (AP) diet and 6 piglets fed a low protein (LP) diet with normal
      energy provision. As measured over 48 h, recoveries of the methionine load as
      urinary total S was 106% in the AP group but only 69% in the LP group (P < 0.05).
      On the baseline diets the N/S balance ratio in the AP group was 36, whereas that
      in the LP group was 30 (P < 0.05); immediately after the methionine load, this
      ratio remained constant in the AP group but decreased further, to 26 (P < 0.05)
      in the LP group. These results indicate that protein-deficient piglets accumulate
      relatively more S than N from their diet, and under these conditions a
      significant portion of the S derived from a methionine load is retained in
      nonprotein compounds. Urinary S excretion, a simple nontracer measurement, can
      provide an accurate measure of SAA catabolism, and the N/S balance ratio is a
      potentially useful indicator of changes in nonprotein SAA stores of growing
      piglets.

PMID- 12612149
TI  - Dietary eritadenine and ethanolamine depress fatty acid desaturase activities by
      increasing liver microsomal phosphatidylethanolamine in rats.
AB  - The effects of eritadenine, a constituent of the Lentinus edodes mushroom, and
      ethanolamine, the base constituent of phosphatidylethanolamine (PE), on fatty
      acid desaturase activities and lipid profiles were investigated comparatively in
      rats. Rats were fed a control diet or a diet supplemented with either eritadenine
      (0.05 g/kg) or ethanolamine (8 g/kg) for 14 d. Eritadenine and ethanolamine had
      marked hypocholesterolemic effects. The concentration of liver microsomal PE was
      significantly increased and the ratio of phosphatidylcholine (PC) to PE was
      significantly decreased by both eritadenine and ethanolamine. These changes in
      phospholipid profile were also observed in the mitochondria and plasma membranes
      in the liver. The activities of the Delta5-, Delta6- and Delta9-desaturases in
      liver microsomes were significantly decreased by eritadenine and ethanolamine;
      there was a significant correlation between the activity of Delta5- or Delta6
      desaturase and the proportion of PE in the total phospholipids or the PC/PE
      ratio. Reflecting decreased Delta5- and Delta6-desaturase activities, the 20:4(n
      6)/18:2(n-6) ratio was significantly decreased by eritadenine and ethanolamine in
      PC of the liver microsomes, mitochondria and plasma membranes. Although the
      20:4(n-6)/18:2(n-6) ratio of liver microsomal PE was also significantly decreased
      by eritadenine and ethanolamine, the fatty acid composition of
      phosphatidylinositol and phosphatidylserine was less affected by these compounds.
      Eritadenine and ethanolamine increased the proportion of 16:0-18:2 and decreased
      the proportion of 18:0-20:4 in liver PC. The results suggest that dietary
      eritadenine and ethanolamine might lead to decreases in desaturase activities and
      changes in fatty acid and molecular species composition of PC through an increase
      in liver microsomal PE.

PMID- 12612151
TI  - Intestinal uptake of quercetin-3-glucoside in rats involves hydrolysis by lactase
      phlorizin hydrolase.
AB  - Quercetin has antioxidant, anti-inflammatory, antiproliferative and
      anticarcinogenic properties. In plant foods, quercetin occurs mainly bound to
      various sugars via a beta-glycosidic link. We hypothesized that lactase phlorizin
      hydrolase (LPH), an enzyme at the brush border membrane of intestinal cells, is
      involved in the in vivo intestinal uptake of quercetin-sugars. To study this, we
      measured the appearance of quercetin metabolites in plasma and perfusate after
      perfusing the jejunum and ileum with 50 micro mol/L quercetin-3-glucoside in an
      in situ rat perfusion model. LPH was inhibited by the selective LPH inhibitor N
      butyldeoxygalactonojirimycin (0, 0.5, 2 or 10 mmol/L) (n = 5 rats/group).
      Quercetin in plasma and perfusion buffer was determined by HPLC with CoulArray
      detection. Results are given as means +/- SEM. In the perfusion buffer, 13.8 +/-
      0.7 micro mol/L quercetin-3-glucoside was hydrolyzed during intestinal passage.
      Co-perfusion with 0.5, 2 and 10 mmol/L N-butyldeoxygalactonojirimycin resulted in
      38% (P < 0.05), 50% (P < 0.01) and 67% (P < 0.01) less hydrolysis, respectively.
      Plasma concentrations of quercetin in the corresponding groups were 36% (P =
      0.12), 55% (P < 0.01) and 75% (P < 0.01) lower than in controls (1.23 +/- 0.22
      micro mol/L). These data suggest that LPH is a major determinant of intestinal
      absorption of quercetin-3-glucoside in rats.

PMID- 12612152
TI  - Bone resorption activity of all-trans retinoic acid is independent of vitamin D
      in rats.
AB  - The mechanism by which all-trans retinoic acid (ATRA) induces bone resorption is
      unknown. However, an interaction between vitamin A and vitamin D has been
      established. In fact, although the mechanism is still unclear, vitamin A has been
      shown to be a weak antagonist of the actions of vitamin D. Taking into account
      this interaction and the influence of vitamin D on other calcitropic hormones,
      such as parathyroid hormone, the effect of vitamin D on ATRA-induced bone
      resorption was investigated. Vitamin D-deficient rats were fed diets containing 0
      or 150 micro g of ATRA/g of diet. The rats then were orally administered 0 or 625
      ng of cholecalciferol (vitamin D(3)) daily. Various bone parameters were measured
      after 3-8 wk. Regardless of the presence or absence of vitamin D(3), ATRA was
      able to cause bone resorption. In addition to examining the effect of vitamin D
      on ATRA-induced bone resorption under normal conditions, this effect also was
      studied under conditions that inhibit bone mineralization or growth by altering
      dietary calcium (Ca) and phosphorus (P) levels. Changes in dietary levels of Ca
      and P did not affect the ability of ATRA to cause bone resorption. Interestingly,
      despite its ability to stimulate bone resorption, ATRA did not affect serum
      calcium or phosphorus levels. Overall, the ability of ATRA to cause bone
      resorption is not dependent on vitamin D(3), dietary Ca or dietary P.

PMID- 12612153
TI  - Immunoglobulin and cytokine production from spleen lymphocytes is modulated in
      C57BL/6J mice by dietary cis-9, trans-11 and trans-10, cis-12 conjugated linoleic
      acid.
AB  - We evaluated the effect of cis-9, trans-11 (9c,11t) and trans-10, cis-12
      (10t,12c) conjugated linoleic acid (CLA) on the immune system in C57BL/6J mice.
      Mice were fed experimental diets containing 0% CLA (controls), 1% 9c,11t-CLA, 1%
      10t,12c-CLA or a 1:1 mixture (0.5% + 0.5%) of these two CLA isomers for 3 wk.
      Relative spleen weights of all CLA fed mice were greater than the controls.
      Spleen lymphocytes isolated from the mice fed 10t,12c-CLA produced more
      immunoglobulin (Ig)A and IgM but not IgG when stimulated with concanavalin A
      (ConA) compared with controls. IgA production from unstimulated spleen
      lymphocytes was greater in the 10t, 12c-CLA group than in controls. Conversely,
      9c,11t-CLA did not affect the production of any of the Ig subclasses. Lymphocytes
      isolated from 9c,11t-CLA fed mice produced more tumor necrosis factor-alpha than
      the control group. The proportion of B cells in the spleen lymphocyte population
      was significantly lower in the 9c,11t-CLA group, and higher in the 10t,12c-CLA
      group than in the controls. Compared with the control group, the percentage of
      CD4(+) T cells was lower in the 10t,12c-CLA group, and the percentage of CD8(+) T
      cells was higher in the 9c,11t-CLA group. Furthermore, the percentage of CD8(+) T
      cells was higher in the 1:1 mixture group than in controls. The CD4(+)/CD8(+)
      ratio was lower in the 1:1 mixture group than in controls. These results suggest
      that 9c,11t and 10t,12c-CLA can stimulate different immunological effects and
      that the simultaneous intake of the two isomers can change the T cell population.

PMID- 12612154
TI  - Socioeconomic gradients in body weight of German children reverse direction
      between the ages of 2 and 6 years.
AB  - In Western societies, there is an inverse socioeconomic status (SES) gradient in
      overweight, but its onset is unknown. It was the aim of this study to assess the
      onset of the SES gradient in overweight children from birth to age 5-7 y. This
      was a cross-sectional and longitudinal study of 1326 children [668 boys and 658
      girls; median age, 6.3 y; interquartile range (IQR), 0.4 y] in Kiel, northwest
      Germany. We assessed parental education as an indicator of SES, parental body
      mass index (BMI) (fathers: median age, 37.0 y; IQR: 8.0 y; mothers: median age,
      34.0 y; IQR, 6.5 y), BMI of mothers before pregnancy, and breastfeeding
      practices. We found a positive SES gradient in birthweight, which was further
      enhanced by parental overweight. SES gradients in nutritional status disappeared
      at the age of 1 and 2 y. In contrast, in 5- to 7-y-old children, there was an
      inverse SES gradient in BMI and overweight, which was further enhanced by
      parental overweight. We concluded that (i) SES gradients in nutritional state
      show considerable changes during the first years of life, (ii) the inverse SES
      gradient in overweight becomes manifest between years 2 and 6 of life and (iii)
      parental BMI enhances SES gradients in birthweight and BMI at 5-7 y of age.

PMID- 12612155
TI  - Soy product intake is inversely associated with serum homocysteine level in
      premenopausal Japanese women.
AB  - Soybeans, which are an excellent source of folate, vitamin B-6 and minerals, may
      reduce serum homocysteine level. However, there is a possibility that dietary soy
      raises the serum homocysteine level because isoflavones, which are weak estrogens
      contained in soybeans, may exert antiestrogenic effects in a high estrogen
      environment, such as in premenopausal women. The present study examined a cross
      sectional relationship between soy product intake and serum homocysteine level in
      201 premenopausal Japanese women. Intakes of soy products, folate, methionine and
      vitamins B-6 and B-12 were estimated by a semiquantitative food frequency
      questionnaire. Folate status was also assessed by measuring serum folate. Soy
      product intake in terms of soy protein as well as soy isoflavone intake was
      modestly but significantly inversely associated with serum homocysteine level (r
      = -0.15, P = 0.04) after controlling for covariates. Soy product intake was also
      significantly positively correlated with serum folate (r = 0.15, P = 0.04).
      Although it is unclear the extent to which each component of soy, such as folate
      and isoflavones, is associated with the serum homocysteine concentration, this
      biochemical complex appears to have a favorable effect on homocysteine metabolism
      in premenopausal women.

PMID- 12612156
TI  - Vitamin B-12 status is associated with bone mineral content and bone mineral
      density in frail elderly women but not in men.
AB  - Subclinical vitamin B-12 deficiency is common in the elderly. Encouraged by early
      indications, we investigated the plasma vitamin B-12 status in association with
      bone mineral content (BMC) and bone mineral density (BMD) in frail elderly
      people. Data of 194 free-living Dutch frail elderly (143 women and 51 men) were
      available. BMC and BMD were measured by dual energy X-ray analysis. Biochemical
      analyses were performed on plasma or serum including vitamin B-12, methylmalonic
      acid, homocysteine, 25-hydroxy vitamin D and parathyroid hormone. Women had
      higher plasma vitamin B-12 (288 and 238 pmol/L, respectively) and lower plasma
      homocysteine levels (15.8 and 21.3 micro mol/L, respectively) than men. Of the
      total explained variance of BMC and BMD in women (46 and 22%, respectively), 1.3
      3.1% was explained by plasma vitamin B-12, in addition to weight and height or
      energy intake. In men, the variance of BMC and BMD was explained by weight,
      smoking and/or height (total R(2) was 53 and 25%, respectively), but not by
      plasma vitamin B-12. Osteoporosis occurred more often among women whose vitamin B
      12 status was considered marginal or deficient than in women with a normal
      status, i.e., the prevalence odds ratios (after adjustment for weight, age and
      calcium intake) (95% confidence intervals) were 4.5 (0.8;24.8) and 6.9
      (1.2;39.4), respectively. These results suggest that vitamin B-12 status is
      associated with bone health in elderly women. Future studies on bone health
      should take into account a possible role of vitamin B-12 status in different
      populations.

PMID- 12612158
TI  - Apoptotic loss of thymic lymphocytes in acute murine zinc deficiency.

PMID- 12612157
TI  - Food products containing free tall oil-based phytosterols and oat beta-glucan
      lower serum total and LDL cholesterol in hypercholesterolemic adults.
AB  - This randomized, double-blind, controlled trial evaluated the influence of low
      fat, low saturated fat food products that contained free tall oil-based
      phytosterols (TOP) and oat beta-glucan (from whole oats and bran concentrate) on
      serum lipid concentrations in adults with mild-to-moderate hypercholesterolemia.
      After a 5-wk National Cholesterol Education Program Step I diet lead-in period,
      112 subjects incorporated one of two treatments into their diets for 6 wk: food
      products (cereal, snack bar and beverage) that provided 1.8 g TOP and 2.8 g beta
      glucan/d and contained < or =3.0 g total fat and < or =1.0 g saturated fat
      (TOP/beta-glucan treatment) or similar control foods. The serum LDL cholesterol
      response from baseline to the end of study was significantly larger in the
      TOP/beta-glucan treated group than in the control group, in which there was no
      change (-3.7 vs. 0.4%; P = 0.013). Likewise, total cholesterol decreased in the
      TOP/beta-glucan treatment group and did not change significantly in the controls
      (-2.3 vs. 0.8%; P = 0.043). Serum HDL cholesterol and triglyceride responses did
      not differ between the groups. The results of this trial suggest that consumption
      of a group of low fat, TOP and beta-glucan- containing foods is a useful adjunct
      in the dietary management of hypercholesterolemia.

PMID- 12612160
TI  - The need for maternal zinc supplementation in developing countries: an unresolved
      issue.
AB  - Maternal zinc deficiency during pregnancy has been related to adverse pregnancy
      outcomes. Most studies in which pregnant women have been supplemented with zinc
      to examine effects on pregnancy outcome have been carried out in industrialized
      countries and the results have been inconclusive. This review discusses
      preliminary findings of eight randomized, controlled intervention trials
      performed recently in less-developed countries. It is based on evidence presented
      by investigators and discussed during a workshop held in Wageningen, The
      Netherlands in June 2001. Preliminary findings from these studies indicate
      maternal zinc supplementation has a beneficial effect on neonatal immune status,
      early neonatal morbidity and infant infections. With respect to labor and
      delivery complications, gestational age at birth, maternal zinc status and health
      and fetal neurobehavioral development, evidence is conflicting and more research
      is required. Data currently available do not support the hypothesis that maternal
      zinc supplementation promotes intrauterine growth. Thus despite the emerging
      evidence for a positive effect of zinc on some outcomes of pregnancy, the
      workshop concluded that the full results of studies carried out need to be known
      and that more research is required to determine the benefits of large-scale
      introduction of zinc supplementation of pregnant women in less-developed
      countries.

PMID- 12612161
TI  - Sugar and fat--from genes to culture.

PMID- 12612162
TI  - Sugars and fats: the neurobiology of preference.
AB  - The appetite for specific foods and nutrients may be under neuroregulatory
      control. In animal studies, fat intake is increased by both opioids and galanin
      and reduced by enterostatin, whereas carbohydrate intake is increased by
      neuropeptide Y (NPY). However, what may be affected is the consumption of
      preferred foods rather than macronutrients. Fat and sugars are highly preferred
      whether consumed separately or as mixtures in foods. Studies suggest that
      sustained consumption of sugars and fats may have additional metabolic
      consequences; among these are neurochemical changes in brain sites involved in
      feeding and reward, some of which are also affected by drugs of abuse.
      Furthermore, the consumption of fats and sugars alters tissue expression of
      uncoupling proteins, which are also influenced by neuroregulatory peptides and
      may be markers of energy expenditure. These data suggest that these palatable
      nutrients may influence energy expenditure through changes in central
      neuropeptide activity. Fats and sugars could affect central reward systems,
      thereby increasing food intake, and might have an additional effect on energy
      expenditure. Such palatable substances may contribute to the observed increase in
      the body weight of populations from affluent societies during the past few
      decades.

PMID- 12612163
TI  - Sugar and fat: cravings and aversions.
AB  - Food cravings are extremely common, particularly among women. Cravings are
      frequently reported for specific types of foods, including chocolate and foods
      high in both sugar and fat. Cravings for specific macronutrients, such as
      carbohydrate, have been postulated to result from a physiological need to alter
      neurotransmitters in such states as eating disorders, affective disorders or
      obesity. However, studies of such cravings are often confounded by differing
      sensory properties of high and low carbohydrate foods. There is some evidence
      that sweet, high fat foods are preferred by women with binge-eating disorders and
      that those preferences are mediated by the endogenous opioid system. Aversion to
      fat is seen primarily in women with anorexia nervosa. However, it is possible
      that changes in fat preference may be achieved through behavioral or
      pharmacological approaches. An understanding of food cravings and aversions may
      lead to improved methods for the prevention and treatment of obesity and eating
      disorders.

PMID- 12612164
TI  - Fat and sugar: an economic analysis.
AB  - As incomes rise, the share of income spent on food decreases. To Engel's law
      should be added the observation that the diet structure changes as well. Incomes
      and the macronutrient composition of the diet are linked at the aggregate and
      most likely-the individual level. People in higher income nations consume more
      added sugars and fats than do people in lower income nations. Lower income
      consumers within rich nations consume lower-quality diets than do higher income
      consumers. The lowering of energy costs ($/MJ) through technological innovation
      has been most marked for foods containing added sugars and fat. Although
      wealthier persons in poor nations are more likely to be overweight, obesity in
      the United States is associated with lower incomes. Obesity in the United States
      and similar societies may be a socioeconomic, as opposed to a medical, problem
      and one that is related to diet structure and diet costs.

PMID- 12612165
TI  - Pricing effects on food choices.
AB  - Individual dietary choices are primarily influenced by such considerations as
      taste, cost, convenience and nutritional value of foods. The current obesity
      epidemic has been linked to excessive consumption of added sugars and fat, as
      well as to sedentary lifestyles. Fat and sugar provide dietary energy at very low
      cost. Food pricing and marketing practices are therefore an essential component
      of the eating environment. Recent studies have applied economic theories to
      changing dietary behavior. Price reduction strategies promote the choice of
      targeted foods by lowering their cost relative to alternative food choices. Two
      community-based intervention studies used price reductions to promote the
      increased purchase of targeted foods. The first study examined lower prices and
      point-of-purchase promotion on sales of lower fat vending machine snacks in 12
      work sites and 12 secondary schools. Price reductions of 10%, 25% and 50% on
      lower fat snacks resulted in an increase in sales of 9%, 39% and 93%,
      respectively, compared with usual price conditions. The second study examined the
      impact of a 50% price reduction on fresh fruit and baby carrots in two secondary
      school cafeterias. Compared with usual price conditions, price reductions
      resulted in a four-fold increase in fresh fruit sales and a two-fold increase in
      baby carrot sales. Both studies demonstrate that price reductions are an
      effective strategy to increase the purchase of more healthful foods in community
      based settings such as work sites and schools. Results were generalizable across
      various food types and populations. Reducing prices on healthful foods is a
      public health strategy that should be implemented through policy initiatives and
      industry collaborations.

PMID- 12612166
TI  - Strategies for intervention: commentary and debate.
AB  - The typical American diet is top-heavy in comparison with the Food Guide Pyramid
      high in added sugars and fats at the Pyramid's tip, and low in most other food
      components at the Pyramid's base, especially fruit and green leafy vegetables.
      Improving the healthfulness of the diet would therefore require not only a major
      reduction in the consumption of fats and sweets but also a sharp increase in the
      consumption of vegetables and fruit. This report discusses the potential effects
      on diet quality of three general dietary strategies for obesity prevention and
      treatment: (a) reducing the fat content of foods, (b) increasing nutrition
      knowledge and (c) manipulating food prices. It concludes that improving food
      choices may require a combination of strategies and interventions carefully
      targeted at changing specific behaviors among diverse population groups.

PMID- 12612168
TI  - Interaction of dietary calcium and protein in bone health in humans.
AB  - Protein has both positive and negative effects on calcium balance, and the net
      effect of dietary protein on bone mass and fracture risk may be dependent on the
      dietary calcium intake. In addition to providing substrate for bone matrix,
      dietary protein stimulates the production of insulin-like growth factor-1 (IGF
      1), a factor that promotes osteoblast-mediated bone formation. Protein also
      increases urinary calcium losses, by several proposed mechanisms. Increasing
      calcium intake may offset the negative impact of dietary protein on urinary
      calcium losses, allowing the favorable effect of protein on the IGF-1 axis to
      dominate. Several, although not all, studies are either compatible with or
      support this hypothesis. Protein supplements significantly reduced bone loss in
      elderly hip-fracture patients in a study in which both the protein and control
      groups received supplemental calcium. In an observational study, total protein
      intake was positively associated with favorable 3-y changes in femoral neck and
      total body bone mineral density in volunteers who received supplemental calcium
      citrate malate and vitamin D, but not in volunteers taking placebos. In
      conclusion, an adequate calcium intake may help promote a favorable effect of
      dietary protein on the skeleton in older individuals.

PMID- 12612169
TI  - Low protein intake: the impact on calcium and bone homeostasis in humans.
AB  - Increasing dietary protein results in an increase in urinary calcium. Despite
      over 80 y of research, the source of the additional urinary calcium remains
      unclear. Because most calcium balance studies found little effect of dietary
      protein on intestinal calcium absorption, it was assumed that the skeleton was
      the source of the calcium. The hypothesis was that the high endogenous acid load
      generated by a protein-rich diet would increase bone resorption and skeletal
      fracture. However, there are no definitive nutrition intervention studies that
      show a detrimental effect of a high protein diet on the skeleton and the
      hypothesis remains unproven. Recent studies from our laboratory demonstrate that
      dietary protein affects intestinal calcium absorption. We conducted a series of
      short-term nutrition intervention trials in healthy adults where dietary protein
      was adjusted to either low, medium or high. The highest protein diet resulted in
      hypercalciuria with no change in serum parathyroid hormone. Surprisingly, within
      4 d, the low protein diet induced secondary hyperparathyroidism that persisted
      for 2 wk. The secondary hyperparathyroidism induced by the low protein diet was
      attributed to a reduction in intestinal calcium absorption (as assessed by dual
      stable calcium isotopes). The long-term consequences of these low protein-induced
      changes in calcium metabolism are not known, but they could be detrimental to
      skeletal health. Several recent epidemiological studies demonstrate reduced bone
      density and increased rates of bone loss in individuals habitually consuming low
      protein diets. Therefore, studies are needed to determine whether low protein
      intakes directly affect rates of bone resorption, bone formation or both.

PMID- 12612170
TI  - Dietary animal and plant protein and human bone health: a whole foods approach.
AB  - Urinary calcium excretion is strongly related to net renal acid excretion. The
      catabolism of dietary protein generates ammonium ion and sulfates from sulfur
      containing amino acids. Bone citrate and carbonate are mobilized to neutralize
      these acids, so urinary calcium increases when dietary protein increases. Common
      plant proteins such as soy, corn, wheat and rice have similar total S per g of
      protein as eggs, milk and muscle from meat, poultry and fish. Therefore
      increasing intake of purified proteins from either animal or plant sources
      similarly increases urinary calcium. The effects of a protein on urinary calcium
      and bone metabolism are modified by other nutrients found in that protein food
      source. For example, the high amount of calcium in milk compensates for urinary
      calcium losses generated by milk protein. Similarly, the high potassium levels of
      plant protein foods, such as legumes and grains, will decrease urinary calcium.
      The hypocalciuric effect of the high phosphate associated with the amino acids of
      meat at least partially offsets the hypercalciuric effect of the protein. Other
      food and dietary constituents such as vitamin D, isoflavones in soy, caffeine and
      added salt also have effects on bone health. Many of these other components are
      considered in the potential renal acid load of a food or diet, which predicts its
      effect on urinary acid and thus calcium. "Excess" dietary protein from either
      animal or plant proteins may be detrimental to bone health, but its effect will
      be modified by other nutrients in the food and total diet.

PMID- 12612171
TI  - Is the interaction between dietary protein and calcium destructive or
      constructive for bone?

PMID- 12612172
TI  - Biomarkers of nutritional exposure and nutritional status: an overview.

PMID- 12612174
TI  - Methodologic and statistical considerations regarding use of biomarkers of
      nutritional exposure in epidemiology.
AB  - In nutritional epidemiology, accurate quantification of nutritional exposure is
      critical. Even moderate flaws in measurement can lead to sizeable distortions in
      estimations of the effects of exposure. In many situations, this will lead to
      inaccurate direct estimation of exposure effects. In others, it will make it
      difficult to control for the confounding effects of nutritional exposure.
      Biomarkers offer important opportunities to advance research in nutritional
      epidemiology; their objectivity and potentially greater accuracy give them the
      potential to substantially lessen distortions that might result from imperfect
      measurements. Clearly, the accuracy of biomarkers as indicators of nutritional
      exposure is critical to their value. It is likely that establishing the accuracy
      of biomarkers will require some reference to self-reports, even if those reports
      are not as accurate as the biomarkers they are used to test. The goal of this
      paper is to describe aspects of accuracy-reproducibility, reliability and
      validity-as they apply to biomarkers in nutritional epidemiology.

PMID- 12612173
TI  - Biologic and methodologic issues for nutritional biomarkers.
AB  - Nutritional biomarkers are used for a variety of purposes in large-scale
      population surveys and epidemiologic studies as well as smaller clinical studies.
      The main reasons for using nutritional biomarkers are to provide measures of
      nutritional status that have less error than dietary data, nutrient status for
      nutrients with inadequate dietary data, to obtain a more proximal and integrated
      assessment of nutrient status that incorporates metabolism, to assess dietary
      change and compliance in intervention studies, and dietary intake for the
      validation of dietary questionnaires. However, often there is oversight by the
      investigators regarding biologic and laboratory issues, which have implications
      for the utility of nutritional biomarkers. This article reviews some of the
      physiologic issues that contribute to between-person variability in nutrient
      status and the utility and meaning of specimens from various body compartments.
      Issues related to the collection and storage of biologic specimens are addressed,
      although it is recommended that investigators contact laboratory colleagues at
      the beginning of any study for updated information. The necessity for blind
      quality surveillance of laboratory analyses beyond the normal procedures employed
      by collaborating laboratories also is addressed. The advantages and disadvantages
      of nutritional biomarkers are reviewed, especially in comparison with using
      dietary methodology.

PMID- 12612175
TI  - Laboratory issues: use of nutritional biomarkers.
AB  - Biomarkers of nutritional status provide alternative measures of dietary intake.
      Like the error and variation associated with dietary intake measures, the
      magnitude and impact of both biological (preanalytical) and laboratory
      (analytical) variability need to be considered when one is using biomarkers. When
      choosing a biomarker, it is important to understand how it relates to nutritional
      intake and the specific time frame of exposure it reflects as well as how it is
      affected by sampling and laboratory procedures. Biological sources of variation
      that arise from genetic and disease states of an individual affect biomarkers,
      but they are also affected by nonbiological sources of variation arising from
      specimen collection and storage, seasonality, time of day, contamination,
      stability and laboratory quality assurance. When choosing a laboratory for
      biomarker assessment, researchers should try to make sure random and systematic
      error is minimized by inclusion of certain techniques such as blinding of
      laboratory staff to disease status and including external pooled standards to
      which laboratory staff are blinded. In addition analytic quality control should
      be ensured by use of internal standards or certified materials over the entire
      range of possible values to control method accuracy. One must consider the effect
      of random laboratory error on measurement precision and also understand the
      method's limit of detection and the laboratory cutpoints. Choosing appropriate
      cutpoints and reducing error is extremely important in nutritional epidemiology
      where weak associations are frequent. As part of this review, serum lipids are
      included as an example of a biomarker whereby collaborative efforts have been put
      forth to both understand biological sources of variation and standardize
      laboratory results.

PMID- 12612176
TI  - Markers of the validity of reported energy intake.
AB  - Energy intake (EI) is the foundation of the diet, because all other nutrients
      must be provided within the quantity of food needed to fulfill the energy
      requirement. Thus if total EI is underestimated, it is probable that the intakes
      of other nutrients are also underestimated. Under conditions of weight stability,
      EI equals energy expenditure (EE). Because at the group level weight may be
      regarded as stable in the timescale of a dietary assessment, the validity of
      reported EI can be evaluated by comparing it with either measured EE or an
      estimate of the energy requirement of the population. This paper provides the
      first comprehensive review of studies in which EI was reported and EE was
      measured using the doubly labeled water technique. These conclusively demonstrate
      widespread bias to the underestimation of EI. Because energy requirements of
      populations or individuals can be conveniently expressed as multiples of the
      basal metabolic rate (BMR), EE:BMR, reported EI may also be expressed as EI:BMR
      for comparison. Values of EI:BMR falling below the 95% confidence limit of
      agreement between these two measures signify the presence of underreporting. A
      formula for calculating the lower 95% confidence limit was proposed by Goldberg
      et al. (the Goldberg cutoff). It has been used by numerous authors to identify
      individual underreporters in different dietary databases to explore the variables
      associated with underreporting. These studies are also comprehensively reviewed.
      They explore the characteristics of underreporters and the biases in estimating
      nutrient intake and in describing meal patterns associated with underreporting.
      This review also examines some of the problems for the interpretation of data
      introduced by underreporting and particularly by variable underreporting across
      subjects. Future directions for research are identified.

PMID- 12612177
TI  - Urine nitrogen as a biomarker for the validation of dietary protein intake.
AB  - When validated for completeness, 24-h urine nitrogen obtained from repeated 24-h
      urine collections has provided useful insights into the validity of dietary
      assessments, underreporting behaviors and the structure of measurement errors
      that are associated with different methods. This is particularly so when nitrogen
      is combined with another marker in 24-h urine samples, potassium. Although the
      collection of 24-h urine is a tedious procedure, the method is readily accessible
      and comparatively inexpensive. Other markers of dietary intake and intermediate
      risk markers may also be measured in the 24-h urine that is obtained.

PMID- 12612178
TI  - Biomarkers of fat and fatty acid intake.
AB  - Unlike other macronutrients such as protein, the amounts and types of fat in the
      human diet vary tremendously across cultures and over time have changed
      significantly within Westernized countries. Studies of the effect that fat
      sources, fat amounts and changes in fat intake have on human disease are
      extremely difficult to conduct with traditional dietary assessment methods for a
      number of reasons. These include the hidden nature of many fats, the variation in
      fatty acids contained in foods and feed and the sensitivity of individuals to
      questions about fat intake in their diets. For these reasons biomarkers of fat
      intake are particularly desirable. Fat and fat-soluble substances have the
      advantages over other nutrients of a long half-life and readily accessible
      storage depots (in the absence of starvation, undernutrition or eating
      disorders). Technological advances in quantitative measurements of individual
      fatty acids, with the help of gas chromatography and mass spectrometry
      (GCMS)((3)) and high performance liquid chromatography (HPLC), made possible the
      study of specific isomers of minor fatty acids from small tissue samples.
      Technological advances also opened the gateways to the study of fats that
      represent less than 1% of the total fat profiles, such as decosahexanoic acid
      (DHA), eicosapentanoic acid (EPA) and conjugated linoleic acid (CLA). Biological
      advances enhanced our appreciation of the differences between fats of differing
      chain lengths within a family, including the saturated fats. Challenges remain,
      such as assessing total fat intake, discriminating the contribution of
      endogenously produced fats, determining how to evaluate the importance of
      relative versus absolute contributions of fat and accounting for the factors that
      influence deposition and mobilization of individual fats within and between
      individuals. Factors that can influence deposition and mobilization include
      genetic variation, disease status, lifestyle differences (i.e., alcohol
      consumption and smoking), circulating apolipoprotein levels and the hormonal
      milieu of the individual and the source tissue.

PMID- 12612179
TI  - Antioxidant nutrients and chronic disease: use of biomarkers of exposure and
      oxidative stress status in epidemiologic research.
AB  - Oxidation of lipid, nucleic acids or protein has been suggested to be involved in
      the etiology of several chronic diseases including cancer, cardiovascular
      disease, cataract, age-related macular degeneration and aging in general. A large
      body of research has investigated the potential role of antioxidant nutrients in
      the prevention of these and other chronic diseases. This review concentrates on
      the following antioxidant nutrients: beta-carotene and other carotenoids, vitamin
      E, vitamin C and selenium. The first part of the review emphasizes the utility of
      biological markers of exposure for these nutrients and the relationship to
      dietary intake data. The second part considers functional assays of oxidative
      stress status in humans including the strengths and limitations of various assays
      available for use in epidemiologic research. A wide variety of functional assays
      both in vivo and ex vivo, are covered, including various measures of lipid
      oxidation (thiobarbituric acid reactive substances, exhaled pentane/ethane, low
      density lipoprotein resistance to oxidation, isoprostanes), DNA oxidation
      (oxidized DNA bases such as 8-OHdG, autoantibodies to oxidized DNA, modified
      Comet assay) and protein oxidation (protein carbonyls). Studies that have
      examined the effects of antioxidant nutrients on these functional markers are
      included for illustrative purposes. The review concludes with a discussion of
      methodologic issues and challenges for studies involving biomarkers of exposure
      to antioxidant nutrients and of oxidative stress status.

PMID- 12612180
TI  - Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism.
AB  - One-carbon metabolism is a network of interrelated biochemical reactions that
      involve the transfer of one-carbon groups from one compound to another. The
      coenzymes necessary for several of these reactions include the B-vitamins,
      folate, vitamin B-12, vitamin B-6 and riboflavin (vitamin B-2), whereas important
      intermediary compounds in this schema include methionine and choline. There has
      been renewed interest in one-carbon metabolism during the past several years,
      engendered by recent insights that indicate that modest dietary inadequacies of
      the abovementioned nutrients, of a degree insufficient to cause classical
      deficiency syndromes, can still contribute to important diseases such as neural
      tube defects, cardiovascular disease and cancer. Traditional means of assessing
      nutrient exposure with food frequency questionnaires, and nutrient status with
      plasma and urine vitamin assays, has some genuine validity and utility. Assessing
      the concentration of appropriate intermediary compounds, such as plasma
      homocysteine for folate and methylmalonic acid for vitamin B-12, provides further
      insights because they appear to add a degree of sensitivity that does not exist
      with the more traditional assays. There may also be value in developing measures
      that integrate the status of all these nutrients and express it as a functional
      "methylation capacity" of the individual. Plasma or tissue concentrations of S
      adenosylmethionine and S-adenosylhomocysteine, and genomic DNA methylation are
      two potential candidates in this regard although much work is yet to be done to
      define the nature of these relationships.

PMID- 12612181
TI  - Biomarkers of trace mineral intake and status.
AB  - The emerging public health importance of zinc and selenium and the continuing
      public health challenges of iron and iodine draw attention to the unmet need for
      improved biomarkers of trace element status. Currently available biomarkers of
      these four trace elements are critiqued including the outstanding lack of
      satisfactory biomarkers for the assessment of zinc intake and status. Other trace
      elements are reviewed briefly including copper, for which human dietary
      deficiencies and excesses have been documented, and chromium, which is of
      possible but unconfirmed public health significance. Evolving strategies of
      considerable potential include molecular techniques such as the measurement of
      metallothionein mRNA in lymphocytes as a biomarker of zinc status, an assay that
      can now be performed with a dried blood spot. The judicious application of tracer
      techniques also has a role in advancing the quality of zinc biomarkers. Also of
      special current interest is full definition of the potential of plasma-soluble
      transferrin receptor concentrations as the biomarker of choice for the detection
      of early functional iron deficiency.

PMID- 12612182
TI  - Isoflavonoid and lignan phytoestrogens as dietary biomarkers.
AB  - Isoflavones and lignans are biologically active plant-food constituents that have
      potential chemopreventive properties. Quantitation of isoflavones and lignans in
      humans is necessary to establish the benefits and risks of exposure to these
      compounds in populations and to determine which components of a mixed diet
      contribute to the exposure. Isoflavones and lignans are metabolized by colonic
      bacteria to more biologically active metabolites; thus both the parent compounds
      and the metabolites are measured routinely. Isoflavonoids (genistein, daidzein,
      dihydrodaidzein, O-desmethylangolensin and equol) and lignans (enterolactone,
      enterodiol, matairesinol and secoisolariciresinol) can be quantified in various
      body fluids. Typically, high concentrations of isoflavonoids in urine and serum
      are associated with soy consumption, and high concentrations of lignans are
      associated primarily with intake of whole grains and other fiber-containing plant
      foods. Controlled feeding studies and nutritional epidemiologic studies
      demonstrate a linear dose response between dietary intake and urinary excretion
      of isoflavones. Lignan excretion is associated positively with dietary fiber
      intake as well as with diets that are on average higher in fiber and carbohydrate
      and lower in fat; thus lignans have also been proposed as a marker of healthier
      dietary patterns. The complex interactions between the colonic environment and
      the external and internal factors that modulate it contribute to significant
      variation in serum and urinary phytoestrogen levels among individuals.
      Understanding these sources of variation is important to be able to use these
      measures effectively as dietary biomarkers.

PMID- 12612183
TI  - Food mutagens.
AB  - Several lines of evidence indicate that diet and dietary behaviors can contribute
      to human cancer risk. One way that this occurs is through the ingestion of food
      mutagens. Sporadic cancers result from a gene-environment interactions where the
      environment includes endogenous and exogenous exposures. In this article, we
      define environment as dietary exposures in the context of gene-environment
      interactions. Food mutagens cause different types of DNA damage: nucleotide
      alterations and gross chromosomal aberrations. Most mutagens begin their action
      at the DNA level by forming carcinogen-DNA adducts, which result from the
      covalent binding of a carcinogen or part of a carcinogen to a nucleotide. However
      the effect of food mutagens in carcinogenesis can be modified by heritable
      traits, namely, low-penetrant genes that affect mutagen exposure of DNA through
      metabolic activation and detoxification or cellular responses to DNA damage
      through DNA repair mechanisms or cell death. There are some clearly identified
      (e.g., aflatoxin) and suspected (e.g., N-nitrosamines, polycyclic aromatic
      hydrocarbons or heterocyclic amines) food mutagens. The target organs for these
      agents are numerous, but there is target-organ specificity for each. Mutagenesis
      however is not the only pathway that links dietary exposures and cancers. There
      is growing evidence that epigenetic factors, including changes in the DNA
      methylation pattern, are causing cancer and can be modified by dietary
      components. Also DNA damage may be indirect by triggering oxidative DNA damage.
      When considering the human diet, it should be recognized that foods contain both
      mutagens and components that decrease cancer risk such as antioxidants. Thus
      nutritionally related cancers ultimately develop from an imbalance of
      carcinogenesis and anticarcinogenesis. The best way to assess nutritional risks
      is through biomarkers, but there is no single biomarker that has been
      sufficiently validated. Although panels of biomarkers would be the most
      appropriate, their use as a reflection of target-organ risk remains to be
      determined. Also even when new biomarkers are developed, their application in
      target organs is problematic because tissues are not readily available. For now
      most biomarkers are used in surrogate tissues (e.g., blood, urine, oral cavity
      cells) that presumably reflect biological effects in target organs. This article
      reviews the role of food mutagens in mutagenesis and carcinogenesis and how their
      effects are modified by heritable traits and discusses how to identify and
      evaluate the effects of food mutagens.

PMID- 12612184
TI  - Diagnosis and management of sexually transmitted disease pathogens among
      adolescents.

PMID- 12612185
TI  - Coagulation disorders.

PMID- 12612186
TI  - Diagnosis and treatment of ADHD in school-age children in primary care settings:
      a synopsis of the AAP Practice Guidelines. American Academy of Pediatrics.

PMID- 12612187
TI  - Index of suspicion.

PMID- 12612188
TI  - Question from the clinician: back to sleep.

PMID- 12612189
TI  - Atlantoaxial dislocation.

PMID- 12612190
TI  - Cerebral energy metabolism in phenylketonuria: findings by quantitative In vivo
      31P MR spectroscopy.
AB  - Both severe impairments of brain development in untreated infants and acute
      reversible neurotoxic effects on brain function are clinical features of
      phenylketonuria (PKU). For determining whether impairments of cerebral energy
      metabolism play a role in the pathophysiology of PKU, quantitative in vivo 31P
      magnetic resonance spectroscopy (MRS) was performed in a supratentorial voxel of
      11 adult PKU patients and controls. Peak areas of inorganic phosphate;
      phosphocreatine; alpha-, beta-, and gamma-ATP; NAD; phosphomonoesters;
      phosphodiesters; and a broad phospholipid signal were converted to millimolar
      concentrations. Mg2+, pH, ADP, the phosphorylation potential, and the relative
      velocity of oxidative metabolism V/Vmax were derived. Clinical evaluation
      included mutation analysis, neurologic investigation, intelligence testing,
      magnetic resonance imaging, and concurrent plasma and brain phenylalanine (Phe),
      the last by 1H-MRS. Phe loading was performed in five patients with an oral dose
      of 100 mg/kg body wt L-Phe monitored by spectral EEG analysis. Under steady-state
      conditions, 31P-MRS revealed normal values for ATP, phosphocreatine, NAD,
      phosphomonoesters, phosphodiesters, Mg2+, and pH in PKU. ADP (+11%) and the
      phosphorylation potential (+22%) were increased. Peak areas of inorganic
      phosphate (-22%) and phospholipid (-8%) were decreased. ADP correlated with
      concurrent plasma (r = 0.65) and brain (r = 0.55) Phe. During the Phe load, blood
      Phe levels increased steeply. EEG revealed slowing of background activity. The
      phosphorylation potential decreased, whereas ADP and V/Vmax increased. In vivo
      31P-MRS demonstrated subtle abnormalities of cerebral energy metabolism in PKU in
      steady-state conditions that were accentuated by a Phe load, indicating a link
      between Phe neurotoxicity and imbalances of cerebral energy metabolism.

PMID- 12612191
TI  - No correlation between cerebral palsy and cytokines in postnatal blood of
      preterms.

PMID- 12612192
TI  - Neonatal cytokines and cerebral palsy in very preterm infants.
AB  - To examine the relationship of cytokines in blood of very preterm neonates with
      later diagnosis of spastic cerebral palsy (CP) compared with infants of similar
      gestational age without CP, we measured concentrations of inflammatory cytokines
      and other substances in archived neonatal blood by recycling immunoaffinity
      chromatography. Subjects were surviving children born before 32 wk gestational
      age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107
      control children. The initial analyses were augmented by measurement of 11
      cytokines by a bead-based flow analytic system (Luminex) in an additional 37
      children with CP and 34 control children from the same cohort. Concentrations of
      examined substances did not differ by presence of indicators of infection in
      mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines
      were significantly related to neonatal ultrasound abnormalities (periventricular
      leukomalacia, ventricular enlargement, or moderate or severe germinal matrix
      hemorrhage). None of the substances measured either by immunoaffinity
      chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor
      necrosis factor-alpha, was related to later diagnosis of CP or its subtypes.
      Inflammatory cytokines in neonatal blood of very premature infants did not
      distinguish those with later diagnoses of CP from control children.

PMID- 12612193
TI  - Developmental expression of NCS-1 (frequenin), a regulator of Kv4 K+ channels, in
      mouse heart.
AB  - The channel proteins responsible for the cardiac transient outward K+ current
      (Ito) of human and rodent heart are composed, in part, of pore-forming Kv4.3 or
      Kv4.2 principal subunits. Recent reports implicate K+ channel interacting
      proteins (members of the neuronal Ca2+-binding protein family) as subunits of the
      Ito channel complex. We reported that another Ca2+-binding protein, frequenin [or
      neuronal calcium center protein-1 (NCS-1)], also functions as a Kv4 auxiliary
      subunit in the brain. By examining cardiac expression of NCS-1, the aim of this
      study was to examine the potential physiologic relevance of this protein as an
      additional regulator of cardiac Ito. Immunoblot analysis demonstrates NCS-1
      protein to be expressed in adult mouse ventricle at levels comparable to that
      found in some brain regions. Cardiac NCS-1 protein expression levels are much
      higher in fetal and neonatal mouse hearts when compared with the adult.
      Immunocytochemical analysis of isolated neonatal mouse ventricular myocytes
      demonstrates co-localization of NCS-1 and Kv4.2 proteins at the sarcolemma. Given
      its high levels of expression in the heart, NCS-1 should be considered an
      important potential Kv4 regulatory subunit, particularly in the immature heart.

PMID- 12612194
TI  - Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human
      normal and cystic fibrosis airway epithelia.
AB  - Human airway epithelia express Ca2+-activated Cl- channels (CaCC) that are
      activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems
      to be up-regulated in the airways of cystic fibrosis (CF) patients. In the
      present study, we examined the role of basolateral K+ channels in CaCC-mediated
      Cl- secretion in native nasal tissues from normal individuals and CF patients by
      measuring ion transport in perfused micro Ussing chambers. In the presence of
      amiloride, UTP-mediated peak secretory responses were increased in CF compared
      with normal nasal tissues. Activation of the cAMP pathway further increased CaCC
      mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion
      transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated
      hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+
      channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased
      CaCC-mediated Cl- secretion in normal and CF tissues. Expression of hSK4 as well
      as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase
      PCR on native nasal tissues. We conclude that Ca2+-activated Cl- secretion in
      native human airway epithelia requires activation of Ca2+-dependent basolateral
      K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion
      in native CF airway epithelia, and may have a therapeutic effect in the treatment
      of CF lung disease.

PMID- 12612195
TI  - Neonatal skin in mice and humans expresses increased levels of antimicrobial
      peptides: innate immunity during development of the adaptive response.
AB  - The expression of antimicrobial peptides and proteins is an important innate
      immune defense mechanism that has recently been shown to be essential for
      cutaneous defense against invasive bacterial disease. Newborns have an immature
      cellular immune defense system that leads to increased susceptibility to
      infections. Here we show that skin from embryonic and newborn mice, as well as
      human newborn foreskin, express antimicrobial peptides of the cathelicidin and
      beta-defensin gene families. Immunohistochemistry and in situ hybridization
      demonstrated abundant cathelicidin protein and mRNA is present in normal skin
      during the perinatal period. Quantitative real-time PCR showed mouse cathelicidin
      expression (CRAMP) is 10- to 100-fold greater in the perinatal period than adult.
      Murine beta-defensins-1 and -4 and human beta-defensin-2 were also present in
      newborn skin. Combined, human cathelicidin (LL-37/hCAP/18) and beta-defensin-2
      demonstrated synergistic antimicrobial activity and efficiently killed group B
      Streptococcus, an important neonatal pathogen. Antimicrobial peptides may
      therefore provide a compensatory innate defense mechanism during development of
      cellular immune response mechanisms in the newborn period.

PMID- 12612196
TI  - Pulse transit time as a measure of arousal and respiratory effort in children
      with sleep-disordered breathing.
AB  - The upper airway resistance syndrome (UARS) is associated with neurobehavioral
      morbidity in children. The diagnostic gold standard for UARS is esophageal
      manometry. However, this is invasive. Furthermore, upper airway obstructive
      events in sleeping children frequently terminate without visible electrocortical
      (EEG) arousal. The pulse transit time (PTT) is a noninvasive marker of blood
      pressure and, therefore, subcortical arousal. Blood pressure elevation,
      associated with respiratory arousal from sleep, results in a drop in the PTT. We
      hypothesized that: 1) the PTT is a more sensitive measure of respiratory arousal
      than EEG; and 2) the PTT arousal index can distinguish children with UARS from
      those with primary snoring. Polysomnography, including esophageal manometry and
      PTT, was measured prospectively in 24 symptomatic children and 10 normal
      controls. Apnea, hypopnea, and respiratory effort-related arousal events
      terminated in a PTT arousal 91%, 83%, and 80% of the time, and in an EEG arousal
      in 55%, 51%, and 43% (all p < 0.05), respectively. The PTT arousal index was
      significantly greater in children with UARS (6.8 events/h) than primary snoring
      (2.2 events/h) (p < 0.05). We conclude that, in children, PTT arousals are a more
      sensitive measure of obstructive events than visible EEG arousals.

PMID- 12612197
TI  - The development of pediatric gastroenterology: a historical overview.

PMID- 12612198
TI  - Total energy expenditure and physical activity in children treated with home
      parenteral nutrition.
AB  - Determining total energy expenditure (TEE) and its components in children treated
      with home parenteral nutrition (CHPN) under free-living conditions is an
      important consideration in the assessment of energy requirements and the
      maintenance of health. The aim of this study was to assess TEE and physical
      activity in CHPN. Eleven CHPN (three girls and eight boys; median age, 6.0 y;
      range, 4.5-15.0 y) were compared with 11 healthy children (three girls and eight
      boys; median age, 6.0 y, range, 4.5-14.0 y) after pairing for sex, age, and
      weight. Underlying diseases included chronic intractable diarrhea (n = 5), short
      bowel syndrome (n = 3), and intestinal dysmotility (n = 3). None of these
      children had inflammatory disease or recent infection when studied. Fat-free mass
      (FFM), measured by body impedance analysis, fat mass (FM), measured by skinfold
      thickness, and energy intake were similar between the two groups, suggesting that
      CHPN had normal body composition and energy intake. Resting energy expenditure
      (REE), measured by indirect calorimetry, and TEE, assessed by a technique using
      24-h heart-rate monitoring calibrated against indirect calorimetry and physical
      activity using a triaxial accelerometer, were simultaneously recorded and were
      also similar in the two groups. Sleeping energy expenditure (SEE), expressed per
      kilogram of FFM, was significantly greater in the CHPN group (median, 0.15;
      range, 0.10-0.23 kJ/min/kg FFM versus median, 0.12; range, 0.09-0.21 kJ/min/kg
      FFM for controls; p < 0.05, Wilcoxon rank test). These findings were explained by
      the high correlation between the energy flow infused by parenteral nutrition and
      sleeping energy expenditure (p < 0.05, Spearman test) and also-diet induced
      thermogenesis (p < 0.05 Spearman test). These results suggest that the energy
      requirements of children on long-term home parenteral nutrition programs do not
      differ from controls and that cyclic parenteral nutrition does not interfere with
      physical activity.

PMID- 12612199
TI  - Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in acute
      pyelonephritis and renal scarring.
AB  - The aim of the present study was to elucidate the role of matrix
      metalloproteinase-9 (MMP-9), and its main inhibitor tissue inhibitor of
      metalloproteinases-1 (TIMP-1), in acute pyelonephritis and the process of renal
      scarring. Urine samples from 40 children with acute pyelonephritis, 16 children
      at 6-wk follow-up and 15 children with nonrenal fever were analyzed using ELISA.
      MMP-9 and TIMP-1 levels were compared with the outcome of pyelonephritis as
      measured by renal static scintigraphy. A mouse model of acute ascending
      pyelonephritis was used to localize the sites of production and the kinetics of
      MMP-9 and TIMP-1 using immunohistochemistry and ELISA. Human renal epithelial
      A498 cells, primary mesangial cells and monocytic THP-1 cells were stimulated by
      Escherichia coli. MMP-9 and TIMP-1 mRNA was analyzed by reverse transcription-PCR
      (RT-PCR) and protein production by ELISA. We demonstrate a significant increase
      of MMP-9 and TIMP-1 in the urine of children with acute pyelonephritis. Both
      proteins were produced mainly by leukocytes, and TIMP-1 also by resident kidney
      cells. Cells reacted differently after stimulation by bacteria. In mesangial
      cells and monocytes a decreased constitutive TIMP-1 production was found, which
      was in contrast to epithelial cells. Out of 40 children with pyelonephritis, 23
      had higher urinary TIMP-1 than MMP-9 levels. These children had significantly
      more severe changes in both acute and follow-up scintigraphy scans indicating
      higher degree of acute tissue damage and renal scarring. Thus, our findings
      suggest an association between TIMP-1 and the process of renal scarring.

PMID- 12612200
TI  - Airway smooth muscle changes in the nitrofen-induced congenital diaphragmatic
      hernia rat model.
AB  - In the fetal rat, nitrofen induces congenital diaphragmatic hernia (CDH) and
      pulmonary vascular remodeling similar to what is observed in the human condition.
      Airway hyperactivity is common in infants with CDH and attributed to the
      ventilator-induced airway damage. The purpose of this study was to test the
      hypothesis that airway smooth muscle mechanical properties are altered in the
      nitrofen-induced CDH rat model. Lungs from nitrofen-exposed fetuses with hernias
      (CDH) or intact diaphragm (nitrofen) and untreated fetuses (control) were studied
      on gestation d 21. The left intrapulmonary artery and bronchi were removed and
      mounted on a wire myograph, and lung expression, content, and immunolocalization
      of cyclooxygenases COX-1 and COX-2 were evaluated. Pulmonary artery muscle in the
      CDH group had significantly (p < 0.01) lower force generation compared with
      control and nitrofen groups. In contrast, the same generation bronchial smooth
      muscle of the CDH and nitrofen groups developed higher force compared with
      control. Whereas no differences were found in endothelium-dependent pulmonary
      vascular muscle tone, the epithelium-dependent airway muscle relaxation was
      significantly decreased (p < 0.01) in the CDH and nitrofen groups. The lung mRNA
      levels of COX-1 and COX-2 were increased in the CDH and nitrofen groups. COX-1
      vascular and airway immunostaining, as well as COX-1 and COX-2 lung protein
      content, were increased in the CDH group. This is the first report of airway
      smooth muscle abnormalities in the nitrofen-induced fetal rat model of CDH. We
      speculate that congenital airway muscle changes may be present in the human form
      of this disease.

PMID- 12612201
TI  - Kinematic quality of reaching movements in preterm infants.
AB  - Many preterm infants may experience so-called minor developmental disorders;
      however, in general, the problems in motor behavior are not detected until school
      age. To introduce therapies aimed at the prevention of these problems, we need to
      increase our knowledge of motor function and dysfunction at early age. The
      present study focused on the organization of reaching movements in full-term and
      preterm infants without cerebral palsy. The reaching behavior of premature
      infants (n = 63) was assessed longitudinally at the corrected ages of 4 and 6 mo.
      Clinical assessments were made at 6 and 12 mo of age. On the basis of the
      infant's morbidity during the early stay in the neonatal intensive care unit, the
      preterm infants were allocated into a high-risk and a low-risk group. Results
      from a previous study in full-term infants (n = 13) were included. Kinematics of
      reaching movements in supine position were measured, and the analysis focused on
      movement velocity and movement units. A compound parameter of kinematic variables
      was created, reflecting the quality of reaching movements. The present study
      showed that at the age of 4 mo, low-risk preterm infants showed more often
      optimal reaching behavior than full-term and preterm high-risk infants. This
      better reaching performance was related to a better general motor and behavioral
      development during the first year of life. At the age of 6 mo, the advantage of
      the low-risk group in reaching behavior had disappeared and a disadvantage in the
      form of nonoptimal reaching behavior of the high-risk group emerged.

PMID- 12612202
TI  - Neonatal blood carnitine concentrations: normative data by electrospray tandem
      mass spectometry.
AB  - Despite a number of published reports, there is limited information about
      carnitine metabolism in the newborn. To establish normative data, we analyzed
      whole-blood carnitine concentrations in 24,644 newborns at age 1.85 +/- 0.95 d
      and umbilical cord whole blood and plasma carnitine concentrations in 50 full
      term newborns. Total carnitine (TC), free carnitine (FC), and acylcarnitine (AC)
      were measured by electrospray tandem mass spectrometry. AC/FC ratios were derived
      from these measurements. The entire cohort was stratified according to TC values
      into a middle TC group representing 90% of the population and lower and upper TC
      groups representing 5% of the population, respectively. Normative data were
      derived from the middle TC group of full-term infants (N = 19,595). TC was 72.42
      +/- 20.75 microM, FC was 44.94 +/- 14.99 microM, AC was 27.48 +/- 8.05 microM,
      and AC/FC ratio was 0.64 +/- 0.19 (+/-SD). These values differed significantly
      from umbilical cord whole blood TC values of 31.27 +/- 10.54 microM determined in
      50 samples. No meaningful correlation was found between TC and gestational age or
      birth weight in any group. In controlled analyses, prematurity was not associated
      with TC levels, whereas low birth weight (<2500 g) and male sex were
      significantly associated with higher TC levels. The association of low birth
      weight with higher TC values may be related to decreased tissue carnitine uptake.
      The sex effect may be related to hormonal influences on carnitine metabolism. Our
      study provides normative data of carnitine values measured by the highly precise
      method of electrospray tandem mass spectrometry in a large cohort of newborns and
      provides the basis for future studies of carnitine metabolism in health and
      disease states during the neonatal period.

PMID- 12612203
TI  - Early childhood determinants of organochlorine concentrations in school-aged
      children.

PMID- 12612204
TI  - Breast milk fatty acids, eicosanoids, and cytokines in mothers with and without
      allergic disease.
AB  - Allergic disease (AD), including atopic eczema, asthma, allergic rhinitis, and
      food allergy, is characterized by an imbalance between cytokines produced by
      distinct T-helper cell subtypes. Whether this imbalance can be transferred from
      mother to breast milk remains to be established. The objective was to investigate
      the concentrations and interactions of nutritional and inflammatory factors in
      breast milk. Breast milk samples were collected from mothers with AD (n = 43) and
      without AD (n = 51). The concentrations of transforming growth factor (TGF)
      beta2, tumor necrosis factor-alpha, IL-4, IL-10, prostaglandin E2, and cysteinyl
      leukotrienes were measured by immunoassays and fatty acid composition by gas
      chromatography. Mothers with AD had a lower concentration of TGF-beta2 in breast
      milk [median (interquartile range), 420 (278-701) ng/L] compared with those
      without AD [539 (378-1108) ng/L; p = 0.003], whereas other cytokines,
      prostaglandin E2, and cysteinyl leukotriene concentrations or fatty acid
      composition were not significantly different between the groups. The breast milk
      inflammatory factors and fatty acid composition were shown to be related. A
      positive association was observed between TGF-beta2 and the proportion of
      polyunsaturated fatty acids (p = 0.038) and a negative association between TGF
      beta2 and the proportion of saturated fatty acids (p = 0.029) in breast milk. The
      reduced TGF-beta2 concentration in the breast milk of mothers with AD may
      interfere with the development of the mucosal immune system of the breast-fed
      infant. The observed associations between nutritional and inflammatory factors in
      breast milk suggest that it may be possible to influence the immunologic
      properties of breast milk by dietary intervention of the mother.

PMID- 12612206
TI  - Bronchoalveolar lavage surfactant protein a, B, and d concentrations in preterm
      infants ventilated for respiratory distress syndrome receiving natural and
      synthetic surfactants.
AB  - Surfactant proteins (SPs) play an important role in surfactant metabolism and
      function. Understanding their relative contribution to clinical outcome remains
      incomplete. Exogenous surfactants differ in their SP content and physiologic
      effects. The aims of this study were to measure bronchoalveolar lavage (BAL) SP
      concentrations from preterm infants ventilated for respiratory distress syndrome
      and to assess their association with clinical outcome. Fifty preterm infants
      randomized to receive a natural or synthetic surfactant were lavaged each day for
      the first week and twice weekly thereafter using a standardized nonbronchoscopic
      technique. BAL SP-A, SP-B, and SP-D concentrations were measured using ELISA.
      Median BAL SP-A, SP-B, and SP-D concentrations for the whole cohort rose
      significantly during the first postnatal week (p < 0.05). SP-A concentration did
      not differ between outcome groups. BAL SP-B concentration rose significantly in
      lungs that were not supplemented with SP-B. Infants dying had significantly lower
      BAL SP-B concentrations on d 2 and 6 compared with survivors. BAL SP-D
      concentrations were significantly lower on d 2 and 3 among infants in
      supplemental oxygen on d 28 compared with those in air. BAL SP-A and SP-D
      concentrations did not differ significantly between infants randomized to receive
      a natural or synthetic surfactant. Lower BAL SP-B and SP-D but not SP-A
      concentrations were associated with worse clinical prognosis.

PMID- 12612207
TI  - Effects of dietary sphingomyelin on central nervous system myelination in
      developing rats.
AB  - Human milk contains sphingomyelin (SM) as a major component of the phospholipid
      fraction. Galactosylceramide (cerebroside), a metabolite of sphingolipids,
      increases along with CNS myelination, and is generally considered a universal
      marker of myelination in all vertebrates. l-Cycloserine (LCS) is an inhibitor of
      serine palmitoyltransferase (SPT), a rate-limiting enzyme for sphingolipid
      biosynthesis that is reported to show increased activity with development of the
      rat CNS. The present study examined the effects of dietary SM on CNS myelination
      during development in LCS-treated rats. From 8 d after birth, Wistar rat pups
      received a daily s.c. injection (100 mg/kg) of LCS. From 17 d after birth, the
      animals were fed an 810 mg/100g of bovine SM-supplemented diet (SM-LCS group) or
      a nonsupplemented diet (LCS group). At 28 d after birth, the animals were killed
      and subjected to biochemical and morphometric analyses. The myelin dry weight,
      myelin total lipid content, and cerebroside content were significantly lower in
      the SM-LCS and LCS groups than in a group not treated with LCS (the non-LCS
      group). However, these levels were significantly higher in the SM-LCS group than
      in the LCS group. Morphometric analysis of the optic nerve revealed that the axon
      diameter, nerve fiber diameter, myelin thickness, and g value (used to compare
      the relative thickness of myelin sheaths around fibers of different diameter)
      were significantly lower in the LCS group than in the other groups, but were
      similar in the SM-LCS and non-LCS groups. These findings suggest that dietary SM
      contributes to CNS myelination in developing rats with experimental inhibition of
      SPT activity corrected].

PMID- 12612208
TI  - Effect of exogenous surfactant on the development of surfactant synthesis in
      premature rabbit lung.
AB  - Surfactant replacement is an effective therapy for neonatal respiratory distress
      syndrome. Full recovery from respiratory distress syndrome requires development
      of endogenous surfactant synthesis and metabolism. The influence of exogenous
      surfactant on the development of surfactant synthesis in premature lungs is not
      known. We hypothesized that different exogenous surfactants have different
      effects on the development of endogenous surfactant production in the premature
      lung. We treated organ cultures of d 25 fetal rabbit lung for 3 d with 100 mg/kg
      body weight of natural rabbit surfactant, Survanta, and Exosurf and measured
      their effects on the development of surfactant synthesis. Additional experiments
      tested how these surfactants and Curosurf affected surfactant protein (SP) SP-A,
      SP-B, and SP-C mRNA expression. Surfactant synthesis was measured as the
      incorporation of 3H-choline and 14C-glycerol into disaturated phosphatidylcholine
      recovered from lamellar bodies. Randomized-block ANOVA showed significant
      differences among treatments for incorporation of both labels (p < 0.01), with
      natural rabbit surfactant less than control, Survanta greater than control, and
      Exosurf unchanged. Additional experiments with natural rabbit surfactant alone
      showed no significant effects in doses up to 1000 mg/kg. Survanta stimulated
      disaturated phosphatidylcholine synthesis (173 +/- 41% of control; p = 0.01),
      increased total lamellar body disaturated phosphatidylcholine by 22% (p < 0.05),
      and increased 14C-disat-PC specific activity by 35% (p < 0.05). The response to
      Survanta was dose-dependent up to 1000 mg/kg. Survanta did not affect surfactant
      release. No surfactant altered the expression of mRNA for SP-A, SP-B, or SP-C. We
      conclude that surfactant replacement therapy can enhance the maturation of
      surfactant synthesis, but this potential benefit differs with different
      surfactant preparations.

PMID- 12612209
TI  - Non-protein-bound transition metals and hydroxyl radical generation in
      cerebrospinal fluid of newborn infants with hypoxic ischemic encephalopathy.
AB  - Among various hypothetical mechanisms for the in vivo production of reactive
      oxygen species, transition metal-catalyzed reactions in cooperation with a
      biologic reducing agent like ascorbic acid or superoxide may be some of the most
      important. In the present study, we retrospectively examined the existence of non
      protein-bound metal ions, an essentially hazardous pro-oxidant form of various
      transition metals, and the occurrence of metal-catalyzed reactive oxygen species
      production in cerebrospinal fluid (CSF) of 10 infants with hypoxic ischemic
      encephalopathy (HIE) subsequent to perinatal asphyxia and 12 control infants
      within 72 h of birth. Non-protein-bound iron was detected in eight out of 10 CSF
      samples from the HIE infants and its level was significantly correlated with
      Sarnat's clinical stage, whereas none of the control infants had detectable non
      protein-bound iron levels. Non-protein-bound copper was below the detection limit
      in all CSF samples from both groups. Ascorbic acid was significantly increased in
      the CSF of HIE infants when compared with that of controls (means, 664.9 versus
      449.4 microM, p = 0.008). ortho-Tyrosine and meta-tyrosine, which are highly
      specific and sensitive markers of protein oxidation induced by hydroxyl radicals,
      were significantly higher in HIE infants than in controls when evaluated by the
      ratio relative to their source amino acid, phenylalanine [means, 110.5 versus
      75.4, p = 0.018 for ortho-tyrosine/phenylalanine; 104.6 versus 67.7 (nM/microM x
      10(2)), p = 0.048 for meta-tyrosine/phenylalanine]. Both ratios were
      significantly correlated with non-protein-bound iron, but not with ascorbic acid.
      Our preliminary observations provide direct evidence that hydroxyl radicals are
      generated in the CNS during asphyxiation. Iron chelation therapy could be worth
      developing as a neuroprotective strategy for perinatal asphyxia.

PMID- 12612210
TI  - Induction of uncoupling protein 3 gene expression in skeletal muscle of preterm
      newborns.
AB  - Prematurity is associated with delayed postnatal activation of mitochondrial
      oxidative phosphorylation and impaired switch from glycolytic to oxidative
      metabolism. Fatty acids (FA), which represent a major energy substrate in mature
      muscle cells, are engaged in the postnatal activation of genes of energy
      metabolism and lipid oxidation. To understand the mechanism activating
      mitochondria in human newborns, expression of the genes for mitochondrial
      uncoupling proteins (UCP) was characterized in autopsy samples of skeletal (n =
      28) and cardiac (n = 13) muscles of preterm neonates, who mostly died during the
      first postnatal month, and two aborted fetuses. Transcripts levels for UCP2,
      UCP3, and also for genes engaged in the transport of FA between cytoplasm and
      mitochondria were measured using real-time reverse transcriptase PCR. In
      accordance with studies in mice, our results document postnatal induction of UCP3
      gene expression in skeletal muscle, involvement of nutritional FA in the
      induction, and a role of UCP3 in mitochondrial FA oxidation. They suggest
      impaired postnatal activation of UCP3 gene in neonates delivered before
      approximately 26 wk of gestation. Mean levels of the UCP3 transcript in skeletal
      muscle were by two orders of magnitude higher than in the heart. In contrast to
      UCP3, the UCP2 gene was active in fetuses, and its expression was not affected by
      nutrition. Our results support a role of UCP3 in postnatal activation of lipid
      oxidation in skeletal muscle and suggest the involvement of UCP3 in the delayed
      activation of mitochondrial energy conversion in very immature preterm neonates.

PMID- 12612211
TI  - Developmental pathways in musculoskeletal neoplasia: involvement of the Indian
      Hedgehog-parathyroid hormone-related protein pathway.
AB  - There are many crucial genes and signaling pathways in the proper development of
      an organism. Pathologies may arise from a deregulation of these pathways. The
      Indian Hedgehog-PTH-related protein (Ihh-PTHrP) pathway is vital in the proper
      development of endochondral bones, such as the long bones. The Ihh-PTHrP pathway
      regulates the rate at which chondrocytes within the growth plate proliferate and
      differentiate. Thus, this pathway allows for the longitudinal growth of bones.
      However, a disruption in this pathway may lead to enchondromas and
      osteochondromas, which are both childhood cartilaginous neoplasms. Recently, our
      lab identified a mutant receptor for PTHrP in enchondroma samples. Mice
      expressing this mutant receptor and mice with increased Ihh activity develop
      conditions similar to human enchondromatosis. Linkage analysis shows an
      association between EXT genes and osteochondromas in hereditary multiple
      exostoses syndrome. Studies in Drosophila and mice suggest EXT gene products play
      a role in the diffusion of hedgehog proteins. A mutation in EXT genes may result
      in an abnormal Ihh diffusion pattern leading to an osteochondroma. There are
      agents that inhibit Hedgehog signaling. These agents may be useful in the
      treatment of enchondromas and osteochondromas. This review will discuss the
      discovery of the Ihh-PTHrP pathway and its involvement in neoplasia, and will
      suggest possible novel therapeutic agents in the treatment of these cartilaginous
      neoplasms.

PMID- 12612212
TI  - Adaptation of glucose production and gluconeogenesis to diminishing glucose
      infusion in preterm infants at varying gestational ages.
AB  - In preterm infants low plasma glucose concentrations are frequently observed. We
      hypothesized that the infants' ability to adapt endogenous glucose production to
      diminishing exogenous supply is disturbed, but will improve with increasing
      gestational age. Glucose production rate and gluconeogenesis were measured using
      stable isotope techniques with [6,6-2H2]glucose and [2-13C]glycerol in 19 preterm
      infants (10 < or = 30 wk and nine >30 wk gestational age) on d 5.0 +/- 1.4 of
      life. Exogenous glucose was administered at a rate of 33 micromol x kg-1 x min-1
      followed by 22 micromol x kg-1 x min-1. In the first 2 h after the decrease in
      exogenous supply, plasma glucose concentration declined comparably in both
      groups: < or =30 wk, from 4.3 +/- 1.2 to 3.2 +/- 0.9 mM; >30 wk, from 3.7 +/- 0.7
      to 3.0 +/- 0.6 mM. Thereafter, only in infants >30 wk an increase was observed,
      to 3.4 +/- 0.8 mM. Glucose production rate increased comparably in both groups: <
      or =30 wk, from 6.0 +/- 4.1 to 8.8 +/- 3.4 micromol x kg-1 x min-1; >30 wk, from
      7.8 +/- 4.6 to 11.6 +/- 5.2 micromol x kg-1 x min-1. This increase was equivalent
      to approximately 30% of the decline in exogenous glucose. Gluconeogenesis
      increased comparably in both groups: <30 wk, from 3.2 +/- 1.2 to 4.5 +/- 1.3
      micromol x kg-1 x min-1; >30 wk, from 4.3 +/- 1.9 to 6.8 +/- 2.9 micromol x kg-1
      x min-1. We conclude that preterm infants can only partly compensate a decline in
      exogenous glucose supply by increasing endogenous glucose production rate,
      probably because of limitations in the final common pathway of intracellular
      glucose metabolism (i.e. glucose-6-phosphatase). The ability to maintain the
      plasma glucose concentration after a decrease in exogenous supply is better
      preserved in infants >30 wk owing to more efficient adaptation of peripheral
      glucose utilization.

PMID- 12612213
TI  - Parenteral glycerol enhances gluconeogenesis in very premature infants.
AB  - We have previously demonstrated that very premature infants receiving total
      parenteral nutrition maintain normoglycemia primarily by glucose produced via
      gluconeogenesis and that the lipid emulsion is most important in supporting
      gluconeogenesis. It is, however, not clear whether this is a result of the
      glycerol or the fatty acid constituent. The purpose of the present study was to
      determine the effect of intravenous supplemental glycerol alone on glucose
      production and gluconeogenesis. Twenty infants (birth weight, 1014 +/- 32 g;
      gestational age, 27 +/- 1 wk) were studied on d 4 +/- 1 (mean +/- SE). All
      infants received glucose at 17 micromol/kg x min for 9 h (after an initial study
      hour with 33 micromol/kg x min). Eight infants received no additional substrate
      during the study, and 12 infants received supplemental glycerol at 5 (n = 6) or
      10 micromol/kg x min (n = 6) over the last 5 h of study. In infants receiving
      glucose alone, between period 1 (study hours 4-5) and period 2 (study hours 9
      10), rates of glucose production ([U-13C]glucose) decreased from 12.9 +/- 1.2 to
      7.4 +/- 0.9 micromol/kg x min (p < 0.01). This was the result of decreased
      glycogenolysis but no change in gluconeogenesis ([U-13C]glucose mass isotopomer
      distribution analysis) (5.1 +/- 0.6 versus 5.7 +/- 0.4 micromol/kg x min) (ns).
      Glycerol infusion at 5 and 10 micromol/kg x min, respectively, maintained glucose
      production (despite comparable decrease in glycogenolysis) by increasing
      gluconeogenesis from 4.3 +/- 0.2 to 6.3 +/- 0.5 (p < 0.03), and 6.0 +/- 0.7 to
      8.8 +/- 0.8 micromol/kg/min (p < 0.01). In very premature infants, parenteral
      glycerol enhances gluconeogenesis and attenuates time dependent decrease in
      glucose production.

PMID- 12612214
TI  - Effect of chondroitinase ABC on purulent sputum from cystic fibrosis and other
      patients.
AB  - Cystic fibrosis (CF) patients develop chronic lung infections associated with
      airway obstruction by viscous and insoluble mucus secretions. Although mucus
      glycoproteins (mucins) are thought to be responsible for mucus plugs, other
      glycoconjugate components of airway secretions have not been systematically
      evaluated. The aim of the present study was to determine whether chondroitin
      sulfate proteoglycans (CSPG) contribute to the insolubility of CF sputum. Sputa
      obtained from 18 CF patients were incubated with chondroitinase ABC (ChABC) or
      buffer (control) for 18 h at 37 degrees C, and after centrifugation at 12,000 g,
      the volume of the insoluble pellet and turbidity of the supernatant were
      determined as measures of solubility. ChABC caused a 70-90% reduction in
      supernatant turbidity and a 60-70% decrease in pellet volume of the 13 purulent
      CF sputa, but had much less effect on the five nonpurulent CF sputa tested.
      Similar results were obtained with two non-CF purulent and two non-CF,
      nonpurulent sputa. Gel electrophoresis, Western blot, and slot blot immunoassays
      with antichondroitin sulfate and antimucin antibodies revealed that purulent
      sputa (CF and non-CF) contained more CSPG and less mucin than nonpurulent sputa.
      In vitro mixing experiments showed that mucin in nonpurulent sputa was reduced
      upon incubation with purulent sputa, presumably because of degradation or a loss
      of immunoreactive mucin epitopes from leukocyte and/or bacterial enzymes present
      in purulent sputa. Our results suggest that CSPG contribute more significantly
      than mucins to the insolubility of purulent tracheobronchial secretions from CF
      patients. Because purulent sputa from non-CF patients showed a similar pattern,
      our observations with CF sputa may have wider applicability.

PMID- 12612215
TI  - Functional attenuation of UFD1l, a 22q11.2 deletion syndrome candidate gene,
      leads to cardiac outflow septation defects in chicken embryos.
AB  - Microdeletion of chromosome 22q11.2 is commonly associated with congenital
      cardiovascular defects that involve development of cranial neural crest cells
      (NCC) that emigrate through the pharyngeal arches. UFD1l is one of several
      candidate genes for 22q11.2 deletion syndrome (22q11DS). UFD1l encodes a protein
      whose yeast counterpart is involved in a ubiquitin-dependent proteolytic
      degradation pathway; however, the role of UFD1L in NCC development remains
      unknown. Mouse embryos that lack Ufd1l die before organogenesis. We have
      therefore studied the function of Ufd1l in the chick system. Chick Ufd1l encoded
      a 307-amino acid protein that was highly conserved with mouse and human UFD1L.
      Chick Ufd1l was expressed in the developing neural tube, NCC, and mesenchyme of
      the head and pharyngeal arch structures, as well as in the conotruncal region
      (cardiac outflow tract), consistent with the clinical features of 22q11DS. To
      determine loss-of-function effects of chick Ufd1l in NCC, we infected cardiac NCC
      with a retrovirus expressing antisense Ufd1l transcripts in chick embryos before
      their migration. Morphologic analysis of infected embryos at a later
      developmental stage demonstrated that functional attenuation of chick Ufd1l in
      cardiac NCC resulted in an increased incidence of conotruncal septation defects.
      These data suggest that Ufd1l may play a role in cardiac NCC during conotruncal
      septation.

PMID- 12612216
TI  - Intraamniotic endotoxin increases lung antioxidant enzyme activity in preterm
      lambs.
AB  - Proinflammatory stimulation resulting from intraamniotic endotoxin improves lung
      function, increases surfactant protein mRNA expression and protein content,
      increases alveolar and lung saturated phosphatidylcholine pools, and accelerates
      lung morphometric maturation in fetal sheep. The mechanism for induction of lung
      maturation does not involve an increase in fetal cortisol. The effect of
      endotoxin on the maturation of a different lung system, the antioxidant enzyme
      (AOE) system, has not been examined. Therefore, we hypothesized that
      intraamniotic endotoxin would produce acceleration of AOE activity in fetal sheep
      at similar doses and schedule of administration to those producing lung
      functional and surfactant maturation. In a dose-response study, intraamniotic
      injections of 1, 4, 20, or 100 mg of Escherichia coli 055:beta5 endotoxin were
      administered 7 d before preterm delivery of sheep at 125 d gestation. In a study
      examining time interval of administration before delivery, 20 mg of endotoxin was
      injected at either 1-, 2-, 4-, 7-, or 15-d intervals before preterm delivery at
      125 d. Doses of 1-100 mg of endotoxin produced significant increases in
      glutathione peroxidase activity; doses of 4-100 mg significantly increased
      catalase activity, whereas doses of 20-100 mg resulted in significant increases
      in total superoxide dismutase activity. Glutathione peroxidase activity was
      elevated within 2 d, whereas superoxide dismutase was increased by 4 d and
      catalase activity increased by 7 d after endotoxin. No AOE increases were
      sustained for 15 d. Endotoxin increased fetal lung AOE activity at similar dosing
      amounts and intervals to those producing maturation of lung function and
      surfactant. Thus, mechanisms involving proinflammatory stimulation, unrelated to
      glucocorticoid hormones, can induce maturation of the AOE system of the fetal
      lung.

PMID- 12612217
TI  - Chronic moderate hypoxia and protein malnutrition both induce growth retardation,
      but have distinct effects on arterial endothelium-dependent reactivity in the
      chicken embryo.
AB  - Deviations in the rate of intrauterine growth may change organ system
      development, resulting in cardiovascular disease in adult life. Arterial
      endothelial dysfunction often plays an important role in these diseases. The
      effects of two interventions that reduce fetal growth, chronic hypoxia and
      protein malnutrition, on arterial endothelial function were investigated. Eggs of
      White Leghorn chickens were incubated either in room air or in 15% O2 from d 6
      until d 19 of the 21-d incubation. Protein malnutrition was induced by removal of
      10% of the total albumen content at d 0. In vitro reactivity of the femoral
      artery in response to vasodilators was measured at d 19. Both chronic hypoxia and
      protein malnutrition reduced embryonic body weight at d 19 by 14% without
      affecting relative brain weight. Chronic hypoxia or protein malnutrition did not
      change sensitivity to the exogenous nitric oxide donor, sodium nitroprusside
      (5.74 +/- 0.15 versus 5.85 +/- 0.23 and 6.05 +/- 0.18 versus 6.01 +/- 0.34,
      respectively). Whereas protein malnutrition did not modify arterial sensitivity
      to acetylcholine (7.00 +/- 0.10 versus 7.12 +/- 0.05), chronic hypoxia reduced
      sensitivity to this endothelium-dependent vasodilator (6.57 +/- 0.07 versus 7.02
      +/- 0.06). In the presence of Nomega-nitro-l-arginine methyl ester, this
      difference in sensitivity to acetylcholine was no longer apparent (6.31 +/- 0.13
      versus 6.27 +/- 0.06), indicating that chronic exposure to hypoxia reduced
      sensitivity to acetylcholine by lowering nitric oxide release. In additional
      experiments, a decrease in basal nitric oxide release in arteries of 3- to 4-wk
      old chickens that had been exposed to in ovo chronic hypoxia was observed
      (increase in K+ contraction: -0.16 +/- 0.33 N/m versus 0.68 +/- 020 N/m). Protein
      malnutrition and chronic hypoxia both induce disproportionate growth retardation,
      but only the latter impairs arterial endothelial function. Intrauterine exposure
      to chronic hypoxia induces changes in arterial endothelial properties that may
      play a role in the development of cardiovascular disease in adult life.

PMID- 12612218
TI  - Squalene and noncholesterol sterols in serum and lipoproteins of children with
      and without familial hypercholesterolemia.
AB  - Squalene and noncholesterol sterols, e.g. lathosterol and plant sterols, the
      respective markers of cholesterol synthesis and absorption, are transported with
      cholesterol in serum lipoproteins. Their concentrations and ratios to cholesterol
      in serum and lipoproteins have not been carefully compared, especially in
      children and in marked hypercholesterolemia. Thus, we measured these variables
      with gas-liquid chromatography in 18 children with and 29 without familial
      hypercholesterolemia, all aged 5-17 y. Concentrations of most noncholesterol
      sterols were higher in serum, LDL, and intermediate density lipoprotein in the
      children with than those without familial hypercholesterolemia. Despite
      accumulation of noncholesterol sterols mainly in LDL (75% in familial
      hypercholesterolemia and 55% in non-familial hypercholesterolemia, p < 0.001),
      their ratios were mostly similar in serum and lipoproteins of the two groups. The
      ratios of squalene and lathosterol were higher in VLDL and intermediate density
      lipoprotein, whereas in LDL that of lathosterol was lower than the respective
      serum values in both groups. Absorption marker sterol ratios were highest in HDL
      in both groups. Thus, even though the ratios of noncholesterol sterols to
      cholesterol in serum reflect, in general, synthesis and absorption of
      cholesterol, their ratios in different lipoproteins could give additional
      information of cholesterol metabolism.

PMID- 12612219
TI  - Transepidermal water loss in developing rats: role of aquaporins in the immature
      skin.
AB  - In the extremely preterm infant, high transepidermal water loss (TEWL) can result
      in severe dehydration. TEWL has been attributed to the structural properties of
      the epidermis but might also be influenced by mechanisms that facilitate water
      transport. To investigate whether aquaporins (AQP) may be involved in the extreme
      losses of water through immature skin, we examined the presence and cellular
      distributions of AQP-1 and AQP-3 in embryonic and adult rat skin by
      immunohistochemistry. The expression of AQP mRNA in skin was analyzed with the
      use of semiquantitative reverse transcription-PCR. In rat pups of different
      embryonic (E) and postnatal (P) ages (days), TEWL and skin hydration were
      measured. AQP-1 was detected in dermal capillaries, and AQP-3 was abundant in
      basal epidermal layers. Both AQP displayed several times higher expression in
      embryonic than in adult skin. TEWL was highest at embryonic day 18 (E18) (133 +/-
      18 g/m2h) and lower at E20 (25 +/- 1 g/m2h) and P4 (9 +/- 2 g/m2h). Skin
      hydration measured as skin electrical capacitance paralleled TEWL, being highest
      in fetal skin (794 +/- 15 pF at E18) and decreasing to 109 +/- 11 pF at E20 and
      to 0 +/- 0 pF at P4. We conclude that, as in infants, water loss through the skin
      of rats decreases markedly with maturation during the perinatal period. The
      expression and cellular localization of the AQP are such that they might
      influence skin hydration and water transport and contribute to the high losses of
      water through the immature skin.

PMID- 12612220
TI  - Effectiveness of pulse oximetry screening for congenital heart disease in
      asymptomatic newborns.
AB  - OBJECTIVE: To determine the sensitivity, specificity, predictive value, and
      accuracy of a program of pulse oximetry screening of asymptomatic newborns for
      critical congenital cardiovascular malformation (CCVM). METHODS: Pulse oximetry
      was performed on asymptomatic newborns in the well-infant nurseries of 2
      hospitals. Cardiac ultrasound was performed on infants with positive screens
      (saturation <or=95% at >24 hours). Data regarding true and false positives as
      well as negatives were collected and analyzed. RESULTS: Oximetry was performed on
      11 281 asymptomatic newborns, and 3 cases of CCVM were detected (total anomalous
      pulmonary venous return x2, truncus arteriosus). During the study interval, there
      were 9 live births of infants with CCVM from a group of 15 fetuses with CCVM
      detected by fetal echocardiography. Six infants with CCVM were symptomatic before
      screening. There was 1 false-positive screen. Two infants with negative screens
      were readmitted (coarctation, hypoplastic left pulmonary artery with aorto
      pulmonary collaterals). Other cardiac diagnoses in the database search were
      nonurgent, including cases of patent foramen ovale, peripheral pulmonic stenosis,
      and ventricular septal defect. The prevalence of critical CCVM among all live
      births was 1 in 564 and among the screened population was 1 in 2256 (sensitivity:
      60%; specificity: 99.95%; positive predictive value: 75%; negative predictive
      value: 99.98%; accuracy: 99.97%). CONCLUSIONS: This screening test is simple,
      noninvasive, and inexpensive and can be administered in conjunction with state
      mandated screening. The false-negative screen patients had lesions not amenable
      to detection by oximetry. The sensitivity, specificity, and predictive value in
      this population are satisfactory, indicating that screening should be applied to
      larger populations, particularly where lower rates of fetal detection result in
      increased CCVM prevalence in asymptomatic newborns.

PMID- 12612221
TI  - Does gatekeeping control costs for privately insured children? Findings from the
      1996 medical expenditure panel survey.
AB  - OBJECTIVE: Gatekeeping requirements were widely adopted by health insurers in an
      attempt to control costs in the mid-1990s, but empirical evidence demonstrating
      decreased health expenditures for children enrolled in such plans is lacking.
      METHODS: We analyzed data from 3254 children with private health insurance
      sampled in the 1996 Medical Expenditure Panel Survey (MEPS) to compare total per
      capita health expenditures among gatekeeping versus indemnity plan enrollees.
      This sample represents 40.4 million privately insured American children. Total
      expenditures were defined as payments from all sources, including third-party and
      out-of-pocket payments, but excluding administrative costs. MEPS data are based
      on information provided by patients, health care providers, and hospitals.
      Gatekeeping plans included all children enrolled in health maintenance
      organizations or other plans requiring a primary care gatekeeper. All others were
      considered indemnity plan enrollees. RESULTS: Mean total per capita annual
      expenditures for children in gatekeeping versus indemnity plans differed by <1%
      (887 dollars vs 881 dollars, respectively). Third-party payments by gatekeeping
      plans on behalf of their beneficiaries were 636 dollars versus 595 dollars by
      indemnity plans. Out-of-pocket payments were on average 62 dollars less for
      gatekeeping enrollees than for indemnity enrollees. After multivariate
      adjustment, mean per capita expenditures were approximately 4% lower for
      gatekeeping enrollees than for indemnity enrollees. CONCLUSION: In 1996, total
      per capita annual health expenditures for children in gatekeeping plans were
      approximately 8 dollars less than for those in indemnity plans. These data
      indicate that gatekeeping is not an effective cost-containment method for
      children.

PMID- 12612223
TI  - Pulmonary outcome at 1 year corrected age in premature infants treated at birth
      with recombinant human CuZn superoxide dismutase.
AB  - OBJECTIVE: To examine whether treatment of premature infants with intratracheal
      recombinant human CuZn superoxide dismutase (r-h CuZnSOD) reduces
      bronchopulmonary dysplasia and improves pulmonary outcome at 1 year corrected
      age. DESIGN: Three hundred two premature infants (600-1200 g birth weight)
      treated with exogenous surfactant at birth for respiratory distress syndrome were
      randomized to receive either intratracheal r-h CuZnSOD (5 mg/kg in 2 mL/kg
      saline) or placebo every 48 hours (as long as intubation was required) for up to
      1 month of age. Short-term, as well as longer-term pulmonary outcome was
      assessed. RESULTS: There were no differences between groups in the incidence of
      death or the development of bronchopulmonary dysplasia (oxygen requirement with
      an Edwards chest radiograph score of >or=3) at 28 days of life or 36 weeks'
      postmenstrual age. r-h CuZnSOD was well-tolerated and not associated with
      significant increases in any adverse event. At a median of 1 year corrected age,
      health assessments and physical examinations were performed on 209 (80%)
      surviving infants, with complete data available on 189 infants. Thirty-seven
      percent of placebo-treated infants had repeated episodes of wheezing or other
      respiratory illness severe enough to require treatment with asthma medications
      such as bronchodilators and/or corticosteroids compared with 24% of r-h CuZnSOD
      treated infants, a 36% reduction. In infants <27 weeks' gestation, 42% treated
      with placebo received asthma medications compared with 19% of r-h CuZnSOD-treated
      infants, a 55% decrease. Infants <27 weeks' gestation who received r-h CuZnSOD
      also had a 55% decrease in emergency department visits and a 44% decrease in
      subsequent hospitalizations. Growth measurements and the results of physical
      examinations were comparable between groups. CONCLUSIONS: These data indicate
      that treatment at birth with r-h CuZnSOD may reduce early pulmonary injury,
      resulting in improved clinical status when measured at 1 year corrected age. r-h
      CuZnSOD appears to be a safe and effective therapy that improves pulmonary
      outcome in high-risk premature infants.

PMID- 12612222
TI  - Soluble E-selectin, soluble L-selectin and soluble ICAM-1 in bronchopulmonary
      dysplasia, and changes with dexamethasone.
AB  - OBJECTIVE: To evaluate longitudinal change in arterial blood plasma levels of
      soluble adhesion molecules in infants of <30 weeks' gestation with respiratory
      distress syndrome (RDS) and to look for differences in these levels in neonates
      who subsequently developed bronchopulmonary dysplasia (BPD) compared with those
      neonates who did not, and also to investigate the effect of dexamethasone
      treatment on levels of soluble adhesion molecules in plasma. METHODS: We measured
      plasma concentrations of soluble L-selectin (sL-selectin), soluble E-selectin (sE
      selectin), and soluble intercellular adhesion molecule-1 on days 1, 3, 7, 14, 21,
      and 28 of life and before and 2 to 3 days after initiating a 6-day course of
      dexamethasone treatment. Infants with RDS were followed until discharge and were
      classified as non-BPD and either 1) BPD day 28 reflecting oxygen requirement on
      day 28 but not at 36 corrected weeks or 2) BPD 36 weeks reflecting oxygen
      requirement at 36 (corrected) weeks' gestation. The classification of presence or
      absence of BPD by oxygen requirement was supported by and was consistent with
      radiologic findings of BPD for all infants. The difference between BPD day 28 and
      BPD 36 weeks was supported by more extensive radiologic effects in the latter.
      RESULTS: The arterial plasma level of sL-selectin in infants who had RDS and did
      not develop BPD was significantly decreased compared with term healthy infants,
      as was the level of sE-selectin. Compared with infants who had RDS and did not
      develop BPD, sL-selectin levels were even further decreased in infants who had
      RDS and did develop BPD both at birth and throughout the first 4 weeks of life
      (day 1 through day 28). Infants with BPD also showed increasing levels of sE
      selectin during this period of time, whereas infants without BPD did not. Levels
      of soluble intercellular adhesion molecule-1 in infants without BPD were not
      different from infants with BPD initially but increased in infants with BPD
      compared with infants without BPD, significant on day 28 in both groups.
      Dexamethasone treatment increased concentration of sL-selectin and decreased
      concentration of sE-selectin. CONCLUSIONS: Low sL-selectin may be an early
      indicator of enhanced risk for BPD. Low levels of sL-selectin and increasing
      levels of sE-selectin may be risk factors for BPD. The effects of dexamethasone
      treatment include significant modulation of adhesion molecules.

PMID- 12612224
TI  - Clinical effects of L-carnitine supplementation on apnea and growth in very low
      birth weight infants.
AB  - OBJECTIVE: Systemic carnitine deficiency may present with apnea, hypotonia, and
      poor growth. Premature infants often manifest these symptoms and are at risk of
      developing carnitine deficiency because of immaturity of the biosynthetic
      pathway, lack of sufficient predelivery transplacental transport, and lack of
      sufficient exogenous supplementation. This study was undertaken to examine the
      effect of carnitine supplementation in premature infants. METHODS: Eighty preterm
      infants <1500 g were enrolled in a prospective, double-blind, placebo-controlled
      study of carnitine supplementation within 96 hours of delivery. Growth, length of
      hospital stay, and frequency and severity of apnea were the primary outcome
      measures. RESULTS: Weight gain and change in length, fronto-occipital head
      circumference, mid arm circumference, and triceps skinfold thickness were similar
      between the carnitine-supplemented and placebo groups. The amount and severity of
      apnea and the overall length of hospitalization were also similar between the 2
      groups. The carnitine levels in the supplemented group were significantly higher
      than in the placebo group at 4 and 8 weeks after study entry. CONCLUSION:
      Although preterm infants <1500 g have low carnitine levels, routine
      supplementation with carnitine has no demonstrable effect on growth, apnea, or
      length of hospitalization and thus seems to be unnecessary.

PMID- 12612226
TI  - Prolongation of satiety after low versus moderately high glycemic index meals in
      obese adolescents.
AB  - BACKGROUND: One in 5 American children is overweight, despite a decrease in total
      fat consumption. This has sparked an interest in the carbohydrate composition of
      diets, including the glycemic index (GI). OBJECTIVE: To investigate whether a low
      GI meal replacement (LMR) produced similar metabolic, hormonal, and satiety
      responses in overweight adolescents as a low-GI whole-food meal (LWM) when
      compared with a moderately high-GI meal replacement (HMR). METHODS: Randomized,
      crossover study comparing LMR, HMR, and LWM in 16 (8 male/8 female) adolescents
      during 3 separate 24-hour admissions. The meal replacements consisted of a shake
      and a nutrition bar. Identical test meals were provided at breakfast and lunch.
      Metabolic and hormonal indices were assessed between meals. Measures of
      participants' perceived satiety included hunger scales and ad libitum food
      intake. RESULTS: The incremental areas under the curve for glucose were 46% and
      43% lower after the LMR and LWM, respectively, compared with the HMR. Insulin's
      incremental area under the curve was also significantly lower after both low GI
      test meals (LMR = 36%; LWM = 51%) compared with the HMR. Additional food was
      requested earlier after the HMR than the LMR (3.1 vs 3.9 hours, respectively),
      although voluntary energy intake did not differ. CONCLUSIONS: Differences in
      insulin response between the meal replacements occurred, and prolongation of
      satiety after the LMR, based on time to request additional food, was observed. We
      speculate that the prolonged satiety associated with low GI foods may prove an
      effective method for reducing caloric intake and achieving long-term weight
      control.

PMID- 12612225
TI  - Chronic lung disease of prematurity and intrauterine growth retardation: a
      population-based study.
AB  - OBJECTIVE: To determine the risk of chronic lung disease (CLD) in small for
      gestational age (SGA) preterm infants in comparison to appropriately grown and
      large for gestational age (LGA) infants. METHODS: Observational study derived
      from a geographically defined population (Trent Health Region, United Kingdom).
      All preterm infants of <or=32 completed weeks' gestation born to Trent resident
      mothers admitted to neonatal units between 1995 and 1999 (inclusive) were
      included. Birth weight percentiles were created for the whole population, and
      infants were classified as SGA infants (if <10th percentile), appropriately grown
      (if between 25th and 75th percentiles-reference group), and LGA infants (if
      >or=90th centile). Both mortality and CLD rates (using both 28 days' and 36
      weeks' postmenstrual age [PMA] definitions) were determined for these groups of
      infants. RESULTS: Four thousand fifty-one preterm infants <or=32 weeks' gestation
      were identified. SGA infants showed higher mortality before 28 days' postnatal
      age and 36 weeks' PMA as compared with reference group infants (odds ratio [OR]:
      2.01, 95% confidence interval [CI]: 1.49-2.72; and OR: 2.00, 95% CI: 1.49-2.69),
      respectively. SGA infants showed a significantly greater risk of developing CLD,
      both at 28 days' and 36 weeks' PMA as compared with the reference group infants
      (OR: 1.34, 95% CI: 1.03-1.74; and OR: 1.87, 95% CI: 1.39-2.51), respectively. LGA
      infants showed a trend toward a reduced incidence of CLD in comparison to the
      reference group, which was statistically significant for the 36 weeks' definition
      (OR: 0.76-28 weeks, 95% CI: 0.57-1.01; and OR: 0.55-36 weeks, 95% CI: 0.37-0.81).
      CONCLUSIONS: Fetal growth seems to influence mortality in general and morbidity,
      attributable to CLD, in particular in preterm infants. SGA preterm infants are at
      higher risk of death before 28 days' and 36 weeks' PMA and CLD by both
      definitions. LGA infants show reduced risk of CLD.

PMID- 12612227
TI  - Scheduled follow-up after a pediatric emergency department visit for asthma: a
      randomized trial.
AB  - OBJECTIVES: Follow-up with a primary care provider (PCP) is recommended after an
      emergency department (ED) visit for asthma to assess clinical status and develop
      a management plan to improve future care. However, previous ED-based studies of
      urban children with asthma have reported low follow-up rates. The objective of
      this study was to determine whether scheduling an appointment at the time of an
      ED visit improves PCP follow-up for urban children. A secondary goal was to
      assess the effect of this intervention on short-term health outcomes and the use
      of recommended preventive controller medications. METHODS: This randomized trial
      enrolled a convenience sample of children who were 2 to 18 years old and
      discharged after treatment for acute asthma in an urban children's hospital ED.
      Both intervention and control subjects were instructed to follow up with their
      PCP within 3 to 5 days. Study staff assisted intervention subjects to call their
      PCP from the ED and schedule an appointment. When follow-up could not be
      scheduled, assistance continued after ED discharge by telephone until an
      appointment date was confirmed. Study outcomes included PCP visits, asthma
      related morbidity, and daily use of preventive medication 4 weeks after the ED
      visit. Outcomes were assessed by telephone interview and confirmed by PCP record
      review. RESULTS: A total of 278 eligible subjects were enrolled over 8 months;
      intervention and control groups were similar by demographic variables and PCP
      type as well as by asthma history, symptoms, and previous medication use. Only
      38% of subjects reported using a daily controller medication, although 70%
      described persistent asthma symptoms for which these are recommended. For the
      intervention group, follow-up appointments were successfully obtained during the
      ED visit for 24% of subjects; when unsuccessful, a median of 3 telephone calls
      (range: 1-14) were needed to confirm that an appointment had been scheduled.
      During the 4 weeks after the ED visit, intervention subjects were more likely
      than controls to follow up with their PCP (64% vs 46%; relative probability for
      follow-up: 1.4; 95% confidence interval: 1.1-1.7). Study groups did not differ in
      return ED visits, missed school or work, or the percentage reporting daily use of
      a controller medication (58% vs 54%) 4 weeks after the ED visit. The median time
      to the next PCP visit was shorter among intervention subjects (13 vs 54 days).
      CONCLUSIONS: Scheduling an appointment after an ED visit increased the likelihood
      that urban children with asthma would follow up with a PCP. An appointment could
      not be obtained during the ED visit for most children. Other interventions are
      needed to improve linkage between ED and primary care for asthma and to improve
      the use of controller medications.

PMID- 12612228
TI  - Internet-enabled interactive multimedia asthma education program: a randomized
      trial.
AB  - OBJECTIVE: To determine whether health outcomes of children who have asthma can
      be improved through the use of an Internet-enabled interactive multimedia asthma
      education program. METHODS: Two hundred twenty-eight children with asthma
      visiting a pediatric pulmonary clinic were randomly assigned to control and
      intervention groups. Children and caregivers in both groups received traditional
      patient education based on the National Asthma Education and Prevention Program.
      Intervention group participants received additional self-management education
      through the Interactive Multimedia Program for Asthma Control and Tracking.
      Pediatric Asthma Care Knowledge Survey, Pediatric Asthma Caregiver's Quality of
      Life Questionnaire, asthma symptom history, spirometry, and health services
      utilization data were collected at the initial visit and at 3 and 12 months.
      RESULTS: Interactive Multimedia Program for Asthma Control and Tracking
      significantly increased asthma knowledge of children and caregivers, decreased
      asthma symptom days (81 vs 51 per year), and decreased number of emergency
      department visits (1.93 vs 0.62 per year) among the intervention group
      participants. The intervention group children were also using a significantly
      lower average daily dose of inhaled corticosteroids (434 vs 754 micro g
      [beclomethasone equivalents]) at visit 3. Asthma knowledge of all 7- to 17-year
      old children correlated with fewer urgent physician visits (r = 0.37) and less
      frequent use of quick-relief medicines (r = 0.30). CONCLUSIONS: Supplementing
      conventional asthma care with interactive multimedia education can significantly
      improve asthma knowledge and reduce the burden of childhood asthma.

PMID- 12612229
TI  - Randomized clinical trial of pacifier use and bottle-feeding or cupfeeding and
      their effect on breastfeeding.
AB  - OBJECTIVE: To enhance breastfeeding practices, the World Health Organization
      discourages pacifiers and bottle-feeding. However, the effect of artificial
      nipples on breastfeeding duration is poorly defined. The effects of 2 types of
      artificial nipple exposure on breastfeeding duration were evaluated: 1)
      cupfeeding versus bottle-feeding for the provision of in-hospital supplements and
      2) early (2-5 days) versus late (>4 weeks) pacifier introduction. METHODS: A
      total of 700 breastfed newborns (36-42 weeks, birth weight >or=2200 g) were
      randomly assigned to 1 of 4 intervention groups: bottle/early pacifier (n = 169),
      bottle/late pacifier (n = 167), cup/early pacifier (n = 185), or cup/late
      pacifier (n = 179). The cup/bottle intervention was invoked for infants who
      received supplemental feedings: cup (n = 251), bottle (n = 230). Data were
      collected at delivery and at 2, 5, 10, 16, 24, 38, and 52 weeks' postpartum.
      Intervention effects on breastfeeding duration were evaluated with logistic
      regression and survival analyses. RESULTS: Supplemental feedings, regardless of
      method (cup or bottle), had a detrimental effect on breastfeeding duration. There
      were no differences in cup versus bottle groups for breastfeeding duration.
      Effects were modified by the number of supplements; exclusive and full
      breastfeeding duration were prolonged in cup-fed infants given >2 supplements.
      Among infants delivered by cesarean, cupfeeding significantly prolonged
      exclusive, full, and overall breastfeeding duration. Exclusive breastfeeding at 4
      weeks was less likely among infants exposed to pacifiers (early pacifier group;
      odds ratio: 1.5; 95% confidence interval: 1.0-2.0). Early, as compared with late,
      pacifier use shortened overall duration (adjusted hazard ratio: 1.22; 95%
      confidence interval: 1.03-1.44) but did not affect exclusive or full duration.
      CONCLUSIONS: There was no advantage to cupfeeding for providing supplements to
      the general population of healthy breastfed infants, but it may have benefitted
      mother-infant dyads who required multiple supplements or were delivered by
      cesarean. Pacifier use in the neonatal period was detrimental to exclusive and
      overall breastfeeding. These findings support recommendations to avoid exposing
      breastfed infants to artificial nipples in the neonatal period.

PMID- 12612230
TI  - Effects on breastfeeding of changes in maternity length-of-stay policy in a large
      health maintenance organization.
AB  - OBJECTIVE: The purpose of this study was to evaluate the effects on breastfeeding
      rates of a private-sector early discharge program and a subsequent government
      mandate guaranteeing 48 hours of hospital coverage. METHODS: Interrupted time
      series analyses were conducted on retrospective data from the automated medical
      records of a large health maintenance organization in eastern Massachusetts. A
      population of 20 366 mother-infant pairs with normal vaginal deliveries between
      October 1990 and March 1998 was identified. This study period spanned the 2
      interventions of interest: 1) the introduction of a new health maintenance
      organization protocol of 1 postpartum overnight hospitalization followed by a
      nurse home visit for normal vaginal deliveries, then 2) Massachusetts state
      minimum coverage legislation. Breastfeeding initiation and breastfeeding
      continuation among initiators (exclusive or with supplements) into the third
      month of life were determined through a text search of the first 90 days of
      infants' automated medical records. RESULTS: Both policies had dramatic impacts
      on length of stay (LOS); postpartum LOS <2 nights rose from 29% of pairs to 65%
      when the early discharge program was implemented, then fell to 15% after the
      state mandate. Breastfeeding initiation, however, rose gradually from 71% in the
      fourth quarter of 1990 to 82% in the first quarter of 1998, with no changes after
      the interventions. Continuation of breastfeeding among those who initiated
      remained constant at 73%. Younger maternal age, primiparity, low socioeconomic
      status, and nonwhite race all were found to be risk factors for lower rates of
      breastfeeding (either initiation or continuation), but there was no evidence of a
      decline in breastfeeding associated with shorter LOS among these vulnerable
      groups. CONCLUSIONS: Early postpartum discharge with outpatient breastfeeding
      support and a home visitor program has no adverse effects on initiation or
      continuation of breastfeeding.

PMID- 12612231
TI  - Interpretation of traumatic lumbar punctures: who can go home?
AB  - OBJECTIVE: To determine whether a ratio of observed to predicted (O:P)
      cerebrospinal fluid (CSF) white blood cells (WBCs) after a traumatic lumbar
      puncture (LP) can be used to predict which patients do not have meningitis and
      can safely be discharged from the hospital. METHODS: A retrospective medical
      record review was performed on 2 cohorts of previously healthy children who had
      received an LP at Children's Memorial Hospital in Chicago, IL. All children were
      older than 1 month and had a red blood cell (RBC) count in the CSF >500/mm(3).
      Cohort 1 consisted of children who were examined in 1990 through 1999 and had CSF
      cultures positive for a bacterial pathogen. Cohort 2 consisted of children who
      were tested during January through December 1999 and had a CSF culture negative
      for any bacterial pathogen. Exclusion criteria included patients who received
      antibiotics within 72 hours before evaluation, patients with a previous
      neurosurgical procedure or CNS bleed, and patients whose complete blood count was
      not done within 6 hours of LP. The predicted CSF WBC count was calculated using
      the formula CSF WBC (predicted) = CSF RBC x (blood WBC/blood RBC). The O:P ratio
      was obtained by dividing the observed CSF WBC by the predicted CSF WBC. The
      simple ratio of WBCs to RBCs was also calculated. Sensitivity, specificity,
      positive predictive value, and negative predictive value were calculated to
      predict the absence of disease. Receiver operator characteristic curves were
      generated for the O:P ratio and the WBC:RBC ratio. Continuous variables were
      analyzed with Mann-Whitney U test. RESULTS: Among the 57 patients who fit all of
      the study criteria, 12 (21%) had positive CSF cultures for bacterial pathogens.
      The patients with meningitis were significantly older (median: 7.8 months; range:
      1-106 months) than the patients without meningitis (median: 1.3 months; range: 1
      139 months). The O:P ratio was significantly lower in the patients without
      meningitis (median: 0.064; range: 0.000054-1.09) as compared with patients with
      meningitis (median: 1.26; range: 0.045-4.72). The WBC:RBC ratio was significantly
      lower in the patients without meningitis (median: 0.001; range: 0-4.46) as
      compared with patients with meningitis (median: 1.98; range: 0.04-24.45). The
      specificity and positive predictive value of an O:P ratio <or=0.01 and a WBC:RBC
      ratio <or=1:100 were 100% predicting the absence of disease. The area under the
      curve for the O:P ratio (0.981) did not differ significantly from the area under
      the curve for the WBC:RBC ratio (0.970). CONCLUSION: A WBC:RBC ratio of <or=1:100
      (0.01) and an O:P ratio of <or=0.01 identified a large group of patients without
      meningitis. Using these methods in children younger than 1 month, the majority of
      patients without meningitis can be differentiated from those with meningitis
      despite the CSF abnormalities associated with a traumatic LP. However, the
      clinician should examine all clinical and laboratory information before opting
      not to treat a child after a traumatic LP.

PMID- 12612232
TI  - Prolonging small feeding volumes early in life decreases the incidence of
      necrotizing enterocolitis in very low birth weight infants.
AB  - OBJECTIVE: Approximately 90% of infants who develop necrotizing enterocolitis
      (NEC) do so after being fed. Previous prospective studies have shown that infants
      given small enteral feedings for the first 7 to 10 days of feeding do not have an
      increased risk for NEC compared with those given no feedings. Although
      neonatologists now commonly increase feeding volumes, no study has compared the
      risk for NEC between infants fed these small volumes and those fed volumes that
      are increased slowly. The purpose of this study was to compare the risks and
      benefits of small and increasing feeding volume. METHODS: In a randomized,
      controlled trial, we randomly assigned 141 preterm infants in the newborn
      intensive care unit to be fed 10 days using 1 of 2 schedules. One group was fed
      20 mL/kg/d for the first 10 study days (minimal). The other group (advancing) was
      fed 20 mL/kg/d on study day 1; feeding volume was increased by 20 mL/kg/d up to
      140 mL/kg/d, which was maintained until study day 10. The main outcome measure
      was incidence of NEC; secondary outcomes were maturation of intestinal motor
      patterns, time to reach full enteral feedings, and incidence of late sepsis.
      RESULTS: The study was closed early because 7 infants who were assigned to
      advancing feeding volumes developed NEC, whereas only 1 infant fed minimal
      feeding volumes did, or 10% versus 1.4%. Although infants who were fed minimal
      volumes established full enteral feeding volumes later than infants who were fed
      advancing volumes, maturation of intestinal motor patterns and the incidence of
      late sepsis and feeding intolerance was similar in the 2 groups. CONCLUSION:
      Given that advancing feeding volumes increase the risk of NEC without providing
      benefits for motor function or feeding tolerance, neonatologists should consider
      using minimal feeding volumes until future trials assess the safety of advancing
      feeding volumes.

PMID- 12612233
TI  - Violence exposure and substance use in adolescents: findings from three
      countries.
AB  - OBJECTIVE: To investigate relationships between exposure to community violence
      (witnessing and victimization) and reported substance use (cigarettes, alcohol,
      marijuana, and hard drugs) in a cross-national sample of adolescents, after
      controlling for the level of the adolescents' own violent behavior. METHOD: A
      self-report survey was conducted in 3380 14- to 17-year-old adolescents in urban
      communities of 3 different countries: Antwerp, Belgium (N = 958); Arkangelsk,
      Russia (N = 1036); and New Haven, Connecticut (N = 1386). RESULTS: In all 3
      countries, levels of reported smoking, alcohol use, marijuana use, and hard drug
      use showed increases with adolescent exposure to violence. Although positively
      related, substance use was increased less markedly in US adolescents who
      witnessed violence. CONCLUSION: Current findings further emphasize the
      association between violence exposure and potential severe physical and
      psychosocial health problems in adolescents. In addition, the findings suggest
      that violence exposure and its consequences are a worldwide urban phenomenon.
      Cross-national differences were found, however, that warrant additional research,
      and prospective studies are needed to investigate the pathways from violence
      exposure to substance abuse.

PMID- 12612234
TI  - Early-onset group B streptococcal infection after a combined maternal and
      neonatal group B streptococcal chemoprophylaxis strategy.
AB  - OBJECTIVE: In January 1995, a combined maternal and neonatal protocol for
      prevention of early-onset group B streptococcal (GBS) infection was implemented
      that consisted of a risk factor-based approach for maternal intrapartum
      chemoprophylaxis using ampicillin combined with a single intramuscular dose of
      penicillin given to all newborns within 1 hour of delivery. The objective of this
      study was to review the cases of early-onset GBS infections that occurred from
      1995 to 1999 to identify factors associated with their continued occurrence
      despite implementation of a GBS chemoprophylaxis protocol. METHODS: Infants
      <or=72 hours of age with early-onset GBS infection born at Parkland Memorial
      Hospital in Dallas from January 1995 to December 1999 were identified through a
      prospective laboratory-based surveillance system. Maternal and infant medical
      records were reviewed for clinical and demographic data. RESULTS: There were 32
      cases (0.47/1000 live births) of early-onset GBS infection for the 5-year period.
      This represented a 76% reduction compared with the rate from 1986 to 1994
      (1.95/1000), when there was no protocol for GBS chemoprophylaxis. Thirteen cases
      (41%) did not have any identifiable maternal risk factor. Of the 19 cases (59%)
      with risk factors, maternal intrapartum fever was the most frequent (15 [79%]),
      followed by prematurity (6 [32%]) and prolonged rupture of membranes (6 [32%]).
      Among the 19 mothers with risk factors, 15 (79%) mothers received intrapartum
      chemoprophylaxis, and 12 (80%) of the 15 mothers had intrapartum fever. Only 33%
      of mothers with risk factors received >or=2 doses of intrapartum
      chemoprophylaxis, and among those with intrapartum fever, 25% received >or=2
      doses. None of the 32 infants with early-onset GBS infection received the
      combination of intrapartum ampicillin and postnatal penicillin. CONCLUSIONS: A
      combined obstetric and neonatal chemoprophylaxis protocol significantly reduced
      early-onset GBS infection. Maternal intrapartum fever was the most frequent risk
      factor associated with failure of chemoprophylaxis.

PMID- 12612235
TI  - Functional disability and school activity limitations in 41,300 school-age
      children: relationship to medical impairments.
AB  - OBJECTIVE: Our purpose was to examine the contribution of medical impairments to
      functional disability and school activity limitations in 41,300 school-age
      children participating in the 1994-1995 National Health Interview Survey.
      METHODS: The 1994 and 1995 National Health Interview Survey and Disability
      Interview Supplement samples provide International Classification of Diseases,
      Ninth Revision medical impairment codes for children with functional limitations
      or school activity limitations in a nationally representative US sample.
      Functional limitations were distributed as follows: mobility 12.4/1000 (95%
      confidence interval [CI]: 11.1-13.6), self-care 8.8/1000 (95% CI: 7.7-9.8),
      communication 52.9/1000 (95% CI: 50.2-55.5), and learning 104.6/1000 (95% CI:
      100.7-108.4). Functional disability status was classified as 4.1% mild, 5.9%
      major, and 1.9% multiple. School activity limitations included 4.1% needing or
      receiving special education, 0.7% unable to attend, and 0.9% limited attendance.
      We categorized International Classification of Diseases, Ninth Revision
      impairment codes reported in conjunction with medical usage as physical disorders
      (n = 1251; eg, leukemia, diabetes), asthma (n = 916), neurodevelopmental
      disorders (n = 802; eg, cerebral palsy, epilepsy, mental retardation, autism,
      blindness, deafness), and learning-behavior disorders (n = 806; eg, attention
      deficit/hyperactivity disorder, learning disability, anxiety) for children with
      functional or school activity limitations. Of children with multiple functional
      disabilities, 29.9% had neurodevelopmental disorders, 27.1% had learning-behavior
      disorders, 18.1% had physical disorders, 4.2% had asthma, and 20.8% did not have
      an identified medical impairment because they had not received medical services
      in the past year. Among children requiring special education, physical disorders
      accounted for 9.4%, neurodevelopmental disorders for 16.7%, learning and behavior
      disorders for 17%, asthma for 3.4%, and 53.4% did not have an identified medical
      impairment because they had not received medical services in the past year.
      CONCLUSIONS: Chronic health impairments, neurodevelopmental disorders, learning
      behavior disorders, and functional limitations in essential activities are
      required to understand the complexity of disability in school-age children. A
      large number of children with functional disability or school activity
      limitations have not received ongoing medical services.

PMID- 12612237
TI  - Childhood abuse, neglect, and household dysfunction and the risk of illicit drug
      use: the adverse childhood experiences study.
AB  - OBJECTIVE: Illicit drug use is identified in Healthy People 2010 as a leading
      health indicator because it is associated with multiple deleterious health
      outcomes, such as sexually transmitted diseases, human immunodeficiency virus,
      viral hepatitis, and numerous social problems among adolescents and adults.
      Improved understanding of the influence of stressful or traumatic childhood
      experiences on initiation and development of drug abuse is needed. METHODS: We
      examined the relationship between illicit drug use and 10 categories of adverse
      childhood experiences (ACEs) and total number of ACEs (ACE score). A
      retrospective cohort study of 8613 adults who attended a primary care clinic in
      California completed a survey about childhood abuse, neglect, and household
      dysfunction; illicit drug use; and other health-related issues. The main outcomes
      measured were self-reported use of illicit drugs, including initiation during 3
      age categories: <or=14 years, 15 to 18 years, or as an adult (>or=19 years);
      lifetime use for each of 4 birth cohorts dating back to 1900; drug use problems;
      drug addiction; and parenteral drug use. RESULTS: Each ACE increased the
      likelihood for early initiation 2- to 4-fold. The ACE score had a strong graded
      relationship to initiation of drug use in all 3 age categories as well as to drug
      use problems, drug addiction, and parenteral drug use. Compared with people with
      0 ACEs, people with >or=5 ACEs were 7- to 10-fold more likely to report illicit
      drug use problems, addiction to illicit drugs, and parenteral drug use. The
      attributable risk fractions as a result of ACEs for each of these illicit drug
      use problems were 56%, 64%, and 67%, respectively. For each of the 4 birth
      cohorts examined, the ACE score also had a strong graded relationship to lifetime
      drug use. CONCLUSIONS: The ACE score had a strong graded relationship to the risk
      of drug initiation from early adolescence into adulthood and to problems with
      drug use, drug addiction, and parenteral use. The persistent graded relationship
      between the ACE score and initiation of drug use for 4 successive birth cohorts
      dating back to 1900 suggests that the effects of adverse childhood experiences
      transcend secular changes such as increased availability of drugs, social
      attitudes toward drugs, and recent massive expenditures and public information
      campaigns to prevent drug use. Because ACEs seem to account for one half to two
      third of serious problems with drug use, progress in meeting the national goals
      for reducing drug use will necessitate serious attention to these types of
      common, stressful, and disturbing childhood experiences by pediatric practice.

PMID- 12612236
TI  - Sleep and neurobehavioral characteristics of 5- to 7-year-old children with
      parentally reported symptoms of attention-deficit/hyperactivity disorder.
AB  - OBJECTIVES: This study examined the hypothesis that domains of neurobehavioral
      function would be selectively affected by sleep-disordered breathing (SDB).
      Therefore, we assessed potential relationships between objectively measured sleep
      disturbances and neurobehavioral function in children with reported symptoms of
      attention-deficit/hyperactivity disorder (ADHD) and also determined the incidence
      of snoring and other sleep problems in 5- to 7-year-old children in the local
      community and potential relationships to parental snoring and passive smoking.
      METHODS: Parents of 5- to 7-year-old children in public schools were surveyed
      about their child's sleeping habits using a validated questionnaire. The
      questionnaire also asked whether they believed their child to be hyperactive or
      have ADHD. Children with reported symptoms of ADHD and control children were
      randomly selected and invited to the Sleep Medicine Center for an overnight
      polysomnographic assessment and a battery of neurocognitive tests. RESULTS: The
      questionnaire response rate was 47.6% (n = 5728). Frequent and loud snoring was
      reported for 673 children (11.7%). Similarly, 418 (7.3%) children were reported
      to have hyperactivity/ADHD, 313 (76.5%) of which were boys. Eighty-three children
      with parentally reported symptoms of ADHD were invited for full evaluation at the
      Sleep Medicine Center together with 34 control children. After assessment with
      the Conners' Parent Rating Scale, 44 children were designated as having
      "significant" symptoms of ADHD, 27 as "mild," and 39 designated as "none"
      (controls). Overnight polysomnography indicated that obstructive sleep apnea was
      present in 5% of those with significant ADHD symptoms, 26% of those with mild
      symptoms, and 5% of those with no symptoms. In the cohort, no sleep variable
      accounted for more than a negligible proportion of the variance in domains of
      neurobehavioral function. CONCLUSIONS: An unusually high prevalence of snoring
      was identified among a group of children designated as showing mild symptoms of
      ADHD based on the Conners' ADHD index identified from a community sample.
      However, whereas SDB is not more likely to occur among children with significant
      ADHD symptoms, it is significantly highly prevalent among children with mild
      hyperactive behaviors. Sleep studies further revealed that rapid eye movement
      disturbances are more likely to occur in children with significant symptoms, and
      they seem to impose significant but mild effects on daytime neurobehavioral
      functioning. We conclude that in children with significant symptoms of ADHD, the
      prevalence of SDB is not different from that of the general pediatric population
      and that rapid eye movement sleep in these children is disturbed and may
      contribute to the severity of their behavioral manifestations. Furthermore, SDB
      can lead to mild ADHD-like behaviors that can be readily misperceived and
      potentially delay the diagnosis and appropriate treatment.

PMID- 12612238
TI  - Intravenous bisphosphonate therapy in children with osteogenesis imperfecta.
AB  - OBJECTIVE: Several studies have reported beneficial effects of bisphosphonates in
      children with osteogenesis imperfecta (OI); however, these studies have differed
      in the protocols they used, and none has been independently replicated. We
      intended to confirm the efficacy of a specific intravenous bisphosphonate
      protocol in children with moderate to severe OI. METHODS: We used the protocol
      described by Glorieux et al and performed a prospective clinical trial in 6
      children who were aged 22 months to 14 years. Each patient received intravenous
      pamidronate therapy for a minimum of 2 years in cycles of 1 mg/kg daily over 3
      consecutive days at a mean cycle interval of 3.8 months. Outcome measures
      included lumbar spine areal bone mineral density (BMD) and z score, fracture
      rate, and occupational therapy functional assessment with serial Pediatric
      Evaluation of Disability Inventory. RESULTS: While on therapy, the average annual
      increase in areal BMD was 48% and the average annual increase in BMD z score was
      1.0. This increase in z score is statistically significant. There was no clear
      correlation between changes in BMD and fracture rate. All patients experienced
      functional improvement in mobility. CONCLUSIONS: Our results support the findings
      of Glorieux et al that cyclic administration of intravenous pamidronate in
      children with OI has beneficial effects with respect to BMD z scores and physical
      disability. Long-term follow-up will be required to determine whether
      bisphosphonate therapy will decrease fracture rates and increase mobility in
      children with moderate to severe OI.

PMID- 12612239
TI  - Physical and psychosocial health in children who have had Kawasaki disease.
AB  - OBJECTIVE: The purpose of this study was to examine the physical and psychosocial
      well-being of children who have had Kawasaki disease (KD), including the
      influence of coronary artery status on health and health perceptions. METHODS:
      The Child Health Questionnaire (CHQ) measures overall physical and psychosocial
      well-being in children 5 to 18 years. To study the long-term impact of KD on
      overall health status, we mailed the CHQ to patients without a history of
      coronary artery abnormalities (normal group), with regressed aneurysms (regressed
      group), with current coronary aneurysms <8 mm (mild-moderate aneurysm group), and
      with giant aneurysms >or=8 mm (giant group). RESULTS: Of 201 questionnaires
      mailed, 174 were delivered and 110 (63%) were completed. Median age (range) at
      completion was 10.5 years (5.1-17.9 years) and at illness onset was 3.1 years
      (0.2-12 years). There were no significant differences in psychosocial summary
      scores in any of the Kawasaki groups when compared with the US population sample.
      Physical summary scores were also similar to the US population sample in the
      normal coronary, mild-moderate aneurysm, and regressed aneurysm groups. However,
      the giant aneurysm group had significantly lower physical summary scores compared
      with the US population sample. Among subscales, general health perceptions in the
      KD groups were lower than in the US population sample, reaching statistical
      significance in all but the mild to moderate aneurysm group. In addition, parents
      whose children have had KD reported a higher proportion of anxiety issues,
      allergies, and orthopedic/bone/joint issues in their children than did the
      general US population sample. We did not find any difference in the incidence of
      attentional, behavioral, or learning issues when compared with the US population
      sample. CONCLUSIONS: KD patients without coronary artery aneurysms were similar
      to the general population in their general physical and psychosocial health.
      However, the parents of children in all KD groups reported lower general health
      perceptions than parents in the US population sample, suggesting that long-term
      concerns about their children's health exist regardless of overall health status.
      In addition, children with giant coronary artery aneurysms had lower overall
      physical summary scores.

PMID- 12612240
TI  - Use of complementary and alternative medical therapies among children with
      special health care needs in southern Arizona.
AB  - OBJECTIVE: The objective of this study was to assess the frequency and type of
      complementary and alternative medicine (CAM) therapies used by families of
      children with special health care needs in southern Arizona, as well as the
      correlates of their use. METHODS: Families of 376 children who were receiving
      services in a regional facility that serves children with special health care
      needs and were residing in southern Arizona were surveyed regarding CAM use.
      RESULTS: Sixty-four percent of these families reported using CAM for their child.
      The most common CAM therapies were spiritual healing/prayer/blessings. Of the
      conditions that were evaluated as correctable, the use rate was 24% as compared
      with a 76% use rate for children with a nonrepairable condition. Use of CAM for
      the child was strongly related to the use of CAM in the past by the family member
      who responded to the survey. The reasons that parents most frequently chose for
      using CAM were advice from a medical practitioner and advice from a family
      member. CONCLUSIONS: Use of CAM for children with special health care needs is
      common. Its frequency and type are significantly associated with the child's
      condition and prognosis.

PMID- 12612241
TI  - How readable are child safety seat installation instructions?
AB  - OBJECTIVES: To measure the required reading level of a sample of child safety
      seat (CSS) installation instructions and to compare readability levels among
      different prices of CSSs to determine whether the lower cost seats to which low
      income parents have greater access are written to a lower level of education.
      METHODS: A CD-ROM containing CSS installation instructions was obtained from the
      National Highway Traffic Safety Administration. Pricing information was obtained
      for available models from an Internet-based company that provides comparative
      shopping information. Paper copies of the instruction sets were generated, and
      their readability levels were determined using the SMOG test. A second rater was
      used in addition to the primary investigator to assess interrater reliability of
      the SMOG as applied to the instruction sets. RESULTS: The readability of
      instruction sets ranged from the 7th- to 12th-grade levels, with an overall mean
      SMOG score of 10.34. No significant associations were found to exist between
      readability and seat prices; this was observed whether the data were treated as
      continuous or categorical. CONCLUSIONS: CSS instruction manuals are written at a
      reading level that exceeds the reading skills of most American consumers. These
      instruction sets should be rewritten at a lower reading level to encourage the
      proper installation of CSSs.

PMID- 12612242
TI  - Risk of seizures in survivors of newborn heart surgery using deep hypothermic
      circulatory arrest.
AB  - OBJECTIVE: To identify pre- and intraoperative variables associated with
      postoperative acute neurologic events (ANEs), including seizures and coma, in
      newborn survivors of congenital heart surgery undergoing deep hypothermic
      circulatory arrest (DHCA), and to risk-stratify this population on the basis of
      preoperative risk variables for the purpose of designing future neuroprotection
      trials. METHODS: Survivors of newborn heart surgery who were enrolled in a
      neuroprotection trial provided a comprehensive database for the evaluation of pre
      and intraoperative variables that influence the postoperative occurrence of ANEs
      (seizures or coma). Patients with hypoplastic heart syndrome were excluded. After
      characterization of the study population, stepwise logistic regression, combined
      with clinical judgment, was used to identify variables that were most likely to
      be associated with an increased risk of seizures in the study sample and that
      were most likely to be generalized to other populations. RESULTS: Data were
      available on 164 nonhypoplastic left heart syndrome survivors who underwent
      newborn heart surgery using DHCA. ANEs occurred in 31 (18.9%) including "seizures
      alone" (n = 28), "coma alone" (n = 2) or "seizures and coma" (n = 1). A
      preoperative risk model was constructed demonstrating that infants with a genetic
      condition and aortic arch obstruction had a 47.8% risk of ANEs compared with all
      other remaining infants, who had a 9.9% risk. It was also found that prolonged
      DHCA time (>or=60 minutes) can be a significant risk for infants who have a
      preexisting genetic condition; however, infants who have genetic conditions and
      do not undergo prolonged DHCA time or have an aortic arch obstruction are not at
      increased risk of ANEs. CONCLUSIONS: This study provides new information about
      the occurrence of ANEs after newborn heart surgery. Seizures or coma, which
      appeared in approximately 19% of all non-hypoplastic left heart syndrome
      survivors, were not random events but were significantly associated with specific
      types of congenital heart disease, the presence of genetic conditions, and
      prolonged DHCA time. The 3 identified variables permitted individual cases to be
      assigned to low-, intermediate-, or high-risk categories. Because neonatal
      seizures are a good surrogate marker of long-term neurologic outcome, these
      models provide useful information to stratify individual patients for risk of
      seizures in future neuroprotection trials.

PMID- 12612243
TI  - Can the initial history predict whether a child with a head injury has been
      abused?
AB  - OBJECTIVE: Previous studies of child abuse have used the presenting history as
      part of the case definition of abuse. Thus, data from these studies cannot be
      used to determine the diagnostic utility of historical features for identifying
      cases of abuse. The objective of this study was to determine the diagnostic
      utility of certain historical features for identifying cases of abusive head
      trauma. METHODS: We retrospectively studied all children, aged 0 to 3 years, who
      had acute traumatic intracranial injury and were admitted to a tertiary care
      pediatric hospital from 1993 to 2000. Cases were categorized as either "definite
      abuse" or "not definite abuse" on the basis of radiologic, ophthalmologic, and
      physical examination findings, without regard to the presenting history. RESULTS:
      Forty-nine (30%) of 163 children met the criteria for definite abuse. Having no
      history of trauma had a high specificity (0.97) and positive predictive value
      (PPV; 0.92) for abuse. Among the subgroup of patients with persistent neurologic
      abnormality at hospital discharge (n = 34), having a history of no or low-impact
      trauma had a specificity of 1.0 and a PPV of 1.0 for definite abuse. Injuries
      were blamed on home resuscitative efforts in 12% of definite abuse cases and 0%
      of not definite abuse cases. The initial history of trauma was changed in 9% of
      definite abuse cases, as compared with 0% of not definite abuse cases.
      CONCLUSION: Among young children with a head injury, certain historical features
      have high specificity and PPV for diagnosing child abuse.

PMID- 12612244
TI  - Atopic dermatitis and asthma: parallels in the evolution of treatment.
AB  - OBJECTIVES: To review epidemiologic correlations between asthma and atopic
      dermatitis (AD), identify common features in disease pathophysiology, and review
      steps involved in the development of asthma therapy guidelines to assess the
      appropriateness of a similar process and approach for AD. METHODS: A 7-member
      panel representing specialists in dermatology, allergy, asthma, immunology, and
      pediatrics from around the United States convened to review the current
      literature and evolving data on AD. Participants presented reviews to the panel
      on the epidemiology of asthma and AD, the genetic predisposition to allergic
      disease, the current understanding of the immunopathophysiology of AD,
      interrelationships between the pathologic pathways of asthma and AD, evolving
      treatment concepts and options in AD, and the applicability of the asthma
      treatment model and how it may be adapted for guideline development for AD.
      Commentary and criticism were recorded for use in document preparation. RESULTS:
      There are clear epidemiologic parallels in asthma and AD. Importantly, AD
      frequently is the first manifestation of an atopic diathesis, which occurs in
      genetically predisposed individuals and also includes asthma and allergic
      rhinitis. Up to 80% of children with AD will eventually develop allergic rhinitis
      or asthma later in childhood. This classic "atopic triad" has numerous
      pathophysiologic elements in common, including cyclic nucleotide regulatory
      abnormalities, immune cell alterations, and inflammatory mediators and allergic
      triggers. New therapeutic options that target underlying immune mechanisms are
      available, and their place among treatments for AD is becoming established.
      Guidelines of care have been developed for asthma. The panel noted that the
      National Institutes of Health/National Heart, Lung, and Blood Institute
      guidelines for diagnosis and management of asthma, first issued in 1991, had a
      tremendous positive impact on many aspects of asthma treatment. It not only
      created a heightened awareness that asthma is a disease of chronic inflammation,
      but it also provided unified approaches for therapy and opened new areas of basic
      science and clinical research. In addition, the guidelines spurred interactions
      among physicians of various specialties and stimulated a great quantity of
      research in asthma therapy. It is anticipated that AD therapy guidelines would
      have similar positive outcomes. CONCLUSIONS: The panel concluded that, on the
      basis of current information and evolving therapeutic options, a clear rationale
      exists to support AD guideline development. The many parallels between AD and
      asthma suggest that processes and approaches used for the asthma therapy
      guidelines would be appropriate for AD.

PMID- 12612245
TI  - Hospital-reported medical errors in children.
AB  - CONTEXT: Medical errors are an important problem for hospitalized adult
      inpatients. However, medical errors in children remain comparatively
      understudied, and published research has been relatively limited. OBJECTIVES: To
      investigate the national rates of hospital-reported medical errors in pediatric
      inpatients over the period 1988-1997; and to determine the association of patient
      and hospital characteristics with the occurrence of hospital-reported medical
      errors in children. DESIGN, SETTING, AND PATIENTS: A nonconcurrent cohort study
      of hospitalized nonnewborn pediatric patients in the United States <or=18 years
      of age. Data from the Healthcare Cost and Utilization Project for the years 1988,
      1991, 1994, and 1997 were used for these analyses. MAIN OUTCOME MEASURE: The
      occurrence of hospital-reported medical errors. RESULTS: The national rate of
      hospital-reported medical errors in hospitalized children ranged from 1.81 to
      2.96 per 100 discharges. These medical error rates were statistically lower in
      1988, with the years 1991, 1994, and 1997 not being statistically different from
      each other. There were no consistent differences in the rates of medical errors
      when stratified by gender, race, payor status, or median household income of the
      patient's zip code across years. There was, however, a statistically significant
      relationship between higher median household income and increasing medical error
      rates; this trend was consistent across all 4 years. Similarly, children with
      special medical needs or dependence on a medical technology also had
      significantly higher rates of hospital-reported medical errors. Although hospital
      size did not seem to be related to the rate of medical errors, private for-profit
      hospitals consistently reported lower rates, whereas urban teaching hospitals in
      all years but 1997 reported higher rates of medical errors. CONCLUSIONS: These
      data highlight both the strengths and limitations of administrative data in the
      investigation of medical errors. Substantively, they suggest fruitful areas for
      additional and more detailed study, notably children with special medical needs.

PMID- 12612246
TI  - Effect of position on sleep, heart rate variability, and QT interval in preterm
      infants at 1 and 3 months' corrected age.
AB  - OBJECTIVE: Prone sleeping position has a strong link to sudden infant death
      syndrome (SIDS), and the "Back to Sleep" campaign has played an important role in
      reducing SIDS. We tested the hypothesis that the mechanism of the sleep position
      effect is based on changes in sleep, arousal, heart rate variability (HRV), and
      the QT interval of the electrocardiogram. STUDY DESIGN: We studied 16 premature
      infants longitudinally, at 1 and 3 months' corrected age. Videosomnography
      recordings were made during the infants' normal daytime naps. Each infant was
      recorded in both supine and prone positions. The recordings were analyzed in 30
      second epochs, which were classified as awake, active sleep (AS), quiet sleep
      (QS), or indeterminate sleep. Electrocardiogram data were sampled with an
      accuracy of 1 millisecond. Time domain analysis of HRV was measured by standard
      deviation of all R-R intervals and by the square root of the mean of the sum of
      the squares of the differences between adjacent R-R intervals. Frequency domain
      analysis was done for low frequency (0.04-0.14 Hz) and high frequency (0.15-0.5
      Hz) HRV. We measured QT, JT, and R-R intervals during AS and QS for each
      position. RESULTS: We found no significant differences between supine and prone
      position, either in total sleep time or in percentage of QS. Percentage of AS was
      significantly lower in the supine position, but only at 1 month corrected age.
      The incidence of short, spontaneous, sleep transitions was significantly higher
      in supine, also only at 1 month corrected age. Time domain analysis of HRV showed
      a significantly lower variability in prone, but only during QS. Frequency domain
      analysis of HRV showed no differences between the 2 sleeping positions. Both QT
      and JT intervals were significantly longer in prone during QS, but only at 1
      month corrected age. CONCLUSIONS: Despite the commonly held belief, prone
      position did not substantially increase total sleep at these ages. On the other
      hand, prone sleeping decreased the number of sleep transitions at 1 month
      corrected age, increased QT and JT intervals, and reduced HRV, thereby
      potentially increasing the vulnerability for SIDS. This study supports "Back to
      Sleep" as the position of choice not only for term but also for preterm infants
      after discharge home.

PMID- 12612247
TI  - Use of an electronic medical record improves the quality of urban pediatric
      primary care.
AB  - OBJECTIVE: To evaluate the quality of pediatric primary care, including
      preventive services, before and after the introduction of an electronic medical
      record (EMR) developed for use in an urban pediatric primary care center.
      METHODS: A pre-postintervention analysis was used in the study. The intervention
      was a pediatric EMR. Routine health care maintenance visits for children <5 years
      old were reviewed, and documentation during preintervention (paper-based, 1998)
      and postintervention visits (computer-based, 2000) was compared. RESULTS: A total
      of 235 paper-based visits and 986 computer-based visits met study criteria.
      Twelve clinicians (all attendings or nurse practitioners) contributed an average
      of 19.4 paper-based visits (range: 5-39) and 7 of these clinicians contributed an
      average of 141 computer-based visits each (range: 61-213). Computer-based
      clinicians were significantly more likely to address a variety of routine health
      care maintenance topics including: diet (relative risk [RR]: 1.09), sleep (RR:
      1.46), at least 1 psychosocial issue (RR: 1.42), smoking in the home (RR: 15.68),
      lead risk assessment (RR: 106.54), exposure to domestic or community violence
      (RR: 35.19), guns in the home (RR: 58.11), behavioral or social developmental
      milestones (RR: 2.49), infant sleep position (RR: 9.29), breastfeeding (RR:
      1.99), poison control (RR: 3.82), and child safety (RR: 1.29). Trends toward
      improved lead exposure, vision, and hearing screening were seen; however,
      differences were not significant. Users of the system reported that its use had
      improved the overall quality of care delivered, was well-accepted by families,
      and improved guidance quality; however, 5 of 7 users reported that eye-to-eye
      contact with patients was reduced, and 4 of 7 reported that use of the system
      increased the duration of visits (mean: 9.3 minutes longer). All users
      recommended continued use of the system. CONCLUSION: Use of the EMR in this study
      was associated with improved quality of care. This experience suggests that EMRs
      can be successfully used in busy urban pediatric primary care centers and, as
      recommended by the Institute of Medicine, must play a central role in the
      redesign of the US health care system.

PMID- 12612248
TI  - Sleep position of low birth weight infants.
AB  - OBJECTIVES: To describe sleep positions among low birth weight infants,
      variations in sleep position according to birth weight, and changes in sleep
      position over time. To analyze risk factors and influences associated with prone
      sleep. DESIGN: Prospective cohort study. SETTING: Massachusetts and Ohio, 1995
      1998. STUDY PARTICIPANTS: Mothers of 907 low birth weight infants. RESULTS: At 1,
      3, and 6 months after hospital discharge, the prevalence of prone sleeping was
      15.5%, 26.8%, and 28.3%, respectively. The corresponding rates for supine
      sleeping were 23.8%, 37.9%, and 50.2% and for side sleeping were 57.3%, 32.4%,
      and 20.6%. Very low birth weight (VLBW) infants (<1500 g) were most likely to be
      placed in the prone position. From 1995 through 1998, prone sleeping 1 month
      after hospital discharge declined among all low birth weight infants from 19.9%
      to 11.4%; among VLBW infants, the decline in prone sleeping was replaced almost
      entirely by an increase in side sleeping, whereas in larger low birth weight
      infants, it was replaced primarily by supine sleeping. Among mothers who placed
      their infants to sleep in nonprone positions, professional medical advice was
      cited most frequently as the most influential reason, whereas among mothers of
      prone-sleeping infants, the infant's preference was cited most frequently.
      However, mothers of prone-sleeping VLBW infants also frequently cited the
      influence of medical professionals and nursery practices as most important in the
      choice of sleeping position. The factors most strongly associated with prone
      sleeping were single marital status (odds ratio [OR]: 3.0; 95% confidence
      interval [CI]: 1.5-6.2), black race (OR: 2.6; 95% CI: 1.5-4.5), birth weight
      <1500 g (OR: 2.4; 95% CI: 1.3-4.3), and multiparity (OR: 2.1, 95% CI: 1.2-3.5).
      CONCLUSIONS: Prone sleep decreased among low birth weight infants from 1995 to
      1998. However, VLBW infants, who are at very high risk for sudden infant death
      syndrome, are more likely to sleep prone than larger low birth weight infants.

PMID- 12612249
TI  - Child disobedience and noncompliance: a review.
AB  - Child disobedience and noncompliance is a recurring problem frequently brought to
      the attention of pediatricians and others working with children and their
      parents. This article reviews empirical studies concerning childhood
      noncompliance. Definitions of noncompliance (also called disobedience) are
      presented, and observational studies that have measured noncompliance in the
      laboratory and at home are reviewed. Studies show considerable variability in the
      prevalence of noncompliance, but demonstrate that it is a frequent problem for
      parents. Longitudinal data from the Pittsburgh Youth Study are presented to more
      closely examine the onset and stability of noncompliance in childhood and
      adolescence. Evidence suggests that extreme childhood noncompliance is relatively
      stable over time, peaking slightly during early adolescence and decreasing during
      late adolescence. Studies indicate that for some children noncompliance predicts
      aggression and externalizing problems. Antecedents of noncompliance including
      parental discipline techniques and child characteristics are reviewed. Parent
      training programs designed to reduce noncompliance are described, and the
      effectiveness of such programs is examined.

PMID- 12612250
TI  - Addressing parents' concerns: do vaccines cause allergic or autoimmune diseases?
AB  - Anecdotal case reports and uncontrolled observational studies in the medical
      literature claim that vaccines cause chronic diseases such as asthma, multiple
      sclerosis, chronic arthritis, and diabetes. Several biological mechanisms have
      been proposed to explain how vaccines might cause allergic or autoimmune
      diseases. For example, allergic diseases might be caused by prevention of early
      childhood infections (the "hygiene hypothesis"), causing a prolongation of
      immunoglobulin E-promoting T-helper cell type 2-type responses. However, vaccines
      do not prevent most common childhood infections, and large well-controlled
      epidemiologic studies do not support the hypothesis that vaccines cause
      allergies. Autoimmune diseases might occur after immunization because proteins on
      microbial pathogens are similar to human proteins ("molecular mimicry") and could
      induce immune responses that damage human cells. However, wild-type viruses and
      bacteria are much better adapted to growth in humans than vaccines and much more
      likely to stimulate potentially damaging self-reactive lymphocytes. Consistent
      with critical differences between natural infection and immunization, well
      controlled epidemiologic studies do not support the hypothesis that vaccines
      cause autoimmunity. Flaws in proposed biological mechanisms that explain how
      vaccines might cause chronic diseases are consistent with the findings of many
      well-controlled large epidemiologic studies that fail to show a causal
      relationship.

PMID- 12612251
TI  - Promoting the appropriate use of oral antibiotics: there is some very good news.

PMID- 12612252
TI  - Not as pink as you think!

PMID- 12612253
TI  - The relationship of neonatal feeding practices and the pathogenesis and
      prevention of necrotizing enterocolitis.

PMID- 12612254
TI  - Restraining the unsustainable.

PMID- 12612255
TI  - Thimerosal and autism?

PMID- 12612256
TI  - Medical information systems in pediatrics.

PMID- 12612258
TI  - An unanticipated benefit of the treatment of preterm infants with CuZn superoxide
      dismutase.

PMID- 12612257
TI  - Born-Alive Infants Protection Act of 2001, Public Law No. 107-207.

PMID- 12612259
TI  - Medical treatment of recurrent intussusception associated with intestinal
      lymphoid hyperplasia.
AB  - Intestinal lymphoid hyperplasia (ILH) is an uncommon cause of recurrent
      intussusception in infants and young children. Surgical treatment has been
      suggested in the management of this disorder. We report 2 cases in which
      recurrent intussusception was associated with ILH. A short course of steroids
      resulted in resolution of both symptoms and hyperplasia. We conclude that when
      recurrent intussusception occurs in association with ILH, and no other lead point
      can be identified, it is important that treatment with steroids is considered
      before resorting to a more radical surgical approach.

PMID- 12612260
TI  - Toe tourniquet syndrome in association with maternal hair loss.
AB  - Increased hair loss a few months after delivering an infant is a common
      postpartum condition known as telogen effluvium. A much less common condition
      involving young infants is the hair-thread tourniquet syndrome, or toe tourniquet
      syndrome, which involves hair or thread becoming so tightly wrapped around an
      appendage that pain, injury, and sometimes loss of the appendage result. This
      case report is the first known description of the hair-thread tourniquet syndrome
      in association with maternal telogen effluvium. A literature review shows that
      accidental cases involving human hair almost always involve the toes, and usually
      occur at the age when mothers are experiencing excessive hair loss. This
      association is significant in that anticipatory guidance of new parents
      experiencing rapid hair loss may prevent cases of the toe tourniquet syndrome and
      its associated morbidity.

PMID- 12612261
TI  - Aspiration of fruit gel snacks.
AB  - Aspiration of a foreign body is common in children and can cause upper airway
      obstruction, leading to significant morbidity or mortality. We report 3 cases of
      aspiration of a popular fruit-flavored gel snack that led to cardiopulmonary
      arrest and death in 1 case and respiratory failure in 2 other cases. There is
      increasing concern about the safety of this gel snack and its risk of aspiration,
      even in older children. Pediatricians should advise parents and children about
      the dangers of eating this candy during their health maintenance visits.

PMID- 12612262
TI  - Chronic ingestion of a zinc-based penny.

PMID- 12612263
TI  - Health supervision for children with Turner syndrome.
AB  - This report is designed to assist the pediatrician in caring for the child in
      whom the diagnosis of Turner syndrome has been confirmed by karyotyping. The
      report is meant to serve as a supplement to the American Academy of Pediatrics'
      "Recommendations for Preventive Pediatric Care" and emphasizes the importance of
      continuity of care and the need to avoid its fragmentation by ensuring a medical
      home for every girl with Turner syndrome. The pediatrician's first contact with a
      child with Turner syndrome may occur during infancy or childhood. This report
      also discusses interactions with expectant parents who have been given the
      prenatal diagnosis of Turner syndrome and have been referred for advice.

PMID- 12612264
TI  - Consent for emergency medical services for children and adolescents.
AB  - Pediatric patients frequently seek medical treatment in the emergency department
      (ED) unaccompanied by a legal guardian. Current state and federal laws and
      medical ethics recommendations support the ED treatment of minors with an
      identified emergency medical condition, regardless of consent issues. Financial
      reimbursement should not limit the minor patient's access to emergency medical
      care or result in a breach of patient confidentiality. Every clinic, office
      practice, and ED should develop policies and guidelines regarding consent for the
      treatment of minors. The physician should document all discussions of consent and
      attempt to seek consent for treatment from the family or legal guardian and
      assent from the pediatric patient. Appropriate medical care for the pediatric
      patient with an urgent or emergent condition should never be withheld or delayed
      because of problems with obtaining consent. This statement has been endorsed by
      the American College of Surgeons, the Society of Pediatric Nurses, the Society of
      Critical Care Medicine, the American College of Emergency Physicians, the
      Emergency Nurses Association, and the National Association of EMS Physicians.

PMID- 12612265
TI  - Physicians' roles in coordinating care of hospitalized children.
AB  - The care of hospitalized children has become increasingly complex and intense and
      often involves multiple physicians beyond the traditional primary care attending
      physician. Pediatric and adult subspecialists and surgeons, teaching attending
      physicians, and hospitalists may all participate in the care of hospitalized
      children. This report summarizes the responsibilities of the primary care
      physician, attending physician, and other involved physicians to ensure that
      children receive appropriate, coordinated, and comprehensive inpatient care that
      is delivered within the context of their medical home and is appropriately
      continued on an outpatient basis.

PMID- 12612266
TI  - Health supervision for children with sickle cell disease.

PMID- 12612267
TI  - Immune deficiency and hearing loss in CHARGE Association.

PMID- 12612268
TI  - Unreliable medical experts.

PMID- 12612269
TI  - More on "it's about their children".

PMID- 12612270
TI  - The schizophrenic career of a "monster drug".

PMID- 12612271
TI  - Stimulus-induced drop episodes in Coffin-Lowry syndrome.
AB  - OBJECTIVE: Coffin-Lowry syndrome (CLS) is a rare disorder characterized by
      moderate to severe mental retardation, facial dysmorphism, tapering digits, and
      skeletal deformity. Paroxysmal drop attacks occur in patients with CLS,
      characterized by sudden loss of muscle tone induced by unexpected tactile or
      auditory stimuli. Our objective is to characterize these attacks better using
      neurophysiologic studies. METHODS: We report 2 teenage boys with CLS and stimulus
      induced drop episodes (SIDEs). Simultaneous surface electromyogram (EMG) and
      video electroencephalogram were performed during SIDEs on our 2 patients.
      RESULTS: Both patients had SIDEs stimulated by a loud noise, unexpected light
      touch stimulation, or visual threat that were characterized by abrupt episodes of
      complete or partial loss of lower extremity tone. These events were not
      associated with impairment of consciousness, and immediate recovery was noted.
      Simultaneous surface EMG and video electroencephalogram revealed no epileptiform
      discharges in either patient. In the first patient, after unexpected tactile or
      auditory stimulation, tonic EMG activity in paraspinal muscles was lost briefly,
      similar to that seen in cataplexy. In the second patient, at 6 years of age,
      sudden nonepileptic drop episodes were induced by an unexpected tactile,
      auditory, or visual stimulation. At 11 years of age, his episodes had changed to
      brief myoclonic jerk and tonic spasm that were triggered by unexpected tactile
      and auditory stimuli. An increase in tonic EMG activity occurred during the
      attacks, consistent with hyperekplexia. CONCLUSIONS: Our data suggest that SIDEs
      in CLS are a heterogeneous group of nonepileptic events that may manifest
      features of both cataplexy and hyperekplexia, even in the same patient.

PMID- 12612272
TI  - Outcomes of infant sleep problems: a longitudinal study of sleep, behavior, and
      maternal well-being.
AB  - OBJECTIVES: In a community sample of children aged 3 to 4 years with previous
      infant sleep problems, we aimed to 1) establish proportions with recurring,
      persisting, and resolving sleep problems; 2) identify early predictors of later
      sleep problems; and 3) identify comorbidities of persistent or recurrent sleep
      problems at age 3 to 4 years. METHODS: A follow-up community survey was conducted
      of mothers of children aged 3 to 4 years who had, as 8- to 10-month-old infants
      with identified sleep problems, participated in a community-based, randomized,
      controlled trial of a brief sleep intervention from 3 middle-class local
      government areas in Melbourne, Australia. Infant sleep problems (standardized
      maternal questionnaire), maternal well-being (Edinburgh Postnatal Depression
      Scale), child behavior problems (Child Behavior Check List for ages 1.5 to 5
      years), marital satisfaction (Dyadic Adjustment Scale), and family functioning
      (General Functioning Scale, McMaster Family Assessment Device) were measured.
      RESULTS: Seventy-three percent (114 of 156) of mothers responded, 36 (32%) of
      whom reported a current problem with their child's sleep. Current sleep problems
      were similar regardless of infant sleep intervention. Twelve percent (14 of 114)
      reported that their child's sleep problem had persisted, and 19% (21 of 113)
      reported that it had recurred. Children with current sleep problems were more
      likely still to be nursed to sleep by an adult and had slightly higher mean
      scores on Child Behavior Check List subscales for Aggressive Behavior (54 vs 52)
      and Somatic Problems (55 vs 53). Their mothers had higher Edinburgh Postnatal
      Depression Scale scores (median: 8 vs 5) and more difficulties with their partner
      undermining the management of their child. However, early depression did not
      predict current sleep problems. Families of children with sleep problems were
      functioning as well as those without sleep problems. CONCLUSIONS: Persistence or
      recurrence of infant sleep problems in the preschool years is common and is
      associated with slightly higher child behavior problems and maternal depression
      scores. Results suggest that depressive symptoms are a result rather than cause
      of sleep problems. Despite this, families of children with sleep problems are
      functioning well.

PMID- 12612273
TI  - Continuity of care for children in foster care.
AB  - OBJECTIVE: To compare the continuity of care experienced by children who are in
      foster care with that of children who are not in foster care and are covered
      under Medicaid managed care and Medicaid fee-for-service (FFS). METHODS: This
      retrospective cohort study used Medicaid claims/encounter data from Washington
      state. A total of 903 children who were in foster care and continuously enrolled
      in Medicaid for 24 months (1998-1999) were matched by age, gender, and
      rural/urban residence to 903 Medicaid managed care enrollees and 903 FFS
      beneficiaries who were not in foster care. Indices of the continuity of primary
      care experienced were calculated for each patient, and differences in continuity
      among the cohorts were assessed by running 3 multiple linear regression models
      for all possible pairings of cohorts, controlling for age, gender, rural/urban
      residence, and total number of primary care visits. RESULTS: Foster care status
      was associated with decreased continuity of care relative to nonfoster managed
      care status (beta = -0.12; 95% confidence interval [CI]: -0.15 to -0.09).
      Nonfoster FFS status was associated with lower continuity than managed care (beta
      = -0.09; 95% CI: -0.12 to -0.06) and slightly higher continuity than foster care
      status (beta = 0.03; 95% CI: 0.01-0.06). CONCLUSION: Although not dramatically
      different, continuity seems somewhat lacking for children in foster care. It is
      unclear to what degree the observed difference is confounded by the managed
      care/FFS distinction. As the enrollment of children in foster care into managed
      care plans has been controversial, efforts to promote the consistency of contact
      with providers while maintaining the flexibility afforded by FFS coverage seem
      warranted.

PMID- 12612274
TI  - Caregiver-physician medication concordance and undertreatment of asthma among
      inner-city children.
AB  - OBJECTIVE: To assess the extent to which caregivers and their child's physician
      agree about the prescribed asthma medication regimen and evaluate factors
      associated with medication concordance. METHODS: A cross-sectional, descriptive
      survey was administered to 318 caregivers of inner-city children with asthma,
      aged 5 to 12 years, and their caregiver-identified primary care physician at
      elementary schools and participants' homes. Concordance between caregiver- and
      physician-reported controller medication prescription was measured. RESULTS: Only
      42% of physicians and 32% of caregivers reported a controller medication
      prescription (78% agreement, kappa = 0.54; 95% confidence interval: 0.45-0.63)
      despite that 73% of the children were rated by their caregiver as currently
      experiencing persistent asthma symptoms. When the physician reported a controller
      prescription, 38% of the caregivers denied use of a controller. Having a course
      of oral steroids in the past year (chi(2) = 9.85) and positive caregiver beliefs
      toward asthma care (chi(2) = 18.40) were associated with caregiver-physician
      concordance. Multivariate analysis found that when caregivers had high Asthma
      Beliefs Scale summary scores versus low scores, they were almost 10 times as
      likely to be concordant with the physician (odds ratio: 9.76; 95% confidence
      interval: 2.85-33.46). CONCLUSIONS: Our data support previous reports of
      physician underprescribing of controller medication among inner-city children.
      However, even when prescribed by a physician, more than one third of caregivers
      did not report a controller prescription, and this discordance was related to
      caregivers' beliefs about treatment. Efforts to improve physician adherence to
      asthma guidelines will not result in proper treatment unless caregiver-physician
      communication about asthma therapy is improved.

PMID- 12612275
TI  - Maternal gestational diabetes, birth weight, and adolescent obesity.
AB  - OBJECTIVE: Obesity increases risk of many adverse outcomes, but its early origins
      are obscure. Gestational diabetes mellitus (GDM) reflects a metabolically altered
      fetal environment associated with high birth weight, itself associated with later
      obesity. Previous studies of GDM and offspring obesity, however, have been few
      and conflicting. The objectives of this study were to examine associations of
      birth weight and GDM with adolescent body mass index (BMI) and to determine the
      extent to which the effect of GDM is explained by its influence on birth weight
      or by maternal adiposity. METHODS: We conducted a survey of 7981 girls and 6900
      boys, 9 to 14 years of age, who are participants in the Growing Up Today Study, a
      US nationwide study of diet, activity, and growth. In 1996, participants reported
      height, weight, diet, activity, and other variables by self-administered mailed
      questionnaire. We linked these data with information reported by their mothers,
      participants in the Nurses' Health Study II, including GDM, height, current
      weight, and child's birth weight. We excluded births <34 weeks' gestation and
      mothers who had preexisting diabetes. We defined overweight as BMI (kg/m(2))
      >95th percentile, and at risk for overweight as 85th to 95th percentile, for age
      and gender from US national data. RESULTS: Mean birth weight was 3.4 kg for girls
      and 3.6 kg for boys. Among the 465 subjects whose mothers had GDM, 17.1% were at
      risk for overweight and 9.7% were overweight in early adolescence. In the group
      without maternal diabetes, these estimates were 14.2% and 6.6%, respectively. In
      multiple logistic regression analysis, controlling for age, gender, and Tanner
      stage, the odds ratio for adolescent overweight for each 1-kg increment in birth
      weight was 1.4 (95% confidence interval: 1.2-1.6). Adjustment for physical
      activity, television watching, energy intake, breastfeeding duration, mother's
      BMI, and other maternal and family variables reduced the estimate to 1.3 (1.1
      1.5). For offspring of mothers with GDM versus no diabetes, the odds ratio for
      adolescent overweight was 1.4 (1.1-2.0), which was unchanged after controlling
      for energy balance and socioeconomic factors. Adjustment for birth weight
      slightly attenuated the estimate (1.3; 0.9-1.9); adjustment for maternal BMI
      reduced the odds ratio to 1.2 (0.8-1.7). CONCLUSIONS: Higher birth weight
      predicted increased risk of overweight in adolescence. Having been born to a
      mother with GDM was also associated with increased adolescent overweight.
      However, the effect of GDM on offspring obesity seemed only partially explained
      by its influence on birth weight, and adjustment for mother's own BMI attenuated
      the GDM associations. Our results only modestly support a causal role of altered
      maternal-fetal glucose metabolism in the genesis of obesity in the offspring.
      Alternatively, GDM may program risk for a postnatal insult leading to obesity, or
      it may merely be a risk marker, not in the causal pathway.

PMID- 12612276
TI  - Pediatrician beliefs about spirituality and religion in medicine: associations
      with clinical practice.
AB  - OBJECTIVES: Identify pediatrician (faculty and resident) beliefs about
      spirituality and religion (SR) in medicine and the relationship of those beliefs
      to SR behavior and experiences in clinical practice. METHODS: A self-report
      questionnaire was administered to full-time pediatric faculty (N = 65) and
      residents (N = 56) of an urban children's hospital affiliated with a school of
      medicine. The response rate was 70.8% among faculty (n = 46) and 78.6% among
      residents (n = 44). Respondents indicated the extent of their SR inquiry and the
      frequency of their SR experiences (requests by patients or families to discuss SR
      or pray), routinely and during health crisis, and rated 19 belief statements
      about SR in pediatrics. RESULTS: Few pediatricians routinely ask about SR issues.
      Faculty were more likely than residents to ask about religious affiliation,
      whereas residents were more likely to be asked to pray during health crises, to
      believe that SR has health relevance, and to perceive pediatrician-initiated
      prayer as appropriate. Composite scores indicated that physicians who did not
      expect negative patient reactions to SR inquiry and prayer, who believed more
      strongly that SR is relevant to pediatric outcomes, and who felt more capable
      with SR inquiry were more likely to engage in SR inquiry and to experience SR
      requests. CONCLUSIONS: Pediatrician beliefs with respect to health relevance of
      SR, patient reactions to SR inquiry, and physician capabilities regarding SR in
      the clinic are strongly related to their clinical practice concerning SR inquiry
      and experiences. Correction of physician misperceptions about SR issues and
      incorporation of religious sensitivity into physician training may remove
      barriers to both patient and physician SR inquiry.

PMID- 12612277
TI  - Frequency of surgery among children who have adenotonsillar hypertrophy and
      improve after treatment with nasal beclomethasone.
AB  - OBJECTIVE: To describe the long-term outcome of a cohort of children with
      symptomatic adenotonsillar hypertrophy treated with aqueous nasal beclomethasone.
      METHODS: The children enrolled completed a 4-week single-blind, saline solution
      controlled crossover study of aqueous beclomethasone (total: 400 micro g/d). In a
      24-week open-label follow-on study, beclomethasone 200 micro g/d was offered to
      all patients. During a 100-week follow-up, the degree of nasal obstruction and
      the frequency of adenotonsillectomy were assessed. RESULTS: Fifty-three children
      of the 60 enrolled completed the study. After the 4-week crossover trial, the
      severity of nasal obstruction of 24 children (45%) significantly decreased during
      the use of nasal steroids, but no child improved when saline solution was used.
      At 24, 52, and 100 weeks, the 24 children who had initially improved showed a
      significant decrease of the severity of nasal obstruction and of the frequency of
      adenotonsillectomy (54% vs 83%) compared with the 29 children who had not
      responded after the initial steroidal therapy. CONCLUSIONS: Evidence from this
      study suggests that 45% of children with adenoidal hypertrophy improved after 2
      weeks of steroidal therapy. Among these children, an additional 24-week treatment
      at a lower steroid dosage was associated with a significant 52- and 100-week
      clinical improvement and with reduction of adenotonsillectomy compared with
      children (55%) who had not responded after the initial 2-week steroidal therapy.

PMID- 12612278
TI  - Teaching testicular self-examination: education and practices in pediatric
      residents.
AB  - OBJECTIVE: Although testicular cancer is the most common cancer among 15- to 35
      year-old male individuals, physicians seldom conduct testicular self-examination
      (TSE) education, thus potentially missing opportunities for early detection.
      Pediatric residents should be learning TSE skills training and be encouraged to
      incorporate them into routine practice. There are no published studies addressing
      the medical education and practices of pediatric residents regarding testicular
      cancer and TSE. The purpose of this study was to determine the prevalence of
      pediatric residents who teach TSE to their adolescent patients, and significant
      factors related to teaching TSE. METHODS: A cross-sectional study was conducted
      of all pediatric residents at 2 pediatric residency programs during the 2000 to
      2001 academic year. A self-administered, 37-item Internet-based questionnaire was
      developed, pilot-tested, and then used. Statistical analyses included frequency
      distributions, univariate analysis, correlation coefficient, and logistic
      regression. RESULTS: A total of 129 (61%) of the eligible pediatric residents
      participated. Fourteen (29%) of the male residents reported performing TSE on
      themselves at least once a month, and 30 (61%) reported performing TSE at least
      every 3 months. The most frequent reason cited for not performing TSE monthly was
      "know how, but forget to do it" (97%). Forty (40%) of all residents reported
      teaching TSE to their 12- to 21-year-old male patients during a routine annual
      physical examination. The 2 most common reasons for not teaching TSE were "never
      thought about including it" (36%) and "lack of time" (29%). The senior-level
      residents reported teaching TSE to their male patients during a routine annual
      physical examination more often (51%) than the first-year pediatric residents
      (21%; odds ratio [OR]: 3.99; 95% confidence interval [CI]: 1.5-10.5). There was
      no difference in teaching TSE between the male residents who report performing
      TSE (43%) and those who do not perform TSE (37%; OR: 1.27; 95% CI: 0.36-4.5) and
      between male and female residents (OR: 0.9; 95% CI: 0.44-1.9). There was no
      association between knowledge of TSE and testicular cancer with teaching TSE or
      practicing TSE. In a logistic regression model, confidence in testicular
      examination (OR: 3.1; 95% CI: 1.2-7.9), confidence teaching TSE (OR: 3.6; 95% CI:
      1.2-10.9), and knowing someone with testicular cancer (OR: 2.4; 95% CI: 1.0-5.8)
      were associated with residents' teaching TSE to their patients. CONCLUSION: Fewer
      than half of the pediatric residents teach TSE to their adolescent patients.
      Confidence in performing a testicular examination, confidence in teaching TSE,
      and knowing someone with testicular cancer were the most important factors
      related to teaching TSE. This information could be used to design an educational
      intervention to increase physician promotion of TSE and ultimately increase young
      males' TSE practices. Additional studies are recommended to determine the
      generalizability of these results.

PMID- 12612279
TI  - Survey of current practice of pediatric electrophysiologists for asymptomatic
      Wolff-Parkinson-White syndrome.
AB  - OBJECTIVE: To determine the approach that pediatric electrophysiologists use as
      they evaluate asymptomatic patients with Wolff-Parkinson-White (WPW) syndrome
      regarding electrophysiologic testing and radio frequency ablation. METHODS: A 21
      question survey was mailed to 66 pediatric electrophysiologists who had
      voluntarily submitted patient data at any time to the Pediatric Radio Frequency
      Ablation Registry since its inception in 1990. The survey addressed issues
      regarding physician experience with electrophysiologic testing and radio
      frequency ablation, risk assessment, electrophysiology study, and factors that
      influence the decision to perform radio frequency ablation in asymptomatic
      patients. RESULTS: Returned surveys (43 of 66 [65%]) were analyzed blindly. The
      43 physicians who responded were experienced, with 37 reporting >5 years of
      performing radio frequency ablation and 30 having performed >200 radio frequency
      ablation procedures. Thirty-six of the 43 electrophysiologists used invasive
      electrophysiologic study for risk stratification in asymptomatic patients with
      WPW. Electrophysiologic findings guided selection of patients for radio frequency
      ablation procedures. Expected radio frequency ablation outcome quotes to the
      family were consistent with recently published data from the Electrophysiology
      Society regarding current-era experience with radio frequency ablation.
      CONCLUSION: The majority of responding electrophysiologists use invasive
      electrophysiologic study both to stratify risk for asymptomatic WPW and to select
      appropriate patients for radio frequency ablation. This current practice should
      be communicated to other pediatric cardiologists and pediatricians.

PMID- 12612280
TI  - Pediatric generalized joint hypermobility with and without musculoskeletal
      complaints: a localized or systemic disorder?
AB  - OBJECTIVES: Children with generalized hypermobility of the joints and
      musculoskeletal complaints frequently visit pediatric clinics, but many show no
      currently known collagen or other possibly related diseases. Whether the symptoms
      are confined to the musculoskeletal system is unknown. We assessed whether such
      children have detectable differences in laxity of connective tissue present in
      organ systems other than joints. We also assessed whether children with
      generalized joint hypermobility and musculoskeletal complaints have more profound
      systemic changes in connective tissue of various organ systems as compared with
      children with generalized joint hypermobility without musculoskeletal complaints.
      METHODS: Anthropometrics, range of joint motion, muscle strength, skin
      extensibility, blood pressure, quantitative ultrasound measurements of bone, and
      degradation products of collagen were studied in 15 prepubertal children with
      generalized joint hypermobility and musculoskeletal complaints and compared with
      a population-based reference group of 95 nonsymptomatic prepubertal children.
      Symptomatic hypermobile children were also compared with children of the
      population-based reference group who had asymptomatic hypermobility of the joints
      (n = 16). RESULTS: Children with symptomatic generalized joint hypermobility had
      significantly higher skin extensibility (5.6 mm/15 kPa, 95% confidence interval
      [CI]: 4.0-7.1), lower quantitative ultrasound measurements (speed of sound: -26.8
      m/s; 95% CI: -41.1 to -12.6) in bone, and lower systolic and diastolic blood
      pressure (-8.0 mmHg, 95% CI: -13.3 to -2.8; and -6.0 mmHg, 95% CI: -10.0 to -2.2,
      respectively) as compared with the total reference group. Also, they had
      significantly lower excretion of urinary hydroxylysylpyridinoline cross-links
      (mean difference: -51.3 micro mol/mmol; 95% CI: -92.2 to -10.4) as well as
      lysylpyridinoline cross-links (-18.7 micro mol/mmol; 95% CI: -36.9 to -0.5). Age,
      gender, body weight, height, and particularly cross-links excretion did not
      explain group differences in clinical and bone characteristics. After adjustment
      for age, gender, body weight, and height, children with symptomatic generalized
      joint hypermobility (n = 15) had significantly higher total range of joint motion
      (117.8 degrees; 95% CI: 77.7-158.0), skin extensibility (3.5 mm/15 kPa; 95% CI:
      1.6-5.3), lower quantitative ultrasound measurements in bone (speed of sound: 
      27.9 m/s; 95% CI: -48.4 to -7.5), borderline lower diastolic blood pressure (-4.9
      mmHg; 95% CI: -10.7-0.9), and significantly higher degradation products in urine
      (hydroxyproline/creatinine: 21.2 micro mol/mmol; 95% CI: 2.3-40.1) as compared
      with asymptomatic hypermobile children of the total reference group (n = 16).
      After adjustment for possible confounders, children with generalized joint
      hypermobility without musculoskeletal complaints had a significantly higher total
      range of joint motion and more profound skin extensibility, as compared with the
      reference group (n = 79). CONCLUSIONS: Clinically manifested symptoms in
      otherwise healthy children with generalized joint hypermobility are accompanied
      by increases in the laxity of other body tissues. Thus, generalized joint
      hypermobility with musculoskeletal symptoms does not seem to be restricted to
      joint tissues. In symptomatic hypermobile children, a more systemic derangement
      was also present as compared with asymptomatic hypermobile children.

PMID- 12612281
TI  - Allergen-specific immunoglobulin E antibodies in wheezing infants: the risk for
      asthma in later childhood.
AB  - OBJECTIVE: To evaluate whether the measurement of specific immunoglobulin E (IgE)
      antibodies to food and/or inhalant allergens in infants who are hospitalized for
      wheezing can be used to predict later asthma. METHODS: Eighty-two children who
      were hospitalized for wheezing at <2 years of age were followed prospectively
      until early school age. The baseline data and the characteristics of infancy had
      been collected at enrollment. At school age, the children were evaluated for
      asthma and allergic manifestations, including skin prick tests to common inhalant
      allergens. Frozen serum samples obtained during the index episode of wheezing
      were available for 80 children for determination of food and inhalant allergen
      specific serum IgE antibodies by fluoroenzyme-immunometric assay, UniCAP,
      applying the Phadiatop Combi allergen panel. RESULTS: Asthma was present in 32
      (40%) children at school age. Food-specific IgE antibodies of >or=0.35 kU/L were
      found in 37 (46%) wheezing infants, but only specific IgE to wheat and to egg
      white at the level of >or=0.35 kU/L were significantly associated with later
      asthma. In regard to specific IgE to the mixture of food allergens, the cutoff
      level of >or=0.70 proved to be significant. Inhalant allergen-specific IgE of
      >or=0.35 kU/L was found only in 14 cases (18%), but when present, it was
      significantly predictive of asthma. Elevated levels of specific IgE antibodies to
      food or inhalant allergens were significantly associated with allergic rhinitis
      and skin-test reactivity at school age. CONCLUSIONS: When present in wheezing
      infants, specific IgE of >or=0.35 kU/L to wheat, egg white, or inhalant allergens
      are predictive of later childhood asthma. Consequently, detection of those
      specific IgE antibodies in wheezing infants may facilitate the early diagnosis of
      asthma, especially in cases with no clinically evident atopic manifestations.

PMID- 12612282
TI  - A mutation in mitochondrial DNA-encoded cytochrome c oxidase II gene in a child
      with Alpers-Huttenlocher-like disease.
AB  - OBJECTIVE: Cytochrome c oxidase (COX) deficiency has been demonstrated in some
      patients with Alpers-Huttenlocher disease, but no genetic background has been
      identified. Our objective was to determine the molecular defect underlying the
      mitochondrial respiratory chain deficiency in a child with Alpers-Huttenlocher
      like progressive cerebrohepatic disease. METHODS: The entire coding region of
      mitochondrial DNA was analyzed by conformation-sensitive gel electrophoresis and
      sequencing. Biochemical and morphologic investigations were performed on tissue
      biopsy material, including oximetric and spectrophotometric analyses of oxidative
      phosphorylation, histochemistry, and electron microscopy. RESULTS: Postmortem
      histologic examination revealed a marked loss of neurons in the olivary nuclei
      and a spongy change in the calcarine cortex, fatty infiltration and micronodular
      cirrhosis of the liver, and atrophic ovaries. A novel heteroplasmic 7706G>A
      mutation was found in the COX II gene. The median degree of the mutant
      heteroplasmy was 90% in 5 tissues examined but was lower in the blood of
      asymptomatic maternal relatives. The distribution of the mutant heteroplasmy was
      skewed to the left in single muscle fibers of the proband and her mother. The
      7706G>A mutation converts a hydrophobic alanine in a conserved transmembrane
      segment to hydrophilic threonine. CONCLUSIONS: The 7706G>A mutation is pathogenic
      and may lead to impaired dioxygen transfer to the active site of COX. The
      clinical phenotype of this patient resembled that in Alpers-Huttenlocher disease,
      suggesting that analysis of mitochondrial DNA is worthwhile in patients with a
      progressive cerebrohepatic disease.

PMID- 12612283
TI  - Central venous catheter removal versus in situ treatment in neonates with
      enterobacteriaceae bacteremia.
AB  - OBJECTIVE: To determine how often neonates with Enterobacteriaceae (ENTB)
      bacteremia can be treated successfully without removing central venous catheters
      (CVCs). METHODS: A retrospective cohort study was conducted of ENTB bacteremia
      and CVCs in infants in a neonatal intensive care unit during a 7-year period
      (1994-2000). Cases of ENTB bacteremia were identified from a microbiology
      database and limited to late-onset cases occurring after 3 days of age. RESULTS:
      There were 53 cases of ENTB bacteremia in infants with CVCs. Blood cultures were
      positive for ENTB within a median of 10 hours (range: 5-43). Timing of CVC
      removal was at the discretion of attending neonatologists. Fifteen cases had
      early-removal CVC (ER-CVC) within 2 days, and 38 cases had late-removal CVC (LR
      CVC) >2 days after the first positive blood culture for ENTB. There were no
      significant differences between infants in the ER-CVC and LR-CVC groups for case
      fatality, recurrence, or duration of ENTB bacteremia. Although 16 (42%) of 38
      (95% confidence interval [CI]: 26%-59%) LR-CVC cases required CVC removal to
      resolve ENTB bacteremia, 17 (45%) of 38 (95% CI: 29%-62%) LR-CVC cases were
      treated successfully without removal of CVCs. ENTB bacteremia was successfully
      treated without CVC removal in 85% of 13 LR-CVC cases with 1 day of bacteremia in
      contrast to 24% of 25 LR-CVC cases with >1 day of bacteremia (relative risk: 3.5;
      95% CI: 1.7-7.4). CVC removal was required to resolve ENTB bacteremia in 9 (82%)
      of 11 LR-CVC cases with severe thrombocytopenia compared with 7 (32%) of 22 LR
      CVC cases without severe thrombocytopenia (relative risk: 2.6; 95% CI: 1.3-5.0).
      CONCLUSIONS: Retention of CVCs was successful in 45% of cases of ENTB bacteremia
      in which it was attempted, but success was unlikely when bacteremia lasted >1
      day. ENTB bacteremia cases associated with severe thrombocytopenia rarely
      resolved unless CVCs were removed.

PMID- 12612284
TI  - Impact of protease inhibitor substitution with efavirenz in HIV-infected
      children: results of the First Pediatric Switch Study.
AB  - OBJECTIVE: Simplification of antiretroviral regimen in human immunodeficiency
      virus (HIV)-infected children has not yet been investigated. In general, children
      have a more difficult time maintaining viral suppression because of many factors,
      including frequent nonadherence and less availability of antiretrovirals in
      palatable forms. In addition, many serious metabolic complications have emerged
      in HIV-infected adults and are believed to be attributable to antiretroviral
      therapy. Some of these complications--hypercholesterolemia, hypertriglyceridemia,
      and insulin resistance--are believed to be the result of the use of protease
      inhibitor (PI) therapy, whereas the cause of others, such as lipodystrophy,
      remains undetermined. Recent reports underline that children experience long-term
      metabolic abnormalities in the same manner that adults do, and perhaps these
      consequences are even more worrisome in children secondary to long-term expected
      survival. We report here the results of the first open-label PI-switch study in
      HIV-infected children. METHODS: Seventeen children, 24 to 160 months of age
      (median: 120), were enrolled into the study. All were receiving a stable PI
      containing antiretroviral regimen that containing 2 to 3 nucleoside analogue
      reverse transcriptase inhibitors (NRTIs) in addition to 1 to 2 PIs for a median
      duration of 21 months (range: 5-50) before study entry. All children had HIV-1
      RNA <400 copies/mL at screening; their baseline plasma HIV-1 RNA level had been
      <400 copies/mL for a median of 13 months (range: 4-55) before study entry. All
      patients were naive to nonnucleoside reverse transcriptase inhibitor therapy.
      Their protease inhibitor(s) was switched to efavirenz while their NRTI therapy
      was maintained. RESULTS: All children were heavily pretreated; 88% of the
      patients had previous NRTIs, and 41% had previous PI use. The most common PI at
      study entry was nelfinavir (47%), followed by ritonavir (29%), then amprenavir
      (18%); only 1 was on saquinavir/ritonavir. At study entry, the duration of
      previous antiretroviral therapy was between 21 and 123 months (median: 88). All
      patients completed the 48-week study. No acquired immunodeficiency syndrome
      defining events occurred. There were no rashes and no changes in liver
      transaminases. Mild, transient insomnia and dizziness each occurred in 1 child.
      Two other subjects (6 and 8 years old) experienced unusual vivid dreams, mostly
      pleasant, which decreased in intensity and frequency after the first 12 weeks of
      the study. One subject, a 10-year-old girl, had an episode of generalized seizure
      at week 6; study drugs were not interrupted, and seizure never recurred. The
      patient had a strong family history of epilepsy, although she had never
      experienced previous seizures. No anticonvulsants were given. Sixteen of 17
      patients had HIV-1 RNA levels of <50 copies/mL (1 HIV-1 RNA was 61 copies/mL) at
      week 48. The mean CD4% remained stable initially from a mean of 35.1% (+/-2.8%)
      at baseline to 36.8% (+/-5%) at week 24, but increased to 38% (+/-6%) at week 48.
      Fasting triglycerides decreased from a mean of 126 mg/dL (+/-50) at baseline to
      86 mg/dL (+/-45) at week 24 and to 94 mg/dL (+/-38) at week 48. At study entry,
      12 (71%) of 17 children had triglyceride levels greater than the 95th percentile
      for age, race, and gender, compared with only 6 (35%) of 17 at week 48. Fasting
      cholesterol levels decreased from a mean of 203 mg/dL (+/-50) at baseline to 173
      mg/dL (+/-31) at week 24 and to 174 mg/dL (+/-27) at week 48. At study entry, 5
      (29%) of 17 children had cholesterol levels greater than the 95th percentile for
      age, race, and gender, compared with only 1 (6%) of 17 at week 48. The decrease
      in low-density lipoprotein cholesterol was also significant, from a mean baseline
      of 124 mg/dL (+/-42) to 100 mg/dL (+/-28) at week 24 and to 105 mg/dL (+/-20) at
      week 48. High-density lipoprotein (HDL) cholesterol did not change significantly,
      but the changes in cholesterol:HDL ratio, a better marker of atherogenic risk,
      significantly decreased from a mean baseline of 3.8 (+/-0.8) to 3.2 (+/-0.7) at
      week 24 and to 3 (+/-0.6) at week 48. Detailed dietary history revealed no
      significant changes during the study. In addition, none of the patients initiated
      therapy with lipid-lowering agents. There were no significant changes in insulin
      or C-peptide throughout the study period. In addition, anthropometric
      measurements that included mid-thigh and mid-arm circumferences, triceps and
      thigh skinfolds, and waist:hip ratio were stable throughout the study period. For
      bioelectrical impedance measurements, lean body mass increased from a mean
      baseline of 32.1 lb (+/-9.3) to 35.7 lb (+/-11.4) at week 24 and to 36.5 lb (+/
      11.5) at week 48. Bioelectrical impedance measurements of fat content were
      unchanged throughout the study period. CONCLUSION: This is the first study in
      children to evaluate the substitution of PI in a virologically successful regimen
      with efavirenz, a potent once-daily nonnucleoside reverse transcriptase inhibitor
      therapy. We were able to show significant improvement in fasting total
      cholesterol, low-density lipoprotein cholesterol, triglycerides, and, more
      important, the cholesterol:HDL ratio. In addition, switching to an efavirenz
      containing regimen was well tolerated and successfully maintained virologic
      suppression in all HIV-infected children in this study. This study should
      encourage large randomized trials to investigate simplification strategies in HIV
      infected children.

PMID- 12612285
TI  - Transient suppression of atopy in early childhood is associated with high
      vaccination coverage.
AB  - OBJECTIVE: To analyze prevalences of allergic sensitization and atopic disease in
      relation to vaccination coverage. METHODS: A German atopy risk-enhanced birth
      cohort of 1314 neonates who were born in 1990 in 5 German cities was studied. A
      total of 943 children participated in the follow-up visit at 5 years of age.
      Atopic symptoms and diagnoses (derived from structured interviews), total serum
      immunoglobulin E, and specific immunoglobulin E against 9 common allergens (CAP
      Radio-Allergo-Sorbent Test Fluoro-Enzyme Immunoassay) were evaluated. Children
      were grouped into dose percentiles according to cumulative doses of any vaccine
      given up to 5 years of age (<10%, 0-11 doses; 10%-50%, 12-14 doses; 51%-90%, 15
      20 doses; >90%, 21-27 doses). RESULTS: The cumulative vaccine dose was inversely
      related to atopic dermatitis prevalences at 6 months (13.8%, 5.2%, 5.1%, and
      4.5%), 2 years (16.9%, 10.9%, 7.4%, and 3.7%), 3 years (27.6%, 16.4%, 13.5%, and
      4.5%), and 5 years (28.3%, 16.0%, 9.3%, and 11.9%). Asthma followed a similar
      pattern at age 3 (22.4%, 8.6%, 6.7%, and 6.3%), age 4 (20.0%, 8.6%, 8.9%, and
      8.1%), and age 5 (20.8%, 12.6%, 10.3%, and 5.5%). Allergic sensitization rates
      were inversely related to the cumulative vaccine dose at age 2 (37.5%, 29.1%,
      23.8%, and 12.9%). CONCLUSION: Children with a higher vaccination coverage seemed
      to be transiently better protected against development of atopy in the first
      years of life.

PMID- 12612286
TI  - Tagum study II: follow-up study at two years of age after prenatal exposure to
      mercury.
AB  - OBJECTIVES: To correlate the presence and levels of total mercury (THg) in cord
      blood and meconium indicating prenatal exposure with developmental milestones at
      2 years and to compare these subjects with controls of comparable age using
      cognitive adaptive test and clinical linguistic auditory milestone scale
      (CAT/CLAMS). METHODS: In 48 of the original Tagum (T) subjects, cord blood and
      meconium Hg levels, head circumference (HC) at birth, and duration of
      breastfeeding were correlated with CAT/CLAMS at 2 years. At 2 years, THg levels
      using cold atomic vapor absorption spectrometry were determined in the hair of 46
      T subjects and 88 Saranggani (S) controls; THg levels in blood were tested in 48
      T subjects and 45 S controls. These levels were correlated with CAT/CLAMS. Both
      groups had standard physical and neurologic examinations, hearing screen using
      transitory evoked otoacoustic emissions, serum glutamate pyruvate transaminase,
      and routine urinalysis. A prevalidated Socioeconomic Means Test was given to both
      groups. RESULTS: The Hg level in cord blood was negatively correlated with
      CAT/CLAMS at 2 years. The HC at birth was negatively correlated with levels of Hg
      in hair of T subjects 2 years later. HC at birth and 2 years hence were
      positively correlated with CAT/CLAMS. The following were significantly higher in
      S controls than in T subjects: expressive language quotient 82.569 +/- 2.21
      versus 71.57 +/- 2.61; CLAMS 87.96 +/- 2.43 versus 77.67 +/- 2.51; CAT 90.57 +/-
      2.22 versus 83.15 +/- 1.43; and full-scale developmental quotient 89.31 +/- 2.14
      versus 80.56 +/- 1.86. Fifteen percent of T subjects had global delay (full-scale
      developmental quotient <or=70) versus 5.48% in S controls. Hg levels in hair and
      blood in both T subjects and S controls at 2 years showed no correlation with
      CAT/CLAMS. The duration of breastfeeding in both groups likewise showed no
      correlations with CAT/CLAMS. CONCLUSION: The study suggests that prenatal Hg
      exposure is correlated with lower scores in neurodevelopmental screening, but
      more so in the linguistic pathway. Other confounding factors cannot be
      eliminated.

PMID- 12612288
TI  - Concerns of poor quality of life should not deprive patients of the opportunity
      of curative surgery.

PMID- 12612287
TI  - Maternal colonization and neonatal sepsis caused by Edwardsiella tarda.
AB  - A case of neonatal sepsis caused by Edwardsiella tarda, a bacterium usually
      associated with freshwater ecosystems, is described. The infant's mother was
      immersed in lake water during the sixth month of pregnancy and had vaginal and
      gastrointestinal colonization with the same strain of E tarda as the infant at
      the time of delivery. This case suggests that maternal exposures to contaminated
      bodies of water during pregnancy may represent a risk to newborns.

PMID- 12612289
TI  - Leukotriene receptor antagonists as add-on therapy for adults with asthma.
AB  - Assessment of the current evidence for the use of leukotriene receptor
      antagonists as add-on therapy at steps 3 and 4 of the guidelines for adults with
      moderate to severe asthma.

PMID- 12612291
TI  - Quality of life following lung cancer surgery.
AB  - BACKGROUND: Patients with non-small cell bronchogenic carcinoma have a limited
      survival. Quality of life (QoL) is therefore an issue of importance in this group
      of patients. The aim of the present study was to evaluate QoL in lung cancer
      patients after open surgery. METHODS: During a 4 year period (1997-2000) 194
      patients with primary bronchogenic carcinoma of the lung underwent surgery at the
      Department of Thoracic and Cardiovascular Surgery in Uppsala, Sweden; 132
      patients were alive on 1 April 2001. These patients received the Short Form-36
      (SF-36) health questionnaire, Hospital Anxiety and Depression (HAD) scale, and
      special questions related to pulmonary symptoms (response rate 85%). Patients who
      underwent coronary bypass surgery (CABG) served as a comparison group (response
      rate 91%). Corresponding estimates of QoL in healthy controls were obtained from
      the SF-36 manual for the Swedish population. RESULTS: Lung cancer patients
      differed from CABG patients in only one subgroup of the SF-36 (role physical),
      but had poorer QoL than healthy controls. No difference in anxiety was found
      between the lung cancer patients and the CABG patients, but the latter were more
      likely to suffer from depression (5.0% v 3.0%). Current smokers scored lower in
      the mental health dimension assessment. CONCLUSION: Lung cancer patients who
      undergo open traditional surgical resection have a QoL comparable to that of CABG
      patients. Lung cancer patients have poorer physical function because of reduced
      pulmonary function, but show no sign of increased anxiety or depression. Those
      who continued to smoke after surgery had impaired mental health.

PMID- 12612292
TI  - Regulation of matrix metalloprotease activity in malignant mesothelioma cell
      lines by growth factors.
AB  - BACKGROUND: The extracellular matrix metalloproteases (MMPs) produced by tumour
      and stromal cells are believed to play a key role in tumour cell invasion and
      metastasis. Malignant mesothelioma is a highly aggressive tumour. Previous
      studies have shown that malignant mesothelioma cells express MMP-1, -2, -3, -7
      and -9. However, the regulation of MMP expression in malignant mesothelioma cells
      has not been thoroughly investigated. METHODS: The effects of a number of growth
      factors on the secretion of MMP-2, -3 and -9 in malignant mesothelioma cells were
      studied by substrate zymography. The expression of relevant growth factor
      receptors in malignant mesothelioma cells was also examined using RT-PCR.
      RESULTS: The exposure of malignant mesothelioma cells to different growth factors
      including epidermal growth factor (EGF), transforming growth factor-alpha,
      amphiregulin, heparin binding EGF, beta-cellulin (BTC), stem cell factor, insulin
      like growth factors I and II, acidic and basic fibroblast growth factors, and
      hepatocyte growth factor increased secretion of MMP-9 and/or MMP-3. EGF receptor
      ligands BTC and EGF had the most potent effect on MMP-9 and MMP-3 production,
      respectively. Production of MMP-2 was not affected by any growth factors used in
      this study. We have also demonstrated mRNA expression of different growth factor
      receptors in malignant mesothelioma cells, and found that the tyrosine kinase
      inhibitor genistein inhibited the increased production of MMPs resulting from
      stimulation with different growth factors. CONCLUSION: This study shows, for the
      first time, the broad extent of regulation of MMPs by various growth factors in
      malignant mesothelioma cells.

PMID- 12612294
TI  - Effect of montelukast added to inhaled budesonide on control of mild to moderate
      asthma.
AB  - BACKGROUND: Proinflammatory leukotrienes, which are not completely inhibited by
      inhaled corticosteroids, may contribute to asthmatic problems [corrected]. A 16
      week multicentre, randomised, double blind, controlled study was undertaken to
      study the efficacy of adding oral montelukast, a leukotriene receptor antagonist,
      to a constant dose of inhaled budesonide. METHODS: A total of 639 patients aged
      18-70 years with forced expiratory volume in 1 second (FEV(1)) > or =55%
      predicted and a minimum predefined level of asthma symptoms during a 2 week
      placebo run in period were randomised to receive montelukast 10 mg (n=326) or
      placebo (n=313) once daily for 16 weeks. All patients received a constant dose of
      budesonide (400-1600 microg/day) by Turbuhaler throughout the study. RESULTS:
      Mean FEV(1) at baseline was 81% predicted. The median percentage of asthma
      exacerbation days was 35% lower (3.1% v 4.8%; p=0.03) and the median percentage
      of asthma free days was 56% higher (66.1% v 42.3%; p=0.001) in the montelukast
      group than in the placebo group. Patients receiving concomitant treatment with
      montelukast had significantly (p<0.05) fewer nocturnal awakenings and
      significantly (p<0.05) greater improvements in beta agonist use and morning peak
      expiratory flow rate (PEFR). CONCLUSIONS: For patients with mild airway
      obstruction and persistent asthma symptoms despite budesonide treatment,
      concomitant treatment with montelukast significantly improves asthma control.

PMID- 12612295
TI  - Randomised controlled trial of montelukast plus inhaled budesonide versus double
      dose inhaled budesonide in adult patients with asthma.
AB  - BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in
      asthma but have little impact on cysteinyl leukotrienes. This may partly explain
      persistent airway inflammation during chronic ICS treatment and failure to
      achieve adequate asthma control in some patients. This double blind, randomised,
      parallel group, non-inferiority, multicentre 16 week study compared the clinical
      benefits of adding montelukast to budesonide with doubling the budesonide dose in
      adults with asthma. METHODS: After a 1 month single blind run in period, patients
      inadequately controlled on inhaled budesonide (800 microg/day) were randomised to
      receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or
      budesonide 1600 microg/day (n=441) for 12 weeks. RESULTS: Both groups showed
      progressive improvement in several measures of asthma control compared with
      baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the
      last 10 weeks of treatment compared with baseline in both the montelukast +
      budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min).
      During days 1-3 after start of treatment, the change in AM PEF from baseline was
      significantly greater in the montelukast + budesonide group than in the double
      dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of
      action in the montelukast group. Both groups showed similar improvements with
      respect to "as needed" beta agonist use, mean daytime symptom score, nocturnal
      awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and
      asthma specific quality of life. Both montelukast + budesonide and double dose
      budesonide were generally well tolerated. CONCLUSION: The addition of montelukast
      to inhaled budesonide is an effective and well tolerated alternative to doubling
      the dose of inhaled budesonide in adult asthma patients experiencing symptoms and
      inadequate control on budesonide alone.

PMID- 12612298
TI  - Association of CCR5Delta32 with reduced risk of childhood but not adult asthma.
AB  - BACKGROUND: A number of potential candidate genes have been implicated in the
      pathogenesis of asthma. A 32 base pair deletion in the CCR5 gene renders this
      chemokine receptor non-functioning and has been shown to be associated with a
      reduced prevalence of asthma in childhood. The mechanism may be related to
      impairment of pathogen entry into cells and modified host inflammatory response.
      We sought to determine the influence of the CCR5Delta32 mutation on asthma and
      allergy in the transition from childhood to adulthood. METHODS: 627 individuals
      first studied as part of a whole population schoolchildren cohort in 1989 when
      aged 8-12 years were followed up 10 years later for respiratory and allergy
      symptoms and laboratory markers of atopy. CCR5Delta32 status was also
      characterised and the association with childhood and adulthood symptoms
      determined. RESULTS: The follow up sample was representative of the original
      cohort except for a slightly greater prevalence of symptomatic individuals. As
      children, none who were homozygous for the CCR5Delta32 mutation had a current
      physician's diagnosis of asthma. In multivariate analysis and controlling for
      known confounders, the protective effect of carrying the allele in childhood was
      highly significant (OR 0.31, 95% CI 0.14 to 0.72, p=0.006). There was no
      protective association with "current asthma" as classified in adulthood within
      the same population. Subjective or laboratory markers of atopy in childhood or
      adulthood were not associated with the CCR5Delta32 mutation. Methacholine
      bronchial hyperresponsiveness in adulthood was also unrelated to gene carrier
      status. CONCLUSIONS: In a population with a high allelic frequency for the
      CCR5Delta32 mutation, a significant protection against childhood asthma is
      evident which is independent of atopy. This protection is lost in the transition
      between childhood and early adulthood. The contribution of different genetic
      candidates to the expression of asthma may change with advancing maturity and
      confound the interpretation of association and linkage studies unless age is
      taken into account.

PMID- 12612296
TI  - Bronchodilation by an inhaled VPAC(2) receptor agonist in patients with stable
      asthma.
AB  - BACKGROUND: The synthetic vasoactive intestinal peptide (VIP) analogue Ro 25-1553
      is a selective VIP-PACAP type 2 (VPAC(2)) receptor agonist that causes a
      bronchodilatory effect in guinea pigs in vivo. The effect of Ro 25-1553 given by
      inhalation to patients with asthma was studied and compared with that of a long
      acting beta(2) adrenoceptor agonist. METHODS: Twenty four patients with moderate
      stable asthma participated in a double blind, randomised, placebo controlled,
      crossover study. The primary variable was bronchodilatory effect (increase in
      forced expiratory volume in 1 second, FEV(1)) after inhalation of Ro 25-1553 (100
      microg or 600 microg) and formoterol (4.5 microg), respectively. Putative side
      effects were characterised by monitoring sitting blood pressure, serum potassium,
      electrocardiography and echocardiography. RESULTS: Inhalation of 600 microg Ro 25
      1553 caused a rapid bronchodilatory effect (geometric mean increase in FEV(1)
      compared with placebo) within 3 minutes of 6% (95% CI 4 to 9), as did inhalation
      of formoterol (8% (95% CI 5 to 10)). The corresponding maximum bronchodilatory
      effect during 24 hours was similar for 600 microg Ro 25-1553 (7% (95% CI 4 to
      10)) and the reference bronchodilator formoterol (10% (95% CI 7 to 12)). However,
      for both doses of Ro 25-1553 the bronchodilatory effect was attenuated 5 hours
      after inhalation whereas formoterol still had a bronchodilatory effect 12 hours
      after inhalation. Neither Ro 25-1553 nor formoterol produced any clinically
      relevant side effects. No drug related difference in adverse events was observed.
      CONCLUSION: Inhalation of a synthetic selective VPAC(2) receptor agonist
      constitutes a promising approach for bronchodilation in patients with asthma.

PMID- 12612299
TI  - Systemic activity of inhaled corticosteroid treatment in asthmatic children:
      corticotrophin releasing hormone test.
AB  - BACKGROUND: A study was undertaken to assess the function of the hypothalamic
      pituitary-adrenal axis (HPA) in a group of asthmatic children before and after
      treatment with inhaled corticosteroids. METHODS: Thirty prepubertal patients of
      mean (SD) age 6.7 (1.8) years were treated with inhaled corticosteroids. All
      children underwent a corticotrophin releasing hormone (CRH) test with evaluation
      of serum cortisol and adrenocorticotrophin hormone (ACTH) levels before and after
      3 months of treatment. Twenty four hour urine samples were also collected to
      measure free cortisol (UFC) excretion. RESULTS: Subjects showed no difference
      between basal serum cortisol levels (mean change -18; 95% CI -41 to 5; p=0.118)
      and delta (peak minus basal) levels (mean change -13; 95% CI -38 to 12; p=0.308)
      before and after treatment, whereas the peak cortisol level (mean change -31; 95%
      CI -55 to -7; p=0.013) and area under the curve (AUC) (mean change -175; 95% CI 
      288 to -63; p=0.003) after CRH were significantly lower following treatment.
      Basal, peak and AUC ACTH were significantly lower after treatment (p<0.05,
      p=0.004 and p=0.003, respectively), while delta ACTH was similar before and after
      treatment ((mean change -12; 95% CI - 31 to -7; p=0.199). No significant
      reduction in 24 hour UFC was observed after the treatment period (before 14.9
      (7.1), after 15.0 (11.6); mean change 0.1, 95% CI -5.2 to 5.4; p=0.967). No
      correlation was found between UFC and any of the parameters of cortisol excretion
      following the CRH test, either before or after treatment. CONCLUSIONS: These data
      suggest that, at the dosage and for the treatment period used, inhaled steroids
      do not seem to suppress the HPA axis in the majority of patients. The CRH test
      may be more sensitive than 24 hour UFC and morning plasma cortisol levels in
      evaluating systemic activity of inhaled corticosteroid treatment.

PMID- 12612301
TI  - Nutrition and respiratory health in children in six Central and Eastern European
      countries.
AB  - BACKGROUND: The results of studies on the effect of nutrition on respiratory
      diseases are inconsistent. The role of nutrition in children's respiratory health
      was therefore analysed within the cross sectional Central European Study on Air
      Pollution and Respiratory Health (CESAR). METHOD: A total of 20 271 children aged
      7-11 were surveyed in six European countries. Respiratory health and food intake
      were assessed using questionnaires. Associations between four symptoms and
      nutritional factors were evaluated using logistic regression, controlling for
      area plus other potential confounders. RESULTS: All symptoms showed initial
      associations with nutritional factors. Low consumption of fish and of summer and
      winter fruit were the most consistent predictors. In a fully adjusted model low
      fish intake remained a significant independent predictor of persistent cough
      (OR=1.18; 95% CI 1.04 to 1.34), wheeze ever (OR=1.14; 95% CI 1.03 to 1.25) and
      current wheeze (OR=1.21; 95% CI 1.06 to 1.39) and a weaker predictor of winter
      cough (OR=1.10; 95% CI 0.99 to 1.23). Low summer fruit intake was a predictor of
      winter cough (OR=1.40; 95% CI 1.10 to 1.79) and persistent cough (OR=1.35; 95% CI
      1.01 to 1.82). Low winter fruit intake was associated with winter cough (OR=1.28;
      95% CI 1.09 to 1.51). Associations between symptoms and vegetable intake were
      inconsistent. Low summer intake was significantly associated with winter cough
      (OR=1.23; 95% CI 1.03 to 1.47) but, overall, winter intake had inverse
      associations with both coughs. Associations between winter vegetable intake and
      wheeze varied considerably between countries. CONCLUSION: A number of
      associations were found between respiratory symptoms and low intake of fish,
      fruit and vegetables in children. Low fish intake was the most consistent
      predictor of poor respiratory health. Fruit and vegetable intake showed stronger
      associations with cough than with wheeze.

PMID- 12612303
TI  - Passive smoking and lung function in alpha(1)-antitrypsin heterozygote
      schoolchildren.
AB  - BACKGROUND: A study was performed to determine whether Pi heterozygotes exposed
      to smoking have a higher risk of reduced lung function than Pi M homozygotes.
      METHODS: The effect of passive smoking on lung function was investigated in a
      cross sectional study of 997 primary and secondary schoolchildren aged 11-13
      years categorised by Pi phenotype as either PiM homozygotes or Pi heterozygotes.
      Data on respiratory health and risk factors were collected by questionnaire, lung
      function was measured by spirometric tests, bronchial hyperresponsiveness was
      evaluated by methacholine test, atopic status was evaluated by skin prick
      testing, and a blood sample was collected to determine Pi phenotype. Urinary
      cotinine and creatinine concentrations were determined and assessment of exposure
      was made from questionnaire data and urinary cotinine concentrations. The results
      were analysed by multiple regression analysis. RESULTS: Sixty one subjects (6.1%)
      were found to be Pi heterozygotes. Lung function did not differ between
      homozygotes and heterozygotes. There was a reduction in lung function in subjects
      exposed to parental smoking in the overall sample: FEV(1)/FVC ratio (-0.78%),
      FEF(25-75) (-0.11 litres), and FEF(75) (-0.13 litres). Interaction terms between
      parental smoking and Pi status were significant with regard to FEV(1)/FVC ratio
      (p=0.035) and FEF(50) (p=0.023). In subjects exposed to parental smoking the
      decrement in lung function in Pi heterozygotes tended to be greater (FEV(1)/FVC
      ratio = -2.57, FEF(25-75) = -0.30, FEF(50) = -0.43, and FEF(75) = -0.29) than in
      PiM homozygotes. These results did not change significantly when the urinary
      cotinine concentration was used as an exposure variable. CONCLUSIONS: The
      detrimental effect of environmental tobacco smoke on lung function in
      schoolchildren is confirmed. This harmful effect is greater in Pi heterozygotes
      than in PiM homozygotes.

PMID- 12612305
TI  - Investigation of mycobacterial colonisation and invasion of the respiratory
      mucosa.
AB  - BACKGROUND: The pathogenesis of Mycobacterium avium complex and Mycobacterium
      tuberculosis in the respiratory tract is poorly understood, as are the reasons
      for their differing virulence. We have previously shown that their initial
      adherence to the mucosa is identical. METHODS: The interaction of M avium
      complex, M tuberculosis, and M smegmatis with human respiratory tissue was
      investigated in an organ culture model with an air interface. Tissue was infected
      for intervals up to 14 days and assessed by scanning electron microscopy for
      adherent bacteria or cultured for recoverable bacteria. RESULTS: The mean number
      of adherent bacteria/mm(2) (and the viable count of macerated tissue, cfu/ml) at
      15 minutes, 3 and 24 hours, 7 and 14 days were: M avium complex 168 (153), 209
      (136), 289 (344), 193 (313), 14140 (16544); M tuberculosis 30 (37), 39 (23), 48
      (53), 1 (760), 76 (2186); M smegmatis 108 (176), 49 (133), 97 (81), 114 (427), 34
      (58), (n=6). There was no significant change in morphology between infected and
      uninfected tissue or tissue infected with the different species over 14 days. The
      number of M avium complex on the mucosa and recovered from tissue increased over
      time (p=0.03). M tuberculosis decreased on the surface, but recoverable bacteria
      increased (p=0.01). M smegmatis numbers on the mucosa and recovered from tissue
      decreased. Sectioned tissue showed M avium complex and M tuberculosis in
      submucosal mucus glands and M tuberculosis penetrating epithelial cells in one
      experiment. CONCLUSIONS: The initial adherence to the mucosa of the three species
      was similar, but after 14 days they varied in their interaction with the tissue
      in a manner compatible with their pathogenicity.

PMID- 12612304
TI  - Relationship between exhaled NO, respiratory symptoms, lung function, bronchial
      hyperresponsiveness, and blood eosinophilia in school children.
AB  - BACKGROUND: Exhaled nitric oxide (eNO) may serve as a non-invasive marker of
      airway inflammation but its relationship with other commonly used measures has
      not been evaluated. METHODS: Levels of eNO in a sample of 450 children aged 7-12
      years out of a total sample of 2504 school children living in different urban
      areas near motorways were determined. The aim of this cross-sectional study was
      to explore the relationship between eNO, impairment of lung function (PEF, FVC,
      FEV(1) and MMEF), bronchial hyperresponsiveness (BHR), and blood eosinophilia in
      children with and without atopy as assessed by skin prick testing. RESULTS:
      Regression analysis showed that wheezing and nasal discharge and conjunctivitis
      that had occurred during the previous 12 months were positively associated with
      eNO levels in atopic children (relative increase of 1.48 and 1.41, respectively;
      p<0.05) but not in non-atopic children. Similarly, BHR and the number of blood
      eosinophils per ml were positively associated with eNO levels in atopic children
      (relative increase of 1.55 and 2.29, respectively; p<0.05) but not in non-atopic
      children. The lung function indices PEF, FVC, FEV(1) and MMEF were not associated
      with eNO levels. CONCLUSIONS: In addition to conventional lung function tests and
      symptom questionnaires, eNO is a suitable measure of airway inflammation and its
      application may reinforce the power of epidemiological surveys on respiratory
      health.

PMID- 12612307
TI  - Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B
      levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in
      patients with idiopathic alveolar proteinosis.
AB  - BACKGROUND: Conventional measures of the severity of alveolar proteinosis (AP)
      include alveolar-arterial oxygen gradient ([A - a]DO(2)), vital capacity (VC),
      and carbon monoxide transfer factor (TLCO), but alternative serological measures
      have been sought. Granulocyte-macrophage colony stimulating factor (GM-CSF)
      neutralising autoantibody is found in patients with idiopathic acquired AP. We
      have investigated the interrelationships between the levels of this antibody and
      those of surfactant protein (SP)-A and -B, lactate dehydrogenase (LDH), and
      conventional measures of disease severity, and the capacity of these parameters
      to predict the response to rhGM-CSF treatment. METHODS: Blood levels of anti-GM
      CSF antibodies, SP-A, SP-B, LDH, and [A - a]DO(2), VC, and TLCO were measured
      before rhGM-CSF treatment and every 2 weeks thereafter in 14 patients with AP.
      RESULTS: At baseline, high levels of anti-GM-CSF antibodies and increased SP-A
      and SP-B levels were seen in all patients, and LDH was raised in 83%. SP-A was
      highly correlated with [A - a]DO(2), VC, and TLCO (p</=0.02), but other markers
      were not. Only a normal LDH level was predictive of a response to rhGM-CSF
      treatment (p=0.03). During treatment a correlation between conventional and
      serological variables within patients was seen only between SP-A and [A - a]DO(2)
      (p=0.054), LDH levels and [A - a]DO(2) (p=0.010), and LDH levels and VC
      (p=0.019). CONCLUSIONS: Of the serological parameters studied, only SP-A and LDH
      levels were correlated with conventional measures of disease severity, with LDH
      most accurately reflecting [A - a]DO(2) and vital capacity. Only a normal LDH
      level predicted a higher likelihood of response to treatment with GM-CSF.

PMID- 12612308
TI  - Plasma concentrations of fluticasone propionate and budesonide following
      inhalation from dry powder inhalers by healthy and asthmatic subjects.
AB  - BACKGROUND: All currently available inhaled corticosteroids reach the systemic
      circulation and have the potential to produce adverse effects with long term use.
      This risk is often assessed by measuring the effect of different inhaled
      corticosteroids on the hypothalamic-pituitary-adrenal (HPA) axis in healthy
      subjects. Absorption of fluticasone propionate and its effects on the HPA axis
      are greater in healthy subjects than in subjects with moderately severe asthma,
      but we have failed to show any difference in morning budesonide plasma levels or
      systemic effects between healthy and asthmatic subjects following inhalation of
      budesonide. To provide more information on the absorption of fluticasone
      propionate and budesonide, we have compared the plasma levels of both drugs over
      8 hours in healthy and asthmatic subjects. METHODS: The area under the plasma
      concentration-time curves (AUC) and the maximum concentration (Cmax) of
      fluticasone propionate and budesonide after a single inhaled dose of each drug
      were compared in 12 healthy control subjects and 12 subjects with moderately
      severe asthma. RESULTS: Peak plasma levels of budesonide occurred much earlier
      and were approximately 20-fold higher than those of fluticasone propionate in
      both healthy and asthmatic subjects. The AUC and Cmax for fluticasone propionate
      were lower by 307 (95% CI 62 to 522) pg/ml/h or 43% (p=0.02) and 52 (95% CI -11
      to 115) pg/ml or 39% (p=0.1) in subjects with asthma compared with healthy
      control subjects. In contrast, the AUC and Cmax for budesonide were almost
      identical between the two groups (mean differences 826 (95% CI -1493 to 3143)
      pg/ml/h (p=0.5) and 157 (95% CI -1026 to 1339) pg/ml (p=0.8). CONCLUSIONS:
      Following inhalation, healthy subjects have higher plasma levels of fluticasone
      propionate than subjects with asthma whereas budesonide plasma levels are similar
      in the two groups of subjects. Comparing the systemic effects of budesonide and
      fluticasone propionate in healthy subjects is unlikely to be relevant to subjects
      with asthma.

PMID- 12612309
TI  - Chronic obstructive pulmonary disease . 7: Management of COPD.
AB  - A review of the management of COPD is presented, with particular emphasis on the
      effect on the approach to management of new information which has become
      available in the 5 years since the BTS guidelines on COPD were published. A major
      problem is the effective implementation of what is already known, and allocation
      of the resources necessary to make this available to all who might benefit.

PMID- 12612311
TI  - Ethics and decision making in end stage lung disease.
AB  - Most physicians believe they do more good than harm, and these duties of helping
      and not harming the patient are rooted in the Hippocratic oath, the good
      Samaritan tradition, and the Order of the Knight Hospitallers founded in the 11th
      century to care for pilgrims and those wounded in the Crusades.(1) In recent
      times the simple principles of beneficence and non-maleficence have been
      augmented and sometimes challenged by a rising awareness of patient/consumer
      rights, and the public expectation of greater involvement in medical, social and
      scientific affairs which affect them. In a publicly funded healthcare system in
      which rationing (explicit or otherwise) is inevitable, the additional concepts of
      utility and distributive justice can easily come into conflict with the
      individual's right to autonomy. Possible treatment options for end stage lung
      disease include transplantation and long term invasive ventilation which are
      challenging in resource terms. Other interventions such as pulmonary
      rehabilitation and palliative care are relatively low cost but not uniformly
      accessible.

PMID- 12612310
TI  - Lung cancer . 3: Fluorescence bronchoscopy: clinical dilemmas and research
      opportunities.
AB  - Recent developments in the detection of pre-invasive lesions of the large airways
      by fluorescence bronchoscopy are reviewed and the clinical and biological
      implications discussed.

PMID- 12612312
TI  - Pulmonary granulomas after tumour necrosis factor alpha antagonist therapy.
AB  - Tumour necrosis factor alpha (TNFalpha) antagonists are an established
      therapeutic option in Crohn's disease and rheumatoid arthritis. In recently
      published studies these agents have been used with great success, but little is
      known about any side effects or long term consequences. They increase the
      frequency of infections with mycobacteria, where TNFalpha is thought to be an
      important host defence factor. We describe one patient who was treated with
      TNFalpha antagonists and later developed pulmonary granulomas with caseating
      necrosis without detection of mycobacteria or any other pathogens. Possible
      mechanisms involved in this newly recognised side effect are discussed.

PMID- 12612313
TI  - Revision of BTS guidelines for treatment of asthma.

PMID- 12612314
TI  - Caffeine and exhaled nitric oxide.

PMID- 12612315
TI  - Morbid obesity and hypersomnolence in several members of an ancient royal family.

PMID- 12612316
TI  - Chronic respiratory failure.

PMID- 12612317
TI  - Clinical challenges posed by new biotechnology.

PMID- 12612319
TI  - Effects of the civil procedure rules on clinical negligence claims.
AB  - The frequency with which clinicians can expect to face allegations of clinical
      negligence and court proceedings related to those allegations is likely to
      increase in coming years. The processes of investigation and defence have been
      modified by the introduction of the Civil Procedure Rules in 1999. This review
      outlines these developments and emphasises the need for speedy and comprehensive
      responses by doctors involved in such procedures.

PMID- 12612318
TI  - Present treatment options for atrial fibrillation.
AB  - Atrial fibrillation is the commonest sustained cardiac arrhythmia. It accounts
      for >35% of all hospital admissions for cardiac arrhythmias in the United States.
      The presence of atrial fibrillation increases the mortality of a population by up
      to twofold. The risk of stroke increases from 1.5% in patients with atrial
      fibrillation from 50-59 years of age to up to 23.5% for such patients aged 80-89
      years. Although the diagnosis of atrial fibrillation is usually straightforward,
      effective treatment is not. This article will discuss how rhythm control of
      atrial fibrillation can best be achieved, the controversy over the rhythm versus
      rate control, the maintenance of sinus rhythm with antiarrhythmic drugs after
      cardioversion, and prevention of thromboembolism. Finally, the recent advances in
      various non-pharmacological approaches for the treatment of atrial fibrillation
      will be highlighted.

PMID- 12612320
TI  - Juvenile myoclonic epilepsy: under-appreciated and under-diagnosed.
AB  - Juvenile myoclonic epilepsy (JME) is a hereditary, idiopathic, generalised
      epilepsy and is found in 5%-11% of patients with epilepsy. It is characterised by
      myoclonic jerks, occasional generalised tonic-clonic seizures, and sometimes
      absence seizures. JME continues to be under-appreciated and under-diagnosed.
      Accurate diagnosis is important as it usually responds well to treatment with
      appropriate anticonvulsants and misdiagnosis often results in unnecessary
      morbidity. In addition lifelong therapy is usually indicated as the natural
      history is one of relapse off treatment, even after a prolonged seizure-free
      period.

PMID- 12612321
TI  - Migraine, memory loss, and "multiple sclerosis ". Neurological features of the
      antiphospholipid (Hughes') syndrome.
AB  - The antiphospholipid syndrome (APS, Hughes' syndrome), first described in 1983,
      is a prothrombotic disease in which neurological events feature prominently.
      Strokes, transient ischaemic attacks, and headaches (including migraine) are
      important complications. However, it is clear that other neurological symptoms,
      including diplopia, memory loss, ataxia, and "multiple sclerosis-like" features
      are common. A notable feature of Hughes' syndrome is the clinical response to
      anticoagulants; features such as headache and memory loss often improving
      dramatically with appropriate warfarin dosage. APS may well become recognised as
      an important (and potentially treatable) cause of neurological disease.

PMID- 12612322
TI  - Brachial plexus injury as an unusual complication of coronary artery bypass graft
      surgery.
AB  - Brachial plexus injury is an unusual and under-recognised complication of
      coronary artery bypass grafting especially when internal mammary artery
      harvesting takes place. It is believed to be due to sternal retraction resulting
      in compression of the brachial plexus. Although the majority of cases are
      transient, there are cases where the injury is permanent and may have severe
      implications as illustrated in the accompanying case history.

PMID- 12612323
TI  - Management of stroke.
AB  - This article outlines the current evidenced based practice for stroke care. It
      outlines many of the recommendations in the National Clinical Guidelines for
      Stroke published by the Royal College of Physicians. It also covers all aspects
      of multidisciplinary stroke care from initial assessment and acute treatment to
      rehabilitation strategies and management of complications. The article concludes
      with an examination of the latest evidence for secondary prevention of
      cerebrovascular disease.

PMID- 12612324
TI  - Are district general hospital patients with unstable angina at a disadvantage?
AB  - OBJECTIVE: To determine whether patients with non-ST elevation acute coronary
      syndromes requiring coronary angiography and revascularisation have inferior
      access to these services if admitted to district general hospitals (DGHs)
      compared with similar patients admitted to a base hospital containing a tertiary
      cardiac centre. DESIGN: Prospective, consecutive monitoring of all patients with
      acute coronary syndromes accepted by the tertiary cardiac centre for angiography
      and revascularisation over a three month period (1 April to 30 June 2002).
      PARTICIPANTS: All patients accepted for angiography from DGHs and from within the
      base hospital with a diagnosis of acute coronary syndromes. SETTING: Tertiary
      cardiac facility (Manchester Heart Centre at Manchester Royal Infirmary (MRI)).
      MAIN OUTCOME MEASURE: Time waited from referral to angiography and
      revascularisation. RESULTS: A total of 184 patients with a diagnosis of non-ST
      elevation acute coronary syndromes underwent angiography with a view to
      revascularisation. Of these, 89 (48%) were admitted initially to MRI and 95 (52%)
      were admitted to a feeder DGH. DGH patients waited significantly longer from
      admission to angiography than MRI patients (median 13 days (25th-75th percentiles
      7-19) v 5 days (3-8) respectively; p<0.0005). DGH patients therefore also waited
      longer from admission to revascularisation (15 days (6-20) v 6 days (3-9)
      respectively). Once transferred into the Manchester Heart Centre, DGH patients
      underwent angiography within a median of 1 day (1-2). More DGH patients than
      those from MRI underwent both coronary artery bypass grafting (21 (22%) v 8 (9%)
      respectively; p=0.015) and percutaneous coronary intervention (44 (46%) v 32
      (36%) respectively; p=NS). CONCLUSION: Patients admitted to feeder DGHs with non
      ST elevation acute coronary syndromes wait significantly longer for access to
      invasive coronary assessment and revascularisation than similar patients admitted
      in the hospital that incorporates the tertiary cardiac centre. This inequity of
      access is determined by postcode rather than clinical priority.

PMID- 12612325
TI  - Illumination of x-rays: the usual lights exposed.
AB  - AIMS: Faced with pressure of work and limited resource, doctors frequently use
      the nearest available light to examine x-ray films. The aim of this study was to
      examine the relative intensities of hospital light sources, and to compare these
      with the light intensity guidelines (1500 to 3000 candelas) of the British
      Institute of Radiology. METHODS: The relative intensities of seven hospital light
      sources were examined using a standard light meter at a constant 30 cm from the
      source. A control group of 10 individual consultant's x-ray viewing boxes were
      compared with six other ward based light sources. RESULTS: Only two light sources
      approached the British Institute of Radiology light intensity x-ray viewing
      criteria: the x-ray viewing boxes of consultant radiologists with a median light
      intensity of 3503 candelas (chi(2)=13.3, df 1; p=0.0001), and daylight from north
      facing windows with a median of 1464 candelas when overcast (chi(2)=8.571, df 1;
      p=0.003) and 4669 candelas in sunshine (chi(2)= 6.364, df 1; p=0.0001).
      CONCLUSION: Few hospital light sources met the British Institute of Radiology
      guidelines. The long held high regard of artists for northern light appears
      justified even in the environment of a British district general hospital.

PMID- 12612326
TI  - Dr D G James FRCP and the Fellowship of Postgraduate Medicine.
AB  - Dr D G James recently retired as Vice President of the Fellowship of Postgraduate
      Medicine. The following article is based on a speech given at a dinner at the
      Athenaeum Club on 10 October 2002 to thank Dr James for his contributions to the
      Fellowship of Postgraduate Medicine over 50 years.

PMID- 12612327
TI  - Phthiriasis palpebrarum.

PMID- 12612328
TI  - Thallium poisoning: emphasis on early diagnosis and response to haemodialysis.
AB  - Thallium poisoning is known for its diverse manifestations and these can delay
      the diagnosis if a clear history of poisoning is not forthcoming. A 42 year old
      man presented on the third day of illness with flaccid quadriparesis and
      paresthesia, which were confused with Guillain-Barre syndrome. Because of
      associated loose motions, skin lesions, and liver and kidney dysfunction arsenic
      poisoning was considered. In the second week he developed ophthalmoplegia,
      nystagmus, and neck tremor and later developed alopecia, and thallium poisoning
      was suspected. His serum thallium level on the 18th day of illness was 40 980
      micro g/ml. He was subjected to haemodialysis, potassium supplementation,
      laxatives, and B complex supplementation. He showed significant improvement after
      haemodialysis and at three months he was able to walk with support. At six months
      of follow up he was independent for activities of daily living. Severe
      paresthesia, ophthalmoplegia, cerebellar and extrapyramidal signs, and alopecia
      are highly suggestive of thallium poisoning. Haemodialysis may be effective even
      in the third week of poisoning.

PMID- 12612329
TI  - Simultaneous bilateral spontaneous pneumothorax in a patient with recurrent,
      extraosseous multiple myeloma.
AB  - A patient with simultaneous bilateral spontaneous pneumothorax (SBSP) due to
      pulmonary and pleural manifestations of recurrent multiple myeloma is presented.
      The patient died in shock of unknown cause. The diagnosis was suspected from
      pleural fluid examination showing an exudate with numerous plasmocytes.
      Macroscopically and histologically, the visceral organs and the bone marrow were
      infiltrated with multiple monoclonal proliferations of plasma cells staining
      positively for IgG and lambda chains. SBSP is a rare condition and may be caused
      by trauma, parenchymal lung disease, infections, or neoplasms. This is the first
      report of SBSP caused by pleuropulmonary infiltration of multiple myeloma.

PMID- 12612330
TI  - Roth's spots: an unusual presentation of HIV.
AB  - A 46 year old Nigerian man presented with a four week history of progressive
      bilateral visual loss. He had been unwell, with weight loss, fever, and night
      sweats for six months. Dilated fundoscopy revealed macular haemorrhages and
      diffuse Roth's spots. The patient was found to be severely anaemic and a bone
      marrow aspirate revealed a T cell lymphoma with a decreased CD4+ T cell count.
      The patient consented for testing for HIV which proved positive.

PMID- 12612331
TI  - D-lactic acidosis secondary to short bowel syndrome.
AB  - A 12 year old boy presented with 11 episodes of weakness, ataxia, nausea, slurred
      speech, dehydration, and sometimes severe lethargy bordering on coma. A year
      previously the boy had small intestinal resections leaving 20 cm of small bowel
      remaining. D-lactic acidosis was diagnosed on the basis of a D-lactate level of
      5.23 mmol/l. The clinical presentation of the disease is recurrent episodes of
      unusual neurological manifestations and severe metabolic acidosis. The diagnosis
      is dependent on the presentations and the plasma D-lactate level. Development of
      the syndrome seems to be the effect of the accumulation of D-lactic acid.

PMID- 12612332
TI  - Hydatid cyst of liver.
AB  - Hydatid disease of the liver is still endemic in certain parts of the world. The
      diagnosis of non-complicated hydatid cyst of the liver depends on clinical
      suspicion. Ultrasonography and computed tomography, the most important diagnostic
      tools, are helpful for determining the complications and planning treatment. The
      modern treatment of hydatid cyst of the liver varies from surgical intervention
      to percutaneous drainage or medical therapy. Surgery is still the treatment of
      choice and can be performed by the conventional or laparoscopic approach.
      Percutaneous drainage and treatment of the cyst with hypertonic saline or alcohol
      seems to be a good alternative to surgery in selected cases.

PMID- 12612334
TI  - An audit of job application forms in response to adverts in the British Medical
      Journal.
AB  - OBJECTIVE: The aim of this study was to examine the speed of response of human
      resources departments to requests for job application forms for posts advertised
      in the British Medical Journal (BMJ). Of particular interest was the closing date
      for applications, postage cost, and the period to reply. DESIGN: Twenty posts
      were randomly selected and application forms requested by telephone and then 20
      by letter on two separate dates from the BMJ Classified (issues of 21 July 2001
      and 28 July 2001). During the first week the forms were requested by telephone on
      receipt of the BMJ (Friday afternoon). During the second week the forms were
      requested by first class post. All letters were sent out on Saturday morning.
      OUTCOME MEASURES: The date of receipt of the application form/information pack,
      the cost of postage, and the closing date for application were recorded for each
      position. RESULTS: Fifteen forms were received after the telephone application
      and 18 forms after the letter applications. One trust sent two replies spaced one
      week apart for the same job and two replies contained job application forms for
      the wrong job. The response rates to telephone requests varied from four to 10
      days and by letter from three to 12 days. The minimum time between the reply
      being received and the closing date was one day, and the maximum 21 days. The
      time between the closing date for applications and the start date of the job
      varied from minus one week (closing date before advertisement) to three months.
      Thirteen replies gave no indication of the start date of the job. The cost of
      postage varied from 27p to pound 1.90. Thirty one trusts used first class
      postage. CONCLUSION: There is very limited scope to return job application forms
      on time, and significant delays in sending out application forms and information
      packs compound this problem. It is recommended that trust human resources
      departments place advertisements early and respond promptly to requests for
      application forms.

PMID- 12612333
TI  - The sweet cake that reaches parts other cakes can't!
AB  - This is a case report of a previously healthy woman of 56 years who presented
      with a life threatening tetraparesis, severe hypokalaemia, hypertension, and
      raised muscle enzymes. The cause of was finally found to be unusual and very much
      "local". Initial inquiry into her drug history was negative until she was made
      aware that herbal remedies could cause serious adverse reactions. She then
      mentioned that she had been eating a large number of "Pontefract cakes" (a
      liquorice sweet) for the management of her chronic constipation. This case
      highlights the importance of asking about herbal remedies when taking a drug
      history in all patients, including those admitted as medical emergencies.

PMID- 12612335
TI  - Neck pain disguised as spondyloarthrosis.

PMID- 12612337
TI  - "Question mark" aorta.

PMID- 12612336
TI  - Severe relapsing sulphonylurea-induced hypoglycaemia: a diagnostic and
      therapeutic challenge.

PMID- 12612341
TI  - Genome-wide single-nucleotide polymorphism analysis defines haplotype patterns in
      mouse.
AB  - The nature and organization of polymorphisms, or differences, between genomes of
      individuals are of great interest, because these variations can be associated
      with or even underlie phenotypic traits, including disease susceptibility. To
      gain insight into the genetic and evolutionary factors influencing such
      biological variation, we have examined the arrangement (haplotype) of single
      nucleotide polymorphisms across the genomes of eight inbred strains of mice.
      These analyses define blocks of high or low diversity, often extending across
      tens of megabases that are delineated by abrupt transitions. These observations
      provide a striking contrast to the haplotype structure of the human genome.

PMID- 12612342
TI  - Human specific loss of olfactory receptor genes.
AB  - Olfactory receptor (OR) genes constitute the basis for the sense of smell and are
      encoded by the largest mammalian gene superfamily of >1,000 genes. In humans,
      >60% of these are pseudogenes. In contrast, the mouse OR repertoire, although of
      roughly equal size, contains only approximately 20% pseudogenes. We asked whether
      the high fraction of nonfunctional OR genes is specific to humans or is a common
      feature of all primates. To this end, we have compared the sequences of 50 human
      OR coding regions, regardless of their functional annotations, to those of their
      putative orthologs in chimpanzees, gorillas, orangutans, and rhesus macaques. We
      found that humans have accumulated mutations that disrupt OR coding regions
      roughly 4-fold faster than any other species sampled. As a consequence, the
      fraction of OR pseudogenes in humans is almost twice as high as in the non-human
      primates, suggesting a human-specific process of OR gene disruption, likely due
      to a reduced chemosensory dependence relative to apes.

PMID- 12612343
TI  - Myosin isoforms show unique conformations in the actin-bound state.
AB  - Crystallographic data for several myosin isoforms have provided evidence for at
      least two conformations in the absence of actin: a prehydrolysis state that is
      similar to the original nucleotide-free chicken skeletal subfragment-1 (S1)
      structure, and a transition-state structure that favors hydrolysis. These weak
      binding states differ in the extent of closure of the cleft that divides the
      actin-binding region of the myosin and the position of the light chain binding
      domain or lever arm that is believed to be associated with force generation.
      Previously, we provided insights into the interaction of smooth-muscle S1 with
      actin by computer-based fitting of crystal structures into three-dimensional
      reconstructions obtained by electron cryomicroscopy. Here, we analyze the
      conformations of actin-bound chicken skeletal muscle S1. We conclude that both
      myosin isoforms in the nucleotide-free, actin-bound state can achieve a more
      tightly closed cleft, a more downward position of the lever arm, and more stable
      surface loops than those seen in the available crystal structures, indicating the
      existence of unique actin-bound conformations.

PMID- 12612346
TI  - Why tobacco litigation?

PMID- 12612347
TI  - Glamour puff.
AB  - Australia has a total ban on tobacco advertising and promotion . . .but tobacco
      marketing goes on.

PMID- 12612345
TI  - Watching proteins fold one molecule at a time.
AB  - Recent theoretical work suggests that protein folding involves an ensemble of
      pathways on a rugged energy landscape. We provide direct evidence for
      heterogeneous folding pathways from single-molecule studies, facilitated by a
      recently developed immobilization technique. Individual fluorophore-labeled
      molecules of the protein adenylate kinase were trapped within surface-tethered
      lipid vesicles, thereby allowing spatial restriction without inducing any
      spurious interactions with the environment, which often occur when using direct
      surface-linking techniques. The conformational fluctuations of these protein
      molecules, prepared at the thermodynamic midtransition point, were studied by
      using fluorescence resonance energy transfer between two specifically attached
      labels. Folding and unfolding transitions appeared in experimental time traces as
      correlated steps in donor and acceptor fluorescence intensity. The size of the
      steps, in fluorescence resonance energy transfer efficiency units, shows a very
      broad distribution. This distribution peaks at a relatively low value, indicating
      a preference for small-step motion on the energy landscape. The time scale of the
      transitions is also distributed, and although many transitions are too fast to be
      time-resolved here, the slowest ones may take >1 sec to complete. These extremely
      slow changes during the folding of single molecules highlight the possible
      importance of correlated, non-Markovian conformational dynamics.

PMID- 12612344
TI  - Spectroscopic and morphological studies of human retinal lipofuscin granules.
AB  - The emission properties of ocular lipofuscin granules isolated from human retinal
      pigment epithelial cells are examined by using steady-state fluorescence
      spectroscopy and spectrally resolved confocal microscopy. The shape of the
      emission spectrum of a thick sample of lipofuscin granules dried on glass varies
      with excitation energy. The polarization of this emission is wavelength
      dependent, exhibiting significant polarization near the excitation wavelength and
      becoming mostly depolarized over the majority of the emission spectrum. These
      results show that the yellow-emitting fluorophores [e.g., A2E (2-[2,6-dimethyl-8
      (2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hydroxyethyl)
      4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]
      pyridinium)] are excited as a result of energy transfer within the granules and
      therefore are not the dominant blue-absorbing chromophores within lipofuscin
      granules. Atomic force microscopy images show lipofuscin granules to be an
      aggregated structure. Bulk and in vivo emission measurements must therefore take
      into account the effect of Raleigh scattering. When corrected for scattering, the
      emission spectrum of a thick lipofuscin deposit or intracellular lipofuscin
      resembles that for A2E. The sum of the emission spectra of a collection of
      individual granules also resembles the emission spectrum of A2E, but the spectrum
      of individual granules varies significantly. This result suggests that the
      agreement between the emission spectra of lipofuscin and A2E is fortuitous, and
      the collective data indicate the presence of several blue-absorbing chromophores
      in lipofuscin and show A2E is not the dominant yellow-emitting fluorophore in
      many of the granules studied.

PMID- 12612348
TI  - USA: the battle for the bars.

PMID- 12612349
TI  - Fiji: finger for BAT.

PMID- 12612350
TI  - Canada: demolishing the power walls.

PMID- 12612351
TI  - Thailand: victories and defeats in the long war.

PMID- 12612352
TI  - Japan: smoke clouds over the land of the rising sun.

PMID- 12612354
TI  - Hong Kong, China: return of the butt people.

PMID- 12612355
TI  - Doctors' manifesto.

PMID- 12612356
TI  - Review of the quality of studies on the economic effects of smoke-free policies
      on the hospitality industry.
AB  - OBJECTIVE: To compare the quality and funding source of studies concluding a
      negative economic impact of smoke-free policies in the hospitality industry to
      studies concluding no such negative impact. DATA SOURCES: Researchers sought all
      studies produced before 31 August 2002. Articles published in scientific journals
      were located with Medline, Science Citation Index, Social Sciences Citation
      Index, Current Contents, PsychInfo, Econlit, and Healthstar. Unpublished studies
      were located from tobacco company websites and through internet searches. STUDY
      SELECTION: 97 studies that made statements about economic impact were included.
      93% of the studies located met the selection criteria as determined by consensus
      between multiple reviewers. DATA EXTRACTION: Findings and characteristics of
      studies (apart from funding source) were classified independently by two
      researchers. A third assessor blind to both the objective of the present study
      and to funding source also classified each study. DATA SYNTHESIS: In studies
      concluding a negative impact, the odds of using a subjective outcome measure was
      4.0 times (95% confidence interval (CI) 1.4 to 9.6; p = 0.007) and the odds of
      not being peer reviewed was 20 times (95% CI 2.6 to 166.7; p = 0.004) that of
      studies concluding no such negative impact. All of the studies concluding a
      negative impact were supported by the tobacco industry. 94% of the tobacco
      industry supported studies concluded a negative economic impact compared to none
      of the non-industry supported studies. CONCLUSION: All of the best designed
      studies report no impact or a positive impact of smoke-free restaurant and bar
      laws on sales or employment. Policymakers can act to protect workers and patrons
      from the toxins in secondhand smoke confident in rejecting industry claims that
      there will be an adverse economic impact.

PMID- 12612357
TI  - A meta-analysis of the efficacy of over-the-counter nicotine replacement.
AB  - OBJECTIVE: To determine whether over-the-counter (OTC) nicotine replacement
      therapy (NRT) is pharmacologically efficacious, whether it produces abstinence
      rates similar to those in prescription settings, and to estimate the long term
      (that is, greater than six month) abstinence rate with OTC NRT. METHOD:
      Systematic literature review. DATA SOURCES: Medline, Psych Abstracts,
      bibliographies, requests of scientists. STUDY SELECTION: Studies comparing OTC
      NRT versus OTC placebo or studies comparing OTC NRT versus prescription NRT that
      reported abstinence rates and for which a full study report was available. DATA
      EXTRACTION: Two of the authors independently reviewed studies and compared
      results. DATA SYNTHESIS: Meta-analysis was performed by first testing for
      homogeneity across studies, then combining odds ratios (ORs) weighting by inverse
      variance and proportions weighting by study sample size. RESULTS: One OTC NRT
      versus OTC placebo nicotine gum study was excluded due to small sample size and
      different setting. The four remaining studies were randomised trials of nicotine
      versus placebo patch with ORs of 2.1-3.2. These outcomes were homogenous and when
      combined resulted in an OR favouring NRT of 2.5 (95% confidence interval (CI) 1.8
      to 3.6). Among the two randomised and two non-randomised trials of OTC NRT versus
      prescription NRT, one small study had an OR of 0.3, two others had ORs of 1.0 and
      1.4, and a fourth study had an OR of 3.6. These results were not homogenous;
      however, when combined via a random effects model the estimated OR was not less
      than 1.0--that is, OR 1.4 (95% CI 0.6 to 3.3). The long term (that is, greater
      than six months) quit rates for OTC NRT was 1% and 6% in two studies and 8-11% in
      five other studies. These results were not homogenous; however, when combined the
      estimated OR was 7% (95% CI 4% to 11%). CONCLUSIONS: OTC NRT is pharmacologically
      efficacious and produces modest quit rates similar to that seen in real world
      prescription practice.

PMID- 12612358
TI  - The behaviour of purchasing smuggled cigarettes in Taiwan.
AB  - OBJECTIVE: Since market liberalization in 1987, the Taiwan Tobacco and Wine
      Monopoly Bureau (TTWMB) annual statistics indicate that both the demand for
      imported cigarettes as well as the number of seized smuggled packs have increased
      with an average revenue loss of NT dollars 4942 million over the past 15 years.
      The NT dollars 10 average increase in cigarette prices after Taiwan entered the
      World Trade Organization (WTO) and the implementation of the Tobacco and Alcohol
      Tax Law in 2002 are forcing policy makers to examine smuggling even more closely.
      This study evaluates factors that affect an individual smoker's decision to
      purchase smuggled cigarettes, particularly when faced with higher prices. DESIGN:
      437 male smokers of imported cigarettes were drawn from a national interview
      survey on cigarette consumption, which the Division of Health Policy Research at
      the National Health Research Institutes conducted during the year 2000. Multiple
      logistic regression models were used to analyse the behaviour of purchasing
      smuggled cigarettes with respect to demographic factors, economic factors,
      smoking behaviour, and other variables. RESULTS: Cigarette price was the driving
      factor most closely linked to the purchase of smuggled cigarettes--a 1% increase
      in cigarette price raised the likelihood of purchasing smuggled cigarettes at
      least 2.60 times (95% confidence interval (CI) 1.08 to 6.26). Smokers who spent
      more than NT 1000/month dollars on cigarettes were twice as likely to purchase
      smuggled cigarettes as those who spent less than NT 1000 dollars (odds ratio (OR)
      2.34, 95% CI 1.48 to 3.70). Betel nut chewers were more likely to purchase
      smuggled cigarettes (OR 1.80, 95% CI 1.09 to 2.90). Smokers who opposed cigarette
      taxation policy were 1.69 times more likely to buy smuggled cigarettes. Personal
      income was not significantly associated with smuggled cigarettes purchases.
      CONCLUSIONS: This study evaluates what causes smokers to purchase smuggled
      cigarettes. We have determined that cigarette price is the most important factor
      and that betel nut vendors are the main suppliers. Our study provides policy
      makers with information that can help them develop effective strategies to curb
      cigarette smuggling after Taiwan's recent cigarette tax reform, which has
      increased cigarette prices.

PMID- 12612359
TI  - First, tell the truth: a dialogue on human rights, deception, and the use of
      smokeless tobacco as a substitute for cigarettes.
AB  - The use of smokeless tobacco as a substitute for cigarettes raises many
      scientific and ethical issues, as the fictitious discussion below reveals.

PMID- 12612360
TI  - Economic burden of smoking in Korea.
AB  - OBJECTIVE: To support tobacco control policies in Korea by providing the
      estimated annual economic burden attributed to cigarette smoking. METHODS: The
      following two different approaches were used to estimate the cost: "disease
      specific" and "all causes". In the disease specific approach, we focused on
      estimating direct and indirect costs involved in treatments of cardiovascular,
      respiratory, and gastrointestinal diseases, and cancer as a result of smoking, by
      using an epidemiologic approach-the population attributable risk (PAR). To
      compute PAR, the relative risks of smoking in terms of physician visits, hospital
      admission, and death were estimated using the Cox proportional hazard model. In
      the all causes approach, we examined the differences in direct and indirect costs
      between smokers and non-smokers for all conditions and types of disease. The
      major data source was the Korea Medical Insurance Corporation cohort study, which
      had complete records of smoking status as of 1992 for 115 682 male and 67 932
      female insured workers. RESULTS: By the disease specific approach, the estimated
      costs attributable to smoking in 1998 in Korea ranged from US 2269.42 million
      dollars (4.89 million dollars per 100,000 population; 0.59% of gross domestic
      product (GDP)) to 2956.75 million dollars (6.37 million dollars; 0.78% of GDP).
      The all causes approach yielded a minimum cost of 3154.75 million dollars (6.79
      million dollars; 0.82% GDP) and a maximum of 4580.25 million dollars (9.86
      million dollars; 1.19% GDP). CONCLUSION: The study confirms that smoking places a
      substantial economic burden on Korean society. In light of this, our study
      provides evidence for a strong need to develop a national policy to effectively
      control tobacco consumption in Korea.

PMID- 12612361
TI  - The uninsured and Medicaid Oregon tobacco user experience in a real world, phone
      based cessation programme.
AB  - OBJECTIVE: To describe the experience of uninsured and Medicaid Oregon tobacco
      users who registered in Free & Clear (F&C), a telephone based cessation programme
      including five scheduled outbound calls. DESIGN AND SETTING: Using a
      retrospective cohort design, 1334 (423 uninsured, 806 Medicaid, and 105
      commercially insured) Oregon tobacco users who registered in F&C between 18
      November 1998 and 28 February 2000 were identified and followed for 12 months
      post-registration; 648 (48.6%) were successfully contacted at 12 months.
      Information was collected from the F&C database. Unconditional logistic
      regression, adjusted for race and education, was used. RESULTS: The seven day
      quit rate at 12 months, assuming non-respondents were smokers, was 14.8% (95%
      confidence interval (CI) 13.0 to 16.9). This rate was significantly higher among
      commercially insured participants (v Medicaid but not uninsured) and among
      participants who completed > or = 5 calls (v < 5 calls). The quit rate for those
      contacted at 12 months was 30.6% (95% CI 27.0% to 34.3%) and varied, however not
      significantly, by insurance and number of calls. After adjustment, respondents
      who completed > or = 5 calls were 60% more likely to quit tobacco (odds ratio
      (OR) 1.6, 95% CI 0.9 to 3.1), and uninsured respondents who completed > or = 5
      calls were 70% more likely to quit tobacco (OR 1.7, 95% CI 0.9 to 3.5), relative
      to those who completed < 5 calls, but the difference was not significant.
      CONCLUSIONS: The quit rates are similar to those reported in efficacy trials. The
      observed variation in quitting tobacco for respondents by number of calls
      completed and by insurance merits further investigation concentrating on
      increasing compliance with the call schedule, particularly for the uninsured.

PMID- 12612363
TI  - Can parents who smoke socialise their children against smoking? Results from the
      Smoke-free Kids intervention trial.
AB  - OBJECTIVE: To evaluate Smoke-free Kids, a new home based programme to assist
      parents who smoke in socializing their children against smoking. DESIGN: Two year
      randomised controlled trial. PARTICIPANTS: At baseline, 887 adult smokers who had
      an abstinent child in the third grade (ages 7-8 years); 671 adults and children
      were retained through the 24 month follow up. INTERVENTION: Programme modules,
      newsletters, incentives, support calls. OUTCOMES: Anti-smoking socialisation;
      susceptibility to smoking. RESULTS: Of 327 parents randomised to treatment, 210
      obtained adequate treatment by using at least three of five core modules.
      Programme efficacy analyses, which compared these parents with controls (n =
      344), showed that exposure to adequate treatment predicted significantly higher
      levels in nearly all categories of anti-smoking socialisation three months post
      intervention. Two years post-baseline, children of parents who reported adequate
      treatment scored significantly higher than controls on attributes that reduce
      susceptibility to smoking, and they scored significantly lower than controls on
      attributes that raise susceptibility to smoking. Programme effectiveness analyses
      compared all parents randomised to treatment (n = 327) with controls (n = 344).
      Treatment effects were evident for several socialisation outcomes; however, these
      effects were smaller and less consistent than those from the efficacy analyses.
      Similarly, although treated children scored higher than controls on attributes
      that reduce susceptibility and lower than controls on attributes that raise
      susceptibility, several of these between-group differences were not significant.
      CONCLUSIONS: Given adequate exposure to the Smoke-free Kids programme,
      significant beneficial effects were observed on anti-smoking socialisation in
      households where parents smoke cigarettes, and significant beneficial effects
      were observed on children's susceptibility to smoking after two years. Improving
      programme acceptance and utilisation is necessary before programme effectiveness
      can be demonstrated.

PMID- 12612364
TI  - Smoking and financial stress.
AB  - AIM: Stress relief is commonly provided as a reason for smoking. However, it is
      plausible that the cost of smoking may create financial stress, particularly
      among the poor. The aim of the study was to examine the relationship between
      smoking and financial stress. DESIGN: Cross sectional survey of households from
      private dwellings conducted by the Australian Bureau of Statistics (ABS), using a
      stratified multistage area sample design. SETTING: Australia, 1998-99.
      PARTICIPANTS: Nationally representative sample of households (n = 6892). MAIN
      OUTCOME MEASURES: The outcome measures of objective financial stress were two
      dichotomous variables indicating whether the household had experienced any
      financial stress or severe financial stress in the past 12 months. RESULTS: The
      odds of experiencing any financial stress were 1.5 (95% confidence interval (CI)
      1.3 to 1.7) times greater, and the odds of severe financial stress were twice
      (95% CI 1.6 to 2.5) as large for smoking households than non-smoking households.
      The effect of smoking on financial stress did not vary significantly across
      categories of income. Among smoking households, higher percentage of total
      household expenditure on tobacco was significantly related to financial stress.
      CONCLUSIONS: Given data were cross sectional, firm conclusions cannot be drawn
      about the causal relationship between smoking and financial stress. It is likely
      that they both affect each other. Undoubtedly, expenditure on tobacco will reduce
      available funds that could otherwise be used to ameliorate financial stress.

PMID- 12612365
TI  - The importance of social sources of cigarettes to school students.
AB  - OBJECTIVE: To discover the importance of social sources of tobacco to young
      people as opposed to commercial sources; to describe the peer market for
      cigarettes in schools and the consequences for young people of their involvement
      in it. STUDY DESIGN: Cross sectional questionnaire survey, one-to-one interviews,
      and focus groups. SETTING: Seven schools in Birmingham, UK. SUBJECTS: All
      students in two randomly selected classes from each school completed the
      questionnaire, and never smokers, occasional smokers, and regular smokers were
      interviewed. RESULTS: Two thirds of occasional smokers and one quarter of regular
      smokers obtained cigarettes socially, mostly for free. A few smokers regularly
      bought their cigarettes from others. Among friendship groups, both smokers and
      non-smokers were involved in the exchange of cigarettes, often for money, which
      is a common activity. A few young people use the selling of cigarettes to fund
      their own smoking. Some young people, smokers and non-smokers, are involved in
      semi-commercial selling of cigarettes. All school students are aware of where to
      purchase cigarettes from non-friends, which is only used "in emergency" because
      of the high price. One school had a strong punishment policy for students caught
      with cigarettes. In this school, more people bought singles from the peer market
      and the price was higher. CONCLUSIONS: The passing and selling of cigarettes in
      school is a common activity, which from the young persons perspective, ensures
      that all share cross counter purchases. A few people are prepared to use the peer
      market for monetary gain and it appears to be responsive to external conditions.
      The peer market might mean that efforts to control illegal sales of cigarettes
      are not as effective as hoped.

PMID- 12612366
TI  - Smoking mothers and snuffing fathers: behavioural influences on youth tobacco use
      in a Swedish cohort.
AB  - OBJECTIVE: To analyse the influences of parental use of cigarettes and snus (the
      Swedish variety of smokeless tobacco) on offspring's behaviour. DESIGN:
      Prospective cohort study. SETTING: The Stockholm County of Sweden. SUBJECTS: 2232
      adolescents recruited in the fifth grade (mean age 11.6 years) with follow up in
      the eighth grade. MAIN OUTCOME MEASURES: Self reported tobacco use (ever and
      current use of cigarettes and/or snus) in the eighth grade. RESULTS: Parents'
      tobacco use was associated with adolescents' current use of cigarettes and snus
      (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.8 to 3.9 if both parents
      used tobacco v neither parent). Mother's cigarette smoking was associated with
      adolescents' current exclusive smoking (OR 2.4, 95% CI 1.6 to 3.6). Father's use
      of snus was associated with current exclusive use of snus among boys (OR 3.0, 95%
      CI 1.4 to 6.4), but not with current cigarette use. The overall prevalence of
      current smoking was lower among children whose fathers used snus than among those
      whose fathers smoked. CONCLUSIONS: Parental smoking, especially maternal smoking,
      enhances the risk of tobacco experimentation in youths, as does paternal use of
      smokeless tobacco. However, the transition to regular cigarette smoking is not
      likely to be affected by paternal use of smokeless tobacco. Contextual factors,
      in particular declining smoking trends and negative social acceptance of smoking,
      can explain most of these findings.

PMID- 12612368
TI  - Measuring the accumulated hazards of smoking: global and regional estimates for
      2000.
AB  - OBJECTIVE: Current prevalence of smoking, even where data are available, is a
      poor proxy for cumulative hazards of smoking, which depend on several factors
      including the age at which smoking began, duration of smoking, number of
      cigarettes smoked per day, degree of inhalation, and cigarette characteristics
      such as tar and nicotine content or filter type. METHODS: We extended the Peto
      Lopez smoking impact ratio method to estimate accumulated hazards of smoking for
      different regions of the world. Lung cancer mortality data were obtained from the
      Global Burden of Disease mortality database. The American Cancer Society Cancer
      Prevention Study, phase II (CPS-II) with follow up for the years 1982 to 1988 was
      the reference population. For the global application of the method, never-smoker
      lung cancer mortality rates were chosen based on the estimated use of coal for
      household energy in each region. RESULTS: Men in industrialised countries of
      Europe, North America, and the Western Pacific had the largest accumulated
      hazards of smoking. Young and middle age males in many regions of the developing
      world also had large smoking risks. The accumulated hazards of smoking for women
      were highest in North America followed by Europe. CONCLUSIONS: In the absence of
      detailed data on smoking prevalence and history, lung cancer mortality provides a
      robust indicator of the accumulated hazards of smoking. These hazards in
      developing countries are currently more concentrated among young and middle aged
      males.

PMID- 12612370
TI  - Zebras in Russia! Where next?
AB  - The zebra may seem an odd choice as a brand image for a new cigarette in Russia,
      but subtle tobacco marketing forces are, as always, at work.

PMID- 12612369
TI  - Increase in common cold symptoms and mouth ulcers following smoking cessation.
AB  - OBJECTIVE: To examine changes in reports of common cold symptoms and mouth ulcers
      following smoking cessation. It was hypothesised that reports of these symptoms
      would increase on stopping smoking. DESIGN: Smokers were assessed one week before
      stopping smoking (baseline), then after one, two, and six weeks of smoking
      abstinence. PARTICIPANTS: 174 smokers attending a seven week smoking cessation
      programme combining behavioural support with nicotine patches. MAIN OUTCOME
      MEASURES: Self reports of cold symptoms, mouth ulcers, and smoking abstinence
      (validated using expired carbon monoxide) were recorded on each measurement
      occasion. RESULTS: Following one, two, and six weeks of smoking abstinence 73.0%
      (127/174), 57.5% (100/174), and 44.8% (78/174) of the participants, respectively,
      maintained continuous abstinence and provided reports of cold symptoms and mouth
      ulcers. For those abstinent from smoking for six weeks, relative to baseline, a
      significant increase in reports of the number of cold symptoms was observed
      following one and two weeks of smoking abstinence (p = 0.009 and p = 0.038,
      respectively) and an increase in reports of mouth ulcers after one and two weeks
      of abstinence (p = 0.004 and p = 0.008, respectively). Following one week of
      abstinence significant increases in reports of sore throat, coughing, deafness,
      and sneezing were observed (p = 0.049, p < 0.001, p< 0.039, and p < 0.003,
      respectively). CONCLUSIONS: This is the first study to systematically document
      significant increases in cold symptoms and mouth ulcers following smoking
      cessation. Smokers should be informed that they have an increased chance of
      experiencing these symptoms on stopping smoking. Being psychologically prepared
      for these effects may reduce their impact on the attempt to stop smoking.

PMID- 12612371
TI  - Malawi: addicted to the leaf.
AB  - The east African country of Malawi, one of the poorest in the world, derives most
      of its economic income from tobacco production. The challenges facing Malawi if
      it is to decrease its dependence on the leaf are discussed here.

PMID- 12612372
TI  - Tobacco industry statements in the US Department of Justice lawsuit.

PMID- 12612374
TI  - Listening between the lines: what BAT really thinks of its consumers in the
      developing world.

PMID- 12612373
TI  - Eclipse: does it live up to its health claims?

PMID- 12612375
TI  - Seasonality in cigarette sales: patterns and implications for tobacco control.

PMID- 12612376
TI  - Way-out developments at BATCO.

PMID- 12612377
TI  - Interest in nicotine replacement therapy among pregnant smokers.

PMID- 12612378
TI  - How to critique consultancy reports?

PMID- 12612379
TI  - Voodoo cigarillos: bidis in disguise?

PMID- 12612380
TI  - Smoking in children's picture books.

PMID- 12612381
TI  - Cigarette use among male and female grade 8-10 students of different ethnicity in
      South African schools.
AB  - OBJECTIVES: To provide data on the prevalence of cigarette use by male and female
      South African students of different ethnic backgrounds in grades 8-10 (ages < or
      = 11 to > or = 17 years), their age of initiation of cigarette use, as well as
      their access to cigarettes through underage sales. DESIGN: A nationally
      representative survey was conducted using self administered questionnaires
      translated into seven languages. SETTING: School based. PARTICIPANTS: Students in
      grades 8-10 in all of South Africa's nine provinces. OUTCOME MEASURES: The
      prevalence data for current users of cigarettes (smoked on one or more days in 30
      days preceding the survey), and for the age of initiation (first smoking
      cigarettes before the age of 10) were analysed. RESULTS: Of the 160 selected
      schools, 123 schools participated in the survey. The completed survey comprised
      6045 of 7074 selected students; 23% of the sample reported being current users of
      cigarettes. Significantly more males (28.8%) than females (17.5%), and
      significantly more "Coloured" students than "Black/African" students were
      classified as current smokers. Sex was the strongest contributor to the
      prediction of current smoking status. On the issue of age of initiation, 18.5% of
      students reported having first smoked cigarettes before the age of 10 years with
      more "Black/African" students than "Coloured" having done so. CONCLUSIONS: In
      order to tailor tobacco control programmes to the needs of students, historical
      "racial"/ethnic and sex differences have to be taken into account. Specific
      determinant studies are needed to understand these differences and to develop
      appropriate responses.

PMID- 12612382
TI  - Taxol-based eluting stents from theory to human validation: clinical and
      intravascular ultrasound observations.
AB  - Treatment with antiproliferative drugs via coated stents appears to be a
      promising approach to both mechanically remodel target lesions and biologically
      reduce neointimal hyperplasia. Drug-eluting stents can maximize local drug
      effects and minimize the potential for systemic toxic effects. The purpose of
      this review is to describe the effects of a lipophilic microtubular inhibitor,
      paclitaxel, a strong antiproliferative agent under clinical investigation, and to
      define the vascular response to taxol-based eluting stents by intravascular
      ultrasound.

PMID- 12612383
TI  - Direct stenting may limit myocardial injury during percutaneous coronary
      intervention.
AB  - BACKGROUND: Direct coronary stenting has been shown to be safe and feasible, with
      a demonstrable reduction in cost, procedural time and radiation exposure. Direct
      stenting may limit distal embolization of atherosclerotic plaque and consequently
      reduce myocardial cell injury following percutaneous coronary intervention, which
      may have important prognostic implications. METHODS AND RESULTS: We assessed
      cardiac troponin I (cTnI) release in the 24 hours following direct coronary
      stenting (DS) as compared to stenting with balloon predilatation (PD) in a total
      of 311 patients and 440 vessels/lesions (vessel to lesion ratio = 1:1) (DS: n =
      107 patients and 149 vessels/lesions; PD: n = 204 patients and 291
      vessels/lesions). The 2 groups were well matched except for a greater proportion
      of diabetic patients in the PD group (21%) compared to the DS group (11%) (p <
      0.05). There were no significant differences in the distribution of target lesion
      site or angiographic complexity between the 2 groups. Primary angiographic
      success was achieved in 97% of vessels in the DS group and 98% of vessels in the
      PD group (p = NS). DS failed in 7/114 patients (6%) deemed suitable for DS by the
      operator, but all stents were subsequently successfully deployed following
      balloon predilatation. Abciximab (ReoPro , Eli Lilly Company, Indianapolis,
      Indiana) was used in 11 patients (10%) in the DS group and 24 patients (12%) in
      the PD group ( p = 0.68). The post-procedural median (IQR) peak cTnI
      concentrations were 0.2   0.1  g/L in the DS group and 0.5   0.3  g/L in the PD
      group (p = 0.02). Post-procedural cTnI concentrations were > 0.2  g/L in 11
      patients (10%) in the DS group and in 53 patients (26%) in the PD group (X2 =
      58.6; p < 0.0001). The rate of major adverse cardiac events at 6 18 month follow
      up was 8% in the DS group and 15% in the PD group (X2 = 38.5; p = 0.02).
      CONCLUSION: Direct stenting without balloon predilatation is associated with
      lower post-procedural cTnI concentrations and lower incidence of major adverse
      events compared to traditional stenting with predilatation.

PMID- 12612384
TI  - Direct stenting: good for the patient, good for all?

PMID- 12612385
TI  - Practice and outcomes of percutaneous coronary intervention in the community
      before drug-eluting stents: a report from the HCA database.
AB  - BACKGROUND: Percutaneous coronary intervention (PCI) using balloon angioplasty
      and/or intracoronary stents has increasingly become the treatment choice for
      myocardial revascularization. While acute clinical outcomes of the community
      based PCI procedures have been examined, much less is known about long-term
      revascularization rates, disease progression and other adverse outcomes. METHODS
      AND RESULTS: Information on patient demographics, coronary risk factors, lesion
      characteristics, procedures and outcomes were derived from an HCA, Inc. database
      on all patients undergoing a PCI procedure in one of four community cardiac
      catheterization laboratories. A total of 3,192 consecutive patients were enrolled
      from July 1, 1999 through September 30, 2000. Analysis was limited to those
      patients undergoing PCI of native vessels with stents or conventional balloon
      angioplasty; target lesions in bypass grafts or those treated with atherectomy
      were excluded. Approximately one-third of enrolled patients were surveyed
      concerning their utilization of cardiovascular services 1 year following their
      initial procedure. The 1-year target lesion revascularization (TLR) was 9.9%
      while target vessel revascularization was 13.5%. Overall, 27.6% of patients
      underwent repeat revascularization within 1 year; 24.7% underwent at least 1
      additional PCI and 5.6% underwent coronary artery bypass graft surgery. A total
      of 4.5% of patients reported an interval acute myocardial infarction with a major
      adverse cardiac event rate of 30.3% at 1 year. CONCLUSION: While clinically
      significant restenosis remains a problem for 10 15% of patients undergoing PCI,
      progression of coronary artery disease elsewhere appears to be an equally
      powerful driver in the need for recurrent revascularization. This analysis of
      contemporary PCI practice prior to drug-eluting stent utilization suggests that
      while these novel devices will likely reduce the incidence of TLR, many patients
      with coronary artery disease will still require additional revascularization for
      disease progression.

PMID- 12612386
TI  - A randomized multicenter trial comparing a new, low-pressure versus a
      conventional coronary stent: primary results from the CONSERVE trial.
AB  - Because it is uncertain whether high-pressure stent deployment may contribute to
      more exuberant neointimal proliferation, a new stent, the LP , was constructed to
      allow full expansion at   10 atmospheres (atm). We compared in a randomized trial
      the 6-month target vessel revascularization (TVR) and other clinical outcomes of
      the LP  stent with the most commonly used Food and Drug Administration-approved
      stent (Guidant Duett  and Tristar  stents) in 1,003 patients without a recent
      myocardial infarction. The first 150 patients assigned the LP  stent also
      underwent repeat angiography at 6 months. Baseline characteristics for the two
      groups were balanced, except for an excess of unstable angina in the LP  group.
      There was slight excess in failure to deliver the LP  stent (3.4% versus 1.4%; p
      = 0.04), and similar 7-day rates of procedural success without ischemic
      complications (92% versus 93%; p = 0.53). More patients in the LP  group had pre
      dilation (72% versus 58%; p < 0.001) and post-dilatation (61% versus 50%; p =
      0.001). The stent deployment pressure was significantly lower, as expected, in
      the LP  group (10   2 ATM versus 13   4 atm; p < 0.001). At 30 days, the
      incidence of major adverse cardiac events was similar. At 6 months, the incidence
      of TVR was 10% and 7.8%, respectively (p = 0.28), hazard ratio was 0.79 (0.52
      1.21), and absolute difference was 2.2% (-2.3% to 6.7%), well within the range of
      equivalency set at 7.5%. Patients without post-dilatation had a significantly
      higher rate of revascularization with the LP  stent than with the Guidant  stent
      (p = 0.02). Thus, the new LP  stent achieves rates of revascularization that are
      not inferior to the Guidant  stent, but this effect cannot be linked to lower
      pressure deployment.

PMID- 12612388
TI  - Carotid stenting: a gordian knot to be unraveled.

PMID- 12612387
TI  - Early and late reactions following the use of iopamidol 340, iomeprol 350 and
      iodixanol 320 in cardiac catheterization.
AB  - GOAL: To investigate the incidence of early (< 24 hours) and late (> 24 hours to
      7 days) reactions to 3 contrast agents commonly used in cardiac catheterization.
      METHODS AND RESULTS: A total of 2,108 patients undergoing cardiac catheterization
      in a Regional Cardiothoracic Unit were randomly assigned to receive 1 of 3
      commonly used contrast agents in a prospective, double-blind study. The contrast
      agents were iopamidol 340 (Niopam ), a nonionic monomer; iomeprol 350 (Iomeron ),
      a nonionic dimer; and iodixanol 320 (Visipaque ), a nonionic dimer. The main
      outcome measures were the incidence of early (< 24 hours) reactions following
      catheterization and the incidence of late (24 hours to 7 days) reactions. Early
      reactions, excluding patients with heat on left ventriculography as the sole
      symptom, were relatively common (7.4%), but there was no significant difference
      between the 3 agents (p = 0.35). Late skin reactions, excluding reactions solely
      at the site of the arterial puncture and continuations of early urticarial
      reactions, were also relatively common (5.4%), but the incidence differed between
      the 3 agents. Such reactions occurred in 2.7% of those receiving iopamidol 340
      (Niopam ), 3.5% of those receiving iomeprol 350 (Iomeron ) and 10.4% of those
      receiving iodixanol 320 (Visipaque ) (p < 0.01). CONCLUSION: The incidence of
      early adverse reactions is similar with these 3 contrast agents. However, late
      skin reactions are significantly more common with iodixanol 320 (Visipaque ) than
      with the other 2 agents. Although such reactions were rarely troublesome,
      patients should be advised accordingly.

PMID- 12612389
TI  - Renal angioplasty under protection of the PercuSurge GuardWire Plus System.
AB  - Renal artery revascularization with angioplasty may preserve renal function and
      facilitate hypertension control. However, in a significant proportion of
      patients, renal function may deteriorate after the procedure. Distal
      microembolization has been implicated as a possible cause; it may be prevented
      with distal protection during the procedure. We report a case of successful renal
      angioplasty and stenting using the PercuSurge GuardWire Plus system.

PMID- 12612390
TI  - Heart center implementation and start-up: the Parma Community General Hospital
      experience.

PMID- 12612391
TI  - Breaking some of the rules.

PMID- 12612392
TI  - Reteplase thrombolysis for treatment of mechanical valve thrombosis.

PMID- 12612393
TI  - Premature coronary artery disease in systemic lupus erythematosus with extensive
      reocclusion following coronary artery bypass surgery.
AB  - A 21-year-old woman with a history of systemic lupus erythematosus (SLE)
      presented to the emergency room with a chief complaint of substernal chest pain
      and palpitations. She had undergone a four-vessel coronary artery bypass graft
      operation with separate saphenous vein grafts to the left anterior descending
      (LAD), obtuse marginal (OM) 1 and 2, and distal right coronary arteries (RCA) 8
      months prior to admission. The patient underwent angiography of the coronary
      vessels, which showed severe diffuse disease with a long, 90% narrowing of the
      vein graft to the LAD and closed vein grafts to OM1 and OM2. The RCA graft showed
      mild diffuse disease. An intervention was done in which the LAD was stented twice
      with subsequent TIMI 3 flow. Advances in medical therapy and a better
      understanding of the disease have contributed to a dramatic improvement in the
      long-term survival of patients with SLE. However, despite the overall long-term
      improvement, coronary artery disease remains a major cause of morbidity and
      mortality with an incidence of approximately nine-fold greater than would be
      expected for this population.

PMID- 12612395
TI  - Subacute development of a coronary artery pseudoaneurysm after primary
      angioplasty and stenting for acute myocardial infarction.
AB  - Three months after successful primary angioplasty with stent implantation for an
      acute myocardial infarction, we were confronted with an intra-stent
      pseudoaneurysm. It was located at the proximal part of the left anterior
      descending coronary artery and associated with an early severe restenosis on a
      marginal branch; the choice was made for surgical treatment. Despite a review of
      the literature and an examination of the procedural data, we were not able to
      explain the pseudoaneurysm. We assume that either the guidewire perforated the
      arterial wall when it cleared the occlusion or a non-angiographically visible
      dissection provoked this phenomenon.

PMID- 12612394
TI  - Aortic root and extensive coronary dissections complicating recanalization of
      chronic right coronary artery occlusion: refraining from stenting may have a
      favorable outcome!
AB  - Aortic root dissection is a rare, potentially life-threatening complication of
      revascularization procedures. We report a case of recanalization of chronic total
      occlusion of the right coronary artery. A huge coronary dissection with a false
      lumen was created using commercially available guidewires during attempts to
      establish a connection with the distal true vessel lumen. In addition, an aortic
      root dissection from the right coronary cusp occurred. The patient was
      asymptomatic and a decision was made to refrain from stent deployment in order
      not to close communications between the false, true lumen and branches. The
      hospital stay was uneventful and the patient was discharged on conservative
      management. Control angiography at 3 months revealed patency of the right
      coronary artery with complete healing of the aortic wall dissection and improved
      clinical status of the patient.

PMID- 12612396
TI  - Results of the Companion Trial--another breakthrough in electrophysiology.

PMID- 12612397
TI  - Mechanical reperfusion of acute right coronary artery occlusion after
      radiofrequency catheter ablation and long-term follow-up angiography.
AB  - Coronary artery injury is a rare complication of radiofrequency catheter
      ablation. We describe the case of a 12-year-old girl who had an acute distal
      right coronary artery (RCA) occlusion during radiofrequency catheter ablation of
      a postero-septal accessory pathway treated with mechanical reperfusion utilizing
      an angioplasty guidewire. Coronary angiography performed at 1-year follow-up
      depicted normal left ventricular function, patent descending posterior artery and
      total occlusion of the postero-lateral branch, which was filled through a rich
      collateral circulation from the RCA marginal branch.

PMID- 12612398
TI  - Adiposity, central body fat distribution and blood pressure among young Bengalee
      adults of Kolkata, India: sexual dimorphism.
AB  - A cross-sectional study of 174 men and 153 women of Bengalee ethnicity was
      undertaken to compare levels of adiposity, central body fat distribution and
      blood pressure. The mean age of both the sexes were similar (men = 20.1 years;
      women = 20.0 years). Significantly more women (n = 42, 27.5%) were overweight
      (body mass index, BMI > or = 25.0 kg/m2) as compared with men (19, 10.9%). Men
      were significantly taller and heavier. They also had significantly greater mean
      waist (WC) and mid upper arm (MUAC) circumferences compared with women. On the
      other hand, women had significantly (p < 0.001) greater mean BMI, biceps (BSF),
      triceps (TSF) and subscapular (SSF) skinfolds. The mean values of systolic (SBP),
      diastolic (DBP) and mean arterial (MAP) blood pressure were significantly greater
      among men. These significant differences existed even after controlling for BMI.
      Regression analyses revealed that sex had significant effect on all these
      variables even after controlling for BMI. Correlation studies showed that WC was
      found to be much more strongly correlated than BMI with SBP, DBP and MAP, in both
      sexes. However, when the effect of WC (along with BMI) was also controlled for,
      there was no significant sex difference in blood pressure.

PMID- 12612399
TI  - Effects of room temperature on physiological and subjective responses during
      whole-body bathing, half-body bathing and showering.
AB  - The effects of bathroom thermal conditions on physiological and subjective
      responses were evaluated before, during, and after whole-body bath (W-bath), half
      body bath (H-bath) and showering. The air temperature of the dressing room and
      bathroom was controlled at 10 degrees C, 17.5 degrees C, and 25 degrees C. Eight
      healthy males bathed for 10 min under nine conditions on separate days. The water
      temperature of the bathtub and shower was controlled at 40 degrees C and 41
      degrees C, respectively. Rectal temperature (Tre), mean skin temperature (Tsk),
      blood pressure (BP), heart rate (HR), body weight loss and blood characteristics
      (hematocrit: Hct, hemoglobin: Hb) were evaluated. Also, thermal sensation (TS),
      thermal comfort (TC) and thermal acceptability (TA) were recorded. BP decreased
      rapidly during W-bath and H-bath compared to showering. HR during W-bath was
      significantly higher than for H-bath and showering (p < 0.01). The double
      products due to W-bath during bathing were also greater than for H-bath and
      showering (p < 0.05). There were no distinct differences in Hct and Hb among the
      nine conditions. However, significant differences in body weight loss were
      observed among the bathing methods: W-bath > H-bath > showering (p < 0.001). W
      bath showed the largest increase in Tre and Tsk, followed by H-bath, and
      showering. Significant differences in Tre after bathing among the room
      temperatures were found only at H-bath. The changes in Tre after bathing for H
      bath at 25 degrees C were similar to those for W-bath at 17.5 degrees C and 10
      degrees C. TS and TC after bathing significantly differed for the three bathing
      methods at 17.5 degrees C and 10 degrees C (TS: p < 0.01 TC: p < 0.001).
      Especially, for showering, the largest number of subjects felt "cold" and
      "uncomfortable". Even though all of the subjects could accept the 10 degrees C
      condition after W-bath, such conditions were intolerable to half of them after
      showering. These results suggested that the physiological strains during H-bath
      and showering were smaller than during W-bath. However, colder room temperatures
      made it more difficult to retain body warmth after H-bath and created thermal
      discomfort after showering. It is particularly important for H-bath and showering
      to maintain an acceptable temperature in the dressing room and bathroom, in order
      to bathe comfortably and ensure warmth.

PMID- 12612400
TI  - Menstrual cycle effects on performance of mental arithmetic task.
AB  - The purpose of this research was to identify the relationship between task
      performance and menstrual cycle. The difference of performance on menstrual cycle
      phase was investigated. The task was the mental arithmetic task which involved
      the non-sequential and higher order cognitive processes. The duration of the
      experiment was twenty minutes. Two-way analysis of variance by repeated-measures
      design was used to examine the differences in task performance between phases and
      temporal variations. Results showed that there was a significant difference in
      correct input time during temporal variations though there was no significant
      difference between phases. Moreover, the relationships between phases and intra
      individual variations in task performance were examined using coefficient of
      variance (CV). CVs were plotted in three dimensions to examine the relationships
      between intra-individual variations and phases. Based on CVs, the subjects who
      showed differences were classified into two groups: those with a small difference
      in three phases and those with a difference every phase. The phase which
      indicated large CV changed with individuals.

PMID- 12612401
TI  - Fascicle length of gastrocnemius muscles in monozygous twins.
AB  - A large inter-individual variation is seen in muscle fascicle length of the
      athletes but the reasons for this phenomenon are unclear. The purpose of this
      study was to determine whether genetic factors contribute to the variances in
      muscle architectural characteristics. Nine monozygous twin pairs (3 males and 6
      females), mean age 23 years (range 17-40) were studied. Fascicle length,
      pennation angle, and muscle thickness of the medial (MG) and lateral (LG)
      gastrocnemius muscles were measured in vivo by B-mode ultrasound. In the LG
      muscle intrapair resemblance (P < 0.01) for fascicle length (r = 0.98), pennation
      angle (r = 0.94) and muscle thickness (r = 0.86) were observed. In MG muscle,
      however, there was no intrapair resemblance for fascicle length (r = 0.66, P >
      0.05), although pennation angle (r = 0.73, P < 0.05) and muscle thickness (r =
      0.86, P < 0.01) were significant. Mean percent intrapair difference in LG and MG
      muscles were 1.8% and 5.1% for fascicle length, 11.3% and 12.3% for pennation
      angle and 12.4% and 9.9% for muscle thickness, respectively. There is intrapair
      difference between muscle thickness and pennation angle in both MG (r = 0.69, P <
      0.05) and LG (r = 0.70, P < 0.05) muscles. However, no significant correlation
      was observed for intrapair difference between muscle thickness and fascicle
      length in both muscles (MG, r = 0.46; LG, r = 0.40). It appears that genetic
      predisposition is the predominant factor for the determination of muscle fascicle
      length. However, a lack of intrapair resemblance in MG fascicle length raises the
      possibility that fascicle length may be further influenced by external
      environmental factors such as physical training.

PMID- 12612402
TI  - The visual effects of wooden interiors in actual-size living rooms on the
      autonomic nervous activities.

PMID- 12612403
TI  - Thermodynamics of partitioning of benzocaine in some organic solvent/buffer and
      liposome systems.
AB  - The thermodynamics of partitioning of benzocaine (BZC) were studied in
      octanol/buffer (ROH/W), isopropyl myristate/buffer (IPM/W), cyclohexane/buffer
      (CH/W), and dimyristoyl phosphatidylcholine (DMPC) and dipalmitoyl
      phosphatidylcholine (DPPC) liposome systems. In all cases the partition
      coefficients were greater than unity; therefore the free energies of transfer
      were negative, that is, the processes of transfer of BZC from aqueous media to
      organic systems were spontaneous. The partition coefficients were approximately
      three-fold higher in DMPC liposomes compared with the ROH/W system in the 30
      degrees -40 degrees C temperature range. The enthalpies of transfer from aqueous
      media to ROH and IPM were negative, but positive for CH, while this property was
      negative for DMPC liposomes and positive for DPPC liposomes. The entropies of
      transfer were positive in almost all cases, except for DMPC. The results
      presented here confirm the lipophilic nature of BZC.

PMID- 12612404
TI  - Interaction of the antimalarial agents halofantrine and lumefantrine with lipid
      bilayers.
AB  - The effects of antimalarial drugs halofantrine and lumefantrine on the
      fluoresence anisotropy of diphenylhexatriene (DPH)-containing phospholipid
      vesicles have been examined. Lumefantrine increases DPH anisotropy, indicating a
      condensing effect on bilayers of dipalmitoylphosphatidyl choline (DPPC),
      dioleoylphosphatidylcholine (DOPC), egg lecithin and mouse erythrocyte membranes
      (including membranes isolated from plasmodial-infected mice). Its condensing
      effect is more pronounced in bilayers of lower microviscosity. In contrast,
      increases or decreases in DPH anisotropy are observed with halofantrine,
      depending on the nature of the lipid. Decreases in anisotropy, which reflect a
      perturbing effect, are observed in bilayers of high microviscosity (for example,
      gel state of DPPC bilayers). Increases in anisotropy are observed in bilayers of
      low microviscosity (such as DOPC and egg lecithin bilayers). The perturbing
      effect of halofantrine is further confirmed by the increases in permeability of
      calcein-containing DPPC vesicles in the presence of the drug. However the
      perturbative effects of halofantrine are observed to the same magnitude in
      uninfected and plasmodial-infected erythrocyte membranes, and may not be relevant
      to the antimalarial action of the drug. In contrast, the condensing effect of
      lumefantrine is significantly greater in infected erythrocyte membranes and may
      contribute to its antimalarial action.

PMID- 12612405
TI  - Six new constituents from an Ascomycete, Chaetomium quadrangulatum, found in a
      screening study focused on monoamine oxidase inhibitory activity.
AB  - A screening study focusing on monoamine oxidase inhibitory activity on the EtOAc
      extract of an Ascomycete Chaetomium quadrangulatum, which previously gave five
      unique chromones possessing this activity (chaetoquadrins A-E (1-5)), this time
      afforded six new constituents termed chaetoquadrins F-K (6-11) in addition to 1
      5. The structures of 6-11 have been deduced on the basis of spectral and chemical
      data, and 7 and 8 have shown appreciable monoamine oxidase inhibitory activity.

PMID- 12612406
TI  - Paeonins A and B, lipoxygenase inhibiting monoterpene galactosides from Paeonia
      emodi.
AB  - Paeonins A and B, new monoterpene galactosides have been isolated from the
      chloroform-soluble fraction of the roots of Paeonia emodi and showed potent
      lipoxygenase inhibitory activity. The structures of 1 and 2 have been assigned on
      the basis of spectral analysis including one- and two-dimensional NMR techniques.

PMID- 12612407
TI  - New lignan glycosides from Chinese medicinal plant, Sinopodophillum emodi.
AB  - Two new podophillotoxin glucosides, L-picropodophillotpxin 7'-O-(beta-D
      glucopyranosyl-(1-->6)-beta-D-glucopyranoside) (2) and L-picropodophillotpxin 7'
      O-beta-D-glucopyranoside (3), were isolated from Chinese medicinal plant,
      Sinopodophillum emodi, together with 4 known compounds, podophillotoxin (1),
      podorhizol 4'-O-beta-D-glucopyranoside (4), deoxypodophillotoxin (5), and
      dehydropodophillotoxin (6). The structures of 2 and 3 were finally determined by
      the extensive decouping and nuclear Overhauser effect (NOE) experiments in NMR
      spectra and circular dichroism (CD) spectra. Compound 2 is the second example of
      podophillotoxin diglucoside, and both the first one and 2 were isolated from S.
      emodi. X-ray crystal structure analysis of 1, 5, and 6 was carried out. Compounds
      1 and 5 showed the different conformations from those reported.

PMID- 12612408
TI  - Four new diarylheptanoids from the roots of Juglans mandshurica.
AB  - Four new diarylheptanoids (1-4), along with two known tetralones (5, 6), were
      isolated from the roots of Juglans mandshurica and their structures were
      elucidated on the basis of spectroscopic studies.

PMID- 12612409
TI  - New approach to a novel axially chiral ligand showing spontaneous enrichment of
      axial chirality.
AB  - We have synthesized novel axially chiral ligand with two chiral centers, (R)
      (R)(2)- and (S)-(S)(2)-2,2'-bis(2,2,2-trifluoro-1-hydroxyethyl)biphenyl (1),
      which showed a high asymmetric induction when used as ligand. Here, another new
      approach to 1 by kinetic and thermodynamic resolution is presented which gave
      these ligands in a much shorter steps, in a higher yield, and in a higher
      enantiomeric excess.

PMID- 12612410
TI  - Highly-oxygenated isopimarane-type diterpenes from Orthosiphon stamineus of
      Indonesia and their nitric oxide inhibitory activity.
AB  - From the methanolic extract of Indonesian Orthosiphon stamineus, nine new highly
      oxygenated isopimarane-type diterpenes [7-O-deacetylorthosiphol B (1), 6
      hydroxyorthosiphol B (2), 3-O-deacetylorthosiphol I (3), 2-O-deacetylorthosiphol
      J (4), siphonols A-E (5-9)] have been isolated together with nine known
      diterpenes [orthosiphols H (10), K (11), M (12) and N (13); staminols A (14) and
      B (15); neoorthosiphols A (16) and B (17); norstaminol A (18)]. Their structures
      were determined based on the spectroscopic data. The isolated diterpenes
      inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-activated
      macrophage-like J774.1 cells. Compounds 4-7, 9, 10, 14, and 17 showed inhibitory
      activities more potent (IC(50), 10.8-25.5 microM) than a positive control N(G)
      monomethyl-L-arginine (L-NMMA; IC(50), 26.0 microM).

PMID- 12612412
TI  - Glochidionionosides A-D: megastigmane glucosides from leaves of Glochidion
      zeylanicum (Gaertn.) A. Juss.
AB  - Five megastigmane glucosides were isolated from the leaves of Glochidion
      zeylanicum. One of them was a known compound, blumenol C O-beta-D-glucopyranoside
      (1), and the structures of the four new compounds, glochidionionosides A-D (2-5),
      were mainly elucidated by spectroscopic methods, including a modified Mosher's
      method. The absolute configurations of the six-membered ring of
      glochidionionoside D (5) were deduced by beta-D-glucopyranosylation-induced shift
      trends in the (13)C-NMR spectra and confirmed by X-ray analysis as its p
      bromobenzoate (5b), and the axis chirality of C-7 was determined to be R.

PMID- 12612411
TI  - Synthesis and antihyperglycemic activity of erythrose, ribose and substituted
      pyrrolidine containing thiazolidinedione derivatives.
AB  - A series of erythrose, ribose, and substituted pyrrolidine containing 2,4
      thiazolidinediones were synthesized. Among them, thirteen unsaturated
      thiazolidinediones, six saturated thiazolidinediones and two unsaturated
      malonates were evaluated for their ability to enhance glucose utilization in
      cultured L6 myocytes. On the basis of the in vitro activity, 5-[4-[2-(1-benzyl
      3,4-bis-benzyloxypyrrolidin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione 24b
      was selected as the candidate for further pharmacological studies.

PMID- 12612413
TI  - Oxidation of cyclopropane terpenoids with ruthenium tetraoxide.
AB  - Oxidation products of cyclopropanoid terpenes, (-)-carane (4), (+)-cyclosativene
      (5), laurinterol methyl ether (6), and thujopsane (7), with ruthenium tetraoxide
      were investigated.

PMID- 12612414
TI  - Cycloadditions of 1-substituted 1,3-butadienes with 4- or 3-substituted 2(1H)
      quinolones acting as dienophiles.
AB  - Cycloadditions of 1,3-butadiene derivatives having an electron-rich group at the
      1-position with 4- or 3-substituted 2(1H)-quinolones were carried out to give the
      richly functionalized phenanthridines under both atmospheric and high pressure
      conditions. Furthermore, the reactivity of 4- or 3-substituted 2(1H)-quinolones
      acting as a dienophile with 1-substituted dienes was examined using MO
      calculation.

PMID- 12612415
TI  - Modification by fluoride, bromide, iodide, thiocyanate and nitrite anions of
      reaction of a myeloperoxidase-H2O2-Cl- system with nucleosides.
AB  - The influence of fluoride (F(-)), bromide (Br(-)), iodide (I(-)), thiocyanate
      (SCN(-)) and nitrite (NO(2)(-)) on the reaction of a myeloperoxidase-H(2)O(2)-Cl(
      ) system with a nucleoside mixture was studied. The reaction was carried out
      under mildly acidic conditions and terminated by N-acetylcysteine. Without the
      additional anions, quantity of nucleosides consumed fell in the following order:
      2'-deoxyguanosine>2'-deoxycytidine>>2'-deoxythymidine>2'-deoxyadenosine
      asymptotically equal to 0. F(-) did not affect the reaction. Br(-) increased the
      consumption of 2'-deoxycytidine and 2'-deoxythymidine, but decreased that of 2'
      deoxyguanosine. I(-), SCN(-) and NO(2)(-) suppressed the reaction. These results
      suggest that Br(-) has a unique effect in relation to nucleoside damage caused by
      myeloperoxidase.

PMID- 12612416
TI  - Steroidal saponins from rhizomes of Tupistra wattii Hook. f.
AB  - Chemical examination of the fresh rhizomes of Tupistra wattii HOOK. f. led to the
      isolation of three new steroidal saponins, wattoside G (1), H (2), and I (3),
      together with one known steroidal saponin, (25S)-1beta,3beta,4beta
      trihydroxyspirotan-5beta-yl-O-beta-D-glucopyranoside (4). The structures of 1-3
      were established to be (25R)-1beta,2beta,3beta,5beta-tetrahydroxyspirostan-4beta
      yl-O-beta-D-xylopyranoside (1), (24S,25S)-24-[(beta-D-glucopyranosyl)oxy]
      1beta,2beta,3beta,4beta,5beta,7beta-hexahydroxyspirostan-6-one (2), and (24S,25S)
      1beta,3beta-dihydroxy-5beta-spirostan-24-yl-O-beta-D-glucopyranosyl-(1-->6)-beta
      D-glucopyranoside (3) on the basis of detailed analyses of physical, chemical,
      and spectral data. The isolated compounds were evaluated for cytotoxic activity
      against the cancer cell line K562 in vitro.

PMID- 12612417
TI  - Inhibitory activities of novel pyrimidine derivatives on the contact
      hypersensitivity reaction.
AB  - In order to obtain novel topically applied anti-inflammatory compounds containing
      an inexpensive anti-oxidative moiety without chirality, we synthesized compound
      2c derivatives having a di-tert-butylphenol moiety, and evaluated by topical
      administration their anti-inflammatory potentials on picryl chloride-(PC) induced
      contact hypersensitivity reaction (CHR) in mice. In the course of our structure
      activity relationship (SAR) studies on the pyrimidine or the anti-oxidative
      moiety and the linker between them, the most potent compounds (10, 11) were
      obtained by the insertion of a C2 unit in compound 2c. The potencies of these
      compounds were 2-fold greater than that of 1. Compounds 10 and 11 were considered
      to be useful lead compounds having inexpensive anti-oxidative moieties without
      chirality.

PMID- 12612418
TI  - Leflunomide analogues as potential antiinflammatory agents.
AB  - A series of leflunomide (1a) analogues were examined for antiinflammatory
      activity using the carrageenan-induced paw edema assay. Some of the compounds
      were significantly more potent than leflunomide, particularly those with electron
      donating or negative inductive groups situated in the phenyl rings. In contrast,
      all the nonsubstituted compounds or with further chain-extension in the 4
      position of the rings led to a decrease in activity. The LD(50) values of the
      most active compounds (1d, g-j) in male ICR mice were significantly greater than
      those of either 1a or its active metabolite 2 and therefore merit further study.

PMID- 12612419
TI  - Alkaloids from Eucharis amazonica (Amaryllidaceae).
AB  - Thirteen alkaloids have been isolated from dried bulbs and leaves of flowering
      Eucharis amazonica (Amaryllidaceae). The alkaloids, 7-methoxyoxoassoanine, 6-O
      methylpretazettine and apohaemanthamine, are reported for the first time from a
      natural source.

PMID- 12612420
TI  - A new stilbene with tyrosinase inhibitory activity from Chlorophora excelsa.
AB  - A new stilbene, 4-[(2"E)-7"-hydroxy-3",7"-dimethyloct-2"-enyl]-2',3,4',5
      tetrahydroxy-trans-stilbene (1), and the known compound chlorophorin (2) were
      isolated from the heartwood of Chlorophora excelsa. Both 1 and 2 showed
      tyrosinase inhibitory activity with IC(50) values of 96 and 1.3 microM,
      respectively.

PMID- 12612421
TI  - Pd/C-catalyzed chemoselective hydrogenation in the presence of a phenolic MPM
      protective group using pyridine as a catalyst poison.
AB  - Employment of a Pd/C-pyridine combination as a catalyst is a very useful method
      for the selective removal (hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl
      ester protective groups and for the selective hydrogenation of nitro and olefin
      functions of phenol derivatives protected with the MPM group. These
      discriminatory results are apparently attributable to the effect of pyridine. The
      MPM group could be extensively applied to chemoselective hydrogenation as a
      protective group for phenolic hydroxyl functions.

PMID- 12612422
TI  - Synthesis of (+/-)-trans- or cis-(5-aminomethyltetrahydrofuranyl)imidazole by
      Mitsunobu cyclization: synthetic studies toward novel histamine H3 or H4-ligands.
AB  - The (+/-)-trans- or cis-4(5)-(5-aminomethyltetrahydrofuranyl)imidazole [1 and 2]
      were synthesized by the Mitsunobu cyclization, starting from L-glutamic acid.

PMID- 12612423
TI  - Two novel ravenelones from the edible mushroom Pulveroboletus ravenelii.
AB  - Two novel butenolides, isoravenelone (1) and ravenelone (2), and a large amount
      of a known compound, vulpinic acid (3), were isolated from the methanolic extract
      of the Japanese fungus Pulveroboletus ravenelii (Boletales). These structures
      were elucidated by two dimensional (2D) NMR, MS, IR and UV spectra, and X-ray
      crystallographic analysis.

PMID- 12612424
TI  - Loniceroside C, an antiinflammatory saponin from Lonicera japonica.
AB  - A new triterpenoid saponin, loniceroside C was isolated from the aerial parts of
      Lonicera japonica. Its structure was established to be 3-O-beta-D-glucopyranosyl
      hederagenin 28-O-alpha-L-rhamnopyranosyl (1-->2)-[beta-D-xylopyranosyl(1-->6)]
      beta-D-glucopyranosyl ester by spectroscopic techniques and chemical
      transformations. Loniceroside C showed in vivo antiinflammatory activity against
      mouse ear edema provoked by croton oil.

PMID- 12612425
TI  - Effect of TRX-liposomes size on their prolonged circulation in rats.
AB  - Newly formulated cationic liposomes (TRX-liposomes) with four different mean
      diameters were injected into twelve male rats via the lateral tail vein in order
      to evaluate the effect of liposomal size on pharmacokinetic parameters. TRX
      liposomes disappeared from the blood according to the one-compartment model and
      demonstrated maximum and minimum half-lives of ca. 14 h (mean diameter of 114.3
      nm) and ca. 5 h (mean diameter of 285.9 nm), respectively. This prolonged half
      life tended to decrease at the boundary of 114.3 nm mean diameter. The optimal
      size (114.3 nm) for prolonged circulation of TRX-liposomes was consistent with
      that of pegylated liposomes such as Doxil((R)), however, the half-life was
      different among these liposomes. The electric charge of the TRX-liposomal surface
      is assumed to be responsible for this difference. The results of the present
      study will be very useful in the design of long-circulating cationic liposomes.

PMID- 12612426
TI  - Novel synthesis of flavonoids of Scutellaria baicalensis Georgi.
AB  - A concise and efficient total synthesis of the flavonoids baicalein, oroxylin A
      and wogonin was described. Intramolecular oxidative cyclization followed by
      demethylation of chalcone 1, readily prepared from trimethoxyphenol, afforded,
      depending upon the controlled conditions, baicalein or oroxylin A in excellent
      yields. Demethylation of 1 yielded 3, which, by oxidation with I(2)/dimethyl
      sulfoxide (DMSO), was readily converted to oroxylin A and wogonin after column
      chromatography.

PMID- 12612427
TI  - Studies on the constituents of Leonurus sibiricus L.
AB  - Two new furanoditerpene-lactones, LS-1 (1) and LS-2 (2), were isolated along with
      four known furanoditerpene-lactones 3, 4, 5 and 6 from the aerial part of
      Leonurus sibiricus L. The structures of the new compounds were determined by
      spectroscopic means. Compounds 1-6 isolated here exhibited moderate cytotoxic
      activity (IC(50)=50-60 microg/ml) against leukemia cells (L 1210) in tissue
      culture.

PMID- 12612428
TI  - Indonesian medicinal plants. XXV. Cancer cell invasion inhibitory effects of
      chemical constituents in the parasitic plant Scurrula atropurpurea
      (Loranthaceae).
AB  - Six fatty acids (1-6), two xanthines (7, 8), two flavonol glycosides (9, 10), one
      monoterpene glucoside (11), one lignan glycoside (12), and four flavanes (13-16)
      were clarified by a bioassay-guided separation as chemical constituents of
      Scurrula atropurpurea (Loranthaceae), a parasitic plant of the tea plant Thea
      sinensis (Theaceae). Among these constituents, it was found that the alkynic
      fatty acid octadeca-8,10,12-triynoic acid (6) exhibits a more potent inhibitory
      effect on cancer cell invasion in vitro than flavanes [(+)-catechin (13), (-)
      epicatechin (14), (-)-epicatechin-3-O-gallate (15) and (-)-epigallocatechin-3-O
      gallate (16)].

PMID- 12612429
TI  - Characterization of hydrazine derivative: proposed decomposition mechanism and
      structure elucidation of decomposition compounds.
AB  - Decomposition of protected hydrazine diol (1) hemi-oxalate, a key intermediate of
      the potent indolocarbazole-based DNA topoisomerase I inhibitor (2), was
      investigated. Spectroscopic analysis revealed that the main decomposition
      compounds of the hydrazine derivative were a peroxide (3) and an alcohol
      derivative (4). The peroxide derivative (3) was proposed to form in the presence
      of oxygen- and/or H(2)O-generated radicals, which was subsequently reduced to the
      more stable alcohol derivative (4). A plausible decomposition mechanism was
      proposed and our findings were substantiated by chemical conversion.

PMID- 12612430
TI  - Preparation of 9-hydroxy grayanotoxin derivatives and their acute toxicity in
      mice.
AB  - Novel 9alpha and 9beta-hydroxy grayanotoxin II derivatives were prepared by photo
      sensitized oxygenation of iso-grayanotoxin II and oxidation of grayanotoxin II
      tetraacetate with selenium dioxide respectively. The lethal dosage of 9alpha and
      9beta-hydroxy grayanotoxin II were lower than that of grayanotoxin II. In
      addition, the lethal dosage of 9beta-hydroxy-dihydro grayanotoxin II was higher
      than that of dihydro grayanotoxin II.

PMID- 12612431
TI  - Three cycloartane glycosides from Cimicifuga rhizome and their immunosuppressive
      activities in mouse allogeneic mixed lymphocyte reaction.
AB  - One known (1) and two new cycloartane triglycosides, 20S,22R,23S,24R
      16beta,23;22,25-diepoxy-cycloartane-3beta,23,24-triol 3-O-beta-D-glucopyranosyl
      (1-->2)-beta-D-glucopyranosyl-(1-->2)-beta-D-xylopyranoside (2) and
      20S,22R,23S,24R-16beta,23;22,25-diepoxy-cycloartane-3beta,23,24-triol 3-O-(6-O
      trans-isoferuloyl-beta-D-glucopyranosyl)-(1-->2)-beta-D-glucopyranosyl-(1-->2)
      beta-D-xylopyranoside (3), were isolated from a commercial Cimicifuga Rhizome.
      Their structures were determined by two dimensional (2D) NMR spectroscopic
      analysis and chemical evidence. These compounds suppressed the proliferation of
      lymphocytes in mouse allogeneic mixed lymphocyte reaction.

PMID- 12612432
TI  - 2 alpha-(3-hydroxypropyl)- and 2 alpha-(3-hydroxypropoxy)-1 alpha,25
      dihydroxyvitamin D3 accessible to vitamin D receptor mutant related to hereditary
      vitamin D-resistant rickets.
AB  - Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by
      mutations in the vitamin D receptor, which lead to resistance to 1alpha,25
      dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. We found that the A ring-modified
      analogues, 2alpha-(3-hydroxypropyl)- and 2alpha-(3-hydroxypropoxy)
      1alpha,25(OH)(2)D(3), (O1C3 and O2C3) can bind better than the natural hormone to
      the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the
      hydrogen bond to the 1alpha-hydroxyl group of 1alpha,25(OH)(2)D(3).

PMID- 12612433
TI  - Fate of orally administered 15N-labeled polyamines in rats bearing solid tumors.
AB  - We studied absorption, distribution, metabolism, and excretion of polyamines
      (putrescine, spermidine, and spermine) in the gastrointestinal tract using (15)N
      labeled polyamines as tracers and ionspray ionization mass spectrometry (IS-MS).
      The relatively simple protocol using rats bearing solid tumors provided useful
      information. Three (15)N-labeled polyamines that were simultaneously administered
      were absorbed equally from gastrointestinal tract, and distributed within tissues
      at various concentrations. The uptake of (15)N-spermidine seemed preferential to
      that of (15)N-spermine since the concentrations of (15)N-spermidine in the liver
      and tumors were higher, whereas those of (15)N-spermine were higher in the
      kidney, probably due to the excretion of excess extracellular spermine. Most of
      the absorbed (15)N-putrescine seemed to be lost, suggesting blood and tissue
      diamine oxidase degradation. Concentrations of (15)N-spermidine and (15)N
      spermine in the tumor were low. We also describe the findings from two rats that
      were administered with (15)N-spermine. The tissue concentrations of (15)N
      spermine were unusually high, and significant levels of (15)N-spermidine were
      derived from (15)N-spermine in these animals.

PMID- 12612434
TI  - Functional disorders of the oxidative phosphorylation system in the heart
      mitochondria of mice with juvenile visceral steatosis.
AB  - Mice with juvenile visceral steatosis (JVS) develop remarkable cardiac
      hypertrophy and exhibit an increased number of mitochondria in their heart.
      However, the biochemical characteristics and physiological functions of these
      mitochondria cardiac are little known. Here we show that the respiratory
      activities at state 3 with glutamate plus malate or succinate in the heart
      mitochondria of JVS mice were greatly decreased to 47% or 77%, respectively,
      compared with those of control mice. The contents of cytochromes a+a(3), b, and
      c+c(1) in the heart mitochondria of these mice were also decreased, to 51%, 45%,
      and 79%, respectively, of those of the control mice. Oligomycin-sensitive ATPase
      activitiy in these mitochondria, however, was increased to about 2 times over
      that of the control mice. Surprisingly, the ATP-Pi exchange activity of the heart
      mitochondria of JVS mice was greatly decreased, to 35% of that of control mice.
      On the other hand, the expression levels of 2 subunits of H(+)-ATP synthase,
      i.e., coupling factor 6 and alpha subunit, in heart mitochondria from control and
      JVS mice were almost the same. These results indicate that the coordinate
      regulation of mitochondrial proliferation and gene expression for components of
      the oxidative phosphorylation system was markedly defective in the heart of JVS
      mice. Our current results also suggest the presence of a novel regulatory
      mechanisms of ATP synthase activities in the heart.

PMID- 12612435
TI  - Effects of inorganic anions on the activation of acid sialidases.
AB  - An acid sialidase partially purified from porcine liver was activated by
      incubation at 37 degrees C under acidic pH. This activation was dependent on pH,
      time and temperature, but not inhibited by amastatin, an inhibitor of
      aminopeptidase A, in contrast to the case of human placental sialidase. The
      effects of inorganic anions on the two sialidases from porcine liver and from
      human placenta were investigated. Among the anions tested, halide ions,
      especially chloride and bromide ions, markedly enhanced the activation of the two
      sialidases. However, nitrate, sulfate, sulfite and pyrosulfite ions rarely
      affected the activation of sialidase from porcine liver, while all of them
      enhanced the activation of human placental sialidase. The activation of the
      enzyme from porcine liver was depressed at concentrations of greater than 100 mM
      of sodium chloride, whereas the enzyme from human placenta was held at maximum
      activation until 1 M sodium chloride. These results suggest the possibility of
      the participation of enzyme functions different from that of human placental
      sialidase in the activation process of sialidase.

PMID- 12612436
TI  - Papyriflavonol A from Broussonetia papyrifera inhibits the passive cutaneous
      anaphylaxis reaction and has a secretory phospholipase A2-inhibitory activity.
AB  - Papyriflavonol A, a new prenylated flavonol isolated from Broussonetia
      papyrifera, selectively inhibits recombinant human secretory phospholipase A(2)s
      (sPLA(2)s). Papyriflavonol A was found to inhibit human group IIA and V sPLA(2)s
      potently and irreversibly in a dose-dependent manner, with respective IC(50)
      values of 3.9 and 4.5 microM. The inhibitory effects of papyriflavonol A against
      bovine group IB (IC(50) of 76.9 microM) and the human group X (IC(50) of 225
      microM) sPLA(2)s were weaker than those against human group IIA and V sPLA(2)s,
      and human group IIF sPLA(2) was not inhibited. In addition, papyriflavonol A
      potently inhibited the stimulus-induced production of leukotriene C(4) with an
      IC(50) value of approximately 0.64 microM in mouse bone marrow-derived mast
      cells. In addition, papyriflavonol A significantly reduced IgE-dependent passive
      cutaneous anaphylaxis in rats. These results indicate that papyriflavonol A
      provides a basis for novel types of antiinflammatory drugs.

PMID- 12612437
TI  - Cyclosporine a augments P-glycoprotein expression in the regenerating rat liver.
AB  - In the liver, the multidrug resistance (MDR) protein P-glycoprotein (P-gp) is
      physiologically expressed at the bile canalicular membrane, where it participates
      in the biliary excretion of various lipophilic drugs and xenobiotics. Previous
      studies showed that the immunosuppressive agent cyclosporine A (CsA) modulates P
      gp and exerts a hepatotrophic influence in the regenerating liver. Hepatocytes
      isolated from regenerating rat liver, after 2/3 partial hepatectomy (PH 2/3),
      were used as an in vivo experimental model of cells with high proliferating
      activity in order to investigate whether CsA influences cellular levels of P-gp
      in those cells. Male Wistar rats were treated with CsA (20 mg/kg body weight) for
      4 d preoperatively and 1 d postoperatively, and regenerating hepatocytes were
      isolated by collagenase perfusion 12, 24 and 48 h after PH 2/3. Flow cytometry
      and Western blotting studies with the monoclonal antibodies C494 and C219 showed
      that after PH 2/3, cellular levels of P-gp were initially suppressed, 12 h after
      PH 2/3, by 23%, but were significantly elevated thereafter, 24 and 48 h after PH
      2/3 by 28% and 73%, respectively. In CsA pretreated animals, P-gp levels were
      increased even in normal hepatocytes by 34%, and an additional augmentation was
      seen in hepatocytes from 24 and 48 h regenerating livers (60% and 56%,
      respectively). In summary, we demonstrate for the first time that CsA has an
      additive effect on the expression of P-glycoprotein during liver regeneration in
      the rat. Therefore, induction of P-gp might also be considered in patients
      receiving CsA after liver transplantation for hepatocellular carcinoma and
      chemotherapy as an adjuvant treatment for the prevention of tumor recurrence.

PMID- 12612438
TI  - Radioprotective effect of Panax ginseng on the phosphatases and lipid
      peroxidation level in testes of Swiss albino mice.
AB  - The Panax ginseng has been used as traditional medicine for past several years
      among oriental people. The present investigation has been made to assess the
      radioprotective efficacy of ginseng root extract in the testicular enzymes of
      Swiss albino mice. The Swiss albino mice were divided into different groups. (i)
      Ginseng treated group: The animals were administered 10 mg/kg body weight ginseng
      root extract i.p. (ii) Radiation treated group: The animals were exposed to 8 Gy
      gamma radiation at the dose rate of 1.69 Gy/min at the distance of 80 cm. (iii)
      Combination group: Animals were administered ginseng extract continuously for 4 d
      and on 4th day they were irradiated to 8 Gy gamma radiation after 30 min of
      extract administration. The animals from above groups were autopsied on day 1, 3,
      7, 14 and 30. Biochemical estimations of acid and alkaline phosphatases and Lipid
      peroxidation (LPO) in testes were done. In ginseng treated group acid and
      alkaline phosphatases activity and LPO level did not show any significant
      alteration. In irradiated animals there was a significant increase in acid
      phosphatase activity and LPO level. However, significant decline in alkaline
      phosphatase activity was observed. The treatment of ginseng before irradiation
      causes significant decrease in acid phosphatase and LPO level and significant
      increase in alkaline phosphatase activity. One of the cause of radiation damage
      is lipid peroxidation. Due to lipid peroxidation, lysosomal membrane permeability
      alters and thus results in release of hydrolytic enzymes. So, an increase in acid
      phosphatase was noticed after radiation treatment. The alkaline phosphatase
      activity is associated with membrane permeability and different stages of
      spermatogenesis. Due to membrane damage and depletion of germ cells of testes
      after irradiation the enzyme activity was decreased. Ginseng markedly inhibits
      lipid peroxidation. It acts in indirect fashion to protect radical processes by
      inhibition of initiation of free radical processes and thus reduces the radiation
      damages in testes of Swiss albino mice.

PMID- 12612439
TI  - Anti-hyperglycemic effect of fangchinoline isolated from Stephania tetrandra
      Radix in streptozotocin-diabetic mice.
AB  - Kampo medicine, Stephania tetrandra Radix (Stephania) in Boi-ogi-to increases the
      blood insulin level and falls the blood glucose level in streptozotocin (STZ)
      diabetic ddY mice. These actions of Stephania are potentiated by Astragalus
      membranaceus Bunge Radix (Astragali) in Boi-ogi-to (Liu et al., J. Traditional
      Med., 17, 253-260, 2000). In the present study, actions of bis-benzylisoquinoline
      alkaloids isolated from Stephania were investigated in the hyperglycemia of STZ
      diabetic mice. A main bis-benzylisoquinoline alkaloid, fangchinoline (0.3-3
      mg/kg) significantly fell the blood glucose level of the diabetic mice in a dose
      dependent manner. The effect of fangchinoline was 3.9-fold greater than that of
      water extract of Stephania. However, another main compound, tetrandrine (1-100
      mg/kg) did not have any effect. The water extract of Astragali did not affect
      singly but potentiated the anti-hyperglycemic action of fangchinoline (0.3
      mg/kg). Out of used compounds (1 mg/kg) isolated from Stephania, fangchinoline,
      fangchinoline 2'-N-alpha-oxide and 2'-N-norfangchinoline, which are substituted
      with 7-hydroxy side chain for 7-O-methyl side chain, decreased to near 50% of
      high blood glucose level. In addition, tetrandrine 2'-N-beta-oxide, tetrandrine
      2'-N-alpha-oxide, tetrandrine 2-N-beta-oxide, fangchinoline 2'-N-alpha-oxide,
      which are added to 2- or 2'-N-oxide side chain, also decreased to near 50% of the
      high blood glucose level. In conclusion, fangchinoline but not tetrandrine from
      Stephania shows the anti-hyperglycemic action in the STZ-diabetic mice. The
      demethylation of 7-O-position and/or addition of 2- or 2'-N-oxide side chain in
      bis-benzylisoquinoline compounds in Stephania have a role for the induction of
      the anti-hyperglycemic actions.

PMID- 12612440
TI  - Effects of nefiracetam on cerebral adenylyl cyclase activity in rats with
      microsphere embolism-induced memory dysfunction.
AB  - The effects of nefiracetam on the cerebral adenylyl cyclase (AC) activity of
      animals with microsphere embolism-induced memory dysfunction were examined.
      Sustained cerebral ischemia in the right cerebral hemisphere was induced by an
      injection of microspheres into the right internal carotid artery of rats. To
      examine learning and memory function, the water maze test was performed from day
      7 to day 10 after the operation. The escape latency of the microsphere-embolized
      (ME) rat in the water maze task was longer than that of the sham-operated (Sham)
      rat, suggesting that spatial memory dysfunction occurred in the ME rat. Gsalpha
      and Gi(1/2)alpha protein levels in the cerebral cortex, striatum and hippocampus
      of the ME rat, when determined on day 11, were similar to those of the Sham rats.
      The basal AC activity in the striatum, but not in the other two regions, of the
      ME rat decreased. The AC activity in the presence of 10 microM colforsin daropate
      (Col), a direct stimulator of AC, was increased by approximately 20-fold in sham
      animals and 7- to 10-fold in the ME rat. Treatment of the ME rat with 10 mg/kg/d
      nefiracetam p.o. from day 1 to day 10 after the operation shortened the escape
      latency, restored the basal AC activity in the striatum, and reversed the Col
      induced increases in AC in these three regions without any changes in the
      cerebral Gsalpha and Gi(1/2)alpha protein levels. These results suggest that
      nefiracetam-mediated activation of AC activity may contribute to the improvement
      of memory and learning function in sustained cerebral ischemia.

PMID- 12612441
TI  - Trachea relaxing effects and beta2-selectivity of SPFF, a newly developed
      bronchodilating agent, in guinea pigs and rabbits.
AB  - In this paper we evaluated the bronchodilator effects of SPFF [2-(4-amino-3
      chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol chloride], a newly
      synthesized beta(2) adrenergic agonist in guinea pigs and rabbits, in comparison
      with other beta(2) adrenergic agonists, isoprenaline or salbutamol. We studied in
      vitro the bronchodilator effects of SPFF and isoprenaline on isolated guinea pig
      trachea strips with or without the precontraction of bronchocontractors
      (acetylcholine and histamie). The positive chronotropic effects of SPFF and
      isoprenaline on isolated guinea pig left atria were also tested in vitro. Potency
      values (pD(2), pA(2) or ED(50)) were determined from the cumulative concentration
      response curves. The results showed that SPFF and isoprenaline dose-dependently
      relaxed the isolated guinea pig trachea strips and the pD(2) values of both drugs
      were 7.66+/-0.68 and 8.79+/-0.19, respectively. Moreover, we confirmed that the
      bronchodilator effect of SPFF was due to the activation of beta(2) adrenoceptor
      because this effect was easily antagonized by ICI-118551 (pA(2) 8.90+/-0.01), a
      specific beta(2) adrenoceptor antagonist. SPFF also dose-dependently relaxed the
      isolated guinea pig trachea strip precontraction with acetylcholine or histamine
      with ED(50) values of 10.2+/-0.7 microM and 550+/-38.2 nM, respectively.
      Furthermore, the positive chronotropic effect of SPFF on isolated guinea pig left
      atria (pD(2) 5.41+/-0.38) was much weaker than that of isoprenaline (pD(2) 8.75+/
      0.24), which implied that SPFF was more selective to airway beta(2) adrenoceptor
      than isoprenaline; the beta(1)/beta(2) selectivity assay also showed that SPFF
      was about 162 times more selective to beta(2) adrenoceptor than isoprenaline. A
      radioligand binding experiment using guinea pig lung and cardiac ventricle as
      beta(2) and beta(1) adrenoceptor sources, respectively, also demonstrated that
      SPFF possesses high affinity (27.3 nM) and selectivity (4.6 fold) to beta(2)
      adrenoceptors. The protective effects of SPFF and salbutamol on bronchospasm
      induced by bronchoconstrictor aerosol in guinea pigs in vivo were investigated,
      and the Konzett and Rossler experiment in rabbits in vivo was also carried out.
      SPFF significantly prolonged the latency time of histamine and acetylcholine
      induced asphyxiation collapse in guinea pigs: the ED(50) value of SPFF i.g. was
      0.32+/-0.05 mg.kg(-1) in this experiment. Meanwhile, the ED(50) values of
      salbutamol was 2.37+/-0.22, which meant that the bronchorelaxation effect of
      salbutamol was about 6 times less potent than that of SPFF. The Konzett and
      Rossler experiment performed in anesthetized rabbit showed that intraduodenal
      administration of SPFF exerted action of longer duration than salbutamol. From
      the results above we suggested that SPFF was a potent, long-acting bronchodilator
      with relatively higher beta(2) adrenoceptor selectivity.

PMID- 12612442
TI  - An extract of the root of Lithospermun erythrorhison accelerates wound healing in
      diabetic mice.
AB  - Many people suffer from intractable bedsores, which sometimes develop because of
      chronic metabolic failure in patients. An extract of the root of Lithospermun
      erythrorhison (SK) has been reported to have an effect on wound healing. However,
      the effects of SK have not been studied in chronic wounds, such as bedsores. The
      healing-impaired diabetic (db/db) mouse is a good model for the investigation of
      clinical healing therapies. Therefore, we examined whether SK accelerates wound
      healing in db/db mice. Full-thickness round wounds of 6-mm diameter were created
      on the backs of mice. After applying SK, we covered the wound with a film
      dressing to keep it moist. At three weeks, wound closure was complete in SK
      treated mice but not in controls. Capillary vessel number and collagen synthesis
      increased early in wound healing in SK-treated wounds. At this time, vascular
      endothelial growth factor (VEGF)-positive neutrophils had infiltrated the wound
      and the appearance of apoptotic fibroblasts and endothelial cells in the
      granulation tissue was more advanced than in the controls. Where the wound was
      covered with epithelium, there tended to be less infiltration of VEGF-positive
      cells and apoptotic cells. These results suggest that the inflammatory phase was
      shortened, and the proliferative and maturation phases were advanced by SK. It is
      known that SK also has antibacterial activity. Therefore, we conclude that SK is
      useful for wound healing in db/db mice, and could potentially help patients with
      intractable bedsores.

PMID- 12612443
TI  - Preventive effect of phosphoenolpyruvate on hypoxemia induced by oleic acid in
      Guinea pigs.
AB  - Oleic acid-induced hypoxemia is an animal model of acute respiratory distress
      syndrome (ARDS). Increased capillary permeability is a cause of hypoxemia in lung
      injury. Endothelial cells form a major capillary barrier, and disruption of the
      barrier appears to involve a decreased level of ATP in the cells.
      Phosphoenolpyruvate (PEP) is an endogenous substance that is one of the ATP
      precursors and can cross some cell membranes via anion exchanger. We examined the
      effect of PEP on oleic acid-induced lung injury in guinea pigs. An intravenous
      injection of oleic acid (15 microl/kg) caused severe hypoxemia. Pretreatment with
      PEP at a dose of 2, 20, or 200 micromol/kg attenuated the oleic acid-induced
      decrease in the arterial partial pressure of oxygen in a dose-dependent manner.
      Furthermore, PEP attenuated the oleic acid-induced increase in vascular
      permeability in the proximal and distal bronchi, as indicated by the
      extravascular leakage of Evans Blue dye. The combination of PEP with ATP (4
      micromol/kg) showed no additional inhibitory effect on oleic acid-induced lung
      injury, compared with PEP alone. We suggest that PEP is a promising candidate to
      prevent hypoxemia in acute lung injuries associated with increased vascular
      permeability, such as ARDS.

PMID- 12612444
TI  - Enhancement of neurite outgrowth in PC12 cells stimulated with cyclic AMP and NGF
      by 6-acylated ascorbic acid 2-O-alpha-glucosides (6-Acyl-AA-2G), novel lipophilic
      ascorbate derivatives.
AB  - It has been shown that ascorbate (AsA) and its stable derivative, ascorbic acid 2
      O-alpha-glucoside (AA-2G), do not elicit neurite outgrowth in PC12 cells.
      However, these ascorbates are synergistically enhanced by both dibutyryl cyclic
      AMP (Bt(2)cAMP)- and nerve growth factor (NGF)-induced neurite outgrowth in this
      model. In the present study, the effects of a series of novel lipophilic
      ascorbate derivatives, 6-acylated ascorbic acid 2-O-alpha-glucosides (6-Acyl-AA
      2G), on neurite outgrowth induced by Bt(2)cAMP and NGF were examined in PC12
      cells. We found that all the tested acylated ascorbate derivatives enhanced
      neurite formation induced by both agents in a dose-dependent manner. Of the 6
      Acyl-AA-2G derivatives, 6-octanoyl ascorbic acid 2-O-alpha-glucoside (6-Octa-AA
      2G) enhanced the Bt(2)cAMP-induced phosphorylated MAPK p44 and p42 expression. A
      alpha-glucosidase inhibitor, castanospermine, completely abrogated the promotion
      of neurite outgrowth and MAPK expression by 6-Octa-AA-2G. Addition of 6-Octa-AA
      2G (0.5 mM) to PC12 cells caused a rapid and significant increase in
      intracellular AsA content, which reached a maximum and was maintained from 12 to
      24 h after the culture. These findings suggest that 6-Acyl-AA-2G is rapidly
      hydrolyzed to AsA within the cell and enhances neurite differentiation through
      the interaction with the inducer-activated MAPK pathway.

PMID- 12612445
TI  - Overexpression of NP95 mRNA by tumor promoters in the promotion phase of a two
      stage BALB/3T3 cell transformation assay.
AB  - We studied altered gene expressions in BALB/3T3 cells treated by different tumor
      promoters in the promotion phase of a transformation assay, an in vitro model of
      a two-stage carcinogenicity test, using fluorescent mRNA differential display
      analysis. Expression of the NP95 gene, which was previously found to be the gene
      of a murine nuclear protein associated with cell proliferation, was increased in
      the cultures treated by 12-O-tetradecanoylphorbol-13-acetate (TPA), okadaic acid,
      and orthovanadate. The upregulation of NP95 mRNA was confirmed by reverse
      transcription-PCR, and Northern blot. TPA, okadaic acid, and orthovanadate
      enhanced cell proliferation as measured by a 5-bromo-2'-deoxyuridine
      incorporation assay. The expression level of NP95 mRNA was not affected by the
      treatment with typical carcinogens benzo[a]pyrene and 3-methylcholanthrene at
      concentrations at which they act as initiators of cell transformation. These
      facts may imply that the enhancement of cell transformation by these tumor
      promoters is due, at least in part, to the acceleration of cell proliferation.
      NP95 mRNA was also increased in the transformed BALB/3T3 cells. Overexpression of
      NP95 may also participate in the maintenance of the transformed phenotype.

PMID- 12612446
TI  - Effects of iridoids on lipoxygenase and hyaluronidase activities and their
      activation by beta-glucosidase in the presence of amino acids.
AB  - Enzyme inhibitory activities of 14 iridoids previously obtained from two
      Malaysian medicinal plants, Saprosma scortechinii and Rothmannia macrophylla,
      were evaluated in vitro using soybean lipoxygenase and bovine testis
      hyaluronidase. Most of the iridoids, including asperulosidic acid, paederosidic
      acid, and an epimeric mixture of gardenogenins A and B, did not show any effect
      on the enzyme activities, except for the bis-iridoids, which inhibited the
      lipoxygenase activity with their IC(50) values of approximately 1.3 times that of
      a known inhibitor, fisetin. Structural modification of asperulosidic acid and
      paederosidic acid through enzymatic hydrolysis by beta-glucosidase resulted in
      their inhibition towards the enzyme activities, and these activities were
      enhanced by the presence of some amino acids (lysine, leucine or glutamic acid)
      or ammonium acetate. Mixtures of gardenogenins A and B; isomers of non-glucosidic
      iridoids, incubated with amino acid or ammonium acetate did not show any
      inhibitory effect on the enzyme activities during the 6 h incubation period,
      except for lysine where spontaneous reaction between the iridoids and amino acid
      resulted in the inhibition of lipoxygenase activity. The results from these
      biomimetic reactions suggested that the iridoid aglycons and the intermediates
      formed by these reactive species could inhibit the enzyme activities, and thus
      substantiate previous reports that the formation of iridoidal aglycons is a
      prerequisite for the iridoid glycosides to demonstrate some of the biological
      activities. In addition, the results also indicated that it is worthwhile to
      further explore these intermediates as potential anti-inflammatory agents.

PMID- 12612447
TI  - Efficient gene transfer to hepatoblastoma cells through asialoglycoprotein
      receptor and expression under the control of the cyclin A promoter.
AB  - Specific gene delivery into hepatoma cells by liposomes and specific gene
      expression under the control of the cyclin A promoter were examined in HepG2
      cells, a hepatoblastoma cell line that overexpresses cyclin A. A plasmid carrying
      the luciferase gene under the cyclin A promoter sequence was condensed with poly
      L-lysine and encapsulated into anionic asialofetuin-labeled liposomes (AF
      liposomes), which were preferentially taken up by hepatocytes through the action
      of the asialoglycoprotein receptor (AgpR). AF-liposomes delivered plasmids to the
      hepatoma cells by receptor-mediated endocytosis through the AgpR, and transgene
      expression could be achieved under the control of the cyclin A promoter.
      Furthermore, a fusogenic lipid, DOPE, as a liposomal component was required for
      the enhancement of transfection efficiency of AF-liposomes.

PMID- 12612448
TI  - Trypsinogen hL expressed in the human lung is a new member of the trypsinogen
      family.
AB  - Molecular cloning of cDNA encoding a new member of the trypsinogen family, named
      trypsinogen hL, was carried out by PCR using human lung cDNAs as templates. The
      primary structure of trypsinogen hL was found to be a prepro-protein and a
      catalytic triad, 64His, 108Asp and 201Ser. It was also found that trypsinogen hL
      is specifically expressed in the human lung, the expression level being 30-times
      higher than those in other tissues tested. A phylogenic tree analysis showed that
      trypsinogen hL is a new member of the trypsinogen family, a family of serine
      protease family proteins.

PMID- 12612449
TI  - Tryptanthrin inhibits interferon-gamma production by Peyer's patch lymphocytes
      derived from mice that had been orally administered staphylococcal enterotoxin.
AB  - Tryptanthrin, a biologically active compound found in the medicinal plant
      Polygonum tinctorium, reportedly has several biological activities. We
      investigated the effects of tryptanthrin on cytokine production by lymphocytes in
      response to staphylococcal enterotoxin B (SEB), which causes a variety of
      disorders in humans based on its induction of large amounts of immunostimulatory
      cytokines. Tryptanthrin dose-dependently inhibited interferon-gamma (IFN-gamma)
      and interleukin-2 production by mouse spleen cells and Peyer's patch (PP)
      lymphocytes in vitro. The efficacy of tryptanthrin was further studied in a mouse
      model in vivo. Tryptanthrin was administered orally 2 h after an oral challenge
      with SEB. Nineteen hours after SEB administration, PP lymphocytes were prepared,
      and IFN-gamma production by PP lymphocytes was examined. The production of IFN
      gamma increased after SEB administration, and the elevated IFN-gamma production
      was significantly inhibited by tryptanthrin treatment. These results suggest that
      tryptanthrin may be effective in the treatment of disorders of the intestines,
      such as food poisoning, that are associated with activated lymphocytes.

PMID- 12612450
TI  - Effect of restraint and footshock stress and norepinephrine treatment on gastric
      emptying in rats.
AB  - We investigated the effects of restraint and footshock stress and norepinephrine
      treatment on gastric emptying. The gastric emptying was significantly inhibited
      by restraint stress. beta(3)-adrenergic antagonist canceled the inhibition of
      gastric emptying caused by restraint stress, while beta(1)-, beta(2)-, alpha(1)-,
      and alpha(2)-adrenergic antagonists did not affect the inhibition. Norepinephrine
      treatment also inhibited gastric emptying. The inhibition by norepinephrine
      treatment was canceled by beta(1)-, beta(2)-, and beta(3)-adrenergic antagonists,
      but not by alpha(1)- and alpha(2)-adrenergic antagonists. On the other hand,
      footshock stress did not affect gastric emptying. These results suggest that
      beta(3)-adrenoceptors play an important role in the inhibition of gastric
      emptying caused by restraint stress, while nonspecific beta-adrenoceptors are
      involved in that caused by norepinephrine treatment.

PMID- 12612451
TI  - Characterization of (-)-matairesinol as a potent inhibitor of casein kinase I in
      vitro.
AB  - The inhibitory effects of (-)-matairesinol (MTS) isolated from Thujopsis
      dolabrata var. hondai on the activities of four distinct Ser/Thr-protein kinases
      [two casein kinases (CK-I and CK-II), A-kinase and C-kinase] were determined in
      vitro. It was found that (i) MTS inhibits the activities of CK-I and C-kinase
      alpha (ID(50)=approx. 10 microM) in a dose-depedent manner, but high doses are
      required to inhibit A-kinase activity (ID(50)=approx. 90 microM); (ii) the
      autophosphorylation of CK-I is more sensitive to MTS (ID(50)=approx. 0.2 microM);
      (iii) MTS inhibits CK-I activity in a manner similar to that observed with CK-I-7
      (a CK-I inhibitor); and (iv) the compound inhibits CK-I activity by affecting ATP
      binding in a mixed type manner. These results indicate that MTS is a potent CK-I
      inhibitor in vitro.

PMID- 12612452
TI  - Antinociceptive effects of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridine in
      mice: structure-activity relation study of matrine-type alkaloids part II.
AB  - N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were synthesized as
      derivatives of matrine-type alkaloids, and the structure-activity relations were
      examined by the acetic acid-induced abdominal contraction test. The
      antinociceptive potencies of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines
      were significantly lower than those of (+)-matrine. The antinociceptive effects
      of N-benzyloctahydropyrido[3,2,1-ij][1,6]naphthyridines are approximately 5.6 to
      6.5 times less than those of N-benzoyloctahydropyrido[3,2,1
      ij][1,6]naphthyridine. These findings suggest that the amide group of matrine
      type alkaloids is an essential functional group that influences antinociceptive
      potency. The antinociceptive effect of 4c was markedly antagonized by
      pretreatment with Naloxone, and that of 3c partially so.

PMID- 12612453
TI  - Inhibitory effect of norditerpenes on LPS-induced TNF-alpha production from the
      Okinawan soft coral, Sinularia sp.
AB  - An ethanol (EtOH) extract of the soft coral (Sinularia sp.), collected in
      Okinawa, demonstrated a potent inhibitory effect on lipopolysaccharide (LPS)
      induced tumor necrosis factor-alpha (TNF-alpha) production by murine macrophage
      like cells (RAW264.7). The activity-guided purification of the EtOH extract
      resulted in the isolation of two norditerpenes, norcembrenolide (1) and
      sinuleptolide (2). These structures were identified from the spectroscopic data.
      Norcembrenolide (1) and sinuleptolide (2) inhibited TNF-alpha production in a
      dose-dependent manner, and showed a more potent effect than prednisolone at the
      concentration of 33 microg/ml. They also exhibited an inhibitory effect on nitric
      oxide (NO) production not influenced by cytotoxicity.

PMID- 12612454
TI  - Hypolipemic effect of Cyclocarya paliurus (Batal) Iljinskaja in lipid-loaded
      mice.
AB  - We investigated the inhibitory effect of Cyclocarya paliurus (Batal.) Iljinskaja
      (C. paliurus) extract on postprandial hyperlipemia in mice. A single oral
      administration of C. paliurus extract (250 mg/kg) suppressed an increase in
      plasma triacylgycerol (TG) levels when fed with 5 ml/kg of lard and olive oil.
      The inhibition rates were 28.6% and 24.1%, respectively, but free fatty acid
      (FFA) levels in plasma were not significantly affected as compared with control
      group mice. In addition, C. paliurus extract showed inhibitory activity toward
      pancreatic lipase, a key enzyme of dietary TG absorption, with an IC(50) of 9.1
      microg/ml in vitro. Our results suggested that the hypolipemic action of C.
      paliurus extract was probably interrelated with suppression of the activity of
      digestive lipase, and as a result, the blood lipid level was reduced.

PMID- 12612455
TI  - Different contribution of CYP2C19 in the in vitro metabolism of three proton pump
      inhibitors.
AB  - A series of clinical studies on the cytochrome P450 2C19 (CYP2C19) genotype and
      the pharmacokinetics and pharmacodynamics of three proton pump inhibitors (PPIs),
      omeprazole, lansoprazole and rabeprazole, have been conducted to establish the
      individualized pharmacotherapy based on the CYP2C19 genotyping, and in the
      present study, the CYP2C19 genotype-dependency was more pronounced for omeprazole
      than the other two. Herein, to validate further the difference among 3 PPIs in
      CYP2C19 genotype-dependency on the phenotype, a comparative in vitro study was
      conducted using the human liver microsomes and newly developed anti-human CYP
      antibodies. The residual concentrations of omeprazole and lansoprazole in 5 lots
      of human liver microsomes were dependent on the CYP2C19 activities, however, for
      rabeprazole, there was no correlation. The hydroxylation of omeprazole was more
      inhibited by anti-CYP2C19 antibody than lansoprazole, whereas anti-CYP3A4
      antibody showed similar inhibition. In conclusion, the relative contribution of
      CYP2C19 on total metabolism of 3 PPIs elucidated herein coincided with the
      CYP2C19 genotype-dependent pharmacokinetics.

PMID- 12612456
TI  - Multidrug resistance in Serratia marcescens and cloning of genes responsible for
      the resistance.
AB  - Six clinically isolated strains of Serratia marcescens were tested for their drug
      resistance. All showed fairly high resistance to many antimicrobial agents tested
      including norfloxacin, streptomycin, ampicillin, erythromycin, tetracycline,
      chloramphenicol, and antimicrobial dyes. Using the drug-hypersensitive strain of
      Escherichia coli KAM32 as the host, we cloned the genes responsible for multidrug
      resistance from chromosomal DNA of one of the strains of S. marcescens, NUSM8906.
      We obtained 28 hybrid plasmids that made host cells resistant to several
      antimicrobial agents. Many of the transformants harboring each of the plasmids
      showed multidrug resistance, and some showed resistance to specific drugs. The
      hybrid plasmids were classified into several groups based on their drug
      specificity. It appears that each class of plasmid carries different types of
      drug resistance genes. Analysis of such genes will reveal the multiple mechanisms
      involved in multidrug resistance in S. marcescens.

PMID- 12612458
TI  - A guest editorial: complementary and alternative medicine and women's health-
      time to catch up!

PMID- 12612457
TI  - Isolation of nitrophenols from diesel exhaust particles (DEP) as vasodilatation
      compounds.
AB  - The compounds in diesel exhaust particles (DEP) that are responsible for
      vasodilatation were isolated and characterized for the first time. From benzene
      extract of DEP, 2-methyl-4-nitrophenol, 3-methyl-4-nitrophenl and 4-nitrophenol
      were isolated, and their vasodilatation activities were confirmed. 3-methyl-4
      nitrophenol caused dilatation of rat thoracic artery, and the other two
      nitrophenols, also showed vasodilatation activities.

PMID- 12612459
TI  - Group B streptococcus: prevention of early-onset neonatal sepsis.
AB  - Group B streptococcus (GBS) was recognized as a major pathogen of neonatal
      disease in the 1970s. With a case-fatality rate of 5% to 20%, prevention of GBS
      neonatal disease has been an ongoing concern. The Centers for Disease Control and
      Prevention (CDC), and American College of Obstetricians and Gynecologists (ACOG)
      published guidelines for preventive strategies in 1996. These strategies, either
      a risk-based or a culture-based program, have been responsible for reduced
      incidence of GBS-newborn disease from 1.7 to 0.4 per 1,000 live births in the
      years 1993 to 1999. However, there has been considerable variability in practice
      patterns. Reanalysis now shows that a culture-based prevention strategy provides
      greater reduction in early-onset neonatal disease than a risk-based protocol. The
      CDC replacement guidelines of August 2002 recommend culture-based GBS prevention;
      the risk-based strategy is no longer supported. Continued efforts to eradicate
      GBS-newborn disease require an understanding of the pathogen, colonization, and
      transmission, GBS sampling and detection methods, and maternal therapy. Until a
      reliable vaccination against GBS is developed, prevention of neonatal GBS disease
      will rely upon intrapartum treatment of maternal carriers. TARGET AUDIENCE:
      Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After
      completion of this article, the reader will be able to define the pathogen,
      describe the methods of transmission and detection, and outline the current
      recommendations for maternal group B streptococcus therapy.

PMID- 12612460
TI  - The potential of stem cells.
AB  - Although stem cells have held the fascination of scientists for years, the
      attention of the general public has recently been captured by the derivation of
      human embryonic stem cells. In this review we describe the historical experiments
      leading up to the isolation of human embryonic stem cells and discuss recent
      advances in our understanding of both embryonic and somatic stem cells. Select
      examples are used to illustrate the potential of stem cells, both in the sense of
      their ability to differentiate into specific cell types and in the sense of their
      power to treat various diseases and conditions. Also discussed are recent studies
      describing current progress toward the treatment of Parkinson disease, spinal
      cord injuries, diabetes, and cardiac disease. TARGET AUDIENCE: Obstetricians &
      Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this
      article, the reader will be able to describe the various types of stem cells,
      outline potential clinical uses of stem cells, and summarize the somatic cell
      transdifferentiation debate.

PMID- 12612462
TI  - Strategy for the provision of positron emission tomography in the United Kingdom.

PMID- 12612461
TI  - Antenatal causes of cerebral palsy: associations between inherited
      thrombophilias, viral and bacterial infection, and inherited susceptibility to
      infection.
AB  - Cerebral palsy rates of 2 in every 1,000 births have varied little over the last
      40 years, despite improvements in obstetric care. In the past, cerebral palsy was
      thought to be due to poor obstetric care and management; however, epidemiological
      studies have refuted this, suggesting that there is usually an antenatal timing
      to the neuropathology of cerebral palsy. There are many known risk factors for
      cerebral palsy, including multiple gestation, prematurity, and low birth weight.
      Recently, intrauterine infection, maternal pyrexia, and the presence of
      thrombophilic disorders (thrombophilia) have been identified as major risk
      factors for subsequent cerebral palsy. This review examines the links between
      intrauterine infection, the fetal inflammatory response, and thrombophilia as
      possible causes of cerebral palsy. The interactions of viral or bacterial
      infections during pregnancy, normal or abnormal fetal cytokine responses, and
      hereditary fetal thrombophilias as antenatal causes of the neuropathology of
      cerebral palsy are now areas of research priority. TARGET AUDIENCE: Obstetricians
      & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this
      article, the reader will be able to describe the condition cerebral palsy, list
      the risk factors for the development of cerebral palsy, outline the ultrasound
      findings associated with cerebral palsy, and point out other conditions
      associated with cerebral palsy.

PMID- 12612463
TI  - Alterations of myocardial presynaptic sympathetic innervation in patients with
      multi-vessel coronary artery disease but without history of myocardial
      infarction.
AB  - In patients with myocardial infarction, left ventricular sympathetic denervation
      exceeds the size of the scar tissue. However, little is known about the regional
      innervation in patients with coronary artery disease (CAD) but no myocardial
      infarction. Using positron emission tomography (PET) with N-ammonia and C
      hydroxyephedrine (HED), resting perfusion and presynaptic sympathetic innervation
      were studied in eight patients (seven males, one female; 58+/-9 years) with multi
      vessel CAD and no history of myocardial infarction. Using polar map analysis of
      the PET data, the results were regionally compared with normal databases. The
      mean HED retention was 8.0%+/-2.0% x min(-1). Myocardial resting perfusion was
      normal in 23 of 24 vascular territories. Despite normal resting perfusion,
      significantly reduced HED retention, indicating dysinnervation, was found in 14
      of 23 (61%) vascular territories (six of eight patients). Of the dysinnervated
      territories, 11 (79%) showed angiographically severe stenosis (>or=90% of native
      vessel/coronary artery bypass graft), eight (57%) showed ischaemia (myocardial
      perfusion scintigraphy/stress-electrocardiogram) and 12 (86%) had been
      revascularized. Of the nine segments with normal innervation, two (22%) revealed
      severe stenosis, two (22%) showed ischaemia and seven (78%) had been
      revascularized. It can be concluded that, in patients with advanced CAD and
      normal left ventricular function, dysinnervation can occur in the absence of
      myocardial infarction. This is consistent with the hypothesis that sympathetic
      neurones are more susceptible than myocytes to ischaemic damage.

PMID- 12612464
TI  - Gated stress-only 99mTc myocardial perfusion SPECT imaging accurately assesses
      coronary artery disease.
AB  - In today's cost containment environment it is important to consider changes to
      standard protocols which would reduce cost, particularly if there is no
      significant loss of diagnostic accuracy. The aim of the present study was to
      assess the usefulness of a gated stress-only Tc sestamibi protocol in comparison
      to conventional gated dual isotope rest-stress myocardial perfusion single photon
      emission computed tomography (SPECT) in the detection and localization of
      coronary artery disease (CAD). Sixty-five consecutive patients (65+/-10 years, 22
      women) who had undergone conventional gated perfusion SPECT were chosen
      retrospectively. Fifty-three of these 65 patients had previous coronary
      arteriography, 45 with at least one stenosis, eight without stenosis, and 12 of
      these 65 patients had <5% likelihood of CAD. Three readers interpreted the gated
      stress-only and dual isotope studies in separate sessions blinded to (1). their
      previous readings, (2). the interpretation by others, and (3). the angiographic
      results. Readers used a five-point scale to score their visual and quantitative
      assessment of perfusion, function and compromised vascular territory. Their
      average score was used for determination of the accuracy by using receiver
      operating characteristic (ROC) analysis of the techniques. The areas under ROC
      curves were determined for the detection of CAD and localization of vascular
      territories. Fifty-four of these patients had 97 significant stress induced
      perfusion defects as determined by the CEqual quantitative program. The agreement
      between protocols for the assessment of reversibility in these 97 defects was
      analysed. There were no statistically significant differences between dual
      isotope rest/stress and gated stress-only studies for the detection and
      localization of CAD. The area under the dual isotope rest/stress ROC curve was
      0.78+/-0.07 compared to the area under the gated stress-only ROC curve of 0.80+/
      0.06, resulting in P=0.30. For the combined vessels comparison of the area under
      the dual isotope rest/stress ROC curve was 0.73+/-0.04 versus the area under the
      gated stress-only ROC curve of 0.74+/-0.04, resulting in P=0.27. Similar non
      significant differences were obtained when comparing the area under the dual
      isotope versus gated stress-only ROC curves for the left anterior descending
      vascular territory (LAD, 0.61+/-0.08 vs 0.660.08, P=0.14), the left circumflex
      vascular territory (LCX, 0.82+/-0.07 vs 0.81+/-0.06, P =0.47) or the right
      coronary vascular territory (RCA, 0.80+/-0.06 vs 0.78+/-0.06, P=0.28). The
      analysis of the reversibility of stress induced perfusion defects yielded a
      global agreement between protocols of 93% (kappa=0.42). The differences were due
      to the expert readers, using the gated stress-only protocol, misinterpreting some
      patients with attenuation artefacts, subendocardial infarction and functional
      stunning. These results show that the lower cost gated stress-only myocardial Tc
      myocardial perfusion SPECT studies are comparable to the conventional dual
      isotope studies when the clinical question is the detection and localization of
      coronary artery disease. Nevertheless, we also showed that this approach is
      limited when attempting to interpret the reversibility of stress induced
      perfusion defects in patients who exhibit attenuation artefacts, subendocardial
      infarction and functional stunning.

PMID- 12612465
TI  - Comparison of 99mTc-sestamibi-18F-fluorodeoxyglucose dual isotope simultaneous
      acquisition and rest-stress 99mTc-sestamibi single photon emission computed
      tomography for the assessment of myocardial viability.
AB  - Dual isotope simultaneous acquisition single photon emission computed tomography
      (DISA SPECT) offers the advantage of obtaining information on myocardial
      perfusion using Tc-sestamibi ( Tc-MIBI) and metabolism using F-fluorodeoxyglucose
      ( F-FDG) in a single study. The prerequisite is that the Tc-MIBI images are not
      degraded by scattered 511 keV photons or poor count statistics due to the lower
      efficiency of the extra high energy (EHE) collimator. Therefore, we compared the
      registered Tc-MIBI uptake and image quality of DISA and single isotope
      acquisition. Furthermore, we investigated whether DISA yields additional
      information for the assessment of myocardial viability in comparison with rest
      stress Tc-MIBI. Nineteen patients with known coronary artery disease and
      irreversible perfusion defects on previous rest-stress MIBI test studies were
      investigated. After oral glucose loading and simultaneous injection of 600 MBq of
      Tc-MIBI and 185 MBq of F-FDG at rest, DISA was performed using energy windows of
      140 (+/-15%), 170 (+/-20%) and 511 keV (+/-15%). Planar 140 keV images were
      corrected for scatter by subtraction using the 170 keV window. The single and
      dual isotope Tc-MIBI images were both displayed in a polar map with 128 segments
      normalized to maximum counts. F-FDG and Tc-MIBI images were visually scored for a
      perfusion-metabolism mismatch pattern using nine regions per heart. There was an
      excellent correlation (r =0.93, P<0.0001) between the Tc-MIBI uptake detected in
      the single and dual isotope acquisition. The average difference between the dual
      and single isotope Tc-MIBI uptake was -1.2% (not significantly different from
      zero) and the coefficient of variation of the difference was 8.7%. Of the 79
      regions with irreversible perfusion defects on previous rest-stress Tc-MIBI, six
      regions in five patients showed a perfusion-metabolism mismatch pattern. We
      conclude that DISA does not affect the quality of the Tc-MIBI images.
      Furthermore, F-FDG- Tc-MIBI DISA may show viability in a small but significant
      (7.6%, P<0.0034) number of regions with irreversible perfusion defects on rest
      stress Tc-MIBI.

PMID- 12612466
TI  - Comparison of automatic quantification software for the measurement of
      ventricular volume and ejection fraction in gated myocardial perfusion SPECT.
AB  - The aim of this study was to compare the performance of three different software
      packages for the calculation of ejection fraction (EF) and end diastolic volume
      (EDV) from gated myocardial single photon emission computed tomography studies.
      Two hundred patients undergoing gated stress myocardial perfusion scans were
      analysed retrospectively. Patients were grouped as follows: small heart (n=31),
      normal perfusion scan (n=71), and scan with perfusion defects (n=98). EF and EDV
      were calculated for each using QGS (Cedars Sinai, Los Angeles, CA), 4D-MSPECT
      (University of Michigan, Ann Arbor, MI), and ECT (Emory University, Atlanta, GA).
      Bland-Altman plots, repeated measures ANOVA, and linear regression analysis were
      used to compare methods. Correlation coefficients between the methods for both EF
      and EDV were high, greater than 0.9. However, Bland-Altman plots revealed a large
      standard deviation of the difference between methods, preventing the confident
      estimate of the value of one method from an observation of another. Despite good
      correlation, the variance between methods was high. These algorithms behave
      differently, produce widely variable results from one another, and should not be
      used interchangeably. It may prove prudent for laboratories to independently
      validate the software algorithm that is chosen against a 'gold standard' using
      their own population.

PMID- 12612467
TI  - Cardiac innervation and clinical correlates in idiopathic Parkinson's disease.
AB  - We evaluated the cardiac innervation status of patients with idiopathic
      Parkinson's disease (IPD), in order to recognize cardiac dysautonomia at an early
      clinical stage, using I- -iodobenzylguanidine ( I-MIBG) scintigraphy and its
      relation to other clinical and laboratory parameters. Fourteen patients with IPD
      at Hoehn-Yahr stage I and 11 age-matched controls were studied. Patients were
      scored according to the Unified Parkinson's Disease Rating Scale (UPDRS) in
      aspects of daily life activities, cognitive and emotional status and motor
      examination. All patients underwent 5 min electrocardiographic recordings in
      order to assess the heart rate variability. Planar I-MIBG studies at 15 min and 3
      h after intravenous injection of 185 MBq were performed. Heart-to-mediastinum
      (H/M) ratios were calculated. Plasma catecholamine levels were also evaluated.
      The mean H/M ratios in patients and controls were 1.84+/-0.40 and 2.35+/-0.29,
      respectively (P <0.05). Although the mean plasma adrenaline and noradrenaline
      levels were in the normal range, a weak inverse correlation existed between the
      noradrenaline levels and late I-MIBG H/M ratios (r =-0.442), which was not
      statistically significant. There were no correlations between the other
      parameters. Eight patients had normal electrocardiography, whereas four had
      findings of autonomic imbalance. In conclusion, cardiac dysautonomia is common
      and seems to occur independent of the clinical stage and symptoms in patients
      with IPD. I-MIBG scintigraphy is a powerful tool in its assessment.

PMID- 12612468
TI  - 11C-choline PET for the detection of bone and soft tissue tumours in comparison
      with FDG PET.
AB  - We assessed and compared the usefulness of C-choline positron emission tomography
      (PET) with that of 2-[ F]fluoro-2-deoxy-D-glucose (FDG) PET for the
      differentiation between benign and malignant bone and soft tissue tumours. A
      total of 43 patients with 45 lesions were included. C-choline PET and FDG PET
      were performed from 5 and 40 min, respectively, after injection of 275-370 MBq
      tracer. PET data were evaluated by using the standardized uptake value (SUV) and
      were analysed according to the pathological data. C-choline uptake in
      malignancies was 4.9+/-2.1 (n=14), which was significantly higher than that in
      benign lesions (2.5+/-1.7, n=31) (P <0.0001). The sensitivity, specificity and
      accuracy of C-choline PET were 100%, 64.5% and 75.6%, respectively, when 2.59 of
      the SUV was used as the cut-off value. The FDG uptake in malignancies was 5.1+/
      4.2 (n=14) and was also significantly larger than that in benign lesions 2.9+/
      2.9 (n=31) (P<0.003). The sensitivity, specificity and accuracy of FDG PET were
      85.7%, 41.9% and 55.6%, respectively (cut-off=1.83). The C-choline uptake in the
      lesions correlated with FDG uptake ( r=0.61, P<0.003). In receiver operating
      characteristic (ROC) analysis, the area under the ROC curve for C-choline PET
      (area=0.847) was higher than that for FDG PET (area=0.717). This study showed
      that C-choline PET was superior to FDG PET in differentiation between malignant
      and benign lesion in bone and soft tissue tumours. C-choline PET might be useful
      as a screening method for malignant bone and soft tissue tumours.

PMID- 12612469
TI  - Melanoma patients evaluated by four different positron emission tomography
      reconstruction techniques.
AB  - One hundred and nineteen patients with malignant melanoma were studied using 2-[
      F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET). The images
      were reconstructed using ordered subset expectation maximization with and without
      attenuation correction and filtered backprojection with and without attenuation
      correction. The most probable draining lymph node chains were surgically explored
      and the tumour volume was quantified at histology. The four different
      reconstructions of the PET images were retrospectively graded on a five-point
      scale by two blind readers and compared with the tumour volume. The readers
      agreed within +/-1 grade 93% (529/568) of the time. Comparing the areas under the
      receiver operating characteristic (ROC) curves gave 0.698, 0.668, 0.694 and 0.684
      for the four reconstruction techniques. The lowest value comparing any pair of
      the four reconstruction techniques was P=0.371. Thus, none of the reconstruction
      techniques gave significantly better results than any of the others. The
      sensitivity of detection was 85% for tumour volumes of 113 m or more (about 6 mm
      in diameter), but only 4% for tumours less than this size. It can be concluded
      that the use of attenuation correction gives aesthetically more pleasing images,
      but the sensitivity and specificity are not significantly improved.

PMID- 12612471
TI  - Uptake of radiolabelled alpha-fetoprotein by experimental mammary adenocarcinoma
      and adenoma: in vivo and in vitro studies.
AB  - The biodistribution of iodine-labelled alpha-fetoprotein ( I-AFP) in experimental
      mammary tumours was studied. C3H mice with subcutaneously transplanted mammary
      adenocarcinoma and Sprague-Dawley rats treated with -methyl- -nitrosourea for
      mammary adenoma induction were used as animal models. The accumulation of
      labelled I-AFP in mouse mammary adenocarcinoma was significantly higher than that
      in rat mammary adenoma. The tumour/muscle radioactivity ratios increased with
      time and, 48 h after intravenous injection, were estimated as 23.4 and 6.7,
      respectively. For experiments, extracts from both mammary tumours were prepared.
      The extracts were subjected to sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis (SDS-PAGE), transferred to polyvinylidene difluoride (PVDF)
      membranes and incubated with I-AFP. A single major AFP-binding protein with a
      molecular weight of about 30 kDa was detected in both extracts. The amount of AFP
      binding protein was clearly higher for adenocarcinoma than for adenoma. In the
      presence of cross-linking reagent, I-AFP formed a complex (about 100 kDa) with
      adenocarcinoma proteins.

PMID- 12612470
TI  - Contribution of 99mTc-anti-carcinoembryonic antigen antibody and 99mTc-sestamibi
      scintimammography in the evaluation of high risk palpable breast lesions.
AB  - Mammography is the screening test of choice for breast cancer. Its low
      specificity leads to a large number of unnecessary biopsies. Scintimammography,
      with either Tc-sestamibi (MIBI) or Tc-anti-carcinoembryonic antigen (CEA) Fab',
      has been proposed as a non-invasive test to lower the high false positive rate of
      mammography in certain patients. The two agents have not been compared, nor has
      their combined application been evaluated. We performed a prospective, non
      randomized, open-label, single-centre study of 32 women with clinically and
      mammographically suspected breast cancer [Breast Imaging Reporting and Data
      System (BI-RADS, American College of Radiology) 4 or 5]. All patients underwent
      Tc-MIBI and Tc-anti-CEA Fab' scintimammography, and the results were correlated
      with histopathology. Overall, the accuracies for MIBI and CEA scans were 90.3%
      (28/31) and 77.4% (24/31), respectively. The probability of disease after
      mammography was 0.939+/-0.081 (95% confidence interval, CI). The post-mammography
      probabilities after positive MIBI or CEA scan were 0.965 and 0.960, respectively,
      and after negative MIBI or CEA scan 0.750 and 0.875, respectively. None of the
      above differences is significant. The post-test probability when both scans were
      positive (irrespective of which was performed first) was 0.977. It can be
      concluded that there are indications that scintimammography with Tc-MIBI is
      superior to that with Tc-anti-CEA Fab' when these tests are used as screening
      tests for breast cancer. However, mammography remains the screening test of
      choice for highly suspicious clinically palpable breast lesions. In this group of
      patients, the application of scintimammography with either Tc-MIBI or Tc-anti-CEA
      Fab' (alone or in combination) offers no additional advantage.

PMID- 12612472
TI  - 123I-Interleukin-2: biochemical characterization and in vivo use for imaging
      autoimmune diseases.
AB  - We describe in detail the labelling of interleukin-2 with I ( I-IL2), its
      biochemical characterization, the binding assay and its use for the detection of
      tissues infiltrated with mononuclear cells. Human recombinant IL2 was labelled
      using an enzymatic method and its biochemical characterization was performed
      using high performance liquid chromatography (HPLC) analysis of cyanogen bromide
      cleaved protein. biological and binding assays were performed on CTLL-2 cell line
      and on activated peripheral blood lymphocytes. studies were performed 1 h after
      administration of 2-3 mCi of I-IL2 in 10 newly diagnosed type 1 diabetes
      patients, five pre-diabetic patients, 10 Hashimoto's thyroiditis patients, 10
      coeliac disease patients and 10 normal volunteers. I-IL2 scintigraphy allowed the
      detection and quantification of activated mononuclear cells in several affected
      tissues. In detail, I-IL2 accumulation was detected in the thyroid of all
      patients affected by Hashimoto's thyroiditis, in the bowel of all coeliac disease
      patients and in the pancreas of all pre-type 1 diabetic patients. By contrast, in
      newly diagnosed type 1 diabetics, I-IL2 scan was positive in five of the 10
      studied patients. I-IL2 scintigraphy may be useful for studying autoimmune
      phenomena and in diagnostic protocols to evaluate the presence of other tissue
      involvement in patients with an organ-specific autoimmune disease.

PMID- 12612473
TI  - Radionuclide scintigraphy in the evaluation of gastro-oesophageal reflux in post
      operative oesophageal atresia and tracheo-oesophageal fistula patients.
AB  - Gastro-oesophageal reflux (GOR) is a major cause of morbidity in children who
      undergo surgical repair for oesophageal atresia with tracheo-oesophageal fistula
      (OA/TOF). We performed a retrospective analysis to determine the incidence of GOR
      on radionuclide scintigraphy in symptomatic and asymptomatic OA/TOF patients in
      the first post-operative year. A total of 124 patients (74 males, 50 females),
      with a mean age of 3.5 months (range, 20 days to 12 months), were studied. Of
      these 124 patients, 67 were symptomatic and 57 were asymptomatic. On radionuclide
      scintigraphy, 73 patients (48 symptomatic and 25 asymptomatic) had reflux. Of the
      48 symptomatic patients with scintigraphic studies positive for reflux, 79.2%
      (38) had proximal reflux and 20.8% (10) had distal reflux, whereas, of the 57
      asymptomatic patients, 48% (12) had proximal reflux and 52% (13) had distal
      reflux. There was a significantly higher incidence of GOR in symptomatic children
      than in asymptomatic children (P<0.01). In particular, there was a significantly
      higher incidence of proximal GOR in symptomatic children than in asymptomatic
      children (P<0.001). In conclusion, the severity and incidence of GOR were
      significantly higher in symptomatic than asymptomatic OA/TOF patients in their
      first post-operative year. Scintigraphic evidence of proximal reflux correlates
      with the presence of symptomatic GOR.

PMID- 12612474
TI  - Differences between 99mTc-sestamibi and 99mTc-tetrofosmin uptake in thyroid and
      salivary glands: comparison with 99mTc-pertechnetate in 86 subjects.
AB  - Tc-tetrofosmin seems to show a prolonged thyroid retention when compared with Tc
      sestamibi; this may explain its poorer performance in the dual-phase parathyroid
      scintigraphy. In order to verify objectively whether and to what extent Tc
      sestamibi and Tc-tetrofosmin uptake and retention differ in the thyroid gland, we
      performed a head-to-head comparison between the tracers in 86 euthyroid subjects
      enrolled in five centres. Data were compared with those of Tc-pertechnetate
      obtained from the same subjects. For comparison purposes, quantitative data from
      the salivary glands were also obtained. Tc-sestamibi showed a higher early
      thyroid uptake (2.26+/-0.52 vs. 2.01+/-0.49, respectively; P<0.002) and a lower
      retention (1.4+/-0.37 vs. 1.65+/-0.58, respectively; P<0.002) when compared with
      Tc-tetrofosmin. This finding provides an objective basis for the poorer results
      of Tc-tetrofosmin in dual-phase parathyroid scintigraphy. Delayed Tc-tetrofosmin
      salivary gland uptake was unexpectedly high and approached the Tc-pertechnetate
      value (2.29+/-0.56 vs. 2.46+/-0.75, respectively; P =not significant). This
      finding should be kept in mind in order to avoid interpretation pitfalls in
      thyroid and parathyroid imaging with Tc-tetrofosmin, as well as in other
      oncological imaging of the neck region. This study definitely establishes that Tc
      tetrofosmin and Tc-sestamibi are not twin but rather sibling tracers.

PMID- 12612475
TI  - Differentiation of soft tissue haemangioma by 201Tl scintigraphy.
AB  - Radiological diagnosis of deep soft tissue is often difficult. In the present
      study, thallium-201 ( Tl) uptake into haemangiomas and deep malignant soft tissue
      tumours was investigated in order to assess its clinical utility. Tl scintigraphy
      was reviewed in four patients presenting with soft tissue haemangiomas. Early and
      delayed planar images, obtained at 15 min and 3 h following the intravenous
      injection of Tl (111 MBq), were examined. The Tl uptake ratio was calculated by
      dividing the count density of the tumour region of interest (ROI) by that of the
      background ROI. Results were compared with those of five cases of
      rhabdomyosarcoma and a single instance of angiosarcoma. All haemangioma lesions
      demonstrated increased Tl uptake in early images. However, Tl uptake in delayed
      images was markedly decreased. No significant differences were observed in the
      early uptake ratio between haemangiomas (1.60-2.72) and reference malignant
      tumours (1.48-2.45); however, the difference was significant in delayed images
      (range, 1.01-1.26 vs. 1.43-2.03, respectively) ( P<0.02). Deep soft tissue
      haemangiomas revealed Tl accumulation in early images; however, a rapid washout
      was observed in delayed images. This distinctive feature may facilitate the use
      of Tl scintigraphy in the diagnosis of haemangiomas.

PMID- 12612476
TI  - Background and educational characteristics of prelingually deaf children
      implanted by five years of age.
AB  - PURPOSE: This study documents child, family and educational characteristics of a
      large representative sample of 8- to 9-yr-old prelingually deaf children who
      received a cochlear implant by 5 yr of age. Because pre-existing factors such as
      the child's gender, family characteristics, additional handicaps, age at onset of
      deafness and at implant, may affect postimplant outcomes, these variables must be
      accounted for before the impact of educational factors on performance with an
      implant can be adequately determined. Classroom variables that may affect
      postimplant outcomes include placement in public or private, mainstream or
      special education, oral or total communication environments. Other intervention
      variables include type and amount of individual therapy, experience of the
      therapist and parent participation in therapy. Documenting these characteristics
      for a large representative sample of implanted children can provide clinicians
      and researchers with insight regarding the types of families who sought early
      cochlear implantation for their children and the types of educational programs in
      which they placed their children after implantation. It is important to undertake
      studies that control for as many of these factors as possible so that the
      relative benefits of specific educational approaches for helping children to get
      the most benefit from their cochlear implant can be identified. METHOD: Over a 4
      yr period, 181 children from across the US and Canada, accompanied by a parent,
      attended a cochlear implant research camp. Parents completed questionnaires in
      which they reported the child's medical and educational history, characteristics
      of the family, and their participation in the child's therapy. The parent listed
      names and addresses of clinicians who had provided individual speech/language
      therapy to the child and signed permission for these clinicians to complete
      questionnaires describing this therapy. RESULTS: To the extent that this sample
      is representative of those families seeking a cochlear implant for their child,
      especially during the initial period of device availability, this population can
      be characterized as follows. Most parents had normal hearing, were of majority
      (white) ethnicity and had more education and higher incomes than the general
      population. The families tended to be intact with both a mother and a father who
      involved their hearing-impaired child in family activities on a regular basis.
      The children were enrolled in the full range of educational placements available
      across the United States and Canada. Fairly even distributions of children from
      public and private schools, special education and mainstream classes and oral and
      total communication methodologies were represented. Educational placement changed
      as children gained increased experience with a cochlear implant. They received an
      increased emphasis on speech and auditory skills in their classroom settings and
      tended to move from private school and special education settings to public
      school and mainstream programs. These data support the position that early
      cochlear implantation is a cost effective procedure that allows deaf children to
      participate in a normal school environment with hearing age mates.

PMID- 12612477
TI  - Statistical analysis and interpretation in a study of prelingually deaf children
      implanted before five years of age.
AB  - This article describes the major statistical analyses used in a large-scale study
      of prelingually deaf children implanted before 5 yr of age. Two major challenges
      posed by the data were the need to reduce the number of outcome measures to a
      reasonable number while retaining the important information underlying the
      multiple measures, and the need to determine the unique contributions of multiple
      sets of predictor variables. The approach taken-principal components analysis of
      the outcome measures followed by hierarchical multiple regression-provided a
      compromise between statistical complexity and ease of interpretation.

PMID- 12612478
TI  - Factors associated with development of speech perception skills in children
      implanted by age five.
AB  - OBJECTIVE: This study investigated factors contributing to speech perception
      outcomes in children with prelingual deafness after 4 to 7 yr of multichannel
      cochlear implant use. The analysis controlled for the effects of child, family
      and implant characteristics so that educational factors most conducive to maximum
      implant benefit could be identified. DESIGN: One hundred eighty-one 8- and 9-yr
      old children from across the US and Canada who received a cochlear implant by age
      5 were administered a battery of speech perception tests. Type and amount of
      educational intervention since implantation constituted the independent
      variables. Characteristics of the child, the family, and the implant itself
      constituted intervening variables. A series of multiple regression analyses
      determined the amount of variance in speech perception ability accounted for by
      the intervening variables and the amount of additional variance attributable to
      independent variables. RESULTS: The children achieved an average level of about
      50% open-set speech perception through listening alone and almost 80% through
      lipreading and listening together, but with scores for individual children
      ranging from 0 to 100% correct. Over half of the variance in speech perception
      scores was predicted by characteristics of the child, family, implant and
      educational program. Significant predictors of good speech perception included
      greater nonverbal intelligence, smaller family size, longer use of the updated
      SPEAK/CIS processing strategy, a fully active electrode array, greater electrical
      dynamic range between threshold and maximum comfort level, and greater growth of
      loudness with increasing stimulus intensity. After the variance due to these
      variables was controlled, the primary rehabilitative factor associated with good
      speech perception skill development was educational emphasis on oral-aural
      communication. CONCLUSIONS: Children with profound hearing loss achieved
      unprecedented levels of speech perception skill 4 to 7 yr after cochlear
      implantation. Use of an updated speech processor, such as SPEAK, contributed
      significantly to improved speech perception skills, even in children who were
      initially fitted with an earlier strategy, such as M-PEAK. In addition, the
      audiologist who programs the cochlear implant makes an important contribution to
      the child's successful outcome with the device. A well-fitted map, as evidenced
      by a wide dynamic range and optimal growth of loudness characteristics,
      contributed substantially to the child's ability to hear speech. Finally, the
      classroom communication mode used in the child's school affects speech perception
      outcome. Children whose educational program emphasized dependence on speech and
      audition for communication were better able to use the information provided by
      the implant to understand speech.

PMID- 12612479
TI  - Factors associated with development of speech production skills in children
      implanted by age five.
AB  - OBJECTIVE: This study investigated speech production outcomes and the factors
      influencing the outcomes in children who had 4 to 6 yr of experience with a
      multichannel cochlear implant. Production variables examined included speech
      intelligibility, accuracy of consonant and vowel production, percentage of
      plosives and fricatives produced, duration of sentences, percentage of time
      involved in communication breakdowns during a communication sample, and responses
      to a speech usage questionnaire. DESIGN: 181 children between the ages of 8 and 9
      yr who received a multichannel cochlear implant before age 5 yr participated as
      subjects. Independent variables were the amount and type of educational
      intervention and intervening variables were distributed across child, family and
      implant characteristics. Multiple regression analyses provided a measure of the
      amount of variance associated with speech production skills accounted for by the
      intervening and independent variables. RESULTS: Performance for the key words in
      the speech intelligibility measured averaged 63.5% for the group of children.
      Accuracy of phoneme production was higher for consonants (68.0%) than for vowels
      (61.6%) for the group. More plosives were present for acoustic analyses (91.6%)
      than were fricatives (78.4%). Duration for the speech intelligibility sentences
      averaged 2572.3 msec. Communication breakdowns occurred on average 14.5% of the
      time involved in a language sample. Significant predictors of high levels of oral
      communication skills included higher nonverbal intelligence, gender, longer use
      of SPEAK processing strategy, a fully active electrode array, greater dynamic
      range, and greater growth of loudness. The primary rehabilitative factors
      contributing to high levels of oral communication were an emphasis on oral-aural
      communication and classrooms that emphasized dependence on speech and listening.
      CONCLUSIONS: Speech production performance in children with cochlear implants is
      influenced by nonverbal intelligence, gender, implant characteristics including
      the length of time using the newest speech processing strategies, and educational
      programs emphasizing oral-aural communication. Factors previously thought to be
      major contributors to speech production performance, such as age of onset of
      deafness and age of implantation, did not appear to play significant roles in
      predicting levels of speech production performance.

PMID- 12612480
TI  - Language skills of children with early cochlear implantation.
AB  - OBJECTIVE: This study investigated factors contributing to the comprehension and
      production of English language by children with prelingual deafness after 4 to 7
      yr of multichannel cochlear implant use. The analysis controlled for the effects
      of child and family characteristics so that educational factors most conducive to
      maximum implant benefit could be identified. DESIGN: A battery of language tests
      were administered to 181 8- and 9 yr-old children from across the United States
      and Canada who received a cochlear implant by age 5. Tests of comprehension,
      verbal reasoning, narrative ability and spontaneous language production were
      administered either in speech and sign or in the child's preferred communication
      mode. These constituted the Total Language measures. Spoken Language measures
      were derived from a speech-only language sample. Type and amount of educational
      intervention since implantation constituted the independent variables.
      Characteristics of the child and the family were considered intervening
      variables. A series of multiple regression analyses determined the amount of
      variance in Total Language and Spoken Language ability accounted for by the
      intervening variables and the amount of additional variance attributable to the
      independent variables. RESULTS: More than half of the children (with performance
      intelligence quotients in the average range) exhibited language skills that were
      similar to those of hearing 8 to 9 yr olds on measures of verbal reasoning,
      narrative ability, utterance length, and lexical diversity. Significant
      predictors of language ability were similar for Total and for Spoken Language
      outcomes and included greater nonverbal intelligence, smaller family size, higher
      socio-economic status and female gender. Age at receiving an implant did not
      affect language outcome. After the variance due to these variables was
      controlled, the primary rehabilitative factors associated with linguistic outcome
      were amount of mainstream class placement and an educational emphasis on speech
      and auditory skills. CONCLUSIONS: Use of a cochlear implant has had a dramatic
      impact on the linguistic competence of profoundly hearing-impaired children. More
      than half of the children in this sample with average learning ability produced
      and understood English language at a level comparable with that of their hearing
      age mates. Such mature language outcomes were not typical of children with
      profound hearing loss who used hearing aids. Use of a visual (i.e., sign)
      language system did not provide the linguistic advantage that had been
      anticipated. Children educated without use of sign exhibited a significant
      advantage in their use of narratives, the breadth of their vocabulary, in their
      use of bound morphemes, in the length of their utterances and in the complexity
      of the syntax used in their spontaneous language. An oral educational focus
      provided a significant advantage for both spoken and total language skills.

PMID- 12612481
TI  - Predictors of reading skill development in children with early cochlear
      implantation.
AB  - OBJECTIVE: The present study sought to document the word reading and
      comprehension levels attained by children who were implanted by 5 yr of age. It
      was hypothesized that the improved speech perception abilities acquired with
      cochlear implantation would promote phonological coding skills and facilitate the
      acquisition of beginning reading skills. DESIGN: Three subtests from diagnostic
      reading assessment batteries standardized on hearing children were administered
      to 181 children between 8 yr 0 mo and 9 yr 11 mo of age who had 4 to 6 yr of
      implant experience. In addition, a battery of processing measures was
      administered including a lexical decision task, a rhyme task and the digit span
      subtest of the Wechsler Intelligence Scale for Children. RESULTS: Over half of
      the children scored within the average range for their age compared with the
      normative data for hearing children. Reading competence was associated with
      higher nonverbal intelligence, higher family socio-economic status, female gender
      and later onset of deafness (between birth and 36 mo). After variance due to
      these child and family characteristics was removed, reading competence was
      associated with mainstream educational placement, use of an updated implant
      speech processor with a wide dynamic range, and speech processing characteristics
      that included longer memory span and use of phonological coding strategies.
      Reading outcome was most highly predicted by linguistic competence and,
      secondarily, by speech production skill. CONCLUSION: Children who experience
      severe to profound deafness early in their development have a better prognosis
      for normal literacy development than ever before. To the extent that use of a
      cochlear implant is associated with greater use of phonological coding strategies
      for decoding print, longer working memory spans for short-term storage of
      phonemes, words and sentences and accelerated language development for reading
      comprehension, it should have a facilitative effect on the acquisition of
      literacy.

PMID- 12612482
TI  - Personal, social, and family adjustment in school-aged children with a cochlear
      implant.
AB  - OBJECTIVE: The present study sought to document the psycho-social adjustment of
      181 school-aged deaf children who have had a cochlear implant for 4 or more yr
      and to examine parental satisfaction with the outcome of the implantation process
      on their child's life and on their family's life in general. DESIGN: Three
      measures were employed. One measure was a self-report instrument designed to
      assess perceived self-competence in children, one was a rating scale completed by
      parents that sought to assess the degree of their child's personal-social
      adjustment, and the third was a questionnaire given to parents on which they
      rated their satisfaction with aspects of the cochlear implant and how it had
      affected their child's functioning within the context of family life. RESULTS:
      Children generally perceived themselves (and parents perceived their children) as
      being competent and well adjusted in most aspects of daily life. Parents
      expressed a generally positive view of cochlear implantation and its effects on
      family life. None of the social-emotional adjustment measures was significantly
      related to the speech perception, speech production or language skills the child
      achieved postimplant. However, the parents' satisfaction with their child's
      cochlear implantation was significantly related to their child's speech and
      language achievements. On the perceived self-competence instrument, younger
      children and those with longer use of the updated SPEAK speech processor gave
      themselves higher ratings. Parent ratings of their child's adjustment tended to
      be higher for girls than for boys, for more rather than less intelligent
      children, and for children enrolled in private as opposed to public school
      settings. CONCLUSIONS: Deaf children who have used a cochlear implant for 4 to 6
      yr report that they are coping successfully with the demands of their social and
      school environment, regardless of their speech and language achievements after
      implantation. Parents' ratings indicate that these children are emotionally and
      socially well adjusted and that they have benefited from cochlear implantation.
      To the extent that the children and their parents accurately reported their
      attitudes and feelings regarding their experiences at home and at school, these
      results represent an impressive level of personal and social adjustment when
      compared with previous literature on adjustment problems in deaf children. The
      extent to which these results are associated with cochlear implantation has not
      been determined and awaits comparative data from children without implants.

PMID- 12612483
TI  - Conversational fluency of children who use cochlear implants.
AB  - PURPOSE: Children who have significant hearing loss often experience difficulty
      in engaging in everyday conversations. They may spend an inordinate amount of
      time in communication breakdown or in silence. The purpose of the present
      investigation was to assess the oral conversation fluency of young cochlear
      implant users using both objective and subjective measuring procedures.
      Conversational fluency relates to how smoothly a conversation unfolds. The
      children's performance was compared with that of children who have normal
      hearing, and related to other measures of communication skill and other child
      variables. DESIGN: One hundred eighty-one cochlear implant users and 24 children
      with normal hearing engaged in conversations with a clinician, using an oral mode
      of communication. Audio-video tapes of the conversations were analyzed to yield
      the following measures: percent of time the child and clinician spent trying to
      repair a breakdown in communication, percent of time the two spent sitting in
      silence, and the ratio between the amount of time the child spoke and the amount
      of time the clinician spoke. In addition, for the cochlear implant users, 10
      judges viewed excerpts of the tapes and gave their impressions and reactions to
      the children and their conversations, using five-point rating scales. The
      objective and subjective measures were related to the children's speech
      intelligibility, mean length utterance, and speech recognition in both an
      auditory-only and auditory-plus-vision condition. RESULTS: The cochlear implant
      users spent significantly more time in communication breakdown and in silence
      than the children with normal hearing, and children who are in an educational
      placement that emphasizes oral communication spent less time in breakdown than
      children who are in educational placement that use both speech and sign. Speech
      intelligibility and receptive language were the best predictors of communication
      breakdown. Judges perceived children who spent less time in communication
      breakdown more favorably than children who spent more time, and reacted to them
      more positively. Finally, there was a high correlation between the subjective
      measures of the conversation and the objective measures. CONCLUSIONS: Educational
      programs should provide explicit instruction to promote conversational fluency.
      The results show a need for communication therapy, and suggest that the children
      will be perceived and reacted to more favorably if they learn how to manage
      communication difficulties. The results also support the need for extensive
      speech-language therapy for these children. The objective measures employed in
      this investigation appear to be a valid and useful means for assessing
      conversational fluency.

PMID- 12612484
TI  - Acoustic characteristics of the speech of young cochlear implant users: a
      comparison with normal-hearing age-mates.
AB  - OBJECTIVE: The primary objective of this study was to compare select acoustic
      characteristics of the speech of deaf children who use cochlear implants (young
      cochlear implant users) with those of children with normal hearing. A secondary
      objective of this study was to examine the effect, if any, of the deaf child's
      education (oral versus total communication) on the similarity of these acoustic
      characteristics to those of normal-hearing age-mates. DESIGN: Speech was recorded
      from 181 young cochlear implant users and from 24 children with normal hearing.
      All speech was produced by imitation, and consisted of complete sentences.
      Acoustic measures included voice onset time (/t/, /d/), second formant frequency
      (/i/, /[U0254]/), spectral moments (mean, skew and kurtosis of /s/ and
      /[U0283]/), a nasal manner metric, and durations (of vowels, words, and
      sentences). RESULTS AND DISCUSSION: A large percentage (46 to 97%) of the young
      cochlear implant users produced acoustic characteristics with values within the
      range found for children with normal hearing. Exceptions were sentence duration
      and vowel duration in sentence-initial words, for which only 23 and 25%,
      respectively, of the COCHLEAR IMPLANT users had values within the normal range.
      Additionally, for most of the acoustic measures, significantly more COCHLEAR
      IMPLANT users from oral than from total communication settings had values within
      the normal range. CONCLUSIONS: Compared with deaf children with hearing aids
      (from previous studies by others), deaf children who use cochlear implants have
      improved speech production skills, as reflected in the acoustic measures of this
      study. Placement in an oral communication educational setting is also associated
      with more speech production improvement than placement in a total communication
      setting.

PMID- 12612487
TI  - Changing UI practice: this report challenges nurses to lead the way in managing
      incontinence.

PMID- 12612485
TI  - Measures of working memory span and verbal rehearsal speed in deaf children after
      cochlear implantation.
AB  - Large individual differences in spoken word recognition performance have been
      found in deaf children after cochlear implantation. Recently, Pisoni and Geers
      (2000) reported that simple forward digit span measures of verbal working memory
      were significantly correlated with spoken word recognition scores even after
      potentially confounding variables were statistically controlled for. The present
      study replicates and extends these initial findings to the full set of 176
      participants in the CID cochlear implant study. The pooled data indicate that
      despite statistical "partialling-out" of differences in chronological age,
      communication mode, duration of deafness, duration of device use, age at onset of
      deafness, number of active electrodes, and speech feature discrimination,
      significant correlations still remain between digit span and several measures of
      spoken word recognition. Strong correlations were also observed between speaking
      rate and both forward and backward digit span, a result that is similar to
      previously reported findings in normal-hearing adults and children. The results
      suggest that perhaps as much as 20% of the currently unexplained variance in
      spoken word recognition scores may be independently accounted for by individual
      differences in cognitive factors related to the speed and efficiency with which
      phonological and lexical representations of spoken words are maintained in and
      retrieved from working memory. A smaller percentage, perhaps about 7% of the
      currently unexplained variance in spoken word recognition scores, may be
      accounted for in terms of working memory capacity. We discuss how these
      relationships may arise and their contribution to subsequent speech and language
      development in prelingually deaf children who use cochlear implants.

PMID- 12612486
TI  - Epilogue: major findings, conclusions and implications for deaf education.

PMID- 12612488
TI  - Executive summary: a look at the proceedings of the symposium, "The State of the
      Science on Urinary Incontinence.".

PMID- 12612489
TI  - Behavioral interventions in young and middle-age women: simple interventions to
      combat a complex problem.

PMID- 12612490
TI  - Gender, race, and culture in research on UI: sensitivity and screening are
      integral to adequate patient care.
AB  - Urinary incontinence is a significant health care problem affecting women and men
      of all races and cultures. Existing literature provides a limited evidence base
      with which to influence UI practice. More research is needed to fully understand
      the influences of gender, race, culture, or ethnicity on the patient's experience
      of UI and its management. The matter is particularly relevant for nurses who want
      to understand and help people cope with the adverse physical and psychosocial
      consequences of this chronic, socially isolating, and potentially devastating
      disorder.

PMID- 12612491
TI  - Treatment of urinary incontinence in men and older women: the evidence shows the
      efficacy of a variety of techniques.

PMID- 12612492
TI  - Urinary incontinence in the frail elderly: even when it's too late to prevent a
      problem, you can still slow its progress.

PMID- 12612493
TI  - Discussion and recommendations: overcoming barriers to nursing care of people
      with urinary incontinence: a two-day discussion generates inspiration and
      recommendations.

PMID- 12612495
TI  - A review of common sleep disorders.
AB  - What should clinicians know about sleep disorders? This article briefly
      introduces the reader to sleep medicine and succinctly reviews common sleep
      disorders. First, the authors describe the diagnostic tools unique to sleep
      medicine: the over-night polysomnogram and the multiple sleep latency test. Next,
      the authors review essential features of a subset of the sleep, described in the
      International Classification of Sleep Disorders-Revised, that sleep disorder
      specialists commonly evaluate, diagnose, and treat. The disorders reviewed
      include the intrinsic and circadian rhythm subsets of the dyssomnias group and
      the parasomnia group of sleep disorders. The authors identify the core signs and
      symptoms, polysomnogram findings, multiple sleep latency test findings, and
      treatment of these disorders.

PMID- 12612496
TI  - Psychological status and levels of sleepiness-alertness among patients with
      insomnia.
AB  - Are symptoms of daytime sleepiness relevant among patients with insomnia?
      Patients with insomnia frequently report daytime consequences secondary to their
      difficulty initiating and maintaining sleep. The purpose of this study was to
      determine the frequency of daytime sleepiness as defined by a self-reported
      measure of daytime sleepiness (the Epworth Sleepiness Scale). In addition, the
      study characterized the patients' psychological status using the Symptom
      Checklist-90-Revised. The study corroborated a relatively high frequency of
      excessive daytime sleepiness and psychiatric conditions among patients with
      insomnia. Furthermore, the results of the study suggest variation in
      psychological distress levels, according to the different levels of
      sleepiness/alertness.

PMID- 12612497
TI  - Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder
      and schizophrenia?
AB  - Does narcolepsy, a neurological disease, need to be considered when diagnosing
      major mental illness? Clinicians have reported cases of narcolepsy with prominent
      hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia. In
      some bipolar disorder patients with narcolepsy, the HH resulted in their
      receiving a more severe diagnosis (ie, bipolar disorder with psychotic features
      or schizoaffective disorder). The role of narcolepsy in psychiatric patients has
      remained obscure and problematic, and it may be more prevalent than commonly
      believed. Classical narcolepsy patients display the clinical "tetrad"--cataplexy,
      hypnagogic hallucinations, daytime sleep attacks, and sleep paralysis. Over 85%
      also display the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since
      1998, discoveries in neuroanatomy and neurophysiology have greatly advanced the
      understanding of narcolepsy, which involves a nearly total loss of the recently
      discovered orexin/hypocretin (hypocretin) neurons of the hypothalamus, likely by
      an autoimmune mechanism. Hypocretin neurons normally supply excitatory signals to
      brainstem nuclei producing norepinephrine, serotonin, histamine, and dopamine,
      with resultant suppression of sleep. They also project to basal forebrain areas
      and cortex. A literature review regarding the differential diagnosis of
      narcolepsy, affective disorder, and schizophrenia is presented. Furthermore, it
      is now possible to rule out classical narcolepsy in difficult psychiatric cases.
      Surprisingly, psychotic patients with narcolepsy will likely require stimulants
      to fully recover. Many conventional antipsychotic drugs would worsen their
      symptoms and make them appear to become a "chronic psychotic," while in fact they
      can now be properly diagnosed and treated.

PMID- 12612498
TI  - Obstructive sleep apnea and depression.
AB  - Is there an association between obstructive sleep apnea (OSA) and depression? OSA
      is a common breathing-related sleep disorder. There have been reports that
      depressive symptoms can be associated with this sleep disorder. A number of
      investigations have addressed this issue. Although some have found no
      correlation, most studies have concluded that there is an association between OSA
      and depressive symptoms. Other investigations have shown that depressive symptoms
      improve with treatment of OSA, and that untreated OSA may contribute to treatment
      resistance in some cases of mood disorders. Within the framework of current
      psychiatric diagnostic criteria, the depressive symptoms associated with OSA can
      be viewed as a combination of a mood disorder secondary to a primary medical
      condition and an adjustment disorder with depressed mood. The question of whether
      OSA causes depressive symptoms can perhaps be best answered by viewing OSA and
      depression as having certain symptoms that are common to both disorders.

PMID- 12612499
TI  - Rhythmic movement disorder in children.
AB  - How should sleep-related rhythmic movements in children be assessed and treated?
      Rhythmic movement disorder (RMD) represents an unusual variety of childhood
      parasomnia characterized by repetitive motion of the head, trunk, or extremities,
      which usually occurs during the transition from wakefulness to sleep or arises
      during sustained sleep. Although the condition most often affects infants and
      toddlers in a transient and self-limited fashion, the condition occasionally
      persists in a problematic fashion, which may nevertheless be amenable to
      treatment. Since RMD may occasionally cause injury or resemble nocturnal seizure,
      prompt recognition, and appropriate management on the part of the clinician is
      essential. This article will examine the spectrum of RMD in children, including
      their common clinical manifestations; data regarding their epidemiology and
      natural history; the role of polysomnography, electroencephalography; and other
      diagnostic testing. Potential causes of the condition and available methods of
      treatment are also examined.

PMID- 12612500
TI  - Melatonin and jet lag syndrome: experimental model and clinical implications.
AB  - What is the effect of melatonin on jet lag syndrome? Jet lag desynchronizes the
      internal sleep-wakefulness cycle with the environmental light/dark cycle. Advance
      (but not delay) of light onset is known to abolish pineal N-acetyltransferase
      activity and urine excretion of 6-sulphatoxymelatonin. Measurements of pineal
      serotonin, the substrate of melatonin biosynthesis; N-acetylserotonin (NAS), the
      immediate melatonin precursor; and melatonin (high-performance liquid
      chromatography-fluorimetric method) in the animal (rat) model of jet lag revealed
      that prolonged delay of dark-phase onset disrupted the rhytms in comparable ways
      as the advance of light-phase onset. Advance of dark phase onset resulted in less
      severe disturbances of rhythms as compared with the advance of light phase onset.
      Melatonin, but not NAS, injections at the beginning of a new dark period
      accelerated recovery of NAS and melatonin, but not serotonin, rhythms.
      Spontaneously hypertensive rats were more sensitive to advance of light onset and
      less responsive to melatonin injections than normotensive rats. NAS and methylene
      blue, an inhibitor of monoamine oxidase A, attenuated light-induced disruption of
      NAS but not melatonin rhythms. We draw the following conclusions from our data:
      the beginning of the dark period may be preferable to the beginning of light
      period as the arrival time on eastward flights; the efficacy of melatonin in
      alleviating jet lag may be enhanced by administering it before, during and after
      rapid transition through time zones; and hypertension may exaggerate jet lag
      syndrome.

PMID- 12612501
TI  - Three new drugs for hyperlipidemia.

PMID- 12612502
TI  - Peginterferon alfa-2a (Pegasys) for chronic hepatitis C.

PMID- 12612504
TI  - Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective
      randomized study.
AB  - BACKGROUND: Pancreatitis is the most frequent complication of ERCP. Injury to the
      papilla during ERCP could obstruct pancreatic duct outflow and initiate
      pancreatitis. A randomized prospective study was performed to evaluate the effect
      of pancreatic duct stent placement on the frequency and severity of post-ERCP
      pancreatitis in a selected group of patients. METHODS: The study group consisted
      of patients over 18 years of age at high risk for post-ERCP pancreatitis because
      of a difficult cannulation, sphincter of Oddi manometry, and/or the performance
      of endoscopic sphincterotomy. Patients were prospectively randomized to have a
      pancreatic duct stent placed or no stent upon completion of the ERCP. The
      endoprosthesis used was either a 5F nasopancreatic catheter or 5F, 2-cm long
      pancreatic stent. Study endpoints were the frequency and severity of post-ERCP
      pancreatitis. RESULTS: Patients undergoing pancreatic duct stent placement had a
      lower frequency of post-ERCP pancreatitis as compared with those in the control
      group (28% vs. 5%; p < 0.05). Pancreatitis tended to be less severe in patients
      who had pancreatic duct drainage. CONCLUSIONS: Pancreatic duct stent insertion
      after ERCP reduces the frequency of post-ERCP pancreatitis in patients at high
      risk for this complication.

PMID- 12612505
TI  - Impact of upper endoscopy on satisfaction in patients with previously
      uninvestigated dyspepsia.
AB  - BACKGROUND: In patients with uninvestigated dyspepsia who undergo endoscopy, the
      presence of abnormal findings guides subsequent management. However, upper
      endoscopy is "negative" in the majority of these patients, and the value of
      endoscopy in these individuals has been questioned. This study evaluated the
      impact of endoscopy on patient satisfaction in patients with previously
      uninvestigated dyspepsia. METHODS: The study was a secondary analysis of data
      obtained from a double-blind, randomized placebo-controlled trial, evaluating a 6
      week course of omeprazole versus placebo in 140 patients with uninvestigated
      dyspepsia who were followed for up to 1 year. The setting was the primary care
      outpatient clinics at the Houston Veterans Affairs Hospital. Participants had to
      be 18 years of age or older with at least a 1-week history of dyspepsia
      (epigastric discomfort) without alarm features. Satisfaction was measured at each
      visit with the Severity of Dyspepsia Assessment, a validated, reliable dyspepsia
      related health measure that has a satisfaction scale (scores 2-23; higher scores
      indicate greater satisfaction). Patients unresponsive to empiric therapy with
      placebo or omeprazole based on predefined criteria underwent endoscopy. Severity
      of Dyspepsia Assessment satisfaction scores were analyzed for 5 visits: 2 closest
      in time to, but before, the day of endoscopy (Times 1 and 2); immediately before
      endoscopy (Time 3); and the 2 visits closest in time after endoscopy (Times 4 and
      5). After determining there was no difference in treatment failure rates between
      patients who received placebo or omeprazole, data from these groups were
      combined. The mean Severity of Dyspepsia Assessment satisfaction scores for Times
      1 through 5 in all patients who underwent endoscopy were compared as well as for
      subgroups with positive and negative endoscopic findings with a repeated-measures
      analysis of variance. RESULTS: Data on all 5 visits were available in 62
      patients, 36 of whom had a negative endoscopy. For all patients the mean scores
      for Time 2 (8.5; 95% CI [7.4, 9.6]), and Time 3 (7.6; 95% CI [6.6, 8.6]) were
      significantly lower than those for Time 4 (13.7; 95% CI [12.2, 15.3]) and Time 5
      (14.4; 95% CI [12.9, 15.9]). The mean score for Time 1 (11.1; 95% CI [9.5, 12.6])
      was significantly lower than the mean score for Time 5. Similar significant
      improvements in satisfaction scores were observed in subgroups with negative and
      positive findings. CONCLUSIONS: In patients with previously uninvestigated
      dyspepsia, endoscopy leads to improved patient satisfaction regardless of the
      endoscopic findings.

PMID- 12612506
TI  - Prospective evaluation of 4-mm diameter endoscopes for esophagoscopy in sedated
      and unsedated patients.
AB  - BACKGROUND: Unsedated esophagoscopy with small-diameter endoscopes is generally
      well tolerated but of limited sensitivity for the diagnosis of esophageal mucosal
      disease. This study evaluated the sensitivity of esophagoscopy performed with new
      4-mm diameter prototype battery-powered and video endoscopes. Patient tolerance
      for an unsedated examination with the 4-mm endoscopes was assessed and the
      performance characteristics of the battery-powered and video 4-mm endoscopes were
      compared. METHODS: Patients referred for EGD were recruited to undergo an
      additional examination with a 4-mm endoscope. A prototype 60-cm long, 4-mm
      diameter battery-powered fiberoptic esophagoscope was used in the first 24
      patients and a prototype 60-cm long, 4-mm diameter video esophagoscope in the
      next 27 patients. Examiners who were unaware of patient history and procedure
      indications recorded esophageal findings, ease of intubation, optical quality (5
      point visual scale), and time for examination of the esophagus and then recorded
      esophageal findings after the standard EGD. RESULTS: The sensitivity,
      specificity, and accuracy for identification of Barrett's esophagus was 100%;
      overall sensitivity, accuracy, and specificity for detecting esophageal lesions
      were, respectively, 91%, 98%, and 99%. Patient tolerance (assessed by symptom
      scores for choking, pain, and discomfort) and acceptability of unsedated
      esophagoscopy with the 4-mm diameter instruments were significantly better than
      in a historical group of patients examined with a 3-mm diameter endoscope. The
      optical quality of video endoscope was rated as superior to that of battery
      powered endoscope, and esophageal examination was performed significantly quicker
      with the video versus the battery-powered endoscope (68 vs. 137 seconds; p =
      0.001). CONCLUSIONS: Unsedated esophagoscopy with 4-mm diameter endoscopes may be
      an alternative to EGD for screening for Barrett's esophagus. Given the current
      state of endoscopic technology, a minimum diameter of 4 mm is required for
      satisfactory esophageal imaging.

PMID- 12612507
TI  - Accuracy of esophagoscopy performed by a non-physician endoscopist with a 4-mm
      diameter battery-powered endoscope.
AB  - BACKGROUND: A cost-effective technique is needed for screening of a broad
      population at risk for esophageal cancer. A solution would be to have non
      physician endoscopists perform esophagoscopy with small-caliber battery-powered
      endoscopes. METHODS: In a prospective blinded study, the diagnostic accuracy of
      sedated esophagoscopy performed by a trained nurse practitioner with a battery
      powered 4-mm diameter endoscope was compared with that for a sedated standard
      video-endoscopy performed by a gastroenterologist. Patients were recruited to
      undergo peroral esophagoscopy by the nurse practitioner followed by sedated
      standard endoscopy by the supervising gastroenterologist, each blinded to the
      findings of the other. Major esophageal findings of nurse practitioner and
      gastroenterologist were compared. RESULTS: Findings in 40 patients were analyzed.
      In 4 patients both endoscopists could not assess the presence or absence of
      columnar-lined esophagus because of severe erosive esophagitis (n = 3) or severe
      candida-esophagitis (n = 1). By using sedated standard endoscopy as the standard,
      on a per finding basis, esophagoscopy by the nurse practitioner had a sensitivity
      for columnar-lined esophagus of 89%: 95% CI [75%, 97%] and specificity of 96%:
      95% CI [84%, 99%]. The missed columnar epithelium was a 3 x 3-mm island. For all
      lesions, the sensitivity of endoscopy performed by the nurse practitioner with
      the battery-powered endoscope was 75%: 95% CI [67%, 82%] and specificity 98%: 95%
      CI [96%, 99%]. The nurse practitioner missed all of 4 rings (3 considered
      clinically irrelevant). CONCLUSION: Esophagoscopy with a battery-powered 4-mm
      diameter endoscope by a non-physician endoscopist is feasible and accurate in
      detecting esophageal pathologies. It may be an efficient screening method for the
      detection of columnar-lined esophagus. There was a distinct underestimate of the
      presence of esophageal rings.

PMID- 12612508
TI  - Cost-effectiveness of screening a population with chronic gastroesophageal
      reflux.
AB  - BACKGROUND: Persons with chronic esophageal reflux are at increased risk for the
      development of Barrett's esophagus and adenocarcinoma. Recently developed
      ultrathin endoscopes are less expensive and better tolerated than standard
      endoscopes, they can be used without sedation, and are sensitive and specific for
      Barrett's esophagus. The cost-effectiveness of one-time screening strategies were
      evaluated for 50-year-old patients with chronic reflux: no screening, standard
      endoscopy, and screening by an ultrathin endoscope. METHODS: Markov models were
      created to simulate the clinical course for patients with chronic reflux. Costs
      and quality-adjusted life-years were estimated from cancer registry data,
      published medical data, and expert opinion. RESULTS: Under baseline assumptions,
      no screening resulted in average costs of $11,785 per person and 19.3226 quality
      adjusted life-years. Ultrathin endoscopy screening resulted in costs of $12,119
      per person and 19.3326 quality-adjusted life-years, yielding a marginal cost
      effectiveness ratio of $55,764 per quality-adjusted life-year. Using standard
      endoscopy yielded costs of $12,332 with only slightly greater effectiveness,
      yielding a marginal cost-effectiveness ratio of $709,260 when compared with
      ultrathin endoscopy and $86,833 compared with no screening. Results were most
      sensitive to variation in the incidence of cancer in the population with
      Barrett's esophagus. CONCLUSIONS: Screening for Barrett's esophagus with
      ultrathin endoscopy is more cost-effective than standard endoscopy, and both
      strategies appear to improve quality-adjusted life-years among patients with
      chronic reflux at costs that are similar to those of other accepted preventive
      measures.

PMID- 12612509
TI  - Effect of nalbuphine on the motility of the sphincter of Oddi in patients with
      suspected sphincter of Oddi dysfunction.
AB  - BACKGROUND: Nalbuphine is an ideal supplementary analgesic drug for midazolam
      induced conscious sedation during operative endoscopy because it has no
      cardiovascular effect and only a moderate depressive effect on respiration.
      However, no data are available as to whether nalbuphine is suitable as an
      analgesic drug during endoscopic sphincter of Oddi manometry. The aim of the
      present study was to investigate the effect of nalbuphine on the sphincter of
      Oddi motility in patients with a suspected sphincter of Oddi dysfunction.
      METHODS: Seventeen patients who were suspected clinically to have SOD after
      cholecystectomy were prospectively investigated. Five mg of midazolam was
      administered intravenously before the procedure to induce conscious sedation.
      After approximately 5 minutes of stationary sphincter of Oddi manometry recording
      (baseline), either 10 mg of nalbuphine or saline solution (placebo) was
      administered intravenously in random fashion and pressure was recorded for a
      further 5 minutes. Maximum sphincter of Oddi basal pressure and average phasic
      contraction amplitude and frequency were measured before and after the infusion
      of the drug or saline solution. RESULTS: Nalbuphine administration effectively
      enhanced the sedation obtained with midazolam without any adverse effect. When
      the sphincter of Oddi manometric periods before and after the administration of
      nalbuphine versus placebo were compared, there was a significantly increased
      basal sphincter of Oddi pressure only in the nalbuphine group: respectively, 49
      (18) and 77 (29) mm Hg (p = 0.003) versus 51 (24) and 49 (23) mm Hg (p = 0.9).
      The phasic contraction amplitude did not change in response to nalbuphine, but
      the phasic contraction frequency increased significantly, from 5 (3) to 8 (4) per
      minute (p = 0.04). CONCLUSIONS: Nalbuphine has a stimulatory effect on sphincter
      of Oddi motility in patients with a suspected sphincter of Oddi dysfunction.
      Nalbuphine should not be used as premedication before endoscopic ERCP if
      sphincter of Oddi manometry is to be performed.

PMID- 12612510
TI  - A prospective, randomized trial of endoscopic hemoclip placement and distilled
      water injection for treatment of high-risk bleeding ulcers.
AB  - BACKGROUND: Although endoscopic hemoclip therapy is widely used in the treatment
      of GI bleeding, there are few prospective trials that assess its efficacy. This
      study evaluated the efficacy and safety of hemoclip placement and distilled water
      injection for the treatment of high-risk bleeding ulcers. METHODS: Seventy-nine
      patients with major stigmata of ulcer hemorrhage were randomly assigned to either
      endoscopic hemoclip placement (n = 39) or injection with distilled water (n =
      40). RESULTS: Initial hemostasis was achieved in all patients treated with
      hemoclips and 39 treated by distilled water injection (respectively, 100.0% vs.
      97.5%; p = 1.00). Bleeding recurred in 4 and 11 of patients, respectively, in the
      hemoclip and water injection groups. It occurred significantly more frequently in
      the injection group (hemoclip, 10.3%; injection, 28.2%; p = 0.04). No major
      procedure-related complication occurred in either group. Emergency operations
      were performed in 5.1% of patients treated with hemoclips versus 12.5% of those
      in the water injection group (p = 0.43). Hospital days and mortality rate were
      similar in both groups. CONCLUSION: Endoscopic hemoclip placement is a safe and
      effective hemostatic method that is superior to distilled water injection for
      treatment of bleeding peptic ulcer.

PMID- 12612512
TI  - Clinical usefulness of a new infrared videoendoscope system for diagnosis of
      early stage gastric cancer.
AB  - BACKGROUND: Infrared light can penetrate tissue more deeply than visible light.
      Therefore, an infrared video endoscope may be useful for assessment of gastric
      submucosal vessels. However, the resolution of currently available infrared video
      endoscope systems has been unsatisfactory. A new infrared video endoscope system
      was developed and its clinical utility assessed for diagnosis of early stage
      gastric cancer. METHODS: Twenty-five patients with early stage gastric cancer and
      8 with gastric adenoma underwent endoscopy with the infrared video endoscope
      system after intravenous injection of indocyanine green. RESULT: Indocyanine
      green pooling did not appear in adenomas and some intramucosal gastric cancers,
      whereas it was noted in all submucosally invasive gastric cancers. Tumors not
      exhibiting indocyanine green pooling were intramucosal, well-differentiated
      adenocarcinomas of low height (flat-type cancers). CONCLUSION: These results
      suggest that our new infrared video endoscope provides valuable information about
      the submucosal aspect of early stage gastric cancer. Infrared video endoscopy may
      become a powerful technique for determining whether to perform endoscopic mucosal
      resection.

PMID- 12612511
TI  - Single bolus of midazolam versus bolus midazolam plus meperidine for colonoscopy:
      a prospective, randomized, double-blind trial.
AB  - BACKGROUND: The aim of this study was to determine whether a single bolus of
      meperidine in addition to midazolam improves patient tolerance during
      colonoscopy. METHODS: Consecutive patients undergoing outpatient colonoscopy were
      randomly assigned in double-blind fashion to receive a single rapid intravenous
      bolus of 5 mg of midazolam and placebo (Group A, n = 125) or 5 mg midazolam plus
      50 mg meperidine (Group B, n = 128). Tolerance (4-point scale: 1 excellent, 4
      unbearable), pain (4-point scale: 1 none, 4 severe) and willingness to undergo
      another colonoscopy were assessed 24 to 48 hours later in a telephone interview
      conducted by an independent observer blinded to the regimen of sedative
      medication. RESULTS: Significantly more patients in Group A reported moderate or
      severe pain (28% vs. 9%; p < 0.001), poor or unbearable tolerance (18% vs. 6%; p
      < 0.01) and unwillingness to undergo colonoscopy again in the future (14% vs. 5%;
      p < 0.05). By multivariate analysis, randomization to the midazolam group and
      younger age were the only variables independently associated with the risk of
      reporting at least one of these outcomes. Recovery time, frequency of oxygen
      desaturation, and need for supplemental oxygen were not significantly different
      between the 2 groups. CONCLUSIONS: The addition of a single bolus of meperidine
      to midazolam improves patient tolerance and lessens pain during colonoscopy
      without significantly increasing the frequency of side effects or prolonging
      recovery time.

PMID- 12612513
TI  - Clinicopathologic features of ileocolonic malignant lymphoma: analysis according
      to colonoscopic classification.
AB  - BACKGROUND: The aims of this study were to classify primary ileocolonic lymphomas
      according to colonoscopic findings and to determine the clinicopathologic
      relationship according to classes. METHODS: Thirty-two patients (22 men, 10
      women; age range 29 to 75 years) with primary malignant lymphoma of the terminal
      ileum and/or colorectum were studied. The clinicopathologic features were
      evaluated according to colonoscopic findings. RESULTS: Thirty-six lesions in 32
      patients were endoscopically classified as follows: fungating (14, 39%),
      ulcerofungating (11, 31%), infiltrative (5, 14%), ulceroinfiltrative (4, 11%),
      and ulcerative (2, 6%). Location of the lesions was as follows: terminal ileum,
      15 (42%); colorectum, 14 (39%); both regions, 7 (19%). The most common
      histopathologic types were diffuse large cell (22, 69%) and large cell
      immunoblastic (5, 16%). There was no relationship between the endoscopic findings
      and histologic types. In 9 patients (28%), the clinical manifestation was
      intussusception, and all were found endoscopically to have the fungating type
      lesion. CONCLUSIONS: Primary ileocolonic lymphomas can be classified
      endoscopically into fungating, ulcerative, infiltrative, ulcerofungating, and
      ulceroinfiltrative types. Among these, fungating and ulcerofungating are the most
      frequent. Intussusception is a common clinical finding in ileocolonic lymphomas,
      occurring mainly in patients with the fungating type of lesion.

PMID- 12612514
TI  - Lack of endoscopic visualization of intestinal villi with the "immersion
      technique" in overt atrophic celiac disease.
AB  - BACKGROUND: The endoscopic appearance of the duodenal folds can predict the
      presence of celiac disease. However, endoscopic alterations can be minimal and
      the disease can have a "patchy" distribution histopathologically. The observation
      that intestinal villi can be better visualized when the duodenum is filled with
      water led to the development of an endoscopic "immersion technique" to assess
      celiac disease. METHODS: Endoscopy with duodenal biopsies was performed in 20
      patients with malabsorption syndrome (positive for antiendomysial antibodies) and
      in 30 patients with reflux-like symptoms (negative for antiendomysial
      antibodies). Duodenal hypotonia was induced pharmacologically, water was
      introduced, and the mucosa was observed for the presence of villi. Photographs
      were obtained for subsequent analysis. The endoscopic appearance was classified
      from 1 (folds certainly present) to 4 ("scalloped valvulae"); villous structures
      were classified from 1 (definitely present) to 3 (definitely absent). RESULTS:
      Celiac disease was confirmed histopathologically in all patients with positive
      antiendomysial antibodies. The endoscopic appearance of the duodenum with air
      insufflation alone had a positive predictive value for the diagnosis of celiac
      disease of 84% and a specificity of 87%. Visualization of villi with the
      "immersion technique" had a higher positive predictive value (99%) and
      specificity (99%). CONCLUSIONS: A lack of visualization of intestinal villi in
      the descending duodenum with the "immersion technique" may increase the
      diagnostic accuracy of endoscopy for celiac disease. This technique could also be
      useful for targeting duodenal biopsies.

PMID- 12612516
TI  - Use of methylene blue to identify the minor papilla or its orifice in patients
      with pancreas divisum.
AB  - BACKGROUND: In some patients with pancreas divisum, minor papilla cannulation is
      difficult because of uncertain identification of the papilla or its orifice, even
      after pancreatic secretory stimulation with secretin or cholecystokinin agonist.
      METHODS: Two techniques with methylene blue were used to identify the minor
      papilla and its orifice more clearly in a series of patients: spraying methylene
      blue over duodenal mucosa in the region suspected to contain the minor papilla
      with/without secretin or cholecystokinin agonist administration, and injection of
      contrast medium containing methylene blue into the ventral pancreatic duct by
      means of the major papilla in cases of incomplete pancreas divisum. Results were
      reviewed retrospectively. RESULTS: From January 2001 to May 2002, minor papilla
      cannulation with conventional methods initially failed in 38 of 305 patients with
      pancreas divisum because of an inconspicuous minor papilla orifice. Methylene
      blue was used to identity the minor papilla orifice in 14 of 38 patients
      (spraying, 13; injection, 1). Minor papilla cannulation was successful in 12 of
      14 (86%) patients (spraying 11, injection 1). Mild pancreatitis developed in 1
      patient. CONCLUSIONS: Methylene blue spraying or injection appears to be a
      helpful technique for identification of the inconspicuous minor papilla orifice
      in patients with pancreas divisum.

PMID- 12612515
TI  - Colonoscopy: practice variation among 69 hospital-based endoscopists.
AB  - BACKGROUND: The medical profession, payers, and patients are interested
      increasingly in the quality of endoscopic procedures, including colonoscopy. The
      American Society for Gastrointestinal Endoscopy has recommended "report cards" by
      which endoscopists may keep track of certain key elements of their practice
      including indications, findings, duration, technical end points, complications,
      and patient satisfaction. METHODS: The GI-Trac endoscopy reporting database
      includes many of the data points recommended by ASGE for report cards. Seven
      hospital centers in North America have been collecting data prospectively for
      varying periods since 1994. These data were aggregated and analyzed by individual
      endoscopist. A total of 69 endoscopists performed 17,868 colonoscopies. RESULTS:
      Twelve percent of the endoscopists reported that more than 20% of procedures they
      performed were completely normal. The average time taken by 27% of endoscopists
      was more than 40 minutes (without trainees involved), and only 55% achieved a
      cecal intubation rate of over 90%; for 9% the rate was less than 80%.
      Complication rates were too low for individual comparisons. CONCLUSION: These
      data provide an idea of colonoscopy performance by individual endoscopists in
      mainly academic centers. Incorporating all recommended data elements in future
      reporting databases will contribute to meaningful bench marking and to quality
      improvement efforts.

PMID- 12612517
TI  - Occult pancreatobiliary reflux in patients with a normal pancreaticobiliary
      junction.
AB  - BACKGROUND: The aim of this study was to investigate pancreatobiliary reflux in
      individuals with a normal pancreaticobiliary junction. METHODS: Seventy-four
      patients with a normal pancreaticobiliary junction, as determined by ERCP,
      underwent secretin injection MRCP before cholecystectomy. Based on changes in the
      diameter of the biliary system after secretin injection, patients were
      categorized into enhanced or nonenhanced groups. RESULTS: Biliary amylase was
      measured in the 4 patients allocated to the enhanced group and 60 in the
      nonenhanced group. The mean (SD) biliary amylase level in the gallbladder was
      123,723 (115,125) IU/L in the enhanced group and 238 (507) IU/L in the
      nonenhanced group (p < 0.0001). The mean (SD) biliary amylase level in
      gallbladders with carcinoma (n = 7) was 68,281 (106,500) IU/L, which was
      significantly higher than that in gallbladders without carcinoma (p < 0.01).
      CONCLUSION: Pancreatobiliary reflux similar to that seen in patients with
      pancreaticobiliary maljunction can occur in individuals with a normal
      pancreaticobiliary junction and may be associated with carcinoma of the
      gallbladder. Secretin injection MRCP is useful for identifying these individuals.

PMID- 12612518
TI  - Biology versus terminology: East meets West in surgical pathology.

PMID- 12612519
TI  - Ultrathin crossroads: is smaller better?

PMID- 12612521
TI  - Assisting at gastroscopy.

PMID- 12612522
TI  - Giant Brunner's gland hamartoma.

PMID- 12612523
TI  - Early stage gastric cancer.

PMID- 12612524
TI  - Superior mesenteric artery occlusion.

PMID- 12612525
TI  - Superior mesenteric artery syndrome with obstructing duodenal bezoar.

PMID- 12612526
TI  - B-cell lymphoma and arterial esophageal bleeding.

PMID- 12612527
TI  - Crohn's disease: aphthoid to longitudinal ulcers.

PMID- 12612528
TI  - Endoscopic suturing for treatment of GERD.

PMID- 12612529
TI  - Diagnostic potential of near-infrared Raman spectroscopy in the colon:
      differentiating adenomatous from hyperplastic polyps.
AB  - BACKGROUND: Near-infrared Raman spectroscopy is a promising optical technique for
      GI tissue diagnosis. This study assessed the diagnostic potential of near
      infrared Raman spectroscopy in the colon by evaluating its ability to distinguish
      between adenomatous and hyperplastic polyps. METHODS: Ex vivo and in vivo Raman
      spectra of colon polyps were collected by using a custom-built, fiber-optic, near
      infrared Raman spectroscopic system. Multivariate statistical techniques,
      including principal component analysis and linear discriminant analysis, were
      used to develop diagnostic algorithms for classifying colon polyps based on their
      spectral characteristics. With the number of samples available, spectral
      classification of polyps was tested by using a leave-one-out, cross-validation
      method. RESULTS: Fifty-four ex vivo Raman spectra were analyzed (20 hyperplastic,
      34 adenomatous). The spectral-based diagnostic algorithms identified adenomatous
      polyps with 91% sensitivity, 95% specificity, and 93% accuracy. In vivo, adenomas
      (n = 10) were distinguished from hyperplastic polyps (n = 9) with 100%
      sensitivity, 89% specificity, and 95% accuracy. CONCLUSIONS: Near-infrared Raman
      spectroscopy differentiated adenomatous from hyperplastic polyps with high
      diagnostic accuracy. To our knowledge, this is the first demonstration of the
      potential of near-infrared Raman spectroscopy for differentiation of colonic
      polyps during GI endoscopy.

PMID- 12612530
TI  - Endoscopic cryotherapy for the treatment of bleeding mucosal vascular lesions of
      the GI tract: a pilot study.
AB  - BACKGROUND: Thermal therapy is the cornerstone of endoscopic treatment of
      bleeding mucosal lesions of the GI tract. However, there is a 20% failure rate
      and contact devices may be cumbersome in the treatment of large bleeding areas. A
      pilot study was conducted to evaluate the safety and efficacy of endoscopic
      cryotherapy for bleeding mucosal vascular lesions. METHODS: Patients with
      recurrent bleeding from diffuse mucosal vascular lesions were treated with
      cryotherapy and had endoscopic and clinical follow-up. RESULTS: Twenty-six
      patients with gastric and duodenal arteriovenous malformations (n = 7),
      watermelon stomach (n = 7), radiation-induced gastritis (n = 5), and radiation
      induced proctitis (n = 7) were treated with mean of 3.4 (1.6) sessions. The best
      results were achieved in patients with radiation-induced proctitis, with
      cessation of bleeding in all 7 patients. Cryotherapy was also effective in
      patients with multiple arteriovenous malformations (86%) and watermelon stomach
      (71%). It was less effective in patients with radiation-induced damage to stomach
      and duodenum, although all patients in this group were debilitated because of
      disseminated malignancy. CONCLUSIONS: Cryotherapy is a safe and effective
      treatment for bleeding from diffuse mucosal lesions of the GI tract. Bleeding
      from radiation-induced proctitis and multiple arteriovenous malformations is
      particularly responsive to endoscopic cryotherapy.

PMID- 12612531
TI  - Fragility of the esophageal mucosa: a pathognomonic endoscopic sign of primary
      eosinophilic esophagitis?
AB  - BACKGROUND: Primary eosinophilic esophagitis, a chronic inflammatory disorder of
      the esophagus, evokes recurrent dysphagia. Endoscopy is often unremarkable, and
      no consensus exists regarding management of resultant dysphagia. The response of
      a series of patients with primary eosinophilic esophagitis to dilation is
      reported together with a description of a possibly pathognomonic sign: fragile
      esophageal mucosa, for which the term "crepe-paper" mucosa is introduced.
      METHODS: Five men underwent endoscopy because of dysphagia confirmed (clinically,
      endoscopically, and histologically) to be caused by primary eosinophilic
      esophagitis and were treated by bouginage. OBSERVATIONS: All patients had
      extremely fragile, inelastic, and delicate mucosa, which tore easily even with
      minor trauma. After the procedure, patients remained asymptomatic for 3 to 24
      months. CONCLUSIONS: Primary eosinophilic esophagitis is characterized by fragile
      esophageal mucosa that readily tears in response to minor trauma during otherwise
      uneventful diagnostic endoscopy. This "crepe-paper" sign may alert endoscopists
      to the presence of the disease when other mucosal alterations are lacking.
      Dilation is effective for patients with symptoms with minimal morbidity, despite
      development of disquieting lesions in response to the procedure.

PMID- 12612532
TI  - Bowel explosion with colonic perforation during argon plasma coagulation for
      hemorrhagic radiation-induced proctitis.

PMID- 12612533
TI  - Spontaneous regression of Epstein-Barr virus-associated T-cell lymphoma of the
      stomach.

PMID- 12612534
TI  - Intestinal strictures can impede wireless capsule enteroscopy.

PMID- 12612535
TI  - Intraductal papillary mucinous tumor of the pancreas and multiple adenomas of the
      colon.

PMID- 12612538
TI  - Gardner's syndrome in an HIV-infected patient.

PMID- 12612537
TI  - Videocapsule impaction at the cricopharyngeus: a first report of this
      complication and its successful resolution.

PMID- 12612536
TI  - Percutaneous endoscopic cecostomy for management of refractory constipation in an
      adult patient.

PMID- 12612539
TI  - Primary gastric melanoma presenting as a nonhealing ulcer.

PMID- 12612540
TI  - Endoscopic hemoclip application for the treatment of a large gastric polyp
      causing intermittent outlet obstruction.

PMID- 12612541
TI  - Successful treatment of a gastric Dieulafoy's lesion with a hemoclip in a newborn
      infant.

PMID- 12612542
TI  - The use of CO2 in colonoscopy.

PMID- 12612544
TI  - Is endoscopic ligation therapy with large detachable snares and elastic bands
      really safe and effective?

PMID- 12612546
TI  - F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector
      function of immunoglobulins.
AB  - High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging
      complement fragments C3b and C4b. We tested the hypothesis that exogenous
      immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby
      neutralizing their pro-inflammatory effects. Single-cell calcium measurements in
      HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a
      and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG
      and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2)
      generation and histamine release from HMC-1 cells and whole-blood basophils were
      also suppressed by exogenous immunoglobulins. In a mouse model of asthma,
      immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a
      mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2
      IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot
      analyses suggested a physical association between anaphylatoxins and the constant
      region of F(ab)2. This binding could interfere with the role of C3a and C5a in
      inflammation.

PMID- 12612548
TI  - Weapons of mass protection.

PMID- 12612547
TI  - Adult mouse astrocytes degrade amyloid-beta in vitro and in situ.
AB  - Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized
      by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the
      earliest neuropathological changes in AD is the accumulation of astrocytes at
      sites of Abeta deposition, but the cause or significance of this cellular
      response is unclear. Here we show that cultured adult mouse astrocytes migrate in
      response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD
      lesions, and cease migration upon interaction with immobilized Abeta(1-42). We
      also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on
      Abeta-laden brain sections from a mouse model of AD associate with the Abeta
      deposits and reduce overall Abeta levels in these sections. Our results suggest a
      novel mechanism for the accumulation of astrocytes around Abeta deposits,
      indicate a direct role for astrocytes in degradation of Abeta and implicate
      deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments
      that increase removal of Abeta by astrocytes may therefore be a critical
      mechanism to reduce the neurodegeneration associated with AD.

PMID- 12612549
TI  - Editors' statement on considerations of biodefence and biosecurity.

PMID- 12612550
TI  - Prediction of epileptic seizures: are nonlinear methods relevant?

PMID- 12612552
TI  - Humoral immunity and atherosclerosis.

PMID- 12612554
TI  - Nebulous new rules rouse fear and loathing in laboratories.

PMID- 12612555
TI  - Asian nations approach cloning consensus.

PMID- 12612558
TI  - US budget bares bleak trends for biomedical science.

PMID- 12612559
TI  - Fruit genome projects ripen on the vine.

PMID- 12612561
TI  - Public brawl over breast implants: round 3.

PMID- 12612560
TI  - UK to regulate 'serious' genetic tests.

PMID- 12612562
TI  - SCID trials to remain on the 'bubble'.

PMID- 12612563
TI  - Julie Gerberding.

PMID- 12612567
TI  - Cancer T cell therapy expands.

PMID- 12612568
TI  - PAR1 signaling: more good than harm?

PMID- 12612571
TI  - Arrhythmias of the heart: beyond ion channels.

PMID- 12612569
TI  - Kaposi virus scores cancer coup.

PMID- 12612572
TI  - Neurons inhibit neurogenesis.

PMID- 12612573
TI  - siRNAs knock down hepatitis.

PMID- 12612574
TI  - Mend the gap.

PMID- 12612576
TI  - Immunotherapy: past, present and future.

PMID- 12612578
TI  - Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
AB  - CD4+CD25+ regulatory T cells are essential for the active suppression of
      autoimmunity. Here we report that the forkhead transcription factor Foxp3 is
      specifically expressed in CD4+CD25+ regulatory T cells and is required for their
      development. The lethal autoimmune syndrome observed in Foxp3-mutant scurfy mice
      and Foxp3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not
      from a cell-intrinsic defect of CD4+CD25- T cells. CD4+CD25+ regulatory T cells
      rescue disease development and preferentially expand when transferred into
      neonatal Foxp3-deficient mice. Furthermore, ectopic expression of Foxp3 confers
      suppressor function on peripheral CD4+CD25- T cells. Thus, Foxp3 is a critical
      regulator of CD4+CD25+ regulatory T cell development and function.

PMID- 12612579
TI  - Aire regulates negative selection of organ-specific T cells.
AB  - Autoimmune polyendocrinopathy syndrome type 1 is a recessive Mendelian disorder
      resulting from mutations in a novel gene, AIRE, and is characterized by a
      spectrum of organ-specific autoimmune diseases. It is not known what tolerance
      mechanisms are defective as a result of AIRE mutation. By tracing the fate of
      autoreactive CD4+ T cells with high affinity for a pancreatic antigen in
      transgenic mice with an Aire mutation, we show here that Aire deficiency causes
      almost complete failure to delete the organ-specific cells in the thymus. These
      results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by
      failure of a specialized mechanism for deleting forbidden T cell clones,
      establishing a central role for this tolerance mechanism.

PMID- 12612580
TI  - Plasma cell differentiation and the unfolded protein response intersect at the
      transcription factor XBP-1.
AB  - The transcription factor X-box binding protein 1 (XBP-1) is essential for the
      differentiation of plasma cells and the unfolded protein response (UPR). Here we
      show that UPR-induced splicing of XBP-1 by the transmembrane endonuclease IRE1 is
      required to restore production of immunoglobulin in XBP-1-/- mouse B cells,
      providing an integral link between XBP-1, the UPR and plasma cell
      differentiation. Signals involved in plasma cell differentiation, specifically
      interleukin-4, control the transcription of XBP-1, whereas its post
      transcriptional processing is dependent on synthesis of immunoglobulins during B
      cell differentiation. We also show that XBP-1 is involved in controlling the
      production of interleukin-6, a cytokine that is essential for plasma cell
      survival. Thus, signals upstream and downstream of XBP-1 integrate plasma cell
      differentiation with the UPR.

PMID- 12612581
TI  - An essential role for Scurfin in CD4+CD25+ T regulatory cells.
AB  - The molecular properties that characterize CD4+CD25+ regulatory T cells (TR
      cells) remain elusive. Absence of the transcription factor Scurfin (also known as
      forkhead box P3 and encoded by Foxp3) causes a rapidly fatal lymphoproliferative
      disease, similar to that seen in mice lacking cytolytic T lymphocyte-associated
      antigen 4 (CTLA-4). Here we show that Foxp3 is highly expressed by T(R) cells and
      is associated with T(R) cell activity and phenotype. Scurfin-deficient mice lack
      T(R) cells, whereas mice that overexpress Foxp3 possess more T(R) cells. In Foxp3
      overexpressing mice, both CD4+CD25- and CD4-CD8+ T cells show suppressive
      activity and CD4+CD25- cells express glucocorticoid-induced tumor-necrosis factor
      receptor-related (GITR) protein. The forced expression of Foxp3 also delays
      disease in CTLA-4-/- mice, indicating that the Scurfin and CTLA-4 pathways may
      intersect and providing further insight into the T(R) cell lineage.

PMID- 12612582
TI  - Transcription-associated mutational asymmetry in mammalian evolution.
AB  - Although mutation is commonly thought of as a random process, evolutionary
      studies show that different types of nucleotide substitution occur with widely
      varying rates that presumably reflect biases intrinsic to mutation and repair
      mechanisms. A strand asymmetry, the occurrence of particular substitution types
      at higher rates than their complementary types, that is associated with DNA
      replication has been found in bacteria and mitochondria. A strand asymmetry that
      is associated with transcription and attributable to higher rates of cytosine
      deamination on the coding strand has been observed in enterobacteria. Here, we
      describe a qualitatively different transcription-associated strand asymmetry in
      mammals, which may be a byproduct of transcription-coupled repair in germline
      cells. This mutational asymmetry has acted over long periods of time to produce a
      compositional asymmetry, an excess of G+T over A+C on the coding strand, in most
      genes. The mutational and compositional asymmetries can be used to detect the
      orientations and approximate extents of transcribed regions.

PMID- 12612583
TI  - Localized mutations in the gene encoding the cytoskeletal protein filamin A cause
      diverse malformations in humans.
AB  - Remodeling of the cytoskeleton is central to the modulation of cell shape and
      migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein
      that regulates re-organization of the actin cytoskeleton by interacting with
      integrins, transmembrane receptor complexes and second messengers. We identified
      localized mutations in FLNA that conserve the reading frame and lead to a broad
      range of congenital malformations, affecting craniofacial structures, skeleton,
      brain, viscera and urogenital tract, in four X-linked human disorders:
      otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120),
      frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS;
      OMIM 309350). Several mutations are recurrent, and all are clustered into four
      regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and
      14/15. Our findings contrast with previous observations that loss of function of
      FLNA is embryonic lethal in males but manifests in females as a localized
      neuronal migration disorder, called periventricular nodular heterotopia (PVNH;
      refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic
      manifestations in the newly described mutations indicate that they have gain-of
      function effects, implicating filamin A in signaling pathways that mediate
      organogenesis in multiple systems during embryonic development.

PMID- 12612584
TI  - Mutations in SOX2 cause anophthalmia.
AB  - A submicroscopic deletion containing SOX2 was identified at the 3q breakpoint in
      a child with t(3;11)(q26.3;p11.2) associated with bilateral anophthalmia.
      Subsequent SOX2 mutation analysis identified de novo truncating mutations of SOX2
      in 4 of 35 (11%) individuals with anophthalmia. Both eyes were affected in all
      cases with an identified mutation.

PMID- 12612585
TI  - Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with
      idiopathic generalized epilepsies.
AB  - Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder
      affecting about 0.4% of the world's population. Mutations in ten genes causing
      distinct forms of idiopathic epilepsy have been identified so far, but the
      genetic basis of many IGE subtypes is still unknown. Here we report a gene
      associated with the four most common IGE subtypes: childhood and juvenile absence
      epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with
      grand mal seizures on awakening (EGMA; ref. 8). We identified three different
      heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated
      families with IGE. These mutations result in (i) a premature stop codon
      (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid
      substitution (G715E). All mutations produce functional alterations that provide
      distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117
      cause a loss of function of ClC-2 channels and are expected to lower the
      transmembrane chloride gradient essential for GABAergic inhibition. G715E alters
      voltage-dependent gating, which may cause membrane depolarization and
      hyperexcitability.

PMID- 12612586
TI  - A mouse model of episodic ataxia type-1.
AB  - Episodic ataxia type-1 (EA1) is a dominant human neurological disorder
      characterized by stress-induced attacks of ataxia. EA1 is caused by mutations in
      the voltage-gated potassium channel Kv1.1, and affected individuals are
      heterozygous. Here we introduced the V408A EA1 mutation into mice using
      homologous recombination. In contrast to Kv1.1 null mice, homozygous V408A/V408A
      mice died after embryonic day 3 (E3). V408A/+ mice showed stress-induced loss of
      motor coordination that was ameliorated by acetazolamide, a carbonic anhydrase
      inhibitor that minimizes EA1 symptoms in human patients. We made
      electrophysiological recordings from cerebellar Purkinje cells in both V408A/+
      mice and their wild-type littermates. V408A/+ mice showed a greater frequency and
      amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) than
      did wild type; however, the amplitude or frequency of miniature IPSCs and the
      basket cell firing frequency did not differ between groups. The stress-induced
      motor dysfunction in V408A mice is similar to that of family members harboring
      the EA1 allele, and our findings suggest that these behavioral changes are linked
      to changes in GABA release.

PMID- 12612587
TI  - Synthesis of a poly(vinylpyrrolidone-co-dimethyl maleic anhydride) co-polymer and
      its application for renal drug targeting.
AB  - We have synthesized a polymeric drug carrier, polyvinylpyrrolidone-co-dimethyl
      maleic anhydride [poly(VP-co-DMMAn)], for use in renal drug delivery. About 80%
      of the 10-kDa poly(VP-co-DMMAn) selectively accumulated in the kidneys 24 h after
      intravenous administration to mice. Although this accumulated poly(VP-co-DMMAn)
      was gradually excreted in the urine, about 40% remained in the kidneys 96 h after
      treatment. Poly(VP-co-DMMAn) was taken up by the renal proximal tubular
      epithelial cells and no cytotoxicity was noted. Higher doses did not produce
      toxicity in the kidneys or other tissues. In contrast, polyvinylpyrrolidone of
      the same molecular weight did not show any tissue-specific distribution. Poly(VP
      co-DMMAn)-modified superoxide dismutase accumulated in the kidneys after
      intravenous administration and accelerated recovery from acute renal failure in a
      mouse model. In contrast, polyvinylpyrrolidone-modified superoxide dismutase and
      native superoxide dismutase were not as effective. Thus, poly(VP-co-DMMAn) is a
      useful candidate as a targeting carrier for renal drug delivery systems.

PMID- 12612589
TI  - Can research be planned?

PMID- 12612590
TI  - Comment on Frank Gannon's editorial 'The foot soldiers of science' in EMBO
      reports, November 2002.

PMID- 12612591
TI  - Comment on Jack Parker's article 'How much is a scientist worth?' in EMBO
      reports, November 2002.

PMID- 12612588
TI  - Enhancement of therapeutic protein in vivo activities through glycoengineering.
AB  - Delivery of protein therapeutics often requires frequent injections because of
      low activity or rapid clearance, thereby placing a burden on patients and
      caregivers. Using glycoengineering, we have increased and prolonged the activity
      of proteins, thus allowing reduced frequency of administration. Glycosylation
      analogs with new N-linked glycosylation consensus sequences introduced into the
      protein were screened for the presence of additional N-linked carbohydrates and
      retention of in vitro activity. Suitable consensus sequences were combined in one
      molecule, resulting in glycosylation analogs of rHuEPO, leptin, and Mpl ligand.
      All three molecules had substantially increased in vivo activity and prolonged
      duration of action. Because these proteins were of three different classes
      (rHuEPO is an N-linked glycoprotein, Mpl ligand an O-linked glycoprotein, and
      leptin contains no carbohydrate), glycoengineering may be generally applicable as
      a strategy for increasing the in vivo activity and duration of action of
      proteins. This strategy has been validated clinically for glycoengineered rHuEPO
      (darbopoetin alfa).

PMID- 12612593
TI  - Towards responsible animal research. Addressing the ethical dimension of animal
      experimentation and implementing the 'Three R's' principle in biomedical
      research.

PMID- 12612594
TI  - Linking investigators. A centralized linking facility for data sharing and
      coordination of samples in tissue banks.

PMID- 12612595
TI  - China's leap forward in biotechnology. An interview with Zhu Chen, director of
      the Chinese National Human Genome Center of Shanghai and vice president of the
      Chinese Academy of Sciences.

PMID- 12612596
TI  - The big and small of drug discovery. Biotech versus pharma: advantages and
      drawbacks in drug development.

PMID- 12612597
TI  - Government rhetoric and their R&D expenditure. A score-card for governments'
      investments into science and future technologies.

PMID- 12612598
TI  - Fish genomes flying. Symposium on Medaka Genomics.

PMID- 12612599
TI  - Hsp90 reaches new heights. Conference on the Hsp90 chaperone machine.

PMID- 12612600
TI  - Priming the nucleosome: a role for HMGB proteins?
AB  - The high-mobility-group B (HMGB) chromosomal proteins are characterized by the
      HMG box, a DNA-binding domain that both introduces a tight bend into DNA and
      binds preferentially to a variety of distorted DNA structures. The HMGB proteins
      seem to act primarily as architectural facilitators in the manipulation of
      nucleoprotein complexes; for example, in the assembly of complexes involved in
      recombination and transcription. Recent genetic and biochemical evidence suggests
      that these proteins can facilitate nucleosome remodelling. One mechanism by which
      HMGB proteins could prime the nucleosome for migration is to loosen the wrapped
      DNA and so enhance accessibility to chromatin-remodelling complexes and possibly
      also to transcription factors. By constraining a tight loop of untwisted DNA at
      the edge of a nucleosome, an HMGB protein could induce movements in the contacts
      between certain core histones that would result in an overall change in
      nucleosome structure.

PMID- 12612601
TI  - Modification with SUMO. A role in transcriptional regulation.
AB  - Small ubiquitin-related modifier (SUMO) is a protein moiety that is ligated to
      lysine residues in a variety of target proteins. The addition of SUMO can
      modulate the ability of proteins to interact with their partners, alter their
      patterns of subcellular localization and control their stability. It is clear
      that SUMO influences many different biological processes, but recent data suggest
      that it is particularly important in the regulation of transcription. Indeed,
      several transcription factors, such as Sp3, c-Jun, c-Myb and various nuclear
      receptors, have recently been shown to be subject to sumoylation and, although
      this modification can have a positive influence, a growing body of evidence
      highlights its role in the negative regulation of transcription. This review
      summarizes recent experiments focusing on sumoylation and transcriptional
      repression.

PMID- 12612602
TI  - The kangaroo genome. Leaps and bounds in comparative genomics.
AB  - The kangaroo genome is a rich and unique resource for comparative genomics.
      Marsupial genetics and cytology have made significant contributions to the
      understanding of gene function and evolution, and increasing the availability of
      kangaroo DNA sequence information would provide these benefits on a genomic
      scale. Here we summarize the contributions from cytogenetic and genetic studies
      of marsupials, describe the genomic resources currently available and those being
      developed, and explore the benefits of a kangaroo genome project.

PMID- 12612603
TI  - Distinct macroscopic structures developed from solutions of chemical compounds
      and periodic proteins.
AB  - By controlling the growth of inorganic crystals, macro-biomolecules, including
      proteins, play pivotal roles in modulating biomineralization. Natural proteins
      that promote biomineralization are often composed of simple repeats of peptide
      sequences; however, the relationship between these repetitive structures and
      their functions remains largely unknown. Here we show that an artificial protein
      containing a repeated peptide sequence allows NaCl, KCl, CuSO(4) and sucrose to
      form a variety of macroscopic structures, as represented by their dendritic
      configurations. Mutational analyses revealed that the physicochemical
      characteristics of the protein, not the peptide sequence per se, were responsible
      for formation of the dendritic structures. This suggests that proteins that
      modulate crystal growth may have evolved as repeat-containing forms at a
      relatively high rate. These observations could serve as the basis for developing
      new genetic programming systems for creation of artificial proteins able to
      modulate crystal growth from inorganic compounds, and may thus provide a new tool
      for nano-biotechnology.

PMID- 12612604
TI  - Identification of short 'eukaryotic' Okazaki fragments synthesized from a
      prokaryotic replication origin.
AB  - Although archaeal genomes encode proteins similar to eukaryotic replication
      factors, the hyperthermophilic archaeon Pyrococcus abyssi replicates its circular
      chromosome at a high rate from a single origin (oriC) as in Bacteria. In further
      elucidating the mechanism of archaeal DNA replication, we have studied the
      elongation step of DNA replication in vivo. We have detected, in two main
      archaeal phyla, short RNA-primed replication intermediates whose structure and
      length are very similar to those of eukaryotic Okazaki fragments. Mapping of
      replication initiation points further showed that discontinuous DNA replication
      in P. abyssi starts at a well-defined site within the oriC recently identified in
      this hyperthermophile. Short Okazaki fragments and a high replication speed imply
      a very efficient turnover of Okazaki fragments in Archaea. Archaea therefore have
      a unique replication system showing mechanistic similarities to both Bacteria and
      Eukarya.

PMID- 12612605
TI  - A novel, inducible, eukaryotic gene expression system based on the quorum-sensing
      transcription factor TraR.
AB  - Bacteria adapt their pattern of gene expression in response to a variety of
      external cues, including fluctuations in population density. This type of
      bacterial cell-to-cell communication is referred to as quorum-sensing. Quorum
      sensing systems are present in many bacterial species and constitute a large
      collection of ligands and cognate receptors. The availability of such diversity
      offers interesting opportunities for biotechnological exploitation. We describe
      here the transformation of the quorum-sensing system of Agrobacterium tumefaciens
      into a transcription regulatory system that works in mammalian cells. The A.
      tumefaciens TraR protein was fused to the eukaryotic activation domain of NF
      kappaB p65, generating a novel chimaeric transcriptional activator that
      stimulates gene transcription in different human cell lines from a minimal
      promoter containing the TraR DNA recognition sequence in the presence of the
      Agrobacterium quorum-sensing signal molecule N-(3-oxo-octanoyl)homoserine lactone
      (3-oxo-C(8)-HSL). The basal level of transcription was low in the absence of 3
      oxo-C(8)-HSL, and gene expression was stimulated up to 1,000-fold at a saturating
      concentration of 3-oxo-C(8)-HSL.

PMID- 12612608
TI  - Stop-transfer efficiency of marginally hydrophobic segments depends on the length
      of the carboxy-terminal tail.
AB  - Hydrophobic stop-transfer sequences generally serve to halt the translocation of
      polypeptide chains across the endoplasmic reticulum membrane and become
      integrated as transmembrane alpha-helices. Using engineered glycosylation sites
      as topology reporters, we show that the length of the nascent chain between a
      hydrophobic segment and the carboxy terminus of the protein can affect stop
      transfer efficiency. We also show that glycosylation sites located close to a
      protein's C terminus are modified in two distinct kinetic phases, one fast and
      one slow. Our findings suggest that membrane integration of a hydrophobic segment
      is not simply a question of thermodynamic equilibrium, but can be influenced by
      details of the translocation mechanism.

PMID- 12612606
TI  - Wnt1 and Wnt5a induce cyclin D1 expression through ErbB1 transactivation in HC11
      mammary epithelial cells.
AB  - Constitutive expression of Wnt1 and Wnt5a in HC11 mammary cells led to elevated
      TCF transcriptional activity. Intriguingly, Wnt-expressing cells also displayed
      activation of ErbB1 and mitogen-activated protein kinase (MAPK), in contrast to
      control HC11 cells, which did not. Furthermore, conditioned media harvested from
      Wnt-expressing cells stimulated ErbB1 and the MAPK cascade when added to control
      cells. This process was rapid and could be blocked by an ErbB1 antibody that
      interferes with ligand binding and by matrix metalloproteinase (MMP) inhibitors.
      These results suggest that in mammary cells Wnt binding to its receptor, Frizzled
      (Fz), transactivates ErbB1, probably by MMP-mediated release of soluble ErbB1
      ligands. Importantly, Wnt-transactivated ErbB1 was responsible for MAPK
      activation and the increased levels of cyclin D1 present in the Wnt-expressing
      HC11 cells. Our finding that Wnts transactivate ErbB1 in addition to stimulating
      the prototypic beta-catenin/TCF pathway may help to explain why wnt1 is a potent
      oncogene in the mammary gland.

PMID- 12612607
TI  - Growth-rate dependent RNA polyadenylation in Escherichia coli.
AB  - RNA polyadenylation occurs not only in eukaryotes but also in bacteria. In
      prokaryotes, polyadenylated RNA molecules are usually degraded more efficiently
      than non-modified transcripts. Here we demonstrate that two transcripts, which
      were shown previously to be substrates for poly(A) polymerase I (PAP I),
      Escherichia coli lpp messenger RNA and bacteriophage lambda oop RNA, are
      polyadenylated more efficiently in slowly growing bacteria than in rapidly
      growing bacteria. Intracellular levels of PAP I varied in inverse proportion to
      bacterial growth rate. Moreover, transcription from a promoter for the pcnB gene
      (encoding PAP I) was shown to be more efficient under conditions of low bacterial
      growth rates. We conclude that efficiency of RNA polyadenylation in E. coli is
      higher in slowly growing bacteria because of more efficient expression of the
      pcnB gene. This may allow regulation of the stability of certain transcripts
      (those subjected to PAP I-dependent polyadenylation) in response to various
      growth conditions.

PMID- 12612609
TI  - Non-reciprocal regulation of the redox state of the glutathione-glutaredoxin and
      thioredoxin systems.
AB  - Our studies in yeast show that there is an essential requirement for either an
      active thioredoxin or an active glutathione (GSH)-glutaredoxin system for cell
      viability. Glutathione reductase (Glr1) and thioredoxin reductase (Trr1) are key
      regulatory enzymes that determine the redox state of the GSH-glutaredoxin and
      thioredoxin systems, respectively. Here we show that Trr1 is required during
      normal cell growth, whereas there is no apparent requirement for Glr1. Analysis
      of the redox state of thioredoxins and glutaredoxins in glr1 and trr1 mutants
      reveals that thioredoxins are maintained independently of the glutathione system.
      In contrast, there is a strong correlation between the redox state of
      glutaredoxins and the oxidation state of the GSSG/2GSH redox couple. We suggest
      that independent redox regulation of thioredoxins enables cells to survive in
      conditions under which the GSH-glutaredoxin system is oxidized.

PMID- 12612610
TI  - IKCa1 activity is required for cell shrinkage, phosphatidylserine translocation
      and death in T lymphocyte apoptosis.
AB  - Apoptotic cell volume decrease (AVD) and exposure of phosphatidylserine (PtdSer)
      at the cell surface are early events in apoptosis. However, the ion channels
      responsible for AVD, and their relationship to PtdSer translocation and cell
      death are poorly understood. Real-time analysis of calcium-induced apoptosis in
      lymphocytes and thymocytes showed that AVD occurs rapidly, and precedes PtdSer
      translocation. Blockers of the K(+) channel IKCa1 completely inhibited AVD.
      Blockade of IKCa1, and hence AVD, also completely prevented PtdSer translocation
      and cell death. Thus, IKCa1-mediated AVD is the earliest-defined essential step
      in calcium-induced apoptosis, required for both PtdSer translocation and cell
      death.

PMID- 12612611
TI  - Prion pathogenesis in the absence of Toll-like receptor signalling.
AB  - To reach the brain from peripheral sites, prions must colonize various cell types
      within the lymphoreticular compartment. However, no prion entry receptors are yet
      known. Toll-like receptors (TLRs) are pattern-recognition receptors that bind a
      multitude of pathogens and are therefore candidates as effectors of prion entry.
      Moreover, injection of unmethylated CpG oligodinucleotides, which stimulate TLR9,
      has been reported to delay peripherally initiated scrapie. We therefore studied
      prion infection in MyD88(-/-) mice, which are defective in TLR signalling.
      Despite subtle defects in splenic microarchitecture, MyD88(-/-) mice challenged
      intraperitoneally or intracerebrally were fully susceptible to disease and died
      of scrapie after similar incubation times to those of wild-type mice. Splenic
      infectivity titres rose to similar levels with the same kinetics, and brains
      showed similar histopathological changes. TLR signalling therefore does not have
      any major role in prion pathogenesis, and the protective effect of TLR
      stimulation is unlikely to result from direct interactions with prions.

PMID- 12612612
TI  - Analysis of the landmark protein Bud3 of Ashbya gossypii reveals a novel role in
      septum construction.
AB  - Cell division in fungal cells requires the coordination of three different
      processes: determination of the site of division, actomyosin ring formation, and
      the concomitant contraction of this ring together with chitin deposition at
      septal sites. This report describes the isolation of the AgBUD3 homologue and the
      characterization of Bud3 protein function in Ashbya gossypii. Bud3 fused to green
      fluorescent protein was shown to localize transiently either as a single ring to
      multiple sites of future septation or as a double ring to newly established
      septa. Deletion of AgBUD3 leads to a striking change in actin ring localization
      involving the mislocalization of AgCyk1, which is required for actin ring
      assembly. Aberrant chitin accumulation occurs subsequently, generating
      delocalized septa. Thus, in A. gossypii, Bud3 acts as a landmark, tagging future
      septal sites, and is involved in the positioning of the contractile ring, whereas
      it does not direct lateral branching.

PMID- 12612614
TI  - De novo formation, fusion and fission of mammalian COPII-coated endoplasmic
      reticulum exit sites.
AB  - Transport between the endoplasmic reticulum (ER) and Golgi is mediated by the
      sequential action of the COPII and COPI coat complexes. COPII subunits are
      recruited to the ER membrane where they mediate the selection of cargo for
      transport to the Golgi, and also membrane deformation and vesicle formation. New
      ER exit sites can be generated by lateral growth and medial fission (in Pythium
      sp.) or by de novo formation (in Pichia pastoris) but it is not known how
      mammalian ER exit sites form. Here, time-lapse imaging of COPII-coated structures
      in live mammalian cells reveals that the number of ER export sites increases
      greatly during interphase by de novo formation. These results show the fusion of
      pre-existing ER export sites and the fission of larger structures. These three
      mechanisms of de novo formation, fusion and fission probably cooperate to
      regulate the size of these sites in mammalian cells.

PMID- 12612613
TI  - A single gene that promotes interaction of a phytopathogenic bacterium with its
      insect vector, Drosophila melanogaster.
AB  - Insects are major vectors of plant and animal disease, and bacterial
      phytopathogens are often disseminated by flies. We have previously reported that
      some isolates of the phytopathogenic bacterial species Erwinia carotovora infect
      Drosophila and activate an immune response. Using a genetic screen, we have now
      identified two genes that are required by E. carotovora to infect Drosophila. One
      of these genes has a regulatory role whereas the other, evf, confers an
      infectious phenotype: its transfer to non-infectious Erwinia strains or to
      several enterobacteria improves survival in the gut and triggers the immune
      response. Overexpression of Erwinia virulence factor (evf) allowed bacteria to
      colonize the apical side of the gut epithelium and in some cases to spread to the
      body cavity. Our results demonstrate a specific interaction between plant
      pathogens and flies that promote their dissemination.

PMID- 12612615
TI  - The effect of noradrenergic drugs on the recovery of walking after spinal cord
      injury.
AB  - Clonidine, a noradrenergic agonist has been associated with improved walking in
      both spinal cat and spinal cord injured (SCI) subjects. OBJECTIVES: The objective
      of this brief review is to compare the effects of clonidine on walking
      capabilities in SCI subjects with functionally complete and incomplete spinal
      cord injuries. STUDY DESIGN/METHODS: Both oral administration and intrathecal
      injection of clonidine were investigated. A motorized treadmill was used and
      harness support provided in most of the SCI subjects as no walking capabilities
      could be observed overground. A single subject design was used in these chronic
      SCI subjects. SETTING: Canada and France. RESULTS: In complete SCI subjects while
      receiving clonidine, none of the subjects was able to initiate independent
      stepping. In contrast, the greatest effects were found in SCI subjects with
      injuries that are incomplete but still severely disabling while minimal effects
      could be observed in the more functional SCI subjects. These effects on walking
      are observed in measures of walking speed, and electromyographic and kinematic
      patterns. Regardless of effects on walking, however, a consistent decrease of the
      flexor reflex amplitude could be observed in all SCI subjects independent of the
      severity of the lesion. CONCLUSION: This review demonstrated that clonidine could
      be a powerful anti-spasmodic drug in addition to improving locomotion in a
      limited number of SCI subjects. The mechanism, significance and implications of
      these results will be discussed.

PMID- 12612616
TI  - Implanted functional electrical stimulation: an alternative for standing and
      walking in pediatric spinal cord injury.
AB  - STUDY DESIGN: Post intervention, repeated measures design, comparing two
      interventions. SETTING: Orthopedic pediatric hospital specializing in spinal cord
      injury. METHODS: Nine subjects, ages 7-20 years, received an eight-channel
      implanted lower extremity functional electrical stimulation (FES) system for
      standing and walking. Electrodes were placed to stimulate hip and knee extension,
      and hip abduction and adduction. Standing and walking were achieved through
      constant stimulation to the implanted muscles, allowing a swing through gait
      pattern with an assistive device. After training with FES and long leg braces
      (LLB), subjects were tested in eight upright mobility activities, which were
      scored based upon completion time and level of independence. RESULTS: Seven
      subjects completed data collection. These subjects completed four activities
      faster (P<0.02) and five activities more independently (P<0.025) with FES as
      compared to LLB. Transitions between sitting and standing, which were scored in
      isolation for two mobility activities, were achieved faster and with more
      independence with FES. In addition, subjects reported preferring FES for the
      majority of activities. No activity required more time or more assistance to
      complete with FES as compared to LLB. CONCLUSION: The implanted FES system
      provided these subjects with enhanced functional abilities over traditional LLB
      and decreased the need for physical assistance by a caregiver, suggesting that it
      is a realistic alternative for upright mobility in a pediatric population with
      spinal cord injury.

PMID- 12612617
TI  - Anterior cervical dynamic ABC plating with single level corpectomy and fusion in
      forty-two patients.
AB  - STUDY DESIGN: Forty-two consecutive patients undergoing dynamic ABC plated one
      level ACF utilizing iliac crest autograft (38 patients) and fibula allografts
      (four patients) were evaluated. The unique ABC slotted plate design allows for up
      to 10 mm of cephalad and 10 mm of caudad plate migration. OBJECTIVES: To evaluate
      the incidence and etiology of complications in forty-two patients undergoing
      anterior cervical dynamic ABC plating (Aesculap, Tuttlingen, Germany), during one
      level anterior corpectomy with fusion (ACF). SETTING: New York, USA. METHODS:
      Serial dynamic X-ray and 2 Dimensional CAT Scan (2D-CT) studies, obtained 3, 6,
      and up to 12 months postoperatively, in 42 patients documented the presence of
      fusion or complications including plate or graft extrusion or pseudarthrosis.
      RESULTS: Four (9.5%) of 42 patients developed postoperative plate or graft
      related complications during the average follow up interval of 34 months. One
      patient, with a plate/graft extrusion, required a second two level ACF with
      posterior wiring and fusion (PWF). Two patients with pseudarthroses and one
      patient with a delayed iliac crest strut fracture required secondary PWF.
      CONCLUSIONS: Effective arthrodesis and a low incidence of complications following
      one level ACF performed utilizing dynamic ABC plates were attributed to reduced
      stress shielding and greater graft compression afforded by the unique plate
      design. Applying dynamic ABC plates for one level ACF was biomechanically
      advantageous with low morbidity.

PMID- 12612618
TI  - Changes of cervical spinal cord and cervical spinal canal with age in
      asymptomatic subjects.
AB  - STUDY DESIGN: Prospective study on magnetic resonance imaging (MRI) and
      radiographic findings of the cervical spine. OBJECTIVE: To elucidate the age
      related changes of the cervical spinal cord and the cervical spinal canal and the
      relationship between the spinal cord and the spinal canal in asymptomatic
      subjects using MRI and radiography. SETTING: Tokyo, Japan. METHODS: The
      transverse area of the cervical spinal cord and the ratio of the anteroposterior
      diameter to the transverse diameter (RAPT) were investigated, using MRI in 229
      asymptomatic subjects. The sagittal spinal canal diameter and anteroposterior
      diameter of the cervical vertebral body were also measured on plain lateral
      radiographs. The canal body ratio (CBR), which was defined as the diameter of the
      spinal canal divided by that of the vertebral body, was calculated. RESULTS: The
      transverse spinal cord area correlated negatively with age. RAPT did not
      correlate with age. The CBR correlated negatively with age. The correlation
      between spinal cord area and CBR was significant but weak and the correlation
      between RAPT and CBR was not significant. CONCLUSION: The transverse area of the
      cervical spinal cord measured by MRI decreased with age, while RAPT remained
      unchanged. The bony spinal canal became narrower with age. The spinal cord area
      and the shapes of the spinal cord were independent from the spinal canal diameter
      in asymptomatic subjects. These facts should be considered when evaluating
      radiological findings in patients with cervical spinal disorders.

PMID- 12612619
TI  - Pott's paraplegia in patients with severely deformed dorsal or dorsolumbar
      spines: treatment and prognosis.
AB  - STUDY DESIGN: Pott's paraplegic patients with severe spinal deformity were
      reviewed retrospectively after being treated with chemotherapy and/or
      decompressive surgery. OBJECTIVES: To determine the most appropriate treatment
      protocol and to predict the prognosis for Pott's paraplegics with severe spinal
      deformity. SETTING: Catholic University of Korea Medical Center and Moon-Kim's
      Institute of Orthopedic Research, Seoul, Korea from 1971 to 1996. METHOD: In this
      study, there were 33 patients (eight children and 25 adults), ranging from 13 to
      56 years of age. They developed spinal tuberculosis at the age of 9 years (range,
      2-29 years), and remained neurologically symptom free from an average of 16 years
      (range, 4-27 years). Four adults who responded well to treatment initially
      suffered relapses of paraplegia. Only six patients had previously received a full
      course of triple chemotherapy. Seven (two children, five adults) had healed
      disease, and 26 (six children, 20 adults) had active disease. Eleven cases had
      frequent drainage from the sinuses. Kyphoscoliosis was found in 11 patients: four
      children and seven adults. The remaining patients had kyphosis only. Among the 26
      patients with active tuberculosis, 10 had triple chemotherapy itself and the rest
      had additional decompression surgery (10 anterior and six posterior). All seven
      patients with healed tuberculosis were subjected only to surgery (two anterior
      and five posterior). RESULTS: In seven patients with healed tuberculosis, surgery
      did not improve neurologically except in one child patient. In four patients, the
      severity of paralysis remained unchanged and two patients, deteriorated
      neurologically after surgery. In six children with active tuberculosis, there
      were remarkable neurological recoveries by either conservative treatment or
      surgical decompression. Seven adults with active tuberculosis recovered slowly,
      improving by one or two Frankel grades (three Frankel C, three D, one E). In 11
      out of 13 surgically treated adults with active disease, paralysis that had
      persisted for less than 3 months gradually improved by one or two Frankel grades.
      One Frankel A and one Frankel B paraplegic patients who had paralysis that had
      lasted through 6 months did not recover after surgery. CONCLUSION: The
      neurological recovery of Pott's paraplegics with severe spinal deformity resulted
      in three different outcomes: (1) severe deformity is different from moderate and
      mild deformities; (2) patients with healed tuberculosis had poorer prognosis than
      patients with active tuberculosis; (3) children had better prognosis than adults.
      Furthermore, patients with paralysis persisting over 6 months did not recover
      neurologically after surgery.

PMID- 12612620
TI  - Use of the ring fixator in the treatment of fractures of the lower extremity in
      long-term paraplegic and tetraplegic patients.
AB  - STUDY DESIGN: Retrospective study. OBJECTIVES: To examine the value of operative
      fracture stabilization by means of the ring fixator in fractures of the lower
      extremity in the presence of chronic paralysis caused by transverse lesions of
      the spinal cord. SETTING: A specialist center for the treatment of spinal cord
      injuries in Germany. METHODS: Clinical examination of the lower extremities with
      side-for-side comparison, radiological investigation of the fractures, patient
      survey. PATIENTS: In 21 patients with chronic spinal cord lesions, 22 fractures
      of the lower extremities were treated with the ring fixator. RESULTS: At follow
      up a mean of 41.5 months after fracture healing it could be shown that movement
      in the knee and ankle joints on the same side as the fracture was not restricted
      by more than 10 degrees in any of our patients. No losses affecting activities of
      daily living were reported, and 19 of the 21 patients were satisfied with the
      result achieved with this technique. After four of the 22 operations there were
      complications. Malalignments were visible radiologically following five of the
      fractures. CONCLUSIONS: In osteoporosis-induced fractures of the lower
      extremities in chronically paraplegic and tetraplegic patients, fracture
      stabilization with the ring fixator, with fewer complications and better results
      in terms of joint mobility, is superior to the conservative treatment so far
      given preference in the literature. It should be offered as an alternative to
      conservative treatment in the case of pathological fractures.

PMID- 12612621
TI  - Evaluation of sprint exercise testing protocols in wheelchair athletes.
AB  - STUDY DESIGN: Comparison of five different exercise testing protocols with
      different speeds on a treadmill with seven wheelchair athletes. OBJECTIVE: To
      determine which speed and duration in an exercise protocol is best to test
      wheelchair athletes performing sprint races on a track. SETTING: Swiss Paraplegic
      Centre, Nottwil, Switzerland. METHODS: Three elite and four junior wheelchair
      athletes (18.7+/-6.8 years, 52.1+/-9.7 kg and 165.3+/-19.3 cm) performed five
      different exercise testing protocols at different speeds on a treadmill until
      exhaustion. Maximal effort treadmill (0.7% incline) testing protocols were
      performed using three timeframes. The first was focussing on short duration tests
      (S1 and S2) where incremental increases in velocity (0.42 and 0.1 m.s(-1)) were
      required from a stationary start. The second were medium duration tests (M1 and
      M2) where the athlete started at their 200 m and 800 m personal best time (mean
      velocities) and then had the velocity increased 1 km.h(-1) by every 10 and 60 s
      respectively. The long duration test (L) started at 14 km.h(-1) and velocity was
      increased by 2 km.h(-1) every 120 s. Maximal heart rate, maximal concentration of
      lactate, maximal speed, and maximal duration of the test were measured. RESULTS:
      The highest concentration of lactate and the highest heart rates were measured in
      the longest tests. CONCLUSION: During maximal effort testing wheelchair athletes
      are able to produce higher lactate concentrations when tested for longer
      duration. Post test lactate assessments provide little information in short
      duration testing protocols. Sequential lactate assessments post-test may provide
      additional information on the rate of recovery for middle distance wheelchair
      athletes and warrants further investigation.

PMID- 12612622
TI  - A prototype of an adjustable advanced reciprocating gait orthosis (ARGO) for
      spinal cord injury (SCI).
AB  - OBJECTIVE: To develop a reciprocating gait orthosis which could be used in
      different sized patients. DESIGN: Clinical trial and orthotic development.
      SETTING: A large rehabilitation hospital in Rome, Italy PATIENTS AND METHODS: To
      carry out this project normal reciprocating gait orthosis parts were used. The
      device was modified to adjust the hip-ankle height, and the hip-hip distance. It
      was tested, by five patients already walking with standard ARGO, to evaluate the
      performances of the orthosis. The device has been tested on seven newly injured
      patients fulfilling specific criteria of different height and weight. MAIN
      OUTCOME MEASURES: Prototype suitability; patients appreciation. RESULTS: The
      device can be used for persons between 1.60 m and 1.85 m tall, weighing up to 100
      kg. The orthosis allows an upright position without the use of the hands, and
      walking with a walker or with two canes. The foot orthosis cover sizes 36-40
      (British 3-7) and 41-45 (British 7-11). With the exception of donning, doffing
      and lifting, the walking performances of the prototype and the general
      appreciation is comparable with those of a standard device. After a short period
      of training all seven patients were able to walk in the parallel bars. All of
      them expressed general appreciation for the device; despite this only four
      patients wanted the orthosis, two refused it and one has not decided yet.
      CONCLUSIONS: The prototype allows the same standing and walking performances of
      normal ARGO. It could be used in spinal cord injury patients to let them test the
      potential of the device and thus be useful in the effort to reduce the percentage
      of ARGO rejection.

PMID- 12612623
TI  - Deep vein thrombosis and heterotopic ossification in spinal cord injury: a 3 year
      experience at the Swiss Paraplegic Centre Nottwil.
AB  - STUDY DESIGN: Retrospective review of patient data. OBJECTIVES: (i) To determine
      the incidence and time of deep vein thrombosis (DVT) under low molecular weight
      heparin (LMWH) prophylaxis in spinal cord injury (SCI), (ii) to determine the
      incidence and time of heterotopic ossification (HO) and (iii) to assess a
      possible aetiologic relationship in the pathogenesis of DVT and HO. SETTING:
      Swiss Paraplegic Centre, Nottwil. METHODS: We analyzed the incidence of DVT and
      HO in 1209 SCI patients (275 first rehabilitations) at the Swiss Paraplegic
      Centre Nottwil from 1998 to 2000. Clinical files and laboratory data were
      scrutinised for particularities preceding DVT and HO. RESULTS: The incidence of
      DVT was 6.55% for first rehabilitation compared to only 1.59% in all patients
      hospitalised. DVT was complicated by pulmonary embolism (PE) in 1.45% and 0.47%
      respectively. Incidence of HO was 8% for first rehabilitation and 1.82% for all
      patients hospitalised. In first rehabilitation patients the peak for DVT occurred
      around day 30 contrary to HO with a peak around day 120. In single patients HO
      was identified by MRI as a rapidly progressing process. Laboratory profiles were
      inflammatory in both HO and DVT. Increased physical activity preceding HO was
      observed in four patients. In two patients acute HO was complicated by
      ipsilateral DVT. CONCLUSION: Prophylaxis with LMWH and elastic stockings
      significantly reduces the frequency of DVT during first rehabilitation in SCI.
      DVT and HO are both associated with laboratory parameters of non-infectious
      inflammation. The later onset of HO coinciding with ongoing mobilisation, argues
      for a different pathogenetic mechanism. Acute HO of the hip region appears to
      favour ipsilateral DVT by well known thrombogenic mechanisms.

PMID- 12612624
TI  - In reply to S Vaidyanathan et al regarding bladder management.

PMID- 12612626
TI  - Postoperative deterioration secondary to suboptimal cervical decompression.

PMID- 12612630
TI  - Cognitive neuroscience of human social behaviour.
AB  - We are an intensely social species--it has been argued that our social nature
      defines what makes us human, what makes us conscious or what gave us our large
      brains. As a new field, the social brain sciences are probing the neural
      underpinnings of social behaviour and have produced a banquet of data that are
      both tantalizing and deeply puzzling. We are finding new links between emotion
      and reason, between action and perception, and between representations of other
      people and ourselves. No less important are the links that are also being
      established across disciplines to understand social behaviour, as
      neuroscientists, social psychologists, anthropologists, ethologists and
      philosophers forge new collaborations.

PMID- 12612631
TI  - Neural mechanisms for the recognition of biological movements.
AB  - The visual recognition of complex movements and actions is crucial for the
      survival of many species. It is important not only for communication and
      recognition at a distance, but also for the learning of complex motor actions by
      imitation. Movement recognition has been studied in psychophysical,
      neurophysiological and imaging experiments, and several cortical areas involved
      in it have been identified. We use a neurophysiologically plausible and
      quantitative model as a tool for organizing and making sense of the experimental
      data, despite their growing size and complexity. We review the main experimental
      findings and discuss possible neural mechanisms, and show that a learning-based,
      feedforward model provides a neurophysiologically plausible and consistent
      summary of many key experimental results.

PMID- 12612632
TI  - Neural mechanisms for detecting and remembering novel events.
AB  - The ability to detect and respond to novel events is crucial for survival in a
      rapidly changing environment. Four decades of neuroscientific research has begun
      to delineate the neural mechanisms by which the brain detects and responds to
      novelty. Here, we review this research and suggest how changes in neural
      processing at the cellular, synaptic and network levels allow us to detect,
      attend to and subsequently remember the occurrence of a novel event.

PMID- 12612633
TI  - Flutter discrimination: neural codes, perception, memory and decision making.
AB  - Recent studies combining psychophysical and neurophysiological experiments in
      behaving monkeys have provided new insights into how several cortical areas
      integrate efforts to solve a vibrotactile discrimination task. In particular,
      these studies have addressed how neural codes are related to perception, working
      memory and decision making in this model. The primary somatosensory cortex drives
      higher cortical areas where past and current sensory information are combined,
      such that a comparison of the two evolves into a behavioural decision. These and
      other observations in visual tasks indicate that decisions emerge from highly
      distributed processes in which the details of a scheduled motor plan are
      gradually specified by sensory information.

PMID- 12612635
TI  - Our changeable memories: legal and practical implications.
AB  - The malleability of memory is becoming increasingly clear. Many influences can
      cause memories to change or even be created anew, including our imaginations and
      the leading questions or different recollections of others. The knowledge that we
      cannot rely on our memories, however compelling they might be, leads to questions
      about the validity of criminal convictions that are based largely on the
      testimony of victims or witnesses. Our scientific understanding of memory should
      be used to help the legal system to navigate this minefield.

PMID- 12612634
TI  - Primary visual cortex and visual awareness.
AB  - The primary visual cortex (V1) is probably the best characterized area of primate
      cortex, but whether this region contributes directly to conscious visual
      experience is controversial. Early neurophysiological and neuroimaging studies
      found that visual awareness was best correlated with neural activity in
      extrastriate visual areas, but recent studies have found similarly powerful
      effects in V1. Lesion and inactivation studies have provided further evidence
      that V1 might be necessary for conscious perception. Whereas hierarchical models
      propose that damage to V1 simply disrupts the flow of information to extrastriate
      areas that are crucial for awareness, interactive models propose that recurrent
      connections between V1 and higher areas form functional circuits that support
      awareness. Further investigation into V1 and its interactions with higher areas
      might uncover fundamental aspects of the neural basis of visual awareness.

PMID- 12612636
TI  - Beyond phrenology, at last.
AB  - Although integration is a widely acknowledged goal in neuroscience, our approach
      to the function of biological entities often places boundaries that defy
      integration. Mapping across systems - from the genome to cognitive function -
      will require innovative methods that can identify every contributing component to
      a function, and instantaneously scale numerous changes in large data sets to
      consequences over the entire biological hierarchy.

PMID- 12612637
TI  - Quality control in the endoplasmic reticulum.
AB  - The endoplasmic reticulum (ER) has a quality-control system for 'proof-reading'
      newly synthesized proteins, so that only native conformers reach their final
      destinations. Non-native conformers and incompletely assembled oligomers are
      retained, and, if misfolded persistently, they are degraded. As a large fraction
      of ER-synthesized proteins fail to fold and mature properly, ER quality control
      is important for the fidelity of cellular functions. Here, we discuss recent
      progress in understanding the conformation-specific sorting of proteins at the
      level of ER retention and export.

PMID- 12612638
TI  - How the ubiquitin-proteasome system controls transcription.
AB  - Gene transcription and ubiquitin-mediated proteolysis are two processes that have
      seemingly nothing in common: transcription is the first step in the life of any
      protein and proteolysis the last. Despite the disparate nature of these
      processes, a growing body of evidence indicates that ubiquitin and the proteasome
      are intimately involved in gene control. Here, we discuss the deep mechanistic
      connections between transcription and the ubiquitin-proteasome system, and
      highlight how the intersection of these processes tightly controls expression of
      the genetic information.

PMID- 12612639
TI  - Mannose 6-phosphate receptors: new twists in the tale.
AB  - The two mannose 6-phosphate (M6P) receptors were identified because of their
      ability to bind M6P-containing soluble acid hydrolases in the Golgi and transport
      them to the endosomal-lysosomal system. During the past decade, we have started
      to understand the structural features of these receptors that allow them to do
      this job, and how the receptors themselves are sorted as they pass through
      various membrane-bound compartments. But trafficking of acid hydrolases is only
      part of the story. Evidence is emerging that one of the receptors can regulate
      cell growth and motility, and that it functions as a tumour suppressor.

PMID- 12612640
TI  - Signal dispersal and transduction through the endocytic pathway.
AB  - During cell signalling, information that is encoded by ligands travels from one
      place, the source, to another, the target, where signals are transduced by
      receptors. Evidence has emerged recently that uncovers a role for the endocytic
      pathway in the secretion of ligands at the source, their dispersion through
      developing target tissues and the transduction of the signals from endocytic
      compartments. As a result, endosomes have become the focus of attention in cell
      cell communication studies.

PMID- 12612641
TI  - Signalling to and from tight junctions.
AB  - Tight junctions have long been regarded as simple barriers that separate
      compartments of different compositions, but recent research indicates that
      different types of signalling proteins and transduction pathways are associated
      with these junctions. They receive and convert signals from the cell interior to
      regulate junction assembly and function, and transmit signals to the cell
      interior to modulate gene expression and cell behaviour.

PMID- 12612642
TI  - Integration from proteins to organs: the Physiome Project.
AB  - The Physiome Project will provide a framework for modelling the human body, using
      computational methods that incorporate biochemical, biophysical and anatomical
      information on cells, tissues and organs. The main project goals are to use
      computational modelling to analyse integrative biological function and to provide
      a system for hypothesis testing.

PMID- 12612643
TI  - Towards an e-biology of ageing: integrating theory and data.
AB  - Ageing is a highly complex process; it involves interactions between numerous
      biochemical and cellular mechanisms that affect many tissues in an organism.
      Although work on the biology of ageing is now advancing quickly, this inherent
      complexity means that information remains highly fragmented. We describe how a
      new web-based modelling initiative is seeking to integrate data and hypotheses
      from diverse biological sources.

PMID- 12612644
TI  - The development of COX2 inhibitors.
AB  - Aspirin, arguably the world's favourite drug, has been around since the late
      nineteenth century, but it wasn't until the late 1970s that its ability to
      inhibit prostaglandin production by the cyclooxygenase enzyme was identified as
      the basis of its therapeutic action. Early hints of a second form of the
      cyclooxygenase that was differentially sensitive to other aspirin-like drugs
      ultimately ushered in an exciting era of drug discovery, culminating in the
      introduction of an entirely new generation of anti-inflammatories. This article
      reviews the story of this discovery and looks at the future of cyclooxygenase
      pharmacology.

PMID- 12612645
TI  - ADMET in silico modelling: towards prediction paradise?
AB  - Following studies in the late 1990s that indicated that poor pharmacokinetics and
      toxicity were important causes of costly late-stage failures in drug development,
      it has become widely appreciated that these areas should be considered as early
      as possible in the drug discovery process. However, in recent years,
      combinatorial chemistry and high-throughput screening have significantly
      increased the number of compounds for which early data on absorption,
      distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has
      in turn driven the development of a variety of medium and high-throughput in
      vitro ADMET screens. Here, we describe how in silico approaches will further
      increase our ability to predict and model the most relevant pharmacokinetic,
      metabolic and toxicity endpoints, thereby accelerating the drug discovery
      process.

PMID- 12612646
TI  - Tamoxifen: a most unlikely pioneering medicine.
AB  - For more than 25 years, tamoxifen has been the gold standard for the endocrine
      treatment of all stages of oestrogen-receptor-positive breast cancer, and the
      World Health Organization lists tamoxifen as an essential drug for the treatment
      of breast cancer. It is estimated that more than 400,000 women are alive today as
      a result of tamoxifen therapy, and millions more have benefited from palliation
      and extended disease-free survival. Interestingly, tamoxifen also became the
      first cancer chemopreventive approved by the Food and Drug Administration (FDA)
      for the reduction of breast-cancer incidence in both pre- and post-menopausal
      women at high risk. However, 40 years ago, it was hard to imagine that a non
      toxic targeted treatment for breast cancer could be developed at all.

PMID- 12612647
TI  - Effect of pegylation on pharmaceuticals.
AB  - Protein and peptide drugs hold great promise as therapeutic agents. However, many
      are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys,
      generate neutralizing antibodies and have a short circulating half-life.
      Pegylation, the process by which polyethylene glycol chains are attached to
      protein and peptide drugs, can overcome these and other shortcomings. By
      increasing the molecular mass of proteins and peptides and shielding them from
      proteolytic enzymes, pegylation improves pharmacokinetics. This article will
      review how PEGylation can result in drugs that are often more effective and
      safer, and which show improved patient convenience and compliance.

PMID- 12612648
TI  - Combinatorial compound libraries for drug discovery: an ongoing challenge.
AB  - Almost 20 years of combinatorial chemistry have emphasized the power of numbers,
      a key issue for drug discovery in the current genomic era, in which it has been
      estimated that there might be more than 10,000 potential targets for which it
      would be desirable to have small-molecule modulators. Combinatorial chemistry is
      best described as the industrialization of chemistry; the chemistry has not
      changed, just the way in which it is now carried out, which is principally by
      exploiting instrumentation and robotics coupled to the extensive use of computers
      to efficiently control the process and analyse the vast amounts of resulting
      data. Many researchers have contributed to the general concepts as well as to the
      technologies in present use. However, some interesting challenges still remain to
      be solved, and these are discussed here in the context of the application of
      combinatorial chemistry to drug discovery.

PMID- 12612649
TI  - Biotech's twentieth birthday blues.

PMID- 12612650
TI  - Big physics, small doses: the use of AMS and PET in human microdosing of
      development drugs.
AB  - The process of early clinical drug development has changed little over the past
      20 years despite an up to 40% failure rate associated with inappropriate drug
      metabolism and pharmacokinetics of candidate molecules. A new method of obtaining
      human metabolism data known as microdosing has been developed which will permit
      smarter candidate selection by taking investigational drugs into humans earlier.
      Microdosing depends on the availability of two ultrasensitive 'big-physics'
      techniques: positron emission tomography (PET) can provide pharmacodynamic
      information, whereas accelerator mass spectrometry (AMS) provides pharmacokinetic
      information. Microdosing allows safer human studies as well as reducing the use
      of animals in preclinical toxicology.

PMID- 12612651
TI  - ATM and related protein kinases: safeguarding genome integrity.
AB  - Maintenance of genome stability is essential for avoiding the passage to
      neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by
      a swift transduction of the DNA-damage signal to many cellular pathways. A prime
      example is the cellular response to DNA double-strand breaks, which activate the
      ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM
      mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia
      (A-T). Understanding ATM's mode of action provides new insights into the
      association between defective responses to DNA damage and cancer, and brings us
      closer to resolving the issue of cancer predisposition in some A-T carriers.

PMID- 12612652
TI  - RecQ helicases: caretakers of the genome.
AB  - RecQ helicases are highly conserved from bacteria to man. Germline mutations in
      three of the five known family members in humans give rise to debilitating
      disorders that are characterized by, amongst other things, a predisposition to
      the development of cancer. One of these disorders--Bloom's syndrome--is uniquely
      associated with a predisposition to cancers of all types. So how do RecQ
      helicases protect against cancer? They seem to maintain genomic stability by
      functioning at the interface between DNA replication and DNA repair.

PMID- 12612653
TI  - Does the ribosome translate cancer?
AB  - Ribosome biogenesis and translation control are essential cellular processes that
      are governed at numerous levels. Several tumour suppressors and proto-oncogenes
      have been found either to affect the formation of the mature ribosome or to
      regulate the activity of proteins known as translation factors. Disruption in one
      or more of the steps that control protein biosynthesis has been associated with
      alterations in the cell cycle and regulation of cell growth. Therefore, certain
      tumour suppressors and proto-oncogenes might regulate malignant progression by
      altering the protein synthesis machinery. Although many studies have correlated
      deregulation of protein biosynthesis with cancer, it remains to be established
      whether this translates directly into an increase in cancer susceptibility, and
      under what circumstances.

PMID- 12612654
TI  - A role for mitochondrial enzymes in inherited neoplasia and beyond.
AB  - Mitochondrial defects have been associated with neurological disorders, as well
      as cancers. Two ubiquitously expressed mitochondrial enzymes--succinate
      dehydrogenase (SDH) and fumarate hydratase (FH, fumarase)--catalyse sequential
      steps in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in
      the genes encoding these enzymes cause predispositions to two types of inherited
      neoplasia syndromes that do not share any component tumours. Homozygous mutations
      in the same genes result in severe neurological impairment. Understanding this
      link between inherited cancer syndromes and neurological disease could provide
      further insights into the mechanisms by which mitochondrial deficiencies lead to
      tumour development.

PMID- 12612655
TI  - Neuroblastoma: biological insights into a clinical enigma.
AB  - Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous
      system and is the most common solid tumour in childhood. Interestingly, most
      infants experience complete regression of their disease with minimal therapy,
      even with metastatic disease. However, older patients frequently have metastatic
      disease that grows relentlessly, despite even the most intensive multimodality
      therapy. Recent advances in understanding the biology and genetics of
      neuroblastomas have allowed classification into low-, intermediate- and high-risk
      groups. This allows the most appropriate intensity of therapy to be selected -
      from observation alone to aggressive, multimodality therapy. Future therapies
      will focus increasingly on the genes and biological pathways that contribute to
      malignant transformation or progression.

PMID- 12612656
TI  - Translational approaches to improving cervical screening.
AB  - Screening programmes for cervical cancer using the current test--the Pap smear-
      have markedly reduced the incidence of the disease. However, an individual Pap
      test is of limited sensitivity and is difficult and expensive to perform.
      Increased understanding of the molecular pathogenesis of cervical cancer
      indicates that new approaches to screening might offer increased accuracy,
      affordability and the potential for automation. Such approaches exemplify how
      improved understanding of the biology of neoplasia might be translated into
      clinical benefit.

PMID- 12612657
TI  - Cancer selection.
AB  - Cancers are often thought to be selectively neutral. This is because most of the
      individuals that they kill are post-reproductive. Some cancers, however, kill the
      young and so select for anticancer adaptations that reduce the chance of death.
      These adaptations could reduce the somatic mutation rate or the selective value
      of a mutant clone of cells, or increase the number of stages required for
      neoplasia. New theory predicts that cancer selection--selection to prevent or
      postpone deaths due to cancer--should be especially important as animals evolve
      new morphologies or larger, longer-lived bodies, and might account for some of
      the differences in the causes of cancer between mice and men.

PMID- 12612658
TI  - Nanotechnology: don't forget the big picture.

PMID- 12612659
TI  - Materials departments are facing up to education and recruitment concerns.

PMID- 12612660
TI  - Dopant mapping for the nanotechnology age.

PMID- 12612662
TI  - Fracture mechanics: How does bone break?

PMID- 12612663
TI  - Molecular electronics: Cool computing.

PMID- 12612664
TI  - Nanoporous materials: A selective magnetic sponge.

PMID- 12612665
TI  - Semiconductor nanocrystals: Shape matters.

PMID- 12612666
TI  - Quantum optics: Boosting photon storage.

PMID- 12612667
TI  - Shape-memory alloys: Combinatorial high jinks.

PMID- 12612669
TI  - The role of soft colloidal templates in controlling the size and shape of
      inorganic nanocrystals.
AB  - In the past decade, colloidal solutions have been assumed to be very efficient
      templates for controlling particle size and shape. A large number of groups have
      used reverse micelles to control the size of spherical nanoparticles. This makes
      it possible to determine the various parameters involved in such processes, and
      demonstrates that nanoparticles can be considered to be efficient nanoreactors.
      However, some discrepancies arise. There are few reports concerning the control
      of particle shape, and it is still rather difficult to determine the key
      parameters, such as the adsorption of salts and other molecules, and the
      synthesis procedure. Here, we discuss these controls of the size and shape of
      inorganic nanomaterials.

PMID- 12612670
TI  - Properties of diamond under hydrostatic pressures up to 140 GPa.
AB  - Diamond is the archetypal covalent material. Each atom in an sp(3) configuration
      is bonded to four nearest neighbours. Because of its remarkable properties,
      diamond has been extensively studied. And yet our knowledge of the properties of
      diamond under very high pressure is still incomplete. Although diamond is known
      to be the preferred allotrope of carbon at high pressure, the possibility of
      producing under pressure high-density polymorphs of diamond, including metallic
      forms, has been discussed. Structural changes have already been reported in
      diamond under non-hydrostatic pressures around 150 GPa and large deformation.
      However, measurements of the properties of diamond under hydrostatic pressure
      have been limited to below 40 GPa. Here, we report accurate measurements of the
      volume and of the optical phonon frequency of diamond under hydrostatic pressure
      up to 140 GPa. We show that diamond is more compressible than currently expected.
      By combining the volume and the frequency pressure shifts, we deduce that diamond
      remains very stable under pressure: it is a Gruneisen solid up to at least 140
      GPa, and the covalent bond is even slightly strengthened under pressure. Finally,
      the optical phonon frequency versus pressure is calibrated here to be used as a
      pressure gauge for diamond anvil cell studies in the multi-megabar range.

PMID- 12612671
TI  - Synthesis and size-dependent properties of zinc-blende semiconductor quantum
      rods.
AB  - Dimensionality and size are two factors that govern the properties of
      semiconductor nanostructures. In nanocrystals, dimensionality is manifested by
      the control of shape, which presents a key challenge for synthesis. So far, the
      growth of rod-shaped nanocrystals using a surfactant-controlled growth mode, has
      been limited to semiconductors with wurtzite crystal structures, such as CdSe
      (ref. 3). Here, we report on a general method for the growth of soluble nanorods
      applied to semiconductors with the zinc-blende cubic lattice structure. InAs
      quantum rods with controlled lengths and diameters were synthesized using the
      solution-liquid-solid mechanism with gold nanocrystals as catalysts. This
      provides an unexpected link between two successful strategies for growing high
      quality nanomaterials, the vapour-liquid-solid approach for growing nanowires,
      and the colloidal approach for synthesizing soluble nanocrystals. The rods
      exhibit both length- and shape-dependent optical properties, manifested in a red
      shift of the bandgap with increased length, and in the observation of polarized
      emission covering the near-infrared spectral range relevant for
      telecommunications devices.

PMID- 12612672
TI  - Self-adjusted synthesis of ordered stable mesoporous minerals by acid-base pairs.
AB  - Although the chemical diversity of ordered composite mesoporous materials has
      been expanding during the past decade, progress has been limited by the need for
      a general synthetic approach that is predictive and makes use of well developed
      fundamental chemical principles. Researchers have previously used the interaction
      of organic-inorganic (OI) species that are present during the nucleation of the
      composite phase, and several synthesis pathways, such as direct surfactant
      inorganic interaction (S+I-, S-I+, S0I0) and mediated interaction (S+X-I+, S-X+I
      ), have been proposed. Here we describe a new perspective in which the self
      adjusted inorganic-inorganic (II) interplay between two or more inorganic
      precursors is guided by acid-base chemistry considerations, and in this simple
      way we produce an overall 'framework' for the sophisticated combination of
      synergic inorganic acid-base precursor pairs. We propose several new routes and
      demonstrate their versatility and validity through the successful syntheses of a
      wide variety of highly ordered, large-pore, homogeneous, stable and
      multicomponent mesostructured minerals, including metal phosphates and metal
      borates, as well as various metal oxides and mixed metal oxides. We show that the
      highly ordered mesostructured metal phosphates can be moulded into morphologies
      of choice, and that they show interesting physicochemical properties.

PMID- 12612673
TI  - Mechanistic fracture criteria for the failure of human cortical bone.
AB  - A mechanistic understanding of fracture in human bone is critical to predicting
      fracture risk associated with age and disease. Despite extensive work, a
      mechanistic framework for describing how the microstructure affects the failure
      of bone is lacking. Although micromechanical models incorporating local failure
      criteria have been developed for metallic and ceramic materials, few such models
      exist for biological materials. In fact, there is no proof to support the widely
      held belief that fracture in bone is locally strain-controlled, as for example
      has been shown for ductile fracture in metallic materials. In the present study,
      we provide such evidence through a novel series of experiments involving a double
      notch-bend geometry, designed to shed light on the nature of the critical failure
      events in bone. We examine how the propagating crack interacts with the bone
      microstructure to provide some mechanistic understanding of fracture and to
      define how properties vary with orientation. It was found that fracture in human
      cortical bone is consistent with strain-controlled failure, and the influence of
      microstructure can be described in terms of several toughening mechanisms. We
      provide estimates of the relative importance of these mechanisms, such as
      uncracked-ligament bridging.

PMID- 12612674
TI  - Encoding microcarriers by spatial selective photobleaching.
AB  - Bead-based assays on very large numbers of molecules in gene expression studies,
      drug screening and clinical diagnostics, require the encoding of each of the
      microspheres according to the particular ligand bound to its surface. This allows
      mixing the uniquely encoded microspheres and subjecting them to an assay
      simultaneously. When a particular microsphere gives a positive reaction, the
      substance on its surface can be identified by reading the code. Previously
      reported techniques for colour encoding polymer microspheres only allow for a
      limited number of unique codes. Graphical encoding methods use metallic
      particles, which are rather uncommon in screening applications. Here, we
      demonstrate a new approach to encode polymer microspheres that are commonly used
      in screening applications, such as polystyrene microspheres, with a method that
      provides a virtually unlimited number of unique codes. Patterns can be written in
      fluorescently dyed microspheres by 'spatial selective photobleaching' and can be
      identified by confocal microscopy. Such encoded microparticles can find broad
      application in the collection and analysis of genetic information, high
      throughput screening, medical diagnostics and combinatorial chemistry, and can
      also be used for labelling of consumer goods or as security labels to prevent
      counterfeiting.

PMID- 12612675
TI  - Optically induced multispin entanglement in a semiconductor quantum well.
AB  - According to quantum mechanics, a many-particle system is allowed to exhibit non
      local behaviour, in that measurements performed on one of the particles can
      affect a second one that is far away. These so-called entangled states are
      crucial for the implementation of most quantum information protocols and, in
      particular, gates for quantum computation. Here we use ultrafast optical pulses
      and coherent techniques to create and control spin-entangled states in an
      ensemble of non-interacting electrons bound to donors (at least three) and at
      least two Mn2+ ions in a CdTe quantum well. Our method, relying on the exchange
      interaction between localized excitons and paramagnetic impurities, can in
      principle be applied to entangle an arbitrarily large number of spins.

PMID- 12612676
TI  - Identification of novel compositions of ferromagnetic shape-memory alloys using
      composition spreads.
AB  - Exploration of new ferroic (ferroelectric, ferromagnetic or ferroelastic)
      materials continues to be a central theme in condensed matter physics and to
      drive advances in key areas of technology. Here, using thin-film composition
      spreads, we have mapped the functional phase diagram of the Ni-Mn-Ga system whose
      Heusler composition Ni(2)MnGa is a well known ferromagnetic shape-memory alloy. A
      characterization technique that allows detection of martensitic transitions by
      visual inspection was combined with quantitative magnetization mapping using
      scanning SQUID (superconducting quantum interference device) microscopy. We find
      that a large, previously unexplored region outside the Heusler composition
      contains reversible martensites that are also ferromagnetic. A clear relationship
      between magnetization and the martensitic transition temperature is observed,
      revealing a strong thermodynamical coupling between magnetism and martensitic
      instability across a large fraction of the phase diagram.

PMID- 12612677
TI  - Synthesis of cubic zirconium and hafnium nitride having Th3P4 structure.
AB  - High-pressure synthesis is a powerful method for the preparation of novel
      materials with high elastic moduli and hardness. Additionally, such materials may
      exhibit interesting thermal, optoelectronic, semiconductuing, magnetic or
      superconducting properties. Here, we report on the high-pressure synthesis of
      zirconium and hafnium nitrides with the stoichiometry M3N4, where M = Zr, Hf.
      Synthesis experiments were performed in a laser-heated diamond anvil cell at
      pressures up to 18 GPa and temperatures up to 3,000 K. We observed formation of
      cubic Zr3N4 and Hf3N4 (c-M3N4) with a Th3P4-structure, where M-cations are
      eightfold coordinated by N anions. The c-M3N4 phases are the first binary
      nitrides with such a high coordination number. Both compounds exhibit high bulk
      moduli around 250 GPa, which indicates high hardness. Moreover, the new nitrides,
      c-Zr3N4 and c-Hf3N4, may be the first members of a larger group of transition
      metal and/or lanthanide nitrides with interesting ferromagnetic or
      superconducting behaviour.

PMID- 12612678
TI  - A nanoporous molecular magnet with reversible solvent-induced mechanical and
      magnetic properties.
AB  - Interest in metal-organic open-framework structures has increased enormously in
      the past few years because of the potential benefits of using crystal engineering
      techniques to yield nanoporous materials with predictable structures and
      interesting properties. Here we report a new efficient methodology for the
      preparation of metal-organic open-framework magnetic structures based on the use
      of a persistent organic free radical (PTMTC), functionalized with three
      carboxylic groups. Using this approach, we create an open-framework structure
      Cu3(PTMTC)2(py)6(CH3CH2OH)2(H2O), which we call MOROF-1, combining very large
      pores (2.8-3.1 nm) with bulk magnetic ordering. MOROF-1 shows a reversible and
      highly selective solvent-induced 'shrinking-breathing' process involving large
      volume changes (25-35%) that strongly influence the magnetic properties of the
      material. This magnetic sponge-like behaviour could be the first stage of a new
      route towards magnetic solvent sensors.

PMID- 12612681
TI  - A framework for excellence.

PMID- 12612679
TI  - Peptides with selective affinity for carbon nanotubes.
AB  - Because of their extraordinary electronic and mechanical properties, carbon
      nanotubes have great potential as materials for applications ranging from
      molecular electronics to ultrasensitive biosensors. Biological molecules
      interacting with carbon nanotubes provide them with specific chemical handles
      that would make several of these applications possible. Here we use phage display
      to identify peptides with selective affinity for carbon nanotubes. Binding
      specificity has been confirmed by demonstrating direct attachment of nanotubes to
      phage and free peptides immobilized on microspheres. Consensus binding sequences
      show a motif rich in histidine and tryptophan, at specific locations. Our
      analysis of peptide conformations shows that the binding sequence is flexible and
      folds into a structure matching the geometry of carbon nanotubes. The hydrophobic
      structure of the peptide chains suggests that they act as symmetric detergents.

PMID- 12612682
TI  - Chances and challenges in Europe.

PMID- 12612684
TI  - Ferrofluids: Magnetic strings and networks.

PMID- 12612685
TI  - Bio-nanotechnology: Two-way traffic.

PMID- 12612686
TI  - Photonic crystals: Microassembly in 3D.

PMID- 12612689
TI  - Not too big, not too small: the appropriate scale.
AB  - The tools we use at the human scale, whether mechanical, medical or
      microelectronic, depend on materials for which some other scale of length or time
      is critical. Often this is the mesoscale, between the scales of engineering and
      of atomic science. Linking underlying processes to what we handle is sometimes
      called 'spanning' (or 'bridging') length scales, giving the impression that the
      mesoscale is a swamp to be crossed without getting mud on our boots. This is
      misleading: we do not wish to span the mesoscale, but to work at the appropriate
      scale, and to connect that to our human needs. The appropriate scale need not
      rule out multiscale computer modelling, in which some supercode integrates
      relevant scales in one pass, hoping to combine the best of methods for two or
      more levels. But the reality for such attempts, too often, is that the worst of
      both regimes are found. Happily, simpler strategies at a judicious scale will
      often suffice.

PMID- 12612690
TI  - Magnetic domain-wall dynamics in a submicrometre ferromagnetic structure.
AB  - As fabrication technology pushes the dimensions of ferromagnetic structures into
      the nanoscale, understanding the magnetization processes of these structures is
      of fundamental interest, and key to future applications in hard disk drives,
      magnetic random access memory and other 'spintronic' devices. Measurements on
      elongated magnetic nanostructures highlighted the importance of nucleation and
      propagation of a magnetic boundary, or domain wall, between opposing magnetic
      domains in the magnetization reversal process. Domain-wall propagation in
      confined structures is of basic interest and critical to the performance of a
      recently demonstrated magnetic logic scheme for spintronics. A previous study of
      a 500-nm-wide NiFe structure obtained very low domain-wall mobility in a three
      layer device. Here we report room-temperature measurements of the propagation
      velocity of a domain wall in a single-layer planar Ni80Fe20 ferromagnetic
      nanowire 200 nm wide. The wall velocities are extremely high and, importantly,
      the intrinsic wall mobility is close to that in continuous films, indicating that
      lateral confinement does not significantly affect the gyromagnetic spin damping
      parameter to the extreme extent previously suggested. Consequently the prospects
      for high-speed domain-wall motion in future nanoscale spintronic devices are
      excellent.

PMID- 12612691
TI  - Direct observation of dipolar chains in iron ferrofluids by cryogenic electron
      microscopy.
AB  - A key issue in research on ferrofluids (dispersions of magnetic colloids) is the
      effect of dipolar interactions on their structure and phase behaviour, which is
      not only important for practical applications but gives fundamental insight in
      dipolar fluids in general. In 1970, de Gennes and Pincus predicted a Van der
      Waals-like phase diagram and the presence of linear chains of particles in
      ferrofluids in zero magnetic field. Despite many experimental studies, no direct
      evidence of the existence of linear chains of dipoles has been reported in the
      absence of magnetic field, although simulations clearly show the presence of
      chain-like structures. Here, we show in situ linear dipolar structures in
      ferrofluids in zero field, visualized on the particle level by electron cryo
      microscopy on thin, vitrified films of organic dispersions of monodisperse
      metallic iron particles. On systematically increasing the particle size, we find
      an abrupt transition from separate particles to randomly oriented linear
      aggregates and branched chains or networks. When vitrified in a permanent
      magnetic field, these chains align and form thick elongated structures,
      indicating lateral attraction between parallel dipole chains. These findings show
      that the experimental model used is well suited to study the structural
      properties of dipolar particle systems.

PMID- 12612692
TI  - Growth of 'dizzy dendrites' in a random field of foreign particles.
AB  - Microstructure plays an essential role in determining the properties of
      crystalline materials. A widely used method to influence microstructure is the
      addition of nucleating agents. Observations on films formed from clay-polymer
      blends indicate that particulate additives, in addition to serving as nucleating
      agents, may also perturb crystal growth, leading to the formation of irregular
      dendritic morphologies. Here we describe the formation of these 'dizzy dendrites'
      using a phase-field theory, in which randomly distributed foreign particle
      inclusions perturb the crystallization by deflecting the tips of the growing
      dendrite arms. This mechanism of crystallization, which is verified
      experimentally, leads to a polycrystalline structure dependent on particle
      configuration and orientation. Using computer simulations we demonstrate that
      additives of controlled crystal orientation should allow for a substantial
      manipulation of the crystallization morphology.

PMID- 12612693
TI  - Stripe phases from isotropic repulsive interactions.
AB  - One of the most striking signatures of self-organization is spontaneous pattern
      formation. Among the morphologies observed, stripes are intrinsically fascinating
      and have potential for technological applications including nanolithography and
      nanoelectricity. Examples of materials featuring stripe patterns include Langmuir
      monolayers, magnetic films, lipid monolayers, liquid crystals and polymer films.
      Stripe formation is generally attributed to the competition between short-range
      attractive forces and long-range repulsion arising from dipole interactions. Here
      we show that stripe phases may result from a different mechanism based on a
      purely repulsive isotropic short-range pair potential with two characteristic
      length scales. We consider a two-dimensional (2D) assembly of particles
      consisting of a hard core surrounded by a soft corona and find that at densities
      where the hard-and-soft core radii compete with each other, decreasing the
      temperature induces a transition from a disordered state to an orientationally
      ordered phase characterized by stripe patterns.

PMID- 12612694
TI  - The development of grain-orientation-dependent residual stressess in a cyclically
      deformed alloy.
AB  - There have been numerous efforts to understand and control the resistance of
      materials to fracture by repeated or cyclic stresses. The micromechanical
      behaviours, particularly the distributions of stresses on the scale of grain size
      during or after mechanical or electrical fatigue, are crucial to a full
      understanding of the damage mechanisms in these materials. Whether a large
      microstress develops during cyclic deformation with a small amount of monotonic
      strain but a large amount of accumulated strain remains an open question. Here,
      we report a neutron diffraction investigation of the development of intergranular
      stresses, which vary as a function of grain orientations, in 316 stainless steel
      during high-cycle fatigue. We found that a large intergranular stress developed
      before cracks started to appear. With further increase of fatigue cycles, the
      intergranular stress decreased, while the elastic intragranular stored energy
      continued to grow. One implication of our findings is that the ratio between the
      intergranular and intragranular stored energies during various stages of fatigue
      deformation may validate the damage mechanism and can be used as a fingerprint
      for monitoring the state of fatigue damage in materials.

PMID- 12612695
TI  - Fully reversible, dislocation-based compressive deformation of Ti3SiC2 to 1 GPa.
AB  - Dislocation-based deformation in crystalline solids is almost always plastic.
      Here we show that polycrystalline samples of Ti3SiC2 loaded cyclically at room
      temperature, in compression, to stresses up to 1 GPa, fully recover on the
      removal of the load, while dissipating about 25% (0.7 MJ x m(-3)) of the
      mechanical energy. The stress-strain curves outline fully reversible, rate
      independent, closed hysteresis loops that are strongly influenced by grain size,
      with the energy dissipated being significantly larger in the coarse-grained
      material. At temperatures greater than 1,000 degrees C, the loops are open, the
      response is strain-rate dependent, and cyclic hardening is observed. This
      hitherto unreported phenomenon is attributed to the reversible formation and
      annihilation of incipient kink bands at room-temperature deformation. At higher
      temperatures, the incipient kink bands dissociate and coalesce to form regular
      irreversible kink bands. The loss factor for Ti3SiC2 is higher than most woods,
      and comparable to polypropylene and nylon. The technological implications of
      having a stiff, lightweight machinable ceramic that can dissipate up to 25% of
      the mechanical energy per cycle are discussed.

PMID- 12612696
TI  - A new phase diagram for layered antiferromagnetic films.
AB  - Magnetic multilayer films provide convenient model systems for studying the
      physics of antiferromagnetic films and surfaces. Here we report on the magnetic
      reversal and domain structure in antiferromagnetically coupled Co/Pt multilayers
      that are isomorphic to layered antiferromagnetic films with perpendicular
      magnetic anisotropy. We observe two distinct remanent states and reversal modes
      of the system. In mode 1 the magnetization in each layer reverses independently,
      producing an antiferromagnetic remanent state that shows full lateral correlation
      and vertical anticorrelation across the interlayers. In mode 2 the reversal in
      adjacent layers is locally synchronized with a remanent state that is vertically
      correlated but laterally anticorrelated in ferromagnetic stripe domains.
      Theoretical energy calculations of the two ground states identify a new phase
      boundary that is in good agreement with our experimental results.

PMID- 12612697
TI  - Microassembly of semiconductor three-dimensional photonic crystals.
AB  - Electronic devices and their highly integrated components formed from
      semiconductor crystals contain complex three-dimensional (3D) arrangements of
      elements and wiring. Photonic crystals, being analogous to semiconductor
      crystals, are expected to require a 3D structure to form successful
      optoelectronic devices. Here, we report a novel fabrication technology for a
      semiconductor 3D photonic crystal by uniting integrated circuit processing
      technology with micromanipulation. Four- to twenty-layered (five periods)
      crystals, including one with a controlled defect, for infrared wavelengths of 3
      4.5 microm, were integrated at predetermined positions on a chip (structural
      error <50 nm). Numerical calculations revealed that a transmission peak observed
      at the upper frequency edge of the bandgap originated from the excitation of a
      resonant guided mode in the defective layers. Despite their importance, detailed
      discussions on the defective modes of 3D photonic crystals for such short
      wavelengths have not been reported before. This technology offers great potential
      for the production of optical wavelength photonic crystal devices.

PMID- 12612698
TI  - Tunable subpicosecond optoelectronic transduction in superlattices of self
      assembled ErAs nanoislands.
AB  - In applications as diverse as fibre-optic communications and time-domain or
      terahertz spectroscopy, researchers are keen on ultrafast optoelectronic
      transducers that can be tailored to specific needs. The molecular beam epitaxy of
      photoconductors composed of equidistant layers of self-assembled ErAs-islands in
      a III-V semiconductor matrix, which act as efficient non-radiative carrier
      capture sites, enables this flexibility. Here, photocurrent autocorrelation
      techniques are applied to metal-semiconductor-metal photodetectors patterned on
      ErAs:GaAs superlattices. The experiments demonstrate that the electrical response
      speed can be conveniently tuned over at least two orders of magnitude starting
      from 190 fs by increasing the thickness of the GaAs spacer separating adjacent
      ErAs layers. The same concept is applied to the narrower bandgap InGaAs matrix.
      We demonstrate an electron lifetime of approximately 1 ps for this material. This
      brings closer the prospect of implementing terahertz technology at the important
      optical communication wavelengths of 1.3 and 1.55 microm.

PMID- 12612700
TI  - ?

PMID- 12612701
TI  - [Out-patient services in Lombardy during 1999]
AB  - This study describes the basic elements of the information service set up in
      Lombardy about out-patients' departments and instrumental diagnosis. The authors
      report the main results obtained in 1999 and discuss the merits and defect of
      such flow of information. Its aim is to show the figures of the health services
      offered: more than 100 million were provided (more than 11 services pro-capita)
      to the local citizens in 1999. The study describes the distribution of these
      services (total and pro-capita distribution) according to age, gender and
      municipality; it also makes a detailed account of some economic indicators (pro
      capita expenses and health care cost). With regard to the whole extent of the
      services offered (including citizens outside Lombardy), the study also provides
      information about the distribution and frequency of each specific branch, place,
      price and kind of service.

PMID- 12612702
TI  - [A Survey About Immunization Coverage In A Sample Of Children Born In The First
      Semester 1999]
AB  - In compliance with the WHO recommendations, the Livorno ASL n degrees 6 (Local
      Health Unit - Tuscany, Italy) has carried out a survey about immunization
      coverage so as to improve its knowledge of the local situation. The study
      concerned immunization coverage and breastfeeding of resident children between 24
      and 30 months of age. The authors used a questionnaire that was filled in by the
      children's parents. The immunization coverage turned out to be similar to the
      ICONA study as regards mandatory vaccinations (over 95% at the 24th month of
      age), and better than the ICONA study as regards recommended vaccinations.
      Breastfeeding was better than previous Italian studies (87.9% at discharge). The
      authors consider this study a good method for recognizing local situations and
      organizing specific educational strategies.

PMID- 12612703
TI  - [Smoke addiction amongst young people: a survey carried out on a sample of
      students in the Potenza Health Unit n. 2 (Basilicata - Italy)]
AB  - The authors have studied smoke addiction amongst youngsters by distributing a
      questionnaire to the last year students of a high school in Potenza (Health Unit
      2). The aim was to appreciate the extent of smoke addiction so as to devise a
      programme of health education. The results have shown an early and widespread
      smoke addiction amongst young people, which is quite contradictory if compared
      with a high level of awareness of the damages caused by the smoke. Relevant data
      stress the importance of a health education program on the matter addressed to
      the students of preparatory schools who are the subjects exposed at the highest
      risk.

PMID- 12612704
TI  - [Malaria: an Issue of Public Health]
AB  - The Authors have analyzed the epidemiological situation in Italy as regards
      malarial infections during the years 1960-1999. They paid special attention to
      the risk of malaria importation connected with an increased number of
      intercontinental journeys. The possibility of its reintroduction was assessed
      through the analysis of environmental and climatic factors on the Anopheles
      populations still living on our territory. Other infectious factors have also
      been analyzed (e. g. blood-transfusion). The authors suggest potential strategies
      for individual and environmental prevention and stress the need for better
      information activities.

PMID- 12612705
TI  - [The integration between hospitals and territorial services in order to grant
      continuity in Health Care]
AB  - This study focuses on the interaction between hospitals and territorial services,
      namely the interaction between health services and activities aimed at providing
      continuous health care to the population. It is one major subject of the Health
      Reform, whose implementation has been in progress for more than thirty years and
      is described by the authors as very controversial.

PMID- 12612706
TI  - ?

PMID- 12612707
TI  - ?

PMID- 12612708
TI  - [Reflux esophagitis in children].

PMID- 12612709
TI  - Upper gastrointestinal bleeding in a Brazilian hospital: a retrospective study of
      endoscopic records.
AB  - BACKGROUND: Upper gastrointestinal bleeding is a frequent and potentially severe
      complication of most digestive diseases of the upper gastrointestinal tract.
      Upper endoscopy has a crucial role in the diagnosis and treatment of upper
      gastrointestinal bleeding, however epidemiological studies are still limited in
      our country. Aims - To assess the clinical characteristics, endoscopic accuracy,
      treatment efficiency and clinical outcome of patients admitted to the endoscopic
      unit with upper gastrointestinal bleeding. METHODS: A retrospective study of
      consecutive records from patients who underwent emergency endoscopy for upper
      gastrointestinal bleeding was performed during a period of 2 years. RESULTS: Most
      patients were male 68.7%, with a mean age of 54.5 +/- 17.5 years. A bleeding site
      could be detected in 75.6% of the patients. Diagnostic accuracy was greater
      within the first 24 hours of the bleeding onset, and in the presence of
      hematemesis. Peptic ulcer was the main cause of upper gastrointestinal bleeding
      (35%). The prevalence of variceal bleeding (20.45%) indicates a high rate of
      underlying liver disease. Endoscopic treatment was performed in 23.86% of the
      patients. Permanent hemostasis was achieved in 86% of the patients at the first
      endoscopic intervention, and in 62.5% of the patients after rebleeding. Emergency
      surgery was seldom necessary. The average number of blood units was 1.44 +/- 1.99
      per patient. The average length of hospital stay was 7.71 +/- 12.2 days.
      Rebleeding was reported in 9.1% of the patients. The overall mortality rate of
      15.34% was significantly correlated with previous liver disease. CONCLUSIONS:
      Diagnostic accuracy was related to the time interval between the bleeding episode
      and endoscopy, and to clinical presentation. Endoscopic therapy was an effective
      tool for selected patients. The resulting increased duration of hospitalization
      and higher mortality rate in the patients submitted to therapeutic endoscopy were
      attributed to a higher prevalence of variceal bleeding and underlying liver
      disease.

PMID- 12612710
TI  - [Hepatic artery system variations correlated to split-liver surgery: anatomic
      study in cadavers].
AB  - BACKGROUND: The liver donor shortage and the higher demand on liver
      transplantation led to advanced liver surgery techniques in order to better
      utilization of the cadaveric liver donors. That is why the split-liver technique
      had been applicated in liver transplantation where the liver after been divided
      into two lobes would be implanted in two recipients. AIMS: This paper has the
      goal of study both the extra-hepatic arterial distribuition and anatomie of the
      liver with application on the split-liver transplantation separating the liver in
      right and left hepatic lobe. PATIENTS AND METHODS: The authors studied 60 livers
      from fresh cadaver looking at hepatic artery and its main anatomic variations
      correlating with split-liver surgery. The liver was split into two portions,
      right and left lobe. RESULTS: The total liver weight was 1536 +/- 361,8 g, right
      hepatic lobe 890,3 +/- 230,9 g and left hepatic lobe 649,3 +/- 172,6 g. Common
      hepatic trunk was found in one (1,6%) case and came from superior mesenteric
      artery and in another one (1,6%), both left hepatic artery and left gastric
      artery came from the abdominal aorta. The right hepatic artery raised from celiac
      trunk in 44 (73,3%) cases, and in 15 (25%) from superior mesenteric artery it was
      acessory in 11 (18,3%) cases and dominant in 4 (6,6%). The left hepatic artery
      was acessory of left gastric artery in 2 (3,3%) cases. Hepatic artery
      trifurcation was found in 9 (15%) cases out of this 6 (10%) to segment IV, 2
      (3,3%) to segment III and 1 (1,6%) to segment II. Also we found 2 (3,3%) medium
      hepatic artery to segment IV. CONCLUSION: Hepatic artery variations allowed liver
      section into right and left hepatic lobe.

PMID- 12612711
TI  - [Colonic polyps diagnosis by conventional video colonoscopes and chromoscopy with
      indigo carmine dye solution].
AB  - BACKGROUND: Magnification colonoscopy and contrast chromoscopy with indigo
      carmine dye solution have been used to differentiate neoplastic polyps (adenomas
      and adenocarcinomas) from non-neoplastic (hyperplastic, inflammatory, juvenile)
      in an attempt to obviate endoscopic polypectomy. On the other hand, little
      published information exists concerning conventional video colonoscopes and
      chromoscopy for polyp histology prediction. Aim - To assess usefullness of
      conventional video colonoscopes and contrast chromoscopy with indigo carmine
      solution for differential diagnosis of colon polyps. METHODS: In a routine
      colonoscopy series, we performed chromoscopy with conventional video colonoscopes
      before endoscopic excision of detected polyps. If a sulcus pattern was observed
      on the surface of the lesion, it was classified as neoplastic. Polyps were
      classified as non-neoplastic if no sulcus was detected on its surface. These
      observations were then compared with histology. RESULTS: In the study period (18
      months), we detected 133 polyps in 53 patients. We were able to compare results
      of histology and chromoscopy in 126 lesions. The sensitivity, specificity,
      diagnostic accuracy, negative predictive value, and positive predictive value
      were 56,4%, 79,2%, 65,1%, 52,8%, and 81,5%, respectively. CONCLUSION: On the base
      of the presented data, we concluded that conventional video colonoscopes and
      contrast chromoscopy with indigo carmine solution is not a good technique for
      differential diagnosis of colon polyps.

PMID- 12612712
TI  - Surgical treatment of the non-complicated gastroesophageal reflux: fundoplication
      without division of the short gastric vessels.
AB  - BACKGROUND: There is today a significant greater number of laparoscopic
      antireflux procedures for the surgical treatment of gastroesophageal reflux
      disease and there are yet controversies about the necessity of division of the
      short gastric vessels and full mobilization of the gastric fundus to perform an
      adequate fundoplication. AIM: To verify the results of the surgical treatment of
      non-complicated gastroesophageal reflux disease performing Rossetti modification
      of the Nissen fundoplication. Patients and Methods - Fourteen patients were
      operated consecutively and prospectively (mean age 44.07 years); all had erosive
      esophagitis without Barrett's endoscopic signals (grade 3, Savary-Miller) and
      they were submitted to the Rossetti modification of the Nissen fundoplication.
      Endoscopy, esophageal manometry and pHmetry were performed before the procedure
      and around 18 months postoperatively. RESULTS: There was no morbidity, transient
      dysphagia average was 18.42 days; there was no register of dehiscence or
      displacement of the fundoplication and only one patient revealed a light
      esophagitis at postoperative endoscopy; the others presented a normal endoscopic
      view of the distal esophagus. All noticed a marked improvement of preoperative
      symptoms. Lower esophageal sphincter pressure changed from 5.82 mm Hg
      (preoperative mean) to 12 mm Hg (postoperative mean); lower esophageal sphincter
      relaxing pressure, from 0.38 mm Hg to 5.24 mm Hg and DeMeester score, from 16.75
      to 0.8. CONCLUSION: Rossetti procedure (fundoplication without division of the
      short gastric vessels) is an effective surgical method to treat gastroesophageal
      reflux disease.

PMID- 12612713
TI  - [Trends in the occurrence (1980-1999) and clinical features of Crohn's disease
      and ulcerative colitis in a university hospital in southeastern Brazil].
AB  - BACKGROUND: Crohn's disease and ulcerative colitis are regarded as uncommon in
      developing countries, but studies on their occurrence in Brazil are scarce. Aims 
      To determine the occurrence of Crohn's disease and ulcerative colitis in a
      Brazilian university hospital throughout a 20-year period, and analyze the
      demographical, clinical and evolutive features of these cases. METHODS: The
      frequencies of new cases of Crohn's disease and ulcerative colitis admitted from
      January 1980 up to December 1999 were calculated and a descriptive analysis of
      the features of all cases seen from January 1990 up to December 1999 was
      performed. RESULTS: A total of 257 new cases (126 with Crohn's disease and 131
      with ulcerative colitis) was recorded. The frequencies of admissions for both
      Crohn's disease and ulcerative colitis have increased progressively from 40 up to
      61 cases/10.000 new admissions and Crohn's disease gradually became more common
      than ulcerative colitis. For both diseases, there was predominance of women, age
      at admission in the range of 30-40 years, Caucasian origin, married state and non
      smokers. Digestive symptoms presented were similar to those already described for
      both diseases and there were no differences between Crohn's disease and
      ulcerative colitis regarding the frequencies of general complaints and extra
      intestinal manifestations (29.5% vs 23.3%), including thromboembolism (5.9% vs
      5.4%). Obstruction and/or perforation were seen in up to 59.2% of Crohn's disease
      cases, whereas 53.7% of all ulcerative colitis cases presented as severe forms.
      In Crohn's disease cases with obstruction, smoking was significantly more common
      than in non-complicated cases. In ulcerative colitis cases of increased severity,
      general complaints, extra-intestinal manifestations and pancolitis were
      significantly more frequent than in less severe forms. CONCLUSIONS: For the last
      20 years, there have been an increased frequency of admission of inflammatory
      bowel diseases, and Crohn's disease have become more prevalent than ulcerative
      colitis. Demographical, clinical and evolutive features of these diseases seems
      to be similar to those already described, but there seems to be a predominance of
      more severe forms of both diseases.

PMID- 12612714
TI  - [Manometric evaluation of distal esophagus of rabbits submitted to open and
      laparoscopic fundoplication].
AB  - BACKGROUND: Total fundoplication used in gastroesophageal reflux treatment, may
      be performed according to two techniques: laparotomy and laparoscopy. AIM: To
      study the lower esophageal sphincter in rabbits submitted to open and
      laparoscopic fundoplication. MATERIAL AND METHODS: Electromanometry studies of
      esophagus were carried out in 40 male rabbits, through the pull trough technique
      and infusion of the catheters with distilled water. The pressure width (mm Hg)
      and the length (cm) of the lower esophageal sphincter were measured in basal
      conditions (moment 1). The 40 animals were divided into four groups of 10
      animals, according to the following surgical procedure: group 1: open total
      fundoplication; group 2: median laparotomy and dissection of gastroesophageal
      junction; group 3: laparoscopy total fundoplication; group 4: pneumoperitonium
      and dissection of the gastroesophageal junction. In moment 2 (1 week after the
      surgery) the manometry of the esophagus was performed in every animals. RESULTS:
      In groups 1 (open fundoplication) and 3, an increase of pressure width and length
      of the lower esophageal sphincter was observed. In groups 2 and 4, the pressure
      width and length of the lower esophageal sphincter presented no significant
      alteration. CONCLUSIONS: The fundoplication affects the antireflux
      gastroesophagic barrier and it becomes more efficient, because the pressure and
      the length of the lower esophageal sphincter increased after the pos-operated
      step of the surgery. This effect was observed in the two studied techniques, the
      laparotomy and the laparoscopy.

PMID- 12612715
TI  - [Fatal toxic megacolon due to cytomegalovirosis in a patient with ulcerative
      colitis: case report and review].
AB  - BACKGROUND: The toxic megacolon is a rare and severe complication of ulcerative
      colitis. In general it complicates patients with active colitis that are
      resistant to clinical treatment and, in some cases, the developing factor is
      unknown. Cytomegalovirus infection in humans in general is a subclinical
      condition. However, in patients with immunodeficiency the primary infection or
      the reactivation of latent infection could have enormous clinical effects. One of
      these effects is the toxic megacolon. AIM: To report a case of fatal toxic megac
      lon due to cytomegalovirosis in a patient with ulcerative colitis. PATIENT: A
      male patient, 38 years old, with complaints of diarrhea and weight loss. The
      diagnosis of ulcerative colitis was made and a vigorous immunossupressive therapy
      was performed. RESULTS: Due to the evolution to a toxic megacolon the patient was
      submitted to colectomy. In the post-operatory period there were severe clinical
      complications and the patient died. The pathological study of the colon revealed
      active ulcerative colitis, associated with confluent ulcerations and numerous
      cells with cytomegalic nuclear inclusions. CONCLUSION: The cytomegalovirosis must
      be considered as one of the causal agent of toxic megacolon in ulcerative
      colitis.

PMID- 12612716
TI  - [Nutritional therapy in liver transplantation].
AB  - BACKGROUND: Malnutrition, sometimes severe is common in patients with chronic
      hepatic diseases who are candidates for liver transplantation. Nutritional
      therapy can induce partial or total correction of such deficiencies, improving
      clinical conditions and prognosis of patients who face the great defiance of
      liver transplantation. AIMS: Brief revision of hepatic role in the metabolism of
      several nutrients. Description of available methods of dietary therapy and its
      application both under different abnormal hepatic conditions and pre and post
      transplant periods. The role of nutritional intervention in metabolic side
      effects due to immunosuppressive drugs. CONCLUSION: Nutritional therapy is a
      valuable adjuvant resource to the clinical treatment of candidates and submitted
      patients to hepatic transplantation providing better prognosis and improved life
      quality.

PMID- 12612718
TI  - [Reflux esophagitis in children: histological and morphometric study].
AB  - BACKGROUND: Gastroesophageal reflux disease is a frequent cause of morbidity in
      childhood, including esophagitis and recurrent respiratory symptoms; however
      histological and morphometric studies in esophageal biopsies of children are
      scarce. AIM: To study histological and morphometric findings in children with
      reflux esophagitis. PATIENTS AND METHODS: We studied 26 esophageal biopsies of
      children (mean age: 4.1 years +/- 3.4) with reflux esophagitis, which prevailed
      in boys (84.6%); post-prandial vomiting (76.9%) and repetitive bronchopneumonia
      (38.5%) were the most frequent symptoms. The diagnosis was made by X-ray in 18,
      by pH evaluation in 5 and by scintilography in 3 patients. The control group was
      formed by seven children without reflux symptoms who died from meningococcemia or
      congenital heart malformation (mean age: 2.5 years +/- 2.3). Histological
      variables were studied by hematoxylin-eosin and periodic acid of Schiff stain,
      inflammatory infiltrate, epithelial and basal layer thickness, papillary length
      and its ratio with the thickness of the epithelium. Morphometry was performed at
      a digital system connected to pro-image software. Student's t test, Mann-Whitney
      test, Fisher and Pearson's correlation methods were used for the statistical
      analysis. RESULTS: Epithelial and basal zone thickness, papillary length and its
      rate with thickness of epithelium, among the reflux group patients were higher
      than the control group. Eosinophils, neutrophils and "balloon cells" were not
      observed in the control group. Intraepithelial capillaries occurred in 11 cases
      in the reflux group (mean diameter: 59 mum). CONCLUSION: Epithelial and basal
      zone thickness, papillary length and its ratio with thickness of epithelium,
      resulted greater in the gastroesophageal reflux group than in the control group.
      There was a direct correlation between thickness of epithelium, basal zone
      thickness and papillary length, showing increased epithelial cell turnover.
      Eosinophils, neutrophils and "balloon cells" were observed only in patients with
      gastroesophageal reflux, thus serving as specific markers of this disease.

PMID- 12612717
TI  - Assessment of effectiveness of different dosage regimens of pantoprazole in
      controlling symptoms and healing esophageal lesions of patients with mild erosive
      esophagitis.
AB  - BACKGROUND: Gastroesophageal reflux disease is a very common affection, and
      esophageal involvement is particularly frequent. The means to effectively control
      symptoms and improve esophageal inflammation in these patients is to reduce
      esophageal acid exposure. For this purpose, we use gastric proton pump inhibitor,
      that can suppress gastric acid secretion. AIM: To compare the effectiveness of
      two different pantoprazole dosage regimens (20 and 40 mg/day), in controlling
      symptoms and healing esophageal lesions of patients with mild erosive
      esophagitis. MATERIAL AND METHODS: Fifty-seven patients with endoscopically
      confirmed mild erosive esophagitis characterized as non-confluent erosions in the
      distal esophagus, were randomly to be treated either with pantoprazole 20 mg/day
      (group I, 28 patients) or 40 mg/day (group II, 29 patients) over a period of 4
      weeks. After treatment completion, the patients were assessed for clinical and
      endoscopic outcome, i.e., absence of erosions in distal esophagus and improvement
      of gastroesophageal reflux symptoms. RESULTS: At the end of the treatment, 73.1%
      of the patients in group I and 85.7% of the patients in group II had endoscopic
      improvement. We also observed, that 88.5% of the patients in group I and 92.9% of
      the patients in group II had complete elimination of heartburn and regurgitation.
      CONCLUSION: Pantoprazole dosage regimens of 20 mg/day and 40 mg/day provide
      equivalent effectiveness in controlling symptoms and healing esophageal lesions
      of mild esophagitis.

PMID- 12612719
TI  - Infection by cytomegalovirus in patients with neonatal cholestasis.
AB  - BACKGROUND: Neonatal cholestasis syndrome with an intra or extrahepatic origin
      has been associated to viral infections. The participation of the cytomegalovirus
      in the etiopathogenesis of neonatal hepatitis has been already known for some
      time, but only recently there have been indications that this virus may be one of
      the possible etiological factors for extrahepatic biliary atresia. AIMS: To
      assess the prevalence of infection by cytomegalovirus in patients with
      intrahepatic cholestasis and extrahepatic cholestasis. To compare the clinical
      characteristics of the intrahepatic cholestasis and extrahepatic cholestasis
      groups with the cytomegalovirus serological results. Patients and Methods - This
      study consisted of 76 patients with neonatal cholestasis who were admitted
      between January 1980 and January 1999 when they underwent a cytomegalovirus
      serologic study using the ELISA method. A case note was kept on each patient with
      the following data: age of patient at admission, serologic result for
      cytomegalovirus, history of maternal infection, prematurity, fetal distress,
      birth weight, ponderal gain, choluria and fecal acholia. The final anatomic
      diagnosis of cholestasis was based on the results of an abdominal
      ultrasonography, a liver biopsy and its evolution. The patients were then divided
      into two groups: group I - intrahepatic cholestasis and group II - extrahepatic
      cholestasis. Each of these groups were then divided into two subgroups: subgroup
      A - positive serology (IgM) for cytomegalovirus and subgroup B - negative
      serology (IgM) for cytomegalovirus. RESULTS: The frequency of positive serology
      (IgM) for cytomegalovirus was 29.4% in children with intrahepatic cholestasis and
      28.5% in children with extrahepatic cholestasis. In comparison with group IIB,
      group IIA presented a higher rate of maternal infection history. The patients in
      group IIA demonstrated a delayed access to the service in comparison with group
      IA. The groups did not demonstrate any significant differences regarding the
      onset age of jaundice, choluria and fecal acholia, birth weight and ponderal
      gain. CONCLUSIONS: The positive (IgM) seroprevalence for cytomegalovirus in
      children with intrahepatic cholestasis and extrahepatic cholestasis is high. The
      history of maternal infection was more common in extrahepatic cholestasis
      patients with positive serology for cytomegalovirus. There was a delay in the
      referral of these patients which resulted in a late diagnosis and surgical
      treatment.

PMID- 12612720
TI  - [Therapeutic challenges in chronic obstructive coronary artery disease].

PMID- 12612722
TI  - Prognostic value of technetium-99m-labeled single-photon emission computerized
      tomography in the follow-up of patients after their first myocardial
      revascularization surgery.
AB  - OBJECTIVE: To assess the prognostic value of Technetium-99m-labeled single-photon
      emission computerized tomography (SPECT) in the follow-up of patients who had
      undergone their first myocardial revascularization. METHODS: We carried out a
      retrospective study of 280 revascularized patients undergoing myocardial
      scintigraphy under stress (exercise or pharmacological stress with dipyridamole)
      and at rest according to a 2-day protocol. A set of clinical, stress
      electrocardiographic and scintigraphic variables was assessed. Cardiac events
      were classified as "major" (death, infarction, unstable angina) and "any" (major
      event or coronary angioplasty or new myocardial revascularization surgery).
      RESULTS: Thirty-six major events occurred as follows: 3 deaths, 11 infarctions,
      and 22 unstable anginas. In regard to any event, 22 angioplasties and 7 new
      surgeries occurred in addition to major events, resulting a total of 65 events.
      The sensitivity of scintigraphy in prognosticating a major event or any event
      was, respectively, 55% and 58%, showing a negative predictive value of 90% and
      83%, respectively. Diabetes mellitus, inconclusive stress electrocardiography,
      and a scintigraphic visualization of left ventricular enlargement were
      significant variables for the occurrence of a major event. On multivariate
      analysis, abnormal myocardial scintigraphy was a predictor of any event.
      CONCLUSION: Myocardial perfusion tomography with Technetium-99m may be used to
      identify high-risk patients after their first myocardial revascularization
      surgery.

PMID- 12612721
TI  - Improvement in left ventricular dysfunction after surgical correction of mitral
      regurgitation.
AB  - OBJECTIVE: To evaluate whether left ventricular end-systolic (ESD) diameters < or
      = 51mm in patients (pt) with severe chronic mitral regurgitation (MR) are
      predictors of a poor prognosis after mitral valve surgery (MVS). METHODS: Eleven
      pt (aged 36 +/- 13 years) were studied in the preoperative period (pre), median
      of 36 days; in the early postoperative period (post1), median of 9 days; and in
      the late postoperative period (post2), mean of 38.5 +/- 37.6 months. Clinical and
      echocardiographic data were gathered from each pt with MR and systolic diameter >
      or = 51 mm (mean = 57 +/- 4mm) to evaluate the result of MVS. Ten patients were
      in NYHA Class III/IV. RESULTS: All but 2 pt improved in functional class. Two pt
      died from heart failure and infectious endocarditis 14 and 11 months,
      respectively, after valve replacement. According to ejection fraction (EF) in
      post2, we identified 2 groups: group 1 (n=6), whose EF decreased in post1, but
      increased in post2 (p=0.01) and group 2 (n=5), whose EF decreased progressively
      from post1 to post2 (p=0.10). All pt with symptoms lasting < or = 48 months had
      improvement in EF in post2 (p=0.01). CONCLUSION: ESD > or = 51 mm are not always
      associated with a poor prognosis after MVS in patients with MR. Symptoms lasting
      up to 48 months are associated with improvement in left ventricular function.

PMID- 12612723
TI  - Doppler tissue imaging to assess systolic function in Chagas' disease.
AB  - OBJECTIVE: To assess the usefulness of Doppler tissue imaging (DTI) for
      evaluating the systolic function of chagasic patients with and without
      electrocardiographic abnormalities, in comparision with echocardiographic study.
      METHODS: We studied 77 patients divided into 3 groups as follows: group 1 -
      control; group 2 - chagasic patients with normal electrocardiographic findings;
      and group 3 - chagasic patients with abnormal electrocardiographic findings. The
      following parameters were assessed: left ventricular dimensions and ejection
      fraction, left atrial dimensions and diastolic function on echocardiography.
      Systolic velocity and regional isovolumic contraction time (IVCTr) of the septal,
      anterior, lateral, posterior and inferior left ventricular walls were assessed on
      DTI. RESULTS: Left ventricular cavitary dimensions, ejection fraction and DTI
      systolic wave showed significant differences between groups 1 and 3 and between
      groups 2 and 3, which were not found between groups 1 and 2. IVCTr allowed a
      statistically significant discrimination among the 3 groups. CONCLUSION: DTI
      allowed discrimination among the different groups assessed, being superior to
      echocardiography in identifying early abnormalities of contractility, and,
      therefore, potentially useful for detecting incipient myocardial alterations in
      chagasic patients with normal electrocardiographic findings.

PMID- 12612724
TI  - Predictive factors of in-hospital mortality and of severe perioperative
      complications in myocardial revascularization surgery.
AB  - OBJECTIVE: To investigate preoperative predictive factors of severe perioperative
      intercurrent events and in-hospital mortality in coronary artery bypass graft
      (CABG) surgery and to develop specific models of risk prediction for these
      events, mainly those that can undergo changes in the preoperative period.
      METHODS: We prospectively studied 453 patients who had undergone CABG. Factors
      independently associated with the events of interest were determined with
      multiple logistic regression and Cox proportional hazards regression model.
      RESULTS: The mortality rate was 11.3% (51/453), and 21.2% of the patients had 1
      or more perioperative intercurrent events. In the final model, the following
      variables remained associated with the risk of intercurrent events: age > or = 70
      years, female sex, hospitalization via SUS (Sistema nico de Sa de - the Brazilian
      public health system), cardiogenic shock, ischemia, and dependence on dialysis.
      Using multiple logistic regression for in-hospital mortality, the following
      variables participated in the model of risk prediction: age > or = 70 years,
      female sex, hospitalization via SUS, diabetes, renal dysfunction, and cardiogenic
      shock. According to the Cox regression model for death within the 7 days
      following surgery, the following variables remained associated with mortality:
      age > or = 70 years, female sex, cardiogenic shock, and hospitalization via SUS.
      CONCLUSION: The aspects linked to the structure of the Brazilian health system,
      such as factors of great impact on the results obtained, indicate that the events
      investigated also depend on factors that do not relate to the patient's intrinsic
      condition.

PMID- 12612725
TI  - Catheter ablation of atriofascicular Mahaim fibers guided by the activation
      potential.
AB  - OBJECTIVE: To determine whether recording of the activation potential may be used
      as an isolated criterion to guide catheter ablation of atriofascicular Mahaim
      fibers. METHODS: We studied 6 patients (5 females, mean age of 26 +/- 7.3 years)
      with paroxysmal tachycardias with a wide QRS complex, whose electrophysiological
      study diagnosed atriofascicular Mahaim fibers. Mapping and catheter ablation were
      performed in sinus rhythm, guided only by the recording of the activation
      potential of the fiber. RESULTS: Efficacy in ablation was achieved in all
      patients. The fibers were located in the right lateral region of the tricuspid
      ring in 3 patients, right posterolateral region in 2, and right anterolateral
      region in 1. A mean of 5.3 +/- 3 radiofrequency applications was performed. The
      mean fluoroscopy time was 46.6 +/- 25 minutes, and the mean duration of the
      procedure was 178.6 +/- 108 minutes. No complication occurred. In a mean 20-month
      follow-up, all patients were asymptomatic and receiving no antiarrhythmic drugs.
      CONCLUSION: Catheter ablation of Mahaim fibers may be performed with good safety
      and efficacy by mapping the activation potential of the tricuspid ring in sinus
      rhythm.

PMID- 12612726
TI  - Percutaneous implantation of endoprostheses in the carotid arteries.
AB  - OBJECTIVE: To assess the in-hospital evolution of patients undergoing
      percutaneous stent placement in the carotid arteries. METHODS: From August 1996
      to April 2001, we studied 86 patients with carotid arterial obliterative lesions
      > 70% who were treated with percutaneous stent placement in the carotid arteries.
      We assessed the rate of success of the implantation and of the procedure, the
      types of stents used, mortality rate, and neurological complications. RESULTS:
      Successful implantation was obtained in 98.9% of the cases, and the procedure was
      successful in 91.8%. The Wallstent was the most frequently used stent (73
      patients - 77%). Cerebral strokes occurred as follows: 3 (3.2%) transient
      ischemic attacks, 1 (1.1%) minor stroke, and 3 (3.1%) major strokes. One (1.1%)
      patient died during hospitalization. CONCLUSION: The high rate of success of
      stent implantation (98.9%) in addition to the low rate of cerebral stroke/death
      (4.2%) showed the efficiency and safety of percutaneous stent placement in
      carotid arteries.

PMID- 12612727
TI  - Assessment of the techniques of blood pressure measurement by health
      professionals.
AB  - OBJECTIVE: To assess blood pressure measurement by health professionals of a
      public hospital in S o Paulo State. METHODS: Semi-structured interviews and
      direct observation were performed with a verification list according to the
      criteria reported by Perloff et al. One hundred and five health professionals
      took part in the study. After measuring blood pressure, the level of concordance
      between the way the procedure was performed and the recommended one was assessed.
      RESULTS: Nurses and nurse's aides abided by 40% of the recommended procedures for
      adequate blood pressure measurement. The other categories of health professionals
      (nursing and medicine teachers, physicians, residents, and nursing students)
      abided by approximately 70%. CONCLUSION: Permanent educational activities aiming
      at standardizing blood pressure measurement should be implemented among the
      different categories of health professionals.

PMID- 12612728
TI  - Right atrial lipoma.
AB  - Benign cardiac tumors are rare, and lipomas are among those less frequently
      found. We report the case of a 48-year-old male complaining of high blood
      pressure and epistaxis in the last 2 months, with a diagnosis of right atrial
      lipoma established on echocardiography, magnetic resonance imaging, and
      anatomicopathological examination. The tumor was successfully removed, and up to
      42 months after surgical excision, no evidence of tumor relapse was observed.

PMID- 12612729
TI  - [Clinic-radiographic correlation. Case 1/2003 - Instituto do Coracao do Hospital
      das Clinicas da FMUSP ].

PMID- 12612730
TI  - [Prognostic value of ST segment elevation resolution during myocardial
      perfusion].

PMID- 12612731
TI  - [Cardiovascular effects of the exposure to a microgravitational environment].

PMID- 12612733
TI  - [Treatment of chronic Chagas' disease with an association of nifurtimox and
      corticoid].
AB  - Ten patients with chronic Chagas' disease were treated with nifurtimox (8-9
      mg/kg/day) associated with betamethasone (9 mg/day initially and then gradually
      reduced) during 60 days, with one exception. It was intended to combine the
      respective anti-parasitic and anti-inflammatory actions of these drugs. The
      expected stimulating effect of betamethasone on the infection could possibly
      enhance the anti-Trypanosoma cruzi action of nifurtimox. Long term persistence of
      negative xenodiagnosis, used to control the results, was observed in only one of
      the cases. Regaridng the other patients, post-treatment positivity of
      xenodiagnosis and serological testes attested the failure of this therapy. As
      this study has demonstrated, adequate and long term follow-up of treated cases is
      necessary to ensure correct conclusions.

PMID- 12612734
TI  - [Anti-live Leishmania (Viannia) braziliensis promastigote antibodies, detected by
      flow cytometry, to identify active infection in american cutaneous
      leishmaniasis].
AB  - In the current study we described initial standardization steps of a new
      methodology to detect anti-live Leishmania (Viannia) braziliensis promastigote
      antibodies by flow cytometry, followed by analysis of its applicability to
      clinical studies. We have studied 39 individuals with positive conventional
      serology to leishmaniasis, classified according to the absence/presence of
      cutaneous lesions (L- and L+). The results were expressed as percentage of
      positive fluorescent parasites (PPFP). Data analysis at dilution of 1:1,024,
      allowed the distinction of 95% of L+ patients as a group of high reactivity
      (PPFP>50%) and 72% of L- individuals as a group of low reactivity (PPFP<50%). The
      analysis of immunofluorescence assay titers did not show any relationship with
      the absence/presence of lesion. Together, our data support the applicability of
      flow cytometry to identify cases of active infection, which has not been possible
      through conventional serological reactions.

PMID- 12612735
TI  - Aminoquinolone WR6026 as a feasible substitute for gentian violet in Chagas'
      disease prophylaxis in preserved blood for transfusional purposes.
AB  - The search for a colorless, nontoxic and efficient drug to prevent transfusion
      associated Chagas' disease (TACD) has been underway unsuccessfully since 1953
      when gentian violet was preconized and to date is still being used as the only in
      vitro trypanocidal agent. The recent findings of aminoquinolone "WR6026" as a
      trypanocidal agent, led the authors to study the metabolism of red cells stored
      with this compound, the main objective of which was to define its applicability
      in TACD control. Ten units of human whole blood collected in CPDA-1 were divided
      into two equal satellite bags. One had "WR6026" (final concentration 62.5 g/mL)
      added and the other was used as a control, both were stored at 4 C. At baseline,
      day 7, 14, 21 and 28, samples were taken for the following measurements:
      adenosine triphosphate (ATP), hemoglobin, electrolytes (sodium and potassium),
      gases (pO2 and pCO2) and osmotic fragility. The results of tests and control were
      analyzed through parametric t-student test. The results were similar in both
      groups throughout the experiment except for the level of ATP on day 14, which
      presented significantly higher values in the tests when compared with the
      controls (p = 0.012). It was concluded that WR6026 does not interfere in the
      preservation and probably the viability of the erythrocytes also until day 28 of
      storage. Consequently the authors suggest that WR6026 could emerge as a colorless
      substitute for gentian violet in the control of TACD in endemic areas.

PMID- 12612736
TI  - Prevalence of intestinal nematodes in alcoholic patients.
AB  - We report the results of a retrospective study on the frequency of intestinal
      nematodes among 198 alcoholic and 440 nonalcoholic patients at the University
      Hospital Cassiano Antonio Moraes in Vit ria, ES, Brazil. The control sample
      included 194 nonalcoholic patients matched according to age, sex and neighborhood
      and a random sample of 296 adults admitted at the same hospital. Stool
      examination by sedimentation method (three samples) was performed in all
      patients. There was a significantly higher frequency of intestinal nematodes in
      alcoholics than in controls (35.3% and 19.2%, respectively), due to a higher
      frequency of Strongyloides stercoralis (21.7% and 4.1%, respectively).
      Disregarding this parasite, the frequency of the other nematodes was similar in
      both groups. The higher frequency of S. stercoralis infection in alcoholics could
      be explained by immune modulation and/or by some alteration in corticosteroid
      metabolism induced by chronic ethanol ingestion. Corticosteroid metabolites would
      mimic the worm ecdisteroids, that would in turn increase the fecundity of females
      in duodenum and survival of larvae. Consequently, the higher frequency of
      Strongyloides larvae in stool of alcoholics does not necessarily reflect an
      increased frequency of infection rate, but only an increased chance to present a
      positive stool examination using sedimentation methods.

PMID- 12612737
TI  - [Human accidents with monkeys in relation to prophylactic treatment for rabies,
      in the Municipal district of Sao Paulo, Brazil].
AB  - Although the Municipal District of S o Paulo has rabies under epidemic control
      (last case of rabies in humans was registered in 1981) and 95.4% of its
      population resides within the urban area, there are reports of human accidents
      involving wild animals and of these, monkeys are involved in the largest number
      of cases. In the period from 1996 to 1999, 69,967 victims of accidents with
      animals were attended, of which 267 were accidents with monkeys. In this work the
      monthly and annual incidence of the occurrence of such accidents was studied, as
      well as the antirabies treatment provided.

PMID- 12612738
TI  - [Serological diagnosis of dengue and yellow fever infections in suspected cases
      from Para State, Brazil, 1999].
AB  - From June to December 1999, 785 serum samples were obtained from patients
      clinically suspected of having dengue or yellow fever. The patients were referred
      by public health centers distributed within the six mesoregions of Par  State,
      Brazil. Serum samples were tested for Flavivirus antibodies by hemagglutination
      inhibition test and for dengue and yellow fever viruses by enzyme-linked
      immunosorbent assay for IgM detection. Of the sera collected, 563 (71.7%) were
      positive by HI test and out of these 150 (26.6%) were positive by ELISA-IgM.
      Dengue virus was responsible for most of the recent infections in all regions;
      yellow fever cases detected in the current study were restricted to the Maraj 
      and Southeast regions.

PMID- 12612739
TI  - The use of protein hydrolysate improves the protein intestinal absorption in
      undernourished mice infected with Schistosoma mansoni.
AB  - Patients residing in endemic areas for schistosomiasis in Brazil are usually
      undernourished and when they develop the hepatosplenic clinical form of the
      disease should usually receive hospital care, many of them being in need of
      nutritional rehabilitation before specific treatment can be undertaken. In the
      mouse model, investigations carried out in our laboratory detected a reduced
      aminoacid uptake in undernourished animals which is aggravated by a superimposed
      infection with Schistosoma mansoni. However, in well-nourished infected mice no
      dysfunction occurs. In this study, we tried to improve the absorptive intestinal
      performance of undernourished mice infected with S. mansoni by feeding them with
      hydrolysed casein instead of whole casein. The values obtained for the
      coefficient of protein intestinal absorption (cpia) among well-nourished mice
      were above 90% (either hydrolysed or whole protein). In undernourished infected
      mice, however, the cpia improved significantly after feeding them with hydrolysed
      casein, animals reaching values close to those obtained in well-nourished
      infected mice.

PMID- 12612740
TI  - [Avian habitats as sources of Cryptococcus neoformans in the city of Campo
      Grande, Mato Grosso do Sul, Brazil].
AB  - Cryptococcus neoformans is an encapsulated yeast agent of human and animal
      cryptococcosis. The variety neoformans is an important cause of mortality in AIDS
      patients throughout the world. It has already been isolated worldwide from
      different environmental sources, including avian habitats. However, in spite of
      the occurrence of human cases of cryptococcosis, there are no studies on the
      ecology of this agent in the Brazilian Central-Western region. To study
      saprophytic sources of C. neoformans in the city of Campo Grande, 20 samples of
      avian droppings from distinct environments within the city were collected. The
      samples were suspended in sterile saline and then smeared on niger seed agar
      medium. Five days later smooth dark-brown colonies were subcultivated for
      identification by morphophysiologic tests. The variety and serotype was
      determined. C. neoformans var. neoformans serotype A was isolated from 10 (50%)
      of the samples collected. Consequently, the saprophytic presence of C. neoformans
      is related to avian habitats.

PMID- 12612741
TI  - [Prevalence of intestinal helminths in three regions of Minas Gerais State].
AB  - A parasitological assay of feces, through the Kato-Katz method, was undertaken in
      18,973 schoolchildren (7 to 14 years old), at primary school level, from a public
      school of the State of Minas Gerais. Three mesoregions were studied: Tri ngulo
      Mineiro/ Alto Para ba ( 60 municipalities); northwest Minas Gerais (13) and
      south/south-west regions of Minas Gerais (144). Among the examined children,
      15,545 (82%) were negative; 2,863 (15%) were infected with a single species of
      helminthes and 565 (3%) were infected by more than one species. The prevalence
      rates were: A. lumbricoides 10.3%; T. trichiura 4.7%; hookworm 2.9%; E.
      vermicularis 1.2%; H. nana 0.4% and Taenia sp 0.2%. The largest helminthes
      prevalence/mesoregion were for T. trichiura (24.2%) and A. lumbricoides (18.7%)
      in the south/south-west region; hookworm (12.1%) and Taenia sp (0.7%) in the
      northwest region of Minas Gerais. Intestinal helminthiasis is still regarded as a
      serious public health problem, including regions where the socio-economic
      conditions are more favorable.

PMID- 12612742
TI  - Structural changes in the jejunal mucosa of mice infected with Schistosoma
      mansoni, fed low or high protein diets.
AB  - The effects of high and low-protein diets on the structure of the jejunal mucosa
      were studied in Schistosoma mansoni infected mice (morphology and
      histomorphometry). Weaning male albino mice were infected with 80 cercariae, fed
      with high (20%) or low-protein (5%) diets and compared to uninfected controls
      under the same conditions. Mice were sacrificed 12 weeks after infection. Animals
      submitted to a low-protein diet showed lower weight curves, mainly when infected.
      In the jejunal mucosa, finger-like villi were the predominant pattern among
      uninfected high-protein fed animals, while the infected ones showed leaf-shaped
      and flattened villi in most cases. Undernourished infected mice had 65.7% leaf
      shaped villi. A significant increase in the number of goblet cells was seen in
      infected mice. A decrease in the number of absorptive cells was detected in
      undernourished mice, particularly in infected ones.

PMID- 12612743
TI  - [Emergencies in patients with Chagas' disease in Buenos Aires city, Argentina].
AB  - The objective of this work was to evaluate the most frequent causes of emergency
      in patients with Chagas disease. Between January 1998-January 1999, individuals
      with Chagas disease inside the shock-room of Santojanni Hospital in Buenos Aires
      city, were included in a prospective study. For the statistical analysis, X  test
      with Yates correction has been used. From a total of 1.680 patients entered,
      there were 95 (6%) with reactive serology for Chagas disease. In 31 individuals
      the enter cause was syncope, in 28 cardiac insufficiency, in 18 acute coronary
      events, in 5 stroke, in 3 acute edema of hypertensive lung and in 2 acute
      encephalitis associated to AIDS. In conclusion, significant association has been
      observed between: 1) presence of cardiopathy and hospitalization, 2) cardiac
      insufficiency, syncope, acute encephalitis and mortality, 3) cardiopathy
      development and mortality and 4) origin place and mortality.

PMID- 12612744
TI  - [Developmental characteristics of Cysticercus cellulosae in the human brain and
      heart].
AB  - The present study aimed to evaluate the prevalence of cysticercosis, to classify
      the developmental phases of cysticerci found in human brains and hearts, and
      differentiate these according to the macro and microscopic aspects of the general
      pathological processes, and to compare the process found in the brains and
      hearts. Protocols from autopsies performed at the Hospital of the School of
      Medicine of the Triangulo Mineiro, Uberaba, MG, Brazil, in the period from 1970
      to 2000 were reviewed. The prevalence of cysticercosis was verified in 71 cases,
      of which 53 (74.6%) were encephalic cysticercosis and 18 (25.3%) cardiac
      cysticercosis. Nineteen cysticerci were analyzed, from 9 brains and 10 hearts.
      The cysticerci were classified according to their developmental stage: vesicular,
      colloidal vesicular, granular nodular and calcified nodular, with similarities
      between the macroscopic and microscopic diagnoses. Among the pathological
      processes found beta-fibrilosis and endocardial fibroelastosis are underscored.
      In addition, it was demonstrated that this classification may be applied both to
      encephalic and cardiac cysticercosis.

PMID- 12612745
TI  - [Antifungal activity of Caryocar brasiliensis (Caryocaraceae) against
      Cryptococcus neoformans].
AB  - The widespread occurrence of cryptococcosis mainly in immunocompromised patients
      and the side effects of available drugs which are effective against this mycosis
      have led investigators to search for new antimycotic agents. Caryocar
      brasiliensis derived compounds were investigated against Cryptococcus neoformans
      using the agar dilution method. Based on MIC values, the best results were
      obtained with a concentration of < 250 g/mL of cuticular waxes of the Caryocar
      brasiliensis leaf collected during the dry period (170.8mm of precipitation)
      which inhibited the growth of 91.3% (21/23) Cryptococcus neoformans isolates.

PMID- 12612746
TI  - Predictors of an unsatisfactory response to pentavalent antimony in the treatment
      of American visceral leishmaniasis.
AB  - Although treatment of visceral leishmaniasis with pentavalent antimony is usually
      successful, some patients require second-line drug therapy, most commonly with
      amphotericin B. To identify the clinical characteristics that predict an
      inadequate response to pentavalent antimony, a case-control study was undertaken
      in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in
      which the staff physicians of a hospital prescribed second-line therapy with
      amphotericin B after determining that treatment with pentavalent antimony had
      failed. The control group consisted of 97 patients that were successfully treated
      with pentavalent antimony. A chart review using univariate and multivariate
      analysis was performed. The cure rate was 90% with amphotericin B. The odds ratio
      for the prescription of amphotericin B was 10.2 for children less than one year
      old, compared with individuals aged over 10 years. Patients who presented
      coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These
      data support either undertaking a longer course of therapy with pentavalent
      antimony for children or using amphotericin B as a first-line agent for children
      and individuals with coinfections. It also suggests that chemoprophylaxis
      directed toward bacterial coinfection in small children with VL may be indicated.

PMID- 12612747
TI  - [Identification of infectious agents in the lungs in autopsies of patients with
      acquired immunodeficiency syndrome].
AB  - Lung diseases are frequently observed in individuals infected with HIV. The aim
      of this study was to identify infectious agents in the lungs in the autopsied
      individuals with AIDS performed between march 1990 and july 2000 at the school of
      medicine (Uberaba- Brazil), using histochemical and immunohistochemical
      techniques. Analysis was made on lungs obtained from 40 individuals with AIDS.
      Infectious agents were observed in 34 (85%) cases of the 40 analyzed. Regarding
      fungis, Pneumocystis carinii was found in 8 (19.1%)cases; Cryptococcus sp in 4
      (9.5%)cases, Histoplasma sp in 2 (4.8%)cases and Candida sp in 1 (2.4%)case.
      Association of Pneumocystis carinii, Citomegalovirus and Cryptococcus sp, was
      observed in one case, and in another, the association of CMV, and Toxoplasma
      gondii. There were 5 cases with Candida sp, CMV and Pneumocystis carinii
      associated with bacteria. In conclusion, this study shows that following
      bacterial agents fungi were the second most common infectious agents in post
      mortem examination of the lungs from patients with AIDS, being Pneumocystis
      carinii the most prevalent.

PMID- 12612748
TI  - [Clinical and immunological consequences of the association between HTLV-1 and
      strongyloidiasis].
AB  - Strongyloidiasis is one of most important forms of helminthiasis in tropical
      countries and epidemiologic studies have shown the association of this parasitic
      disease with HTLV. It has been observed in regions where both these agents are
      endemic and coinfection may result in an increase in the disseminated forms of
      strongyloidiasis as well as recurrent strongyloidiasis. While HTLV-1 is related
      to a high production of IFN-gamma; and deviation of the immune response towards a
      Th1 response, the protection against helminths is associated with Th2 like immune
      response. Individuals infected with HTLV and S. stercoralis have a reduction in
      the production of IL-4, IL-5, IL-13 and parasitic IgE response, all of which are
      factors participating in the defense mechanism against S. stercoralis. These
      abnormalities are the basis for the occurrence of an increase in the severe forms
      of strongyloidiasis among patients infected with HTLV-1.

PMID- 12612749
TI  - [American cutaneous leishmaniasis associated with HIV/AIDS: report of four
      clinical cases].
AB  - The co-infection American cutaneous leishmaniasis and AIDS has recently been
      described in the literature, observing differences between the clinical and
      immunological behavior of these patients. Four cases are reported here, attended
      at the Brasilia University Hospital, with diagnoses of infection by Leishmania
      species and immunodeficiency virus, with a view to illustrating the clinical
      presentations, course and therapeutic responses.

PMID- 12612750
TI  - Disseminated cutaneous sporotrichosis in a patient with AIDS: report of a case.
AB  - We describe a case report of disseminated cutaneous sporotrichosis as the initial
      presentation of AIDS in a 24-year-old HIV-positive male patient. He presented
      multiple ulcerated skin lesions distributed over the face, thorax, legs and arms.
      Biopsy of one of the cutaneous lesions was suggestive of sporotrichosis and
      culture isolated Sporothrix schenckii. Itraconazole was started and the lesions
      progressively resolved after 15 days of medication. The patient was discharged
      with this medication but he did not return for follow-up. He died three months
      later in another hospital. Therapy of sporotrichosis in HIV-infected patients
      remains unclear and the response to therapy is variable. Itraconazole is highly
      concentrated in the skin and is one of the options for treatment of disseminated
      sporotrichosis.

PMID- 12612751
TI  - [Typhoid fever: relapse due to antimicrobial resistance. Case report].
AB  - We report for the first time in the Brazilian Amazon a typhoid fever patient with
      clinical and laboratorial resistance to chloramphenicol, drug of election for
      this disease in our region. The relapse was observed at the 7th day after the end
      of treatment and the patient was treated with ciprofloxacin.

PMID- 12612752
TI  - [Association between reported annual gold mining extraction and incidence of
      malaria in Mato Grosso-Brazil, 1985-1996].
AB  - A secondary data analysis was performed using an ecological design to study the
      association between malaria incidence rates, the reported annual production of
      gold mining extraction and monetary investments for the control of malaria from
      1985 to 1996 in Mato Grosso, Brazil. A positive and statistically significant
      (p<0.001) association between the amount of gold extracted and MIR was obtained
      in multivariate regression analysis, even after allowing for financial
      investments in malaria control activities. This finding contributes to an
      understanding of the decrease observed in malaria incidence in Mato Grosso during
      the last decade, in view of the significant decrease in gold mining within the
      region during this period.

PMID- 12612753
TI  - [Chagas' disease in the Amazon: an overview of the current situation and
      perspectives for prevention].
AB  - American Trypanosomiasis (Chagas' disease) due to Trypanosoma cruzi in the Amazon
      Region has become a target of scientific preoccupation in recent years because of
      the wide dispersion of infected vectors and intensive human migration into the
      region. An European Community and Latin America Triatominae Network international
      workshop held in July 2002 analyzed the general situation and the perspectives of
      human Chagas' disease in the area, concluding that although its occurrence
      remains sporadic, there is strong potential for the disease to spread, and a
      requirement for an integrated surveillance effort to be shared by all countries
      of the region.

PMID- 12612754
TI  - Magnetic resonance imaging of the liver in hepatosplenic schistosomiasis mansoni.

PMID- 12612755
TI  - New migraine prophylactic drug options.

PMID- 12612757
TI  - An experimental model for the transplantation of fetal central nervous system
      cells to the injured spinal cord in rats.
AB  - INTRODUCTION: Traumatic spinal cord injury is one of the most disabling
      conditions occurring in man and thus stimulates a strong interest in its
      histopathological, biochemical, and functional changes, primarily as we search
      for preventive and therapeutic methods. PURPOSE: To develop an experimental model
      for transplantation of cells from the fetal rat central nervous system to the
      site of an injured spinal cord of an adult rat in which the transplanted cells
      survive and become integrated. This experimental model will facilitate
      investigations of factors that promote regeneration and functional recovery after
      spinal cord trauma. MATERIAL AND METHODS: Fifteen adult Wistar rats underwent
      laminectomy, and an spinal cord lesion was made with microdissection. Fetal
      spinal cord tissue was then transplanted to the site of the injury. The rats were
      monitored over a 48-hour period, and then their vertebral column was completely
      removed for histological analysis. RESULTS: In 60% of transplanted rats, the
      fetal tissue at the injured site remained viable in the site of the lesion.

PMID- 12612756
TI  - Adrenocortical tumors: results of treatment and study of Weiss's score as a
      prognostic factor.
AB  - PURPOSE: The differential diagnosis between benign and malignant adrenal cortical
      tumors circumscribed to the gland is controversial. One hundred and seven
      patients with adrenal cortex tumors (excluding those with primary
      hyperaldosteronism) were studied to assess the 5-year survival rate of adults,
      children, patients stratified by pathological stage, and patients stratified
      according to Weiss's score of <3 or >3. METHODS: The patients were evaluated both
      clinically and biochemically. One hundred and five patients underwent surgery and
      were classified pathologically as stages I, II, III, or IV. The tumors were
      weighed, measured, and classified according to Weiss's criteria and divided into
      2 groups: <3 and >3. RESULTS: After 5 years, the survival rate was 77.5% for the
      whole group, 74.61% for the adults, 84.3% for the children, 100% for stage I,
      83.9% for stage II, 33% for stage III, and 11.7% for stage IV groups.
      Additionally, after 5 years, 100% of the patients with tumors with Weiss's score
      <3 were alive compared to 61.65% of those with Weiss's score >3. The average
      weights of the tumors of score <3 and >3 were 23.38 g   41.36 g and 376.3  
      538.76 g, respectively, which is a statistically significant difference. The
      average sizes of tumors of Weiss's score <3 and >3 were 3.67   2.2 cm and 9.64  
      5.8 cm, respectively, which is also a statistically significant difference.
      CONCLUSIONS: Weiss's score may be a good prognostic factor for tumors of the
      adrenal cortex. Additionally, there was a statistically significant difference
      between the average weight and size of tumors with benign behavior (Weiss's score
      <3) and those with malignant behavior (Weiss's score >3).

PMID- 12612758
TI  - Quantitative analysis of collagen and elastic fibers in the transversalis fascia
      in direct and indirect inguinal hernia.
AB  - PURPOSE: Our previous studies demonstrated structural and quantitative age
      related changes of the elastic fibers in transversalis fascia, which may play a
      role in inguinal hernia formation. To verify whether there were differences in
      the extracellular matrix between direct and indirect inguinal hernia, we studied
      the amount of collagen and elastic fibers in the transversalis fascia of 36 male
      patients with indirect inguinal hernia and 21 with direct inguinal hernia.
      MATERIAL AND METHODS: Transversalis fascia fragments were obtained during
      surgical intervention and underwent histological quantitative analysis of
      collagen by colorimetry and analysis of elastic fibers by histomorphometry.
      RESULTS: We demonstrated significantly lower amounts of collagen and higher
      amounts of elastic fibers in transversalis fascia from patients with direct
      inguinal hernia compared to indirect inguinal hernia patients. The transversalis
      fascia from direct inguinal hernia patients showed structural changes of the
      mature and elaunin elastic fibers, which are responsible for elasticity, and
      lower density of oxytalan elastic fibers, which are responsible for resistance.
      These changes promoted loss of resiliency of the transversalis fascia.
      CONCLUSION: These results improve our understanding of the participation of the
      extracellular matrix in the genesis of direct inguinal hernia, suggesting a
      relationship with genetic defects of the elastic fiber and collagen synthesis.

PMID- 12612760
TI  - Analysis of human leukocyte antigens class II-DR in Brazilian children and
      adolescents with systemic lupus erythematosus.
AB  - OBJECTIVE: To analyze the frequency of human leukocyte antigens class II-DR in
      children and adolescents with systemic lupus erythematosus. PATIENTS AND METHODS:
      Fifty-fiveBrazilian systemic lupus erythematosus children and adolescents and 308
      healthy individuals were studied. Gender, race, and age of onset of systemic
      lupus erythematosus were recorded. The human leukocyte antigens typing of class
      II-DR was carried out by polymerase chain reaction amplification with sequence
      specific primers (PCR-SSP). Data were analyzed statistically using the chi square
      test with Yates' correction, Fisher's exact test, and Bonferroni's correction.
      RESULTS: Human leukocyte antigen-DR 15 was the most frequently detected antigen
      in this group of children and adolescents, and it also occurred more frequently
      in the female group, in children with onset of systemic lupus erythematosus
      between 0 and 9 years and between 10 to 14 years, and in the Black race group,
      but these associations were not statistically significants. CONCLUSION: In this
      group of children and adolescents with a high degree of racial admixture, we
      could not verify a significant association between human leukocyte antigens class
      II-DR and systemic lupus erythematosus.

PMID- 12612759
TI  - Salivary gland tumors in a Brazilian population: a retrospective study of 124
      cases.
AB  - Salivary gland tumors constitute a highly heterogeneous histopathologic group.
      There are few epidemiological studies of large series of benign and malignant
      salivary gland tumors in Brazil. MATERIAL AND METHODS: Hospital records of 124
      patients with salivary gland tumors diagnosed from January 1993 to December 1999
      were reviewed. The patients were analyzed according to gender, age, size,
      location, and histopathology of the tumor. RESULTS AND CONCLUSIONS: Patients with
      benign and malignant tumors presented with a mean age of 47.7 and 48.8 years,
      respectively. The frequency of benign tumors was 80% (n = 99) and malignant
      tumors 20% (n = 25). Tumors were localized in the parotid gland 71% (n = 88), in
      the submandibular gland 24% (n = 30), and in the minor salivary glands 5% (n =
      6). The most common benign tumors were pleomorphic adenoma in 84% (n = 84) and
      Warthin's tumor in 13% (n = 13). Among malignant tumors, mucoepidermoid carcinoma
      was the most common in 52% (n = 13), adenoid cystic carcinoma occurred in 20% (n
      = 5), and carcinoma ex pleomorphic adenoma was detected in 12% (n = 3).

PMID- 12612761
TI  - Thumb metastasis from small cell lung cancer treated with radiation.
AB  - A rare case of thumb metastasis from small cell lung cancer is presented. The
      patient underwent local radiotherapy with complete palliation of symptoms. She
      died 4 months later with disseminated disease. Considerations about incidence,
      treatment, and physiopathology of this kind of dissemination are made.
      Conservative treatment of finger metastasis with radiation may be considered due
      to the poor outcome of these patients.

PMID- 12612762
TI  - Prostate innervation and local anesthesia in prostate procedures.
AB  - The nerve supply of the human prostate is very abundant, and knowledge of the
      anatomy contributes to successful administration of local anesthesia. However,
      the exact anatomy of extrinsic neuronal cell bodies of the autonomic and sensory
      innervation of the prostate is not clear, except in other animals. Branches of
      pelvic ganglia composed of pelvic (parasympathetic) and hypogastric (sympathetic)
      nerves innervate the prostate. The autonomic nervous system plays an important
      role in the growth, maturation, and secretory function of this gland. Prostate
      procedures under local anesthesia, such as transurethral prostatic resections or
      transrectal ultrasound-guided prostatic biopsy, are safe, simple, and effective.
      Local anesthesia can be feasible for many special conditions including
      uncomplicated prostate surgery and may be particularly useful for the high-risk
      group of patients for whom inhalation or spinal anesthesia is inadvisable.

PMID- 12612763
TI  - New migraine preventive options: an update with pathophysiological
      considerations.
AB  - BACKGROUND: The pharmacological treatment of migraine may be acute or preventive.
      Frequent, severe and long-lasting migraine attacks require prophylaxis. Multiple
      threads of research over the last 15 years have led to the concept that migraine
      is generated from a hyperexcitable brain. A variety of causes for
      hyperexcitability of the brain in migraine have been suggested. These causes
      include low cerebral magnesium levels, mitochondrial abnormalities, dysfunctions
      related to increased nitric oxide or the existence of a P/Q type calcium
      channelopathy. The better knowledge about migraine pathophisiology led us to
      discuss new treatment options. OBJECTIVES: The aim of the present study is to
      present an evidence-based review of some new drugs or some agents that even
      though available for a long time, are not frequently used. METHODS/RESULTS: We
      present a review of anticonvulsants with various mechanisms of action such as
      lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam and zonisamide. We
      also review natural products, like riboflavin and magnesium, botulinum toxin A, a
      specific CGRP antagonist and the anti-asthma medication montelukast, with
      pathophysiological discussion. CONCLUSIONS: We aimed to present an update of
      newer or less frequently used preventive migraine therapies, drugs that might
      reduce the burden and the costs of a disease that should be considered as a
      public health problem all around the world.

PMID- 12612764
TI  - Nutrition for the pediatric surgical patient: approach in the peri-operative
      period.
AB  - Nutrition is essential for maintenance of physiologic homeostasis and growth.
      Hypermetabolic states lead to a depletion of body stores, with decreased
      immunocompetence and increased morbidity and mortality. The purpose of this paper
      is to provide an update regarding the provision of appropriate nutrition for the
      pediatric surgical patient, emphasizing the preoperative and postoperative
      periods. Modern nutritional support for the surgical patient comprises numerous
      stages, including assessment of nutritional status, nutritional requirements, and
      nutritional therapy. Nutritional assessment is performed utilizing the clinical
      history, clinical examination, anthropometry, and biochemical evaluation.
      Anthropometric parameters include body weight, height, arm and head
      circumference, and skinfold thickness measurements. The biochemical evaluation is
      conducted using determinations of plasma levels of proteins, including album, pre
      albumin, transferrin, and retinol-binding protein. These parameters are subject
      to error and are influenced by the rapid changes in body composition in the peri
      operative period. Nutritional therapy includes enteral and/or parenteral
      nutrition. Enteral feeding is the first choice for nutritional therapy. If
      enteral feeding is not indicated, parenteral nutrition must be utilized. In all
      cases, an individualized, adequate diet (enteral formula or parenteral solution)
      is obligatory to decrease the occurrence of overfeeding and its undesirable
      consequences.

PMID- 12612765
TI  - Growth of cell populations of the intralobular duct in the submandibular gland of
      the mouse during postnatal development.
AB  - The growth of cell populations of intercalated ducts (ID), striated ducts (SD)
      and convoluted granular tubules (CGT) of the submandibular gland of the mouse was
      analyzed, during the period of 14 to 84 days of postnatal life, by means of
      morphometric methods. The absolute number of cells in each type of duct was
      submitted to curve fitting by means of linear regression analysis, and the
      obtained equations were: y = 13.22 + 0.87x for ID cells in the growth period of
      14 to 84 days; y = -18.82 + 3.69x and y = 176.03 - 1.93x for SD cells in the
      periods of growth and decay of cells, from 14 to 35 and 35 to 84 days,
      respectively; and y = 90.59 + 4.60x for CGT cells in the growth period of 28 to
      84 days. Based on these equations, the daily accumulation (growth rate) or loss
      (decaying rate) of cells in the period covered by each equation was calculated.
      Thus, the rate of growth of ID cells was 0.87 x 10(5) cells/day; the growth and
      decline rates of SD cells were 3.69 x 10(5) cells/day and -1.93 x 10(5)
      cells/day, respectively; and the growth rate of CGT cells was 4.60 x 10(5)
      cells/day. The analysis of the accumulation or loss of cells and the balance of
      cell populations in the various types of ducts revealed that SD cells were
      transformed into CGT cells and that the growth of these cells  population also
      depends on the formation of new cells through proliferative activity, probably in
      the intercalated ducts.

PMID- 12612766
TI  - Influence of irradiation on collagen content during wound healing in diabetic
      rats.
AB  - The aim of the present experimental research was to investigate the effects of
      electron irradiation on the collagen content and on the organization of the
      granulation tissue of skin, in diabetic rats. In this study, 48 Wistar rats were
      assigned to 4 groups: control, irradiated, diabetic and irradiated diabetic.
      First, diabetes mellitus was induced in the last two groups, by means of a single
      intravenous injection of streptozotocin. Fifteen days later, all animals
      underwent a surgery in order to create an excisional wound on their anterior
      dorsal skin. On the third post-operative day, only an approximately 1-cm-wide
      area around the wounds was exposed to 1 Gy of 6 MeV electron beam radiation,
      which was delivered in a single dose. Wound healing was examined by means of
      polarized light microscopy at 4-, 7-, 13- and 21-day time intervals after
      wounding. Based upon an essentially qualitative evaluation, it was possible to
      conclude that local electron irradiation and diabetes' associated dysfunctions
      caused a decrease in the collagen content of newly-formed tissue, which was more
      pronounced in irradiated diabetic animals. The macromolecular organization of
      granulation tissue was delayed in irradiated, diabetic and irradiated diabetic
      animals, in relation to what was observed in control animals.

PMID- 12612767
TI  - Measurement of the optical density of packable composites: comparison between
      direct and indirect digital systems.
AB  - The aim of this study was to measure the optical density of four packable
      composite resins with widths of 1, 2, 3 and 4 mm, by means of Digora (direct) and
      DentScan DentView (indirect) digital imaging systems, in order to compare both
      methods. Twenty acrylic plates, with the proposed thicknesses, were used, each
      one containing a sample of each resin. Each acrylic plate was radiographed three
      times, under a standardized technique. For the Digora system, an optical plate
      was used under each resin sample, and, for the DentScan DentView system, occlusal
      films were employed, totalizing 60 exposures for each system. Optical plates and
      films were scanned and three consecutive optical readouts were carried out,
      totalizing 1,440 readouts. The results were submitted to statistical analysis and
      revealed that the average optical density of the four resins always increased as
      thickness increased. Regarding the comparisons between the composite resins, in
      both analysis the resin with the greater optical density was Surefil followed by
      Prodigy Condensable, Alert and Solitaire . The correlations between the results
      of Digora and DentScan DentView were significant for the different thicknesses
      and materials. The observed tendency is that as the values obtained with the
      Digora system increase, so do the values obtained with DentScan DentView . While
      thickness increased, the values of optical density in both Digora and DentScan
      DentView tended to approach each other. The Digora system presented smaller
      amplitude between the results obtained in adjacent thicknesses.

PMID- 12612768
TI  - Morphologic analysis, by means of scanning electron microscopy, of the effect of
      Er: YAG laser on root surfaces submitted to scaling and root planing.
AB  - The purpose of this study was to morphologically evaluate, by means of scanning
      electron microscopy, the effects of Er:YAG laser on the treatment of root
      surfaces submitted to scaling and root planing with conventional periodontal
      instruments. Eighteen root surfaces (n = 18), which had been previously scaled
      and planed, were assigned to 3 groups (n = 6). The control Group (G1) received no
      further treatment; Group 2 (G2) was irradiated with Er:YAG laser (2.94 mum), with
      47 mJ/10 Hz, in a focused mode with air/water spray during 15 s and with 0.57
      J/cm of fluency per pulse; Group 3 (G 3) was irradiated with Er:YAG laser (2.94
      mum), with 83 mJ/10 Hz, in a focused mode with air/water spray during 15 s and
      with 1.03 J/cm2 of fluency per pulse. We concluded that the parameters adopted
      for Group 3 removed the smear layer from the root surface, exposing the dentinal
      tubules. Although no fissures, cracks or carbonized areas were observed, an
      irregular surface was produced by Er:YAG laser irradiation. Thus, the
      biocompatibility of the irradiated root surface, within the periodontal healing
      process, must be assessed.

PMID- 12612769
TI  - Periodontopathogens in the saliva and subgingival dental plaque of a group of
      mothers.
AB  - The aim of this study was to assess the periodontal condition and the presence of
      putative periodontal pathogens in 30 Brazilian mothers, aging 21-40 years (28.4  
      4.49 years), and in their children, aging 5-6 years, since mothers can be a
      source of pathogens and, thus, influence their children's bacteriological and
      clinical condition. Besides assessing the plaque index (PI), gingival index (GI)
      and pocket probing depth (PD), the survey analyzed four subgingival dental plaque
      samples from mothers and children, as well as a sample of stimulated saliva from
      mothers. Those samples were analyzed by means of the slot immunoblot (SIB)
      technique, in order to determine the presence of Actinobacillus
      actinomycetemcomitans (Aa), Prevotella nigrescens (Pn), Porphyromonas gingivalis
      (Pg) and Treponema denticola (Td). The mean values and standard deviations of the
      evaluated clinical variables for mothers and children were, respectively: 1.86  
      0.67 and 1.64   0.68 for PI, and 1.24   0.67 and 0.82   0.37, for GI. Only for
      mothers, the total PD was 1.81   0.69 mm, and the PD of four sites was 4.03  
      1.40 mm. The Wilcoxon test revealed significant difference (p < 0.05) between
      mothers and their children only as to GI. The most prevalent bacteria in mothers
      were, in decreasing order: Aa, Pn, Pg and Td. The children presented patterns of
      oral hygiene and bacterial profiles similar to those of their mothers, in spite
      of the fact that most of them did not present enough subgingival plaque for
      testing. The comparison between mothers' subgingival dental plaque and saliva
      samples revealed statistically significant differences (p < 0.05) for all
      bacteria, with greater positivity and scores in the saliva, which demonstrates
      that it is an indicator of oral colonization and can work as a vehicle for the
      transmission of periodontopathogens from mothers to their children.

PMID- 12612770
TI  - [Comparison between gingival and periodontal ligament fibroblasts from the same
      subject].
AB  - The objective of this study was to compare fibroblasts from the periodontal
      ligament (PLF) and gingival fibroblasts (GF) as to morphology, proliferation rate
      and protein synthesis. PLF and GF were explanted from tissues of the same
      patient. To characterize and compare the morphology of cells, PLF and GF were
      plated and analyzed under phase-contrast and optical microscopies. Proliferation
      rates were determined by means of automated counts carried out in days 1, 4, 7,
      15 and 21, and also by means of the bromodeoxyuridine labelling index (BrdU).
      Total protein content was analyzed by means of electrophoresis in 10%
      polyacrylamide gel and zimography containing gelatin as substrate. PLF were
      bigger and more elongated than GF in subconfluence and confluence conditions. The
      proliferative rate of PLF was higher than that of GF at 1, 4, and 7 days (p <
      0.05). At 15 and 21 days, there was no statistically significant difference as to
      the number of cells. PLF presented a significantly greater proliferative
      potential, in relation to GF (p < 0.05). The synthesis of protein in a period of
      24 hours was similar for both PLF and GF. Our results demonstrated that PLF and
      GF are different as to morphology and proliferative capacity, however, they do
      not differ as to protein synthesis.

PMID- 12612771
TI  - Cervical shaping in curved root canals: comparison of the efficiency of two
      endodontic instruments.
AB  - The aim of this study was to determine the removal of dentin produced by number
      25 (0.08) Flare files (Quantec Flare Series, Analytic Endodontics, Glendora,
      California, USA) and number 1 e 2 Gates-Glidden burs (Dentsply - Maillefer,
      Ballaigues, Switzerland), in the mesio-buccal and mesio-lingual root canals,
      respectively, of extracted human permanent inferior molars, by means of measuring
      the width of dentinal walls prior and after instrumentation. The obtained values
      were compared. Due to the multiple analyses of data, a nonparametric test was
      used, and the Kruskal-Wallis test was chosen. There was no significant difference
      between the instruments as to the removal of dentin in the 1st and 2nd
      millimeters. However, when comparing the performances of the instruments in the
      3rd millimeter, Flare files promoted a greater removal than Gates-Glidden drills
      (p > 0.05). The analysis revealed no significant differences as to mesial wear,
      which demonstrates the similar behavior of both instruments. Gates-Glidden drills
      produced an expressive mesial detour in the 2nd and 3rd millimeters, which was
      detected trough a statistically significant difference in the wear of this region
      (p > 0.05). There was no statistically significant difference between mesial and
      lateral wear when Flare instruments were employed.

PMID- 12612772
TI  - [Intratubular penetration of root canal sealers].
AB  - The purpose of this study was to evaluate the capacity of penetration of four
      endodontic sealers (Endo Fill, Sealapex, AH Plus and Pulp Canal Sealer) into
      dentinal tubules. Seventy-two extracted human maxillary anterior teeth were
      utilized in this study. The teeth were cleaned and shaped by means of the
      balanced-forces technique. The work length was established at 1 mm beyond the
      apex. Copious irrigation with 10 ml of 5.25% sodium hypochlorite was carried out.
      The teeth were divided in 8 groups - 4 had the smear layer maintained, and 4 had
      it removed. The smear layer was removed with a commercial solution of 17% EDTA,
      and the root canal system was flushed for 3 min. Finally, the roots were
      irrigated with 3 ml of 5.25% sodium hypochlorite. All teeth were sealed by means
      of the technique of the condensation wave with a medium nonstandardized cone.
      After filling, the roots were grooved, longitudinally split and examined under a
      scanning electron microscope (SEM). The focus of observation was the interface
      between the dentin and the sealing material. The Rickert sealer (Pulp Canal)
      presented the maximum penetration depths into the dentinal tubules, and Sealapex,
      the minimum. The Spearman test was used to determine whether there were
      significant differences between the groups. The removal of smear layer allowed
      significant penetration of the sealers (p <= 0.01).

PMID- 12612773
TI  - [Spectrophotometric and visual analysis of internal dental bleaching utilizing
      laser and heat as catalyzing sources].
AB  - This experiment aimed at evaluating, in vitro, the chromatic alteration of dental
      crowns submitted to internal bleaching. Color alterations were evaluated by means
      of spectrophotometric analysis and visual observation, at the following
      experimental phases: initial reading (LI), after-darkening reading (LE),
      immediate after-bleaching reading (LC), bleaching checked after 15 days (LC15)
      and after 30 days (LC30). After finding the values of L* (luminosity), a* and b*
      (shade and saturation), which made it possible to quantify the chromatic
      alterations of the specimens, color differences (deltaE ) were assessed by means
      of the CIE Lab Program. The statistical analysis of the results did not reveal
      any significant difference between conventional bleaching and bleaching activated
      by Er:YAG laser. No statistical difference was observed between the results after
      15 and 30 days, for both experimental groups.

PMID- 12612774
TI  - Wear and superficial roughness of glass ionomer cements used as sealants, after
      simulated toothbrushing.
AB  - The purpose of this study was to evaluate, in vitro, the properties (wear and
      roughness) of glass ionomer cements that could influence their indication as pit
      and fissure sealants. The utilized materials were Fuji Plus, Ketac-Molar and
      Vitremer (in two different proportions: 1:1 and  :1). The resin-based sealant
      Delton was used as control. By means of an electronic balance (precision of 10-4
      g), wear was measured in function of weight loss after simulated toothbrushing.
      Superficial roughness was determined by means of a surface roughness-measuring
      apparatus. The results revealed that diluted Vitremer and Fuji Plus were less
      resistant to toothbrushing abrasion and had the greatest increase in superficial
      roughness. Although in clinical situations luting or diluted ionomer cements are
      often utilized as alternatives to resin-based sealants, the resultsof this study
      revealed that the properties of those cements are worse than those of restorative
      ionomers, whichpresented results similar to those of the evaluated resin sealant.

PMID- 12612775
TI  - [Correlation between degree of conversion, microhardness and inorganic content in
      composites].
AB  - The purpose of this study was to evaluate the correlation between degree of
      conversion and microhardness in dental composites, as well as the effect of the
      inorganic content and type of photo-curing unit on these parameters. Three
      indirect composites (Artglass, Solidex and Zeta LC) were polymerized by means of
      three different laboratorial units (UniXS, Solidilite and an experimental
      device). For each material, fifteen samples were prepared using a metal matrix.
      The degree of conversion was analyzed by means of infrared spectroscopy, and
      microhardness was also assessed. The inorganic content was measured by means of
      thermogravimetric analysis (TGA). The Pearson s test was carried out in order to
      determine correlations. The degree of conversion of Artglass ranged from 37.5% to
      79.2%, and its microhardness, from 32.4 to 50.3 (r = 0.904). The degree of
      conversion of Solidex ranged from 41.2% to 60.4%, and its microhardness, from
      33.3 to 44.1 (r = 0.707). The degree of conversion and the microhardness of Zeta
      LC ranged from 62.0% to 78.0% and from 22.6 to 33.6, respectively (r = 0.710). It
      was concluded that the utilization of different photo-curing units caused
      variations on the degree of conversion, as a result of specific characteristics
      of each unit. For each material, there was strong correlation between the degree
      of conversion and microhardness. In addition, when different materials were
      compared, microhardness was more affected by filler content than by the degree of
      conversion.

PMID- 12612776
TI  - [Effect of the methods of photoactivation and insertion on the hardness of
      composite resins].
AB  - The purpose of this study was to assess the effect of methods of photoactivation
      and insertion on the Knoop hardness of the Z100 and Alert composite resins. The
      specimens were confected in cavities measuring 4 x 4 mm. The insertion of
      material was carried out by means of two methods: single-portion technique and
      insertion of two 2-mm-thick layers. When inserted in a single portion, the resin
      was compressed with a static load of 1 kgf on a glass slab recovered with a
      polyester strip, in order to remove the excess of material. After the removal of
      the glass slab and polyester strip, the materials were photoactivated by means of
      continuous light emitted by a XL 3000 unit with a light intensity of 520 mW/cm2
      for 40 seconds; double pulse, with light emission of 150 mW/cm2 for 10 seconds,
      plus 30 seconds with light intensity of 520 mW/cm2 emitted by a XL 3000 unit; and
      pulsatile light of 520 mW/cm emitted by the Optilux 400 unit, turned on for 2
      seconds and off for 2 seconds, during 60 seconds. The two layers of the material
      submitted to double insertion were photoactivated in the same conditions as the
      bulk-inserted material, and the excess of material was also removed from the
      second layer. After storage in a stove at 37 C and 100% relative humidity for 24
      hours, the specimens were embedded in polyester resin, trimmed and polished with
      sandpaper and diamond slurry. Knoop hardness was assessed in 4 depths with a HMV
      Shimadzu penetrometer under the load of 50 g during 30 seconds. The data
      submitted to ANOVA and Tukey's test revealed that Z100 presented greater hardness
      values; double insertion was better than single insertion; the hardness at the
      surface was smaller than that at the bottom of the specimen, regardless of other
      factors. For Z100, all activation methods produced smaller hardness values when
      double insertion was carried out. Meanwhile, for Alert, continuous light promoted
      statistical similarity between the insertion techniques. For Z100, there was
      statistical similarity between the activation methods only when the double
      insertion technique was employed. There was statistical similarity between the
      double-pulse and pulsatile-light techniques for Alert, when the single-portion
      insertion technique was carried out.

PMID- 12612777
TI  - [Dose-response effect of a dentifrice formulation with low fluoride concentration
      - an in vitro study].
AB  - The utilization of dentifrices with low fluorine concentration, for children
      under 6 years of age, has been suggested to reduce the risks of dental fluorosis.
      However, in order to have anticariogenic potential, the dentifrice should form
      loosely-bound fluorine (CaF2) on dental enamel. Considering that the formation of
      CaF2 is a function inversely related to pH, dentifrices with pH 5.5, with 275,
      550 and 1,100 ppm F (NaF/silica) were developed in order to assess dose-response
      effects. A comparison between those dentifrices, a placebo product and the Crest
      toothpaste (positive control - standard) was carried out. Furthermore, the
      bioavailability of dentifrices, in terms of formation of total fluorine (TF),
      CaF2, and fluorapatite (FA) on human dental enamel, was evaluated. An ion
      specific electrode was utilized for the determination of the dosage of fluorine.
      The results revealed that the dentifrice with 550 ppm F was more effective than
      both the placebo and the dentifrice with 275 ppm, presenting no difference in
      relation to the positive control (p > 0.05). A dose-effect correlation was
      observed as to the CaF2 formed. In conclusion, the modified formulation with 550
      ppm F can be considered as effective as the standard dentifrice with 1,100 ppm,
      and its utilization would be safer with regard to dental fluorosis.

PMID- 12612778
TI  - [Cross-sectional study of the evolution of the primary dentition: shape of dental
      arches, overjet and overbite].
AB  - The aim of this study was to evaluate the characteristics (shape of dental
      arches, overjet and overbite) of the primary dentition of 6- to 39-month-old
      children from four nurseries of Rio de Janeiro, Brazil, and to associate them to
      gender and dentition phase. It was observed that 68.6% of the children presented
      round upper arch, while 31.4% had triangular upper arch; 92% of the children
      presented U-shaped lower arch and 8% had square-shaped lower arch. Moderate
      overjet was observed in 38.3% of the children, and slight overjet, in 30.3%.
      Severe (26.6%) and negative (25.5%) overbites were the most prevalent modalities
      of that condition. There was no association between gender and the studied
      characteristics. There was statistically significant association between the
      dentition phase and the shape of the arch, overjet and overbite (p < 0.001, chi
      square test). It was possible to observe, in the present study, that early signs
      of malocclusions appeared when first primary molars erupted, as the posterior
      vertical dimension of occlusion increased. It was, thus, verified that early
      signs of malocclusions appear as the primary dentition develops. It is very
      important that the first dental visit occur during the first year of age, since
      it allows the pediatric dentist to prevent or carry out an early diagnosis of
      malocclusions in the primary dentition.

PMID- 12612779
TI  - [Effect of the discontinuity of the zygomatic arch on facial growth in young
      rats].
AB  - The results of experimental studies on the zygomatic arch during the growth
      period, through excisions or fractures, are controversial. In this study, the
      effect of a discontinuity of the zygomatic arch on facial growth was
      experimentally evaluated, without tissual damage or deviations. One-month-old
      rats were submitted to a surgical procedure in order to obtain a one-milimeter
      wide discontinuity of the right zygomatic arch. The left side served as a
      control. After three months, the rats were sacrificed, their skull and
      hemimandibles were dissected, and radiographs were obtained. Cephalometric
      measurements were carried out in order to assess the dimensions of the
      infratemporal fossa, maxilla and mandible, by means of a computer system. There
      was no significant difference between the experimental and control sides as to
      the measurements pertaining to the maxilla and mandible. Significant difference
      was observed in the anteroposterior length of the infratemporal fossa. It was
      concluded that the consequences of a discontinuity of the zygomatic arch on
      facial growth are restricted to the structure itself.

PMID- 12612780
TI  - [Dental caries in 12- and 15-year-old schoolchildren from public and private
      schools in Salvador, Bahia, Brazil, in 2001].
AB  - The aim of this paper was to assess the caries experience of 12- and 15-year-old
      schoolchildren from public and private schools in Salvador, Bahia, Brazil, and to
      identify the access of children to dental services and the coverage of such
      services, which might be related to differences between the groups. Cross
      sectional data were obtained from 3,313 clinical exams, which followed the WHO
      (1997) criteria for the diagnosis of dental caries. The analysis was carried out
      by means of the Student's t test, the chi-square test and analysis of covariance.
      There were no differences regarding DMFT and frequency of caries-free individuals
      between public and private schools. However, while F (filled teeth) was the most
      prevalent component of the index in subjects from private schools, M (missing
      teeth) was the most common in those from public schools. The access to dental
      services in the last year was the only variable associated to the differences
      between both groups. Thus, the importance of access to dental services and social
      benefits must be pointed out in order to guarantee equity in oral health.

PMID- 12612781
TI  - Kinetic comparisons of mesophilic and thermophilic aerobic biomass.
AB  - Kinetic parameters describing growth and decay of mesophilic (30 degrees C) and
      thermophilic (55 degrees C) aerobic biomass were determined in continuous and
      batch experiments by using oxygen uptake rate measurements. Biomass was
      cultivated on a single soluble substrate (acetate) in a mineral medium. The
      intrinsic maximum growth rate ( micro (max)) at 55 degrees C was 0.71+/-0.09 h(
      1), which is 1.5 times higher than the micro (max) at 30 degrees C (0.48+/-0.11
      h(-1)). The biomass decay rates increased from 0.004 h(-1) at 30 degrees C to
      0.017 h(-1) at 55 degrees C. Monod constants were very low for both types of
      biomass: 9+/-2 mg chemical oxygen demand (COD) l(-1)at 30 degrees C and 3+/-2 mg
      COD l(-1)at 55 degrees C. Theoretical biomass yields were similar at 30 and 55
      degrees C: 0.5 g biomass COD (g acetate COD)(-1). The observed biomass yields
      decreased under both temperature conditions as a function of the cell residence
      time. Under thermophilic conditions, this effect was more pronounced due to the
      higher decay rates, resulting in lower biomass production at 55 degrees C
      compared to 30 degrees C.

PMID- 12612782
TI  - Characterization of Aureobasidium pullulans isolated from airborne spores in
      Thailand.
AB  - Isolates from air in several locations in Thailand were identified as
      Aureobasidium pullulans PR with dark pigmentation (Loei province), A. pullulans
      SU with an unusual conidial apparatus (Chiangmai province), and A. pullulans CU
      with burgundy-red pigmentation (from a shady area in Bangkok). The internal
      transcribed spacer sequences of the rDNA of A. pullulans SU and A. pullulans CU
      confirmed that they were A. pullulans. Both A. pullulans CU and A. pullulans PR
      preferred 30 degrees C and pH 7.5 for exopolysaccharide (EPS) production, while
      A. pullulans SU preferred 25 degrees C and pH 6.5. All three isolates preferred
      glucose over sucrose and (NH(4))(2)SO4 over peptone for EPS production. Under
      optimal conditions, A. pullulans PR produced EPS yields of up to 0.225 g g(-1),
      followed by A. pullulans CU (0.185 g g(-1)) and A. pullulans SU (0.158 g g(-1)).
      Amylase activities were detected during the course of EPS production but
      gradually decreased as the EPS yields increased. IR spectra suggest that the EPS
      from these isolates was pullulan. EPS from the three isolates were partially
      sensitive to pullulanase.

PMID- 12612783
TI  - Production of exopolysaccharides from a thermophilic microorganism isolated from
      a marine hot spring in flegrean areas.
AB  - A thermophilic strain isolated from sea sand at Maronti, near Sant' Angelo
      (Ischia), is described. The organism grows well at an optimal temperature of 60
      degrees C at pH 7.0. The thermophilic bacterium, named strain 4004, produces an
      exocellular polysaccharide (EPS) in yields of 90 mg/l. The EPS fraction was
      produced with all substrates tested, although a higher yield was obtained with
      sucrose or trehalose as sole carbon source. During growth, the EPS content was
      proportional to the biomass. Three fractions (EPS1, EPS2, EPS3) were obtained
      after purification. Quantitative monosaccharide analysis of the EPSs revealed the
      presence of mannose:glucose:galactose in a relative ratio of 0.5:1.0:0.3 in EPS1,
      mannose:glucose:galactose in a relative ratio of 1.0:0.3:trace in EPS2, and
      galactose:mannose:glucosamine:arabinose in a relative ratio of 1.0:0.8:0.4:0.2 in
      EPS3. The average molecular mass of EPS3 was determined to be 1x10(6) Da. From
      comparison of the chemical shift values in (1)H and (13)C spectra, we conclude
      that EPS3 presents a pentasaccharide repeating unit.

PMID- 12612784
TI  - Antimicrobial efficacy of a silver-zeolite matrix coating on stainless steel.
AB  - A silver- and zinc-containing zeolite matrix (AgION) used as a coating for
      stainless steel was tested for antimicrobial efficacy against Escherichia coli
      25922, Staphylococcus aureus 25923, Pseudomonas aeruginosa 27853, and Listeria
      monocytogenes 7644. Assays were performed on flat coupon surfaces and in formed
      steel cups. AgION reduced microbial colony-forming units when compared to
      uncoated steel surfaces under all conditions tested. Percent reductions ranged
      from 84.536 to 99.999 after 4 h exposure, and from 99.992 to 100 after 24 h in
      all cases. The durability of the coatings declined most markedly when the coating
      had been applied with a wet process and scrubbed between uses with a test tube
      brush. Powder-coated surfaces cleaned with a towel retained a high degree of
      activity after five cycles of use.

PMID- 12612785
TI  - Protocol for laboratory testing of crude-oil bioremediation products in
      freshwater conditions.
AB  - In 1993, the Environmental Protection Agency, National Risk Management Research
      Laboratory (EPA, NRMRL), with the National Environmental Technology Application
      Center (NETAC), developed a protocol for evaluation of bioremediation products in
      marine environments [18]. The marine protocol was adapted for application in
      freshwater environments by using a chemically defined medium and an oil-degrading
      consortium as a positive control. Four products were tested using the modified
      protocol: two with nutrients and an oleophilic component; one with nutrients,
      sorbent, and organisms; and one microbial stimulant. A separate experiment
      evaluated the use of HEPES and MOPSO buffers as replacements for phosphate
      buffer. The oleophilic nutrient products yielded oil degradation similar to the
      positive control, with an average alkane removal of 97.1+/-2.3% and an aromatic
      hydrocarbon removal of 64.8+/-1.2%. The positive control, which received inoculum
      plus nutrients, demonstrated alkane degradation of 98.9+/-0.1% and aromatic
      degradation of 52.9+/-0.1%. The sorbent-based product with inoculum failed to
      demonstrate oil degradation, while the microbial stimulant showed less oil
      degradation than the positive control. Replacement of phosphate buffer with other
      buffers had no significant effect on one product's performance. Differences in
      product performance were easily distinguishable using the protocol, and
      performance targets for alkane and aromatic hydrocarbon degradation are
      suggested.

PMID- 12612786
TI  - Purification of alternanase by affinity chromatography.
AB  - The enzyme alternanase, produced by Bacillus sp. NRRL B-21195, hydrolyzes
      alternan, a polysaccharide produced by certain strains of Leuconostoc
      mesenteroides that consists of glucose linked by alternating alpha(1-->6),
      alpha(1-->3) linkages. The main product of enzymatic hydrolysis by alternanase is
      a novel cyclic tetrasaccharide of glucose that also has alternating linkages
      between the glucose moieties. An improved purification scheme for alternanase has
      been developed that incorporates the use of isomaltosyl units linked to agarose
      for selectively binding the alternanase enzyme. Bound enzyme was eluted with 0.5
      M sodium chloride and was nearly pure after this procedure. When followed by
      preparative isoelectric focusing, a single band of 117 kDa was measured when the
      purified protein was analyzed by HPLC size-exclusion chromatography/multiangle
      light scattering. The purification procedure can be scaled to permit large
      quantities of enzyme to be purified in high (36%) yield.

PMID- 12612787
TI  - Scale-up of stirring as foam disruption (SAFD) to industrial scale.
AB  - Foam disruption by agitation-the stirring as foam disruption (SAFD) technique-was
      scaled up to pilot and production scale using Rushton turbines and an up-pumping
      hydrofoil impeller, the Scaba 3SHP1. The dominating mechanism behind SAFD-foam
      entrainment-was also demonstrated at production scale. The mechanistic model for
      SAFD defines a fictitious liquid velocity generated by the (upper) impeller near
      the dispersion surface, which is correlated with complete foam disruption. This
      model proved to be scalable, thus enabling the model to be used for the design of
      SAFD applications. Axial upward pumping impellers appeared to be more effective
      with respect to SAFD than Rushton turbines, as demonstrated by retrofitting a
      12,000 l bioreactor, i.e. the triple Rushton configuration was compared with a
      mixed impeller configuration from Scaba with a 20% lower ungassed power draw. The
      retrofitted impeller configuration allowed 10% more broth without risking
      excessive foaming. In this way a substantial increase in the volumetric
      productivity of the bioreactor was achieved. Design recommendations for the
      application of SAFD are given in this paper. Using these recommendations for the
      design of a 30,000 l scale bioreactor, almost foamless Escherichia coli
      fermentations were realised.

PMID- 12612788
TI  - Significance of the non-oxidative route of the pentose phosphate pathway for
      supplying carbon to the purine-nucleotide pathway in Corynebacterium
      ammoniagenes.
AB  - To evaluate the strategy of supplying ribose 5-phosphate to the purine-nucleotide
      pathway exclusively via the nonoxidative route, the glucose 6-phosphate
      dehydrogenase gene zwf was disrupted in inosine- and 5'-xanthylic acid-producers
      of Corynebacterium ammoniagenes. In both producers, interruption of the oxidative
      route caused a decrease in production yields of about 50%. Attempts to increase
      the capacity of the nonoxidative route through overexpression of the
      transketolase or transaldolase gene in the zwf mutants led to no discernable
      effects on production, indicating that, in C. ammoniagenes, the nonoxidative
      route alone cannot provide sufficient ribose 5-phosphate for high-level
      production, although nonoxidative synthesis of the precursor is possible.

PMID- 12612789
TI  - Cost of managing digital diagnostic images for a 614-bed hospital.
AB  - The cost of recording and archiving digital diagnostic imaging data is presented
      for a Radiology Department serving a 614 bed University-Hospital with a large
      outpatient population. Digital diagnostic imaging modalities include computed
      tomography, nuclear medicine, ultrasound, and digital radiography. The archiving
      media include multiformat video film recordings, magnetic tapes, and disc
      storage. The estimated cost per patient for the archiving of digital diagnostic
      imaging data is presented.

PMID- 12612791
TI  - The Lichtenstein repair in 2002: an overview of causes of recurrence after
      Lichtenstein tension-free hernioplasty.
AB  - Lichtenstein tension-free hernioplasty began in 1984. Based on our own mistakes,
      in the late 1980s, we established a set of key principles and reported the causes
      of our recurrences. Recently, other authors analyzing the causes of their own
      recurrences with tension-free repair are drawing the same conclusions. This
      indicates that others are repeating our previously reported mistakes. To prevent
      recurrence, the mesh size was increased to 7.5x15 cm to extend well beyond the
      boundary of the inguinal floor and give the mesh a dome-shaped laxity to
      compensate for the increased intra-abdominal pressure and mesh shrinkage. Wide
      extension of the mesh beyond the inguinal floor and the dome-shaped laxity of the
      mesh served to further reduce recurrence rate. Following the key principles of
      the Lichtenstein tension-free hernioplasty, which can be facilitated by using a
      recently developed prosthesis that addresses all the key principles of the
      procedure, achieves the best result.

PMID- 12612790
TI  - Wrapping the visceral sac into a bilateral mesh prosthesis in groin hernia
      repair.
AB  - Almost 40 years of lucky existence is enough time for questioning and/or updating
      the Stoppa method for hernia repair. In this paper, the author reports the
      circumstances of the birth of this method more than 30 years ago, recalls its
      innovative principles, describes its technical aspects, and exposes its good
      results. Not simply approving old concepts, the author concludes with critical
      remarks with regard to a so-called political correctness of today's groin hernia
      repair, which gives great importance to reducing patient trauma arising from
      surgery. For belief without doubt can be wrong belief!

PMID- 12612792
TI  - Breaking strength and tissue elasticity after Shouldice repair.
AB  - There are few objective studies in the surgical literature on the strength of an
      inguinal hernia repair during the immediate postoperative period. To provide the
      relevant advice and recommendations on physical activities during the period of
      convalescence, a study on the strength of the Shouldice repair was carried out.
      Twenty-eight Shouldice repairs were performed on 17 fresh human cadavers (11
      male, 17 female, mean age 79.9+/-6.2 years). Following the excision of the
      transversalis fascia, the breaking strength and tissue elasticity were measured
      using an automated test device. All tissue ruptures occurred outside the limits
      of the Shouldice repair. Mean breaking strength was 53.9+/-20.1 N, showing no
      significant differences between males and females. The measured overall
      elasticity of tissue samples was 4.6+/-2.3 N/cm. Again there was no marked
      difference between genders. However, breaking strength and elasticity were found
      to be significantly affected by age. The Shouldice repair demonstrated a higher
      tensile strength when compared to the surrounding tissue. Strength after a
      Shouldice repair of the floor of the inguinal canal was found to be several times
      higher than could be attained under physiologic conditions. Therefore, an early
      postoperative return to normal activity can be recommended.

PMID- 12612793
TI  - Joint mobility in adult patients with groin hernias.
AB  - The basic mechanisms of hernia formation remain mostly unknown, but several
      studies suggest that a connective-tissue pathology, affecting mainly the collagen
      metabolism, could play a role in the genesis of groin hernias. It would be
      interesting to know if this pathology can express some clinical signs other than
      the hernia. Our study focused on the joint mobility and the diagnostic criteria
      for benign joint hypermobility syndrome. Sixty male adult patients with inguinal
      hernias and 62 control subjects without hernias, age-matched, were compared,
      taking into account anamnestic criteria (family history of groin hernia, joint
      sprain, joint dislocation, skin striae, major arthralgia) and joint mobility.
      This was assessed by using Beighton criteria and measuring the range of movement
      of five joints (extension of the fifth finger, thumb, wrist, elbow, and knee).
      The frequency of the positive anamnestic criteria was not statistically different
      between the two groups. Nevertheless, a family history of groin hernia was
      observed in 25% of the hernia patients, against 16% in the control subjects (
      P=0.23). The mean Beighton score was 0.30 in the hernia patients and 0.29 in the
      control population. The movement range of the five examined joints was similar in
      the two groups. In conclusion, patients with a groin hernia presented neither
      joint hypermobility nor clinical evidence of a benign joint hypermobility
      syndrome. Although abnormal collagen metabolism is likely implicated in hernia
      formation, this pathology does not seem to have clinical repercussion on joint
      mobility.

PMID- 12612794
TI  - Evaluation of pain and disability in plug repair with the aid of a personal
      digital assistant.
AB  - The purpose of this paper is to illustrate the method of real-time data
      collection using a hand-held personal digital assistant (PDA) in the operating
      suite, hospital, and office. The technique for the placement of a round Atrium
      ProLite self-forming, layered polypropylene plug in 155 hernia repairs is
      described. The study measured postoperative pain by the number of pills used
      (6.6) and categorizes patient return to work according to sedentary, manual, and
      standing with an average return to work time of 15.6 days for unilateral repair
      and 20.4 days for bilateral repair. Return to normal daily activity was within
      22.3 days for unilateral- and 28.5 days for bilateral repair.

PMID- 12612795
TI  - Structural alterations of prosthetic meshes in humans.
AB  - The use of prosthetic mesh in abdominal wall hernia surgery is a well-accepted
      practice. What is not settled, however, is the type of prosthesis that best suits
      the purpose. The narrow choice today means a prosthesis of polyester or
      polypropylene. These are available in many designs, configuration of weave,
      thickness of weave and strand, and size of pore. There has been a pervasive
      feeling that these materials "shrink". To what extent they do has not been
      accurately defined. This study was designed to measure such "shrinkage".
      Interestingly, our measurements revealed that prosthetic meshes could "expand" as
      well as "shrink". The extent to which they do varies between -40% and 58.5%.
      Whereas it was felt that fibrocyte activity and its eventual scar formation
      accounted for the "shrinkage" of the mesh, we have discovered that structural
      alterations in the size of the mesh pores can be affected by distilled water,
      saline, blood, formalin, bleach, as well as in vivo implantation. Prosthetic
      meshes are, therefore, not the inert materials they are claimed to be and can
      expand as well as shrink. We have, unfortunately, not been able to correlate the
      degree or direction of change to any known parameter.

PMID- 12612796
TI  - Inguinal hernioplasty: the gold standard of hernia repair.
AB  - On the basis of a critical review of 936 inguinal hernioplasties performed in 8
      years, the authors present their good long-term results with tension-free
      techniques including the original Lichtenstein technique, Lichtenstein with a
      sutured mesh and annulorrhaphy of the deep inguinal ring, and Lichtenstein with
      plug. The only two recurrences in this case series occurred with the original
      technique. Suturing of the mesh and deep inguinal ring annulorrhaphy proved to be
      reliable and inexpensive. Results were equivalent with the use of the plug,
      despite the presence of an additional foreign body. In conclusion, the results
      obtained with the three variants are practically equivalent, and the choice of
      technique may depend on the preference and experience of the surgeon.

PMID- 12612797
TI  - Comparison of PTFE, pericardium bovine and fascia lata for repair of incisional
      hernia in rat model, experimental study.
AB  - Incisional hernia is a frequent complication of abdominal surgery developing in
      11-20 % of patients undergoing an abdominal operation. Regarding morbidity and
      loss of manpower, incisional hernias continue to be a fundamental problem for
      surgeons. In this experimental study, three commonly used mesh materials (Goretex
      PTFE; Tutoplast Fascia lata; Tutopatch Pericardium bovine) were compared
      according to effectiveness, strength, adhesion formation, histological changes,
      and early complications. Three groups, each consisting of 14 rats, have been
      formed as group A: polytetrafluoroethylene (PTFE), group B: pericardium bovine
      and group C: fascia lata. Evaluations were achieved at the end of the first and
      second postoperative week, respectively. Adhesion formation, wound maturation,
      bursting pressure, and tensile strength were evaluated. No statistically
      significant difference regarding adhesion formation was observed between groups
      although adhesion formation was less significant in PTFE and pericardium bovine
      groups than in the fascia lata group. Bursting pressure and tensile strength
      values were significantly higher in PTFE group than in the fascia lata group (
      P<0.05). No statistically significant difference was observed between groups
      regarding wound maturation. In this experimental model, PTFE and pericardium
      bovine were found to be superior to fascia lata in abdominal wall repair.

PMID- 12612798
TI  - Ventral hernia repair: a study of current practice.
AB  - Ventral wall hernias are common; despite this, there are no guidelines on the
      best surgical management. The aim of this study was to examine the types of
      repair in use for abdominal wall hernias in the West of Scotland over a 3-month
      period. Data were gathered on 120 patients. There were 60 incisional, 32
      umbilical, and 28 epigastric hernias. The main indication for repair was pain
      (78%), while 12 patients (10%), presented acutely with incarceration or
      strangulation. The most common method of repair was sutured (55%), followed by
      mesh (29%) and Mayo repair (16%). There was no correlation between use of mesh
      and hernia size or whether repair was for a recurrent hernia. Surgical practice
      varies widely in the repair of ventral wall hernias. Clinical trials are required
      to establish the best method of repair for this common condition.

PMID- 12612799
TI  - Intrascrotal hernia of the ureter and fatty hernia.
AB  - Intrascrotal hernia of the ureter is a rare event. We describe here one such
      case. There are two anatomic types of such ureteral hernias. The paraperitoneal
      type has a peritoneal indirect sac, which pulls the ureter with it. The
      extraperitoneal ureteral hernia is without a peritoneal sac. In such cases, which
      are almost always indirect hernias, there is usually a large amount of fat. It
      is, in fact, retroperitoneal fat, which slides, and pulls the ureter with it by
      gravity. Such a case is a genuine prolapse of the retroperitoneal structures.
      This anomaly, which has been rarely studied, is worth knowing about, because the
      ureter may be damaged during hernia dissection. The surgeon should be cautious
      when discovering huge fatty hernias, and should avoid the excision of fat and
      simply return the fatty mass to its normal place after its separation from the
      cord.

PMID- 12612800
TI  - Amyand's hernia: a report of two cases.
AB  - In 2000-2001 two patients with acute appendicitis in the right inguinal hernia
      (Amyand's hernia) and the symptoms of incarcerated hernia were operated on in
      emergency. One patient with the symptoms of local peritonitis was subjected to
      hernioplasty and appendectomy. The second underwent midline inferior laparotomy,
      because of diffuse peritonitis with appendectomy and hernioplasty. Both patients
      were operated by Shouldice's method. None of the patients developed recurrent
      disease. The presented cases point to the necessity of considering acute
      appendicitis in the differential diagnosis of incarcerated right inguinal hernia.

PMID- 12612801
TI  - Laparoscopic repair of congenital diaphragmatic hernia with prosthesis: a case
      report.
AB  - We report here our experience in the treatment of a large congenital
      diaphragmatic hernia, an uncommon pathology, approachable by laparoscopy. The
      patient was a 33-year-old woman with trisomy 21 syndrome, who only complained of
      colicky abdominal pain and a cough for 7 months before the hospitalization.
      Thoracic and abdominal CT scans showed a large anteromedial diaphragmatic hernia
      with slippage of the colon into the mediastinum and posterior displacement of the
      cardiovascular structures. The patient underwent laparoscopic repair of the
      hernia. The colon was put back in the abdomen; the defect (8x4 cm) was repaired
      by a Composix mesh (PTFE-polypropylene), fixed to the diaphragm by nonabsorbable
      stitches and staples. The patient was discharged on the third postoperative day.
      The postoperative course was uneventful. Follow-up at 18 months didn't show any
      complications or recurrence. We believe laparoscopic repair of diaphragmatic
      hernia to be the elective surgical choice, because of its technical feasibility
      and certain intra- and postoperative advantages.

PMID- 12612802
TI  - Observation of an excess of fragile-X premutations in a population of males
      referred with spinocerebellar ataxia.
AB  - Premutations of the fragile-X (FRAXA) gene were thought to have no clinical
      effects until recent reports of an increased incidence of premature ovarian
      failure in females and a late-onset neurological disorder in males. These
      patients were identified from families including typical fragile-X males with a
      full mutation. By analysing a cohort of patients with neurodegenerative disorders
      referred for genetic analysis of spinocerebellar ataxia genes, we have found that
      3 of 59 males carry the premutation. Our patients extend the phenotype associated
      with the FRAXA premutation and indicate that it may account for a proportion of
      undiagnosed neurodegenerative disorders.

PMID- 12612805
TI  - Occan, a novel transposon in the Fot1 family, is ubiquitously found in several
      Magnaporthe grisea isolates.
AB  - We investigated a DNA fragment and its flanking region deleted in the spontaneous
      Pi-a virulent mutant of Magnaporthe grisea Ina168. A new transposon-like sequence
      was identified from a region adjacent to the deleted fragment and was named
      Occan. Occan contained a 2,259-bp ORF interrupted by one 63-bp intron and had
      both a TA dinucleotide and 77 bp of perfect inverted repeats at both termini,
      without direct repeats. These features indicated that Occan is a member of the
      Fot1 family. RT-PCR analysis confirmed the expression of the putative transposase
      and the presence of an intron. Southern analysis of pulse-field gel
      electrophoresis-separated chromosomes indicated that Occan was dispersed in all
      chromosomes of the rice pathogen, Ina168. Copy numbers of Occan were also
      preserved in a host-specific manner amongst M. grisea isolates. In particular,
      rice pathogens contained a large number of the element inserted into their
      genome. Phylogenetic analysis with other known members of the Fot1 family
      revealed that Occan was dissimilar to any other known elements and it is thus
      proposed that Occan be separated to a new subfamily.

PMID- 12612804
TI  - Ionizing irradiation effects on S-phase in checkpoint mutants of the yeast
      Saccharomyces cerevisiae.
AB  - In mammalian cells, gamma-irradiation activates checkpoint controls to delay
      entry into, or passage through S-phase, while chronic exposure to methyl
      methanesulfonate or hydroxyurea causes a similar delay in yeast. In yeast, at
      least five genes are involved: RAD9, RAD17, RAD24, RAD53 and MEC1, a homologue of
      ATM. Here, using flow cytometry analysis and alkaline sucrose gradient
      centrifugation of labeled, newly made DNA, we demonstrate, in synchronized RAD
      wild-type Saccharomyces cerevisiae cells, that: (1) gamma-irradiation at START
      delays entry into S-phase, (2) irradiation shortly before or during early S-phase
      delays completion of S-phase and (3) the latter response is largely a consequence
      of replicon initiation inhibition. The delay produced by irradiation during early
      S-phase depends on the function of the checkpoint genes RAD9, RAD17, RAD24,
      RAD53, MEC1 and MEC3. However, at least four, RAD17, RAD53, MEC1, MEC3, are not
      needed to delay S-phase progression when cells are irradiated shortly before S
      phase begins.

PMID- 12612806
TI  - Characterization of spontaneous mutants of Magnaporthe grisea expressing stable
      resistance to the Qo-inhibiting fungicide azoxystrobin.
AB  - The class of Qo-inhibiting fungicides (QoIs) act as respiration inhibitors by
      binding to the Qo center of cytochrome b. The longevity of these fungicides has
      been challenged by the selection of fungal sub-populations resisting high doses
      of QoI fungicides, with a G143A amino acid exchange in the cytochrome b target
      site identified as the most common cause of resistance. In contrast, the
      mechanism of alternative respiration, as another mechanism of fungal QoI
      resistance, has thus far not been affiliated with practical resistance. In the
      present study, azoxystrobin-resistant mutants of Magnaporthe grisea were
      generated and characterized. Emergence of these spontaneous mutants was
      facilitated when resting melanized mycelia were allowed to escape full inhibition
      by azoxystrobin. This escape was related to the intactness of alternative
      respiration, indicating that residual expression of this rescue mechanism was
      involved in the spontaneous emergence of target-site mutants. The two mutants
      characterized resisted high doses of the QoI, azoxystrobin, with resistance
      factors exceeding 1,000. Two different mutations of the cytochrome b gene were
      identified as exchanges of guanine, leading to a G143A or a G143S amino acid
      exchange. Resistance of both target-site mutants remained stable during four
      consecutive disease cycles in the absence of azoxystrobin. Several parameters
      tested to measure fitness penalties inherent to the mutational changes revealed
      that the G143A mutant was not compromised. In contrast, the conidia production of
      the G143S mutant was significantly lower under both saprophytic and pathogenic
      conditions of reproduction.

PMID- 12612807
TI  - An improved transformation protocol for the human fungal pathogen Candida
      albicans.
AB  - Commonly used protocols for the transformation of the dimorphic human fungal
      pathogen Candida albicans rely on established methods for the yeast Saccharomyces
      cerevisiae. With respect to transformation efficiency, however, there is a great
      difference between these two organisms when using the lithium acetate procedure.
      Here we present a modified version of this protocol for use with C. albicans.
      Among the different parameters tested, two turned out to be particularly relevant
      and, when combined, resulted in an up to 10-fold increase in transformation
      efficiency (400-500 integrative transformants) compared with previous protocols:
      first, adjusting the heat shock applied to the cells to 44 degrees C for C.
      albicans instead of 42 degrees C for S. cerevisiae and, second, treating C.
      albicans cells with lithium acetate in an overnight incubation instead of for 30
      min as used for S. cerevisiae. With these modifications, the lithium acetate
      procedure becomes a very efficient and reliable tool for C. albicans
      transformation.

PMID- 12612803
TI  - Strategies for the identification of virulence determinants in human pathogenic
      fungi.
AB  - The incidence of fungal infections is increasing in different countries. The
      current available therapy of these infections does not satisfy all requirements
      in terms of specificity and therapeutic index, a fact that has stimulated the
      scientific community to identify fungal virulence determinants. Several
      pathogenic fungi are opportunistic and, therefore, identification of virulence
      genes is difficult, given their close relationship with host cells. In recent
      years, the development of genetic tools in several pathogenic fungi has enabled
      the development of genetic strategies for their identification. These include
      several strategies based on the phenotypic analysis of strains or environmental
      conditions in which the expression of the putative gene(s) is either altered or
      deleted; and this is accomplished through the development of in vitro or in vivo
      systems. In the near future, this research will produce a better picture of
      fungal pathogenesis and therefore define novel promising targets in antifungal
      therapy.

PMID- 12612809
TI  - PET-CT: accuracy of PET and CT spatial registration of lung lesions.
AB  - PET-CT scanners offer the unique ability to acquire PET and CT data with rapid
      full body registration. The purpose of this study was to evaluate the accuracy of
      spatial registration between PET and CT data in patients with fluorine-18 fluoro
      2-deoxy- D-glucose (FDG)-avid lung lesions. PET, CT and fused PET-CT images from
      244 consecutive clinical patients undergoing whole-body FDG PET-CT imaging (GE
      Discovery LS, CT attenuation correction, OSEM reconstruction) were evaluated.
      Inclusion criteria for this analysis were lung lesions clearly defined on both
      PET and CT, lesion diameter less than 5 cm and clear borders. Patients were
      allowed to breathe freely during both PET and CT image acquisitions. The spatial
      coordinates of the visually estimated centers of the lesion were determined
      independently for PET and CT images and compared. Thirty-six patients (26
      females, 10 males) with a total of 48 lesions were included (19 lung cancer
      patients with 26 lesions, 17 patients with 22 lung metastases). The average lung
      lesion diameter was 15.6+/-9 mm. The mean distance between the center of lesions
      independently determined for both PET and CT was 7.55+/-4.73 mm. Misregistration
      tended to be more pronounced in the lower lungs (10.2+/-6.55 mm) than in the
      upper lungs (6.67+/-4.28 mm) ( P=0.063). Misregistration also tended to be
      slightly more pronounced in the left lung (8.33+/-5.05 mm) than in the right lung
      (6.25+/-3.92 mm) ( P=0.059). In conclusion, with a dedicated PET-CT scanner and
      this clinically practical imaging algorithm, registration is usually accurate,
      but spatial misregistration of primary lung lesions does occur.

PMID- 12612808
TI  - Transformation of Pythium aphanidermatum to geneticin resistance.
AB  - Conditions for the production of protoplasts and gene transfer in Pythium
      aphanidermatum were investigated. Efficient protoplast generation was possible
      after culture of mycelium in potato dextrose broth followed by digestion with
      0.5% (w/v) each of cellulase and beta- d-glucanase. Plasmid pHAMT35N/SK encoding
      the nptII gene under control of the Ham34 promoter from the oomycete Bremia
      lactucae was used to define electroporation parameters for gene transfer. A
      square-wave electroporation pulse of 2500 V/cm at 50 microF capacitance
      reproducibly produced transformants, albeit at low efficiency (0.1-0.4
      transformants from approximately 10(5) regenerable protoplasts per microgram of
      DNA). Thirty-two independent transformants exhibited wild-type growth on potato
      dextrose agar amended with geneticin at 50 microg/ml, a concentration that near
      completely inhibited the growth of untransformed P. aphanidermatum. Southern blot
      analysis indicated that transforming DNA was integrated into the oomycete genome
      and that the DNA was stably inherited through sporogenesis. Growth on geneticin
      free media, the ability to form zoospores or oospores, and the ability to cause
      disease in sugarbeet seedlings in the laboratory were indistinguishable between a
      subset of the transformed isolates and the progenitor isolate 898B. Co
      electroporation of pHAMT35N/SK with plasmid pACT-GUS encoding the Escherichia
      coli gusA gene controlled by oomycete transcriptional promoter and terminator
      sequences or with pEGFP encoding enhanced green fluorescent protein under the
      control of the immediate early promoter from the mammalian cytomegalovirus
      produced, respectively, stable beta-glucuronidase and transient expression of
      blue-green fluorescence. Application of the technique to studies on the
      biochemical basis for pathogenesis in this agriculturally important group of
      fungi is discussed.

PMID- 12612810
TI  - A comparison of radionuclide thyroid angiography, (99m)Tc-MIBI scintigraphy and
      power Doppler ultrasonography in the differential diagnosis of solitary cold
      thyroid nodules.
AB  - We prospectively studied 43 patients with solitary cold thyroid nodules greater
      than 1.5 cm in diameter to determine the comparative diagnostic value of
      radionuclide thyroid angiography (RTA), technetium-99m methoxyisobutylisonitrile
      ((99m)Tc-MIBI) scintigraphy and power Doppler ultrasonography (PDUS) in the
      differentiation of benign and malignant thyroid nodules. Perfusion of the nodules
      in RTA was compared with the perfusion in the surrounding normal thyroid tissue
      and classified as follows: 0, avascular; 1, hypovascular; 2, isovascular; 3,
      hypervascular. (99m)Tc-MIBI uptake in the nodules compared with that in
      surrounding thyroid tissue was scored for both early and delayed images as
      follows: 0, cold; 1, decreased; 2, equal; 3, increased. PDUS patterns were
      classified as nodule vascularisation patterns. The malignancy criteria were set
      as follows: hypervascular nodule with rapid washout in RTA; complex ring sign
      with anarchic structure or delta sign in PDUS, and positive retention and
      increased uptake in the nodule in the early and delayed (99m)Tc-MIBI images.
      These data were compared with the histopathological results. Histology revealed
      thyroid carcinoma in nine patients (five cases of papillary carcinoma, three of
      follicular carcinoma and one of medullary carcinoma) and benign conditions in 34
      patients (30 cases of nodular goitre, three of lymphocytic thyroiditis and one of
      follicular adenoma). Sensitivity, specificity and accuracy were, respectively,
      0.89, 1.00 and 0.97 for RTA, 1.00, 0.76 and 0.81 for PDUS, and 0.67, 0.91 and
      0.86 for (99m)Tc-MIBI scintigraphy (when nodules with increased uptake in both
      the early and the delayed images and a positive retention index were considered
      as malignant). RTA, (99m)Tc-MIBI scintigraphy and PDUS could be helpful in the
      preoperative assessment of solitary cold thyroid nodules. In this study, RTA was
      found to be the most accurate and specific method for differentiation of
      malignant from benign thyroid nodules.

PMID- 12612811
TI  - Peritumoural versus subareolar administration of technetium-99m nanocolloid for
      sentinel lymph node detection in breast cancer: preliminary results of a
      prospective intra-individual comparative study.
AB  - The scintigraphic detection of sentinel lymph nodes (SNs) in early-stage breast
      cancer is a widely accepted diagnostic method. However, which radiotracer
      administration mode should be used is still controversial. This prospective study
      aimed to intra-individually compare the detection rates obtained after
      peritumoural versus subareolar injection with regard to SN number and
      localisation. Fifty-one women (age, 32-76 years) with breast cancer were
      investigated on two consecutive days. On day 1, 140-400 MBq technetium-99m
      nanocolloid was injected along the peripheral tumour margins. Static
      lymphoscintigrams of the axilla, thorax and neck were taken in various views 1
      and 19 h p.i. On day 2, 10 MBq (99m)Tc-nanocolloid was injected subareolarly in
      the clock position of the tumour and dynamic and static scans were performed
      immediately. Thereafter, 30 MBq (99m)Tc-nanocolloid was administered peri
      subareolarly and lymphoscintigrams were acquired in a dynamic and static manner.
      In 49/51 women, the different injection techniques disclosed the identical number
      and location of SNs in the axilla. In seven patients, the peritumoural injection
      detected additional SNs in the parasternal group. Axillary SNs were detected as
      early as 2-15 min following subareolar injection, both in the clock position and
      peri-subareolarly, as compared with about 1 h after peritumoural administration.
      Sixteen patients showed at least one tumour-positive SN, and nine also had tumour
      positive non-SNs. One patient with a tumour-negative SN, visualised concordantly
      by both subareolar and peritumoural administration, demonstrated two metastatic
      non-SNs, yielding a false-negative rate of 5.9%. In conclusion, a simple
      subareolar injection in the clock position is sufficient for SN detection in
      breast cancer, if it is accepted that parasternal lymph node detection has no
      therapeutic consequences.

PMID- 12612812
TI  - Radiological diagnosis of the constitutional disorders of bone. As easy as A, B,
      C?
AB  - Although many constitutional disorders of bone are individually rare,
      collectively they make up a large group of disorders. They are broadly classified
      into osteochondrodysplasias and dysostoses. Because of the rarity of some of
      these conditions, they can be difficult to diagnose. Members of the International
      Dysplasia Group meet regularly to update and clarify the nomenclature. The last
      meeting was in Oxford in 2001. This article attempts to highlight the differences
      between the osteochondrodysplasias and the dysostoses, and provides a systematic
      approach to their radiological diagnosis.

PMID- 12612813
TI  - A longitudinal study using tibial ultrasonometry as a bone assessment technique
      in children with acute lymphoblastic leukaemia.
AB  - BACKGROUND: Several longitudinal studies have shown contradictory results
      regarding the change in bone status in children with acute lymphoblastic
      leukaemia (ALL) using dual-energy X-ray absorptiometry as the bone assessment
      technique. OBJECTIVE: To determine whether a more recently developed bone
      assessment technique which does not use radiation, tibial ultrasonometry, can be
      used for the detection of short-term changes. PATIENTS AND METHODS: From January
      1997 to February 2001, 37 patients (25 boys, 12 girls, mean age 9.0 years, range
      3.0-16.8 years) were included in a longitudinal study to assess changes in bone
      status induced by the disease itself and/or treatment. Of these 37 patients, 35
      had a measurement at the start of therapy (t0), 26 at 6 months (t6), 24 at 12
      months (t12), 11 at 24 months (t24) and 9 at 36 months (t36). For assessment of
      bone mass, the tibial ultrasound (US) device SoundScan Compact was used, which
      measures the speed of sound (SOS) along the cortex of the tibia over a fixed
      length of 5 cm at the mid-tibial point. RESULTS. The SOS standard deviation (SD)
      scores were significantly lower at t6, t12, t24 and t36 than at baseline (t0).
      The biggest change was found between t0 and t6. During follow-up, no significant
      correlation was found between changes from baseline of height SD scores and SOS
      SD scores, indicating that tibial ultrasonometry was not measuring growth. After
      ending therapy (t36), no further growth retardation was found. CONCLUSIONS: Short
      term changes of SOS SD scores in children with ALL can be detected by tibial
      ultrasonometry. Tibial ultrasonometry measures a change in bone status, not
      growth.

PMID- 12612814
TI  - The pattern of skeletal anomalies in the cervical spine, hands and feet in
      patients with Saethre-Chotzen syndrome and Muenke-type mutation.
AB  - BACKGROUND: Saethre-Chotzen syndrome (SCS) and Muenke-type mutation (MTM) are
      complex syndromes with craniosynostosis and skeletal anomalies including
      syndactyly, carpal and tarsal fusions, and cervical spine abnormalities.
      OBJECTIVE: In this study, we analysed radiographs of the cervical spine, hands
      and feet of a large patient population with genetically proven SCS and MTM. The
      aim was to describe the pattern of skeletal anomalies and to determine whether
      specific features are present that could help differentiate between the two
      entities. MATERIALS AND METHODS: Radiographs of 43 patients (23 males, 20
      females) with SCS (n=35) or MTM (n=8) were evaluated. The median age was 8 years
      (range 1 month-36 years). All radiographs were reviewed by two radiologists.
      RESULTS: In the hands and feet, a variety of anomalies such as brachyphalangy,
      clinodactyly, partial syndactyly, partial carpal or tarsal fusion, and cone
      shaped epiphyses were noted. Duplicated distal phalanx of the hallux (n=12/35)
      and triangular deformity of the epiphysis of the distal phalanx of the hallux
      (n=10/35) were detected in SCS only; calcaneo-cuboid fusion (n=2/35) was detected
      in MTM only. In the cervical spine, fusion of vertebral bodies and/or the
      posterior elements occurred only in patients with SCS. CONCLUSIONS: Pathognomonic
      signs for SCS are the triangular shape of the epiphysis and duplicated distal
      phalanx of the hallux. Calcaneo-cuboid fusion was detected in MTM only. These
      signs may be helpful in the differentiation of SCS from MTM.

PMID- 12612815
TI  - The hand in Smith-Magenis syndrome (deletion 17p11.2): evaluation by
      metacarpophalangeal pattern profile analysis.
AB  - BACKGROUND: Brachydactyly has been described on physical examination in patients
      with Smith-Magenis syndrome (SMS). Metacarpophalangeal pattern profile analysis
      (MCPPPA), a method of graphic depiction of the relative size of the bones of the
      hand, has been used to objectively evaluate radiographs of the hand in patients
      with SMS in two small series: a single case and a study of four patients. This
      technique has confirmed brachydactyly and has suggested conflicting MCPPPA
      results. OBJECTIVE: The purpose of our study was to evaluate the hand by MCPPPA
      in a large series of patients with SMS. PATIENTS AND METHODS: We measured the
      bones of the hand and performed MCPPPA in 29 confirmed cases of SMS. RESULTS: Our
      results in 29 patients demonstrated a different MCPPPA in patients with SMS than
      previously reported. The analysis confirmed brachydactyly and the previously
      described trend of more pronounced shortening of the distal bones relative to the
      more proximal bones, but also demonstrated a previously undescribed pattern:
      relative enlargement of the proximal phalanx of the thumb and middle phalanx of
      the fifth finger. However, statistical analysis suggested that the pattern was
      not highly characteristic. CONCLUSION: MCPPPA of 29 patients with SMS
      demonstrates a pattern different than previously reported, but not highly
      characteristic.

PMID- 12612816
TI  - Assessment of image quality of a standard and two dose-reducing protocols in
      paediatric pelvic CT.
AB  - BACKGROUND: Concerns exist regarding the effect of radiation dose from paediatric
      pelvic CT scans and the potential later risk of radiation-induced neoplasm and
      teratogenic outcomes in these patients. OBJECTIVE: To assess the diagnostic
      quality of CT images of the paediatric pelvis using either reduced mAs or
      increased pitch compared with standard settings. MATERIALS AND METHODS: A
      prospective study of pelvic CT scans of 105 paediatric patients was performed
      using one of three protocols: (1) 31 at a standard protocol of 200 mA with
      rotation time of 0.75 s at 120 kVp and a pitch factor approximating 1.4; (2) 31
      at increased pitch factor approaching 2 and 200 mA; and (3) 43 at a reduced
      setting of 100 mA and a pitch factor of 1.4. All other settings remained the same
      in all three groups. Image quality was assessed by radiologists blinded to the
      protocol used in each scan. RESULTS: No significant difference was found between
      the quality of images acquired at standard settings and those acquired at half
      the standard mAs. The use of increased pitch factor resulted in a higher
      proportion of poor images. CONCLUSIONS: Images acquired at 120 kVp using 75 mAs
      are equivalent in diagnostic quality to those acquired at 150 mAs. Reduced
      settings can provide useful imaging of the paediatric pelvis and should be
      considered as a standard protocol in these situations.

PMID- 12612817
TI  - The value of anal endosonography compared with magnetic resonance imaging
      following the repair of anorectal malformations.
AB  - BACKGROUND: Surgery for anorectal malformations (ARMs) attempts to position the
      neo-anus anatomically within the anal sphincter complex. Currently, MRI is the
      imaging modality of choice in determining the position of the neo-anus after
      reconstructive surgery. OBJECTIVE: The aim of this study was to compare the
      accuracy of anal endosonography (AES) with conventional MRI in demonstrating the
      anatomy of the neo-anus following repair of ARMs. MATERIALS AND METHODS: Fourteen
      children (ten girls, four boys), born with ARMs (four low, ten high) underwent
      both AES and pelvic MRI following anorectoplasty. The results of both
      investigations were compared with muscle stimulation and were reported blindly by
      a clinician and a radiologist. RESULTS: AES findings were comparable with MRI in
      9 of the 14 cases. In four cases, MRI and AES findings differed, with nerve
      stimulation supporting AES but not MRI. CONCLUSIONS: AES is an accurate
      alternative to MRI in the assessment of anorectoplasty. It provides more detailed
      information and can be performed under anaesthesia in combination with a surgical
      procedure.

PMID- 12612818
TI  - Brachytelephalangy with sparing of the fifth distal phalanx: a feature highly
      suggestive of Keutel syndrome.
AB  - Keutel syndrome (KS) is a rare, autosomal recessive condition characterized by
      diffuse cartilaginous calcification, nasal hypoplasia, brachytelephalangy, and
      peripheral pulmonary stenosis. A review of the literature produced only 15
      reported patients, of whom plain radiographs of the hand or a detailed report are
      available for review in ten. A distinctive pattern of broadening and shortening
      of the first through fourth distal phalanges, with sparing of the fifth distal
      phalanx, is seen in seven of these patients. Two additional patients with Keutel
      syndrome and this identical finding are presented. I suggest that this pattern of
      brachytelephalangy is sensitive and highly suggestive of the diagnosis of Keutel
      syndrome.

PMID- 12612819
TI  - The effect of screening sonography on the positive rate of enemas for
      intussusception.
AB  - BACKGROUND: The referring physicians at our institution used the enema as a
      diagnostic test in children with suspected intussusception. OBJECTIVE: To
      determine the change in rate of positive enema findings performed for suspected
      intussusception with the intervention of screening ultrasound (US). MATERIALS AND
      METHODS: Since October 1995, 224 children (mean age 2.2 years) with suspected
      intussusception were referred for enema examination. In January 2001, US was
      introduced as a screening test for intussusception. Enemas were performed for all
      children with positive US findings and were offered for those with negative US
      findings if clinical suspicion persisted. RESULTS: Before 2001, 184 children
      underwent enema with intussusception documented in 40 (22%). Since January 2001,
      40 children have been seen with suspected intussusception (12/40 positive or
      30%). Two directly underwent enema (1/2 positive); 38 children underwent US. In
      12 of 38 children, the US finding was positive, and an intussusception was found
      at enema examination in 11 of 12. In 26 cases, the US finding was negative. Seven
      of the 26 children with a negative sonogram finding had an enema, which was also
      negative. Nineteen enemas were canceled. With a screening US, the positive rate
      for enemas is now 58% (11/19). We know of no case of intussusception missed at
      US. CONCLUSION: Screening US has decreased unnecessary enemas for clinically
      suspected intussusception, increasing positive findings from 22% to 58%. This has
      in turn reduced children's exposure to radiation.

PMID- 12612821
TI  - Radiological features of late-onset lymphoedema in Noonan's syndrome.
AB  - Noonan's syndrome is a multiple congenital anomaly syndrome with diverse
      manifestations. Lymphatic abnormalities occur in less than 20% of patients. We
      report a 14-year-old boy who presented with swollen lower limbs and dysmorphic
      features characteristic of Noonan's syndrome. The radiological features of this
      unusual case of late-onset lymphoedema in association with Noonan's syndrome are
      presented.

PMID- 12612820
TI  - Childhood idiopathic chondrolysis of the hip: MRI features.
AB  - BACKGROUND: Childhood idiopathic chondrolysis of the hip (ICH) causes progressive
      destruction of the articular cartilage of the hip joint with associated bone
      remodelling. The MRI features of this disease have not previously been described.
      OBJECTIVE: To document the MRI features of childhood ICH and determine which
      features may help distinguish ICH from other causes of hip joint destruction in
      the paediatric population. MATERIALS AND METHODS: A retrospective review of the
      MRI examinations of children with clinically diagnosed ICH. All children had
      undergone synovial biopsy and/or joint aspiration with plain hip radiography to
      exclude causes of secondary chondrolysis. RESULTS: Ten MRI examinations were
      performed on six children. Cartilage loss, small hip joint effusions, bone
      remodelling and significant regional muscle wasting were seen in all children.
      Cartilage loss was most severe in the central part of the joint. Synovial
      enhancement was not a constant feature of ICH. Serial imaging in three children
      showed disease progression. CONCLUSIONS: MRI in ICH clearly demonstrates
      cartilage loss and enables delineation of bone and muscle abnormalities. It is
      helpful in the differential diagnosis of hip joint disease in children and may
      provide further information on the progression and aetiology of ICH.

PMID- 12612822
TI  - Intramuscular juvenile xanthogranuloma: sonographic and MR findings.
AB  - BACKGROUND: Juvenile xanthogranuloma is a rare benign lesion, most often
      cutaneous or subcutaneous, and found in infants. OBJECTIVE: To review the imaging
      approach to an intramuscular mass in an infant. METHODS: A case is reported of a
      2-month-old boy who presented with a solitary left arm mass which was evaluated
      with ultrasound and MRI and then biopsied. RESULTS: Imaging demonstrated a well
      defined homogeneous solid mass located in the triceps muscle. The mass was
      resected and pathology revealed intramuscular juvenile xanthogranuloma.
      CONCLUSION: Intramuscular juvenile xanthogranuloma, although extremely rare, has
      imaging features similar to those of more common malignant tumors of infancy. The
      imaging findings are nonspecific, but this diagnosis should be considered in the
      differential of a solid intramuscular mass in an infant.

PMID- 12612823
TI  - Malignant transformation of a chiasmatic pilocytic astrocytoma in a patient with
      diencephalic syndrome.
AB  - Chiasmatic gliomas with metastatic spread are rare in children and are usually
      associated with diencephalic syndrome. They are mostly pilocytic astrocytomas and
      their transformation to high-grade astrocytomas has never previously been
      reported in the pediatric population. We report leptomeningeal spread of a
      chiasmatic pilocytic astrocytoma in a child presenting with diencephalic
      syndrome. He was treated with chemotherapy and radiation. The tumor recurred with
      transformation into a high-grade astrocytoma. Radiation therapy may have played a
      role in transformation of the tumor, but more research is needed to further
      clarify the biological behavior of this tumor.

PMID- 12612824
TI  - Giant mycotic aneurysm of the internal carotid artery in a child: endovascular
      treatment.
AB  - We present a case of a giant mycotic aneurysm of the left internal carotid artery
      in a child, the result of direct extension of a deep neck space infection. This
      lesion is life threatening and may put the patient at risk of unwarranted biopsy
      or drainage if not recognized. Diagnosis and treatment planning rely heavily on
      cross-sectional imaging, and angiography is frequently necessary. This case is
      unique for two reasons: (1) we present for the first time the MRI findings and
      (2) we describe an alternative to surgical ligation -- neurointerventional
      embolotherapy. Minimally invasive transcatheter embolization was successfully
      performed on our patient to occlude the abnormal left internal carotid artery
      segment.

PMID- 12612825
TI  - Schimke immuno-osseous dysplasia: two cases.
AB  - We report two patients with Schimke immuno-osseous dysplasia (SIOD). SIOD is
      characterised by growth retardation, renal failure, spondylo-epiphyseal
      dysplasia, specific phenotype and defective cellular immunity. These two children
      demonstrated a bone dysplasia with characteristic radiographic appearances. We
      postulate that SIOD should be considered in all cases of growth failure with an
      unclassifiable bone dysplasia. Repeated urine tests for proteinuria could be
      helpful in reaching the correct diagnosis.

PMID- 12612826
TI  - Giant trichophytobezoar in a pediatric patient with trichotillomania.
AB  - We report a case of a 13-year-old girl with trichotillomania. A plain abdominal
      radiograph and axial CT scan revealed a well-defined mass within the stomach.
      Gastrotomy was performed and a 19 x 11 x 2-cm trichophytobezoar was delivered
      intact.

PMID- 12612827
TI  - Benign costal mesenchymal hamartoma in a neonate.

PMID- 12612828
TI  - Connectivity of neutral networks, overdispersion, and structural conservation in
      protein evolution.
AB  - Protein structures are much more conserved than sequences during evolution. Based
      on this observation, we investigate the consequences of structural conservation
      on protein evolution. We study seven of the most studied protein folds,
      determining that an extended neutral network in sequence space is associated with
      each of them. Within our model, neutral evolution leads to a non-Poissonian
      substitution process, due to the broad distribution of connectivities in neutral
      networks. The observation that the substitution process has non-Poissonian
      statistics has been used to argue against the original Kimura neutral theory,
      while our model shows that this is a generic property of neutral evolution with
      structural conservation. Our model also predicts that the substitution rate can
      strongly fluctuate from one branch to another of the evolutionary tree. The
      average sequence similarity within a neutral network is close to the threshold of
      randomness, as observed for families of sequences sharing the same fold.
      Nevertheless, some positions are more difficult to mutate than others. We compare
      such structurally conserved positions to positions conserved in protein
      evolution, suggesting that our model can be a valuable tool to distinguish
      structural from functional conservation in databases of protein families. These
      results indicate that a synergy between database analysis and structurally based
      computational studies can increase our understanding of protein evolution.

PMID- 12612829
TI  - MDM-1 and MDM-2: two mutator-derived MITE families in rice.
AB  - Numerous miniature inverted repeat transposable elements (MITEs) are present in
      the rice genome but their transposition mechanisms are unknown. In this report,
      we present evidence that two novel MITE families may have arisen from Mutator
      related transposable elements and thus may use a transposition mechanism similar
      to that of Mutator elements. Two families of novel MITEs, namely, MDM-1 and MDM
      2, were identified by searching for MITEs nested with Kiddo, a previously
      identified MITE family. MDM-1 and MDM-2 bear hallmarks of Mutator elements, such
      as long terminal inverted repeats (LTIRs), 9-bp target-site duplications (TSDs),
      and putative transposase binding sites. Strikingly, the MDM-1 family has a 9-bp
      terminus identical to that of a rice Mutator-like element ( MULE-9) and the MDM-2
      family has an 8-bp terminus identical to that of the maize autonomous Mutator
      element MuDR. A putative transposase homologous to MURA protein is identified for
      the MDM-2 family. Thus, these two novel MITE families, with a total copy number
      of several hundred in rice, are designated Mutator-derived MITEs ( MDMs).
      Interestingly, sequence decay analysis of MDM families revealed a number of
      insertion site duplications (ISDs) in the alignment gaps, and widespread
      historical nesting events are proposed to account for the existence of these
      ISDs. In addition to its value for discovering new MITEs, the nesting analysis
      approach used in this study simultaneously identifies MITE insertion
      polymorphisms.

PMID- 12612830
TI  - Evolution of the vertebrate cytosolic malate dehydrogenase gene family:
      duplication and divergence in actinopterygian fish.
AB  - A general correlation between neural expression and negative charge in isozymes
      suggests charge represents an adaptation to the neural environment.
      Interestingly, a notable exception exists in teleost fish. Two cytosolic malate
      dehydrogenase (MDH) isozymes have different spatial expression patterns in
      certain fishes: one is expressed in all tissues and the second is expressed
      primarily in the eye and skeletal muscle. While the neural MDH isozyme is
      negatively charged, the difference in charge between the two isozymes is not as
      pronounced as that observed in other gene families (e.g., triosephosphate
      isomerase and lactate dehydrogenase). Most tetrapods express a single cytosolic
      MDH isozyme, and it has been demonstrated recently that the pair of isozymes
      found in teleosts results from a gene duplication sometime after the separation
      of teleosts and tetrapods, although the exact timing of this duplication has not
      been inferred. Phylogenetic analyses suggest that the duplication of teleost
      isozymes occurred during the radiation of actinopterygian fish, consistent with
      the timing of duplication at other loci. Using inferred amino acid sequences, we
      examine the pattern of change following the duplication and across the rest of
      the MDH gene tree. Comparison between the MDH gene family and another gene family
      that shows a larger charge differential among members (triosephosphate isomerase)
      indicates that the smaller charge difference between MDH isozymes is best
      explained by greater constraint on amino acid change directly following the
      duplication, not greater constraint across the entire gene tree. This difference
      in constraint might result from the wider pattern of expression of the "neural"
      MDH isozyme.

PMID- 12612831
TI  - Evolution of vertebrate voltage-gated ion channel alpha chains by sequential gene
      duplication.
AB  - Phylogenetic analysis of alpha chains of voltage-gated ion channels revealed that
      extensive gene duplication has occurred among both Ca(2+) and Na(+)-channels
      since the origin of vertebrates. Rather than showing a pattern of gene
      duplication consistent with the hypothesis of polyploidization early in
      vertebrate history, both Ca(2+) and Na(+) channels showed patterns of sequential
      gene duplication associated with specialization of the gene products. In the case
      of Na(+) channels, the phylogeny supported the hypothesis that the ancestral
      vertebrate gene had an expression pattern including both central and peripheral
      nervous system cells and that duplication of vertebrate Na(+) channel genes has
      repeatedly been followed by specialization for the central nervous system, the
      peripheral nervous system, or muscle cells. Thus, cephalization in vertebrate
      evolution has been accompanied by specialization of this important family of
      neuromuscular proteins along the central-peripheral axis.

PMID- 12612832
TI  - Interisland evolution of Trimeresurus flavoviridis venom phospholipase A(2)
      isozymes.
AB  - Trimeresurus flavoviridis snakes inhabit the southwestern islands of Japan. A
      phospholipase A(2) (PLA(2)), named PL-Y, was isolated from Okinawa T.
      flavoviridis venom and its amino acid sequence was determined from both protein
      and cDNA. PL-Y was unable to induce edema. In contrast, PLA-B, a PLA(2) from
      Tokunoshima T. flavoviridis venom, which is different at only three positions
      from PL-Y, is known to induce edema. A new PLA(2), named PLA-B', which is similar
      to PLA-B, was cloned from Amami-Oshima T. flavoviridis venom gland. Three T.
      flavoviridis venom basic [Asp(49)]PLA(2) isozymes, PL-Y (Okinawa), PLA-B
      (Tokunoshima), and PLA-B' (Amami-Oshima), are identical in the N-terminal half
      but have one to four amino acid substitutions in the beta1-sheet and its
      vicinity. Such interisland sequence diversities among them are due to isolation
      in the different environments over 1 to 2 million years and appear to have been
      brought about by natural selection for point mutation in their genes. Otherwise,
      a major PLA(2), named PLA2, ubiquitously exists in the venoms of T. flavoviridis
      snakes from the three islands with one to three synonymous substitutions in their
      cDNAs. It is assumed that the PLA2 gene is a prototype among T. flavoviridis
      venom PLA(2) isozyme genes and has hardly undergone nonsynonymous mutation as a
      principal toxic component. Phylogenetic analysis based on the amino acid
      sequences revealed that T. flavoviridis PLA(2) isozymes are clearly separated
      into three groups, PLA2 type, basic [Asp(49)]PLA(2) type, and [Lys(49)]PLA(2)
      type. Basic [Asp(49)]PLA(2)-type isozymes may manifest their own particular toxic
      functions different from those of the isozymes of the PLA2 type and
      [Lys(49)]PLA(2) type.

PMID- 12612833
TI  - Tests for positive selection on immune and reproductive genes in closely related
      species of the murine genus mus.
AB  - We examine variation among species of Mus in four genes involved in reproduction
      and the immune response for evidence of positive selection: the sperm recognition
      gene Zp-3, the testis-determining locus Sry, the testicular cell surface matrix
      protein Tcp-1, and the immune system protein beta(2) m. We use likelihood ratio
      tests in the context of a well-supported phylogeny to determine whether models
      that allow for positively selected sites fit the sequences better than models
      that assume purifying selection. We then apply a Bayesian approach to identify
      particular sites in each gene that have a high posterior probability of being
      under positive selection. We find no evidence of positive selection on the Tcp-1
      gene, but for Zp-3, Sry, and beta(2) m, models that allow for positively selected
      sites fit the sequences better than alternatives. For each of these genes, we
      identify sites that have a high (> 95%) posterior probability of being positively
      selected. For Zp-3, two of these sites occur near the sperm-binding region, while
      one occurs in a region whose functional role remains unstudied but where the
      pattern of change predicts functional importance. A single site in Sry shows an
      elevated rate of replacement substitution but occurs in a region of apparently
      little functional importance; therefore, relaxation of functional constraints may
      better explain the rapid evolution of this site. Three sites in beta(2) m have a
      posterior probability > 50% of being under positive selection. While the
      functional role for two of these sites is unknown, the third is known to
      influence the ability of MHC class I molecules to present antigens to the immune
      system; therefore, the elevated rate of replacement substitutions at this site is
      consistent with selection acting to promote variability in immune system
      proteins.

PMID- 12612834
TI  - Pearl, a novel family of putative transposable elements in bivalve mollusks.
AB  - While genome sequencing projects have discovered numerous types of transposable
      elements in diverse eukaryotes, there are many taxa of ecological and
      evolutionary significance that have received little attention, such as the
      molluscan class Bivalvia. Examination of a 0.7-MB genomic sequence database from
      the cupped oyster Crassostrea virginica revealed the presence of a common
      interspersed element, CvA. CvA possesses subterminal inverted repeats, a tandemly
      repeated core element, a tetranucleotide microsatellite region, and the ability
      to form stable secondary structures. Three other less abundant repetitive
      elements with a similar structure but little sequence similarity were also found
      in C. virginica. Ana-1, a repetitive element with similar features, was
      discovered in the blood ark Anadara trapezia by probing a genomic library with a
      dimeric repeat element contained in intron 2 of a minor globin gene in that
      species. All of these elements are flanked by the dinucleotide AA, a putative
      target-site duplication. They exhibit structural similarity to the sea urchin Tsp
      family and Drosophila SGM insertion sequences; in addition, they possess regions
      of sequence similarity to satellite DNA from several bivalve species. We suggest
      that the Crassostrea repetitive elements and Ana-1 are members of a new MITE-like
      family of nonautonomous transposable elements, named pearl. Pearl is the first
      putative nonautonomous DNA transposon to be identified in the phylum Mollusca.

PMID- 12612835
TI  - Genetic and ecological correlates of intraspecific variation in pitviper venom
      composition detected using matrix-assisted laser desorption time-of-flight mass
      spectrometry (MALDI-TOF-MS) and isoelectric focusing.
AB  - The ability to detect biochemical diversity in animal venoms has wide-ranging
      implications for a diverse array of scientific disciplines. Matrix-assisted laser
      desorption time-of-flight mass spectrometry (and, for comparative purposes,
      isoelectric focusing) were used to characterize venoms from a geographically
      diverse sample of Trimeresurus stejnegeri ( n < 229) from Taiwan. Previously
      unrealized levels of heterogeneity were detected in venom phospholipase A(2)
      isoforms (PLA(2)) and in whole venom profiles. Geographic variation in venom was
      primarily between Taiwan and two Pacific islets. Despite the common assumption
      that venom variation is a product of neutral molecular evolution, statistical
      testing failed to link venom variation with phylogenetic descent convincingly.
      Instead, pronounced differences in venom composition may be the product of
      natural selection for regional diets or of independent founder effects. More data
      are required on the functional differences between the isoforms to distinguish
      between these alternatives.

PMID- 12612836
TI  - Probabilistic analysis indicates discordant gene trees in chloroplast evolution.
AB  - Analyses of whole-genome data often reveal that some genes have evolutionary
      histories that diverge from the majority phylogeny estimated for the entire
      genome. We present a probabilistic model that deals with heterogeneity among gene
      trees, implement it via the Gibbs sampler, and apply it to the plastid genome.
      Plastids and their genomes are transmitted as a single block without
      recombination, hence homogeneity among gene trees within this genome is expected.
      Nevertheless, previous work has revealed clear heterogeneity among plastid genes
      (e.g., Delwiche and Palmer 1996). Other studies, using whole plastid genomes of
      various algae and land plants, found little additional heterogeneity (Martin et
      al. 1998; Adachi et al. 2000). We augment the earlier studies by using a data set
      of 14 taxa: 6 land plants, 2 green algae, a diatom, 2 red algae and a
      cryptophyte, the cyanelle of the glaucocystophyte Cyanophora, and the blue-green
      alga Synechocystis as an outgroup. Contrary to the earlier analyses, we cannot
      find even a single, dominant consensus tree. Therefore, we formulate a
      probabilistic model that divides the genes into two sets: those that follow the
      consensus tree and those that have independent gene trees. No particular tree is
      supported by more than three-fourths of the genes. But the set of genes that
      follows a certain tree is fairly independent of data processing and the method of
      analysis. With one possible exception, we find no evidence for collinear or
      functionally related genes to follow similar trees. The phylogenetic pattern also
      seems independent of bias in amino acid composition. Among possible explanations
      for the observed phenomenon, the hypothesis that different genes have different
      covarion structures is difficult to assess. But gene duplication may be possible
      through the inverted or direct repeat regions, while horizontal gene transfer
      seems less likely. In contrast to green algae and land plants, inverted repeat
      regions in red algae and in Cyanophora show abundant differences among the
      copies. Thus, genes may get duplicated when they are recruited into the inverted
      repeat region and one of the two copies may be lost after leaving the inverted
      repeat region.

PMID- 12612837
TI  - Macronuclear molecules encoding actins in spirotrichs.
AB  - The nucleotide sequences of 16 newly reported and 8 previously reported actin
      encoding macronuclear DNA molecules in spirotrichs have been compared. As
      described for the eight previously reported molecules, the first 50 bases
      (noncoding) inside the telomere at both 5' strands in additional actin molecules
      are purine-rich. This anomalous base composition might serve as a signal to
      identify macronuclear molecules in micronuclear DNA during development. The 50
      base segment upstream of the ATG in the 5' leaders of the actin molecules
      contains extensive, conserved sequence motifs that are possibly promoter
      elements. The 3' noncoding trailers contain virtually no conserved sequence
      motifs. With one exception, the 3' trailers contain a second stop codon (TGA) 36
      bases on average downstream of the primary stop codon. Excluding Moneuplotes
      crassus, amino acid identities in actin I range from 78 to 100%, with variations
      distributed nonrandomly along the sequence. Phylogenetic trees based on the actin
      nucleotide sequences of 22 spirotrichs define the evolutionary relationships of
      their actin-encoding molecules. The actin phylogeny, while well supported by
      posterior probabilities, does not always coincide with the phylogeny defined in
      rDNA analyses or classical taxonomic classifications.

PMID- 12612838
TI  - Alpha/beta hydrolase2, a predicated gene adjacent to mad in Drosophila
      melanogaster, belongs to a new global multigene family and is associated with
      obesity.
AB  - The experimental validation of genes predicted from genomic sequence and the
      identification of functions for these genes is an increasingly important task. We
      report a multidisciplinary analysis of CG3488, a predicted gene adjacent to
      Mothers against dpp in Drosophila melanogaster. We cloned and sequenced a cDNA
      corresponding to CG3488 and we show that it is expressed in embryos. A
      computational analysis shows that CG3488 contains a number of conserved domains
      present in enzymes capable of lipid hydrolysis. A phylogenetic analysis shows
      that CG3488 is the homolog of human alpha/beta hydrolase2 and that these genes
      belong to a novel multigene family with members in animals, plants, fungi, and
      bacteria. A genetic analysis shows that heterozygosity for a chromosomal deletion
      that removes CG3488 dominantly enhances the excess lipid phenotype associated
      with a mutation in adipose, an uncloned obesity gene. Further, overexpression of
      a CG3488 transgene rescues this obesity phenotype. Overall, the data suggests
      that CG3488 functions as a lipase and that analyses of its homologs will provide
      unique insights into lipid metabolism in many species.

PMID- 12612839
TI  - Effects of GC content and mutational pressure on the lengths of exons and coding
      sequences.
AB  - It has been hypothesized that the length of an exon tends to increase with the GC
      content because stop codons are AT-rich and should occur less frequently in GC
      rich exons. This prediction assumes that mutation pressure plays a significant
      role in the occurrence and distribution of stop codons. However, the prediction
      is applicable not to all exons, but only to the last coding exon of a gene and to
      single-exon CDS sequences. We classified exons in multiexon genes in eight
      eukaryotic species into three groups-the first exon, the internal, and the last
      exon-and computed the Spearman correlation between the exon length and the
      percentage GC (%GC) for each of the three groups. In only five of the species
      studied is the correlation for the last coding exon greater than that for the
      first or internal exons. For the single-exon CDS sequences, the correlation
      between CDS length and %GC is mostly negative. Thus, eukaryotic genomes do not
      support the predicted relationship between exon length and %GC. In prokaryotic
      genomes, CDS length and %GC are positively correlated in each of the 68
      completely sequenced prokaryotic genomes in GenBank with genomic GC contents
      varying from 25 to 68%, except for the wall-less Mycoplasma genitalium and the
      syphilis pathogen Treponema pallidum. Moreover, the average CDS length and the
      genomic GC content are also positively correlated. After correcting for genome
      size, the partial correlation between the average CDS length and the genomic GC
      content is 0.3217 ( p < 0.025).

PMID- 12612840
TI  - GC-biased mutation pressure and ORF lengthening.

PMID- 12612841
TI  - [Globe rupture after blunt ocular trauma--editorial to: Wenzel M, Aral H.
      Indirect traumatic rupture of the globe without conjunctival injury].

PMID- 12612842
TI  - [Prof. Carl Wilhelm von Zehender (1819-1916)--first professor of ophthalmology
      and co-founder of the ophthalmological clinic at the University of Rostock-
      commemorative lecture at the 100th DOG meeting in Berlin from 26.9 to 29.9.2002].
AB  - The Grand-ducal University Eye Department in Rostock was solemnly inaugurated 16
      May 1892. According to many years of studies in Europe and on efforts to build
      this clinic, construction was outlined by Professor Carl Wilhelm v. Zehender, but
      the drafts were executed by the "Grossherzoglich-Mecklenburgisch-Schwerinschen
      Medicinalcommission" and Landbaumeister Schlosser in winter 1888/89. Professor v.
      Zehender, who originated from a very ancient Swiss family, was born in Bremen, 21
      May 1819. He studied medicine in Goettingen, Jena, Prague, Paris and Vienna.
      During this time he developed a lifelong friendship with Albrecht v. Graefe. 1856
      he took over the medical care for the hereditary duke Georg von Mecklenburg
      Strelitz and published the "Correspondenzblatt fur Aerzte im Grossherzoglichen
      Mecklenburg-Strelitz". 1857, during a conference in Heidelberg, his initiative
      led in the long run to the establishment of the "Heidelberger Ophthalmologische
      Gesellschaft", the forerunner of the "Deutsche Ophthalmologische Gesellschaft",
      which was founded in 1920. In 1863 the first edition of "Klinische Monatsblaetter
      fur Augenheilkunde" was published as a periodical; the cover page bore its name
      as the founder of the magazine. In 1866, after the death of the hereditary duke
      and a professorship in his hometown Berne, he became honorary professor of the
      Rostock University, and from 1869 onwards he chaired the clinic as a regular
      professor. After all his efforts to build his own hospital had failed, he
      demonstratively and finally resigned from his professorship in 1889. He went to
      Munich and became editor of the " Klinische Monatsblaetter fur Augenheilkunde".
      In 1907 he moved with his wife via Eutin to Warnemuende. There the nestor of
      world ophthalmologists died at the age of 98. His burial place without gravestone
      is situated in today's landscape park "Stephan Jantzen". So far all efforts of
      the author and of the Rostock University Eye Department taken after 1980 to
      create a worthy note to this exceptional ophthalmologist in the Baltic Sea resort
      Warnemuende were unsuccessful, also for financial reasons. But on 2.9.2002 with
      the help of the Lighthouse Club of Warnemuende a memorial plaque to Prof. C. W.
      v. Zehender was mounted on the guest house "Margarete". This plaque commemorates
      Professor Zehender's merits in establishing the DOG, planning and building the
      eye clinic of the university of Rostock.

PMID- 12612844
TI  - [Initial results obtained with the multifocal lens MF4].
AB  - BACKGROUND: Most patients depend on glasses for near vision after a cataract
      surgery with implantation of a monofocal IOL. Implantation of a multifocal IOL
      offers these patients the possibility to become independent of glasses. The aim
      of this study was to gain clinical experience with the multifocal MF4-Lens
      (IOLtech, France). PATIENTS AND METHODS: The MF4-lens was implanted in 80 eyes of
      40 patients. Corrected and uncorrected near and far vision acuity were evaluated
      3 months postop. Patients' satisfaction, the appearance of disturbing optical
      phenomena and the dependence on glasses were ascertained by means of an anonymous
      questionnaire. RESULTS: No surgical complications occurred in the course of this
      study. Three months after surgery, 92 % of all patients had an uncorrected visual
      acuity of 0.5 (20/40) or better. The binocular, uncorrected visual acuity was
      0.63 (20/32) or better. The corrected far-vision acuity was 0.5 (20/40) or
      better. 86 % of all patients had an uncorrected near-vision acuity of 0.8 (20/25)
      and 45 % an uncorrected near-vision acuity of 1.0 (20/20). 94 % of the patients
      were satisfied with the results of the surgery. 38 % reported on glare and 45 %
      noticed halos. 67 % of all patients were totally independent of glasses, 27 %
      needed glasses frequently and 6 % generally. CONCLUSION: The implantation of the
      multifocal MF4-lens is an effective procedure in particular for near-vision
      acuity and patient satisfaction. The majority of patients were less dependent on
      glasses.

PMID- 12612843
TI  - [Ophthalmia nodosa caused by the hairs of the bird spider (family Theraphosidae)
      or hairy megalomorph (known in the US as tarantula)--case report and review of
      the literature].
AB  - BACKGROUND: Bird spiders, known in the US as tarantulas, are large hairy spiders
      that have become increasingly popular as pets in the Western world. We present a
      patient with a red irritated eye from exposure to the hairs of a spider of the
      Theraphosidae family, and review the literature. PATIENT AND METHODS: We report
      on a 28-year old patient who was referred to our clinic with a red irritated eye
      following playing with a Chilean rose-haired bird spider (known in the US as
      tarantula). In addition, we reviewed the literature concerning similar cases
      using the Medline database and cited literature in the retrieved articles.
      RESULTS: Our patient displayed theraphosidae (tarantula) hairs in the cornea of
      the right eye and developed a uveitis and a retinochoroiditis with associated
      vitritis. Treatment with topical corticosteroids resulted in an improvement of
      signs and symptoms, although the improvement was slow and incomplete. The disease
      process consists of a granulomatous reaction to the spider hairs. Hairs of
      Theraphosidae spiders (tarantulas) may cause inflammation at all levels of the
      eye, from the conjunctiva to retina. We were able to identify 14 cases of
      Ophthalmia nodosa secondary to the exposure to the tarantula hairs in the
      literature. Therapy includes removal of the offending hairs when possible and
      topical treatment with steroids. CONCLUSION: Although the large hairy bird
      spiders (tarantulas) are considered harmless pets, ophthalmia nodosa is a
      potential danger when handling them. Ophthalmia nodosa has an unknown prognosis
      and may be difficult to manage.

PMID- 12612845
TI  - [Ultrasound biomicroscopy of conjunctival lesions].
AB  - BACKGROUND: The value of ultrasound biomicroscopy in the diagnosis of
      conjunctival lesions is not well established. PATIENTS AND METHODS: For the
      examination of conjunctival lesions, we used an ultrasound biomicroscope
      (Humphrey, Zeiss, Oberkochen) with a high frequency transducer (30 MHz). Between
      January 2000 and August 2001, 28 patients (16 female, 12-male) with conjunctival
      lesions, aged 9 to 81 years, were available for this study. RESULTS: Histological
      examination of the excised tissue displayed the presence of a compound naevus
      (8/28), cysts (6/28), inflammatory processes (3/28), granulomatous processes
      (2/28), lymphomas (2/28), foreign bodies (2/28), a pterygium (2/28), a malignant
      melanoma (1/28), a primary acquired melanosis (1/28), and a conjunctival
      amyloidosis (1/28). Using ultrasound biomicroscopy we were able to demonstrate a
      cystic tumour in the six patients (21 %) with a cyst of the conjunctiva. In
      patients suffering from solid tumours of the conjunctiva the definite diagnosis
      could not be made with ultrasound biomicroscopy alone. The eight patients with
      compound naevus displayed a somewhat heterogeneous sonographic structure within
      the tumour. In the patient with a foreign body we were able to demonstrate
      posterior shadowing of the underlying tissue. CONCLUSION: For evaluation of
      conjunctival lesions caused by a cyst or a solid tumour, ultrasound biomicroscopy
      may be an additional diagnostic tool, e. g. for assessing the margins of the
      tumour. However, up to now it is not possible to differentiate between different
      lesions solely by means of ultrasonography.

PMID- 12612846
TI  - [Indirect traumatic rupture of the globe without conjunctival injury].
AB  - BACKGROUND: Blunt injuries are frequent causes of ocular trauma. Rupture of the
      globe without conjunctival injury following ocular contusions may be as dangerous
      as ruptures with opened conjunctiva, but is much more difficult to diagnose.
      PATIENTS AND METHODS: Retrospective analysis of 13 inpatients of the University
      Ophthalmological Hospital in 1991-1995 with rupture of the globe but without
      conjunctival injury following ocular contusion. These were 5 % of all the
      patients with through-through injuries of the eye wall. RESULTS: The
      characteristic finding in all 13 patients has been hyposphagma, hyphema, vitreal
      haemorrhage and loss of visual acuity to "finger counting" or less. At the time
      of the first examination, in 6 of the 13 patients intraocular pressure was
      between 3 mm Hg and 16 mm Hg. One patient had had an initial pressure of 3 mm Hg,
      but at the time of surgery, the eye had a stable normalized pressure.
      Postoperatively three of the 13 patients attained final visual acuities between
      80/200 and 140/200 after at least 6 months, the remaining patients achieved not
      more than 5/200. CONCLUSION: In patients after blunt eye trauma rupture of the
      globe may occur in patients without damaging the conjunctiva and with normalised
      intraocular pressure. In such cases with intraocular bleeding and loss of vision
      it may be essential to open the conjunctiva and explore the sclera in order to be
      sure that there has not been a rupture of the sclera and to have the opportunity
      to perform pars-plana vitrectomy in time.

PMID- 12612847
TI  - [Sclerochoroidal calcification--a rare disease pattern--report on two patients,
      differential diagnosis and review of the literature].
AB  - BACKGROUND: Idiopathic sclerochoroidal calcification is a benign calcification at
      the level of the choroid and the sclera. Due to the location of the lesions
      mainly between the superior temporal vascular arcade and the equator, there is no
      visual disturbance. Diagnosis of idiopathic sclerochoroidal calcification is made
      by the typical fundus appearance in combination with ultrasonic findings.
      PATIENTS: 1. A 55-year old male patient showed multifocal slightly prominent
      lesions in the superiotemporal fundus of the left eye. 2. In a 60-year old male
      patient found multifocal slight prominent whitish lesions were found in the
      superior fundus from temporal to nasal of both eyes. Visual acuity was unaffected
      by the lesions. The borderlines of visual field were normal. RESULTS: Echography
      revealed a highly reflective lesion with orbital shadowing. Fluorescein
      angiography showed a normal pattern besides the lesions with a late
      hyperfluorescence staining of the lesion itself. Calcium and phosphorus levels
      were normal with no signs of abnormal calcium metabolism. CONCLUSIONS: Idiopathic
      sclerochoroidal calcification is a benign disorder which is diagnosed by the
      typical ophthalmoscopic picture in combination with standardised echography.
      Computed tomography can confirm the diagnosis. The most important differential
      diagnosis is choroidal osteoma, others are choroidal metastasis, choroidal
      amelanotic naevus and choroiditis. The early diagnosis of a sclerochoroidal
      calcification is important to avoid all the implications for the patient to which
      a misdiagnosis can lead.

PMID- 12612848
TI  - [Evaluation of a prospective card for prematures: retro- and prospective
      evaluation of 2393 histories].
AB  - BACKGROUND: Is it really true, that prematures have an accelerated maturation,
      are very intelligent and--with or without ectopic macula--get as myopic as
      Annette von Droste-Hulshoff was? To find a time schedule in prevention or early
      detection of retinopathy of prematurity (ROP) and also to detect risk factors, we
      looked for critical phases in the development of premature babies in analogy to
      those found in the development of other mammals. PATIENTS AND METHODS: We
      examined the data of 294 children (1981-84) retrospectively and then
      prospectively those of 100 children from 1984 - 93 and of further 1999 babies
      since then. All findings were noted in the International Committee for
      Retinopathy of Prematures scheme (ICROP 1984). We elaborated a time table which
      shows in parallel the actual dated and the age of the baby in gestational months,
      duration of oxygen application, birth weight, safety index s of the ancient
      Korner-Bossi and known risk factors, recently the blood serum glucose levels. In
      this so-called prospective card we noted the time table of developing ROP in 31
      children. Furthermore, we chose matched pairs for these ROP-babies out of the
      data of 1200 healthy babies and evaluated risk factors such as days of oxygen
      supply and blood glucose levels. Finally, we transformed our data into an excel
      data base and calculated the economic advantages of examinations by our method.
      RESULTS: After an adaptation to recent data we showed the epidemiology,
      therapeutic attempts and a critical review of so-called risk factors. Risk babies
      had a Korner-Bossi index of less than 1.0; this corresponds to a birth weight of
      less than 1000 g, a gestational age of less than 29 weeks, and oxygen application
      for more than 3 days. During the last 15 years, age and weight of the prematures
      decreased steadily. The onset of ROP occurred always between the 35th and the
      40th gestational week. In spontaneous regression, cicatricional stages mostly
      started in the 41st week. CONCLUSION: In order to win time for the examinator and
      to avoid stress for the baby, the prospective card proved very useful. It was
      helpful also in medico-legal discussions. The prospective card made it evident
      that the babies pass critical maturation stages during all their development,
      before as well as after birth. In screening premature babies, this critical phase
      requires to be respected.

PMID- 12612850
TI  - ["Masquerade foreign body" of the conjunctiva].
AB  - CASE REPORT: An eight months old child presented with a "red eye" and a corneal
      erosion since a week. The parents reported on a "hair" which was invisible most
      of the time but appeared intermittently at the lid margin. The medical history
      was otherwise unremarkable. In general anaesthesia, a long structure could be
      easily extracted. The tapering structure disclosed several tiny hair-like
      filaments sprouting from the thickened end. This end was embedded within a fold
      of conjunctiva, thus giving the impression of a hair sheath. Clinically, an
      ectopic "giant hair" was supposed. Histology, however, revealed plants cells and
      a birefringence too high for a hair so that a diagnosis of a plant foreign body
      was established. CONCLUSION: Conjunctival foreign bodies may be overlooked
      especially in young children with no history of foreign body acquisition. They
      may occur as a "masquerade foreign body".

PMID- 12612849
TI  - [Myokymia of the obliquus superior muscle and cryptogenetic epilepsy].
AB  - BACKGROUND: Myokymia of the obliquus superior muscle is a rare episodic
      microtremor caused by uncontrolled activities of the trochlearis nerve fibres.
      Epilepsy is also caused by spontaneous discharges of neurons. In our report we
      present an associated epilepsy which to the best of our knowledge is described
      for the first time. PATIENT: An 61-year old man with twitches of the right eye
      for 6 weeks and a subjective feeling of eye movement was investigated at our
      hospital. His history was void of any ophthalmologic diseases. However, he
      suffered from cryptogenetic epilepsy known since childhood. The morphological and
      orthoptical findings of his eyes were normal. During the slit-lamp investigation
      a unilateral rotating microtremor of the right eye induced by looking downward
      was seen. The neurologic investigation, magnetic resonance imaging and assessment
      of the thyreoid function did not show further pathological results. The patient
      underwent treatment with carbamazepine. Under this therapy he did not show any
      symptoms of myokymia during follow-up. SUMMARY: To the best of our knowledge this
      is the first case of myokymia of the obliquus superior muscle associated to
      epilepsy. To our opinion, any case of this syndrome should be investigated for
      epilepsy. A causal relation is unlikely since the most probable etiologies are
      either spontaneous discharges of trochlear nucleus neurons or a close contact
      between vessel and nerve analogously to trigeminal neuralgia.

PMID- 12612851
TI  - [VI: Confidence intervals--an alternative for p values].
AB  - Confidence intervals combine the ideas of clinical relevance and statistical
      significance by using one instructive expression, which enables remarkable
      reduction of table structures and result sections in scientific publications.
      Confidence interval based conclusions can be transferred from a clinical trial to
      its underlying study population with respect to a residual statistical error
      probability, i.e. the significance concept is retained. However, their
      presentation using the original unit of the clinical endpoint under consideration
      allows for immediate interpretation of the results' clinical impact. For example,
      the comparison of two therapy groups based on a binary endpoint becomes feasible
      using the relative risk's confidence interval. If "1" is not contained in the
      interval, the therapy groups significantly differ concerning this endpoint. The
      larger the interval turns out, the less precise the characterisation of the
      "real" risk value based on the study risk estimate. The larger the risk estimate
      turns out, the more clinical relevance.

PMID- 12612852
TI  - [Prevention of dementias: state of the art].
AB  - Dementias of late life constitute a major public health challenge. Alzheimer
      disease (AD) is the most common form. Epidemiological studies suggest that the
      use of nonsteroidal anti-inflammatory drugs, wine and coffee consumption and
      regular physical activity may delay onset of AD or reduce rate of progression.
      Preclinical research in animals and epidemiological studies in humans have shown
      that estrogen substitution strategies and lipid lowering statins may be
      beneficial. Thus, despite the lack of prospective studies and, therefore,
      consensus, different pharmacological strategies for persons at high risk for
      Alzheimer's disease are discussed.

PMID- 12612854
TI  - [Syncope with cardiac arrest in a 30-year-old woman].
AB  - HISTORY AND ADMISSION FINDINGS: A 30-year-old woman presented with a cardiac
      arrest, which spontaneously converted into a regular sinus rhythm. The patient
      had no prior history of cardiovascular diseases. On admission, the cardiovascular
      clinical examination of this young female was regular. INVESTIGATIONS: On
      admission, discrete inferior repolarisation changes were documented which were
      slightly progressive during the next day. Electrophysiologic examination of the
      heart was regular, angiography showed a coronary fistula and an atypical descense
      of the circumflex artery from the right coronary artery. DIAGNOSIS: Right
      coronary artery fistula to the right ventricle. Atypical descense of the
      circumflex artery from the right coronary artery. TREATMENT AND COURSE: During
      hospitalisation no arrhythmias or pauses were revealed. The patient underwent
      cardiac pacemaker implantation. We plan a transcatheter closure of the fistula.
      CONCLUSIONS: Coronary fistulas are a rare cause of cardiac arrhythmias.
      Angiography performed at an early stage is therefore crucial in the initial
      assessment of a young adult presenting with cardiac arrest and subsequent changes
      in the ECG, as a small proportion may have coronary vascular abnormalities. The
      occlusion of the fistula by transcatheter or cardiac surgery is appropriate,
      especially as the risks of the interventions are limited.

PMID- 12612853
TI  - [Identification of wrong or inadequate nutrition of elderly patients in an acute
      admissions hospital].
AB  - BACKGROUND AND OBJECTIVE: Wrong or inadequate nutrition can lead to an increased
      morbidity and mortality as well as a raised perioperative rate of complications.
      Endangered patients should be identified quickly, reliably and cost-effectively
      on admission. This study aimed at developing a 3-step assessment, using a
      previously evaluated questionnaire. PATIENTS AND METHODS: Between February and
      July 2001, the nutritional state was prospectively obtained, in the first three
      days after admission, by questionnaire (based on a questionnaire developed at the
      Bethanien Hospital, Heidelberg) and objective measurements of 408 hospitalized
      patients aged over 70 years (139 men, 269 women, average age 82.2 years). Body
      mass index (BMI) was calculated for each patient and in those in whom it was over
      25, concentrations of albumin, calcium, vitamin D and lymphocyte count as well as
      triceps skin fold thickness were also obtained. RESULTS: 22 of the 408 patients
      (5.4%) had a BMI of < or = 18.5 (step 1). 191 patients (46.8%) answered
      affirmatively four or more of the questions, placing them in the group of "in
      danger of malnutrition". The "objective" parameters were present in all patients
      wih a BMI < 25. Abnormal levels were found only in patients who had already been
      identified through their questionnaire (four or more positive answers). 310
      answered positively to question 8 and 11 (step 2). When additionally answers to
      questions 1, 2, 6, 7 and 10 were included (at least four additional positive
      answers in the Bethanian questionnaire, step 3) 175 patients in danger of
      malnutrition (91.6%) were identified. CONCLUSION: The 3-step assessment (BMI and
      questions answered positively) correctly identified 90% of elderly patients in
      danger of malnutrition. This assessment thus ensured effective provision of
      nutritional care in an acute-admissions hospital.

PMID- 12612855
TI  - [Occupationally acquired tuberculosis in an administrative assistant: aspects of
      an expert report].
AB  - HISTORY: Since the age of 48 years an administrative assistant had been treated
      with immunosuppressive drugs for a mixed connective tissue disease. She was in
      direct personal contact with newly arrived Africans while working at an
      admittance centre for refugees. At the age of 53 years the symptoms changed with
      increasing joint pains and loss of weight. The immunosuppressive therapy with
      corticoids was increased. A total hip arthroplasty followed. An infection of the
      wound occurred and many revisions of the scar tissue followed. After a total knee
      arthroplasty an epileptic seizure occurred. A tuberculous meningoencephalitis was
      diagnosed. Mycobacterium tuberculosis was detected in urine, sputum and in
      secretions of different joints. A detailed analysis revealed Mycobacterium
      tuberculosis var. africanum. At the age of 59 years the patient died during a
      period of rehabilitation, the clinical signs indicating pulmonary embolism.
      CONCLUSIONS: The haematogenous spread of Mycobacterium tuberculosis was
      undoubtedly exacerbated by the immunosuppressive therapy. As a preventive measure
      a competent occupational consultation could have stopped the occupational
      exposure to Mycobacteria by transferring the patient during immunosuppressive
      therapy. The change of symptoms had been misclassified as worsening of the mixed
      connective tissue disease. Considering legal aspects of the German social
      insurance system the criteria of an occupational disease would have been
      fulfilled.

PMID- 12612856
TI  - [Antibiotic-associated diarrhea].

PMID- 12612857
TI  - [Benefits beyond the bones -- vitamin D against falls, cancer, hypertension and
      autoimmune diseases].

PMID- 12612858
TI  - [Relevance of the melanocortinergic system for body weight regulation].

PMID- 12612859
TI  - [The accusation of double standard in the debate on embryonic stem cell
      research].

PMID- 12612860
TI  - [Can dialysis be conducted too often?].

PMID- 12612862
TI  - [Vitamin D and calcium do not prevent bone loss in rheumatoid arthritis].

PMID- 12612863
TI  - Mitochondrial DNA haplogroups do not play a role in the variable phenotypic
      presentation of the A3243G mutation.
AB  - Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in
      association with either MELAS (mitochondrial myopathy, encephalopathy, lactic
      acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes
      (ranging from diabetes and deafness to a mixture of chronic progressive external
      ophthalmoplegic symptoms and strokelike episodes) were studied by use of high
      resolution restriction fragment length polymorphism analysis and control-region
      sequencing. A total of 34 different haplotypes were found, indicating that all
      instances of the A3243G mutation are probably due to independent mutational
      events. Haplotypes were distributed into 13 haplogroups whose frequencies were
      close to those of the general Spanish population. Moreover, there was no
      statistically significant difference in haplogroup distribution between patients
      with MELAS and those with disease phenotypes other than MELAS. Overall, these
      data indicate that the A3243G mutation harbors all the evolutionary features
      expected from a severely deleterious mtDNA mutation under strong negative
      selection, and they reveal that European mtDNA backgrounds do not play a
      substantial role in modulating the mutation's phenotypic expression.

PMID- 12612864
TI  - Linkage analysis of extremely discordant and concordant sibling pairs identifies
      quantitative-trait loci that influence variation in the human personality trait
      neuroticism.
AB  - Several theoretical studies have suggested that large samples of randomly
      ascertained siblings can be used to ascertain phenotypically extreme individuals
      and thereby increase power to detect genetic linkage in complex traits. Here, we
      report a genetic linkage scan using extremely discordant and concordant sibling
      pairs, selected from 34,580 sibling pairs in the southwest of England who
      completed a personality questionnaire. We performed a genomewide scan for
      quantitative-trait loci (QTLs) that influence variation in the personality trait
      of neuroticism, or emotional stability, and we established genomewide empirical
      significance thresholds by simulation. The maximum pointwise P values, expressed
      as the negative logarithm (base 10), were found on 1q (3.95), 4q (3.84), 7p
      (3.90), 12q (4.74), and 13q (3.81). These five loci met or exceeded the 5%
      genomewide significance threshold of 3.8 (negative logarithm of the P value).
      QTLs on chromosomes 1, 12, and 13 are likely to be female specific. One locus, on
      chromosome 1, is syntenic with that reported from QTL mapping of rodent
      emotionality, an animal model of neuroticism, suggesting that some animal and
      human QTLs influencing emotional stability may be homologous.

PMID- 12612866
TI  - "Systolic and diastolic dysfunction" in heart failure? Time for a new paradigm.

PMID- 12612865
TI  - Geographic distribution of disease mutations in the Ashkenazi Jewish population
      supports genetic drift over selection.
AB  - The presence of four lysosomal storage diseases (LSDs) at increased frequency in
      the Ashkenazi Jewish population has suggested to many the operation of natural
      selection (carrier advantage) as the driving force. We compare LSDs and
      nonlysosomal storage diseases (NLSDs) in terms of the number of mutations, allele
      frequency distributions, and estimated coalescence dates of mutations. We also
      provide new data on the European geographic distribution, in the Ashkenazi
      population, of seven LSD and seven NLSD mutations. No differences in any of the
      distributions were observed between LSDs and NLSDs. Furthermore, no regular
      pattern of geographic distribution was observed for LSD versus NLSD mutations
      with some being more common in central Europe and others being more common in
      eastern Europe, within each group. The most striking disparate pattern was the
      geographic distribution of the two primary Tay-Sachs disease mutations, with the
      first being more common in central Europe (and likely older) and the second being
      exclusive to eastern Europe (primarily Lithuania and Russia) (and likely much
      younger). The latter demonstrates a pattern similar to two other recently arisen
      Lithuanian mutations, those for torsion dystonia and familial
      hypercholesterolemia. These observations provide compelling support for random
      genetic drift (chance founder effects, one approximately 11 centuries ago that
      affected all Ashkenazim and another approximately 5 centuries ago that affected
      Lithuanians), rather than selection, as the primary determinant of disease
      mutations in the Ashkenazi population.

PMID- 12612868
TI  - Worsening renal function: what is a clinically meaningful change in creatinine
      during hospitalization with heart failure?
AB  - INTRODUCTION: Worsening renal function during hospitalization for heart failure,
      defined as elevation in creatinine during admission, predicts adverse outcomes.
      Prior studies define worsening renal function using various creatinine
      elevations, but the relative value of definitions is unknown. METHODS AND
      RESULTS: In a prospective cohort of 412 patients hospitalized for heart failure,
      we compared a spectrum of worsening renal function definitions (absolute
      creatinine elevations >/=0.1 to >/=0.5 mg/dL and 25% relative elevation from
      baseline) and associations with 6-month mortality, readmission, and functional
      decline. Creatinine elevation >/=0.1 mg/dL occurred in 75% of patients, and
      elevation >/=0.5 mg/dL occurred in 24% of patients. Risk of death rose with
      higher creatinine elevations (adjusted hazard ratio [HR] = 0.89, 1.19, 1.67,
      1.91, and 2.90 for elevations >/=0.1 to >/=0.5 mg/dL). Maximum sensitivity of any
      definition for predicting mortality was 75% and maximum specificity was 79%. High
      creatinine elevation was a more important predictor of death than was a single
      measure of baseline creatinine. CONCLUSIONS: Larger creatinine elevations predict
      highest risk of death, yet even minor changes in renal function are associated
      with adverse outcomes. The choice of a "best definition" for worsening renal
      function has implications for the number of patients identified with this risk
      factor and the magnitude of risk for mortality.

PMID- 12612867
TI  - The effect of digoxin on the quality of life in patients with heart failure.
AB  - BACKGROUND: The Digitalis Investigation Group (DIG) trial was a randomized double
      blind placebo-controlled study that examined the effect of digoxin on mortality
      in 7,788 patients with heart failure and sinus rhythm. A prespecified substudy
      evaluated the effect of digoxin therapy on health-related quality of life (HQOL)
      in a subset of these patients. METHODS: Patients in the DIG trial had clinical
      heart failure and were randomized to either digoxin or placebo in addition to
      their baseline diuretic and angiotensin-converting enzyme therapy (n = 7,788).
      The patients in this substudy had HQOL measured using a self-administered
      questionnaire employing scales that measured general health, physical
      functioning, depression, anger, anxiety, life satisfaction, and disease specific
      measures. A subjective assessment by the investigator and a 6-minute walk test
      evaluated functional status. HQOL was measured at baseline and at the 4- and 12
      month follow-up visits. RESULTS: The baseline characteristics of the patients in
      the quality of life substudy (n = 589) were comparable to the remaining patients
      in the study (n = 7,199) by age and other clinical measures, including history of
      prior myocardial infarction or etiology of heart failure; heart failure was of
      shorter duration and the ejection fraction was slightly better than in the main
      trial. Within the substudy, patients receiving digoxin (n = 298) or placebo (n =
      291) were also similar in baseline characteristics. There was no statistically
      significant difference in any HQOL measure between the digoxin and the placebo
      groups at baseline. At the 4-month visit, only perceived health was improved in
      the digoxin group. At 12 months, there was no statistically significant
      difference in perceived health, physical functioning, Minnesota Living with Heart
      Failure, depression, anxiety, anger, Ladder of Life, or the 6-minute walk between
      the digoxin and placebo groups. CONCLUSION: In this subset of the DIG population,
      digoxin therapy had no effect on the HQOL in patients with heart failure in sinus
      rhythm.

PMID- 12612869
TI  - Beware the rising creatinine level.

PMID- 12612870
TI  - Body mass and survival in patients with chronic heart failure without cachexia:
      the importance of obesity.
AB  - BACKGROUND: Cachexia in chronic heart failure carries a poor prognosis, but
      little is known about the influence of body mass on the prognosis of noncachectic
      heart failure patients. METHODS: We studied 589 consecutive chronic heart failure
      patients followed for at least a year, in whom there were accurate baseline data
      for body mass. RESULTS: Average age was 64.5 +/- 12.4 years, left ventricular
      ejection fraction (LVEF) 30.9 +/- 0.73%. Cachexia was present in 64. Noncachectic
      patients were divided into quintiles of body mass index (BMI), Q1 (BMI 22.2 +/-
      1.5) to Q5 (BMI 34.1 +/- 2.8). There was no difference among the 5 groups in age,
      exercise capacity or LVEF. Survival was greatest in Q4 (1-year survival [95%
      confidence interval (CI)]) 0.91 (0.85-0.96) and 3-year survival 0.81 (0.73-0.89).
      Relative risks compared with Q4 were Q1: 2.3 (1.4-3.8); Q2: 1.7 (1.1-2.9); Q3:
      1.8 (1.1-3.0); and Q5: 1.5 (0.9-2.5). In multivariate analysis of 1 year follow
      up, peak oxygen consumption (hazard ratio with 95% CI) (0.89 [0.82-0.97]; P
      =.006), LVEF (0.94 [0.91-0.97]; P =.0002) and BMI (0.90 [0.82-0.98]; P =.02)
      independently predicted 1-year survival with a combined Chi;(2) value of 42.4.
      Age (1.01 [0.98-1.05] and diagnosis (1.56 [0.78-3.11]) was not a predictor of
      survival. CONCLUSION: In patients with chronic heart failure, increasing BMI is
      not an adverse prognostic feature. Thinner patients appear to have a poorer
      prognosis.

PMID- 12612871
TI  - Undertreatment of hyperlipidemia in patients with coronary artery disease and
      heart failure.
AB  - BACKGROUND: Coronary artery disease patients with heart failure (CAD+HF) are at
      high risk for cardiovascular events. We examined the frequency of lipid
      assessment and prescription of lipid-lowering agents in outpatients with combined
      CAD+HF compared with patients with CAD alone. METHODS: We analyzed an
      administrative data set from the Quality Assurance Program II, a Merck & Co.,
      Inc., sponsored national retrospective chart audit of 41,487 CAD patients seen at
      296 ambulatory medical practices. About 34% of these patients had CAD+HF.
      RESULTS: Documentation of low-density lipoprotein (LDL) cholesterol was
      significantly lower in patients with CAD+HF (53%) compared with those with CAD
      alone (69%). Lipid-lowering drugs were prescribed in only 36% of patients with
      CAD+HF, compared with 52% of patients with CAD alone. Lipid levels alone did not
      justify this disparity. Patients with documented LDL cholesterol values were 4
      times more likely to receive a prescription for a lipid-lowering medication than
      those without recorded values. Other predictors of lipid-lowering prescription
      included: younger age, history of myocardial infarction, revascularization, care
      by a cardiologist, and geographic region. CONCLUSIONS: Patients with CAD, HF, and
      advanced age simultaneously experience among the highest risk and the lowest
      lipid-lowering treatment rates. Strategies to increase LDL testing and
      aggressively treat patients with heart failure and CAD are warranted.

PMID- 12612872
TI  - Gender differences in quality of life are minimal in patients with heart failure.
AB  - BACKGROUND: Prior investigators have suggested that quality of life differs in
      men and women with heart failure, especially in the physical functioning domain.
      The purpose of this study was to compare quality of life in men and women with
      heart failure to determine if differences exist after controlling for functional
      status, age, and ejection fraction. METHODS: Data from a sample of 640 men and
      women (50% each) matched on New York Heart Association functional classification
      and age were used for this secondary analysis. Scores on the Minnesota Living
      with Heart Failure Questionnaire were compared at baseline and 3 months after
      enrollment using multivariate techniques with ejection fraction controlled.
      Treatment group (intervention versus control) was controlled statistically at 3
      months because the original data were drawn from experimental and quasi
      experimental studies in which an improvement in quality of life had been a goal
      of the intervention. The sexes differed on marital status, so this variable was
      controlled in analyses as well. RESULTS: In all analyses, quality of life was
      minimally worse in women compared with men (1-3 points at most). None of the
      differences reached statistical significance except for emotional quality of life
      at baseline (P =.03). By 3 months, both men and women reported significantly
      improved and comparable quality of life and there were no significant differences
      between them. CONCLUSION: Quality of life is similar in men and women with heart
      failure when functional status, age, ejection fraction, and marital status
      differences are controlled.

PMID- 12612873
TI  - A practical guide to exercise training for heart failure patients.
AB  - BACKGROUND: Exercise training has been shown to improve exercise capacity in
      patients with heart failure. We sought to examine the optimal strategy of
      exercise training for patients with heart failure. METHODS: Review of the
      published data on the characteristics of the training program, with comparison of
      physiologic markers of exercise capacity in heart failure patients and healthy
      individuals and comparison of the change in these characteristics after an
      exercise training program. RESULTS: Many factors, including the duration,
      supervision, and venue of exercise training; the volume of working muscle; the
      delivery mode (eg, continuous vs. intermittent exercise), training intensity; and
      the concurrent effects of medical treatments may influence the results of
      exercise training in heart failure. Starting in an individually prescribed and
      safely monitored hospital-based program, followed by progression to an ongoing
      and progressive home program of exercise appears to be the best solution to the
      barriers of anxiety, adherence, and "ease of access" encountered by the heart
      failure patient. CONCLUSIONS: Various exercise training programs have been shown
      to improve exercise capacity and symptom status in heart failure, but these
      improvements may only be preserved with an ongoing maintenance program.

PMID- 12612876
TI  - What is needed to satisfy the American College of Surgeons Commission on Cancer
      (COC) requirements for the pathologic reporting of cancer specimens?

PMID- 12612874
TI  - Selective activation of N-acyl-D-glucosamine 2-epimerase expression in failing
      human heart ventricular myocytes.
AB  - BACKGROUND: O-linked N-acyl-glycosylation may regulate protein function by
      competing with phosphorylation of serine residues. Availability of substrate for
      this process is regulated, in part, by N-Acyl-D-glucosamine 2-epimerase (NAGE),
      which interconverts N-acetyl-glucosamine (GlcNAc) and N-acetylmannosamine
      (ManNAc). NAGE is also a putative renin-binding protein. This study tested the
      hypothesis that NAGE is present in the human heart and that NAGE expression is
      increased in the failing human heart. METHODS AND RESULTS: Ribonuclease
      protection assays (RPAs) demonstrated increased NAGE gene expression in failing
      hearts from subjects with idiopathic dilated and ischemic cardiomyopathies
      compared with nonfailing hearts. In situ reverse transcriptase-polymerase chain
      reaction, using primers designed to localize NAGE mRNA, demonstrated that, in
      nonfailing hearts, NAGE gene expression was restricted to endothelial cells and
      not detectable in cardiac myocytes. However, in failing human hearts NAGE gene
      expression was selectively activated in cardiac myocytes, but not endothelial
      cells. Immunohistochemistry confirmed that the pattern of NAGE protein expression
      corresponded to the pattern of gene expression. CONCLUSIONS: NAGE gene and
      protein expression were selectively activated in left ventricular myocytes from
      end-stage failing human hearts.

PMID- 12612875
TI  - Cardiac contractility modulation with nonexcitatory electric signals improves
      left ventricular function in dogs with chronic heart failure.
AB  - BACKGROUND: Nonexcitatory electrical, signals termed cardiac contractility
      modulation (CCM) have been shown to improve contractile force of isolated
      papillary muscles. In this study, we examined the effects of CCM signal delivery
      on left ventricular function in dogs with chronic heart failure (HF). METHODS AND
      RESULTS: Chronic HF (ejection fraction </=35%) was produced in 7 dogs by
      intracoronary microembolizations. The CCM signal was delivered during the
      absolute refractory period using a lead implanted in the anterior coronary vein.
      A right ventricular and an atrial lead were implanted and used for timing of the
      CCM signal delivery. Hemodynamic measurements were made at baseline and at 1, 2,
      3, 4, 5, and 6 hours after initiating CCM signal delivery. Ejection fraction
      increased from 31 +/- 1% at baseline to 41 +/- 1% at 1 hour (P <.05), 42 +/- 1%
      at 3 hours (P <.05), and 44 +/- 2% at 6 hours (P <.05). Similarly, stroke volume
      increased from 26 +/- 2 mL to 31 +/- 3 mL at 1 hour (P <.05), 33 +/- 3 mL at 3
      hours (P <.05), and 34 +/- 3 mL at 6 hours (P <.05). There were no significant
      changes compared to baseline in ejection fraction or stroke volume in 5 HF
      control dogs studied for up to 4 hours. CONCLUSION: In dogs with HF, CCM signal
      delivery for 6 hours elicited marked improvement in LV function. This novel
      approach may represent a useful adjunctive therapy for the treatment of patients
      with HF.

PMID- 12612877
TI  - Recommendations for the reporting of extra-adrenal paragangliomas. The
      Association of Directors of Anatomic and Surgical Pathology.

PMID- 12612879
TI  - Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of
      memory and activated T cells.
AB  - Certain systemic conditions predispose patients to excessive lymphocyte responses
      to immune-perturbing drugs, which may progress to malignant lymphoma. Many
      pathologists and clinicians believe that differentiation of pseudolymphoma from
      cutaneous T cell lymphoma (CTCL) can be reliably made through phenotypic and
      molecular analysis. We encountered 15 cases of atypical cutaneous T-cell lymphoid
      hyperplasia in the setting of drug therapy. We explored phenotypic anomalies
      using antibodies to CD2, 3, 4, 7, 8, 20, 30 and CD62 K and sought T-cell receptor
      gene rearrangements by a polymerase chain reaction methodology. The lymphoid
      infiltrates showed reproducible CD7 and/or CD62 K deletion in concert with T cell
      clonality and variable CD30 positivity-findings similar to those of CTCL-but the
      rashes resolved or improved substantially after drug modulation. We hypothesize
      that the infiltrates represent an unrepressed expansion of CD7- and CD62 K
      negative activated memory T lymphocytes in response to antigenic triggers. We
      propose the term "drug-induced reversible lymphoid dyscrasia" to describe this
      entity.

PMID- 12612878
TI  - Recommendations for the reporting of tissues removed as part of the surgical
      treatment of common malignancies of the eye and its adnexa. The Association of
      Directors of Anatomic and Surgical Pathology.

PMID- 12612880
TI  - Lack of human herpesvirus 8 and Epstein-Barr virus in Kikuchi's histiocytic
      necrotizing lymphadenitis.
AB  - Kikuchi's histiocytic necrotizing lymphadenitis is a self-limited disorder that
      typically involves the cervical lymph nodes of young women. Although a viral
      etiology has been postulated, a definitive viral agent has not been identified.
      Recent reports have suggested that human herpesvirus 8 (HHV 8) or Epstein-Barr
      virus (EBV) may play an etiologic role. We investigated the presence of HHV 8 and
      EBV in archival tissue from 34 cases of Kikuchi's histiocytic necrotizing
      lymphadenitis. We examined 29 cases for HHV 8 using a nested polymerase chain
      reaction (PCR) on paraffin-embedded or frozen tissue, and 24 cases for EBV RNA
      using in situ hybridization (ISH) for EBER1. Controls included reactive lymph
      nodes from 8 adult women presenting with cervical or axillary lymphadenopathy.
      The study patients included 7 men and 27 women with a mean age of 28 years. All
      patients were previously healthy without evidence of immunocompromise and
      presented with cervical, axillary, or inguinal lymphadenopathy. Two cases
      exhibited EBV RNA by ISH; this was confirmed by PCR for EBV DNA. HHV 8 DNA was
      not amplified by nested PCR in any of the cases of Kikuchi's histiocytic
      necrotizing lymphadenitis or reactive lymph nodes; control PCR demonstrated the
      presence of amplifiable DNA in all cases. These findings suggest that HHV 8 and
      EBV do not play causative roles in Kikuchi's histiocytic necrotizing
      lymphadenitis.

PMID- 12612881
TI  - The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung.
AB  - Rb protein in its hypophosphorylated form acts as a cell cycle regulator for G1
      arrest. Both cyclin D1 overexpression and P16(INK4) loss of protein produce
      persistent hyperphosphorylation of Rb with resultant evasion of cell cycle
      arrest. To better establish the mechanisms of loss of Rb function in
      neuroendocrine lung tumors, we performed an immunohistochemical analysis of the
      P16(INK4)/cyclin D1/Rb pathway in the spectrum of neuroendocrine tumors,
      including 34 typical carcinoids (TCs), 25 atypical carcinoids (ACs), 42 large
      cell neuroendocrine carcinomas (LCNECs), and 79 small cell lung carcinomas
      (SCLCs). Absence of Rb expression was not observed in TCs but was seen in 21% of
      ACs, 68% of LCNECs, and 87% of SCLCs. P16 was expressed in 91% of TCs, 77% of
      ACs, 78% of LCNECs, and 93% of SCLCs. Cyclin D1 was overexpressed in 6% of TCs,
      20% of ACs, 9.5% of LCNECs, and 1.3% of SCLCs. There was an inverse relationship
      between Rb and P16 in high-grade tumors (P < 0.001) and a direct relationship
      between cyclin D1 and Rb (P < 0.001) in all tumors, demonstrating that P16 and
      cyclin D1 act exclusively on the Rb pathway for cell cycle regulation. Overall,
      the Rb pathway (Rb/P16(INK4)/cyclin D1) was altered more frequently in ACs than
      in TCs (P = 0.001) and more frequently in LCNECs than in ACs (P = 0.001).
      Although Rb-negative tumors had shorter survival in the overall group (P < 0.001)
      as a result of lack of Rb in most SCLCs, cyclin D1 overexpression and P16 loss
      did not influence survival in any individual category. We conclude that Rb
      pathway of G1 arrest is consistently compromised in high-grade neuroendocrine
      lung tumors (92%), primarily through loss of Rb protein, and is intact in low
      grade TCs. In ACs an intermediate level of alterations (59%) is seen, consistent
      with their less-aggressive behavior compared with high-grade tumors. The specific
      profile of the Rb pathway parameters might provide specific therapeutic targets
      in neuroendocrine lung tumors.

PMID- 12612882
TI  - Loss of cables protein expression in human non-small cell lung cancer: a tissue
      microarray study.
AB  - Loss of heterozygosity (LOH) on chromosome 18q is common in lung cancer. The
      genes involved in LOH on 18q in lung cancer have not been well characterized.
      Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been
      identified and mapped to human chromosome 18q11-12. Cables inhibits cell growth
      and suppresses tumor formation in nude mice, making it a candidate gene for 18q
      LOH in lung cancer. Little is known regarding Cables protein expression in human
      non-small cell lung cancer (NSCLC). In this study we examined Cables expression
      in 163 NSCLC and nonneoplastic lung specimens using tissue microarrays. Strong
      nuclear staining was present in normal lung and bronchial tissue. We also
      evaluated the Cables protein expression pattern and its correlation with
      histopathologic features and with clinical course of NSCLC. The results of the
      present study demonstrate for the first time that numerous NSCLCs (45%) lose
      Cables expression. Furthermore, more adenocarcinomas show a loss of this novel
      protein than do squamous counterparts. The relationship between tumor histology
      type and Cables expression appears to be statistically significant (P = 0.028).
      Our results suggest that Cables may be involved in the pathogenesis of NSCLC.

PMID- 12612883
TI  - Expression of multidrug resistance-associated proteins in rhabdomyosarcomas
      before and after chemotherapy: the relationship between lung resistance-related
      protein (LRP) and differentiation.
AB  - Rhabdomyosarcomas generally respond well to chemotherapy, and the residual
      lesions often are better differentiated than their primaries. This phenomenon may
      be explained by selective multidrug resistance (MDR) of differentiated tumor cell
      populations. We assess the role of MDR proteins in chemotherapy-induced
      differentiation in rhabdomyosarcomas in a clinical setting. Paraffin-embedded
      samples of 13 pairs of primary untreated rhabdomyosarcomas and their residual,
      recurrent, or metastatic lesions after chemotherapy were assessed for expression
      of MDR proteins, including P-glycoprotein (Pgp), multidrug resistance-associated
      protein (MRP-1), and lung resistance-related protein (LRP). Expression was
      semiquantitatively scored based on the percentage of isolated immunoreactive
      tumor cells as follows: 0, negative; 0.5, <5%; 1, 5% to 25%; 2, 26% to 50%; 3,
      51% to 75%, and 4, >75%. All specimens after chemotherapy, except the late
      recurrences, were better differentiated than their primary, untreated specimens.
      Pgp or MRP-1 expression did not change significantly, but LRP expression
      increased significantly after chemotherapy. In both untreated and treated
      samples, LRP was expressed primarily in differentiated cells. The findings
      indicate that the in vivo expression of LRP, but not of Pgp and MRP-1, is induced
      by chemotherapeutic treatment in rhabdomyosarcomas. The preferential expression
      of LRP in differentiated cells and the subsequent more extensive expression after
      chemotherapy suggests that LRP plays a role in therapy-induced differentiation.

PMID- 12612884
TI  - Metaplasia of the duodenum shows a Helicobacter pylori-correlated differentiation
      into gastric-type protein expression.
AB  - The origin of gastric metaplasia of the duodenum (GMD) remains enigmatic. We
      studied expression of mucins and trefoil peptides in GMD to gain insight into its
      phenotype and origin. We examined duodenal tissue of 95 patients (0 to 83 years
      old, 26 with gastric Helicobacter pylori infection) for the presence of GMD.
      Expression was examined immunohistochemically of secretory mucins (MUC2, MUC5AC,
      MUC5B, and MUC6), trefoil peptides (TFF1, TFF2, and TFF3), and sucrase-isomaltase
      (SI). GMD, found in 37 patients, correlated positively to gastric H. pylori
      infection, age, and villus atrophy. MUC2 and TFF3, expressed in normal goblet
      cells, were absent from 100% and 87% of GMD, respectively. GMD ubiquitously
      expressed MUC5AC, whereas MUC5AC expression in adjacent goblet cells was closely
      correlated with the extent of GMD. TFF1, TFF2, and MUC6 were found in 84%, 92%,
      and 65% of GMD, respectively. MUC5B was absent from epithelium and GMD. SI,
      expressed by villus enterocytes, was absent from GMD. Brunner's glands
      ubiquitously expressed MUC5B, MUC6, and TFF2. GMD was characterized by the
      expression of gastric-type proteins MUC5AC, MUC6, TFF1, and TFF2 and the absence
      of intestinal markers MUC2, TFF3, and SI. In terms of the location of metaplastic
      cells, our results suggest that epithelial cells migrating toward villus tips
      switch to gastric-type secretory cells. Positive correlation with infection
      suggests an inductive role H. pylori in the development of GMD.

PMID- 12612885
TI  - Immunohistochemical visualization of histone H1 phosphorylation in squamous
      intraepithelial lesions of the gynecologic tract.
AB  - Immunohistochemical staining was performed on gynecologic tract squamous
      intraepithelial lesions using a novel phosphorylation-specific monoclonal
      antibody (designated 12D11) that detects histone H1 when phosphorylated at a
      cyclin-dependent kinase (CDK)-responsive epitope. Findings were compared to
      immunostaining by MIB-1, an extensively studied antibody probe of proliferation.
      Routinely fixed and processed archival sections were subjected to distinct
      antigen retrieval and staining protocols for each antibody and were processed for
      immunodetection of either Ki-67 (with MIB-1) or phosphohistone H1, using a
      streptavidin-biotin kit and diaminobenzidine as chromagen. For 12D11 staining,
      antigen retrieval was performed at pH 4.0, and the antibody incubation buffer was
      supplemented with 1.0 M NaCl. Both 12D11 and MIB-1 stained parabasal cells in
      normal squamous epithelium. Staining by 12D11 and MIB-1 of cells in progressively
      higher strata was found to correlate with the severity of lesions. The mean
      proportion of positively stained cells was higher in MIB-1-stained sections than
      in 12D11-stained sections in normal squamous epithelium and in all grades of
      squamous intraepithelial lesions. We conclude that the changes in expression
      patterns of CDK-phosphorylated histone H1 in the spectrum of gynecologic squamous
      intraepithelial lesions are similar to staining patterns obtained with the
      proliferation probe MIB-1. The differing proportion of cells stained by MIB-1 and
      12D11 suggests that phosphohistone H1 may be a useful alternative proliferation
      marker that detects a different subpopulation of cycling cells in premalignant
      squamous lesions.

PMID- 12612886
TI  - Prognostic implications of CD95 receptor expression in clear cell renal
      carcinomas.
AB  - The CD95 (Apo-1/Fas) receptor-ligand system is a key regulator of apoptosis. Down
      regulation of CD95 receptor and up-regulation of CD95 ligand has been reported in
      a variety of human tumors and is thought to confer a selective survival
      advantage. To explore the relevance of the CD95 system for tumor progression and
      prognosis in clear cell renal cell carcinomas (RCCs), we analyzed CD95 receptor
      and ligand expression in formalin-fixed tissue from 149 clear cell RCCs by
      immunohistochemistry. CD95 ligand expression could not be detected in
      nonneoplastic tubule epithelia and in clear cell RCCs. In contrast, CD95 receptor
      expression was found in the great majority of clear cell RCCs, and no down
      regulation of CD95 receptor protein was evident when compared with nonneoplastic
      tubule epithelia. Although a significant increase (P = 0.004) of CD95 receptor
      expression was evident from well-differentiated (G1) to poorly differentiated
      (G3) RCCs, CD95 receptor expression was not correlated with tumor stage or
      survival of RCC patients. In conclusion, clear cell RCCs differ from other types
      of human cancer by their failure to down-regulate CD95 receptor expression or up
      regulate CD95 ligand expression during tumor progression. These ex vivo
      observations suggest that down-regulation of CD95 receptor expression may not
      provide an additional selective growth advantage to RCC cells and thus further
      confirm our previous in vitro observations on a functional impairment of CD95
      mediated apoptosis in RCC.

PMID- 12612887
TI  - High diagnostic accuracy of adrenal core biopsy: results of the German and
      Austrian adrenal network multicenter trial in 220 consecutive patients.
AB  - Incidentally detected adrenal tumors are a common finding during abdominal
      ultrasonography, computed tomography, and magnetic resonance imaging. Although
      most of these lesions are benign adenomas, adrenocortical carcinomas and
      metastases constitute 5% to 10% of all tumors. Adrenal biopsy may be helpful, but
      its diagnostic value is controversial and disputed, and prospective studies have
      not yet been performed. Therefore, the diagnostic accuracy of adrenal core biopsy
      was evaluated in a prospective multicenter study involving 8 surgical centers in
      Germany and Austria. A total of 220 biopsies from surgical specimens of the
      adrenal gland were punctured in an ex vivo approach and processed for
      pathohistologic diagnosis using paraffin sections, routine staining, and
      immunohistochemistry (keratin KL1, vimentin, S100 protein, chromogranin A,
      synaptophysin, neuron-specific enolase, D11, MiB-1, and p53 protein). The
      evaluating pathologist was blinded for clinical data from the patients. A total
      of 89 adrenal adenomas (40.5%), 22 adrenal carcinomas (10.0%), 55
      pheochromocytomas (25.0%), 15 metastases (6.8%), 16 adrenal hyperplasias (7.2%),
      and 23 other tumors (10.5%) were studied. Nine cases were excluded due to
      incomplete data (n = 2) or insufficient biopsy specimen (n = 7). In the remaining
      211 tumors, compared with the final diagnoses of the surgical specimen, bioptic
      diagnoses were absolutely correct in 76.8% of the cases, nearly correct in 13.2%
      of the cases, and incorrect in 10% of the cases. Pheochromocytomas were correctly
      diagnosed in 96% of the cases, cortical adenomas were correctly or nearly
      correctly reported in 91% of the cases, cortical carcinomas were correctly or
      nearly correctly reported in 76% of the cases, and metastases were correctly or
      nearly correctly reported in 77% of the cases. Of the 39 malignant lesions, only
      4 were misclassified, 2 as benign and 2 as possibly malignant. This resulted in
      an overall sensitivity for malignancy of 94.6% and specificity of 95.3%. Our
      findings suggest that adrenal core biopsy is a useful method for identifying and
      classifying adrenal tumorous lesions if sufficient biopsy specimens can be
      obtained. However, in clinical practice it remains to be shown whether the
      benefits of biopsy outweigh the risks of the procedure.

PMID- 12612888
TI  - Histologic changes resembling acute rejection in a liver transplant patient
      treated with terbinafine.
AB  - We present a case of histologic changes resembling acute cellular rejection in a
      liver transplant patient treated with terbinafine. Approximately 5 years after
      orthotopic liver transplantation, a 51-year-old Hispanic man developed elevated
      liver enzyme levels. A biopsy sample was interpreted as acute cellular rejection,
      and the patient was treated with increased immunosuppression. Review of
      medications showed that the patient had been started on terbinafine approximately
      4 weeks earlier for onychomycosis, and it was discontinued. A follow-up visit 2
      weeks later revealed progressive jaundice, malaise, and nausea, and evaluation of
      a second liver biopsy sample revealed marked centrilobular cholestasis and severe
      bile duct damage, consistent with terbinafine hepatotoxicity. Although these
      histologic changes have been described in treated patients with both normal and
      abnormal livers, the potential for confusion with acute rejection in patients
      with hepatic transplantation has not previously been reported.

PMID- 12612889
TI  - Spindle epithelial tumor with thymus-like differentiation of the thyroid: a case
      report with pathological and molecular genetics study.
AB  - We report an unusual case of spindle epithelial tumor with thymus-like
      differentiation (SETTLE) of the thyroid present in a 6-year-old boy. The tumor,
      located at both the left lobe and isthmus, was a circumscribed mass with slightly
      gritty whorled appearance. Microscopically, the lobulated, highly cellular,
      spindle cell neoplasm was arranged in intersecting bundles and fascicles
      separated by fibrous bands. Benign-appearing glands entrapped within fibrous
      bands and foci of squamous differentiation within spindle cells were observed.
      Immunohistochemically, the spindle cells were diffusely positive for
      cytokeratins, vimentin, and alpha-smooth muscle actin and patchily reactive for
      muscle-specific actin and epithelial membrane antigen, exhibiting myoepithelial
      differentiation. The spindle cells were also patchily immunopositive for p53
      protein. Molecular genetic analysis revealed Ki-ras gene mutations at codons 13
      (GGC(gly) to AGC(ser)) and 15 (GGC(gly) to AGC(ser)) on the same allele. Mutation
      of the p53 gene was not detected. This is the first report on Ki-ras oncogene
      mutations in a case of SETTLE.

PMID- 12612894
TI  - Incontinence considered at interdisciplinary conference.

PMID- 12612890
TI  - Immunohistochemical analysis of retroperitoneal Mullerian cyst.
AB  - Retroperitoneal cysts are uncommon diseases, and benign nonneoplastic Mullerian
      cysts are extremely rare among the known cases. We report a case of a 35-year-old
      woman with a retroperitoneal Mullerian cyst with the tubal type of epithelium.
      The patient presented with a large (20 cm in diameter), palpable abdominal mass.
      This multilocular cystic mass was resected from the retroperitoneum between the
      descending colon and the left renal fascia. Histologically, it was lined by
      monolayered low-cuboidal to columnar cells without atypia that resembled tubal
      epithelium, including cilia. Loose fibrous tissue and incomplete smooth muscle
      bundles were identified beneath the epithelium of the lining. Immunohistochemical
      tests showed that the lining cells were strongly positive for cytokeratins (CKs)
      (polyclonal, 7, 18, CAM 5.2, AE1/AE3), epithelial membrane antigen, cancer
      antigen 125, progesterone receptor, and estrogen receptor. The lining cells were
      also occasionally weakly positive for CK5/6. They tested negative for CK20,
      carcinoembryonic antigen, calretinin, and CD 10.

PMID- 12612892
TI  - New activating mutation in GI stromal tumors.

PMID- 12612895
TI  - Does irritable bowel syndrome really exist? Reactions to the proposed motility
      based classification system.

PMID- 12612896
TI  - Image of the month. Gastric wall abscess.

PMID- 12612897
TI  - Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a
      proof of concept endoscopic study.
AB  - BACKGROUND AND AIMS: NCX-4016 is a nitric oxide-releasing derivative of aspirin
      with antiplatelet activity. The aim of this study was to investigate the effect
      of NCX-4016 on gastrointestinal mucosa and platelet functions in healthy human
      volunteers. METHODS: This was a parallel-group, double-blind, placebo-controlled
      study. Forty healthy subjects were randomly allocated to receive 7 days of
      treatment with NCX-4016 (400 and 800 mg twice daily), equimolar doses of aspirin
      (200 and 420 mg twice daily), or placebo. Upper endoscopies were performed before
      and at the end of the treatment period, and gastroduodenal lesions were graded
      using a predefined scoring system. Basal and posttreatment platelet aggregation
      in response to arachidonic acid (AA) and serum thromboxane (TX) B(2) and AA
      stimulated platelet TXB(2) production were investigated. RESULTS: Mucosal
      endoscopic injury score on day 7 was 0.63 +/- 0.16 in the placebo group and 11.0
      +/- 3.0 and 16.1 +/- 1.6 in healthy volunteers treated with 200 and 420 mg
      aspirin twice daily (P < 0.0001 vs. placebo). NCX-4016 was virtually devoid of
      gastric and duodenal toxicity, resulting in a total gastric and duodenal
      endoscopic score of 1.38 +/- 0.3 and 1.25 +/- 0.5 (P < 0.0001 vs. aspirin, not
      significant vs. placebo). NCX-4016 inhibited AA-induced platelet aggregation as
      well as serum TXB(2) and platelet TXB(2) generation induced by AA to the same
      extent as aspirin (not significant vs. aspirin). CONCLUSIONS: In this study, we
      have proven the concept that addition of an NO-donating moiety to aspirin results
      in a new chemical entity that maintains cyclooxygenase-1 and platelet inhibitory
      activity while nearly avoiding gastrointestinal damage.

PMID- 12612899
TI  - Screening for colorectal cancer in Chinese: comparison of fecal occult blood
      test, flexible sigmoidoscopy, and colonoscopy.
AB  - BACKGROUND AND AIMS: Fecal occult blood testing (FOBT), flexible sigmoidoscopy
      (FS), and colonoscopy are the most commonly recommended screening tests for
      colorectal cancer. The aim of this study was to compare the accuracy and safety
      of these 3 screening procedures in a general population of ethnic Chinese.
      METHODS: Asymptomatic adults older than 50 years were recruited from the general
      public through health exhibitions. All enrolled subjects were offered FOBT and
      full colonoscopy under sedation. Advanced colonic lesions (defined as adenoma >
      or = 10 mm, villous adenoma, adenoma with moderate or severe dysplasia, or
      invasive cancer) were recorded. Lesions at the distal 40 cm in the left colon and
      rectum were taken as findings of FS. RESULTS: A total of 505 subjects (56% women;
      mean age +/- SD, 56.5 +/- 5.4 years) were enrolled, and 476 (94.3%) had a
      complete colonoscopy. Advanced colonic neoplasms were documented in 63 subjects
      (12.5%), of which 45 had lesions in the distal colon and 26 in the proximal
      colon. Among the 385 subjects with a normal distal colon, 14 (3.6%) had advanced
      lesions in the proximal colon that would be missed by FS alone. The sensitivity
      and specificity of FOBT for advanced colonic lesions were 14.3% and 79.2% and the
      sensitivity and specificity of FS were 77.8% and 83.9%, respectively. Combining
      FOBT with FS would not significantly improve the results of FS alone. Among these
      505 subjects who underwent colonoscopy and 148 who underwent polypectomy, there
      was no perforation and only one occurrence of postpolypectomy bleeding recorded.
      CONCLUSIONS: Colonoscopy is a safe and accurate method for the screening of
      colorectal neoplasms in Chinese subjects.

PMID- 12612900
TI  - Gastrin induces proliferation in Barrett's metaplasia through activation of the
      CCK2 receptor.
AB  - BACKGROUND AND AIMS: Factors associated with the development and malignant
      progression of Barrett's esophagus are poorly understood. Gastrin is a mitogen
      capable of inducing growth in normal and malignant gastrointestinal mucosa. It is
      unknown whether gastrin can influence cellular events in the esophagus in
      Barrett's. METHODS: Reverse-transcription polymerase chain reaction (RT-PCR) and
      northern analysis for the cholecystokinin (CCK(2)) receptor were performed on
      normal, inflamed, metaplastic, and malignant esophageal mucosa. Real-time PCR
      quantified expression of the receptor. [(125)I]-G17-autoradiography localized the
      CCK(2) receptor in mucosal sections. [(3)H]-thymidine and bromodeoxyuridine
      (BrdU) incorporation determined proliferation in response to G17 in biopsy
      specimens incubated ex vivo. Proliferation and signaling studies were performed
      on OE33(E) cells transfected with the CCK(2) receptor. RESULTS: RT-PCR identified
      receptor expression in 3 of 9 controls, 5 of 7 patients with esophagitis, 10 of
      10 patients with Barrett's metaplasia, and 7 of 12 esophageal adenocarcinomas.
      Real-time PCR quantified expression in 10 patients with Barrett's showing a level
      of expression 2 orders of magnitude higher than in 12 control patients. [(125)I]
      G17 bound to epithelia within glandular regions of Barrett's mucosa. Ten nmol/L
      G17 induced a 2-fold (n = 7, P = 0.0257, t test) increase in [(3)H]-thymidine
      incorporation in mucosal biopsy specimens, abolished by the addition of the
      CCK(2) receptor antagonist L-740, 093. One nmol/L G17 induced a 1.94- +/- 0.13
      fold (n = 6, t test, P = 0.001) increase in [(3)H]-thymidine incorporation in
      OE33(E)(GR) cells, abolished by L-740, 093. CONCLUSIONS: Gastrin induces
      proliferation via the CCK(2) receptor in Barrett's mucosa. This may have
      implications for the management of patients with Barrett's esophagus in whom
      gastrin is elevated by acid-suppression therapy.

PMID- 12612901
TI  - P14 methylation in human colon cancer is associated with microsatellite
      instability and wild-type p53.
AB  - BACKGROUND AND AIMS: Colorectal cancers with high levels of microsatellite
      instability (MSI-H) have an unexplained low rate of p53 gene mutations. Most such
      cancers have the CpG island methylator phenotype (CIMP+) with methylation and
      transcriptional silencing of the mismatch repair gene MLH1. The p14 (ARF) gene on
      chromosome 9p is deleted and/or silenced by hypermethylation in a subset of human
      malignancies. There is evidence suggesting that p14 suppresses tumorigenicity by
      stabilizing the p53 protein. METHODS: We investigated the role of p14 in
      colorectal cancer by determining its methylation status in cancers that were
      studied previously for microsatellite instability, CIMP, and mutations of p53 and
      K-RAS. RESULTS: p14 methylation was present in 21 of 94 cases overall (22%) and
      was frequent particularly in the subgroups with MSI-H (52% [11 of 21] vs. 14% [10
      of 72], P = 0.004), in CIMP+ cases (40% [19 of 48] vs. 4% [2 of 46], P < 0.001),
      and in cases without p53 alterations (36% [17 of 47] vs. 7% [3 of 44], P =
      0.004). Of 91 fully characterized cases, 41 (45%) had p53 mutations alone, 17
      (19%) had p14 methylation alone, 30 (33%) had neither, but only 3 (3%) had both
      p53 mutations and p14 methylation. p14 methylation is an early event in
      colorectal carcinogenesis, being detectable in normal aging epithelium by using
      sensitive assays. CONCLUSIONS: In colorectal cancer, p14 methylation is
      associated with the presence of microsatellite instability and with absence of
      p53 mutations. The results provide a possible explanation for the paucity of p53
      mutations in colon cancers with microsatellite instability.

PMID- 12612902
TI  - The North American Study for the Treatment of Refractory Ascites.
AB  - BACKGROUND AND AIMS: The clinical utility of transjugular intrahepatic
      portosystemic shunts (TIPS) vis-a-vis total paracentesis in the management of
      refractory ascites is unclear. METHODS: A multicenter, prospective, randomized
      clinical trial was performed in which 109 subjects with refractory ascites were
      randomized to either medical therapy (sodium restriction, diuretics, and total
      paracentesis) (n = 57) or medical therapy plus TIPS (n = 52). The principal end
      points were recurrence of tense symptomatic ascites and mortality. RESULTS: A
      technically adequate shunt was created in 49 of 52 subjects. TIPS plus medical
      therapy was significantly superior to medical therapy alone in preventing
      recurrence of ascites (P < 0.001). The total number of deaths in the 2 groups was
      identical (TIPS vs. medical therapy alone: 21 vs. 21). There were no significant
      differences in the 2 arms with respect to overall and transplant-free survival.
      There was a higher incidence of moderate to severe encephalopathy in the TIPS
      group (20 of 52 vs. 12 of 57; P = 0.058). There were no significant differences
      in the number of subjects who developed liver failure (7 vs. 3), variceal
      hemorrhage (5 vs. 8), or acute renal failure (3 vs. 2). There were also no
      significant differences between the 2 groups in the frequency of emergency
      department visits, medically indicated hospitalizations, or quality of life.
      CONCLUSIONS: Although TIPS plus medical therapy is superior to medical therapy
      alone for the control of ascites, it does not improve survival, affect
      hospitalization rates, or improve quality of life.

PMID- 12612903
TI  - Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after
      liver transplantation: a randomized study.
AB  - BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver
      transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use
      of antiviral therapy in this situation remains controversial. This study aimed to
      assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent
      hepatitis C following liver transplantation. METHODS: Transplant recipients with
      recurrent chronic hepatitis C were randomized to receive either no treatment or
      therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day
      ribavirin for 1 year. Patients were followed up for 6 months after the end of
      treatment. The primary end point was loss of HCV RNA 6 months after the end of
      treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo,
      24). Sixteen patients were withdrawn from the study; 12 (43%) were from the
      treated group (mainly for anemia [7 patients]) and 4 (17%) from the control
      group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%)
      at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas
      no patient in the control group lost HCV RNA at any point (P = 0.036 at the end
      of follow-up). However, there was no significant histologic improvement.
      CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a
      sustained virologic response in 21% of transplant recipients with recurrent
      hepatitis C. However, 43% discontinued therapy due to adverse events (primarily
      severe anemia). Strategies to enable treatment with lower doses of ribavirin need
      to be explored.

PMID- 12612904
TI  - A quantitative gene expression study suggests a role for angiopoietins in focal
      nodular hyperplasia.
AB  - BACKGROUND AND AIMS: Although the pathogenesis of focal nodular hyperplasia (FNH)
      of the liver remains unclear, a vascular mechanism has been suspected. To gain
      insight into the pathogenesis of FNH, we performed a large-scale quantitative
      study of gene expression in FNH. METHODS: Quantitative expression level of 209
      selected genes was assessed using real-time reverse-transcription polymerase
      chain reaction in 14 cases of FNH and compared with their expression level in 13
      cases of liver cirrhosis, 4 adenomas, and 15 hepatocellular carcinomas. RESULTS:
      Among the 7 genes, the expression of which was significantly up-regulated or down
      regulated in FNH, the most informative markers for the diagnosis of FNH as
      assessed using the receiving operative curve and area under the curve (AUC) were
      angiopoietin-1 (Ang-1; AUC, 0.82) and angiopoietin-2 (Ang-2; AUC, 0.80). These 2
      genes are involved in the regulation of vasculogenesis. In FNH, Ang-1 was
      significantly up-regulated, Ang-2 was down-regulated, and the Ang-1/Ang-2 ratio
      was highly and specifically increased in FNH compared with normal liver or other
      groups of lesions (FNH, 15.2-fold increase; HCC, 2.78; adenoma, 2.28; cirrhosis,
      1.92; P < 0.01 for FNH vs. all groups, analysis of variance). Tie-2 messenger
      RNA, the receptor of Ang-1 and Ang-2, was detected at the same level in FNH as in
      normal liver. Ang-1 protein was detected on Western blot of FNH and expressed by
      endothelial cells of dystrophic vessels and sinusoids as shown by
      immunohistochemistry. CONCLUSIONS: A specific increase of Ang-1/Ang-2 ratio in
      FNH, in the presence of the functional Tie-2 receptor, might be involved in the
      formation of hyperplastic and dystrophic vessels of FNH.

PMID- 12612905
TI  - Isolation-stress increases small intestinal sensitivity to chemotherapy in rats.
AB  - BACKGROUND AND AIMS: Severe gastrointestinal damage often complicates the use of
      chemotherapeutic agents such as methotrexate for anticancer treatment.
      Psychologic stress is known to be detrimental to normal intestinal physiology. We
      set out to determine if psychologic stress adds to the intestinal damage provoked
      by chemotherapy. METHODS: Rats were treated with various doses of methotrexate
      and housed either alone, which induces mental stress, or maintained in groups of
      3 animals. Treatment was evaluated by (immuno)histologic parameters. RESULTS:
      Epithelial crypt damage, increased lysozyme expression, decreased sucrase
      isomaltase and sodium/glucose transporter 1 expression, and pathologic changes in
      mucin and trefoil factor protein expression could be prevented by avoiding
      isolation. Enhanced cytotoxicity of methotrexate through isolation was about 2
      fold and involved an augmented inhibition of proliferation, increased epithelial
      apoptosis, increased villus damage, and delayed recovery. We could not identify a
      role for mucosal mast cells in the increased epithelial damage under isolated
      conditions. CONCLUSIONS: The clear beneficial effects of avoiding mental stress
      on the protection of the intestinal epithelium during cytostatic drug-treatment
      may be an important element for the treatment of cancer patients.

PMID- 12612907
TI  - Leptin mediates Clostridium difficile toxin A-induced enteritis in mice.
AB  - BACKGROUND & AIMS: Leptin regulates energy homeostasis and participates in the
      regulation of the hypothalamic-pituitary-adrenal axis. Although hyperleptinemia
      is described in experimental colitis, its role in the pathophysiology of
      enterotoxin-mediated diarrhea and inflammation remains unclear. We examined the
      role of leptin in the inflammatory diarrhea induced by toxin A from Clostridium
      difficile, the causative agent of antibiotic-related colitis. METHODS: Toxin A
      (10 microg) or buffer were administered in ileal loops of leptin-deficient
      (ob/ob), leptin-resistant (db/db), or wild-type mice and enterotoxic responses
      were measured. RESULTS: In toxin A-treated wild-type mice, circulating leptin and
      corticosterone levels were increased compared with buffer-injected animals. Toxin
      A also stimulated increased mucosal expression of the Ob-Rb at the messenger RNA
      (mRNA) and protein level. Ob/ob and db/db mice were partially protected against
      toxin A-induced intestinal secretion and inflammation, and this effect was
      reversed by leptin administration in ob/ob, but not db/db, mice. Basal- and toxin
      A-stimulated plasma corticosterone levels in ob/ob and db/db mice were higher
      compared with toxin A-treated wild-type mice. To assess whether the effect of
      leptin in intestinal inflammation is mediated by corticosteroids we performed
      adrenalectomy experiments in db/db and wild-type mice. Our results suggested that
      the diminished intestinal response to toxin A in db/db mice was related only in
      part to increased levels of corticosteroids. CONCLUSIONS: Leptin plays an
      important role in regulating the severity of enterotoxin-mediated intestinal
      secretion and inflammation by activating both corticosteroid-dependent and 
      independent mechanisms.

PMID- 12612906
TI  - T helper type-2 cells induce ileal villus atrophy, goblet cell metaplasia, and
      wasting disease in T cell-deficient mice.
AB  - BACKGROUND & AIMS: T helper (Th) 1 and Th2 cell subsets significantly influence
      the pathological features of inflammation in the gastrointestinal tract in a
      distinct manner. It is now established that the transfer of CD4(+)CD45RB(Hi)
      (RB(Hi)) T cells to either severe combined immunodeficient (SCID) or recombinase
      activation gene 2-deficient (RAG(-/-)) mice results in a severe granulomatous
      hypertrophic colitis mediated by Th1 cells. We have modified this approach to
      address the role of Th2 cells. METHODS: RB(Hi) T cells from wild-type (Wt) mice
      or mice genetically predisposed to Th2 responses (interferon-gamma-defective [IFN
      gamma(-/-)]) with or without B cells were transferred to T cell receptor (TCR)
      beta and delta-chain-defective (TCR(-/-)) or SCID mice. RESULTS: Transfer of Wt
      RB(Hi) T cells induced wasting disease with severe colitis in the TCR(-/-) mice.
      In contrast, IFN-gamma(-/-) RB(Hi) T cells induced severe weight loss and
      hypoalbuminemia without significant inflammation in the colon. The small
      intestine of these mice exhibited villus atrophy, a decrease in brush-border
      enzymes, reduced enterocyte proliferation, and an increased number of goblet
      cells. The presence of B cells was necessary for these changes, because SCID
      recipients required cotransfer of B cells, together with IFN-gamma(-/-) RB(Hi) T
      cells for ileal lesions to develop. Treatment of TCR(-/-) recipients of IFN
      gamma(-/-) RB(Hi) T cells with anti-IL-4 mAb abrogated both the wasting disease
      and the villus atrophy. CONCLUSIONS: Dysregulated Th2 cells cause atrophic
      changes and goblet cell transformation in the small intestinal epithelium and
      wasting disease mediated by excess interleukin-4 and B cells.

PMID- 12612908
TI  - ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell
      dependent release of TNF-alpha/IL-6 in mice.
AB  - BACKGROUND & AIMS: Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6
      mediate hepatocyte proliferation in vivo, suggesting that local and systemic
      inflammatory reactions may trigger hepatic regeneration after major tissue loss.
      METHODS: Wild-type, intercellular adhesion molecule (ICAM)-1-/-, and neutropenic
      induced mice were subjected to 70% hepatectomy. Three different approaches to
      block and/or deplete liver macrophages (Kupffer cells) were used. RESULTS: We
      found that liver from ICAM-1-deficient mice exhibited impaired regeneration after
      partial hepatectomy. This finding is associated with dramatic decrease in
      leukocyte recruitment and tissue TNF-alpha and IL-6 levels. All markers of
      hepatocyte proliferation were restored in ICAM-/- mice by injections of
      recombinant IL-6. Neutropenic animals and liver macrophage (Kupffer cell)
      depletion resulted in similar failure of regeneration with low levels of TNF
      alpha and IL-6. CONCLUSIONS: The data suggest a novel pathway in which ICAM-1
      binds to leukocytes after hepatectomy, triggering hepatocyte proliferation
      through Kupffer cell-dependent release of TNF-alpha and IL-6.

PMID- 12612909
TI  - Liver regeneration in heparin-binding EGF-like growth factor transgenic mice
      after partial hepatectomy.
AB  - BACKGROUND & AIMS: Heparin-binding epidermal growth factor-like growth factor (HB
      EGF), a member of the EGF family, is synthesized in the form of a membrane
      anchored precursor (proHB-EGF), which subsequently is processed proteolytically
      to mature HB-EGF. This study describes the effects of HB-EGF on liver
      regeneration after 70% partial hepatectomy in proHB-EGF transgenic mice with
      liver-specific expression. METHODS & RESULTS: No significant differences in
      liver/body weight ratios and in bromodeoxyuridine (BrdU)-labeling index (the
      ratios of BrdU-positive hepatocyte nuclei) were found between adult transgenic
      and wild-type mice. However, in regenerating liver after partial hepatectomy,
      transgenic mice had higher liver/body weight ratios than wild-type mice and at
      120 hours reached a level equal to that before partial hepatectomy. The BrdU
      labeling index was about 5 times higher in the livers of transgenic mice compared
      with the wild type (51.5% vs. 10.2%, respectively; P < 0.01) at 48 hours after
      partial hepatectomy. Activation of microtubule-associated protein kinase after
      partial hepatectomy was higher and earlier in the transgenic mice as compared
      with the wild-type mice. Soluble HB-EGF was increased in the liver (at 8 min)
      after partial hepatectomy, indicating that the shedding of proHB-EGF occurred
      after partial hepatectomy. CONCLUSIONS: The transgenic expression of HB-EGF
      accelerates the proliferation of hepatocytes after partial hepatectomy,
      suggesting that HB-EGF functions as a hepatotrophic factor in vivo.

PMID- 12612910
TI  - Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through
      endoplasmic reticulum stress.
AB  - BACKGROUND & AIMS: Ethanol impairs the mitochondrial transport of reduced
      glutathione (GSH), resulting in lower mitochondrial GSH (mGSH) levels. Our
      purpose was to evaluate the role of acetaldehyde on the regulation of mGSH in
      HepG2 cells. METHODS: mGSH levels and transport, mitochondrial membrane
      microviscosity, and lipid composition were determined in mitochondria isolated
      from acetaldehyde-treated HepG2 cells. RESULTS: The major ultrastructural changes
      of acetaldehyde-treated HepG2 cells included cytoplasmic lipid droplets and
      appearance of swollen mitochondria. Acetaldehyde depleted the mGSH pool size in a
      time- and dose-dependent fashion with spared cytosol GSH levels. Kinetics of GSH
      transport into isolated mitochondria from HepG2 cells showed 2 saturable,
      adenosine triphosphate-stimulated, high- and low-affinity components. Treatment
      with acetaldehyde increased the Michaelis constant for the high- and low-affinity
      components, with a greater impact on the former. These changes were due to
      increased mitochondrial microviscosity by enhanced cholesterol deposition because
      preincubation with the fluidizing agent, 2-(2-methoxyethoxy) ethyl 8-(cis-2-n
      octylcyclopropyl) octanoate, normalized the initial transport rate of GSH into
      isolated mitochondria. Isolated mitochondria from rat liver enriched in free
      cholesterol reproduced the disturbing effects of acetaldehyde on GSH transport.
      The acetaldehyde-stimulated mitochondrial cholesterol content was preceded by
      increased levels of endoplasmic reticulum (ER)-responsive gene GADD153 and
      transcription factor sterol regulatory element-binding protein 1 and mimicked by
      the ER stress-inducing agents tunicamycin and homocysteine. Finally, the mGSH
      depletion induced by acetaldehyde sensitized HepG2 cells to tumor necrosis factor
      (TNF)-alpha-induced apoptosis that was prevented by cyclosporin A, GSH ethyl
      ester, and lovastatin. CONCLUSIONS: Acetaldehyde sensitizes HepG2 cells to TNF
      alpha by impairing mGSH transport through an ER stress-mediated increase in
      cholesterol.

PMID- 12612911
TI  - Macrophage migration inhibitory factor is a critical mediator of severe acute
      pancreatitis.
AB  - BACKGROUND & AIMS: Macrophage migration inhibitory factor (MIF), originally
      described as an inhibitor of the random migration of macrophages, has been shown
      recently to be involved in the pathogenesis of several inflammatory diseases such
      as sepsis. The aim of this study was to clarify the role of MIF in acute
      pancreatitis (AP). METHODS: Hemorrhagic necrotizing pancreatitis and edematous
      pancreatitis were induced by the injection of taurocholic acid (TCA pancreatitis)
      and cerulein (cerulein pancreatitis), respectively, on male Wistar rats. MIF
      levels in ascitic fluids, serum, and the organs were determined. The effects of
      anti-MIF antibody were examined on the prognosis of rats with TCA pancreatitis
      and of female CD-1 mice with choline-deficient, ethionine-supplemented, diet
      induced model of severe AP. In addition, serum MIF levels in AP patients and in
      healthy controls were measured. RESULTS: Serum and ascitic MIF levels in TCA
      pancreatitis were increased rapidly and decreased gradually thereafter. Ascitic
      MIF levels were also increased in cerulein pancreatitis, but to a lesser degree.
      MIF level was increased in the lung in TCA pancreatitis, but not in the pancreas
      and the liver. Prophylactic (1 hour before and immediately after induction)
      administration of anti-MIF antibody significantly improved the survival rate of
      rats with TCA pancreatitis. The survival rate of mice with severe AP was also
      improved significantly by the antibody treatment. Serum MIF levels were higher in
      severe AP patients than mild AP patients and healthy controls. CONCLUSIONS: These
      results suggest a role of MIF in the pathogenesis of severe AP.

PMID- 12612912
TI  - Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP
      dependent secretion in cholangiocytes.
AB  - BACKGROUND & AIMS: The biliary epithelium is involved both in bile production and
      in the inflammatory/reparative response to liver damage. Recent data indicate
      that inflammatory aggression to intrahepatic bile ducts results in chronic
      progressive cholestasis. METHODS: To understand the effects of nitric oxide on
      cholangiocyte secretion and biliary tract pathophysiology we have investigated:
      (1) the effects of proinflammatory cytokines on NO production and expression of
      the inducible nitric oxide synthase (NOS2), (2) the effects of NO on cAMP
      dependent secretory mechanisms, and (3) the immunohistochemical expression of
      NOS2 in a number of human chronic liver diseases. RESULTS: Our results show that:
      (1) tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma, synergically
      stimulate NO production in cultured cholangiocytes through an increase in NOS2
      gene and protein expression; (2) micromolar concentrations of NO inhibit
      forskolin-stimulated cAMP production by adenylyl cyclase (AC), cyclic adenosine
      monophosphate (cAMP)-dependent fluid secretion, and cAMP-dependent Cl(-) and
      HCO(3)(-) transport mediated by cystic fibrosis transmembrane conductance
      regulator (CFTR) and anion exchanger isoform 2, respectively; (3) cholestatic
      effects of NO and of proinflammatory cytokines are prevented by NOS-2 inhibitors
      and by agents (manganese(III)-tetrakis(4-benzoic acid)porphyrin [MnTBAP], urate,
      trolox) able to block the formation of reactive nitrogen oxide species (RNOS);
      (4) NOS2 expression is increased significantly in the biliary epithelium of
      patients with primary sclerosing cholangitis (PSC). CONCLUSIONS: Our findings
      show that proinflammatory cytokines stimulate the biliary epithelium to generate
      NO, via NOS2 induction, and that NO causes ductular cholestasis by a RNOS
      mediated inhibition of AC and of cAMP-dependent HCO(3)(-) and Cl(-) secretory
      mechanisms. This pathogenetic sequence may contribute to ductal cholestasis in
      inflammatory cholangiopathies.

PMID- 12612913
TI  - Alterations of brain activity associated with resolution of emotional distress
      and pain in a case of severe irritable bowel syndrome.
AB  - BACKGROUND & AIMS: The association of psychosocial disturbances with more severe
      irritable bowel syndrome (IBS) is well recognized. However, there is no evidence
      as to how these associations might be mediated. Functional magnetic resonance
      imaging (fMRI) offers an opportunity to study whether activation of the cingulate
      cortex, an area involved with the affective and pain intensity coding might be
      linked to poorer clinical status with IBS. In this case report, we found an
      association between the severity of a patient's clinical symptoms and
      psychosocial state, with activation of the cingulate cortex. We also found that
      clinical and psychosocial improvement was associated with reduced cingulate
      activation. METHODS: Observational case report of a young woman observed for 16
      years with a history of sexual abuse, psychosocial distress, and functional GI
      complaints. Psychosocial, clinical, and fMRI assessment was performed when the
      patient experienced severe symptoms and again 8 months later when clinically
      improved. RESULTS: During severe illness, the patient had major psychosocial
      impairment, high life stress, a low visceral pain threshold, and activation of
      the midcingulate cortex (MCC), prefrontal area 6/44, and the somatosensory
      cortex, areas associated with pain intensity encoding. When clinically improved,
      there was resolution in activation of these 3 areas, and this was associated with
      psychosocial improvement and an increased threshold to rectal distention.
      CONCLUSIONS: Activation of the MCC and related areas involved with visceral pain
      encoding are associated with poor clinical status in patients with severe IBS and
      psychosocial distress and appear to be responsive to clinical improvement.

PMID- 12612915
TI  - Oxidants and antioxidants in alcohol-induced liver disease.
AB  - Although there are numerous experimental data indicating that oxidative stress
      plays a role in the initiation and progression of alcohol-induced liver disease
      (ALD), this work has yet to translate into an accepted antioxidant therapy for
      ALD in humans. With a better understanding of the mechanisms by which oxidative
      stress leads to liver damage during alcohol exposure, therapies that are more
      targeted at the cellular/molecular level may be applied in the clinic with
      potentially greater success. This article discusses the general concepts of
      oxidative stress and how it relates to current hypotheses in alcohol-induced
      liver injury, as well as lists several key questions that remain to be addressed
      in this field: (1) Which prooxidants are involved in ALD? (2) What are the
      sources of prooxidants in the liver during alcohol exposure? (3) How are oxidants
      involved in alcohol-induced liver injury? (4) Can a rational and effective
      antioxidant therapy against ALD be developed?

PMID- 12612916
TI  - American Gastroenterological Association medical position statement: guidelines
      on osteoporosis in gastrointestinal diseases.

PMID- 12612914
TI  - Pathology of mouse models of intestinal cancer: consensus report and
      recommendations.

PMID- 12612918
TI  - Mandate to modify a medicinal mantra: maybe not yet?

PMID- 12612917
TI  - AGA technical review on osteoporosis in gastrointestinal diseases.

PMID- 12612919
TI  - Pancreatitis and associated lung injury: when MIF miffs.

PMID- 12612920
TI  - When bile ducts say NO: the good, the bad, and the ugly.

PMID- 12612921
TI  - Can gastrografin heal the obstructed bowel?

PMID- 12612923
TI  - Hypercholesterolemia in primary biliary cirrhosis: getting to the heart of the
      matter?

PMID- 12612925
TI  - Cost-effectiveness of screening for colorectal cancer: the dollar is in the
      details.

PMID- 12612926
TI  - Pathogenesis of sodium retention in preascites: have we reached the heart of the
      problem?

PMID- 12612932
TI  - Should patients with IBS be submitted to painful rectal distention in clinical
      practice?

PMID- 12612931
TI  - Pancreatitis from bile reflux-again?

PMID- 12612934
TI  - An enormous ventral (epigastric) hernia as a cause of acute pancreatitis:
      Pfeffer's closed duodenal loop model in the animal, first seen in a human.

PMID- 12612935
TI  - Effect of iron depletion in patients with nonalcoholic fatty liver disease
      without carbohydrate intolerance.

PMID- 12612937
TI  - High frequency of CCR5-delta32 homozygosity in HCV-infected, HIV-1-uninfected
      hemophiliacs results from resistance to HIV-1.

PMID- 12612938
TI  - HCV chronic infection and CCR5-delta32/delta32.

PMID- 12612942
TI  - Progression of chronic renal disease.
AB  - Risk factors for progression of kidney disease include hypertension, proteinuria,
      male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein
      diets, phosphate retention, and metabolic acidosis. Angiotensin II production
      upregulates the expression of transforming growth factor-beta1, tumor necrosis
      factor-alpha, nuclear factor-kappaB, and several adhesion molecules and
      chemoattractants. In addition to angiotensin, other vasoactive compounds, such as
      thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with
      one of several growth factors may ameliorate the progression of kidney disease:
      insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic
      protein-7.

PMID- 12612943
TI  - Effects of oral adsorbent on gene expression profile in uremic rat kidney: cDNA
      array analysis.
AB  - BACKGROUND: An oral adsorbent, AST-120, is effective in removing such uremic
      toxins as indoxyl sulfate and delays the progression of chronic renal failure. To
      elucidate the molecular mechanisms underlying the renoprotective effects of AST
      120, the complementary DNA (cDNA) array method was used to survey the alteration
      in gene expression profiles of uremic rat kidneys in response to AST-120.
      METHODS: Six weeks after five-sixth nephrectomy, 10 uremic rats were divided into
      two groups: those administered AST-120 and control uremic rats. Rats subjected to
      sham operation also were included as normal rats. After administration of AST-120
      for 18 weeks, renal tissues were analyzed by cDNA array. RESULTS: Among the 343
      genes selected as expressed, control uremic rats showed significantly increased
      levels of 139 genes and significantly decreased levels of 45 genes compared with
      normal rats. AST-120 treatment attenuated expression levels of 43 of the 139
      upregulated renal genes and 21 of the 45 downregulated renal genes in uremic rat
      kidney. Those genes could be subdivided into several functional categories,
      including cytokine (transforming growth factor-beta1 [TGF-beta1], etc),
      intracellular signaling, transcription, translation, channel and transporter
      (organic anion transporter 1 [OAT1], etc), metabolism, and protease and its
      inhibitor. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR)
      analysis showed that AST-120 significantly increased OAT1 renal expression and
      tended to decrease TGF-beta1, tissue inhibitor of metalloproteinase-1 (TIMP-1),
      and endothelin-1 renal expression in uremic rats. There were statistically
      significant positive correlations between cDNA array-based and RT-PCR-based gene
      expression levels of TGF-beta1, TIMP-1, and endothelin-1. CONCLUSION: The cDNA
      array method determines changes in the gene expression profile in uremic rat
      kidney in response to AST-120 and provides new insights into elucidation of the
      molecular mechanism underlying the renoprotective effects of AST-120.

PMID- 12612944
TI  - The role of chemokines and chemokine receptors in progressive renal diseases.
AB  - Chemokines are members of a growing family of chemotactic cytokines, which induce
      recruitment of select leukocyte subpopulations. Additionally, they can activate
      leukocyte effector functions, are involved in the balance between proliferation
      and apoptosis, modulate angiogenesis, and regulate fibroblast functions. Most
      intrinsic renal cells can express chemokines on stimulation in vitro. Induction
      of chemokines and infiltration of chemokine receptor-bearing cells has been shown
      in a variety of animal models of renal diseases, as well as in human diseases and
      allograft rejection. This overview gives a short introduction into chemokines and
      current aspects of their role in progressive human kidney diseases.

PMID- 12612945
TI  - Progression of diabetic nephropathy.
AB  - BACKGROUND: Diabetic nephropathy, a kidney disease caused by diabetes, is the
      most devastating and money-consuming complication in patients with diabetes
      throughout the world. The cardinal lesion of diabetic nephropathy resides in
      renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is
      responsible for the development and progression of diabetic nephropathy through
      metabolic derangements, including increased oxidative stress, renal polyol
      formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases
      (MAPKs), and accumulation of advanced glycation end products, as well as such
      hemodynamic factors as systemic hypertension and increased intraglomerular
      pressure. METHODS: We examined whether inhibition of the PKC-MAPK pathway could
      inhibit functional and pathological abnormalities in glomeruli from diabetic
      animal models and cultured mesangial cells exposed to high glucose condition
      and/or mechanical stretch. RESULTS: Direct inhibition of PKC by PKC beta
      inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model of
      type 2 diabetes. We also found that inhibition of MAPK by PD98059, an inhibitor
      of MAPK, or mitogen-activated extracellular regulated protein kinase kinase
      prevented enhancement of activated protein-1 (AP-1) DNA binding activity and
      fibronectin expression in cultured mesangial cells exposed to mechanical stretch
      in an in vivo model of glomerular hypertension. CONCLUSION: These findings
      highlight the important role of PKC-MAPK pathway activation in mediating the
      development and progression of diabetic nephropathy.

PMID- 12612946
TI  - Recent advances in management of type 2 diabetes and nephropathy: lessons from
      the RENAAL study.
AB  - BACKGROUND: Diabetic nephropathy has become the single most important cause of
      end-stage renal disease (ESRD) worldwide. Strategies to slow the rate of loss of
      renal function in these patients recently have been developed. The renin
      angiotensin-aldosterone system has proven to be an important target for
      intervention. METHODS: The Reduction of Endpoints in NIDDM with the Angiotensin
      II Receptor Antagonist Losartan (RENAAL) study was a randomized, double-blind,
      multinational, clinical trial that studied 1,513 patients with type 2 diabetes
      and nephropathy for a mean of 3.4 years. Patients were administered either
      losartan or placebo, each in addition to conventional antihypertensive therapy,
      with dosage adjustments as necessary to achieve a target blood pressure of less
      than 140/less than 90 mm Hg. RESULTS: The study showed a significant benefit of
      losartan, beyond the effects of lowering blood pressure, on the primary composite
      end point of doubling serum creatinine level, ESRD, or death (-16%; P = 0.02).
      Losartan reduced the incidence of serum creatinine level doubling (-25%; P =
      0.006) and ESRD (-28%; P = 0.002), but had no effect on rate of death. The
      composite end point of cardiovascular morbidity and mortality was similar in the
      two groups. The rate of first hospitalization for heart failure was reduced in
      the losartan group (-32%; P = 0.005), as was proteinuria (-35%; P < 0.001). The
      RENAAL study also provided the opportunity to evaluate risk factors that predict
      ESRD in patients with type 2 diabetes in whom blood pressure was aggressively
      treated. In our multivariate model, four independent risk factors, proteinuria
      (most important), serum creatinine level, hypoalbuminemia, and anemia, were
      identified that predicted the development of ESRD. CONCLUSION: Proteinuria is the
      single most powerful predictor of ESRD in patients with type 2 diabetes and
      nephropathy. Thus, it is imperative that it be assessed in all patients with type
      2 diabetes to identify those at risk for progressive renal disease. The routine
      availability of the urinary albumin-creatinine ratio as a diagnostic test
      provides an important opportunity to further improve the prognosis of individuals
      with type 2 diabetes and nephropathy.

PMID- 12612947
TI  - Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low
      protein diet: Czech multicenter study.
AB  - BACKGROUND: Our study is designed to establish whether supplementation with
      erythropoietin (EPO) exerts additional beneficial metabolic effects in patients
      with chronic renal failure (CRF) treated with keto acids (KAs) on a low-protein
      diet (LPD). METHODS: A long-term, prospective, randomized study was designed to
      use three therapeutic protocols: (A) EPO plus KAs plus LPD (group I), (B) EPO
      plus LPD (group II), and (C) LPD (group III). One hundred eighty-six randomly
      selected patients (90 men, 96 women; age, 22 to 78 years) with a creatinine
      clearance of 22 to 36 mL/min were monitored at the beginning and at every 6
      months for 3 years. RESULTS: During the study period, glomerular filtration rate
      measured as inulin clearance decreased slightly (from 26.2 +/- 3.4 to 23.4 +/-
      4.1 mL/min in group I), 27.4 +/- 4.8 to 20.2 +/- 4.4 mL/min in group II, and 26.8
      +/- 3.6 to 17.4 +/- 4.1 mL/min in group III; P < 0.01). Serum urea levels also
      declined (P < 0.01), more pronouncedly in group I (P < 0.025). In group I, there
      was a significant increase in levels of leucine (P < 0.01) and albumin (P < 0.01)
      and a decrease in proteinuria (P < 0.01). Analysis of the lipid spectrum showed a
      mild, yet significant, decrease in total cholesterol and low-density lipoprotein
      cholesterol levels (P < 0.025), more pronounced in group I. In group I, there was
      a decrease in plasma triglyceride levels (from 362.85 +/- 115.05 mg/dL [4.1 +/-
      1.3 mmol/L] to values as low as 203.55 +/- 70.80 mg/dL [2.3 +/- 0.8 mmol/L]; P <
      0.01), whereas high-density lipoprotein cholesterol levels increased (from 34.75
      +/- 7.72 mg/dL [0.9 +/- 0.2 mmol/L] to 46.33 +/- 7.72 mg/dL [1.2 +/- 0.2 mmol/L];
      P < 0.025). Mean arterial blood pressure was stable. CONCLUSION: EPO
      supplementation in patients with CRF administered KAs potentiates the beneficial
      effects on metabolism of proteins, amino acids, and lipids. Long-term
      coadministration of EPO, KA, and LPD was associated with a delay in progression
      of renal failure and reduction in proteinuria.

PMID- 12612948
TI  - Effect of nonsupplemented low-protein diet on very late stage CRF.
AB  - BACKGROUND: There are few reports of the effect of a low-protein diet on very
      late-stage chronic renal failure (CRF), eg, serum creatinine level greater than
      10 mg/dL (884 micromol/L). In this retrospective study, we examined the effects
      of a very low-protein diet in patients with very late-stage CRF. METHODS: A very
      low-protein diet (0.25 to 0.54 g/kg body weight/d [0.39 +/- 0.01g/kg body
      weight/d]) without supplementation of essential amino acids or keto analogues was
      administered to 76 patients with very late-stage CRF who had serum creatinine
      levels greater than 10 mg/dL (884 micromol/L). Twenty-one patients with the same
      serum creatinine level and protein intake of 0.55 to 1.2 g/kg body weight/d (0.68
      +/- 0.03 g/kg body weight/d) were observed in lieu of controls. RESULTS: Blood
      urea nitrogen was significantly suppressed to 43.1 +/- 1.9 g/dL (15.4 +/- 0.7
      mmol/L) in the low-protein group compared with 111.2 +/- 7.0 mg/dL (39.7 +/- 2.5
      mmol/L; P < 0.001) in the control group. The rate of decline in glomerular
      filtration rate (creatinine clearance) was 36-fold slower with the low-protein
      diet (-7.1 +/- 1.0 versus -0.2 +/- 0.4 mL/mon, respectively; P < 0.001).
      Nutritional state in the low-protein group exceeded that of the control group.
      Consequently, the renal survival rate improved significantly (P < 0.0001). All
      patients in the control group were initiated on dialysis treatment within 6
      months from a serum creatinine level of 10 mg/dL (884 micromol/L). Conversely,
      58% of the low-protein group are still on predialysis treatment. CONCLUSION: A
      severe low-protein diet is effective not only in preventing deterioration in
      renal function, but also in maintaining nutritional state despite no
      supplementation of essential amino acids or keto analogues, even as serum
      creatinine level is more than 10 mg/dL (884 micromol/L).

PMID- 12612949
TI  - Effect of combined treatment of oral sorbent with protein-restricted diet on
      change of reciprocal creatinine slope in patients with CRF.
AB  - BACKGROUND: Low-protein diet (LPD) is one therapy and AST-120, an oral carbon
      adsorbent, is the other therapy to reduce blood levels of indoxyl sulfate in
      patients with chronic renal failure (CRF). Based on the different mechanisms of
      reducing indoxyl sulfate levels, the addition of AST-120 to an LPD was
      investigated. METHODS: Seven hundred twenty-two patients with chronic
      glomerulonephritis (CGN) and 162 patients with diabetic nephropathy (DN) were
      stratified by protein intake: less than 0.50 g/kg/d (0.50-g/kg/d group), 0.51 to
      0.65 g/kg/d (0.65-g/kg/d group), and 0.66 to 0.80 g/kg/d (0.80-g/kg/d group). To
      analyze the effect of combined AST-120 therapy (6 g/d) in patients on LPD
      therapy, the slope of the reciprocal of serum creatinine (1/Cr slope), which
      represents progression of CRF, was applied. RESULTS: (1) In patients with CGN,
      the addition of AST-120 with an LPD was as follows: the 1/Cr slope in the 0.50
      g/kg/d (n = 152), 0.65-g/kg/d (n = 318), and 0.80-g/kg/d (n = 252) groups changed
      significantly from -430 x 10(-5) to -83 x 10(-5), -333 x 10(-5) to -102 x 10(-5),
      and -431 x 10(-5) to -116 x 10(-5) dL/mg/wk. (2) In patients with DN, the
      addition of AST-120 with an LPD was as follows: the 1/Cr slope in the 0.65-g/kg/d
      (n = 74) and 0.80-g/kg/d (n = 68) groups changed significantly from -602 x 10(-5)
      to -125 x 10(-5) and -646 x 10(-5) to -185 x 10(-5) dL/mg/wk. CONCLUSION: It is
      suggested that the addition of AST-120 to a mild LPD provides the comparable
      effect with a strict LPD in the point of suppressing the progress of CRF.

PMID- 12612950
TI  - Effects of the oral adsorbent AST-120 on tryptophan metabolism in uremic
      patients.
AB  - BACKGROUND: Tryptophan (TRP), an essential amino acid, is bound mostly to albumin
      in plasma. However, it is reported that binding is inhibited by indoles that
      accumulate in uremic plasma. This may be responsible for the malnutrition
      observed in uremic patients. AST-120, an oral adsorbent of uremic toxins, can
      reduce concentrations of indoxyl sulfate (IS), the most abundant indolic
      metabolite in uremic plasma. We therefore investigated whether AST-120 recovers
      TRP binding to plasma proteins and improves the nutritional state of uremic
      patients. METHODS: The in vitro binding ratio of TRP to bovine serum albumin
      (BSA) was measured in the presence of IS by the equilibrium dialysis technique.
      In addition, five predialysis patients with chronic renal failure (CRF) were
      administered AST-120 for 2 months. Plasma concentrations of total TRP, IS, and
      free TRP were measured in five healthy volunteers (normal [N] group) and five
      patients with CRF before and after 2 weeks of AST-120 therapy (6 g/d). Their
      nutritional statuses also were compared before and after 2 months of AST-120
      administration. RESULTS: IS inhibited in vitro binding of TRP to BSA in a dose
      dependent manner. Total TRP concentrations and protein-binding ratios in patients
      with CRF (0.90 +/- 0.08 mg/dL and 68.7% +/- 6.8%, respectively) were
      significantly lower than those in the N group (2.45 +/- 0.45 mg/dL and 92.0% +/-
      1.4%, respectively). However, a 2-week administration of AST-120 significantly
      reduced IS levels from 1.79 +/- 1.01 to 1.15 +/- 0.85 mg/dL (N group, 0.06 +/-
      0.01 mg/dL), increased total TRP levels (1.16 +/- 0.18 mg/dL), and improved the
      TRP plasma protein-binding ratio to 83.1% +/- 3.8%, whereas total protein and
      albumin levels remained unchanged. After 2 months of AST-120 administration,
      serum albumin and transferrin levels increased significantly. CONCLUSION: AST-120
      improves nutritional state, at least partly through correcting impaired TRP
      metabolism, in patients with CRF.

PMID- 12612951
TI  - New therapies for advanced glycation end product nephrotoxicity: current
      challenges.
AB  - BACKGROUND: The role of advanced glycation end products (AGEs) in diabetic
      nephropathy has been developed during several years of research and increasingly
      complex AGE biochemistry. However, the structural diversity of AGE chemistry has
      created new challenges in the search for AGE-based inhibition therapies. RESULTS:
      The challenges include the need to standardize measurements of serum and tissue
      AGE levels, identifying nephrotoxic AGE compounds, understanding the cell
      biological state of AGEs in the diabetic kidney, determining the mechanism of
      action of selective inhibition of the glycation cascade, and forming
      complementary therapies. CONCLUSION: Current challenges in the development of new
      therapies for AGE nephrotoxicity are reviewed.

PMID- 12612952
TI  - Effects of a diet rich in advanced glycation end products in the rat remnant
      kidney model.
AB  - BACKGROUND: Food-derived advanced glycation end product (AGE)-analogues, the
      Maillard reaction products (MRPs), are formed during heat processing. Mainly low
      molecular weight MRPs are absorbed partially into the circulation and
      subsequently excreted in urine. In the presence of renal insufficiency, their
      removal is impaired, with a prolonged increase in plasma levels. Although
      bioactivity of orally absorbed MRPs has been shown in both experimental and human
      studies, its relevance in renal insufficiency still is unclear. METHODS: In the
      rat remnant-kidney model (five-sixth nephrectomy [5/6NX]), effects of an AGE-rich
      and an AGE-poor diet were investigated during a period of 6 weeks and compared
      with effects in sham-operated healthy (control [CTRL]) rats on renal function
      (serum creatinine level and proteinuria). In the AGE-rich diet, 25% wt/wt of
      cornstarch was replaced by bread crusts. RESULTS: Despite pair feeding, the AGE
      rich diet resulted in a significant increase in body weight, including weight of
      the kidney, liver, and heart, in both the CTRL and experimental groups. The AGE
      rich diet also enhanced proteinuria in CTRL rats by a factor of 2 and in 5/6NX
      rats by a factor of 8. Renal function (serum creatinine level and creatinine
      clearance) in healthy CTRLs did not change significantly. In the 5/6NX group,
      glomerular filtration rate (GFR) tended to even higher levels. CONCLUSION:
      Administration of an AGE-rich diet for 6 weeks does not impair GFR, but induces
      an increase in proteinuria, in particular, in the 5/6NX rats, indicating
      detrimental effects on the kidney.

PMID- 12612953
TI  - Are advanced glycation end products cardiovascular risk factors in patients with
      CRF?
AB  - BACKGROUND: Chronic renal failure (CRF) is characterized by enhanced formation
      and accumulation of advanced glycation end products (AGEs), which are involved in
      the pathogenesis of vascular damage. Their role as risk factors for
      cardiovascular complications is still unknown. This study aims to investigate
      whether elevated serum levels of the AGEs pentosidine, N(epsilon)
      carboxymethyllysine (CML), and the 3-deoxyglucosone-derived imidazolone involve a
      greater risk for cardiovascular events (CVEs) and left ventricular hypertrophy
      (LVH). METHODS: Patients with CRF (n = 99), on maintenance hemodialysis (HD)
      therapy (n = 84), and renal transplant recipients (RTRs; n = 50) were included.
      Pentosidine was measured by high-performance liquid chromatography, and CML and
      imidazolone, by enzyme-linked immunosorbent assays. Statistical analyses were
      performed using Mann-Whitney U test, logistic regression analysis, and Cox
      proportional hazards model. RESULTS: At baseline in all investigated groups,
      patients with a history of CVEs or LVH showed greater mean serum AGE levels. By
      retrospective data analysis, significant odds ratios for increases in CML and
      imidazolone levels were calculated for LVH in HD patients, as well as for
      increases in CML levels for CVEs in RTRs, respectively. By prospective data
      analysis, serum AGE levels could not be evaluated as independent risk factors for
      CVEs in all investigated groups. CONCLUSION: From these preliminary results,
      serum AGE levels could not be identified as independent risk factors for CVEs or
      LVH in patients with CRF. Prospective studies are needed to answer this question.

PMID- 12612954
TI  - Formation of advanced glycation end products during CAPD.
AB  - Advanced glycation end products (AGEs) are formed during the nonenzymatic
      reaction of sugars with proteins. Conventional peritoneal dialysis fluids (PDFs)
      lead to the formation of AGEs in the peritoneal membrane that are associated with
      histopathologic changes and loss of ultrafiltration. PDFs may cause AGE formation
      because of a high glucose concentration or reactive glucose degradation products
      (GDPs), which are formed during heat sterilization of PDFs. This formation of
      GDPs is strongly pH dependent, which is exploited in newly developed double
      chamber bag PDFs. Accordingly, 3-deoxyglucosone levels in double-chamber bag PDFs
      are reduced by approximately 80%, and levels of the GDPs acetaldehyde,
      formaldehyde, and methylglyoxal are less than the detection limit. Using an in
      vitro model that mimics regular changes in PDFs during continuous ambulatory
      peritoneal dialysis treatment, the contribution of high glucose versus GDP
      concentrations to AGE formation was investigated. The latter was determined by
      measuring protein bound N(epsilon)-(carboxymethyl)-lysine (CML) and imidazolone
      by enzyme-linked immunosorbent assay. In this model, more than 85% of imidazolone
      and more than 70% of CML were formed by GDPs, whereas only a minor part resulted
      from a high glucose concentration per se. New in vivo investigations suggest that
      GDPs from PDFs also can exert systemic effects after absorption into the blood
      circulation. Imidazolone levels in blood serum decrease significantly after
      switching from single- to double-chamber PDFs. In summary, the use of double
      chamber PDFs may decrease not only local, but also systemic AGE formation.

PMID- 12612955
TI  - Role of advanced glycation end products and growth factors in peritoneal
      dysfunction in CAPD patients.
AB  - High levels of glucose degradation products in peritoneal dialysis fluids are
      believed to cause excess accumulation of advanced glycation end products (AGEs)
      in the peritoneum during continuous ambulatory peritoneal dialysis (CAPD)
      treatment, resulting in functional and structural changes in the peritoneal
      membrane of CAPD patients. In this study, we investigated whether AGEs, the
      receptor for AGE (RAGE), and growth factors are involved in deteriorating
      ultrafiltration (UF) capacity of the peritoneal membrane in patients on CAPD
      therapy. Immunohistochemical staining showed that ODI-GLC19, a novel monoclonal
      anti-AGE antibody, was localized exclusively in peritoneal cells, in contrast to
      imidazolone, localized mostly in peritoneal degenerative collagen. Numbers of ODI
      GLC19- and RAGE-positive cells in the peritoneum were increased significantly in
      CAPD patients, even before a decrease in UF capacity, compared with patients with
      nonrenal disease. Cells positive for ODI-GLC19 were identified as myofibroblasts
      and RAGE-positive cells and partly as CD68-positive macrophages in the
      peritoneum. The peritoneal membrane was thickened significantly in CAPD patients,
      especially patients with low UF. The number of blood vessels was increased
      significantly in CAPD patients with low UF. Transforming growth factor-beta1,
      macrophage colony-stimulating factor, and vascular endothelial growth factor were
      recognized in the peritoneum of CAPD patients, especially those with low UF,
      where imidazolone was deposited. Focal hepatocyte growth factor expression was
      noted in the peritoneum of patients with low UF in moderate intensity,
      specifically in the area without severe structural changes. In conclusion,
      progressive accumulation of AGEs in the peritoneum may promote peritoneal
      expression of various growth factors and subsequently deteriorate UF capacity in
      CAPD patients.

PMID- 12612956
TI  - An inhibitor of advanced glycation end product formation reduces N epsilon
      (carboxymethyl)lysine accumulation in glomeruli of diabetic rats.
AB  - BACKGROUND: An inhibitor of advanced glycation, OPB-9195, retards the progression
      of nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non
      insulin-dependent diabetes mellitus. The aim of this study is to evaluate
      histologically the role of N(epsilon)-(carboxymethyl)lysine (CML) in the
      development of diabetic nephropathy and investigate whether inhibition of CML
      accumulation by OPB-9195 is associated directly with the prevention of glomerular
      lesions in OLETF rats. METHODS: Kidneys of OLETF and Long-Evans Tokushima Otsuka
      rats were obtained at ages 7, 20, 50, and 68 weeks after collecting their blood
      and urine samples. OPB-9195 had been administered to the rats from age 24 weeks
      to the end of the experiments. CML in kidneys was detected by using a monoclonal
      antibody against CML according to an indirect immunofluorescence technique. CML
      positive glomerular area was measured using NIH Image software (Research Services
      Branch of NIMH, Bethesda, MD). Hyalinized and/or sclerotic areas in glomeruli and
      mesangial and glomerular volume were measured using a point-counting technique.
      RESULTS: CML-positive area in glomeruli correlated closely not only with urinary
      albumin excretion (r = 0.912; P = 0.001), but also with volumes of mesangium and
      hyalinized and/or sclerotic lesions (r = 0.859; P = 0.0019 and r = 0.833; P =
      0.0027, respectively). Treatment with OPB-9195 reduced CML-positive area and
      prevented the increase in mesangial volume, with no significant change in
      glomerular volume at age 68 weeks. The volume of hyalinized and/or sclerotic
      lesions also decreased by treatment with OPB-9195 in three of four rats at age 68
      weeks. CONCLUSION: CML is a major advanced glycation end product contributing to
      the development of diabetic nephropathy, and inhibition of its accumulation by
      OPB-9195 results in amelioration of glomerular lesions in OLETF rats.

PMID- 12612957
TI  - Non-high-density lipoprotein cholesterol: a target of lipid-lowering in dialysis
      patients.
AB  - BACKGROUND: The finding of an increased prevalence and levels of atherogenic
      lipoproteins in the context of normal plasma total and low-density lipoprotein
      (LDL) cholesterol (LDL-C) levels in hemodialysis (HD) patients highlights the
      need to look beyond the basic assessment of plasma concentrations of total
      cholesterol and LDL-C. Measurement of atherogenic lipoproteins (remnant
      lipoprotein particles [RLPs], particularly intermediate-density lipoprotein
      [IDL]), is not routinely performed at the present time. METHODS: The National
      Cholesterol Education Program guidelines indicate that the secondary goal in
      persons with triglyceride levels greater than 200 mg/dL is non-high-density
      lipoprotein cholesterol (HDL-C). Non-HDL-C comprises all RLPs, including IDL, as
      well as atherogenic small dense LDL. RESULTS: We propose, for practical reasons,
      that non-HDL-C be used as a primary target in HD patients when lipid-lowering
      therapy is indicated. However, it remains unclear whether and how effective
      statins are in lowering remnant particle levels in dialysis patients. Recent data
      show that both simvastatin and atorvastatin reduce non-HDL-C levels effectively.
      Atorvastatin preferentially reduces RLP levels in patients with combined
      hyperlipidemia. CONCLUSION: The safety profile of statins predisposes
      prescription of this class of drugs to correct dyslipidemia or modulate
      lipoprotein particle composition in uremic patients. Whether atorvastatin
      influences myocardial infarction or all-cause mortality by adequately correcting
      dyslipidemia should be seen fairly quickly in the 1,252 dialysis patients with
      diabetes randomly assigned in the ongoing Die Deutsche Diabetes Dialyse study.

PMID- 12612958
TI  - Intima-media thickness of carotid artery predicts cardiovascular mortality in
      hemodialysis patients.
AB  - BACKGROUND: Cardiovascular disease is the leading cause of death in patients with
      end-stage renal disease (ESRD). Previous studies showed that patients with ESRD
      had increased intima-media thickness of the carotid artery (CA-IMT). In the
      present study, we examined whether CA-IMT would predict cardiovascular mortality
      in patients with ESRD. METHODS: The cohort consisted of 438 patients with ESRD
      treated with hemodialysis. CA-IMT was measured by high-resolution B-mode
      ultrasonography. RESULTS: During the follow-up period of 30 months, 82 deaths,
      including 44 cardiovascular fatal events, occurred. Compared with those with CA
      IMT less than 1.0 mm, those with moderately increased CA-IMT (1.0 to 2.0 mm) and
      those with severely increased CA-IMT (>or=2.0 mm) showed a significantly greater
      risk for death from cardiovascular causes; odds ratios were 3.17 (95% confidence
      interval [CI], 1.41 to 7.17; P = 0.005) and 10.20 (95% CI, 3.67 to 28.3; P <
      0.0001), respectively, in a multivariate Cox analysis including age, sex,
      duration of hemodialysis therapy, presence of diabetes mellitus, blood pressure,
      body mass index, and high-density lipoprotein and non-high-density lipoprotein
      cholesterol levels as covariates. Conversely, CA-IMT was not significantly
      associated with noncardiovascular mortality. CONCLUSION: These results indicate
      that increased CA-IMT is an independent predictor of cardiovascular mortality in
      the hemodialysis population.

PMID- 12612959
TI  - Role of iron in atherosclerosis.
AB  - The importance of iron in injury is derived from the ease with which iron is
      reversibly oxidized and reduced and thus able to participate in the generation of
      powerful oxidant species, such as hydroxyl radical, and in lipid peroxidation.
      There is compelling mechanistic evidence for the potential role of iron in
      atherosclerosis: the role of iron in oxidizing low-density lipoprotein (LDL),
      iron chelators prevent endothelial cell damage by oxidized LDL, the ability of
      iron to cause endothelial cell damage, and iron chelators prevent endothelial
      cell dysfunction and vascular smooth muscle proliferation. In addition to these
      effects, important in atherosclerosis, ample experimental evidence suggests a
      role of iron in myocardial reperfusion injury. Epidemiological data have provided
      conflicting results, with several studies reporting an association between iron
      stores and progression of carotid atherosclerosis or acute myocardial infarction,
      whereas others argue against such an association. However, the availability of
      catalytic iron and the susceptibility of an individual may be more important than
      overall iron body status. Studies that address these issues, as well as those
      designed to establish cause and effect, are needed before one can reach
      meaningful conclusions about the role of iron in atherosclerosis and the
      therapeutic implications for patients.

PMID- 12612960
TI  - The role of lipogenesis in the development of uremic hyperlipidemia.
AB  - BACKGROUND: It is well documented that hypertriglyceridemia in renal failure
      mostly is a result of impaired plasma triglyceride (TG) removal. However, the
      role of TG production in its development is obscure. Therefore, our attention was
      given to the gene expression of lipogenic enzymes participating in TG
      biosynthesis. METHODS: We measured some lipogenic enzyme activities, protein
      abundance (Western blot analysis), and messenger RNA level (Northern blot
      analysis) in liver and epididymal white adipose tissue (WAT) of rats with
      surgically induced renal failure (two-stage subtotal nephrectomy).
      Simultaneously, plasma TG and very low-density lipoprotein (VLDL) concentrations
      in uremic animals were determined. RESULTS: An increase in plasma TG and VLDL
      concentrations in rats with renal failure was observed. It was associated with an
      increase in fatty acid synthase and adenosine triphosphate-citrate lyase (ACL)
      gene expression in liver and WAT. Moreover, increased activities of malic enzyme,
      glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase were
      found. CONCLUSION: Results of the present study provide some evidence that the
      accumulation of TG-rich lipoproteins in renal insufficiency could be related in
      part to increased lipogenic enzyme gene expression and, consequently, TG
      overproduction.

PMID- 12612962
TI  - Vascular calcification in dialysis patients: pathogenesis and consequences.
AB  - BACKGROUND: Vascular calcification is believed to have a crucial role in the
      excess cardiovascular mortality and morbidity in patients with end-stage renal
      disease (ESRD). METHODS AND RESULTS: Recent evidence suggests that uremic
      vascular calcification is an active cell-mediated process resembling osteogenesis
      in bone, rather than passive precipitation of calcium and phosphorus in the
      setting of deranged mineral metabolism. To date, several bone-associated proteins
      (osteopontin, bone sialoprotein, alkaline phosphatase, and type I collagen) have
      been shown in histological sections of vessels obtained from patients with ESRD
      or calcific uremic arteriolopathy. In in vitro experiments, the addition of
      uremic serum upregulates osteopontin expression by cultured vascular smooth
      muscle cells (VSMCs). CONCLUSION: We are only beginning to understand the process
      by which VSMCs transform into osteoblast-like cells, although phosphorus may have
      a key role. Additional factors mediating or modulating the development of
      vascular calcification in patients with ESRD remain to be identified. Further
      understanding of the pathophysiological state of uremic vascular calcification is
      needed to design effective therapeutic strategies to intervene with this
      devastating condition in the ESRD population.

PMID- 12612961
TI  - Hyperhomocysteinemia and its relationship to cardiovascular disease in ESRD:
      influence of hypoalbuminemia, malnutrition, inflammation, and diabetes mellitus.
AB  - BACKGROUND: In the general population, a mildly elevated plasma total
      homocysteine (tHcy) level is an independent and graded risk factor for
      cardiovascular disease (CVD). In patients with end-stage renal disease (ESRD),
      CVD is highly prevalent and a major cause of premature mortality, and plasma tHcy
      levels are as much as three to four times greater than in the general population.
      Several other risk factors, such as diabetes mellitus (DM), inflammation, and
      malnutrition, also are prevalent and contribute to CVD in patients with ESRD, and
      there are strong associations between inflammation, malnutrition, and
      hypoalbuminemia in these patients. Several investigations in patients with ESRD
      have shown the important role of vitamin status for plasma tHcy, but little
      attention has been given to the influence of nutritional status. However, it is
      obvious that hypoalbuminemia is of interest because a substantial fraction of
      tHcy (>70%) is protein bound, mainly to albumin. RESULTS: In studies of patients
      with ESRD in whom the prevalence of hyperhomocysteinemia was very high (>90%),
      tHcy level was strongly related to serum albumin level, and patients with
      malnutrition had lower levels of both tHcy and serum albumin than those with
      normal nutritional status. Furthermore, inflammation, DM, and CVD are associated
      with hypoalbuminemia and therefore a lower degree of hyperhomocysteinemia. In our
      studies, in different groups of patients with ESRD, we showed that greater tHcy
      levels were associated with lower CVD mortality. However, this apparently
      paradoxical association between lower CVD mortality and lower plasma tHcy levels
      (although still abnormally high) does not refute the concept that
      hyperhomocysteinemia is a risk factor for CVD because almost all patients may
      have had long-standing elevated plasma tHcy levels within a range that makes them
      prone to develop atherosclerosis. Instead, a potentially detrimental effect of
      hyperhomocysteinemia on CVD in patients with ESRD may be obscured by the
      influence of hypoalbuminemia, whatever the cause, because hypoalbuminemia and its
      causes are strong predictors of mortality. CONCLUSION: Our findings imply that
      nutritional status and serum albumin level, as well as the presence of
      inflammation and DM, should be taken into consideration when evaluating tHcy as a
      risk factor for CVD in patients with ESRD.

PMID- 12612963
TI  - New strategies for the treatment of secondary hyperparathyroidism.
AB  - Classic pathogeneses of secondary hyperparathyroidism (2HPT), hyperphosphatemia,
      vitamin D deficiency, and hypocalcemia, have been treated by the administration
      of phosphorus binders and vitamin D derivatives. However, these therapies have
      not brought about a successful result. The main reason could be attributed to
      hypercalcemia resulting from the administration of calcium salts as a phosphorus
      binder and the calcemic action of vitamin D. To prevent hypercalcemia, non
      calcium-containing phosphorus binders and vitamin D analogues, which suppress
      parathyroid hormone (PTH) secretion with minimum calcemic action, have been
      developed. Furthermore, calcimimetics that stimulate the calcium-sensing receptor
      of parathyroid cells and suppress PTH secretion are now under clinical trial.
      Direct injection therapy of vitamin D analogues or calcimimetics into the
      parathyroid gland also has been reported. These new strategies are expected to
      effectively and safely suppress 2HPT, which has been resistant to conventional
      medical treatments.

PMID- 12612964
TI  - Renal osteodystrophy: role of calcimimetics.
AB  - In patients with secondary hyperparathyroidism (HPT), increased parathyroid
      hormone (PTH) secretion is triggered by low plasma calcitriol levels,
      hypocalcemia, and hyperphosphatemia. Vitamin D analogues have been used
      successfully to reduce PTH levels, but increases in serum calcium, phosphorus,
      and calcium x phosphorus ion product levels may occur. Second-generation
      calcimimetics have been shown to suppress PTH levels and also reduce calcium x
      phosphorus ion product. Potential indications are patients with secondary HPT,
      particularly those who respond to calcitriol therapy with an increase in calcium
      x phosphorus ion product. Coadministration of active vitamin D compounds may be
      necessary to overcome intestinal malabsorption of calcium and maintain
      normocalcemia in patients on long-term treatment with calcimimetics.

PMID- 12612965
TI  - Multicenter clinical trial of 22-oxa-1,25-dihydroxyvitamin D3 for chronic
      dialysis patients.
AB  - BACKGROUND: Conventional calcitriol treatment can suppress parathyroid hormone
      (PTH) secretion in hemodialysis patients, although it can cause refractory
      hyperparathyroidism in some patients. We attempted to elucidate clinical outcomes
      of intravenous 22-oxa-1,25-dihydroxyvitamin D(3) (OCT) treatment and their
      determinants in a multicenter clinical trial. METHODS: One hundred one patients
      with serum PTH levels greater than 300 pg/mL (300 ng/L) and serum calcium levels
      less than 11 mg/dL (2.74 mmol/L) were recruited. OCT was administered
      intravenously at the end of each dialysis session. The dose was decreased by 5
      microg when serum PTH level was less than 300 pg/mL or serum calcium level was
      greater than 11 mg/dL. RESULTS: OCT was administered for 4.8 months to 101
      patients (average age, 55.1 years) who were on dialysis therapy for 15.9 years.
      Percentages of decrease in PTH levels greater than 30% were obtained in 44
      patients (43.5%). These patients were on dialysis therapy for a shorter duration
      than those who showed less than 30% decreases (13.0 +/- 3.3 versus 17.9 +/- 3.0
      years). Multiple regression analysis of the final PTH level or percentage of
      decrease in PTH level with respect to initial PTH level, serum calcium level,
      serum phosphate level, age, and dialysis therapy duration showed that
      determinants of percentages of decrease in PTH levels were initial serum calcium
      and phosphate levels. Conversely, significant determinants of the final PTH level
      were initial PTH levels and initial calcium levels. CONCLUSION: These results
      show that the decrease in PTH levels by OCT therapy could be predicted in
      patients with low calcium, PTH, and alkaline phosphatase levels; high phosphate
      levels; and short dialysis therapy duration before the start of OCT
      administration.

PMID- 12612966
TI  - Nutrition in daily hemodialysis.
AB  - BACKGROUND: Reports of improved patient outcomes using very long hemodialysis
      sessions have rekindled interest in alternatives to the standard thrice weekly
      hemodialysis regimen. METHODS: A review of the current literature was undertaken
      to determine the effect of daily hemodialysis on nutritional indices. Several
      regimens that deliver longer treatments were considered, including thrice weekly
      dialysis for 6 to 8 hours, short daily hemodialysis (5 to 7 times per week) for
      1.5 to 2.5 hours, and nocturnal hemodialysis for 6 to 8 hours. An increasing
      number of centers are experimenting with the latter 2 treatment schedules the
      results of which are reported herein. RESULTS: Nutritional status is an important
      predictor of outcome in end-stage renal disease (ESRD) patients. Nutritional
      status of patients can be improved by increasing the dose of conventional
      hemodialysis or by using biocompatible membranes. Therefore, it should not be
      surprising that daily hemodialysis treatments may affect nutrition. Beyond the
      effect that the enhanced clearance of small-molecular-weight substances may have
      on nutrition, the daily modalities open another dimension of depuration because
      of the ability to remove larger-molecular-weight substances to an extent that has
      never been approached by conventional hemodialysis. CONCLUSION: The preliminary
      data from the studies evaluating the influence of daily and nocturnal
      hemodialysis on nutrition status suggest a beneficial effect. In particular, a
      striking lowering of phosphorus level occurs with nocturnal hemodialysis.
      However, there is little prospective and randomized information on the effects of
      the modalities on incident patients. The number of patients enrolled in daily
      hemodialysis is only in the hundreds. Prospective clinical trials are required to
      delineate the full potential of these therapies as well the differences between
      them. Both daily and nocturnal regimens should be explored in future studies.

PMID- 12612967
TI  - Carnitine and hemodialysis.
AB  - Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely
      present in all cells from prokaryotic to eukaryotic. It is an important element
      in the beta-oxidation of fatty acids. A lack of carnitine in hemodialysis
      patients is caused by insufficient carnitine synthesis and particularly by the
      loss through dialytic membranes, leading in some patients to carnitine depletion
      with a relative increase of esterified forms. The authors found a decrease in
      plasma-triglyceride and increase of high-density lipoprotein cholesterol (HDL
      Chol) in dialysis patients during carnitine treatment. Many studies have shown
      that L-carnitine supplementation leads to improvements in several complications
      seen in uremic patients, including cardiac complications, impaired exercise and
      functional capacities, muscle symptoms, increased symptomatic intradialytic
      hypotension, and erythropoietin-resistant anemia, normalizing the reduced
      carnitine palmitoyl transferase activity in red cells. In addition, carnitine
      supplementation may improve protein metabolism and insulin resistance. Recently,
      carnitine supplementation has been approved by the US Food and Drug
      Administration not only for the treatment, but also for the prevention of
      carnitine depletion in dialysis patients. Regular carnitine supplementation in
      hemodialysis patients can improve their lipid metabolism, protein nutrition,
      antioxidant status, and anemia requiring large doses of erythropoietin, It also
      may reduce the incidence of intradialytic muscle cramps, hypotension, asthenia,
      muscle weakness, and cardiomyopathy.

PMID- 12612968
TI  - Homocysteine in uremia.
AB  - Hyperhomocysteinemia is an independent cardiovascular risk factor that possibly
      accounts for about one of 5 cardiovascular deaths. It is conceivable that the
      importance of hyperhomocysteinemia will increase when other risk factors, such as
      hypertension or hypercholesterolemia, will become less prevalent in the general
      population. In chronic renal failure (CRF), high plasma homocysteine levels are a
      common finding and in uremia almost the rule. However, a small subset of patients
      remains normohomocysteinemic. The cause of hyperhomocysteinemia in CRF, whether
      it lies in an impaired renal or extrarenal metabolism or through uremic retention
      toxins, is still under intensive scrutiny. As for the consequences of high
      homocysteine levels in the general population and in patients with CRF, these are
      many-fold and linked to the mechanism of homocysteine toxic action. In fact,
      homocysteine can be harmful to cells because (1) it evokes oxidative stress
      (through the production of reactive oxygen species), (2) binds to nitric oxide,
      (3) produces homocysteinylated proteins, or (4) leads to the accumulation of its
      precursor, S-adenosylhomocysteine, a potent inhibitor of biological
      transmethylations. Macromolecule hypomethylation is a common feature in CRF and
      uremia with possible functional consequences. Nutritional or pharmacologic
      interventions have been proposed in the treatment of hyperhomocysteinemia, while
      the results of large clinical trials designed to assess if lowering homocysteine
      levels is effective in reducing cardiovascular risk, are pending.

PMID- 12612969
TI  - Liver metabolism in CRF.
AB  - Alteration in liver function are not typically present in patients with uremic
      syndrome, but varying degrees of liver dysfunction were observed in animals with
      experimental uremia and, to a lesser degree, in patients with chronic renal
      failure. This article summarizes the data obtained during the last 2 decades on
      protein, carbohydrate, and lipid metabolism by the liver in uremia and molecular
      aspects of regulation of lipids and protein synthesis. Particular attention is
      given to the role of cytosolic calcium ([Ca(2+)](i)) regulation and calcium
      signal transduction in hepatocytes in chronic renal failure. It is proposed that
      the parathyroid hormone (PTH)-mediated increase in the [Ca(2+)](i) of hepatocytes
      in chronic renal failure is a major signal for the downregulation of hepatic
      receptors for PTH-PTHrP, vasopressin and angiotensin II as well as as hepatic
      lipase. It is possible that the mRNA of other hormone receptors and various
      proteins of the liver cells are affected similarly by the elevated basal levels
      of [Ca(2+)](i) in CRF.

PMID- 12612970
TI  - Nutritional management of dialysis patients: balancing among nutrient intake,
      dialysis dose, and nutritional status.
AB  - BACKGROUND: Recommended protein intake for dialysis patients is much higher
      compared with allowance for normal adults. The authors tried to make a
      consideration on balancing among nutrient intake, dialysis dose, and nutritional
      status in maintenance dialysis patients. METHODS: In 57 patients, 13 on
      hemodialysis (HD) and 44 on continuous ambulatory peritoneal dialysis (CAPD),
      serum urea nitrogen (SUN), albumin, weekly creatinine clearance of CAPD, and body
      protein mass by multifrequency bioelectrical impedance analysis were measured.
      Energy intake was examined from the patients' food diary by a registered
      dietitian, and protein intake was estimated by both the patients' food diary and
      calculation of protein equivalent nitrogen appearance. RESULTS: In HD patients,
      predialysis SUN levels significantly correlated with the amounts of protein
      intake (r = 0.893; P < 0.001), and there was no correlation between post- and
      next predialysis SUN levels. In CAPD patients, SUN levels significantly
      correlated with the amounts of protein intake (r = 0.645; P < 0.001), and there
      was no correlation between SUN levels and weekly Ccr. The amounts of protein
      intake were significantly correlated with body protein mass (r = 0.365; P =
      0.014), and there were significantly positive relationships between the amounts
      of protein intake and energy intake in both HD (r = 0.798; P < 0.001) and CAPD
      patients (r = 0.631; P = 0.006). CONCLUSION: Whereas higher intake of protein
      requires higher doses of dialysis, lower intake of protein with sufficient energy
      intake requires lower doses of dialysis, and both could give the same effects on
      nutritional status.

PMID- 12612971
TI  - Body fat mass in hemodialysis patients.
AB  - BACKGROUND: Changes in body fat mass in a large number of hemodialysis patients
      is unknown. METHODS: Body fat mass and lean body mass were measured by dual x-ray
      absorptiometry (DXA) in 561 patients with hemodialysis duration less than 180
      months (62.3 +/- 11.5 years old; mean +/- SD). RESULTS: Fat mass tended to
      increase during the first 3 years of hemodialysis, and it tended to decrease
      thereafter. Between hemodialysis duration and the fat mass index, there was a
      significant positive correlation within the first 36-month period of hemodialysis
      (r = 0.124; P < 0.05; n = 245), and a significant negative correlation during the
      period of 36 to 180 months. (r = -0.192; P < 0.001; n = 316). There was no
      tendency of change in the lean body mass index. CONCLUSION: Considering the
      results together with the authors previous prospective study results, which show
      significant fat mass increase in the first year of hemodialysis, the present
      cross-sectional study may suggest that fat mass gradually increases in the first
      3 years and decreases thereafter. Fat mass is suggested to be a nutritional
      parameter in hemodialysis patients.

PMID- 12612972
TI  - Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of
      indoxyl sulfate in patients on hemodialysis.
AB  - BACKGROUND: Intestinal microflora is deranged in hemodialysis (HD) patients as
      increased aerobacteria such as Escherichia coli, and decreased anaerobacteria
      such as bifidobacteria. Indole, a precursor of indoxyl sulfate, is produced by E
      coli but not by bifidobacteria. The serum levels of indoxyl sulfate are increased
      markedly in HD patients and cannot be reduced efficiently by HD because of its
      albumin binding. METHODS: To compare the effect of oral administration of
      Bifidobacterium longum in gastro-resistant seamless capsule (Bifina) on indoxyl
      sulfate levels with that of Bifidobacteria in powder formulation (Lac B), Bifina
      was administered to 11 HD patients for 5 weeks, and Lac B to another group of 11
      HD patients for 5 weeks. The authors measured the serum level of indoxyl sulfate
      by using high-performance liquid chromatography. RESULTS: The pre-HD serum levels
      of indoxyl sulfate significantly decreased in Bifina-treated patients (before,
      4.9 +/- 1.7 mg/dL, 4.5 mg/dL, mean +/- SD, median, after 5 weeks, 3.5 +/- 1.3
      mg/dL, 3.8 mg/dL; P < 0.005). However, they did not decrease in the Lac B-treated
      patients (before, 4.8 +/- 1.4 mg/dL, 4.5 mg/dL, after 5 weeks, 5.2 +/- 2.0 mg/dL,
      5.1 mg/dL). CONCLUSION: Oral administration of Bifina to HD patients is effective
      in reducing the serum levels of indoxyl sulfate by correcting the intestinal
      microflora. Gastro-resistant seamless capsule prevents bifidobacteria from its
      inactivation in acidic gastric juice, and allows it to be actived in the
      intestine.

PMID- 12612974
TI  - Assessing glycemic control in patients with diabetes and end-stage renal failure.
AB  - Blood glucose monitoring is important in optimizing long-term outcomes in
      diabetic patients. Reliance on near-patient testing and the use of longer term
      measures of glycation are the current cornerstones. However, as this review
      details, there are significant problems using blood tests as measures of
      metabolic control in uremic diabetic patients.

PMID- 12612973
TI  - Long-term protein intake control in kidney transplant recipients: effect in
      kidney graft function and in nutritional status.
AB  - BACKGROUND: Reduction in renal mass is followed by progressive renal failure. The
      reduction in filtration surface area, caused by the absence of 50% of renal mass,
      in patients with customary salt intake is followed by expansion of extracellulary
      volume and systemic and glomerular hypertension. High protein intake may
      contribute to renal allograft injury arising from insufficient renal mass.
      METHODS: The authors studied outcome of 48 patients with kidney transplant to
      whom normocaloric diets and moderate intake of protein (0.8 g/kg), of sodium (3
      g/d), and lipids (no more than 30% of total energy) were prescribed. Monthly 24
      hour urea excretion and 24-hour sodium excretion were measured. Renal function
      was assessed by creatinine clearances and by renal scintigraphy. The 30 patients
      who followed prescriptions exactly were the compliant group (group 1). The other
      18, who followed the diet prescribed only partially (their intakes were 1.4 g/kg
      of protein and 5 g/d of sodium) were the control group (group 2). RESULTS:
      Patients of the compliant group maintained unchanged renal function, whereas
      patients of the control group lost more than 40% of excretion efficiency as a
      mean. CONCLUSIONS: Dietary restrictions of protein and sodium can stabilize renal
      function in patients with kidney transplant. Wider use of this treatment is
      indicated.

PMID- 12612975
TI  - An index for renal outcome in ANCA-associated glomerulonephritis.
AB  - BACKGROUND: The aim of this study is to analyze the predictive value of clinical,
      serological, and histological parameters for renal outcome in antineutrophil
      cytoplasmic autoantibody (ANCA)-associated glomerulonephritis by multivariate
      analysis and create an index valid for clinical use. METHODS: Data from 160
      patients with Wegener's granulomatosis, microscopic polyangiitis, and idiopathic
      rapidly progressive glomerulonephritis without immune deposits (renal-limited
      vasculitis) were collected. The Cockcroft formula was used to assess renal
      function expressed by glomerular filtration rate (GFR) at the time of renal
      biopsy (t = 0) and 1 year later (t = 1). Other clinical parameters were age, sex,
      and diagnosis. ANCA test results were scored as cytoplasmic ANCA/antiproteinase 3
      (anti-PR3) or perinuclear ANCA/antimyeloperoxidase (anti-MPO) positive or
      negative. Histological data included normal glomeruli, fibrinoid necrosis,
      extracapillary proliferation, granulomas, interstitial edema, focal and diffuse
      infiltrates, fibrosis, tubular cylinders/casts, tubular atrophy, tubular
      necrosis, sclerosis, mesangial proliferation, mesangial matrix expansion,
      arteriosclerosis, and infiltrates in arterioles. In a separate analysis, we
      explored whether there were histological differences between patients with anti
      PR3 and anti-MPO ANCA test results. RESULTS: Forty percent of the variation in
      renal function at the time of biopsy can be explained by the presence or absence
      of tubular atrophy, normal glomeruli, fibrinoid necrosis, extracapillary
      proliferation, and age. Renal function at the time of biopsy is the best
      predictor for renal function at t = 1 in patients with ANCA-associated
      glomerulonephritis. Together with normal glomeruli, fibrinoid necrosis, and age,
      it explains more than 60% of the variation in GFR at t = 1. ANCA subtype has no
      independent contribution in predicting patient prognosis. Results translated into
      a clinically relevant index: GFR at t = 1 = 36.96 + 0.65* (GFR at t = 0) + 10.52
      (if normal glomeruli present) + 7.72 (if fibrinoid necrosis present) - 0.42*
      (age). CONCLUSION: The index created with results from this study provides an
      indication of renal outcome in patients diagnosed with ANCA-associated
      glomerulonephritis.

PMID- 12612976
TI  - Histologic and immunohistologic study and clinical presentation of ANCA
      associated glomerulonephritis with correlation to ANCA antigen specificity.
AB  - BACKGROUND: The major antigen specificities of antineutrophil cytoplasmic
      antibodies (ANCA) are for proteinase 3 (PR3) and myeloperoxidase (MPO). Only a
      limited number of studies have systematically assessed renal pathology with
      respect to ANCA antigen specificity. METHODS: The authors evaluated renal biopsy
      light microscopy and immunofluorescence findings, clinical presentation, and
      outcome in 135 patients with ANCA-associated vasculitides. RESULTS: Patients were
      divided into 3 groups: PR3-ANCA (n = 55), MPO-ANCA (n = 74), and ANCA of other
      specificities (n = 6). The mean duration of renal disease at biopsy was
      significantly longer in patients with MPO-ANCA than in those with PR3-ANCA (6.9 v
      3.0 months). Immunofluorescence results showed mostly pauci-immune
      glomerulonephritis (n = 129) and rarely diffuse granular glomerular immune
      deposits suggesting immune complex deposition (n = 6). A focal form of crescentic
      glomerulonephritis was more frequent (P < 0.001), and glomerular necrosis was
      more prominent (P = 0.013) in the PR3-ANCA group, whereas diffuse crescentic
      glomerulonephritis, glomerulosclerosis, and interstitial fibrosis predominated in
      the MPO-ANCA group (P < 0.001). Extraglomerular vasculitis, present in 22.2%, and
      chronic vascular lesions indicative of previous vasculitis, present in 11.9% of
      patients, correlated with systemic involvement. CONCLUSION: The evolution of the
      pathologic lesions of PR3-ANCA and MPO-ANCA-associated glomerulonephritis seems
      to be similar. Differences in histopathology could be explained by the
      observation that in patients with PR3-ANCA, kidney biopsy was performed soon
      after renal involvement appeared, and focal active lesions were prevalent,
      whereas in patients with MPO-ANCA, kidney biopsy was done late in the course of
      the disease, and diffuse chronic sclerotic lesions predominated. Renal
      extraglomerular small vessel vasculitis appeared to be predictive of systemic
      involvement.

PMID- 12612977
TI  - Steroid-sensitive nephrotic syndrome: from childhood to adulthood.
AB  - BACKGROUND: The clinical presentation, treatment, and outcome of steroid
      sensitive nephrotic syndrome (SSNS) during childhood have been extensively
      studied. Conversely, few data regarding the outcome in adulthood of childhood
      SSNS have been published previously. We undertook to conduct a retrospective
      study of the outcome in adulthood of a large cohort of patients diagnosed with an
      SSNS during childhood. METHODS: We identified all children born between 1970 and
      1975 who had been admitted to our institution for an SSNS. Data regarding the
      outcome in adulthood of these patients were obtained through mailed
      questionnaires or phone calls to patients and/or their parents or through
      attending physicians. RESULTS: One hundred seventeen patients were identified.
      Data regarding the outcome of SSNS in adulthood were available for 102 patients
      (87.2%). Forty-three patients (42.2%) experienced at least one relapse of
      nephrotic syndrome in adulthood. By univariate analysis, young age at onset (<6
      years) and more severe disease in childhood, indicated by a greater number of
      relapses (12.9 for adulthood relapsers versus 5.4 for adulthood nonrelapsers; P <
      0.0001) and more frequent use of immunosuppressors (74.4% versus 31.6%; P <
      0.0001) or cyclosporine (42.9% versus 7.3%; P < 0.0001) were predictive of the
      occurrence of SSNS relapse in adulthood. Conversely, relapse rate in the first 6
      months of disease was not predictive of further relapses in adulthood. By
      multivariate analysis, only number of relapses during childhood was predictive of
      adulthood relapses (P < 0.0058). Long-term side effects of steroids were found in
      44.2% of adulthood relapsers; the most frequent were osteoporosis and excess
      weight. CONCLUSION: The incidence of childhood SSNS relapses in adulthood was
      relatively high in our study. Further studies are required to assess long-term
      complications in adults with relapses and a history of prolonged steroid and
      immunosuppressor use.

PMID- 12612978
TI  - Different glycosylation profile of serum IgA1 in IgA nephropathy according to the
      glomerular basement membrane thickness: normal versus thin.
AB  - BACKGROUND: Abnormal glycosylation of immunoglobulin A1 (IgA1) has been
      implicated in the pathophysiological characteristics of IgA nephropathy, leading
      to failure of normal clearance mechanisms and mesangial deposition of serum IgA1.
      Furthermore, systematic measurement of glomerular basement membrane (GBM)
      thickness by electron microscopy evidenced two different subgroups: IgA
      nephropathy with normal GBM (N-GBM) and thin GBM (T-GBM). This finding prompted
      us to study comparatively the profile of N- and O-glycosylation of IgA1 in the
      two subgroups. METHODS: Using lectin-binding properties, sialylation and
      galactosylation of serum IgA1, isolated on jacalin-conjugated agarose, were
      investigated in male and female patients with IgA nephropathy with T-GBM (n = 22)
      and N-GBM (n = 22) compared with matched (age and sex) healthy controls (n = 22).
      Sambacus nigra agglutinin (SNA) and Maackia amurensis agglutinin (MAA) were
      designed to examine the detection of Neu5Acalpha2,6- and Neu5Acalpha2,3-linked
      galactose, respectively. Helix aspersa agglutinin (HAA) was used to examine the
      expression of terminal N-acetylgalactosamine of the O-linked glycans in the hinge
      region of IgA1. RESULTS: The following galactosylation abnormalities were
      confirmed in the common subgroup with N-GBM: a trend to an alpha2,6
      oversialylation (SNA binding) of native IgA1 associated with a defect in its
      terminal galactose (HAA binding); these two findings were predominant in male
      patients (P < 0.05 and 0.01 for SNA and HAA, respectively). No change in MAA was
      observed. Conversely, no significant anomaly was found in the T-GBM variant,
      which could indicate the absence or low magnitude of galactosylation defects (not
      significant) or another yet unidentified defect. CONCLUSION: The present study
      evidenced differences in glycosylation profiles of serum IgA1 according to GBM
      thickness (N-GBM versus T-GBM) in patients with IgA nephropathy. These data
      raised the possibility of different mechanisms for IgA1 glomerular deposition.

PMID- 12612979
TI  - A controlled, prospective study of the effects of atorvastatin on proteinuria and
      progression of kidney disease.
AB  - BACKGROUND: Chronic kidney diseases, particularly if presenting with significant
      proteinuria, are commonly associated with substantial alteration of serum lipid
      levels. Experimental evidence suggests that lipid abnormalities may contribute to
      the progression of kidney disease. However, studies in humans on the subject are
      scarce. METHODS: In a prospective, controlled open-label study, the authors have
      evaluated the effects of one-year treatment with atorvastatin, a 3-hydroxy-3
      methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, versus no treatment on
      proteinuria and progression of kidney disease in 56 patients with chronic kidney
      disease. Before randomization, all patients had already been treated for one year
      with angiotensin-converting enzyme (ACE) inhibitors or angiotensin AT1 receptor
      antagonists (ARBs) and other antihypertensive drugs. RESULTS: By the end of one
      year treatment, urine protein excretion decreased from 2.2 +/- 0.1 to 1.2 +/- 1.0
      g every 24 hours (P < 0.01) in patients treated with atorvastatin in addition to
      ACE inhibitor and ARBs. By contrast, urinary protein excretion decreased only
      from 2.0 +/- 0.1 to 1.8 +/- 0.1 g every 24 hours (P value not significant) in
      patients who did not receive atorvastatin in addition to ACE inhibitor or ARBs.
      During this time, creatinine clearance decreased only slightly and not
      significantly (from 51 +/- 1.8 to 49.8 +/- 1.7) in patients treated with
      atorvastatin. By contrast, during the same period of observation, creatinine
      clearance decreased from 50 +/- 1.9 to 44.2 +/- 1.6 mL/min (P < 0.01) in patients
      who did not receive atorvastatin. CONCLUSIONS: This study has shown that
      treatment with atorvastatin in addition to a regimen with ACE inhibitors or ARBs
      may reduce proteinuria and the rate of progression of kidney disease in patients
      with chronic kidney disease, proteinuria, and hypercholesterolemia. The benefits
      appear to occur in addition to those of treatment with ACE inhibitor and ARBs.

PMID- 12612980
TI  - B-type natriuretic peptide and renal function in the diagnosis of heart failure:
      an analysis from the Breathing Not Properly Multinational Study.
AB  - BACKGROUND: Both B-type natriuretic peptide (BNP) and renal function are
      prognostic indicators of survival in patients with congestive heart failure
      (CHF). However, relationships between BNP, renal function, and heart failure as
      an emergency diagnosis are unknown. METHODS: The Breathing Not Properly
      Multinational Study was a prospectively designed diagnostic test evaluation study
      conducted in seven centers. Of 1,586 participants who presented with acute
      dyspnea, 1,452 patients (91.6%) had both BNP level and baseline estimated
      glomerular filtration rate (eGFR) available. Patients with an eGFR less than 15
      mL/min/1.73 m2 and those on dialysis therapy were excluded. The final diagnosis
      was adjudicated by two independent cardiologists who were blinded to BNP results.
      RESULTS: The final diagnosis was CHF in 715 patients (49.2%). Raw and log-log
      transformed correlations between BNP and eGFR values were r = -0.19 and r = -0.17
      for those with CHF and r = -0.20 and r = -0.31 for those without CHF (both P <
      0.0001 for r not equal 0). Mean BNP levels were 561.6 pg/mL (162.3 fmol/mL),
      647.5 pg/mL (187.1 fmol/mL), 745.6 pg/mL (215.5 fmol/mL), and 850.7 pg/mL (245.8
      fmol/mL) for those with CHF and 85.4 pg/mL (24.7 fmol/mL), 131.7 pg/mL (38.1
      fmol/mL), 297.2 pg/mL (85.9 fmol/mL), and 285.0 pg/mL (82.3 fmol/mL) for those
      without CHF in eGFR categories of 90 or greater, 89 to 60, 59 to 30, and less
      than 30 mL/min/1.73 m2, respectively. The area under the receiver operating
      characteristic curve and optimum cut points for BNP were 0.91 and 70.7 pg/mL
      (20.4 fmol/mL), 0.90 and 104.3 pg/mL (30.1 fmol/mL), 0.81 and 201.2 pg/mL (58.1
      fmol/mL), and 0.86 and 225.0 pg/mL (65.0 fmol/mL) for the eGFR categories of 90
      or greater, 89 to 60, 59 to 30, and less than 30 mL/min/1.73 m2, respectively.
      CONCLUSION: Renal function correlates weakly with BNP and influences the optimal
      cut point for BNP, particularly in those with an eGFR less than 60 mL/min/1.73
      m2.

PMID- 12612981
TI  - Association of dietary protein intake and microalbuminuria in healthy adults:
      Third National Health and Nutrition Examination Survey.
AB  - BACKGROUND: The relationship between dietary protein intake (DPI) and
      microalbuminuria (MA) is unclear. We investigated whether DPI was associated with
      urinary albumin level in a population sample of persons with normal kidney
      function. METHODS: We addressed this question in adults aged 20 to 80 years from
      the Third National Health and Nutrition Examination Survey (n = 12,422). DPI was
      assessed from a 24-hour dietary recall and quantified as percentage of total
      energy intake. MA is defined as urinary albumin-creatinine ratio 30 mg/g (3
      mg/mmol) or greater. RESULTS: In multivariable logistic regression models
      adjusted for sociodemographic characteristics and coronary heart disease risk
      factors, DPI was not associated with MA in normotensive or nondiabetic persons.
      In crude models, odds ratios (ORs) for MA were 1.9 (95% confidence interval, 1.2
      to 3.0) in persons with hypertension (n = 3,433) and 2.4 (95% confidence
      interval, 1.1 to 5.2) in those with diabetes (n = 1,165) in the highest (>19%)
      versus lowest (<11.7%) quintile of DPI. However, in models adjusted for the
      concurrent prevalence of diabetes or hypertension, this association attenuated to
      nonsignificance. Persons in the highest quintile of DPI who had both hypertension
      and diabetes (n = 634) had a significantly elevated OR for MA (3.3; 95%
      confidence interval, 1.4 to 7.8) compared with those in the lowest quintile.
      CONCLUSION: DPI is not associated with MA in healthy persons or those with
      isolated hypertension or diabetes. However, in persons with both conditions, high
      DPI is associated with increased prevalence of MA. These findings suggest the
      need for further research on weight-loss strategies for high-risk persons.

PMID- 12612983
TI  - Health-related quality of life in Australian adults with renal insufficiency: a
      population-based study.
AB  - BACKGROUND: Health-related quality of life is increasingly recognized as an
      important outcome in clinical research and patient care. Although there are a
      large number of reports of quality of life in the setting of end-stage renal
      disease, the impact of lesser degrees of renal impairment in the general
      population has not been described. METHODS: Data relating to quality of life
      measured by the Medical Outcomes Study 36-Item Short Form (SF-36) was available
      for 10,525 participants (93.6%) of the Australian Diabetes, Obesity and Lifestyle
      Study, a randomly selected representative sample of the Australian population
      aged 25 years or older. Results are examined by category of renal function
      (Cockcroft-Gault estimated glomerular filtration rate: normal, > or =60
      mL/min/1.73 m2; renal insufficiency, <60 mL/min/1.73 m2). RESULTS: Significant
      impairment in health-related quality of life was seen with renal insufficiency
      for all SF-36 scales except Vitality and Mental Health. Adjusting for the
      substantial comorbidity associated with renal insufficiency, scores for Physical
      Functioning, Role-Physical, General Health, Vitality, and Role-Emotional were
      significantly lower. Examination of age-specific effects on health-related
      quality of life showed that mental health was particularly impaired in the
      younger age group, and Physical Functioning, in the older age group with renal
      insufficiency. Patterns of impairment were similar in men and women. CONCLUSION:
      Results from this study indicate that the current emphasis on clinical
      interventions aimed at preserving renal function are likely to improve the
      negative impact of kidney disease on health-related quality of life; however,
      prospective studies are needed to confirm these findings.

PMID- 12612982
TI  - High-normal blood pressure and microalbuminuria.
AB  - BACKGROUND: High-normal blood pressure (BP) is associated with increased
      cardiovascular risk compared with optimal BP, but no study has specifically
      examined the association between high-normal BP and microalbuminuria, an
      established predictor of future cardiovascular events. METHODS: This was a cross
      sectional study of normotensive (systolic BP [SBP] < 140 mm Hg, diastolic BP
      [DBP] < 90 mm Hg) individuals without diabetes with no hypertension history
      enrolled in the Third National Health and Nutrition Examination Survey. BP was
      categorized as high normal (SBP, 130 to 139 mm Hg or DBP, 85 to 89 mm Hg), normal
      (SBP, 120 to 129 mm Hg or DBP, 80 to 84 mm Hg), and optimal (SBP < 120 mm Hg and
      DBP < 80 mm Hg). We also separately examined SBP, DBP, mean arterial pressure
      (MAP), and pulse pressure. Microalbuminuria was defined using sex-specific cutoff
      values (urine albumin-creatinine ratio > or = 17 and < or = 250 microg/mg [> or
      =1.0 and < or =28 mg/mmol] for men and > or = 25 and < or = 355 microg/mg for
      women [> or =3 and < or =40 mg/mmol]). We used multivariate logistic regression
      to analyze the association between different BP measurements and
      microalbuminuria. RESULTS: Compared with optimal BP, high-normal BP was
      significantly associated with increased odds of microalbuminuria (odds ratio
      [OR], 2.13; 95% confidence interval [CI], 1.51 to 3.01). Similarly, MAP (OR,
      1.41; 95% CI, 1.15 to 1.74 per 10-mm Hg increment), SBP (OR, 1.27; 95% CI, 1.09
      to 1.48 per 10-mm Hg increment), and DBP (OR, 1.29; 95% CI, 1.06 to 1.57 per 10
      mm Hg increment) were significantly associated with microalbuminuria. CONCLUSION:
      High-normal BP is significantly associated with microalbuminuria compared with
      optimal BP and may be a biomarker of the increased cardiovascular risk observed
      in this population.

PMID- 12612984
TI  - Health-related quality of life and associated outcomes among hemodialysis
      patients of different ethnicities in the United States: the Dialysis Outcomes and
      Practice Patterns Study (DOPPS).
AB  - BACKGROUND: In the United States, an association between mortality risk and
      ethnicity has been observed among hemodialysis patients. This study was developed
      to assess whether health-related quality of life (HRQOL) scores also vary among
      patients of different ethnic backgrounds. Associations between HRQOL and adverse
      dialysis outcomes (ie, death and hospitalization) also were assessed for all
      patients and by ethnicity. METHODS: Data are from the Dialysis Outcomes and
      Practice Patterns Study for 6,151 hemodialysis patients treated in 148 US
      dialysis facilities who filled out the Kidney Disease Quality of Life Short Form.
      We determined scores for three components of HRQOL: Physical Component Summary
      (PCS), Mental Component Summary (MCS), and Kidney Disease Component Summary
      (KDCS). Patients were classified by ethnicity as Hispanic and five non-Hispanic
      categories: white, African American, Asian, Native American, and other. Multiple
      linear regression models were used to estimate differences in HRQOL scores among
      ethnic groups, using whites as the referent category. Cox regression models were
      used for associations between HRQOL and outcomes. Regression models were adjusted
      for sociodemographic variables, delivered dialysis dose (equilibrated Kt/V), body
      mass index, years on dialysis therapy, and several laboratory/comorbidity
      variables. RESULTS: Compared with whites, African Americans showed higher HRQOL
      scores for all three components (MCS, PCS, and KDCS). Asians had higher adjusted
      PCS scores than whites, but did not differ for MCS or KDCS scores. Compared with
      whites, Hispanic patients had significantly higher PCS scores and lower MCS and
      KDCS scores. Native Americans showed significantly lower adjusted MCS scores than
      whites. The three major components of HRQOL were significantly associated with
      death and hospitalization for the entire pooled population, independent of
      ethnicity. CONCLUSION: The data indicate important differences in HRQOL among
      patients of different ethnic groups in the United States. Furthermore, HRQOL
      scores predict death and hospitalization among these patients.

PMID- 12612985
TI  - Left ventricular hypertrophy and endothelial dysfunction in chronic hemodialysis
      patients.
AB  - BACKGROUND: Endothelial dysfunction (ED), which is a risk factor for
      atherosclerosis, has been reported recently in chronic hemodialysis (CHD)
      patients. In this study, we aim to investigate the association of ED and presence
      of left ventricular hypertrophy (LVH) in CHD patients. METHODS: One hundred four
      CHD patients (47 men, 57 women; mean age, 45 +/- 12 years) and 49 age- and sex
      matched controls were included. Mean time on dialysis therapy was 62 months.
      Echocardiographic examination and flow-mediated endothelium-dependent (EDD) and
      endothelium-independent dilatation (EID) of the brachial artery, measured by high
      resolution ultrasonography, a noninvasive method for assessing endothelial
      function, were performed on a nondialysis day. RESULTS: LVH was detected in 72
      CHD patients (69%). Patients with LVH had a lower EDD (9.3% +/- 6.1% versus 12.1%
      +/- 8.3%; P = 0.06), but the difference was not significant. Mean EID was
      significantly lower in CHD patients with LVH (13.6% +/- 7.6% versus 18.6% +/-
      9.8%; P = 0.008). Left ventricular mass index (LVMI) correlated with both EDD (r
      = -0.22; P = 0.03) and EID (r = -0.32; P = 0.002). Patients with LVH had a
      greater rate of hypertension (35 of 72 versus 7 of 32 patients; P = 0.02) and
      lower hemoglobin levels (11.0 +/- 1.8 versus 11.8 +/- 1.6 g/dL [110 +/- 18 versus
      118 +/- 16 g/L]; P = 0.05). CHD patients had a lower EDD (10.2% +/- 6.9% versus
      20.9% +/- 7.6%; P < 0.001) and EID (15.0% +/- 8.5% versus 27.8% +/- 8.5%; P <
      0.001) compared with controls. In linear regression analysis for predicting LVMI,
      presence of hypertension, hemoglobin level, and EID, but not EDD, were found to
      be independent variables. CONCLUSION: EID, which may reflect decreased elasticity
      of arteries, contributes to the development of LVH in CHD patients, in addition
      to hypertension and anemia.

PMID- 12612986
TI  - Perturbation of autocrine/paracrine loops of burst-forming units of erythroid
      derived cells in rHuEPO-hyporesponsive hemodialysis patients.
AB  - BACKGROUND: Quantitative or qualitative abnormalities of erythroid progenitors in
      patients with chronic renal failure (CRF) could be the major factor for
      recombinant human erythropoietin (rHuEPO) hyporesponsiveness and severe anemia in
      hemodialysis (HD) patients receiving rHuEPO therapy. METHODS: Purified 1 x 10(4)
      circulating CD34+ cells isolated from rHuEPO-hyporesponsive HD patients (EPO-H; n
      = 10), rHuEPO-responsive non-HD patients with CRF (EPO-R; n = 8), nonanemic HD
      patients without rHuEPO therapy (EPO-W/O; n = 10), and healthy volunteer controls
      (CON; n = 10) were subjected to a methylcellulose culture system supplemented
      with rHuEPO, recombinant human interleukin-3 (IL-3), recombinant human stem cell
      factor (SCF), and recombinant human granulocyte-macrophage colony-stimulating
      factor (GM-CSF) for 14 days. RESULTS: The average number of burst-forming units
      of erythroids (BFU-Es) was significantly less in the EPO-H group compared with
      the CON and EPO-W/O groups. Furthermore, colony size also was significantly
      smaller in the EPO-H group. Total RNAs were extracted from approximately 100
      colonies/patient and subjected to complementary DNA expression array studies of
      268 growth factors, cytokines, chemokines, and their receptors. A characteristic
      cluster upregulated in the EPO-R and EPO-W/O groups and downregulated in the EPO
      H group was identified that contained various cytokines and growth factors,
      including IL-6, GM-CSF, vascular endothelial growth factor B, IL-9, IL-3,
      leukemia inhibitory factor, and interferon alpha-2, and such receptors as
      thrombopoietin receptor, IL-9 receptor, and colony-stimulating factor 1 receptor.
      CONCLUSION: These data suggest that the cross-talk network or autocrine/paracrine
      regulatory loop is critically impaired in BFU-E-derived cells in EPO-H patients,
      and investigation of these cluster genes would facilitate the development of
      novel therapeutic strategies for such patients.

PMID- 12612987
TI  - The methylentetrahydrofolate reductase C677T point mutation is a risk factor for
      vascular access thrombosis in hemodialysis patients.
AB  - BACKGROUND: Many reports indicate that a high homocysteine (Hcy) level is a
      potential risk factor for such thrombotic diseases as arteriosclerosis,
      myocardial infarction, and cerebral infarction in healthy individuals or
      hemodialysis (HD) patients. The methylentetrahydrofolate reductase (MTHFR) C677T
      polymorphism has been reported to be closely related to plasma Hcy level.
      METHODS: Using a cross-sectional design in this study, the relationship between
      arteriovenous fistula (AVF) obstruction and the MTHFR C677T point mutation was
      examined in 337 HD patients. RESULTS: Results of multivariate analysis showed no
      significant influence of age, HD therapy duration, sex, or the presence of
      diabetes mellitus, cerebral infarction, or myocardial infarction. Only the
      presence of the MTHFR C677T polymorphism yielded a significant difference.
      Percentages of patients who experienced AVF obstruction were as follows: CC
      (12.6%), CT (20.3%), and TT (31.8%). The number of those who experienced
      obstruction was significantly larger with the TT than CC (P < 0.01). Moreover,
      total obstruction episode ratios were as follows: CC, 1 in 107.21
      episodes/patient-month; CT, 1 in 74.08 episodes/patient-month; and TT, 1 in 50.33
      episodes/patient-month. Episode percentages tended to be greater when the degree
      of mutation was greater, and a significant difference was observed between the CC
      and TT alleles (P < 0.01). CONCLUSION: Although AVF obstruction is affected by
      numerous factors, there was a strong relationship between MTHFR C677T mutation
      and AVF obstruction. These findings suggest that the MTHFR C677T point mutation
      could serve as an important indicator in identifying susceptibility to AVF
      obstruction.

PMID- 12612988
TI  - Permanent cessation of menses and postmenopausal hormone use in dialysis
      dependent women: the HELP study.
AB  - BACKGROUND: Earlier onset of menopause is associated with an increased risk for
      cardiovascular disease, especially among women with surgical menopause.
      Information on age at or reasons for the permanent cessation of menses among
      women with end-stage renal disease (ESRD) remains limited, although
      cardiovascular disease accounts for more than half of all cardiovascular deaths
      in this population. METHODS: We used data from the Hemodialysis and Estrogen
      Levels in Postmenopausal Patients Study to examine the reported age when menses
      permanently ceased, reasons for the permanent cessation of menses, and prevalence
      of surgical menopause. We also investigated the frequency of current and past
      postmenopausal hormone (PMH) use among dialysis-dependent women and their views
      toward PMH therapy. RESULTS: Among 238 postmenopausal hemodialysis-dependent
      women, median age when menses permanently ceased was 48 years. Permanent
      cessation of menses was attributed to natural causes in 65%, surgical reasons in
      30% (16%, hysterectomy without bilateral oophorectomy; 14%, hysterectomy with
      bilateral oophorectomy), kidney failure in 2%, radiation or chemotherapy in 1%,
      and other causes in 2%. Among women with a history of bilateral oophorectomy, 71%
      became menopausal before the age of 35 years. Current and past PMH use was
      reported by 6% and 17% of the women, respectively, whereas 77% were never
      administered hormones. Only 2% stated a kidney doctor ever recommended PMH
      therapy, and 54% said they would not take PMHs if prescribed by their kidney
      doctor. CONCLUSION: Many women with ESRD experience surgical menopause before the
      age of 35 years, which may contribute to the excess cardiovascular mortality
      among women with ESRD. PMH use remains low among dialysis-dependent women.
      However, two randomized controlled trials have noted a significantly increased
      risk for cardiovascular events in women administered estrogen in combination with
      progestin. Thus, risks associated with PMH use may outweigh the benefits in a
      population with a very high rate of cardiovascular disease, such as
      postmenopausal hemodialysis-dependent women.

PMID- 12612990
TI  - Oral nutritional supplementation increases caloric and protein intake in
      peritoneal dialysis patients.
AB  - BACKGROUND: Malnutrition is highly prevalent in peritoneal dialysis (PD) patients
      and is associated with a poor prognosis. Attempts to improve nutritional status
      with enteral supplements have yielded poor results. METHODS: We performed a
      crossover-design trial on 13 PD patients to investigate whether these patients
      reduce their food intake after drinking oral nutritional supplements. Patients
      attended three visits in which they were administered a standard oral nutritional
      supplement either 2 hours or 30 minutes before lunch or a placebo drink 30
      minutes before lunch. Lunch was provided as a self-select buffet-style meal, and
      food intake was measured. Total intake was calculated by adding the nutritional
      content of the oral supplement. RESULTS: Patients showed poor food intake, with
      mean values equaling only 18% of the recommended daily intake for calories and
      34% for protein. Drinking the supplement 2 hours before lunch resulted in a
      significant increase compared with the placebo visit in total caloric (430 to 843
      kcal; P < 0.001) and protein intake (27.6 to 41.3 g; P = 0.006). No significant
      difference in total intake was detected between drinking the supplement 2 hours
      versus 30 minutes before lunch. CONCLUSION: These results indicate that oral
      nutritional supplements administered before a meal may significantly increase
      caloric and protein intakes of PD patients.

PMID- 12612989
TI  - Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety
      of higher-dose (> or =250 mg) administration.
AB  - BACKGROUND: Almost all hemodialysis (HD) patients require intravenous iron
      therapy to correct their anemia and maintain their iron stores. Sodium ferric
      gluconate complex (SFGC) is approved by the Food and Drug Administration (FDA)
      for treatment of iron deficiency anemia in HD patients at individual doses up to
      125 mg over 10 minutes (12.5 mg/min) and has been shown to have a superior safety
      profile compared with iron-dextran. Higher individual doses of SFGC would permit
      more rapid repletion of iron stores and greater flexibility in maintenance iron
      therapy as well as simplify treatment of peritoneal dialysis patients and chronic
      kidney disease patients. METHODS: The authors reviewed the safety and
      tolerability of higher-dose SFGC infusions (> or =250 mg) in 144 HD patients who
      were previously tolerant to a single 125-mg dose of SFGC. These 144 patients
      received a total of 590 doses of > or =250 mg of SFGC; 571 doses were 250 mg
      SFGC, and most of these were infused over 1 hour, an infusion rate of 4.17
      mg/min. The other 19 doses were 312.5 mg (n = 1), 375 mg (n = 14), and 500 mg (n
      = 4). Infusion rates varied from 1.22 mg/min to 25.0 mg/min. RESULTS: Only one
      patient was considered intolerant to higher-dosing SFGC after having pruritus
      after a second 250-mg dose of SFGC. Three patients had nonserious events that did
      not preclude further dosing of SFGC. CONCLUSION: Administration of 250 mg SFGC
      over 1 hour is safe and well tolerated. Individual doses of 375 mg and 500 mg
      SFGC also were well tolerated, but further research and experience are needed to
      confirm the safety and tolerance of these doses.

PMID- 12612991
TI  - Albumin at the start of peritoneal dialysis predicts the development of
      peritonitis.
AB  - BACKGROUND: Both peritonitis and serum albumin level are associated with
      morbidity and mortality in peritoneal dialysis (PD) patients. Severe cases of
      peritonitis result in hypoalbuminemia. However, it is not clear whether
      hypoalbuminemia predicts the development of peritonitis. METHODS: We performed a
      retrospective analysis of a prospectively collected database from six centers in
      western Pennsylvania and West Virginia. Incident PD patients with a Charlson
      Comorbidity Index (CCI) score at the start of PD therapy and serum albumin level
      measured within 30 days of initiation were selected. Poisson regression was used
      to analyze predictors of peritonitis. RESULTS: Three hundred ninety-three
      patients had a CCI score and serum albumin level measured at the start of PD
      therapy. Overall peritonitis rate was 0.65 episodes/dialysis-year. Significant
      univariate predictors were albumin level (rate ratio [RR], 0.79 per 1-g/dL [10
      g/L] increase; 95% confidence interval [CI], 0.65 to 0.95; P = 0.015), male sex
      (P = 0.003), and being dialyzed in the Veterans Administration (RR, 1.97; 95% CI,
      1.48 to 2.62; P < 0.001) or other center (RR, 1.68; 95% CI, 1.92 to 5.62; P <
      0.001). Although CCI score correlated inversely with albumin level (r = -0.305; P
      < 0.001), CCI score was only marginally predictive of peritonitis (P = 0.068). In
      multivariate analysis, predictors were albumin level (RR, 0.74; 95% CI, 0.31 to
      1.75; P = 0.002) and race (RR, 1.36; P = 0.024). Patients with an initial serum
      albumin level less than 2.9 g/dL (29 g/L) had a peritonitis rate of 1.5
      episodes/dialysis-year compared with 0.6 episodes/dialysis-year for patients with
      an initial serum albumin level of 2.9 g/dL or greater (P < 0.001). CONCLUSION:
      Hypoalbuminemia at the start of PD therapy is an independent predictor of
      subsequent peritonitis. Intervention studies to decrease peritonitis risk in this
      high-risk subset of patients are needed.

PMID- 12612992
TI  - Empirical aminoglycosides for peritonitis do not affect residual renal function.
AB  - BACKGROUND: Aminoglycosides have been proven to be an efficacious treatment for
      peritonitis in peritoneal dialysis patients for many years. Consequently, they
      have been recommended in previous guidelines for the empirical treatment of
      peritonitis. However, with the increasing emphasis on preserving residual renal
      function (RRF), there has been concern about the nephrotoxic potential of these
      compounds. The 2000 International Society of Peritoneal Dialysis (ISPD)
      guidelines recommended that aminoglycosides not be used in patients with RRF, and
      that ceftazidime be used instead. In 1997, in response to the 1996 ISPD
      guidelines, we changed our peritonitis regimen from vancomycin and ciprofloxacin
      to cefazolin and gentamicin. The aim of this study is to compare the change in
      renal function occurring after treatment of peritonitis with and without
      gentamicin. METHODS: Using 6-monthly urine and dialysis clearance measurements,
      preperitonitis and postperitonitis RRF (mean of 24-hour urea and creatinine
      clearance) were determined for 70 peritonitis episodes treated with the
      aminoglycoside-based regimen (group A), 61 episodes treated without
      aminoglycosides (group B), and 74 control patients without peritonitis (group C).
      RESULTS: Group A had mean declines in estimated glomerular filtration rate and
      urine output of -0.08 +/- 0.50 mL/min/mon and -8.82 +/- 88.09 mL/24 h/mon
      compared with -0.17 +/- 0.27 mL/min/mon and -34.68 +/- 69.58 mL/24 h/mon in group
      B and -0.20 +/- 0.39 mL/min/mon and -14.61 +/- 77.33 mL/24 h/mon in group C,
      respectively. There were no significant differences between groups. CONCLUSION:
      In our patients, there was no evidence of an accelerated decline in RRF when
      using an empirical regimen containing aminoglycosides for peritonitis. Because
      there are few data to contradict this finding, we recommend the continued use of
      these drugs in peritonitis regimens, even in patients with significant RRF.

PMID- 12612993
TI  - Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a
      prospective study in Queensland, Australia.
AB  - BACKGROUND: Nonmelanoma skin cancer (NMSC) is a significant clinical problem
      after renal transplantation, particularly in areas of high UV light exposure. A
      single-center prospective study of a population of Queensland renal transplant
      recipients was performed with the aims of: (1) establishing NMSC incidence and
      tumor accrual post-renal transplantation, and (2) developing a clinically derived
      predictive index to identify transplant recipients at greatest risk. METHODS:
      Three hundred ten of 398 transplant recipients (78%) who underwent baseline
      assessment between July 1999 and April 2000 were reassessed a mean of 18 +/- 3.5
      (SD) months later. A structured interview, full skin examination, biopsy of
      suspicious lesions, and review of medical and pathological records were used to
      determine the number and types of NMSC arising between the two assessments.
      Incidence (percentage of the population developing NMSC per year) and tumor
      accrual (number of tumors per person per year) were calculated. A clinically
      derived predictive index was generated using stepwise logistic regression models.
      RESULTS: Overall NMSC incidence was 28.1% and increased with duration of
      immunosuppression therapy: 18.8%, 24.8%, 33.3%, and 47.1% at less than 5, 5 to
      10, 10 to 20, and greater than 20 years of immunosuppression therapy,
      respectively. Mean NMSC accrual was 1.85 +/- 3.84 tumors/person/y, increasing to
      3.35 +/- 4.29 tumors/person/y after 20 years of immunosuppression therapy. Renal
      transplant recipients were stratified into categories of high and low NMSC risk
      by using predictive indices. CONCLUSION: Clinically derived predictive indices
      can allow NMSC risk stratification of an Australian transplant population and may
      provide an evidence-based and cost-effective approach to developing a targeted
      clinical NMSC surveillance program.

PMID- 12612994
TI  - Vascular function in children after renal transplantation.
AB  - BACKGROUND: Atherosclerotic complications are the main cause of death in adult
      patients with renal failure. Endothelial dysfunction is a hallmark of early
      atherosclerotic changes. The numerous risk factors for endothelial dysfunction
      present in adults are present in children with renal failure, as well. In
      addition to this, increased stiffness of the arterial tree conveys an increased
      risk for cardiovascular mortality. The aim of this study is to investigate
      whether pediatric kidney recipients already show endothelial dysfunction and have
      increased arterial stiffness. METHODS: We investigated 20 pediatric kidney
      recipients with stable graft function and 20 healthy children. Endothelial
      function was studied noninvasively with ultrasound and digital signal analysis
      equipment as the percentage of post-ischemic flow-mediated dilatation (FMD) of
      the brachial artery. Parameters of arterial distensibility were calculated from
      distension of the brachial artery during the cardiac cycle, pulse pressure, and
      baseline diameter. RESULTS: FMD was significantly less in patients (7.7% +/-
      5.4%) than controls (15.0% +/- 7.1%; P < 0.001), indicating endothelial
      dysfunction in pediatric kidney recipients. Impairment of FMD was found
      predominantly in patients being treated for hypertension. Arterial distensibility
      was diminished in patients (3.4 +/- 2.8 versus 5.7 +/- 3.3 10(-3)/mm Hg; P <
      0.02), indicating increased stiffness of the arterial tree. Patients had a
      greater baseline diameter of the brachial artery adjusted for height than healthy
      controls at equal blood pressure. CONCLUSION: These findings suggest arterial
      wall changes in pediatric renal transplant recipients. They are already at risk
      for premature development of atherosclerotic complications and cardiovascular
      mortality.

PMID- 12612995
TI  - Cyclosporine treatment for patients with CRF who developed pure red blood cell
      aplasia following EPO therapy.
AB  - Human recombinant erythropoietin is the main treatment for anemia in renal
      patients. Recently, there have been case reports of pure red blood cell aplasia
      (PRCA) developing in renal patients administered erythropoietin, probably because
      of neutralizing antibodies detected in all these patients. All reports were from
      the West, and most patients were treated with erythropoietin-alpha. Cyclosporine
      is an immunosuppressive agent used to treat a spectrum of autoimmune conditions.
      We report a series of Chinese renal patients who developed PRCA after treatment
      with erythropoietin-alpha, suggesting that this is a problem worldwide. They were
      treated successfully with cyclosporine and became transfusion independent.

PMID- 12612996
TI  - Adenovirus infection of a renal allograft.
AB  - One month after renal transplantation, a 60-year-old man developed acute
      allograft dysfunction associated with gross hematuria and dysuria. Urinary
      cytological examination showed viral inclusion-bearing epithelial cells. A renal
      transplant biopsy specimen showed granulomatous interstitial nephritis, tubular
      necrosis, and ground glass-like intranuclear viral inclusion bodies in tubular
      cells caused by an adenovirus (ADV) infection. A reduction in baseline
      immunosuppressive therapy resulted in rapid normalization of allograft function
      and ultimately viral clearance. We report this case not only to illustrate an
      exceptional manifestation of an ADV infection in a renal allograft, but also to
      highlight the beneficial effect of reduction in immunosuppressive therapy on
      viral replication and clinical outcome.

PMID- 12612997
TI  - Iodine toxicity treated with hemodialysis and continuous venovenous
      hemodiafiltration.
AB  - Continuous mediastinal irrigation with povidone-iodine is used commonly for
      treating severe postoperative mediastinitis. However, concurrent iodine toxicity
      has been reported, particularly in patients with renal dysfunction (likely
      because absorbed iodine is renally excreted). The authors were consulted on a 45
      year-old patient with mediastinitis who had renal and hepatic dysfunction while
      being treated with mediastinal irrigation of povidone-iodine. The povidone-iodine
      irrigation was discontinued because he had toxic plasma iodine levels. Despite
      this, his condition worsened, and the iodine levels remained elevated. Thus,
      hemodialysis (HD) was initiated using high-flux membranes followed by continuous
      venovenous hemodiafiltration (CVVHDF; 2 L/h of hemofiltration and 2 L/h of HD).
      Plasma and effluent iodine levels were measured repeatedly to determine iodine
      clearance by these 2 modalities (HD, 120 mL/min; CVVHDF, 37 mL and 44 mL/min on
      days 1 and 2, respectively). Hepatic and renal functions improved with decreasing
      plasma iodine levels. Based on this experience and after reviewing the literature
      the authors conclude that: (1) iodine irrigation can increase blood iodine levels
      significantly, especially in the setting of renal failure, and lead to increased
      morbidity and mortality; (2) plasma iodine levels should be monitored in patients
      with renal insufficiency; and (3) HD and CVVHDF are effective at clearing iodine.
      The authors suggest that patients that are at high risk or already developing
      signs of iodine toxicity should have the iodine irrigation discontinued and may
      benefit from renal replacement therapy (RRT). Alternatively, concomitant RRT
      during iodine irrigation may be attempted to maintain the systemic iodine levels
      at nontoxic levels.

PMID- 12612998
TI  - Hemolytic uremic syndrome in association with typhoid fever.
AB  - BACKGROUND: Hemolytic uremic syndrome (HUS) has been associated with typhoid
      fever caused by Salmonella typhi. The pathogenesis of HUS in the context of S
      typhi infection is not known. The authors report on a patient with typhoid fever
      in whom HUS and myocarditis developed during the course of his illness and in
      whom there was no evidence of a Shiga-toxin (Stx)-producing organism. METHODS:
      Antibodies directed against the Escherichia coli O157:H7 and S typhi
      lipopolysaccharide (LPS) were sought in the serum sample taken during the acute
      phase using line-blot immunoassays. Polymerase chain reaction was performed to
      detect the presence of stx1 and stx2 genes in the patient's S typhi isolate.
      RESULTS: There was no evidence for immunoglobulin (Ig) M and IgA against the LPS
      of E coli O157:H7, whereas anti-S typhi LPS IgM and IgA were strongly positive.
      In the polymerase chain reaction, DNA from the Stx-producing E coli controls
      yielded stx1 and stx2 fragments of the expected sizes on agarose gel
      electrophoresis, whereas no stx1 and stx2 fragments were obtained from the S
      typhi isolate. The S typhi did, however, yield a band when amplified with primers
      specific for viaB, an S typhi gene. CONCLUSION: S typhi may be responsible for
      some cases of HUS, and the inciting toxin may not be Stx.

PMID- 12612999
TI  - Granulomatous interstitial nephritis.

PMID- 12613000
TI  - Isolated renal giant cell arteritis, not so rare a cause of renal failure?

PMID- 12613001
TI  - Rofecoxib-induced acute interstitial nephritis.

PMID- 12613002
TI  - Obstructive ARF caused by an inflammatory abdominal aortic aneurysm.
AB  - Inflammatory abdominal aortic aneurysms are rare entities characterized by dense
      fibrosis typically enveloping the aortic wall and adjacent structures with
      distinctive clinical features that differentiate them from typical
      atherosclerotic aneurysms. The inflammatory process can involve the renal
      excretory pathways, causing ureteral obstruction in 20% of cases. The authors
      report 2 cases of complete obstructive anuria secondary to inflammatory aneurysms
      and discuss the most appropriate management for these situations of
      hydronephrosis. Surgical repair of the aneurysm usually leads to regression of
      the inflammatory reaction.

PMID- 12613003
TI  - Withdrawal of interferon-alpha results in prompt resolution of thrombocytopenia
      and hemolysis but not renal failure in hemolytic uremic syndrome caused by
      interferon-alpha.
AB  - This case report describes 2 patients with chronic myeloid leukemia in whom
      hemolytic uremic syndrome developed while being treated with interferon-alpha and
      hydroxycarbamide. Hemolytic uremic syndrome was recognized by progressive renal
      dysfunction, thrombocytopenia, microangiopathic hemolytic anemia, and histologic
      features of thrombotic microangiopathy in the kidney. Although renal dysfunction
      progressed to dialysis-dependent renal failure in one patient despite treatment
      with prednisolone and plasmapheresis but not in other, withdrawal of the
      treatment resulted in a prompt resolution of thrombocytopenia and
      microangiopathic hemolytic anemia in both patients.

PMID- 12613004
TI  - ARF requiring hemodialysis after accidental perchloroethylene ingestion.
AB  - Perchloroethylene (PCE) is an unsaturated chlorinated hydrocarbon in the form of
      a colorless, volatile liquid that is used as an industrial organic solvent for
      metal degreasing and for dry cleaning. The majority of cases of PCE intoxication
      have occurred by chronic inhalation, and PCE has been implicated previously in
      the development of mild renal dysfunction. However, the acute effects of PCE on
      the kidney are not well characterized, and the authors know of no reports of
      renal biopsy findings in the human. Here the case of a 32-year-old man who
      manifested by semicomatose state and oliguric acute renal failure requiring
      dialysis after accidental ingestion of 75 g of PCE is presented. A renal biopsy
      performed on the 19th day after ingestion showed features characteristic of
      severe acute tubular necrosis: aggregations of triangular or rhomboid crystals in
      the tubular lumens. A von Kossa stain showed that the crystal deposits were
      strongly positive for calcium. After 5 hemodialyses and conservative treatment,
      renal function gradually returned to normal.

PMID- 12613005
TI  - Resolution of massive uremic tumoral calcinosis with daily nocturnal home
      hemodialysis.
AB  - BACKGROUND: Derangements in bone mineral metabolism are an invariable consequence
      of end-stage renal disease (ESRD). Extraosseous tumoral calcification is a
      relatively uncommon complication that can be associated with substantial
      morbidity. METHODS: The authors report a case of an ESRD patient who had severe
      tumoral calcification of his shoulder, hands, and feet despite daily conventional
      hemodialysis. Conversion to daily nocturnal hemodialysis (DNHD) led to a dramatic
      resolution of his calcific deposits within only 9 months of initiating this form
      of renal replacement therapy. RESULTS: After initiating DNHD, the patient's serum
      phosphate level, which had been exceedingly difficult to control, normalized
      within the first week. Despite maintaining a high dialysate calcium (Ca) bath up
      to 4.2 mEq/L (2.1 mmol/L; to maintain calcium balance and suppress parathyroid
      hormone [PTH]), there was ongoing dissolution of the calcific deposits. This
      occurred with relatively preserved bone mineral density. The Ca x phosphorus
      (PO4) product decreased from 85 mg2/dL2 (6.80 mmol2/L2) and remained less than 55
      mg2/dL2 (4.4 mmol2/L2) throughout the patient's course on DNHD. PTH levels fell
      precipitously early on but then rose again several months after starting DNHD.
      This PTH rebound as well as the possible mechanisms underlying the dissolution of
      this patient's extraosseous calcifications are explored further. CONCLUSION:
      Extraosseous tumoral calcification associated with ESRD is an uncommon but
      potentially serious complication in this patient population. DNHD, by offering
      superior phosphate clearance, can facilitate the dissolution of these calcific
      deposits over a relatively short period. This effect can be seen despite using
      high calcium concentration dialysate to maintain calcium balance and mitigate
      hyperparathyroidism.

PMID- 12613007
TI  - [A clinical study on renal pelvic and ureteral cancer].
AB  - We investigated the clinicopathological features of 62 patients with transitional
      cell carcinoma of the renal pelvis and/or ureter who underwent total
      nephroureterectomy at our department from April, 1987 to October, 2000. The
      patients consisted of 48 males and 14 females, with a mean age of 67 years,
      ranging from 46 to 86 years. The mean follow-up period was 40 months. The 1-, 3-
      and 5-year cause-specific survival rates (Kaplan-Meier's method) for all of the
      patients were 90.8, 82.9%, and 68.6%, respectively. The prognostic significance
      of the 5 pathological factors (grade, pT, pV, pL and pN) were evaluated. All
      these factors affected the survival rates significantly in univariate analysis
      using the generalized Wilcoxon test. According to multivariate analysis by the
      Cox proportional hazard model, the most influential prognostic factor was grade.

PMID- 12613008
TI  - [A case report of a patient with emphysematous cystitis who was cured by early
      cystectomy under a life threatening condition].
AB  - A 80-year-old female with insulin-dependent diabetes mellitus (IDDM) visited our
      hospital on November 24, 1999, because of nausea, vomiting and macrohematuria.
      Cystoscopy demonstrated a diffuse hyperemic mucosa and gas-filled vesicles in the
      submucosa. Despite treatment with antibiotics, infection was not controlled and
      metabolic acidosis was increased. Simple cystectomy and ureterocutaneostomy were
      performed. Histological examination showed whole mucosal necrosis and vacuolation
      with aerogenesis in the submucosa and muscle layer of the bladder. Urine and
      mucosal surface cultures revealed Escherichia coli infection. After operation,
      the general condition was improved. Thirty six cases of emphysematous cystitis
      have been reported in Japan including this case. Successful treatment with
      cystectomy under the life threatening condition was reported for the first time.

PMID- 12613009
TI  - [Iatrogenic ureteral injury and the development of vesico-vaginal fistula: a
      complication of total hysterectomy for multiple myoma uteri].
AB  - A 42-year-old woman underwent total hysterectomy for multiple myoma uteri.
      Postoperatively the patient complained of lower abdominal pain and total
      incontinence. She had also developed left-sided hydronephrosis. Left nephrostomy
      was constructed and necessary investigations were done. It was diagnosed as a
      case of left ureteral injury with vesico-vaginal fistula. Repair of vesico
      vaginal fistula and reimplantation of the left ureter were performed in a single
      setting three months after the injury. Subsequently, the nephrostomy was removed.
      Hydronephrosis was improved with an excellent outcome of fistula repair.

PMID- 12613010
TI  - [A case of intrascrotal schwannoma].
AB  - A 70-year-old male was admitted to our hospital with the chief complaint of a
      left intrascrotal mass. A painless, solid and elastic-hard mass was palpable in
      the left scrotum. The testis, epididymis and spermatic cord could not be palpated
      separately from the mass. Tumor resection was performed. The tumor was 13 x 7.5 x
      3.0 cm in size and 285 g in weight. Histological diagnosis was schwannoma. To our
      knowledge, the case was considered as the sixth reported in Japan.

PMID- 12613011
TI  - [Genital tuberculosis occurring in the spermatic cord: a case report].
AB  - Genital tuberculosis occurring in the spermatic cord is a rare disease. A 70-year
      old man presented with a mass on the left side of the scrotum which had been
      painless and had gradually enlarged over the previous 4 months. Surgical excision
      was performed. The tumorous mass was located in the spermatic cord but did not
      connect with the testis or epididymis. The removed specimen was 15 x 20 x 15 mm
      in size and weighed 6 g. Histopathological diagnosis was tuberculosis. At
      present, 27 months after surgery, recurrence has not been found.

PMID- 12613012
TI  - [Hyperchloremic metabolic acidosis after ileal conduit reconstruction: a case
      report].
AB  - A 70-year-old man visited our hospital with the complaint of appetite loss. He
      had undergone an ileal conduit reconstruction due to bilateral ileo-ureteral
      stenosis 3 months before. Blood gas analysis showed metabolic acidosis (pH 7.091,
      pO2 120.5 mmHg, pCO2 20.9 mmHg, HCO3 6.1 mmHg), and blood analysis revealed serum
      chloride 121 mmol/l (normal range: 99-110). Sodium bicarbonate was immediately
      administered, his condition improved. We concluded that reabsorption of urine
      from the ileal conduit due to dehydration had caused hyperchloremic metabolic
      acidosis. He was given sodium bicarbonate 2 g per day, and his blood gas analysis
      and serum electrolytes remained within normal limits.

PMID- 12613013
TI  - [Ureter cancer of complete double renal pelvis and ureter: a case report].
AB  - A 66-year-old man presented at our hospital with left back pain. Intravenous
      pyelography, computerized tomography and magnetic resonance imaging revealed
      ureteral tumors of the complete left double renal pelvis and the ureter. An
      endoscopic examination disclosed a papillary tumor from the left ureteral orifice
      of the lower pole of the kidney. A transurethral resection of the tumor was done,
      and the pathological features revealed transitional cell carcinoma (PTa, grade
      2). A left nephroureterectomy and a partial cystectomy were also carried out;
      macroscopic examinations showed a non-papillary tumor on the middle portion of
      the left ureter originating from the upper pole of the kidney. Microscopic
      examinations revealed transitional cell carcinoma (PT3, grade 3, PL1, PV1).
      Adjuvant chemotherapy (M-VAC) was administered but discontinued because of severe
      side effects. Dispite recurrence with retro-peritoneal lymph node metastasis, the
      patient is alive and again undergoing M-VAC chemotherapy 22 months after the
      initial surgery. However, the evaluation of the chemotherapy was "no change".

PMID- 12613014
TI  - [Clinical statistics of the operations during a 20-year period at the Department
      of Urology, Nissei Hospital: 1982-2001].
AB  - A clinical statistics survey of the operations was performed at the Department of
      Urology, Nissei Hospital during a 20-year period from 1982 to 2001. The total
      number of operations was 3,164, and the number of extracorporeal shock wave
      lithotripsy procedures was 143. Operations for urogenital malignancies
      urolithiasis and prostatic hyperplasia numbered 893 (28.2%), 328 (10.4%), and 767
      (24.2%), respectively. The total number of operations has been decreasing owing
      to the development of new diagnostic and therapeutic modalities.

PMID- 12613015
TI  - [Clinical effects of a 3-month formulation LH-RH agonist, TAP-144-SR (3M) in
      prostate cancer patients].
AB  - TAP-144-SR (3M) is a 3-month sustained releasing injection of a super-active
      agonist of luteinizing hormone releasing hormone (LH-RH), leuprorelin acetate. At
      the Department of Urology of Gunma University Hospital, TAP-144-SR (3M) was
      injected once subcutaneously into 10 prostatic cancer patients who had had no
      treatment in the past to investigate safety, serum testosterone levels, drug
      concentrations and efficacy. In safety, no problematic adverse reactions
      occurred, and the drug was well tolerated. Serum testosterone levels elevated
      temporarily up to 2 days after injection and then were reduced rapidly. The
      levels were reduced below the castration level (100 ng/dl) after 3 weeks and then
      remained reduced up to 12 weeks. Serum TAP-144 levels including metabolite M-I,
      elevated to maximal plasma concentration up to 3 hours after injection and then
      were maintained at about 0.2 ng/ml between 1 week and 12 weeks after injection.
      With respect to the anti-tumor effects, the response rate according to "criteria
      of prostate cancer" at 12 weeks after injection was 100% (stable response cases)
      and the ratio of PSA normalization at 12 weeks was 90%. These results showed that
      an injection of TAP-144-SR (3M) was well tolerated in prostate cancer patients
      having no prior treatment and inhibited serum testosterone persisting for at
      least 12 weeks so that TAP-144-SR (3M) was concluded to be safe and clinically
      effective for prostate cancer patients.

PMID- 12613016
TI  - [Clinical effects of a 3-month formulation LH-RH agonist, TAP-144-SR (3M) in
      prostate cancer patients].
AB  - A randomized, multicenter, double-blind, parallel-group study was conducted in
      order to evaluate the hormonal kinetics, pharmacokinetics, efficacy and safety of
      TAP-144-SR (3M) a three-month sustained-release injectable preparation of
      leuprorelin acetate, a highly active luteinizing hormone-releasing hormone (LH
      RH) derivative by comparing the treatment with two subcutaneous doses of the test
      medication TAP-144-SR (3M) and the treatment with six subcutaneous doses of the
      reference medication TAP-144-SR (1M), a 1-month sustained-release injectable
      preparation. Study participants were 103 patients with prostate cancer in whom a
      stable anti-tumor effect had been obtained with Leuplin Injection 3.75. The
      hormonal kinetics revealed that the proportion of the patients "maintaining the
      castration level of serum testosterone (maximum serum testosterone level during
      treatment below the castration level [100 ng/dl])" was 100% in both treatment
      groups. With regard to the efficacy, the proportions of the patients in whom the
      anti-tumor effects (> or = Stable) of the baseline treatment prior to the
      initiation of the treatment with the study medication were maintained during the
      study treatment period (6 months) were comparable; 84.0% with TAP-144-SR (1M) and
      80.4% with TAP-144-SR (3M). On evaluation of the pharmacokinetics, the mean value
      of AUC1-12w of the serum TAP-144 concentration (including the metabolite M-I) for
      the treatment with TAP-144-SR (3M) was 77.0% that of the treatment with TAP-144
      SR (1M). Adverse events were similar in the subjects on TAP-144-SR (3M) and in
      those on TAP-144-SR (1M). There existed no big differences in kind, incidence or
      time of occurrence of adverse events between two groups. TAP-144-SR (3M) showed
      no clinically relevant findings in particular. These results indicate that one
      dose of TAP-144-SR (3M) is comparable to three doses of the already approved
      Leuplin injection 3.75 in serum testosterone level-inhibitory effect, efficacy
      and safety. Hence, it is considered that TAP-144-SR (3M) is a drug suitable for
      treatment of prostate cancer over a prolonged period of time.

PMID- 12613018
TI  - [Current and future aspects of human tumor immunotherapy].

PMID- 12613017
TI  - [Clinical application of molecular oncology].

PMID- 12613019
TI  - [Biomechanical analysis of the failure load of the metastatic thoracic vertebrae:
      a sheep model study].

PMID- 12613020
TI  - [Identification of a factor, which binds to HIF-1 alpha and regulates the
      function of HIF-1 alpha].

PMID- 12613021
TI  - [The mechanism for reduced expression of gelsolin, tumor suppressor protein, in
      bladder cancer].

PMID- 12613022
TI  - [Pathogenic role of T cells in primary infection of Streptococcus pyogenes].

PMID- 12613023
TI  - [A study on the microheterogeneity of alpha-fetoproteins produced by fetal liver
      and gynecologic tumors].

PMID- 12613024
TI  - [Ovarian function of patients with cervical carcinoma treated with radical
      hysterectomy and ovarian transposition].

PMID- 12613025
TI  - [Multivariate analysis of histopathologic prognostic factors in invasive cervical
      carcinoma treated with radical hysterectomy including paraaortic
      lymphadenectomy].

PMID- 12613026
TI  - [Evaluation of fallopian tubes in infertile women by using laparoscopy and
      falloposcopy].

PMID- 12613028
TI  - Why do co-solvents enhance the solubility of solutes in supercritical fluids? New
      evidence and opinion.
AB  - The effects of two polar co-solvents, chlorodifluoromethane and acetone, on the
      solubility and enthalpy of a solution of 1,4-naphthoquinone in supercritical (SC)
      CO2 were studied. We found that the dissolution process becomes less exothermic
      in the presence of the co-solvents relative to that in pure CO2, although the
      solubility is enhanced significantly by the co-solvents. This indicates that the
      increase in the solubility by adding co-solvents results from the increase of the
      entropy of solution. On the basis of the unexpected results we propose a new
      mechanism for the solubility enhancement of the solute by the co-solvents in
      supercritical fluids (SCF); this should be applicable to cases in which the local
      density of the SC solvent around the solute and the co-solvent is larger, and the
      co-solvent associates preferentially with the solute. The results are also very
      important for the understanding of other fundamental questions of SCF science,
      such as the effect of co-solvents on the thermodynamic and kinetic properties of
      the reactions in SCFs.

PMID- 12613027
TI  - An efficient synthesis of liquid crystalline gigantocycles combining banana
      shaped and rod-like mesogenic units.
AB  - The synthesis of monodisperse gigantocycles with 63, 87, and 147 ring atoms on
      the gram scale is described. These molecules were assembled from terphenylene
      derivatives and long, flexible chains which were mainly aliphatic, with terminal
      alkyne groups. The latter allowed for ring formation through oxidative alkyne
      dimerization in high yield (80-87%). The combination of a rod-like and a banana
      shaped mesogen connected by flexible chains within the backbone of a ring gives
      rise to nematic and smectic mesophases.

PMID- 12613029
TI  - Temperature dependence of helical structures of poly(phenylacetylene) derivatives
      bearing an optically active substituent.
AB  - The temperature dependence of the helical conformations for the homopolymers of
      phenylacetylene derivatives bearing an optically active substituent, such as the
      (R)-((1-phenylethyl)carbamoyl)oxy and (R)-((1-(1-naphthyl)ethyl)carbamoyl)oxy
      groups at the phenyl group, and their copolymers with achiral phenylacetylenes
      were investigated in solution using circular dichroism (CD) and absorption
      spectroscopies. The magnitude of the induced CD (ICD) of the optically active
      homopolymers increased with decreasing temperature and was accompanied by a
      blueshift in their absorption maxima. On the other hand, the copolymers with
      achiral phenylacetylenes exhibited interesting ICD changes with temperature,
      depending on the bulkiness of the achiral comonomers. The copolymers with a less
      bulky phenylacetylene had a very intense ICD at low temperatures, the ICD pattern
      was almost opposite to those of the chiral homopolymers, while the copolymers
      with the most bulky phenylacetylene bearing a tert-butyldiphenylsiloxy group at
      the para position showed an ICD change similar to that of the optically active
      homopolymers. However, the copolymers with the phenylacetylene bearing a tert
      butyldimethylsiloxy group with intermediate bulkiness at the para position showed
      no ICD change with temperature. These results indicate that the prevailing helix
      sense of the chiral-achiral random copolymers of the phenylacetylenes is
      determined by a delicate interaction between the chiral and achiral side chains.
      The thermodynamic stability parameters for the helical conformations of the
      homopolymers and copolymers of the phenylacetylenes were estimated from the
      temperature dependence of the ICDs.

PMID- 12613032
TI  - Inductive effects in isolated molecules: 4-substituted bicyclo[2.2.2]octane-1
      carboxylic acids.
AB  - Energies of sixteen 4-substituted bicyclo[2.2.2]octane-1-carboxylic acids, their
      anions, and pertinent 1-substituted bicyclo[2.2.2]octanes were calculated within
      the framework of density functional theory at the B3LYP/6-311 + G(d,p) level.
      Substituent effects were evaluated separately in the acid molecule and in the
      anion in terms of isodesmic homodesmotic reactions. In both cases, the
      substituent effects are proportional and of opposite sense, that in the anion
      being eight times greater; in the effect on acidity they are summed. The
      calculated acidities are in agreement with experimental values with a standard
      deviation of 1.1 kJ mol-1, and are recommended as a model for evaluating the
      inductive effect of various substituents, whether they are experimentally
      accessible or not. The resulting values are closely related to other scales but
      can be determined more reliably, particularly when compared with the previous
      quantum chemical method. We also checked electrostatic calculations and confirmed
      their very approximate character, particularly in the case of unsymmetrical
      substituents or of substituents with zero dipole moment.

PMID- 12613031
TI  - C-C bond-forming reactions of Ir(III)-alkenyls and nitriles or aldehydes:
      generation of reactive hydride- and alkyl-alkylidene compounds and observation of
      a reversible 1, 2-H shift in stable hydride-Ir(III) alkylidene complexes.
AB  - Nucleophilic attack of the beta-carbon of an Ir(III)-alkenyl functionality onto
      the alpha-carbon of a coordinated nitrile- or aldehyde occurs intramoleculary to
      yield initially iridacyclic structures. Nitriles give rise to isolable complexes
      that contain delocalized five-membered rings (iridapyrroles, e.g. 3'-8') in a
      reaction catalyzed by H2O (for some of these syntheses, Ir(III)-eta 3-allyl
      derivatives may be used as the source of the Ir(III)-alkenyl moiety). In
      contrast, the alkenyl-to-aldehyde C-C coupling gives transient iridacycles that
      evolve by a fast alkyl-to-alkylidene migration and beta-H elimination. The end
      products (13* and 14*) contain an elaborated chelating alkoxide-olefin ligand.
      Addition of [H(OEt2)2][BAr'4] to the iridapyrroles effects stereospecific
      protonation of the beta-ring carbon. Those iridapyrroles which contain an
      additional metal-alkyl functionality (e.g. 3a*, alkyl = C2H5) afford highly
      reactive cationic alkyl-alkylidene intermediates that evolve instantaneously by
      migratory insertion/beta-H elimination. The end products also contain an
      elaborated, chelating ligand, although this time with an olefin and imine
      terminus compared with the previous ligand. Contrary to this result, protonation
      of the hydride-iridapyrrole complex 8a* in weakly coordinating solvents permits
      isolation of two unusual cationic cis-hydride-alkylidene compounds 11*, which
      undergo reversible 1,2-H shifts.

PMID- 12613030
TI  - Zeolite GdNaY nanoparticles with very high relaxivity for application as contrast
      agents in magnetic resonance imaging.
AB  - In this paper we explore Gd(3+)-doped zeolite NaY nanoparticles for their
      potential application as a contrast agent in magnetic resonance imaging (MRI).
      The nanoparticles have an average size of 80-100 nm, as determined by TEM and
      XRD. A powdered sample loaded with La3+ was characterised by means of
      multinuclear solid-state NMR spectroscopy. The NMR dispersion (NMRD) profiles
      obtained from aqueous suspensions of samples with Gd3+ doping ratios of 1.3-5.4
      wt% were obtaining at different temperatures. The relaxivity increases
      drastically as the Gd3+ loading decreases, with values ranging between 11.4 and
      37.7 s-1 mM-1 at 60 MHz and 37 degrees C. EPR spectra of aqueous suspensions of
      the samples suggest that an interaction between neighbouring Gd3+ ions within the
      same particle produces a significant increase in the transversal electronic
      relaxation rates in samples with a high Gd3+ content. The experimental NMRD and
      EPR data are explained with the use of a model that considers the system as a
      concentrated aqueous solution of Gd3+ in the interior of the zeolite that is in
      exchange with the bulk water outside the zeolite. The results obtained indicate
      that the Gd3+ ion is immobilised in the interior of the zeolite and that the
      relaxivity is mainly limited by the relatively slow diffusion of water protons
      from the pores of the zeolite channels into the bulk water.

PMID- 12613033
TI  - Mechanism of CIT-6 and VPI-8 crystallization from zincosilicate gels.
AB  - The crystallisation of CIT-6, a large-pore zincosilicate with the framework
      topology of zeolite Beta and synthesised from clear hydrogels that contain,
      tetraethylammonium (TEA+), Li+ and Zn2+ cations, proceeds initially through the
      formation of an amorphous solid that incorporates all the initial Zn species.
      Nucleation of the *BEA phase is effected by reorganisation of the amorphous
      phase, whereas crystal growth involves the incorporation of soluble species also.
      A highly crystalline CIT-6 material is obtained after 164 h of synthesis at 140
      degrees C. Scanning electron microscopy (SEM) shows that this sample exhibits two
      different types of crystals: well-defined pseudo-cubic crystals and rounded
      crystals. The latter has a broad crystal-size distribution. If crystallisation is
      continued with longer synthesis times, the VPI-8 crystalline phase appears, and a
      new population of needle-shaped crystals is detected in the SEM images. This new
      crystalline phase is nucleated on the surface of the rounded CIT-6 crystals,
      which disappear as the crystallisation progresses, while no changes are observed
      in the population of pseudo-cubic CIT-6 crystals. At higher crystallisation
      temperatures these phase transformations are accelerated, and the formation of
      VPI-8 is favoured over that of CIT-6.

PMID- 12613034
TI  - Metal-induced assembling/disassembling of fluorescent naphthalenediimide
      derivatives signalled by excimer emission.
AB  - The new quadridentate bischelating ligands 2 and 3 display in solution the
      typical absorption and emission properties expected for naphthalenediimide
      derivatives. Spectrophotometric studies show that systems 2 and 3 interact with
      Zn(II), Cd(II) and Cu(I) in CHCl3 or MeCN according to an apparent 1:1
      stoichiometry. Molecular modelling, ESI-MS and 1H NMR experiments indicate that
      the complex species formed in the presence of stoichiometric amounts of metal ion
      are nonhelical [2 + 2] adducts. The metal-induced self-assembling process is
      signalled by an intense excimer-type emission caused by the intramolecular
      interaction of two naphthalenediimide subunits that face each other in the [2 +
      2] adduct, as shown by molecular modelling studies. In the presence of excess
      metal ion, a disassembling process takes place, leading to a dinuclear complex
      with a 2:1 metal/ligand stoichiometry, in which the intramolecular excimer is no
      longer allowed to form because the interaction between the naphthalenediimide
      subunits has been lost. Thus, the overall metal-induced assembling/disassembling
      process is signalled by the appearance and disappearance of the excimer band in
      the emission spectrum.

PMID- 12613035
TI  - Post-assembly processing of [2]rotaxanes.
AB  - The concept of using [2]rotaxanes that carry one or more surrogate stoppers which
      can subsequently be converted chemically into other structural units, resulting
      in the formation of new interlocked molecular compounds, is introduced and
      exemplified. Starting from simple NH2(+)-centered/crown-ether-based [2]rotaxanes,
      containing either one or two benzylic triphenylphosphonium stoppers, the well
      known Wittig reaction has been employed to make, 1) other [2]rotaxanes, 2) higher
      order rotaxanes, 3) branched rotaxanes, and 4) molecular shuttles--all isolated
      as pure compounds, following catalytic hydrogenations of their carbon-carbon
      double bonds, obtained when aromatic aldehydes react with the ylides produced
      when the benzylic triphenylphosphonium derivatives are treated with strong base.
      The two starting [2]rotaxanes were characterized fully in solution and also in
      the solid state by X-ray crystallography. The new interlocked molecular compounds
      that result from carrying out post-assembly Wittig reactions on two [2]rotaxanes
      were characterized by (dynamic) 1H NMR spectroscopy. In the case of a molecular
      shuttle in which the crown ether component is dibenzo[24]-crown-8 (DB24C8),
      shuttling is slow on the 1H NMR timescale, even at high temperatures. However,
      when DB24C8 is replaced by benzometaphenylene[25]-crown-8 as the ring component
      in the molecular shuttle, the frequency of the shuttling is observed to be around
      100 Hz in [D4]methanol at 63 degrees C.

PMID- 12613036
TI  - Modeling of prebiotic catalysis with adenylated polymeric templates: crystal
      structure studies and kinetic characterization of template-assisted phosphate
      ester hydrolysis.
AB  - We have synthesized and characterized novel, copper-metalated, polymeric
      templates that contain adenine nucleobases. These promote hydrolysis of non
      natural and natural phosphate ester substrates in a highly efficient and
      catalytic fashion. The crystal structure of the cooper-containing adenylated
      monomer reveals the formation of a polymeric array, through coordination to both
      N1 and N7 atoms. Possible implications of these studies for prebiotic catalysis,
      involving synergism between adenine and copper ions, are also discussed.

PMID- 12613037
TI  - The synthesis of a novel cyclo-Se3-bridged trinuclear Ru complex.
AB  - The reaction of [[RuCl[P(OCH3)3]2]2(mu-Se2)(mu-Cl)2] with four equivalents of
      NaPF6 gave [[Ru[P(OCH3)3]2(CH3CN)3]2(mu-Se2)](PF6)3 and [[Ru[P(OCH3)3]2(CH3CN)(mu
      Cl)]2(mu-cyclo-Se3)[Ru[P(OCH3)3]2(CH3CN)3]](PF6)4. The former is a Ru(II) Ru(III)
      mixed-valent paramagnetic compound. The X-ray structural analysis of the latter
      compound revealed that it has a novel mu-cyclo-Se3 neutral ligand and three
      Ru(II) atoms.

PMID- 12613038
TI  - On the enantioselective hydrogenation of isomeric methyl 3-acetamidobutenoates
      with RhI complexes.
AB  - The enantioselective hydrogenation of E- and Z-methyl 3-acetamidobutenoate, key
      intermediates in the synthesis of a pharmaceutically important chiral beta-amino
      acid, with RhI catalysts in MeOH as solvent has been investigated in detail. As
      chiral ligands, Et-DuPHOS, Me4-BASPHOS, DI-PAMP, DIOP, HO-DIOP and Et-Ferro-TANE
      have been employed. The particular role of oxyfunctionalization in some
      diphosphine catalysts is addressed in relation to the E/Z geometry of the
      substrate and the dependency of the ee on the H2 pressure. Kinetic investigations
      with [Rh(diphosphane)(MeOH)2]-BF4, taking into consideration the special nature
      of the precatalyst [[Rh-(cod)2]BF4/ligand versus [Rh(cod)ligand)]BF4], NMR
      spectroscopic measurements and the H2 pressure dependence of the observed
      enantioselectivity provide evidence that the reaction proceeds via an
      "unsaturated route" mechanism. This mechanism correlates to catalytic features
      found in the past for the hydrogenation of related unsaturated alpha-amino acid
      precursors. The influence of the temperature was similarly investigated. A
      nonlinear dependency of the enantiomeric ratio as a function of the reciprocal of
      the temperature has been found. The correlation between temperature and H2
      pressure and their effects on the enantioselectivity is discussed. In general,
      the highest enantioselectivities for the hydrogenation of both isomeric
      substrates can be achieved at room temperature and below, whereas the fastest
      conversion takes place at 30-50 degrees C.

PMID- 12613039
TI  - Alkylation of carbonyl compounds in water: formation of C-C and C-O bonds in the
      presence of surfactants.
AB  - The formation of C-C and C-O bonds by the reaction of enolate intermediates with
      electrophilic substrates commonly requires strong bases, aprotic solvents and
      very low temperatures. A way of performing the same reactions with sodium
      hydroxide at moderate temperatures in aqueous surfactant solutions is presented.
      Different halides, ketones and surfactants (cationic, zwitterionic and anionic)
      have been used. The results obtained show that the amount of ketone alkylation is
      much higher and that the reactions are faster in the presence than in the absence
      of surfactant aggregates. The hydrolysis of the halide is minimised in the
      presence of cationic or zwitterionic surfactants.

PMID- 12613040
TI  - Homo- and heterochiral alkylzinc fencholates: linear or nonlinear effects in
      dialkylzinc additions to benzaldehyde.
AB  - Scalemic mixtures of chiral anisyl fenchols with different ortho-substituents (X)
      in the anisyl moieties [X = H (1), Me (2), SiMe3 (3) and tBu (4)] are employed as
      pre-catalysts in enantioselective additions of diethylzinc to benzaldehyde. While
      a remarkable asymmetric depletion is apparent for X = H and Me, a linear
      relationship between the enantiomeric purity of the chiral source and the product
      1-phenylpropanol is observed for X = SiMe3 and tBu. X-ray single crystal analyses
      show that racemic methylzinc fencholates obtained from 1 (X = H) and 2 (X = Me)
      yield homochiral dimeric complexes, while for 3 (X = SiMe3) and 4 (X = tBu) the
      heterochiral dimeric alkylzinc structures are formed. The enantiopure fenchols 1
      4 all yield homochiral dimeric methylzinc complexes. Computed relative energies
      of homo- and heterochiral fencholate dimers with X = H and Me reveal an intrinsic
      preference for the formation of the homochiral dimers, consistent with the
      observed negative NLE. In contrast, similar stabilities are computed for homo-
      and heterochiral complexes of ligands 3 (X = SiMe3) and 4 (X = tBu), in agreement
      with the absence of a nonlinear effect for bulky ortho-subsituents.

PMID- 12613041
TI  - Polymer rings and chains consisting of doubly silyl-bridged metallocenes.
AB  - With the formation of novel organometallic macromolecules in mind, the
      polycondensation of transition metal ions and bridged cyclopentadienyl ligands
      was studied. To this end solvated salts MX2 (M = Fe, Ni, and Cr) were treated
      with a ligand that consisted of two doubly silyl-bridged cyclopentadienyl anions.
      For M = Fe and diluted solutions a series of rings Oi was obtained that consisted
      of a minimum of six (O6) and up to 17 (O17) ferrocene moieties in the backbone.
      They were separated partly by medium pressure liquid chromatography. The
      macrocycles were established by high-resolution MALDI-TOF mass spectroscopy which
      also yielded the molecular weight, the polydispersion, and the mean ring size,
      chi n, of the mixture of reaction products. When the reaction temperature was
      decreased from 25 degrees C to -20 degrees C, chi n increased from 8.1 to 10.8.
      Ferrocene-containing chains, lambda j, with 2 < or = j < or = 12 were obtained in
      addition to rings in the presence of water; the terminal groups were
      cyclopentadiene moieties. The reaction of two ferrocene-fused cyclopentadienyl
      anions with [FeCl2(thf)1.5] gave chains consisting of exclusively uneven numbers
      of ferrocenes. For M = Ni and Cr the formation of doubly silyl-bridged
      nickelocenes and chromocenes was proven by NMR spectroscopy. MALDI-TOF mass
      spectroscopy showed nickelocene-containing chains accompanied by some rings. For
      M = Fe the H,H-DQF COSY spectra established the structure of O7, O8, and O9. The
      oxidation of the ferrocene-containing ring O7 with I2, NOPF6, and AgPF6 gave
      ionic species [O7]n+ which suffered from low stability. The ring-closing reaction
      is discussed, and the relative abundance of the various rings is related to MNDO
      calculations.

PMID- 12613043
TI  - Novel estradiol derivatives labeled with Ru, W, and Co complexes. Influence on
      hormone-receptor affinity of several organometallic groups at the 17 alpha
      position.
AB  - In order to elucidate the extent to which recognition of the estrogen receptor is
      influenced by addition of an organometallic substituent at the 17 alpha position,
      modification of 17 beta-estradiol at this position was carried out by using the
      organometallic groups -C identical to C(eta 5-C5H4)RuCp, CH2-(eta 5-C5H4)RuCp, -C
      identical to C-(eta 5-C5H4)-W(CO)3(Me), -(C identical to CCHO)Co2(CO)6, and -(C
      identical to CCH2OH)Co2(CO)6. The relative binding affinity (RBA) values for
      estradiol receptor alpha showed that recognition was good (RBA between 20 and
      13.5%) when the organometallic moiety was attached at the end of a rigid alkyne
      spacer. However, the affinity of the modified hormone for the receptor was
      severely reduced (RBA = 1%) for a substituent such as -CH2-(eta 5-C5H4)RuCP, in
      which the spacer is reduced to a single flexible sp3 carbon atom, allowing the
      organometallic moiety greater freedom of movement around the attachment point.
      The RBA values found were in agreement with results obtained from a molecular
      modeling study in which 5, an organometallic hormone with a rigid spacer, or 7, a
      molecule with a flexible spacer, was inserted into the cavity of the recently
      characterized Ligand-Binding Domain of estrogen receptor alpha.

PMID- 12613044
TI  - Twistophane macrocyles with integrated 6,6'-connected-2,2'-bipyridine units: a
      new lead class of fluorescence sensors for metal ions.
AB  - The new twistophane macrocycles 2 and 3 have been synthesised; these compounds
      are composed of a cyclically conjugated dehydrobenzoannulene framework that
      incorporates 6,6'-connected-2,2'-bipyridine moieties for the purpose of
      coordinating metal ions. The cyclophanes were characterised by spectroscopic
      techniques, and shown by molecular mechanics calculations to be helically twisted
      and chiral molecules that may exist in several possible ground state
      conformations. UV/vis spectroscopic studies revealed that 2, 3 and precursor 9
      bind with different selectivities to particular members of the following small
      group of metal analytes: CuII, AgI, HgII, Tl1 and PdII. Significantly, 2, 3 and 9
      signal the presence of CuII ions through fluorescence emission quenching output
      responses. Furthermore, cyclophane 3 exhibited a particularly sensitive
      protontriggered chromogenic fluorescence response. With respect to their unique
      structural features, high analyte selectivity coupled with their enhanced and
      characteristic fluorescence emission responses, these molecules are among the
      first examples representing a new lead class of chemosensory materials. Compounds
      2, 3 and 9 and derivatives thereof may, therefore, be expected to find many
      future applications in the detection of metal-based environmental pollutants,
      biologically important trace elements and monitoring proton fluxes.

PMID- 12613042
TI  - Experimental evidence for the existence of non-exo-anomeric conformations in
      branched oligosaccharides: NMR analysis of the structure and dynamics of
      aminoglycosides of the neomycin family.
AB  - It is commonly known that the exo-anomeric effect is a major factor governing the
      conformational behavior of naturally occurring oligosaccharides. Conformational
      flexibility in these molecules mainly concerns the aglycon psi angle since phi is
      restricted by this stereo-electronic effect. In fact, to the best of our
      knowledge no case of a natural glycoside adopting a non-exo-anomeric conformation
      in solution has yet been reported. With respect to the flexibility among
      naturally occurring carbohydrates, branched type oligosaccharides including sugar
      residues glycosidated at contiguous positions (such as blood type carbohydrate
      antigens Lewis X) have been considered as the paradigm of rigid saccharides--the
      rigidity being enhanced by van der Waals interactions. Herein, we demonstrate
      unambiguously that both common beliefs are not to be generalized. For example in
      neomycin B, a branched oligosaccharide antibiotic, a large number of non-exo
      anomeric conformations was detected in solution for the first time in naturally
      occurring sugars. This unusual behavior is attributed to branching. Here, polar
      contacts between non-vicinal sugar units lead to an enhanced flexibility of the
      ribose glycosidic torsion phi. The influence of sugar flexibility on RNA
      recognition will also be discussed.

PMID- 12613045
TI  - Homoleptic lanthanide complexes of chelating bis(phosphanyl)amides: synthesis,
      structure, and ring-opening polymerization of lactones.
AB  - Treatment of the bis(phosphanyl)amide (Ph2P)2NH with KH in boiling THF followed
      by crystallization from THF/n-pentane leads to [K(thf)n][N(PPh2)2] (n = 1.25,
      1.5). Reaction of [K(thf)n][N(PPh2)2] with anhydrous yttrium or lanthanide
      trichlorides in a 3:1 molar ratio afforded homoleptic bis(phosphanyl)amide
      complexes [Ln[N(PPh2)2]3] (Ln = Y, Er) as large crystals in good yields.
      [Ln[N(PPh2)2]3] can also be obtained by reaction of the homoleptic
      bis(trimethylsilyl)amides of Group 3 metals and lanthanides [Ln[N(SiMe3)2]3] (Ln
      = Y, La, Nd) with three equivalents of (Ph2P)2NH in boiling toluene. The single
      crystal X-ray structures of these complexes always show eta 2 coordination of the
      ligand. Dynamic behavior of the ligand is observed in solution and is caused by
      rapid exchange of the two different phosphorus atoms. [Ln[N(PPh2)2]3] was used as
      catalyst for the polymerization of epsilon-caprolactone. Significant differences
      in terms of correlation of theoretical and experimental molecular weights as well
      as polydispersities were observed depending on the nature of Ln. On the basis of
      the crystal structure of the heteroleptic complex [Lu[N(PPh2)2]3(thf)], we
      suggest that in the initiation step of epsilon-caprolactone polymerization the
      lactone adds to the lanthanide atom to form a sevenfold coordination sphere
      around the central atom.

PMID- 12613046
TI  - Introduction: new approaches to established themes in the history of psychiatry.

PMID- 12613047
TI  - English medical experts and the claims for shock occasioned by railway collisions
      in the 1860s issues of law, ethics, and medicine.

PMID- 12613049
TI  - Eugen Bleuler and forensic psychiatry.
AB  - The list of Eugen Bleuler's writings shows that he grappled with forensic issues
      quite early, even before he became a full professor in 1898. Bleuler regularly
      prepared forensic criminal expert's reports himself until emeritus status was
      conferred on him in 1927. Analysis of his writings indicates that his position
      remained explicitly deterministic. In Bleuler's later work, that position was
      integrated into the natural philosophy vitalistic theory of mnemism, itself part
      of a more comprehensive theory, without any corrections to its content. Eugen
      Bleuler always remained a critic of criminal law, although it can be seen from
      later expert's reports that he for the most part accepted the existing system for
      the administration of justice for practical reasons. However, Bleuler always
      defended the idea that punishment should not be based on the moral guilt of the
      perpetrator but rather on the prospect of curing him.

PMID- 12613048
TI  - James Kiernan and the responsible pervert.

PMID- 12613051
TI  - Historical profiles of criminal insanity.

PMID- 12613050
TI  - A terrible responsibility. Murder and the insanity defence in England 1908-1939.

PMID- 12613052
TI  - Lunatic to patient to person: nomenclature in psychiatric history and the
      influence of patients' activism in North America.

PMID- 12613054
TI  - Use of theory to interpret elements of change.
AB  - Actions useful in reducing unacceptable variation in physicians' clinical
      activities have been identified through critical reviews of randomized controlled
      trials, and, from them, Richard Grol proposed six elements of effective change
      for mounting programs to improve clinical practice. The elements include
      consideration of the complex reality of clinical practice, attention to the
      designated change, analysis of the target group and setting, mixed interventions
      to address needs, and a plan of action. Although empirically based, the elements
      lack a theoretical underpinning that explains why the elements work. This article
      interprets the elements using theories separately advanced by Dewey, Slotnick,
      and Wenger to suggest ways for understanding what studies have shown.

PMID- 12613055
TI  - Permanent small groups: group dynamics, learning, and change.
AB  - INTRODUCTION: The concept of "communities of practice," a special facet of social
      constructivist learning theory, provides a new template against which we can
      examine the learning that goes on within permanent small groups of physicians. We
      interviewed participants and facilitators about the dynamics of these groups,
      their learning in conjunction with these groups, and the role the facilitator
      played to see the extent to which they captured the essence of communities of
      practice. METHODS: Semistructured interviews were conducted with physicians known
      to be participants or facilitators of small groups that met regularly. A constant
      comparative method was used for data gathering and analysis leading to coded
      themes, categories, and subcategories. The coding schemas were tested, the
      analyses were reviewed, and data were recoded as necessary. To ensure accuracy,
      interviewees were provided with a preliminary copy of the manuscript to ensure
      that the interpretation of the data was appropriately handled. RESULTS:
      Interviews were conducted with 10 facilitators and 22 group members representing
      24 different groups of physicians. The groups appeared to function as communities
      of practice in which the members were supportive of each other's learning and
      respectful of one another, reporting little conflict. Members preferred to agree
      to disagree rather than pursue a "right" answer or consensus. Most of the
      discussion focused on scientific information and the way in which their
      colleagues approached common problems. Practice refinement rather than new
      directions in patient care appeared to be the goal. The facilitators in these
      groups played a key role in providing administrative support for the group and
      often the energy needed to sustain them. DISCUSSION: Small groups that meet
      regularly provide a supportive network to share knowledge and validate clinical
      experience. There is some evidence that the groups have the potential to become
      communities of practice but do not actually achieve that level of sharing.
      Research needs to be done to determine how these groups could become more
      powerful as communities of practice and vehicles for more substantive learning
      and change.

PMID- 12613057
TI  - Use of referral reply letters for continuing medical education: a review.
AB  - INTRODUCTION: Referrals between generalists and specialists are a central
      component of the health care system and necessitate effective communication
      between the involved providers. Despite the high prevalence of patient referrals
      and their crucial role in continuity and quality of care, the medical literature
      demonstrates that generalists may receive little or no information about the care
      their patients received and little information about the appropriateness of the
      referral or recommendations for follow-up care. General practitioners (GPs)
      prefer teaching that is directly related to their clinical work rather than
      traditional continuing education such as formal lectures. The purpose of this
      review is to assess the role of referral reply letters in the continuing
      education of GPs. METHODS: A comprehensive literature search was conducted to
      November 2001 using MEDLINE, EMBASE, the Cochrane Library, and the Research and
      Development Resource Base developed by Continuing Education, Faculty of Medicine,
      University of Toronto, to identify studies that examined the use of referral
      letters for the transfer of information from specialists to referring physicians.
      Data on methodology, unit of analysis, main outcome measures, and results were
      extracted. RESULTS: Of 1,250 articles retrieved, 9 met the eligibility criteria.
      Three of these analyzed the content of referral reply letters and 6 described the
      results of surveys of general and specialty physicians. DISCUSSION: Little
      educational content is currently included in letters from specialists to
      referring GPs. GPs are receptive to the use of referral replies as sources of
      learning.

PMID- 12613056
TI  - Randomized controlled trials of continuing medical education: what makes them
      most effective?
AB  - INTRODUCTION: It is essential that professional standards of excellence are
      demonstrated in the continuing medical education (CME) curriculum and research.
      METHODS: This review examines 20 randomized controlled trial (RCT) studies in CME
      and their effect on physician performance and/or patient health care outcomes. A
      systematic evaluation of the 20 RCT articles was performed. The investigators of
      the trials were interviewed using a standardized interview schedule. Citations
      from science and social science publications were compiled to obtain an
      unobtrusive measure of the influence of the trials. RESULTS: Investigators were
      most often motivated to build on earlier research of others, their own earlier
      research, or a combination of others' earlier research and their own. The most
      effective educational strategies used multiple interventions, two-way
      communications, printed and graphic materials in person, and locally respected
      health personnel as educators. Statistically significant findings more often
      related to physician performance than to patient health care outcomes. The most
      effective studies were the ones in which the educational methods were cost
      effective, findings could be generalized to other physician groups, the studies
      were implemented elsewhere in multisite health care and health-related programs
      and had the most citations. Investigators interviewed about their RCTs provided
      advice for future directions of CME curriculum development and research.
      DISCUSSION: CME program directors should determine what physicians need to learn,
      should reach out to nonparticipating physicians, and should focus on relevant
      problem areas. These problem areas should be ones in which it is possible to make
      changes, particularly in patient health care outcomes.

PMID- 12613058
TI  - Physician communities of practice: where learning and practice are inseparable.
AB  - Physicians interact with peers and mentors to frame issues, brainstorm, validate
      and share information, make decisions, and create management protocols, all of
      which contribute to learning in practice. It is likely that working together in
      this way creates the best environment for learning that enhances professional
      practice and professional judgment. So convincing are the arguments for this view
      that management practices already are changing to foster the integration of
      learning and practice. This article describes a program of research that is
      planned to assess the effectiveness of information and communication technologies
      that purport to support and enhance learning in practice.

PMID- 12613059
TI  - Changing physicians' behavior: what works and thoughts on getting more things to
      work.
AB  - Health services research consistently demonstrates a gap between research-based
      best clinical practice and what doctors actually do. Traditionally, the
      profession of medicine has behaved as if dissemination of research findings in
      peer-reviewed journals will eliminate this gap, even though professionals
      typically have less than 1 hour per week to read. This problem is complicated by
      the fact that physicians have not been trained generally to appraise published
      research, which is of variable quality in any event. Physicians interested in
      changing their practices also encounter organizational, peer group, and
      individual barriers at the same time as they face information overload and
      patient expectations. In a word, physicians' abilities to manage information is
      overwhelmed. This article both summarizes initiatives to improve physicians'
      information management through efforts to synthesize available evidence and
      describes the current evidence base of effectiveness and efficiency of
      dissemination and implementation strategies. We conclude that there is an
      imperfect evidence base to support decisions regarding strategies that are likely
      to be appropriate and effective under varying circumstances. Since this problem
      is compounded by the lack of a theoretical base for conceptualizing physician
      behavior change, we suggest exploring the applicability of behavioral theories to
      the understanding of professional behavior change. We also suggest exploring the
      use of theory-based process evaluations alongside randomized trials of
      dissemination and implementation strategies to further test theories and to
      explore causal mechanisms. Further research is required to explore determinants
      of provider behavior to better identify modifiable and non-modifiable effect
      modifiers, to develop methods of identifying barriers and facilitators to change,
      and to estimate the efficiency of dissemination and implementation strategies in
      the presence of different barriers and effect modifiers.

PMID- 12613060
TI  - Changing physicians' competence and performance: finding the balance between the
      individual and the organization.
AB  - There are serious problems associated with the underuse, overuse, and misuse of
      health care. Part of the solution involves changing practicing physicians'
      competence and performance, but this proves to be a difficult task. People differ
      widely in their views of how the behavior of physicians can be effectively
      changed. Some approaches focus on improving the knowledge, skills, or attitudes
      of professionals, whereas others believe in changing the social interaction and
      collaboration within teams or changing the organizational or political context.
      Some believe in self-motivation and regulation by those who need to change,
      whereas others emphasize external stimuli, pressure, or control. However,
      systematic reviews show that no current approach is superior for all purposes and
      target groups and that we may need them all, well integrated, to achieve
      effective improvements in patient care. Educational activities for professionals
      are not sufficient and should be combined with activities and measures at other
      levels. Those wishing to improve the competence and performance of physicians
      must be aware of the limitations of educational approaches and know how to
      integrate these with approaches that focus on teams, organizations, or the
      political or economic context. Teachers of physicians need to develop their
      knowledge and skills in these areas to be successful.

PMID- 12613061
TI  - In our hands and in our hearts: finding solutions to the staffing crisis.
AB  - The report of the Workforce Commission contains many strategic and tactical
      recommendations to the staffing challenges presented in the preceding five areas.

PMID- 12613062
TI  - Building the public trust: closing the gap between public perception and public
      expectation.

PMID- 12613063
TI  - Our ailing healthcare system: a look beyond the symptoms.

PMID- 12613064
TI  - Broadening perspectives on mobile medical outreach to homeless people.
AB  - Using data collected by Project Renewal's mobile medical services to homeless
      people in New York City, this paper discusses a tension between an emergency
      medicine model of outreach and that of primary care. In the former model,
      clinicians evaluate clients on the basis of presenting complaints and refer them,
      as necessary, for specialized treatment. The latter is a broader model of
      comprehensive outreach and/or treatment, where clinicians screen clients and
      assess them for various conditions offering ongoing evaluation and treatment on
      site. The model of outreach is applicable for some homeless clients, but the
      prevalence and overlap of physical complaints, infectious diseases, substance
      abuse, and psychiatric symptoms among homeless people in New York City has
      resulted in an evolution toward broader approaches to outreach in this
      population. Improvements in diagnostic testing and increasingly portable medical
      technology may make the mobile delivery of medical care to homeless persons
      increasingly feasible.

PMID- 12613065
TI  - Strategies for surveying families of Medicaid-insured children by telephone.

PMID- 12613067
TI  - Case management and access to services for homeless women.
AB  - Previous research on case management for homeless persons has not sufficiently
      addressed access to services for women of reproductive age. This cross-sectional
      study estimates the proportion of homeless women with case managers and the
      associations of case management with access to shelter; food stamps; Special
      Supplemental Nutrition Program for Women, Infants, and Children (WIC); and
      general medical care. Nine hundred seventy-four homeless women were sampled in
      Los Angeles County in 1997 and asked about their use of services and whether they
      had case managers. Approximately 56 percent of respondents had case managers.
      Having a case manager was associated with greater odds of using food stamps and
      of finding shelter without difficulty in the previous 30 days, but not with use
      of WIC or with unmet needs for medical care. More assertive forms of outreach may
      be necessary to link this population to case managers and a broader range of
      services.

PMID- 12613066
TI  - Racial disparities in the incidence of lung cancer: the Savannah River Region
      Health Information System cancer registry, 1991-95.

PMID- 12613068
TI  - Varieties of health services utilization by underserved Mexican American women.
AB  - Varieties of health services utilization by medically underserved patients were
      examined in 250 Mexican American women attending a primary care clinic in San
      Diego, California. Less than half (48.4 percent) of these medically underserved
      women had obtained clinical preventive services conforming to recommended
      guidelines, 34.4 percent reported having obtained an annual physical examination
      in the past year, and 66.0 percent reported visiting a doctor only when they were
      sick. Lack of any form of health insurance, including Medi-Cal, was associated
      with underutilization of primary care services to a greater degree than the other
      variables examined. However, other factors such as full-time employment, low
      education, dissatisfaction with primary care delivery, and cultural preference
      for traditional ethnomedical alternative forms of health care, constitute
      important barriers to utilization of primary care services. Efforts to provide
      health care to the medically underserved must take these barriers into
      consideration if they are to be successful.

PMID- 12613069
TI  - Factors associated with health-compromising behavior among the homeless.
AB  - This exploratory study examined a set of sociodemographic, risk, and protective
      factors associated with health-compromising behavior among the homeless. One
      hundred and sixty-one homeless adults living in a midsize, southern metropolitan
      area were surveyed. Information was collected using structured in-depth
      interviews that assessed residential and event histories, life circumstances,
      mental and physical health symptoms, and health-related risk behaviors (drug and
      alcohol use, risky sexual practices, sleeping outdoors, aggressive behavior, and
      weapon possession). Descriptive results showed differences in health-compromising
      behavior for ascribed characteristics such as age, race, and gender. Younger
      people, nonwhites, and men took more risks. Multivariate results indicated that
      while sociodemographic risk factors were important predictors of health
      compromising behavior for people who are homeless, other variables, including
      childhood memories, victimization, and local nativism, were also significant. The
      implications of these findings are explored in the larger context of a social
      policy framework.

PMID- 12613070
TI  - Use of the Health Care for the Homeless Program services and other health care
      services by homeless adults.
AB  - This study examined factors associated with the use of the Health Care for the
      Homeless Program and other health care services by homeless adults. A total of
      941 homeless adults were identified in 52 soup kitchens in U.S. communities.
      Descriptive statistics and logistic regression models were applied. Among
      homeless adults, having dental problems was the most robust factor associated
      with their use of Health Care for the Homeless Program services (odds ratio [OR]
      = 2.50, 95 percent confidence interval [CI] = 1.44-4.32). Among homeless adults
      who did not visit Health Care for the Homeless Program services during last six
      months, the number of emergency room visits was the most powerful factor
      associated with their use of other health care services (OR = 1.15, 95 percent CI
      = 1.05-1.26). The results of the study can help health care providers better
      serve homeless adults to meet their health needs.

PMID- 12613071
TI  - Immunization predictors in rural adults under 65 years of age.
AB  - The specific study goal was to identify predictors of influenza and pneumonia
      immunizations in rural adults 18 to 64 years of age in Appalachia. The survey
      data used were collected from 931 adults from eight rural counties as part of a
      larger study. Information collected included influenza and pneumonia vaccination
      status, demographic and insurance coverage information, and immunization-related
      knowledge and beliefs. Immunization rates were 41.3 percent for influenza and
      19.9 percent for pneumonia. Logistic regression analysis indicated that perceived
      disease susceptibility, perceived benefit, perceived harm, and insurance coverage
      for immunizations were significant predictors of both types of immunization, with
      insurance coverage being the strongest predictor. The findings can be used in
      development of promotional campaigns for increasing immunizations in this
      underserved rural population.

PMID- 12613072
TI  - Hospital resource utilization among patients with sickle cell disease.
AB  - In the United States, sickle cell disease primarily affects African Americans and
      carries a high risk of disability, making its sufferers particularly vulnerable.
      Sickle cell patients often experience unexpected, intermittent, and life
      threatening complications leading to high levels of emergency room use and
      frequent hospitalizations. Using national discharge data from not-for-profit
      hospitals, this study explores the relationship between patient and hospital
      characteristics and hospital resource use by sickle cell patients. A random
      effects least squares regression analysis was used to examine relationships
      between patient and hospital characteristics and hospital charges and length of
      stay. Patient characteristics, especially severity measures, related
      significantly to total hospital charges, length of stay, and average daily
      charges, but few hospital characteristics were associated significantly with
      these outcomes.

PMID- 12613073
TI  - The history of external fixation.
AB  - Even though external fixation is considered to be a rather "new" trend in
      orthopedics and traumatology, in fact it has been something used by physicians
      and surgeons for thousands of years. In the mid 1800's, external fixation would
      see some substantial growth and evolution, pioneered by physicians and surgeons
      whose principles are still in use today. Through the 1900's, the indications and
      usage would continue to expand, not to mention the modernization of the external
      fixation apparatus. Many surgeons in this era are notable for their work with
      external fixation, especially Gavriel Ilizarov, considered to be the father of
      external fixation. Further research and development with external fixation needs
      to be performed and, with time, will more than likely become fully integrated
      into modern clinical practice.

PMID- 12613074
TI  - External fixation indications and patient selection.
AB  - Since its modest beginnings in the mid-nineteenth century, external fixation has
      seen great changes in its design and application. Once thought of as chiefly a
      fracture management tool, this modality has found its way into the arenas of
      corrective osteotomies, Charcot management, limb lengthening, nonunion treatment,
      and malalignment correction. As external fixation has evolved, great improvements
      in associated complications have also occurred. This is attributed to evolving
      frame design, subsequent increased stability, and advances in pin/wire insertion
      techniques. Paley and Herzenberg describe three factors to consider when
      evaluating whether to use external or internal fixation [2]. 1. Risk versus
      benefit of the method used for that specific indication. 2. Surgeon's experience
      with the specific method. 3. Ability to treat the potential complications of the
      surgery. The authors agree with these factors but would also include
      psychological tolerance, compliance with postoperative self-treatment, and
      personal hygiene. In this article the indications for external fixation were
      described in terms of pathology and individual patient factors were discussed for
      the surgeon's consideration. The surgeon must consider the patient's bone
      quality, age, cognitive ability, psychological tolerance, and compliance level.
      With these factors kept in mind and evaluated appropriately, the surgeon should
      be able to select the patient and indications for which external fixation will
      yield a superior result.

PMID- 12613075
TI  - Forefoot applications of external fixation.
AB  - The use of external fixation in foot and ankle surgery has steadily increased
      with the advent of devices geared toward the foot and ankle that have evolved
      over the past decade, as well as a greater understanding of the indications and
      advantages of external fixation. The application of external fixators in the
      forefoot may at first glance seem both limited and possibly overkill, but once
      the basics of external fixation and the types of devices available are understood
      the options for use become numerous.

PMID- 12613076
TI  - External fixation of the foot and ankle. Elective indications and techniques for
      external fixation in the midfoot.
AB  - Although external fixation is widely used for treatment of fractures, limb
      deformities, and bone lengthening; use of external devices is still evolving.
      Elective cases for treatment of the midfoot and published research on external
      fixation specifically for surgical treatment of midfoot pain and deformity are
      scarce. Indications for elective external fixation in the midfoot are limited
      because rigid internal fixation in this area is relatively easy and successful.
      This article discusses podiatric conditions that can be treated advantageously by
      external fixation when elective surgery is done. The article also describes
      methods of external fixation appropriate for podiatric surgical reconstruction in
      patients with these conditions.

PMID- 12613077
TI  - External fixators for elective rearfoot and ankle arthrodesis. Techniques and
      indications.
AB  - Since its introduction to the western hemisphere in the mid 1980's, Gavriel
      Ilizarov's ring fixator system has been studied extensively and shown to be a
      superior mechanical construct for stabilizing limb segments. This newfound form
      of external fixation has radically changed many elements of foot and ankle
      reconstruction, providing a modular device that can accommodate the complex limb
      deformities while performing multiple tasks. This article summarizes the authors'
      experience with compression arthrodesis of the rearfoot and ankle using external
      fixation.

PMID- 12613078
TI  - Use of external fixation in the reconstruction of the Charcot foot and ankle.
AB  - External fixation allows the progressive foot and ankle surgeon to approach
      Charcot foot and ankle deformities in a new way. Surgeons can now correct Charcot
      pathology with percutaneous techniques using a new generation of external
      fixation frames. These fixators allow the surgeon to adjust or manipulate the
      Charcot foot after surgery and the patient early weightbearing. External fixation
      provides the foot and ankle surgeon the opportunity to reconstruct and stabilize
      this destructive disease.

PMID- 12613079
TI  - Use of external fixation to correct deformities of the lower leg.
AB  - With the development of modern external fixation by Ilizarov and the
      modifications that have been made to his method, we now have another tool with
      which to surgically address a deformity of the lower extremity. It is widely
      recognized that a malaligned lower extremity is a major cause of the development
      and progression of arthrosis of the hip, knee and ankle. Early recognition of a
      [figure: see text] malaligned limb or joint, coupled with proper preoperative
      planning and realistic patient expectations, may significantly reduce the
      incidence of arthrosis and improve the overall quality of life for the patient.

PMID- 12613080
TI  - External fixation in trauma of the foot and ankle.
AB  - External fixation as a modality is a versatile and minimally invasive
      stabilization option that should not be forgotten even as new and specially
      designed implants for nearly each bone become more fashionable. As a temporary
      traction device, the external fixator can help condition the soft tissues and, if
      closed reduction was sufficient, it can stay in place for definitive treatment.
      The external fixator can be used as an intraoperative distraction device and as a
      helpful tool for reduction, which can stay in place as a temporary
      immobilization. External fixation instead of plaster cast allows for better care
      of skin and soft tissues. External fixation also has its advantages as a
      minimally invasive external compression device in specific indications for
      arthrodesis, especially in infected cases.

PMID- 12613081
TI  - Synthes tubular external fixation system for isolated subtalar arthrodesis.
AB  - The authors present the use of the AO/ASIF tubular system for isolated subtalar
      arthrodesis. Internal and external fixation are both acceptable means of
      promoting successful arthrodesis. Appropriate patient selection is vital when
      considering external fixation. Indications, operative technique, and a discussion
      are included as well as two case studies.

PMID- 12613082
TI  - Cardiopulmonary issues in athletes. Preface.

PMID- 12613083
TI  - Physiological effects of exercise on the cardiopulmonary system.
AB  - The cardiopulmonary adaptations made to dynamic and static exercise show the
      amazing ability of the human body to alter physiological processes in order to
      meet metabolic demands. A remarkable partnership that allows individuals to
      maximize their abilities and obtain goals exists between the cardiovascular and
      pulmonary systems. The adaptations of the cardiopulmonary system depend heavily
      on the intensity, duration, frequency, and type of exercise being performed.
      Although most of this article examined dynamic and static exercise separately,
      the majority of individuals train using a combination of these two modes. The
      overall adaptations will vary with the chosen degree of each exercise mode. An
      appropriate exercise program allows for improvements in the cardiopulmonary
      system that help develop and maintain fitness levels.

PMID- 12613084
TI  - Preparticipation cardiovascular screening.
AB  - Regular aerobic exercise provides many health benefits regardless of age, and
      should be promoted by health care providers to all patients. In older athletes,
      coronary artery disease is the most common cause of sudden death. There is
      widespread consensus, however, that the overall health benefits derived from
      exercise outweigh the risks of participation. Screening should focus on
      identifying signs and symptoms of underlying cardiovascular disease by obtaining
      a personal and family history and performing a focused physical examination
      according to the recommendations of the AHA. Exercise testing is recommended in
      males older than 40 and females older than 50, and individuals with cardiac risk
      factors. Cardiovascular PPE screening in young athletes remains a challenge,
      because potentially fatal abnormalities are uncommon and in some cases are
      undetectable without sophisticated testing. Most sudden cardiac deaths in
      athletes are caused by anomalies that are clinically silent, are rare, or are
      difficult to detect by history and physical examination. Many athletes may not
      experience symptoms consistent with heart disease or may not report family
      histories of sudden cardiac death. Important clues to a cardiac abnormality
      include history of syncope, chest pain, and family history of sudden death. Any
      underlying condition suspected on the basis of history or physical examination
      requires further diagnostic evaluation before the athlete can be cleared for
      activity. Currently there is considerable variability and inconsistency among
      state requirements for PPEs. A national adoption of a more uniform PPE screening
      process should be encouraged. The screening process should include the AHA's
      cardiovascular screening recommendations, as this would assist in closing the gap
      between screening practices recommended by sports medicine experts and the
      reality of current screening practices. Although the extent of screening
      continues to be debated, clinical guidelines for performing PPEs and determining
      clearance have been established. Without a uniform implementation of the current
      guidelines, it will not be possible to assess the value of the current
      cardiovascular screening recommendations in detecting and preventing
      cardiovascular death in young athletes. Physicians should be aware of the
      emerging role of genetic testing for cardiovascular diseases in athletes with a
      family history of heart disease or sudden death. Advances in the diagnosis and
      understanding of cardiovascular disease may provide better tools for preventing
      sudden death of young athletes in the future [11].

PMID- 12613085
TI  - Chest pain in athletes.
AB  - The symptom of chest pain in the athlete can represent anything from a
      nonspecific musculoskeletal strain to a life-threatening condition such as
      tension pneumothorax. For the physician charged with evaluating this patient
      population, a thorough knowledge of the possible etiologies, their usual
      diagnostic algorithms, available imaging modalities, and potential therapeutic
      options is essential. Although the vast majority of patients with traumatic chest
      pain will not harbor significant pathology, the clinician must be prepared for
      those few who do have such conditions, and be prepared to intervene in an
      appropriate, time-sensitive fashion.

PMID- 12613086
TI  - Sudden cardiac death.
AB  - Sudden cardiac death is a rare but devastating event. The majority of cases in
      young athletes are caused by congenital cardiac abnormalities that are routinely
      clinically silent before causing sudden death. An optimal screening practice to
      help identify underlying asymptomatic cardiac abnormalities has met with much
      debate. Beyond the American Heart Association's recommendations for
      cardiovascular screening guidelines for the preparticipation physical examination
      [47], there are conflicting views regarding the use of more advanced diagnostic
      screening tests. Athletes in whom a potentially life-threatening cardiovascular
      abnormality is found face the probability of being restricted from participating
      in certain types of athletic activity. Participation guidelines for athletes with
      cardiovascular disease are detailed in the recommendations of the 26th Bethesda
      Conference [36]. Future goals should continue to focus on the prevention of SCD.
      The development of a cost-effective screening process that incorporates the use
      of echocardiography, although having its own set of inherent limitations, may
      prove to be the most viable option.

PMID- 12613087
TI  - The assessment and management of arrhythmias and syncope in the athlete.
AB  - In recent years the media have reported on the unexpected deaths of prominent
      athletes and highlighted the sudden cardiac death syndrome. In some cases, there
      may have been no preceding symptoms to alert coaches or physicians of the
      impending event. Although sudden cardiac death is rare, there are a number of
      clinical syndromes that can be diagnosed by careful screening of asymptomatic or
      minimally symptomatic athletes. In many of these conditions, appropriate
      intervention can substantially reduce the risk of death. Cardiac arrhythmia and
      syncope are particularly important symptoms in athletes and may be the initial
      manifestations of a potentially lethal condition. In this article we pay specific
      attention to assessing the cardiac risk of athletes presenting with these
      symptoms.

PMID- 12613088
TI  - Congenital heart disease and exercise.
AB  - Though initially challenging, the process of determining appropriate levels of
      exercise for patients with congenital heart disease can be broken down into
      several practical steps: List 1: Summary of approach to CHD patients and exercise
      Get the records: Surgical reports, diagnostic test results, office visits,
      admissions [table: see text] Obtain family history: Family members with sudden
      death increase risk. Thorough physical exam: Special attention to auscultation of
      murmurs Appropriate diagnostic testing: Noninvasive testing is usually adequate.
      Review guidelines: 26th Bethesda Conference, 1994 [13] Make recommendation: Be
      specific about types of exercise allowed. Reassess at least annually: Patients'
      status may change over time [24]. The use of this algorithm and review of
      available guidelines, in combination with selected consultation with other
      specialists, should allow the sports physician to prescribe exercise for the
      majority of these patients confidently. Examples of several congenital defects of
      varying severity, and the appropriate exercise prescription, are listed in Table
      1.

PMID- 12613089
TI  - Exercise considerations in hypertension, obesity, and dyslipidemia.
AB  - Sports medicine practitioners who care for a wide array of athletes and active
      individuals will consistently face issues regarding chronic cardiovascular
      diseases and their associated risk factors. Among these, hypertension, obesity,
      and dyslipidemia are common clinical conditions that may be encountered even
      amongst elite caliber athletes. Consequently, those entrusted with the care of
      this active population must recognize the presence of these disorders and feel
      comfortable with their management in the face of continued sports or exercise
      participation. This article reviews the pathophysiology of these conditions as
      they relate to athletes and outlines the value of continued exercise in the
      management of each of these entities while addressing the specific and unique
      treatment needs of active individuals.

PMID- 12613090
TI  - Exercise considerations in coronary artery disease, peripheral vascular disease,
      and diabetes mellitus.
AB  - Physical inactivity is a risk factor for cardiovascular disease. Regular aerobic
      and resistance training increases exercise capacity and plays a role both in the
      primary and secondary prevention of cardiovascular disease. Patients with
      coronary artery disease, peripheral vascular disease, or diabetes mellitus must
      be considered individually when prescribing exercise because their clinical
      status can vary greatly. In addition, a majority of these patients have multiple
      comorbid disorders such as renal, neurologic, and retinal disease that may affect
      their ability to exercise safely. Therefore, a preparticipation medical
      evaluation is required. An exercise prescription should be tailored to each
      person's unique set of circumstances and reflect an effort to maximize the
      anticipated benefits while minimizing the risks.

PMID- 12613091
TI  - Cardiac rehabilitation secondary prevention programs.
AB  - Contemporary cardiac rehabilitation programs are more accurately described as
      "secondary prevention centers." They offer comprehensive care for the patient
      with cardiovascular disease, resulting in decreased mortality, improvement of
      most cardiac risk factors, and an enhanced quality of life. Although overall
      participation has increased with enhanced recognition of the importance of
      secondary prevention, 80% of eligible patients still do not participate, in part
      due to lack of insurance reimbursement. This rate can be significantly increased
      by specific endorsement from the physician.

PMID- 12613092
TI  - Pulmonary disorders and exercise.
AB  - The respiratory system rarely limits exercise in the normal subject. In patients
      with chronic pulmonary processes or in the elite athlete, however, the
      respiratory system may indeed be the limiting factor. Common respiratory
      disorders include chest pain syndromes, cough, exercise-induced asthma, and vocal
      cord dysfunction. Chronic lung diseases such as asthma, COPD, and interstitial
      lung disease impact exercise capacity and endurance. Exercise testing can be
      useful to distinguish acute and chronic pulmonary causes of dyspnea during
      exercise, as well as to differentiate between cardiac and pulmonary causes.

PMID- 12613094
TI  - Imaging of cardiopulmonary diseases.
AB  - Clear physiologic adaptations to endurance and resistance training occur in the
      myocardium. These morphologic changes have been identified primarily by
      echocardiography. In the evaluation of the symptomatic athlete, imaging is a
      valuable tool. To differentiate athletic hypertrophy from hypertrophic
      cardiomyopathy, echocardiography, or MRI may be used, although the latter may be
      superior in the accurate assessment of wall thickness. Either imaging modality
      may be used to differentiate athletic dilatation from dilated cardiomyopathy in
      which systolic dysfunction always accompanies the dilatation. To exclude
      anomalous coronary arteries, either MRI or CT is a reasonable examination,
      although the latter requires x-ray exposure and iodinated contrast dye. Chest
      radiograph continues to be the standard imaging modality for athletic lung
      disease, whereas fluoroscopy and laryngoscopy are useful for identifying vocal
      cord dysfunction. Knowledge of the utility of these different imaging modalities
      is crucial to the practitioner of sports medicine.

PMID- 12613093
TI  - Environmental and infectious conditions in sports.
AB  - The hearts and lungs of athletes are subject to damage from a wide array of
      infections and environmental factors. Mild to moderate exercise has been shown to
      be beneficial to overall health, and strenuous exercise simply requires proper
      rest and rehabilitation to ensure its beneficial effects as well. Simple colds
      and URTIs are very common in athletes and do not usually require significant
      intervention. Any suspected cardiac infection mandates a thorough evaluation and
      proper management to prevent catastrophic consequences. High altitudes can be
      helpful in enhancing performance, but caution must be exercised at even modest
      altitude to prevent serious complications. With diving, participants should know
      their time limits and ascend properly to avoid serious complications. Keeping the
      heart and lungs in a good state of health is a major priority for the weekend
      warrior and world-class athletes alike. A thorough knowledge of infections and
      environmental issues in the cardiopulmonary health of athletes should always be
      of highest priority.

PMID- 12613095
TI  - Aripiprazole. The newest antipsychotic agent for treatment of schizophrenia.

PMID- 12613096
TI  - Are abused women mentally ill?
AB  - A secondary data analysis study was conducted on Derogatis Brief Symptom
      Inventory (BSI) data derived from a larger intervention study of community-based
      abused women (N = 50). The purpose was to improve understanding of the effect
      domestic violence has on mental health, given the symptomatology observed in this
      population. A psychological distress symptom profile was developed and compared
      with BSI normative data. Findings were unexpected and suggest the necessity to re
      examine the assumptions harbored about interpersonal violence in research and
      practice.

PMID- 12613097
TI  - The latex allergic psychiatric patient.
AB  - Latex allergy is an immune system illness affecting an increasing number of
      individuals. People with latex allergy often experience anxiety and fear about
      real and potential exposure to products containing natural rubber latex. Nurses
      working in acute care and general medical-surgical areas are more likely to be
      aware of this emerging illness than nurses working on a psychiatric unit. The
      nature of latex allergy and the immune system response are described in this
      article. People with latex allergy may react when they are exposed to latex
      allergens or specific foods. This article identifies nursing interventions and
      describes those appropriate for people with anxiety or fear responses. Patients
      with latex allergy can be managed when nursing staff understand both the medical
      and psychiatric aspects of care.

PMID- 12613098
TI  - Psychiatric nursing & medication adherence.
AB  - A survey was developed to determine whether the rapidly changing context of
      mental health care has significantly influenced how psychiatric nurses assess and
      intervene in issues related to medication adherence. A sample of 126 psychiatric
      nurses working in Veterans Affairs mental health treatment facilities in northern
      California, Hawaii, and Nevada identified the most effective methods for tracking
      medication adherence, as well as successful adherence interventions. Despite the
      challenge imposed by changing work environments, psychiatric nurses use creative
      and innovative approaches to improve their patients' medication adherence.
      Interventions for enhancing patient adherence with prescribed regimens are
      identified. Essential role dimensions related to medication adherence defined by
      the nurses in this survey included providing medication education, tracking
      patient adherence, assessing medication effectiveness, providing individualized,
      tailored adherence interventions, and collaborating with other health care
      providers in medication planning. Study findings support using nurses to their
      full potential and highlight nurses' need for more educational opportunities and
      consultation with experts (e.g., clinical pharmacists).

PMID- 12613099
TI  - Injuries in Jamaica.

PMID- 12613100
TI  - The establishment of a Jamaican all-injury surveillance system.
AB  - The impact of injuries on the Jamaican health care system is a growing problem.
      Based on the successful implementation of a Violence-Related Injury Surveillance
      System (VRISS) in the Accident and Emergency (A&E) department of the Kingston
      Public Hospital (KPH), Ministry of Health (MOH) officials decided to expand the
      system to the Jamaica Injury Surveillance System (JISS), allowing for the
      surveillance of both intentional and unintentional injuries. A working group
      designed the expanded injury surveillance system based on the International
      Classification of External Causes of Injury. The expanded system allowed for the
      collection of data on all injuries seen in the A&E departments by adding four
      injury projects to the computerized A&E registration process. These were (1)
      unintentional injury, (2) violence-related injury, (3) suicide attempt (also
      known as intentional self-harm) and (4) motor vehicle-related injuries. The
      expanded JISS was implemented at the KPH and four additional hospitals across the
      island. The geographic distribution of these hospitals provided a reflection of
      rural and urban, highland and coastal communities and their distinctive injury
      profiles. Data collected at registration were printed on trauma sheets and
      reviewed by medical staff before being incorporated into the patient's record.
      Monthly reports detailing demographics and summary statistics were generated and
      made available at the local and national level. By monitoring the national injury
      profile, the JISS provides data to support needed policy changes to minimize the
      impact of injuries on the health services and on the health of the population.

PMID- 12613101
TI  - A profile of injuries in Jamaica.
AB  - This study analyses 6 months of data from three hospitals participating in the
      computerized emergency room-based Jamaica Injury Surveillance System (JISS) since
      1999. The categories of injuries tracked were unintentional, violence-related and
      motor vehicle-related. The resultant data showed that injuries comprised 17%
      (12,179) of all Accident and Emergency (A&E) department registrations for the
      period. The highest percentage of injuries were violence-related (51%, 6,380),
      followed by unintentional injuries (33%, 4,030) and motor vehicle-related (15%,
      1,769). Injury profiles varied by institution with the majority of Cornwall
      Regional Hospital's and Kingston Public Hospital's injuries being intentional
      while that of May Pen Hospital was unintentional. The data also demonstrate that
      young males are at highest risk for all types of injuries as well as for the more
      severe injuries requiring hospital admission. The risk factor data provided
      through the JISS will inform and guide private and public sector efforts to
      address the problem of injuries in Jamaica.

PMID- 12613102
TI  - Comparative evaluation of different modes of a national accident and emergency
      department-based injury surveillance system: Jamaican experience.
AB  - The objective was to conduct a comparative evaluation of two injury surveillance
      systems in operation in the Accident and Emergency departments of public
      hospitals in Jamaica. The evaluation was conducted at 12 hospitals across Jamaica
      offering varying levels of service delivery. It was designed in three phases: (1)
      a retrospective review of surveillance system data; (2) prospective process
      evaluation; (3) system environment evaluation. These data were analysed to
      determine the sensitivity and specificity of the manual Accident & Emergency
      Statistical Report (A&ESR) versus the computer-based Patient administration
      system/Jamaica injury surveillance system (PAS/JISS), and to determine an injury
      registration rate. Results showed a variation from 8% to 27% in injury
      registration rates at the hospitals reviewed. The sensitivity of the computer
      based PAS ranged from 29.7% to 97.1% while the sensitivity of the manual system
      ranged from 22.1% to 100%. The computer-based system generally detected a greater
      percentage of injuries. Problems were identified with missing data fields in the
      computer-based system, while problems of recording and transcription were
      identified in the manually-based system. Recommendations were made to improve
      data quality in both data collection systems. Although shortcomings were
      identified with the A&ESR, the system is performing the function for which it was
      designed, that of tracking A&E workload. The PAS/JISS is more user-friendly and a
      truer reflection of the injury situation.

PMID- 12613103
TI  - Implementing a hospital-based violence-related injury surveillance system--a
      background to the Jamaican experience.
AB  - Violence, a leading cause of injuries and death, is recognized as a major public
      health problem. In 1996, injuries were the second leading cause of
      hospitalizations in Jamaica. The estimated annual cost of in-patient care for
      injuries was 11.6 million US dollars. To develop strategies to reduce the impact
      of violence-related injuries on Jamaican health care resources, the Ministry of
      Health, Division of Health Promotion and Protection (MOH/DHPP) in collaboration
      with the Centers for Disease Control and Prevention and the Tropical Metabolic
      Research Institute, University of the West Indies Mona, designed and implemented
      a violence-related injury surveillance system (VRISS) at Kingston Public Hospital
      (KPH). In 1998, the VRISS, based on the International Classification of External
      Cause of Injury (ICECI), was implemented in the accident and emergency (A&E)
      department of Jamaica's tertiary care hospital, KPH. VRISS collects demographic,
      method and circumstance of injury, victim-perpetrator relationship and patient's
      discharge status data. From 8/1/98 to 7/31/99, data on 6,107 injuries were
      collected. Injuries occurred primarily among males aged 25-44 years. Most
      injuries (54%; 3171) were caused by use of a sharp object. Nearly half (49%;
      2992) were perpetrated by acquaintances. The majority, 70% (4,252), were the
      result of a fight or argument and 17% were admitted to the hospital. The VRISS
      utilized A&E department data to characterize violence-related injuries in
      Jamaica, a resource-limited environment. These data will be used to guide
      intervention development to reduce violence-related injuries in Jamaica.

PMID- 12613104
TI  - Surveillance of interpersonal violence in Kingston, Jamaica: an evaluation.
AB  - Injuries are among the leading causes of death in Jamaica. Homicide rates have
      been sharply increasing since 1991. In 1997, the rate of homicide (45/100,000) in
      Jamaica was over five times the US rate in 1997 (7.9/100,000). In response to
      this problem and the alarming increase in non-fatal assaultive injuries, the
      Jamaican Ministry of Health together with the CDC established a Violence-Related
      Injury Surveillance System (VRISS) using patient registration data from Kingston
      Public Hospital. The VRISS was evaluated for usefulness, and for system
      attributes: system acceptability, simplicity, flexibility, sensitivity, and
      predictive value positive (PVP). System-identified cases were compared with
      clinical records and data from direct patient interviews. The surveillance system
      was flexible, acceptable to clinical staff and Ministry officials, and moderately
      sensitive, detecting 62% to 69% of violent injuries identified from clinical
      records and a patient survey. The system's predictive value positive was high,
      with 86% of potential cases confirmed as actual cases. Although adequate, system
      sensitivity was reduced by incomplete or no registration of patients during
      periods of staff shortage. In conclusion, despite some logistic shortcomings, the
      system appeared promising for collecting limited information on non-fatal
      interpersonal violent injuries. With modification and expansion, the system may
      be capable of collecting unintentional-injury data also.

PMID- 12613106
TI  - The Jamaican Injury Surveillance System: lessons learnt.

PMID- 12613105
TI  - Non-fatal violence-related injuries in Kingston, Jamaica: a preventable drain on
      resources.
AB  - Using data for a one-year period from the Kingston Public Hospital (KPH) in
      Jamaica, we describe patterns of non-fatal violence-related injuries, and carry
      out simulation analysis to estimate rates of hospital admission under various
      injury reduction scenarios, and the potential savings that can be realized by
      reducing violent crimes. In this period there were 6107 registered violence
      related visits to the KPH representing 11.5% of all recorded visits. Of these
      16.6% (1001) were admitted. The most common methods of inflicting injury was by
      stabbing (52.1%), blunt injuries (37.9%) and gunshot wounds (7.3%). Multivariate
      analyses indicated that gunshot injuries, stab injuries, being male between the
      ages of 15 and 44 years, receiving the injury in November or December, and being
      injured by a stranger or unknown assailant, were significant correlates of a
      higher probability of admission. Simulation analysis with various injury
      reduction scenarios indicated decreases in the probability of admission ranging
      from 12% to 44%, with estimated savings of up to 31% of the annual supplies
      budget of KPH.

PMID- 12613107
TI  - The emergence and treatment of anorexia and bulimia nervosa. A comprehensive and
      practical model.
AB  - The objective was to propose and describe a new bio-psycho-social model of
      emergence and maintenance of anorexia nervosa and bulimia nervosa, and
      demonstrate its application to treatment. An original model, based on literature
      review and our own clinical experience, was created. Therapeutic guidelines were
      derived from the theoretical model and applied in the treatment of 97 anorexia
      and bulimia nervosa patients presented at the eating disorders unit at Kaplan
      Hospital in Israel over 18 months. A team comprising a pediatrician, a child
      psychiatrist, a dietician, and trained nurses collaborated in a comprehensive
      systemic therapeutic approach involving parents, schools, and community agents.
      RESULTS: Ninety-one girls and six boys were treated in the eating disorder unit
      (55 had AN, 29 had BN and 13 had EDNOS). Thirty-seven patients were hospitalized
      and sixty were treated in the outpatient clinic. Mean hospitalization time of the
      first five patients was 108 days. Mean hospitalization time of the remaining 32
      patients was reduced to 32 days. The mean number of outpatient clinic
      interventions was 12. At the one-year follow up, 74 patients were doing well in
      all respects. Fourteen patients still needed a lot of supervision in eating. Five
      are still hospitalized and four were lost to follow up. CONCLUSIONS: The proposed
      model proves to be more than just another theory in that it is successfully
      applied in treatment. Short systemic therapy is very effective. The longer the
      delay in drastic, aggressive treatment, the worse the prognosis. Extended
      hospitalization periods worsen the prognosis. Weakness of the parental unit is a
      strong indication for inpatient care. The longer the experience in treating
      eating disorders, the shorter the hospitalization and number of interventions.

PMID- 12613108
TI  - The role of the family physician in eating disorders.
AB  - The steady increase in Eating Disorders (ED) during the last three decades has
      raised increasing concern over the early diagnosis and treatment of this disease.
      Due to the multi-factorial etiology of ED, treatment is complex, prolonged, and
      demands a team approach. Family physicians are often approached first for
      consultation following the patient's initial physical complaints. For this
      reason, the general practitioner can play a critical role in the early diagnosis
      and treatment of these disorders. By asking the appropriate questions and
      providing relevant information, the family physician (FP) may be able to refer
      the patient to treatment necessary for recovery, as well as assist in this
      process. Because the family physician typically has previous acquaintance with
      the patient and her family, he or she may be of considerable import to creating a
      therapeutic liaison and support framework with the professional team. This
      article will discuss the potential involvement and significance of the family
      physician in the successful diagnosis, prevention, and treatment of ED. The
      importance of the FP in the decision for hospitalization, referral, and follow-up
      is emphasized, as well as the pivotal role of the FP as a multi-disciplinary team
      coordinator.

PMID- 12613109
TI  - The treatment of eating disorders as addiction among adolescent females.
AB  - As science and medicine enter the new millennium, the influences of genetics and
      neurochemistry as high-risk determinants in the etiology and development of
      eating disorders are increasingly manifest in professional literature. Eating
      disorders are now recognized as major medical and psychiatric problems affecting
      millions throughout the world. Psychoeducational, cognitive, behavioral, and
      psychopharmacologic treatments form the basis of most interventions which, for
      the most part, tend to view the eating disorder as a symptom of underlying
      psychopathology. The Israel Counseling and Treatment Center of the North has been
      treating eating disorders as addictive disease by applying the twelve step
      program of the Anonymous Fellowships as an adjunct to counseling and treatment
      for those who suffer from compulsive overeating and bulimia. Following the
      ongoing program of interventions with adults, a counseling group for adolescent
      females was co-facilitated under the supervision of the author. A co-therapist,
      in recovery from bulimia and comulsive overeating, uses the twelve step
      philosophy and served as a role model in this group intervention. Another sample
      of adolescent females was offered individual counseling adhering to the same
      addiction treatment approach. Success rates were operationally defined and
      measured by weight loss in the obese population and the cessation of purging
      behaviors among bulimic subjects for a six-month period. The two adolescent
      treatment samples had success rates of 62% and 33% respectively. A higher success
      rate of 71% was observed with adult bulimic females who participated in group
      counseling. A mean weight loss of 3.9 kg for the small sample of adolescents and
      a 9.7 kg. mean weight loss for obese adults in treatment was reported. The
      theoretical basis of the addiction treatment paradigm for eating disorders is
      presented. Results and problems encountered specific to treating the adolescent
      population are discussed.

PMID- 12613110
TI  - Anorexia nervosa and the family: effects on younger sisters to anorexia nervosa
      patients.
AB  - The aim of this study was to describe and analyze the experience of the sister of
      the anorexia nervosa (AN) patient. This experience was examined in terms of the
      illness, the sister herself, and relations within the family during the course of
      coping with AN. A qualitative study method was employed in an attempt to
      understand the complexity and nature of a younger sister's subjective experience
      regarding an anorexia patient. Nine sisters of AN patients in the active stage of
      the illness were interviewed. Data were gathered through in-depth, semi
      structured taped interviews and content-analyzed by using the layer system
      theory. The findings provide the sister's personal perspective in regard to her
      emotional experience in the shadow of the illness and in regard to the systemic
      processes that take place in the course of a family's coping with the illness.
      The findings are divided into six main content categories: (1) structural
      processes; (2) family dynamic processes; (3) emotional processes; (4) change in
      life functions; (5) body image; and (6) narrative of the illness. Two theoretical
      concepts are presented that analyze the reality of the sister as an individual
      and of the family as a system. The first concept relates to the illness as a new
      member of the family system. The second concept relates to the sister's emotional
      experience as one of duality. These two concepts underscore the implications of
      the illness in terms of placing the sister at risk of developing additional
      pathological symptoms. The present study provides an in-depth description,
      explanation, and analysis of the younger sister's experience, thus elucidating
      risks to her emotional and mental functioning. In addition, it opens a window to
      the world of a family coping with the illness, and clarifies processes of change
      taking place within it.

PMID- 12613111
TI  - Treatment of eating disorders in a division of adolescent medicine.
AB  - We present a report on a study of 638 adolescent patients with eating disorders
      treated at the North Shore University Hospital between 1980 and 1994. Data from
      the study are presented in this paper, together with a discussion of the
      implications for treatment in adolescent medicine settings.

PMID- 12613112
TI  - Chronic fatigue syndrome and eating disorders: concurrence or coincidence?
AB  - In this report we present four patients who were found to have both an eating
      disorder and the chronic fatigue syndrome (CFS). Two of the patients presented
      for evaluation of an eating disorder and also had CFS, while two of the patients
      presented for evaluation of CFS and also had an eating disorder. In all four
      patients the eating disorder preceded the CFS. We consider the question of
      whether the occurrence of these two disorders in the same patients is merely a
      coincidence; whether an eating disorder can act as a precipitant for CFS, perhaps
      through the exacerbation of an underlying vascular instability; and whether
      overlapping etiologies may predispose some adolescents to develop both disorders.
      We also discuss similarities (including diagnostic dilemmas, cultural influences,
      psychological correlates, demographic similarities, perceptual biases, and
      cardiovascular effects) encountered in the management of both of these disorders.

PMID- 12613113
TI  - Cultural factors in orthodox Jewish adolescents treated in a day program for
      eating disorders.
AB  - This study explores the specific role of culture and religion in the development
      of eating disorders (ED) in Orthodox Jewish female adolescents. We present eight
      cases admitted to a Day Treatment Program (DTP) for Eating Disorders.
      Additionally, some preliminary comparisons are examined between Orthodox and all
      other patients, and also between ultra and modern Orthodox patients. All eight
      adolescents were transferred from inpatient care, three met program treatment
      goals, two left prematurely, and three required re-hospitalization. The only
      significant differences between the Orthodox group and all other patients were on
      length of stay in the DTP and current use of psychotropic medications. Overall,
      results suggest that Orthodox patients and all other patients show similar ED
      presentation and course. However, there are unique cultural and religious
      circumstances, which require consultation with rabbinic authorities.

PMID- 12613114
TI  - Three case reports on the relationship between anorexia nervosa and obsessive
      compulsive disorder.
AB  - The literature has demonstrated that both food-related and non food-related
      obsessions and compulsions are common in patients with eating disorders and that
      eating disorders are common in patients with obsessive-compulsive disorder (OCD).
      It has become increasingly important, therefore, to evaluate the clinical and
      etiological relationships between these disorders. The authors present three
      patients with anorexia nervosa and obsessive-compulsive disorder. In two of the
      cases, OCD symptoms preceded onset of the eating disorder by several years. In
      the third case, OCD symptoms began after the onset of weight loss. In all three
      cases, obsessive-compulsive symptoms had a significant effect on attempts to
      treat the eating disorder. Medication, utilized in one of the three patients, was
      helpful in treatment of the OCD but did not have a major effect on the eating
      disorder. There remains much to learn about the epidemiology, etiology, treatment
      and outcome of those who have comorbid eating disorders and OCD. These cases
      highlight some of the issues encountered in management of patients with these
      combined conditions.

PMID- 12613115
TI  - The citizen therapist and family-centered community building: introduction to a
      new section of the journal.

PMID- 12613116
TI  - The family Re-Union initiative: a springboard for family-centered community
      building, locally and nationally.
AB  - Family Re-Union is an ongoing conference series and family policy initiative
      launched in 1992 by Al and Tipper Gore. It has been the springboard for a new
      wave of family-centered community building efforts, including the development of
      an educational program to prepare a new generation of community builders. We
      summarize the history of this family-centered community building movement and
      discuss how it builds upon and differs from earlier approaches to community
      development. We describe Family Re-Union and some of the ongoing work it has
      fueled. And we suggest ways family professionals can take part in this work.

PMID- 12613117
TI  - The Families and Democracy Project.
AB  - The Families and Democracy Project moves family therapists and other
      professionals into the community via a critique of traditional provider/consumer
      models of family services, a set of principles about the civic engagement of
      families in partnership with professionals, and a set of public practices for
      working on community problems. We describe the Families and Democracy model and
      three specific projects. We distinguish the model from traditional hierarchical
      and collaborative models of working with families. And we discuss lessons we have
      learned, and our plans to take this work to its next developmental stage.

PMID- 12613118
TI  - Healing internalized racism: the role of a within-group sanctuary among people of
      African descent.
AB  - This article addresses the role of a "within-group" sanctuary for healing
      internalized racism among people of African descent. Internalized racism is
      distinguished from racism, juxtaposing the different experience of those who are
      oppressed and those who are privileged by racism. It is suggested that a context
      consisting exclusively of persons of African descent can provide an optimally
      safe space for initial stages of healing from internalized racism. The anxiety
      that a collective of African descendants can generate among whites, and
      subsequently among those of African descent, is examined by raising questions as
      to its possible meanings. Whites are encouraged to use their privilege to support
      such self-determined sanctuaries, rather than to obstruct them. People of African
      descent are encouraged to tolerate the anxiety that can be generated without
      "changing back," and to examine whether internalized racism is also implicated.

PMID- 12613119
TI  - Dominant and marginalized discourses in interracial couples' narratives:
      implications for family therapists.
AB  - This study explores inter-racial couples' family histories, their experiences of
      their life together, and the dominant and subordinate discourses employed in
      negotiating racial and ethnic differences. Ten black-white couples were
      interviewed individually and conjointly. Dominant discourses that emerged from
      the couples' narratives included those of homogamy, hypersensitivity of persons
      of color, and the insignificance of familial and societal history. Interracial
      partners also simultaneously subverted these prevailing ideologies by voicing
      experience associated with life at the margins of the society. Dominant and
      subordinate dicourses used by therapists and interracial couples in the therapy
      room are examined to integrate marginalized "truths" crucial to effective work
      with interracial couples and persons of color.

PMID- 12613120
TI  - Racism in Mexico: cultural roots and clinical interventions.

PMID- 12613121
TI  - Making up for lost time: the experience of separation and reunification among
      immigrant families.
AB  - In the United States today, one-fifth of the nation's children are growing up in
      immigrant homes. In the process of migration, families undergo profound
      transformations that are often complicated by extended periods of separation
      between loved ones--not only from extended family members, but also from the
      nuclear family. Though many families are involved in these transnational
      formulations, there has heretofore been little sense of the prevalence of these
      forms of family separations, nor of the effects on family relations. Further,
      such research has generally been conducted with clinical populations using
      Western theoretical frameworks and perspectives of families, limiting its
      applicability to immigrant families. The data presented in this article are
      derived from a bicoastal; interdisciplinary study of 385 early adolescents
      originating from China, Central America, the Dominican Republic, Haiti, and
      Mexico. Findings from this study indicate that fully 85% of the participants had
      been separated from one or both parents for extended periods. While family
      separations are common to all country-of-origin groups, there are clear
      differences between groups in lengths of separations as well as people from whom
      the youth are separated. Descriptive statistics of country-of-origin prevalence,
      patterns, and outcomes are presented. Results of analyses of variance indicate
      that children who were separated from their parents were more likely to report
      depressive symptoms than children who had not been separated. Further,
      qualitative data from youth, parent, and teacher perspectives of the experience
      of separation and reunification provide evidence that the circumstances and
      contexts of the separations lead to a variety of outcomes. We conclude with a
      discussion of attenuating and complicating factors family therapists should
      consider in the assessment and treatment of immigrant families.

PMID- 12613122
TI  - Expressed emotion attitudes and individual psychopathology among the relatives of
      bipolar patients.
AB  - This study investigated the relationships between expressed emotion (EE) and
      individual psychopathology among 82 biological and non-biological relatives of 66
      patients with bipolar I disorder. Relatives' psychopathology was assessed via the
      Structured Clinical Interview for DSM-III-R, Patient Version (SCID-P) and the
      General Behavior Inventory (GBI), a self-report measure of lifetime subsyndromal
      mood disturbances. We hypothesized that relatives who held high-EE critical,
      hostile, and/or overinvolved attitudes toward their bipolar family member, as
      measured via the Camberwell Family Interview, would be more likely to have DSM
      III-R Axis I diagnoses on the SCID, as well as more mood and temperamental
      disturbances on the GBI, than those who held low-EE attitudes. The findings did
      not support a significant relationship between overall EE status and
      psychopathology in family members. However, relatives without significant Axis I
      pathology scored significantly higher than those with Axis I pathology on one
      measure of EE, emotional overinvolvement. The findings are discussed with
      reference to explanations for the genesis of high-EE attitudes.

PMID- 12613123
TI  - Communication, conflict, and commitment: insights on the foundations of
      relationship success from a national survey.
AB  - The key relationship dynamics of communication, conflict, and commitment were
      investigated using data from a randomly sampled, nationwide phone survey of
      adults in married, engaged, and cohabiting relationships. Findings on
      communication and conflict generally replicated those of studies using more
      indepth or objective measurement strategies. Negative interaction between
      partners was negatively associated with numerous measures of relationship quality
      and positively correlated with divorce potential (thinking or talking about
      divorce). Withdrawal during conflict by either or both partners, though quite
      common, was associated with more negativity and less positive connection in
      relationships. The most frequently reported issue that couples argue about in
      first marriages was money, and in re-marriages it was conflict about children.
      Overall, how couples argue was more related to divorce potential than was what
      they argue about, although couples who argue most about money tended to have
      higher levels of negative communication and conflict than other couples. Further,
      while the male divorce potential was more strongly linked to levels of negative
      interaction, the female was more strongly linked to lower positive connection in
      the relationship. Consistent with the commitment literature, higher reported
      commitment was associated with less alternative monitoring, less feeling trapped
      in the relationship, and greater relationship satisfaction.

PMID- 12613124
TI  - A hereditary disorder in the family and the family life cycle: Huntington disease
      as a paradigm.
AB  - The implications of predictive DNA-testing for Huntington's Disease (HD) for the
      transitions in the family life cycle are described. HD is a hereditary disorder
      leading to personality changes, uncontrollable movements, cognitive impairment,
      and ultimately death in mostly adults. People at risk have the possibility to
      detect whether or not they carry the disease provoking-gene, but no treatment is
      available. In this article, we will highlight the complex implications of pre
      symptomatic testing by describing six different cases, interpreted by following
      the theoretical framework of Carter and McGoldrick (see pp. 684). HD interferes
      strongly with the "normal" transitions in the life cycle. It is not so much the
      test result itself that may be disrupting, but the changed expectations and
      possibilities for the future. As a family disease, HD forces its members to cope,
      one way or another, with disturbing events and untimely deaths. Some families are
      able to make some transitions, while becoming blocked at other transition points;
      this may differ between families. Being able to cope with HD in the family for a
      certain time does not necessarily imply that problems will never occur. Because
      any family member may eventually need help, it is important to then help the
      family discover what hinders them from making the transition to the next life
      stage, and to resolve these issues so that they can move on.

PMID- 12613125
TI  - Effects of family interaction on the child's behavior in single-parent or
      reconstructed families.
AB  - The effects of the family interaction on children's behavior were studied in
      single-parent or reconstructed families (N = 63) in a white population in
      Finland. The focus was on the spousal and the parent-child interaction. Teachers
      assessed children's behavior and parents were interviewed. The interviews were
      analyzed qualitatively using the grounded-theory method. The boundary ambiguity
      theory developed by Pauline Boss was used to examine the interaction in the
      families. About two fifths of the parents reported that their spousal interaction
      was good, family boundaries were clear, and the children were taken care of
      together. Another two fifths interacted only because of the child and family
      boundaries were ambiguous. In 14 families the involvement of the noncustodial
      parent was both physically and psychologically low. The physically close but
      psychologically distant parent-child interaction seemed to affect the child's
      behavior detrimentally, whereas children with physically and psychologically
      close interaction with their parents showed less behavioral problems. The
      children with behavioral problems were more likely to have problems with both
      parents. They were also more likely to have a stepparent with whom they had
      conflicts. In conclusion, a good interaction between the parents and clarified
      family boundaries protect children's mental health after their parents' divorce
      or separation.

PMID- 12613126
TI  - PACHIQ-R: the Parent-Child Interaction Questionnaire--revised.
AB  - The PACHIQ (Parent-Child Interaction Questionnaire) is designed to help
      clinicians and researchers assess how parents view relationship with their
      children (PACHIQ-Parent version), and how children evaluate their relationship
      with their parents (PACHIQ-Child version). The items in this questionnaire refer
      to both interpersonal behavior and feelings. Conceptually, the PACHIQ is based on
      learning theory and structural systems theory. The development of the PACHIQ was
      described by Lange, Blonk and Wiers (1998). The present article reports
      additional psychometric data obtained in the development and validation of a
      revised, shorter version of the questionnaire (PACHIQ-R). We present norm tables
      for families with children who are referred for psychological treatment, and norm
      tables for families in the normal Dutch population. The PACHIQ-R displays a two
      factor structure with factors interpreted as Conflict Resolution and Acceptance.
      The parent version of the PACHIQ-R contains 21 items, the child version 25 items.

PMID- 12613128
TI  - Major alternatives to the Classic Experimental Design.
AB  - In summary, giving up any of the three defining features of the Classic
      Experimental Design has (at least) two important effects. Each concession creates
      a significant threat to our confidence that any improvements observed were
      actually attributable to the treatment we are studying. At the same time, each
      concession opens a door by enhancing, sometimes greatly, the feasibility of
      conducting work in settings that are the most true to everyday clinical practice.
      When the work is thoughtfully and responsibly conducted, the alternative designs
      can contribute to clinical knowledge in a way that is equally important to the
      contributions made by work that conforms to the stringent requirements of the
      "Classic" design. In the next article, we will discuss single-time-point designs,
      along with the important dictum, memorized by most everyone who has taken a
      course called "Introduction to Research" or "Introduction to Statistics" that
      correlation is not causation.

PMID- 12613127
TI  - Can the Family Assessment Device (FAD) be used with school aged children?
AB  - This article examines the usefulness of the Family Assessment Device(FAD) in
      assessing family functioning with school-aged children (under 12 years of age)
      compared to children 12 and older and mothers. FAD reports from 194 children with
      asthma (132 under 12 years; 62 12 years and older) were evaluated in comparison
      to mothers' FAD reports as well as mothers' reports on two other family
      functioning measures: the Family Inventory of Life Events (FILE) and the Impact
      on Family (IOF) scale, both relevant to functioning in families with children
      with asthma. Although FAD scale reliabilities were lowest in younger children
      (alpha = 48-.79), good concurrent validity was found with mothers' reports on the
      three different measures of family functioning. Older childrens' FAD scales
      showed good reliability (> .70) but poorer agreement with the various maternal
      measures. With modifications to make items more structured and simplified, the
      FAD could be tried with younger children, although documentation of improved
      reliability is needed before more widespread use with school-aged children is
      advocated. The measure already shows good agreement with maternal report in this
      younger age group, which likely would be strengthened with improved reliability.
      FAD reports in older children correlated less well with maternal measures, but
      may represent nonredundant information on family health from an independent
      perspective and are worth considering in addition to mothers' perspectives.

PMID- 12613129
TI  - To test or not to test: interest in genetic testing for Alzheimer's disease among
      middle-aged adults.
AB  - Based on a hypothetical scenario positing 100 percent accuracy in test results,
      we examined interest in genetic testing for Alzheimer's disease (AD) among adult
      children, 40-60 years of age, who have a living parent with a diagnosis of
      probable AD (N = 108), and a matched comparison group of persons with no parental
      history of AD (N = 150). For both groups, planning for the future was the most
      important reason cited for being tested; lack of good treatment options and
      concerns about losing health insurance were the most important reasons for not
      being tested. Hierarchical regression was used to examine the effects of
      sociodemographic characteristics, subjective perceptions of memory functioning,
      concerns about having and developing AD, and mastery on interest in being tested.
      Personal concerns about developing AD and mastery emerged as significant
      predictors and subsample membership approached significance, although the full
      model explained just 18 percent of the variance. Because persons in the
      comparison group were more likely to report an interest in being tested,
      educational efforts about genetic testing should not be restricted only to family
      members of persons with a diagnosis of AD.

PMID- 12613130
TI  - Domestic violence and elderly dementia sufferers.
AB  - Domestic violence is a serious national public health issue, and elderly dementia
      sufferers are not exempt from this form of aggression. This manuscript discusses
      the general nature of domestic violence, reviews the empirical findings of
      domestic violence in dementia sufferers, and outlines some of the warning signs
      and intervention strategies that could be considered for remediation in the
      presence of such abuse.

PMID- 12613131
TI  - Age- or stage-appropriate? Recreation and the relevance of Piaget's theory in
      dementia care.
AB  - In this study, the immediate effects (within 10 minutes) of age- and stage
      appropriate activities and two control activities were observed in 56 dementia
      sufferers. Compared with the control activities, the two experimental treatment
      conditions elicited greater reductions in agitation and negative emotion and
      increases in positive emotion and duration of activity. Stage-appropriate
      activity was superior to age-appropriate activity in increasing positive emotion
      and had about the same effect in reducing negative emotion and agitation. The
      study also addressed the idea that people with Alzheimer's disease may regress
      through Piaget's stages of cognitive development and thus display the play
      interests associated with each stage. There was a significant relationship
      between cognitive level and type of Piagetian play observed; however, Piaget's
      descriptions of play were not entirely appropriate for persons with with
      Alzheimer's disease.

PMID- 12613132
TI  - Intergenerational activities involving persons with dementia: an observational
      assessment.
AB  - Although benefits of intergenerational programs (IGP) have been identified for
      older adults, adults with dementia are rarely targeted for such programs.
      Characteristics of dementia challenge caregivers to find appropriate activities
      that successfully engage the adults. With consideration of participants'
      abilities and interests, beneficial IGP can be facilitated. A co-located program
      for children and seniors was assessed for effects of IGP on adults with dementia.
      Results indicate that affect was higher during IGP for treatment group members
      than during non-IGP activities for treatment and comparison group members.
      Behaviors supporting personhood were common during IGP and non-IGP activities for
      treatment and comparison group members. Cognitive ability was unassociated with
      participation in IGP and affect during IGP. Findings suggest IGPs are appropriate
      and effective for persons with dementia.

PMID- 12613133
TI  - The Caregiver Vigilance Scale: application and validation in the Resources for
      Enhancing Alzheimer's Caregiver Health (REACH) project.
AB  - This article reports on the measurement properties of Caregiver Vigilance, a four
      item caregiver self-report of perceived oversight demand for Alzheimer's disease
      and related disorders family caregiving. The self-report uses data from the
      Resources for Enhancing Alzheimer's Caregiver Health (REACH) project, a multisite
      National Institutes of Health (NIH) sponsored study of over 1,200 family
      caregivers. Results indicate that the items were clearly understood by the
      racially/ethnically diverse respondents; and, when responses were transformed
      into a summary scale and analyzed, unidimensionality was evident and internal
      consistency reliability favorably demonstrated. We suggest using the Caregiver
      Vigilance Scale in conjunction with traditional burden measures to systematically
      include the caregiving time associated with protectively watching over care
      recipients and the daily duration of this responsibility. We also highlight the
      practical utility of selected items for potential use in the caregiver assessment
      process.

PMID- 12613134
TI  - Electromyographic validation of the trapezius and serratus anterior muscles in
      rowing exercises with middle and closed grip.
AB  - Because the lack of specialized textbooks on the select and indication of basic
      exercises for physical conditioning programmes, an electromyographic study of the
      trapezius (upper portion) (TS) and the serratus anterior (lower portion) (SI)
      muscles in rowing exercises with middle and closed grip in three different
      modalities, upright, sitting and bent over was performed. The tests were carried
      out with 24 male volunteers, 18 to 25 years old, by using a two-channel TECA TE 4
      electromyograph and Hewlett Packard surface electrodes. For exercises execution,
      a supine bench, a straight board and a 1,20 m-long bar made of light wood were
      used. The results showed that TS acted preferentially with closed grip sitting
      and bent over modalities, and presented no difference among the grips for upright
      rowing. SI acted preferentially with closed grip in all modalities, however, with
      activity levels that do not justify its indication for physical conditioning
      programmes.

PMID- 12613136
TI  - Comparison of motor unit action potential characteristics and hand dominance
      using monopolar needle electrodes in the abductor pollicis brevis and abductor
      digiti minimi muscles.
AB  - This study examined specific electrical characteristics of voluntary single motor
      unit action potentials (SMUAPs): amplitude, duration, phase change, and rate of
      rise. These characteristics, which were detected from two intrinsic muscles of
      the hand--the abductor pollicis brevis and the abductor digiti minimi--were
      compared to hand dominance. Forty subjects participated in the study. Five
      characteristics were detected from each muscle using the quadrant technique while
      the subject produced a minimal isometric contraction. Based on results of an
      ANOVA [two-factor with replication] test, our study revealed no significant
      difference between muscles in the dominant and non-dominant hands. Descriptive
      statistics for each muscle characteristic are presented. This study has
      identified parameters for SMUAP characteristics detected in non-impaired
      individuals ranging in age from 20 to 43 years. The normative parameters serve as
      a valuable base from which one may examine potential neuronal damage from
      cumulative trauma disorders.

PMID- 12613135
TI  - Phrenic and intercostal repetitive nerve stimulation: a useful
      electroneurophysiological method to detect the respiratory status of myasthenia
      gravis patients.
AB  - OBJECTIVE: To get a comprehensive recognition about the profile of phrenic
      repetitive nerve stimulation (PRNS) and intercostal repetitive nerve stimulation
      (IRNS) in healthy people, to investigate the electrophysiological features about
      respiratory function of myasthenia gravis (MG) patients, and to detect the
      predictive value of IRNS and PRNS on the respiratory deterioration of MG patients
      during the pulse treatment with large dosage of adrenal corticosteroid. SUBJECTS
      AND METHODS: Bilateral PRNS and IRNS with stimulation frequency of 3 and 5 Hz
      were tested in 28 healthy people and 113 MG patients; limb and cranial repetitive
      nerve stimulation (RNS), clinical score and forced vital capacity (FVC) were also
      recorded from those MG patients. Further more, PRNS and IRNS of 36 MG patients
      were tested 3 days before the beginning of their adrenal corticosteroid pulse
      treatment, FVC, clinical score and respiratory changes of the MG patients were
      simultaneously observed. RESULTS: For healthy people, there were no significant
      differences in the results of PRNS or IRNS in different age, sex and testing
      sides. After combining the left result with the right one, the amplitude
      decrement percentage in PRNS and IRNS was less than 7%. PRNS had more technical
      difficulty than IRNS. For 113 MG patients, FVC was dependent on the values of
      PRNS, IRNS and facial RNS. A subclinical respiratory dysfunction was found in
      patients with type I and II MG. The abnormal rate of PRNS in type IIb MG was
      similar to that in type III and IV MG, even though a difference in the percentage
      of amplitude decrement between them was observed. Meanwhile, both the abnormal
      rate and the percentage of amplitude decrement of IRNS had no difference between
      type IIb MG and type III and IV MG. The general incidence of abnormal PRNS and
      abnormal IRNS were higher than those of decreased FVC and clinical dyspnea, and
      the sensitivity of PRNS in type IIa MG patients was higher than that of IRNS.
      Among 36 MG patients under the adrenal corticosteroid pulse treatment, 14 showed
      the newly clinical dyspnea or worsened original one 2 to 13 days after the
      beginning of the therapy. There were significant difference of the above
      parameters between the patients with and without respiratory deterioration during
      the treatment. Logistic regression analysis showed that when the mean value of
      the bilateral IRNS amplitude decrement was larger than 30%, the odds ratio of the
      occurrence of the respiratory deterioration was 19.523, for both 3 and 5 Hz
      stimulation. CONCLUSIONS: It is recommended that PRNS and IRNS will be defined as
      abnormal when their amplitude reduces more than 15%. PRNS and IRNS are
      neurophysiological indices reflecting the damage of respiratory muscles in MG,
      they are helpful in evaluating the clinical condition correctly and making the
      classification of MG properly. It is necessary to test the PRNS and IRNS in type
      II MG patients regularly. Although the respiratory damage during the adrenal
      corticosteroid treatment was correlated with PRNS, IRNS, FVC, MG clinical score
      and type, only IRNS had predictive value on the respiratory deterioration during
      the treatment.

PMID- 12613137
TI  - The reorganisation of motor units in different motor neuron disorders.
AB  - A study was made of the degree and sequence of neurophysiological changes during
      motor unit reorganisation in motor neuron disease (MND), spinal muscular atrophy
      (SMA), and prior polio. Concentric needle EMG was used in conjunction with our
      own computerized EMG-LAB system. Motor unit action potential (MUAP) parameters
      were measured in 543 muscles on weak and maximum effort. MUAP amplitude and area
      were found to increase in the early stages of damage, declining to normal or
      subnormal values in the course of the disease. It was concluded that in MND there
      is a pathological sequence: denervation--reinnervation--terminal denervation. The
      increase in MUAP amplitude and area in the early stages of lesion, reflecting
      reinnervation, was much greater in SMA than MND and most marked in prior polio.
      The eventual decrease is an expression of terminal decompensation.

PMID- 12613138
TI  - A-waves and electrophysiologically established diagnoses.
AB  - The aim of this study was to investigate the presence of A-waves in cases
      referred to our electromyography laboratory with various diagnoses and
      documentation of electrophysiologic diagnoses with A-waves. In cases where at
      least 3 motor nerves were analysed, during F response studies, A-waves having
      stabile latencies and amplitudes from minimum one third of submaximal and
      supramaximal stimuli were evaluated. Electrophysiologic diagnoses and the related
      nerves of cases with A-waves were recorded. A-waves were obtained from 38 out of
      1604 cases (2.36%). Most of the cases (57.8%) with established A-waves consisted
      of patients with radiculopathies. A-waves were detected mostly in tibial nerve.
      Electrophysiologic analysis of 5 cases with A-waves has given normal results.
      Although mechanism of A-waves is not known completely, we suggest when obtained
      it must be remarked during routine electrophysiologic examination.

PMID- 12613139
TI  - Disposable concentric needle electromyography electrodes artifact discharge
      mimicking positive sharp waves.
AB  - OBJECTIVES: To determine a new artifact discharge produced from the disposable
      concentric needle (DCN) electromyography (EMG) electrodes. METHODS: We have
      recorded the activity obtained after the first insertion of 41 DCN (37 mm) and 36
      DCN (50 mm) in several muscles during the rest. The number of the patients was 77
      (26 males, 51 female). RESULTS: We observed an artifact discharge (AD) resembling
      positive sharp waves (PSWs) in 31 patients of 77 insertions. The AD occurred with
      18 of 41 insertions of DCN 37 mm and 13 of DCN 50 mm. The artifact resolved when
      the needle has been moved in the muscle or in the adipose subcutaneous tissue.
      CONCLUSION: This AD should be recognized when using DCN electrodes to avoid
      confusion with PSWs. Recognizing these artifacts during needle EMG is important
      to avoid false positive results.

PMID- 12613140
TI  - Lower extremity neuromuscular recovery following anterior cruciate ligament
      reconstruction; a 2-week case study.
AB  - The lower extremity neuromuscular recovery of a 31-year-old male physical therapy
      student during the initial 2-weeks following anterior cruciate ligament
      reconstruction was evaluated by measuring involved side vastus medialis (VM),
      gluteus maximus (GMAX) and gastrocnemius (GASTROC) electromyographic (EMG)
      signals (1000 Hz), plantar forces (50 Hz), and knee pain as the subject performed
      a series of volitional, maximal effort unilateral, isometric leg presses (6 sec)
      in a modified continuous passive motion device. Data were standardized to pre
      operative values and graphically plotted for split middle technique, celeration
      line assessment. From 1-8 hours post-surgery, EMG amplitudes and plantar forces
      decreased, pain increased, and plantar force location shifted toward the
      forefoot. From 9-12 hours post-surgery, EMG amplitudes and plantar forces
      increased and pain decreased. By 24 hours post-surgery, pain decreased to pre
      operative levels. From 24-72 hours post-surgery, EMG amplitudes and plantar
      forces increased. From 1-2 weeks post-surgery, EMG amplitudes and plantar forces
      increased. From 9 hours-2 weeks post-surgery, plantar force location shifted
      toward the pre-operative location. Sequential increases were observed for GMAX,
      GASTROC, and VM EMG amplitudes. By 2 weeks post-surgery, plantar forces and VM
      EMG amplitudes remained reduced. Reduced plantar forces and VM EMG amplitude at 2
      weeks post-surgery suggest a need for greater focus on restoring VM function
      before attempting closed kinetic chain exercises that require the full shock
      absorption capabilities of the quadriceps femoris muscle group.

PMID- 12613141
TI  - Effect of continued stretching of the affected arm in patients with
      cerebrovascular diseases by examining H-reflex characteristics.
AB  - To investigate excitability of spinal neural function during stretching excises
      in patients with cerebrovascular disease (CVD), H-reflex was analyzed before,
      during and after 1 min. continued stretching of the affected arm. 10 hemiparesis
      patients with hypertonus and hyperreflex, mean age of 53.2 years were tested. H
      reflex was recorded from the abductor pollicis brevis on the affected side after
      stimulation of median nerve in supine position. The persistence, amplitude and
      amplitude ratio of H/M during stretching were lower than those before and after
      in the patients with moderately increased muscle tonus. In patients with slightly
      and markedly increased, H-reflex was same before, during and after continued
      stretching. It is suggested that excitability of spinal neural function during 1
      min. continued stretching was inhibited in the patients with moderately increased
      muscle tonus caused by CVD.

PMID- 12613142
TI  - Vitamin B12 deficiency neurological syndromes: a clinical, MRI and
      electrodiagnostic study.
AB  - BACKGROUND: Vegetarianism is an important cause of vitamin B12 deficiency,
      especially in countries like India. We managed 17 patients with neurological
      syndrome due to vitamin B12 deficiency in a tertiary care referral teaching
      hospital which caters to relatively affluent population. AIM: To evaluate
      neurophysiological and MRI changes in patients presenting with vitamin B12
      deficiency neurological syndrome and interpret these is the light of reported
      autopsy findings. SETTING: Tertiary care referral teaching hospital. METHODS:
      Patients with vitamin B12 deficiency neurological syndrome diagnosed by low serum
      vitamin B12 and/or megaloblastic bone marrow were subjected to clinical
      evaluation and spinal MRI. The neurophysiological tests included nerve conduction
      studies, tibial somatosensory evoked potential (SEP), motor evoked potential
      (MEP) and visual evoked potential (VEP) studies. The recovery was defined on the
      basis of 6 months Barthel Index score into complete, partial or poor. RESULTS:
      There were 17 patients with vitamin B12 deficiency neurological syndrome, 3 were
      females and 12 lactovegetarian. The clinical syndrome was that of myelopathy in
      8, myeloneuropathy in 5, dementia myelopathy in 3 and neuropathy in 1 patient.
      All the patients had impaired joint position and vibration sensation in the lower
      limbs and 4 had in upper limbs as well. Lower limbs were spastic in 13 and upper
      limbs in 2 patients. Spinal MRI revealed T2 hyperintensity in cervicodorsal
      region in 6 and cord atrophy in 3 patients. Sural nerve conduction was abnormal
      in 8 and peroneal conduction in 5 patients. In one patient all sensory nerve
      conductions were unrecordable but motor conductions were normal. Tibial SEP was
      abnormal in 12 out of 15 and lower limb MEP in 8 out of 12 patients. P100 latency
      of VEP was prolonged in 7 out of 13 patients. Right to left asymmetry was present
      in tibial SEP in 4 and VEP in 2 patients. At 6 months followup 2 patients
      improved completely, 7 partially and 3 had poor recovery. Clinical recovery
      correlated with MEP but not with SEP or MRI changes. CONCLUSION: The evoked
      potential and MRI changes in vitamin B12 deficiency neurological syndrome are
      consistent with focal demyelination of white matter in spinal cord and optic
      nerve. Myelopathic presentation is commoner and SEP is more frequently abnormal.
      The outcome at 6 months correlated with MEP changes.

PMID- 12613144
TI  - [Characteristics and causes of death in 283 patients with implanted
      defibrillators].
AB  - The implantable automatic defibrillator has proved its superiority over
      pharmacological treatments for preventing mortality by serious ventricular
      arrhythmia. We studied the cause of death in a population of 283 consecutive
      patients implanted between February 1988 and December 2000 (age at implantation:
      58 +/- 14.7 years; extremes: 15-78 years, 45 females, ejection fraction: 0.39 +/-
      0.15) and followed up over a median of 25 months (extremes = 1 day-163 months).
      RESULTS: At the end of follow up, 55 patients had died (average age: 62.7 +/-
      12.6 years, extremes: 15-79 years, 7 females). All except 2 had a cardiopathy:
      ischaemic cardiopathy (n = 38, 36 IDDM), dilated cardiomyopathy (n = 14),
      arrhythmogenic dysplasia of the right ventricle (n = 1). The median interval
      between implantation and death was 35 months (extremes = 1 day-137 months). The
      causes of death were the following: cardiac insufficiency (n = 24), refractory
      arrhythmias (n = 13), other cardiac causes (n = 8), extra-cardiac pathologies (n
      = 10). The deceased patients had presented an average of 86.6 +/- 23.4
      ventricular arrhythmias (extremes = 0-1309) but 18 of them (33%) did not present
      any during follow up. CONCLUSIONS: Cardiac insufficiency is the prime cause of
      death in refractory arrhythmias; on patient in 4 dies from ventricular
      arrhythmia, despite the defibrillator and one deceased patient in 3 had no
      arrhythmia during follow up.

PMID- 12613145
TI  - [Return to work after cardiac valvular surgery. Retrospective study of a series
      of 105 patients].
AB  - This was a retrospective study realised by a mailed questionnaire of the medical
      and socio-professional conditions of return to work in patients with valvular
      heart disease aged 20 to 59 and operated in the cardiac surgery department of
      Rennes University Hospital in 1998. The results concern 105 patients of whom 78
      were working before surgery and 27 were unemployed, and 53 were professionally
      active after surgery. The average age was 48 +/- 9 years and the male/female
      ratio was 2.38. After surgery, 78.4% of patients were NYHA Stages I or II,
      compared with 38.1% before surgery. Three main surgical procedures were carried
      out, sometimes in association: aortic valve replacement (71.4%), mitral valve
      replacement (21%) and mitral valvuloplasty (11.4%). Valve replacement was with a
      mechanical prosthesis in 83% of cases, a bioprosthesis in 11% of cases and a
      homograft in 6% of cases. Return to work (67.9%) after an average of 5.3 +/- 3.9
      months was correlated with the following factors: age: 50 years old patients or
      more, were less likely to return to work (p < 0.02); postoperative NYHA stage:
      patients in stages III and IV were less likely to return to work (p < 0.03); the
      time off work before surgery: the longer the time (threshold > 6 months) the less
      likely the patients are to return to work (p < 0.03). Return to work was
      preferred to non-return (p < 0.03). This study shows the difficulties of
      professional rehabilitation of patients despite a satisfactory general condition.
      This is partially explained by the difficult economic context which favorises
      invalidity but also by the lack of information concerning the role of works
      doctors in the return to work. The realisation of a liaison file with permission
      of the person concerned between the general practitioner, the cardiologist and a
      medico-social security doctor and works doctor should remedy the difficulties in
      communication and sustain a policy of return to work.

PMID- 12613146
TI  - [Study of non-invasive hemodynamic parameters in pulmonary edema: hypoalbuminemia
      is a factor frequently associated with acute diastolic cardiac insufficiency].
AB  - SUBJECT: A critical diminution of the gradient between plasma oncotic pressure
      (PO) and pulmonary capillary pressure (PCP) is the origin of the formation of
      haemodynamic pulmonary oedema (OAP), but the respective contribution of these two
      haemodynamic forces as a function of the type of cardiac insufficiency is not
      known. METHOD: 74 cases of OAP were included (78 +/- 15 years old, 43 diastolic
      defined by an ejection fraction greater than 45%, and 31 systolic), and 33
      control subjects. PO and PCP were calculated respectively from total protein and
      albumin serum levels, and from transthoracic echocardiography with the new
      Doppler indices using refilling flow propagation speed in colour TM or the study
      of pulmonary venous flow, at the start of treatment. RESULTS: The gradient was
      very significantly diminished in those with diastolic and systolic cardiac
      insufficiency compared to the control group (p < 0.001), with no difference
      between the two types of OAP. An elevation of PCP > or = 18 mm Hg was the
      principal haemodynamic factor in the critical diminution of the gradient in the
      systolic group and in the diastolic group with ischaemic or valvular cardiopathy.
      In parallel with the elevation in PCP was a state of plasma hypo-oncocity < or =
      18 mm Hg, consecutive with a significant diminution of albuminaemia, contributing
      to the critical diminution of the gradient in 41% of diastolic cases versus 3% of
      systolic cases. CONCLUSION: Hypo-albuminaemia is a factor frequently favouring
      acute diastolic cardiac insufficiency in elderly subjects and must be sought
      systematically.

PMID- 12613147
TI  - [Early study of myocardial perfusion with MRI in revascularized infarcts].
AB  - The aim of this work is to study the regional myocardial perfusion by MRI early
      after revascularised myocardial infarction and to compare it with regional
      function. This prospective work has included 15 patients with acute first
      myocardial infarction that was precociously revascularised. A myocardial MRI was
      performed between D2 and D10 after myocardial infarction. The regional myocardial
      thickening was evaluated from cine-MRI sequences. For the study of myocardial
      perfusion, the first pass of the contrast agent was analysed from curves of the
      signal evolution versus time. The signal enhancement on late images acquired 10
      minutes after the perfusion of the contrast agent was also evaluated. Among 384
      studied myocardial segments, those with a normal gadolinium first pass curve had
      a relative thickening of 46 +/- 38%. The segments with a severely reduced first
      pass kinetic have a markedly reduced relative thickening (14 +/- 20%) in relation
      with myocardial hypoperfusion. The myocardial enhancement is frequently seen in
      the infarct territory and appears related to a reduced regional contractility.
      The myocardium is enhanced on late images in 12% of the normally perfused
      segments. These segments have a mildly reduced wall thickening (3.36 +/- 2.84 mm
      vs 4.42 +/- 2.83 mm). The segmental contractility in a reperfused myocardial
      infarction appears to depend both on the myocardial perfusion which reflects the
      microvascularisation and on the myocardial enhancement which is linked to
      myocardial structural alterations. MRI appears to be an adequate method to
      evaluate these abnormalities and allows an easy assessment of the no-reflow
      phenomenon, if present.

PMID- 12613148
TI  - [Investigation of hyperaldosteronism in the hypertensive patient. Why? When?
      How?].
AB  - Primary aldosteronism (PA) has been regarded for a long time as being a rare
      cause of arterial hypertension, but its prevalence has recently been reassessed
      as about 10%. This etiology should obviously be sought in the following settings:
      hypertension associated with hypokaliemia < 3.6 mmol/L (or < 3.9 mmol/L on ACE
      inhibitors): refractory hypertension: severe hypertension occurring before 40
      years of age, especially in women. It must be reminded that more than 20% of PA
      are normokaliemic. Most of the authors recommend to use the aldosterone/renin
      ratio (ARR) as a screening test within these selected patients. When ARR turns
      out to be equal to or higher than 23 (if aldosterone and renin are given in pg/mL
      or ng/L), a suppression testing should be performed, using salt loading and/or
      fludrocortisone. Computed tomography scanning yields a specificity of 58% and a
      positive predictive value of 72%, only. Adenoma and hyperplasia have to be
      distinguished, using either NP-59 scintigraphy or adrenal venous samplings. Such
      a strategy appears to be useful, for the following reasons: removal of an adenoma
      results in a significant blood pressure lowering and in a blood pressure
      normalization in 95% and in 32% of the patients, respectively; in patients with
      hyperplasia, spironolactone therapy is followed by a 20% mean reduction in blood
      pressure.

PMID- 12613149
TI  - [Cognitive decline and hypertension].
AB  - The prevalence and incidence of degenerative and vascular dementia increase
      exponentially with age. Several studies in recent years have implicated
      hypertension as a risk factor not only for vascular dementia but also for
      degenerative dementia such as Alzheimer's disease. This is an important finding
      because it suggests that the treatment of hypertension could reduce the incidence
      of dementia. In particular, the results of the Syst-Eur study, showing that a
      calcium inhibitor, nitrendipine, could reduce not only the incidence of stroke
      but also that of dementia, should be confirmed.

PMID- 12613150
TI  - [Angioplasty of a right coronary artery arising from a single coronary artery
      during acute myocardial infarction].
AB  - The authors report the case of a patient admitted for acute inferior myocardial
      infarction with right ventricular extension secondary to occlusion of the right
      coronary artery arising from a single coronary artery treated by angioplasty and
      stenting by a right radial approach after treatment with Abxicimab.

PMID- 12613151
TI  - [A platypnea-orthodeoxia syndrome].
AB  - We report the case of a 68 years old patient with platypnea orthodeoxia syndrome
      who has been clinically suspected on cutaneous saturation position's variation.
      It has been confirmed by transthoracic and transesophageal echocardiography
      (TEE). TEE showed the size of patent foramen ovale (PFO), visualised the right to
      left shunt. A right heart angiography confirmed echocardiographic data and
      allowed successful closure by a Cardioseal percutaneous transcatheter button
      device implantation. Symptom's disappearance and a TEE control after 2 months
      confirmed the success of the procedure.

PMID- 12613152
TI  - [Metastasis stimulating a myocardial infarction].
AB  - A patient with a history of bronchial carcinoma was admitted to the coronary care
      unit with chest pain suggestive of infarction and an ECG showing changes
      compatible with acute lateral wall infarction. The coronary arteries were shown
      to be normal and echocardiography revealed an intracardiac mass which MRI
      confirmed to be a direct extension of the pulmonary tumour. Echocardiography
      should be performed systematically in patients with chest pain and ECG changes of
      ischaemia who also have progressive oncological disease.

PMID- 12613153
TI  - [Mitral insufficiency related to a spasm of the left anterior descending artery.
      A case report].
AB  - We report the case of a female patient of 76 years old admitted to our hospital
      for a pre-operative assessment of a symptomatic mitral regurgitation (MR) whose
      transthoracic echocardiography revealed only a trivial regurgitation. The
      occurrence during hospital stay of an acute pulmonary edema contemporary to the
      occurrence of a huge MR permitted to suspect the diagnosis of a paroxystic
      ischemic MR. Angiographic and hemodynamic evaluation revealed only a non
      significant atheromateous plaque located in the distal LAD. The infusion of
      Methylergometrine triggered a severe spasm at the site of that plaque, associated
      with a huge MR visualized by TTE with restricted movements of both leaflets,
      responsible for an acute pulmonary edema occurring on the table of the
      catheterization laboratory. Recovery was quickly obtained after intravenous
      injection of Nitroglycerin, which removed the spasm and valvular regurgitation.
      The diagnosis of paroxystic ischemic mitral regurgitation was confirmed and a
      treatment based on high dosage of calcium-blocker was decided. After a follow-up
      of more than one year, the patient remains asymptomatic and the regurgitation has
      never occurred.

PMID- 12613154
TI  - Historical generations and psychology. The case of the Great Depression and World
      War II.
AB  - The author assembles a theory of historical generations from dispersed sources in
      the social and behavioral sciences and in the humanities, differentiates the
      theory from formulations of other generation concepts, and applies it to central
      features in the lives of persons in the generation of the Great Depression and
      World War II. The application of the theory to historical materials explains how
      a commitment to social interdependence emerged as the signature orientation of
      the generation of the Great Depression and World War II. Challenges to the
      perspective of contextualism stem from the theory's hypotheses about linkages
      that mediate between cataclysmic events and psychological processes, the
      influence of historical generations on many of psychology's everyday concerns,
      and instructive comparisons with a body of growing research on processes
      involving adaptations to different cultures.

PMID- 12613156
TI  - American Psychological Association policy in context. The development and
      evaluation of guidelines for professional practice.

PMID- 12613155
TI  - Research ethics for mental health science involving ethnic minority children and
      youths.
AB  - In response to U.S. Public Health Service projects promoting attention to
      disparities in the outcomes of mental health treatments, in July 2001, the
      American Psychological Association, the National Institute of Mental Health, and
      the Fordham University Center for Ethics Education convened a group of national
      leaders in bioethics, multicultural research, and ethnic minority mental health
      to produce a living document to guide ethical decision making for mental health
      research involving ethnic minority children and youths. This report summarizes
      the key recommendations distilled from these discussions.

PMID- 12613158
TI  - Accredited internship and postdoctoral programs for training in psychology: 2002.

PMID- 12613157
TI  - Ethical principles of psychologists and code of conduct.

PMID- 12613159
TI  - Accredited doctoral programs in professional psychology: 2002.

PMID- 12613160
TI  - Romantic versus realistic views of psychology.

PMID- 12613161
TI  - Postmoderninism and the values of Science.

PMID- 12613162
TI  - As defined, unification is inevitable.

PMID- 12613163
TI  - Theory knitting reconsidered.

PMID- 12613164
TI  - Seeing the forest and seeing the trees in psychology.

PMID- 12613165
TI  - E pluribus unum.

PMID- 12613166
TI  - Swinging pendulums.

PMID- 12613167
TI  - Neglected aspects and unsupported claims.

PMID- 12613168
TI  - Women in academe: is the glass completely full?.

PMID- 12613169
TI  - Modern methods of drug discovery: an introduction.

PMID- 12613170
TI  - Proteomics.

PMID- 12613171
TI  - Bioinformatics.

PMID- 12613172
TI  - High-throughput screening technologies.

PMID- 12613173
TI  - Natural products for lead identification: nature is a valuable resource for
      providing tools.

PMID- 12613174
TI  - Combinatorial chemistry: mixture-based combinatorial libraries of acyclic and
      heterocyclic compounds from amino acids and short peptides.

PMID- 12613175
TI  - Computational approaches towards the quantification of molecular diversity and
      design of compound libraries.

PMID- 12613176
TI  - The role of protein 3D-structures in the drug discovery process.

PMID- 12613177
TI  - NMR-based screening methods for lead discovery.
AB  - Diversity and robustness of NMR based screening methods make these techniques
      highly attractive as tools for drug discovery. Although not all screening
      techniques discussed here may be applicable to any given target, there is however
      a good chance that at least one of the described methods will prove productive in
      finding several medium affinity ligands. A comparison of each of the methods is
      given in Table 1. For drug targets of molecular weight < 30 kDa SAR by NMR
      appears to be the method of choice since it yields detailed information about the
      location of the binding site. It remains to be seen whether 15N-1H-TROSY based
      screening techniques will prove useful for larger protein targets, especially
      considering the added effort needed for spectral assignment and the increased
      complexity due to spectral overlap. Nevertheless, with the application of new
      cryo-cooled NMR probes, 15N-1H-HSQC based screening can now be considered a high
      throughput method. Ligand-based NMR screening methods can be used for protein
      targets of virtually any size, but are restricted in the ligand's binding
      affinity range. Because sufficient ligand-protein dissociation rates are needed,
      only binding of ligands with low (milimolar) to intermediate (micromolar)
      affinities is detectable. It is expected that cryo-cooled NMR probe technology
      will also advance ligand detected NMR screening to the high throughput level.
      Certainly protein and ligand concentrations can be lowered drastically and
      experiment times can be shortened with increased sensitivity. However, spectral
      overlap will be of major concern when mixtures of up to 100 compounds are to be
      screened. For such applications only techniques for which the signals of bound
      ligands survive will be useful, and sophisticated software will be needed to
      deconvolute the spectra of multiple bound ligands. Although only ligands with
      medium to low affinities can be found, ligand based NMR screening has been used
      as an effective prescreening tool for assay based high throughput screening.
      Identifying a large ensemble of medium affinity ligands may not only aid in
      building a binding site pharmacophore model (see Chapter 11), but also may yield
      crucial information for overcoming tissue availability, toxicity, or even
      intellectual property related problems. Although NMR based screening is only one
      of the more recent additions to the bag of tools used in drug discovery [1, 2],
      its simplicity and wide range of application (including protein-protein and
      protein-nucleic acid interactions) has attracted much attention. Advances in NMR
      instrumentation and methodology have already paved the road for NMR based
      screening to become a high throughput technique. In addition to this, NMR is
      exceptional in the amount of detailed structural [table: see text] information it
      can provide. Not only can NMR readily reveal the binding site (15N-1H-HSQC
      screening) or the conformation of the bound ligand (transfer NOE), but it can
      also supply information that enables precise docking of the ligand to the
      protein's binding pocket (isotope-filtered NOESY). NMR data can therefore provide
      a natural connection between experimental HTS and combinatorial chemistry
      techniques with computational methods such as 3D-database searching (see Chapter
      10), virtual screening (docking) and structure-based ligand design (see also
      Chapter 8).

PMID- 12613178
TI  - Structure-based design of combinatorial libraries.

PMID- 12613179
TI  - 3D QSAR in modern drug design.

PMID- 12613180
TI  - Physicochemical concepts in drug design.

PMID- 12613182
TI  - Oseltamivir for influenza.
AB  - Oseltamivir (pronounced os-el-ta-mi-veer; Tamiflu--Roche), an oral anti-influenza
      drug that inhibits influenza virus neuraminidase, is now available in the UK. It
      has recently been licensed throughout the EU for use, when influenza is
      circulating in the community, in the treatment of patients with early influenza
      like symptoms, and for prophylaxis in people who have had close contact with
      someone with influenza. Oseltamivir is the second neuraminidase inhibitor to be
      licensed in the UK, the other being zanamivir (Relenza--GlaxoSmithKline), which
      is taken by inhalation and licensed only for treatment. Previously, we concluded
      that there was insufficient evidence that treatment with zanamivir prevented
      serious complications in people most at risk from influenza to recommend its use.
      Here we review the efficacy and safety of oseltamivir and discuss its role in the
      management of influenza.

PMID- 12613181
TI  - Computer-aided prediction of drug toxicity and metabolism.

PMID- 12613183
TI  - Contraception in teenagers.
AB  - Among countries of the 'developed world', the teenage birth rate in the UK is
      second only to that in the USA. The UK rate is nearly five times that in the
      Netherlands, over three times that in France and over twice that in Germany. For
      example, in the UK in 1998, there were 30.8 births per 1,000 15-19 year-olds.
      There is no single explanation for the high rate. It is probably due to a complex
      interaction between factors such as inadequate sex education; poor communication
      within families and with sexual partners; poor access to, and mistrust of, health
      services by young people (including specific concerns about confidentiality);
      risk-taking behaviour; and erratic use of contraception. With this in mind, here
      we explore how healthcare professionals can best deliver advice and help on
      contraception and related sexual health issues to teenagers.

PMID- 12613184
TI  - Looking back and moving forward.

PMID- 12613185
TI  - Needed protection for students with diabetes.

PMID- 12613186
TI  - Dealing with controversy: the lessons of implementing BMI screenings.

PMID- 12613187
TI  - Literature reviews in the research process.

PMID- 12613188
TI  - Key players in crisis planning, response, and prevention.

PMID- 12613189
TI  - Bipolar disorder and African Americans.

PMID- 12613190
TI  - Musings of a mother: life with a chronic medical condition.

PMID- 12613191
TI  - Growth, survival and migration: the Trk to cancer.

PMID- 12613192
TI  - The role of growth factor signaling in malignancy.

PMID- 12613193
TI  - TGF-beta signaling alterations in cancer.

PMID- 12613194
TI  - Notch in malignancy.

PMID- 12613195
TI  - cAMP signaling in cancer genesis and treatment.

PMID- 12613196
TI  - PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling.

PMID- 12613197
TI  - Wnt signaling in human cancer.

PMID- 12613198
TI  - Ras signaling, deregulation of gene expression and oncogenesis.

PMID- 12613199
TI  - Role of the RB tumor suppressor in cancer.
AB  - Apart from their coordinated inactivation by DNA tumor viral oncoproteins, the
      pRB and p53 tumor suppressor pathways were not known to be connected ten years
      ago. Within the last decade, our appreciation of how these pathways are
      interconnected has grown substantially. The checks and balances that exist
      between pRB and p53 involve the regulation of the G1/S transition and its
      checkpoints, and much of this is under the control of the E2F transcription
      factor family. Following DNA damage, the p53-dependent induction of p21CIP1
      regulates cyclin E/Cdk2 and cyclin A/Cdk2 complexes both of which phosphorylate
      pRB, leading to E2F-mediated activation. Similarly, E2F1-dependent induction of
      p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53
      stabilization and potentially p53-mediated apoptosis or cell cycle arrest. From
      the existing mouse models discussed above, we also know that proliferation, cell
      death and differentiation of distinct tissues are also intimately linked through
      entrance and exit from the cell cycle, and thus through pRB and p53 pathways.
      Virtually all human tumors deregulate either the pRB or p53 pathway, and often
      times both pathways simultaneously, which is critical for crippling cellular
      defense against neoplasia. The next decade of cancer research will likely see
      these two tumor suppressor pathways only merge even more.

PMID- 12613200
TI  - The Re1/NF-kappa B/I kappa B signal transduction pathway and cancer.

PMID- 12613201
TI  - StAT signaling in cancer: insights into pathogenesis and treatment strategies.

PMID- 12613202
TI  - Steroid hormone receptor signaling in cancer.
AB  - SHRs function as hormone activated, sequence specific DNA binding transcription
      factors that recruit multiple coactivator and other proteins to specific genes
      and generally stimulate transcription of these genes. SHR may have further
      genomic actions, that do not involve direct DNA binding, through protein-protein
      interactions with other sequence specific transcription factors, although these
      may still involve weak binding to nonconsensus steroid responsive elements in
      vivo. SHRs also appear to have nongenomic effects mediated through interactions
      with cytoplasmic signaling proteins. The major functions of SHRs in normal adult
      tissues appear to involve stimulation of differentiation, rather than
      proliferation. In contrast, the ER alpha and AR directly stimulate the growth of
      breast and prostate cancers, respectively, indicating a critical change in their
      functions. The ER alpha and AR appear to undergo further adaptation in tumor
      cells in response to hormonal therapies, that render these therapies ineffective.
      Understanding the molecular basis for these changes in SHR function during cancer
      development and progression may provide new targets for the generation of drugs
      to prevent and treat steroid stimulated cancers.

PMID- 12613203
TI  - Cell death signaling in maligancy.

PMID- 12613204
TI  - Ceramide and sphingosine 1-phosphate in anti-cancer therapies.

PMID- 12613205
TI  - Walters and Richards comment on the examination of terminal digits of questioned
      data as used by the Office of Research Integrity (ORI) of the Public Health
      Service in misconduct cases.

PMID- 12613206
TI  - Advance Tissue Sciences, Inc. Interview by Semahat S Demir.

PMID- 12613207
TI  - Advances in medical infrared imaging.

PMID- 12613208
TI  - From tanks to tumors.
AB  - "Tanks to Tumors" succeeded in bringing several different communities together-
      medical, military, academic, industrial, and engineering. They worked together in
      panels to determine how the United States might adopt thermal imaging diagnostic
      technology in an orderly and demonstrable way for the early detection of breast
      cancer and other conditions. The panel recommendations will serve to guide the
      transition of military technology developments in ATR, the VDL, and IR sensors to
      the civilian medical community. The result will be a new tool in the war against
      breast cancer--a major benefit to the military and civilian population. A CD of
      the workshop proceedings is available at no cost through Advanced Concepts
      Analysis, Falls Church, Virginia; +1 703 914 9237; e-mail: diakides@erols.com.

PMID- 12613209
TI  - Targeting breast cancer detection with military technology.

PMID- 12613210
TI  - Digital infrared thermal imaging of human skin.

PMID- 12613211
TI  - Imaging of skin thermal properties with estimation of ambient radiation
      temperature.

PMID- 12613212
TI  - Thermal image analysis for polygraph testing.

PMID- 12613213
TI  - Human thermal models for evaluating infrared images.

PMID- 12613214
TI  - Infrared functional imaging applied to Raynaud's phenomenon.

PMID- 12613215
TI  - Infrared imaging: making progress in fulfilling its medical promise.

PMID- 12613216
TI  - Quantifying the relevance and stage of disease with the Tau image technique.

PMID- 12613217
TI  - A corneal endothelium cell analyzer for slit lamps.

PMID- 12613218
TI  - Fourier-based reconstruction for CT: a parallel processing perspective.

PMID- 12613219
TI  - Improving stereotactic surgery using 3-D reconstruction.

PMID- 12613220
TI  - Pitfalls and paths to success in interdisciplinary scientific database research.

PMID- 12613221
TI  - Intention detection using a neuro-fuzzy EMG classifier.

PMID- 12613222
TI  - Modeling electric field transfer of excitation at cell junctions.

PMID- 12613223
TI  - Synthetic receptors prepared by organized assembly of organic molecules.

PMID- 12613224
TI  - The origin of electroshock therapy for treatment of psychiatric illnesses.

PMID- 12613225
TI  - Roles and requirements for a research microarray database.

PMID- 12613226
TI  - DNA-based molecular lithography for nanoscale fabrication.

PMID- 12613227
TI  - Limited smallpox vaccination to resume in United States.

PMID- 12613228
TI  - ALLHAT finds diuretics best for initial hypertension therapy.

PMID- 12613229
TI  - HHS hears pharmacy's perspective on regulatory reform.

PMID- 12613230
TI  - Statin fails to meet expectations.

PMID- 12613231
TI  - Involving new practitioners in your professional organization.

PMID- 12613232
TI  - Pharmacist-run influenza immunization clinic for health workers.

PMID- 12613233
TI  - Managing drug shortages: seven years' experience at one health system.
AB  - A health system's experience in monitoring drug shortages since 1996 within the
      organization and since 2001 on a national level is described. Since January 1996,
      the Drug Information Service (DIS) at the University of Utah Hospitals and
      Clinics (UUHSC) has systematically prepared written bulletins to affected
      practitioners when drug shortages occurred. The DIS began providing information
      on a national level to the American Society of Health-System Pharmacists in
      January 2001. A total of 224 drug shortages were tracked from January 1996 to
      June 2002. All shortages at UUHSC were also national shortages, but only about
      two thirds of national shortages also affected UUHSC. The most common reasons for
      shortages were manufacturing problems (28%) and product discontinuation (20%).
      The most frequently represented pharmacologic-therapeutic categories were central
      nervous system agents (24%) and serums, toxoids, and vaccines (17%). Of the 119
      shortages in 2001, 70 (59%) were still ongoing as of the end of June 2002. The
      most common potential safety problems were that clinicians might be unfamiliar
      with the alternative agent (54%) and that the alternative's dosage requirement
      was different (50%). Over half of the shortages were cost neutral, but the
      assessment did not include substantial potential indirect costs. Detailed
      information on drug shortages collected by a health system's drug information
      service since 1996 indicated a trend toward more frequent shortages.

PMID- 12613234
TI  - Evaluation of outpatient adverse drug reactions leading to hospitalization.
AB  - Outpatient adverse drug reaction (ADR)related hospitalization through the
      emergency department of a nonprofit hospital and the contributing factors are
      reviewed. Patients who were hospitalized because of suspected ADRs were selected
      from daily admissions reports and patient medication profiles from 1997 and 1998
      by the pharmacy department of a nonprofit community teaching hospital. Hospital
      charges for individual patients were obtained from the institution's accounting
      system. Suspected drugs, their therapeutic class, and the organ systems involved
      in the ADRs were identified. A total of 191 patients who had a complete medical
      history and cost information were included in the study. Of those patients, 56%
      were female, and 45% of the patients were 75 years of older. The average hospital
      charge per ADR patient was $9491. Room and board accounted for more than 50% of
      total charges. The average length of stay for study patients was 8.0 +/- 10.3
      days. Major therapeutic classes implicated in ADRs included antidiabetic agents
      (27.8%), anticoagulants (15.2%), anticonvulsants (10.0%), beta-blockers (7.9%),
      and angiotensin-converting-enzyme inhibitors (7.9%). Organ systems most commonly
      involved in ADR admissions were the endocrine (30.9%) and cardiovascular (24.1%)
      systems. The implicationed therapeutic groups and organ systems exhibited a
      different pattern from those of earlier ADR studies. The elderly and the poor are
      most affected by ADRs. The availability of new drugs and the shift in disease
      treatment necessitate the continuous monitoring of new ADRs. Patients and family
      members should be integral components of a multidisciplinary strategy for
      minimizing the personal and social impact of ADRs.

PMID- 12613235
TI  - Alteration of vancomycin pharmacokinetics during cardiopulmonary bypass in
      patients undergoing cardiac surgery.
AB  - The alteration of vancomycin pharmacokinetics during cardiopulmonary bypass (CPB)
      in patients undergoing cardiac surgery was studied. Eighteen patients were
      enrolled in the study. Vancomycin (1 g) was intravenously infused one to two
      hours before surgery. Blood samples were taken before, during, and after CPB.
      Serum drug concentrations were determined by an automated fluorescence
      polarization immunoassay and adjusted, with a bayesian analysis, to a bi
      compartmental model implemented in a pharmacokinetic system program. Serum
      creatinine, hematocrit, and plasma proteins were also measured before, during,
      and after CPB. During CPB, serum creatinine, hematocrit, and plasma protein
      values all decreased significantly (p < 0.05). Serum vancomycin concentration
      also diminished abruptly with CPB (7.04 micrograms/mL; 95% confidence interval,
      5.70-8.38 micrograms/mL) but increased moderately during the next 30 minutes,
      probably attributable to redistribution into plasma from tissue stores.
      Vancomycin's apparent volume of distribution showed an important increase during
      CPB (58.8%) (p < 0.0005), and its systemic clearance also increased significantly
      after CPB (19.7%) (p < 0.0005). The decrease in serum vancomycin concentration
      seems mediated by the hemodilution associated with the pump prime volume.
      Vancomycin's mean +/- S.D. nadir serum concentration before the next dose was
      7.13 +/- 2.1 micrograms/mL. In patients undergoing cardiac surgery and treated
      prophylactically with a 1-g preoperative i.v. dose of vancomycin, the onset of
      CPB was associated with a drop in serum vancomycin concentration.

PMID- 12613236
TI  - Medication noncompliance after kidney transplantation.

PMID- 12613237
TI  - Initiatives to control drug costs associated with an independent physician
      association.

PMID- 12613238
TI  - Warfarin-associated hypoprothrombinemia: an unusual presentation.

PMID- 12613239
TI  - What pharmacists need to know about the women's health initiative estrogen plus
      progestin trial.

PMID- 12613240
TI  - Raising pharmacists' cultural awareness.

PMID- 12613241
TI  - Community health system gains a research committee.

PMID- 12613242
TI  - Medications purchased in Mexico.

PMID- 12613243
TI  - Combined FISH and immunolabeling on paraffin-embedded tissue sections for the
      study of microchimerism.

PMID- 12613244
TI  - Shotgun library construction in a day.

PMID- 12613245
TI  - Normalization of a cDNA library cloned in lambda ZAP by a long PCR and cDNA
      reassociation procedure.

PMID- 12613246
TI  - High-throughput expression-PCR using universal plasmid-specific primers.

PMID- 12613247
TI  - Titration of non-occluded baculovirus using a cell viability assay.

PMID- 12613248
TI  - Extended stability of Taq DNA polymerase and T4 DNA ligase at various
      temperatures.

PMID- 12613249
TI  - Reverse slot blot for the verification of cDNAs identified through differential
      display.

PMID- 12613250
TI  - Culturing of avian embryos for time-lapse imaging.
AB  - Monitoring morphogenetic processes, at high resolution over time, has been a long
      standing goal of many developmental cell biologists. It is critical to image
      cells in their natural environment whenever possible; however, imaging many warm
      blooded vertebrates, especially mammals, is problematic. At early stages of
      development, birds are ideal for imaging, since the avian body plan is very
      similar to that of mammals. We have devised a culturing technique that allows for
      the acquisition of high-resolution differential interference contrast and
      epifluorescence images of developing avian embryos in a 4-D (3-D + time) system.
      The resulting information, from intact embryos, is derived from an area
      encompassing several millimeters, at micrometer resolution for up to 30 h.

PMID- 12613251
TI  - DNA shuffling method for generating estrogen receptor alpha and beta chimeras in
      yeast.
AB  - To facilitate our study of the molecular basis for the estrogen receptor (ER)
      subtype selectivity of novel ligands, we used DNA shuffling to construct chimeric
      ERs having ligand binding domains derived from both ER alpha and ER beta. The
      efficiency of chimera generation was low with traditional DNA shuffling
      protocols. Furthermore, ER ligand binding domain sequences lack convenient
      restriction sites for introducing chimeric ligand binding domain sequences into
      expression vectors. To overcome these problems, we developed a modified strategy
      whereby chimeric sequences were exclusively amplified from among the reassembled
      products from DNA shuffling using a special pair of PCR primers whose 3' ends
      specifically match the alpha and beta sequences, respectively, and whose 5' ends
      match sequences outside the ER beta ligand binding domain. When chimeric ligand
      binding domain DNA sequences, amplified with these primers, were co-transformed
      into a yeast strain with a linearized expression vector for ER beta, an active
      expression vector was produced by homologous recombination. Twenty-two different
      crossover sites were found; most occurred when there was a stretch of eight or
      more identical base pairs in both sequences, and many were concentrated in the
      regions important for studying ligand binding and transactivation. This method
      should prove to be useful for generating chimeric gene products from parent
      templates that share relatively low sequence identity.

PMID- 12613252
TI  - Lighting up cells with quantum dots.

PMID- 12613253
TI  - Subtracted restriction fingerprinting--a tool for bacterial genome typing.
AB  - Reproducible, discriminative, high-throughput methods are required for the
      identification of bacterial strains and isolates in a clinical environment. A new
      molecular typing method for bacteria was developed and tested on Salmonella and
      E. coli species. The technique is called subtracted restriction fingerprinting
      and is based on double restriction enzyme digestion of genomic DNA followed by
      end labeling. The "detection" enzyme produces TTAA overhangs that are filled in
      with digoxigenated nucleotides for subsequent detection, while the "subtraction"
      enzyme produces GCGC overhangs that are filled in with biotinylated nucleotides
      that permit the removal of this subset of fragments with either streptavidin
      coated magnetic particles or AffiniTip streptavidin columns. The two restriction
      enzymes are selected to produce a fragment size profile suitable for a specific
      analytical system. In this demonstration of the principle of subtracted
      restriction fingerprinting, analysis of Salmonella enterica subsp. enterica
      serovar Dublin and E. coli on a 30-cm 1.2% agarose gel revealed up to 50 sharp
      evenly spaced bands, which were sufficient for the discrimination between various
      isolates and substrains. The restriction enzyme combinations suitable for the
      analysis of Salmonella and E. coli are presented. The method requires fewer
      enzymatic steps than amplified fragment length polymorphism, does not need the
      specialized DNA preparation essential for pulsed field gel electrophoresis, and
      has a higher reproducibility than PCR-based methods.

PMID- 12613254
TI  - Development, characterization, and validation of a sensitive primate-specific
      quantification assay for forensic analysis.
AB  - Accurate human-specific DNA quantification is essential for forensic casework
      analysis. In this work, we describe a microplate-based quantification assay that
      utilizes the PCR amplification of human-specific TH01 primers. This method
      enables the reliable quantification of human DNA samples from 0.2 to 40 ng, even
      in mixtures with nonhuman DNA. Analysis of samples can be semi-automated using 96
      well microplates and a spreadsheet-based concentration calculator for high
      throughput demands. We have used this quantification method with more than 15,000
      forensic samples.

PMID- 12613255
TI  - SoFAR: software for fully automatic evaluation of real-time PCR data.
AB  - Quantitative real-time PCR has proven to be an extremely useful technique in life
      sciences for many applications. Although a lot of attention has been paid to the
      optimization of the assay conditions, the analysis of the data acquired is often
      done with software tools that do not make optimum use of the information provided
      by the data. Particularly, this is the case for high-throughput analysis, which
      requires a careful characterization and interpretation of the complete data by
      suitable software. Here we present a software solution for the robust, reliable,
      accurate, and fast evaluation of real-time PCR data, called SoFAR. The software
      automatically evaluates the data acquired with the LightCycler system. It applies
      new algorithms for an adaptive background correction of signal trends, the
      calculation of the effective signal noise, the automated identification of the
      exponential phases, the adaptive smoothing of the raw data, and the correction of
      melting curve data. Finally, it provides information regarding the validity of
      the results obtained. The SoFAR software minimizes the time required for
      evaluation and increases the accuracy and reliability of the results. The
      software is available upon request.

PMID- 12613256
TI  - Maximizing production of estrogen receptor beta with the baculovirus expression
      system.
AB  - Steroid hormone/nuclear receptor expression in cultured insect cell lines is
      routinely driven by a baculovirus vector. An advantage of the baculovirus
      production of these receptors is that large amounts of functional receptors are
      obtained for subsequent in vitro studies. Most laboratories produce nuclear
      receptors in Spodoptera frugiperda (Sf)9 cells. However, no one has determined
      whether this cell line is optimal for the production of any nuclear receptor. We
      compared the time course and level of estrogen receptor beta (ER beta) production
      from a baculovirus in two S. frugiperda cell lines, IPLB-SF21AE (Sf21) and Sf9,
      and two Trichloplusia ni cell lines, Tn368 and BTI-TN5b1-4 (High Five). Cells
      were harvested at various times (0.5-5 days) after infection. ER beta expression
      and activity was determined by specific [3H]estradiol (E2) binding, Western blot
      analysis, and estrogen response element (ERE) binding in vitro. The highest
      functional, bioactive ER beta expression both at the earliest time after
      infection and in the amount of ER beta produced/cell was with the Sf21 cell line.
      Baculovirus expressed ER beta-bound EREs with high affinity in a DNA sequence
      dependent manner. We conclude that Sf21 cells are the best-suited cells for ER
      beta production.

PMID- 12613257
TI  - Characterization of lacZ complementation deletions using membrane receptor
      dimerization.
AB  - We describe the screening of lacZ deletions in mammalian cells and the discovery
      of a novel pair of lacZ deletions that can undergo alpha-complementation only
      when they are fused to peptides that interact with each other. The two lacZ
      deletions, delta N 11-75 and delta C 82-1023, were first characterized by fusing
      to two small interacting peptides and were then further analyzed by fusing to
      three membrane receptors (G protein-coupled receptors alpha 2cAR and D2DRL and
      receptor tyrosine kinase insulin receptor) that were known to form homodimers in
      the membrane. Histochemical and quantitative FACS assays demonstrated that the
      novel deletions have much lower level of association with each other, thus
      offering a much lower background in monitoring membrane protein interactions
      compared to previously published lacZ deletions. Furthermore, our method has the
      exciting potential to monitor simultaneously membrane receptor dimerization and
      localization to the cell surface of living cells.

PMID- 12613258
TI  - DHPLC-based method for DNA methylation analysis of differential methylated
      regions from imprinted genes.
AB  - The bisulfite genomic sequencing method is one of the most widely used techniques
      for methylation analysis in heterogeneous unbiased PCR, amplifying for both
      methylated and unmethylated alleles simultaneously. However, it requires labor
      intensive and time-consuming cloning and sequencing steps. In the current study,
      we used a denaturing high-performance liquid chromatography (DHPLC) procedure in
      a complementary way with the bisulfite genomic sequencing to analyze the
      methylation of differentially methylated regions (DMRs) of imprinted genes. We
      showed reliable and reproducible results in distinguishing overall methylation
      profiles of DMRs regions of human SNRPN, H19, MEST/PEG1, LIT1, IGF2, TSSC5, WT1
      antisense, and mouse H19, Mest/Peg1, Igf2R imprinted genes. These DHPLC profiles
      were in accordance with bisulfite genomic sequencing data and may serve as a type
      of "fingerprint," revealing the overall methylation status of DMRs associated
      with sample heterogeneity. We conclude that DHPLC analysis could be used to
      increase the throughput efficiency of methylation pattern analysis of imprinted
      genes after the bisulfite conversion of genomic DNA and unbiased PCR
      amplification.

PMID- 12613259
TI  - TM4: a free, open-source system for microarray data management and analysis.

PMID- 12613260
TI  - Method for printing functional protein microarrays.
AB  - Piezoelectric dispensing of proteins from borosilicate glass capillaries is a
      popular method of protein biochip fabrication that offers the advantages of
      sample recovery and noncontact with the printing substrate. However, little
      regard has been given to the quantitative aspects of dispensing minute volumes (1
      nL or less) at the low protein concentrations (20 micrograms/mL or less)
      typically used in microprinting. Specifically, loss of protein sample due to
      nonspecific adsorption to the glass surface of the dispensing capillaries can
      limit the amount of protein delivered to the substrate. We demonstrate the
      benefits of a low ionic strength buffer containing the carrier protein BSA that
      effectively minimizes the ionic strength-dependent phenomenon of nonspecific
      protein adsorption to borosilicate glass. Over the concentration range of 20-2.5
      micrograms/mL, the dispensing of a reference IgG in 10 mM PBS including 0.1% BSA
      resulted in the deposition of 3.6- to 44-fold more IgG compared to the deposition
      of IgG in standard 150 mM PBS in the absence of BSA. Furthermore, when the IgG
      was dispensed with carrier protein, the resulting spots exhibited a more uniform
      morphology. In a direct immunoassay for cholera toxin, capture antibody spots
      dispensed in 10 mM PBS containing 0.1% BSA produced fluorescent signals that were
      2.8- to 4.3-fold more intense than antibody spots that were dispensed in 150 mM
      PBS without BSA. Interestingly, no differences were observed in the specific
      activities of the capture antibodies as a result of printing in the different
      buffers. The implications of these results on the future development of protein
      biochips are discussed.

PMID- 12613261
TI  - Probe generation directly from small numbers of cells for DNA microarray studies.
AB  - Recently, we described a technique that allows us to prepare probes for
      expression profiling from 0.5-1 microgram RNA without template or signal
      amplification. However, we were unable to use this method to study cells
      harvested by needle biopsy, cell sorting, or laser capture microdissection. Here
      we give a new protocol for amplifying RNA with multiple reaction cycles and
      preparing fluorescent probes from approximately 10 cells. We use random 9-mers
      with a T3 RNA polymerase recognition sequence on the 5' end for every round of
      cDNA synthesis except the first. The latter is primed with oligo(dT) with a T7
      RNA polymerase recognition sequence on the 5' end. Results were highly
      reproducible and reliable, and the products generated using our method seemed
      comparable to those produced using the RiboAmp RNA kit when both were used to do
      two cycles of amplification. To test our method's utility, we lysed cells
      directly into reverse transcription buffer containing RNase inhibitor and
      performed three rounds of RNA amplification. The expression profiles of mouse C2
      and NIH 3T3 cells obtained with 11,232-element arrays using amplified RNAs were
      similar to those seen when probes were prepared from unamplified templates.

PMID- 12613262
TI  - RNA amplification strategies for cDNA microarray experiments.
AB  - The biological materials available for cDNA microarray studies are often
      limiting. Thus, protocols have been developed to amplify RNAs isolated from
      limited amounts of tissues or cells. RNA amplification by in vitro transcription
      is the most widely used among the available amplification protocols. Two means of
      generating a dsDNA template for the RNA polymerase are a combination of reverse
      transcription with conventional second-strand cDNA synthesis and a combination of
      the switch mechanism at the 5' end of RNA templates (SMART) with reverse
      transcription, followed by PCR. To date, there has been no systematic comparison
      of the efficiency of the two amplification strategies. In this study, we
      performed and analyzed a set of six microarray experiments involving the use of a
      "regular" (unamplified) microarray experimental protocol and two different RNA
      amplification protocols. Based on their ability to identify differentially
      expressed genes and assuming that the results from the regular protocol are
      correct, our analyses demonstrated that both amplification protocols achieved
      reproducible and reliable results. From the same amount of starting material, our
      results also indicated that more amplified RNA can be obtained using conventional
      second-strand cDNA synthesis than from the combination of SMART and PCR. When the
      critical issue is the amount of starting RNA, we recommend the conventional
      second-strand cDNA synthesis as the preferred amplification method.

PMID- 12613263
TI  - Automated high-throughput probe production for DNA microarray analysis.
AB  - DNA microarrays have become an established tool for gene expression profiling.
      Construction of these microarrays using immobilized cDNAs is a common
      experimental strategy. However, this is extremely laborious, requiring the
      preparation of hundreds or thousands of cDNA probes. To minimize this initial
      bottleneck, we developed a comprehensive high-throughput robotic system to
      prepare DNA probes suitable for microarray analysis with minimal user
      intervention. We describe an automated system using the MultiPROBE Nucleic Acid
      Purification Workstation to provide the liquid handling and other functions
      needed to optimize this process. We were able to carry out fully automated
      plasmid cDNA isolation, PCR assay setup, and PCR purification and also to direct
      the characterization and tracking of DNA probes during processing. Protocols
      began with the initial preparation of a plasmid DNA archive of bacterial stocks
      in parallel 96-well plates (192 samples/run) and continued through to the
      dilution and reformatting of chip-ready DNA probes in 384-well format. These and
      other probe production procedures and additional instrument systems were used to
      process fully a set of mouse cDNA clones that were then validated by differential
      gene expression analysis.

PMID- 12613264
TI  - Cutaneous wound analysis using hyperspectral imaging.
AB  - A correlative bright-field and hyperspectral analysis of full-thickness,
      cutaneous wounds in a porcine model was undertaken to investigate the efficacy of
      hyperspectral imaging as an alternate method for wound identification. Analysis
      of a randomly selected specimen yielded distinct spectral signatures for
      cutaneous regions of interest including the epidermis, injured dermis, and normal
      dermis. The scanning of the entire specimen group using these hyperspectral
      signatures revealed an exclusionary, pseudo-color pattern whereby a central wound
      region was consistently defined by a unique spectral signature. An algorithm was
      derived as an objective tool for the comparison of the wound regions defined by
      the hyperspectral classification versus the pathologists' manual tracings. The
      dimensions of the wound identified in the hyperspectral assay did not differ
      significantly from the wound region identified by the pathologists using standard
      bright-field microscopy. These data indicate that hyperspectral analysis may
      provide a high-throughput alternative for wound estimation that approximates
      standard bright-field imaging and pathologist evaluation.

PMID- 12613265
TI  - [Obesity in children and adolescents in Germany. Significant and persistent
      increase of prevalence. Appeal to treatment].
AB  - In Germany, the number of overweight children and adolescents is increasing. The
      increase in the prevalence of obesity shows considerable regional differences.
      Related to recent German reference data with an expected prevalence of 3%, we
      find today in some regions a prevalence of 7% in 5- to 6-year-olds and 8% in 13-
      to 15-year-olds. While the reasons for this development are not fully clear, it
      may be assumed that the increase in physical inactivity, together with the ready
      availability of an abundance of high-energy foods are significant contributing
      factors. A large percentage of children and adolescents suffering from obesity
      also have considerable co-morbidity. It is to be expected that this will in the
      future considerably increase the financial burden on public health care and
      society as a whole. Effective prevention and therapeutic countermeasures are
      necessary to deal with this problem.

PMID- 12613266
TI  - [Ethical principles of clinical trials in minors].
AB  - Clinical trials in volunteers and patients are essential to ensure rational
      treatment of patients. As a rule, drugs are routinely developed for adults, but
      children are excluded. A major reason for this restriction are ethical
      justifications, in particular the lack of autonomy on the part of children. The
      principle of fairness, however, requires that everyone should benefit from
      progress. Industry, science and society are therefore called upon to find ways of
      making available safe and adequate treatment for children as quickly as possible,
      by defining the required conditions for pediatric clinical trials. Important
      principles are minimal risk, minimal invasivity, rapid decision-making, and
      careful documentation of trial results. Dynamic ethical principles, such as
      autonomy and competence in adolescents must be considered on equal footing with
      existing international GCP guidelines. Aspects of child psychology indicate that
      the autonomy of adolescents should be respected. Where economic incentives for
      such trials are absent, for example, in the case of non-pharmacological problems,
      pediatric trials must be considered a task for society as a whole.

PMID- 12613267
TI  - [Tick-borne encephalitis and Lyme borreliosis. Spread of pathogens and risk of
      illness in a tick-borne encephalitis region].
AB  - A knowledge of the distribution of tick-borne agents and the related risks of
      contracting diseases are essential to ensure an appropriate response between
      hysteria and disregard, and to decide the appropriateness of vaccination.
      Illustrated by the German town of Lohr a. M. (Bavaria), the prevalence of TBE
      virus and Borrelia burgdorferi in ticks was investigated and compared, and the
      respective risk of contracting disease from a bite assessed. Using the polymerase
      chain reaction (PCR), a total of 1657 ticks obtained from five different biotopes
      around Lohr were examined for the TBE-virus, and 408 ticks for Borrelia
      burgdorferi. The results were compared with earlier findings in other regions of
      Germany. The risk of contracting illness was estimated on the basis of
      transmission and manifestation rates, together with epidemiological data from the
      region. The prevalence of TBE-virus was 0.12% (95% CI: 0.05-0.44%) in the ticks
      investigated. This is comparable with that in 4 other regions rated as TBE-risk
      regions, but significantly lower than that in rated high-risk regions. Borrelia
      burgdorferi was detected in 14.9% (11.8-19.0%) of adult ticks, roughly twice the
      prevalence found in nymphs (7.2%, range 4.6-11.7%). On the basis of these
      prevalences, the risk of contracting meningitis/encephalitis from a tick bite is
      about 1:10,000, and the risk for Lyme Borreliosis is about 1:100, the latter
      requiring that the tick remains attached for at least 2-3 days.

PMID- 12613268
TI  - [Immunomodulation by herbal agents. A double-blind study in a medical university
      hospital involving a hepatitis B vaccine adjuvant model].
AB  - AIMS: Using the hepatitis B vaccination as a model, to investigate the extent to
      which the herbal immunomodulator, Esberitox N, supports seroconversion. METHOD:
      346 medical students participated in the placebo-controlled, randomized double
      blind study. They took 3 x 2 tablets of the test substances daily, beginning 3
      days prior to the injection and ending two weeks after it. The target outcomes
      were seroconversion and the level of the anti-HBs titer. RESULTS: The data of 157
      volunteers treated with the test substance, and 161 treated with placebo were
      analysed. After the first injection, the seroconversion rate was 22% in both test
      substance and placebo groups, and showed no advantage for the volunteers
      receiving the test substance. After the second injection, 89% of all members of
      each group revealed seroconversion. After the first injection, anti-HBs titers
      were appreciably higher in the test substance group (n = 34) than in the placebo
      group (n = 36; PWilcoxon = 0.003). The respective median values were 37.0 IU/L
      (95% CI: 18-68) and 15.5 IU/L (95% CI: 8-30). CONCLUSION: The immunomodulator
      tested has negligible influence on seroconversion, but does enhance the immune
      response of subjects experiencing seroconversion.

PMID- 12613269
TI  - [Evidence-based guidelines as tools for medical knowledge transfer. The work mode
      of the Medical Knowledge Network evidence.de].
AB  - The amount of medical knowledge is growing with increasing speed. Physicians are
      confronted with more and more--and often useless--information. However, the time
      lag between the creation of new knowledge and its implementation into daily
      medical practice is often exceeding a decade. In view of these challenges the
      knowledge network of the medical faculty of the University Witten/Herdecke is
      focusing on two different tasks: It provides evidence based medical guidelines in
      a format that is meant for easy access and use in daily practice. It
      scientifically explores different ways of presenting and transferring evidence
      based guidelines in order to develop better and easier ways of implementation.
      National and international guidelines and studies are screened, evaluated,
      updated and adapted for its use in the academic network by a team of five
      university based physicians. In addition, clinical specialists as well as primary
      care physicians provide expertise for detailed scientific adaptations and for
      adequate implementation strategies. The implementation process of the guidelines
      among the faculty based primary care physicians is continuously monitored and
      evaluated. The main goal of this concept is to create a learning environment for
      the complex process of medical knowledge transfer.

PMID- 12613270
TI  - [Treatment of neuropathic pain syndrome. Results of an open study on the efficacy
      of a pyrimidine nucleotide preparation].
AB  - BACKGROUND AND METHOD: In a study carried out in the years 2000 and 2002, 40
      patients with diabetic polyneuropathy were treated with a daily dose of 2 x 2
      capsules of the pyrimidine nucleotide preparation, Keltican N for a period of
      three months. The structured neurological findings in accordance with the
      Neuropathy Disability Score (NDS), the conduction velocity of the peroneal and
      sural nerves, and pain sensation on the basis of a visual analog scale. RESULTS:
      All parameters showed a trend towards improvement. The difference in the sensory
      conduction velocity of the sural nerve and in the subjective pain score was
      significant.

PMID- 12613271
TI  - [Early diagnosis and treatment of Alzheimer's disease. Implementation in the
      doctor's office].
AB  - The efficacy of antidemential agents proven in comprehensive studies and by
      clinical experience, now justifies an active and positive approach by the general
      physician to the diagnosis and treatment of patients with dementia. The proposals
      on how to implement diagnostic and therapeutic measures in the doctor's office
      comply both with medical quality criteria and the requirements for
      appropriateness of treatment and considerations of economy stipulated by German
      law. They therefore provide the basis for a modern diagnostic work-up and
      treatment strategy, which will also meet economical demands.

PMID- 12613272
TI  - [Percutaneous endoscopic gastrostomy (PEG). Course, nutrition and care in 233
      consecutive patients].
AB  - AIM: To evaluate the course, nutrition and care of PEG tubes on the basis of data
      collected from 233 consecutive patients. PATIENTS AND METHOD: Between 1.1.1990
      and 31.3.1996, a total of 243 PEG tubes were implanted in 233 patients--56.5%
      male and 43.5% female--with an average age of 66.2 years. 57.3% had neurological,
      and 19.4% neurosurgical, diseases, 11.2% suffered polytraumatization or severe
      burns, and 8.2% had a malignancy. Patients stayed with the implanted tube on
      average 153 days, with neurological patients leading the field at 189 days.
      RESULTS: The overall complication rate was 14.5%, with the most common
      complication being local infection, which occurred in 5.4% of the cases. Severe
      complications were seen in 1.2%. One patient developed a necrotizing fasciltis,
      and in two others, migration of the tube was observed. 52.2% of the patients died
      with the tube still in place. In 33.6%, the PEG tube was removed after a mean of
      82.7 days, when adequate oral nutrition again became possible. CONCLUSION: In
      this study, PEG proved an effective method for enteral nutrition over the middle
      to-long-term in multimorbid and intensive care patients, as well as in those with
      malignant disease.

PMID- 12613273
TI  - [Influence of ACE inhibitor spirapril on left ventricular hypertrophy].
AB  - BACKGROUND: In view of the prevalence of left ventricular hypertrophy (LVH) in
      patients with essential hypertension, (15-30%), with an increased risk (2-4 x) of
      developing myocardial infarction, heart failure or malignant arrhythmia, possibly
      even leading to sudden cardiac death, effective reversal of LVH is a major aim of
      treatment. For this purpose, angiotensin-converting enzyme (ACE) inhibitors have
      proved to be most suitable. METHOD: In an open bicentric study involving 37
      hypertensive patients with LVH confirmed by echocardiography, the effect of
      spirapril in reversing the left ventricular mass index (LVMI) and diastolic left
      ventricular wall thickness was investigated after 3 and 6 months. RESULTS: The
      LVMI decreased by 14.7% after 3, and by 27.3% after 6 months, irrespective of
      whether spirapril was given alone or in addition to other antihypertensive pre
      medication. The results may be due to the proven 24-hour effect of spirapril in
      conjunction with the very long half-life.

PMID- 12613274
TI  - Web alert. The chemistry of metabolic and toxicological processes.

PMID- 12613275
TI  - Genomic biomarkers of toxicity.
AB  - The difference between measuring changes in gene expression levels in a
      toxicogenomics study and actually achieving reduced drug development costs is in
      the knowledge of which gene expression changes are predictive of toxicity.
      Whether the cost savings are in high-throughput screening, in discovery or in
      preclinical, testing, the application of genomics, proteomics or metabonomics
      will require a clear understanding of what these methods actually measure.
      Results of studies published over the past year have set valuable benchmarks for
      genomic studies, transforming this technology into a source of candidates for
      validation as predictive biomarkers of toxicity. This review will summarize some
      of the publications that have achieved this transformation, and the steps that
      are still needed for the implementation of predictive tests derived from these
      genomic biomarkers of toxicity.

PMID- 12613276
TI  - Evaluation of the toxicological relevance of CYP3A4 induction.
AB  - CYP3A4 is the most abundant cytochrome P450 in human liver, comprising
      approximately 30% of the total liver P450 content. This enzyme has an important
      role in endogenous processes, most notably steroid catabolism, and also plays a
      fundamental role in the metabolism of more than half of the clinically used drugs
      currently prescribed. The majority of CYP3A substrates are also capable of
      upregulating CYP3A activity, mainly through transcriptional activation. The
      molecular mechanisms that underlie the transcriptional activation of CYP3A4 are
      complex, with many steroid hormone nuclear receptors, including GR, PXR, VDR and
      CAR, playing a role in these mechanisms. However, the net result of
      transcriptional activation is an increase in the metabolism of the inducing
      compounds and, therefore, increased clearance. An important side effect of this
      transcriptional activation is that co-administered chemicals metabolized by CYP3A
      may also have their pharmacokinetics altered. Such changes can result in reduced
      clinical efficacy of drugs, resulting in poor patient response, or the
      development of an adverse drug response. This review will examine examples of
      established interactions caused through transcriptional activation of CYP3A4, and
      speculate on whether such effects are clinically important and should be
      considered during the design of treatment regimes or, alternatively, are
      relatively minor and cause little physiological effects.

PMID- 12613277
TI  - Metabolite identification in drug discovery.
AB  - Recent developments in the technologies and approaches to identify metabolites in
      a drug discovery environment are reviewed. Samples may be generated using either
      in vitro systems--typically, but not exclusively, liver subcellular fractions,
      such as microsomes, or whole cells, such as hepatocytes. Alternatively,
      metabolites are generated in vivo using excreta obtained following dosing in
      preclinical species. Recombinant drug metabolizing enzymes or microorganisms may
      offer alternate vectors. New techniques, such as the use of solid-phase
      microextraction, have found application in the isolation of metabolites from
      biological matrices. However, this is still dominated by the use of preparative
      chromatography, which has advanced through the use of mass-directed detection.
      Detection and structural elucidation by mass spectrometry have improved markedly
      with increases in sensitivity, allowing lower abundance metabolites to be
      detected, and increases in selectivity, with the use of high-resolution time-of
      flight and quadrupole-time-of-flight instruments. Finally, higher field strength
      magnets coupled with novel probe designs and increased use of liquid
      chromatographic hyphenation techniques continue to drive the capabilities of
      nuclear magnetic resonance spectroscopy as the definitive structural elucidation
      tool.

PMID- 12613278
TI  - Drug metabolism and pharmacokinetics in drug discovery.
AB  - The discovery and development of new drugs seems to be an inefficient process,
      since too few new chemical entities (NCEs) successfully make it to the market.
      Because one of the main reasons for failure in development is thought to be poor
      pharmacokinetics (PK), drug metabolism and PK (DMPK) have assumed a central role
      within the field of drug discovery. A good development candidate requires a
      balance of potency, safety and PK; therefore, techniques that can help understand
      these characteristics are employed to enable researchers to design more robust
      candidates. A number of new in silico, in vitro and in vivo techniques are
      available to screen compounds for key absorption, distribution, metabolism and
      excretion (ADME) characteristics, which, when applied within a rational strategy,
      can make a major contribution to the design and selection of successful NCEs.

PMID- 12613279
TI  - Disease-related determinants of susceptibility to drug-induced idiosyncratic
      hepatotoxicity.
AB  - Idiosyncratic adverse drug reactions, including unpredictable hepatotoxicity,
      remain a serious challenge in drug development. Besides patient-specific
      susceptibility factors (genetic and/or acquired), determinants of the underlying
      disease may also predispose the patient to a drug's potential toxicity. Examples
      include viral infections, inflammatory conditions, neurodegenerative diseases and
      type II diabetes. This review focuses on diseases (therapeutic indications) often
      associated with mitochondrial abnormalities, and which are treated with drugs
      mechanistically linked to potential mitochondrial toxicity, thus superimposing
      these mitochondrial events. The need for an increased use of animal models of
      human disease in mechanistic investigations and drug candidate selection will
      also be emphasized.

PMID- 12613280
TI  - New insights into the pharmacological and toxicological effects of thalidomide.
AB  - The molecular activity of thalidomide comprises a wide range of mechanisms.
      Alteration of cytokine synthesis and release may be as important as changes in
      lymphocyte trafficking and leukocyte migration. Since endothelial cells play an
      important role in leukocyte extravasation and maintenance of inflammatory
      processes in the affected tissue, thalidomide-induced alterations of cellular
      adhesion molecules, and consequently changes of interaction of leukocytes with
      the endothelial cell layer, will result in modulation of the response in
      inflammation and immunity. Thalidomide mainly reduces tumor necrosis factor (TNF)
      alpha production by macrophages, and its TNF alpha antagonist properties explain
      the beneficial effects in several TNF alpha-associated complications of severe
      diseases. Pathophysiologically relevant alterations most likely include gene
      regulatory effects, with interference in growth factor-dependent pathways known
      to be involved in teratogenesis, and effects on the transcriptional control of
      the inflammatory response via nuclear factor (NF)-kappa B. The effects of
      thalidomide, its enantiomers and analogs, on a broad range of diseases, and their
      differential pharmacokinetic and pharmacodynamic properties, give the scope for
      ongoing investigations in the search for analogs with better selectivity but
      without thalidomide-related side effects and teratogenicity.

PMID- 12613281
TI  - In vitro hematotoxicity testing in drug development: a review of past, present
      and future applications.
AB  - Conventional hematotoxicity testing usually begins at the preclinical studies
      stage, and is valuable for monitoring the clinical status of subjects in clinical
      trials. However, as it is based on mature blood elements and related parameters,
      and not the cells producing these elements, it is not predictive. All
      proliferating cell systems, including lympho-hematopoiesis, exhibit a similar
      organizational structure that includes stem cells and their immediate progeny,
      the progenitor cells. These populations are the dose-limiting target populations
      for most drugs, especially anticancer drugs, as well as other compounds. In vitro
      assays detecting stem and progenitor cell populations are highly predictive, and
      new high-throughout colony-forming assays using human hematopoietic tissue allow
      hematotoxicity testing to be performed throughout drug development.
      Chronotoxicology and chronotherapeutics constitute a special application, and can
      predict the best time of the day to administer anticancer drugs.

PMID- 12613282
TI  - New understanding in cardiotoxicity.
AB  - Interest in cardiotoxicity has dramatically increased during the past two years,
      leading to exciting progress in our understanding of the field. Both clinical and
      experimental animal studies have emphasized the role of cardiotoxicity in
      myocardial pathogenesis. Exploration of the cardiotoxicity of air pollution and
      highly active antiretroviral therapy (HAART) through experimental animal studies
      have led to mechanistic insights. Novel therapeutic approaches are also under
      development. Continued efforts to investigate the mechanisms of cardiotoxicity
      induced by well-known drugs and chemicals, such as Adriamycin, have also
      generated critical insights into cardiac response to toxicants. Recognition of
      the significance of cardiotoxicity in myocardial pathogenesis has resulted in the
      identification of many other drugs or chemicals, such as arsenic trioxide, whose
      cardiotoxicity is of major concern in clinical applications. Mitochondrial
      cardiomyopathy, along with control of myocardial cell death, has also become an
      extensively studied subject. Ionic transport across the inner membrane of
      mitochondria, especially the function of mitochondrial ATP-sensitive K+ channels
      and the Ca(2+)-activated K+ channels in myocardial protection against oxidative
      injury, has attracted a great deal of attention. Novel approaches, such as
      functional genomics, proteomics and metabonomics, should significantly improve
      our understanding of cardiotoxicity.

PMID- 12613283
TI  - Informatics and multivariate analysis of toxicogenomics data.
AB  - The application of genomics methods to toxicology holds great promise.
      Toxicogenomics data mapping gene expression to predict toxicity and understand
      mechanisms are emerging, with data suggesting the possibility to classify, and
      eventually predict, toxic responses. The overall process of informatics analysis
      of microarray data is summarized. The relationship between the bioinformatics of
      gene expression and toxicogenomics is discussed, with reference to emerging
      themes that may be important as the field of toxicogenomics evolves. Emerging
      themes include the choice and validation of statistical methods, the use of gene
      annotation and the impact of genome sequence projects.

PMID- 12613284
TI  - Role of predictive metabolism and toxicity modeling in drug discovery--a summary
      of some recent advancements.
AB  - In this article, we discuss recent advances and selected publications in the area
      of computer-based (in silico) metabolism and toxicity prediction, and comment on
      the opportunities for prediction of metabolism-based toxicity. The article also
      discusses the growing interest and importance of in silico prediction of
      metabolism and toxicity as tools to assist in library design and lead
      optimization. In addition, we consider the status of commercial metabolism and
      toxicity databases, and the need for future improvement, since data is often from
      older studies and from structures not typically considered as 'drug-like'. The
      article highlights the current status and potential of in silico models for
      property prediction, and the potential for linkage with vivo models to improve
      the integration of metabolism and toxicity into the drug discovery process and
      extrapolation to clinical studies. The article underscores that the future
      development, integration and application of in silico models will require a
      balance of local and global model approaches. The article also indicates that
      implementation and integration of models into drug discovery processes needs to
      be carried out in a rational and systematic manner, if we are to fully capitalize
      on the opportunity presented by in silico predictive modeling.

PMID- 12613285
TI  - Communicating a diagnosis of cystic fibrosis to an adult: what physicians need to
      know.
AB  - Ten percent of cystic fibrosis (CF) diagnoses are confirmed in adults. No disease
      specific research is available to guide nonpediatricians in communicating these
      diagnoses or to determine whether prevalent bad-news guidelines apply. In this
      phenomenological study, the author asked 36 individuals to describe their adult
      diagnosis experiences, reactions, and preferences. Data analysis revealed that
      most respondents were satisfied with their diagnosis interviews. Participants
      described different physician styles in delivering the diagnosis and a range of
      reactions on learning that they had CF. They urged that physicians appreciate the
      impact of a CF diagnosis on adults, assess the personal characteristics that
      could affect individuals' responses, and develop relevant patient-education
      techniques. Interactions of disease characteristics with individuals' personal
      situations appeared to be more important than physicians' approaches in
      determining how participants experienced and responded to the diagnosis. That no
      typical interview emerged rendered a one-fits-all guideline unrealistic for
      communicating CF diagnoses to adults.

PMID- 12613286
TI  - Psychological distress among minority and low-income women living with HIV.
AB  - The growing incidence of HIV infection among low-income and minority women makes
      it important to investigate how these women adjust to living with HIV and AIDS.
      Psychological distress associated with HIV infection may compound the adjustment
      difficulties and increase the barriers to care associated with living in poverty.
      The authors surveyed 100 women who were receiving HIV care at a public hospital
      in the southeastern United States on measures of depression, anxiety, life
      stress, social support, and coping; they also assessed demographic and medical
      characteristics of the sample. Participants' annual incomes were low (87% <
      $10,000), and most participants were minorities (84% African American). Their
      levels of depression, stress, and anxiety symptoms were elevated relative to
      community norms. Greater anxiety and depression symptoms were associated with
      women who reported higher stress, using fewer active coping strategies, and
      perceiving less social support (ps < .001).

PMID- 12613287
TI  - Childhood posttraumatic stress disorder and efforts to cope after Hurricane
      Floyd.
AB  - The authors report on the level of posttraumatic stress disorder (PTSD)
      experienced by fourth-grade children 6 months after Hurricane Floyd and describe
      the children's efforts to cope with their stress. All of the children they
      studied were directly affected by the hurricane, secondary to the destruction of
      their school by floodwaters. The homes of 37% of these children were also
      flooded. Ninety-five percent of the children experienced at least mild symptoms
      of PTSD, and 71% had symptoms that were moderate to very severe. Children who
      reported that their homes were flooded were 3 times more likely to report
      symptoms than those whose homes were not flooded, and the girls were twice as
      likely as the boys to report symptoms. The high PTSD prevalence rates are
      comparable to findings from other studies involving violence in which 94% of the
      victims reported experiencing symptoms. For further analyses, the authors used
      symptom clusters of hyperarousal, numbing/avoidance, and reexperiencing symptoms.

PMID- 12613288
TI  - Behavioral medicine in Hungary: past, present, and future.
AB  - During the socialist period before 1989, training in behavioral medicine and
      behavioral science was not a priority in Hungary's medical schools despite the
      nation's long tradition of psychosomatic and behavioral medicine. In this
      article, the authors review the development of behavioral medicine and behavioral
      science in Hungarian medical schools and outline some of the problems and future
      challenges these departments face. The resistance of faculty members has
      influenced the acceptance of behavioral medicine and behavioral science courses,
      attitudes toward the acceptance of departments of behavioral science, and
      evaluations of the staff's scientific research. Although research is emphasized
      in these departments of behavioral medicine, closer integration of teaching,
      research, and health policy is necessary. The primary message of this approach is
      that modern physicians should see beyond molecular substances and perceive humans
      from a total biopsychosocial perspective.

PMID- 12613289
TI  - How to navigate your way through the JCAHO process.

PMID- 12613290
TI  - Getting the inside word on surveyors: does it help?

PMID- 12613291
TI  - Integrated software system for improving medical equipment management.
AB  - The evolution of biomedical technology has led to an extraordinary use of medical
      devices in health care delivery. During the last decade, clinical engineering
      departments (CEDs) turned toward computerization and application of specific
      software systems for medical equipment management in order to improve their
      services and monitor outcomes. Recently, much emphasis has been given to patient
      safety. Through its Medical Device Directives, the European Union has required
      all member nations to use a vigilance system to prevent the reoccurrence of
      adverse events that could lead to injuries or death of patients or personnel as a
      result of equipment malfunction or improper use. The World Health Organization
      also has made this issue a high priority and has prepared a number of actions and
      recommendations. In the present workplace, a new integrated, Windows-oriented
      system is proposed, addressing all tasks of CEDs but also offering a global
      approach to their management needs, including vigilance. The system architecture
      is based on a star model, consisting of a central core module and peripheral
      units. Its development has been based on the integration of 3 software modules,
      each one addressing specific predefined tasks. The main features of this system
      include equipment acquisition and replacement management, inventory archiving and
      monitoring, follow up on scheduled maintenance, corrective maintenance, user
      training, data analysis, and reports. It also incorporates vigilance monitoring
      and information exchange for adverse events, together with a specific application
      for quality-control procedures. The system offers clinical engineers the ability
      to monitor and evaluate the quality and cost-effectiveness of the service
      provided by means of quality and cost indicators. Particular emphasis has been
      placed on the use of harmonized standards with regard to medical device
      nomenclature and classification. The system's practical applications have been
      demonstrated through a pilot evaluation trial.

PMID- 12613292
TI  - Vibrotactile stimulation system to treat apnea of prematurity.
AB  - We modified a system that uses vibrotactile stimulation (VTS) to treat apnea (a
      cessation of respiration) in neonates in order to make the system more portable
      and easier to use by clinicians and nurses. The biomedical engineering department
      at Hartford Hospital (Hartford, CT) together with the Neonatology Division at the
      Connecticut Children's Medical Center (CCMC) (Hartford, CT) has been involved in
      developing the VTS system. Clinical trails were conducted in the neonatal
      intensive care unit of CCMC, and further preliminary data were collected. The
      main components of the system are a Tacaid vibrotactile stimulator (Audiological
      Engineering, Somerville, MA), a neonatal physiological monitor (Model 511; CAS
      Medical Inc, Branford, CT), a laptop computer running Windows 95 by Microsoft,
      National Instruments' data acquisition cards DAQCard-1200 and DAQCard-5102, and a
      software application developed by Premise Development Corporation, Hartford, CT.
      Heart rate, oxygen saturation, pulse, thoracic impedance, nasal airflow, and
      electrocardiogram are recorded from the monitor to the laptop. Whenever an apneic
      spell is detected, the nurse has the option of triggering a 3-second, 10-V, 250
      Hz square-wave pulse to the transducer. The vibrotactile transducer is placed
      noninvasively with tape on the infant's thorax. This stimulus should arouse the
      infant and end the apneic event. To facilitate clinical study, the system
      provides voice and visual prompts for the clinician and nurses. Preliminary data
      continue to support both the safety and efficacy of the VTS.

PMID- 12613293
TI  - Blood flow measurement from plethysmographic pulse waves without venous
      occlusion.
AB  - An air plethysmograph with a sensitive phototransducer was constructed so that
      plethysmographic volume-change pulsations could be displayed in detail without
      using venous occlusion. Software was developed to allow analysis of the pulses
      using a modification of the backward extrapolation technique. This allowed
      calculation of the forward arterial blood flow and noninvasive derivation of the
      resting arterial flow waveform. There is good reproducibility of the technique,
      with 8% variability between pairs of measurements at rest and 4% variability
      after hand exercise. Direct comparison made with blood flows measured by venous
      occlusion plethysmography showed good average agreement. The mean blood flow for
      venous occlusion (rest and exercise) was 0.76 +/- 0.07 mL/beat (mean +/- SEM),
      and the mean blood flow for backward extrapolation (rest and exercise) was 0.74
      +/- 0.09 mL/beat (mean +/- SEM). This corresponds to 3.86 +/- 0.36 mL/min/100 mL
      and 3.76 +/- 0.46 mL/min/100 mL, respectively. Important assumptions when using
      this method are that venous return is constant and that forward arterial flow is
      over before the end of the cardiac cycle.

PMID- 12613294
TI  - How 4 departments are responding.... Developing ways to cut costs in the face of
      budget pressures.

PMID- 12613295
TI  - How to safely maintain equipment where hazardous materials may lurk.
AB  - The best protection is preparation. Assess any equipment/device that requires
      repair or maintenance for potential contamination or source of injury, such as
      sharp edges. Know where your protective apparel is located and use it. Review
      decontamination procedures and keep disinfectants available. Know your employee
      report of injury program and seek medical care whenever you have concerns
      regarding potential injury or exposure. Know your policies and procedures and
      where to find them if you need further information. Your infection control staff
      should be available 24 hours a day. The standard personal protective equipment
      that your employer is required to make available to you should include gloves,
      masks, eye protection, and gowns. In addition, if you are expected to enter a
      negative pressure room while a patient is in Airborne Precautions, you must be
      properly fit tested with an N95 respirator prior to entering the room. This
      respirator is very similar to a normal mask, but is able to filter out particles
      such as the TB bacterium. Infection control boils down to 2 commandments: 1. Wash
      your hands! 2. Use your head/common sense: If it looks soiled--clean it. If you
      have concerns--ask for clarification. If you think you have been exposed--seek
      medical assistance.

PMID- 12613296
TI  - IT certification for the biomedical profession.

PMID- 12613297
TI  - The fundamentals of.... Automated external defibrillators.

PMID- 12613298
TI  - Helping to reduce human error in health care technology.

PMID- 12613299
TI  - Conducting the right investigation.

PMID- 12613300
TI  - A test to evaluate your career.

PMID- 12613301
TI  - More than just credentials: the personal and financial rewards of certification.

PMID- 12613302
TI  - Soda pop controversy/conspiracy.

PMID- 12613303
TI  - Maxillary molar transposition.

PMID- 12613304
TI  - Shear strength of sealants placed with non-rinse conditioning compared to a
      conventional acid etch-rinse technique.
AB  - The present study compared the shearing strength of a non-rinse conditioning
      (NRC) compomer sealant to that of a conventional sealant. Thirty molars and
      premolars were sectioned longitudinally. The resulting halves were divided into 4
      groups. Cylinders of sealants were bonded to the sections using a gelatin capsule
      as a matrix, as follows: Group A (n = 15) NRC + Prime & Bond + Dyract Seal; Group
      B (n = 15) same as group A but with phosphoric acid and rinse; Group C (n = 15)
      conventional phosphoric acid + Helioseal; Group D (n = 15) NRC + Helioseal. After
      immersing the specimens in water for 7 days, the samples were mounted on the
      Instron testing machine at a 20 mm/min crosshead speed. The results were
      subjected to ANOVA with Scheffe test, with a significant level of .05. No
      shearing strength values could be obtained for the specimens of group D. Some
      cylinders separated from the enamel while still immersed in the water, and in
      others the adhesion was too low, and no readings could be observed. For all
      groups, failure occurred at the sealant-enamel interface. The mean value for
      group A was 5.33 MPa, significantly less than that of groups B 9.12 MPa and C
      9.63 MPa (p < 0.006). No significant difference of the mean shear strength was
      evident between groups B and C. No rinse conditioning with Dyract Seal led to a
      considerably lower bond strength value than Dyract Seal and Helioseal with
      phosphoric acid and rinsing.

PMID- 12613305
TI  - Restorative material for children's teeth: preferences of parents and children.
AB  - The purpose of the study was to assess the preferences of parents and children
      regarding amalgam or tooth colored restoration material for the children's teeth
      and some associated factors. One hundred and 24 children aged 4 to 12 years of
      age (Mean age-7.3 +/- 2.4) who needed at least 1 dental restoration were selected
      for the study. After a dental examination, the parents were asked to complete a
      questionnaire requesting demographic information, preference of restoration
      material for their children's teeth, and influencing factors. The children were
      then asked to answer questions on which material they preferred and what
      influenced their decision. More parents preferred tooth colored restorations to
      amalgam restorations for their children's teeth. However, 12 percent of the
      parents preferred amalgam. For 40 percent of the parents, the restoration
      material did not matter. For most parents (76 percent), whether the tooth was
      primary or permanent did not influence their choice. The highest concern was
      given to the implications of a restoration material on the health of the body or
      the tooth. Half of the children preferred tooth colored restorations. For nearly
      30 percent, the restoration material did not matter. Significantly, more younger
      children than older children noted the filling's visual prominence as an
      important factor (30 percent and 3 percent, respectively). Younger children were
      more influenced by their parents' preferences than older children. It is
      concluded that tooth colored restorations are preferred to amalgam by both
      parents and children.

PMID- 12613306
TI  - In vitro study of laser diode 655 nm diagnosis of occlusal caries.
AB  - The aim of this in vitro study was to evaluate the performance of a new laser
      method (DIAGNOdent, KaVo) by comparing it to the visual inspection, conventional
      bitewing radiography and digital bitewing radiography. Fifty fresh permanent
      teeth with clinically sound or suspicious fissures were selected. The teeth were
      submitted to the diagnostic tests by 2 examiners independently after calibration.
      The laser examination was repeated to assess the reproducibility. The teeth were
      sectioned right in the spot that showed the highest value by the laser device.
      Histological examination of sections (40x magnification) served as gold standard.
      The results showed that: 1) the intra and interobserver agreement for the
      DIAGNOdent was excellent (values over 0.87); 2) the sensitivity, specificity and
      predictive values were very high; 3) and the Spearman correlation coefficient of
      DIAGNOdent was the best one (R = 0.81), followed by visual inspection (R = 0.68).

PMID- 12613307
TI  - Adequacy of mandibular premolar position despite early loss of its deciduous
      molar.
AB  - The mandibular second premolar (MnP2) tooth is one of the most commonly impacted
      teeth. Early loss of its deciduous predecessor has long been suggested to be a
      factor in the etiology of the MnP2 impaction. In this study, panoramic
      roentgenograms were used to measure the angular position of the unerupted MnP2 in
      85 children. The study was carried out to test whether early loss of the lower
      second primary molar (dM2) correlates with MnP2 malpositions that are measurably
      greater than those from a control sample. The results show a small and
      statistically insignificant difference between the mean angles in cases with
      (79.6 degrees) and without (83.2 degrees) dM2. To eliminate individual factors,
      e.g., genetics, 2 sides of the same patient, with and without dM2, were compared.
      The group with the missing dM2 on one side showed higher angle differences,
      compared with the control group. However, the differences were still small
      (approximately 4 degrees) and statistically insignificant. Our findings do not
      show a significant influence of early loss of dM2 on the inclination of the
      unerupted MnP2, suggesting that environmental factors may be of less
      significance, compared with genetic ones.

PMID- 12613308
TI  - A computerized analysis of dental arch morphology in early permanent dentition.
AB  - To determine the positions of teeth and the size and shape of the dental arches,
      53 dental casts of children (29 boys and 24 girls) with their early permanent
      dentition and normal occlusions were examined. The coordinates of cusp tips and
      line angles of anterior teeth and cusp tips, contact points, and fossa of
      posterior teeth were digitized. Computer-generated curves were created for both
      arches using a polynomial model. There were 2 cusp-to-fossa relations and 4 cusp
      to-marginal ridge relations for posterior segment intercuspation. Mean values of
      posterior arch lengths were statistically larger in boys than in girls. Mean
      curves of boys' dental arch forms were larger than those of girls and the ranges
      between the largest and smallest curves for both arches in boys were larger than
      those in girls. The boys' and girls' smallest curves for both arches were almost
      the same size.

PMID- 12613309
TI  - The width of clinically-defined keratinized gingiva in the mixed dentition.
AB  - Some authors have noticed a clear decrease of the width of keratinized gingiva
      when they compared the width over deciduous and newly erupted permanent teeth.
      The aim of this cross-sectional study was to assess the width of keratinized
      gingiva over permanent and deciduous teeth present in 6 to 11-year old children
      in an urban environment. The greatest width of keratinized gingiva was found over
      deciduous canines and permanent incisors. When comparing the width of keratinized
      gingiva over deciduous canines and molars and permanent first incisors and first
      molars, statistically significant differences were found only between 6- and 11
      year-old groups. The findings do not seem to support previously published data,
      but do suggest that periodontal mucogingival surgery is not needed before the
      patient reaches the adult age, since there is a tendency of an increase of the
      width of keratinized gingiva.

PMID- 12613310
TI  - Inflammatory follicular cyst associated with an endodontically treated primary
      molar: a case report.
AB  - This is a case study of an inflammatory follicular cyst associated with an
      endodontically treated deciduous molar with radiographic and microscopic
      diagnosis. This cystic lesion represents a typical follicular cyst that arose in
      association with periapical inflammation from a non-vital deciduous molar and
      involved the follicle of the unerupted successor premolar. This paper describes
      the case and discusses diagnosis, histogenesis, and controversies regarding
      terminology.

PMID- 12613311
TI  - Inverted impaction of primary incisors: a case report.
AB  - Dental and radiological findings of a 5-year-old female patient show inverted
      impaction of the maxillary primary incisors. Family and personal histories of the
      patient were unremarkable. There were no abnormalities in general growth and
      development nor was there any history of trauma.

PMID- 12613312
TI  - Dental characteristics of patients with Duchenne muscular dystrophy.
AB  - A comprehensive assessment of the dental characteristics of 23 patients with
      Duchenne muscular dystrophy (DMD) was carried out, based on dental records, oral
      examinations and dental models. Decreasing muscle function was associated with
      increased plaque and calculus accumulation, leading to gingival inflammation, but
      caries experience was low. Disturbances in tooth form, number and eruption of the
      second premolars were observed in 39% of patients. Anterior and posterior open
      bites were common, associated with lip incompetence, mouth breathing,
      macroglossia and tongue thrusting. Maxillary and mandibular arch breadths were
      significantly larger, on average, in the DMD group than in controls. Rather than
      a normal parabolic arch form, the dental arches in DMD patients tended to be
      hyperbolic, with the posterior teeth being displaced buccally, consistent with an
      imbalance between the lingual and facial musculature.

PMID- 12613313
TI  - Initial acquisition and transmission of mutans streptococci in children at day
      nursery.
AB  - The purposes of this study were to determine the age at the initial acquisition
      of mutans streptococci (MS) and to determine the transmission of MS among
      children at day nursery by describing the occurrence of genotypes prepared by
      chromosomal DNA fingerprinting of the bacteria using restriction endonuclease
      EcoRI and HaeIII. The samples were 39 children (23 boys and 16 girls) aged 0-5
      years old, 14 pairs of parents and 6 nursery caretakers of a day nursery in
      Hiroshima city, Japan. The children had no dental caries throughout the
      experiment. Plaque samples of the children were taken using toothbrushes at 1
      month intervals for 30 months. The initial acquisition of MS occurred between the
      ages of 8 months and 52 months with a mean age of 24.2 months. The cumulative
      probability of initial acquisition of MS increased rapidly at the age of 12 to 25
      months after 10 to 20 primary teeth had erupted. Transmission of MS was found
      between child and mother (33.3%), child and father (8.3%) and child and others
      including amongst the children (58.4%), but no evidence of MS transmission from
      nursery caretakers was found. Two children acquired MS from intra- and extra
      familial transmission. This study suggests that the child's environment also
      plays a role in the initial acquisition and transmission of MS, in addition to
      the oral condition of the children.

PMID- 12613314
TI  - Prevalence of Candida albicans in oral cavities and root canals of children.
AB  - The aim of this study was to examine the prevalence of C. albicans in the oral
      cavities and root canals of children. Twenty healthy and caries-free children and
      13 children with caries, were screened. Imprint samples and sterile paper points
      were used to obtain the samples from oral cavities and root canals respectively.
      The production of germ tubes and the development of chlamydospores identified
      yeast cultures. Sixty-nine percent of children with caries and 5% of caries-free
      children were found to be Candida carriers. The difference in candidal prevalence
      between two groups was significant (p < 0.05). Sixty-one point five percent of
      children were positive for Candida in the root canal. Since, increase in the C.
      albicans in the oral cavity provides a potential source of the fungus
      particularly when resistance falls below a certain threshold, attention to
      strategies for the reduction of this pervasive and persistent pathogen becomes
      important. Therefore, reduction of caries and or introduction of antifungal
      agents during root canal treatment of children may be offered.

PMID- 12613315
TI  - Orofacial manifestations of congenital insensitivity to pain with anhidrosis: a
      report of 24 cases.
AB  - PURPOSE: To report the incidence and severity of the oral and dental
      manifestations associated with congenital insensitivity to pain with anhidrosis
      (CIPA). METHODS: Young children with CIPA underwent orofacial examination. The
      tongue, lips, and buccal mucosa were examined for soft tissue disorder. Missing
      and luxated teeth were recorded. RESULTS: Twenty four patients (14 males and 10
      females, mean age 60 months, range 9-144 months) with CIPA showed moderate to
      severe self-mutilation. Oral self-mutilation, such as biting injuries and
      scarring of soft tissues (tongue, lip, and buccal mucosa) were found in all
      patients. Fingertip biting was also found in most patients. Among infant
      patients, the mutilation was typically characterized by decubital ulcers of the
      tongue. Many edentulous areas due to previously extracted teeth were also found.
      CONCLUSIONS: Early diagnosis and specific dental care for patients with CIPA can
      be helpful in prevention of the fingertip biting and orofacial manifestations
      seen in this disorder.

PMID- 12613316
TI  - Dental fear and knowledge of children treated by certified pediatric dentists and
      general practitioners.
AB  - The purpose of this study was to compare knowledge regarding preventive measures
      and reported dental fear, of children treated by certified pediatric dentists
      (CPDs) to those treated by general practitioners (GPs). A questionnaire was given
      to 300 children, 150 were treated by GPs and the others by CPDs. Children treated
      by CPDs provided more correct answers to questions about prevention of oral
      disease (p < 0.001). However, the percentage of children that showed good
      knowledge was small (14%-82%), and the differences between the two groups on the
      various questions was only 7%-20%. Children treated by CPDs reported more
      frequently that they were not afraid of dental treatments (75.3% vs. 39.3%),
      loved their dentists (50% vs. 31.5%) and received prizes (85.3% vs. 32.7%). These
      findings suggest that CPDs invest more effort in communication and education of
      their patients concerning preventive dentistry. There is a need to improve these
      skills of GPs and CPDs.

PMID- 12613317
TI  - Stressful situations for toddlers: indications for dental anxiety?
AB  - The present study was undertaken to examine if daily anxiety-provoking situations
      can predict dental anxiety in a toddler. Parents of 73 toddlers were sent 2
      questionnaires: 1) the Dental Subscale of the Children's Fear Survey Schedule
      (CFSS-DS), and 2) the Inventory of Stressful Situations (ISS), a list of 16
      questions developed to assess anxiety in daily stressful situations. This
      investigation was repeated one year later. Forty-eight parents completed all
      questionnaires. Results show a clear correlation between daily stressful
      situations at the age of 3 and dental anxiety at the age of 3 (r = .62, p < 0.01,
      two-tailed) and at the age of 4 (r = .49, p < 0.01, two-tailed). Regression
      analyses revealed that the ISS at the age of 3 predicted dental anxiety at the
      age of four; however, it did not contribute additionally if the CFSS-DS score at
      the age of three was included. CONCLUSION: Daily anxiety-provoking situations in
      3-year-old children may be related to dental anxiety at the age of 4.

PMID- 12613318
TI  - Parents' assessment and children's reactions to a passive restraint device used
      for behavior control in a private pediatric dental practice.
AB  - PURPOSE: The purpose of this study was to compare parents' acceptance of passive
      restraint with their personal perception of their own anxiety, their evaluation
      of their child's emotional state while being restrained and the treating
      dentist's perception of their levels of stress. METHODS: A convenience sample of
      100 children who needed passive restraint in order to complete their restorative
      dental needs were included in the study. After the dental treatment was
      completed, surveys were mailed to the parents who were in the operatory during
      the restorative procedure, asking them to evaluate their level of stress, their
      view of how their child accepted the passive restraint device and their view of
      the success of the procedure. The treating dentist also evaluated their apparent
      levels of apprehension and the behavior of the children while being restrained,
      using the Sarnat Scale. There were 42 replies to the survey. RESULTS: The results
      showed that the difference between the percentage of parents that felt no anxiety
      vs. moderate to severe anxiety was not significant. Ten percent of the parents
      felt their child did not mind being restrained, while the balance was evenly
      split between feeling that their child was either unhappy but accepting or
      unhappy and not accepting of restraint. CONCLUSIONS: For the population studied,
      the use of passive restraint was acceptable to most parents, as those in this
      study did not view it negatively. They were clam while observing their child
      being treated and happy with their decision for its use. The results suggest that
      most parents will accept this modality for behavior control.

PMID- 12613319
TI  - The rate of child abuse and neglect cases per population totals decreased since
      the mid 1990s ... but!
AB  - The rate of child abuse and neglect cases per population may have been
      decreasing, but there have been increases in the actual number of cases. A review
      of federal reports serves as an alert for dental practitioners to maintain their
      vigilance as 1) primary care providers of children, and 2) mandated reporters of
      child abuse.

PMID- 12613320
TI  - The prevalence of early childhood caries in 12- to 36-month-old children in
      Recife, Brazil.
AB  - The purpose of the present study was to evaluate the prevalence of early
      childhood caries among preschool children aged between 12 and 36 months from poor
      communities in the city of Recife, Brazil. This prevalence was evaluated along
      with the type and duration of feeding, supplementary diet in terms of
      cariogenicity and quantity of sugar intake. Of the 468 children studied, 28.46%
      presented caries and the association between the variable of a cariogenic diet
      and caries was strongly significant (x2 = 13.36 and p < 0.001). From the results
      of the present study it is possible to draw the following conclusions: the
      prevalence of early childhood caries in poor children aged 12-36 months in the
      city of Recife is in accordance with that found in other Brazilian cities, but is
      very high compared to that of the world population. Early childhood caries was
      not found to be related to the type of feeding; however, the number of sugary
      snacks between meals and a cariogenic diet were strongly related to early
      childhood caries. The prevalence of early childhood caries increases with age;
      and the first signs of the carious lesions were only detected after the eruption
      of the first molars, starting at 18 months.

PMID- 12613321
TI  - Improving utilization of preventive dental services by Medicaids-enrolled
      children: focus on the parents.
AB  - The Access to Baby and Child Dentistry (ABCD) program was implemented in
      Washington State in 1995 to increase utilization of dental services for children
      enrolled in Medicaid. The program has increased utilization of services;
      nevertheless, only 54 percent of Medicaid-enrolled children in ABCD who received
      care were given a topical fluoride treatment. To gain a better understanding of
      why children may not be receiving topical fluoride treatment, we interviewed
      parents. Focus group research found strong parental support for preventive
      services. Parents were willing to take their children to regular dental visits,
      but lack of knowledge of benefits was common. This lack of knowledge translated
      into a failure to fully utilize the topical fluoride benefits. We recommend that
      the program continue to encourage participation of dentists, regularly update
      information about program benefits for both dentists and parents, and enhance the
      visibility of the program in the community.

PMID- 12613322
TI  - Millennium children.
AB  - A federal agency's extensive report on the well-being of our children at the
      beginning of the new millennium provides an opportunity to review the many
      achievements and remaining concerns about the health and social environment of
      the children in our communities and in many of our dental practices.

PMID- 12613323
TI  - [Integrated treatments of rectal carcinoma (review)].
AB  - We have reviewed the international literature regarding the treatment of rectal
      carcinoma. Over the last decades the evolution of treatment methods has led to a
      drastic fall in the incidence of local recurrences which has gone from a wide
      range (15-40%) to a much lower figure (10%). This favourable result has been
      reached also due to improvement in surgical techniques (total mesorectal
      excision) and to the use of an association of preoperative radio and
      chemotherapy. However, the drugs and dosage of these as well as of the RT still
      have to be defined. In our experience the integrated treatment has brought a
      downstaging of the T in 60% of cases and of the N in 15%.

PMID- 12613324
TI  - [Results of extended lymphadenectomy in the surgical treatment of gastric
      carcinoma. Considerations on data from the literature].
AB  - In the surgical response to gastric carcinoma the use of extensive
      lymphadenectomy (D2) is still being debated. In Japan D2 is the operation of
      choice and the numerous selected case studies emphasize better long term survival
      at all stages with this operation. In the West D2 has not obtained the same
      approval, besides which it is burdened by higher postoperative morbidity and
      mortality. The important prospective non-selective trials have not shown
      differences in the general rates of survival between D1 and D2: the analysis of
      subgroups, instead, shows better results for stages II and IIIA. The distal
      splenopancreasectomy and the lack of experience of the surgeons worsen the
      results of D2. Therefore, when reanalyzing the results of the trials in the light
      of this information a difference is obtained in the rates of survival in favour
      of D2 for a wider category of patients. The age of the patient necessitates
      strict preoperative selection. In some selected cases D2 may be performed; for
      the majority of older patients the operation of choice is D1 extended to the
      celiac lymph nodes.

PMID- 12613325
TI  - [Videolaparoscopic surgery in the treatment of colorectal disease: our experience
      with 200 patients].
AB  - In this article we examine our experience over the last 4 years, from 1998 to
      2001, in the surgical treatment of colorectal disease using the laparoscopic
      approach. We treated 200 patients, 54 of whom presented benign disease and 146
      malignancies. The operations were performed by a team of surgeons and nurses
      experienced in advanced laparoscopy. Over this period, the duration of the
      surgical intervention was gradually reduced by 17%. The conversion rate from
      laparoscopy to open procedures was also reduced (mean rate 11%). Canalization and
      the resumption of walking and nutrition were reasonably fast. Postoperative
      complications occurred in 22% of cases The number of fistulas and anastomotic
      dehiscences was high (10/200 = 5%), due both to evaluation errors and the choice
      of surgical material. At present, on applying the criteria of traditional open
      surgery, this figure is also coming down. Bleeding complications (12/200 = 6%)
      can also be ascribed to the learning curve (2 bleeds in the trocar site and 2
      haematomas in the Pfannenstiel laparotomy site) and are therefore likely to be
      reduced. Bleeding during the surgical procedures, however, was very low, with a
      mean value of 69.6 ml. Laparoscopic surgery for colorectal disease is well
      standardized and we believe there should be no doubts as to its use in benign
      disease. Its use in oncological surgery, though theoretically correct, needs to
      be confirmed by the trials currently in progress. The results we have obtained in
      our experience, after completion of the learning curve, agree with the figures
      reported in the literature.

PMID- 12613326
TI  - ["Sequential" treatment: is it the best alternative in cholecysto-choledochal
      lithiasis?].
AB  - Laparoscopic cholecystectomy has become the treatment of choice for patients with
      symptomatic cholelithiasis. About 10-20% of patients with gallbladder stones may
      also present associated common bile duct stones. The management of the latter
      remains controversial because many different surgical strategies are available:
      laparoscopic treatment (laparoscopic common bile duct exploration), sequential
      endoscopic and laparoscopic treatment (endoscopic retrograde
      cholangiopancreatography/endoscopic sphincterotomy [ERCP/ES] prior to
      laparoscopic cholecystectomy), inverted sequential endoscopic-laparoscopic
      treatment (laparoscopic cholecystectomy followed by ERCP/ES), and combined
      endoscopic-laparoscopic treatment (laparoscopic cholecystectomy with
      intraoperative ERCP/ES). The aim of this study was to evaluate the efficacy and
      safety of sequential endoscopic-laparoscopic treatment in patients with
      cholecystocholedocholithiasis. We retrospectively analyzed the clinical,
      biochemical and radiological features of 552 patients operated on for
      cholelithiasis from 1991 to 2001. Common bile duct stones were suspected on the
      basis of increased serum levels of bilirubin, GOT, GPT, GGT, alkaline
      phosphatase; presence of jaundice; history of pancreatitis or cholangitis;
      dilated common bile duct (diameter > 8 mm) or common bile duct stones at
      hepatobiliary ultrasonography; presence of common bile duct stones at MR
      cholangiography or at i.v. cholangiography. In patients with suspected common
      bile duct stones, preoperative ERCP was performed; if common bile duct stones
      were confirmed, ES was performed. When common bile duct stones were not suspected
      preoperatively, laparoscopic cholecystectomy was performed directly. Overall
      morbidity, mortality and conversion rates in the two groups were evaluated. Of
      552 patients admitted for cholelithiasis, 62 (11.3%) underwent preoperative ERCP
      for suspected common bile duct stones. In 41 patients (66.1%) common bile duct
      stones were identified and ES with common bile duct stone extraction was
      performed in 40 patients (clearance: 97.5%). The overall morbidity was 16% (10
      cases of post-ERCP acute pancreatitis); no mortality occurred. The conversion
      rate during subsequent laparoscopic cholecystectomy was 4.8%. In the group of
      patients with no suspicion of common bile duct stones, the conversion rate was
      4.9%. Sequential treatment cannot be considered the best approach for patients
      with cholecystocholedocholithiasis because of its morbidity rate and the high
      rate of negative preoperative ERCP findings. Combined endoscopic-laparoscopic
      treatment seems to present more advantages, especially in term of morbidity,
      hospital stay and patient compliance and may, in future, be considered the
      treatment of choice for patients with cholecystocholedocholithiasis.

PMID- 12613327
TI  - [Surgical treatment of solitary thyroid nodule].
AB  - In this report we examine the surgery of solitary thyroid nodules, outlining the
      operations performed and the diagnostic-instrumental procedures aimed at
      identifying the degree of malignancy of the lesion. If intraoperative cytological
      and histological examination of a nodule show that it is benign, we perform
      lobectomy. In a total of 400 cases, we performed 52 (13%) nodule resections, 276
      (69%) hemithyroidectomies, and 72 (18%) extended resections comprising the
      isthmus and Laluette pyramid. Twenty-five patients (5%) were affected by
      differentiated cancers arising in the nodule. In this group, the carcinoma
      diagnosis, revealed by fine the needle aspiration and confirmed at the
      intraoperative examination, allowed us to perform a total thyroidectomy in a
      single session in 21 cases (84%); more specifically, total thyroidectomy only was
      performed in 14 (56%) cases, while in 7 cases (28%) a laterocervical lymph-node
      resection was also necessary due to the presence of lymph nodes of increased
      volume. We had three cases with lesions of the recurrent nerve (0.6%) and 30 with
      irritation of the superior laryngeal nerve (6%) which caused temporary
      hypoaesthesia of the larynx and hoarseness. Moreover, four patients (8%)
      presented temporary postoperative hypoparathyroidism. No instances of permanent
      hypoparathyroidism were observed. The report concludes by analysing a number of
      surgical techniques for the treatment of solitary thyroid nodules.

PMID- 12613328
TI  - [Surgical treatment of acute respiratory failure caused by mediastinal goiter.
      Clinical experience and results].
AB  - In the regions where goitre is endemic, onset of the disease with acute
      respiratory insufficiency caused by thyroid compression is an uncommon situation
      requiring a rapid diagnosis and urgent surgical treatment. From January 1997 to
      December 2000 we observed 81 patients with thyroid pathologies, (69 males and 12
      females; mean age 64 years). We found colloid-cystic goitre in 39 cases,
      adenomatous goitre in 26, carcinoma in 12, Hurthle's cell tumours in 3 and
      inflammatory disease in 1. All patients underwent thyroidectomy. Nine patients
      (11%) presented acute respiratory insufficiency caused by thyroid compression,
      with various associated phonesis disorders; in these cases we performed emergency
      surgery with postoperative maintenance of tracheal intubation or tracheotomy or
      the possible positioning of a self-expanding tracheal stent. In these 9 patients
      there were 4 deaths (44%), 3 in the immediate postoperative period and one after
      10 months. We also observed one hydropneumothorax. Functional recovery was
      achieved in the remaining 5 patients. The treatment of this clinical picture
      requires urgent tracheal intubation, before the use of diagnostic tools, and it
      is important to maintain it after the surgical procedure for as long as is
      necessary for the tracheal wall to be reconstituted. In the severest cases a
      temporary tracheotomy is needed or the positioning of a tracheal stent, which
      offers a valid and effective alternative.

PMID- 12613329
TI  - [Impact of preoperative locoregional chemotherapy with fluorodeoxyuridine on the
      outcome of liver resection].
AB  - The aim of the study was to evaluate the effects of preoperative intra-arterial
      hepatic chemotherapy (IAHC) on the outcome of liver resections for hepatic
      metastases from colorectal cancer. Twelve patients (IAHC group) treated by IAHC
      with fluorodeoxyuridine (FUdR) and subsequent liver resection and 40 patients who
      underwent liver resection without preliminary IAHC (non-IAHC group) were analysed
      comparatively in terms of age, gender, concomitant diseases, previous abdominal
      surgery, type of hepatic resection, use of portal clamping, and associated
      surgical procedures. For the purposes of the study, length of operation,
      intraoperative blood losses, perioperative transfusions, length of
      hospitalisation, complications and mortality were also recorded. The two groups
      were comparable (p = n.s.) for those variables affecting the perioperative
      course. As regards the end points of the study, no significant differences were
      recorded in length of operation, intraoperative blood losses, perioperative
      transfusions [except for more postoperative plasma transfusions in the IAHC group
      (16.7% vs 5.0%, p = 0.009)] and postoperative complications (9.1% vs 17.5%, p =
      0.415). Postoperative mortality consisted in one patient in the IAHC group.
      Postoperative hospitalization was significantly longer in the non-IAHC group
      (median: 8 vs 10, range: 6-13 vs 5-33 days; p = 0.004). IAHC does not negatively
      affect the outcome of subsequent liver resection.

PMID- 12613331
TI  - [Role of endoscopy in the treatment of non-variceal upper gastrointestinal
      hemorrhage].
AB  - Over the past three decades important progress has been made in the diagnosis and
      treatment of non-variceal upper gastrointestinal bleeding. We discuss the
      endoscopic techniques available today in combination therapies. The data in the
      literature regarding endoscopic techniques are discordant and no single technique
      has proved statistically superior in the management of bleeding. We believe that
      the initial injection approach is still the procedure of choice, particularly
      when performed by less expert endoscopists.

PMID- 12613330
TI  - ["Tension-free" hernioplasty with prosthesis: comparison of 2 techniques].
AB  - The paper evaluates the results of the surgical therapy of primary inguinal
      hernia in adult subjects performed in our Institution from 1994 to 2000. The
      Trabucco and Lichtenstein procedures were compared. Two hundred and fifteen
      patients--123 Trabucco and 92 Lichtenstein--were enrolled in the study. A file
      was created for each patient with details of personal data, procedures,
      anaesthesia and postoperative course. A form regarding the present state of each
      patient was filled in, mainly by phone, but sometimes by physical examination, if
      patients complained of problems. The results were evaluated statistically using
      the Fisher f and X2 tests. Only four parameters showed significant differences:
      wound swelling, constipation and days off work were less frequent with the
      Trabucco procedure, while there was less loss of the foreign body sensation in
      the Lichtenstein patients (6.7% vs. 18.3%). No recurrences were detected. The
      results of the two procedures can be considered comparable.

PMID- 12613332
TI  - [Advantages of surgical treatment of hemorrhoids with mechanical sutures].
AB  - The use of circular staplers for the treatment of haemorrhoids is a new technique
      that makes for better correction of the physiopathology of the condition, affords
      greater patient comfort and reduces health-care expenditure. This technique,
      which was invented by A. Longo in 1993, pulls up the haemorrhoidal cushions into
      their anatomical position, reduces or avoids postoperative pain, sparing the
      sensitive fibres of the anal canal, avoids anal canal stenosis and is not
      complicated by faecal incontinence. The authors present their experience in 41
      patients affected by symptomatic haemorrhoidal prolapse and treated with a
      mucosal rectal prolapsectomy using a circular stapler. Each patient was followed
      up for 6 months to assess the incidence of complications and the degree of
      patient satisfaction. The results were compared with those reported in the
      literature, obtained using the Milligan-Morgan procedure. The Longo technique,
      which can be performed in the one-day surgery setting, allows very good relief of
      postoperative pain, rapid functional recovery and an early return to work, with a
      saving in health-care expenditure as compared with conventional treatment.

PMID- 12613333
TI  - [Surgical treatment of anal stenosis following hemorrhoid surgery. Results of 150
      combined mucosal advancement and internal sphincterotomy].
AB  - The aim of the study was to evaluate the efficacy of anoplasty by mucosal
      advancement combined with internal sphincterotomy for the treatment of iatrogenic
      anal stenosis. From January 1990 to December 2000, 149 patients with post
      haemorrhoidectomy anal strictures underwent internal sphincterotomy and mucosal
      advancement flap anoplasty. Seventy-one percent of patients were operated on
      under local anaesthesia by perineal block according to Marti. In 90 percent of
      the patients, postoperative pain was mild. No significant complications were
      seen. The mean hospital stay was two days. Ninety-seven percent of patients were
      well satisfied with the surgical result one year after operation. Current
      surgical options for the treatment of post-haemorrhoidectomy anal stricture are
      reported and the advantages of mucosal advancement flap anoplasty outlined.

PMID- 12613334
TI  - [Integrated project for the translational research on pancreatic ductal
      carcinoma].
AB  - The narrow chances of therapy and the poor prognosis of pancreatic cancer make
      basic research a crucial way for both a better knowledge and a possible
      improvement in the treatment of this disease. The very limited availability of
      pancreatic specimen for genetic and biological studies forced the researchers to
      plan "in vitro" and "in vivo" models in order to overcome this handicap. Among
      the animal models, the one according to Fu et al. seemed to be the most helpful
      and effective approach. Nevertheless, being this model complex and failing in
      main perspective applications, an enlarged project perpetuating B-lymphocytes of
      the patients, successfully xenografting from vitally criopreserved specimen and
      developing cell lines from xenografts was planned. According to the aim of our
      project, a really perpetual and renewable bank of tumoral and normal tissue from
      patients suffering from pancreatic carcinoma was obtained. This model is also
      expected to be an effective approach for the evaluation of experimental
      chemotherapeutic schedules and new gene therapy assessment.

PMID- 12613335
TI  - ["Forgotten" goiter: clinical case and review of the literature].
AB  - "Forgotten" goitre is an extremely rare disease. It is a mediastinic thyroid mass
      found after total thyroidectomy. In this paper we report a case of "forgotten"
      goitre and review the various diagnostic and therapeutic problems posed by the
      condition. A number of possible solutions that can be implemented for this
      disease are identified.

PMID- 12613336
TI  - [Thyroid metastasis from renal carcinoma. Clinical case].
AB  - Metastatic thyroid tumours are uncommon among reported clinical cases, but are
      more frequent in autopsy series. The most common sites of the primary tumours are
      the breast (21%), kidney (12%) and lung (11%) and in some cases are detected only
      at autopsy. The clinical presence of thyroid tumefaction, whether associated or
      not with compressive symptoms, in a patient with a history of surgical treatment
      for renal cell carcinoma should lead to the suspicion of a metastatic nodule. The
      most important diagnostic technique is cytological examination after fine needle
      aspiration biopsy, combined with immunohistochemical staining. Total
      thyroidectomy, whether associated or not with radiation therapy, is the procedure
      of choice in these cases, when possible, above all in the presence of regional
      symptoms. In spite of treatment, however, the prognosis of metastatic disease is
      very poor. Therapeutic measures allow a mean survival of 34 months in the various
      reported series. The authors report the case of a 66-year-old female patient who
      had undergone left-side nephrectomy for a renal cell carcinoma 7 years earlier.
      The woman presented an increased thyroid volume mainly on the right side, with
      signs of tracheal compression. Ultrasonography of the thyroid gland and fine
      needle aspiration cytology showed malignant features. Scintigraphy strongly
      suggested the presence of a cold nodule in the right lobe. Subsequently, total
      thyroidectomy was performed and the histological examination revealed that the
      nodule was composed of tumour cells with abundant clear cytoplasm and round
      nuclei; with the characteristics of the renal cell carcinoma resected 7 years
      previously. Since computed tomography revealed secondaries in the lungs, the
      patient is still being managed with chemotherapy, with arrest of the metastatic
      progression, and is in a fairly good clinical condition.

PMID- 12613337
TI  - Warthin's tumour of the parotid gland.
AB  - The authors, after examining two recent cases, explain a number of basic concepts
      regarding the diagnosis and therapy of Warthin's tumour of the parotid gland.
      Despite their low frequency, such tumours are very important because of their
      aetiopathogenesis, which is still controversial, and the recent increase in their
      incidence in females. Today, the diagnostic protocol, undertaken after the
      necessary clinical examination, relies mainly on ultrasonography and CT, but only
      a postoperative histological examination is capable of yielding a sure diagnosis
      and establishing the main histomorphological characteristics of the tumour. The
      therapeutic approach can be limited to conservative treatment, sparing the
      parotid gland and its vascularization and innervation.

PMID- 12613338
TI  - [Pancreatic metastasis from clear cell renal carcinoma: a clinical case].
AB  - Renal cell carcinoma rarely metastasizes to the pancreas. In this report we
      describe a case of late pancreatic metastases in a seventy-year-old woman,
      surgically treated 21 years before for renal clear-cell carcinoma. Preoperative
      staging revealed the presence of four pancreatic lesions. A distal pancreatectomy
      and splenectomy were performed, and the postoperative period was complication
      free. Histopathological analysis revealed metastases from renal clear-cell
      carcinoma. This case shows that in patients operated on for renal clear-cell
      carcinoma we have to consider the possibility of late metastases to the pancreas.
      Therefore, these patients should be submitted to long-term follow-up. In keeping
      with the current literature, we advocate aggressive surgical treatment in
      pancreatic metastases from renal clear-cell carcinoma.

PMID- 12613339
TI  - [Cavernous hemangioma of the adrenal glands: a clinical case].
AB  - Cavernous haemangiomas of the adrenal gland are rare and the preoperative
      diagnosis is very difficult. We report the case of a patient admitted for
      aspecific abdominal pain. Instrumental diagnostic investigations (ultrasonography
      and CT scan) revealed an adrenal mass of uncertain interpretation which was
      surgically removed and histologically diagnosed as a cavernous haemangioma.

PMID- 12613340
TI  - Transduodenal excision of giant tumour of the ampulla of Vater: a case report.
AB  - Carcinoma of the papilla is a rare cancer of the digestive tract; 5% of all
      gastrointestinal tract malignant neoplasms are periampullary. The authors report
      and discuss the case of one of their patients aged 79 years suffering from a
      tumour of the papilla. The case was characterized by the large size of the
      neoplasm (5.5 cm in diameter) and by the poor clinical conditions of the patient,
      who was suffering from Parkinson's disease and was at high operative risk. The
      surgical strategy chosen involved transduodenal excision of the tumour with
      duodenum-bile duct anastomosis and internal duodenum-Wirsung duct anastomosis.
      The authors first examine the hypothesis that carcinoma of the papilla may
      represent the evolution of an adenomatous lesion and then go on to assess the
      therapeutic strategy adopted in the treatment of these neoplasms: in patients at
      high operative risk a transduodenal excision of the tumour with duodenum-bile
      duct anastomosis and internal duodenum-Wirsung duct anastomosis may be a valid
      alternative to the conventional Whipple procedure.

PMID- 12613341
TI  - [State of lucid delirium after orthotopic liver transplantation. Clinical case].
AB  - Neuropsychiatric complications after liver transplantation are common and have an
      incidence ranging from 0.5% to 47% in several international reports. They are due
      to different causes (coagulation, haemodynamic or electrolyte disorders,
      infections, immunosuppressive drugs). In patients receiving cyclosporin and
      tacrolimus, headache, tremors, dysarthria, seizures and delirium are the most
      common disorders and are not always related to toxic drug concentrations or
      overdosage. We report the case of a liver transplant patient receiving
      cyclosporin who presented a state of lucid delirium with a mystic persecutory
      content. in the first few postoperative days. Cyclosporin was withdrawn and the
      patient switched to tacrolimus, initially combined with chlorpromazine and later
      with clotiapine. She rapidly improved and recovered completely within a few days.
      At follow-up the patient is doing well and can remember the episode of delirium
      perfectly well. Psychiatric evaluation preoperatively and during follow-up is
      important to recognize and treat these complications, which can prevent the full
      recovery of transplanted patients and also increase the cost of this procedure.

PMID- 12613342
TI  - Acute onset of non-Hodgkin's lymphoma with bowel perforation in a patient with
      over 15 years' HIV positivity. A case report.
AB  - The authors report a rare case of acute onset of ileal non-Hodgkin's lymphoma
      with acute abdomen due to bowel perforation. The patient, a man aged 36 years,
      had been HIV-positive for more than 15 years. The patient had been on continuous,
      differentiated pharmacological treatment for the previous 5 years, and in the
      last month had had repeated episodes of fever with no clear aetiopathogenesis.
      Physical examination yielded negative findings and abdominal and chest CT failed
      to reveal any obvious lesions. The patient was admitted as an emergency case with
      a picture of acute abdomen and was immediately operated on; ileal perforation due
      to multiple lymphomatous lesions in the small bowel was diagnosed. The
      histological diagnosis was large-cell non-Hodgkin's lymphoma type B. After the
      operation, the patient was treated by chemotherapy and, currently, after a 12
      month follow-up, is in good general condition.

PMID- 12613343
TI  - [Peritoneal multicystic mesothelioma: unusual case of localization in the left
      lobe of the liver].
AB  - Peritoneal multicystic mesothelioma is a very rare clinical condition. This
      neoplastic variant has a high incidence of recurrence after surgical resection.
      It usually occurs in middle-aged women with a previous history of gynaecological
      surgery and presents with the symptoms of an abdominal or pelvic mass. The case
      reported here is that of a 58-year-old woman, characterised first by a left liver
      lobe tumour and then by a subsequent episode of emission of cystic matter from an
      abdominal fistula. The relevant literature is reviewed and the clinical aspects
      and treatment of this disease are discussed.

PMID- 12613344
TI  - Intermittent small bowel obstruction by jejunal enteroliths in a patient with a
      Crohn's disease stricture.
AB  - Small bowel obstruction is most frequently due to postoperative or inflammatory
      adhesions, intestinal neoplasms, hernias, or bezoars. Intermittent small bowel
      obstruction may be secondary to a Crohn's disease stricture or to chronic
      adhesive peritonitis. Enterolithiasis, usually associated with jejunal
      diverticulosis or with a Meckel diverticulum, should be considered in patients
      who have not previously undergone abdominal surgical procedures. X-ray evidence
      of stones in the abdominal field, outside the common sites, i.e. gallbladder,
      kidney, bladder, should suggest a diagnosis of enterolithiasis. The authors
      report a case of multiple enteroliths in a patient with a segmental ileal
      stricture and ulcerations (diagnosed as Crohn's disease) causing frequent,
      intermittent occlusive symptoms, treated by segmental ileal resection.

PMID- 12613345
TI  - [Laparoscopic treatment in a case of torsion of ovarian benign mature teratoma.
      Clinical case and review of the literature].
AB  - Benign mature teratomas account for approximately 10-17% of all ovarian neoplasms
      and are the type of ovarian neoplasm most likely to occur during a woman's
      reproductive life. Bilateral localization is observed in some 10-15% of cases and
      the estimated incidence of malignant degeneration is 0.5-1.8%. The authors report
      a case of a 35-year-old woman admitted with discontinuous abdominal and pelvic
      pain. Imaging procedures showed an adnexal mass with the appearance of a dermoid
      cyst. The patient underwent laparoscopic ovarian cystectomy with preservation of
      the adnexal gland. After a review of the international literature and a
      description of the clinical features of the disease the authors go on to stress
      the advantages of laparoscopic management of benign ovarian teratomas.

PMID- 12613346
TI  - Acupuncture: the best of the rest.

PMID- 12613347
TI  - Models and the early detection of disease: methodological considerations.

PMID- 12613348
TI  - Statistical models for screening: planning public health programs.

PMID- 12613349
TI  - Survival analysis methods in cancer studies.

PMID- 12613350
TI  - Cox proportional hazards regression models for survival data in cancer research.

PMID- 12613351
TI  - Some aspects of analysis of gene array data.

PMID- 12613352
TI  - An analysis of gene array data related to cell adhesion and prostate cancer.

PMID- 12613353
TI  - Spatial analysis of disease.
AB  - In this chapter, we have reviewed the history of the spatial analysis of disease
      and the statistical methods used for the exploratory analysis, testing and
      modeling of spatial patterns. In the next chapter, the principles described here
      will be illustrated.

PMID- 12613354
TI  - Spatial analysis of disease--applications.
AB  - The application of spatial statistical analysis to health data has reached
      adolescence. The theory and the software are both still maturing. We are drawing
      upon the experiences of the geostatisticians in modeling surfaces and the
      econometricians in modeling time series. "New and improved" computer algorithms
      are constantly being provided to implement the evolving theory or to improve the
      processing in terms of stability, reliability, and efficiency. We will come of
      age when we have the theory, the software, and the process to reliably produce
      "generalized spatio-temporal" models suitable for health data. In the meantime,
      biostatisticians need to acknowledge when their data is not independently
      distributed and to consider the spatial correlation in their analysis. This
      chapter provided examples using four available methods. The methods were spatial
      filtering, identifying clusters using the spatial scan statistic, hierarchical
      modeling, and conditional autoregression modeling.

PMID- 12613355
TI  - Cancer diagnostics: statistical methods.

PMID- 12613356
TI  - Case study: evaluating accuracy of cancer diagnostic tests.

PMID- 12613357
TI  - [The best of hypertension in 2002].
AB  - This year, the writing of "Best of hypertension 2002" was completed by the
      coordinators of 4 working groups of the French Society of Hypertension, in
      various domains: (a) the working group on BAroreflex and VARiability (BAVAR): it
      appeared mandatory to evaluate the influence of calculation methods on the values
      of spontaneous baroreflex sensitivity, through an european study (The EuroBaVar
      collaboration study); (b) the working group on Blood Pressure Measurement, was
      first involved in the establishment of an international protocol for the
      validation of self blood pressure measurement, then validated, according to this
      procedure and in collaboration with the French Medicine Agency, several apparatus
      dedicated to the French market; (c) the working group on epidemiology: after the
      publication of the IHPAF study (Incidence de l'hypertension dans la population
      active francaise), which unmasked the influence of social and professional
      determinants on blood pressure control, this group settled down ancillary studies
      in French Indias, the INAPAG study (INcidence de l'hypertension arterielle dans
      la population Antilles-Guyane), and the PHAPPG study (Prevalence de
      l'hypertension arterielle dans la population precaire guadeloupeenne); finally
      (d) the working group for continuous medical education settled down a national
      diploma, entitled "Hypertension and renal and cardiovascular risk".

PMID- 12613358
TI  - [The best of cardiac failure in 2002].
AB  - From 1989 to 1999, the incidence of cardiac failure appears stable but its
      prevalence has increased up to three folds. Obesity increases the risk of
      development of cardiac failure. In genetics, mutations in some proteins of
      muscular cells may lead to the occurrence of dilated cardiomyopathy. The interest
      of Brain Natriuretic Peptid was confirmed in case of acute dyspnea or diastolic
      dysfunction as well as its prognostic role in the functional capacity and the
      occurrence of sudden death. In the therapeutic field, a great disappointment came
      from the results of studies on omapatrilat. Despite its advantageous hemodynamic
      effects, this drug is not more efficacious than any ACE-inhibitor, but with much
      more side effects. New drugs (levosimendan, nesiritide) appear interesting in the
      acute heart failure. The short-term as well as long-term effects of cardiac
      resynchronization are confirmed. Implantable cardioverting defibrillators
      decrease the mortality of patients with a past history of myocardial infarction
      with severe left ventricle dysfunction. The artificial heart Jarvik 2000 appears
      to be hopeful for patients on waiting lists for heart transplantation.

PMID- 12613359
TI  - [The best of arrhythmias in 2002].
AB  - In the era of evidence based medicine the year 2002 will be remembered
      principally for having brought the results of two large trials in areas of daily
      preoccupation for rhythmologists: those of atrial fibrillation and of prevention
      of rhythmic sudden death. The Atrial Fibrillation Following Investigation of
      Rhythm Management (AFFIRM) study compared strategies for controlling frequency
      and rhythm in atrial fibrillation for subjects aged over 65 years or having at
      least one risk factor for cerebral vascular accident. In an unexpected fashion,
      although in accordance with other recent results, the two strategies are
      equivalent in terms of mortality. It also underlined the necessity of continuing
      anticoagulation with an INR > 2. even when it is proposed to maintain the rhythm.
      In the matter of primary prevention of sudden coronary death, the Multicenter
      Automatic Defibrillator Implantation Trial II (MADIT II) had the originality of
      evaluating patients with no other risk factor than a severe alteration in left
      ventricular ejection fraction (30% Pounds). This "simple" selection of patients
      at risk allowed a mortality reduction of 30% to be demonstrated by the placement
      of a ventricular defibrillator, in addition to that brought about by optimal
      conventional treatment. In the chapter on syncope, the Framingham study delivers
      information in terms of incidence and long term prognosis, in a non selected
      population. Even if these results are difficult to compare with those recent
      studies using notably the inclination test, they remind us of the poor prognosis
      of cardiac origin syncope and the absence of excess mortality in patients
      affected by vagal syncope. The significance of these very wide series does not
      preclude drawing the greatest attention to the work by the Bordeaux team who have
      been able to provide evidence, in 27 patients with relapsing idiopathic
      ventricular fibrillation, of the initiator role of extra-systoles originating
      from the distal Purkinje network. A medium term cure was obtainable by ablation
      of these extra-systoles. This work of course allows the prospect of application
      to other types of malign ventricular arrhythmias.

PMID- 12613360
TI  - [The best of echocardiography in 2002].
AB  - The role of echocardiography in cardiology practice continues to increase both in
      the everyday evaluation of patients and in the field of research. Nearly 3500
      bibliographic references on the subject were available in 2002... The advances
      achieved during one year often seem modest but reviewing the last 3 to 5 years,
      the progress of this method in clinical management has been significant. 2002
      will be remembered as the year in which 3D echocardiography, a technical
      revolution, became a routine tool. The matricial transducer generating a conic
      ultrasound beam from 3000 crystals allows routine visualisation of the heart in
      movement in three dimensions. In Doppler tissue imaging, the publications guide
      usage of this mode for identifying myocardial deformation during the cardiac
      cycle rather than simple abnormalities of wall motion as in initial experiences.
      Promising experimental results must be validated in clinical usage for this to
      become an everyday tool or analysis of regional myocardial contractility. A
      pioneer publication of clinical validation versus MRI showed excellent
      correlations both for healthy and abnormal myocardial segments. Contrast
      echocardiography has benefited from the introduction of new contrast agents
      tested in animals and new methods of image processing. It can be used in clinical
      practice to evaluate left ventricular function in difficult patients (chamber
      opacification). Semi-quantitative evaluation of myocardial perfusion by the
      transthoracic approach remains a field of research for expert centres in France.
      Finally, investigation of patients to determine the cause of systemic embolism
      has made additional progress as teams using harmonic imaging have identified high
      risk plaques of atheroma in over 90% of cases.

PMID- 12613361
TI  - [The best of cardiac pacing in 2002].
AB  - The year 2002 was marked by the publication of several studies for which the
      results have above all brought confirmation but also disappointment. One of them
      has even revealed a new therapeutic approach. In patients affected by sinus
      dysfunction the MOST study has shown the absence of superiority of DDD
      stimulation over VVI stimulation in respect of death and cerebral vascular
      accidents. However, double chamber stimulation reduces the risk of atrial
      fibrillation, the signs of cardiac insufficiency and slightly improves the
      quality of life. In the field of multisite stimulation, the MIRACLE study has in
      patients with moderate to severe cardiac insufficiency confirmed the results of
      the MUSTIC study with a significant improvement relating to the 6 minute walking
      test, the NYHA class, the quality of life, and the ejection fraction. The 12 and
      24 month follow up of patients included in the MUSTIC study has shown the
      persistence of the observed short term benefit. Hopes for prevention of atrial
      fibrillation by atrial stimulation piloted by special algorithms have not been
      confirmed by the results of the PIPAF study except for patients with
      predominantly spontaneous AV conduction. The significance of stimulation in
      disabling vaso-vagal syncope has been questioned by the publication of the
      results of the VPS 2 study. Cardiac stimulation could in the future constitute a
      new treatment for sleep apnoea syndrome because it has been reported that atrial
      overdrive significantly reduces the amount of central or obstructive apnoea.

PMID- 12613362
TI  - [The best of clinical pharmacology in 2002].
AB  - The results of several large therapeutic cardiovascular trials were reported in
      2002. The LIFE study concluded that losartan is superior compared to atenolol in
      terms of prevention of cardiovascular morbidity and mortality, the benefit being
      for CVA without changing the incidence of myocardial infarction. The OPTIMAAL
      study stated the disappointing results of post-infarct losartan. The IONA study
      represents a first demonstration with nicorandil of benefit not only in angina
      crises but equally on cardiac morbidity and mortality. The HPS study confirms the
      benefit of a statin in secondary prevention but for the first time, no matter
      what the initial level of LDL-cholesterol. Finally in the LIPS study, it is
      reported that statins reduce major cardiovascular events after coronary
      angioplasty. The year 2002 was marked elsewhere by imagination after the
      publication of the RAVEL study on coated stents delivering anti-proliferative
      drugs in order to avoid coronary restenosis. Three drugs were the subject of work
      confirming their potential significance in cardiovascular pathology: a)
      ezetimibe, representing a new class of cholesterol lowering drugs with which the
      association with statins seems especially synergic, b) nesiritide recombinant
      type B natriuretic peptide, whose significance was confirmed in acute cardiac
      insufficiency. c) levosimendan (calcium sensitisor) which moreover can be a
      significant treatment in cardiac decompensation as suggested by the LIDO study
      with a follow up of 180 days. By contrast, omapatrilate did not confirm its
      potential superiority over ACE inhibitors in the treatment of cardiac
      insufficiency. Some encouraging data were reported in 2002 in the field of
      therapeutic angiogenesis as much at the myocardial level as in lower limb
      arteritis. Finally, 2002 was marked by the publication of the WHI study which
      intensified suspicions regarding hormonal substitution treatment, confirming the
      advantage of not only secondary but perhaps primary cardiovascular prevention.

PMID- 12613363
TI  - [The best of pediatric cardiology in 2002].
AB  - This past year has been remarkable for considerable advance in the field of
      interventional cardiology for congenital heart disease. Ostium secundum atrial
      defect is by now cured by percutaneous closure with excellent results. Closure of
      patent foramen ovale (PFO) in patients with paradoxical embolism is still
      controversial. Nevertheless, some studies demonstrate the efficiency of this
      procedure, reducing the incidence of ischemic events. In cases of platypnoea
      orthodeoxia syndrome occurring in patients having undergone pneumonectomy or
      presenting dilatation of ascending aorta, closure of PFO with an occluder gives
      spectacular results with disappearance of dyspnea and cyanosis. Other more
      complex procedures such as closure of membranous ventricular septal defect,
      replacement of an pulmonary or aortic valve are still to be assessed. As the last
      point let us underline the progress of foetal cardiology, the studies of sudden
      death in children an adolescents, and the care of adults with congenital heart
      disease.

PMID- 12613364
TI  - [The best of coronary atheroma and interventional cardiology in 2002].
AB  - The year 2002 in interventional cardiology was monopolised by the concept of the
      active stent. Each step of the restenosis process can be targeted by the active
      principle: platelet thrombosis, inflammation, smooth muscle cell migration,
      smooth muscle cell proliferation. At this stage, only sirolimus and paclitaxel
      have successfully completed the clinical validation process in simple lesions.
      Certain questions remain unresolved: far from 0% restenosis, why are these
      devices less effective in lesions at high risk of restenosis? Why does sirolimus
      stent usage create effects of restenosis on the edges and why is it present in
      cases of positive remodelling of the artery for which the clinical role is still
      unknown? Above all, will the late escapement of the restenotic process observed
      in the animal model have a clinical correlation when there is a longer follow up?
      It is still too soon to know if paclitaxel will raise the same questions.
      Indications not yet completely validated for the metallic endoprosthesis are
      disappearing little by little: acute infarction, long lesions. At last restenosis
      has been put in its proper place: the rate of re-intervention at 9 months remains
      less than 15% in the whole of the Presto study; systematic angiographic follow up
      at 6 months in the Trends study shows a restenosis rate of 13% on average. So the
      boundary between active stent and metallic stent seems more blurred than in 2001
      when the results of the sirolimus studies were not available. The detection of
      ruptured or about to rupture plaque is a challenge which seems to be in hand now
      with techniques such as endocoronary echography or even more emergent techniques
      such as thermography, optical coherence tomography, or elastography. Which
      plaques should be treated? With medication? With mechanical tools? The work of
      the Lyon team on the clinical follow up of unstable plaques reveals a good
      prognosis for these plaques once the "guilty" lesion has been treated. The future
      of these techniques is thus perhaps more orientated towards primary prevention
      than towards secondary prevention.

PMID- 12613365
TI  - [The best of thrombosis in 2002].
AB  - In the area of myocardial infarction one is reminded of the publication of the
      CADILLAC study which has reopened the debate on the systematic use of GpIIbIIIa
      inhibitors in the acute phase of myocardial infarction complementing primary
      angioplasty with the placement of an endoprosthesis. New modalities for
      thrombolysis are in the course of evaluation, notably Eptibaphide Alteplase
      combination in the INTRO-AMI study and Tenecteplase Abciximab in association with
      enoxaparine or non-fractionated heparin in the TIMI 23 study. Several studies
      comparing angioplasty to lysis have been published. STOPAMI 2 evaluated
      myocardial salvage in the framework of primary angioplasty with placement of an
      endoprosthesis combined with abciximab infusion in comparison with half dose
      fibrinolysis associated with abciximab. CAPTIM is a strategy evaluation comparing
      the results of pre-hospital fibrinolysis with primary angioplasty. With the RITA
      3 study the interventional approach definitely comes top in comparison with a
      conservative approach for the treatment of unstable angina. One is equally
      reminded of the changes in the ACC/AHA recommendations for the management of
      unstable angina. The debate continues on the indications for thrombolysis in
      submassive pulmonary embolus. In the therapeutic area, one is reminded of the
      update on the interactions between angiotensin converting enzymes and aspirin in
      treatment and long term coronary syndrome. Finally, at the end of 2001, the work
      of French teams was published concerning the evaluation of risk of relapse for
      cerebral vascular accident in the presence of a foramen ovale or an aneurysm of
      the inter-atrial septum.

PMID- 12613366
TI  - [The best of vascular medicine in 2002].
AB  - During this year, cellular therapy with bone mononuclear cells of critical leg
      ischemia was demonstrated to be a new therapeutic approach in critical leg
      ischemia. This treatment, as well as gene therapy, is an important step forward
      in this pathology when there is no other therapeutic option. In venous
      thromboembolism, the usefulness of fibrinolytic therapy in severe pulmonary
      embolism associated with right ventricular dysfunction or pulmonary-artery
      hypertension was demonstrated. Fondaparinux appears also to be a promising agent
      for prophylaxis of deep vein thrombosis. Finally, the publication of the WHI
      trial (Women Health Initiative) confirms the absence of any benefit of hormone
      replacement therapy in primary cardiovascular prevention.

PMID- 12613367
TI  - [The best of nuclear cardiology and MRI in 2002].
AB  - In Nuclear Cardiology, the year 2002 was marked by a great number of studies on
      the gated-SPECT, which allows joint analysis of left ventricle perfusion and
      contraction. Even if conventional perfusion tomoscintigraphy confirms its
      foreground role, notably for prognostic evaluation, the value of the gated-SPECT
      is particularly significant in all areas of its use: coronary heart disease
      screening, prognosis evaluation, and myocardial viability assessment. Cavitary
      tomoscintigraphy allows direct evaluation of the ejection fraction and volumes in
      both ventricles. This innovative technique has been the subject of a great deal
      of methodological validation work, and will very likely replace traditional
      isotopic angiography in the future. At last, the value of MIBG scintigraphy for
      prognostic evaluation, of cardiac insufficiency has been defined, as has its
      significance for providing evidence of the effect of betablockers on pre-synaptic
      sympathetic innervation. The year 2002 has also been very fertile for
      technological innovations, methodological work, and in clinical studies
      concerning cardiac MRI. In particular, the significance of MRI for evaluating
      myocardial viability and the transmural extension of necrosis is now well
      established. Similarly, MRI is becoming an inescapable element in the assessment
      of congenital cardiopathy. However, its diffusion on a wider scale will only be
      possible if there is direct collaboration between cardiologists and radiologists.

PMID- 12613368
TI  - [The best of valvular heart disease in 2002].
AB  - For AS, besides a very thorough update by Carabello on their management, new
      experimental work confirms that the pathophysiology of the condition is closer to
      atherosclerotic and inflammatory processes than pure degeneration. Moreover this
      year brings a batch of long term post-operative results, one of which is an
      important series relating to 2194 bioprostheses followed up for 15 years. The
      choice of valvular substitute between 60 and 70 years old is the subject for
      several studies. A series of 259 re-operations for bioprosthesis deterioration
      allows quantification of the operative risk to which those with this substitute
      are subjected in case of degeneration. Finally, the strategy to adopt in a
      patient with an indication for aortocoronary bypass but also with a not-tight AS
      is discussed (abstention, decalcification, or "preventive" valvular
      replacement?). For aortic insufficiency (AI) some new results for the Ross
      operation have been published and the first publications reporting on the
      attempts of experimental positioning of bioprostheses via the percutaneous route
      in animals are appearing. As for mitral valvulopathies, MI has carved a
      privileged place. Much work this year relates amongst other things to functional
      MI in dilated cardiomyopathies with dilatation of the ring, to the natural
      history of mitral valvular prolapse detailed in an important series of 833
      patients, and to the evolutive risk of atrial fibrillation (AF) with MI and its
      treatment during plasty or mitral valvular replacement procedures. Anticoagulant
      treatment for mechanical prostheses is the subject of much work drawn from a
      large German prospective study (GELIA) confirming the general tendency for
      alleviation of intensity in aortic especially but also mitral valvulopathies,
      stressing the advantages of autocontrol. Finally, the Valvulopathy Working Group
      of the European Society of Cardiology publishes its recommendations for
      asymptomatic valvulopathies, recalling the echographic criteria of dilatation and
      left ventricular function to be retained for operative indications, emphasising
      furthermore the significance of the stress test in the follow up of asymptomatic
      AS.

PMID- 12613370
TI  - Dying patients as research subjects.

PMID- 12613371
TI  - The newly and nearly dead.

PMID- 12613372
TI  - Reproductive ethics.

PMID- 12613373
TI  - Physician-assisted death.

PMID- 12613374
TI  - Physician-assisted death.

PMID- 12613375
TI  - Physician-assisted death.

PMID- 12613376
TI  - About face.

PMID- 12613377
TI  - Personal genome sequencing: the answer to all of our worries.

PMID- 12613378
TI  - Man made mouse.

PMID- 12613379
TI  - "All's love, yet all's law".

PMID- 12613380
TI  - Going to pot.

PMID- 12613381
TI  - Two faces of health care quality improvement.

PMID- 12613382
TI  - Dying of gallstones.

PMID- 12613383
TI  - Physician-assisted suicide: a conservative critique of intervention.

PMID- 12613384
TI  - Revisiting ethical guidelines for research with terminal wean and brain-dead
      participants.
AB  - Some research is too risky to be conducted on anyone with a life expectancy of
      more than a few hours. Yet under some circumstances, the research can still be
      carried out by using subjects who are either brain dead or are soon to undergo a
      terminal wean, and who have articulated values that inclusion in the study can
      honor. So argues a team of ethicists and researchers at M.D. Anderson Cancer
      Center, where such research was recently undertaken.

PMID- 12613385
TI  - Body values: the case against compensating for transplant organs.
AB  - Proposals to compensate families for transplantable organs are gathering
      momentum. The proposals assume that the body is dissociable from the self and can
      be treated like property. But such a view is out of step with the rest of the
      culture.

PMID- 12613386
TI  - Managed care organizations and the rationing problem.
AB  - By and large, neither bioethicists nor economists have offered a satisfactory
      account of how managed care organizations should ration health care. Both
      disciplines would like to guarantee adequate care to all without defining
      adequacy. But it cannot be done. The more we rely on market forces to distribute
      health care, the more we need a national standard of care.

PMID- 12613387
TI  - Health care coverage for not-yet-born children.

PMID- 12613388
TI  - Professor Bhalachandra Babaji Dikshit (1902-1977): physiologist and
      pharmacologist, teacher and administrator.

PMID- 12613389
TI  - Airway rapidly adapting receptors--sensors of pulmonary extra-vascular fluid
      volume.
AB  - The factors regulating transfer of fluid into the pulmonary extra-vascular space
      and the role of sensory receptors of the airways in detecting such fluid fluxes
      are reviewed and discussed. It is concluded that the rapidly adapting receptors
      (RARs) located in apposition to bronchial venules are highly sensitive to changes
      in the pulmonary extra-vascular space produced by mild elevations of left atrial
      pressure, plasmapheresis and pulmonary lymphatic obstruction and their activation
      causes respiratory stimulation, an increase in tracheal tone and cough. There is
      a reflex diuresis also following the stimulation of these receptors by pulmonary
      lymphatic obstruction. It is proposed that the RARs function as a sensory
      component of the pulmonary defence mechanisms which preserve the 'milieu
      interior'.

PMID- 12613390
TI  - The use of nuclear magnetic resonance for assessment of time variation in
      composition of human milk and colostrum: a case study during pregnancy and post
      partum.
AB  - Nuclear Magnetic Resonance (NMR) Spectra were collected on milk and colostrum
      obtained from the author during the pregnancy and post-partum periods for two
      births. Peak features in the downfield region, containing antibody and aromatic
      resonances (6.0 to 9.0 ppm), varied over time. This time variation pattern, while
      nearly identical for milk following the author's two births, differed
      dramatically from the colostrum of another woman in labor. A possible pattern
      unique to each woman should be further investigated by monitoring NMR spectra on
      a larger sample. Downfield peak pattern variations were less intense between five
      women in later stages of lactation. Other spectral regions showed only minor
      variations with time and patterns did not differ significantly. These five women
      excreted proteins and/or small aromatic compounds in a time variant pattern
      assessable with NMR spectrocopy.

PMID- 12613391
TI  - Effect of ambient temperature on brain temperature and sleep-wakefulness in
      medial preoptic area lesioned rats.
AB  - The changes in brain temperature and sleep-wakefulness were studied in rats
      during their exposure to different ambient temperatures of 18 degrees C, 24
      degrees C and 30 degrees C, before and after N-methyl D-aspartic acid lesion of
      the medial preoptic area. The medial preoptic area lesion produced a decrease in
      sleep, and increase in brain temperature except at 30 degrees C. Increase and
      decrease in brain temperature with slow wave sleep and paradoxical sleep
      respectively, were observed both in normal and lesioned rats. Sleep-wakefulness
      and brain temperature cycle durations were increased and their frequencies
      decreased at higher ambient temperature in normal rats. After the medial preoptic
      area lesion, sleep-wakefulness cycle duration was decreased and frequency
      increased at 30 degrees C. There was no significant change in brain temperature
      cycles at higher ambient temperature in lesioned rats. The medial preoptic area,
      in normal rats, possibly interlinks the neuronal circuits involved in regulating
      brain temperature and sleep-wakefulness cycles. The medial preoptic area is
      essential for increasing the sleep-wakefulness cycle duration with higher ambient
      temperature. The possible contribution of the increased brain temperature
      variation in producing sleep-wakefulness changes cannot be ruled out. The results
      of the study show that this area may serve as a fine tuning mechanism which helps
      to interlink the sleep-wakefulness with the thermoregulation.

PMID- 12613392
TI  - Effect of Yoga asanas on nerve conduction in type 2 diabetes.
AB  - Twenty Type 2 diabetic subjects between the age group of 30-60 years were studied
      to see the effect of 40 days of Yoga asanas on the nerve conduction velocity. The
      duration of diabetes ranged from 0-10 years. Subject suffering from cardiac,
      renal and proliferative retinal complications were excluded from the study Yoga
      asanas included Suryanamskar. Tadasan, Konasan, Padmasan Pranayam,
      Paschimottansan Ardhmatsyendrasan, Shavasan, Pavanmukthasan, Sarpasan and
      Shavasan. Subjects were called to the cardio-respiratory laboratory in the
      morning time and were given training by the Yoga expert. The Yoga exercises were
      performed for 30-40 minutes every day for 40 days in the above sequence. The
      subjects were prescribed certain medicines and diet. The basal blood glucose,
      nerve conduction velocity of the median nerve was measured and repeated after 40
      days of Yogic regime. Another group of 20 Type 2 diabetes subjects of comparable
      age and severity, called the control group, were kept on prescribed medication
      and light physical exercises like walking. Their basal & post 40 days parameters
      were recorded for comparison. Right hand and left hand median nerve conduction
      velocity increased from 52.81 +/- 1.1 m/sec to 53.87 +/- 1.1 m/sec and 52.46 +/-
      1.0 to 54.75 +/- 1/1 m/sec respectively. Control group nerve function parameters
      deteriorated over the period of study, indicating that diabetes is a slowly
      progressive disease involving the nerves. Yoga asanas have a beneficial effect on
      glycaemic control and improve nerve function in mild to moderate Type 2 diabetes
      with sub-clinical neuropathy.

PMID- 12613393
TI  - Modulation of cold pressor-induced stress by shavasan in normal adult volunteers.
AB  - Shavasan is known to enhance one's ability to combat stressful situations. The
      present study was planned to determine if shavasan could modulate the
      physiological response to stress induced by cold pressor test (CPT) and the
      possible mechanisms involved. Ten normal adults were taught shavasan and
      practiced the same for a total duration of seven days. RR interval variation
      (RRIV), deep breathing difference (DBD), and heart rate, blood pressure & rate
      pressure-product (RPP) response to CPT were measured before and immediately after
      shavasan. Shavasan produced a significant increase in DBD and an appreciable but
      statistically insignificant increase in RRIV suggesting an enhanced
      parasympathetic activity. Significant blunting of cold pressor-induced increase
      in heart rate, blood pressure and RPP by shavasan was seen during and even five
      minutes after CPT suggesting that shavasan reduces the load on the heart by
      blunting the sympathetic response. It is concluded that shavasan can enhance
      one's ability to withstand stress induced by CPT and this ability can be achieved
      even with seven days of shavasan training.

PMID- 12613394
TI  - Study of yoga asanas in assessment of pulmonary function in NIDDM patients.
AB  - Certain yoga asanas if practiced regularly are known to have beneficial effects
      on human body. These yoga practices might be interacting with various, somato
      neuro-endocrine mechanisms to have therapeutic effects. The present study done in
      twenty four NIDDM patients of 30 to 60 year old, provides metabolic and clinical
      evidence of improvement in glycaemic control and pulmonary functions. These
      middle-aged subjects were type II diabetics on antihyperglycaemic and dietary
      regimen. Their baseline fasting and postprandial blood glucose and glycosylated
      Hb were monitored along with pulmonary function studies. The expert gave these
      patients training in yoga asanas and were pursed 30-40 min/day for 40 days under
      guidance. These asanas consisted of 13 well known postures, done in a sequence.
      After 40 days of yoga asanas regimen, the parameters were repeated. The results
      indicate that there was significant decrease in fasting blood glucose levels
      (basal 190.08 +/- 90.8 in mg/dl to 141.5 +/- 79.8 in mg/dl). The postprandial
      blood glucose levels also decreased (276.54 +/- 101.0 in mg/dl to 201.75 +/-
      104.1 in mg/dl), glycosylated hemoglobin showed a decrease (9.03 +/- 1.4% to 7.83
      +/- 2.6%). The FEV1, FVC, PEFR, MVV increased significantly (1.81 +/- 0.4 lt to
      2.08 +/- 0.4 lt, 2.20 +/- 0.6 lt to 2.37 +/- 0.5 lt, 3.30 +/- 1.0 lt/s to 4.43 +/
      1.4 lt/s and 64.59 +/- 25.7 lt min to 76.28 +/- 28.1 lt/min respectively).
      FEV1/FVC% improved (85 +/- 0.2% to 89 +/- 0.1%). These findings suggest that
      better glycaemic control and pulmonary functions can be obtained in NIDDM cases
      with yoga asanas and pranayama. The exact mechanism as to how these postures and
      controlled breathing, interact with somato-neuro-endocrine mechanism affecting
      metabolic and pulmonary functions remains to be worked out.

PMID- 12613395
TI  - A study on predictors of Peak Expiratory Flow Rate in Muslim subjects (aged 18 to
      20 years) of Karnataka.
AB  - This study aims to develop Peak Expiratory Flow Rate (PEFR) predictors for
      Karnataka Muslim male and female subjects of aged 18 to 20 years. PEFR was
      recorded in a standing position using mini Wright Peak Flow Meter on one hundred
      and four (104) healthy male and sixty one (61) healthy female subjects.
      Anthropometrical measurements i.e. height, weight, body surface area and body
      mass index were calculated. Statistically significant correlation were found in
      both sexes between PEFR and standing height (male, r = 0.94, P < 0.001; female, r
      = 0.95, P < 0.001), weight (male, r = 0.56, P < 0.001; female, r = 0.70, P <
      0.001) and body surface area (male, r = 0.68, P < 0.001; female, r = 0.57, P <
      0.001). The correlation between PEFR and body mass index were not found
      statistically significant in both sexes (male, r = 0.081; female, r = 0.17). The
      prediction equation for Karnataka male and female Muslim subjects (aged 18 to 20
      years) based on height, weight and body surface area and multiple regression
      equation based on all those physical parameters have been developed (PEFR (l/m)
      (male) = 1.7304 x height + 0.155 x weight + 140.45 x BSA + 5.02; PEFR (l/m)
      (female) = 2.0448 x height--16.08 weight + 664.697 x BSA--101.24).

PMID- 12613396
TI  - Physical fitness: a comparative study between students of residential (Sainik)
      and non-residential schools (aged 12-14 years).
AB  - Physical Fitness Index (PFI), of fifty Residential (Sainik) School children (Mean
      +/- SD, 13.18 +/- 0.48 yrs) and forty four Non-Residential school children (Mean
      +/- SD, 13.15 +/- 0.66 yrs) of Bijapur, Karnataka, was assessed by Harvard Step
      Test. Their height (cm), weight (kg), chest circumference (cm), and mid arm
      circumference (cm) were recorded as physical anthropometry. Body Mass Index (BMI)
      was also calculated (kg/m2). Results indicated that Non-Residential School
      children had poor physical anthropometry and showed a less PFI score (Mean +/-
      SD, 60.56 +/- 13.49), as compared to Residential (Sainik) School children (Mean
      +/- SD, 85.7 +/- 16.91). Regular physical activity with uniform diet and better
      physical composition attributed higher physical fitness in the children of
      Residential (Sainik) school in comparison to their sedentary Non-Residential
      counter part.

PMID- 12613397
TI  - Impact of psychological stress, gender and colour on visual response latency.
AB  - The measure of visual reaction time has been used to evaluate the processing
      speed of Central Nervous System and the co-ordination between the sensory and
      motor systems. As the reaction time is influenced by different factors, the
      impact of psychological stress, gender effect and the colour of objects in
      modulating the reaction time have been investigated in this study. 32 male and 38
      female medical students in the age group of 18-21 yrs participated as subjects.
      It was observed that a) the males had a visual reaction time lesser than their
      female counterparts b) response latency for green colour was lesser than that for
      red in both the males and the female subjects and c) psychological stress
      resulted in a significant decline in the reaction time to green colour in males.
      The longer reaction time in females could be due to the effect of female sex
      hormones, which reduced the velocity of nerve impulse and increased the synaptic
      delay. Green colour evoked a faster response due to its stronger stimulation on
      the visual receptors.

PMID- 12613398
TI  - Effect of partial ileal bypass on the lipid profile in the hyperlipedemic
      rabbits.
AB  - The hypocholesterolemic effect of partial ideal bypass was studied in two groups
      of healthy albino rabbits. Both groups of rabbits were made hypercholesterolemic
      by feeding them cholesterol suspended in groundnut oil (1 ml/kg bw) at a dose of
      100 ml/kg bw/day for one week. Group I rabbits were subjected to partial ileal
      bypass and group II rabbits were sham operated. Weekly estimation of serum lipid
      profiles were done for four more weeks while continuing cholesterol feed. After
      end of 5th week, it was found that partial ileal bypass not only prevented but
      also brought down its level from 132.8 mg% to 44.8 + 2.24 mg%, as compared to
      sham operates group where cholesterol level was 279 + 5.84 mg%. There was
      improvement in other parameters of lipid profiles namely HDL-C & LDL-C + VLDL-C
      and TAG.

PMID- 12613399
TI  - Effect of ursodeoxycholic acid on hydrogen peroxide induced lipid peroxidation in
      sheep liver mitochondria.
AB  - The effect of various concentrations of ursodeoxycholic acid (UDCA), a potent
      hepatoprotective agent on hydrogen peroxide-induced mitochondrial swelling was
      evaluated in vitro to find out the mechanism of action of the drug. Aliquots of
      sheep liver mitochondria were pre-incubated with various concentrations of UDCA
      [0-600 micrograms] and swelling was induced by hydrogen peroxide [1 mM]. Swelling
      was assessed at various time intervals and lipid peroxide, reduced glutathione
      status were also evaluated simultaneously. UDCA minimized hydrogen peroxide
      induced swelling in a dose-dependent manner. Time-dependent elevation in the
      level of lipid peroxides was noted in mitochondria treated with hydrogen peroxide
      and this elevation was minimized in UDCA pre-treatment. UDCA also maintains the
      reduced glutathione level in mitochondria. UDCA acts against the oxidative stress
      imposed in liver mitochondria. It reduces lipid peroxidation-induced
      abnormalities such as swelling and thiol group depletion and the anti lipid
      peroxidative efficacy of the drug may be related to its hydrophilic nature which
      might protect the hydrophobic regions of the mitochondrial membranes which are
      prone for free radical-mediated reactions.

PMID- 12613400
TI  - Improvement in oxidative status with yogic breathing in young healthy males.
AB  - The modern living lifestyle is known to produce various physical and
      psychological stresses and subject the individual to produce oxidative stresses
      as well. The aim of this study has been to assess the effect of yogic breathing
      exercises (pranayama) on the oxidatives stress. The study group consisted of 30
      young male volunteers, trained for the purpose of this study and an equal number
      of controls were used. The free radicals and Super oxide dismutase levels were
      measured before the study and at the end of the study. The free radicals were
      decreased significantly in the study group but the SOD was increased
      insignificantly as compared to the control group. Yogic breathing exercises not
      only help in relieving the stresses of life but also improve the antioxidant
      status of the individual. An improvement in the antioxidant status is helpful in
      preventing many pathological processes that are known with impaired antioxidant
      system of body.

PMID- 12613401
TI  - Effect of partial replacement of visible fat by ghee (clarified butter) on serum
      lipid profile.
AB  - A randomised controlled trial with a parallel design was conducted on 24 healthy
      young volunteers who were divided into two groups. After a lead-in period of 2
      wk, the experimental group (n = 11; 9 male, 2 female) had for 8 wk a
      lactovegetarian diet providing about 25% of the energy intake in the form of fat,
      of which ghee provided 10 en% and the remaining fat energy came from mustard oil
      and invisible fat. The control group (n = 13; 8 male, 5 female) had a similar
      diet except that all visible fat was in the form of mustard oil. In neither group
      was there any significant change in the serum lipid profile at any point in time.
      At 8 wk, 2 volunteers in the experimental group, and 1 volunteer in the control
      group had more than 20% rise in serum total cholesterol as compared to their 0 wk
      values. There was also an appreciable increase in HDL cholesterol at 8 wk in the
      experimental group, but it was not statistically significant. Consuming ghee at
      the level of 10 en% in a vegetarian diet generally has no effect on the serum
      lipid profile of young, healthy, physically active individuals, but a few
      individuals may respond differently.

PMID- 12613402
TI  - Effect of oral contraceptives on respiratory function.
AB  - The present study was carried out to assess the lung functions in oral
      contraceptive administered women. Lung function tests were carried out with
      Spirometer (Vitallograph Compact II). A significant increase in vital capacity
      (VC) was observed in these women as compared to normal control. There was also a
      significant decrease in forced expiratory volume in 1 sec./vital capacity
      (FEV1/VC%) and forced expiratory volume in 1 sec./forced vital capacity
      (FEV1/FVC%) among oral contraceptive administered women as compared to controls.
      Further, a significant increase in peak expiratory flow rate (PEF), reduction in
      forced expiratory flow rate (FEF75-85%) and FEF75% were observed among oral
      contraceptive administered women as compared to controls. The increase in VC and
      PEF might be due to the synthetic form of progesterone (progestins) present in
      oral contraceptive pills which causes hyperventilatory changes. Synthetic
      progesterone during luteal phase of menstrual cycle might increase the static and
      dynamic volumes of lung i.e. VC and PEF. But FEF75% showed a decrease which might
      be due to the lower neuromuscular coordination during breathing.

PMID- 12613403
TI  - Effect of cigarette smoking and 3.2% ethanol alone or together on RBC and
      platelet counts in rats.
AB  - The present study was conducted on 32 rats divided into four groups. Group C
      served as control, Group S rats were exposed to cigarette smoke alone, Group SE
      to cigarette smoke and ethanol (3.2%) and Group E to ethanol alone for twelve
      weeks. The basal RBC and platelet count were determined and compared with the
      values obtained at the end of 12 weeks. A significant increase in RBC and
      platelet counts was seen in Groups S (P < 0.001 and P < 0.01 respectively) and SE
      (P < 0.01 for both counts). The increase in group SE is less than that seen in
      Group S. Ethanol consumption alone has shown a significant decrease (P < 0.01) in
      RBC count and apparent decrease in platelet count as compared to control. This
      study indicates that cigarette smoke is damaging to health alone or when combined
      with ethanol.

PMID- 12613404
TI  - Effect of starvation stress on lipid peroxidation and lipid profile in rabbits.

PMID- 12613405
TI  - Brainstem auditory evoked potential in diabetes mellitus.

PMID- 12613406
TI  - Platelet aggregation patterns in normotensive and hypertensive subjects.

PMID- 12613407
TI  - Evaluation and management of occult and obscure gastrointestinal bleeding.
AB  - Gastrointestinal (GI) bleeding is a commonly encountered primary care clinical
      challenge. The AGA Medical Position Statement: Evaluation and Management of
      Occult and Obscure Gastrointestinal Bleeding, reviewed in this month's clinical
      practice guideline column, summarizes recommendations for the initial diagnostic
      approach and management for occult bleeding, as well as the subsequent diagnostic
      and management approach for obscure bleeding. The recommendations have
      applicability in primary care as nurse practitioners (NPs) assess the cause of
      occult bleeding and consult with specialists when obscure bleeding occurs.

PMID- 12613408
TI  - Health maintenance throughout the life span for individuals with Down syndrome.
AB  - PURPOSE: To describe the routine health maintenance needs of individuals with
      Down syndrome who have specialized health needs associated with the multi-system
      impact of the diagnosis. DATA SOURCES: Review of scientific literature including
      peer-reviewed articles, books, and online resources. CONCLUSION: In addition to
      the routine health maintenance needs of all persons, those with Down syndrome
      have specialized needs. Failure to address these specific health maintenance
      concerns may lead to misdiagnoses and failure to reach the highest level of
      function possible. IMPLICATIONS FOR PRACTICE: Patients with Down syndrome who
      have legitimate, treatable diagnoses may be misdiagnosed as having behavior
      problems or dementia. Failure to identify abnormalities such as cardiac problems
      or sleep apnea may shorten life and interfere with ability to live life to the
      fullest.

PMID- 12613409
TI  - Carpal tunnel syndrome: current theory, treatment, and the use of B6.
AB  - PURPOSE: To present the current state of the science of pathophysiology,
      assessment and treatment of carpal tunnel syndrome, including the use of
      pyridoxine (B6). DATA SOURCES: Selected research articles, texts, Websites,
      personal communications with experts, and the authors' own clinical experience.
      CONCLUSIONS: Much is yet to be learned about carpal tunnel syndrome. While the
      basic treatment of NSAIDs and nighttime splints seems universally accepted, much
      controversy remains. The use of vitamin B6 as a treatment is one such controversy
      requiring further investigation. IMPLICATIONS FOR PRACTICE: Current treatment for
      carpal tunnel syndrome should include NSAIDs, nighttime splinting, ergonomic
      workstation review, and vitamin B6 200 mg per day.

PMID- 12613410
TI  - Considerations in the management of the patient with comorbid depression and
      anxiety.
AB  - PURPOSE: To provide clinicians with guidelines for the assessment, evaluation,
      diagnosis, and management of comorbid depression and anxiety in the primary care
      setting. DATA SOURCES: Research-based articles in the medical and psychiatric
      literature, literature reviews by experts in the field, and DSM-IV-TR.
      CONCLUSIONS: Comorbid anxiety and depression occurs at a high rate in primary
      care, and is costly to both the individual and to society. These patients most
      often present in primary care settings, have more severe symptoms, and require
      more health care resources. The presentation of depression and anxiety together
      pose complicated diagnostic and treatment challenges, leading to inadequate
      diagnosis and treatment resulting in unnecessary patient distress and increased
      utilization of health care services. IMPLICATIONS FOR PRACTICE: This article is a
      review of comorbid depression and anxiety with a focus upon societal and patient
      significance and impact, under recognition and under treatment, diagnostic
      challenges, medical comorbidity, treatment considerations, and educational
      strategies. Effective assessment, evaluation, diagnosis and treatment can lead to
      better treatment outcomes and improved quality of life in primary care patients.

PMID- 12613411
TI  - Evaluation of a rape protocol: a five year follow-up with nurse managers.
AB  - PURPOSE: To evaluate the use and effectiveness of a protocol developed for
      emergency nurses and other medical personnel to use with survivors of sexual
      assault. The Ohio Department of Health (ODH) Protocol for the Treatment of Adult
      Sexual Assault Survivors was developed by a multi-disciplinary team in 1991-92 as
      a written guide to provide comprehensive, standardized, non-judgmental, and
      equitable treatment for survivors. In 1993, this 118-page manual was sent to all
      Ohio hospitals. In 1994, a follow-up video and training guide were also
      delivered. In 1997, Victims Rights Advocacy, a non-profit agency in Ohio, and the
      Center for Social Work Research at The University of Texas at Austin
      collaboratively conducted an evaluation of the utilization and effectiveness of
      this protocol at Ohio hospitals. DATA SOURCES: Emergency departments at Ohio
      hospitals were asked to complete a mailed survey regarding their policies and
      procedures for treating sexual assault patients. Telephone calls were made to the
      hospitals that did not return a survey, and site visits were conducted at 20
      hospitals in diverse areas of Ohio. CONCLUSIONS: Overall, respondents concurred
      that hospitals can benefit from using a standardized protocol, such as the ODH
      Protocol, for treating victims of sexual assault. Survey participants also
      indicated that training is needed on several topics, especially testifying in
      court, cultural awareness, and the needs of special populations, such as male,
      gay, lesbian, and bisexual survivors. In addition, findings indicate that
      survivors need more follow-up services, and written information about these
      services should be provided to them. IMPLICATIONS FOR PRACTICE: Nurse
      practitioners can improve the treatment of sexual assault survivors in their
      communities through a variety of actions, such as gathering information about
      available protocols and training opportunities for personnel, and becoming
      familiar with resources that can help victims.

PMID- 12613412
TI  - Procedures taught in family nurse practitioner programs in the United States.
AB  - PURPOSE: To determine the most frequently taught procedures and how important it
      is to teach these procedures in Family Nurse Practitioner (FNP) programs in the
      United States according to FNP program directors. DATA SOURCES: Each of the 178
      directors of FNP programs in the United States was mailed a survey to complete
      anonymously. The survey, designed for this study, listed 78 procedures. Directors
      were asked to indicate whether or not the procedure is taught in their FNP
      program and how important they think it is that FNP programs in the United States
      should teach that procedure. A total of 114 (64%) responded. CONCLUSIONS: A total
      of 10 of the 78 procedures were taught in 50% or more of the FNP programs. These
      procedures were: obtaining Papanicolau smears, testing visual acuity, audiometry,
      tympanometry, splinting of extremities, interpreting 12-Lead electrocardiograms,
      interpreting blood gases, local infiltration of anesthetics, single layer wound
      closure, and fluorescein staining of the eyes. The directors believed that six of
      these were very important to teach in FNP programs. IMPLICATIONS FOR PRACTICE:
      The findings of this study can be used to plan course content related to
      procedures in new FNP programs or to revise course content in existing programs.
      The study results are helpful to individuals who develop continuing education
      courses to target skills that NPs may find valuable or may need for their current
      employment setting but were not taught in their educational programs.

PMID- 12613413
TI  - Religions challenged over HIV prejudice.

PMID- 12613414
TI  - Another door opens.

PMID- 12613415
TI  - Life potential.

PMID- 12613416
TI  - Change of service. Interview by Pat Healy.

PMID- 12613417
TI  - Distance learning.

PMID- 12613418
TI  - Can you trust a no-blame culture?

PMID- 12613420
TI  - In my hands.

PMID- 12613421
TI  - Down the pan. Many school toilet blocks are outdated and unhygienic.

PMID- 12613422
TI  - Modernising the 12-hour shift.
AB  - AIM: To evaluate a year-long trial of a nursing shift pattern involving two 12
      hour and two six-and-a-quarter-hour shifts. METHOD: Twenty four nurses, four
      night sisters and two ward therapists were asked to complete a semi-structured
      questionnaire, and there was a 100 per cent response rate. Data on ward sickness,
      use of agency nurses, and 'untoward incidents' during the year were also
      analysed. RESULTS: Every nurse and therapist involved in the trial gave positive
      feedback regarding the new shift pattern. There was also a significant drop in
      sporadic sickness rates and agency nurse use during the year. CONCLUSION: A shift
      pattern involving two 12-hour and two six-and-a-quarter-hour shifts appears to
      hold benefits for nurses' health, wellbeing and job satisfaction.

PMID- 12613423
TI  - Nutrition in pregnancy: the facts and fallacies.
AB  - In addition to state registered dietitians, nurses and other health professionals
      face the challenge of communicating clear and consistent information about food,
      health and balanced diets to a wide range of clients. There are many
      misconceptions surrounding nutrition. Nutrition in pregnancy demands extra
      attention because the health of the mother and baby is affected. Pregnant women
      need specific information about nutrition.

PMID- 12613424
TI  - Undernutrition in hospital patients.
AB  - Undernutrition is a serious condition affecting significant numbers of patients
      in hospital. It increases the risk of mortality, delays recovery and increases
      the cost of hospitalisation. The prevention of undernutrition in hospital
      patients should be a priority for all healthcare professionals and requires a
      collaborative multidisciplinary approach.

PMID- 12613425
TI  - Assess your options.

PMID- 12613426
TI  - Whistling in the dark: a thing of the past.

PMID- 12613427
TI  - Violence towards the caregiver. A growing crisis for professional nursing.
AB  - The violence that permeates society at large does not stop at the hospital walls.
      Indeed, there exists mounting evidence (Carroll, 1998; Morgan, 1999; Trossman,
      2001) to suggest that workplace abuse of healthcare professionals, specifically
      nurses, by patients is a common and widespread problem. New research indicates
      that violence in the health care workplace is actually a global phenomenon.
      International Labor Organization [ILO]; International Council of Nurses [ICN];
      The World Health Organization [WHO]; Public Services International [PSI], (2001).
      More than 30 percent of nurses recently surveyed in seven states reported having
      been the victims of work place violence in the previous year. Patients had
      assaulted most of these nurses. (Colorado Nurses Association [CNA], 1998) Nurses
      are dying and suffering injuries at work as a result of violence (Doody 1995).
      The purpose of this paper is to increase nurses' awareness of the risk factors
      for violence in health care settings and to provide strategies for reducing
      nurses' exposure to these factors.

PMID- 12613428
TI  - A more comprehensive approach to sexual offenders.

PMID- 12613429
TI  - Youth homicide: a review of the literature and a blueprint for action.
AB  - This article first synthesizes the literature on clinical and empirical findings
      related to youth homicide. Thereafter, it reviews the literature with respect to
      the treatment of juvenile homicide offenders. Although a large body of literature
      exists, many questions regarding etiology, associated risk factors, intervention
      strategies, and long-term outcomes remain unanswered. The article concludes with
      recommendations to guide future research efforts with the aim of increasing
      understanding of etiological factors associated with juvenile homicide and
      designing effective intervention strategies. Greater advances in knowledge will
      follow with the implementation of enhanced methodological designs that examine
      juvenile homicide across four distinct time frames: the years preceding the
      homicide, the time period immediately following the homicide, the incarcerative
      or treatment period, and the post-release period.

PMID- 12613430
TI  - An empirical assessment of content in criminal psychological profiles.
AB  - Although criminal psychological profiling has been in use by law enforcement
      agencies for almost three decades, there is a paucity of empirical research
      examining the technique. A fundamental issue that has received little attention
      is the empirical evaluation of information contained in profiles composed by
      professional profilers. In this study, a group of profilers, police officers,
      psychologists, college students, and self-declared psychics were given
      information from a solved murder investigation, after which the participants
      composed a written profile predicting the probable offender. Professional
      profilers tended to write more lengthy profiles that contained more information
      about the nonphysical attributes of the offender and more information about the
      crime scene or the offender's behavior before, during, and after the crime. These
      results are discussed in terms of their implication for our broader understanding
      of the technique of profiling and future directions for research into profiling.

PMID- 12613431
TI  - Preventing filicide in families with autistic children.
AB  - Autism is a complex neurodevelopmental disorder that affects social behaviors and
      parent-child interaction. It has been associated with an increased risk of social
      victimization, and a recent rise in number of acts of filicide of developmentally
      disabled children has included several cases of autism. In this article, possible
      risk factors for filicidal behavior in families with autistic children and
      prevention strategies are reviewed.

PMID- 12613432
TI  - The inpatient evaluation and treatment of a self-professed budding serial killer.
AB  - The authors present the case of a man who was hospitalized after claiming that he
      was about to become a serial killer. The patient presented with extensive written
      homicidal fantasies and homicidal intentions without evidence of actual homicidal
      acts. In addition to routine assessments, hospital staff members used case
      conferences, psychological testing, outside forensic consultation, and a forensic
      review process to make decisions regarding diagnosis, treatment planning, and
      discharge. The patient was discharged after 8 months of inpatient treatment and
      was apparently free of homicidal impulses or symptoms of severe mental illness. A
      2-year court commitment allowed for the enactment and potential enforcement of a
      discharge plan that was endorsed by the patient, the hospital, and community care
      providers. The authors review diagnostic and risk management issues. Comparisons
      with known features of typical serial killers are made.

PMID- 12613433
TI  - From animal cruelty to serial murder: applying the graduation hypothesis.
AB  - Although serial murder has been recorded for centuries, limited academic
      attention has been given to this important topic. Scholars have attempted to
      examine the causality and motivations behind the rare phenomenon of serial
      murder. However, scant research exists which delves into the childhood
      characteristics of serial murderers. Using social learning theory, some of these
      studies present supporting evidence for a link between childhood animal cruelty
      and adult aggression toward humans. Based on five case studies of serial
      murderers, we contribute to the existing literature by exploring the possible
      link between childhood cruelty toward animals and serial murder with the
      application of the graduation hypothesis.

PMID- 12613434
TI  - Survival analysis of criminal recidivism of boot camp graduates using elements
      from general and developmental explanatory models.
AB  - This is a 5-year follow-up study of recidivism among 601 male graduates of a boot
      camp for adults in a southern state. Cox's proportional hazard analysis is used
      to determine the hazard rate of recidivism (arrest or parole violation) of
      several elements of general and developmental models. Analyses are conducted
      according to age of onset of unlawful behavior (10 years old or younger and older
      than 10 years). Findings indicate that caregiving factors have inverse relations
      with the hazard of recidivism, whereas low self-control, deficits in social
      skills, peer association with criminals, gang membership, drug use and sales, and
      carrying weapons have positive relationships with this hazard. These findings are
      observed irrespective of the age when persons begin committing offenses.
      Implications of the findings for theoretical models is discussed.

PMID- 12613435
TI  - [Who should implant the permanent pacemaker: the cardiologist or the
      cardiovascular surgeon?].

PMID- 12613436
TI  - An experimental contribution to the concept of "jumping wave" phenomenon in the
      interventricular septum.
AB  - OBJECTIVE: The purpose of this study was to evaluate the existence of a
      histologically bipartite interventricular septum and the electrical independence
      of both septal masses, as well as to understand the changes of septal activation
      fronts in the presence of bundle branch blocks. METHODOLOGY: We examined the
      histological characteristics of both septal masses in 12 canine hearts.
      Furthermore, in another 11 anesthetized dog hearts, we analyzed morphological and
      chronological data of intraseptal records with normal activation and in the
      presence of proximal blocks. RESULTS: A histological discontinuity between the
      two septal masses in canine hearts seems to exist. Analysis of intraseptal and
      intracavitary electrical records confirmed slow transmission of the activation
      fronts from one septal mass to the other when proximal blocks were present.
      Morphological and chronological changes of the intracavitary complexes agree with
      the "jumping wave" phenomenon theory. CONCLUSIONS: These results support the
      validity of this approach to the activation of both septal masses and explain the
      chronological and morphological changes of the intracavitary records in the
      presence of ventricular blocks. In addition, this approach is a useful tool to
      detect the possible coexistence of dead septal tissue.

PMID- 12613437
TI  - [Mitral valvuloplasty. The double balloon technique compared with the "Nucleus"
      single balloon technique].
AB  - Mitral stenosis requires mechanical management once the area decreases to
      critical values. We began practicing mitral valvuloplasty in 1994 with the double
      balloon technique and, since 1996, we have been performing the procedure using a
      single balloon called "Nucleus". We compare the immediate results of both
      techniques. We included 31 patients divided in two similar groups: group A
      (double balloon) of 15 patients, average Wilkins score of 7.13 +/- .80, mitral
      valve area pre-valvuloplasty of .83 +/- .25 cm2 and transmitral gradient of 17.06
      +/- 7.6 mmHg; group B (Nucleus balloon) of 16 patients, Wilkins score of 7.6 +/-
      .71, mitral valve area 1.05 +/- .33 cm2, transvalvular gradient of 14.26 +/- 5.00
      mmHg. Post-valvuloplasty valvular area increased in group A and group B,
      respectively, to 1.99 +/- .49 cm2 and 2.67 +/- .63 cm2 (p < .001); gradient
      decreased to 5.55 +/- 2.50 mmHg, and 2.95 +/- 2.32 mmHg (p < .001). Increase of
      mitral insufficiency of one grade was present on one patient of each group; one
      patient of group A had significant interatrial shunt after the procedure. The
      mitral valvuloplasty yields better results and is more practical when performed
      with the Nucleus balloon than with the double balloon.

PMID- 12613438
TI  - [Clinical and paraclinical course in patients with lower infarction with and
      without precordial ST segment depression].
AB  - OBJECTIVE: To know the early (30 days) and mid-term (6 months) clinical and
      paraclinical evolution of patients surviving an inferior infarct with or without
      precordial depression of the ST segment (RST). MATERIAL AND METHODS: We studied
      all patients with inferior myocardial infarction during 1998. Patients were
      divided in two groups according to the presence or absence of a significant and
      persistent low level of RST (> 2 mm for more than 24 h) at the precordial leads.
      We compared the clinical, paraclinical evolution and survival at 30 days and 6
      months after infarction. RESULTS: We studied 127 patients, 93 of them had
      persistent RST depression in the precordial leads, whereas the other 34 only
      presented changes at the inferior wall. The study revealed that those patients
      with changes in the anterior wall had a slightly higher frequency of cardiac
      failure, conduction disorders, deterioration of the left ventricular function,
      and plurivascular coronary disease. Likewise, it was flaund that RST depression
      at the precordial leads induced a greater mortality at 6 months. CONCLUSIONS: In
      patients with inferior myocardial infarction, the precordial depression of RST
      seems to be associated with an adverse clinical and paraclinical evolution, as
      well as a higher mortality. However, the differences are not statistically
      significant, therefore more studies are needed to elucidate this point.

PMID- 12613439
TI  - [Non-bacterial thrombotic endocarditis as paraneoplastic manifestation of
      pulmonary adenocarcinoma].
AB  - Non bacterial thrombotic endocarditis is characterized by the presence of non
      infected vegetation in aortic or mitral valves associated with systemic arterial
      emboli. Non-bacterial thrombotic endocarditis is a common complication of
      neoplastic diseases: adenocarcinoma of the lung, another adenocarcinomas,
      myeloma, lymphoma, leukemia, carcinoma of the pancreas, breast, cervix, colon and
      stomach. We report a case of non-bacterial thrombotic endocarditis localized in
      the aortic and mitral valves and systemic emboli as the first manifestation of
      adenocarcinoma of the lung.

PMID- 12613440
TI  - [Myocardial infarction simultaneous with Buerger disease (obliterating
      thromboangiitis). A case report].
AB  - BACKGROUND: Few cases of Buerger's disease concurring with visceral disorders,
      i.e., cardiac disease characterized by coronary obstruction have been published.
      We report the case of a 56 years old patient, with Buerger's disease concurring
      with ischemic heart disease: extensive anterior myocardial infarction,
      thrombosis, and obstruction of the left anterior descending coronary artery,
      evidenced through coronariography. DESCRIPTION OF THE CASE: Male patient, 56
      years old, severe smoker since the age of 15, obese, normal blood pressure,
      carrier of Buerger's disease for 15 years, without symptoms or signs of rheumatic
      disorders, and negative immunological tests, with antecedents of an old extensive
      myocardial infarction secondary to diffuse disease of the left anterior
      descending artery. At present, with symptoms and signs of ischemic cardiopathy
      and angiographic images suggesting the presence of thrombi inside the anterior
      descending coronary artery, of gracile aspect (corkscrew image), severe and
      diffusely obstructed (80%), and poor distal vascular bed. DISCUSSION: Causal
      association between Buerger's disease and coronary disease is rare and difficult
      to demonstrate in the absence of immunological and histopathological tests. Data
      provided by coronariography do not evidence a common origin for both diseases.
      However, the angiographic image of the gracile coronary artery, corkscrew-shaped,
      and with intraluminal thrombi suggests dissemination of the thromboangiitis to
      the coronary arterial bed. CONCLUSION: The concurrence of Buerger's disease with
      coronary pathology is rare. Coronary dissemination is difficult to demonstrate
      with only coronariography data; however, there are data in the medical literature
      suggesting that coronary obstruction, in these cases, results from the
      dissemination of the vasculopathy.

PMID- 12613441
TI  - [The target of reperfusion in acute coronary ischemic syndrome with ST segment
      elevation. The major paradigm: "Beyond TIMI 3 flow: the TIMI 4 or myocardial
      tissue-level perfusion"].
AB  - Treatment for ST- elevation acute coronary syndromes (acute myocardial
      infarction: AMI) has advanced rapidly in the last decade with major improvements
      in early fibrinolytic therapy (FT), primary percutaneous interventions (PCI) with
      the aid of platelet glycoprotein IIb/IIIa inhibitors. Recent interest has shifted
      from infarct related artery (IRA) patency to microvascular perfusion in the
      evaluation of patients with AMI. It is well known that establishing epicardial
      patency after AMI (TIMI 3 E) is not synonymous with tissue-level perfusion (TIMI
      4M). Microvascular dysfunction due to the roles of platelet and inflammatory
      mediators in the no-reflow phenomenon occurs in a substantial proportion of
      patients despite thrombolytic therapy or PCI procedures. Techniques are now
      available that measure real tissue-level perfusion and also therapy is directed
      to optimize myocardial perfusion in patients with AMI. Despite advances,
      contemporary FT strategies with the combination of platelet glycoprotein IIb/IIIa
      inhibitors restore normal coronary flow (TIMI 3) in the IRA in only 50-75% and
      PCI achieves TIMI 3 flow rates in 90-95%, but only with modest reductions in
      mortality, but with significant reductions in rethrombosis of the IRA or stents,
      reinfarctions and in some patients with benefits in ventricular dysfunction.
      Therefore moving beyond the importance of TIMI 3 flow, the TIMI 4 flow, or
      improving tissue-level perfusion in the setting of AMI seems to be the paradigm
      for the treatment of ST-elevation acute coronary syndromes.

PMID- 12613442
TI  - [Electric therapy for heart failure].
AB  - The different means for treating congestive heart failure have not yet achieved
      the improvement in quality of life and the prognosis of people with terminal
      stage cardiac disease. Some treatment resources, such as cardiac transplant, are
      only accessible for a selected group of patients. In the last decade, the
      interest on the role of electromechanic disturbances has grown and has motivated
      special interest for the use of the pacemaker as a tool for the treatment of
      congestive heart failure. During this period we have seen an important progress
      of this kind of treatment and, nowadays, multicenter studies have shown the
      hemodynamic improvement of the patients treated with this method. Selection of
      patients for this kind of treatment should be careful; although today it can be
      known which patients can benefit from this device in the treatment of congestive
      heart failure.

PMID- 12613443
TI  - Immunohistochemical profile of common epithelial neoplasms arising in the kidney.
AB  - To distinguish common epithelial tumors arising in the kidney may have
      significant implications, in terms of molecular ontogeny and prognosis. It is
      important to investigate the distribution of immunoexpression of commonly used
      markers among renal neoplasms and to develop a useful panel as an adjunct to
      histologic examination, which could lead to the accurate diagnosis of both
      primary and metastatic tumors. Immunohistochemical stains for CD10, vimentin
      (VIM), E-cadherin (E-CD), cytokeratins (CK) 7, 8, 19, and 20, high molecular
      weight keratin (HCK), and peanut lectin agglutinin (PL) (Arachis hypogaea) were
      performed on 45 (96 for CK7, CK20) conventional (CC), 20 papillary (PC), and 6
      (24 for CK7, CK20) chromophobe renal carcinomas (CPC); 12 oncocytomas (OC); 5
      collecting duct carcinomas (CDC), and 25 urothelial carcinomas of the renal
      pelvis (UC). Reactivity for CD10 was evaluated on the basis of the presence of
      cell surface staining; that for all CKs, cytoplasmic/membranous staining; and
      that for PL, luminal staining. Both CD10 and VIM were predominantly expressed in
      CC and PC; E-CD in CPC, OC, and UC; CK7 in PC, CPC, and UC; CK8 and CK19 in CDC
      and UC; CK20 in UC; HCK in CDC and UC; and PL in CDC. CC and OC were
      predominantly CK7-/CK20-; PC, CK7+/20-; CPC, CK7+/CK20- or CK7-/CK20-; and UC,
      CK7+/CK20- or CK7+/CK20+. CDC showed slight predominance of CK7-/20- over
      CK7+/CK20-. CC was most frequently CD10+/CK7-/HCK-/PL-; PC, CD10+/CK7+/HCK-/PL-;
      CPC, CD10-/CK7+/HCK-/PL-; OC, CD10-/CK7-/HCK-/ PL-; CDC, CD10-/CK7+/HCK-/PL+ or
      CD10-/CK7-/ HCK+/PL+; and UC, CD10-/CK7+/HCK+/PL-. Discriminant analysis
      suggested that CD10/CK7/HCK/PL may be a useful primary immunopanel for
      distinguishing among CC, PC, CDC, and UC.

PMID- 12613444
TI  - Surgery of cystic neoplasms.
AB  - Neoplastic cysts of the pancreas have been recognized since the nineteenth
      century, and although differences between neoplastic and proliferative cysts were
      acknowledged, they were treated similarly, first by marsupialization and later by
      internal drainage. Increased awareness of the malignant potential of neoplastic
      cysts, as well as advances in surgical techniques, made excision the preferred
      treatment for these lesions as early as the 1940s, but errors in diagnosis were
      frequent, and even to this date, continue to account for cases of pancreatic
      cystic tumors treated by drainage.

PMID- 12613445
TI  - [Jean Guillaume Auguste Lugol (1788-1851): his life and his works: a brief
      encounter, 150 years after his death].
AB  - J.G.A. Lugol was born on August 18th, 1788 at Montauban. Medical student in
      Paris, he was admitted as an intern of the hospital 1807. Medical doctor in 1812,
      he was appointed acting physician at Saint-Louis hospital of Paris in 1819 and
      named head of a department in the same establishment, a post he held till he
      retired in 1851. After his death on September 16th, 1851 at Neuilly-sur-Seine,
      his elder child, his daughter Adele-Augustine, married Paul Broca in 1857. French
      pioneer of iodine therapy, Lugol is famous for his iodine-iodurretted solution,
      still registered in the French Codex and present in most foreign Pharmacopoeia,
      and also for his four books on scrofulous diseases and their treatment (1829,
      1830, 1831, 1834) These publications gather a wealth of the detailed observations
      of an excellent practitioner who constantly proved a great independence of spirit
      towards some medical concepts "a la mode", especially those sustained by
      Broussais. He was very close to his patients and to his medical students, who
      admired the quality of his lessons, the efficiency of his therapeutic
      innovations, his intellectual uprightness as well as his success in private
      practice.

PMID- 12613446
TI  - Impact of clinical symptoms and referral volume on endoscopy for detecting peptic
      ulcer and gastric neoplasms.
AB  - BACKGROUND: We investigated the volume of dyspeptic patients referred by general
      practitioners (GPs) to upper gastrointestinal endoscopy and the impact on
      endoscopic findings. We also examined the correlation between clinical symptoms
      and endoscopic findings. METHODS: We collected data on patients sent for upper
      gastrointestinal endoscopy by GPs of 30 healthcare centres in 1996 in our
      hospital referral area of 260,000 inhabitants. In addition, national and local
      cancer registries were used to enumerate the gastric cancer cases detected in
      1996. RESULTS: The study population consisted of 3378 patients, mean age 58 years
      (interquartile range 25 years, male:female 1:1.3). Among the 30 healthcare
      centres, referral volumes for upper gastrointestinal endoscopy varied from 0.6 to
      9.2 per 1000 inhabitants per year (median 3.3/1000/year). In healthcare units
      with 'high' (> or = 3.3/1000/year, 15 healthcare units, 1297 patients) and 'low'
      (<3.3/1000/year, 15 healthcare units, 2065 patients) referral volumes, the
      detection rates were as follows: duodenal ulcer (DU) 3.5% (n = 46) versus 4.0% (n
      = 83, P = 0.5), gastric ulcer (GU) 4.9% (n = 64) versus 5.3% (n = 110, P = 0.6),
      gastropathy 43.8% (n = 568) versus 35.6% (n = 736, P < 0.001), gastric cancer
      0.5% (n = 6) versus 0.5% (n = 11, P = 0.8), gastric polyps 2.4% (n = 31) versus
      1.5% (n = 30, P < 0.05). Independent risk factors for gastric cancer were age (OR
      6.5 per decade, 95% CI 2.4-17.9), male sex (OR 5.5, 95% CI 1.8-17.1) and alarming
      symptoms and/or signs (OR 3.6, 95% CI 1.2-10.7); for GU, Helicobacter pylori (OR
      2.6, 95% CI 1.9-3.5) and alarming symptoms (OR 2.0, 95% CI 1.4-2.7); for DU, male
      sex (OR 1.6, 95% CI 1.1-2.2) and H. pylori (OR 3.9, 95% CI 2.7-5.5); and for
      gastric polyp(s), age (OR 2.0 per decade, 95% CI 1.1-3.5) and high referral
      volume (OR 1.7, 95% CI 1.0-2.0). A high referral volume did not associate
      positively either with the number of peptic ulcers or gastric cancer.
      CONCLUSIONS: Alarm symptoms associate strongly with significant gastric lesions
      such as GU and cancer. Increased referral volume results in an increased number
      of gastropathy and gastric polyp(s), but not of peptic ulcer or cancer.

PMID- 12613447
TI  - Crucell: biopharmaceuticals--as human as they get.

PMID- 12613449
TI  - Recent references.

PMID- 12613448
TI  - Linear stability analysis of retrieval state in associative memory neural
      networks of spiking neurons.
AB  - We study associative memory neural networks of the Hodgkin-Huxley type of spiking
      neurons in which multiple periodic spatiotemporal patterns of spike timing are
      memorized as limit-cycle-type attractors. In encoding the spatiotemporal
      patterns, we assume the spike-timing-dependent synaptic plasticity with the
      asymmetric time window. Analysis for periodic solution of retrieval state reveals
      that if the area of the negative part of the time window is equivalent to the
      positive part, then crosstalk among encoded patterns vanishes. Phase transition
      due to the loss of the stability of periodic solution is observed when we assume
      fast function for direct interaction among neurons. In order to evaluate the
      critical point of this phase transition, we employ Floquet theory in which the
      stability problem of the infinite number of spiking neurons interacting with
      function is reduced to the eigenvalue problem with the finite size of matrix.
      Numerical integration of the single-body dynamics yields the explicit value of
      the matrix, which enables us to determine the critical point of the phase
      transition with a high degree of precision.

PMID- 12613450
TI  - The Zoological Society Prize. Molecular and cellular approaches to planarian
      regeneration.

PMID- 12613451
TI  - The Zoological Society Prize. Control of eukaryotic flagella and cilia.

PMID- 12613452
TI  - The Zoological Society Prize. Taxonomy of invertebrates. Towards a better
      understanding of biodiversity.

PMID- 12613453
TI  - Zoological Society Young Investigator Award. Analysis of endostyle- and
      pharyngeal gill-specific genes: insight into the origin and evolution of
      chordates.

PMID- 12613454
TI  - Zoological Society Young Investigator Award. The biology of dicyemid mesozoans.

PMID- 12613455
TI  - Naturwissenschaften--the long-standing official organ of the German Society of
      Natural Scientists and Physicians.

PMID- 12613456
TI  - IgA antibodies to human immunodeficiency virus in serum, saliva and urine for
      early diagnosis of immunodeficiency virus infection in Ugandan infants.
AB  - The value of HIV-1 IgA antibodies for early diagnosis of HIV infection in infants
      in serum, saliva and urine was investigated at Mulago Hospital, Kampala.
      Sensitivity and specificity in serum of HIV-infected infants at different ages
      were: 0 to 1 months, 88 and 95%; 1 to 3 months, 88 and 97%; 4 to 6 months, 80 and
      96%. They decreased between 67 and 77% and 80 to 91%, respectively, in older age
      groups. Sensitivity for saliva was lower (53 to 79%) and urine only 37 to 62%,
      although specificity was reasonably high (>85%). The high proportion of infants
      with raised HIV IgA in the first months of life (88%) may represent prenatal
      infection. Sensitivity of serum and especially salivary and urinary HIV IgA is
      too low to be of practical value for early diagnosis of HIV infection in infants.

PMID- 12613457
TI  - Severe Raynaud's phenomenon with chronic hepatis C disease treated with
      interferon.
AB  - Severe Raynaud's phenomenon developed in a 5-year-old girl with chronic hepatitis
      C infection at the fifth month of interferon therapy in the absence of
      cryoglobulinemia and other conditions commonly associated with secondary
      Raynaud's phenomenon. Although interferon therapy was promptly discontinued,
      Raynaud's phenomenon persisted for 4 months with appearance of necrotic-ulcerous
      lesions at the tips of fingers.

PMID- 12613458
TI  - Disseminated Acanthamoeba infection in a human immunodeficiency virus-infected
      infant.
AB  - Infection with Acanthamoeba is difficult to diagnose and treat. We present the
      first case of disseminated Acanthamoeba infection in an HIV-infected infant. The
      infant survived 2 years with treatment with several agents having anti
      Acanthamoeba activity in vitro.

PMID- 12613459
TI  - Capofungin therapy for Aspergillus lung infection in a boy with chronic
      granulomatous disease.
AB  - Neutrophils of patients with chronic granulomatous disease (CGD) are profoundly
      defective in killing microorganisms. As in patients with chemotherapy-induced
      neutropenia, CGD patients are highly susceptible to life-threatening invasive
      Aspergillus infections, and conventional antimycotic treatment is not always
      successful. The new drug, caspofungin, was used to treat Aspergillus lung
      infection in one child with CGD.

PMID- 12613460
TI  - Fatal influenza A virus infection in a child vaccinated against influenza.
AB  - We report a fatal infection with influenza A virus in a 13-year-old child who had
      been vaccinated against influenza. Influenza A virus RNA was detected by PCR in
      lungs, bronchi and myocardium. A penicillin-sensitive strain of Staphylococcus
      aureus was also isolated from her bronchi. This case indicates that a primary
      viral pneumonia with influenza A virus complicated by a bacterial superinfection
      with S. aureus can run a fatal course even in a vaccinated child.

PMID- 12613461
TI  - Capnocytophaga gingivalis bacteremia detected only on quantitative blood cultures
      in a child with leukemia.
AB  - Capnocytophaga species are inhabitants of the normal mouth flora. We describe the
      case of a 6-year-old-girl with leukemia and poor oral hygiene who developed
      bacteremia caused by Capnocytophaga gingivalis. The organism was detected only on
      quantitative blood cultures.

PMID- 12613462
TI  - Capnocytophaga canimorsus meningitis in a newborn: an avoidable infection.
AB  - Capnocytophaga canimorsus causes dog-bite wound induced sepsis in adults, but
      infection may follow mucous membrane exposure. Systemic infection in children is
      extremely rare. A neonate with frequent exposure to a family dog and no cutaneous
      infection developed C. canimorsus meningitis. Suspicion of this pathogen requires
      laboratory consultation. Parental counseling can limit the risk of pet acquired
      infections.

PMID- 12613463
TI  - Pterygium surgery in Croatia.

PMID- 12613464
TI  - Small intestinal manometry.
AB  - Gastrointestinal motility is an integrated process including myoelectrical and
      contractile activity, tone, compliance and transit. The techniques for the
      assessment of gastrointestinal motility are multiple and all have their
      advantages and disadvantages. In the case of suspected abnormal upper gut
      transit, gastric and small bowel transit scintigraphy followed by small
      intestinal (antroduodenojejunalileal) manometry is recommended. Small bowel
      manometry can identify patterns suggestive of myopathy, neuropathy or
      obstruction. Information on procedures, indications, significance, pitfalls and
      guidelines for small bowel manometry is provided in this paper. In this context
      the potentials of small intestinal manometry for scientific experimental study of
      neurohumoral agents, such as serotonin receptor agonists and antagonists, on
      small intestinal motility is presented.

PMID- 12613465
TI  - Depinning transition of a driven interface in the random-field Ising model around
      the upper critical dimension.
AB  - We investigate the depinning transition for driven interfaces in the random-field
      Ising model for various dimensions. We consider the order parameter as a function
      of the control parameter (driving field) and examine the effect of thermal
      fluctuations. Although thermal fluctuations drive the system away from
      criticality, the order parameter obeys a certain scaling law for sufficiently low
      temperatures and the corresponding exponents are determined. Our results suggest
      that the so-called upper critical dimension of the depinning transition is five
      and that the systems belongs to the universality class of the quenched Edward
      Wilkinson equation.

PMID- 12613467
TI  - The Croatian Glagolitic Rule of St. Benedict.

PMID- 12613468
TI  - Bringing managed care home to people with chronic, disabling conditions:
      prospects and challenges for policy, practice, and research.
AB  - This article examines the challenges and opportunities inherent in the idea that
      home care organizations may be able to reinvent themselves into managed care
      systems for the frail elderly and chronically ill. Data come from three sources:
      (a) existing literature, (b) a survey with experts, and (c) insights from an
      organization with direct experience in designing and implementing first- and
      second-generation managed care programs. The authors conclude that although even
      the best-positioned home care organizations will face significant challenges in
      transitioning to managed care systems (e.g., establishing medical linkages,
      building managed care capacity, securing funding, dealing with regulatory
      hurdles), changes in the environment may enable these challenges to be overcome.
      Home care organizations are beginning to use innovative techniques to manage
      care, and those with a strong commitment to the chronically ill may be interested
      and capable of pursuing the option of becoming home-based managed chronic care
      programs.

PMID- 12613469
TI  - Managed long-term care: care integration through care coordination.
AB  - The New York State managed long-term care demonstration program combines
      traditional home, community, and institutional long-term care services with other
      benefits integral to maximizing overall well-being for a frail elderly
      population. A distinguishing feature of the model is the responsibility to
      coordinate both covered and noncovered services. This article, a case study of
      VNS CHOICE, a managed long-term care plan that serves 2,500 New York City
      residents, describes the program's operating structure, service delivery model,
      and care management strategies. By providing a capitated Medicaid long-term care
      benefit, VNS CHOICE can utilize a broad array of services, offer significant
      flexibility to care management staff, and support member and family involvement
      in care planning. Its broad care coordination responsibility allows it to achieve
      integrated care without integrated financing.

PMID- 12613470
TI  - Evaluation of the managed community care demonstration project.
AB  - The purpose of this article is to describe the impact of a capitated community
      care demonstration in Illinois that attempted to increase the range of services
      provided while constraining overall costs. The authors examined the
      implementation and outcomes, using pretest and posttest measures of client
      satisfaction, range of services, agency costs, and nursing home admissions.
      Demonstration clients (n = 752) had a mean age of 80, and an average of two
      activities of daily living impairments. The number of covered services increased
      from 3 at baseline to 14 during the demonstration, whereas the mean number of
      services used increased from 1 to 2.5. Satisfaction with care remained stable and
      agency average costs declined. The capitation rate more closely approximated
      agency costs than customary fee-for-service (FFS) and provided a fixed deductible
      for clients. No difference was seen in nursing home admissions compared to
      clients served under FFS in the same geographic location. These results imply
      that capitation increased the range of covered services, maintained client
      satisfaction, increased efficiency, and did not affect rate of nursing home
      admissions. Capitated home- and community-based services needs to be tested in
      other locations and with other providers.

PMID- 12613472
TI  - Managed long-term care: limits and lessons.
AB  - In the mid-1990s, states began to reduce their reliance on commercial health
      plans in the primary and acute care markets. At the same time, however, many
      states are for the first time encouraging these plans to participate in long-term
      care programs. The evidence suggests, however, that commercial health plans will
      not provide a quick cure to the long-term care system. At the same time, several
      states have managed long-term care initiatives that do not rely on commercial
      health plans but that do an excellent job of case management and that also seem
      to be among the national leaders in offering home and community-based services.
      Oregon provides one example, but so does the traditional managed long-term care
      system in Arizona and the Community Options Program in Wisconsin. The current
      efforts in Arizona and Wisconsin to abandon these models and to embrace
      competition may therefore be a mistake.

PMID- 12613473
TI  - Role of newer fluoroquinolones in lower respiratory tract infections.

PMID- 12613474
TI  - Recurrent bleeding from the tip of index finger and mucocutaneous telangiectases.
      Osler-Weber-Rendu syndrome.

PMID- 12613475
TI  - A triad of radiologic signs. Tuberculosis of the 1st metatarsophalangeal joint.

PMID- 12613476
TI  - [Combining clinical investigation with molecular genetics research: to push
      forward the study of hereditary colorectal carcinoma into a higher level in
      China].

PMID- 12613477
TI  - Behavior of the respiratory system under dynamic conditions.

PMID- 12613479
TI  - Another place for an ACE?

PMID- 12613478
TI  - Useful G-protein-coupled receptor websites.

PMID- 12613480
TI  - 5 things you should know about ABIs.

PMID- 12613481
TI  - No effect of oral treatment with an intestinal bacterial strain, Lactobacillus
      rhamnosus (ATCC 53103), on birch-pollen allergy: a placebo-controlled double
      blind study.

PMID- 12613482
TI  - [Following treatment of common bile duct lithiasis by endoscopic sphincterotomy,
      should it be completed by cholecystectomy?].

PMID- 12613483
TI  - [Preventive oophorectomy in women exhibiting BRCA mutations].

PMID- 12613484
TI  - Leveraging local funds to expand coverage in lean times.
AB  - "Lean times" is the phrase that defines most states' current budget environments.
      State revenue estimates for fiscal year 2002 continue to be revised downward, and
      the outlook for fiscal year 2003 is generally pessimistic. In these tight
      budgetary times, many states have made, or are considering making, cuts in state
      health care spending. One way to reduce spending and the number of uninsured is
      to leverage local dollars.

PMID- 12613485
TI  - [Recognizing the "neck-tongue" syndrome].

PMID- 12613486
TI  - [Kawasaki's disease in adults: a case report].

PMID- 12613487
TI  - [Pituitary stalk interruption syndrome. The little African girl didn't grow].

PMID- 12613488
TI  - Money multiplies. Revenue cycle solutions lead three-tiered update of healthcare
      system's business office.

PMID- 12613489
TI  - Bibliography. Current word literature. Erythroid system and its diseases.

PMID- 12613490
TI  - Bibliography. Current word literature. Vascular Biology.

PMID- 12613492
TI  - 2001 Report of the American Association of Feline Practitioners and Academy of
      Feline Medicine Advisory Panel on feline retrovirus testing and management.

PMID- 12613493
TI  - Managing the refractory case of feline IBD.

PMID- 12613494
TI  - Diastolic function--is this the key to successful management of many feline
      cardiomyopathies?

PMID- 12613495
TI  - Advanced therapeutic approaches for the management of uraemia--'the met and unmet
      needs'.

PMID- 12613496
TI  - [Republican Scientific-Practical Conference "Diagnosis and Treatment of
      Ulcerative Disease at Outpatient Facilities and Polyclinics and at Therapeutic
      and Surgical Hospital Departments". April 25-26, 2002, Tver'].

PMID- 12613497
TI  - Twin registers across the globe: what's out there in 2002?
AB  - Twin research offers the greatest power for the genetic analysis of complex
      multifactorial traits and diseases in humans. Modern twin analyses extend beyond
      the classical twin study for estimating the heritability of a trait. The human
      genome project can fulfil its promises only after functional characterisation of
      single genes in the context of genetic background and environment. Twin research
      can make a major contribution in that regard. Twin research is greatly
      facilitated by the willingness, motivation, cooperation, and generosity of the
      participants and their families. A second important aspect is the availability of
      twin registries that serve as a resource for genetic epidemiology. Currently,
      there is no systematic overview of the twin collections worldwide. This special
      issue will help to overcome the limited accessibility of this resource by
      providing basic information on most of the existing twin registers. Furthermore,
      an additional goal is to facilitate collaboration between registers. Some basic
      principles, potentials, and problems will be exemplified by my personal
      experience in the Berlin Twin Study.

PMID- 12613498
TI  - The Norwegian Institute of Public Health Twin Panel: a description of the sample
      and program of research.
AB  - The Norwegian Institute of Public Health in Oslo has an ongoing program of twin
      research using population-based cohorts of twins. The current database includes
      information on twins identified through the Medical Birth Registry of Norway and
      born from 1967-1979, altogether 15,370 twins. This is a longitudinal study with a
      cohort sequential design whereby new cohorts are recruited into the study at 5-6
      year intervals. Sub-samples of these twins have participated in questionnaire
      studies and clinical assessment sub-projects. These projects include national and
      international collaborations. Our primary areas of interest include mental health
      and psychological well-being, obesity, asthma and allergies, health behaviors and
      health perceptions, comorbidity, and perinatal influences on health outcomes.
      This paper provides a brief overview of the data, sample, and the various
      research projects associated with this twin program of research.

PMID- 12613499
TI  - Effects of simvastatin on bone regeneration in the mandibles of ovariectomized
      rats and on blood cholesterol levels.
AB  - The purpose of this study was to evaluate the effects of simvastatin on guided
      bone regeneration in the mandibles of ovariectomized rats, and to observe their
      blood cholesterol levels. Seventy female rats were divided into two groups:
      control and treated, both groups containing normal and ovariectomized rats. A
      month after ovariectomy a bone defect was created in the mandible, and was
      covered by a polytetrafluoroethylene membrane. The treated groups received
      simvastatin orally for 15 or 30 days. The rats were sacrificed 15, 30 or 60 days
      after surgery, at which time a blood sample was extracted for blood cholesterol
      level analysis and the mandible was extracted for densitometric, histological and
      morphometric analysis. All specimens underwent analysis of variance. The
      ovariectomized animals had higher cholesterol levels than the treated normal
      animals, and no significant difference was found between the different treatment
      periods and the sacrifice times. The densitometric, histological and morphometric
      analysis showed that the treated ovariectomized animals developed more new bone
      than the control ovariectomized rats, but no significant difference was observed
      between the treatment periods. It can be concluded that the deficiency of
      estrogen increased the level of blood cholesterol and that the simvastatin aided
      new bone formation in the ovariectomized animals.

PMID- 12613500
TI  - Submentovertex cephalometric analysis of Class II subdivision malocclusions.
AB  - Submentovertex cephalometric analysis was used to assess the mandibular symmetry
      of 20 patients with Class II subdivision malocclusion and 20 controls with Class
      I occlusions. Using the intercondylar line and the intercondylar axis, the
      relative differences were measured between mandibular landmarks in both
      anteroposterior and transverse dimensions. Anteroposterior and transverse
      differences between left and right mandibular positions and the transverse
      position of the dental midline showed a statistically significant difference
      between the groups. The position of the coronoid process also differed between
      the two groups. We conclude that the entire mandibular dentition is rotated in
      Class II subdivision malocclusions.

PMID- 12613501
TI  - Hepatocyte growth factor (HGF) system in gingiva: HGF activator expression by
      gingival epithelial cells.
AB  - Hepatocyte growth factor (HGF) acts as a mitogen, motogen, morphogen, and anti
      apoptotic factor for various kinds of epithelial cells. We previously showed that
      periodontal ligament and gingival fibroblasts secreted an HGF-like
      chemoattractant for a gingival epithelial cell line and found that the HGF
      content of gingival crevicular fluid was well correlated with clinical parameters
      and interleukin-1beta level. Since HGF is secreted as an inactive form (proHGF),
      and converted to an active form by serine proteases such as HGF activator (HGFA),
      extracellular processing of proHGF is presumed to be critical in the regulation
      of HGF activity. To examine the role of the HGF system in epithelial invasion
      followed by loss of connective tissue attachment in periodontitis, mRNA
      expression of HGF, its receptor (c-met) and HGFA in gingival tissues was
      monitored. Ten gingival biopsies were obtained, and epithelium and connective
      tissues were separated by enzymatic digestion. The gene expression of HGF and
      keratinocyte growth factor (KGF) in gingival connective tissue, and c-met, HGFA
      and KGF receptor (KGFR) in gingival epithelial tissues was monitored using RT
      PCR. Furthermore, HGFA protein in the conditioned medium of cultured primary
      gingival epithelial cells was examined using Western blotting. All the connective
      tissue samples expressed KGF, and 8 out of 10 samples expressed HGF. All the
      epithelial samples expressed KGFR and c-met, whereas 5 out of 10 samples
      expressed HGFA. Protein expression of HGFA by cultured primary gingival
      epithelial cells was also confirmed. In terms of local production and activation
      of HGF in gingival tissue, these results suggest that synergistic expression of
      HGF in connective tissue and HGFA expression in epithelium may contribute to
      disease progression in periodontitis.

PMID- 12613502
TI  - An improved method for detecting mutans streptococci using a commercial kit.
AB  - The improved detection of mutans streptococci (MS) in individuals was
      investigated using several modifications to a commercially available kit,
      Dentocult SM. Significantly better detection of MS was achieved using plaque from
      the four approximal surfaces at two interdental spaces than with saliva (P <
      0.001). Furthermore, the MS estimates for approximal surfaces at the same
      interdental space were similar (kappa = 0.654) suggesting that differentiating
      the two surfaces does not improve the detection of MS, and that increasing the
      number of interdental spaces sampled is a more effective option. This study also
      evaluated a modification to the standard Dentocult SM site strip method in which
      two strips were incubated per broth vial so that plaque from eight interdental
      spaces could be tested at the same time (new method). The results were compared
      to those obtained when one strip was incubated per broth vial (standard method).
      Although the MS estimates by the new and standard methods were comparable (kappa
      = 0.721), the efficiency of MS detection was improved significantly by increasing
      the number of sites used for MS estimates (P = 0.01). In conclusion, MS detection
      at eight interdental spaces is recommended using the new Dentocult SM method.

PMID- 12613503
TI  - Effect of rinsing hydrocolloid impressions using acidic electrolyzed water on
      surface roughness and surface hardness of stone models.
AB  - The present study investigated the effect on the surface quality of resultant
      stone models of rinsing hydrocolloid impressions using acidic electrolyzed water.
      Two brands of alginate impression materials (Aroma Fine DFIII, Jeltrate Plus), an
      agar impression material (Ajisai) designed for agar/alginate combined impression,
      and dental stone (New Plastone) were used to make the test specimens. For the
      rinsing of impressions, acidic electrolyzed water having a pH value of 2.3, an
      oxidation-reduction potential of 1,230 mV, and a residual chlorine concentration
      of 45.0 ppm, was prepared. Alginate, agar and agar/alginate combined impressions
      were rinsed using acidic electrolyzed water or tap water for 30 sec and 3 min,
      and as a control, these impressions were not rinsed with any water. Disk-shaped
      stone specimens obtained from rinsed impressions were evaluated with respect to
      surface roughness (Ra) and surface hardness (scratch depth), and scanning
      electron microscope (SEM) observations were performed. The stone specimens
      obtained from rinsed impressions using acidic electrolyzed water showed a surface
      quality equivalent to that of the stone specimens obtained from the rinsed
      impression using tap water. This result suggests that the use of acidic
      electrolyzed water for rinsing is an acceptable treatment for hydrocolloid
      impressions, so long as the rinsing time is from 30 sec to 3 min.

PMID- 12613504
TI  - Synthesis of organic-inorganic hybrid fillers at the molecular level and their
      application to composite resin.
AB  - The objective of this study was to synthesize a hybrid type filler composed of an
      organic component with inorganic component at the molecular level and to examine
      the properties of the filler. The composite resin was prepared by mixing
      synthesized filler with monomer and its physical properties were also examined.
      An organic-inorganic hybrid filler was synthesized by using 3
      methacryloxypropyltrimethoxysilane (3-MPTS), methyltriethyoxysilane (MTES) and
      methanol silica sol. Firstly, poly3-methacryloxypropyltrimethoxysilane (poly3
      MPTS) was synthesized by polymerization of 3-MPTS. A gelation product was
      obtained by graft-polymerization of poly3-MPTS with condensed organopolysiloxane
      after the hydrolysis of 3-MPTS, MTES and methanol silica sol. The gelation
      product was dried and ground to a filler. From the results of thermogravimetry
      differential thermal analysis (TG-DTA), the organic-inorganic hybrid filler was
      found to be composed of 16.5 wt% organic component, 83.1 wt% inorganic component
      and 0.4 wt% residual water. A trial composite resin was prepared by mixing 55 wt%
      dimethacryloxyethyl 2,2,4-trimethylhexamethylene diurethane (UDMA), 15 wt%
      triethyleneglycol dimethacrylate (TEGDMA), 30 wt% 1-fluoro-1,3,3,5,5-penta
      (methacryloxyethyleneoxy) cyclotriphosphazene [P3N3(F)1 (EMA)5] as a base monomer
      and then 32.0 wt% of this monomer was mixed with 68.0 wt % of synthesized filler
      and a photo initiator, comphorquinone (CQ), was added. Compressive strength of
      the trial visible-light cured composite resin showed 397.0 MPa, and flexural
      strength and elastic modulus showed 142.5 MPa and 11.5 GPa, respectively. From
      the results, it was demonstrated that the present organic-inorganic hybrid filler
      at the molecular level can be used as a composite resin filler.

PMID- 12613505
TI  - The effect of parachlorophenol and camphorated parachlorophenol on nitric oxide
      production by a murine macrophage cell line, RAW264.7.
AB  - The aim of this study was to determine the effect of parachlorophenol (PCP) and
      camphorated parachlorophenol (CMCP) on nitric oxide (NO) production by a murine
      macrophage cell line, RAW264.7. The cells were incubated on plastic disks with
      either PCP or CMCP. Plastic adherent and nonadherent cells were subsequently
      stimulated with recombinant mouse IFN-gamma or bacterial lipopolysaccharide
      (LPS). Nitric oxide (NO) levels detected from the culture supernatants were
      determined by the Griess reaction. The results showed that PCP and CMCP diluted
      at 10(-1) but not at 10(-3) suppressed NO production by both plastic adherent and
      nonadherent cells, suggesting that both phenolic compounds may suppress NO
      production by murine macrophages in a dose-dependent manner.

PMID- 12613506
TI  - An alternative method for fabricating a closed hollow obturator: a clinical
      report.
AB  - This article describes a procedure in which the fabrication of a closed hollow
      obturator can be made with three sections of a denture flask by using silicone.
      Ease of fabrication while controlling the thickness of the hollow portion and
      eliminating leakage and discoloration are major advantages of this technique
      while minimizing laboratory and clinical appointment time.

PMID- 12613507
TI  - Satisfaction of orthognathic surgical patients in a Malaysian population.
AB  - Thirty-one patients treated at the Faculty of Dentistry, University of Malaya,
      were assessed for their satisfaction following orthognathic surgery. The female
      to male ratio was 22:9 with an age range of 17 to 36. Almost all patients (97%)
      listed appearance as one of their rationales for surgery. More males (78%) than
      females (59%) wanted functional improvement, while more females (91%) than males
      (33%) hoped for improvement in self-confidence. All patients reported esthetic
      improvement while 68% each reported improvement in mastication and self
      confidence. Slightly more than half (52%) chose esthetic improvement as the
      single most important factor resulting in satisfaction. Almost ninety percent of
      male patients claimed satisfaction with functional improvement, while 68% of
      those who found satisfaction in improved self-confidence were females. Eighty
      seven percent rated their post-surgical changes as being well accepted by their
      family. The impact of these findings on the success of the surgery and the need
      to reinforce verbal communication with printed pamphlets are emphasized.

PMID- 12613508
TI  - The term "primary intraosseous carcinoma".

PMID- 12613509
TI  - Survivin an important determinant for prognosis in adult T-cell leukemia: a novel
      biomarker in practical hemato-oncology.
AB  - Survivin is a 16.5-kDa protein that belongs to the inhibitor of apoptosis (IAP)
      family. It is expressed at high levels in the G2/M phase and is rapidly down
      regulated after cell-cycle arrest. It was suggested that survivin plays a pivotal
      role in linking cell death and cell proliferation. Although present during fetal
      development, survivin disappears in terminally differentiated adult tissues. Its
      expression is aberrantly enhanced in transformed cell lines, and in all the most
      common human cancers. Adult T-cell leukemia (ATL), which is abundant with Fas
      (Apo-1/CD95), has the characteristic feature of high tumor burden, suggesting
      that ATL cells probably prolong their lives as a result of escape from apoptosis.
      Survivin is prominently and consistently expressed in all cases of ATL and ATL
      cell lines. Its mRNA expression levels among the subtypes of ATL and ATL cell
      lines are characteristic and informative, low in chronic type, low to high in
      acute type and extremely high in ATL cell lines. In addition, when the survivin
      mRNA expression is higher, the survival of the patient is shorter. Its
      overexpression may account for a growth advantage in vivo and subsequently the
      malignant behavior of ATL. So quantification of survivin mRNA is important for
      clinical laboratory examinations. Among all of the current clinical tests for
      survivin mRNA quantification, the real time PCR is desirable. Despite some
      technological problems of standardization, quantification of survivin mRNA was
      shown to be a biological marker for clinical stages or minimal residual disease
      (MRD).

PMID- 12613510
TI  - Tryptase a novel biochemical marker of acute myeloid leukemia.
AB  - Despite maturation arrest, blast cells in acute myeloid leukemia (AML) are often
      capable of expressing lineage-restricted (granulomonocytic or myelomastocytic)
      differentiation antigens. Tryptases are lineage-associated serine proteases
      primarily expressed in mast cells, and less abundantly in blood basophils. We
      have recently shown that myeloblasts in a group of patients with AML
      (approximately 40%) produce significant amounts of tryptase(s). In these
      patients, serum tryptase levels are elevated (> 15 ng/ml) and reflect the total
      burden of leukemic cells. In most cases, myeloblasts express alpha-tryptase mRNA
      in excess over beta-tryptase mRNA, and secrete the respective protein (= pro
      alpha-tryptase) in a constitutive manner. It was also found that these AML blasts
      frequentlyco-express tryptase with additional mast cell lineage- and/or basophil
      related differentiation antigens including KIT (CD117), histamine, and 2D7. We
      hypothesize that tryptase-positive AMLs arise from a leukemic progenitor that
      exhibits a limited potential to differentiate into mast cells and/or basophils.

PMID- 12613511
TI  - Hematopoietic potential of neural stem cells: plasticity versus heterogeneity.
AB  - Organ-specific stem cells have been identified in a variety of mammalian tissues.
      These cells hold great promise for cellular therapy if they can reliably produce
      functional progeny of specific lineages. A central dogma in development has been
      that organ-specific stem cells are restricted to making the differentiated cell
      types of the tissue from which they are isolated. However, a substantial body of
      evidence exists that stem-cell populations from neural and hematopoietic tissues
      can generate the other cell types, suggesting that adult organ-specific stem
      cells may have a broader differentiation potential than originally thought. It
      remains unclear whether this apparent stem cell plasticity is attributable to
      transdifferentiation of tissue specific stem cells, the co-existence of multiple
      stem cells with different potentials, or resident totipotent stem cells in these
      tissues. Recent evidence, in fact, indicates that there may be a fourth
      explanation for the "apparent" plasticity of stem cells: cell fusion. Here, the
      authors critically examine the existing data to assess the extent of phenotypic
      conversion of bone marrow-to-brain and brain-to-blood and discuss some of the
      contentious issues surrounding these studies. We conclude that there is strong
      evidence for a multipotent neurohematopoietic stem-cell population in human and
      mouse brain, although further characterization of these cells will be required if
      the goal of engineering tissues for therapeutic applications is to be realized.

PMID- 12613512
TI  - Development of human lymphohematopoiesis defined by CD34 and CD81 expression.
AB  - Human blood cells, except for erythrocytes and platelets, express CD81, a member
      of the transmembrane 4 superfamily (TM4SF). CD81 is also expressed on most of
      human immature hematopoietic cells, CD34+ cells, which are divided into three
      populations according to the expression of CD34 and CD81; CD34+CD81+,
      CD34+CD81(High) and CD34(Low)CD81+. Myeloid and lymphoid progenitors exist in the
      CD34+CD81+ population, and megakaryocytic progenitors are only in CD34(Low)CD81+
      population. Erythroid and multipotential progenitors are shared by CD34+CD81+ and
      CD34(Low)CD81+ populations, but multipotential progenitors in the CD34+CD81+
      population have already lost most of their myeloid potential. NK cells and mast
      cells can be generated from all three populations. Long-term repopulating (LTR)
      lymphohematopoietic stem cells are present in the CD34+CD81+ population. Based on
      these findings, we propose a model for the development of CD34+CD81+
      lymphohematopoietic stem cells. Along the differentiation cascade from CD34+CD81+
      lymphohematopoietic stem cells, there appear to be pathways to CD34(Low)CD81 + or
      CD34+CD81(High) cells, even if they are indirect. CD34(Low)CD81+ pathways define
      the loss of LTR ability, and lymphoid and myeloid potentials, whereas
      CD34+CD81(High) pathways represent the exclusive commitment to NK cells and mast
      cells.

PMID- 12613513
TI  - Treatment of adult T-cell leukemia-lymphoma by CHOP followed by therapy with
      antinucleosides, alpha interferon and oral etoposide.
AB  - Adult T-cell leukemia-lymphoma (ATLL) has a very bad prognosis and remains
      resistant to conventional therapy. Promising results have been reported with the
      combination of zidovudine (AZT) and alpha-interferon (IFN). METHOD: A combination
      with IFN and antinucleoside [AZT or zalcitabine (ddC)] was applied since 1995 in
      Martinique (French West Indies). An initial treatment with two cycles of CHOP was
      added to reduce initial tumoral burden, followed by antiretroviral (ARV) therapy
      associated with etoposide. We report the characteristics and outcomes of 29
      patients diagnosed with an ATLL between 1990 and 1999. The overall median
      survival was 8 months. A striking improvement of survival was observed when
      comparing the periods between 1990-1994 and 1995-1999 (17 months versus 3 months,
      p = 0.004). During the second period, seven patients received a therapy with oral
      etoposide, antinucleoside and IFN, among which, six patients received an initial
      induction CHOP chemotherapy. No major toxicity was observed with this strategy.
      In conclusion, the progression of survival since 1995 suggests that a therapeutic
      approach combining initial polychemotherapy with CHOP followed by ARV drugs, IFN
      and oral etoposide is an interesting option in treating patients with ATLL.

PMID- 12613514
TI  - Quantitative monitoring of BCR/ABL transcript during STI-571 therapy.
AB  - PCR for the BCR/ABL fusion transcript provides a highly sensitive and specific
      method for detecting minimal residual disease in patients with chronic myeloid
      leukemia (CML). We sought to determine if quantitative PCR measurement of
      peripheral blood BCR/ABL transcript can be used to monitor response in CML
      patients with clinically evident disease while receiving the protein tyrosine
      kinase inhibitor STI-571. Serial bone marrow cytogenetics and peripheral blood
      BCR/ABL mRNA levels were measured in 17 patients [9 with chronic phase (CP) and 8
      with accelerated phase or blast crisis (AP/BC)] during 1 year of treatment.
      Overall, quantitative PCR BCR/ABL transcript level decreased by a median of 0.9
      log during the first 3 months, and by 1.6 logs by 12 months. Among cytogenetic
      responders (6 CP and 2 AP/BC), median BCR/ABL copy number was 0.9 and 2.1 logs
      lower than baseline after 3 and 12 months of treatment, respectively. No patient
      became PCR-negative for BCR/ABL. Among cytogenetic non-responders, BCR/ABL
      transcript level decreased by 0.4 logs after 3 months, with no subsequent
      reductions. At study entry, BCR/ABL expression in cytogenetic responders and non
      responders was similar. However, BCR/ABL expression became significantly
      different 3 months after treatment (p = 0.02), and increasingly different with
      continued therapy (p = 0.04, 0.005, 0.0008 at 6, 9 and 12 months, respectively).
      Our results demonstrate that PBMC BCR/ABL mRNA levels correlate well with
      response to STI-571. This non-invasive, rapid and sensitive PCR-based assay can
      be used to monitor response to STI-571.

PMID- 12613515
TI  - Rapid screening of leukemia fusion transcripts in acute leukemia by real-time
      PCR.
AB  - We established a real-time PCR method that can simultaneously detect 10 different
      fusion transcripts (major, minor and micro BCR/ABL, AML1/MTG8, PML/RARalpha,
      CBFbeta/MYH11, TEL/AML1, E2A/PBX1, MLL/AF4, and MLL/AF9) together with Wilms'
      tumor gene (WT1) transcripts. This screening method allowed the processing of six
      specimens concomitantly and required only one working day from RNA extraction to
      final results. Fifty-seven bone marrow (BM) samples from patients with acute
      leukemia were retrospectively screened for the presence of fusion and WT1
      transcripts without knowledge of the cytogenetic data, and the fusion transcripts
      were detected in 20 of 57 samples (35.1%). The concordance between the present
      method and cytogenetic analysis was examined in 38 samples in which the
      cytogenetic data were available. In 12 of 38 samples, the PCR results agreed with
      the cytogenetic data, whereas in 4 of the remaining 26 samples, the
      translocations were detected by real-time PCR alone because of the insufficient
      number of metaphases obtained and presumably the submicroscopic or masked
      translocations. The WT1 levels ranged from 400 to 690,000 copies/microg RNA in BM
      from leukemia patients, whereas 0-470 copies/microg RNA were found in BM cells
      from BMT donors. This real-time PCR method enables rapid and efficient
      characterization of acute leukemia in addition to subsequent evaluation of
      minimal residual diseases.

PMID- 12613516
TI  - Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of
      individual patient data from five studies.
AB  - Trials to determine the effect of thalidomide in patients with Myelofibrosis with
      Myeloid Metaplasia (MMM) have produced inconclusive results due to different
      criteria for response and heterogeneous study participants. We undertook a pooled
      analysis to assess the effects of such treatment on a larger series of cases and
      with a uniform assessment of response. We used updated data on 62 individual
      patients from 5 phase II trials that evaluated thalidomide therapy in MMM
      patients. Responsewas judged on individual disease parameters, on the improvement
      of the Dupriez risk categories and on the improvement of a 6 point "severity
      score" based on myeloproliferative and myelodepletive indexes of the disease.
      Overall, using standard dose of thalidomide, i.e. starting with no less than 100
      mg/day, 49 patients (79%) had more than 4 weeks of therapy. Twenty-nine percent
      of patients with moderate to severe anemia showed an increase in hemoglobin or
      reduction/abolishment of blood transfusion requirements, 38% with moderate to
      severe thrombocytopenia had an increase in platelet counts, and 41% with high
      grade splenomegaly demonstrated a measurable reduction in splenic size. These
      effects led to an absolute decrease in the "severity" score in 44.9% of the
      patients. Major disease severity and high degrees of splenomegaly before therapy
      predicted response with a probability of 61.9%. However, worsening of the
      "severity" score was observed in 20.4% of the patients, 18% having a
      "myeloproliferative reaction" with leukocytosis and/or thrombocytosis. Sixty-six
      percent of the patients discontinued the drug before 6 months of treatment due to
      intolerance. In conclusion, there is a small but clear improvement of disease
      severity with thalidomide therapy in MMM. The potential for myeloproliferative
      reactions and the unfavorable dose-related toxicity profile argue for future
      studies using lower doses of this drug.

PMID- 12613517
TI  - Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large
      B-cell and follicular center lymphoma: correlation with clinical outcome.
AB  - ASPP2 interacts with the tumor suppressor protein p53, promotes damage-induced
      apoptosis, and can specifically stimulate p53 apoptotic function. Thus, ASPP2 may
      function as a tumor suppressor and/or play a role in the cellular response to
      cytotoxic injury. To explore the role of ASPP2 in human cancer, we determined
      ASPP2 expression in two lymphoma subtypes with differing clinical outcomes:
      diffuse large B-cell lymphoma (DLBCL) and follicular center lymphoma (FCL). A
      real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was
      developed to detect ASPP2 mRNA. Sixty-one DLBCL and twenty-three FCL cases were
      analyzed and normalized ASPP2 levels were expressed relative to an mRNA standard.
      We found that ASPP2 mean expression strongly correlated with lymphoma subtype:
      DLBCL = 11.74 and FCL = 4.99 (p = 0.029, unpaired 2-tailed t-test). Importantly,
      ASPP2 expression was variable in DLBCL but not FCL (DLBCL-range, 0.04-94.6; FCL
      range, 1.2-15.0). In these DLBCL cases, serum lactate dehydrogenase (LDH) was an
      independent predictor of survival with median survival in the high LDH group of
      24 months and median survival not achieved in the normal-low LDH group (p =
      0.014, Log-Rank Test). Mean ASPP2 levels trended toward an inverse correlation
      with LDH levels: High LDH, ASPP2 = 6.2; Normal-low LDH, ASPP2 = 18.2 (p = 0.074,
      unpaired 2-tailed t-test). In the DLBCL cases with ASPP2 levels > 7.8, only 10%
      (1/10) had a high LDH, in contrast to cases with ASPP2 levels < 7.8 in which 59%
      (26/44) had a high LDH (p = 0.011, Fisher Exact Test). Thus, low ASPP2 mRNA
      levels may correlate with poor clinical outcome in lymphoma which is consistent
      with the hypothesis that ASPP2 may play a role in tumor formation and/or
      sensitivity to cytotoxic agents. Larger studies as well as analysis of different
      tumor types are warranted.

PMID- 12613518
TI  - Alternation of epirubicin and mitoxantrone in CHOP-like regimens retains efficacy
      and reduces overall toxicity in elderly patients with high and intermediate grade
      non-Hodgkin lymphomas.
AB  - Mitoxantrone and Epirubicin are active agents in non-Hodgkin's lymphomas (NHL).
      These drugs have reduced cardiotoxicity and therefore are indicated in treatment
      of elderly patients. Cyclophosphamide, mitoxantrone, vincristine and
      methylprednisone (CNOP) and cyclophosphamide, epirubicin, vincristine and
      methylprednisone (CEOP) are combination chemotherapy and contain Mitoxantrone and
      Epirubicin that have been shown to be effective in treatment of NHL of
      intermediate and highgrade of malignancy in the elderly. Since Mitoxantrone and
      Epirubicin are partially non-cross resistant their combined use may diminish
      emergence of resistant neoplastic clones and may be associated with enhanced anti
      neoplastic activity. In this study, a polychemotherapy schedule alternating 3
      cycles of CEOP and 3 cycles of CNOP, was used in a single center between December
      1988 and April 1995 to treat 41 previously untreated patients, over 60 years of
      age affected by intermediate or high grade non-Hodgkin's lymphoma according to
      the Working Formulation. In treated patients, 57.5% achieved complete response,
      35% partial response and 7.5% were non-responders. Overall survival was 52.4 % at
      4 years, Disease free survival (DFS) for complete responders was 48.9%. Only one
      case of severe extrahematological toxicity (grade 3-4 WHO) was observed. Severe
      mucositis (grade 3-4 WHO) was absent, and delayed administration of chemotherapy
      was required in only 7/230 cycles. No treatment related deaths were registered.
      This regimen achieved results comparable to that of other anthracycline or
      mitoxantrone based chemotherapy, but determined lower toxicity. Alternating CEOP
      and CNOP may improve overall toxicity.

PMID- 12613519
TI  - Echocardiographic evaluation of acute cardiotoxicity in the treatment of Hodgkin
      disease according to the German Hodgkin's Lymphoma Study Group.
AB  - Echocardiography is a sensitive method for detecting wall motion abnormalities,
      as well as for monitoring cardiotoxicity during treatment with anthracyclines.
      Using echocardiography, this study investigated possible acute cardiotoxicty
      associated with primary treatment of Hodgkin's disease according to German
      Hodgkin's Lymphoma Study Group (GHSG) clinical trial protocols for adults. A
      group of 88 patients (48 men) was registered in the prospective, randomized
      clinical trial involving the treatment of Hodgkin's disease using third and
      fourth generation GHSG protocols. These patients were monitored by
      echocardiography. The average age was 34 years (range, 18-65; median, 32). The
      average anthracycline dose was 174 mg/m2 (median 200 mg/m2), and the average
      mediastinum irradiation dose was 21 Gy (median 30 Gy). Left ventricle end
      systolic diameter (ESD) and left ventricle end-diastolic diameter (EDD), as well
      as fractional shortening (FS) and ejection fraction (EF) (M-mode calculation)
      were evaluated, as was the presence of pericardial effusion and wall motion
      abnormalities. The examinations were conducted before and at the end of therapy
      (up to 2 months). Results show that all evaluated parameters changed from one
      follow-up examination to the other, but these changes did not reach statistical
      significance. ESD increased from 30 +/- 4 to 31 +/- 4 mm. EDD increased from 49
      +/- 4 to 49 +/- 5 mm. Ejection fraction changed from 69 +/- 7 to 66 +/- 7% and
      fractional shortening was unchanged (from 38 +/- 7 to 38 +/- 7%). In seven
      patients (8%), we observed new wall motion abnormalities characterized by
      hypokinesis without decrease of left ventricular function. Significant changes in
      the amount of pericardial effusion were not observed. In four patients (5%),
      there was progression of Hodgkin's disease. In conclusion, treatment according to
      third and fourth generation clinical trial protocols of the GHSG leads only to
      minimal wall motion changes, without concomitant reduction of left ventricular
      function, thus not meeting the criteria, acute cardiotoxicity.

PMID- 12613520
TI  - Are activation markers (CD25, CD38 and CD103) predictive of sensitivity to purine
      analogues in patients with T-cell prolymphocytic leukemia and other
      lymphoproliferative disorders?
AB  - T-cell prolymphocytic leukemia (T-PLL) is a rare lymphoproliferative disorder
      with distinctive clinical and laboratory features. It is often resistant to
      conventional chemotherapy, but complete or partial responses have been documented
      with the use of purine analogues. We report on two cases of T-PLL with a slightly
      different immunophenotype but a remarkably different response to pentostatin. We
      discuss the possible therapeutic implications of this finding and establish a
      comparison between immunophenotype and sensitivity to purine analogues in
      patients with T-PLL and other chronic lymphoproliferative disorders.

PMID- 12613521
TI  - Recurrent B-cell neoplasms after Rituximab therapy: an immunophenotypic and
      genotypic study.
AB  - Rituximab has been widely used to treat relapsing or advanced stage B-cell
      neoplasms with an efficacy of about 50%. However, approximately 40-50% of
      Rituximab treated patients will recur. It is not clear whether these recurrent
      diseases have the same immunophenotype as that of the original tumors. At the
      City of Hope, we treated 91 cases of CD20-positive B-cell neoplasms with
      Rituximab in combination with chemotherapy and hematopoietic stem cell
      transplantation between August 1999 and December 2000. Thirty-five of 91 patients
      (38%) experienced recurrence during the time period within one year from
      treatment. Tumor cells from all of the recurrent patients expressed one or more B
      cell antigens (CD19, CD20, CD22, CD45RA, or CD79a). However, thirteen of 35
      recurrent cases showed aberrant loss of CD20 expression (37%) by
      immunohistochemical or flow cytometric studies. Pre- and post-Rituximab treated
      tumor cell DNA was successfully extracted from archival paraffin sections,
      hematoxylin and eosin (H and E) stained slides, smears, or frozen cells in 10 of
      13 CD20 negative recurrent cases. PCR studies for immunoglobulin (Ig) heavy chain
      gene rearrangements were performed in all these cases. Five cases showed
      identical Ig heavy chain gene rearrangements in the paired specimens. PCR assay
      for Ig kappa (kappa) gene rearrangement was performed in the five paired
      specimens lacking detectable Ig heavy chain gene rearrangements; 2 of them showed
      identical Igkappa gene rearrangements. Three pairs showed unmatched Ig heavy
      chain and Igkappa gene rearrangements, probably due to poor quality of recovered
      DNA. Aberrant loss of CD20 antigens may be a mechanism of treatment resistance
      and should be considered in the immunophenotyping of recurrent Rituximab-treated
      B-cell neoplasms; therefore, a panel of B cell markers is recommended for the
      immunologic diagnosis of recurrent B cell malignancies after Rituximab therapy.
      Seven of ten pairs of recurrent CD20-negative cases showed identical Ig heavy
      chain and Igkappa gene rearrangements by PCR assay, strongly suggesting that the
      pre- and post-Rituxan treated B cell neoplasms are clonally-related.

PMID- 12613522
TI  - Lymphoplasmacytic lymphoma with monoclonal gammopathy-related pseudo-Gaucher cell
      infiltration in bone marrow and spleen--diagnostic and therapeutic dilemmas.
AB  - Gaucher-like cells have occasionally been described in various haematological
      malignancies including Hodgkin's disease, non-Hodgkin's lymphoma, multiple
      myeloma (MM) and chronic myelogenous leukaemia (CML). A special type of this
      phenomenon is crystal-storing histocytosis or the so-called pseudo-pseudo Gaucher
      cells (PPGC) in which crystalline protein storage in macrophages is induced by
      paraproteinemia. Here we describe a 54-year-old man with an initial suspicion of
      Gaucher disease and monoclonal IgA gammopathy in whom a correct diagnosis of
      lymphoplasmacytic lymphoma (LPL) with massive infiltration of bone marrow and
      spleen by PPGC was confirmed by immunological, ultrastructural and molecular
      characterisation. The activity of leukocyte beta-glucocerebrosidase was only
      slightly elevated (7.3 nmol/mg protein/1 h) which ruled out the diagnosis of
      classic Gaucher's disease. The patient received two courses of CHOP without
      improvement and anti-CD20 monoclonal antibody (rituximab) with only temporary
      stabilisation. Subsequently, he underwent splenectomy because of prolonged severe
      pancytopenia and a suspicion of hypersplenism. After splenectomy significant
      haematological improvement was observed. Following anti-CD20 therapy, changes in
      immunoprofile and morphology of tumour cells were evident. Before treatment the
      population of LPL was more divergent, with expression of LCA, CD20, CD38 and
      CD138. However, after the treatment, there were more mature plasma cells which no
      longer expressed CD20 antigen-this picture was more consistent with the diagnosis
      of plasma cell myeloma. Similarly, in the spleen there were no CD-20-positive
      cells evident. Finally, the patient received two courses of VAD vincristine,
      doxorubicin, dexamethasone) with further haematological improvement but complete
      response was not achieved.

PMID- 12613523
TI  - Trofosfamide as salvage therapy for anaplastic large cell lymphoma relapsing
      after high-dose chemotherapy.
AB  - Patients with relapsed aggressive lymphoma after high dose chemotherapy have a
      very poor prognosis and long-term survival is rare. Most patients are not
      eligible for allogeneic stem cell transplantation in this setting and treatment,
      therefore, becomes palliative. A few studies have shown that trofosfamide, an
      oral alkylating agent, may be effective as palliative treatment in non-Hodgkin's
      lymphoma. Trofosfamide therapy is considered rather non-toxic with an overall
      response rate from 50 to 80%. Most responses are, however, partial and their
      duration is short. We report a patient with a very aggressive ALK + anaplastic
      large cell lymphoma (ALCL), relapsing shortly after high dose chemotherapy.
      Unrelated allogeneic transplantation was hot possible. After several
      radio/chemotherapy regimens trofosfamide was started as palliative treatment.
      This therapy resulted in a complete remission, still ongoing, 27 months after
      termination of intravenous cytotoxic therapy and 16 months after withdrawal of
      trofosfamide. Thus, in this particular case, trofosfamide turned out to be an
      unexpectedly effective salvage therapy for an otherwise very aggressive relapsing
      ALCL.

PMID- 12613524
TI  - Jak3 expression and genomic sequence in pediatric acute lymphoblastic leukemia.
AB  - Janus tyrosine kinase 3 (JAK3) is one of several key regulatory enzymes in B-cell
      precursors which is highly conserved between multiple species. The gene for Jak3
      has been mapped to human chromosome 19p12-13.1 and encompasses 23 exons.
      Constitutively high levels of JAK3 activity may contribute to drug resistance and
      enhanced clonogenicity of leukemic B-cell precursors from children and infants
      with acute lymphoblastic leukemia (ALL). As part of a systematic effort to
      accurately determine the genomic sequence of Jak3 gene in normal and leukemic B
      cell precursors, we sequenced a relatively short region of Jak3 spanning two
      introns, originally termed introns 10 and 11. This genomic sequence appeared in
      certain RT-PCR products from our analysis of Jak3 gene expression in pediatric,
      as well as infant, primary ALL cells. Unexpectedly, a gap in the original Jak3
      genomic sequence was found in intron 10 across the sequence matching to an Alu
      element. Furthermore, the sequence obtained from intron 11 did not match at all
      to that previously reported, and the length of the intron was much larger than
      expected at 1.1 kb. Homology to Alu elements (three regions, 699 bp total) and a
      LINE2 element (one region, 189 bp total) were seen across the entire region
      covering exons 10-12 (2.1 kb total). Two potential single nucleotide
      polymorphisms (SNPs) were observed in intron 11. No apparent genomic mutation was
      found across this region in leukemic B-cell precursors from any of the ALL
      patients examined. This newly described sequence corrects the previous published
      genomic sequence from this region rather than identifying an insertion or
      translocation specific to these ALL cases. Our results significantly extend
      previous efforts to determine the genomic sequence of Jak3 and analyze its
      expression in childhood pro-B ALL and other forms of ALL.

PMID- 12613525
TI  - Cytotoxic activity of T- and NK-cell lymphoma cells is not dependent on a mature
      cytotoxic phenotype.
AB  - Cytotoxic T- and NK-cell neoplasms constitute a rare clinico-pathological entity
      associated with aggressive clinical behaviour and a poor prognosis. The entity
      comprises a heterogenous group of different diseases classified by histologic,
      immunologic as well as clinical features. Recently, expression patterns of
      "cytotoxicity-associated proteins" such as T-cell intracellular antigen (TIA),
      perforin and granzyme B have been applied to differentiate between an immature
      (TIA positive) and a mature (TIA and perforin and/or granzyme B positive)
      phenotype of these malignant cells. In particular, expression of perforin and
      granzyme B are considered to mediate cytotoxic activity. This study assesses
      histology/cytology, immunophenotype, expression of "cytotoxicity-associated
      proteins" and the actual exhibition of cytotoxic activity of lymphoma cells of 10
      patients suffering from different T- and NK-cell neoplasms. As investigated by
      PKH67 labelling of the target cells 6 out of 10 samples exhibited cytotoxic
      activity. Thus, all samples of lymphoma cells with a mature phenotype exhibited
      cytotoxic activity. Nevertheless, the ability to induce cytotoxic cell lysis was
      neither restricted to mature lymphoma cells, nor to lymphoma cells expressing
      "cytotoxicity-associated proteins": two samples with an immature phenotype and
      one CD4 positive sample, completely lacking expression of "cytotoxic proteins" as
      well as NK cell-associated markers, destroyed target cells. Artificial activation
      of a mature cytotoxic phenotype by cell culture conditions or contact of lymphoma
      cells with target cells was excluded by demonstrating the absence of perforin
      expression after the incubation period in two exemplary cases. In conclusion, we
      demonstrate that the exhibition of cytotoxic activity is neither restricted to
      cells with a mature phenotype, nor does it depend on the expression of the
      "cytotoxicity-associated proteins" TIA, perforin or granzyme B.

PMID- 12613526
TI  - Effects of IL-6 variants in multiple myeloma: growth inhibition and induction of
      apoptosis in primary cells.
AB  - Interleukin-6 (IL-6) plays a pathogenetic role in B-cell malignancies and is a
      growth factor for multiple myeloma (MM) cells. Elevated serum IL-6 levels and a
      higher proliferative activity of bone marrow plasma cells are poor prognostic
      factors in MM patients. In addition to clinical trials with anti-IL-6 monoclonal
      antibodies, an alternative therapeutic approach based on the use of IL-6 receptor
      (R) super-antagonists (Sants) has been proposed. Sants are variants of the native
      cytokine characterized by a wild type affinity for the ligand-specific receptor
      chain IL-6R alpha and by a reduced ability to bind and/or dimerize the signaling
      chain gp-130. We report the in vitro effects of four different Sants on cell
      kinetic modulation and induction of apoptosis of primary cells from MM patients.
      Ten MM samples were cultured in the presence of four different Sants and
      heterogeneous effects in terms of reduction of proliferation and induction of
      apoptosis could be observed. A decrease of the S phase cells (> or = 25%) coupled
      with the induction of apoptosis was obtained in 4/10 samples: three of these
      samples had a diploid DNA stem line and an inferior initial percentage of S phase
      cells. Serum IL-6 concentrations did not correlate with the anti-proliferative
      activities of the Sants. Cell growth inhibition was observed especially in
      samples with soluble IL-6R serum concentrations > 200 ng/ml. We conclude that
      Sants can exert antiproliferative effects on selected MM samples. Such effects
      may depend on the availability of large amounts of soluble IL-6R. Further studies
      should aim at defining the conditions necessary for optimal antiproliferative
      activity.

PMID- 12613527
TI  - Renin expression in hematological malignancies and its role in the regulation of
      hematopoiesis.
AB  - It has been demonstrated that some myeloid blasts express renin, but normal bone
      marrow (BM) does not display this expression. The aim of the present work was to
      analyze the renin expression in different hematological malignancies and
      different myeloid cell lines. We investigated the expression of renin by RT-PCR
      in BM from patients with hematological malignancies (106 patients), in nine
      normal BM from healthy donors and in leukemic cell lines (K562, KU812, MEG-01, U
      937 and HL60), as well in K562 cell line subjected to differentiation treatments.
      We have observed renin expression in cells from acute myeloid leukemia (AML),
      chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cases.
      The highest frequency was observed in AML-non acute promyelocytic leukemia(APL)
      cases (47.2% of the cases). The disappearance of this expression was associated
      with the status of complete remission of AML. Renin is expressed in some myeloid
      human leukemia cell lines such as K562, KU812 and MEG-01. However, when K562
      cells were treated with inducers of growth inhibition and/or differentiation, the
      expression did not disappear, indicating that renin expression is associated with
      a blastic phenotype rather than with cell proliferation. The obtained findings
      suggest that the renin expression could have a role on the disease development
      and could be used as an aberrant marker of leukemia.

PMID- 12613528
TI  - Effect of rhGM-CSF on the kinetics of hematopoiesis in long-term marrow cultures
      from patients with acute myelogenous leukemia.
AB  - In the present study, we have assessed the effects of recombinant human
      Granulocyte-Macrophage Colony-Stimulating Factor (rhGM-CSF) in Dexter-type long
      term marrow cultures (LTMC) from patients with acute myelogenous leukemia (AML).
      Addition of rhGM-CSF to AML LTMC resulted in a significant increase in the number
      of total nucleated cells (1.3-4.3-fold, as compared to untreated cultures).
      However, a simultaneous decrease in the numbers of myeloid progenitor cells (CFU)
      was observed. Interestingly, there was a selective stimulation of the growth of
      leukemic progenitors (AML-CFU). Indeed, whereas on day 0 these cells were
      detected in only 2 patients, between weeks 1 and 5 they were detected in 10 of
      the 14 patients included in the study. It is noteworthy that around 50% of the
      cells detected in the non-adherent fraction of rhGM-CSF-treated AML LTMC were
      blasts, whereas in untreated cultures, blasts corresponded to only 23% of the non
      adherent cells, and the majority corresponded to cells of the monocyte-macrophage
      lineage. These results indicate that rhGM-CSF is a cytokine with a significant
      stimulatory activity for the in vitro growth of AML progenitor andblast cells,
      and, together with previous reports in the literature, suggest that the use of
      rhGM-CSF in clinical settings must be taken with caution since this cytokine,
      although beneficial in reducing the risk of infections after chemotherapy, may
      induce the reappearance of the disease after treatment. Further studies should be
      encouraged to understand in greater detail the effects of rhGM-CSF, and other
      cytokines, on the hematopoietic system of AML patients.

PMID- 12613529
TI  - Absence of somatic hypermutation in the open reading frame of the bcl-2 gene
      participating in the t(14;18) chromosomal translocation in follicular lymphoma.
AB  - The information concerning potential effects of somatic hypermutation on bcl-2
      sequences translocated to the immunoglobulin heavy chain gene (IgH) locus in
      follicular lymphoma (FL) is rather limited. We analysed the complete open reading
      frame (ORF) of the bcl-2 gene for the presence of mutations in 24 bcl-2/IgH
      positive diagnostic FL samples by the single strand conformation polymorphism
      (SSCP) technique. A prior analysis on many of these FL samples had revealed a
      consistent pattern of somatic hypermutation in IgH genes. Abnormally migrating
      bands on SSCP gels were identified only in 4/24 samples. This result provides
      strong support for the notion that in FL the translocated bcl-2 coding region is
      not targeted by somatic hypermutation.

PMID- 12613530
TI  - Multiple myeloma associated with lactic acidosis.
AB  - Type B lactic acidosis is rare among patients with malignant diseases. To date
      only one case report has documented lactic acidosis occurring in a patient with
      multiple myeloma (MM). Our patient, a 55-year-old black man, was diagnosed with
      stage IIIA immunoglobulin G-kappa (IgG-kappa) MM in September 1995. He was found
      to have severe lactic acidosis at the time of second relapse. During the terminal
      phase of his disease, he required multiple hospitalizations for management of
      lactic acidosis and other complications of his MM. No other cause of his elevated
      lactate levels was identified. Although type B lactic acidosis may more commonly
      occur in patients with leukemia or lymphoma, it may rarely present in patients
      with rapidly progressive and refractory MM.

PMID- 12613531
TI  - Intra-cerebral relapse following prolonged remission after autologous stem cell
      transplantation for multiple myeloma.
AB  - Central nervous system (CNS) myeloma is a rare phenomenon, especially so after
      high-dose therapy (HDT) and stem cell transplantation. We describe a case of
      isolated CNS relapse of myeloma post autologous transplantation that followed a
      prolonged progression-free interval. Issues regarding the pathophysiology and
      management of this unusual complication are discussed.

PMID- 12613532
TI  - Extranodal non-Hodgkin lymphoma presenting as a soft tissue mass in the proximal
      femur in a HIV(+) patient.
AB  - Primary soft tissue non-Hodgkin lymphomas (NHL) are very rare especially among
      HIV-1 infected patients. We describe a patient with HIV-1 infection who presented
      with acute pain of the right proximal femur. The clinical and laboratory
      investigation revealed a high grade centroblastic B-cell lymphoma of soft tissue.
      The patient was treated by surgical resection of the tumor, chemotherapy and
      local radiotherapy with no serious side effects. After 36 mdnths of follow up he
      is in excellent clinical condition, with his lymphoma in complete remission.

PMID- 12613533
TI  - Therapy-related myelodysplastic syndrome with monosomy 5 and 7 following
      successful therapy for acute promyelocytic leukemia with anthracyclines.
AB  - Myelodysplastic syndrome (MDS) in patients treated for acute promyelocytic
      leukemia (APL) is a rare event. We describe a patient with APL who developed MDS
      40 months after entering complete remission (CR). Karyotypic analysis revealed
      monosomy 5 and 7, which are cytogenetic changes usually occurring after the use
      of alkylating agents. The patient had received only anthracyclines as potential
      leukemogenic drugs. A review of the literature on t-AML/MDS occurring after
      successful therapy for APL showed three similar cases. These observations suggest
      that anthracyclines may cause t-AML/MDS similar to that induced by alkylating
      agents.

PMID- 12613534
TI  - Spontaneous reversion from blast to chronic phase after withdrawal of imatinib
      mesylate in a patient with chronic myelogenous leukemia.
AB  - Imatinib mesylate, a specific inhibitor of the BCR-ABL tyrosine kinase, has been
      very effective in the treatment of chronic myeloid leukemia (CML) in chronic
      phase with high rates of hematological and cytogenetic remissions. Resistance to
      therapy can develop and transformation to blast crisis may occur, particularly in
      patients without a cytogenetic response. We report a case of a patient with CML
      treated in chronic phase who developed blast crisis; withdrawal of imatinib
      mesylate resulted in spontaneous reversion to chronic phase.

PMID- 12613535
TI  - It is ALL in the heart: a patient with acute lymphoblastic leukemia and cardiac
      infiltration at time of diagnosis.
AB  - We report an unusual case of acute lymphoblastic leukemia (ALL) in a 15-year-old
      boy where a mass lesion, presumed to be a cardiac metastasis, was noted in the
      right ventricular wall and cavity at the time of initial routine
      echocardiography. The lesion resolved, without surgical intervention, following
      the institution of multi-agent chemotherapy.

PMID- 12613536
TI  - Successful treatment of posttransplant lymphoproliferative disorder in a renal
      transplant patient by autologous peripheral blood stem cell transplantation.
AB  - Posttransplant lymphoproliferative disorder (PTLD), a well recognized
      complication of organ transplantation, comprises a wide spectrum of heterogeneous
      lymphoid proliferations ranging from self-limiting mononucleosis through
      aggressive monoclonal non-Hodgkin's lymphoma (NHL). There has been marginal
      success in treating PTLD using a number of treatment modalities, including
      combination chemotherapy. There have been few reports of the use of high dose
      chemotherapy with stem cell rescue as a treatment for PTLD. We report a renal
      allograft recipient who developed PTLD of the diffuse large cleaved B cell, NHL
      type. Reduction of immunosuppression was initially effective, however the patient
      relapsed, and was treated successfully with CHOP chemotherapy. Two years later he
      again relapsed and was treated with high dose melphalan followed by autologous
      peripheral blood stem cell transplantation (PSCT). The patient has remained in
      complete remission for 4 years with no major organ toxicities and a functioning
      renal allograft on minimal immunosuppression. This case illustrates a potential
      role for high dose chemotherapy with stem cell transplantation for the treatment
      of PTLD.

PMID- 12613537
TI  - Prostatic involvement of a testicular lymphoma in a patient with myasthenia
      gravis on long-term azathioprine.
AB  - Side effects of long-term use of azathioprine in myasthenia gravis are
      infrequently reported. We present a patient who developed non-Hodgkin's lymphoma
      after eight years of azathioprine treatment for myasthenia gravis. He presented
      unusually with testicular lymphoma spreading to the prostate and the illness
      followed a particularly aggressive course.

PMID- 12613538
TI  - Immunohistochemical identification of HER-2/neu overexpression and CD117 (c-kit)
      expression in multiple myeloma.
AB  - Multiple myeloma (MM) is the most common plasma cell dyscrasia. Conventional
      therapy results in a median survival of 3-5 years. Patients with B-cell disorders
      and coexistent HER-2/neu overexpression in solid tumors have a poorer prognosis
      than those without an underlying B-cell disorder. This, and the recent success of
      the tyrosine kinase inhibitor, imatinib mesylate in chronic myelogenous leukemia,
      led us to evaluate the incidence and role of c-kit (CD117) and HER-2/neu
      overexpression in MM. We conducted a retrospective study to determine the
      incidence of HER-2/neu and c-kit overexpression in MM. HER-2/neu overexpression
      was evaluated using the DAKO Hercep test and c-kit overexpression was assessed
      using conventional immunohistochemistry (IHC); 69 patients with a diagnosis of MM
      were identified, of whom, 31 patients (19 males and 12 females) had an adequate
      pathological specimen available for IHC testing; 4 out of 31 patients (12.9%)
      showed HER-2/neu overexpression, while 5/31 (16.13%) showed CD117 expression. Two
      patients (6.45%) showed both HER-2/neu and c-kit overexpression. Although both
      HER-2/neu and c-kit are not expressed very frequently in patients with MM, there
      appears to be a subgroup of patients in whom, either one or both these oncogenes
      is overexpressed. Given our small sample size, it is difficult to comment on the
      effect of CD117 and/or HER-2/neu overexpression on survival. Future larger
      studies are needed to define the association in MM and to determine if the
      presence of one (CD117 or HER-2/neu) has an effect on overexpression of the other
      oncoprotein. Furthermore, it would be beneficial to identify the molecular nature
      of the interplay between HER-2/neu and c-kit, if any. Target-directed signal
      transduction inhibition therapy using tyrosine kinase inhibitors, may be a
      distinct possibility in a select group of patients with MM.

PMID- 12613539
TI  - From the discovery of neuropilin to the determination of its adhesion sites.
AB  - Neuropilin (NRP) and plexin (Plex) that are now known to be semaphorin receptors
      were initially identified as antigens for monoclonal antibodies (MAbs) that bound
      to particular neuropiles and plexiform layers of the Xenopus tadpole optic
      tectum, several years before the discovery of semaphorin. The extracellular
      segment of the NRP protein is a mosaic of 3 functionally different protein motifs
      that are thought to be involved in molecular and/or cellular interactions,
      suggesting that NRP serves in a various cell-cell interaction by binding a
      variety of molecules. The first identified function of NRP was the cell adhesion
      activity; Cell reaggregation study using NRP-expressing cell lines revealed that
      NRP can mediate cell adhesion via heterophilic molecular interaction. Later, NRP
      was shown to bind semaphorins and vascular endothelial growth factor (VEGF). It
      was also shown that NRP makes receptor complexes with Plex to propagate
      semaphorin signals.

PMID- 12613540
TI  - Neuropilins as Semaphorin receptors: in vivo functions in neuronal cell migration
      and axon guidance.
AB  - After the initial discovery of neuropilin-1 as an epitope on axons recognized by
      a monoclonal antibody, neuropilins were rediscovered in the search for receptors
      mediating the repulsive actions of class 3 Semaphorins, notably Sema3A.
      Neuropilins are the ligand binding moieties in the class 3 Semaphorin receptor
      complexes, with the signaling moieties apparently provided by members of the
      plexin family. In their capacity as Semaphorin receptors, neuropilins have been
      shown to transduce repulsive guidance signals that direct a large variety of cell
      migration and axon guidance events. We summarize their demonstrated roles in
      driving axon fasciculation, channeling various axonal populations, inhibiting
      axonal branching, creating exclusion zones for axons, and providing directional
      guidance cues by being presented in gradients. In addition to their roles in
      repulsive axon guidance, evidence is accumulating that neuropilins also transduce
      some attractive guidance functions of Semaphorins.

PMID- 12613541
TI  - The role of neuropilin in vascular and tumor biology.
AB  - Neuropilin-1 (NRP1) and NRP2 are related transmembrane receptors that function as
      mediators of neuronal guidance and angiogenesis. NRPs bind members of the class 3
      semaphorin family, regulators of neuronal guidance, and of the vascular
      endothelial growth factor (VEGF) family of angiogenesis factors. There is
      substantial evidence that NRPs serve as mediators of developmental and tumor
      angiogenesis. NRPs are expressed in endothelial cells (EC) and bind VEGF165. NRP1
      is a co-receptor for VEGF receptor-2 (VEGFR2) that enhances the binding of
      VEGF165 to VEGFR2 and VEGF165-mediated chemotaxis. NRP1 expression is regulated
      in EC by tumor necrosis factor-alpha, the transcription factors dHAND and Ets-1,
      and vascular injury. During avian blood vessel development NRP1 is expressed only
      in arteries whereas NRP2 is expressed in veins. Transgenic mouse models
      demonstrate that NRP1 plays a critical role in embryonic vascular development.
      Overexpression of NRP1 results in the formation of excess capillaries and
      hemorrhaging. NRP1 knockouts have defects in yolk sac, embryo and neuronal
      vascularization, and in development of large vessels in the heart. Tumor cells
      express NRPs and bind VEGF165. NRP1 upregulation is positively correlated with
      the progression of various tumors. Overexpression of NRPI in rat tumor cells
      results in enlarged tumors and substantially enhanced tumor angiogenesis. On the
      other hand, soluble NRP1 (sNRP1) is an antagonist of tumor angiogenesis.
      Semaphorin 3A binds to EC and tumor cells. It also inhibits EC motility and
      capillary sprouting in vitro. VEGF165 and Sema3A are competitive inhibitors for
      NRP1 mediated functions in EC and neurons. These results suggest that NRP1 is a
      novel regulator of the vascular system.

PMID- 12613542
TI  - Neuropilin-1 in the immune system.
AB  - The neuropilin-1 (NRP1) and neuropilin-2 (NRP2) receptors can bind the class 3
      semaphorin subfamily and the heparin-binding forms of vascular endothelial growth
      factor (VEGF) and placenta growth factor (PlGF). The functions of NRP1 and NRP2
      have been extensively studied in neurons where they act in axon guidance and in
      endothelial cells where they promote angiogenesis and cell migration. In this
      chapter, we will present evidences indicating that neuropilin-1 is likely to
      mediate contacts between the dendritic cells and the T lymphocytes via homotypic
      interactions and is essential for the initiation of the primary immune response.
      These results emphasize the molecular similarities between the nervous and the
      immune systems and open new areas in the modulation of the immune response.

PMID- 12613543
TI  - Structural and functional relation of neuropilins.
AB  - Neuropilin is a type I transmembrane protein and the molecular mass is 120 kDa.
      Two homologues, Neuropilin-1 and -2, are identified. The primary structure of
      Neuropilin-1 and Neuropilin-2 is well conserved and is divided into four domains,
      CUB (a1/a2) domain, FV/FVIII (b1/b2) domain, MAM (c) domain, and (d) domain that
      contains a transmembrane and a short cytoplasmic region. Both Neuropilin-1 and
      Neuropilin-2 have truncated and secreted form of splice variants. Neuropilins act
      as a receptor for two different extracellular ligands, class 3 semaphorins and
      specific isoforms of vascular endothelial growth factor. In both cases,
      neuropilin requires an additional transmembrane molecule to exhibit biological
      activity. Plexin-A is essential for class 3 semaphorin signaling. Vascular
      endothelial cell growth factor (VEGF) receptor is the major receptor for VEGF and
      neuropilin acts as isoform specific co-receptor for VEGF. The CUB and FV/FVIII
      domains of Neuropilin are the binding sites of semaphorin and VEGF. The MAM
      domain mediates semaphorin signaling to Plexin-A. Cross talk between semaphorin
      and VEGF on neuropilin suggests that class 3 semaphorins and the secreted forms
      of neuropilin act as antagonists to VEGF and its related growth factors.

PMID- 12613544
TI  - The function of neuropilin/plexin complexes.
AB  - Neuropilins bind the secreted class 3 semaphorins with high affinity but require
      a member of the plexin family to form receptors that are able to activate
      downstream signal transduction cascades. In this receptor complex neuropilins act
      as the ligand-binding subunit while plexins function as the signal-transducing
      subunit in the induction of cytoskeletal collapse by semaphorins. The cytoplasmic
      domain is highly conserved within the plexin family and interacts with Rho-like
      GTPases.

PMID- 12613545
TI  - The interaction of Neuropilin-1 and Neuropilin-2 with tyrosine-kinase receptors
      for VEGF.
AB  - The Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) receptors were initially
      described as receptors for axon guidance factors belonging to the class-3
      Semaphorin sub-family. Subsequently, it was found the Neuropilins also function
      as receptors for some forms of vascular endothelial growth factor (VEGF). VEGF165
      binds to both NRP1 and to NRP2 but VEGF121, does not bind to either of these
      receptors. VEGF145 on the other hand, binds to NRP2 but not to NRP1. Additional
      VEGF family members such as the heparin binding form of placenta growth factor
      (PlGF-2) and VEGF-B bind to NRP1, and it was also shown that both PlGF-2 and VEGF
      C bind to NRP2. The intracellular domains of the Neuropilins are short, and do
      not suffice for independent transduction of biological signals subsequent to
      Semaphorin or VEGF binding. It was shown that both Neuropilins can form complexes
      with receptors belonging to the Plexin family, and that such Plexin/Neuropilin
      complexes are able to transduce signals following the binding of class-3
      Semaphorins to Neuropilins. The VEGF165 induced proliferation and migration of
      cells that express the VEGF tyrosine-kinase receptor VEGFR2 is enhanced in the
      presence of NRP1, suggesting that Neuropilins may also form complexes with VEGF
      tyrosine-kinase receptors such as VEGFR2. However, it is not yet clear whether
      VEGFR2 and NRPI form complexes and contrasting results have been reported with
      regard to this issue. In contrast, it was recently reported by two laboratories
      that Neuropilins can form complexes with the second tyrosine-kinase receptor of
      VEGF, VEGFR1. However, the biological function of these complexes is still
      unclear.

PMID- 12613546
TI  - The function of neuropilin/L1 complex.
AB  - L1, a cell adhesion molecule of the Ig superfamily (IgCAM) plays a critical role
      in the formation of neuronal networks. This is reflected by the variety of
      clinical signs associated with the X-linked recessive neurological disorder that
      is caused by mutations in the L1 gene. L1 regulates the formation of axon
      fascicles and promotes neurite outgrowth through interaction with a wide spectrum
      of binding partners including cell adhesion molecules and extra-cellular matrix
      components. Here we describe the emerging evidence that indicates, in addition to
      these well-established functions, that L1 participates in the signaling of a
      secreted guidance cue of the Semaphorin family, Sema3A. Three types of
      experimental evidence support L1 as a key component of the Sema3A receptor
      complex. First, L1-deficient axons do not respond to Sema3A-induced
      chemorepulsion. Second, L1 and NRP1, the neuropilin responsible for Sema3A
      binding, associate through their extracellular domains, forming a cell surface
      heterocomplex. Third, a soluble form of L1 modulates axonal responsiveness to
      Sema3A, by converting Sema3A chemorepulsion into attraction.

PMID- 12613547
TI  - Neuropilin and its ligands in normal lung and cancer.
AB  - Neuropilins (NRPs) are receptors for class 3 Semaphorins and function as co
      receptors for Vascular endothelial growth factor isoforms, VEGF165 and VEGF145
      and related molecules. NRPs are expressed in a variety of neural and non-neural
      tissues and are required for normal development. Interestingly, class 3
      Semaphorins and VEGF compete for common NRP binding. As a consequence,
      Semaphorins and VEGF appear to be mutually antagonistic. In the lung, NRP levels
      increase during development and NRPs and Semaphorins are involved in lung
      branching, probably by altering cell morphology or by regulating cell motility
      and migration. During lung tumorigenesis, both NRP and VEGF expression increase
      on dysplastic lung epithelial cells; SEMA3F expression is reduced and SEMA3F
      protein is delocalized from the membrane to the cytoplasm. In lung cancers,
      SEMA3F staining correlates inversely with tumor stage with high SEMA3F associated
      with less aggressive tumors. Conversely, more aggressive tumors are associated
      with increased VEGF staining and a corresponding loss in membranous SEMA3F.

PMID- 12613548
TI  - Neuropilin and class 3 semaphorins in nervous system regeneration.
AB  - Injury to the mature mammalian central nervous system (CNS) is often accompanied
      by permanent loss of function of the damaged neural circuits. The failure of
      injured CNS axons to regenerate is thought to be caused, in part, by neurite
      outgrowth inhibitory factors expressed in and around the lesion. These include
      several myelin associated inhibitors, proteoglycans, and tenascin-R. Recent
      studies have documented the presence of class 3 semaphorins in fibroblast-like
      meningeal cells present in the core of the neural scar formed following CNS
      injury. Class 3 semaphorins display neurite growth-inhibitory effects on growing
      axons during embryonic development. The induction of the expression of class 3
      semaphorins in the neural scar and the persistent expression of their receptors,
      the neuropilins and plexins, by injured CNS neurons suggest that they contribute
      to the regenerative failure of CNS neurons. Neuropilins are also expressed in the
      neural scar in a subpopulation of meningeal fibroblast and in neurons in the
      vicinity of the scar. Semaphorin/neuropilin signaling might therefore also be
      important for cell migration, angiogenis and neuronal cell death in or around
      neural scars. In contrast to neurons in the CNS, neuropilin/plexin positive
      neurons in the PNS do display long distance regeneration following injury.
      Injured PNS neurons do not encounter a semaphorin positive neural scar.
      Furthermore, Semaphorin 3A is downregulated in the regenerating spinal motor
      neurons themselves. This was accompanied by a transient upregulation of
      Semaphorin 3A in the target muscle. These observations suggest that the injury
      induced regulation of Semaphorin 3A in the PNS contributes to successful
      regeneration and target reinnervation. Future studies in genetically modified
      mice should provide more insight into the mechanisms by which neuropilins and
      semaphorins influence nervous system regeneration and degeneration.

PMID- 12613549
TI  - Statistical smoothing of neuronal data.
AB  - The purpose of smoothing (filtering) neuronal data is to improve the estimation
      of the instantaneous firing rate. In some applications, scientific interest
      centres on functions of the instantaneous firing rate, such as the time at which
      the maximal firing rate occurs or the rate of increase of firing rate over some
      experimentally relevant period. In others, the instantaneous firing rate is
      needed for probability-based calculations. In this paper we point to the very
      substantial gains in statistical efficiency from smoothing methods compared to
      using the peristimulus-time histogram (PSTH), and we also demonstrate a new
      method of adaptive smoothing known as Bayesian adaptive regression splines
      (DiMatteo 1, Genovese C R and Kass R E 2001 Biometrika 88 1055-71). We briefly
      review additional applications of smoothing with non-Poisson processes and in the
      joint PSTH for a pair of neurons.

PMID- 12613550
TI  - Coincidence detection with dynamic synapses.
AB  - Recent experimental findings show that the efficacy of transmission in cortical
      synapses depends on presynaptic activity. In most neural models, however, the
      synapses are regarded as static entities where this dependence is not included.
      We study the role of activity-dependent (dynamic) synapses in neuronal responses
      to temporal patterns of afferent activity. Our results demonstrate that, for
      suitably chosen threshold values, dynamic synapses are capable of coincidence
      detection (CD) over a much larger range of frequencies than static synapses. The
      phenomenon appears to be valid for an integrate-and-fire as well as a Hodgkin
      Huxley neuron and various types of CD tasks.

PMID- 12613551
TI  - An exact method to quantify the information transmitted by different mechanisms
      of correlational coding.
AB  - We derive a new method to quantify the impact of correlated firing on the
      information transmitted by neuronal populations. This new method considers, in an
      exact way, the effects of high order spike train statistics, with no
      approximation involved, and it generalizes our previous work that was valid for
      short time windows and small populations. The new technique permits one to
      quantify the information transmitted if each cell were to convey fully
      independent information separately from the information available in the presence
      of synergy-redundancy effects. Synergy-redundancy effects are shown to arise from
      three possible contributions: a redundant contribution due to similarities in the
      mean response profiles of different cells; a synergistic stimulus-dependent
      correlational contribution quantifying the information content of changes of
      correlations with stimulus, and a stimulus-independent correlational contribution
      term that reflects interactions between the distribution of rates of individual
      cells and the average level of cross-correlation. We apply the new method to
      simultaneously recorded data from somatosensory and visual cortices. We
      demonstrate that it constitutes a reliable tool to determine the role of cross
      correlated activity in stimulus coding even when high firing rate data (such as
      multi-unit recordings) are considered.

PMID- 12613552
TI  - Likelihood approaches to sensory coding in auditory cortex.
AB  - Likelihood methods began their evolution in the early 1920s with R A Fisher, and
      have developed into a rich framework for inferential statistics. This framework
      offers tools for the analysis of the differential geometry of the full likelihood
      function based on observed data. We examine likelihood functions derived from
      inverse Gaussian (IG) probability density models of cortical ensemble responses
      of single units. Specifically, we investigate the problem of sound localization
      from the observation of an ensemble of neural responses recorded from the primary
      (Al) field of the auditory cortex. The problem is framed as a probabilistic
      inverse problem with multiple sources of ambiguity. Observed and expected Fisher
      information are defined for the IG cortical ensemble likelihood functions.
      Receptive field functions of multiple acoustic parameters are constructed and
      linked to the IG density. The impact of estimating multiple acoustic parameters
      related to the direction of a sound is discussed, and the implications of
      eliminating nuisance parameters are considered. We examine the degree of acuity
      afforded by a small ensemble of cortical neurons for locating sounds in space,
      and show the predicted patterns of estimation errors, which tend to follow
      psychophysical performance.

PMID- 12613553
TI  - Information encoding and computation with spikes and bursts.
AB  - Neurons compute and communicate by transforming synaptic input patterns into
      output spike trains. The nature of this transformation depends crucially on the
      properties of voltage-gated conductances in neuronal membranes. These intrinsic
      membrane conductances can enable neurons to generate different spike patterns
      including brief, high-frequency bursts that are commonly observed in a variety of
      brain regions. Here we examine how the membrane conductances that generate bursts
      affect neural computation and encoding. We simulated a bursting neuron model
      driven by random current input signal and superposed noise. We consider two
      issues: the timing reliability of different spike patterns and the computation
      performed by the neuron. Statistical analysis of the simulated spike trains shows
      that the timing of bursts is much more precise than the timing of single spikes.
      Furthermore, the number of spikes per burst is highly robust to noise. Next we
      considered the computation performed by the neuron: how different features of the
      input current are mapped into specific output spike patterns. Dimensional
      reduction and statistical classification techniques were used to determine the
      stimulus features triggering different firing patterns. Our main result is that
      spikes, and bursts of different durations, code for different stimulus features,
      which can be quantified without a priori assumptions about those features. These
      findings lead us to propose that the biophysical mechanisms of spike generation
      enables individual neurons to encode different stimulus features into distinct
      spike patterns.

PMID- 12613554
TI  - Adaptive encoding in the visual pathway.
AB  - In a natural setting, the mean luminance and contrast of the light within a
      visual neuron's receptive field are constantly changing as the eyes saccade
      across complex scenes. Adaptive mechanisms modulate filtering properties of the
      early visual pathway in response to these variations, allowing the system to
      maintain differential sensitivity to nonstationary stimuli. An adaptive variant
      of the reverse correlation technique is used to characterize these changes during
      single trials. Properties of the adaptive reverse correlation algorithm were
      investigated via simulation. Analysis of data collected from the mammalian visual
      system demonstrates the ability to continuously track adaptive changes in the
      encoding scheme. The adaptive estimation approach provides a framework for
      characterizing the role of adaptation in natural scene viewing.

PMID- 12613555
TI  - Influence of subthreshold nonlinearities on signal-to-noise ratio and timing
      precision for small signals in neurons: minimal model analysis.
AB  - Subthreshold voltage- and time-dependent conductances can subserve different
      roles in signal integration and action potential generation. Here, we use minimal
      models to demonstrate how a non-inactivating low-threshold outward current
      (I(KLT)) can enhance the precision of small-signal integration. Our integrate-and
      fire models have only a few biophysical parameters, enabling a parametric study
      of I(KLT) effects. I(KLT) increases the signal-to-noise ratio (SNR) for firing
      when a subthreshold 'signal' EPSP is delivered in the presence of weak random
      input. The increased SNR is due to the suppression of spontaneous firings to
      random input. In accordance, SNR grows as the EPSP amplitude increases. SNR also
      grows as the unitary synaptic current's time constant increases, leading to more
      effective suppression of spontaneous activity. Spike-triggered reverse
      correlation of the injected current indicates that, to reach spike threshold, a
      cell with I(KLT) requires a briefer time course of injected current. Consistent
      with this narrowed integration time window, I(KI.T) enhances phase-locking.
      measured as vector strength, to a weak noisy and periodically modulated stimulus.
      Thus subthreshold negative feedback mediated by I(KLT) enhances temporal
      processing. An alternative suppression mechanism is voltage- and time-dependent
      inactivation of a low-threshold inward current. This feature in an integrate-and
      fire model also shows SNR enhancement, in comparison with a case when the inward
      current is non-inactivating. Small-signal detection can be significantly improved
      in noisy neuronal systems by subthreshold negative feedback, serving to suppress
      false positives.

PMID- 12613556
TI  - Analysis of neural coding through quantization with an information-based
      distortion measure.
AB  - We discuss an analytical approach through which the neural symbols and
      corresponding stimulus space of a neuron or neural ensemble can be discovered
      simultaneously and quantitatively, making few assumptions about the nature of the
      code or relevant features. The basis for this approach is to conceptualize a
      neural coding scheme as a collection of stimulus-response classes akin to a
      dictionary or 'codebook', with each class corresponding to a spike pattern
      'codeword' and its corresponding stimulus feature in the codebook. The neural
      codebook is derived by quantizing the neural responses into a small reproduction
      set, and optimizing the quantization to minimize an information-based distortion
      function. We apply this approach to the analysis of coding in sensory
      interneurons of a simple invertebrate sensory system. For a simple sensory
      characteristic (tuning curve), we demonstrate a case for which the classical
      definition of tuning does not describe adequately the performance of the cell
      studied. Considering a more involved sensory operation (sensory discrimination),
      we also show that, for some cells in this system, a significant amount of
      information is encoded in patterns of spikes that would not be discovered through
      analyses based on linear stimulus-response measures.

PMID- 12613557
TI  - Informative prosodic boundaries.
AB  - In principle, a prosodic boundary in an utterance might affect its interpretation
      in a local, context-independent fashion. In a right-branching language like
      English, the presence of a large prosodic boundary might signal the end of the
      current constituent, requiring the following constituent to be attached high in
      the syntactic tree. We present three listening experiments that test an
      alternative position suggested in Carlson, Clifton, and Frazier (2001) as the
      "informative boundary" hypothesis. This hypothesis claims that the interpretation
      of a prosodic boundary is determined not by its absolute size but by its size
      relative to relevant certain other boundaries. Experiment 1 confirmed the
      predictions of this hypothesis in phrases like the old men and women with very
      large houses, manipulating the boundaries before and and with. Experiment 2
      investigated the effect in a variety of diverse syntactic structures, varying
      syntactic category and status (head vs. nonhead) of the ambiguous constituent. It
      confirmed the predictions of the informative boundary hypothesis in every
      structure tested except for '-ly' adverbs that are ambiguous between a manner
      interpretation and a speaker-evaluation interpretation. Experiment 3 demonstrated
      that sentence interpretation was affected by the size of the late boundary
      relative to a relevant early boundary, but not relative to an early boundary that
      was predicted to be irrelevant.

PMID- 12613558
TI  - Identification of regional varieties by intonational cues. An experimental study
      on Hamburg and Berlin German.
AB  - Two experiments examined the commonly held belief that regional varieties of
      German can be identified by intonational features alone. In both experiments,
      listeners were presented with regional intonational contours of German. In the
      first experiment, listeners judged contours of Hamburg urban vernacular compared
      with contours of Northern Standard German. In the second experiment, listeners
      judged contours of Berlin urban vernacular compared with contours of both
      Northern Standard German and Low Alemannic German. The performance of listeners
      was found to vary with their linguistic experience. Listeners who were familiar
      both with the local variety and with some nonlocal variety by personal contact
      performed better than listeners who were familiar with the local variety only.
      Moreover, also listeners not familiar with Hamburg German and Berlin German,
      respectively, were found to perform the identification test with some success.
      This led to the conclusion that overall success rates do not only depend on true
      recognition of local contours but may additionally be enhanced by using some kind
      of elimination strategy. A second factor that affected performance was the choice
      of speaker for generating the carrier utterances. In the first experiment, all
      carrier utterances were produced by a speaker of Northern Standard German. In the
      second experiment, two sets of carrier utterances were used. The first set was
      obtained from a speaker of Northern Standard German and the second set from a
      speaker of Berlin urban vernacular. As expected, Berlin contours were better
      identified when presented with an utterance that was produced by a speaker of
      Berlin urban vernacular. However, no uniform effect was found for the different
      contours that were examined.

PMID- 12613559
TI  - Prosodic finality and sentence type in French.
AB  - Prosodic boundaries are marked in speech by modifications to dimensions such as
      F0, duration, and segmental quality. The experiment reported here tests the
      hypothesis that modifications at the end of a prosodic domain may be amplified or
      attenuated depending on the type of sentence (statement or question). The
      prosodic modifications investigated here for French are sentence-final
      lengthening and vowel devoicing, which is related to changes in voice quality.
      Six native speakers of French read 10 matched sets of sentences, which included
      both statements and questions. Measurements were made of the last vowel in each
      test sentence and of sentence-medial vowels in control sentences. Statement-final
      vowels were less periodic and more often devoiced than vowels at the end of
      questions or sentence-medial vowels, but question-final vowels were lengthened
      more than statement-final vowels. These results occurred in questions both with
      and without a final pitch rise, suggesting that sentence type is more important
      than final intonation contour in determining how prosodic finality is marked. The
      difference between statements and questions thus appears to be in the relative
      importance of lengthening and voice quality modification in marking finality, not
      in the overall extent to which it is marked.

PMID- 12613560
TI  - Early sound patterns in the speech of two Brazilian Portuguese speakers.
AB  - Sound patterns in the speech of two Brazilian-Portuguese speaking children are
      compared with early production patterns in English-learning children as well as
      English and Brazilian-Portuguese (BP) characteristics. The relationship between
      production system effects and ambient language influences in the acquisition of
      early sound patterns is of primary interest, as English and BP are characterized
      by differing phonological systems. Results emphasize the primacy of production
      system effects in early acquisition, although even the earliest word forms show
      evidence of perceptual effects from the ambient language in both BP children. Use
      of labials and coronals and low and midfront vowels in simple syllable shapes is
      consistent with acquisition data for this period across languages. However,
      potential ambient language influences include higher frequencies of dorsals, use
      of multisyllabic words, and different phone types in syllable-offset position.
      These results suggest that to fully understand early acquisition of sound systems
      one must account for both production system effects and perceptual effects from
      the ambient language.

PMID- 12613561
TI  - Further evidence for systematic reliability differences between explicit and
      implicit memory tests.
AB  - Meier and Perrig (2000) as well as Buchner and Wippich (2000) have shown that
      simple dissociations between explicit and implicit memory measures need not
      reflect functional dissociations of hypothetical underlying memory systems.
      Instead, such dissociations may also result from the fact that some widely used
      implicit memory measures are simply less reliable than the explicit measures with
      which they have been compared. We extend this argument in two ways. First, we
      show that illusion-based memory measures such as the priming measures derived
      from fame and preference judgement tasks are also subject to the reliability
      problem. Second, we show that yes-no and two-alternative forced-choice paradigms
      should, and in fact do, yield virtually identical results as far as the
      reliability of the memory tests is concerned.

PMID- 12613562
TI  - The impact of different directed forgetting instructions on implicit and explicit
      memory: new evidence from a modified process dissociation procedure.
AB  - In contrast to previous research on directed forgetting, the present studies
      adopted a recent modification of the process dissociation procedure (Jacoby,
      1991; Richardson-Klavehn & Gardiner, 1995) to accommodate the cross-contamination
      of memory test performance by implicit and explicit memorial factors. In
      Experiment 1, 120 subjects were compared in global directed forgetting, item-by
      item directed forgetting, and control conditions on estimates of voluntary
      conscious memory, involuntary conscious memory, and involuntary unconscious
      memory performance. In Experiment 2, 80 subjects were compared in specific
      directed forgetting and control conditions on estimates of voluntary conscious
      memory, involuntary conscious memory, and involuntary unconscious memory
      performance. Subjects showed significant decrements in voluntary and involuntary
      conscious memory performance following instructions for directed forgetting in
      all conditions. None of the directed forgetting conditions showed a decrement in
      involuntary unconscious memory performance. Results suggest that, regardless of
      instruction type, directed forgetting prevents the conscious expression of
      memorial information (both voluntary and involuntary) while leaving unconscious
      memory intact.

PMID- 12613563
TI  - An investigation of phonology and orthography in spoken-word recognition.
AB  - The possible influence of initial phonological and/or orthographic information on
      spoken-word processing was examined in six experiments modelled after and
      extending the work Jakimik, Cole, and Rudnicky (1985). Following Jakimik et al.,
      Experiment 1 used polysyllabic primes with monosyllabic targets (e.g., BUCKLE
      BUCK/[symbol: see text]; MYSTERY-MISS,/[symbol: see text]). Experiments 2, 3, and
      4 used polysyllabic primes and polysyllabic targets whose initial syllables
      shared phonological information (e.g., NUISANCE-NOODLE,/[symbol: see text]),
      orthographic information (e.g., RATIO-RATIFY,/[symbol: see text]), both (e.g.,
      FUNNEL-FUNNY,/[symbol: see text]), or were unrelated (e.g., SERMON
      NOODLE,/[symbol: see text]). Participants engaged in a lexical decision
      (Experiments 1, 3, and 4) or a shadowing (Experiment 2) task with a single-trial
      (Experiments 2 and 3) or subsequent-trial (Experiments 1 and 4) priming
      procedure. Experiment 5 tested primes and targets that varied in the number of
      shared graphemes while holding shared phonemes constant at one. Experiment 6 used
      the procedures of Experiment 2 but a low proportion of related trials. Results
      revealed that response times were facilitated for prime-target pairs that shared
      initial phonological and orthographic information. These results were confirmed
      under conditions when strategic processing was greatly reduced suggesting that
      phonological and orthographic information is automatically activated during
      spoken-word processing.

PMID- 12613564
TI  - Semantic effects in word naming: evidence from English and Japanese Kanji.
AB  - Three experiments investigated whether reading aloud is affected by a semantic
      variable, imageability. The first two experiments used English, and the third
      experiment used Japanese Kanji as a way of testing the generality of the findings
      across orthographies. The results replicated the earlier findings that readers
      were slower and more error prone in reading low-frequency exception words when
      they were low in imageability than when they were high in imageability (Strain,
      Patterson, & Seidenberg, 1995). This result held for both English and Kanji even
      when age of acquisition was taken into account as a possible confounding
      variable, and the imageability effect was stronger in Kanji compared to English.

PMID- 12613565
TI  - The effect of orthographic uniqueness and deviation points on lexical decisions:
      evidence from unilateral and bilateral-redundant presentations.
AB  - Words with an early or late orthographic uniqueness point and nonwords with an
      early or late orthographic deviation point were presented to the left, right, or
      both visual fields simultaneously. In Experiment 1, 20 participants made lexical
      decision judgements to horizontal stimulus presentations. In Experiment 2, a
      further 20 participants completed the task using vertical presentations to
      control for attentional biases. Consistent with previous research, words with
      earlier orthographic uniqueness points prompted faster responses across visual
      fields, regardless of stimulus orientation. Although research has suggested that
      the left hemisphere's superiority for language processing stems from a
      comparatively parallel processing strategy, with the right hemisphere reliant
      upon a serial mechanism, left and right visual field presentations were not
      differentially affected by orthographic uniqueness point. This suggests that
      differential sequential effects previously reported result during processes other
      than retrieval from the lexicon. The overall right visual field advantage
      observed using horizontal presentations disappeared when stimuli were presented
      vertically. Contrary to expectations, there was a facilitatory effect of late
      orthographic deviation point for horizontal nonword presentations. Overall, the
      results were interpreted as being consistent with predictions of a cohort model
      of word recognition, and they highlighted the effect of stimulus orientation on
      left and right hemisphere word recognition.

PMID- 12613566
TI  - Effects of response eccentricity and relative position on orthogonal stimulus
      response compatibility with joystick and keypress responses.
AB  - When unimanual left-right movement responses are made to up-down stimuli,
      performance is better with the up-right/down-left mapping when responding in the
      right hemispace and with the up-left/down-right mapping when responding in the
      left hemispace. We evaluated whether this response eccentricity effect is
      explained best in terms of rotational properties of the hand (the end-state
      comfort hypothesis) or asymmetric coding of the stimulus and response
      alternatives (the salient features coding hypothesis). Experiment 1 showed that
      bimanual keypresses yield a response eccentricity effect similar to that obtained
      with unimanual movement responses. In Experiment 2, an inactive response
      apparatus was placed to the left or right of the active response apparatus to
      provide a referent. For half of the participants, the active and inactive
      apparatuses were joysticks, and for half they were response boxes with keys. For
      both response types, an up-right/down-left advantage was evident when the
      relative position of the active response apparatus was right but not when it was
      left. That bimanual keypresses yield similar eccentricity and relative location
      effects to those for unimanual movements is predicted by the salient features
      coding perspective but not by the end-state comfort hypothesis.

PMID- 12613567
TI  - Reduced timing variability during bimanual coupling: a role for sensory
      information.
AB  - On a repetitive tapping task, the within-hand variability of intertap intervals
      is reduced when participants tap with two hands as compared to one-hand tapping.
      Because this bimanual advantage can be attributed to timer variance (Wing
      Kristofferson model, 1973a, b), separate timers have been proposed for each hand,
      whose outputs are then averaged (Helmuth & Ivry, 1996). An alternative notion is
      that action timing is based on its sensory reafferences (Aschersleben & Prinz,
      1995; Prinz, 1990). The bimanual advantage is then due to increased sensory
      reafference. We studied bimanual tapping with the continuation paradigm.
      Participants first synchronized their taps with a metronome and then continued
      without the pacing signal. Experiment 1 replicated the bimanual advantage.
      Experiment 2 examined the influence of additional sensory reafferences. Results
      showed a reduction of timer variance for both uni- and bimanual tapping when
      auditory feedback was added to each tap. Experiment 3 showed that the bimanual
      advantage decreased when auditory feedback was removed from taps with the left
      hand. Results indicate that the sensory reafferences of both hands are used and
      integrated into timing. This is consistent with the assumption that the bimanual
      advantage is at least partly due to the increase in sensory reafference. A
      reformulation of the Wing-Kristofferson model is proposed to explain these
      results, in which the timer provides action goals in terms of sensory
      reafferences.

PMID- 12613568
TI  - On the nature of insight solutions: evidence from skill differences in anagram
      solution.
AB  - According to the Gestalt psychologists, problem solutions that pop into mind
      suddenly with no awareness of the process by which they were generated are
      objectively as well as subjectively sudden. Thus, such pop-out solutions are
      qualitatively different from search solutions, which are constructed
      incrementally. The authors tested this claim in the domain of anagram solution.
      Experiment 1 documented that anagrams yield pop-out solutions, especially among
      highly skilled solvers. The results of Experiment 2 indicated that both pop-out
      and search solutions depended on the gradual accumulation of partial information,
      contrary to the Gestalt view of problem solving. Nevertheless, some aspects of
      the Experiment 2 results, as well as new analyses of an anagram study reported
      elsewhere, suggest that there may in fact be a qualitative difference between pop
      out and search solutions. In particular, pop-out solutions may result from
      parallel processing of the constraints on the rearranged order of the anagram
      letters, whereas search solutions may result from a serial hypothesis-testing
      procedure. Like dynamite, the insightful solution explodes on the solver's
      cognitive landscape with breathtaking suddenness, but if one looks closely, a
      long fuse warns of the impending reorganization. (Durso, Rea, & Dayton, 1994, p.
      98)

PMID- 12613569
TI  - Cytokines and chemokines in autoimmune disease: an overview.

PMID- 12613570
TI  - Cytokines and chemokines--their receptors and their genes: an overview.

PMID- 12613571
TI  - Cytokine and cytokine receptor genes in the susceptibility and resistance to
      organ-specific autoimmune diseases.

PMID- 12613572
TI  - Cytokines, lymphocyte homeostasis and self tolerance.

PMID- 12613573
TI  - The role of cytokines as effectors of tissue destruction in autoimmunity.

PMID- 12613574
TI  - Cytokines in the treatment and prevention of autoimmune responses-a role of IL
      15.

PMID- 12613575
TI  - Cytokines in the pathogenesis and therapy of autoimmune encephalomyelitis and
      multiple sclerosis.

PMID- 12613576
TI  - Chemokines in experimental autoimmune encephalomyelitis and multiple sclerosis.

PMID- 12613577
TI  - Cytokines and chemokines in the pathogenesis of murine type 1 diabetes.

PMID- 12613578
TI  - Immunoregulation by cytokines in autoimmune diabetes.

PMID- 12613579
TI  - Cytokines in the pathogenesis of rheumatoid arthritis and collagen-induced
      arthritis.

PMID- 12613580
TI  - Cytokines and chemokines in virus-induced autoimmunity.

PMID- 12613581
TI  - Cytokines and chemokines in human autoimmune skin disorders.

PMID- 12613582
TI  - Involvement of cytokines in the pathogenesis of systemic lupus erythematosus.

PMID- 12613583
TI  - Cytokines, chemokines and growth factors in the pathogenesis and treatment of
      inflammatory bowel disease.

PMID- 12613584
TI  - Enantioselective catalysis in fine chemicals production.
AB  - The application of enantioselective catalysis to the fine chemicals industry has
      great potential both from economic and ecological points of view, but to date has
      not been widely implemented on a technical scale. The author hopes that the award
      of the 2001 Chemistry Nobel Prize in this field will give the necessary impetus
      to future applications.

PMID- 12613585
TI  - Enzymology of acyl chain macrocyclization in natural product biosynthesis.
AB  - Polyketides and nonribosomal peptides constitute a large and diverse set of
      natural products with biological activity in microbial survival and pathogenesis,
      as well as broad pharmacological utility as antineoplastics, antibiotics or
      immunosupressants. These molecules are biosynthesized by the ordered condensation
      of monomer building blocks, acyl-CoAs or amino acids, leading to construction of
      linear acyl chains. Many of these natural products are constrained to their
      bioactive conformations by macrocyclization whereby, in one of the terminal steps
      of biosynthesis, parts of the molecule distant in the constructed linear acyl
      chain are covalently linked to one another. Typically, macrocyclization is
      catalyzed by a thioesterase domain at the C-terminal end of the biosynthetic
      assembly line, although alternative strategies are known. The enzymology of these
      macrocyclization catalysts, their structure, mechanism, and catalytic
      versatility, is the subject of this review. The diversity of macrocyclic
      structures accessed by enzyme catalyzed cyclization of linear acyl chains as well
      as their inherent substrate tolerance suggests their potential utility in
      reprogramming natural product biosynthesis pathways or accessing novel
      macrocyclic structures.

PMID- 12613586
TI  - Anchor chain length alters the apparent mechanism of chloride channel function in
      SCMTR derivatives.
AB  - Two membrane-anchored heptapeptides have been prepared and their pore-formation
      behavior in phospholipid bilayer membranes has been found to differ profoundly as
      a result only of alkyl chain length.

PMID- 12613587
TI  - Low molecular weight organogelators for water.
AB  - Mono-urea serine derivatives with low molecular weights were prepared in one step
      and show remarkable self-assembling and gelation properties in water.

PMID- 12613588
TI  - Helical templating of polyiodide networks at a binuclear metallo complex.
AB  - A homobimetallic supramolecular helicate has been prepared from a new multimodal
      ligand, and used to template the formation of two polyiodide networks, one
      containing an unprecedented figure-of-eight polyiodide helix, the other dominated
      by peripheral C-H...I polyiodide chain interactions.

PMID- 12613589
TI  - Synthesis and characterization of hyperbranched mesoporous silica SBA-15.
AB  - Branched mesoporous silica SBA-15 materials have been prepared in a simple
      process using non-ionic surfactant in acidic conditions in the presence of metal
      ions.

PMID- 12613591
TI  - Indium nitride crystals with flower-like structure.
AB  - Preparation of indium nitride at atmospheric pressure has been examined by means
      of halide chemical vapour deposition; from the SEM observations of the crystals
      deposited onto an Si(100) substrate it was found that they showed flower-like
      structure.

PMID- 12613590
TI  - Binding of an inhibitor of the p53/MDM2 interaction to MDM2.
AB  - The mode of action of the secondary metabolite chlorofusin, which antagonises the
      interaction between p53 and MDM2, involves direct binding to the N-terminal
      domain of MDM2.

PMID- 12613592
TI  - Synthesis, structure and magnetism of a unique dodecanuclearcopper(II) 'picture
      frame' held in a 4 x 4 grid-like assembly.
AB  - The synthesis, structure and preliminary magnetic studies of a novel
      dodecanuclearcopper(II) grid-like assembly are reported.

PMID- 12613593
TI  - New method for attachment of biomolecules to porous silicon.
AB  - Biomolecules have been attached to porous silicon by a new linking method that
      forms a direct Si-C bond on the surface and retains the photoluminescence of the
      porous silicon.

PMID- 12613594
TI  - The consequences of an interstitial N atom in the FeMo cofactor of nitrogenase.
AB  - The atom-centred FeMo cofactor of nitrogenase most likely contains N, resting at
      the [NMoFe7]18+ redox level, inserted from N2, and subsequently restricting the
      modes of binding of substrate to the NFe6 core.

PMID- 12613595
TI  - Pure silica BETA colloidal zeolite assembled in thin films.
AB  - Pure silica nanoscale zeolite BETA with monomodal particle size distribution was
      synthesized from a colloidal precursor solution and successfully applied for the
      preparation of hydrophobic ultrathin films on silicon wafers via spin coating.

PMID- 12613596
TI  - A new reactivity pattern of low-valent transition-metal hydroxo complexes:
      straightforward synthesis of hydrosulfido complexes via reaction with carbon
      disulfide.
AB  - A new basic transformation linking two important classes of transition metal
      compounds; namely, hydroxo and hydrosulfido complexes has been discovered.

PMID- 12613597
TI  - Equilibrium potentials and charge transport of an I-/I3- redox couple in an ionic
      liquid.
AB  - Equilibrium potentials and charge transport of an I-/I3- redox couple in an ionic
      liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, are
      revealed by using a microelectrode technique, where the anomaly of the charge
      transport at high concentrations of the redox couple with comparable [I-] and [I3
      ] can be attributed to the exchange reaction of I- + I3- --> I3- + I-.

PMID- 12613598
TI  - Direct Zn-diamine promoted reduction of C=O and C=N bonds by
      polymethylhydrosiloxane in methanol.
AB  - Ketones and imines are chemoselectively reduced at room temperature in methanol
      to the corresponding alcohols and amines in high yields in a one-step procedure
      using polymethylhydrosiloxane (PMHS) and a simple zinc-diamine catalyst.

PMID- 12613599
TI  - Novel Cr-PNP complexes as catalysts for the trimerisation of ethylene.
AB  - Cr(III) complexes of tridentate PNP ligands have been prepared and evaluated as
      catalysts for ethylene trimerisation, with several giving high activity and
      excellent selectivity towards 1-hexene when activated with methylaluminoxane.

PMID- 12613600
TI  - A rigid cavity containing tetra-cobalt(III) [2 x 2] grid complex.
AB  - The synthesis and structure of a rigid, cavity containing tetra-cobalt(III) [2 x
      2] grid complex using an unusual bis(bipyridine)dimethoxynaphthyridine ligand is
      described.

PMID- 12613601
TI  - A reagentless electrochemical biosensor based on a protein scaffold.
AB  - Apo-myoglobin, labeled with the environmentally sensitive redox probe
      RuII(NH3)4(1,10-phenanthroline-5-maleimide)2+, was immobilized onto gold
      electrodes modified with 11-mercaptoundecanoic acid and subsequently labeled with
      biotin; avidin binding to the immobilized biotin was specifically and
      quantitatively detected by a change in cyclic voltammetry of the co-immobilized
      probe.

PMID- 12613602
TI  - Solvent-free synthesis and purification of poly[2-(dimethylamino)ethyl
      methacrylate] by atom transfer radical polymerization.
AB  - Solvent-free synthesis of well-defined poly[2-(dimethylamino)ethyl methacrylate]
      (PDMAEMA) (co)polymers was performed by atom transfer radical polymerization
      conducted under very mild conditions (in bulk at 25 degrees C). The pH-dependence
      and the thermo-responsive behaviour of PDMAEMA in aqueous solution were operated
      to isolate and purify the (co)polymers without using any organic solvent or
      further catalyst extraction. The viscosity in aqueous solution of so-purified
      PDMAEMA homopolymers and their block copolymers with poly(ethylene glycol) (PEG)
      was studied as a function of molar mass and concentration and a typical
      polyelectrolyte behaviour was observed, these catalyst-deprived polycations are
      able to form stable and non toxic complexes with DNA, showing good transfection
      efficacies in gene therapy.

PMID- 12613603
TI  - Facile deposition of [60]fullerene on the electrode by electrochemical oxidative
      polymerization of thiophene.
AB  - It was found that [60]fullerene encapsulated in anionic calix[8]arenes can be
      readily deposited by electrochemical oxidative polymerization of
      ethylenedioxythiophene: the resultant electrode generates a photocurrent wave
      (ca. 100 nA cm(-2)) in response to visible light irradiation.

PMID- 12613604
TI  - Photo-induced colour generation and colour erasing switched by the sol-gel phase
      transition.
AB  - The controlled colour generation and colour erasing phenomena of alkylammonium
      polyoxomolybdate complexes were first observed in the trans-(1R,2R)-1,2
      bis(undecylcarbonylamino)cyclohexane organogel system using the sol-gel phase
      transition.

PMID- 12613605
TI  - First high thermally stable organo-inorganic 3D polymer scandium derivative as a
      heterogeneous Lewis acid catalyst.
AB  - Sc2(OOCC2H4COO)2.5(OH), a new hybrid organic-inorganic polymer, has been
      hydrothermally obtained; the crystal structure of this material has been
      established by single crystal X-ray diffraction; having high thermal stability it
      can be used as an effective Lewis acid catalyst and can be easily recycled and
      reused without any appreciable loss in activity.

PMID- 12613606
TI  - The effect of ion energy upon plasma polymerization deposition rate for acrylic
      acid.
AB  - A novel technique, which allows the importance of ion energy in plasma polymer
      film growth to be investigated, without perturbation of any other plasma
      parameter (particle densities or temperatures) or, in principle, perturbation of
      particle (neutral or ion) fluxes is applied in the plasma polymerisation of
      acrylic acid and new insight into polymer formation is gleaned.

PMID- 12613607
TI  - Enantioselective total synthesis of (-)-heliannuol A.
AB  - An efficient and enantiocontrolled total synthesis of (-)-heliannuol A has been
      accomplished by employing ring closing metathesis and sequential
      diastereoselective epoxidation and regioselective reductive cleavage of the
      epoxide ring.

PMID- 12613608
TI  - Growth of individual hydrogen-bonded nanostructures on gold monolayers.
AB  - The growth of individual nanometer-sized (3.4 +/- 1.4 nm) hydrogen bonded
      assemblies 1(2) x (DEB)6 on gold monolayers was achieved through an exchange
      reaction between single isolated calix[4]arene dimelamine 2 (1.1 +/- 0.2 nm)
      embedded in hexanethiol monolayers and double rosette hydrogen bonded assembly
      1(3) x (DEB)6 in solution. The growth process was monitored by tapping mode
      atomic force microscopy (TM-AFM).

PMID- 12613609
TI  - Highly selective Friedel-Crafts monoalkylation using micromixing.
AB  - Highly selective Friedel-Crafts monoalkylation of aromatic compounds with N
      acyliminium ions has been achieved by efficient 1:1 mixing using a
      multilamination-type micromixer.

PMID- 12613610
TI  - Engineering redox functions in a nucleic acid binding protein.
AB  - A nucleic acid binding protein, rop, has conserved topology with a number of
      redox proteins; this is exploited to engineer haem binding, expanding its
      function as a redox protein.

PMID- 12613611
TI  - N-PtIV-H/N-H...PtII intramolecular redox equilibrium in a product of H-C(sp2)
      cleavage and unusual alkane/arene C-H bond selectivity of
      ([2.1.1]pyridinophane)PtII(CH3)+.
AB  - T-shaped 14 valence electron (eta2-L)PtMe+ (based on DFT geometry optimization, L
      = [2.1.1]-2,6-pyridinophane) reacts with benzene to give (eta3-L) PtIV(Ph)2H+ and
      methane; the latter cation is in thermal equilibrium with the N-protonated PtII
      tautomer (eta2-L-H)Pt(Ph)2+, and these complexes react with ethane or
      cyclopentane to produce benzene and (L)PtH(olefin)+.

PMID- 12613612
TI  - Silver nanoparticle growth in 3D-hexagonal mesoporous silica films.
AB  - The 3D-hexagonal mesoporous films are used as templates to grow uniform silver
      nanoparticles. The grafting of hydrophobic groups at the pore surface,
      significantly slows down the silver ion diffusion, anchoring small silver
      clusters in micropores and leading to organized domains of silver particles in
      mesopores with a narrow size distribution.

PMID- 12613613
TI  - Sidewall functionalization of single-walled carbon nanotubes with organic
      peroxides.
AB  - Single-wall carbon nanotubes (SWNTs) and their fluorinated derivatives (F-SWNTs)
      were reacted with organic peroxides including benzoyl and lauroyl peroxide to
      produce phenyl and undecyl sidewall functionalized SWNTs, respectively, which
      were characterized by Raman, FTIR, and UV-Vis-NIR spectra as well as TGA/MS,
      TGA/FTIR, and TEM data.

PMID- 12613614
TI  - Chemical and transient spectroscopic evidence for C2-C3 cleavage of 2,3
      diaryloxetane radical cations.
AB  - Electron transfer cycloreversion of the methoxy substituted oxetane 1b results in
      the production of trans-anethole and benzaldehyde through C2-C3 bond cleavage.
      trans-Anethole radical cation has been detected as transient intermediate by
      laser flash photolysis.

PMID- 12613615
TI  - Understanding the building-up process of three dimensional open-framework metal
      phosphates: acid degradation of the 3D structures to lower dimensional
      structures.
AB  - Acid degradation of 3D zinc phosphates primarily yields a one-dimensional ladder
      compound, an observation that is significant considering that the latter forms 3D
      structures on heating in water.

PMID- 12613616
TI  - Highly proton conductive polyimide electrolytes containing fluorenyl groups.
AB  - Novel sulfonated polyimides containing fluorenyl groups show good thermal and
      oxidative stability as well as a high proton conductivity of 1.67 S cm(-1) at 120
      degrees C and 100% RH.

PMID- 12613617
TI  - Synthesis and characterization of highly ordered mesoporous thin films with -COOH
      terminated pore surfaces.
AB  - Highly ordered mesoporous inorganic-organic hybrid thin films with covalently
      bonded carboxylic acid (-COOH) terminal groups on the pore surfaces were
      synthesized by evaporation induced self-assembly of tetraethoxysilane,
      organosilanes, and a nonionic surfactant followed by acid hydrolysis and
      characterized using transmission electron microscopy (TEM), X-ray diffraction
      (XRD), Fourier transform infrared (FTIR) spectroscopy, surface acoustic wave
      (SAW) based N2 sorption, and thermogravimetric analysis (TGA) techniques.

PMID- 12613618
TI  - Phosphazenium chloride catalysts immobilized on SBA-15 mesoporous material and
      silica gel: new exceptionally active catalysts for the chlorination of organic
      acids.
AB  - Novel reusable phosphazenium chloride catalysts immobilized on SBA-15 mesoporous
      material and silica gel show exceptional activities and selectivities even in the
      continuous chlorination reaction of organic acids with thionyl chloride or
      phosgene.

PMID- 12613619
TI  - Secondary nucleation of the beta-polymorph of L-glutamic acid on the surface of
      alpha-form crystals.
AB  - Evidence is presented for the secondary nucleation of beta-L-glutamic acid on the
      surface of the alpha-polymorph, using a combination of Scanning Electron
      Microscopy and Raman spectroscopy.

PMID- 12613620
TI  - 'Nucleo-nanocages': designed ternary oligodeoxyribonucleotides spontaneously form
      nanosized DNA cages.
AB  - DNA three-way junctions formed from three 30-mer oligonucleotides that contain
      single-chained self-complementary sticky ends spontaneously self-assemble into
      'nucleo-nanocages': the exo- and endo-nuclease digestion experiments indicate
      that defects such as the single and double strand end structures are absent on
      the spherical nano-assemblies, providing clear evidence for the closed nanocage
      structure.

PMID- 12613621
TI  - Gas phase oxidation of alcohols to aldehydes or ketones catalysed by supported
      gold.
AB  - Primary and secondary aliphatic alcohols are smoothly oxidised by air to the
      corresponding carbonyl derivatives with high selectivity using 1% Au on silica.

PMID- 12613622
TI  - The anionic thia-Fries rearrangement of aryl triflates.
AB  - Aryl triflates undergo LDA-mediated rearrangement to generate o-hydroxyaryl
      trifluoromethylsulfones. In some cases, partitioning between rearrangement and
      aryne generation can be controlled.

PMID- 12613623
TI  - Design and synthesis of potent N1-substituted indole melatonin receptor agonists.
AB  - The design and expeditious synthesis of two new indole analogs with up to 5-fold
      potency of that of melatonin is described.

PMID- 12613624
TI  - Conformational studies on phenyl thioglycosides: a remote effect on disaccharide
      linkage by phenyl aglycons attenuates recognition of galabiosides by a bacterial
      adhesin.
AB  - Phenyl S-galabiosides display altered conformational properties, as compared to
      phenyl O-galabiosides, characterised by a remote effect on the galabiose
      intersaccharidic glycoside bond by the phenyl aglycon, resulting in significantly
      lowered affinity for the PapG class II adhesin of uropathogenic E. coli.

PMID- 12613626
TI  - Modulating the efficiency of Ru(II) luminescence via ion binding-induced
      conformational restriction of bipyridyl ligands.
AB  - Conformational restriction imposed upon Ru(bpy)32+ crown ether complexes by metal
      ion binding leads to enhanced luminescence.

PMID- 12613625
TI  - Highly enantioselective synthesis of alpha,alpha-disubstituted malonamic acids
      through asymmetric hydrolysis of dinitriles with Rhodococcus sp. CGMCC 0497.
AB  - Highly enantioselective hydrolysis of alpha,alpha-disubstituted malononitriles by
      the strain Rhodococcus sp. CGMCC 0497 expressing both nitrile hydratase and
      amidase activity to give (R)-alpha,alpha-disubstituted malonamic acids which
      could be converted to valuable (R)- or (S)-alpha-alkylated amino acids are
      reported and the yields of the products are improved remarkably at a lower
      reaction temperature.

PMID- 12613627
TI  - The reaction of 'GaI' with a 1,3-diyne: synthesis, characterisation and
      reactivity of a novel C-C coupled ene-diyne-bis(gem-organodigallium(III))
      complex.
AB  - Treatment of 'GaI' with a 1,3-diyne, Me3SiC[triple bond]CC[triple bond]CSiMe3,
      leads to C-C coupling reactions and the isolation of the novel organogallium
      species, [Ga4I8[C8(SiMe3)4]], as two isomeric forms; their X-ray crystal
      structures show them to contain the first structurally authenticated gem
      organodigallium fragments and to exhibit rare examples of Ga-alkyne pi
      interactions.

PMID- 12613628
TI  - Molecular recognition. Electrostatic effects in supramolecular self-assembly.
AB  - A di-positively charged metal-based receptor is shown to form 1:1 or 2:1
      association complexes with rigid, linear two-site guests depending on the site
      separation, suggesting that electrostatic repulsion controls the association
      nuclearity.

PMID- 12613629
TI  - Novel synthesis of highly active Pt/C cathode electrocatalyst for direct methanol
      fuel cell.
AB  - A 40 wt% Pt/C cathode electrocatalyst with controlled Pt particle size of
      approximately 2.9 nm showing better performance than commercial catalyst for
      direct methanol fuel cell was prepared by a polyol process with water but without
      using stabilizing agent.

PMID- 12613630
TI  - Direct preparation of polyfunctional amino-substituted arylmagnesium reagents via
      an iodine-magnesium exchange reaction.
AB  - The successive addition of PhMgCl and i-PrMgCl to functionalised iodoanilines
      allows their conversion to the corresponding amino-functionalised Grignard
      reagents, which react smoothly with a range of electrophiles in high yield.

PMID- 12613631
TI  - Preparation, structure, and some coordination properties of 2-chloro-3,3-diphenyl
      3-thioxo-1-(2,4,6-tri-t-butylphenyl)-1,3-diphosphapropene.
AB  - A sterically encumbered 3-thioxo-1,3-diphosphapropene, bearing a P=C-P=S
      skeleton, was prepared, characterised, and allowed to react with a
      carbonyltungsten(0) reagent and iodine affording the corresponding chelate
      tungsten(0) complex and charge-transfer complex with iodine, respectively, which
      were analysed by the X-ray crystallography.

PMID- 12613632
TI  - C-H activation of imidazolium salts by Pt(0) at ambient temperature: synthesis of
      hydrido platinum bis(carbene) compounds.
AB  - A zerovalent platinum(carbene) complex with two monoalkene ligands, which is able
      to activate C-H bonds of imidazolium salts at room temperature to yield isolable
      hydrido platinum(II) bis(carbene) compounds, has been synthesised for the first
      time.

PMID- 12613633
TI  - Unexpected switch in regioselectivity of tether-directed Bingel-type
      biscyclopropanations depending on the leaving groups at tethered active ethylene
      moieties.
AB  - The regioselectivity of tether-directed Bingel-type biscyclopropanations of
      [60]fullerene was switched depending on the leaving groups at tethered active
      methylene moieties; the reactions of [60]fullerene with unhalogenated tethered
      bis(active methylene) derivatives/I2 and with brominated derivatives in the
      presence of 1,7-diazabicyclo[5.4.0]undec-7-ene gave trans-4-adducts
      predominantly, while the reactions with chlorinated derivatives afforded
      equatorial-adducts almost exclusively.

PMID- 12613634
TI  - The colourful fluorescence from readily-synthesised 3,4-diaryl-substituted
      maleimide fluorophores.
AB  - A new synthesis procedure has been developed for a series of maleimide-based
      fluorophores, exhibiting a large variation of emission spectra spanning the
      entire visible range.

PMID- 12613635
TI  - Potassium-zinc induced synergic enhancement of the basicity of
      hexamethyldisilazide (HMDS) towards methylbenzene molecules.
AB  - While neither KHMDS nor Zn(HMDS)2 can unilaterally metallate toluene under the
      conditions studied, the bilateral base 'KZn(HMDS)3' can smoothly do so to produce
      the benzyl product [[KZn(HMDS)2(CH2Ph)]infinity], which exists in the crystal as
      an infinite spiral chain of benzyl (ambi-sigma, pi)-linked (KNZnN) rings.

PMID- 12613636
TI  - Hydrothermal synthesis of perovskite nanotubes.
AB  - A low-temperature hydrothermal reaction has been utilized to generate crystalline
      barium titanate and strontium titanate nanotubes, which have been characterized
      by means of X-ray diffraction and transmission electron microscopy, coupled with
      energy dispersive X-ray analysis.

PMID- 12613637
TI  - Dioxygen activation by a dinuclear nickel thiolate complex: structural
      characterization of the ligand oxidized product.
AB  - A (mu-SR)2-nickel(II) dimer derived from a ligand with carboxamido nitrogen and
      thiolato sulfur donors reacts with O2 to afford an oxidized product in which
      phenyl groups of the ligand frames are oxidized to nickel-bound phenolates.

PMID- 12613638
TI  - Three-fold interpenetrating three-dimensional networks based on C
      methylcalix[4]resorcinarene incorporating benzophenone guest molecules.
AB  - A new solid based on C-methylcalix[4]resorcinarene and the linker molecule bis(4
      pyridylmethylidyne)hydrazine (bpmh) has been prepared, in which brick-wall sheets
      are linked in the third dimension to give networks with three intersecting
      perpendicular channels; the networks interpenetrate three-fold, but nevertheless
      leave cavities capable of including sizable guest molecules.

PMID- 12613639
TI  - An electrogenerated poly(pyrrole-benzophenone) film for the photografting of
      proteins.
AB  - A photoreactive organic polymer was prepared by oxidative electrochemical
      polymerization of a pyrrole-benzophenone derivative on conductive surfaces; the
      resulting polypyrrolic film allowed, upon irradiation, the reagentless covalent
      grafting of proteins.

PMID- 12613640
TI  - Fluorophore-capped cyclodextrins as efficient chemical-to-light energy
      converters.
AB  - Bisbenzimidazole-capped cyclodextrins, capable of forming supramolecules, harvest
      chemical energy from the oxidation reaction of a bis(aryl)oxalate and emit light
      two orders of magnitude more efficiently than fluorescein does.

PMID- 12613641
TI  - Electrochemistry of P450cin: new insights into P450 electron transfer.
AB  - Electrochemistry of bacterial cytochrome P450cin (CYP176A) reveals that,
      unusually, substrate binding does not affect the heme redox potential, although a
      marked pH dependence is consistent with a coupled single electron/single proton
      transfer reaction in the range 6 < pH < 10.

PMID- 12613642
TI  - A polycatenar mesogen with a perfluorinated moiety showing continuous phase
      transformation between a smectic A phase and a structured, fluid, optically
      isotropic phase.
AB  - A polycatenar mesogen consisting of a four aromatic ring system with three long
      alkoxy chains and a bulky perfluorinated substituent has been synthesized and
      found to show the polymorphism of a cubic phase, a columnar phase and a smectic A
      phase, including a structured, fluid, optically isotropic phase with the phase
      transformation between the smectic A phase and the isotropic phase occurring
      continuously.

PMID- 12613643
TI  - A novel synthesis of tetrahydrofuran via alkoxy radical cyclisation.
AB  - Tetrahydrofurans were synthesised via 5-exo-trig cyclisation of alkoxy radical
      generated by unprecedented 1,5-hydrogen shift from hydroxyl group to vinyl
      radical.

PMID- 12613644
TI  - Novel supramolecular architectures in group 13 perfluoroaryl complexes. Synthesis
      and structures of [AlMe(C6F5)(mu-Me)]2 and GaMe(C6F5)2.
AB  - Novel supramolecular architectures are observed in the solid state structures of
      [AlMe(C6F5)(mu-Me)]2 (1) and Ga(C6F5)2Me (2) via pi-pi stacking between C6F5
      rings and intermolecular aryl-F-->Ga interactions, respectively.

PMID- 12613646
TI  - A novel three-dimensional coordination polymer constructed with mixed-valence
      dimeric copper(I,II) units.
AB  - A novel three-dimensional coordination polymer with a mixed-valence localized
      copper(I,II) dimeric unit, [Cu2(4-pya)3]n (4-pya = 4-pyridinecarboxylate), was
      hydrothermally synthesized via a simultaneous in-situa redox and hydrolysis
      reaction of Cu(II) and 4-cyanopyridine and crystallographically characterized to
      be a twofold interpenetrated three-dimensional coordination network with a cubic
      [Cu16(4-pya)12] building unit.

PMID- 12613647
TI  - The contrasting behaviour of bridged amido-cyclopentadienyl (constrained
      geometry) group 15 chlorides and cations derived therefrom.
AB  - The first group 15 amido-cyclopentadienyl (constrained geometry) cations have
      been prepared and structurally characterized; the structure of the stibenium
      cation is different from those of the corresponding phosphenium and arsenium
      cations.

PMID- 12613648
TI  - A simple strategy for preparation of sensor arrays: molecularly structured
      monolayers as recognition elements.
AB  - The spreader-bar approach is a simple method for producing a huge variety of
      receptors with different selectivities. A sensor-array consisting of five such
      receptors is presented. A pattern recognition provides selective detection of
      different purines and pyrimidines.

PMID- 12613645
TI  - Novel intermolecular carbon radical addition to a nitrone: asymmetric synthesis
      of alpha-amino acids.
AB  - A nitrone was used as a synthetically useful radical acceptor in carbon-carbon
      bond-forming radical reactions; the intermolecular addition of alkyl radicals to
      chiral glyoxylic nitrone was studied; a high degree of stereocontrol in radical
      addition to glyoxylic nitrone was achieved to provide a new method for asymmetric
      synthesis of alpha-amino acids.

PMID- 12613649
TI  - Acoustic wave sensor for barium based on poly[Ni(salen)(crown)] recognition
      chemistry.
AB  - Interfacial recognition of barium by a crown ether receptor is quantified using
      an acoustic wave sensor, and the isotherm characteristics rationalized in terms
      of solution complexation chemistry and polymer materials properties.

PMID- 12613650
TI  - Charge transfers influence on the spin ground state of manganese and iron
      superoxide dismutases: a DFT study on a model of the reduced active site
      interacting with O2-.
AB  - From DFT and time-dependent DFT calculations on Mn(II)SOD and Fe(II)SOD active
      site models interacting with O2- we have determined that metal-to-ligand charge
      transfers stabilise the S = 2 and S = 5/2 spin states as ground spin states for
      the [Mn(II)SOD-02-] and [Fe(II)SOD-O2-] model complexes, respectively. These
      charge transfers are ruled by the electronic configuration of the metal ion, and
      they can be determinant in the catalysis reaction.

PMID- 12613651
TI  - The redox thermodynamics of microperoxidase are dependent on the solvent medium.
AB  - The redox thermodynamics of the heme undecapeptide, microperoxidase have been
      examined in aqueous buffer and in glycerol. The change in E(o)' on transition
      from water to glycerol is dominated by the change in deltaS(o)'.

PMID- 12613652
TI  - Rh2(OAc)4-catalyzed reactions of alpha-diazoimides: a simple and novel synthesis
      of mono- and bis(2,3-fused perhydrooxazol-4-one) systems.
AB  - Simply, trapping the intermediate isomunchnone 1,3-dipoles by the external oxygen
      nucleophiles resulted in new heterocyclic systems and the use of diols led to the
      formation of four carbon-oxygen bonds in a single operation which eventually
      delivered bis(2,3-fused perhydrooxazol-4-one) systems.

PMID- 12613653
TI  - Organoruthenium(II) and (III) amidinates, (eta5-C5Me5)Ru(eta-amidinate) and (eta5
      C5Me5)RuCl(eta-amidinate), as unique redox catalysts for the intramolecular
      Kharasch reactions: facile access to a pyrrolizidine alkaloid skeleton under mild
      conditions.
AB  - A novel organoruthenium(III) amidinate, (eta5-C5Me5)RuCl(eta-iPrN=C(Me)NiPr) (2),
      has been prepared by oxidation of organoruthenium amidinate, (eta5-C5Me5)Ru(eta
      iPrN=C-(Me)NiPr) (1), by organic chlorides; both 1 and 2 are found to be good
      catalysts for atom-transfer cyclization of N-allyltrichloroacetamides which are
      useful for successful preparation of a pyrrolizidine alkaloid skeleton under mild
      conditions.

PMID- 12613654
TI  - The genetic enhancement of memory.

PMID- 12613656
TI  - Colloidal drug carriers: achievements and perspectives.
AB  - Colloidal drug carriers such as liposomes and nanoparticles are able to modify
      the distribution of an associated substance. They can therefore be used to
      improve the therapeutic index of drugs by increasing their efficacy and/or
      reducing their toxicity. If these delivery systems are carefully designed with
      respect to the target and route of administration, they may provide one solution
      to some of the delivery problems posed by new classes of active molecules such as
      peptides, proteins, genes, and oligonucleotides. They may also extend the
      therapeutic potential of established drugs such as doxorubicin and amphotericin
      B. This article discusses the use of colloidal, particulate carrier systems (25
      nm to 1 microm in diameter) in such applications. In particular, systems which
      show diminished uptake by mononuclear phagocytes are described. Specific
      targeting of carriers to particular tissues or cells is also considered.

PMID- 12613657
TI  - Amelogenin gene splice products: potential signaling molecules.
AB  - The amelogenins, the major proteins of the developing tooth enamel matrix, are
      highly conserved throughout most species studied. The gene structure is similar,
      with a set of seven exons and intervening introns, and remarkable conservation of
      particular exon sizes over divergent species. Studies of exon skipping and
      consequent alternative gene splicing suggest that, in vertebrates, exon
      definition is crucial. In this mechanism, exon size is important. If too small,
      an exon can be readily skipped, if too large, internal cryptic splice sites may
      be utilized. Other factors, such as intron length and specific nucleotide
      sequences at the splice boundaries also modulate splicing efficiency, but
      amelogenin gene splicing conforms well to the generalized exon length model.
      Exons 1, 2 and 7 are not subject to splicing that affects the secreted protein
      product, but exons 3, 4 and 5 are at the lower boundary of exon size, rendering
      them, 4 and 5 especially, subject to skipping. On the other hand, exon 6 is very
      long and has cryptic splicing sites that can be used. In the mouse, nine distinct
      splice product proteins have been detected. The question now is the functions of
      these products. The larger forms, those that contain the intact proline-rich,
      hydrophobic exon 6 domains, are important for enamel mineralization. Recent work
      suggests that the small proteins resulting from deletion of a major part of
      amelogenin gene exon 6 via utilization of a cryptic site may have signal
      transduction functions during tooth development. Furthermore, new work also
      suggests that odontoblasts transiently express the small amelogenins during the
      period that epithelial-mesenchymal signaling between preodontoblasts and
      preameloblasts determines the course of tooth development. The same peptides have
      been demonstrated to act on non-odontogenic cells and effect their phenotypic
      expression patterns in vitro, and to induce bone formation in implants in vivo.

PMID- 12613655
TI  - Molecular mechanisms of N-acetylcysteine actions.
AB  - Oxidative stress generated by an imbalance between reactive oxygen species (ROS)
      and antioxidants contributes to the pathogenesis of arthritis, cancer,
      cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and
      growth factors stimulate ROS production as signaling mediators. Antioxidants such
      as N-acetylcysteine (NAC) have been used as tools for investigating the role of
      ROS in numerous biological and pathological processes. NAC inhibits activation of
      c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1
      and nuclear factor kappa B transcription factor activities regulating expression
      of numerous genes. NAC can also prevent apoptosis and promote cell survival by
      activating extracellular signal-regulated kinase pathway, a concept useful for
      treating certain degenerative diseases. NAC directly modifies the activity of
      several proteins by its reducing activity. Despite its nonspecificity, ability to
      modify DNA and multiple molecular modes of action, NAC has therapeutic value for
      reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage
      erosion, acetaminophen detoxification and transplant prolongation.

PMID- 12613658
TI  - Keratins: a structural scaffold with emerging functions.
AB  - Intermediate filament proteins form an essential part of the cytoskeleton and
      provide topological order to cells and tissues. These features result from their
      intrinsic property of self-organization and their response to extrinsic cues.
      Keratins represent the largest subgroup among all intermediate filament proteins
      and are differentially expressed as pairs of type I and type II intermediate
      filament proteins in epithelia. Their primary function is to impart mechanical
      strength to cells. This function is illustrated by patients with keratin
      mutations and by gene-deficient mice. Additional functions include their
      participation in the response to stress, cell signalling and apoptosis, and thus
      the keratin cytoskeleton appears far more dynamic than previously anticipated.
      This may result from hyperphosphorylation and possibly from interaction with
      associated proteins. How signalling networks affect keratin organization,
      turnover and function and vice versa will be a major challenge for future
      investigations.

PMID- 12613659
TI  - Orexins and their receptors: structural aspects and role in peripheral tissues.
AB  - Orexins, also named hypocretins, were discovered in 1998 by subtractive cDNA
      cloning or orphan receptor technologies. Prepro-orexin is enzymatically matured
      into two peptides, orexin-A and orexin-B which are 33- and 28-amino-acid
      peptides, respectively. Two cloned orexin receptors OX1R and OX2R are serpentine
      G-protein-coupled receptors, both of which bind orexins and are coupled to Ca2+
      mobilization. Orexins are neuropeptides present in hypothalamic neurons that
      project throughout the central nervous system to nuclei involved in the control
      of feeding, sleep-wakefulness, neuroendocrine homeostasis and autonomic
      regulation. The interest of investigators in orexins has focused on narcolepsy,
      since genetic or experimental alterations of the orexin system are associated
      with this sleep disorder. However, orexins are not restricted to the hypothalamus
      and together with their receptors they are expressed in peripheral tissues. This
      new multifaceted aspect of orexin biology is reviewed here in descriptions of (i)
      the proform, maturation and structure of orexins, (ii) the structure, signal
      transduction and pharmacology of orexin receptors and (iii) the expression of
      orexins and orexin receptors as well as their biological role in the hypothalamus
      pituitary-adrenal axis, gastrointestinal tract, endocrine pancreas and other
      peripheral tissues.

PMID- 12613660
TI  - Circular proteoglycans from sponges: first members of the spongican family.
AB  - Species-specific cell adhesion in marine sponges is mediated by a new family of
      modular proteoglycans whose general supramolecular structure resembles that of
      hyalectans. However, neither their protein nor their glycan moieties have
      significant sequence homology to other proteoglycans, despite having protein
      subunits equivalent to link proteins and to proteoglycan monomer core proteins,
      and glycan subunits equivalent to hyaluronan and to the glycosaminoglycans of
      hyalectans. In some species, these molecular components are assembled into a
      structure with a circular core formed by the link protein- and hyaluronan-like
      subunits. Besides their involvement in cell adhesion, these sponge proteoglycans,
      for which we propose the term spongicans, participate in signal transduction
      processes and are suspected to play a role in sponge self-nonself recognition.
      Their in vivo roles and the mild methods used to purify large amounts of
      functionally active spongicans make them ideal models to study the functions and
      possible new applications of proteoglycans in biomedical research.

PMID- 12613661
TI  - Transgenic and knock-out mice for deciphering the roles of EGFR ligands.
AB  - Generation of genetically engineered mice with either gain-of-function or loss-of
      function mutations is the most popular technique for determining gene functions
      and the interrelationship between molecules in vivo. These models have provided a
      wealth of information about the developmental and physiological roles of
      oncogenes and growth factors. To date, transgenic techniques have been used
      extensively to study the functions of the epidermal growth factor (EGF) family.
      This review highlights some of the major recent findings pertinent to the EGF
      receptor (EGFR) and its ligands with special reference to elucidating how EGF and
      its related growth factors work together to regulate reproduction, growth and
      development. Finally, future investigations on ligand-ligand communications, EGFR
      and its ligands in neural stem cell research, and the mechanisms of EGFR
      signaling and trafficking in cells are also suggested.

PMID- 12613662
TI  - Structure and function of RGD peptides involved in bone biology.
AB  - This review focuses on recent papers that describe the involvement of the RGD
      sequence in bone biology and incorporate the use of synthetic RGD peptides to
      develop new drugs or control the bioactivity of materials used for bone
      regeneration. Because in vivo bone function is completely dependent on
      angiogenesis and vessels, the present publication is focused on physiology,
      pathophysiology and therapeutics of RGD peptides dedicated to bone cells and
      endothelial systems. It appears that alphavbeta3, alphavbeta5 and alphaIIbbeta3
      are the integrins most reported to be involved in bone function and RGD sequence
      binding. The specificity of RGD peptides depends on backbone conformation,
      orientations of the charged side chains of Arg and Asp residues, and hydrophobic
      moieties flanking the Asp residue. Despite of recent progress in integrins and
      RGD peptide structures and function, future work should focus on integrin
      selectivity of RGD-based agents, model structure and activity-selectivity
      relationships.

PMID- 12613663
TI  - Protein misfolding and disease: the case of prion disorders.
AB  - Recent findings strongly support the hypothesis that diverse human disorders,
      including the most common neurodegenerative diseases, arise from misfolding and
      aggregation of an underlying protein. Despite the good evidence for the
      involvement of protein misfolding in disease pathogenesis, the mechanism by which
      protein conformational changes participate in the disease is still unclear. Among
      the best-studied diseases of this group are the transmissible spongiform
      encephalopathies or prion-related disorders, in which misfolding of the normal
      prion protein plays a key role in the disease. In this article we review recent
      data on the link between prion protein misfolding and the pathogensis of
      spongiform encephalopathies.

PMID- 12613664
TI  - Cerivastatin: a cellular and molecular drug for the future?
AB  - The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA
      reductase inhibitor lovastatin received FDA approval in the USA. Ten years later,
      the sixth compound of this class came onto the world market--the fully synthetic
      statin cerivastatin. A number of clinical studies had confirmed its high
      pharmacological efficacy, its excellent pharmacokinetic properties with fast and
      nearly complete absorption after oral uptake, a linear kinetic over a broad
      concentration range, and its favorable safety profile. The greatest advantages,
      of cerivastatin, however, are its lipophilicity, its high bioavailability of
      about 60% after oral application and its potency at 100-fold lower doses compared
      to other lipophilic statins. Nevertheless, the most exciting findings are
      certainly its non-lipid-related, pleiotropic effects at the cellular and
      molecular level. Statin therapy was also found to reduce mortality in cases where
      cholesterol levels or atherosclerotic plaque formation remained unaltered.
      However, cerivastatin improves endothelial dysfunction, possesses anti
      inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative,
      plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent
      tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem
      to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is
      no longer on the market because of some problematic side effects, it could be one
      of the most potent cellular and molecular drugs for the future.

PMID- 12613666
TI  - Solution structure and activity of mouse lysozyme M.
AB  - The three-dimensional structure of mouse lysozyme M, glycoside hydrolase, with
      130 amino acids has been determined by heteronuclear NMR spectroscopy. We found
      that mouse lysozyme M had four alpha-helices, two 3(10)helices, and a double- and
      a triple-stranded anti-parallel beta-sheet, and its structure was very similar to
      that of hen lysozyme in solution and in the crystalline state. The pH activity
      profile of p-nitrophenyl penta N-acetyl-beta-D-chitopentaoside hydrolysis by
      mouse lysozyme M was similar to that of hen lysozyme, but the hydrolytic activity
      of mouse lysozyme M was lower. From analyses of binding affinities of lysozymes
      to a substrate analogue and internal motions of lysozymes, we suggest that the
      lower activity of mouse lysozyme M was due to the larger dissociation constant of
      its enzyme-substrate complex and the restricted internal backbone motions in the
      molecule.

PMID- 12613665
TI  - Small, novel proteins from the mistletoe Phoradendron tomentosum exhibit highly
      selective cytotoxicity to human breast cancer cells.
AB  - Four novel proteins (phoratoxins C-F) have been isolated from the North American
      mistletoe Phoradendron tomentosum. The amino acid sequences of these phoratoxins
      were determined unambiguously using a combination of Edman degradation and
      trypsin enzymatic digestion, and by electrospray ionization tandem mass
      spectrometry sequencing. Phoratoxins C, E and F consist of 46 amino acid
      residues; and phoratoxin D of 41. All proteins had six cysteines, similar to the
      earlier described phoratoxins A and B, which are thionins. The cytotoxicity of
      each protein was evaluated in a human cell line panel that represented several
      cytotoxic drug-resistance mechanisms. For the half-maximal inhibitory
      concentrations (IC50 values) of the different cell lines in the panel,
      correlation with those of standard drugs was low. The most potent cytotoxic
      phoratoxin C was further tested on primary cultures of human tumor cells from
      patients. The solid tumor samples from breast cancer cells were 18 times more
      sensitive to phoratoxin C than the tested hematological tumor samples.

PMID- 12613667
TI  - Increased demyelination and axonal damage in metallothionein I+II-deficient mice
      during experimental autoimmune encephalomyelitis.
AB  - Metallothioneins I+II (MT-I+II) are antioxidant, neuroprotective factors. We
      previously showed that MT-I+II deficiency during experimental autoimmune
      encephalomyelitis (EAE) leads to increased disease incidence and clinical
      symptoms. Moreover, the inflammatory response of macrophages and T cells,
      oxidative stress, and apoptotic cell death during EAE were increased by MT-I+II
      deficiency. We now show for the first time that demyelination and axonal damage
      are significantly increased in MT-I+II deficient mice during EAE. Furthermore,
      oligodendroglial regeneration, growth cone formation, and tissue repair including
      expression of trophic factors were significantly reduced in MT-I+II-deficient
      mice during EAE. Accordingly, MT-I+II have protective and regenerative roles in
      the brain.

PMID- 12613668
TI  - Regulation of caldesmon activity by Cdc2 kinase plays an important role in
      maintaining membrane cortex integrity during cell division.
AB  - To study the mitosis-specific phosphorylation of caldesmon (CaD), we generated a
      mutant of the C-terminal fragment (amino acids 244-538) of human fibroblast CaD
      (CaD39-6F), as well as a mutant of the full-length CaD (CaD-6F), in which all six
      potential phosphorylation sites for Cdc2 kinase were abolished. The mitotic CaD39
      6F-overexpressing cells required more time to progress from anaphase start to 50%
      cytokinesis, exhibited larger size, and abnormally formed numerous small blebs.
      In contrast, overexpression of the wild-type C-terminal fragment of CaD (CaD39)
      did not result in abnormal bleb formation, but led to larger size and prolonged
      the time requirement between anaphase start and 50% cytokinesis. Similar abnormal
      blebs were also observed in the CaD-6F-overexpressing cells. CaD-6F
      overexpressing cells did not show larger size but required more time to progress
      from anaphase start to 50% cytokinesis. These results suggest that mitosis
      specific phosphorylation of CaD plays a role in inhibiting bleb formation and
      that the N-terminal fragment of CaD is required for cell size determination.

PMID- 12613669
TI  - Thiazolidinediones, a class of anti-diabetic drugs, inhibit Id2 expression
      through a PPARgamma-independent pathway in human aortic smooth muscle cells.
AB  - Inhibitor of DNA binding (Id2) is a member of the helix-loop-helix family of
      transcription regulators that is known to play important roles in the
      proliferation and differentiation of many cell types. Overexpression of Id2 has
      been reported to result in significant enhancement of vascular smooth muscle cell
      growth via increased S phase entry. We hypothesized that downregulation of Id2
      gene expression by thiazolidinediones (TZDs), a class of anti-diabetic drugs and
      peroxisome proliferator-activated receptor gamma (PPARgamma) activators, might
      contribute to the anti-atherosclerotic and anti-hypertensive effects of the
      PPARgamma. Here we document that TZDs, including troglitazone and ciglitazone,
      repress Id2 gene expression in a doses- and time-dependent manner. However,
      GW7845, a high-affinity and non-TZD PPARgamma activator, had no inhibitory effect
      on Id2 gene expression. In addition, PPARgamma antagonist GW9662 did not rescue
      TZD-induced Id2 repression. Taken together, our data suggest that TZDs repress
      Id2 expression through a PPARgamma-independent pathway.

PMID- 12613670
TI  - Six views of embodied cognition.
AB  - The emerging viewpoint of embodied cognition holds that cognitive processes are
      deeply rooted in the body's interactions with the world. This position actually
      houses a number of distinct claims, some of which are more controversial than
      others. This paper distinguishes and evaluates the following six claims: (1)
      cognition is situated; (2) cognition is time-pressured; (3) we off-load cognitive
      work onto the environment; (4) the environment is part of the cognitive system;
      (5) cognition is for action; (6) off-line cognition is body based. Of these, the
      first three and the fifth appear to be at least partially true, and their
      usefulness is best evaluated in terms of the range of their applicability. The
      fourth claim, I argue, is deeply problematic. The sixth claim has received the
      least attention in the literature on embodied cognition, but it may in fact be
      the best documented and most powerful of the six claims.

PMID- 12613673
TI  - Negative information: both presence and absence of spatial pattern elements guide
      rats' spatial choices.
AB  - Rats learn the spatial pattern in which hidden caches of food are located. Once
      the pattern is learned, finding one or more baited locations provides (positive)
      information about the remaining baited locations. In the present experiment, we
      examined whether negative information (the absence of food in a location) would
      also be used in locating the remaining baited locations. Rats were tested in an
      apparatus containing a matrix of vertical poles, on top of which food could be
      hidden. At the beginning of the trial, the location of the baited poles was
      unpredictable, but the poles were always arranged in a linear pattern. The rats
      learned the pattern and used both positive and negative information in locating
      baited poles.

PMID- 12613672
TI  - Operant variability: evidence, functions, and theory.
AB  - Although responses are sometimes easy to predict, at other times responding seems
      highly variable, unpredictable, or even random. The inability to predict is
      generally attributed to ignorance of controlling variables, but this article is a
      review of research showing that the highest levels of behavioral variability may
      result from identifiable reinforcers contingent on such variability. That is,
      variability is an operant. Discriminative stimuli and reinforcers control it,
      resulting in low or high variability, depending on the contingencies. Schedule-of
      reinforcement effects are orderly, and choosing to vary or repeat is lawfully
      governed by relative reinforcement frequencies. The operant nature of variability
      has important implications. For example, learning, exploring, creating, and
      problem solving may partly depend on it. Abnormal levels of variability,
      including those found in psychopathologies such as autism, depression, and
      attention deficit hyperactivity disorder, may be modified through reinforcement.
      Operant variability may also help to explain some of the unique attributes of
      voluntary action.

PMID- 12613675
TI  - Dissociating perception and action in Kanizsa's compression illusion.
AB  - When a horizontally elongated surface is occluded in the middle by a larger
      surface, it appears narrower than its true width (Kanizsa's compression
      illusion). We report that a similar compression effect occurs for closed-loop
      visuomotor matches of size, but not for otherwise comparable open-loop "mimed"
      reaching or size-matching visuomotor responses. Our study is the first in which a
      comparison of size perception in personal space with bilateral actions performed
      with both hands (instead of precision grips employing the thumb and the index
      finger) is used to investigate motor responses to Kanizsa's compression illusion.
      Implications for the current debate on the existence of dissociations between
      spatial perception and visually controlled actions in personal space are
      discussed.

PMID- 12613674
TI  - Vertical meridian asymmetry in spatial resolution: visual and attentional
      factors.
AB  - We investigated whether spatial resolution would be the same in the lower and
      upper halves of the vertical meridian (VM) of our visual field and whether
      attention would affect them differentially. It has been reported that (1)
      attending to the target's location improves performance in a texture segregation
      task when the observer's spatial resolution is too low (peripheral locations) but
      impairs it when resolution is already too high (central locations) for the task.
      This finding indicates an enhanced spatial resolution at the attended location
      (Yeshurun & Carrasco, 1998,2000), (2) observers' contrast sensitivity is higher
      in the lower than in the upper VM, a phenomenon known as vertical meridian
      asymmetry (VMA), an asymmetry determined by visual rather than by attentional
      factors (Carrasco, Talgar, & Cameron, 2001). In the present texture segregation
      task, performance was assessed under neutral- and peripheral-cue conditions.
      Transient covert attention was systematically manipulated by using a peripheral
      cue that indicated the target's location and its onset. Observers reported the
      interval containing a target patch appearing at one of a number of eccentricities
      in a large texture pattern along the VM. We found that (1) performance peaked at
      farther eccentricities in the lower than in the upper visual VM, indicating that
      resolution was higher in the lower half, and (2) the peripheral cue affected
      performance along the VM uniformly, indicating that the degree of enhanced
      resolution brought about by transient attention was constant along the VM. Thus,
      we conclude that the VMA for spatial resolution is determined by visual, not
      transient covert attentional, constraints.

PMID- 12613676
TI  - A crossmodal attentional blink between vision and touch.
AB  - There is currently a great deal of interest regarding the possible existence of a
      crossmodal attentional blink (AB) between audition and vision. The majority of
      evidence now suggests that no such crossmodal deficit exists unless a task switch
      is introduced. We report two experiments designed to investigate the existence of
      a crossmodal AB between vision and touch. Two masked targets were presented
      successively at variable interstimulus intervals. Participants had to respond
      either to both targets (experimental condition) or to just the second target
      (control condition). In Experiment 1, the order of target modality was blocked,
      and an AB was demonstrated when visual targets preceded tactile targets, but not
      when tactile targets preceded visual targets. In Experiment 2, target modality
      was mixed randomly, and a significant crossmodal AB was demonstrated in both
      directions between vision and touch. The contrast between our visuotactile
      results and those of previous audiovisual studies is discussed, as are the
      implications for current theories of the AB.

PMID- 12613677
TI  - Delayed working memory consolidation during the attentional blink.
AB  - After the detection of a target (T1) in a rapid stream of visual stimuli, there
      is a period of 400-600 msec during which a subsequent target (T2) is missed. This
      impairment in performance has been labeled the attentional blink. Recent theories
      propose that the attentional blink reflects a bottleneck in working memory
      consolidation such that T2 cannot be consolidated until after T1 is consolidated,
      and T2 is therefore masked by subsequent stimuli if it is presented while T1 is
      being consolidated. In support of this explanation, Giesbrecht & Di Lollo (1998)
      found that when T2 is the final item in the stimulus stream, no attentional blink
      is observed, because there are no subsequent stimuli that might mask T2. To
      provide a direct test of this explanation of the attentional blink, in the
      present study we used the P3 component of the event-related potential waveform to
      track the processing of T2. When T2 was followed by a masking item, we found that
      the P3 wave was completely suppressed during the attentional blink period,
      indicating that T2 was not consolidated in working memory. When T2 was the last
      item in the stimulus stream, however, we found that the P3 wave was delayed but
      not suppressed, indicating that T2 consolidation was not eliminated but simply
      delayed. These results are consistent with a fundamental limit on the
      consolidation of information in working memory.

PMID- 12613678
TI  - Volatile visual representations: failing to detect changes in recently processed
      information.
AB  - Research documenting people's inability to detect large changes in visual scenes
      suggests that visual representations may be sparse and volatile, providing no
      cumulative record of the attended items in a scene. However, these studies have
      failed to control for attention. Thus, the visual system may construct a
      cumulative record of all attended stimuli and still miss such changes, because
      they involve items that were never attended to. In two experiments, subjects saw
      12-digit arrays and identified either the highest digit in the array (Experiment
      1) or the lowest digit not in the array (Experiment 2). Subsequent change
      detection tasks revealed that subjects often failed to detect changes that
      involved the same digits they had previously identified to perform the digit
      tasks successfully. This provides additional evidence that our usable visual
      representations are relatively impoverished and volatile.

PMID- 12613671
TI  - The role of prefrontal cortex in working-memory capacity, executive attention,
      and general fluid intelligence: an individual-differences perspective.
AB  - We provide an "executive-attention" framework for organizing the cognitive
      neuroscience research on the constructs of working-memory capacity (WMC), general
      fluid intelligence, and prefrontal cortex (PFC) function. Rather than provide a
      novel theory of PFC function, we synthesize a wealth of single-cell, brain
      imaging, and neuropsychological research through the lens of our theory of normal
      individual differences in WMC and attention control (Engle, Kane, & Tuholski,
      1999; Engle, Tuholski, Laughlin, & Conway, 1999). Our critical review confirms
      the prevalent view that dorsolateral PFC circuitry is critical to executive
      attention functions. Moreover, although the dorsolateral PFC is but one critical
      structure in a network of anterior and posterior "attention control" areas, it
      does have a unique executive-attention role in actively maintaining access to
      stimulus representations and goals in interference-rich contexts. Our review
      suggests the utility of an executive-attention framework for guiding future
      research on both PFC function and cognitive control.

PMID- 12613679
TI  - Overt and covert object-based attention.
AB  - To examine the role of perceptual object representations in the control of eye
      movements and attention, a pair of experiments adapted the object-cuing paradigm
      of Egly, Driver, and Rafal (1994) to require eye movements. Displays were pairs
      of adjacent rectangles, each containing two characters. Observers were asked to
      make a speeded judgment of a target character's orientation, and a cue was
      provided prior to target/distractor onset to indicate the target's likely
      location. Gaze-contingent presentation of target and distractors was used to
      demand overt scanning of displays. Eye movements during task performance evinced
      two forms of object-based effects. First, saccades following fixation on an
      invalidly cued item were more likely to be made within the cued rectangle than
      between rectangles. Second, saccades within the cued rectangle were preceded by
      shorter dwell times than saccades between rectangles. Extrafoveal processing of
      stimuli within the cued rectangle, however, was not facilitated, suggesting that
      covert attention was not allocated more densely within the cued than within the
      uncued object.

PMID- 12613680
TI  - Temporal tuning in the acquisition of cognitive skill.
AB  - The temporal tuning hypothesis suggests that individuals adjust the timing of
      cognitive performances to achieve temporal coordination of mental processes and
      the data on which they operate, and that this adjustment becomes more precise
      with practice. Participants in two experiments performed self-paced multiple-step
      arithmetic tasks in which the information needed for each step was briefly
      displayed at the participants' request. Timing constraints were manipulated by
      varying between subjects the delay between requests and displays of information.
      In Experiment 1, both operators and operands appeared step by step, and
      participants achieved a modest degree of temporal adjustment that did not change
      with practice. In Experiment 2, participants could preview operators while
      operands appeared step by step. In that experiment, participants achieved more
      precise temporal adjustment, and the amount of adjustment increased with
      practice. These results demonstrate the phenomenon of temporal tuning in symbolic
      cognitive skills and suggest some constraints on the ability to anticipate the
      time course of one's mental processes.

PMID- 12613681
TI  - The processing of consonants and vowels in reading: evidence from the fast
      priming paradigm.
AB  - We assessed the early encoding of consonant and vowel information in the reading
      of English, using the fast priming paradigm. With 30-msec prime durations, gaze
      durations on target words were shorter when preceded by high-frequency consonant
      same primes (which shared consonant information with the target word; e.g., lake
      like) than when preceded by vowel-same primes (which shared vowel information
      with the target word; e.g., line-like), but there were no priming effects for low
      frequency primes. With 45-msec prime durations, however, there was no effect of
      prime frequency and gaze durations on target words were shortened equally when
      they were preceded by consonant-same primes and vowel-same primes, as compared
      with control primes (e.g., late-like). The results suggest that the processing of
      consonants is more rapid than that of vowels, providing further evidence for the
      distinction between consonant and vowel processing in the reading of English.

PMID- 12613682
TI  - Bias in masked word identification: unconscious influences of repetition priming.
AB  - The beneficial influence of a prior study episode on subsequent identification of
      a word includes a large bias component, revealed in the forced-choice variant of
      the masked word identification test. In that type of test, subjects show a
      preference for a studied probe over a nonstudied probe, regardless of which one
      matches the masked target word. The forced-choice test was used in the present
      experiments to test the possibility that this bias effect is due to conscious
      recollection. Results show that bias was strongly attenuated (1) by changes in
      modality between study and test, and (2) under certain conditions, by using a
      conceptually driven study task. The bias effect was found only when probes were
      orthographically similar to one another, as predicted by the counter model
      (Ratcliff & McKoon, 1997). These results provide strong evidence that the bias
      effect is not mediated by conscious recollection.

PMID- 12613683
TI  - Foreign language knowledge can influence native language performance in
      exclusively native contexts.
AB  - In three experiments, we studied the influence of foreign language knowledge on
      native language performance in an exclusively native language context.
      Trilinguals with Dutch as their native and dominant language (L1), English as
      their second language (L2), and French as their third language (L3) performed a
      word association task (Experiment 1) or a lexical decision task (Experiments 2
      and 3) in L1. The L1 stimulus words were cognates with their translations in
      English, cognates with their translations in French, or were noncognates. In
      Experiments 1 and 2 with trilinguals who were highly proficient in English and
      relatively low in proficiency in French, we observed shorter word association and
      lexical decision times to the L1 words that were cognates with English than to
      the noncognates. In these relatively low-proficiency French speakers, response
      times (RTs) for the L1 words that were cognates with French did not differ from
      those for the noncognates. In Experiment 3, we tested Dutch-English-French
      trilinguals with a higher level of fluency in French (i.e., equally fluent in
      English and in French). We now observed faster responses on the L1 words that
      were cognates with French than on the noncognates. Lexical decision times to the
      cognates with English were also shorter than those to then oncognates. The
      results indicate that words presented in the dominant language, to naive
      participants, activate information in the nontarget, and weaker, language in
      parallel, implying that the multilinguals' processing system is profoundly
      nonselective with respect to language. A minimal level of nontarget language
      fluency seems to be required, however, before any weaker language effects become
      noticeable in L1 processing.

PMID- 12613684
TI  - Naming pictures at no cost: asymmetries in picture and word conditional naming.
AB  - We report a striking finding about naming and categorization of pictures and
      reading aloud and categorization of words. The categorization of a word before
      reading it aloud leads to an increase in response time as compared with the
      condition in which naming is not conditional on the categorization of the word.
      Quite differently, no cost is associated with the conditional naming of pictures.
      Results are discussed in terms of multiple procedures operating on pictorial and
      verbal stimuli to retrieve phonological forms.

PMID- 12613685
TI  - Proactive interference effects on sentence production.
AB  - Proactive interference refers to recall difficulties caused by prior similar
      memory-related processing. Information-processing approaches to sentence
      production predict that retrievability affects sentence form: Speakers may word
      sentences so that material that is difficult to retrieve is spoken later. In this
      experiment, speakers produced sentence structures that could include an optional
      that, thereby delaying the mention of a subsequent noun phrase. This subsequent
      noun phrase was either (1) conceptually similar to three previous noun phrases in
      the same sentence, leading to greater proactive interference, or (2) conceptually
      dissimilar, leading to less proactive interference. Speakers produced more thats
      (and were more disfluencies) before conceptually similar noun phrases, suggesting
      that retrieval difficulties during sentence production affect the syntactic
      structures of sentences that speakers produce.

PMID- 12613686
TI  - Does relocating information in text depend on verbal or visuospatial abilities?
      An individual-differences analysis.
AB  - In this individual-differences study, we evaluated the prevalent view that
      relocating information in a previously read text depends primarily on
      visuospatial abilities. Participants read a text, answered fill-in-the-blank test
      questions, and identified which page and line in the original text contained the
      sentence in each question. They also completed a battery of verbal and
      visuospatial tasks. Performance on verbal tasks was highly predictive of the
      accuracy of both page and line identifications, and this correlation remained
      significant even after we controlled for performance on visuospatial tasks. In
      contrast, performance on visuospatial tasks was not predictive of either page or
      line identification accuracy, once verbal abilities were controlled for. These
      results suggest an important role for verbal abilities in relocation of text
      information and a lesser role for visuospatial abilities than has previously been
      assumed.

PMID- 12613687
TI  - Backward associative strength determines source attributions given to false
      memories.
AB  - Source attributions for falsely remembered material were investigated in two
      experiments. A male and a female speaker each presented either an entire word
      list or half of the items from each of multiple Deese-Roediger-McDermott (DRM)
      lists commonly used in this paradigm. In the latter condition the tendency of
      each list half to activate a nonpresented, critical list theme item was
      manipulated. All of the list halves differed in backward associative strength
      (BAS), and each was presented by one or the other of the two speakers. In these
      correlated conditions, when critical items were falsely recognized (Experiments 1
      and 2) or recalled (Experiment 2), source attributions were more frequently made
      to the speaker of the list items with the higher average BAS. This source
      attribution effect appears to result from the binding of list item source
      characteristics to activated critical items during encoding, as opposed to being
      the result of a biased retrieval process. The results are interpreted as
      consistent with an activation/monitoring account of false memory in the DRM
      paradigm.

PMID- 12613688
TI  - Serial position effects in semantic memory: reconstructing the order of verses of
      hymns.
AB  - Serial position effects (primacy and recency) have been consistently demonstrated
      in both short- and long-term episodic memory tasks. The search for corresponding
      effects in semantic memory tasks (e.g., reconstructing the order of U.S.
      presidents) has been confounded by factors such as differential exposure to
      stimuli. In the present study, the stimuli were six-verse hymns that would have
      been sung from the first to the last verse by churchgoers on numerous occasions.
      Participants were presented with the verses of each hymn in random order and were
      required to reconstruct the correct order. Primacy and recency effects were
      significantly more evident for churchgoers than for nonchurchgoers. Moreover,
      error gradients were steeper than chance for churchgoers but not for
      nonchurchgoers; in other words, churchgoers' errors were more likely to be close
      to the correct position than further away. These findings provide the first
      unequivocal demonstration of serial position effects in semantic memory.

PMID- 12613689
TI  - When wrong predictions provide more support than right ones.
AB  - Correct predictions of rare events are normatively more supportive of a theory or
      hypothesis than correct predictions of common ones. In other words, correct bold
      predictions provide more support than do correct timid predictions. Are lay
      hypothesis testers sensitive to the boldness of predictions? Results reported
      here show that participants were very sensitive to boldness, often finding
      incorrect bold predictions more supportive than correct timid ones. Participants
      were willing to tolerate inaccurate predictions only when predictions were bold.
      This finding was demonstrated in the context of competing forecasters and in the
      context of competing scientific theories. The results support recent views of
      human inference that postulate that lay hypothesis testers are sensitive to the
      rarity of data. Furthermore, a normative (Bayesian) account can explain the
      present results and provides an alternative interpretation of similar results
      that have been explained using a purely descriptive model.

PMID- 12613690
TI  - Comparing supervised and unsupervised category learning.
AB  - Two unsupervised learning modes (incidental and intentional unsupervised
      learning) and their relation to supervised classification learning are examined.
      The approach allows for direct comparisons of unsupervised learning data with the
      Shepard, Hovland, and Jenkins (1961) seminal studies in supervised classification
      learning. Unlike supervised classification learning, unsupervised learning
      (especially under incidental conditions) favors linear category structures over
      compact nonlinear category structures. Unsupervised learning is shown to be
      multifaceted in that performance varies with task conditions. In comparison with
      incidental unsupervised learning, intentional unsupervised learning is more rule
      like, but is no more accurate. The acquisition and application of knowledge is
      also more laborious under intentional unsupervised learning.

PMID- 12613691
TI  - Fruits and vegetables categorized: an application of the generalized context
      model.
AB  - In the study reported in this paper, we investigated the categorization of well
      known and novel food items in the categories fruits and vegetables. Predictions
      based on Nosofsky's (1984,1986) generalized context model (GCM), on a
      multiplicative-similarity prototype model, and on an instantiation model as
      applied in Storms, De Boeck, and Ruts (2001) were compared. Despite suggestions
      in the literature that prototype models predict categorization from large
      categories better than exemplar models do, our results showed that the exemplar
      based GCM yielded clearly better predictions than did a (multiplicative
      similarity) prototype model.

PMID- 12613692
TI  - Is signal detection theory fundamentally flawed? A response to Balakrishnan
      (1998a, 1998b, 1999).
AB  - For nearly 50 years, signal detection theory (SDT; Green & Swvets, 1966;
      Macmillan & Creelman, 1991) has been of central importance in the development of
      psychophysics and other areas of psychology. The theory has recently been
      challenged by Balakrishnan (1998b), who argues that, within SDT, an alternative
      index is "better justified" than d' and who claims to show (1998a, 1999) that SDT
      is fundamentally flawed and should be rejected. His evidence is based on new
      nonparametric measures that he has introduced and applied to experimental data.
      He believes his results show that basic assumptions of SDT are not supported-in
      particular, that payoff and probability manipulations do not affect the position
      of the decision criterion. In view of the importance of SDT in psychology, these
      claims deserve careful examination. They are critically reviewed here. It appears
      that it is Balakrishnans arguments that fail, and not SDT

PMID- 12613694
TI  - Developing schools of public health. Forward.

PMID- 12613695
TI  - Public health challenges of the 21st century and the role of schools of public
      health in Central and Eastern Europe.

PMID- 12613696
TI  - The Hebrew University--Hadassah Braun School of Public Health and Community
      Medicine: its international role and experience.
AB  - For more than 40 years the Hebrew University-Hadassah Braun School of Public
      Health and Community Medicine has been involved in the training of public health
      professionals from Israel and around the world. The Israeli MPH course has
      graduated more than 600 professionals who occupy senior posts in the Israeli
      health service system. The parallel International MPH (IMPH) course (in English)
      has produced almost 600 graduates from some 80 countries, especially in the
      developing world. They have returned home to make a major contribution to public
      health and the public's health is their countries. In recent years there has been
      a growing number of graduates from countries in Eastern Europe and those of the
      former Soviet Union. The School has defined its mission as improving the health
      of the population of Israel and internationally through training, research, and
      service. Recently a special PhD program for outstanding graduates of the IMPH has
      been instituted. This international experience has laid the foundation for
      growing collaboration and support for newly developing Schools of Public Health
      in Europe and elsewhere.

PMID- 12613697
TI  - ASPHER PEER review: a discussion of its role in the joint Open Society Institute
      (OSI)--Association of Schools of Public Health in the European Region (ASPHER)
      program.

PMID- 12613698
TI  - The institutionalization of public health training and the health sciences.
AB  - The health of the population is determined by a number of ecological determinants
      in addition to medical care. Therefore a close relationship exists with the
      social and political context in a society. With regard to the health care system,
      schools of public health as institutions for training, research, and services
      have to focus on four main deficits in the area of information, prevention,
      social gradients, and the regulation of health care delivery. A task profile
      derives which comprises (a) training for research and services, (b) monitoring
      population health and setting of priorities, (c) applied research on public
      health, (d) consulting the decision makers, and (e) intervention and public
      accountability. How to perform in these areas has to be related to basic ethical
      principles, notably, equity, participation, subsidiarity, sustainability, and
      efficiency. Furthermore, international trends in modern education have to be
      considered as for the European Union in the Bologna Declaration of 1999, with
      reference to academization and internationalization of advanced studies. The
      resulting institutional profile of modern schools of public health is
      characterized by their academic basis, interdisciplinarity, and multi
      professionality. The paradigm of the New Public Health is an equal merger of
      medical and social sciences, a predominantly postgraduate study program, an
      international scope, close links to the government, local networks with service
      institutions, and a focus on contemporary health issues. In the former socialist
      economies of Central and Eastern Europe a regional collaboration beyond borders
      (the concept of regionality) is apt to support the achievement of international
      standards of excellence for newly developing schools of public health.

PMID- 12613699
TI  - What should an MPH graduate be able to do at the end of the training period?
AB  - In sports or the arts, some people have natural talents. Others need considerable
      training to develop passable abilities. Some start off as "naturals" and when
      they receive training, it helps them to soar that much higher--to fine-tune their
      natural abilities. Teach a natural athlete a new throw or serve or swing and he
      or she will pick it up right away and add it as a new tool to the bag of tricks.
      Less talented people need the same training even more, and they don't pick up the
      skills as fast. The same is true for good feelings and positive experiences. Some
      people are depressed, anxious, angry, or burned out, with shut-off or deadened
      feelings. Others are naturally cheerful and happy, able to express strong views
      and feel deep emotions. The latter are the ones who are needed in public health,
      and schools of public health should attract, select, and encourage their sense of
      commitment and optimism, during their training and with suitable follow-up
      support afterwards as well. And by the way, some good luck helps too.

PMID- 12613700
TI  - Student criteria, assessment, involvement in planning of MPH contents, and follow
      up.

PMID- 12613701
TI  - Curriculum development for schools of public health.

PMID- 12613702
TI  - Service role of schools of public health: in between research and education?
AB  - This paper is meant to serve as a basis for discussion regarding the service or
      external role of schools of public health (SPHs). A number of countries in
      Eastern Europe are developing and establishing their own SPHs, at the same time
      trying to come to terms with the development of the public health function, its
      organisation, and its core activities in their respective countries. Although the
      position and the role of a school of public health cannot be seen outside the
      context in which it is functioning, including it's institutional setting, a
      thorough analysis of this context would be beyond the scope of this paper. The
      paper therefore concentrates on the roles of a school of public health,
      specifically the service role, and will seek to define that role. Further, the
      paper will look at how this role has been translated into the mission and
      policies of the SPH and how this role is operationalised. Finally, points for
      consideration and actions to be taken are suggested when defining the service
      role of a SPH.

PMID- 12613704
TI  - Summary of working group presentations.

PMID- 12613703
TI  - Resources for development of training in public health and health managment in
      Eastern Europe: the Kaunas experience.
AB  - The aim of this paper is to review the resources and steps required for
      development and evaluation of training in public health and management of public
      health as experienced in Kaunas University of Medicine, Lithuania. The transition
      from Departments of Social Medicine and Hygiene to a Faculty of Public Health of
      international standards requires a process of adaptation and development of human
      resources more than physical facilities. After restoration of independence in
      1990, rapid development of training in public health was started in Lithuania.
      Great support was provided by the international projects Baltic Rim Partnership
      for Public Health (BRIMHEALTH) and European Union Trans-European Mobility Scheme
      for University Students (TEMPUS). Undergraduate and postgraduate training
      programs were successfully implemented in the Faculty of Public Health, Kaunas
      University of Medicine. Lithuanian experience could serve as an example of
      success and pitfalls in training a critical mass of professionals who should act
      as powerful advocates for health, promoting analysis, continuity and success of
      public health interventions, and health care reforms in countries in transition.

PMID- 12613705
TI  - Developing schools of public health in countries of Eastern Europe and the
      Commonwealth of Independent States.
AB  - Countries of Eastern Europe and the Commonwealth of Independent States are facing
      a combination of difficulties in health including high rates of mortality from
      preventable diseases, and pressures for reform of their health care systems. The
      development of schools of public health is an important priority for
      international aid and for national government attention. This provides a
      challenge of integrating experience from many countries in the industrialized
      world and academic centers of excellence in the field of public health.
      Traditional departments of social hygiene within medical academies need to evolve
      to educate new generations of doctors to cope with challenges facing the health
      systems in these countries. Development of post-graduate centers of training will
      also be needed as independent schools of public health within single or multi
      faculty universities to train health workers in a New Public Health. This paper
      outlines the mission of a school of public health (SPH), and the steps needed to
      achieve its objectives, with examples of several schools at relatively advanced
      and moderate levels of development. The purpose is to provide guidelines for
      those SPHs under development that are seeking international support and
      resources.

PMID- 12613706
TI  - The teaching of social sciences, health behavior, and health behavior change in
      public health.

PMID- 12613707
TI  - Teaching statistics in schools of public health.
AB  - Biostatistics plays an important role in the education and training of public
      health students. The aim of this paper is to discuss issues associated with the
      teaching of biostatistics for master in public health (MPH) students. It
      characterizes the student body, describes the aims of teaching statistics, and
      considers how and what should be taught. This paper reflects my experience in
      both coordinating and teaching biostatistics in the Braun School of Public
      Health, which is part of the Hebrew University-Hadassah Medical Center. The
      school runs two MPH programs: an Israeli program and an international one.

PMID- 12613708
TI  - Training in survey and research methods within a Master of Public Health program.
AB  - Sound decision-making and practice in public health, as in other disciplines, is
      contingent upon information that is properly collected, analyzed, and
      interpreted. We describe the content and teaching methods of a graduate course in
      investigative methods in public health taught within the framework of a Master of
      Public Health (MPH) program. Following the progressive steps of carrying out
      research, we highlight the main concepts and skills that a student of public
      health should be exposed to. This includes the formulation of the study purpose
      and objectives, basic study designs, definition and selection of the study
      population and study variables, issues related to the actual collection of data
      in the field including the reliability and validity of the information, and
      preparing the data for analysis. We describe the teaching methods that are
      employed including frontal lectures, individual and group-based exercises, and
      the use of simulated data to develop skills in the critical reading of published
      literature and data analysis. The integration of the learned concepts and tools
      into course workshops and dissertation work is also addressed. Together with
      training in epidemiology, statistics and other quantitative and qualitative
      methodologies, this course provides a solid basis for MPH graduates to tackle the
      public health challenges that await them.

PMID- 12613709
TI  - Principles for planning the teaching of health promotion in an MPH course.
AB  - The Ottawa Charter on Health Promotion defined the term Health Promotion as "the
      process of enabling people to increase control over, and to improve, their
      health". It also specifies that "to reach a state of complete physical mental and
      social well-being, an individual or group must be able to identify and to realize
      aspirations, to satisfy needs, and to change or cope with the environment". Three
      main strategies for promoting health were stated: advocacy, enabling, and
      mediating. A great emphasis was put on policy. The Jakarta Declaration at the 4th
      International Conference on Health Promotion in 1997 reconfirmed the Ottawa
      Charter and added to it that "Health Promotion is carried out by and with people,
      not on or to people". The learning objectives of health promotion should refer to
      the values and strategies of 'Health 21', to the strategies and areas of action
      in health promotion as specified in the Ottawa Charter, and it should be relevant
      to the needs of the society that the participants are going to serve. The main
      goal of a training program in health promotion should be to develop competence in
      health promotion. "Competence" refers to the combination of three domains:
      attitudes, knowledge, and skills. Each school of public health or planners of an
      MPH course should decide upon the right mix of these three domains, according to
      their institute's mission and goals.

PMID- 12613710
TI  - The Research Forum for MPH students.
AB  - Over the years, the experience with the Research Forum has shown that the
      framework is effective in providing the time frame and the academic support for
      the preparation of the proposals. It provides the students with an additional
      opportunity for the integration of knowledge gained during the MPH core and
      elective courses and for developing skills in writing and appraising a proposal
      or an essay on a public health issue. For the faculty it is another instance in
      which methodological issues are stressed, public health themes are discussed, and
      a systematic approach is emphasized. This process helps the students to achieve
      high academic levels for their proposals, and the final theses or papers are
      enhanced. This is evidenced by the fact that many of these works are also
      published in peer-reviewed journals, a sample of which is shown in the
      references. Students from Countries of Eastern Europe and the Commonwealth of
      Independent States have the opportunity to apply to the Soros Foundation Open
      Society Institute (OSI) for projects on their return to their home institution,
      which may include a continuation of their research project or master's paper
      topic. This project is to be carried out during the first year of their return
      home with financial support up to $5,000. These projects have been presented to
      Braun SPH faculty at summer seminars held in Russia in 2001 and 2002.

PMID- 12613711
TI  - Teaching Mother and Child Health in schools of public health.
AB  - Mothers and children constitute the majority of the population and can be
      considered vulnerable populations. Their health is essential for personal,
      community, and country development. The ultimate goal of Mother and Child Health
      (MCH) teaching in schools of public health is to improve the health of women and
      children. This can be achieved by preparing professionals in the foundations of
      MCH either as practitioners, policy makers, or researchers. The content of MCH
      teaching should answer the local needs and include international and global
      aspects, considering the multifactorial determinants of health. Courses can be
      integrated into the MPH program or constitute a track within the MPH. Teaching
      methods should be interactive, including classroom activity and fieldwork.
      Faculty should be multidisciplinary.

PMID- 12613712
TI  - Principles for planning the teaching of health policy in an MPH program.
AB  - This position paper is intended to suggest starting points for discussion
      regarding three issues: (A) background considerations related to development of
      an MPH health policy curriculum; (B) subjects to be considered for inclusion in
      MPH health policy curricula; (C) teaching methods.

PMID- 12613713
TI  - Principles for planning the teaching of evidence-based medicine/clinical
      epidemiology for MPH and medical students.
AB  - Medical decision-making requires increasing skills in communication, information
      retrieval, and formulating and answering focused clinical questions. Medical
      students need increasing exposure to the principles of evidence-based medicine
      and methodologic training in epidemiology and biostatistics in order to cope with
      the explosion of medical information and in order to appraise, interpret, and
      perform clinical research. This review summarizes the principles applied to
      teaching these subjects to medical students, as well as to students in Master's
      programs who will pursue careers in public health or clinical research.

PMID- 12613714
TI  - Teaching public health related to the elderly.
AB  - It has become axiomatic that the world is aging, not just in the developed
      countries, but in the less developed regions as well. In 1992 the global elderly
      population (age 65+) was estimated to be almost 350,000,000 persons, or more than
      6% of the world total. During that year the net balance of the world's elderly
      grew by more than 800,000 persons each month. Projections to the year 2010
      indicate that the net monthly gain will rise to more than 1.1 million elderly
      people. In the early 1990s, 26 countries had more than 2,000,000 elderly persons.
      The projections suggest that this number could increase to more than 50 nations
      by the year 2025. And this increase in number of elderly leads to an absolute
      rise in problems of age-related diseases, such as Alzheimer's disease,
      cardiovascular disease, stroke, and osteoporosis (with related falls and
      fractures). At the same time, there is a school of thought that emphasizes the
      elderly are living longer and healthier lives through better awareness of healthy
      nutrition, exercise, and other lifestyle factors, as well as improving access to
      modern medical care that is itself more effective than in previous decades. While
      the public health practitioner will not be called upon to treat individuals with
      these pathologies, it is important to know something about them in order to
      understand their effect on health care systems and to help plan for preventive
      and health promotion programmes. The preparation of the public health person
      requires an understanding of these issues and thus some tools for program
      development for primary, secondary, and tertiary prevention for this high-risk
      group.

PMID- 12613715
TI  - Planning the teaching of community health (COPC) in an MPH program.
AB  - The Community Medicine approach, focussed on an active assessment of health
      status with a subsequent provision of health care directed to the community as a
      whole, is recommended today as a means for addressing the fragmentation of health
      services. In parallel, in recent years the Community Medicine approach has been
      incorporated in a growing number of health academic institutions. In this paper
      it is suggested that the teaching of Community Medicine should be an active
      process in a practical environmental in which students could be involved with
      real life situations. Our teaching methods are illustrated by the experience of
      the Community Oriented Primary Care (COPC) Workshop of the School of Public
      Health and Community Medicine in Jerusalem. This Workshop is included in the
      curriculum after the core courses in the Israeli and in the International MPH
      Program at the Braun SPH. The central component of the workshop are the
      workgroups of 6-8 students with the assistance of a tutor member of the School's
      staff. The group, resembling a health team, focussed its work in the assignment
      of planning a proposal for the development of a community health program in the
      students' communities. The workshop is an illustration of the problem-based
      learning method carried out by public health workers of different professions
      background and with diverse practical experience reproducing a real life
      situation in a classroom environment. Repeated evaluations done by students has
      shown a positive assessment as measured by a reported adequate acquisition of
      knowledge, having an useful experience and practicing skills.

PMID- 12613716
TI  - Principles for planning the teaching of dental public health in an MPH course.
AB  - Dental public health should be presented to MPH students as an integral component
      in the general promotion of health. Students should be presented with the
      "dental" component in public health and the "public health" component in
      dentistry. Dental examples should be utilized to illustrate most of the other
      disciplines taught in the MPH course. The underlying principals that determine
      the teaching of dental public health within an MPH course include: the
      associations between oral and general health; oral health as an integral
      component in quality of life; basic concepts in the understanding of oral health
      and disease; the prevalence of oral diseases; oral diseases as a specific
      characteristic of industrialized-urbanized-developed societies; the methods of
      measuring dental health in epidemiological surveys; the patterns of changing
      dental epidemiology around the world; the social component of dental disease; the
      promotion of oral health as an important, typical, example of successful public
      health efforts; socio-economic-political aspects of oral health promotion; dental
      health care delivery systems in different regions; members of the expanded oral
      health team and the potential of including the general health team; oral health
      promotion for the geriatric population; specific examples of planning,
      implementation, monitoring and evaluation of community oral health programs.

PMID- 12613717
TI  - Teaching nutrition in an International Master of Public Health program.
AB  - The health of populations is related to the norms and characteristics of society
      and its socio-economic organization. The causes of food-related ill health are
      located at the national and international levels and the cure must be sought in
      good governance. Thus, it is obvious that a Master's Degree in International
      Public Health must include a thorough overview of the "food chain" from "plough
      to plate" within the political, economical, socio-economic changes,
      environmental, industrial, scientific, and health contexts. Nutritional
      deficiencies are addressed by a variety of measures, including food supply and
      utilization programs, specific supplementation for high-risk groups, and food
      fortification to reach a general population. All are part of a wide-based public
      health nutrition approach, applicable in developed, redeveloping, and newly
      developing countries. This article is based on experience in teaching Public
      Health Nutrition to a mixed group of foreign students from different countries.
      Our goal is to prepare students for a variety of public health careers related to
      nutrition and health. The aim of this course is to introduce current roles and
      aspects of food and nutrition policy, focusing on food and nutrition security,
      human rights for food and nutrition, and the complex interactions among local and
      global systems. Students are introduced to nutrition screening, assessment, and
      research skills, and nutrition in emergency situations and in disaster relief.
      During the course the students learn about the design and the evaluation of
      nutrition interventions at the individual, community, and national level. The
      course gives a broad-based examination of major themes related to development and
      underdevelopment, poverty and wealth, equality and inequality. It also introduces
      program planning from the perspective of international organisations such as the
      World Food Program and the Food and Agriculture Organisation and the World Health
      Organisation of the United Nations. More specific objectives include: 1. To
      define the nutritional problems at the level of the individual, family, the
      community, and the nation. Use of Causal Modelling. 2. To learn in what ways data
      may be gathered. 3. To suggest methods of intervention according to priorities.
      4. To monitor the effects of such interventions. 5. To assess the scientific
      evidence underlying the connections between diet and disease.

PMID- 12613719
TI  - Teaching epidemiology inside and outside the classroom.
AB  - There is no single ideal way of teaching epidemiology. Teaching can take place in
      different situations, and its techniques and content may differ. A good teaching
      programme is one that is geared to its students' needs, capacity, interests and
      preferences, and exploits available teaching situations and techniques to provide
      learning opportunities that will achieve the educational objectives. This paper
      reviews some features of the teaching of epidemiology inside and outside the
      classroom. It starts with a discussion of the main factors that affect the choice
      of methods and then deals in turn with conventional classroom methods, laboratory
      teaching (problem-solving and other exercises), self-instruction, problem
      oriented projects, and distance learning. Separate consideration is then given to
      teaching in the hospital and in the field (with special attention to teaching in
      a community health center).

PMID- 12613718
TI  - Communicable disease control: an introductory course for MPH students.
AB  - Persons preparing for careers in public health practice need a solid academic
      grounding in the principles of communicable disease control before arriving on
      the job. We have developed an introductory course in infectious disease control
      for the Master of Public Health program in Jerusalem, which includes instruction
      in the following broad areas: How do micro-organisms spread and cause disease?
      How do we investigate and control an outbreak? What are the basics of primary
      prevention by immunization and what can mass immunization accomplish? What is the
      importance of routine ongoing communicable disease surveillance? What are the
      essentials of Travel Medicine? How can public health officials provide useful
      information to a concerned citizenry by intelligent cooperation with the media?
      How can immunization programs and other programs for infectious disease control
      be kept current with the help of expert advisory committees? What are the best
      resources available to the public health practitioner in the area of infectious
      disease control? Armed with the essentials, the practitioner will have the tools
      to approach communicable disease problems in an orderly and rational way even in
      an atmosphere of public and professional ignorance and apprehension.

PMID- 12613720
TI  - What to teach with regard to mental health in an MPH program?
AB  - Mental health is one of the important subjects of the "New Public Health". Mental
      illness is one of the major causes of morbidity and even mortality, and
      traditional separation from health care systems has left mental illness poorly
      attended. New technologies and concepts allow for management of mental illness in
      the community, but this requires adequate organization and resources. Mental
      health policy requires a population-based approach, just as other issues in
      health, with prevention at the primary, secondary, and tertiary levels, as with
      physical disease. Thus training in mental health issues is an important element
      of a basic MPH program. We will consider the following issues: 1. Mental health
      training for whom? 2. A brief sketch of the mental health scenario in Europe; 3.
      What should be the proper reply to the mental health needs in Europe? 4.
      Suggested profile of an MPH graduate; 5. Recommended syllabus.

PMID- 12613721
TI  - The MPH programme, University of Wales College of Medicine (UWCM), Cardiff,
      Wales.

PMID- 12613722
TI  - Types of medical errors commonly reported by family physicians.
AB  - In a group of studies about medical errors in family medicine, the five error
      types most often observed and reported by U.S. family physicians were: (1) errors
      in prescribing medications; (2) errors in getting the right laboratory test done
      for the right patient at the right time; (3) filing system errors; (4) errors in
      dispensing medications; and (5) errors in responding to abnormal laboratory test
      results. "Errors in prescribing medications" was the only one of these five error
      types that was also commonly reported by family physicians in other countries.

PMID- 12613723
TI  - Noninvasive treatments for umbilical granulomas.

PMID- 12613724
TI  - Accurate information on drug effects on pregnancy is crucial.

PMID- 12613725
TI  - Importance of preconception counseling.

PMID- 12613726
TI  - Chronic rhinitis: allergic or nonallergic?

PMID- 12613727
TI  - Common benign skin tumors.
AB  - Benign skin tumors are commonly seen by family physicians. The ability to
      properly diagnose and treat common benign tumors and to distinguish them from
      malignant lesions is a vital skill for all family physicians. Any lesions for
      which the diagnosis is uncertain, based on the history and gross examination,
      should be biopsied for histopathologic examination to rule out malignancy.
      Lipomas are technically subcutaneous soft tissue tumors, not skin tumors, and
      controversy exists about whether keratoacanthomas have malignant potential;
      however, both are discussed in this article because they are common tumors
      evaluated by family physicians. Diagnosis usually is based on the appearance of
      the lesion and the patient's clinical history, although biopsy is sometimes
      required. Treatment includes excision, cryotherapy, curettage with or without
      electrodesiccation, and pharmacotherapy, and is based on the type of tumor and
      its location. Generally, excision is the treatment of choice for lipomas,
      dermatofibromas, keratoacanthomas, pyogenic granulomas, and epidermoid cysts.
      Cherry angiomas and sebaceous hyperplasia are often treated with laser therapy
      and electrodesiccation. Common treatments for acrochordons and seborrheic
      keratoses are cryotherapy and shave excision. Referral is indicated if the family
      physician is not confident with the diagnostic evaluation or treatment of a
      lesion, or if a biopsy reveals melanoma.

PMID- 12613728
TI  - Diagnostic and therapeutic injection of the wrist and hand region.
AB  - Joint injection of the wrist and hand region is a useful diagnostic and
      therapeutic tool for the family physician. In this article, the injection
      procedures for carpal tunnel syndrome, de Quervain's tenosynovitis,
      osteoarthritis of the first carpometacarpal joint, wrist ganglion cysts, and
      digital flexor tenosynovitis (trigger finger) are reviewed. Indications for
      carpal tunnel syndrome injection include median nerve compression resulting from
      osteoarthritis, rheumatoid arthritis, diabetes mellitus, hypothyroidism,
      repetitive use injury, and other traumatic injuries to the area. For the first
      carpometacarpal joint, injection may be used to treat pain secondary to
      osteoarthritis and rheumatoid arthritis. Pain associated with de Quervain's
      tenosynovitis is treated effectively by therapeutic injection. If complicated by
      pain or paresthesias, wrist ganglion cysts respond to aspiration and injection.
      Painful limitation of motion occurring in trigger fingers of patients with
      diabetes or rheumatoid arthritis also improves with injection. The proper
      technique, choice and quantity of pharmaceuticals, and appropriate follow-up are
      essential for effective outcomes.

PMID- 12613729
TI  - Antiviral drugs in the immunocompetent host: part I. Treatment of hepatitis,
      cytomegalovirus, and herpes infections.
AB  - Since the release of amantadine in 1966, other agents designed to fight a diverse
      range of viral infections have been released. Part I of this two-part article
      focuses on agents used to manage hepatitis, cytomegalovirus, and herpes
      infections. In patients with chronic hepatitis B, interferon alfa-2b or
      lamivudine is the treatment of choice. Pegylated interferon alfa-2a or -2b, along
      with ribavirin, is standard treatment for patients with chronic hepatitis C.
      Although treatment of cytomegalovirus infections generally is supportive, there
      have been reports of severely ill patients who improved after receiving
      ganciclovir or foscarnet. Oral antiviral agents for initial and recurrent herpes
      simplex virus infections have been shown to shorten the duration of lesions.
      Treatment of herpes zoster infections with antiviral drugs shortens the course of
      infection and decreases symptoms. Studies have shown that antiviral treatment can
      prevent prolonged post-herpetic neuralgia, although this use remains
      controversial.

PMID- 12613730
TI  - Antiviral drugs in the immunocompetent host: part II. Treatment of influenza and
      respiratory syncytial virus infections.
AB  - Family physicians should be familiar with the various drugs available for
      treating and preventing viral infections. Part II of this two-part article
      focuses on agents used to manage influenza and respiratory syncytial virus.
      Rimantadine and amantadine traditionally have been used to prevent and treat
      influenza type A infections. The neuraminidase inhibitors zanamivir and
      oseltamivir have a broadened spectrum of activity in the treatment and prevention
      of influenza types A and B. Ribavirin has been used in some high-risk infants to
      treat respiratory syncytial virus infections, and palivizumab can be used for
      prophylaxis.

PMID- 12613731
TI  - Recognition and management of exercise-induced bronchospasm.
AB  - Exercise-induced bronchospasm is an obstruction of transient airflow that usually
      occurs five to 15 minutes after physical exertion. Although this condition is
      highly preventable, it is still underrecognized and affects aerobic fitness and
      quality of life. Diagnosis is based on the results of a detailed history,
      including assessment of asthma triggers, symptoms suggestive of exercise-induced
      bronchoconstriction, and a normal forced expiratory volume at one second at rest.
      A trial of therapy with an inhaled beta agonist may be instituted, with the
      subsequent addition of inhaled anti-inflammatory agents or ipratropium bromide.
      Nonpharmacologic measures, such as increased physical conditioning, warm-up
      exercises, and covering the mouth and nose, should be instituted. If symptoms
      persist, pulmonary function testing is warranted to rule out underlying lung
      disease.

PMID- 12613732
TI  - Information from your family doctor. What you should know about exercise-induced
      bronchospasm.

PMID- 12613733
TI  - Screening for prostate cancer: recommendations and rationale.

PMID- 12613734
TI  - Information from your family doctor. Flu and colds.

PMID- 12613735
TI  - Information from your family doctor. Influenza vaccine.

PMID- 12613736
TI  - Information from your family doctor. Antibiotics: when they can and can't help.

PMID- 12613737
TI  - Information from your family doctor. Acute bronchitis.

PMID- 12613738
TI  - Information from your family doctor. Sore throat.

PMID- 12613739
TI  - Diagnosis and management of group A streptococcal pharyngitis.

PMID- 12613740
TI  - The study of infectious intestinal disease in England: socio-economic impact.
AB  - To assess the socio-economic impact of infectious intestinal disease (IID) on the
      health care sector, cases and their families, cases of IID ascertained from a
      population cohort component and those presenting to general practices were sent a
      socio-economic questionnaire 3 weeks after the acute episode. The impact of the
      illness was measured and the resources used were identified and costed. The
      duration, severity and costs of illness linked to viruses were less than those
      linked to bacteria. The average cost per case of IID presenting to the GP was
      Pound Sterling253 and the costs of those not seeing a GP were Pound Sterling34.
      The average cost per case was Pound Sterling606 for a case with salmonella, Pound
      Sterling315 for campylobacter, Pound Sterling164 for rotavirus and Pound
      Sterling176 for SRSV. The estimated cost of IID in England was Pound Sterling743m
      expressed in 1994/5 prices. The costs of IID are considerable and the duration of
      the illness was found to be longer than previous reports have suggested.

PMID- 12613741
TI  - Outbreaks of typhoid fever in the United States, 1960-99.
AB  - Although the incidence of typhoid fever in the United States has been low since
      the 1940s, Salmonella Typhi continues to cause outbreaks. We reviewed reported
      outbreaks of typhoid fever from 1960 to 1999. There were 60 outbreaks; in 54,
      exposure occurred within the United States. These 54 outbreaks accounted for 957
      total cases (median 10) and 4 deaths. In 36 (67%) outbreaks the route of
      transmission was identified, and in 16 (62%) of the 26 foodborne outbreaks an
      asymptomatic carrier was identified by culture or serology. The median incubation
      period was 2 weeks. Isolates from 10 (40%) of 25 outbreaks were phage type E1.
      The average frequency of outbreaks decreased from 1.85/year during 1960-79 to
      0.85/year during 1980-99 (P=0.0001). S. Typhi outbreaks in the United States are
      generally small in size but can cause significant morbidity, and are often
      foodborne, warranting thorough investigation.

PMID- 12613743
TI  - An extensive outbreak of staphylococcal food poisoning due to low-fat milk in
      Japan: estimation of enterotoxin A in the incriminated milk and powdered skim
      milk.
AB  - An extensive outbreak of staphylococcal food poisoning occurred in Kansai
      district in Japan. As many as 13,420 cases frequently ingested dairy products
      manufactured by a factory in Osaka City. The main ingredient of these dairy
      products was powdered skim milk manufactured by a factory in Hokkaido.
      Staphylococcal enterotoxin A (SEA) (< or = 0.38 ng/ml) was detected in low-fat
      milk and approx. 3.7 ng/g in powdered skim milk. The total intake of SEA per
      capita was estimated mostly at approx. 20-100 ng. The assumed attack rate was
      considerably lower than those reported in previous outbreaks. SEA exposed at
      least twice to pasteurization at 130 degrees C for 4 or 2 s retained both
      immunological and biological activities, although it had been partially
      inactivated. The present outbreak was unusual in that the thermal processes had
      destroyed staphylococci in milk but SEA had retained enough activity to cause
      intoxication.

PMID- 12613742
TI  - Campylobacter spp. in Icelandic poultry operations and human disease.
AB  - We describe the observed relationship of campylobacter in poultry operations to
      human cases in a closed environment. During 1999 in Iceland, domestic cases of
      campylobacteriosis reached peak levels at 116/100,000 and in 2000 dropped to
      33/100,000. Approximately 62% of broiler carcass rinses were contaminated with
      Campylobacter spp. in 1999. During 2000, only 15% of the broiler flocks tested
      Campylobacter spp. positive. In 2000, carcasses from flocks which tested positive
      on the farms at 4 weeks of age were subsequently frozen prior to distribution. We
      suggest that public education, enhanced on-farm biological security measures,
      carcass freezing and other unidentified factors, such as variations in weather,
      contributed to the large reduction in poultry-borne campylobacteriosis. There is
      no immediate basis for assigning credit to any specific intervention. We continue
      to seek additional information to understand the decline in campylobacteriosis
      and to create a risk assessment model for Campylobacter spp. transmission through
      this well defined system.

PMID- 12613744
TI  - Variation in management of community-acquired pneumonia requiring admission to
      Alberta, Canada hospitals.
AB  - Previous studies have shown small area variation in the rate of admission to
      hospital for patients with community-acquired pneumonia. We determined the rates
      of admission and length of stay for patients with community-acquired pneumonia in
      Alberta and the factors influencing admission rates and length of stay. Using
      hospital abstracts, hospital admissions for community-acquired pneumonia from 1
      April 1994 to 31 March 1999 were compared. We classified Alberta hospitals
      according to geographical regions, by the number of beds, and by number of
      community-acquired pneumonia cases. There were 12,000 annual hospital discharges
      for community-acquired pneumonia costing over $40 million per year. The overall
      in-hospital mortality rate was 12% and the 1 year mortality rate was 26%.
      Compared with rural hospitals, regional and metropolitan hospitals admitted
      patients with greater severity of illness as demonstrated by greater in-hospital
      mortality, cost per case and comorbidity. Age-sex adjusted hospital discharge
      rates were significantly below the provincial average in both urban regions.
      Hospital discharge rates for residents in all rural regions and 4 of 5 regions
      with a regional hospital were significantly higher than the provincial average.
      After adjusting for comorbidity, the relative risk for a longer length of stay
      was 22% greater in regional hospitals and about 30% greater in urban hospitals
      compared to rural hospitals. Seasonal variation in the admission rate was
      evident, with higher rates in the winter of each year. We conclude that rural
      hospitals would be likely to benefit from a protocol to help with the admission
      decision and urban hospitals from a programme to reduce length of stay.

PMID- 12613745
TI  - Meningococcal disease and social deprivation: a small area geographical study in
      Gwent, UK.
AB  - Although meningococcal disease is known to be linked to characteristics of
      individuals associated with social deprivation, there is only limited evidence of
      a relation with area-based measures of deprivation. In a small area geographical
      study, we ascertained 295 confirmed or probable cases occurring between 1996 and
      1999 in the socially diverse resident population of Gwent Health Authority,
      equating to an average annual rate of 13.2 per 100,000. Incidence rates of
      meningococcal disease increased from 8.1 per 100,000 in the least deprived fifth
      of enumeration districts to 19.8 per 100,000 in the most deprived fifth, a
      relative risk of 2.4 (95% CI 1.7-3.6). In Poisson regression, the percentage
      change in the incidence rate arising from a unit change in the enumeration
      district Townsend score, was 9.4% (95% CI 6.2-12.6%). Strongest associations were
      found for the under 5 age group, serogroup B disease and with the overcrowding
      variable component of the Townsend index. Our study quantifies the strength of
      the relation between meningococcal disease and social deprivation at small area
      level and provides further evidence of the need for action to reduce health
      inequalities.

PMID- 12613746
TI  - Genetic analysis of capsular status of meningococcal carrier isolates.
AB  - The meningococcal capsule is the primary virulence factor with systemic isolates
      requiring full expression of the capsule but with capability to down-regulate the
      capsule in order to invade. The meningococcal capsular operon is composed of a
      number of genes that are involved in capsular synthesis and transport.
      Differences in capsular synthesis genes may allow discrimination between
      meningococcal serogroups whereas absence of genes for either synthesis or
      transport imply that the meningococcus is unencapsulated. Although mechanisms
      such as slipped-strand mispairing and acquisition of insertion sequences have
      been demonstrated to be involved in regulation of capsular expression, few
      studies have addressed the mechanisms of capsular expression in carrier isolates.
      Following a community-based intervention programme for an outbreak of
      meningococcal disease, we collected meningococcal carrier isolates from the
      intervention area and control areas. We undertook genetic analysis of the
      capsular operon and the mechanisms of capsular regulation, together with an
      investigation of the potential of capsular genes to identify the genogroup of non
      serogroupable isolates. Use of the siaD gene allowed the discrimination of 30/89
      (34%) non-serogroupable isolates into B, C, W135 and Y with a siaA gene PCR
      permitting the characterization of a further 6 isolates whose capsules contained
      sialic acid. Slipped-strand mispairing was evident in only 4 of 13 genogroupable
      B isolates and the insertion sequence IS1301 was found in 2 of 36 siaA-positive
      isolates. Of 51 non-genogroupable isolates 25 (49%) were shown to be ctrA
      negative. There was a higher percentage of ctrA-positive isolates (P<0.001)
      amongst meningococcal strains obtained from those sampled in non-intervention
      schools than those sampled at intervention schools. The ctrA-negative isolates
      warrant further investigation of their genotypic organization since such
      avirulent strains may be important in conferring natural protection against
      invasive disease. We found that after mass antibiotic prophylaxis, recolonization
      occurs preferentially with non-pathogenic meningococcal strains. This as
      implications for assessment of the benefits of mass antibiotic and vaccination
      programmes for outbreak control. Previously expressed concerns of increased risk
      due to removal of protective ora may have been overstated.

PMID- 12613747
TI  - Tetanus in England and Wales, 1984-2000.
AB  - A review of national tetanus surveillance in England and Wales during 1984-2000
      was undertaken to evaluate the surveillance system and national vaccination
      policy. Hospital Episode Statistics for tetanus in England for fiscal years
      1989/90-1995/6 were also examined to estimate under-reporting. A total of 175
      cases of tetanus were reported, giving an annual incidence of 0.20 per million,
      the lowest levels ever recorded. The highest incidence was in those aged over 64
      years (0.66 per million) with no significant sex difference. Twenty (11%) cases
      were reported in people who were eligible for routine childhood vaccination.
      Outdoor injuries were the commonest reported exposure risk. Tetanus case under
      reporting was estimated as 54-64%. We conclude that GPs should ensure that all
      their patients are fully vaccinated, targeting those born before 1961. High
      childhood tetanus vaccination coverage remains a priority. As the disease becomes
      rarer, enhanced tetanus case surveillance is essential for tetanus immunization
      policy evaluation.

PMID- 12613749
TI  - No association between Helicobacter pylori and Mycobacterium tuberculosis
      infections among gastrointestinal clinic attendees in Lima, Peru.
AB  - Helicobacter pylori (HP) infection can cause hypochlorhydria, a positive risk
      factor for Mycobacterium tuberculosis (MTB) infection. This study examined the
      association between HP and MTB infections among persons attending the Policlinico
      Peruano Japones Gastrointestinal Clinic in Lima, Peru. From 23 June 2000 to 18
      August 2000, consenting 18-55 year olds who attended the clinic for gastric
      biopsy gave blood for HP serologic testing, underwent tuberculin skin testing
      (TST) and completed a social and medical history. Of 128 participating patients,
      78 (61%) were TST positive for MTB, and 107 (84%) were infected with HP by
      serology. Of the patients who were HP positive, 67 (63%) developed positive TST
      reactions compared to 11 (52%) of 21 HP-seronegative subjects (OR 1.29; 95% CI
      0.54-3.11; P = 0.6). There was no association after adjusting for covariates of
      H. pylori infection (OR 0.78; 95% CI 0.23-2.71; P = 0.7). However, study power
      was limited by high prevalence of the two infections.

PMID- 12613748
TI  - Febrile gastroenteritis after eating on-farm manufactured fresh cheese--an
      outbreak of listeriosis?
AB  - An outbreak of febrile gastroenteritis affected consumers of on-farm manufactured
      dairy products from a summer farm in Sweden. Symptoms included diarrhoea, fever,
      stomach cramps and vomiting in 88, 60, 54 and 21% of cases identified. The median
      incubation period was 31 h. A cohort study with 33 consumers showed an attack
      rate of 52% and an association between the total amount of product eaten and
      illness (P=0.07). Twenty-seven of 32 (84%) stool samples cultured for Listeria
      monocytogenes tested positive, although there was no association between clinical
      disease and the isolation of L. monocytogenes. In addition, gene sequences for
      VTEC and ETEC were detected in 6 and 1 subjects, respectively. Bacteriological
      analysis of cheese samples revealed heavy contamination with L. monocytogenes and
      coagulase positive staphylococci in all of them and gene markers for VTEC in one
      of them. Molecular profiles for L. monocytogenes isolated from dairy products,
      stool samples and an abscess from 1 patient who developed septic arthritis were
      identical. Results of both microbiological and epidemiological analyses point to
      L. monocytogenes as the most likely cause of this outbreak. The finding of
      markers for VTEC in some humans and cheese samples means that a mixed aetiology
      at least in some cases cannot be conclusively ruled out.

PMID- 12613750
TI  - Non-specific alert system for dengue epidemic outbreaks in areas of endemic
      malaria. A hospital-based evaluation in Cayenne (French Guiana).
AB  - The emergence of dengue haemorrhagic fever is a public health problem in Latin
      America and the Caribbean. This study, carried out in French Guiana where malaria
      is endemic, evaluated the value and the limitations of a non-specific alert
      system including all patients admitted to the emergency department of Cayenne
      Hospital, between 1 January 1996 and June 2001. Four indices were studied on a
      weekly basis: the emergency malaria negative index (EMN), the EMN
      thrombocytopenia index (EMNT), the dengue suspected index: EMNT/EMN ratio; and
      the number of hospitalized patients with dengue fever according to the Department
      of Medical Information. These indices were retrospectively compared with data
      from the Arbovirus Reference Centre at the Pasteur Institute in French Guiana.
      Using the non-specific indices, we were able to identify four clear epidemics,
      two of which were shown to be linked to dengue. Variations in the incidence of
      malaria had no marked effect on this alert system. We propose that this simple,
      cheap, sensitive and reactive alert system be used to improve the serological and
      virological monitoring of dengue and to facilitate adequate and timely vector
      control measures. It could be used in all regions at risk of dengue and malaria.

PMID- 12613751
TI  - Use of RT-PCR on oral fluid samples to assist the identification of measles cases
      during an outbreak.
AB  - This study investigated the occurrence of mild modified measles cases during an
      outbreak in Niteroi, RJ, Brazil by using RT-PCR on oral fluid samples. From
      August to December 1997 a total of 76 patients with rash were seen at the study
      sites. Confirmed diagnosis by serology was achieved in 47 cases: measles (39.5%),
      rubella (13.2%), HHV-6 (3.9%), human parvovirus B19 (3.9%), dengue fever (3%).
      For 19 of the 29 patients without a conclusive diagnosis paired serum and saliva
      samples were available for further tests. In four of them, measles virus RNA was
      detected by RT-PCR in saliva samples in the absence of specific IgM in serum
      samples. Vaccination histories obtained from three of the RT-PCR positive cases
      showed that individuals previously immunized can still be infected and contribute
      to the circulation of measles virus. This study demonstrated the usefulness of RT
      PCR on non-invasive clinical samples for the investigation of measles cases.

PMID- 12613752
TI  - Detection of human rotavirus serotype G6 in Hungary.
AB  - During an ongoing survey of human rotavirus serotypes, we demonstrated for the
      first time the circulation of serotype G6 in two regions of Hungary. Of five
      rotavirus seasons surveyed to date (1994-9), serotype G6 was found in all seasons
      except 1994-5 at an overall prevalence of 1.4% (17 of 1252) and ranging from 0.6
      to 4.5%. Children infected with G6 strains were older (mean age, 3.3 years) than
      children infected with the four (G1-G4) globally common serotypes (mean age, 2.1
      years; unpaired Student's t test, P<0.001). Our data indicate that rotavirus
      serotype G6 may be an epidemiologically important G serotype in Hungary.

PMID- 12613753
TI  - Monitoring the spread of myxoma virus in rabbit Oryctolagus cuniculus populations
      on the southern tablelands of New South Wales, Australia. I. Natural occurrence
      of myxomatosis.
AB  - A survey of rabbit populations in the southern tablelands of New South Wales,
      Australia, was carried out to establish the pattern of occurrence of myxomatosis
      in preparation for a deliberate release of myxoma virus. Myxomatosis was first
      detected in December and cases were found on most sites through to May. The
      serological profiles of rabbit populations suggested that their susceptibility to
      myxoma virus was generally low in winter and highest in spring and summer
      reflecting the presence of increasing numbers of susceptible young rabbits. This
      was consistent with the pattern of rabbit breeding, as determined from the
      distribution of births and reproductive activity in females and males, which
      occurred maximally in spring and early summer. The serology and age structure of
      rabbit populations on sites suggested that some rabbit populations can escape an
      annual myxomatosis epizootic. Although fleas were present on rabbits throughout
      the year and therefore not considered to be a limiting factor in the spread of
      myxomatosis, their numbers peaked at times coincident with peak rabbit breeding.
      It was concluded that mid to late spring was an optimal time for a deliberate
      release.

PMID- 12613754
TI  - Monitoring the spread of myxoma virus in rabbit Oryctolagus cuniculus populations
      on the southern tablelands of New South Wales, Australia. II. Selection of a
      strain of virus for release.
AB  - To be able to study the dynamics of myxoma virus spread following a release in
      the field, a strain of virus is required that is both highly transmissible and
      readily differentiated from other field strains. Eight strains of virus of known
      virulence for laboratory rabbits and with previously mapped and sequenced
      restriction fragment length polymorphisms, were used to infect groups of
      seronegative wild rabbits. Based on these trials, and on the nature of the DNA
      polymorphism, a virus designated Brooklands/2-93 was chosen as a strain suitable
      for experimental release. These trials confirmed that resistance to myxomatosis
      within wild rabbit populations continues to be substantial and that some rabbits
      are highly resistant. These rabbits probably have little role in transmission of
      virus. Most of the virus strains tested induced very small or invisible primary
      lesions at the inoculation site. Thus the secondary skin sites such as eyelids,
      face and ears may be critical for transmission.

PMID- 12613755
TI  - Monitoring the spread of myxoma virus in rabbit Oryctolagus cuniculus populations
      on the southern tablelands of New South Wales, Australia. III. Release,
      persistence and rate of spread of an identifiable strain of myxoma virus.
AB  - An identifiable strain of myxoma virus was introduced into four local populations
      of wild rabbits Oryctolagus cuniculus on the southern tablelands of New South
      Wales (NSW) and its spread in the presence of other field strains was monitored
      for 6 months. The main vector in this region was considered to be the European
      rabbit flea Spilopsyllis cuniculi. Each population of rabbits was of a high
      density and living in groups of warrens covering areas from 59 to 87 hectares.
      Rabbits occupying centrally located warrens were inoculated with the virus in
      late September or early October (spring) and the subsequent appearance of
      myxomatosis across the sites monitored by trapping, shooting and visual
      observations. Samples, taken from rabbits with myxomatosis, were examined by
      polymerase chain reaction (PCR) that allowed identification of the introduced
      strain. On all four sites the introduced virus spread from the inoculated rabbits
      in the centrally located warrens to rabbits in surrounding warrens. On Sites 1
      and 3, this spread continued across the entire site persisting for at least 118
      and 174 days respectively. On Sites 2 and 4, the virus was detected for 78 and 62
      days respectively and the subsequent inability to detect the introduced virus
      correlated with the appearance of an unrelated field strain. Using three
      different methods of calculation, rates of spread ranged from 3.7 to 17.8 m d(
      1).

PMID- 12613756
TI  - Bartonella infection in sylvatic small mammals of central Sweden.
AB  - Sylvatic small mammals were captured in rural habitats near Uppsala, Sweden, to
      measure the prevalence of bartonella infections, characterize bacterial isolates
      and identify their host range, and increase our understanding of host-pathogen
      ecology. During 7 nights of trapping at 3 localities, 236 small mammals were
      captured (trap success 30%). Bartonella were isolated from bloods of Apodemus
      flavicollis (19 of 110 tested), Apodemus sylvaticus (6/25), Clethrionomys
      glareolus (9/60), Microtus agrestis (1/3), Mus musculus (1/18), and Sorex araneus
      (3/20). Nucleotide sequencing (a 338 bp fragment of the gltA gene) of 40 isolates
      yielded 6 unique genotypes. Five of the 6 genotypes were most similar to other
      known bartonella isolated from Old World small-mammal hosts. The most frequent
      genotype (83%) was isolated from A. flavicollis and M. musculus and was identical
      to Bartonella grahamii, a recently demonstrated human pathogen. These two hosts
      were most frequently captured in and around human structures and work places,
      thus providing conditions that could potentially lead to frequent human
      infections.

PMID- 12613757
TI  - Molecular characterization of Leptospira spp. strains isolated from small rodents
      in Croatia.
AB  - We report the isolation and characterization of 16 Leptospira spp. strains
      isolated from small rodents captured in 11 different regions of inland Croatia.
      Large NotI and SgrAI restriction fragment allowed us to assign 10 isolates to the
      serovar istrica, 5 isolates to the serovar tsaratsovo and 1 isolate to the
      serovar lora. The phylogenetic analysis conducted from the sequences of the first
      330 bp from the 16S rDNA gene revealed that the strains belonged to three
      different species, L. borgpetersenii, L. kirschneri and L. interrogans. Carrier
      rates in eight rodent species varied from 0 to 71.4%. Mus musculus showed the
      highest infection level and confirmed its role as a major reservoir of the
      serogroup Sejroe. For the first time we reported the occurrence of serovars
      tsaratsovo and lora in Croatia.

PMID- 12613758
TI  - Sequence heterogeneity of the small subunit ribosomal RNA genes among
      blastocystis isolates.
AB  - Genes encoding small subunit ribosomal RNA (SSUrRNA) of 16 Blastocystis isolates
      from humans and other animals were amplified by the polymerase chain reaction,
      and the corresponding fragments were cloned and sequenced. Alignment of these
      sequences with the previously reported ones indicated the presence of 7 different
      sequence patterns in the highly variable regions of the small subunit ribosomal
      RNA. Phylogenetic reconstruction analysis using Proteromonas lacertae as the
      outgroup clearly demonstrated that the 7 groups with the different sequence
      patterns are separated to form independent clades, 5 of which consisted of the
      Blastocystis isolates from both humans (B. hominis) and other animals. The
      presence of 3 higher order clades was also clearly supported in the phylogenetic
      tree. However, a relationship among the 4 groups including these 3 higher order
      clades was not settled with statistical confidence. The remarkable heterogeneity
      of small subunit ribosomal RNAs among different Blastocystis isolates found in
      this study confirmed, with sequence-based evidence, that these organisms are
      genetically highly divergent in spite of their morphological identity. The highly
      variable small subunit ribosomal RNA regions among the distinct groups will
      provide useful information for the development of group-specific diagnostic
      primers.

PMID- 12613759
TI  - Association of Borrelia afzelii with rodents in Europe.
AB  - Borrelia burgdorferi sensu lato (s.l.) is maintained in nature by complex
      zoonotic transmission cycles, involving a large variety of vertebrates as hosts
      and hard ticks of the genus Ixodes as vectors. Recent studies suggest that the
      genospecies of B. burgdorferi s.l. and sometimes their subtypes are propagated by
      different spectra of hosts, mainly birds and rodents. In order to test the
      concept of host-association, we analysed the relationships between Borrelia
      genospecies, rodent hosts and I. ricinus ticks in an endemic focus of Lyme
      borreliosis in western Slovakia. Rodents and questing ticks were collected at a
      forested low land locality near Bratislava. Tick infestation levels on rodents
      were determined, and spirochaete infections in ticks and in ear punch biopsies
      were analysed by PCR followed by genotyping. Mice were more heavily infested with
      ticks than bank voles, and a higher proportion of mice was infected with
      spirochactes than voles. However, the infectivity of soles was much higher than
      that of mice. The vast majority of infections detected in the skin and in ticks
      feeding on the rodents represented B. afzelii. In contrast, more than half of all
      infections in questing ticks collected in the same region of Slovakia were
      identified as B. valaisiana and B. garinii. In conclusion, whilst the study
      reveals that mice and voles play different quantitative roles in the ecology of
      Lyme borreliosis, it demonstrates that B. afzelii is specifically maintained by
      European rodents, validating the concept of host-association of B. burgdorferi
      s.l.

PMID- 12613760
TI  - Consequence of Hoechst 33342-mediated Leishmania DNA topoisomerase-I inhibition
      on parasite replication.
AB  - This study reports that inhibition of Leishmania Topo-I with the minor groove
      binding ligands (MGBLs) Hoechst 33342 (Ho342) blocks parasite growth in culture
      by mechanisms involving DNA breakage. While Ho342 inhibited the replication of
      several species of Leishmania in a dose- and time-dependent manner, Ho258 was not
      effective. Cytofluorometric analysis suggested that superior effectiveness of
      Ho342 over Ho258 was attributed to Leishmania parasites being more permeable
      toward Ho342. This observation was supported by the ability of both Ho342 and
      Ho258 to block the relaxation of supercoiled pBR322 DNA by Leishmania Topo-I. The
      Ho342 specificity toward L. donovani Topo-I was reinforced by the observation
      that increased Topo-I gene expression and Topo-I activity in Leishmania was
      paralleled by augmented resistance for this compound. Furthermore, the capacity
      of NaCl treatment to reverse MGBL-mediated DNA break suggests that Ho342
      targetted Topo-I. Moreover, we observed that Ho342-inducible arrest of Leishmania
      growth was accompanied by G1 arrest and induction of cell death that closely
      resembles apoptosis. Taken together, our results suggest that MGBL compounds show
      promise as Topo-I inhibitors against Leishmania infection.

PMID- 12613761
TI  - Characterization of human infection by Leishmania spp. in the Northwest of
      Argentina: immune response, double infection with Trypanosoma cruzi and species
      of Leishmania involved.
AB  - The aims of this study were to characterize human American tegumentary
      leishmaniasis, which includes cutaneous, mucocutaneous and mucosal leishmaniasis,
      in Northwest Argentina, to determine the prevalence of double infection with
      Trypanosoma cruzi and to identify the species of Leishmania in this area. Most of
      the 330 leishmaniasis patients presented cutaneous ulcers (96.1%), 2.4%
      mucocutaneous and 1.5% the mucosal form ('espundia'). The aetiological agents,
      determined by isoenzyme electrophoresis, were identified as Leishmania (Viannia)
      braziliensis in 16 out of 20 isolates and in the remaining 4 as Leishmania
      (Leishimania) amazonensis, the first ever-documented in Argentina. Sera analysed
      by ELISA and IFA using complex antigen from both T. cruzi and L. braziliensis
      showed a very high percentage of positives (66.3-78.2%). When antigens for
      specific diagnosis of Chagas' disease were used, 40.9% of the leishmaniasis
      patients were also found to be infected by T. cruzi. These results indicate that
      the strong immune response against T. cruzi gave no protection to Leishmania, in
      spite of the serological cross-reaction between these parasites. In addition, we
      showed that more than 40% of the patients would be misdiagnosed as chagasic if
      complex antigens, as epimastigotes or soluble fraction from epimastigotes, were
      used in IFA or ELISA. This is of paramount importance not only because patients'
      treatment would be associated to misdiagnosis but the fact that in many countries
      in Central and South America, a positive test for Chagas' disease means a
      rejection for those seeking employment.

PMID- 12613762
TI  - Effects of the isolation methodology on protein profiles of blood trypomastigotes
      of Trypanosoma cruzi.
AB  - Blood trypomastigotes of Trypanosoma cruzi were isolated from infected athymic
      rnu/rnu rats and purified by an improved procedure of DEAE-Sephacel ion-exchange
      chromatography. Elution into a buffer supplemented with bovine serum albumin
      avoided column-induced changes on the surface of the parasites. Biotin-labelled
      bovine serum albumin, fluorescence microscopy, flow cytometry and Western blot
      analysis revealed a very intense binding of albumin to the parasite. Incubation
      and washing of cells without protein supplementation did not result in any damage
      or lysis of parasites but it did cause extensive shedding of cellular and surface
      proteins into the supernatant which could be prevented by using the protein
      supplemented buffer. A decreasing yield of high molecular weight cellular
      proteins in relation to centrifugal force was a general phenomenon observed in
      scanning densitometry of SDS gels after isolation in either protein-supplemented
      buffer or protein-free buffer. The quantity of shed cellular components increased
      with increasing centrifugal force. In contrast, quantities of high molecular
      weight, biotin-labelled surface proteins increased with greater centrifugal
      force, indicating labelling of otherwise inaccessible residues. These data
      emphasize the importance of protein supplementation of buffers with proteins and
      of choosing low centrifugation forces (<400 g) during investigations of T. cruzi.

PMID- 12613763
TI  - Morphological changes in the reproductive organs of male and female Schistosoma
      mansoni worms caused by streptozotocin, a drug used to induce diabetes mellitus.
AB  - Host metabolic changes have been observed to affect Schistosoma mansoni egg
      production, worm survival and morphology. We examined worms recovered from
      streptozotocin-induced diabetic mice by morphometric and morphological analysis
      through brightfield and confocal laser scanning microscopy. Tegument thickness
      was slightly smaller and changes in the reproductive organs were observed in 23
      30% and consecutively 88-100% of the worms. The testicular lobes had a large
      diminution of cells in one or more of the lobes, which was associated with a lack
      of spermatozoids in the seminal vesicle. Ovaries were atrophied, manifested by a
      complete or large reduction in oocytes but other parts of the reproductive system
      like the vitelline glands were mainly unaffected. Streptozotocin (STZ) instead of
      hyperglycaemia caused the degeneration since worms from mice injected with a non
      diabetogenic dose, or with nicotinamide to prevent diabetes showed the same
      alterations. The drug did not affect worm survival or pairing. We conclude that
      STZ, an alkylating agent that provokes chromosome and DNA damage, changes the
      morphology of ovaries and testicular lobes in S. mansoni worms in vivo. This is
      the first report of STZ action in helminths and we suggest that STZ affects
      oogenesis and spermatogenesis and might cause sterilization of schistosomes.

PMID- 12613764
TI  - Detection of Opisthorchis viverrini in experimentally infected bithynid snails
      and cyprinoid fishes by a PCR-based method.
AB  - A PCR procedure for the detection of Opisthorchis viverrini in experimentally
      infected bithynid snails and cyprinoid fishes was developed. This procedure was
      based on primers designed from a pOV-A6 specific probe sequence giving a 330 base
      pair product. The detection was accomplished in host tissue homogenates to which
      a single cercaria or metacercaria was introduced. PCR can detect as little as a
      single cercaria artificially inoculated in a snail or a single metacercaria
      artificially inoculated in a fish sample. The method gave a 100% positivity rate
      for all infected snails or fishes. The method did not yield a 330 base-pair
      amplified product with other digenean fluke DNAs such as Haplorchis taichui,
      Centrocestus spp., Echinostoma malayanum, Fasciola gigantica, animal
      schistosomes, Paragonimus heterotremus or Haplorchoides spp. The assay has great
      potential for application in epidemiological surveys of both snail and fish
      intermediate hosts as well as for investigation of foodborne parasites in
      freshwater fishes.

PMID- 12613765
TI  - Occurrence of intermediate hosts and structure of digenean communities of the
      black-headed gull, Larus ridibundus (L.).
AB  - The factors contributing to the similarity between digenean parasite assemblages
      parasitizing the black-headed gull were investigated. Thirteen different digenean
      species from the digestive tract and the bursa of Fabricus were found. We
      predicted that the structure of parasite communities is not random at either
      component community or infracommunity levels. We searched for nested patterns in
      the digenean community, and explored the possible factors contributing to
      nestedness. We found that digenean species which occupy a narrow range of
      intermediate hosts are placed out of order in the nested matrix. The influence of
      several variables related to the water reservoir, geographical distances, and the
      abundance of intermediate hosts on the species diversity and similarity of
      parasite communities were tested as well. Because of the complexity in bird
      digenean life-cycles we supposed that intermediate hosts and ecological
      characters of their environment could play a major role. We showed that the
      presence of intermediate hosts is the factor limiting the qualitative and
      quantitative similarity of parasite communities among different host populations
      as well as influencing the digenean species diversity in the definitive host. The
      similarity in abundance of intermediate hosts between different localities was
      facilitated by the presence of vegetation in water reservoir and more diversified
      type of water bottom. Digenean species diversity was higher when the water
      reservoir was exposed to temporal drying. We hypothesized that this factor could
      facilitate the inclusion of molluscs infected by digeneans in the diet of birds.
      Both species diversity and dominance were influenced by the bottom type of water
      reservoir and temporal drying up. Geographical distances between localities
      influenced the quantitative similarity of digenean communities as well as species
      richness.

PMID- 12613766
TI  - The effect of the anthelmintic emodepside at the neuromuscular junction of the
      parasitic nematode Ascaris suum.
AB  - Here we report on the action of the novel cyclo-depsipeptide anthelmintic,
      emodepside, on the body wall muscle of the parasitic nematode, Ascaris suum.
      Emodepside caused (i) muscle relaxation, (ii) inhibition of muscle contraction
      elicited by either acetylcholine (ACh), or the neuropeptide, AF2 (KHEYLRFamide)
      and (iii) a rapid relaxation of muscle tonically contracted by ACh. The
      inhibitory action of emodepside on the response to ACh was not observed in a
      denervated muscle strip, indicating that it may exert this action through the
      nerve cord, and not directly on the muscle. Electrophysiological recordings
      showed emodepside elicited a Ca(++)-dependent hyperpolarization of muscle cells.
      Furthermore, the response to emodepside was dependent on extracellular K+,
      similar to the action of the inhibitory neuropeptides PF1 and PF2 (SDPNFLRFamide
      and SADPNFLRFamide). Thus emodepside may act at the neuromuscular junction to
      stimulate release of an inhibitory neurotransmitter or neuromodulator, with a
      similar action to the PF1/PF2 neuropeptides.

PMID- 12613767
TI  - On the interpretation of age-intensity profiles and dispersion patterns in
      parasitological surveys.
AB  - The present paper describes how age-intensity profiles of macroparasite burdens
      are affected by processes underlying the distribution of the parasite numbers in
      host populations. In a comparative way, we consider the following 6 processes:
      (i) age-dependent exposure, (ii) parasite-induced host mortality, (iii)
      heterogeneity within, the host population, (iv) clumped infection, (v) density
      dependent parasite mortality and (vi) density-dependent parasite establishment.
      For each of these processes, we show typical patterns in the age-intensity
      profile and provide, if possible, explicit and simple solutions for the age
      dependent mean parasite burden and the corresponding dispersion patterns.
      Emphasis is given to density-dependent parasite establishment and to age
      intensity profiles resulting from the superposition of different processes. By
      means of 2 examples we show that the interpretation of observed patterns can be
      ambiguous if more than 1 process takes place. These findings underline that age
      intensity profiles should be interpreted on the basis of available a priori
      knowledge about the processes assumed to be involved. For purposes of testing
      different hypotheses, a simulation program is provided with which discrepancies
      between model prediction and data can be explored.

PMID- 12613768
TI  - Narrative based medicine.

PMID- 12613769
TI  - Maternal fever at birth and non-verbal intelligence at age 9 years in preterm
      infants.
AB  - To test the hypothesis that characteristics of perinatal infection are associated
      with long-term cognitive limitations among preterm infants, we analyzed data from
      294 infants (142 females, 152 males) < or = 1500 g birthweight and <37 completed
      weeks of gestation who were examined at age 9 years. We identified 47 children
      (20 females, 27 males) who had a non-verbal Kaufman Assessment Battery for
      Children (K-ABC) scale standard value below 70, i.e. more than 2 SDs below the
      age-adjusted mean. The 247 children (122 females, 125 males) with a score > or =
      70 served as control participants. Maternal nationality and education, and low
      gestational age were significantly associated with a K-ABC non-verbal standard
      value <70. Both neonatal brain damage (intraventricular hemorrhage) and long-term
      sequelae (cerebral palsy [CP], diagnosed at age 6 years) were significantly
      associated with a below-normal non-verbal K-ABC score. Maternal fever at birth
      was present in five cases (11%) and eight controls (3%; odds ratio 3.6, 95%
      confidence interval 1.1 to 11.4). Clinical chorioamnionitis and preterm labor
      and/or premature rupture of membranes (as opposed to toxemia and other initiators
      of preterm delivery) were also more common among cases than control participants.
      When adjusting for potential confounders such as gestational age, maternal
      education and nationality, and CP, the risk estimate for maternal fever remained
      unchanged (3.8, 0.97 to 14.6). We conclude that perinatal infection might indeed
      contribute to an increased risk for long-term cognitive deficits in preterm
      infants.

PMID- 12613770
TI  - Assessing the impact of pediatric epilepsy and concomitant behavioral, cognitive,
      and physical/neurologic disability: Impact of Childhood Neurologic Disability
      Scale.
AB  - Epilepsy has a significant impact on a child's life, the extent to which is based
      on four factors: epilepsy, cognition, behavioral, and physical/neurologic
      function. This study evaluates the ability of the 44-item Impact of Childhood
      Neurologic Disability Scale (ICND) to assess each of these four realms. Parents
      of children (aged 2 to 18 years) with epilepsy rated their child's overall
      quality of life and completed the ICND. External validation compared the ICND
      with (1) neurologists' reports of children's behavior, cognitive abilities,
      physical/neurologic disability, and epilepsy; and (2) parents, teachers, and
      children's ratings on six 'criterion standard' questionnaires. Families of 68
      children with epilepsy only and 29 children with 'epilepsy-plus' (additional
      cognitive, behavioral, or physical/neurologic disability; 39 males, 58 females;
      mean age at testing 10 years 3 months [SD 4.5] age range 2 to 17 years)
      participated. Internal consistency was excellent (Cronbach's alpha=0.92) as was
      test-retest reliability (intraclass correlation=0.89). Caregivers distinguished
      the impact of each of the four realms. Scores were negatively related to quality
      of life (Pearson's r=-0.59). Children with high ICND scores had more difficulties
      at home and school. Their parents saw them as less rewarding and adaptable and
      the children saw themselves as less intelligent and less popular with more
      emotional problems. In addition, children with 'epilepsy-plus' had significantly
      higher total ICND scores as well as markedly elevated scores within each of the
      four realms when compared with the epilepsy-only group. It is concluded that the
      ICND is an accurate, quick measurement tool reflecting the impact of behavior,
      cognitive learning ability, physical/neurologic disability, and epilepsy on
      children and their families.

PMID- 12613771
TI  - Hemispatial neglect in young children with early unilateral brain damage.
AB  - Hemispatial neglect is commonly observed in adults following right-hemisphere
      brain lesions. Given the potential for reorganization in the developing brain,
      spatial neglect may not be apparent following early unilateral damage. This study
      aimed to determine whether infants who experienced pre- or perinatal focal brain
      lesions showed evidence of spatial neglect. Study participants were 33
      infants/toddlers (22 males, 11 females; age range 6 to 48 months); 27 preschool
      children (14 males, 13 females; age range 28 to 75 months) with either left
      hemisphere (LH) or right hemisphere (RH) damage of pre- or perinatal onset (total
      60), and 36 control individuals (15 females, 21 males; age range 28 to 75
      months). Participants were assessed using two object-removal preference tasks.
      Control children showed no lateralized preference for object removal. Those with
      LH or RH damage preferentially removed objects from the side of the board
      ipsilateral to the lesion first and the contralateral side last. These results
      suggest that spatial neglect may be found in young children even after very early
      unilateral brain damage. Further, in contrast to the adult pattern, contralateral
      neglect is present for up to 6 years after either LH or RH damage. This pattern
      suggests that there may be a different distribution of attention to space in the
      developing brain as compared with the mature brain. The persistence of spatial
      neglect suggests that there are some limitations on plasticity in the developing
      human brain.

PMID- 12613773
TI  - Behavioural and emotional characteristics in children with Sotos syndrome and
      learning disabilities.
AB  - In contrast to physical characteristics, the developmental and behavioural
      characteristics of children with Sotos syndrome are not well documented. Data
      from a survey of 27 children (17 males and 10 females; mean age 10 years 7
      months; range 6 to 15 years) with mild and moderate learning disabilities were
      obtained concerning school placement, social networks, adaptive competence, and
      behavioural problems and compared with a control group matched for cognitive
      level and age. Ten children attended a mainstream school (with remedial
      assistance), eight were placed in a school for children with learning
      disabilities, nine children attended other special schools. Social contact
      problems and anxious behaviour were reported as the most prominent
      characteristics of children with Sotos syndrome. Some implications for
      psychological counselling and educational support are discussed.

PMID- 12613772
TI  - Modes and patterns of self-mutilation in persons with Lesch-Nyhan disease.
AB  - Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder
      associated with cognitive impairment, choreoathetosis, hyperuricemia, and the
      hallmark symptom of severe and involuntary self-mutilation. This study examines
      data gathered from a survey of 64 families in the USA and abroad regarding the
      self-injury of their family members who have LND. The individuals with LND ranged
      in age from 1 to 40 years (mean 16 years 7 months, SD 11 years 2 months) and,
      with the exception of one, were males. The most common initial mode of self
      mutilation, and the most frequently cited past or current behavior, was biting of
      lips and/or fingers. Other behaviors, in order of frequency, included head
      banging, extension of arms when being wheeled through doorways, tipping of
      wheelchairs, eye-poking, fingers in wheelchair spokes, and rubbing behaviors.
      Hierarchical cluster analysis identified patterns of association among the types
      of self-mutilation. Modes of self-mutilation in which external surfaces (such as
      a wheelchair component) served as instruments of self-injury tended to co-occur,
      as did biting of lips and fingers.

PMID- 12613774
TI  - Behavioural phenotype in foetal alcohol syndrome and foetal alcohol effects.
AB  - A sample of 12 children (seven males, five females; mean age 6 years 7 months, SD
      2 years 6 months, range 2 years 4 months to 12 years 1 month) with moderate-to
      severe foetal alcohol syndrome (FAS) and another sample of 26 children (12 males,
      14 females; mean age of 6 years 2 months SD 2 years 10 months, range 2 years 6
      months to 12 years 8 months) with mild FAS or foetal alcohol effects (FAE) as
      well as a sample of 15 age- and sex-matched control children with unspecific
      intellectual disability were compared using the Developmental Behaviour Checklist
      (DBC). There were significant differences (p=0.01) between the groups on five of
      six subscales of the DBC with controls scoring lower on the disruptive, self
      absorbed, anxiety, antisocial behaviour, and communication disturbance scales.
      The DBC profiles of the two foetal alcohol exposed groups did not differ from
      each other. It is concluded that quantitative behaviour measurement provides
      insights into specific behavioural phenotypes of FAS/FAE.

PMID- 12613775
TI  - Why parents of children with neurodevelopmental disabilities requiring
      gastrostomy feeding need more support.
AB  - This was a qualitative research study of parental perceptions of gastrostomy
      feeding before surgery using an in-depth interview in the parental home to
      examine the factors parents consider when gastrostomy feeding is recommended and
      to identify the need for support. Participants were a subgroup of families taking
      part in a larger research study evaluating gastrostomy placement in children with
      severe neurodevelopmental disabilities at a major paediatric centre in the UK
      between 1998 and 2000. Parents of 22 children (13 males, nine females; mean age 4
      years 8 months [SD 3 years 6 months]; age range 1 year 1 month to 13 years 3
      months) were interviewed. Categories of disability were: cerebral palsy (n=10), a
      syndrome of chromosomal or genetic origin (n=10), and unconfirmed diagnoses
      (n=2). Thirteen children were recommended for a gastrostomy and seven were
      recommended for a gastrostomy with an antireflux procedure. Four families were
      undecided about surgery at the time of the interview, two of whom went ahead with
      the procedure some time later. Parental accounts of oral and tube feeding were
      both contradictory and ambivalent. Concerns about the loss of oral feeding, which
      was regarded as having a range of psychosocial effects for the child and family,
      were raised. Both oral and tube feeding have multiple meanings for parents and
      signify more than obtaining an adequate nutritional intake. The need for
      additional information about the risks and benefits of gastrostomy and how tube
      feeding fits into the context of everyday life were dominant themes. The
      biomedical emphasis on health and weight-gains may fail to reflect parental
      concerns about tube and oral feeding. There is a need for greater practical and
      emotional support for families feeding children with severe disabilities.

PMID- 12613776
TI  - Uptime normative values in children aged 8 to 15 years.
AB  - The 'Uptimer' is a custom-made lightweight battery-operated remote activity
      monitor that records the amount of time an individual spends in the upright
      position, which is also known as 'uptime'. The aims of this study were to
      determine levels of uptime over 24 hours and the relation between uptime and a
      child's age, sex, height, weight, and body mass index (BMI). Uptime was recorded
      in 529 normally developing children (318 females, 211 males), aged between 8 and
      15 years. All children wore an Uptimer continuously for a 24-hour period that
      included a typical school day. Mean uptime for children in this study was 5.4
      hours (SD 1.3; range 1.5 to 10.3 hours), over a 24-hour period. Uptime followed
      approximately a normal distribution in this population and did not have a linear
      relation to age, height, weight, nor BMI. Results of this study may be used as a
      normative database for the evaluation of uptime in children with physical
      disabilities.

PMID- 12613777
TI  - Health status of Australian children with mild to severe cerebral palsy: cross
      sectional survey using the Child Health Questionnaire.
AB  - The aim of this study was to describe child health and well-being across the
      spectrum of cerebral palsy (CP) and to report on psychometric properties of the
      Child Health Questionnaire (CHQ) in this population. Parents of 80 individuals
      (45 males, 35 females; mean age 11 years 4 months, SD 3 years 6 months; range 5
      to 18 years) attending a CP clinic in Victoria, Australia were surveyed. Measures
      included the CHQ PF-50, a 50-item parent-reported heath status measure; severity
      of CP, based on the Gross Motor Function Classification System; and cognitive
      status and presence of epilepsy. CHQ data were compared with normative data
      collected in Victoria two years earlier. The CHQ demonstrated good psychometric
      properties for children with CP. Children with CP had markedly poorer health on
      every CHQ scale than those in the normative sample. Health status did not vary by
      cognitive status or epilepsy. Children with severe CP had the poorest physical
      health, but psychosocial health and emotional impact on parents were similar for
      mild and severe CP showing that these should not be assumed to be less prevalent
      when CP is mild.

PMID- 12613778
TI  - Effect of muscle activity and botulinum toxin dilution volume on muscle
      paralysis.
AB  - The purpose of this study was to evaluate the effects of botulinum toxin A (BTX
      A, Botox) dilution volume and post-injection exercise with electrical stimulation
      on muscle paralysis. We injected 10 units of BTX-A diluted with 0.1 ml (B1, n=8)
      or 0.5 ml (B5, n=8) normal saline into both gastrocnemius muscles of 16 New
      Zealand white rabbits; two controls received no BTX-A. After BTX-A injection, all
      rabbits received calf muscle stretching exercise and electrical stimulation for 2
      hours on the left leg. The compound muscle action potential (CMAP) decrease was
      most pronounced at 1 week and progressive recovery was observed (i.e. recovery
      from paralysis, increase of CMAP). There was a significant decrease of CMAP
      amplitudes in the B5 group compared with the B1 group at week 1 and week 4
      (p<0.001). Left limbs with stretching exercise and electrical stimulation showed
      lower CMAP amplitudes compared with control right limbs of all rabbits. To
      maximize the muscle paralysis effect of BTX-A, increasing dilution volume and
      performing post-injection stretching exercise with electrical stimulation may be
      a promising strategy for increasing the beneficial effect of BTX-A treatment.
      Future studies are needed to investigate the clinical application of this
      finding.

PMID- 12613779
TI  - Comorbid Asperger and Tourette syndromes with localized mesencephalic,
      infrathalamic, thalamic, and striatal damage.
AB  - We describe the coexistence of Asperger and Tourette syndromes (AS and TS) caused
      by discrete hypoxic-ischaemic necrosis of the midbrain, infrathalamic and
      thalamic nuclei, and striatum in an adolescent male with positive family history
      for tics and obsessive-compulsive disorder. Behavioural ratings, cognitive tests,
      and volumetric measurements of the basal ganglia were performed in the patient
      and five other individuals with AS-TS unassociated with MRI lesions. Cognitive
      deficits in attentional, executive, and visual-spatial domains were found both in
      the patient and control AS-TS group, though deficits were more severe in the
      former. MRI showed reduction of the left basal ganglia volume compared with the
      right in the patient, whereas the control group showed reduction of right basal
      ganglia volume compared with the left. It is suggested that individuals with a
      genetic predisposition to TS may develop AS and TS after involvement of midbrain
      and related components of basal ganglia-thalamocortical circuits normally
      implicated in the integration of emotional, cognitive, and motor functions.

PMID- 12613780
TI  - Hyperbaric oxygen and cerebral palsy: no proven benefit and potentially harmful.

PMID- 12613781
TI  - Inverted faces.

PMID- 12613782
TI  - A sideways look at configural encoding: two different effects of face rotation.
AB  - Inversion has a disproportionate disruptive effect on the recognition of faces.
      This may be due to the disruption of holistic or configural encoding employed to
      recognise upright faces. The paradigm developed by Tanaka and Farah (1993
      Quarterly Journal of Experimental Psychology, Section A 46 225-246) was used to
      investigate the effect of 90 degrees (or orthogonal) rotation on configural
      encoding. Faces learnt in the orthogonal condition were not recognised as well as
      upright faces, but a whole-face advantage was found in both cases. This whole
      face advantage did not occur for inverted faces. It appears that 90 degrees
      rotation affects recognition but not specifically configural encoding. It is
      concluded that rotating a face can have at least two different effects on face
      processing depending on the range of rotation. Implications for the nature of
      facial dimensions and the expertise account of the inversion effect are
      considered.

PMID- 12613783
TI  - Attending to faces: change detection, familiarization, and inversion effects.
AB  - We tested detection of changes to eye position, eye color (brightness), mouth
      position, and mouth color in frontal views of faces. Two faces were presented
      sequentially for 555 ms each, with a blank screen of 120 ms separating the two.
      Faces were presented either both upright or both inverted. Measures of detection
      (d') were calculated for several different degrees of change for each of the four
      dimensions of change. We first compared results to an earlier experiment that
      used an oddity design, in which subjects indicated which of three simultaneously
      viewed and otherwise identical faces had been altered on one of these four
      dimensions. Subjects in both of these experiments were partially cued, in that
      they knew the four possible types of changes that could occur on a given trial.
      The change-detection results correlated well with the oddity data. They confirmed
      that face inversion had little effect upon detection of changes in eye color, a
      moderate effect upon detection of eye-position or mouth-color changes, and caused
      a drastic reduction in the detection of mouth-position changes. An experiment in
      which uncued and fully cued subjects were compared showed that cueing
      significantly improved detection of feature color changes, but there was little
      difference between upright and inverted faces. Full cueing eliminated all effects
      of inversion. Compared to partial cueing, changes in mouth color were poorly
      detected by uncued subjects. Last, a change in the frequency of the base
      (unaltered) face in an experiment from 75% to 40% showed that increased short
      term familiarity decreased the detection of eye changes and increased the
      detection of mouth changes, regardless of face orientation and the type of change
      made (color or position). We conclude that uncued subjects encode the spatial
      relations of features more than the colors of features, that mouth color in
      particular is not considered a relevant dimension for encoding, and that
      familiarization redistributes attention from more to less salient facial regions.
      Inversion effects are not simply an exaggeration of the salience effects revealed
      by withdrawing cueing, but represent an interaction of spatial encoding with
      salience, in that the greatest inversion effects occur for spatial shifts in less
      salient facial regions, and can be eliminated through the use of focused
      attention.

PMID- 12613784
TI  - Cue gradient and cue density interact in the detection and recognition of objects
      defined by motion, contrast, or texture.
AB  - The human visual system is able to extract an object from its surrounding using a
      number of cues. These include foreground/background gradients in disparity,
      motion, texture, colour, and luminance. We have investigated normal subjects'
      ability to detect objects defined by either motion, texture, or luminance
      gradients. The effects of manipulating cue density and cue foreground/background
      gradient on both detection and recognition accuracy were also investigated. The
      results demonstrate a simple additive relationship between cue density and cue
      gradient across forms defined by motion, luminance, and texture. The results are
      interpreted as evidence for the notion that form parsing is achieved via a
      similar algorithm across anatomically distinct processing streams.

PMID- 12613786
TI  - Information regarding structure and lightness based on phenomenal transparency
      influences the efficiency of visual search.
AB  - Phenomenal transparency reflects a process which makes it possible to recover the
      structure and lightness of overlapping objects from a fragmented image. This
      process was investigated by the visual-search paradigm. In three experiments,
      observers searched for a target that consisted of gray patches among a variable
      number of distractors and the search efficiency was assessed. Experiments 1 and 2
      showed that the search efficiency was greatly improved when the target was
      distinctive with regard to structure, based on transparency. Experiment 3 showed
      that the search efficiency was impaired when a target was not distinctive with
      regard to lightness (ie perceived reflectance), based on transparency. These
      results suggest that the shape and reflectance of overlapping objects when
      accompanied by transparency can be calculated in parallel across the visual
      field, and can be used as a guide for visual attention.

PMID- 12613787
TI  - Correlation between stereoanomaly and perceived depth when disparity and motion
      interact in binocular matching.
AB  - The aim of this study was to find out to what extent binocular matching is
      facilitated by motion when stereoanomalous and normal subjects estimate the
      perceived depth of a 3-D stimulus containing excessive matching candidates.
      Thirty subjects viewed stimuli that consisted of bars uniformly distributed
      inside a volume. They judged the perceived depth-to-width ratio of the volume by
      adjusting the aspect ratio of an outline rectangle (a metrical 3-D task).
      Although there were large inter-subject differences in the depth perceived, the
      experimental results yielded a good correlation with stereoanomaly (the inability
      to distinguish disparities of different magnitudes and/or signs in part of the
      disparity spectrum). The results cannot be explained solely by depth-cue
      combination. Since up to 30% of the population is stereoanomalous, stereoscopic
      experiments would yield more informative results if subjects were first
      characterized with regard to their stereo capacities. Intriguingly, it was found
      that motion does not help to define disparities in subjects who are able to
      perceive depth-from-disparity in half of the disparity spectrum. These
      stereoanomalous subjects were found to rely completely on the motion signals.
      This suggests that the perception of volumetric depth in subjects with normal
      stereoscopic vision requires the joint processing of crossed and uncrossed
      disparities.

PMID- 12613785
TI  - Endogenous shifts of covert attention operate within multiple coordinate frames:
      evidence from a feature-priming task.
AB  - The locations of visual objects and events in the world are represented in a
      number of different coordinate frameworks. For example, a visual transient is
      known to attract (exogenous) attention and facilitate performance within an
      egocentric framework. However, when attention is allocated voluntarily to a
      particular visual feature (ie endogenous attention), the location of that feature
      appears to be variously encoded either within an allocentric framework or in a
      spatially invariant manner. In three experiments we investigated the importance
      of location for the allocation of endogenous attention and whether egocentric
      and/or allocentric spatial frameworks are involved. Primes and targets were
      presented in four conditions designed to vary systematically their spatial
      relationships in egocentric and allocentric coordinates. A reliable effect of
      egocentric priming was found in all three experiments, which suggests that
      endogenous shifts of attention towards targets defined by a particular feature
      operate in an egocentric representation of visual space. In addition, allocentric
      priming was also found for targets primed by their colour or shape. This suggests
      that attending to targets primed by nonspatial attributes results in facilitation
      that is localised in more than one coordinate frame of spatial reference.

PMID- 12613788
TI  - Aging and the perception of speed.
AB  - Two experiments were conducted to explore the potential effects of aging upon the
      perception and discrimination of speed. In the first experiment, speed difference
      thresholds were obtained for younger and older observers for a variety of
      standard speeds ranging from slow to fast. The second experiment was designed to
      evaluate the observers' ability to discriminate differences in the speed of
      moving patterns in the presence of significant amounts of noise (the noise was
      manipulated by limiting the lifetimes of individual moving stimulus elements).
      The results of both experiments revealed a significant deterioration in the
      ability of the older observers to perceive or detect differences in speed. While
      the presence of noise was found to affect the observers' discrimination
      performance, it affected both younger and older observers' thresholds in a
      proportionally equivalent manner-the older observers were no more affected by
      noise than the younger observers.

PMID- 12613789
TI  - Coherent perspective jitter induces visual illusions of self-motion.
AB  - Palmisano et al (2000 Perception 29 57-67) found that adding coherent perspective
      jitter to constant-velocity radial flow improved visually induced illusions of
      self-motion (vection). This was a surprising finding, because unlike pure radial
      flow, this jittering radial flow should have generated sustained visual-
      vestibular conflicts--previously thought to always reduce/impair vection. We
      attempted to ascertain the essential stimulus features for this jitter advantage
      for vection by examining three novel types of jitter display. While adding
      incoherent jitter to radial flow was found to impair vection, adding coherent non
      perspective jitter had little effect on this subjective experience (contrary to
      the notion that jitter improves vection by reducing adaptation to radial flow).
      Importantly, we found that coherent perspective jitter not only improves the
      vection induced by radial flow, but it also appears to induce modest vection by
      itself (demonstrating that vection can still occur when there is an extreme
      mismatch between actual and expected vestibular activity). These results suggest
      that the previously demonstrated advantage for coherent perspective jitter was
      due (in part at least) to jittering vection combining with forwards vection in
      depth to produce a more compelling overall vection experience.

PMID- 12613790
TI  - Hearing foreign voices: does knowing what is said affect visual-masked-speech
      detection?
AB  - We investigated audio-visual (AV) perceptual integration by examining the effect
      of seeing the speaker's synchronised moving face on masked-speech detection
      ability. Signal amplification and higher-level cognitive accounts of an AV
      advantage were contrasted, the latter by varying whether participants knew the
      language of the speaker. An AV advantage was shown for sentences whose mid-to
      high-frequency acoustic envelope was highly correlated with articulator movement,
      regardless of knowledge of the language. For low-correlation sentences, knowledge
      of the language had a large impact; for participants with no knowledge of the
      language an AV inhibitory effect was found (providing support for reports of a
      compelling AV illusion). The results indicate a role for both sensory enhancement
      and higher-level cognitive factors in AV speech detection.

PMID- 12613791
TI  - An application of the Muller-Lyer illusion.

PMID- 12613792
TI  - Thermodynamics and kinetics of solute transfer in reversed-phase liquid
      chromatography.
AB  - In this study, the thermodynamic and kinetic behavior of a homologous series of
      fatty acids is examined using a polymeric octadecylsilica stationary phase and a
      methanol mobile phase. The zone profiles are evaluated as the temperature is
      varied from 20 to 60 degrees C and the average pressure from 400 to 4570 p.s.i.
      (1 p.s.i.=6894.76 Pa). The rate constant for solute transfer from mobile to
      stationary phase (k(ms)) appears to be relatively constant with carbon number. In
      contrast, the rate constant from stationary to mobile phase (k(sm)) decreases
      logarithmically with increasing carbon number. This suggests that the mass
      transport processes become progressively slower, owing to the smaller diffusion
      coefficients of the larger solutes in the stationary phase. The activation energy
      decreases slightly in the mobile phase and increases slightly in the stationary
      phase with increasing carbon number. The activation energy in the stationary
      phase ranges from 41.6 to 55.9 kcal/mol, while the thermodynamic change in
      internal energy ranges from -9.8 to -29.0 kcal/mol for C10 to C22, respectively
      (1 cal=4.184 J). The activation volume increases with increasing carbon number in
      both the mobile and stationary phase. The activation volume in the stationary
      phase ranges from 31.7 to 211 cm3/mol, while the thermodynamic change in molar
      volume ranges from -27.1 to -104 cm3/mol for C10 to C22, respectively. These
      large changes in activation energy and volume suggest that the solutes do not
      enter and leave the stationary phase in a single step, but in a stepwise or
      progressive manner.

PMID- 12613793
TI  - Comparison of peak shapes obtained with volatile (mass spectrometry-compatible)
      buffers and conventional buffers in reversed-phase high-performance liquid
      chromatography of bases on particulate and monolithic columns.
AB  - Retention factor, column efficiency and asymmetry factor were recorded for nine
      basic compounds on a number of RP-HPLC columns using phosphate and a variety of
      (MS-compatible) volatile mobile phase buffers of acid and neutral pH, in order to
      assess any effects of the buffer on performance. With formic or acetic acid, some
      phases gave partial or complete solute exclusion effects (reduced or negative k)
      compared with results using phosphate buffers at low pH. Despite its possible
      suppression of mass spectrometer sensitivity, trifluoroacetic acid was useful in
      enhancing retention times of relatively hydrophilic protonated bases, due to ion
      pair effects. Peak shape was relatively poor on some pure silica-based ODS phases
      at pH 7 compared with results at acid pH. At low pH and at pH 7, ammonium and
      potassium phosphate gave very similar k, but the former may be preferable due to
      its volatile cation. Improved peak shapes, attributed to superior silanol masking
      effects, were obtained with ammonium phosphate at pH 7, but not at acid pH.
      Ammonium acetate gave acceptable peak shape at pH 7, but due to very limited
      buffer capacity, poor results were obtained for solutes having a pKa close to the
      mobile phase pH. Due to its instability, ammonium hydrogen carbonate is not a
      viable alternative buffer at pH 7.

PMID- 12613794
TI  - Predictive approaches to gradient retention based on analyte structural
      descriptors from calculation chemistry.
AB  - Quantitative structure retention relationships (QSRRs) were applied to predict
      reversed-phase HPLC gradient retention. The performance of the recently
      recommended QSRR models was compared. One tested model is based on structural
      descriptors from molecular modeling. To quantitatively characterize the structure
      of analytes the following three structural descriptors are employed: total dipole
      moment, electron excess charge of the most negatively charged atom and water
      accessible molecular surface area. Reliability of the resulting gradient
      retention time predictions was compared to that provided by the models relating
      retention to the theoretically calculated logarithm of n-octanol-water partition
      coefficient, log P. The requested values of log P were obtained using three
      commercially available softwares. The predicted retention parameters were
      compared for a series of structurally diversified small molecular mass analytes.
      It has been demonstrated that the retention predictions from both the molecular
      modeling descriptors-based and the log P-based QSRR are characterized by similar
      errors. It has been hypothesized that the optimization of separation based on
      QSRRs and the linear solvent strength theory might be of practical analytical
      value.

PMID- 12613795
TI  - Experimental Van Deemter plots of shear-driven liquid chromatographic separations
      in disposable microchannels.
AB  - We present a new stationary phase coating method, yielding a monolayer of densely
      arrayed porous HPLC beads (d(p)=4 microm) for use in a disposable shear-driven
      flow LC system. The system is inherently suited for whole-column detection
      through the small voids between the individual particles of the layer. The
      chromatographic performance of the system has been characterized by performing a
      series of coumarin dye separation experiments (reversed-phase mode) and by
      measuring the theoretical plate height as a function of the mobile phase
      velocity. The resulting Van Deemter curve, yielding a value of about 90,000
      plates/m near the u=u(opt) velocity, shows good agreement with the theoretical
      expectations, and hence constitutes the first full validation of the theory of
      shear-driven chromatography.

PMID- 12613796
TI  - Potassium and sodium chloride ion pairs are presumed to constitute a complex
      during elution from a Sephadex G-15 column with sodium phosphate buffer.
AB  - When a mixed solution of 0.72 M potassium and sodium chloride was eluted from a
      Sephadex G-15 column with 0.025 M sodium phosphate buffer (pH 7.0), the elution
      profiles of ions showed that the potassium and chloride ion pair from the sample
      and the sodium and chloride ion pair produced by ion-exchange reaction, were
      eluted in the same fractions as if they constituted a complex. When a mixed
      solution of different concentrations of potassium and sodium chloride was eluted
      with the same buffer, the excess amount of one ion pair over the other was eluted
      freely from the presumed complex.

PMID- 12613797
TI  - Validation of high-performance liquid chromatography methods for pharmaceutical
      analysis. Understanding the differences and similarities between validation
      requirements of the US Food and Drug Administration, the US Pharmacopeia and the
      International Conference on Harmonization.
AB  - One of the most critical factors in developing pharmaceutical drug substances and
      drug products today is ensuring that the HPLC analytical test methods that are
      used to analyze the products generate meaningful data. The US Food and Drug
      Administration (FDA) and United States Pharmacopeia (USP) have each recognized
      the importance of this to the drug development process and have separately
      increased validation requirements in recent years. A third source, the
      International Conference on Harmonization (ICH), has added requirements that,
      when combined with the previous two sources, have led to three different sets of
      validation requirements leaving the industry in a state of confusion. This paper
      is written to clear up the confusion over the validation requirements that are
      presented by each of these three sources.

PMID- 12613798
TI  - Hypercrosslinked polystyrene as a novel type of high-performance liquid
      chromatography column packing material. Mechanisms of retention.
AB  - An experimental material, Chromalite 5HGN (Purolite, UK), that represents
      hypercrosslinked polystyrene as a new type of neutral stationary phase for HPLC
      was examined. The material contains no functional groups, but is compatible with
      any kind of nonpolar and highly polar mobile phase, and even with water. It is
      chemically resistant and thermally stable. When using aqueous organic mobile
      phases, Chromalite 5HGN works similar to standard C18 reversed-phase packings,
      but is characterized by much greater hydrophobicity and, sometimes, unusual
      selectivity. When using nonpolar mobile phases, i.e. under "quasi normal-phase"
      conditions, the retention is mostly governed by the interactions between pi
      electronic systems of the adsorbent and adsorbate. Adding highly polar, even
      hydrophilic solvents into the mobile phase, leads to a shift of retention times
      toward the "reversed-phase" kind of chromatography, which gives an additional
      possibility in fine tuning the column selectivity.

PMID- 12613799
TI  - Preparation of a polybutadiene stationary phase immobilized by gamma radiation
      for reversed-phase high-performance liquid chromatography.
AB  - Polybutadiene (PBD) has been immobilized on HPLC silica by gamma radiation doses
      in the range from 5 to 180 kGy. Columns prepared from these reversed-phase
      materials, as well as from similar non-irradiated materials, were tested with
      standard sample mixtures and characterized by elemental analysis (% C) and
      infrared spectroscopy. A low dose of 5 kGy is sufficient to produce a layer of
      immobilized PBD which functions as an efficient and stable stationary phase.
      Higher doses give thicker immobilized layers having less favorable
      chromatographic properties.

PMID- 12613800
TI  - Chromatographic evaluation of self-immobilized stationary phases for reversed
      phase liquid chromatography.
AB  - The preparation of stationary phases for HPLC using polymers deposited on silica
      usually includes an immobilization step involving cross-linking by free radicals
      induced by ionizing radiation or by other radical initiators. The present paper
      reports changes which occur at ambient temperature in the character of
      poly(methyloctylsiloxane) deposited on porous silica particles as a function of
      the time interval between particle loading and column packing. Column performance
      and retention factors increase with time and these changes are attributed to
      rearrangement (self-assembly) which result in "self-immobilization" of the
      polymer molecules on the silica surface.

PMID- 12613801
TI  - High-performance liquid chromatographic stationary phases based on
      poly(methyloctylsiloxane) immobilized on silica. III. Stability evaluations.
AB  - Several reversed-phase materials for high-performance liquid chromatography were
      obtained by deposition of poly(methyloctylsiloxane) (PMOS) on HPLC silica
      particles, followed by immobilization using different procedures. Each phase had
      characteristic physicochemical and chromatographic properties. The present work
      evaluates the stability of these phases with both neutral and basic mobile
      phases. All of the stationary phases were quite stable to neutral mobile phase,
      with less stability at higher pH. However, one thermally immobilized phase
      presented high stability even at an elevated temperature with a pH 10.0 mobile
      phase.

PMID- 12613802
TI  - Preparation of a molecularly imprinted polymer for the solid-phase extraction of
      scopolamine with hyoscyamine as a dummy template molecule.
AB  - Molecularly imprinted polymers (MIPs) selective for scopolamine were produced
      using hyoscyamine (a close structural analogue) as template molecule. The
      produced polymers were used as media for solid-phase extraction, exhibiting
      selective binding properties for the analyte from biological samples. Human and
      calf urine and serum were processed on the MIP under various extraction
      protocols. The best performance was observed after loading the analyte in aqueous
      environment facilitating retention on the MIP by non-selective hydrophobic
      interactions. The MIPs were subsequently washed using an optimised solvent system
      to enable selective desorption of the analyte. Other related and non-related
      compounds were accessed to evaluate molecular recognition properties. Recoveries
      of up to 79% were achieved for the analyte of interest from biological samples.

PMID- 12613804
TI  - Characterization of a novel diol column for high-performance liquid
      chromatography.
AB  - For the investigation of a diol phase (Inertsil Diol column) in hydrophilic
      interaction chromatography, urea, sucrose and glycine were used as test
      compounds. The chromatographic conditions were investigated for optimal column
      efficiency. The column temperature used in common reversed-phase liquid
      chromatography could also be used for the separation and the flow-rate should be
      adjusted to 0.3-0.5 ml/min to optimize column efficiency. It is suggested that
      the velocity of the hydrophilic interaction is slower than the hydrophobic
      interaction in RPLC. The addition of trifluoroacetic acid is effective for the
      retention of glycine, but ineffective for urea and sucrose. The diol phase
      exhibited sufficient chemical stability even if exposed to water in high
      percentage, and could be applied with isocratic elution for the
      separation/analysis of amino acids and glucose.

PMID- 12613803
TI  - Comparison of monomeric and polymeric chiral stationary phases.
AB  - Two-type polymeric chiral stationary phases (pCSPs) were prepared by surface
      grafting of chiral acryl-type monomers on a silica gel surface modified with 3
      (trimethoxysilyl)propylmethacrylate. The prepared pCSPs were characterized by IR,
      Fr-Raman, scanning electron microscopy, and elemental analysis. In addition, two
      type monomeric chiral stationary phases (mCSPs) were also prepared. The racemic
      analytes were separated using the prepared mCSPs and pCSPs. The separation factor
      (alpha) and capacity factor (k1) of the racemic analytes for the pCSP and mCSP
      were compared. The alpha and k1 values of the mCSP were higher than those of the
      pCSP.

PMID- 12613805
TI  - New generation of sterically protected C18 stationary phases containing embedded
      urea groups for use in high-performance liquid chromatography.
AB  - New monofunctional C18 urea stationary phases with sterically protecting dimethyl
      and diisopropyl groups were prepared by a single step modification process.
      ProntoSil spherical silica (3 microm) was chemically modified with the
      monofunctional ethoxysilanes, [(3-octadecylurea)propyl]dimethyl and [(3
      octadecylurea)propyl]diisopropyl ethoxysilanes. The phases were characterized by
      elemental analysis, infrared and solid-state 29Si and 13C NMR spectroscopies.
      Chromatographic characterizations of the new phases in 50x3.9 mm HPLC columns
      were performed by the separation of two different test mixtures, containing
      nonpolar, polar and highly basic compounds.

PMID- 12613806
TI  - Evaluation of the applicability and the stability of a C18 stationary phase
      containing embedded urea groups.
AB  - Chromatographic evaluations of a new C18 urea phase in 150x3.9 mm HPLC columns,
      involving the separation of different test mixtures, indicate good performance
      for both polar and basic compounds when compared with a commercial C18 reversed
      phase and also show promising results for the separation of some herbicides. An
      aging study was performed by passing a potassium phosphate mobile phase buffered
      at pH 7 through 50x3.9 mm HPLC columns. The column stability was evaluated by
      means of the chromatographic parameters obtained for the separation of some
      compounds of the Neue test mixture, containing apolar, polar and highly basic
      analytes. The applicability of the new C18 urea phase was evaluated with a
      herbicide mixture.

PMID- 12613807
TI  - Titanium(IV) tungstosilicate and titanium(IV) tungstophosphate: two new inorganic
      ion exchangers.
AB  - Crystalline phases of Ti(IV) tungstosilicate and Ti(IV) tungstophosphate have
      been synthesised. The ion-exchange capacities of Ti(IV) tungstosilicate and
      Ti(IV) tungstophosphate have been reported as 0.44 and 0.80 mequiv./g,
      respectively. Both materials show monofunctional ion-exchange characteristic and
      are stable in 0.1 M solutions of HNO3, HCl, H2SO4 and acetone and benzene. Ti(IV)
      tungstosilicate is found to be more stable thermally than Ti(IV) tungstophosphate
      (loss in ion-exchange capacity was found as 58 and 80%, respectively for samples
      heated at 200 degrees C). The Kd values for heavy metals such as Pb, Hg, Cd, Sb,
      Co, Zn, Ni, Fe, Cr etc. have been reported in demineralised water and two
      surfactant media by batch processes. Cr3+, Fe3+ and Sn4+ are totally adsorbed on
      both the materials in demineralised water while a decrease in Kd value with
      increase in concentration of two surfactants is reported. On the basis of Kd
      values for metal ions, thirteen binary separations and five ternary separations
      on Ti(IV) tungstosilicate and thirteen different binary separations and four
      different ternary separations on Ti(IV) tungstophosphate have been achieved.
      Separation of methylamine from ethylamine has been done by GC on a column packed
      with Ti(IV) tungstophosphate.

PMID- 12613808
TI  - Temperature influence on the dynamic binding capacity of a monolithic ion
      exchange column.
AB  - This work investigates the influence of temperature on the binding capacity of
      bovine serum albumin (BSA), soybean trypsin inhibitor and L-glutamic acid to a
      CIM (DEAE) weak anion-exchange disk monolithic column. The binding capacity was
      determined experimentally under dynamic conditions using frontal analysis. The
      effect on the dynamic binding capacity of dimers present in the BSA solution has
      been evaluated and a closed-loop frontal analysis was used to determine the
      equilibrium binding capacities. The binding capacity for both BSA and soybean
      trypsin inhibitor increased with increasing temperature. In the case of L
      glutamic acid, an increase in the binding capacity was observed with temperature
      up to 20 degrees C. A further increase in temperature caused a decrease of the
      dynamic binding capacity.

PMID- 12613809
TI  - Reversed-phase liquid chromatography of biologically active lipophilic chelators.
      II. Improvement of chromatographic performance and selected applications in
      biochemical analysis.
AB  - Lipophillic derivatives of strong calcium chelator BAPTA--DP-b99 and DP-109--are
      potential drug substances for cerebrovascular and neurodegenerative diseases. The
      previously published reversed phase HPLC methods for these compounds suffered
      from integration problems due to gradient dip, insufficient repeatability and
      peak shape. A C4 column rapidly aged. The addition of acetic acid to the organic
      part and of ammonium acetate to the aqueous part results in more symmetric peaks,
      improves method precision and solves integration problems. Washing the column in
      both directions with a combination of methanol, tetrahydrofuran and water extends
      its use. The improved methods are sensitive, selective, reproducible, and
      stability indicating. Impurities and degradation products were identified by LC
      MS. Versatile detection techniques can be used with these HPLC methods, allowing
      performance of bioanalysis with mass spectrometric or flow scintillation
      detectors. The bioanalytical application of these methods is illustrated by
      examples of pharmacokinetic and metabolic studies with the labeled compounds.

PMID- 12613810
TI  - Use of an on-line, precolumn photochemical reactor in high-performance liquid
      chromatography of naphthodianthrones in Hypericum perforatum preparations.
AB  - A method has been developed for the determination of naphthodianthrones in
      Hypericum perforatum L. extracts and phytopharmaceutical preparations by high
      performance liquid chromatography combined with on-line, precolumn photochemical
      conversion followed by photodiode-array detection. The chromatographic separation
      was performed on a C18 column under isocratic reversed-phase conditions. An on
      line, precolumn photochemical reactor equipped with a knitted PTFE reaction coil
      around a visible light source was used in order to transform the light sensitive
      naphthodianthrones, protohypericin and protopseudohypericin, very easily into the
      non-protoforms, hypericin and pseudohypericin, respectively. Two UV chromatograms
      (photochemical reactor "on" and "off") were compared and were quite useful in
      characterizing the sample. Validation studies demonstrated that this HPLC method
      is simple, rapid, reliable and reproducible. The time-consumptive manual
      irradiation of the samples is omitted by this automated on-line irradiation step.
      The developed method was successfully applied to the quality control of Hypericum
      perforatum L. extracts and its phytopharmaceutical preparations.

PMID- 12613811
TI  - Determination of organic peroxides by liquid chromatography with on-line post
      column ultraviolet irradiation and peroxyoxalate chemiluminescence detection.
AB  - A HPLC method was developed for the simultaneous determination of organic
      peroxides and hydrogen peroxide with peroxyoxalate chemiluminescence (PO-CL)
      detection following on-line UV irradiation. Organic peroxides [i.e., benzoyl
      peroxide (BP), tert.-butyl hydroperoxide (BHP), tert.-butyl perbenzoate (BPB),
      cumene hydroperoxide (CHP)] were UV irradiated (254 nm, 15 W) to generate
      hydrogen peroxide, which was determined by PO-CL detection. The conditions for UV
      irradiation and PO-CL detection were optimized by a flow injection analysis (FIA)
      system. Generation of hydrogen peroxide from peroxides with on-line UV
      irradiation also was confirmed by the FIA system by incorporating an enzyme
      column reactor immobilized with catalase. The separation of four organic
      peroxides and hydrogen peroxide by HPLC was accomplished isocratically on an ODS
      column within 30 min. The detection limits (signal-to-noise ratio=3) were 1.1
      microM for hydrogen peroxide, 6.8 microM for BP, 31.3 microM for BHP, 7.5 microM
      for BPB and 1.3 microM for CHP. The proposed method was applied to the
      determination of BP in wheat flour.

PMID- 12613812
TI  - Microchannel-assisted thermal-lens spectrometry for microchip analysis.
AB  - Microchannel-assisted thermal lens spectrometry (MATLS) was developed for
      microchip analysis. This method utilized a photothermal effect in a very small
      space and rapid thermal conduction between a solid-liquid interface to produce a
      temperature gradient in the microchannel. In order to examine the mechanism
      experimentally, we constructed a detection system of laser defocus setup in which
      an excitation beam was not tightly focused, but it irradiated the microchannel
      homogeneously. The signal intensity dependence on modulation frequency of
      excitation and on solvent was investigated with the laser defocusing setup. The
      results of this investigation indicated that the mechanism of MATLS worked as
      expected. Since the mechanism of MATLS does not require directivity and coherence
      of the laser beam, other incoherent lightsources can be used as excitation light
      for sensitive detections. Finally, we considered some future applications
      utilizing the mechanism.

PMID- 12613813
TI  - (2-Naphthoxy)acetyl chloride, a simple fluorescent reagent.
AB  - In continuing the search for fluorescent reagents for analytical derivatization
      in chromatography, we found a simple chemical, (2-naphthoxy)acetyl chloride, with
      potential fluorophore/chromophore characteristics for the highly sensitive
      detection of analytes with an amino function. The reagent has an auxochrome (a
      substituted alkoxy moiety) attached to the fluorophoric/chromophoric naphthalene
      system, resulting in favorable spectrophotometric properties. The reagent can be
      easily prepared from (2-naphthoxy)acetic acid and has been used in organic
      synthesis; it is initially introduced as a fluorescent reagent to derivatise
      amantadine and memantine (amino pharmaceuticals) as model analytes. The resulting
      naphthoxy derivatives of the drugs can be analyzed at sub-microM levels by HPLC
      with fluorimetric detection (excitation wavelength 227 nm, emission wavelength
      348 nm). Application of the reagent to the fluorimetric derivatization of
      important biological amines for sensitive detection can be expected.

PMID- 12613814
TI  - Ammonium hydrogencarbonate, an excellent buffer for the analysis of basic drugs
      by liquid chromatography-mass spectrometry at high pH.
AB  - Ammonium hydrogencarbonate buffer has been found to be especially useful for high
      pH HPLC analysis of samples from both combinatorial and medicinal chemistry
      sources. Satisfactory results were obtained by the standard diode array,
      evaporative light-scattering, and MS detection by using this buffer at a
      concentration of 10 mM. From a practical standpoint, ammonium hydrogencarbonate
      is an ideal buffer for chromatographers since it provides excellent
      chromatographic behaviour and reproducible separation. In addition to this, its
      volatility makes it an essential tool for rapid LC-MS product identification.
      Ammonium hydrogencarbonate was tested for a number of drug-like compounds
      analysed as mixtures, and data obtained were compared to those from the classical
      and MS-friendly buffers widely used by chromatographers: trifluoroacetic and
      formic acids. The results of this study revealed the suitability of this buffer
      for routine HPLC application in research laboratories.

PMID- 12613815
TI  - Determination of enrofloxacin and its metabolite ciprofloxacin in goat milk by
      high-performance liquid chromatography with diode-array detection. Optimization
      and validation.
AB  - A high-performance liquid chromatography-diode array detection method (HPLC-DAD)
      combined with liquid chromatography-mass spectrometry was developed for the
      determination of enrofloxacin and its metabolite ciprofloxacin in goat milk. The
      HPLC-DAD method validation was compliant with the "DG SANCO 1805/2000" European
      regulation. The residues were extracted from milk with phosphate buffer, purified
      on a C18 Speedisk cartridge SPE (Baker) and then analysed using HPLC-DAD set at
      277 nm. The decision limit (CCa) calculated by spiking samples at 100 microg/kg
      with both analytes, taking into account the maximum residue limit (MRL) of 100
      microg/kg established by the European Union for the sum of enrofloxacin and its
      metabolite ciprofloxacin in milk, was 105.3 microg/kg for enrofloxacin and 105.5
      microg/kg for ciprofloxacin. The detection capability (CCbeta) was 110.7 and
      110.9 microg/kg for enrofloxacin and ciprofloxacin, respectively. The mean
      recoveries of the method, calculated by spiking samples at 50, 100 and 150
      microg/kg were 84% for enrofloxacin and 88% for ciprofloxacin. The limit of
      quantification was 20 microg/kg for both analytes. The HPLC-DAD validated method
      was successfully applied for the first time in goats milk, and proved to be
      suitable for the sensitive and accurate quantification and confirmation analysis
      of enrofloxacin and ciprofloxacin for regulatory purposes.

PMID- 12613816
TI  - Validation of a high-performance liquid chromatography method for the
      determination of oxytetracycline, tetracycline, chlortetracycline and doxycycline
      in bovine milk and muscle.
AB  - High-performance liquid chromatography with diode-array detection (HPLC-DAD) was
      optimised and validated for the determination of tetracyclines in bovine milk and
      tissues. Milk and tissue samples were extracted and purified using a solid-phase
      extraction HLB Oasis cartridge and analysed using HPLC-DAD set at 365 nm. The
      analyses were carried out using the mobile phase of 0.01 M oxalic acid
      acetonitrile-methanol (60:25:15, v/v/v) on a C8 column (250 x 4.6 mm I.D., 5
      microm). Recoveries of tetracyclines from spiked samples at the three
      concentrations (0.5, 1 and 1.5) of the maximum residues limits (corresponding to
      100 microg/kg for milk and the muscle) were higher than 81.1% in milk and 83.2%
      in muscle. The method was successfully validated for bovine milk and muscle in
      compliance with requirements set by draft SANCO/ 1805/ 2000 European Decision.
      The decision limit (CCalpha) was in the range 113.2-127.2 microg/kg and 107.7
      129.9 micro/kg for all compounds in milk and muscle, respectively. The detection
      capability (CCbeta) was in the range 117.2-131.3 microg/kg and 114.9-133.1
      microg/kg for all compounds in milk and muscle, respectively.

PMID- 12613817
TI  - Determination of amoxycillin in human plasma by direct injection and coupled
      column high-performance liquid chromatography.
AB  - This work reports the use of multidimensional HPLC by coupling a restricted
      access medium (RAM) bovine serum albumin (BSA) octadecyl column (100 x 4.6 mm
      I.D., 10 microm particle size and 120 A pore size) to an octadecyl Hypersil
      column (150 x 4.6 mm I.D., 5 microm particle size and 120 A pore size) to the
      analysis of amoxycillin in human plasma by direct injection. Ion pairing was
      necessary to extract amoxycillin with good recovery from the plasma proteins. To
      prepare the spiked samples, aliquots (60 microl) of the appropriated standard
      solutions were added to each culture tube containing an 180 microl of plasma and
      a solution of 0.30 mM tetrabuthylammonium phosphate (60 microl). They were
      vortexed for 15 s and then 290 microl were transferred to autosampler vials.
      Aliquots (250 microl) of the spiked plasma samples were injected to a column
      switching HPLC system. An analysis time of 25 min with no time spent on sample
      preparation was achieved. The developed method showed good selectivity,
      sensitivity, accuracy and precision for direct analysis of this polar low
      wavelength ultraviolet absorption antibiotic using only 180 microl of human
      plasma. The validated method proved to be reliable and sensitive for the
      determination of amoxycillin in plasma samples of five healthy volunteers to whom
      test and reference formulations were administered as an oral dose (500 mg).

PMID- 12613818
TI  - Use of high-performance liquid chromatographic and microbiological analyses for
      evaluating the presence or absence of active metabolites of the antifungal
      posaconazole in human plasma.
AB  - Posaconazole (SCH 56592) is a novel broad spectrum triazole antifungal agent that
      is currently in phase III clinical trials for the treatment of systemic fungal
      infections. This study was initiated to determine if orally administered
      posaconazole to humans would result in the formation of active metabolite(s).
      Plasma samples from a multiple-rising dose study in healthy volunteers were
      analyzed by validated HPLC and microbiological methods. The HPLC analysis
      involved extraction with a mixture of organic solvent (methylene chloride-hexane)
      followed by separation on a C18 column and quantification by UV absorbance at 262
      nm. The microbiological assay was performed utilizing an agar diffusion method
      using Candida pseudorropicalis ATCC 46764 as the test organism. Potency was
      determined by comparing the growth inhibition zones produced by the test sample
      to those produced by standard concentrations prepared in plasma. Individual and
      mean plasma concentration-time profiles were similar for both HPLC and
      microbiological assays. The area under the plasma concentration-time curves of
      the microbiological and HPLC results were similar with a mean (RSD) ratio of
      105.5% 15.3%), indicating that there was no relevant biologically active
      metabolite of posaconazole in human plasma.

PMID- 12613819
TI  - Determination of PNU-248686A, a novel matrix metalloproteinase inhibitor, in
      human plasma by liquid chromatography-tandem mass spectrometry, following protein
      precipitation in the 96-well plate format.
AB  - A sensitive, specific and high-throughput analytical method for the quantitation
      of PNU-248686A (I), in human plasma has been developed. I, sodium (2R)-3-[[(4'
      chloro(1,1'-biphenyl)-4-yl]sulfonyl]-2-hydroxy-2-[(phenylsulfanyl)methyl]
      propanoate, is an orally active matrix metalloproteinase (MMP) inhibitor
      developed for the treatment of solid tumors over-expressing MMPs. Concentrations
      of I, as free acid, were determined in human plasma by LC-MS-MS after plasma
      protein precipitation in the 96-well plate format. Aliquots of plasma (50 microl)
      were placed into the plates and 0.2 ml of methanol was added. The plates were
      shaken for 5 min and centrifuged at 1500 g for 10 min. Aliquots of 10 microl of
      the supernatants were then directly injected into the LC-MS-MS system. A Symmetry
      Shield C. column (50 x 2.1 mm, 3.5 microm) was used to perform the
      chromatographic analysis. The mobile phase was 5 mM ammonium formate buffer
      solution pH 5.0-acetonitrile (60:40. v/v) with a flow-rate of 0.3 ml/min.
      Retention time of I was about 1.2 min. Total cycle time was 2.5 min. MS detection
      used the Applied Biosystems-MDS Sciex API 3000 with TurbolonSpray interface and
      single reaction monitoring (461 --> 251 m/z transition) operated in negative ion
      mode. Calibration curves were constructed by plotting the area of the compound
      (y) against its concentration (x). A weighed linear regression (weighting factor
      1/x(2)) was used to calculate I concentrations in quality control and unknown
      samples. The method was fully validated over the range of 5.0-5000 ng/ml. The
      suitability and robustness of the method for in vivo samples was confirmed by
      analysis of plasma samples from a pilot clinical study.

PMID- 12613820
TI  - Selective extraction of salbutamol from human plasma with the use of
      phenylboronic acid.
AB  - An investigation was conducted on the usage of a single-step extraction procedure
      involving the retention of a phenylboronate-salbutamol complex on an end-capped
      C18 solid-phase sorbent to determine the level of salbutamol in human plasma
      samples. Propranolol, a beta-blocker, was chosen as the internal standard for
      this assay. In this solid-phase clean-up method, 50 mM sodium carbonate buffer,
      pH 9.60, was used for conditioning the column as well as washing the endogenous
      interference. Under the optimal conditions, the recovery of salbutamol from
      spiked plasma samples was found to be high and reproducible with mean recoveries
      (n = 3) of more than 90% after elution by using 50% 1 M trifluoroacetic acid in
      methanol. This sample clean-up step was effectively analyzed under reversed-phase
      high-performance liquid chromatography with fluorimetric detection. The method
      was successfully applied to the routine measurement of salbutamol in human plasma
      from the bioequivalence study on the different administration route of
      salbutamol. Quantification of salbutamol was convincingly reported with the
      correlation of coefficient of 0.9980 for the concentration range from 0 to 1000
      ng ml(-1). An adequate precision was achieved with both between- and within-day
      precisions of less than 10% (n = 6) for 100 and 1000 ng ml(-1) and less than 15%
      (n = 6) for 10 ng ml(-1).

PMID- 12613821
TI  - Determination of benzophenones in a cosmetic matrix by supercritical fluid
      extraction and capillary electrophoresis.
AB  - Benzophenones are common additives in commercial sunscreen products. These UV
      absorbers were extracted by supercritical fluid extraction (SFE), and then
      analyzed by capillary zone electrophoresis (CZE) and high-performance liquid
      chromatography. This study was applied to identify the contents of benzophenones
      in cosmetic matrix, and simultaneously, to investigate the behavior of migration
      in CZE. Adding non-ionic surfactant (Tween 20) to optimize the separation in the
      CZE operation improves resolution. In SFE, we chose carbon dioxide with 2.5%
      modifier of 10% aqueous phosphoric acid-MeOH (1:1) as the supercritical fluid.
      Real recoveries of up to 92% with relative standard deviations of less than 4.0%
      were achieved. These analytical techniques were also applied to assay
      benzophenones for ten commercial sunscreen cosmetics. We found benzophenone 3 was
      the most commonly used sunscreen additive in Taiwan.

PMID- 12613822
TI  - Pharmacokinetics of metronidazole in rat blood, brain and bile studied by
      microdialysis coupled to microbore liquid chromatography.
AB  - Metronidazole is a synthetic nitroimidazole-derived antibacterial and
      antiprotozoal agent used for the treatment of infections involving gram-negative
      anaerobes. The aim of this study is to develop an in vivo microdialysis with
      microbore high-performance liquid chromatographic system for the pharmacokinetic
      study of metronidazole in rat blood, brain and bile. In addition, to investigate
      the disposition mechanism of metronidazole, the P-glycoprotein modulator and
      cytochrome P450 inhibitor were concomitantly administered. Separation of
      metronidazole from various biological fluids was applied to a microbore reversed
      phase ODS 5 microm (150 x 1 mm I.D.) column. Its mobile phase consists of an
      acetonitrile-50 mM monosodium phosphate buffer (pH 3.0) containing 0.1%
      triethylamine (10:90, v/v) with a flow-rate of 0.05 ml/min. The UV detector
      wavelength was set at 317 nm. The results suggest that metronidazole penetrates
      the blood-brain barrier (BBB) and goes through hepatobiliary excretion. However,
      these pathways of BBB penetration and hepatobiliary excretion of metronidazole
      may not be related to the P-glycoprotein.

PMID- 12613823
TI  - Mass spectrometry-compatible ICH (International Conference on Harmonization)
      impurity analysis with a high-pH mobile phase advantages and pitfalls.
AB  - Recent advances in bonding chemistry and novel silica synthesis have
      significantly extended the pH range of silica-based HPLC columns. This extended
      range now enables the analysis of water-soluble basic drugs at high pH without
      ion-pairing reagents, thus offering an alternative approach to assay or impurity
      analyses. This paper describes the many advantages and potential pitfalls of
      using high-pH mobile phases in the development of MS-friendly LC gradient
      impurity analytical methods for water-soluble basic drugs under International
      Conference on Harmonization (ICH) guidelines. Operating at high-pH provides
      excellent peak shapes and retention, and accentuates selectivity differences of
      structurally similar impurities and degradants. However, several problems unique
      to the use of high-pH mobile phases, such as column lifetime, robustness of pH
      adjustments, peak fronting, and on-column dimerization, were encountered. Each of
      these problems is discussed with its respective remedy.

PMID- 12613824
TI  - Quantitation of amino acids and amines in the same matrix by high-performance
      liquid chromatography, either simultaneously or separately.
AB  - A literature overview is presented of chromatographic methods currently in use to
      determine amino acids and mines (i) simultaneously, (ii) in the presence of each
      other by separate methods, or (iii) amines alone subsequent to their isolation
      from amino acids. Separation, derivatization and chromatographic conditions are
      summarized. Advantages and drawbacks of all three possibilities are discussed and
      criticized in detail.

PMID- 12613826
TI  - Separation of proteins on polymeric stationary phases grafted with various amine
      groups.
AB  - Six polymeric stationary phases with various amine groups were prepared by
      surface grafting of glycidyl methacrylate on silica gel surface and its
      subsequent amination. The six kinds of amines, namely, triethylamine,
      diethylamine, ethylenediamine (EDA), hexaethylenediamine (HEDA),
      diethylenetriamine (DETA) and triethylenetetraamine (TETA) were used in this
      study. The separation of bovine serum albumin (BSA) and chicken egg albumin (CEA)
      on the polymeric stationary phase with various amines was investigated. The
      affinity degree of BSA was higher than CEA for the EDA, HEDA and DETA columns,
      whereas the affinity degree of CEA was higher than BSA for the TETA column.

PMID- 12613825
TI  - New aspects of the simultaneous analysis of amino acids and amines as their o
      phthaldialdehyde derivatives by high-performance liquid chromatography. Analysis
      of wine, beer and vinegar.
AB  - A new high-performance liquid chromatography method is described for the
      simultaneous quantitation of amino acids and amines for 37 compounds (20 amino
      acids + 17 amines), as their o-phthaldialdehyde (OPA)-3-mercaptopropionic acid
      derivatives, within 53 min. Based on previously documented stoichiometric and
      reaction mechanism studies, derivatizations have been carried out with the OPA-SH
      group = 1:50 containing reagents. Reliability and reproducibility of analyses
      have been considerably improved. Average reproducibility data in a wide
      concentration range of derivatives had RSD < or = 3.4%.

PMID- 12613827
TI  - Development and characterization of an immobilized enzyme reactor based on
      glyceraldehyde-3-phosphate dehydrogenase for on-line enzymatic studies.
AB  - The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been
      extensively studied as a target for new drugs to be used in the treatment of
      various parasitic diseases. The standard approach to the determination of GAPDH
      activity utilizes solubilized free enzyme and is limited by the enzyme's low
      stability. In the current study the stability of GAPDH was significantly
      increased through the covalent immobilization of the enzyme on a wide-pore silica
      support containing glutaraldehyde (Glut-P). The optimal conditions for the
      immobilization were: 100 mg Glut-P stationary phase, approximately 150 microg of
      enzyme dissolved in pyrophosphate buffer (15 mM, pH 8.5). The mixture was gently
      agitated for 6 h at 4 degrees C. Under these conditions 91.3% of protein was
      immobilized on 100 mg of Glut-P support with retention of 2.97% of the initial
      enzymatic activity. The activity of the immobilized GAPDH was stable for over 30
      days. The GAPDH-Glut-P stationary phase was packed into a glass column to produce
      a GAPDH immobilized enzyme reactor (GAPDH-IMER). The activity and kinetic
      parameters of the GAPDH-IMER were investigated and the results demonstrated that
      the enzyme retained its activity and sensitivity to the competitive inhibitor
      agaric acid.

PMID- 12613829
TI  - Measurements of the major isoforms of vitamins A and E and carotenoids in the
      blood of people with spinal-cord injuries.
AB  - We used reversed-phase HPLC with diode array detection to simultaneously measure
      the major isoforms of vitamins A, E, and the carotenoids in serum from 55 healthy
      people with spinal cord injuries. Typically, the method measured retinol (vitamin
      A), alpha-tocopherol (vitamin E) and beta-carotene, alpha-carotene, lutein,
      lycopene, and cryptoxanthin (carotenoids). gamma-Tocopherol (vitamin E), 25
      hydroxycalciferol (vitamin D), and the carotenoid zeaxanthin could also be
      measured when they were present in high concentrations. Healthy people with
      spinal cord injuries were more likely than similar people without injuries to
      have low concentrations of alpha-tocopherol, and to a lesser extent retinol and
      beta-carotene.

PMID- 12613828
TI  - Analysis of DNA adducts of acetaldehyde by liquid chromatography-mass
      spectrometry.
AB  - A highly sensitive method using liquid chromatography-electrospray ionization
      mass spectrometry (LC-ESI-MS) was developed for the analysis of DNA adducts of
      acetaldehyde (AA). AA, which is the primary oxidative metabolite of ethanol, is
      considered to possess carcinogenic activity. AA reacts with the exocyclic amino
      group of guanine in DNA to form N2-ethylguanine (Et-Gua) and 1,N2-propanoguanine
      (Pr-Gua) adducts. With the present method, such adducts were detected as the base
      forms from DNA chains using depurination in the pretreatment process. In our
      measurement with LC-ESI-MS, the limits of detection (LODs) of the Et-Gua and Pr
      Gua adducts of the base forms were 3.0 x 10(-10) and 1.0 x 10(-9) M,
      respectively, and the LODs are about two orders of magnitude lower than those of
      the nucleoside forms. Calf thymus DNA samples treated with AA and NaBH3CN were
      analyzed by this method. Et-Gua was clearly detected and, in the absence of
      NaBH3CN, Pr-Gua was detected predominantly. Furthermore, the method was also
      applied to study whether or not these two adducts are formed in DNA of cultured
      HL-60 cells during exposure to AA for 24 h. Pr-Gua was clearly detected and
      traces of Et-Gua were also detected in the DNA of the cells. Although the
      sensitivity of this method is lower by at least oneorder of magnitude than the
      32P-postlabeling assay, currently the most sensitive method, our method does not
      involve complex enzymatic reactions for the postlabeling and the use of
      troublesome radioactive materials. Furthermore, it enables structural
      identification of guanine adducts. The present method would be a useful tool for
      studies of Et-Gua and Pr-Gua adducts in connection with carcinogenesis.

PMID- 12613830
TI  - Pharmacokinetic study of free mangiferin in rats by microdialysis coupled with
      microbore high-performance liquid chromatography and tandem mass spectrometry.
AB  - Mangiferin (2-beta-D-glucopyranosyl-1,3,6,7-tetrahydroxyxanthen-9-one) has been
      isolated from the herbal root of Anemarrhena asphodeloides Bung showing
      antioxidative, antiviral, and anticancer effect. An in vivo microdialysis
      sampling method coupled to microbore high-performance liquid chromatography
      (HPLC) was employed for continuous monitoring of free mangiferin in rat blood.
      Microdialysis probes were inserted into the jugular vein/right atrium and brain
      striatum of Sprague-Dawley rats, and mangiferin at doses of 10, 30 or 100 mg/kg
      were then administered via the femoral vein. Dialysates were collected every 10
      min and injected directly into a microbore HPLC system. Mangiferin was separated
      by a reversed-phase C18 microbore column (150 x 1 mm) from dialysate within 10
      min. The mobile phase consisted of acetonitrile-0.05% phosphoric acid
      tetrahydrofuran (10:75:15, v/v/v) with a flow-rate of 0.05 ml/min. The wavelength
      of the UV detector was set at 257 nm. The limit of quantification for mangiferin
      was 0.05 microg/ml and in vivo recovery of mangiferin at concentrations of 1, 5
      and 10 microg/ml was in range of 37.7-39.8%. The results indicate that the
      pharmacokinetics of mangiferin at doses of 10-30 mg/kg reveals a linear relation,
      while doses of 30-100 mg/kg show a nonlinear pharmacokinetic phenomenon.
      Mangiferin was undetectable in brain dialysate. The proposed method provides a
      technique for rapid and sensitive analysis of free mangiferin in rat blood and
      further application in pharmacokinetic study. Furthermore, the metabolites of
      mangiferin in the rat bile were confirmed by LC electrospray ionization (ESI)
      tandem mass spectrometry (MS-MS).

PMID- 12613831
TI  - Determination of herbicides and a metabolite in human urine by liquid
      chromatography-electrospray ionization mass spectrometry.
AB  - A method was developed to determine simazine, atrazine and their metabolite, 2
      chloro-4,6-diamino-1,3,5-triazine, in urine. The presence of these herbicides in
      urine may reflect possible exposure to pesticides. Sample preparation involved
      protein precipitation and solid-phase extraction. The samples were analyzed by
      high-performance liquid chromatography-mass spectrometry. The detection limits
      were 0.4 microg/l and the analytes have a linear response in the interval 6-800
      microg/l. The precision of the method was reflected in the RSD of < 2.4% for the
      herbicides studied. Based on the detectable herbicide levels from spiked urine
      samples collected from unexposed volunteers, this method can be used to determine
      the low levels necessary for establishing reference values of the selected
      herbicides and the metabolite.

PMID- 12613832
TI  - Application of new high-performance liquid chromatography and solid-phase
      extraction materials to the analysis of pesticides in human urine.
AB  - A method for the simultaneous determination of diuron and linuron pesticides in
      human urine was developed, using both solid-phase extraction (SPE) and high
      performance liquid chromatography (HPLC) phases made in our own laboratory. These
      materials were prepared by sorption of polysiloxanes onto a silica surface,
      followed by immobilization. The HPLC columns were prepared from
      poly(methyloctylsiloxane), PMOS, immobilized onto silica with microwave radiation
      while the SPE cartridges where made with poly(methyloctadecylsiloxane),
      immobilized thermally. Method validation was performed for diuron and linuron for
      three fortification levels. The recoveries obtained were 85-103%, the inter- and
      intra-assay precisions were less than 1.6 and 1.8%, respectively. The limits of
      quantitation and detection for diuron were 2.4 and 8.0 microg/l and for linuron
      were 5.0 and 12 microg/l, respectively.

PMID- 12613833
TI  - On-column concentration of bisphenol A with one-step removal of humic acids in
      water.
AB  - An efficient extraction method for bisphenol A from environmental water including
      contaminants was developed using surface selective localization of functional
      group, on a polymeric separation device. The polymer utilized in this study was
      prepared through a kind of molecular imprinting technique, namely fragment
      imprinting effect utilizing a pseudo-template molecule (p-tert.-butylphenol)
      instead of bisphenol A. The concentration of bisphenol A onto the polymer device
      prepared, up to 1000 times concentration from environmental water including
      contaminants (humic acids), was achieved very easily with interesting exclusion
      effect for humic acids. The results obtained in this study suggest that molecular
      imprinting with the pseudo-template molecule is quite an effective way for
      selective concentration of the diluted target molecule from other contaminants
      including similar functional group with the target molecule.

PMID- 12613834
TI  - Process monitoring of anaerobic azo dye degradation by high-performance liquid
      chromatography-diode array detection continuously coupled to membrane filtration
      sampling modules.
AB  - Process integrated microfiltration and ultrafiltration based membrane sampling
      modules were compared by means of HPLC with diode array detection based
      monitoring of an anaerobic azodye biodegradation process. The sampling matrix
      consisted of anaerobic sludge from a municipal wastewater treatment plant. The
      hydrolysed azo dye Reactive Black 5 (RB5-H) and three products (ionic and
      nonionic) released from reductive cleavage under anaerobic conditions were
      continuously monitored by simultaneously separation by ion-pair chromatography.
      Microfiltration membrane-based sampling showed no retention for any compound
      observed. Sampling by ultrafiltration significantly retained the observed ionic
      compounds between 58 and 83% whereas a nonionic compound was not retained. On
      line monitoring of an oxygen-sensitive compound was possible whereas off-line
      detection failed. Robust long time monitoring could be performed for up to 1 week
      without cleaning the membrane.

PMID- 12613835
TI  - Binding of environmental pollutants to the corn protein zein studied by high
      performance liquid chromatography.
AB  - The interaction of 16 ring-substituted phenols and anilines with the corn protein
      zein was studied by reversed-phase high-performance liquid chromatography by
      preparing silica- and alumina-based stationary phases coated with various
      concentrations of zein. The relationship between the strength of interaction and
      the physicochemical parameters of solutes was elucidated by principal component
      analysis followed by the nonlinear mapping technique. The binding of each phenol
      and aniline derivative to zein has been demonstrated. It was established that the
      electrostatical parameters of solutes exert the highest influence on the
      interaction and the involvement of hydrophobic binding forces is of secondary
      importance. The binding characteristics of phenol and aniline derivatives were
      different.

PMID- 12613836
TI  - Mechanistic study of enantiomeric recognition with native gamma-cyclodextrin by
      capillary electrophoresis, reversed-phase liquid chromatography, nuclear magnetic
      resonance spectroscopy, electrospray mass spectrometry and circular dichroism
      techniques.
AB  - The possible mechanisms for the chiral recognition of 2(S)-(3,5-bis
      trifluoromethyl-phenyl)-2-[3(S)-(4-fluorophenyl)-4-(1H-[1,2,4]triazol-3-ylmethyl)
      morpholin-2(R)-yloxy]-ethanol (compound A) and its enantiomer with native gamma
      cyclodextrin (gamma-CD) were investigated using capillary electrophoresis (CE),
      reversed-phase liquid chromatography (RPLC), proton (1H), fluorine (19F) and
      carbon (13C) nuclear magnetic resonance spectroscopy (NMR), electrospray mass
      spectrometry (ESI-MS) and circular dichroism (CD). All experiments provided clear
      evidence of the formation of diastereomeric complexes between the enantiomers and
      gamma-CD. Proton, fluorine and carbon NMR spectra suggested that both aromatic
      rings, with mono-fluoro and bis-tri-fluoro functional groups, on the guest
      molecule were partially included into the cavity of the gamma-CD. ESI-MS spectra
      indicated that the diastereomeric complexes have a 1:1 stoichiometric ratio. The
      binding constants of the diastereomeric complexes obtained by CE, RPLC and CD
      were compared. The effects of the gamma-CD concentration, organic modifiers and
      temperature on the CE-chiral separation were also investigated.

PMID- 12613837
TI  - Enantiomer separation of N-protected amino acids by non-aqueous capillary
      electrophoresis and high-performance liquid chromatography with tert.-butyl
      carbamoylated quinine in either the background electrolyte or the stationary
      phase.
AB  - A non-aqueous CE method was developed for evaluating the chiral discrimination
      potential of cinchona alkaloids and different kinds of carbamoylated derivatives
      of quinine and quinidine type chiral selectors towards acidic analytes, in
      particular a series of various Bz (benzoyl), DNB (3,5-dinitrobenzoyl) and DNZ
      (3,5-dinitrobenzyloxycarbonyl) amino acid derivatives. In this study, the
      enantioselectivity values obtained in non-aqueous CE with tert.-butyl
      carbamoylated quinine as chiral additive have been compared with the values found
      for the same series of selectands in HPLC using the same selector immobilized
      onto silica as chiral stationary phase. Similarly to the background electrolyte
      used in CE an ethanol-methanol mixture (60:40, v/v) containing 100 mM octanoic
      acid and 12.5 mM ammonia has been selected as HPLC mobile phase. Under these
      conditions, a good correlation (r = 0.954) between the enantioselectivities
      observed with the two techniques has been obtained. Thus the non-aqueous CE
      method can be applied as a screening tool for the rapid evaluation of the chiral
      discrimination potential of a large set of newly developed chiral selectors
      derived from quinine and related alkaloids.

PMID- 12613838
TI  - Enantioseparation of racemic N-acylarylalkylamines on various amino alcohol
      derived tau-acidic chiral stationary phases.
AB  - Five tau-acidic chiral stationary phases (CSPs), CSP 4, CSP 5, CSP 6, CSP 7 and
      CSP 8, were prepared by connecting the N-(3,5-dimethylbenzoyl) derivative of (R)
      alaninol, (S)-leucinol, (1S,2R)-ephedrine and (S)-tert-leucinol and the O-(3,5
      dinitrobenzoyl) derivative of (R)-phenylglycinol to silica gel through a
      carbamate or urea linkage. The CSPs were applied to the resolution of various
      racemic N-acyl-1-naphthylaminoalkanes by chiral HPLC, and the chromatographic
      resolution results were compared with those of previously reported CSPs (CSP 2,
      CSP 3), which are derived from N-(3,5-dinitrobenzoyl)-(1S,2R)-norephedrine and N
      (3,5-dinitrobenzoyl-(R)-phenylglycinol. Based on a comparison of the resolution
      results for each CSP, the role of each functional group on the five chiral
      selectors is explained.

PMID- 12613839
TI  - Quantitation and test of enantiomeric purity of the L-ketohexoses by liquid
      chromatography with dual refractive index and laser-based chiroptical detection.
AB  - Experimental data for the synthetic methods of preparation of the L-ketohexoses
      have been lacking an analytical method for monitoring the chemical or enzymatic
      reactions described. Dual refractive index and laser-based chiroptical detection
      provides an ideal method for following the reactions, since the refractive index
      detector quantifies the amount of analyte, while the ratio of optical rotation to
      refractive index response allows the enantiomer mole fraction to be determined.
      Sulfonated polystyrenedivinylbenzene resin in the Ca form as the stationary phase
      with H2O at 80 degrees C as the eluent gives base-line separation of sorbose,
      fructose, tagatose, and psicose. Dependent on the complexity of the reaction
      mixture, analysis times range from 20 to 60 min.

PMID- 12613840
TI  - Enantiomeric resolution of a series of chiral sulfoxides by high-performance
      liquid chromatography on polysaccharide-based columns with multimodal elution.
AB  - The enantiomeric resolution of a series of 20 asymmetric sulfoxides was
      systematically investigated by HPLC using multimodal elution with amylose
      trisR(S)-1-phenylethylcarbamate], amylose tris(3,5-dimethoxyphenylcarbamate) and
      amylose and cellulose tris(3,5-dimethylphenylcarbamate) phases. The sulfoxide
      series was composed of aromatic, olefinic and ketosulfoxides, sulfinyl acids and
      esters. This work has shown that enantioselectivity and enantioresolution of the
      polysaccharide-based columns can be achieved by changing the type and composition
      of the mobile phase, widening the applicability of these chiral phases.

PMID- 12613841
TI  - Separation of peptides by pressurized capillary electrochromatography.
AB  - A pressurized electrochromatography (pCEC) instrument with gradient capability
      was used in this work for separation of peptides. Three separation modes, namely,
      pCEC, high-performance liquid chromatography and capillary electrophoresiscan be
      carried out with the instrument. In pCEC mode, the mobile phase is driven by both
      electroosmotic flow and pressurized flow, facilitating fine-tuning in selectivity
      of neutral and charged species. A continuous gradient elution can be carried out
      conveniently on this instrument, which demonstrates that it is more powerful than
      isocratic pCEC for separation of complicated samples. The effects of applied
      voltage, supplementary pressure and ion-pairing agents on separation of peptides
      in gradient pCEC were investigated. The effects of flow-rate of the pump and the
      volume of the mixer on resolution were also evaluated.

PMID- 12613842
TI  - Capillary electrophoretic separation of enantiomers in a high-pH background
      electrolyte by means of the single-isomer chiral resolving agent octa(6-O-sulfo)
      gamma-cyclodextrin.
AB  - The new, alkali-stable, single-isomer, sulfated gamma-cyclodextrin, the sodium
      salt of octa(6-O-sulfo)-gamma-cyclodextrin (OS) was used for the first time to
      separate the enantiomers of non-ionic, acidic, basic and ampholytic analytes by
      capillary electrophoresis in high-pH aqueous background electrolytes. The
      effective mobilities and separation selectivities were found to follow trends
      similar to those observed earlier in acidic aqueous background electrolytes. OS
      proved to be a broadly applicable chiral resolving agent and afforded adequate
      peak resolution values with short separation times for a number of non-ionic,
      weak acid, weak base and ampholytic analytes.

PMID- 12613843
TI  - Non-aqueous capillary electrophoresis of the positional isomers of a sulfated
      monosaccharide.
AB  - A non-aqueous capillary electrophoresis (NACE) method coupled to indirect
      absorbance detection has been developed for the separation of the three
      positional isomers of monosulfated fucose. The optimized electrolyte was composed
      of 12 mM ethanolamine, 2 mM trimesic acid buffer in a methanol-ethanol (1:1, v/v)
      mixture. As the retained electrolyte entails no separating agent other than the
      pH buffer, the NACE separation of the positional isomers has been ascribed mainly
      to selective ion-pairing with the electrolyte counter-ion and the possibility of
      a selective solvation effect in the alcohol mixture. In the absence of pure
      isomeric standards, peak identification was completed by MS and NMR spectroscopy
      and selective enzymatic desulfation. This method should be of interest for the
      structure elucidation of monosulfated fucose-based polysaccharides and for the
      screening of sulfoesterase of unknown activity.

PMID- 12613844
TI  - High-performance capillary zone electrophoretic assay for markers of diabetic
      nephropathy in plasma and urine.
AB  - A new high-performance capillary zone electrophoretic assay for creatine (Cr),
      creatinine (Cn), urea (U) and uric acid (Ua), markers of human diabetic
      nephropathy, both in plasma and urine has been developed with UV detection at 200
      nm. The plasma sample was deproteinized with trichloroacetic acid and centrifuged
      at 10 000 rpm for 10 min. The urine sample was diluted 20-fold with buffer before
      analysis. The optimum separation conditions for the markers was investigated with
      respect to the concentration of the buffer, the pH, the voltage and the capillary
      temperature. Baseline separation was achieved in 25 mmol/L phosphate buffer (pH
      3.45) using a 21 cm x 75 microm I.D. fused-silica capillary at 40 degrees C with
      an electric field of 1190 V/cm. The calibration curves showed good linearity in
      the range 3.5-1000, 0.18-700, 500-5000 and 2-800 microM (r2 min > 0.998) for Cr,
      Cn, U and Ua, respectively. The proposed method also has a high reproducibility
      (peak area RSD max < 3%) and has been successfully applied to the determination
      of clinical samples.

PMID- 12613845
TI  - Indirect capillary electrophoresis with 8-anilino-1-naphthalenesulfonic acid as a
      fluorescence probe for determining the apparent stability constant of an
      inclusion complex formed between a cyclodextrin and a solute.
AB  - An indirect capillary electrophoresis (CE) method was developed based on two
      competitive chemical equilibria for determining the stability constant of an
      inclusion complex formed between a cyclodextrin and a solute. 8-Anilino-1
      naphthalenesulfonic acid was employed as a fluorescence probe. A linear
      relationship between mobility difference and concentration of uncomplexed ligand
      was theoretically established and experimentally verified. The principle of the
      method was explained using an example of determining stability constant of an
      inclusion complex formed between a ligand of hydroxypropyl-beta-cyclodextrin and
      a solute of amantadine. The stability constant was determined to be approximately
      2 x 10(2) M(-1). It was calculated without knowledge of the mobility of the
      complex measured at saturating ligand concentrations. This indirect method can be
      applied to solutes and ligands lacking signal response on the selected detector
      in the CE. In addition, the indirect method is valid for both charged and neutral
      solutes and ligands.

PMID- 12613846
TI  - Invited review: production and digestion of supplemented dairy cows on pasture.
AB  - Literature with data from dairy cows on pasture was reviewed to evaluate the
      effects of supplementation on intake, milk production and composition, and
      ruminal and postruminal digestion. Low dry matter intake (DMI) of pasture has
      been identified as a major factor limiting milk production by high producing
      dairy cows. Pasture DMI in grazing cows is a function of grazing time, biting
      rate, and bite mass. Concentrate supplementation did not affect biting rate (58
      bites/min) or bite mass (0.47 g of DM/bite) but reduced grazing time 12 min/d per
      kilogram of concentrate compared with unsupplemented cows (574 min/d).
      Substitution rate, or the reduction in pasture DMI per kilogram of concentrate,
      is a factor which may explain the variation in milk response to supplementation.
      A negative relationship exists between substitution rate and milk response; the
      lower the substitution rate the higher the milk response to supplements. Milk
      production increases linearly as the amount of concentrate increases from 1.2 to
      10 kg DM/d, with an overall milk response of 1 kg milk/kg concentrate. Compared
      with pasture-only diets, increasing the amount of concentrate supplementation up
      to 10 kg DM/d increased total DMI 24%, milk production 22%, and milk protein
      percentage 4%, but reduced milk fat percentage 6%. Compared with dry ground corn,
      supplementation with nonforage fiber sources or processed corn did not affect
      total DMI, milk production, or milk composition. Replacing ruminal degradable
      protein sources with ruminal undegradable protein sources in concentrates did not
      consistently affect milk production or composition. Forage supplementation did
      not affect production when substitution rate was high. Fat supplementation
      increased milk production by 6%, without affecting milk fat and protein content.
      Increasing concentrate from 1.1 to 10 kg DM/d reduced ruminal pH 0.08 and NH3-N
      concentration 6.59 mg/dl, compared with pasture-only diets. Replacing dry corn by
      high moisture corn, steam-flaked or steam-rolled corn, barley, or fiber-based
      concentrates reduced ruminal NH3-N concentration 4.36 mg/dl. Supplementation did
      not affect in situ pasture digestion, except for a reduction in rate of
      degradation when high amounts of concentrate were supplemented. Supplementation
      with energy concentrates reduced digestibility of neutral detergent fiber and
      intake of N but did not affect digestibility of organic matter or flow of
      microbial N.

PMID- 12613847
TI  - The impact of fortification with conjugated linoleic acid (CLA) on the quality of
      fluid milk.
AB  - The effects of added conjugated linoleic acid (CLA) on the sensory, chemical, and
      physical characteristics of 2% total fat (wt/wt) fluid milk were studied. Milks
      with 2% (wt/wt) total fat (2% CLA, 1% CLA 1% milkfat, 2% milkfat) were made by
      the addition of cream or CLA triglyceride oil into skim milk followed by HTST
      pasteurization and homogenization. The effects of adding vitamin E (200 ppm) and
      rosemary extract (0.1% wt/wt based on fat content) were investigated to prevent
      lipid oxidation. HTST pasteurization resulted in a significant decrease of the
      cis-9/trans-11 isomer and other minor CLA isomers. The cis-9/trans-11 isomer
      concentration remained stable through 2 wk of refrigerated storage. A significant
      loss of both the cis-9/trans-11 and the cis-10/trans-12 isomers occurred after 3
      wk of refrigerated storage. The loss was attributed to lipase activity from
      excessive microbial growth. No differences were found in hexanal or other common
      indicators of lipid oxidation between milks with or without added CLA (P > 0.05).
      Descriptive sensory analysis revealed that milks with 1 or 2% CLA exhibited low
      intensities of a "grassy/vegetable oil" flavor, not present in control milks. The
      antioxidant treatments were deemed to be ineffective, under the storage
      conditions of this study, and did not produce significant differences from the
      control samples (P > 0.05). CLA-Fortified milk had significantly lower L* and b*
      values compared with 2% milkfat milk. No significant differences existed in
      viscosity. Consumer acceptability scores (n = 100) were lower (P < 0.05) for CLA
      fortified milks compared to control milks, but the addition of chocolate flavor
      increased acceptability (P < 0.05).

PMID- 12613848
TI  - Sialyloligosaccharides in human and bovine milk and in infant formulas:
      variations with the progression of lactation.
AB  - Several lines of research support a role for human milk oligosaccharides in the
      defense of breast-fed infants against pathogens. Some ofthese oligosaccharides
      contain at least one moiety of sialic acid and are, thus, termed
      sialyloligosaccharides. These constitute a significant component (>1 g/L) of
      human milk. It is well established that milk composition varies among species,
      and previous reports have indicated that one ofthe differences between human and
      bovine milk is precisely their contents of sialyloligosaccharides. Because most
      infant formulas are manufactured with bovine milk components, it follows that
      formula-fed and breast-fed infants ingest dissimilar quantities of these
      carbohydrate structures. To ascertain these differences and their impact along
      lactation, the contents of oligosaccharide-bound sialic acids and major
      sialyloligosaccharides in samples of human and bovine milk (obtained at different
      lactation stages) were determined. In addition, infant formulas were assayed for
      their sialyloligosaccharide contents. Seven sialyloligosaccharides were
      identified in human milk; namely, 3'-sialyl-3-fucosyllactose and sialyllacto-N
      tetraoses (a and b+c), the predominant structures at all lactation stages. Five
      sialyloligosaccharides were identified in bovine milk, of which 6'
      sialyllactosamine and 3'-sialyllactose were the most abundant. In addition,
      sialyloligosaccharides in human and bovine milk decreased along lactation, and
      infant formulas did not contain significant amounts of sialyloligosaccharides.
      The results point to the general conclusion that regarding both qualitative and
      quantitative aspects, milk from humans and cows and infant formulas have
      different oligosaccharide contents. In this sense, bottle-fed infants are subject
      to reduced sialyloligosaccharide intake as compared to breast-fed infants.

PMID- 12613849
TI  - Effect of salt on structure-function relationships of cheese.
AB  - Our objective was to determine the effect of salt on structural and functional
      properties of cheese. Unsalted Muenster cheese was obtained on 1 d, vacuum
      packaged, and stored for 10 d at 4 degrees C. The cheese was then cut into blocks
      that were vacuum packaged. After 4 d of storage at 4 degrees C, cheese blocks
      were high-pressure injected one, three, or five times, with a 20% (wt/wt) sodium
      chloride solution. Successive injections were performed 24 h apart. After 40 d of
      storage at 4 degrees C, cheese blocks were analyzed for chemical, structural, and
      functional attributes. Injecting sodium chloride increased the salt content of
      cheese, from 0.1% in the control, uninjected cheese to 2.7% after five
      injections. At the highest levels, salt injection promoted syneresis, and, after
      five injections, the moisture content of cheese decreased from 41 to 38%.
      However, the increased salt content caused a net weight gain. Cheese pH, soluble
      nitrogen, and total and soluble calcium content were unaffected. Cheese injected
      five times had a 4% increased area of cheese occupied by protein matrix compared
      with uninjected cheese. Hardness, adhesiveness, and initial rate of cheese flow
      increased, and cohesiveness decreased upon salt injection. However, the final
      extent of cheese flow, or melting was unaffected. We concluded that adding salt
      to cheese alters protein interactions, such that the protein matrix becomes more
      hydrated and expands. However, increasing the salt content of cheese did not
      cause an exchange of calcium with sodium. Therefore, calcium-mediated protein
      interactions remain a major factor controlling cheese functionality.

PMID- 12613850
TI  - Oxidation and textural characteristics of butter and ice cream with modified
      fatty acid profiles.
AB  - The primary objective of this study was to evaluate oxidation and firmness of
      butter and ice cream made with modified milkfat containing enhanced amounts of
      linoleic acid or oleic acid. The influence of the fatty acid profile of the HO
      milkfat relating to product properties as compared with the influence the fatty
      acid profile of the HL milkfat was the main focus of the research. Altering the
      degree of unsaturation in milkfat may affect melting characteristics and
      oxidation rates, leading to quality issues in dairy products. Three milkfat
      compositions (high-oleic, high-linoleic, and control) were obtained by modifying
      the diets of Holstein cows. Ice cream and butter were processed from milkfat
      obtained from cows in each dietary group. Butter and ice cream samples were
      analyzed to determine fatty acid profile and firmness. High-oleic milkfat
      resulted in a softer butter. Solid fat index of high-oleic and high-linoleic
      milkfat was lower than the control. Control ice cream mix had higher viscosity
      compared with high-oleic and high-linoleic, but firmness of all ice creams was
      similar when measured between -17 and -13 degrees C. Nutritional and textural
      properties of butter and ice cream can be improved by modifying the diets of
      cows.

PMID- 12613851
TI  - The use of lithium chloride to study human milk micelles.
AB  - Various methods have been used to study the dissociation of milk micelles in
      attempts to determine their structure and the interactions that stabilize them.
      These include the addition of urea, cooling to alter hydrophobic bonding, the
      addition of EDTA to sequester calcium, and changes in pH to alter molecular
      charge. For this study, the mild chaotropic agent LiCl was added to human milk
      micelles, and measurements were made on the relative percentages of the six
      different phosphorylation levels of beta-casein (CN) at various LiCl
      concentrations for different lengths of time and at different temperatures. Added
      LiCl had little effect at 37 degrees C but caused maximal dissociation, mainly of
      the beta-CN species with higher phosphorylation levels, at 23 degrees C and 4
      degrees C between 1 and 2 M concentration. Comparison was made with 2-M additions
      of NaCl, MgCl2, and KCl at 4 degrees C, with LiCl showing the only appreciable
      change. The results suggest that Li+ may displace Ca2+ in protein-Ca2+-protein or
      protein-colloidal calcium phos+ phate-protein salt bridges and that the
      nonphosphorylated form of human beta-CN may change its conformation and mode of
      interaction upon phosphorylation. Lithium chloride may be useful to study the
      dissociation of the different CN in bovine milk micelles.

PMID- 12613852
TI  - Optimization and validation of a rapid method to determine citrate and inorganic
      phosphate in milk by capillary electrophoresis.
AB  - Quantification of phosphate and citrate compounds is very important because their
      distribution between soluble and colloidal phases of milk and their interactions
      with milk proteins influence the stability and some functional properties of
      dairy products. The aim of this work was to optimize and validate a capillary
      electrophoresis method for the rapid determination of these compounds in milk.
      Various parameters affecting analysis have been optimized, including type,
      composition, and pH of the electrolyte, and sample extraction. Ethanol,
      acetonitrile, sulfuric acid, water at 50 degrees C or at room temperature were
      tested as sample buffers (SB). Water at room temperature yielded the best overall
      results and was chosen for further validation. The extraction time was checked
      and could be shortened to less than 1 min. Also, sample preparation was
      simplified to pipet 12 microl of milk into 1 ml of water containing 20 ppm of
      tartaric acid as an internal standard. The linearity of the method was excellent
      (R2 > 0.999) with CV values of response factors <3%. The detection limits for
      phosphate and citrate were 5.1 and 2.4 nM, respectively. The accuracy of the
      method was calculated for each compound (103.2 and 100.3%). In addition, citrate
      and phosphate content of several commercial milk samples were analyzed by this
      method, and the results deviated less than 5% from values obtained when analyzing
      the samples by official methods. To study the versatility of the technique, other
      dairy productssuch as cream cheese, yogurt, or Cheddar cheese were analyzed and
      accuracy was similar to milk in all products tested. The procedure is rapid and
      offers a very fast and simple sample preparation. Once the sample has arrived at
      the laboratory, less than 5 min (including handling, preparation, running,
      integration, and quantification) are necessary to determine the concentration of
      citric acid and inorganic phosphate. Because of the speed and accuracy of this
      method, it is promising as an analytical quantitative testing technique.

PMID- 12613853
TI  - Detection and localization of a peptidoglycan hydrolase in Lactobacillus
      delbrueckii subsp. bulgaricus.
AB  - Peptidoglycan hydrolase activities in Lactobacillus delbrueckii subsp. bulgaricus
      were detected by analysis of bacterial extracts on denaturing polyacrylamide gel
      electrophoresis containing lyophilized Micrococcus lysodeikticus cells as
      substrate. A hydrolase with an estimated molecular mass of 80 kDa was found to
      cross-react on Western blot with monoclonal antibodies raised against muramidase
      2 of Enterococcus hirae. These antibodies were also used to demonstrate that the
      method of cell sample preparation affected protein detection. Slot and Western
      blots indicate that the peptidoglycan hydrolase from L. bulgaricus is bound to
      the cell wall. Immuno-labeling followed by optical and electron microscopic
      observations suggest that this hydrolase is intracellular and restricted mainly
      to the space between the membrane and the cell wall.

PMID- 12613854
TI  - Effect of calcium and water injection on structure-function relationships of
      cheese.
AB  - Our objectives were to determine the effect of calcium and water injection on
      cheese structure and to relate changes in structure to changes in functional
      properties of cheese. Cheese with fat and moisture content similar to that of low
      moisture part-skim Mozzarella was made according to a direct-acid,
      stirred/pressed-curd procedure. The cheese was then cut into blocks that were
      high-pressure-injected from one to five times, with either water or a 40% calcium
      chloride solution. Successive injections were performed 24 h apart. After 42 d of
      refrigerated storage, cheese microstructure and functionality were analyzed. When
      injected three or more times, water tended to increase cheese weight. The
      control, uninjected cheese, had the typical structure of a stirred/pressed-curd
      cheese: protein matrix interspersed with areas that originally contained fat
      and/or serum. Injecting water increased the area of cheese matrix occupied by
      protein, but it did not affect textural properties or melting of cheese. In
      contrast, when calcium was injected, a decrease in cheese weight was observed
      that was manifested through syneresis. The moisture content and pH of the cheese
      decreased as well. Calcium injection also decreased the area of cheese matrix
      occupied by protein. Cheese hardness increased, and cohesiveness and melting of
      cheese decreased upon calcium injection. We concluded that adding calcium to
      cheese alters how the proteins interact, which is manifested as changes in cheese
      microstructure. Such changes in cheese structure provide an understanding of
      changes in functional attributes of the cheese.

PMID- 12613855
TI  - Influence of coagulant level on proteolysis and functionality of mozzarella
      cheeses made using direct acidification.
AB  - Nonfat (0% fat), reduced-fat (11% fat), and control (19% fat) mozzarella cheeses
      were made using direct acidification to test the influence of three levels
      (0.25X, 1X, and 4X) of coagulant concentration on proteolysis, meltability and
      rheological properties of cheeses during 60 d of storage at 5 degrees C. Changes
      in meltability, level of intact alpha(s1)-casein and beta-casein (by capillary
      electrophoresis), 12.5% TCA-soluble nitrogen, and complex modulus were measured.
      There were differences in rate of proteolysis and functional properties as a
      function of fat content of the cheese, but some of these differences could be
      attributed to differences in moisture contents of the cheeses. As fat level
      decreased, the percent moisture-in-nonfat-substance of the cheeses also
      decreased. Cheeses with the lower fat contents (and consequently the lowest
      moisture-in-nonfat-substance content) had slower rates of proteolysis. Fat
      content influenced the complex modulus of the cheese, with the biggest effect
      occurring when fat content was reduced from 11 to 0%. Coagulant level had only a
      small effect on initial modulus. Cheeses became softer during storage, and the
      decrease in modulus was influenced by the level of coagulant. At 0.25X, there was
      very little decrease in modulus after 60 d, while at 1X and 4X coagulant levels
      the softening of the cheese was more evident. The influence of coagulant level
      and fat content on cheese melting was similar to their effects on complex
      modulus. In general, higher fat contents promoted more melting and so did higher
      coagulant levels. Melting increased during storage although very little change
      was observed in the nonfat cheese.

PMID- 12613856
TI  - Purification and partial characterization of psychrotrophic Serratia marcescens
      lipase.
AB  - Serratia marcescens isolated from raw milk was found to produce extracellular
      lipase. The growth of this organism could contribute to flavor defects in milk
      and dairy products. Serratia marcescens was streaked onto spirit blue agar
      medium, and lipolytic activity was detected after 6 h at 30 degrees C and after
      12 h at 6 degrees C. The extracellular crude lipase was collected after
      inoculation of the organism into nutrient broth and then into skim milk. The
      crude lipase was purified to homogeneity by ion-exchange chromatography and gel
      filtration. The purified lipase had a final recovered activity of 45.42%. Its
      molecular mass was estimated by SDS-PAGE assay to be 52 kDa. The purified lipase
      was characterized; the optimum pH was likely between 8 and 9 and showed about 70%
      of its activity at pH 6.6. The enzyme was very stable at pH 8 and lost about 30%
      of its activity after holding for 24 h at 4 degrees C in buffer of pH 6.6. The
      optimum temperature was observed at 37 degrees C and exhibited high activity at 5
      degrees C. The thermal inactivation of S. marcescens lipase was more obvious at
      80 degrees C; it retained about 15% of its original activity at 80 degrees C and
      was completely inactivated after heating at 90 degrees C for 5 min. Under optimum
      conditions, activity of the enzyme was maximum after 6 min. The Michaelis-Menten
      constant was 1.35 mM on tributyrin. The enzyme was inhibited by a concentration
      more than 6.25mM. Purified lipase was not as heat-stable as other lipases from
      psychrotrophs, but it retained high activity at 5 degrees C. At pH 6.6, the pH of
      milk, purified lipase showed some activity and stability. Also, the organism
      demonstrated lipolytic activity at 6 degrees C after 12 h. Therefore, S.
      marcescens and its lipase were considered to cause flavor impairment during cold
      storage of milk and dairy products.

PMID- 12613857
TI  - Effect of immunoglobulin G from cows immunized with ferric citrate receptor
      (FecA) on iron uptake by Escherichia coli.
AB  - The effects of immunoglobulin (Ig) G from cows immunized with the ferric citrate
      receptor (FecA) on iron uptake by Escherichia coli were investigated. Receptor
      FecA was purified from E. coli UT5600/pSV66. Cows were immunized with 400 microg
      purified FecA three times at 21 d intervals during late lactation and the
      nonlactating period. Immunoglobulin G was purified by protein G affinity
      chromatography from colostral whey from cows immunized with FecA and from
      unimmunized control cows. The purified IgG from FecA immunized cows had higher
      IgG titers against FecA compared with control IgG. Fifteen E. coli isolated from
      intramammary infections and E. coli UT5600/pSV66 were grown in an iron-depleted
      medium containing 1 mM citrate to induce FecA. The bacterial cells were mixed
      with 0, 2, and 4 mg/ml purified IgG, and 55Fe was added to the assay. After 5,
      10, and 15 min incubations at 37 degrees C, samples were passed through 0.45-pm
      pore size filters. Filters were washed with saline three times, and the
      radioactivity of 55Fe taken up by the bacterial cells on the filters was measured
      by a liquid scintillation counter. The measurements were expressed as numbers of
      55Fe atoms per colony-forming unit and transformed to log10. The assay was
      repeated three times for each isolate in a partially balanced incomplete block
      design. The presence of IgG decreased 55Fe uptake by E. coli mastitis isolates
      and E. coli UT5600/pSV66. Anti-FecA IgG reduced 55Fe uptake by E. coli greater
      than IgG from unimmunized cows.

PMID- 12613858
TI  - Fossomatic cell-counting on ewe milk: comparison with direct microscopy and study
      of variation factors.
AB  - Using the Fossomatic method (FSCC) a total of 23,003 analytical SCC observations
      were carried out on 6400 aliquots taken from 80 individual ewe milk samples with
      the objective of studying the influence of 4 preservation procedures (without
      preservation, potassium dichromate, azidiol, and bronopol), 2 storage
      temperatures (ambient and refrigeration), 10 milk ages (3,6,12, and 24h, and
      2,3,4,5,7, and 9d postcollection), and two analytical temperatures (40 and 60
      degrees C). In addition, each sample was analyzed with direct microscopic method
      (DMSCC), using 3 different stainings for each sample: methylene blue (MB), May
      Grunwald-Giemsa (MGG) and Pyronin Y-methyl green (PGM). This allowed DMSCC and
      FSCC (at 24 h of age) to be compared. The reference DMSCC from MB staining was a
      reliable method in ewe milk, though more specific stainings such as MGG and PMG
      slightly improve the residual standard deviation for repeated SCC. Between DMSCC
      and FSCC, the highest coefficients of correlation (0.972 to 0.996) corresponded
      to preserved and refrigerated milk, and the lowest (0.708 to 0.919) to
      unpreserved and ambient stored aliquots. Except for the unpreserved and ambient
      stored aliquots, SCC values were similar in all aliquots. Under FSCC,
      preservation, storage and analytical temperature, milk age, and most of the
      interactions showed a significant effect on SCC variation. In preserved samples,
      logSCC values ranged between 5.67 (bronopol) and 5.62 (azidiol). The higest
      values (5.72) were for unpreserved milk, which showed false overestimation of SCC
      due to bacterial proliferation. LogSCC was higher at 60 degrees C (5.68) than at
      40 degrees C (5.65). The interaction between age, preservation and storage
      temperature showed no cell degeneration in properly handled samples over the 9 d
      of study.

PMID- 12613859
TI  - Opsonic activity of serum and whey from cows immunized with the ferric citrate
      receptor.
AB  - The effects of immunizing dairy cows with the ferric citrate receptor, FecA, on
      the opsonic activity of serum and whey were measured in a phagocytosis assay.
      Fifteen cows were assigned to five blocks of three cows based on date of expected
      parturition. Cows within a block were randomly assigned to one of three
      treatments: 1) FecA immunization, 2) immunization with a commercially available
      Escherichia coli J5 bacterin, and 3) unimmunized controls. Cows were challenged
      at approximately 21 DIM by intramammary infusion of E. coli 727 into one mammary
      quarter. Escherichia coli 727 were opsonized for the phagocytosis assay with
      either 10% heat-inactivated serum or 50% heat-inactivated whey collected from
      each cow at calving, immediately before challenge and 7 d after challenge. Cows
      immunized with FecA or the E. coli J5 bacterin had increased IgG titers against
      FecA and E. coli 727 compared with unimmunized control cows. However, sera and
      whey collected from cows immunized with FecA did not enhance opsonization of E.
      coli 727 compared with sera and whey from control cows. Immunization with the E.
      coli J5 bacterin increased opsonization of sera greater than immunization with
      FecA. Immunoglobulin M antibody titer against E. coli 727 in whey and phagocytic
      indexes were positively correlated. The phagocytic index of whey immediately
      before challenge and 7 d after challenge were negatively associated with peak
      bacterial counts in mammary quarters challenged with E. coli 727. Results of the
      current trial suggest that the immune response resulting from immunization with
      FecA did not enhance opsonization and in vitro phagocytosis of E. coli 727.

PMID- 12613860
TI  - 5'-deiodinase activity and circulating thyronines in lactating cows.
AB  - To investigate the correlation between lactation and thyroid hormone metabolism,
      the authors studied concentrations of total and free thyroxine (T4 and fT4),
      triiodothyronine (T3 and fT3), and reverse triiodothyronine (rT3) in plasma and
      milk, as well as liver and mammary gland 5'-deiodinase (5'D) activity in dry,
      early, middle, and late lactating dairy cows. Cows in early lactation show lower
      plasma levels of T4 and rT3 than dry, middle, and late lactating animals, whereas
      T3 shows the lowest plasma levels in the dry period; free T4 and T3 show a
      similar pattern. In early lactation there is a clear decrease in liver 5'D
      associated with a notable increase in mammary 5'D. Concentrations of T4 and T3 in
      milk drop significantly in the first few days after delivery, whereas rT3
      increases up to the fourth month. The findings suggest a relationship between the
      hypothyroid status of lactating cows and the rearrangement of organ-specific 5'
      deiodinase activity related to the maintenance of the udder's function.

PMID- 12613862
TI  - The relationship between milk production and antibody response to ovalbumin
      during the peripartum period.
AB  - Suboptimal innate and immune mechanisms of host resistance during the peripartum
      period may contribute to increased incidence of mastitis. To evaluate
      associations between antibody response to ovalbumin and milk production during
      the peripartum period, 136 Holstein cows and heifers from three herds with known
      antibody response profiles, were evaluated for projected 305-d milk, protein, and
      fat yield. Using a previously described index (Wagter et al., 2000), cows were
      quantitatively classified based on their profile of antibody response to
      ovalbumin into high, average, or low antibody response groups. The single-effect
      antibody response group contributed significantly to variation in fat and protein
      yield, but not milk yield. The interaction between antibody response and parity
      significantly contributed to the variation in milk, fat, and protein yields;
      therefore the effects of group were reported on a within-parity basis. Among
      first-parity cows, low responders had a higher fat and protein yield than high or
      average antibody responder animals. Among older cows (parity 3 or greater) milk
      yield was significantly higher for those in the high antibody response group
      compared with average and low response groups. However, no significant
      differences in fat or protein yields were observed between high and low antibody
      response groups. These results suggest the possibility to select cows for
      enhanced immune response with no adverse effects on yield. That first-parity cows
      with low antibody response produce more fat and protein may be offset by the fact
      that mastitis occurrence was highest in this group in two out of three herds
      investigated. Selection for high immune response may prove beneficial to herd
      life by maintaining optimal yield, yet minimizing occurrence of disease.

PMID- 12613861
TI  - Efficacy of intramammary tilmicosin and risk factors for cure of Staphylococcus
      aureus infection in the dry period.
AB  - The objective ofthis study was to evaluate the efficacy of intramammary
      tilmicosin, administered at drying-off, for eliminating Staphylococcus aureus
      infection, and to identify risk factors for S. aureus cure during the dry period.
      A total of 219 naturally infected cows, representing 308 quarters, were
      randomized to receive either one of two treatments at drying-off. Cows received
      either an intramammary infusion of 500 mg of benzathine cloxacillin, or a sterile
      solution containing 1,500 mg of tilmicosin. All cows had quarter milk samples
      taken aseptically three times before dry-off, and at wk 1, 2, and 4 of the
      subsequent lactation. Overall, 62% of cows and 67.5% of quarters infected with S.
      aureus cured during the dry period. The cure following administraton of
      tilmicosin was 67.3 and 72.5% for cows and quarters, respectively. By comparison,
      the cure achieved with cloxacillin was 56.9 and 62.9% of cows and quarters. Cows
      receiving tilmicosin were 2.1 times more likely to cure. The cure rate for cows
      decreased as the linear score on the last DHI test increased, and as the amount
      of S. aureus being shed increased. Quarters that cultured positive multiple times
      before drying-off were less likely to cure. Staphylococcus aureus infections
      located in front quarters of the udder were 2 times more likely to cure than
      those in hind quarters. Results of this study demonstrate that intramammary
      tilmicosin at drying-off is efficacious in curing existing S. aureus during the
      dry period. Risk factors associated with the cure of S. aureus were identified.

PMID- 12613863
TI  - Effects of corn grain conservation method on feeding behavior and productivity of
      lactating dairy cows at two dietary starch concentrations.
AB  - Effects of conservation method of corn grain and dietary starch concentration on
      dry matter intake (DMI) and productivity of lactating dairy cows were evaluated.
      Eight ruminally and duodenally cannulated Holstein cows (55 +/- 15.9 d in milk;
      mean +/- SD) were used in a duplicated 4 x 4 Latin square design with a 2 x 2
      factorial arrangement of treatments. Experimental diets contained either ground
      high-moisture corn (HM) or dry ground corn (DG) at two dietary starch
      concentrations (32 vs 21%). Mean particle size and dry matter (DM) concentration
      of corn grain were 1863 pm and 63.2%, and 885 microm and 89.7%, for HM and DG,
      respectively. DMI was lower for HM compared to DG treatment in high-starch diets
      (20.8 vs 22.5 kg/d), but similar for the HM and DG treatments in low-starch diets
      (19.7 vs 19.6 kg/d). This reduction in DMI is attributed to smaller meal size for
      HM compared to DG in high-starch diets (1.9 vs 2.3 kg of DM for high-starch
      diets; 2.1 vs 2.0 kg of DM for low-starch diets). Faster starch fermentation for
      HM in high-starch diets might result in satiety with smaller meal size. Milk
      yield was greater when cows were fed high-starch diets compared to low-starch
      diets (38.6 vs 33.9 kg/d) regardless of corn grain treatment. High-starch diets
      increased solids-corrected milk yield by 3.3 kg (35.2 vs 31.9 kg/d) compared to
      low-starch diets for cows fed DG, but did not increase for cows fed HM. This was
      because of a lower milk fat concentration for cows fed HM in high-starch diets.
      Reducing ruminal starch fermentation by substituting DG for HM can increase the
      productivity of lactating cows fed high-starch diets.

PMID- 12613864
TI  - Effects of corn grain conservation method on ruminal digestion kinetics for
      lactating dairy cows at two dietary starch concentrations.
AB  - Effects of conservation method of corn grain and dietary starch concentration on
      ruminal digestion kinetics were evaluated. Eight ruminally and duodenally
      cannulated Holstein cows (55 +/- 15.9 days in milk; mean +/- SD) were used in a
      duplicated 4 x 4 Latin square design with a 2 x 2 factorial arrangement of
      treatments. Experimental diets contained either ground high moisture corn (HM) or
      dry ground corn (DG) at two dietary starch concentrations (32 vs. 21%). Mean
      particle size and dry-matter concentration of corn grain were 1,863 microm and
      63.2%, and 885 microm and 89.7%, for HM and DG, respectively. Starch
      digestibility in the rumen was greater for HM treatments compared with DG
      treatments, but starch digestibility in the total tract was not affected by
      conservation method of corn grain because of compensatory digestion in the
      intestines. The difference in ruminal starch digestibility between HM and DG
      treatment was greater for high-starch diets (71.1 vs. 46.9%) compared with low
      starch diets (58.5 vs. 45.9%). This interaction is attributed to a greater
      difference in first-order digestion rate of starch between HM and DG treatment in
      high-starch diets (28.2 vs. 14.6%/h) compared with low-starch diets (16.8 vs.
      12.2%/h). This suggests that ruminal starch digestion is a second-order reaction
      limited by enzyme activities as well as substrate availability; ruminal contents
      of cows fed low-starch diets may have insufficient amylolytic activity for
      maximal starch digestion when readily fermentable starch is available. Rate of
      neutral detergent fiber digestion in the rumen was slower for high-starch diets
      and HM treatments compared with low-starch diets and DG treatments, respectively.
      Effects of corn grain conservation method on ruminal digestion kinetics are
      greatly altered by starch concentration of diets.

PMID- 12613865
TI  - Effects of diet fermentability on efficiency of microbial nitrogen production in
      lactating dairy cows.
AB  - Effect of diet fermentability on efficiency of microbial N production was
      evaluated. Eight ruminally and duodenally cannulated Holstein cows (55 +/- 15.9
      days in milk; mean +/- SD) were used in a duplicated 4 x 4 Latin square design
      with a 2 x 2 factorial arrangement of treatments. Experimental diets contained
      either ground high moisture corn (HM) or dry ground corn (DG) at two dietary
      starch concentrations (32 vs. 21%). All diets were formulated for 18% CP, and the
      sources of dietary protein were alfalfa silage (50% of forage at DM basis),
      soybean meal, distillers grain, and blood meal. The amount of OM truly fermented
      in the rumen varied from 7.7 (DG at 21% dietary starch) to 11.3 kg/d (HM at 32%
      dietary starch) among treatments, and was greater for high starch diets and HM
      treatments compared with low starch diets and DG treatments, respectively.
      Microbial N flow was greater for high starch diets compared with low starch
      diets, but was not affected by corn grain treatment. Microbial efficiency was
      lower for HM compared with DG treatment (39.7 vs. 48.4 g of microbial N/kg of
      true ruminally degraded OM), but was not affected by dietary starch
      concentration. Microbial efficiency was positively correlated with rate of
      passage for OM and starch (r = 0.77 and 0.75, respectively). Rapid passage rate
      may have decreased microbial turnover in the rumen, enhancing microbial
      efficiency. Microbial efficiency was negatively correlated with rate of starch
      digestion (r = -0.55), consistent with the energy spilling theory. However,
      energy spilling did not appear to be from lack of ammonia or low ruminal pH.
      Microbial efficiency was not related to ruminal ammonia concentration, daily mean
      ruminal pH, or minimum ruminal pH. Rate of starch availability and rates of
      passage for starch and OM from the rumen are important determinants of efficiency
      of microbial protein synthesis in vivo.

PMID- 12613866
TI  - Corn silage management: effects of hybrid, chop length, and mechanical processing
      on digestion and energy content.
AB  - Two experiments were conducted to evaluate the effects of chop length and
      mechanical processing of two hybrids of whole plant corn on digestion and energy
      content of the total mixed ration (TMR). The experimental designs in experiments
      1 and 2 were 6 x 6 and 4 x 4 Latin squares, respectively. In the first
      experiment, Pioneer hybrid 3845 was harvested at three theoretical lengths of
      cut: 11.1, 27.8, and 39.7 mm. At each chop length, corn was harvested with and
      without mechanical processing using a John Deere 5830 harvester with an onboard
      kernel processor. In the second experiment, Pioneer hybrid Quanta was harvested
      at two theoretical lengths of cut: 27.8 and 39.7 mm, with and without mechanical
      processing. In both experiments, the increase in the theoretical length of cut of
      corn silage increased the average length of cut and tended to increase the
      percentage of particles greater than 19 mm and lower the percentage of particles
      between 8 and 19 mm. In experiment 1, apparent total tract dry matter, organic
      matter, and neutral detergent fiber (NDF) digestibilities were lower for cows fed
      diets containing corn silage harvested at a short chop length (11.1 mm) than for
      corn silage harvested at a long chop length (39.7 mm). The lower total tract
      digestibility of nutrients may have contributed to the lower TDN, metabolizable
      energy (percentage of digestible energy), and NEL concentration of diets
      containing the short chop length corn silage (experiment 1). In experiment 2,
      total tract starch digestibility was greater for cows fed medium chop (27.8 mm)
      corn silage diets, and total tract NDF digestibility was greater for cows fed
      long chop (39.7 mm) corn silage diets. The opposing effect of total tract starch
      and fiber digestibilities between chop lengths may have contributed to the lack
      of difference in energy content of the diets in experiment 2. The TDN and NEL
      concentrations of the processed corn silage diets were greater than the
      unprocessed corn silage diets in experiment 1. The increase in energy
      concentration for the processed corn silage diet was due to greater total tract
      digestibility of organic matter and ether extract. Total tract starch
      digestibility was greater, and total tract NDF digestibility was lower for cows
      fed processed corn silage diets than unprocessed corn silage diets in experiment
      2. The opposing effect of total tract starch and fiber digestibilities between
      processed and unprocessed corn silage may have contributed to the lack of
      difference in energy content of the diets.

PMID- 12613867
TI  - Effects of hot, humid weather on milk temperature, dry matter intake, and milk
      yield of lactating dairy cows.
AB  - Lactating cows were exposed to moderate and hot, humid weather to determine the
      effect of increasing ambient temperature, relative humidity, or temperature
      humidity index (THI) on intake, milk yield, and milk temperature. Minimum and
      maximum temperatures averaged 17.9 and 29.5 degrees C (cool period) and 22.5 and
      34.4 degrees C (hot period), and minimum and maximum THI averaged 63.8 and 76.6
      (cool period) and 72.1 and 83.6 (hot period). Environmental conditions had minor
      effects on intake and milk yield during the cool period. During the hot period,
      the THI 2 d earlier and mean air temperature 2 d earlier had the greatest impact
      on milk yield and DMI, respectively. Both breeds maintained milk temperature
      within normal ranges during the cool period, but Holstein and Jersey p.m. milk
      temperatures averaged 39.6 and 39.2 degrees C during the hot period. Current day
      mean air temperature during the hot period had the greatest impact on cow p.m.
      milk temperature, and minimum air temperature had the greatest influence on a.m.
      milk temperature. Dry matter intake and milk yield declined linearly with
      respective increases in air temperature or THI during the hot period and milk
      temperature increased linearly with increasing air temperature. Dry matter intake
      and milk yield both exhibited a curvilinear relationship with milk temperature.
      Environmental modifications should target the effects of high temperatures on cow
      body temperature and should modify the environment at critical times during the
      day when cows are stressed, including morning hours when ambient temperatures are
      typically cooler and cows are not assumed to be stressed.

PMID- 12613868
TI  - Lactational effect of propionic acid and duodenal glucose in cows.
AB  - Five dairy cows were arranged in a 5 x 5 Latin square design to compare the
      effects of two amounts of either duodenal glucose or ruminal propionic acid (C3)
      on milk yield and composition. Treatments consisted of a grass silage-based diet
      supplemented with glucogenic nutrients either infused in the rumen as a mixture
      of volatile fatty acids (control) or pure C3 (1.72 and 3.45 Mcal/d) or in the
      duodenum as glucose (1.72 and 3.45 Mcal/d). Treatments were isoenergetic and
      isonitrogenous and contained 100 and 115% of energy and protein requirements
      according to INRA (1989), respectively. Only C3 treatments significantly modified
      ruminal volatile fatty acid composition and linearly increased C3 percentage (up
      to 25.5%). Both treatments substantially decreased milk fat yield and content,
      and linearly increased milk and protein yields. Although no significant
      differences between glucose and C3 were highlighted for milk yield and
      composition, it seems that mechanisms involved in milk fat decrease are
      different. Indeed, whereas C3 treatments decreased fatty acid production in an
      homogeneous way, short- and long-chain fatty acids decreased and medium-chain
      fatty acid production increased with glucose treatments. A bibliographical study
      confirmed that increasing glucogenic precursors (GP) supply curvilinearly
      increase milk yield, linearly increase milk protein content (+ 0.04% per Mcal of
      GP) and curvilinearly decrease milk fat content (- 0.14% per Mcal of GP). Thus,
      it appears important to account for the nature of energy supplied by the ration
      in formulation.

PMID- 12613870
TI  - Dietary protein to metabolizable energy ratios on feed efficiency and structural
      growth of prepubertal Holstein heifers.
AB  - Sixty Holstein heifers, 124.5 +/- 1.1 d of age and 124.9 +/- 2.5 kg of BW, were
      used to evaluate the influence of dietary crude protein to metabolizable energy
      ratio (CP:ME) on feed efficiency, structural growth, and body condition score.
      Treatment rations containing a specific CP:ME ratio were assigned to heifers in a
      complete randomized block design with treatment periods lasting 20 wk. The CP:ME
      ratios were 48.3, 59.1, 67.5, and 76.5 g of CP per Mcal of ME. The CP:ME ratios
      were altered by adjusting the concentration of CP (12.0,15.2, 17.4, and 19.7% CP)
      with similar amounts of ME (2.6 Mcal/kg DM) across all treatment rations. BW was
      recorded weekly on two consecutive days and used to adjust dry matter intake to
      allow approximately 0.80 kg/d gain. Average daily gain did not differ between the
      treatment rations, 0.74, 0.81, 0.81, 0.77 kg/d, low to highest CP:ME ratio,
      respectively. Dry matter intake showed a quadratic effect for the treatment
      rations, 3.30, 3.41, 3.48, and 3.39 kg/d, low to highest CP:ME ratio,
      respectively, and averaged 2.0% BW. Feed efficiency improved linearly with
      increasing CP:ME ratios, 4.76, 4.42, 4.35, and 4.33, respectively. The increased
      CP:ME ratios were accompanied by increasing levels of plasma urea N, 9.88, 13.34,
      14.94, and 16.57 mg/dl, respectively. A trend toward linear increases in wither
      and hip height growth resulted with increasing CP:ME. Hip width growth was
      quadratic with increasing CP:ME ratios. Observed linear effects in feed
      efficiency and some structural growth measurements demonstrate positive results
      when feeding CP:ME ratios >48.3 to Holstein heifers between 125 and 234 kg of BW
      and gaining 0.80 kg/d.

PMID- 12613869
TI  - Increasing dietary levels of cracked pima cottonseed increase plasma gossypol but
      do not influence productive performance of lactating Holstein cows.
AB  - Lactating Holstein cows were fed diets with increasing levels of cracked Pima
      cottonseed to determine its effects on plasma gossypol concentrations as well as
      milk yield and composition and dry matter (DM) intake in a short-term study. All
      diets contained 12.8% cottonseed, 43.5% concentrate, and 43.7% chopped alfalfa
      hay on a DM basis. The proportion of whole Upland cottonseed to cracked Pima
      cottonseed in the four dietswas 100:0, 67:33, 33:67, and 0:100. Four primiparous
      cows were fed the diets in a 4 x 4 Latin square design, and three multiparous
      cows were fed the diets in a Youden square design with five periods. All periods
      were 35 d. Upland and cracked Pima cottonseed contained 0.64 and 1.00% total
      gossypol (DM) with 41 and 52% of gossypol as the (-) isomer, respectively.
      Gossypol is a natural defense compound in the plant that protects it against
      pests and diseases, but can have antinutritional quality effects when consumed by
      dairy cattle. Total plasma gossypol concentrations increased linearly with
      increasing proportions (100:0, 67:33, 33:67, and 0:100) of cracked Pima
      cottonseed in the diet for primiparous (4.4, 6.0, 7.7, and 8.9 microg/ml) and
      multiparous (4.3, 7.3, 9.7, and 11.4 microg/ml) cows, respectively. While
      primiparous cows responded similarly to gossypol intake, the response of plasma
      gossypol intake in multiparous cows differed among cows. This indicates the
      importance of animal variation when relating plasma gossypol levels with gossypol
      intake. Milk yield, as well as its components and DM intake, were not affected by
      increasing dietary inclusion levels of cracked Pima cottonseedup to 8.6% of DM
      intake for either primiparous or multiparous cows, even though plasma gossypol
      concentrations increased sharply over this dietary inclusion range. Although the
      highest dietary inclusion level of Pima cottonseed (i.e., 12.8%) numerically
      depressed performance of cows of both parities, these differences failed to reach
      statistical significance in these short-term trials with few cows.

PMID- 12613872
TI  - Corn silage management: effects of hybrid, maturity, inoculation, and mechanical
      processing on fermentation characteristics.
AB  - Two experiments were conducted to evaluate the effects of hybrid, maturity,
      mechanical processing, and inoculation of corn silage on fermentation
      characteristics. In experiment 1, Pioneer hybrid 3845 corn silage was harvested
      at three maturities (hard dough, one-third milkline, two-thirds milkline). In
      experiment 2, Pioneer hybrids 3845 and Quanta were harvested at three maturities
      (one-third milkline, two-thirds milkline, and blackline). In both experiments,
      corn silage was harvested at each maturity with and without mechanical processing
      and with and without inoculation. In experiments 1 and 2, corn silage was
      harvested at a theoretical length-of-cut of 6.4 and 12.7 mm, respectively.
      Maturity at harvest tended to have a greater impact on silage fermentation
      characteristics of corn silage than mechanical processing and inoculation. In
      experiments 1 and 2, corn silage harvested at the earliest maturity tended to
      have decreased dry matter content and increased water-soluble carbohydrate
      concentrations during the ensiling process than corn silage harvested at advanced
      maturities. In experiment 2, pH levels were lower for corn silage harvested at
      the early maturity (one-third milkline) compared with advanced maturities (two
      thirds milkline and blackline) by 57 d after ensiling. The difference in pH can
      be explained by the greater concentration of water-soluble carbohydrates at the
      early maturity (one-third ML) soon after ensiling (2, 3, 6 and 10 d after
      ensiling) compared with advanced maturities (two-thirds ML and BL). The increased
      water-soluble carbohydrate concentrations in the less mature corn silage provided
      nutrients for bacteria to grow and produce primarily lactic acid (6, 10, and 57 d
      after ensiling) and some acetic acid (2, 3, 6, and 10 d after ensiling) which
      reduced the pH of corn silage more than at the advanced maturities. There was a
      slight change in silage fermentation characteristics when corn silage was
      inoculated with Pioneer 1132 inoculant in experiment 1. The inoculated corn
      silage had increased temperature, lactate and acetate concentrations, and lower
      water-soluble carbohydrate and pH levels compared with uninoculated corn silage.
      Dry matter recovery tended to be greater for processed corn silage in experiment
      1, and greater for unprocessed corn silage in experiment 2. It appears that when
      fermentation was greater (increased temperature and lactate concentration 57 d
      after ensiling) the dry matter recovery was lower.

PMID- 12613871
TI  - Milk production, nutrient utilization, and endocrine responses to increased
      postruminal lysine and methionine supply in dairy cows.
AB  - The effect of increased postruminal supply of lysine and methionine was
      investigated in a production trial involving 64 dairy cows in early lactation.
      Within each of two basal rations, based on either corn silage or grass silage,
      rations were either naturally deficient in lysine or fortified with 24 g of
      lysine in a rumen-protected form and naturally deficient in methionine or
      fortified with 12 g of methionine in a rumen-protected form. The data were
      analyzed separately for the four lysine and the four methionine treatment groups.
      Milk production, body weight gain, and plasma concentrations of insulin-like
      growth factor-I, bovine somatotropin, insulin, glucose, nonesterified fatty
      acids, and urea were monitored over a 12-wk period. Supplementation with
      protected methionine led to increases in milk fat and protein contents of 2.4 and
      1.8 g/kg of milk, respectively. Supplementation with protected lysine or
      methionine numerically increased protein yield comparable to values reported in
      the literature, but the treatment effects were not statistically significant.
      Efficiency of utilization of absorbed amino acids for milk protein synthesis and
      efficiency of utilization of metabolizable energy for milk production were not
      significantly altered in response to increased postruminal lysine and methionine
      flow, but a numerically increased efficiency of utilization of total amino acids
      was observed. No significant effect of lysine or methionine supplementation was
      observed on endocrine parameters nor on plasma metabolite concentrations.
      However, across treatment groups, high milk yield was correlated with low plasma
      insulin-like growth factor-I concentrations (r = -0.44) and partially with low
      plasma nonesterified fatty acids concentration and insulin levels (r = -0.26),
      while body weight gain was negatively correlated (r = -0.33) with elevated plasma
      bovine somatotropin concentrations.

PMID- 12613873
TI  - Predicting average feed intake of lactating Holstein cows fed totally mixed
      rations.
AB  - A dry matter intake (DMI) prediction equation was estimated by using a data file
      that contained 124 treatment means collected from published studies. Animal
      factors considered for inclusion in the prediction model were body weight (BW)
      and its natural logarithm, BW(0.75), milk yield (MY) and its natural logarithm,
      milk fat and protein yields, month of lactation and its square, as well as its
      natural logarithm. The dietary factors considered were the percentages of neutral
      detergent fiber, acid detergent fiber, crude protein and hemicellulose in the
      ration dry matter together with the square of all these predictors. The multiple
      regression model selected by using the maximum R2 method include both animal and
      dietary factors as independent variables. The accuracy of this DMI prediction
      equation was evaluated and compared with that of five other equations previously
      published by using three independent datasets also containing treatment means
      collected from literature. Even though the latest NRC equation was slightly more
      accurate than the equation proposed in this study with the three evaluation
      datasets, the latter can be used for some applications for which the NRC equation
      is not appropriate.

PMID- 12613874
TI  - Monensin by fat interactions on trans fatty acids in cultures of mixed ruminal
      microorganisms grown in continuous fermentors fed corn or barley.
AB  - In previous studies, monensin (M) and unsaturated plant oils independently
      increased trans fatty acid concentrations in cultures of mixed ruminal
      microorganisms. This study was conducted to determine if combining M with plant
      oil yielded interactions on trans fatty acid concentrations in cultures of mixed
      ruminal microorganisms or their effects were additive. Four continuous fermentors
      were fed 14 g of dry feed per day (divided equally between two feedings),
      consisting of alfalfa hay pellets (30% of DM) and either a high corn (HC) or a
      high barley (BB) concentrate (70% of DM) in each of two fermentors. Within each
      grain type, one fermentor was supplemented with M (25 ppm), and the other
      fermentor was supplemented with 5% soybean oil (SBO) during d 5 to 8. Monensin
      and SBO were added together in all fermentors during d 9 to 12. Samples were
      taken at 2 h after the morning feeding on the last day of each period and
      analyzed for fatty acids by gas-liquid chromatography. A second run of the
      fermentors followed the same treatment sequence to give additional replication.
      Average pH across all treatments was 6.15, which was reduced by M but not
      affected by SBO. Monensin reduced the ratio of acetate to propionate (A:P), which
      averaged 2.03 across all treatments; fat decreased A:P in cultures not receiving
      M but increased it in the presence of M. Monensin and SBO altered the
      concentration of several trans fatty acids, but the only interaction was a grain
      x M x SBO interaction for trans-10 C18:1. The increase in trans-10 C18:1 by the M
      and SBO combination exceeded the sum of increases in trans-10 C18:1 for each
      individual feed additive, but only for KB. For the HC diet, M increased trans-10
      C18:1 more than fat alone and more than the M and SBO combination. The results of
      this study show that M and SBO effects are additive for all trans FA except for
      trans-10 C18:1. In the case of trans-10 C18:1, M and SBO interacted to give
      higher trans-10 C18:1 concentrations in ruminal contents than would be expected
      simply by adding their individual effects, but only for HB. Because some trans
      fatty acid isomers have been associated with milk fat depression in dairy cows,
      these results suggest more severe depressions in milk fat content when cows are
      fed M along with unsaturated plant oils.

PMID- 12613875
TI  - Direct-fed microbial supplementation on the performance of dairy cattle during
      the transition period.
AB  - The influence of a direct-fed microbial (DFM) on the prepartum period and the
      effects on production performance during the postpartum period was investigated
      using 64 multiparous Holstein cows. Two close-up dry cow diets were fed to two
      groups of 32 cows each starting 21 d precalving as follows: 1) no DFM and 2) DFM.
      Post-calving cows were fed a lactation ration with or without DFM
      supplementation.The direct-fed microbial (DFM) supplement contained 2 * 109
      viable yeast cells and 5 * 109 cfu of bacteria (Enterococcus faecium) per cow per
      day, top dressed in a 90-g supplement [corrected].The DMI during the prepartum
      period was not affected by DFM supplementation. During the postpartum period,
      DMI, milk yield, and milk protein content were higher for cows receiving DFM
      supplementation compared with no DFM. Blood glucose and insulin levels were
      higher and NEFA levels were lower for cows receiving DFM during the postpartum
      period. These data suggest that targeted DFM supplementation increased DMI and
      milk production postpartum. Blood metabolite information would suggest this
      response was associated with more glucose being made available and less fatty
      acids being mobilized from lipid stores.

PMID- 12613876
TI  - The effect of treating alfalfa with Lactobacillus buchneri 40788 on silage
      fermentation, aerobic stability, and nutritive value for lactating dairy cows.
AB  - Lactobacillus buchneri 40788 and enzymes (beta-glucanase, alpha-amylase,
      xylanase, and galactomannase) were applied to chopped alfalfa (39% DM) to study
      their effects on the fermentation and nutritive value of the silage. Alfalfa was
      treated with nothing, or L. buchneri 40788, for a final application rate of 1 x
      10(5), 5 x 10(5), or 1 x 10(6) cfu/g of fresh forage and ensiled in laboratory
      silos for 2, 4, 8, and 56 d. Treatment with L. buchneri 40788 had few effects on
      the end products of fermentation through 8 d of ensiling. However, after 56 d of
      ensiling, treated silages had a higher pH (4.55 vs. 4.38) and higher
      concentrations of acetic acid (6.40 vs. 4.24%), propionic acid (0.18 vs. 0.06%),
      and ammonia-N (0.35 vs. 0.29%) when compared to untreated silage. Lactic acid was
      also numerically lower in treated (3.51%) than untreated (4.12%). Silages treated
      with the moderate and highest dose of L. buchneri 40788 also resulted in greater
      recoveries of DM than did untreated silage. Alfalfa (43% DM) was also untreated
      or treated with a commercial application of L. buchneri 40788 (4 x 10(5) cfu/g, a
      commercial dose) in farm-scale bag silo. Holstein cows were fed a diet comprised
      of 32% untreated or treated alfalfa silage, 11% corn silage, 5% chopped alfalfa
      hay, and 52% of concentrate (DMB) for a 6-wk treatment period. Dry matter intake
      and milk composition were unaffected by treatment, but cows fed silage treated
      with L. buchneri 40788 produced 0.8 kg more milk than did cows fed untreated
      silage. Treated silage had a higher concentration of acetic acid (5.67 vs. 3.35%)
      but lower lactic acid (3.50 vs. 4.39%) than untreated silage. When exposed to
      air, the total mixed ration containing treated alfalfa silage remained stable for
      100 h, whereas the ration containing untreated silage spoiled after 68 h.
      Treating alfalfa silage with L. buchneri 40788 increased the concentration of
      acetic acid, and when the silage was combined into a total mixed ration and fed
      to lactating cows, it improved the aerobic stability of the ration and increased
      milk production.

PMID- 12613877
TI  - Reassessment of biases in predicted nitrogen flows to the duodenum by NRC 2001.
AB  - The appearance of numerous plots in recent literature from which the residuals
      are plotted against observed values (Y) to assess a model's potential bias raises
      this question: should residuals be regressed against Y or against predicted
      values (Y)? The answer requires knowing the expected relationship under the
      assumption of an unbiased model. The objectives of this paper are: 1) to derive
      the expected relationship between residuals, Y, and Y; 2) to determine whether Y
      or Y should be used for the assessment of bias; and 3) to reassess the extent of
      mean and linear bias in the prediction of N flows to the duodenum by the NRC
      (2001). In the simplest case, we can assume a true model of the form Y = Xbeta +
      epsilon. This model is estimated by Y = Xb + e, and Y = Xb. The correlation
      between the residual vector e and the vector of observations Y can easily be
      derived. The numerator of the correlation coefficient is shown to be equal to
      e'e, the residual sum of squares. The denominator of this correlation is equal to
      the square root of e'e multiplied by the total sum of squares. Algebraic
      simplifications show that the correlation between e and Y is equal to the square
      root of (1-R2). That is, under the assumption of an unbiased model, the residuals
      are correlated with the observed values and the slope of e regressed on Y is
      equal to (1-R2). Thus, a graph of e versus Y will show a positive slope between e
      and Y unless the model is a perfect predictor (i.e., R2 is equal to 1.0).
      Significant slopes linking e to Y have been erroneously interpreted as evidence
      of biased models in the NRC (2001). Conversely, the slope of e regressed on Y is
      expected to be zero under the assumption of an unbiased model. Therefore,
      residuals should be regressed against Y and not Y. When Y, as opposed to Y, was
      used to assess biases in the prediction of flows to the duodenum of microbial N,
      nonammonia-nonmicrobial N and nonammonia N in NRC (2001), mean biases became
      nonsignificant and linear biases over the range of predicted values are of the
      same magnitude or smaller than the standard errors of measurements reported in
      literature. Thus, although N flow predictions from NRC (2001) may not be precise,
      they appear to have insignificant and inconsequential biases.

PMID- 12613878
TI  - In vitro versus in situ ruminal biohydrogenation of unsaturated fatty acids from
      a raw or extruded mixture of ground canola seed/canola meal.
AB  - Raw or extruded blends of ground canola seeds and canola meal were used to
      compare in vitro and in situ lag times and rates of disappearance due to ruminal
      biohydrogenation of unsaturated fatty acids. The in situ study resulted in higher
      lag times for biohydrogenation for polyunsaturated fatty acids and lower rates of
      biohydrogenation of unsaturated fatty acids than the in vitro study, so the in
      situ biohydrogenation of polyunsaturated fatty acids was not complete at 24 h of
      incubation. With both methods, rates of biohydrogenation of polyunsaturated fatty
      acids were higher than for cis-delta9C18:1. Extrusion did not affect the rate of
      biohydrogenation of cis-delta9C18:1, but resulted in higher rates of
      biohydrogenation of polyunsaturated fatty acids with higher proportions of trans
      intermediates of biohydrogenation at 4 h of incubation in vitro and at 8 h of
      incubation in situ. These results suggest that extrusion affects the
      isomerization of polyunsaturated fatty acids, rather than the hydrogenation
      steps. In conclusion, in vitro and in situ methods can both show differences of
      ruminal metabolism of unsaturated fatty acids due to processing, but the methods
      provide very different estimates of the rates of disappearance due to
      biohydrogenation.

PMID- 12613879
TI  - Quantitative trait loci mapping of functional traits in the German Holstein
      cattle population.
AB  - A whole-genome scan to detect quantitative trait loci (QTL) for functional traits
      was performed in the German Holstein cattle population. For this purpose, 263
      genetic markers across all autosomes and the pseudoautosomal region of the sex
      chromosomes were genotyped in 16 granddaughter-design families with 872 sons. The
      traits investigated were deregressed breedingvalues for maternal and direct
      effects on dystocia (DYSm, DYSd) and stillbirth (STIm, STId) as well as maternal
      and paternal effects on nonreturn rates of 90 d (NR90m, NR90p). Furthermore,
      deregressed breeding values for functional herd life (FHL) and daughter yield
      deviation for somatic cell count (SCC) were investigated. Weighted multimarker
      regression analyses across families and permutation tests were applied for the
      detection of QTL and the calculation of statistical significance. A ten percent
      genomewise significant QTL was localized for DYSm on chromosome 8 and for SCC on
      chromosome 18. A further 24 putative QTL exceeding the 5% chromosomewise
      threshold were detected. On chromosomes 7, 8, 10, 18, and X/Yps, coincidence of
      QTL for several traits was observed. Our results suggest that loci with influence
      on udder health may also contribute to genetic variance of longevity. Prior to
      implementation of these QTL in marker assisted selection programs for functional
      traits, information about direct and correlated effects of these QTL as well as
      fine mapping of their chromosomal positions is required.

PMID- 12613880
TI  - Genetic change for clinical mastitis in Norwegian cattle: a threshold model
      analysis.
AB  - Records of clinical mastitis on 1.6 million first-lactation daughters of 2,411
      Norwegian Cattle sires that were progeny tested from 1978 through 1998 were
      analyzed with a threshold model. The main objective was to infer genetic change
      for the disease in the population. A Bayesian approach via Gibbs sampling was
      used. The model for the underlying liability had age at first calving, month x
      year of calving, herd x 3-year-period, and sire of the cow as explanatory
      variables. Posterior mean (SD) of heritability of liability to clinical mastitis
      was 0.066 (0.003). Genetic evaluations (posterior means) of sires both in the
      liability and observable scales were computed. Annual genetic change of liability
      to clinical mastitis for progeny tested bulls born from 1973 to 1993 was
      assessed. The linear regression of mean sire effect on year of birth had a
      posterior mean (SD) of -0.00018 (0.0004), suggesting a nearly constant genetic
      level for clinical mastitis. However, an analysis of sire posterior means by
      birth-year of daughters indicated an approximately constant genetic level in the
      cow population from 1976 to 1990 (-0.02%/yr), and a genetic improvement
      thereafter (-0.27%/yr). This reflects more emphasis on mastitis in selection of
      bulls in recent years. Corresponding results obtained with a standard linear
      model analysis were -0.01% and -0.23% per year, respectively (regression of sire
      predicted transmitting ability on birth-year of daughters). Genetic change seems
      to be slightly understated with the linear model, assuming the threshold model
      holds true.

PMID- 12613881
TI  - Application of a multiple-trait herd cluster model for genetic evaluation of
      dairy sires from seventeen countries.
AB  - The multiple-trait across country evaluation method is currently used for
      international genetic evaluation of dairy sires. This method simultaneously
      combines national estimated breeding value (EBV) of sires in all countries and
      produces a separate breeding value to be used in each of the 24 countries that
      participate in the service. The major drawbacks to this method are the large
      number of genetic parameters that must be estimated and the large number of EBV
      produced for each sire. In the current method, each sire receives an EBV for each
      separate environment, and environments change at the country borders. It is
      unreasonable to assume that each country contains only one homogeneous
      environment and that every country has a distinctly different environment from
      all others. In the present study, an alternative method for international sire
      evaluation was utilized. Herds were grouped according to important management,
      climatic, and genetic factors rather than country borders. Data consisted of
      16,403,413 first lactation cows in Australia, Austria, Belgium, Canada, Czech
      Republic, Estonia, Finland, Germany, Hungary, Ireland, Israel, Italy, The
      Netherlands, New Zealand, South Africa, Switzerland, and the United States. Herds
      were grouped according to 13 descriptive herd variables, including temperature,
      rainfall, peak yield, persistency, herd-size, age at calving, seasonality of
      calving, standard deviation of milk yield, culling percentage, fat-to-protein
      ratio, days to peak yield, percent of North American Holstein genes, and average
      PTA milk of sires. Variables were weighted by their relative importance in
      explaining genotype by environment interactions between herds. Herds were grouped
      into seven clusters; clusters ranged in size from 4805 to 59,272 herds and
      1,414,966 to 3,966,431 cows. The proposed model predicts EBV for dairy sires
      based on the production environment in which their progeny wili perform, rather
      than the country where they will be located.

PMID- 12613882
TI  - Genotype x environment interactions in conventional versus pasture-based dairies
      in Canada.
AB  - The objective of this study was to evaluate effects of genotype x environmental
      interaction (GxE) on dairy traits among herds in Canada that practice intensive
      rotational grazing versus conventional methods that rely on stored feeds. Based
      on responses to questionnaires, 22 herds were selected for the grazing group and
      the conventional group consisted of 34 large free-stall dairies. Production data
      consisted of 6,749 lactations of 2,817 cows in the grazing herds and 29,371
      lactations of 12,774 cows in the control herds. Subsets of data for reproduction
      and conformation also were created. Per cow production was greater in the
      conventionally managed herds (9,947 kg of milk) than in the grazing herds (9,400
      kg). Phenotypic data were regressed on sire predicted transmitting abilities
      (PTA) and genetic correlations for all traits were estimated between
      environments. A scaling effect was observed across environments for yield traits,
      as phenotypic differences among cows were greater than predicted by sire PTA in
      conventional herds and consistent with sire PTA in grazing herds. Heritabilities
      for yield also were greater in conventional herds. Other effects of GxE were
      minor, with genetic correlations of near 0.90 or greater for all traits. Among
      yield traits, genetic correlation was lowest for fat (0.88 with SE = 0.04). These
      results demonstrate that effects of GxE are small between the two types of
      management systems analyzed and that graziers can accurately select sires based
      on national rankings.

PMID- 12613883
TI  - Understanding dry eye syndrome.
AB  - It was my great pleasure to have had the opportunity to give the conference
      address in addition to being honored by the Professor Dohlman Award. I am proud
      of the progress in the understanding of dry eye that has been made over the past
      couple of decades. However, the clinical application of the knowledge that has
      accumulated lies in the future. Thus far no effective medication has ever been
      developed for the treatment of severe dry eye. Cyclosoporine may become the first
      eyedrops to be used, and a series of new drugs containing androgens,
      immunomodulators, secretagogues, P2Y2 receptor agonists, and others may follow. I
      believe that medication for the treatment of dry eye will be developed in the not
      to distant future, and I hope that at the 4th conference in a few years time, we
      will be able to share these new treatments for the management of dry eye
      patients.

PMID- 12613884
TI  - GDNF family signalling in exocrine tissues: distinct roles for GDNF and neurturin
      in parasympathetic neuron development.

PMID- 12613885
TI  - The influence of aging in the insulin-signaling system in rat exocrine glands.

PMID- 12613886
TI  - Cloning, partial sequencing and expression of rabbit lacrimal gland beta
      hexosaminidase.

PMID- 12613888
TI  - M3 receptor autoimmunity: losing tolerance to a familiar protein.

PMID- 12613887
TI  - Differential expression of adenylyl cyclase mRNAs in lacrimal glands of NZB/NZW
      and NOD pre-autoimmune mice.

PMID- 12613889
TI  - Presence of alpha-and beta-integrin subunits in rabbit lacrimal gland acinar
      cells cultured on a laminin-rich matrix.

PMID- 12613890
TI  - The effects of sensory and parasympathetic denervation on the kinases and
      initiation factors controlling protein synthesis in the lacrimal gland.

PMID- 12613892
TI  - Somatostatin-like immunoreactivity (SLIR) in rat harderian and meibomian glands
      and glands of Zeis.

PMID- 12613891
TI  - Familial dysautonomia in review: diagnosis and treatment of ocular
      manifestations.

PMID- 12613893
TI  - Neuronal nitric oxide synthase is expressed in the mouse lacrimal gland and
      neurons of pterygopalatine ganglion.

PMID- 12613894
TI  - Effects of ageing on secretagogue-evoked protein output, peroxidase secretion and
      protein synthesis in the isolated rat lacrimal gland.

PMID- 12613895
TI  - Effects of ageing on changes in morphology of the rat lacrimal gland.

PMID- 12613896
TI  - The role of gap junctions in lacrimal acinar cells: the formation of tears.

PMID- 12613897
TI  - Lipase mRNAs expressed in lacrimal and harderian glands.

PMID- 12613898
TI  - Gender-related differences in gene expression of the lacrimal gland.

PMID- 12613899
TI  - Identification of androgen-regulated genes in the lacrimal gland.

PMID- 12613900
TI  - Identification of androgen receptors in rabbit lacrimal gland by
      immunohistochemsitry.

PMID- 12613901
TI  - Androgen influence on lymphocyte gene expression.

PMID- 12613902
TI  - Potential role of disrupted lacrimal acinar cells in dry eye during pregnancy.

PMID- 12613903
TI  - A new model system for studying lacrimal physiology using cultured lacrimal gland
      acinar cells on Matrigel rafts.

PMID- 12613904
TI  - Genetic separation of the human lacritin gene ("LACRT") and triple A (Allgrove)
      syndrome on 12q13.

PMID- 12613905
TI  - Ca2+ signaling in polarized exocrine cells.

PMID- 12613907
TI  - A model of fluid secretion by the acinar cells of the mouse lacrimal gland.

PMID- 12613906
TI  - Role of Ca2+ and protein kinase C in cholinergic, and alpha1-adrenergic agonists
      and EGF stimulated mitogen-activated protein kinase activity in lacrimal gland.

PMID- 12613908
TI  - Cytoskeletal participation in stimulated secretion and compensatory apical plasma
      membrane retrieval in lacrimal gland acinar cells.

PMID- 12613909
TI  - Glycolipid-rich membrane microdomains in lacrimal acinar cell endomembrane
      compartments.

PMID- 12613910
TI  - Epidermal growth factor traffic in lacrimal acinar cells.

PMID- 12613911
TI  - Immunolocalization and physiological effect of serotonin in the porcine lacrimal
      gland.

PMID- 12613912
TI  - Effects of preganglionic parasympathetic denervation on the rabbit lacrimation.

PMID- 12613913
TI  - Prolactin inhibits carbachol-dependent secretion by lacrimal acinar cells in
      vitro.

PMID- 12613914
TI  - Effect of overexpression of protein kinase C alpha on rat lacrimal gland protein
      secretion.

PMID- 12613915
TI  - Epidermal growth factor stimulates fluid transport in SV40 transformed rabbit
      lacrimal gland cells.

PMID- 12613916
TI  - Nucleoside and nucleotide stimulation of fluid secretion in the pigmented rabbit
      conjunctiva.

PMID- 12613917
TI  - Metabolism and transport of purinergic receptor agonists in rabbit conjunctival
      epithelial cells.

PMID- 12613918
TI  - Potency and duration of action of synthetic P2Y2 receptor agonists on Schirmer
      scores in rabbits.

PMID- 12613920
TI  - Mucins and ocular surface disease.

PMID- 12613919
TI  - Mechanism by which bacterial flagellin stimulates host mucin production.

PMID- 12613921
TI  - Functional processing of ocular mucins.

PMID- 12613922
TI  - ErbB2 and its ligand Muc4 (sialomucin complex) in rat lacrimal gland.
AB  - The lacrimal gland is an important source of components for the ocular tear
      fluid. Though mucins are not generally considered a product of the lacrimal
      gland, our results clearly show Muc4/SMC is produced by the gland in soluble and
      membrane forms. The secreted, soluble form is likely produced for the soluble
      phase of the ocular tear film. Analyses of ErbB2 and the Muc4/SMC-ErbB2 complex
      in the lacrimal gland suggest a second function for Muc4/SMC, a role in cell
      regulation through ErbB signaling. The nature of those signals and the cell
      functions they regulate will be subjects for future investigations.

PMID- 12613923
TI  - Role of mitogen-activated protein kinase in cholinergic stimulation of
      conjunctival goblet cell secretion.

PMID- 12613924
TI  - Isolation and characterization of human goblet cells in vitro: regulation of
      proliferation and activation of mitogen-activated protein kinase by EGF and
      carbachol.

PMID- 12613925
TI  - Human conjunctival epithelium in culture: a tool to assay new therapeutic
      strategies for dry eye.

PMID- 12613927
TI  - Topically applied 15-(S)-HETE stimulates mucin production by corneal epithelium.

PMID- 12613926
TI  - Ocular TFF-peptides: new mucus-associated secretory products of conjunctival
      goblet cells.

PMID- 12613928
TI  - Effects of 15(S)-HETE on human conjunctival mucin secretion.

PMID- 12613929
TI  - Evaluation of the effects of 15(S)-HETE on corneal epithelial cells: an
      electrophysiological and cytochemical study.

PMID- 12613930
TI  - Preservation of corneal integrity by the mucin secretagogue 15(S)-HETE in a
      rabbit model of desiccation-induced dry eye.

PMID- 12613931
TI  - Purification and chemical characterization of the high molecular weight
      glycoconjugate fraction of the bovine tear film and comparison to mucins from
      other sources.

PMID- 12613932
TI  - Sialic acid in normal and dry eye tear fluid.

PMID- 12613933
TI  - Gefarnate stimulates goblet cell repopulation following an experimental wound to
      the tarsal conjunctiva in the dry eye rabbit.

PMID- 12613934
TI  - Mucin ophthalmic solution treatment of dry eye.

PMID- 12613935
TI  - The lacunar sulci: a new test to measure the shrinkage of ocular surface, and its
      relation with the number of goblet cells.

PMID- 12613936
TI  - Meibomian gland and tear film lipids: structure, function and control.

PMID- 12613937
TI  - Androgen regulation of lipogenesis.

PMID- 12613939
TI  - The lipid layer and stability of tears in human newborns.

PMID- 12613938
TI  - Sex steroids, the meibomian gland and evaporative dry eye.

PMID- 12613940
TI  - Interface properties of simplified tear-like fluids in relation to lipid and
      aqueous layers composition.
AB  - The Langmuir trough approach to the study of the physical properties of an in
      vitro system representing the natural tear lipid-aqueous interface gives useful
      information on the effect produced by changes of composition of both phases. We
      found that variations of the composition of the lipid mixture affect more
      strongly the characteristics of the film rather than changes in the aqueous phase
      composition. Therefore, future investigations should consider the possibility of
      searching for and optimising additions of lipid mixtures to the natural tear
      film. These novel mixtures should stabilise the lipid layer, and thus treat the
      evaporative Dry Eye Syndrome. More critical and worthy of further investigation
      is the effect of surface-active water-soluble components that can reduce and
      ultimately destroy the lipid film integrity and effectiveness. The beneficial
      effect of water-soluble components, either naturally occurring or artificially
      added, may be more precisely compared with possible side effects on the stability
      of the lipid tear layer. In any case, these side effects may be largely
      compensated by the presence of stability enhanced lipid composition. The present
      work may be considered as an introductory investigation that takes the physical
      chemical approach into the realm of debated data about the tear film structure
      and properties. Refining the model we have adopted in the present work is
      certainly necessary. For instance, introducing into the model tear composition
      other components such as ceramides and cerebrosides will provide insight to their
      contribution to the packing structure. We may also couple different techniques
      such as measuring elastic and rheological properties of the films that may be
      relevant to its physiological behaviour.

PMID- 12613941
TI  - Effect of an oil and water emulsion on tear evaporation rate.

PMID- 12613942
TI  - Evaporation from the human tear film studied by interferometry.

PMID- 12613943
TI  - The effects of dietary and pharmacological manipulation on lipid production in
      the meibomian and harderian glands of the rabbit.

PMID- 12613944
TI  - Correlations between nutrient intake and the polar lipid profiles of meibomian
      gland secretions in women with Sjogren's syndrome.

PMID- 12613945
TI  - Impact of androgen deficiency on the lipid profiles in human meibomian gland
      secretions.

PMID- 12613946
TI  - Gender-associated differences in gene expression of the meibomian gland.

PMID- 12613947
TI  - Androgen control of gene expression in the rabbit meibomian gland.

PMID- 12613949
TI  - Estrogen and progesterone effects on the morphology of the mouse meibomian gland.

PMID- 12613948
TI  - Androgen influence on gene expression in the meibomian gland.

PMID- 12613950
TI  - Gene expression and fat deposit in primary cultures of rat meibomian gland cells.

PMID- 12613951
TI  - The effects of anionic and zwitterionic phospholipids on the tear film lipid
      layer.

PMID- 12613952
TI  - Alleviation of computer-induced eye discomfort syndrome and associated lipid
      layer changes.

PMID- 12613953
TI  - Effects of fluorescein instillation methods on the tear film lipid layer.

PMID- 12613954
TI  - Blinking frequency and the thickness of the lipid layer.

PMID- 12613955
TI  - Assessment of meibomian gland function by a newly-developed laser meibometer.

PMID- 12613956
TI  - The tear film and defense against infection.

PMID- 12613957
TI  - Nerve growth factor (NGF): an important molecule for trophism and healing of the
      ocular surface.

PMID- 12613958
TI  - Changes in the diurnal pattern of the distribution of gelatinases and associated
      proteins in normal and pathological tear fluids: evidence that the PMN cell is a
      major source of MMP activity in tear fluid.

PMID- 12613959
TI  - Protection of human efferent tear ducts by antimicrobial peptides.

PMID- 12613960
TI  - Tear lipocalin: structure, function and molecular mechanisms of action.

PMID- 12613961
TI  - Vitamin E associated with the lipocalin fraction of human tears.

PMID- 12613962
TI  - Characterization of a lipophilin in rabbit tears.

PMID- 12613964
TI  - Age-related changes in human tear composition and stability.

PMID- 12613965
TI  - Dynamic surface activity of biological fluids, ophthalmic solutions and
      nanostructures.

PMID- 12613963
TI  - The role of lipocalin in determining the physical properties of tears.

PMID- 12613966
TI  - Mass spectrometric techniques applied to the analysis of human tears: a focus on
      the peptide and protein constituents.

PMID- 12613968
TI  - Immunodacryochemistry (immunoferning): a new screening method for proteins in
      tears.

PMID- 12613967
TI  - Insulin, insulin receptor and insulin-like growth factor-I receptor on the human
      ocular surface.

PMID- 12613969
TI  - Different concentrations of amino acids in tears of normal and human dry eyes.

PMID- 12613970
TI  - Changes in the tear protein patterns of diabetic patients using two-dimensional
      electrophoresis.

PMID- 12613971
TI  - Enzymatic mechanisms in corneal ulceration with specific reference to familial
      dysautonomia: potential for genetic approaches.

PMID- 12613972
TI  - Pathological keratinization of ocular surface epithelium.

PMID- 12613973
TI  - Experimentally induced dry eye produces ocular surface inflammation and
      epithelial disease.

PMID- 12613974
TI  - In vivo confocal microscopy for studying corneal diseases and conditions
      associated with corneal nerve damage.

PMID- 12613975
TI  - Ocular surface changes in type 1 diabetic patients.

PMID- 12613976
TI  - Serum- and serum deprivation-induced transcriptional profiles of cultured
      conjunctival epithelial cells.

PMID- 12613977
TI  - Shear-induced ATP release by cultured rabbit corneal epithelial cells.

PMID- 12613978
TI  - The role of nitric oxide in ocular surface diseases.
AB  - For the first time, the current series of studies provide a possible
      pathophysiologic mechanism of NO-induced ocular surface disease. NO is present in
      tear and aqueous humor and is suspected of having an important physiological role
      in maintaining normal homeostasis of the ocular surface. NO concentrations are
      higher in aqueous humor compared to tears, though some variability exists between
      different species. When inflammation was induced by PTK wounding or LPS, three
      forms of NOS expression were seen in corneal cells. Each isoform of NOS was
      expressed uniquely according to the specific location of inflammation. When
      concentrations of NO peaked, the levels of iNOS were markedly increased in
      fibroblasts and inflammatory cells. The correlation between NO and inflammation
      was confirmed by treatment with NOS inhibitor, which abrogated the amount of both
      NO and inflammation. The tissue damage by NO was measured by nitrotyrosine
      formation. Damage was detected mainly in inflammatory cells, especially those
      localized in and around the limbal vessel. It is likely that expression of iNOS
      in limbal fibroblasts has other roles related to survival of limbal stem cells
      and fibroblasts as well. Because the main source of NO are fibroblasts, we were
      able to determine the effect of various concentrations of NO on cell viability
      using a fibroblast culture system. Cell viability increased in dose dependent
      manner from 10 microM to 500 microM of the NO generator SNAP, but decreased at
      concentrations above 1000 microM, suggesting that the in vivo mechanism of cell
      death was indirect, through specific biologic pathways. Therefore, the
      pathophysiological mechanism of NO action is bimodal with a toxicological
      component in ocular surface diseases. Furthermore, its concentration and
      interaction with other oxygen mediators appear to vary depending on the degree of
      inflammation.

PMID- 12613979
TI  - Relationship between in vitro toxicity of benzalkonium chloride (BAC) and
      preservative-induced dry eye.

PMID- 12613980
TI  - Corneal epithelial permeability and dry eye treatment.

PMID- 12613981
TI  - Observation of tear film in recurrent corneal erosion and epithelial basement
      membrane dystrophy.

PMID- 12613982
TI  - The effect of tear film and ocular surface management on myopic LASIK outcomes.

PMID- 12613983
TI  - A comparison of corneal and conjunctival sensitivity to a thermally cooling
      stimulus.

PMID- 12613984
TI  - The effect of acupuncture on the temperature of the ocular surface in
      conjunctivitis sicca measured by non-contact thermography: preliminary results.

PMID- 12613985
TI  - Role of immunity and inflammation in corneal and ocular surface disease
      associated with dry eye.

PMID- 12613986
TI  - Dry eye and delayed tear clearance: "a call to arms.".
AB  - Dry eye may activate components of the ocular surface early warning system.
      Ocular surface stresses in dry eye, such as hyperosmolarity, could activate
      cellular stress pathways such as MAPKs. IL-1 and MMP-9 produced by the ocular
      surface epithelial cells may mediate initial events in the inflammatory cascade
      of dry eye through a dynamic interplay between them on the ocular surface.

PMID- 12613987
TI  - Innate immunity in th e cornea: a putative role for keratocytes in the chemokine
      response to viral infection of the human corneal stroma.
AB  - Existing evidence suggests that chemokine expression by virus-infected cells is a
      common response to viral infection. By such a mechanism, non-immunologic cells
      may participate in the generation of an early innate immune response to
      infection. In the absence of classic immunologic cells in the corneal stroma,
      keratocytes may play a similar role in the corneal responses to viral infection.

PMID- 12613988
TI  - The role of ICAM-1 as a signal protein for predisposition of ocular surface
      inflammation.

PMID- 12613989
TI  - Flow cytometric analysis of the inflammatory marker HLA DR in dry eye syndrome:
      results from 12 months of randomized treatment with topical cyclosporin A.

PMID- 12613990
TI  - Pathogenesis of autoimmune lacrimal gland disease in MRL/MPJ mice.

PMID- 12613991
TI  - ICAM-1: its role in the pathophysiology of immune activation in the MRL/LPR
      mouse.

PMID- 12613992
TI  - Proinflammatory cytokine inhibition of lacrimal gland secretion.

PMID- 12613993
TI  - Effect of anti-inflammatory cytokines on the activation of lymphocytes by
      lacrimal gland acinar cells in an autologous mixed cell reaction.

PMID- 12613994
TI  - IL-2 immunoreactive proteins in lacrimal acinar cells.

PMID- 12613995
TI  - Immunopathogenesis of conjunctival histopathologic alteration in non-Sjogren's
      keratoconjunctivitis sicca.

PMID- 12613996
TI  - Topical cyclosporine A (2%) eyedrops in the therapy of atopic
      keratoconjunctivitis and keratoconjunctivitis vernalis.

PMID- 12613997
TI  - Apoptosis: the eyes have it.

PMID- 12613998
TI  - Apoptosis in the cornea in response to epithelial injury: significance to wound
      healing and dry eye.

PMID- 12613999
TI  - Mechanisms of apoptosis in human corneal epithelial cells.

PMID- 12614000
TI  - A functional unit for ocular surface immune defense formed by the lacrimal gland,
      conjunctivaand lacrimal drainage system.

PMID- 12614001
TI  - Role of tear anti-acanthamoeba IgA in Acanthamoeba keratitis.

PMID- 12614002
TI  - Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in the
      conjunctiva--a potential link between lymphangiogenesis and leukocyte trafficking
      on the ocular surface.

PMID- 12614003
TI  - Human lacrimal drainage-associated lymphoid tissue (LDALT) belongs to the common
      mucosal immune system.

PMID- 12614004
TI  - The crypt system of the human conjunctiva.

PMID- 12614005
TI  - Organized mucosa-associated lymphoid tissue in human nasolacrimal ducts.

PMID- 12614006
TI  - Contact lenses and tear film interactions.

PMID- 12614007
TI  - Effects of O2 transmissibility on corneal epithelium after daily and extended
      contact lens wear in rabbit and man.

PMID- 12614008
TI  - Influence of the tear film composition on tear film structure and symptomatology
      of soft contact lens wearers.

PMID- 12614010
TI  - An evaluation of mucin balls associated with high-DK silicone-hydrogel contact
      lens wear.

PMID- 12614009
TI  - Evaluation of the pre-lens tear film forming on three disposable contact lenses.

PMID- 12614011
TI  - Cells collected from the corneal surface in Sjogren's syndrome, dry eye, and
      normals.

PMID- 12614012
TI  - The thickness of the post-lens tear film measured by interferometry.

PMID- 12614013
TI  - Tear lipid composition of hydrogel contact lens wearers.

PMID- 12614014
TI  - Conjunctival characteristics of contact lens wearers and nonwearers and their
      association with symptomatology.

PMID- 12614015
TI  - Dry eye symptomatology of contact lens wearers and nonwearers.

PMID- 12614016
TI  - Contact lens-induced papillary conjunctivitis is associated with increased
      albumin deposits on extended wear hydrogel lenses.

PMID- 12614017
TI  - Surface protein profile of extended-wear silicon hydrogel lenses.

PMID- 12614018
TI  - The detection of kinin activity in contact lens wear.

PMID- 12614019
TI  - Immunoblotting and tear sampling techniques for the study of contact lens-induced
      variations in tear protein profiles.

PMID- 12614020
TI  - Interaction between the contact lens and the ocular surface in the etiology of
      superior epithelial arcuate lesions.

PMID- 12614021
TI  - Clinical benefits and physical properties of addition of hydroxypropyl
      methylcellulose to a multi-purpose contact lens care solution.

PMID- 12614022
TI  - Epidemiology of dry eye syndrome.

PMID- 12614023
TI  - Immunogenetics of autoimmune exocrinopathy in the nod mouse: more than meets the
      eye.

PMID- 12614024
TI  - Results of a dry eye questionnaire from optometric practices in North America.

PMID- 12614025
TI  - The effect of hormone replacement therapy on the symptoms and physiologic
      parameters of dry eye.

PMID- 12614026
TI  - Impaired neurotransmission in lacrimal and salivary glands of a murine model of
      Sjogren's syndrome.

PMID- 12614027
TI  - Menopause, hormone replacement therapy and tear function.

PMID- 12614029
TI  - Dry eye associated with chronic graft-versus-host disease.

PMID- 12614028
TI  - IDD3 and IDD5 alleles from nod mice mediate Sjogren's syndrome-like autoimmunity.

PMID- 12614030
TI  - Contribution of neurogenic inflammation to irritable eye syndrome.

PMID- 12614031
TI  - Ocular drying associated with oral antihistamines (loratadine) in the normal
      population-an evaluation of exaggerated dose effect.

PMID- 12614032
TI  - Evaluation of the time to "natural compensation" in normal and dry eye subject
      populations during exposure to a controlled adverse environment.

PMID- 12614033
TI  - Diagnosis and treatment of the dry eye: a clinical perspective.

PMID- 12614034
TI  - Dry eye syndromes: diagnosis, clinical trials and pharmaceutical treatment-
      'improving clinical trials'.

PMID- 12614035
TI  - Using osmolarity to diagnose dry eye: a compartmental hypothesis and review of
      our assumptions.

PMID- 12614036
TI  - Reliability of measurements of tear physiology.

PMID- 12614037
TI  - Use of cevimeline, a muscarinic M1 and M3 agonist, in the treatment of Sjogren's
      syndrome.

PMID- 12614038
TI  - Drug development issues in pharmacological treatments for dry eye.

PMID- 12614039
TI  - Alternative reference values for tear film break up time in normal and dry eye
      populations.

PMID- 12614040
TI  - Ocular sensations and symptoms associated with tear break up.

PMID- 12614041
TI  - Evaluation of the akorn dry eye test (DET) as a predictor of contact lens
      comfort.

PMID- 12614042
TI  - Predicting optical effects of tear film break up on retinal image quality using
      the Shack-Hartmann aberrometer and computational optical modeling.

PMID- 12614043
TI  - Improvement of tear stability following warm compression in patients with
      meibomian gland dysfunction.

PMID- 12614044
TI  - An evaporative stress test for borderline dry eye detection.

PMID- 12614045
TI  - Tear production measurement, basal or reflex assessment?

PMID- 12614046
TI  - Innovative dry eye diagnosis system using microbalance technology.

PMID- 12614047
TI  - The repeatability of diagnostic tests and surveys in dry eye.

PMID- 12614048
TI  - Association of clinical diagnostic tests and dry eye surveys: the NEI-VFQ-25 and
      the OSDI.

PMID- 12614049
TI  - Economic and quality of life impact of dry eye symptoms in women with Sjogren's
      syndrome.

PMID- 12614050
TI  - Patient-reported versus doctor-diagnosed dry eye: the assessment of symptoms.

PMID- 12614051
TI  - Keratoconjunctitis sicca versus dry mouth and autoantibodies in primary and
      secondary Sjogren's syndrome.

PMID- 12614052
TI  - Tear spreading rates: post-blink.

PMID- 12614053
TI  - Near vision accommodation in horizontality with VDT: why low blinking and dry
      eye?

PMID- 12614054
TI  - Analysis of tear protein patterns for the diagnosis of dry eye.

PMID- 12614055
TI  - The significance of salivary gland ultrasonography in the diagnosis of dry eye
      syndrome.

PMID- 12614056
TI  - The effect of nasal mucosal stimulation on Schirmer tests in Sjogren's syndrome
      and dry eye patients.

PMID- 12614057
TI  - A simple method of detecting the anti-inflammatory action of topical dry eye
      treatments.

PMID- 12614058
TI  - Efficacy of sodium hyaluronate eye drops of different osmolarities in the
      symptomatic treatment of dry eye patients.

PMID- 12614059
TI  - Topical non-preserved diclofenac therapy for keratoconjunctivitis sicca.

PMID- 12614061
TI  - Efficacy of autologous serum treatment in patients with severe dry eye.

PMID- 12614060
TI  - The effect of botulinum toxin a treatment on tear function parameters and on the
      ocular surface.

PMID- 12614062
TI  - Ocular safety of INS365 ophthalmic solution, a P2Y2 agonist, in patients with
      mild to moderate dry eye disease.

PMID- 12614063
TI  - Ocular surface reconstruction with amnotic membrane transplantation in chemical
      burn.

PMID- 12614064
TI  - Surgical reconstruction of the tear meniscus at the lower lid margin for
      treatment of conjunctivochalasis.

PMID- 12614065
TI  - The effect of punctal occlusion on tear lactoferrin in aqueous deficient dry eye
      patients.

PMID- 12614066
TI  - Silicon punctal plug insertion in the treatment of severe dry eye.

PMID- 12614067
TI  - Application of atelocollagen solution for lacrimal duct occlusion.

PMID- 12614068
TI  - Atelocollagen punctal occlusion for the treatment of the dry eye.

PMID- 12614069
TI  - Fiberscopic observation of canaliculi after punctal plug extrusion.

PMID- 12614070
TI  - Neural stem cells for CNS repair: state of the art and future directions.

PMID- 12614072
TI  - In vivo gene transfer into corneal epithelial progenitor cells by viral vectors.

PMID- 12614071
TI  - Particle-mediated gene transfer to ocular surface epithelium.

PMID- 12614073
TI  - Gene therapy for the prevention of corneal haze after
      photorefractive/phototherapeutic keratectomy excimer laser surgery.

PMID- 12614074
TI  - Ex vivo preservation and expansion of human limbal epithelial stem cells on
      amniotic membrane for treating corneal diseases with total limbal stem cell
      deficiency.

PMID- 12614075
TI  - Corneal blindness from end-stage Sjogren's syndrome and graft-versus-host
      disease.

PMID- 12614076
TI  - Closing address: The academic perspective.

PMID- 12614077
TI  - Industry perspective.

PMID- 12614078
TI  - Osteoclast activity around loaded and unloaded implants: a histological study in
      the beagle dog.
AB  - The mechanisms of bone loss around dental implants are poorly understood. The
      osteoclast is the most important bone-resorbing cell. Humoral factors seem able
      to stimulate the differentiation of osteoclasts from mononuclear phagocytes.
      Bacterial lipopolysaccharides seem to be directly involved in inflammatory bone
      loss by stimulation of the survival and fusion of preosteoclasts. Excessive load
      seems to be able to cause bone loss. The aim of this paper was to evaluate the
      presence and number of osteoclasts in peri-implant bone in control (unloaded) and
      test (loaded) implants in order to determine if loading per se could be a
      contributing factor in peri-implant bone resorption. Forty-eight implants were
      inserted in the mandibles of 4 beagle dogs. After 3 months, a prosthetic
      superstructure was inserted on 24 implants, whereas in 24 implants only the
      healing screws were positioned. Twenty-four implants (12 test and 12 control)
      were retrieved at 6 months, and 24 implants (12 test and 12 control) were
      retrieved at 12 months. All implants were osseointegrated. The number of
      osteoclasts found in the crestal bone in the first 3 mm from the implant surface
      was evaluated. The mean number of osteoclasts were the following: control
      implants (6 months), 5.66 +/- 0.81; control implants (12 months), 2.55 +/- 1.05;
      test implants (6 months), 5.25 +/- 1.55; and test implants (12 months), 2.5 +/-
      1.0. No statistically significant differences were observed between the control
      and test implants. According to our data, loading does not seem to have a
      relevant importance on the osteoclast activation in peri-implant bone.

PMID- 12614079
TI  - Bone response to zirconia ceramic implants: an experimental study in rabbits.
AB  - This study analyzes the bone response to zirconia ceramic implants inserted in
      New Zealand white mature male rabbits. The implants were inserted into the tibia,
      and each rabbit received 4 implants. All the animals were euthanatized after 4
      weeks. A total of 20 implants were retrieved. Implants and surrounding tissues
      were immediately fixed in 4% paraformaldehyde and 0.1% glutaraldehyde in 0.15
      molar cacodylate buffer at 4 degrees C and pH 7.4 to be processed for histology.
      The specimens were processed to obtain thin ground sections with the Precise 1
      Automated System. The slides were observed in normal transmitted light under a
      Leitz Laborlux microscope. A great quantity of newly formed bone was observed in
      close contact with zirconia ceramic surfaces; in some areas, many osteoblasts
      were present directly on the zirconia. Percentage of bone-implant contact was
      68.4% +/- 2.4%. Mature bone, with few marrow spaces, was present. Small actively
      secreting osteoblasts were present in the most coronal and apical portions of the
      implant. No inflamed or multinucleated cells were present. This study concluded
      that these implants are highly biocompatible and osteoconductive.

PMID- 12614080
TI  - Bone contact around acid-etched implants: a histological and histomorphometrical
      evaluation of two human-retrieved implants.
AB  - The surface characteristics of dental implants play an important role in their
      clinical success. One of the most important surface characteristics of implants
      is their surface topography or roughness. Many techniques for preparing dental
      implant surfaces are in clinical use: turning, plasma spraying, coating, abrasive
      blasting, acid etching, and electropolishing. The Osseotite surface is prepared
      by a process of thermal dual etching with hydrochloric and sulfuric acid, which
      results in a clean, highly detailed surface texture devoid of entrapped foreign
      material and impurities. This seems to enhance fibrin attachment to the implant
      surface during the clotting process. The authors retrieved 2 Osseotite implants
      after 6 months to repair damage to the inferior alveolar nerve. Histologically,
      both implants appeared to be surrounded by newly formed bone. No gaps or fibrous
      tissues were present at the interface. The mean bone-implant contact percentage
      was 61.3% (+/- 3.8%).

PMID- 12614081
TI  - The "Loma Linda stent": a screw-retained resin stent.
AB  - This article describes a technique in which an acellular dermal allograft is used
      in combination with a photopolymerized acrylic resin stent to increase the zone
      of keratinized tissue around osseointegrated dental implants. During the second
      stage surgery, a split thickness labial flap is reflected and apically
      repositioned by being sutured onto the periosteum and connective tissue. The
      acellular dermal allograft is then sutured onto the recipient site. The acrylic
      resin is trimmed and secured with temporary abutments to the implants, fitting
      passively over the graft and then photopolymerized intraorally. The stent is left
      for 1 week to secure the graft in place. This technique offers an alternative
      mucogingival procedure for increasing the zone of keratinized tissue around
      osseointegrated dental implants.

PMID- 12614083
TI  - Oral insulin--a perspective.
AB  - Diabetes mellitus is generally controlled quite well with the administration of
      oral medications or by the use of insulin injections. The current practice is the
      use of one or more doses, intermediate or long acting insulin per day. Oral
      insulin is a promising yet experimental method providing tight glycemic control
      for patients with diabetes. A biologically adhesive delivery systems offer
      important advantage over conventional drug delivery systems. The engineered
      polymer microspheres made of erodable polymer display strong adhesive
      interactions with gastrointestinal mucus and cellular lining can traverse both
      the mucosal epithelium and the follicle associated epithelium covering the
      lymphoid tissue of Peyer's patches. Alginate, a natural polymer recovered from
      seaweed is being developed as a nanoparticle for the delivery of insulin without
      being destroyed in the stomach. Alginate is in fact finding application in
      biotechnology industry as thickening agent, a gelling agent and a colloid
      stabilizer. Alginate has in addition, several other properties that have enabled
      it to be used as a matrix for entrapment and for the delivery of a variety of
      proteins such as insulin and cells. These properties include: a relatively inert
      aqueous environment within the matrix; a mild room temperature encapsulation
      process free of organic solvents; a high gel porosity which allows for high
      diffusion rates of macromolecules; the ability to control this porosity with
      simple coating procedures and dissolution and biodegradation of the system under
      normal physiological conditions.

PMID- 12614082
TI  - Use of HTR synthetic bone as an augmentation material in conjunction with
      immediate implant placement: a case report.
AB  - Immediate placement of dental implants (DI) in fresh extraction sockets is
      associated with remaining voids around the DI and often a partial dehiscence or
      thin facial alveolar plate. Bioplant HTR synthetic bone (HTR) was used as a ridge
      preservation/augmentation material in conjunction with this method of DI
      placement. A 61-year-old white woman requiring extraction of tooth 12 opted for
      immediate DI placement. HTR was used to fill the remaining socket void and
      enhance the facial ridge width, and primary closure was attempted with sutures.
      DI uncovering was performed at about 6 months. Measurements were taken to the
      nearest 0.5 mm of the internal socket width and total site width at DI placement
      and uncovering. The internal socket width was essentially maintained (6.8 vs 6.6
      mm), and the total ridge width showed a change from 8.7 to 9.1 mm. The results of
      this case suggest that HTR is a useful adjunct in the placement of immediate DIs
      for the preservation of ridge width.

PMID- 12614084
TI  - Preparation and characterization of the inclusion complex of furosemide with
      hydroxypropyl-beta-cyclodextrin.
AB  - A highly hydrophobic drug, furosemide, was treated with 2-Hydroxypropyl-beta
      Cyclodextrin in an attempt to produce modified compounds with increased water
      solubility. Following a freeze-drying process, the interactions of furosemide and
      cyclodextrin led to the formation of an inclusion complex, whose dissolution rate
      in water was studied by the solubility method. Furthermore, mechanical mixtures
      of furosemide and cyclodextrin were also prepared and tested for their
      solubility. The reaction products were characterized in the solid state by
      differential scanning calorimetry (DSC), which provided some evidence about
      complexation. Additional evidence was obtained by recording the 1H NMR spectra of
      aqueous solutions of these same products. The study of phase solubility was based
      on the Higuchi & Connors method and showed an impressive enhancement of the
      miscibility of furosemide with water. In fact, a 11 fold increase of the drug
      solubility was recorded for the inclusion complex, in the first stages of
      dissolution. The experimental results of this work show that 2-Hydroxypropyl-beta
      Cyclodextrin is an efficient complexation agent for furosemide. Combination of
      those two substances can be carried out by simple techniques, providing easy
      control and the obtained inclusion complex is characterized by acceptable water
      solubility and increased dissolution rate.

PMID- 12614085
TI  - Effects of enzymatic treatments on the biomechanical properties of screws made of
      bone.
AB  - Nowadays, bone tissue employed to manufacture screws used as osteosynthesis
      material is obtained from organ donors. But in different medical fields there is
      an increasing need to use xenogenic grafts and implants, which still imply risks
      of transmission of some diseases and antigenicity. Two different autoclaving
      programs (A1, A2) and an alternative to reduce the antigenicity of screws made of
      xenogenic bone based on enzymatic treatment are analyzed from a biomechanical
      point of view. 128 screws made of bovine femur bone were employed. Some of them
      were partially demineralized with 0.6 N HCl, enzymatically digested with
      collagenase (specific) and pepsin (nonspecific) and then autoclaved. The
      specimens were subjected to tension, shear and screw torque tests and
      histologically evaluated. Compared to A1, A2 sterilization method (134 degrees C
      but higher vacuum and longer time) considerably reduced the mechanical strength
      of specimens. The enzymatic digestion, expected to reduce antigenicity, did not
      affect the screw superficial structure and would not modify the bone
      biomechanical properties per se, but maybe because of the association with
      autoclaving and partial demineralization.

PMID- 12614086
TI  - Synthesis, physical properties and preliminary investigation of hemocompatibility
      of polyurethanes from aliphatic resources with castor oil participation.
AB  - The synthesis of polyurethanes (PURs) from oligoetherdiol, two low molecular
      diols, castor oil and 4,4'-Methylenebis(cyclohexylisocyanate) is described. These
      polymers are characterized by measurements of the mechanical bulk and surface
      properties, preliminary investigation of compatibility with human blood and
      calcification in static conditions. The critical surface energy of synthesized
      PURs is similar to the critical surface energy of natural surfaces. Material
      induced hemolysis and the changes of platelet counts in blood samples after
      contact with PURs are very low. Static seven-weeks-calcification testing in a
      synthetic calcification fluid did not indicate calcification by optical density
      measurements and by visual inspection and computer image processing of the X-ray
      films for PURs with and without castor oil.

PMID- 12614087
TI  - Adsorption of bovine serum albumin onto surface-modified polyhydroxyethyl
      methacrylate beads.
AB  - The adsorption of bovine serum albumin (BSA) onto poly(2-hydroxyethyl
      methacrylate) (PHEMA) beads modified by using the pair of hexamethylene
      diisocyonate-suberic acidbis-N-hydroxy succinimide has been studied as a function
      of protein concentration and adsorption time. The adsorption studies were carried
      out in phosphate buffer solution (PBS) at pH = 7.4. The isotherm data have been
      analysed using the Langmuir model and the adsorption parameters Q0 and b were
      calculated. It is determined that the adsorbed amount of BSA increases by the
      increase of the adsorption time and BSA concentration until a certain value.
      PHEMA beads were characterized by using FTIR spectra and SEM analysis. The
      adsorption of BSA onto PHEMA beads were clearly observed from SEM micrographs.
      The swelling tests of the beads were performed at 37 degrees C in PBS.

PMID- 12614088
TI  - Effect of a multivitamin and mineral supplement on infection and quality of life.
      A randomized, double-blind, placebo-controlled trial.
AB  - BACKGROUND: Use of multivitamin and mineral supplements is common among U.S.
      adults, yet few well-designed trials have assessed the reputed benefits.
      OBJECTIVE: To determine the effect of a daily multivitamin and mineral supplement
      on infection and well-being. DESIGN: Randomized, double-blind, placebo-controlled
      trial. SETTING: Primary care clinics at two medical centers in North Carolina.
      PARTICIPANTS: 130 community-dwelling adults stratified by age (45 to 64 years or
      >or=65 years) and presence of type 2 diabetes mellitus. INTERVENTION:
      Multivitamin and mineral supplement or placebo taken daily for 1 year.
      MEASUREMENTS: Incidence of participant-reported symptoms of infection, incidence
      of infection-associated absenteeism, and scores on the physical and mental health
      subscales of the Medical Outcomes Study 12-Item Short Form. RESULTS: More
      participants receiving placebo reported an infectious illness over the study year
      than did participants receiving multivitamin and mineral supplements (73% vs.
      43%; P < 0.001). Infection-related absenteeism was also higher in the placebo
      group than in the treatment group (57% vs. 21%; P < 0.001). Participants with
      type 2 diabetes mellitus (n = 51) accounted for this finding. Among diabetic
      participants receiving placebo, 93% reported an infection compared with 17% of
      those receiving supplements (P < 0.001). Medical Outcomes Study 12-Item Short
      Form scores did not differ between the treatment and placebo groups. CONCLUSIONS:
      A multivitamin and mineral supplement reduced the incidence of participant
      reported infection and related absenteeism in a sample of participants with type
      2 diabetes mellitus and a high prevalence of subclinical micronutrient
      deficiency. A larger clinical trial is needed to determine whether these findings
      can be replicated not only in diabetic persons but also in any population with a
      high rate of suboptimal nutrition or potential underlying disease impairment.

PMID- 12614089
TI  - Addressing alcohol problems in primary care: a cluster randomized, controlled
      trial of a systems intervention. The screening and intervention in primary care
      (SIP) study.
AB  - BACKGROUND: Screening and intervention for alcohol problems can reduce drinking
      and its consequences but are often not implemented. OBJECTIVE: To test whether
      providing physicians with patients' alcohol screening results and simple
      individualized recommendations would affect the likelihood of a physician's
      having a discussion with patients about alcohol during a primary care visit and
      would affect subsequent alcohol use. DESIGN: Cluster randomized, controlled
      trial. SETTING: Urban academic primary care practice. PARTICIPANTS: 41 faculty
      and resident primary care physicians and 312 patients with hazardous drinking.
      INTERVENTIONS: Providing physicians with alcohol screening results (CAGE
      questionnaire responses, alcohol consumption, and readiness to change) and
      recommendations for their patients at a visit. MEASUREMENTS: Patient self-report
      of discussions about alcohol use immediately after the physician visit and
      alcohol use 6 months later. RESULTS: Of 312 patients, 240 visited faculty
      physicians, 301 (97%) completed the outcome assessment after the office visit,
      and 236 (76%) were followed for 6 months. Faculty physicians in the intervention
      group tended to be more likely than faculty physicians in the control group to
      give patients advice about drinking (adjusted proportion, 64% [95% CI, 47% to
      79%] vs. 42% [CI, 33% to 53%]) and to discuss problems associated with alcohol
      use (74% [CI, 59% to 85%] vs. 51% [CI, 39% to 62%]). Resident physicians' advice
      and discussions did not differ between groups. Six months later, patients who saw
      resident physicians in the intervention group had fewer drinks per drinking day
      (adjusted mean number of drinks, 3.8 [CI, 1.9 to 5.7] versus 11.6 [CI, 5.4 to
      17.7]). CONCLUSIONS: Although effects seem to differ by physician level of
      training, prompting physicians with alcohol screening results and recommendations
      for action can modestly increase discussions about alcohol use and advice to
      patients and may decrease alcohol consumption.

PMID- 12614090
TI  - Intentional weight loss and death in overweight and obese U.S. adults 35 years of
      age and older.
AB  - BACKGROUND: Although weight loss improves risk factors for cardiovascular and
      metabolic disease, it is unclear whether intentional weight loss reduces
      mortality rates. OBJECTIVE: To examine the relationships among intention to lose
      weight, weight loss, and all-cause mortality. DESIGN: Prospective cohort study
      using a probability sample of the U.S. population. SETTING: Interviewer
      administered survey. PARTICIPANTS: 6391 overweight and obese persons (body mass
      index > or = 25 kg/m2) who were at least 35 years of age. MEASUREMENTS: Intention
      to lose weight and weight change during the past year were assessed by self
      report in 1989. Vital status was followed for 9 years. Hazard rate ratios (HRRs)
      were adjusted for age, sex, ethnicity, education, smoking, health status, health
      care utilization, and initial body mass index. RESULTS: Compared with persons not
      trying to lose weight and reporting no weight change, those reporting intentional
      weight loss had a 24% lower mortality rate (HRR, 0.76 [95% CI, 0.60 to 0.97]) and
      those with unintentional weight loss had a 31% higher mortality rate (HRR, 1.31
      [CI, 1.01 to 1.70]). However, mortality rates were lower in persons who reported
      trying to lose weight than those in not trying to lose weight, independent of
      actual weight change. Compared with persons not trying to lose weight and
      reporting no weight change, persons trying to lose weight had the following HRRs:
      no weight change, 0.80 (CI, 0.65 to 0.99); gained weight, 0.94 (CI, 0.65 to
      1.37); and lost weight, 0.76 (CI, 0.60 to 0.97). CONCLUSIONS: Attempted weight
      loss is associated with lower all-cause mortality, independent of weight change.
      Self-reported intentional weight loss is associated with lower mortality rates,
      and weight loss is associated with higher mortality rates only if it is
      unintentional.

PMID- 12614091
TI  - Minimal prevalence of authorship misrepresentation among internal medicine
      residency applicants: do previous estimates of "misrepresentation" represent
      insufficient case finding?.
AB  - BACKGROUND: High rates of authorship misrepresentation have been documented among
      medical trainees. OBJECTIVE: To assess misrepresentation among internal medicine
      residency applicants while comparing searches used by previous authors (searches
      1 and 2) to a more comprehensive strategy (search 3). DESIGN: Review of 497
      residency applications. SETTING: Two university-based internal medicine residency
      programs. MEASUREMENTS: Search 1 was limited to MEDLINE. Search 2 added Current
      Contents, Science Citation Index, and BIOSIS and included searching journals by
      hand. Search 3 added seven other databases and contacts to librarians, editors,
      and coauthors. RESULTS: 224 applicants reported 634 articles; 630 (99%) were
      verified. The number of applicants with misrepresented citations varied depending
      on the search used (56 applicants [25%] in search 1 vs. 34 applicants [15%] in
      search 2 vs. 4 applicants [1.8%] in search 3). CONCLUSIONS: Using a comprehensive
      search, we found substantially less misrepresentation than had been reported.
      Previous studies probably overestimated the magnitude of the problem.

PMID- 12614092
TI  - A critical overview of homeopathy.
AB  - Homeopathy is a 200-year-old therapeutic system that uses small doses of various
      substances to stimulate autoregulatory and self-healing processes. Homeopathy
      selects substances by matching a patient's symptoms with symptoms produced by
      these substances in healthy individuals. Medicines are prepared by serial
      dilution and shaking, which proponents claim imprints information into water.
      Although many conventional physicians find such notions implausible, homeopathy
      had a prominent place in 19th-century health care and has recently undergone a
      worldwide revival. In the United States, patients who seek homeopathic care are
      more affluent and younger and more often seek treatment for subjective symptoms
      than those who seek conventional care. Homeopathic remedies were allowed by the
      1939 Pure Food and Drug Act and are available over the counter. Some data--both
      from randomized, controlled trials and laboratory research--show effects from
      homeopathic remedies that contradict the contemporary rational basis of medicine.
      Three independent systematic reviews of placebo-controlled trials on homeopathy
      reported that its effects seem to be more than placebo, and one review found its
      effects consistent with placebo. There is also evidence from randomized,
      controlled trials that homeopathy may be effective for the treatment of
      influenza, allergies, postoperative ileus, and childhood diarrhea. Evidence
      suggests that homeopathy is ineffective for migraine, delayed-onset muscle
      soreness, and influenza prevention. There is a lack of conclusive evidence on the
      effectiveness of homeopathy for most conditions. Homeopathy deserves an open
      minded opportunity to demonstrate its value by using evidence-based principles,
      but it should not be substituted for proven therapies.

PMID- 12614093
TI  - Alzheimer disease: current concepts and emerging diagnostic and therapeutic
      strategies.
AB  - Alzheimer disease is a complex neurodegenerative dementing illness. It has become
      a major public health problem because of its increasing prevalence, long
      duration, high cost of care, and lack of disease-modifying therapy. Over the past
      few years, however, remarkable advances have taken place in understanding both
      the genetic and molecular biology associated with the intracellular processing of
      amyloid and tau and the changes leading to the pathologic formation of
      extracellular amyloid plaques and the intraneuronal aggregation of
      hyperphosphorylated tau into neurofibrillary tangles. The identification of
      disease-causing autosomal dominant mutations as well as gene polymorphisms that
      alter the risk for pathology indicate that Alzheimer disease is a genetically
      complex disorder. This progress in our understanding of the molecular pathology
      has set the stage for clinically meaningful advances in diagnosis and treatment.
      Emerging diagnostic methods that are based on biochemical and imaging biomarkers
      of disease-specific pathology hold the potential for accurately diagnosing
      Alzheimer disease at the earliest stage of the illness--the time when disease
      modifying treatment will be most effective. Currently available cholinesterase
      inhibition therapy targets the cognitive symptoms. However, the goal of new
      therapies under development is halting the pathologic cascade and potentially
      reversing the course of the disease. If these new therapies are successful, they
      will represent a remarkable medical advance for patients and the families who
      care for them.

PMID- 12614094
TI  - Diagnostic evaluation of elderly patients with mild memory problems.
AB  - This case-based discussion focuses on the clinical presentation and diagnostic
      assessment of a uniquely challenging group of elderly patients: those with
      symptoms of mild memory problems. Such patients present a challenge to clinicians
      because of flux in our understandings of normal, age-related cognitive changes;
      of cognitive changes due to neurodegenerative illnesses; and of the relationships
      between depression and cognitive impairment. In addition, symptoms of memory
      problems may be reported by an observer rather than by the patient. These
      challenges warrant stepwise evaluation of elderly patients who present with
      symptoms of memory loss.

PMID- 12614095
TI  - Importance of identifying the overweight patient who will benefit the most by
      losing weight.
AB  - Because being overweight increases the risk for type 2 diabetes, hypertension,
      and coronary heart disease, the rapid increase in the prevalence of overweight
      and obesity in the United States represents a major health problem. The
      relationship between overweight and obesity and these conditions is probably due
      to insulin resistance and compensatory hyperinsulinemia. However, although it is
      known that weight loss in insulin-resistant and hyperinsulinemic persons will be
      of substantial metabolic benefit, it is equally well established that many
      overweight and obese persons are not insulin resistant. In the absence of insulin
      resistance and its manifestations, the risk for type 2 diabetes, hypertension,
      and coronary heart disease is reduced and the metabolic benefit of weight loss in
      the substantial number of overweight persons who are insulin sensitive is
      relatively minimal. Consequently, it is important to identify which overweight
      persons are most likely to be insulin resistant by considering their family
      history; blood pressure; and plasma glucose, triglyceride, and high-density
      lipoprotein cholesterol concentrations. Thoughtful use of this information will
      help identify the subset of persons who will benefit the most from intense
      therapeutic efforts to lose weight.

PMID- 12614096
TI  - Management of the clinically inapparent adrenal mass ("incidentaloma").
AB  - The National Institutes of Health Consensus Development Program convened
      surgeons, endocrinologists, pathologists, biostatisticians, radiologists,
      oncologists, and other health care professionals, as well as members of the
      general public, to address the causes, prevalence, and natural history of
      clinically inapparent adrenal masses, or "incidentalomas"; the appropriate
      evaluation and treatment of such masses; and directions for future research.
      Improvements in abdominal imaging techniques have increased detection of adrenal
      incidentalomas, and because the prevalence of these masses increases with age,
      appropriate management of adrenal tumors will be a growing challenge in our aging
      society. To address six predetermined questions, the 12-member nonfederal,
      nonadvocate state-of-the-science panel heard presentations from 21 experts in
      adrenal incidentalomas and consulted a systematic review of medical literature on
      the topic provided by the Agency for Healthcare Research and Quality and an
      extensive bibliography developed by the National Library of Medicine. The panel
      recommended a 1-mg dexamethasone suppression test and measurement of plasma-free
      metanephrines for all patients with an adrenal incidentaloma; additional
      measurement of serum potassium and plasma aldosterone concentration-plasma renin
      activity ratio for patients with hypertension; and surgery for patients with
      biochemical evidence of pheochromocytoma, patients with tumors greater than 6 cm,
      and patients with tumors greater than 4 cm who also meet other criteria. The
      panel also advocated a multidisciplinary approach to managing adrenal
      incidentalomas. The statement is an independent report of the panel and is not a
      policy statement of the National Institutes of Health or the federal government.

PMID- 12614097
TI  - A role for multivitamins in infection?

PMID- 12614098
TI  - Finding ping.

PMID- 12614100
TI  - The greenhouse effect.

PMID- 12614101
TI  - Ciprofloxacin versus tobramycin for neutropenic fevers.

PMID- 12614102
TI  - Ciprofloxacin versus tobramycin for neutropenic fevers.

PMID- 12614104
TI  - Reversible myopathy after statin therapy in patients with normal creatine kinase
      levels.

PMID- 12614105
TI  - Chronic HIV infection.

PMID- 12614106
TI  - Long-term medical care of testicular cancer survivors.

PMID- 12614110
TI  - Hope for the best, and prepare for the worst.

PMID- 12614111
TI  - Summaries for patients. The effect of a vitamin and mineral supplement on
      infection and self-reported health.

PMID- 12614112
TI  - Summaries for patients. Do applicants to internal medicine residency programs
      misrepresent publications?

PMID- 12614113
TI  - Summaries for patients. The relationship between intentional weight loss and
      mortality.

PMID- 12614114
TI  - Summaries for patients. Finding and treating alcohol problems in primary care.

PMID- 12614115
TI  - Annual physical examination: necessary or needless?.

PMID- 12614116
TI  - Prehospital fibrinolysis was as good as primary angioplasty after myocardial
      infarction.

PMID- 12614117
TI  - An interventional strategy was better than a conservative strategy in unstable
      angina or non-ST-elevation MI.

PMID- 12614118
TI  - Homocysteine-lowering therapy improved outcomes after percutaneous coronary
      intervention.

PMID- 12614119
TI  - Warfarin alone or with aspirin was superior to aspirin alone after acute
      myocardial infarction but increased bleeding.

PMID- 12614120
TI  - Heparin plus alteplase reduced morbidity more than heparin alone in submassive
      pulmonary embolism.

PMID- 12614121
TI  - Review: beta-blockers, sotalol, amiodarone, and biatrial pacing all reduce atrial
      fibrillation after heart surgery.

PMID- 12614122
TI  - Losartan was more effective than atenolol for isolated systolic hypertension and
      left ventricular hypertrophy.

PMID- 12614123
TI  - Annual screening with mammography and breast examination did not reduce breast
      cancer mortality in women 40 to 49 years of age.

PMID- 12614124
TI  - Review: mammography reduces breast cancer mortality rates.

PMID- 12614126
TI  - Review: risks and benefits of HRT comparing various sources of evidence.

PMID- 12614125
TI  - Review: observational studies adjusting for socioeconomic status and lifestyle
      show no association between HRT and CAD.

PMID- 12614127
TI  - Review: antileukotrienes are less effective than inhaled corticosteroids in
      chronic asthma.

PMID- 12614128
TI  - Review: respiratory rehabilitation improves health-related quality of life in
      chronic obstructive pulmonary disease.

PMID- 12614129
TI  - Hydrocortisone and fludrocortisone improved 28-day survival in septic shock and
      adrenal insufficiency.

PMID- 12614130
TI  - Review: beta-lactam alone was better than beta-lactam plus aminoglycoside for
      cancer patients with neutropenia.

PMID- 12614131
TI  - Review: antifungals absorbed or partially absorbed from the GI tract prevent oral
      candidiasis in cancer patients receiving treatment.

PMID- 12614132
TI  - Surgery was associated with greater long-term treatment success than wrist
      splinting in the carpal tunnel syndrome.

PMID- 12614133
TI  - Cervical spine manipulation was not better than mobilization for improving
      outcomes in neck pain.

PMID- 12614134
TI  - Arthroscopic surgery was not effective for relieving pain or improving function
      in osteoarthritis of the knee.

PMID- 12614135
TI  - Review: tegaserod or alosetron is effective for the irritable bowel syndrome.

PMID- 12614136
TI  - Upper gastrointestinal event risk with COX-2 inhibitors depended on known risk
      factors.

PMID- 12614137
TI  - Review: low dose was as effective as standard dose tricyclic antidepressants in
      adults with depression.

PMID- 12614138
TI  - Prophylactic citalopram reduced recurrences of unipolar major depression.

PMID- 12614139
TI  - The combined use of duplex ultrasonography and magnetic resonance angiography
      most accurately diagnosed carotid artery stenosis.

PMID- 12614140
TI  - Review: most disease management programs for providers and patients lead to
      improvements in care.

PMID- 12614141
TI  - Numbers needed to treat derived from meta-analysis: a word of caution.

PMID- 12614142
TI  - MRC/BHF Heart Protection Study.

PMID- 12614143
TI  - Dynamic nuclear and cytoplasmic glycosylation: enzymes of O-GlcNAc cycling.

PMID- 12614144
TI  - Backbone dynamics of green fluorescent protein and the effect of histidine 148
      substitution.
AB  - Green fluorescent protein (GFP) and its mutants have become valuable tools in
      molecular biology. GFP has been regarded as a very stable and rigid protein with
      the beta-barrel shielding the chromophore from the solvent. Here, we report the
      15N nuclear magnetic resonance (NMR) studies on the green fluorescent protein
      (GFPuv) and its mutant His148Gly. 15N NMR relaxation studies of GFPuv show that
      most of the beta-barrel of GFP is rigid on the picosecond to nanosecond time
      scale. For several regions, including the first alpha-helix and beta-sheets 3, 7,
      8, and 10, increased hydrogen-deuterium exchange rates suggest a substantial
      conformational flexibility on the microsecond to millisecond time scales.
      Mutation of residue 148 located in beta-sheet 7 is known to have a strong impact
      on the fluorescence properties of GFPs. UV absorption and fluorescence spectra in
      combination with 1H-15N NMR spectra indicate that the His148Gly mutation not only
      reduces the absorption of the anionic chromophore state but also affects the
      conformational stability, leading to the appearance of doubled backbone amide
      resonances for a number of residues. This suggests the presence of two
      conformations in slow exchange on the NMR time scale in this mutant.

PMID- 12614145
TI  - Caldesmon binding to actin is regulated by calmodulin and phosphorylation via
      different mechanisms.
AB  - Smooth muscle caldesmon (CaD) binds F-actin and inhibits actomyosin ATPase
      activity. The inhibition is reversed by Ca2+/calmodulin (CaM). CaD is also
      phosphorylated upon stimulation at sites specific for mitogen-activated protein
      kinases (MAPKs). Because of these properties, CaD is thought to be involved in
      the regulation of smooth muscle contraction. The molecular mechanism of the
      reversal of inhibition is not well understood. We have expressed His6-tagged
      fragments containing the sequence of the C-terminal region of human (from M563 to
      V793) and chicken (from M563 to P771) CaD as well as a variant of the chicken
      isoform with a Q766C point mutation. By cleavages with proteases, followed by
      high-speed cosedimentation with F-actin and mass spectrometry, we found that
      within the C-terminal region of CaD there are multiple actin contact points
      forming two clusters. Intramolecular fluorescence resonance energy transfer
      between probes attached to cysteine residues (the endogenous C595 and the
      engineered C766) located in these two clusters revealed that the C-terminal
      region of CaD is elongated, but it becomes more compact when bound to actin.
      Binding of CaM restores the elongated conformation and facilitates dissociation
      of the C-terminal CaD fragment from F-actin. When the CaD fragment was
      phosphorylated with a MAPK, only one of the two actin-binding clusters
      dissociated from F-actin, whereas the other remained bound. Taken together, these
      results demonstrate that while both Ca2+/CaM and MAPK phosphorylation govern
      CaD's function via a conformational change, the regulatory mechanisms are
      different.

PMID- 12614146
TI  - Inhibitory specificity change of the ovomucoid third domain of the silver
      pheasant upon introduction of an engineered Cys14-Cys39 bond.
AB  - The ovomucoid third domain from silver pheasant (OMSVP3), a typical Kazal-type
      inhibitor, strongly inhibits different serine proteases of various specificities,
      i.e., chymotrypsin, Streptomyces griseus protease, subtilisin, and elastase.
      Structural studies have suggested that conformational flexibility in the reactive
      site loop of the free inhibitor may be related to broad specificity of the
      ovomucoid. On the basis of the structural homology between OMSVP3 and ascidian
      trypsin inhibitor (ATI), which has a cystine-stabilized alpha-helical (CSH) motif
      in the sequence, we prepared the disulfide variant of OMSVP3, introducing an
      engineered disulfide bond between positions 14 and 39 near the reactive site
      (Met18-Glu19) by site-directed mutagenesis. The disulfide variant P14C/N39C
      retained potent inhibitory activities toward alpha-chymotrypsin (CHT) and S.
      griseus proteases A and B (SGPA and SGPB), while this variant lost most of its
      inhibitory activity toward porcine pancreatic elastase (PPE). We determined the
      solution structure of P14C/N39C, as well as that of wild-type OMSVP3, by two
      dimensional nuclear magnetic resonance (2D NMR) methods and compared their
      structures to elucidate the structural basis of the inhibitory specificity
      change. For the molecular core consisting of a central alpha-helix and a three
      stranded antiparallel beta-sheet, essentially no structural difference was
      detected between the two (pairwise rmsd value = 0.41 A). In contrast to this, a
      significant difference was detected in the loop from Cys8 to Thr17, where in
      P14C/N39C it has drawn approximately 4 A nearer the central helix to form the
      engineered Cys14-Cys39 bond. Concomitantly, the Tyr11-Pro12 cis-peptide linkage,
      which is highly conserved in ovomucoid third domains, was isomerized to the trans
      configuration. Such structural change in the loop near the reactive site may
      possibly affect the inhibitory specificity of P14C/N39C for the corresponding
      proteases.

PMID- 12614147
TI  - Water molecule rearrangements around Leu93 and Trp182 in the formation of the L
      intermediate in bacteriorhodopsin's photocycle.
AB  - After the chromophore's isomerization in the initial photochemical event in
      bacteriorhodopsin, the primary photoproduct K makes a thermal transition to the L
      intermediate, which prepares the pigment for Schiff base deprotonation in the
      following step (L --> M). Substantial changes in the hydrogen bonding of internal
      water molecules take place upon L formation. Some of these mobile waters are
      probably involved in changing the pK of the Schiff base and perhaps that of the
      proton acceptor Asp85 to allow proton movement [Maeda, A. (2001) Biochemistry
      (Moscow) 66, 1555-1569]. Here we show that mutations of Leu93 and Trp182,
      residues close to the 13-methyl group of the chromophore, allow the formation of
      L at much lower temperatures than in the wild type (80 K instead of 140 K).
      Moreover, an intense band due to weakly bound water that is peculiar for L was
      already present in the initial (unphotolyzed) state of each mutant at 2632 cm(-1)
      (in D2O) but not in the wild type. This unique, intense water band is shifted
      compared to the L band at 2589 cm(-1) but coincides with the band seen in L', the
      all-trans photoproduct of wild-type L formed at 80 K. We propose that the L93M
      and W182F mutations induce changes in the hydrogen bonding of one or more water
      molecules in the unphotolyzed states of these pigments, which are similar to
      those H-bonding changes that take place upon formation of L in the wild type, and
      thus facilitate the formation of L even at 80 K. We infer that L formation
      involves perturbation of a site which includes retinal, Trp182, and Leu93, and
      this structure is temporarily stabilized by rearranged hydrogen bonds with water
      molecules.

PMID- 12614148
TI  - Resonance Raman investigation of the interaction of thromboxane synthase with
      substrate analogues.
AB  - Thromboxane synthase is a hemethiolate enzyme that catalyzes the isomerization of
      prostaglandin H2 to thromboxane A2. We report the first resonance Raman (RR)
      spectra of recombinant human thromboxane synthase (TXAS) in both the presence and
      the absence of substrate analogues U44069 and U46619. The resting enzyme and its
      U44069 complex are found to have a 6-coordinate, low spin (6c/ls) heme, in
      agreement with earlier experiments. The U46619-bound enzyme is detected as a
      6c/ls heme too, which is in contradiction with a previous conclusion based on
      absorption difference spectroscopy. Two new vibrations at 368 and 424 cm(-1) are
      observed upon binding of the substrate analogues in the heme pocket and are
      assigned to the second propionate and vinyl bending modes, respectively. We
      interpret the changes in these vibrational modes as the disruption of the protein
      environment and the hydrogen-bonding network of one of the propionate groups when
      the substrate analogues enter the heme pocket. We use carbocyclic thromboxane A2
      (CTA2) to convert the TXAS heme cofactor to its 5-coordinate, high spin (5c/hs)
      form, as is confirmed by optical and RR spectroscopy. In this 5c/hs state of the
      enzyme, the Fe-S stretching frequency is determined at 350 cm(-1) with excitation
      at 356.4 nm. This assignment is supported by comparison to the spectrum of
      resting enzyme excited at 356.4 nm and by exciting at different wavelengths.
      Implications of our findings for substrate binding and the catalytic mechanism of
      TXAS will be discussed.

PMID- 12614149
TI  - Phosphorylation triggers domain separation in the DNA binding response regulator
      NarL.
AB  - DNA binding proteins of two-component signal transduction systems in
      microorganisms are activated by phosphorylation through an unknown mechanism.
      NarL is an example from the nitrate/nitrite signal transduction system of
      Escherichia coli. NarL consists of N- and C-terminal domains, the latter of which
      contains the DNA binding elements. To explore the mechanism of activation, single
      nitroxide side chains were introduced, one at a time, at nine different sites
      throughout the C-terminal domain to monitor the tertiary structure and the status
      of the surface in contact with the N-terminal domain. In addition, three pairs of
      doubly labeled proteins were prepared to monitor the interdomain distance using
      the magnetic dipolar interaction. The results of these site-directed spin
      labeling studies reveal that phosphorylation at a distant site in the N-terminal
      domain triggers domain separation, likely by a hinge-bending motion. This in turn
      presents key elements of the C-terminal domain for docking to the DNA target in
      the configuration described in the recent crystal structure. The data also imply
      that a single conformation of unphosphorylated NarL exists in solution, and there
      is no detectable equilibrium between the closed and open conformations.

PMID- 12614150
TI  - Role of a heterogeneous free state in the formation of a specific RNA
      theophylline complex.
AB  - The helical regions of RNA are generally very stable, but the single-stranded and
      loop regions often exist as an ensemble of conformations in solution. The
      theophylline-binding RNA aptamer forms a very stable structure when bound to the
      bronchodilator theophylline, but the theophylline binding site is not stably
      formed in the absence of ligand. The kinetics for theophylline binding were
      measured here by stopped-flow fluorescence spectroscopy to probe the mechanism
      for theophylline binding in this RNA aptamer. The kinetic studies showed that
      formation of the RNA-theophylline complex is over 1000 times slower than a
      diffusion-controlled rate, and the high affinity of the RNA-theophylline complex
      arises primarily from a slow dissociation rate for the complex. A theophylline
      independent rate was observed for formation of the theophylline-RNA complex at
      high theophylline concentration, indicating that a conformational change in the
      RNA is the rate-limiting step in complex formation under these conditions. The
      RNA-theophylline complex requires divalent metal ions, such as Mg2+, to form a
      high-affinity complex, and there is a greater than 10000-fold reduction in
      affinity for theophylline in the absence of Mg2+. This decrease in binding
      affinity in the absence of Mg2+ results primarily from an increased dissociation
      rate for the complex. The implications of an ensemble of conformations in the
      free state of this theophylline-binding RNA are discussed and compared with
      mechanisms for formation of protein-ligand complexes.

PMID- 12614151
TI  - Structures of human thymidylate kinase in complex with prodrugs: implications for
      the structure-based design of novel compounds.
AB  - Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise
      phosphorylation to their triphosphate form to become therapeutically active. In
      many cases it is this activation pathway that largely determines the efficacy of
      the drug. To gain further understanding of the determinants for efficient
      conversion by the enzyme thymidylate kinase (TMPK) of clinically important
      thymidine monophosphate analogues to the corresponding diphosphates, we solved
      the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp
      at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP,
      d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In
      conjunction with steady-state kinetic data, our structures shed light on the
      effect of 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on
      the catalytic rate. We observe a direct correlation between the rate of
      phosphorylation of an NMP and its ability to induce a closing of the enzyme's
      phosphate-binding loop (P-loop). Our results show the drastic effects that slight
      modifications of the substrates exert on the enzyme's conformation and, hence,
      activity and suggest the type of substitutions that are compatible with efficient
      phosphorylation by TMPK.

PMID- 12614152
TI  - A potent novel anti-HIV protein from the cultured cyanobacterium Scytonema
      varium.
AB  - A new anti-HIV protein, scytovirin, was isolated from aqueous extracts of the
      cultured cyanobacterium Scytonema varium. The protein displayed potent
      anticytopathic activity against laboratory strains and primary isolates of HIV-1
      with EC50 values ranging from 0.3 to 22 nM. Scytovirin binds to viral coat
      proteins gp120, gp160, and gp41 but not to cellular receptor CD4 or other tested
      proteins. This unique protein consists of a single 95-amino acid chain with
      significant internal sequence duplication and 10 cysteines forming five
      intrachain disulfide bonds.

PMID- 12614153
TI  - Roles of Leu249, Lys252, and Leu253 in membrane segment M3 of sarcoplasmic
      reticulum Ca2+-ATPase in control of Ca2+ migration and long-range intramolecular
      communication.
AB  - Point mutants with alterations to Leu249, Lys252, Leu253, Asp254, and Glu255 in
      membrane segment M3, and Pro824, Lys825, and Glu826 in loop L6-7, of the
      sarcoplasmic reticulum Ca2+-ATPase were analyzed functionally by steady-state and
      transient kinetic methods. In mutants Leu249Ala, Lys252Glu, and Leu253Ala, the
      rate of Ca2+ dissociation from the cytoplasmically facing high-affinity Ca2+
      sites was increased 4- to 7-fold relative to wild type, and in Leu249Ala and
      Lys252Glu the rate of Ca2+ binding was increased as well. Substitution of Lys252
      with arginine, alanine, glutamine, or methionine affected Ca2+ interaction much
      less, indicating that the negative charge of the glutamate is particularly
      disturbing. These findings may be understood on the basis of the hypothesis that
      a water-accessible channel leading between membrane segments M1 and M3 in the
      thapsigargin-bound Ca2+-free structure [Toyoshima, C., and Nomura, H. (2002)
      Nature 418, 605-611] is closely related to the migration pathway for Ca2+. The
      effects of alanine mutations to Leu249 and Leu253 on Ca2+ dissociation may arise
      from destabilization of the hydrophobic wall lining the pathway. In mutant
      Lys252Glu, unfavorable interaction between the glutamate and L6-7 may open the
      pathway. In addition, Leu253Ala, and to a lesser extent some of the other
      mutations, reduced the rate of the E1PCa2 to E2P transition of the phosphoenzyme,
      enhanced the rate of dephosphorylation of E2P, and reduced the apparent affinity
      for vanadate, suggesting interference with the conformational change of the
      phosphoenzyme and the function of the catalytic site in E2 and E2P.

PMID- 12614154
TI  - Motor domain mutation traps kinesin as a microtubule rigor complex.
AB  - Conventional kinesin is a highly processive, microtubule-based motor protein that
      drives the movement of membranous organelles in neurons. Using in vivo genetics
      in Drosophila melanogaster, Glu164 was identified as an amino acid critical for
      kinesin function [Brendza, K. M., Rose, D. J., Gilbert, S. P., and Saxton, W. M.
      (1999) J. Biol. Chem. 274, 31506-31514]. Glu164 is located at the beta-strand
      5a/loop 8b junction of the catalytic core and projects toward the microtubule
      binding face in close proximity to key residues on beta-tubulin helix alpha12.
      Substitution of Glu(164) with alanine (E164A) results in a dimeric kinesin with a
      dramatic reduction in the microtubule-activated steady-state ATPase (5 s(-1) per
      site versus 22 s(-1) per site for wild-type). Our analysis shows that E164A binds
      ATP and microtubules with a higher affinity than wild-type kinesin. The rapid
      quench and stopped-flow results provide evidence that ATP hydrolysis is
      significantly faster and the precise coordination between the motor domains is
      disrupted. The data reveal an E164A intermediate that is stalled on the
      microtubule and cannot bind and hydrolyze ATP at the second head.

PMID- 12614155
TI  - Partial rescue of functional interactions of a nonpalmitoylated mutant of the G
      protein G alpha s by fusion to the beta-adrenergic receptor.
AB  - Most heterotrimeric G-protein alpha subunits are posttranslationally modified by
      palmitoylation, a reversible process that is dynamically regulated. We analyzed
      the effects of Galpha(s) palmitoylation for its intracellular distribution and
      ability to couple to the beta-adrenergic receptor (betaAR) and stimulate adenylyl
      cyclase. Subcellular fractionation and immunofluorescence microscopy of stably
      transfected cyc(-) cells, which lack endogenous Galpha(s), showed that wild-type
      Galpha(s) was predominantly localized at the plasma membrane, but the mutant C3A
      Galpha(s), which does not incorporate [(3)H]palmitate, was mostly associated with
      intracellular membranes. In agreement with this mislocalization, C3A-Galpha(s)
      showed neither isoproterenol- or GTPgammaS-stimulated adenylyl cyclase activation
      nor GTPgammaS-sensitive high-affinity agonist binding, all of which were present
      in the wild-type Galpha(s) expressing cells. Fusion of C3A-Galpha(s) with the
      betaAR [betaAR-(C3A)Galpha(s)] partially rescued its ability to induce high
      affinity agonist binding and to stimulate adenylyl cyclase activity after
      isoproterenol or GTPgammaS treatment. In comparison to results with the WT
      Galpha(s) and betaAR (betaAR-Galpha(s)) fusion protein, the betaAR-(C3A)Galpha(s)
      fusion protein was about half as efficient at coupling to the receptor and
      effector. Chemical depalmitoylation by hydroxylamine of membranes expressing
      betaAR-Galpha(s) reduced the high-affinity agonist binding and adenylyl cyclase
      activation to a similar degree as that observed in betaAR-(C3A)Galpha(s)
      expressing membranes. Altogether, these findings indicate that palmitoylation
      ensured proper localization of Galpha(s) and facilitated bimolecular interactions
      of Galpha(s) with the betaAR and adenylyl cyclase.

PMID- 12614156
TI  - Structure of human pro-chymase: a model for the activating transition of granule
      associated proteases.
AB  - Human chymase is a protease involved in physiological processes ranging from
      inflammation to hypertension. As are all proteases of the trypsin fold, chymase
      is synthesized as an inactive "zymogen" with an N-terminal pro region that
      prevents the transition of the zymogen to an activated conformation. The 1.8 A
      structure of pro-chymase, reported here, is the first zymogen with a dipeptide
      pro region (glycine-glutamate) to be characterized at atomic resolution. Three
      segments of the pro-chymase structure differ from that of the activated enzyme:
      the N-terminus (Gly14-Gly19), the autolysis loop (Gly142-Thr154), and the 180s
      loop (Pro185A-Asp194). The four N-terminal residues (Gly14-Glu15-Ile16-Ile17) are
      disordered. The autolysis loop occupies a position up to 10 A closer to the
      active site than is seen in the activated enzyme, thereby forming a hydrogen bond
      with the catalytic residue Ser195 and occluding the S1' binding pocket.
      Nevertheless, the catalytic triad (Asp102-His57-Ser195) is arrayed in a geometry
      close to that seen in activated chymase (all atom rmsd of 0.52 A). The 180s loop
      of pro-chymase is, on average, 4 A removed from its conformation in the activated
      enzyme. This conformation disconnects the oxyanion hole (the amides of Gly193 and
      Ser195) from the active site and positions only approximately 35% of the S1-S3
      binding pockets in the active conformation. The backbone of residue Asp194 is
      rotated 180 degrees when compared to its conformation in the activated enzyme,
      allowing a hydrogen bond between the main-chain amide of residue Trp141 and the
      carboxylate of Asp194. The side chains of residues Phe191 and Lys192 of pro
      chymase fill the Ile16 binding pocket and the base of the S1 binding pocket,
      respectively. The zymogen positioning of both the 180s and autolysis loops are
      synergistic structural elements that appear to prevent premature proteolysis by
      chymase and, quite possibly, by other dipeptide zymogens.

PMID- 12614157
TI  - Inhibition of nuclear import mediated by the Rev-arginine rich motif by RNA
      molecules.
AB  - The HIV-1 Rev protein plays a pivotal role in viral replication, and therefore,
      inhibition of its function should block the progression of the virus-induced
      immune deficiency syndrome (AIDS). Here, RNA molecules have been shown to inhibit
      import of the HIV-1 Rev protein into nuclei of permeabilized cells. Nuclear
      uptake of biotinylated recombinant His-tagged Rev-GFP was assessed in nuclear
      extracts from digitonin-permeabilized cells by binding to either importin beta
      receptors or nickel molecules immobilized on a microtiter plate. Using this
      method together with fluorescence microscopy, we determined that nuclear import
      of Rev is inhibited by the addition of a reticulocyte lysate which routinely is
      used as a source of nuclear import receptors. This inhibition was released by
      treatment with the RNase enzyme. Also t-RNA molecules and the oligoribonucleotide
      RRE IIB, namely, the second stem structure of the Rev responsive element (RRE) of
      the viral RNA, inhibit Rev nuclear import. Similar results were obtained when BSA
      molecules with covalently attached Rev-arginine rich motif (ARM) peptides were
      used as a nuclear transport substrate, indicating that the nuclear import
      inhibition of the Rev protein is due to the presence of the ARM domain. Binding
      experiments revealed that the RNA molecules inhibit the interaction between the
      ARM region and importin beta, implying that the RNA prevents the formation of the
      import complex. The implication of our results for the regulation of the nuclear
      import of Rev as well as for the use of RNA molecules as antiviral drugs is
      discussed.

PMID- 12614159
TI  - The synaptic complex of RecA protein participates in hybridization and inverse
      strand exchange reactions.
AB  - RecA protein catalyzes strand exchange between homologous single-stranded and
      double-stranded DNAs. In the presence of ATPgammaS, the post-strand exchange
      synaptic complex is a stable end product that can be studied. Here we ask whether
      such complexes can hybridize to or exchange with DNA, 2'-OMe RNA, PNA, or LNA
      oligonucleotides. Using a gel mobility shift assay, we show that the displaced
      strand of a 45 bp synaptic complex can hybridize to complementary
      oligonucleotides with different backbones to form a four-stranded (double D-loop)
      joint that survives removal of the RecA protein. This hybridization reaction,
      which confirms the single-stranded character of the displaced strand in a
      synaptic complex, might initiate recombination-dependent DNA replication if it
      occurs in vivo. We also show that either strand of the heteroduplex in a 30 bp
      synaptic complex can be replaced with a homologous DNA oligonucleotide in a
      strand exchange reaction that is mediated by the RecA filament. Consistent with
      the important role that deoxyribose plays in strand exchange, oligonucleotides
      with non-DNA backbones did not participate in this reaction. The hybridization
      and strand exchange reactions reported here demonstrate that short synaptic
      complexes are dynamic structures even in the presence of ATPgammaS.

PMID- 12614158
TI  - Elements located upstream and downstream of the major splice donor site influence
      the ability of HIV-2 leader RNA to dimerize in vitro.
AB  - An essential step in the replication cycle of all retroviruses is the
      dimerization of genomic RNA prior to or during budding and maturation of the
      viral particle. In HIV-1, a 5' leader region site termed stem-loop 1 (SL1)
      promotes RNA dimerization in vitro and influences dimerization in vivo. In HIV-2,
      two sequences promote dimerization of RNA fragments in vitro: the 5'-end of the
      primer-binding site (PBS) and a stem-loop region homologous to the HIV-1 SL1
      sequence. Because HIV-2 RNA constructs of different lengths use these two
      dimerization signals disproportionately, we hypothesized that other sequences
      could modulate their relative utilization. Here, we characterized the influence
      of sequences upstream and downstream of the major splice donor site on the
      formation of HIV-2 RNA dimers in vitro using a variety of RNA constructs and
      dimerization and electrophoresis protocols. We first assayed the formation of
      loose or tight dimers for 1-444 and 1-561 model RNAs. Although both RNAs could
      form PBS-dependent loose dimers, the 1-561 RNA was unable to make SL1-dependent
      tight dimers. Using RNAs truncated at their 5'- and/or 3'-ends and by making
      compensatory base substitutions, we found that two elements interfere with the
      formation of SL1-dependent tight dimers. The cores of these elements are located
      at nucleotides 189-196 and 543-550. Our results suggest that base pairing between
      these sequences prevents the formation of SL1-dependent tight dimers, probably by
      sequestering SL1 in a stable intramolecular arrangement. Moreover, we found that
      nucleotides downstream of SL1 decreased the rate of tight dimerization.
      Interestingly, dimerization at 37 degrees C in the presence of nucleocapsid
      protein increased the yield of SL1-mediated tight dimerization in vitro, even in
      the presence of the two interfering elements, suggesting a relationship between
      the nucleocapsid protein and activation of the SL1 dimerization signal in vivo.

PMID- 12614160
TI  - Transcriptional regulation of the nuclear gene encoding the alpha-subunit of the
      mammalian mitochondrial F1F0 ATP synthase complex: role for the orphan nuclear
      receptor, COUP-TFII/ARP-1.
AB  - Our laboratory has been studying the transcriptional regulation of the nuclear
      gene (ATPA) that encodes the alpha-subunit of the mammalian mitochondrial F1F0
      ATP synthase complex. We have previously determined that the regulatory factor,
      upstream stimulatory factor 2 (USF2), can stimulate transcription of the ATPA
      gene through the cis-acting regulatory element 1 in the upstream promoter of this
      gene. In this study, we used the yeast one-hybrid screening method to identify
      another factor, COUP-TFII/ARP-1, which also binds to the ATPA cis-acting
      regulatory element 1. Binding of the orphan nuclear receptor, COUP-TFII/ARP-1, to
      the ATPA regulatory element 1 was confirmed using electrophoretic mobility shift
      experiments, and COUP-TFII/ARP-1-containing complexes were detected in HeLa cell
      nuclear extracts. A mutational analysis indicated that the binding site for COUP
      TFII/ARP-1 in the ATPA regulatory element 1 is an imperfect direct repeat of a
      nuclear receptor response element (A/GGGTCA) with a spacer of three nucleotides.
      Functional assays in HeLa cells showed that COUP-TFII/ARP-1 represses the ATPA
      promoter activity in a dose- and sequence-dependent manner. Furthermore,
      cotransfection assays demonstrated that COUP-TFII/ARP-1 inhibits the USF2
      mediated activation of the wild-type ATPA gene promoter but not a mutant promoter
      that is defective in COUP-TFII/ARP-1-binding. Overexpression of USF2 reversed the
      COUP-TFII/ARP-1-mediated repression of the ATPA promoter. Mobility shift assays
      revealed that COUP-TFII/ARP-1 and USF2 compete for binding to the ATPA regulatory
      element 1. Thus, the ATPA gene is regulated by a multifunctional binding site
      through which the transcription factors, COUP-TFII/ARP-1 and USF2, bind and exert
      their antagonistic effects.

PMID- 12614161
TI  - Nature of full-length HMGB1 binding to cisplatin-modified DNA.
AB  - HMGB1, a highly conserved non-histone DNA-binding protein, interacts with
      specific DNA structural motifs such as those encountered at cisplatin damage,
      four-way junctions, and supercoils. The interaction of full-length HMGB1,
      containing two tandem HMG box domains and a C-terminal acidic tail, with
      cisplatin-modified DNA was investigated by hydroxyl radical footprinting and
      electrophoretic gel mobility shift assays. The full-length HMGB1 protein binds to
      DNA containing a 1,2-intrastrand d(GpG) cross-link mainly through domain A, as
      revealed by footprinting, with a dissociation constant K(d) of 120 nM. Site
      directed mutagenesis of intercalating residues in both HMG domains A and B in
      full-length HMGB1 further supports the conclusion that only one HMG box domain is
      bound to the site of cisplatin damage. Interaction of the C-terminal tail with
      the rest of the HMGB1 protein was examined by EDC cross-linking experiments. The
      acidic tail mainly interacts with domain B and linker regions rather than domain
      A in HMGB1. These results illuminate the respective roles of the tandem HMG boxes
      and the C-terminal acidic tail of HMGB1 in binding to DNA and to the major DNA
      adducts formed by the anticancer drug cisplatin.

PMID- 12614162
TI  - Effect of protein dynamics upon reactions that occur in the heme pocket of
      horseradish peroxidase.
AB  - Free base and Pd porphyrin derivatives of horseradish peroxidase show long-lived
      excited states that are quenched by the presence of the peroxidase inhibitor,
      benzhydroxamic acid. The relaxation times of the excited-state luminescence and
      the rates of the quenching reaction for these derivatives of peroxidase were
      monitored as a function of pH, temperature, and viscosity with the view of
      examining how protein dynamics affect the quenching reaction. As solvent
      viscosity increases, the rate decreases, but at the limit of very high viscosity
      (i.e., high glycerol or sugar glass) the quenching still occurs. A model is
      presented that is consistent with the known structure of the enzyme-inhibitor
      complex. It is considered that the inhibitor is held at an established position
      but that solvent-dependent and independent motions allow a limited diffusion of
      the two reactants. Since there is a steep dependence upon distance and
      orientation, the diffusion toward the favorable position for reaction enhances
      the reaction rate. The solvent viscosity dependent and independent effects were
      separated and analyzed. The importance of internal reaction dynamics is
      demonstrated in the observation that rigidity of solvent imposed by incorporating
      the protein into glass at room temperature allows the reaction to occur, while
      the reaction is inhibited at low temperature. The results emphasize that protein
      dynamics plays a role in determining reaction rates.

PMID- 12614163
TI  - Insulin induction of apolipoprotein AI, role of Sp1.
AB  - Apolipoprotein AI (apo AI) is the major protein component of serum high-density
      lipoproteins. The abundance of apo AI correlates inversely with the risk of
      ischemic heart disease (IHD) and thus enhanced expression of the protein is
      expected to reduce the risk of IHD. Our previous studies show that insulin
      enhances apo AI promoter activity and this action requires the GC-rich insulin
      response core element (IRCE, -411 to -404). The motif binds to a ubiquitous
      transcription factor Sp1. We have extended studies that examine insulin induction
      of apo AI using a 41 bp (-425 to -385) fragment of apo AI DNA linked to the trout
      metallothionein TATA box and fused to luciferase (pIRCE-Luc). Luc activity in Hep
      G2 cells transfected with pIRCE-Luc was stimulated by insulin, an insulin mimetic
      bisperoxo (1,10-phenanthroline) oxovanadate (bpv) and the phorbol ester (PDBu).
      Our previous studies showed that insulin action on apo AI gene transcription
      flowed down two signaling pathways: Ras-raf and PI3K, leading to activation of
      the MAPK and PKC kinases, respectively. In contrast, PDBu activates only the PKC
      pathway. Although insulin and PDBu activation of apo AI were distinct, the
      cascades involved all appeared to target Sp1. Furthermore, exposure of
      transfected cells to okadaic acid or a phosphatase inhibitor also increased Luc
      activity and suggested a potential role for phosphorylation, likely involving
      Sp1. If true, then changes in the IRCE binding activity of Sp1 should be detected
      following exposure to MAPK, PKC, or the protein phosphatase I (PPI) alone and in
      various combinations followed by assaying the ability of Sp1 to bind the IRCE.
      Sp1 binding activity increased with either MAPK or PKC. Although exposure to PPI
      also affected IRCE binding activity of Sp1, whether it increased or decreased was
      dependent on the order of exposure to the protein. In summary, the IRCE alone can
      mediate the stimulatory effects of insulin, bpv, and PDBu, and Sp1 enhances these
      responses that may arise from phosphorylation of the protein.

PMID- 12614164
TI  - Identification of protein tyrosine phosphatases associating with the PDGF
      receptor.
AB  - Protein tyrosine phosphatase (PTP) in-gel assays were used to explore association
      of PTPs with the platelet-derived growth factor beta-receptor (PDGFbetaR). Five
      PTP activity bands of approximately 120, approximately 70, approximately 60,
      approximately 53, and approximately 45 kDa could be detected in PDGFbetaR
      immunoprecipitates and were identified by immunodepletion experiments as PTP
      PEST, SHP-2, an active fragment of SHP-2, PTP-1B, and T-cell PTP, respectively.
      The PTP pattern that was obtained was similar in PDGFbetaR immunoprecipitates
      from HEK 293 cells overexpressing the human PDGFbetaR and from murine
      fibroblasts. Association of PTP-1B with the PDGFbetaR was stabilized by
      pretreatment of the cells with hydrogen peroxide. The epidermal growth factor
      receptor (EGFR) immunoprecipitated from fibroblasts, and c-Kit isolated from CHRF
      myeloid cells, were associated with partially overlapping but quantitatively
      different patterns of PTPs. PTP-PEST was the predominant PTP in EGFR
      immunoprecipitates, and SHP-1 appeared in c-Kit immunoprecipitates. We propose
      that the differential association of PTPs with different RTKs is related to their
      respective contributions to regulation of RTK signaling.

PMID- 12614165
TI  - Bifunctional abietadiene synthase: mutual structural dependence of the active
      sites for protonation-initiated and ionization-initiated cyclizations.
AB  - Abietadiene synthase from grand fir catalyzes two sequential, mechanistically
      distinct cyclizations, of geranylgeranyl diphosphate and of copalyl diphosphate,
      in the formation of a mixture of abietadiene isomers as the committed step of
      diterpenoid resin acid biosynthesis. Each reaction is independently conducted at
      a separate active site residing in what were considered to be structurally
      distinct domains typical of terpene cyclases. Despite the presence of an unusual
      250-residue N-terminal insertional element, a tandem pair of charged residues
      distal to the insertion was shown to form a functional part of the C-terminal
      active site. Because abietadiene synthase resembles the ancestral plant terpene
      cyclase, this observation suggests an early evolutionary origin of catalytically
      important positively charged residues at the N-terminus of enzymes of this
      general class. A series of N- and C-terminal truncations of this enzyme were
      constructed and characterized, both alone and as mixtures of adjacent polypeptide
      pairs, to assess the proposed domain architecture, the function of the
      insertional element, and the role of presumptive interdomain contacts. These
      studies indicated a requirement for the insertional element in functional folding
      and allowed definition of the minimum primary structure of N- and C-terminal
      active site peptides. Most importantly, the results showed that, although the two
      active sites of abietadiene synthase are catalytically independent, substantial
      contact between the two regions is essential for the functional competence of
      this enzyme. Thus, the two cyclization sites of abietadiene synthase cannot be
      dissected into catalytically distinct domains, and, therefore, abietadiene
      synthase is unlikely to have arisen by fusion of two previously independent
      genes.

PMID- 12614166
TI  - Control of adenosylmethionine-dependent radical generation in biotin synthase: a
      kinetic and thermodynamic analysis of substrate binding to active and inactive
      forms of BioB.
AB  - Biotin synthase (BS) is an AdoMet-dependent radical enzyme that catalyzes the
      insertion of sulfur into saturated C6 and C9 atoms in the substrate dethiobiotin.
      To facilitate sulfur insertion, BS catalyzes the reductive cleavage of AdoMet to
      methionine and 5'-deoxyadenosyl radicals, which then abstract hydrogen atoms from
      the C6 and C9 positions of dethiobiotin. The enzyme from Escherichia coli is
      purified as a dimer that contains one [2Fe-2S]2+ cluster per monomer and can be
      reconstituted in vitro to contain an additional [4Fe-4S]2+ cluster per monomer.
      Since each monomer contains each type of cluster, the dimeric enzyme could
      contain one active site per monomer, or could contain a single active site at the
      dimer interface. To address these possibilities, and to better understand the
      manner in which biotin synthase controls radical generation and reactivity, we
      have examined the binding of AdoMet and DTB to reconstituted biotin synthase. We
      find that both the [2Fe-2S]2+ cluster and the [4Fe-4S]2+ cluster must be present
      for tight substrate binding. Further, substrate binding is highly cooperative,
      with the affinity for AdoMet increasing >20-fold in the presence of DTB, while
      DTB binds only in the presence of AdoMet. The stoichiometry of binding is ca.
      2:1:1 AdoMet:DTB:BS dimer, suggesting that biotin synthase has a single
      functional active site per dimer. AdoMet binding, either in the presence or in
      the absence of DTB, leads to a decrease in the magnitude of the UV-visible
      absorption band at approximately 400 nm that we attribute to changes in the
      coordination environment of the [4Fe-4S]2+ cluster. Using these spectral changes
      as a probe, we have examined the kinetics of AdoMet and DTB binding, and propose
      an ordered binding mechanism that is followed by a conformational change in the
      enzyme-substrate complex. This kinetic analysis suggests that biotin synthase is
      evolved to bind AdoMet both weakly and slowly in the absence of DTB, while both
      the rate of binding and the affinity for AdoMet are increased in the presence of
      DTB. Cooperative binding of AdoMet and DTB may be an important mechanism for
      limiting the production of 5'-deoxyadenosyl radicals in the absence of the
      correct substrate.

PMID- 12614167
TI  - Conformational behavior and aggregation of alpha-synuclein in organic solvents:
      modeling the effects of membranes.
AB  - Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of alpha
      synuclein are pathological hallmarks of neurodegenerative diseases such as
      Parkinson's disease, dementia with Lewy bodies (DLB), and multiple systemic
      atrophy. The molecular mechanisms underlying the aggregation of alpha-synuclein
      into such filamentous inclusions remain unknown, although many factors have been
      implicated, including interactions with lipid membranes. To model the effects of
      membrane fields on alpha-synuclein, we analyzed the structural and fibrillation
      properties of this protein in mixtures of water with simple and fluorinated
      alcohols. All solvents that were studied induced folding of alpha-synuclein, with
      the common first stage being formation of a partially folded intermediate with an
      enhanced propensity to fibrillate. Protein fibrillation was completely inhibited
      due to formation of beta-structure-enriched oligomers with high concentrations of
      methanol, ethanol, and propanol and moderate concentrations of trifluoroethanol
      (TFE), or because of the appearance of a highly alpha-helical conformation at
      high TFE and hexafluoro-2-propanol concentrations. At least to some extent, these
      conformational effects mimic those observed in the presence of phospholipid
      vesicles, and can explain some of the observed effects of membranes on alpha
      synuclein fibrillation.

PMID- 12614168
TI  - Human gene 2 relaxin chain combination and folding.
AB  - Relaxin is a small 6 kD two-chain peptide member of the insulin superfamily that
      is principally produced in the corpus luteum of the ovary and which plays a key
      role in connective tissue remodeling during parturition. Like insulin, it is
      produced on the ribosome as preprohormone that undergoes oxidative folding and
      subsequent proteolytic processing to yield the mature insulin-like peptide. In
      contrast to the now considerable insight into insulin chain folding and
      oxidation, comparatively little is known about the folding pathway of relaxin. A
      series of synthetic pairwise serine substituted relaxin A-chain cysteine
      analogues was prepared, and their oxidation behavior was studied both on their
      own and in the presence of native relaxin B-chain. It was observed that native S
      reduced A-chain oxidized rapidly to a bicyclic product, whereas individual
      formation of each of the intramolecular disulfide bonds between Cys11 and Cys24
      and the native Cys10 and Cys15 was considerably slower. Curiously, the non
      native, isomeric Cys11-Cys15 disulfide bond formed most rapidly, although
      circular dichroism spectroscopy analysis showed this product to be devoid of
      secondary structure. This suggested that it may in fact be an intermediate in the
      subsequent formation of the native Cys10-Cys15 intramolecular disulfide.
      Combination of the native A-chain with the B-chain proceeded rapidly as compared
      with the A-chain analogue that lacked the intramolecular disulfide bond
      suggesting that this latter element is required as a first step in the folding
      process. It is therefore probable that relaxin is generated from its constituent
      A- and B-chains in a stepwise organization manner similar to that of insulin
      chain combination and folding. Further studies showed that the efficiency of
      combination of A-chain to B-chain was not markedly influenced by reaction
      temperature and that a reasonable yield of relaxin could be obtained on
      combination of the preoxidized A-chain with the S-reduced B-chain.

PMID- 12614169
TI  - Regulation of the RYR1 and RYR2 Ca2+ release channel isoforms by Ca2+-insensitive
      mutants of calmodulin.
AB  - Calmodulin (CaM) may function as a regulatory subunit of ryanodine receptor (RYR)
      channels, modulating both channel activation and inhibition by Ca2+; however,
      mechanisms underlying differences in CaM regulation of the RYR isoforms expressed
      in skeletal muscle (RYR1) and cardiac muscle (RYR2) are poorly understood. Here
      we use a series of CaM mutants deficient in Ca2+ binding to compare determinants
      of CaM regulation of the RYR1 and RYR2 isoforms. In submicromolar Ca2+,
      activation of the RYR1 isoform by each of the single-point CaM mutants was
      similar to that by wild-type apoCaM, whereas in micromolar Ca2+, RYR1 inhibition
      by Ca2+CaM was abolished by mutations targeting CaM's C-terminal Ca2+ sites. In
      contrast to the RYR1, no activation of the cardiac RYR2 isoform by wild-type CaM
      was observed, but rather CaM inhibited the RYR2 at all Ca2+ concentrations (100
      nM to 1 mM). Consequently, whereas the apparent Ca2+ sensitivity of the RYR1
      isoform was enhanced in the presence of CaM, the RYR2 displayed the opposite
      response (RYR2 Ca2+ EC50 increased 7-10-fold in the presence of 5 microM wild
      type CaM). CaM inhibition of the RYR2 was nonetheless abolished by each of four
      mutations targeting individual CaM Ca2+ sites. Furthermore, a mutant CaM
      deficient in Ca2+ binding at all four Ca2+ sites significantly activated the RYR2
      and acted as a competitive inhibitor of RYR2 regulation by wild-type Ca2+CaM. We
      conclude that Ca2+ binding to CaM determines the effect of CaM on both RYR1 and
      RYR2 channels and that isoform differences in CaM regulation reflect the
      differential tuning of Ca2+ binding sites on CaM when bound to the different
      RYRs. These results thus suggest a novel mechanism by which CaM may contribute to
      functional diversity among the RYR isoforms.

PMID- 12614170
TI  - Flash-induced relaxation changes of the EPR signals from the manganese cluster
      and YD reveal a light-adaptation process of photosystem II.
AB  - By exposing photosystem II (PSII) samples to an incrementing number of excitation
      flashes at room temperature, followed by freezing, we could compare the Mn
      derived multiline EPR signal from the S2 oxidation state as prepared by 1, 5, 10,
      and 25 flashes of light. While the S2 multiline signals exhibited by these
      samples differed very little in spectral shape, a significant increase of the
      relaxation rate of the signal was detected in the multiflash samples as compared
      to the S2-state produced by a single oxidation. A similar relaxation rate
      increase was observed for the EPR signal from Y(D*). The temperature dependence
      of the multiline spin-lattice relaxation rate is similar after 1 and 5 flashes.
      These data are discussed together with previously reported phenomena in terms of
      a light-adaptation process of PSII, which commences on the third flash after dark
      adaptation and is completed after 10 flashes. At room temperature, the fast
      relaxing, light-adapted state falls back to the slow-relaxing, dark-adapted state
      with t(1/2) = 80 s. We speculate that light-adaptation involves changes necessary
      for efficient continuous water splitting. This would parallel activation
      processes found in many other large redox enzymes, such as Cytochrome c oxidase
      and Ni-Fe hydrogenase. Several mechanisms of light-adaptation are discussed, and
      we find that the data may be accounted for by a change of the PSII protein matrix
      or by the light-induced appearance of a paramagnetic center on the PSII donor
      side. At this time, no EPR signal has been detected that correlates with the
      increase of the relaxation rates, and the nature of such a new paramagnet remains
      unclear. However, the relaxation enhancement data could be used, in conjunction
      with the known Mn-Y(D) distance, to estimate the position of such an unknown
      relaxer. If positioned between Y(D) and the Mn cluster, it would be located 7-8 A
      from the spin center of the S2 multiline signal.

PMID- 12614171
TI  - Infrared spectroscopy of human cells and tissue: detection of disease.
AB  - An objective method for the analysis of tissue section is described that uses the
      chemical composition of the tissue, rather than cell morphology, as an indicator
      for the state of health of the cells in the tissue. The chemical composition of
      cells and tissue, and small variations therein, are determined by an objective,
      quantitative spectral measurement carried out in the infrared spectral region.
      This method does not utilize any stains or chemical treatment of the sample, but
      uses an inherent optical property of all materials. The spectral information is
      converted to false color images by unsupervised mathematical methods. The false
      color maps reveal the same anatomical features of the tissue that can be
      confirmed using a variety of common histopathological procedures, and may be used
      to differentiate between normal and diseased areas of the tissue.

PMID- 12614172
TI  - Noninvasive native fluorescence imaging of head and neck tumors.
AB  - Fluorescence images were acquired from ex vivo head and neck tumor specimens. The
      excitation and emission wavelength combinations were selected to image emission
      from native tissue fluorophores (collagen, tryptophan, elastin and nicotinamide
      adenine dinucleotide). Two dimensional intensity ratio maps were generated from
      the fluorescence images and compared to histology images. The ratio maps
      accurately distinguished the regions of tumor from normal tissue in the
      specimens. Additional features, such as collagen capsules, blood vessels, mucus
      glands and muscles were evident in the fluorescence images.

PMID- 12614173
TI  - Clinical applications of proton MR spectroscopy in oncology.
AB  - Proton magnetic resonance spectroscopy (H1-MRS) has been increasingly receiving
      more attention from radiologists, neurosurgeons, radiation and medical
      oncologists in the "in situ" clinical evaluation of human tumors. The utilization
      of H1-MRS, especially in human brain tumors, coupled to both routine magnetic
      resonance imaging (MRI) and functional MRI techniques provides greater
      information concerning tumor grading and extension and characterization of the
      normal surrounding tissue than what is possible with any other imaging technique
      alone. In this paper, we will review the current status of proton MR spectroscopy
      with emphasis on its clinical utility to diagnose tumors, its utility in planning
      surgical and radiation therapy interventions, and in its use in monitoring tumor
      treatment.

PMID- 12614174
TI  - Applications of dynamic contrast enhanced MRI in oncology: measurement of tumor
      oxygen tension.
AB  - A new model based on an extension of the Krog's cylindrical model was developed
      to calculate tumor oxygen tension (pO(2)) from the H-1 dynamic contrast enhanced
      MRI (DCE-MRI) measurements. The model enables one to calculate the tumor pO(2)
      using the vascular volume fraction (f(b)) obtained by the DCE-MRI. The proposed
      model has three parameters. For small values of f(b) one assumes that there
      exists a linear relationship between and f(b). The constant of proportionality in
      this case is given by C(1) - the oxygen tension per vascular volume fraction. For
      larger values of f(b) a modified version of Krogh model using two parameters is
      developed and here C(2) - is the integrated blood oxygen tension, and C(3) -
      given by the combination of the oxygen diffusion coefficient, solubility of
      oxygen in the tissue, capillary radius, and tissue metabolic consumption rate.
      The parameters of the model can be determined by performing simultaneous in-vivo
      F-19 MRI oxygen tension measurement and dynamic Gd-DTPA enhanced MRI on the same
      tumor. Dynamic MRI data can be used with a compartmental model to calculate tumor
      vascular volume fraction on a pixel by pixel basis. Then tumor oxygen tension map
      can be calculated from the vascular volume fraction by the extended Krogh model
      as described above. In the present work, the model parameters were determined
      using three rats bearing Walker-256 tumors and performing simultaneous F-19 and
      DCE MRI on the same tumor. The parameters obtained by fitting the model equation
      to the experimental data were: C(1) = 983.2 +/- 133.2torr, C(2) = 58.20 +/- 2.4
      torr, and C(3) = 1.7 +/- 0.1 torr. The performance of the extended Krogh model
      was then tested on two additional rats by performing both F-19 and DCE-MRI
      studies and calculating the pO(2) (H-1) using the model and comparing it with the
      pO(2) (F-19) obtained from the F-19 MRI. It was found that the measurements
      obtained by both techniques had a high degree of correlation [pO(2) (H-1) = (1.01
      +/- 0.07) pO(2) (F-19) + (0.91 +/- 0.05) and r=0.96], indicating the
      applicability of the proposed model in determining pO(2) from the DCE-MRI.

PMID- 12614176
TI  - The radiation oncologist's perspective on stereotactic radiosurgery.
AB  - Unfavorable gliomas: The basis for single-fraction stereotactic radiosurgery
      (SRS) is largely historical in nature and rooted in conventional thinking. This
      is derived from the original use of SRS in the treatment of arteriovenous
      malformations (AVMs), where the benefit of single-fraction high-dose radiation is
      clearly optimal in terms of addressing AVM obliteration kinetics. However, tumor
      cell kinetics are not the same as AVM obliteration kinetics and therefore may not
      be optimally addressed by single-fraction SRS. In addition, fractionated (F) SRS,
      as compared to single-fraction SRS, should allow for sparing of normal tissue
      damage. The relatively noninvasive nature of SRS allows for the potential of
      exploiting the use of FSRS and also allows for consideration of delivering FSRS
      in a split-course fashion. This provides an additional advantage over what can
      normally be achieved by use of stereotactic brachytherapy, in that sterotactic
      brachytherapy is likely to be performed only once in the course of a patient's
      primary treatment. This strategy exploits tumor and/or normal tissue cell
      kinetics, inclusive of attempting to counteract the initial accelerated tumor
      growth phase pre-CEBRT(conventional external beam radiation therapy), thereby
      decreasing the rate of clinical tumor progression during CEBRT. This split-course
      design should also help to counteract the effect of accelerated tumor
      repopulation post-CEBRT. Our unique experience with this approach in patients
      with unfavorable gliomas will be reviewed. Brain metastases: While whole brain
      radiation therapy (WBRT) remains a standard of care in patients with brain
      metastases, is potential neurocognitive morbidity remains a poorly understood
      concern. Despite this, and with an increasing role of surgery and/or SRS in the
      primary management of patients with brain metastasis, recently reported
      experiences withholding WBRT as part of primary therapy for brain metastases have
      not analyzed the potential effects on neurological functional status and/or
      neurocognition associated with the increased risk of brain tumor recurrence seen
      with such a strategy. We recently evaluated the risk of symptomatic brain tumor
      recurrence and associated neurologic deficit in 36 patients treated for newly
      diagnosed unresected brain metastases treated by Gamma Knife SRS alone followed
      by planned observation. Among the 17 patients (47%) developing brain tumor
      recurrence, 71% (12/17) were symptomatic and 59% (10/17) had an associated
      neurologic deficit. Also of interest, the author (WFR) performed a secondary
      analysis of a randomized phase III study of accelerated hyperfractionation (AH)
      versus standard accelerated fractionation (AF) in patients with unresected brain
      metastases. Control of brain metastases had a significant impact on MMSE. It is
      only among patients with 'uncontrolled" brain metastases that a drop in MMSE
      score is seen. Details of these studies, along with others, will be reviewed and
      implications with regards to the complementary role of WBRT in patients
      undergoing SRS for brain metastases will be discussed.

PMID- 12614175
TI  - Combined structural and functional imaging of the breast.
AB  - Scintimammography, or single gamma nuclear imaging of the breast, has shown
      promise as a way of characterizing certain biological properties of suspicious
      breast masses. Conventional scintimammography, performed using large clinical
      gamma cameras and prone patient positioning suffers from several drawbacks
      including poor sensitivity for small (> 1 cm) lesions and no reliable method for
      correlating scintigraphic findings with those of other imaging modalities. We are
      developing a system designed to overcome some of these problems. The system
      combines x-ray mammography with scintimammography on a common gantry. The x-ray
      and gamma ray images are obtained in quick succession, with the breast in a
      common configuration under mild compression. A digital x-ray detector is used,
      permitting rapid assessment of lesion location prior to gamma imaging, and
      enabling fusion of the x-ray transmission and gamma emission information in a
      single digital image. In a pilot clinical diagnostic study, the system has
      demonstrated high pathology-proven accuracy in differentiating benign and
      malignant masses.

PMID- 12614177
TI  - Initial clinical results of stereotactic radiotherapy for the treatment of
      craniopharyngiomas.
AB  - The efficacy and toxicity of stereotactic radiotherapy (SRT) for the treatment of
      craniopharyngioma has been retrospectively evaluated in 16 patients. The median
      tumor diameter was 2.8 cm (range 1.5-6.1) and the median tumor volume was 7.7 cc
      (range 0.7-62.8). SRT was delivered to a single isocenter using a dedicated 6 MV
      linear accelerator to patients immobilized with a relocatable stereotactic head
      frame. The three-year actuarial overall survival was 93% and the rate of survival
      free of any imaging evidence of progressive disease was 75%. The three-year
      actuarial survival rates free of solid tumor growth or cyst enlargement were 94%
      and 81% respectively. Our results suggest that SRT is a safe and effective
      treatment approach for patients with craniopharyngioma. Long-term follow-up is
      required to determine whether the normal tissue-sparing inherent with SRT results
      in reduction of the neurocognitive effects of conventional radiotherapy for
      craniopharyngioma. SRT can be delivered to craniopharyngioma that may be
      difficult to treat with stereotactic radiosurgery due to proximity of the optic
      chiasm. Further clinical experience is necessary to determine the clinical
      utility of beam shaping in the setting of SRT.

PMID- 12614178
TI  - Computed tomography-guided salvage brachytherapy of recurrent large nonresectable
      familial colo-rectal cancer in the pelvis: case report.
AB  - Here we present the first reported case of three-dimensional CT-guided salvage
      brachytherapy of recurring colorectal cancer in the pelvis after failed radiation
      therapy, total colectomy, and chemotherapy. Initial CEA was 67.0 ng/mL and tumor
      volume 93 cm3 with no metastasis outside the pelvis. A total of 333 seeds of
      Iodine-125 were delivered to the entire target, with dosage of 150 to 200 Gy as
      calculated by post-implant CT dosimetry with Varian MMS software. CEA 12 months
      after implant decreased to 5.7 ng/mL. Clinical and biochemical results are
      encouraging; however long-term data in a greater universe of patients are
      required.

PMID- 12614179
TI  - Efficient tumor antigen loading of dendritic antigen presenting cells by
      transimmunization.
AB  - Extracorporeal photochemotherapy (ECP), or photopheresis, was originally
      introduced for the management of patients with cutaneous T cell lymphoma (CTCL).
      Today, ECP remains the only FDA approved tumor-targeting selective immunotherapy
      for the treatment of any cancer. The key cellular events permitting ECP-induced
      anti-tumor immunity against CTCL are the induction of apoptotis in the malignant
      T cells, and the induction of monocyte-to-dendritic cell (DC) differentiation. In
      standard ECP, leukocytes extracorporeally exposed to psoralen and ultraviolet A
      light (UVA) are circulated back to the patient. However, recent findings suggest
      that co-incubation of these cells prior to re-infusion allows for more efficient
      phagocytosis and processing of the apoptotic malignant T cells by the newly
      formed DCs. Moreover, such a co-incubation step permits the direct external
      manipulation of this system and the design of strategies to augment the
      production of tumor-loaded DCs. These considerations have led to the development
      of Transimmunization, so named because it causes transfer of tumor antigens to
      newly formed dendritic cells capable of initiating immunization against the tumor
      cells, as the replacement technology for ECP. We will review the scientific
      understanding of ECP and explain how this can lead a more efficient, potentially
      broadly applicable, immunotherapy for cancer.

PMID- 12614180
TI  - Enhancing the effectiveness of drug-based cancer therapy by electroporation
      (electropermeabilization).
AB  - Many conventional chemotherapeutic drugs, as well as DNA for cancer gene therapy,
      require efficient access to the cell interior to be effective. The cell membrane
      is a formidable barrier to many of these drugs, including therapeutic DNA
      constructs. Electropermeabilization (EP, often used synonymously with
      "electroporation") has become a useful method to temporarily increase the
      permeability of the cell membrane, allowing a broad variety of molecules
      efficient access to the cell interior. EP is achieved by the application of short
      electrical pulses of relatively high local field strength to the target tissue of
      choice. In cancer therapy, EP can be applied in vivo directly to the tumor to be
      treated, in order to enhance intracellular uptake of drugs or DNA. Alternatively,
      EP can be used to deliver DNA into cells of healthy tissue to achieve longer
      lasting expression of cancer-suppressing genes. In addition, EP has been used in
      ex vivo therapeutic approaches for the transfection of a variety of cells in
      suspension. In this paper, we communicate results related to the development of a
      treatment for squamous cell carcinomas of the head and neck, using
      electropermeabilization to deliver the drug bleomycin in vivo directly into the
      tumor cells. This drug, which is not particularly effective as a conventional
      therapeutic, becomes highly potent when the intracellular concentration is
      enhanced by EP treatment. In animal model experiments we found a drug dose of 1
      U/cm(3) tumor tissue (delivered in 0.25 mL of an aqueous solution/cm3 tumor
      tissue) and an electrical field strength of 750 V/cm or higher to be optimal for
      the treatment of human squamous cell tumors grown subcutaneously in mice. Within
      24-48 hours, the majority of tumor cells are rapidly destroyed by this bleomycin
      electroporation therapy (B-EPT). This raises the concern that healthy tissue may
      be similarly affected. In studies with large animals we showed that normal muscle
      and skin tissue, normal tissue surrounding major blood vessels and nerves, as
      well as healthy blood vessels and nerves themselves, are much less affected than
      tumor tissue. Normal tissues did show acute, focal, and transitory effects after
      treatment, but these effects are relatively minor under standard treatment
      conditions. The severity of these effects increases with the number of electric
      pulse cycles and applied voltage. The observed histological changes resolved 20
      to 40 days after treatment or sooner, even after excessive EP treatment. Thus, B
      EPT is distinct from other ablative therapies, such as thermal, cryo, or
      photodynamic ablation, which equally affect healthy and tumor tissue. In
      comparison to surgical or radiation therapy, B-EPT also has potential as a tissue
      sparing and function-preserving therapy. In clinical studies with over 50 late
      stage head and neck cancer patients, objective tumor response rates of 55-58%,
      and complete tumor response rates of 19-30% have been achieved.

PMID- 12614181
TI  - Alphavirus vectors as tools in cancer gene therapy.
AB  - Alphavirus vectors, particularly those based on the replicon of Semliki Forest
      virus, have shown great potential as gene delivery vehicles for various
      applications in cancer gene therapy. The rapid production of high-titer
      recombinant SFV particles, which show impressive transduction rates in various
      mammalian cell lines, primary cultures and in vivo, results in high levels of
      transgene expression. Additionally, SFV vectors induce apoptosis in transduced
      host cells, which can further increase their efficiency in tumor therapy. Because
      of the broad host range some attempts to target the gene delivery have been
      engineered for Sindbis virus vectors, where IgG binding domains of protein A have
      been introduced into the envelope structure of the recombinant particles to allow
      attachment of virus to host cells through the interaction of protein A with
      monoclonal antibodies. SFV vectors have also been employed for the production of
      retrovirus-like particles for establishment of long-term gene expression. Tumor
      vaccine approaches have been taken by injection of SFV vectors as naked RNA
      molecules, DNA plasmids or recombinant particles to achieve both therapeutic and
      prophylactic efficacy. The continuous improvement of alphavirus vectors will
      further expand the application range in the future.

PMID- 12614183
TI  - Pharmacoeconomics of asthma treatment.
AB  - The burden of asthma is increasing in terms of prevalence, severity of symptoms
      and other markers of asthma control. Poor control of symptoms is a major issue
      that can result in adverse clinical and economic outcomes. Prescribing costs are
      the most obvious and visible expense in asthma care but these are but the tip of
      the iceberg. We need to take all factors into account when considering the
      overall costs of asthma treatments and recognise that treatment that results in
      better asthma control may result in lessening of both direct and indirect costs.
      To assess this accurately, health economic evaluations need to be undertaken in
      relevant settings, on representative populations. They need to use appropriate
      measures of asthma outcome. Drug-related costs need to take into account savings
      made by decreased costs of other prescribed medication and patient factors must
      be taken into account. We need information that is applicable to the types of
      patients we see in the real world to make proper cost analyses. Such information
      can come from 'pragmatic' randomised trials, from retrospective claims analysis
      from observational studies or using primary care clinical and prescribing
      databases.

PMID- 12614184
TI  - The cost of adverse drug reactions.
AB  - In addition to their impact on human health, adverse drug reactions (ADRs) also
      have significant impact on healthcare costs. These costs are essentially hospital
      costs, in particular arising from an increase in length of stay caused by an ADR.
      Although it has been estimated that the occurrence of an ADR during
      hospitalisation or leading to hospitalisation is responsible for a cost of
      approximately EURO2800, several studies have also pointed out that the structure
      of ADR cost is heterogeneous, a factor which must be taken into account when
      developing preventive strategies. ADR cost evaluation remains difficult from a
      methodological point of view given that most studies have only evaluated the
      direct cost. Because of the substantial annual estimated cost of ADRs in
      industrialised countries, it is necessary to implement preventive programmes,
      with different strategies consisting of: educational programmes; identifying risk
      groups; implementing good drug practice; and clinical and laboratory monitoring
      for ADRs. Promoting pharmacoeconomic studies and co-operation between clinicians,
      medical pharmacologists and pharmacists remains the key factor for preventing
      ADRs and decreasing their costs.

PMID- 12614185
TI  - Economic evaluation of osteoarthritis treatment in Europe.
AB  - Osteoarthritis is one of the leading causes of disability. Among the available
      treatments, NSAIDs are the most common. The present paper reviews economic
      studies conducted in the last five years on the treatment of osteoarthritis in
      Europe. The majority focus on NSAID therapy, mainly comparing COX2-specific
      inhibitors against COX non-specific inhibitors. The reviewed studies estimate
      healthcare costs only. The final results indicate that, owing to the lower
      incidence of adverse events, COX2-specific inhibitors should now dominate over
      traditional NSAIDs. However, the differences found in the methods used to measure
      costs suggest that results should be interpreted with caution. To estimate costs,
      authors used diverse values that were not always consistent with the studies'
      perspective. Furthermore, many did not report resource consumption patterns,
      making comparisons among the studies difficult, as economic results are
      influenced by the price/charging policies of different countries. Economic
      evaluations have the potential to affect health policy by assisting the ranking
      and prioritisation obligations of decision makers. In this context, it is
      important to meet strict methodological guidelines.

PMID- 12614186
TI  - Cost-effectiveness of interferon-alpha2 as adjuvant therapy in malignant
      melanoma.
AB  - An extensive literature review on clinical trials and economic studies published
      on the use of IFN-alpha as adjuvant therapy in stage II - III (AJCC 1992)
      malignant melanoma was performed. Large clinical trials with sufficient follow-up
      were selected to assess the efficacy. Medico-economic studies, based on the
      results of several of these trials, were analysed to estimate the cost
      effectiveness ratios of IFN in this disease. IFN-alpha demonstrated efficacy as
      adjuvant therapy in malignant melanoma with high-dose regimens in patients with
      overt regional nodal disease (so-called high-risk patients) and with low-dose
      regimens in stage IIA and -B patients without clinically detectable nodes (so
      called intermediate risk patients). This efficacy was associated with high rates
      of severe side effects using a high-dose regimen. Based on these assumptions,
      economic analyses performed in different settings and using several methods to
      extrapolate clinical results are producing similar results of extra costs for IFN
      associated with a medical benefit. Incremental cost-effectiveness ratios provided
      are (< US dollars 50,000 per life year gained) in the range of current and widely
      used medical strategies in different diseases and settings. This should allow the
      recommendation of the use of IFN-alpha therapy in malignant melanoma, using high
      doses in high-risk patients and low doses in intermediate-risk patients. In the
      final decision of whether or not to treat, however, the patient has to be
      informed that IFN will probably only delay events, with the possibility of any
      curative effect being uncertain. This limited effect has to be balanced with the
      severe impact on quality of life of high-dose regimen and with the fact that many
      patients in whom low doses are indicated would not recur in the absence of
      treatment. It is also clear that patients with only a positive sentinel node are
      to be considered with the intermediate risk group in which they were evaluated.

PMID- 12614187
TI  - Database studies in asthma pharmacoeconomics: uses, limitations and quality
      markers.
AB  - Asthma is a common chronic disease resulting in significant morbidity and health
      resource utilisation, and multiple therapeutic options exist. Clinicians and
      healthcare providers need accurate information on the clinical and cost-
      effectiveness of asthma treatments to make informed decisions on management
      strategies. Randomised, controlled trials demonstrate cause and effect
      relationships between treatments and outcomes, but their tight entry criteria and
      strict study protocols mean that their results cannot automatically be
      generalised or used for economic modelling. There is a need for observational
      data to examine the effectiveness of alternative interventions in routine
      practice. Clinical and administrative databases are a possible information source
      for observational studies, and are increasingly used in asthma clinical,
      epidemiological and economic research. This paper examines the types of database
      used, the advantages and limitations of such studies and considers quality
      markers. High quality database studies can provide important epidemiological and
      economic information that can be of value in understanding the causes and
      effective management of asthma.

PMID- 12614188
TI  - The economics of TB control in developing countries.
AB  - Tuberculosis is one of the world's biggest killers and the burden is skewed
      towards developing countries, where the relative share of this disease is
      largest. This has much to do with poor living conditions and less developed
      public health systems. Nevertheless, even with these factors taken into account,
      the mortality from this disease is still unjustifiably high given the fact that
      it is treatable in the vast majority of cases with relatively inexpensive drugs.
      There are three main reasons for this situation: a low propensity to seek
      healthcare when sick; poor diagnosis upon seeking care; and high levels of non
      compliance with treatment when diagnosed. Taken in combination, this means that
      of those who seek care, some get appropriate diagnosis at their first contact,
      while many do not. Unfortunately, not all of those who are diagnosed actually
      begin treatment and of those who do, a smaller percentage actually complete it.
      This article will look at each of these issues, and in particular their costs, in
      turn, and suggest areas in which economics can help to develop solutions to them.

PMID- 12614190
TI  - Pharmacological management of Cronkhite-Canada syndrome.
AB  - Cronkhite-Canada syndrome (CCS) is a rare, non-inherited gastrointestinal
      polyposis syndrome associated with characteristic ectodermal abnormalities. A
      number of potentially life-threatening complications including malnutrition,
      gastrointestinal bleeding and infection may occur in affected patients and CCS is
      fatal in many cases. The optimal therapy for CCS is not known but several
      treatment options have been described. Nutritional support, antibiotics,
      corticosteroids, anabolic steroids, histamine-receptor antagonists and surgical
      treatment have all been used with varying degrees of success. Unfortunately,
      controlled therapeutic trials have not been possible because of the rarity of the
      disease. Most recently, a combination regimen using histamine-receptor
      antagonists, cromolyn sodium, prednisone and suppressive antibiotics has been
      described. The reported treatment options and rates of success are reviewed.

PMID- 12614189
TI  - Current pharmacotherapy for the treatment of severe burns.
AB  - The pharmacotherapy of burn care has evolved from the first topical antibiotics
      instituted > 30 years ago. These have helped greatly to reduce the incidence of
      burn wound sepsis, but a better understanding of the principles of burn care has
      resulted in earlier burn wound excision and complete coverage with autograft,
      cadaver skin, synthetic dressings, and amnion. This has markedly reduced septic
      complications and ameliorated the hypermetabolic response to burn injury. The
      hypermetabolic response, which is mediated by hugely increased levels of
      circulating catecholamines, prostaglandins, glucagon and cortisol, causes
      profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis,
      reduced bone mineralisation, reduced linear growth, and increased energy
      expenditure. Supportive therapy and pharmacological manipulation, acutely and
      during rehabilitation, with growth hormone, insulin and related proteins,
      oxandrolone and propranolol can ameliorate the hypermetabolic response, improving
      survival and long-term outcome. Despite judicious use of topical and systemic
      antibiotics, opportunistic nosocomial bacterial resistance threatens to annul the
      improved survival of patients with severe burns. Patterns of emerging resistance
      encountered in burn units need to be considered, in light of a decreasing
      antibiotic armamentarium. A holistic approach to pharmacotherapy of severely
      burned patients including current practice in antimicrobial control, analgesia,
      sedation, and anxiety management is required. Current therapy of frequently
      encountered problems, such as post-burn pruritus, prophylaxis of deep venous
      thrombosis and peptic ulceration, and pharmacological manipulation of inhalation
      injury in the burned patient is described. Current pharmacotherapy to ameliorate
      psychosocial problems associated with burns such as acute stress disorder,
      depression and post traumatic stress disorder are discussed. Better analgesics,
      newer antibiotics and immune stimulating drugs are required to reduce mortality
      and morbidity in large burns.

PMID- 12614191
TI  - Review of ibandronate in the treatment of osteoporosis.
AB  - Several antiresorptive treatments that reduce the risk of osteoporotic fracture
      are now available, including bisphosphonates. Ibandronate is a new potent
      bisphosphonate, currently under development, with unique features. In several
      animal models of human osteoporosis, it has been shown to inhibit bone resorption
      and improve bone mechanical properties. Ibandronate is more potent than most
      current bisphosphonates. Several dosages and schedules have been tested in
      humans. With the oral daily dose of 2.5 mg, a reduction of 62% in the incidence
      of vertebral fracture has been demonstrated in a randomised, placebo-controlled
      trial. In the same trial, a reduction of 50% has been observed - for the first
      time using a bisphosphonate - with an intermittent regimen (20 mg every other day
      for the first 24 days, followed by 9 weeks without the treatment). In contrast,
      another randomised, placebo-controlled trial failed to find a significant
      reduction in vertebral fracture risk using an dose of 1 mg i.v. every 3 months.
      Thus, ibandronate can be considered as a promising new option for the treatment
      of postmenopausal osteoporotic women.

PMID- 12614192
TI  - Long-term use of sildenafil.
AB  - The treatment of erectile dysfunction (ED) has been revolutionised by new agents
      to inhibit the enzyme PDE5. The scientific basis of this treatment of ED includes
      relaxation of the corpus cavernosum smooth muscle tissue by inhibition of PDE5
      that breaks down cGMP, the key pathway for the production of erectile function in
      humans. Many clinical studies, both pre- and post-marketing, have demonstrated
      the clinical efficacy and safety of sildenafil (Viagra, Pfizer) - the first
      approved selective PDE inhibitor for the treatment of ED. Sildenafil is
      inhibitory of PDE5 at a rate tenfold higher than for the next PDE (PDE6), which
      produces visual changes through the retinal rods. Its clinical effectiveness has
      been well documented in the majority of men with ED irrespective of aetiology.
      The aetiology of ED, also, does not appear to effect the function of sildenafil
      in relaxing corpus cavernosum smooth muscle tissue. Adverse events are usually
      associated with the vascular changes from PDE5 inhibition. These include headache
      and flushing. Each of these adverse events, however, declines with medication
      use. With the use of sildenafil, it has been clearly, clinically demonstrated
      that the selective inhibition of PDE5 is an appropriate, effective, safe method
      for the treatment of ED of all aetiologies and severities.

PMID- 12614193
TI  - ACE inhibitors or AT-1 antagonists - which is OPTIMAAL after acute myocardial
      infarction?
AB  - OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II
      Antagonist Losartan) is the first major study to compare an angiotensin II Type 1
      antagonist losartan (Cozaar trade mark, Merck) with an ACE inhibitor captonpril
      (Capoten trade mark, Elan) after myocardial infarction in patients with left
      ventricular dysfunction. Patients were assigned to a target dose of losartan 50
      mg/day and captopril 50 mg t.i.d., as tolerated. The primary end point was all
      cause mortality and there were 499 (18%) and 447 (16%) deaths in the losartan and
      captopril group, respectively (p = 0.07). However, there were significantly more
      cardiovascular deaths with losartan (420, 15%) than with captopril (363, 13%; p =
      0.03). Losartan was better tolerated than captopril with fewer patients
      discontinuing medication (17 versus 23% for losartan and captopril,
      respectively). In conclusion, if tolerated, captopril should remain the preferred
      treatment for patients after complicated acute myocardial infarction.

PMID- 12614194
TI  - c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function:
      new target proteins for JNK signalling in mitochondrion-dependent apoptosis.
AB  - The molecular mechanisms underlying the initiation and control of the release of
      cytochrome c during mitochondrion-dependent apoptosis are thought to involve the
      phosphorylation of mitochondrial Bcl-2 and Bcl-x(L). Although the c-Jun N
      terminal kinase (JNK) has been proposed to mediate the phosphorylation of Bcl
      2/Bcl-x(L) the mechanisms linking the modification of these proteins and the
      release of cytochrome c remain to be elucidated. This study was aimed at
      establishing interdependency between JNK signalling and mitochondrial apoptosis.
      Using an experimental model consisting of isolated, bioenergetically competent
      rat brain mitochondria, these studies show that (i) JNK catalysed the
      phosphorylation of Bcl-2 and Bcl-x(L) as well as other mitochondrial proteins, as
      shown by two-dimensional isoelectric focusing/SDS/PAGE; (ii) JNK-induced
      cytochrome c release, in a process independent of the permeability transition of
      the inner mitochondrial membrane (imPT) and insensitive to cyclosporin A; (iii)
      JNK mediated a partial collapse of the mitochondrial inner-membrane potential
      (Deltapsim) in an imPT- and cyclosporin A-independent manner; and (iv) JNK was
      unable to induce imPT/swelling and did not act as a co-inducer, but as an
      inhibitor of Ca-induced imPT. The results are discussed with regard to the
      functional link between the Deltapsim and factors influencing the permeability
      transition of the inner and outer mitochondrial membranes. Taken together, JNK
      dependent phosphorylation of mitochondrial proteins including, but not limited
      to, Bcl-2/Bcl-x(L) may represent a potential of the modulation of mitochondrial
      function during apoptosis.

PMID- 12614195
TI  - Expression cloning and characterization of a novel gene that encodes the RNA
      binding protein FAU-1 from Pyrococcus furiosus.
AB  - We systematically screened a genomic DNA library to identify proteins of the
      hyperthermophilic archaeon Pyrococcus furiosus using an expression cloning
      method. One gene product, which we named FAU-1 (P. furiosus AU-binding),
      demonstrated the strongest binding activity of all the genomic library-derived
      proteins tested against an AU-rich RNA sequence. The protein was purified to near
      homogeneity as a 54 kDa single polypeptide, and the gene locus corresponding to
      this FAU-1 activity was also sequenced. The FAU-1 gene encoded a 472-amino-acid
      protein that was characterized by highly charged domains consisting of both
      acidic and basic amino acids. The N-terminal half of the gene had a degree of
      similarity (25%) with RNase E from Escherichia coli. Five rounds of RNA-binding
      site selection and footprinting analysis showed that the FAU-1 protein binds
      specifically to the AU-rich sequence in a loop region of a possible RNA ligand.
      Moreover, we demonstrated that the FAU-1 protein acts as an oligomer, and mainly
      as a trimer. These results showed that the FAU-1 protein is a novel heat-stable
      protein with an RNA loop-binding characteristic.

PMID- 12614196
TI  - Increased expression of the lipocalin 24p3 as an apoptotic mechanism for MK886.
AB  - MK886, a strong proapoptotic agent, is an inhibitor of 5-lipoxygenase (LOX)
      through binding to the 5-LOX-activating protein (FLAP). Although MK886-induced
      apoptosis is through a FLAP-independent pathway, the precise mechanisms are not
      understood. In the present study, a possible role of 24p3, a lipocalin, in MK886
      induced apoptosis was investigated. Exposure of murine prolymphoid progenitor
      cells (FL5.12) to 20 microM MK886 for 16 h dramatically increased 24p3 mRNA and
      protein expression. Induction could also be achieved with another FLAP inhibitor,
      MK591. The induction of 24p3 by MK886 was dose- and time-dependent. The up
      regulated 24p3 mRNA expression by MK886 was enhanced a further 3.1-fold by
      WY14643, an activator of peroxisome-proliferator-activated receptor alpha,
      whereas ciglitazone, an activator of peroxisome-proliferator-activated receptor
      gamma attenuated the MK886-induced 24p3 expression by more than 50%. Neither
      WY14643 nor ciglitazone alone had any effect on the expression of 24p3. The
      induction of 24p3 by MK886 was dependent on the synthesis of new protein(s),
      since cycloheximide, an inhibitor of protein synthesis, prevented this effect. In
      all cases, including the inhibition of MK886-induced 24p3 protein expression by
      stable transfection with antisense cDNA of 24p3, the extent of apoptosis closely
      paralleled 24p3 levels. Apoptosis induced by MK886, or enhanced by WY14643, was
      accompanied by the cleavage and activation of caspase-3. The overexpression of
      bcl-2 or bcl-x(L) in FL5.12 cells inhibited apoptosis induced by MK886 as well as
      the enhancement of apoptosis by WY14643. Thus 24p3 is an MK886-inducible gene and
      may play an important role in MK886-induced apoptosis.

PMID- 12614197
TI  - Kinetic, spectroscopic and thermodynamic characterization of the Mycobacterium
      tuberculosis adrenodoxin reductase homologue FprA.
AB  - The genome sequence of the pathogenic bacterium Mycobacterium tuberculosis
      revealed numerous cytochrome P450 enzymes, which require accessory redox enzymes
      for catalytic function (ferredoxin reductase and ferredoxin). The most likely
      ferredoxin reductase is encoded by fprA, and its structure resembles eukaryotic
      adrenodoxin reductases. We have cloned, expressed and purified the flavoenzyme
      product of the fprA gene in Escherichia coli. FprA reduces various electron
      acceptors using either NADPH or NADH as the electron donor, but discriminates in
      favour of NADPH (apparent K (m) for NADH=50.6+/-3.1 microM; NADPH=4.1+/-0.3
      microM from ferricyanide reduction experiments). Stopped-flow studies of
      reduction of the FprA FAD by NADPH demonstrate increased flavin reduction rate at
      low NADPH concentration (<200 microM), consistent with the presence of a second,
      kinetically distinct and inhibitory, pyridine nucleotide-binding site, similar to
      that identified in human cytochrome P450 reductase [Gutierrez, Lian, Wolf,
      Scrutton and Roberts (2001) Biochemistry 40, 1964-1975]. Flavin reduction by NADH
      is slower than with NADPH and displays hyperbolic dependence on NADH
      concentration [maximal reduction rate ( k (red))=25.4+/-0.7 s(-1), apparent K
      (d)=42.9+/-4.6 microM]. Flavin reoxidation by molecular oxygen is more rapid for
      NADH-reduced enzyme. Reductive titrations show that the enzyme forms a species
      with spectral characteristics typical of a neutral (blue) FAD semiquinone only on
      reduction with NADPH, consistent with EPR studies. The second order dependence of
      semiquinone formation on the concentration of FprA indicates a disproportionation
      reaction involving oxidized and two-electron-reduced FprA. Titration of FprA with
      dithionite converts oxidized FAD into the hydroquinone form; the flavin
      semiquinone is not populated under these conditions. The midpoint reduction
      potential for the two electron couple is -235+/-5 mV (versus the normal hydrogen
      electrode), similar to that for adrenodoxin reductase (-274 mV). Our data provide
      a thermodynamic and transient kinetic framework for catalysis by FprA, and
      complement recent spectrophotometric and steady-state studies of the enzyme
      [Fischer, Raimondi, Aliverti and Zanetti (2002) Eur. J. Biochem. 269, 3005-3013].

PMID- 12614198
TI  - Encoding of progesterone stimulus intensity by intracellular [Ca2+] ([Ca2+]i) in
      human spermatozoa.
AB  - Progesterone induces a biphasic Ca(2+) influx and consequent acrosome reaction in
      human spermatozoa. We have used two procedures to vary the stimulus (dosage and
      prior receptor desensitization) to investigate the encoding of stimulus strength
      by intracellular [Ca(2+)] ([Ca(2+)](i)). Acrosome reaction and amplitude (but not
      kinetics) of the transient [Ca(2+)](i) response (population measurement) showed
      sigmoidal dose sensitivity over the range 0.3 nM-3 microM, saturating at
      approximately 300 nM (ED(50) approximately 30 nM). The amplitude of the sustained
      response saturated at 3 microM. Single-cell imaging showed that the amplitudes of
      both transient and sustained [Ca(2+)](i) responses were highly dose-dependent,
      but that their frequency of occurrence and kinetics were largely dose
      independent. Fluorimetric measurements confirmed that progesterone-induced
      [Ca(2+)](i) influx was subject to desensitization, with second and subsequent
      applications of 3 microM progesterone being ineffective. However, sequential
      additions of 3 nM, 30 nM and 3 microM progesterone generated transient
      [Ca(2+)](i) responses at each concentration, the amplitude and duration of the
      response to 3 microM progesterone being reduced compared with non-pretreated
      cells. Single-cell imaging revealed that pretreatment had no effect on the
      proportion of responsive cells, but single-cell responses, similarly to
      population responses, were smaller and markedly reduced in duration, consistent
      with an effect of desensitization on a late component of the [Ca(2+)](i)
      transient. We conclude that the strength of the progesterone stimulus, when
      varied by dosage or by desensitization, is encoded by an analogue [Ca(2+)](i)
      signal. Dose dependency of the acrosome reaction is therefore determined not by
      the number of progesterone-responsive cells but by variation in the probability
      of exocytosis in a 'constant' responsive population.

PMID- 12614200
TI  - Bone marrow manifestation of Lyme disease (Lyme Borreliosis).

PMID- 12614199
TI  - Identification of regions involved in the binding of alpha-bungarotoxin to the
      human alpha7 neuronal nicotinic acetylcholine receptor using synthetic peptides.
AB  - The neuronal alpha7 nicotinic acetylcholine receptor (AChR) binds the neurotoxin
      alpha-bungarotoxin (alpha-Bgt). Fine mapping of the alpha-Bgt-binding site on the
      human alpha7 AChR was performed using synthetic peptides covering the entire
      extracellular domain of the human alpha7 subunit (residues 1-206). Screening of
      these peptides for (125)I-alpha-Bgt binding resulted in the identification of at
      least two toxin-binding sites, one at residues 186-197, which exhibited the best
      (125)I-alpha-Bgt binding, and one at residues 159-165, with weak toxin-binding
      capacity; these correspond, respectively, to loops C and IV of the agonist
      binding site. Toxin binding to the alpha7(186-197) peptide was almost completely
      inhibited by unlabelled alpha-Bgt or d -tubocurarine. Alanine substitutions
      within the sequence 186-198 revealed a predominant contribution of aromatic and
      negatively charged residues to the binding site. This sequence is homologous to
      the alpha-Bgt binding site of the alpha1 subunit (residues 188-200 in Torpedo
      AChR). In competition experiments, the soluble peptides alpha7(186-197) and
      Torpedo alpha1(184-200) inhibited the binding of (125)I-alpha-Bgt to the
      immobilized alpha7(186-197) peptide, to native Torpedo AChR, and to the
      extracellular domain of the human alpha1 subunit. These results suggest that the
      toxin-binding sites of the neuronal alpha7 and muscle-type AChRs bind to
      identical or overlapping sites on the alpha-Bgt molecule. In support of this,
      when synthetic alpha-Bgt peptides were tested for binding to the recombinant
      extracellular domains of the human alpha7 and alpha1 subunits, and to native
      Torpedo and alpha7 AChR, the results indicated that alpha-Bgt interacts with both
      neuronal and muscle-type AChRs through its central loop II and C-terminal tail.

PMID- 12614201
TI  - Intramedullary abscess in a patient with disseminated Scedosporium apiospermum
      infection.

PMID- 12614202
TI  - Therapeutic challenges in childhood sickle cell disease. Part 1: current and
      future treatment options.

PMID- 12614203
TI  - Therapeutic challenges in childhood sickle cell disease. Part 2: a problem
      orientated approach.

PMID- 12614204
TI  - Guidelines for the management of the acute painful crisis in sickle cell disease.

PMID- 12614205
TI  - Endothelial stimulation by small lymphocytic lymphoma correlates with secreted
      levels of basic fibroblastic growth factor.
AB  - Lymph nodes (LN) involved with small lympho- cytic lymphoma (SLL) reportedly
      contain increased numbers of microvessels that may constitute a therapeutic
      target in this disease. We investigated the secretion of the angiogenic growth
      factor, basic fibroblastic growth factor (bFGF), from primary tissue cultures of
      15 LN with SLL and 10 reactive LN. bFGF was detected from the resulting
      conditioned media (CM) in 13/15 SLL samples (mean 92 +/- 30, range 5-420 pg/ml)
      but was undetectable in CM from all reactive lymph nodes. CM was also used in a
      72-h human umbilical vein endothelial cell (HUVEC) proliferation assay. HUVEC
      proliferation increased in the presence of SLL CM (70 +/- 17%, range -4-194%),
      proportional to secreted levels of bFGF (R2 = 0.95), and was reversed by
      depleting bFGF from CM. Previous SLL studies have examined either patient serum
      samples or paraffin-embedded lymph node tissue sections. This is the first study
      to examine the secretion of an angiogenic growth factor from primary cultures of
      lymph node cells. Our results indicate that bFGF is probably the primary mediator
      responsible for increased angiogenesis in involved nodes. These findings may be
      pertinent to future investigation into the mechanisms of increased angiogenesis
      in SLL.

PMID- 12614206
TI  - Prognostic features of splenic lymphoma with villous lymphocytes: a report on 129
      patients.
AB  - Splenic lymphoma with villous lymphocytes (SLVL) is a low-grade B-cell lymphoma
      defined in the World Health Organization classification as the leukaemic form of
      splenic marginal zone lymphoma. Presenting features and response to therapy have
      been described, but information on prognostic factors is scanty. Clinical,
      laboratory and follow-up data were collected on 129 patients with SLVL to
      determine features predicting disease behaviour and survival. Diagnosis was made
      on clinical, morphological and immunophenotypic features and, where available,
      bone marrow and spleen histology. Median age was 69 years (range 39-90 years) and
      male:female ratio, 0.9. The majority had splenomegaly, but lymphadenopathy and
      hepatomegaly were rare. Median Hb was 11.8 g/dl, white blood cell count was 16 x
      10(9)/l and platelet count was 145 x 10(9)/l; 27% of patients had monoclonal
      protein in serum and/or urine. While 27% of patients remained untreated, 10%
      transformed to high-grade lymphoma. Median follow-up was 61 months and median
      survival was 13 years, with 72% of patients alive at 5 years. Cox regression
      analysis showed that increasing age, anaemia, thrombocytopenia and lymphocytosis
      > 16 x 10(9)/l were independent adverse predictors of overall survival. However,
      only anaemia and lymphocytosis > 16 x 10(9)/l remained highly significant
      independent prognostic factors when only deaths due to lymphoma were analysed.
      Splenectomized patients fared better than those receiving chemotherapy only (P =
      0.001 for SLVL deaths). We conclude that SLVL is mainly a disease of the elderly
      with a relatively benign course but, when treatment is required, splenectomy is
      beneficial.

PMID- 12614207
TI  - Upregulation of CXCR1 by proliferating cells in patients with lymphoproliferative
      disease of granular lymphocytes.
AB  - The expression and the functional activities of different chemokine receptors (CC
      motif: CCR1, CCR2, CCR3, CCR5, CCR6; CXC motif: CXCR1, CXCR2, CXCR3, CXCR4,
      CXCR5) were investigated in 12 patients with lymphoproliferative disease of
      granular lymphocytes (LDGL). Six patients were characterized by the proliferation
      of CD3+ve GL and six patients by the expansion of CD3-ve GL. The interleukin 8
      (IL-8/CXCL8) receptor CXCR1 was expressed in 12/12 patients, the CXCR4 in 6/12
      patients (four CD3+ve and two CD3-ve) and the CXCR3 in 3/12 patients (one CD3+ve
      and two CD3-ve). CXCR1 was expressed only by proliferating GL. Other CC and CXC
      receptors were not expressed on proliferating GL (< 2%). In functional assays,
      purified GL from the patients displayed significant migration in response to
      specific chemokines, indicating that CXCR1, CXCR3 and CXCR4 were functionally
      active in these patients. In addition, a significant reduction of IL-8/CXCL8
      mediated cell migration was reported in the presence of anti-CXCR1 monoclonal
      antibody. Our results indicate that expanding cells from patients with LDGL
      express specific CXCR. These data may help to define functional properties of
      proliferating GL in patients with LDGL and contribute toward the understanding of
      the complex clinical features of this disease. In particular, as CXCR1 was
      expressed in all of the patients studied, we speculate that abnormal expression
      of this receptor on proliferating GL might play a role in the pathogenesis of
      neutropenia, which represents a common feature in LDGL patients.

PMID- 12614208
TI  - Acute basophilic leukaemia: eight unsuspected new cases diagnosed by electron
      microscopy.
AB  - We report eight new patients with de novo acute basophilic leukaemia (ABL)
      diagnosed by electron microscopy (EM) in 184 patients with poorly differentiated
      AML who were selected for ultrastructural analysis between the years 1989 and
      2002. Morphology by light microscopy, cytochemistry, immunophenotyping and
      cytogenetics did not enable an accurate diagnosis in any of these patients. In
      almost all the patients, the blasts showed reactivity for HLA-DR and CD34. EM
      studies demonstrated the presence of basophilic granules in the leukaemic blasts.
      These granules were membrane bound and their contents varied in appearance from
      uniformly electron dense to partially speckled or electron lucent. Theta granules
      were present in only three patients and no mast-cell type granules were observed.
      By light microscopy, the myeloperoxidase reaction was positive in three patients
      in an unusual coarse granular pattern. Ultrastructural demonstration of
      peroxidase in the granules, nuclear membrane and profiles of endoplasmic
      reticulum was observed in all eight patients. The reaction in the granules showed
      a particular speckled pattern. The outcome was unfavourable in six of our eight
      patients. As a definitive diagnosis of ABL may be made only by EM, we suggest
      including such studies as an integral part of the diagnostic work-up of acute
      leukaemia cases that lack differentiation markers.

PMID- 12614210
TI  - Prognostic factors and outcome for children after second central nervous system
      relapse of acute lymphoblastic leukaemia.
AB  - The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and
      XI) recruited 3,702 children with ALL between January 1985 and March 1997.
      Seventy-nine children had central nervous system (CNS) involvement in their first
      two relapses. Fourteen children survived at a median follow-up of 22 months from
      second relapse; seven (9%) in third remission, two in later remissions and five
      with disease. Factors predictive of survival from second relapse were site
      (isolated CNS was better than combined CNS, P = 0.02) and time from diagnosis to
      second CNS relapse (longer time was better, P = 0.004). Prognosis after second
      CNS relapse is extremely poor, and palliative therapy is appropriate.

PMID- 12614209
TI  - Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late
      antigen (VLA)-4- and VLA-5-dependent mechanism.
AB  - The adhesion of haematopoietic progenitor cells (HPC) to the bone marrow
      microenvironment is a process regulated by cytokines. In this study, we have
      shown that flt3-ligand (FL), a growth factor that controls early haematopoiesis,
      regulated the function and expression of the beta-1 integrins, very late antigen
      (VLA)-4 and VLA-5 on HPC. The modulation of the adhesiveness of HPC by FL was
      studied by adhesion assays on umbilical vein endothelial cells (HUVEC).
      Stimulation by FL induced two peaks of increased adhesiveness of HPC. The first
      peak was at around 30 min and was mechanistically related to an activation of the
      beta-1 integrins, mainly VLA-4 and VLA-5. The second peak was at around 12 h and
      was related to increased expression of VLA-4 and VLA-5. The control of HPC
      adhesiveness by FL is a previously unreported property of FL that may be
      important for the homing and the retention of flt3-expressing HPC within the bone
      marrow microenvironment.

PMID- 12614211
TI  - Extragastric mucosa-associated lymphoid tissue lymphoma showing the regression by
      Helicobacter pylori eradication therapy.
AB  - A 69-year-old man presented with right neck tumour. Primary thyroid MALT lymphoma
      occurring in Hasimoto's thyroiditis was diagnosed. He was also diagnosed to have
      gastric cancer with Helicobacter pylori infection. After subtotal gastrectomy by
      itself, thyroid lymphoma became smaller transiently. Then the patient was treated
      with H. pylori eradication therapy, resulting in the complete disappearance of
      lymphoma. Although H. pylori organisms were not detected in the lymphoma tissue
      by polymerase chain reaction (PCR), it might be implicated in the pathogenesis of
      extragastric MALT lymphomas.

PMID- 12614212
TI  - Outcome of autologous transplantation for mantle cell lymphoma: a study by the
      European Blood and Bone Marrow Transplant and Autologous Blood and Marrow
      Transplant Registries.
AB  - Mantle cell lymphoma (MCL) has an aggressive clinical course with a median
      survival < 3 years and is incurable with conventional chemotherapy. A large
      multicentre study with adequate follow-up may clarify the role of significant
      factors affecting outcome in autologous stem cell transplantation for MCL.
      Patients receiving an autologous transplant for MCL between 1988 and 1998, and
      reported to the European Blood and bone Marrow Transplant (EBMT) registry or
      Autologous Blood and Marrow Transplant Registry (ABMTR), were included. Expert
      haematopathology review was required on all identified patients. Disease and
      transplant details were requested from the transplant centres, and the final
      cohort of patients with verified pathology, adequate clinical information and
      follow-up was analysed. One hundred and ninety-five patients were included in the
      analyses (149 EBMT, 46 ABMTR) with a median follow-up of 3.9 years. The 2 year
      and 5 year overall survival were 76% and 50%, and progression free survival was
      55% and 33% respectively. Disease status at transplant was the most significant
      factor affecting survival: patients with chemosensitive disease but not in first
      complete remission (CR1) were 2.99 times (95% CI: 1.66-5.38, P < 0.001) more
      likely to die than patients transplanted in CR1. Autologous transplantation
      probably improves survival in patients with MCL especially if performed in first
      CR.

PMID- 12614213
TI  - Prospective evaluation of cell kinetics, yields and donor experiences during a
      single large-volume apheresis versus two smaller volume consecutive day
      collections of allogeneic peripheral blood stem cells.
AB  - We report cell kinetics, yields and donation experiences of 20 demographically
      matched allogeneic peripheral blood stem cell (PBSC) donors who were
      prospectively assigned to undergo either a single 25 l or two consecutive daily
      15 l (15 l x 2) apheresis procedures. Procedures were performed using
      prophylactic intravenous calcium administration after standard granulocyte colony
      stimulating factor (GCSF) mobilization (10 microg/kg/d). Central line placements
      (two each), initial CD34 cell counts (0.077 vs 0.078 x 10(9)/l) and yields (7.9
      vs 8.1 x 10(8) CD34 cells) were similar in the two groups; however, 25 l donors
      spent significantly less time both in the clinic (7.5 vs 10.8 h) and with central
      venous catheters in place (8.5 vs 29.5 h) than 15 l x 2 donors. End-procedure
      platelet counts were below 100 x 10(9)/l in one out of 10 25 l donors versus five
      out of 10 in 15 l x 2 donors (41%vs 53% mean decrease in platelet counts, P =
      0.02). PBSC collection efficiency increased by 37% after 15 l of the 25-l volume
      had been processed, compared with no significant change during 15 l x 2
      procedures. Results similar to these prospective findings were also observed in
      CD34 yields, symptoms and platelet counts in additional 25 l and 15 l procedures
      performed during the same period and evaluated retrospectively. This study
      indicates that a single 25-l apheresis procedure results in similar yields and
      symptoms, but less donor thrombocytopenia and inconvenience than two consecutive
      daily 15-l procedures.

PMID- 12614214
TI  - A prospective study of recombinant activated factor VII administered by
      continuous infusion to inhibitor patients undergoing elective major orthopaedic
      surgery: a pharmacokinetic and efficacy evaluation.
AB  - After surgery in haemophilia, haemostasis is difficult to maintain in the
      presence of an antifactor VIII antibody. This study assessed the pharmacokinetics
      of recombinant activated factor VII (rFVIIa) and its efficacy in securing post
      operative haemostasis in haemophiliacs with inhibitors. Continuous infusion of
      rFVIIa was evaluated for elective major orthopaedic surgery in nine patients with
      neutralizing antibodies to FVIII and at high risk of bleeding. After an initial
      preoperative bolus of 90 micro g/kg, rFVIIa was infused at a fixed rate of 50
      micro g/kg/h for a median of 20 d (range 7-20 d). The median plasma FVII
      coagulant activity (FVII:C) at 24 h, 72 h and 20 d after surgery was 38 IU/ml
      (range 22-169 IU/ml), 45 IU/ml (range 17-88 IU/ml) and 31 IU/ml (range 27-46
      IU/ml) respectively. The median plasma FVIIa:C at the same time points was 51
      (range 24-211), 63 (range 22-99) and 44 (range 28-76) IU/ml respectively. Median
      total rFVIIa clearance remained stable during the rFVIIa continuous infusion
      period and was 40 (range 9-70), 34 (range 17-86) and 48 (range 32-55)ml/kg/h at
      the end of 24 h, 72 h and 20 d infusion respectively. Post-operatively, there
      were bleeds in six patients, which settled readily after a single bolus of rFVIIa
      (60 micro g/kg). There was a good clinical outcome for all patients. These data
      indicate that rFVIIa infusion at 50 micro g/kg/h achieves continuous plasma FVII
      procoagulant activity in excess of 30 IU/ml (12-15 nmol/l) and provides adequate
      haemostatic control for inhibitor patients during major orthopaedic surgery.

PMID- 12614215
TI  - DDAVP enhances the ability of blood monocytes to form rosettes with activated
      platelets by increasing the expression of P-selectin sialylated ligands on the
      monocyte surface.
AB  - The mechanism through which DDAVP (1-deamino-8-d-arginine vasopressin) promotes
      blood coagulation is not completely understood. As blood monocytes have been
      identified as a target for DDAVP, we investigated whether this drug increased
      monocyte adhesion to activated platelets, which would result in the close
      intercellular contact that is necessary for a juxtacrine effect on platelets
      and/or endothelium at sites of vascular injury. Monolayers of non-confluent
      monocytes adhered to glass slides were incubated with thrombin-activated,
      formaldehyde-fixed platelets before and after the adherent monocytes were
      stimulated with DDAVP or n-formyl-methyl-leucyl-phenylalanine (fMLP). The number
      of platelets involved in rosettes with monocytes was quantified, and the effect
      of DDAVP or fMLP on the monocyte surface expression of P-selectin ligands and
      CD11b/CD18 was assessed. DDAVP or fMLP increased the number of activated
      platelets involved in rosettes with monocytes by 2.8- and 4.9-fold respectively.
      EDTA and inhibitors of the P-selectin/counter-receptor interaction decreased the
      platelet numbers in rosettes by 80-90%, whereas inhibitors of the integrin
      mediated adhesion reduced rosettes by 40-50%. Blocking the P-selectin
      glycoprotein ligand-1 (PSGL-1) with the monoclonal antibody, Pl-1, decreased the
      platelet numbers in rosettes by only 50%. In contrast, surface expression of the
      sialylated ligands of P-selectin and, to a lesser extent, of CD11b/CD18 increased
      upon monocyte activation with DDAVP or fMLP, whereas it decreased slightly with
      PSGL-1. These results indicate that DDAVP enhanced the ability of blood monocytes
      to bind activated platelets, mainly by increasing the expression of P-selectin
      sialylated ligands on the monocyte surface. A similar effect was achieved with
      fMLP.

PMID- 12614216
TI  - ADAMTS13 gene defects in two brothers with constitutional thrombotic
      thrombocytopenic purpura and normalization of von Willebrand factor-cleaving
      protease activity by recombinant human ADAMTS13.
AB  - Genetic analysis of the ADAMTS13 locus identified six mutations in the ADAMTS13
      genes of two brothers suffering from constitutional thrombotic thrombocytopenic
      purpura (TTP): a stop codon leading to a truncated protein on the paternal
      ADAMTS13 allele and five amino acid exchanges on the maternal allele, three of
      which were single nucleotide polymorphisms. The other two mutations, not detected
      in 230 sequenced alleles of healthy control subjects, are, therefore, probably
      responsible, alone or as part of a combination, for the severe ADAMTS13
      deficiency. We also investigated the feasibility of using recombinant ADAMTS13
      (rADAMTS13) for normalization of von Willebrand factor-cleaving protease (VWF-cp)
      activity in plasma of the two congenitally deficient patients. Addition of
      rADAMTS13 to their plasma restored the VWF-processing pattern to normal,
      suggesting the potential usefulness of rADAMTS13 for therapy and prophylaxis of
      familial TTP.

PMID- 12614217
TI  - Standardization of activated protein C resistance testing: effect of residual
      platelets in frozen plasmas assessed by commercial and home-made methods.
AB  - We investigated 42 plasmas prepared at different centrifugation speeds with three
      activated protein C (APC) resistance methods. The APC ratio for fresh platelet
      poor plasma declined significantly after freezing and thawing. This effect was
      more evident with the original method (average reduction 11.3%) than with either
      the home-made (3.8%) or the modified method (3.2%). No significant decrease in
      the APC ratio was observed after freezing and thawing of platelet-free plasmas
      from the same patients. When frozen platelet-poor plasma was centrifuged at high
      speed after thawing and before testing, there was no significant decrease in the
      APC ratio, in comparison with fresh platelet-poor plasma using the home-made and
      modified methods.

PMID- 12614218
TI  - Tumour necrosis factor-alpha transcription in transferrin-stimulated human blood
      mononuclear cells: is transferrin receptor involved in the signalling mechanism?
AB  - Transferrin (Tf) and tumour necrosis factor-alpha (TNF-alpha) participate in
      immune response regulation. We studied the capacity of Tf to modulate 'in vitro'
      TNF-alpha secretion, membrane expression and transcription by human blood
      mononuclear cells (BMNC). Women 25-45 years of age with normal iron status (n =
      20) or with iron deficiency (ID, n = 20) due to gynaecological bleeding were
      studied. BMNC were incubated with different proportions of Fe-exempt and Fe
      saturated Tf (apo-Tf:holo-Tf). Apo-Tf or holo-Tf uniformly induced TNF-alpha
      secretion in the cell supernatants from both groups. Nevertheless, cytokine
      levels were significantly lower in ID subjects. For all Tf-Fe saturations
      assayed, mean TNF-alpha levels varied between 1.4-1.6 ng/ml and 0.4-0.7 ng/ml for
      normal and ID women respectively (P < 0.001). The addition of apo-Tf enhanced TNF
      alpha secretion in a dose-dependent manner, but the cytokine levels were lower in
      ID group. Tf did not induce pro-TNF-alpha expression in monocytes and lymphocytes
      from either group. Tf-treated cells from normal individuals expressed
      approximately two to three times more TNF-alpha mRNA than cells from ID subjects.
      Mean values ranged 96-110 atmol/ml in normal women and 24-31 atmol/ml in ID women
      for all Tf-Fe saturation levels tested (P < 0.001). These results show that Tf
      induced TNF-alpha secretion is transcriptionally regulated. The impaired TNF
      alpha transcription in cells from ID subjects indicates that the quality of the
      immune response is linked to the Fe status of mononuclear cells.

PMID- 12614219
TI  - Abnormal telomere metabolism in Fanconi's anaemia correlates with genomic
      instability and the probability of developing severe aplastic anaemia.
AB  - Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by
      progressive bone marrow failure and a susceptibility to cancer. Haematopoietic
      stem cell transplantation is the only curative method for restoring normal
      haematopoiesis, and survival is improved if the transplant is carried out before
      severe complications occur. However, the evolution of FA is difficult to predict
      because of the absence of known prognostic factors and the unknown function of
      the genes involved. In studying 71 FA patients, a correlation was found between
      severe aplastic anaemia (SAA) and the individual annual telomere-shortening rate
      (IATSR) in peripheral blood mononuclear cells (P < 10(-3)). Spontaneous apoptosis
      was highest in SAA patients or patients with high IATSR (> 200 bp/year) (P <
      0.01, n = 18). Univariate and multivariate analyses showed that significant
      relative risks for evolution towards SAA were high IATSR (P < 10(-4)), and that a
      high number of chromosome breakages occurred in the presence of nitrogen mustard
      (P < 0.001). A high IATSR was also associated with an increased frequency of
      malignancy (P < 0.01). Thus, these biological parameters were related to the
      spontaneous evolution of FA and could be used as prognostic factors. These data
      indicated that telomeres might play a role in the evolution of bone marrow
      failure and malignant transformation in FA.

PMID- 12614220
TI  - Development and functional characterization of human bone marrow mesenchymal
      cells immortalized by enforced expression of telomerase.
AB  - To create immortal mesenchymal cell lines, we transduced primary human bone
      marrow mesenchymal cells with telomerase reverse transcriptase (TERT). TERT+
      mesenchymal cells continued to grow for > 2 years; parallel TERT- cultures
      underwent senescence after 15 weeks. TERT+ mesenchymal cells did not form foci in
      soft agar, had a normal karyotype and could differentiate into osteoblasts and
      chondrocytes. Their capacity to support leukaemic lymphoblasts and normal CD34+
      haematopoietic cells was equal to or greater than that of primary cells; 42 TERT+
      mesenchymal cell clones varied in their supporting capacity. Immortalized
      mesenchymal cells offer a promising tool for identifying molecules that regulate
      human haematopoiesis.

PMID- 12614221
TI  - Involvement of cytotoxic granules in the apoptosis of aplastic anaemia.
AB  - To study the involvement of cytotoxic granules in apoptosis of aplastic anaemia
      (AA), we analysed bone marrow clot sections of AA for apoptosis and perforin,
      granzyme B and T-cell intracellular antigen-1 (TIA-1) expression. Perforin, TIA-1
      expression and apoptosis were significantly increased in AA patients compared
      with control subjects, but granzyme B was not. TIA-1 was significantly correlated
      with apoptotic cells of AA. No correlation was found between perforin and
      apoptotic cells of AA. These results suggest that perforin and TIA-1 play a role
      in the pathogenesis of AA. TIA-1 is implicated as an effector in the apoptosis of
      AA.

PMID- 12614222
TI  - Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose
      in anaemic patients using positron emission tomography.
AB  - Parenteral iron-polysaccharide complexes are increasingly applied. The
      pharmacokinetics of iron sucrose have been assessed by our group using positron
      emission tomography (PET). A single intravenous injection of 100 mg iron as iron
      (III) hydroxide-polymaltose complex, labelled with a tracer in the form of
      52Fe/59Fe, was similarly assessed in six patients using PET for about 8 h. Red
      cell utilization was followed for 4 weeks. Iron polymaltose was similarly
      distributed to the liver, spleen and bone marrow. However, a larger proportion of
      this complex was rapidly distributed to the bone marrow. The shorter
      equilibration phase for the liver, about 25 min, indicates the minimal role of
      the liver for direct distribution. Splenic uptake also reflected the
      reticuloendothelial handling of this complex. Red cell utilization ranged from
      61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no
      saturation of marrow transport systems at this dose level. In conclusion, high
      red cell utilization of iron polymaltose occurred in anaemic patients. The major
      portion of the injected dose was rapidly distributed to the bone marrow. In
      addition, the reticuloendothelial uptake of this complex may reflect the safety
      of polysaccharide complexes. Non-saturation of transport systems to the bone
      marrow indicated the presence of a large interstitial transport pool, which might
      possibly be transferrin.

PMID- 12614223
TI  - Relative importance of female-specific and non-female-specific effects on
      variation in iron stores between women.
AB  - Women have lower iron stores than men because of iron loss during their
      reproductive years. However, variation between women could result from
      differences in iron loss, aspects of iron homeostasis common to men and women, or
      a combination of both. We compared the effects of age, menopause, menstrual blood
      loss and the number of pregnancies (sex-specific factors), and the effects of
      genetic variation, on markers of iron stores. We assessed how much the same genes
      or other familial factors influence iron status in both men and women. Data from
      2,039 female twins who participated in studies of reproductive health and iron
      status were used to estimate the proportions of variation that could be ascribed
      to genes, environment and measured factors. Significant effects of age,
      menopausal status and magnitude of menstrual blood loss were demonstrated,
      accounting for up to 18% of variance in serum ferritin in this sample, but number
      of children had no significant effect. Genetic effects were more than twice as
      great as sex-specific effects. The within-pair similarity of ferritin values in
      dizygotic female twin pairs was greater than for dizygotic opposite-sex pairs,
      but this difference was not quite significant, consistent with a minor role for
      sex-specific factors; and the opposite-sex within-pair differences did not
      diminish significantly with age. We conclude that the contribution of genetic
      differences between women to variation in iron stores outweighs the comparatively
      small effects of interindividual variation in iron loss through variation in
      menstruation and number of pregnancies.

PMID- 12614224
TI  - De novo deletion within the telomeric region flanking the human alpha globin
      locus as a cause of alpha thalassaemia.
AB  - We have identified and characterized a Scottish individual with alpha
      thalassaemia, resulting from a de novo 48 kilobase (kb) deletion from the
      telomeric flanking region of the alpha globin cluster which occurred as a result
      of recombination between two misaligned repetitive elements that normally lie
      approximately 83 kb and 131 kb from the 16p telomere. The deletion removes two
      previously described putative regulatory elements (HS-40 and HS-33) but leaves
      two other elements (HS-10 and HS-8) intact. Analysis of this deletion, together
      with eight other published deletions of the telomeric region, showed that they
      all severely downregulated alpha globin expression. Together they defined a 20.4
      kb region of the human alpha cluster, which contains all of the positive cis
      acting elements required to regulate alpha globin expression. Comparative
      analysis of this region with the corresponding segment of the mouse alpha globin
      cluster demonstrated conserved non-coding sequences corresponding to the putative
      regulatory elements HS-40 and HS-33. Although the role of HS-40 as an enhancer of
      alpha globin expression is fully established, these observations suggest that the
      role of HS-33 and other sequences in this region should be more fully
      investigated in the context of the natural human and mouse alpha globin loci.

PMID- 12614225
TI  - Different levels of p38 MAP kinase activity mediate distinct biological effects
      in primary human erythroid progenitors.
AB  - There have been conflicting reports regarding the role of p38 mitogen-activated
      protein kinase (MAPK) in the regulation of differentiation, proliferation and
      apoptosis in erythroid cell lines. We have, therefore, examined the functions of
      this kinase in primary human erythroid progenitors. Cells in steady-state culture
      showed low-level p38 MAPK activity, which decreased further within 1 h of growth
      factor withdrawal and increased over a limited range within minutes of re
      exposure of cells to erythropoietin or stem cell factor, demonstrating the link
      between low-level p38 MAPK activity and the prevailing growth factor milieu. Use
      of the p38 MAPK-specific inhibitor SB203580 demonstrated that this level of
      activity was necessary for (1) optimal proliferation, (2) erythroid burst-forming
      unit migration and (3) full upregulation of E-cadherin and CD36 expression, but
      not haemoglobin A or glycophorin A expression, during human erythroid
      differentiation. In contrast, cells deprived of growth factors for an 8-h period,
      following a transient decrease in p38 MAPK activity, demonstrated sustained,
      substantial and caspase-independent increases in p38 MAPK activity, and its
      blockade using SB203580 reduced the proportion of erythroblasts undergoing
      apoptosis by 40 +/- 7%, demonstrating a role for p38 MAPK in apoptosis induction
      in human erythroblasts. Thus, in primary human erythroblasts, different
      environmental conditions induce different levels of p38 MAPK activity, which have
      distinct functions.

PMID- 12614226
TI  - Haematological effects of the C282Y HFE mutation in homozygous and heterozygous
      states among subjects of northern and southern European ancestry.
AB  - High frequencies of the C282Y and H63D mutations of the HFE gene occur in
      European populations, even though homozygous and compound heterozygous states are
      associated with hereditary haemochromatosis, which is a disease that decreases
      fitness. This suggests that heterozygotes may possess a selective advantage. HFE
      mutations increase iron absorption in patients with haemochromatosis, and the
      mean transferrin saturations and ferritin levels are mildly increased in
      heterozygotes, suggesting that HFE mutations may protect against iron depletion
      and iron deficiency anaemia. In this study of 23,681 Caucasian adults, mean
      transferrin saturation, serum ferritin and haemoglobin levels were significantly
      higher in subjects carrying HFE mutations compared with wild types. Analysed by
      ethnicity, mean haemoglobin and mean erythrocyte volume (MCV) were significantly
      lower in those with a southern versus northern European ancestry. C282Y mutation
      carriers had an increased mean haemoglobin level in both ethnic groups.
      Prevalence of non-anaemic iron deficiency was significantly lower among female
      carriers of the C282Y mutation compared with HFE wild types. However, prevalence
      of frank iron deficiency anaemia did not differ significantly among genotypes.
      Quantile:quantile plots showed a small but significant upward shift in the mid
      range of the haemoglobin distribution among C282Y mutation carriers that was
      consistent with an increased mean haemoglobin level without significant changes
      in the anaemic range.

PMID- 12614227
TI  - ATP-dependent vesiculation in red cell membranes from different hereditary
      stomatocytosis variants.
AB  - The hereditary stomatocytoses are a group of dominant haemolytic anaemias that
      show two main features: invaginated, 'stomatocytic' morphology; and a membrane
      leak to the univalent cations Na and K. A patient with the most severe variant of
      these conditions was reported to show a defect in an in vitro process of ATP
      dependent endocytic vesiculation (ADEV), which is found in normal red cells. We
      have examined this endocytosis process in 11 leaky red cell pedigrees available
      to us in the UK. ADEV in broken membranes was absent only in the two most
      severely affected, 'overhydrated' pedigrees studied, both of which showed a
      deficiency in the membrane raft protein, stomatin. The process was present,
      although typically diminished by about 10-20% compared with normal red cells, in
      all others. The cross-linker dimethyl adipimate (DMA), which could correct the
      cation leak in some of these patients, also corrected the ADEV defect in the same
      patients. In those patients in whom DMA had no effect on the ion leak, ADEV was
      not absent. In normal cells, this process of vesiculation was inhibited by
      inhibitors of membrane 'raft' function, by an antistomatin antibody and by
      vanadate and N-ethyl maleimide, but not by inhibitors of a number of kinases.
      These data highlight the heterogeneity of these conditions. A mechanism is
      discussed by which a defect in raft-based endocytosis could lead to the
      exaggerated surface exposure of an ion channel, which could then function
      constitutively, i.e. 'leak'.

PMID- 12614228
TI  - High-dose cyclophosphamide does not eradicate paroxysmal nocturnal
      haemoglobinuria haematopoiesis in mice carrying a Piga gene mutation.
AB  - Recently, high-dose cyclophosphamide (HD CY) has been used in the treatment of
      aplastic anaemia. Several reports have suggested that the treatment may either
      eradicate or suppress mutant clonal haematopoiesis such as paroxysmal nocturnal
      haemoglobinuria (PNH). We therefore treated mice that have a proportion of blood
      cells deficient in GPI-anchor molecules (PIGA-) with HD CY, and monitored their
      peripheral blood counts during and after treatment. HD CY produced a transient
      myelosuppression; however, the contribution of PIGA- haematopoiesis to the
      peripheral blood remained unchanged, suggesting that HD CY is unlikely to
      eliminate an existing PNH clone in patients treated for aplastic anaemia.

PMID- 12614229
TI  - Gene polymorphisms associated with diminished activity of 5,10
      methylenetetrahydrofolate reductase do not explain the clinical manifestations of
      cobalamin deficiency.

PMID- 12614230
TI  - Recombinant factor VIIa for refractive haemorrhage in autoimmune idiopathic
      thrombocytopenic purpura.

PMID- 12614231
TI  - Ca2+ ionophore-induced dendritic cell differentiation in a patient with defective
      Ca2+ ionophore-induced platelet aggregation.

PMID- 12614233
TI  - Plasma protein Z deficiency is common in women with antiphospholipid antibodies.

PMID- 12614232
TI  - A spectrum of skin reactions caused by the tyrosine kinase inhibitor imatinib
      mesylate (STI 571, Glivec).

PMID- 12614234
TI  - Intensive triathlon training induces low peripheral CD34+ stem cells.

PMID- 12614236
TI  - Reducing human error in urology: lessons from aviation.

PMID- 12614237
TI  - Surgical skills training and the role of skills centres.

PMID- 12614238
TI  - Professionalism, publication and the preparation of papers.

PMID- 12614239
TI  - Radical prostatectomy or watchful waiting?

PMID- 12614240
TI  - Hormonal therapy as an adjuvant to radical radiotherapy for locally advanced
      prostate cancer.

PMID- 12614241
TI  - Health-related quality of life in men with metastatic prostate cancer: the
      misleading effect of lead-time bias.
AB  - OBJECTIVE: To ascertain whether the difference in health-related quality of life,
      which appears to be worse in men with metastatic prostate cancer when the
      metastases are noted at initial diagnosis than during follow-up after treatment
      for clinically localized disease, can be attributed to previous local control or
      to some form of measurement bias. PATIENTS AND METHODS: We analysed by univariate
      and multivariate methods 375 men with metastatic prostate cancer who were
      enrolled in CaPSURE, a national observational cohort of patients with prostate
      cancer treated in community and academic settings throughout the USA. In
      particular, we assessed whether group differences in health-related quality of
      life were explained by the timing of metastatic diagnosis in the course of their
      disease. Health-related quality of life was measured with the RAND 36-Item Health
      Survey (SF-36). RESULTS: After controlling for relevant covariates (age,
      comorbidity and ethnicity), multivariate models suggested that men whose
      metastases were noted at the time of initial diagnosis scored 5-15 points worse
      in all eight domains of the SF-36. CONCLUSION: Men who are diagnosed with
      metastatic prostate cancer during the follow-up after treatment for clinically
      localized disease report a better quality of life than those who are metastatic
      at the time of diagnosis, not because the primary treatment confers any benefit
      but because they are followed more closely over time and diagnosed with
      metastases earlier in the course of their disease. This apparent difference in
      quality of life is an effect of lead-time bias in the diagnosis of metastasis.

PMID- 12614242
TI  - Decisional regret and quality of life after participating in medical decision
      making for early-stage prostate cancer.
AB  - OBJECTIVE: To determine the effect of men's reported levels of involvement in
      medical decision-making and quality of life (QoL) on their levels of decisional
      regret after definitive treatment. PATIENTS AND METHODS: Men referred to a
      hospital-based resource centre completed QoL and decisional-regret measures after
      definitive treatment for localized prostate cancer. Data from these
      questionnaires were linked with a previous study conducted to determine if
      providing individualized information to men newly diagnosed with prostate cancer
      would lower their levels of psychological distress and enable them to become more
      active participants in treatment decision-making. The preferred role in medical
      decision-making and QoL had previously been measured at the time of diagnosis and
      the assumed role at 4 months after the definitive treatment decision. This postal
      survey was conducted approximately 18 months after diagnosis. RESULTS: Of 74 men,
      67 (91%) responded; the mean (sd) time since definitive treatment was 10.3 (4.7)
      months and the mean age of the men 62.5 (6.9) years. Radical prostatectomy was
      the most frequent treatment (72%). Most (94%) patients participated in medical
      decision-making either actively or collaboratively and did not regret their
      treatment choice. The type of definitive treatment received had no effect on
      decisional regret; patients' QoL scores were similar to the levels before
      treatment. Levels of sexual function were significantly lower after definitive
      treatment, but urinary incontinence was not significantly affected. Men who had
      neoadjuvant hormone therapy reported having significantly more treatment-related
      symptoms. CONCLUSIONS: There is no evidence that providing information to
      facilitate participation in medical decision-making causes decisional regret or
      psychological distress within the first year after definitive treatment. A
      longitudinal follow-up of these patients is required to adequately assess the
      long-term effects of treatment on QoL and decisional regret.

PMID- 12614243
TI  - Intermittent androgen suppression in patients with prostate cancer.
AB  - OBJECTIVES: To evaluate intermittent androgen suppression (IAS) in patients with
      prostate cancer and to try to define predictive factors for biochemical
      progression. PATIENTS AND METHODS: From 1989 to 2001, 146 patients received IAS
      as a primary treatment for localized, advanced or metastatic prostate cancer (72
      men) or as a treatment for prostate-specific antigen (PSA) recurrence after
      radical prostatectomy (RP) and/or radiation therapy (74 men). Androgen
      deprivation treatment (ADT) was continued up to 6 months after PSA became
      undetectable or a nadir PSA level was reached. ADT was then re-instituted when
      the PSA level was> 4 ng/mL for patients who had RP or> 10 ng/mL for the others.
      RESULTS: After a mean (range) follow-up of 45.6 (12-196.9) months, 24 patients
      had biochemical progression. These patients were younger than those with no
      biochemical progression (67 vs 72 years, P = 0.004) and had a statistically
      higher Gleason score (7.21 vs 6.52, P = 0.01) and PSA level (111.1 vs 32.1 ng/mL,
      P = 0.05), and a shorter first phase without treatment (7.6 vs 11.2 months, P =
      0.05). Overall 5-year metastatic disease free survival of 91.3%. The overall 5
      year biochemical recurrence-free survival was 68%. Using multivariate analysis, a
      Gleason score of >or= 8 (P = 0.021), first-phase duration with no treatment of <
      1 year (P = 0.044), positive lymph nodes or metastatic disease at the time of
      starting IAS (P = 0.023) and age < 70 years (P = 0.037) were the strongest
      predictors of biochemical progression. CONCLUSION: IAS appeared to be a feasible
      treatment; the best candidates being those aged> 70 years with localized prostate
      cancer and a Gleason score of <or= 7.

PMID- 12614244
TI  - Does hormonal manipulation in conjunction with permanent interstitial
      brachytherapy, with or without supplemental external beam irradiation, improve
      the biochemical outcome for men with intermediate or high-risk prostate cancer?
AB  - OBJECTIVE: To determine whether hormonal manipulation improves the biochemical
      outcome for men with intermediate or high-risk prostate cancer and undergoing
      permanent brachytherapy with or without supplemental external beam radiation
      therapy. PATIENTS AND METHODS: From April 1995 to August 2000, 350 patients with
      intermediate-risk (225 men; a Gleason score of >or= 7 or a prostate specific
      antigen, PSA, level of >or= 10 ng/mL or clinical stage >or= T2b) or high-risk
      features (125 men; two or three of a Gleason score of >or= 7 or PSA >or= 10 ng/mL
      or clinical stage >or= T2b) underwent transperineal ultrasonography-guided
      permanent brachytherapy. No patient underwent pathological lymph node staging. Of
      these patients, 293 received supplemental external beam radiation therapy (EBRT),
      141 received hormonal manipulation, with 82 having hormonal therapy for <or= 4
      months (median 4) for cytoreduction, while 59 had neoadjuvant and adjuvant
      hormonal manipulation (median 8 and 12 months for intermediate- and high-risk,
      respectively). The median patient age was 68.5 years. No patient was lost to
      follow-up. The mean (sd) and median follow-up was 50 (18) and 49 months
      (calculated from the day of implantation). Biochemical disease-free (BDF)
      survival was defined using a consensus definition. The clinical variables
      evaluated for BDF survival included risk group, Gleason score, patient age,
      clinical T-stage and pretreatment PSA. Treatment variables included use of
      hormonal manipulation stratified into cytoreductive (<or= 4 months) vs adjuvant
      (> 4 months) regimens, supplemental EBRT, isotope and dosimetric variables.
      RESULTS: For intermediate-risk patients, the 6-year actuarial BDF survival rates
      were 98%, 96% and 100% for hormone naive, cytoreductive and adjuvant treatment,
      respectively (P = 0.693); for high-risk patients the respective values were 79%,
      94% and 92% (P = 0.046). When stratified by pretreatment PSA, hormonal
      manipulation improved the outcome for patients with a PSA of >or= 10 ng/mL (P =
      0.019), but not for those with < 10 ng/mL (P = 0.661). Hormonal status was not
      statistically significant in predicting biochemical outcome when stratified by
      Gleason score. The follow-up in hormone-naive patients was significantly longer
      than that in hormonally manipulated patients, at 55 (20) vs 43 (15) months (P <
      0.001). In a multivariate analysis only the Gleason score predicted failure in
      intermediate-risk patients, while pretreatment PSA, the use of hormonal
      manipulation and Gleason score predicted the outcome in high-risk patients (P =
      0.035). For both hormone-naive and hormonally manipulated BDF patients, the
      median PSA level after implantation was < 0.1 ng/mL. CONCLUSION: In patients
      treated by permanent prostate brachytherapy, hormonal manipulation improved the
      biochemical outcome for those at high-risk and those with an initial PSA of >or=
      10 ng/mL, but not for those with intermediate-risk features. The use of hormonal
      therapy for> 4 months conferred no additional biochemical advantage over short
      course regimens. Because the follow-up in hormone-naive patients was longer than
      that for those receiving hormonal manipulation, additional follow-up will be
      mandatory to confirm the durability of these findings.

PMID- 12614245
TI  - The fear of prostate cancer in men with lower urinary tract symptoms: should
      symptomatic men be screened?
AB  - OBJECTIVE: To explore the concerns and worries in men with uncomplicated lower
      urinary tract symptoms (LUTS, but no evidence of prostate cancer) relating to
      their symptoms. PATIENTS AND METHODS: There is no current prostate cancer
      screening programme in the UK. Evidence suggests that men with LUTS have the same
      risk of prostate cancer as aged-matched asymptomatic men. However, most men with
      LUTS are 'screened' with a digital rectal examination (DRE) and prostate specific
      antigen (PSA) testing as part of routine assessment. Whether this screening
      offers any benefit to patients and whether national screening for prostate cancer
      and subsequent early treatment offer any long-term survival or quality of life
      benefit is uncertain. Thus 30 men with uncomplicated LUTS were qualitatively
      interviewed to explore their concerns and worries about their symptoms.
      Interviews were transcribed verbatim and subjected to content analysis using
      validated techniques. RESULTS: Of the 30 men, 22 (73%) expressed a fear of
      prostate cancer at the time of their initial presentation. This fear was
      independent of race, social class and symptom severity; older men were less
      worried. Of the 22, 15 (68%) stated that after reassurance their symptoms were
      less bothersome and easier to cope with. CONCLUSIONS: These findings suggest
      there is a considerable gain in health by explicitly addressing the concerns of
      prostate cancer in men with uncomplicated LUTS. Informing these men of their true
      risk of prostate cancer (before or after a DRE and PSA estimate) may alleviate
      much of the bother associated with their symptoms. Despite no evidence of any
      greater risk of prostate cancer than in asymptomatic men, symptomatic men should
      continue to be screened after appropriate counselling.

PMID- 12614246
TI  - A prospective and randomized study of primary hormonal therapy for patients with
      localized or locally advanced prostate cancer unsuitable for radical
      prostatectomy: results of the 5-year follow-up.
AB  - OBJECTIVE: To evaluate the effect of primary hormonal therapy for patients with
      localized and locally advanced prostate cancer. PATIENTS AND METHODS: Patients
      with stage T1b-T3 prostate cancer who were not scheduled for radical
      prostatectomy were allocated into two groups: group 1 (73 men) received
      luteinizing hormone-releasing hormone (LHRH) agonist monotherapy and group 2 (78
      men) received LHRH agonist and chlormadinone acetate. Patients were followed
      using serum prostate specific antigen levels, prostate size and the detection of
      distant metastasis for 5 years. RESULTS: The median (range) follow-up was 78 (63
      87) months. The 5-year progression-free survival rate was significantly higher in
      group 2 (68%) than in group 1 (47%). However, the overall and cause-specific
      survival rate at 5 years were similar in both groups, at 72% and 93% in group 1,
      and 64% and 89% in group 2, respectively. CONCLUSION: The overall survival rates
      of the both groups were no different from that of the normal Japanese population
      of the same age group. Although this study did not include an untreated group,
      i.e. watchful waiting, these results might indicate the usefulness of primary
      hormonal therapy in controlling localized and locally advanced prostate cancer.
      The 5-year observation period is still short and the study is continuing to
      determine the 10-year survival.

PMID- 12614247
TI  - The number of lymph nodes examined and staging accuracy in renal cell carcinoma.
AB  - OBJECTIVE: To determine the number of lymph nodes that need to be examined to
      accurately stage the pN variable in patients undergoing radical nephrectomy (RN)
      for renal cell carcinoma (RCC). PATIENTS AND METHODS: We reviewed the operative
      and pathology reports of 725 patients with RCC submitted for RN. All tumours were
      classified using the fifth edition of the Tumour-Nodes-Metastasis classification.
      For each patient the number of lymph nodes removed was recorded. The patients
      were divided into five different groups according to the number of nodes removed,
      i.e. group 1, 1-4; group 2, 5-8; group 3, 9-12; group 4, 13-16; and group 5, >or=
      17. We evaluated the factors that affected the number of lymph nodes removed with
      nodal dissection and the variables that influenced the incidence of nodal
      involvement. RESULTS: Lymphadenectomy was performed in 608 patients (83.8%); in
      these patients the rate of lymph node metastases was 13.6%. The median (range)
      number of nodes removed was 9 (1-43); there was a statistically significant
      correlation between the number of nodes removed and the percentage of nodal
      involvement (r = 0.6; P < 0.01). The rate of pN+ was significantly higher in the
      patients with >or= 13 than in those with < 13 nodes examined (20.8% vs 10.2%; P <
      0.001). For organ-confined and locally advanced tumours there was a statistically
      significant difference in the pN+ rate between patients with < 13 or >or= 13
      nodes examined (3.4% vs 10.5%, and 19.7% vs. 32.2%, respectively). CONCLUSIONS:
      The proportion of tumours classified as pN+ increased with the number of lymph
      nodes examined. In RCC,> 12 lymph nodes need to be assessed for optimal staging.

PMID- 12614248
TI  - A randomized, double-blind crossover study of tamsulosin and controlled-release
      doxazosin in patients with benign prostatic hyperplasia.
AB  - OBJECTIVE: To compare the effects of the doxazosin gastrointestinal therapeutic
      system, extended-release (doxazosin-GITS) formulation, and tamsulosin, another
      alpha1-antagonist, on total International Prostate Symptom Score (IPSS) and
      maximum urinary flow rate (Qmax) in treating patients with benign prostatic
      hyperplasia (BPH). PATIENTS AND METHODS: Data were analysed from a prospective,
      randomized, double-blind, crossover study of men aged 50-80 years with
      concomitant BPH and hypertension as inclusion criteria. Fifty-two men were
      treated in four phases: phase I, placebo run-in for 2 weeks; phase II, first
      study drug doxazosin-GITS or tamsulosin for 8 weeks; phase III, washout with
      placebo for 2 weeks; and phase IV, second study drug tamsulosin or doxazosin-GITS
      for 8 weeks. Doxazosin-GITS was started at 4 mg/day and tamsulosin at 0.4 mg/day,
      and then titrated to 8 mg/day and 0.8 mg/day, respectively, after 4 weeks of
      therapy if the increase in Qmax was < 3 mL/s or the reduction in total IPSS was <
      30%. Efficacy assessments included the IPSS and Qmax. Changes in blood pressure
      were not analysed, as most patients were actually not hypertensive. Endpoint
      efficacy data were analysed using an analysis of covariance model, with terms for
      sequence, phase, patients and sequence within patients, in addition to the
      baseline as covariate. Forty-seven men were treated in both efficacy arms of the
      study and were evaluable for analysis. RESULTS: Doxazosin-GITS and tamsulosin
      significantly relieved lower urinary tract symptoms and significantly increased
      Qmax from baseline (P = 0.001). Doxazosin-GITS produced significantly greater
      improvements than tamsulosin in total IPSS (P = 0.019) and obstructive subscores
      (P = 0.004) at the last treatment visit. The difference between doxazosin-GITS
      and tamsulosin in improving Qmax approached significance in favour of the former
      (mean change from baseline 2.6 vs 1.7 mL/s, respectively; between-group
      difference P = 0.089). Both treatments were well tolerated. CONCLUSIONS:
      Treatment with doxazosin-GITS was significantly more effective than tamsulosin in
      relieving lower urinary tract symptoms.

PMID- 12614249
TI  - Differences between nocturics and non-nocturics in voiding patterns: an analysis
      of frequency-volume charts from community-dwelling elderly.
AB  - OBJECTIVE: To evaluate differences between elderly people with and without
      nocturia (waking up in the night to void) in terms of voiding habits, urine
      production and voided volumes. SUBJECTS AND METHODS: Nocturics or= two
      voids/night) and non-nocturics (< one void/night) were recruited from a
      questionnaire survey. Subjects were asked to complete a 3-day frequency-volume
      chart, including time and volume of each void, and their bedtime and waking time.
      Diaries from 108 non-nocturics and 116 nocturics were analysed. The number of
      voids, urine production, largest and average voided volumes were analysed using
      repeated-measures analysis of variance models, controlling for variables such as
      age, gender, body weight and gender-diagnosis interaction. RESULTS: Nocturnal
      urine volume was higher in nocturics than in non-nocturics. The difference
      between the groups was larger among the men (estimated difference 384 mL) than
      among the women (227 mL), but highly statistically significant (P < 0.001) in
      both genders. Among the men the diurnal urine and 24-h urine volumes were
      significantly higher in nocturics (difference, diurnal 131 mL, 24-h 462 mL, both
      P < 0.001). In the women the diurnal urine volume was lower in nocturics than in
      non-nocturics (difference 147 mL P = 0.0022) with no difference detected in 24-h
      urine volume. The largest voided volume was significantly less in nocturics than
      in non-nocturics; the difference was larger in women (128 mL, P < 0.001) than in
      men (42 mL, P = 0.0027). The average voided volume was 85 mL less (P < 0.001) in
      nocturics. The overlap between the groups in nocturnal urine and voided volumes
      was substantial and several significant covariates identified. The ratio between
      nocturnal urine volume and largest voided volume was the most statistically
      significant predictor of the number of nocturnal voids. CONCLUSION: Elderly
      nocturics had a higher nocturnal urine production and lower volume per void than
      non-nocturics. Differences between nocturics and non-nocturics in urine
      production and largest voided volume did not follow the same pattern in men and
      women. Nocturia was a result of a mismatch between nocturnal urine volume and
      largest voided volume, rather than abnormal values in either. The treatment of
      nocturia should be directed at one or both of these factors, depending on the
      findings from the 3-day frequency-volume chart of the individual.

PMID- 12614250
TI  - The mesh wallstent in the treatment of detrusor external sphincter dyssynergia in
      men with spinal cord injury: a 12-year follow-up.
AB  - OBJECTIVE: To assess the long-term effectiveness of the UroLume trade mark
      wallstent (Pfizer Inc., UK) in the treatment of detrusor external sphincter
      dyssynergia (DESD) in quadriplegic patients. PATIENTS AND METHODS: Twelve
      patients with quadriplegia secondary to spinal trauma underwent external striated
      sphincter stenting with the UroLume wallstent instead of an external
      sphincterotomy for DESD (mean age 41.8 years, range 26-65). The level of injury
      was C4 in two, C5 in four, C6 in four, C7 in one and T6 in one. All patients were
      shown by preoperative video-cystometrography (VCMG) to have DESD and high
      pressure, hyper-reflexic bladders with incomplete emptying. RESULTS: Seven of the
      12 patients had a mean (range) follow-up of 12.7 (12.17-13.6) years; two others
      were lost to follow-up at 1 and 3 years and both remained free of complications
      during that time. Two patients developed encrustation causing obstruction,
      requiring stent removal within a year of insertion. Another patient with an
      adequately functioning stent died 7 years after surgery (chest infection).
      Urodynamic follow-up of the seven patients showed a significantly sustained
      reduction in maximum detrusor pressure and duration of detrusor contraction at>
      10 years of follow-up. Five of the seven patients developed bladder neck
      dyssynergia of varying degrees, as shown on VCMG; all were successfully treated
      with bladder neck incision. There were no problems with stent migration, urethral
      erosion, erectile dysfunction or autonomic dysreflexia. CONCLUSION: Permanent
      urethral stenting using the UroLume wallstent is effective in managing DESD and
      provides an acceptable long-term alternative to sphincterotomy. Subsequent
      bladder neck dyssynergia is the main complication but this can be managed
      successfully with bladder neck incision. Importantly, unlike sphincterotomy,
      there is no significant interference with erectile function. Also, the procedure
      is reversible, minimally invasive and requires a shorter hospital stay.

PMID- 12614251
TI  - Simplified bladder training augments the effectiveness of tolterodine in patients
      with an overactive bladder.
AB  - OBJECTIVES: To compare the efficacy of tolterodine plus simplified bladder
      training (BT) with tolterodine alone in patients with an overactive bladder.
      PATIENTS AND METHODS: In a multicentre, single-blind study at 51 Scandinavian
      centres, 505 patients aged >or= 18 years with symptoms of urinary frequency (>or=
      8 micturitions/24 h) and urgency, with or without urge incontinence, were
      randomized to oral treatment with either tolterodine 2 mg twice daily plus
      simplified BT or tolterodine alone. Changes in voiding diary variables were
      evaluated after 2, 12 and 24 weeks of treatment. The patients' perceptions of
      their bladder symptoms and tolerability (adverse events) were also determined.
      RESULTS: In all, 501 patients (75% women) were evaluable on an intention-to-treat
      basis (244 on tolterodine + BT and 257 on tolterodine alone). Tolterodine
      significantly reduced the voiding frequency and increased the volume voided per
      void at all sample times; these effects were significantly increased by adding
      BT. At the end of the study the median percentage reduction in voiding frequency
      was greater with tolterodine + BT than with tolterodine alone (33% vs 25%, P <
      0.001), while the median percentage increase in volume voided per void was 31%
      with tolterodine + BT and 20% with tolterodine alone (P < 0.001). There was a
      median of 81% fewer incontinence episodes than at baseline with tolterodine
      alone, which was not significantly different from that with tolterodine + BT (-
      87%). The two groups had comparable median percentage reductions in urgency
      episodes. Some 76% of patients on tolterodine + BT reported an improvement in
      their bladder symptoms relative to baseline, compared with 71% on tolterodine
      alone. Tolterodine was well tolerated; the most common adverse event was mild dry
      mouth. CONCLUSION: Tolterodine 2 mg twice daily is an effective and well
      tolerated treatment for an overactive bladder, the effectiveness of which can be
      augmented by a simplified BT regimen.

PMID- 12614252
TI  - Day-case holmium laser enucleation of the prostate for gland volumes of < 60 mL:
      early experience.
AB  - OBJECTIVE: To examine the safety and effectiveness of holmium laser enucleation
      of the prostate (HoLEP), as a day-case procedure for selected patients. PATIENTS
      AND METHODS: Thirty-eight men underwent HoLEP as a day-case procedure; they were
      discharged with an indwelling catheter for 48 h with 'Hospital In The Home'
      nursing management. They were evaluated for symptomatic and flow rate
      improvements after 3 months. Morbidity, length of stay, the duration of
      catheterization and readmission rates were evaluated. RESULTS: The objective
      symptom score and flow-rate improvements were equivalent to those previously
      published for transurethral resection of the prostate (TURP). There were five
      minor complications, three of which required readmission to hospital and one
      repeat surgery. The mean stay after surgery was 302 min. CONCLUSIONS: Day-case
      HoLEP is a safe and effective treatment for symptomatic benign prostatic
      hyperplasia. The outcomes are equivalent to those from TURP. Whilst there were
      three re-admissions to hospital, two only required an overnight stay and no
      patient required a blood transfusion.

PMID- 12614253
TI  - Rotoresect for bloodless transurethral resection of the prostate: a 4-year follow
      up.
AB  - OBJECTIVE: To report the results and long-term follow-up of transurethral
      resection of the prostate (TURP) with a new resection device, the Rotoresect
      (Karl Storz, Tuttlingen, Germany). PATIENTS AND METHODS: Most endoscopic
      resection techniques for benign prostatic tissue aim for high ablation rates and
      minimal bleeding. Available resection electrodes are effective, but cause high
      blood loss (loop electrode), or less bleeding but poorer ablation rates
      (electrovaporization). To resolve these conflicts the Rotoresect was developed in
      1995; it consists of a specially designed rotating resection electrode, driven by
      a micromotor, and a high-frequency current to enable simultaneous coagulation,
      vaporization and mechanical tissue removal during resection. To date, 84 patients
      with benign prostatic hyperplasia have had their prostate resected with this
      device (mean prostate size 46.0, sd 18.4 mL) and have been assessed for up to 4
      years. RESULTS: During resection there was very little bleeding, with no
      significant changes in haemoglobin or sodium levels. The mean (sd) duration of
      catheterization was 1.4 (1.1) days; the urinary peak flow rate was improved from
      9.7 (3.2) to 24.2 (8.23) mL/s and the residual urine volume reduced from 187.3
      (109.6) to 22.7 (19.5) mL. The International Prostate Symptom Score and quality
      of-life index were both improved, from 24.0 (7.5) to 4.1 (2.7), and 4.2 (3.2) to
      0.8 (0.9), respectively. Overall the results were stable during the 4 years of
      follow-up. CONCLUSION: The Rotoresect combines the advantages of standard
      resection (high ablation rate) by actively rotating the resection electrode, and
      the haemostatic effect of electrovaporization (minimal blood loss) by
      simultaneous tissue coagulation and vaporization.

PMID- 12614254
TI  - A novel testosterone gel formulation normalizes androgen levels in hypogonadal
      men, with improvements in body composition and sexual function.
AB  - OBJECTIVE: To compare the safety and efficacy of two doses of a new testosterone
      gel formulation (Testim Auxilium Pharmaceuticals, Inc., Norristown, PA, USA) to a
      permeation-enhanced testosterone patch (Andropatch), GlaxoSmithKline, UK) for
      treating men with confirmed low serum testosterone levels, and associated signs
      and symptoms of hypogonadism. PATIENTS AND METHODS: In all, 208 men were
      randomized and treated at 29 centres in Denmark, Germany, Netherlands, Sweden and
      the UK. The men were treated for 90 days, and the pharmacokinetics and treatment
      effectiveness of Testim at two doses (50 and 100 mg/day, delivering a daily dose
      of 5 and 10 mg testosterone, respectively) and Andropatch (2 x 2.5 mg patches,
      each delivering 2.5 mg testosterone and containing 12.2 mg of testosterone) were
      compared. Pharmacokinetic profiles were obtained, body composition measured, and
      mood and sexual function data recorded. RESULTS: Testim produced dose-dependent
      improvements in all pharmacokinetic variables compared with Andropatch. The mean
      increases from baseline to 90 days in testosterone were 12.41, 6.54 and 3.82
      nmol/L for Testim 100 and 50 mg/day and the Andropatch, respectively. Both doses
      of Testim significantly improved positive and negative mood over baseline;
      Andropatch did not. All three treatments increased lean body mass, and the higher
      dose of Testim produced a significant decrease in percentage body fat. At all
      sample times both doses of Testim significantly improved sexual performance,
      sexual motivation, sexual desire and spontaneous erections. Andropatch provided
      insignificant improvements from baseline at all sample times for sexual desire,
      an inconsistent improvement in sexual motivation, but no effect on spontaneous
      erections. These results are similar to those previously reported for
      testosterone replacement therapy in hypogonadal men, suggesting that
      normalization of serum testosterone restores sexual function. However, the
      present data suggest that higher serum testosterone levels may further improve
      sexual function. Gel treatment was well tolerated, while patch treatment produced
      higher rates of application-site reactions and study discontinuation. CONCLUSION:
      The favourable pharmacokinetic profile and treatment outcome, combined with the
      enhanced tolerability of Testim, suggest that this new gel formulation is a safe
      and effective treatment in men with low serum testosterone levels and associated
      signs and symptoms of hypogonadism.

PMID- 12614255
TI  - Testicular growth and gonadotrophin response associated with varicocele repair in
      adolescent males.
AB  - OBJECTIVE: To measure testicular volume and the gonadotrophin response to
      gonadotrophin-releasing hormone (GnRH) stimulation in adolescents undergoing left
      varicocelectomy. PATIENTS AND METHODS: Thirteen adolescents undergoing
      varicocelectomy had their testicular volume and endocrine function evaluated
      before and after surgery. RESULTS: The initial left testicular volume was
      consistently smaller than the right but after surgery both increased. Baseline
      follicle-stimulating hormone (FSH) levels and the FSH response to GnRH
      stimulation increased after surgery. There were no differences in luteinizing
      hormone and testosterone levels, and no changes in Tanner staging. CONCLUSIONS:
      Unilateral varicocelectomy with ipsilateral testicular atrophy results in
      bilateral testicular growth and increased FSH levels. In adolescent development,
      elevated FSH levels in conjunction with an increased response to the GnRH
      stimulation test represent a normal physiological response. The GnRH stimulation
      test cannot be used to determine which adolescent would benefit from surgical
      repair.

PMID- 12614256
TI  - Enterocystoplasty in childhood: a second look at the effect on growth.
AB  - OBJECTIVE: To re-evaluate the assumption that enterocystoplasty in children has a
      detrimental effect on linear growth (which is almost exclusively based upon a
      chance finding in a retrospective study 10 years ago) in a larger cohort and with
      a longer follow-up. PATIENTS AND METHODS: The original 12 children who had
      impaired linear growth in a previous study 10 years earlier were re-measured. A
      larger cohort was identified from the 242 children and adolescents who had
      undergone enterocystoplasty between 1982 and 1997. Patients with conditions
      involving organ systems apart from the urinary tract, and those with
      myelomeningocele, malignant diseases, reduced glomerular filtration rate and
      incomplete notes were excluded. In the definitive study cohort (123; mean age at
      operation 8.6 years; mean age at investigation 16.8 years) enterocystoplasty had
      been undertaken using colon in 70, ileum in 37, a combination of both in 11,
      ileocaecal segments in three and stomach in two patients. RESULTS: Of the
      original 12 patients, six had regained or surpassed their preoperative position
      on their growth charts. In all patients with a known target centile range the
      final height was within their genetic growth potential. In the cohort of 123
      patients, 1215 height and weight measurements had been recorded. The distribution
      of percentile positions before and after enterocystoplasty showed a normal
      configuration, with 83% and 80% of patients growing within two standard
      deviations of the 50th percentile. After surgery, 85% either remained on the same
      or reached a higher centile. Nineteen (15.5%) were in a lower position, with a
      similar tendency in the weight centile. A clinically relevant growth disorder was
      recognized in four patients with a complete endocrinological evaluation; in none
      of these was enterocystoplasty thought to be a causal factor. CONCLUSIONS: It is
      very unlikely that the loss of the preoperative percentile position on the growth
      curve in 15% of children after enterocystoplasty is a consequence of the surgery.
      Rather it is a non-specific phenomenon that has to be considered in any clinical
      population of the same size and age distribution after the same length of time.

PMID- 12614257
TI  - Healing of unstented tubularized incised plate urethroplasty: an experimental
      study in a rabbit model.
AB  - OBJECTIVE: To develop a rabbit model to study the temporal healing taking place
      after an unstented tubularized incised plate urethroplasty (TIPU). MATERIALS AND
      METHODS: The study comprised 13 New Zealand white rabbits (3-4 kg); the ventral
      wall of the penile urethra was excised to create a hypospadias-like defect. A
      vertical incision was made in the dorsal urethral plate and the incised urethra
      tubularized. Two animals were killed at 2 days and two at 5 days after surgery,
      and the remainder killed at 2, 6 and 12 weeks (three each). A retrograde
      urethrogram was taken at autopsy. Serial sections of the penis were stained with
      haematoxylin and eosin, and Masson trichrome for microscopy. RESULTS: There were
      no deaths related to the procedure and all animals voided spontaneously.
      Retrograde urethrograms showed no fistulae or stricture. Microscopic examination
      at 2 and 5 days showed partial coverage of the incision with regenerating
      urothelium. At 2 weeks there was full-thickness urothelium with a mild
      inflammatory reaction. At 6 and 12 weeks, remodelling of the peri-urethral
      connective tissue with minimal fibrosis completed the healing. CONCLUSION: The
      mechanism of healing of the incised urethral plate involves normal urothelial
      regeneration into the depth of the incised defect, which explains the gain in
      urethral diameter after TIPU. Urine flow, during normal voiding, might be
      responsible for keeping the incised plate open during urothelial regeneration. A
      urethral stent was not necessary for normal healing in this model.

PMID- 12614258
TI  - The role of the human bladder lamina propria myofibroblast.
AB  - OBJECTIVES: To describe the ultrastructure and relationship to nerves of the
      myofibroblast in the human bladder lamina propria, and discuss its possible role
      in bladder function, including sensing stretch, as the response of the bladder to
      stretch has been thoroughly investigated by afferent nerve recordings, but
      specialized stretch sensing organs have yet to be identified. MATERIALS AND
      METHODS: Flexible cystoscopic bladder biopsies were obtained from patients with
      detrusor hyper-reflexia and from controls. Systematic electron micrographs were
      obtained throughout the lamina propria, and the presence and location of cells
      with ultrastructural characteristics of myofibroblasts noted, together with their
      relation to surrounding nerves. RESULTS: Within the lamina propria there was a
      layer of cells with the cytological characteristics of both fibroblasts and
      smooth muscle cells, that included bundles of fine cytoplasmic filaments, dense
      bodies, linear arrays of subsurface vacuoles, and the presence of an interrupted
      basal lamina. This combination of features is characteristic of the
      myofibroblast. These cells had close contacts with unmyelinated axonal
      varicosities containing a mixture of clear and large dense-cored vesicles, or
      clear vesicles alone. CONCLUSIONS: There is a layer of cells with the
      ultrastructural characteristics of myofibroblasts within the human bladder lamina
      propria. Their close contacts with nerves containing both small clear, and small
      clear with dense-cored, vesicles implies they have both an efferent and an
      afferent nerve supply, possibly functioning as a bladder stretch receptor.
      Furthermore, because of their similarities with the interstitial cells of Cajal
      in the gut, which are claimed to modulate small intestinal function, we discuss
      other possible roles for bladder lamina propria myofibroblasts.

PMID- 12614259
TI  - Intraprostatic ethanol chemoablation via transurethral and transperineal
      injection.
AB  - OBJECTIVES: To further assess the safety and feasibility of prostatic
      chemoablation with ethanol and to address previous concerns associated with
      transperineal injection using a canine model. MATERIALS AND METHODS: The study
      included 25 dogs; normal saline or 98% dehydrated ethanol were injected into the
      prostate using both routes, at volumes of 25-50% of the total prostate volume.
      The prostate and adjacent structures were examined grossly and
      histopathologically after the dogs were killed humanely at 4 h, 7 days and 12
      weeks after injection. RESULTS: Transperineal injection resulted in tissue
      necrosis in all prostates and significant extraprostatic necrosis in two of three
      animals treated. With transurethral injection, the control groups showed minimal
      change, whereas the group injected with ethanol resulted in lesions with variable
      necrosis and location. CONCLUSIONS: Intraprostatic chemoablation is possible with
      ethanol injection both transperineally and transurethrally. Transperineal ethanol
      injections were associated with more extraprostatic necrosis. Transurethral
      injections resulted in larger amounts of necrosis in the prostatic parenchyma
      with minimal extraprostatic effects. However, the extent of prostatic
      necrosis/ablation was inconsistent and further research is warranted.

PMID- 12614260
TI  - Matrix metalloproteinases (MMPs) in bladder cancer: the induction of MMP9 by
      epidermal growth factor and its detection in urine.
AB  - OBJECTIVES: To investigate the matrix metalloproteinases (MMPs) 2 and 9 in
      bladder cancer cell lines stimulated with epidermal growth factor (EGF), and to
      investigate the presence of gelatinases in the urine of patients with bladder
      tumours, in relation to the stage and grade of tumour and the EGF receptor (EGFR)
      status. PATIENTS, SUBJECTS AND METHODS: Conditioned media from cultured tumour
      cells were analysed by zymography. Urine samples from 28 patients with
      transitional cell carcinoma and 12 normal volunteers were also analysed. Western
      blotting was used to verify the bands of gelatinolytic activity. The EGFR status
      of the tumours was assessed by immunohistochemistry. RESULTS: MMP9 was induced by
      EGF in the RT112 but not the RT4 bladder tumour cell line, whereas MMP2
      production was unaffected by EGF. Gelatin zymography of urine samples from
      patients with bladder tumours showed high levels of MMP activity, with 78%
      positive for MMP9 and 28% positive for MMP2. The total gelatinolytic and MMP9
      activity were significantly higher in patients with high-stage invasive tumours
      than in those with superficial tumours (P < 0.05), and were higher than in normal
      controls. Gelatinolytic activity at 130 and 200 kDa in urine was identified as
      MMP9 and MMP2. There was no significant relationship of urinary MMP9 activity to
      EGFR status of the tumour. CONCLUSION: EGF induces MMP9 but not MMP2 in bladder
      cells. Analysis of urinary gelatinases is a useful noninvasive technique and both
      total gelatinase and MMP9 activity are associated with high stages of bladder
      tumours.

PMID- 12614261
TI  - Thymidine phosphorylase levels as a prognostic factor in renal cell carcinoma.
AB  - OBJECTIVE: To investigate the relationship between thymidine phosphorylase (TP),
      a vascular growth factor, and established prognostic factors for renal cell
      carcinoma (RCC), e.g. histological grade or Tumour-Node-Metastasis (TNM)
      classification. PATIENTS AND METHODS: TP levels were measured in RCC tissue
      (tumour TP) and in adjacent non-neoplastic kidney tissue (normal tissue TP),
      using a sandwich-type enzyme-linked immunosorbent assay. The 59 patients,
      diagnosed with organ-confined RCC before surgery and who had undergone radical
      nephrectomy, were divided into two groups according to their prognosis after
      surgery. Group 1 (nine patients) had a poor prognosis and group 2 (50) had no
      evidence of disease within a 65-month follow-up. The relationships among TP
      level, TNM classification, histological subtypes, V factor and prognosis, and of
      tumour TP to normal tissue TP levels were investigated. Multiple regression
      analysis was used to determine the importance of factors associated with
      increased TP levels. RESULTS: Normal tissue TP levels correlated with
      histological grade (r = 0.31, P < 0.01); in patients with venous invasion or with
      a poor prognosis, the levels were significantly higher than in those without (P <
      0.05 and < 0.001, respectively). The normal tissue TP levels were also
      significantly higher in the non-clear cell than in the clear cell subtype.
      Multiple regression analysis showed that the independent factor associated with
      elevated normal tissue TP levels was histological grade (R2 = 0.189, P < 0.01).
      There was no correlation between tumour TP and other factors. CONCLUSION: Normal
      tissue TP levels in localized hypervascular RCC were associated with histological
      grade. These data suggest that normal tissue TP levels could be a prognostic
      factor.

PMID- 12614262
TI  - Overexpression of cyclooxygenase-2 in high-grade human transitional cell
      carcinoma of the upper urinary tract.
AB  - OBJECTIVE: To examine cyclooxygenase (COX)-2 expression (a key enzyme in the
      synthesis of prostaglandins, and involved in carcinogenesis of human epithelial
      tumours) in human transitional cell carcinomas (TCCs) of the renal pelvis and
      ureter, and to determine whether COX-2 expression correlates with the
      clinicopathological characteristics of the disease. MATERIALS AND METHODS:
      Specimens from 144 patients with TCC of the upper urinary tract who had undergone
      nephroureterectomy were analysed immunohistochemically, and 23 were also analysed
      by immunoblotting. RESULTS: Immunoblot analysis showed COX-2 immunoreactivity in
      17 (74%) of 23 tumours, but not in normal transitional epithelium. COX-2 was
      localized to the cytoplasm of cancer cells and expressed in 108 (75%) of 144
      tumours, as assessed by immunohistochemical analysis. COX-2 expression correlated
      with tumour grade (P < 0.008), being detected in one of nine grade 1, 77 (79%) of
      97 grade 2 and 30 (79%) of 38 grade 3 tumours. Other variables including tumour
      stage were not associated with COX-2 expression. CONCLUSIONS: We show for the
      first time that COX-2 is frequently expressed in TCC of the upper urinary tract
      and is associated with the degree of tumour cell differentiation, indicating that
      COX-2 may be involved in TCC carcinogenesis at an early and/or late stage, and
      could be a useful target for chemoprevention of this type of cancer.

PMID- 12614263
TI  - As we enter the new year, several new drugs will be launched globally.

PMID- 12614264
TI  - Functional bladder evaluation with temporary vesicostomy occlusion in the home
      situation.

PMID- 12614265
TI  - Primitive neuroectodermal tumour of the kidney with spontaneous regression of
      pulmonary metastases after nephrectomy.

PMID- 12614266
TI  - The agony and the ecstasy: acute urinary retention after MDMA abuse.

PMID- 12614268
TI  - Nocturia in relation to sleep, somatic diseases and medical treatment in the
      elderly.

PMID- 12614270
TI  - Hand-assisted laparoscopic nephrectomy: complications related to the hand-port
      site.

PMID- 12614269
TI  - Leuprorelin acetate granulomas: recurrent subcutaneous nodules mimicking
      metastatic deposits at injections sites.

PMID- 12614271
TI  - Preventing clot retention after urological surgery.

PMID- 12614275
TI  - Where is the alloimmune response initiated?

PMID- 12614276
TI  - Acquired tolerance to renal allografts in humans.

PMID- 12614277
TI  - Infectious etiology of bronchiolitis obliterans: the respiratory viruses
      connection - myth or reality?
AB  - A variety of viruses, such as the influenza viruses A and B, the human
      respiratory syncytial virus, the parainfluenza viruses, and the adenoviruses,
      cause seasonal respiratory tract infections in young children and adults. Also,
      studies indicate that these viruses are an important group of pathogens in
      pediatric and adult lung transplant recipients. More importantly, accumulating
      data on these infections among lung transplant patients suggest that these
      illnesses may have immediate and long-term implications for the function of the
      transplanted lung, including the development of bronchiolitis obliterans. This is
      important because patient survival and allograft function in lung transplantation
      remain limited by the development of bronchiolitis obliterans. Models of lung
      transplantation indicate that respiratory viral infections cause acute and
      chronic airway damage after transplantation. The mechanism leading to allograft
      damage by respiratory viruses may be related to the production of alloreactive
      cytokines such as interleukin (IL)-1, tumor necrosis factor, IL-6 and IL-8 during
      viral replication. Current clinical data are suggestive of a possible role for
      respiratory viruses in the development of bronchiolitis obliterans, but further
      control studies are required to evaluate the significance of respiratory virus
      infections as a causal factor in the development of bronchiolitis obliterans in
      lung transplantation.

PMID- 12614278
TI  - Prevention of and treatment for hepatitis B virus infection after liver
      transplantation in the nucleoside analogues era.
AB  - Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has
      significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather
      ineffective in patients with pretransplant viremia. Moreover, long-term HBIG
      administration is very expensive and may be associated with emergence of escape
      HBV mutants. Lamivudine has been widely used in the management of HBV transplant
      patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of
      post-transplant HBV recurrence, but to try and minimize development of resistant
      HBV strains, it should start within the last 6 months of the anticipated
      transplantation timing. Preemptive post-transplant lamivudine monotherapy is
      associated with progressively increasing HBV recurrence rates, but combined
      therapy with lamivudine and HBIG at relatively low dosage is currently the most
      effective approach in this setting, even in HBV-DNA-positive patients, who also
      receive lamivudine in the pretransplant period. The most frequent therapy for
      post-transplant HBV recurrence is lamivudine, but the increasing resistance rates
      represent a rather challenging problem. Adefovir dipivoxil and entecavir are
      currently the most promising agents for lamivudine-resistant HBV strains. All
      these advances in anti-HBV therapy have made HBV liver disease an indication for
      liver transplantation irrespective of viral replication status, a complete turn
      around from 10 years ago.

PMID- 12614279
TI  - Secondary lymphoid organs are important but not absolutely required for allograft
      responses.
AB  - The role of secondary lymphoid organs in adaptive immune responses following
      transplantation is controversial. To examine the requirement for peripheral
      lymphoid organs in mounting immune responses to transplantation antigens,
      lymphotoxin alpha-deficient (LTalpha-/-) and LTbeta-receptor-deficient (LTbetaR-/
      ) mice that lack lymph nodes and Peyer's patches were used as recipients of fully
      allogeneic heart and skin grafts. Splenectomized LTalpha-/- and LTbetaR-/- mice
      effectively rejected skin and cardiac allografts, although with delayed kinetics
      when compared with wild-type controls. In addition, initial skin allograft
      challenge in splenectomized LTbetaR-/- mice resulted in accelerated rejection of
      subsequent donor cardiac allografts when compared with heart rejection in
      nonsensitized controls. Thus, although peripheral lymphoid organs play an
      important role in allowing allograft responses to occur, they do not appear to be
      absolutely required for either acute allograft rejection, or T-cell priming.
      These results suggest that immunologic events capable of leading to allograft
      rejection can successfully occur at sites other than classical secondary lymphoid
      organs.

PMID- 12614280
TI  - The effect of low versus high dose of streptozotocin in cynomolgus monkeys
      (Macaca fascilularis).
AB  - Streptozotocin (STZ) is often used to induce diabetes in animal models. However,
      morbidity associated with STZ and its ability to induce diabetes vary with
      different dosages among different animal species, including nonhuman primates. To
      find an optimal dose of STZ that would cause diabetes with minimal toxicity, we
      compared low and high doses of STZ. Male cynomolgus monkeys (3-6 years old) were
      given a single dose of 100 mg/kg (high dose, 4 animals) or 55 mg/kg (low dose, 20
      animals) of STZ. Blood glucose levels, intravenous glucose tolerance test
      (IVGTT), pancreatic biopsies, liver function tests (LFTs), liver biopsies, kidney
      function tests, and kidney biopsies were performed periodically. Animals from
      both groups developed diabetes within 24 h after administration of STZ. Serum C
      peptide levels in both groups decreased from 2 to 8 ng/mL before STZ to between
      0.01 and 0.6 ng/mL after STZ. Animals with the high dose of STZ developed
      transient vomiting within minutes after injection. During the first week after
      STZ injection, high-dose animals developed elevated LFTs, BUN and creatinine. In
      contrast, low-dose animals had normal liver and kidney function tests.
      Histological analysis showed that animals given the high dose of STZ developed
      marked steatosis of the liver and tubular injury in the kidneys, whereas animals
      given the low dose of STZ had normal-looking liver and kidney histology. The
      pancreatic islets in both groups were indistinguishable by immunoperoxidase
      staining for insulin, and showed either no insulin-positive cells or rare insulin
      positive cells. Glucagon staining was normal. Over time, low-dose diabetic
      monkeys remained persistently hyperglycemic with negligible C-peptide stimulation
      by intravenous glucose. We conclude that low-dose STZ at 55 mg/mL successfully
      induces diabetes in cynomolgus monkeys with minimal liver and kidney toxicity.

PMID- 12614281
TI  - Involvement of the mitochondrial pathway in cold storage and rewarming-associated
      apoptosis of human renal proximal tubular cells.
AB  - The cellular and molecular mechanisms of cold storage-ATN are not well
      characterized. In our earlier studies, cold storage caused necrosis of human
      proximal tubular epithelial (RPTE) cells, whereas apoptosis was prominent during
      rewarming. An intriguing finding was the pronounced swelling of the mitochondria
      in the cold, which promoted us to further characterize its role in rewarming
      associated apoptosis. Human proximal tubular epithelial cells were cold stored in
      University of Wisconsin (UW) solution for 48 h followed by 24 h of rewarming in
      regular cell culture medium. During the cold storage, there was no significant
      change in the Bcl-2 to Bax protein ratio, mitochondrial location of cytochrome C
      or caspse-3 activity. However, during rewarming, the Bcl-2 to Bax ratio
      increased, cytochrome C was translocated to cytosol, and caspase-3 was activated:
      events and timing were consistent with the occurrence of apoptosis during
      rewarming. In a time-course experiment, mitochondrial swelling was discernable by
      electron microscopy as early as at 2 h. Cold storage of isolated-mitochondria for
      2 h was attended by an increase in the opening of the permeability transition
      pores (PTP), suggesting PTP opening as an early mechanism for mitochondrial
      swelling. Addition of antioxidants (deferoxamine or 2-methyaminochroman) to the
      storage solution suppressed mitochondrial pore opening and swelling, Bcl-2 to Bax
      ratio increase, cytochrome C translocation, caspase-3 activation as well as
      rewarming-induced apoptosis. Our data demonstrate for the first time that
      apoptosis following cold storage and rewarming of human renal tubular cells is
      accompanied by specific mitochondrial events, and that these events and apoptosis
      can be suppressed by adding antioxidants to the cold storage solution.

PMID- 12614282
TI  - Survival and metabolic function of syngeneic rat islet grafts transplanted in the
      omental pouch.
AB  - Many sites have been tested in an effort to identify the most ideal site to
      support islet function and viability. The aim of this study was to evaluate an
      omental pouch site for islet transplantation and compare it with the renal
      subcapsular space. All streptozotocine-induced diabetic rats receiving 2000
      syngeneic islets in the omental pouch (n = 13) or under the kidney capsule (n =
      10) returned to normoglycemia. At 7 days post-transplant and throughout the
      follow-up period, the mean blood glucose value in both groups was < 9.0 mM. At 4
      and 8 weeks post-transplant, both groups displayed normal and similar glucose
      tolerance curves. Gain in the recipient's body weight after transplantation was
      similar between the two groups. At the end of follow up prompt hyperglycemia was
      observed in all rats after removal of the islet graft. No significant differences
      were found in the insulin contents of the harvested grafts, irrespective of the
      transplantation site. Histological examination of the grafts showed numerous well
      granulated insulin-containing cells in both sites. The results indicate that the
      omental pouch is a viable site which offers a safe, convenient and efficacious
      alternative to the renal subcapsular space to transplant islets in rodents.

PMID- 12614283
TI  - Human ABO blood group is important in survival and function of porcine working
      hearts.
AB  - Pig organs express alphaGal antigen and thus are hyperacutely rejected if
      perfused by human blood. Human B/A antigens are similar to pig alphaGal antigen,
      suggesting that the corresponding antibodies may cross-react. Our purpose was to
      determine if there is a human ABO blood-group difference in porcine-human
      xenotransplantation. Plasma from six A, five B, seven AB, and six O individuals
      pooled by blood group were tested in an ex-vivo porcine working heart model.
      Blood-group A plasma-perfused hearts survived 20 +/- 14 min (n = 5), B 241 +/- 9
      min (n = 3), AB 151 +/- 37 min (n = 5), and O 9 +/- 1 min (n = 8). A and O were
      different (p < 0.001) from B and AB. Function was significantly better in group
      B. Edema accumulation and creatine kinase change was highest in A and O. All
      groups had comparable levels of anti-alphaGal antibody, as well as comparable
      perfusion and operative conditions. Multivariate linear regression analysis
      showed the anti-B antibody levels to be predictive of survival (p < 0.001). At
      higher plasma concentrations, hearts perfused with B plasma survived longer (p =
      0.01) than AB (218 +/- 45 min, n = 4 vs. 6 +/- 0 min, n = 3). These results
      suggest a human ABO blood-group difference in porcine-to-human
      xenotransplantation, which may be mediated by the anti-A and anti-B antibodies.

PMID- 12614284
TI  - Blockade of macrophage colony-stimulating factor reduces macrophage proliferation
      and accumulation in renal allograft rejection.
AB  - Macrophage accumulation within an acutely rejecting allograft occurs by
      recruitment and local proliferation. To determine the importance of M-CSF in
      driving macrophage proliferation during acute rejection, we blocked the M-CSF
      receptor, c-fms, in a mouse model of acute renal allograft rejection. C57BL/6
      mouse kidneys (allografts, n = 20) or BALB/c kidneys (isografts, n = 5) were
      transplanted into BALB/c mice. Anti-c-fms antibody (AFS98) or control Ig (50
      mg/kg/day, i.p.) was given daily to allografts from days 0-5. All mice were
      killed day 6 postoperatively. Expression of the M-CSF receptor, c-fms, was
      restricted to infiltrating CD68+ macrophages. Blockade of c-fms reduced
      proliferating (CD68+/BrdU+) macrophages by 82% (1.1 v 6.2%, p < 0.001),
      interstitial CD68+ macrophage accumulation by 53% (595 v 1270/mm2, p < 0.001),
      and glomerular CD68+ macrophage accumulation by 71% (0.73 V 2.48 CD68+ cells per
      glomerulus, p < 0.001). Parameters of T-cell involvement (intragraft CD4+, CD8+
      and CD25+ lymphocyte numbers) were not affected. The severity of
      tubulointerstitial rejection was reduced in the treatment group as shown by
      decreased tubulitis and tubular cell proliferation. Macrophage proliferation
      during acute allograft rejection is dependent on the interaction of M-CSF with
      its receptor c-fms. This pathway plays a significant and specific role in the
      accumulation of macrophages within a rejecting renal allograft.

PMID- 12614285
TI  - Outcomes of renal transplantation following bone marrow transplantation.
AB  - This single center retrospective study was undertaken to determine the outcome of
      kidney transplantation (KT) after bone marrow transplantation (BMT) and also to
      determine the need for immunosuppressive therapy after KT when the BMT marrow
      donor is the KT donor. Kidney transplantation was performed in 10 patients with
      BMT nephropathy (BMTN). In six patients, the KT donor was the BMT donor; these
      individuals were given no long-term immunosuppression. Four other patients
      received KT from donors who were not the marrow donor (two living donors, two
      cadaveric donors). After median follow up of 34 months, no patient had an episode
      of acute rejection. All graft losses (n = 4) resulted from patient death. Three
      were because of infectious processes, including two infectious deaths in patients
      not on immunosuppression. Median estimated actuarial patient and graft survival
      (Kaplan-Meier) was 105 months. We conclude that patients with BMTN who receive KT
      from their marrow donor do not require immunosuppression. Whether
      immunosuppressive therapy is given or not, outcome appears to be determined
      largely by BMT-related immune dysfunction.

PMID- 12614286
TI  - Multicenter randomized prospective trial of steroid withdrawal in renal
      transplant recipients receiving basiliximab, cyclosporine microemulsion and
      mycophenolate mofetil.
AB  - Corticosteroids withdrawal from immunosuppressive regimens has thus far been
      associated with increased risk of acute rejection episodes. In this study,
      basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a
      maintenance regimen consisting of cyclosporine microemulsion and mycophenolate
      mofetil was studied for its effectiveness in allowing early corticosteroid
      withdrawal in de novo renal allograft recipients. Primary renal transplant
      recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate
      mofetil, were randomized to either corticosteroid withdrawal at day four post
      transplantation (n = 40) or standard steroid therapy (n = 43). The primary
      endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized
      subjects who underwent transplantation and received at least one dose of
      basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy
      proven acute rejection at 12 months was not significantly different between the
      steroid withdrawal group (20%) and the standard treatment group (16%). Patient
      and graft survival was 100% in the steroid withdrawal group while one death in a
      patient with a functioning graft occurred in the standard steroid group. Seventy
      two percent of the steroid withdrawal group remained off steroids at 6 months
      post-transplant. Allograft function and incidence of adverse events and
      infections were similar between the two groups. Rapid and early corticosteroid
      withdrawal among renal transplant recipients receiving basiliximab induction and
      daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not
      associated with an increased risk of acute rejection.

PMID- 12614287
TI  - Non-resective ablation and liver transplantation in patients with cirrhosis and
      hepatocellular carcinoma (HCC): safety and efficacy.
AB  - We investigated the efficacy of nonresective ablation techniques and the tumor
      free survival of cirrhotic patients undergoing liver transplantation for
      hepatocellular carcinoma (HCC). In group 1, 11 HCC patients were treated with
      these techniques and transplanted. On the waiting list, patients were treated to
      complete ablation, judged by gadolinium-enhanced MRI and alpha-fetoprotein (AFP)
      levels. Group 1 was compared with a concurrent group of 10 liver transplant
      patients (group 2) with incidental HCC (stages T1 three patients, T2 seven
      patients). The group 1 patients received 36 procedures (4 alcohol ablations, 14
      trans -hepatic artery chemo-embolizations, 15 trans -hepatic chemo-infusions, and
      3 radio frequency ablations) for treatment of 13 liver masses. Tumor-node
      metastasis (TNM) stage was reduced in eight patients (72.7%), unchanged in two
      patients and increased in one patient before transplantation. The mean waiting
      time for transplantation was 12.9 7.6 months. Both groups had a tumor-free
      survival of 100%, at 30 12 months post transplant. On pathology, 54.5% of
      explanted livers had residual viable HCC after tumor treatment, and 36.4% (4/11)
      explants had synchronous lesions. Non-resective ablation therapy is safe and
      effective in reducing the HCC progression in cirrhotic patients awaiting liver
      transplantation. The cancer-free survival rate in this treatment group is equal
      to that for incidental T1-T2 HCCs.

PMID- 12614288
TI  - Worth continuing doing ex situ liver graft splitting? A single-center analysis.
AB  - Grafts for split liver transplantation can be prepared in situ during the
      retrieval operation, or ex situ on the back table. The in situ technique has
      theoretical advantages because it minimizes the cold ischemic time and allows
      excellent hemostasis at the cut surface. However, in situ liver division prolongs
      the retrieval procedure, may precipitate hemodynamic instability in the donor,
      and may cause logistical difficulties for some centers. This report is a single
      center analysis comparing results of ex situ liver division (group I: 1992-97;
      and group II: 1998-2001) before and after a new protocol for liver graft division
      was introduced in our center. Eighty-nine split liver transplants (SLT) were
      reviewed retrospectively. Vascular complications were less common in group II
      (3.3% vs. 20%; p = 0.04), and 1-year graft survival increased from 59% to 78% (p
      = 0.03). Since 1998, 1-year graft survival of SLT has been similar to that of
      conventional liver graft transplantation in our center (78% and 74%,
      respectively). In conclusion, good results can be achieved from splitting livers
      ex situ and this procedure should be considered when the in situ technique is not
      feasible.

PMID- 12614289
TI  - Thrombotic micro-angiopathy with sirolimus-based immunosuppression: potentiation
      of calcineurin-inhibitor-induced endothelial damage?
AB  - Thrombotic microangiopathy is a rare but important finding in the context of
      organ transplantation. Acute renal insufficiency in the setting of hemolysis and
      thrombocytopenia, a triad that constitutes 'hemolytic uremic syndrome', can be
      associated with, or triggered by, conditions such as verocytotoxin-producing
      Escherichia coli, viral infections, malignant hypertension, scleroderma,
      allograft rejection, lupus erythematosus, pregnancy, and medications including
      mitomycin C, calcineurin inhibitors, and oral contraceptives. After renal
      transplantation, it can occur, as either a de novo episode, or recurrent disease.
      Calcineurin inhibitors have long been associated with post-transplantation
      thrombotic microangiopathy. Sirolimus has been used as a primary
      immunosuppressant in patients transplanted with a history of earlier hemolytic
      uremic syndrome, and also as rescue therapy in patients with calcineurin
      inhibitor-associated thrombotic microangiopathy. We describe four cases where
      there was significant thrombotic microangiopathy in the context of
      contemporaneous or contiguous calcineurin inhibitor and sirolimus usage. As the
      intrarenal cyclosporin concentration is thought to be significantly elevated when
      cyclosporin and sirolimus are used together, this may explain these findings, and
      mandates caution in their co-administration.

PMID- 12614291
TI  - Liver transplantation in children with metabolic disorders in the United States.
AB  - We studied pediatric liver transplantation for metabolic disease in a large
      national cohort to determine whether smaller studies suggesting a survival
      advantage for these recipients could be corroborated. We also hoped to determine
      whether higher survival rates in recipients with metabolic disease are associated
      with lack of structural liver disease, and to evaluate these recipients' risk
      factors for mortality. Data from the Scientific Registry of Transplant Recipients
      were used to analyze nationwide results (1990-99) of pediatric liver
      transplantation for patients with biliary atresia and metabolic disease. Adjusted
      patient survival rates for children with metabolic disease at 1 and 5 years were
      94% and 92%, respectively, - significantly higher than for recipients with
      biliary atresia (90% and 86%) (p = 0.008). Cox regression models identified
      recipient black race [relative risk (RR) = 5.1] and simultaneous transplantation
      of other organs (RR = 3.2) as significant risk factors for mortality in the
      metabolic group. Adjusted survival rates for metabolic patients with structural
      and nonstructural liver diseases were similar to each other at both 1 and 5
      years. Children with metabolic disease had significantly higher adjusted short-
      and long-term post-transplant survival rates than those with biliary atresia.
      Structural disease was not a risk factor for worse outcomes.

PMID- 12614290
TI  - Discordance between ALT values and fibrosis in liver transplant recipients
      treated with ribavirin for recurrent hepatitis C.
AB  - Hepatitis C virus (HCV) recurrence is a serious problem after orthotopic liver
      transplantation (OLT). The role of ribavirin as a single agent to treat recurrent
      HCV is controversial. Our aim was to evaluate the correlation between alanine
      aminotransferase (ALT) levels and histological findings in OLT recipients treated
      with ribavirin monotherapy for recurrent HCV. The mean [+/- standard error (SE)]
      age of 11 patients was 50.1 (SE +/- 8.6) years. The estimated mean dose and
      duration of ribavirin treatment (+/- SE) was 661.5 (+/- 52.5) mg and 20.4 (+/-
      1.7) months, respectively. Five patients required either dose reduction or
      erythropoietin. We found a significant decrease of mean (+/- SE) ALT value from
      246 +/- 44.8 U/L to 109.4 +/- 49.1 U/L (p = 0.002) in patients treated with
      ribavirin. However, there was also significant worsening of interface activity (p
      = 0.03) and fibrosis (p = 0.02). No significant association was found between ALT
      values and (i) stage of hepatic fibrosis, (ii) interface activity, (iii) lobular
      activity and (iv) HCV RNA values. Our results suggest that HCV disease can
      progress despite a significant decrease in ALT values. ALT values are inadequate
      markers of the ribavirin monotherapy and can lead to erroneous conclusions of
      efficacy.

PMID- 12614292
TI  - The relationship between donor age and cadaveric renal allograft survival is
      modified by the recipient's blood pressure.
AB  - Increasing donor age correlates with reduced renal allograft survival. In this
      study we analyzed variables that may modify this relationship. The study included
      1285 cadaveric kidney allograft recipients followed for 7.2 + 4.5 years. By Cox,
      increasing donor age beyond 30 years was associated with significant increases in
      the hazard ratio for graft loss [age 31-46, hazard ratio (HR) = 1.4, p = 0.02; 46
      60, HR = 1.55, p = 0.008; > 60, HR = 1.68, p = 0.03]. Increasing donor age was
      significantly associated with: older and heavier recipients; higher creatinine
      and blood pressure (BP) 6 months post-transplant; and lower total cyclosporine
      dose during the first year. Of interest, the 6-month serum creatinine and the BP
      level modified significantly the relationship between age and survival. Thus,
      increasing donor age was significantly related to reduced graft survival only in
      patients with a 6-month creatinine < 2 mg/dL. Furthermore, donor age related
      significantly to graft survival only among patients with higher BP levels 6 month
      post transplant. It is concluded that increasing donor age is associated with
      reduced cadaveric graft survival, but that relationship is significantly modified
      by graft function and BP. These data suggest that poorly functioning kidneys have
      reduced survival irrespective of age. Furthermore, elevated BP levels may have a
      particularly negative effect on the survival of older grafts.

PMID- 12614293
TI  - Incidence of renal and liver rejection and patient survival rate following
      combined liver and kidney transplantation.
AB  - Multiple organ transplantations are used to treat chronic multiple organ failure.
      However, long-term mortality and graft tolerance remain to be evaluated. We
      carried out a retrospective and comparative analysis of 45 patients who underwent
      a combined liver and kidney (LK) transplantation (LKT) from the same donor. They
      were compared to 86 matched patients who underwent kidney (K) transplantation
      (KT). All patients had an organic renal failure associated with cirrhosis (n =
      35) or with inherited disease (n = 10). Nineteen (42.9%) had been transplanted
      previously. The patients' survival rate was 85% at 1 year and 82% at 3 years.
      Seven patients died within the first 3 months, due to severe polymicrobial
      infection. Two patients in the LK population (4.2%) developed acute rejection of
      the kidney graft compared to 24 of the 86 matched renal transplanted patients
      (32.6%). In parallel, acute liver rejection was observed in 14 cases (31.1%) in
      the LK population. The occurrence of acute rejection was not associated with
      panel-reactive lymphocytotoxic antibodies (n = 16), nor with positive cross
      matches (n = 3). Four of the 45 patients (8.8%) subsequently developed chronic
      renal allograft rejection, and 16 cases of chronic hepatic dysfunction were noted
      (42.2%). In conclusion, the overall survival rate following combined liver kidney
      transplantation is acceptable, and LKT can be proposed to patients with kidney
      failure associated with liver dysfunction, primary oxaluria or amyloid
      neuropathy. The main cause of mortality in this population was severe infectious
      complications. The frequency of acute kidney rejection was lower than in single
      transplantation.

PMID- 12614294
TI  - Pretransplant interferon prevents hepatitis C virus-associated glomerulonephritis
      in renal allografts by HCV-RNA clearance.
AB  - The purpose of this study was to examine the effect of pretransplant interferon
      administration on the occurrence of post-transplant de novo glomerulonephritis in
      hepatitis C virus (HCV)-positive renal allografts. From December 1992 to December
      2000, 78 HCV-positive patients received a renal allograft in our unit. Fifteen
      out of 78 received pretransplant interferon for 1 year. Hepatitis C virus was
      investigated by serology and qualitative polymerase chain reaction (PCR).
      Hepatitis C virus-related de novo glomerulonephritis (membranoproliferative or
      membranous) was suggested by proteinuria (>1.5 g/24 h) and/or microhematuria and
      always diagnosed by renal biopsy. Of 15 HCV-positive recipients who received
      pretransplant interferon, 10 (67%) became HCV-RNA negative at the time of
      transplantation and only one out of the 15 (6.7%) developed de novo
      glomerulonephritis (this patient was HCV-RNA positive at transplantation). Among
      non-interferon-treated allograft recipients, 28.7% had negative HCV-RNA and 12
      out of 63 (19%) developed de novo glomerulonephritis (9, membranoproliferative; 3
      membranous), all 12 having positive HCV-RNA at transplantation (p < 0.0001). In
      conclusion, pretransplant interferon may reduce the occurrence of post-transplant
      HCV-related de novo glomerulonephritis. Our results suggest that the indication
      for pretransplant interferon should be extended to treat all HCV-RNA positive
      candidates for renal transplantation.

PMID- 12614295
TI  - BK nephropathy: what is the role of antiviral therapy?

PMID- 12614296
TI  - Treatment of refractory BK virus-associated nephropathy with cidofovir.
AB  - BK virus-associated nephropathy (BKVN) has become recognized as an important
      cause of allograft dysfunction in renal transplant recipients and despite
      reduction in immunosuppression, 30-40% of recipients ultimately progress to
      allograft loss. Cidofovir is an antiviral agent that demonstrates in vitro
      activity against murine polyomavirus and has been proposed for treatment of BKVN
      in renal allograft recipients. We describe the clinical course, renal function,
      serial renal histology and urine and blood viral load measurements in two
      consecutive patients with refractory BKVN who were treated with low-dose
      cidofovir (0.25 mg/kg IV). In each case, renal dysfunction and BK viral load
      progressed despite reduced immunosuppression, and persistent BK virus infection
      was documented in serial renal allograft biopsy specimens. Administration of low
      dose cidofovir was associated with clearance of BK virus DNA from blood and
      allograft, and stabilization of renal function in both patients, without
      significant toxicity. These preliminary data suggest that low-dose cidofovir may
      be tolerated, even among renal transplant recipients with significant renal
      dysfunction due to BKVN. Prospective, controlled trials are warranted to further
      define the optimal dose, toxicity and potential role of cidofovir in renal
      transplant recipients with BK virus nephropathy.

PMID- 12614297
TI  - Time-to-event modeling of competing risks with intervening states in
      transplantation.
AB  - The criteria for the selection of who among the persons on the waiting is to
      receive an organ that has become available and who is to be placed on the list to
      begin with are the most contentious issues in organ transplantation. The
      decisions of whom to list and whom to transplant should take into account the net
      benefit to the individual patient and to the affected group as a whole. We
      present a method to compute the survival benefit by means of fully parametric
      modeling of the competing events (transplantation, death while awaiting the
      transplant, removal for other reasons), taking into account the transplant as an
      intervening state on the path to death post-transplant, and apply it to decisions
      whether to list or not list and whether to transplant or to leave on the waiting
      list or to remove from the list. The data were obtained from the Organ
      Procurement and Transplantation Network. They describe the outcomes of listings
      in January, 1996 through June, 1999, with a follow up of at least 1 year possible
      for all cases. The models produce estimates of event probabilities that accord
      well with the observed probabilities and predictions of the survival benefit due
      to transplantation that range from small negative values to increases in survival
      probability of 20-40% points in liver and heart transplantation, with the larger
      benefits generally seen in the more severely ill transplant candidates. These
      estimates are stable under variations of case mix, as ascertained by bootstrap
      analysis. The survival benefit of alternative actions can be calculated for the
      complex circumstances encountered clinically - competing sequential events whose
      probability evolves over time. The range and stability of the estimates are
      sufficient to permit the use of this measure to rank candidates for listing and
      for transplantation.

PMID- 12614298
TI  - Review article: esomeprazole--the first proton pump inhibitor to be developed as
      an isomer.
AB  - Omeprazole is a racemate, from which the R- and S-isomers can be isolated. At the
      cellular level, both of these isomers convert to the same inhibitor of the H+,K+
      ATPase and produce the same reduction in gastric acid secretion. However, the S
      isomer, esomeprazole, is metabolized more slowly and reproducibly than the R
      isomer and omeprazole, and therefore produces higher plasma concentrations for
      longer and, as a result, inhibits gastric acid production more effectively and
      for longer. Thus, esomeprazole has the pharmacological properties of a more
      effective form of treatment for disorders related to gastric acid secretion.
      Clinical studies have confirmed the anticipated increased efficacy, but have
      shown no evidence of impaired tolerability or increased toxicity when compared
      with omeprazole.

PMID- 12614299
TI  - Review article: pharmacology of esomeprazole and comparisons with omeprazole.
AB  - Plasma concentration measurements have confirmed that the advantageous hepatic
      metabolism of esomeprazole results in a greater delivery of acid suppressant to
      the systemic circulation, compared with an equal dose of omeprazole. Also, this
      superior delivery has been shown to cause a more consistent and greater
      suppression of pentagastrin-stimulated gastric acid secretion by esomeprazole, 20
      mg, compared with omeprazole, 20 mg. The superior acid-suppressant properties of
      esomeprazole have been revealed by extensive 24-h intragastric pH-monitoring
      studies. Compared with omeprazole, 20 mg, esomeprazole, 20 mg and 40 mg, has been
      shown to give superior outcomes on three key measures of antisecretory effect:
      (1) consistency amongst individuals; (2) duration over the 24-h cycle; (3)
      overall impact on pH. As there is a substantial increment of acid control from
      esomeprazole, 20 mg, to esomeprazole, 40 mg, this latter dose is the most
      appropriate to investigate for modern initial therapy of reflux disease, with the
      aim of achieving the highest possible response rates in the shortest possible
      time.

PMID- 12614300
TI  - Review article: gastric acidity--comparison of esomeprazole with other proton
      pump inhibitors.
AB  - Gastric acid suppression is the most effective medical therapy to control acidic
      gastro-oesophageal reflux: individuals in whom therapy fails usually have
      inadequate acid suppression. Twenty-four-hour intragastric pH-metry measures the
      percentage of time that gastric pH is above 4 or 3, the critical thresholds for
      tissue damage and symptom generation in the distal oesophagus. Effective medical
      therapy must control gastric acidity throughout the daytime, including the
      postprandial period. It is therefore useful to report the percentage of patients
      in whom gastric acidity is controlled above pH 4 for at least 16 out of 24 h.
      Esomeprazole was compared with standard-dose proton pump inhibitors in healthy
      volunteers and patients with gastro-oesophageal reflux disease. Esomeprazole, 40
      mg daily, was significantly more effective at controlling gastric acidity above
      pH 4 for more than 16 h than lansoprazole, 30 mg daily (38% of individuals vs.
      5%, respectively). Esomeprazole, 40 mg daily, also suppressed gastric acidity
      more effectively and in more individuals than pantoprazole, 40 mg daily, and
      rabeprazole, 20 mg daily. Esomeprazole, 20 mg daily, was significantly more
      effective at controlling gastric acidity than lansoprazole, 15 mg daily. The
      improved acid control with esomeprazole compared with other proton pump
      inhibitors is likely to result in superior healing rates and improved symptom
      relief, with fewer therapy-resistant patients.

PMID- 12614302
TI  - Review article: initial therapy of reflux disease with esomeprazole.
AB  - Large clinical trials in patients with reflux oesophagitis have shown
      esomeprazole, 40 mg once daily, to be convincingly superior in the healing of
      oesophagitis when compared with both omeprazole, 20 mg once daily, and
      lansoprazole, 30 mg once daily. The greatest advantage for esomeprazole is with
      healing of the more severe grades of oesophagitis. Esomeprazole, 40 mg once
      daily, has also been shown to be significantly superior in the treatment of
      heartburn. Studies in endoscopy-negative patients, or in both oesophagitis and
      endoscopy-negative patients, have demonstrated good efficacy for esomeprazole,
      with high levels of symptom control achieved in the first 7 days of therapy.

PMID- 12614303
TI  - Review article: esomeprazole, 40 mg once daily, compared with lansoprazole, 30 mg
      once daily, in healing and symptom resolution of erosive oesophagitis.
AB  - BACKGROUND: Proton pump inhibitors are the most effective agents for treating
      erosive oesophagitis, but their relative efficacies have not been well
      characterized in large clinical trials. AIM: To compare standard doses of
      esomeprazole and lansoprazole in healing oesophagitis and resolving accompanying
      symptoms. METHODS: This was a US, multicentre, randomized, double-blind trial and
      included 5241 adult patients (intention-to-treat) with endoscopically documented
      erosive oesophagitis. Patients were randomized to esomeprazole, 40 mg once daily,
      or lansoprazole, 30 mg once daily, for up to 8 weeks. The primary end-point,
      endoscopic healing at Week 8, was assessed using life-table analysis and a log
      rank test. Secondary endpoints included healing at Week 4, healing according to
      baseline severity of oesophagitis, control of heartburn and side-effects.
      RESULTS: Healing rates were 92.6% with esomeprazole and 88.8% with lansoprazole
      at Week 8 (P = 0.0001, log-rank test). A significant difference was also observed
      at Week 4. Sustained resolution of heartburn occurred faster and in a larger
      proportion of patients treated with esomeprazole. Both agents were well
      tolerated. CONCLUSIONS: Esomeprazole produced significantly higher oesophagitis
      healing rates than lansoprazole over all grades of oesophagitis. Esomeprazole
      also provided better control of heartburn and was associated with a greater
      proportion of patients with sustained resolution of symptoms.

PMID- 12614304
TI  - Esomeprazole 20 mg and lansoprazole 15 mg in maintaining healed reflux
      oesophagitis: Metropole study results.
AB  - INTRODUCTION: Esomeprazole, the first proton pump inhibitor to be developed as an
      optical isomer, has demonstrated more effective healing vs. omeprazole and
      lansoprazole in patients with reflux oesophagitis (RO). However, RO recurs in a
      high proportion (approximately 80%) of these patients within 12 months of initial
      therapy, highlighting the importance of maintenance treatment. Previous studies
      have shown esomeprazole to be effective as maintenance therapy in healed RO
      patients. AIM: This study was conducted to compare esomeprazole 20 mg once daily
      (o.d.) with lansoprazole 15 mg o.d. for the prevention of recurrence of RO.
      METHODS: 1391 patients with endoscopically verified RO (LA classification) were
      enrolled in this randomized, double-blind, parallel-group, multicentre trial.
      During the initial healing phase of the study, all patients received 4-8 weeks'
      open treatment with esomeprazole 40 mg: 1236 healed (identified by endoscopy at 4
      and 8 weeks) and symptom-free (i.e. no heartburn or acid regurgitation) patients
      were randomized to 6 months' maintenance treatment with esomeprazole 20 mg o.d.
      or lansoprazole 15 mg o.d. Time to relapse (relapse of RO and/or discontinuation
      due to symptom recurrence) was analysed using a log-rank test. RESULTS:
      Esomeprazole maintained a significantly higher proportion of patients in
      remission than lansoprazole over the 6-month course of treatment (P < 0.0001,
      intention-to-treat analysis). After 6 months' treatment, 83% of esomeprazole
      recipients were in remission compared with 74% of lansoprazole recipients (life
      table estimates). Esomeprazole gave a longer time to relapse than lansoprazole
      irrespective of baseline LA Grade, significantly so for baseline LA Grades B, C
      and D (P < 0.05 for each comparison). Significantly more patients were free from
      heartburn in the esomeprazole group compared with the lansoprazole group at 1, 3
      and 6 months (P < 0.05). Significant differences at 6 months between esomeprazole
      20 mg o.d. and lansoprazole 15 mg o.d. were also observed for control of
      epigastric pain and acid regurgitation (P < 0.05 and P < 0.001, respectively).
      Both treatment regimens were well tolerated. CONCLUSION: Esomeprazole 20 mg o.d.
      is a more effective maintenance treatment than lansoprazole 15 mg o.d. for
      symptom-free patients with healed RO.

PMID- 12614306
TI  - Reflux disease management strategy: initial therapy.

PMID- 12614307
TI  - Overview: initial and long-term management of gastro-oesophageal reflux disease.
AB  - Initial management of gastro-oesophageal reflux disease aims to confirm a symptom
      based diagnosis, to relieve symptoms, to reassure the patient as to the treatable
      nature of reflux disease, and to initiate risk management and healing of
      oesophagitis. The aims of long-term management include adequate control of
      symptoms, prevention of complications, and improvement of quality of life.
      Management options in terms of use of proton pump inhibitors are either daily
      therapy (maintenance), intermittent courses of therapy (for example, 4 weeks,
      then cease and observe), or on-demand therapy. This overview discusses the
      advantages and disadvantages of these different strategies for the management of
      reflux disease.

PMID- 12614309
TI  - Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in
      newly diagnosed epilepsy.
AB  - OBJECTIVES: To compare topiramate (TPM) with investigator's choice of
      carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with
      newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy
      diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or
      VPA (1250 mg/day) as preferred therapy based on the patient's clinical
      presentation. Based on investigators' treatment choice, patients (n=613) were
      assigned to the CBZ or VPA treatment branch. Within each branch, patients were
      randomized to double-blind treatment with the traditional antiepileptic drugs
      (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind
      treatment until exiting the study or until 6 months after last patient
      randomized. RESULTS: No statistically significant differences between fixed doses
      of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to
      first seizure, and the proportion of patients seizure-free during the last 6
      months of treatment. TPM 100 mg/day was associated with the fewest
      discontinuations due to adverse events. CONCLUSION: In patients with newly
      diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as
      effective as therapeutic doses of CBZ and VPA.

PMID- 12614310
TI  - Muscular cramps: proposals for a new classification.
AB  - Muscle cramps are involuntary, painful, sudden contractions of the skeletal
      muscles. They are present in normal subjects under certain conditions (during a
      strong voluntary contraction, sleep, sports, pregnancy) and in several
      pathologies such as myopathies, neuropathies, motoneuron diseases, metabolic
      disorders, hydroelectrolyte imbalances or endocrine pathologies. There has been
      considerable uncertainty in the literature regarding the classification and
      nomenclature of muscle cramps, both because the term "cramp" is used to indicate
      a variety of clinical features of muscles, leading to its use as an imprecise
      "umbrella" term that includes stiffness, contractures and local pain, and because
      the spectrum of the diseases in which it appears is wide. The purpose of the
      present study is to propose a simple classification to provide a framework to
      better recognize the full spectrum of phenomenology of muscle cramps.

PMID- 12614311
TI  - Emergence and progress of white matter lesion in brain check-up.
AB  - White matter lesion (WML) is thought to emerge and progress with increasing age
      but has not yet been well investigated. In this study of WML, risk factors and
      prevalence added to emergence rate (%/person year) and progress speed [increase
      of leukoencephalopathy score (LES)/person year] were investigated in 1674 brain
      check-up subjects from August 1993 to August 2001. Significant (P < 0.01) risk
      factors were aging and hypertension. Prevalence rate (%) was 0 in 20-29 years,
      1.4 in 30-39 years, 4.2 in 40-49 years, 20.9 in 50-59 years, 42.6 in 60-69 years,
      and 73.9 in 70-years. Emergence rate was 0 in 20-29 years, 0.7 in 30-39 years,
      1.5 in 40-49 years, 3.4 in 50-59 years, 6.0 in 60-69 years, and 20 in 70-years.
      And progress speed was 0.12 in 40-49 years, 0.15 in 50-59 years, 0.21 in 60-69
      years, and 0.21 in 70-years. WML begins to emerge early in middle age and both
      prevalence and severity increase with age.

PMID- 12614312
TI  - Personality traits in multiple sclerosis (MS) patients with and without fatigue
      experience.
AB  - OBJECTIVES: To determine the impact of personality characteristics on feelings of
      fatigue in multiple sclerosis (MS) patients and to compare the results with the
      impact of bodily impairment. PATIENTS AND METHODS: Eighty patients with definite
      MS (mean age 38.5 +/- 9.0 years, 62 females) were surveyed using questionnaires
      assessing fatigue experience and personality traits (German Freiburg Personality
      Inventory-Revised; FPI-R) and by clinical examination assessing the Expanded
      Disability Status Scale. RESULTS: Increased levels of "neuroticism", and
      "excitability" and decreased levels of "extraversion" were found to relate
      independent of fatigue scores (0.21 < beta < 0.52; 0.05 < P < 0.0001). The impact
      of these personality traits on fatigue (partial R2 ranging up to 0.32; 0.02 < P <
      0.0001) was much higher than the impact of physical impairment (partial R2
      ranging up to 0.04; not significant). CONCLUSION: Our results support a
      psychological model of fatigue in MS. FPI-R-items over-weighted somatic sources
      of the fatigue syndrome in MS and may specifically relate to fatigue experience
      in chronical disorders.

PMID- 12614313
TI  - Piribedil and bromocriptine in Parkinson's disease: a single-blind crossover
      study.
AB  - INTRODUCTION: Clinicians switch from one dopamine agonist to another for various
      reasons. However, each change may inadvertently result in certain potential risks
      such as decreased medication efficacy or new side-effects. OBJECTIVE: We
      evaluated the tolerability of a switch of bromocriptine to piribedil using two
      conversion ratios as a primary outcome measure, with motor function as a
      secondary outcome measure, in patients with mild to moderate Parkinson's disease
      (PD). METHODS: Twenty consecutive patients with mild to moderate PD (Hoehn and
      Yahr, stage II-III) on treatment with stable doses of bromocriptine and levodopa
      were randomized to two groups of 10 patients each, to receive piribedil based on
      1:5 or 1:10 conversion ratios. Blinded evaluations were performed: 1) United
      Parkinson's Diseased Rating Scale (UPDRS) scores both in 'on' and 'off', 2) Open
      ended interviews for adverse events, 3) Epworth Sleepiness Scale, 4) Purdue
      Pegboard assessment during 'on' and 'off', 5) Hand-arm movement test during 'on'
      and 'off', and 6) Walking test during 'on' and 'off'. RESULTS: Major adverse
      events included 'sleep attacks' in one patient and minor side-effects included
      giddiness, nausea, hallucinations, sleepiness and lethargy. However, these were
      mild and 19 (95%) of the 20 patients completed the study. There was a significant
      improvement in both the UPDRS 'off' total and motor scores at 1 month compared
      with baseline for the group on 1:10 ratio. The walking times during the 'off'
      state at 1 and 2 months were significantly better compared with baseline in the
      1:5 group. There were otherwise no significant differences in the rating tests
      during both 'off' and 'on' states before and after the bromocriptine switch.
      CONCLUSIONS: We demonstrated that patients with mild to moderate PD who were on
      relatively low doses of bromocriptine can be safely switched to piribedil based
      on a conversion ratio of either 1:5 or 1:10. However, the higher conversion ratio
      has to be carried out with caution in patients with daytime somnolence.

PMID- 12614314
TI  - Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study.
AB  - CONTEXT: Machado-Joseph Disease (MJD/SCA3) is an autosomal dominant
      spinocerebellar degeneration that evolves to disability and death. Experimental
      data have shown that serotonin is an important cerebellar neurotransmitter and
      that impairment of the serotoninergic cerebellar system can induce cerebellar
      ataxia. OBJECTIVES: To evaluate the efficacy of fluoxetine, a serotonin reuptake
      inhibitor, in treating neurologic dysfunction in patients with MJD. PATIENTS AND
      METHODS: Thirteen MJD patients were treated with fluoxetine (20 mg/day) and were
      followed-up for 6 weeks. Outcome measures included functional capacity,
      standardized neurologic and cognitive ratings. The Montgomery-Asberg depression
      rating scale was used to control depressive symptoms. RESULTS: There was no
      significant improvement in motor abilities after 6 weeks of treatment.
      CONCLUSIONS: These results suggest that fluoxetine has no benefit in motor
      function of patients with MJD/SCA3.

PMID- 12614315
TI  - Searching for modulating effects of SCA2, SCA6 and DRPLA CAG tracts on the
      Machado-Joseph disease (SCA3) phenotype.
AB  - CONTEXT: Machado-Joseph disease (MJD/SCA3) is an autosomal dominant cerebellar
      ataxia of adult onset. The variability in age at onset and the complex and
      heterogeneous neurologic findings indicate that MJD, caused by a major gene, is
      modulated by modifier factors. OBJECTIVE: To study if the polymorphic CAG repeats
      at other loci (namely, SCA2, SCA6 and DRPLA) thus acted as modifier factors of
      this disease. DESIGN: Case-control. SETTING: Ambulatory care in a referral
      center. PATIENTS: A convenience sample of 39 unrelated, Brazilian patients with
      MJD. MAIN OUTCOME MEASURES: age of onset, anticipation, clinical subtypes and
      neurological findings. RESULTS: Fasciculations were associated with CAG repeat
      length of the long SCA2 allele (Mann-Whitney U-test, P < 0.03, after Bonferroni
      procedure). Other measures (age of onset, anticipation, clinical types and other
      neurological signs) were not associated with CAG repeat length of SCA2, SCA6 and
      DRPLA genes. CONCLUSIONS: The present results show that the CAG tract of SCA2
      gene interferes with MJD phenotype. Further studies, with patients of other
      origins and with typing of other (CAG)n loci, are necessary.

PMID- 12614316
TI  - Long-term follow-up of 44 patients with brachial monomelic amyotrophy.
AB  - OBJECTIVES: Monomelic amyotrophy of a single upper limb termed "brachial
      monomelic amyotrophy" (BMMA) is a benign lower motor neuron disorder in the
      young, with male preponderance, insidious onset of atrophy and weakness,
      electromyographic evidence of neurogenic pattern without conduction block, slow
      progression for 2-4 years followed by a stationary course. The aim of the study
      was to determine whether (i) atrophy and weakness in the affected limb progresses
      beyond 5 years; (ii) the illness spreads to the other limbs; and (iii) the
      disease progresses to amyotrophic lateral sclerosis. MATERIAL AND METHODS: Forty
      four patients who had a duration of illness of 5 years or more at the last follow
      up examination were included in the study. Assessment of symptom profile,
      neurologic deficit and disability was performed at variable intervals during the
      follow-up period. RESULTS: Progression of the disease was seen in 37 (84.1%)
      patients, up to 5 years in 35 (79.5%), 6 years in one and 8 years in another
      patient. In seven patients (15.9%) the atrophy was accidentally noticed and no
      further change in the neurologic deficit was observed thereafter. Subsequent to
      attaining a stationary course, none of the 44 subjects developed fresh symptoms
      or signs during a mean follow-up period of 9.7 years (range 2.5-23). The mean
      duration of illness at last follow-up was 12.8 years (range 5-26.5) and in 22
      (50%) subjects the disease duration was more than 10 years. Seven patients
      (15.9%) at presentation had minimal involvement of contralateral upper limb with
      gross asymmetry and later one more patient developed similar features. Thus, in
      only a small proportion (18.2%) of patients the neurologic deficit had extended
      beyond the confines of one upper limb. None of the patients developed involvement
      of cranial nerves, lower limbs or pyramidal signs. CONCLUSIONS: Progression of
      the neurologic deficit in the affected limb was seen up to 5 years in the
      majority followed by a stationary phase with no evidence of fresh neurologic
      deficit during the follow-up period. Spread to the contralateral upper limb with
      minimal neurologic deficit was seen in less than a fifth of the patients, but
      involvement of lower limbs was not observed. BMMA did not evolve to amyotrophic
      lateral sclerosis. These observations underscore the benign and self limiting
      course of BMMA.

PMID- 12614317
TI  - Evidence favoring the involvement of CC chemokine receptor (CCR) 5 in T
      lymphocyte accumulation in optic neuritis.
AB  - OBJECTIVE: To define the relationships between levels of chemokine receptor
      (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and
      control patients (CON). MATERIALS AND METHODS: Expression of CCR5 and related
      receptors CCR1 and CCR3 on CD4- and CD8-positive T-cells in peripheral blood
      mononuclear cells (PBMC) and CSF was determined by flow cytometry in 20 patients
      with ON, 16 control patients with lumbar spondylosis, 20 healthy controls (HC)
      and 16 patients with rheumatoid arthritis (RA). RESULTS: CCR5+CD4+ and CD8+ T
      cells were enriched in CSF, compared with PBMC, in both ON and CON patients (all
      P < 0.001), and the percentages of CD4+/CCR5+ (r = 0.917) and CD8+/CCR5+ (r =
      0.828) cells in PBMC and CSF were strongly and directly correlated. CCR5+ T-cells
      produce high amounts of tumor necrosis factor-alpha (TNF-alpha) and very low
      amounts of interleukin-5 (IL-5). Closely related receptors (CCR1, CCR3) were not
      altered. CONCLUSIONS: Our data suggest an involvement of CCR5 in T-cell
      accumulation in the inflamed central nervous system.

PMID- 12614318
TI  - Focal and segmental primary dystonia in north-western Germany--a clinico-genetic
      study.
AB  - OBJECTIVES: To determine the frequency of familial focal and segmental dystonias
      in a large patient cohort with primary dystonia from north-western Germany.
      MATERIALS AND METHODS: In this study, 130 patients with focal or segmental
      dystonia were examined and a family history was obtained. Whenever possible,
      affected relatives were examined (a total of 789 first-degree relatives). Data on
      disease duration, age at disease onset and age of the patients were investigated
      by Student's t-test and a segregation analysis was performed by Weinberg's
      proband method. RESULTS: Age at onset of disease was significantly later in the
      blepharospasm group. Only in the writer's cramp group were women outnumbered by
      men. A positive family history was found in 15 of the 130 index patients (11.5%).
      None of 102 index patients tested carried the GAG deletion in the DYT1 gene.
      CONCLUSIONS: In accordance with previous series our study provides evidence that
      primary focal dystonia may have a genetic etiology, most probably caused by an
      autosomal dominant trait with reduced penetrance.

PMID- 12614319
TI  - Spontaneous internal carotid artery dissection and alpha-1-antitrypsin
      deficiency.
AB  - Spontaneous cervical arterial dissection is an important cause of juvenile
      stroke. However, etiopathology and genetic background remain poorly understood.
      We report on a 45-year-old-male patient with homozygous alpha-1-antitrypsin
      (alpha-1-AT) deficiency in whom internal carotid artery dissection occurred in
      the absence of any other known risk factors. The relevance of alpha-1-AT
      deficiency for spontaneous cervical arterial dissections is discussed.

PMID- 12614320
TI  - New developments in dementia.

PMID- 12614323
TI  - Expanding the association between the APOE gene and the risk of Alzheimer's
      disease: possible roles for APOE promoter polymorphisms and alterations in APOE
      transcription.
AB  - Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the
      elderly. Predominantly this disease is sporadic in nature with only a small
      percentage of patients exhibiting a familial trait. Early-onset AD may be
      explained by single gene defects; however, most AD cases are late onset (> 65
      years) and, although there is no known definite cause for this form of the
      disease, there are several known risk factors. Of these, the epsilon4 allele of
      the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The epsilon4
      allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles
      generated by cysteine/arginine substitutions at two polymorphic sites. The
      possession of the epsilon 4 allele is recognized as the most common identifiable
      genetic risk factor for late-onset AD across most populations. Unlike the
      pathogenic mutations in the amyloid precursor or those in the presenilins, APOE
      epsilon4 alleles increase the risk for AD but do not guarantee disease, even when
      present in homozygosity. In addition to the cysteine/arginine polymorphisms at
      the epsilon2/epsilon3/epsilon4 locus, polymorphisms within the proximal promoter
      of the APOE gene may lead to increased apoE levels by altering transcription of
      the APOE gene. Here we review the genetic and biochemical evidence supporting the
      hypothesis that regulation of apoE protein levels may contribute to the risk of
      AD, distinct from the well known polymorphisms at the epsilon2/epsilon3/epsilon4
      locus.

PMID- 12614324
TI  - The Tat antagonist neomycin B hexa-arginine conjugate inhibits gp-120-induced
      death of human neuroblastoma cells.
AB  - Several patients with acquired immunodeficiency syndrome (AIDS) develop
      neurological complications, which are referred to as human immunodeficiency virus
      (HIV)-associated dementia (HAD). The HIV-1 coat glycoprotein gp-120 has been
      proposed as the major etiologic agent for neuronal loss reported postmortem in
      the brain of AIDS patients. Chemokine receptors may play a role in gp-120
      triggered neurotoxicity, both in vitro and in vivo, thus being an intriguing
      target for developing therapeutic strategies aimed to prevent or reduce neuronal
      damage occurring during HIV infection. We have previously shown that human CHP100
      neuroblastoma cells express CXCR4 and CCR5 chemokine receptors and that
      interaction between gp-120 and these receptors contributes to cytotoxicity
      elicited by the protein. Here, we examined the neuroprotective potential of
      neomycin B hexa-arginine conjugate (NeoR), a recently synthesized compound with
      anti-HIV activity. We found that gp-120-triggered death is significantly reduced
      by NeoR, and this protective effect seems related to the ability of NeoR to
      interact with CXCR4 receptors. The ability of NeoR to cross the blood-brain
      barrier, as demonstrated in mice by systemic administration of the fluorescein
      conjugate drug, makes this compound a powerful and attractive therapeutic agent.

PMID- 12614325
TI  - Pattern of levodopa-induced striatal changes is different in normal and MPTP
      lesioned mice.
AB  - While levodopa-induced neurochemical changes have been studied in animal models
      of Parkinson's disease, very little is known regarding the effects of levodopa
      administration in normal animals. The present study investigates the effects
      normal and MPTP-lesioned mice chronically treated with two different doses of
      levodopa. We assess changes in striatal dopamine (DA) receptor binding, striatal
      DA receptor mRNA levels and striatal neuropeptide precursor levels
      (preproenkephalin-A [PPE-A]; preprotachykinin [PPT]; preproenkephalin-B [PPE-B]).
      The extent of the lesion was measured by striatal DA transporter binding and
      stereological estimation of the number of tyrosine hydroxylase immunoreactive
      neurones in the substantia nigra pars compacta (SNc). In non-lesioned animals,
      chronic levodopa treatment induced an increase in PPE-A mRNA, whereas both D3R
      binding and PPE-B mRNA levels were dramatically increased in the lesioned animals
      in a dose dependent manner. The present results show that chronic levodopa
      administration may induce pathophysiological changes, even in the absence of a
      lesion of the nigro-striatal pathway, suggesting that the sensitization process
      involves predominantly the indirect striatofugal pathway in non-lesioned animals,
      whereas the direct pathway is primarily involved in lesioned animals.

PMID- 12614327
TI  - Chloroquine induces activation of nuclear factor-kappaB and subsequent expression
      of pro-inflammatory cytokines by human astroglial cells.
AB  - Chloroquine, an antimalarial lysosomotropic base, is known for its anti
      inflammatory effects and therefore used for treatment of autoimmune diseases.
      Given its anti-inflammatory effects, it has been under clinical trials to modify
      neurodegenerative processes. In this study, we examined whether chloroquine has
      an anti-inflammatory effect in the CNS by determining the in vitro effects of
      chloroquine on LPS-induced expression of cytokines by glial cells. We observed
      that (i) chloroquine augmented LPS-induced expression of pro-inflammatory
      cytokines such as lymphotoxin (LT)-beta, tumor necrosis factor (TNF)-alpha,
      interleukin (IL)-1alpha, IL-1beta and IL-6 in human astroglial cells, while the
      same treatment suppressed LPS-induced expression of cytokines in monocytic and
      microglial cells; (ii) chloroquine alone induced expression of pro-inflammatory
      cytokines in a dose- and time-dependent manner in astroglial cells; (iii) other
      lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal
      effects on cytokine expression; and (iv) chloroquine induced the activation of
      nuclear factor-kappa B in astroglial cells, which is a required component of
      chloroquine induction of cytokines. These results suggest that chloroquine may
      evoke either anti- or pro-inflammatory responses in the CNS depending on the
      cellular context.

PMID- 12614326
TI  - Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin
      transporter knockout mice.
AB  - The aim of the present studies was to determine the effects of reduced or absent
      serotonin (5-HT) transporters (5-HTTs) on 5-HT2A and 5-HT2C receptors. The
      density of 5-HT2C receptors was significantly increased in the amygdala and
      choroid plexus of 5-HTT knockout mice. On the other hand, the density of 5-HT2A
      receptors was significantly increased in the hypothalamus and septum, but reduced
      in the striatum, of 5-HTT knockout mice. However, 5-HT2A mRNA was not changed in
      any brain region measured. 5-HT2C mRNA was significantly reduced in the choroid
      plexus and lateral habenula nucleus of these mice. The function of 5-HT2A
      receptors was evaluated by hormonal responses to (+/-)-1-(2,5-dimethoxy-4
      iodophenyl)-2-aminopropane (DOI). Oxytocin, but not adrenocorticotrophic hormone
      or corticosterone, responses to DOI were significantly greater in 5-HTT knockout
      mice. In addition, Gq and G11 proteins were not significantly changed in any
      brain region measured. The present results suggest that the constitutive
      alteration in the function of 5-HTTs changes the density of 5-HT2A and 5-HT2C
      receptors in a brain region-specific manner. These changes may not be mediated by
      alterations in their gene expression or in the level of Gq/11 proteins. The
      alterations in these receptors may be related to the altered behaviors of 5-HTT
      knockout mice.

PMID- 12614328
TI  - An age-related increase in resistance to DNA damage-induced apoptotic cell death
      is associated with development of DNA repair mechanisms.
AB  - Neurons in the developing brain die via apoptosis after DNA damage, while neurons
      in the adult brain are generally resistant to these insults. The basis for this
      resistance is a matter of conjecture. We report here that cerebellar granule
      neurons (CGNs) in culture lose their competence to die in response to DNA damage
      as a function of time in culture. CGNs at either 1 day in vitro (DIV) or 7 DIV
      were treated with the DNA damaging agents camptothecin, UV or gamma-irradiation
      and neuronal survival measured. The younger neurons were effectively killed by
      these agents, while the older neurons displayed a significant resistance to
      killing. Neuronal survival did not change with time in culture when cells were
      treated with C2-ceramide or staurosporine, agents which do not target DNA. The
      resistance to UV irradiation developed over time in culture and was not due to
      changes in mitotic rate. Increases in DNA strand breakage, up-regulation of the
      levels of both p53 and its phosphorylated form and nuclear translocation of p53
      were equivalent in both older and younger neurons, indicating a comparable p53
      stress response. In addition, we show that treatment of older neurons with
      pharmacological inhibitors of distinct components of the DNA repair machinery
      promotes the accumulation of DNA damage and sensitizes these cells to the toxic
      effects of UV exposure. These data demonstrate that older neurons appear to be
      more proficient in DNA repair in comparison to their younger counterparts, and
      that this leads to increased survival after DNA damage.

PMID- 12614329
TI  - Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell
      proliferation in cultured human glioma cells.
AB  - Glial cell proliferation in culture is under the control of metabotropic
      glutamate (mGlu) receptors. We have examined whether this control extends to
      human glioma cells. Primary cultures were prepared from surgically removed human
      glioblastomas. RT-PCR combined with western blot analysis showed that most of the
      cultures (eight out of 11) expressed group-II mGlu receptors. In two selected
      cultures (MZC-12 and FCN-9), the mGlu2/3 receptor antagonist, LY341495, slowed
      cell proliferation when applied to the growth medium from the second day after
      plating. This effect was reversible because linear cell growth was restored after
      washing out the drug. LY341495 reduced glioma cell proliferation at
      concentrations lower than 100 nm, which are considered as selective for mGlu2/3
      receptors. In addition, its action was mimicked by the putative mGlu2/3 receptor
      antagonist (2S)-alpha-ethylglutamate. The anti-proliferative effect of LY341495
      was confirmed by measuring [methyl-3H]-thymidine incorporation in cultures
      arrested in G0 phase of the cell cycle and then stimulated to proliferate by the
      addition of 10% fetal calf serum or 100 ng/mL of epidermal growth factor (EGF).
      In cultures treated with EGF, LY341495 was also able to reduce the stimulation of
      the mitogen-activated protein kinase (MAPK) pathway, as well as the induction of
      cyclin D1. Both effects, as well as decreased [methyl-3H]-thymidine
      incorporation, were partially reduced by co-addition of the potent mGlu2/3
      receptor agonist, LY379268. We conclude that activation of group-II mGlu
      receptors supports the growth of human glioma cells in culture and that
      antagonists of these receptors should be tested for their ability to reduce
      tumour growth in vivo.

PMID- 12614331
TI  - Mitochondrial oxidation of 4-hydroxy-2-nonenal in rat cerebral cortex.
AB  - 4-hydroxy-trans-2-nonenal (HNE) is a neurotoxic product of lipid peroxidation
      whose levels are elevated in multiple neurodegenerative diseases and CNS trauma.
      The detoxification of HNE may take the route of glutathione conjugation to the C3
      carbon and the oxidation or reduction of the C1 aldehyde. In this work, we
      examined whether the oxidation of HNE to its corresponding carboxylic acid, 4
      hydroxy-trans-2-nonenoate (HNEAcid) was detoxifying event, if it occurred in rat
      cerebral cortex, and in which subcellular compartments. Our results show that
      HNEAcid did not form protein adducts and was non-toxic to Neuro 2A cells. HNEAcid
      formation occurred in rat cerebral cortex slices following exposure to HNE in a
      time-dependent and dose-dependent fashion. Homogenate studies indicated that
      HNEAcid formation was NAD+ dependent. Subcellular fractionation demonstrated that
      mitochondria had the highest specific activity for HNEAcid formation with a KM of
      21 micro m HNE. These data indicate that oxidation of HNE to its corresponding
      acid is a major detoxification pathway of HNE in the CNS and that mitochondria
      play a role in this process.

PMID- 12614330
TI  - cAMP-induced differentiation of human neuronal progenitor cells is mediated by
      nuclear fibroblast growth factor receptor-1 (FGFR1).
AB  - Activation of cAMP signaling pathway and its transcriptional factor cyclic AMP
      response element binding protein (CREB) and coactivator are key determinants of
      neuronal differentiation and plasticity. We show that nuclear fibroblast growth
      factor receptor-1 (FGFR1) mediates cAMP-induced neuronal differentiation and
      regulates CREB and CREB binding protein (CBP) function in alpha-internexin
      expressing human neuronal progenitor cells (HNPC). In proliferating HNPC, FGFR1
      was associated with the cytoplasm and plasma membrane. Treatment with dB-cAMP
      induced nuclear accumulation of FGFR1 and caused neuronal differentiation,
      accompanied by outgrowth of neurites expressing MAP2 and neuron-specific
      neurofilament-L protein and enolase. HNPC transfected with nuclear/cytoplasmic
      FGFR1 or non-membrane FGFR1(SP-/NLS), engineered to accumulate exclusively in the
      cell nucleus, underwent neuronal differentiation in the absence of cAMP
      stimulation. In contrast, FGFR1/R4, with highly hydrophobic transmembrane domain
      of FGFR4, was membrane associated, did not enter the nucleus and failed to induce
      neuronal differentiation. Transfection of tyrosine kinase-deleted dominant
      negative receptor mutants, cytoplasmic/nuclear FGFR1(TK-) or nuclear FGFR1(SP
      /NLS)(TK-), prevented cAMP-induced neurite outgrowth. Nuclear FGFR1 localized in
      speckle-like domains rich in phosphorylated histone 3 and splicing factors,
      regions known for active RNA transcription and processing, and activated the
      neurofilament-L gene promoter. FGFR1(SP-/NLS) transactivated CRE, up-regulated
      phosphorylation and transcriptional activity of CREB and stimulated the activity
      of CBP several-fold. Thus, cAMP-induced nuclear accumulation of FGFR1 provides a
      signal that triggers molecular events leading to neuronal differentiation.

PMID- 12614332
TI  - Site-directed mutagenesis of rabbit LAT1 at amino acids 219 and 234.
AB  - The availability of amino acids in the brain is regulated by the blood-brain
      barrier (BBB) large neutral amino acid transporter type 1 (LAT1) isoform, which
      is characterized by a high affinity (low Km) for substrate large neutral amino
      acids. The hypothesis that brain amino acid transport activity can be altered
      with single nucleotide polymorphisms was tested in the present studies with site
      directed mutagenesis of the BBB LAT1. The rabbit has a high Km LAT1 large neutral
      amino acid transporter, as compared to the low Km neutral amino acid transporter
      at the human or rat BBB. The rabbit LAT1 was cloned from a rabbit brain capillary
      cDNA library. Alignment of the amino acid sequences of rabbit, human, and rat
      LAT1 revealed two radical amino acid residues that differ in the rabbit relative
      to the rat or human LAT1. The G219D mutation had a modest effect on the Km and
      Vmax of tryptophan transport via cloned rabbit LAT1 in frog oocytes, but the
      W234L variant reduced the Km by 64% and the Vmax by 96%. Conversely, LAT1
      transport of either tryptophan or phenylalanine was nearly normalized when the
      double mutation W234L/G219D variant was produced. These studies show that marked
      changes in the affinity and capacity of the LAT1 are caused by single nucleotide
      polymorphisms and that phenotype can be restored with a double mutation.

PMID- 12614334
TI  - Estrogen activates protein kinase C in neurons: role in neuroprotection.
AB  - It has been previously demonstrated that estrogen can protect neurons from a
      variety of insults, including beta-amyloid (Abeta). Recent studies have shown
      that estrogen can rapidly modulate intracellular signaling pathways involved in
      cell survival. In particular, estrogen activates protein kinase C (PKC) in a
      variety of cell types. This enzyme plays a key role in many cellular events,
      including regulation of apoptosis. In this study, we show that 17beta-estradiol
      (E2) rapidly increases PKC activity in primary cultures of rat cerebrocortical
      neurons. A 1 h pre-treatment with E2 or phorbol-12-myristate-13-acetate (PMA), a
      potent activator of PKC, protects neurons against Abeta toxicity. Protection
      afforded by both PMA and E2 is blocked by pharmacological inhibitors of PKC.
      Further, depletion of PKC levels resulting from prolonged PMA exposure prevents
      subsequent E2 or PMA protection. Our results indicate that E2 activates PKC in
      neurons, and that PKC activation is an important step in estrogen protection
      against Abeta. These data provide new understanding into the mechanism(s)
      underlying estrogen neuroprotection, an action with therapeutic relevance to
      Alzheimer's disease and other age-related neurodegenerative disorders.

PMID- 12614333
TI  - The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical
      neuron cultures.
AB  - Cysteine availability is normally the rate-limiting factor in glutathione
      synthesis. How neurons obtain cysteine from extracellular space is not well
      established. Here we used mouse cortical neuron cultures to examine the role of
      the excitatory amino acid transporters (EAATs) in neuronal cysteine uptake. The
      cultured neurons expressed both EAAT2 and EAAT3. Cysteine uptake was
      predominantly (> 85%) Na+-dependent, with an apparent Km of 37 microm. Cysteine
      uptake was reduced by the EAAT substrates l-glutamate and l-aspartate and by
      synthetic EAAT inhibitors. The non-selective EAAT inhibitor threo-beta
      hydroxyaspartate had a significantly greater maximal inhibitory effect than did
      the EAAT2-selective inhibitor, dihydrokainate, indicating uptake by both EAAT2
      and EAAT3. Serine, a substrate of ASC uptake system, had negligible effects on
      cysteine uptake at 10-fold excess concentrations. To assess the functional
      importance of EAAT-mediated cysteine uptake in neuronal glutathione synthesis,
      cultures were treated with diethylmaleate to deplete glutathione, then incubated
      with cysteine in the presence or absence of EAAT inhibitors. Threo-beta
      benzyloxyaspartate and the non-transportable inhibitor threo-beta
      hydroxyaspartate both inhibited the cysteine-dependent glutathione synthesis. The
      findings suggest that neuronal EAAT activity can be a rate-limiting step for
      neuronal glutathione synthesis and that the primary function of EAATs expressed
      by neurons in vivo may be to transport cysteine.

PMID- 12614336
TI  - Serotonin catabolism depends upon location of release: characterization of
      sulfated and gamma-glutamylated serotonin metabolites in Aplysia californica.
AB  - Serotonin is a vital neurotransmitter for the functioning of the nervous system
      in species throughout the animal phyla. Despite its ubiquitous nature, the
      metabolism of this molecule has yet to be completely elucidated in even the most
      basic of organisms. Two novel serotonin catabolites, serotonin-O-sulfate and
      gamma-glu-serotonin-O-sulfate, are chemically characterized using capillary
      electrophoresis with wavelength-resolved fluorescence detection and electrospray
      mass spectrometry, and the formation of gamma-glu-serotonin in Aplysia
      californica is confirmed. These novel compounds appear to be synthesized
      enzymatically, and known mammalian enzymes exist for all serotonin
      transformations observed here. The pathway of serotonin inactivation depends upon
      the type of neuronal tissue subjected to neurotransmitter incubation, with
      assorted serotonin products observed in distinct locations. Initially
      demonstrated to be in the metacerebral cell (MCC) soma, the new serotonin
      metabolite serotonin-O-sulfate may contribute to important functions in the
      serotonergic system beyond simple serotonin inactivation.

PMID- 12614335
TI  - The role of the Ca2+-sensitive tyrosine kinase Pyk2 and Src in thrombin
      signalling in rat astrocytes.
AB  - We have recently demonstrated that multiple signalling pathways are involved in
      thrombin-induced proliferation in rat astrocytes. Thrombin acts by protease
      activated receptor-1 (PAR-1) via mitogen-activated protein kinase activity.
      Signalling includes both Gi/(betagamma subunits)-phosphatidylinositol 3-kinase
      and a Gq-phospholipase C/Ca2+/protein kinase C (PKC) pathway. In the present
      study, we investigated the possible protein tyrosine kinases which might be
      involved in thrombin signalling cascades. We found that, in astrocytes, thrombin
      can evoke phosphorylation of proline-rich tyrosine kinase (Pyk2) via PAR-1. This
      process is dependent on the increase in intracellular Ca2+ and PKC activity.
      Moreover, in response to thrombin stimulation Pyk2 formed a complex with Src
      tyrosine kinase and adapter protein growth factor receptor-bound protein 2
      (Grb2), which could be coprecipitated. Furthermore, both thrombin-induced Pyk2
      phosphorylation and extracellular signal-regulated kinase (ERK) 1/2
      phosphorylation can be attenuated by Src kinase inhibitor 4-amino-5-(4
      chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. From these data we conclude
      that PAR-1 uses Ca2+- and PKC-dependent Pyk2 to activate Src, thereby leading to
      ERK1/2 activation, which predominantly recruits Grb2 in rat astrocytes.

PMID- 12614337
TI  - Involvement of PI3'-K, mitogen-activated protein kinase and protein kinase B in
      the up-regulation of the expression of nNOSalpha and nNOSbeta splicing variants
      induced by PRL-receptor activation in GH3 cells.
AB  - It is well known that GH-PRL secreting GH3 cells express constitutive neuronal
      nitric oxide synthase (nNOS) and produce nitric oxide (NO*). In addition, these
      cells possess plasma membrane prolactin (PRL) receptors which can be responsible
      for an autocrine 'short-loop' feedback. The aim of the present study was to
      investigate whether the activation of PRL receptors modulates the expression of
      the different spliced forms of nNOS gene, and the transductional mechanisms
      involved in this action. In GH3 cells, both exon 2-containing nNOSalpha and exon
      2-lacking nNOSbeta were time-dependently expressed, whereas the other two
      isoforms eNOS and iNOS were not. The antibodies directed against the residues 53
      68 of the external domain common to both the long and short form of rat PRL
      receptors, and the selective D2 agonist cabergoline (1 nm) reduced both basal and
      exogenous PRL-induced expressions of nNOSalpha and nNOSbeta, but to a greater
      extent for the beta splicing form. In line with these results, oPRL (1 and 10
      microm) added to the incubation medium increased to a greater extent the
      expression of nNOSbeta form than of the nNOSalpha. The receptor and non-receptor
      protein tyrosine kinase (PTK) inhibitors, genistein (10 microm), the Src-specific
      tyrosine kinase inhibitor PP2 (100 microm), the MAPK inhibitor PD 098059 (50 nm)
      and the two PI3'-K inhibitors, wortmannin (300 nm) and LY-294002 (25 microm)
      prevented both basal and exogenous PRL-induced expression of nNOSalpha and
      nNOSbeta isoforms. In addition, exogenous PRL induced a phosphorylation of
      protein kinase B (PKB) (Akt) that was prevented both by the two MAPK inhibitors
      PD 098059 and U 0126, and by the PI3'-K inhibitors wortmannin and LY-294002. Up
      regulation of the expression of the two splicing forms of nNOS elicited by PRL
      receptor activation was mirrored by the increased synthesis of NO*. In
      conclusion, PRL receptor activation up-regulated the expression of both nNOSalpha
      and nNOSbeta proteins via a PTK, PI3'-K, MAPK and PKB signalling transduction
      components. This action may represent the molecular mechanism by which PRL exerts
      the 'short-loop' feedback on its own secretion.

PMID- 12614338
TI  - Dopamine-dependent responses to cocaine depend on corticotropin-releasing factor
      receptor subtypes.
AB  - The effects on locomotor response to cocaine challenge, acquisition of cocaine
      conditioned place preference and cocaine-induced dopamine (DA) release in nucleus
      accumbens and ventral tegmental area by the non-specific corticotropin-releasing
      factor (CRF) receptors antagonist alpha-helical CRF, the selective CRF receptor
      subtype 1 antagonist CP-154,526 and the selective CRF receptor subtype 2
      antagonist anti-sauvagine-30 (AS-30) were investigated in rats. Both alpha
      helical CRF (10 microg, i.c.v.) and CP-154,526 (3 microg, i.c.v.) decreased the
      cocaine-induced distance travelled, whereas AS-30 (3 microg, i.c.v.) did not show
      such an effect. The CRF receptor antagonists also have significant effects on
      stereotype counts induced by cocaine injection, in which the alpha-helical CRF or
      CP-154,526 but not AS-30 did significantly reduce the stereotype counts. alpha
      Helical CRF (10 microg) prior to each injection of cocaine blocked cocaine
      conditioned place preference with no significant difference observed in the time
      spent in the drug-paired side between post- and pre-training and both 1 and 3
      microg CP-154,526 also had significant inhibitory effects on cocaine-induced
      place preference. However, pre-treatment with an i.c.v. infusion of AS-30 (1 or 3
      microg) prior to each injection of cocaine did not affect the acquisition of
      conditioned place preference. The alpha-helical CRF and CP-154,526 reduced
      extracellular DA levels of nucleus accumbens and ventral tegmental area in
      response to the injection of cocaine. However, both alpha-helical CRF and CP
      154,526 did not modify extracellular DA levels under basal conditions. In
      contrast, the i.c.v. infusion of AS-30 had no effects on either the basal DA or
      the cocaine-induced increase in DA release in nucleus accumbens and ventral
      tegmental area. These findings demonstrate that activation of the CRF receptor is
      involved in behavioral and neurochemical effects of cocaine challenge and cocaine
      reward and that the role of CRF receptor subtypes 1 and 2 in cocaine-induced
      locomotion, reward and DA release is not identical. The CRF receptor subtype 1 is
      largely responsible for the action of the CRF system on cocaine locomotion and
      reward. These results suggest that the CRF receptor antagonist, particularly the
      CRF receptor subtype 1 antagonist, might be of some value in the treatment of
      cocaine addiction and cocaine-related behavioral disorders.

PMID- 12614339
TI  - Glutamate levels and transport in cat (Felis catus) area 17 during cortical
      reorganization following binocular retinal lesions.
AB  - Glutamate is known to play a crucial role in the topographic reorganization of
      visual cortex after the induction of binocular central retinal lesions. In this
      study we investigated the possible involvement of the glial high-affinity Na+/K+
      dependent glutamate transporters in cortical plasticity using western blotting
      and intracortical microdialysis. Basal extracellular glutamate levels and the re
      uptake activity for glutamate have been determined by comparing the extracellular
      glutamate concentration before and during the blockage of glutamate removal from
      the synaptic cleft with the potent transporter inhibitor l-trans-pyrrolidine-3,4
      dicarboxylic acid. In cats with central retinal lesions we observed increased
      basal extracellular glutamate concentrations together with a decreased re-uptake
      activity in non-deprived, peripheral area 17, compared with the sensory-deprived,
      central cortex of the same animal as well as the topographically matching regions
      of area 17 in normal subjects. Western blotting experiments revealed a parallel
      decrease in the expression level of the glial glutamate transporter proteins GLT
      1 and GLAST in non-deprived cortex compared with sensory-deprived cortex of
      lesion cats and the corresponding regions of area 17 of normal subjects. This
      study shows that partial sensory deprivation of the visual cortex affects the
      removal of glutamate from the synaptic cleft and implicates a role for glial
      neuronal interactions in adult brain plasticity.

PMID- 12614340
TI  - Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002
      in a rat model of l-DOPA-induced dyskinesia.
AB  - We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate
      the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals
      rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not
      elicit any abnormal involuntary movements on its own, but failed to reduce the
      severity of dyskinesia when coadministered with L-DOPA. A second experiment was
      undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty
      five animals were allotted to four groups to receive a 21-day treatment with: (i)
      KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA
      (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only
      produced a significant relief of motor disability in the rotarod test in the
      absence of any abnormal involuntary movements. Combined treatment with L-DOPA and
      KW-6002 improved rotarod performance to a significantly higher degree than did
      each of the two drugs alone. However, this combined treatment induced dyskinesia
      to about the same degree as did L-DOPA alone. In situ hybridization
      histochemistry showed that KW-6002 treatment alone caused an approximately 20%
      reduction in the striatal levels of preproenkephalin mRNA, whereas neither the
      coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the
      expression of this transcript in the dopamine-denervated striatum. Either alone
      or in combination with L-DOPA, KW-6002 did not have any modulatory effect on
      prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the
      dopamine-denervated striatum. These results show that monotreatment with an
      adenosine A2a receptor antagonist can relieve motor disability without inducing
      behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine
      lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect
      but not the dyskinesiogenic potential of the latter drug.

PMID- 12614341
TI  - GABA-induced neurite outgrowth of cerebellar granule cells is mediated by GABA(A)
      receptor activation, calcium influx and CaMKII and erk1/2 pathways.
AB  - During neuronal development, GABAA-mediated responses are depolarizing and induce
      an increase in the intracellular calcium concentration. Since calcium
      oscillations can modulate neurite outgrowth, we explored the capability of GABA
      to induce changes in cerebellar granule cell morphology. We find that treatment
      with GABA (1-1000 microm) induces an increase in the intracellular calcium
      concentration through the activation of GABA(A) receptors and voltage-gated
      calcium channels of the L-subtype. Perforated patch-clamp recordings reveal that
      this depolarizing response is due to a chloride reversal potential close to - 35
      mV. When cells are grown in depolarizing potassium chloride concentrations, a
      shift in reversal potential (Erev) for GABA is observed, and only 20% of the
      cells are depolarized by the neurotransmitter at day 5 in vitro. On the contrary,
      cells grown under resting conditions are depolarized after GABA application even
      at day 8. GABA increases the complexity of the dendritic arbors of cerebellar
      granule neurons via a calcium-dependent mechanism triggered by voltage-gated
      calcium channel activation. Specific blockers of calcium-calmodulin kinase II and
      mitogen-activated protein kinase kinase (KN93 and PD098059) implicate these
      kinases in the intracellular pathways involved in the neuritogenic effect of
      GABA. These data demonstrate that GABA exerts a stimulatory role on cerebellar
      granule cell neuritogenesis through calcium influx and activation of calcium
      dependent kinases.

PMID- 12614342
TI  - BDNF heightens the sensitivity of motor neurons to excitotoxic insults through
      activation of TrkB.
AB  - The survival promoting and neuroprotective actions of brain-derived neurotrophic
      factor (BDNF) are well known but under certain circumstances this growth factor
      can also exacerbate excitotoxic insults to neurons. Prior exploration of the
      receptor through which BDNF exerts this action on motor neurons deflects
      attention away from p75. Here we investigated the possibility that BDNF acts
      through the receptor tyrosine kinase, TrkB, to confer on motor neurons
      sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a
      dominant negative TrkB mutant or a TrkB function blocking antibody, and found
      that this protected motor neurons against excitotoxic insult in cultures of mixed
      spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed
      spinal cord neuron cultures is also neuroprotective indicating that endogenously
      produced BDNF participates in vulnerability to excitotoxicity. We next examined
      the intracellular signaling cascades that are engaged upon TrkB activation.
      Previously we found that inhibition of the phosphatidylinositide-3'-kinase
      (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that
      expression of a constitutively active catalytic subunit of PI3'K, p110, confers
      excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel
      studies with purified motor neurons confirm that these events are likely to be
      occuring specifically within motor neurons. The abrogation of BDNF's capacity to
      accentuate excitotoxic insults may make it a more attractive neuroprotective
      agent.

PMID- 12614343
TI  - In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in
      C57Bl/6J mice.
AB  - The extracellular regulated kinase (ERK) pathway was studied to determine its
      role in neuronal plasticity related to the development of nicotine dependence.
      Levels and phosphorylation state of ERK, cAMP response element binding protein
      (CREB) and proline-rich/Ca2+-activated tyrosine kinase (PYK2), and levels of
      tyrosine hydroxylase (TH), were determined using western blotting. C57Bl/6J mice
      received acute or chronic nicotine (200 microg/mL) in their drinking water or
      were withdrawn from nicotine for 24 h following chronic exposure. CREB
      phosphorylation was reduced in the nucleus accumbens following chronic nicotine,
      consistent with previous reports that decreased accumbens CREB activity increases
      drug reinforcement. In contrast, CREB phosphorylation was increased in the
      prefrontal cortex following chronic nicotine exposure and in the ventral
      tegmental area during nicotine withdrawal. In addition, total and phosphorylated
      ERK decreased in the amygdala following chronic nicotine exposure, but ERK
      phosphorylation increased in the prefrontal cortex. TH levels increased in both
      the amygdala and prefrontal cortex, supporting the hypothesis that increased
      catecholaminergic tone contributes to nicotine reinforcement. Overall, these
      results support a role for ERK and CREB activity in neural plasticity associated
      with nicotine dependence.

PMID- 12614345
TI  - Functional metabotropic glutamate receptors are expressed in oligodendrocyte
      progenitor cells.
AB  - We investigated the expression of metabotropic glutamate receptor (mGluR)
      isoforms in CG-4 rodent oligodendroglial progenitor cells (OPC) and rat brain
      oligodendrocytes. Our RT-PCR analysis detected mRNAs for mGluR3 and mGluR5
      isoforms in OPCs. Although neurons express both mGluR5a and mGluR5b splice
      variants, only mGluR5a was identified in OPCs. Antibodies to mGluR2/3 and mGluR5
      detected the corresponding receptor proteins in immunoblots of OPC membrane
      fractions. Furthermore, immunocytochemical analysis identified mGluR5 in
      oligodendrocyte marker O4-positive OPCs. The expression of mGluR5 was also
      demonstrated in oligodendrocyte marker (O4 and O1) positive cells in white matter
      of postnatal 4- and 7-day-old rat brain sections using immunofluorescent double
      labelling and confocal microscopy. The mGluR5 receptor function was assessed in
      CG-4 OPCs with fura-2 microfluorometry. Application of the mGluR1/5 specific
      agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced calcium oscillations, which
      were inhibited by the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)
      pyridine hydrochloride (MPEP). The DHPG induced calcium oscillations required
      Ca2+ release from intracellular stores. In OPCs the group II mGluR agonist
      (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) decreased forskolin
      stimulated cAMP synthesis, indicating the presence of functional mGluR3. The
      newly identified mGluR3 and mGluR5a may be involved in the differentiation of
      oligodendrocytes, myelination and the development of white matter damage.

PMID- 12614344
TI  - Apolipoprotein E enhances uptake of soluble but not aggregated amyloid-beta
      protein into synaptic terminals.
AB  - The cellular mechanism by which apolipoprotein E (apoE) affects the pathogenesis
      of Alzheimer's disease (AD) is not understood. We have examined the effect of
      apolipoprotein E on the internalization of exogenous amyloid-beta 1-40 (Abeta40)
      into a rat brain crude synaptosomal preparation. Abeta40 peptide in soluble
      (within 1 h of dilution in buffer) or aggregated (aged 4 days before dilution in
      buffer) form was pre-incubated with lipidated apoE then added to synaptosomes;
      intraterminal amyloid-beta labeling was quantified using flow cytometry following
      immunolabeling with the anti-Abeta (10G4) antibody. The number of Abeta-positive
      synaptosomes was increased ( approximately 50%) by treatment with a soluble
      Abeta/apoE mixture compared with treatment with soluble Abeta40 alone. However,
      when the Abeta was aggregated, less sodium dodecyl sulfate (SDS)-stable
      Abeta/apoE complex was formed and the addition of apoE decreased the number of
      Abeta-positive terminals. The addition of the lipoprotein-receptor related
      protein (LRP) antagonist receptor-associated protein (RAP) inhibited the apoE
      induced increase in synaptosomal Abeta, and controls treated with trypsin and
      heparinase confirm intraterminal localization of the majority of the soluble
      Abeta. The apoE-mediated increase in Abeta labeling was confirmed in intact cells
      by immunocytochemistry of dorsal root ganglion (DRG) neurons. These results
      suggest that complex formation with apoE enhances internalization of soluble
      Abeta uptake into terminals.

PMID- 12614347
TI  - T cell activation I: proximal events.

PMID- 12614348
TI  - An evolutionary and structural perspective on T cell antigen receptor function.
AB  - After a brief overview of the themes and variations that occur in the family of
      receptors containing immunoreceptor tyrosine-based activation motifs (ITAMs), and
      of recent structural data on the ligand-binding subunits of these receptors, we
      use these data to revisit how information on the state and quality of occupancy
      of the binding site of the T cell antigen receptor (TCR) is conveyed to the
      proximal components of the TCR transduction cassette.

PMID- 12614349
TI  - An architectural perspective on signaling by the pre-, alphabeta and gammadelta T
      cell receptors.
AB  - The T cell antigen receptor (TCR) is a multimeric complex composed of an antigen
      binding clonotypic heterodimer and a signal transducing complex consisting of the
      CD3 dimers (CD3gammaepsilon and CD3deltaepsilon) and a TCR-zeta homodimer. In all
      jawed vertebrates there are two T cell lineages, alphabeta and gammadelta,
      distinguished by the clonotypic subunits contained within their TCRs (TCR-alpha
      and -beta or TCR-gamma and -delta, respectively). A third receptor complex, the
      preTCR, is only expressed on immature T cells. The preTCR, which contains the
      invariant pre-Talpha (pTalpha) chain in lieu of TCR-alpha, plays a critical role
      in the early development of alphabeta lineage cells. The subunit composition of
      the signal transducing complexes of the pre-, alphabeta- and gammadeltaTCRs was
      previously thought to be identical. However, recent data demonstrate that there
      are significant differences in the signal transducing complexes of these three
      TCRs. For example, alphabetaTCRs contain both CD3gammaepsilon and CD3deltaepsilon
      dimers, whereas gammadeltaTCRs contain only CD3gammaepsilon dimers. Moreover,
      preTCR function appears to be unaffected in the absence of CD3delta, suggesting
      that CD3deltaepsilon dimers are dispensable for pre-TCR assembly. In this review,
      we summarize current data relating to the subunit composition of the pre-,
      alphabeta- and gammadeltaTCRs and discuss how these structural differences may
      impact receptor signaling and alphabeta/gammadelta lineage determination.

PMID- 12614350
TI  - Initiation of TCR signaling: regulation within CD3 dimers.
AB  - The number of possible T cell activation outcomes resulting from T cell receptor
      (TCR) engagement suggests that the TCR is able to differentially activate a
      myriad of signaling pathways depending on the nature of the stimulus. The complex
      structural organization of the TCR itself could underlie this diversity of
      responses. Assembly and stoichiometric studies have helped us to shed some light
      on the initiation of TCR signaling. The TCR is composed of TCR and CD3 dimers.
      Changes in the interaction between CD3 subunits within the CD3 dimers and in the
      interaction of these dimers with the TCR heterodimer could be the triggering
      mechanism that initiates the first activation events. One of the hallmarks of
      these early changes in TCR conformation is the induced recruitment of the adapter
      protein Nck to a proline-rich sequence of the cytoplasmic tail of CD3epsilon, but
      there may be others. According to our most recent observations, the TCR is
      organized in pre-existing clusters within plasma membrane microdomains,
      exhibiting a complexity above and beyond that of dimer composition complexity.
      How the presence of TCR in clusters influences TCR avidity and propagation of TCR
      signals is something that has yet to be investigated.

PMID- 12614351
TI  - The formation and functions of the 21- and 23-kDa tyrosine-phosphorylated TCR
      zeta subunits.
AB  - The interaction between the T cell receptor (TCR) and its cognate antigen/major
      histocompatibility complex (MHC) complex activates a cascade of intracellular
      protein phosphorylations within the T cell. The signals are initiated by the
      specific phosphorylation of two tyrosine residues located in a conserved sequence
      motif termed an ITAM (immune receptor-based tyrosine activation motif). There are
      10 ITAMs in the TCR complex, and 6 of these ITAMs are present in the TCR zeta
      homodimer. Following TCR stimulation, the TCR zeta subunit forms two tyrosine
      phosphorylated intermediates of 21- and 23-kDa, respectively. The dramatic and
      diverse biological responses of T cells are proposed to be partly regulated by
      the relative ratios of the 21- vs. 23-kDa phosphorylated forms of TCR zeta that
      are induced following TCR ligation. In this review, we describe a stepwise model
      of zeta phosphorylation required for the formation of these two phosphorylated
      derivatives. We describe the kinases and phosphatases controlling these
      phosphorylation processes. In addition, we present some preliminary findings from
      ongoing studies that discuss the contributions of each phosphorylated form of
      zeta on T cell development, TCR signaling, T cell anergy induction, and T cell
      survival.

PMID- 12614352
TI  - Thymic selection revisited: how essential is it?
AB  - Intrathymic T cell development represents one of the best studied paradigms of
      mammalian development. Lymphoid committed precursors enter the thymus and the
      Notch1 receptor plays an essential role in committing them to the T cell
      lineages. The pre-T cell receptor (TCR), as an autonomous cell signaling
      receptor, commits cells to the alphabeta lineage while its rival, the
      gammadeltaTCR, is involved in generating the gammadelta lineage of T cells.
      Positive and negative selection of immature alphabetaTCR-expressing cells are
      essential mechanisms for generating mature T cells, committing them to the CD4
      and CD8 lineages and avoiding autoimmunity. Additional lineages of alphabetaT
      cells, such as the natural killer T cell lineage and the CD25+ regulatory T cell
      lineage, are formed when the alphabetaTCR encounters specific ligands in suitable
      microenvironments. Thus, positive selection and receptor-instructed lineage
      commitment represent a hallmark of the thymus. Ectopically expressed organ
      specific antigens contribute to thymic self-nonself discrimination, which
      represents an essential feature for the evolutionary fitness of mammalian
      species.

PMID- 12614354
TI  - On the role of self-recognition in T cell responses to foreign antigen.
AB  - The key role of the thymus in shaping the peripheral T cell receptor (TCR)
      repertoire has been appreciated for nearly a quarter of a century. For most of
      that time, a single model has dominated thinking about the physiological role of
      the positive selection process mediated by TCR recognition of self-peptides and
      major histocompatibility complex (MHC) molecules. This developmental filter was
      believed to populate secondary lymphoid tissues with T cells bearing receptors
      best able to recognize unknown foreign peptides associated with the particular
      allelic forms of the MHC molecules present in an individual. More recently, self
      recognition has been suggested to regulate the viability of naive T cells. Here
      we focus on new results indicating that a critical contribution of positive
      selection to host defense is insuring that each peripheral T cell can use self
      recognition to (i) enhance TCR signaling sensitivity upon foreign antigen
      recognition and (ii) augment the clonal expansion that accompanies limiting
      foreign antigen display at early points in an infectious process. We also detail
      new insights into the intracellular signaling circuitry that underlies the
      effective discrimination between low- and high-quality ligands of the TCR and
      speculate on how this design might facilitate an additional contribution of self
      recognition to T cell activation in the presence of foreign stimuli.

PMID- 12614353
TI  - The Ras/MAPK cascade and the control of positive selection.
AB  - Immature double positive (DP) thymocytes bearing a T cell receptor (TCR) that
      interacts with self-major histocompatibility complex (MHC) molecules receive
      signals that induce either their differentiation (positive selection) or
      apoptosis (negative selection). Furthermore, those cells that are positively
      selected develop into two different lineages, CD4 or CD8, depending on whether
      their TCRs bind to MHC class II or I, respectively. Positive selection therefore
      involves rescue from the default fate (death), lineage commitment, and
      progression to the single positive (SP) stage. These are probably temporally
      distinct events that may require both unique and overlapping signals. Work in the
      past several years has started to unravel the signaling networks that control
      these processes. One of the first pathways identified as important for positive
      selection was Ras and its downstream effector, the Erk mitogen-activated protein
      kinase (MAPK) cascade. In this review we examine the factors that connect the TCR
      to the Ras/Erk cascade in DP thymocytes, as well as what we know about the
      downstream effectors of the Ras/Erk cascade important for positive selection. We
      also consider the possible role of this cascade in CD4/CD8 lineage development,
      and the possible interactions of the Ras/Erk cascade with Notch during these cell
      fate determination processes.

PMID- 12614355
TI  - The influence of the src-family kinases, Lck and Fyn, on T cell differentiation,
      survival and activation.
AB  - The src-family kinases p56lck (Lck) and p59fyn (Fyn) are expressed in T cells and
      are among the first signaling molecules to be activated downstream of the T cell
      receptor (TCR). Evidence is emerging that although closely related, these
      signaling molecules have discrete functions during development, maintenance and
      activation of peripheral T cells. For example, during thymopoiesis Lck is
      uniquely able to provide all the signals required for pre-TCRbeta selection,
      although Fyn can substitute for a subset of these. Positive selection of CD4
      single-positive (SP) cells is also critically dependent on the expression of Lck
      but not Fyn, while differentiation of CD8 SP cells proceeds relatively
      efficiently in the absence of Lck. In naive peripheral T cells either Lck or Fyn
      can transmit TCR-mediated survival signals, and yet only Lck is able to trigger
      TCR-mediated expansion signals under conditions of lymphopenia. Stimulation of
      naive T cells by antigenic stimuli is also severely compromised in the absence of
      Lck, but more subtly impaired by the absence of Fyn. We discuss recent
      experiments addressing how these two src-kinase family members interface with
      downstream signaling pathways to regulate these diverse aspects of T cell
      behavior.

PMID- 12614356
TI  - The role of Tec family kinases in T cell development and function.
AB  - Three members of the Tec family kinases, Itk, Rlk and Tec, have been implicated
      in signaling downstream of the T cell receptor (TCR). The activity of these
      kinases in T cells has been shown to be important for the full activation of
      phospholipase C-gamma1 (PLC-gamma1). Disruption of Tec family signaling in Itk-/-
      and Rlk-/-Itk-/- mice has multiple effects on T cell development, cytokine
      production and T-helper cell differentiation. Furthermore, mice possessing
      mutations in signaling molecules upstream of PLC-gamma1, such as Src homology 2
      (SH2) domain-containing phosphoprotein of 76 kDa (SLP-76), linker for activation
      of T cells (LAT) and Vav1, or in members of the nuclear factor for activated T
      cells (NFAT) family of transcription factors, which are downstream of PLC-gamma1,
      have been found to have similar phenotypes to Tec family-deficient mice,
      emphasizing the importance of this pathway in regulating T cell activation,
      differentiation and homeostasis.

PMID- 12614357
TI  - Role of protein tyrosine phosphatases in T cell activation.
AB  - The last decade has seen an exponentially increasing interest in the molecular
      mechanisms of signal transduction. In T cells, much of the focus has been on
      protein tyrosine kinase (PTK)-mediated signaling from the T cell receptor (TCR)
      and cytokine receptors, while the study of protein tyrosine phosphatases
      (PTPases) has lagged behind. However, recent discoveries have revealed that
      several PTPases play important roles in many different aspects of T cell
      physiology. We predict that the phosphatases will become a 'hot topic' in the
      field within the next few years. This review summarizes the current understanding
      of the regulation and biology of PTPases in T lymphocyte activation.

PMID- 12614358
TI  - The roles of membrane microdomains (rafts) in T cell activation.
AB  - Detergent-resistant membrane microdomains enriched in sphingolipids, cholesterol
      and glycosylphosphatidylinositol-anchored proteins play essential roles in T cell
      receptor (TCR) signaling. These 'membrane rafts' accumulate several cytoplasmic
      lipid-modified molecules, including Src-family kinases, coreceptors CD4 and CD8
      and transmembrane adapters LAT and PAG/Cbp, essential for either initiation or
      amplification of the signaling process, while most other abundant transmembrane
      proteins are excluded from these structures. TCRs in various T cell
      subpopulations may differ in their use of membrane rafts. Membrane rafts also
      seem to be involved in many other aspects of T cell biology, such as functioning
      of cytokine and chemokine receptors, adhesion molecules, antigen presentation,
      establishing cell polarity or interaction with important pathogens. Although the
      concept of membrane rafts explains several diverse biological phenomena, many
      basic issues, such as composition, size and heterogeneity, under native
      conditions, as well as the dynamics of their interactions with TCRs and other
      immunoreceptors, remain unclear, partially because of technical problems.

PMID- 12614360
TI  - Role of Shc in T-cell development and function.
AB  - Shc is a prototype adapter protein that is expressed from the earliest stages of
      T-cell development. Shc becomes rapidly tyrosine phosphorylated after T-cell
      receptor (TCR) engagement. Expression of dominant negative forms of Shc in T-cell
      lines had also suggested a role for this adapter downstream of the TCR. However,
      until recently, the relative significance of Shc compared to several other
      adapters in T cells was unclear. Mice lacking Shc expression specifically in the
      T-cell lineage together with inducible expression of dominant negative Shc in
      transgenic mice have revealed an essential and nonredundant role for Shc in
      thymic T-cell development. Functional defects in a Jurkat T-cell line lacking Shc
      expression also suggest a role for Shc in mature T-cell functions. While the
      requirement of Shc in T-cell signaling is now established, precisely what
      signaling pathways downstream of Shc make this adapter unique are less clear.
      Although the Shc-mediated activation of the extracellular signal regulated kinase
      (Erk)/mitogen-activated protein kinase (MAPK) pathway could be one component, Shc
      likely signals to other pathways in T cells that are not yet discovered. A better
      molecular understanding of Shc function in the future could provide insights into
      how multiple adapters coordinate the various outcomes downstream of the TCR.

PMID- 12614359
TI  - Transmembrane adapters: attractants for cytoplasmic effectors.
AB  - Transmembrane adapter proteins (TRAPs) are a relatively new and growing family of
      proteins that include linker for activation of T cells (LAT), phosphoprotein
      associated with glycosphingolipid-enriched micro domains (PAG)/C-terminal Src
      kinase (Csk) binding protein (Cbp), SHP2-interacting transmembrane adapter
      protein (SIT), T cell receptor interacting molecule (TRIM), and the recently
      identified non-T cell activation linker (NTAL) and pp30. TRAPs share several
      common structural features, but more importantly they possess multiple sites of
      tyrosine phosphorylation, by which they act as scaffolds for recruiting cytosolic
      adapter and/or effector proteins. The membrane association of TRAPs places them
      near to the immunoreceptors, a position from which they coordinate and modulate
      the signals they receive to produce an appropriate cellular response.

PMID- 12614361
TI  - Kinetic perspectives of T cell antigen receptor signaling. A two-tier model for T
      cell full activation.
AB  - T-cell activation consists of multiple layers of signaling events. Interleukin-2
      production is of interest for many, since its expression determines a critical
      difference between partial and full T-cell activation. To achieve full activation
      of T cells, it is necessary for the T-cell antigen receptor (TCR) to be engaged
      for an extended period of time. However, why extended stimulation is required for
      full T-cell activation is not understood at the molecular level. In this review,
      orchestrated events of TCR signal transduction will be analyzed in a kinetic
      manner and connected toward the understanding of the mechanism of T-cell
      activation. Based on recent results, a model of the mechanism that dictates the
      threshold between partial and full T-cell activation is proposed.

PMID- 12614362
TI  - Known and potential functions for the SLP-76 adapter protein in regulating T-cell
      activation and development.
AB  - The hematopoietic adapter protein SLP-76 is a critical component of multiple
      biochemical signaling 'circuits' in T cells that integrate proximal signaling
      events initiated by ligation of the T-cell receptor (TCR) into more distal
      pathways. Given the important role ascribed to TCR signaling in directing the
      outcome of thymocyte selection, it seems likely that SLP-76 may also function in
      signaling pathways that ultimately impact the establishment of the peripheral T
      cell repertoire. It is generally accepted that the peripheral T-cell repertoire
      is selected in large part during T-cell development in the thymus. Molecular
      interactions between the TCR and self-peptide/major histocompatibility complexes
      expressed on thymic stromal elements dictate the fate of developing thymocytes.
      Thymocyte survival and further maturation (positive selection) require an active
      signal delivered to the cell as a consequence of TCR ligation. This raises the
      intriguing question of how a thymocyte can, for a narrow window of developmental
      time, obtain responsiveness to self while maintaining tolerance to these same
      determinants upon export to the periphery. This article reviews the current
      literature describing SLP-76-dependent signaling pathways in mature T cells and
      developing thymocytes. A potential role for this critical signaling intermediate
      in integrating signals leading to positive and negative selection of the
      peripheral T-cell repertoire is also discussed.

PMID- 12614363
TI  - All roads lead to actin: the intimate relationship between TCR signaling and the
      cytoskeleton.
AB  - Regardless of cell type, the regulation of the actin cytoskeleton is tightly
      linked to vital biological properties such as polarity, motility, cell-cell
      contact, exocytosis and proliferation. In the immune system, where rapid and
      efficient response to antigen-provoked stimuli is crucial, an overwhelming amount
      of data implicate the actin cytoskeleton and its regulators as central to immune
      function. Increasingly, the cytoskeleton is considered an essential amplification
      step in T cell receptor (TCR)-, costimulatory-, and integrin-mediated signaling.
      Advances in genetic manipulation and confocal imaging have led to a keener
      appreciation of the importance of TCR signal integration by the actin
      cytoskeleton. This review outlines recent advances in elucidating the regulation
      of T cell function through the actin cytoskeleton. We also examine intriguing
      parallels between the immune system and other models of cytoskeletal regulation.

PMID- 12614364
TI  - Gene therapy ethics and haemophilia: an inevitable therapeutic future?
AB  - Haemophilia was recognized early on as an ideal candidate for a gene transfer
      approach to therapy. In the past decade, gene transfer experimentation in the
      haemophilias has indeed played an integral role in furthering the science in the
      global field of gene therapy. However, these expectations have placed haemophilia
      gene transfer researchers under pressure to succeed in a scientific domain in
      which successes are infrequent and progress is necessarily slow. These same
      expectations have also fueled the perception of gene therapy as the inevitable
      therapeutic goal for the youngest children with haemophilia. In this paper, we
      will discuss the ethical implications of this perception in light of anticipated
      benefits, acceptable risk, perceived consumer need and the unknown cost of this
      intervention. A framework for the future study and therapeutic implementation of
      gene transfer technology in this specific population is proposed. Public debate
      on this issue that includes the voices of the intended beneficiaries, especially
      the parents of the youngest children with haemophilia and the children
      themselves, is encouraged.

PMID- 12614365
TI  - Historical and political implications of haemophilia in the Spanish royal family.
AB  - The political implications of haemophilia in the marriage of King Alfonso XIII of
      Spain and Princess Victoria Eugenie Battenberg of England have been reviewed in
      recent books on history. However, the fact that they had haemophilic sons also
      affected their personal relationship. In this article, we review the consequences
      haemophilia bore on their lives. We feel great compassion for families who suffer
      the illness, be it ordinary people or members of royalty; however, in this case,
      it can be said that when the disease affected a royal couple, the political
      consequences were great.

PMID- 12614366
TI  - In vivo recovery and safety of human factor VIII product AAFACT in patients with
      haemophilia A.
AB  - AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived
      coagulation factor VIII concentrate obtained from plasma of voluntary, non
      remunerated blood donors, is manufactured and marketed in the Netherlands by
      Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70
      previously treated haemophilia A patients were included (73% severe, 14% moderate
      and 13% mild haemophilia A). Most of these patients were followed during 4 years
      for the appearance of adverse events, possible transmissions of blood-borne
      viruses and the occurrence of antibodies against FVIII. The efficacy of treatment
      was determined in each patient by the in vivo recovery of FVIII. During this
      study, only six adverse events, possibly related to the use of AAFACT, were
      reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV
      and HCV in the seronegative patients have not been observed. In none of the
      patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during
      this study was not different from the in vivo recovery observed in eight patients
      during the preregistration study. There was a correlation of in vivo recovery
      with age and body weight. From these results, we conclude that the clinical usage
      of this human plasma-derived FVIII product is efficient and safe.

PMID- 12614367
TI  - Continuous intravenous infusion of a plasma-derived factor IX concentrate
      (Mononine) in haemophilia B.
AB  - This prospective, multicentre, open-label study evaluated the efficacy and safety
      of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX
      (Human) Monoclonal Antibody Purified] administered by continuous intravenous
      (CIV) infusion to patients with haemophilia B. Admission criteria included
      documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight
      patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were
      enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor
      IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A
      median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset
      of 13 non-emergency patients 7-21 days prior to CIV infusion to determine
      pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a
      bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed
      by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was
      administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for
      107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV
      infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy
      was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight
      oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for
      all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse
      events that were possibly related to study medication but were not deemed serious
      by the investigator and were mainly because of local irritation at the infusion
      site. FIX CIV infusion therapy is safe and effective in the treatment of
      haemophilia B patients undergoing surgery, exposed to trauma, or experiencing
      severe spontaneous haemorrhage.

PMID- 12614368
TI  - Experience with a new percutaneous port system, Percuseal, for intravenous
      injection in patients with haemophilia, von Willebrand disease and severe alpha1
      antitrypsin deficiency.
AB  - We have implanted a new port system (Percuseal) in altogether 13 patients with
      haemophilia A, B, von Willebrand disease and alpha1-antitrypsin deficiency in
      order to facilitate venous access. The Percuseal system differs from subcutaneous
      ports, such as Port-a-Cath, in that the upper part of the device protrudes above
      the skin. In this way, the patient can easily puncture the port membrane under
      the guidance of his eyes without penetrating the skin. In the present study
      cohort, a number of complications occurred. These were mainly caused by repeated
      local infections (in five patients), which made it necessary to replace the ports
      in three of the patients and to permanently remove the ports as the first option
      in two of the patients. In one patient, the port was removed because of
      inconvenience when doing physical exercise. In one additional patient, a severe
      systemic infection occurred, causing spondylitis. Despite the high infection
      rate, most patients considered the device very convenient to use. Because of the
      side-effects seen in our study, the Percuseal port in its present form is not to
      be recommended for regular use. A reconstruction of the port, making it smaller
      and giving it an antibacteriostatic cap, may possibly make this kind of port
      system a feasible alternative to use in order to improve pharmacoeconomics in the
      prophylactic treatment of haemophilia and patients with alpha1-antitrypsin
      deficiency.

PMID- 12614369
TI  - Genotype and phenotype of haemophilia A in Thai patients.
AB  - To study genotype and phenotype correlation of haemophilia A in Thai patients,
      molecular defects of the factor VIII (FVIII) gene were examined and their
      correlation with clinical phenotypes were evaluated. The molecular pathologies of
      FVIII in Thai patients were found to be heterogeneous. The most common mutation
      was FVIII intron 22 inversion accounting for about 30% of the severe cases while
      gene deletion was rare. Sixteen point mutations were identified, comprising two
      nonsense mutations (R-5X and R1966X), five missense mutations (T233I, D542Y,
      G1850V, W2229S and G2325C), five nucleotide deletions (1145delT, 1187-8delACAC,
      1191-4delA, 1458delGA and 1534delA), three nucleotide insertions (1439-41insA,
      1934insTA and 2245insACTA) and one splicing defect (IVS15+1G>T). Nine mutations
      (T233I, D542Y, 1145delT, 1458delGA, 1534delA, 1934insTA, W2229S, 2245insACTA and
      G2325C) were novel, firstly identified in Thai patients. The genotypes were found
      to correlate with clinical phenotypes in a majority of cases. However, in five
      patients the molecular defects did not correlate with clinical severity and
      FVIII:C level. Cellular and molecular mechanisms were proposed to be responsible
      in amelioration of clinical severity caused by deleterious mutations. Carrier
      detection by direct mutation analysis was also demonstrated.

PMID- 12614370
TI  - Analysis of haemophilia B database and strategies for identification of common
      point mutations in the factor IX gene.
AB  - Haemophilia B is an X-linked recessively inherited bleeding disorder caused by
      heterogeneous mutations spanning the entire factor IX gene. As spontaneous germ
      line mutations are known to occur mostly at CpG dinucleotides in the FIX gene,
      control of the disease would require continuous carrier detection and mutation
      screening. Identification of point mutations, the most common type of mutation in
      FIX gene, is more challenging compared with deletion and insertion mutations. We
      examined the haemophilia B database to identify specific nucleotides in the FIX
      gene that are mutated in relatively large number of patients and the variability
      (if any) in the mutational hotspots at CpG dinucleotides. It was found that while
      mutations responsible to account for all 2348 haemophilia B patients covered 20%
      of the FIX cDNA, only 1% of the cDNA involving mostly CpG dinucleotides accounted
      for mutation in 42.41% of the patient pool. Thus, only 27 nucleotides need to be
      investigated to identify the common point mutations, among which 15 are predicted
      to undergo change in restriction sites on mutation. It is interesting to note
      that seven nucleotides occurring in CpG dinucleotides do not have any reported
      mutation despite each of those being predicted to harbour mutation as a result of
      transition and having mutations recorded in the database for the neighbouring
      nucleotides. Strikingly large number of mutation in codon 296 causing T to M
      change in catalytic domain originally proposed to be the result of the founder
      effect also contains largest number of haplotype suggesting recurrence of de novo
      mutation.

PMID- 12614371
TI  - Inherited bleeding disorders in Indian women with menorrhagia.
AB  - In order to define the prevalence of haemostatic defects in women presenting with
      menorrhagia in our region, the coagulation data on women bleeders investigated in
      the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200
      menorrhagic women investigated were characterized to have an inherited bleeding
      disorder; 221 of these 337 women presented with menorrhagia alone while 116 also
      had other associated bleeding manifestations as prolonged bleeding from injury
      site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and
      major bleeds like intracerebral bleeding. The tests performed included bleeding
      time (BT), platelet count, prothrombin time (PT), prothrombin consumption index
      (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine
      diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation
      studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin.
      Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor
      assay and electron microscopy were performed wherever necessary. Inherited
      platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these,
      isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's
      thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight
      (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and
      Bernard-Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the
      platelet function defect could not be classified into any specific subtypes.
      Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst
      these, von Willebrand disease (vWD) was the most frequent being seen in 40
      (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X
      deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII
      deficiency in one (0.3%) of the patients. It is concluded that although
      hereditary platelet function defects constitute a large majority of women
      bleeders in India but among the coagulation defects, vWD is the commonest as
      reported from the caucasian population. It is thus suggested that in women
      presenting with menorrhagia, screening tests for haemostasis especially for vWD
      and inherited platelet function defects must be performed.

PMID- 12614372
TI  - Haemophilic arthropathy of the hip in children--prognosis and long-term follow
      up.
AB  - The aim of this study was to report on the long-term follow-up of haemophilic
      children with avascular femoral head necrosis and to determine whether
      radiographic findings at initial diagnosis have any prognostic value. Seven
      patients with avascular necrosis of the femoral head were clinically and
      radiographically observed over a period of 5-50 years. The average age of
      patients at first diagnosis was 7.1 years. At follow-up, three of seven patients
      claimed to have occasional mild pain in the affected hip, four of seven showed
      loss of range of motion in the hip joint and two of seven patients showed a limp.
      Only one patient was clinically completely inconspicuous. The radiographically
      measured caput-collum-diaphysis angle at follow-up was pathologic in four cases
      and in one case a lateral subluxation of the femoral head was found. There was
      marked deformation of the femoral head in three of seven cases and a further two
      hips showing slight incongruency. Owing to the small patient-number, a statement
      concerning the prognostic value of defined radiographic signs cannot be made. As
      expected, the more 'risk signs' radiographically found, the higher the likelihood
      that patients will suffer arthrosis at a later stage. We propose that a clear
      distinction between haemophilic arthropathy of the hip and Legg-Calve-Perthes
      disease should be made. In cases where radiographic changes are also found in the
      vicinity of the acetabulum, it is indicative for haemophilic arthropathy.

PMID- 12614373
TI  - Analgesic use and pain coping among patients with haemophilia.
AB  - Pain is an important consequence of bleeding episodes in haemophilia. Previous
      research has included pain frequency and severity among measures of illness
      related disability and quality of life in haemophilia, but little systematic
      evidence exists about analgesic use and pain coping in haemophilia. This paper
      reports cross-sectional findings from a national survey of patients with severe
      haemophilia type A and type B. Respondents provided information about pain
      frequency, pain coping strategies (using the haemophilia-adapted CSQ), use of
      analgesics and other drugs, and described any concerns they had about their drug
      use. Participants registered with comprehensive care haemophilia centres did not
      differ from the rest of the sample on any of the factors recorded. Over one-third
      of participants expressed concerns about their drug use, the most frequent of
      which were about dependence on prescribed analgesics. Pain frequency was the most
      important predictor of analgesic use, but pain coping, and specifically negative
      thoughts about pain, was associated with concerns about drug use independently of
      other factors, including analgesic use and pain frequency. Further research will
      be needed to evaluate possible interventions to promote more effective pain
      coping in haemophilia, and to examine the possible effects of pain coping on
      illness outcomes beyond analgesic use, such as well-being and quality of life.

PMID- 12614374
TI  - Promoting safer sex among HIV-positive youth with haemophilia: theory,
      intervention, and outcome.
AB  - The goal of the project was to develop and evaluate theory-based interventions
      designed to change sexual behaviour and promote safer sex practices of HIV
      seropositive young men and adolescents with haemophilia to prevent transmission
      to sexual partners and offspring. Safer sex was defined as abstinence, consistent
      condom use, or 'outercourse' (intimate, non-intercourse sexual behaviour). This
      project utilized the Transtheoretical Model developed by Prochaska and
      DiClemente, which describes behaviour change as an incremental, stage-based
      process. The 1-year intervention protocol consisted of two individual sessions
      and two peer-centred activities. One hundred and four adolescents, residing in 22
      states, participated. Pre- and post-intervention evaluations were conducted to
      measure stage progression for participants. The number who were in the action or
      maintenance stage of change for safer sex was significantly greater at post-test
      than at pre-test (79 vs. 62%, P < 0.0001). Participants also reported an
      increased use of outercourse. In addition, significant increases in self-efficacy
      and knowledge regarding safer sex were demonstrated. Following these stage-based
      interventions, participants were significantly more likely to be engaging in
      safer sex behaviours than they were previously. These intervention activities can
      be adapted for use with other adolescent populations and for other behaviour
      change goals in adolescents with haemophilia.

PMID- 12614375
TI  - Third and fourth Workshops of the European Paediatric Network for Haemophilia
      Management.

PMID- 12614376
TI  - Severe spontaneous intracranial haematoma in a HIV-negative 66-year-old mild
      haemophiliac. Complete recovery with the use of 1-month factor VIII replacement.
AB  - Intracranial haemorrhage is the most feared manifestation of haemophilia and is
      usually seen in severe forms. We report herein the case of a 66-year-old HIV
      negative patient with mild haemophilia (factor VIII: 7%) who presented with a
      spontaneous and massive intracranial haematoma causing hemiplegia and aphasia. We
      discuss the management of this peculiar situation emphasizing the need for rapid
      and adapted FVIII replacement. A complete recovery was obtained using this
      strategy combined with initial resuscitation measures and subsequent physical
      therapy.

PMID- 12614377
TI  - Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von
      Willebrand's disease.
AB  - A middle-aged woman was admitted to the hospital after being found unconscious at
      home. A brain CT scan excluded an intracranial bleed or other focal abnormality.
      Laboratory analysis showed hyponatraemia (sodium: 121 mmol L(-1)) and a low
      plasma osmolality, with normal sodium excretion and urine osmolality. A diagnosis
      of hyponatraemic coma was made. The patient was treated with water restriction;
      24 h later the sodium was 135 mmol L(-1) and the patient was neurologically fully
      recovered. The patient, who suffered from von Willebrand's disease, had received
      desmopressin and ibuprofen for analgesia 2 days before after a dental
      intervention. She had received desmopressin several times in the past without any
      complications. A few patients treated with desmopressin for coagulation
      abnormalities have been reported to develop water intoxication and severe
      hyponatraemia resulting in seizures and coma. By inhibiting prostaglandin
      synthesis, non-steroid anti-inflammatory agents (NSAIDs) potentiate the effect of
      water reabsorption in the renal tubules of vasopressin, therefore enhancing water
      retention. Desmopressin and NSAIDs should not be used in combination in patients
      with bleeding disorders, but it is often followed in clinical practice. In
      addition, this is probably not an unusual situation in patients treated with
      desmopressin for other 'non-haemorrhagic' indications. This report emphasizes the
      need for practitioners to be aware of this rare but severe complication.

PMID- 12614378
TI  - Misdiagnosis by milk box.

PMID- 12614379
TI  - The clinical phenotype modulation of haemophilia by prothrombotic gene mutations.

PMID- 12614380
TI  - Epilepsy control in the 21st century: leave no child behind.

PMID- 12614381
TI  - Modulation of cortical nitric oxide synthase, glutamate, and redox state by
      nifedipine and taurine in PTZ-kindled mice.
AB  - PURPOSE: Correlation between pentylenetetrazol (PTZ)-induced kindling and the
      cortical nitric oxide synthase (NOS), intracellular calcium [Ca2+]i, glutamate,
      and free radicals was studied in mice, as well as the modulatory action of
      nifedipine and taurine on these parameters. METHODS: Male Swiss albino mice were
      used. Mice in one group received a single convulsive dose of PTZ (50 mg/kg, i.p),
      and were killed 24 h later. To induce kindling, PTZ was injected in a
      subconvulsive dose (40 mg/kg, i.p.) every other day for 3 weeks. One kindled
      group was used as control, whereas two other groups were injected 30 min before
      PTZ with either nifedipine (30 mg/kg, i.p) or taurine (100 mg/kg, i.p). All three
      kindled groups were killed 24 h after the last injection. RESULTS: Compared with
      normal control group, PTZ-kindled mice had significantly higher levels of
      [Ca2+]i, malonaldehyde (MDA), NOS, and lactate dehydrogenase (LDH) but had lower
      levels of superoxide dismutase (SOD) and reduced glutathione (GSH). Acute
      seizures of the same intensity did not induce these alterations, indicating their
      link to the kindling phenomenon and not to seizure activity. The effect of
      taurine, known as an antioxidant, was more pronounced than that of the Ca2+
      channel blocker, nifedipine. The first drug reversed the PTZ-kindled action on
      [Ca2+]i, NOS, LDH, GSH, and SOD, whereas nifedipine restored only LDH and GSH
      levels. However, both drugs did not restore the elevated MDA level. CONCLUSIONS:
      This study suggests that free radicals, as well as NOS, are implicated in PTZ
      induced kindling, and that antioxidants could play a role in controlling the
      accompanying changes.

PMID- 12614382
TI  - Hippocampal programmed cell death after status epilepticus: evidence for NMDA
      receptor and ceramide-mediated mechanisms.
AB  - PURPOSE: Status epilepticus (SE) can result in acute neuronal injury with
      subsequent long-term age-dependent behavioral and histologic sequelae. To
      investigate potential mechanisms that may underlie SE-related neuronal injury, we
      studied the occurrence of programmed cell death (PCD) in the hippocampus in the
      kainic acid (KA) model. METHODS: In adult rats, KA-induced SE resulted in DNA
      fragmentation documented at 30 h after KA injection. Ceramide, a known mediator
      of PCD in multiple neural and nonneural tissues, increased at 2-3 h after KA
      intraperitoneal injection, and then decreased to control levels before increasing
      again from 12 to 30 h after injection. MK801 pretreatment prevented KA-induced
      increases in ceramide levels and DNA fragmentation, whether there was reduction
      in seizure severity or not (achieved with 5 mg/kg and 1 mg/kg of MK801,
      respectively). RESULTS: Both ceramide increases and DNA fragmentation were
      observed after KA-induced SE in adult and in P35 rats. Ceramide did not increase
      after KA-induced SE in P7 pups, which also did not manifest any DNA
      fragmentation. Intrahippocampal injection of the active ceramide analogue C2
      ceramide produced widespread DNA fragmentation, whereas the inactive ceramide
      analogue C2-dihydroceramide did not. CONCLUSIONS: Our data support the hypotheses
      that (a) N-methyl-d-aspartate-receptor activation results in ceramide increases
      and in DNA fragmentation; (b) ceramide is a mediator of PCD after SE; and (c)
      there are age-related differences in PCD and in the ceramide response after SE.
      Differences in the ceramide response could, potentially, be responsible for
      observed age-related differences in the response to SE.

PMID- 12614383
TI  - Epileptogenesis induced by alternate-site kindling in bilateral hippocampi.
AB  - PURPOSE: Alternate-site kindling (AK), which has been known to induce so-called
      kindling antagonism, was performed in the bilateral hippocampi to reveal neural
      mechanisms underlying hippocampal kindling. METHODS: Ten adult rabbits were used.
      Daily kindling stimulation consisted of a 1- s train of 50 pulses (pulse
      duration, 1 ms) of 80 to 200 microA (base-to-peak), which was higher than the
      afterdischarge (AD) threshold. The concurrent alternating stimulations were
      delivered to the right and left hippocampus once every 24 h. RESULTS: All animals
      developed a stage 5 convulsion with a mean of 28.1 +/- 3.3 (mean +/- SEM)
      stimulations. The right and left hippocampus received 14.8 +/- 1.7 and 14.6 +/-
      1.6 stimulations, respectively. Behavioral stages induced by stimulation of the
      right or left hippocampus evolved to generalized seizures along a similar course.
      Kindling antagonism was not observed. The two sides showed similar increases in
      AD duration, and similar chronologic changes in interictal discharge (IID)
      frequency. Simple A-type IID and complex types of IID appeared at higher rates,
      whereas simple B-type IID remained at a relatively low level. CONCLUSIONS: The
      present AK procedure did not induce kindling antagonism, but it induced
      progression of kindling manifestations. The origin of simple B-type IID is known
      to be in the contralateral side, and its intracellular counterpart corresponds to
      a sequence of small depolarization followed by large hyperpolarization,
      suggesting that plastic changes in the feed-forward inhibitory system play an
      important role in hippocampal kindling.

PMID- 12614384
TI  - Neuronal cell death in hippocampus induced by homocysteic acid in immature rats.
AB  - PURPOSE: To examine the morphologic alterations in the cerebral cortex and
      hippocampus of immature rats 6 days after the generalized clonic-tonic seizures
      induced by homocysteic acid (HCA). METHODS: Seizures were induced by bilateral
      intracerebroventricular infusion of HCA (600 nmol per each side) in 12-day-old
      rats. After 6 days, rat pups were transcardially perfused under deep ether
      anesthesia with heparinized normal saline and subsequently with the fixation
      solution (4% paraformaldehyde in phosphate buffer, pH 7.4, for light microscopy)
      or with Karnovsky's solution (4% paraformaldehyde and 2% glutaraldehyde in
      phosphate buffer, pH 7.4, for electron microscopic analysis). Nissl stain and the
      DNA-specific dye bis-benzimide (Hoechst 33342) were used. RESULTS: No pathologic
      changes were found in the cerebral cortex, whereas serious alterations occurred
      in the hippocampus. A total loss of CA3 pyramidal cells was observed, with marked
      changes in the CA1 region and dentate gyrus. A prominent glial reaction was seen
      in many regions of the hippocampal formation. A slight dilatation of the cerebral
      ventricles was noticed in some experimental as well as control animals. In the
      granule cell layer of the dentate gyrus, neurons with segmented or fragmented
      nuclei in various stages of degeneration were detected, displaying the features
      of apoptotic death. CONCLUSIONS: These findings demonstrate the vulnerability of
      the immature rat brain, which most likely reflects both the direct neurotoxic
      effect of HCA and prolonged seizure activity. The relative contribution of these
      two factors still remains to be assessed.

PMID- 12614385
TI  - Role of the superior colliculus and the intercollicular nucleus in the brainstem
      seizure circuitry of the genetically epilepsy-prone rat.
AB  - PURPOSE: The neuronal network responsible for the convulsive behavior associated
      with sound-induced seizures in genetically epilepsy-prone rats (GEPRs) is
      believed to include the inferior colliculus and other brainstem structures such
      as the deep layers of the superior colliculus (DLSC), periaqueductal gray, and
      pontine reticular formation. However, previous studies also suggested that the
      DLSC and the nearby intercollicular nucleus (ICN) are part of a midbrain
      anticonvulsant zone capable of suppressing tonic convulsions when activated with
      bicuculline. Our aim in this study was to investigate the role of the superior
      colliculus (SC) and the ICN in generalized tonic-clonic seizures (GTCSs).
      METHODS: Bilateral lesions of the SC and the ICN as well as bicuculline infusions
      into the ICN were used to assess the role of this dorsal midbrain region in
      brainstem seizures induced by sound stimulation in GEPR-9s and GEPR-3s. RESULTS:
      Lesions of the SC markedly attenuated audiogenic seizure (AGS) severity by
      abolishing all behavioral components except the wild running. Lesions of the ICN
      significantly reduced seizure severity in GEPR-9s, but were somewhat less
      effective than SC lesions. Bicuculline infusion into the deep layers of the SC
      and/or the ICN produced audiogenic-like seizures in GEPR-9s. CONCLUSIONS: These
      findings support the hypothesis that the SC and ICN are important components of
      the brainstem seizure network, but suggest they are not necessary for the wild
      running component of the seizure. The results further indicate that stimulation
      of the tectum facilitates GTCSs. Thus these findings suggest that the dorsal
      midbrain, when stimulated, is proconvulsant rather than anticonvulsant regarding
      brainstem seizures in GEPRs.

PMID- 12614386
TI  - An examination of calcium current function on heterotopic neurons in hippocampal
      slices from rats exposed to methylazoxymethanol.
AB  - PURPOSE: To study voltage-dependent calcium currents (VDCCs) on hippocampal
      heterotopic neurons by using whole-cell patch-clamp techniques in brain slices
      prepared from methylaxozymethanol (MAM)-exposed rats. METHODS: Whole-cell voltage
      clamp recordings were obtained from visually identified neurons in acute brain
      slices by using an infrared differential interference contrast (IR-DIC) video
      microscopy system. Heterotopic neurons were compared with normotopic pyramidal
      cells in hippocampal slices from MAM-exposed rats or CA1 pyramidal neurons in
      slices from controls. RESULTS: Heterotopic neurons expressed a prominent VDCC,
      which exhibited a peak current maximum around -30 mV (holding potential, -60 mV)
      and an inactivation time constant of 48.2 +/- 2.4 ms (n = 91). VDCC peak current
      and inactivation time constants were similar for normotopic (n = 92) and CA1
      pyramidal cells (n = 40). Pharmacologic analysis of VDCC, on heterotopic,
      normotopic, and CA1 pyramidal cells, revealed an approximately 70% blockade of
      peak Ca2+ current with nifedipine and amiloride (L- and T-type channel blockers,
      respectively). Inhibition of VDCC, for all three cell types, also was similar
      when more specific Ca2+ channel antagonists were used [e.g., omega-conotoxin GVIA
      (N-type), omega-agatoxin KT (P/Q-type), and sFTX-3.3 (P-type)]. VDCC modulation
      by norepinephrine (NE) or adrenergic receptor-specific agonists [clonidine
      (alpha2), isoproterenol (beta), and phenylephrine (alpha1)] was similar for
      heterotopic and CA1 pyramidal cells. CONCLUSIONS: Heterotopic neurons do not
      appear to exhibit Ca2+ channel abnormalities that could contribute to the
      reported hyperexcitability associated with MAM-exposed rats.

PMID- 12614387
TI  - Effects of age and polytherapy, risk factors of valproic acid (VPA)
      hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in
      people with epilepsy taking VPA.
AB  - PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) used for generalized
      and absence seizures. It has a rare but potentially fatal hepatotoxicity side
      effect, and many researchers believe that reactive metabolites of VPA could be
      involved. We demonstrated here that the thiol conjugates of (E)-2,4-diene VPA
      were significantly elevated in a high-risk group of patients. METHODS: Thirty
      four patients with seizures were divided into three groups. Group A (n = 14) were
      being treated with VPA; group B (n = 12) received VPA as well as other AEDs that
      do not induce P450-VPA metabolism; and group C (n = 8) received VPA and AEDs that
      induce P450-VPA metabolism. The NAC conjugates of (E)-2,4-diene VPA (NAC I and
      NAC II) were identified in the urine of patients by gas chromatography/mass
      spectrography NICI analysis. RESULTS: VPA monotherapy (group A) or VPA
      polytherapy with non-P450-enzyme-inducing drugs (group B), showed that patients
      younger than 7.5 years excreted significantly higher concentrations of the two
      conjugates compared with older patients (older than 7.5 years) in the same groups
      (p < 0.05). Patients receiving VPA polytherapy with P450-enzyme-inducing drugs
      were all older than 7. 5 years (group C). They excreted significantly higher
      concentrations of NAC I and NAC II compared with patients in groups A and B who
      were older than 7.5 years (p < 0.05). CONCLUSIONS: There were no significant
      differences in the excretion of NAC I and NAC II between patients in group C and
      those who were 7.5 years or younger in groups A and B. High doses of VPA also
      were a significant factor associated with elevated NAC I and NAC II among young
      patients and in polytherapy patients.

PMID- 12614388
TI  - Pharmacodynamic analysis of the interaction between tiagabine and midazolam with
      an allosteric model that incorporates signal transduction.
AB  - PURPOSE: The objective of this study was to characterize quantitatively the
      pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of
      the gamma-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an
      inhibitor of synaptic GABA uptake. METHODS: The in vivo concentration-response
      relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD)
      modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence
      and the presence of a steady-state plasma concentration of MDL. The EEG response
      in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point.
      RESULTS: Infusion of MDL resulted in a mean steady-state plasma concentration of
      66 +/- 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed.
      MDL inhibited TGB clearance by 20 +/- 7 ml/min/kg from the original value of 89
      +/- 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were
      observed. The concentration-EEG relation of TGB was described by the sigmoid-Emax
      model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 +/- 10
      microV, EC50 = 392 +/- 20 ng/ml, and nH = 3.1 +/- 0.3. These values were not
      significantly different in the presence of MDL. Factors that may explain the lack
      of synergism were identified by a mechanism-based interaction model that
      separates the receptor activation from the signal-transduction process. High
      efficiency of signal transduction and the presence of a baseline response were
      shown to diminish the degree of synergism. CONCLUSIONS: We conclude that the in
      vivo pharmacodynamic interaction between MDL and TGB is additive rather than
      synergistic. This strongly suggests that allosteric modulation of the antiseizure
      activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic
      advantage.

PMID- 12614389
TI  - The effects of adjunctive topiramate on cognitive function in patients with
      epilepsy.
AB  - PURPOSE: We investigated possible cognitive effects of topiramate (TPM) in
      polypharmacy on patients with intractable epilepsy. METHODS: Study 1 evaluated 22
      consecutively admitted patients whose antiepileptic drugs (AEDs) on admission to
      the Montreal Neurological Hospital included TPM. Performance on
      neuropsychological tests administered on and subsequently off TPM was analyzed.
      Four patients also were tested before taking TPM, allowing comparisons off, then
      on, and then off the drug again. Measures included intellectual function, verbal
      and nonverbal memory, language, word and design fluency, somatosensory
      sensitivity, and motor skills. In Study 2, 16 patients at the Minnesota Epilepsy
      Group were tested first off, then on TPM with nine cognitive tasks that measured
      concentration, verbal fluency, language, and psychomotor speed. RESULTS: In Study
      1, significant (p < or = 0.01) improvements were observed off TPM on 13 measures
      including verbal and nonverbal fluency and certain verbal and perceptual tasks.
      Notably, verbal learning and memory were unaffected; a limited effect was
      observed on nonverbal memory. Patients tested 3 times scored better in both tests
      off TPM compared with on this drug. In Study 2, declines on TPM were observed on
      all measures, significantly (p < or = 0.05) for tests of fluency, sustained
      concentration, and visual motor processing speed. CONCLUSIONS: TPM was associated
      with declines in fluency, attention/concentration, processing speed, language
      skills, and perception; working memory but not retention was affected. As the two
      studies used an opposite order of testing on versus off TPM, our results clearly
      show a performance decrement while patients are taking TPM, without respect to
      which condition is tested first.

PMID- 12614390
TI  - Electrocardiographic changes at the onset of epileptic seizures.
AB  - PURPOSE: We studied heart-rate (HR) changes at the transition from the preictal
      to the ictal state in patients with focal epilepsies to gain some insight into
      the mechanisms involved in the neuronal regulation of cardiovascular function.
      METHODS: We assessed ECG changes during 145 seizures recorded with scalp EEG in
      58 patients who underwent video-EEG monitoring. Consecutive RR intervals were
      analyzed with a newly developed mathematical method for a total of 90 s. RESULTS:
      Ictal-onset tachycardia occurred in 86.9% of all seizures, whereas bradycardia
      was documented only in 1.4%. The incidence as well as the amount of ictal HR
      increase was significantly more pronounced in patients with mesial temporal lobe
      epilepsy (TLE) as compared with those with non-lesional TLE or extratemporal
      epilepsy. Moreover, right hemispheric seizures were associated with ictal-onset
      tachycardia. On average, ictal HR increase preceded EEG seizure onset by 13.7 s
      in TLE patients and 8.2 s in patients with extratemporal epilepsy. This
      difference was significant. Ictal HR changes could be classified according to
      their temporal evolution into two different patterns. These two patterns differed
      significantly between the temporal lobe and the extratemporal epilepsy patient
      group. CONCLUSIONS: Epileptic discharges directly influence areas of the central
      autonomic network, thus regulating HR and rhythm. Such changes occur before ictal
      discharges appear on surface electrodes. Our newly developed method may be of
      potential use for clinical applications such as automatic seizure-detection
      systems. Moreover, our method might help to clarify further the basic mechanisms
      of interactions between heart and brain.

PMID- 12614391
TI  - Anterior thalamic mediation of experimental seizures: selective EEG spectral
      coherence.
AB  - PURPOSE: Physiological evidence has shown that the anterior thalamus (AN) and its
      associated efferents/afferents constitute an important propagation pathway for
      pentylenetetrazol (PTZ)-mediated generalized seizures in rodents. Previous work
      demonstrated metabolic, physical, chemical, and electrical stimulation data
      supporting a role for AN in the expression of PTZ seizures. We now extend these
      observations through examination of neuroelectric signal indicators during
      seizure epochs. We show that the EEG recorded from AN is highly coherent with
      surface cortical (CTX) EEG during the immediate preconvulsant period and during
      the ictal stateough. METHODS: Awake rats were continuously infused with PTZ until
      clonic seizures were recorded by using both subcortical AN, posterior thalamus
      (PT), or hippocampal (HPC) bipolar electrodes and cortical EEG. Through the
      signal-analysis techniques of ordinary and partial coherence, it was possible to
      focus selectively on signal correlations between AN and CTX (AN/CTX) by removing
      the effects of unaffiliated regions such as PT and HPC. RESULTS: Coherence of
      PT/CTX was observed to be modest, and partial coherence of PT/CTX with the
      effects of AN/CTX removed did not improve the signal coherence of PT/CTX (PT/CTX
      AN). In contrast, AN/CTX coherence was observed to be high, with undiminished
      correlation when PT/CTX influence was removed (AN/CTX-PT). The most robust band
      of AN/CTX coherence was centered around the spike-wave clonic frequency of 1-3
      Hz. Partial multiple coherence-analysis techniques were used to remove the
      possible signal contributions from hippocampus in addition to PT. The AN/CTX
      coherence remained fully preserved in the low-frequency bands. CONCLUSIONS: These
      data provide electrophysiologic evidence supporting the special role of the
      anterior thalamus in the propagation of seizure activity between subcortex and
      cortex.

PMID- 12614392
TI  - Metabolic properties of band heterotopia differ from those of other cortical
      dysplasias: a proton magnetic resonance spectroscopy study.
AB  - PURPOSE: To assess the biochemical properties of band heterotopia in comparison
      with other cortical developmental malformations (CDMs) by using proton magnetic
      resonance spectroscopy (1H-MRS). METHODS: We performed localized single-voxel 1H
      MRS studies on 13 patients [five band heterotopia (BH), two focal cortical
      dysplasia (CD), two unilateral CD, one bilateral perisylvian dysplasia, three
      hemimegalencephaly]. CDMs other than BH were categorized as CD. Spectra were
      acquired from volumes of interest (VOIs) localized in the CD and in normal
      appearing cortex on the contralateral side. In BH patients, the VOIs were the
      external cortex and the laminar heterotopia. For the BH study, spectra also were
      obtained from the cortex of age-matched normal volunteers. RESULTS: The spectra
      of CD lesions were characterized by significantly lower ratios of N-acetyl
      aspartate to creatine (NAA/Cr) and by higher choline to Cr (Cho/Cr) ratios than
      in the contralateral remote cortex (p = 0.01 and 0.01, respectively). The NAA/Cr
      and Cho/Cr ratios of the external cortex of BH were not significantly different
      from those of normal volunteers. The NAA/Cr ratio of the laminar heterotopia was
      not significantly different from that of the external cortex (p = 0.12) or normal
      volunteers (p = 0.60), whereas Cho/Cr was significantly higher in laminar
      heterotopias than in the external cortex (p = 0.04) or controls (p = 0.03).
      CONCLUSIONS: 1H-MRS can distinguish between the metabolic properties of BH and
      CD.

PMID- 12614393
TI  - Abnormal neuroimaging in patients with benign epilepsy with centrotemporal
      spikes.
AB  - PURPOSE: Neuroimaging procedures are usually unnecessary in benign epilepsy of
      childhood with centrotemporal spikes (BECTS) but are often performed before a
      specific diagnosis has been reached. By definition, BECTS occurs in normal
      children; however, recent reports have shown that it also can affect children
      with static brain lesions. We evaluated the prevalence of abnormal neuroimaging
      in BECTS and assessed whether the lesions had influenced the clinical and EEG
      expression of this epilepsy. RESULTS: Among 98 consecutive cases first referred
      between 1984 and 1999, neuroimaging had been performed in 71 (72%) [magnetic
      resonance imaging (MRI), 20; computed tomography (CT), 59; MRI+CT, eight]. In ten
      (14.8%), neuroradiologic procedures were abnormal: enlargement of lateral
      venticles in five cases including a shunted hydrocephalus in two (no etiology in
      one, neonatal intraventricular hemorrhage in one), a moderate ventricular
      dilation in one (neonatal distress), a slight ventricular dilation and
      hypersignal intensities in the white matter in one (premature birth at 27 weeks),
      and a moderate enlargement of the right temporal horn in one. A right hippocampal
      atrophy, a biopercular polymicrogyria, a cavum septum pellucidum, a small cystic
      lesion located in the epiphysis, and an agenesis of the corpus callosum with
      macrocrania also were observed once each. The outcome was benign in all, in
      accordance with the overall prognosis of BECTS. CONCLUSIONS: This study confirms
      that neuroimaging may be abnormal in patients with BECTS and shows that the
      presence of brain lesions has no influence on the prognosis. Conversely, BECTS
      can be diagnosed in patients with brain lesions with or without significant
      neurologic history or abnormalities.

PMID- 12614394
TI  - Stratifying differences on ictal/interictal subtraction SPECT images.
AB  - PURPOSE: Subtraction of interictal from ictal single-photon emission computed
      tomography (SPECT) yields numerous foci that encompass a range of pixel values
      scattered in the brain. This preliminary study evaluated the significance of this
      range of values. METHODS: Subtraction images were obtained by registering,
      normalizing, and subtracting interictal from ictal SPECT for 13 patients. Pixel
      values of the resulting foci were divided into two groups: group I with 75-100%
      and group II with 50-75% of the maximal pixel value. Locations of these foci were
      determined, and concordance with surgical outcomes and scalp and invasive EEG
      findings was evaluated. RESULTS: In 10 of 13 cases, group I foci showed good
      concordance with ictal scalp EEG. In addition, group I foci corresponded well to
      invasive EEG findings in nine of 10 cases. Group I foci had bilateral
      distributions in seven of 13 cases. In 10 of 13 cases, group I foci corresponded
      well to regions of surgical resection. Of these 10 patients, nine showed good
      concordance with scalp EEG, eight showed good invasive EEG concordance, and eight
      were seizure free after resection. Conversely, group II foci had good concordance
      with ictal scalp EEG in only five of 13 cases, and invasive EEG findings, in only
      five of 10 cases. Group II foci had bilateral distributions in 10 of 13 cases.
      All 10 cases underwent unilateral surgical resections, and all had good surgical
      outcomes. In six of 13 cases, group II foci showed concordance with surgical
      sites. Of these six foci, four had poor concordance with scalp EEG, one had poor
      concordance with invasive EEG, and five had good surgical outcomes. Sensitivity
      and specificity for seizure localization of Group I foci were 40% and 88%
      respectively while sensitivity and specificity of Group II foci were 20% and 79%
      respectively. CONCLUSIONS: Our data demonstrate that foci with 75-100% of maximal
      pixel values show good concordance with seizure foci, whereas foci of 50-75% may
      not. Therefore stratifying ictal/interictal differences may improve the
      specificity and localizing value of subtraction SPECT.

PMID- 12614395
TI  - Seizure control and cognitive outcome after temporal lobectomy: a comparison of
      classic Ammon's horn sclerosis, atypical mesial temporal sclerosis, and tumoral
      pathologies.
AB  - PURPOSE: Neuropathologic examination of resected tissue after anterior temporal
      lobectomy (ATL) for treatment of complex partial seizures revealed several
      distinct histologic substrates. Our study examined the relation between
      neuropathology, seizure control, and cognition in ATL patients and described
      preliminary profiles to aid in the prediction of outcome. METHODS: Of the 149
      patients who underwent ATL from 1980 to 1999, long-term follow-up was available
      for 145. Specimens from 124 of the 145 patients had histologic findings
      consistent with one of three diagnoses: classic Ammon's horn sclerosis (cAHS; n =
      75), atypical mesial sclerosis (Atypical; n = 21), or low-grade tumor (Tumor; n =
      28). The other 20 patients had diverse pathologies that were insufficient for
      analysis. ATL patients underwent a complete preoperative and 68 underwent a
      postoperative neuropsychological evaluation. RESULTS: Of the 145 patients, 84% of
      cAHS, 57% of Tumor, and 29% of Atypical patients had a > or =95% reduction in
      seizure frequency. Neuropsychological testing suggested that cAHS patients
      demonstrate more generalized preoperative cognitive impairment than do the
      Atypical or Tumor patients. The Atypical group recalled significantly less
      nonverbal material after surgery than did the cAHS or Tumor groups.
      Stratification by both pathology and surgery side revealed that the right
      Atypical patients declined more on information processing and set shifting.
      CONCLUSIONS: Patients with cAHS or Tumor demonstrated better seizure control and
      fewer declines in cognitive functioning after ATL than did the Atypical patients,
      highlighting the need to investigate this group as a distinct entity.

PMID- 12614396
TI  - Presurgical evaluation of epilepsy by brain diffusion: MR-detected effects of
      flumazenil on the epileptogenic focus.
AB  - PURPOSE: After focal status epilepticus, focal alterations of the apparent
      diffusion coefficient (ADC) have been demonstrated in the epileptogenic zone by
      using diffusion-weighted magnetic resonance (MR)imaging (DWI). Effects of
      flumazenil on an epileptogenic focus have been demonstrated by EEG recordings,
      but not by functional MRI. We hypothesized that dynamic spatiotemporal
      alterations of brain diffusion of the epileptogenic focus after application of
      flumazenil will be detectable by DWI and correlate with the epileptogenic zone.
      METHODS: Twelve adult patients considered for epilepsy surgery with medically
      intractable temporal lobe epilepsy (TLE; n = 7), extratemporal lobe epilepsy
      (ETE; n = 2), and TLE+ETE (n = 3) were prospectively examined with DWI
      interictally (serving as baseline) and 10 min after application of 1 mg
      flumazenil i.v. RESULTS: The baseline interictal ADC was significantly elevated
      in the hippocampus on the ictogenic side in the patients with TLE (p = 0.002) as
      compared with healthy volunteers. The following changes of the mean ADC were seen
      in different regions of interest (ROIs) after injection of flumazenil: decreases
      in the hippocampus on the seizure-onset side by 14.8% (p = 0.005); decreases in
      the parahippocampal gyrus on both sides by 6.8% (epileptogenic side; p = 0.044)
      or 7.9% (nonepileptogenic side; NS), respectively; decreases in the cortex on the
      nonictogenic side by 7.9% (p = 0.047); and no significant changes of the ADC in
      the other ROIs. CONCLUSIONS: ADC decreases measured after application of
      flumazenil were seen in the seizure-onset zone as revealed by EEG and structural
      MRI and are an indicator of focus localization in patients with TLE.

PMID- 12614397
TI  - Lateralising value of neuropsychological protocols for presurgical assessment of
      temporal lobe epilepsy.
AB  - PURPOSE: To estimate the value of neuropsychological measurements in determining
      the side of seizure onset for presurgical assessment in patients with temporal
      lobe epilepsy. The lateralising value of neuropsychological protocols was
      evaluated for all patients and in subpopulations depending on surgical outcome
      with regard to seizure control, speech dominance, neuropathology, and need for
      intracranial EEG recordings. METHODS: A battery of neuropsychological procedures
      was carried out preoperatively in 125 patients who underwent left (n = 66) or
      right (n = 59) temporal lobectomies. Binary logistic regression analysis was
      performed to find sets of variables that allowed the best prediction of the side
      of seizure onset (assumed to be the operated-on side). RESULTS: Combinations of
      noninvasive neuropsychological tests and Wada subscores showed the highest
      lateralising values: 80.8% for all patients, 79.4% in seizure-free patients,
      86.0% in patients not rendered seizure free, 85.7% in left speech patients, 77.8%
      in non-left speech patients, 89.3% in patients with mesial temporal sclerosis
      (MTS), 78.1% in non-MTS patients, 80.3% in patients who underwent intracranial
      EEG recordings, and 77.3% in those who did not. CONCLUSIONS: The lateralising
      value (80-90%) of neuropsychological protocols appears similar to that of other
      tests widely accepted for lateralisation (ictal and interictal scalp EEG and
      neuroimaging). Attention should be paid to neuropsychological results,
      particularly from the Wada test, during presurgical assessment of temporal lobe
      epilepsy, as they can provide strong support for findings from other lateralising
      tests, particularly in patients with presumed MTS or in left-speech patients.

PMID- 12614398
TI  - Depression in intractable partial epilepsy varies by laterality of focus and
      surgery.
AB  - PURPOSE: Depression sometimes occurs after surgical treatment for medically
      intractable partial epilepsy. The risk of pre- and postsurgical depression may
      vary by laterality of seizure focus. We reviewed the pre- and postsurgical
      psychological assessments and clinical courses of patients to identify those at
      highest risk for postsurgical mood disorders. METHODS: Depression status was
      assessed in a consecutive series of epilepsy patients before and 1 year after
      epilepsy surgery with the use of Scale 2 of the MMPI-2 and a clinical depression
      index (CDI) scoring the occurrence of depressive symptoms, psychiatric referral,
      or attempted/completed suicide. Outcome at 1 year was modeled by regression
      techniques as functions of preoperative mood measurements, side of epilepsy
      surgery, and preoperative verbal intelligence. RESULTS: The CDI and Scale 2 MMPI
      2 correlated significantly (r = 0.341; p < or = 0.01). Left (n = 54 subjects) and
      right (n = 53) surgery groups did not differ by sex, seizure outcome, age,
      education, age at first seizure, duration of epilepsy, or intellect. Higher
      presurgical depressive morbidity (p = 0.0037) and right-sided surgery (p =
      0.0003) predicted higher postoperative CDI. Higher preoperative Scale 2 scores,
      indicating worse depressive traits, predicted worse postoperative Scale 2 scores
      (p < 0.0001). Although side of surgery did not predict Scale 2 scores, Scale 2
      scores of patients with preoperative right-sided foci tended to have worse
      postsurgical Scale 2 scores (p = 0.08). Findings for the temporal lobectomy
      subgroup (n = 90) were similar to those of the overall sample. CONCLUSIONS:
      Patients undergoing right hemispheric epilepsy surgery, especially those with
      high presurgical depression-related morbidity, may be particularly susceptible to
      clinical depression. Our findings support other studies that show an
      interhemispheric modulation of depressive traits and symptoms.

PMID- 12614399
TI  - Quantitative interictal subdural EEG analyses in children with neocortical
      epilepsy.
AB  - PURPOSE: We studied the relation between quantitative interictal subdural EEG
      data and visually defined ictal subdural EEG findings in children with
      intractable neocortical epilepsy, and determined whether interictal EEG data are
      predictive of ictal EEG onset zones. METHODS: Thirteen children (aged 1.2-15.4
      years) underwent prolonged intracranial EEG recording, using 48- to 120-channel
      subdural electrodes. Three distinct 10-min segments of the continuous interictal
      EEG recording were selected for each patient, and the spike frequency for each
      channel was determined by using an automatic spike-detection program.
      Subsequently the average spike frequency of each electrode was compared with
      ictal assessment (onset, spread, and no early ictal involvement). In addition, 50
      distinct interictal spikes were averaged for each patient, and the amplitude and
      latency after the leading spike (averaged spike showing the earliest peak) were
      measured for each electrode and analyzed with respect to ictal EEG findings.
      RESULTS: Reproducibility of the spike-frequency pattern derived from three 10-min
      segments was high (Kendall's W, 0.85 +/- 0.08). Electrodes showing the highest
      spike frequency, the highest spike amplitude, and the leading spike were found to
      be a part of the seizure onset in 13 of 13, 12 of 13, and 10 of 13 cases,
      respectively. There was significant correlation between ictal assessment and
      spike frequency as well as spike amplitude. A receiver operating characteristics
      analysis showed that a cutoff threshold at 14% of the maximal spike frequency
      resulted in a specificity of 0.90 and a sensitivity of 0.77 for the detection of
      seizure-onset electrodes. CONCLUSIONS: Quantitative interictal subdural EEG may
      predict ictal-onset zones in children with intractable neocortical epilepsy.

PMID- 12614400
TI  - EEG in children with early-onset benign occipital seizure susceptibility
      syndrome: Panayiotopoulos syndrome.
AB  - PURPOSE: We analyzed sequential changes in the localization of EEG foci along
      with age to identify a specific EEG pattern, and the relation between the
      clinical manifestations and the EEG pattern in patients with Panayiotopoulos
      syndrome (PS). METHODS: The subjects were 76 children, who had been followed up
      >2 years with repeated EEG examinations at 6-month intervals. Analysis of EEG
      findings included the determination of localization of spike foci, as a function
      of age, by using cross-sectional data, and the identification of subgroups with
      homogeneous EEG patterns. Then we compared certain clinical features among these
      subgroups. RESULTS: In the cross-sectional EEG study, the occipital EEG spike
      focus was most frequently seen between ages 2 and 5 years. Independent and
      synchronous frontopolar and occipital spikes (Fp-O spikes) and
      centroparietotemporal (CPT) EEG spike foci had increased incidences between ages
      4 and 7 years, and between ages 6 and 10 years, respectively. We subclassified
      the 76 patients into the following five subgroups based on the evolutional
      changes in epileptic EEG foci, which frequently showed shifting, multiplications,
      and generalization: (a) persistent occipital focus group (O group), (b) Fp-O
      spikes group (Fp-O pattern group), (c) generalized EEG pattern group, (d) CPT
      foci group (CPT group), and (e) no epileptic EEG focus group. The Fp-O group
      showed the latest age at onset of epilepsy. The generalized EEG pattern group had
      the highest frequency of seizures as well as recurrences of status epilepticus
      (SE), as well as the longest active seizure period among the five groups.
      CONCLUSIONS: These results indicated that the EEG foci in most of patients with
      PS are frequently shifting location, multiplying, and propagating diffusely with
      age, rather than persistently localizing in the occipital region. In addition,
      the EEG patterns showed a certain trend and roughly corresponded to certain
      clinical characteristics. However, the prognosis of the seizures appeared to be
      favorable regardless of the EEG pattern.

PMID- 12614401
TI  - The predictive value of electroencephalogram during early infancy for later
      development of West syndrome in infants with cystic periventricular leukomalacia.
AB  - PURPOSE: The aim of this study was to elucidate a predictive value of
      electroencephalogram (EEG) during early infancy for later development of West
      syndrome (WS) in premature infants with cystic periventricular leukomalacia
      (PVL). METHODS: The subjects of this study were 19 infants with cystic PVL born
      between 1992 and 1996. EEGs were recorded at 3 months of corrected age (CA) in
      all of them. We divided these 19 infants into the following two groups; group A
      (n = 9), no paroxysmal discharge was recognized; and group B (n = 10), paroxysmal
      discharges were recognized. RESULTS: In none of the infants in group A did WS
      develop. Subsequent EEGs were normal in all infants in group A. WS developed in
      seven of 10 infants in group B. The occurrence of WS is significantly higher in
      group B than in group A. The mean age at the onset of WS was 6 months of CA.
      Paroxysmal discharges in infants in group B were observed as irregular spikes-and
      waves and polyspikes-and-waves, mainly in bilateral parietooccipital areas. In
      seven of eight patients with severe MRI findings in group B, WS developed.
      CONCLUSIONS: Paroxysmal discharges during early infancy were correlated with
      later development of WS in infants with cystic PVL. The possibility of developing
      WS had increased in the children with the combination with EEG and MRI findings.

PMID- 12614402
TI  - Physical and hormonal profile of male sexual development in epilepsy.
AB  - PURPOSE: This study was designed to investigate the effect of epilepsy and
      antiepileptic drugs (AEDs) on both the physical and hormonal aspects of the
      sexual development of male patients with epilepsy. METHODS: One hundred thirty
      male subjects with epilepsy, their age ranging between 8 and 18 years (mean, 14
      +/- 2.9 years), entered the study; all were taking AEDs. Anthropometric
      measurements [height, weight, and body mass index (BMI)], testicular volume,
      penile length, and pubarche were assessed in the studied groups, as well as
      measurement of the levels of testosterone (T), free testosterone (FT), estradiol
      (E2), lutenizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin
      (PRL), and the results were compared with those of a control group. RESULTS: In
      this study, male patients older than 16 years were significantly shorter than
      their matched controls. The mean values of testicular volume and penile length
      were significantly lower in the patients in the different age subgroups, and the
      pubic hair staging (pubarche) was delayed in the patients older than 16 years.
      The mean values of total testosterone, estradiol, LH, and FSH serum levels were
      significantly higher, whereas the mean values of free testosterone, total-T/E2,
      total. T/LH, and FT/E2 ratios were lower in the patient subgroups compared with
      their age-matched controls. There were no significant changes in the mean basal
      PRL serum levels in the patients compared with the controls. The present study
      demonstrated a reduction in the testicular volume and penile length,
      significantly lower mean values of free testosterone and total-T/E2, and a higher
      mean value of E2 in the patients receiving polytherapy in the age subgroup older
      than 16 years compared with those on monotherapy; however, there was no
      demonstrable effect of seizure control or the duration of illness in any of the
      studied parameters. CONCLUSIONS: There is a delay in the sexual development of
      male patients with epilepsy in the different age subgroups, with endocrine
      changes in the form of increase in the total testosterone, but the free
      testosterone is lower, and an increase in estradiol, with lower T/LH levels.
      Patients receiving polytherapy, especially those older than 16 years, were more
      likely to have delayed gonadarch and disturbances in their hormonal profile.

PMID- 12614403
TI  - The diagnostic significance of video-EEG monitoring findings on pseudoseizure
      patients differs between neurologists and psychiatrists.
AB  - PURPOSE: The diagnosis of psychogenic pseudoseizures has improved with the
      availability of video-electroencephalography (EEG) monitoring; however, the
      outcome of this difficult disorder has remained poor. In an attempt to elucidate
      factors contributing to this poor outcome, we hypothesized that neurologists and
      psychiatrists differ in their views of the diagnosis and management of
      psychogenic pseudoseizure patients. METHODS: The hypothesis was tested by using a
      brief anonymous questionnaire administered to neurologists and psychiatrists at
      continuing medical education (CME) conferences. RESULTS: We found that
      neurologists and psychiatrists differ significantly in their opinion as to the
      accuracy of the video-EEG procedure; psychiatrists view video-EEG as often
      inaccurate in the diagnosis of psychogenic pseudoseizures compared with
      neurologists (p < 0.001). Neurologists, more frequently than psychiatrists,
      thought that patients' own psychopathology rather than "doctors dropping the
      ball" was a predominant factor in contributing to therapeutic failure, but this
      difference between specialties did not reach statistical significance.
      CONCLUSIONS: Resolving the differences between neurologists and psychiatrists
      would be helpful in caring for psychogenic pseudoseizure patients. These results
      support the need to encourage psychiatrists to have an integral involvement in
      epilepsy centers and to improve the understanding of psychogenic pseudoseizures
      in both disciplines.

PMID- 12614404
TI  - Lipoprotein(a) concentration increases during treatment with carbamazepine.
AB  - PURPOSE: Treatment with carbamazepine (CBZ) is known to affect apolipoprotein B
      containing lipoprotein concentrations in serum. However, little is known about
      the effects of anticonvulsant drugs (AEDs) on lipoprotein(a) [Lp(a)], although
      Lp(a) has been characterized as independent cardiovascular risk factor. We
      investigated prospectively the effect of CBZ on lipoprotein(a) concentration in
      normolipidemic healthy adults. METHODS: Twenty male volunteers were included in
      the study. Lp(a) levels were determined before and 69 +/- 19 days after CBZ
      administration by using an enzyme-linked immunoassay. RESULTS: CBZ (mean plasma
      concentration, 6.6 +/- 0.6 microg/ml) caused a significant increase in Lp(a)
      concentrations, with a median change of +19.5% (95% CI: +8.2, +53.3; p < 0.001).
      Total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides
      also increased significantly. CONCLUSIONS: Although the precise mechanism of
      action of CBZ on Lp(a) elevation remains uncertain, it might be related to its
      enzyme-inducing properties. During treatment with CBZ, special focus should be
      given to elevated LDL cholesterol and Lp(a) concentrations with regard to
      increased risk for atherosclerotic vascular diseases.

PMID- 12614405
TI  - Tonic-absence seizures: an underrecognized seizure type.
AB  - PURPOSE: The individual electroclinical patterns--tonic seizures with generalized
      paroxysmal fast activity (GPFA, activity >13 Hz), and absence seizures with
      generalized slow spike-and-wave activity (GSS&W, <3 Hz)--have been extensively
      described in the literature. However, only passing reference was made to the
      pattern of GPFA followed by GSS&W. In addition, these descriptions were
      formulated in the pre-EMU (Epilepsy Monitoring Unit) era, without benefit of
      video/clinical correlation. We now characterize this underrecognized seizure
      type. METHODS: We retrospectively reviewed the data from eight patients with
      seizures that demonstrated this stereotyped EEG and clinical pattern. RESULTS: We
      identified eight patients (six female patients; age 6-29 years; age at seizure
      onset, neonate to 10 years) who were evaluated at the Columbia University
      Epilepsy Monitoring Units between 1993 and 2002. All eight had an International
      League Against Epilepsy (ILAE) diagnosis of symptomatic generalized epilepsy,
      with six of eight manifesting multiple seizure types, six of eight with mild
      static encephalopathy, and two with normal cognition. A total of 29 seizures of
      this pattern was recorded; 26 of 29 seizures demonstrated GPFA (frequency between
      14 and 30 Hz, lasting 2-8 s) followed by GSS&W (frequency range between 1 and 2
      Hz, lasting 3-50 s). The predominant clinical correlate was bilateral tonic
      activity followed by a period of inattentiveness. In general, these seizures were
      differentiated from the patient's typical tonic seizures by this protracted
      period of impaired attentiveness. CONCLUSIONS: We describe a heretofore
      underrecognized and poorly characterized seizure type in patients with
      symptomatic generalized epilepsy, which we have termed tonic-absence seizures.
      Clinically and electrographically, this consists of a tonic seizure with GPFA
      followed by an absence seizure with GSS&W.

PMID- 12614406
TI  - Expressive aprosody and amusia as a manifestation of right hemisphere seizures.
AB  - PURPOSE: Aprosody and amusia are disorders commonly associated with right
      hemisphere abnormalities. They are regarded as negative phenomena and usually
      seen after strokes. We report a case of a patient who had both expressive
      aprosody and amusia as a clinical manifestation of right temporooccipital
      seizures. METHODS: A 43-year-old woman had a 1-month history of monotonic speech
      and difficulty singing. Her examination revealed both expressive aprosody and
      amusia. Magnetic resonance imaging of the head was normal, but her EEG revealed
      several electrographic seizures of right temporooccipital origin. RESULTS:
      Treatment with phenytoin (PHT) almost immediately caused her speech and singing
      to return to baseline. A repeated EEG was normal CONCLUSIONS: Seizures of right
      temporooccipital origin can manifest with expressive aprosody and amusia.

PMID- 12614407
TI  - Successful neurosurgical treatment of childhood complex partial status
      epilepticus with focal resection.
AB  - The treatment of complex partial status epilepticus continues to be
      controversial, especially with regard to the intensity of the treatment. Medical
      therapy and drug-induced coma are sometimes required. Rarely this may not be
      effective. A healthy 4-year old girl was first seen in complex partial status
      epilepticus. She had a 1-year history of cryptogenic partial-onset seizures.
      Detailed magnetic resonance imaging (MRI) studies were normal. Her course was
      refractory to multiple medical therapies and multiple subpial transection (MST).
      An urgent epilepsy surgery evaluation resulted in a focal cortical resection
      being performed over the right mesial parietal region with resultant seizure
      freedom and no significant neurologic deficit 2 years later. This patient
      illustrates the need to consider occult focal cortical dysplasia as a cause of
      nonconvulsive status epilepticus (NCSE) in children, and if it is not responsive
      to medical management, the utility of performing an urgent epilepsy surgery
      evaluation.

PMID- 12614408
TI  - Familial dysautonomia (Riley-Day syndrome) may be associated with epilepsy.

PMID- 12614409
TI  - Noninvasive imaging, treatment, and microscopic confirmation of clearance of
      basal cell carcinoma.
AB  - BACKGROUND: The diagnosis of basal cell carcinoma (BCC) is generally established
      by skin biopsy followed by tissue preparation and microscopic analysis. Treatment
      of BCC is often accomplished by surgical excision. OBJECTIVE: To confirm the
      presence of BCC with a noninvasive imaging technique, to treat the patient with a
      topical immune response modifier, and to confirm the clearance of BCC
      noninvasively. METHODS: Confocal microscopy (CM) is a noninvasive technique for
      real-time imaging of skin in vivo. Imiquimod, an immune response modifier, is
      applied topically by the patient to the skin lesion. RESULTS: The presence of BCC
      was confirmed with CM. Posttreatment CM imaging confirmed the clearance of BCC
      from the entire treatment field. Both the pretreatment and the posttreatment CM
      findings were confirmed by invasive biopsy. CONCLUSION: The ability to use CM to
      image in real time without discomfort to the patient makes it a powerful tool to
      assist in the diagnosis of skin disease.

PMID- 12614410
TI  - Injecting 1000 centistoke liquid silicone with ease and precision.
AB  - BACKGROUND: Since the Food and Drug Administration approved the use of the 1000
      centistoke liquid silicone, Silikon 1000, for intraocular injection, the off
      label use of this injectable silicone oil as a permanent soft-tissue filler for
      facial rejuvenation has increased in the United States. Injecting liquid silicone
      by the microdroplet technique is the most important preventive measure that one
      can use to avoid the adverse sequelae of silicone migration and granuloma
      formation, especially when injecting silicone to improve small facial defects
      resulting from acne scars, surgical procedures, or photoaging. OBJECTIVE: To
      introduce an easy method for injecting a viscous silicone oil by the microdroplet
      technique, using an inexpensive syringe and needle that currently is available
      from distributors of medical supplies in the United States. METHOD: We suggest
      the use of a Becton Dickinson 3/10 cc insulin U-100 syringe to inject Silikon
      1000. This syringe contains up to 0.3 mL of fluid, and its barrel is clearly
      marked with an easy-to-read scale of large cross-hatches. Each cross-hatch
      marking represents either a unit value of 0.01 mL or a half-unit value of 0.005
      mL of fluid, which is the approximate volume preferred when injecting liquid
      silicone into facial defects. Because not enough negative pressure can be
      generated in this needle and syringe to draw up the viscous silicone oil, we
      describe a convenient and easy method for filling this 3/10 cc diabetic syringe
      with Silikon 1000. RESULTS: We have found that by using the Becton Dickinson 3/10
      cc insulin U-100 syringe, our technique of injecting minute amounts of Silikon
      1000 is facilitated because each widely spaced cross-hatch on the side of the
      syringe barrel is easy to read and measures exact amounts of the silicone oil.
      These lines of the scale on the syringe barrel are so large and clearly marked
      that it is virtually impossible to overinject the most minute amount of silicone.
      CONCLUSION: Sequential microdroplets of 0.01 cc or less of Silikon 1000 can be
      measured and injected with the greatest ease and precision so that inadvertent
      overdosing and complications can be avoided.

PMID- 12614411
TI  - Posttraumatic lipoma: analysis of 10 cases and explanation of possible
      mechanisms.
AB  - BACKGROUND: Trauma and lipoma are the most frequently met occurrences in clinical
      routine. Although lipomas are well-known fatty tumors both clinically and
      pathologically, the precise etiology is still unknown. Generally, posttraumatic
      lipomas are known as "pseudolipoma," which describes herniation of deeper fat
      through Scarpa's layer secondary to trauma. Here we present 10 patients with
      lipoma secondary to blunt trauma in different anatomical sites. OBJECTIVES: To
      correlate trauma and lipoma relationships and to discuss the possible
      pathogenetic mechanism by reviewing literature. METHODS: Ten patients (12
      lipomas) after blunt trauma were presented, and data of patients were reviewed.
      Ultrasonography and/or nuclear magnetic resonance were employed for diagnosis in
      addition to physical examination. All tumors were verified by histopathologic
      examinations. Patients were followed for a minimum of 6 months. RESULTS: The
      average age was 34. Four of the lesions (12 altogether) were located on an upper
      extremity, 5 on a lower extremity, 2 on the trunk, and 1 on the neck. Excision of
      tumors and primary closure were performed in 92% of the lesions, and only one
      liposuction was performed. Aesthetic results were achieved in all patients. There
      were no complications and recurrences. CONCLUSION: The effect of blunt trauma on
      fat tissue may be explained by different theories. We summarized possible
      mechanisms into two groups according to our observations and review of the
      literature: The first was related to mature adiposities and mainly a mechanical
      effect, and the second was differentiations of the preadipocytes to lipoma by the
      promoting factors. We speculate that only traumas that serve as a cause of fat
      necrosis may trigger the formation of the lipoma, and local inflammation
      secondary to fat necrosis may affect adipocytes and promote new formation of
      lipoma.

PMID- 12614412
TI  - Ambulatory phlebectomy versus compression sclerotherapy: results of a randomized
      controlled trial.
AB  - BACKGROUND: Although no randomized controlled trial has assessed the effects of
      either compression sclerotherapy or ambulatory phlebectomy, both techniques are
      used to treat varicose veins worldwide. We performed a randomized controlled
      trial to compare recurrence rates of varicose veins and complications after
      compression sclerotherapy and ambulatory phlebectomy. METHODS: From September
      1996 to October 1998, we randomly allocated 49 legs to compression sclerotherapy
      and 49 legs to ambulatory phlebectomy. Our primary outcome parameters were as
      follows: recurrence rates at 1 and 2 years and complications related to therapy.
      Eighty-two patients were included, of whom 16 were included with both of their
      legs. The number of treated legs was therefore 98, but two patients were lost to
      follow-up. RESULTS: One year recurrence amounted to 1 out of 48 for phlebectomy
      and 12 out of 48 for compression sclerotherapy (P<0.001); at 2 years, six
      additional recurrences were found, but then solely for compression sclerotherapy
      (P<0.001). Significant differences in complications occurring more in phlebectomy
      than in compression sclerotherapy therapy were blisters, teleangiectatic matting,
      scar formation, and bruising from bandaging. CONCLUSION: Our results show that
      ambulatory phlebectomy is an effective therapy for varicose veins of the leg.
      Recurrence rates are significantly lower than for compression sclerotherapy
      therapy. If varicose veins persist 4 weeks after compression sclerotherapy, it
      can be argued that to reduce the risk of future recurrence ambulatory phlebectomy
      should be considered as the better treatment option.

PMID- 12614413
TI  - Shave excision of benign facial melanocytic naevi: a patient's satisfaction
      survey.
AB  - BACKGROUND: Shave excision is a simple and quick procedure that is widely used
      for removal of benign naevi. Limited published data are available on patient
      acceptability of this procedure or its potential cosmetic outcomes. OBJECTIVES:
      To assess the patient's satisfaction with the procedure, to assess the risk of
      recurrence, and to determine the patient's perception of the scar. METHODS:
      Questionnaires were sent to 93 consecutive patients who had shave excision of
      benign facial naevi. RESULTS: Seventy-six patients (82%) with a total of 83 naevi
      responded. Twenty-eight percent of naevi were reported to have recurred 12 months
      after shave excision. A significantly higher recurrence rate was found with hairy
      naevi (41%, P= 0.04). More than half of the patients reported no scar or had a
      white and flat scar. Nineteen percent of scars were depressed, and 15% were
      raised; 7% were pigmented. The majority of patients were satisfied with the
      results. CONCLUSIONS: Despite a high recurrence rate, most patients were
      satisfied with the cosmetic outcomes after shave excision of benign facial naevi.
      The results of this study have helped us to provide our patients with more
      accurate information regarding cosmetic outcomes.

PMID- 12614414
TI  - Corrective hair restoration techniques for the aesthetic problems of
      temperoparietal flaps.
AB  - BACKGROUND: Temperoparieto-occipital flaps (Juri flap) and temperoparietal flaps
      (Elliott) were commonly performed in the previous decades but have fallen out of
      favor for the most part with the development of follicular unit hair
      transplantation. Besides high complication rates, these procedures created
      straight abrupt hairlines in many cases, posterior hair direction, hair density
      that was disproportionately thick, and blunt temperofrontal angles. OBJECTIVE:
      Because there are many patients who live with cosmetic deformities created by
      previous flap procedures, the objective of this article is to present a series of
      techniques that will restore these patients to normal cosmesis. METHODS: The
      techniques for amelioration of poor cosmesis secondary to flap procedures are (1)
      undulating follicular unit grafting anterior to the hairline, (2) removal of 2-
      to 3-mm cylinders of hair-bearing scalp at the anterior hairline, (3) removal of
      2- to 3-mm cylinders of hair-bearing scalp from within the flap itself, and (4)
      appropriate fusiform excision techniques to create a normal temperofrontal angle.
      RESULTS: The combination of the aforementioned techniques has restored a very
      natural cosmesis in patients who have poor aesthetics after flap surgery.
      CONCLUSION: Many patients exist who have had Juri and Elliott flaps. Although the
      cosmetic deformities that are created from these flaps are difficult to improve,
      they can be ameliorated effectively through a series of maneuvers that are
      described in this article.

PMID- 12614415
TI  - Multiple symmetric lipomatosis: Korean experience.
AB  - BACKGROUND: Multiple symmetric lipomatosis (MSL) is a rare disorder that is
      characterized by abnormal adipose tissue growth mainly at the neck, abdominal
      wall, back, shoulder girdle, and arms. A suggested mechanism for accumulation of
      adipose tissue is a defect in the lipolytic pathway of fat cell. OBJECTIVE: To
      evaluate the clinical, morphologic, and biochemical findings in Korean patients.
      METHOD: A total of 32 patients with MSL were evaluated retrospectively. Ten
      patients were seen at our hospital. The remaining 22 patients from literature
      were reviewed. Biochemical analyses and neurologic studies were performed.
      RESULTS: All cases were a sporadic form of MSL. The age of onset ranged from 26
      to 70 years (mean of 49.4 years). The male-to-female ratio was 31:1. All but two
      patients were alcoholics with a daily intake of more than 80 g of alcohol for at
      least 10 years. In metabolic studies of 17 patients, a Fredrickson type IIb or IV
      hyperlipoproteinemia was found in three patients. High-density lipoprotein
      cholesterol values were higher in three patients. A glucose tolerance test was
      abnormal in five patients. A high prevalence of neurologic abnormalities was
      observed. Clinical signs of peripheral neuropathy were present in 11 of 13
      patients. Central nervous system involvement was found clinically in 3 of 13
      patients. CONCLUSION: The surgical removal of the fatty tissue and abstinence
      from alcohol are essential for relieving the patients from functional impairment.
      Not only metabolic studies of lipid abnormalities but also a complete neurologic
      examination were required in order to improve the quality of life in MSL
      patients.

PMID- 12614416
TI  - Dermatologic surgery in the demented patient.
AB  - BACKGROUND: Dementia is an organic mental disorder that is characterized by a
      general loss of intellectual abilities involving impairment of memory, judgment,
      and abstract thinking as well as changes in personality. Demented patients are a
      growing subgroup within the practice of dermatologic surgery and especially in
      Mohs surgery. These patients often have other medical and social concerns in
      addition to their dementia. OBJECTIVE: Demented patients require specific
      knowledge of their problems to care for them properly, especially in cases in
      which prolonged procedures are required such as Mohs surgery. METHODS: A review
      the literature is given regarding this subgroup of patients and how to best
      prepare and care for them before, during, and after dermatologic surgery.
      RESULTS: Demented patients often have other medical concerns and therefore have
      associated medications, medical ailments, postsurgical care, and social and
      mental challenges. CONCLUSION: The dermatologic surgeon needs to be aware of the
      special concerns of demented patients, especially in prolonged and potentially
      complicated surgeries. Not only do they have mental challenges, but they often
      have other medical and social challenges that need to be specifically accounted
      for before, during, and after dermatologic surgery.

PMID- 12614417
TI  - Fluorodeoxyglucose-positron emission tomography imaging versus sentinel node
      biopsy in the primary staging of melanoma patients.
AB  - BACKGROUND: Positron emission tomography (PET) imaging is superior to
      conventional techniques for the evaluation of patients with stage III and stage
      IV cutaneous melanoma. Several studies have highlighted the advantages of this
      noninvasive technique for the assessment of lymph node involvement. OBJECTIVE: To
      compare PET imaging with sentinel node biopsy for primary staging of cutaneous
      melanoma and to discuss the technical limitations of PET scanning. METHODS:
      Twenty-five consecutive patients with a histologic diagnosis of melanoma with a
      Breslow thickness equal or greater to 1 mm underwent a preoperative PET to assess
      lymph node involvement. RESULTS: Sentinel node biopsy and PET showed a
      sensitivity of 100% and 22%, respectively, in the identification of lymph node
      metastases. CONCLUSION: PET is not a sensitive technique for the primary staging
      of cutaneous melanoma.

PMID- 12614418
TI  - Laser-assisted hair removal in Asian skin: efficacy, complications, and the
      effect of single versus multiple treatments.
AB  - BACKGROUND: Alexandrite laser hair removal can be quite successful in lighter
      skin types. Effective hair removal in Asians can be difficult, and multiple
      treatments are usually required for effective treatment. OBJECTIVE: To evaluate
      the safety and efficacy of alexandrite laser hair removal in Asian skin, to
      determine the benefit of multiple treatments, and to evaluate the value of test
      patches before laser treatment. METHODS: One hundred forty-four Asian subjects
      with Fitzpatrick skin types III to V were treated with a cooled 40-ms alexandrite
      laser with fluences of 16 to 24 J/cm2. Initially, all treated subjects underwent
      test patch application. After test patch application, 35 subjects with 66
      anatomic sites received three treatments. Thirty-five subjects with 66 anatomic
      sites received two treatments, and 74 subjects with 124 anatomic received a
      single treatment. All subjects were followed for 9 months after their final
      treatment. RESULTS: In subjects that were treated three times, a 55% hair
      reduction was noted at 9 months after the third treatment. In subjects treated
      two times, a 44% hair reduction was noted at 9 months after the second treatment.
      In subjects treated only one time, a 32% hair reduction was noted at 9 months
      after the single treatment. No subjects had scarring or long-term pigmentary
      changes. There appeared to be no correlation between test patch acute
      complications and those seen after actual treatments. CONCLUSION: Although Asian
      skin can be effectively treated with a cooled, long-pulsed alexandrite laser,
      complications do occur. Laser hair removal efficacy was increased with multiple
      treatments. There does not appear to be an exact correlation in Asian skin
      between complications occurring after test patch treatment and those seen with
      subsequent treatments.

PMID- 12614419
TI  - A prospective trial of fungal colonization after laser resurfacing of the face:
      correlation between culture positivity and symptoms of pruritus.
AB  - BACKGROUND: After full-face laser resurfacing of the face, patients often
      complain of pruritus, which may be intense. It has been suggested that some cases
      of postresurfacing pruritus may be associated with subclinical fungal infection.
      OBJECTIVE: To determine whether intense pruritus after laser resurfacing of the
      face is correlated with simultaneous fungal growth of the treated skin. METHODS:
      Twelve adult female patients undergoing combined full-face laser resurfacing with
      CO2 and erbium:YAG lasers for chronic photodamage or acne scarring were enrolled
      in a prospective study. Fungal cultures were obtained by swabbing the facial skin
      of each patient immediately before, 3 days after, and 6 days after the laser
      procedure. At the same points in time, investigators completed objective
      assessments of the patients' facial skin, and patients reported the sensations
      that they were experiencing. RESULTS: Six patients (50%) complained of
      significant pruritus (3 or greater on a scale of 0 to 5). In four of the six
      cases (67%), at least one of the three fungal cultures obtained grew fungal
      organisms, including Candida albicans (2 cultures), Candida parapsilosis,
      Aureobasidium pullulans, and Fusarium species. In no instances did culture
      positivity occur in the absence of significant pruritus. A statistically
      significant relationship (P=0.0143) was found to exist between at least one of
      the three cultures being positive and the emergence of significant posttreatment
      pruritus. Physician ratings of clinical signs did not correlate with patient
      reports of pruritus, other symptoms, or culture positivity. CONCLUSION:
      Colonization or subclinical infection with fungi, particularly Candida spp., may
      be associated with significant postlaser resurfacing pruritus. Antifungal
      prophylaxis may mitigate this discomfort. Further research is required to confirm
      and expand these results.

PMID- 12614420
TI  - Silicone gel sheeting for the management and prevention of onychocryptosis.
AB  - BACKGROUND: Onychocryptosis, commonly referred to as ingrown nails, has many
      therapeutic alternatives for its management. Although mild cases can be treated
      conservatively, in severe cases, surgical treatment is preferred. Silicone gel
      sheeting is found to be effective in the treatment of hypertrophic scars and
      keloids. OBJECTIVE: To document the effectiveness of silicone gel sheeting in the
      management of patients with onychocryptosis and in the prevention of the
      recurrences by breaking the devil's circle, which usually took place after the
      surgical procedures used in the treatment of the onychocryptosis. METHODS:
      Fourteen patients were enrolled in the study. Entry criteria required the
      presence of slight (2 patients), moderate (2 patients), or severe (10 patients)
      onychocryptosis. The simple technique used in the study was the excision of the
      one-quarter part of the lesional side of the nail plate without excising the
      granulation tissue. After 24 hours, the silicone was placed on the granulation
      tissue and the exposed nail bed. Silicone gel sheet was bandaged loosely without
      applying any pressure. Patients entering the study were given detailed
      instructions in applying and using the gel for 12 hours during the daytime. The
      study lasted for 14 months and was composed of a treatment period of 4 months and
      a follow-up period of 10 months. The patients were evaluated every 2 weeks in the
      first month and then monthly. The change in thickness of granulation tissue was
      evaluated by comparing them with the baseline photographs and those taken at each
      visit. RESULTS: The management and prevention of onychocryptosis were achieved in
      12 of 14 patients (85.71%). The silicone gel sheeting treatment was well
      tolerated except for an occasional transient exudation, which was resolved when
      the treatment was withdrawn. CONCLUSION: The results show that the new method
      that we used for the treatment of onychocryptosis is successful in reducing the
      thickness of the hypertrophic nail fold and prevents the recurrence of the
      condition during the regrowth of the nail plate by breaking the devil's circle.
      The advantage of this method is that it is not destructive to the nail matrix and
      the adjacent tissue.

PMID- 12614421
TI  - A method of augmenting the cheek area through SMAS, subSMAS, and subcutaneous
      tissue recruitment during facelift surgery.
AB  - BACKGROUND: As the human face ages, there is a depletion of fat that occurs in
      the submalar region. Various techniques such as fat transfers, fillers,
      alloplastic implants, and composite rhytidectomies have been used to augment this
      area in the past. OBJECTIVE: To describe a technique that augments the submalar
      areas during facelift surgery without the use of fat transfer, fillers,
      alloplastic implants, or a risky composite technique. METHOD: An oval is scribed
      over the depressed submalar areas preoperatively. During facelift surgery, a
      fusiform area is scribed over the SMAS. This fusiform is scribed so that the
      medial end is directed at the center of the submalar depression, and the lateral
      end is toward the posterior earlobe. A defect is created within the lateral
      aspect of the fusiform, but not the medial portion. The fusiform is subsequently
      closed with a 2-0 Ethibond suture using three horizontal mattress sutures and two
      interrupted sutures. Upon closure of this defect, SMAS, subSMAS, and subcutaneous
      tissue overlying the SMAS are recruited into the submalar defect by the simple
      phenomenon of dog-ear formation. Additionally, there is a component of frank
      elevation of the tissues inferior to the medial aspect of the fusiform and
      submalar space. RESULTS: The aforementioned technique has been performed on 123
      patients over 7 years and has resulted in consistently good improvement in the
      submalar space. The procedure is not difficult to learn, and good results can be
      achieved with initial cases. The learning curve was not found to be steep, with
      good results being achieved quickly. CONCLUSION: Depression of the submalar space
      plays a significant role in creating an aged face. In the past, various fillers
      and/or alloplastic implants have been used to augment this region. A low-risk
      method is described that mobilizes SMAS, subSMAS, and subcutaneous tissues into
      the submalar space through the phenomenon of dog-ear formation after fusiform
      closure.

PMID- 12614422
TI  - Laser Dopplers to determine cutaneous blood flow.
AB  - BACKGROUND: Laser Dopplers can be useful in determining the relative amount of
      blood flowing through superficial skin. These instruments may be useful in
      assessing blood flow in healing wounds, flaps, and grafts. OBJECTIVE: To review
      the theory and types of laser Dopplers available. METHODS: This work includes a
      review of the literature. RESULTS: Laser Dopplers potentially have a broad range
      of applications in dermatologic surgery and dermatology. Because laser Dopplers
      can quantify blood flow, the course of wound healing over time can be studied;
      however, for predicting viability of skin flaps and grafts, laser Dopplers have
      not been able to supplant clinical assessment. CONCLUSION: Laser Dopplers provide
      an additional means of assessing superficial blood flow in the skin. This blood
      flow, which can be quantified, may be useful in studying wound and flap and graft
      healing.

PMID- 12614423
TI  - The crisscross tie-over tacking suture revisited.
AB  - BACKGROUND: Deep pexing or tacking sutures can be useful in certain situations
      encountered in dermatologic surgery when surface concavities require recreation.
      OBJECTIVE: To examine and discuss some pexing suture techniques that have been
      described in the past and to outline alternatives. METHODS: Pexing suture
      techniques are presented in a series of schematic diagrams that follow. RESULTS:
      The crisscross tie-over tacking suture as described by Albertini is shown as well
      as a modification that theoretically lessens complication risk. The pexing buried
      vertical mattress suture is then presented. CONCLUSION: The dermatologic surgeon
      may find pexing or deep tacking sutures helpful in selected cases.

PMID- 12614424
TI  - Reconstruction of a large surgical defect involving the lower eyelid and
      infraorbital cheek.

PMID- 12614425
TI  - Hair dresser's syndrome: a case report of an interdigital pilonidal sinus and
      review of the literature.
AB  - BACKGROUND: Hair dresser's disease is produced by short hairs that penetrate the
      interdigital spaces of the hand. OBJECTIVE: A case and review of the literature
      of pilonidal sinus in the interdigital web are reported. METHODS: Surgical
      excision and secondary healing are the preferred methods of treatment to prevent
      recurrence. We have performed a rotation flap for the defect formed after
      excision. RESULTS: The patient was not hospitalized, and postoperative patient
      comfort prevention of the recurrences was achieved. CONCLUSION: This acquired
      occupational disease is rare and preventable. The personal hygiene and use of
      protective barrier creams or gloves could prevent the formation of the disease.

PMID- 12614426
TI  - Late-onset superficial lymphatic malformation: report of a case and review of the
      literature.
AB  - BACKGROUND: Superficial lymphatic malformations are predominantly developmental
      malformations of infancy, but they may arise at any age. OBJECTIVE: To describe a
      patient with a late-onset superficial lymphatic malformation. METHODS: Case
      report and literature review. RESULTS: A 53-year-old woman was evaluated for a
      colored lesion that developed spontaneously on the anterior abdominal wall. The
      lesion was treated by surgical excision. Findings on histopathologic examination
      of the specimen were consistent with superficial lymphatic malformation. There
      was no recurrence of the lesion at 4 months after the operation. CONCLUSION:
      Superficial lymphatic malformations can develop in adults spontaneously without
      the presence of any predisposing condition. Because the majority of such late
      onset malformations reported in the literature are localized lesions similar to
      the one in our patient, surgical removal with inclusion of subcutaneous tissue
      usually results in cure without recurrence.

PMID- 12614427
TI  - Radiation therapy for the salvage of unresectable subungual squamous cell
      carcinoma.
AB  - BACKGROUND: A case of subungual squamous cell carcinoma, which is a rare
      malignancy and has an elusive etiology, is reported. OBJECTIVE: To present
      radiation therapy as a viable treatment option to amputation for surgically
      unresectable subungual squamous cell cancer. METHODS: A 69-year-old man with a 16
      year-old history of subungual squamous cell carcinoma of the left thumb was
      treated by external beam radiation therapy. In this case, bone invasion precluded
      the patient from successfully completing Moh's micrographic surgery. RESULTS: The
      treated thumb at 17 months after radiation therapy remained tumor free.
      CONCLUSION: Radiation therapy should be considered a treatment option for nail
      bed squamous cell carcinoma before considering amputation and perhaps as salvage
      for all unresectable lesions.

PMID- 12614428
TI  - Giant fibrosarcoma arising in dermatofibrosarcoma protuberans on the scalp during
      pregnancy.
AB  - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignant soft
      tissue tumor of subcutaneous tissues that has a propensity for local recurrence;
      however, it seldom metastasizes. Most lesions occur over the trunk or proximal
      extremities, and there is slight male preponderance. DFSP is rare on the head and
      neck. Less than 5% tumors are located on the scalp. OBJECTIVE: To describe a case
      of giant fibrosarcoma arising in DFSP on the scalp during pregnancy. METHOD: In
      our patient, the tumor was on scalp and measured 15 x 11 x 7 cm. The recurrent
      tumor that developed in the same region was measured 33 x 30 x 15 cm.
      Histopathologic examination of this mass revealed fibrosarcoma. The mass was
      excised from the subperiosteal plane with a 3-cm free margin. Because of the high
      possibility of recurrence, the defect site was reconstructed with a split
      thickness skin graft. RESULTS: After 1 year of follow-up, no recurrence or
      metastasis was detected. CONCLUSION: We present a unique case in which the person
      has a giant fibrosarcoma on her scalp arising from DFSP with fibrosarcomatous
      change during pregnancy.

PMID- 12614429
TI  - Giant condyloma acuminatum.
AB  - BACKGROUND: Giant condyloma acuminatum is a warty lesion that is characterized by
      its large size and propensity to infiltrate into deeper tissues contrasting with
      its microscopically benign pattern. It is proposed that giant condyloma
      represents an intermediate lesion between condyloma acuminatum and verrucous
      carcinoma. OBJECTIVE: A primary therapeutic option of giant condyloma is radical
      surgery with or without adjunctive chemotherapy. Because of the tumor's large
      extent in this case, curative therapy would have been achieved by wide surgical
      excision. METHOD: We present a morphologically and histologically classic example
      of giant condyloma with respect to origin from common genital warts. The reason
      for extensive exophytic growth was due to delay in therapy because of the
      patient's self neglect but not due to immune deficiency. The patient was treated
      with wide surgical excision. RESULTS: The postoperative period was uneventful,
      allowing satisfactory functional and cosmetic results. CONCLUSION: This case is
      an interesting case because of its exceptionally huge size without any deep
      tissue involvement and tissue atypia. This suggests that giant condyloma is an
      intermediate condition that exhibits a continuous tendency for growth.

PMID- 12614430
TI  - Primary malignant melanoma of the maxillary gingiva.
AB  - BACKGROUND: Mucosal malignant melanoma arising from the mucosa of the head and
      neck region is a rare entity, accounting for approximately 0.2% of all melanomas.
      Most of these lesions (80%) have occurred on the maxillary anterior gingival
      area, especially on the palatal and alveolar mucosa. OBJECTIVE: Mucosal malignant
      melanomas are more aggressive than cutaneous melanomas. On the other hand,
      complex anatomy of this area makes complete surgical excision difficult. Thus,
      early diagnosis and treatment are important. METHODS: We presented primary
      malignant melanoma of the maxillary gingiva in two cases. CONCLUSION: In mucosal
      malignant melanoma, survival rates may be increased by early diagnosis and
      treatment. The clinician must carefully examine oral cavity, and pigmented
      lesions should be biopsied. Because some melanomas may be amelanotic, a high
      index of suspicion is necessary.

PMID- 12614431
TI  - Venous lakes: a report of 32 cases treated by carbon dioxide laser vaporization.
AB  - Venous lakes (VL) are acquired venous ectasies of the superficial dermal venules,
      usually observed in older people. Thirty-two adult patients with VL in several
      localizations were treated by carbon dioxide laser vaporization. Two passes were
      performed to each lesion within the same session. A continuous and defocused
      mode, with a power density of 5 W/cm2, was used in the first pass, and a
      continuous focused mode with the same power density was in the second pass.
      Photographic controls were performed before and after treatment. VLs were
      removed, and the smooth surface of the treated area was re-established by a
      single laser session. Only one case recurred after the treatment. No significant
      secondary effects were observed. Carbon dioxide laser is a good and safe method
      for treatment of skin VL. With adequate cautions, excellent cosmetic results can
      be obtained with a single session of treatment.

PMID- 12614433
TI  - Endovenous laser treatment.

PMID- 12614434
TI  - Dermatologists as surgeons.

PMID- 12614435
TI  - Tumescent axillary liposuction and curretage with axillary scarring: not an
      important sequela.

PMID- 12614436
TI  - The endotoxin paradigm: a note of caution.

PMID- 12614437
TI  - Hormones not hygeine? Birth order and atopy.

PMID- 12614438
TI  - Vernal keratoconjunctivitis: evidence for immunoglobulin E-dependent and
      immunoglobulin E-independent eosinophilia.

PMID- 12614439
TI  - Comparative, complementary and relevant: the immunological basis of ovine lung
      allergic responses.

PMID- 12614440
TI  - Adenosine monophosphate bronchial provocation and the actions of asthma therapy.

PMID- 12614441
TI  - Endotoxin levels in Estonian and Swedish house dust and atopy in infancy.
AB  - BACKGROUND: Immune responses, including those to allergens, may be T helper (Th)2
      skewed in newborns. In order to redress the fetal Th1/Th2 imbalance, Th1
      stimulating factors, such as bacterial endotoxin, may be required. The increasing
      prevalence and severity of atopic diseases in industrialized countries, which are
      in marked contrast with the low prevalence of allergy among children in the
      formerly socialist countries of Europe, have been suggested to be caused by a
      reduced microbial stimulation. AIM: To relate the endotoxin levels in house dust
      from two countries with a low (Estonia) and a high (Sweden) prevalence of allergy
      to the development of atopic disease and sensitization in the children during the
      first 2 years of life. METHODS: The study included 108 children from Tartu,
      Estonia and 111 children from Linkoping, Sweden. Skin prick tests were performed
      at 3, 6, 12 and 24 months of age, and questionnaires were distributed to the
      families. At 24 months, a paediatrician examined the children. Dust samples were
      collected from mattresses and carpets and the endotoxin concentration was
      determined by a chromogenic Limulus assay. RESULTS: The endotoxin levels were
      higher in Estonian than in Swedish house dust (median levels 29 (range 0.25-280)
      and 14 (range 0.25-99) EU/mg dust, respectively, P < 0.001). Furthermore, the
      levels were inversely related to the development of atopic disease and
      sensitization in the Swedish, but not in the Estonian, children. CONCLUSIONS: The
      low prevalence of atopic disease in Estonia may, at least in part, be related to
      the high endotoxin levels in this country. The findings support that high levels
      of endotoxin, or other bacterial products with Th1-stimulating properties, might
      protect children from developing atopic disease.

PMID- 12614442
TI  - Reproductive history and allergic rhinitis among 31145 Danish women.
AB  - BACKGROUND AND OBJECTIVE: A successful pregnancy is associated with a strong
      skewing of the immune system towards a Th2-type immune response. Because such a
      deviation is also the hallmark of allergic disease, it was investigated whether
      allergic rhinitis in women was associated with an increased likelihood of
      becoming pregnant and having a successful outcome of pregnancies. MATERIAL AND
      METHODS: Information on allergic rhinitis and reproductive history was obtained
      for 31145 pregnant women who participated in a national birth cohort study in
      Denmark during September 1997 to March 2000, and for whom complete information on
      siblings and place of residence and birth was available via the Civil
      Registration System. Data were analysed using logistic regression. RESULTS: Women
      who had previously been pregnant (OR = 0.91, 95% CI 0.85-0.98) or who had given
      birth previously (OR = 0.91, 95% CI 0.85-0.98) were less likely to report
      allergic rhinitis than others. The number of previous spontaneous abortions,
      gestational week of the first spontaneous abortion and fertility treatment were
      not associated with allergic rhinitis. Women who had waited less than a year to
      become pregnant more often had allergic rhinitis (OR = 1.18, 95% CI 1.06-1.32, P
      = 0.002) than women who had waited for more than a year. Early age at menarche
      was associated with an increased likelihood of allergic rhinitis (Ptrend =
      0.003). CONCLUSIONS: Our findings did not support the hypothesis that an atopic
      genotype overall should be associated with an increased likelihood of successful
      outcome of pregnancies, but it might be associated with a decreased waiting time
      to pregnancy.

PMID- 12614443
TI  - Fetal exposure to intact immunoglobulin E occurs via the gastrointestinal tract.
AB  - BACKGROUND: Consideration of the evolutionary significance of IgE might provide
      insight into the immunological interactions occurring in utero and during early
      post-natal life that regulate later atopic disease. OBJECTIVE: We postulated that
      the fetal gut is exposed to intact amniotic fluid IgE that might interact with
      local IgE receptors. METHODS: IgE levels in matched maternal blood and amniotic
      fluid (n = 47) or breast milk (n = 15) collected from pregnant women in the UK
      (Southampton) and Brazil (Sao Paulo) were studied. Expression of IgE receptors,
      Fc epsilon RI and Fc epsilon RII (CD23), in fetal gastrointestinal tract (n = 19)
      and skin (n = 11) was examined immunohistochemically. RESULTS: Human amniotic
      fluid at 16-18 weeks' gestation contained intact IgE at levels that increased as
      maternal circulating levels increased (Spearman's rho = 0.897; P < 0.001).
      Circulating IgE levels from women in Sao Paulo, Brazil, associated positively not
      only with term (> 37 weeks' gestation) amniotic fluid (rho = 0.993; P < 0.001)
      but also breast milk IgE levels (rho = 0.785; P = 0.001). Maternal levels of IgE
      did not change significantly over pregnancy and fetal circulating levels of IgE
      were very low (< 0.6 IU/mL). Low-affinity IgE receptors (CD23) were expressed in
      lymphoid follicles of the fetal gut from 16 weeks of gestation (6/8), but not
      from 11 to 16 weeks (0/11) or in the skin. CONCLUSION: Amniotic fluid contains
      intact IgE that might bind to CD23+ cells within the lymphoid follicles of the
      fetal gastrointestinal tract. The evolutionary significance of these interactions
      might be to prepare the immune system for helminthic parasite exposure at birth
      via IgE-mediated antigen focusing, or "education" of the developing immune system
      about the prevailing extrauterine environment. However, at present in societies
      where helminthosis is not a significant health issue, this pathway may still be
      operational and associated with the development of atopic disease.

PMID- 12614444
TI  - Breastfeeding and the prevalence of symptoms of allergic disorders in Japanese
      adolescents.
AB  - BACKGROUND: Environmental factors acting early in life are key determinants of
      the incidence of allergic disease. Whether breastfeeding is protective against
      allergic disorders remains controversial. OBJECTIVE: The present cross-sectional
      study examined the relationship between feeding patterns in the first 3 months of
      life and the prevalence of symptoms of wheeze, atopic eczema, and
      rhinoconjunctivitis during the past 12 months in Japanese adolescents. METHODS:
      The subjects were 5614 of 9008 students (62%) aged 12-15 years from all public
      junior high schools in Suita, Japan in 2001. This study used the diagnostic
      criteria of the International Study of Asthma and Allergies in Childhood.
      Adjustment was made for gender, grade, number of older siblings, and parental
      history of allergy. RESULTS: Feeding pattern was unrelated to the prevalence of
      wheeze or rhinoconjunctivitis. The prevalence of atopic eczema was significantly
      higher in children who had been breastfed than in artificial milk feeders
      (adjusted odds ratios = 1.40 and 1.56, 95% confidence intervals: 1.01-1.98 and
      1.13-2.22 for mixed milk intake and breastfeeding only vs. artificial milk
      consumption, respectively; P = 0.01 for linear trend). When children were divided
      according to a positive or negative allergic history in at least one parent, an
      increased prevalence of atopic eczema associated with breastfeeding was found in
      children with a negative parental allergic history compared with those with a
      positive parental allergic history. CONCLUSION: The findings suggest that
      breastfeeding may be associated with an increased prevalence of atopic eczema,
      especially among children without a parental history of allergy.

PMID- 12614445
TI  - Age-related T cell responses to allergens in childhood.
AB  - BACKGROUND: T cell priming, as determined by allergen-induced proliferative
      responses, is believed to occur principally in early childhood in both atopic and
      non-atopic infants under the influence of multiple factors including
      environmental allergen exposure. It is considered that T cell priming with
      expansion of Th2 cells is a crucial factor in the development of atopic disease.
      OBJECTIVE: To examine T cell priming to commonly encountered allergens in
      childhood in relation to age. METHODS: In a cross-sectional study T cell
      proliferation in relation to age was examined for three common allergens,
      ovalbumin (OVA), house dust mite (HDM) and rye grass pollen (RYE), in atopic and
      non-atopic children. The effect of age on Th1 (IFN-gamma) and Th2 (IL-5 and IL
      13) cytokine production in response to these allergens was investigated to
      examine the possibility of immune deviation with time. RESULTS: A significant
      increase in T cell proliferation with age was observed with RYE among atopic
      children only. However, the same was not observed with the two other allergens
      studied (i.e. OVA and HDM). In addition, RYE-induced (but not HDM or OVA)
      cytokine production showed an increased Th2 deviation with age as reflected in
      the increasing IL-5/IFN-gamma and IL-13/IFN-gamma ratios only among the atopic
      subjects with rye grass pollen sensitivity. CONCLUSION: These findings suggest
      that grass pollen sensitivity in childhood is accompanied by a progressive
      accumulation of allergen-primed T cells and progressive deviation of the allergen
      induced cytokine response towards a Th2 response in atopic subjects throughout
      childhood.

PMID- 12614447
TI  - Local release of eosinophil peroxidase following segmental allergen provocation
      in asthma.
AB  - BACKGROUND: Eosinophil peroxidase (EPO) is an eosinophilic basic protein, which
      leads to increased permeability and damage of bronchial epithelial cells in
      asthma. OBJECTIVE: As little is known about its local expression and release in
      humans the intracellular expression in lung and peripheral eosinophils and the
      concentrations of EPO in bronchoalveolar lavage (BAL) fluid and serum was
      investigated in patients with asthma. METHODS: Twelve mild atopic asthmatic and
      nine control subjects underwent segmental sham and allergen challenge. EPO
      concentrations in BAL fluid and serum were determined by immunoassay and flow
      cytometry was used to determine the intracellular expression of EPO in BAL
      derived and peripheral eosinophils. RESULTS: In asthmatic patients a large
      increase in BAL eosinophils--total cells: median 9.5 x 10(6) (range: 0.5 to 455.0
      x 10(6)); relative: 38% (1 to 91%)--was detectable 24 h following allergen
      challenge, but peripheral blood eosinophil counts did not change. Concentrations
      of EPO in BAL fluid increased from 1 microg/L (1.0 to 6.8 microg/L) to 42
      microg/L (5.6 to 379.6 microg/L; P < 0.01) after allergen but not after saline
      challenge (1.5 microg/L; 1.0 to 21.9 microg/L), whereas in control subjects all
      measurements were below the detection limit. Serum concentrations of EPO
      increased slightly from 18.3 microg/L (3.0 to 56.8 microg/L) to 27 microg/L (3.8
      to 133.9 microg/L; P < 0.05) 24 h after allergen challenge in asthmatic patients.
      Furthermore, the intracellular expression of EPO (measured as mean fluorescence
      intensity) was decreased in BAL eosinophils compared with blood eosinophils (mean
      fluorescence intensity 29 (7 to 71) vs. 48 (20 to 85); P < 0.01) after allergen
      challenge. CONCLUSION: The finding of increased EPO concentrations in the BAL
      fluid and decreased intracellular EPO expression in pulmonary eosinophils of
      asthmatic patients reflects the allergen-triggered release of EPO into the
      bronchial space.

PMID- 12614446
TI  - Atopy and serum eosinophil cationic protein in 110 white children with vernal
      keratoconjunctivitis: differences between tarsal and limbal forms.
AB  - BACKGROUND: A predominance of Th2 response has been suggested in vernal
      keratoconjunctivitis (VKC), and a high prevalence of IgE-sensitized (IgE-S)
      patients has been reported (positive skin prick test or serum-specific-IgE).
      Palpebral and bulbar VKC are considered to be expressions of the same disease and
      only occasional racial and histopathological differences are described between
      the two forms. Tear levels of eosinophil cationic proteins have been correlated
      with the severity of ocular symptoms; however, there is no published study that
      demonstrates the presence of serum markers of disease activity. OBJECTIVE: This
      study was performed to evaluate the prevalence of IgE-sensitization in palpebral,
      bulbar and mixed VKC and to determine possible useful markers of disease activity
      in peripheral circulation. METHODS: A total of 110 white VKC patients (mean age
      8.3 years, range 3.2-18 years) were evaluated for ocular score in the active
      phase of the disease. Skin prick tests and serum-specific IgE for common
      allergens, serum-total IgE, peripheral blood eosinophil counts (PBECs) and serum
      eosinophil cationic protein (s-ECP) were determined. Fifteen age-matched non-IgE
      S control children underwent the same determinations. RESULTS: s-ECP, PBECs and s
      total IgE were significantly higher in IgE-S than in non-IgE-S VKC patients and
      in non-IgE-S VKC patients than in controls. A lower prevalence of IgE-S patients
      was found in bulbar vs. tarsal (P = 0. 050) or mixed forms (P = 0.002). The score
      of giant papillae was strongly correlated with s-ECP levels (P < 0.001) and with
      PBECs (P = 0.001). CONCLUSIONS: Our data suggest that an overall eosinophilic
      response is present in VKC independently of IgE-sensitization; bulbar forms,
      unlike tarsal and mixed forms, were associated with a low prevalence of IgE
      sensitization. Serum ECP was a useful marker of disease activity in tarsal and
      mixed forms.

PMID- 12614448
TI  - Blood basophil numbers in chronic ordinary urticaria and healthy controls:
      diurnal variation, influence of loratadine and prednisolone and relationship to
      disease activity.
AB  - BACKGROUND: The basopenia of chronic urticaria relates to histamine releasing
      autoantibodies in the serum of patients with autoimmune urticaria. This reduction
      in circulating basophils may be due to active recruitment into weals. If so, it
      might be expected that numbers in blood would be reduced when urticaria is active
      and increased after treatment. The primary aim of this study was to look at
      diurnal variation of basophil numbers in patients with chronic ordinary urticaria
      (not physical or vasculitic) in relation to disease activity and the effect of
      treatment with antihistamines and corticosteroids, and to compare the results
      with healthy controls. A secondary aim was to compare a standard manual counting
      method with automated basophil counts and to look at numbers of other circulating
      leucocytes that might be relevant to urticaria pathogenesis. METHODS: Manual
      basophil counts using a toluidine blue stain and automated 5-part differentials
      (Coulter Gen. S) were performed at 4-hourly intervals from 08.00 to 20.00 in 10
      healthy controls (six women, age 24 to 63 years) and seven chronic urticaria
      patients (five women, 24 to 50 years). All chronic urticaria patients had severe
      daily or almost daily urticaria. Only one of six chronic urticaria sera showed in
      vitro basophil histamine releasing activity. Counts were performed without
      treatment, after a week of taking loratadine 10 mg daily and after 3 days of
      adding prednisolone at 0.6 mg/kg/day (maximum 40 mg). Daily urticarial activity
      scores (UAS) were derived from weal numbers and itch, maximum 7. RESULTS: There
      was no significant overall diurnal variation of basophil numbers in healthy
      controls or chronic urticaria patients. Mean (SE) manually counted basophil were
      higher in healthy controls than chronic urticaria (43.4/ microL (2.1) vs. 4.4
      (0.8), P < 0.001). Basophil counts were reduced in healthy controls on steroids
      (19.2 (1.9), P < 0.001) but increased in chronic urticaria (8.9 (1.9), P <
      0.001). Loratadine did not influence them. UAS fell on treatment (3.3 (0.4)
      baseline, 1.4 (0.5) on loratadine and 0.5 (0.2) on prednisolone with loratadine,
      P < 0.001). There was a negative linear correlation between basophil numbers and
      UAS in untreated chronic urticaria patients (P = 0.001, Spearman rank
      correlation). Manual and automated basophil counts showed poor agreement.
      Lymphocyte numbers were lower in chronic urticaria than healthy controls.
      Neutrophils increased whereas lymphocytes and eosinophils decreased in all
      subjects on prednisolone. They were unaffected by loratadine. CONCLUSION: The
      results are consistent with the hypothesis that circulating basophils may be
      recruited from blood into urticarial weals during disease activity. Automated
      counts are not suitable for assessing basophil numbers in chronic urticaria. The
      relevance of reduced lymphocyte numbers in chronic urticaria needs to be
      explored.

PMID- 12614449
TI  - Calcineurin antagonists differentially affect mediator secretion, p38 mitogen
      activated protein kinase and extracellular signal-regulated kinases from
      immunologically activated human basophils.
AB  - BACKGROUND: Basophils participate in allergic diseases by invading affected
      tissues and secreting histamine, leukotriene (LT)C4, IL-4 and IL-13 following
      FcepsilonRI cross-linking. A reduction of basophil mediator production is
      therefore of considerable therapeutical interest. Macrolactam derivatives, which
      inhibit calcineurin activation, may be candidates for antiallergic therapy as
      they reduce both symptoms of inflammatory skin disease in animal models and mast
      cell degranulation. OBJECTIVE: To investigate the effects of the calcineurin
      antagonists ascomycin and cyclosporin A on IgE-dependent mediator release from
      human basophils. METHODS: Basophils were purified by Ficoll density
      centrifugation, elutriation and negative selection. Histamine release was
      measured spectrofluorometrically; LTC4, IL-4 and IL-13 secretions were assayed by
      enzyme-linked immunosorbent assay (ELISA). Lysed cells were subjected to Western
      blotting using specific antibodies to phospho-p38 mitogen-activated protein
      kinase (MAPK) and extracellular signal-regulated kinase (ERK)-1 and -2. RESULTS:
      Ascomycin (0.01 nm to 1 micro m) and cyclosporin A (0.1 nm to 10 micro m)
      strikingly inhibited (maximally 100%) anti-IgE-induced histamine and cytokine
      release from basophils, and these actions were unaffected by IL-3 priming.
      Ascomycin, however, was less potent at blocking LTC4 secretion, whereas
      cyclosporin A was unable to block production of this mediator. In immunoblotting
      studies, ascomycin and cyclosporin A reduced IgE-dependent p38 MAPK activation
      but were less potent at reducing ERK phosphorylation in basophils. CONCLUSION:
      Calcineurin antagonists like ascomycin and cyclosporin A block IgE-dependent
      basophil degranulation and cytokine synthesis. Calcineurin may target p38 MAPK
      activation, but seems to have less activity on ERK phosphorylation. This is
      paralleled by a reduced or even absent effect of calcineurin antagonists on
      eicosanoid production.

PMID- 12614450
TI  - The health-related quality of life effects of once-daily cetirizine HCl in
      patients with seasonal allergic rhinitis: a randomized double-blind, placebo
      controlled trial.
AB  - BACKGROUND: Seasonal allergic rhinitis (SAR) is characterized by subjectively
      irritating symptoms that can have a substantial impact on the patient's health
      related quality of life (HRQL), adversely affecting physical and social or work
      activity, interpersonal relationships, and general psychological well-being. The
      objective of this study was to test the effect of cetirizine HCl 10 mg once daily
      on the HRQL of adult patients 18-65 years of age with SAR, concurrently assessing
      safety and efficacy. METHODS: Randomized double-blind, placebo-controlled,
      parallel group trial conducted during the 1999 spring SAR season at 19 centers in
      the US. Following a 1-week placebo run-in period, qualified patients were
      randomized to cetirizine 10 mg, or placebo once daily for a 2-week treatment
      period. Change in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and
      Total Symptom Severity Complex (TSSC) scores from baseline were the primary
      outcomes of interest. RESULTS: Of the 611 patients enrolled, 403 (66%) were
      randomized. Cetirizine-treated patients reported significantly greater
      improvement in overall HRQL (P < 0.001) and in each of the seven domains of the
      RQLQ at all time-points (P < 0.05 to < 0.001) than the placebo group. They also
      experienced significantly greater symptom relief (P < 0.001) and were more
      satisfied with treatment (65% vs. 44%) compared to the placebo group.
      Correlations between symptomatic relief and overall HRQL improvement were
      moderate to strong and statistically significant (r = 0.49-0.68, P < 0.01).
      CONCLUSIONS: Results of this study are consistent with previous investigations,
      suggesting cetirizine HCl 10 mg taken once daily in the morning offers
      symptomatic relief that improves the HRQL of adults suffering from SAR.

PMID- 12614451
TI  - Anti-inflammatory effects of high-dose montelukast in an animal model of acute
      asthma.
AB  - BACKGROUND: Asthmatic inflammation is mediated by a network of cytokines,
      chemokines and adhesion molecules. Corticosteroids are the only effective agents
      available to control asthmatic inflammation. We investigated the effect of high
      dose montelukast (MK), a selective cysteinyl leukotriene receptor 1 antagonist,
      on mediators of airway inflammation. OBJECTIVE: The aim of this study was to
      determine the effect of a 3-day course of high-dose MK on mediators of airway
      inflammation induced by a single allergen challenge in sensitized mice. METHODS:
      Ovalbumin (OVA)-sensitized BALB/c mice were treated with 25 mg/kg of MK or saline
      intravenously for 3 days. On the third day, a single inhalation challenge with
      OVA was given. Cellular infiltration was assessed in the bronchoalveolar lavage
      (BAL) and in the lung. Expression of IL-4, IL-5, IL-13 and eotaxin in the BAL,
      and the lung was determined. Serum IL-5 and total IgE was measured. IL-5 and
      eotaxin mRNA expression in the lung was determined. Finally, eotaxin and VACM-1
      expression in the lung was assessed by immunohistochemistry. RESULTS: MK reduced
      the number of eosinophils in the BAL by > 90%. There was also significant
      reduction in IL-5 in the BAL, lung and the serum, and IL-5 mRNA expression in the
      lung. IL-4 level in the lung and BAL, and IL-13 level in the lung also
      significantly decreased. Serum IgE level and lung VCAM-1 expression was also
      significantly lower in treated animals, but eotaxin protein and mRNA expression
      in the lung remained unchanged. CONCLUSION: MK exerts its anti-inflammatory
      effect through the suppression of T helper type-2 (Th2) cytokines. The use of
      high-dose MK as an anti-inflammatory agent in acute asthma should be further
      explored.

PMID- 12614452
TI  - Induction of allergic inflammation in the lungs of sensitized sheep after local
      challenge with house dust mite.
AB  - BACKGROUND: Previous sheep models of asthma are based on sheep sensitized to
      nematode (Ascaris) allergens and these have been used to evaluate the
      physiological and pharmacological effects of potential anti-asthma agents. The
      immunological mechanisms associated with the allergic response in sheep lungs has
      not been examined in detail. OBJECTIVE: To develop an experimental sheep model of
      allergic lung inflammation based on a relevant major human allergen, house dust
      mite, and to define the immunological features of the allergic response in this
      model. METHODS: Sheep immunized subcutaneously with solubilized house dust mite
      extract were given a single bronchial challenge with house dust mite.
      Bronchoalveolar lavage (BAL) and peripheral blood leucocytes were collected
      before and after challenge for flow cytometry, and tissue samples were taken post
      mortem (48 h post-challenge) for histology and immunohistochemical analyses.
      RESULTS: Immunizations with 50 microg house dust mite induced an allergen
      specific IgE response in 50 to 60% of sheep (allergic sheep), with higher antigen
      doses increasing specific IgG1 but not IgE. Lung challenge of allergic sheep with
      house dust mite led to the initial recruitment of neutrophils (at 6 h post
      challenge) followed by eosinophils and activated lymphocytes into the lung tissue
      and BAL, similar to the late-phase allergic response seen in human asthma.
      Eosinophil recruitment peaked at 48 h post-challenge, representing 10 to 33% of
      BAL leucocytes in allergen-challenged allergic sheep compared to 0 to 3% in
      allergen-challenged control (naive) sheep. Lymphocytes recovered from the lung
      after allergen challenge were enriched for CD4+ T cells and were more activated
      than lymphocytes in blood. There was significant down-regulation of CD62L (L
      selectin) and CD49d (VLA-4) expression after allergen challenge on BAL
      eosinophils and lymphocytes compared to blood. In addition, VCAM-1 (ligand for
      VLA-4) was up-regulated on blood vessels of allergen-challenged lungs.
      Eosinophils, CD4+ T cells and CD45R+ B cells were the most prominent leucocytes
      found in lung tissue 48 h after allergen challenge. CONCLUSION: This study
      demonstrates, for the first time, the ability of house dust mite to induce
      allergic responses in sheep lungs. This novel sheep model of allergic lung
      inflammation using relevant human allergens, exhibits similarities to human
      asthmatic disease and will be a useful tool for studies of the immunological and
      physiological mechanisms of allergic asthma.

PMID- 12614453
TI  - Elicitation of the allergic reaction in beta-lactoglobulin-sensitized Balb/c
      mice: biochemical and clinical manifestations differ according to the structure
      of the allergen used for challenge.
AB  - BACKGROUND: Mouse models of allergy are used to study the mechanisms of induction
      and perpetuation of bronchopulmonary hyper-reactivity (BHR) as related to
      eosinophils and specific IgE. OBJECTIVE: Our aim was to adapt the current model
      for the study of bovine beta-lactoglobulin (BLG), a major cow's milk allergen,
      and to further analyse the mechanisms of the acute and late allergic reaction.
      METHODS: Female Balb/c mice were sensitized intraperitoneally with BLG and the
      influence of the adjuvant and of the BLG dose on the IgE response was analysed,
      IgE and IgG1 epitopes being characterized. Once optimized, this model was applied
      to the study of the active phase of allergy in the respiratory tract after a
      single airway challenge using native or denatured BLG, which contains only linear
      epitopes. RESULTS: An immediate allergic reaction was characterized by the rapid
      release of histamine into the bronchoalveolar lavage fluids. Prostaglandin (PG)D2
      was only present when the standard histamine-releasing agent compound 48/80 or
      denatured BLG were used as triggers, whereas native BLG induced leukotriene
      release. Twenty-four hours after challenge, BHR, eosinophil influx, IL-4 and IL-5
      production, plasma exudation and mucus production were very much increased,
      differently depending on the allergen structure, and indicated the occurrence of
      the late allergic reaction. Our results show that the murine model can be used to
      study the mechanisms of allergy to clinically relevant antigens, such as those
      contained in cow's milk. The acute allergic reaction, which depends on the
      structural feature of the allergen, is composed of two distinct pathways
      characterized by peptido-leukotrienes or PGD2 production, which may result from
      distinct activation intensities of mast cells, leading to distinct late
      reactions. CONCLUSION: This study thus demonstrates a clear link between the
      structural feature of a protein, and the physiopathology of the experimental
      asthmatic reaction.

PMID- 12614454
TI  - Extended freeze-dried Mycobacterium bovis Bacillus Calmette-Guerin induces the
      release of interleukin-12 but not tumour necrosis factor-alpha by alveolar
      macrophages, both in vitro and in vivo.
AB  - BACKGROUND: Airway hyper-responsiveness (AHR), chronic airway inflammation and
      predominance of the T helper type-2 (Th2; IL-4, IL-5, IL-13) over the Th1 (IL-2,
      IFN-gamma) immune response are hallmarks of asthma. Alveolar macrophages (AM) are
      the most numerous cells in the airway lumen, where they represent the first
      immune cell population encountered by inhaled antigens. AM act as antigen
      presenting cells (APC) and they release various soluble mediators and enzymes. AM
      thus play a prominent role in the modulation of the local immunity in airways. In
      allergic airways, AM have been implicated in the pathogenesis of inflammation by
      promoting the Th2 versus the Th1 cytokine patterns. OBJECTIVES: Infections with
      attenuated bacteria or challenges with bacterial products may involve AM. Such
      stimuli have been shown to potentially restore the Th1/Th2 balance in asthmatic
      airways, but they also induce the release of inflammatory mediators. We
      investigated the response of AM when stimulated by two preparations of non
      proliferating Bacillus Calmette-Guerin (BCG). METHODS: We evaluated the cytokine
      production by AM from BP2 and C57BL/6 mice when cultured with heat-killed (HK)
      and extended freeze-dried (EFD) BCG. We then investigated in vivo the release of
      soluble factors in the airway lumen of mice after instillation of these BCG
      preparations. Finally, we studied the profile of cytokine transcripts in the lung
      of mice pre-treated with BCG and then challenged with ovalbumin (OVA). RESULTS:
      HK BCG induced the production of both TNF-alpha and IL-12, and did not prevent
      high levels of Th2 cytokine transcripts. In contrast, EFD BCG induced a response
      dominated by the production of IL-12, with no later over-expression of Th2
      cytokine transcripts. CONCLUSION: Our results show that EFD BCG induce the
      release of the Th1-promoting cytokine IL-12 by AM, without the deleterious
      effects of HK BCG. These data suggest that EFD BCG may be considered as a
      potential novel treatment to restore the Th1/Th2 imbalance in asthma.

PMID- 12614455
TI  - The increase in allergic disease: environment and susceptibility. Proceedings of
      a symposium held at the Royal Society of Edinburgh, 4th June 2002.

PMID- 12614457
TI  - Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way.
AB  - Mycobacteria activate a series of macrophage signalling pathways upon engaging
      host cell receptors and during the invasion process. These signals initiate a
      cascade of events leading to the production of immune effector molecules
      including cytokines, chemokines and reactive nitrogen intermediates. This
      response by the macrophage is critical for the control of the mycobacterial
      infection and, not surprisingly, pathogenic mycobacteria have evolved mechanisms
      to limit this macrophage activation. Recent data has suggested that macrophages
      infected with pathogenic compared to non-pathogenic mycobacteria are restricted
      in their activation of the mitogen activated protein kinase (MAPK) pathways.
      Mitogen activated protein kinase activation in macrophages appears to play an
      important role in promoting antimycobacterial activity and in the production of
      various effector molecules following a mycobacterial infection. Therefore, the
      ability of pathogenic mycobacteria to limit MAPK activity is likely an important
      virulence mechanism and may be a potential therapeutic target.

PMID- 12614458
TI  - Toll receptors and pathogen resistance.
AB  - Toll receptors in insects, mammals and plants are key players that sense the
      invasion of pathogens. Toll-like receptors (TLRs) in mammals have been
      established to detect specific components of bacterial and fungal pathogens.
      Furthermore, recent evidence indicates that TLRs are involved in the recognition
      of viral invasion. Signalling pathways via TLRs originate from the conserved
      Toll/IL-1 receptor (TIR) domain. The TIR domain-containing MyD88 acts as a common
      adaptor that induces inflammatory cytokines; however, there exists a MyD88
      independent pathway that induces type I IFNs in TLR4 and TLR3 signalling. Another
      TIR domain-containing adaptor, TIRAP/Mal has recently been shown to mediate the
      MyD88-dependent activation in the TLR4 and TLR2 signalling pathway. Thus,
      individual TLRs may have their own signalling systems that characterize their
      specific activities.

PMID- 12614459
TI  - Clostridium perfringens epsilon toxin rapidly decreases membrane barrier
      permeability of polarized MDCK cells.
AB  - Epsilon toxin is produced by Clostridium perfringens types B and D which are
      responsible for fatal intestinal diseases in animals. The main biological
      activity of epsilon toxin is the production of oedema in various organs. We have
      previously found that epsilon toxin forms a large membrane complex in MDCK cells
      which is not internalized into cell, and induces cell volume enlargement and loss
      of cell viability (Petit, L., Gibert, M., Gillet, D., Laurent-Winter, C., Boquet,
      P., Popoff, M. R. (1997) J Bacteriol 179, 6480-6487). Here, we show that epsilon
      toxin is very potent to decrease the trans-epithelial electrical resistance of
      polarized MDCK cells grown on filters without altering the organization of the
      junctional complexes. The dose-dependent decrease in trans-epithelial electrical
      resistance, more marked when the toxin was applied to the apical side than to the
      basal side of MDCK cells, was associated with a moderate increase of the
      paracellular permeability to low-molecular-weight compounds but not to
      macromolecules. Epsilon toxin probably acts by forming large membrane pores which
      permit the flux of ions and other molecules such as the entry of propidium iodide
      and finally to the loss of cell viability.

PMID- 12614460
TI  - JlpA of Campylobacter jejuni interacts with surface-exposed heat shock protein
      90alpha and triggers signalling pathways leading to the activation of NF-kappaB
      and p38 MAP kinase in epithelial cells.
AB  - Campylobacter jejuni is a leading cause of acute bacterial gastroenteritis in
      humans. The mechanism by which C. jejuni interacts with host cells, however, is
      still poorly understood. Our previous study has shown that the C. jejuni surface
      lipoprotein JlpA mediates adherence of the bacterium to epithelial cells. In this
      report, we demonstrated that JlpA interacts with HEp-2 cell surface heat shock
      protein (Hsp) 90alpha and initiates signalling pathways leading to activation of
      NF-kappaB and p38 MAP kinase. Gel overlay and GST pull down assays showed that
      JlpA interacts with Hsp90alpha. Geldanamycin, a specific inhibitor of Hsp90, and
      anti-human Hsp90alpha antibody significantly blocked the interaction between JlpA
      and Hsp90alpha, suggesting a direct interaction between JlpA and HEp-2 cell
      surface-exposed Hsp90alpha. The treatment of HEp-2 cells with GST-JlpA initiated
      two signalling pathways: one leading to the phosphorylation and degradation of
      IkappaB and nuclear translocation of NF-kappaB; and another one to the
      phosphorylation of p38 MAP kinase. The activation of NF-kappaB and p38 MAP kinase
      in HEp-2 cells suggest that JlpA triggers inflammatory/immune responses in host
      cells following C. jejuni infection.

PMID- 12614461
TI  - The Haemophilus influenzae Hap autotransporter mediates microcolony formation and
      adherence to epithelial cells and extracellular matrix via binding regions in the
      C-terminal end of the passenger domain.
AB  - The pathogenesis of non-typable Haemophilus influenzae disease begins with
      colonization of the nasopharynx and is facilitated by bacterial adherence to
      respiratory mucosa. The H. influenzae Hap autotransporter is a non-pilus adhesin
      that promotes adherence to epithelial cells and selected extracellular matrix
      proteins and mediates bacterial aggregation and microcolony formation. In
      addition, Hap has serine protease activity. Hap contains a 110 kDa internal
      passenger domain called HapS and a 45 kDa C-terminal translocator domain called
      Hapbeta. In the present study, we sought to define the structural basis for Hap
      adhesive activities. Based on experiments using a panel of monoclonal antibodies
      against HapS, a deletion derivative lacking most of HapS and a purified fragment
      of HapS, we established that adherence to epithelial cells is mediated by
      sequences within the C-terminal 311 residues of HapS. In additional experiments,
      we discovered that bacterial aggregation is also mediated by sequences within the
      C-terminal 311 residues of HapS and occurs via HapS-HapS interaction between
      molecules on neighbouring organisms. Finally, we found that adherence to
      fibronectin, laminin and collagen IV is mediated in part by sequences within the
      C-terminal 311 residues of HapS and in full by sequences within the C-terminal
      511 residues of HapS. Taken together, these results demonstrate that all Hap
      adhesive activities reside in the C-terminal portion of HapS. Coupled with
      earlier observations, the current results establish that HapS adhesive activities
      and HapS protease activity are contained in separate modules of the protein.

PMID- 12614462
TI  - TyeA of Yersinia pseudotuberculosis is involved in regulation of Yop expression
      and is required for polarized translocation of Yop effectors.
AB  - Type III secretion-dependent translocation of Yop (Yersinia outer proteins)
      effector proteins into host cells is an essential virulence mechanism common to
      the pathogenic Yersinia species. One unique feature of this mechanism is the
      polarized secretion of Yops, i.e. Yops are only secreted at the site of contact
      with the host cell and not to the surrounding medium. In vitro, secretion occurs
      in Ca2+-depleted media, a condition believed to somehow mimic cell contact. Three
      proteins, YopN, LcrG and TyeA have been suggested to control secretion and
      mutating any of these genes results in constitutive secretion. In addition, in Y.
      enterocolitica TyeA has been implied to be specifically required for delivery of
      a subset of Yop effectors into infected cells. In this work we have investigated
      the role of TyeA in secretion and translocation of Yop effectors by Y.
      pseudotuberculosis. An in frame deletion mutant of tyeA was found to be
      temperature-sensitive for growth and this phenotype correlated to a lowered
      expression of the negative regulatory element LcrQ. In medium containing Ca2+,
      Yop expression was somewhat elevated compared to the wild-type strain and low
      levels of Yop secretion was also seen. Somewhat surprisingly, expression and
      secretion of Yops was lower than for the wild-type strain when the tyeA mutant
      was grown in Ca2+-depleted medium. Translocation of YopE, YopH, YopJ and YopM
      into infected HeLa cells was significantly lower in comparison with the isogenic
      wild-type strain and Yop proteins could also be recovered in the tissue culture
      medium. This indicated that the tyeA mutant had lost the ability to translocate
      Yop proteins by a polarized mechanism. In order to exclude that the defect in
      translocation seen in the tyeA mutant was a result of lowered
      expression/secretion of Yops, a double lcrQ/tyeA mutant was constructed. This
      strain was de-repressed for Yop expression and secretion but was still impaired
      for translocation of both YopE and YopM. In addition, the low level of YopE
      translocation in the tyeA mutant was independent of the YopE chaperone YerA/SycE.
      TyeA was found to localize to the cytoplasm of the bacterium and we were unable
      to find any evidence that TyeA was secreted or surface located. From our studies
      in Y. pseudotuberculosis we conclude that TyeA is involved in regulation of Yop
      expression and required for polarized delivery of Yop effectors in general and is
      not as suggested in Y. enterocolitica directly required for translocation of a
      subset of Yop effectors.

PMID- 12614463
TI  - Cerebral dysfunction in chronic hepatitis C infection.
AB  - A number of studies have reported an association between chronic hepatitis C
      (HCV) infection and significant impairments in health-related quality of life
      (QOL), which are independent of the severity of liver disease. There are numerous
      reports documenting the prevalence of symptoms such as fatigue and depression in
      chronic HCV infection, which may in part account for the reductions in quality of
      life. Although there are a large number of potential explanations for these
      symptoms, including depression and anxiety associated with the diagnosis of HCV
      infection or substance abuse, there has been recent interest in the possibility
      of a biological effect of HCV infection on cerebral function. There is emerging
      evidence of mild, but significant neurocognitive impairment in HCV infection,
      which cannot be attributed to substance abuse, coexistent depression or hepatic
      encephalopathy. In vivo magnetic resonance spectroscopy and neurophysiological
      studies have suggested that a biological mechanism may underlie these cognitive
      findings. The recent detection of HCV genetic sequences in post mortem brain
      tissue raises the intriguing possibility that HCV infection of the central
      nervous system may be related to the reported neuropsychological symptoms and
      cognitive impairment.

PMID- 12614464
TI  - Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and
      correlation with the response to combination therapy with interferon and
      ribavirin.
AB  - Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C
      virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent
      protein kinase (PKR) and may therefore interfere with the response to IFN
      therapy, but controversy still exists regarding the relevance of this. This study
      aimed to assess whether mutations in these regions correlated with the response
      to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed
      in 57 HCV-1b patients who had received IFN-alpha2b (3 or 5 MU three times weekly)
      and ribavirin (800-1200 mg per day) for 24 weeks. The amino acid sequences of the
      NS5A and PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) were deduced
      from the corresponding coding sequence, which were determinated by direct
      sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty
      (36%) patients achieved a sustained virological response (SVR). The mean number
      of amino acid substitutions in the NS5A-PKR binding domain (2209-2274),
      interferon sensitivity-determining region (ISDR) (2209-2248), and E2-PePHD
      sequence (659-670) in patients with and without SVR were 4.53 +/- 3.31 vs 2.83 +/
      1.78 (P = 0.094), 2.45 +/- 2.74 vs 1.03 +/- 1.32 (P = 0.042) and 0.25 +/- 0.70
      vs 0.03 +/- 0.17 (P = 0.109), respectively. Patients with a mutant-type (>/= 4)
      NS5A-ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type
      (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of
      the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid
      substitutions) revealed that the mutation in NS5A-ISDR (>/= 4 vs < 4) was the
      only independent variable of treatment outcome. Our study showed that NS5A-ISDR
      mutations were correlated with the SVR to combination therapy in chronic HCV-1b
      patients in Taiwan.

PMID- 12614465
TI  - TT virus has a ubiquitous diffusion in human body tissues: analyses of paired
      serum and tissue samples.
AB  - The tissue tropism and possible correlation with liver disease of the TT virus
      (TTV) as well as its prevalence and genotype distribution remain undefined. TTV
      DNA was investigated in paired sera and tissue samples from 144 patients, and
      sera and cerebrospinal fluids (CSF) from additional six subjects. Of the 144
      tissue samples, 128 were liver biopsy specimens from subjects with hepatic
      disease while 16 were surgically obtained nonliver specimens from patients with
      extrahepatic disease. TTV cloning, sequencing and genotype analyses were
      performed on isolates from sera, tissue specimens and peripheral blood
      mononuclear cells of two patients with hepatic and four patients with
      extrahepatic pathologies, as well as from sera and CSFs of two subjects. TTV was
      found in 100% of the examined tissues and in 60.1 and 50% of sera from patients
      with hepatic and extrahepatic pathologies, respectively. Moreover, TTV was
      detected in four of the six CSFs analysed but only in two correspondent sera.
      Genotyping revealed the coexistence of multiple TTV genotypes and genetic
      variants in each infected individual, and the analysis of TTV mRNA showed the
      presence of transcripts in all the six different tissues studied. These results
      indicate that the entire adult population in our area is more likely infected by
      TTV, although several subjects are not viraemic and that TTV infects many
      different human tissues and is able to invade the central nervous system.

PMID- 12614466
TI  - The impact of prior hepatitis B virus infection on liver histology and the
      response to interferon therapy in chronic hepatitis C.
AB  - Patients with chronic hepatitis C frequently have antibodies to the hepatitis B
      core antigen (anti-HBc), indicative of prior hepatitis B virus (HBV) infection.
      In these patients, persistence of HBV may exacerbate liver injury and diminish
      the response to treatment. The aim of this study was to evaluate the relationship
      between previous HBV infection and liver histology and the sustained virologic
      response (SVR) to interferon (IFN)-based therapy in patients with chronic
      hepatitis C. A total of 132 HBsAg-negative, treatment-naive patients were
      evaluated. Using multiple logistic regression analysis, the impact of anti-HBc
      positivity on the rate of SVR was determined. Progression to bridging fibrosis or
      cirrhosis was assessed using Cox proportional hazards regression and Kaplan-Meier
      survival analysis. The median age of the patients was 47 years (IQR, 37-60), 57%
      were male, and 73% had genotypes 1, 4, 5, or 6. Fifty-one patients (39%) were
      anti-HBc-positive. The prevalence of moderate to severe necroinflammatory
      activity (P = 0.36) and progression to bridging fibrosis or cirrhosis (log-rank P
      = 0.83) was similar between anti-HBc-positive and -negative patients. After a
      median of 48 weeks (IQR, 26-52) of therapy (IFN, n = 116; IFN and ribavirin, n =
      16), 23 patients (17%) achieved a SVR; the rate of response was similar in anti
      HBc-positive and -negative patients (18%vs 17%, P = 1.00). After controlling for
      age, gender, genotype, fibrosis, and treatment regimen, anti-HBc status did not
      independently affect the rate of SVR (anti-HBc-positive vs negative: odds ratio,
      1.36; 95% confidence interval, 0.45 to 4.06; P = 0.58). In conclusion, previous
      HBV infection does not affect liver histology or the response to IFN-based
      therapy in patients with chronic hepatitis C.

PMID- 12614467
TI  - Efficacy of prolonged 5 million units of interferon in combination with ribavirin
      for relapser patients with chronic hepatitis C.
AB  - summary. Retreatment of relapser patients with chronic hepatitis C with the
      standard dose of interferon (IFN) of 3 million units (MU) thrice weekly (tiw)
      plus ribavirin for 24 weeks achieves a sustained response in 30 and 73% of
      patients with genotype 1 and 2 or 3, respectively. The aim of this study was to
      evaluate the efficacy and safety of IFN alpha-2b induction therapy, followed by
      prolonged treatment with a high dose of IFN alpha-2b plus ribavirin in relapser
      patients. A total of 119 patients were randomized to receive IFN alpha-2b 5 MU
      daily (Group A: 59 patients) or IFN alpha-2b 5 MU tiw (Group B: 60 patients) for
      4 weeks followed by IFN (5 MU tiw) and ribavirin (1000-1200 mg/day) for 48 weeks
      in both groups. The primary end point was hepatitis C virus (HCV)-RNA clearance
      at week 24 after the end of treatment. A sustained virological response (SVR) was
      achieved in 68 and 60% of Group A and B patients, respectively (P = 0.37).
      Logistic regression analysis identified genotype 2 or 3 as the only independent
      factor associated with response, whereas induction regimen and baseline viraemia
      levels did not affect the response. The overall SVR was 53 and 72% in patients
      with genotype 1 or 4 and 2 or 3, respectively. In conclusion, induction IFN
      therapy does not enhance the SVR to a 48-week combination therapy. Our study
      suggests that relapsed patients with genotype 1 or 4 may achieve significant
      response rates of approximately 50%, if retreated with 5 MU tiw IFN plus
      ribavirin for 48 weeks.

PMID- 12614468
TI  - Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV
      and hepatitis C virus (HCV) co-infected patients.
AB  - To assess the factors associated with liver fibrosis in human immunodeficiency
      virus and hepatitis C virus (HIV/HCV) co-infected patients eligible for anti-HCV
      therapy, we performed an observational, single-centred, cross-sectional study of
      180 HIV/HCV co-infected patients who underwent liver biopsy between May 1998 and
      November 2001. A total of 126 patients with a known date of HCV infection were
      evaluated. Liver fibrosis was defined as a Knodell stage of fibrosis 1-4. The
      mean age was 36.7 (3.8) years, 81% were male and had a mean age of 20.5 (3.8)
      years at HCV infection. Mean CD4 cell count and plasma HIV-1 RNA load at the time
      of biopsy were 552 cell/mm3 (239) and 2.5 log10 (0.9), respectively; 118 patients
      had been on antiretroviral therapy (ART) for a median of 45 months (Q1-Q3: 21-75)
      and 84 on protease inhibitor for a median of 12.0 months (Q1-Q3: 0-29.5); 55 had
      an AIDS event or a CD4 cell count nadir < 200 cells/mm3 prior to biopsy. Median
      histological activity index was 6 and 27% had a Knodell stage of fibrosis 0. On
      the multivariate analysis time on ART (OR for 6 months extra: 0.954, 95% CI:
      0.859-0.994), CD4 cell count at the time of liver biopsy (OR for 100 cells/mL
      increase: 0.740, 95% CI: 0.670-0.905), age at HCV infection acquisition (OR for 5
      years extra: 2.594, 95% CI: 1.326-5.133) and alcohol intake (> 50 g/day) (OR:
      2.73, 95% CI: 1.108-6.731) were associated with liver fibrosis. Hence ART should
      be a priority in HIV/HCV co-infected patients eligible for anti-HCV treatment as
      it is a protective factor for liver fibrosis.

PMID- 12614469
TI  - Long-term liver histology improvement in patients with chronic hepatitis C and
      sustained response to interferon.
AB  - A retrospective multicentre survey was conducted to evaluate, in patients with
      chronic hepatitis C, the long-term liver histological changes induced by
      interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All
      patients had received a 6-12-month IFN-alpha course (6-18 MU/week) and had
      successively undergone clinical, biochemical and virological follow-up for at
      least 36 months (range: 36-76). In each patient, two liver biopsies had been
      performed: 1-6 months before treatment and, 12-76 months after its completion. In
      87 patients with biochemical and virological sustained response persisting for 12
      months after therapy, post-treatment liver necroinflammation and fibrosis mean(+/
      SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9
      +/- 2.2 vs 6.8 +/- 2.9 and 0.8 +/- 1.0 vs 1.2 +/- 1.1, respectively; P < 0.01).
      In 25 patients who relapsed within 1 year, necroinflammation and fibrosis post
      treatment mean scores were similar to pretreatment scores (7.4 +/- 3.2 vs 6.9 +/-
      3.1 and 1.8 +/- 1.3 vs 1.6 +/- 1.2, respectively; P > 0.05). On an individual
      basis, necroinflammation decreased in 87% of sustained responders but only in 36%
      of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained
      responders but only in 14% of relapsers (P < 0.001). In sustained responders with
      biopsies performed 12-23 months (n=34), 24-35 months (n=26) or more than 36
      months (n=27) after treatment, a progressive decrease of mean necroinflammatory
      score was observed (-2.6 +/- 2.1, -4.1 +/- 3.4 and -5.2 +/- 3.7 points,
      respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3
      +/- 0.6, -0.3 +/- 0.7 and -0.7 +/- 0.9 points, respectively; P < 0.05). Hence,
      among chronic hepatitis C patients treated with IFN, those with a 12-month
      sustained response, unlike those who relapse, have a long-term progressive
      reduction and, in some cases, a complete regression of liver histological damage.

PMID- 12614470
TI  - Cross-sectional survey of the extent and indicators of hepatitis C virus
      infection in Houston Department of Health and Human Services' sexually
      transmitted disease clinics.
AB  - To evaluate the prevalence and indicators of hepatitis C virus (HCV) infection in
      Houston and determine the effectiveness of targeted HCV screening in sexually
      transmitted disease (STD) clinics. We performed a cross-sectional survey in low
      risk and high-risk groups in Houston. This included a blinded survey of HCV
      conducted in 1010 STD clinic clients having serological syphilis tests, and 1885
      multi-speciality group practice patients having metabolic blood work. This was
      followed with a targeted hepatitis C survey of 822 high-risk clients from STD
      clinics. The seroprevalence of hepatitis C infection in the blinded survey was
      3.9% (95% CI 3.0-4.8) in the multi-speciality group and 5.0% (95% CI 3.7-6.3) in
      the STD clinics. Prevalence of hepatitis C infection among targeted STD clinic
      clients was significantly higher at 15.3% (95% CI 12.7-17.7). Risk factors that
      correlated with HCV infection after logistic regression included: injection drug
      use (OR = 10, 95% CI = 3.4-30.3), heroin use (OR = 6.6, 95% CI = 2.2-20.5), non
      transfusion/ transplantation blood exposure (OR = 3.0, 95% CI = 1.3-6.9), sharing
      equipment to snort drugs (OR = 2.5, 95% CI 1.2-5.4), and age above 25 years (OR =
      51, 95% CI = 9-47). This study demonstrates that targeting clients in STD clinics
      for known risk behaviours is an effective way to identify cases of HCV infection.
      STD clinics allow access to clients with both drug use and sexual risk behaviours
      and are a useful location for targeting hepatitis C screening and prevention
      efforts.

PMID- 12614471
TI  - Hepatitis B in St Petersburg, Russia (1994-1999): incidence, prevalence and force
      of infection.
AB  - Hepatitis B (HB) is thought to be an expanding health problem in Russia. The
      incidence of infection was estimated from mandatorily reported HB cases in St
      Petersburg. The two-sided t-test for independent samples and the LOESS (locally
      weighted regression) smoother were used to compare the age at infection for
      symptomatic, asymptomatic and chronic infections, by gender. The force of
      infection was estimated from seroprevalence data (907 sera taken in 1999) using a
      newly developed nonparametric method based on local polynomials, as well as an
      earlier method based on isotonic regression and kernel smoothers. With the local
      polynomial method, pointwise confidence intervals (95%) were constructed by
      bootstrapping. On average, men contracted HB infection at a significantly younger
      age than women (in 1999, 21.8 vs 22.7 years, respectively). The overall male to
      female ratio was 1.92. In 1999 the overall incidence almost doubled compared with
      the preceding years and tripled among the age groups with highest incidence (15
      29-year olds: 85% of cases in 1999). The incidence increase was associated with a
      lower average age at infection (24.1 years in 1994 vs 22.1 years in 1999). The
      age and gender-specific force of infection estimates generally confirmed the
      incidence estimates and emphasized the usefulness of local polynomials to do
      this. Hence HB transmission in St Petersburg occurs mainly in young adults. The
      dramatic increase of infections in 1999 was probably due to injecting drug use.
      Without intervention, HB virus is expected to continue to spread rapidly with a
      greater proportion of female infections caused by sexual transmission. These
      trends may also provide an indication for HIV transmission.

PMID- 12614472
TI  - Seroprevalences of hepatitis B and C among health care workers in Turkey.
AB  - We determined the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus
      (HCV) among health care workers (HCWs) at Gulhane Military Medical Academy,
      Haydarpasa Training Hospital in Istanbul, Turkey. Between April 1998 and
      September 2000, 702 HCWs were included in the study. The blood samples were
      tested for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody
      (anti-HBs) and HCV antibody (anti-HCV) using third-generation tests, with
      confirmation by reverse transcriptase-polymerase chain reaction. Seroprevalence
      rates were compared with those detected in 5670 blood donors during the same
      period. HBsAg, anti-HBs and anti-HCV were detected in 21 (3.0%), in 480 (68.4%)
      and in 2 (0.3%) of 702 HCWs respectively. HBsAg and anti-HCV rates were 2.1 and
      0.4% in blood donors, respectively. These data show that the prevalence rates of
      HBV and HCV were similar with prevalence rates detected in randomized blood
      donors showing that universal infection-control precautions and encouraging HBV
      vaccination reduces HCW infection with hepatotropic viruses.

PMID- 12614473
TI  - The utility of melatonin in reducing cerebral damage resulting from ischemia and
      reperfusion.
AB  - The brain is highly susceptible to focal or global ischemia. Unless ischemia is
      promptly reversed, reperfusion produces further cerebral damage. Acute
      thrombolysis or defibrinogenation is effective only in selective patients with
      ischemic stroke and carries a significant risk of bleeding complications. Whereas
      numerous neuroprotectants were shown to be effective in experimental studies,
      none of them have been shown to work in clinical trials. The major pathogenetic
      mechanisms of ischemia/reperfusion injury include excitotoxicity, disturbed
      calcium ion homeostasis, overproduction of nitric oxide and other free radicals,
      inflammation, and apoptosis. Nitric oxide and other free radicals, the key
      mediators of excitotoxicity and disturbed calcium ion homeostasis, cause direct
      injury and also indirectly damage via inflammation and apoptosis. Melatonin is a
      potent free radical scavenger and an indirect antioxidant. This mini review
      summarizes the in vivo and in vitro evidence that melatonin protects against
      ischemia/reperfusion injury. There is convincing evidence from the literature
      that melatonin treatment is highly effective in different in vivo and in vitro
      models of excitotoxicity or ischemia/reperfusion in multiple animal species.
      Melatonin is safe and non-toxic in humans, and its administration via the oral
      route or intravenous injection is convenient. While more experimental studies
      should be conducted to further explore the neuroprotective mechanisms and to
      document any synergistic or additive protection from combining melatonin with
      thrombolysis, defibrinogenation or other neuroprotectants, interested clinical
      scientists should consider planning phase II and III studies to confirm the
      benefit of melatonin as an acute stroke treatment or a preventive measure for
      stroke patients.

PMID- 12614474
TI  - Seasonal changes in melatonin concentrations in female Iberian red deer (Cervus
      elaphus hispanicus).
AB  - In deer, most of the earlier investigations on pineal function examined the
      effects of artificial photoperiods or the administration of melatonin to
      manipulate reproduction. However, endogenous melatonin rhythms have not been
      studied in red deer. Thus, we monitored seasonal changes in plasma melatonin
      concentrations in 16 adult female Iberian red deer living in outdoor enclosures.
      Blood was sampled on the day of each seasonal change every 3-4 hr overnight and 1
      hr before and after sunset and sunrise. In addition, in six of the previous
      hinds, blood sampling during the hour prior and after sunset and sunrise was
      collected every 20 min. Significant differences were found both in amplitude and
      duration of the nocturnal plasma melatonin profiles in the four seasonal changes
      (P < 0.01). The nocturnal mean level of melatonin, the duration of nocturnal
      secretion levels and maximal concentrations were significantly higher at the
      winter solstice than in summer solstice or equinoxes (P < 0.05). Moreover, the
      mean overnight concentrations were significantly higher at the spring equinox and
      winter solstice than during the summer solstice and autumn equinox (P < 0.05). A
      pronounced elevation from low levels was recorded 1 hr after sunset, remained
      elevated during the hours of darkness and declined to low levels 1 hr after dawn.
      Concentrations close to sunrise were higher than those near sunset at all changes
      of season (P < 0.05). These results show for the first time in red deer that the
      pineal gland of the adult female is highly responsive to both daily and seasonal
      changes in natural environmental illumination, although overnight levels lasted
      longer than the photoperiodic night is all cases, particularly at the winter
      solstice.

PMID- 12614475
TI  - Melatonin modulates the action of near infrared radiation on cell adhesion.
AB  - The adhesion of human cervical cancer (HeLa) cells to a glass matrix is evaluated
      following their irradiation in a suspension with a pulsed near-infrared (IR)
      light-emitting diode (wavelength 820 nm, pulse repetition frequency 10 Hz,
      irradiation dose 16-120 J/m2) when melatonin (4 x 10(-11) to 4 x 10(-5) m) is
      added to cell suspension immediately before or after the irradiation. Also, the
      dependence of visible-to-near-IR radiation (600-840 nm, 52 J/m2) on cell adhesion
      (action spectrum) is recorded in absence and presence of melatonin (4 x 10(-6)
      m). It is found that melatonin in pharmacological concentrations (but not in
      physiological range) inhibited cell adherence. Irradiation of cells before or
      after melatonin treatment normalizes cell adhesion to control level. Melatonin in
      pharmacological concentrations eliminates stimulation of cell attachment induced
      by irradiation. Pre-treatment (but not post-treatment) with melatonin in the
      physiological concentration eliminates cell adhesion stimulation induced by
      irradiation. Melatonin modifies the light action spectrum significantly in near
      IR region (760-840 nm only). Thus, the peak at 820-830 nm characteristic for the
      light action spectrum is fully reduced.

PMID- 12614476
TI  - Melatonin reduces lipid peroxidation and nitric oxide during irradiation-induced
      oxidative injury in the rat liver.
AB  - Radiation therapy is a popular and useful tool in the treatment of cancer.
      Melatonin participates in the regulation of a number of important physiological
      and pathological processes. Melatonin, a powerful endogenous antioxidant, plays a
      role in the reduction of oxidative damage. Thirty adult rats were divided into
      five equal groups. On the day of the experiment, groups I and II were injected
      with 5 or 10 mg/kg melatonin, respectively, while group III received isotonic
      NaCl solution. Thirty minutes later, groups I, II and III were exposed to 6.0 Gy
      whole body ionizing radiation in a single fraction. Group IV was injected with 5
      mg/kg melatonin but was not irradiated. The final group was reserved as sham
      treated. Liver malondialdehyde (MDA) and nitric oxide (NO*) levels were measured
      in all groups. Whole body irradiation caused a significant increase in liver MDA
      and NO* levels. Hepatic MDA and NO* levels in irradiated rats that were
      pretreated with melatonin (5 or 10 mg/kg) were significantly decreased.
      Malondialdehyde and NO* levels were reduced in a dose-related manner by
      melatonin. The data show that melatonin reduces liver damage inflicted by
      irradiation when given prior to the exposure to ionizing radiation. The
      radioprotective effect of melatonin is likely achieved by its ability to function
      as a scavenger for free radicals generated by ionizing radiation.

PMID- 12614478
TI  - Preventive effect of melatonin on the progression of alpha-naphthylisothiocyanate
      induced acute liver injury in rats.
AB  - The preventive effect of melatonin on the progression of alpha
      naphthylisothiocyanate (ANIT)-induced acute liver injury with cholestasis was
      examined in rats treated once with the hepatotoxin [75 mg/kg body weight (BW),
      i.p.]. In rats treated with ANIT alone, liver injury with cholestasis occurred 24
      hr after treatment and progressed at 48 hr, judging from the serum levels of
      hepatobiliary marker enzymes and components. Melatonin (10 or 100 mg/kg BW) was
      orally administered to the ANIT-treated rats, 24 hr after the hepatotoxin
      treatment at which time hepatic injury had already developed. The administered
      indoleamine prevented the progression of liver cell damage rather than biliary
      cell damage more effectively at the higher dose than at the lower dose. In rats
      treated with ANIT alone, the serum and hepatic concentrations of thiobarbituric
      acid reactive substances, an index of lipid peroxidation, and the hepatic
      activity of myeloperoxidase, an index of tissue neutrophil infiltration,
      increased 24 hr after treatment and further increased at 48 hr. In the liver of
      rats treated with ANIT alone, Cu,Zn-superoxide dismutase activity decreased 24 hr
      after treatment and was further reduced at 48 hr, although there was no change in
      Mn-superoxide dismutase activity. Catalase and Se-glutathione peroxidase
      activities also decreased at 48 hr, while reduced glutathione concentrations
      remained increased at 24 and 48 hr. The melatonin administered to the ANIT
      treated rats attenuated the increases in serum and hepatic concentrations of
      thiobarbituric acid reactive substances and the decreases in hepatic activities
      of Cu,Zn-superoxide dismutase, catalase, and Se-glutathione peroxidase found at
      48 hr after the hepatotoxin treatment more effectively at the higher dose than at
      the lower dose; on the other hand, melatonin treatment had no effect on the
      increases in hepatic myeloperoxidase activity and reduced glutathione
      concentration found at 48 h. These results indicate that orally administered
      melatonin at pharmacological doses prevents the progression of ANIT-induced acute
      liver injury, mainly liver cell damage, in rats, and suggest that the
      administered melatonin exerts these preventive effects through its direct and
      indirect antioxidant actions.

PMID- 12614479
TI  - Melatonin protects SHSY5Y neuronal cells but not cultured astrocytes from
      ischemia due to oxygen and glucose deprivation.
AB  - As a potent free radical scavenger and antioxidant, melatonin protects brain
      tissue against ischemia-reperfusion injury, partly via suppression of ischemia
      induced production of nitric oxide, when given before ischemia-reperfusion or
      within 2 hr of onset of ischemia. In this study, we examined the neuroprotective
      effect of melatonin in an in vitro model of ischemia. Primary cultured astrocytes
      were subjected to 4 or 8 hr of oxygen-glucose deprivation (OGD), and cultured
      SHSY5Y human neuronal cells were exposed to 1 hr of OGD. Melatonin was added to
      the medium at the commencement of OGD to achieve different final concentrations,
      and cell death was quantified using the measurement of 3-(4,5-dimethylthiazol-2
      yl)-2,5-diphenyl-tetrazolium bromide (MTT) at 24 hr after reversion of OGD.
      Treatment with melatonin did not affect the astrocytic cell death following 4 or
      8 hr of OGD. The relative MTT values of the neuronal cells were (as mean +/-
      S.E.M.) 59.1 +/- 2.4% in the vehicle-treated OGD group and 80.1 +/- 2.7%, 82.5 +/
      2.9%, 74.1 +/- 2.3%, 64.2 +/- 2.3%, 62.7 +/- 2.8%, and 61.0 +/- 3.9% in the OGD
      groups treated with melatonin at 10(-3), 10(-4), 10(-5), 10(-6), 10(-7), and 10(
      8) m, respectively. Reduction in cell death was significant following treatment
      with melatonin at 10(-3), 10(-4), or 10(-5) m. Reverse transcription-polymerase
      chain reaction showed that human mt1 and MT2 membrane receptors were not
      expressed in the cultured neuronal cells. Our results show that melatonin co
      treatment protects cultured neuronal cells but not astrocytes against OGD-induced
      cell death in a dose-dependent manner and that the neuroprotection is independent
      of its known membrane receptors.

PMID- 12614480
TI  - Characterization of melatonin high-affinity binding sites in purified cell nuclei
      of the hamster (Mesocricetus auratus) harderian gland.
AB  - In the present paper, binding of melatonin to purified cell nuclei from harderian
      glands of male and female hamsters was assessed. Binding of 125I-melatonin to
      cell nuclei fulfills the criteria for binding to a receptor site. Binding
      kinetics exhibit properties such as dependence on time and temperature as well as
      reversibility, saturability, high affinity and specificity. The dissociation
      constants (K(D)) and the number of binding sites (B(max)) for the binding of 125I
      melatonin to harderian gland nuclei were 260 +/- 56 pm and 12.2 +/- 0.8 fmol/mg
      protein in male glands, and 280 +/- 43 pm and 9.8 +/- 0.6 fmol/mg protein in
      female glands, respectively. Competition experiments showed IC50 values for
      melatonin of 250 +/- 45 pm and 290 +/- 68 pm in male and female glands,
      respectively. Other indoleamines such as N-acetylserotonine and 5
      metoxytryptamine showed IC50 values in the micromolar range, suggesting that the
      binding sites are specific for melatonin. Hill analyses of the data show nH
      values of 0.96-0.98, suggesting the existence of a single class of binding sites.
      These data indicate that specific 125I-melatonin binding sites exist in the cell
      nuclei of Harderian glands in male as well as in female hamsters, without
      significant differences between them. The K(D) and B(max) values obtained from
      the binding in both sexes correlates well with the concentration of melatonin
      described in these respective Harderian glands. It is hypothesized that the
      nuclear binding sites of melatonin here described could be a physiological
      melatonin receptor, which may be involved in the genomic-dependent antioxidant
      effects of melatonin on hamster Harderian glands elsewhere reported.

PMID- 12614481
TI  - Purification and immunohistochemical analysis of calcium-binding proteins
      expressed in the chick pineal gland.
AB  - The pineal gland is a site of melatonin production, of which intracellular
      calcium ions (Ca2+) are likely involved in various aspects. To investigate the
      identity of molecules responsible for the Ca2+-dependent processes in the pineal
      cells, we prepared a cellular extract from 2000 chick pineal glands and isolated
      a series of Ca2+-binding proteins by taking advantage of their Ca2+-dependent
      hydrophobic interaction with phenyl-Sepharose beads. The proteins identified by
      micro-sequencing analysis included calmodulin, neurocalcin, sorcin, annexin II
      and annexin V. Immunohistochemical analysis of the chick pineal sections revealed
      that both calmodulin and sorcin are expressed in the follicular and
      parafollicular pinealocytes. On the other hand, neurocalcin was expressed in a
      few neuron-like cells located predominantly in the parafollicular layer of the
      pineal follicle. These results suggest that calmodulin and sorcin may contribute
      to cellular functions in the chick pinealocytes.

PMID- 12614482
TI  - Maternal transfer of photoperiodic information in Siberian hamsters. vi. effects
      of time-dependent 1-hr melatonin infusions in the mother on photoperiod-induced
      testicular development of her offspring.
AB  - We tested in Siberian hamsters the nature of the maternal signal that relays
      photoperiodic information to the developing fetuses. As previous investigations
      have identified maternal hormonal and circadian components in this process, the
      specific goal of this presentation is to determine quality of the signal that
      connotes daylength when it is imparted to the fetus. Does the function of the
      signal received by the fetus best support the coincidence or duration hypotheses
      of photoperiodic induction? Pregnant hamsters received 1 or 8 hr melatonin or
      vehicle infusions everyday. Juveniles of intact mothers gestated on 16 hr of
      light per day (16L) experienced maximal suppression of testicular development
      when reared on 14L. However, when intact mothers gestated on 10L received a 1-hr
      melatonin infusion daily at 20:00-21:00 hr, their young responded to 14L with
      greatly accelerated testicular development. In the absence of the maternal pineal
      gland (and, therefore, the maternal melatonin signal), the effects of maternal
      melatonin infusions were reversed. Here, only the juveniles of 16L-gestated
      females infused at 20:00-21:00 hr daily responded to 14L with enhanced testicular
      development. All other groups showed the same extent of gonadal development,
      independent of the time or type of infusion their mothers received. Testicular
      development on 14L of all juveniles from pinealectomized mothers gestated on 10L
      was of the same magnitude, regardless of the type and time of infusion their
      mothers received during pregnancy. The results suggest that the maternal signal
      transferred to the fetuses during gestation consists not only of the daily
      melatonin signal, but also some circadian-based component that greatly affects
      the effect of the former. The timing, and not the duration, of the maternal
      melatonin signal with respect to the animals' (mother and fetus) circadian day is
      of crucial importance in the transfer of photoperiodic information from mother to
      fetus.

PMID- 12614483
TI  - Melatonin treatment protects against ischemia/reperfusion-induced functional and
      biochemical changes in rat urinary bladder.
AB  - Reactive oxygen metabolites play important roles in ischemia/reperfusion (I/R)
      injury in several systems. The aim of this study was to investigate the role of
      melatonin against I/R injury of the rat urinary bladder. The abdominal aorta was
      clamped to induce ischemia for 30 min, then the animals were subjected to 60 min
      of reperfusion. Melatonin (10 mg/kg, i.p.) or the vehicle (control 1% alcohol
      i.p.) was administered before I/R. After decapitation, the bladder was removed
      and the tissue was either used for functional studies or stored for measurement
      of products of lipid peroxidation (LP), glutathione (GSH) levels and
      myeloperoxidase activity (MPO). Bladder strips were suspended in oxygenated
      Tyrode's buffer at 37 degrees C and isometric contractions to carbachol (CCh; 10(
      8)-10(-4) m) were recorded. In the I/R group, the contractile responses of the
      bladder strips were lower than those of the control group (P < 0.01-0.001) and
      were reversed by treatment with melatonin (P < 0.05-0.001). LP which was higher
      in I/R group compared with control (27.68 +/- 1.69 and 10.59 +/- 1.27 nmol/g,
      respectively; P < 0.001) was partially reversed by melatonin (19.01 +/- 1.85
      nmol/g; P < 0.01). Similarly, GSH showed a decrease in the I/R group compared
      with controls (0.27 +/- 0.03 and 0.43 +/- 0.04 micromol/g, respectively; P <
      0.05) and melatonin prevented this effect completely (0.45 +/- 0.04 micromol/g; P
      < 0.05). MPO activity in the I/R group (4.19 +/- 0.08 U/g) was significantly
      higher than that of the control group (1.41 +/- 0.08 U/g; P < 0.001) and
      melatonin treatment reduced MPO levels compared with I/R alone (3.16 +/- 0.07; P
      < 0.001). Melatonin almost completely reversed the low contractile responses of
      rat urinary bladder strips to CCh and prevented oxidative tissue damage following
      I/R.

PMID- 12614486
TI  - European trends in diabetes technology--continuous glucose measurements and
      computerized information-processing tools.

PMID- 12614485
TI  - Implications of a RAD54L polymorphism (2290C/T) in human meningiomas as a risk
      factor and/or a genetic marker.
AB  - BACKGROUND: RAD54L (OMIM 603615, Locus Link 8438) has been proposed as a
      candidate oncosupressor in tumours bearing a non-random deletion of 1p32, such as
      breast or colon carcinomas, lymphomas and meningiomas. In a search for RAD54L
      mutations in 29 menigiomas with allelic deletions in 1p, the only genetic change
      observed was a silent C/T transition at nucleotide 2290 in exon 18. In this
      communication the possible association of the 2290C/T polymorphism with the risk
      of meningiomas was examined. In addition, the usefulness of this polymorphism as
      a genetic marker within the meningioma consensus deletion region in 1p32 was also
      verified. The present study comprises 287 blood control samples and 70
      meningiomas from Spain and Ecuador. Matched blood samples were only available
      from Spanish patients. RESULTS: The frequency of the rare allele-T and
      heterozygotes for the 2290C/T polymorphism in the blood of Spanish meningioma
      patients and in the Ecuadorian meningioma tumours was higher than in the control
      population (P < 0.05). Four other rare variants (2290C/G, 2299C/G, 2313G/A,
      2344A/G) were found within 50 bp at the 3' end of RAD54L. Frequent loss of
      heterozygosity for the 2290C/T SNP in meningiomas allowed to further narrow the
      1p32 consensus region of deletion in meningiomas to either 2.08 Mbp - within
      D1S2713 (44.35 Mbp) and RAD54L (46.43 Mbp) - or to 1.47 Mbp - within RAD54L and
      D1S2134 (47.90 Mbp) - according to recent gene mapping results. CONCLUSION: The
      statistical analysis of genotypes at the 2290C/T polymorphism suggest an
      association between the rare T allele and the development of meningeal tumours.
      This polymorphism can be used as a genetic marker inside the consensus deletion
      region at 1p32 in meningiomas.

PMID- 12614487
TI  - Insulin resistance and endothelial dysfunction in atherosclerosis: implications
      and interventions.
AB  - Current research suggests that insulin resistance is associated with endothelial
      dysfunction, which is considered an early but significant step in the
      pathogenesis of atherosclerosis. Both insulin resistance and endothelial
      dysfunction appear to precede the development of overt hyperglycemia in patients
      with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance,
      endothelial dysfunction may be a critical early target for preventing
      atherosclerosis and cardiovascular disease. Insulin-sensitizing agents-
      specifically, thiazolidinediones (TZDs)--may be useful for preventing or
      mitigating endothelial dysfunction. In vitro and clinical data show that TZDs can
      limit thrombotic, inflammatory, and oxidative changes that contribute to
      endothelial dysfunction. For example, TZDs have been shown to lower blood levels
      of plasminogen activator inhibitor-1, a prothrombotic substance, in patients with
      diabetes or insulin resistance. In obese patients, TZD treatment can improve
      vascular reactivity and reduce monocyte expression of nuclear factor kappa-B, a
      transcription factor that contributes to inflammation and oxidative damage. In
      patients with overt diabetes or insulin resistance, TZD treatment can lower blood
      levels of C-reactive protein and interleukin-6, markers of inflammation and
      cardiovascular risk. These beneficial effects of TZDs may help to decrease the
      risk of vascular damage and atherosclerosis in patients with insulin resistance
      or diabetes.

PMID- 12614488
TI  - Type 1 diabetes islet autoantibody markers.
AB  - The diagnosis of type 1 diabetes versus other forms of diabetes such as type 2
      diabetes is paramount to guiding proper therapy. Several islet autoantibodies
      have been identified that serve to diagnose immune-mediated, type 1a diabetes in
      clinically ambiguous cases. These autoantibodies also serve to predict type 1
      diabetes in nondiabetic individuals. The most useful islet autoantibodies include
      islet cell cytoplasmic autoantibodies, insulin autoantibodies, glutamic acid
      decarboxylase autoantibodies, and insulinoma-associated-2 autoantibodies. Once
      type 1 diabetes can be safely and reliably prevented, large-scale islet
      autoantibody screening programs of the general pediatric population may be
      warranted. It is controversial whether islet autoantibodies influence the course
      of type 1 diabetes following diagnosis.

PMID- 12614490
TI  - Pharmacokinetics and glucodynamics of rapid-, short-, and intermediate-acting
      insulins: comparison of jet injection to needle syringe.

PMID- 12614489
TI  - Laboratory testing for glycated hemoglobin in the general community: are we
      following the clinical recommendations?

PMID- 12614491
TI  - Using CAVE technology for functional genomics studies.
AB  - We have established the first Java 3D-enabled CAVE (CAVE automated virtual
      environment). The Java application programming interface allows the complete
      separation of the program development from the program execution, opening new
      application domains for the CAVE technology. Programs can be developed on any
      Java-enabled computer platform, including Windows, Macintosh, and Linux
      workstations, and executed in the CAVE without modification. The introduction of
      Java, one of the major programming environments for bioinformatics, into the CAVE
      environment allows the rapid development applications for genome research,
      especially for the analysis of the spatial and temporal data that are being
      produced by functional genomics experiments. The CAVE technology will play a
      major role in the modeling of biological systems that is necessary to understand
      how these systems are organized and how they function.

PMID- 12614492
TI  - Illness representation, coping and outcome in irritable bowel syndrome (IBS).
AB  - OBJECTIVE: Irritable bowel syndrome has no observable symptom markers and there
      is little that the medical profession can do to help sufferers. Psychotherapy,
      antidepressants and drugs aimed at the most problematic symptoms have been shown
      to have limited efficacy. In an attempt to help understand the illness better,
      and to suggest alternative forms of intervention, the study tested whether
      outcome might be influenced by patients' representation of their illness and by
      their coping strategies. METHOD: All members of the IBS Network (an independent
      charitable support network based in the UK) were invited to participate via their
      quarterly newsletter, and 209 completed questionnaires were returned.
      Participants completed the Illness Perception Questionnaire (IPQ), the COPE, and
      the Hospital Anxiety and Depression Scale (HADS), and rated their quality of life
      and their satisfaction with their health. RESULTS: The reporting of serious
      consequences was associated with lower quality of life and lower satisfaction
      with health, and with higher scores for anxiety and depression (p <.001). Weaker
      control beliefs were related to lower quality of life, lower satisfaction with
      health, and higher depression scores (p <.01). Lower illness scores were
      associated with more satisfaction with health (p <.01), but not with quality of
      life (p >.05). Psychological causal attribution of IBS was positively correlated
      with anxiety (p <.001) and depression (p <.01). Path analyses based on multiple
      linear regression demonstrated that (1) the reporting of serious consequences was
      a strong independent predictor of outcome; (2) coping mediated the link between
      representation and outcome; and (3) when predicting depression, coping strategies
      predicted coping independently of representation dimensions. CONCLUSIONS: The
      findings indicate that the illness representations of IBS sufferers can have
      significant implications for outcome. Therapeutic interventions based on illness
      representations may prove useful for treatment.

PMID- 12614493
TI  - The Transplant Effects Questionnaire (TxEQ): The development of a questionnaire
      for assessing the multidimensional outcome of organ transplantation - example of
      end stage renal disease (ESRD).
AB  - OBJECTIVES: To develop a questionnaire to assess the responses of transplant
      recipients to the receipt of an organ, including their self-care behaviour.
      DESIGN: Following a literature review, open-ended interviews and a focus group, a
      transplant questionnaire was developed. Two studies (Study 1: N = 231, Study 2: N
      = 105) were conducted to evaluate its psychometric properties. METHODS: A pool of
      51 items was derived from themes identified in published studies and from
      interviews and a focus group discussion with renal transplant recipients. These
      were constructed into a questionnaire and were then administered to two renal
      transplant out-patients populations. Item responses of study sample 1 were
      subjected to principal components analysis (PCA) using varimax rotation to
      examine the structure of responses. In order to investigate the stability of the
      factor structure found in Study 1, item responses of the second sample were
      subjected to confirmatory factor analysis (CFA) using structural equation
      modelling. RESULTS: PCA indicated six factors that accounted for 64.2% of the
      variance. With extraneous items omitted, the final questionnaire derived from
      Study 1 has 24 items clustered around five conceptual coherent factors: worry
      about transplant (22.1%), guilt regarding donor (11.9%), disclosure (9.58%),
      medication adherence (8.73%), and responsibility (6.63%). CFA on the final 24
      item version of the TxEQ revealed that the resulting model was a good fit for the
      Study 2 data (RMSEA = 0.08, pclose =.005). CONCLUSIONS: The TxEQ has potential
      application as a measure in the area of transplantation research. CFA
      demonstrated that the factor structure of the TxEQ is consistent across different
      renal transplant out-patients populations. Further research is currently in
      progress to assess other groups of transplant recipients and to examine its
      relationship to other measures.

PMID- 12614494
TI  - Optimism and adaptation to chronic disease: The role of optimism in relation to
      self-care options of type 1 diabetes mellitus, rheumatoid arthritis and multiple
      sclerosis.
AB  - OBJECTIVES: To determine the role of optimistic beliefs in adaptation processes
      of three chronic diseases different in controllability by self-care. It was
      expected that optimism towards the future would relate to adaptation
      independently of the controllability of disease. Optimism regarding one's coping
      ability should be beneficial in controllable diseases. Unrealistic optimism was
      expected to be beneficial in uncontrollable disease. DESIGN: The cross-sectional
      design involved 104 patients with type 1 diabetes, 95 patients with rheumatoid
      arthritis and 98 patients with multiple sclerosis, recruited via their physician
      at the out-patient department of five hospitals. METHOD: Confirmatory Factor
      Analysis (LISREL) was employed to confirm a three-dimensional approach of
      optimism: outcome expectancies, efficacy expectancies and unrealistic thinking.
      Multi-sample analysis by path modelling was used to examine whether the
      relationship of the three optimistic beliefs with coping (CISS-21), depression
      and anxiety (HADS), and physical functioning (SF-36) differs with the
      controllability based on the self-care options of chronic disease. RESULTS: These
      show that when chronic disease must be controlled by self-care, physical health
      depends more strongly on positive efficacy expectancies. In contrast, when self
      care options for controlling chronic disease are limited, physical health depends
      more strongly on positive unrealistic thinking and relates negatively to positive
      efficacy expectancies. The impact of the three optimistic beliefs on mental
      health is independent of the controllability by self-care. CONCLUSION: Optimistic
      beliefs are differently beneficial for physical health dependent on the
      controllability of chronic disease. Unrealistic beliefs are helpful when patients
      are confronted with moderately to largely uncontrollable disease where self-care
      options are limited, in contrast to positive efficacy expectancies that are
      helpful when patients deal with largely controllable disease where self-care is
      required.

PMID- 12614495
TI  - Cholesterol control, medication adherence and illness cognition.
AB  - OBJECTIVE: To examine the relation between illness cognitions and two measures of
      adherence in patients with hypercholesterolaemia, a disease marked by chronically
      high cholesterol. DESIGN: Cross-sectional. Based on the self-regulation model
      (Leventhal, Diefenbach, & Leventhal, 1992), patients' illness cognitions were
      predicted to be related to cholesterol control and medication adherence. Patients
      with illness cognitions consonant with an experts' mental model of
      hypercholesterolaemia were expected to show better control and adherence. METHOD:
      Hypercholesterolaemic patients (N = 169) were recruited at a university-based
      general medicine clinic. Patients completed a survey that assessed beliefs about
      hypercholesterolaemia and medication-taking behaviour. Cholesterol levels were
      obtained from patients' medical charts. RESULTS: Low-density lipoprotein (LDL)
      cholesterol control was related to believing that hypercholesterolaemia is a
      stable, asymptomatic disease with severe coronary consequences, and self-report
      of medication adherence was related to believing that the disease has severe
      coronary consequences (ps <.05). LDL cholesterol differences between groups low
      and high in various illness beliefs ranged between 0.04 and 0.24 mmol/l (2 and 9
      mg/dl) which translated to between 1% and 18% lower LDL cholesterol levels.
      CONCLUSION: The present study shows several relations that have not been
      previously demonstrated between better LDL cholesterol control and illness
      cognition, cognitions that were similar to an expert or physician's mental model
      of hypercholesterolaemia. The magnitude of differences in patient cholesterol
      levels was small but may be clinically important.

PMID- 12614496
TI  - Living with Huntington's disease: Illness perceptions, coping mechanisms, and
      patients' well-being.
AB  - OBJECTIVES: To describe the illness perceptions and coping mechanisms of patients
      with Huntington's disease (HD), and to assess their role in the well-being of
      these individuals. DESIGN: A single group, cross-sectional study. METHODS: In 77
      individuals with a clinically confirmed diagnosis of HD, illness perceptions,
      coping mechanisms, motor and cognitive performance, and well-being were assessed
      by means of questionnaire-guided interviews, and subjected to correlational
      analyses, t-tests and two-stage regression analyses. RESULTS: HD patients'
      illness perceptions were characterized by a strong illness identity, combined
      with beliefs about a long duration of HD, perceived negative consequences for
      their daily lives, and little hope for cure or improvement of their symptoms. In
      turn, the coping strategies that HD patients reported adopting to deal with their
      disease were comparable with those adopted by reference individuals dealing with
      everyday life stressful situations. Where the well-being of HD patients is
      concerned, compared with Dutch community sample, HD patients scored significantly
      lower on measures of physical well-being and general health. Both illness
      perceptions and coping mechanisms were significant predictors of patients' well
      being. CONCLUSIONS: More systematic research within a health psychology framework
      is justified in order to assess the role of illness perceptions and coping
      mechanisms in the well-being of HD patients.

PMID- 12614497
TI  - The structure of beliefs about the causes of heart attacks: A network analysis.
AB  - OBJECTIVES: To explore the structure of causal beliefs about heart attack, using
      network analysis, in particular to determine whether there is a consensual
      representation and, if so, which putative causes of heart attacks were perceived
      as being proximal or distal causes and which were perceived to mediate the
      effects of other causes. METHODS: A total of 107 adult respondents completed
      questionnaires, indicating the extent to which they perceived each of eight
      agents as causes of a heart attack, as well as whether they perceived that each
      of these eight causal agents, in turn, causally affects each of the other seven
      causal agents. RESULTS: A consensual representation was produced, indicating how
      these eight agents were perceived as causally relating to each other, and to
      heart attack. Three key features were evident. First, the type of work a person
      does was perceived to be a distal cause of heart attack, operating mainly through
      stress and high blood pressure. Second, the causal impact of stress on heart
      attack was not seen as mediated by behaviour, but mediated via blood pressure.
      Third, the causal impact of genes on heart attack was perceived as unmediated by
      behaviour or physiological processes. CONCLUSIONS: The general public appears to
      share a reasonably complex view of how different agents lead to heart attack.
      This complexity would not be elicited by standard methods, suggesting that the
      network analysis method may be usefully employed as either a process or an
      outcome measure in health-promotion research.

PMID- 12614498
TI  - Failing in spousal caregiving: The 'identity-relevant stress' hypothesis to
      explain sex differences in caregiver distress.
AB  - OBJECTIVES: This study examined a possible explanation for the frequently
      reported finding that female caregivers perceive more psychological distress than
      do male caregivers. Our 'identity-relevant stress' hypothesis asserts that
      feelings of incompetence with respect to caregiving are more strongly associated
      with psychological distress in women than in men. Women who feel competent with
      respect to caregiving may report levels of distress as low as that of male
      caregivers. DESIGN: This study has a cross-sectional design. METHODS:
      Psychological distress (CES-D) was measured in 32 female and 36 male partners of
      patients suffering from various types of cancer. Furthermore, partners'
      perceptions of caregiving performance and patients' perceptions of partners'
      supportive and unsupportive behaviour were assessed. RESULTS: Only among female
      partners were self-efficacy and personal accomplishment regarding caregiving
      found to be positively linked to distress. Also, in contrast to male partners,
      female partners reported more distress when they acted less supportively.
      CONCLUSION: The difference in psychological distress between female and male
      caregivers seems to be carried by a subgroup of partners who feel that they are
      not doing a very good job at caregiving.

PMID- 12614499
TI  - Judgments of the rule-related behaviour of health care professionals: An
      experimental study.
AB  - OBJECTIVES: To explore the judgments of rule-related behaviour by health care
      professionals and the general public in the UK, against a background in which
      clinical guidelines and protocols are proliferating. DESIGN: A questionnaire
      survey was used in which short scenarios describing medical practice were
      presented to a sample of health care professionals and members of the general
      public. METHODS: The health care sample consisted of 315 nurses, doctors and
      midwives from three English National Health Service (NHS) Trusts who volunteered
      to take part in the study. A stratified sample of members of the general public
      (N = 350) was recruited via a market research organization. Three types of
      behaviour (compliance with a protocol, violation of a protocol, and
      improvization, where no protocol exists) and three types of outcome for the
      patient (good, bad, poor) were manipulated within nine scenarios. Respondents
      were asked to make judgments about (1) the inappropriateness of behaviour (2)
      likelihood that they would take further action and (3) responsibility for the
      outcome. RESULTS: Findings suggest that the process of care has a greater effect
      on judgments of the behaviour of health care professionals than does the outcome
      of that behaviour. This was equally true of the professional and public samples.
      CONCLUSIONS: The study has both theoretical and practical implications. First,
      information about a behaviour's relationship to existing rules has a stronger
      influence than the consequence of the behaviour on attributions of
      responsibility. Secondly, using clinical protocols as a way of managing risk in
      the NHS may be counterproductive unless full compliance is achieved.

PMID- 12614500
TI  - Applying the Transtheoretical Model of Change to exercise in young Chinese
      people.
AB  - OBJECTIVES: The objective of the present study was to test the application of the
      Transtheoretical Model of Change (TTM) in relation to exercise behaviour of 298
      Hong Kong Chinese undergraduates. DESIGN AND METHODS: A cross-sectional design
      was used. Respondents completed measures of stages of change, self-efficacy,
      processes of change, decisional balance, exercise and demographic data. RESULTS:
      Significant effects for stage of change were found for self-efficacy, pros,
      exercise and nine of the 10 processes of change. In general, scores on these
      variables were found to increase across the stages although post hoc tests
      revealed slightly different patterns of significant differences. Cons were not
      found to differ significantly across stages of change. The relationship between
      self-efficacy and processes of change was dependent on stage of change.
      CONCLUSIONS: The results support some of the assumptions of the TTM but raise
      questions about the predicted relationships between stages of change and
      processes of change and between self-efficacy and processes of change at each
      stage of change. The practical implications of the findings for the development
      of interventions to improve young people's exercise levels are discussed.

PMID- 12614501
TI  - The influence of autonomous and controlling motives on physical activity
      intentions within the Theory of Planned Behaviour.
AB  - OBJECTIVES: This study aimed to examine how general motives from self
      determination theory (SDT; Deci & Ryan, 1985) influence intentions to engage in
      physical activity within the Theory of Planned Behaviour (TPB; Ajzen, 1985). It
      was hypothesized that the general motives will influence intentions only when
      mediated by the specific cognitions of attitude, subjective norms and perceived
      behavioural control (PBC) from the TPB. DESIGN: A cross-sectional study assessing
      psychological variables from two theoretical perspectives. METHOD: Self-report
      questionnaires were administered to 1088 children aged 12-14 years. The
      children's intentions, attitudes, subjective norms and PBC towards participating
      in physical activity were assessed using a TPB questionnaire. A modified verson
      of Ryan and Connell's (1989) perceived locus of causality (PLOC) inventory was
      used to measure controlling and autonomous motives for participating in physical
      activity. RESULTS: These data were analysed using structural equation modelling.
      The resulting well-fitting model demonstrated that attitude and PBC mediated the
      influence of autonomous motives to perform physical activity on physical activity
      intentions. The presence of autonomous motives resulted in the effects of the
      controlling motives being attenuated to zero. CONCLUSIONS: The present results
      indicate that general autonomous motives to participate in physical activity act
      as sources of information when childen make their judgments regarding their
      specific attitudes and PBC. Attitudes and PBC are necessary to translate these
      general motives from SDT into intentions in the TPB. In terms of targets for
      intervention, practitioners may positively influence intentions by providing a
      choice of physical activities to foster increased autonomy in children.

PMID- 12614502
TI  - Can the Theory of Planned Behaviour mediate the effects of age, gender and
      multidimensional health locus of control? 
AB  - OBJECTIVES: The present paper reports two studies designed to test the ability of
      the theory of planned behaviour (TPB) to mediate the effects of age, gender and
      multidimensional health locus of control (MHLC) on behavioural intentions and
      behaviour. DESIGN: Two studies are reported. Study 1 (N = 124) employed a cross
      sectional design and examined three self-reported health-related behaviours: safe
      sex (condom use), binge drinking and drink-driving. Study 2 (N = 201) employed a
      prospective design and examined actual attendance at health screening. METHODS:
      Respondents completed questionnaires containing measures of MHLC and TPB. The
      data were analysed using a combination of bivariate correlations and hierarchical
      multiple regression. RESULTS: Study 1 showed that the TPB was a superior
      predictor of health-related behavioural intentions than both demographic
      variables and MHLC. Study 2 corroborated the findings of Study 1, and showed that
      TPB variables were useful predictors of actual behaviour, although the TPB failed
      to fully mediate the effects of gender on screening attendance. CONCLUSIONS:
      Whilst the TPB accounted for significant proportions of the variance in health
      related behavioural intentions and behaviour, it failed to completely mediate the
      effects of demographic variables. Future work is required to identify social
      cognitive variables that will fully mediate the effects of demographics.

PMID- 12614503
TI  - Individually elicited versus modal normative beliefs in predicting attendance at
      breast screening: Examining the role of belief salience in the Theory of Planned
      Behaviour.
AB  - OBJECTIVE: To examine the influence of an individually derived versus modal
      subjective norm component of the Theory of Planned Behaviour (TPB) in predicting
      attendance at breast screening. DESIGN: A prospective, longitudinal design was
      employed using a postal questionnaire at Time 1 and objective attendance data
      from screening records at Time 2. METHOD: Questionnaires were sent to 1000 women
      from East Kent due to be invited for X-ray mammography under the UK's National
      Health Service Breast Screening Programme. The TPB constructs were used to
      predict attendance, with a focus on subjective norm. Two versions of the
      questionnaire were distributed: one assessed subjective norm using individually
      generated normative beliefs (individual condition) and the other provided a list
      of modal referents (modal condition). RESULTS: The mean number of normative
      referents in the individual condition was just two, almost all of whom were
      family members, in contrast to the modal condition where 'GP' led the rank table.
      The results suggest that a more senstive measure of subjective norm is attained
      using individually derived beliefs. Structural equation modelling revealed that,
      contrary to theoretical prediction, the effect on attendance of the individually
      derived subjective norm was not entirely mediated by intention: an independent
      contribution to attendance was shown. In the modal condition the construct was
      entirely mediated by intention. CONCLUSIONS: For health behaviours that have
      implications for others as well as self, measuring individually salient normative
      beliefs may both improve theoretical prediction and yield information of
      potential value for designing intervention programmes.

PMID- 12614504
TI  - Sickle cell disease: Pain, coping and quality of life in a study of adults in the
      UK.
AB  - OBJECTIVE: To examine the relationship between pain, coping, and quality of life
      in adult patients with sickle cell disease (SCD) in the UK, and to assess the
      influence of these factors on the utilization of health services. DESIGN: This
      cross-sectional study involved 96 adult patients with SCD attending hospitals in
      London. METHOD: Interview and questionnaire study involving standard measures of
      pain, health service utilization, coping responses (measured with the Coping
      Strategies Questionnaire - revised for SCD), and quality of life (measured by the
      SF36). Data concerning clinical history, complications and haemoglobin levels
      were also collected. RESULTS: The number and duration of painful sickle cell
      episodes in the past 12 months varied widely between patients. We found that
      49.5% of accident and emergency visits and 45% of hospitalizations were of 10.4%
      (10) patients. Pain experience accounted for 12.3% of hospital and general
      practice service use, independently of age, sex, number of SCD complications and
      haemoglobin levels. Three higher order factors emerged from analysis of the
      coping strategies questionnaire, reflecting active behavioural and cognitive
      coping, affecting coping, and passive adherence (e.g. resting, taking fluids).
      Active coping was positively associated with the number of pain episodes, while
      passive adherence coping was related to pain intensity. Psychological coping was
      unrelated to health service utilization. Marked impairment on many dimensions of
      quality of life was apparent in the analyses of the SF36. Affective coping was
      associated with impaired quality of life independently of demographic and
      clinical variables. CONCLUSIONS: It is evident that sickle cell disease involves
      not only severe recurrent pain, but also other impairments in health-related
      quality of life. Psychological coping patterns are relevant both to the
      experience of pain, and to broader adjustment. Patients may benefit from
      interventions that enhance the use of appropriate pain coping techniques and
      other strategies to improve quality of life.

PMID- 12614505
TI  - The psychosocial experience of people with sickle cell disease and its impact on
      quality of life: Qualitative findings from focus groups.
AB  - OBJECTIVES: In this exploratory study, an in-depth analysis of accounts of the
      experiences of people with sickle cell disease (SCD) was undertaken to gain an
      understanding of the psychosocial impact of the disease. An additional aim of the
      study was to determine whether these experiences could be conceptualized in terms
      of quality of life as defined by the World Health Organization (WHOQOL) with the
      intention of informing psychosocial research. DESIGN: This study utilized a
      series of non-directive, patient-led, focus groups that specifically addressed
      the ways in which sickle cell disease impacts on life. Participants were
      recruited from four centres in London and eight focus group discussions (each one
      hour in length) were held separately for each centre. METHOD: Altogether 32 hours
      of focus group materials were tape-recorded and transcribed verbatim. Data were
      analysed using a phenomenological approach to identify emerging themes. RESULTS:
      Six themes were identified: Growing up with SCD; Education; Impact of the
      unremitting nature of the disease; Employment; Effects on relationships; and
      Hospitalization. CONCLUSION: This research has clearly shown that SCD carries a
      huge psychosocial burden impacting on physical, psychological, social and
      occupational well-being as well as levels of independence and environment. These
      aspects of life are equivalent to the core domains of the multi-dimensional
      WHOQOL and consequently we have argued that SCD undermines quality of life in
      important ways. The paper provides a rich source of qualitative data to
      complement quantitative findings and provides detail of the complex human
      processes and experiences consequent on a life-long chronic illness such as SCD.

PMID- 12614506
TI  - Appraisal and psychological distress six months after diagnosis of breast cancer.
AB  - OBJECTIVES: Four in ten women with breast cancer experience high levels of
      anxiety or depression, despite advances in oncology treatments. The study
      investigates the role of psychosocial, disease and treatment characteristics, and
      appraisal processes to better understand factors contributing to this high
      psychological morbidity. DESIGN: A postal survey was employed to observe
      psychological morbidity in women 2 and 6 months after initial diagnosis and
      treatment of breast cancer. The study was conducted as an adjunct to an
      Australian multi-centre feasibility study of an evidence-based specialist breast
      nurse (SBN) model of care. METHODS: In total, 195 women with a new diagnosis of
      early or locally advanced breast cancer completed the data collection relating to
      this study. Psychosocial, disease and treatment information for each woman at
      diagnosis was recorded in research logs. Women completed the GHQ-12 questionnaire
      2 months after diagnosis, and at 6 months they completed the GHQ-12 and an
      appraisal process questionnaire designed by the National Breast Cancer Centre
      (NBCC). Bivariate and multiple regression analyses were undertaken to build a
      statistical model to account for GHQ-12 scores at 6 months. RESULTS: According to
      the GHQ-12, 43% of women had a likely affective disorder at either 2 or 6 months
      after diagnosis. Point prevalence decreased from 2 to 6 months yet remained
      substantial compared with general population statistics. Psychological
      functioning in women with breast cancer is related to a woman's psychiatric
      history, grade of tumour, and her appraisal processes. Most importantly, improved
      psychological functioning from 2 to 6 months after diagnosis is related to a
      woman having a lower primary appraisal of threat and a greater secondary
      appraisal of self-efficacy in terms of having confidence in her own ability to
      cope with concerns associated with the illness. CONCLUSION: Appraisal processes
      play a significant role in psychological adjustment to breast cancer. Adjustment
      may be facilitated by ensuring that the treatment team responds to shortfalls in
      a woman's appraisal of her illness and her perceived ability to cope, especially
      where a difficult prognosis is evident.

PMID- 12614507
TI  - Personality and coping traits: A joint factor analysis.
AB  - OBJECTIVES: The main objective of this paper is to explore the structural
      similarities between Eysenck's model of personality and the dimensions of the
      dispositional COPE. Costa et al. {Costa P., Somerfield, M., & McCrae, R. (1996).
      Personality and coping: A reconceptualisation. In (pp. 44-61) Handbook of coping:
      Theory, research and applications. New York: Wiley} suggest that personality and
      coping behaviour are part of a continuum based on adaptation. If this is the
      case, there should be structural similarities between measures of personality and
      coping behaviour. This is tested using a joint factor analysis of personality and
      coping measures. DESIGN: Cross-sectional survey. METHODS: The EPQ-R and the
      dispositional COPE were administered to 154 participants, and the data were
      analysed using joint factor analysis and bivariate associations. RESULTS: The
      joint factor analysis indicated that these data were best explained by a four
      factor model. One factor was primarily unrelated to personality. There was a COPE
      neurotic-introvert factor (NI-COPE) containing coping behaviours such as denial,
      a COPE-extroversion (E-COPE) factor containing behaviours such as seeking social
      support and a COPE-psychoticism factor (P-COPE) containing behaviours such as
      alcohol use. This factor pattern, especially for NI- and E-COPE, was interpreted
      in terms of Gray's model of personality {Gray, J. A. (1987) The psychology of
      fear and stress. Cambridge: Cambridge University Press}. NI-, E-, and P-COPE were
      shown to be related, in a theoretically consistent manner, to perceived coping
      success and perceived coping functions. CONCLUSIONS: The results indicate that
      there are indeed conceptual links between models of personality and coping. It is
      argued that future research should focus on identifying coping 'trait complexes'.
      Implications for practice are discussed.

PMID- 12614508
TI  - Persuading school-age cyclists to use safety helmets: Effectiveness of an
      intervention based on the Theory of Planned Behaviour.
AB  - OBJECTIVES: To design and evaluate a theory-based intervention to encourage the
      use of protective helmets in school-age cyclists. DESIGN: Two-by-three mixed
      design on 97 cyclists who did not initially use a helmet: Condition
      (intervention/control) x Time (pre-intervention/immediately post-intervention/5
      month follow-up). METHOD: The intervention builds on a previous study using the
      Theory of Planned Behaviour in which we identified a small number of salient
      beliefs that predict intention to use a safety helmet and helmet use (Quine et
      al., 1998). Participants were randomly assigned to intervention or control
      conditions. The intervention group was presented with a booklet containing a
      series of persuasive messages based on the identified salient beliefs, and the
      control group was presented with a different series of messages concerning a
      cycling proficiency and bicycle maintenance course. Initial beliefs were measured
      just before the intervention at Time 1, by questionnaire. The immediate effects
      of the intervention were evaluated by questionnaire at Time 2. Five months later,
      at Time 3, the long-term effects of the intervention on beliefs, intentions, and
      behaviour were assessed. RESULTS: The behavioural, normative and control beliefs
      and intentions of intervention participants became more positive than those of
      control participants, and the effect was maintained over time. There was also a
      significant effect on behaviour: at 5-month follow-up, none of the 49 control
      children had taken up helmet wearing, while 12 (25%) of the 48 intervention
      children had. CONCLUSIONS: The results suggest that in order to promote lasting
      helmet use in young cyclists, we need to change their beliefs. The intervention
      reported here may present an inexpensive solution to the problem of persuading
      adolescents to use safety helmets. The results point to the value of social
      cognition theories such as the Theory of Planned Behaviour in the design of
      effective interventions to change health behaviours.

PMID- 12614509
TI  - Salient beliefs and intentions to prescribe antibiotics for patients with a sore
      throat.
AB  - OBJECTIVES: General practitioners (GPs) in the UK continue to prescribe
      antibiotics for patients with sore throats despite evidence that they are
      ineffective and can contribute to the growth of antibiotic resistance in the
      population. This study uses the theory of planned behaviour (TPB) to investigate
      the strength of intention to prescribe antibiotics, and to identify the salient
      beliefs associated with this intention. DESIGN: Cross-sectional study testing
      hypotheses derived from the TPB. METHOD: A 66-item postal questionnaire was
      distributed to a random sample of GPs in one NHS region (N = 185). The
      questionnaire included measures of intention to prescribe antibiotics, attitude,
      behavioural beliefs and evaluations, normative beliefs and evaluations, perceived
      behavioural control, control beliefs, and past prescribing. RESULTS: Two-thirds
      of the GPs returned complete questionnaires (N = 126, 68%). The majority intended
      to prescribe antibiotics for less than half of their patients with sore throats
      (N = 69, 55%). The variables specified in TPB predicted 48% of the variance in
      intention, with past behaviour adding a further 15%. Seven salient beliefs
      distinguished between doctors who intend to prescribe antibiotics and those who
      do not. CONCLUSIONS: Attitudes towards antibiotics and control beliefs are
      important predictors of intention to prescribe, as predicted by TPB.
      Interventions could target salient beliefs associated with motivation to
      prescribe.

PMID- 12614510
TI  - Perceptions of threat, benefits, and barriers in breast self-examination amongst
      young asymptomatic women.
AB  - AIM: Young age at diagnosis of breast cancer is a negative prognostic factor, but
      early detection of breast pathology may improve prognosis. The present study
      examined the role of health perceptions (Health Belief Model; HBM) in young
      women's breast self-examination (BSE). It was hypothesized that cues to action,
      health motivation, and perceptions of threat (vulnerability, severity), benefits,
      and barriers, will predict BSE, but that threat perceptions will be more powerful
      predictors than benefits and barriers. METHOD: Questionnaire data from 178
      asymptomatic women (aged 18-35 years) living in the northwestern region of
      England were analysed. RESULTS: Using hierarchical logistic regression
      controlling for demographic factors, only severity and barriers emerged as
      important predictors; lower perceived seriousness of breast cancer and fewer
      perceived obstacles to practising BSE predicted performance of BSE. For every
      unit increment on the severity and barrier scales, the odds of a respondent
      performing BSE decreased by approximately 8 and 20%, respectively. CONCLUSIONS:
      The results provide qualified support for the HBM. Perceived barriers was the
      most powerful predictor, although respondents assessed breast-cancer severity
      based on early detection through BSE. Implications for clinical interventions are
      considered.

PMID- 12614511
TI  - Psychometric evaluation of the Hospital Anxiety and Depression Scale (HADS) among
      female cardiac patients.
AB  - OBJECTIVES: To examine the dimensionality, structure, and reliability of the HADS
      among female cardiac patients. DESIGN: Data were collected by self-administered
      questionnaires at two times - admission to hospital and at 2-month follow-up.
      METHOD: Confirmatory factor analysis was used to examine the dimensionality and
      structure of the HADS. Internal consistency was assessed by computing Cronbach
      alpha. Pearson product-moment correlation coefficients were calculated to assess
      test-retest reliability. RESULTS: A two-factor model, in which the subscales were
      permitted to correlate, was found to provide a good fit to the scale's 14 items
      compared to single factor and orthogonal two-factor models. These two factors
      explained 41.4% of the total variance. The anxiety and depression subscales were
      moderately correlated (r =.60), with good internal consistency and test-retest
      reliability found for the subscales and total HADS scores. CONCLUSIONS: These
      results provide support for the HADS as a reliable measure for the assessment of
      anxiety and depression symptomatology among female cardiac patients.

PMID- 12614512
TI  - Physical contact experience and coping ability: A study of survivors of
      myocardial infarction.
AB  - OBJECTIVE: This study investigates the hypothesis that interpersonal physical
      contact experience contributes importantly to the capacity to cope with stress.
      DESIGN: Participants with differing physical contact experience were compared in
      respect of their coping with a standard adverse life event. METHOD: A total of
      137 survivors of a first myocardial infarction was assessed for their physical
      contact experience and/or their coping when admitted to hospital, at discharge
      and then 3 months later. Also, at 6 months post-infarct and 6 months post
      discharge respectively, data relevant to their coping were collected from
      hospitals and general practitioners. RESULTS: The participants with satisfactory
      and unsatisfactory physical contact experience did not differ on measures of
      stress and general coping. However, those with satisfactory experience emerged as
      having adjusted significantly better psychologically than those with negative
      experience in childhood and the present combined. Yet, the 'satisfactory'
      participants also spent a significant 5 days longer in hospital and increased
      their GP usage more than twice as much as their 'unsatisfactory' counterparts.
      CONCLUSIONS: Each kind of physical contact experience may be linked with a
      different aspect of coping ability, satisfactory experience with psychological
      adjustment, and unsatisfactory experience with physical resilience.

PMID- 12614513
TI  - The influence of poster prompts on stair use: The effects of setting, poster size
      and content.
AB  - OBJECTIVES: There is evidence that poster prompts increase stair use. The present
      study was concerned with the effects of poster size, poster message, and setting
      on stair use. DESIGN: Using a quasi-experimental design, four observational
      studies were undertaken in which stair and escalator use were logged during 2
      week baseline periods and 2-week intervention periods. METHODS: In the first two
      studies, observations were undertaken in two shopping centres (total N = 30,018)
      with the size of poster varying. In the other two studies (total N = 37,907), one
      in a shopping centre and one in a train station, two poster messages were tested
      in both sites. RESULTS: Pedestrian traffic volume was controlled for
      statistically. There were significant increases in stair use with A1- and A2-,
      but not A3-size posters. Overall, the two different poster messages were both
      effective in encouraging stair use. Interactions between gender and message
      setting, however, reflected the fact that the 'stay healthy, save time' poster
      had little impact on female shoppers but was highly effective for female
      commuters. CONCLUSION: These results suggest that developers of health-promotion
      posters pay attention to poster size. They also indicate that it is insufficient
      to segment audiences by gender without considering the setting and motivational
      context.

PMID- 12614514
TI  - Hypersensitivity to efavirenz treated with corticosteroids in a 6-year-old child.
AB  - We report a case of the successful use of corticosteroids to treat
      hypersensitivity caused by efavirenz in a pediatric patient. A 6-year-old HIV
      infected patient developed a diffuse erythematous rash and fever after being
      switched to a regimen containing efavirenz. Use of prednisone at a dose of 1
      mg/kg every other day for 2 weeks on rechallenge resulted in successful
      reinstitution of the regimen.

PMID- 12614515
TI  - Prevalence of oral lesions and percent CD4+ T-lymphocytes in HIV-infected
      children on antiretroviral therapy.
AB  - This study examined prevalence of oral lesions and how it relates to CD4
      percentages in vertically infected children with HIV undergoing combination
      antiretroviral therapy. One hundred two HIV-infected children between the ages of
      3 and 15 years attending a specialized pediatric outpatient clinic were examined
      for oral lesions, and their CD4 percent and viral load extracted from their
      medical records. Of the 102 HIV-infected children, 69% had evidence of oral
      pathology and 31% were disease free. The proportion with disease was: 20.6% had
      conventional gingivitis, 19.6% had dental caries in their primary and permanent
      teeth combined, 13.7% had depapillated tongue, 3.9% had early childhood caries,
      2.9% had oral candidiasis, 2% had bilateral enlarged parotid gland, 1% had median
      rhomboid glossitis, 1% had enlarged cervical lymph nodes and 2% had other
      developmental abnormalities. In the group with no evidence of suppression 15% had
      gingival lesion, 14% tongue lesion, and 1% parotid enlargement, and in the severe
      suppression group 55% had gingival lesion, 45% had tongue lesion, 9% had enlarged
      cervical lymph nodes, and another 9% had parotid gland enlargement. The
      association between conventional gingivitis and low CD4 percent was statistically
      significant (p = 0.001). Compared to previous studies, overall prevalence
      estimates of oral lesions in this study was low. Children with low CD4 percent
      had more oral lesions, consistent with results from other HIV studies.

PMID- 12614516
TI  - HIV-infected inpatients in the HAART era: how do hepatitis C virus coinfected
      patients differ?
AB  - We compared the demographics and clinical characteristics of HIV-infected
      patients with and without hepatitis C virus (HCV) coinfection hospitalized at
      Cook County Hospital, Chicago, Illinois, from October 1999 through September
      2000. Two hundred three (40%) of the 510 patients were coinfected with HCV. HCV
      coinfected patients were less likely to be on highly active antiretroviral
      therapy (HAART) and were frequently hospitalized with higher CD4 counts for non
      HIV-related medical problems including complications of liver disease.

PMID- 12614517
TI  - Development pharmaceutics of microbicide formulations. Part I: preformulation
      considerations and challenges.
AB  - Microbicides, the compounds and formulations that can prevent transmission of
      sexually transmitted diseases (STDs)/HIV are being pursued actively as a
      promising AIDS intervention. The drug development chain for a topical microbicide
      differs significantly from that of any systemic or topical compound/formulation
      regarding to time line, cost, activities, and milestones. This is in part because
      of the lack of standard in vitro models to assess efficacy, and complex ethical
      issues in clinical trials of microbicides. Several factors, including changes in
      the physiology of the cervix and vagina with age and menstrual cycle,
      intercourse, as well as leakage of the formulation from the vagina may affect
      their design, development, and performance. Selection and development of optimal
      microbicide delivery systems (gel/cream, pessary, film, tablet, foam, etc.),
      their inactive ingredients, manufacturing details, and packaging system are
      dependent on the properties of active drug, or their preformulation parameters
      (PP). The PP of the active drug substance needs to be evaluated in initial stages
      of drug discovery and development so that the most suitable delivery system can
      be selected. Some PP of microbicide agents include physical state, organoleptic
      properties (color, odor, appearance, taste, etc.), molecular weight, aqueous
      solubility, hygroscopicity, acidity/alkalinity, permeability and absorption
      characteristics, stability in solid/solution state, and inherent bioadhesiveness.
      Thus, a well-coordinated, planned, and implemented preformulation program can
      help in not only accelerating microbicide formulation development, but also to
      minimize unforeseen failures in subsequent stages of the development. The
      objective of this review is to highlight the significance of PP, suggesting a
      systematic preformulation program.

PMID- 12614518
TI  - Evaluation of adherence to antiretroviral therapy in Italian HIV patients.
AB  - We studied factors associated with treatment adherence in 88 male and 21 female
      adults (age range, 24-65 years) with HIV infection undergoing therapy with HIV-1
      protease inhibitors (PIs) in Italy. Data on sociodemographic variables, clinical
      and psychological symptoms, treatment compliance, physician/patient relationship,
      and psychosocial characteristics were obtained by means of semistructured
      interviews. Every subject also compiled two self-report questionnaires: Coping
      Orientations to Problem Experiences (COPE) and Medical Outcomes Study-HIV (MOS
      HIV) in order to evaluate the use of coping strategies and quality of life. We
      found a high rate of adherence to HIV therapies (almost 90% of patients had taken
      at least 80% of medication in the previous 7 days). No significant differences
      were found between adherence and nonadherence groups as measured by self-report.
      Few significant differences were found when data laboratory were used. When a
      Bonferroni corrected p level of <0.001 was used, only a comparison on Mental
      Disengagement subscale of COPE was statistically significant.

PMID- 12614519
TI  - New guidance for clinical trials.

PMID- 12614520
TI  - Research in stroke rehabilitation: confounding effects of the heterogeneity of
      stroke, experimental bias and inappropriate outcomes measures.

PMID- 12614521
TI  - Response to Worthington on nutritional quality of organic versus conventional
      fruits, vegetables, and grains.

PMID- 12614523
TI  - Great revolutionary leaders of alternative medicine: a fascinating journey back
      in time.

PMID- 12614522
TI  - Initial cost of care results in medically supervised water-only fasting for
      treating high blood pressure and diabetes.

PMID- 12614524
TI  - The biofield hypothesis: its biophysical basis and role in medicine.
AB  - This paper provides a scientific foundation for the biofield: the complex,
      extremely weak electromagnetic field of the organism hypothesized to involve
      electromagnetic bioinformation for regulating homeodynamics. The biofield is a
      useful construct consistent with bioelectromagnetics and the physics of
      nonlinear, dynamical, nonequilibrium living systems. It offers a unifying
      hypothesis to explain the interaction of objects or fields with the organism, and
      is especially useful toward understanding the scientific basis of energy
      medicine, including acupuncture, biofield therapies, bioelectromagnetic
      therapies, and homeopathy. The rapid signal propagation of electromagnetic fields
      comprising the biofield as well as its holistic properties may account for the
      rapid, holistic effects of certain alternative and complementary medical
      interventions.

PMID- 12614525
TI  - Does mindfulness meditation contribute to health? Outcome evaluation of a German
      sample.
AB  - OBJECTIVES: This exploratory study is the first systematic outcome evaluation to
      examine the effects of an 8-week meditation-based program in mindfulness in a
      German sample. DESIGN: Twenty-one (21) participants with chronic physical,
      psychologic, or psychosomatic illnesses were examined in a longitudinal pretest
      and post-treatment design with a 3-month follow-up. OUTCOME MEASURES: Both
      quantitative and qualitative data were gathered. Emotional and general physical
      well-being, sense of coherence, overall psychologic distress, and satisfaction
      with life were measured with standardized instruments. RESULTS: Overall, the
      interventions led to high levels of adherence to the meditation practice and
      satisfaction with the benefits of the course, as well as effective and lasting
      reductions of symptoms (especially in psychologic distress, well-being, and
      quality of life). Changes were of moderate-to-large effect sizes. Positive
      complementary effects with psychotherapy were also found. CONCLUSIONS: These
      findings warrant controlled studies to evaluate the efficacy and cost
      effectiveness of mindfulness-based stress reduction as an intervention for
      chronic physical and psychosomatic disorders in Germany.

PMID- 12614526
TI  - Acupuncture and bronchial asthma: a long-term randomized study of the effects of
      real versus sham acupuncture compared to controls in patients with bronchial
      asthma.
AB  - BACKGROUND: Acupuncture has traditionally been used in China in the treatment of
      bronchial asthma and is being increasingly applied in Western countries. Although
      there are many published studies on acupuncture and asthma, few meet the
      scientific criteria necessary to prove the effectiveness of acupuncture.
      OBJECTIVE: To examine the short- and long-term effects of real versus sham or no
      acupuncture in patients with bronchial asthma. DESIGN: Randomized partially
      blinded study with three parallel groups. SUBJECTS: Sixty-six (66) patients of
      both genders (mean age, 39 years) with mild-to-moderate persistent bronchial
      asthma. INTERVENTIONS: After 2 weeks of run-in, the patients with asthma were
      randomized to receive either real (23 patients) or sham acupuncture (23 patients)
      or no acupuncture (20 patients). Two acupuncture periods (each 4 weeks) within
      the first 4 months were followed by a 6-month observation. MEASUREMENTS: Primary
      outcome was the change of peak expiratory flow (PEF) variability at the end of
      the two treatment periods. Secondary outcomes were changes in forced expiratory
      volume in 1 second (FEV1), airway responsiveness, symptoms of asthma, the use of
      asthma drugs, and patients' well-being. Moreover, the effect of the intervention
      on eosinophils and eosinophil cationic protein (ECP) in blood and sputum was
      assessed. RESULTS: PEF variability decreased in all groups. In a subgroup of
      patients whose asthma medication remained fairly unchanged, PEF variability
      decreased significantly after needling of real as well as sham points at month 4
      and 5 compared to controls (p < or = 0.005). However, there was no difference in
      the decrease of PEF variability between patients who had the blinded treatment
      with real or sham acupuncture. Most of the other functional and clinical
      variables did not differ from those obtained in controls. Eosinophils and ECP in
      blood and sputum decreased in all groups, but the only significant differences
      were found in blood eosinophil count at 4 months between sham acupuncture and the
      control group (p < 0.05) and at 10 months between real and sham acupuncture (p <
      0.05) suggesting a possible effect on eosinophilic inflammation. CONCLUSIONS: In
      view of the fact that the effects after real and sham acupuncture compared to
      controls who had no needling at all were small, in all likelihood clinically
      irrelevant, our data do not seem to support the use of acupuncture in the
      management of pharmacologically well-treated patients with mild-to-moderate
      persistent asthma.

PMID- 12614528
TI  - Effect of Reiki treatments on functional recovery in patients in poststroke
      rehabilitation: a pilot study.
AB  - OBJECTIVES: The three objectives of this study were: (1) to evaluate the
      effectiveness of Reiki as an adjunctive treatment for patients with subacute
      stroke who were receiving standard rehabilitation as inpatients, (2) to evaluate
      a double-blinded procedure for training Reiki practitioners, and (3) to determine
      whether or not double-blinded Reiki and sham practitioners could determine which
      category they were in. DESIGN: A modified double-blinded, placebo-controlled
      clinical trial with an additional historic control condition. SETTING: The stroke
      unit of a major rehabilitation hospital. SUBJECTS: Fifty (50) inpatients with
      subacute ischemic stroke, 31 male and 19 female. INTERVENTIONS: There were four
      conditions: Reiki master, Reiki practitioner, sham Reiki, and no treatment
      (historic control). Subjects received up to 10 treatments over a 2(1/2)-week
      period in addition to standard rehabilitation. OUTCOME MEASURES: Functional
      independence measure (FIM), and Center for Epidemiologic Studies--Depression (CES
      D) measure. RESULTS: No effects of Reiki were found on the FIM or CES-D, although
      typical effects as a result of age, gender, and time in rehabilitation were
      detected. Blinded practitioners (sham or reiki) were unable to determine which
      category they were in. Sham Reiki practitioners reported greater frequency of
      feeling heat in the hands compared to Reiki practitioners. There was no reported
      difference between the sham and the real Reiki practitioners in their ability to
      feel energy flowing through their hands. Post hoc analyses suggested that Reiki
      may have had limited effects on mood and energy levels. CONCLUSION: Reiki did not
      have any clinically useful effect on stroke recovery in subacute hospitalized
      patients receiving standard-of-care rehabilitation therapy. Selective positive
      effects on mood and energy were not the result of attentional or placebo effects.

PMID- 12614529
TI  - Beyond randomization.
AB  - Conventional opinion states that randomization is the appropriate way to allocate
      participants to treatments in biomedical studies. The most frequently cited
      justification is that it is the only method that guarantees balance between
      treatment groups with respect to all prognostic factors, whether measured or not.
      Here it is shown by simple arguments that this justification is false and
      misleading. Design-adaptive allocations are an alternative to randomization that
      are easy to implement, and virtually guarantee better balance than randomization,
      for both measured and unmeasured factors. The fraction of studies that will
      exhibit severe imbalance under randomization is not always trivial. For this
      reason, in small studies or studies with subgroup analyses or many prognostic
      factors, design-adaptive allocation is an attractive alternative to
      randomization. These considerations are particularly relevant to complementary
      and alternative medicine studies, where resources are relatively scarce, and
      otherwise underpowered studies might lead to premature termination of promising
      research paths.

PMID- 12614530
TI  - Critical factors for credibility in clinical trials: Comments on Aickin's "Beyond
      randomization".

PMID- 12614531
TI  - Outcome measurement in complementary and alternative medicine: unpicking the
      effects.
AB  - The issues of what outcomes to measure and how this is central to the development
      of a sound knowledge base for evidence-based practice are examined. Within
      complementary and alternative medicine (CAM) there is a crucial debate over what
      is meant by an "effect" of a set of CAM treatment sessions. The goal of this
      paper is promote debate and reflection on why outcome measurement is important,
      the range of specific effects that need to be measured, and ways to take forward
      their measurement. It is argued that monitoring the achievement of desired
      outcomes needs to be recognized as an essential step in evidence-based practice,
      with effectiveness, achieved effects/outcomes--both positive and negative--and
      quality assurance inextricably linked together in an evidence spiral. The choice
      of outcome measures must also match the desired outcomes of the key participants,
      specifically those of the user. Three types of effects of a CAM intervention are
      conceptualized: (1) those arising from the philosophy and practice of health and
      healing; (2) factors arising from the relationship between user and practitioner:
      and (3) those factors brought about by the set of techniques used to enhance the
      healing process. Their conceptual separation clarifies what should be measured
      and raises questions about the adequacy of available measuring instruments. This
      delineation of effects has relevance beyond CAM to conventional medicine and
      discussions over the nature of the placebo effect. Measurement of all three types
      of effect is essential, in research and in practice, if the full effect of a CAM
      discipline is to be recognized. Further work is needed to develop and validate
      measures that address the multiple effects of CAM and to explore the nature and
      form of the three types of effect within different CAM disciplines.

PMID- 12614532
TI  - Protective effects of Rasayanas on cyclophosphamide- and radiation-induced
      damage.
AB  - Rasayanas are a group of herbal drug preparations widely used in Ayurveda to
      improve the general health of the body. In mice, Rasayanas are potent
      myeloprotective agents against chemotherapeutic agents and radiation. Rasayanas
      are also effective myeloprotectors in patients with cancer undergoing
      chemotherapy and/or radiotherapy. In this study, we provide further evidence to
      support the chemoprotective and radioprotective efficacy of four Rasayanas in
      mice. Rasayanas were found to reduce the loss of body weight and organ weight
      induced by cyclophosphamide and radiation significantly. Rasayanas were also
      found to protect tissue from cytotoxic injury associated with reduced serum and
      liver lipid peroxides, alkaline phosphatase, and glutamate pyruvate transaminase
      in cyclophosphamide- and radiation-treated animals. These results suggest the
      potential chemoprotective and radioprotective effects of Rasayanas, which require
      further study to explore their complete usefulness in cancer therapy.

PMID- 12614533
TI  - Psychophysiologic effects of Hatha Yoga on musculoskeletal and cardiopulmonary
      function: a literature review.
AB  - Yoga has become increasingly popular in Western cultures as a means of exercise
      and fitness training; however, it is still depicted as trendy as evidenced by an
      April 2001 Time magazine cover story on "The Power of Yoga." There is a need to
      have yoga better recognized by the health care community as a complement to
      conventional medical care. Over the last 10 years, a growing number of research
      studies have shown that the practice of Hatha Yoga can improve strength and
      flexibility, and may help control such physiological variables as blood pressure,
      respiration and heart rate, and metabolic rate to improve overall exercise
      capacity. This review presents a summary of medically substantiated information
      about the health benefits of yoga for healthy people and for people compromised
      by musculoskeletal and cardiopulmonary disease.

PMID- 12614534
TI  - Flavonoid and botanical approaches to prostate health.
AB  - Benign prostatic hyperplasia (BPH) is a common problem among aging men that
      produces significant morbidity and health care costs. Contention exists as to
      whether currently available surgical and pharmacologic options for BPH are
      appropriate for men in the watchful-waiting stage. Recently, the possible
      benefits of phytotherapies (plant-derived preparations) in treating BPH and
      prostate cancer are being considered. Several phytotherapies, including saw
      palmetto, Pygeum africanum, curbicin, and isoflavone-containing supplements (red
      clover [Trifoleum pratense] and soy), are widely used in patients with BPH.
      Evidence suggests that the consumption of isoflavones found in legumes is related
      to lower rates of BPH and prostate cancer among Asian men. When evaluating
      natural therapies, the physician should look for a product that relieves symptoms
      and is safe, contains a health-conferring ingredient with a defined mechanism of
      action, and is standardized for that ingredient. Phytotherapies, particularly
      isoflavone-containing supplements, are likely to have an important role in the
      management of patients in the watchful-waiting stage of BPH.

PMID- 12614535
TI  - Sympathetic Resonance Technology: scientific foundation and summary of biologic
      and clinical studies.
AB  - Sympathetic Resonance Technology (SRT; Clarus Products, International, L.L.C.,
      San Rafael, CA) is a novel technology used in consumer health care products to
      protect humans from the potentially harmful effects of stress. A summary of the
      previously unpublished studies on SRT, both basic and clinical, is presented.
      These studies collectively show that SRT mitigates the stress response for a
      variety of stressors such as chemical and electromagnetic stress in various
      biologic systems and multiple levels of organization, ranging from the molecular
      to the behavioral. A rudimentary model of how SRT may work at the level of the
      biofield, the endogenous electromagnetic field of the organism, is proposed. By
      interacting with key component frequencies in the biofield, SRT may stabilize the
      organism homeodynamically, thereby protecting it from the effects of stressful
      stimuli.

PMID- 12614536
TI  - Effects of a lectin- and a viscotoxin-rich mistletoe preparation on clinical and
      hematologic parameters: a placebo-controlled evaluation in healthy subjects.
AB  - BACKGROUND AND OBJECTIVES: Mistletoe preparations, which are widely used among
      patients with cancer in Germany, have immunomodulating properties in vitro and in
      vivo. The aim of this evaluation was to determine and compare the effects of a
      lectin-rich (Iscador Qu [IQ] special, Weleda Company, Schwabisch, Gmund,
      Germany.) and a lectin-poor but viscotoxin-rich (Iscador Pini [IP] Weleda
      Company) mistletoe preparation on clinical and hematologic parameters in healthy
      subjects. DESIGN: In a double-blinded study, 48 volunteers were randomized to one
      of three groups: 16 received IQ or IP in increasing doses or placebo twice per
      week subcutaneously for 12 weeks. The differential blood count and the acute
      phase markers haptoglobin and C-reactive protein were examined weekly and the
      symptoms were scored using standardized questionnaires. RESULTS: IQ resulted in
      significant eosinophilia (315 +/- 109) beginning at week 5 (until week 12)
      compared to IP (183 +/- 120) or placebo (200 +/- 179). Furthermore, the acute
      phase marker haptoglobin was significantly increased in the IQ group during week
      4. Dose-dependent local reactions (LRs) at the injection site occurred in all
      subjects who received mistletoe preparations but were stronger in the IQ-treated
      subjects than in the IP-treated group. The LRs observed in the IQ-treated group
      were characterized by stronger itching and longer latency than LRs in the IP
      treated group (p < 0.05). Severe side-effects did not occur in any of the
      probands. CONCLUSIONS: IQ but not IP can induce eosinophilia in healthy
      individuals, and this may be related to its content of mistletoe lectins. In
      contrast, exposure to the viscotoxin-enriched extract IP did not result in
      specific changes of hematologic parameters. Furthermore, intensity and time
      course of local reactions seemed to depend on the concentration of mistletoe
      lectins in those extracts.

PMID- 12614537
TI  - Teaching evidence-based complementary and alternative medicine: 5. Interpreting
      the results of a study on therapy and applying them to a patient.
AB  - Practicing evidence-based complementary and alternative medicine (CAM) requires
      that practitioners develop an ability to understand and appropriately apply the
      results of published studies addressing questions related to their clinical
      practice. This paper describes a process by which CAM practitioners can interpret
      the results of studies evaluating therapeutic interventions and then determine if
      they can apply these results to their patients. We describe a process for
      interpreting the results of a study on therapy that involves determining the
      estimate of the magnitude of the therapy's effect and determining the precision
      of this estimate. We then describe a process for determining whether the results
      of a study on therapy can be applied to a given patient that involves determining
      the extent to which patients in the study differ from the patient being treated
      and determining if the study addressed all outcomes of interest.

PMID- 12614538
TI  - Closing comment: Evidence-based complementary and alternative medicine: is it a
      viable concept?

PMID- 12614539
TI  - Paradigms of health and disease: a framework for classifying and understanding
      complementary and alternative medicine.
AB  - The number of complementary and alternative medicines (CAMs) being utilized by
      North America health care consumers is growing at an astounding rate. There is a
      need by both health care providers and consumers to categorize CAM in order to
      make meaningful comparisons and informed decisions on their use. Four paradigms
      of health and illness are proposed that classify medicines according to the basic
      assumptions of health and disease associated with each medicine. CAMs classified
      in the body paradigm are those that work through biologic mechanisms, or in other
      words, target biologic factors as the primary determinants of health. The mind
      body paradigm extends the body paradigm to include factors such as stress,
      psychologic coping styles, and social supports as primary determinants of health
      and disease. The body-energy paradigm assumes health and disease are functions of
      the flow and balances of life energies. The body-spirit paradigm assumes that one
      or more transcendental aspects or personalities existing outside the limitations
      of the material universe can influence health and disease. It is postulated that
      there is a hierarchical relation among the four paradigms, such that each
      paradigm essentially subsumes the assumptions of the previous ones, but adds
      additional assumptions that qualify the previous ones. Implications of this
      framework for clarifying many contemporary issues in health care are discussed.

PMID- 12614540
TI  - Blending the boundaries: steps toward an integration of complementary and
      alternative medicine into mainstream practice.
AB  - Complementary and alternative medicine (CAM) is growing in popularity among
      patients traditionally seen in an allopathic setting. A literature review and
      information search was conducted to determine the trend in demand for and the
      availability of CAM in the United States. The results of major surveys show that
      there is an increase in the use of CAM in the United States. The best predictor
      of CAM use is higher level of education. In addition, findings reveal that the
      field of CAM is poorly researched. Many studies in CAM therapies have flaws, such
      as insufficient statistical power, poor controls, inconsistent treatment, and
      lack of comparisons. The National Center for Complementary and Alternative
      Medicine of the National Institutes of Health, has declared their top strategic
      priority to be investing in research. Currently, more than 70 medical schools
      offer some type of training in alternative medicine, although there are few
      guidelines for curriculum and there is considerable heterogeneity in content,
      format, and requirements among CAM courses. As patients have greater access to
      information, their needs and values change. They become more involved in their
      overall health care and are taking a more natural and holistic approach to
      achieving well-being. Health care practitioners, both allopathic and alternative,
      must be well informed. There is an imperative to make CAM research a high
      priority. Valid and reliable empirical data must document the clinical efficacy
      and safety of CAM practices. In order to integrate CAM into the mainstream, there
      must be a coordinated effort among all the entities involved. Physicians need to
      be familiar with proven CAM therapies in order to advise patients about these
      modalities and the potential benefits and limitations. CAM practitioners should
      be licensed and regulated in scope of practice to provide a high standard of
      care, and be sufficiently educated in conventional medical science(s) in order to
      recognize how, where, and why their respective complementary practice is most
      effective for integration.

PMID- 12614541
TI  - Ethical dimensions in the borderland between conventional and
      complementary/alternative medicine.
AB  - Consumer enthusiasm for complementary and alternative medicine presents complex
      challenges for conventional Western biomedically dominated health care systems
      and for those who practice within them. In particular, this trend forces new
      ethical dilemmas related to how we create consensus about the nature of ethical
      clinical practice and what constitutes evidence sufficient for public health
      policy. In this paper, we examine the historical context into which complementary
      and alternative medicine has been introduced, and consider the ethical and
      scientific challenges with which it confronts mainstream health systems.

PMID- 12614542
TI  - Healing the caregiver.
AB  - When treating seriously ill patients, those working in the healing professions
      may be particularly vulnerable to their own stress symptoms. Left unattended,
      these professionals may go down the dark road leading to burnout, with impaired
      effectiveness as caregivers, diseases rooted in stress, as well as increased
      suicides, drug and alcohol addiction, and exacerbation of personality disorders.
      Early intervention may help reduce the associated problems. In this paper, we
      present an elementary debriefing system, a psychotherapeutic approach, to be used
      by the affected individual. While this methodology may be far more simplistic
      than those utilized in different schools of healing or caregiving, its appeal is
      its simplicity and practicality. We are proposing that the individual caregiver
      systematically consider the following: the Background of the situation; how it
      Affects thinking and feeling; the Troublesome element(s); how one is Handling
      element(s); and an Empathetic/empowering conclusion (BATHE). Ideally, these
      considerations may help alleviate caregivers' anguish in troublesome situations
      and may complement their awareness of their patients' suffering as well.

PMID- 12614545
TI  - Occurrence probability of structured motifs in random sequences.
AB  - The problem of extracting from a set of nucleic acid sequences motifs which may
      have biological function is more and more important. In this paper, we are
      interested in particular motifs that may be implicated in the transcription
      process. These motifs, called structured motifs, are composed of two ordered
      parts separated by a variable distance and allowing for substitutions. In order
      to assess their statistical significance, we propose approximations of the
      probability of occurrences of such a structured motif in a given sequence. An
      application of our method to evaluate candidate promoters in E. coli and B.
      subtilis is presented. Simulations show the goodness of the approximations.

PMID- 12614546
TI  - Using substitution matrices to estimate probability distributions for biological
      sequences.
AB  - Accurately estimating probabilities from observations is important for
      probabilistic-based approaches to problems in computational biology. In this
      paper we present a biologically-motivated method for estimating probability
      distributions over discrete alphabets from observations using a mixture model of
      common ancestors. The method is an extension of substitution matrix-based
      probability estimation methods. In contrast to previous such methods, our method
      has a simple Bayesian interpretation and has the advantage over Dirichlet
      mixtures that it is both effective and simple to compute for large alphabets. The
      method is applied to estimate amino acid probabilities based on observed counts
      in an alignment and is shown to perform comparably to previous methods. The
      method is also applied to estimate probability distributions over protein
      families and improves protein classification accuracy.

PMID- 12614547
TI  - Efficient algorithms for quantitative trait loci mapping problems.
AB  - Rapid advances in molecular genetics push the need for efficient data analysis.
      Advanced algorithms are necessary for extracting all possible information from
      large experimental data sets. We present a general linear algebra framework for
      quantitative trait loci (QTL) mapping, using both linear regression and maximum
      likelihood estimation. The formulation simplifies future comparisons between and
      theoretical analyses of the methods. We show how the common structure of QTL
      analysis models can be used to improve the kernel algorithms, drastically
      reducing the computational effort while retaining the original analysis results.
      We have evaluated our new algorithms on data sets originating from two large F(2)
      populations of domestic animals. Using an updating approach, we show that 1-3
      orders of magnitude reduction in computational demand can be achieved for matrix
      factorizations. For interval-mapping/composite-interval-mapping settings using a
      maximum likelihood model, we also show how to use the original EM algorithm
      instead of the ECM approximation, significantly improving the convergence and
      further reducing the computational time. The algorithmic improvements makes it
      feasible to perform analyses which have previously been deemed impractical or
      even impossible. For example, using the new algorithms, it is reasonable to
      perform permutation testing using exhaustive search on populations of 200
      individuals using an epistatic two-QTL model.

PMID- 12614548
TI  - Bayesian estimation of the number of inversions in the history of two
      chromosomes.
AB  - We present a Bayesian approach to the problem of inferring the history of
      inversions separating homologous chromosomes from two different species. The
      method is based on Markov Chain Monte Carlo (MCMC) and takes full advantage of
      all the information from marker order. We apply the method both to simulated data
      and to two real data sets. For the simulated data, we show that the MCMC method
      provides accurate estimates of the true posterior distributions and in the
      analysis of the real data we show that the most likely number of inversions in
      some cases is considerably larger than estimates obtained based on the parsimony
      inferred number of inversions. Indeed, in the case of the Drosophila repleta-D.
      melanogaster comparison, the lower boundary of a 95% highest posterior density
      credible interval for the number of inversions is considerably larger than the
      most parsimonious number of inversions.

PMID- 12614550
TI  - Mutation-replication statistics of polymerase chain reactions.
AB  - The variability of the products of polymerase chain reactions, due to mutations
      and to incomplete replications, can have important clinical consequences. Sun
      (1995) and Weiss and von Haeseler (1995) modeled these errors by a branching
      process and introduced estimators of the mutation rate and of the efficiency of
      the reaction based, for example, on the empirical distribution of the mutations
      of a random sequence. This distribution involves a noncanonical branching Markov
      chain which, although easy to describe, is not analytically tractable except in
      the infinite-population limit. These authors for the infinite-target limit, and
      Wang et al. (2000) for finite targets, solved the infinite-population limit. In
      this paper, we provide bounds of the difference between the finite-target finite
      population case and its finite-target infinite-population approximation. The
      bounds are explicit functions of the efficiency of the reaction, the mutation
      rate per site and per cycle, the size of the target, the number of cycles, and
      the size of the initial population. They concern every moment and, what might be
      more surprising, the histogram itself of the distributions. The bounds for the
      moments exhibit a phase transition at the value 1 - 1/N = 3/4 of the mutation
      rate per site and per cycle, where N = 4 is the number of letters in the encoding
      alphabet of DNA and RNA. Of course, in biological contexts, the mutation rates
      are much smaller than 3/4.

PMID- 12614549
TI  - Distinguishing features of 16S rDNA gene for five dominating bacterial genus
      observed in bioremediation.
AB  - Defining a microbial community and identifying bacteria, at least at the genus
      level, is a first step in predicting the behavior of a microbial community in
      bioremediation. In biological treatment systems, the most dominating groups
      observed are Pseudomonas, Moraxella, Acinetobactor, Burkholderia, and
      Alcaligenes. Our interest lies in identifying the distinguishing features of
      these bacterial groups based on their 16S rDNA sequence data, which could be used
      further for generating genus-specific probes. Accordingly, 20 sequences
      representing different species from each genus above were retrieved, which
      constituted a training set. A 16-dimensional feature vector comprised of
      transition probabilities of nucleotides was considered and each sampled sequence
      was expressed in terms of these features. A stepwise feature selection method was
      used to identify features that are distinct across the species of these five
      groups. Wilk's lambda selection criterion was used and resulted in a subset with
      six distinguishing features. The discriminating efficacy of this subset was
      tested through multiple group discriminant analysis. Two linear composites, as a
      function of these features, could discriminate the test set of forty-five
      sequences from these groups with 95% accuracy, thereby ascertaining the relevance
      of the identified features. The geometric representation of feature correlation
      in the reduced discriminant space demonstrated the dominance of identified
      features in specific groups. These features independently or in combination could
      be used to generate genus-specific patterns to design probes, so as to develop a
      tracking tool for the selected group of bacteria.

PMID- 12614551
TI  - Predicting CNS permeability of drug molecules: comparison of neural network and
      support vector machine algorithms.
AB  - Two different machine-learning algorithms have been used to predict the blood
      brain barrier permeability of different classes of molecules, to develop a method
      to predict the ability of drug compounds to penetrate the CNS. The first
      algorithm is based on a multilayer perceptron neural network and the second
      algorithm uses a support vector machine. Both algorithms are trained on an
      identical data set consisting of 179 CNS active molecules and 145 CNS inactive
      molecules. The training parameters include molecular weight, lipophilicity,
      hydrogen bonding, and other variables that govern the ability of a molecule to
      diffuse through a membrane. The results show that the support vector machine
      outperforms the neural network. Based on over 30 different validation sets, the
      SVM can predict up to 96% of the molecules correctly, averaging 81.5% over 30
      test sets, which comprised of equal numbers of CNS positive and negative
      molecules. This is quite favorable when compared with the neural network's
      average performance of 75.7% with the same 30 test sets. The results of the SVM
      algorithm are very encouraging and suggest that a classification tool like this
      one will prove to be a valuable prediction approach.

PMID- 12614552
TI  - Ethics, education, common sense and medicine.

PMID- 12614553
TI  - Histological alterations after irradiation of cartilage using Ho:YAG laser.
AB  - OBJECTIVE: The authors carried out an experimental study to evaluate the
      histological alterations after irradiation of cartilage using Holmium:YAG
      (Ho:YAG) laser VersaPulse Select 60 watts and Infra Tome Delivery Systems 30
      degrees Handpiece (spot size at fiber tip 0.4 mm; Coherent Medical, Palo Alto,
      CA). BACKGROUND DATA: Recently, some authors reported cases with articular
      cartilage damage following arthroscopic laser surgery in the knee joint for the
      treatment of articular cartilage or meniscal pathology. MATERIALS AND METHODS:
      The cartilage specimens immersed in saline were exposed to Ho:YAG laser
      irradiation. The laser wavelength was 2.1 microm, and pulse duration was 250
      microsec. Power settings were 0.2-1 joules per pulse and 10-15 Hz. Total laser
      energy used in these procedures was 1.5 K joules. During the procedures, the
      handpiece was used at an angle of 30 degrees and at a distance of 1 mm. RESULTS:
      Electron microscopic evaluation demonstrated that the ultrastructure of the
      cartilage is preserved in both experiment and control groups. CONCLUSION: When
      Ho:YAG laser is used in optimal dosage (optimal joule and Hertz) with optimal
      technique (keeping the handpiece at an appropriate angle and distance) and
      avoiding overtreatment, it does not cause cartilage damage.

PMID- 12614554
TI  - Effects of the Er:YAG laser irradiation on titanium implant materials and
      contaminated implant abutment surfaces.
AB  - OBJECTIVE: The purpose of this study was to examine the morphological changes and
      temperature increases of the titanium after Er:YAG laser irradiation, and also to
      investigate the effect of this laser on debridement of contaminated healing
      abutments. BACKGROUND DATA: Mechanical instruments have been used for the
      cleaning of implant abutment surfaces, however, most of them are not appropriate
      for the application to titanium surface. Recently, the Er:YAG laser has been
      expected to have a promising ability for the debridement of implant surface.
      MATERIALS AND METHODS: Experiments were composed of three parts. At first, ten
      titanium round plates were exposed to the Er:YAG laser irradiation at 30-200
      mJ/pulse and the surface changes were observed by stereomicroscope and scanning
      electron microscope. Secondly, the surface temperature changes of 60 titanium
      plates during and after Er:YAG laser irradiation at 30 and 50 mJ/pulse were
      measured by thermographic equipment. At last, calculus on the surface of six
      contaminated healing abutments was removed by Er:YAG laser or ultrasonic scaler,
      and the treated surfaces were examined by stereomicroscope. RESULTS: Under 50
      mJ/pulse, distinct morphological changes were not observed and the elevation of
      surface temperature was minimal, especially in the use of water-cooling. The
      Er:YAG laser at 30 mJ/pulse and 30 Hz with water spray was capable of effectively
      removing plaque and calculus on the implant abutments without injuring their
      surfaces. CONCLUSION: This study indicates that the Er:YAG laser can be a novel
      technical modality for the debridement of implant abutment surface.

PMID- 12614555
TI  - Influence of linearly polarized near-infrared irradiation on deformability of
      human stored erythrocytes.
AB  - OBJECTIVE: To investigate the influence of linearly polarized near-infrared
      irradiation using the Super Lizer trade mark on deformability of human
      erythrocytes. BACKGROUND DATA: Not only low-powered laser but also linearly
      polarized near-infrared beams have some biostimulation effects on various
      tissues. There were some reports of erythrocyte deformability improved by low
      powered He-Ne laser irradiation. MATERIALS AND METHODS: Human erythrocyte samples
      stored for three weeks were adjusted to 30% hematocrit. Erythrocyte deformability
      presented as the filter filtration rate was measured. RESULTS: There was no
      difference of the filter filtration rate between control group without
      irradiation and the group of 125 mJ/cm(2) exposure level at a wavelength of 830
      nm. However, the groups of 625 and 1,250 mJ/cm(2) exposure levels at a wavelength
      of 830 nm showed higher filter filtration rates compared to the control group.
      CONCLUSION: Linearly polarized near-infrared irradiation in a range of 625-1,250
      mJ/cm(2) exposure level at a wavelength of 830 nm improved deformability of human
      stored erythrocytes.

PMID- 12614556
TI  - Anticancer effect of combined intratumor cisplatin injection and interstitial KTP
      laser therapy on xenografted squamous cell carcinoma.
AB  - OBJECTIVE: This study was conducted to evaluate the synergistic effect of
      cisplatin and interstitial KTP laser therapy induced hyperthermia in vitro and in
      vivo (interstitial laser chemotherapy, ILCT). METHODS: In vitro study: human
      hypopharyngeal squamous carcinoma cell line (SNU-1041) was incubated in 1 mL of
      media containing various concentrations (0, 1, 2, 5, 10, 20, 50, 100 ng/mL) of
      cisplatin in 37 degrees and 43 degrees C for 2 hours. The viability of the cell
      was evaluated by MTT assay. In vivo study: human squamous cell carcinoma tumors
      were grown as subcutaneous transplants in nude mice and injected into tumor with
      cisplatin-epigel 100 microg, followed by interstitial laser therapy (ILT) via 0.6
      mm diffuser fiber tips (532 nm, 1.0J/mm(3)). RESULTS: In vitro study: the
      viability of tumor cells incubated with 10 ng/mL of cisplatin was 62% and 28% in
      37 degrees C and 43 degrees C, respectively (p = 0.02). In vivo study: the tumor
      volume in 4 weeks after treatment was 179 mm(3) in ILT group and 27 mm(3) in ILCT
      group. The ILCT group showed 8 (80%) complete remission of tumors at 4 weeks
      follow up, while tumor remission occurred in only 3 (30%) in ILT group (p <
      0.05). CONCLUSION: These results suggest ILCT may become an effective treatment
      for head and neck carcinoma with minimal functional deficit.

PMID- 12614557
TI  - A comparative study on compositional changes and Knoop hardness measurement of
      the cavity floor prepared by Er:YAG laser irradiation and mechanical bur cavity.
AB  - OBJECTIVE: This present study was performed to compare the compositional changes
      of human dentin and, Knoop hardness of the cavity floor prepared by Er:YAG laser
      irradiation with that of the conventional bur cavity. BACKGROUND DATA: There are
      still no reports on the compositional changes of dental hard tissues and
      microhardness of the cavity floor prepared by Er:YAG laser irradiation. MATERIALS
      AND METHODS: Fifteen laser and 15 bur cavities were cross-sectioned, and
      subjected to atomic analysis by SEM-EDX and Knoop hardness testing. Statistical
      analyses were performed using the Mann-Whitney U test; a value of p < 0.01 was
      considered significant. Cross sections of the remaining five laser and five bur
      cavities were examined by light microscopy and then by SEM. RESULTS: The results
      showed that the quantities of Ca (Ca weight %) and P (P weight %) were increased
      significantly in the laser cavities, but no significant differences were found
      between the Ca/P ratio and Knoop hardness number of laser and bur cavities. The
      results of SEM observation revealed that the lased cavity surface was irregular,
      and there was also the absence of a smear layer; the orifice of dentinal tubules
      was exposed. CONCLUSION: Er:YAG laser device produces minimal thermal induced
      changes of dental hard tissue compositions; Ca/P ratio and Knoop hardness of the
      lased cavity floor was almost similar to the bur cavities.

PMID- 12614558
TI  - Contribution of phototherapy to the treatment of episiotomies.
AB  - OBJECTIVE: The purpose of this study was an objective consideration of possible
      benefits of phototherapy implemented with therapeutic laser or possibly polarized
      light in treating episiotomy, which is the most frequent obstetric intervention.
      MATERIALS AND METHODS: In the present study, the authors treated a total of 2,436
      women. The light sources were as follows: a laser of a wave length 670 nm, power
      20 mW, with continuous alternations of frequencies 10 Hz, 25 Hz, and 50 Hz, a
      polarized light source of a 400-2,000 nm wavelength in an interval of power 20 mW
      and frequency 100 Hz and a monochromatic light source of a 660 nm wavelength and
      power 40 mW, with simultaneous application of a magnetic field at an induction 8
      mT. RESULTS: The work demonstrated high healing effects with minimum secondary
      complications in the treatment of episiotomies using a therapeutic laser at an
      energy density of 2 J/cm(2). The application of polarized light at an energy
      density of 5 J/cm(2) also exerted favorable therapeutic effects.

PMID- 12614560
TI  - Laser literature watch.

PMID- 12614559
TI  - Effect of Nd:YAG laser irradiation on the hardness and elastic modulus of human
      dentin.
AB  - OBJECTIVE: The purpose of this study was to investigate the changes of hardness
      and elastic modulus of human dentin after Nd:YAG laser irradiation. BACKGROUND
      DATA: The application of Nd:YAG laser in dental hard tissues has been widely
      studied. However, little information is available about the mechanical properties
      of teeth after Nd:YAG laser irradiation. METHODS: The human dentin was irradiated
      by Nd:YAG laser through a 400-microm optic bare fiber. The parameters in laser
      delivery were 100 mJ/pulse--10 pps--4 sec and 150 mJ/pulse--10 pps--4 sec. Both
      the hardness and elastic modulus were obtained using an Instron microhardness
      tester and Vickers indenter. The indentations were then examined under a scanning
      electron microscope. RESULTS: The hardness and elastic modulus of irradiated
      human dentin in the energy of 100 mJ/pulse--10 pps--4 sec and 150 mJ/pulse--10
      pps--4 sec were 44.7 kg/mm(2) and 22.8 GPa, and 46.9 kg/mm(2) and 21.4 GPa,
      respectively. These values were significantly lower than that of non-irradiated
      dentin by the Student's t test. CONCLUSION: Our study demonstrated that Nd:YAG
      laser irradiation would reduce the hardness and elastic modulus of human dentin.

PMID- 12614561
TI  - Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer.
AB  - We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific,
      vespid, and pathogenesis proteins) gene as a direct target of p53 with
      proapoptotic activities in various cancer cell lines, including prostate cancer.
      To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector
      capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used
      this vector in an orthotopic, metastatic mouse model of prostate cancer. A single
      intratumoral administration of AdmRTVP-1 gene therapy significantly reduced
      primary tumor wet weight compared with control Adbetagal-injected tumors at two
      time points after injection with two different vector doses (p < or = 0.01 at 7
      and 14 days). Spontaneous metastasis to lung was also significantly reduced (p <
      or = 0.02). Evaluation of treated tumors revealed increased apoptosis and lower
      microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1
      inhibited endothelial cell sprouting compared with Adbetagal, confirming its
      antiangiogenic activity. These therapeutic activities were associated with a
      significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this
      aggressive model of prostate cancer. Interestingly, there were significant
      increases in the infiltration of tumor-associated macrophages, dendritic cells,
      and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1
      treated tumors compared with Adbetagal control-treated tumors. In addition,
      significantly increased natural killer and cytotoxic T lymphocyte activities were
      demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic
      properties of AdmRTVP-1 gene therapy demonstrated in this study provide new
      opportunities for gene and immunotherapy of prostate cancer and potentially other
      malignancies.

PMID- 12614562
TI  - Delivery of ciliary neurotrophic factor via lentiviral-mediated transfer protects
      axotomized retinal ganglion cells for an extended period of time.
AB  - Ciliary neurotrophic factor (CNTF) has recently been demonstrated to be one of
      the most promising neurotrophic factors to improve both the survival and
      regeneration of injured retinal ganglion cells (RGCs). In the present study, we
      used optic nerve transection as an in vivo model to evaluate the effectiveness of
      a self-inactivating, replication-deficient lentiviral-mediated transfer of human
      ciliary neurotrophic factor (SIN-PGK-CNTF) on the survival of axotomized adult
      rat RGCs. Counts of dextran-fluorescein isothiocyanate conjugated (D-FITC)
      retrogradely labeled RGCs revealed that the percentage of RGCs was drastically
      reduced (<90% cell death) 21 days after optic nerve transection. Retinal sections
      stained with X-gal revealed that intravitreal injection of the control LacZ
      expressing lentiviral vector (LV-LacZ) resulted in the transduction of RGCs and
      retinal pigment epithelium (RPE) cells. A single intravitreal injection of LV
      CNTF at the time of axotomy significantly enhanced RGC survival at 14 and 21 days
      postaxotomy compared to controls. These results demonstrate for the first time
      that rapid and prolonged delivery of CNTF using lentiviral-mediated gene transfer
      to the retina is an effective treatment for rescuing axotomized RGCs for an
      extended period of time. These results suggest that early and continuous
      administration of CNTF could serve as a potential treatment for retinal disorders
      involving optic neuropathy and RGC injury such as in glaucoma.

PMID- 12614563
TI  - Highly efficient and tumor-restricted gene transfer to malignant gliomas by
      replication-competent retroviral vectors.
AB  - The first large randomized phase III trial in gene therapy demonstrated no
      improvement in the survival of patients injected with packaging cells that
      produced conventional replication-defective retroviral vectors carrying the
      herpes simplex virus thymidine kinase gene, a disappointing result that was
      attributed to extremely poor levels of transduction efficiency. To circumvent
      this problem, we have developed a modified replication-competent retrovirus (RCR)
      that is capable of transducing human glioma cell lines A-172, U-87, T-98G, U-373,
      and U-138 and rat glioma cell lines C6 and 9L, over multiple infection cycles in
      vitro, resulting in a tremendous enhancement in transduction efficiency over
      conventional replication-defective retroviral vectors at the same dose. Whereas
      the transduction efficiency of conventional retroviral vectors injected into
      preestablished subcutaneous U-87 tumors at a dose of 1.0 x 10(5) transducing
      units (TU) was only 0.2% at 6 weeks postinjection, the same dose of RCR vector
      resulted in up to 97.2% transduction. When RCR vectors at a dose of 1.0 x 10(4)
      TU were injected into preestablished intracranial U-87 tumors, transduction
      efficiency at 2 and 3 weeks was 74 and 98.1%, respectively. Notably, however,
      intracranial injection of RCR vectors did not result in detectable infection of
      normal brain cells. Furthermore, using a sensitive polymerase chain reaction
      assay, no detectable RCR signal could be observed in any extracerebral tissues,
      including lung, liver, kidney, upper gastrointestinal tract (esophagus and
      stomach), lower gastrointestinal tract (colon and small intestine), skin, spleen,
      and bone marrow. Treatment of U-87 intracranial gliomas with RCR vectors carrying
      the yeast cytosine deaminase suicide gene followed by 5-fluorocytosine prodrug
      administration resulted in 100% survival over a 60-day follow-up period, compared
      with 0% survival of control groups receiving vector alone or prodrug alone. Our
      results demonstrate that RCR vectors can achieve therapeutically significant
      levels of transduction in malignant human gliomas, and that RCR vector spread
      after intratumoral injection is restricted to the tumor itself.

PMID- 12614564
TI  - Periocular gene transfer of sFlt-1 suppresses ocular neovascularization and
      vascular endothelial growth factor-induced breakdown of the blood-retinal
      barrier.
AB  - Vascular endothelial growth factor (VEGF) is a critical stimulus for both retinal
      and choroidal neovascularization, and for diabetic macular edema. We used mouse
      models for these diseases to explore the potential of gene transfer of soluble
      VEGF receptor-1 (sFlt-1) as a treatment. Intravitreous or periocular injection of
      an adenoviral vector encoding sFlt-1 (AdsFlt-1.10) markedly suppressed choroidal
      neovascularization at rupture sites in Bruch's membrane. Periocular injection of
      AdsFlt-1.10 also caused significant reduction in VEGF-induced breakdown of the
      blood-retinal barrier, but failed to significantly inhibit ischemia-induced
      retinal neovascularization. Periocular delivery of an adenoviral vector encoding
      pigment epithelium-derived factor (PEDF), another secreted protein, resulted in
      high levels of PEDF in the retinal pigmented epithelium and choroid, but not in
      the retina. This may explain why periocular injection of AdsFlt-1.10 inhibited
      choroidal, but not retinal neovascularization. Periocular delivery offers
      potential advantages over other routes of delivery and the demonstration that
      sFlt-1 enters the eye from the periocular space in sufficient levels to achieve
      efficacy in treating choroidal neovascularization and retinal vascular
      permeability is a novel finding that has important clinical implications. These
      data suggest that periocular gene transfer of sFlt-1 should be considered for
      treatment of choroidal neovascularization and diabetic macular edema.

PMID- 12614565
TI  - Dual vectors expressing murine factor VIII result in sustained correction of
      hemophilia A mice.
AB  - Hemophilia A is a sex-linked disorder that results from a deficiency of
      functional factor VIII and is currently treated by protein replacement therapies.
      Within the past decade, gene therapy efforts have come to the forefront of novel
      therapeutics. In this work, a dual-vector approach was employed in which
      recombinant adeno-associated viral (rAAV) vectors expressing the heavy and light
      chains of the murine factor VIII gene were delivered either intramuscularly or
      intravenously to a mouse model of hemophilia A. From in vitro work, it was
      determined that coinfection with both vectors is required as heterodimerization
      of the heavy and light chains occurs intracellularly. In vivo, therapeutic levels
      of factor VIII expression were achieved throughout the duration of the study (22
      weeks). Intravenous and intramuscular delivery resulted in a maximal average
      expression of 31.4 +/- 6.4 and 29 +/- 6.5% of normal murine factor VIII levels,
      respectively. Western blots of cryoprecipitate as well as immunostaining of
      injection sites with an anti-murine factor VIII light chain antibody also
      confirmed the expression of factor VIII. Because the murine form of the gene was
      used in the mouse model, less than 1 Bethesda unit of inhibitors was noted. This
      work demonstrates the feasibility of using rAAV vectors for the long-term
      treatment of hemophilia A.

PMID- 12614566
TI  - Gene therapy for killing p53-negative cancer cells: use of replicating versus
      nonreplicating agents.
AB  - Research has focused on the use of viral vectors to attack p53-negative cancer
      cells. Such agents may be nonreplicating, whereas others are replicating. This
      paper uses mathematical models to study the conditions under which therapy can
      lead to tumor remission. It is found that the optimal characteristics of the
      vector can be quite different depending on whether the virus replicates or not.
      If it does not replicate, the rate of virus-induced tumor cell killing should be
      maximized. If the virus does replicate, the rate of virus-induced cell killing
      should be kept small. If the virus is too lytic in cancer cells, viral spread is
      compromised, resulting in persistence of both virus and tumor. This has important
      implications for choosing the correct techniques to evaluate replicating viruses
      in culture. A low multiplicity of infection must be used for evaluation, because
      this mimicks the spread of the virus through an established tumor. If a high
      multiplicity of infection is used, the virus that appears most efficient in this
      evaluation can be least efficient at eradicating the cancer in vivo. Theoretical
      results are discussed in the context of experimental data.

PMID- 12614567
TI  - Adenovirus-catheter compatibility increases gene expression after delivery to
      porcine myocardium.
AB  - Endomyocardial injection of adenoviral gene vectors enables localized delivery to
      comprised myocardial tissue. However, many materials used in endomyocardial
      delivery catheters may not be compatible with adenoviral gene vectors. In this
      study, a series of catheter-based endocardial and epicardial (direct
      visualization) procedures were performed to assess catheter-adenovirus
      compatibility in an in vivo model. A standard Nitinol-stainless steel (Ni-SS)
      catheter was compared with a novel Stiletto catheter designed for improved
      biocompatibility. In 4 animals 40 endocardial injections of adenovirus encoding
      beta-galactosidase (beta-Gal) were performed with the 2 catheters. After
      sectioning of the hearts only 8 of 20 Ni-SS beta-Gal+ sites could be identified
      (40% retrieval) whereas 16 of the 20 Stiletto injection sites were identified
      (80%). Within these areas successful transfection was observed (12.2 +/- 4.0 beta
      Gal+ cells/high-power field [HPF] in the Ni-SS group vs. 30.1 +/- 6.8 beta-Gal+
      cells/HPF in the Stiletto group; p = 0.03). After epicardial delivery to distinct
      areas of the myocardium adenoviral delivery as assayed by beta-galactosidase
      protein activity was >21 +/- 16-fold (range, 5 to >43-fold) greater than after
      Stiletto delivery. In conclusion, this study highlights the importance of
      adenovirus-material compatibility in gene delivery to the myocardium. Efficiency
      was greater when using the catheter designed to enhance biocompatibility.

PMID- 12614568
TI  - High cloning capacity of in vitro packaged SV40 vectors with no SV40 virus
      sequences.
AB  - In vitro packaging of plasmid DNA using recombinant SV40 capsid proteins is a
      potentially useful procedure that overcomes some restrictions of the other SV40
      systems such as the requirement for SV40 sequences and the limitation in size of
      DNA that can be packaged. The in vitro packaging system uses the four SV40
      proteins (VP1, VP2, VP3, and agno) or VP1 only. The ability to confer drug
      resistance by three ABC transporter genes (MDR 1, MRP 1, or MXR) was determined
      using the surrogate fluorescent substrates rhodamine-123 or calcein AM and their
      specific inhibitors, or by using specific antibodies to the transporters to
      detect cell surface expression by fluorescence-activated cell sorter analysis
      (FACS). A green fluorescent protein plasmid (EGFP-C1) was also used to monitor
      gene transfer. The packaged plasmids ranged in size from 4.2 to 17.6 kb, and only
      slightly affected particle size as determined by electron microscopy. When 9.5 kb
      and larger plasmids were packaged using all SV40 proteins, MDR1 expression was
      decreased compared to VP1 alone. The size of the 15.2 kb DNA after packaging was
      the same as the original DNA. Packaging with SV40 capsid proteins in vitro does
      not require any SV40 sequences. Using either the MDR1 or the GFP gene we could
      demonstrate enhanced expression when cells were pretreated with phorbol 12
      myristate 13-acetate (PMA) at low concentrations. Interferon-gamma did not alter
      expression. We conclude that in vitro packaging is more flexible then previously
      realized, permitting packaging of at least 17 kb plasmid DNA without the
      requirement for any viral sequences. This system combines efficient gene delivery
      of the SV40 viral vector with the presumed safety of nonviral vectors.

PMID- 12614569
TI  - Development of a gene therapy strategy for the restoration of survival motor
      neuron protein expression: implications for spinal muscular atrophy therapy.
AB  - Spinal muscular atrophy (SMA) is a motor neuron degeneration disorder, and
      manifests itself in patients as muscle weakness and paralysis that ultimately
      leads to death. Currently, there is no effective treatment for this disease. As a
      first step in developing a treatment for SMA, we are examining whether delivery
      of the gene encoding survival motor neuron (SMN) protein to primary fibroblast
      cell lines derived from SMA patients can lead to restoration of nuclear-staining
      foci, called gems, which are absent in patients with severe SMA. Using adenovirus
      mediated gene delivery, we show that SMN can be efficiently expressed in patient
      fibroblasts, and leads to restoration of nuclear gems, which are thought to be
      important for the functional rescue of the SMA phenotype. The number of gems per
      cell is equal to or greater than those found in fibroblasts of normal
      individuals. Furthermore, ectopic expression of SMN also caused relocalization of
      Gemin2, an SMN-interacting protein, to gems. Overall, this work is the first
      demonstration of the feasibility of virus-based delivery of the SMN-coding gene
      to restore the normal SMN expression pattern in SMA patient-derived cells, and
      holds promise for gene therapy of SMA, as a potential long-term therapy for this
      devastating childhood disease.

PMID- 12614570
TI  - Vocal clans in sperm whales (Physeter macrocephalus).
AB  - Cultural transmission may be a significant source of variation in the behaviour
      of whales and dolphins, especially as regards their vocal signals. We studied
      variation in the vocal output of 'codas' by sperm whale social groups. Codas are
      patterns of clicks used by female sperm whales in social circumstances. The coda
      repertoires of all known social units (n = 18, each consisting of about 11
      females and immatures with long-term relationships) and 61 out of 64 groups
      (about two social units moving together for periods of days) that were recorded
      in the South Pacific and Caribbean between 1985 and 2000 can be reliably
      allocated into six acoustic 'clans', five in the Pacific and one in the
      Caribbean. Clans have ranges that span thousands of kilometres, are sympatric,
      contain many thousands of whales and most probably result from cultural
      transmission of vocal patterns. Units seem to form groups preferentially with
      other units of their own clan. We suggest that this is a rare example of
      sympatric cultural variation on an oceanic scale. Culture may thus be a more
      important determinant of sperm whale population structure than genes or
      geography, a finding that has major implications for our understanding of the
      species' behavioural and population biology.

PMID- 12614571
TI  - North Atlantic Oscillation and timing of spring migration in birds.
AB  - Migrant birds have been trapped on the island of Helgoland (southeastern North
      Sea) since 1909, with methods and sampling effort remaining unchanged throughout
      the last four decades. In 12 short/medium-distance migrants and 12 long-distance
      migrants (23 passerines plus the European woodcock) sample sizes were sufficient
      to calculate mean spring passage (msp) times and to relate these to climate
      change. All but one species, passing Helgoland en route to their breeding areas
      (mainly in Scandinavia), show a trend towards earlier msp-time, which is
      significant in 7 short/medium-distance migrants and 10 long-distance migrants.
      The msp-times advanced by 0.05-0.28 days per year, short/medium-distance migrants
      not differing from long-distance migrants. In 23 out of the 24 species, earlier
      msp-times coincide with local warmer msp-temperatures (significantly in 11 and 7
      species of the two groups, respectively). Even more striking is the relation to a
      large-scale phenomenon, the North Atlantic Oscillation (NAO), during the last
      four decades. Again, in 23 out of the 24 species, an earlier msp-time coincides
      with higher NAO indices (significantly in 9 and 12 species, respectively). The
      NAO index can also explain differences and similarities in spring migration
      strategies, as well as migration routes within Europe.

PMID- 12614573
TI  - Nutrient content of earthworms consumed by Ye'Kuana Amerindians of the Alto
      Orinoco of Venezuela.
AB  - For the Makiritare (Ye'Kuana) native people of the Alto Orinoco (Venezuela),
      earthworms (Anellida: Glossoscolecidae) are an important component of the diet.
      Two species in particular are widely consumed: 'kuru' (Andiorrhinus kuru n. sp.)
      and 'motto' (Andiorrhinus motto). We analysed eviscerated kuru body proper, and
      whole and smoked preparations of motto for their content of protein and amino
      acids, fatty acids and 20 minerals and trace elements. The samples contained
      large amounts of protein (64.5-72.9% of dry weight), essential amino acids,
      calcium and iron together with notable quantities of other important elements,
      indicating that these earthworms contain potentially useful quantities of many
      nutrients that are critical to the health of the humans who consume them.

PMID- 12614572
TI  - Trade-off between immunocompetence and growth in magpies: an experimental study.
AB  - A trade-off between immunity and growth has repeatedly been suggested, mainly
      based on laboratory and poultry science, but also from experiments where
      parasitism intensity was manipulated in field bird populations. However, as
      resource allocation to different activities (or organs) during growth is
      difficult to manipulate, this trade-off has only been experimentally tested by
      studying the effects of non-pathogenic antigens. By providing some nestling
      magpies (Pica pica) with methionine, a sulphur amino acid that specifically
      enhances T-cell immune response in chickens, we investigated this trade-off by
      directly affecting allocation of limited resources during growth. Results were in
      accordance with the hypothetical trade-off because nestlings fed with methionine
      showed a lower growth rate during the four days of methionine administration, but
      a larger response when fledglings were challenged with phytohaemagglutinin (a
      measure of the intensity of T-lymphocyte-mediated immune responsiveness) than
      control nestlings. Surprisingly, we found that control and experimental nestlings
      fledged with similar body mass, size and condition, but experimental nestlings
      suffered less from blood parasites (Haemoproteus) and had fewer lymphocytes (a
      widely used measure of health status) than control nestlings, suggesting a
      negative effect of blood parasites or other pathogens on nestling growth.

PMID- 12614574
TI  - Long-term fitness consequences of female extra-pair matings in a socially
      monogamous passerine.
AB  - Whether female birds choose extra-pair mating partners to obtain genetic fitness
      benefits is intensely debated. The most straightforward and crucial test of 'good
      genes' models of female extra-pair mating is the comparison of naturally 'cross
      fostered' maternal half-siblings sharing the same rearing environment as any
      systematic differences in performance between the two categories of offspring
      phenotype can be attributed to differential paternal genetic contribution. We
      analysed local recruitment and first-year reproductive performance of maternal
      half-siblings in the coal tit (Parus ater), a passerine bird with high levels of
      extra-pair paternity. We provide a highly comprehensive measure of the long-term
      fitness consequences of female extra-pair matings based on a large sample of 736
      within-pair offspring (WPO) and 368 extra-pair offspring (EPO) from 91 first and
      55 second broods, from which 132 breeders recruited into the study population. In
      contrast to predictions derived from 'good genes' models, we found no differences
      in local recruitment and seven parameters of first-year reproductive performance
      when comparing WPO and EPO. These results question the universal validity of
      findings in other bird species supporting 'good genes' models, particularly as
      they are based on the best approximation to female fitness obtained so far.

PMID- 12614575
TI  - Are reproductive skew models evolutionarily stable?
AB  - Reproductive skew theory has become a popular way to phrase problems and test
      hypotheses of social evolution. The diversity of reproductive skew models
      probably stems from the ease of generating new variations. However, I show that
      the logical basis of skew models, that is, the way in which group formation is
      modelled, makes use of hidden assumptions that may be problematical as they are
      unlikely to be fulfilled in all social systems. I illustrate these problems by re
      analysing the basic concessive skew model with staying incentives. First, the
      model assumes that dispersal is an all-or-nothing response: all subordinates
      disperse as soon as concessions drop below a certain value. This leads to a
      discontinuous 'cliff-edge' shape of dominant fitness, and it is not clear that
      selection will balance a population at such an edge. Second, it is assumed that
      subordinates have perfect knowledge of their benefits if they stay in the group.
      I examine the effects of relaxing these two assumptions. Relaxing the first one
      strengthens reproductive skew theory, but relaxing the latter makes evolutionary
      stability disappear. In cases where subordinates cannot accurately measure
      benefits provided by the individual dominant with which they live, so that their
      behaviour instead evolves as a response to population-wide average benefits, the
      logic of reproductive skew models does not apply. This warns against too
      indiscriminate an application of reproductive skew theory to problems in social
      evolution: for example, transactional models of extra-pair paternity assume
      perfect knowledge of paternity, which is unlikely to hold true in nature. It is
      recommended that models specify the mechanisms by which individuals can adjust
      their behaviour to that of others, and pay attention to changes that occur in
      evolutionary versus behavioural time.

PMID- 12614576
TI  - Female multiple mating behaviour, early reproductive failure and litter size
      variation in mammals.
AB  - Female promiscuity is widespread among mammals, although its function is poorly
      understood. Recently, much interest has been generated by the hypothesis that
      female promiscuity, combined with post-copulatory paternity-biasing mechanisms,
      may function to reduce the costs of reproductive failure resulting from genetic
      incompatibility. Here, a comparative approach is used to determine if average
      rates of reproductive failure differ for polytocous mammal species with
      contrasting levels of female multiple-mating behaviour. After control for
      phylogeny, promiscuous species were found to have significantly lower rates of
      early reproductive failure than monogamous and polygynous species, in which
      females are relatively monandrous. Monandrous females appear to compensate for
      higher early reproductive failure with increased ova production, and thus produce
      comparable average litter sizes to those of more promiscuous females. However,
      there is significantly more variation around the average litter sizes produced by
      relatively monandrous females. These findings are broadly consistent with
      predictions of the genetic incompatibility avoidance hypothesis, although it is
      emphasized that alternative explanations cannot be ruled out on the basis of the
      comparative evidence presented. Further studies are needed to explore ecological
      correlates of multiple-mating behaviour, to investigate potential post-copulatory
      paternity-biasing mechanisms, and to identify the causes of reproductive failure
      in natural mammal populations.

PMID- 12614577
TI  - Orientation at night: an innate moon compass in sandhoppers (Amphipoda:
      Talitridae).
AB  - The supralittoral amphipod Talitrus saltator is well known for its capacity for
      astronomical orientation using the sun and moon as compasses. It has also been
      demonstrated that the sun compass is innate in this species. In our experiments,
      we released inexpert (naive) young born in the laboratory into a confined
      environment under the full moon and in the absence of the horizontal component of
      the magnetic field. They were allowed to see the natural sky and the moon only at
      the moment of release. The young individuals were obtained in the laboratory by
      crossing adult individuals from the same and different populations of
      sandhoppers. The young from intrapopulation crosses were well oriented towards
      the directions corresponding to those of their parents, whereas the young from
      interpopulation crosses were oriented in an intermediate direction. Therefore,
      our experiments demonstrate in the sandhopper T. saltator that sea-land moon
      orientation relies on an innate chronometrically compensated mechanism.

PMID- 12614578
TI  - A snail with unbiased population sex ratios but highly biased brood sex ratios.
AB  - Extraordinary sex ratio patterns and the underlying sex-determining mechanisms in
      various organisms are worth investigating, particularly because they shed light
      on adaptive sex-ratio adjustment. Here, we report an extremely large variation in
      the brood sex ratio in the freshwater snail, Pomacea canaliculata. In eight
      rearing series originating from three wild populations, sex ratios were highly
      variable among broods, ranging continuously from almost exclusively males to
      almost exclusively females. However, sex ratios were similar between broods from
      the same mating pair, indicating that sex ratio is a family trait. Irrespective
      of the large variations, the average sex ratios in all rearing series were not
      significantly different from 0.5. We argue that Fisher's adaptive sex-ratio
      theory can explain the equal average sex ratios, and the results, in turn,
      directly support Fisher's theory. Polyfactorial sex determination (in which sex
      is determined by three or more genetic factors) is suggested as the most likely
      mechanism producing the variable brood sex ratio.

PMID- 12614579
TI  - Top-down or bottom-up regulation of intra-host blood-stage malaria: do malaria
      parasites most resemble the dynamics of prey or predator?
AB  - Knowledge of the factors that limit parasite numbers offers hope of improved
      intervention strategies as well as exposing the selective forces that have shaped
      parasite life-history strategies. We develop a theoretical framework with which
      to consider the intra-host regulation of malaria parasite density. We analyse a
      general model that relates timing and magnitude of peak parasite density to
      initial dose under three different regulatory processes. The dynamics can be
      regulated either by top-down processes (upgradable immune regulation), bottom-up
      processes (fixed immune response and red blood cell (RBC) limitation) or a
      mixture of the two. We define and estimate the following key parameters: (i) the
      rate of RBC replenishment; (ii) the rate of destruction of uninfected RBCs; and
      (iii) the maximum parasite growth rate. Comparing predictions of this model with
      experimental results for rodent malaria in laboratory mice allowed us to reject
      functional forms of immune upregulation and/or effects of RBC limitation that
      were inconsistent with the data. Bottom-up regulation alone was insufficient to
      account for observed patterns without invoking either localized depletion of RBC
      density or merozoite interference. By contrast, an immune function upregulated in
      proportion to either merozoite or infected RBC density was consistent with
      observed dynamics. An immune response directed solely at merozoites required
      twice the level of activation of one directed at infected RBCs.

PMID- 12614580
TI  - Honesty and cheating in cleaning symbioses: evolutionarily stable strategies
      defined by variable pay-offs.
AB  - Game-theory models have indicated that the evolution of mixed strategies of
      cheating and honesty in many mutualisms is unlikely. Moreover, the mutualistic
      nature of interspecific interactions has often been difficult to demonstrate
      empirically. We present a game-theory analysis that addresses these issues using
      cleaning symbioses among fishes as a model system. We show that the assumption of
      constant pay-offs in existing models prevents the evolution of evolutionarily
      stable mixed strategies of cheating and honesty. However, when interaction pay
      offs are assumed to be density dependent, mixed strategies of cheating and
      honesty become possible. In nature, cheating by clients often takes the form of
      retaliation by clients against cheating cleaners, and we show that mixed
      strategies of cheating and honesty evolve within the cleaner population when
      clients retaliate. The dynamics of strategies include both negative and positive
      effects of interactions, as well as density-dependent interactions. Consequently,
      the effects of perturbations to the model are nonlinear. In particular, we show
      that under certain conditions the removal of cleaners may have little impact on
      client populations. This indicates that the underlying mutualistic nature of some
      interspecific interactions may be difficult to demonstrate using simple
      manipulation experiments.

PMID- 12614581
TI  - Hamilton goes empirical: estimation of inclusive fitness from life-history data.
AB  - Hamilton's theory of kin selection is one of the most important advances in
      evolutionary biology since Darwin. Central to the kin-selection theory is the
      concept of inclusive fitness. However, despite the importance of inclusive
      fitness in evolutionary theory, empirical estimation of inclusive fitness has
      remained an elusive task. Using the concept of individual fitness, I present a
      method for estimating inclusive fitness and its components for diploid organisms
      with age-structured life histories. The method presented here: (i) allows
      empirical estimation of inclusive fitness from life-history data; (ii)
      simultaneously considers all components of fitness, including timing and
      magnitude of reproduction; (iii) is consistent with Hamilton's definition of
      inclusive fitness; and (iv) adequately addresses shortcomings of existing methods
      of estimating inclusive fitness. I also demonstrate the application of this new
      method for testing Hamilton's rule.

PMID- 12614582
TI  - Biological identifications through DNA barcodes.
AB  - Although much biological research depends upon species diagnoses, taxonomic
      expertise is collapsing. We are convinced that the sole prospect for a
      sustainable identification capability lies in the construction of systems that
      employ DNA sequences as taxon 'barcodes'. We establish that the mitochondrial
      gene cytochrome c oxidase I (COI) can serve as the core of a global
      bioidentification system for animals. First, we demonstrate that COI profiles,
      derived from the low-density sampling of higher taxonomic categories, ordinarily
      assign newly analysed taxa to the appropriate phylum or order. Second, we
      demonstrate that species-level assignments can be obtained by creating
      comprehensive COI profiles. A model COI profile, based upon the analysis of a
      single individual from each of 200 closely allied species of lepidopterans, was
      100% successful in correctly identifying subsequent specimens. When fully
      developed, a COI identification system will provide a reliable, cost-effective
      and accessible solution to the current problem of species identification. Its
      assembly will also generate important new insights into the diversification of
      life and the rules of molecular evolution.

PMID- 12614583
TI  - Modelling infection as a two-step process combining gene-for-gene and matching
      allele genetics.
AB  - The genetic basis of infection determines the dynamics of host-parasite
      coevolution and associated phenomena such as local adaptation and the evolution
      of sex and recombination. Here, we present parasite resistance as a two-step
      process in which hosts must first detect parasites and then eradicate them;
      failure at either step results in infection. The model incorporates 'matching
      allele' (MA) genetics for detection and 'gene-for-gene' (GFG) genetics for
      eradication. We found that the oscillatory dynamics were similar to pure GFG
      genetics when the cost of 'virulence' alleles was low, but resembled pure MA
      genetics when the cost was high. The magnitude of the cost that switched the
      dynamics from GFG dominated to MA dominated depended on the genetic architecture
      of defence (i.e. the number of GFG and MA loci).

PMID- 12614584
TI  - Delayed transplantation of olfactory ensheathing glia promotes
      sparing/regeneration of supraspinal axons in the contused adult rat spinal cord.
AB  - The aim of this study was to determine the preferred time and environment for
      transplantation of olfactory ensheathing glia (OEG) into the moderately contused
      adult rat thoracic spinal cord. Purified OEG were suspended in culture medium
      with or without fibrinogen and injected into the contused cord segment at 30 min
      or 7 days after injury. Control animals received a contusion injury only or
      injection of only medium 7 days after contusion. The effects on axonal
      sparing/regeneration and functional recovery were evaluated 8 weeks after injury.
      The grafts largely filled the lesion site, reducing cavitation, and appeared
      continuous with the spinal nervous tissue. Whereas in 7d/medium only animals, 54%
      of spinal tissue within a 2.5-mm-long segment of cord centered at the injury site
      was spared, significantly more tissue was spared in 0 d/OEG-medium (73%), 0 d/OEG
      fibrin (66%), 7 d/OEG-medium (70%), and 7 d/OEG-fibrin (68%) grafted animals.
      Compared with controls, the grafted animals exhibited more serotonergic axons
      within the transplant, the surrounding white matter, and the spinal cord up to at
      least 20 mm caudal to the graft. Retrograde tracing revealed that all but the 0
      d/OEG-fibrin graft promoted sparing/regeneration of supraspinal axons compared
      with controls. Overall, the 7 d/OEG-medium group resulted in the best response,
      with twice as many labeled neurons in the brain compared with 7 d/medium only
      controls. Of the labeled neurons, 68% were located in the reticular formation,
      and 4% in the red, 4% in the raphe, and 5% in the vestibular nuclei. Hindlimb
      performance was modestly but significantly improved in the 7 d/OEG-medium group.
      Our results demonstrate that transplantation of OEG into the moderately contused
      adult rat thoracic spinal cord promotes sparing/regeneration of supraspinal axons
      and that 7 d transplantation is more effective than acute transplantation of OEG.
      Our results have relevant implications for future surgical repair strategies of
      the contused spinal cord.

PMID- 12614585
TI  - A new approach to CNS repair using chimeric peripheral nerve grafts.
AB  - We have examined whether transplanted freeze-thawed peripheral nerve (PN) sheaths
      repopulated ex vivo with purified adult Schwann cells (SCs) support the
      regeneration of adult rat retinal ganglion cell (RGC) axons. Cultured adult SCs
      were derived from donor rats or from the host animals themselves. We also
      transplanted PN sheaths filled with neonatal SCs or donor adult olfactory
      ensheathing glia (OEG). 100,000 cells were injected into 1.5-cm lengths of freeze
      thawed PN. After 2 days in culture, repopulated PN segments were grafted onto the
      transected optic nerve of adult Fischer rats. Three weeks later, 6% fluorogold
      (FG) was applied to distal PN. Retrogradely labeled RGCs were counted in retinal
      wholemounts and PN grafts were processed for immunohistochemistry. As expected,
      there was no RGC axon regeneration in cell-free grafts. Regrowth was also absent
      in neonatal SC- and adult OEG-filled grafts, which contained only small numbers
      of surviving donor cells. Many cells were, however, seen in adult SC repopulated
      PN grafts, intermingled with pan-neurofilament(+) and GAP-43(+) fibers. SCs were
      aligned along the grafts and were S-100(+), p75(+). Ultrastructurally, SCs were
      associated with myelinated and unmyelinated axons. Hundreds of FG-labeled RGCs
      were seen in retinas of rats with congeneic or allogeneic PN sheaths repopulated
      with either donor or autologous (host-derived) adult SCs. Intraocular CNTF
      injections significantly increased the number of regenerating RGCs in donor and
      autologous adult SC groups. The use of chimeric grafts to bridge CNS tissue
      defects could provide a clinical alternative to using multiple PN autografts, the
      harvesting of which would exacerbate peripheral dysfunction in already injured
      patients.

PMID- 12614586
TI  - Physical size does not determine the unique histopathological response seen in
      the injured mouse spinal cord.
AB  - Mice display a wound healing process after spinal cord injury that has not been
      seen in any other species. Rather than exhibiting progressive necrosis and
      cavitation at the injury site, the mouse lesion site fills in with connective
      tissue. The connective tissue matrix then undergoes a remodeling in which it
      contracts, drawing the two ends of the injured spinal cord closer together. One
      possible explanation for this unique wound healing response is that the spinal
      cord is much smaller in mice than in rats or other species that have been
      analyzed. To evaluate this possibility, we compared the histopathological
      response to spinal cord injury in mice, hamsters (in which the spinal cord is
      similar in size to that in mice), and rats. Crush injuries were produced at T9,
      and lesion area and cavitation were assessed using quantitative morphometry at 1,
      3, and 8 weeks post-injury. Both hamsters and rats exhibited large lesions and
      areas of cavitation that increased from 1 to 3 weeks and then stabilized. In
      mice, the lesion site contained compact meshworks of cells and connective tissue
      that decreased in size over time. In rats, the cavities contained substantial
      degeneration debris, whereas in hamsters, cavities were fluid-filled cysts with
      minimal debris. Hamsters had the largest lesions relative to the cross-sectional
      area of the spinal cord, despite having a spinal cord similar in size to the
      mouse. These results indicate that the physical size of the spinal cord does not
      determine the unique histopathological responses after spinal cord injury in
      mice.

PMID- 12614587
TI  - Decreased neural damage after spinal cord injury in tPA-deficient mice.
AB  - Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen
      to plasmin. It plays an important role in the nervous system, including the
      processes of neuronal migration, neurite outgrowth, and neuronal plasticity. tPA
      has also been suggested to have a role in several neuropathological conditions,
      such as cerebral ischemia, seizures, and demyelinating diseases. To investigate
      the role of tPA in spinal cord injury, wild-type mice and mice with homozygous
      tPA deficiency (tPA(-/-) mice) were subjected to spinal cord contusion and the
      differences of hindlimb function, electrophysiological changes, and
      histopathological changes were assessed for 6 weeks. Functional recovery was
      greater in tPA(-/-) mice than in wild-type mice throughout the observation
      period. The time course of myoelectric motor-evoked potentials supported the
      hindlimb functional findings. Histological examination showed that injured areas
      were smaller in tPA(-/-) mice than wild-type mice on Luxol fast blue staining or
      myelin basic protein and neurofilament protein immunostaining at 6 weeks after
      contusion. Electron microscopy showed that the white matter was better preserved
      in tPA(-/-) mice than in wild-type mice. The expression of tPA protein was
      widespread on the first day after contusion and this expression was detected for
      at least a week. Activation of microglia/macrophages and apoptotic cell death
      were significantly reduced in tPA(-/-) mice after contusion. This study shows
      that neural damage is decreased in tPA(-/-) mice after spinal cord injury.
      Suppression of tPA production may help to decrease secondary injury after spinal
      cord contusion.

PMID- 12614588
TI  - Evaluation of conditions for calpain inhibition in the rat spinal cord: effective
      postinjury inhibition with intraspinal MDL28170 microinjection.
AB  - Calpains (calcium-activated cysteine proteases) are strongly implicated in the
      secondary damage that follows contusion injury to the spinal cord. Calpains are
      activated within a few minutes following injury and their elevated activity
      persists for 24 h, thereby providing a reasonable window of opportunity for
      postinjury inhibition. Previous studies demonstrated decreased axonal damage and
      neurofilament proteolysis with postinjury intravenous administration of
      relatively low concentrations of the calpain inhibitors leupeptin, E-64-D, and
      calpeptin. We sought to determine if conditions under which calpain inhibitors
      were administered in previous studies resulted in effective calpain inhibition,
      and to identify conditions that result in significant calpain inhibition
      following spinal cord injury. Contusive spinal cord injury was produced in female
      Long-Evans rats using the NYU impactor at the 12.5-25-mm height setting. The
      results demonstrate that intravenous administration of 1 mg/kg E-64-D or 250
      micro g/kg calpeptin does not inhibit total calpain activity in the rat spinal
      cord, measured using a BODIPY-FL labeled casein assay. Intravenous administration
      of MDL28170 (20 mg/kg) resulted in mild calpain inhibition and a modest decrease
      in the proteolysis of calpain substrates alpha-spectrin and MAP2. Intraspinal
      microinjection of 50 nmoles/19 micro g MDL28170, either 30 min prior to or 20 min
      following contusion injury, resulted in a more robust inhibition of total calpain
      activity and greater attenuation of alpha-spectrin breakdown and MAP2
      proteolysis. The decreased proteolysis persisted 24 h postinjury. Together, the
      results demonstrate that direct microinjection of the calpain inhibitor MDL28170
      is more effective than intravenous infusion in reducing calpain activity and
      decreasing the injury-induced proteolysis of calpain substrates.

PMID- 12614589
TI  - Noninvasive cerebrovascular autoregulation assessment in traumatic brain injury:
      validation and utility.
AB  - A moving correlation index (Mx-CPP) of cerebral perfusion pressure (CPP) and mean
      middle cerebral artery blood flow velocity (CBFV) allows continuous monitoring of
      dynamic cerebral autoregulation (CA) in patients with severe traumatic brain
      injury (TBI). In this study we validated Mx-CPP for TBI, examined its prognostic
      relevance, and assessed its relationship with arterial blood pressure (ABP), CPP,
      intracranial pressure (ICP), and CBFV. We tested whether using ABP instead of CPP
      for Mx calculation (Mx-ABP) produces similar results. Mx was calculated for each
      hemisphere in 37 TBI patients during the first 5 days of treatment. All patients
      received sedation and analgesia. CPP and bilateral CBFV were recorded, and GOS
      was estimated at discharge. Both Mx indices were calculated from 10,000 data
      points sampled at 57.4Hz. Mx-CPP > 0.3 indicates impaired CA; in these patients
      CPP had a significant positive correlation with CBFV, confirming failure of CA,
      while in those with Mx < 0.3, CPP was not correlated with CBFV, indicating intact
      CA. These findings were confirmed for Mx-ABP. We found a significant correlation
      between impaired CA, indicated by Mx-CPP and Mx-ABP, and poor outcome for TBI
      patients. ABP, CPP, ICP, and CBFV were not correlated with CA but it must be
      noted that our average CPP was considerably higher than in other studies. This
      study confirms the validity of this index to demonstrate CA preservation or
      failure in TBI. This index is also valid if ABP is used instead of CPP, which
      eliminates the need for invasive ICP measurements for CA assessment. An
      unfavorable outcome is associated with early CA failure. Further studies using
      the Mx-ABP will reveal whether CA improves along with patients' clinical
      improvement.

PMID- 12614590
TI  - L-arginine and free radical scavengers increase cerebral blood flow and brain
      tissue nitric oxide concentrations after controlled cortical impact injury in
      rats.
AB  - To examine the mechanism of the increase in cerebral blood flow induced by L
      arginine administration after traumatic brain injury, the cerebral hemodynamic
      effects of L-arginine, D-arginine, and the free radical scavengers superoxide
      dismutase (SOD) and catalase were compared in the controlled cortical impact
      injury model in rats. Animals were anesthetized with isoflurane. Measured
      parameters included mean blood pressure, intracranial pressure, cerebral blood
      flow using laser Doppler flowmetry (LDF) and brain tissue nitric oxide (NO)
      concentrations using an NO electrode. L-arginine, but not D-arginine,
      administration resulted in a significant increase in tissue NO concentrations and
      an improvement in LDF at the impact site, compared to control animals given
      saline. Administration of SOD alone and in combination with catalase resulted in
      a significant increase in brain tissue NO concentrations. However, LDF was
      consistently improved only when both SOD and catalase were given. These studies
      support the theory that L-arginine administration improves post-traumatic
      cerebral blood flow by increasing NO production. Free radical production after
      trauma may also contribute to the reduction in CBF by inactivating NO.

PMID- 12614591
TI  - Time course of cortical hemorrhages after closed traumatic brain injury:
      statistical analysis of posttraumatic histomorphological alterations.
AB  - We examined 305 autopsied brains for histomorphological alterations to determine
      the time course of reactions in cortical hemorrhages following traumatic closed
      brain injury. Eighteen morphological criteria were considered: red blood cells
      (RBCs), polymorphonuclear leukocytes (PMNs), macrophages (Ms), RBC-containing Ms,
      hemosiderin, hematoidin, lipid-containing Ms, fibroblasts, endothelial cells,
      collagenous fibres, gemistocytic astrocytes, fibrillary gliosis, hemosiderin
      containing astrocytes, neuronal damage, neuronophagy, axonal swelling (beta
      amyloid precursor protein: beta-APP), axonal bulbs (van Gieson stain), and
      mineralisation of neurons. The interval between the time of brain injury and
      death ranged from 1 min to 58 years. Following routine staining and
      immunohistochemical staining of microglia (CD68), astrocytes (GFAP) and injured
      axons (beta-APP), paraffin sections were examined by light microscopy for the
      presence of the selected histomorphological features. For each cytomorphological
      phenomenon, the time at which it could be demonstrated for the first time and for
      the last time (observation period) was determined. The relative frequency of each
      criterion was established for each observation period. The limits of confidence
      for the respective relative frequencies were estimated with a reliability of 95%
      according to Clopper and Pearson. An apparent correlation was found between the
      frequency of a given histomorphological phenomenon and the length of the
      posttraumatic interval. To check for accuracy of prediction, half of the cases
      (group 1; n = 153) were used to develop a multistage evaluation model; half
      (group 2; n = 152) were used to evaluate the validity of the data of group 1.
      Applying this model, 117 of the 152 control group cases (76.97%) could be
      correctly classified and further 26 cases (17.11%) being assigned to an interval
      close to the correct interval. Thus, this model allows classification of the
      correct posttraumatic interval or an interval close to the correct posttraumatic
      interval in about 95% of cases. We developed a software program that allows the
      estimation of survival time of TBI based on the relative frequency of the 18
      morphological features. Applying this software will help to estimate the
      posttraumatic interval of cortical hemorrhages following TBI of unknown survival
      time.

PMID- 12614592
TI  - ET-1 contributes to age-dependent G protein impairment after brain injury.
AB  - Previous studies have observed that endothelin-1 (ET-1) concentration is elevated
      in CSF and contributes to impaired cerebral hemodynamics following fluid
      percussion brain injury (FPI) in an age-dependent manner. This study was designed
      to characterize the effects of FPI on the vascular activity of two activators of
      a pertussin toxin-sensitive G protein, mastoparan and mastoparan-7, as a function
      of age and the role of ET-1 in such effects in newborn (1-5 days old) and
      juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Mastoparan
      (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more by FPI in
      newborn versus juvenile pigs (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1%,
      newborn; 9 +/- 1 and 15 +/- 1 vs. 6 +/- 1 and 9 +/- 1%, juvenile). Similar
      results were observed for mastoparan-7, but the inactive analogue mastoparan-17
      had no effect on pial diameter. BQ123 (10(-6) M), an ET-1 antagonist, partially
      restored impaired mastoparan dilation after FPI in the newborn but not in the
      juvenile (3 +/- 1 and 5 +/- 1 vs. 7 +/- 1 and 11 +/- 1%, newborn; 6 +/- 1 and 9
      +/- 1 vs. 6 +/- 1 and 10 +/- 1%, juvenile). These data show that G protein
      activation elicits cerebrovasodilation that is blunted following FPI in an age
      dependent manner. These data suggest that ET-1 contributes to the impairment of G
      protein-mediated vasodilation in an age-dependent manner after FPI.

PMID- 12614593
TI  - Delayed treatment of hemoglobin neurotoxicity.
AB  - Hemoglobin is an oxidative neurotoxin that may contribute to cell injury after
      CNS trauma and hemorrhagic stroke. Prior studies have demonstrated that
      concomitant treatment with iron-chelating antioxidants prevents its
      neurotoxicity. However, the efficacy of these agents when applied hours after
      hemoglobin has not been determined, and is the subject of the present
      investigation. Consistent with prior observations, an increase in reactive oxygen
      species generation, detected by 2',7'-dichlorofluorescin oxidation, was observed
      when mixed neuronal/astrocyte cultures prepared from mouse cortex were exposed to
      hemoglobin alone. However, this oxidative stress developed slowly. A significant
      increase in the dichlorofluorescein signal compared with control, untreated
      cultures was not observed until four hours after addition of hemoglobin, and was
      followed by loss of membrane integrity and propidium iodide staining. Treating
      cultures with the 21-aminosteroid U74500A or the ferric iron chelator
      deferoxamine four hours after initiating hemoglobin treatment markedly attenuated
      reactive oxygen species production within 2 h. Continuous exposure to 5 micro M
      hemoglobin for 24 h resulted in death of about three-quarters of neurons, without
      injuring astrocytes. Most neuronal loss was prevented by concomitant treatment
      with U74500A; its effect was not significantly attenuated if treatment was
      delayed for 2-4 h, and it still prevented over half of neuronal death if
      treatment was delayed for 8 h. Similar neuroprotection was produced by delayed
      treatment with deferoxamine or the lipid-soluble iron chelator phenanthroline.
      None of these agents had any effect on neuronal death when added to cultures 12 h
      after hemoglobin. These results suggest that hemoglobin is a potent but slowly
      acting neurotoxin. The delayed onset of hemoglobin neurotoxicity may make it an
      attractive target for therapeutic intervention.

PMID- 12614595
TI  - Integrated neonatal care: vital topics that complement neonatal nursing.

PMID- 12614596
TI  - Integrated Nursing Care: vital issues important in the humane care of the
      newborn.
AB  - Neonatal nurses are in a unique and powerful position to influence the lives of
      infants and families. The essence of the profession of nursing is an obligation
      to care. The art and science of caring demands individualization and flexibility
      in judgment and decision-making. Nursing is a process of facilitation that
      involves mutual interactive communication toward an individual, family,
      community, or system and is directed toward further development. When the nurse's
      relationship is one of mutuality with the family there is a synchronous process
      of the nurse supporting the family in supporting the infant's emerging
      development. The neurobehaviourally supportive approach is one that is
      individualized and therefore the plan of care for each infant must be thoroughly
      designed. This humane and integrated approach to care ensures families'
      competence and confidence in their readiness for the infant's discharge from the
      intensive care nursery.

PMID- 12614597
TI  - Neonatal individualized care in practice: a Swedish experience.
AB  - A family-centred, developmentally supportive approach to newborn intensive care
      referred to as NIDCAP (Newborn Individualized Developmental Care and Assessment
      Programme) has caught considerable interest during recent years. In this paper we
      review the scientific context behind its conceptual framework and summarize our
      experience from 10 years of training, implementation and research. We present the
      short- and long-term medical and developmental outcome of our Swedish NIDCAP
      studies as well as attitudes of nursing staff and neonatologists. Furthermore,
      ethical issues and scientific obstacles concerning this concept of care are
      discussed.

PMID- 12614598
TI  - Facilitating infant adaptation: the nursery environment.
AB  - The physical and social environment of the nursery is a direct and indirect
      influence on the development of premature infants. Qualities in the environment
      affect physiological stability and provide sensory experience that is relevant to
      brain development. Adaptation of the prematurely born infant to the unexpected
      surroundings of the neonatal intensive care unit can be facilitated when the
      infant's developmental needs are understood and characteristics of the
      environment are adapted accordingly. The need for environmental change is
      revealed by the infant's behaviour, that is, his interactions with the
      environment. The environment also affects the behaviour of caregivers, who like
      the baby need to be able to do their best in this challenging situation.

PMID- 12614599
TI  - Developmental progression of feeding skills: an approach to supporting feeding in
      preterm infants.
AB  - Infants born prematurely, with congenital or acquired medical conditions, or who
      have extended stays in the neonatal intensive care unit (NICU) are at higher risk
      of developing feeding and nutritional problems than are full-term, healthy
      newborns. Because of the complex nature of feeding, it is necessary to have a
      thorough understanding of the developmental nature of this skill. The importance
      of recognizing stability in the physiologic, motor and state systems and using
      stability to determine both readiness to begin nipple feeding and progress in
      feeding, is discussed. Intervention strategies to promote stability leading to
      successful feeding are also described. Viewing infant feeding from a
      developmental skill acquisition perspective can guide the caregiver in
      determining how challenging it is for the infant, and therefore is useful in
      supporting the progression of feeding.

PMID- 12614600
TI  - Positive Touch and massage in the neonatal unit: a British approach.
AB  - There is now a general trend towards a more baby friendly, family centred
      approach in the Neonatal Unit. Aspects of that approach-including positive touch
      and massage- are gaining in popularity. This has caused much debate due to the
      ambiguity surrounding the implementation and validity of the interventions. Here
      the impact of these complementary practices (not to be confused with
      complementary therapies) is discussed. A review of the author's approach and
      potential guidelines for implementation is provided.

PMID- 12614601
TI  - Preterm infant massage therapy studies: an American approach.
AB  - Preterm infants have been noted to benefit from massage therapy. Following
      massage therapy protocols using moderate pressure preterm infants have gained 31
      49% more weight on average. Some studies have also shown length and head
      circumference growth and bone mineral density increases associated with massage
      therapy. These studies are reviewed in this paper along with discussion of
      potential underlying mechanisms.

PMID- 12614602
TI  - Benefits of infant massage for mothers with postnatal depression.
AB  - Infant massage by the mother has been popular in many cultures, especially India,
      and is growing in popularity in the West. Mothers with postnatal depression often
      have problems interacting with their infants. A small controlled study has shown
      that attending a massage class can help such mothers relate better to their
      babies. The mechanisms by which this is achieved are not clear but may include
      learning to understand their babies' cues and the release of oxytocin.

PMID- 12614603
TI  - A second symmetry mismatch at the portal vertex of bacteriophage T7: 8-fold
      symmetry in the procapsid core.
AB  - Like other bacteriophages, T7 has a singular vertex that is the site of a
      symmetry mismatch involving the portal/connector protein, a 12-fold ring at the
      vertex site which is also a 5-fold axis for the icosahedral capsid. In the mature
      virion, a 6-fold-symmetric tail extends outwards from the connector. T7 also has
      a cylindrical "core" that assembles on the inner surface of the connector during
      procapsid formation, is retained in the mature virion, and is required for
      infectivity. We have investigated the core structure by cryo-electron microscopy
      and image analysis of procapsids and find that it observes 8-fold symmetry.
      Stoichiometry data indicate that its major constituent is an octamer of gp15.

PMID- 12614604
TI  - Spontaneous hotspot mutations resistant to mismatch correction in Escherichia
      coli: transcription-dependent mutagenesis involving template-switching
      mechanisms.
AB  - The generation and stabilization of spontaneous mutations are affected by many
      factors, including the accuracy of DNA replication, the generation of spontaneous
      DNA lesions, and the capacity of mutation-avoidance systems. However, little is
      known about the causes of spontaneous mutations in cells with fully active
      mutation-avoidance systems. Using the rpsL forward mutation assay, we previously
      found that the directionality of replication fork movement significantly affects
      spontaneous mutagenesis in Escherichia coli. In particular, sequence
      substitutions and a hotspot type of single-base frameshift, both of which are
      caused by quasipalindrome-directed mutagenesis, appeared to depend on the
      directionality of the replication fork. These mutations are also resistant to
      post-replicative mismatch correction. Here, we show that the level of
      transcription of the rpsL gene strongly affects spontaneous mutagenesis at two
      mutational hotspot sites in the target sequence, one for a T-->G base
      substitution and the other for a+1 single-base frameshift. Mutation frequencies
      at the hotspot sites were below a detectable level when the transcription of the
      target sequence was tightly suppressed, but were dramatically increased when the
      target sequence was highly transcribed. Both of the hotspot mutations were also
      dependent on the directionality of the replication fork and were caused by
      quasipalindrome-directed mutagenesis. The frequencies of the hotspot mutations
      were unchanged in a mismatch-repair deficient strain, indicating that the hotspot
      mutations are resistant to the mismatch correction. Based on these findings, we
      propose a novel mutagenic process for these hotspot mutations that depends on
      transcription and involves template-switching mechanisms induced by spontaneous
      DNA lesions.

PMID- 12614605
TI  - Mutagenesis of cysteine 280 of the reverse transcriptase of human
      immunodeficiency virus type-1: the effects on the ribonuclease H activity.
AB  - Retroviral reverse transcriptases (RTs) have both DNA polymerase and ribonuclease
      H (RNase H) activities. The RT of human immunodeficiency virus type-1 (HIV-1) is
      composed of two subunits. The p51, which is the smaller subunit, shares with the
      larger p66 subunit the same amino-terminal part (which encompasses the DNA
      polymerase domain) and lacks the carboxyl-terminal segment of the p66 (which is
      the RNase H domain). The structure of the polymerase domain of HIV-1 RT resembles
      a right hand (with fingers, palm and thumb subdomains) linked to the RNase H
      domain. Chemical modifications by thiol-specific reagents of cysteine 280,
      located in alpha helix I in the thumb subdomain of the polymerase domain, affect
      substantially only the RNase H activity. Also, the substitution of a serine for
      C280 did not alter any of the RT activities. Here we have systematically modified
      the C280 residue to either of the following residues: W, P, H, L, M, Y, Q, E or
      R. Only the first two mutations lead to a marked reduction in the RNase H
      activity, whereas none of the mutations affected the polymerase function to a
      significant extent. As expected, due to their impaired RNase H, the C280W and
      C280P mutants also had a very low DNA strand-transfer activity. It is also
      apparent from subunit-directed mutagenesis that each of the RT subunits
      contributes to the level of RNase H activity, yet the contribution of the p51
      subunit to this activity is somewhat higher than that of the p66. Steady-state
      kinetic analyses have indicated that the RNase H activity was reduced mainly due
      to the sharp increase in the K(m) rather than changes in the k(cat) values. This
      suggests that the modifications of C280 lead to an impaired affinity of HIV-1 RT
      towards the RNA-DNA substrate.

PMID- 12614606
TI  - Allosteric regulation of the transcription factor NFAT1 by multiple
      phosphorylation sites: a mathematical analysis.
AB  - NFAT transcription factors are activated through dephosphorylation by the
      phosphatase calcineurin. Experimental data show that 13 conserved phosphorylation
      sites conspire to control the transition between an inactive and an active
      conformation. We propose a quantitative model of the underlying molecular
      mechanisms that may generally apply to highly phosphorylated proteins.
      Mathematical analysis shows that multiple phosphorylation sites result in a
      threshold for protein activation. Its sharpness increases with the number of
      sites, thus providing a rationale for the involvement of the large number of
      serine residues in NFAT activation. The model predicts that nuclear kinases exert
      a larger control on the activation threshold than cytoplasmic kinases, and that
      the NFAT activation kinetics can discriminate between input signals of different
      amplitude.

PMID- 12614607
TI  - Structure-function analysis of enoyl thioester reductase involved in
      mitochondrial maintenance.
AB  - Candida tropicalis enoyl thioester reductase Etr1p and the Saccharomyces
      cerevisiae homologue Mrf1p catalyse the NADPH-dependent reduction of trans-2
      enoyl thioesters in mitochondrial fatty acid synthesis (FAS). Unlike prokaryotic
      enoyl thioester reductases (ETRs), which belong to the short-chain
      dehydrogenases/reductases (SDR), Etr1p and Mrf1p represent structurally
      distinguishable ETRs that belong to the medium-chain dehydrogenases/reductases
      (MDR) superfamily, indicating independent origin of two separate classes of ETRs.
      The crystal structures of Etr1p, the Etr1p-NADPH complex and the Etr1Y79Np mutant
      were refined to 1.70A, 2.25A and 2.60A resolution, respectively. The native fold
      of Etr1p was maintained in Etr1Y79Np, but the mutant had only 0.1% of Etr1p
      catalytic activity remaining and failed to rescue the respiratory deficient
      phenotype of the mrf1Delta strain. Mutagenesis of Tyr73 in Mrf1p, corresponding
      to Tyr79 in Etr1p, produced similar results. Our data indicate that the
      mitochondrial reductase activity is indispensable for respiratory function in
      yeast, emphasizing the significance of Mrf1p (Etr1p) and mitochondrial FAS for
      the integrity of the respiratory competent organelle.

PMID- 12614608
TI  - Crystal structure and evolution of a prokaryotic glucoamylase.
AB  - The first crystal structures of a two-domain, prokaryotic glucoamylase were
      determined to high resolution from the clostridial species Thermoanaerobacterium
      thermosaccharolyticum with and without acarbose. The N-terminal domain has 18
      antiparallel strands arranged in beta-sheets of a super-beta-sandwich. The C
      terminal domain is an (alpha/alpha)(6) barrel, lacking the peripheral subdomain
      of eukaryotic glucoamylases. Interdomain contacts are common to all prokaryotic
      Family GH15 proteins. Domains similar to those of prokaryotic glucoamylases in
      maltose phosphorylases (Family GH65) and glycoaminoglycan lyases (Family PL8)
      suggest evolution from a common ancestor. Eukaryotic glucoamylases may have
      evolved from prokaryotic glucoamylases by the substitution of the N-terminal
      domain with the peripheral subdomain and by the addition of a starch-binding
      domain.

PMID- 12614609
TI  - Investigations on the maturation and regulation of archaebacterial proteasomes.
AB  - The 20S proteasome (core particle, CP) is a multifunctional protease complex and
      composed of four heptameric subunit rings arranged in a hollow, barrel-shaped
      structure. Here, we report the crystal structure of the CP from Archaeoglobus
      fulgidus at 2.25A resolution. The analysis of the structure of early and late
      assembly intermediates of this CP gives new insights in the maturation of
      archaebacterial CPs and indicates similarities to assembly intermediates observed
      in eukaryotes. We also show a striking difference in mechanism and regulation of
      substrate access between eukaryotic and archaebacterial 20S proteasomes. While
      eukaryotic CPs are auto-inhibited by the N-terminal tails of the outer alpha-ring
      by imposing topological closure with a characteristic sequence motif (YDR-motif)
      and show regulatory gating this segment is disordered in the CP and differently
      structured in the alpha(7)-sub-complex of A.fulgidus leaving a pore leading into
      the particle with a diameter of 13A. Mutagenesis and functional studies indicate
      the absence of regulatory gating in the archaeal 20S proteasome.

PMID- 12614610
TI  - Chromatin fiber folding: requirement for the histone H4 N-terminal tail.
AB  - We have developed a self-assembly system for nucleosome arrays in which
      recombinant, post-translationally unmodified histone proteins are combined with
      DNA of defined-sequence to form chromatin higher-order structure. The nucleosome
      arrays obtained are highly homogeneous and sediment at 53S when maximally folded
      in 1mM or 100mM MgCl(2). The folding properties are comparable to established
      systems. Analytical ultracentrifugation is used to determine the consequence of
      individual histone tail domain deletions on array folding. Fully compacted
      chromatin fibers are obtained with any one of the histone tails deleted with the
      exception of the H4 N terminus. The region of the H4 tail, which mediates
      compaction, resides in the stretch of amino acids 14-19.

PMID- 12614611
TI  - Conformational and hydration effects of site-selective sodium, calcium and
      strontium ion binding to the DNA Holliday junction structure d(TCGGTACCGA)(4).
AB  - The role of metal ions in determining the solution conformation of the Holliday
      junction is well established, but to date the picture of metal ion binding from
      structural studies of the four-way DNA junction is very incomplete. Here we
      present two refined structures of the Holliday junction formed by the sequence
      d(TCGGTACCGA) in the presence of Na(+) and Ca(2+), and separately with Sr(2+) to
      resolutions of 1.85A and 1.65A, respectively. This sequence includes the ACC core
      found to promote spontaneous junction formation, but its structure has not
      previously been reported. Almost complete hydration spheres can be defined for
      each metal cation. The Na(+) sites, the most convincing observation of such sites
      in junctions to date, are one on either face of the junction crossover region,
      and stabilise the ordered hydration inside the junction arms. The four Ca(2+)
      sites in the same structure are at the CG/CG steps in the minor groove. The
      Sr(2+) ions occupy the TC/AG, GG/CC, and TA/TA sites in the minor groove, giving
      ten positions forming two spines of ions, spiralling through the minor grooves
      within each arm of the stacked-X structure. The two structures were solved in the
      two different C2 lattices previously observed, with the Sr(2+) derivative
      crystallising in the more highly symmetrical form with two-fold symmetry at its
      centre. Both structures show an opening of the minor groove face of the junction
      of 8.4 degrees in the Ca(2+) and Na(+) containing structure, and 13.4 degrees in
      the Sr(2+) containing structure. The crossover angles at the junction are 39.3
      degrees and 43.3 degrees, respectively. In addition to this, a relative shift in
      the base pair stack alignment of the arms of 2.3A is observed for the Sr(2+)
      containing structure only. Overall these results provide an insight into the so
      far elusive stabilising ion structure for the DNA Holliday junction.

PMID- 12614612
TI  - Interaction and assembly of murine pre-replicative complex proteins in yeast and
      mouse cells.
AB  - Eukaryotic cells coordinate chromosome duplication by the assembly of protein
      complexes at origins of DNA replication by sequential binding of member proteins
      of the origin recognition complex (ORC), CDC6, and minichromosome maintenance
      (MCM) proteins. These pre-replicative complexes (pre-RCs) are activated by cyclin
      dependent kinases and DBF4/CDC7 kinase. Here, we carried out a comprehensive
      yeast two-hybrid screen to establish sequential interactions between two
      individual proteins of the mouse pre-RC that are probably required for the
      initiation of DNA replication. The studies revealed multiple interactions among
      ORC subunits and MCM proteins as well as interactions between individual ORC and
      MCM proteins. In particular CDC6 was found to bind strongly to ORC1 and ORC2, and
      to MCM7 proteins. DBF4 interacts with the subunits of ORC as well as with MCM
      proteins. It was also demonstrated that CDC7 binds to different ORC and MCM
      proteins. CDC45 interacts with ORC1 and ORC6, and weakly with MCM3, -6, and -7.
      The three subunits of the single-stranded DNA binding protein RPA show
      interactions with various ORC subunits as well as with several MCM proteins. The
      data obtained by yeast two-hybrid analysis were paradigmatically confirmed in
      synchronized murine FM3A cells by immunoprecipitation of the interacting
      partners. Some of the interactions were found to be cell-cycle-dependent;
      however, most of them were cell-cycle-independent. Altogether, 90 protein-protein
      interactions were detected in this study, 52 of them were found for the first
      time in any eukaryotic pre-RC. These data may help to understand the complex
      interplay of the components of the mouse pre-RC and should allow us to refine its
      structural architecture as well as its assembly in real time.

PMID- 12614613
TI  - Ligand-induced conformational changes and a mechanism for domain closure in
      Aspergillus nidulans dehydroquinate synthase.
AB  - In order to investigate systematically substrate and cofactor-induced
      conformational changes in the enzyme dehydroquinate synthase (DHQS), eight
      structures representing a series of differently liganded states have been
      determined in a total of six crystal forms. DHQS in the absence of the substrate
      analogue carbaphosphonate, either unliganded or in the presence of NAD or ADP, is
      in an open form where a relative rotation of 11-13 degrees between N and C
      terminal domains occurs. Analysis of torsion angle difference plots between sets
      of structures reveals eight rearrangements that appear relevant to domain closure
      and a further six related to crystal packing. Overlapping 21 different copies of
      the individual N and C-terminal DHQS domains further reveals a series of pivot
      points about which these movements occur and illustrates the way in which widely
      separated secondary structure elements are mechanically inter-linked to form
      "composite elements", which propagate structural changes across large distances.
      This analysis has provided insight into the basis of DHQS ligand-initiated domain
      closure and gives rise to the proposal of an ordered sequence of events involving
      substrate binding, and local rearrangements within the active site that are
      propagated to the hinge regions, leading to closure of the active-site cleft.

PMID- 12614614
TI  - Ca2+ causes release of myosin heads from the thick filament surface on the
      milliseconds time scale.
AB  - We have used electron microscopy to study the structural changes induced when
      myosin filaments are activated by Ca2+. Negative staining reveals that when Ca2+
      binds to the heads of relaxed Ca2+ -regulated myosin filaments, the helically
      ordered myosin heads become disordered and project further from the filament
      surface. Cryo-electron microscopy of unstained, frozen-hydrated specimens
      supports this finding, and shows that disordering is reversible on removal of
      Ca2+. The structural change is thus a result of Ca2+ binding alone and not an
      artifact of staining. Comparison of the two techniques suggests that negative
      staining preserves the structure induced by Ca2+ -binding. We therefore used a
      time-resolved negative staining technique to determine the time scale of the
      structural change. Full disordering was observed within 30 ms of Ca2+ addition,
      and had started to occur within 10 ms, showing that the change occurs on the
      physiological time scale. Comparison with studies of single heavy meromyosin
      molecules suggests that an increased mobility of myosin heads induced by Ca2+
      binding underlies the changes in filament structure that we observe. We conclude
      that the loosening of the array of myosin heads that occurs on activation is real
      and physiological; it may function to make activated myosin heads freer to
      contact actin filaments during muscle contraction.

PMID- 12614615
TI  - Dynamic features of cAMP-dependent protein kinase revealed by apoenzyme crystal
      structure.
AB  - To better understand the mechanism of ligand binding and ligand-induced
      conformational change, the crystal structure of apoenzyme catalytic (C) subunit
      of adenosine-3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) was
      solved. The apoenzyme structure (Apo) provides a snapshot of the enzyme in the
      first step of the catalytic cycle, and in this unliganded form the PKA C subunit
      adopts an open conformation. A hydrophobic junction is formed by residues from
      the small and large lobes that come into close contact. This "greasy" patch may
      lubricate the shearing motion associated with domain rotation, and the opening
      and closing of the active-site cleft. Although Apo appears to be quite dynamic,
      many important residues for MgATP binding and phosphoryl transfer in the active
      site are preformed. Residues around the adenine ring of ATP and residues involved
      in phosphoryl transfer from the large lobe are mostly preformed, whereas residues
      involved in ribose binding and in the Gly-rich loop are not. Prior to ligand
      binding, Lys72 and the C-terminal tail, two important ATP-binding elements are
      also disordered. The surface created in the active site is contoured to bind ATP,
      but not GTP, and appears to be held in place by a stable hydrophobic core, which
      includes helices C, E, and F, and beta strand 6. This core seems to provide a
      network for communicating from the active site, where nucleotide binds, to the
      peripheral peptide-binding F-to-G helix loop, exemplified by Phe239. Two
      potential lines of communication are the D helix and the F helix. The conserved
      Trp222-Phe238 network, which lies adjacent to the F-to-G helix loop, suggests
      that this network would exist in other protein kinases and may be a conserved
      means of communicating ATP binding from the active site to the distal peptide
      binding ledge.

PMID- 12614617
TI  - Equilibrium and kinetics of the allosteric transition of GroEL studied by
      solution X-ray scattering and fluorescence spectroscopy.
AB  - We have studied the ATP-induced allosteric structural transition of GroEL using
      small angle X-ray scattering and fluorescence spectroscopy in combination with a
      stopped-flow technique. With X-ray scattering one can clearly distinguish the
      three allosteric states of GroEL, and the kinetics of the transition of GroEL
      induced by 85 microM ATP have been observed directly by stopped-flow X-ray
      scattering for the first time. The rate constant has been found to be 3-5s(-1) at
      5 degrees C, indicating that this process corresponds to the second phase of the
      ATP-induced kinetics of tryptophan-inserted GroEL measured by stopped-flow
      fluorescence. Based on the ATP concentration dependence of the fluorescence
      kinetics, we conclude that the first phase represents bimolecular non-cooperative
      binding of ATP to GroEL with a bimolecular rate constant of 5.8 x 10(5)M(-1)s(-1)
      at 25 degrees C. Considering the electrostatic repulsion between negatively
      charged GroEL (-18 of the net charge per monomer at pH 7.5) and ATP, the rate
      constant is consistent with a diffusion-controlled bimolecular process. The ATP
      induced fluorescence kinetics (the first and second phases) at various ATP
      concentrations (< 400 microM) occur before ATP hydrolysis by GroEL takes place
      and are well explained by a kinetic allosteric model, which is a combination of
      the conventional transition state theory and the Monod-Wyman-Changeux model, and
      we have successfully evaluated the equilibrium and kinetic parameters of the
      allosteric transition, including the binding constant of ATP in the transition
      state of GroEL.

PMID- 12614616
TI  - Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease
      from Plasmodium falciparum.
AB  - Malaria remains a human disease of global significance and a major cause of high
      infant mortality in endemic nations. Parasites of the genus Plasmodium cause the
      disease by degrading human hemoglobin as a source of amino acids for their growth
      and maturation. Hemoglobin degradation is initiated by aspartic proteases, termed
      plasmepsins, with a cleavage at the alpha-chain between residues Phe33 and Leu34.
      Plasmepsin II is one of the four catalytically active plasmepsins that has been
      identified in the food vacuole of Plasmodium falciparum. Novel crystal structures
      of uncomplexed plasmepsin II as well as the complex with a potent inhibitor have
      been refined with data extending to resolution limits of 1.9A and 2.7A, and to R
      factors of 17% and 18%, respectively. The inhibitor, N-(3-[(2-benzo[1,3]dioxol-5
      yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl)-propionyl]-amino]-1-benzyl
      2-(hydroxypropyl)-4-benzyloxy-3,5-dimethoxy-benzamide, belongs to a family of
      potent non-peptidic inhibitors that have large P1' groups. Such inhibitors could
      not be modeled into the binding cavity of the structure of plasmepsin II in
      complex with pepstatin A. Our structures reveal that the binding cavities of the
      new complex and uncomplexed plasmepsin II are considerably more open than that of
      the pepstatin A complex, allowing for larger heterocyclic groups in the P1', P2'
      and P2 positions. Both complexed and uncomplexed plasmepsin II crystallized in
      space group P2, with one monomer in the asymmetric unit. The structures show
      extensive interlocking of monomers around the crystallographic axis of symmetry,
      with areas in excess of 2300A(2) buried at the interface, and a loop of one
      monomer interacting with the binding cavity of the 2-fold related monomer.
      Electron density for this loop is only fully ordered in the complexed structure.

PMID- 12614618
TI  - Crystal structure of the plant PPC decarboxylase AtHAL3a complexed with an ene
      thiol reaction intermediate.
AB  - The Arabidopsis thaliana protein AtHAL3a decarboxylates 4'
      phosphopantothenoylcysteine to 4'-phosphopantetheine, a step in coenzyme A
      biosynthesis. Surprisingly, this decarboxylation reaction is carried out as an
      FMN-dependent redox reaction. In the first half-reaction, the side-chain of the
      cysteine residue of 4'-phosphopantothenoylcysteine is oxidised and the
      thioaldehyde intermediate decarboxylates spontaneously to the 4'
      phosphopantothenoyl-aminoethenethiol intermediate. In the second half-reaction
      this compound is reduced to 4'-phosphopantetheine and the FMNH(2) cofactor is re
      oxidised. The active site mutant C175S is unable to perform this reductive half
      reaction. Here, we present the crystal structure of the AtHAL3a mutant C175S in
      complex with the reaction intermediate pantothenoyl-aminoethenethiol and FMNH(2).
      The geometry of binding suggests that reduction of the C(alpha)=C(beta) double
      bond of the intermediate can be performed by direct hydride-transfer from N5 of
      FMNH(2) to C(beta) of the aminoethenethiol-moiety supported by a protonation of
      C(alpha) by Cys175. The binding mode of the substrate is very similar to that
      previously observed for a pentapeptide to the homologous enzyme EpiD that
      introduces the aminoethenethiol-moiety as final reaction product at the C
      terminus of peptidyl-cysteine residues. This finding further supports our view
      that these homologous enzymes form a protein family of homo-oligomeric flavin
      containing cysteine decarboxylases, which we have termed HFCD family.

PMID- 12614619
TI  - Supramodular structure and synergistic target binding of the N-terminal tandem
      PDZ domains of PSD-95.
AB  - PDZ domain proteins play critical roles in binding, clustering and subcellular
      targeting of membrane receptors and ion channels. PDZ domains in multi-PDZ
      proteins often are arranged in groups with highly conserved spacing and
      intervening sequences; however, the functional significance of such tandem
      arrangements of PDZs is unclear. We have solved the three-dimensional structure
      of the first two PDZ domains of postsynaptic density protein-95 (PSD-95 PDZ1 and
      PDZ2), which are closely linked to each other in the PSD-95 family of scaffold
      proteins. The two PDZs have limited freedom of rotation and their C-terminal
      peptide-binding grooves are aligned with each other with an orientation
      preference for binding to pairs of C termini extending in the same direction.
      Increasing the spacing between PDZ1 and PDZ2 resulted in decreased binding
      between PDZ12 and its dimeric targets. The same mutation impaired the functional
      ability of PSD-95 to cluster Kv1.4 potassium channels in heterologous cells. The
      data presented provide a molecular basis for preferential binding of PSD-95 to
      multimeric membrane proteins with appropriate C-terminal sequences.

PMID- 12614620
TI  - NMR structure of the HIV-1 regulatory protein VPR.
AB  - The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved
      regulatory gene product, Vpr (96 residues, 14kDa), which is incorporated into
      virions. In the infected cells, Vpr, expressed late in the virus cycle, is
      believed to function in the early phases of HIV-1 replication, such as nuclear
      migration of pre-integration complex, transcription of the proviral genome, viral
      multiplication by blocking cells in G2 phase and regulation of apoptosis
      phenomenon. Vpr has a critical role in long term AIDS disease by inducing
      infection in non-dividing cells such as monocytes and macrophages. To gain
      insight into the structure-function relationships of Vpr, the (1-96)Vpr protein
      was synthesized with 22 labeled amino acids. Its 3D structure was analyzed in the
      presence of CD(3)CN and in pure water at low pH and refined by restrained
      simulated annealing. The structure of the protein is characterized by three well
      defined alpha-helices: 17-33, 38-50 and 56-77 surrounded by flexible N and C
      terminal domains. In contrast to the structure obtained in the presence of TFE,
      the three alpha-helices are folded around a hydrophobic core constituted of Leu,
      Ile, Val and aromatic residues as illustrated by numerous long range NOEs. This
      structure accounts for the interaction of Vpr with different targets.

PMID- 12614621
TI  - Flexibility of alpha-helices: results of a statistical analysis of database
      protein structures.
AB  - Alpha-helices stand out as common and relatively invariant secondary structural
      elements of proteins. However, alpha-helices are not rigid bodies and their
      deformations can be significant in protein function (e.g. coiled coils). To
      quantify the flexibility of alpha-helices we have performed a structural
      principal-component analysis of helices of different lengths from a
      representative set of protein folds in the Protein Data Bank. We find three
      dominant modes of flexibility: two degenerate bend modes and one twist mode. The
      data are consistent with independent Gaussian distributions for each mode. The
      mode eigenvalues, which measure flexibility, follow simple scaling forms as a
      function of helix length. The dominant bend and twist modes and their harmonics
      are reproduced by a simple spring model, which incorporates hydrogen-bonding and
      excluded volume. As an application, we examine the amount of bend and twist in
      helices making up all coiled-coil proteins in SCOP. Incorporation of alpha-helix
      flexibility into structure refinement and design is discussed.

PMID- 12614622
TI  - FRET-based in vivo screening for protein folding and increased protein stability.
AB  - Fluorescence resonance energy transfer (FRET) was used to establish a novel in
      vivo screening system that allows rapid detection of protein folding and protein
      variants with increased thermodynamic stability in the cytoplasm of Escherichia
      coli. The system is based on the simultaneous fusion of the green fluorescent
      protein (GFP) to the C terminus of a protein X of interest, and of blue
      fluorescent protein (BFP) to the N terminus of protein X. Efficient FRET from BFP
      to GFP in the ternary fusion protein is observed in vivo only when protein X is
      folded and brings BFP and GFP into close proximity, while FRET is lost when BFP
      and GFP are far apart due to unfolding or intracellular degradation of protein X.
      The screening system was validated by identification of antibody V(L)
      intradomains with increased thermodynamic stabilities from expression libraries
      after random mutagenesis, bacterial cell sorting, and colony screening.

PMID- 12614623
TI  - Higher-order interhelical spatial interactions in membrane proteins.
AB  - Higher-order interactions are important for protein folding and assembly. We
      introduce the concept of interhelical three-body interactions as derived from
      Delaunay triangulation and alpha shapes of protein structures. In addition to
      glycophorin A, where triplets are strongly correlated with protein stability, we
      found that tight interhelical triplet interactions exist extensively in other
      membrane proteins, where many types of triplets occur far more frequently than in
      soluble proteins. We developed a probabilistic model for estimating the value of
      membrane helical interaction triplet (MHIT) propensity. Because the number of
      known structures of membrane proteins is limited, we developed a bootstrap method
      for determining the 95% confidence intervals of estimated MHIT values. We
      identified triplets that have high propensity for interhelical interactions and
      are unique to membrane proteins, e.g. AGF, AGG, GLL, GFF and others. A
      significant fraction (32%) of triplet types contains triplets that may be
      involved in interhelical hydrogen bond interactions, suggesting the prevalent and
      important roles of H-bond in the assembly of TM helices. There are several well
      defined spatial conformations for triplet interactions on helices with similar
      parallel or antiparallel orientations and with similar right-handed or left
      handed crossing angles. Often, they contain small residues and correspond to the
      regions of the closest contact between helices. Sequence motifs such as GG4 and
      AG4 can be part of the three-body interactions that have similar conformations,
      which in turn can be part of a higher-order cooperative four residue spatial
      motif observed in helical pairs from different proteins. In many cases, spatial
      motifs such as serine zipper and polar clamp are part of triplet interactions. On
      the basis of the analysis of the archaeal rhodopsin family of proteins, tightly
      packed triplet interactions can be achieved with several different choices of
      amino acid residues.

PMID- 12614624
TI  - Exploiting the co-evolution of interacting proteins to discover interaction
      specificity.
AB  - Protein interactions are fundamental to the functioning of cells, and high
      throughput experimental and computational strategies are sought to map
      interactions. Predicting interaction specificity, such as matching members of a
      ligand family to specific members of a receptor family, is largely an unsolved
      problem. Here we show that by using evolutionary relationships within such
      families, it is possible to predict their physical interaction specificities. We
      introduce the computational method of matrix alignment for finding the optimal
      alignment between protein family similarity matrices. A second method, 3D
      embedding, allows visualization of interacting partners via spatial
      representation of the protein families. These methods essentially align
      phylogenetic trees of interacting protein families to define specific interaction
      partners. Prediction accuracy depends strongly on phylogenetic tree complexity,
      as measured with information theoretic methods. These results, along with
      simulations of protein evolution, suggest a model for the evolution of
      interacting protein families in which interaction partners are duplicated in
      coupled processes. Using these methods, it is possible to successfully find
      protein interaction specificities, as demonstrated for >18 protein families.

PMID- 12614625
TI  - Design and characterization of a hyperstable p16INK4a that restores Cdk4 binding
      activity when combined with oncogenic mutations.
AB  - Cyclin-dependent kinase inhibitor p16(INK4a) is the founding member of the INK4
      family of tumor suppressors capable of arresting mammalian cell division.
      Missense mutations in the p16(INK4a) gene (INK4a/CDKN2A/MTS1) are strongly linked
      to several types of human cancer. These mutations are evenly distributed
      throughout this small, ankyrin repeat protein and the majority of them disrupt
      the native secondary and/or tertiary structure, leading to protein unfolding,
      aggregation and loss of function. We report here the use of multiple stabilizing
      substitutions to increase the stability of p16(INK4a) and furthermore, to restore
      Cdk4 binding activity of several defective, cancer-related mutant proteins.
      Stabilizing substitutions were predicted using four different techniques. The
      three most effective substitutions were combined to create a hyperstable
      p16(INK4a) variant that is 1.4 kcal/mol more stable than wild-type. This
      engineered construct is monomeric in solution with wild-type-like secondary and
      tertiary structure and cyclin-dependent kinase 4 binding activity. Interestingly,
      these hyperstable substitutions, when combined with oncogenic mutations R24P,
      P81L or V126D, can significantly restore Cdk4 binding activity, despite the
      divergent features of each destabilizing mutation. Extensive biophysical studies
      indicate that the hyperstable substitutions enhance the binding activity of
      mutant p16 through several different mechanisms, including an increased amount of
      secondary structure and thermostability, reduction in exposed hydrophobic
      surface(s) and/or a reduced tendency to aggregate. This apparent global
      suppressor effect suggests that increasing the thermodynamic stability of p16 can
      be used as a general strategy to restore the biological activity to defective
      mutants of this important tumor suppressor protein.

PMID- 12614627
TI  - The concept of allostasis in biology and biomedicine.
AB  - Living organisms have regular patterns and routines that involve obtaining food
      and carrying out life history stages such as breeding, migrating, molting, and
      hibernating. The acquisition, utilization, and storage of energy reserves (and
      other resources) are critical to lifetime reproductive success. There are also
      responses to predictable changes, e.g., seasonal, and unpredictable challenges,
      i.e., storms and natural disasters. Social organization in many populations
      provides advantages through cooperation in providing basic necessities and
      beneficial social support. But there are disadvantages owing to conflict in
      social hierarchies and competition for resources. Here we discuss the concept of
      allostasis, maintaining stability through change, as a fundamental process
      through which organisms actively adjust to both predictable and unpredictable
      events. Allostatic load refers to the cumulative cost to the body of allostasis,
      with allostatic overload being a state in which serious pathophysiology can
      occur. Using the balance between energy input and expenditure as the basis for
      applying the concept of allostasis, we propose two types of allostatic overload.
      Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in
      activation of the emergency life history stage. This serves to direct the animal
      away from normal life history stages into a survival mode that decreases
      allostatic load and regains positive energy balance. The normal life cycle can be
      resumed when the perturbation passes. Type 2 allostatic overload begins when
      there is sufficient or even excess energy consumption accompanied by social
      conflict and other types of social dysfunction. The latter is the case in human
      society and certain situations affecting animals in captivity. In all cases,
      secretion of glucocorticosteroids and activity of other mediators of allostasis
      such as the autonomic nervous system, CNS neurotransmitters, and inflammatory
      cytokines wax and wane with allostatic load. If allostatic load is chronically
      high, then pathologies develop. Type 2 allostatic overload does not trigger an
      escape response, and can only be counteracted through learning and changes in the
      social structure.

PMID- 12614628
TI  - How useful is energy balance as a overall index of stress in animals?

PMID- 12614629
TI  - Stress by any other name .....?

PMID- 12614630
TI  - Allostasis: a neural behavioral perspective.

PMID- 12614632
TI  - A model for social control of sex change: interactions of behavior,
      neuropeptides, glucocorticoids, and sex steroids.
AB  - The optimal regulation of vertebrate sexual development and reproductive function
      involves integration of internal physiological signals, indicative of an
      individual's sexual status and capability for reproduction, with signals from the
      external environment. While these environmental cues are diverse, and oftentimes
      species-specific, the induction of sexual readiness is typically carried out
      through the same basic components of the hypothalamic-pituitary-gonadal axis
      conserved among vertebrates. Therefore, species exhibiting diverse patterns of
      reproduction can contribute to the understanding of the general mechanisms
      underlying the expression of adult sexual phenotypes. The bluehead wrasse,
      Thalassoma bifasciatum, is a tropical coral reef fish that displays social
      control of sex change, whereby dominant males inhibit sex change in other members
      of the social group using aggressive interactions. In many fish species and
      vertebrates in general, individuals that lose these interactions often experience
      increased serum glucocorticoids, which can have a subsequent impact on their
      physiology and behavior. We discuss glucocorticoid regulation of both
      neuropeptide gene transcription and the major steroid biosynthetic pathways as
      potential mechanisms involved in the regulation of sex change in the bluehead
      wrasse. We present a model describing behavioral regulation of sex change in the
      bluehead wrasse and then describe the potential mechanistic roles of
      glucocorticoids, gonadal steroids, and neuropeptides in generating the changes
      predicted by the model. Through the use of alternative model systems it is
      possible to observe novel interactions among the neuroendocrine axes that
      regulate major life history events, like reproduction. These insights may then
      shed light on similar functional mechanisms underlying behavioral regulation of
      reproduction in all vertebrates.

PMID- 12614633
TI  - Stress, reproduction, and adrenocortical modulation in amphibians and reptiles.
AB  - While the hypothalamo-pituitary-adrenocortical (HPA) response to stress appears
      to be conserved in vertebrates, the manner in which it is activated and its
      actions vary. We examine two trends in the stress biology literature that have
      been addressed in amphibian and reptilian species: (1). variable interactions
      among stress, corticosterone, and reproduction and (2). adrenocortical
      modulation. In the first topic we examine context-dependent interactions among
      stress, corticosterone, and reproduction. An increasing number of studies report
      positive associations between reproduction and corticosterone that contradict the
      generalization that stress inhibits reproduction. Moderately elevated levels of
      stress hormones appear to facilitate reproduction by mobilizing energy stores. In
      contrast, pronounced activation of the HPA axis and extremely elevated levels of
      stress hormones appear to inhibit reproduction. Much of these contrasting effects
      of stress and reproduction can be explained by expanding the Energetics-Hormone
      Vocalization Model, proposed for anuran calling behavior, to other taxa. In the
      second topic, a number of amphibians and reptiles modulate their HPA stress
      response. Adrenocortical modulation can occur at multiple levels and due to a
      variety of factors. However, we have little information as to the physiological
      basis for the variability. We suggest that several ecologically based ideas, such
      as variability in the length of the breeding season and lifetime reproductive
      opportunities, can be used to explain the utility of adrenocortical modulation in
      these taxa.

PMID- 12614634
TI  - Chronic stress effects on memory: sex differences in performance and
      monoaminergic activity.
AB  - Increasing evidence suggests that the time course of advantageous versus
      deleterious effects of stress on physiologic function is also apparent in some
      brain functions, including learning and memory. This article reviews the effects
      of chronic stress on behavioral performance and, more importantly, shows that sex
      of the subject, as well as duration and intensity of stress, is an important
      determinant of the functional/behavioral, neurochemical, and anatomical
      consequences of the stress. Following chronic stress (7-28 days of restraint, 6
      h/day), male and female rats were tested on a visual memory task (object
      recognition) and two spatial memory tasks (object placement and radial arm maze).
      At 21 days, stress impaired males on all tasks while females were either enhanced
      (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally,
      the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the
      sex-specific responses to stress is considered. Behavioral and neurochemical
      assessments following chronic stress in ovariectomized females, with and without
      estradiol, suggest that estrogen exerts both organizational and activational
      influences on the observed sex differences in response to stress. Furthermore,
      stress differentially affected central transmitter levels in the frontal cortex,
      hippocampus, and amygdala depending on sex. The possible role of these sex
      specific changes in neurotransmitter levels in mediating behavioral differences
      in response to stress is discussed. While these results are thus far limited to a
      few studies and require both further investigation and verification, chronic
      stress appears to be associated with distinct, sex-differentiated
      behavioral/cognitive and neurochemical responses. We conclude that sex
      differences must be taken into account when investigating or describing stress
      and associated sequalae.

PMID- 12614635
TI  - Neuroendocrine aspects of hypercortisolism in major depression.
AB  - A consistent finding in biological psychiatry is that hypothalamic-pituitary
      adrenal (HPA) axis physiology is altered in humans with major depression. These
      findings include hypersecretion of cortisol at baseline and on the dexamethasone
      suppression test. In this review, we present a process-oriented model for HPA
      axis regulation in major depression. Specifically, we suggest that acute
      depressions are characterized by hypersecretion of hypothalamic corticotropin
      releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal
      cortisol. In chronic depressions, however, enhanced adrenal responsiveness to
      ACTH and glucocorticoid negative feedback work in complementary fashion so that
      cortisol levels remain elevated while ACTH levels are reduced. In considering the
      evidence for hypercortisolism in humans, studies of nonhuman primates are
      presented and their utility and limitations as comparative models of human
      depression are discussed.

PMID- 12614636
TI  - Are subordinates always stressed? A comparative analysis of rank differences in
      cortisol levels among primates.
AB  - Among primate species there is pronounced variation in the relationship between
      social status and measures of stress physiology. An informal meta-analysis was
      designed to investigate the basis of this diversity across different primate
      societies. Species were included only if a substantial amount of published
      information was available regarding both social behavior and rank-related
      differences in stress physiology. Four Old World and three New World species met
      these criteria, including societies varying from small-group, singular
      cooperative breeders (common marmoset and cotton top tamarin) to large-troop,
      multi-male, multi-female polygynous mating systems (rhesus, cynomolgus, talapoin,
      squirrel monkeys, and olive baboon). A questionnaire was formulated to obtain
      information necessary to characterize the stress milieu for individuals in
      particular primate societies. We standardized cortisol values within each species
      by calculating the ratio of basal cortisol concentrations of subordinates to
      those of dominants in stable dominance hierarchies and expressing the ratio as a
      percentage (relative cortisol levels). The meta-analysis identified two variables
      that significantly predicted relative cortisol levels: subordinates exhibited
      higher relative cortisol levels when they (1). were subjected to higher rates of
      stressors, and (2). experienced decreased opportunities for social (including
      close kin) support. These findings have important implications for understanding
      the different physiological consequences of dominant and subordinate social
      status across primate societies and how social rank may differ in its behavioral
      and physiological manifestations among primate societies.

PMID- 12614637
TI  - Environmental and endocrine correlates of tactic switching by nonterritorial male
      tree lizards (Urosaurus ornatus).
AB  - Animals often exhibit individual variation in their behavioral responses to the
      same stimuli in the biotic or abiotic environment. To elucidate the endocrine
      mechanisms mediating such behavioral variation, we have been studying a species
      of lizard with two distinct male phenotypes. Here we document behavioral
      variation across years in one of the two male phenotypes of the tree lizard,
      Urosaurus ornatus, and present hormone data that support an endocrine mechanism
      underlying this behavioral variation. Nonterritorial male tree lizards appear to
      be nomadic rovers in some years and sedentary satellites in others, whereas
      territorial males are always territorial. This behavioral variation by
      nonterritorial males was correlated with environmental conditions. In
      environmentally harsher years (as assessed by rainfall), nonterritorial males
      appear to behave as nomads, whereas in more benign years they are more site
      faithful. A between-year comparison of levels of corticosterone and testosterone
      for the two male phenotypes supports a model for how hormones underlie the males'
      reproductive tactics, particularly the nonterritorial males' behavioral
      plasticity. In an environmentally harsher (drier) year, both types of males had
      higher corticosterone levels than in a milder (wetter) year, but only
      nonterritorial males had lower testosterone in the relatively harsher year. We
      propose that disruptive selection for individual variation in hormonal responses
      to environmental cues may be a common mechanism underlying the evolution of
      alternative male reproductive tactics in this and other species.

PMID- 12614638
TI  - Rapid corticosterone-induced impairment of amplectic clasping occurs in the
      spinal cord of roughskin newts (taricha granulosa).
AB  - Courtship clasping, a reproductive behavior in male roughskin newts (Taricha
      granulosa), is rapidly blocked by an action of corticosterone (CORT) at a
      specific neuronal membrane receptor. The CORT-induced impairment of clasping in
      behaving newts appears to be mediated partly by an elimination of clasping
      related activity in medullary reticulospinal neurons. Previous studies of rapid
      CORT actions in Taricha have focused on the brain, so existence of CORT action in
      the spinal cord or peripheral nervous system has not been assessed. The present
      study used newts with a high cervical spinal transection to examine potential
      spinal or peripheral CORT effects on clasping by the hindlimbs in response to
      pressure on the cloaca. Spinal transection causes clasps elicited by cloacal
      stimulation to be very sustained beyond the termination of the eliciting
      stimulus. In spinally transected newts, CORT caused a dose-dependent depression
      in the duration as well as quality of the clasp that appeared within 10 min of
      injection. CORT selectively impaired the usual sustained maintenance of a clasp
      after termination of cloacal stimulation, but not clasp elicitation during
      stimulation. These effects were not produced by dexamethasone, a synthetic
      glucocorticoid that binds poorly to the CORT membrane receptor. The CORT effect
      on clasp maintenance but not clasp elicitation implies selective action on an
      intraspinal generator for clasping but not on sensory or efferent neuromuscular
      aspects of the response. These results indicate the presence in the newt spinal
      cord of the CORT membrane receptor that exerts functional effects distinctly
      different from those on the brainstem.

PMID- 12614639
TI  - Learning to fear and cope with a natural stressor: individually and socially
      acquired corticosterone and avoidance responses to biting flies.
AB  - Animals learn to recognize and respond to a variety of dangerous factors, with
      biting and blood-feeding flies being among the most prevalent of natural
      stressors. Here we describe the behavioral avoidance and hormonal
      (corticosterone) stress responses to biting fly exposure and the roles of
      individual and social learning in the acquisition of these fear-associated
      responses. Male mice exposed to a single 30-min session of attack by intact
      biting flies (stable fly, Stomoxys calcitrans L.) exhibited increased plasma
      corticosterone levels and active self-burying responses to avoid the flies. When
      exposed 24 h later to altered flies whose biting mouth parts were removed and
      were incapable of biting, the mice displayed conditioned increases in
      corticosterone and avoidance responses. This conditioned increase in
      corticosterone and self-burying was also acquired through social learning without
      direct individual experience with the intact biting flies. Fly naive "observer"
      mice that witnessed other "demonstrator" mice being attacked by biting flies, but
      were not exposed to intact flies themselves, displayed increases in
      corticosterone levels and self-burying to avoid flies when exposed 24 h later to
      altered flies. The social learning was not due to social facilitation or
      sensitization. Observers had to witness the self-burying avoidance responses of
      the demonstrator to the biting flies in order to subsequently recognize a
      potential threat to themselves and display the appropriate responses. These
      individually and socially acquired conditioned fear responses are likely part of
      the mechanisms that allow animals to defend themselves from biting and blood
      feeding arthropods.

PMID- 12614640
TI  - Behavioral and adrenocortical responses to mate separation and reunion in the
      zebra finch.
AB  - The adaptive value of social affiliation has been well established. It is
      unclear, however, what endogenous mechanisms may mediate affiliative behavior.
      The Australian zebra finch (Taeniopygia guttata) breeds colonially and adults
      maintain lifelong pair bonds that may be disrupted in the wild due to high
      mortality rates. Many of its natural, social behaviors are maintained in
      laboratory conditions, making this species well suited for studying the
      mechanisms of affiliation. This study examines the behavioral and neuroendocrine
      responses to pair mate separation and reunion in zebra finches. We measured
      plasma corticosterone (CORT) and behavioral changes following separation from a
      pair bonded mate, and again upon reintroducing the mate or an opposite-sex
      cagemate. Plasma CORT concentrations were: (1). elevated during pair mate
      separation, even in the presence of other same-sex individuals, and (2). reduced
      to baseline upon reunion with the pair mate but not upon re-pairing with a new
      opposite-sex partner. These findings show that zebra finches exhibit hormonal
      responses to separation and reunion specifically with a bonded pair mate and not
      with other familiar conspecifics. In addition, alterations in behavior during
      separation and reunion are consistent with monogamous pair bond maintenance. This
      study presents evidence for adrenocortical involvement in avian pair bonding, and
      for hypothalamic-pituitary-adrenal activation in response to an ecologically
      relevant social stressor.

PMID- 12614641
TI  - Integrating stress physiology, environmental change, and behavior in free-living
      sparrows.
AB  - As weather deteriorates, breeding animals have a diverse array of options to
      ensure survival. Because of their mobility, birds can easily abandon territories
      to seek out benign conditions away from the breeding site. The timing of
      abandonment, however, may have repercussions for territory size, mate quality,
      reproductive success, and survival. There is a large body of evidence indicating
      that the adrenocortical response to stress plays a role in mediating the onset
      and maintenance of this behavioral switch. Here we develop a model describing the
      interactions of weather, food availability, body condition, and stress physiology
      in initiating departure from the breeding site. We tested the model using a
      population of white-crowned sparrows breeding at high elevation in the Sierra
      Nevada, where severe weather at the beginning of the breeding season often
      induces temporary abandonment of breeding territories and facultative altitudinal
      migration to lower elevation refugia. The data show that (1). during inclement
      weather, exogenous corticosterone delays return to the breeding site after
      territory abandonment; (2). during good weather, exogenous corticosterone alone
      does not induce territory abandonment, but does increase activity range around
      the breeding site; and (3). the magnitude of the corticosteroid response to
      stress is inversely related to body condition of the sparrow.

PMID- 12614643
TI  - Social correlates of stress in adult males of the great gerbil, Rhombomys opimus,
      in years of high and low population densities.
AB  - The great gerbil, Rhombomys opimus, is the most social species in the
      Gerbillinae. The social structure consists of family groups that occupy isolated
      systems of burrows consisting of one breeding male, from one to seven females,
      and juveniles. During a year of peak density and one of density decline, we
      studied the influence of group size, group composition, local density, and
      distance to the nearest groups on fecal corticosterone and testosterone
      concentrations in breeding males. We also examined the relationship of hormone
      concentrations to the survival of males during the summer drought between the
      spring and the fall. We found that males differed in concentrations of steroid
      hormones. Concentrations of testosterone were lower whereas those of
      corticosterone tended to be higher in a year of high population densities
      compared with higher testosterone and lower corticosterone in a year with a lower
      density. This finding suggests that stress may be greater in higher densities
      because of increased social contact. Stepwise regression analysis revealed a
      positive and significant influence of the number of adult females in a family
      group on concentrations of fecal corticosterone and testosterone in adult males.
      Concentrations of corticosterone were also significantly higher in males that
      disappeared from family groups between the spring and the fall compared with
      males still alive in family groups in the fall. There was no change in
      concentrations of testosterone. These results suggest that social interactions
      within large family groups may be an important source of stress for adult males.

PMID- 12614642
TI  - Glucocorticoids are necessary for enhancing the acquisition of associative
      memories after acute stressful experience.
AB  - Exposure to acute stressful experience can enhance the later ability to acquire
      new memories about associations between stimuli. This enhanced learning is
      observed during classical eyeblink conditioning of both hippocampal-dependent and
      -independent learning. It can be induced within minutes of the stressful event
      and persists for days. Here we examined the role of the major stress hormones
      glucocorticoids in the enhancement of learning after stress. In the first two
      experiments, it was determined that adrenalectomy (ADX), with and without
      replacement of basal levels of corticosterone, prevented the stress-induced
      enhancement of trace conditioning, a task that is dependent on the hippocampus
      for acquisition. In a third experiment, demedullation, which removes the adrenal
      medulla but leaves the adrenal cortex and corticosterone levels intact, did not
      affect the enhancement of learning after stress. In a fourth experiment, ADX
      prevented the stress-induced enhancement of delay conditioning, a hippocampal
      independent task. In a final experiment, it was determined that one injection of
      stress levels of corticosterone enhanced new learning within minutes but not new
      learning 24 h later. Together these results suggest that endogenous
      glucocorticoids are necessary and sufficient for transiently enhancing
      acquisition of new associative memories and necessary but insufficient for
      persistently enhancing their acquisition after exposure to an acute stressful
      experience.

PMID- 12614644
TI  - Benefits and costs of increased levels of corticosterone in seabird chicks.
AB  - Seabird chicks respond to food shortages by increasing corticosterone (cort)
      secretion, which is probably associated with fitness benefits and costs. To
      examine this, we experimentally increased levels of circulating cort in captive
      black-legged kittiwake chicks fed ad libitum. We found that cort-implanted chicks
      begged more frequently and were more aggressive compared to controls. These
      behavioral modifications must be beneficial to chicks as they facilitate
      acquisition of food from the parents and might trigger brood reduction and
      reduced competition for food. Cort-implanted chicks also increased food intake;
      however, their growth rates were similar to controls. To examine the costs of
      chronically increased circulating levels of cort, we removed cort implants and,
      after a 10-day recovery period, tested cognitive abilities of young kittiwakes.
      We found that the ability of kittiwakes to associate a visual cue with the
      presence of food in a choice situation was compromised by the experimental
      elevation of cort during development. To examine the long-term costs of increased
      levels of cort, 8 months later we tested the performance of the same individuals
      in a spatial task requiring them to make a detour around a barrier in order to
      escape from an enclosure. Individuals treated with cort during development took
      significantly more time to solve this task compared to controls. The results of
      this study suggest that the adrenocortical response of a developing bird to
      environmental stressors is associated with both benefits (increased food intake,
      foraging behavior, and aggression) and costs (low growth efficiency and
      compromised cognitive abilities later in life). This provides an evolutionary
      framework for relating juvenile physiological traits to fitness of birds in
      subsequent life-history stages.

PMID- 12614645
TI  - Short-term fasting affects locomotor activity, corticosterone, and corticosterone
      binding globulin in a migratory songbird.
AB  - Unpredictable events such as severe storms lead to an increase in circulating
      corticosterone (CORT) in breeding birds. This increase is often accompanied by
      elevations in foraging and irruptive behavior. We were interested in determining
      if acute food restriction (such as might occur during inclement weather) is a
      sufficient cue to elicit an increase in locomotor activity, increase CORT
      secretion, and/or decrease circulating levels of corticosterone binding globulin
      (CBG) in white-crowned sparrows (Zonotrichia leucophrys gambelii). Male Z.l.
      gambelii were housed individually in environmental chambers on long days (LD
      20:4) to simulate breeding season daylength. Birds were fed ad libitum, and on
      select days, food was removed 2 h after lights on (fasted treatment), or was
      removed and replaced (control). We analyzed CORT and CBG levels after 1, 2, 6, 22
      (lights on), and 23 h under fasted and control conditions. We also measured
      activity during the 23-h experiment. Activity levels were increased under fasted
      conditions during the daytime relative to control conditions, but activity levels
      did not differ between treatments during the night. Fasting as little as 1, 2,
      and 6 h significantly increased total CORT levels above baseline (control),
      although after 22 h, total CORT levels under fasted conditions matched those
      under control conditions. Plasma CBG decreased after the 22-h fast, and remained
      low after the 23-h fast. This change was sufficient to significantly elevate free
      CORT levels in fasted birds relative to ad libitum food conditions, despite the
      lack of difference in total CORT levels.

PMID- 12614646
TI  - Facilitation of hypothalamic-pituitary-adrenal responses to novel stress
      following repeated social stress using the resident/intruder paradigm.
AB  - Our goal in these studies was to characterize some specific aspects of
      hypothalamic-pituitary-adrenal (HPA) activity in rats exposed to repeated social
      stress. We used a modification of the resident/intruder paradigm in which male
      intruder rats were subjected to defeat and then separated from the resident by an
      enclosure for a total of 30 min on Day 1. On Days 2-7, intruder rats were exposed
      to different resident rats every day through a wire mesh enclosure for 30 min in
      order to minimize injurious physical contact between the two rats. The intruder
      rats gained significantly less weight than controls over the 7-day period of
      stress though basal corticosterone levels and adrenal and thymus weights were not
      significantly different between the two groups. On Day 8, repeatedly stressed
      rats exhibited facilitation of HPA responses to novel restraint compared to
      controls but no differences in negative feedback sensitivity to dexamethasone
      (0.05 or 0.2 mg/kg) were observed. Thus, the HPA axis of socially stressed rats
      remains responsive to a stimulus that has never been encountered. Using this type
      of repeated presentation to an aggressive resident allows us to examine the
      neuroendocrine and behavioral consequences, and their underlying neural
      mechanisms, of exposure to a stressor that is social in nature and naturalistic
      for rodents.

PMID- 12614647
TI  - Female dominance status and fecal corticoids in a cooperative breeder with low
      reproductive skew: ring-tailed lemurs (Lemur catta).
AB  - Many studies have shown that low dominance status within a social group is
      associated with elevated glucocorticoid hormone production, a common index of
      physiological stress. However, the reverse may be true among cooperatively
      breeding female mammals with high reproductive skew; that is, high dominance
      status is associated with elevated glucocorticoid levels. Elevated glucocorticoid
      levels in these dominant females may be a product of their being the only breeder
      within a group or may result from other challenges associated with high status.
      To test this difference, we studied fecal corticoid levels in cooperative
      breeding females with low reproductive skew (i.e., where reproduction is not
      limited to dominant group members): ring-tailed lemurs (Lemur catta). We
      collected behavioral and fecal corticoid data from 39 ring-tailed lemur females
      from eight groups across three sites. In seven of the eight groups, either one or
      both of the two most dominant females (ranks 1 and 2) exhibited the highest fecal
      corticoid levels in the groups. The best predictor of corticoid levels in high
      ranking females was the proportion of aggressive agonistic interactions they
      initiated. For the lower-ranking females the best predictors of elevated
      corticoid levels were being the recipient of aggressive attacks and being
      relatively close to one's nearest neighbors. These results differ from many
      studies of caged male mammals where subordinate individuals often exhibit the
      highest glucocorticoid levels of a group. Furthermore, the results indicate that
      reproduction itself is not the primary reason for higher glucocorticoid levels
      among dominant cooperative-breeding females, but that some other factor must
      account for these elevated levels.

PMID- 12614648
TI  - Subordination stress alters alternative splicing of the Slo gene in tree shrew
      adrenals.
AB  - It was previously hypothesized that stress hormones regulate the alternative
      splicing of Slo potassium channels, thereby tuning the intrinsic excitability of
      adrenal chromaffin cells. Male tree shrews subjected to chronic stress by
      exposure to a dominant male develop robust symptoms with parallels to human
      depression. We report here that adrenals from males subjected to 4-6 weeks of
      subordination have a significantly smaller proportion of Slo transcripts with the
      optional STREX exon (STRess-axis regulated EXon) than unstressed male adrenals.
      Female adrenals (unstressed) had even lower levels than stressed males. These
      data suggest both behavioral regulation and sexual dimorphism in ion channel
      structure. We hypothesize that chromaffin cell excitability and sympathoadrenal
      function will be altered, and speculate that this may favor passive coping
      responses in subordinate males and females.

PMID- 12614649
TI  - Is a wild mammal kept and reared in captivity still a wild animal?
AB  - This study compared domestic guinea pigs (Cavia aperea f. porcellus; DGP) and two
      different populations of the wild cavy (Cavia aperea), its ancestor, to examine
      whether rearing of wild mammals in captivity affects their behavior and
      physiological stress responses. One population of wild cavies consisted of wild
      trapped animals and their first laboratory-reared offspring (WGP-1). The animals
      of the other population were reared in captivity for about 30 generations (WGP
      30). The spontaneous behavior of each of six groups of WGP-1 and WGP-30 and nine
      groups of DGP, each consisting of one adult male and two adult females, was
      analyzed quantitatively. Blood samples of the males were taken to determine
      cortisol, epinephrine, and norepinephrine concentrations. In addition, the
      exploratory behavior of 60-day-old male WGP-1, WGP-30, and DGP was investigated
      in an exploration apparatus. The domesticated animals displayed significantly
      less aggression, but significantly more sociopositive and male courtship behavior
      than their wild ancestors. In addition, DGP were much less attentive to their
      physical environment. Surprisingly, no behavioral difference was found between
      WGP-1 and WGP-30. Basal cortisol concentrations did not differ between wild and
      domestic guinea pigs. Catecholamine concentrations, however, as well as the
      challenge values of cortisol, were distinctly reduced in the DGP. WGP-1 and WGP
      30 did not differ with respect to their endocrine stress responses. In the
      exploration apparatus both forms of wild cavies were much more explorative than
      the domestic animals. These data suggest that the long-term breeding and rearing
      of wild guinea pigs in captivity do not result in significant changes in behavior
      and hormonal stress responses. It appears to take much longer periods of time and
      artificial selection by humans to bring about characters of domestication in wild
      animals.

PMID- 12614651
TI  - Acute and chronic restraint stress alter the incidence of social conflict in male
      rats.
AB  - Stress and elevated stress hormone levels are known to alter cognition, learning,
      memory, and emotional responses. Three weeks of chronic stress or glucocorticoid
      exposure is reported to alter neuronal morphology in the hippocampus, the
      amygdala, and the prefrontal cortex, and to decrease neurogenesis in the dentate
      gyrus. Here we examine the effects of acute and chronic restraint stress exposure
      on the incidence of emotional responses throughout a 3-week period among adult
      rat conspecifics. Our data indicate that acute restraint stress (i.e., a single 6
      h exposure) results in a significant reduction in aggressive conflicts among
      stressed males compared to experimental controls. In contrast, on Days 14 and 21,
      repeatedly restrained rats exhibited significantly more aggressive behaviors than
      controls. Blood samples taken 18 h after the last restraint session indicate that
      plasma concentrations of the stress hormone corticosterone (CORT) in stressed
      rats were equivalent to those of unstressed rats; however, the number of
      individually initiated aggressive acts observed positively correlated with plasma
      CORT measures taken at the end of the study. In contrast to studies of
      psychosocial stress or intruder paradigms, here we observe spontaneous emotional
      responses to an uncontrollable stressor in the homecage. This study provides a
      novel examination of the effects of chronic restraint stress on emotional
      responses in the home environment among cagemates. These results indicate that
      acute and chronic restraint stress alter the incidence of aggression, and
      emphasize the relevance of this model of chronic stress to studies of stress
      responsive disorders characterized by aggressive behavior.

PMID- 12614650
TI  - Differences in basal and stress-induced HPA regulation of wild house mice
      selected for high and low aggression.
AB  - Male wild house mice, selected for short (SAL) and long (LAL) attack latency,
      show distinctly different behavioral strategies in coping with environmental
      challenges. In this study, we tested the hypothesis that this difference in
      coping style is associated with a differential stress responsiveness of the
      hypothalamic-pituitary-adrenal (HPA) system. SAL rather than LAL mice showed a
      clear fluctuation in circulating corticosterone concentrations around the
      circadian peak with significantly higher levels in the late light phase. LAL mice
      showed lower basal ACTH levels and higher thymic and spleen weights compared to
      SAL. Under basal conditions, glucocorticoid receptor (GR) and mineralocorticoid
      receptor (MR) mRNA in the hippocampus and corticotropin-releasing hormone (CRH)
      mRNA in the paraventricular nucleus of the hypothalamus were not different
      between the two lines. Forced swimming for 5 min induced high immobility behavior
      in LAL mice which was associated with an enhanced and prolonged corticosterone
      response as compared to SAL, while absolute ACTH levels did not differ. In
      addition, LAL mice showed an increase in hippocampal MR mRNA (but not GR) and
      hypothalamic CRH mRNA at 24 h after forced swimming. In conclusion, a genetic
      trait in coping style of wild house mice is associated with an idiosyncratic
      pattern of HPA activity, and greater responsiveness of physiological and
      molecular stress markers in LAL mice. In view of the profound differences in
      behavioral traits and stress system reactivity, these mouse lines genetically
      selected for attack latency present an interesting model for studying the
      mechanism underlying individual variation in susceptibility to stress-related
      psychopathology.

PMID- 12614652
TI  - Evidence that acute serotonergic activation potentiates the locomotor-stimulating
      effects of corticotropin-releasing hormone in juvenile chinook salmon
      (Oncorhynchus tshawytscha).
AB  - The present study investigated whether the serotonergic system is involved in
      mediating the behavioral effects of corticotropin-releasing hormone (CRH) in
      juvenile spring chinook salmon, Oncorhynchus tshawytscha. An
      intracerebroventricular (ICV) injection of CRH induced hyperactivity. The effect
      of CRH was potentiated in a dose-dependent manner by the concurrent
      administration of the serotonin (5-HT) selective reuptake inhibitor fluoxetine.
      However, administration of fluoxetine alone had no effect on locomotor activity,
      suggesting that the locomotor-stimulating effect of CRH is mediated by the
      activation of the serotonergic system. Conversely, ICV injections of the 5-HT(1A)
      receptor antagonist NAN-190 attenuated the effect of CRH on locomotor activity
      when given in combination with CRH but had no effect when administered alone.
      These results provide the first evidence to support the hypothesis that the
      effect of CRH on locomotor activity in teleosts is mediated by activating the
      serotonergic system.

PMID- 12614653
TI  - Neuroendocrinology of context-dependent stress responses: vasotocin alters the
      effect of corticosterone on amphibian behaviors.
AB  - The ability of an animal to respond with appropriate defensive behaviors when
      confronted with an immediate threat can affect its survival and reproductive
      success. In the roughskin newt (Taricha granulosa), exogenous corticosterone
      (CORT) rapidly blocks and vasotocin (VT) enhances reproductive behaviors (mainly
      clasping behavior). Electrophysiological studies have shown that pretreatment of
      male Taricha with VT counteracts the inhibitory effects of CORT on neuronal
      activity in the medulla. To test whether similar interactions between VT and CORT
      influence reproductive behaviors in Taricha, we recorded the time spent and
      incidence of clasping in males injected with VT or vehicle at 60 min and then
      CORT or vehicle at 5 min before presentation of a female. This study found that
      clasping behavior is suppressed in males that received vehicle and then CORT, but
      is not suppressed in males that received VT and then CORT. Considering these
      results and the possibility that the performance of clasping behaviors might
      cause increases in endogenous VT activity, we tested whether the suppressive
      effects of CORT administration on clasping behavior would occur in males that had
      recently clasped females. The study found that, in contrast to males that had
      been isolated from females, CORT administration did not suppress clasping
      behavior in males that had been allowed to clasp females for 60 min prior to the
      hormone injection. Our results suggest that, at least in this amphibian and
      perhaps in other animals, the neuroendocrine regulation of alternative behavioral
      responses to threats involves functional interactions between corticosteroids and
      VT-like peptides.

PMID- 12614654
TI  - Repeated exposure to social stress alters the development of agonistic behavior
      in male golden hamsters.
AB  - In male golden hamsters, exposure to social stress during puberty alters
      aggressive behavior. Interestingly, agonistic behavior undergoes two major
      transitions during puberty: a decline in attack frequency and a shift from play
      fighting to adult-like aggression. Based on previous observations, we developed
      an approach for characterizing offensive responses as play fighting or adult
      like. The present studies had two aims. First, we validated our approach by
      looking at the development of attack types during puberty. Second, we looked at
      the effects of repeated social stress on the development of agonistic behavior by
      repeatedly exposing individuals to aggressive adults during puberty. In the first
      phase of the study, our results point to three different developmental periods.
      Initially, animals engage in agonistic behavior though attacks targeted at the
      face and cheeks. This period lasts from Postnatal Day 20 (P-20) to P-40 (early
      puberty). This phase corresponding to play fighting is followed by a transitional
      period characterized by attacks focused on the flanks (from P-40 to P-50, mid
      puberty). Afterward, animals perform adult-like aggression characterized by
      attacks focused on the belly and rear. Our data also show that repeated exposure
      to aggressive adults has two separate effects on the development of agonistic
      behavior. Repeated social stress accelerated the onset of adult-like agonistic
      responses. Furthermore, attack frequency, while decreasing during puberty,
      remained at a higher level in early adulthood in stressed animals. These results
      show that repeated exposure to social stress during puberty alters the
      development of agonistic behavior both qualitatively and quantitatively.

PMID- 12614655
TI  - The hormonal costs of subtle forms of infant maltreatment.
AB  - We show here that subtle forms of maltreatment during infancy (below 1 year of
      age) have potential consequences for the functioning of the child's
      adrenocortical response system. Infants who received frequent corporal punishment
      (e.g., spanking) showed high hormonal reactivity to stress (a repeated separation
      from mother, combined with the presence of a stranger). In addition, infants who
      experienced frequent emotional withdrawal by their mothers (either as a result of
      maternal depression, or mother's strategic use of withdrawal as a control tactic)
      showed elevated baseline levels of cortisol. It was suggested that there are
      hormonal "costs" when mothers show response patterns (intentionally or
      unintentionally) that limit their utility as a means of buffering the child
      against stress. The hormonal responses shown by infants may alter the functioning
      of the hypothalamic-pituitary-adrenal (HPA) axis in ways that, if continued, may
      foster risk for immune disorders, sensitization to later stress, cognitive
      deficits, and social-emotional problems.

PMID- 12614656
TI  - Rapid glucocorticoid stimulation and GABAergic inhibition of hippocampal
      serotonergic response: in vivo dialysis in the lizard anolis carolinensis.
AB  - Central serotonin (5-HT) is activated during stressful situations and aggressive
      interactions in a number of species. Glucocorticoids secreted peripherally during
      stressful events feed back on central systems and may affect 5-HT mediation of
      stress-induced behavioral events. To test the neuromodulatory effect of stress
      hormone secretion, serotonin overflow was measured from the hippocampus of the
      lizard Anolis carolinensis. Microdialysis was used to collect repeated samples
      from anesthetized lizards, with perfusate measured by HPLC with electrochemical
      analysis. Following initially high levels of 5-HT, concentrations stabilized to
      basal levels after approximately 2 h. Intracortical infusion of 200 ng/ml
      corticosterone evoked transient increases in 5-HT release of approximately 400%.
      The effect of corticosterone on 5-HT overflow appears to be dose dependent as 20
      ng/ml stimulated an increase of 200%, whereas 2 ng/ml stimulated a 50% increase.
      Administration of 0.1 and 1 ng/ml GABA via the dialysis probe significantly
      inhibited 5-HT overflow by 20 and 40%, respectively. The duration of GABA
      inhibition is greater than the stimulatory response for glucocorticoids. Short
      lived glucocorticoid stimulation of 5-HT release suggests a possible mechanism
      for endocrine mediation of continuously changing social behavioral events.

PMID- 12614657
TI  - Anatomical and functional evidence for a stress-responsive, monoamine
      accumulating area in the dorsomedial hypothalamus of adult rat brain.
AB  - The dorsomedial hypothalamus (DMH) plays an important role in relaying
      information to neural pathways mediating neuroendocrine, autonomic, and
      behavioral responses to stress. Evidence suggests that the DMH is a structurally
      and functionally diverse integrative structure that contributes to both
      facilitation and inhibition of the hypothalamo-pituitary-adrenal axis, depending
      on the nature of the stimulus and the specific neural circuits involved. Previous
      studies have determined that stress or stress-related stimuli elevate tissue
      concentrations of serotonin (5-hydroxytryptamine; 5-HT), 5-hydroxyindoleacetic
      acid (5-HIAA), dopamine, and noradrenaline selectively within the DMH. In order
      to determine the specific region of the rat DMH involved, we used high
      performance liquid chromatography with electrochemical detection to measure
      tissue concentrations of 5-HT, 5-HIAA, dopamine, and noradrenaline within five
      different subregions of the DMH in adult female Lewis and Fischer rats
      immediately or 4 h following a 30-min period of restraint stress. Compared to
      unrestrained control rats, restrained rats had elevated concentrations of 5-HT, 5
      HIAA, dopamine, and noradrenaline immediately after a 30-min period of restraint
      and had elevated concentrations of 5-HT 4 h following the onset of a 30-min
      period of restraint stress. These effects were confined to a specific region that
      included medial portions of the dorsal hypothalamic area and dorsal ependymal,
      subependymal, and neuronal components of the periventricular nucleus.
      Furthermore, these effects were observed in Lewis rats, but not Fischer rats, two
      closely related rat strains with well-documented differences in neurochemical,
      neuroendocrine, autonomic, and behavioral responses to stress. These data provide
      support for the existence of a stress-responsive, amine-accumulating area in the
      DMH that may play an important role in the differential stress responsiveness of
      Lewis and Fischer rats.

PMID- 12614658
TI  - Trauma and bereavement: examining the impact of sudden and violent deaths.
AB  - The intersection between trauma and bereavement has only recently been explored.
      Prior studies of bereavement have often neglected to measure posttraumatic stress
      disorder (PTSD) symptoms; the few that have offer equivocal findings concerning
      the role of PTSD symptomatology following loss. Few studies have explored the
      relationship between PTSD and the other psychological sequelae more commonly
      associated with loss. The current investigation assessed PTSD symptoms over time
      following the death of a spouse, using violence and the suddenness of the loss as
      potential outcome predictors. In addition, the relationship between PTSD and
      depression symptoms was assessed. Violent death predicted PTSD symptoms and the
      persistence of depression over time. The suddenness of the loss was not related
      to PTSD symptoms. This investigation suggests that violent death results in
      development of PTSD symptoms over and above the normal grief response and thus,
      may contribute to a more severe grief response.

PMID- 12614659
TI  - Injury severity, prior trauma history, urinary cortisol levels, and acute PTSD in
      motor vehicle accident victims.
AB  - This study examined the relationship between prior history of traumatic events,
      life threat, and injury severity experienced during a motor vehicle accident
      (MVA), and posttraumatic stress disorder (PTSD) assessed 1 month after the
      accident. In addition, initial urinary cortisol levels after the accident were
      examined as a possible mediator of this relationship. Fifteen-hour urinary
      cortisol samples were collected from MVA victims upon admission to the trauma
      unit. In the hospital, subjective life threat was measured and objective Injury
      Severity Scores (ISSs) were computed. One month after the accident, participants
      were assessed for prior history of traumatic experiences, presence of acute PTSD,
      and levels of intrusive and avoidant thoughts and behaviors. Victims, who met
      PTSD diagnostic criteria, reported more prior traumatic events, and significantly
      greater life threat despite receiving significantly lower ISSs than victims who
      did not develop PTSD. The relationships between ISSs and PTSD symptoms and prior
      trauma history and PTSD symptoms were mediated by cortisol levels. Results
      suggest that cortisol levels in the acute aftermath of a traumatic event may
      serve as a mechanism through which various factors may increase risk for PTSD.

PMID- 12614660
TI  - Anxiety sensitivity, self-reported motives for alcohol and nicotine use, and
      level of consumption.
AB  - We examined the relationship between anxiety sensitivity, alcohol and nicotine
      use, and drinking and smoking motives in a nonclinical university population.
      Participants (n=293) completed the 16-item Anxiety Sensitivity (AS) Index and a
      drinking and smoking history questionnaire. Sixty percent of participants
      completed the Drinking Motives Questionnaire and 29% completed the Smoking
      Motives Questionnaire. Level of alcohol and cigarette consumption was not related
      to AS but was related to motives. AS was directly related to coping-related
      drinking and moderated the relationship between level of smoking and mood-related
      smoking motives. Although AS may be more predictive of coping-related drinking
      motives than of level of alcohol consumption, given the relationship between
      these types of drinking motives and abusive drinking, high AS individuals might
      be an at-risk group due to their reasons for drinking. In addition, striking
      differences were found between drinkers who smoke and those who do not smoke,
      suggesting that this subgroup may also represent an at-risk group of drinkers.

PMID- 12614661
TI  - Too much thinking about thinking?: Metacognitive differences in obsessive
      compulsive disorder.
AB  - Negative appraisals of intrusive thoughts and beliefs about the importance of
      thoughts are considered core mechanisms in cognitive models of obsessive
      compulsive disorder (OCD). In refinements of cognitive theory, differences in
      metacognitive processes have been emphasized. Cartwright-Hatton and Wells [J.
      Anxiety Disord. 37 (1997) 279-296] found that cognitive self-consciousness (CSC),
      a tendency to be aware of and monitor thinking, was the only metacognitive
      dimension that differentiated OCD patients from patients with generalized anxiety
      disorder. To evaluate the relative importance of different cognitive processes to
      OCD, we administered an expanded CSC scale and two state-of-the-art measures of
      thought appraisals and beliefs. Scores on the CSC scale reliably differentiated
      OCD patients (n=30), from an anxious comparison group (OAD, n=25) after
      controlling for scores on the two cognition measures. The tendency to excessively
      reflect upon one's cognitive processes may increase opportunities for negative
      appraisals of intrusive thoughts, foster over-importance of thought beliefs, and
      increase the likelihood of developing OCD.

PMID- 12614662
TI  - Embarrassment and social phobia: the role of parasympathetic activation.
AB  - The few studies on the psychophysiology of embarrassment have suggested
      involvement of parasympathetic activation. However, blushing, the hallmark of
      embarrassment and a prominent symptom in social phobia, is more likely to be
      produced by cervical sympathetic outflow. Hitherto, there has been no evidence of
      parasympathetic innervation of the facial blood vessels. In this study, a group
      of social phobics and control participants watched, together with a 2-person
      audience, a previously made videotape of themselves singing a children's song.
      Self-report measures confirmed that this task induced embarrassment. While two
      measures of respiratory sinus arrhythmia (RSA) during the task did not indicate
      heightened parasympathetic tone, increased heart rate (HR) and skin conductance
      marked sympathetic activation. Thus, our data do not support the notion that an
      increase in parasympathetic activation plays a significant role in social phobia
      and embarrassment. Social anxiety and embarrassment both resulted in sympathetic
      activation.

PMID- 12614663
TI  - On the physiological symptom constellation in youth with Generalized Anxiety
      Disorder (GAD).
AB  - To investigate the physiological symptom constellation of Generalized Anxiety
      Disorder (GAD)/Overanxious Disorder (OAD) in children, the present study examined
      parent and child reports. Children (N=47; aged 9-13) were evaluated to meet
      criteria for a diagnosis of GAD. Child physiological symptoms were assessed
      including: (a) inability to sit still/relax, (b) difficulty paying
      attention/concentrating, (c) irritability/getting upset easily, (d) muscle aches,
      and (e) sleep disturbance. Separate child and parent reports were significantly
      discordant for each of the GAD somatic symptoms. Parents also endorsed
      significantly more somatic symptoms than their GAD children. Furthermore, 9- to
      11-year-olds reported fewer somatic symptoms than 11- to 13-year-olds, whereas
      the number of parental endorsements of child symptoms remained consistent across
      child ages. Results of a separate analysis of treatment sensitivity suggest that
      somatic symptoms were responsive to cognitive-behavioral treatment (CBT) for
      anxiety. When assessing GAD in children, discrepancies between parent and child
      report of somatic symptomatology, as well as a child's age and developmental
      level, should be considered.

PMID- 12614664
TI  - The long-term course of panic disorder--an 11 year follow-up.
AB  - BACKGROUND: The purpose of this study was to assess the naturalistic long-term
      course of panic disorder over a period of 11 years. METHOD: Thirty DSM-III-R
      panic disorder patients, who had suffered from panic disorder for 6 years on
      average and who had taken part in an 8-week multicenter drug trial, were included
      in the intent-to-follow-up group to be reinterviewed 11 years after the end of
      the trial. At baseline and at follow-up the same instruments were used to assess
      frequency of panic attacks, level of phobic avoidance, and disabilities.
      Treatments received during the follow-up period and attempted suicides were
      assessed with a structured interview. Periods of well-being during the follow-up
      period were elicited retrospectively with a specifically designed longitudinal
      chart. RESULTS: Twenty-four patients could actually be reinterviewed after 11.3
      years. While at baseline all patients had suffered from panic attacks and had
      been severely disabled on a number of measures, 66.7% had no panic attack during
      the year before follow-up. During the month before follow-up 87.5% had no panic
      attack, and 54% showed no or only mild phobic avoidance. In the areas of work and
      family life 90% showed no or only mild disabilities, whereas in the area of
      social life this percentage was lower (67%). Thirty-three percent of the patients
      were completely remitted according to a composite remission criterion.
      CONCLUSIONS: Panic disorder is not a uniformly chronic and progressing disorder.
      Over a period of 11 years there is a good chance of recovery from panic attacks
      and disabilities, and full remission is also possible.

PMID- 12614665
TI  - Intolerance of uncertainty in obsessive-compulsive disorder.
AB  - Pathological doubt, a prominent feature of obsessive-compulsive disorder (OCD),
      may be related to difficulty tolerating ambiguous or uncertain situations. This
      is thought to be particularly true of those patients with checking compulsions.
      Intolerance of uncertainty (IU) has been studied extensively within the domains
      of worry and generalized anxiety; however, it has received relatively little
      empirical attention in OCD patients. We administered the Intolerance of
      Uncertainty Scale [Personality and Individual Differences 17 (1994) 791] to 55
      clinic patients with OCD, 43 of whom had checking compulsions, and 14 nonanxious
      controls. OC checkers showed greater IU than did OC noncheckers and NACs. The
      latter two groups did not differ from each other. Furthermore, both repeating and
      checking rituals were associated with IU. Pathological doubt may be understood
      not only in terms of knowledge-based constructs, but also patients' emotional
      reaction to feelings of uncertainty. We discuss the implications for increasing
      tolerance via cognitive-behavioral therapy.

PMID- 12614666
TI  - Cognitive-behavioral treatment of food neophobia in adults.
AB  - Food neophobia is an eating disturbance defined as the fear of trying new foods.
      In its extreme, the disorder can lead to malnutrition, limited social
      functioning, and psychological difficulties. Successful treatment of food
      neophobia in children has been reported, but if those children are not provided
      with treatment, it stands to reason that the disorder may follow them into
      adulthood. To date, adult cases have not been described in the literature and the
      prevalence in adults is unknown. Our paper will review the methods used to treat
      children with the disorder then delineate how the procedures were modified for an
      adult population, giving two case examples.

PMID- 12614667
TI  - The CRF1 receptor antagonist antalarmin reduces volitional ethanol consumption in
      isolation-reared fawn-hooded rats.
AB  - Corticotropin releasing factor is a neuropeptide associated with the integration
      of physiological and behavioural responses to stress. More recently,
      corticotropin releasing factor has been implicated in the actions of abused
      drugs, including ethanol. Moreover, previous studies have demonstrated that the
      non-selective corticotropin releasing factor receptor antagonist, alpha-helical
      corticotropin releasing factor(9-41), can diminish some of the behavioural
      effects associated with ethanol withdrawal, whilst the selective corticotropin
      releasing factor(1) receptor antagonist CP-154,526 has been beneficial in
      decreasing stress-induced relapse into alcohol-seeking behaviour. However, as yet
      the ability of selective corticotropin releasing factor compounds to modulate
      volitional ethanol consumption has not been investigated. For these reasons the
      present study aims to examine the effects of antalarmin, a selective, centrally
      acting corticotropin releasing factor(1) receptor antagonist, on both the
      initiation and maintenance of ethanol consumption in isolation-reared Fawn-Hooded
      rats. Here we demonstrate that whilst both antalarmin and diazepam can decrease
      the acquisition of an ethanol-preferring phenotype by Fawn-Hooded rats, only
      antalarmin can alter established, volitional ethanol consumption. This ability of
      antalarmin to reduce established ethanol consumption is apparently unrelated to
      changes in ingestive behaviour, or a generalised anxiolytic action. For these
      reasons, such drugs may provide a new therapeutic approach for the treatment of
      alcoholism; however, this requires further investigation.

PMID- 12614668
TI  - Dual effect of Zn2+ on multiple types of voltage-dependent Ca2+ currents in rat
      palaeocortical neurons.
AB  - The effects of Zn(2+) were evaluated on high-voltage-activated Ca(2+) currents
      expressed by pyramidal neurons acutely dissociated from rat piriform cortex.
      Whole-cell, patch-clamp experiments were carried out using Ba(2+) (5 mM) as the
      charge carrier. Zn(2+) blocked total high-voltage-activated Ba(2+) currents with
      an IC(50) of approximately 21 microM. In addition, after application of non
      saturating Zn(2+) concentrations, residual currents activated with substantially
      slower kinetics than control Ba(2+) currents. Both of the above-mentioned effects
      of Zn(2+) were also observed in high-voltage-activated currents recorded in the
      presence of nearly-physiological concentrations of extracellular Ca(2+) (1 and 2
      mM) rather than Ba(2+). Under the latter conditions, 30 microM Zn(2+) inhibited
      high-voltage-activated currents somewhat less than observed in extracellular
      Ba(2+) (approximately 47% and approximately 41%, respectively, vs. approximately
      59%), but slowed Ca(2+)-current activation to very similar degrees. All of the
      pharmacological components in which Ba(2+) currents could be dissected (L-, N-,
      P/Q-, and R-type) were inhibited by Zn(2+), the percentage of current blocked by
      30 microM Zn(2+) ranging from 34 to 57%. Moreover, the activation kinetics of all
      pharmacological Ba(2+) current components were slowed by Zn(2+). Hence, the lower
      activation speed observed in residual Ba(2+) currents after Zn(2+) block is due
      to a true slowing of macroscopic Ca(2+)-current activation kinetics and not to
      the preferential inhibition of a fast-activating current component. The
      inhibitory effect of Zn(2+) on Ba(2+) current amplitude was voltage-independent
      over the whole voltage range explored (-60 to +30 mV), hence the Zn(2+)-dependent
      decrease of Ba(2+) current activation speed is not the consequence of a voltage-
      and time-dependent relief from block. Zn(2+) also caused a slight, but
      significant, reduction of Ba(2+) current deactivation speed upon repolarization,
      which is further evidence against a depolarization-dependent unblocking
      mechanism. Finally, the slowing effect of Zn(2+) on Ca(2+)-channel activation
      kinetics was found to result in a significant, extra reduction of Ba(2+) current
      amplitude when action-potential-like waveforms, rather than step pulses, were
      used as depolarizing stimuli. We conclude that Zn(2+) exerts a dual action on
      multiple types of voltage-gated Ca(2+) channels, causing a blocking effect and
      altering the speed at which channels are delivered to conducting states, with
      mechanism(s) that could be distinct.

PMID- 12614669
TI  - Modulation of the voltage-gated sodium- and calcium-dependent potassium channels
      in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial
      nerve transsection: an in situ hybridization study.
AB  - We investigated whether the expression in the vestibular and facial nuclei of the
      voltage-dependent Na alpha I and Na alpha III channels and of the Ca(2+)
      activated K(+)-channel subunits, small-conductance (SK) 1, SK2 and SK3, is
      affected by unilateral inner-ear lesion including both labyrinthectomy and
      transsection of the facial nerve. Specific sodium (Na alpha I, Na alpha III) and
      potassium (SK1, SK2, SK3) radioactive oligonucleotides were used to probe
      sections of rat vestibular and facial nuclei by in situ hybridization methods.
      The signal was detected with films or by emulsion photography. Animals were
      killed at various times following the lesion: 1 day, 3 days, 8 days or 30 days.
      In normal adult animals, mRNAs for Na alpha I, and SK1, SK2, and SK3 channels
      were found in several brainstem regions including the lateral, medial, superior
      and inferior vestibular nuclei and the facial nuclei. In contrast, there was
      little Na alpha III subunit mRNA anywhere in the brainstem. Following unilateral
      inner ear lesion in rats, the medial vestibular nuclei were probed with Na alpha
      I, Na alpha III, SK1, SK2 and SK3 oligonucleotide probes: autoradiography
      indicated no difference between the two sides, at any of the times studied. Na
      alpha I and SK2 mRNAs were less abundant and Na alpha III, SK1 and SK3 mRNAs were
      more abundant in the axotomized facial nuclei motoneurons than in controls.
      Removal of vestibular input did not affect the abundance of the mRNAs for the
      sodium- or calcium-dependent potassium channels in the deafferented vestibular
      nuclei. There is thus no evidence that modulation of these conductances
      contributes to the recovery of a normal resting discharge of the deafferented
      vestibular neurons and consequently to the functional recovery of the postural
      and oculomotor deficits observed at the acute stage. However, facial axotomy
      induced a long-term modulation of both Na and SK conductances mRNAs in the facial
      motoneurons ipsilateral to the lesion. Presumably, retrograde injury factors
      resulting from axotomy were able to alter durably the membrane properties and
      thus the excitability of the facial motoneurons.

PMID- 12614670
TI  - Effects of the alpha 2-adrenoreceptor antagonist dexefaroxan on neurogenesis in
      the olfactory bulb of the adult rat in vivo: selective protection against
      neuronal death.
AB  - A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has
      been hypothesised to be the critical factor underlying the evolution of central
      neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism
      Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's
      disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press
      Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating
      central noradrenergic transmission, afford neuroprotection in vivo in models of
      cerebral ischaemia, excitotoxicity and devascularization-induced
      neurodegeneration. The present study utilised the rat olfactory bulb as a model
      system for examining the effects of the selective alpha(2)-adrenoceptor
      antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival
      and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'
      deoxyuridine labelling) and cell death associated with DNA fragmentation
      (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'
      triphosphate nick end-labelling assay) were quantified following a 7-day
      treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times
      daily), followed by a 3-day washout period. The number of terminal
      dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end
      labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated
      rats, this difference being greatest and significant in the subependymal layer (
      52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more
      numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences
      were detected in the proliferating region of the subventricular zone. Terminal
      dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end
      labelling combination with glial fibrillary acidic protein or neuronal-specific
      antigen immunohistochemistry revealed that terminal dideoxynucleotidyl
      transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive
      nuclei were associated primarily with a neuronal cell phenotype. These findings
      suggest that dexefaroxan increases neuron survival in the olfactory bulb of the
      adult rat in vivo, putatively as a result of reducing the apoptotic fate of
      telencephalic stem cell progenies.

PMID- 12614671
TI  - Association of ATP synthase alpha-chain with neurofibrillary degeneration in
      Alzheimer's disease.
AB  - Amyloid deposits and neurofibrillary tangles (NFT) are the two hallmarks that
      characterize Alzheimer's disease (AD). In order to find the molecular partners of
      these degenerating processes, we have developed antibodies against insoluble AD
      brain lesions. One clone, named AD46, detects only NFT. Biochemical and
      histochemistry analyses demonstrate that the labeled protein accumulating in the
      cytosol of Alzheimer degenerating neurons is the alpha-chain of the ATP synthase.
      The cytosolic accumulation of the alpha-chain of ATP synthase is observed even at
      early stages of neurofibrillary degenerating process. It is specifically observed
      in degenerating neurons, either alone or tightly associated with aggregates of
      tau proteins, suggesting that it is a new molecular event related to
      neurodegeneration. Overall, our results strongly suggest the implication of the
      alpha-chain of ATP synthase in neurofibrillary degeneration of AD that is
      illustrated by the cytosolic accumulation of this mitochondrial protein, which
      belongs to the mitochondrial respiratory system. This regulatory subunit of the
      respiratory complex V of mitochondria is thus a potential target for therapeutic
      and diagnostic strategies.

PMID- 12614672
TI  - Low-frequency depression of synaptic responses recorded from rat visual cortex.
AB  - To characterize the low-frequency depression (LFD) of synaptic transmission in
      the visual cortex, we recorded field potentials and minimal excitatory
      postsynaptic potentials (EPSPs) from layer II/III following intracortical
      stimulation at various frequencies in cortical slices of rats. Field potentials
      were stable at 0.017 Hz, but showed an amplitude depression at 0.033-0.1 Hz at
      stimulus intensity of 1.5 times the threshold for induction of the postsynaptic
      component and at 0.1-0.2 Hz at intensity of 1.2 times the threshold. The LFD was
      input-specific and its magnitude correlated with the stimulus frequency. An
      interruption of stimulation for 15 min yielded a nearly complete recovery from
      LFD. Minimal EPSPs tested at 0.1-1.7 Hz often showed LFD with similar features.
      However, some inputs were stable or even facilitated during repeated stimulation.
      At 0.1 and 0.2 Hz, >50% of inputs were stable, whereas 10% and 25% were
      depressed, respectively. At 0.5 and 1.7 Hz, LFD was observed in >60% and 80% of
      inputs, respectively. The magnitude of LFD strongly varied across inputs. In 3 of
      the 41 inputs analyzed, LFD was so strong that these inputs became virtually
      silent. Occurrence of responses to the second pulse in the paired-pulse paradigm
      when the first response was absent and recovery of depressed EPSPs following
      stimulus interruption or shift to a lower frequency suggest that these synapses
      were presynaptically silent due to a lowered probability of transmitter release.
      Altogether, the results indicate that testing intervals of <10 or even < or =30 s
      cannot be regarded as completely neutral. At the single-cell level, frequency
      dependent changes were strongly heterogeneous across different inputs. LFD and
      its spontaneous recovery may underlie the previously described "post-rest"
      potentiation, and should be taken into account when considering information
      processing in cortical networks.

PMID- 12614673
TI  - Immunological characterization of T-type voltage-dependent calcium channel CaV3.1
      (alpha 1G) and CaV3.3 (alpha 1I) isoforms reveal differences in their
      localization, expression, and neural development.
AB  - Low voltage-activated calcium channels (LVAs; "T-type") modulate normal neuronal
      electrophysiological properties such as neuronal pacemaker activity and rebound
      burst firing, and may be important anti-epileptic targets. Proteomic analyses of
      available alpha 1G/Ca(V)3.1 and alpha 1I/Ca(V)3.3 sequences suggest numerous
      potential isoforms, with specific alpha 1G/Ca(V)3.1 or alpha 1I/Ca(V)3.3 domains
      postulated to be conserved among isoforms of each T-type channel subtype. This
      information was used to generate affinity-purified anti-peptide antibodies
      against sequences unique to alpha 1G/Ca(V)3.1 or alpha 1I/Ca(V)3.3, and these
      antibodies were used to compare and contrast alpha 1G/Ca(V)3.1 and alpha
      1I/Ca(V)3.3 protein expression by western blotting and immunohistochemistry. Each
      antibody reacted with appropriately sized recombinant protein in HEK-293 cells.
      Regional and developmental differences in alpha 1G/Ca(V)3.1 and alpha 1I/Ca(V)3.3
      protein expression were observed when the antibodies were used to probe regional
      brain dissections prepared from perinatal mice and adult rodents and humans.
      Mouse forebrain alpha 1G/Ca(V)3.1 (approximately 240 kDa) was smaller than
      cerebellar (approximately 260 kDa) alpha 1G/Ca(V)3.1, and expression of both
      proteins increased during perinatal development. In contrast, mouse midbrain and
      diencephalic tissues evidenced an alpha 1I/Ca(V)3.3 immunoreactive doublet
      (approximately 230 kDa and approximately 190 kDa), whereas other brain regions
      only expressed the small alpha 1I/Ca(V)3.3 isoform. A unique large alpha
      1I/Ca(V)3.3 isoform (approximately 260 kDa) was expressed at birth and eventually
      decreased, concomitant with the appearance and gradual increase of the small
      alpha 1I/Ca(V)3.3 isoform. Immunohistochemistry supported the conclusion that
      LVAs are expressed in a regional manner, as cerebellum strongly expressed alpha
      1G/Ca(V)3.1, and olfactory bulb and midbrain contained robust alpha 1I/Ca(V)3.3
      immunoreactivity. Finally, strong alpha 1I/Ca(V)3.3, but not alpha 1G/Ca(V)3.1,
      immunoreactivity was observed in brain and spinal cord by embryonic day 14 in
      situ. Taken together, these data provide an anatomical and biochemical basis for
      interpreting LVA heterogeneity and offer evidence of developmental regulation of
      LVA isoform expression.

PMID- 12614674
TI  - Postnatal development of the vesicular GABA transporter in rat cerebral cortex.
AB  - Light and electron microscopic immunocytochemical techniques and Western blotting
      were used to investigate the postnatal development of the vesicular GABA
      transporter (VGAT) in the rat somatic sensory cortex. VGAT immunoreactivity was
      low at birth, it increased gradually through the first and second weeks of life
      and achieved the adult pattern during the third week. At postnatal day (P)0-P5,
      VGAT immunoreactivity was associated exclusively to fibers and puncta. Electron
      microscopic studies performed at P5 showed that all identified synaptic contacts
      formed by VGAT-positive axonal swellings were of the symmetric type and that a
      substantial proportion of the boutons appeared not to have formed synapses. From
      P10 onward, labeled puncta were both scattered in the neuropil and in apposition
      to unstained cellular profiles; VGAT was also expressed in few GABAergic cell
      bodies. Western blottings at the same postnatal ages revealed a 55-kDa band whose
      intensity was weak at P0 (17% of adult), it increased constantly until P15 (P2:
      35%; P5: 44%; P10: 68%; P15: 97%), and then leveled off. Overall, the present
      results show that during neocortical development the expression of VGAT slightly
      precedes the complete maturation of inhibitory synaptogenesis and suggest that it
      may contribute to the formation of neocortical GABAergic circuitry.

PMID- 12614675
TI  - Re-establishment of neurochemical coding of preganglionic neurons innervating
      transplanted targets.
AB  - We investigated the effect on neurochemical phenotype of changing the targets
      innervated by sympathetic preganglionic neurons. In neonatal rats, the adrenal
      gland was transplanted into the neck, to replace the postganglionic neurons of
      the superior cervical ganglion. Transplanted adrenal glands survived, and
      contained noradrenergic and adrenergic chromaffin cells, and adrenal ganglion
      cells. Retrograde tracing from the transplants showed that they were innervated
      by preganglionic neurons that would normally have supplied postganglionic neurons
      of the superior cervical ganglion. The neurochemical phenotypes of preganglionic
      axons innervating transplanted chromaffin cells were compared with those
      innervating the normal adrenal medulla or superior cervical ganglion neurons. As
      in the normal adrenal gland, preganglionic nerve fibres apposing transplanted
      chromaffin cells were cholinergic. The peptide and calcium-binding protein
      content of preganglionic fibres was similar in normal and transplanted adrenal
      glands. In both cases, cholinergic fibres immunoreactive for enkephalin targeted
      adrenergic chromaffin cells, whilst cholinergic fibres with co-localised
      calretinin-immunoreactivity innervated noradrenergic chromaffin cells and adrenal
      ganglion cells. In contrast to the innervation of normal adrenal glands, these
      axons lacked immunoreactivity to nitric oxide synthase. In a set of control
      experiments, the superior cervical ganglion was subjected to preganglionic
      denervation in rat pups the same age as those that received adrenal transplants,
      and the ganglion was allowed to be re-innervated over the same time course as the
      adrenal transplants were studied. When the superior cervical ganglion was re
      innervated by preganglionic nerve fibres, we observed that all aspects of
      chemical coding were restored, including cholinergic markers, nitric oxide
      synthase, enkephalin, calcitonin gene-related peptide and calcium binding
      proteins in predicted combinations, although the density of nerve fibres was
      always lower in re-innervated ganglia. These data show that the neurochemical
      phenotypes expressed by preganglionic neurons re-innervating adrenal chromaffin
      cells are selective and similar to those seen in the normal adrenal gland. Two
      explanations are advanced: either that contact of preganglionic axons with novel
      target cells has induced a switch in their neurochemical phenotypes, or that
      there has been target-selective reinnervation by pre-existing fibres of
      appropriate phenotype. Regardless of which of these alternatives is correct, the
      restoration of normal preganglionic codes to the superior cervical ganglion
      following denervation supports the idea that the target tissue influences the
      neurochemistry of innervating preganglionic neurons.

PMID- 12614676
TI  - Activity-dependent change in the protein level of brain-derived neurotrophic
      factor but no change in other neurotrophins in the visual cortex of young and
      adult ferrets.
AB  - Neurotrophins are suggested to play a role in activity-dependent plasticity of
      visual cortex during the critical period of postnatal development. Thus, the
      concentration of neurotrophins in the cortex is expected to change with
      development and/or with alteration in neuronal activities. To test this, we
      measured protein levels of nerve growth factor, brain-derived neurotrophic
      factor, neurotrophin-3 and neurotrophin-4/5 in visual cortex of young (postnatal
      day 38-46, at the peak of the critical period) and adult ferrets with two-site
      enzyme-immunoassay systems. Measurements were carried out also in somatosensory
      cortex, hippocampus and cerebellum as control. With development the level of
      brain-derived neurotrophic factor did not significantly change, while those of
      the other neurotrophins changed in the visual cortex. A blockade of visual inputs
      for 24 h by an injection of tetrodotoxin into both eyes significantly decreased
      brain-derived neurotrophic factor protein level in the visual cortex, but not in
      the other regions in both young and adult ferrets. On the other hand, no
      significant decrease was seen in the protein level of the other neurotrophins in
      the visual cortex of young and adult ferrets. A monocular injection of
      tetrodotoxin in young ferrets resulted in the reduction of brain-derived
      neurotrophic factor by approximately half that by binocular injection. The degree
      of the decrease in the contralateral cortex to the injected eye was significantly
      larger than that in the ipsilateral cortex, reflecting that the contralateral eye
      is dominantly represented in the cortex in ferrets. Blockade of cortical neuronal
      activities by a GABA(A) receptor agonist led to a remarkable reduction of brain
      derived neurotrophic factor protein in the visual cortex. These results suggest
      that the level of brain-derived neurotrophic factor protein in visual cortex is
      regulated by activities of cortical neurons.

PMID- 12614677
TI  - Sast124, a novel splice variant of syntrophin-associated serine/threonine kinase
      (SAST), is specifically localized in the restricted brain regions.
AB  - Syntrophin is an adaptor protein that binds signaling molecules to the dystrophin
      associated protein complex, which connects extracellular matrix to intracellular
      cytoskeleton for construction and maintenance of the postsynaptic structures in
      the neuromuscular junction and the CNS. Among these signaling molecules, a family
      of microtubule-associated serine/threonine kinases has a unique structural
      feature with a serine/threonine kinase domain and a postsynaptic density protein
      95/discs large/zona occludens-1 domain. In the present study, we identified
      syntrophin-associated serine/threonine kinase-124, a novel splice variant of the
      syntrophin-associated serine/threonine kinase which is a member of the
      microtubule-associated serine/threonine kinases family. Comparing to the original
      clone (syntrophin-associated serine/threonine kinase-170), syntrophin-associated
      serine/threonine kinase-124 is truncated just downstream of the postsynaptic
      density protein-95/discs large/zona occludens-1 domain. Using a monoclonal
      antibody specifically recognizing syntrophin-associated serine/threonine kinase
      124, strong expression of the protein was observed in neurons of the
      subventricular zone and granule cells of the olfactory bulb, Islands of Calleja,
      hippocampal dentate gyrus and cerebellum. syntrophin-associated serine/threonine
      kinase-124 is selectively localized in the nuclei of neurons and distinct from
      syntrophin-associated serine/threonine kinase-170, which is interacting with
      syntrophin on the cell surface. Considering the tissue and subcellular
      distributions of syntrophin-associated serine/threonine kinase-124, it is
      suggested that syntrophin-associated serine/threonine kinase-124 may have
      functions in transcriptional regulation for the features commonly shared by these
      neurons. On the other hand, syntrophin-associated serine/threonine kinase-124 was
      also localized in glia-like cell bodies in the corpus callosum and fiber bundles
      in the spinal trigeminal and solitary tracts, suggesting syntrophin-associated
      serine/threonine kinase-124 may have other functions in these types of cells.

PMID- 12614678
TI  - Differential regulation of beta-arrestin 1 and beta-arrestin 2 gene expression in
      rat brain by morphine.
AB  - Beta-arrestins are a family of regulatory and scaffold proteins functioning in
      signal transduction of G protein-coupled receptors including opioid receptors.
      Upon agonist stimulation, beta-arrestins bind to opioid receptors phosphorylated
      by G protein-coupled receptor kinases and promote receptor internalization and
      desensitization. Studies indicated that beta-arrestins are required in the
      development of morphine tolerance in mice. In the current study, we investigated
      the potential regulatory effects of morphine administration on beta-arrestin 1
      and beta-arrestin 2 mRNA levels in different brain regions in rat using in situ
      hybridization method. Our results showed that the acute morphine administration
      (10 mg/kg) resulted in approximately 30% reduction in both beta-arrestin 1 and
      beta-arrestin 2 mRNA levels in hippocampus while the chronic morphine treatment
      (10 mg/kg, b.i.d., for 9 days) caused no significant change in level of either
      beta-arrestin mRNA. In locus coeruleus, both acute and chronic morphine
      treatments resulted in significant decreases (over 50%) in beta-arrestin 1 mRNA
      level but failed to induce any change in the level of beta-arrestin 2 gene
      expression. The acute morphine administration had no significant effect on beta
      arrestin 1 or beta-arrestin 2 mRNA level in periaqueductal gray and cerebral
      cortex. However, after chronic morphine treatment, beta-arrestin 2 mRNA level
      decreased by 40% in periaqueductal gray and increased by 25% in cerebral cortex,
      in strong contrast to the unchanged beta-arrestin 1 mRNA level in these two brain
      regions. Furthermore, spontaneous or naloxone-precipitated withdrawal of morphine
      that did not affect the level of beta-arrestin 1 mRNA resulted in an aberrant
      increase (100% over control) in beta-arrestin 2 mRNA level in hippocampus. Our
      results thus demonstrated for the first time that opiate administration regulates
      level of beta-arrestin mRNAs in brain and the expression of beta-arrestin 1 and
      beta-arrestin 2 subtypes is differentially regulated in locus coeruleus,
      periaqueductal gray, and cerebral cortex by morphine. These data suggest that
      beta-arrestin 1 and beta-arrestin 2 may play different roles in the development
      of opioid tolerance and dependence.

PMID- 12614679
TI  - Abnormal kainic acid receptor density and reduced seizure susceptibility in
      dystrophin-deficient mdx mice.
AB  - Duchenne muscular dystrophy is characterized by a defect in dystrophin, which
      often causes mental retardation in addition to progressive muscular weakness. As
      dystrophin is localized in synaptic regions of the CNS, cognitive abnormalities
      associated with Duchenne muscular dystrophy are attributable to synaptic
      dysfunction. We report that dystrophin-deficient mdx mice were more resistant to
      kainic acid-induced seizures but not to GABA antagonist-induced seizures compared
      with the control mice. The kainic-acid receptor density in the brain was
      significantly lower in the mdx than in the control, although the density of
      muscarinic cholinergic receptors, another important neurotransmitter receptor for
      cognitive function, was normal. Moreover, mdx had significantly lower Timm
      staining intensity in the mossy fibers, which originate from the dentate granule
      cells and terminate on the pyramidal cells in the CA3 of the hippocampus. These
      results suggest that an instability of neurotransmitter receptors, such as
      kainate-type glutamate receptors, on synaptic membranes due to the disruption of
      dystrophin complex induces inefficient neurotransmission in Duchenne muscular
      dystrophy patients.

PMID- 12614680
TI  - The organochlorine pesticides gamma-hexachlorocyclohexane (lindane), alpha
      endosulfan and dieldrin differentially interact with GABA(A) and glycine-gated
      chloride channels in primary cultures of cerebellar granule cells.
AB  - The neurotoxic organochlorine pesticides gamma-hexachlorocyclohexane, alpha
      endosulfan and dieldrin induce in mammals a hyperexcitability syndrome
      accompanied by convulsions. They reduce the GABA-induced Cl(-) flux. The
      strychnine-sensitive glycine receptor also regulates Cl(-)-flux inhibitory
      responses. We studied the effects of these compounds on Cl(-) channels associated
      with glycine receptors in cultured cerebellar granule cells in comparison to the
      GABA(A) receptor. Both GABA (EC(50): 5 microM) and glycine (EC(50): 68 microM)
      increased (36)Cl(-) influx. This increase was antagonized by bicuculline and
      strychnine, respectively. Lindane inhibited with similar potency both GABA(A)
      (IC(50): 6.1 microM) and glycine (5.0 microM) receptors. alpha-Endosulfan and
      dieldrin inhibited the GABA(A) receptor (IC(50) values: 0.4 microM and 0.2
      microM, respectively) more potently than the glycine receptor (IC(50) values: 3.5
      microM and 3 microM, respectively). Picrotoxinin also inhibited the glycine
      receptor, although with low potency (IC(50)>100 microM). A 3D pharmacophore
      model, consisting of five hydrophobic regions and one hydrogen bond acceptor site
      in a specific three-dimensional arrangement, was developed for these compounds by
      computational modelling. We propose that the hydrogen bond acceptor moiety and
      the hydrophobic region were responsible for the affinity of these compounds at
      the GABA(A) receptor whereas only the hydrophobic region of the molecules was
      responsible for their interaction with the glycine receptors. In summary, these
      compounds could produce neuronal hyperexcitability by blocking glycine receptors
      besides the GABA(A) receptor. We propose that two zones of the
      polychlorocycloalkane pesticide molecules (a lipophilic zone and a polar zone)
      differentially contribute to their binding to GABA(A) and glycine receptors.

PMID- 12614681
TI  - Isolation of a set of genes expressed in the choroid plexus of the mouse using
      suppression subtractive hybridization.
AB  - The choroid plexus produces cerebrospinal fluid, providing a specialized
      environment for the CNS. We previously demonstrated that choroid plexus ependymal
      cells can enhance nerve regeneration in vivo and promote neurite outgrowth in
      vitro. To understand the molecular mechanisms of choroid plexus functions, we
      isolated genes predominantly expressed in the mouse choroid plexus using
      suppression subtractive hybridization. Out of the 49 complementary DNA (cDNA)
      fragments isolated in two types of screening, 43 matched known sequences in the
      database and six were novel. In one type of screening where choroid plexus cDNAs
      were subtracted with cerebral cortex cDNAs, transthyretin and phosphodiesterase I
      alpha were predominant. This is consistent with previous reports and supports the
      authenticity of our approach. In the other type of screening, cDNAs derived from
      the choroid plexus of neonatal (postnatal day 5) mice were subtracted with cDNAs
      from the choroid plexus of adult mice. RNA blot and/or in situ hybridization
      confirmed abundant expression, in the mouse choroid plexus, of the mRNA encoding
      gelsolin, phospholipid transfer protein, ATP-binding cassette transporter A8
      (ABCA8), androgen-inducible aldehyde reductase, and Na(+)/sulfate cotransporter
      SUT-1. Also, one novel gene (FS88) was found to be expressed in the choroid
      plexus from neonatal mice. Our data suggest that the choroid plexus cells produce
      molecules involved in processes such as prevention of fibrillization of amyloid
      beta-protein (transthyretin and gelsolin), lipid metabolism (phospholipid
      transfer protein and ABCA8), and detoxification (androgen-inducible aldehyde
      reductase).

PMID- 12614682
TI  - Episodic neonatal hypoxia evokes executive dysfunction and regionally specific
      alterations in markers of dopamine signaling.
AB  - Perinatal ischemic-anoxic and prolonged anoxic insults lead to impaired
      dopaminergic signaling and are hypothesized to contribute, at least in part, to
      the pathogenesis of disorders of minimal brain dysfunction such as attention
      deficit hyperactivity disorder. We hypothesized that subtle intermittent hypoxic
      insults, occurring during a period of critical brain development, are also
      pathogenic to dopaminergic signaling, thereby contributing to behavioral and
      executive dysfunction. Between postnatal days 7 and 11, rat pups were exposed to
      either 20-s bursts of isocapnic hypoxic gas, compressed air, or were left
      undisturbed with the dam. On postnatal days 23 pups were instrumented with
      electroencephalographic/electromyographic electrodes and sleep-wake architecture
      was characterized. Locomotor activity was assessed between postnatal days 35 and
      38, learning, and working memory evaluated between postnatal days 53 and 64. Rats
      were killed on postnatal day 80 and tyrosine hydroxylase, vesicular monoamine
      transporter, dopamine transporter, and dopamine D1 receptors were quantified in
      the prefrontal cortex, primary sensorimotor cortex, and precommissural striatum
      by Western blot analyses. Post-hypoxic pups spent less time awake and more time
      in rapid-eye-movement sleep during the lights-on phase of the circadian cycle,
      were hyperlocomotive, and expressed impaired working memory. Striatal expression
      of vesicular monoamine transporter and D1 receptor proteins were increased in
      post-hypoxic rats, consistent with depressed dopaminergic signaling. These
      observations lead to the intriguing hypothesis that intermittent hypoxia
      occurring during a period of critical brain development evokes behavioral and
      neurochemical alterations that are long lasting, and consistent with disorders of
      minimal brain dysfunction.

PMID- 12614683
TI  - Correlated multisecond oscillations in firing rate in the basal ganglia:
      modulation by dopamine and the subthalamic nucleus.
AB  - Previous studies from this laboratory have shown that many neurons in the basal
      ganglia have multisecond (<0.5 Hz) periodicities in firing rate in awake rats.
      The frequency and regularity of these oscillations are significantly increased by
      systemically injected dopamine (DA) agonists. Because oscillatory activity should
      have greater functional impact if shared by many neurons, the level of
      correlation of multisecond oscillations was assessed by recording pairs of
      neurons in the globus pallidus and substantia nigra pars reticulata in the same
      hemisphere, or pairs of globus pallidus neurons in opposite hemispheres in awake,
      immobilized rats. Cross-correlation (90-180 s lags) and spectral analysis were
      used to characterize correlated oscillations. Thirty-eight percent of pairs
      recorded in baseline (n=50) demonstrated correlated multisecond oscillations.
      Phase relationships were near 0 or 180 degrees. DA agonist injection
      significantly increased the incidence of correlation (intra- and
      interhemispheric) to 94% (n=17). After DA agonist injection, phase relationships
      of globus pallidus/substantia nigra neuron pairs were exclusively concentrated
      near 180 degrees, and phases of interhemispheric pairs of globus pallidus neurons
      were concentrated near 0 degrees. After subthalamic nucleus lesion (n=8), the
      incidence of correlated multisecond oscillations (or of multisecond oscillations
      per se) was not changed, although the consistent phase relationship between the
      globus pallidus and substantia nigra pars reticulata was disrupted. Subthalamic
      lesion also blocked apomorphine-induced decreases in oscillatory period and
      increases in oscillation amplitude, and significantly attenuated apomorphine
      induced changes in mean firing rate. The data demonstrate that multisecond
      oscillations in the basal ganglia can be correlated between nuclei, and that DA
      receptor activation increases the level of correlation and organizes internuclear
      phase relationships at these multisecond time scales. While the subthalamic
      nucleus is not necessary for generating or transmitting these slow oscillations,
      it is involved in DA agonist-induced modulation of mean firing rate, oscillatory
      period, and internuclear phase relationship. These data further support a role
      for DA in modulating coherent oscillatory activity in the basal ganglia, and for
      the subthalamic nucleus in shaping the effects of DA receptor stimulation on
      basal ganglia output.

PMID- 12614684
TI  - Mecamylamine interactions with galantamine and donepezil: effects on learning,
      acetylcholinesterase, and nicotinic acetylcholine receptors.
AB  - Patch-clamp recordings of single ion channel activity demonstrated that
      donepezil, but not galantamine, could be blocked by the nicotinic cholinergic
      antagonist mecamylamine, suggesting that galantamine acted at a separate
      (allosteric) site. The aim of this experiment was to demonstrate at a whole
      organism, behavioral level that galantamine, but not donepezil, could reverse
      mecamylamine-induced learning impairment. Forty-four young female rabbits
      received 15 sessions in the 750-ms delay eyeblink classical conditioning
      procedure, after one of five drug treatments: 0.5 mg/kg mecamylamine, 3.0 mg/kg
      donepezil, 0.5 mg/kg mecamylamine plus 3.0 mg/kg galantamine, 0.5 mg/kg
      mecamylamine plus 3.0 mg/kg donepezil, or sterile saline vehicle. An additional
      24 young female rabbits were tested in the explicitly unpaired condition after
      treatment with the same mecamylamine plus galantamine or donepezil combinations
      or with vehicle. In a previous study we demonstrated that 3.0 mg/kg galantamine
      facilitated learning in young rabbits. Donepezil (3.0 mg/kg) did not facilitate
      learning in this experiment. However, both galantamine and donepezil reversed the
      deleterious effects of mecamylamine on learning. Significant differences in
      plasma and brain acetylcholinesterase levels were detected among the drug
      treatment groups. Fifteen daily injections did not produce statistically
      significant changes in nicotinic receptor binding in any of the five treatment
      groups. One possible interpretation of these results is that donepezil affected
      nicotinic acetylcholine receptors by raising the synaptic level of acetylcholine
      and hence, the probability of receptor activation, whereas galantamine bound to
      distinct allosteric sites not blocked by mecamylamine.

PMID- 12614685
TI  - Intracerebroventricular administration of endothelin-1 impairs the habituation of
      rats to a novel environment in conjunction with brain serotonergic activation.
AB  - The effects of i.c.v. administration of endothelin-1, at a low dose that does not
      produce abnormal behaviors such as barrel-rolling, on the emotional state of rats
      exposed to a novel environment were examined. Changes in the emotional state of
      rats with a novel environment were evaluated in terms of changes in exploratory
      activity in the hole-board apparatus, i.e., locomotor activity as well as the
      number and duration of rearing and head-dipping behaviors. Rats treated with
      i.c.v. saline showed marked exploratory behaviors immediately after exposure to
      the hole-board apparatus, but these exploratory behaviors decreased rapidly with
      time. On the other hand, the habituation of rats to a novel environment was
      prolonged by the i.c.v. administration of endothelin-1 (0.3 and 1 pmol).
      Furthermore, we also found that i.c.v. administration of endothelin-1 (1 pmol)
      significantly increased the serotonin (5-hydroxytryptamine) turnover in some
      brain regions, i.e., the cerebral cortex, hippocampus and midbrain, and the
      inhibition of brain 5-hydroxytryptamine synthesis by treatment with p
      chlorophenylalanine (200 mg/kg/day, s.c.) for 2 days suppressed the behavioral
      effects of endothelin-1 (1 pmol, i.c.v.). In addition, i.c.v. administration of
      endothelin-1 (1 pmol) did not affect the spontaneous motor activity of rats. The
      present study demonstrated that i.c.v. administration of low doses of endothelin
      1 impairs the habituation of rats to a novel environment in conjunction with
      brain 5-hydroxytryptaminergic activation. These results suggest that the central
      endothelin system may play a significant role in mediating emotionality.

PMID- 12614686
TI  - Brain neurotransmitter turnover rates during rat intravenous cocaine self
      administration.
AB  - The turnover rates of dopamine, norepinephrine, serotonin, aspartate, glutamate
      and GABA were measured in 27 brain regions of rats self-administering cocaine and
      in yoked cocaine- and yoked vehicle-infused controls using radioactive pulse
      labeling procedures to identify brain neuronal systems underlying self
      administration. Changes in the activity of heretofore unrecognized dopamine,
      norepinephrine, serotonin, glutamate and GABA innervations of the forebrain
      specific to cocaine self-administration were found. This included innervations of
      the nucleus accumbens, ventral pallidum, lateral hypothalamus and the anterior
      and posterior cingulate, entorhinal-subicular and visual cortices. Turnover rates
      also were calculated using metabolite/neurotransmitter ratios which were
      inconsistent with the pulse-label technologies indicating that ratio procedures
      are not accurate measures of neurotransmitter utilization. Results with the pulse
      label technique provide evidence of the involvement of neuronal systems in
      cocaine self-administration not previously known, some of which may have a
      broader role in brain reinforcement processes for natural reinforcers (i.e. food,
      water, etc.) since drugs of abuse are thought to produce reinforcing effects by
      modulating activity in these endogenous systems.

PMID- 12614687
TI  - Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of
      cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in
      rats.
AB  - Recent evidence has demonstrated a critical role for the basolateral amygdala
      complex in the reinstatement of extinguished drug-seeking behavior produced by
      drug-paired cues. In the current study, we utilized a model of the acquisition
      and expression of cocaine-stimulus associative pairing in order to study the role
      of cholinergic input to the basolateral amygdala in mediating conditioned-cued
      reinstatement. Male, Sprague-Dawley rats were first trained daily to self
      administer i.v. cocaine on a fixed ratio 1 schedule of reinforcement. The
      muscarinic acetylcholine receptor antagonist, scopolamine, was directly infused
      into the basolateral amygdala prior to: a) classically conditioned pairing of a
      tone+light stimulus with cocaine infusions (acquisition), or b) testing of
      conditioned-cued reinstatement following a period of withdrawal from cocaine and
      extinction of cocaine-paired lever responding. Infusion of scopolamine just prior
      to the classical conditioning trial produced a dose-dependent disruption of
      cocaine-seeking behavior maintained by cocaine-paired cues during the
      reinstatement test. In contrast, infusion of scopolamine prior to the
      reinstatement test had no effect on conditioned-cued reinstatement of cocaine
      seeking behavior. These results indicate a crucial role for cholinergic
      innervation of muscarinic acetylcholine receptors in the basolateral amygdala
      during the formation, but not the expression, of stimulus-reward associations
      that mediate cue-induced cocaine-seeking behavior.

PMID- 12614688
TI  - Membrane properties of identified lateral and medial perforant pathway projection
      neurons.
AB  - The physiological characteristics of neurons that project to the hippocampus and
      dentate gyrus via the medial perforant pathway (projection neurons) are well
      known, but the characteristics of neurons that project to these areas via the
      lateral perforant pathway (projection neurons) are less well known. We have used
      retrograde tracing and whole-cell recording in brain slices to compare the
      membrane and firing properties of medial perforant pathway and lateral perforant
      pathway projection neurons in layer II of the medial and lateral entorhinal
      cortex. The properties of medial perforant pathway projection neurons were
      identical to those reported previously for spiny stellate neurons in the medial
      entorhinal cortex. In contrast, lateral perforant pathway projection neurons were
      characterized by a higher input resistance, a lack of time-dependent inward
      (anomalous) rectification, and a lack of prominent depolarizing spike
      afterpotentials. Voltage-clamp recordings suggest that the absence of anomalous
      rectification in lateral perforant pathway projection neurons is due to smaller
      hyperpolarization activated cation currents in these cells, and the lack of
      depolarizing afterpotential may be due to smaller low-threshold calcium currents.
      Persistent sodium current was also smaller in lateral perforant pathway
      projection neurons, but the difference in persistent sodium current between
      medial perforant pathway and lateral perforant projection neurons was much less
      pronounced than the difference in low voltage activated currents. These results
      underscore the functional differences between the medial entorhinal cortex and
      lateral entorhinal cortex, and may help to explain the differing abilities of
      these cortical areas to participate in certain types of network activity.

PMID- 12614689
TI  - Septal GABAergic and hippocampal cholinergic systems interact in the modulation
      of anxiety.
AB  - According to Gray [(1982) The neuropsychology of anxiety: an enquiry into the
      function of the septo-hippocampal system. Oxford: Oxford University Press; (1991)
      Neural systems, emotion and personality. In: Neurobiology of learning, emotion,
      and affect (Madden J, ed), pp 273-306. New York: Raven Press; Gray JA, McNaughton
      N (2000) The neuropsychology of anxiety. Oxford: Oxford University Press], the
      septum and the hippocampus act in concert to control anxiety. In the present
      study we examined a possible interaction between septal GABAergic and hippocampal
      cholinergic systems in the shock-probe burying test, an animal model of anxiety.
      In experiment 1, we found that a 10-ng infusion of muscimol in the medial septum
      produced a significant suppression of burying behavior, whereas lower doses (2.5
      and 5.0 ng) did not. In experiment 2, we found a significant suppression of
      burying behavior after a 20-microg infusion of physostigmine into the dorsal
      hippocampus, but not after lower-dose infusions (5 and 10 microg). In experiment
      3, we infused combined sub-effective doses of physostigmine and muscimol in the
      hippocampus and medial septum respectively. The combination of sub-effective
      doses of physostigmine (5 microg) and muscimol (2.5 ng) significantly reduced
      burying of the shock probe. The results indicate that the hippocampal cholinergic
      and septal GABAergic systems act synergistically in the modulation of anxiety.

PMID- 12614690
TI  - Social representations of HIV/AIDS in Central and Eastern Europe.
AB  - Although a relatively recent epidemic, HIV is now increasing in Eastern Europe
      faster than anywhere else in the world. In the study reported in this paper, we
      interviewed 511 business people and health professionals in five Central and
      Eastern European nations: Estonia, Georgia, Hungary, Poland and Russia, deriving
      our questions primarily from a Social Representations perspective. Respondents
      also freely completed their associations with the stimulus word 'AIDS'. Our
      findings indicate that, although there is considerable agreement about the threat
      posed by the epidemic, there are also notable cultural differences in
      attributions about the origin and spread of the virus and the nature of those
      groups at risk of infection. These findings are interpreted in the light of the
      historical legacies of the Communist era, as well as the real economic and social
      challenges faced by the population of this region.

PMID- 12614691
TI  - Trends in mortality attributable to current alcohol consumption in east and west
      Germany.
AB  - There is emerging awareness of alcohol as a cause of the persisting health divide
      between east and west Germany. This study quantifies the burden of alcohol
      attributable mortality in the two parts of Germany in the 1990s, taking account
      of both adverse and beneficial effects of alcohol. We used an epidemiological
      approach that applies cause-specific alcohol attributable fractions derived from
      published relative risks and data on the distribution of alcohol consumption in
      east and west Germany in 1990/1992 and 1998 to mortality data for the two regions
      in 1992 and 1997, thus producing an estimate of the number of alcohol
      attributable deaths 'caused' or 'prevented'. Including the cardio-protective
      effect of alcohol, there were about 1.4% more deaths among men aged 20+ in 1992
      in Germany than would have been expected in a non-drinking population, while
      there were 0.1% fewer deaths among women. By 1997, this had increased to 1.8%
      excess male deaths and 0.1% excess female deaths. In 1997, alcohol 'caused' 9.0%
      of all deaths in east German men compared with 5.6% in the west (women east:
      2.5%; women west: 2.2%). At the same time, alcohol 'prevented' 5.2% deaths in
      east German men compared with 4.3% in the west, while there were 2.9% and 2.0%
      fewer deaths in women. This resulted in a net excess of deaths due to alcohol,
      except east German women, where 0.3% deaths were estimated to have been averted
      by alcohol. Although by 1997 net deaths 'caused' by alcohol had increased in the
      west and declined in the east, the burden of mortality due to alcohol among men
      remained highest in the east whereas in women the order had reversed.Mortality
      attributable to alcohol contributes considerably to overall mortality and to the
      east-west gap in Germany. This study points to the need for comprehensive
      policies on alcohol in Germany to close the persisting east-west health gap.

PMID- 12614692
TI  - Socioeconomic differences in dietary patterns among middle-aged men and women.
AB  - The aim of the study is to (i) identify common dietary patterns, (ii) study
      socioeconomic differences in these dietary patterns, and (iii) assess whether
      they contribute to socioeconomic differences in biological risk factors. The data
      come from the Whitehall II study of London civil servants, who participated in
      the third phase (1991-1993) and were 39-63-years old (N=8004). Food frequency
      questionnaire and socioeconomic background information was from a questionnaire,
      and biological risk factors from a medical screening. Six dietary patterns were
      identified. In reference to high employment grade men, the odds ratios of low
      grade men consuming the 'unhealthy' or the 'very unhealthy' diet were 1.26 and
      3.34, respectively, while the odds for the 'French' diet was 0.13. Among women
      the corresponding odds were 2.98, 6.19 and 0.25. Adjusting for spouse's
      socioeconomic status and to a lesser extent smoking and exercise as well as job
      control attenuate these grade differences somewhat. Among men and women adjusting
      for dietary patterns accounted for about 25-50 per cent of grade differences in
      HDL and serum triglyceride levels.

PMID- 12614693
TI  - Behavioral risk factors for STD/HIV transmission in Bangladesh's trucking
      industry.
AB  - To examine behaviors that could influence STD/HIV transmission in Bangladesh's
      trucking industry, a survey was orally administered to 388 truck drivers/helpers
      at Tejgaon truck stand in Dhaka. A two-tiered sampling strategy was used: 38
      trucking agencies were randomly selected and a mean of 10.2 subjects was
      recruited from each agency. Focus group and in-depth interviews were also
      conducted. The focus was on behaviors that affect (i) exposure to STD/HIV
      infection, (ii) efficiency of transmission of infection and (iii) duration of
      infectiousness. The findings illustrated that intravenous drug use was not an
      important risk factor; only 1 subject had used drugs intravenously. Sexual risk
      behaviors, however, were prevalent: the mean number of sexual partners in the
      past year was 4.57 (SD=8.70) and in the past 3 months was 1.82 (SD=3.27).
      Premarital and extramarital sex was common, often with commercial sex workers
      (CSW); 54% of all subjects had relations with at least 1 CSW in the past year. In
      a multiple logistic regression analysis, subjects who engaged in other types of
      socially risky behavior (drinking alcohol, ingesting or smoking recreational
      drugs, having sex with other men) were significantly (p<0.05) more likely to have
      had sex with a CSW in the past year. While 7.2% of subjects had a male sex
      partner in the past year, 21% had ever had one (likely youthful experimentation
      for most). Condom use was very infrequent: of the 343 subjects who had ever had
      sexual intercourse only 31% had ever used a condom and most of those subjects had
      used only once or occasionally. Having sex with CSWs, being married, having heard
      of AIDS and age were significantly associated (p<0.05) with ever use of condoms.
      Frequently, subjects who had genital symptoms either did not have those symptoms
      treated at all or treated in a timely fashion, and over 1/3 did not change their
      sexual behavior while infected. To reduce the potential for the spread of STD/HIV
      in this population, appropriate treatment practices for sexually transmitted
      infections need to be encouraged and condom use promoted, particularly in the
      context of casual sexual relations.

PMID- 12614694
TI  - An examination of social capital and social disorganisation in neighbourhoods in
      the British household panel study.
AB  - Recent developments in social science research suggest that social environmental
      factors may be important for explaining community variations in health. We
      investigate the structural sources of two mechanisms that produce community
      variations in health. Using survey data collected from a representative cross
      section of British households we examine variations in neighbourhood social
      capital and neighbourhood social disorganisation across a sample of British
      neighbourhoods. Adjusting for respondent's attributes, we assess the effects of
      neighbourhood characteristics measured by the 1991 census in Britain. The results
      show that concentrated affluence, residential instability and ethnic
      heterogeneity predict social capital for women. Population density is the only
      neighbourhood characteristic to predict social capital for men. For both men and
      women concentrated disadvantage and population density are associated with social
      disorganisation. Residential instability is additionally associated with social
      disorganisation for women. For women it was found that neighbourhood
      characteristics interact with individual social class in accounting for
      variations in social capital, the effects of neighbourhood characteristics being
      larger for those in professional and managerial and skilled non-manual
      occupations. The results show that neighbourhood structural characteristics
      influence social organisation processes. This helps establish a link between the
      structural characteristics of neighbourhoods and individual health outcomes.

PMID- 12614695
TI  - Public health ethics: teaching survey and critical review.
AB  - The last decade has witnessed development of the new field of public health
      ethics, as well as growing emphasis on the importance of ethics education to both
      students and graduates of the health care professions. Using a topic-based
      interpretation of public health ethics this paper presents a questionnaire survey
      of the nature and content of teaching of public health ethics to medical
      undergraduates and public health postgraduate students in the United Kingdom.
      Completed questionnaires were returned by 76.9% (20/26) of medical schools and
      76.7% (23/30) of institutions teaching postgraduate public health courses. Public
      health ethics was described as being taught in 75% of medical schools and 52% of
      institutions providing postgraduate education. However, in both types of location
      the content and nature of teaching was patchy and often minimal. If medical
      schools and postgraduate institutions are serious about improving the discussion
      and teaching of ethical issues in public health, there will need to be
      considerable investment and commitment, accompanied by creativity and
      imagination. In parallel, the debate about the meaning of, and approaches to,
      public health ethics needs to be broadened and enriched. The topic-based
      interpretation of public health ethics has limitations. Alternatives are explored
      and critically reviewed.

PMID- 12614696
TI  - The effect of point of reference on the association between self-rated health and
      mortality.
AB  - This study examines the effect of point of reference on the predictive validity
      of self-rated health for mortality in a 5-year follow-up period. Two self-rated
      health measures are examined: an age group comparative question and a global
      question with no explicit point of reference. The baseline data (SweOld) is a
      nationally representative interview survey among Swedish people aged 77+ in 1992.
      Mortality for the 1992-1996 period was analysed using Cox proportional hazards
      regression models. Age-referential self-rated health was found to be a better
      predictor of elderly men's mortality both in non-adjusted models and in models
      adjusting for age and both self-rated health measures. In separate analyses, both
      measures were found to be equally strong predictors of women's mortality. When
      adding both measures into the model simultaneously, the age-referential question
      lost much of its predictive power. The findings suggest that self-rated health
      measures are not insensitive to differences in question wording.

PMID- 12614697
TI  - Trust and the development of health care as a social institution.
AB  - Health systems are inherently relational and so many of the most critical
      challenges for health systems are relationship and behaviour problems. Yet the
      disciplinary perspectives that underlie traditional health policy analysis offer
      only limited and partial insights into human behaviour and relationships. The
      health sector, therefore, has much to learn from the wider literature on
      behaviour and the factors that influence it. A central feature of recent debates,
      particularly, but not only, in relation to social capital, is trust and its role
      in facilitating collective action, that is co-operation among people to achieve
      common goals. The particular significance of trust is that it offers an
      alternative approach to the economic individualism that has driven public policy
      analysis in recent decades. This paper considers what the debates on trust have
      to offer health policy analysis by exploring the meaning, bases and outcomes of
      trust, and its relevance to health systems. It, first, presents a synthesis of
      theoretical perspectives on the notion of trust. Second, it argues both that
      trust underpins the co-operation within health systems that is necessary to
      health production, and that a trust-based health system can make an important
      contribution to building value in society. Finally, five conclusions are drawn
      for an approach to health policy analysis that takes trust seriously.

PMID- 12614698
TI  - Nostalgic and nostophobic referencing and the authentication of nurses' use of
      complementary therapies.
AB  - In recent years what can loosely be described as a sociology of complementary and
      alternative medicine (CAM) has begun to emerge. Although work has been conducted
      with lay therapists, orthodox practitioners, and consumers, overall, research in
      this area remains patchy and underdeveloped. Despite its role at the forefront of
      integration, the sociological study of the apparent affinity between nursing and
      CAM is virtually non-existent. This paper provides an exploratory analysis of how
      writers within the CAM nursing sub-world adopt a recourse to history (nostalgic
      and nostophobic referencing) as a strategy to authenticate the relationship
      between nursing and CAM and so facilitate continuing integration. A text
      analysis, of articles written on CAM in four nursing journals, was conducted.
      Eighty papers satisfied the inclusion criteria. Evidence is presented of the way
      in which writers attempt to authenticate integration of CAM through reference to
      its apparent interconnectedness with the historically grounded core of nursing
      values, and more specifically, with the key historical figure of the nurse
      Florence Nightingale (1820-1910). It is argued that these rhetorical strategies
      can be understood in the context of the need to engage in (primarily) intra
      professional persuasion: to protect and develop the values of their nursing sub
      world over alternatives. The findings are preliminary. Themes identified are
      illustrative of the potential offered by an analysis of nostalgic and nostophobic
      referencing in this context, and not a definitive account of it. Further research
      should examine individually produced texts from other sources, and documents
      produced by relevant professional bodies.

PMID- 12614699
TI  - Tobacco dependence: adolescents' perspectives on the need to smoke.
AB  - To address the need for a better understanding of the perspective of Canadian
      youths on tobacco dependence, a qualitative study using ethnographic techniques
      was conducted to describe the patterns of language that they use to describe
      tobacco dependence and the meaning that it has for them. The study was comprised
      of three inter-related phases: (1) A secondary analysis of 47 individual
      unstructured interviews with adolescents was completed to identify the words and
      phrases they use to explain tobacco dependence; (2) contrast and structural
      questions focusing on tobacco dependence were developed and used in open-ended
      interviews with 13 adolescents. Data analysis of the transcribed interviews
      resulted in a set of 60 key phrases that represented the primary ways youths
      describe the need to smoke; and (3) interviews were conducted with 14 adolescents
      that involved an open card sort using the set of 60 key phrases. All card sorts
      and transcribed interview data were analyzed to identify domains representing
      types of tobacco dependence and sub-types within each domain. From their
      descriptions about the need to smoke, five aspects of tobacco dependence were
      identified: social, pleasurable, empowering, emotional, and full-fledged. This
      study provides a step in elucidating the construct of tobacco dependence among
      the young. Further research is required to extend this understanding and to
      develop appropriate measures.

PMID- 12614700
TI  - The role of performance indicators in changing the autonomy of the general
      practice profession in the UK.
AB  - Performance indicators (PIs) are widely used across the UK public sector, but
      they have only recently been applied to clinical care. In doing so, they
      challenge a previously guarded aspect of clinical autonomy-the assessment of work
      performance. This "challenge" is specific to a primary care setting and in the
      general practice profession. This paper reviews the qualitative findings from an
      empirical study within one English primary care group on the response to a set of
      clinical PIs relating to general practitioners (GPs) in terms of the effect upon
      their clinical autonomy. Prior to interviews with GPs, primary care teams
      received feedback on their clinical performance as judged by indicators. Five
      themes were crucial in understanding GPs responses: the credibility of PIs, the
      growing need to demonstrate competence, perceptions of autonomy, the ulterior
      purpose of PIs, and the identity of the assessor of their performance. PIs are
      playing a key role in changing the locus of performance assessment along two
      dimensions: location and expertise. As the locus helps to determine the nature of
      clinical autonomy, it is likely to have implications for the nature of the
      general practice profession.

PMID- 12614701
TI  - Charitable food assistance as symbolic gesture: an ethnographic study of food
      banks in Ontario.
AB  - Community-based charitable food assistance programs have recently been
      established in several affluent nations to distribute public and corporate food
      donations to 'the needy'. In Canada, food banks comprise the primary response to
      hunger and food insecurity, but problems of unmet food need persist. We conducted
      an ethnographic study of food bank work in southern Ontario to examine the
      functioning of these extra-governmental, charitable food assistance programs in
      relation to problems of unmet need. Our results suggest that the limited,
      variable and largely uncontrollable supply of food donations shaped the ways in
      which food assistance was defined and the practices that governed its
      distribution. Workers framed the food assistance as a supplement or form of acute
      hunger relief, but generally acknowledged that the food given was insufficient to
      fully meet the needs of those who sought assistance. In response to supply
      limitations, workers restricted both the frequency with which individual clients
      could receive assistance and the amount and selection of food that they received
      on any one occasion. Food giving was essentially a symbolic gesture, with the
      distribution of food assistance dissociated from clients' needs and unmet needs
      rendered invisible. We conclude that, structurally, food banks lack the capacity
      to respond to the food needs of those who seek assistance. Moreover, the
      invisibility of unmet need in food banks provides little impetus for either
      community groups or government to seek solutions to this problem.

PMID- 12614702
TI  - How did Finland's economic recession in the early 1990s affect socio-economic
      equity in the use of hospital care?
AB  - The study evaluates the changes in socio-economic equity in the use of general
      hospital care in Finland from the late 1980s to the mid 1990s. In the early 1990s
      the Finnish economy plunged into a deep recession which slashed over 10% of GDP
      and resulted in a 12% decrease in national health expenditure. At the same time,
      the administration and financing of specialised health services were reformed.
      The impact on general hospital care was controversial: budgets were reduced but
      better productivity increased the supply of many services. According to the
      study, data, based on individual linkage of nationwide hospital registers to
      disposable family income data in population censuses, overall acute general
      hospital admission rates among Finns aged 25-74 increased by over 10% from 1988
      to 1996. For some surgical procedures, such as cataract, coronary
      revascularisation and some orthopaedic operations, rates more than doubled. In
      both years, lower-income groups generally used hospital care more than the better
      off. However, there was a slight shift towards a pro-rich distribution, mainly
      due to a larger increase in surgical care among the high-income groups. In 1988
      the lowest income quintile used 8% and in 1996 15% fewer operations than the
      highest. For individual procedures and surgical diagnostic categories, the
      general trends of increasing disparities were similar. Despite cuts in
      expenditures in the early 1990s, the Finnish general hospital system based on
      public funding and provision managed to increase the supply of services. However,
      this increase coincided with widening socio-economic discrepancies in the use of
      surgical services. The paper proposes that these increasing inequities were due
      to certain features of the Finnish health care system which create social
      discrepancies in access to hospital care. These include the high profile of the
      private sector in specialised ambulatory care and in the supply of some elective
      procedures, and semi-private public hospital services requiring supplementary
      payments from patients.

PMID- 12614703
TI  - Reliability of health utility measures and a test of values clarification.
AB  - This study examines the test-retest reliability of two methods of establishing
      health preference weights and assesses the effectiveness of a brief values
      clarification exercise. Survey participants were randomly allocated to one of two
      groups and received either a standard protocol for eliciting health preferences
      (comparison group) or an augmented protocol designed to encourage reflection and
      deliberation (intervention group). Preferences were elicited on three occasions
      over 5 weeks. The results show that the two valuation methods each had acceptable
      levels of test-retest reliability. No significant differences were found in
      preference weights over time or between intervention and comparison groups. The
      values-clarification exercise had some impact on individual answers, but the
      changes cancelled each other out at the group level. There was no discernable
      intervention effect at the group level. It is premature to draw conclusions from
      one study about why, or even how, a person's valuations might change over time,
      but our results support the use of current valuation techniques for group-level
      analyses.

PMID- 12614704
TI  - Marital status changes and body weight changes: a US longitudinal analysis.
AB  - The role of spouse is associated with better health. The dynamics of spousal
      roles can be represented by marital trajectories that may remain stable or may
      change by entry into marriage, dissolution of marriage, or death of a spouse.
      Body weight is an important health-related characteristic that has been found to
      have mixed relationships with marital status. This analysis examined changes in
      marital status and body weight in 9043 adults in the US National Health and
      Nutrition Epidemiological Follow-up Survey (NHEFS), a longitudinal national study
      that interviewed and measured adults in a baseline assessment and reassessed them
      again in a follow-up approximately 10 years later. Men's and women's weights were
      differently associated with marital changes. Women who were unmarried at baseline
      and married at follow-up had greater weight change than those who were married at
      both times. Analysis of weight loss and weight gain separately revealed that
      sociodemographic variables, including marital change, were more predictive of
      variation in weight loss than weight gain. Unmarried women who married gained
      more weight than women married at both times. Men who remained divorced/separated
      and men who became widowed lost more weight than men married at both baseline and
      follow-up. These findings suggest that changes in social roles, such as entering
      or leaving marriage, influence physical characteristics such as body weight.

PMID- 12614705
TI  - Evaluating the influence of implicit models of mental disorder on processes of
      shared decision making within community-based multi-disciplinary teams.
AB  - This paper reports findings from a qualitative study concerning the influence of
      implicit models of mental disorder on shared decision making within community
      based mental health teams. One-hundred participants representing five distinct
      multi-agency groups: psychiatrists, community psychiatric nurses, approved social
      workers, patients and informal carers operating within Leicestershire, England
      were interviewed using a standard case vignette describing a person whose
      behaviour suggests he may have schizophrenia. The results showed that each of the
      study's multi-agency groups implicitly supports a complex range of model
      dimensions regarding the nature of schizophrenia, the appropriateness of specific
      forms of treatment and care, and their respective rights and obligations towards
      each other. The influence of these implicit model patterns on processes of shared
      decision making are discussed through evaluating their contribution to our
      understanding of the power relationships existing between various practitioner
      groups (including informal carers), and between practitioners and patients during
      clinical encounters.

PMID- 12614706
TI  - Spirituality and attempted suicide among American Indians.
AB  - American Indians exhibit suicide-related behaviors at rates much higher than the
      general population. This study examines the relation of spirituality to the
      lifetime prevalence of attempted suicide in a probability sample of American
      Indians. Data were derived from a cross-sectional sample of 1456 American Indian
      tribal members (age range 15-57yr) who were living on or near their Northern
      Plains reservations between 1997 and 1999. Data were collected by personal
      interviews. Commitment to Christianity was assessed using a measure of beliefs.
      Commitment to tribal cultural spirituality (or forms of spirituality deriving
      from traditions that predate European contact) was assessed using separate
      measures for beliefs and spiritual orientations. Results indicated that neither
      commitment to Christianity nor to cultural spirituality, as measured by beliefs,
      was significantly associated with suicide attempts (p(trend) for
      Christianity=0.22 and p(trend) for cultural spirituality=0.85). Conversely,
      commitment to cultural spirituality, as measured by an index of spiritual
      orientations, was significantly associated with a reduction in attempted suicide
      (p(trend)=0.01). Those with a high level of cultural spiritual orientation had a
      reduced prevalence of suicide compared with those with low level of cultural
      spiritual orientation. (OR=0.5, 95% CI=0.3, 0.9). This result persisted after
      simultaneous adjustment for age, gender, education, heavy alcohol use, substance
      abuse and psychological distress. These results are consistent with anecdotal
      reports suggesting the effectiveness of American Indian suicide-prevention
      programs emphasizing orientations related to cultural spirituality.

PMID- 12614707
TI  - The role of choice in health education intervention trials: a review and case
      study.
AB  - Although the randomized, controlled trial (RCT) is considered the gold standard
      in research for determining the efficacy of health education interventions, such
      trials may be vulnerable to "preference effects"; that is, differential outcomes
      depending on whether an individual is randomized to his or her preferred
      treatment. In this study, we review theoretical and empirical literature
      regarding designs that account for such effects in medical research, and consider
      the appropriateness of these designs to health education research. To illustrate
      the application of a preference design to health education research, we present
      analyses using process data from a mixed RCT/preference trial comparing two
      formats (Group or Self-Directed) of the "Women take PRIDE" heart disease
      management program. Results indicate that being able to choose one's program
      format did not significantly affect the decision to participate in the study.
      However, women who chose the Group format were over 4 times as likely to attend
      at least one class and were twice as likely to attend a greater number of classes
      than those who were randomized to the Group format. Several predictors of format
      preference were also identified, with important implications for targeting
      disease-management education to this population.

PMID- 12614710
TI  - Revealing all.

PMID- 12614708
TI  - The new subjective medicine: taking the patient's point of view on health care
      and health.
AB  - Calls to respect patient autonomy and produce patient-centered outcomes have
      recently brought the patient's point of view back into the center of clinical
      medicine. Bioethics has argued that patient values must be respected in health
      care decisions. But it has generally not questioned medicine's goals, including
      its definition of health. For bioethics, health has remained an objective
      biological fact. However, pressures to improve the cost-effectiveness of medical
      care have increased interest in the subjective health and quality of life of
      patients. Perceived health, health-related quality of life, and health-state
      utilities bring health assessment progressively closer to the patient's
      perspective. Now even death's harm to patients is qualified by the value patients
      place on their health state. Medicine's epidemiological transition from acute to
      chronic disease is thus prompting an epistemological transition from primarily
      objective to primarily subjective evidence of health and health care
      effectiveness. Now some of the most important patient outcomes, like patient
      choices before them, are valid because they are subjective. Pathophysiology is
      appropriately becoming a means to produce health as it is defined from the
      patient's point of view. The physicians' job description will be changed to focus
      on patients' lives rather than patients' bodies. Definitive evaluations of
      medical effectiveness will occur within patients' lives rather than within
      doctors' hospitals. This further incorporation of patient subjectivity should
      carry us well beyond informed consent and the other protections for patient
      autonomy bequeathed to us by bioethics.

PMID- 12614712
TI  - Research centre to develop treatments for tropical diseases.

PMID- 12614713
TI  - No funds to control meningitis outbreak in Africa.

PMID- 12614714
TI  - Initiative to unify control of HIV/AIDS and tuberculosis.

PMID- 12614715
TI  - Germany's smallpox jab plan meets with resistance.

PMID- 12614716
TI  - Arrest spurs alert about "select agents" regulations.

PMID- 12614719
TI  - Bush emergency relief promises US 7.5 billion dollars for HIV drugs.

PMID- 12614720
TI  - Infectious diseases research boost.

PMID- 12614724
TI  - WHA to confirm Jong-Wook Lee as new Director-General.

PMID- 12614725
TI  - Antimicrobial resistance: can we see the wood for the trees?

PMID- 12614726
TI  - Countering HIV/AIDS in the face of scarcity.

PMID- 12614727
TI  - Nitric oxide in HIV-1 perinatally infected children treated with highly active
      antiretroviral therapy.

PMID- 12614729
TI  - Epstein-Barr virus-recent advances.
AB  - Epstein-Barr virus is a tumorigenic herpes virus that is ubiquitous in the adult
      population. The virus is generally spread to and between young children through
      salivary contact, and only causes clinical illness where primary infection is
      delayed until adolescence or beyond, when an intense immunopathological reaction
      leads to the symptoms of infectious mononucleosis in roughly 50% of cases. More
      than 90% of the world's population carry Epstein-Barr virus as a life-long,
      latent infection of B lymphocytes. Recent data show that by mimicking B-cell
      antigen-activation pathways the virus enters the long-lived memory B lymphocyte
      pool where it evades immune elimination by severely restricting its own gene
      expression. By influencing B-cell survival mechanisms Epstein-Barr virus may
      induce tumours such as B lymphoproliferative disease and Hodgkin's disease.
      Vaccines are being developed to prevent and/or treat these conditions, but an
      animal model is required to study pathogenesis before a rational vaccine strategy
      can be formulated.

PMID- 12614730
TI  - Modern laboratory diagnosis of tuberculosis.
AB  - One-third of the global population is believed to be infected with bacteria of
      the Mycobacterium tuberculosis complex, the causative agent of tuberculosis. More
      than 8 million new cases of tuberculosis occur annually leading to 2 million
      deaths. Mortality is particularly high in those coinfected with HIV and where the
      bacteria are multiple-drug-resistant strains--ie, strains resistant to at least
      isoniazid and rifampicin. Early diagnosis of tuberculosis and drug resistance
      improves survival and by identifying infectious cases promotes contact tracing,
      implementation of institutional cross-infection procedures, and other public
      health actions. This review addresses significant advances made in the diagnosis
      of infection, clinical disease, and drug resistance over the past decade. It
      proposes operational criteria for a modern diagnostic service in the UK (as a
      model of a low-incidence country) and explores some of the economic issues
      surrounding the use of these techniques.

PMID- 12614731
TI  - Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action
      and clinical management.
AB  - Cases of active tuberculosis have been reported worldwide with the use of
      therapeutic agents that inhibit tumour necrosis factor (TNF) alpha. TNFalpha has
      a central role in mycobacterial infection and disease. Accordingly, progression
      of recently acquired tuberculosis infection or reactivation of remotely acquired
      infection should be expected with the use of anti-TNF agents. The available in
      vitro and epidemiological evidence for the two currently approved agents,
      infliximab and etanercept, shows that the risk of development of active
      tuberculosis is greater with infliximab. Tuberculin skin testing (TST) should be
      undertaken before any significant immunosuppressive therapy including these
      agents, though the possibility of false-negative reactions in immunocompromised
      populations must be borne in mind. A positive TST should be followed by medical
      assessment and chest radiography, as well as by other tests judged appropriate by
      the physician to identify active disease. Active tuberculosis must be treated
      appropriately before initiation of treatment with an anti-TNF agent. Treatment of
      latent tuberculosis can be considered on an individual basis for TST-negative
      patients receiving anti-TNF agents when significant risk factors for infection
      are present.

PMID- 12614732
TI  - Impact of current transplantation practices on the changing epidemiology of
      infections in transplant recipients.
AB  - The spectrum of infections in transplant recipients has been substantially
      affected by novel immunosuppressive regimens and the use of antimicrobial agents.
      Epidemiology and presentation of traditional opportunistic pathogens has changed.
      Invasive aspergillosis and cytomegalovirus occur later in the post-transplant
      period. The incidence of infections that were previously encountered rarely--eg,
      BK virus nephropathy--has increased, the clinical course of hepatitis C virus
      recurrence has become more aggressive, the risk factors for invasive
      aspergillosis have changed, and non-aspergillus moulds are occurring more
      commonly in transplant recipients. Recognition of these trends as they unfold has
      significant implications for the clinical care of the transplant recipients, for
      providing insights into the pathogenesis, and for continually improving the
      approaches to the management of infections.

PMID- 12614733
TI  - The development of Lapdap, an affordable new treatment for malaria.
AB  - There is much discussion on how new drugs can be developed for use in developing
      countries at a price that makes them accessible to those who need them most. The
      development of a new antimalarial, chlorproguanil/dapsone (Lapdap), provides an
      example of a way this can be achieved. The idea of combining chlorproguanil with
      dapsone came from studies done in east Africa in the 1980s. These studies showed,
      both in vivo and in vitro, that chlorproguanil/dapsone had advantages over
      sulphadoxine/pyrimethamine. A public-private partnership was established
      subsequently to manage a development programme of a fixed ratio tablet of this
      drug combination. The partnership comprised GlaxoSmithKline (formerly SmithKline
      Beecham), the World Health Organization (WHO), and the UK's Department for
      International Development (DFID). All clinical, toxicological, and pharmaceutical
      chemistry studies are complete and the findings have been submitted for
      regulatory approval. The question now is how Lapdap might be used safely and
      appropriately if it receives regulatory approval. A public-health group has been
      formed by WHO (with funding from DFID and the Gates Foundation) to research into
      this issue. The Lapdap development team completed its objective of submitting
      Lapdap for drug registration within a period of 5 years and at a low cost.
      Experience with the development of Lapdap may provide a model for the
      introduction of other new drugs developed primarily for use in developing
      countries.

PMID- 12614734
TI  - Ill from eel?

PMID- 12614737
TI  - Tim Tucker--Director of the South African AIDS Vaccine Initiative. Interviewed by
      Pam Das.

PMID- 12614735
TI  - Providing HIV/AIDS care in Mbarara, Uganda.

PMID- 12614740
TI  - Harmonious coexistence.

PMID- 12614741
TI  - Mathematical model of corneal surface smoothing after laser refractive surgery.
AB  - PURPOSE: To construct a quantitative model of corneal surface smoothing after
      laser ablation for refractive correction. DESIGN: Experimental study,
      interventional case series, and meta-analysis of literature. METHODS: A theory of
      epithelial smoothing in response to corneal contour change is derived from
      differential equations that describe epithelial migration, growth, and loss.
      Computer simulations calculate the effects on postoperative epithelial thickness,
      topography, refraction, and spherical aberration. Model parameter is matched with
      laser in situ keratomileusis (LASIK) outcome in literature and in a retrospective
      study of primary spherical myopic (77 eyes) and hyperopic (19 eyes) corrections.
      Surgically induced refractive change was the main outcome measure. RESULTS:
      Simulated epithelial remodeling after myopic ablation produces central epithelial
      thickening, reduction in achieved correction, and induction of oblate spherical
      aberration. Simulation of hyperopic ablation shows peripheral epithelial
      thickening, a larger reduction in correction, and induction of prolate spherical
      aberration. Simulation using a minus cylinder laser ablation pattern shows
      decreased astigmatism correction and increased hyperopic shift. In the LASIK
      series, linear regression of achieved correction vs ablation setting in hyperopic
      and minus cylinder corrections shows slopes of 0.97, 0.71, and 0.74,
      respectively. These clinical results match model predictions when the smoothing
      constant is set at 0.32, 0.63, and 0.55 mm, respectively. CONCLUSIONS: Epithelial
      thickness modulations after ablation can be modeled mathematically to explain
      clinically observed regression and induction of aberration. The cornea appears to
      smooth over ablated features smaller than approximately 0.5 mm. The model
      provides an approach for designing ablation patterns that precompensate for the
      smoothing to improve final outcome.

PMID- 12614742
TI  - Impact of interocular differences in corneal asphericity on binocular summation.
AB  - PURPOSE: To evaluate the impact that interocular differences in corneal
      asphericity (Q) exert on binocular summation measured as the contrast-sensitivity
      function. DESIGN: Interventional case series. METHODS: A total of 92 emmetropic
      subjects took part in the experiment, classified according to the interocular
      differences in corneal asphericity (deltaQ) measured with an EyeSys-2000 corneal
      topographer. Fifty-four subjects had deltaQ < 0.1; 21 subjects had 0.1 < or =
      deltaQ < or = 0.2; and 17 had deltaQ > 0.2. The contrast-sensitivity function
      (CSF) was measured monocularly (for each eye) and binocularly with a B VAT II
      device. The spatial frequencies used were as follows: 2.4, 3.7, 6.0, 9.2, 12, 15,
      20, and 24 cycles per degree. RESULTS: Although the binocular CSF for the three
      groups studied was greater than the monocular in all the spatial frequencies
      studied, there were significant differences in binocular summation. The average
      binocular summation (for all the spatial frequencies) for the group with deltaQ <
      0.1 was 1.46, significantly higher than the group with 0.1 < or = deltaQ < or =
      0.2, in which the average binocular summation was 1.39 (P = .035), which was also
      significantly higher than the group deltaQ > 0.2, for which the average binocular
      summation was 1.26 (P < .0001). In this last group, the summation decreased to
      the level of the probability summation. CONCLUSIONS: Differences in corneal
      asphericity may affect the binocular visual function by diminishing the binocular
      contrast-sensitivity function. This result may have important implications in
      refractive surgery given that, although the subject becomes emmetropic, if
      interocular differences are induced in corneal asphericity, it could reduce
      binocular visual performance.

PMID- 12614743
TI  - Effect of steroid pulse therapy with and without orbital radiotherapy on Graves'
      ophthalmopathy.
AB  - PURPOSE: To report the effect of high-dose intravenous corticosteroid pulse
      therapy with and without orbital radiotherapy on Graves' ophthalmopathy. DESIGN:
      Nonrandomized clinical trial. METHODS: We selected 39 Japanese patients (age
      range, 22-64 years; mean, 48 years; 31 women, 8 men) who had active Graves'
      ophthalmopathy among 195 consecutive patients. In the first 20 patients, high
      dose intravenous methylprednisolone pulse therapy (1 g per day for 3 successive
      days, repeated 3 times within 3 weeks) followed by 24-Gy orbital radiotherapy was
      performed. In the other 19 of the 39 patients, high-dose intravenous
      methylprednisolone pulse therapy without orbital radiotherapy was performed.
      Coronal computed tomography (CT) of the orbit and exophthalmometry were performed
      before the corticosteroid pulse therapy, and 1 and 6 months after the
      corticosteroid pulse therapy. The maximum coronal section area of the most
      hypertrophic rectus muscle in each eye was measured based on orbital CT imaging.
      RESULTS: Clinical findings at study entry were not significantly different
      between the two groups. No significant difference was found in the maximum
      coronal section area of the most hypertrophic rectus muscle and the results of
      exophthalmometry measurements in both groups before the therapy. Extraocular
      muscle hypertrophy was significantly reduced 1 month and 6 months after the
      therapy (P < .01) in both groups. However, no beneficial therapeutic effect on
      proptosis was observed in either group at 1 month and 6 months after the therapy.
      No significant difference in the therapeutic effect on extraocular muscle
      hypertrophy and proptosis was found between the two groups. CONCLUSIONS: Orbital
      irradiation after corticosteroid pulse therapy had no beneficial therapeutic
      effects on rectus muscle hypertrophy or proptosis of active Graves'
      ophthalmopathy during the 6-month follow-up period.

PMID- 12614744
TI  - Combined phacoemulsification, intraocular lens implantation, and vitrectomy for
      eyes with coexisting cataract and vitreoretinal pathology.
AB  - PURPOSE: To report the preoperative, intraoperative, and postoperative outcomes
      of combining phacoemulsification and posterior chamber intraocular lens (IOL)
      implantation with pars plana vitrectomy in eyes with significant cataract and
      coexisting vitreoretinal pathology. DESIGN: Retrospective, consecutive,
      interventional case series. METHODS: Charts of patients undergoing combined
      procedures at the Wilmer Ophthalmologic Institute between March 1995 and May 2000
      were reviewed. RESULTS: In all, 122 eyes of 111 patients were identified. Patient
      ages ranged from 27 to 89 years (mean 65). Forty-three eyes had diabetic
      retinopathy; 11 had undergone vitrectomy previously. Macular pathology (hole,
      membrane, choridal neovascularization) was present in 69 eyes. The most common
      indications for surgery were diabetic vitreous hemorrhage, macular hole,
      epiretinal membrane, and retinal detachment. In all cases, phacoemulsification
      and IOL implantation were performed before vitreoretinal surgery. Preoperative
      vision ranged from 20/30 to light perception and postoperative vision ranged from
      20/20 to no light perception. In 105 patients vision improved, in 7 there was no
      change, and in 10 vision decreased. Postoperative complications included
      opacification of the posterior capsule, increased intraocular pressure, corneal
      epithelial defects, vitreous hemorrhage, retinal detachment and iris capture by
      the IOL. CONCLUSIONS: Combined surgery is a reasonable alternative in selected
      patients. Techniques that may simplify surgery and reduce complications include:
      careful, limited, curvilinear capsulorhexis; in-the-bag placement of IOLs; use of
      IOLs with larger optics; suturing of cataract wounds before vitrectomy; use of
      miotics and avoidance of long-acting dilating drops in patients with intravitreal
      gas; and use of wide-field viewing systems.

PMID- 12614746
TI  - New surgical treatment for superior limbic keratoconjunctivitis and its
      association with conjunctivochalasis.
AB  - PURPOSE: To introduce a new surgical procedure for treating superior limbic
      keratoconjunctivitis (SLK) and to suggest the association of SLK with
      conjunctivochalasis. DESIGN: Interventional case series. METHODS: Six eyes of
      five patients with long-standing severe ocular irritation unresponsive to
      treatment with topical steroid and artificial tears were operated on using our
      new procedure. This technique consists of four steps as follows: (1) Rose bengal
      (RB) staining is used to localize the abnormal conjunctival area; (2) an arc-like
      conjunctival incision is placed from the 2 to the 10 o'clock position adjacent
      and distal to the RB-stained area; (3) the conjunctiva is resected to form a
      crescent using the arc-like incision as the base; the size of the resection is
      determined by conjunctival redundancy after removal of the subconjunctival
      connective tissue; and (4) the crescent conjunctival opening is closed with
      interrupted sutures. In two eyes, the new surgical procedure was performed
      together with surgery for inferior bulbar conjunctivochalasis. RESULTS: In all
      operated eyes, RB staining had disappeared by the end of the second postoperative
      week; recovery from symptoms and loss of inflammation were recorded by 1 month
      after treatment. In the case with the longest follow-up (14 months), there was
      cytologic evidence of goblet cell recovery at 3 months after the operation. In
      another, there was normalization of the nucleo/cytoplasmic ratio of conjunctival
      cells without the appearance of goblet cells. CONCLUSIONS: Our treatment very
      effectively resolved symptoms associated with SLK, even in eyes unresponsive to
      conventional therapy with eye drops. Considering that we did not address the
      diseased part of the conjunctiva but rather the adjacent conjunctival redundancy,
      we propose that superior bulbar conjunctivochalasis is involved in the
      pathogenesis of SLK.

PMID- 12614745
TI  - Topical tacrolimus treatment of atopic eyelid disease.
AB  - PURPOSE: To describe the effects of topical tacrolimus treatment of severe atopic
      eyelid disease. DESIGN: Interventional consecutive case series. METHODS: A
      description of clinical findings and therapeutic response for five consecutive
      adult patients (mean age, 56.2 years; range 44-62) treated with topical
      tacrolimus for severe atopic eyelid disease at one institution. RESULTS: Five
      patients with bilateral atopic eyelid disease that was refractory to treatment
      with topical corticosteroids were treated with tacrolimus 0.03% ointment, applied
      to the affected eyelid skin of both eyes twice daily. Eyelid induration,
      erythema, and eczematous changes were substantially improved within 1 to 3 weeks
      after initiation of topical tacrolimus treatment in all patients. There was an
      associated decrease in ocular surface irritation and inflammatory signs in each
      of four patients who also had atopic keratoconjunctivitis. No adverse effect
      associated with tacrolimus treatment was noted during continued treatment for 5
      to 14 months. All patients were able to discontinue longstanding use of topical
      corticosteroid drugs. CONCLUSIONS: Application of topical tacrolimus on eyelid
      skin may be effective for treatment of severe atopic dermatitis of the eyelids,
      and may have secondary benefits for atopic keratoconjunctivitis. Topical
      tacrolimus may be used for at least 1 year without apparent adverse reaction in
      some patients, although the rate of adverse reaction cannot be determined from
      this small series.

PMID- 12614747
TI  - Surgical management of anterior chamber epithelial cysts.
AB  - PURPOSE: To review management strategies for treatment of anterior chamber
      epithelial cysts. DESIGN: Retrospective review of consecutive interventional case
      series. METHODS: Charts of patients treated for epithelial ingrowth over a 10
      year period by a single surgeon were reviewed. Cases of anterior chamber
      epithelial cysts were identified and recorded, including details of ocular
      history, preoperative and postoperative acuity, intraocular pressure (IOP), and
      ocular examination, type of surgical intervention, and details of further
      procedures performed. RESULTS: Seven eyes with epithelial cysts were identified.
      Patient age ranged from 1.5 to 53 years at presentation. Four patients were
      children. In four eyes, cysts were secondary to trauma, one case was presumably
      congenital, one case developed after corneal perforation in an eye with Terrien's
      marginal degeneration, and one case developed after penetrating keratoplasty
      (PK). Three eyes were treated with vitrectomy, en bloc resection of the cyst and
      associated tissue, fluid-air exchange and cryotherapy. The last four eyes were
      treated with a new conservative strategy of cyst aspiration (three cases) or
      local excision (one keratin "pearl" cyst), and endolaser photocoagulation of the
      collapsed cyst wall/base. All epithelial tissue was successfully eradicated by
      clinical criteria; one case required repeat excision (follow-up, 9 to 78 months,
      mean 45). Two eyes required later surgery for elevated IOP, two for cataract
      extraction and one for repeat PK. Final visual acuity ranged from 20/20 to hand
      motions, depending on associated ocular damage. Best-corrected visual results
      were obtained in the more conservatively managed eyes. CONCLUSIONS: Anterior
      chamber epithelial cysts can be managed conservatively in selected cases with
      good results. This strategy may be particularly useful in children's eyes, where
      preservation of the lens, iris, and other structures may facilitate amblyopia
      management.

PMID- 12614748
TI  - Conjunctival hyperemia in healthy subjects after short-term dosing with
      latanoprost, bimatoprost, and travoprost.
AB  - PURPOSE: To evaluate conjunctival hyperemia after short-term use of latanoprost
      0.005%, bimatoprost 0.03% and travoprost 0.004% in normal adults. DESIGN:
      Prospective, randomized, double-masked crossover active controlled comparison.
      METHODS: We evaluated conjunctival hyperemia by a standard photographic measure
      at the slit lamp and by anterior segment photographs in healthy subjects after
      dosing for 5 days with latanoprost, bimatoprost, or travoprost. Conjunctival
      hyperemia was evaluated at 24-hour trough (hour 0) and at hour 1 after dosing.
      Each subject was crossed over between periods after a 1-week washout interval.
      RESULTS: Twenty-eight subjects (mean age 26 +/- 9 years) completed this study.
      Several comparisons were noted to be significant between groups by slit-lamp
      biomicroscopy: first, at hour 0 latanoprost had significantly less hyperemia than
      bimatoprost; second, at hour 0 latanoprost showed significantly less change than
      bimatoprost compared with the study baseline (visit 2); third, at hour 1
      latanoprost had significantly less hyperemia than travoprost; fourth, at hour 1
      latanoprost demonstrated significantly less change from baseline in hyperemia
      than travoprost (visit 2); fifth, at hour 1 latanoprost had less change in
      hyperemia than bimatoprost or travoprost between the study and the nonstudy eye
      (P = .03); and last, at hour 1 latanoprost showed significantly less change than
      bimatoprost and travoprost compared with hour 0 (P = .04). Additionally, similar
      grades were observed by photographs with latanoprost demonstrating the lowest
      levels of hyperemia. Subjects complained less about other people noticing their
      red eye with latanoprost than bimatoprost or travoprost (P = .048). No serious
      adverse events were noted. CONCLUSIONS: This study suggests that latanoprost may
      cause significantly less short-term conjunctival hyperemia on average than
      bimatoprost or travoprost in healthy subjects.

PMID- 12614749
TI  - Relation of diabetic macular edema to cytokines and posterior vitreous
      detachment.
AB  - PURPOSE: To investigate whether angiotensin II (AII) or vascular endothelial
      growth factor (VEGF) is related to diabetic macular edema (DME) in patients with
      and without posterior vitreous detachment (PVD). DESIGN: A case-control study.
      METHODS: Vitreous fluid samples were obtained at vitreoretinal surgery from 28
      eyes of 28 DME patients without PVD, 8 eyes of 8 DME patients with PVD, 14 eyes
      of 14 nondiabetic patients, and 8 eyes of diabetic patients without retinopathy.
      The VEGF levels in vitreous fluid and plasma were determined by enzyme-linked
      immunosorbent assay, while AII levels were measured by radioimmunoassay. RESULTS:
      The vitreous levels of AII and VEGF were significantly higher in DME patients
      with or without PVD than in nondiabetic patients or diabetic patients without
      retinopathy (without PVD: P < .0061, P < .0001, P = .0261, and P < .0001; with
      PVD: P < .0012, P < .0001, P = .0473, and P < .0001, respectively). There was no
      significant difference in the vitreous levels of AII or VEGF between patients
      with or without PVD (P = .4948 and P = .6642, respectively). The vitreous level
      of AII significantly correlated with that of VEGF in DME patients without PVD (P
      = .576) or with PVD (P = .488). AII and VEGF levels in vitreous fluid were
      significantly higher than the respective plasma levels. CONCLUSIONS: We found
      that the vitreous levels of AII and VEGF were elevated in DME patients
      irrespective of the status of PVD. Angiotensin II and VEGF may be induced in the
      eyes and be related to the pathogenesis of DME.

PMID- 12614750
TI  - The effect of indocyanine-green on functional outcome of macular pucker surgery.
AB  - PURPOSE: To compare functional results after surgery for macular pucker either
      with or without indocyanine-green staining of the internal limiting membrane
      (ILM) and to evaluate the ultrastructure of the tissue removed. DESIGN:
      Retrospective analysis of two successive, consecutive, interventional case
      series. METHODS: Functional outcome (visual acuity, Goldmann perimetry) of 48
      eyes of 48 consecutive patients with (group 1, n = 20) or without (group 2, n =
      28) intraoperative use of indocyanine-green (ICG) was retrospectively analyzed.
      For statistical analysis, best-corrected visual acuity measured at the last
      presentation was considered. Only patients with an idiopathic macular pucker were
      included. Surgery consisted of three-port pars plana vitrectomy, and removal of
      epiretinal tissue and the ILM in a second step. Commercially available ICG with a
      concentration of.05% and an osmolarity of 275 mOsm was used to stain the ILM. The
      surgical technique used for both groups was identical, except the use of ICG.
      Epiretinal tissue of all eyes was harvested and prepared for ultrastructural
      analysis using light and electron microscopy. RESULTS: Follow-up time was 8.5
      months in group 1 and 5.4 months in group 2. Whereas patients operated on without
      ICG experienced a significant improvement of median best-corrected visual acuity
      from 20/63 (range, 20/400 to 20/32) preoperatively to 20/40 (range, 20/200 to
      20/25) postoperatively (P < .001), median best-corrected visual acuity remained
      20/63 before (range, 20/200 to 20/63) and after (range, 20/400 to 20/20) (P > .9)
      ICG-assisted peeling. There was a statistically significant difference (P = .013)
      in best-corrected postoperative visual acuity of patients with and without the
      use of ICG. An improvement of vision was noted in 86% of patients without and 55%
      of patients with ICG-assisted surgery. Thirty-five percent of patients after ICG
      application presented with a deterioration of visual acuity. Furthermore, we
      observed large visual field defects in 7 of 20 patients after ILM staining. No
      visual field defects were noted after conventional peeling. Histologic analysis
      revealed clear differences between the two groups concerning the amount of
      cellular elements adjacent to the retinal surface of the ILM: There was more
      cellular debris visible in specimens after ICG application during surgery.
      Additionally, in contrast to surgery without ILM staining, epiretinal cells had
      ruptured and lost their cellular integrity after ICG-assisted vitrectomy.
      CONCLUSIONS: Indocyanine green-assisted surgery for macular pucker might have an
      adverse effect on functional outcome. Although there were obvious differences in
      the ultrastructure of tissue removed during surgery, our observations cannot be
      explained by histologic analysis alone. Other, so far unknown mechanisms of
      action must be considered.

PMID- 12614751
TI  - Prevalence and characteristics of foveal retinal detachment without macular hole
      in high myopia.
AB  - PURPOSE: To report the prevalence of foveal retinal detachment without macular
      hole in a large number of highly myopic eyes using optical coherence tomography
      (OCT), and to clarify the demographic characteristics associated with foveal
      retinal detachment in these eyes. DESIGN: A consecutive, prospective,
      observational case series. METHODS: In 134 eyes of 78 consecutive patients with
      high myopia (refractive error of -8 diopters or more), we performed complete
      ophthalmic examinations and studied cross-sectional images of the macula with
      OCT. The patients were divided into two groups according to the presence (group
      1, n = 78 eyes of 45 patients) or absence (group 2, n = 56 eyes of 33 patients)
      of posterior staphyloma. Slit-lamp examination with a Goldmann three-mirror lens
      indicated that none of the eyes had a macular hole. RESULTS: In seven of 78 eyes
      (9.0%) with posterior staphyloma (group 1), OCT revealed foveal retinal
      detachment. Two of the seven eyes had foveal retinoschisis. Optical coherence
      tomography revealed no retinal detachment or retinoschisis in any eye without
      posterior staphyloma (group 2). Visual acuity of the seven eyes with foveal
      retinal detachment ranged from 20/40 to 20/200. Two of the seven eyes had visual
      acuity 20/50 or better. No patients complained of recent, progressive visual
      impairment. All seven eyes with foveal retinal detachment had severe myopic
      fundus changes (focal chorioretinal atrophy or bare sclera). CONCLUSIONS: In
      highly myopic eyes with posterior staphyloma, the prevalence of foveal retinal
      detachment without macular hole was 9.0%. In eyes with this type of retinal
      detachment, visual acuity varies and foveal retinal detachment tends to be missed
      on routine examination. Periodic examination using OCT is recommended for highly
      myopic eyes with severe myopic degenerative changes and posterior staphyloma.

PMID- 12614752
TI  - Clinicopathologic study after submacular removal of choroidal neovascular
      membranes treated with verteporfin ocular photodynamic therapy.
AB  - PURPOSE: To report the clinicopathologic findings after submacular removal of
      choroidal neovascular membranes (CNV) treated with verteporfin ocular
      photodynamic therapy. DESIGN: Interventional case series. METHODS: Retrospective
      review of eight eyes of eight patients who underwent submacular surgery for CNV
      after having previously received verteporfin ocular photodynamic therapy for
      presumed ocular histoplasmosis (one patient), age-related macular degeneration
      ([AMD] three patients) pathologic myopia (two patients), punctate inner
      choroiditis (one patient), and idiopathic CNV (one patient). All cases had
      undergone ocular photodynamic therapy with verteporfin using standard protocols.
      Six of eight patients suffered a submacular hemorrhage after ocular photodynamic
      therapy, and two of eight patients refused further ocular photodynamic therapy.
      All patients subsequently had submacular surgery with removal of the CNV. One
      membrane was routinely processed, sectioned, and stained with hematoxylin and
      eosin. Five membranes were stained with toluidine blue for light microscopic
      examination. Semithin (1.0 microm) sections were cut and stained with uranyl
      acetate-lead citrate for transmission electron microscopy. RESULTS: Choroidal
      neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29
      days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days
      (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic)
      after verteporfin ocular photodynamic therapy. Histopathologic and
      ultrastructural examination showed areas of vascular occlusion at 3 days that
      were not seen at later time points. All specimens had patent CNV. There were
      signs of vascular damage with extravasated erythrocytes and fibrin, pigment
      clumping in cells, and inflammatory cells in all but the 3-day specimen.
      CONCLUSIONS: This case series presents data only from patients who refused repeat
      treatment with ocular photodynamic therapy or who developed submacular hemorrhage
      after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days
      after verteporfin ocular photodynamic therapy showed partial vascular occlusion
      that was not present in later specimens. These later specimens demonstrated
      evidence of vascular damage. Verteporfin ocular photodynamic therapy does not
      appear to lead to permanent and complete occlusion of the CNV. Thus, treatments
      that lead to permanent closure of CNV without damage to the retinal pigment
      epithelium and sensory retina are still needed.

PMID- 12614753
TI  - Mapping posterior vitreous detachment by optical coherence tomography in eyes
      with idiopathic macular hole.
AB  - PURPOSE: To determine the relationship between posterior vitreous detachment and
      idiopathic macular hole. DESIGN: Observational case series. METHODS: In a
      prospective study, the posterior hyaloid face was scanned from the posterior pole
      to the far periphery by optical coherence tomography in 25 eyes (22 patients)
      with an idiopathic macular hole (stage 1 = 1, stage 2 = 7, stage 3 = 10, and
      stage 4 = 7), and a map of the posterior vitreous detachment was constructed.
      RESULTS: One eye with a stage 1 macular hole had a posterior vitreous detachment
      confined to the vascular arcade, but attached to the fovea. In all seven eyes at
      stage 2, the detached posterior hyaloid enlarged upward beyond the superior
      vascular arcade, but stopped at the margin of inferior vascular arcade. In two
      cases, the posterior vitreous detachment also extended temporally and
      superonasally. In all cases, the vitreous face remained attached to the fovea.
      Six of the 10 eyes at stage 3 had larger partial posterior vitreous detachment
      that extended not only upward, but also beyond the inferior vascular arcade,
      while in the other four eyes, the size and position of the posterior vitreous
      detachment was similar to stage 2 macular holes. However, unlike stage 2, the
      posterior vitreous detachment included the fovea in all eyes. All seven eyes with
      a stage 4 macular hole had complete posterior vitreous detachment that extended
      to the far periphery in all directions. CONCLUSION: There is a close correlation
      between the stage of the macular hole and the degree of posterior vitreous
      detachment. This close correlation suggests that progression of idiopathic
      macular hole is related to enlargement of the posterior vitreous detachment.

PMID- 12614754
TI  - Reproducibility and clinical application of a newly developed stabilized retinal
      laser Doppler instrument.
AB  - PURPOSE: To describe a newly developed stabilized retinal laser Doppler
      instrument, to report the reproducibility of retinal blood flow measurements, and
      to present examples of its clinical application. DESIGN: Experimental study.
      METHODS: The intrasession, intersession, and interobserver reproducibility of
      retinal blood flow measurements obtained using the Canon Laser Blood Flowmeter
      model CLBF 100 was assessed. Intrasession: the coefficients of variation (CV) for
      repeated measurements (5X) of retinal vessel diameter (D), time-average
      centerline blood velocity (V(av)), and blood flow (F) were calculated at 18 sites
      along temporal retinal arteries and 18 sites along temporal retinal veins using
      both eyes in six healthy volunteers. Intersession: the correlation coefficients
      and average differences between two sets of measurements at the same 36 retinal
      sites made by one examiner on two different days were calculated. Interobserver:
      the correlation coefficients and average differences between two sets of
      measurements at nine sites (five arterial and four venous) in five eyes of five
      of the volunteers made by two examiners on the same day were calculated. Results
      from two patients, one with branch retinal vein occlusion (BRVO), and one with
      central retinal vein occlusion (CRVO), are used to illustrate abnormal retinal
      circulatory characteristics. RESULTS: intrasession: CV (mean +/- SD) for D,
      V(av), and F were 5.5% +/- 2.2%, 13.1% +/- 6.3%, and 13.8% +/- 4.7% in arteries
      and 3.5% +/- 2.1%, 11.9% +/- 5.9%, and 12.7% +/- 5.5% in veins.
      Intersession/interobserver: strong correlations between measurements made by one
      examiner on two different days and by two examiners on the same day were found in
      D, V(av), and F. Average differences in F were 16.4% +/- 12.8% for intersession
      and 12.6% +/- 7.0% for interobserver comparisons. Results from the patient with
      BRVO show marked differences in flow characteristics in the affected quadrant
      compared with an unaffected quadrant in the same eye, and to the fellow eye.
      Results from the patient with CRVO show a dramatic improvement in flow
      characteristics after clearing of the occlusion. CONCLUSIONS: The reproducibility
      results and the fact that blood flow is measured in actual units of microl/min
      indicate that the instrument can be used for reliable comparison of blood flow
      characteristics at different retinal vascular sites in the same eye, at
      comparable sites in both eyes, and for comparison between patients and healthy
      control subjects.

PMID- 12614755
TI  - Adult-onset foveomacular vitelliform dystrophy: a study by optical coherence
      tomography.
AB  - PURPOSE: To evaluate the morphology of adult-onset foveomacular vitelliform
      dystrophy (AFVD) using optical coherence tomography (OCT) and to correlate the
      OCT findings with those of biomicroscopy and fluorescein angiography (FA).
      DESIGN: Prospective observational case series. METHODS: A complete ophthalmologic
      examination, including visual acuity, fundus biomicroscopy, FA, and OCT was
      performed in 21 eyes of 14 consecutive patients with AFVD. RESULTS: Mean age at
      presentation was 64 years (range, 39 to 84 years), and best-corrected visual
      acuity ranged from 20/25 to 20/400 (median 20/50). Sixteen of 21 eyes (11
      patients) exhibited late staining of lesions on FA. In these 16 eyes, OCT
      revealed that AFVD material consists of a hyperreflective structure located
      between the photoreceptor and the retinal pigment epithelium layers. The retinal
      pigment epithelium layer was linear and was not elevated, unlike what is observed
      in retinal pigment epithelium detachment. Five other eyes (x4 patients) without
      late staining in FA showed, by OCT, a hyperreflective area at the level of the
      retinal pigment epithelium band, with no material visible between the
      photoreceptor and retinal pigment epithelium layers. In all 21 eyes, the retina
      overlying the hyperreflective structure was raised by the pseudovitelliform
      material and was markedly thinned. CONCLUSIONS: Optical coherence tomography is a
      noninvasive useful tool that provides new information on the morphology of AFVD.
      It demonstrates, better than biomicroscopy, the location of the yellowish
      material under the sensory retina but above the retinal pigment epithelium,
      corresponding angiographically to the late staining. The foveal thinning found by
      OCT in all cases probably explains the progressive visual loss and possible
      evolution toward a full-thickness macular hole.

PMID- 12614756
TI  - A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point
      mutation (Phe112Ser) in the FOXC1 gene.
AB  - PURPOSE: Mutations of the forkhead transcription factor gene FOXC1 result in
      anterior segment anomalies. No description of the spectrum of defects resulting
      from a single point mutation of this gene exists in the ophthalmology literature.
      We have screened all available patients with Axenfeld-Rieger genes (PITX2 and
      FOXC1). In this report, we clinically characterize the spectrum of ocular and
      systemic manifestations in one family resulting from a previously reported point
      mutation (Phe112Ser) in FOXC1. DESIGN: Observational case series. METHODS: Ten
      members of a multigenerational family were examined for signs of glaucoma,
      anterior segment abnormalities, and systemic features of Axenfeld-Rieger
      syndrome. The examinations were performed in an ophthalmology examination room or
      in the patients' homes. Blood was obtained from 10 members and screened for
      mutations in FOXC1 using direct DNA sequencing. RESULTS: A single mutation
      causing a T to C change in codon 112 (Phe112Ser) of FOXC1 was present in six
      members of the family. Five of these six patients were examined and all
      demonstrated anterior segment anomalies. One patient had Axenfeld anomaly, one
      had Rieger syndrome, and one had both Axenfeld anomaly and Peters anomaly.
      Additionally, some members demonstrated cardiac abnormalities, which may be
      secondary to their FOXC1 mutation. CONCLUSIONS: A wide spectrum of clinical
      phenotypes can result from a single point mutation of FOXC1. This report confirms
      that Rieger syndrome (with dental and facial abnormalities) can be caused by a
      mutation in FOXC1. It is also the first report of Peters anomaly being caused by
      a FOXC1 mutation.

PMID- 12614757
TI  - White spot syndromes of the retina: a hypothesis based on the common genetic
      hypothesis of autoimmune/inflammatory disease.

PMID- 12614758
TI  - Are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR
      complex) specific autoimmune diseases?

PMID- 12614760
TI  - Iris color and intraocular pressure: the Blue Mountains Eye Study.
AB  - PURPOSE: To assess the relationship between iris color and intraocular pressure
      (IOP). DESIGN: Population-based, cross-sectional study. METHODS: The Blue
      Mountains Eye Study examined 3,654 largely Caucasian participants, aged 49 to 97
      years, from 1992 to 1994. Information was collected about glaucoma risk factors,
      and Goldmann applanation IOP measurements were taken. Iris color was assessed by
      comparing the undilated appearance of each eye with three standard photographs.
      Participants who had previous cataract or glaucoma surgery and those using
      glaucoma medications were excluded. RESULTS: Mean IOP measurements increased with
      increasing grades of iris pigmentation. After simultaneous adjustment for
      variables associated with IOP, mean measurements were 15.92 mm Hg for blue iris
      color, 16.04 mm Hg for hazel or green, 16.11 mm Hg for tan-brown, and 16.49 mm Hg
      for dark brown (P for trend = .001). CONCLUSIONS: This study demonstrates a
      modest but statistically significant association between increasing iris color
      and IOP.

PMID- 12614759
TI  - Retinal endovascular surgery and intravitreal triamcinolone acetonide for central
      vein occlusion in young adults.
AB  - PURPOSE: To report the results of retinal endovascular surgery and intravitreal
      triamcinolone acetonide on two eyes of two patients younger than 40 years of age
      with central vein occlusion. DESIGN: Interventional case reports from a study
      approved by the Institutional Review Board of North Broward Medical Center,
      Pompano Beach, Florida. METHODS: Two men, ages 37 and 39, with unilateral central
      vein occlusion were treated with retinal endovascular surgery and intravitreal
      triamcinolone acetonide. The main outcome measure was recovery of visual acuity.
      RESULTS: One patient recovered 8 lines of visual acuity, the other recovered 11
      lines. There was rapid clearance of intraretinal hemorrhage and edema in both
      cases. CONCLUSIONS: Retinal endovascular surgery and intravitreal triamcinolone
      acetonide may promote recovery of visual acuity in eyes of young adults with
      central vein occlusion.

PMID- 12614761
TI  - Surgery for subfoveal choroidal neovascularization in toxoplasmic
      retinochoroiditis.
AB  - PURPOSE: To report a case of subfoveal choroidal neovascularization in a patient
      with toxoplasmic retinochoroiditis who underwent surgical excision. DESIGN:
      Interventional case report. METHODS: A 36-year-old woman with toxoplasmic
      retinochoroiditis presented with sudden dimness of vision and metamorphopsia in
      the left eye. The patient was examined with ophthalmoscopy and fluorescein
      angiography. RESULTS: Fundus examination and fluorescein angiography of the left
      eye revealed a subfoveal choroidal neovascularization. Pars plana vitrectomy with
      submacular surgery was performed, with a postoperative improvement of visual
      acuity and resolution of the distortion. CONCLUSIONS: This case report describes
      a case of subfoveal choroidal neovascularization associated with toxoplasmic
      retinochoroiditis that responded remarkably well to vitrectomy surgery.

PMID- 12614762
TI  - Episcleral pseudomelanoma: late complication of scleral tunnel incision.
AB  - PURPOSE: To describe two patients who developed scleral thinning as a late
      complication of scleral tunnel incision for cataract extraction. DESIGN:
      Observational case report and interventional case report. METHODS: A 75-year-old
      man had an asymptomatic gray-brown subconjunctival nodule in the location of the
      healed scleral tunnel incision for cataract surgery. A 62-year-old man had a
      biopsy of a brown conjunctival nodule at the site of a scleral tunnel incision
      for cataract surgery. RESULTS: The 75-year-old patient with prolapsed uveal
      tissue was followed up for 4 years without change in the wound defect. The 62
      year-old patient had a biopsy because the exposed ciliary body mimicked a
      melanoma. CONCLUSIONS: Scleral defects with herniated uveal tissue as a late
      sequela of scleral tunnel incision for cataract surgery should be differentiated
      from melanoma and can be safely observed for years when covered by conjunctiva.

PMID- 12614763
TI  - Peripheral keratitis associated with erythema elevatum diutinum.
AB  - PURPOSE: To describe a case of peripheral keratitis associated with erythema
      elevatum diutinum (EED), an unusual immune-complex-mediated cutaneous vasculitis.
      DESIGN: Observational case report. METHODS: A 25-year-old man who was diagnosed
      15 months previously with erythema elevatum diutinum presented with an
      inflammatory peripheral keratitis of the left eye. RESULTS: Serologic
      investigations for systemic disorders associated with vasculitic peripheral
      ulcerative keratitis were unremarkable. As the sclerokeratitis was thought to
      represent an ocular extension of the patient's cutaneous vasculitis, dapsone
      therapy was initiated and resulted in a rapid response of both the cutaneous and
      the ocular inflammation. CONCLUSIONS: Erythema elevatum diutinum should be
      included in the differential diagnosis of vasculitic peripheral keratitis.

PMID- 12614764
TI  - A novel mutation of M1S1 gene found in a Vietnamese patient with gelatinous
      droplike corneal dystrophy.
AB  - To identify the genetic defect in the M1S1 gene responsible for gelatinous
      droplike corneal dystrophy (GDLD) in a Vietnamese family.Experimental study.
      Blood samples were collected from a patient and the unaffected members of a GDLD
      affected family. Fifty normal unrelated subjects of Vietnamese origin were used
      as controls. Genomic DNA was extracted from blood leukocytes. DNA analysis of the
      M1S1 gene was performed using polymerase chain reaction and direct sequencing.
      Sequencing of the M1S1 gene revealed a deletion of a 12-base-pair (bp) fragment
      from nucleotide positions 772 to 783 [772 to 783del(ATCTATTACCTG)], resulting in
      a loss of four amino acids at codons 258 to 261 (L258-liter261del). Yet, an
      insertion of nucleotide T in place of the missing sequence (772insT) was found.
      This combined mutation was homozygous in the GDLD-affected patient and
      heterozygous in his unaffected son and younger sister. Such genetic alteration
      was excluded in the control population. This is the first report of a mutational
      analysis performed in a Vietnamese patient with GDLD. In this family, the novel
      772 to 783del(ATCTATTACCTG) + 772insT mutation on the M1S1 gene was well
      cosegregated with the phenotype and thus expected to cause GDLD. Although the
      M1S1 gene was responsible for GDLD in Vietnamese patients, the mutation found
      here is completely different from that previously reported in Japanese patients,
      where GDLD is most frequently seen.

PMID- 12614765
TI  - Mycobacterium chelonae interface infection after endokeratoplasty.
AB  - PURPOSE: To report a case of interface infection by Mycobacterium chelonae in a
      patient who underwent endokeratoplasty. DESIGN: Interventional case report.
      SETTING: Clinical practice. METHODS: Two weeks after endokeratoplasty, a 74-year
      old woman developed multiple enlarging interface infiltrates in her right eye.
      Cultures performed on the preservation medium grew Mycobacterium chelonae.
      Penetrating keratoplasty (PK) surgery was performed after failure of conservative
      antibiotic therapy, including topical and systemic clarithromycin. RESULTS: Five
      months after PK surgery, the graft was clear and no signs of extraocular or
      intraocular inflammation were present. Cultures taken from the corneal interface
      at the time of PK surgery confirmed the presence of M. chelonae. Acid-fast
      bacilli were seen in the excised corneal button. CONCLUSIONS: M. chelonae should
      be ruled out as a possible etiologic agent when postoperative infection of the
      corneal interface occurs. Surgical intervention can lead to eradication of the
      infection when conservative treatment fails.

PMID- 12614766
TI  - Retinal capillary hemangioma treatment by indocyanine green-mediated
      photothrombosis.
AB  - PURPOSE: To describe the clinical, angiographic and optical coherence tomography
      (OCT) findings of a patient with a large retinal capillary hemangioma who was
      treated by indocyanine green-mediated photothrombosis. Interventional case
      report. METHODS: An 18-year-old male patient was treated at a tertiary referral
      center with a novel laser-dye procedure that uses low-irradiance 810-nm laser and
      intravenous indocyanine green injection and was prospectively evaluated with
      fluorescein and indocyanine green angiography, as well as OCT. RESULTS: Vision
      improved from 20/125 to 20/32 + 1 at 1-year follow-up. Fundus photography showed
      marked reduction of a 3 disk diameters retinal capillary hemangioma. Both
      fluorescein and indocyanine green angiography demonstrated reduced tumor
      perfusion and narrowing of the lesion feeder and draining vessels as early as 5
      days after indocyanine green-mediated photothrombosis; OCT showed immediate
      decrease in retinal elevation and complete resolution of subretinal fluid within
      2 months of treatment. Minimal laser-induced effects were noted in the vicinity
      of the tumor. CONCLUSIONS: Photothrombosis using low-intensity, 810-nm light to
      direct laser energy continuously at the tumor after intravenous indocyanine green
      infusion was effective in restoring macular architecture and improving vision in
      a patient with a large peripheral retinal capillary hemangioma by means of
      substantial occlusion of the tumor vasculature and resolution of subretinal
      fluid.

PMID- 12614767
TI  - Resolution of leukemic retinopathy following treatment with imatinib mesylate for
      chronic myelogenous leukemia.
AB  - PURPOSE: To report a case of leukemic retinopathy before and after treatment with
      imatinib mesylate (formerly STI-571) for chronic myelogenous leukemia (CML).
      DESIGN: Interventional case report. METHODS: A 58-year-old man diagnosed with
      stable phase CML (SP-CML) presented with blurry vision. Fundoscopy revealed
      several flame-shaped hemorrhages in the macular region in both eyes. One month
      after this initial visit, imatinib therapy was initiated. RESULTS: : The patient
      noticed improvement in his visual as well as his medical symptoms; on repeat
      examination 6 months after the initial visit, the retinal hemorrhages had
      resolved and remained so after 18 months. CONCLUSIONS: Imatinib appears to be an
      effective treatment for SP-CML, and the improvement in visual and medical
      symptoms in our case report correlates with this.

PMID- 12614768
TI  - Retinal angioma in a patient with Cowden disease.
AB  - PURPOSE: To report a rare case of ocular localization of Cowden disease. DESIGN:
      Case report. METHODS: A 50-year-old woman with a history of multiple tumors was
      diagnosed with Cowden disease. A PTEN gene mutation was found. Visual acuity of
      the left eye had decreased 2 years before diagnosis. RESULTS: Visual acuity was
      20/20 in the right eye and 20/200 in the left eye. Right eye fundus examination
      showed an epiretinal membrane associated with a peripheral and temporal inferior
      angiomatous lesion. Treatment consisted of cryoapplication and surgical removal
      of the epiretinal membrane after central vitrectomy. Although the anatomic result
      was satisfactory, the patient's visual acuity remained unchanged. CONCLUSIONS:
      Hamartomatous ocular lesions have been described in Cowden disease. We are
      unaware, however, of such retinal angiomatous lesions in patients with PTEN gene
      mutations.

PMID- 12614769
TI  - Indoor mold spore exposure: a possible factor in the etiology of multifocal
      choroiditis.
AB  - PURPOSE: To report on the correlation between indoor mold exposure and a case of
      multifocal choroiditis (MFC). DESIGN: Observational case report. METHODS: A 37
      year-old woman diagnosed with MFC who had had extensive mold exposure underwent
      an allergic evaluation, including a comprehensive environmental history, physical
      examination, radioallergosorbent test, and skin testing. RESULTS: The patient's
      vision deteriorated after numerous recurrences of MFC triggered by exposure to
      extremely high mold environments (mold counts recorded between 3,000 and 13,000
      mold spores/m(3)). CONCLUSIONS: Exposure to high indoor mold count environments
      may be a factor in the etiology of MFC. Further studies are indicated.

PMID- 12614770
TI  - Peripheral retinal nonperfusion associated with chronic myeloid leukemia.
AB  - PURPOSE: To report a case of peripheral retinal nonperfusion and chronic myeloid
      leukemia in a 23-year-old woman. DESIGN: Observational case report. METHODS: A
      complete ophthalmic and systemic evaluation was performed. RESULTS: Ophthalmic
      examination revealed peripheral retinal nonperfusion with retinal
      neovascularization in both eyes. Fluorescein angiography of both eyes showed a
      marked midperipheral and peripheral avascular retina temporally with
      arteriovenous anastomosis and seafan neovascularizations. Blood work showed no
      abnormalities, although marked leucocytosis (up to 750 x 10(9)/l) and
      thrombocytosis (646 x 10(9)/l) were present in 1998 when the patient was
      diagnosed with leukemia. Following treatment, the patient has been in remission.
      CONCLUSIONS: Peripheral retinal nonperfusion with retinal neovascularization may
      occur as a complication of chronic myeloid leukemia. In contrast to other studies
      describing this association, our patient had a bilateral peripheral retinal
      nonperfusion with seafan neovascularizations without relapse of the myeloid
      leukemia and without any of the other retinal signs associated with chronic
      myeloid leukemia, such as tortuosity of veins, intraretinal or preretinal
      hemorrhages, and cotton-wool exudates.

PMID- 12614771
TI  - Axonal loss after traumatic optic neuropathy documented by optical coherence
      tomography.
AB  - PURPOSE: To report longitudinal retinal nerve fiber layer (RNFL) thickness
      measurements using optical coherence tomography (OCT) in a patient with traumatic
      optic neuropathy. DESIGN: Observational case report. METHODS: A 14-year-old boy
      with severe optic nerve trauma had repeated OCT scans of the peripapillary
      retinal nerve fiber layer at 3 days, 20 days, 40 days, and 70 days after injury.
      RESULTS: There was gradual loss of nerve fibers as shown by the OCT color-coded
      map, RNFL thickness profile, and RNFL thickness measurements around the optic
      disk. At 70 days of follow-up, severe thinning of the RNFL was observable.
      CONCLUSIONS: These findings suggest that OCT is able to assess and monitor axonal
      loss after traumatic optic neuropathy.

PMID- 12614772
TI  - Primary orbital leiomyosarcoma: a case report with MRI findings.
AB  - PURPOSE: To present a case of a primary orbital leiomyosarcoma and the
      corresponding magnetic resonance imaging (MRI) appearance. DESIGN: Observational
      case report. METHODS: Correlation of MRI with clinicopathologic findings.
      RESULTS: A 56-year-old woman presented with a 10-month history of diplopia in
      left gaze and left exophthalmos. An enhanced MRI of the left orbit revealed an
      extraconal, peripheral-enhancing mass measuring 2 cm in maximal diameter with
      displacement of the medial rectus muscle. The mass was excised, and the diagnosis
      of leiomyosarcoma was made by pathologic examination. CONCLUSIONS: Although
      computed tomography scan and ultrasound have been the imaging modalities used
      previously to evaluate cases of primary orbital leiomyosarcoma, MRI can provide
      important additional information regarding tumor characterization that is useful
      in the diagnosis and treatment of this rare malignancy.

PMID- 12614773
TI  - Transient impaired vision, external ophthalmoplegia, and internal ophthalmoplegia
      after blepharoplasty under local anesthesia.
AB  - PURPOSE: To report a case of transient bilateral vision impairment with external
      ophthalmoplegia and internal ophthalmoplegia after blepharoplasty under local
      anesthesia. DESIGN: Interventional case report. METHODS: A 70-year-old man
      underwent bilateral upper blepharoplasty under local anesthesia. During orbital
      fat removal additional anesthetic was injected into both medial fat pads for pain
      control. RESULTS: Immediate postoperative examination revealed bilateral
      decreased visual acuity and internal ophthalmoplegia in the right eye. An
      exotropia was present with marked limitation of right eye adduction. These
      findings resolved completely 3 hours postoperatively. CONCLUSIONS: Local
      anesthesia during blepharoplasty can enervate the optic nerve, ciliary ganglion,
      and extraocular muscle nerves. Local anesthesia should be injected judiciously
      during orbital fat removal to avoid this reversible but alarming event.

PMID- 12614774
TI  - Ehrlichiosis optic neuritis.
AB  - PURPOSE: To describe a case of ehrlichiosis optic neuritis. DESIGN: Single
      observational case report. METHODS: A 41-year-old woman with symptoms and
      clinical and imaging signs consistent with optic neuritis presented to a tertiary
      care academic center for comprehensive neuro-ophthalmic evaluation. Main outcome
      measures included preoptic and postoptic neuritis polyvalent ehrlichiosis titers
      and magnetic resonance imaging (MRI) of orbits with gadolinium. RESULTS:
      Ehrlichiosis titers drawn 11 days before onset of eye symptoms were negative.
      Titers drawn 7 days after symptoms began were positive. The optic nerve enhanced
      with gadolinium on MRI. CONCLUSIONS: Ehrlichiosis can cause optic neuritis and
      should be considered in patients with optic neuritis after a febrile, flu-like
      illness in an endemic area.

PMID- 12614775
TI  - Simultaneous ipsilateral temporal fossa and orbital dermoid cysts.
AB  - PURPOSE: To describe a case of simultaneous dermoid cysts in the lateral orbit
      and temporal fossa. DESIGN: Interventional case report. METHODS: A 7-year-old boy
      with a lateral orbital mass and infratemporal fossa mass underwent computed
      tomography and surgical excision. RESULTS: Intraoperatively, two distinct cystic
      lesions were identified. The orbital lesion extended just beneath the lateral
      rim. The temporal fossa lesion extended posteriorly along the temporal fossa. No
      bony defect in the lateral orbital wall was identified, and each distinct lesion
      was completely excised. CONCLUSIONS: To our knowledge, this is the first reported
      case of multiple dermoid cysts in the orbital region. When imaging studies
      demonstrate separate cystic lesions and do not reveal a bony defect in the
      lateral orbital wall, multiple lesions should be suspected.

PMID- 12614776
TI  - Herpes zoster virus sclerokeratitis and anterior uveitis in a child following
      varicella vaccination.
AB  - PURPOSE: To report a case of herpes zoster virus sclerokeratitis with anterior
      uveitis following vaccination with live attenuated varicella vaccine (Oka
      strain). DESIGN: Case report. METHODS: The case records of the patient were
      reviewed retrospectively. Pertinent literature citations were identified using
      MEDLINE. RESULTS: A 9-year-old boy presented with herpes zoster ophthalmicus 3
      years following vaccination with live attenuated varicella vaccine (Oka strain).
      Examination of the affected eye revealed a moderate follicular response on the
      palpebral conjunctiva, decreased corneal sensation, mildly elevated intraocular
      pressure, diffuse anterior scleritis with marginal keratitis, and a moderately
      severe anterior uveitis. Amplified DNA from fluid taken from the base of a
      cutaneous vesicle produced wild-type varicella zoster virus (VZV) DNA, not Oka
      strain. CONCLUSIONS: Herpes zoster virus infection needs to be considered in all
      patients who present with scleritis, keratitis, or anterior uveitis, regardless
      of their varicella vaccination status.

PMID- 12614777
TI  - Tonic pupil and sarcoidosis.
AB  - PURPOSE: To present a case of tonic pupil associated with enhancement in the
      region of the ciliary ganglion on magnetic resonance imaging in a patient with
      sarcoidosis. DESIGN: Observational case report. METHODS: A 52-year-old woman with
      sarcoidosis had a right pupil exhibiting sectoral palsy to light and light-near
      dissociation. RESULTS: Topical administration of 0.1% pilocarpine demonstrated
      supersensitivity of the right pupillary sphincter muscle. Magnetic resonance
      imaging (MRI) with contrast revealed enhancement in the region of the right
      ciliary ganglion. CONCLUSIONS: Tonic pupil may be a manifestation of sarcoidosis,
      and in such cases, MRI may show enhancement at the level of the ciliary ganglion.
      Sarcoidosis should be included in the differential diagnosis of tonic pupil.

PMID- 12614778
TI  - Iris cyst secondary to latanoprost mimicking iris melanoma.
AB  - PURPOSE: To report an ocular side effect of topical latanoprost therapy. DESIGN:
      Single interventional case report. METHODS: A 73-year-old woman on latanoprost
      for primary open-angle glaucoma developed an iris cyst simulating an iris
      melanoma. RESULTS: The lesion disappeared over 8 weeks when latanoprost was
      stopped. CONCLUSIONS: In managing patients with iris-pigmented lesions, the list
      of medications should be reviewed. If the patient takes latanoprost, a trial off
      latanoprost is warranted.

PMID- 12614792
TI  - Neurocognitive deficit following mitral valve surgery.
AB  - OBJECTIVE: Neurocognitive deficit is an important complication in patients
      undergoing open heart surgery. The aim of this prospective, contemporary study
      was to objectively measure neurocognitive brain function following mechanical
      mitral valve replacement and mitral valve repair. METHODS: Forty consecutive,
      unselected patients (mechanical valve replacement n=20, mean age 65+/-14; valve
      repair n=20, mean age 64+/-7, P=0.896) entered this prospective, contemporary
      study. Neurocognitive function was objectively measured by means of P300 auditory
      evoked potentials (peak latencies, ms) and two standard psychometric tests (Mini
      Mental State Examination, Trailmaking Test A (TTA)), preoperatively, 7 days and 4
      months postoperatively. RESULTS: Before operation, neurocognitive brain function
      was comparable in both patients groups (mechanical valve replacement versus valve
      repair: P300 potentials 374+/-25 versus 378+/-46 ms; P=0.791 and TTA 57+/-15
      versus 54+/-10 s; P=0.552). Following mechanical valve replacement,
      neurocognitive function continuously worsened (7 day-follow-up: P300 potentials
      392+/-28, P=0.001 versus preop and TTA 65+/-17, P=0.0001; 4-month follow-up: P300
      potentials 406+/-39, P=0.0004; TTA 69+/-17, P=0.0001). Interestingly,
      neurocognitive brain function was unaffected in patients undergoing valve repair
      (7-day follow-up: P300 potentials 386+/-40, P=0.890 versus preop and TTA: 53+/
      10, P=0.644; 4-month follow-up: P300 potentials 374+/-36, P=0.166 and TTA 54+/
      11, P=0.147). At 4-month follow-up, patients with mechanical prostheses performed
      worse as compared to valve repair (P300 potentials: P=0.024; TTA P=0.014).
      CONCLUSION: As shown by P300 auditory evoked potentials and Trailmaking Test A,
      there is marked neurocognitive damage related to mechanical valve replacement,
      whereas mitral valve repair does not affect neurocognitive function. This finding
      supports the beneficial effect of mitral valve repair over mechanical valve
      replacement in the decision-making tree of borderline cases, which are suitable
      for both types of procedure.

PMID- 12614793
TI  - The dome of the left atrium: an alternative approach for mitral valve repair.
AB  - OBJECTIVE: Surgical repair of mitral insufficiency is most commonly performed
      through a left atriotomy via the inter-atrial groove or trans-atrial (septal)
      approach. While the dome of the left atrium approach has been described for
      mitral replacement concerns have been raised about its adequacy for complex
      repairs. We report our experience with mitral valve repair carried out through
      the dome of the left atrium, in comparison with more standard approaches.
      METHODS: One hundred and thirty-one consecutive patients undergoing mitral valve
      repair for regurgitation were reviewed retrospectively between 1995 and 2001.
      Three groups were created based on their surgical approach: inter-atrial groove
      group (n=43), trans-atrial group (n=18), and dome of the left atrium group
      (between the superior vena cava and the ascending aorta; n=70). RESULTS: The
      three groups were similar in terms of pre-operative variables except for
      significantly older patients in the inter-atrial groove group (P<0.001). The
      etiology of MR was 24% ischemic (P=ns between groups) and 52% of patients had a
      concomitant procedure, most commonly coronary artery bypass grafting (P=ns).
      Valve repairs were achieved using Carpentier techniques including: ring
      annuloplasty (n=130), isolated posterior leaflet resection (n=69), isolated
      anterior leaflet (n=11), or bi-leaflet repair (n=19). The overall mortality was
      4% with a median length of hospitalization of 7 days and these did not differ
      significantly between groups. However, longer CPB times (P<0.01) and requirement
      for prolonged mechanical ventilation (P=0.002) were more frequent in the inter
      atrial groove group. CONCLUSION: We report a simple, alternative approach for
      mitral valve repair via the dome of the left atrium that provides similar outcome
      to other commonly used approaches.

PMID- 12614794
TI  - Surgical radiofrequency ablation induces coronary endothelial dysfunction in
      porcine coronary arteries.
AB  - OBJECTIVES: Surgical radiofrequency ablation is increasingly used during open
      heart surgery for the treatment of chronic atrial fibrillation. The purpose of
      this study was to determine the effects of application of radiofrequency on
      coronary endothelial function and structure and establish the relationship
      between coronary lesions and distance of radiofrequency application. METHODS: Six
      Landrace swine (25.9+/-2.0 kg) were included in the study. With the heart kept
      beating, three epicardial radiofrequency lesions (20 W, 20 s duration, 60 degrees
      C) 2 cm in length each, were created 1, 5 and 10 mm away from the left anterior
      descending and the right coronary arteries. The circumflex artery served as
      control. Coronary rings were placed in organ chambers. After contraction to KCl
      and prostaglandin F2alpha, endothelium-dependent relaxations to bradykinin were
      studied. Gomori trichrome and hematoxylin-eosin safran staining were used for
      histological evaluation. RESULTS: Exposure to radiofrequency 1 mm from the
      coronary arteries caused a significant decrease in endothelium-independent
      contractions to KCl and endothelium-dependent relaxations to bradykinin compared
      to controls (P<0.05). No significant decrease of endothelium-dependent
      relaxations occurred for rings exposed to radiofrequency at a distance of 5 and
      10 mm, compared to controls. Histological examination showed endothelial
      disruption and medial smooth muscle cells at different stages of necrosis up to 5
      mm from the radiofrequency application site. CONCLUSIONS: Radiofrequency may
      induce coronary endothelial functional and morphological damages when applied
      less than 5 mm from the artery. Caution must be exerted during left atrial
      radiofrequency application due to the proximity of the circumflex artery.

PMID- 12614795
TI  - The hemodynamic performance of standard bileaflet valves is impaired by a tilted
      implantation position.
AB  - OBJECTIVES: Severe sclerosis of the native aortic annulus can result in a tilted
      implantation position of mechanical prostheses. In this study, the effects of
      tilting and rotation on the hemodynamic performance of standard bileaflet valves
      were assessed in an extracorporeal mock circulatory system. METHODS: A pulsatile
      mock circulation driven by a Berlin Heart system was developed. Main
      physiological components of the human circulation were mimicked. SJM-AHPJ
      prostheses (21, 23, 25 mm) were mounted in an artificial aortic root containing
      physiologically oriented coronary ostia. All experiments were performed under
      constant conditions (stroke volume 60 ml, heart rate 70 bpm, systolic pressure
      130 mmHg). Hydrostatic pressures were measured via fluid-filled catheters,
      transvalvular flow by ultrasonic probes. Data were digitally recorded at 50 Hz.
      Multiple pressure, volume, energy, and dimension parameters were derived off
      line. Each valve was tested in a 0 degrees (untilted) versus 20 degrees (tilted)
      position at three axial rotation angles (0 degrees, 45 degrees, 90 degrees ).
      Tilting was performed independent of rotation by elevation of the prosthesis in
      the non-coronary sinus. RESULTS: In all valves and all rotation angles, tilting
      resulted in a size-dependent significant increase of mean pressure gradient
      (range, 28-35% [21 mm valve], 59-96% [23 mm valve], 124-220% [25 mm valve]),
      valvular resistance (39-51, 84-121, 177-332%), regurgitation volume (84-148, 32
      131, 93-118%), and systolic energy loss (113-146, 30-132, 69-213%), as well as a
      decrease of total stroke volume (2-5, 0-11, 3-10%), effective stroke volume (6
      11, 9-14, 14-22%), cardiac output (6-11, 8-14, 13-22%), and effective opening
      area (16-24, 32-37, 47-57%). The strongest impairment of hemodynamic performance
      was seen at 90 degrees rotation with reference to total and effective stroke
      volume, cardiac output, mean pressure gradient, and regurgitation fraction.
      CONCLUSIONS: Tilting of bileaflet valves resulted in a significant impairment of
      systolic and diastolic hemodynamics. Superiority of larger valves diminished in
      the tilted position. The strongest tilting effect was seen at 90 degrees
      rotation. Such a position should therefore be avoided or surgically corrected by
      rotating the valve.

PMID- 12614796
TI  - Mechanical heart valve patients can manage oral anticoagulant therapy themselves.
AB  - OBJECTIVES: Thromboembolism and anticoagulant related bleeding are still the most
      common complications in mechanical heart valve patients. Management of the oral
      anticoagulant therapy is therefore a key determinant for these clinical
      complications. We hypothesize that patients selected to self-managed oral
      anticoagulant therapy have a better treatment quality than patients in
      conventional oral anticoagulant therapy. The aim of this study was to assess the
      time within the therapeutic International Normalized Ratio (INR) target range and
      the incidence of clinical complications in our group of patients, and compare
      these data with published data on conventional management. METHODS: Mechanical
      heart valve patients (N=94) with a mean age of 47.6 years (range 4.2-76.6 years)
      were trained in home blood analysis of INR using a CoaguChek home coagulometer
      and coumarin dosage adjustment. After training, the patients were followed by
      weekly INR measurements. The therapeutic range was a target INR +/-0.5. The
      indications for initiating oral anticoagulant therapy were: aortic valve (N=62),
      mitral valve (N=29), tricuspid valve (N=1) and multiple valves (N=2). RESULTS:
      The mean observation time was 2.1 years (range 0.04-6.2 years), and the total
      number of patient-years was 197. The patients were within the therapeutic INR
      target range for a median of 76.0% (range 32.1-100.0%) of the time. There were
      two major thromboembolic events and five major bleedings events, comprised of two
      deep vein thromboses (both in the same patient), four episodes of epistaxis and
      one case of gastrointestinal bleeding. All the events required short
      hospitalization, and after treatment all the patients were discharged from the
      hospital without any sequelae or other complications. Using published work as
      references the expected number of major thromboembolic and bleeding complications
      in conventional management was four and 12, respectively. CONCLUSIONS: Self
      management of oral anticoagulant therapy provides a good treatment quality for
      mechanical heart valve patients. We therefore consider self-management of oral
      anticoagulant therapy as an equally as good or potentially better treatment
      option for selected patients compared to conventional management.

PMID- 12614798
TI  - Biological vs. mechanical aortic root replacement.
AB  - OBJECTIVES: Although age and co-existing coronary disease are major determining
      factors when deciding valve choice (mechanical vs. biological) in simple aortic
      valve replacement, no studies have documented selection criterion for biological
      (BIO) vs. mechanical (MECH) aortic root prosthesis. METHODS: Two hundred and
      twenty-one consecutive patients underwent elective aortic root replacement with
      either BIO (homograft, n=111, Freestyle, n=25) or MECH composite grafts (n=85).
      Median age in BIO was 53 years and in MECH 54 years (P=NS). Groups were similar
      in gender, NYHA class and ejection fraction (BIO, EF=59% vs. MECH, EF=55%), but
      the need for concomitant coronary artery bypass grafting (CABG) did differ
      between groups (MECH=35% vs. BIO=17%, P=0.003). Mean follow-up was 42+/-28 months
      for mortality and 39+/-28 months for morbidity. RESULTS: Full root replacement
      was performed in 213 patients (96%) and hemi-root in eight (4%). The most common
      underlying etiologies were annulo-aortic ectasia (n=82, 37%), calcified
      degenerative (n=73, 33%) and bicuspid/congenital aortic valve disease (n=39,
      18%). Operative mortality was 1.5% for BIO and 2.4% for MECH (P=0.5). By
      univariate analysis there was a trend towards greater 5-year survival in BIO
      (92.4% vs. 88.2%, P=0.068). By multivariate analysis, increasing age (HR=2.4,
      P=0.003), previous valve replacement (HR=4.7, P=0.024), concomitant CABG (HR=3.7,
      P=0.032), and perioperative stroke (HR=9.9, P=0.0005) were all independent
      predictors of late death. The 5-year freedom from valve-related complications was
      similar in both groups (BIO=93% vs. MECH=86%, P=0.5). CONCLUSIONS: Elective
      aortic root replacement is an exceedingly safe operation. At mean follow-up of 4
      years, there is no meaningful difference in early or mid term valve-related
      results between BIO and MECH aortic root replacement. Continued evaluation for
      late valve-related complications in this cohort will be necessary to determine
      the advantages, if any, of one prosthesis over the other.

PMID- 12614797
TI  - Performance of stentless versus stented aortic valve bioprostheses in the elderly
      patient: a prospective randomized trial.
AB  - OBJECTIVES: Although stentless aortic bioprostheses are believed to offer
      improved outcomes, benefits remain unsubstantiated. The aim of our study was to
      compare stentless with stented bioprostheses, with regard to postoperative
      changes in left ventricular mass and hemodynamic performance, in the elderly
      patient. METHODS: Forty patients with aortic stenoses, over the age of 75 years,
      were randomized to receive either the stented Perimount (n=20) or the stentless
      Prima Plus (n=20) bioprosthesis. Left ventricular mass regression, effective
      orifice area, ejection fraction and mean gradients were evaluated at discharge, 6
      months and 1 year after surgery. RESULTS: Overall a significant decrease in left
      ventricular mass was found 1 year postoperatively. However, there was no
      significant difference in the rate of left ventricular mass regression between
      the groups. Furthermore, 1 year postoperatively, the hemodynamic performance of
      the valves and the change in the ejection fraction did not differ between the
      groups. CONCLUSIONS: Our study shows that in a randomized cohort of elderly
      patients with aortic stenosis, we were not able to detect significant
      differences, with regard to hemodynamic performance and regression of left
      ventricular mass, between the stentless and stented valve groups. To our
      surprise, previously reported findings of non-randomized trials that showed
      faster and more complete regression of left ventricular mass and hemodynamic
      benefits of stentless valves were not reproducible.

PMID- 12614799
TI  - Early and medium-term results after modified Fontan operation in adults.
AB  - OBJECTIVE: Single ventricle palliation is rarely performed in adults and the
      results are less optimal than in children. In this article we analyze our
      experience with the modified Fontan operation in this age group. METHODS: Data of
      15 consecutive patients with single ventricle with a mean age of 26 (range 16-38)
      years, who underwent Fontan operation between 3/92 and 1/2000 were
      retrospectively analyzed. Five patients had previously had an aortopulmonary
      shunt in childhood and two patients had previously received a bi-directional
      cavopulmonary shunt as adults. Eleven patients were preoperatively in NYHA class
      III and four in class II. The main factors for the selection of the patients
      before surgery were well-developed pulmonary arteries with lower lobe index
      120+30 mm/m(2), pulmonary artery pressure <18 mmHg, good cardiac function and
      enddiastolic systemic ventricular pressure <12 mmHg. The lateral tunnel Fontan
      operation (LTFO) was performed in ten patients and extracardiac Fontan operation
      (ECFO) in five. A fenestration 4-5 mm in size was constructed in all patients
      with LTFO and in three of five patients with ECFO. RESULTS: There was one
      intraoperative and one late death (total mortality 13%). The mean extubation time
      and hospital stay were 24 h and 21 days, respectively. Severe postoperative
      complications were observed in three patients (20%). Two LTFO patients out of a
      total of eight patients (53%) with perioperative arrhythmias received a permanent
      pacemaker due to bradyarrhythmia. During the median follow-up of 5.0 (range 2.3
      10.1) years, four patients developed arrhythmias; one of them had new onset
      bradyarrhythmia after LTFO and required permanent pacemaker implantation. The
      median postoperative oxygen saturation was 93% (range 90-98%). NYHA class
      improved significantly in 12 survivors. Cardiac catheterization (0.5-4 years
      postoperatively, n=12) showed excellent Fontan hemodynamics in all patients.
      CONCLUSIONS: The modified Fontan operation can be performed in adults with
      acceptable early and midterm mortality and morbidity and leads to either complete
      or marked relief of cyanosis and enhanced exercise tolerance in all survivors.
      Postoperative arrhythmias are one of the main drawbacks but the incidence of
      arrhythmias after ECFO seems to be lower. The long-term follow-up has yet to be
      established.

PMID- 12614800
TI  - Pulmonary artery banding: long-term telemetric adjustment.
AB  - OBJECTIVE: Adjustment of pulmonary blood flow is difficult in pulmonary artery
      banding for complex congenital heart defects. A new wireless, battery free,
      telemetrically controlled, implantable device (FloWatch, EndoArt, S.A., Lausanne,
      Switzerland) allowing for progressive occlusion/reopening of the device through a
      remote control at the wanted percentage of occlusion (adjustable pulmonary artery
      banding) underwent experimental evaluation. METHODS: Eleven mini-pigs underwent
      FloWatch implantation around the main pulmonary artery through left thoracotomy.
      The first group (n=4), mean age 18.2+/-0.1 weeks, mean body weight 12.0+/-0.1 kg,
      underwent FloWatch implantation as device tolerance test. The second group (n=7),
      mean age 8.6+/-3.4 weeks, mean body weight 5.1+/-1.5 kg, underwent functional
      evaluation: at implantation, 1, 3, 5, 8 and 10 weeks after implantation, the
      device was progressively occluded and reopened, with Doppler evaluation of the
      developed pressure gradient. RESULTS: The four mini-pigs of first group were
      sacrificed at mean age of 42.3+/-0.1 weeks, mean body weight 25.1+/-3.2 kg (mean
      interval of 24 weeks after implantation); the device was still functioning and
      histology revealed almost normal morphology of the pulmonary artery. In all seven
      mini-pigs of second group the possibility of narrowing/releasing the pulmonary
      artery was confirmed at implantation and during follow-up: at last control their
      mean age was 20.5+/-2.8 weeks and the body weight 12.7+/-3.7 kg. CONCLUSIONS:
      Complete adjustment of pulmonary blood flow is now possible with an implantable
      device allowing for pulmonary artery banding with early and late telemetric flow
      control.

PMID- 12614801
TI  - Postinfarction ventricular septal defect closure with Amplatzer occluders.
AB  - OBJECTIVE: Postinfarction ventricular septal defect (PIVSD) is a rare and life
      threatening complication with high risk of both surgical and medical treatment.
      Another option available now is transcatheter closure. The purpose of this paper
      is to report the results of such treatment with Amplatzer occluders. METHOD:
      Seven patients aged from 51 to 71 years were included. The procedure was
      performed between 2 and 10 weeks after myocardial infarction. One patient had
      double residual VSD (2 months after previous surgery) and another, coexisting
      critical stenosis of right coronary artery (RCA). All patients were in III/IV
      NYHA class, on intropes, one patient on aortic balloon counterpulsation. Venous
      jugular approach was used to close the VSD in six patients, venous transfemoral
      in one patient. Implantation of six Ampaltzer atrial septal occluders (ASO) and
      one muscular Amplatzer VSD occluder (VSO) were performed. RESULTS: All procedures
      but two were finished successfully. In one patient, the defect could not be
      entered neither from the venous nor the arterial side due to unusual oblique
      course (which was confirmed during subsequent operation). In the second patient
      (2 weeks after MI), the reason was unstable position of 24 mm ASO (probably due
      to necrotic borders of VSD). Immediate significant clinical improvement was
      achieved in all patients, in whom PIVSD was closed with Amplatzer occluders. In
      one postsurgical patient, two ASO were used; in another patient, prior to VSD
      closure, PTCA and stent implantation to RCA was performed. The stretched diameter
      of PIVSD ranged from 8 to 22 mm, the size of implanted Amplatzer occluders from
      12 to 24 mm. Fluoroscopy time was 60 min (18-120). During the procedure,
      ventricular fibrillation requiring defibrillation was observed in three patients.
      One patient died 1 week after the procedure because of multiorgan failure and
      increasing mitral incompetence (MI). CONCLUSIONS: Despite some technical
      problems, implantation of Amplatzer occluders, is an attractive option of
      treatment of patients with subacute PIVSD.

PMID- 12614802
TI  - Predictors of cerebrovascular events in patients subjected to isolated coronary
      surgery. The importance of aortic cross-clamping.
AB  - OBJECTIVE: Stroke is a major complication after coronary surgery, occurring in 1
      4% of the patients. In this study, we evaluate the incidence and pre- and
      intraoperative risk factors for the development of a cerebrovascular accident
      (CVA) and the impact of such an event on perioperative mortality and on hospital
      length of stay. METHODS: Data from 4567 patients submitted to isolated coronary
      artery bypass grafting (CABG) with hypothermic ventricular fibrillation between
      1992 and 2001 were entered prospectively into a dedicated computerized database
      and analyzed retrospectively at this time. Univariate and multivariate analyses
      were performed where appropriate. RESULTS: The incidence of postoperative CVA was
      2.5% (116 patients). Multivariable logistic regression identified the following
      variables to be independent predictors of a postoperative CVA: cerebrovascular
      disease (P<0.001; odds ratio (OR), 2.66), peripheral vascular disease (P<0.001;
      OR, 2.33), number of periods of aortic cross-clamping (P=0.019; OR, 1.31 per each
      period of aortic cross-clamping), LV dysfunction (P=0.012; OR, 1.82) and age
      (P=0.008; OR, 1.28 per each 10 years). Non-elective surgery showed a marginal
      significance (P=0.08; OR 1.83). The 30-day mortality for patients who experienced
      a CVA was 16.4% versus 0.6% for patients who did not (P<0.001). Postoperative CVA
      increased the length of hospital stay threefold to 20.3+/-28.3 days as compared
      with patients who did not have a postoperative CVA (7.6+/-4.2 days; P<0.001).
      CONCLUSIONS: Postoperative CVA dramatically increases the mortality and length of
      stay after CABG. Identification of predisposing factors permits preoperative risk
      stratification and may facilitate improved patient selection or optimization. Our
      study adds evidence to the superiority of the fibrillation technique over
      intermittent cross-clamping of the aorta, among non-cardioplegic techniques, in
      terms of neurological protection.

PMID- 12614803
TI  - Neurocognitive impairment and driving performance after coronary artery bypass
      surgery.
AB  - OBJECTIVE: Neurocognitive impairment is common after cardiac surgery but few
      studies have examined the relationship between postoperative neuropsychological
      test performance and everyday behavior. The influence of postoperative cognitive
      impairment on car driving has previously not been investigated. The purpose of
      this study was to evaluate neurocognitive function and driving performance after
      coronary artery bypass grafting (CABG). METHODS: Twenty-seven patients who
      underwent coronary artery bypass grafting with standard cardiopulmonary bypass
      technique and 20 patients scheduled for percutaneous coronary intervention (PCI)
      under local anesthesia (control group) were enrolled in this prospective study
      conducted from April 1999 to September 2000. Complete data were obtained in 23
      and 19 patients, respectively. The patients underwent neuropsychological
      examination with a test battery including 12 tests, a standardized on-road
      driving test and a test in an advanced driving simulator before and 4-6 weeks
      after intervention. RESULTS: More patients in the coronary artery bypass grafting
      group (n=11, 48%) than in the percutaneous coronary intervention group (n=2, 10%)
      showed a cognitive decline after intervention (P=0.01). In the on-road driving
      test, patients who underwent coronary artery bypass grafting deteriorated after
      surgery in the cognitive demanding parts like traffic behavior (P=0.01) and
      attention (P=0.04). Patients who underwent percutaneous intervention deteriorated
      in maneuvering of the vehicle (P=0.04). No deterioration was detected in the
      simulator in any of the groups after intervention. Patients with a cognitive
      decline after intervention also tended to drop in the on-road driving scores to a
      larger extent than did patients without a cognitive decline. CONCLUSION: This
      study indicates that cognitive functions important for safe driving may be
      influenced after cardiac surgery.

PMID- 12614804
TI  - Intermittent antegrade warm myocardial protection compared to intermittent cold
      blood cardioplegia in elective coronary surgery--do we have to change?
AB  - OBJECTIVE: Intermittent antegrade warm blood cardioplegia (IAWBC) is a simple and
      cost-effective method of myocardial preservation. However, there are only few
      prospective trials comparing this type of cardioplegia to established
      cardioplegic strategies in elective on-pump coronary surgery with respect to
      myocardial protection and outcome. METHODS: In a prospective, randomized trial
      IAWBC (33 degrees C) (n=100) was compared to intermittent antegrade cold (4
      degrees C) blood cardioplegia (n=100), regarding clinical outcome and myocardial
      protection using cardiac troponin-I (cTNI) and creatine kinase MB isoenzyme (CK
      MB) measurements to assess ischemia. RESULTS: Preoperative parameters were
      comparable in both groups. Results demonstrated no differences in-between the
      groups regarding mortality (2.0% both), incidence of perioperative myocardial
      infarction (2 versus 3%), need for intra-aortic balloon pump (3 versus 4%),
      length of ICU stay (2.0+/-2.5 versus 2.1+/-3.0 days) and incidence of
      postoperative atrial fibrillation (41 versus 34%). However, the necessity of
      defibrillation after cardiac arrest (18 versus 43%, P<0.001) was significantly
      less frequent and of lower intensity (3.4+/-10.8 versus 10.8+/-20.6 J, P<0.001)
      in the IAWBC-group. Postoperatively the ischemia markers were significantly lower
      in the IAWBC-group, cTNI within the first 72 h (from P<0.001 to P=0.013) and even
      CK-MB within the first 24 h (from P=0.004 to P<0.011). CONCLUSION: IAWBC is a
      safe and simple method in elective on-pump coronary artery bypass surgery.
      Significantly lower ischemic markers suggest an improved myocardial protection
      compared to cold blood cardioplegia in these patients.

PMID- 12614805
TI  - Diameter changes of occluded venous coronary artery bypass grafts in electron
      beam tomography: preliminary findings.
AB  - OBJECTIVE: To differentiate acute from chronic graft occlusions through diameter
      measurements by means of electron beam tomography (EBT). METHODS: Contrast
      enhanced EBT volume studies were carried out in 37 patients with one or more
      occluded venous coronary bypass grafts. Seventeen of 37 patients did not meet the
      inclusion criteria and were excluded from the assessment. The remaining 20
      patients had a total of 39 bypasses (16 patent, 23 occluded) and were assigned to
      one of three groups: group A consisted of patent grafts only (patent grafts, 13
      patients). Group B comprised 11 of 23 occluded grafts diagnosed within 10 days
      after bypass surgery (acutely occluded grafts, ten patients). Group C contained
      12 of 23 bypass occlusions that were at least 6 months old as documented by
      coronary angiography (chronically occluded grafts, ten patients). The mean graft
      diameter was determined by repetitive measurements on a workstation through
      blinded readers. The Mann-Whitney-U-test for unpaired samples was used for
      statistical evaluation. RESULTS: Mean graft diameter for groups A-C (patent,
      acutely, and chronically occluded bypasses, respectively) was 3.9 mm (+/-0.6;
      n=16), 5.4 mm (+/-1.9; n=11), and 0.3 mm (+/-.9; n=12), respectively (P<0.01
      each). Sensitivity and specificity for the detection of acute and chronic
      occlusions were 87 and 92% (cut-off 4.5 mm), respectively, and 92 and 96% (cut
      off 1 mm), respectively. CONCLUSIONS: EBT may allow for non-invasive
      differentiation between acute and chronic venous coronary bypass occlusions. This
      could help prevent unnecessary invasive recanalization procedures. Body veins may
      conserve their ability to increase in diameter in acute thrombosis when
      transplanted as coronary bypasses.

PMID- 12614806
TI  - ICU readmission after cardiac surgery.
AB  - OBJECTIVES: The increasing cost of intensive care unit (ICU) care and limited
      resources lead us to evaluate predictors of ICU readmission in a large group of
      patients undergoing coronary artery bypass surgery (CABG) at one institution.
      METHODS: Two thousand one hundred and seventeen consecutive patients undergoing
      CABG surgery between January 1999 and August 2001 were reviewed retrospectively.
      The reasons for readmission were determined by reviewing the physician's progress
      notes, the nurse's progress notes and the discharge summary. RESULTS: A total of
      75 patients were readmitted to ICU during the study period for a readmission rate
      of 3.6%. Eight of these were readmitted a second time, and three a third time,
      for a total of 86 readmissions. Forty-seven patients died, for a mortality of 2%
      among patients that were not readmitted to the ICU, compared to 17% among those
      who were readmitted (P<0.0001). Median hospital length of stay was 6 days for
      patients not readmitted and 23 days for those readmitted (P<0.0001). The most
      common reason for readmission was respiratory failure, accounting for 47% of
      readmissions (n=40). Multivariate analysis using a stepwise logistic regression
      analysis revealed that preoperative renal failure (odds ratio 2.13; CI 1.03-4.41)
      and prolonged mechanical ventilation of >24 h (odds ratio 10.52; CI 6.18-17.91)
      were the only independent predictors for readmission to the ICU after CABG.
      CONCLUSIONS: Identification of patients that have preoperative renal failure or
      that required initial ventilation for more than 24 h after CABG may help to
      identify patients at risk of ICU readmission. Preemptive strategies designed to
      optimize these high-risk patients may improve outcomes.

PMID- 12614807
TI  - Early and late outcome of myocardial revascularization with and without
      cardiopulmonary bypass in high risk patients (EuroSCORE > or = 6).
AB  - OBJECTIVE: To evaluate 30-day and late results in high risk patients (European
      score (EuroSCORE) > or = 6) who underwent isolated myocardial revascularization
      with and without cardiopulmonary bypass (CPB). METHODS: From November 1994 to
      December 2001, 1266 patients with EuroSCORE > or = 6 underwent isolated
      myocardial revascularization. Among them, applying the propensity score, we were
      able to select 1020 patients operated on without CPB (group A, n=510) and with
      CPB (group B, n=510) with the same preoperative characteristics. The only
      differences were the higher incidence of patients with age between 61 and 65
      years (9.4% in group A vs. 13.9% in group B, P=0.025) and the lower number of
      anastomoses/patient in group A (1.8+/-0.9 vs. 2.8+/-0.9, P<0.001). EuroSCORE were
      identical in both groups (7.8%). RESULTS: Thirty-day mortality was higher in
      group B (5.9 vs. 3.1%, P=0.035). Group A showed a lower incidence of
      cerebrovascular accidents (CVAs) (0.6 vs. 3.1%, P=0.003), whereas incidence of
      acute myocardial infarction (AMI) was similar (2.0% in group A vs. 2.5% in group
      B, P=ns). Early negative primary end-points and early major events incidences
      were higher in group B (8.2 vs. 3.9%, P=0.004, and 14.5 vs. 7.1%, P<0.001,
      respectively). Stepwise logistic regression confirmed that CPB was an independent
      predictor for higher early mortality (Odds ratio (OR) 2.0) and CVA, negative
      primary end-points and early major events incidences (OR 4.6, 2.3 and 2.4,
      respectively). Five-year freedom from the events explored (death due to any
      cause, cardiac death, AMI, AMI on a grafted area, redo/percutaneous transluminal
      coronary angioplasty (PTCA), redo/PTCA on a grafted area, target cardiac events
      (cardiac death, AMI in a grafted area and redo/PTCA in a grafted area) and any
      event were similar in both groups. CONCLUSIONS: In high risk patients myocardial
      revascularization without CPB shows better early outcome and similar clinical
      late results.

PMID- 12614808
TI  - The effect of obesity on mid-term survival following coronary artery bypass
      surgery.
AB  - OBJECTIVE: Several studies have shown no significantly increased risk of in
      hospital mortality for obese patients after coronary artery bypass grafting
      (CABG). However, the effect of obesity on mid-term survival has not been
      adequately studied. We set out to examine whether mid-term survival following
      CABG is affected by obesity. METHODS: We performed a retrospective study of 4713
      consecutive patients undergoing isolated CABG between April 1997 and September
      2001. Body mass index (BMI) was used as the measure of obesity, with 3429
      patients categorised as non-obese (BMI<30 kg/m(2)), and 1284 patients as obese
      (BMI> or = 30 kg/m(2)). Patient records were linked to the National Strategic
      Tracing Service, which records all deaths in the community, to establish current
      vital status. Deaths occurring over time were described using Kaplan-Meier
      techniques. To control for differences in patient characteristics, we used Cox
      proportional hazards analysis to calculate adjusted hazard ratios (HR) and 95%
      confidence intervals (CI). RESULTS: Three hundred and thirty (7.0%) deaths
      occurred during the study period, with a mean follow-up of 2.4+/-1.4 years. The
      crude HR of mid-term mortality for obese patients was 1.09 (95% CI 0.86-1.39;
      P=0.457). After adjustment for core pre-operative factors, the adjusted HR of mid
      term mortality for obese patients was 1.28 (95% CI 1.01-1.64; P=0.048). The
      adjusted freedom from death in the obese patients at 30 days, 1, 2, 3, and 4
      years was 97.9, 95.9, 94.2, 92.4 and 90.5%, respectively, compared with 98.4,
      96.8, 95.5, 94.0 and 92.5% for the non-obese patients. CONCLUSIONS: Although in
      hospital mortality after CABG does not seem to be adversely affected by obesity
      there appears to be a significant increase in mortality in obese patients during
      a 4-year follow-up period.

PMID- 12614809
TI  - Chest injury due to blunt trauma.
AB  - OBJECTIVE: Given its importance in trauma practice, we aimed to determine the
      pathologies associated with blunt chest injuries and to analyze the accurate
      identification of patients at high risk for major chest trauma. METHODS: We
      reviewed our experience with 1490 patients with blunt chest injuries who were
      admitted over a 2-year period. Patients were divided into three groups based on
      the presence of rib fractures. The groups were evaluated to demonstrate the
      relationship between the number of rib fractures and associated injuries. The
      possible effects of age and Injury Severity Score (ISS) on mortality were
      analyzed. RESULTS: Mean hospitalization time was 4.5 days. Mortality rate was 1%
      for the patients with blunt chest trauma, 4.7% in patients with more than two rib
      fractures and 17% for those with flail chest. There was significant association
      between the mortality rate and number of rib fractures, the patient's age and
      ISS. The rate of development of pneumothorax and/or hemothorax was 6.7% in
      patients with no rib fracture, 24.9% in patients with one or two rib fractures
      and 81.4% in patients with more than two rib fractures. The number of rib
      fractures was significantly related with the presence of hemothorax or
      pneumothorax. CONCLUSION: Achieving better results in the treatment of patients
      with chest wall injury depend on a variety of factors. The risk of mortality was
      associated with the presence of more than two rib fractures, with patients over
      the age of 60 years and with an ISS greater than or equal to 16 in chest trauma.
      Those patients at high risk for morbidity and mortality and the suitable approach
      methods for them should be acknowledged.

PMID- 12614810
TI  - A review of 24 patients with bronchial ruptures: is delay in diagnosis more
      common in children?
AB  - OBJECTIVE: Bronchial ruptures due to blunt chest traumas are rarely encountered
      injuries. Because they occur seldom in pediatric age groups, even total ruptures
      of bronchi can be overlooked in the absence of accompanying lesions. This
      condition may result in a delay of diagnosis that consequently leads to
      irreversible septic changes in the lungs, which make resections unavoidable. The
      determination of predisposing factor(s) may be valuable in predicting and
      prevention of such situations. METHOD: We reviewed the records of 24 patients
      with bronchial ruptures hospitalized between January 1974 and December 2001 in
      Ataturk Center for chest disease and chest surgery. We divided the cases as
      'early' and 'delayed' and each group consisted of 'adult (age>15 years)' and
      'pediatric (age<15 years)' patients. RESULTS: On reviewing the records of these
      patients, we observed that 75% of the delayed cases were under the age of 11
      years when they survived the thoracic trauma. CONCLUSION: The susceptibility of
      children to delays is emphasized and the possible causes are discussed in the
      light of world literature. Simple approaches to minimize the number of
      misdiagnosed pediatric cases are highlighted.

PMID- 12614811
TI  - Factors associated with cardiac rhythm disturbances in the early post
      pneumonectomy period: a study on 259 pneumonectomies.
AB  - OBJECTIVE: To identify predisposing factors associated with cardiac rhythm
      disturbances during the early post-pneumonectomy period (first 7 postoperative
      days). MATERIALS AND METHODS: During the study period (1995-1999), 259
      pneumonectomies were performed for malignant (244 cases) or benign disease (15
      cases). Postoperative monitoring of patients included continuous arterial
      pressure - rhythm monitoring and pulse oximetry. Cardiac rhythm disturbances
      during the intensive care unit stay were detected on the monitor screen and
      recorded with a 12-lead electrocardiogram. Cardiac rhythm disturbances associated
      with electrolytes or fluid balance abnormality, mediastinal deviation or surgical
      postoperative complications were excluded from the study. Age of patients,
      preexisting cardiac disease, side of pneumonectomy, intrapericardial procedures,
      stage of the malignant disease, expected postoperative FEV(1)<1200 ml,
      intraoperative transfusions of packed red cells, elevated right heart pressures,
      low postoperative serum magnesium levels and long operative times were considered
      as predisposing factors for the development of post-pneumonectomy cardiac rhythm
      disturbances. Statistical analysis has been made using logistic regression
      analysis, Student t-test and chi-square test. RESULTS: Cardiac rhythm
      disturbances were detected in 49 patients (18.91%). Atrial fibrillation/flutter
      (31 cases), supraventricular tachycardia (14 cases), and premature ventricular
      contractions (four cases) were the observed rhythm disturbances. Right
      pneumonectomy versus left pneumonectomy (P<0.0001) and intrapericardial
      pneumonectomy versus standard pneumonectomy (P<0.0001) were identified as strong
      predisposing factors for the establishment of post-pneumonectomy cardiac rhythm
      disturbances. Patients who established post-pneumonectomy cardiac rhythm
      disturbances had significantly higher (P=0.024) right ventricular systolic
      pressure (42.50+/-15.50 mmHg) when compared with patients who had postoperative
      sinus rhythm (29.07+/-7.71 mmHg) and had also longer operative times than
      patients who did not develop rhythm disturbances (P=0.015). Mortality rate in
      patients who developed post-pneumonectomy rhythm disturbances was 20.40%.
      CONCLUSIONS: Cardiac rhythm disturbances observed early after pneumonectomy are
      mainly of supraventricular origin, complicating right and intrapericardial
      pneumonectomies, patients with elevated right heart pressures and long operative
      times, and are associated with high mortality rates.

PMID- 12614812
TI  - The impact of thoracic surgical access on early shoulder function: video-assisted
      thoracic surgery versus posterolateral thoracotomy.
AB  - OBJECTIVE: Whether video-assisted thoracic surgery (VATS) is associated with less
      shoulder dysfunction when compared with posterolateral thoracotomy (PLT) remains
      unclear. We therefore conducted this prospective study to assess the shoulder
      function in patients following major lung resection using either the VATS or PLT
      approach. METHODS: Twenty-nine consecutive patients were prospectively recruited
      into the study. Eighteen patients underwent major lung resection through VATS
      (VATS group) and 11 patients through PLT (open group). Shoulder function was
      measured preoperatively, and postoperatively at 1 week, 1 month and at 3 months.
      All assessments were done by two experienced physiotherapists using the American
      Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form. RESULTS:
      Shoulder strength was significantly better preserved in the VATS group at 1 week
      after surgery when compared with the PLT group (92 versus 81% of preoperative
      value; P=0.024). VATS patients also had better range of motion especially with
      respect to external rotation at 1 week (98 versus 91%; P=0.015) and forward
      elevation at 1 month (98 versus 93%; P=0.024) and 3 months after surgery (100
      versus 96%; P=0.021). Analgesic requirement was significantly less in the VATS
      group postoperatively at 1 week (P=0.009) and 1 month (P=0.004). CONCLUSIONS:
      VATS major lung resection is associated with significantly less shoulder
      dysfunction and pain medication requirement in the early postoperative period
      when compared to the PLT approach.

PMID- 12614813
TI  - Long-term outcomes following VATS lobectomy for non-small cell bronchogenic
      carcinoma.
AB  - OBJECTIVES: Despite advantages regarding pain and muscle function, video-assisted
      thoracic surgery (VATS) lobectomy is infrequently performed and is particularly
      controversial in bronchogenic carcinoma. We have, therefore, reviewed our
      experience with VATS lobectomy for non-small cell lung cancer (NSCLC) in an
      attempt to define the long-term results of VATS lobectomy in this setting.
      METHODS: Patients were selected for surgery on the basis of clinical Stage I or
      II disease with routine use of thoracic/upper abdominal CT scanning and cervical
      mediastinoscopy. VATS resection was performed using the endoscopic hilar
      dissection technique. All related hilar nodes were cleared and supportative
      sampling of mediastinal stations beyond the reach of mediastinoscopy was
      undertaken. Perioperative data were collected prospectively and oncologic
      outcomes were assessed by 6 monthly census. RESULTS: One hundred and fifty eight
      patients (mean age 66 years) underwent 159 VATS lobectomies for NSCLC between May
      1992 and December 2001. One patient underwent staged bilateral resections. Twenty
      further procedures were uneventfully converted to open thoracotomy (rate=11.2%).
      The median operation time was 130 min and median operative blood loss was 60 ml.
      The median postoperative stay was 6 days. One patient (0.6%) died following VATS
      resection from acute respiratory distress syndrome (ARDS). Two VATS resection
      patients died following discharge but within 30 days of surgery. Combined,
      inpatient and 30-day outpatient mortality was, therefore, 1.8%. The stage
      distribution for resected lesions was: Stage I, 117; II, 33 and III, 8. Mean
      follow-up was 38 months (range: 1-107). Tumour recurred in 36 patients presenting
      as local recurrence in the hilum or mediastinum in nine (25%), metastatic disease
      in 23 (63.9%) and unknown pattern in four (11.1%). Kaplan-Meier calculated
      probabilities of freedom from cancer related or associated death at 60 months
      were Stage I, 77.9%; II, 51.4% and III, 28.6%. CONCLUSION: VATS lobectomy is a
      safe procedure which is associated with a low probability for conversion to open
      thoracotomy. The patterns of cancer recurrence do not suggest inadequate local
      clearance while the long-term survival data for Stage I NSLC cases is
      encouraging. We believe that this technique should become the operation of choice
      for early stage NSCLC.

PMID- 12614814
TI  - Comparison of computed tomography and systematic lymph node dissection in
      determining TNM and stage in non-small cell lung cancer.
AB  - OBJECTIVE: To compare computed tomography (CT)-based clinical TNM and staging to
      surgical-pathological staging with systematic lymph node dissection in primary
      non-small cell lung cancer. METHODS: The study included 49 non-small cell lung
      cancer patients that underwent lung resection and systematic lymph node
      dissection between 1997 and 2001. Preoperative clinical and CT findings were
      compared with surgical-pathological findings. Lymph nodes with a shortest
      diameter of over 1 cm on CT were considered abnormal, but did not contraindicate
      surgery. Patients with CT indicating an invasive T4 tumor, pleural carcinosis, or
      bulky N2 disease were excluded. RESULTS: Sixty-five percent (32/49) had
      epidermoid carcinoma, and 25% (12/49) had adenocarcinoma. N2 metastases were
      found in 12% (6/49). The clinical T category was correct in 71% (35/49), and the
      N category in 55% (27/49). The sensitivity for detecting N2 disease was 67%
      (4/6), and the specificity was 81% (35/43). The positive predictive value for N2
      disease was 33% (4/12), and the negative predictive value was 95% (35/37). Node
      by-node agreement on N2 metastatic location was 17% (1/6). Skip N2 metastases
      without any N1 involvement were found in 4% (2/49), or 33% (2/6) of all N2 cases.
      The clinical stage was correct in 45% (22/49), and complete TNM agreement was 37%
      (18/49). CONCLUSIONS: The clinical TNM and staging based on CT are inaccurate.
      The sensitivity for detecting N2 disease is poor, especially on node-by node
      basis. Preoperative exclusion of N2 metastases is quite reliable, but a positive
      finding should always be verified. Systematic mediastinal lymph node dissection
      is necessary to detect N2 metastases inaccessible to cervical mediastinoscopy,
      and skip N2 metastases without N1 involvement.

PMID- 12614815
TI  - Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison
      with adenocarcinoma of the lung.
AB  - OBJECTIVE: Bronchioloalveolar carcinoma (BAC) is considered a subtype of
      adenocarcinoma of the lung, without pleural, stromal or vascular invasion (World
      Health Organization (WHO) classification). Previous reports had demonstrated a
      better prognosis following surgery for patients affected by early stage BAC than
      those affected by other type of non-small cell lung cancer (NSCLC). We aim to
      analyse differences between stage I peripheral nodular BAC and stage I peripheral
      adenocarcinoma of the lung, METHODS: From January 1, 1993 to December 31, 1999,
      1158 patients were submitted to surgical resection for NSCLC. Out of them, 28
      patients (2.4%) resulted affected by stage I peripheral pure BAC and 80 (6.9%) by
      stage I peripheral adenocarcinoma. We made a comparison between these two groups.
      RESULTS: The percentage of females in BAC patients was similar to that registered
      in adenocarcinoma patients (21.4 vs. 17.5%). No differences were detected between
      smokers in BAC and adenocarcinoma patients (P=0.331). The upper lobes were the
      most common sites of the primary tumour in both tumour subtypes (71.4 vs. 67.5%).
      Relapse of disease was less frequent in BAC than in adenocarcinoma patients (14.2
      vs. 33.7%); recurrent disease developed intrathoracic with higher frequency in
      BAC patients (75 vs. 33.3%). Both 5-year disease-free and long-term survival were
      significantly higher in patients affected by BAC (81 vs. 51% and 86 vs. 71%,
      respectively) (P<0.05); when analysis is performed by dividing stage IA from IB
      tumours, BAC patients resulted to have higher DFS (stage IA, 93 vs. 58% -
      P=0.044; stage IB, 61 vs. 32.5%) and higher long-term survival (stage IA, 92 vs.
      79%; stage IB, 75 vs. 56%). CONCLUSION: Patients with stage I pure BAC have
      significantly longer disease-free and overall survival than those with similar
      stage adenocarcinoma. Even if classified as subtype of adenocarcinoma, BAC is
      characterised by clinical behaviour less aggressive than similar stage
      adenocarcinoma.

PMID- 12614816
TI  - Subtotal esophagectomy with extended 2-field lymph node dissection for thoracic
      esophageal cancer.
AB  - OBJECTIVE: To examine the efficacy of the Ivor Lewis esophagectomy with extended
      2-field lymph node dissection for thoracic esophageal carcinoma we reviewed our
      experience. METHODS: We analyzed the cases of 147 consecutive patients who
      underwent subtotal esophagectomy with extended 2-field lymph node dissection
      through Ivor Lewis approach for esophageal cancer from January 1996 through
      December 2000. Eighty-six patients were operated on for cancer of the midthoracic
      esophagus, 48 for cancer of the lower thoracic esophagus, and 13 for cancer of
      the aortal segment of the esophagus. No patient had received chemotherapy or
      radiotherapy before operation. RESULTS: There were 113 men (76.9%) and 34 women.
      Median age was 57 years (range 51-65 years). Postsurgical pathological studies
      revealed squamous cell carcinoma in 139 patients (94.6%), adenocarcinoma in five
      (3.4%), and adenosquamous carcinoma in three (2%). Positive abdominal and/or
      mediastinal lymph nodes were found in 122 patients (82.9%). At mean 43 nodes
      (range from 32 up to 75) were studied for each patient. Even in T(1)-T(2) tumors
      mediastinal or abdominal lymph nodes are involved in up to 80% of cases. However,
      in T(3)-T(4) stages the frequency of lymph node involvement is significantly
      higher (P<0.05). Postsurgical staging was as follows: stage I in three patients
      (2%), stage IIa in 20 (13.6%), stage IIb in 29 (19.7%), stage III in 54 (36.8%),
      and stage IV in 41 (27.9%). All distant metastases were lymphogenous. The
      operative mortality rate was 6.1%, and complications occurred in 62 patients
      (42.1%). The overall 5-year survive rate was 28.8% (median survival 36.1 months).
      The 5-year survival rate for patients in stage IIa was 59%; for those in stage
      IIb, 39.5%; for patients in stage III, 26.7%; and 0% for patients in stage IV.
      CONCLUSIONS: Subtotal esophagectomy with extended 2-field lymph node dissection
      through Ivor Lewis approach for esophageal cancer is a safe operation. Long-term
      survival is stage dependent. Effective multimodality treatment may be helpful for
      patients with advanced disease.

PMID- 12614817
TI  - An unusual case of breathlessness.

PMID- 12614818
TI  - Giant thymolipoma in association with myasthenia gravis.

PMID- 12614819
TI  - Ochronosis of the aorta.

PMID- 12614820
TI  - Thoracoscopical water jet lavage in coagulated hemothorax.
AB  - We propose the use of a pulsatile high-speed irrigation device during video
      assisted thoracoscopy for retained, in part coagulated hemothorax. Blood clots
      and membranes adhering to intrathoracic structures are easily removed by the
      water jet without damaging underlying structures. The efficient dilution of the
      sticky retained blood and the fragmented coagula enable their quick removal over
      a suction catheter.

PMID- 12614821
TI  - Complete thoracic ectopia cordis.
AB  - Thoracic ectopia cordis is a rare congenital defect with very few reported
      survivors after surgical correction. We report a case of complete thoracic
      ectopia cordis with double outlet right ventricle. The diagnosis was established
      antenatally and a repair was undertaken soon after birth. The child remained
      stable and was extubated on the fifth post-operative day. Forty-eight hours later
      the child succumbed to an unexplained respiratory arrest. Also presented is a
      review of the different surgical strategies for this unusual condition.

PMID- 12614822
TI  - Tricuspid valve papillary fibroelastoma: an unusual cause of intermittent
      dyspnea.
AB  - A 67-year-old woman was referred for investigation of intermittent dyspnea, which
      was known for years but had been worsening over the previous 3 months. Two
      dimensional echocardiography revealed the presence of a mass attached to the
      anterior leaflet of the tricuspid valve. The patient was successfully operated on
      to excise the right atrial mass and preserve the tricuspid apparatus.
      Morphological examination of the excised tissue led to the diagnosis of papillary
      fibroelastoma. Surgical treatment should be considered when such a tumor is
      diagnosed, even in asymptomatic patients, because of the possible risk of
      embolization.

PMID- 12614823
TI  - Reversal of radial artery 'string sign' at 6 months follow-up.
AB  - The clinical importance of radial artery string sign is still debated. We present
      a case of reversal of radial artery string sign in 6 months with concomitant
      involution of competitive flow arising from an important collateral coronary
      circulation to an occluded right coronary artery. The hypothesis that the string
      sign is an extreme form of autoregulation of the radial artery is confirmed, and
      the flow reserve of this conduit is emphasized.

PMID- 12614825
TI  - Median sternotomy closure.

PMID- 12614828
TI  - The effect of caffeine reduction on sleep quality and well-being in persons with
      HIV.
AB  - OBJECTIVES: With reports of high rates of sleep disruption in Human
      Immunodeficiency Virus (HIV) + persons, this study tested whether there were
      differences in sleep quality and well-being between a group of HIV+ persons who
      reduced their caffeine intake from baseline by 90% or greater for 30 days (n=44)
      versus a group of HIV+ persons who continued their usual caffeine consumption
      (n=44). METHODS: Subjects were administered pre- and post-Pittsburgh Sleep
      Quality Index (PSQI), Perceived Well-being Scale-Revised (PWB-R) and MOS-HIV
      Health Survey instruments, with MOS-HIV summary scores used as a covariate.
      RESULTS: On ANCOVA analysis for sleep quality (F=14.032, P<.001), a 35%
      improvement in sleep among experimental subjects was identified. There was no
      significant difference between the two groups on ANCOVA analysis for well-being
      (F=0.111. P=.739). CONCLUSIONS: High levels of caffeine consumption may have an
      exacerbating effect on already prevalent HIV-related sleep pattern disturbances,
      and significant reductions of caffeine may improve sleep quality.

PMID- 12614827
TI  - Sleep disturbance mediates the association between psychological distress and
      immune status among HIV-positive men and women on combination antiretroviral
      therapy.
AB  - OBJECTIVES: This study examined the relationship between psychological distress,
      subjective sleep disturbance and immune status among HIV-positive men and women.
      METHODS: Fifty-seven participants (41 men, 16 women) without AIDS-related illness
      and currently on combination antiretroviral therapy were recruited through
      community advertisement and physician referral. Participants completed the Impact
      of Events Scale (IES) to assess symptoms of psychological distress and the
      Pittsburgh Sleep Quality Index (PSQI) to assess quality of sleep over the past
      month. T-lymphocyte subpopulations were also assessed from early morning blood
      samples. RESULTS: Participants reporting greater psychological distress also
      reported more pronounced sleep disruption. Higher levels of distress and greater
      sleep disturbance were also significantly related to lower T-cytotoxic/suppressor
      (CD3+CD8+) cell counts. Path analysis revealed that the association between
      distress level and CD3+CD8+ cell counts was mediated by poorer subjective sleep
      quality. CONCLUSIONS: These findings suggest that psychological distress may
      impact upon the immune system through its effects on sleep quality.

PMID- 12614829
TI  - Relationship of psychological morbidity and quality of life to illness-related
      disclosure among HIV-infected persons.
AB  - OBJECTIVE: The aim of this study was to examine the relationship between HIV
      related disclosure and quality of life, anxiety and depression among HIV-infected
      subjects in South India. METHODOLOGY: 68 subjects (35 men and 33 women) were
      assessed for quality of life and psychological morbidity using WHOQOL-BREF and
      the Hospital Anxiety and Depression Scale (HADS). Details of disclosure were
      collected using a semistructured interview. RESULTS: Certain disclosure-related
      variables appear to relate significantly with quality of life among HIV-infected
      persons. A positive outcome related to disclosure and extent to which a subject
      felt the need to disclose were significantly associated with higher scores on the
      total quality of life measure and in the social and environmental domains of the
      WHOQOL-BREF. No relationship was found between disclosure-related variables and
      psychological morbidity or other domains of quality of life. The type of
      disclosure (voluntary/without consent) did not appear to influence quality of
      life in this sample. CONCLUSION: Disclosure-related variables may have an
      important influence on QOL in the context of HIV infection in India.

PMID- 12614830
TI  - Concealment of homosexual identity, social support and CD4 cell count among HIV
      seropositive gay men.
AB  - OBJECTIVE: Previous research has indicated that the concealment of homosexuality
      is related to poorer health among gay men with HIV. This study explored
      mechanisms by which concealment of homosexuality may be related to HIV disease
      status by examining associations between concealment of homosexuality, social
      support, social constraints, depressive symptoms and CD4 count among HIV
      seropositive gay men. METHOD: Questionnaires assessing concealment of
      homosexuality, social support, depressive symptoms and social constraints were
      administered to 73 HIV-seropositive gay men. Medical charts were accessed to
      gather HIV disease information including CD4 counts. Regression analyses were
      conducted to examine associations between psychosocial variables and CD4 counts.
      RESULTS: Concealment of homosexuality was associated with lower CD4 count,
      greater social constraints, greater depressive symptoms and less social support.
      The association between concealment of homosexuality and CD4 count varied
      according to level of social support. Among participants with higher levels of
      social support, those with greater concealment had lower CD4 counts than those
      with lower concealment. Concealment of homosexuality was not related to CD4 count
      among participants reporting low social support. CONCLUSION: Concealment of
      homosexuality among HIV-seropositive gay men is associated with lower CD4 counts,
      depressive symptoms and strained social relationships. In addition, the benefits
      of being open about homosexuality may be most evident under conditions of greater
      social support.

PMID- 12614831
TI  - Psychological inhibition and CD4 T-cell levels in HIV-seropositive women.
AB  - OBJECTIVE: This cross-sectional study examined the hypothesis that the capacity
      for emotional expression is a critical moderator of the emotional support-health
      relationship. METHODS: In a sample of 61 HIV-seropositive women without AIDS,
      coping interviews were conducted to assess HIV-specific emotional support and
      emotional expression and inhibition (percentage of positive/negative emotion
      words and inhibition words, respectively). RESULTS: Hierarchical regression
      analyses revealed no relationship between availability of HIV-specific emotional
      support and concurrent CD4 levels and no moderation of emotional expression or
      inhibition. However, a higher percentage of inhibition words was associated with
      lower CD4 T-cell levels controlling for health behaviors, demographics, and
      treatment regimen (DeltaR(2)=.08, P<.05). CONCLUSIONS: These findings are
      consistent with prior theory and research showing a relationship between
      psychological inhibition and deleterious health outcomes.

PMID- 12614832
TI  - Emotional expression and depth processing of trauma and their relation to long
      term survival in patients with HIV/AIDS.
AB  - OBJECTIVE: This study examined the relationship between emotional expression and
      depth processing of trauma and long-term survival of patients living with AIDS. A
      further purpose was to examine the immune, health behavior and psychosocial
      correlates of emotional disclosure and depth processing. METHOD: Subjects wrote
      essays describing their reactions to past traumas; these were scored for
      emotional expression and depth processing (positive cognitive appraisal change,
      experiential involvement, self-esteem enhancement and adaptive coping
      strategies). Two HIV-seropositive groups were recruited for this study; long-term
      survivors (LTS; n=46) patients who had survived at least 4 years past a Category
      C (AIDS defining) symptom prior to starting protease inhibitors and an equivalent
      HIV-seropositive comparison group (ECOMP(LTS); n=89) who had CD4+ cells between
      150 and 500, and had no history of Category C symptoms. The groups were
      equivalent on age, gender, ethnicity, education, employment, income, sexual
      orientation and route of infection. RESULTS: The group LTS were significantly
      higher than the ECOMP(LTS) group on emotional expression and depth processing.
      Depth processing mediated the relationship between emotional expression and long
      term survival status. Depth processing was positively related to CD4+ cell number
      for women. Emotional expression was also significantly related to viral load
      (negatively) and to CD4+ cell number (positively) for women only. Interestingly,
      only depth processing (and not emotional expression) was related to medication
      adherence and to psychosocial variables (perceived stress and social support).
      CONCLUSIONS: Emotional expression and depth processing were related to long-term
      survival, however, depth processing was the mediator for this relationship and
      only depth processing was associated with medication adherence, perceived stress
      and social support. Our results underscore the importance of depth processing
      (and not just emotional expression) of traumatic experiences for people living
      with HIV/AIDS.

PMID- 12614833
TI  - Stress as a predictor of symptomatic genital herpes virus recurrence in women
      with human immunodeficiency virus.
AB  - OBJECTIVE: Genital herpes (Herpes Simplex Virus Type 2, HSV-2) is a significant
      public health problem for HIV+ women, who have high rates of HSV-2 seropositivity
      and elevated risk for HSV-2 associated morbidity and mortality. Life stress has
      been identified as a co-factor in genital herpes recurrence. However, no research
      has evaluated the relationship between stress and genital herpes recurrences in
      HIV+ women. The purpose of this study was to determine whether stress was
      associated with symptomatic genital herpes recurrences in women seropositive for
      HIV and HSV-2. METHODS: Thirty-four HIV-infected African-American and Caribbean
      American women underwent a psychosocial interview, blood draw and gynecologic
      examination to assess gynecologic symptoms (including genital herpes) at study
      entry. Life stress was measured using a 10-item modified version of the Life
      Experiences Survey (LES). Genital herpes recurrence over 1-year follow-up was
      abstracted using medical chart review. RESULTS: Using hierarchical linear
      regression analysis, life stress at study entry was significantly associated with
      number of genital herpes recurrences during 1-year follow-up (beta=.38, P=.03)
      after controlling for HIV disease variables and relevant behavioral factors.
      Recent life stress, in particular, was highly predictive of genital herpes
      recurrence during follow-up (beta=.57, P=.002). The relationship between life
      stress and genital herpes recurrence persisted after controlling for HSV-2 viral
      reactivation (i.e., HSV-2 IgG titers) at study entry. CONCLUSION: These findings
      suggest that stress may be a significant predictor of genital herpes recurrence
      in women with HIV and HSV-2. Stress management interventions may buffer HSV
      related morbidity and mortality in women with HIV.

PMID- 12614834
TI  - Stress and transtheoretical model indicators of stress management behaviors in
      HIV-positive women.
AB  - OBJECTIVE: Women are particularly prone to stress with respect to living with
      HIV. Stress management behaviors can mediate the stress response and improve
      health outcomes in HIV-positive individuals. The purpose of this descriptive
      cross-sectional study was to examine stress and Transtheoretical Model (TTM)
      indicators of stress management behaviors in HIV-positive women. METHODS: 126 HIV
      positive women recruited from diverse HIV-care clinics in northeast Ohio
      completed standardized self-report research instruments to measure stress, stress
      management behaviors, stage of change, self-efficacy, and decisional balance
      (pros and cons). RESULTS: Women reported higher levels of stress in the later
      phase of HIV infection (P<.05). Highly stressed women in this study reported
      infrequently using stress management behaviors and a low level of perceived
      efficacy to manage stress although they perceived the pros of managing stress to
      be high (P<.01). Stress management behaviors were significantly related to stage
      of change (P<.01), self-efficacy (P<.01), and the cons of managing stress
      (P<.05). Graphed patterns of decisional balance examined by stage of change and
      stress management behavior were atypical in this sample. CONCLUSIONS: Clinicians
      and researchers can use the TTM to describe behavioral indicators of stress
      management in HIV+ women. However, further research is needed to more fully
      understand behavioral processes HIV+ women can use to adopt and maintain stress
      management behaviors.

PMID- 12614836
TI  - Viral load and HIV treatment attitudes as correlates of sexual risk behavior
      among HIV-positive gay men.
AB  - OBJECTIVES: People living with HIV who achieve an "undetectable" viral load may
      assume that they are less infectious, leading to increased sexual risk. We
      examined the relation between perceiving that one has an undetectable viral load
      and sexual risk taking among gay men. METHODS: HIV-positive participants (N=60)
      completed measures assessing HIV serostatus, perceived HIV viral load (detectable
      vs. undetectable), sexual risk and treatment attitudes. RESULTS: Contrary to
      hypotheses, HIV-positive men with detectable viral loads were more likely to
      report unprotected anal sex with a nonprimary partner than were men reporting
      undetectable viral loads. Although a significant minority endorsed the belief
      that an HIV-positive partner with an undetectable viral load is less infectious,
      this belief was unrelated to sexual risk. Multivariate analyses showed that the
      strongest predictor of sexual risk was a measure assessing participants' reduced
      concern over HIV stemming from the availability of improved HIV treatments. After
      controlling for reduced HIV concern, viral load status was no longer a
      significant predictor of risk. CONCLUSIONS: Results suggest that reduced concern
      about the consequences of HIV infection may be more important than perceived
      health status as a determinant of risky sex and highlight the need for continued
      prevention efforts among people who are HIV-positive.

PMID- 12614835
TI  - Cognitive-behavioral interventions improve quality of life in women with AIDS.
AB  - OBJECTIVE: We tested the effects of a 10-week group-based cognitive-behavioral
      stress management/expressive-supportive therapy intervention (CBSM+) and a time
      matched individual psychoeducational condition for 330 women with AIDS reporting
      moderate to poor baseline quality of life (QOL). The goal of this study was to
      examine treatment effects on total QOL and 11 QOL domains from baseline to post
      intervention follow-up. METHODS: Participants were assessed at baseline,
      randomized to a treatment condition (individual psychoeducation condition n=180,
      group-based CBSM+ condition n=150), participated in the intervention for 10 weeks
      and assessed again within 4 weeks following the intervention. QOL was measured
      using the Medical Outcomes Study-HIV-30. RESULTS: QOL scores increased over the
      course of both interventions for the total QOL score and three QOL domains:
      cognitive functioning, health distress and overall health perceptions. While
      women in the CBSM+ group condition showed a significant improvement in mental
      health QOL from pre- to post-intervention, women in the individual condition did
      not change. No changes were observed for energy/fatigue, health transition,
      single-item overall QOL, pain, physical well-being, role functioning or social
      functioning in either condition. CONCLUSION: Results suggest that group-based
      CBSM+ and individual psychoeducational interventions are effective at improving
      certain aspects of QOL and that group-based CBSM+ may be particularly effective
      at increasing QOL related to mental health in this population of women with AIDS.

PMID- 12614837
TI  - Personality, quality of life and HAART adherence among men and women living with
      HIV/AIDS.
AB  - Very few studies have documented relations between personality traits and quality
      of life among individuals living with human immunodeficiency virus (HIV)/acquired
      immune deficiency syndrome (AIDS). Some have shown that poor perceived quality of
      life as determined by a sense of purpose may be associated with inadequate
      adherence to highly active antiretroviral treatment (HAART) in this population.
      Although adequate HAART adherence is critical to achieve the full therapeutic
      effects of newly and highly effective regimens, very little is known of how both
      personality factors and HIV-specific quality of life may impact adherence to
      these medication regimens. This study evaluated relations among personality
      traits, quality of life and HAART adherence among 116 men and women living with
      HIV/AIDS. Results showed that personality traits such as neuroticism were
      significantly associated with poorer quality of life, whereas conscientiousness
      and extraversion were associated with better quality of life. In contrast,
      personality traits were not directly related to HAART adherence. Both higher
      overall functioning and lower medication worries scores were significantly
      associated with HAART adherence. Findings suggest that personality traits are
      associated with HIV-specific quality of life on the one hand, and that HIV
      specific quality of life is related to HAART adherence on the other. Future
      studies assessing the efficacy of psychosocial interventions in improving quality
      of life and HAART adherence should consider the role of personality traits in
      promoting better quality of life.

PMID- 12614840
TI  - Nitric oxide and cytochrome oxidase: reaction mechanisms from the enzyme to the
      cell.
AB  - The aim of this work is to review the information available on the molecular
      mechanisms by which the NO radical reversibly downregulates the function of
      cytochrome c oxidase (CcOX). The mechanisms of the reactions with NO elucidated
      over the past few years are described and discussed in the context of the
      inhibitory effects on the enzyme activity. Two alternative reaction pathways are
      presented whereby NO reacts with the catalytic intermediates of CcOX populated
      during turnover. The central idea is that at "cellular" concentrations of NO (</=
      microM), the redox state of the respiratory chain results in the formation of
      either the nitrosyl- or the nitrite-derivative of CcOX, with potentially
      different metabolic implications for the cell. In particular, the role played by
      CcOX in protecting the cell from excess NO, potentially toxic for mitochondria,
      is also reviewed highlighting the mechanistic differences between eukaryotes and
      some prokaryotes.

PMID- 12614841
TI  - Vitamin C and vitamin E restore the resistance of GSH-depleted lens cells to
      H2O2.
AB  - A decline in reduced glutathione (GSH) levels is associated with aging and many
      age-related diseases. The objective of this study was to determine whether other
      antioxidants can compensate for GSH depletion in protection against oxidative
      insults. Rabbit lens epithelial cells were depleted of > 75% of intracellular GSH
      by 25-200 microM buthionine sulfoximine (BSO). Depletion of GSH by BSO alone had
      little direct effect on cell viability, but resulted in an approximately 30-fold
      increase in susceptibility to H(2)O(2)-induced cell death. Experimentally
      enhanced levels of nonprotein sulfhydryls other than GSH (i.e., N-acetylcysteine)
      did not protect GSH-depleted cells from H(2)O(2)-induced cell death. In contrast,
      pretreatment of cells with vitamin C (25-50 microM) or vitamin E (5-40 microM),
      restored the resistance of GSH-depleted cells to H(2)O(2). However,
      concentrations of vitamin C > 400 microM and vitamin E > 80 microM enhanced the
      toxic effect of H(2)O(2). Although levels of GSH actually decreased by 10-20% in
      cells supplemented with vitamin C or vitamin E, the protective effects of vitamin
      C and vitamin E on BSO-treated cells were associated with significant (
      approximately 70%) decreases in oxidized glutathione (GSSG) and concomitant
      restoration of the cellular redox status (as indicated by GSH:GSSG ratio) to
      levels detected in cells not treated with BSO. These results demonstrate a role
      for vitamin C and vitamin E in maintaining glutathione in its reduced form. The
      ability of vitamin C and vitamin E in compensations for GSH depletion to protect
      against H(2)O(2)-induced cell death suggests that GSH, vitamin C, and vitamin E
      have common targets in their actions against oxidative damage, and supports the
      preventive or therapeutic use of vitamin C and E to combat age- and pathology
      associated declines in GSH. Moreover, levels of these nutrients must be optimized
      to achieve the maximal benefit.

PMID- 12614842
TI  - Kinetics of the reactions of nitrogen monoxide and nitrite with ferryl
      hemoglobin.
AB  - Hemoglobin released in the circulation from ruptured red blood cells can be
      oxidized by hydrogen peroxide or peroxynitrite to generate the highly oxidizing
      iron(IV)oxo species HbFe(IV)z=O. Nitrogen monoxide, produced in large amounts by
      activated inducible nitric oxide synthase, can have indirect cytotoxic effects,
      mainly through the generation of peroxynitrite from its very fast reaction with
      superoxide. In the present work we have determined the rate constant for the
      reaction of HbFe(IV)z=O with NO(*), 2.4 x 10(7) M(-1)s(-1) at pH 7.0 and 20
      degrees C. The reaction proceeds via the intermediate HbFe(III)ONO, which then
      dissociates to metHb and nitrite. As these products are not oxidizing and because
      of its large rate, the reaction of HbFe(IV)z=O with NO(*) may be important to
      remove the high valent form of hemoglobin, which has been proposed to be at least
      in part responsible for oxidative lesions. In addition, we have determined that
      the rate constant for the reaction of HbFe(IV)z=O with nitrite is significantly
      lower (7.5 x 10(2) M(-1)s(-1) at pH 7.0 and 20 degrees C), but increases with
      decreasing pH (1.8 x 10(3) M(-1)s(-1) at pH 6.4 and 20 degrees C). Thus, under
      acidic conditions as found in ischemic tissues, this reaction may also have a
      physiological relevance.

PMID- 12614844
TI  - Myeloperoxidase-induced formation of chlorohydrins and lysophospholipids from
      unsaturated phosphatidylcholines.
AB  - The formation of lysophosphatidylcholines and chlorohydrins from unsaturated
      phosphatidylcholines upon the treatment with the myeloperoxidase-hydrogen
      peroxide-chloride system was evaluated by means of matrix-assisted laser
      desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Lyso-products
      were primarily found in phosphatidylcholine samples containing highly unsaturated
      fatty acid residues such as arachidonic or docosahexenoic acid. On the other
      hand, chlorohydrins dominate in mono- or bis-unsaturated phosphatidylcholines. No
      formation of these products was detected in the absence of one of the components
      of the MPO-H(2)O(2)-Cl(-) system or in the presence of MPO inhibitors (sodium
      azide) or scavengers of hypochlorous acid (taurine, methionine). Thus,
      hypochlorous acid formed by the MPO-H(2)O(2)-Cl(-) system is responsible for the
      observed modification in unsaturated phosphatidylcholines. In the presence of the
      complete MPO system, lyso-products and chlorohydrins were only formed at pH
      values lower than pH 6.0 with an optimum at pH 4.3. In contrast, the reagent
      hypochlorous acid caused the formation of these products even at neutral pH
      values, indicating a clear dependence of the yield of products on the presence of
      undissociated HOCl. We conclude that the formation of lysophospholipids and
      chlorohydrins from unsaturated phosphatidylcholines by myeloperoxidase can be
      relevant in vivo under acute inflammatory conditions.

PMID- 12614843
TI  - Mitochondria from females exhibit higher antioxidant gene expression and lower
      oxidative damage than males.
AB  - We have investigated the differential mitochondrial oxidative stress between
      males and females to understand the molecular mechanisms enabling females to live
      longer than males. Mitochondria are a major source of free radicals in cells.
      Those from female rats generate half the amount of peroxides than those of males.
      This does not occur in ovariectomized animals. Estrogen replacement therapy
      prevents the effect of ovariectomy. Mitochondria from females have higher levels
      of reduced glutathione than those from males. Those from ovariectomized rats have
      similar levels to males, and estrogen therapy prevents the fall in glutathione
      levels that occurs in ovariectomized animals. Oxidative damage to mitochondrial
      DNA in males is 4-fold higher than that in females. This is due to higher
      expression and activities of Mn-superoxide dismutase and of glutathione
      peroxidase in females, which behave as double transgenics overexpressing
      superoxide dismutase and glutathione peroxidase, conferring protection against
      free-radical-mediated damage in aging. Moreover, 16S rRNA expression, which
      decreases significantly with aging, is four times higher in mitochondria from
      females than in those from males of the same chronological age. The facts
      reported here provide molecular evidence to explain the different life span in
      males and females.

PMID- 12614845
TI  - Distribution and breakdown of labeled coenzyme Q10 in rat.
AB  - Radioactive coenzyme Q(10) ([(3)H]CoQ) was synthesized in a way that the
      metabolites produced retained the radioactivity. Administration of the lipid to
      rats intraperitoneally resulted in an efficient uptake into the circulation, with
      high concentrations found in spleen, liver, and white blood cells; lower
      concentrations in adrenals, ovaries, thymus, and heart; and practically no uptake
      in kidney, muscle, and brain. In liver homogenate most [(3)H]CoQ appeared in the
      organelles, but it was also present in the cytosol and transport vesicles.
      Mitochondria, purified on a metrizamide gradient, had a very low concentration of
      [(3)H]CoQ, which was mainly present in the lysosomes. All organs that took up the
      labeled lipid also contained water-soluble metabolites. The majority of
      metabolites excreted through the kidney and appeared in the urine. Some
      metabolites were also present in the feces, which further contained
      nonmetabolized [(3)H]CoQ, excreted through the bile. The major metabolites were
      purified from the urine, and the mass spectrometric fragmentation showed that
      these compounds, containing the ring with a short side chain, are phosphorylated.
      Thus, the results demonstrate that CoQ is metabolized in all tissues, the
      metabolites are phosphorylated in the cells, transported in the blood to the
      kidney, and excreted into the urine.

PMID- 12614846
TI  - The effect of dietary nitrate on salivary, plasma, and urinary nitrate metabolism
      in humans.
AB  - Dietary nitrate is metabolized to nitrite by bacterial flora on the posterior
      surface of the tongue leading to increased salivary nitrite concentrations. In
      the acidic environment of the stomach, nitrite forms nitrous acid, a potent
      nitrating/nitrosating agent. The aim of this study was to examine the
      pharmacokinetics of dietary nitrate in relation to the formation of salivary,
      plasma, and urinary nitrite and nitrate in healthy subjects. A secondary aim was
      to determine whether dietary nitrate increases the formation of protein-bound 3
      nitrotyrosine in plasma, and if dietary nitrate improves platelet function. The
      pharmacokinetic profile of urinary nitrate excretion indicates total clearance of
      consumed nitrate in a 24 h period. While urinary, salivary, and plasma nitrate
      concentrations increased between 4- and 7-fold, a significant increase in nitrite
      was only detected in saliva (7-fold). High dietary nitrate consumption does not
      cause a significant acute change in plasma concentrations of 3-nitrotyrosine or
      in platelet function.

PMID- 12614847
TI  - Transcriptional regulation of yeast peroxiredoxin gene TSA2 through Hap1p, Rox1p,
      and Hap2/3/5p.
AB  - In Saccharomyces cerevisiae, the transcription of peroxiredoxin gene TSA2 is
      responsive to various reactive oxygen and nitrogen species. Redox-regulated
      transcriptional activators Yap1p, Skn7p, Msn2p/Msn4p have been shown to play a
      role in regulating TSA2 expression. In this study we show that the transcription
      of TSA2 is under complex control involving additional transcription factors
      Hap1p, Rox1p, and Hap2/3/5p. Deletion of HAP1 led to a 50% reduction of TSA2
      transcriptional activity. As an intracellular oxygen sensor, heme stimulated TSA2
      transcription by activating Hap1p. The induction of TSA2 by H(2)O(2) is also
      mediated in part through Hap1p. Countering the effects of Hap1p was a
      transcriptional repressor Rox1p. Deletion of ROX1 or mutation of Rox1p-binding
      site significantly activated TSA2 transcription. In addition, TSA2 activity was
      diminished in hap2Delta, hap3Delta, hap4Delta, and hap5Delta strains, but was
      stimulated upon overexpression of Hap4p. Hap2/3/5p may cooperate with Msn2/4p to
      activate TSA2 after diauxic shift. Finally, we demonstrated a role for kinases
      Ras1/2p and Hog1p in Msn2/4p-dependent activation of TSA2. In particular, Hog1p
      mediated the response of TSA2 to osmotic and oxidative stress. Taken together,
      our findings suggest that the expression of TSA2 is regulated by a group of
      transcription factors responsive differentially to stress conditions.

PMID- 12614848
TI  - Caspase activation is accelerated by the inhibition of arsenite-induced, membrane
      rafts-dependent Akt activation.
AB  - Renewed interest in arsenic has been shown recently due to its dual nature of
      being a potent toxin and a drug for treatment of acute promyelocytic leukemia
      (APL) because of its ability to trigger caspase activation. Here, we found that
      sodium arsenite (NaAsO(2)) also triggers the signal for activation of Akt and
      downstream glycogen synthase 3beta (GSK3beta). Such Akt/GSK3beta activation was
      abrogated completely by wortmannin, an inhibitor of PI-3 kinase, and greatly by
      pertussis toxin, a G-protein inhibitor. Arsenite-induced Akt phosphorylation also
      was inhibited by sequestrating membrane cholesterol with beta cyclodextrin.
      Reducing reagents/reactive oxygen species (ROS) scavengers reduced arsenite
      induced Akt phosphorylation and beta cyclodextrin reduced arsenite-mediated ROS
      production, suggesting that arsenite-induced G-protein/Akt/GSK3beta pathway is
      membrane raft dependent and redox linked. We also found that a combination of a
      low concentration (1 microM) of arsenite and wortmannin triggers the signal for
      caspase activation, whereas neither of these elements alone did so. These results
      suggested that selective blockade of the arsenite-provoked PI-3 kinase/Akt
      pathway can promote the arsenite-triggered pathway for caspase activation, and
      this may open a new study area for wider applications of arsenic as a drug for
      treating various kinds of leukemia.

PMID- 12614849
TI  - Antioxidant status of the rat nasal cavity.
AB  - Despite extensive interest in the rodent nasal cavity as a target organ for
      toxicity, there is very limited information regarding nasal defenses against
      oxidative stress and xenobiotic-derived oxidants. Using immunohistochemistry, we
      have examined the distribution of Cu,Zn and Mn superoxide dismutase (SOD),
      catalase, glutathione (GSH) peroxidase, and DT-diaphorase in rat nasal tissues.
      In addition, we have determined the concentrations of ascorbate and alpha
      tocopherol and the activities of SOD (combined Cu,Zn and Mn forms), catalase, GSH
      peroxidase, GSH reductase, and DT-diaphorase in nasal respiratory epithelium
      (RE), olfactory epithelium (OE), and in lung. Immunohistochemistry demonstrated
      that all four enzymes were similarly distributed, with the greatest staining
      intensity in dorsal-medial regions of the nasal cavity. In respiratory
      epithelium, ciliated columnar cells and subepithelial glands stained positively,
      while in olfactory tissue the enzymes were detected in the sustentacular cells
      and Bowman's glands. With the exception of SOD, enzyme activities were higher in
      RE than OE, while concentrations of ascorbate and alpha-tocopherol were higher in
      OE than RE. With the exception of catalase, nasal activities were either higher
      than or comparable to those of the lung. Thus, the rat nasal cavity appears to be
      well protected against oxidative damage.

PMID- 12614850
TI  - Naftidrofuryl-driven regulation of endothelial ICAM-1 involves nitric oxide.
AB  - Naftidrofuryl is a selective inhibitor of the 5-HT2 receptor expressed on human
      endothelial cells. This drug has been used over the years to cope with cerebral
      or peripheral ischemic accidents; however, no clear mechanism of action of this
      molecule has been highlighted to explain its vascular effects. In the present
      work, we demonstrate that the involvement of nitric oxide can account for the
      effects of naftidrofuryl. Indeed, naftidrofuryl potently inhibited the TNF-alpha
      triggered increase of intercellular adhesion molecule-1 (ICAM-1) expression as
      well as stress fiber formation in human umbilical vein endothelial cells (HUVEC).
      Moreover, naftidrofuryl induced the expression of type II nitric oxide synthase
      (NOS II) messenger and protein, leading to a noticeable increase in nitric oxide
      synthesis. Furthermore, using the specific NOS II inhibitor 1400W, we verified
      that the observed effects of naftidrofuryl were NOS II-dependent. The biology of
      nitric oxide accounts for the reduction of the vasospasm associated with stroke
      and the strong inhibition of platelet aggregation. In conclusion, our work
      provides evidence for the inhibition of leukocyte recruitment by downregulation
      of CD54/ICAM-1, an additional key factor to be dealt with during thrombotic
      accidents. Importantly, it also highlights a novel NOS II-dependent mechanism of
      action for naftidrofuryl.

PMID- 12614851
TI  - [About standards options and recommendations: "percutaneous liver biopsy"].

PMID- 12614852
TI  - [Renal involvement in Behcet's disease. About six cases].
AB  - PURPOSE: To analyze anatomoclinic and evolutive aspects of the renal involvement
      associated to the Behcet's disease through 6 observations collected in the
      nephrology department from 1985 to 2000 and to make a review of the literature.
      METHODS: Retrospective study, diagnosis of Behcet's disease according to the
      Classification of the International Group Study on the Behcet's disease and renal
      damage confirmed by histology. RESULTS: Our patients all male are aged between 25
      to 55 years with a mean at 34 years old. The renal damage was revelated by a
      nephrotic syndrome in 3 cases and by a proteinuria at 1 to 2.7 g/day in 3 cases.
      Microscopic hematuria was present in 2 cases and arterial hypertension in 2
      cases. The renal insufficiency has been noted in 2 cases of which severe in one
      of them. The renal biopsy showed an amyloidosis AA type in 3 cases, a segmental
      and focal glomerulonephritis in 2 cases and a thrombotic microangiopathy
      associated to a moderate tubulo-interstitiel lesions by toxicity of ciclosporine
      in 1 case. The extrarenal signs were dominated by bipolar aphtosis in all cases,
      necrotic pseudofolliculitis and the no specific cutaneous hyperreactivity in 5
      cases and the erythema nodosum in 1 case. The ocular manifestation has been noted
      in 4 cases and articular manifestation in 3 cases. The vascular manifestation has
      been noted in one case. The treatment was colchicine in 4 cases and prednisone
      and cyclophosphamide in 1 case. Three patients were lost of view and a patient
      died in hemodialysis. The 2 other patients with amylosis had persistent
      proteinuria with a normal renal function. CONCLUSION: The kidney is one of organs
      that can alter the prognosis of the Behcet's disease; so, its screening must be
      realised in each patient with this disease.

PMID- 12614853
TI  - [Severe lactic acidosis in HIV-infected patients treated with nucleosidic reverse
      transcriptase analogs: a report of 9 cases].
AB  - PURPOSE: Symptomatic lactic acidosis requiring intensive care is a rare and
      severe adverse event related to the mitochondrial toxicity of the nucleoside
      analog reverse transcriptase inhibitors (NRTIs). METHOD: We retrospectively
      investigated the clinical and biological features of HIV-infected patients who
      developed severe lactic acidosis syndrome at the University teaching hospital of
      Bordeaux and the regional community hospital, during 1996-2000. RESULTS: Nine
      patients were identified (incidence: 0,9/1000 NRTI treated patient-years), 4 men
      and 5 women with a median age of 36 years. They had a moderate immunodeficiency
      (median CD4+ T lymphocyte counts: 197/mm(3)) and only one of them presented a
      virological failure. The causes of hospital admission were abdominal pain (n =
      6), dyspnea (n = 6), asthenia (n = 5), jaundice (n = 4), and vomiting (n = 2).
      Hepatomegaly was present in 6 patients. Lactic acidosis was found in all cases:
      median pH: 7.28, bicarbonate: 12 mmol/l, anion gap: 27 mEq/l, plasma lactic acid:
      13 mmol/l. Cytolysis (n = 8), cholestasis (n = 6), hepatic failure (n = 4),
      rhabdomyolysis (n = 4) and pancreatitis (n = 2), were also present. Despite
      medical intensive care, seven patients died. The only two post-mortem
      examinations revealed severe hepatic steatosis. Median duration of NRTI therapy
      was 4 years. At presentation, five patients were receiving lamivudine, five
      didanosine, four stavudine and three zidovudine. Six patients were coinfected by
      HCV and/or HBV, four had chronic renal failure and five an immediately preceding
      infectious disease. CONCLUSION: The prognosis of lactic acidosis is severe.
      Nucleosid-analog therapy needs clinical and biological monitoring, specially in
      patients with comorbidities.

PMID- 12614854
TI  - [Lemierre's syndrome: a report of six cases].
AB  - OBJECTIVE: Lemierre's syndrome is a rare but severe condition combining pyrexia,
      cervical pain and pulmonary signs following a pharyngeal infection, usually
      tonsillitis. This infectious disease is still present in our country despite wide
      use of antibiotic therapy in pharyngeal infections. METHODS: In a retrospective
      study conducted between 1995 and 2000 in two departments (infectious diseases and
      critical care unit) of Nice university hospital (Nice, France), we collected and
      analysed six cases of Lemierre's syndrome. RESULTS: We describe a serie of 6
      cases, all of them female patients of mean age 27. We enrolled healthy patients
      whose initial symptom was tonsillitis. Most of these patients showed signs of
      severe sepsis and one died of septic shock. All the others recovered with
      treatment. The mean time between tonsillitis and first sign of sepsis was seven
      days. In four cases, patients received a beta- lactam antimicrobial agent with
      metronidazole. In two cases, patients were treated with amoxicillin-clavulanate.
      All patients were investigated for the presence of internal jugular vein
      thrombosis and were treated by anticoagulants when research was positive.
      CONCLUSIONS: A strong presumptive diagnosis can be made on the basis of clinical
      presentation, secondarily confirmed by para-clinical data. The prognosis depends
      on the speed and quality of management. We therefore wished to raise awareness of
      this condition among our colleagues by reporting our personal experience.

PMID- 12614855
TI  - [Chronic meningitis: aetiologies, diagnosis and treatment].
AB  - PURPOSE: Chronic meningitis are very uncommon and account for less than 10% of
      all meningitis cases. Their symptoms are uncunth and there outcome is insidious.
      Therefore, they remain often unknown. There are only a few published reports on
      this disease, so diagnosis and therapeutic approachs are difficult. CURRENT
      KNOWLEDGE AND KEY POINTS: Positive chronic meningitis diagnosis is easy. However,
      determining the cause of chronic meningitis remains dilemma, as many infectious
      and noninfectious processes (including inflammatory, neoplastic or autoimmune
      aetiologies or as a result of a chemical exposure) can result in the chronic
      meningitis syndrome. In order to institute a pertinent treatment, sometimes
      urgently needed, diagnostic approach must be extremely rigourous and accutely
      orientated. Nevertheless, although extensive investigations, 30% of the
      aetiologies remain undetermined. Only two choices are left for the medical
      physician: an aggressive attitude based on complementary investigations or a
      contemplated therapy with a close clinical and biological control. On the other
      hand, when the patient's condition is quickly deterioring without a clear and
      proved aetiology, it is sometimes necessary to institute an empirical treatment,
      not always properly determined and sometimes contreversial. Besides, few reports
      on prognosis and outcome od idiopathic chronic meningitis have been published.
      FUTURE PROSPECTS AND PROJECTS: After a review of aetiologies and diagnostic
      investigations chronic meningitis, we propose a practical experience attitude
      about management and treatment of chronic meningitis. Thus, large-scale studies
      about the follow up chronic meningitis in long term, in particular those without
      aetiology, treated or no, should improve the outcome of this chronic syndrome.

PMID- 12614856
TI  - [Etiological diagnosis and treatment of chronic urticaria].
AB  - PURPOSE: Urticaria is a muco-cutaneous illness which is characterized by a dermal
      or hypodermal oedema due to a vasodilatation attributed to the release of
      histamine by mast cells and basophils. Urticaria is a very common complaint,
      since among 20% of the population will experience at least one episode of
      urticaria during their life. Chronic urticaria by definition is daily and has
      persisted for at least six weeks. By contrast with acute urticaria, its
      etiological and therapeutic approaches can present a significant challenge,
      leadind to repeated examinations. CURRENT KNOWLEDGE AND KEY POINTS: Questioning
      and clinical examination are essential for the etiological diagnosis of chronic
      urticaria, because they are able to lead rapidly to the suspicion of several
      causes which can be eradicated to treat the symptoms. If no cause is found,
      further investigations may be required. Recent studies have shown the lack of
      profitability of exhaustive laboratory investigations. Thus, many authors at
      present time advise minimal and non expensive investigations which are
      determinated by anamnestic data. But most often, the etiology of urticaria
      remains unknown and this situation leads to the diagnosis of chronic idiopathic
      urticaria. The treatment of chronic urticaria is above all based on the
      elimination of the symptoms, either on a specific fashion if the etiological
      diagnosis is already known, or in a non specific way. The anti-H1 agents are the
      medications of choice for first line treatment. FUTURE PROSPECTS AND PROJECTS:
      Pathophysiology of chronic urticaria is to date well established. As the
      mechanisms responsible for chronic urticaria are better defined, more therapeutic
      agents, which are effective on other targets than histamine, should become
      available. Moreover, recent advances have supported the notion that an underlying
      autoimmune process could account for many cases of chronic "idiopathic"
      urticaria. In such severe and refractory urticaria, immunomodulation therapy may
      bring about clinical improvement.

PMID- 12614857
TI  - [Primary leiomyosarcoma of pulmonary artery: a rare tumor mis-diagnosed as
      pulmonary embolism].
AB  - INTRODUCTION: Primary leiomyosarcoma of the pulmonary artery is an extremely rare
      tumor that is frequently misdiagnosed as chronic pulmonary embolism. EXEGESIS: We
      describe a new case and discuss diagnosis criteria, especially thanks to modern
      imaging techniques. A sarcomatous disease should be ruled out, if obliteration
      progress or is stable, on serial RMI or CT scans images, despite effective anti
      coagulation treatment. CONCLUSION: An early identification and aggressive medical
      and surgical intervention has the potential for long-term survival.

PMID- 12614858
TI  - [Crowned dens syndrome: three new cases].
AB  - INTRODUCTION: Crowned dens syndrome is due to a microcrystalline infringement
      (hydroxyapatite or calcium pyrophosphate) of the retro-odontoidal ligament of
      atlas, often leading to the erroneous diagnosis of meningitis or spondylitis. We
      report on three new cases diagnosed from 1996 to 1999. EXEGESIS: The patients
      complained of cervicalgies, headaches or fever. The initially evoked diagnoses
      were meningitis, spondylodiscitis or endocarditis. Clinical exam found meningism
      and an inflammatory syndrome in all patients. Analysis of the cerebro-spinal
      fluid realised in two cases was normal. The diagnosis of crowned dens syndrome
      was assessed in two cases by cervical CT scan of C1/C2. In the third case,
      chondrocalcinosis of a wrist allowed this diagnosis. We report a probably non
      fortuitous case of crowned dens syndrome associated with genetic hemochromatosis.
      A non steroidal anti-inflammatory treatment allowed a dramatic regression of
      clinical symptoms. CONCLUSION: This entity should be better known; it can mimick
      numerous diagnosis and be responsible for fever in the long course.

PMID- 12614859
TI  - [Periodic paralysis discovered in a 65-year-old woman: one case report].
AB  - INTRODUCTION: Familial hypokalemic periodic paralysis (FHPP) is an autosomal
      dominant disorder which usually begins before thirty years. EXEGESIS: We report a
      case of FHPP occurring in a 65-year-old woman whereas two members of her family
      have symptoms since childhood. Differential diagnosis are discussed. CONCLUSION:
      FHPP must be one of the differential diagnoses in front of an hypokalemic
      paralysis attack, even in the elderly.

PMID- 12614860
TI  - [Compression of the spinal cord revealing a seronegative rheumatoid arthritis].
AB  - INTRODUCTION: Craniocervical junction damages may result in a compression of the
      spinal cord. They may be caused by infectious, tumoral or inflammatory processes.
      Rheumatoid arthritis is probably among rheumatic diseases the most frequent cause
      of atlantoaxial arthritis. Nevertheless involvement of the craniocervical
      junction as the presenting symptom of rheumatoid arthritis is a very rare
      feature. EXEGESIS: We report the case of a 61 years old woman who presented with
      atlantoaxial involvement and spinal cord compression one year before the
      diagnosis of a seronegative rheumatoid arthritis. CONCLUSION: Symptomatic
      craniocervical junction damages may appear. Patients with damages of the
      craniocervical junction and negative investigations should be followed long-term;
      an underlying inflammatory disease may become evident after significant delay.

PMID- 12614861
TI  - [Diffuse osteocondensation].

PMID- 12614862
TI  - [Non ketotic hyperglycemic seizures (one case)].

PMID- 12614863
TI  - [Intrahepatic portosystemic venous shunt].

PMID- 12614864
TI  - [Renal colic due to kidney metastase from larynx cancer].

PMID- 12614866
TI  - A biaryl peptide crosslink in a MetJ peptide model confers cooperative,
      nonspecific binding to DNA that ablates both repressor binding and in vitro
      transcription.
AB  - The MetJ repressor is the archetypal example of the beta-ribbon-helix-helix DNA
      binding motif. A model of the MetJ beta-ribbon (residues 22-28) was prepared by
      forming a dityrosine crosslinked dimer from the heptapeptide KKYTVSI. Using SPR,
      the peptide dimer 2 was shown to bind to dsDNA under physiologically relevant
      conditions, whereas the monomeric peptide did not. The peptide dimer appeared to
      inhibit binding of the MetJ repressor to natural met operators. Based on the
      stoichiometry of binding, the binding of peptide dimer 2 seems both highly co
      operative and to lack sequence specificity. Peptide binding also appears to
      prevent transcription in vitro.

PMID- 12614868
TI  - Solid-phase library synthesis of reversed-statine type inhibitors of the malarial
      aspartyl proteases plasmepsin I and II.
AB  - With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases
      of the malaria parasite Plasmodium falciparum, we have synthesized sets of
      libraries from novel reversed-statine isosteres, using a combination of solution
      phase and solid phase chemistry. The synthetic strategy furnishes the library
      compounds in good to high overall yields and with excellent stereochemical
      control throughout the developed route. The products were evaluated for their
      plasmepsin I and II inhibiting properties and were found to exhibit modest but
      promising activity. The best inhibitor exhibits an in vitro activity of 28%
      inhibition of plasmepsin II at an inhibitor concentration of 0.5 microM (K(i) for
      Plm II=5.4 microM).

PMID- 12614867
TI  - N-Morpholino- and N-diethyl-analogues of palmitoylethanolamide increase the
      sensitivity of transfected human vanilloid receptors to activation by anandamide
      without affecting fatty acid amidohydrolase activity.
AB  - The abilities of 19 analogues of palmitoylethanolamide and two analogues of
      oleoylethanolamide to affect the Ca(2+) influx into human embryonic kidney cells
      expressing the human vanilloid receptor (hVR1-HEK293 cells) in response to
      anandamide (AEA) have been investigated using a FLIPR assay and a bovine serum
      albumin-containing assay medium. Only palmitoylethanolamide produced any effect
      in the absence of AEA. The ability of palmitoylethanolamide to potentiate the
      response to AEA was retained when the N-CH(2)CH(2)OH group was replaced by N
      CH(2)CH(2)Cl,whereas replacement with N-alkyl substituents [from -H up to 
      (CH(2))(12)CH(3)] resulted either in a reduction or in a complete loss of this
      activity. The tertiary amide N-(CH(2)CH(3))(2) (19) and N-morpholino (20)
      analogues of palmitoylethanolamide potentiated the response to 1 microM AEA to a
      greater degree than the parent compound, whereas the N-(CH(3))(2) analogue was
      inactive. 19 and 20 produced leftward shifts in the dose-response curve for AEA
      activation of Ca(2+) influx into hVR1-HEK293 cells. EC(50) values for AEA to
      produce Ca(2+) influx into hVR1-HEK293 cells were 1.1, 1.1, 0.54 and 0.36 microM
      in the presence of 0, 1, 3 and 10 microM 19, respectively. The corresponding
      values for 20 were 1.5, 1.3, 0.77 and 0.17 microM, respectively. The compounds
      did not affect the dose-response curves to capsaicin. The ability of
      oleoylethanolamide to potentiate AEA is retained by the N-CH(2)CH(3) and N
      CH(CH(3))(2) analogues (22 and 23, respectively). 22 and 23 produced a small (
      approximately 25%) inhibition of the binding of [(3)H]-CP55,940 and [(3)H]-WIN
      55,212-2 to CB(1) and CB(2) receptors, respectively, expressed in CHO cells. The
      compounds inhibited the metabolism of 2 microM [(3)H]-AEA by rat brain fatty acid
      amidohydrolase with IC(50) values of 5.6 and 11 microM, respectively. In
      contrast, 19 and 20 were without effect on either binding to CB receptors or
      fatty acid amidohydrolase activity. Minor reductions in the accumulation of 10
      microM [(3)H]-AEA into C6 glioma cells were seen at 10 microM concentrations of
      19 and 20. It is concluded that 19 and 20 selectively enhance AEA effects upon
      VR1 receptors without potentially confounding effects upon CB receptors or fatty
      acid amidohydrolase activity.

PMID- 12614869
TI  - New insights into protein crosslinking via the Maillard reaction: structural
      requirements, the effect on enzyme function, and predicted efficacy of
      crosslinking inhibitors as anti-ageing therapeutics.
AB  - Protein crosslinking via the Maillard reaction with alpha-dicarbonyl compounds
      has been the subject of intense literature scrutiny. We report here a systematic
      study of three previously-neglected aspects of the reaction. Firstly, structural
      requirements were probed. An arginine-free peptide that contains two lysine
      residues, and a lysine-free peptide that contains arginine, were reacted with
      glyoxal, methylglyoxal and biacetyl. Methylglyoxal was able to crosslink in the
      absence of arginine residues, but glyoxal and biacetyl were not. Glyoxal
      crosslinked the lysine-free peptide via the N-terminus, but methylglyoxal and
      biacetyl could not. In this study, crosslinking did not require the presence of
      arginine but did require a free amino group, from a lysine residue, or the N
      terminus. Thus specificity in structural requirements for protein crosslinking by
      alpha-dicarbonyls has been demonstrated. Secondly, protein function following
      glycation was examined by treating ribonuclease A with the three alpha
      dicarbonyls, which were shown both to crosslink the enzyme and impair enzymatic
      activity. Thirdly, the effects of two reported Maillard reaction inhibitors,
      aminoguanidine and 3,5-dimethylpyrazole-1-carboxamidine on the crosslinking
      reaction were assessed, with a parallel measurement of the effect on enzyme
      activity. The results demonstrate that preventing protein crosslinking does not
      necessarily preserve enzyme activity. These results cast doubt on the likely
      efficacy of some purported anti-ageing compounds in vivo.

PMID- 12614870
TI  - The role of dicarbonyl compounds in non-enzymatic crosslinking: a structure
      activity study.
AB  - The Maillard reaction is a complex network of reactions that has been shown to
      result in the non-enzymatic crosslinking of proteins. Recent attention has
      focussed on the role of alpha-dicarbonyl compounds as important in vivo
      contributors to protein crosslinking but, despite extensive research, the
      molecular mechanisms of the crosslinking reaction remain open to conjecture. In
      particular, no relationship between the structure of the carbonyl-containing
      compounds and their activity as crosslinking agents has been established. In an
      effort to elucidate a structure-reactivity relationship, a wide range of
      dicarbonyl compounds, including linear, cyclic, di-aldehyde and di-ketone
      compounds, were reacted with the model protein ribonuclease A and their
      crosslinking activity assessed. Methylglyoxal and glutaraldehyde were found to be
      the most efficient crosslinkers, whilst closely related molecules effected
      crosslinking at a much lower rate. Cyclopentan-1,2-dione was also shown to be a
      reactive crosslinking agent. The efficiency of methylglyoxal and glutaraldehyde
      at crosslinking is thought to be related to their ability to form stable
      heterocyclic compounds that are the basis of protein crosslinks. The reasons for
      the striking reactivity of these two compounds, compared to closely related
      structures is explained by subtle balances between competing pathways in a
      complex reaction network.

PMID- 12614871
TI  - 6-Dimethylamino 1H-pyrazolo[3,4-d]pyrimidine derivatives as new inhibitors of
      inflammatory mediators in intact cells.
AB  - The synthesis of 6-dimethylamino 1H-pyrazolo[3,4-d]pyrimidines substituted at
      positions 1 and 4, and their effects on murine macrophage and human neutrophil
      functions are described. Several compounds and especially 4b-6b are potent
      inhibitors of PGE(2) generation in murine macrophages. This action is related to
      a direct effect on COX-2 activity without affecting the enzyme expression. Some
      of these compounds also inhibited COX-1 and COX-2 in human monocytes and 4b
      showed selectivity for COX-2 inhibition.

PMID- 12614872
TI  - Synthesis and evaluation of trans 3,4-cyclopropyl L-arginine analogues as isoform
      selective inhibitors of nitric oxide synthase.
AB  - Four optically pure conformationally restricted L-arginine analogues syn- 1 and
      anti- 2 trans-3,4-cyclopropyl L-arginine, and syn- 3 and anti-trans-3,4
      cyclopropyl N-(1-iminoethyl) L-ornithine 4 were synthesized. These compounds were
      tested as potential inhibitors against the three isoforms of nitric oxide
      synthase (NOS). Compound 1 was determined to be a poor substrate of NOS, while
      compound 2 was determined to be a poor mixed type inhibitor and did not exhibit
      any isoform selectivity. Syn- 3 and anti-trans-3,4-cyclopropyl N-(1-iminoethyl) L
      ornithine 4 were found to be competitive inhibitors of NOS. These compounds were
      time dependent inhibitors of inducible NOS (iNOS), but not of neuronal NOS (nNOS)
      or endothelial NOS (eNOS). Compound 3 was 10- to 100-fold more potent an
      inhibitor than 4, exhibited a 5-fold increase in nNOS/iNOS and eNOS/iNOS
      selectivity over 4, and displayed tight binding characteristics against iNOS.
      These results indicate that the relative configuration of the cyclopropyl ring in
      the L-arginine analogues significantly affects their inhibitory potential and NOS
      isoform selectivity.

PMID- 12614873
TI  - Structure-activity relationships of xanthene carboxamides, novel CCR1 receptor
      antagonists.
AB  - The structure-activity relationships of xanthene carboxamide derivatives on the
      CCR1 receptor binding affinity and the functional antagonist activity were
      described. Previously, we reported a quaternarized xanthen-9-carboxamide 1 as a
      potent human CCR1 receptor antagonist that was derived from a xanthen-9
      carboxamide lead 2a. Further derivatization of 2a focusing on installing an
      additional substituent into the xanthene ring resulted in the identification of
      2b-1 with IC(50) values of 1.8nM and 13nM in the binding assay using human CCR1
      receptors transfected CHO cells and in the functional assay using U937 cells
      expressing human CCR1 receptors, respectively.

PMID- 12614874
TI  - Prodrugs of biologically active phosphate esters.
AB  - Bioactivatable protecting groups represent an enormously powerful tool to
      increase bioavailability or to generally help deliver drugs to cells. This
      approach is particularly valuable in the case of biologically active phosphates
      because of the high intrinsic hydrophilicity and the multitude of biological
      functions phosphate esters exhibit inside cells. Here, the most prominent masking
      groups used so far are introduced. The stability and toxicology of the resulting
      prodrugs is discussed. Finally, this review tries to cover briefly some of the
      work that describes the usefulness and efficiency of the approach in various
      application areas.

PMID- 12614875
TI  - Inhibition of nucleoside transport by new analogues of nitrobenzylthioinosine.
AB  - Nitrobenzylthioinosine (NBTI, 1) was systematically modified by attachment of
      substituents at positions C6 and N9, and also by substitution of N1 with C. These
      modifications were chosen to reduce the polarity of the new compounds.
      Incorporation of the nitro functionality into a benzoxadiazole ring system was
      considered first. These new nucleosides showed high affinity (1.5-10nM) towards
      the nucleoside transport protein as present on human erythrocyte ghosts. Next,
      modification of this benzoxadiazole ring system with C, S and O in different
      positions produced a number of less polar nucleosides with affinity in the higher
      nanomolar range. Modification of N9 was achieved with different alkyl and alcohol
      substituents. An n-butyl substituent proved best, although all variations yielded
      substantial decreases in affinity. Replacement of N1 by a carbon atom in
      combination with a 2-Cl substituent also resulted in a relatively potent NBTI
      derivative (47 nM).

PMID- 12614876
TI  - Synthesis and anti-tumor-promoting activity of glycoglycerolipid analogues
      lacking the glycerol backbone.
AB  - Glycoglycerolipid analogues lacking the glycerol backbone were prepared through a
      lipase catalyzed transesterification of beta-D-galactosylethylene glycol. The
      inhibitory effect of the resultant isomeric hexanoates at the primary alcoholic
      positions, beta-D-galactosylethylene glycol itself and nonyl beta-D
      galactopyranoside, was tested on Epstein-Barr virus early antigen (EBV-EA)
      activation in Raji cells promoted by the tumor promoter 12-O-tetradecanoylphorbol
      13-acetate (TPA), as a primary screening test for inhibitors of tumor promotion.
      All the compounds assayed were found to be less active than the reference 2-O
      beta-D-galactopyranosylglycerol derivatives, of which they are simplified models,
      indicating that the anti-tumor-promoting activity is very closely related to the
      presence of a free hydroxymethylene group on the glycerol-like aglycone moiety.

PMID- 12614877
TI  - Synthesis, characterization and in vitro anti-invasive activity screening of
      polyphenolic and heterocyclic compounds.
AB  - Invasion is the hallmark of malignant tumors, and is responsible for the bad
      prognosis of the untreated cancer patients. The search for anti-invasive
      treatments led us to screen compounds of different classes for their effect in an
      assay for invasion. Thirty-nine new compounds synthesized in the present study
      along with 56 already reported compounds belonging mainly to the classes of
      lactones, pyrazoles, isoxazoles, coumarins, desoxybenzoins, aromatic ketones,
      chalcones, chromans, isoflavanones have been tested against organotypic
      confronting cultures of invasive human MCF-7/6 mammary carcinoma cells with
      embryonic chick heart fragments in vitro. Three of them (a pyrazole derivative,
      an isoxazolylcoumarin and a prenylated desoxybenzoin) inhibited invasion at
      concentrations as low as 1 microM; instead of occupying and replacing the heart
      tissue within 8 days, the MCF-7/6 cells grew around the heart fragments and left
      it intact, when treated with these compounds. At the anti-invasive concentration
      of 1 microM, the three compounds did not affect the growth of the MCF-7/6 cells,
      as shown in the sulforhodamine B assay. Aggregate formation on agar was not
      stimulated by any of the three anti-invasive compounds, making an effect on the E
      cadherin/catenin complex improbable. This is an invasion suppressor that can be
      activated in MCF-7/6 cells by a number of other molecules. Our data indicate that
      some polyphenolic and heterocyclic compounds are anti-invasive without being
      cytotoxic for the cancer cells.

PMID- 12614879
TI  - Role of solution conformation and flexibility of short peptide ligands that bind
      to the p56(lck) SH2 domain.
AB  - A general approach in drug design is making ligands more rigid in order to avoid
      loss in conformational entropy (deltaS(conf)) upon receptor binding. We
      hypothesized that in the high affinity binding of pYEEI peptide ligands to the
      p56(lck) SH2 domain this loss in deltaS(conf) might be diminished due to
      preorganization of the fourfold negatively charged pYEEI peptide in the bound,
      extended, conformation. A thermodynamic analysis was performed on the peptides Ac
      pYEEI-NH(2), Ac-pYAAI-NH(2) and Ac-pYGGI-NH(2) using surface plasmon resonance
      (SPR) competition experiments to assay affinity constants at different
      temperatures. To study the effect of solution conformation and flexibility a
      computational conformation analysis was performed from which low energy
      conformations in solution were calculated, and S(conf) estimated. It was found
      that the calculated low energy conformations for especially the pYE moiety in
      solution resemble that in the bound state. In the calculated minimum energy
      conformation in solution isoleucine is bent towards the pY aromatic ring, the
      occurrence of such conformation is experimentally confirmed by NMR. The estimated
      values for S(conf) of the EE- and AA-peptide were similar, suggesting no
      predominant role of preorganization of the solution conformation due to
      electrostatic repulsion. Apparently the thermodynamics obey the same entropy
      enthalpy compensation relationship, which also was found to hold for other
      peptides and peptidomimetics binding to p60(src) family SH2 domains. The
      implications of the results for drug design are discussed.

PMID- 12614878
TI  - Synthesis and biological activity of 3,3-diamino-sulfonylacrylonitriles as novel
      inhibitors of glucose induced insulin secretion from beta cells.
AB  - Pinacidil analogues, for example, N-cyano-N'-(3,5-dichlorophenyl)-N"-(3
      methylbutyl)guanidine, 1, have previously been described as potassium channel
      openers on beta cells and smooth muscle cells. In the present study 3,3-diamino
      sulfonylacrylonitrile, a new bioisostere of the cyanoguanidine group, was
      investigated. 3,3-Diamino-sulfonylacrylonitriles were prepared in a two step
      synthesis from the corresponding isothiocyanates and sulfonylacetonitriles.
      Single crystal X-ray crystallography and NMR spectroscopy were used to establish
      the structure of 2-(4-chlorophenylsulfonyl)-3-cyclobutylamino-3-(3,5
      dichlorophenylamino)acrylonitrile 3i. The analysis confirmed that 3i assumes a
      staggered conformation considered as the energetically most favourable. The
      compounds synthesised have been identified as potent inhibitors of glucose
      stimulated insulin secretion from beta cell lines and rat pancreatic islets with
      minimal effects on vascular smooth muscle.

PMID- 12614880
TI  - ortho-Halogen naphthaleins as specific inhibitors of Lactobacillus casei
      thymidylate synthase. Conformational properties and biological activity.
AB  - Thymidylate synthase (TS) (EC 2.1.1.45), an enzyme involved in the DNA synthesis
      of both prokaryotic and eukaryotic cells, is a potential target for the
      development of anticancer and antinfective agents. Recently, we described a
      series of phthalein and naphthalein derivatives as TS inhibitors. These compounds
      have structures unrelated to the folate (Non-Analogue Antifolate Inhibitors,
      NAAIs) and were selective for the bacterial versus the human TS (hTS). In
      particular, halogen-substituted molecules were the most interesting. In the
      present paper the halogen derivatives of variously substituted 3,3-bis(4
      hydroxyphenyl)-1H,3H-naphtho[2,3-c]furan-1-one (1-5) and 3,3-bis(4-hydroxyphenyl)
      1H,3H-naphtho[1,8-c,d]pyran-1-one (6-14) were synthesized to investigate the
      biological effect of halogen substitution on the inhibition and selectivity for
      the TS enzymes. Conformational properties of the naphthalein series were explored
      in order to highlight possible differences between molecules that show species
      specific biological profile with respect to non species-specific ones. With this
      aim, the conformational properties of the synthesized compounds were investigated
      by NMR, in various solvents and at different temperatures, and by computational
      analysis. The apparent inhibition constants (K(i)) for Lactobacillus casei TS
      (LcTS) were found to range from 0.7 to 7.0 microM, with the exception of the
      weakly active iodo-derivatives (4, 10, 13); all] the compounds were poorly active
      against hTS. The di-halogenated compounds 7, 8, 14 showed the highest specificity
      towards LcTS, their specificity index (SI) ranging between 40 and >558. The di
      halogenated 1,8-naphthalein derivatives (7-10) exhibited different conformational
      properties with respect to the tetra-haloderivatives. Though a clear explanation
      for the observed specificity by means of conformational analysis is difficult to
      find, some interesting conformational effects are discussed in the context of
      selective recognition of the compounds investigated by the LcTS enzyme.

PMID- 12614881
TI  - Synthesis and growth inhibition activity of alpha-bromoacrylic heterocyclic and
      benzoheterocyclic derivatives of distamycin A modified on the amidino moiety.
AB  - The design, synthesis and in vitro activities of novel alpha-bromoacryloyl
      pyrazole, imidazole and benzoheterocyclic derivatives of distamycin A, in which
      the amidino moiety has been replaced by moieties of different physico-chemical
      features are described, and the structure-activity relationships are discussed.
      In spite of the relevance of these modifications on the distamycin frame, these
      derivatives showed significant growth inhibitory activity against mouse leukemia
      L1210 cells. Therefore, the presence of the amidino moiety, and in general of a
      basic moiety, is not an absolute requirement for biological activity of alpha
      bromoacrylic derivatives of distamycin.

PMID- 12614882
TI  - Synthesis and cytotoxicity of dihydroartemisinin ethers containing
      cyanoarylmethyl group.
AB  - A new type of ether of dihydroartemisinin containing cyano and aryl groups was
      prepared and tested for cytotoxicity to A549, P388, L1210 and HT29 cells using
      the MTT assay. 12k and 12l were the most cytotoxic compounds. 13 lacking the
      peroxy group showed a 1000-fold less potency than 12l. Similarly, the inactive
      compound 14 indicated that the position of cyano groups was also important. Flow
      cytometry data showed that the compounds caused an accumulation of P388 cells in
      the G(1)-phase of the cell cycle.

PMID- 12614883
TI  - A frame shifted disulfide bridged analogue of angiotensin II.
AB  - N-(2-Mercaptoethyl)glycine [NMGly] was incorporated into the 3 and 5 positions of
      angiotensin II and oxidized to give the corresponding cyclized disulfide
      c[NMGly(3,5)]Ang II. The binding affinity to the angiotensin II receptor (AT(1))
      of this conformationally constrained analogue, which is related to the potent Ang
      II agonist c[Hcy(3,5)]Ang II, was examined. The analogue had no affinity to the
      AT(1) receptor. Theoretical conformational analysis was performed to compare the
      conformational characteristics of model compounds of c[Hcy(3,5)]Ang II and the
      frame shifted analogue c[NMGly(3,5)]Ang II in an attempt to explain the lack of
      affinity.

PMID- 12614884
TI  - A substrate variant as a high-affinity, reversible inhibitor: insight from the X
      ray structure of cilastatin bound to membrane dipeptidase.
AB  - An analysis of the X-ray structure of cilastatin bound to membrane dipeptidase,
      together with docking studies, is presented here to reveal how a simple amide may
      act as a high-affinity, reversible, amidase inhibitor. Cilastatin binds as a
      normal substrate and is orientated in a perfect near-attack conformer for
      formation of a tetrahedral intermediate with the zinc-bound water/hydroxide. This
      intermediate is fated, however, only to revert to its starting components as
      scission of the amide bond is prevented by the precise fit of cilastatin within
      the active site. The cilastatin alkyl end groups that are tightly buttressed
      against amino acid residues on opposite sides of the active site, are aligned
      along the C-N reaction coordinate axis thereby preventing collapse of the
      intermediate via rupture of the C-N bond. Such a feature could have more general
      applicability in the explicit design of substrate variants as selective, tight
      binding, and reversible inhibitors.

PMID- 12614886
TI  - Ibogaine analogues. Synthesis and preliminary pharmacological evaluation of 7
      heteroaryl-2-azabicyclo[2.2.2]oct-7-enes.
AB  - Synthesis of 7-heteroaryl-2-azabicyclo[2.2.2]oct-7-enes by cycloaddition and
      subsequent cross-coupling reaction is described. Binding affinity of these novel
      compounds towards the characteristic receptorial targets of ibogaine is
      illustrated.

PMID- 12614885
TI  - Chiral 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with
      anti-inflammatory activity. Part 11: evaluation of COX-2 selectivity and
      modelling.
AB  - Anti-inflammatory/analgesic 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4
      thiazolidinones] 1, obtained as racemic mixtures (a) and mesoforms (b), have two
      equivalent stereogenic centres (C-2 and C-2') and exist as RR, SS and RS isomers.
      The enantioseparation of 1a provided the single enantiomers that displayed
      different in vitro cyclooxygenase-1/cyclooxygenase-2 selectivity ratios. In
      particular the dextrorotatory compound is a highly selective COX-2 inhibitor and
      the levorotatory one is moderately selective. Instead, RS-meso isomer (1b)
      exhibited similar levels of inhibitory activity on both COX isozymes. The
      diastereo- and enantioselectivity has been explained by molecular modelling of
      RR, SS and RS compounds into COX-1 and COX-2 binding sites. Theoretical results
      indicated SS>RS>RR affinity order towards COX-2 isoenzyme, in agreement with in
      vitro and previous in vivo pharmacological results.

PMID- 12614887
TI  - Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part
      10: identification of inhibitors for the liver microsomal acetoxycoumarin:
      protein transacetylase.
AB  - The quantitative structure-activity relationship (QSAR) studies conducted by us
      earlier revealed the cardinal role of the pyran ring carbonyl group in the
      acetoxy polyphenolic compounds for the acetoxy polyphenol:protein transacetylase
      (TAase) activity. Hence, an attempt was made to examine whether such substrate
      analogues of benzopyran acetates which lack in the pyran ring carbonyl group,
      such as 7-acetoxy-2,3-dihydro-2,2-dimethylbenzopyran (BPA), cetachin pentaacetate
      (CPA) and hematoxylin pentaacetate (HPA) could inhibit the 7,8-diacetoxy-4
      methylcoumarin (DAMC):protein (glutathione-S-transferase) transacetylase
      activity. These compounds were indeed found to remarkably inhibit the TAase
      activity in a concentration dependent manner and exerted their inhibitory action
      very rapidly. Further BPA, CPA and HPA were found to abolish the TAase mediated
      activation of NADPH cytochrome C reductase as well as the inhibition of liver
      microsome catalyzed aflatoxin B(1) (AFB(1))-DNA binding by DAMC very effectively.
      These results strongly suggest that the acetoxybenzopyrans merit as potent
      inhibitors of TAase.

PMID- 12614888
TI  - Water soluble prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2
      (3,4,5-trimethoxyphenyl)cyclopent-2-ene-1-one.
AB  - Fourteen prodrugs of the antitumor agent 3-[(3-amino-4-methoxy)phenyl]-2-(3,4,5
      trimethoxyphenyl)cyclopent-2-ene-1-one (1) were prepared to improve its water
      solubility and potency. These prodrugs include alpha-amino acid (1a-1h),
      aliphatic amino acid (1i-1l), phosphoramidate (1m), and phosphate (1n)
      derivatives. All of the prodrugs showed improved water solubility. A number of
      the amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) exhibited more potent
      antitumor activity compared to the parent compound (1). The phosphate prodrug 1n
      also offered a potent antitumor activity, but the phosphoramidate 1m did not show
      any antitumor activity in vivo. None of the prodrugs exhibited significant
      toxicities in mice. These results indicate that the design and preparation of the
      amino acid prodrugs (1a, 1b, 1d-1f, 1h, 1j, and 1k) and phosphate prodrug (1n)
      are beneficial for enhancing the antitumor activity of 1. The similar approaches
      may be used to improve water solubility and bioactivity of other poorly soluble
      aromatic amines.

PMID- 12614889
TI  - Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9
      carboxylic acid and its esters.
AB  - 4,10-Dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid (1) was
      synthesized by a new approach via the key intermediate 7-[1-aza-2
      (dimethylamino)vinyl]-4-methylquinolin-2(1H)-one (4). Compound 1 and its esters
      were evaluated in cytotoxicity and anti-HIV assays. The 9-carboxyl (1s)-endo-(-)
      borneol ester (9) showed marginal cytotoxic activity in CAK1-1, HOS, KB, and HCT
      8 cells.

PMID- 12614890
TI  - Synthesis and DNA binding studies of a new asymmetric cyanine dye binding in the
      minor groove of [poly(dA-dT)]2.
AB  - A new asymmetric cyanine dye has been synthesised and its interaction with
      different DNA has been investigated. In this dye, BEBO, the structure of the
      known intercalating cyanine dye BO has been extended with a benzothiazole
      substituent. The resulting crescent-shape of the molecule is similar to that of
      the well-known minor groove binder Hoechst 33258. Indeed, comparative studies of
      BO illustrate a considerable change in binding mode induced by this structural
      modification. Linear and circular dichroism studies indicate that BEBO binds in
      the minor groove to [poly (dA-dT)](2), but that the binding to calf thymus DNA is
      heterogeneous, although still with a significant contribution of minor groove
      binding. Similar to other DNA binding asymmetric cyanine dyes, BEBO has a large
      increase in fluorescence intensity upon binding and a relatively large quantum
      yield when bound. The minor groove binding of BEBO to [poly (dA-dT)](2) affords
      roughly a 180-fold increase in intensity, which is larger than to that of the
      commonly used minor groove binding probes DAPI and Hoechst 33258.

PMID- 12614891
TI  - Purification and characterization of an alkaline lipase from a newly isolated
      Pseudomonas mendocina PK-12CS and chemoselective hydrolysis of fatty acid ester.
AB  - Lipase isolated from a soil isolate, Pseudomonas mendocina (PK-12CS)
      chemoselectively hydrolyzed the fatty ester group in presence of arbamate of
      compound 5-amino-2,4-dihydro-3H-1,2,4-triazole-3 ones, a class of compounds which
      are attractive starting materials for the synthesis of triazole annealed
      heterocycles. The enzymatic method provides an easy access to the synthesis of N
      substituted glycine. Under optimized fermentation conditions the culture produced
      3510 Lipolytic Units/mL of cell free fermentation broth in 20 h of fermentation.
      The purified lipase exhibited molecular mass of 80 kDa on SDS polyacrylamide gel
      electrophoresis. The enzyme was stable at room temperature for more than a month
      and expressed maximum activity at 37 degrees C and pH 8.

PMID- 12614892
TI  - New fluorinated derivatives as esterase inhibitors. Synthesis, hydration and
      crossed specificity studies.
AB  - A variety of new fluorinated chemicals have been prepared for the first time and
      tested as inhibitors of esterases, one of the main enzymes involved in pheromone
      catabolism, in two economically important pests, the Egyptian armyworm Spodoptera
      littoralis (SL) and the Mediterranean corn borer Sesamia nonagrioides (SN). Using
      the respective major component of the pheromone as substrate, the K(m) and V(max)
      of the antennal esterase of both insects resulted to be 5.66 x 10(-4) M and 8.47
      x 10(-6) Mmin(-1) for SL and 1.61 x 10(-7) M and 1.25 x 10(-7) Mmin(-1) for SN,
      pointing out that SN esterase has a higher affinity for its corresponding
      substrate than SL. In general, the trifluoromethyl ketones (TFMKs) exhibited
      higher inhibitory potency than the corresponding difluoromethyl ketones (DFMKs)
      or difluoroaldehydes (DFAs). The compounds appeared to hydrate differently in
      aqueous solution, the extent of hydration following the order: alpha,alpha
      DFMKs<alpha,alpha-difluoro-beta-thioalkylmethyl ketones<TFMKs<beta
      thiotrifluoromethyl ketones<alpha,alpha-DFAs. No clear correlation has been found
      between the K(hyd) and the inhibitory potency and no specificity has been found
      when the chemicals were assayed on extracts of both insects.

PMID- 12614893
TI  - Curcumin differentially modulates mRNA profiles in Jurkat T and human peripheral
      blood mononuclear cells.
AB  - Curcumin, the yellow pigment of the rhizome of Curcuma longa is known to inhibit
      the transcription factors AP-1, Egr-1, NF-kappaB, c-myc and several important
      signaling kinases. We therefore investigated the differential effects of curcumin
      in concentation between 1.5 and 13.6 microM on gene expression in T Jurkat CD4(+)
      and human peripheral blood mononuclear cells (PBMCs). Relative quantification
      with reverse transcription real-time PCR (RT-rt-PCR) showed that low
      concentrations of curcumin significantly down-regulated mitogen-induced
      granulocyte macrophage colony stimulating factor (GM-CSF) mRNA (3- to 5-fold at 3
      microM) in a dose- and time-dependent manner in both cell types. In comparison,
      the down-regulation of inducible nitric oxide (iNOS) mRNA levels was less
      pronounced, but interferon gamma (IFN-gamma) mRNA was dose-dependently up
      regulated with curcumin concentrations up to 8.2 microM. Cyclin D1 mRNA
      expression was specifically inhibited in Jurkat T cells and stimulated PBMCs. The
      transcription factors NF-kappaB and NF-ATc were not affected in PBMCs.
      Interleukin-2 (IL-2), and-6 (IL-6) mRNAs levels were not influenced markedly by
      curcumin in stimulated PBMCs, but significantly reduced in stimulated Jurkat T
      cells. In addition, cytotoxic effects and down-regulation of mRNAs, including p65
      and the house-keeping genes could only be measured in Jurkat T cells. These
      findings confirm previous reports on the anti-neoplastic potential of curcumin
      and show that this compound differentially modulates the expression profile of
      Th1 cells and PBMCs.

PMID- 12614894
TI  - Synthesis and structure-affinity relationship investigations of 5-aminomethyl and
      5-carbamoyl analogues of the antipsychotic sertindole. A new class of selective
      alpha1 adrenoceptor antagonists.
AB  - A new class of selective alpha(1) adrenoceptor antagonists derived from the
      antipsychotic drug sertindole is described. The most potent and selective
      compound 1-(2-(4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1
      piperidinyl)ethyl)-2-imidazolidinone (11) binds with 0.50 nM affinity for
      alpha(1) adrenergic receptors and with more than 44 times lower affinity for
      dopamine D(2),D(3), D(4) and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C)
      receptors. The molecular features providing high affinity for adrenergic alpha(1)
      receptors and high selectivity towards dopamine D(2) and serotonin 5-HT(2A) and 5
      HT(2C) receptors are discussed.

PMID- 12614896
TI  - Synthesis and antioxidant properties of a new lipophilic ascorbic acid analogue.
AB  - 4-(4-Hydroxyphenyl)-5-(4-hydroxyphenylmethyl)-2-hydroxyfurane-2-one 1 was
      prepared by an acidic dimerisation of 4-hydroxyphenylpyruvic acid and some of its
      antioxidant and spectroscopic properties have been measured and compared to that
      of ascorbic acid. 1 is as good an antioxidant as ascorbic acid in the DPPH (2,2
      diphenyl-1-picryl hydrazyl radical) test and the inhibition of hydroxyl radical
      and a powerful inhibitor of the Cu(2+) or AAPH (2,2'-azobis-(2-amidinopropane)
      dihydrochloride) induced oxidation of human LDL. 1 gives a stable radical
      characterised by its ESR spectrum similarly to ascorbic acid but in lower
      concentration and with a different reactivity towards nitroxides. Theoretical
      calculations allow us to propose the structure for the radical formed from 1, to
      explain its lower stability than ascorbyl radical and to evaluate the
      lipophilicity of 1.

PMID- 12614895
TI  - Bis-4-aminoquinolines: novel triple-helix DNA intercalators and antagonists of
      immunostimulatory CpG-oligodeoxynucleotides.
AB  - Six dimeric 2-(2-naphthyl)quinolin-4-amines with a linker between the amino
      groups and eight dimeric 2-(4-anilino)quinolin-4-amines linked between the
      anilino groups were synthesized and evaluated for their interaction with
      duplex/triplex DNA's and as antagonists of immunostimulatory
      oligodeoxynucleotides with a CpG-motif (CpG-ODN). The most powerful triple-helix
      DNA intercalator known to date, with high affinity toward T.A.T triplets and
      triplex/duplex selectivity, was found. The potent antagonism of immunostimulatory
      CpG-ODN by several bis-4-aminoquinolines is not related to their DNA
      interactions.

PMID- 12614897
TI  - Substituted heterocyclic thiourea compounds as a new class of anti-allergic
      agents inhibiting IgE/Fc epsilon RI receptor mediated mast cell leukotriene
      release.
AB  - Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of
      allergy and asthma. We synthesized various analogues of indolyl, naphthyl and
      phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and
      examined their in vitro effects on the high affinity IgE receptor/Fc epsilon RI
      mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea
      compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2
      (ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1
      (1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (compound 5) (IC(50)=0.005
      microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea
      compounds tested, there were seven active compounds and the halopyridyl compounds
      N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea (24) and N-[2-(3
      indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea (25) were the most active agents
      and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 and 6.1
      microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4
      hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (37; IC(50)=12.6 microM), N
      [2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (50; IC(50)=16.8
      microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (35; IC(50)=8.5
      microM) were the most active pyridyl thiourea agents. Notably, the introduction
      of electron withdrawing or donating groups had a marked impact on the biological
      activity of these thiourea derivatives and the Hammett sigma values of their
      substituents were identified as predictors of their potency. In contrast,
      experimentally determined partition coefficient values did not correlate with the
      biological activity of the thiourea compounds which demonstrates that their
      liphophilicity is not an important factor controlling their mast cell inhibitory
      effects. These results establish the substituted halopyridyl, indolyl and
      naphthyl thiourea compounds as a new chemical class of anti-allergic agents
      inhibiting IgE receptor/Fc epsilon RI-mediated mast cell LTC(4) release. Further
      lead optimization efforts may provide the basis for new and effective treatment
      as well as prevention programs for allergic asthma in clinical settings.

PMID- 12614898
TI  - Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'
      groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding
      from X-ray crystal structure of inhibitor protease complex.
AB  - A series of HIV-1 protease inhibitors having new tetrahydrofuran P2/P2' groups
      have been synthesised and tested for protease inhibition and antiviral activity.
      Six novel 4-aminotetrahydrofuran derivatives were prepared starting from
      commercially available isopropylidene-alpha-D-xylofuranose yielding six
      symmetrical and six unsymmetrical inhibitors. Promising sub nanomolar HIV-1
      protease inhibitory activities were obtained. The X-ray crystal structure of the
      most potent inhibitor (23, K(i) 0.25 nM) co-crystallised with HIV-1 protease is
      discussed and the binding compared with inhibitors 1a and 1b.

PMID- 12614899
TI  - Modes of antifungal action of alkanols against Saccharomyces cerevisiae.
AB  - Primary aliphatic alcohols from C(6) to C(13) were tested for their antifungal
      activity against Saccharomyces cerevisiae. Undecanol was found to be the most
      potent fungicide followed by decanol. The time-kill curve study showed that
      undecanol was fungicidal against S. cerevisiae at any growth stages. This
      fungicidal activity was not influenced by pH values. The alcohols tested
      inhibited glucose-induced acidification by inhibiting the plasma membrane H(+)
      ATPase. The primary antifungal action of amphipathic medium-chain (C(9)-C(12))
      alkanols comes mainly from their ability as nonionic surfactants to disrupt the
      native membrane-associated function of the integral proteins. Hence, the
      antifungal activity of alkanols is mediated by biophysical process, and the
      maximum activity can be obtained when balance between hydrophilic and hydrophobic
      portions becomes the most appropriate.

PMID- 12614900
TI  - 2,3-Disubstituted quinuclidines as a novel class of dopamine transporter
      inhibitors.
AB  - There is considerable interest in developing dopamine transporter (DAT)
      inhibitors as potential therapies for the treatment of cocaine abuse. We report
      herein our pharmacophore-based discovery and molecular modeling-assisted rational
      design of 2,3-disubstituted quinuclidines as potent DAT inhibitors with a novel
      chemical scaffold. Through 3-D-database pharmacophore searching, compound 12 was
      identified as a very weak DAT inhibitor with K(i) values of 7.3 and 8.9 microM in
      [3H]mazindol binding and in inhibition of dopamine reuptake, respectively.
      Molecular modeling-assisted rational design and chemical modifications led to
      identification of potent analogues (-)-29 and 34 with K(i) values of 14 and 32 nM
      for both compounds in binding affinity and inhibition of dopamine reuptake,
      respectively. Behavioral pharmacological evaluations in rodents showed that 34
      has a profile very different from cocaine. While 34 is substantially more potent
      than cocaine as a DAT inhibitor, it is approximately four times less potent than
      cocaine in mimicking the discriminative stimulus properties of cocaine in rat. On
      the other hand, 34 (3-30 mg/kg) lacks either the locomotor stimulant or
      stereotypic properties of cocaine in mice. Importantly, 34 blocks locomotor
      stimulant activity induced by 20 mg/kg cocaine in mice, with an estimated ED(50)
      of 19 mg/kg. Taken together, our data suggest that 34 represents a class of
      potent DAT inhibitors with a novel chemical scaffold and a behavioral
      pharmacological profile different from that of cocaine in rodents. Thus, 34 may
      serve as a novel lead compound in the ultimate development of therapeutic
      entities for cocaine abuse and/or addiction.

PMID- 12614901
TI  - Antitumor agents 220. Antitumor-promoting effects of cimigenol and related
      compounds on Epstein-Barr virus activation and two-stage mouse skin
      carcinogenesis.
AB  - Cimigenol (1) and 39 related compounds were screened as potential antitumor
      promoters by examining the ability of the compounds to inhibit Epstein-Barr virus
      early antigen (EBV-EA) activation (induced by 12-O-tetradecanoylphorbol-13
      acetate) in Raji cells. Structure-activity relationship analysis indicated that
      compound 1 showed the highest activity and also exhibited significant inhibitory
      effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis
      test. These data suggest that 1 and the related compounds might be valuable anti
      tumor promoters.

PMID- 12614902
TI  - Early and late treadmill training after focal brain ischemia in rats.
AB  - Treadmill training is increasingly recognized as an effective means to promote
      rhythmical vigorous walking and also as a useful method of task-related training.
      The present study endeavored to investigate the effects of early and late
      treadmill training after ligation of the middle cerebral artery. Forty male
      Sprague-Dawley rats were subjected to 60 min right middle cerebral artery
      occlusion (MCAO). All rats were randomly assigned to one of four groups: 24 h
      group, 2 week no training group, early training group (training started 24 h post
      MCAO), and late training group (training started 1 week post MCAO). Infarct
      volume was measured morphometrically. A five-point neurological evaluation scale
      was used to assess the neurological status of rats. Rats sacrificed 24 h post
      MCAO had the largest infarct volume (177.8+/-14.3 mm(3)) and the highest
      neurological score [2(1-4)]. Early treadmill training was found to have
      significant effects in reducing brain infarct volume and in improving neurologic
      function when compared with spontaneous recovery. However, the same effects
      cannot be found in late training. Based on the present findings, we would
      encourage early treadmill training for ischemic brain recovery.

PMID- 12614903
TI  - Brain region-specific changes in the expression of calcium sensor proteins after
      repeated applications of ketamine to rats.
AB  - We investigated the cellular distribution of three calcium sensor proteins,
      visinin-like protein-1 (VILIP-1), VILIP-3, and hippocalcin, in different rat
      brain areas after repeated administration of the non-competitive N-methyl-D
      aspartate receptor antagonist ketamine. In comparison to controls we observed an
      increase in the density of VILIP-1 immunoreactive (IR) hippocampal interneurons
      and presubicular nerve cells in ketamine treated rats, whereas the density of
      VILIP-1 expressing cells was decreased in the Nuc. accumbens of these rats. No
      alterations were seen in the distribution patterns of VILIP-3. The density of
      hippocalcin-expressing neurons was increased in the cingulate cortex of drug
      treated rats. Our experiments show that repeated injections of subanesthetic
      doses of ketamine induce subtle changes in the cellular distribution of calcium
      sensor proteins which in part resemble those recently described in postmortem
      brains of human schizophrenics [Bernstein, H.-G., Braunewell, K.-H., Spilker, C.,
      Danos, P., Baumann, B., Funke, S., Diekmann, S., Gundelfinger, E.D. and Bogerts,
      B., NeuroReport, 13 (2002) 393-396].

PMID- 12614904
TI  - Cerebrospinal fluid biomarkers for disease stage and intensity in cognitively
      impaired patients.
AB  - Biomarkers to monitor the degenerative process in Alzheimer's disease would be of
      great value. We examined the relation between cerebrospinal fluid (CSF) total tau
      (T-tau), phospho-tau (P-tau) and Abeta42 and magnetic resonance imaging (MRI)
      measures of brain atrophy. CSF was taken at baseline and MRI at baseline and at
      16 months follow-up. At baseline, statistically significantly lower Abeta42 were
      found with lower brain volume (r=0.55; P<0.0001) and larger ventricular volume
      (r=-0.53; P<0.001). In contrast, statistically significantly higher T-tau
      (r=0.47; P<0.001) and P-tau (r=0.41; P=0.005) were found with more marked
      ventricular widening during the follow-up period. These results suggest that
      Abeta42 in CSF reflects the stage of the disease, with lower CSF levels as the
      disease progresses, while T-tau and P-tau reflect the intensity of the disease
      process, with higher CSF-levels with a more rapid progression.

PMID- 12614905
TI  - The effects of aging on thermal hyperalgesia and tactile-evoked allodynia using
      two models of peripheral mononeuropathy in the rat.
AB  - The effects of aging on the behavioral manifestations of neuropathic and
      inflammatory pain were investigated using two models of peripheral nerve injury.
      The left sciatic nerve of young and aged Fischer 344 FBNF1 hybrid rats (4-6 and
      24-26 months old, respectively) was ligated using either the chronic constriction
      injury (CCI) model of Bennett and Xie or the partial sciatic nerve ligation
      (PSNL) model of Seltzer et al. A plantar analgesic meter was used to assess age
      related differences in CCI- or PSNL-induced thermal hyperalgesia, and nerve
      injury-induced tactile-evoked allodynia was assessed with von Frey filaments.
      Aged animals subjected to the PSNL procedure developed a more vigorous and longer
      lasting thermal hyperalgesic response than did aged rats post-CCI. The CCI model
      incorporates a more prominent peripheral inflammatory component than the PSNL
      model. These data support the notion that the peripheral inflammatory response is
      diminished in aged rats.

PMID- 12614906
TI  - Electrophysiological correlates of attentional orientation in humans to strong
      intensity deviant nociceptive stimuli, inside and outside the focus of spatial
      attention.
AB  - Laser evoked potentials (LEPs) are electrical brain responses to nociceptive heat
      stimuli. In a recent study [Legrain, V., Guerit, J.M., Bruyer, R. and Plaghki,
      L., Pain, 99 (2002) 21-39.], we found that amplitude at approximately 400 ms was
      increased by rare intensity deviant nociceptive stimuli (P400 effect). In that
      study, laser stimuli were randomly delivered on both hands, and subjects were
      focusing attention on one hand in order to detect rare stimuli. As the P400
      effect was found for rare stimuli when spatial attention was directed both
      towards and away from the stimulated hand, it was postulated to represent a P3a
      component reflecting an involuntary orientation of attention to unexpected
      deviant stimuli. However LEPs to strong and weak intensity stimuli were averaged
      together and some effects could have been underestimated. So, we present a new
      interpretation of the P400 effect based on separate analyses of strong and weak
      intensity deviant stimuli. Indeed, the P400 effect was only observed for strong
      stimuli, and again on both attended and unattended hands. Thus, if the P400
      effect reflects P3a, only strong deviant stimuli provided enough signals to
      induce attentional switching even when they were delivered outside the focus of
      spatial attention. It is suggested that attentional switching could have been
      triggered by neural systems having detected sharp increase of intensity. Weak
      deviant stimuli were not salient enough to induce attentional switching.

PMID- 12614907
TI  - Early onset of post-movement beta electroencephalogram synchronization in the
      supplementary motor area during self-paced finger movement in man.
AB  - A voluntary finger movement is accompanied by an event-related desynchronization
      followed by a short burst of beta oscillations or event-related synchronization.
      These beta bursts are dominant over the contralateral hand representation area,
      but also appear over the midcentral area overlaying the supplementary motor area
      (SMA) and the foot representation area. We show that the induced midcentral beta
      oscillations following movement-offset display not only slightly higher frequency
      components, but have also a significantly earlier onset. These beta oscillations
      arise likely from the SMA. Assuming that the short-lasting beta synchronizations
      at frequencies below 35 Hz after termination of a movement reflect a state of
      localized cortical inhibition, we propose that the induced midcentral
      oscillations reflect the inhibition of networks within the SMA. This assumed
      resetting or inhibitory process within the SMA precedes that of the networks
      within the primary motor hand area.

PMID- 12614908
TI  - Human locomotion: levodopa keeps you straight.
AB  - Locomotion depends on an intact dopamine system. This system seems to be
      functionally asymmetric, as evidenced by an asymmetric turning preference. Using
      a double-blind procedure, the effect of levodopa on the number of veers when
      walking blindfolded along a straight line (20 m) in the middle of a corridor was
      tested in 40 healthy dextral men. One group received 200 mg levodopa, while the
      other group received placebo. We found that (1). subjects veered less after
      levodopa than after placebo, and (2). improved straight-walking tendency was most
      prominent for the levodopa group which veered less often to the right side than
      the placebo group. These findings imply that spatial orientation skills improved
      under levodopa. We conjecture that a task-dependent dopamine demand during our
      task was satisfied by levodopa supplementation, and over-proportionately so by
      the right hemisphere.

PMID- 12614909
TI  - Evidence for sexual difference in astrocytes of adult rat hippocampus.
AB  - We quantified the number of glial fibrillary acidic protein immunoreactive (GFAP
      IR) astrocytes in the CA1 and CA3 areas of the adult rat hippocampus. The dorsal
      and ventral regions of the hippocampus were taken into account to estimate the
      GFAP-IR cells using unbiased stereological techniques. Males had a higher number
      of GFAP-IR astrocytes in the CA3 area, whereas females had more in the CA1 area.
      No sex difference was found between dorsal and ventral regions, although most
      GFAP-IR astrocytes were located in the dorsal hippocampus.

PMID- 12614910
TI  - Fronto-parieto-cerebellar interaction associated with intermanual transfer of
      monkey tool-use learning.
AB  - Prior motor skill learning (original learning; OL) with one hand (original hand;
      OH) can affect relearning of the same skill (transfer learning; TL) with the
      opposite hand (transferred hand; TH). This phenomenon is known as intermanual
      transfer of learning. We explored specialization of brain activation underlying
      tool-use between hands by measuring regional cerebral blood flow in two monkeys
      using positron emission tomography. We found brain activation specified for TL in
      the bilateral prefrontal cortex, bilateral intraparietal sulcus region, and
      cerebellum contralateral to TH. The results suggest that those regions may be
      related to intermanual transfer of tool-use learning, presumably in terms of
      modifying a motor engram specific for OH.

PMID- 12614911
TI  - Adenosine promotes neuronal recovery from reactive oxygen species induced lesion
      in rat hippocampal slices.
AB  - Reactive oxygen species (ROS) are believed to be involved in the pathogenesis of
      several neurological disorders. We now tested whether the endogenous
      neuroprotective substance, adenosine, attenuates the cell damage induced by ROS.
      In rat hippocampal slices, the xanthine oxidase (40 mU/ml) plus xanthine (1 mM)
      (X/XO) system produced a 27.8+/-7.3% (n=3) increase in ROS, measured by
      fluorimetry with 2',7'-dichlorodihydrofluorescein, a 246.9+/-18.4% (n=6) increase
      in the release of tritiated adenosine, and a decrease in synaptic transmission
      that fully recovered after washout. In the presence of the adenosine A(1)
      receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (100 nM), X/XO
      induced a similar inhibition, however synaptic transmission only recovered to
      70.7+/-5.8% of control (n=5). The blockade of A(2A) receptors was devoid of
      effect (n=4). Adenosine is released by ROS-generating systems, and attenuates the
      deleterious cellular consequences of ROS through A(1) receptor activation.

PMID- 12614912
TI  - Reduction of serotonin content by tetrahydropapaveroline in murine mastocytoma
      P815 cells.
AB  - The inhibitory effects of tetrahydropapaveroline on serotonin biosynthesis in
      serotonin-producing murine mastocytoma P815 cells were investigated.
      Tetrahydropapaveroline decreased serotonin content in a concentration-dependent
      manner in P815 cells and showed 44.9% reduction of serotonin content at a
      concentration of 5.0 microM for 24 h. The value of 50% inhibitory concentration,
      IC(50), of tetrahydropapaveroline was 7.5 microM. Under these conditions,
      tryptophan hydroxylase (EC 1.14.16.4, TPH) was inhibited for 24-36 h after
      treatment with tetrahydropapaveroline in P815 cells (46.6% inhibition at 7.5
      microM). In addition, tetrahydropapaveroline inhibited the activity of TPH,
      prepared from the P815 cells (P815-TPH), with the IC(50) value of 8.4 microM.
      Inhibition of P815-TPH by tetrahydropapaveroline was found to be non-competitive
      both with the substrate L-tryptophan and with the cofactor DL-6-methyl-5,6,7,8
      tetrahydropterine. The K(i) value of tetrahydropapaveroline with L-tryptophan was
      9.29 microM. These data indicate that tetrahydropapaveroline leads to a decrease
      in serotonin content by inhibiting TPH activity in P815 cells.

PMID- 12614913
TI  - Gamma-band desynchronization in language areas reflects syntactic process of
      words.
AB  - The aim of this study was to verify the relation between gamma-band activity and
      process of function words. We recorded the neuromagnetic signals in six healthy
      volunteers during silent reading of verbs (verb task) and forming of the past
      tenses (past-tense task) and investigated the spatio-temporal distribution of
      event-related desynchronization (ERD) and synchronization using synthetic
      aperture magnetometry. In both tasks, ERDs were observed simultaneously at
      multiple language-related areas. The left junctional area of inferior frontal
      sulcus and precentral sulcus and the left supramarginal gyrus showed stronger
      and/or longer-lasting ERDs in past-tense task than in verb task. This result
      suggests that the gamma-activities reflect the syntactic process of words.

PMID- 12614914
TI  - Rapid induction of insulin resistance in opioid mu-receptor knock-out mice.
AB  - Role of opioid mu-receptor that has been showed to involve in the insulin
      dependent diabetic rats in the induction of insulin resistance remains unclear.
      The present study is performed to clarify this point. The wild-type mice or
      opioid mu-receptor knockout mice were employed to induce insulin resistance by
      feeding with fructose-rich chow or by the repeated intraperitoneal injections of
      long-acting form of human insulin at 0.5 IU/kg three times daily. The basal
      plasma glucose concentration was not markedly changed in fructose-fed mice
      regardless the presence of opioid mu-receptor or not. However, the plasma glucose
      lowering activity of tolbutamide (10.0 mg/kg) disappeared rapidly in opioid mu
      receptor knockout mice receiving fructose-rich chow as compared to that in wild
      type group. In opioid mu-receptor knockout mice, the elevation of plasma glucose
      concentration and the loss of plasma glucose lowering activity of tolbutamide
      were observed at 15 days after insulin injection. However, similar change was
      obtained at 21 days later of insulin injection in wild-type mice, showing that
      decrease of insulin action was more markedly in opioid mu-receptor knockout mice.
      Our results indicated that opioid mu-receptor is related to the delay of insulin
      resistance induced by fructose-fed method or insulin repeated injection.

PMID- 12614915
TI  - Modafinil increases histamine release in the anterior hypothalamus of rats.
AB  - Modafinil, (RS)-2-(Diphenylmethylsulfinyl)acetamide, is a well known wake
      promoting drug used for the treatment of narcolepsy. We investigated the effect
      of modafinil on the hypothalamic histamine release in the anesthetized rat using
      in vivo microdialysis. Modafinil (150 mg/kg, i.p.) increased histamine release by
      150% of the basal release. The intracerebroventricular (i.c.v.) injection of
      modafinil (1 nmol) also increased histamine release, however, when modafinil (1
      nmol) was injected directly into the tuberomammillary nucleus, a limited region
      where cell bodies of the histaminergic neurons are located, histamine release was
      not altered. These observations suggest that modafinil may promote waking via the
      activation of the histaminergic system, although it does not appear to be a
      direct pharmacological target of modafinil.

PMID- 12614916
TI  - Nitric oxide induces macrophage apoptosis following traumatic brain injury in
      rats.
AB  - This study examined the apoptotic mechanisms of macrophages following a lateral
      fluid percussive brain injury. A marked induction of inducible NO synthase (iNOS)
      immunoexpression was observed in brain macrophages in the subarachnoid space and
      lateral ventricles ipsilateral to the injury. Numerous apoptotic macrophages
      occurred in the same region 7 days after the injury as shown by in situ terminal
      transferase d-UTP nick-end labeling (TUNEL) and caspase-3 immunohistochemistry.
      Double immunofluorescence staining showed that only a small number of TUNEL
      positive cells were iNOS positive; many TUNEL positive cells, however, were
      observed in the vicinity of iNOS positive cells. Administration of aminoguanidine
      resulted in a marked reduction of apoptotic cells in the lesioned area suggesting
      that overproduction of NO is linked to diminution of brain macrophages by
      apoptosis.

PMID- 12614917
TI  - Strain-dependent response to cerebral ischemic preconditioning: differences
      between spontaneously hypertensive and stroke prone spontaneously hypertensive
      rats.
AB  - Ischemic preconditioning (PC) is a phenomenon whereby a brief exposure to
      ischemia renders a tissue more tolerant to a subsequent sustained ischemic
      insult. Animals of the Spontaneously Hypertensive (SHR) and the Spontaneously
      Hypertensive Stroke-Prone (SHR-SP) rat strains produce cerebral infarcts that are
      larger and more reproducible in size than infarcts of normotensive rats. This
      study compared the effects of PC in SHR and SHR-SP rats, under the hypothesis
      that PC may not be as effective in the SHR-SP, a strain genetically predisposed
      to stroke. There were two groups per strain, with between eight and ten animals
      each. The Precondition group (PC) had a 10 min occlusion of the middle cerebral
      artery on day -1. On the same day the Sham group (Sham) received sham surgery. On
      day 0, both groups underwent permanent occlusion of the middle cerebral artery.
      The ischemic lesion was measured on day 1 using T(2)-weighted magnetic resonance
      imaging. Percent hemispheric infarct was significantly reduced in SHR PC vs. SHR
      Sham, SHR-SP PC vs. SHR-SP Sham, and SHR PC vs. SHR-SP PC. Thus, rats of the SHR
      SP strain respond to PC less markedly than SHR animals. Both models may now be
      used to elucidate the mechanisms underlying PC.

PMID- 12614918
TI  - Effects of dietary lead and/or dimercaptosuccinic acid exposure on regional
      serotonin and serotonin metabolite content in rainbow trout (Oncorhynchus
      mykiss).
AB  - The lead (Pb) chelator, meso-2,3-dimercaptosuccinic acid (DMSA) may be effective
      in reversing some of the adverse effects of Pb exposure. Pb-induced behavioral
      deficits observed in fish are due to disruptions in the integrative functioning
      of the medulla, cerebellum, and optic tectum. Pb exposure increased serotonin (5
      HT) content in all three brain regions without an effect on 5-hydroxy-3
      indoleacetic acid (5-HIAA). Pb exposure followed by no Pb in the diet increased 5
      HT and 5-HIAA content in all three brain regions. The replacement of dietary Pb
      with DMSA had no effect on 5-HT and increased 5-HIAA content. DMSA increased 5
      HIAA content in all three brain regions and increased 5-HT content only the optic
      tectum. Treatment with DMSA may be more effective than removal of Pb from the
      diet in reversing Pb-induced alterations in 5-HT.

PMID- 12614919
TI  - Activity and distribution patterns of monkey pallidal neurons in response to
      peripheral nerve stimulation.
AB  - The response patterns of pallidal neurons to electrical stimulation of the median
      and tibial nerves were examined in awake monkeys. Around 30% of the recorded
      neurons responded to the stimulation of either the median or tibial nerve, while
      only 6% responded to the stimulation of both nerves. The vast majority of these
      pallidal neurons displayed monophasic excitation or monophasic inhibition. The
      latency of the excitation was shorter than that of the inhibition. In each
      pallidal segment, the neurons responding to the median nerve stimulation
      (representing the forelimb) tended to be located ventral to those responding to
      the tibial nerve stimulation (representing the hindlimb). The present results
      indicate that the somatotopical arrangement in the globus pallidus can be
      outlined based on the neuronal responses to peripheral nerve stimulation.

PMID- 12614920
TI  - Effects of caloric restriction on cognition and behavior in developing mice.
AB  - The effects of caloric restriction (CR) on cognition and behavior in developing
      mice were investigated in this study. Male and female Kunmin mice were fed a
      standard rodent diet ad libitum (Control); 80% of control (20% CR) or 65% of
      control (35% CR) for 6 months. Body weight gain was significant reduced in CR
      mice relative to control. Learning and memory retention test in a Y maze
      demonstrated that CR increased learning but not retention in male mice, whereas
      CR did not affect learning or retention in females. Open field test revealed no
      difference in exploratory activity between CR and control mice. These findings
      suggest that CR produce sex-dependent effect on cognition, but not exploratory
      activity, in developing animals.

PMID- 12614921
TI  - Dopamine receptor pruning during the peripubertal period is not attenuated by
      NMDA receptor antagonism in rat.
AB  - D(1) and D(2) receptors are overproduced and pruned in the mammalian striatum
      during the periadolescent period. The mechanism that underlies this process in
      striatum is unknown. However, previous research has shown that the activity
      dependent pruning of dendrites and synapses in somatosensory cortex and the
      visual fields is mediated by glutamatergic actions via N-methyl-D- aspartate
      (NMDA) receptor and is prevented by pretreatment with the NMDA antagonist MK-801.
      In order to test the hypothesis that the pruning of dopamine D(1) and D(2)
      receptors that occurs in the striatum after puberty (which occurs at
      approximately 40 days of age; P40), male and female rats were treated with saline
      vehicle or MK-801 (0.3 mg/kg) for 20 or 40 days and sacrificed immediately after
      the 20 day treatment (P60), 40 day treatment (P80), or 40 day treatment with 40
      day recovery (P120). Analyses of the data reveal that none of these three
      treatment regimens altered striatal D(1) or D(2) receptor density in males or
      females relative to vehicle controls. At P60, MK-801 treatment failed to alter
      either D(1) (F1,16=0.06, P>0.5) or D(2) receptors (F1,16=0.39, P>0.5) for either
      sex. Similarly, MK-801 treatment did not affect D(1) or D(2) receptors at P80
      (P>0.3) or at P120 (P>0.7). These data suggest that the normal 40% reduction in
      striatal dopamine receptor density that occurs between puberty and adulthood is
      not dependent on post-pubertal glutamatergic transmission through NMDA receptors.

PMID- 12614922
TI  - Levels of total tau and tau protein phosphorylated at threonine 181 in patients
      with incipient and manifest Alzheimer's disease.
AB  - Cerebrospinal fluid tau protein levels are considered to be a promising marker
      for Alzheimer's disease (AD) and may facilitate early detection. Using the newly
      developed INNOTEST Phospho-Tau((181P)) kit examination of total tau and tau
      protein phosphorylated at threonine 181 (phospho-tau 181) revealed significantly
      (P<0.05) higher values in both patients with incipient and manifest AD than in
      controls. In patients with vascular dementia, phospho-tau 181 levels were not
      different from controls but were significantly lower than in patients with
      manifest AD. These findings suggest that total and phosphorylated tau protein may
      facilitate early detection and differential diagnosis of AD.

PMID- 12614923
TI  - Combination of infarctions in the posterior inferior cerebellar artery and
      anterior spinal artery territories.
AB  - After an episode of vasodilator-induced systemic hypotension, a 75-year-old man
      developed ocular lateropulsion to the right, left-side-dominant quadriparesis,
      loss of superficial sensation below C4 dermatome level, and anuresis. Magnetic
      resonance imaging (MRI) showed infarcts in the right cerebellar hemisphere
      (posterior inferior cerebellar artery territory) and the upper cervical cord
      (anterior spinal artery territory); the combination of posterior inferior
      cerebellar artery (PICA) and anterior spinal artery (ASA) infarcts has not been
      reported previously. Angiography revealed severe stenosis in the bilateral
      vertebral arteries. Hemodynamic hypoperfusion of the stenotic vertebral arteries
      may cause this unusual combination.

PMID- 12614924
TI  - Antiplatelet prescribing patterns for TIA and ischemic stroke: the Indiana
      University experience.
AB  - OBJECTIVE: To evaluate antiplatelet prescribing patterns by Indiana University
      Hospital (IU) neurologists, determine what drives antiplatelet agent decisions,
      and determine changes made with recurrent cerebrovascular events despite proven
      antiplatelet therapy. There are now four approved therapies for secondary
      prevention of cerebrovascular events. As these agents exhibit their effects
      through different pathways, physicians must choose antiplatelet agents based on
      other factors. DESIGN: We retrospectively reviewed charts of neurology patients
      diagnosed with non-fatal ischemic stroke or TIA at IU from January 1, 1997 to
      August 31, 2001. Patients were excluded if: discharge diagnosis was not non-fatal
      ischemic stroke or TIA, they were enrolled in clinical trials, or were placed on
      anticoagulation therapy with warfarin. Patients' antiplatelet agents at discharge
      were reviewed to determine if specific factors led to the choice of antiplatelet
      agent. RESULTS: A total of 177 patients experienced non-fatal ischemic strokes or
      TIAs. Of these, 74 were not on prior antiplatelet therapy and 103 were on
      antiplatelet agents prior to admission. For patients not on therapy, aspirin was
      the most commonly prescribed agent, with a trend for low-dose aspirin. For
      patients already on an antiplatelet agent, typically the dose of aspirin was
      increased or combination therapy initiated. CONCLUSION: Our experience supports
      the use of aspirin as a first-line agent for secondary prevention in
      cerebrovascular disease. For antiplatelet-nai;ve patients, low-dose aspirin is
      the most frequently used agent. For patients previously on antiplatelet agents,
      aspirin dosage is increased or clopidogrel is added. High-dose aspirin and
      ticlopidine use is no longer favored.

PMID- 12614925
TI  - Pseudo-autosomal dominant inheritance of PARK2: two families with parkin gene
      mutations.
AB  - We report two families (Family S and Family N) with early-onset parkinsonism in
      two generations. The mode of inheritance appeared to be autosomal dominant,
      however, haplotye analysis suggested linkage to chromosome 6q25.2-27, the PARK2
      locus, and all affected members were homozygotes in their haplotypes. In Family
      S, the affected father was married to unaffected mother, who carried one disease
      linked haplotype at chromosome 6q25.2-27. In Family N, the unaffected mother
      carried one disease-linked haplotype. Quantitative PCR amplification analysis
      revealed exon 3 deletion in Family S and exon 5 deletion in Family N. The age of
      onset was from 18 to 22 years in Family S and 25 to 42 years in Family N. In both
      of their hometowns, most people lived in the same districts for many generations
      and consanguineous marriages had been common. Thus, the carrier state of the
      parkin gene might have been high in those communities, and marriage of a patient
      and a carrier is expected to result in autosomal dominant like inheritance. We
      conclude that PARK2 cannot be excluded even if the mode of inheritance appears as
      autosomal dominant, when the affected patients are young.

PMID- 12614926
TI  - Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L
      DOPA, homocysteine, and MTHFR genotype.
AB  - In recent years, an intense interest has developed in the association between
      Parkinson's disease (PD) and hyperhomocysteinemia. Homocysteine (Hcy) is a
      neuronal excitotoxic amino acid, and is well known as a risk factor for vascular
      diseases. Some reports suggest that the administration of L-DOPA may promote
      hyperhomocysteinemia and idiopathic atherosclerosis. In this study, we report
      that a mild hypertrophy of the intima-media complex (IMC) of the carotid artery,
      which has been established as a marker for systemic atherosclerosis, is observed
      in PD patients compared with normal subjects. PD patients that were treated with
      L-DOPA for long durations showed a hypertrophic IMC, while the patients that were
      not treated with L-DOPA did not show any hypertrophic changes in the IMC. These
      hypertrophic changes were observed primarily in patients with a Hoehn-Yahr stage
      of 3-5. PD patients with hypertrophic IMC of the carotid artery also exhibited
      elevated plasma levels of Hcy associated with the C677T genotype of 5,10
      methylenetetrahydrofolate reductase (MTHFR). Moreover, a prolonged duration of
      treatment with L-DOPA in patients with MTHFR T/T genotype enhanced the
      hypertrophy of IMC, compared with patients with the C/C or C/T genotype. These
      results suggest that hyperhomocysteinemia promoted by the C677T genotype of MTHFR
      and prolonged treatment with L-DOPA enhances atherosclerosis in PD patients and
      affects their general condition.

PMID- 12614927
TI  - Progress toward motor recovery with active neuromuscular stimulation: muscle
      activation pattern evidence after a stroke.
AB  - Chronic cerebrovascular accident individuals with partial paralysis in an upper
      extremity typically demonstrate difficulty in voluntarily controlling movement
      initiation. This study investigated patterns of electromyogram (EMG) activation
      levels while stroke subjects voluntarily initiated their impaired wrist and
      finger extensor muscles. Twenty subjects were randomly assigned to either a
      unilateral movement/stimulation group or a bilateral movement/stimulation group.
      Participants completed 4 days (6 h over 2 weeks) of active neuromuscular
      stimulation (i.e., 5 s/trial, 90 trials/day, biphasic waveform) on the wrist and
      finger extensors according to group assignments. The EMG activation levels were
      analyzed with a three-factor mixed design Motor recovery protocol x Session block
      x Trial block (2 x 2 x 3) ANOVA with repeated measures on the second and third
      factors. This robust analysis revealed higher EMG activation levels for the
      coupled bilateral movement/stimulation group than the unilateral
      movement/stimulation group. In addition, higher muscle activation levels were
      found for the second session block as well as trial blocks 2 and 3. Overall,
      these findings indicated improved motor capabilities of the impaired muscles as
      evidenced by the higher voluntary EMG activation levels.

PMID- 12614928
TI  - Middle latency auditory-evoked potentials in myotonic dystrophy: relation to the
      size of the CTG trinucleotide repeat and intelligent quotient.
AB  - OBJECTIVE: Major components of MLAEPs are thought to originate in the temporal
      lobe. Absence of the Pb potential has been demonstrated in MLAEPs in Alzheimer's
      disease and demented Parkinson's disease patients. To validate usefulness of
      middle latency auditory-evoked potentials (MLAEPs) in evaluating the central
      nervous system (CNS) involvement of myotonic dystrophy (MyD). METHODS: MLAEPs
      were recorded in eight patients with MyD and nine normal control subjects. In the
      patient group, the size of the CTG triplet repeat expansion within the dystrophia
      myotonica protein kinase (DMPK) gene and the revised Wechsler Adult Intelligence
      Scale (WAIS-R) were also assessed. RESULTS: The latency of the Nb potential
      showed a significant correlation with the size of the CTG repeat expansion
      (r=0.734, P=0.036). The Pb latency also tended to prolong according to CTG
      amplification (r=0.644, P=0.087). The amplitudes of Na and Pa significantly
      increased compared with those of normal control subjects (P=0.024 and 0.016,
      respectively). However, they did not correlate with IQ or CTG amplification.
      CONCLUSIONS: Abnormal MLAEPs may indicate CNS involvement in MyD. Although the
      precise generating mechanisms of Nb are unclear, the correlation of Nb latency
      with CTG amplification suggests that MLAEPs can reflect the extent of genetic
      abnormality.

PMID- 12614929
TI  - Gene expression in the Andes; relevance to neurology at sea level.
AB  - Chronic mountain sickness (CMS), a maladaptation syndrome to chronic hypoxia,
      occurs in the Andes. Gene expression differences in Andeans could explain
      adaptation and maladaptation to hypoxia, both of which are relevant to neurology
      at sea level. Expression of genes responsive to cellular oxygen concentration,
      hypoxia-inducible factor-1alpha (HIF-1alpha), three splicing variants of vascular
      endothelial growth factor (VEGF) and von Hippel-Lindau protein (pVHL) was
      measured by reverse transcription polymerase chain reaction (RT-PCR) in 12 Cerro
      de Pasco (CP) (altitude 4338 m) natives and 15 CMS patients in CP. Thirteen high
      altitude natives living in Lima and five Lima natives were sea level controls. A
      CMS score (CMS-sc) was assigned clinically. Expression was related to the
      clinical assessment. High expression of HIF-1alpha and VEGF-121 was found in CMS
      (P<0.001). Samples from CP had higher expression than those from Lima (P<0.001).
      Expression of HIF-1alpha and VEGF-121 was related to age (P<0.001); adjusting for
      age did not abolish the group effect. Higher CMS-sc was related to expression
      independent of age (P<0.001). VEGF-165 and -189 were expressed only in CMS. Birth
      altitude had no effect on gene expression. pVHL was not quantifiable.HIF-1alpha
      and VEGF-121 participate in adaptation to hypoxia. The high levels may explain
      blood vessel proliferation in Andeans and hold lessons for patients at sea level.
      VEGF-165 expression suggests that it contributes to preservation of neuronal
      function in human chronic hypoxia. VHL mutations may mark those destined to
      develop neural crest tumors which are common in the Andes.

PMID- 12614930
TI  - Microheterogeneity of anti-myelin-associated glycoprotein antibodies.
AB  - Antibodies to the myelin-associated glycoprotein (MAG) are implicated in the
      pathogenesis of an acquired demyelinating polyneuropathy. We studied IgM affinity
      to MAG in 18 patients with anti-MAG antibodies. Binding of sera was tested for
      anti-MAG immunoreactivity in central nervous system (CNS) by ELISA and in CNS and
      peripheral nervous system (PNS) by Western blot analysis. Furthermore,
      immunohistochemical characterization of IgM binding on sural nerve tissue was
      investigated using the indirect peroxidase method. Western blot analysis revealed
      that all sera detected MAG in central myelin, but only eight in peripheral
      myelin. Anti-MAG-IgM-ELISA-titers correlated significantly (p<0.0001) with PNS
      Western blot results. By indirect immunoperoxidase immunohistochemistry, 12 sera
      stained myelin sheaths, while 6 sera showed no staining. These results
      demonstrate considerable variations in antibody binding strength to MAG between
      PNS myelin and CNS myelin. The relevance of these differences for the
      pathogenesis of the neuropathy and clinical impairment remains to be
      demonstrated.

PMID- 12614931
TI  - Mitochondrial dysfunction and death in motor neurons exposed to the glutathione
      depleting agent ethacrynic acid.
AB  - This study investigated the mechanisms of toxicity of glutathione (GSH) depletion
      in one cell type, the motor neuron. Ethacrynic acid (EA) (100 microM) was added
      to immortalized mouse motor neurons (NSC-34) to deplete both cytosolic and
      mitochondrial glutathione rapidly. This caused a drop in GSH to 25% of the
      initial level in 1 h and complete loss in 4 h. This effect was accompanied by
      enhanced generation of reactive oxygen species (ROS) with a peak after 2 h of
      exposure, and by signs of mitochondrial dysfunction such as a decrease in 3-(4,5
      dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide (MTT) (30% less after 4 h).
      The increase in ROS and the MTT reduction were both EA concentration-dependent.
      Expression of heme oxygenase-1 (HO-1), a marker of oxidative stress, also
      increased. The mitochondrial damage was monitored by measuring the mitochondrial
      membrane potential (MMP) from the uptake of rhodamine 123 into mitochondria. MMP
      dropped (20%) after only 1 h exposure to EA, and slowly continued to decline
      until 3 h, with a steep drop at 5 h (50% decrease), i.e. after the complete GSH
      loss. Quantification of DNA fragmentation by the TUNEL technique showed that the
      proportion of cells with fragmented nuclei rose from 10% after 5 h EA exposure to
      about 65% at 18 h. These results indicate that EA-induced GSH depletion rapidly
      impairs the mitochondrial function of motor neurons, and this precedes cell
      death. This experimental model of oxidative toxicity could be useful to study
      mechanisms of diseases like spinal cord injury (SCI) and amyotrophic lateral
      sclerosis (ALS), where motor neurons are the vulnerable population and oxidative
      stress has a pathogenic role.

PMID- 12614932
TI  - Interferon therapy-responsive brain metabolic abnormalities in a case of adult
      onset subacute sclerosing panencephalitis evaluated by 1H MRS analysis.
AB  - We describe a 22-year-old woman with an adult-onset, slowly progressive form of
      subacute sclerosing panencephalitis (SSPE), who was repeatedly evaluated by brain
      magnetic resonance spectroscopy (MRS). The brain lesion spectrum showed a
      decrease in N-acetylaspartate (NAA) resonance, an increase in inositol (Ins)
      resonance, and an unaltered choline signal. These findings suggest neuronal loss
      and reactive gliosis without inflammation, consistent with brain biopsy findings
      showing astrocytic proliferation unaccompanied by lymphocytic infiltrates. The
      unusually protracted clinical course might be attributable to an absence of
      inflammatory infiltrates in the brain. Intraventricular interferon injection plus
      oral inosine pranobex treatment produced a substantial improvement in the MRS
      findings, suggesting the validity of monitoring MRS in SSPE.

PMID- 12614933
TI  - Relationship between the Oxfordshire Community Stroke Project classification and
      vascular abnormalities in patients with predominantly intracranial
      atherosclerosis.
AB  - BACKGROUND: The Oxfordshire Community Stroke Project (OCSP) classification is a
      stroke classification based on clinical features collected at bedside. Previous
      studies reported good correlation between vascular abnormalities and OCSP mainly
      in populations not at risk of intracranial atherosclerosis. There have been
      limited data on the relationship between intracranial atherosclerosis and the
      OCSP classification. METHODS: Consecutive Chinese patients admitted to a regional
      hospital with acute ischemic stroke were studied in Hong Kong. Stroke subtype was
      classified as total or partial anterior circulation infarct (TACI or PACI),
      posterior circulation infarct (POCI), or lacunar infarct (LACI), according to the
      OCSP method. Transcranial Doppler (TCD) was performed whenever possible to
      evaluate the intracranial arteries as well as the carotid arteries. National
      Institute of Health Stroke Scale (NIHSS) was used to assess the severity of
      stroke on admission. RESULTS: Six hundred and ninety-nine consecutive patients
      were studied. On admission, 24 patients were classified as TACI (3.4%), 96 PACI
      (13.7%), 111 POCI (15.9%), and 468 LACI (67.0%). Of the 345 patients who had TCD
      evidence of intracranial or carotid artery abnormalities, 75% had intracranial
      involvement only, 5% extracranial involvement only and 20% had both intracranial
      and extracranial involvement. The frequencies of arterial abnormalities were
      found in 58% of TACIs, 48% of PACIs, 48% of POCIs and 50% of LACIs. There was no
      evidence that the frequencies of arterial abnormalities were different between
      the OCSP groups (P=0.8). Middle cerebral artery velocity was abnormal in 9 TACIs
      (38%), 32 PACIs (33%), 35 POCIs (32%) and 177 LACIs (38%) (P=0.6).
      Vertebrobasilar velocities were abnormal in 4 TACIs (17%), 20 PACIs (21%), 29
      (26%) and 87 LACIs (19%) (P=0.3). The OCSP subtypes were associated with POCIs
      the severity of stroke. NIHSS score of > or =9 was found in 83% of TACIs, 18% of
      PACIs, 9% of POCIs, and 12% of LACIs (P<0.0001). CONCLUSIONS: OCSP classification
      is not significantly related to the presence of vascular abnormalities among
      patients with predominantly intracranial atherosclerosis.

PMID- 12614934
TI  - Tissue inhibitors of matrix metalloproteinases are elevated in cerebrospinal
      fluid of neurodegenerative diseases.
AB  - Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of diseases
      such as Alzheimer's Disease (AD) and amyotrophic lateral sclerosis (ALS).
      Increased expression of MMP-9 and TIMPs has been reported in postmortem AD and
      ALS brain tissue, as well as in ALS cerebrospinal fluid (CSF) and plasma.
      Although individual studies of MMP and TIMP expression in CSF have included AD
      and ALS samples, there are no studies comparing the expression of these proteins
      between neurodegenerative diseases. We measured the levels of matrix
      metalloproteinases (MMPs)-2 and -9 and the tissue inhibitor of MMPs (e.g. TIMP-1
      and TIMP-2) in CSF samples from patients with Parkinson's Disease (PD),
      Huntington's Disease (HD), AD and ALS as compared to age-matched control
      patients. There was constitutive expression of the proform of gelatinase A
      (proMMP-2) on zymography gels in all CSF samples. Unexpectedly, there was an
      additional gelatinolytic band at 130 kDa of unknown etiology in the CSF samples
      of patients with PD (61% of patients studied), AD (61%), HD (25%) and ALS (39%).
      Levels of TIMP-1 were significantly elevated in CSF samples from all disease
      groups. TIMP-2 was significantly increased in CSF of AD and HD patients. MMP-2
      levels did not differ significantly between groups. These findings show that
      TIMPs are elevated in the CSF of patients with neurodegenerative diseases
      suggesting a potential role of these endogenous inhibitors of matrix
      metalloproteinases in neurodegenerative diseases.

PMID- 12614935
TI  - Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a
      large Swiss family with Charcot-Marie-Tooth neuropathy.
AB  - BACKGROUND: The clinical manifestations of CMTX have been well described but the
      natural history has not yet been studied in detail. We studied phenotype
      variability in a family with a Pro 87 to Leu mutation of the connexin 32 (Cx32)
      gene. METHODS: A total of 32 family members, of which 19 patients were affected,
      underwent clinical, electrophysiological, and genetic studies. RESULTS: Onset was
      in the second decade. Clinical features were similar in both sexes when
      quantitative scores were compared, but more males had a steppage gait and
      skeletal deformities. All adult patients had a predominant involvement of the
      thenar muscles. The median values of nerve conduction velocities (NCVs) were not
      statistically different in men and in women. The correlation coefficients were
      low between motor NCVs within the same extremities, indicating nonuniform slowing
      between nerves, the ulnar nerve being the least affected. When disability was
      rated, a strong correlation was seen in male patients between severity of motor
      axonal loss and duration of the disease. The main pathological features were
      axonal loss, clusters of regenerating fibers and paranodal demyelination, the
      hallmark of a Schwann cell pathology. CONCLUSIONS: Our data support the
      hypothesis that clinical disability in CMTX is caused by loss of large myelinated
      axons in men. Furthermore, this study shows that the nerves are not uniformly
      affected in terms of axonal loss. Preventing axonal degeneration and promoting
      axonal regeneration in the most affected nerves might be the best therapeutic
      approaches to ameliorate disability in CMTX.

PMID- 12614936
TI  - Pathological and virological assessment of acute HTLV-I-associated myelopathy
      complicated with encephalopathy and systemic inflammation.
AB  - HTLV-I-associated myelopathy, also known as tropical spastic paraparesis
      (HAM/TSP), is a chronic inflammatory disease of the spinal cord. Acute cases are
      uncommon. We report the case of a 41-year-old woman with acute HAM/TSP
      complicated with encephalitis, an intense inflammatory reaction of the nervous
      system and lymphocytic infiltration of skeletal muscles, liver, salivary, adrenal
      and pituitary glands. The immunohistochemical studies of the lymphocytes
      surrounding blood vessels showed both B- and T-lymphocytes, in similar
      proportion, with both CD4- and CD8-positive cells. In addition, many perivascular
      and scattered macrophages were observed. Adult T-cell leukemia/lymphoma (ATL) was
      ruled out. The marrow aspirate was normal. Serial cerebrospinal fluid (CSF)
      analysis showed presence of HTLV-I antibodies, but without intrathecal synthesis
      of specific antibodies. Determination of HTLV-I viral loads demonstrated
      increased levels in the CSF relative to the peripheral blood and may be
      associated with widespread inflammation. The pathological and immunological
      findings may help understand the role of immune-reactive cells in the
      pathogenesis of HTLV-I-associated myelopathy.

PMID- 12614937
TI  - A brief history of brain iron research.

PMID- 12614938
TI  - Microglia: history, cytology, and reactions.

PMID- 12614939
TI  - Magnetic resonance imaging of brain iron.

PMID- 12614940
TI  - Frataxin and frataxin deficiency in Friedreich's ataxia.

PMID- 12614941
TI  - Pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz
      syndrome).

PMID- 12614942
TI  - Aceruloplasminemia.

PMID- 12614943
TI  - Hereditary ferritinopathy.

PMID- 12614944
TI  - Iron transport proteins in the diseased brain.

PMID- 12614945
TI  - Are myo-inositol, glucose and zinc concentrations in amniotic fluid of fetuses
      with spina bifida different from controls?
AB  - OBJECTIVE: Associations are reported between myo-inositol, glucose, zinc and the
      occurrence of spina bifida. To gain more insight into the pathogenesis of spina
      bifida, the concentrations of myo-inositol, glucose and zinc were determined in
      amniotic fluids from pregnancies with a spina bifida or unaffected control fetus.
      METHODS: Amniotic fluids of 27 pregnancies complicated by spina bifida and 49
      controls were collected at the Department of Obstetrics and Gynecology of the
      University Medical Center Nijmegen in the Netherlands. Myo-inositol, glucose and
      zinc concentrations were determined. By indication, the samples were taken at
      different gestational ages. Therefore, the data were evaluated using multiple
      linear regression analysis to adjust for gestational age. RESULTS: Amniocentesis
      was performed at a more advanced gestational age in the spina bifida group than
      in controls. In the spina bifida group, amniotic fluid myo-inositol, glucose and
      zinc concentrations gradually declined throughout pregnancy. At a gestational age
      of 15 weeks, the estimated mean amniotic fluid glucose and zinc concentrations in
      the spina bifida group were, respectively, significantly lower (p< or =0.5) and
      higher (p< or =0.5) compared with the control group. At the same gestational age,
      the estimated mean myo-inositol concentrations were comparable in both groups. At
      a gestational age of 38 weeks, the estimated mean myo-inositol, glucose and zinc
      concentrations were not significantly different in the spina bifida compared with
      the control group. CONCLUSION: This study may suggest that a derangement in zinc
      and glucose transfer or metabolism is associated with spina bifida. Since
      compounds in amniotic fluid are only a very crude marker of the actual fetal
      condition, studies that focus on the metabolism of these compounds on tissue or
      even cellular level should be performed to clarify their role in the pathogenesis
      and future prevention of spina bifida.

PMID- 12614946
TI  - Maternal infant bonding enhanced after atrial septostomy in cyanotic neonates in
      a general hospital.
AB  - Seventeen newborns in a general hospital had a successful atrial septostomy when
      indicated. Mostly done at the bedside under echocardiographical guidance, the
      successful introduction of this procedure enabled the infants to remain with
      mother to facilitate feeding and bonding prior to elective transfer to a
      children's hospital for corrective surgery. BACKGROUND: Atrial septostomy is a
      well-recognised intervention in the newborn to facilitate atrial mixing in
      transposition of the great arteries (TGA) or to decompress an atrium where the
      connecting AV valve is absent or stenosed, e.g. tricuspid atresia (TA). AIMS: To
      review the outcome of this procedure in a general hospital with appropriate
      neonatal and cardiological facilities. METHODS: Retrospective review over an 11
      year period. RESULTS: Seventeen inborn infants had successful atrial
      septostomies, 11 with TGA and 6 with TA. All done under general anaesthesia, 15
      were performed in the newborn nurseries, under echocardiographic guidance, and 2
      in the catheter laboratory. No complications occurred. Eleven had a prenatal
      diagnosis made. All infants were able to be subsequently nursed by their mothers,
      affording prime time facilitating feeding and bonding. They were electively
      transferred to a children's hospital for corrective surgery. CONCLUSIONS: Atrial
      septostomy can be safely performed in a general hospital with appropriate
      neonatal and cardiological expertise. Such intervention allows for elective
      transfer of the infant for corrective surgery, allowing the infant and mother to
      be initially cared for at the one hospital, thereby facilitating maternal
      contact, feeding and bonding, doing away with the added stress of emergency
      transfer.

PMID- 12614947
TI  - Retinol concentration in maternal and cord serum: its relation to birth weight in
      healthy mother-infant pairs.
AB  - BACKGROUND: Vitamin A is an essential micronutrient for the development and
      growth of the fetus. The objective of this study was to identify a possible
      association between low serum retinol and birth weight in healthy mother-infant
      pairs in Southern Israel. A secondary objective was to examine ethnic differences
      in maternal and cord serum retinol. METHODS: Serum retinol was measured at
      delivery from pairs of healthy mothers and healthy mature newborns. RESULTS: Of
      the 313 mother-infant pairs studied, 56% were Jews and 44% Bedouins. The
      proportion of infants with birth weight of 2500-2999 g was greater among mothers
      with lower serum retinol (<0.7 micromol/l) compared to mothers with normal serum
      retinol (> or =0.7 micromol/l) (p<0.001). Cord retinol <0.7 micromol/l was more
      frequent in infants with birth weight 2500-2990 g compared to infants with birth
      weight > or =3000 g (p=0.006). Using a split model and stepwise multiple
      regression analysis, infant's birth weight was significantly influenced by cord
      retinol concentration in infants born to mothers with low serum retinol;
      gestational age and cord retinol alone explained 27% of the variability of birth
      weight in this group. A higher proportion of Bedouin than Jewish infants had
      serum retinol <0.7 and <0.35 micromol/l (both p<0.001). CONCLUSION: Low cord and
      maternal serum retinol may reflect poor vitamin A status of the newborn and the
      mother, which in turn may affect fetal growth.

PMID- 12614949
TI  - Risk factors for unexplained antepartum fetal death in Norway 1967-1998.
AB  - OBJECTIVE: To relate unexplained antepartum fetal death with maternal and fetal
      characteristics in order to identify risk factors. DESIGN: Population-based study
      based on records of 1,676,160 singleton births with gestational age > or =28
      weeks. Unexplained antepartum fetal death was defined as fetal death before
      labour without known fetal, placental, or maternal pathology. RESULTS: Although
      unexplained fetal mortality in general declined from 2.4 per 1000 births in 1967
      1976 to 1.6 in 1977-1998, the proportion among all fetal deaths increased from
      30% to 43% during the same period of observation. Unexplained fetal death
      occurred later in gestation than explained. From 39 weeks of gestation, the risk
      increased progressively to 50/10,000 in women aged > or =35 years and <10/10,000
      in women <25 years. In birth order > or =5, the risk was particularly high after
      39 weeks of gestation. For birth weight percentile 2.5-9.9 and > or =97.5,
      unexplained fetal death was four and three times more likely to occur,
      respectively. We found an additive effect of maternal age and birth weight
      percentile 2.5-9.9. Women with less than 10 years education had higher risk than
      women with 13 years or more (OR=1.6). Weaker associations were observed with
      female gender, unmarried mothers, and winter season. CONCLUSIONS: Unexplained
      antepartum fetal death occurred later in gestation than explained and was
      associated with high maternal age, multiparity, low education, and moderately low
      and high birth weight percentile. The increased risk in post-term pregnancies and
      the additive effect of maternal age and birth weight percentile 2.5-9.9 suggests
      that older women would benefit from monitoring of fetal growth.

PMID- 12614948
TI  - Ultrastructural localization of aminopeptidase A/angiotensinase and placental
      leucine aminopeptidase/oxytocinase in chorionic villi of human placenta.
AB  - AIMS: Membrane-bound aminopeptidases in human placenta are thought to be involved
      in maintaining homeostasis during pregnancy by metabolizing bioactive peptides
      such as oxytocin and angiotensin at the interface between the fetus and mother.
      Because determining the precise localization of these enzymes is required to
      support this notion, we investigated the ultrastructural localization of two
      principal enzymes, aminopeptidase A (APA; EC 3.4.11.7)/angiotensinase and
      placental leucine aminopeptidase (P-LAP; EC 3.4.11.3)/oxytocinase in human first
      trimester and full-term placenta. METHODS: Immunohistochemical analysis using
      anti-P-LAP and anti-APA antibodies was performed on ultrathin frozen sections of
      fixed human placental villi. RESULTS: Transmission immunoelectron microscopy
      revealed that both enzymes were expressed on the surface of apical microvilli of
      syncytiotrophoblast cells and, to a lesser extent, on the basal infoldings. The
      location of the two enzymes did not vary between the first trimester and full
      term placenta sections, while the staining intensities were slightly enhanced in
      full-term villi. CONCLUSIONS: Our observation that P-LAP and APA are present on
      the microvilli, which is a site of interaction between the mother and fetus,
      suggests possible involvement of these enzymes in cleaving peptide hormones from
      the fetus and mother in order to regulate bioactivity.

PMID- 12614950
TI  - Apoptosis in the developing human brain: a preliminary study of the frontal
      region.
AB  - BACKGROUND: Natural cell death due to apoptotic mechanisms has been described in
      various species. Relatively few studies examined this process in humans. AIM: To
      investigate the distribution of apoptosis in fetal brain tissue. DESIGN: We
      examined apoptosis in the frontal region of human fetal brain by the TUNEL method
      in nine fetuses with no neurological conditions, gestational age 14-26 weeks, and
      three fetuses with structural anomalies of the nervous system (lumbar
      meningomyeloceles, n=2, hydrocephalus, n=1). RESULTS: In normal fetuses, TUNEL
      positive cells were most concentrated in the intermediate zone (IZ) and between
      18 and 22 weeks of gestation; cortical apoptosis was not prominent. The fetus
      with hydrocephalus had increased numbers of TUNEL-positive cells while those with
      neural tube defects did not differ from normals. CONCLUSION: The definition of
      normally occurring apoptosis may provide a basis for further studies directed at
      central nervous system (CNS) malformations.

PMID- 12614951
TI  - Emergence of oropharyngeal, laryngeal and swallowing activity in the developing
      fetal upper aerodigestive tract: an ultrasound evaluation.
AB  - The developing fetal upper aerodigestive system provides the structural support
      for respiratory and ingestive functions necessary to sustain life at birth. This
      study investigated prenatal development of upper aerodigestive anatomy and the
      association of emerging functions as predictors of postnatal feeding skills.
      Biometric measures of oral, lingual, pharyngeal and laryngeal structures were
      obtained in fetuses 15-38 weeks gestational age using a four-plane sonographic
      technique. Accompanying ingestive behaviors were tallied across development. The
      data from 62 healthy controls were compared to seven cases at risk for postnatal
      feeding and swallowing dysfunction (Type II Arnold Chiari Malformation, trisomy
      18, polyhydramnios, intrauterine growth restriction, Brachmann-de Lange
      Syndrome). Significant (p<0.001) linear regressions occurred in pharyngeal and
      lingual growth across gestation while ingestive behavior such as suckling emerged
      in a sequence of basic to complex movement patterns. Jaw and lip movements
      progressed from simple mouth opening to repetitive open-close movements important
      for postnatal suckling. Lingual movements increased in complexity from simple
      forward thrusting and cupping to anterior-posterior motions necessary for
      successful suckling at term. Laryngeal movements varied from shallow flutter-like
      movements along the lumen to more complex and complete adduction-abduction
      patterns. Fetal swallowing primarily occurred in the presence of concomitant oral
      facial stimulatory activity. Significant variations (p<0.01) in the form and
      function of the ingestive system occurred in comparisons of gestational age
      matched controls to at-risk cases. We postulate that prenatal developmental
      indices of emerging aerodigestive skills may guide postnatal decisions for
      feeding readiness and, ultimately, advance the care of the premature, medically
      fragile neonate.

PMID- 12614952
TI  - Criteria of pain response to radiotherapy in advanced cancer patients.

PMID- 12614953
TI  - Herpes zoster: a previously unrecognized complication of epidural steroids in the
      treatment of complex regional pain syndrome.

PMID- 12614954
TI  - Same as it ever was? Life after the OxyContin media frenzy.

PMID- 12614955
TI  - Effectiveness of palliative day care in improving pain, symptom control, and
      quality of life.
AB  - To evaluate the effectiveness of palliative day care in improving pain, symptom
      control, and quality of life (QOL), 120 consecutive new referrals to five
      specialist palliative day care centers were recruited into a prospective
      comparative study. Fifty-three comparison patients were identified as those
      patients receiving usual palliative care services (home care, inpatient care),
      but did not attend day care. Patients were assessed at 3 interviews (baseline, 6
      8 weeks, and 12-15 weeks) using measures of health-related quality of life:
      McGill Quality of Life Questionnaire (MQOL) and Palliative Care Outcome Scale
      (POS). There were two main analyses: 1) patient demographic data were analyzed
      using chi-square (chi(2)), and 2) QOL data were compared, based on distribution
      of scores, using the Mann-Whitney test (MQOL and POS), and Wilcoxon Signed Rank
      for within group differences (POS data only); P < 0.05 was taken as significant.
      The patients were representative of those attending palliative day care in the
      UK. At baseline, the day care group were (non-significantly) worse than the
      comparison group in the MQOL support domain (P = 0.065). The comparison group had
      marginally more severe pain at baseline (P = 0.053) and more severe symptoms at
      second assessment (P = 0.025). Both patient groups maintained overall health
      related quality of life during the three months of the study. Palliative day care
      was not found to improve overall health-related quality of life. The limitations
      of the QOL measures in identifying the effects (patient outcomes) of palliative
      day care and the differences between the two patient groups (age, employment,
      unequal sample sizes) were limitations of the study and indicate the need for
      further research in this area.

PMID- 12614956
TI  - Usability of a computerized PAINReportIt in the general public with pain and
      people with cancer pain.
AB  - We examined usability (completion time, acceptability, and completeness of
      information) of a computerized format for pain assessment, PAINReportIt.
      PAINReportIt is the first interactive software extension of the 1970 McGill Pain
      Questionnaire. Two hundred thirteen patients experiencing pain were recruited for
      this descriptive, comparative study. Subjects used a Microsoft Windows 95/98
      personal computer with a touch-screen to complete 1) PAINReportIt, 2)
      demographic, and 3) acceptability questions. Qualitative and quantitative data
      from the study support PAINReportIt as a feasible method for patients to self
      report their pain. Patients completed the tool in less than 18 minutes on
      average, answered all sections, and scored it high regarding acceptability.
      Improved directions and practice screens would likely improve patients'
      independence in completing PAINReportIt, which would free clinicians to focus
      direct communication on more complex pain issues.

PMID- 12614957
TI  - Longitudinal quality of life in advanced cancer patients: pilot study results
      from a VA medical cancer center.
AB  - To document quality-of-life (QOL), symptom distress and Karnofsky Performance
      Status (KPS) over time, 67 advanced cancer patients completed the Functional
      Assessment of Cancer Therapy (FACT-G) and Memorial Symptom Assessment Scale -
      Short Form (MSAS-SF) from the time of determination of no active anti-cancer
      treatment to death at 3-6 week intervals. The KPS was determined at each time
      point. Statistical analyses with mixed effects models were performed to examine
      the association between changes in QOL, symptom distress and KPS at selected time
      points in the advanced cancer trajectory. Median survival for the population was
      115 days, and a median of 5 interviews was completed per patient. Slow steady
      changes in KPS, MSAS-SF and FACT-G QOL parameters started 6 months prior to
      death, with accelerated decline in the last 2 to 3 months and dramatic increase
      in psychological symptoms during the last month. Different domains changed at
      different rates at different selected time points. The correlation between
      changes in KPS, FACT-G parameters and MSAS-SF subscales at enrollment and near
      death suggests that when patients were stable, changes in KPS correlated
      significantly with changes in sum FACT-G QOL and physical well being, and with
      changes in the MSAS-SF subscales. However, when patients were near death, changes
      in KPS did not correlate with any other changes, and only emotional well being
      reflected changes in physical and psychological symptom distress. The sequence of
      changes, and how determinants of symptom distress and QOL change over time, may
      help clinicians assess the prognosis of terminally ill patients and plan
      appropriate interventions.

PMID- 12614959
TI  - Pain trajectory of Taiwanese with nasopharyngeal carcinoma over the course of
      radiation therapy.
AB  - The purpose of this study was to describe the characteristics and management of
      pain among patients with nasopharyngeal carcinoma (NPC) prior to and during the 7
      week course of radiation therapy (RT) in Taiwan. Twenty-nine men and 11 women
      with NPC participated in this prospective, longitudinal study. A modified Brief
      Pain Inventory was used to assess pain and its interference with daily activities
      weekly. Medical records were reviewed to abstract pain management and disease
      data. Findings showed that the pain intensity and pain interference scores
      escalated prominently at Week 3 and peaked at Week 5, representing the time
      course of RT complications. Pain prior to RT exacerbated the RT-induced mucositis
      pain. The pain related to RT for NPC was often severe and undertreated, and
      affected swallowing and talking more than sleeping or other general activities.
      We recommend interventions to control pain be instituted prior to Week 3 to
      minimize the potentiation of subsequent pain.

PMID- 12614958
TI  - Dying patients' need for emotional support and personalized care from physicians:
      perspectives of patients with terminal illness, families, and health care
      providers.
AB  - This study addressed the emotional and personal needs of dying patients and the
      ways physicians help or hinder these needs. Twenty focus groups were held with
      137 individuals, including patients with chronic and terminal illnesses, family
      members, health care workers, and physicians. Content analyses were performed
      based on grounded theory. Emotional support and personalization were 2 of the 12
      domains identified as important in end-of-life care. Components of emotional
      support were compassion, responsiveness to emotional needs, maintaining hope and
      a positive attitude, and providing comfort through touch. Components of
      personalization were treating the whole person and not just the disease, making
      the patient feel unique and special, and considering the patient's social
      situation. Although the levels of emotional support and personalization varied,
      there was a minimal level, defined by compassion and treating the whole person
      and not just the disease, that physicians should strive to meet in caring for all
      dying patients. Participants also identified intermediate and advanced levels of
      physician behavior that provide emotional and personal support.

PMID- 12614960
TI  - Ongoing distress from emotional trauma is related to pain, mood, and physical
      function in a primary care population.
AB  - The relationship of trauma history to physical and emotional functioning in
      primary care pain patients was examined. Data were drawn from a mailed screening
      questionnaire for a larger study designed to evaluate an intervention for
      improving pain management in primary care. Results indicated that 50.4% of the
      pain patients reported experiencing at least one previous emotionally traumatic
      event. Further, 31% of patients with trauma history continued to be bothered by
      that experience. Finally, patients who continued to be significantly bothered by
      the trauma reported more pain, emotional distress, poorer social functioning, and
      more difficulty with engaging in their daily activities than did patients with
      either no trauma history or who had a trauma history but did not have bothersome
      thoughts of the trauma. These preliminary findings suggest that the experience of
      trauma alone was not related to additional impairments in physical and
      psychosocial functioning. However, the report that one continued to be bothered
      by thoughts of a trauma was associated with greater impairments in functioning.

PMID- 12614961
TI  - Is patient satisfaction a legitimate outcome of pain management?
AB  - Though many studies have measured patient satisfaction with pain management using
      the American Pain Society (APS) Satisfaction Survey or its variants, little is
      known about the relationship among the survey items, or whether items relate to
      satisfaction at all. In an effort to refine the measurement of patient
      satisfaction, a modified version of the APS survey, which was given to 787
      patients as part of a study of postoperative pain management in six community
      hospitals, was subjected to principal components analysis to determine the
      survey's empirical structure. Correlations among the five components found were
      low; a weak relationship (r = -0.24) was discovered between pain intensity and
      satisfaction. A heuristic model estimated by structural equations analysis
      yielded additional insights. Though many items thought to influence patient
      satisfaction were not closely related to patient-reported satisfaction, they
      indicate important clinical factors relevant to quality of care, and thus, to
      continuing quality improvement (CQI) efforts. Results suggest that satisfaction
      was influenced by effectiveness of medication, independent of pain intensity, and
      by communication. Pain severity ratings near the time satisfaction was measured
      were more influential than earlier ratings.

PMID- 12614962
TI  - Cost of opioid-related adverse drug events in surgical patients.
AB  - Opioids have demonstrated efficacy and often are drugs of choice in the
      management of postoperative pain. However, their use is often limited by adverse
      drug events (ADEs). The objective of this study was to determine the ADE rate in
      adult surgical patients who received opioids and the impact of opioid ADEs on
      length of stay (LOS), costs, and mortality. A hospital-based computerized system
      detected potential ADEs. Adult patients were selected if they received at least
      one dose of opioid medication during a surgical hospitalization between 1 January
      1990 and 31 December 1999. Control patients were matched based on matching length
      of stay ([LOS] at least as long as time to ADE), age (within 10 years), sex,
      admission year, major disease category (MDC), and without an ADE. Linear
      regression models were used to determine the predictors of increased LOS, total
      hospital costs, and log-transformed total hospital costs. 60,722 patients
      received opioid medication during their surgical hospitalization and 2.7%
      experienced an opioid-related ADE. The most common clinical manifestations were
      nausea and vomiting (67%), and rash, hives, or itching (33.5%). No statistically
      significant difference was seen in mortality between ADE/non-ADE patients. ADE
      patients had statistically significant increases in LOS (0.53 days) and in log
      transformed cost (16%). The estimated log cost difference of 16%, if applied to
      the median cost patient in the non-ADE group, averaged US$ 840. Opioid-related
      ADEs are common in hospitalized patients and increase LOS and total hospital
      costs.

PMID- 12614963
TI  - An unsuccessful attempt to develop a single-item screen for insomnia in cancer
      patients.
AB  - The focus of this pilot study was to examine issues of criterion validity and
      detection of insomnia utilizing a single item from the Zung Self-Rating
      Depression Scale (ZSDS) as a means to rapidly screen cancer patients in
      ambulatory oncology clinics. In our previous work, we have demonstrated the
      usefulness of other single items for screening purposes, such as for fatigue. The
      sleep item reads "I have trouble sleeping through the night" and is rated on a 4
      point Likert scale ranging from "none or little of the time" to "most or all of
      the time." Fifty-two oncology patients were administered the ZSDS and further
      evaluated with the Pittsburgh Sleep Quality Index (PSQI). The sensitivity and
      specificity of various cutoffs on the ZSDS sleep item were investigated as
      predictors of the PSQI. Results revealed that the ZSDS single-item screen has
      poor sensitivity and specificity for detecting insomnia in cancer patients, and
      that the relationship between insomnia and depression is more complicated than
      anticipated. The use of this single item, or perhaps any single item, as a means
      of screening for sleep disturbances in cancer patients may be problematic. A
      better understanding of insomnia and its measurement are worthwhile areas of
      study.

PMID- 12614964
TI  - Mirtazapine for pruritus.
AB  - Pruritus is a relatively rare but distressing symptom associated with
      cholestasis, renal failure, and malignancies. Medical management recently has
      included the use of ondansetron and paroxetine. We report four patients whose
      pruritus responded to mirtazapine.

PMID- 12614970
TI  - Lower extremity amputations in diabetic Mexican American elders: incidence,
      prevalence and correlates.
AB  - This study was designed to determine the incidence and prevalence of amputations
      in diabetic Mexican American elders and to identify correlates of lower extremity
      amputations. Data for this study came from baseline and two follow-up interviews
      of the Hispanic Established Population for the Epidemiological Study of the
      Elderly (EPESE) conducted in five southwestern states (Texas, California, New
      Mexico, Colorado and Arizona) in 1993-1994. Of the 3050 subjects aged 65 and
      older, 690 reported diabetes, and from these, 60 (8%) reported having at least
      one lower extremity amputation. Losing a leg was the most common type of
      amputation (53%). Twelve percent of respondents reported a new amputation and 40%
      of amputees reported a second amputation during follow-up. Mortality among
      amputees was 46% during a 5-year follow-up. Multiple logistic regression analysis
      showed that being male and having eye problems, hip fracture and diabetes for 10
      or more years were significantly associated with lower extremity amputations at
      baseline, whereas obesity, stroke and 10 or more years with diabetes were
      significantly associated with new amputations at 5-year follow-up. Gender and
      disease history were associated with lower extremity amputations at baseline and
      follow-up. These variables may be useful in developing patient education and
      intervention programs.

PMID- 12614971
TI  - Correlations between surrogate measures of insulin resistance and cardiovascular
      risk factors in obese and overweight patients.
AB  - There are different equations to estimate insulin sensitivity by using OGTT with
      a reasonable approximation to whole body sensitivity obtained with the glucose
      clamp. Further work is needed to address their role in clinical practice as
      markers of the metabolic syndrome and predictors for cardiovascular disease. In
      the present study, we determined plasma glucose and insulin values during an OGTT
      test in 144 overweight and obese individuals. We assessed insulin resistance by
      the use of different equations and established their relationship with
      cardiovascular risk factors associated to the insulin resistance syndrome.
      Distributed the patients by quintiles of body mass index (BMI), the different
      surrogate measures clearly demonstrated that the more obese individuals were the
      most insulin resistant, a similar but not significant trend was observed related
      to the other cardiovascular risk factors. Efforts to use both fasting and post
      load glucose and insulin concentrations to create indexes for routine use in
      clinical practice do not seem to be particularly useful in overweight or obese
      patients, as most of these patients will be insulin-resistant and insulin
      resistance is closely linked but not equal to the metabolic syndrome.

PMID- 12614972
TI  - Effects of coronary artery bypass surgery on diastolic and systolic parameters of
      left ventricle in Type II diabetic patients.
AB  - Diabetes mellitus itself can cause systolic and diastolic dysfunctions of the
      left ventricle in the absence of atherosclerotic coronary artery disease. Effects
      of coronary bypass surgery on the left ventricular functions of Type II diabetic
      patients having atherosclerotic coronary artery disease were investigated. Forty
      eight Type II diabetic and 63 nondiabetic multivessel coronary artery disease
      patients who had no differences in age, sex, drugs used, number of revascularized
      arteries and aortic cross-clamp time were included in the study. Doppler
      echocardiographic examinations before and 6 months after operations were made,
      and early diastolic flow (E), atrial contraction (A), deceleration (DT) and
      isovolumetric relaxation time (IVRT), E/A ratio and systolic parameters like end
      diastolic volume, end-systolic volume, stroke volume and left ventricular
      ejection fraction (LVEF) were measured in sequence. Preoperative and
      postoperative echocardiographic measurements were compared in the same group and
      between groups by paired t and Student's t tests, respectively. P<.05 was
      accepted as statistically significant. E, A, E/A, DT, IVRT and LVEF were
      significantly improved after coronary bypass surgery in Groups I (P<.001, P<.01,
      P<.001, P<.01, P<.0001, P<.01) and II (P<.05, P<.05, P<.001, P<.001, P<.001,
      P<.001). Statistical comparison of values between groups showed better recovery
      in diastolic and systolic functions of diabetic and nondiabetic patients,
      respectively. It was concluded that Type II diabetic coronary patients by time
      could gain as much as the same benefit from coronary bypass surgery that
      nondiabetic patients had.

PMID- 12614973
TI  - Fasting plasma glucose variability as a risk factor of retinopathy in Type 2
      diabetic patients.
AB  - AIMS/HYPOTHESIS: The purpose of this study was to determine whether plasma
      glucose variability, irrespective of glycated hemoglobin (HbA1c), was able to
      predict the onset of retinopathy in Type 2 diabetic patients. METHODS: The study
      was based on a cohort of 130 Type 2 diabetic patients without retinopathy
      recruited from June 1994 to June 1998. The fundus was reexamined between November
      2000 and June 2001, with a mean follow-up period of 5.2 years. Fasting plasma
      glucose (FPG) variability was measured by its variation coefficient (VC).
      Stratified and multivariate models were used to estimate the effect of FPG
      variability and mean HbA1c during follow-up on cumulative incidence (IP) of
      retinopathy. RESULTS: The IP of retinopathy was 36.2% and increased all along the
      quartiles of FPG variability (P=.001). In multivariate analyses, only the last
      quartile of the distribution of VC (OR=3.68; 95% confidence interval (CI) 1.01
      13.4; P=.049) was significant. The term of interaction between mean HbA1c and VC
      was not significant. CONCLUSIONS/INTERPRETATION: FPG variability fulfills
      criteria to be considered a risk factor for retinopathy: A statistically
      significant association exists after adjustment for confounders, time sequence,
      dosage response gradient, and biological plausibility.

PMID- 12614974
TI  - Diabetes education and knowledge in patients with type 2 diabetes from the
      community: the Fremantle Diabetes Study.
AB  - BACKGROUND: Diabetic patients obtain knowledge of the condition from a variety of
      sources. These include education programs and encounters with health-care staff
      such as during instruction on self-monitoring of blood glucose (SMBG). OBJECTIVE:
      To assess whether diabetes knowledge is related to prior attendance at diabetes
      education programs, visits to dieticians or the current use of SMBG in a
      community-based cohort of subjects with type 2 diabetes. PATIENTS: 1264 type 2
      patients from the Fremantle Diabetes Study (FDS) cohort. METHODS: Subjects
      answered 15 standard multiple-choice questions about diabetes and its management.
      Recall of past diabetes education, dietician consultations, and use of SMBG were
      recorded. Analysis of variance was used to determine whether these activities or
      other social and demographic factors predicted diabetes knowledge. RESULTS:
      Attendance at education programs, visits to dieticians, and SMBG were
      independently associated with greater diabetes knowledge. Subjects who were
      older, whose schooling was limited, who were not fluent in English and/or who
      were from Southern European or indigenous Australian ethnic groups had
      significantly lower knowledge scores. Patients who were older, not fluent in
      English or from an indigenous Australian background were significantly less
      likely to have received diabetes education, dietetic advice or to be performing
      SMBG. CONCLUSIONS: Diabetes education programs, diabetes-related visits to
      dieticians and SMBG are associated with, and may be important sources of,
      improved diabetes knowledge in patients with type 2 diabetes. Our data provide
      evidence that barriers to access or utilization of contemporary diabetes
      education confront older patients, minority groups and those with language
      difficulties. These groups are likely to benefit from specialized programs.

PMID- 12614976
TI  - Treatment of onychomycosis in the diabetic patient population.
AB  - Onychomycosis is a common medical condition in patients with diabetes.
      Conflicting data exist as to whether diabetes predisposes patients to the
      disease. Controversy notwithstanding, patients with diabetes have several medical
      conditions (obesity, peripheral neuropathy, and retinopathy) that can inhibit the
      identification or mask the progression of fungal nail infections. In addition,
      vascular insufficiency, impaired wound healing, and compromised immunologic
      status associated with diabetic foot increase the risk of secondary infections in
      diabetic patients with onychomycosis. Such factors contribute to an increased
      morbidity and decreased quality of life in these patients and underscore the need
      for effective antifungal treatment. Oral antifungal agents are generally well
      tolerated, but serious adverse events independent of or associated with a number
      of significant drug interactions have been reported. The availability of a
      topical therapy, ciclopirox topical solution, 8% (Penlac Nail Lacquer), provides
      clinicians with an additional effective and well-tolerated treatment option. In
      order to further increase the efficacy of topical or oral treatment, mechanical
      intervention (e.g., debridement) may be combined with either of these options.
      Choice of appropriate treatment and careful monitoring of fungal nail infections
      can prevent significant morbidity in patients with diabetes.

PMID- 12614975
TI  - Improvement in quality of diabetes control and concentrations of AGE-products in
      patients with type 1 and insulin-treated type 2 diabetes mellitus studied over a
      period of 10 years (JEVIN).
AB  - Advanced glycation end (AGE)-products, a complex and heterogeneous group of
      compounds, have been implicated in diabetes-related long-term complications. Up
      to the present, only few data exist about serum levels of the AGE-proteins N-
      epsilon -carboxymethyllysine (CML) and pentosidine in selection-free populations
      of patients with type 1 and insulin-treated type 2 diabetes mellitus. In the
      present 10-year, population-based trial of patients with insulin-treated diabetes
      mellitus, serum CML and pentosidine levels were examined in correlation to the
      patients' quality of diabetes control and the prevalence of diabetes-related long
      term complications. Jena's St. Vincent Trial (JEVIN) was started in 1989/1990. At
      this time, a centralised diabetes care system existed. After the baseline
      examination of 190 patients (83% of the target population) with insulin-treated
      diabetes mellitus, follow-up examinations were performed in 1994/1995 and
      1999/2000. In 1994/1995, the CML concentration in patients with type 1/type 2
      diabetes mellitus was 1096.47+/-405.50/1136.43+/-405.24 ng/ml. In 1999/2000, it
      was significantly lower (727.49+/-342.91 ng/ml, P=.033/743.76+/-312.47 ng/ml,
      P<.0001). The same tendency showed the AGE-protein pentosidine (type 1: 1994/1995
      203.18+/-118.88 vs. 1999/2000 156.59+/-104.84 pmol/ml [P=.029], type 2: 1994/1995
      189.72+/-67.66 vs. 1999/2000 151.54+/-127.73 pmol/ml [P=.020]). Parallel to the
      decrease in the mean concentration of the AGE-products CML and pentosidine mean
      HbA1c improved and the prevalence of diabetic long-term complications (retino-,
      neuro-, and nephropathy) remained comparable 1999/2000-1989/1990. Comparing the
      data of 1999/2000 with those from 1994/1995, there was not only a substantial
      improvement in patients' quality of diabetes control but also a decrease in the
      concentration of AGE-products. In patients with diabetes mellitus, the AGE
      products seem to be mainly influenced by the quality of diabetes control.
      However, the most important parameter reflecting the risk for development and
      progression of diabetes-related long-term complications seems not to be the AGE
      products, but patients' HbA1c.

PMID- 12614978
TI  - Leptin: metabolic control and regulation.
AB  - Leptin, a protein released from adipose tissue, is being recognized to play an
      integral role in endocrine regulation of metabolism. While it is clearly evident
      that leptin is decreased during caloric restriction, the response of leptin to
      other types of stress has been plagued by conflicting data. With hypoglycemia
      stress, the literature may conflict because experimentally hypoglycemia is
      induced with infusion of insulin, an endocrine factor that can increase leptin
      levels. With exercise, leptin's response may depend on duration and intensity of
      exercise. While it has been clearly shown that the sympathetic nervous system
      (SNS) inhibits leptin secretion in a variety of experimental modes, the
      hypothalamic-pituitary-adrenal (HPA) axis may stimulate leptin secretion. This
      creates a paradox of leptin regulation during stress since both systems are
      activated with stress. If the SNS inhibition overrides the HPA axis' activation
      of leptin secretion, leptin's role during stress may be to allow a shifting of
      fuel consumption towards carbohydrate utilization. In type 1 diabetes mellitus,
      autonomic dysfunction may prevent the fall in leptin during stress. Although
      obesity is associated with type 2 diabetes mellitus, patients may have decreased
      leptin levels, especially when glucose is poorly controlled. This may contribute
      to further obesity and worsening of the disease. The purpose of this review to is
      critically analyze the literature regarding the impact of different types of
      stress on leptin secretion, the function of leptin during stress, and the role of
      leptin in the pathophysiology of diabetes.

PMID- 12614977
TI  - Leptin treatment ameliorates anxiety in ob/ob obese mice.
AB  - We investigated whether or not administered leptin influences anxiety-like
      behavior in ob/ob mice. Repeated intraperitoneal administrations of leptin were
      continued for 5 days. Anxiety was assessed in the standard elevated plus maze.
      Body weight was measured daily. Repeated administrations of leptin significantly
      increased the percentage of the total number of entries in the open arms and the
      number of total entries. The body weight was significantly reduced by 13.2% after
      treatment. Leptin treatment ameliorated not only obesity but also anxiety in
      ob/ob mice. Our results indicate that the treatment of obesity may lead to the
      solution of psychological problems.

PMID- 12614979
TI  - Development of a multiplex real-time quantitative PCR assay to detect Chlamydia
      pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae in respiratory tract
      secretions.
AB  - Atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila and
      Mycoplasma pneumoniae are an important cause of community-acquired pneumonia. The
      available detection methods (culture and serology) either lack sensitivity or
      give only a retrospective diagnosis. In order to improve their detection and
      quantification in respiratory samples, a real-time multiplex PCR, performed in
      two separate reactions, was developed for these three pathogens. The comparison
      of multiplex real-time and conventional PCR assay on 73 respiratory specimens
      showed an overall agreement of 98.3%, corresponding to 95.8%, 100% and 100%
      agreement for C. pneumoniae, L. pneumophila and M. pneumoniae, respectively.
      Clinical application of this multiplex real-time PCR was done on 40 respiratory
      samples from 38 patients with respiratory tract infections. Of 19 serology
      positive patients, 14 were confirmed by the multiplex real-time PCR to be
      infected by either one of the three pathogens. All samples from serology-negative
      patients were negative with the multiplex real-time PCR.

PMID- 12614981
TI  - In vitro Bartonella quintana infection modulates the programmed cell death and
      inflammatory reaction of endothelial cells.
AB  - Bartonella quintana is an epicellular bacterium, which in vivo as well as in
      vitro, invades endothelial cells and develops within them inducing proliferative
      effects that play a pivotal role in neovascular manifestation of this disease. We
      investigated the effect of live Bartonella quintana and its LPS on apoptosis and
      inflammatory response in HUVEC-C, an endothelial cell line. The kinetics of the
      programmed cell death of Bartonella quintana-infected HUVEC-C showed a peculiar
      course. Even if early during infection apoptosis reached a peak after 6 h, later
      on apoptosis was inhibited. Such apoptosis inhibition was not observed during
      Bartonella quintana lipopolysaccharide treatment because LPS-stimulated HUVEC-C
      did progress to cell death. Evaluation of multiple cell signal transduction
      pathways revealed an overexpression of Apaf 1 and caspase 8 in HUVEC-C after 2 h
      of infection, and of bcl-2 starting from 10 h post Bartonella quintana infection.
      Moreover, Bartonella quintana and its LPS showed a different effect on the
      activation of genes involved in inflammatory response as revealed by molecular
      analysis of host cells. Bartonella quintana appears to be able to inhibit
      programmed cell death, inducing intracellular signals leading to survival and
      proliferation through the bcl-2 gene, despite the early increase of inflammatory
      status induced in endothelial cells. This mechanism, together with a poor
      endotoxin ability to stimulate strong inflammatory response, could contribute to
      the capability of the bacteria to persist intracellularly, causing chronic
      disease and producing neovascular manifestations.

PMID- 12614980
TI  - Development and evaluation of genotypic assays for the detection and
      characterization of enterotoxigenic Escherichia coli.
AB  - We developed and evaluated a method to genotypically identify enterotoxigenic
      Escherichia coli (ETEC) and to characterize these organisms with respect to 18 of
      21 known colonization factors (CFs). The method, which is based on polynucleotide
      DNA-DNA colony hybridization, includes a pooled toxin probe assay to identify
      ETEC, and individual probe assays to detect the enterotoxins STp, STh, and LT,
      and the CFs CFA/I, CS1-CS8, CS12-CS15, CS17-CS19, CS21, and CS22. We evaluated
      the pooled toxin probe assay during a cohort study of childhood diarrhea, and the
      individual probe assays against 33 reference strains and 92 clinical ETEC
      isolates. There was close to a complete agreement between the pooled toxin probe
      assay and the individual toxin probe assays, and between the individual CF probe
      assays and the corresponding phenotypic assays.

PMID- 12614982
TI  - Rapid detection of Clostridium difficile in stool using the VIDASR C. difficile
      Toxin A II assay.
AB  - A rapid laboratory diagnosis of Clostridium difficile-associated diarrhea (CDAD)
      is important in patient management and in the administration of appropriate
      therapeutic modalities. The VIDAS(R) C. difficile Toxin A II (CDA 2) assay
      (bioMerieux, Inc., Hazelwood, MO) was compared with the cell culture cytotoxicity
      assay (CCA) for the rapid detection of C. difficile in stool from patients in
      whom C. difficile infection was suspected. Thirty-eight consecutively collected
      CCA-positive stool specimens, and 33 CCA-negative stool specimens were tested by
      the CDA 2 assay. Where appropriate, discordant specimens were repeated and/or
      tested by isolation utilizing cycloserine-cefoxitin-fructose agar (CCFA). Among
      12 discordant stool specimens, 7 were VIDAS(R)-/cytotoxicity+, 2 were VIDAS(R)
      equivocal (E)/cytotoxicity+, 2 were VIDAS(R) E/cytotoxicity-, and 1 was
      VIDAS(R)+/cytotoxicity-. One VIDAS(R) E/cytotoxicity+ lacked sufficient stool to
      be repeated. From the single VIDAS(R)+/cytotoxicity- specimen, C. sordelli was
      isolated. Specimens that were equivocal by VIDAS(R), were omitted from
      incorporation into this study's test parameters. The sensitivity, specificity,
      positive and negative predictive values for the CDA 2 assay were 80.6, 96.8,
      96.7, and 81.1%, respectively. The specimens which yielded false negative
      VIDAS(R) results had low levels of toxin based on endpoint titrations using the
      cytotoxicity assay. Although the CDA 2 assay displayed a reduced sensitivity
      compared with the CCA, the automated assay is rapid (results promulgated within 2
      h), with computer generated readings obviating visual interpretations.
      Recognition of the CDA 2 assay's limitations is important to addressing this
      test's clinical utility.

PMID- 12614983
TI  - Latex agglutination test (LAT) for antigen detection in the cystic fluid for the
      diagnosis of cystic echinococcosis.
AB  - Latex agglutination test (LAT) was standardized and evaluated to detect hydatid
      antigen in fluid samples aspirated from 6 surgically proved human cases of cystic
      echinococcosis (CE), 4 suspected human cases of CE (2 cases of cysts in the liver
      which were not confirmed surgically and 2 cases of pelvic cysts later confirmed
      as abscesses) and 7 cases of hydatid cysts of liver in cattle. Echinococcus
      granulosus scolices and hook lets were seen in aspirated fluid by microscopy and
      the characteristic germinal layer of the cyst wall was demonstrated by
      histopathology in 6 human hydatid cysts operated and removed by surgery. In case
      of cattle hydatid liver cysts no scolices or hook lets were seen in aspirated
      fluid as they were sterile cysts but characteristic laminated layer of the cyst
      wall was demonstrated by histopathology of these cysts. The LAT could detect
      antigen in fluid samples collected from all 6 human cases of surgically proved CE
      and 7 cases of hydatid cyst liver in cattle, thus showing sensitivity of 100%.
      The LAT could detect antigen in fluid samples collected from 2 suspected cases of
      CE liver in humans, which were not operated. The LAT was found to be specific. No
      cross reactivity was observed. The results of the study showed that LAT could be
      employed as a simple and rapid diagnostic procedure, as an alternate to
      microscopy, to confirm the hydatid etiology of a suspected cyst.

PMID- 12614984
TI  - Effectiveness of peptone-yeast extract (P-Y) medium in the cultivation and
      isolation of Entamoeba histolytica/Entamoeba dispar in Turkish patients.
AB  - Amebiasis is a common protozoan infection worldwide, causing serious health
      problems in both children and adults. Today, almost 10% of the world population
      is infected with Entamoeba histolytica/Entamoeba dispar. The aims of this study
      were both the comparison of the reproduction rates and densities of E.
      histolytica/E. dispar in Robinson, Dobell-Laidlaw and P-Y culture media and
      isolation of E. histolytica/E. dispar from stool samples in Peptone-Yeast (P-Y)
      medium. Trophozoites and cysts of E. histolytica/E. dispar, maintained in
      Robinson medium, and stool samples of patients with amebiasis were inoculated
      into P-Y, Robinson and Dobell-Laidlaw culture media. Reproduction rates reached
      their peak levels 48 h after the inoculation in all culture media. Reproduction
      rates in P-Y and Robinson media were found similar; however, they were higher
      than the reproduction rate in Dobell-Laidlaw medium (p < 0.01); there was no
      statistically significant difference between the reproduction rates of P-Y and
      Robinson media (p > 0.05). Twelve isolates from 12 patients were cultivated in P
      Y medium and checked for reproduction everyday for 7 days. Twelve of the 12
      (100%) isolates were cultivated in P-Y medium, indicating that the P-Y was an
      effective medium for the isolation of E. histolytica/E. dispar in stool samples.
      According to these results, P-Y medium could be preferred in immunologic,
      serologic and molecular studies and, thus the definitive diagnosis of amebiasis
      due to its low cost and simple formula.

PMID- 12614985
TI  - In vitro activity of voriconazole, itraconazole, caspofungin, anidulafungin
      (VER002, LY303366) and amphotericin B against aspergillus spp.
AB  - Voriconazole, anidulafungin (VER002, LY303366) and caspofungin are promising
      antifungal agents which provide a good protection against a variety of fungi,
      including yeasts and filamentous fungi. In this study, we tested the in vitro
      efficacy of voriconazole, itraconazole, caspofungin, anidulafungin (VER002,
      LY303366) and amphotericin B, against different species of Aspergillus spp.
      isolated from clinical specimens, using a microdilution broth method and
      following the NCCLS guidelines (document M38-P). We also evaluated the effect
      that time readings have on MIC results. For caspofungin, we determined the
      minimun effective concentration (MEC), defined like the lowest concentration of
      caspofungin causing abnormal hyphal growth. Anidulafungin (VER002, LY303366) was
      the most active antifungal agent tested with MIC(90) of < or =0,03 mg/L. The
      activity of voriconazole, and itraconazole very similar with MIC(90) of 0,12
      mg/L, 0,12 mg/L respectively. For caspofungin the MEC(90) was of 0,25 mg/L.
      Amphotericin B was the lest active antifungal agent studied with MIC(90) of 1
      mg/L. There were no differences between MIC values at 48 and 72 h. These data
      demonstrate promising activity of voriconazole, anidulafungin (VER002, LY303366)
      and caspofungin against Apergillus spp.

PMID- 12614986
TI  - Candida glabrata spinal osteomyelitis involving two contiguous lumbar vertebrae:
      a case report and review of the literature.
AB  - Due to the increase of the immunocompromised population, mucosal and systemic
      infections caused by Candida glabrata, formerly known as Torulopsis glabrata,
      have shown a recent significant increase. We present a case of C. glabrata
      vertebral osteomyelitis which required repeated surgical therapy, a complete L2
      and L3 corporectomy and more than one year of hospitalisation to complete
      healing. We compare this case to eight previously reported cases outlining the
      features of C. glabrata spinal osteomyelitis, including symptoms, diagnosis,
      treatment, evolution and outcome. According to the case presented and in review
      of the literature, we believe that in the absence of abscess and neurologic
      symptoms, medical treatment should be initiated with close clinical, laboratory
      and radiologic follow-up. An unfavorable evolution of these parameters should be
      an indication for aggressive and, if necessary, repeated surgical intervention in
      association with an antifungal treatment.

PMID- 12614987
TI  - "Bacillus hackensackii" sp. nov., a novel carbon dioxide sensitive bacterium
      isolated from blood culture.
AB  - An endospore-forming, gram-positive bacillus was isolated from a patient's blood
      culture. This bacillus did not grow in the presence of 5% carbon dioxide although
      it grew well in ambient air at 37 degrees C. Although the organism thus is an
      aerobic bacterium, its sensitivity to increased carbon dioxide concentration
      places it in a distinct category of gaseous atmospheric requirement: capnophobic.
      Based on its morphology, growth characteristics, biochemical reactions and a
      complete 16S rRNA gene nucleotide sequence analysis, this microorganism
      represents a novel Bacillus species. The clinical significance of this isolate is
      unknown. It is proposed that the bacterium be classified in the genus Bacillus as
      "Bacillus hackensackii".

PMID- 12614988
TI  - Endocarditis due to glycopeptide-intermediate Staphylococcus aureus: case report
      and strain characterization.
AB  - We report a case of infective endocarditis due to vancomycin-intermediate
      Staphylococcus aureus (VISA) that did not respond to high doses of vancomycin.
      Initial vancomycin MIC of the last isolate recovered from blood was 8 micro g/mL,
      but could be induced up to 32 micro g/mL by consecutive growing with vancomycin.
      Clinical response was only accomplished when linezolid was included in therapy.

PMID- 12614990
TI  - Working memory and prefrontal cortex dysfunction: specificity to schizophrenia
      compared with major depression.
AB  - BACKGROUND: A large number of studies suggest the presence of deficits in
      dorsolateral prefrontal cortex function during performance of working memory
      tasks in individuals with schizophrenia. However, working memory deficits may
      also present in other psychiatric disorders, such as major depression. It is not
      clear whether people with major depression also demonstrate impaired prefrontal
      activation during performance of working memory tasks. METHODS: We used
      functional magnetic resonance imaging to assess the patterns of cortical
      activation associated with the performance of a 2-back version of the N-Back task
      (working memory) in 38 individuals with schizophrenia and 14 with major
      depression. RESULTS: We found significant group differences in the activation of
      dorsolateral prefrontal cortex associated with working memory performance.
      Consistent with prior research, participants with schizophrenia failed to show
      activation of right dorsolateral prefrontal cortex in response to working memory
      tasks demands, whereas those with major depression showed clear activation of
      right and left dorsolateral prefrontal cortex as well as bilateral activation of
      inferior and superior frontal cortex. CONCLUSIONS: During performance of working
      memory tasks, deficits in prefrontal activation, including dorsolateral regions,
      are more severe in participants with schizophrenia (most of whom were recently
      released outpatients) than in unmedicated outpatients with acute nonpsychotic
      major depression.

PMID- 12614989
TI  - Studies characterizing 60 kda autoantibodies in subjects with schizophrenia.
AB  - BACKGROUND: Studies suggest that schizophrenic patients have an increased
      prevalence of serum antibodies to neuroblastoma cell proteins migrating at 60
      kilodaltons (kDa). We present work identifying and characterizing 60 kDa antigen
      antibody interactions. METHODS: Sera from schizophrenic subjects and normal
      volunteers were screened by Western blotting. Proteins migrating at 60 kDa were
      characterized by two-dimensional gel electrophoresis and indirect
      immunofluorescent staining of human epithelial cell (HEp-2) slides. Human brain
      and bladder cell complementary deoxyribonucleic acid libraries were screened with
      immunoaffinity-purified antibodies. Complementary deoxyribonucleic acid clones
      were sequenced and compared with published databases. Proteins were generated by
      in vitro transcription/translation and expression in an Escherichia coli BL21
      system. Immunoprecipitation and immunohistochemistry studies were performed.
      RESULTS: Fifteen percent (17/117) of schizophrenic subjects and 3% (2/62) of
      normal volunteers had autoantibodies that reacted with 60 kDa proteins [chi(2)(1)
      = 4.4, p =.037]. Five percent of subjects had autoantibodies directed against 60
      kDa heat shock protein (HSP60) [chi(2)(1) = 3.3, p =.100). Two-dimensional gel
      electrophoresis identified 13 different proteins migrating at 60 kDa; 5 were
      splice variants of HSP60, and 2 corresponded with a protein associated with MYC
      (PAM). CONCLUSIONS: There is an increased prevalence of autoantibodies that bind
      to proteins migrating at 60 kDa in subjects with schizophrenia. Potential target
      antigens include HSP60 and PAM.

PMID- 12614992
TI  - Single-cue delay and trace classical conditioning in schizophrenia.
AB  - BACKGROUND: Classical conditioning provides a means of addressing mechanisms of
      learning and can therefore help understand the pathophysiology of memory
      alteration in schizophrenia. METHODS: Single cue delay and trace eyeblink
      conditioning were used in patients with schizophrenia and matched normal control
      subjects to explore, respectively, cerebellar and hippocampal integrity during
      learning. We measured percent of conditioned (CRs) and unconditioned responses
      (URs), their amplitude, and onset and peak latencies. We also accounted for
      spontaneous blink rates and stimulus-induced responses before learning. RESULTS:
      During delay conditioning, patients showed CRs with longer onset and peak
      latencies and improved efficiency compared to normal volunteers without there
      being differences between patients and normal control subjects in the percentage
      of CRs. During trace conditioning, neither group showed an increase in CRs as a
      function of conditioned stimulus-unconditioned stimulus pairings, in part because
      the level of spontaneous blink rates exceeded the level of CRs; however, patients
      with schizophrenia showed increased responding 150-400 msec after the conditioned
      stimulus and in the last 100-150 msec before the unconditioned stimulus, whereas
      normal control subjects showed only the latter type of responses. The former type
      of response was more frequent in patients with schizophrenia even before either
      trace or delay conditioning. CONCLUSIONS: These results suggest integrity of
      cerebellar mechanisms underlying conditioning, although the altered timing of CRs
      in patients may indicate differences in the modulation of such responses. Both
      the greater CR onset latency during delay and the presence of early nonadaptive
      responses during trace are compatible with the pattern of responding seen in
      animals with hippocampal damage.

PMID- 12614991
TI  - Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry:
      implications for schizophrenia.
AB  - BACKGROUND: Schizophrenia is associated with both reductions in prefrontal
      cortical (PFC) inhibitory markers and in neuron number in the mediodorsal
      thalamus (MDTN), which provides excitatory input to the PFC. To investigate the
      potential pathophysiologic relationship between these observations, we sought to
      provide experimental evidence that a reduction in MDTN neurons can produce
      decreased PFC glutamate decarboxylase (GAD(67)) mRNA expression. METHODS:
      Ibotenic acid was injected bilaterally into MDTN in rats. Four weeks later,
      thalamic lesion volumes were assessed stereologically, and PFC GAD(67) mRNA
      expression was measured using in situ hybridization. RESULTS: Selective MDTN
      lesions produced no changes in PFC GAD(67) mRNA expression, either overall or by
      cortical layer, and lesion volumes and GAD(67) mRNA expression were not
      correlated. CONCLUSIONS: In rats, a substantial lesion of MDTN neurons does not
      decrease PFC GAD(67) mRNA expression. These results do not support the hypothesis
      that decreased PFC GAD(67) mRNA expression in schizophrenia is attributable to a
      reduction in MDTN neuron number.

PMID- 12614993
TI  - Physiologic impairment of olfactory stimulus processing in schizophrenia.
AB  - BACKGROUND: Behavioral studies of olfaction have demonstrated impairments in the
      ability to detect and identify odors in patients with schizophrenia. These
      deficits appear to be independent of either symptom severity or other cognitive
      impairment. Only limited efforts have been made to investigate the
      neurophysiologic substrate of these olfactory abnormalities. This article reports
      the first examination of olfactory electrophysiologic responses in patients with
      schizophrenia. METHODS: Olfactory event-related potential responses to three
      different concentrations of hydrogen sulfide were recorded in a sample of 21
      patients and 20 healthy control subjects. Odors were presented via an
      olfactometer to ensure there was no associated trigeminal nerve stimulation.
      RESULTS: Patients exhibited abnormalities in the amplitudes of the N1 and P2
      components of the olfactory evoked potential, and delayed latency of the P2. The
      N1 abnormality, which denotes primary olfactory cortex activity, was related to
      impaired odor detection threshold sensitivity; the P2 abnormality was related to
      impaired odor identification. CONCLUSIONS: These data indicate the presence of a
      primary physiologic impairment in the olfactory cortex underlying behavioral
      olfactory deficits seen in patients with schizophrenia. This is consistent with
      postmortem and in vitro studies suggesting abnormalities in olfactory receptor
      neurons. Understanding the nature of these physiologic olfactory impairments
      could offer clues to the basic neuropathology of this disorder.

PMID- 12614994
TI  - Dysregulated brain development in adult men with schizophrenia: a magnetic
      resonance imaging study.
AB  - BACKGROUND: Recent imaging evidence suggests that normal brain
      development/maturation of the frontal lobes and association areas is a well
      regulated process consisting of continued myelination and expansion of white
      matter volumes into the late 40s accompanied by complementary reductions in gray
      matter volumes. The possibility that a dysregulation of this process may
      contribute to the syndrome of schizophrenia was investigated using magnetic
      resonance imaging. METHODS: Fifty-two normal adult males and 35 males with
      schizophrenia underwent magnetic resonance imaging. Coronal images were acquired
      using pulse sequences that maximized myelin signal. The age-related change in the
      gray to white matter ratio was used as a measure of developmental dysregulation
      in the schizophrenic subjects and contrasted to the age-related changes of the
      normal control group. RESULTS: Regression analyses on frontal and temporal gray
      to white matter ratio yielded highly significant interactions of diagnosis and
      age for both regions (p =.0003 and p =.01, respectively). In the normal group,
      both frontal and temporal gray to white matter ratios decreased significantly and
      linearly across the age range. In contrast, neither ratio showed meaningful age
      related change in the schizophrenia group. Thus, differences in gray to white
      matter ratio between the groups increased markedly with age, driven primarily by
      the absence of a white matter volume expansion in the patient group. CONCLUSIONS:
      The absence of the normal complementary volume changes in the gray and white
      matter with age in the schizophrenic sample suggests that this dynamic
      developmental process is dysregulated in adult schizophrenic subjects. The
      importance of myelination to the continued maturation and normal functioning of
      the brain has implications for the diagnosis, treatment, and prognosis of
      schizophrenia.

PMID- 12614996
TI  - Smoking, gender, and dietary influences on erythrocyte essential fatty acid
      composition among patients with schizophrenia or schizoaffective disorder.
AB  - BACKGROUND: Prior reports of decreased levels of essential fatty acids among
      schizophrenic patients have generated several hypotheses proposing inherent
      abnormalities in phospholipid and fatty acid metabolism and have provided the
      basis for treatment trials; however, these essential fatty acid aberrations may
      be attributable to uncontrolled factors, such as smoking, rather than
      abnormalities inherent to schizophrenia. METHODS: Erythrocyte fatty acid
      compositions were quantified in 72 medicated schizophrenic or schizoaffective
      patients both at baseline and after 16 weeks of supplementation with 3 g/day of
      either ethyl-eicosapentaenoic acid or placebo. Current smoking status, gender,
      dietary survey, and Montgomery Asburg Depression Rating Scale, Repeatable Battery
      for the Assessment of Neuropsychological Status, Abnormal Involuntary Movement
      Scale, and Positive and Negative Syndrome Scale scores were assessed. RESULTS:
      Schizophrenic patients who smoked had lower baseline erythrocyte docosahexaenoic
      acid percent (2.98 +/-.7 vs. 3.59 +/- 1.2, p <.005) and eicosapentaenoic acid
      (EPA) percent (.39 +/-.13 vs. 47 +/-.22, p <.05), compared with nonsmokers, with
      a significant gender interaction (p <.01) in multivariate analyses of variance.
      Baseline arachidonic acid did not differ. Smokers reported lower dietary intake
      (percent total fat) of linolenic acid (F = 10.1, p <.003) compared with
      nonsmokers. Nonsmoking women reported greater dietary intake of EPA compared with
      smoking men or nonsmokers of either gender. CONCLUSIONS: Smoking status, gender,
      and dietary intake significantly predicted erythrocyte polyunsaturated fatty acid
      status among schizophrenic patients. No evidence was found for subgroups of
      schizophrenia or relationships to specific symptom severity on the basis of
      erythrocyte fatty acids. Prior reports of abnormalities of essential fatty acid
      metabolism among schizophrenic patients may have been an artifact of patients'
      smoking behavior and differences in dietary intake of omega-3 fatty acids.

PMID- 12614995
TI  - The relationship of neuropsychological abilities to specific domains of
      functional capacity in older schizophrenia patients.
AB  - BACKGROUND: This study sought to determine the relative importance of cognitive
      measures in predicting various domains of everyday functional capacity in older
      outpatients with schizophrenia. METHODS: Ninety-three psychiatry outpatients with
      diagnoses of schizophrenia and schizoaffective disorders underwent a
      comprehensive neuropsychiatric evaluation, including neuropsychological testing
      and clinical ratings of psychopathology. Functional capacity was assessed with
      the Direct Assessment of Functional Status, a performance measure of basic and
      instrumental activities of daily living (ADLs/IADLs). RESULTS: Neuropsychological
      performance significantly predicted most ADLs/IADLs measured, except simple
      eating behaviors, time orientation, and grooming. Lower educational level and
      negative symptoms also were associated with worse functional capacity, whereas
      positive symptoms and depressed mood were not. Measures of cognitive functioning
      accounted for more variance in functional capacity than did psychiatric ratings
      of symptoms, and multiple regression analyses demonstrated that
      neuropsychological performance was predictive of functional capacity, over and
      above clinical symptoms. No specific cognitive domains were differentially
      predictive of specific domains of functional capacity. CONCLUSIONS:
      Neurocognitive abilities were more predictive of functional capacity than level
      of clinical symptoms; however, these abilities were not specific predictors of
      functioning. This is consistent with findings of relatively generalized,
      intercorrelated cognitive impairment in schizophrenia and multiply determined
      domains of everyday functioning.

PMID- 12614997
TI  - Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase
      II by psychotropic drugs.
AB  - BACKGROUND: Changes in neuroplasticity have been involved in the pathogenesis of
      psychiatric disorders as well as in psychotropic drug action. Calcium/calmodulin
      dependent protein kinase II (CaM kinase II), an enzyme with a pivotal role in
      synaptic plasticity and cognitive functions, has been implicated in the action of
      anticonvulsants, benzodiazepines, and antidepressants, but little is known as to
      its role in the action of different drugs employed for treatment of psychiatric
      disorders. METHODS: We studied the function and expression of CaM kinase II
      following chronic treatment of rats with two antidepressants, fluvoxamine and
      desipramine, a typical antipsychotic drug, haloperidol, and the typical
      medication for manic-depressive disorder, lithium. RESULTS: Antidepressants
      significantly increased the kinase activity in presynaptic vesicles of
      frontal/prefrontal cortex. Haloperidol induced no change, whereas lithium
      significantly decreased the activity. Kinase activation by antidepressants was
      further demonstrated by increased phosphorylation of exogenously added
      recombinant synaptotagmin. Immunoreactivity of vesicular kinase (alpha-isoform)
      was significantly increased by reuptake blockers but not by the two other drugs.
      Kinetic analysis showed that limiting value of enzymatic velocity (Vmax) of the
      kinase for substrate was also increased by reuptake blockers and decreased by
      lithium; however, neither messenger ribonucleic acid nor protein expression level
      of the kinase was increased in frontal/prefrontal cortex homogenates of
      antidepressant-treated rats, suggesting the involvement of local synaptic
      mechanisms. CONCLUSIONS: These findings show that functional regulation of
      presynaptic CaM kinase II is selectively affected by different psychotropic
      drugs, and suggest local synaptic mechanisms for pharmacological regulation of
      the kinase.

PMID- 12614998
TI  - Reversed cerebellar asymmetry in men with first-episode schizophrenia.
AB  - BACKGROUND: Abnormalities in cerebellar structure and function have been
      implicated in the pathophysiology of schizophrenia. In this study, we
      investigated whether patients experiencing first-episode schizophrenia differed
      from healthy comparison subjects in regional cerebellar volumes or cerebellar
      asymmetry. METHODS: Volumes of four cerebellar regions (right, left; anterior,
      posterior) were measured from contiguous coronal magnetic resonance (MR) images
      in 69 (37 men, 32 women) patients experiencing first-episode schizophrenia and in
      49 (27 men, 22 women) healthy comparison subjects. Patients were rated on the
      Scale for the Assessment of Negative Symptoms and the Schedule for Affective
      Disorders and Schizophrenia-Psychosis/Disorganization before the initiation of
      antipsychotic medication and at the time of the MR imaging exam. RESULTS:
      Patients and healthy comparison subjects did not differ in regional cerebellar
      volumes, but male patients demonstrated significantly reversed anterior and
      posterior asymmetry compared with healthy male subjects. Among male patients,
      greater reversals in a composite measure of cerebellar asymmetry (i.e., torque)
      correlated significantly with increased negative symptoms before the initiation
      of antipsychotic medication. CONCLUSIONS: These findings implicate an aberrant
      neurodevelopmental process involving the metencephalon in the pathophysiology of
      schizophrenia and are consistent with prior studies implicating abnormal
      asymmetry in schizophrenia at the neocortical level.

PMID- 12615000
TI  - Life after transcription--revisiting the fate of messenger RNA.
AB  - Recently, several groups have used high-density DNA microarrays to study mRNA
      turnover. These new data suggest that decay contributes significantly to
      determining mRNA levels, and they should prompt us to refocus our attention on
      the regulatory potential of mRNA decay.

PMID- 12615001
TI  - Evolution of alternative splicing: deletions, insertions and origin of functional
      parts of proteins from intron sequences.
AB  - Alternative splicing is thought to be a major source of functional diversity in
      animal proteins. We analyzed the evolutionary conservation of proteins encoded by
      alternatively spliced genes and predicted the ancestral state for 73 cases of
      alternative splicing (25 insertions and 48 deletions). The amino acid sequences
      of most of the inserts in proteins produced by alternative splicing are as
      conserved as the surrounding sequences. Thus, alternative splicing often creates
      novel isoforms by the insertion of new, functional protein sequences that
      probably originated from noncoding sequences of introns.

PMID- 12615002
TI  - A significant fraction of conserved noncoding DNA in human and mouse consists of
      predicted matrix attachment regions.
AB  - Noncoding DNA in the human-mouse orthologous intergenic regions contains
      "islands" of conserved sequences, the functions of which remain largely unknown.
      We hypothesized that some of these regions might be matrix-scaffold attachment
      regions, MARs (or S/MARs). MARs comprise one of the few classes of eukaryotic
      noncoding DNA with an experimentally characterized function, being involved in
      the attachment of chromatin to the nuclear matrix, chromatin remodeling and
      transcription regulation. To test our hypothesis, we analyzed the co-occurrence
      of predicted MARs with highly conserved noncoding DNA regions in human-mouse
      genomic alignments. We found that 11% of the conserved noncoding DNA consists of
      predicted MARs. Conversely, more than half of the predicted MARs co-occur with
      one or more independently identified conserved sequence blocks. An excess of
      conserved predicted MARs is seen in intergenic regions preceding 5' ends of
      genes, suggesting that these MARs are primarily involved in transcriptional
      control.

PMID- 12615003
TI  - Increase of functional diversity by alternative splicing.
AB  - A large-scale analysis of protein isoforms arising from alternative splicing
      shows that alternative splicing tends to insert or delete complete protein
      domains more frequently than expected by chance, whereas disruption of domains
      and other structural modules is less frequent. If domain regions are disrupted,
      the functional effect, as predicted from 3D structure, is frequently equivalent
      to removal of the entire domain. Also, short alternative splicing events within
      domains, which might preserve folded structure, target functional residues more
      frequently than expected. Thus, it seems that positive selection has had a major
      role in the evolution of alternative splicing.

PMID- 12615004
TI  - Recombination explains isochores in mammalian genomes.
AB  - The mouse Fxy gene was translocated into the highly recombining pseudoautosomal
      region comparatively recently in evolutionary terms. This event resulted in a
      rapid increase of GC content. We investigated the consequences of the
      translocation further by sequencing exons and introns of Fxy in various rodent
      species. We found that the DNA fragment newly located in a highly recombining
      context has acquired every property of a GC-rich isochore, namely increased GC
      content (especially at the third codon positions of exons), shorter introns and
      high density of minisatellites. These results strongly suggest that recombination
      is the primary determinant of the isochore organization of mammalian genomes.

PMID- 12615005
TI  - When ELFs are ORFs, but don't act like them.

PMID- 12615006
TI  - cGMP signalling: different ways to create a pathway.

PMID- 12615007
TI  - Using haplotype blocks to map human complex trait loci.
AB  - Understanding of linkage disequilibrium (LD) in human populations could
      facilitate the discovery of genes that influence complex human diseases. The
      "HapMap" project is now underway to characterize patterns of LD in the human
      genome. A pilot study showed "haplotype blocks" in 51 regions scattered
      throughout the genome. These intriguing results raise important questions about
      the nature of recombination, and highlight practical issues of marker collection,
      the influence of statistical modelling on apparent block structure, and the
      levels of genotyping necessary for studies of common diseases. Knowledge of local
      disequilibrium patterns may help identify common polymorphisms involved in
      complex disease, but completely new analytical methods and experimental designs
      will be required to identify important rare variants.

PMID- 12615008
TI  - Understanding mechanisms of novel gene expression in polyploids.
AB  - Polyploidy has long been recognized as a prominent force shaping the evolution of
      eukaryotes, especially flowering plants. New phenotypes often arise with
      polyploid formation and can contribute to the success of polyploids in nature or
      their selection for use in agriculture. Although the causes of novel variation in
      polyploids are not well understood, they could involve changes in gene expression
      through increased variation in dosage-regulated gene expression, altered
      regulatory interactions, and rapid genetic and epigenetic changes. New research
      approaches are being used to study these mechanisms and the results should
      provide a more complete understanding of polyploidy.

PMID- 12615009
TI  - Of mice and the fragile X syndrome.
AB  - Fragile X syndrome is the most common cause of inherited mental retardation, and
      recently a number of mouse models have been generated to study the condition.
      Knockout of the gene associated with fragile X, Fmr1, results in mild, but
      consistent abnormalities, analogous to the clinical and pathological symptoms
      observed in human patients. Thus, many aspects of the syndrome can now be studied
      in mice, taking full advantage of the benefits of this model organism, including
      the short generation time and unlimited supply of tissue. The experimental data
      suggest that knockout of Fmr1 mildly disturbs a variety of processes in different
      brain regions.

PMID- 12615010
TI  - Bacterial translational control at atomic resolution.
AB  - Translational regulation allows rapid adaptation of protein synthesis to
      environmental conditions. In prokaryotes, the synthesis of many RNA-binding
      proteins is regulated by a translational feedback mechanism involving a
      competition between their natural substrate and their binding site on mRNA, which
      are often thought to resemble each other. This article describes the case of
      threonyl-tRNA synthetase, which represses the translation of its own mRNA. Recent
      data provide the first opportunity to describe at the atomic level both the
      extent and the limit of mimicry between the way this enzyme recognizes tRNA(Thr)
      and its regulatory site in mRNA. The data also give some clues about how the
      binding of the synthetase to its mRNA inhibits translation.

PMID- 12615011
TI  - Lateralization defects and ciliary dyskinesia: lessons from algae.
AB  - Flagella and cilia are two very similar organelles that "beat" to move cells and
      to propel fluid over tissues. They are highly conserved, being found in organisms
      ranging from prokaryotes to plant and animal eukaryotes. In humans, cilia are
      present in almost every organ, and several human conditions involve dysfunctional
      cilia; for example, lateralization defects, where the positions of organs are
      reversed, and primary ciliary dyskinesia, a rare condition where patients suffer
      from recurrent respiratory infections. In this article, we will discuss how
      information gained from studies on algae has aided research into these human
      diseases. These studies found a variety of functions that was previously
      unsuspected, renewing interest in cilia.

PMID- 12615013
TI  - Qualitative evaluation of elderly home residents' fixed and removable prostheses
      in relation to the ADL index.
AB  - Functional diversity and biopsychosocial state is a significant issue, which
      greatly influences elderly oral health and state of fixed and removable
      prostheses. OBJECTIVES: The goal of the investigation was to evaluate the quality
      of fixed and removable prostheses in a group of elderly home residents in
      relation to the ADL index. METHODS: The group consisted of 175 institutionalised
      elderly, mean age 76.8 years. Special care need was assessed on ADL scale. To
      evaluate the quality and need for replacement of fixed and removable prostheses
      Karlsson's and modified Nevalainen et al. indices were used. RESULTS: Spearman's
      correlation analysis showed significant correlation of ADL index scores and both
      Karlsson's index values (rho=-0.468, p<0.01) as well as for modified Nevalainen's
      indices (rho=-0.572, p<0.01). Lower ADL score was correlated with poorer oral
      hygiene and condition of fixed or removable dentures. It was determined that 87%
      of the examined patients were in objective need of fixed, removable or combined
      prosthodontic treatment. CONCLUSIONS: The study showed that lower ADL index
      scores of functionally dependent elderly patients correlate with poorer condition
      of fixed and removable prostheses and greater need of fixed, removable or
      combined prosthodontic treatment.

PMID- 12615014
TI  - Computerized local dental anesthetic systems: patient and dentist satisfaction.
AB  - A computer controlled dental anesthetic delivery system was studied with the
      OBJECTIVE of evaluating and comparing the unit to the traditional method of
      anesthetic delivery. The research design and METHOD of study involved the use of
      trained dentists who used both types of delivery systems on patients seen during
      their routine practice of dentistry. After the dental appointment was finished
      each dentist completed a survey concerning the injection. Patients completed a
      survey before the injection concerning their previous anesthetic experiences and
      completed another survey at the end of the dental appointment concerning the
      injection they had just received. Statistical analyses yielded RESULTS showing
      the two methods were rated very similarly by both patients and dentists.
      CONCLUSIONS resulting from the study are that computer controlled dental
      anesthetic injections and traditional anesthetic injections were accepted equally
      well by both dentists and patients.

PMID- 12615015
TI  - Effects of tooth-conditioning agents on bond strength of a resin-modified glass
      ionomer sealant to enamel.
AB  - OBJECTIVES: The purpose of this study was to evaluate the effects of tooth
      conditioning agents on bond strength of resin-modified glass-ionomer sealant
      (Fuji III LC) to bovine enamel as well as on dissolution of calcium ions from the
      bovine enamel surfaces. METHODS: The enamel surfaces of bovine lower incisors
      were treated with 10 and 20% polyacrylic acid, 12% citric acid and 35% phosphoric
      acid for 20s. Fuji III LC was applied to the etched enamel surfaces, and the
      shear bond strength of each specimen was measured using an Instron Universal
      Testing Instrument. The amounts of calcium ions dissolved from the treated enamel
      surfaces were also measured using a polarized Zeeman atomic absorptiometer.
      RESULTS: In specimens pretreated with distilled water, 10% polyacrylic acid, 20%
      polyacrylic acid, 12% citric acid and 35% phosphoric acid, the mean values of
      shear bond strength were 5.5, 12.5, 15.2, 15.2 and 15.1MPa, respectively, and the
      amounts of Ca(2+) dissolved from the enamel surfaces were 5.6, 41.4, 88.5, 131.6
      and 588.3 microg/cm(2), respectively. CONCLUSIONS: The adhesion of a resin
      modified glass-ionomer sealant to bovine enamel was significantly improved by the
      use of tooth-conditioning agents. Especially, treatment of an enamel surface with
      20% polyacrylic acid results in good shear both strength and relatively small
      degree of enamel erosion.

PMID- 12615016
TI  - Fluoride release from orthodontic band cements-a comparison of two in vitro
      models.
AB  - OBJECTIVES: To compare, in vitro, the fluoride release from a conventional glass
      ionomer cement (Ketac-Cem), a resin-modified glass ionomer cement (3M-Multicure)
      and a polyacid modified composite (Ultra Band-Lok) using a banded tooth model and
      a disc model with the same mean cement weight. METHODS: Forty pairs of caries
      free third molars were collected and divided into two groups, each of 20 teeth.
      One tooth from each pair was banded with Ketac-Cem and the other with Ultra Band
      Lok or 3M-Multicure; the average band size for each cement group was the same.
      Two coats of nail varnish were painted on each tooth to within 1mm of the band
      margin. Five discs (4.5mm diameter and 2mm depth) were prepared for each cement,
      these dimensions having been calculated so that the mean cement weight of the
      banded tooth model matched that of the disc model for each cement. The fluoride
      released into 2ml of deionised water, from each banded tooth or disc, was
      measured at regular intervals over 30 days using an Orion ion-selective electrode
      connected to an ion analyser. RESULTS: At 30 days, for both banded tooth and disc
      models, the mean cumulative fluoride release was greatest from 3M-Multicure
      followed by Ketac-Cem, which in turn released more fluoride than Ultra Band-Lok.
      These differences were all significant (p<0.05). Despite having the same mean
      cement weight, the banded tooth model for Ketac-Cem and 3M-Multicure released
      approximately 3-4 times more cumulative fluoride than the disc model after 30
      days (p<001). For Ultra Band-Lok, both models released comparable levels of
      fluoride (p>0.05). CONCLUSIONS: Cement type, specimen geometry and surface area
      appear to influence significantly fluoride release characteristics.

PMID- 12615017
TI  - Fluoride release from orthodontic cements-effect of specimen surface area and
      depth.
AB  - OBJECTIVE: The aims of this in vitro study were firstly to compare fluoride
      release from a disc model of two orthodontic cements with various surfaces
      varnished, reducing the surface area by 25, 50 and 75%; secondly, to measure the
      fluoride release from previously exhausted discs of the same cements following
      removal of various depths of surface material. METHODS: Forty discs of each
      cement, Fuji Ortho LC and Ultra Band-Lok, (6mm diameter by 3mm) were divided into
      two groups of 20 discs each. For each material, the first group was divided
      further into four groups of five discs, one group acting as control, while the
      other three groups were varnished reducing the surface area by 25, 50 and 75%,
      respectively. The second group was exhausted initially over a 60 day pre
      experimental period and was subsequently divided into four groups of five discs,
      one group acting as control. The other three groups had material ground from one
      of the flat surfaces, to depths of 10, 100 or 1000 microm, to reveal a fresh
      surface. In both studies, the discs were immersed either daily (up to day 20) or
      twice weekly (up to day 60) in fresh 2ml aliquots of deionised water. The
      fluoride concentration in the deionised water was measured at the end of the
      experimental period. RESULTS: For each cement, the relationship between the
      cumulative fluoride release and the percentage of the surface covered was clearly
      non linear at both 5 and 60 days. Fuji Ortho LC proved to release significantly
      greater amounts of fluoride at both 5 days and 60 days compared with Ultra Band
      Lok. The results for Ultra Band-Lok were also significant when compared to the
      control group, but significantly less fluoride was released when compared with
      Fuji Ortho LC. When comparing the 25 and 50% covered discs, the amount of
      fluoride released was not significantly different for both cements. Furthermore,
      the relationship between fluoride release and depth was clearly non linear for
      both cements. CONCLUSIONS: For the materials tested in this study, reducing the
      surface area of the discs did not reduce the cumulative fluoride release in a
      linear fashion. In addition, the previously exhausted discs began to release
      fluoride again, but this fell to concentrations similar to the control discs
      after the initial 5-day period for both cements. This suggests that further
      traces of previously unreleased fluoride had become available from the subsurface
      of these cements. The pattern of fluoride release was similar for all models
      tested.

PMID- 12615019
TI  - Sorption and solubility of resin-based restorative dental materials.
AB  - OBJECTIVES: To measure the water sorption and solubility of different resin-based
      restorative dental materials. METHODS: Eight commercial restorative materials
      were selected: two resin composites (Z100 and Prodigy), four polyacid-modified
      resin composites (Compoglass, Compoglass F, Dyract and Dyract AP), and two light
      cured glass ionomers (Vitremer and Fuji II LC). Five disc specimens were prepared
      of each material, following the manufacturer's instructions, and were grounded
      wet with silicon carbide paper. Water sorption and solubility of the different
      materials were calculated by means of weighting the samples before and after
      water immersion and desiccation. Data were analyzed by one-way ANOVA and Student
      Newman-Keuls tests (P<0.05). RESULTS: Compoglass and Compoglass F showed the
      lowest values of water sorption and solubility, while Vitremer and Fuji II LC
      displayed the highest values. Solubility values of Prodigy, Z100, Dyract and
      Dyract AP did not show significant differences among them, while their water
      sorption values attained some differences and were lower for Prodigy followed by
      Dyract and Z100. CONCLUSIONS: The attained water sorption and solubility values
      are mainly influenced by the generic type of material and variations occurring
      between materials of the same type may result from differences in resin matrix
      compositions.

PMID- 12615018
TI  - Adhesive bond of veneering composites on various metal surfaces using
      silicoating, titanium-coating or functional monomers.
AB  - OBJECTIVES: This study compared the shear bond strength (SBS) between veneering
      composites and titanium (grade 1), a cobalt-chromium-alloy and a high precious
      alloy, which were pretreated using silicoating systems, functional monomers or an
      experimental titanium-dioxide coating system. METHOD: The specimens were sized to
      rectangular plates of 20 x10 x 2mm(3) (l,w,h) and a composite cylinder (height of
      4mm, diameter 5mm) was axially polymerized to the middle of the plates. After
      aging (24h or 150 d storage in distilled water at 37 degrees C, or thermal
      cycling: 6000 x 5 degrees /55 degrees C) the SBS was determined. RESULTS:
      Independent of the type of metal and the conditioning/coating techniques the
      lowest SBSs were found after thermal-cycling. Titanium. The SBS of the silica
      coating systems and the functional monomers did not differ statistically on
      titanium. However, the titanium-dioxide coating method had significantly higher
      values than the other methods. Cobalt-chromium. The highest mean values were
      observed with the titanium-dioxide coating system and the phosphate acid ester.
      Precious alloy. No statistical significant different SBS was found for the
      silicoating and the titanium-dioxide coating methods, while the functional
      monomers were statistically significant (lower) different to both systems.
      CONCLUSION: Generally, the titanium-dioxide coating system achieved the highest
      SBS under different aging conditions and on all three different metal-surfaces.

PMID- 12615020
TI  - Particle versus mercury removal efficiency of amalgam separators.
AB  - OBJECTIVE: The intent of this project was to evaluate the efficiency of three
      commercial amalgam separators based on mercury and particle removal. METHODS:
      Dental wastewater samples were collected from a 54-chair dental clinic and a one
      chair private dental office. Atomic absorption spectrometry was used to measure
      mercury, and a laser diffractometer method to determine the particle size
      distributions. RESULTS: The mercury removal efficiency of the three units ranged
      from 26.5 to 61.8% for the 54-chair clinic and from 80.8 to 94.7% for the one
      chair office. Following treatment, the particle size range of the effluent was
      8.3-19.2 microm for the 54-chair office and 27.5-41.4 microm for the one-chair
      clinic. For particle samples based on the silver-copper and copper standards, the
      three amalgam separators had a particle removal efficiency ranging from 92.3 to
      99.9%. The initial particle size distributions for these samples were all under
      100 microm. CONCLUSIONS: The efficiency of the amalgam separators is influenced
      by the initial concentration of the dental wastewater, the physical setup of the
      discharge system before the dental wastewater reaches the separators, and the
      addition of chemicals to the dental wastewater. In addition, it is likely that
      assessment of efficiency based on particle removal by weight may not be as
      effective as removal based on concentration.

PMID- 12615021
TI  - The effects of filling techniques and a low-viscosity composite liner on bond
      strength to class II cavities.
AB  - OBJECTIVE: The aim of this study was to test the hypothesis that the effects of
      filling technique, cavity configuration and use of a low-viscosity composite
      liner influence resin bond strength to the dentin of class II cavities gingival
      floor; and analyze the failure modes of fractured specimens. METHODS:
      Standardized class II cavities were prepared in the proximal surfaces of freshly
      extracted third molars, which were randomly assigned to 10 experimental groups.
      All prepared surfaces were acid-etched, bonded with Single Bond adhesive system
      and restored with TPH composite, according to each technique: G1 and G2
      horizontal layering, G3 and G4-faciolingual layering, G5 and G6-oblique layering,
      G7 and G8-bulk filling, G9 and G10-control (flat dentin surfaces). Groups were
      tested, with or without a low-viscosity composite liner (Tetric Flow Chroma).
      After storage in water for 24h, teeth were vertically serially sectioned to yield
      a series of 0.8mm thick slabs. Each slab was trimmed into an hourglass shape of
      approximately 0.8mm(2) area at the gingival resin-dentin interface. Specimens
      were tested in tension at 0.5mm/min until failure. Fractured specimens were
      analyzed in an SEM to determine the failure modes. RESULTS: No significant
      difference was found between groups restored with and without a low-viscosity
      composite liner (p>0.05). Among filling techniques, the bulk filling groups
      presented the lowest bond strength values (p<0.05), while incremental filling
      groups did not differ from control (flat dentin surfaces). Failure modes varied
      significantly among groups restored with and without the low-viscosity composite
      liner. SIGNIFICANCE: Bond strengths were not improved when a low-viscosity
      composite liner was applied, but it remarkably influenced the failure modes.
      Incremental techniques improved bond strength.

PMID- 12615022
TI  - Analysis of the properties of silicone rubber maxillofacial prosthetic materials.
AB  - OBJECTIVES: Maxillofacial prosthetic materials are used to replace facial parts
      lost through disease or trauma. Silicone rubbers are the materials of choice,
      however it is widely accepted that these materials do not possess ideal
      properties. The objective of this study was to assess the properties of a range
      of commercially available silicone rubber maxillofacial materials and make
      recommendations for improvements. METHODS: Specimens of five commonly used
      maxillofacial materials were prepared in dental flasks according manufacturers
      instructions. Tear strength, tensile strength, percentage elongation, hardness,
      water absorption and water contact angles were determined for each material.
      RESULTS: The tear strength of Factor II, Cosmesil HC and Nusil were all
      comparable and significantly higher than Cosmesil St and Prestige (p<0.001).
      Nusil had a significantly higher tensile strength and elongation in comparison to
      the other materials (p<0.001) and Cosmesil St and Cosmesil HC were significantly
      harder (p<0.001). Factor II was significantly less wetted and Prestige and
      Cosmsesil St had a significantly higher water absorption in comparison to the
      other materials. CONCLUSIONS: None of the commercially available silicone rubber
      materials possessed ideal properties for use as a maxillofacial prosthetic
      material. Factor II, however, showed more favourable properties due to it's high
      tear strength, softness and ease of manipulation.

PMID- 12615023
TI  - Odontoblast morphology and dental repair.
AB  - OBJECTIVES: To investigate the changes in morphology and activity of pulp
      odontoblasts in response to cavity restoration variables and patient factors.
      METHODS: Class V non exposed cavities were prepared in the intact 1st or 2nd
      premolar teeth of 27 patients, aged between 9 and 17 years-old. Following tooth
      extraction, the area of reactionary dentine and the area of the odontoblasts were
      measured using computerised histomorphometry. RESULTS: The cytoplasm to nucleus
      ratio of the odontoblasts was found to increase beneath cut dentinal tubules,
      following the secretion of reactionary dentine. However, none of the patient or
      preparation variables were found to be correlated with changes in the odontoblast
      cytoplasm to nucleus ratio. CONCLUSIONS: Morphological changes in human
      odontoblasts is directly related to their capacity to repair dentine injuries and
      provide pulp protection. Changes in odontoblast morphology reflect secretory
      activity.

PMID- 12615025
TI  - Neonatal lung disease.

PMID- 12615026
TI  - Approaches to the initial respiratory management of preterm neonates.
AB  - Newly born preterm infants often require respiratory support. Various approaches
      have been taken to provide this support, including elective intubation and
      ventilation, prophylactic surfactant and continuous positive airway pressure
      (CPAP). Elective intubation and ventilation allow the clinician to take control
      of the baby's airway and reduce the support as tolerated. Surfactant can be
      administered prophylactically to prevent lung injury and respiratory
      complications. Many neonatologists, however, advocate a less aggressive approach
      to the provision of support, which includes the application of early nasal CPAP
      with intubation and ventilation only if necessary. Avoiding intubation may be
      effective in minimising ventilator-induced lung injury, but withholding
      surfactant may be detrimental to the infant. In this paper, we examine the
      advantages and disadvantages of the different approaches that can be taken in
      providing respiratory support to preterm neonates shortly after birth and examine
      some strategies that integrate them.

PMID- 12615024
TI  - Fracture resistance of class II preformed ceramic insert and direct composite
      resin restorations.
AB  - OBJECTIVES: This study aimed to compare the fracture resistance of two different
      posterior restorations in class II cavities. METHODS: In this study 24 extracted
      intact human mandibular molars (for testing) and 24 extracted intact human teeth
      (for achieving contact) were used. The test teeth were divided into two groups
      and then mounted in normal anatomic relationship with intact human teeth on the
      same holder. Thus 12 pairs of teeth were constituted in each group. Class II MO
      cavities were prepared on testing teeth in each holder. The other tooth was used
      for achieving contact. The cavities in group 1 were restored with direct
      composite resin with the manufacturer's flowable composite. The cavities in group
      2 were restored with SONICSYS inlays (preformed ceramic insert) according to the
      manufacturer's instructions. The marginal ridges of the restorations were loaded
      at an angle of 13.5 degrees to the long axis of the tooth in an Instron testing
      machine until failure occurred. RESULTS: Analysis of mean failure loads indicated
      that class II SONICSYS inlay restorations (group 2) had a significantly greater
      fracture resistance than did class II direct composite resin restorations with
      flowable composite (P=0.000). CONCLUSIONS: The SONICSYS inlay system provided
      greater fracture resistance than direct composite resin with flowable composite.

PMID- 12615027
TI  - Oxygen monitoring in preterm babies: too high, too low?
AB  - A small randomised trial in 1952 showed that excess oxygen use might well be
      causing a major epidemic of retinal blindness in preterm babies. That single
      study of just 65 babies was enough to throw doubt on a longstanding treatment
      strategy of oxygen therapy and highlighted just how powerful a tool the
      randomised controlled trial could be. Confirmatory evidence from a co-operative
      trial 4 years later involving 212 babies banished all residual doubt and we
      should reproach ourselves that we have still not learnt after 50 years how to
      optimise oxygen delivery to the preterm baby, making further use of this powerful
      research tool. Two well-conducted trials have recently shown that avoiding
      subclinical hypoxaemia (a fractional SaO(2) of less than 92%) in babies more than
      a month old does nothing to improve later growth or development. It is now time
      the same question was asked of babies less than a month old. This is particularly
      important in babies of less than 28 weeks' gestation, who currently remain at
      serious risk of chronic lung disease and permanent retinal damage.

PMID- 12615028
TI  - PEEP--a "cheap" and effective lung protection.
AB  - Mechanical ventilation is a complex therapy with several different parameters
      which can be altered. In preterm and term infants, more attention has been paid
      to the levels of peak inspiratory pressure than to the positive end-expiratory
      pressure (PEEP). An awareness that lung protection can be conferred by an
      appropriate level of PEEP has increasingly stimulated a renewed interest in
      achieving the "best PEEP" strategy. We review the history of the introduction of
      PEEP therapy, some of the early demonstrations of its potential for mischief, the
      evidence on what levels of PEEP are appropriate in infants, some data concerning
      the lung-protective value of PEEP and finally some recent efforts at defining
      measures to determine the so-called "best PEEP". Some of this work has been
      performed in adults with the acute respiratory distress syndrome. In newborns, we
      are regrettably forced to conclude that there is, for the immediate present, no
      easy substitute for sensible clinical observations coupled with a judicious and
      cautious adjustment of PEEP. We anticipate that a more logical application of
      PEEP with individualisation of therapy, based on a pressure-volume relationship,
      will in future enable targeted tests of PEEP as a lung-protection strategy.

PMID- 12615029
TI  - Current strategies in the prevention of respiratory syncytial virus disease.
AB  - Infants infected with respiratory syncytial virus (RSV) develop both upper and
      lower respiratory tract infections resulting in laryngotracheobronchitis,
      bronchiolitis and pneumonia. Premature infants of less than 32 weeks' gestation
      and those with underlying chronic lung disease are particularly susceptible and
      incur significant morbidity and mortality following hospitalisation. Conservative
      RSV prevention strategies focus on the interruption of transmission by proper
      hand-washing techniques and reducing exposure to potential environmental risk
      factors. Major challenges have impeded the development of an RSV vaccine but a
      licensed product may be expected in the near future. Prophylaxis with a humanised
      mouse monoclonal antibody (palivizumab) has been effective in reducing the rate
      of RSV hospitalisation in high-risk premature infants in phase II-IV trials and
      is available for use within internationally approved guidelines. Experimental
      studies evaluating the use of palivizumab in patients with congenital heart
      disease, those with cystic fibrosis and immunosuppressed bone marrow transplant
      recipients are well underway, the results of which are eagerly awaited.

PMID- 12615030
TI  - Effects of childhood respiratory diseases on the anatomical and functional
      development of the respiratory system.
AB  - The anatomical and functional development of the lung appears especially
      vulnerable to a whole range of insults during gestation and the first few years
      of life. A significant proportion of adult lung disease originates in utero or
      early infancy. Most publications on this topic are descriptive retrospective
      studies. An important limitation of these is that structural changes may precede
      abnormalities in lung function and development of symptoms. Little is known with
      certainty with respect to the long-term effects of early insults to the
      respiratory system. Furthermore, the reversibility of the functional and/or
      structural defects is hardly ever adequately investigated and it is probably not
      correct to extrapolate findings from adult studies to paediatric pulmonary
      diseases. Promoting or facilitating optimal lung growth in fetuses and infants
      and reducing the incidence of lower respiratory tract infection in infancy may
      reduce the incidence of adult chronic lung disease in generations to come.

PMID- 12615031
TI  - The role of allergy in the development of airway inflammation in children.
AB  - The primary immune response to allergens is the prototypic T-helper cell type 2
      (Th2) response. This occurs prenatally, favoured by the normal Th2-skewed immune
      response of pregnancy. The immune system matures during the early years of life.
      The immune responses, primarily determined by genetic susceptibility, are also
      influenced by exposure to allergens and infections, which may reverse their
      direction. Although wheezing is observed before 2 years of age, this is usually
      not attributable to allergy, and the majority of the wheezers do not develop
      asthma. The development of allergic asthma can be considered to be a two-stage
      process. The first stage involves the development of allergen-specific
      immunological memory against inhaled allergens. This happens in childhood and
      polarises the immune response towards a Th2 phenotype. These individuals are
      therefore more prone to developing allergic inflammation. Stage two involves the
      consolidation and maintenance of this polarised Th2 response, leading to a state
      of chronic airway inflammation. This second phase is influenced by various
      factors, for example respiratory viral infections, repeated indoor and outdoor
      allergen exposure, environmental tobacco smoke and air pollutants. The persistent
      airway inflammation leads to tissue remodelling and airway hyperresponsiveness,
      the clinical sine qua non of asthma.

PMID- 12615032
TI  - Asthma in adolescence.
AB  - The care of adolescents with asthma has been largely neglected, yet adolescents
      have particular needs that differ from those of children or adults with asthma.
      There are over 800,000 teenagers in the UK who suffer from asthma and
      underdiagnosis and poor treatment are common. The prevalence and level of
      morbidity from asthma in adolescents are as high as or higher than the rates in
      younger schoolchildren. Poor symptom control frequently reflects poor compliance
      with treatment. The beliefs and fears of teenagers about their asthma and its
      treatment are often not recognised or addressed in clinical consultations.
      Improved communication on the part of health professionals, which results in
      negotiating simple management plans that are tailored to the individual patient's
      concerns and goals, is more likely to improve compliance and asthma control than
      are complex plans made unilaterally by the doctor. The transition of care from
      the paediatric to the adult clinic remains a challenge for paediatricians and
      there is a lack of consensus over the best method of achieving this.

PMID- 12615033
TI  - Imaging of paediatric mediastinal abnormalities.
AB  - The mediastinum in children can be a difficult area to assess on the chest
      radiograph: even the normal thymus can give the impression of a mediastinal mass
      lesion. When there is suspicion of a mediastinal mass, its location within the
      mediastinum helps to limit the differential diagnosis. Further imaging with
      ultrasound, computed tomography and magnetic resonance imaging helps to
      characterise the lesion, define its extent and detect complications. Abnormal
      mediastinal contours may also be caused by congenital anomalies of the
      mediastinal vessels, which can be demonstrated non-invasively using magnetic
      resonance imaging. The main purpose of this article is to review the anatomy of
      the mediastinum and imaging of mediastinal mass lesions in children together with
      some vascular anomalies that can simulate a mediastinal mass.

PMID- 12615034
TI  - Bronchoscopy in paediatric intensive care.
AB  - Bronchoscopy is a highly versatile technique in the context of intensive care and
      has many potentially valuable indications. Safety is of paramount importance and
      the risks in critically unstable patients are correspondingly greater than in
      more stable children. The main contraindication to bronchoscopy is if it will
      provide no useful information. The procedure is obviously more risky in children
      with severe hypoxia, uncontrolled bleeding diathesis, cardiac failure or severe
      pulmonary hypertension. Monitoring should include at least oxygen saturation,
      blood pressure (ideally by continuous, invasive monitoring) and preferably
      capnography. Indications for bronchoscopy in paediatric intensive care include
      endobronchial toilet, sometimes instilling recombinant human DNAase even in
      children who do not have cystic fibrosis; checking tube patency and position;
      assisting in a difficult intubation or tube change; achieving the selective
      intubation of a main bronchus; the diagnosis and management of ventilator
      associated pneumonia or the ventilated, immunocompromised host; the assessment of
      lobar collapse or focal hyperinflation; airway stent assessment; assessment of
      stridor on extubation and the diagnosis of any associated disease. New iatrogenic
      complications are also likely to be discovered. The procedure is very safe if
      performed by experienced operators with back-up from doctors skilled in airway
      management and the monitoring of sick children.

PMID- 12615035
TI  - Isolated tracheo-oesophageal fistula.
AB  - Congenital isolated tracheo-oesophageal fistula is a rare malformation that
      presents with a characteristic triad of symptoms: choking and cyanosis on
      feeding, recurrent lower respiratory tract infection and abdominal distension.
      Children are invariably symptomatic from birth, although the symptoms may be
      intermittent and may vary in severity. A high index of suspicion is required
      because the symptoms are not specific. Establishing the diagnosis can be
      difficult and neither radiology nor bronchoscopy is infallible. Surgical division
      of the fistula is curative.

PMID- 12615036
TI  - Tag, you're hit: retroviral insertions identify genes involved in cancer.
AB  - Retroviral integrations have been used for many years to identify genes involved
      in cancer. The recently published mouse genome sequence has allowed large-scale
      identification of potential human cancer genes and their classification into
      distinct signaling pathways.

PMID- 12615037
TI  - Influenza-virus-induced signaling cascades: targets for antiviral therapy?
AB  - Influenza viruses continue to pose a severe threat worldwide, causing thousands
      of deaths and an enormous economic loss every year. The major problem in fighting
      influenza is the high genetic variability of the virus, resulting in the rapid
      formation of variants that escape the acquired immunity against previous virus
      strains, or have resistance to antiviral agents. Every virus depends on its host
      cell and, hence, cellular functions that are essential for viral replication
      might be suitable targets for antiviral therapy. As a result, intracellular
      signaling cascades induced by the virus, in particular mitogen-activated protein
      kinase pathways, have recently come into focus.

PMID- 12615038
TI  - Promises and pitfalls of anti-angiogenic therapy in clinical trials.
AB  - A significant body of research has implicated the process of angiogenesis in the
      growth and spread of tumors. Elucidation of the mechanisms of tumor angiogenesis
      has led to the development of multiple anti-angiogenic agents. However, the
      perceived differences between the results of preclinical studies and those of
      early phases of clinical trials have led to questions being asked regarding the
      efficacy of these agents. There are many reasons for this discrepancy, including
      difficulties in the appropriate interpretation of preclinical data and clinical
      trial design. Further insights into the complex process of angiogenesis are
      essential for the development of effective anti-angiogenic regimens.

PMID- 12615039
TI  - Genetic modifiers of cardiac arrhythmias.
AB  - Rhythmic contraction of a four-chambered mammalian heart is a highly coordinated
      process, requiring a functional conduction system. Both acquired and inherited
      forms of arrhythmia can be life threatening, and are major causes of mortality
      and morbidity in developed nations. Knowledge derived from human genetics and
      from studies of mouse genetic models has led to the discovery of multiple
      molecular defects responsible for arrhythmogenesis, including mutations in ion
      channels, cytoplasmic ion-channel-interacting proteins, gap-junction proteins,
      transcription factors and, most recently, a kinase subunit. However, phenotypic
      expression of a given mutation does not always appear to be uniform in human
      patients, implying a contribution from environmental factors and/or the presence
      of other genetic modifiers. Accumulating evidence suggests that 'multiple hits'
      affecting the interaction and integrity of multiple pathways might be responsible
      for many forms of arrhythmia.

PMID- 12615040
TI  - Non-viral and hybrid vectors in human gene therapy: an update.
AB  - Non-viral DNA vectors have several advantages over viral vectors. For example,
      virus production is expensive and there are safety concerns regarding viral
      manipulations. In addition, the size of the delivered plasmid is limited by the
      size of the viral capsid, whereas this is not a problem with non-viral vectors.
      The major disadvantage of using non-viral DNA delivery vectors, compared with
      their viral counterparts, is the low transfection efficiency. This has resulted
      in low levels of usage in clinical trials. Consequently, the majority of research
      into non-viral gene therapy has been focused on developing more efficient
      vectors.

PMID- 12615041
TI  - Cyclooxygenase-2: a therapeutic target in angiogenesis.
AB  - Angiogenesis has a role in the pathogenesis of several disorders, including
      cancer, chronic inflammatory diseases and retinopathies. Recent evidence
      demonstrates that the production of prostanoids by cyclooxygenase-2 (COX-2)
      promotes the expression of pro-angiogenic factors. Furthermore, inhibition of COX
      2 by non-steroidal anti-inflammatory drugs leads to restricted angiogenesis and
      downregulated production of pro-angiogenic factors, such as vascular endothelial
      growth factor and basic fibroblast growth factor. These findings suggest that COX
      enzymes could be important therapeutic targets in the treatment of pathological
      angiogenesis.

PMID- 12615043
TI  - A new look for brain, behavior, and immunity.

PMID- 12615042
TI  - Mouse models of alopecia: identifying structural genes that are baldly needed.
AB  - The mature hair follicle undergoes a unique developmental cycle, in which phases
      of growth are interspersed with phases of involution and rest. The main effectors
      of this cycle are skin epithelial stem cells that reside in a specialized
      compartment of the follicle. Defects in this cycle, or in the structure of the
      hair produced, often result in alopecia (partial or complete hair loss), a
      condition that affects a significant fraction of the population. Here we discuss
      transgenic mouse models that exhibit alopecia as a primary phenotype, resulting
      from the inactivation of genes encoding structural proteins.

PMID- 12615044
TI  - Critical periods of special health relevance for psychoneuroimmunology.
AB  - Although it is possible to demonstrate an influence of psychological factors on
      immune responses at any point in the life span, there are two periods when the
      effects may have greater implications for health. Our research with nonhuman
      primates indicates that the immaturity of a young infant's immune responses makes
      it more vulnerable, especially during the fetal and neonatal stages. Similarly,
      the natural, age-related process of immune senescence creates a second period of
      increased risk in elderly animals and people. This review summarizes findings
      from a 20-year research program, which support the conclusion that we should give
      special attention to the age of the host in psychoneuroimmunology studies.

PMID- 12615045
TI  - Molecular insights on the cerebral innate immune system.
AB  - All species need an immediate reply to the microbial pathogens that is part of an
      effective immune response and is essential for the survival of most organisms.
      This reply is known as the innate immune response and is characterized by the de
      novo production of mediators that either kill the microbes directly or activate
      phagocytic cells to ingest and kill them. The innate immune response can be
      driven through specific recognition systems, the best example being an
      interaction between the endotoxin lipopolysaccharide (LPS) and its receptors CD14
      and Toll-like receptor 4 (TLR4). For a long time, the brain was considered to be
      a privileged organ from an immunological point of view, owing to its inability to
      mount an immune response and process antigens. Although this is partly true, the
      CNS shows a well-organized innate immune reaction in response to systemic
      bacterial infection and cerebral injury. The CD14 and TLR4 receptors are
      constitutively expressed in the circumventricular organs (CVOs), choroid plexus
      and leptomeninges. Circulating LPS is able to cause a rapid transcriptional
      activation of genes encoding CD14 and TLR2, as well as a wide variety of pro
      inflammatory molecules in CVOs. A delayed response to LPS takes place in cells
      located at boundaries of the CVOs and in microglia across the CNS. Therefore,
      without having direct access to the brain parenchyma, pathogens have the ability
      to trigger an innate immune reaction throughout cerebral tissue. This review
      presents evidence supporting the existence of such a system in the brain, which
      is finely regulated at the transcription level. Transient activation of this
      system is not harmful toward neuronal elements.

PMID- 12615046
TI  - Pavlovian conditioning of endotoxin-tolerance in rats.
AB  - The most fascinating example of the bi-directional interaction between the
      central nervous system (CNS) and immune system is the behavioral conditioning of
      immune functions. We therefore investigated the behavioral conditioning of
      lipopolysaccharide (LPS)-induced endotoxin tolerance using the taste aversion
      paradigm. The conditioned stimulus (CS) saccharin was paired with the
      unconditioned stimulus (UCS) LPS over a five (CONDl) or four (COND2) days
      learning trial. Controls received drinking water with (SHAM) or without (UNT)
      LPS. Endotoxin tolerance was tested by determination of LPS-induced tumor
      necrosis factor (TNF)-alpha release. After the avoidance of the induced endotoxin
      tolerance the CS saccharin was re-presented in all experimental groups. A the end
      of the re-exposure period a complete endotoxin tolerance was noticed in the CONDl
      and COND2-group. In contrast, no effect of saccharin administration was observed
      in the SHAM- or UNT-group. Our data demonstrate for the first time the behavioral
      conditioning of endotoxin tolerance. Furthermore, these results contribute new
      aspects to the mechanisms underlying the development and modulation of endotoxin
      tolerance.

PMID- 12615047
TI  - Immunological consequences of the reversal of social status in C57BL/6J mice.
AB  - The present study has shown that the immune response can be influenced by the
      reversal of animal's social status. For this purpose testing of agonistic
      interactions under the sensory contact conditions was performed for pairs of
      either aggressive or submissive C57BL/6J male mice with preliminary experience of
      10 or 20 daily confrontations. Tests continued for 10 or 20 days, respectively.
      The reversal of aggressive behavior into submissive one in C57BL/6J mice resulted
      in immunosuppression only following 20 daily confrontations compared to the
      controls as well as to aggressive males which did not change their behavior and
      showed the increased immune response. Despite the fact that previous experience
      of defeat was associated with a reduced immune reaction, the occurrence of
      aggressive behavior in formerly submissive mice during 10 or 20 tests of daily
      confrontations produced immunostimulation. It is suggested that changes in the
      neurochemical pattern of the brain can be considered as an underlying basis for
      the linkage between the immune response and specific behavioral profile.

PMID- 12615048
TI  - Alteration of CCK-induced satiety in post-Nippostrongylus brasiliensis-infected
      rats.
AB  - In rats, the nematode Nippostrongylus brasiliensis induces an intestinal
      inflammation, but after the inflammation had resolved and the worm burden
      eliminated, morphological alterations of the intestinal wall, mainly consisting
      of mast cell hyperplasia and enteric nerve remodeling, persist for several weeks.
      Intestinal signals reaching the brain through the vagus nerve and involving
      neuropeptides such as CCK, play a role in the control of food intake. Our
      hypothesis was that neuroimmune alterations of the intestine may alter this
      control. This work was aimed to evaluate whether post-infection alterations of
      the intestinal wall may affect the satiety effects of CCK and further, the role
      of mast cells and their mediators, histamine and serotonin, in post-N.
      brasiliensis-infected rats. In basal conditions, food intake was not different in
      control and post-infected groups of rats. Post-infected rats were characterized
      by prolonged satiety effects of both CCK and histamine but not serotonin. The
      prolonged effect of CCK was reduced when mast cells were previously stabilized by
      ketotifen, which had no effect per se on food intake. No difference was observed
      in the increase of food intake induced by CCK-A and CCK-B receptor antagonists in
      both control and post-infected rats. Mast cell degranulation with compound 48/80
      induced severe anorectic effects that lasted for less than 24h in post-infected
      rats and as long as 6 days in controls. Thus, in our experimental conditions,
      i.e., within 30-50 days post-N. brasiliensis infection, we observed an
      enhancement of the anorectic effect of exogenous CCK involving mast cell
      degranulation and histamine.

PMID- 12615049
TI  - Effects of physical and psychological stressors on behavior, macrophage activity,
      and Ehrlich tumor growth.
AB  - The present study analyzed the effects of physical and psychological stressors on
      behavior, immune function, and serum corticosterone in mice. Adult mice were
      submitted once daily, for 6 days to one of the following conditions: escapable
      (ES) or inescapable (IS) footshocks (0.2 mA) signaled by a tone cue or to a
      psychological stressor (PS) generated through the use of a communication box; in
      this box, mice received no footshock but were exposed to responses delivered by
      IS mice. Results showed that IS and PS: (1). decreased locomotor activity
      observed in an open-field; (2). decreased number of entries into the open arms
      and decreased time spent in the exploration of the open arms of the plus-maze;
      (3). decreased macrophage spreading and phagocytosis; (4). increased macrophage
      H(2)O(2) release; and (5). increased growth of the ascitic form of Ehrlich tumor.
      Behavioral and/or immunological changes were not observed after ES; this absence
      of effects, however, might not be attributed solely to footshock controllability
      since mice of groups ES and IS differed with respect to the psychological setting
      used and the amount of shock they received. An increase of serum corticosterone
      concentrations was also observed in the stressed mice of all groups; this
      increment was higher in animals of group IS. These data provide evidence that
      inescapable footshock and psychological stressors alter, at the same time and in
      mice, stress levels, macrophage activity, and Ehrlich tumor growth. They also
      show that ES and PS induced similarly elevated serum corticosterone
      concentrations, but significantly differ in the immunological and behavioral
      outcomes they produced in mice. These findings suggest that another factor
      besides HPA axis activation might be responsible for behavioral and immunological
      consequences of IS and PS in mice. It is proposed that the final neural link
      between behavioral and immunological changes observed after physical and
      psychological stressors might involve catecholaminergic systems within the
      central nervous system and/or sympathetic autonomic nerve fibers and also opioid
      peptides.

PMID- 12615050
TI  - Adaptive immunity in mice lacking the beta(2)-adrenergic receptor.
AB  - The beta-2-adrenergic receptor (beta(2)AR) is expressed by most lymphocyte
      populations and binds the sympathetic neurotransmitter norepinephrine (NE).
      Stimulation of the beta(2)AR is reported to be the primary mechanism by which
      signals from the sympathetic nervous system influence both cell-mediated and
      humoral immunity. We report here that body/organ weights, lymphoid organ cell
      number/phenotype/histology, the contact sensitivity response, and the amount,
      avidity, and isotype of antibody resulting from a T cell-dependent antibody
      response in beta(2)AR deficient mice (beta(2)AR-/- mice) were all similar to
      measures made in beta(2)AR+/+ mice. Other members of the adrenergic receptor
      family did not appear to compensate for the absence in beta(2)AR expression. In
      contrast, beta(2)AR-/- B cells cultured in vitro were unable to respond to NE in
      a manner similar to beta(2)AR+/+ B cells. Thus, mice in which expression of the
      beta(2)AR gene is defective from early development to adulthood may no longer
      require that NE stimulate the beta(2)AR to maintain immune homeostasis, and this
      may be due to a non-adrenergic mechanism that provides compensation in vivo.

PMID- 12615051
TI  - O-GlcNAc: a regulatory post-translational modification.
AB  - Beta-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational
      modification of nuclear and cytosolic proteins. The enzymes for its addition and
      removal have recently been cloned and partially characterized. While only about
      80 mammalian proteins have been identified to date that carry this modification,
      it is clear that this represents just a small percentage of the modified
      proteins. O-GlcNAc has all the properties of a regulatory modification including
      being dynamic and inducible. The modification appears to modulate transcriptional
      and signal transduction events. There are also accruing data that O-GlcNAc plays
      a role in apoptosis and neurodegeneration. A working model is emerging that O
      GlcNAc serves as a metabolic sensor that attenuates a cell's response to
      extracellular stimuli based on the energy state of the cell. In this review, we
      will focus on the enzymes that add/remove O-GlcNAc, the functional impact of O
      GlcNAc modification, and the current working model for O-GlcNAc as a nutrient
      sensor.

PMID- 12615052
TI  - Predicted molecular structure of the mammalian cell entry protein Mce1A of
      Mycobacterium tuberculosis.
AB  - The proposed role of the mammalian cell entry protein 1A (Mce1A) of Mycobacterium
      tuberculosis is to facilitate invasion of host cells. The structure of Mce1A was
      modelled on the basis of the crystal structure of Colicin N of Escherichia coli
      by fold prediction and threading. Mce1A, as the model predicts, is an alpha/beta
      protein consisting of two major (alpha and beta) domains, connected by a long
      alpha helix. The model further revealed that the protein contains 12 helices, 9
      strands, and 1 turn. The final model of Mce1A was verified through the program
      VERIFY 3D and more than 90% of the residues were in the favourable region. A
      mouse monoclonal antibody, TB1-5 76C, is directed to an epitope within a 60-mer
      peptide that has been shown to promote uptake of bacteria in mammalian cells. We
      show here that the epitope could be narrowed down to a core of 4 amino acids,
      TPKD. Upstream flanking residues, KRR also contributed to binding. Mce2A does not
      promote uptake in mammalian cells and sequence comparison of Mce1A and Mce2A
      indicates that the epitope mediates uptake. The epitope was located at the
      surface of the Mce1A model at the distal beta strand-loop region in the beta
      domain. The localization of this epitope in the model confirms its potential role
      in promoting uptake of M. tuberculosis in host cells.

PMID- 12615053
TI  - Neuroleukin inhibition sensitises neuronal cells to caspase-dependent apoptosis.
AB  - Neuroleukin (NLK) is a multifunctional protein, involved in neuronal growth,
      glucose metabolism, cell motility, and differentiation. Expressed in the brain,
      it supports the growth of embryonic spinal, skeletal motor, and sensory neurons.
      We have previously demonstrated that NLK is up-regulated in the brain during
      Huntington's disease (HD), a neurodegenerative disorder caused by the expansion
      of CAG trinucleotide repeats. In order to study the biological role of NLK, we
      have generated an inducible rat pheochromocytoma PC12 cell line in which the
      expression of NLK is selectively down-regulated by antisense strategy. We show
      here that the block of NLK commits PC12 cells to caspase-dependent apoptosis.
      This priming effect elicited by NLK inhibition is independent from the
      differentiation state of the neuronal cells. These results suggest a general
      protective role of NLK in the control of cell death in neuronal cells.

PMID- 12615054
TI  - C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins.
AB  - MRP2, a member of the ABC protein superfamily, functions as an ATP-dependent
      export pump for anionic conjugates in the apical membranes of epithelial cells.
      It has been reported that the trafficking of MRP2 is modulated by PKC. Adjacent
      to the C-terminal PDZ binding motif, which may be involved in the targeting of
      MRP2, we found a potential PKC phosphorylation site (Ser(1542)). Therefore, we
      examined the interaction of MRP2 and its phosphorylation-mimicking mutants with
      different PDZ proteins (EBP50, E3KARP, PDZK1, IKEPP, beta2-syntrophin, and SAP
      97). The binding of these PDZ proteins to CFTR and ABCA1, other ABC proteins,
      possessing PDZ binding motif, was also studied. We observed a strong binding of
      apically localized PDZ proteins to both MRP2 and CFTR, whereas beta2-syntrophin
      exhibited binding only to ABCA1. The phosphorylation-mimicking MRP2 mutant and a
      phosphorylated C-terminal MRP2 peptide showed significantly increased binding to
      IKEPP, EBP50, and both individual PDZ domains of EBP50. Our results suggest that
      phosphorylation of the MRP2 PDZ binding motif has a profound effect on the PDZ
      binding of MRP2.

PMID- 12615055
TI  - Combined RAR alpha- and RXR-specific ligands overcome N-myc-associated retinoid
      resistance in neuroblastoma cells.
AB  - Retinoids induce human neuroblastoma cells to undergo growth inhibition and
      neuritic differentiation in vitro, through interactions with nuclear retinoid
      receptor proteins. In this study, we found that three different neuroblastoma
      cell lines exhibited wide variation in their responsiveness to the growth
      inhibitory effects of the retinoic acid receptor (RAR) agonist, all-trans
      retinoic acid (aRA). Resistance to the growth inhibitory effect of aRA correlated
      with the presence of N-myc gene amplification and not aRA-induced RAR beta
      levels. Over-expression of N-myc in a neuroblastoma cell line with no endogenous
      N-myc expression caused a marked reduction in retinoid-induced growth inhibition.
      Combination of receptor-specific retinoid agonists for RXR and RAR alpha
      significantly enhanced the sensitivity of N-myc-amplified neuroblastoma cells to
      the growth inhibitory effects of aRA. Our results indicate that combination
      receptor-specific retinoid therapy can overcome N-myc-mediated retinoid
      resistance and may be a more effective chemo-preventive strategy in the disease.

PMID- 12615056
TI  - Both heptad repeats of human respiratory syncytial virus fusion protein are
      potent inhibitors of viral fusion.
AB  - Heptad repeat regions (HR1 and HR2) are highly conserved peptides located in F(1)
      of paramyxovirus envelope proteins. They are important in the process of virus
      fusion and form six-helix bundle structure (trimer of HR1 and HR2 heterodimer)
      post-fusion, similar to those found in the fusion proteins of other enveloped
      viruses, such as retrovirus HIV. Both HR1 and HR2 show potent inhibition for
      virus fusion in some members of paramyxovirus. However, in other members, only
      HR2 gives strong inhibition whereas HR1 does not. Human respiratory syncytial
      virus (hRSV) is a member of paramyxovirus and its crystal structure of HR1 and
      HR2 six-helix bundle was solved lately. Although hRSV HR2 inhibition was
      reported, nevertheless the effect of HR1 on virus fusion is not known. In this
      study, hRSV HR1 and HR2 were expressed as fusion protein separately in
      Escherichia coli system and their complex assembly and virus fusion inhibition
      effect have been analysed. It shows that both HR1 and HR2 (in the fusion form
      with 50-amino-acid fusion partner) of hRSV F protein give strong inhibition on
      virus fusion (IC(50) values are 1.68 and 2.93 microM, respectively) and they form
      stable six-helix bundle in vitro with both in the fusion protein form.

PMID- 12615057
TI  - Exposure to the fern Onychium contiguum causes increase in lipid peroxidation and
      alters antioxidant status in urinary bladder.
AB  - The status of lipid peroxidation, glutathione, glutathione peroxidase,
      glutathione reductase, glutathione-S-transferase, superoxide dismutase, catalase,
      ascorbic acid, and alpha-tocopherol was studied in the urinary bladder of guinea
      pigs exposed to the carcinogenic fern Onychium contiguum. There was significant
      increase in the preformed lipid peroxides in the urinary bladders from fern
      exposed animals. The amount of lipid peroxides produced on incubation of urinary
      bladder homogenates with or without catalyst was significantly higher in the fern
      exposed animals. The concentrations of glutathione and alpha-tocopherol and the
      activities of glutathione reductase and catalase were elevated in the urinary
      bladders of the animals exposed to the fern. No effect was observed on the
      concentration of ascorbic acid and the activities of glutathione peroxidase,
      glutathione-S-transferase, and superoxide dismutase. It is summarized that the
      fern toxins increased oxidative stress in the urinary bladder and antioxidant
      status was altered. However, the altered antioxidant status did not provide
      protection from the toxin induced injury. Histopathology of the urinary bladder
      in the fern exposed animals revealed oedema, haemorrhages, and congestion. This
      is the first study to show increase in lipid peroxidation along with altered
      antioxidant status in the urinary bladder of fern exposed animals.

PMID- 12615058
TI  - Chitosan enhances platelet adhesion and aggregation.
AB  - In this study, chitosan (MW=50,000) was tested for its enhancing platelet
      activity in rabbit platelet suspensions and the possible mechanisms involved were
      further investigated. Our results showed that after initial (5 min) and long-term
      (30 min) contact of platelets with chitosan, the platelet adhesion to chitosan
      coated microtiter plates was dose-dependently increased compared to that of
      solvent control. Similarly, chitosan also dose-dependently increased the platelet
      aggregation and the intracellular free Ca(2+) rise of Fura-2-AM loaded platelets.
      Additionally, in the presence of FITC-labeled anti-CD41/CD61, chitosan
      significantly enhanced the expression of platelet glycoprotein IIb/IIIa complex
      assayed by a flow cytometer. It is concluded that chitosan is an effective
      inducer for platelet adhesion and aggregation and the mechanisms of action of
      chitosan may be associated, at least partly, with the increasing [Ca(2+)](i)
      mobilization and enhancing expression of GPIIb/IIIa complex on platelet membrane
      surfaces.

PMID- 12615059
TI  - Two forms of RNA polymerase II holoenzyme display different abundance during the
      cell cycle.
AB  - We analyzed the composition and abundance of two forms of RNA polymerase II (pol
      II) holoenzyme in synchronized HeLa cells. We did not detect significant changes
      in pol II holoenzyme composition, but we noticed differences in the abundance of
      the two complexes at different stages of the cell cycle. Summarized data from
      several independent experiments demonstrate that pol II holoenzyme, which is
      purified by GST-TFIIS affinity chromatography, is more abundant during G1/S and S
      phases. Another form of pol II holoenzyme, which is purified by anti-CDK7
      antibodies, shows relatively higher amounts in G2/M and early G1 phases.

PMID- 12615060
TI  - Inhibitory and enhancing effects of insertion of central polypurine tract
      sequence on gene expression with vectors derived from human immunodeficiency
      virus type 1.
AB  - Reportedly, in human immunodeficiency virus type 1 (HIV) vectors, insertion of
      central polypurine tract (cPPT) increased expression of transgenes for a short
      period. To test this for a stable condition, we constructed a series of vectors
      carrying a Neo(r) gene as a stable marker driven by a synthetic thymidine kinase
      (hTK) promoter. Transduction efficiency was increased in about 2-fold and
      decreased in about 8-fold by insertion of the reported 178bp and our 282bp cPPTs,
      respectively. PCR analyses revealed that insertion of 282bp cPPT, but not 178bp
      cPPT, impaired integration, although it did not deteriorate nuclear transport
      much. Furthermore, we found that insertion of 282bp cPPT between hTK promoter and
      an upstream LTR sequence reduced reporter gene activity in about 5-fold. This
      inhibitory effect of 282bp cPPT may partly account for the observed decrease in
      transduction efficiency. We suggest that actual effect of cPPT insertion should
      be examined in each HIV vector.

PMID- 12615061
TI  - Semiconductor quantum dot/albumin complex is a long-life and highly photostable
      endosome marker.
AB  - For the purpose of selecting the efficient dispersion condition of hydrophilic
      semiconductor quantum dots (QDs) in biological buffers, the dispersion of the QDs
      mixed with a serum albumin from 9 different species or an ovalbumin was compared
      by a fluorescence intensity analysis. The QDs mixed with sheep serum albumin
      (SSA) showed the highest fluorescence of all when the mixtures were dissolved in
      Dulbecco's MEM. QD/SSA complexes were accumulated in the endosome/lysosome of
      Vero cells and the fluorescence could be detected over a 5-day post-incubation
      period. The photostability of QD/SSA complexes associated with the endosomes was
      detectable, at least, 30 times as long as that of fluorescein-labeled dextran
      involved in endosomes. QD/SSA complex, therefore, can be used as a long-life and
      highly photostable endosome marker.

PMID- 12615063
TI  - Differential gene expression in primary and recurrent carotid stenosis.
AB  - Apoptosis of the cellular components of complex atherosclerotic plaque may lead
      to plaque instability and rupture. In this study, five primary plaques and one
      recurrent fibrointimal lesion obtained from patients undergoing carotid
      endarterectomy for symptomatic carotid stenosis > or = 70% were analyzed by
      immunohistochemistry and cDNA microarray to identify gene expression patterns
      that may determine plaque susceptibility or resistance to apoptosis.
      Immunohistochemistry showed expression of active caspase 3, an effector of
      apoptosis, in macrophages and lymphocytes surrounding the lipid core, in smooth
      muscle cells in the fibrous cap, and media of primary plaques as well as in
      occasional smooth muscle cells in the recurrent lesion. Among the genes
      demonstrating increased expression in primary plaques were IGFR2, DR4, DAPK1,
      Bak, and ERK 1 and 2 and those showing decreased expression included the TNF
      receptors 1 and 2, akt1, and IGFBP3. When comparing the recurrent lesion to the
      normal tissue, the expression of 13 genes was decreased by 3-fold, including
      IGFBP2 and IGFBP3, and none were increased by more than 1.5-fold. The analysis of
      gene expression patterns in primary and recurrent stenotic lesions provides a
      powerful approach to identify the signaling pathways that alter cellular
      apoptotic patterns in such lesions.

PMID- 12615062
TI  - The snake venom disintegrin salmosin induces apoptosis by disassembly of focal
      adhesions in bovine capillary endothelial cells.
AB  - Salmosin, a disintegrin purified from a Korean snake (Agkistrodon halys
      brevicaudus) venom, interacts with integrin alpha(v)beta(3) and inhibits the
      proliferation of bovine capillary endothelial (BCE) cells induced by basic
      fibroblast growth factor (bFGF). We investigated salmosin's mechanism of
      inhibition of BCE cell proliferation by examining changes in the cytoskeleton and
      activation of integrin-mediated signaling molecules. Salmosin disassembled
      cortical actins at focal adhesions and induced cells to be rounded and detached,
      but it did not alter microtubule structures in the early stage of cells being
      rounded. Immunolocalization of paxillin also demonstrated that focal adhesions
      were disassembled by salmosin. In salmosin-treated BCE cells, focal adhesion
      kinase (FAK) was dephosphorylated and expression of paxillin and p130(CAS) was
      decreased, but PI3 kinase, ILK, and beta-catenin were not expressed in decreased
      amounts or modified, suggesting that salmosin inactivated FAK-dependent integrin
      signaling pathways. While BCE cells proliferated normally on plates coated with
      salmosin, cells treated with salmosin eventually underwent apoptosis. These
      observations strongly suggest that salmosin disorganizes focal contacts to detach
      cells by competing with the extracellular matrix (ECM) for direct binding to
      integrin alpha(v)beta(3) on the cell surface, eventually leading to apoptosis.

PMID- 12615064
TI  - Effect of nitric oxide on the transport and release of oxygen in fetal blood.
AB  - It is well known that nitric oxide (NO), the most important vasodilator agent,
      plays an important role in lowering vascular resistance in the human umbilical
      placental circulation and that its deficiency is related to the pathogenesis of
      pre-eclamptic disorder. Besides it has recently been demonstrated that human
      hemoglobin (HbA) is able to transport nitric oxide, as S-nitrosohemoglobin (SNO
      Hb), from the arterial to the venous blood. In the present study we examine the
      functional properties of the adult and fetal nitrosated hemoglobins to see if the
      double transport of oxygen and NO may influence the fetal oxygenation and the
      relation between maternal and fetal blood. Our results show that S-nitrosation
      significantly increases the oxygen affinity of the adult Hb (HbA) with respect to
      native protein (no-nitrosated) while the functional properties of HbF are less
      influenced. The oxygen affinity modification, found for SNO-HbA, was ascribed to
      the nitrosation of cysteine beta 93: really, the same residue is also present in
      the gamma chains of fetal hemoglobin, while the increase of affinity is less
      evidenced; hence, it is probable that the 39 aminoacidic substitutions between
      beta and gamma chains allay the effects of S-nitrosation. As regards the
      physiological modulators (protons, chloride ions, 2,3-diphosphoglyceric acid, and
      temperature), they influence the oxygen affinity of the two hemoglobins S
      nitrosated, in equal mode with respect to the native forms determining the same
      variation on the oxygen affinity. Hence, our results evidence the fact that the
      NO release by SNO-HbA "in vivo" would be limited to regions of extremely low
      oxygen tension (such as hypoxic regions), while in fetus, SNO-HbF would unload
      nitric oxide and oxygen at pressure values close to normal.

PMID- 12615065
TI  - Somatostatin suppresses ghrelin secretion from the rat stomach.
AB  - Ghrelin is an acylated peptide that stimulates food intake and the secretion of
      growth hormone. While ghrelin is predominantly synthesized in a subset of
      endocrine cells in the oxyntic gland of the human and rat stomach, the mechanism
      regulating ghrelin secretion remains unknown. Somatostatin, a peptide produced in
      the gastric oxyntic mucosa, is known to suppress secretion of several
      gastrointestinal peptides in a paracrine fashion. By double immunohistochemistry,
      we demonstrated that somatostatin-immunoreactive cells contact ghrelin
      immunoreactive cells. A single intravenous injection of somatostatin reduced the
      systemic plasma concentration of ghrelin in rats. Continuous infusion of
      somatostatin into the gastric artery of the vascularly perfused rat stomach
      suppressed ghrelin secretion in both dose- and time-dependent manner. These
      findings indicate that ghrelin secretion from the stomach is regulated by gastric
      somatostatin.

PMID- 12615066
TI  - Characterization of zetin 1/rBSPRY, a novel binding partner of 14-3-3 proteins.
AB  - 14-3-3 proteins are ubiquitously expressed proteins which serve as central
      adaptors in different signal transduction cascades. In this study, yeast two
      hybrid screening of a rat brain cDNA library identified a novel gene product
      termed zetin 1/rBSPRY that interacts with 14-3-3 zeta. The zetin 1/rBSPRY gene is
      ubiquitously expressed in a variety of rat tissues, with highest expression being
      found in testis. In adult brain, high levels of zetin 1/rBSPRY mRNA were observed
      in the hippocampus, cerebral cortex, and piriform cortex. Biochemical studies
      confirmed zetin 1/rBSPRY to interact with 14-3-3 zeta. Transient co-transfection
      in COS 7 cells caused a partial redistribution of zetin 1/rBSPRY into 14-3-3 zeta
      enriched submembranous foci at leading edges. Our results suggest a role for
      zetin 1/rBSPRY-14-3-3 interactions at specialized submembrane domains.

PMID- 12615067
TI  - The yeast model for Batten disease: a role for Btn2p in the trafficking of the
      Golgi-associated vesicular targeting protein, Yif1p.
AB  - Btn2p is a novel coiled coil cytosolic protein in Saccharomyces cerevisiae. We
      report that Btn2p interacts with Yif1p, a component of a protein complex at the
      Golgi that functions in ER to Golgi transport. Deletion of Btn2p, btn2-delta,
      results in mis-localiztion of Yif1p to the vacuole. Therefore, Btn2p may have an
      apparent role in intracellular trafficking of proteins. Btn2p was originally
      identified as being up-regulated in a btn1-delta strain, which exhibits
      dysregulation of vacuolar pH, and this up-regulation of Btn2p was presumed to
      contribute to maintaining a stable vacuolar pH [Pearce et al. Nat. Genet. 22
      (1999) 55]. We propose that up-regulation of Btn2p in btn1-delta is an indicator
      of altered trafficking within the cell, and as btn1-delta serves as a model for
      the lysosomal storage disorder Batten disease, that altered intracellular
      trafficking may contribute to some of the cellular pathological hallmarks of this
      disease.

PMID- 12615068
TI  - Dykellic acid inhibits drug-induced caspase-3-like protease activation.
AB  - Dykellic acid is a novel microbial metabolite isolated from the broth of
      Westerdykella multispora F50733. Investigations on the molecular function of
      dykellic acid revealed that this compound partially inhibits calcium influx,
      resulting in a decrease in Ca(2+)-dependent endonuclease activation and DNA
      fragmentation induced by camptothecin. In our experiments, active caspase-3-like
      protease cleavage of procaspase-3, PARP, and cytosolic cytochrome c was inhibited
      by dykellic acid in a concentration-dependent manner when the apoptosis was
      induced by camptothecin as well as doxorubicin. We confirmed that dykellic acid
      did not bind to camptothecin using surface plasmon resonance analysis. These
      results suggest that dykellic acid inhibits drug-induced apoptosis via a caspase
      3-like protease-suppressing mechanism. Our data provide important information on
      the mechanism of action of dykellic acid and indicate that this compound may be
      employed in the treatment of specific caspase-3-like protease-mediated diseases.

PMID- 12615069
TI  - Nuclear localization of Galectin-3 in transformed thyroid cells: a role in
      transcriptional regulation.
AB  - The differential proteomic approach (2D gel analysis coupled to MALDI-MS
      analysis) of nuclear proteins can provide an extremely useful tool to understand
      control of cell proliferation and differentiation. In order to identify possible
      markers of dedifferentiation between normal and cancerous thyroid cells, we used
      a differential proteomics approach by comparing nuclear extracts from the normal
      rat thyroid cell line FRTL-5 and the completely undifferentiated Ki-mol cell
      line, obtained by transformation with the Ki-ras oncogene. Galectin-3 (Gal-3) was
      identified as highly expressed, in the nuclear compartment, only in the
      transformed cell line. By using different human cancer cell lines, we showed that
      Gal-3 is maximally expressed in nuclei of papillary cancer cells. We focused on
      the functional relationship existing between Gal-3 and the thyroid-specific
      transcription factor TTF-1, whose expression is maintained in papillary cancer
      where it can contribute to the proliferating status. By using gel-retardation and
      transient tranfection assays, we demonstrate that Gal-3 upregulates the TTF-1
      transcriptional activity. GST-pulldown experiments demonstrate the occurrence of
      interaction between Gal-3 and TTF-1 homeodomain. Since several lines of evidence
      suggest a role for Gal-3 in controlling proliferation and tumor progression in
      thyroid cancer, the stimulatory activity played by Gal-3 over TTF-1 would account
      for a possible molecular mechanism through which the galectin controls
      proliferation in thyroid cells.

PMID- 12615070
TI  - Expression and characterization of the olfactomedin domain of human myocilin.
AB  - The olfactomedin-domain has been first identified in olfactomedin, an
      extracellular matrix protein of the olfactory neuroepithelium. Members of this
      extracellular domain-family have since been shown to be present in several
      metazoan proteins, such as latrophilins, myocilins, and noelins, but their
      biological function is unknown. The olfactomedin-domain of myocilin is of
      considerable interest, since mutations affecting this domain are associated with
      primary open angle glaucoma. In order to define structural features of this
      domain-type we have expressed the olfactomedin-domain of human myocilin in Pichia
      pastoris. The olfactomedin-domain contains a single disulphide-bond connecting
      Cys-245 and Cys-433 residues; secondary structure predictions and circular
      dichroism studies indicate that it consists primarily of beta-strands. It is
      noteworthy that the majority of mutations associated with severe forms of
      glaucoma affect residues that reside in conserved secondary structural elements
      of the olfactomedin-domain or are otherwise critical for the integrity of this
      protein-fold.

PMID- 12615071
TI  - Fibroblast growth factor 10 is required for proper development of the mouse
      whiskers.
AB  - Fibroblast Growth Factor (FGF) signaling is known to play an important role
      during cutaneous development. To elucidate the role of FGF10 during whisker
      formation, we examined the expression of Fgf10 in normal developing whiskers and
      phenotypes of Fgf10-deficient whiskers. Fgf10 is first expressed in the maxillary
      process, lateral and medial nasal processes, then in the mesenchymal cells
      underneath the future whisker placodes, and in the surrounding mesenchyme of
      developing whiskers. Fgf10-null whiskers exhibit a significant decrease in number
      and their structure is disorganized as revealed by scanning electron microscopy.
      Hair follicle marker genes such as Sonic hedgehog, Patched, and Patched 2 are
      aberrantly expressed in the mutant whiskers. Thus, FGF10 is required for proper
      whisker development mediated by SHH signaling in the mouse.

PMID- 12615072
TI  - Crystal structure of a NO-forming nitrite reductase mutant: an analog of a
      transition state in enzymatic reaction.
AB  - I257E was obtained by site directed mutagenesis of nitrite reductase from
      Achromobacter cycloclastes. The mutant has no enzyme activity. Its crystal
      structure determined at 1.65A resolution shows that the side-chain carboxyl group
      of the mutated residue, Glu257, coordinates with the type 2 copper in the mutant
      and blocks the contact between the type 2 copper and its solvent channel,
      indicating that the accessibility of the type 2 copper is essential for
      maintaining the activity of nitrite reductase. The carboxylate is an analog of
      the substrate, nitrite, but the distances between the type 2 copper and the two
      oxygen atoms of the side-chain carboxyl group are reversed in comparison to the
      binding of nitrite to the native enzyme. In the mutant, both the type 2 copper
      and the N epsilon atom on the imidazole ring of its coordinated residue His135
      move in the substrate binding direction relative to the native enzyme. In
      addition, an EPR study showed that the type 2 copper in the mutant is in a
      reduced state. We propose that mutant I257E is in a state corresponding to a
      transition state in the enzymatic reaction.

PMID- 12615074
TI  - The embryonic Octamer factor 3/4 displays distinct DNA binding specificity from
      those of other Octamer factors.
AB  - The Oct-3/4 is a transcriptional factor expressed rather specifically in inner
      cell mass and embryonic ectoderm during early embryogenesis in mammals. During
      the course of characterizing the regulatory element of embryonic transcriptional
      coactivator UTF1 which is one of the downstream genes of Oct-3/4, we have found
      that Oct-3/4, but not other Octamer factors, shows unique DNA binding
      specificity, being able to bind to variant Octamer sequence (5'-ACTAGCAT-3')
      present in UTF1 regulatory element. Here, we have determined the DNA binding
      property of Oct-3/4 in a systematic manner using all possible one point mutants
      of Octamer sequence as well as completely random sequences. These analyses led to
      the identification of nine distinct nucleotide sequences including the one (5'
      ACTAGCAT-3') present in UTF1 regulatory element which serves rather as specific
      binding site for the Oct-3/4. Moreover, we show that, at least, one of the newly
      identified sequences, 5'-ATCAGCAT-3', exhibits a transcriptional stimulating
      activity equivalent to that of the variant Octamer sequence present in the UTF1
      regulatory region in embryonic stem cells in a pluripotent-state specific manner.

PMID- 12615073
TI  - Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean
      fever gene product.
AB  - Cryopyrin, a member of the Nod protein family mutated in familial cold urticaria
      and Muckle-Wells syndrome, has been recently implicated in inflammation. However,
      the mechanism of activation and regulation of the cryopyrin signaling pathway
      remains poorly understood. We report here that co-expression of cryopyrin with
      its binding partner, ASC, induced both apoptosis and NF-kappaB activation. This
      signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin
      activates downstream targets as reported for other Nod family members. Notably,
      pyrin, the product of the familial Mediterranean fever gene, inhibited cryopyrin
      mediated apoptosis and NF-kappaB activation by disrupting the cryopyrin-ASC
      interaction. These results provide evidence for a cryopyrin signaling pathway
      activated through the induced proximity of ASC, which is negatively regulated by
      pyrin.

PMID- 12615075
TI  - Isolation of chromosaponin I-specific antibody by affinity chromatography.
AB  - Chromosaponin I (CSI), a gamma-pyronyl-triterpenoid saponin isolated from pea and
      other leguminous plants, modulates several developmental processes of plant roots
      and activates the sugar taste receptor cells in blowflies. CSI is a unique
      saponin for its reducing power and biological activities in both plants and
      insects. In the present paper, we described the method of preparation for CSI
      specific antibody using CSI-affinity and soyasaponin I-affinity columns. The
      antibody's-specific binding activity to CSI was confirmed by a bioassay using
      Arabidopsis roots and a ligand-molecule interaction analysis using BIAcore 3000.
      Because of the lability of CSI, the CSI-affinity column was made only by a
      moderate reaction condition in which CSI was coupled to EAH Sepharose 4B in the
      presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC).
      The special control of the reaction temperature was essential to complete the
      coupling reaction; the reaction with EDC at 0 degrees C followed by a gradual
      increase in temperature.

PMID- 12615076
TI  - A phase II detoxification enzyme inducer from lemongrass: identification of
      citral and involvement of electrophilic reaction in the enzyme induction.
AB  - We have developed a simple system for the sensitive detection and measurement of
      glutathione S-transferase (GST) activity that detoxifies polycyclic aromatic
      hydrocarbons using the cultured rat normal liver epithelial cell line, RL34
      cells. Citral (3,7-dimethyl-2,6-octadienal) was isolated from the methanol
      extract of lemongrass (Cymbopogon citratus) and identified as a novel inducer of
      GST. Citral, a mixture of the two stereoisomers geranial and neral, dose- and
      time-dependently induced the total and pi-class-specific activities of GST. The
      structure-activity relationship study revealed that geranial, an E-isomer, was
      mainly responsible for the inducing activity of citral mixture and the aldehyde
      group conjugated with a trans-double bond is an essential structural factor. The
      data were consistent with the in vitro observation that both glutathione (GSH)
      and protein thiol quickly and specifically reacted with the active isomer
      geranial, but not neral. Pretreatment of the cells with diethyl maleate
      significantly enhanced not only the basal activity but also the citral-stimulated
      activity of GST, while pretreatment with N-acetyl-cysteine inhibited it.
      Moreover, the treatment of RL 34 cells with geranial for 30 min significantly
      attenuated the intracellular GSH level, while application for 18 h enhanced it.
      These results strongly suggested that the electrophilic property characterized by
      the reactivity with intracellular nucleophiles including protein thiol or
      glutathione (GSH) plays an important role in the induction of GST. The present
      study also implied the antioxidant role of GST induction by citral in mouse skin,
      providing a new insight into skin cancer prevention.

PMID- 12615077
TI  - Concurrent transcriptional activation of ppa and ppx genes by phosphate
      deprivation in the cyanobacterium Synechocystis sp. strain PCC 6803.
AB  - The cyanobacterium Synechocystis sp. strain PCC 6803 possesses two genes, named
      ppa and ppx, which, respectively, encode proteins involved in the hydrolysis of
      inorganic phosphate polymers, namely, inorganic pyrophosphatase (PPA, EC
      3.6.1.1), an essential enzyme that hydrolyzes pyrophosphate, and
      exopolyphosphatase (PPX, EC 3.6.1.11), a processive enzyme that releases the
      terminal orthophosphate group from linear polyphosphates. Northern blots showed
      that both single-copy genes are induced by long-term inorganic phosphate (P(i))
      starvation, transcript levels being markedly increased (ca. 10- and 20-fold,
      respectively) relative to P(i)-sufficient cells. Concurrent increases of both PPA
      and PPX specific activities and protein levels by P(i) deprivation were also
      observed. On the other hand, a knockout mutant was obtained by insertional
      mutagenesis of ppx, but it could not be achieved with ppa, thus indicating that
      PPA function is essential for cell viability. Moreover, whereas the ppx mutant
      exhibited under P(i)-sufficient conditions lower growth rates than the wild-type
      and was certainly devoid of PPX activity, it showed a severe reduction of the PPA
      levels. These results are the first evidence on the involvement of both PPA and
      PPX in a possible intracellular P(i)-recycling enzymatic process activated under
      P(i)-starvation.

PMID- 12615078
TI  - Oxidant stress enhances Lyso-PAF-AcT activity by modifying phospholipase D and
      phosphatidic acid in aortic endothelial cells.
AB  - Oxidant stress, as a consequence of selenium (Se) deficiency, alters production
      of vasoactive compounds including platelet-activating factor (PAF). Recent
      studies report that enhanced PAF production during Se deficiency is a consequence
      of increased lyso-PAF:acetyl-coenzyme A acetyltransferase (Lyso-PAF-AcT)
      activity. To elucidate the mechanism behind increased Lyso-PAF-AcT activity
      during oxidant stress, phospholipase D (PLD) activity and phosphatidic acid (PA)
      production were examined. Increased PLD activity and PA production were exhibited
      in bovine aortic endothelial cells using a Se-deficient model of oxidant stress.
      The direct effects of PLD and PA on Lyso-PAF-AcT activity were assessed using
      selective inhibitors and repletion experiments. Following the inhibition of PLD
      and addition of exogenous PA, Lyso-PAF-AcT activity significantly decreased and
      increased, respectively. Therefore, Se deficiency enhances Lyso-PAF-AcT activity
      in part by modifying PLD and PA. This suggests a novel link between Se status and
      PAF production, providing potential upstream therapeutic targets for PAF
      regulation under conditions of oxidant stress.

PMID- 12615079
TI  - Phospholipase D prevents apoptosis in v-Src-transformed rat fibroblasts and MDA
      MB-231 breast cancer cells.
AB  - Phospholipase D (PLD) activity is elevated in response to mitogenic and oncogenic
      signals. PLD also cooperates with overexpressed tyrosine kinases to transform rat
      fibroblasts. 3Y1 rat fibroblasts overexpressing the tyrosine kinase c-Src undergo
      apoptosis in response to serum withdrawal. We report here that elevated
      expression of either PLD1 or PLD2 in these cells prevents apoptosis induced by
      serum withdrawal. 3Y1 cells transformed by the activated tyrosine kinase v-Src
      have elevated PLD activity and are resistant to apoptosis induced by serum
      withdrawal. However, if PLD activity is blocked, the v-Src-transformed cells
      underwent apoptosis. MDA-MB-231 cells are a human breast cancer cell line with
      substantially elevated levels of PLD activity. Inhibiting PLD activity in these
      cells similarly rendered them sensitive to the apoptotic insult of serum
      withdrawal. These data indicate that elevated PLD activity generates a survival
      signal(s) allowing cells to overcome default apoptosis programs.

PMID- 12615080
TI  - Production of recombinant xenotransplantation antigen in Escherichia coli.
AB  - The synthesis of sufficient amounts of oligosaccharides is the bottleneck for the
      study of their biological function and their possible use as drug. As an
      alternative for chemical synthesis, we propose to use Escherichia coli as a
      "living factory." We have addressed the production of the Galp alpha(1-3)Galp
      beta(1-4)GlcNAc epitope, the major porcine antigen responsible for xenograft
      rejection. An E. coli strain was generated which simultaneously expresses NodC
      (to provide the chitin-pentaose acceptor), beta(1-4) galactosyltransferase LgtB,
      and bovine alpha(1-3) galactosyltransferase GstA. This strain produced 0.68 g/L
      of the heptasaccharide Galp alpha(1-3)Galp beta(1-4)(GlcNAc)(5), which harbours
      the xenoantigen at its non-reducing end, establishing the feasibility of this
      approach.

PMID- 12615081
TI  - Antioxidant activity of melatonin in Chinese hamster ovarian cells: changes in
      cellular proliferation and differentiation.
AB  - Melatonin is an endogenously generated molecule with free radical scavenging and
      antioxidant properties. Here, we studied the antiproliferative role of melatonin
      and other antioxidants on transformed Chinese hamster ovarian cells. Melatonin
      reduces cell proliferation in a dose- and time-dependent manner. Natural
      antioxidants which appear in edible plants including resveratrol and vitamin E
      mimicked the effect of melatonin. Flow cytometer analysis revealed that melatonin
      treatment reduces the number of cells in S-phase and increases cells in both
      G0/G1 and G2/M gaps. In addition, melatonin, as well as trolox, caused a clear
      morphological change by inducing the cells to become spindle shaped and
      fibroblast-like. Its effect is a reversible phenomenon that disappeared when
      melatonin was withdrawn from the culture medium. GSH levels are increased after
      melatonin treatment but pharmacologically blockade of GSH synthesis did not
      abolish melatonin's antiproliferative effect. Reduction of cell proliferation and
      the apparent induction of cell differentiation overlapped with melatonin's
      ability to change the intracellular redox state of CHO cells. We conclude that
      the cellular redox state may be involved in cellular transformation caused by
      antioxidants such as melatonin and trolox.

PMID- 12615082
TI  - PC12 cell activation by epidermal growth factor receptor: role of
      autophosphorylation sites.
AB  - PC12 cells have been used as a model system for neuronal differentiation due to
      their ability to alter their phenotype to a sympathetic neuron-like cell in
      response to nerve growth factor or fibroblast growth factor. Under some
      conditions, epidermal growth factor (EGF) can also induce PC12 cells to
      differentiate. To study signaling from the EGF receptor without the confounding
      effects of endogenous EGF receptors we generated a chimeric receptor comprised of
      the ectodomain of platelet-derived growth factor (PDGF) receptor in-frame with
      the transmembrane and cytoplasmic domains of EGF receptor, termed PER. Expression
      of PER in PC12 cells confers the ability of PDGF to induce differentiation
      whereas PDGF has no effect on untransfected PC12 cells. This response is kinase
      activity-dependent since a kinase-deficient mutant (K721M) fails to induce
      differentiation in response to PDGF. Mutation of five tyrosine residues that are
      autophosphorylated in response to EGF either individually or in combination had
      minimal effects on the ability of these receptors to induce morphological PC12
      cell differentiation. The PER mutant with all five autophosphorylation sites
      mutated to phenylalanine (5YF) was equivalently capable of interacting with
      several important signaling molecules, including Shc, Grb2, Gab1, phospholipase
      Cgamma, and Cbl. Furthermore, both the phosphatidylinositol 3-kinase (PI3K)/Akt
      and Ras/Erk pathways were activated in a sustained manner when PER or 5YF
      expressing cells were stimulated with PDGF. Our results show that the five
      autophosphorylation sites in the extra-kinase C-terminal domain of EGFR are not
      required for the ability of EGFR to induce morphological differentiation of PC12
      cells.

PMID- 12615083
TI  - In vitro effects of L-arginine and guanidino compounds on NTPDase1 and 5'
      nucleotidase activities from rat brain synaptosomes.
AB  - Tissue accumulation of arginine (Arg), N-acetylarginine (NA), argininic acid (AA)
      and homoarginine (HA) occurs in hyperargininemia, an inborn error of the urea
      cycle. In the present study, we investigated the in vitro effects of Arg, NA, AA
      and HA on NTPDase1 and 5'-nucleotidase activities from synaptosomal cerebral
      cortex of rats. The results showed that Arg enhances NTPDase1 activity at the
      high concentrations tested (1.5 and 3.0mM) for both the ATP and ADP nucleotides.
      Activation was also observed with other guanidino compounds tested: NA, AA and HA
      activated ATP and ADP hydrolysis in all experiments at the concentration of 25
      microM. Besides this, NA and AA activated ATP hydrolysis at a lower concentration
      (1 microM). In another set of experiments, we verified the effect of Arg on
      purified apyrase at pH 8.0 and 6.5 and observed an increase in the enzyme
      activity at all Arg concentrations tested (0.01-3.0mM). In contrast, Arg and the
      other guanidino compounds tested did not alter 5'-nucleotidase activity. These
      results suggest that changes in nucleotide hydrolysis may be involved in the
      brain dysfunction caused by hyperargininemia amongst other potential
      pathophysiological mechanisms involved in this condition.

PMID- 12615084
TI  - Localization of focal adhesion kinase isoforms in cells of the central nervous
      system.
AB  - Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase which in non
      neuronal cells is localized to focal adhesions, where it participates to adhesion
      dependent intracellular signalling. FAK is highly expressed in the central
      nervous system both during development and in the adult. FAK(+), a splice isoform
      of FAK selectively enriched in neurons, contains a three-amino acid insertion in
      the carboxy-terminal sequence responsible for the localization of FAK to focal
      adhesions. Enhanced green fluorescent protein-tagged constructs were used to
      study the targeting of FAK and FAK(+) in neuronal and non-neuronal cells of the
      central nervous system. In transfected non-neuronal cells, both fusion proteins
      colocalized with vinculin in focal contacts. When expressed in hippocampal
      neurons in culture, both chimeras were locally concentrated in the growth cone,
      where they overlapped with F-actin enrichments but not with vinculin. In the
      growth cone of living neurons, the FAK(+) chimera showed a dynamic relocalization
      to membrane ruffles and to the tips of the membrane protrusions induced by
      cytochalasin D treatment, indicating a dependence of FAK distribution on F-actin
      organization. Since virtually identical patterns of distribution were found for
      FAK and FAK(+) chimeras, it follows that the additional insertion in FAK(+) is
      not responsible for the localization of the kinase. Finally, we showed that the
      carboxy-terminal domain of both FAK and FAK(+) is sufficient to mediate the
      localization of the proteins to focal adhesions in non-neuronal cells and to
      maintain their correct intracellular targeting in neurons.

PMID- 12615085
TI  - Age-related differences in NMDA/metabotropic glutamate receptor binding in rat
      substantia nigra.
AB  - Both N-methyl-D-aspartate (NMDA) and quisqualate/AMPA-insensitive metabotropic
      glutamate (mGlu) receptors mediate glutamate neurotransmission in substantia
      nigra (SN). In this work, NMDA and mGlu receptor sites in substantia nigra pars
      compacta (SNC) and pars reticulata were autoradiographically mapped in rat brains
      using specific binding of (+)3H-MK801 or 3H-glutamate, with saturating
      concentrations of NMDA, AMPA and quisqualate. In brains of both adult and
      postnatal day 15 (PN15) male rats, prepared at subjective mid-day of a 12h
      light/12h dark (12h L/12h D) cycle, specific binding at NMDA and mGlu sites in
      substantia nigra was pronounced when compared with control binding. The (+)3H
      MK801 binding in adults was spatially heterogeneous. Overall binding density in
      pars compacta was higher relative to binding density in pars reticulata with a
      mean percent change (Deltaxmacr;%) of 32%. Within the pars reticulata but not
      pars compacta, there were rostro-caudal differences with considerably denser
      binding in the posterior compared with the anterior pars reticulata
      (Deltaxmacr;%=108%). PN15 rats showed a less pronounced heterogeneity in pars
      compacta versus pars reticulata binding, (Deltaxmacr;%=27%), and less rostro
      caudal differentiation in (+)3H-MK801 binding density throughout pars reticulata
      (Deltaxmacr;%=46%). 3H-glutamate binding in both adult and PN15 rats was less
      dense overall than (+)3H-MK801 binding. In adults, there was no difference in
      binding density between pars compacta and pars reticulata (Deltaxmacr;%=0.4%),
      but there were marked heterogeneities when binding was compared between anterior
      versus posterior pars compacta (Deltaxmacr;%=29%), and anterior versus posterior
      pars reticulata (Deltaxmacr;%=25%). This rostro-caudal heterogeneity in 3H
      glutamate binding density was also present in PN15 pars compacta
      (Deltaxmacr;%=45%) but not in pars reticulata. Our findings mirror similar
      anterior/posterior heterogeneities in the GABAergic system in adult and PN15 male
      rats and may reflect a developmental change in both the structure and
      anticonvulsant/proconvulsant properties of substantia nigra pars reticulata (SNR)
      with age.

PMID- 12615086
TI  - Proline induces oxidative stress in cerebral cortex of rats.
AB  - In the present study we investigated the in vivo and in vitro effects of proline
      on some parameters of oxidative stress, such as chemiluminescence, total radical
      trapping antioxidant potential (TRAP) and the activity of the antioxidant enzymes
      catalase, glutathione peroxidase and superoxide dismutase in rat cerebral cortex.
      Ten-day-old rats received one subcutaneous injection of proline (12.8 micromol/g
      body weight), while control rats received saline in the same volumes. The animals
      were killed 1h after injection, the cerebral cortex was isolated and the assays
      immediately carried out. For the in vitro studies, homogenates from cerebral
      cortex of 10-day-old untreated rats were incubated for 1h at 37 degrees C with
      various concentrations of proline (3.0 microM-1.0mM). Results showed that proline
      treated rats presented a decrease of TRAP (30%) and an increase of
      chemiluminescence (78%). In contrast, the activities of catalase, glutathione
      peroxidase and superoxide dismutase were not modified by proline acute treatment.
      Furthermore, the presence of proline in the medium increased chemiluminescence,
      decreased TRAP and the activity of superoxide dismutase at proline concentrations
      similar to those observed in tissues of hyperprolinemic patients (0.5-1.0mM).
      However, catalase and glutathione peroxidase activities were not affected by the
      presence of proline in the medium. The results indicate that proline induces
      oxidative stress in the brain, which may be related, at least in part, to the
      neurological dysfunction observed in hyperprolinemia.

PMID- 12615087
TI  - Hyperphenylalaninemia reduces creatine kinase activity in the cerebral cortex of
      rats.
AB  - Phenylketonuria (PKU) is a metabolic disorder accumulating phenylalanine (Phe)
      and its metabolites in plasma and tissues of the patients. Considering that
      phenylalanine is the main neurotoxic metabolite, and brain energy homeostasis
      seems to be affected in phenylketonuria, our main objective was to investigate
      the effect of acute and chronic hyperphenylalaninemia (HPA) on creatine kinase
      (CK) activity in brain cortex of Wistar rats. Hyperphenylalaninemia was induced
      by subcutaneous administration of 5.2 micromol phenylalanine + 2.4 micromol alpha
      methylphenylalanine (phenylalanine hydroxylase (PAH) inhibitor)/g of body weight.
      We also investigated the in vitro effect of phenylalanine and/or alpha
      methylphenylalanine on creatine kinase activity in the brain cortex of non
      treated rats. The results showed that phenylalanine significantly inhibited
      creatine kinase activity in vitro and reduced the enzyme activity in vivo.
      Considering the importance of creatine kinase for the maintenance of energy
      homeostasis in brain, if this enzyme inhibition also occurs in phenylketonuric
      patients, it is possible that creatine kinase inhibition may be one of the
      mechanisms by which phenylalanine is neurotoxic in phenylketonuria.

PMID- 12615088
TI  - Putting together evidence on declining trends in sexual abuse: a complex puzzle.

PMID- 12615089
TI  - Neighborhood and community connectedness in child maltreatment research.

PMID- 12615090
TI  - Is child sexual abuse declining? Evidence from a population-based survey of men
      and women in Australia.
AB  - OBJECTIVE: Substantiated cases of child sexual abuse (CSA) in the United States
      have declined significantly over the past decade. This may, or may not, reflect
      change in the underlying rate in the general population. This study examines age
      cohort differences in the prevalence of self-reported CSA experiences of men and
      women aged 18-59 years in a community-based sample from a comparable western
      nation. METHOD: In April 2000, we completed a cross-sectional, telephone-based
      survey of a randomly selected national sample of men and women in Australia.
      Volunteers (876 males, 908 females) answered a range of questions about health
      status and sexuality, including unwanted sexual experiences before the age of 16
      years. Of selected adults with publicly-listed telephone numbers, 61% agreed to
      participate. There were few differences between the volunteers and the Australian
      population on demographic variables and health indicators. RESULTS: Non
      penetrative CSA was twice as common among women (33.6%) than men (15.9%).
      Approximately 12% of women and 4% of men reported unwanted penetrative
      experiences. CSA was reported significantly less often by younger males, with a
      linear decline from the oldest to youngest men. Among all females who had
      intercourse before age 16, older women were much more likely than younger women
      to say they were an unwilling partner on the first occasion. If first intercourse
      occurred at age 16 or later, there were no age-cohort differences in risk of
      first-time abuse. Self-reported "openness" and "comfort" during the telephone
      interviews was not systematically related to prevalence of CSA. CONCLUSION: These
      population-based findings provide evidence of a decline in the underlying rate of
      CSA in Australia. Although every measure of CSA inevitably is flawed to some
      extent, these trends in self-report complement official statistics that show
      substantial decline in recent years.

PMID- 12615091
TI  - Social isolation from communities and child maltreatment: a cross-cultural
      comparison.
AB  - OBJECTIVE: The aim of this study is to determine: (1) the differences between
      Spanish and Colombian cultures in relation to community social support variables,
      and (2) the relationships between community social support variables and child
      maltreatment in both cultures. METHOD: The study was based on 670 nonabusive
      families and 166 abusive families. The parents were asked to complete the
      Community Social Support Questionnaire. This instrument measures community social
      support in terms of Community Integration and Satisfaction, membership in
      voluntary organizations and community participation, and use of Community
      Resources of Social Support. RESULTS: Differences between both cultures were
      found in the pattern of community social support for the nonabusive groups.
      However, the relationships between community social support and child
      maltreatment were similar cross-culturally. Our results indicate that in both
      cultures abusive parents show lower levels of community integration,
      participation in community social activities and use of formal and informal
      organizations than the parents that provide adequate care. CONCLUSIONS: The
      results largely support the literature that has repeatedly reported the link
      between social isolation and child maltreatment and they confirm this relation
      within two cultural contexts, Colombian and Spanish, quite different from the
      Anglo-Saxon context, where most of the previous studies have been carried out.

PMID- 12615093
TI  - Working with childhood sexual abuse: a survey of mental health professionals.
AB  - OBJECTIVE: This study aimed to establish the views of a group of mental health
      professionals from various disciplines working in mental health service in a
      British hospital about the needs of clients who had experienced childhood sexual
      abuse. METHOD: Staff members were asked to complete an anonymous survey which
      asked questions relating to knowledge of sexual abuse and its effects, and the
      needs of clients and staff in working with this client group. A total of 54
      people responded to the survey, 42 were female, 11 male. Most (72%) reported
      having over 10 years experience working in mental health, working in both in
      patient and out-patient settings. RESULTS: While respondents were reasonably
      knowledgeable about childhood sexual abuse, they were not very comfortable,
      competent or supported in their work with this client group. There were no
      differences in responses according to the age or gender of respondents, but less
      experienced staff were more likely to feel supported. Those that had received
      training and/or supervision felt significantly more capable in working with this
      client group. CONCLUSIONS: The study offers some support for the development of
      specialist training, consultancy and supervision programs for mental health staff
      in the area of child sexual abuse.

PMID- 12615092
TI  - Development and validation of a brief screening version of the Childhood Trauma
      Questionnaire.
AB  - OBJECTIVE: The goal of this study was to develop and validate a short form of the
      Childhood Trauma Questionnaire (the CTQ-SF) as a screening measure for
      maltreatment histories in both clinical and nonreferred groups. METHOD:
      Exploratory and confirmatory factor analyses of the 70 original CTQ items were
      used to create a 28-item version of the scale (25 clinical items and three
      validity items) and test the measurement invariance of the 25 clinical items
      across four samples: 378 adult substance abusing patients from New York City, 396
      adolescent psychiatric inpatients, 625 substance abusing individuals from
      southwest Texas, and 579 individuals from a normative community sample (combined
      N=1978). RESULTS: Results showed that the CTQ-SF's items held essentially the
      same meaning across all four samples (i.e., measurement invariance). Moreover,
      the scale demonstrated good criterion-related validity in a subsample of
      adolescents on whom corroborative data were available. CONCLUSIONS: These
      findings support the viability of the CTQ-SF across diverse clinical and
      nonreferred populations.

PMID- 12615094
TI  - Childhood emotional invalidation and adult psychological distress: the mediating
      role of emotional inhibition.
AB  - OBJECTIVE: To evaluate a model in which chronic emotional inhibition mediates the
      relationship between a history of childhood emotional invalidation or abuse and
      adult psychological distress. METHOD: One hundred and twenty-seven participants
      completed a series of self-report questionnaires, and a subset of this group
      (n=88) completed an additional measure of current avoidant coping in response to
      a laboratory stressor. Structural equation modeling was used to evaluate and
      compare a full and partial mediational model. RESULTS: Findings strongly
      supported a model in which a history of childhood emotional invalidation (i.e.,
      psychological abuse and parental punishment, minimization, and distress in
      response to negative emotion) was associated with chronic emotional inhibition in
      adulthood (i.e., ambivalence over emotional expression, thought suppression, and
      avoidant stress responses). In turn, emotional inhibition significantly predicted
      psychological distress, including depression and anxiety symptoms. CONCLUSION:
      This study found support for a model in which the relation between recollected
      negative emotion socialization in childhood and adult psychological distress was
      fully mediated by a style of inhibiting emotional experience and expression.
      Although it is likely that childhood emotional inhibition is functional (e.g.,
      reduces parental distress and rejection), results suggest that chronic emotional
      inhibition may have long-term negative consequences for the inhibitor.

PMID- 12615095
TI  - Trends in child maltreatment literature.
AB  - INTRODUCTION: To identify possible gaps in the child maltreatment literature the
      present study examined the development of the child maltreatment literature over
      a 22-year period, including temporal trends for child maltreatment types, the
      characteristics of the research participants, and sources of participant
      recruitment. METHOD: Child maltreatment articles (N=2090) published from 1977 to
      1998 (inclusive) in six specialty journals were coded on type of article, type of
      child maltreatment, gender and parental status of participants, abuse role of
      participants, and recruitment source of participants. RESULTS: Across the period
      studied the annual percentage of quantitative articles (articles with inferential
      statistics) increased, whereas the annual percentage of theoretical articles
      decreased. The annual percentage of articles examining child physical abuse (CPA)
      decreased, whereas the annual percentage of articles examining child sexual abuse
      (CSA) increased. The percentages of articles examining child neglect (CN) or
      child emotional abuse (CEA) remained consistently low. Distinguishing child
      maltreatment types in research articles increased. Males were underrepresented in
      CPA perpetration and CPA adult victimization articles, but adequately represented
      in CSA perpetration and CPA child victimization articles. Females were adequately
      represented in CPA perpetration and CSA child and adult victimization articles.
      Recruitment from universities and outpatient mental health facilities increased;
      recruitment from medical settings decreased. CONCLUSIONS: CN and CEA literatures
      need to be developed first by theoretical, then by quantitative works. In
      addition, the publication of more research on male subjects for CPA perpetration
      and adult CPA victimization is needed.

PMID- 12615096
TI  - Structure-activity relationship study of a diverse set of estrogen receptor
      ligands (I) using MultiCASE expert system.
AB  - The MultiCASE expert system was used to construct a quantitative structure
      activity relationship model to screen chemicals with estrogen receptor (ER)
      binding potential. Structures and ER binding data of 313 chemicals were used as
      inputs to train the expert system. The training data set covers inactive, weak as
      well as very powerful ER binders and represents a variety of chemical compounds.
      Substructural features associated with ER binding activity (biophores) and
      features that prevent receptor binding (biophobes) were identified. Although a
      single phenolic hydroxyl group was found to be the most important biophore
      responsible for the estrogenic activity of most of the chemicals, MultiCASE also
      identified other biophores and structural features that modulate the activity of
      the chemicals. Furthermore, the findings supported our previous hypothesis that a
      6 A distant descriptor may describe a ligand-binding site on an ER. Quantitative
      structure-activity relationship models for the chemicals associated with each
      biophore were constructed as part of the expert system and can be used to predict
      the activity of new chemicals. The model was cross validated via 10 x 10%-off
      tests, giving an average concordance of 84.04%.

PMID- 12615097
TI  - Screening of high production volume chemicals for estrogen receptor binding
      activity (II) by the MultiCASE expert system.
AB  - A structurally and functionally diverse and cross-validated quantitative
      structure-activity knowledge database generated by the MultiCASE expert system
      was used to screen 2526 high production volume chemicals (HPVCs) for their
      estrogen receptor binding activity. 73 HPVCs were found to contain structural
      features or biophores that have been documented as having the ability to bind to
      the estrogen receptor. Potential chemicals were ranked according to their
      quantitatively predicted ER binding potential and the details of the biophores
      found in them are discussed.

PMID- 12615098
TI  - Investigation of acute toxicity of permethrin on guppies Poecilia reticulata.
AB  - Permethrin, a synthetic pyrethroid pesticide and potential toxic pollutant
      contaminating aquatic ecosystems, was investigated in the present study for acute
      toxicity. Guppy fish (Poecilia reticulata) were selected for the bioassay
      experiments. The experiments were repeated 3 times and the 48-h LC(50) was
      determined for the guppies. The static test method of acute toxicity test was
      used. Water temperature was regulated at 20+/-1 degrees C. In addition,
      behavioral changes at each permethrin concentration were observed for the
      individual fish. Data obtained from the permethrin acute toxicity tests were
      evaluated using the probit analysis statistical method. The 48-h LC(50) value for
      guppy was estimated as 245.7 microg/l. Values in the range of 0.05-97.0 microg/l
      have been reported for various other fish species.

PMID- 12615099
TI  - The synaptosomal membrane bound ATPase as a target for the neurotoxic effects of
      pyrethroids, permethrin and cypermethrin.
AB  - Pyrethroids are used widely as insecticides both in agriculture and in
      households. A cellular target of pyrethroids is the sodium channel in the
      membrane. In the present study, the activity of the membrane bound integral
      protein ATPase was studied as a biomarker for the membrane effect of the
      pyrethroids permethrin and cypermethrin. Male Sprague-Dawley rats were used for
      cerebral synaptosome preparation. The isolation of synaptosomes was performed
      with the Percoll gradient method. Both total ATPase and Mg(2+) activated ATPase
      were studied by determining inorganic phosphate liberated from the substrate ATP.
      One hour exposure to permethrin (Biokill) and cypermethrin (Ripcord) insecticide
      products affected ATPase activities. The activity of Na(+), K(+) ATPase decreased
      dose-dependently in 10-50 microM concentrations of permethrin, and Mg(2+)
      activated ATPase increased over twofold in the same concentrations of the active
      components. The effect of the cypermethrin compound Ripcord was not clearly dose
      dependent. The activity of total ATPase was almost entirely lost in the
      concentrations of 100 microM of permethrin and cypermethrin. The results support
      the idea that membrane ATPases are one target of the neurotoxic effect of
      pyrethroid compounds.

PMID- 12615100
TI  - Bioaccumulation and critical body residue of PAHs in the amphipod, Diporeia spp:
      additional evidence to support toxicity additivity for PAH mixtures.
AB  - Polycyclic aromatic hydrocarbons (PAHs) are considered to act additively when
      exposed as congener mixtures. Additive internal concentrations at the site of
      toxic action is the basis for recent efforts to establish a sum PAH guideline for
      sediment-associated PAH toxicity. This study determined the toxicity of several
      PAH congeners on a body residue basis in Diporeia spp. These values were compared
      to the previously established LR(50) value for a PAH mixture based on the molar
      sum of PAH congeners and demonstrated similar LR(50) values for individual PAH.
      These results support the contention that the PAH act at the same molar
      concentration whether present as individual compounds or in mixture. Aqueous
      exposures were conducted for 28 d, and the water was exchanged daily to maintain
      the exposure concentration. The concentration in the exposures declined by an
      average of 22% between water exchanges across all compounds, and ranged from 11%
      to 32%. The toxicokinetics were determined using both time-weighted-average (TWA)
      and time-variable water concentrations and were not statistically different
      between the two source functions. Toxicity was determined for both mortality and
      immobility (failure to swim on prodding) and on both a TWA water concentration
      and a body residue basis. The LC(50) values ranged from 1757 microg l(-1) for
      naphthalene after 10 d exposure to 79.1 microg l(-1) for pyrene after 28 d
      exposure, and the EC(50) ranged from 1587 microg l(-1) for naphthalene after 10 d
      exposure to 38.2 microg l(-1) for pyrene after 28 d exposure. The LR(50) values
      for all congeners at all lengths of exposure were essentially constant and
      averaged 7.5+/-2.6 micromol g(-1), while the ER(50) for immobility averaged 2.6+/
      0.6 micromol g(-1). The bioconcentration factor declined with increasing exposure
      concentration and was driven primarily by a lower uptake rate with increasing
      dose, while the elimination remained essentially constant for each compound.

PMID- 12615101
TI  - Cytochrome p450 induction and gonadal status alteration in common carp (Cyprinus
      carpio) associated with the discharge of dioxin contaminated effluent to the
      Hikiji River, Kanagawa Prefecture, Japan.
AB  - Accumulations of polychlorinated dibenzo-p-dioxins, dibenzofurans and coplanar
      polychlorinated biphenyls were analyzed in common carp (Cyprinus carpio)
      collected in the Hikiji River, Kanagawa Prefecture, Japan in which dioxin
      contaminated effluent was released during the period starting from November 1992
      to March 2000. Higher levels of 2,3,7,8-tetrachlorinated dibenzo-p-dioxin toxic
      equivalents were observed in carps collected downstream to the dioxin release
      site (contaminated site) than the reference site. Modulations of cytochrome p450
      (CYP) enzyme in liver, serum estrogen concentration and gonadal somatic index
      (GSI) were also measured as biomarkers for the contaminants. Total CYP content in
      livers was markedly higher in male and female carps from the contaminated site
      relative to the reference site fish. The expression level of the cytochrome p450
      1A and Ethoxyresorufin O-deethylase activity were significantly higher in female
      carps from the contaminated site than from the reference site. A lower level of
      plasma estrogen was observed in carps from the contaminated site. The GSI in
      female carps from the contaminated site was smaller than that recorded at the
      reference site. The present study indicates that dioxins released to the Hikiji
      River might induce the CYP enzyme and inhibit the reproductive functions in
      common carps dwelling downstream from the release site.

PMID- 12615102
TI  - Geographical scenario uncertainty in generic fate and exposure factors of toxic
      pollutants for life-cycle impact assessment.
AB  - In environmental life-cycle assessments (LCA), fate and exposure factors account
      for the general fate and exposure properties of chemicals under generic
      environmental conditions by means of 'evaluative' multi-media fate and exposure
      box models. To assess the effect of using different generic environmental
      conditions, fate and exposure factors of chemicals emitted under typical
      conditions of (1). Western Europe, (2). Australia and (3). the United States of
      America were compared with the multi-media fate and exposure box model USES-LCA.
      Comparing the results of the three evaluative environments, it was found that the
      uncertainty in fate and exposure factors for ecosystems and humans due to choice
      of an evaluative environment, as represented by the ratio of the 97.5th and 50th
      percentile, is between a factor 2 and 10. Particularly, fate and exposure factors
      of emissions causing effects in fresh water ecosystems and effects on human
      health have relatively high uncertainty. This uncertainty is mainly caused by the
      continental difference in the average soil erosion rate, the dimensions of the
      fresh water and agricultural soil compartment, and the fraction of drinking water
      coming from ground water.

PMID- 12615103
TI  - A qualitative sampling method for monitoring water quality in temporary channels
      or point sources and its application to pesticide contamination.
AB  - A water-sampling device to monitor the quality of water periodically and
      temporarily flowing out of concrete tubes, sewers or channels is described. It
      inexpensively and easily enables a qualitative characterization of contamination
      via these point-source entry routes. The water sampler can be reverse engineered
      with different sizes and materials, once installed needs no maintenance,
      passively samples the first surge, and the emptying procedure is short. In an
      agricultural catchment area in Germany we monitored an emergency overflow of a
      sewage sewer, an outlet of a rainwater sewer and two small drainage channels as
      input sources to a small stream. Seven inflow events were analysed for 20
      pesticide agents (insecticides, fungicides and herbicides). All three entry
      routes were remarkably contaminated. We found parathion-ethyl concentrations of
      0.3 microg l(-1), diuron up to 17.3 microg l(-1), ethofumesate up to 51.1 microg
      l(-1), metamitron up to 92 microg l(-1) and prosulfocarb up to 130 microg l(-1).

PMID- 12615104
TI  - Inhibitory effect of ragweed (Ambrosia artemisiifolia L)-inflorescence extract on
      the germination of Amaranthus hypochondriacus L and growth of two soil algae.
AB  - In this study the ecological importance of common ragweed (Ambrosia
      artemisiifolia L.; Asteraceae) was investigated in in vitro bioassays as it is
      one of the most widespread annual weeds occurring on arable land in Hungary.
      Eight fractions were derived from ragweed inflorescence water extract by low
      vacuum column chromatography and their biological activity was investigated by
      Amaranthus hypochondriacus L. cv. Edit (Amaranthaceae) germination bioassay. As a
      result of the germination bioassay the chromatographic method was modified to
      harvest the most effective fractions in only one fraction, which was used in
      three concentration (10, 50, 100 mg x kg(-1)) for algal growth inhibition
      bioassay. Results showed significant growth inhibition in case of both applied
      algal species.

PMID- 12615105
TI  - Do pharmaceuticals affect freshwater invertebrates? A study with the cnidarian
      Hydra vulgaris.
AB  - Pharmaceuticals enter natural waters through sewage effluent and landfill
      leachates and present an unknown risk to aquatic species including freshwater
      invertebrates. In this study the acute and chronic toxicity of 10 drugs, commonly
      prescribed in the UK i.e. ibuprofen, paracetamol, acetylsalicylic acid,
      amoxicillin, bendroflumethiazide, furosemide, atenolol, diazepam, digoxin,
      amlodipine were assessed using the cnidarian Hydra vulgaris. In a 7 day exposure
      period there were no effects on survival at concentrations up to 1.0 mg l(-1) and
      after 17 days neither feeding nor bud formation were adversely affected. However
      the ability of dissected polyps to regenerate a hypostome, tentacles and foot was
      inhibited by diazepam, digoxin and amlodipine at 10 microg l(-1). It is suggested
      that other drugs targeted at mammalian receptor systems may also affect aquatic
      invertebrates although it is unlikely, at their low environmental concentrations,
      that those examined in this study actually present a risk.

PMID- 12615106
TI  - Biodegradation of chemicals in a standardized test and in environmental
      conditions.
AB  - The estimation of biodegradation rates is an important source of uncertainty in
      chemical risk assessment. The existing OECD tests for ready biodegradability have
      been developed to devise screening methods to determine whether a chemical is
      potentially easily biodegradable, rather than to predict the actual rate, of
      biodegradation in the environment. However, risk assessment needs degradation
      rates. In practice these rates are often estimated (default values) from ready
      biodegradability tests. These tests have many compromising arbitrary features
      compared to the situation in the real environment. One important difference is
      the concentration of the chemical. In wastewater treatment or in the environment
      many chemicals are present at ng l(-1) to microg l(-1) levels whereas in the
      tests the concentrations exceed 10-400 mg carbon per litre. These different
      concentrations of the chemical will lead to different growth kinetics and hence
      different biodegradation rates. At high concentrations the chemical, if it is
      degradable, can serve as a primary substrate and competent microorganisms will
      grow exponentially, resulting in a sigmoid biodegradation curve. At low
      environmental concentrations the chemical does not serve as a primary substrate,
      and therefore does not support significant growth of the degraders, and the
      substrate has a linear biodegradation rate. In this study the biodegradation
      rates of two reference chemicals, aniline and 4-chloroaniline, were compared in a
      standard method and in more realistic conditions at low concentrations, using 14C
      labelled substances and different sources of inocula. Biomass evolution during
      the tests was monitored by adenosine triphosphate measurement and also on the
      basis of the residual 14C-activity in the particulate matter. The results partly
      support the thesis that low concentrations lead to different biodegradation
      kinetics compared to the concentrations used in the standard tests. Furthermore
      the biodegradation rates of the chemicals studied, particularly of 4
      chloroaniline, in Finnish natural waters appeared to be lower than those reported
      in some other countries.

PMID- 12615107
TI  - Detection of hospital wastewater genotoxicity with the SOS chromotest and Ames
      fluctuation test.
AB  - The genotoxic potential of Rouen University Hospital wastewater was evaluated by
      the SOS chromotest (on Escherichia coli PQ37) and Ames fluctuation test on
      Salmonella typhimurium strains TA 98 and TA 100 without metabolic activation. The
      samples were taken during the hospital maximal activity period (8:00 a.m. to 6:00
      p.m.) over three one-week periods of the year. The simultaneous use of SOS
      chromotest and Ames fluctuation test allows us to carry out a preliminary
      screening of the hospital wastewater and to gain some insight by which mechanism
      the genotoxic compounds act. Out of a total of 18 daytime unconcentrated samples
      tested, 10 (55%) are positive in at least one assay. The two tests have different
      sensitivity. Indeed, nine genotoxic samples (50%) are detected by the Ames test,
      and four (22%) by the SOS chromotest. Distribution and intensity of the genotoxic
      response are different at the three periods. In order to explain this phenomenon,
      the influence of the rain levels is discussed. This work showed that the hospital
      wastewater samples tested were overall genotoxic, the response intensity being
      inflected by the pluviometry. Efforts are now under way to try to identify one or
      several genotoxic compounds in order to take precautionary measures to limit
      their release in hospital wastewaters.

PMID- 12615108
TI  - Polybrominated diphenyl ethers in whitefish from Swiss lakes and farmed rainbow
      trout.
AB  - A method for trace analysis of polybrominated diphenyl ethers (PBDE) in fish
      based on gas chromatography/electron ionization high resolution mass spectrometry
      (GC/EI-HRMS) was developed, and levels of PBDE were determined in whitefish
      (Coregonus sp.) from eight Swiss lakes and in rainbow trout (Oncorhynchus mykiss)
      from four Swiss fish farms. PBDE concentrations (sum of PBDE congeners BDE-28,
      BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183) in filet from whitefish
      between 36 and 165 ng/g lipid weight (lw) were found, corresponding to wet weight
      (ww) concentrations of 1.6-7.4 ng/gww. PBDE contents in filet from farmed rainbow
      trout were significantly lower than in wild whitefish (12-24 ng/glw, 0.74-1.3
      ng/gww), and the PBDE congener patterns were different for both species (a higher
      BDE-47 to BDE-99 ratio for farmed rainbow trout compared to wild whitefish was
      found). Whitefish PBDE levels [ng/glw] correlate better with the surface/volume
      ratio of the respective lakes (r(2)=0.70) than with other lake properties such as
      catchment area (size or number of inhabitants) or residence time, suggesting
      atmospheric deposition as an input pathway for PBDE. Based on an average daily
      consumption of 20 g whitefish (Switzerland) with a PBDE content of 7.4 ng/gww
      (highest PBDE concentration detected in this study), a maximum daily intake of
      0.15 microg PBDE was estimated (0.026 microg/day for farmed trout). This number
      corresponds to the lower end of the estimate for the total PBDE intake of the
      Nordic consumer of 0.2-0.7 microg/day.

PMID- 12615109
TI  - Interlaboratory study for the polychlorinated naphthalenes (PCNs): phase 1
      results.
AB  - An interlaboratory study was initiated to investigate consistency in reported
      concentrations of polychlorinated naphthalenes (PCNs). Results are reported from
      the first phase of a study that examined the variability associated with
      different quantification methodologies, instrumentation and standards. Nine
      participating labs from seven countries quantified individual homolog groups,
      summation operator PCN (the sum of 2-8 chlorinated homologs), and selected
      congeners in two test solutions derived from Halowax 1014. The means of the
      reported summation operator PCN values were within less than 15% of the known
      concentrations of the two test solutions and the relative standard deviation
      among laboratories was 11%. However, the among laboratory variability was in the
      range 20-40% for individual PCN homologs and individual PCN congeners. These
      results suggest the need for additional interlaboratory studies and for the
      development of reference materials for PCN analysis. Future PCN interlaboratory
      comparison exercises are discussed that will utilize control materials and
      unknowns consisting of suitable environmental matrices.

PMID- 12615110
TI  - Direct measurement of octanol-water partition coefficients of some
      environmentally relevant brominated diphenyl ether congeners.
AB  - Octanol-water partition coefficients (K(OW)) of nine environmentally relevant
      brominated diphenyl ether (BDE) congeners present in two technical mixtures were
      directly measured using a slow-stir technique. LogK(OW) values of tri- to
      heptabrominated BDE congeners ranged from 5.74 to 8.27, and were related to
      bromine content by the equation logK(OW)=0.621(#Br)+4.12(R(2)=0.970). The
      directly determined K(OW) values were generally lower than those calculated using
      fragment constant methods, particularly at higher levels of bromine substitution.
      The quasi-experimental approach of using fragment constants to modify a
      "backbone" compound of known K(OW) was much more successful than using the
      fragment constants to "build" the entire molecule. The tri- and tetrabrominated
      congeners are in the range of optimum bioaccumulation potential.

PMID- 12615111
TI  - Inoculation of an atrazine-degrading strain, Chelatobacter heintzii Cit1, in four
      different soils: effects of different inoculum densities.
AB  - The possibility to improve atrazine degradation in soils by bioaugmentation was
      studied. The atrazine-mineralizing strain, Chelatobacter heintzii Cit1, was
      inoculated in four sterile and four non-sterile soils, at varying inoculum
      densities. Two soils, which had shown enhanced atrazine mineralization, were used
      to determine which inoculum density was capable of restoring their original
      mineralizing capacity after sterilization. The two other soils, with intermediate
      and low capacity to mineralize atrazine, were used in order to demonstrate that
      atrazine mineralization in such soils could be improved by inoculation.
      Mineralization kinetics were fitted using the Gompertz model. In the case of
      soils adapted to atrazine mineralization, inoculation of C. heintzii did not
      accelerate the rate of atrazine mineralization, which was essentially performed
      by the indigenous microflora. However, with soils that did not mineralize
      atrazine, the introduction of 10(4) cfug(-1) resulted in a 3-fold increase of
      atrazine mineralization capacity.

PMID- 12615112
TI  - Quantitative predictive models for octanol-air partition coefficients of
      polybrominated diphenyl ethers at different temperatures.
AB  - Quantitative predictive models for octanol-air partition coefficients of
      polybrominated diphenyl ethers at different environmental temperatures (T) were
      developed. Partial least squares (PLS) regression was used for model development.
      A list of 18 theoretical molecular structural descriptors was screened by PLS
      analysis. The optimal model was selected from the one containing nine theoretical
      molecular descriptors and 1/T as predictor variables. The cross-validated
      Q(2)(cum) value for the optimal model is 0.975, indicating a good predictive
      ability and stability of the model. Intermolecular dispersive interactions play a
      leading role in governing the magnitude of logK(OA). The lower the E(LUMO) (the
      energy of the lowest unoccupied molecular orbital), the greater the
      intermolecular interactions between octanol and PCB molecules, and thus the
      greater the logK(OA) values.

PMID- 12615113
TI  - Studies into the formation of dioxins in the sintering process used in the iron
      and steel industry. 1. Characterisation of isomer profiles in particulate and
      gaseous emissions.
AB  - Dioxin analyses using a DB5MS chromatography column are presented for samples of
      dust from an electrostatic precipitator and emissions from the main stack of a UK
      sinter plant. The analyses have been repeated using the SP2331 column, for which
      the elution order has been determined for the whole range of tetra to
      octachlorodibenzo-p-dioxins and dibenzofurans, and which provides a larger degree
      of separation than the DB5MS column. Polychlorinated dibenzofurans are present in
      significantly larger amounts in both the dust and stack emissions, and are the
      main contributors to the I-TEQ. Analysis using the SP2331 column for dioxins show
      considerable similarity to those of Bacher et al. for soot from a wood-burning
      fire, but differ markedly from those of Addink et al. for simulation of waste
      incineration. The similarities to Bacher's results are less for the
      dibenzofurans. Comparison of absolute concentrations with reported vapour
      pressures shows the retention of significant dioxin in the dust to involve
      mechanisms other than pure condensation.

PMID- 12615114
TI  - A comparison of TEQ contributions from PCDDs, PCDFs and dioxin-like PCBs in
      sewage sludges from Catalonia, Spain.
AB  - Eight sewage sludges from rural, urban and industrial wastewater treatment plants
      (WWTPs) in Catalonia (Spain) were analysed for polychlorinated dibenzo-p-dioxins
      (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) to determine the present
      levels of contamination. A method based on an automated cleanup system followed
      by an isotope-dilution high-resolution mass spectrometric analysis was employed.
      Total toxicity equivalent (WHO-TEQ) values were calculated using the toxicity
      equivalent factors (WHO-TEFs) proposed by WHO for dioxin-like PCBs, PCDDs and
      PCDFs. The WHO-TEQ(PCDD/F) values for these samples ranged from 4.9 to 20.8 pg/g
      dry weight (d.w.), with a mean value of 9.3 pg/g d.w., whereas WHO-TEQ(PCB)
      levels ranged between 1.9 and 6.6 pg/g d.w., with a mean value of 4.2 pg/g d.w.
      The WHO-TEQ(PCB) contribution varied from 13% to 50%, suggesting that PCB
      contribution on the toxicity of the samples must be taken into account. Moreover,
      these contemporary PCDD, PCDF and PCB concentrations were compared with previous
      data obtained from sewage sludge samples collected during the 80s. Our findings
      show that contemporary PCDD, PCDF and PCB levels have declined since the 80s.

PMID- 12615115
TI  - Estimation of PCDD/F distribution and fluxes in the Venice Lagoon, Italy:
      combining measurement and modelling approaches.
AB  - The available experimental information on the occurrence of PCDD/Fs in the Venice
      Lagoon, Italy, was compiled and used to calculate fugacities for the
      environmental compartments of sediment, suspended particulate matter (SPM), water
      and air and then used to estimate fugacity ratios and assess the likely net
      direction of flux between media. The bottom sediment: SPM fugacity ratios for
      different PCDD/Fs indicate conditions close to equilibrium, suggestive of the
      close coupling of SPM with re-suspended sediment. Sediment/water and the
      sediment/air fugacity ratios suggest that net flux directions vary depending on
      the congener and the location within the lagoon. Net sediment-water-air movement
      (i.e. re-mobilisation/volatilisation) is suggested for the lighter congeners from
      the industrial canals, where the highest PCDD/F concentrations in the lagoon
      occur. The tendency to volatilise increases with decreasing congener molecular
      weight. In contrast, net deposition (air-water-sediment) appears to be occurring
      for the heaviest (hepta- and octa-) substituted PCDD/Fs. OCDF represents a marker
      of the industrial district of the lagoon, decreasing in concentration and as a
      fraction of total PCDD/Fs with increasing distance. The fugacity-based
      quantitative water air sediment interaction (QWASI) mass-balance model was
      applied to the central part of the lagoon. The key parameters for the
      determination of the model output, identified by a sensitivity analysis, were:
      the sediment active depth, the sediment re-suspension and deposition rates, and
      the total input of PCDD/Fs to the system. The QWASI model also indicates the
      tendency for the lighter PCDD/Fs to be released from surface sediment to the
      water column.

PMID- 12615116
TI  - Molecular hologram derived quantitative structure-property relationships to
      predict physico-chemical properties of polychlorinated biphenyls.
AB  - Polychlorinated biphenyls (PCBs) congeners with various degrees of chlorination
      and substitution patterns are among the most widespread and persistent man-made
      organic pollutants. They are toxic, lipophilic and tend to be bioaccumulated. The
      knowledge of the physico-chemical properties is very useful to explain the
      environmental behavior of PCBs and to perform an exposure assessment. In this
      paper, we have used a new molecular representation, the molecular hologram, to
      generate quantitative structure-property relationship models to predict the
      physico-chemical properties of biphenyl and all of its chlorinated congeners. The
      investigated properties include 1-octanol/water partition coefficient (logK(ow)),
      aqueous solubility (-logS(w)), aqueous activity coefficient (-logY(w)), Total
      molecular surface area, Henry's law constant (logH). The results show that this
      new quantitative structure-activity relationship approach presents highly
      predictive models for important physico-chemical properties of PCBs.

PMID- 12615117
TI  - Effect of human dietary exposure levels of genistein during gestation and
      lactation on long-term reproductive development and sperm quality in mice.
AB  - The objective of the present study was to determine the long-term reproductive
      effects of gestational and lactational exposure (0, 0.1, 0.5, 2.5 and 10
      mg/kg/day) to genistein on male mice at levels comparable to or greater than
      human dietary exposures. Testicular growth, sperm count and motility, and sperm
      fertilizing ability in vitro was assessed in male offspring on postnatal days
      (PND) 105 and 315. Selected genes were also examined by real-time PCR to
      determine whether genistein caused changes in gene expression similar to those
      previously observed with diethylstilbestrol (DES). No significant treatment
      related effects on male offspring body weight, anogenital distance, seminal
      vesicle weight or testis weight were observed. There were also no significant
      effects on sperm count, the percent of motile sperm or the number of motile sperm
      at any age. The in vitro fertilizing ability of epididymal sperm was increased
      significantly in the high-dose group approximately 17% (P < 0.001) on PND 105 and
      315. The results indicate that developmental exposure of mice to genistein at
      human exposure levels does not induce adverse effects on sperm quality or changes
      in testicular gene expression similar to DES.

PMID- 12615118
TI  - Effect of chemopreventive compounds from Brassica vegetables on NAD(P)H:quinone
      reductase and induction of DNA strand breaks in murine hepa1c1c7 cells.
AB  - We have compared the effects of aqueous extracts of cooked Brussels sprouts,
      isolated glucosinolates and their breakdown products on the activity of quinone
      reductase [NADPH:quinone-reductase] (QR) and on DNA strand breaks induced by
      hydrogen peroxide in murine hepa1c1c7 cells. QR activity was not significantly
      altered after incubation of the cells with Brussels sprouts extracts. However,
      some of the glucosinolates and in particular their myrosinase-catalysed
      hydrolysis products and the degradation product of indole-glucosinolates, indole
      3-carbinole (I3C), di(indol-3-yl)-methane (DIM) and 2,3-bis(indol-3
      ylmethyl)indole (TRI) effectively induced QR activity. Isolated isothiocyanates
      did not influence the QR activity. The extracts of cooked and autolysed Brussels
      sprouts and some glucosinolates inhibited the DNA strand breaks induced by 100
      microM hydrogen peroxide. Maximum inhibition was by 20-38% after 24 h of
      preincubation. Hydrolysis of the glucosinolates by myrosinase decreased the
      inhibitory effects, whereas I3C, DIM or TRI had no effect on DNA damage.
      Accordingly, the protective effect of Brussels sprouts constituents against
      induction of oxidative DNA damage appears to be unrelated to enzyme inducing
      properties via the antioxidant responsive element. Both of these effects could be
      part of the suggested cancer preventive effect of cruciferous vegetables.

PMID- 12615119
TI  - Some histologic and biochemical evidence for mitigation of cyanide-induced tissue
      lesions by antioxidant vitamin administration in rabbits.
AB  - The effect of antioxidant vitamins on cyanide-induced tissue damage was
      investigated in New Zealand White rabbits using a combination of colorimetric,
      spectrophotometric, enzymatic, gravimetric and histological methods. Three groups
      of rabbits (six per group) were used in a 4-week feeding experiment. One group
      received pure grower's mash, while a second group was fed mash containing 400 ppm
      inorganic cyanide. The third group received daily oral doses of vitamins A, C and
      E, in addition to mash and 400 ppm cyanide. There were significant decreases (P <
      0.05) in activities of superoxide dismutase (SOD), catalase and alkaline
      phosphatase (AP) in the liver, lung and kidney of the two groups given cyanide,
      but the decreases were significantly lower (P < 0.05) in the group fed
      antioxidant vitamins. In addition, the antioxidant vitamin supplementation led to
      marked reductions in the severity of histopathological degeneration in these
      tissues. These results strongly suggest that cyanide-induced tissue lesions may
      be relieved by adequate intake of antioxidant vitamin supplements.

PMID- 12615120
TI  - Effects of sphingomyelin on aberrant colonic crypt foci development, colon crypt
      cell proliferation and immune function in an aging rat tumor model.
AB  - Sphingomyelin (SPM) was assessed in older rats for in vivo effects on multiple
      immune responses and the development of colon preneoplastic lesions. Fifty-four
      week-old rats were injected with 10 mg/kg body weight of the carcinogen
      azoxymethane (AOM), and then treated with 35 mg/kg body weight SPM orally for 6
      weeks beginning 6 weeks after AOM treatment. None of the immune functions tested
      (antibody formation, delayed-type hypersensitivity or natural killer cell
      cytotoxicity) were significantly affected by SPM treatment. Natural killer (NK)
      cell activity was, however, decreased in all rats that were treated with AOM.
      There was a tendency for decreased aberrant crypt foci (ACF) numbers in the SPM
      treated rats but this reduction was only significant for the largest lesions (>
      nine crypts per foci). The decreased ACF numbers were most evident in the
      proximal end of the colon. Colonic crypt cell proliferation was also decreased in
      SPM treated rats. This reduction was primarily in the base of the crypt column.
      Also, low numbers of ACF developed spontaneously in rats not treated with AOM,
      but no ACF were present in non-AOM rats that also received SPM. It appears that
      SPM may have effects on the post-initiation development of preneoplastic lesions
      in the rat colon but not on the immune functions assessed in this study.

PMID- 12615121
TI  - Evaluation of the toxicity of concentrated barley beta-glucan in a 28-day feeding
      study in Wistar rats.
AB  - Beta-glucans are water-soluble cell-wall polysaccharides consisting of (1-->3,1-
      >4)-linked beta-D-glucopyranosyl monomers that comprise a considerable proportion
      of soluble fiber from certain grains including oats and barley. Consumption of
      foods containing beta-glucan or beta-glucan-enriched fractions prepared from
      these grains lower serum cholesterol concentrations in humans and in animal
      models of hypercholesterolemia. The present study was conducted to evaluate the
      toxicity of beta-glucan-enriched soluble fiber from barley in Wistar rats on
      dietary administration at concentrations of 0.7, 3.5 and 7% beta-glucan for 28
      days. There were no adverse effects on general condition and behavior, growth,
      feed and water consumption, feed conversion efficiency, red blood cell and
      clotting potential parameters, clinical chemistry values, and organ weights.
      Necropsy and histopathology findings revealed no treatment-related changes in any
      organ evaluated. A dose-dependent increase in full and empty cecum weight was
      observed. This is a common physiological response of rodents to high amounts of
      poorly digestible, fermentable carbohydrates, and was of no toxicological
      concern. The only finding of possible biological relevance was an increase in the
      number of circulating lymphocytes observed in males. However, the increase was
      not dose-dependent and was not observed in females. Results of this study
      demonstrated that consumption of concentrated barley beta-glucan was not
      associated with any obvious signs of toxicity in Wistar rats even following
      consumption of large quantities.

PMID- 12615122
TI  - A study of the toxicity of five mineral hydrocarbon waxes and oils in the F344
      rat, with histological examination and tissue-specific chemical characterisation
      of accumulated hydrocarbon material.
AB  - Five food-grade mineral hydrocarbon (MHC) materials; a low melting point wax
      (LMPW), a synthetic wax (C80W) and three white oils (N15H, N70H and P70H) were
      administered orally to female Fischer-344 rats for 28 and 90 days at a dose level
      of 2% in the diet. Tissues were examined at autopsy for any treatment-related
      histopathological changes. The histology of target organs was the same as found
      in previous studies on LMPW and mineral oils and similar effects were also
      observed from feeding C80W. Chemical analysis showed no detectable levels of MHCs
      in urine and no discernible differences in the MHC profile in faeces extracts
      compared to diets. The presence of MHCs in most tissues was not always associated
      with observable histological changes. The notable observations were MHC material
      was detected in all tissues of rats fed with diets containing LMPW and C80W. The
      levels found ranged from 0.04 to 1.52% by weight for the LMPW and from 0.01 to
      0.75% for the C80W. MHC material was detected in all samples of small intestine,
      heart and kidney for all groups. Only the livers from rats administered with LMPW
      and C80W were analysed, which were found to contain MHC material. Preferential
      accumulation of MHCs was in the alkane range approximately C(20)-C(35). The
      findings indicate that the size and the structure of individual components play a
      role both in determining their propensity to accumulate in different tissues and
      in the severity of any response that they elicit once they have accumulated. The
      implication of these findings are discussed in the context of specifications for
      'food-grade' mineral hydrocarbons such as used as food additives. The data
      presented here suggests that the current specifications are not prescriptively
      adequate in controlling the amount of MHC material between C(25) and C(35) that
      can accumulate.

PMID- 12615123
TI  - Safety evaluation of a hexose oxidase expressed in Hansenula polymorpha.
AB  - A programme of studies was conducted to establish the safety of hexose oxidase
      (HOX) from Chondrus crispus expressed in the yeast Hansenula polymorpha to be
      used as a processing aid in the food industry. Rat feeding studies were conducted
      to assess acute and subchronic oral toxicity. In addition, the potential of the
      enzyme to cause mutagenicity and chromosomal aberrations was assessed in
      microbial and tissue culture in vitro studies. Acute and subchronic oral toxicity
      was not detected at the highest dosage recommended by OECD guidelines. There was
      no evidence of mutagenic potential or chromosomal aberrations. The no-observed
      adverse-effect level (NOAEL) derived from the 13-week study was 5000 units/kg
      body weight/day. In conclusion it can be considered a safe processing aid for use
      in the food industry.

PMID- 12615124
TI  - Nutritional and radiological impact of dietary potassium on the Pakistani
      population.
AB  - The nutritional status of dietary potassium and the radiological impact of its
      isotope (40)K were estimated for the Pakistani population. Potassium
      concentration was determined in dietary samples by atomic absorption
      spectrometry. An average potassium concentration was 4.54+/-0.89 mg/g, which
      leads to potassium dietary intake of 2.69+/-0.54 g/day and the radiological
      hazard due to (40)K activity was 79.94 Bq/day. The annual and lifetime effective
      doses calculated for the reference Pakistani man weighing 64 kg due to measured
      activity of (40)K were found to be 1.65 x 10(-4) Sv y(-1) and 8.27 x 10(-3) Sv,
      respectively. Measured data showed that the potassium concentration in the
      Pakistani diet is adequate and safe according to international standards.

PMID- 12615125
TI  - Brick tea fluoride as a main source of adult fluorosis.
AB  - An epidemiological survey was conducted in Naqu County, Tibet in September 2001
      to investigate the manifestations of fluorosis in adults caused by the habitual
      consumption of brick tea. Profiles were obtained for the total daily fluoride
      intake, environmental fluoride levels and average urinary fluoride concentration,
      and a physical examination and a skeletal radiographic study were conducted. One
      hundred and eleven 30-78-year-old adults were enrolled. It was found that the
      fluoride level of water sources in Naqu County was 0.10+/-0.03 mg/l; no evidence
      of fluoride air pollution was found, but the brick tea water processed foods-
      zamba and buttered tea--had fluoride contents of 4.52+/-0.74 mg/kg and 3.21+/
      0.65 mg/l, respectively. The adult daily fluoride intake reached 12 mg, of which
      99% originated from the brick tea-containing foods. The positive rate of clinical
      symptoms by physical examination was 89%; furthermore, 42 of the 111 subjects
      were diagnosed by X-ray. The positive examination rate was 83%. Although the
      osteosclerosis-type skeletal fluorosis (overall increased bone matrix density)
      affected 74%, arthropathy and arthritis affected a significant number of the
      patients, resulting in functional disability. The results suggest that this brick
      tea-type fluorosis had even more severe adverse effects on human health compared
      with both the water-type and coal combustion-type fluorosis that occurred in
      other areas of China.

PMID- 12615127
TI  - Occurrence of preformed volatile nitrosamines in preparations of some Nigerian
      medicinal plants: a preliminary report.
AB  - Preparations of some tropical plants of medicinal importance collected from the
      savannah vegetational belt of Nigeria were analysed for preformed volatile N
      nitrosamines. N-nitrosamines were analyzed by chemiluminescence detection on a
      thermal energy analyzer (TEA) following gas chromatographic (GC) separation. Only
      N-nitrosodimethylamine (NDMA) in the range of 1.2-3.4 microg/kg was detected in
      four out of the 29 sample preparations. These preliminary data suggest that
      medicinal plant preparations may be due in part to microbial contamination,
      contributing to N-nitroso compound burden in many developing countries where
      ethnomedicine in still widely practised.

PMID- 12615126
TI  - Analysis of estrogenic activity of foodstuffs and cigarette smoke condensates
      using a yeast estrogen screening method.
AB  - Hormone mimics present in our environment are of concern because such agents
      could potentially reduce fertility and increase sexual dysfunction in wildlife
      and increase the risk of breast and reproductive organ cancers in man. Therefore,
      monitoring of the levels of estrogenic compounds in environmental materials is
      essential in order to prevent their exposure to man and to discover potential
      harmful effects on human health. In the present study, we analyzed estrogenic
      activity in 23 foodstuffs and cigarette smoke condensate samples extracted with
      an organic solvent, using the yeast estrogen screening (YES) system. Three
      soybean-related foodstuffs (soy sauce, tofu, miso), beer, coffee and cigarette
      smoke condensates showed clear estrogenic activity in the YES system. HPLC
      fractionations followed by the YES of these YES-positive samples revealed the
      presence of many estrogenic compounds in cigarette smoke condensates, whereas the
      other samples exerted estrogenic activities in only one or two fractions.
      Genistein was able to be isolated as the major active principle in soy sauce,
      tofu and miso, its concentration in these three foodstuffs ranging from 0.1 to
      394 microg/g or ml. 8-Prenylnaringenin was also isolated from beer extracts as a
      major compound with estrogenic activity present at 0.22-4.0 ng/ml. Estrogenic
      activity of 8-prenylnaringenin with YES was 10-times as high as that of
      genistein, although it was 100-times less than that of 17beta-estradiol. Based on
      our results in vitro, 10 mg miso and 10 ml beer can be calculated to have similar
      estrogenic activity to 1 pmole 17beta-estradiol. It is very important that the
      effects of genistein and 8-prenylnaringenin on human health are elucidated.

PMID- 12615128
TI  - Antimutagenic effect of Lentinula edodes (BERK.) Pegler mushroom and possible
      variation among lineages.
AB  - This study was performed to evaluate the efficiency of four different lineages
      (95/01, L1, 96/22 and JABK) of Lentinula edodes (BERK.) Pegler mushroom
      (shiitake) for inhibiting the N-ethyl-N-nitrosourea (ENU) clastogenicity in vivo.
      Male Swiss mice (10 animals/group) were treated during 15 consecutive days with
      dried mushroom added to basal diet under three different concentrations (1, 5 and
      10%). At day 15, mice were intraperitoneally injected with ENU (50 mg/kg body
      weight) and sacrificed 24 h later for evaluation of micronucleated bone marrow
      polychromatic erythrocytes (MNPCE). Negative and positive controls (10 animals
      each), receiving basal diet and saline or ENU ip injection, respectively, were
      also evaluated. Results showed that pretreatments with diets containing the
      lineages 95/01, L1 and 96/22 reduce the frequencies of MNPCE induced by ENU. The
      absence of an antimutagenic activity for the lineage JABK might be related to
      intrinsic differences among the lineages such as biochemical composition. Taken
      together, our data show that the differences in protective activities of the
      mushrooms need to be clarified in further studies and the mechanisms for such
      activities need to be investigated.

PMID- 12615129
TI  - Investigating genotoxic and hematotoxic effects of N-nitrosodimethylamine, N
      nitrosodiethylamine and N-nitrosodiethanolamine in the hen's egg-micronucleus
      test (HET-MN).
AB  - The hen's egg test for micronucleus induction (HET-MN) combines the use of the
      commonly accepted genetic endpoint "formation of micronuclei" with the well
      characterized and complex model of the incubated hen's egg, which enables
      metabolic activation, elimination and excretion of xenobiotics including mutagens
      and promutagens and does not conflict with animal protection regulations and
      ethical aspects. N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA)
      produced clearly positive, dose-dependent and reproducible results in this assay.
      NDMA revealed, in accordance with literature data, a much higher mutagenicity
      than NDEA. For both compounds the sensitivity of HETMN was to a large extent
      higher than published for the rodent micronucleus test, which is not capable of
      unequivocally identifying NDEA as positive. Additionally, NDEA induced severe
      anemia without obscuring the formation of micronucleated cells. N
      nitrosodiethanolamine (NDELA), which in the literature is described as a non
      mutagenic animal carcinogen, could clearly be confirmed as non-mutagenic in the
      HETMN without showing any disturbing effects on the formation of erythrocytes.
      The micronucleus frequencies of the concurrent negative controls of all
      experiments was in agreement with the historic negative control from 302 eggs and
      412,532 cells. The same is true for the historic control of proliferation marker
      from 61 eggs and 13,020 cells. We interpret these results, which correspond well
      to published data from animal tests, as being further support for using the HET
      MN as a reliable alternative genotoxicity assay system, which is physiologically
      closer to in vivo conditions than in vitro genotoxicity tests, and allows the
      observation of further local and systemic effects.

PMID- 12615130
TI  - Effect of a surfactant, Tween 80, on the formation and secretion of chylomicrons
      in the rat.
AB  - Effects of Tween 80, a nonionic surfactant, on size and number of chylomicrons
      (CM) secreted during lipid absorption in the rat model are reported. Fasted rats
      were loaded with either 154 mM NaCl or 25% (w/w) olive oil emulsion in 154 mM
      NaCl with 0, 0.1, 1 or 10% (w/w) Tween 80. After 3 h, either mesenteric lymph or
      blood was collected and their triacylglycerol-rich lipoprotein fraction (Sf>20
      and Sf>400, respectively) isolated. Triacylglycerol (TAG) and apolipoprotein B48
      (apoB48) concentrations in the lipoprotein fractions were assayed and their
      fluxes (lymph) calculated. TAG:apoB48 ratios, indicative of CM size, were
      determined. The data support the hypothesis that fat loading is accommodated
      mainly by increased average size, rather than number, of CM. Co-administration of
      Tween 80 with olive oil resulted in a significant increase in CM apoB48 secretion
      into the mesenteric lymph duct and in an increased concentration of apoB48 in the
      blood (Sf>400). Also, Tween 80-treated groups exhibited smaller mean CM size
      relative to the olive oil only group in both lymph and blood. The observed effect
      on CM size and number did not appear to be dose dependent at concentrations of
      Tween 80 above 0.1% (w/w). Incorporation of Tween 80 in the diet at 1 or 10%
      (w/w) concentrations reduced the TAG concentration in the stools; however, a
      significant increase in water content was observed at 10% (w/w) concentration. In
      conclusion, Tween 80 at 1 or 10% (w/w) doses can improve the efficiency of the
      digestive system to absorb dietary fat but at high concentrations (10%, w/w) it
      appeared to have a toxic or irritating effect on the gastrointestinal system.
      More importantly, the effect of Tween 80 on size and number of CM is a condition
      that favours a delay in their clearance rate.

PMID- 12615131
TI  - Developmental toxicity of N-methyl-2-pyrrolidone in rats following inhalation
      exposure.
AB  - The developmental toxicity of inhaled N-methyl-2-pyrrolidone (NMP) was studied in
      Sprague-Dawley rats. Pregnant rats were exposed whole body to NMP vapours at
      concentrations of 0, 30, 60 and 120 ppm, 6 h/day, on gestational days (GD) 6
      through 20. Maternal body weight gain was significantly decreased at 60 and 120
      ppm on GD 6-13 and maternal food consumption was reduced at 120 ppm on GD 13-21.
      No significant difference in the gestational weight change corrected for the
      weight of the gravid uterus was observed, whatever NMP concentration. There were
      no adverse effects on embryo/fetal viability or evidence of teratogenicity at any
      concentration tested. Fetal toxicity indicated by reduced fetal weight was
      observed at 120 ppm. Thus, the no-observed-adverse-effect level (NOAEL) for
      maternal and developmental toxicity was 30 and 60 ppm, respectively.

PMID- 12615132
TI  - Lack of sensitization for trimellitate, phthalate, terephthalate and isobutyrate
      plasticizers in a human repeated insult patch test.
AB  - Two hundred and three human volunteers were tested for evidence of sensitization
      to several plasticizers following 3 weeks of dermal application three times a
      week. Tris(2-ethylhexyl)mellitate (TOTM; 1%, v/v), 2,2,4-trimethyl-1,3
      pentanediol-diisobutyrate (TXIB; 1%, v/v), di(2-ethylhexyl)terephthalate (DEHT;
      0.5%, v/v) and diethylphthalate (DEP; 2%, v/v) were applied to the skin of
      volunteers under semi-occlusive patch for 3 consecutive weeks and the reactions
      to a challenge application noted following a 2-week rest period. Slight erythema
      was observed in four individuals exposed to TOTM, two of which resolved within 96
      h and one that occurred only after 96 h. Slight erythema was noted in three
      subjects exposed to TXIB, one of which resolved by 96 h and one that occurred
      only after 96 h. Two subjects had slight erythema to DEHT, one that resolved by
      96 h and one that occurred only after 96 h. One reaction occurred with DEP at 96
      h after challenge. Of the positive responses, one subject reacted to all test
      substances. No subject had a response grade of 1.0 or greater. Because of the low
      response, the overall conclusion is that none of the plasticizers demonstrated
      evidence of sensitization or irritation.

PMID- 12615134
TI  - Phthalates, hormones and offspring sex ratios.

PMID- 12615133
TI  - A simple procedure for reducing lead content in fish.
AB  - The efficiencies of medicinal herbs (damaseisa, and rosemary); plants solutions
      (radish and barley); polypeptide solutions (nisin); neutral solutions (sodium
      chloride) and acidic solutions (acetic acid), as well as tap water, in the
      elimination of lead from naturally contaminated bolty fish were examined. The
      results indicate the efficient role of washing by nisin, damaseisa, radish,
      barley and rosemary compared with acetic acid and sodium sodium chloride
      solutions. It was noticed that nisin and damaseisa solutions (10%) eliminated
      lead completely. On the other hand, washing with tap water provided the least
      effective role in elimination of lead from fish.

PMID- 12615136
TI  - Tooth and jaw: molecular mechanisms of patterning in the first branchial arch.
AB  - The mammalian jaw apparatus is ultimately derived from the first branchial arch
      derivatives, the maxillary and mandibular processes, and composed of a highly
      specialised group of structures. Principle amongst these are the skeletal
      components of the mandible and maxilla and the teeth of the mature dentition.
      Integral to the development of these structures are signalling interactions
      between the stomodeal ectoderm and underlying neural crest-derived
      ectomesenchymal cells that populate this region. Recent evidence suggests that in
      the early mouse embryo, regionally restricted expression of homeobox-containing
      genes, such as members of the Dlx, Lhx and Gsc classes, are responsible for
      generating early polarity in the first branchial arch and establishing the
      molecular foundations for patterning of the skeletal elements. Teeth also develop
      on the first branchial arch and are derived from both ectoderm and the underlying
      ectomesenchyme. Reciprocal signalling interactions between these cell populations
      also control the odontogenic developmental programme, from early patterning of
      the future dental axis to the initiation of tooth development at specific sites
      within the ectoderm. In particular, members of the Fibroblast growth factor
      (Fgf), Bmp, Hedgehog and Wnt families of signalling molecules induce regionally
      restricted expression of downstream target genes in the odontogenic
      ectomesenchyme. Finally, the processes of morphogenesis and cellular
      differentiation ultimately generate a tooth of specific class. Many of the same
      genetic interactions that are involved in early tooth development mediate these
      effects through the activity of localised signalling centres within the
      developing tooth germ.

PMID- 12615137
TI  - Three-dimensional reconstruction studies and morphometric analysis of rudimental
      tooth primordia in the upper incisor region of the sheep (Ovis aries,
      Ruminantia).
AB  - The functional dentition of the domestic sheep lacks all upper incisors and the
      upper canines. Nevertheless, occurrence of a dental lamina and rudimental tooth
      primordia had been described in the upper incisor region of the sheep. The aim of
      this study was to describe temporo-spatial pattern of origin and regression of
      these rudimental tooth primordia by light microscopy, computer-aided three
      dimensional reconstruction and morphometry of the dental epithelium. Transient
      existence of a dental lamina in the upper incisor region of the sheep and three
      epithelial thickenings on its deep mesenchymal margin has been observed at day of
      ontogeny (DO) 48-53. They could not been identified as full-value tooth
      primordia, because they did not induce differentiation of tooth mesenchyme, but
      they could represent last remnants of functional upper incisors in early
      ancestors of ruminants. Additionally, a large rudimental upper canine primordium
      near the sutura maxilloincisiva occurred at DO43, reached early cap stage at DO52
      and started to regress at DO53. Thus, our findings showed a discrepancy between
      the embryonic and adult dental pattern in the sheep. Similar molecular mechanisms
      as described for diastemal tooth rudiments in rodents could be involved during
      regression of rudimental tooth primordia in the upper incisor region of the
      sheep.

PMID- 12615138
TI  - Copper ions inhibit the demineralisation of human enamel.
AB  - Cu2+ is cariostatic in rats reportedly due to it bacteriocidal properties. Here,
      we report the use of a simple abiotic model system to investigate whether Cu2+
      has any inhibitory effect on the acid dissolution of human enamel. Crowns were
      exposed to a sequence of seven 10 mmol/l acetic acid challenges. The mineral
      dissolved during each challenge was then determined. CuSO4 (10 mmol/l) was
      present during the fourth of these challenges. Loss of calcium and phosphate were
      reduced by 57 and 63%, respectively, (P<0.0001) in the presence of Cu2+. Losses
      were also significantly reduced during the next acidic challenge in the absence
      of Cu2+. The degree of protection was found to approach maximum at about 5 mmol/l
      Cu2+. The well-known cariostatic properties of Cu2+ may therefore be due not only
      to its ability to inhibit bacterial growth but also to its ability to directly
      inhibit acid dissolution of enamel.

PMID- 12615139
TI  - Effects of insulin-like growth factor-I on the expression of osteoclasts and
      osteoblasts in the nasopremaxillary suture under different masticatory loading
      conditions in growing mice.
AB  - It is well accepted that mechanical loading inhibits bone resorption and
      increases in vivo bone formation. It is also known that cyclic mechanical
      loading, in particular, can enhance bone formation significantly. These findings
      suggest a significant role for mechanical stimuli in bone remodelling mediated by
      various local growth factors including insulin-like growth factor-I (IGF-I).
      Earlier studies showed that the nasal bone length and premaxillary bone width
      were significantly greater in mice fed a solid diet rather than a granulated
      diet, and that these dimensions increased significantly in a solid-diet group
      treated with IGF-I. The present study sought to examine the effect of IGF-I on
      the expression of osteoclasts and osteoblasts in the nasopremaxillary suture
      subjected to different masticatory loadings. For the solid-diet groups, the
      numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclastic cells
      and osteoblasts were significantly greater in the group injected with IGF-I than
      in the animals injected with physiological saline. In the groups fed a granulated
      diet, no significant differences in the numbers of TRAP-positive osteoclastic
      cells and osteoblasts were found over the entire experimental period between mice
      injected with either IGF-I or physiological saline. It is shown that IGF-I
      significantly induces the expression of osteoclasts and osteoblasts and the
      subsequent bone remodelling, and that the effect may be additive as compared to
      that of mechanical masticatory loading, which seems to be more important in bone
      remodelling in terms of the numbers of osteoclasts and osteoblasts.

PMID- 12615140
TI  - The influence of fluoride on the cellular morphology and synthetic activity of
      the rat dentine-pulp complex in vitro.
AB  - Exposure to high fluoride concentrations in the immediate environment of the
      tissue is recognized to result in the post-translational modification of non
      collagenous dentine extracellular matrix (ECM) components, potentially altering
      dentine mineralization. However, less is known about the effects of fluoride
      exposure on the morphology or metabolism of the cells associated with the dentine
      pulp complex. This study examined the effects of fluoride exposure at defined
      concentrations on the cellular morphology and ECM synthetic activities of
      odontoblasts and pulpal fibroblasts by the culture of tooth sections from male
      Wistar rat incisors in Trowel-type cultures for up to 14 days, in the presence
      and absence of 6mM sodium fluoride. Histomorphometric analysis of the dentine
      pulp complex of sodium fluoride-exposed tooth sections demonstrated no obvious
      gross morphological differences with respect to the odontoblasts and pulpal
      fibroblasts throughout the 14-day culture period, in comparison with unexposed
      tooth sections. No significant differences in odontoblast and pulpal fibroblast
      cell numbers were determined in the absence and presence of fluoride. Image
      analysis examination of odontoblast cytoplasmic:nuclear (C/N) ratios also showed
      no significant differences in fluoride-exposed and unexposed tooth sections,
      although reductions in the C/N ratios of pulpal fibroblasts were evident in
      fluoride-exposed sections at days 10 and 14. No significant differences in
      predentine width were observed in fluoride-exposed and unexposed tooth sections
      over the 14-day culture period. Autoradiography following [3H]proline
      incorporation into the dentine-pulp complex demonstrated inhibition of collagen
      synthesis, particularly by the odontoblasts in tooth sections exposed to 6mM
      sodium fluoride. These findings, in association with those from previous studies,
      imply that dentine ECM alterations may contribute to the altered mineralization
      of dentine during fluorosis, rather than secretory-related changes in odontoblast
      morphology.

PMID- 12615141
TI  - Expression of tumour necrosis factor-alpha in the rat dental follicle.
AB  - Tooth eruption requires the presence of the dental follicle, a loose connective
      tissue sac that surrounds each unerupted tooth. The follicle appears to regulate
      many of the cellular and molecular events of eruption, including the formation of
      osteoclasts needed to resorb alveolar bone to form an eruption pathway. To that
      end, the expression of the tumour necrosis factor-alpha (TNF-alpha) gene was
      examined in the dental follicle as a possible regulator of osteoclastogenesis.
      TNF-alpha was expressed slightly in the dental follicle of the first mandibular
      molar of the rat beginning at day 3 postnatally, but maximal expression was seen
      at day 9, a time that correlates with a slight burst of osteoclast formation seen
      at day 10 postnatally. In vitro, TNF-alpha was not expressed constitutively in
      the follicle cells but incubating them with interleukin 1alpha resulted in a
      strong expression of TNF-alpha after only 0.5h. TNF-alpha itself enhanced
      monocyte chemotactic protein 1 (MCP-1) and vascular endothelial growth factor
      (VEGF) gene expression. It also slightly decreased the expression of
      osteoprotegerin after 3-h incubation but this returned to the control level at
      6h. MCP-1 and VEGF could aid in recruiting mononuclear cells (osteoclast
      precursors) to the dental follicle. In addition to the potential role of TNF
      alpha in tooth eruption, this study suggests that the periodontal ligament
      derived from the dental follicle might have the capacity to synthesize TNF-alpha,
      and thereby contribute to the destructive events of periodontitis.

PMID- 12615142
TI  - Type II collagen and aggrecan mRNA expression by in situ hybridization in rabbit
      temporomandibular joint posterior attachment following disc displacement.
AB  - Pathological changes and mRNA expression were studied in the posterior attachment
      of 40 adult Japanese white rabbits. The right temporomandibular joints of 28
      rabbits were subjected to surgical disc displacement. Joints were studied by
      histochemistry and in situ hybridization. The collagen in the posterior
      attachment became dense, especially near the posterior band of the disc.
      Chondrocytes were found not only in the disc but also in the posterior
      attachment. Sometimes cartilage formation was seen. Type II collagen mRNA
      expression was first detected in the posterior attachment 4 days postoperatively
      and became progressively stronger with time. Aggrecan expression in the posterior
      attachment decreased at first, then increased gradually. It was concluded that,
      in the temporomandibular joint, chondrocytes appear in the posterior attachment
      as a result of biomechanical stimuli and the attachment becomes
      fibrocartilaginous following disc displacement.

PMID- 12615143
TI  - Effect of the phosphodiesterase 4 inhibitor, rolipram, on retinoic acid-increased
      alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2 cell line.
AB  - We have evaluated effects of a phosphodiesterase (PDE) 4 inhibitor on retinoic
      acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2
      clone 8 (10T1/2) cell line. 10T1/2 cells were cultured in minimum essential
      medium (MEM) and 10% fetal bovine serum with or without 1 microM retinoic acid
      and/or the PDE 4 inhibitor, rolipram, and harvested at specific intervals before
      measurement of alkaline phosphatase activity, cAMP production in response to
      parathyroid hormone, osteocalcin synthesis and expression, and phosphodiesterase
      activity. Retinoic acid-increased alkaline phosphatase activity, and slightly
      enhanced cAMP production in response to parathyroid hormone. However, it did not
      affect osteocalcin synthesis and expression. In the presence of retinoic acid,
      PDE 4 activity was not changed. A PDE 4 inhibitor, rolipram, and cAMP analog, 8
      bromo-cAMP dramatically increased retinoic acid's ability to induce alkaline
      phosphatase activity. This is the first report that PDE 4 may be involved in
      regulation of retinoic acid-increased alkaline phosphatase activity.

PMID- 12615144
TI  - Effects of alkaline phosphatase and its inhibitor levamisole on the modulation of
      androgen metabolism by nicotine and minocycline in human gingival and oral
      periosteal fibroblasts.
AB  - The aim of this investigation was to establish the implications of nicotine,
      minocycline, alkaline phosphatase (AP) and its inhibitor levamisole (L) on tissue
      turnover in human gingival and periosteal fibroblasts (HGF, HPF) using [14C]
      testosterone as substrate. Monolayer cultures of HGF and HPF established from
      four patients were incubated in duplicate with serial and optimal concentrations
      of nicotine and minocycline, alone and in combination, for 24h in Eagle's MEM,
      with the substrate [14C]-testosterone. Further experiments were carried out on
      HPF only, to investigate the effects of alkaline phosphatase (AP) and its
      inhibitor levamisole (L) on the metabolism of [14C]-testosterone, followed by the
      effects of L on the modulatory actions of nicotine. The cell-conditioned medium
      was then solvent-extracted, analysed and quantified for steroid metabolites using
      a radioisotope scanner. At low concentrations, nicotine stimulated the synthesis
      of the physiologically active androgen 5alpha-dihydrotestosterone (DHT) from
      [14C]-testosterone, with inhibition at higher concentrations (n=4; P<0.01).
      Minocycline stimulated the synthesis of DHT, with decreased yields in the
      presence of nicotine (n=4; P<0.01), but greater than with nicotine alone.
      Alkaline phosphatase significantly enhanced the synthesis of androgen metabolites
      by HPF (n=4; P<0.01), with inhibition in response to L alone and in combination
      with AP, to less than control values (n=4; P<0.01). L also caused further
      inhibition in the yields of androgen metabolites when incubated with nicotine,
      implying that some of the inhibitory effects of nicotine could be due to
      inhibition of AP activity. CONCLUSION: This investigation has shown that nicotine
      can inhibit the formation of matrix-stimulatory steroid metabolites in
      fibroblasts, partly due to inhibition of AP activity. Minocycline is a useful
      adjunct, in reducing the inhibition of androgen metabolism caused by nicotine.

PMID- 12615145
TI  - Immunohistochemical investigation on the pattern of vimentin expression in
      regenerated and intact monkey and human periodontal ligament.
AB  - The expression of vimentin is well documented in the intact animal and human
      periodontal ligament (PDL), but there is limited information on the pattern of
      vimentin expression in the regenerated PDL. The aim of the present study was to
      investigate the pattern of vimentin expression in the regenerated and intact
      monkey and human PDL. A total of 12 chronic recession-type defects were created
      in three monkeys (Macaca fascicularis) and treated either with guided tissue
      regeneration (GTR), or with an enamel matrix protein derivative (EMD). After 5
      months, the animals were sacrificed and specimens containing the defects and
      surrounding tissues were dissected free, decalcified in EDTA and embedded in
      paraffin. Sections were labelled immunohistochemically by using monoclonal
      antibody against vimentin (VIM 3B4). Twelve patients, each of whom displayed one
      deep intrabony defect scheduled for extraction were treated with GTR, EMD or
      combination of EMD+natural bone mineral (NBM). Following a healing period of 6
      months, the teeth were extracted "en block" and immunohistochemically analysed
      according to the same protocol as described in monkeys. The results revealed that
      in both monkeys and humans the newly formed PDL was labelled similarly for
      vimentin to the intact (non-treated) PDL. In all specimens, the newly formed PDL
      was in continuation with the intact parts of PDL, thus suggesting that the
      mesenchymal cells capable of regenerating the attachment apparatus may have their
      origin in the intact PDL. In conclusion, the present findings indicate that (a)
      the reformed PDL displayed a similar expression of vimentin to the intact
      (original) PDL, and (b) the cells capable of regenerating new PDL and new
      cementum appear to be of mesenchymal origin and their source may be in the intact
      PDL.

PMID- 12615146
TI  - Expression of ATP-binding cassette transporter in human salivary ducts.
AB  - P-glycoprotein expression has been observed in normal tissues as well as
      malignant tumours and thus does not appear to be induced by anticancer drugs.
      Knowledge of the distribution of ATP-binding cassette (ABC) transporters other
      than P-glycoprotein in normal salivary tissue is essential for understanding the
      physiological secretion or excretion of potentially toxic substances. Here the
      expression of ABC transporters was studied immunohistochemically in normal
      salivary gland tissue from nine patients. In striated duct cells, staining was
      strong for P-glycoprotein, multidrug resistance-associated protein (MRP) 1, MRP
      2/canalicular multispecific organic anion transporter (cMOAT), and lung
      resistance-related protein (LRP). The staining intensity of acinar and
      intercalated duct cells for MRP 1 expression was distinct from that for
      MRP2/cMOAT, but was similar to that for P-glycoprotein. LRP was observed as
      particles between the nuclear and luminal membranes in the cytoplasm of
      intercalated duct cells. The expression of ABC transporters suggests that
      numerous transporters other than those studied might be isolated from normal
      salivary tissues. These observations indicate that these ABC transporters may not
      arise from any previous contact with anticancer drugs but are expressed
      physiologically. The achieved drug resistance as well as the physiological
      secretory function of ABC transporters could contribute to the responsiveness to
      chemotherapy of malignant salivary tumours.

PMID- 12615148
TI  - Determination of distance of intra-molecular hydrogen bonding in (Ala-Gly)15 with
      silk I form after removal of the effect of MAS frequency in REDOR experiment.
AB  - It is important to know the structure of silk I (Bombyx mori silk structure
      before spinning in the solid state) in order to understand the mechanism of fiber
      formation at the atomic level. In this study, 15N-dephased, 13C-observe REDOR has
      been carried out to determine the atomic distance of intra-molecular hydrogen
      bond between the 13C=O carbon of the 14th Gly residue and the 15N nitrogen of the
      17th Ala residue of (AG)(6)A[1-13C]GAG[15N]AG(AG)(6) with silk I form after
      removal of the effect of MAS frequency on the re-coupling. The distance was
      determined to be 4.3A, which confirmed the intra-molecular hydrogen bonding
      formation between these two atomic sites.

PMID- 12615147
TI  - Dynamic nuclear polarization at 9T using a novel 250GHz gyrotron microwave
      source.
AB  - In this communication, we report enhancements of nuclear spin polarization by
      dynamic nuclear polarization (DNP) in static and spinning solids at a magnetic
      field strength of 9T (250 GHz for g=2 electrons, 380 MHz for 1H). In these
      experiments, 1H enhancements of up to 170+/-50 have been observed in 1-13C
      glycine dispersed in a 60:40 glycerol/water matrix at temperatures of 20K; in
      addition, we have observed significant enhancements in 15N spectra of unoriented
      pf1-bacteriophage. Finally, enhancements of approximately 17 have been obtained
      in two-dimensional 13C-13C chemical shift correlation spectra of the amino acid U
      13C, 15N-proline during magic angle spinning (MAS), demonstrating the stability
      of the DNP experiment for sustained acquisition and for quantitative experiments
      incorporating dipolar recoupling. In all cases, we have exploited the thermal
      mixing DNP mechanism with the nitroxide radical 4-amino-TEMPO as the paramagnetic
      dopant. These are the highest frequency DNP experiments performed to date and
      indicate that significant signal enhancements can be realized using the thermal
      mixing mechanism even at elevated magnetic fields. In large measure, this is due
      to the high microwave power output of the 250 GHz gyrotron oscillator used in
      these experiments.

PMID- 12615149
TI  - X-filtering for a range of coupling constants: application to the detection of
      intermolecular NOEs.
AB  - A new method for heteronuclear X-filtering is presented, which relies on
      repetitive applications of 90 degrees (1H)-tau(1/41J(HC))-180 degrees (1H,13C)
      tau(1/41J(HC))-90 degrees (1H,13C)-PFG building blocks employing gradient
      mediated suppression of magnetization built up for directly heteronuclear coupled
      protons. Thereby, a range of heteronuclear coupling constants can be suppressed
      by varying the delays of scalar coupling evolution both within and between
      individual transients. To achieve efficient destruction of 13C-coupled protons in
      macromolecular systems, the scalar coupling evolution delays were optimized using
      simulated annealing by including transverse relaxation effects. With a
      combination of regular hard pulses, delays and pulsed field gradients only, this
      method yields sufficient X-filtering to allow the observation of intermolecular
      nuclear overhauser effects in a molecular complex consisting of a 13C, 15N double
      labeled, and an unlabeled protein. This is achieved by exciting magnetization of
      12C- and 14N-bound protons and detecting 13C-bound 1H magnetization in a 3D 13C
      filtered, 13C-edited NOESY-HSQC experiment. The method is tested on the 18 kDa
      homodimeric bacterial antidote ParD.

PMID- 12615150
TI  - Selective suppression and excitation of solid-state NMR resonances based on
      quadrupole coupling constants.
AB  - The dependence of the (Rotor Assisted Population Transfer) RAPT enhancement on
      offset frequency for nuclei experiencing different quadrupolar couplings has been
      exploited to design two new spectral editing schemes, pi/2-RAPT and RAPT-pi-RAPT,
      for the selective excitation or suppression, respectively, of nuclei with large
      quadrupolar couplings. Both approaches are demonstrated on the 87 Rb spectrum of
      Rb(2)SO(4), which contains two resonances with C(q) values of 2.6 and 5.3 MHz.
      The conditions for optimal selectivity are discussed. Combining pi/2-RAPT with
      the RIACT MQ-MAS experiment it is also demonstrated how a pure absorption mode
      triple quantum MQ-MAS spectrum devoid of narrow resonances can be obtained.

PMID- 12615151
TI  - Homonuclear decoupled 13C chemical shift anisotropy in 13C doubly labeled
      peptides by selective-pulse solid-state NMR.
AB  - We describe a new experiment for measuring homonuclear-decoupled anisotropic
      chemical shift patterns in doubly 13C-labeled compounds under magic-angle
      spinning. The experiment combines a pair of selective and non-selective 180
      degrees pulses to suppress the 13C-13C scalar and dipolar interactions. This is
      combined with the recently developed SUPER technique to recouple the chemical
      shift anisotropy. Demonstrations on 13Calpha and 13CO-labeled amino acids and
      peptides show that accurate chemical shift powder patterns can be obtained. This
      permits the use of chemical shift anisotropy for conformational studies of
      suitably extensively 13C-labeled peptides and proteins.

PMID- 12615152
TI  - The new HMQC-based technique for the quantitative determination of heteronuclear
      coupling constants. Application for the measurement of 3J(H'(i),P(i+1)) in DNA
      oligomers.
AB  - A new general J-HMQC-based technique is presented, which allows an accurate
      determination of heteronuclear coupling constants. The most important feature of
      this new approach includes acquisition of the two data sets with and without the
      additional pi(S)-pulse at the end of coupling evolution period. This enables
      preservation and separation of the two orthogonal terms of coupling evolution,
      which are manifested by in- and antiphase cross-peaks, respectively. The coupling
      magnitudes are evaluated by the nonlinear least-squares fitting of the ratios of
      integrated signal volumes for both kinds of signals. The effectiveness of the new
      sequence is demonstrated by determination of the 3J(H3'(i),P(i+1)) couplings in
      DNA octamer duplex d(GCGTACGC)(2) sample. Additionally, the ability of the new
      method for the measurement at the natural abundance level of 13C nuclei is
      presented for the beta-cyclodextrin.

PMID- 12615153
TI  - Long repetition time experiments for measurement of concentrations in systems
      with chemical exchange and undergoing temporal variation-comparison of methods
      with and without correction for saturation.
AB  - The purpose of this paper is to compare two methods for quantifying metabolite
      concentrations using the one-pulse experiment for a sample undergoing chemical
      exchange and subject to an intervention or other temporal variation. The methods,
      LATR-C (Long Acquisition TR (interpulse delay); Corrected for partial saturation)
      and LATR-NC (Long Acquisition TR; Not Corrected), are compared in terms of signal
      to-noise ratio, SNR, per unit time and quantitation errors. Parameters relevant
      to the isolated perfused rat heart are used as a specific application, although
      the results are general. We assume throughout that spin-lattice relaxation times,
      T(1), do not change. For a given flip angle, theta, TR's are calculated which
      result in maximal SNR per unit time under 10%, 5%, and 1% constraints on
      quantitation errors. Additional simulations were performed to demonstrate
      explicitly the dependence of the quantitation errors on TR for a fixed theta. We
      find (i) if the allowed error is large, and when both metabolite concentrations
      and rate constants vary, LATR-C permits use of shorter TR, and hence yields
      greater SNR per unit time, than LATR-NC; (ii) for small allowed error, the two
      methods give similar TR's and SNR per unit time, so that the simpler LATR-NC
      experiment may be preferred; (iii) large values of theta result in similar
      constrained TR's and hence SNR per unit time for the two methods; (iv) the ratio
      of concentrations of metabolites with similar T(1) exhibit similar errors for the
      two methods.

PMID- 12615154
TI  - Variable-frequency EPR study of Mn(2+)-doped NH(4)Cl(0.9)I(0.1) single crystal at
      9.6, 36, and 249.9 GHz: structural phase transition.
AB  - Multifrequency electron paramagnetic resonance studies on the Mn(2+) impurity ion
      in a mixed single crystal NH(4)Cl(0.9)I(0.1) were carried out at 9.62 (X-band) in
      the range 120-295 K, at 35.87 (Q-band) at 77 and 295 K, and at 249.9 GHz (far
      infrared band) at 253 K. The high-field EPR spectra at 249.9 GHz are well into
      the high-field limit leading to a considerable simplification of the spectra and
      their interpretation. Three magnetically inequivalent, but physically equivalent,
      Mn(2+) ions with their respective magnetic Z-axes oriented along the
      crystallographic [100], [010], [001] axes were observed. Simultaneous fitting of
      EPR line positions observed at X-, Q-, and far infra-red bands was performed
      using a least-squares procedure and matrix diagonalization to estimate accurately
      the Mn(2+) spin-Hamiltonian parameters. The temperature variation of the
      linewidth and peak-to-peak intensities of the EPR lines indicate the presence of
      lambda-transitions in the mixed NH(4)Cl(0.9)I(0.1) crystal at 242 and 228 K
      consistent with those observed in the pure NH(4)Cl and NH(4)I crystals,
      respectively. A superposition-model analysis of the spin-Hamiltonian parameters
      reveals that the local environment of the Mn(2+) ion is considerably reorganized
      to produce axially symmetric crystal fields about the respective Z-axes of the
      three magnetically inequivalent ions as a consequence of the vacancy created due
      to charge-compensation when the divalent Mn(2+) ion substitutes for a monovalent
      NH(4)(+) ion in the NH(4)Cl(0.9)I(0.1) crystal. This reorganization is almost the
      same as that observed in NH(4)Cl and NH(4)I single crystals, although the latter
      two are characterized by different, simple cubic and face-centered cubic,
      structures.

PMID- 12615155
TI  - Determination of pore space shape and size in porous systems using NMR
      diffusometry. Beyond the short gradient pulse approximation.
AB  - The influence of finite length gradient pulses on NMR diffusion experiments on
      liquids confined to diffuse between two parallel planes is investigated. It is
      experimentally verified that the pore size decreases when determined using finite
      gradient pulses if the results are analyzed within the short gradient pulse
      approximation. The results are analyzed using the matrix formulation. The
      observed minima in the echo decay profiles are considerably less sharp than
      theoretical analysis would indicate and we suggest that this is due to the
      presence of a distribution of pore sizes in the sample. In addition, effects due
      to the presence of background gradients are discussed. It is argued that effects
      due to the finite length gradient pulses are relatively minor and in realistic
      applications the effects due to inhomogeneities in pore sizes and effects due to
      background gradients will constitute more serious problems in pore size
      determinations by means of NMR diffusometry.

PMID- 12615156
TI  - Multipoint mapping for imaging of semi-solid materials.
AB  - Multipoint k-space mapping is a hybrid between constant-time (single-point
      mapping) and spin-warp imaging, involving sampling of a k-line segment of r
      points per TR cycle. In this work the method was implemented for NMR imaging of
      semi-solid materials on a 400 MHz micro-imaging system and two different k-space
      sampling strategies were investigated to minimize the adverse effects from
      relaxation-induced k-space signal modulation. Signal attenuation from T(2) decay
      results in artifacts whose nature depends on the k-space sampling strategy. The
      artifacts can be minimized by increasing the readout gradient amplitude, by PSF
      deconvolution or by oversampling in readout direction. Finally, implementation of
      a T(2) selective RF excitation demonstrates the feasibility of obtaining short
      T(2) contrast even in the presence of tissues with long-T(2). The method's
      potential is illustrated with 3D proton images of short-T(2) materials such as
      synthetic polymers and bone.

PMID- 12615157
TI  - The Doppler effect in NMR spectroscopy.
AB  - An NMR sample may be subject to motions, such as those due to sample spinning or
      to liquid flow. Is the spectrum of such a sample affected by the Doppler effect?
      The question arises because, instrumental dimensions being much shorter than the
      wavelength, it is the near-field of the precessing magnetic moment which couples
      to the receiver coil, rather than the radiated far-field. We expand the near
      field into plane propagating waves. For each such wave there is another one with
      the same amplitude, propagating in the opposite direction. The Doppler shifts are
      therefore equal and opposite. In the model case of a small fluid sample moving
      with constant velocity, this leads to a distribution of Doppler shifts which is
      symmetrical with respect to the unshifted frequency: there is no net spectral
      shift. We examine the possibility of observing the Doppler distribution in this
      case. We also consider the case of thermal motion of a gas. We draw attention to
      the resolved Doppler splitting of molecular rotational transitions in a
      supersonic burst as observed in a microwave resonator. We also mention briefly
      the Doppler effect in molecular beam spectroscopy.

PMID- 12615158
TI  - Discrimination of 13C NMR signals in solid material with liquid-like behavior
      presenting residual dipolar proton-proton homonuclear interactions: application
      on seeds.
AB  - In this communication, we propose, a modified spin echo fourier transform (SEFT)
      experiment run under magic angle spinning (MAS) to obtain structural informations
      of the liquid-like domains inside complex organic materials. It includes a proton
      proton dipolar decoupling such as BLEW12 or Lee-Goldburg sequence just after the
      180 degrees 13C refocusing pulse and short echo delays are used in order to
      overcome T(2) relaxation. This very easy implemented sequence allows a clear
      discrimination among fast relaxing 13C signals between those with a pure liquid
      like behavior and those presenting residual proton-proton dipolar coupling. The
      interests of the sequence, combined with other classical NMR experiments, are
      illustrated on whole vegetable seeds that represent an example of a complex
      material.

PMID- 12615159
TI  - End-to-end correlation for a C-12 hydrocarbon chain.
AB  - The 19F nuclear spin-lattice relaxation rate constants were measured as a
      function of magnetic field strength for 1,12-diaminododecane labeled at one end
      with a nitroxide radical and at the other with a trifluoromethyl group. The
      magnetic relaxation dispersion profile (MRD) reports the spectral density
      function appropriate to the end-to-end correlation function for the doubly
      labeled molecule. After extrapolation to zero concentration to eliminate the
      intermolecular relaxation contribution to relaxation, the resulting
      intramolecular MRD profile was compared with several model approaches. The
      rotational model for the spectral density functions as included in the Solomon
      Bloembergen-Morgan equations does not describe the data well. The earlier model
      of Freed for nuclear spin relaxation induced by a freely diffusing paramagnetic
      co-solute is not rigorous for this case because the paramagnet is tethered to the
      observed nuclear spin and only a restricted space in the immediate vicinity of
      the nuclear spin is accessible for pseudo-translational diffusion of one end of
      the molecule with respect to the other. A generalization of the Torrey model for
      magnetic relaxation by translational diffusion developed by Nevzorov and Freed,
      which includes the effect of restrictions imposed by the finite length of the
      chain, describes the experiment within experimental errors. A simple modification
      of the Hwang-Freed model that does not specifically include the dynamical effects
      of the finite tether also provides a good approximation to the data when the
      tether chain is sufficiently long.

PMID- 12615160
TI  - The continuous wave electron paramagnetic resonance experiment revisited.
AB  - When the modulation frequency used in continuous wave electron paramagnetic
      resonance (cw EPR) spectroscopy exceeds the linewidth, modulation sidebands
      appear in the spectrum. It is shown theoretically and experimentally that these
      sidebands are actually multiple photon transitions, sigma(+)+kxpi, where one
      microwave (mw) sigma(+) photon is absorbed from the mw radiation field and an
      arbitrary number k of radio frequency (rf) pi photons are absorbed from or
      emitted to the modulation rf field. Furthermore, it is demonstrated that both the
      derivative shape of the lines in standard cw EPR spectra and the distortions due
      to overmodulation are caused by the unresolved sideband pattern of these lines.
      The single-photon transition does not even give a contribution to the first
      harmonic cw EPR signal. Multiple photon transitions are described semiclassically
      in a toggling frame and their existence is proven using second quantization. With
      the toggling frame approach and perturbation theory an effective Hamiltonian for
      an arbitrary sideband transition is derived. Based on the effective Hamiltonians
      an expression for the steady-state density operator in the singly rotating frame
      is derived, completely describing all sidebands in all modulation frequency
      harmonics of the cw EPR signal. The relative intensities of the sidebands are
      found to depend in a very sensitive way on the actual rf amplitude and the
      saturation of single sidebands is shown to depend strongly on the effective field
      amplitude of the multiple photon transitions. By comparison with the analogous
      solutions for frequency-modulation EPR it is shown that the field-modulation and
      the frequency-modulation technique are not equivalent. The experimental data
      fully verify the theoretical predictions with respect to intensities and
      lineshapes.

PMID- 12615161
TI  - Tritrichomonas foetus: characterization of isolates and partial purification of a
      secreted cytotoxin.
AB  - Putative virulence factors including extracellular proteases, hemagglutinin,
      hemolysins, and soluble cytotoxins may play significant roles in the pathogenesis
      of trichomoniasis. The cytotoxicity, hemagglutinating, and hemolytic activity of
      Tritrichomonas foetus isolate ATCC #30003 and several field isolates were
      compared. All isolates were hemolytic toward mouse and bovine erythrocytes but
      not other tested species. The isolates varied significantly in hemagglutinating
      ability and cytotoxin production. A 40,000 Da soluble cytotoxin was partially
      purified and characterized. Chromatography separated cytotoxic activity from
      hemagglutinating and hemolytic activity but not from protease activity. However,
      protease assays indicated that protease activity was inversely correlated with
      cytotoxic activity. Characterization studies indicated that cytotoxic activity
      was destroyed by heat and acidic conditions but repeated freeze/thawing did not
      diminish activity. Target cell specificity assays showed Henle cells were twice
      as sensitive to the effects of the cytotoxin as Vero cells. These results suggest
      that T. foetus isolates vary in the production of virulence factors and produce a
      soluble relatively stable non-protease cytotoxic protein capable of killing
      cultured mammalian cells in vitro.

PMID- 12615163
TI  - In vitro culture and biochemical characterization of six trypanosome isolates
      from Peru and Brazil.
AB  - Six trypanosomatids isolated from different geographical areas from South America
      (Peru and Brazil) and different vectors and reservoir hosts (the triatomine
      Panstrongylus chinai [TP1], Triatoma infestans [TP2], Rhodnius ecuadorensis
      [TP3], R. prolixus [TB1], Didelphys marsupialis [TB2]), and one from a human
      asymptomatic patient [TB3], were characterized using lectin agglutination,
      isoenzyme profile, in vitro culture final metabolite patterns, and compared with
      a reference strain (Trypanosoma cruzi, Maracay strain [TC]). The different
      isolates were cultured in vitro in Grace's medium supplemented with 10%
      inactivated bovine foetal serum. According to our results and the statistical
      study, the isolate obtained from R. ecuadorensis should be designed as a
      Trypanosoma rangeli sp., showing all other isolates strong similarities to T.
      cruzi. Between them, two clusters could be identified, strongly correlating with
      the geographical origin. Cluster I grouped isolates from Peru and T. cruzi
      reference strain, and cluster II grouped the three Brazilian isolates.

PMID- 12615162
TI  - Immunization with a tubulin-rich preparation from Trypanosoma brucei confers
      broad protection against African trypanosomosis.
AB  - Tubulin from Trypanosoma brucei was purified to near homogeneity using a protocol
      which involved treatment with urea with subsequent renaturation and was then used
      to immunize mice. Renatured tubulin further purified by SDS-PAGE (denatured),
      synthetic tubulin peptides (STP), and rat brain tubulin (RbTub) were also used.
      Immunized mice were challenged with T. brucei, Trypanosoma congolense or
      Trypanosoma rhodesiense. Renatured T. brucei tubulin (nTbTub) induced protection
      in all mice tested, of which 60-80% (n = 81) was complete and the remainder
      partial. Denatured T. brucei tubulin (dTbTub), STP, or RbTub induced lower
      antibody levels than nTbTub and did not offer protection. However, in culture,
      the antibodies against dTbTub or STP killed trypanosomes although at lower
      dilutions than nTbTub, but those against RbTub did not. In Western blots anti
      trypanosome antibodies recognized the tubulin of all the trypanosome species
      investigated but not vertebrate tubulin, whereas the anti-RbTUB antibodies
      recognized both trypanosome and vertebrate tubulin. Of the five mice given
      passive immunity by the transfer of anti-nTbTub serum, four were completely
      protected and one partially protected. These data suggest that tubulin is the
      relevant immunogen in the preparation used and could therefore be a promising
      target for the development of a parasite-specific, broad spectrum vaccine.

PMID- 12615164
TI  - A new set of vesicles in Giardia lamblia.
AB  - In the present study it was demonstrated the existence of a new set of membrane
      bounded vesicles in Giardia lamblia. They were found in dividing and non-dividing
      trophozoites studied by routine transmission electron microscopy, freeze-fracture
      and Thiery's technique. Encysting cells were not studied. These vesicles appear
      different to the previously reported components of the Giardia endomembranous
      system, such as the endoplasmic reticulum (ER), lysosome-like peripheral vesicles
      (PV), and the encystation-specific vesicles (ESV) that appear during trophozoite
      differentiation into cysts. They measure 100-150 nm in diameter, and thus are
      smaller than the peripheral vesicles, and the encystation-specific vesicles
      (ESV). They were found in clusters, scattered throughout the cytoplasm, but
      preferentially located close to the nuclei, axonemes, median bodies, and ER
      profiles. These internal vesicles are roughly spherical, and their contents
      present different electron densities and are more electrondense than those of the
      peripheral vesicles. They appeared to be budding from the outer nuclear membrane
      envelope. These cytoplasmic vesicles were found only in cells with very good
      fixation. Only few cells in the same preparation exhibited these vesicles.

PMID- 12615165
TI  - Schistosoma japonicum: effect of artemether on glutathione S-transferase and
      superoxide dismutase.
AB  - Glutathione S-transferase (GST) and superoxide dismutase (SOD) are major
      antioxidant enzymes of schistosomes that are involved in detoxification
      processes. To study the effect of artemether on these enzymes, mice infected with
      adult Schistosoma japonicum, were treated with artemether either at a subcurative
      (100 mg/kg) or a curative dose (300 mg/kg). Schistosomes were recovered 24-72 h
      post-treatment separated by sex and used for GST and SOD activity measurements.
      Female worms showed consistently higher GST inhibitions than males. For instance,
      24 h after administration of 100 mg/kg artemether, GST activities of female worms
      were inhibited by 23.3%, as compared to 12.7% in males. Both activities were
      significantly lower when compared to worms recovered from untreated mice.
      Slightly higher inhibitions were observed at the higher dose of artemether, which
      gradually increased to levels of 52.5-55.1%, 72 h post-treatment. GST inhibitions
      could be reversed by application of 1,4-dithiothreitol at a concentration of 10
      mmol/L. Adding L-cysteine also reduced GST inhibitions, but in female worms, GST
      activities remained significantly higher than in worms from untreated animals.
      Administration of 300 mg/kg artemether resulted in significant reductions of SOD
      activities in both sexes. In conclusion, these results suggest that the
      inhibition of GST and, to a lesser extent also SOD enzymes, could lead to
      increased schistosome susceptibility to oxidant attacks and might be linked with
      the antischistosomal action of artemether.

PMID- 12615166
TI  - Further molecular discrimination of Spanish strains of Echinococcus granulosus.
AB  - We have designed two polymerase chain reaction (PCR) primer sets (PEg9F1-PEg9R1
      and PEg16F1-PEg16R1) and two PCR protocols (Eg9-PCR and Eg16-PCR) for
      discrimination of Echinococcus granulosus genotypes. The oligonucleotide
      sequences originate from two E. granulosus DNA multiplex-PCR amplification
      fragments, previously reported, that allows species-specific discrimination
      between Taenia saginata, Taenia solium, and E. granulosus. The Eg9-PCR, Eg16-PCR,
      and Eg9-PCR linked restriction fragment length polymorphism (RFLP) analysis was
      used to characterize 53 E. granulosus isolates from the central region of Spain,
      highly endemic for echinococcosis. The analysis resulted in: (i) the
      discrimination of E. granulosus from Echinococcus multilocularis; (ii) the
      characterisation and discrimination of discrete E. granulosus strains from Spain;
      and (iii) the identification of two distinct genotypes within E. granulosus
      Spanish pig isolates. To further characterize the genetic variants in pigs,
      fragments of the NADH dehydrogenase I (ND1) and the cytochrome c oxidase subunit
      I (CO1) genes were amplified from parasite DNA and sequenced. The results again
      revealed the presence of two distinct genotypes: the G1 (sheep-dog strain) and G7
      (pig-dog strain) genotypes. This observation could have important consequences
      for human health in Spain. Furthermore, the Eg9-PCR, Eg16-PCR, and Eg9-PCR-RFLP
      protocols can be used as additional methods to discriminate various E. granulosus
      genotypes.

PMID- 12615167
TI  - Detergent-resistant erythrocyte membrane rafts are modified by a Plasmodium
      falciparum infection.
AB  - Detergent resistant membranes (DRMs) have been implicated in numerous cellular
      processes including signal transduction, membrane trafficking, and molecular
      sorting. Flotillins-1 and -2 have recently been shown to be large components of
      erythrocyte DRMs. In this study, we show that a Plasmodium falciparum infection
      disrupts the association of flotillins with erythrocyte DRMs. Flotillins are
      probably released from erythrocyte DRMs through the reduction of cholesterol and
      sphingomyelin levels during the course of a P. falciparum-infection. Although it
      is well known that a P. falciparum infection can modify the host erythrocyte
      membrane, this is the first report that P. falciparum can alter the DRM
      components of erythrocyte membranes.

PMID- 12615169
TI  - Neurodevelopmental disorders in males related to the gene causing Rett syndrome
      in females (MECP2).
AB  - Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause
      Rett syndrome, a well-known and clinically defined neurodevelopmental disorder.
      Rett syndrome occurs almost exclusively in females and for a long time was
      thought to be an X-linked dominant condition lethal in hemizygous males. Since
      the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2
      mutations have, however, also been reported in males. These males phenotypically
      have classical Rett syndrome when the mutation arises as somatic mosaicism or
      when they have an extra X chromosome. In all other cases, males with MECP2
      mutations show diverse phenotypes different from classical Rett syndrome. The
      spectrum ranges from severe congenital encephalopathy, mental retardation with
      various neurological symptoms, occasionally in association with psychiatric
      illness, to mild mental retardation only. We present a 21-year-old male with
      severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic
      scoliosis. A history of early hypotonia evolving into severe spasticity, slowing
      of head growth, breathing irregularities and good visual interactive behaviour
      were highly suggestive of Rett syndrome. He has a de novo missense mutation in
      exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in
      males with MECP2 mutations are reviewed.

PMID- 12615170
TI  - Leber's congenital amaurosis: an update.
AB  - Leber's congenital amaurosis (LCA) is a clinically and genetically heterogeneous
      disorder characterized by severe loss of vision at birth. It accounts for 10-18%
      of cases of congenital blindness. Some patients exhibit only blindness of retinal
      origin whereas others show evidence of a multi-systemic involvement. We review
      the literature relating to this severe disorder, highlighting unresolved
      questions, in particular the nature of the association of LCA with mental
      retardation and with systemic findings and syndromic pictures. In recent years,
      genetic advances in the diagnosis of LCA have opened up new horizons, also from a
      therapeutic point of view. A better understanding of this pathology would be
      valuable for paediatric neurologists.

PMID- 12615171
TI  - What's new in neuromuscular disorders? The congenital myopathies.
AB  - The congenital myopathies are a heterogeneous group of early-onset neuromuscular
      conditions with characteristic findings on muscle biopsy, comprising central core
      disease, minicore myopathy (multi-minicore disease), nemaline myopathy and
      myotubular myopathy. Recent years have seen genetic resolution of a proportion of
      these conditions. The following review summarizes recent genetic findings in the
      congenital myopathies and outlines implications for our understanding of their
      pathophysiological basis and their relation to other neuromuscular disorders.

PMID- 12615172
TI  - Decreased homovanillic acid concentrations in cerebrospinal fluid in children
      without a known defect in dopamine metabolism.
AB  - Homovanillic acid (HVA) is a metabolite of dopamine, reflecting central dopamine
      metabolism, primarily situated in the striatum. Low HVA concentrations in the
      cerebrospinal fluid (CSF) may indicate metabolic deficiencies in the pathways of
      the biosynthesis or catabolism of dopamine. In this retrospective study, we
      investigated the clinical presentation of patients whose HVA concentration in the
      CSF had been determined routinely after spinal taps for a variety of clinical
      reasons. A decrease of HVA concentration in the CSF, due to a defect in the
      biosynthesis or reuptake of dopamine, is expected to cause extrapyramidal
      features. However, we found a remarkable variability in the clinical symptoms.
      Similarly, a decreased HVA concentration in the CSF failed to coincide with
      specific abnormalities at neuroimaging. In view of the diversity of the clinical
      presentation and in the absence of specific enzyme deficiencies, a decrease of
      HVA may be due to dysfunction of dopamine neurons, not resulting in specific
      extrapyramidal symptoms. Thus, with the exception of diseases associated with a
      specific enzyme deficiency in the metabolic pathways involving dopamine, a
      decrease of HVA concentration in the CSF is mainly a secondary or epiphenomenon
      in a variety of clinical conditions.

PMID- 12615173
TI  - Ischaemic stroke from dissection of the craniocervical arteries in childhood:
      report of 12 patients.
AB  - Dissection of craniocervical arteries is the most common non-atherosclerotic
      cause of stroke in young adults. During childhood, it is described primarily as
      isolated reports. Among 59 patients with arterial ischaemic stroke seen
      consecutively in the same institution, 12 had a dissection of a cervical or
      cerebral artery. The diagnosis was established through imaging features. The
      dissection involved the cervical arteries in five patients and intracranial
      arteries in seven. A cervical or facial trauma preceded the onset of cerebral
      ischaemic symptoms in four patients with extracranial dissection by a few minutes
      to 10 days. For another six patients, the stroke occurred during physical
      exertion. The neurological deficit was preceded or associated with an intense
      headache or neck pain in nine patients. Initial treatment consisted of
      anticoagulation therapy in two patients with extracranial dissection, and aspirin
      in nine. There was only one recurrence of stroke after a mean follow-up of 3
      years and 6 months. Four patients had persistent disabling neurological deficit.
      Dissection of cervical or cerebral arteries appears to be a common cause of
      stroke in childhood.

PMID- 12615174
TI  - Frequent seizures with elevated interleukin-6 at the eruptive stage of exanthema
      subitum.

PMID- 12615176
TI  - Central nervous system malformations: gene locations of known human mutations.

PMID- 12615180
TI  - Catecholamines, sympathetic innervation, and immunity.

PMID- 12615181
TI  - Mechanisms of stress-induced modulation of immunity.
AB  - The purpose of this chapter is to discuss the wealth of animal studies of stress
      induced modulation of immunity, and to relate our understanding of stress and
      immunity to clinical populations, particularly cancer patients.

PMID- 12615182
TI  - Stressed to death: implication of lymphocyte apoptosis for psychoneuroimmunology.
AB  - Psychological and physical stressors best exemplify the intercommunication of the
      immune and the nervous systems. It has been shown that stress significantly
      impacts leukocyte cellularity and immune responses and alters susceptibility to
      various diseases. While acute stress has been shown to enhance immune responses,
      chronic stress often leads to immunosuppression. Among many criteria examined
      upon exposure to chronic stress, the reduction in lymphocyte mitogenic response
      and lymphocyte cellularity are commonly assessed. We have reported that chronic
      restraint stress could induce lymphocyte reduction, an effect dependent on
      endogenous opioids. Interestingly, the effect of endogenous opioids was found to
      be exerted through increasing the expression of a cell death receptor, Fas, and
      an increased sensitivity of lymphocytes to apoptosis. Stress-induced lymphocyte
      reduction was not affected by adrenalectomy. In this review, based on available
      literature and our recent data, we will discuss the role of the hypothalamic
      pituitary-adrenal axis and endogenous opioids and examine the mechanisms by which
      chronic stress modulates lymphocyte apoptosis.

PMID- 12615183
TI  - The promotion of tumor metastasis by surgery and stress: immunological basis and
      implications for psychoneuroimmunology.
AB  - This mini-review emphasizes a psychoneuroimmunology (PNI) perspective of the
      hypothesis that stress and surgical excision of the primary tumor can promote
      tumor metastasis. It first establishes the empirical and theoretical basis for
      control of metastasis by cell-mediated immunity (CMI), as well as the interactive
      role of non-immunological risk factors. It then describes the various aspects of
      surgery that suppress CMI, and the neuroendocrine mechanisms mediating
      suppression by stress and surgery. Last, it briefly reviews the empirical
      evidence, from animal and human studies, for the promotion of metastasis by
      stress and surgery, with specific reference to the mediating role of CMI. It is
      concluded that: (a) Immunological mechanisms most likely play a role in limiting
      metastasis in patients with solid tumors. (b) Immunosuppression can be
      deleterious, especially when surgery is conducted early, before the tumor
      develops insurmountable mechanisms to escape immune destruction. (c) The most
      sensitive period for the establishment of metastases is the immediate aftermath
      of surgery. Interventions aiming at reducing stress and immunosuppression should
      thus strive to start beforehand. (d) 'Psychological and physiological insults
      activate similar neuroendocrine mechanisms of immunosuppression. Therefore, a
      multimodal therapeutic approach should be used to prevent tumor metastasis during
      the perioperative period. (e) Studies employing interventions aimed at reducing
      the surgical stress response should preferably assess immunological indices with
      an established clinical relevance, and follow up long-term recurrence provided
      sample size assure statistical power. (f) The progress toward earlier detection
      of cancer, and our growing understanding of immunosuppression, continuously
      improves the chances for successful PNI interventions.

PMID- 12615184
TI  - Stress-induced immunomodulation: Implications for tumorigenesis.

PMID- 12615185
TI  - Sleep in host defense.
AB  - Sleep remains an important enigma in neurobiology; it has a robust adaptive value
      yet its function remains elusive. Changes in sleep are hallmarks of the acute
      phase response to infectious challenge. The molecular regulation of these
      responses involves a cytokine cascade within brain, including interleukin-1 and
      tumor necrosis factor, and several other substances such as growth hormone
      releasing hormone, prolactin, nitric oxide and nuclear factor kappaB. These
      substances are also involved in the regulation of normal spontaneous sleep.
      Fatigue and sleep disturbances are common in cancer patients and in those
      receiving cytokine therapy. Regardless, the role of sleep in cancer is relatively
      uninvestigated.

PMID- 12615186
TI  - Circadian disruption and cancer: sleep and immune regulation.

PMID- 12615187
TI  - Conditioned immunomodulation: research needs and directions.
AB  - Considering the brief time that psychoneuroimmunology has existed as a bona fide
      field of research, a great deal of data has been collected in support of the
      proposition that homeostatic mechanisms are the product of an integrated system
      of defenses of which the immune system is a critical component. It is now clear
      that immune function is influenced by autonomic nervous systems activity and by
      the release of neuroendocrine substances from the pituitary. Conversely,
      cytokines and hormones released by an activated immune system influence neural
      and endocrine processes. Regulatory peptides and receptors, once confined to the
      brain, are expressed by both the nervous and immune systems enabling each system
      to monitor and modulate the activities of the other. It is hardly surprising,
      then, that immunologic reactivity can be influenced by stressful life experiences
      or by Pavlovian conditioning.

PMID- 12615188
TI  - Conditioning, cancer, and immune regulation.

PMID- 12615189
TI  - An interdisciplinary research model to investigate psychosocial cofactors in
      disease: Application to HIV-1 pathogenesis.
AB  - This paper argues for a broader interdisciplinary conceptualization of research
      on psychosocial risk factors and disease that relies on epidemiology, human
      laboratory-based studies, animal studies, in vitro and other mechanistic studies
      and intervention research. A model is proposed that includes the isolation of the
      active ingredients in the proposed psychological or social contributing factor,
      and a determination of their neural substrates, peripheral neurophysiological and
      pathophysiological correlates, and clinical disease outcomes. Research in HIV-1
      pathogenesis provides examples of these kinds of studies. The HIV section
      highlights research that focuses on specific cognitive representations of
      stressful life experiences as active ingredients that shape the affective and
      neurophysiological impact of events. Links between these cognitive states and HIV
      progression, as well as the potential neurophysiologic, virologic, and
      immunologic mediators of these relationships are described. Implications and
      extensions of this model are derived for research on psychosocial factors and
      cancer.

PMID- 12615190
TI  - Hypothalamic-pituitary-adrenal alterations in PTSD: are they relevant to
      understanding cortisol alterations in cancer?
AB  - Recent studies of hypothalamic-pituitary-adrenal axis alterations in PTSD have
      demonstrated a specific type of hyperresponsivity of this stress hormonal system
      characterized by a greater negative feedback inhibition of cortisol, which may
      paradoxically serve to lower cortisol levels. The occurrence of cancer has been
      recently described by many investigators as an event that fulfills the DSM-IV
      criteria for a "traumatic event" that has been demonstrated in some cases to be
      linked with the subsequent development of PTSD. This review considers the extent
      to which neuroendocrine alterations observed in PTSD may be useful in
      understanding cortisol alterations involved in cancer.

PMID- 12615191
TI  - Psychoneuroendocrinology and psychoneuroimmunology of cancer: Plausible
      mechanisms worth pursuing?

PMID- 12615192
TI  - Individual differences, immunity, and cancer: lessons from personality
      psychology.
AB  - Individual differences have an important role in modulating the relationship
      between environmental events such as stressors and the immune system, and stable
      individual differences such as personality may have an important influence not
      only on immunity but on the progression of chronic health problems such as
      cancer. However, the relationships among personality, the immune system, and
      health-especially cancer-are controversial. Looking back to another controversy
      may help inform future research in this area: In the 1960s, Walter Mischel
      questioned whether stable personality traits existed. Responses to this challenge
      included research designs that improved reliability and accounted for both person
      and situation in an interactionist model. Both responses are relevant to current
      research in personality, immunity, and health.

PMID- 12615193
TI  - Loneliness and pathways to disease.
AB  - Social isolation predicts morbidity and mortality from cancer, cardiovascular
      disease, and a host of other causes. The mechanisms by which the social world
      impacts on health are poorly understood, in part because of lack of specificity
      in the conceptualization and operationalization of relevant aspects of social
      relationships and physiological processes. Perceived social isolation, commonly
      termed loneliness, may represent a link between the epidemiological and
      biological levels of analysis. Research is presented that investigates loneliness
      as a social factor of importance in three predisease pathways: health behaviors,
      excessive stress reactivity, and inadequate or inefficient physiological repair
      and maintenance processes. Empirical evidence of autonomic, endocrine, and immune
      functioning suggests that the physiological effects of loneliness unfold over a
      relatively long time period. For cancer patients, interventions should be aimed
      at providing instrumental support for the immediate demands of the disease.

PMID- 12615194
TI  - Individual differences and immune function: Implications for cancer.

PMID- 12615195
TI  - Examining psychosocial factors related to cancer incidence and progression: in
      search of the silver lining.

PMID- 12615196
TI  - Cytokine-induced sickness behavior.
AB  - The behavioral repertoire of humans and animals changes dramatically following
      infection. Sick individuals have little motivation to eat, are listless, complain
      of fatigue and malaise, loose interest in social activities and have significant
      changes in sleep patterns. They display an inability to experience pleasure, have
      exaggerated responses to pain and fail to concentrate. Proinflammatory cytokines
      acting in the brain cause sickness behaviors. These nearly universal behavioral
      changes are a manifestation of a central motivational state that is designed to
      promote recovery. Exaggerated symptoms of sickness in cancer patients, such as
      cachexia, can be life-threatening. However, quality of life is often drastically
      impaired before the cancer becomes totally debilitating. Although basic studies
      in psychoneuroimmunology have defined proinflammatory cytokines as the central
      mediators of sickness behavior, a much better understanding of how cytokine and
      neurotransmitter receptors communicate with each other is needed. Advances that
      have been made during the past decade should now be extended to clinical studies
      in an attempt to alleviate sickness symptoms and improve quality of life for
      cancer patients.

PMID- 12615197
TI  - Cytokines and depression: the need for a new paradigm.
AB  - Considerable clinical and experimental data support the existence of a
      relationship between cytokines and depression. At the experimental level,
      proinflammatory cytokines have been found to induce alterations in brain function
      analogous to the behavioral and biological abnormalities occurring in depressed
      patients, including social withdrawal, cognitive impairment, anhedonia, increased
      activity of the hypothalamus-pituitary-adrenal axis, altered neurotransmission,
      and cross-sensitization with stressors. At the clinical level, the evidence in
      favor of innate immune system activation in depressed patients is still
      controversial, despite accumulating evidence for an increased risk of depressive
      disorders in patients receiving recombinant cytokines for the treatment of cancer
      and viral infection. This last issue has received significant attention recently,
      given that the administration of therapeutic cytokines provides a quasi
      experimental model for studying the mechanisms which underlie the effects of
      cytokines on mood, cognition, and neurovegetative functions. Although the
      vulnerability factors that account for the risk of depression have yet to be
      identified, tryptophan depletion, likely related to the induction of indoleamine
      2,3-dioxygenase enzyme, may represent an important mediator for the development
      of depressed mood in cytokine-treated patients. This paper discusses ways in
      which these emerging data may lead to advances in the recognition and management
      of non-specific neurobehavioral symptoms associated with the development and
      progression of cancer.

PMID- 12615198
TI  - Immune-to-central nervous system communication and its role in modulating pain
      and cognition: Implications for cancer and cancer treatment.
AB  - This paper reviews the nature of communication from the immune system to the
      brain and some implications of this communication for phenomena that are not
      ordinarily considered to be modulated by immune function. Pro-inflammatory
      cytokines released by activated immune cells signal the brain by both blood-borne
      and neural routes, leading to alterations in neural activity. The cascade of
      altered neural activity includes the induction of pro-inflammatory cytokines
      within the brain and spinal cord. The cytokines in the brain, specifically in the
      hippocampus, interfere with the consolidation of memory, while the cytokines
      within the spinal cord exaggerate pain. Activation of this immune-to-central
      nervous system pathway, with the consequent production of cytokines within the
      central nervous system, may be involved in the mediation of a number of phenomena
      that occur during cancer and cancer treatment.

PMID- 12615199
TI  - Cytokines and sickness behavior: implications for cancer care and control.

PMID- 12615200
TI  - Role of fucosyltransferases in leukocyte trafficking: major impact for cutaneous
      immunity.

PMID- 12615201
TI  - Akt is TCL-ish: implications for B-cell lymphoma.

PMID- 12615202
TI  - Dendritic cells under the spell of prostaglandins.

PMID- 12615203
TI  - Hyaluronan--magic glue for the regulation of the immune response?

PMID- 12615204
TI  - Neuro-immune connections: evidence for a neuro-immunological synapse.

PMID- 12615206
TI  - Special attractions for suppressor T cells.

PMID- 12615205
TI  - Opioid G protein-coupled receptors: signals at the crossroads of inflammation.

PMID- 12615207
TI  - Tritope model of restrictive recognition by the TCR.

PMID- 12615209
TI  - NK-CTLs, a novel HLA-E-restricted T-cell subset.

PMID- 12615208
TI  - Quantitative constraints on the scope of negative selection.
AB  - Maturing T cells with a high affinity for self-antigens presented in the thymus
      are deleted in the process of negative selection. Although the expression of
      various "tissue-specific" antigens has been described in the thymus, it is still
      controversial what fraction of all self-antigens induces tolerance by this
      mechanism. We demonstrate that the limited duration of the negative selection
      phase imposes a constraint on the number of self-peptides that can be reliably
      selected against. The analysis supports the theory that negative selection is
      confined to the subset of peptides produced by dendritic cells.

PMID- 12615210
TI  - Viral apoptotic mimicry: an immune evasion strategy developed by the hepatitis B
      virus?
AB  - The co-existence of viruses and organisms for millions of years has influenced
      the evolution of both. Various viral strategies to enter a host and take over the
      control of cells to produce virus progeny have developed. Several antiviral
      (immune) responses have also been developed. The apoptotic death program is a
      conserved feature of eukaryotic cells. In multicellular organisms the binding and
      engulfment of apoptotic material is considered to be the end stage of the
      apoptotic process. Because of its importance, it seems probable that viruses have
      targeted this ancient removal system to suppress immune responses and to
      establish or maintain infection. The possibility that the hepatitis B virus has
      evolved such a mechanism, termed "viral apoptotic-like mimicry", is presented
      here.

PMID- 12615211
TI  - Recognition and clearance of apoptotic cells: a role for complement and
      pentraxins.

PMID- 12615213
TI  - The various and varying roles of specific chaperones in type III secretion
      systems.
AB  - The type III secretion pathway is used by numerous Gram-negative pathogenic
      bacteria to deliver proteins within the membrane or the cytoplasm of eukaryotic
      cells with which these bacteria interact. Secretion is regulated by external
      signals. This requires that, before being secreted, proteins are stored in the
      cytoplasm where they need to be stabilised, separated from other interaction
      partners, and maintained in a secretion-competent state. Specialised, energy
      independent chaperones play various roles in these functions by associating in
      the cytoplasm with proteins before their secretion. Some chaperones are also
      directly involved in modulating transcription in response to secretion.

PMID- 12615214
TI  - The Hrp pilus: learning from flagella.
AB  - Plant pathogenic bacteria deliver avirulence and virulence effector proteins into
      plant cells via the hrp-gene-encoded type III secretion system. A key component
      of this secretion system is a surface appendage called the Hrp pilus. Recent
      results suggest that the Hrp pilus serves as a conduit for type III protein
      secretion and that it is assembled in a manner similar to the flagellum. The Hrp
      pilus is likely to be the functional equivalent of the needle extension,
      assembled by type III secretion systems of mammalian pathogenic bacteria.

PMID- 12615215
TI  - Identifying type III effectors of plant pathogens and analyzing their interaction
      with plant cells.
AB  - Many bacterial pathogens cause disease by injecting virulence proteins
      (effectors) into host cells via the specialized type III secretion system.
      Recently, exceptional progress in identifying effectors was made in the
      phytopathogen Pseudomonas syringae using a novel genetic screen and bioinformatic
      approach. These studies, along with localization experiments, suggest that most
      P. syringae effectors function by targeting the plasma membrane, chloroplasts or
      mitochondria of host cells. The type III secretome of P. syringae is highly
      variable and dynamic, a lesson gleaned from a comparative genomic analysis.
      Variation in the effector repertoire is likely to facilitate the adaptation of P.
      syringae to different hosts.

PMID- 12615216
TI  - Type IV transporters of pathogenic bacteria.
AB  - Type IV transporters are produced by several bacterial pathogens such as
      Agrobacterium tumefaciens, Bordetella pertussis, Brucella spp., Bartonella
      henselae, Helicobacter pylori and Legionella pneumophila. These transporters are
      critical for the pathogenic process in that they export important virulence
      factors across the membranes of the bacteria. Although the virulence factors that
      are exported by these transporters can be either nucleic acid or protein, the
      general mechanism of transport appears to be similar for members of this family.
      Recent findings have shed light on the architecture of type IV transporters and
      the roles that these transporters play in pathogenesis.

PMID- 12615217
TI  - Filamentous phages linked to virulence of Vibrio cholerae.
AB  - The pathogenicity of Vibrio cholerae depends upon its production of two key
      virulence factors: the toxin co-regulated pilus (TCP), a colonization factor, and
      cholera toxin, an exotoxin. Genes encoding both virulence factors were introduced
      into V. cholerae by horizontal gene transfer. The toxin genes are contained
      within the genome of CTXphi, an integrated filamentous phage identified in 1996.
      In the past few years, it has been shown that CTXphi relies on novel processes
      for phage DNA integration, replication and secretion. In addition, expression of
      CTXphi genes--including the toxin genes--and transmission of CTXphi were recently
      found to be promoted by the antirepressor RstC, which is encoded within RS1, a
      newly described satellite phage of CTXphi. The genetic island that encodes TCP
      has also been described as a filamentous phage; however, these sequences are
      unlike the genome of any previously characterized filamentous phage.

PMID- 12615218
TI  - 'Small' talk: Opa proteins as mediators of Neisseria-host-cell communication.
AB  - Opa proteins are variable outer membrane proteins of Neisseria gonorrhoeae and
      Neisseria meningitidis that mediate tight interaction of these pathogens with
      human cells. They have emerged as a paradigm of a bacterial toolbox allowing
      recognition of different host receptors and orchestrating the cell type tropism
      displayed by pathogenic Neisseriae. Recent work has highlighted the molecular
      basis of Opa-protein-host-receptor interaction and has shed new light on the
      functional consequences of this interaction with regard to bacterial attachment,
      invasion, and responses elicited in particular host cells.

PMID- 12615219
TI  - IdeS and SpeB: immunoglobulin-degrading cysteine proteinases of Streptococcus
      pyogenes.
AB  - The Gram-positive bacterium Streptococcus pyogenes is a major human pathogen
      causing substantial morbidity and mortality in society. S. pyogenes has evolved
      numerous molecular mechanisms to avoid the various actions of the human immune
      system and has established means to modulate both adaptive and innate immune
      responses. S. pyogenes produces and secretes proteolytic enzymes, which have an
      important impact on the ability of the bacteria to survive in the human host.
      Prominent among these are two immunoglobulin-degrading enzymes: the newly
      discovered streptococcal cysteine proteinase, IdeS, and the classical cysteine
      proteinase of S. pyogenes, SpeB.

PMID- 12615220
TI  - P. aeruginosa quorum-sensing systems and virulence.
AB  - Quorum sensing is an important mechanism for the regulation of genes in many Gram
      negative and Gram-positive bacteria. In the opportunistic pathogen Pseudomonas
      aeruginosa, the absence of one or more components of the quorum-sensing system
      results in a significant reduction in virulence. Recent advances in the past year
      have demonstrated that the quorum-sensing signal molecule 3O-C(12)-HSL is also a
      potent stimulator of multiple eukaryotic cells and thus may alter the host
      response during P. aeruginosa infections. Therefore, via the regulation of
      multiple factors and the production of 3O-C(12)-HSL, quorum-sensing systems have
      a significant effect on the virulence of the bacteria and also on how the host
      responds to P. aeruginosa infections.

PMID- 12615221
TI  - Recent progress in understanding Bartonella-induced vascular proliferation.
AB  - The ability to induce endothelial cell proliferation is a common feature of human
      pathogenic Bartonella species. Recent data have indicated that bartonellae can
      provoke angioproliferation by at least two independent mechanisms: directly, by
      triggering proliferation and inhibiting apoptosis of endothelial cells; and
      indirectly, by stimulating a paracrine angiogenic loop of vascular endothelial
      growth factor production by infected macrophages. A NF-kappaB-mediated acute
      inflammatory reaction of the Bartonella-infected endothelium appears to be
      critical for the recruitment of monocytes/macrophages and the initiation and
      maintenance of a paracrine angiogenic loop. Given that bartonellae effectively
      adhere to and invade endothelial cells, their ability to trigger
      angioproliferation might represent a dedicated pathogenic strategy for expanding
      the bacterial host cell habitat.

PMID- 12615222
TI  - Virulence determinants and protective antigens of Francisella tularensis.
AB  - Very little is known about virulence mechanisms of the highly virulent bacterium
      Francisella tularensis. Specific genetic features of F. tularensis have been
      obstacles for the development of effective tools for genetic manipulation.
      However, recent genomic sequencing and large-scale proteomic work have resulted
      in a substantial increase in the knowledge of F. tularensis. There is also a
      paucity of information on potential vaccine candidates. Recent work assessing the
      protective efficacy of the F. tularensis lipopolysaccharide has resulted in
      important contributions to the understanding of host-protective mechanisms. T
      cell-mediated immunity appears to be crucial to protect against virulent F.
      tularensis strains. Few other vaccine candidates have been identified.

PMID- 12615223
TI  - Interactions of bacterial pathogens with dendritic cells during invasion of
      mucosal surfaces.
AB  - Recent studies of mucosal immunity suggest a key role for dendritic cells in the
      regulation of gut immune responses, in both physiological and pathological
      conditions. Dendritic cells are widely distributed in the lamina propria of the
      gut and are involved in direct bacterial uptake across mucosal surfaces, which
      questions the role of dendritic cells in innate mucosal responses. Approximately
      400 commensal microbial species are present in the gut lumen. So how do dendritic
      cells distinguish pathogens from luminal microflora? Are the cytokines and
      chemokines induced in dendritic cells tailored to the class of microbes being
      recognized? Several very important questions still need to be addressed.

PMID- 12615224
TI  - The use of transepithelial models to examine host-pathogen interactions.
AB  - Many pathogens must overcome an epithelial barrier in order to establish an
      infection. Unsurprisingly, such pathogens have evolved different mechanisms to
      overcome this obstacle, targeting specific epithelial structures or functions.
      These include disruption of epithelial barrier function, transcytosing from the
      apical to the basolateral membrane domain or inducing cell movement such as
      neutrophil recruitment. When studying these processes in vivo, animal models
      often fail to mimic the disease observed in humans and present a complex system
      in which many variables cannot be controlled. Therefore, in vitro transepithelial
      models that permit the study of a relevant biological surface have been
      developed, to integrate not only interactions between bacteria and epithelial
      cells but also, under certain conditions, to integrate a third cell type, such as
      neutrophils or dendritic cells. Such models are particularly useful for studying
      the bacteria-host relationship as it would occur in the microenvironment of the
      human epithelium and have enhanced our understanding of the unique strategies by
      which pathogenic bacteria exploit host cells to overcome the initial epithelial
      hurdle.

PMID- 12615225
TI  - Tails of two Tirs: actin pedestal formation by enteropathogenic E. coli and
      enterohemorrhagic E. coli O157:H7.
AB  - Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli O157:H7
      (EHEC) form characteristic lesions on infected mammalian cells called actin
      pedestals. Each of these two pathogens injects its own translocated intimin
      receptor (Tir) molecule into the plasma membranes of host cells. Interaction of
      translocated Tir with the bacterial outer membrane protein intimin is required to
      trigger the assembly of actin into focused pedestals beneath bound bacteria.
      Despite similarities between the Tir molecules and the host components that
      associate with pedestals, recent work indicates that EPEC and EHEC Tir are not
      functionally interchangeable. For EPEC, Tir-mediated binding of Nck, a host
      adaptor protein implicated in actin signaling, is both necessary and sufficient
      to initiate actin assembly. In contrast, for EHEC, pedestals are formed
      independently of Nck, and require translocation of bacterial factors in addition
      to Tir to trigger actin signaling.

PMID- 12615226
TI  - Comparison between capillary electrophoresis and high-performance liquid
      chromatography for the stereoselective analysis of carvedilol in serum.
AB  - A high-performance liquid chromatographic (HPLC) assay using a chiral stationary
      phase was developed and validated for the determination of carvedilol enantiomers
      in human serum and was compared with a previously developed capillary
      electrophoresis (CE) method. The CE and the HPLC assay were compared by analyzing
      a series of serum samples containing racemic carvedilol in different
      concentrations using the two methods. The concentrations obtained by the two
      assays were not found to be significantly different indicating that CE and HPLC
      are comparable in terms of reproducibility and precision for the stereoselective
      analysis of carvedilol in human serum.

PMID- 12615227
TI  - Quantitation of film coating on Zantac 75 mg tablets and Epivir HBV 100 mg
      tablets by ICP-AES.
AB  - PURPOSE: To present a selective analytical Inductively Coupled Plasma-Atomic
      Emission Spectroscopy (ICP-AES) method developed and validated for the
      quantitation of tablet film coatings containing titanium. METHODS: Tablet samples
      were decomposed by either digestion or dry ashing. The amount of film tablet
      coating was calculated based on titanium content of the sample. RESULTS: The
      reported ICP-AES method was accurate, precise, sensitive and linear for
      determination of titanium concentrations from 2.9 to 8.6 ppm. CONCLUSION: This
      method provides an accurate determination of the amount of coating on a tablet
      and has general applicability for a variety of coating formulations containing
      different elements.

PMID- 12615228
TI  - Voltammetric and flow amperometric methods for the determination of melatonin in
      pharmaceuticals.
AB  - Melatonin can be sensitively detected in pharmaceuticals by two different and
      simple electrochemical methods: cyclic voltammetry (CV) and amperometric
      detection in a flow injection analysis system (FIA-ED). An adequate pre-treatment
      of the carbon paste electrode in the first case and the employ of a high flow
      rate in the second one were the key for obtaining a very good reproducibility
      (R.S.D. values of 1.5 (n=10) and 1.3% (n=20), respectively). Low limits of
      detection were achieved and with the coupling of a flow system a linear dynamic
      range of three orders of magnitude (from 10(-8) to 10(-5) M) was obtained. Both
      methods were applied to the determination of melatonin in pharmaceuticals. In
      order to best validate these methodologies a fluorescent procedure was developed
      to contrast the results. As no interferences from the matrix were found the
      employ of a separation technique is not necessary. In this way the procedure is
      fastened and simplified. Moreover, the low price, ease of handling, possibility
      of automation and high sample throughput are important advantages that convert
      the flow methodology in an attractive alternative for quality control of
      pharmaceuticals.

PMID- 12615229
TI  - Chiral and non chiral determination of Dopa by capillary electrophoresis.
AB  - The suitability of capillary electrophoresis for determining the enantiomeric
      purity of levodopa in a pharmaceutical formulation also containing benserazide
      was assessed. To this end, the pharmaceutical components were separated in a non
      chiral medium that allowed the total amount of Dopa and that of benserazide to be
      quantified. The addition of a chiral crown ether to the background electrolyte
      allows to separate the enantiomers of this compounds. Optimizing the variables
      influencing the enantioresolution of Dopa affords a resolution high enough
      resolution to determine the amount of dextrodopa (the distomer) contained in
      levodopa (the eutomer) in a pharmaceutical. A relative limit of detection (RLD)
      is proposed as a measure of the lowest detectable enantiomeric impurity. The RLD
      for the determination of dextrodopa contained in levodopa was 0.1% and found to
      depend on the enantiomer migration order. The enantiomeric purity of levodopa in
      the pharmaceutical preparation and dextrodopa from Sigma was 99.5 and 99.95%,
      respectively.

PMID- 12615230
TI  - Fast and single solid phase fluorescence spectroscopic batch procedure for
      (acetyl) salicylic acid determination in drug formulations.
AB  - A solid phase fluorescence spectroscopic batch procedure for (acetyl) salicylic
      acid in drug formulations have been developed. The procedure is based on the
      sorption of salicylic acid (SA) on Sephadex DEAE A-25 anion exchanger gel (100
      mg) by equilibration from an aqueous solution (10 or 25 ml) for 5 min; the
      equilibrated gel is transferred into an 1 mm quartz cell and the native
      fluorescence of SA sorbed on it is directly measured (lambda(ex)=297 nm;
      lambda(em)=405 nm). Good linearity was found in the 10-200 and 5-100 microg l(-1)
      ranges (for 10 and 25 ml sample volume, respectively) with R.S.D. (%) of 2.8 and
      1.1. The procedure was successfully applied to the determination of acetyl
      salicylic acid (ASA) in drug formulations after alkaline hydrolysis to yield SA.

PMID- 12615231
TI  - Enhanced pharmaceutical analysis by CE using dynamic surface coating system.
AB  - The poor repeatability of migration times in capillary electrophoresis (CE)
      within an injection sequence and between capillaries can be a difficulty when
      implementing CE for routine pharmaceutical analysis. The use of a dynamic surface
      coating has been shown to improve the routine performance of CE. The surface
      coating generates an appreciable electro-osmotic flow at low pH, which reduces
      analysis times for basic drugs compared to the low pH buffers typically used in
      CE. The repeatability of migration times and repeatability of migration times
      between capillaries was improved. Peak tailing for basic drugs was also reduced
      which improved peak shapes and peak area integration precision. It is concluded
      that the dynamic coating system is a positive advance in the routine
      implementation of CE into pharmaceutical analysis.

PMID- 12615232
TI  - Characterisation of the 1H and 13C NMR spectra of N-acetylaspartylglutamate and
      its detection in urine from patients with Canavan disease.
AB  - 1H and 13C NMR spectra of N-acetylaspartylglutamate (NAAG) have been recorded and
      interpreted. The values of the 1H chemical shifts and 1H-(1)H coupling constants
      at different pH were obtained by iterative computer fitting of 1-D 1H NMR
      spectra. This provided information on the solution conformation of the
      investigated molecule. Proton-decoupled high resolution 13C NMR spectra of NAAG
      have been measured in a series of dilute water solution of various acidity. These
      data have provided a basis for unequivocal determination of the presence of NAAG
      in the urine sample of a patient suffering from Canavan disease. NMR spectroscopy
      provides a possibility of detecting NAAG in body fluids.

PMID- 12615233
TI  - Determination of the antibacterial trovafloxacin by differential-pulse adsorptive
      stripping voltammetry.
AB  - A differential-pulse adsorptive stripping voltammetric method for the
      determination of trace amounts of the antibacterial trovafloxacin (TRFLX) is
      proposed. The optimal experimental parameters for the drug assay were:
      accumulation potential=-0.30 V (vs. Ag/AgCl), accumulation time=120 s, pulse
      amplitude=50 mV and scan rate=5 mV s(-1) in Britton-Robinson buffer (pH 4.5). The
      linear concentration range of application was 2.0-20.0 ng ml(-1) of TRFLX, with a
      relative standard deviation of 3.6% (for a level of 5.0 ng ml(-1)) and a
      detection limit of 0.6 ng ml(-1). The method was applied to determination of
      TRFLX in human urine and serum samples. It was validated using HPLC as a
      reference method. Recovery levels of the method reached 100% in all cases

PMID- 12615234
TI  - Determination of the composition of Chinese ligustrum lucidum polysaccharide by
      capillary zone electrophoresis with amperometric detection.
AB  - In this paper, capillary zone electrophoresis with amperometric detection was
      firstly applied to indirectly determine the composition of Chinese ligustrum
      lucidum polysaccharide (LLPS) by analyzing its hydrolyzates: fucose, glucose,
      arabinose and rhamnose. Under the selected optimum conditions, the four
      monosaccharides could be perfectly separated within 30 min and showed significant
      current responses at the copper electrode. The linear ranges of fucose, glucose
      and arabinose were all from 5.0 x 10(-6) to 1.0 x 10(-4) mol l(-1) and that of
      rhamnose was from 1.0 x 10(-5) to 1.0 x 10(-4) mol l(-1), and their detection
      limits were lower or near 1.0 x 10(-6) mol l(-1) (S/N=3). Experiments showed that
      the mole ratio of fucose, glucose, arabinose and rhamnose in Chinese LLPS was
      1.80:4.58:2.55:1.91, and the purity of this polysaccharide leached by the
      introduced leaching method was 93.3%. Analyzing polysaccharide by this method has
      some merits of quickness, low-volume sampling, simple instrument, high
      sensitivity and high reproducibility.

PMID- 12615235
TI  - Electroanalytical characteristics of piribedil and its differential pulse and
      square wave voltammetric determination in pharmaceuticals and human serum.
AB  - The electrochemical oxidative behavior of piribedil (PR) was described. It was
      investigated by cyclic, linear sweep, differential pulse (DPV) and square wave
      (SWV) voltammetric techniques. The redox behavior of PR was found irreversible.
      Different parameters were tested to optimize the conditions for the determination
      of PR. The dependence of intensities of currents and potential on pH,
      concentration, scan rate, nature of the buffer was investigated. Two sensitive
      methods for the measurement of PR were described. For analytical purposes, a very
      well resolved diffusion controlled voltammetric peak was obtained in 0.1 M
      H(2)SO(4) and pH 5.7 acetate buffer. The determination peaks are obtained at 1.27
      and 0.95 V for differential pulse and 1.29 and 0.97 V for SWV in 0.1 M H(2)SO(4)
      and pH 5.7 acetate buffer, respectively. The linear response was obtained in the
      ranges of 2 x 10(-6)-1 x 10(-3) M in 0.1 M H(2)SO(4) and 2 x 10(-6)-8 x 10(-4) M
      in pH 5.7 acetate buffer for both techniques. The proposed techniques were
      successfully applied to the determination of PR in tablet dosage forms and human
      serum. Excipients did not interfere in the determination. The necessary
      statistical validation reveals that the proposed methods are free from
      significant systematic errors.

PMID- 12615236
TI  - Utility of formazans and cetylpyridinium chloride in rapid spectrophotometric
      determination of zinc in biological materials and pharmaceutical formulations.
AB  - A facile, rapid and sensitive spectrophotometric method for the determination of
      zinc is performed, based on complexation reaction between the metal ion and 1,5
      diphenyl-3-acetylformazan (I) 1-(o-carboxyphenyl)-3-acetyl-5-acetylformazan (II),
      1-(o-carboxyphenyl)-3-acetyl-5-phenylformazan (III), and 1-(o-carboxyphenyl)-3
      acetyl-5-m-tolylformazan (IV) in the presence of cationic surfactant
      cetylpyridinium chloride (CPC). The important analytical parameters and their
      effects on the reported system are investigated. Zinc reacts with the reagents (I
      IV) and CPC in the ratio 1:1:2 (metal:reagent:CPC) in the pH range 8.5, 7.5, 5.5
      and 6.5 to form a ternary complex with an absorption maximum 616, 656, 672 and
      599 nm, respectively. The reaction was extremely rapid at room temperature, and
      the absorbance value remains unchanged for at least 1 week. The apparent
      stability constant of the complex were found to be 13.1 9.2, 11.4 and 12.3, and
      adheres to Beer's law for 0.05-3.50 microg per 10 ml of zinc. For more accurate
      analysis, Ringbom optimum concentration range was found from 0.08 to 3.20 microg
      per 10 ml of zinc. The apparent molar absorptivity, Sandell sensitivity,
      detection and quantification limits are also calculated. Taking a constant
      concentration of metal ion and determining its concentration in the presence of
      large number of foreign ions tested the effect of foreign ions. The method was
      applied for determination of zinc in serum, human hair and pharmaceutical
      formulations, where excellent agreements between reported and obtained results
      were achieved. The relative standard deviation was better than 1.67%.

PMID- 12615237
TI  - Capillary electrophoresis determination of loratadine and related impurities.
AB  - While HPLC has traditionally been the method of choice for purity determination
      of pharmaceutical substances, capillary electrophoresis (CE) offers a different
      selectivity and hence it is a complementary technique to HPLC. Loratadine, an
      antihistamine, could include in its raw material seven impurities that ought to
      be separated, identified and quantified for drug development and quality control.
      As a complementary tool for undoubtful identification, a CE method has been
      developed. The separation was carried out with an uncoated fused-silica capillary
      (57 cm x 50 microm ID) and was operated at 20 kV potential. Temperature was
      maintained at 25 degrees C. The final separation buffer was prepared with 100 mM
      H(3)PO(4) made up to pH 2.5 with NaOH and with 10% acetonitrile added (v/v).
      Impurities can be detected at the 0.1% level of the active and validation
      parameters for linearity accuracy and precision are adequate for all the analytes
      and that permits to consider the method reliable and suitable for application to
      long-term stability and purity studies.

PMID- 12615238
TI  - Spectrofluorimetric and micelle-enhanced spectrofluorimetric methods for the
      determination of gemfibrozil in pharmaceutical preparations.
AB  - A spectrofluorimetric method for the determination of antihyperlipoproteinemic
      gemfibrozil was developed based on its native fluorescence. This method allows
      the determination of 0.10-6 microg ml(-1) gemfibrozil in aqueous solution
      (without using any buffer solution) with excitation and emission wavelengths of
      276 and 304 nm, respectively. Detection and quantification limits were 0.03 and
      0.10 microg ml(-1), respectively. The fluorescence properties of gemfibrozil in
      micellar media were also studied. It was shown that in the presence of 0.4% Brij
      35 surfactant (pH 4.0, acetic acid-acetate buffer) about 2.4-fold enhancement can
      be achieved in the fluorescence of this drug. Based on the obtained results, a
      micelle-enhanced fluorescence method was also developed that is more sensitive
      than aqueous fluorescence method and has lower detection limit (0.02 microg ml(
      1)). Both methods were applied satisfactorily to the determination of gemfibrozil
      in a commercial pharmaceutical formulation.

PMID- 12615239
TI  - PVC matrix membrane sensor for potentiometric determination of metoclopramide
      hydrochloride in some pharmaceutical formulations.
AB  - The construction and characteristic performance of metoclopramide (MCP)-polyvinyl
      chloride (PVC) membrane sensor are described. The sensor is based on the use of
      MCP-tetraiodomercurate ion pair as electroactive material in PVC matrix in
      presence of dioctylphthalate (DOP) as solvent mediator. MCP membrane sensor shows
      a stable, near Nernstian response over the concentration range 1 x 10(-2)-6 x 10(
      5) M of MCP at 25 degrees C in the pH range 3-7 with cationic slope of 53.0+/
      0.5. The detection limit of 4 x 10(-5) M and the response time of 30-60 s have
      been attained. Selectivity coefficient data for some common ions show negligible
      intereferences. Direct potentiometric determination of 15-3540 microg/ml MCP show
      an average recovery of 98.5% and a mean relative standard deviation (R.S.D.) of
      1.6% at 100.0 microg/ml. The determination of MCP in Primperan tablets,
      injection, and syrup gave results that compare favorably with those obtained by
      the British pharmacopoeia method. Precipitation titrations involving MCP as
      titrant are monitored with the MCP sensor for some potentiometric precipitation
      reaction, e.g. sodium tetraphenylborate (STPB) and phosphomolybdic acid (PMA).

PMID- 12615240
TI  - Two stability-indicating UV spectrophotometric methods for the analysis of
      hydrolyzed tinidazole.
AB  - Two UV spectrophotometric methods have been validated for the analysis of
      hydrolyzed tinidazole solutions. The pH of the samples must be 5.00-7.00 for both
      methods. The multiwavelength method may be used for samples degraded at pH 6-12
      if the amount of conserved 5-nitroimidazole species is at least 93 mol.% of the
      original; the amounts of tinidazole and its two known impurities may be
      determined simultaneously. The accuracy was within 100+/-8% and the repeatability
      of measurement was <or=4% at 0.03-0.33 mM, which was the measuring and
      calibration range. The LOD and LOQ were determined to be 0.003-0.012 mM and
      0.0274 mM, respectively. The single-wavelength method may be used for samples
      degraded at pH 1-5, at least until approximately 50-60% of the original
      tinidazole has decomposed; only the amount of tinidazole can be determined. The
      solutions were measured at 318 nm, and quadratic fitting was used for the
      calibration. The mean accuracies varied between 98.0 and 101.8% and all RSDs were
      <or=1.7% for the precision at 0.041-0.15 mM, which was the measuring range. The
      calibration range was 0.049-0.12 mM. The LOD and LOQ were 0.25 and 0.75 microM,
      respectively. The two methods were shown to produce statistically different
      results by cross-validation. At pH 10.0, tinidazole was decomposed approximately
      30 times faster than its 4-nitro isomer; 2-methyl-4(5)-nitroimidazole was stable
      during the study.

PMID- 12615241
TI  - Differential pulse anodic voltammetric determination of lithium ions in
      pharmaceutical formulations using a carbon paste electrode modified with spinel
      type manganese oxide.
AB  - The use of the differential pulse voltammetry for the determination of lithium
      ions in pharmaceutical samples using a carbon paste electrode modified with
      spinel-type manganese oxide has been examined. The best voltammetric response was
      reached for a modified electrode in borate buffer solution of pH 9.0 and
      submitted to a scan rate of 5 mV s(-1) and a pulse amplitude of 50 mV. This
      electroanalytical procedure was able to determine lithium ions in the
      concentration range of 8.0 x 10(-5)-1.0 x 10(-2) mol l(-1) even in the presence
      of several alkali metals (1.0 x 10(-3) mol l(-1)) with a detection limit of 7.1 x
      10(-7) mol l(-1). Rapidity, precise and good selectivity were also found for the
      determination of lithium ions in pharmaceutical formulations.

PMID- 12615242
TI  - Characterization of enzymatically digested hyaluronic acid using NMR, Raman, IR,
      and UV-Vis spectroscopies.
AB  - Hyaluronic acid (HA) is a linear polysaccharide formed from disaccharide units
      containing N-acetylglucosamine and glucuronic acid. When HA was digested with the
      enzyme hyaluronidase, a double bond is formed. It is known that this double bond
      forms a complex (radical scavenger) with the radicals (ROO, HO) during UV
      irradiation, and reduced the toxicity of the radicals before they are absorbed in
      the human skin. Therefore, the characterization of the double bond formed after
      the enzymatic digestion of HA is very important. In this study, 1H NMR, 13C NMR,
      Raman, infrared (IR), and UV-Vis spectroscopies were used for characterization of
      the double bond of HA after enzymatic digestion. HA derivatives in shape of films
      were tested using Raman and infrared (IR) spectroscopies and the wavenumber of
      the double bond and some other assignment were determined. The 1H and 13C NMR
      spectra were measured for HA derivatives in D(2)O solutions. The chemical shifts
      and coupling constant of 1H and 13C were assigned to the CH=C fragment. The
      relative amount of olefinic proportion in the mixture was obtained from 1H and
      13C NMR spectra. The spectroscopy measurement showed an increase in the double
      bond amount with increasing enzymatic digestion time.

PMID- 12615244
TI  - Seizure of illicitly produced para-fluorofentanyl: quantitative analysis of the
      content of capsules and tablets.
AB  - A gas chromatography/mass spectrometry (GC/MS) method for the quantification of
      para-fluorofentanyl (pFF) in powder and powdered samples was developed and
      validated. The method was applied on a seizure of capsules and tablets, that had
      been confiscated at an illicit production site in the Netherlands. The
      investigated capsules and tablets contained pFF in the range of 33.8-408.7
      microg. As caffeine was detected as being an adulterant, a HPLC/UV method for the
      quantification of caffeine in capsules and tablets was also validated and
      applied. Caffeine was detected in the range of 25.6-108 mg per capsule or tablet.
      Based on an extrapolation of pharmacological and toxicological data of fentanyl,
      it can be argued that the highest detected single dose of pFF could be lethal,
      when administered orally. However, the large variability of the doses observed
      for pFF could mislead abusers, potentially leading to multiple doses and thus
      overdosing.

PMID- 12615243
TI  - Rapid and simple method for the analysis of nateglinide in human plasma using
      HPLC analysis with UV detection.
AB  - Nateglinide (NA) is a novel oral mealtime glucose regulator, recently approved
      for the treatment of type II diabetes mellitus. To facilitate clinical studies
      investigating the dependence of NA elimination on the genotype of cytochrome P450
      isoenzymes, we developed a rapid HPLC method for determination of NA in human
      plasma samples. The validated limit of quantitation (LOQ) of 0.1 microg/ml is low
      enough to allow determination of pharmacokinetic parameters of the substance. The
      intra-assay coefficients of variation (CV) ranged from 1.6 to 12.9% at NA
      concentrations of 0.5-7.5 microg/ml. The inter-assay variation for the same
      plasma concentrations ranged from 3.8 to 8.4%. The calibration was linear in the
      range of 0.1-20 microg/ml. For the quantitation of NA, only 50 microl of plasma
      were needed. Following protein precipitation in human plasma, the samples were
      separated by isocratic reversed phase HLPC and analyzed using ultraviolet
      detection at 210 nm. Sample preparation time and analysis time are both short and
      allow rapid analysis of large sample sets.

PMID- 12615246
TI  - Application of attenuated total reflectance Fourier transform infrared
      spectrometry to the determination of cephalosporin C in complex fermentation
      broths.
AB  - An analytical procedure has been developed for quantitative determination of
      cephalosporin C in complex fermentation broths. The method is based on the
      partial least-square treatment of data obtained by attenuated total reflectance
      Fourier transform infrared (ATR-FTIR) spectrometric method in the wavenumber
      range of 1227-1257 cm(-1). Absorbance spectra were employed for measurement using
      a set of eleven binary aqueous standard solutions of cep halosporin C and
      deacetoxycephalosporin C. The method is simple, rapid and accurate (to within +/
      1.49%). The developed method has been used to measure cephalosporin C in aqueous
      solution of biosynthetic samples only after freeze drying the sample at -30
      degrees C and dissolving it in distilled water.

PMID- 12615245
TI  - Sensitive spectrophotometric method for the determination of indomethacin in
      capsules.
AB  - A simple, sensitive and selective spectrophotometric method for the determination
      of indomethacin (INM) either in pure form or in capsules is described. The method
      is based on the coupling reaction of hydrolyzed INM with diazotized p
      phenylenediamine dihydrochloride (PPDD) in sulphuric acid medium to give a red
      coloured product having the absorption maximum at 510 nm. The product is stable
      for 20 h. Beer's law is obeyed in the concentration range of 0.2-10 microg/ml.
      Results of the proposed method compare favourably with those of the official
      methods and offer the merits of sensitivity and stability. Common excipients used
      as additives in pharmaceutical preparations do not interfere in the proposed
      method.

PMID- 12615247
TI  - Identification of photoproducts of folic acid and its degradation pathways in
      aqueous solution.
AB  - The UV irradiated aqueous solutions of folic acid at pH 2-10 degrade to give
      pterin-6-carboxylic acid and p-aminobenzoyl-L-glutamic acid under aerobic
      conditions. These photoproducts have been identified by TLC, HPLC and
      Spectrophotometric techniques. A reaction scheme for the photodegradation
      pathways of folic acid leading to the formation of the photoproducts in acid and
      alkaline media has been proposed which involves the participation of an enamine
      intermediate.

PMID- 12615248
TI  - Chromatographic determination of high-molecular weight impurities in amoxicillin.
AB  - The separation of high molecular weight impurities in amoxicillin has been
      examined by three methods of gel filtration chromatography (GFC) and reversed
      phase liquid chromatography (RPLC). Specificity of GFC was checked by applying
      the method for the determination of amoxicillin and its related impurities and
      linking of GFC and RPLC. The result shows that for the determination of polymers
      the gel filtration chromatography is a rather simple separation mode as compared
      to RPLC. Regarding the three gel filtration chromatographic methods, the
      separation on the Superdex peptide column is advantageous over other methods of
      determining amoxicillin polymers.

PMID- 12615249
TI  - Determination of dexamethasone acetate in cream by HPLC.
AB  - The aim of this research was to validate a high performance liquid
      chromatographic method for the quantitative determination of dexamethasone
      acetate contained in cream preparation. A MetaSil octadecyl silane (250 x 4.6 mm,
      5 microm) column, a methanol: water (65:35; v/v) mobile phase (1.0 ml min(-1))
      and an UV detector (set at 254 nm) were used to evaluate the parameters:
      linearity, precision, accuracy, specificity, as well as, quantitation and
      detection limits. The calibration curve showed a correlation coefficient of
      0.9999. The precision was demonstrated by the relative standard deviation (RSD)
      of 0.53. The recovery test resulted in an average of 97.85%, what confirmed the
      accuracy of the method. The quantitation and detection limits determined were
      1.41 and 0.47 microg ml(-1), respectively. The specificity test showed there was
      no interference in the drug peak.

PMID- 12615250
TI  - New polyvinyl chloride membrane electrode without inner reference solution for
      the determination of methadone.
AB  - A PVC membrane electrode, without inner reference solution, based on an ion
      association extraction system responding to methadone (MD) is described. It
      incorporates a methadone-tetrakis(4-chlorophenyl)borate ion-pair complex in 2
      nitrophenyloctyl ether. The prepared electrode exhibits a near Nernstian response
      (59.5 mV per decade) over the concentration range 2.5 x 10(-5)-10(-1) M MD in
      solutions of pH 2.0-9.0. The reproducibility of the electrode potentials was +/-1
      mV by day during at least 6 months. Response time was about 5 s for MD
      concentrations between 10(-5) and 10(-1) M. Determinations of MD in
      pharmaceutical preparations (tablets and syrups) by direct potentiometry gave an
      average recovery of 99.3% (w/w) and a mean S.D. of 1.5% (w/w).

PMID- 12615251
TI  - Evaluation of the recently reported USP gradient HPLC method for analysis of anti
      tuberculosis drugs for its ability to resolve degradation products of rifampicin.
AB  - The recently notified USP gradient HPLC method for quantitative determination of
      rifampicin, isoniazid and pyrazinamide in fixed dose combination (FDC)
      formulations was evaluated to determine its ability to resolve major degradation
      products of rifampicin, viz. 3-formylrifamycin SV, rifampicin N-oxide, 25
      desacetyl rifampicin, rifampicin quinone, and the newly reported isonicotinyl
      hydrazone, an interaction product of 3-formylrifamycin and isoniazid. The first
      observation was that the requirements of theoretical plates listed in the given
      method were met for rifampicin, but not for isoniazid and pyrazinamide, even on
      columns of different makes. The resolving power of the method was also dependent
      upon make of the column. On two of the three columns of the three tested, it was
      able to resolve most degradation products, except rifampicin N-oxide and 25
      desacetylrifampicin, which were overlapping. The method was modified and an
      overall satisfactory resolution for all components was obtained by changing the
      buffer: organic modifier ratio of solution B in the gradient from 45:55 to 55:45
      and decreasing the flow rate from 1.5 to 1.0 ml/min, keeping all other conditions
      constant.

PMID- 12615252
TI  - Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest
      pain, and quality of life in patients with coronary artery disease.
AB  - Previous studies have demonstrated that magnesium supplementation improves
      endothelial function in patients with coronary artery disease (CAD). However, the
      impact on clinical outcomes, such as exercise-induced chest pain, exercise
      tolerance, and quality of life, has not been established. In a multicenter,
      multinational, prospective, randomized, double-blind and placebo-controlled
      trial, 187 patients with CAD (151 men, 36 women; mean +/- SD age 63 +/- 10 years,
      range 42 to 83) were randomized to receive either oral magnesium 15 mmol twice
      daily (Magnosolv-Granulat, total magnesium 365 mg provided as magnesium citrate)
      (n = 94) or placebo (n = 93) for 6 months. Symptom-limited exercise testing
      (Bruce protocol) and responses given on quality-of-life questionnaires were the
      outcomes measured. Magnesium therapy significantly increased intracellular
      magnesium levels ([Mg]i) in a substudy of 106 patients at 6 months compared with
      placebo (35.5 +/- 3.7 vs 32.6 +/- 2.9 mEq/L, p = 0.0151). Magnesium treatment
      significantly increased exercise duration time compared with placebo (8.7 +/- 2.1
      vs 7.8 +/- 2.9 minutes, p = 0.0075), and lessened exercise-induced chest pain (8%
      vs 21%, p = 0.0237). Quality-of-life parameters significantly improved in the
      magnesium group. These findings suggest that oral magnesium supplementation in
      patients with CAD for 6 months results in a significant improvement in exercise
      tolerance, exercise-induced chest pain, and quality of life, suggesting a
      potential mechanism whereby magnesium could beneficially alter outcomes in
      patients with CAD.

PMID- 12615253
TI  - Noninvasive coronary flow reserve assessed by transthoracic coronary Doppler
      ultrasound in patients with left anterior descending coronary artery stents.
AB  - Noninvasive measurement of coronary flow reserve (CFR) (hyperemic/flow velocity
      ratio at rest) by transthoracic Doppler echocardiography showed normalization of
      flow in the left anterior descending (LAD) coronary artery early after stenting.
      We hypothesized that noninvasive CFR may reveal in-stent restenosis at follow-up.
      Therefore, we studied 134 patients, 0 to 72 months after successful proximal
      middle LAD stenting, and 38 controls. LAD flow velocity was measured by
      transthoracic Doppler echocardiography during 90 seconds venous adenosine
      infusion (140 microg/kg/min). CFR was measured in diastole. According to
      angiography, patients who received stents were divided into 3 groups: group I,
      <50% LAD in-stent restenosis (n = 83); group II, nonsignificant (50% to 69%) LAD
      in-stent restenosis (n = 17); and group III, significant (> or = 70%) LAD in
      stent restenosis (n = 34). LAD CFR was similar in group I and controls (2.90 +/-
      0.58 vs 3.05 +/- 0.81; p = NS), it was slightly lower in group II (2.42 +/- 0.33)
      compared with controls and group I (p <0.001 vs both), and clearly abnormal (<2)
      in group III (1.38 +/- 0.48) compared with controls, and groups I and II (p
      <0.001). A CFR <2 had 91% sensitivity, 95% specificity, and 96% positive and 97%
      negative predictive values to detect significant stenosis in patients with LAD
      stents. Our data show that noninvasive Doppler assessment of CFR allows
      identification of significant LAD in-stent restenosis, based on a cut-off value
      of <2.

PMID- 12615255
TI  - Contrast echocardiographic evaluation of early changes in myocardial perfusion
      after recanalization therapy in anterior wall acute myocardial infarction and
      their relation with early contractile recovery.
AB  - Temporal changes in myocardial perfusion after recanalization and their relation
      with functional recovery in patients with acute myocardial infarction (AMI) using
      intravenous myocardial contrast echocardiography (MCE) have not yet been
      clarified. To address this issue, 19 patients with first, uncomplicated anterior
      wall AMI were studied using intravenous MCE within 24 hours of recanalization and
      before discharge. MCE was performed using harmonic power Doppler. Each asynergic
      left ventricular (LV) myocardial segment was scored for myocardial perfusion (1 =
      complete, 0.7 = patchy but >50%, 0.3 = patchy <50%, and 0 = absent) and a
      regional perfusion index was calculated within the dysfunctioning myocardium.
      During the day-1 study (11 +/- 2 hours from recanalization), the regional
      perfusion index was 0.4 +/- 0.3 and the LV wall motion score index was 1.9 +/-
      0.2. During the study before discharge (7 +/- 4 days from admission), all but 2
      patients showed an improvement of either perfusion index (0.6 +/- 0.3, p <0.0001)
      or wall motion score index (1.7 +/- 0.4, p <0.0001). Changes in perfusion score
      from 24-hours to before discharge showed a significant correlation with LV
      segment contractile recovery at 2-month of follow-up (R(2) = 0.42, 95% confidence
      interval 0.33 to 0.50, p <0.0001). Thus, our data show that after recanalized
      AMI, there is a significant amount of microvascular obstruction that recovers in
      the days after, and the extent of this perfusion improvement appears to be
      related with early myocardial contractile recovery. Our data provide clinical
      evidence for a transient microvascular dysfunction after successfully recanalized
      AMI.

PMID- 12615254
TI  - Pseudonormalized Doppler total ejection isovolume (Tei) index in patients with
      right ventricular acute myocardial infarction.
AB  - The Doppler total ejection isovolume (Tei) index is useful for estimating global
      cardiac function. However, the relation between the right ventricular (RV) Tei
      index and RV infarction has not been investigated. The relation between the RV
      Tei index and severity of RV infarction was evaluated in 25 patients with
      inferior wall acute myocardial infarction (13 with and 12 without RV infarction).
      RV infarction was diagnosed when right atrial pressure was > or = 10 mm Hg or
      when right atrial pressure/pulmonary capillary wedge pressure was >0.8 by
      catheterization. The RV Tei index was significantly increased in patients with RV
      infarction compared with those without (0.53 +/- 0.15 vs 0.38 +/- 0.14, p <0.05).
      The RV Tei index in patients with severe RV infarction (right atrial pressure >
      or = 15 mm Hg) was significantly smaller compared with those with mild/moderate
      RV infarction (right atrial pressure <15 mm Hg) and showed no significant
      difference in patients with myocardial infarction but without RV infarction (0.44
      +/- 0.09 vs 0.61 +/- 0.16 vs 0.38 +/- 0.14, severe RV infarction vs mild/moderate
      RV infarction vs no RV infarction, p <0.01). The RV Tei index is generally
      increased in patients with RV infarction; however, severe RV infarction can be
      manifested with limited or no increase in the Tei index (pseudonormalization).

PMID- 12615256
TI  - Relation of frequency and severity of mitral regurgitation to survival among
      patients with left ventricular systolic dysfunction and heart failure.
AB  - The goal of this study was to examine the frequency of mitral regurgitation (MR)
      in patients with left ventricular (LV) systolic dysfunction and to relate its
      presence and severity to long-term survival. Remodeling of the left ventricle
      after myocyte injury leads to a progressive change in LV size and shape, and it
      may lead to the development of MR. The frequency of MR and its relation to
      survival in patients with LV systolic dysfunction has not been completely
      characterized. We analyzed the histories, coronary anatomy, and degree of MR in
      patients with symptomatic heart failure and LV ejection fraction <40% who
      underwent cardiac catheterization between 1986 and 2000. Cox's proportional
      hazards modeling was used to assess the independent effect of MR on survival. Two
      thousand fifty-seven patients met study criteria; MR was common in this cohort
      (56.2%). Of patients with MR, 811 (70.1%) had mild (grades 1+ or 2+) and 345
      (29.8%) had moderate or severe (grades 3+ or 4+) regurgitation. Survival rates at
      1, 3, and 5 years were significantly lower in patients with moderate to severe MR
      versus those with mild or no MR (p <0.001). MR was found to be an independent
      predictor of mortality after multivariable analysis (hazards ratio 1.23, 95%
      confidence interval 1.13 to 1.34, p = 0.0001). This relation of MR and survival
      was present in those with ischemic and nonischemic cardiomyopathies. MR is common
      in patients with LV systolic dysfunction and heart failure. After adjusting for
      other clinical variables, the presence of MR independently predicted worsened
      survival.

PMID- 12615257
TI  - Angiographic findings, time course of regional and global left ventricular
      function, and clinical outcome in diabetic patients with acute myocardial
      infarction treated with primary percutaneous transluminal coronary angioplasty.
AB  - There is scarce information available about the outcome of diabetic patients with
      acute myocardial infarction (AMI) treated with percutaneous transluminal coronary
      angioplasty (PTCA). We sought to compare left ventricular (LV) function, and
      angiographic and clinical outcomes in diabetics versus nondiabetics with AMI
      treated with primary PTCA. This study examined 720 consecutive patients with AMI
      treated with primary PTCA, 102 of whom had diabetes. Six-month follow-up coronary
      angiography was obtained in 560 patients (88% of eligible patients). In a
      subgroup of 284 patients, LV function was serially determined by 2-dimensional
      echocardiography. During 6-month follow-up no significant differences were
      observed between diabetics and nondiabetics with regard to restenosis rates
      (31.6% vs 28.2%, p = 0.6), recovery of LV function (6-month wall motion score
      index: 1.8 +/- 0.7 vs 1.8 +/- 0.7, p = 0.88; 6-month LV ejection fraction: 48.5
      +/- 12% vs 51.2 +/- 13%, p = 0.173), nonfatal re-AMI rates (2.9% vs 1.3%, p =
      0.2), and target vessel revascularization rates (21.6% vs 16.8%, p = 0.2). Early
      and late mortality were higher in diabetics than in nondiabetic patients (8.8% vs
      4.2%, p = 0.045 and 11.7% vs 5.5%, p = 0.016, respectively). By Cox analysis,
      diabetes was an independent predictor of both early (odds ratio [OR] 2.4, 95%
      confidence interval [CI] 1.1 to 5.3, p = 0.03) and late mortality (OR 2.37, 95%
      CI 1.16 to 4.84, p = 0.017) as well as 6-month major adverse cardiac events
      (MACEs): death, re-AMI, target vessel revascularization (OR 1.51, 95% CI 1.04 to
      2.18, p = 0.03). Thus, diabetes is an independent predictor of clinical outcome
      even if PTCA is used as the primary reperfusion strategy.

PMID- 12615258
TI  - Prognostic value of pseudonormal and restrictive filling patterns on left
      ventricular remodeling and cardiac events after coronary artery bypass grafting.
AB  - This study was aimed to assess the prognostic value of transmitral flow (TMF)
      patterns on patients after coronary artery bypass grafting (CABG). TMF, left
      ventricular (LV) end-diastolic diameter (LVDd) and LV ejection fraction (LVEF)
      were studied in 102 patients before and after CABG by echocardiography. Patients
      were subdivided into 4 groups according to TMF patterns during hospital stay
      shortly after CABG; group 1 (n = 37) had normal filling patterns; group 2 (n =
      29) had abnormal relaxation patterns; group 3 (n = 24) had pseudonormal patterns;
      and group 4 (n = 12) had restrictive patterns. One year after CABG, LVDd was
      greater and LVEF was lower in groups 3 and 4 than in groups 1 and 2, although
      there were no significant differences in LVDd and LVEF among the 4 groups before
      and shortly after CABG. During the follow-up period of 29 +/- 20 months, 19
      patients had cardiac events. The incidence of cardiac events in groups 3 and 4
      determined by the Kaplan-Meier method was significantly higher than that in
      groups 1 and 2 (Mantel-Cox test, p <0.01). Patients' gender, clinical findings,
      and echocardiographic variables were compared for their ability to predict
      cardiac events by means of the Cox proportional hazards model, and only the LVDd
      and TMF patterns during the hospital stay after CABG were recognized as
      independent predictors of cardiac events (chi-square 4.9 and 11.3, respectively;
      p <0.05). Pseudonormal or restrictive TMF patterns during hospital stay shortly
      after CABG are useful indicators for predicting outcome.

PMID- 12615260
TI  - Optimizing the detection of bidirectional block across the flutter isthmus for
      patients with typical isthmus-dependent atrial flutter.
AB  - The purpose of this study was to show that multipolar electrographic recordings
      along the subeustachian isthmus (SI) can better differentiate slow conduction
      from complete isthmus block after atrial flutter ablation, leading to a lower
      incidence of recurrent atrial flutter (Afl). Despite the presence of various
      techniques to identify bidirectional conduction block (BDB) after isthmus
      ablation for typical Afl, several studies, including a report from a national
      registry, suggest that radiofrequency ablation is still associated with a 15%
      recurrence rate. Thus, techniques that can distinguish slow conduction from
      complete isthmus block have the potential for reducing long-term recurrences. We
      evaluated patients who underwent radiofrequency ablation for typical isthmus
      dependent Afl. Patients were separated into 2 groups. Group A underwent
      assessment of BDB with conventional methods. In group B, BDB was assessed by
      placing a multipolar catheter along the floor of the SI, pacing adjacent to the
      line of radiofrequency application, and assessing electrographic activation on
      either side. One hundred thirty-one cases of Afl ablation were analyzed (86 in
      group A, 45 in group B). Over a mean follow-up period of 17 months, recurrence
      rates of Afl were 16.5% in group A and 4.3% in group B (p = 0.043). Thus,
      assessment of BDB by placement of a multipolar catheter across the SI after
      ablation of typical Afl is associated with a significant reduction in long-term
      recurrence of Afl.

PMID- 12615259
TI  - Effect of plasma C-reactive protein levels in modulating the risk of coronary
      heart disease associated with small, dense, low-density lipoproteins in men (The
      Quebec Cardiovascular Study).
AB  - This purpose of this study was to investigate how plasma C-reactive protein
      (CRP), a nonspecific acute-phase reactant, modulates the risk of coronary heart
      disease (CHD) associated with the small, dense, low-density lipoprotein (LDL)
      phenotype. LDL particle size and plasma CRP were measured in the Quebec
      Cardiovascular Study cohort of 2,025 men free of CHD at baseline, among whom 103
      had a first CHD event during a 5-year follow-up period. Plasma CRP levels were
      measured using the Behring Latex-Enhanced (highly sensitive) CRP assay. LDL
      particle size phenotype was characterized using 2% to 16% polyacrylamide gradient
      gel electrophoresis. There were weak but significant associations between plasma
      CRP levels and features of LDL size, such as the proportion of LDL with a
      diameter <255 A (r = 0.09, p <0.001) and LDL peak particle size (r = -0.09, p
      <0.001). Variations in plasma CRP levels modulated the risk of CHD associated
      with small LDL peak particle size (relative risk 4.3 vs 2.5 in men with high vs
      low plasma CRP levels, respectively) and with an elevated proportion of LDL <255
      A (relative risk 6.6 vs 3.0). Thus, increased plasma CRP levels further elevate
      the risk of CHD associated with having small, dense LDL particles.

PMID- 12615261
TI  - Outcome of patients with dual-chamber pacemakers implanted for the prevention of
      neurally mediated syncope.
AB  - Dual-chamber pacemaker insertion (PI) has been found to reduce the recurrence of
      neurally mediated syncope (NMS) in 3 randomized trials. However, the long-term
      benefits of PI are unknown. To assess the natural history of NMS, we followed a
      cohort of 40 patients who underwent PI for frequent NMS for 46 to 75 months. We
      assessed the reduction in syncope frequency after PI and the time to first
      recurrence of syncope. Sixty months after PI, 32.5% of patients remained free of
      NMS. The frequency of syncope decreased from 0.46 to 0.06 spells/month (before to
      after PI, p = 0.04). Two groups of patients were identified, with responders to
      PI defined as having a 75% decrease in the frequency of NMS. Responders (n = 22)
      experienced a significant decrease in the frequency of NMS (0.31 to 0.01
      spells/month, p <0.0001), whereas nonresponders did not experience a similar
      reduction (p = 0.8). Responders could not be identified by either baseline or
      tilt-test parameters. Patients without an early recurrence of syncope after PI
      (within 6 months) experienced a significant reduction in the frequency of NMS
      (0.24 to 0.02 spells/month, p = 0.0002), although the reduction was not
      significant (p = 0.3) in patients with an early recurrence of syncope. Some, but
      not all, patients respond to permanent PI for NMS. The long-term benefit of
      permanent PI can be predicted by timing of the first recurrence of syncope, but
      not by preimplantation factors.

PMID- 12615262
TI  - Usefulness of tissue Doppler echocardiography for evaluating ventricular function
      in children without heart disease.
AB  - Tissue Doppler echocardiographic imaging (TDI) is a novel method for accurately
      evaluating ventricular function. Currently, scant data are available on the
      distribution of tissue Doppler indexes in healthy children in the age range of 1
      to 18 years. The aims of this study were to assess the distribution of tissue
      Doppler indexes of systolic and diastolic ventricular function in healthy
      children, to assess the influence of age on these indexes, and to compare them
      with conventional Doppler indexes. A total of 151 consecutive children aged 1 to
      18 years were enrolled in the study. Nine different (7 diastolic and 2 systolic)
      TDI parameters were assessed. Peak velocities of systolic and diastolic
      excursions of the mitral and tricuspid annuli were obtained from the apical 4
      chamber view. Mean velocities of early diastolic recoil of mitral and tricuspid
      annuli were measured from the apical 4-chamber view. The mean velocity of early
      diastolic relaxation of the left ventricular posterior wall was measured in the
      parasternal long-axis view. Results showed a statistically significant difference
      in some of the TDI indexes among the different pediatric age groups. Most of the
      TDI indexes showed a very weak correlation with age. There was no significant
      correlation (p >0.05) between peak velocities of the early diastolic mitral
      inflow Doppler pattern (E wave) and the corresponding TDI index. In contrast,
      there was a significant (p <0.001) correlation between the corresponding Doppler
      indexes in the tricuspid annulus. We conclude that TDI is a valuable tool for
      assessing ventricular function, particularly diastolic function. Establishment of
      normative data for TDI in the pediatric age group should broaden the clinical
      applicability of this useful modality for assessing ventricular function.

PMID- 12615264
TI  - Implementing clinical trial results into clinical practice for patients with
      heart failure.

PMID- 12615263
TI  - Importance of high-density lipoprotein cholesterol and triglyceride levels in
      coronary heart disease.

PMID- 12615265
TI  - Using implantable devices to improve end-of-life care.

PMID- 12615266
TI  - How to avoid being swept away by the rising tide of malpractice litigation.

PMID- 12615267
TI  - Effect of uncoated stenting versus balloon angioplasty alone of long coronary
      (>20 mm) versus shorter narrowings on one-year event-free survival.

PMID- 12615268
TI  - Effect of percutaneous coronary angioplasty on myocardial perfusion, function,
      and wall thickness as assessed by quantitative gated single-photon emission
      computed tomography.

PMID- 12615269
TI  - Usefulness of gamma intracoronary radiation for totally occluded in-stent
      restenotic coronary narrowing.

PMID- 12615270
TI  - Comparison of the radial and the femoral approaches in percutaneous coronary
      intervention for acute myocardial infarction.

PMID- 12615271
TI  - C-reactive protein and ST-segment monitoring by continuous 12-lead
      electrocardiogram in patients with primary unstable angina pectoris.

PMID- 12615272
TI  - Effect of atorvastatin (80 mg) and simvastatin (40 mg) on plasma fibrinogen
      levels and on carotid intima media thickness in patients with familial
      hypercholesterolemia.

PMID- 12615274
TI  - Prevalence of interatrial block in a general hospital population.

PMID- 12615273
TI  - Evidence that nonsustained polymorphic ventricular tachycardia causes syncope
      (data from implantable cardioverter defibrillators).

PMID- 12615275
TI  - Comparison of the transseptal approach to the transaortic approach for ablation
      of left-sided accessory pathways in patients with Wolff-Parkinson-White syndrome.

PMID- 12615276
TI  - Monitoring of hepatic function during amiodarone therapy.

PMID- 12615277
TI  - Role of the cryopreserved homograft in isolated elective aortic valve
      replacement.

PMID- 12615278
TI  - Prevalence of and predictors of bicuspid aortic valves in patients with dilated
      aortic roots.

PMID- 12615280
TI  - Relation of extreme left ventricular hypertrophy to age in hypertrophic
      cardiomyopathy.

PMID- 12615279
TI  - Quantification of regional right and left ventricular function by ultrasonic
      strain rate and strain indexes in Friedreich's ataxia.

PMID- 12615281
TI  - Echocardiographic atrioventricular interval optimization in patients with dual
      chamber pacemakers and symptomatic left ventricular systolic dysfunction.

PMID- 12615282
TI  - Usefulness of epoprostenol therapy in the severely ill adolescent/adult with
      Eisenmenger physiology.

PMID- 12615283
TI  - Cosegregation of the Marfan syndrome and the long QT syndrome in the same family
      leads to a severe cardiac phenotype.

PMID- 12615284
TI  - Comparison of aortic elasticity in patients with the marfan syndrome with and
      without aortic root replacement.

PMID- 12615285
TI  - Echocardiographic features of pheochromocytoma of the heart.

PMID- 12615286
TI  - Balance and gait in older adults with systemic hypertension.

PMID- 12615287
TI  - Robert P. Grant, MD.

PMID- 12615289
TI  - National Cholesterol Education Program Adult Treatment Panel-III guidelines and
      the abolition of symptomatic coronary artery disease.

PMID- 12615292
TI  - Mechanisms of plaque stabilization with statins.
AB  - The traditional view of cardiovascular disease held that the degree of stenosis
      defined high-risk lesions and that removal of cholesterol shrank these lesions
      and thereby enlarged the lumen. Advances in understanding of the pathophysiology
      of the acute coronary syndromes refute this view. We now appreciate that vascular
      biology determines plaque stability and that statins stabilize plaque by
      favorably altering this biology. They do so chiefly (but probably not
      exclusively) by cholesterol lowering. In addition to reducing the cholesterol
      content of plaque, lipid lowering inhibits inflammation, and decreases
      collagenolytic activity and thrombotic potential. The role of lipid-independent
      effects remains unclear because many studies used statin concentrations too high
      to have any clinical relevance. However, data suggest that statin-induced
      alterations in the function of small G proteins may contribute to the anti
      inflammatory and antithrombotic actions of statins in clinical practice.

PMID- 12615293
TI  - Effects of statins on inflammation in patients with acute and chronic coronary
      syndromes.
AB  - Inflammation plays a crucial role in the cell biology of atherosclerosis.
      Coronary risk factors, and particularly low-density lipoprotein (LDL)
      cholesterol, injure the endothelium and decrease the bioavailability of nitric
      oxide to promote the expression of proinflammatory genes, cellular adhesion
      molecules, cytokines, chemokines, and growth factors. For example, the expression
      of CD40/CD40 ligand increases cell-mediated immune responses to activate a number
      of inflammatory cells and destabilize atherosclerosis. As part of this response,
      soluble markers of inflammation that are released into the blood offer insights
      into the cell biology of inflammation in atherosclerosis. In groups of patients,
      these markers have provided a means to study inflammatory mechanisms and have
      supported the value of many of our interventions that prevent cardiovascular
      disease. Statins have potent effects to reduce LDL cholesterol in the plasma and
      the artery wall and also appear to have a number of nonlipid effects that
      decrease inflammatory stimuli. Because statins also reduce some soluble markers
      of inflammation, it is likely that at least part of their benefit reflects a
      reduction in vascular inflammation in stable and unstable coronary syndromes.
      Although these inflammatory markers are valuable tools for studying the
      mechanisms of atherosclerosis, their use in clinical practice to stratify
      cardiovascular risk or assess treatment in individual patients requires further
      evaluation.

PMID- 12615294
TI  - Effects of statins on the vasculature: Implications for aggressive lipid
      management in the cardiovascular metabolic syndrome.
AB  - The cardiovascular metabolic syndrome is a family of risk factors that predispose
      patients to develop diabetes and cardiovascular disease. Indeed, macrovascular,
      not microvascular, disease is the leading cause of death in these patients. The 3
      hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert both
      direct and indirect (cholesterol-lowering) effects on the vasculature. Clinical
      trials have shown that these agents reduce cardiovascular disease and
      cerebrovascular disease in persons with diabetes. However, their beneficial
      effects on diabetic dyslipidemia do not account for all of the observed risk
      reduction. Positive effects on nitric oxide metabolism, inflammation,
      coagulability, and adhesion of cells to the vascular endothelium likely
      contribute to the mechanism of action of these agents. These pleiotropic effects
      of statins on the vasculature will be discussed in this review.

PMID- 12615295
TI  - Prevention of stroke and dementia with statins: Effects beyond lipid lowering.
AB  - Stroke is a major cause of mortality and morbidity. The epidemiologic association
      between elevated serum cholesterol and stroke risk is controversial. However,
      recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A
      reductase inhibitors (statins) have demonstrated a significant reduction in
      ischemic stroke without an increase in hemorrhagic stroke. Statins probably
      reduce stroke by a variety of mechanisms, including modulation of precerebral
      atherothrombosis in the aorta and the carotid artery, thus preventing plaque
      disruption and artery-to-artery thromboembolism. Statins also improve endothelial
      homeostasis by increasing the bioavailability of nitric oxide, which orchestrates
      the paracrine antiatherosclerotic functions of the endothelium. Studies in
      experimental models of ischemic stroke show that statin therapy reduces brain
      infarct size and improves neurologic outcome by directly upregulating brain
      endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins
      may also contribute to neuroprotection and stroke prevention. Although the
      clinical benefit of statins largely depends on lowering low-density lipoprotein
      cholesterol, accumulating data indicate that many of the pleiotropic effects of
      statins are attributable to the cellular consequences of depletion of
      intermediates in the cholesterol biosynthetic pathway (isoprenoids). These
      molecules play fundamental roles in cell growth, signal transduction, and
      mitogenesis. In addition to reducing stroke risk, emerging data suggest that
      statins may reduce dementia. Further studies are needed to fully address the role
      of statins in the prevention of stroke in patients without established vascular
      disease and the role of cholesterol modulation in the treatment of dementia.

PMID- 12615296
TI  - Optimizing lipid management in patients with acute coronary syndromes.
AB  - According to the Third Report of the Expert Panel on Detection, Evaluation, and
      Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III),
      patients with low-density lipoprotein (LDL) cholesterol > or = 130 mg/dL should
      be discharged on lipid-lowering therapy. When LDL cholesterol levels are between
      100 and 129 mg/dL, evaluation of ratios of LDL cholesterol/high-density
      lipoprotein (HDL) cholesterol or total cholesterol/HDL cholesterol may provide
      additional insight into a patient's risk status. Patients who were using statin
      therapy before admission for an acute coronary syndrome should be continued on
      lipid-lowering therapy. The American College of Cardiology/American Heart
      Association (ACC/AHA) 2002 guideline update for management of patients with
      unstable angina and non-ST-segment elevation myocardial infarction recommends
      statin therapy at discharge as a class I indication, level of evidence A.
      Furthermore, studies confirm that statin therapy begun early during
      hospitalization can prevent ischemic events in patients who are treated by an
      invasive strategy and those who are treated only by a medical strategy. However,
      studies suggest that patient compliance with a statin regimen after discharge is
      far from optimal. There are 2 programs available to help ensure that appropriate
      patients receive and continue taking lipid-lowering therapy. These programs are
      the Cardiac Hospitalization Atherosclerosis Management Program (CHAMP) and the
      Guidelines Applied in Practice (GAP).

PMID- 12615297
TI  - An overview on the use of a viral pathogen as a bioterrorism agent: why smallpox?

PMID- 12615298
TI  - Smallpox: a potential agent of bioterrorism.
AB  - The events of 11 September 2001, in New York City, and subsequent identification
      of anthrax in the United States Postal System, have generated a new sense of
      awareness for the potential of biological terrorism, if not warfare. Among those
      agents identified by the Centers for Disease Control and Prevention as 'Class A
      Bioterrorist Threats', smallpox is among the most dangerous. The ease of
      transmission of this agent, the lack of immunity in the population at large to
      this agent, and rapidity of its spread, if released, all generate significant
      concern for its deployment. A vaccine directed against smallpox is available but
      it is also associated with significant adverse events-some of which are life
      threatening. Further, no antiviral drug has proven efficacious for therapy of
      human disease, although one licensed drug, cidofovir, does have in vitro
      activity. Regardless, heightened awareness should lead to the development of a
      vaccine without significant adverse events and safe and efficacious antiviral
      drugs. The availability of a vaccine and antiviral drugs that are safe would
      significantly remove any major threat of smallpox deployment by a terrorist.

PMID- 12615299
TI  - Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus
      infections.
AB  - We assessed the activities of 24 different antiviral compounds against smallpox
      (two strains of variola major and one of variola minor), monkeypox, vaccinia and
      cowpox viruses by a neutral red uptake assay. To establish assay parameters, we
      examined viral replication and its inhibition at various times postinfection and
      at several multiplicities of infection. Drugs were selected to target a range of
      functions involved in viral replication. Eight compounds (cidofovir, cyclic HPMPC
      (cHPMPC), HPMPA, ribavirin, tiazofurin, carbocyclic 3-deazaadenosine, 3
      deazaneplanocin A and DFBA (1-(2,4-difluorobenzyloxy)adenosine perchlorate)-a
      derivative of adenosine N1-oxide) inhibited the replication of all three variola
      strains and the other orthopoxviruses at drug concentrations within a
      pharmacologically achievable range. Two others (methisazone and bis-POM-PMEA)
      showed a lesser degree of antiviral effect, while the remainder were inactive. To
      examine possible naturally occurring drug resistance among a large number of
      variola isolates obtained from different geographical regions and at different
      times, we examined the sensitivity of 35 different strains of variola as well as
      other orthopoxviruses to a subset of three of the most active compounds:
      cidofovir, cHPMPC, and ribavirin. Preliminary data indicate that nearly all
      isolates appear to have similar drug sensitivities. These findings are currently
      being verified and expanded.

PMID- 12615300
TI  - Therapy and short-term prophylaxis of poxvirus infections: historical background
      and perspectives.
AB  - The era of antiviral chemotherapy started more than 50 years with the findings by
      Domagk and his colleagues that thiosemicarbazones showed activity against
      vaccinia virus. One of the derivatives, methisazone, was even investigated in the
      prophylaxis of smallpox. With the successful implementation of the smallpox
      vaccine, the use of methisazone was not further pursued. Should there be a threat
      of smallpox or other poxvirus infections, that could not be immediately
      controlled by vaccination, a therapeutic intervention could be envisaged based on
      several therapeutic strategies targeted at such cellular enzymes as IMP
      dehydrogenase, SAH hydrolase, OMP decarboxylase and CTP synthetase, as well as
      viral enzymes such as the DNA polymerase. Most advanced as a therapeutic or early
      prophylactic modality to tackle poxvirus infection is cidofovir, which was found
      active (i) in vitro against all poxviruses studied so far; (ii) in vivo, against
      vaccinia and cowpox virus infections in experimental animal models; as well as
      (iii) some human poxvirus infections, such as molluscum contagiosum. In case of
      an inadvertent poxvirus epidemic, antiviral therapy (i.e. with cidofovir) will
      offer the possibility to provide short-term prophylaxis, or therapy. Cidofovir
      should also allow to treat severe complications of vaccination as may happen in
      for example immunosuppressed patients.

PMID- 12615301
TI  - In vitro activity of potential anti-poxvirus agents.
AB  - The potential use of variola or another orthopoxvirus such as monkeypox as a
      weapon of bioterrorism has stimulated efforts to develop new drugs for treatment
      of smallpox or other poxvirus infections. At the present time only cidofovir is
      approved for use in the emergency treatment of smallpox outbreaks. Although
      cidofovir is very active against the orthopoxviruses in vitro and in animal model
      infections, it is not active when given orally and must be administered with
      precaution so as to avoid renal toxicity. In an attempt to identify alternative
      treatment modalities for these infections we have determined the anti-poxvirus
      activity in vitro of most of the approved antiviral agents as well as a number of
      cidofovir analogs and prodrugs. From these studies, we have identified the
      nucleotide analog, adefovir dipivoxil, some alkoxyalkyl esters of cidofovir and a
      number of prodrugs of cidofovir that warrant further investigation as potential
      therapies for smallpox or other orthopoxvirus infections.

PMID- 12615302
TI  - A review of compounds exhibiting anti-orthopoxvirus activity in animal models.
AB  - Several animal models using mice (most frequently), rabbits, or monkeys have been
      used to identify compounds active against orthopoxvirus infections. The treatment
      of vaccinia virus infections has been well studied in models involving infection
      of scarified skin or eyes, or resulting from intravenous, intraperitoneal,
      intracerebral, or intranasal virus inoculation. Cowpox virus has been used in
      intranasal or aerosol infection studies to evaluate the treatment of lethal
      respiratory infections. Rabbitpox, monkeypox, and variola viruses have been
      employed to a lesser extent than the other viruses in chemotherapy experiments. A
      review of the literature over the past 50 years has identified a number of
      compounds effective in treating one or more of these infections, which include
      thiosemicarbazones, nucleoside and nucleotide analogs, interferon, interferon
      inducers, and other unrelated compounds. Substances that appear to have the
      greatest potential as anti-orthopoxvirus agents are the acyclic nucleotides, (S)
      1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (cidofovir, HPMPC) and 1-[((S)-2
      hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC), and
      the acyclic nucleoside analog, 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine
      (S2242). Other classes of compounds that have not been sufficiently studied in
      lethal infection models and deserve further consideration are thiosemicarbazones
      related to methisazone, and analogs of adenosine-N(1)-oxide and 1
      (benzyloxy)adenosine.

PMID- 12615303
TI  - Defense against filoviruses used as biological weapons.
AB  - The filoviruses, Marburg and Ebola, are classified as Category A biowarfare
      agents by the Centers for Disease Control. Most known human infections with these
      viruses have been fatal, and no vaccines or effective therapies are currently
      available. Filoviruses are highly infectious by the airborne route in the
      laboratory, but investigations of African outbreaks have shown that person-to
      person spread requires direct contact with virus-containing material. In
      consequence, filovirus epidemics can be halted by isolating patients and
      instituting standard infection control and barrier nursing procedures. The
      filovirus disease syndrome resembles that caused by other hemorrhagic fever
      viruses, necessitating studies in a biocontainment laboratory to confirm the
      diagnosis. Some progress has been made in developing vaccines and antiviral
      drugs, but efforts are hindered by the limited number of maximum containment
      laboratories. Terrorists might have great difficulty acquiring a filovirus for
      use as a weapon, but my attempt to do so because of the agents' ability to
      inspire fear. Accurate information is the best tool to prevent panic in the event
      of an attack.

PMID- 12615304
TI  - Molecular diagnostics of viral hemorrhagic fevers.
AB  - This review addresses the diagnostics of viral hemorrhagic fevers (VHFs). In the
      first part, an overview is given on classical methods of VHF diagnostics as well
      as novel molecular diagnostic tools. Currently available polymerase chain
      reaction (PCR) assays for diagnosis of VHF are summarized and discussed. In the
      second part, VHF diagnostics are described in particular for Lassa fever, yellow
      fever, and Crimean-Congo hemorrhagic fever, based on cases that were imported
      into or occurred within Europe. The third part is focussed on important
      differential diagnoses of VHF.

PMID- 12615305
TI  - Arenaviruses other than Lassa virus.
AB  - The family Arenaviridae includes 23 viral species, of which 5 can cause viral
      hemorrhagic fevers with a case fatality rate of about 20%. These five viruses are
      Junin, Machupo, Guanarito, Sabia and Lassa virus, the manipulation of which
      requires biosafety level 4 facilities. They are included in the Category A
      Pathogen List established by the Center for Disease Control and Prevention that
      groups agents with the greatest potential for adverse public health impact and
      mass casualties whether a situation characterized by a ill-intentioned abuse of
      natural or engineered arenavirus would be encountered. The aims of this article
      are to (i) summarize the current situation; (ii) provide information to help
      anticipating the effects to be expected in such a situation; and to (iii)
      emphasize the need for fundamental research to allow the development of
      diagnostic, prevention and therapeutic tools as countermeasures to weaponized
      arenaviruses.

PMID- 12615306
TI  - Viruses of the Bunya- and Togaviridae families: potential as bioterrorism agents
      and means of control.
AB  - When considering viruses of potential importance as tools for bioterrorism,
      several viruses in the Bunya- and Togaviridae families have been cited. Among
      those in the Bunyaviridae family are Rift Valley fever, Crimean-Congo hemorrhagic
      fever, hanta, and sandfly fever viruses, listed in order of priority. Those
      particularly considered in the Togaviridae family are Venezuelan, eastern and
      western equine encephalitis viruses. Factors affecting the selection of these
      viruses are the ability for them to induce a fatal or seriously incapacitating
      illness, their ease of cultivation in order to prepare large volumes, their
      relative infectivity in human patients, their ability to be transmitted by
      aerosol, and the lack of measures available for their control. Each factor is
      fully considered in this review. Vaccines for the control of infections induced
      by these viruses are in varying stages of development, with none universally
      accepted to date. Viruses in the Bunyaviridae family are generally sensitive to
      ribavirin, which has been recommended as an emergency therapy for infections by
      viruses in this family although has not yet been FDA-approved. Interferon and
      interferon inducers also significantly inhibit these virus infections in animal
      models. Against infections induced by viruses in the Togaviridae family,
      interferon-alpha would appear to currently be the most useful for therapy.

PMID- 12615307
TI  - Nipah virus--a potential agent of bioterrorism?
AB  - Nipah virus, a newly emerging deadly paramyxovirus isolated during a large
      outbreak of viral encephalitis in Malaysia, has many of the physical attributes
      to serve as a potential agent of bioterrorism. The outbreak caused widespread
      panic and fear because of its high mortality and the inability to control the
      disease initially. There were considerable social disruptions and tremendous
      economic loss to an important pig-rearing industry. This highly virulent virus,
      believed to be introduced into pig farms by fruit bats, spread easily among pigs
      and was transmitted to humans who came into close contact with infected animals.
      From pigs, the virus was also transmitted to other animals such as dogs, cats,
      and horses. The Nipah virus has the potential to be considered an agent of
      bioterrorism.

PMID- 12615308
TI  - Hantavirus.
AB  - When hantaviruses hit the headlines with the advent in May 1993 of a new disease
      in the USA, and later in the New World from Canada to south Argentina, called
      "hantavirus pulmonary syndrome" (HPS), speculations in the lay press rose from
      the very beginning around the possibilities of a biological warfare (BW) weapon.
      Indeed, the responsible agent of HPS, hantavirus, was almost unknown at that
      moment in the New World, was airborne, seemed to target preferentially young
      adults, and induced a devastating cardio-pulmonary collapse with a high case
      fatality rate (50%), often within hours. It quickly became clear, however, that
      the same scourge had been known for many years in the Old World under different
      and mostly milder presentations. With the rapidly increasing knowledge about
      hantaviruses, it also became clear that they lack many of the potentials of an
      "ideal" BW weapon, as will be explained in this paper.

PMID- 12615309
TI  - Tick-borne encephalitis.
AB  - Tick-borne encephalitis (TBE) is one of the most dangerous human infections
      occurring in Europe and many parts of Asia. The etiological agent Tick-borne
      encephalitis virus (TBEV), is a member of the virus genus Flavivirus, of the
      family Flaviviridae. TBEV is believed to cause at least 11,000 human cases of
      encephalitis in Russia and about 3000 cases in the rest of Europe annually.
      Related viruses within the same group, Louping ill virus (LIV), Langat virus
      (LGTV) and Powassan virus (POWV), also cause human encephalitis but rarely on an
      epidemic scale. Three other viruses within the same group, Omsk hemorrhagic fever
      virus (OHFV), Kyasanur Forest disease virus (KFDV) and Alkhurma virus (ALKV), are
      closely related to the TBEV complex viruses and tend to cause fatal hemorrhagic
      fevers rather than encephalitis. This review describes the clinical
      manifestations associated with TBEV infections, the main molecular-biological
      properties of these viruses, and the different factors that define the incidence
      and severity of disease. The role of ticks and their local hosts in the emergence
      of new virus variants with different pathogenic characteristics is also
      discussed. This review also contains a brief history of vaccination against TBE
      including trials with live attenuated vaccine and modern tendencies in developing
      of vaccine virus strains.

PMID- 12615310
TI  - The potential use of influenza virus as an agent for bioterrorism.
AB  - Influenza A virus has been responsible for widespread human epidemics because it
      is readily transmitted from humans to humans by aerosol. Recent events have
      highlighted the potential of influenza A virus as a bioterrorist weapon: the high
      virulence of the influenza A virus that infected people in Hong Kong in 1997; and
      the development of laboratory methods to generate influenza A viruses by
      transfection of DNAs without a helper virus. Antiviral drugs that are directed at
      functions shared by all influenza A viruses constitute the best line of defense
      against a bioterrorist attack. Consequently, new antiviral drugs need to be
      developed, and the few currently available antiviral drugs should be stockpiled.

PMID- 12615312
TI  - Fatty acid and sterol metabolism: potential antimicrobial targets in apicomplexan
      and trypanosomatid parasitic protozoa.
AB  - Current treatments for diseases caused by apicomplexan and trypanosomatid
      parasites are inadequate due to toxicity, the development of drug resistance and
      an inability to eliminate all life cycle stages of these parasites from the host.
      New therapeutics agents are urgently required. It has recently been demonstrated
      that type II fatty acid biosynthesis occurs in the plastid of Plasmodium
      falciparum and Toxoplasma gondii and inhibitors of this pathway such as triclosan
      and thiolactomycin restrict their growth. Furthermore, Trypanosoma brucei has
      recently been demonstrated to use type II fatty acid biosynthesis for myristate
      synthesis and to be susceptible to thiolactomycin. As this pathway is absent from
      mammals, it may provide an excellent target for novel antimicrobial agents to
      combat these diverse parasites. Leishmania and Trypanosoma parasites produce
      ergosterol-related sterols by a biosynthetic pathway similar to that operating in
      pathogenic fungi and their growth is susceptible to sterol biosynthesis
      inhibitors. Thus, inhibition of squalene 2,3-epoxidase by terbinafine, 14alpha
      methylsterol 14-demethylase by azole and triazole compounds and delta(24)-sterol
      methyl transferase by azasterols all cause a depletion of normal sterols and an
      accumulation of abnormal amounts of sterol precursors with cytostatic or cytoxic
      consequences. However, Leishmania parasites can survive with greatly altered
      sterol profiles induced by continuous treatment with low concentrations of some
      inhibitors and they also have some ability to utilise and metabolise host sterol.
      These properties may permit the parasites to evade treatment with sterol
      biosynthesis inhibitors in some clinical situations and need to be taken into
      account in the design of future drugs.

PMID- 12615313
TI  - Phospholipids in parasitic protozoa.
AB  - Parasitic protozoa are surrounded by membrane structures that have a different
      lipid and protein composition relative to membranes of the host. The parasite
      membranes are essential structurally and also for parasite specific processes,
      like host cell invasion, nutrient acquisition or protection against the host
      immune system. Furthermore, intracellular parasites can modulate membranes of
      their host, and trafficking of membrane components occurs between host membranes
      and those of the intracellular parasite. Phospholipids are major membrane
      components and, although many parasites scavenge these phospholipids from their
      host, most parasites also synthesise phospholipids de novo, or modify a large
      part of the scavenged phospholipids. It was recently shown that some parasites
      like Plasmodium have unique phospholipid metabolic pathways. This review will
      focus on new developments in research on phospholipid metabolism of parasitic
      protozoa in relation to parasite-specific membrane structures and function, as
      well as on several targets for interference with the parasite phospholipid
      metabolism with a view to developing new anti-parasitic drugs.

PMID- 12615314
TI  - Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry
      targets for the development of antitrypanosomatid and antimalarial therapeutics.
AB  - To accelerate progress in the development of therapeutics for protozoan parasitic
      diseases, we are studying enzymes active in co- and post-translational protein
      modification that are already the focus of drug development in other eukaryotic
      systems. Inhibitors of the protein farnesyltransferases (PFT) are well
      established antitumour agents of low cytotoxicity and known pharmokinetic
      properties, while inhibitors of N-myristoyl transferase show both selectivity and
      specificity in the treatment of fungal infections. Here, we summarise the current
      evidence that supports the targeting of these ubiquitous eukaryotic enzymes for
      drug development against trypanosomatid infections and malaria.

PMID- 12615315
TI  - Antiprotozoal activities of phospholipid analogues.
AB  - The antiprotozoal activity of phospholipid analogues, originally developed as
      anti-cancer drugs, has been determined in the past decade. The most susceptible
      parasites are Leishmania spp. and Trypanosoma cruzi with activity also shown
      against Trypanosoma brucei spp., Entamoeba histolytica and Acanthamoeba spp.
      Miltefosine, an alkylphosphocholine, was registered for the oral treatment of
      visceral leishmaniasis (VL) in India in March 2002. This review will focus on the
      biological activities of phospholipid analogues. Biochemical and molecular
      targets and mechanism(s) of action have been studied extensively in tumor cells
      but have not been determined in protozoa.

PMID- 12615316
TI  - High-resolution crystal structure of Trypanosoma brucei UDP-galactose 4'
      epimerase: a potential target for structure-based development of novel
      trypanocides.
AB  - The crystal structure of UDP-galactose 4'-epimerase from the protozoan parasite
      Trypanosoma brucei in complex with the cofactor NAD(+) and a fragment of the
      substrates, UDP, has been determined at 2.0 A resolution (1 A = 0.1 nm). This
      enzyme, recently proven to be essential for this pathogenic parasite, shares 33%
      sequence identity with the corresponding enzyme in the human host. Structural
      comparisons indicate that many of the protein-ligand interactions are conserved
      between the two enzymes. However, in the UDP-binding pocket there is a non
      conservative substitution from Gly237 in the human enzyme to Cys266 in the T.
      brucei enzyme. Such a significant difference could be exploited by the structure
      based design of selective inhibitors using the structure of the trypanosomatid
      enzyme as a template.

PMID- 12615318
TI  - The second largest subunit of Trypanosoma brucei's multifunctional RNA polymerase
      I has a unique N-terminal extension domain.
AB  - In the protist parasite Trypanosoma brucei, RNA polymerase (pol) I transcribes
      the large ribosomal RNA gene unit and, in addition, variant surface glycoprotein
      gene expression sites and procyclin gene transcription units. The multifunctional
      role of RNA pol I in this organism is unique among eukaryotes, but only its
      largest subunit TbRPA1 has been characterized thus far. We have recently
      established the procyclic cell line RPIC which exclusively expresses RNA pol I
      tagged with the protein C epitope at the TbRPA1 C-terminus. In the present study,
      we prepared RPIC cell extracts and immunopurified RNA pol I using anti-protein C
      affinity matrix under high stringency conditions. We were able to identify five
      specific polypeptides on a silver-stained polyacrylamide-SDS gel with apparent
      molecular weights of 200, 180, 55, 29, and 22 kDa. Interestingly, the second
      largest subunit, TbRPA2, is 42-58 kDa larger than counterparts of other
      organisms. We have cloned and sequenced the complete TbRPA2 cDNA and found an
      open reading frame for a polypeptide of 179.5 kDa. The deduced amino acid
      sequence of TbRPA2 contains a unique N-terminal domain of approximately 250 amino
      acids. By raising a polyclonal antibody against a N-terminal peptide sequence of
      TbRPA2, we could specifically detect this polypeptide in immunoblots showing that
      it co-purifies with epitope-tagged TbRPA1. Moreover, we identified the homologous
      gene sequence LmRPA2 in Leishmania major and found that it encodes a homologous
      extension domain. Therefore, the N-terminal extra domain in trypanosomatid RPA2
      polypeptides may serve a parasite-specific function.

PMID- 12615319
TI  - Identification of excretory-secretory products of larval and adult Ostertagia
      ostertagi by immunoscreening of cDNA libraries.
AB  - Excretory-secretory (ES) products of Ostertagia ostertagi, an abomasal nematode
      of cattle, are considered to be important for the development and survival of the
      parasite within the host. To gain insight in the composition of these ES products
      of both larval (L3, L4) and adult life stages of Ostertagia cDNA libraries of the
      parasite were immunoscreened with polyclonal rabbit serum raised against these ES
      products. This approach led to the identification of 41 proteins, amongst which
      are structural proteins such as actin, kinesin and vitellogenin, housekeeping
      proteins such as those involved in protein folding, different metabolic pathways
      or mitochondrial functioning and proteins associated with stress (heat shock
      protein) or antioxidantia (thioredoxin peroxidase). A large number of the
      isolated proteins were similar to hypothetical proteins of the model nematode
      Caenorhabditis elegans. Because somatic proteins can be non-specifically released
      during in vitro culturing as nematodes deteriorate, it was checked if the
      isolated proteins are genuinely secreted. The amino acid sequences of the
      translated cDNAs were investigated for signal peptides and monospecific
      antibodies against the isolated proteins were purified and used to develop
      Western blots of ES and somatic extracts. In this manner it could be proven that
      15 cDNAs code for genuine secreted proteins. The identification of these ES
      antigens allows to select proteins with potential protective capacities, which
      are targets for vaccine development.

PMID- 12615320
TI  - A gene-family encoding small exported proteins is conserved across Plasmodium
      genus.
AB  - A gene-family, named sep, encoding small exported proteins conserved across
      Plasmodium species has been identified. SEP proteins (13-16 kDa) contain a
      predicted signal peptide at the NH(2)-terminus, an internal hydrophobic region
      and a polymorphic, low-complexity region at the carboxy-terminus. One member of
      the Plasmodium berghei family, Pbsep1, encodes an integral membrane protein
      expressed along the entire erythrocytic cycle. Immunolocalisation results
      indicated that PbSEP1 is targeted to the membrane of the parasitophorous vacuole
      up to the early phases of schizogony, while, in late schizonts, it re-locates in
      structures within the syncitium. After erythrocyte rupture, PbSEP1 is still
      detectable in free merozoites thus suggesting its involvement in the early steps
      of parasite invasion. Seven members of the sep-family in Plasmodium falciparum
      have been identified. Two of them correspond to previously reported gene
      sequences included in a family of early transcribed membrane proteins (etramp).
      Structural, functional and phylogenetic features of the sep family, shown in the
      present work, supercede this previous classification. PfSEP proteins are exported
      beyond the parasite membrane and translocated, early after invasion, to the host
      cell compartment in association with vesicle-like structures. Colocalisation
      results indicated that PfSEP-specific fluorescence overlaps, at the stage of
      trophozoite, with that of Pf332, a protein associated with Maurer's clefts,
      membranous structures in the cytosol of parasitised red blood cells, most
      probably involved in trafficking of parasite proteins. The specific signals
      necessary to direct SEP proteins to the vacuolar membrane in P. berghei or to the
      host cell compartment in P. falciparum remain to be determined.

PMID- 12615321
TI  - Regulatory volume decrease in Trypanosoma cruzi involves amino acid efflux and
      changes in intracellular calcium.
AB  - A regulatory volume decrease (RVD) in response to hyposmotic stress has been
      characterized in different life-cycle stages of Trypanosoma cruzi. Hyposmotic
      stress initially caused swelling, but this was rapidly reversed by a compensatory
      volume reversal that was essentially complete by 5 min. Volume recovery was
      associated with an amino acid efflux that accounted for approximately 50% of the
      regulatory volume decrease in all three life-cycle stages. The amino acid efflux
      was selective for neutral and anionic amino acids, but excluded cationic amino
      acids. Acidocalcisomes contained an amino acid pool over four times more
      concentrated than whole-cell levels, but about 90% of this was composed of Arg
      and Lys, so involvement of this pool in amino acid efflux was ruled out.
      Hyposmotic stress induced a rise in intracellular calcium that was dependent on
      influx of calcium across the plasma membrane, since chelation of extracellular
      calcium abolished the response. Influx of calcium was confirmed by demonstration
      of manganese-mediated quenching of intracellular fura-2 fluorescence and partial
      inhibition of the rise in calcium by calcium channel blockers. Manipulation of
      intra- and extracellular calcium levels had minor effects on the initial rate of
      amino acid efflux and no effect on the rate of volume recovery.

PMID- 12615322
TI  - Expression of a recombinant IRP-like Plasmodium falciparum protein that
      specifically binds putative plasmodial IREs.
AB  - Plasmodium falciparum iron regulatory-like protein (PfIRPa, accession AJ012289)
      has homology to a family of iron-responsive element (IRE)-binding proteins (IRPs)
      found in different species. We have previously demonstrated that erythrocyte P.
      falciparum PfIRPa binds a mammalian consensus IRE and that the binding activity
      is regulated by iron status. In the work we now report, we have cloned a C
      terminus histidine-tagged PfIRPa and overexpressed it in a bacterial expression
      system in soluble form capable of binding IREs. To overexpress PfIRPa, we used
      the T7 promoter-driven vector, pET28a(+), in conjunction with the
      Rosetta(DE3)pLysS strain of E. coli, which carries extra copies of tRNA genes
      usually found in organisms such as P. falciparum whose genome is (A+T)-rich. The
      histidine-tagged recombinant protein (rPfIRPa) in soluble form was partially
      purified using His-bind resin. We searched the plasmodial database, plasmoDB, to
      identify sequences capable of forming IRE loops using a specially developed
      algorithm, and found three plasmodial sequences matching the search criteria. In
      gel retardation assays, rPfIRPa bound three 32P-labeled putative plasmodial IREs
      with affinity exceeding the affinity for the mammalian consensus IRE. The binding
      was concentration-dependent and was not inhibited by heparin, an inhibitor of non
      specific binding. Immunodepletion of rPfIRPa resulted in substantial inhibition
      of the signal intensity in the gel retardation assays and in Western blot
      determinations of rPfIRPa protein levels. Endogenous PfIRPa retained all three
      putative 32P-IREs at the same position on the gel as the recombinant PfIRPa.

PMID- 12615323
TI  - Characterization of a unique aspartate-rich protein of the SET/TAF-family in the
      human malaria parasite, Plasmodium falciparum, which inhibits protein phosphatase
      2A.
AB  - A search for physiological inhibitors of protein phosphatases led to the
      identification of a Plasmodium falciparum (Pf) cDNA that had the potential to
      code for an aspartate-rich protein and hence named ARP. The PfARP was virtually
      identical to its Plasmodium berghei counterpart in gene structure and protein
      sequence. The PfARP coding sequence contained two introns, and the predicted
      protein contained 269 amino acid residues. Its primary structure showed
      significant similarity to eukaryotic proteins of the SET and TAF-family that
      included two inhibitors of mammalian serine/threonine protein phosphatase 2A
      (PP2A), namely I1(PP2A) and I2(PP2A). Like the SET and TAF proteins, it had an
      extremely acidic tail. The cDNA was confirmed by recombinant expression in
      bacteria. Native parasitic ARP was purified and was found to be highly
      thermostable. PfARP specifically inhibited the parasitic PP2A at nanomolar
      concentrations, with no effect on PP1, PP2B, PP5, or PPJ. Expression of PfARP in
      HeLa cells led to elevated phosphorylation of c-Jun, and activation of
      transcription factors AP1 and NF-kappa B. These functional properties are also
      characteristic of the SET/TAF-family proteins. The ARP mRNA and protein were
      detectable in all the erythrocytic asexual stages of the parasite, and the
      protein was located mainly in the parasitic cytoplasm. Thus, PfARP is a unique
      cytoplasmic member of the SET/TAF-family and a candidate physiological regulator
      of the Plasmodium PP2A.

PMID- 12615324
TI  - Molecular and biochemical characterization of hexokinase from Trypanosoma cruzi.
AB  - The Trypanosoma cruzi hexokinase gene has been cloned, sequenced, and expressed
      as an active enzyme in Escherichia coli. Sequence analysis revealed 67% identity
      with its counterpart in Trypanosoma brucei but low similarity with all other
      available hexokinase sequences including those of human. It contains an N
      terminal peroxisome-targeting signal (PTS-2) and has a calculated basic
      isoelectric point (pI = 9.67), a feature often associated with glycosomal
      proteins. The polypeptide has a predicted mass of approximately 50 kDa similar to
      that of many non-vertebrate hexokinases and the vertebrate hexokinase isoenzyme
      IV. The natural enzyme was purified to homogeneity from T. cruzi epimastigotes
      and appeared to exist in several aggregation states, an apparent tetramer being
      the predominant form. Its kinetic properties were compared with those of the
      purified recombinant protein. Higher K(m) values for glucose and ATP were found
      for the (His)(6)-tag-containing recombinant hexokinase. However, removal of the
      tag produced an enzyme displaying similar values as the natural enzyme (K(m) for
      glucose = 43 and 60 microM for the natural and the recombinant protein,
      respectively). None of these enzymes presented activity with fructose. As
      reported previously for hexokinases from several trypanosomatids, no inhibition
      was exerted by glucose 6-phosphate (G6-P). In contrast, a mixed-type inhibition
      was observed with inorganic pyrophosphate (PPi, K(i) = 0.5mM).

PMID- 12615325
TI  - Defective sorting of the thrombospondin-related anonymous protein (TRAP) inhibits
      Plasmodium infectivity.
AB  - Thrombospondin-related anonymous protein (TRAP) is a type 1 transmembrane protein
      that plays an essential role in gliding motility and cell invasion by Plasmodium
      sporozoites. It is stored in micronemes-secretory organelles located primarily in
      the apical end of the parasites and is also found on the parasite surface. The
      mechanisms that target TRAP and other sporozoite proteins to micronemes and
      subsequently to the parasite surface are not known. Here we report that the
      micronemal and surface localization of TRAP requires a tyrosine-based motif
      located in its cytoplasmic tail. This motif is analogous to the YXXphi motif (Y:
      tyrosine, X: any amino acid; phi: hydrophobic amino acid) that targets eukaryotic
      proteins to certain sub-cellular compartments and to the plasma membrane.
      Abrogating the Y motif substantially reduces micronemal and cell surface
      localization of TRAP. The infectivity of mutant parasites is substantially
      inhibited. However, there is no significant difference in the amounts of TRAP
      secreted into the culture medium by wild type and mutant parasites, suggesting
      that TRAP destined for secretion bypasses micronemal localization.

PMID- 12615326
TI  - Development of RNA interference revertants in Trypanosoma brucei cell lines
      generated with a double stranded RNA expression construct driven by two opposing
      promoters.

PMID- 12615317
TI  - Comparative gene analysis of Biomphalaria glabrata hemocytes pre- and post
      exposure to miracidia of Schistosoma mansoni.
AB  - The internal defense mechanism of the snail Biomphalaria glabrata during a
      schistosome infection is activated and mediated via the immune effector cells
      known as hemocytes. Since resistance and susceptibility to schistosome infection
      is known to be genetically determined, our interest was to use the EST approach
      as a gene discovery tool to examine transcription profiles in hemocytes of
      resistant snails pre- and post-exposure to Schistosoma mansoni. Comparative
      analysis of the transcripts suggested that parasite exposure caused an active
      metabolic response in the hemocytes. The most abundant transcripts were those
      showing 23-74% similarity to known reverse transcriptases (RT). Further
      characterization by RT-PCR indicated the RT transcripts were expressed in normal
      snails, parasite exposed snails, and the embryonic cell line Bge. To determine
      whether the occurrence of RT transcripts correlates to the presence of functional
      enzyme activity in the snails, RT assays were performed from both resistant and
      susceptible snails, pre- and post-exposure to miracidia, using protein extracts
      from the head-foot and posterior region tissues. Results indicated that in the
      resistant snail, RT activity was greater in the posterior region than in the head
      foot. After exposure, however, RT activity increased dramatically in the head
      foot, with peak activity at 24 h post-exposure. The detection of RT activity in
      B. glabrata was unexpected and the role of this enzyme in the hemocyte-mediated
      killing of parasites is not yet known. However, identification of this and other
      transcripts from these cells by the EST approach provides a useful resource
      towards elucidating the molecular basis of resistance/susceptibility in this
      snail-host parasite relationship.

PMID- 12615327
TI  - Blocking the expression of a calcium binding protein of the protozoan parasite
      Entamoeba histolytica by tetracycline regulatable antisense-RNA.

PMID- 12615328
TI  - Fluorescent chloramphenicol as a substitute for radioactive [14C]-chloramphenicol
      for CAT reporter assays in Plasmodium falciparum.

PMID- 12615329
TI  - Phosphorylation of GPEET procyclin is not necessary for survival of Trypanosoma
      brucei procyclic forms in culture and in the tsetse fly midgut.

PMID- 12615330
TI  - Presence of sialic acid in N-linked oligosaccharide chains and O-linked N
      acetylglucosamine in cruzipain, the major cysteine proteinase of Trypanosoma
      cruzi.

PMID- 12615331
TI  - A unique insertion in Plasmodium berghei glucose-6-phosphate dehydrogenase-6
      phosphogluconolactonase: evolutionary and functional studies.
AB  - Plasmodium berghei glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase
      (G6PD-6PGL) is a bifunctional enzyme with significant sequence similarity in both
      the 6PGL and G6PD domains to the Plasmodium falciparum enzyme. A recombinant form
      of the P. berghei enzyme was found to have both G6PD and 6PGL activities, and
      therefore catalyses the first two steps in the pentose phosphate pathway. Genes
      encoding very similar proteins are also found in three other malarial parasites,
      Plasmodium yoelii, Plasmodium chabaudi and Plasmodium knowlesi. All of these
      predicted enzymes contain unique parasite insertions in corresponding positions
      in the G6PD domain but the insertions differ in size and sequence. Such
      insertions are a common feature of malarial proteins but their origin and
      function is unknown. Excision of the insertion sequence in the P. berghei protein
      renders the G6PD domain inactive, although the 6PGL activity is unaffected.
      Replacing the insertion sequence in P. berghei with the insertion sequence from
      P. falciparum restores some of the G6PD activity and also enhances 6PGL activity.
      We conclude that although the insertions are evolving rapidly they have an
      essential role in the activity of the bifunctional enzyme.

PMID- 12615332
TI  - Trypanosoma cruzi TcSRPK, the first protozoan member of the SRPK family, is
      biochemically and functionally conserved with metazoan SR protein-specific
      kinases.
AB  - A novel SR protein-specific kinase (SRPK) from the SRPK family was identified for
      the first time in a protozoan organism. The primary structure of the protein,
      named TcSRPK, presents a significant degree of identity with other metazoan
      members of the family. In vitro phosphorylation experiments showed that TcSRPK
      has the same substrate specificity relative to other SRPKs. TcSRPK was able to
      generate a mAb104-recognized phosphoepitope, a SRPK landmark. Expression of
      TcSRPK in different Schizosaccharomyces pombe strains lead to conserved
      phenotypes, indicating that TcSRPK is a functional homologue of metazoan SRPKs.
      In functional alternative splicing assays in vivo in HeLa cells, TcSRPK enhanced
      SR protein-dependent inclusion of the EDI exon of the fibronectin minigene. When
      tested in vitro, it inhibited splicing either on nuclear extracts or on splicing
      deficient S100 extracts complemented with ASF/SF2. This inhibition was similar to
      that observed with human SRPK1. This work constitutes the first report of a
      member of this family of proteins and the existence of an SR-network in a
      protozoan organism. The implications in the origins and control of splicing are
      discussed.

PMID- 12615333
TI  - Induction of autophagic cell death in Leishmania donovani by antimicrobial
      peptides.
AB  - We demonstrate that antimicrobial peptides induce an autophagic cell death in the
      protozoan pathogen, Leishmania donovani. In our study, three antimicrobial
      peptides, Indolicidin, and two peptides derived from Seminalplasmin exhibit
      antileishmanial activity with a 50% lethal dose of 3.5 x 10(-5), 3.8 x 10(-4) and
      1.7 x 10(-8) microM, respectively. The action of these antimicrobial peptides on
      the Leishmania cell involves ionic interactions, which are modulated by
      lipophosphoglycan on the parasite's surface. Peptide treatment caused dissipation
      of membrane potential and equilibration of intracellular pH with extracellular
      environment. However, there was no release of intracellular GFP molecules upon
      peptide treatment of a GFP expressing Leishmania clone. Transmission electron
      microscopic studies show extensive intracellular damage including cytoplasmic
      vacuolization and degeneration of cellular organization without disruption of the
      plasma membrane. These peptides induce cell death via a non-apoptotic process as
      shown by lack of nuclear fragmentation or DNA laddering and independent of
      caspase-like activity. Instead, Monodansylcadaverine (MDC), a biochemical marker
      of autophagy specifically labels the vacuoles induced by peptides. Collectively,
      these results indicate that in addition to their effects on the leishmanial
      membrane, these antimicrobial peptides induce pathway(s) for autophagic cell
      death in L. donovani.

PMID- 12615334
TI  - An early ancestor in the evolution of splicing: a Trypanosoma cruzi serine
      arginine-rich protein (TcSR) is functional in cis-splicing.
AB  - A novel serine-arginine-rich protein designated TcSR was identified in
      Trypanosoma cruzi. The deduced amino acid sequence reveals that TcSR is a member
      of the SR protein family of splicing factors that contains two RNA-binding
      domains at the N-terminal side and several serine-arginine repeats at the COOH
      terminus. Over expression of either TcSR or the human SR-protein associated
      splicing factor/splicing factor 2 (ASF/SF2) in wild-type Schizosaccharomyces
      pombe, provoked an elongated phenotype similar to that of fission yeast over
      expressing the SR-containing splicing factor Prp2, a U2AF(65) orthologue. When a
      double mutant strain lacking two SR protein-specific protein kinases was used,
      expression of TcSR or human SR ASF/SF2 splicing factor reverted the mutant to a
      wild-type phenotype. Transient expression of TcSR in HeLa cells stimulated the
      inclusion of the EDI exon of human fibronectin in an in vivo functional
      alternative cis-splicing assay. Inclusion was dependent on a splicing enhancer
      sequence present in the EDI exon. In addition, TcSR and peptides carrying TcSR-RS
      domain sequences were phosphorylated by a human SR protein kinase. These results
      indicate that TcSR is a member of the SR splicing network and that some
      components common to the trans- and cis-splicing machineries evolved from the
      early origins of the eukaryotic lineage.

PMID- 12615335
TI  - Characterisation of the rhoph2 gene of Plasmodium falciparum and Plasmodium
      yoelii.
AB  - The high molecular mass protein complex (RhopH) in the rhoptries of the malaria
      parasite consists of three distinct polypeptides with estimated sizes in
      Plasmodium falciparum of 155kDa (PfRhopH1), 140kDa (PfRhopH2) and 110kDa
      (PfRhopH3). Using a number of reagents, including a new mAb 4E10 that is specific
      for the PfRhopH complex, it was shown that the RhopH complex is synthesised
      during schizogony and transferred intact to the ring stage in newly invaded
      erythrocytes. The genes encoding RhopH1 and RhopH3 have already been identified
      and characterised in both P. falciparum and Plasmodium yoelii. In this report, we
      describe the identification of the gene for RhopH2 in both these parasite
      species. Peptide sequences were obtained from purified RhopH2 proteins and used
      to generate oligonucleotide primers and search malaria sequence databases. In a
      parallel approach, mAb 4E10 was used to identify a clone coding for RhopH2 from a
      P. falciparum cDNA library. The sequences of both P. falciparum and P. yoelii
      genes for RhopH2 were completed and compared. They both contain nine introns and
      there is a high degree of similarity between the deduced amino acid sequences of
      the two proteins. The P. falciparum gene is a single copy gene located on
      chromosome 9, and is transcribed in schizonts.

PMID- 12615337
TI  - Presence of sialic acid in N-linked oligosaccharide chains and O-linked N
      acetylglucosamine in cruzipain, the major cysteine proteinase of Trypanosoma
      cruzi.

PMID- 12615336
TI  - Apical location of a novel EGF-like domain-containing protein of Plasmodium
      falciparum.
AB  - Using bioinformatics analyses of the unfinished malaria genome sequence, we have
      identified a novel protein of Plasmodium falciparum that contains two epidermal
      growth factor (EGF)-like domains near the C-terminus of the protein. The sequence
      contains a single open reading frame of 1572bp with the potential to encode a
      protein of 524 residues containing hydrophobic regions at the extreme N- and C
      termini which appear to represent signal peptide and glycosylphosphatidylinositol
      (GPI)-attachment sites, respectively. RT-PCR analysis has confirmed that the
      novel gene is transcribed in asexual stages of P. falciparum. Antibodies to the
      EGF-like domains of the novel protein are highly specific and do not cross-react
      with the EGF-like domains of MSP1, MSP4, MSP5 or MSP8 expressed as GST fusion
      proteins. Antisera to the C-terminal fragments react with two bands of 80 and
      36kDa in P. falciparum parasite lysates whereas antisera to the most N-terminal
      fusion protein only recognises the 80kDa band, suggesting that the novel protein
      may undergo processing in a similar way to MSP1 and MSP8, but with fewer cleavage
      events. Immunoblot analysis of stage-specific parasite samples reveals that the
      protein is present in trophozoites, schizonts and in isolated merozoites. The
      protein partitions in the detergent-enriched phase after Triton X-114
      fractionation and is localised to the surfaces of trophozoites, schizonts and
      free merozoites in an apical distribution. Based on the accepted nomenclature in
      the field we now designate this protein MSP10. We have shown that the MSP10
      fusion proteins are in a conformation that can be recognised by human immune sera
      and that there is very limited sequence diversity in an approximately lkb region
      of MSP10, encompassing the two EGF-like domains. A sequence similar to MSP10 can
      be identified in the available P. yoelii genomic sequence, offering the
      possibility of ascertaining whether this novel protein can induce host protective
      responses in an in vivo model.

PMID- 12615338
TI  - Identification of a gene encoding a 54 kDa alternative NADH dehydrogenase in
      Trypanosoma brucei.

PMID- 12615339
TI  - The origin of the serum resistance associated (SRA) gene and a model of the
      structure of the SRA polypeptide from Trypanosoma brucei rhodesiense.

PMID- 12615340
TI  - Evidence for exo beta-D-galactofuranosidase in Trypanosoma cruzi.

PMID- 12615341
TI  - Trypanosoma cruzi genome encodes a pteridine reductase 2 protein.

PMID- 12615342
TI  - Cycloheximide-mediated accumulation of transcripts from a procyclin expression
      site depends on the intergenic region.

PMID- 12615344
TI  - The respiratory chain of the thermophilic archaeon Sulfolobus metallicus: studies
      on the type-II NADH dehydrogenase.
AB  - The membranes of the thermoacidophilic archaeon Sulfolobus metallicus exhibit an
      oxygen consumption activity of 0.5 nmol O(2) min(-1) mg(-1), which is insensitive
      to rotenone, suggesting the presence of a type-II NADH dehydrogenase. Following
      this observation, the enzyme was purified from solubilised membranes and
      characterised. The pure protein is a monomer with an apparent molecular mass of
      49 kDa, having a high N-terminal amino acid sequence similarity towards other
      prokaryotic enzymes of the same type. It contains a covalently attached flavin,
      which was identified as being FMN by 31P-NMR spectroscopy, a novelty among type
      II NADH dehydrogenases. Metal analysis showed the absence of iron, indicating
      that no FeS clusters are present in the protein. The average reduction potential
      of the FMN group was determined to be +160 mV, at 25 degrees C and pH 6.5, by
      redox titrations monitored by visible spectroscopy. Catalytically, the enzyme is
      a NADH:quinone oxidoreductase, as it is capable of transferring electrons from
      NADH to several quinones, including ubiquinone-1, ubiquinone-2 and caldariella
      quinone. Maximal turnover rates of 195 micromol NADH oxidized min(-1) mg(-1) at
      60 degrees C were obtained using ubiquinone-2 as electron acceptor, after enzyme
      dilution and incubation with phospholipids.

PMID- 12615343
TI  - The effect of exchange of bacteriopheophytin a with plant pheophytin a on charge
      separation in Y(M210)W mutant reaction centers of Rhodobacter sphaeroides at low
      temperature.
AB  - The bacteriopheophytin a molecules at the H(A) and H(B) binding sites of reaction
      centers (RCs) of the Y(M210)W mutant of Rhodobacter sphaeroides were chemically
      exchanged with plant pheophytin a. The Y(M210)W mutation slows down the formation
      of H(A)(-), presumably by raising the free energy level of the P(+)B(A)(-) state
      above that of P* due to increasing the oxidation potential of the primary
      electron donor P and lowering the reduction potential of the accessory
      bacteriochlorophyll B(A). Exchange of the bacteriopheophytins with pheophytin a
      on the contrary lowers the redox potential of H(A), inhibiting its reduction. A
      combination of the mutation and pigment exchange was therefore expected to make
      the A-side of the RC incapable of electron transfer and cause the excited state
      P* to deactivate directly to the ground state or through the B-side, or both.
      Time-resolved absorption difference spectroscopy at 10 K on the RCs that were
      modified in this way showed a lifetime of P* lengthened to about 500 ps as
      compared to about 200 ps measured in the original Y(M210)W RCs. We show that the
      decay of P* in the pheophytin-exchanged preparations is accompanied by both
      return to the ground state and formation of a new charge-separated state, the
      absorption difference spectrum of which is characterized by bleachings at 811 and
      890 nm. This latter state was formed with a time constant of ca. 1.7 ns and a
      yield of about 30%, and lasted a few nanoseconds. On the basis of spectroscopic
      observations these bands at 811 and 890 nm are tentatively attributed to the
      presence of the P(+)B(B)(-) state, where B(B) is the accessory
      bacteriochlorophyll in the "inactive" B-branch of the cofactors. The B(B)
      molecules in Y(M210)W RCs are suggested to be spectrally heterogeneous, absorbing
      in the Q(y) region at 813 or 806 nm. The results are discussed in terms of
      perturbation of the free energy level of the P(+)B(B)(-) state and absorption
      properties of the B(B) bacteriochlorophyll in the mutant RCs due to a long-range
      effect of the Y(M210)W mutation on the protein environment of the B(B) binding
      pocket.

PMID- 12615345
TI  - Elimination of high-light-inducible polypeptides related to eukaryotic
      chlorophyll a/b-binding proteins results in aberrant photoacclimation in
      Synechocystis PCC6803.
AB  - The hli genes, present in cyanobacteria, algae and vascular plants, encode small
      proteins [high-light-inducible polypeptides (HLIPs)] with a single membrane
      spanning alpha-helix related to the first and third helices of eukaryotic
      chlorophyll a/b-binding proteins. The HLIPs are present in low amounts in low
      light and they accumulate transiently at high light intensities. We are
      investigating the function of those polypeptides in a Synechocystis PCC6803
      mutant lacking four of the five hli genes. Growth of the quadruple hli mutant was
      adversely affected by high light intensities. The most striking effect of the
      quadruple hli mutation was an alteration of cell pigmentation. Pigment changes
      associated with cell acclimation to increasing light intensity [i.e. decrease in
      light-harvesting pigments, accumulation of the carotenoid myxoxanthophyll and
      decrease in photosystem I (PSI)-associated chlorophylls] were strongly
      exacerbated in the quadruple hli mutant, resulting in yellowish cultures that
      bleached in high light and died as light intensities exceeded (>500 micromol
      photon m(-2) s(-1)). However, these pigment changes were not associated with an
      inhibition of photosynthesis, as probed by in vivo chlorophyll fluorescence,
      photoacoustic and O(2)-evolution measurements. On the contrary, the HLIP
      deficiency was accompanied by a stimulation of the photochemical activity,
      especially in high-light-grown cells. Western blot analyses revealed that the PSI
      reaction center level (PsaA/B) was noticeably reduced in the quadruple hli mutant
      relative to the wild type, whereas the abundance of the PSII reaction center
      protein D1 was comparatively little affected. The hli mutations did not enhance
      photoinhibition and photooxidation when cells were exposed over a short term to a
      very high light intensity. Together, the results of this study indicate that
      HLIPs are critical in the adaptation of the cyanobacterium to variations in light
      intensity. The data are consistent with the idea that HLIPs are involved, through
      a direct or indirect means, in nonphotochemical dissipation of absorbed light
      energy.

PMID- 12615346
TI  - Probing connection of PBS with the photosystems in intact cells of Spirulina
      platensis by temperature-induced fluorescence fluctuation.
AB  - Temperature-dependent fluorescence for intact cells of cyanobacterium Spirulina
      platensis was detected to search for the connection of the phycobilisome (PBS)
      with Photosystem I (PSI) and Photosystem II (PSII). Some interesting results were
      obtained from the deconvoluted fluorescence components of C-phycocyanin (C-PC),
      allophycocyanin (APC), PSI and PSII as well as the fluorescence spectra of the
      intact cells at room temperature (RT=25 degrees C) and 0 degrees C. It was
      observed that, compared to those at RT, both of the fluorescence components for
      PSI and APC increased, whereas those for PSII and C-PC decreased at 0 degrees C
      with excitation at 580 nm, that is, the fluorescence for C-PC is not synchronous
      with that for APC, and the fluorescence fluctuation for PSI is not synchronous
      with that for PSII. On the other hand, the decrease in C-PC fluorescence is
      synchronous with the increase in PSI fluorescence, and the increase in APC
      fluorescence is synchronous with the decrease in PSII fluorescence. Therefore, it
      can be readily deduced that PBS should be coupled not only with PSII through the
      terminal acceptors in the APC core but also with PSI through C-PC in PBS rods at
      physiological condition, while at 0 degrees C, a migration of a PBS makes the APC
      partially detached from PSII but the C-PC more efficiently coupled with PSI. The
      results provide good evidences for "mobile PBS" model and "parallel connection"
      model but not for the "spillover" model.

PMID- 12615347
TI  - Quantitative amino acid analysis of bovine NADH:ubiquinone oxidoreductase
      (Complex I) and related enzymes. Consequences for the number of prosthetic
      groups.
AB  - Bovine-heart NADH:ubiquinone oxidoreductase (EC 1.6.5.3; Complex I) is the first
      and most complicated enzyme in the mitochondrial respiratory chain. Biochemistry
      textbooks and virtually all literature on this enzyme state that it contains one
      FMN and at least four iron-sulfur clusters. We show here that this statement is
      incorrect as it is based on erroneous protein determinations. Quantitative amino
      acid analysis of the bovine Complex I, to our knowledge the first reported thus
      far, shows that the routine protein-determination methods used for the bovine
      Complex I overestimate its protein content by up to twofold. The FMN content of
      the preparations was determined to be at least 1.3-1.4 mol FMN/mol Complex I. The
      spin concentration of the electron paramagnetic resonance (EPR) signal ascribed
      to iron-sulfur cluster N2 was determined and accounted for 1.3-1.6 clusters per
      molecule of Complex I. These results experimentally confirm the hypothesis [FEBS
      Lett. 485 (2000) 1] that the bovine Complex I contains two FMN groups and two
      clusters N2. Also the protein content of preparations of the soluble NAD(+)
      reducing [NiFe]-hydrogenase (EC 1.12.1.2) from Ralstonia eutropha, which shows
      clear evolutionary relationships with Complex I, scores too high by the
      colorimetric protein-determination methods. Determination of the FMN content and
      the spin concentration of the EPR signal of the [2Fe-2S] cluster shows that this
      hydrogenase also contains two FMN groups. A third enzyme (Ech), the membrane
      bound [NiFe]-hydrogenase from Methanosarcina barkeri which shows an even stronger
      evolutionary relationship with Complex I, behaves rather normal in protein
      determinations and contains no detectable acid-extractable FMN in purified
      preparations.

PMID- 12615348
TI  - Two EPR-detectable [4Fe-4S] clusters, N2a and N2b, are bound to the NuoI (TYKY)
      subunit of NADH:ubiquinone oxidoreductase (Complex I) from Rhodobacter
      capsulatus.
AB  - NADH:ubiquinone oxidoreductases (Complex I) contain a subunit, TYKY in the bovine
      enzyme and NuoI in the enzyme from Rhodobacter capsulatus, which is assumed to
      bind two [4Fe-4S] clusters because it contains two sets of conserved cysteine
      motifs similar to those found in the 2[4Fe-4S] ferredoxins. It was recently shown
      that the TYKY subunit is not an ordinary 2[4Fe-4S] ferredoxin, but has a unique
      amino acid sequence, which is only found in NAD(P)H:quinone oxidoreductases and
      certain membrane-bound [NiFe]-hydrogenases expected to be involved in redox
      linked proton translocation [FEBS Lett. 485 (2000) 1]. We have generated a set of
      R. capsulatus mutants in which five out of the eight conserved cysteine residues
      in NuoI were replaced by other amino acids. The resulting mutants fell into three
      categories with virtually no, intermediate or quite normal Complex I activities.
      EPR-spectroscopic analysis of the membranes of the C67S and C106S mutants, two
      mutants belonging to the second and third group, respectively, showed a specific
      50% decrease of the EPR signal attributed to cluster N2. It is concluded that the
      NuoI (TYKY) subunit binds two clusters N2, called N2a and N2b, which exhibit very
      similar spectral features when analyzed by X-band EPR spectroscopy.

PMID- 12615349
TI  - The menD and menE homologs code for 2-succinyl-6-hydroxyl-2,4-cyclohexadiene-1
      carboxylate synthase and O-succinylbenzoic acid-CoA synthase in the phylloquinone
      biosynthetic pathway of Synechocystis sp. PCC 6803.
AB  - The genome of the cyanobacterium Synechocystis sp. PCC 6803 contains genes
      identified as menD and menE, homologs of Escherichia coli genes that code for 2
      succinyl-6-hydroxyl-2,4-cyclohexadiene-1-carboxylate (SHCHC) synthase and O
      succinylbenzoic acid-CoA ligase in the menaquinone biosynthetic pathway. In
      cyanobacteria, the product of this pathway is 2-methyl-3-phytyl-1,4
      naphthoquinone (phylloquinone), a molecule used exclusively as an electron
      transfer cofactor in Photosystem (PS) I. The menD(-) and menE(-) strains were
      generated, and both were found to lack phylloquinone. Hence, no alternative
      pathways exist in cyanobacteria to produce O-succinylbenzoyl-CoA. Q-band EPR
      studies of photoaccumulated quinone anion radical and optical kinetic studies of
      the P700(+) [F(A)/F(B)](-) backreaction indicate that in the mutant strains,
      plastoquinone-9 functions as the electron transfer cofactor in the A(1) site of
      PS I. At a light intensity of 40 microE m(-2) s(-1), the menD(-) and menE(-)
      mutant strains grew photoautotrophically and photoheterotrophically, but with
      doubling times slower than the wild type. Both of which are sensitive to high
      light intensities. Low-temperature fluorescence studies show that in the menD(-)
      and menE(-) mutants, the ratio of PS I to PS II is reduced relative to the wild
      type. Whole-chain electron transfer rates in the menD(-) and menE(-) mutant cells
      are correspondingly higher on a chlorophyll basis. The slower growth rate and
      high-light sensitivity of the menD(-) and menE(-) mutants are therefore
      attributed to a lower content of PS I per cell.

PMID- 12615350
TI  - 18O isotope effect in the photosynthetic water splitting process.
AB  - In mass spectroscopic experiments of oxygen evolution in Photosystem II at 50%
      enrichment of H(2)18O, one expects equal signals of 18O(2) and 16O(2) unless one
      of the isotopes is favored by the oxygen evolving complex (OEC). We have observed
      a deviation from this expectation, being a clear indication of an isotope effect.
      We have measured the effect to be 1.14-1.30, which is higher than the
      theoretically predicted value of 1.014-1.06. This together with the strong
      temperature variation of the measured effect with a discontinuity at 11 degrees C
      observed for wild-type tobacco and at 9 degrees C for a yellow-green tobacco
      mutant suggest that an additional mechanism is responsible for the observed high
      isotope effect. The entry of a finite size of water clusters to the cleavage site
      of the OEC can explain the observation.

PMID- 12615351
TI  - HiPIP in Rubrivivax gelatinosus is firmly associated to the membrane in a
      conformation efficient for electron transfer towards the photosynthetic reaction
      centre.
AB  - High potential iron-sulfur protein (HiPIP), a small soluble redox protein, has
      been shown to serve in vivo as electron donor to the photosynthetic reaction
      centre (RC) in Rubrivivax gelatinosus [Biochemistry 34 (1995) 11736]. The results
      of time-resolved optical spectroscopy on membrane-fragments from this organism
      indicates that the photooxidized RC is re-reduced by HiPIP even in the absence of
      the soluble fraction. This implies that a significant fraction of HiPIP can
      firmly bind to the membrane in a conformation able to interact with the RCs. Salt
      treatment of the membrane-fragments abolishes these re-reduction kinetics,
      demonstrating the presence of HiPIP on the membrane due to association with the
      RC rather than due to simple trapping in hypothetical chromatophores. The
      existence of such a functional complex in membranes is confirmed and its
      structure further examined by electron paramagnetic resonance (EPR) performed on
      membrane-fragments. Orientation-dependent EPR spectra of HiPIP were recorded on
      partially ordered membranes, oxidized either chemically or photochemically.
      Whereas hardly any preferential orientation of the HiPIP was seen in the
      chemically oxidised sample, a subpopulation of HiPIP showing specific
      orientations could be photooxidised. This fraction arises from the electron
      transfer complex between HiPIP and the RC.

PMID- 12615352
TI  - The photochemical trapping rate from red spectral states in PSI-LHCI is
      determined by thermal activation of energy transfer to bulk chlorophylls.
AB  - The average fluorescence decay lifetimes, due to reaction centre photochemical
      trapping, were calculated for wavelengths in the 690- to 770-nm interval from the
      published fluorescence decay-associated emission spectra for Photosystem I (PSI)
      light-harvesting complex of Photosystem I (LHCI) [Biochemistry 39 (2000) 6341] at
      280 and 170 K. For 280 K, the overall trapping time at 690 nm is 81 ps and
      increases with wavelength to reach 103 ps at 770 nm. For 170 K, the 690-nm value
      is 115 ps, increasing to 458 ps at 770 nm. This underlines the presence of
      kinetically limiting processes in the PSI antenna (diffusion limited). The
      explanation of these nonconstant values for the overall trapping time band is
      sought in terms of thermally activated transfer from the red absorbing states to
      the "bulk" acceptor chlorophyll (chl) states in the framework of the Arrhenius
      Eyring theory. It is shown that the wavelength-dependent "activation energies"
      come out in the range between 1.35 and 2.7 kcal mol(-1), increasing with the
      emission wavelength within the interval 710-770 nm. These values are in good
      agreement with the Arrhenius activation energy determined for the steady-state
      fluorescence yield over the range 130-280 K for PSI-LHCI. We conclude that the
      variable trapping time in PSI-LHCI can be accounted for entirely by thermally
      activated transfer from the low-energy chl states to the bulk acceptor states and
      therefore that the position of the various red states in the PSI antenna seems
      not to be of significant importance. The analysis shows that the bulk antenna
      acceptor states are on the low-energy side of the bulk antenna absorption band.

PMID- 12615353
TI  - Computer simulation of water in cytochrome c oxidase.
AB  - Statistical mechanics and molecular dynamics simulations have been carried out to
      study the distribution and dynamics of internal water molecules in bovine heart
      cytochrome c oxidase (CcO). CcO is found to be capable of holding plenty of
      water, which in subunit I alone amounts to about 165 molecules. The dynamic
      characterization of these water molecules is carried out. The nascent water
      molecules produced in the redox reaction at the heme a(3)-CuB binuclear site form
      an intriguing chain structure. The chain begins at the position of Glu242 at the
      end of the D channel, and has a fork structure, one branch of which leads to the
      binuclear center, and the other to the propionate d of heme a(3). The branch that
      leads to the binuclear center has dynamic access both to the site where the
      formation of water occurs, and to delta-nitrogen of His291. From the binuclear
      center, the chain continues to run into the K channel. The stability of this
      hydrogen bond network is examined dynamically. The catalytic site is located at
      the hydrophobic region, and the nascent water molecules are produced at the top
      of the energy hill. The energy gradient is utilized as the mechanism of water
      removal from the protein. The water exit channels are explored using high
      temperature dynamics simulations. Two putative channels for water exit from the
      catalytic site have been identified. One is leading directly toward Mg(2+) site.
      However, this channel is only open when His291 is dissociated from CuB. If His291
      is bound to CuB, the only channel for water exit is the one that originates at
      E242 and leads toward the middle of the membrane. This is the same channel that
      is presumably used for oxygen supply.

PMID- 12615354
TI  - Cytochrome c is transformed from anti- to pro-oxidant when interacting with
      truncated oncoprotein prothymosin alpha.
AB  - Many apoptotic signals are known to induce release to cytosol of cytochrome c, a
      small mitochondrial protein with positively charged amino acid residues
      dominating over negatively charged ones. On the other hand, in this group, it was
      shown that prothymosin alpha (PT), a small nuclear protein where 53 of 109 amino
      acid residues are negatively charged, is truncated to form a protein of 99 amino
      acid residues which accumulates in cytosol during apoptosis [FEBS Lett. 467
      (2000) 150]. It was suggested that positively charged cytochrome c and negatively
      charged truncated prothymosin alpha (tPT), when meeting in cytosol, can interact
      with each other. In this paper, such an interaction is shown. (1) Formation of
      cytochrome cz.ccirf;tPT complex is demonstrated by a blot-overlay assay. (2)
      Analytical centrifugation of solution containing cytochrome c and tPT reveals
      formation of complexes of molecular masses higher than those of these proteins.
      The masses increase when the cytochrome c/tPT ratio increases. High concentration
      of KCl prevents the complex formation. (3) In the complexes formed, cytochrome c
      becomes autoxidizable; its reduction by superoxide or ascorbate as well as its
      operation as electron carrier between the outer and inner mitochondrial membranes
      appear to be inhibited. (4) tPT inhibits cytochrome c oxidation by H(2)O(2),
      catalyzed by peroxidase. Thus, tPT abolishes all antioxidant functions of
      cytochrome c which, in the presence of tPT, becomes in fact a pro-oxidant. A
      possible role of tPT in the development of reactive oxygen species- and
      cytochrome c-mediated apoptosis is discussed.

PMID- 12615355
TI  - Passive penetration of nitrate through the plasma membrane of Paracoccus
      denitrificans and its potentiation by the lipophilic tetraphenylphosphonium
      cation.
AB  - Previously, it has been shown that treatment of Paracoccus denitrificans cells
      with phenylglyoxal inhibits the methyl-viologen-linked nitrate reductase activity
      by blocking the nitrate transporter. This inhibition disappears if
      tetraphenylphosphonium cation (TPP(+)) is added to the assay medium. In the
      present paper, the following evidence suggests that the effect of TPP(+) results
      from an increased transmembrane anion permeability and not from transporter
      reactivation or cell lysis. (1) Beside nitrate, TPP(+) also mediated the
      utilisation of chlorate, which normally lacks access to the cytoplasm. (2) The
      TPP(+) pathway had about hundred-times higher K(m) values for nitrate and
      chlorate than nitrate reductase in Triton X-100 permeabilised cells. (3) Although
      the uncoupler CCCP alone failed to overcome the PG block, it stimulated the
      operation of the TPP(+) pathway. (4) The method of continuous variations allowed
      the transport stoichiometry TPP(+)/NO(3)(-) to be determined as 3, indicating
      charge compensation for nitrate movement and the subsequent transmembrane two
      electron redox reaction. Anion uptake was also measured independently from
      passive swelling of uncoupled spheroplasts in iso-osmotic solutions of ammonium
      salts. The permeability to nitrate lay in the permeability sequence Cl(-)<NO(3)(
      )<ClO(4)(-)<SCN(-) and was further enhanced by TPP(+).

PMID- 12615356
TI  - QcrCAB operon of a nocardia-form actinomycete Rhodococcus rhodochrous encodes
      cytochrome reductase complex with diheme cytochrome cc subunit.
AB  - Structural genes encoding quinol-cytochrome c reductase (QcR) were cloned and
      sequenced from nocardia-form actinomycete Rhodococcus rhodochrous. QcrC and qcrA
      encode diheme cytochrome cc and the Rieske Fe-S protein, respectively, while the
      qcrB product is a diheme cytochrome b. These amino acid sequences are similar to
      those of Corynebacterium and Mycobacterium, the members of high G+C content
      firmicutes. The presence of diheme cytochrome cc subunit as a sole c-type
      cytochrome in these organisms suggests the direct elecron transfer to cytochrome
      c oxidase. The N-terminal half of the Rieske Fe-S proteins of these bacteria has
      a unique structure with three transmembrane helices, while the C-terminal half
      sequence is conserved. A phylogenetic tree using the latter region showed that
      high G+C firmicutes form a clear clade with Thermus, but not with low G+C
      firmicutes.

PMID- 12615358
TI  - Loricrin keratoderma: a novel disease entity characterized by nuclear
      accumulation of mutant loricrin.
AB  - Loricrin is the major protein of the cornified cell envelope, a structure that
      replaces the plasma membrane during keratinocyte terminal differentiation.
      Recently, unique heterozygous, insertion mutations in the loricrin gene have been
      found to underlie certain congenital skin abnormalities, the phenotypes of which
      vary considerably. Clinically, these patients can be diagnosed as suffering from
      an ichthyotic variant of Vohwinkel's syndrome (VS), progressive symmetric
      erythrokeratoderma, or congenital ichthyosiform erythroderma born as a collodion
      baby. Common clinical features include hyperkeratosis of the palms and soles with
      digital constriction. Histologic characteristics include parakeratotic
      hyperkeratosis with hypergranulosis and nuclear accumulation of mutant loricrin.
      The unique mutations in the glycine-rich domain of the mutant loricrin form
      arginine-rich nuclear localization sequences (NLSs) that disrupt differentiation
      of keratinocytes. This group of unique genodermatoses caused by distinct loricrin
      mutations is collectively termed as loricrin keratoderma (LK).

PMID- 12615359
TI  - Cinnamic compound metabolism in human skin and the role metabolism may play in
      determining relative sensitisation potency.
AB  - BACKGROUND: trans-Cinnamaldehyde and trans-cinnamic alcohol cause allergic
      contact dermatitis (ACD) in humans; cinnamaldehyde is a more potent sensitiser
      than cinnamic alcohol. These two chemicals are principal constituents of the
      European Standard 'Fragrance Mix', as used in patch testing diagnostics of
      sensitisation to fragrances by clinical dermatologists. As contact sensitisers
      are usually protein reactive compounds, it is hypothesised that cinnamic alcohol
      (not protein-reactive) is a 'prohapten' that requires metabolic activation,
      presumably by cutaneous oxidoreductases, to the protein-reactive cinnamaldehyde
      (a 'hapten'). It is postulated that cinnamaldehyde can be detoxified by aldehyde
      dehydrogenase (ALDH) to cinnamic acid and/or by alcohol dehydrogenase (ADH) to
      cinnamic alcohol. Hence, a variety of metabolic pathways may contribute to the
      relative exposures and hence sensitising potencies of cinnamic alcohol and
      cinnamaldehyde. OBJECTIVE: To evaluate the extent of cinnamaldehyde and cinnamic
      alcohol metabolism in human skin and provide evidence for the role of cutaneous
      ADH and ALDH in such metabolism. METHODS: The extent of cinnamic alcohol and
      aldehyde metabolism was investigated in human skin homogenates and sub-cellular
      fractions. A high performance liquid chromatography method was used for analysis
      of skin sample extracts. Studies were conducted in the presence and absence of
      the ADH/cytochrome P450 inhibitor 4-methylpyrazole and the cytosolic ALDH
      inhibitor, disulfiram. RESULTS: Differential metabolism of cinnamic alcohol and
      cinnamaldehyde was observed in various subcellular fractions: skin cytosol was
      seen to be the major site of cinnamic compound metabolism. Significant metabolic
      inhibition was observed using 4-methylpyrazole and disulfiram in whole skin
      homogenates and cytosolic fractions only. CONCLUSIONS: This study has
      demonstrated that cutaneous ADH and ALDH activities, located within defined
      subcellular compartments, play important roles in the activation and
      detoxification of CAlc and CAld in skin. Such findings are important to the
      development of computational hazard prediction tools for sensitisation (e.g. the
      DEREK program) and also to dermatologists in understanding observed
      interindividual differences, cross-reactivities or co-sensitisation to different
      cinnamic compounds in the clinic.

PMID- 12615360
TI  - Similarly potent action of 1,25-dihydroxyvitamin D3 and its analogues,
      tacalcitol, calcipotriol, and maxacalcitol on normal human keratinocyte
      proliferation and differentiation.
AB  - BACKGROUND: The active vitamin D3 regulates proliferation and differentiation of
      epidermal keratinocytes. Recently topical vitamin D3, tacalcitol, calcipotriol,
      and maxacalcitol are widely used for psoriasis. OBJECTIVE: To examine the effect
      of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on cultured normal keratinocytes (NHK)
      and compared its effect with those of various vitamin D3 analogues. METHODS: Cell
      proliferation of NHK cells was analyzed by MTS, BrdU and 3H-thymidine
      incorporation. The expression of involucrin, transglutaminase 1, keratin 5 and
      keratin 1 was investigated by western blot and PCR amplification and quantitative
      assay. Furthermore, we performed cornified cell envelope (CE) formation assay.
      RESULTS: 1,25(OH)2D3, tacalcitol, calcipotriol, and maxacalcitol decreased NHK
      cell proliferation in a concentration-dependent manner and the maximal effect was
      observed at 10(-7) M. There was no significant difference in the anti
      proliferative effect among the active vitamin D3 analogues. The expression of
      involucrin and transglutaminase 1 were induced by 1,25(OH)2D3 and its analogues
      in mRNA and protein levels. CE formation was also induced by 1,25(OH)2D3 and its
      analogues. There was no significant difference in the potency among these
      chemicals. Keratin 5 and 1 expression was not altered by these active vitamin D3
      analogues. CONCLUSIONS: The present study demonstrated that active vitamin D3
      analogues, tacalcitol, calcipotriol, and maxacalcitol, suppress keratinocyte
      proliferation and induce differentiation with similar potency.

PMID- 12615361
TI  - Changes in environmental humidity affect the water-holding property of the
      stratum corneum and its free amino acid content, and the expression of filaggrin
      in the epidermis of hairless mice.
AB  - BACKGROUND: Seasonal changes affect the condition of skin and may trigger various
      cutaneous disorders. OBJECTIVE: To clarify the effects of the environmental
      humidity on the skin pathology, we studied the effects of the humidity on a water
      holding function of the stratum corneum. METHODS: We evaluated the skin surface
      conductance, amino acid in the stratum corneum, and immunoreactivity of filaggrin
      of the epidermis of hairless mice kept in different environmental humidity.
      RESULTS: Skin surface conductance in the stratum corneum of hairless mice 3-7
      days after transfer from a humid environment (>80% relative humidity) to a dry
      (<10% relative humidity) environment, was significantly lower than that of the
      mice transferred from a normal environment (relative humidity=40-70%) to a dry
      environment. The free amino acid content in the stratum corneum significantly
      decreased 24 h after we transferred the mice from a normal to a dry condition,
      then it recovered to the original level within 3 days, while the mice transferred
      from a humid to a dry condition showed a significantly lower amino acid content
      even 7 days after the transfer. No obvious change was observed in the relative
      composition of the major components of the free amino acids during the
      experiments. Immunoreactivity of filaggrin, which is the main precursor of free
      amino acids in the stratum corneum, also became faint in the epidermis of the
      mice transferred from a humid or normal to a dry environment. CONCLUSION: These
      results suggested that a drastic decrease in the environmental humidity reduced
      the total free amino acid generation and consequently induced skin surface
      dryness in the stratum corneum.

PMID- 12615362
TI  - Lack of evidence for TARC/CCL17 production by normal human keratinocytes in
      vitro.
AB  - BACKGROUND: thymus and activation-regulated chemokine (TARC)/CCL17 is a CC
      chemokine that selectively attracts Th2-type lymphocytes. Immunohistochemical
      analyses have revealed that TARC is expressed in the epidermal keratinocytes of
      atopic dermatitis (AD), suggesting TARC involvement in the pathogenesis of the
      disease. However, keratinocyte TARC production has been described only in the
      transformed keratinocyte cell line HaCaT. OBJECTIVE: to examine TARC production
      in normal human epidermal keratinocytes (NHEK) in vitro. METHODS: the expression
      of TARC mRNA and protein were examined in NHEK and HaCaT cells stimulated with
      various cytokines. RESULTS: stimulation with inflammatory cytokines, including
      interleukin (IL)-1, IL-4, IL-6, IL-10, interferon (IFN)-alpha, IFN-beta, IFN
      gamma, and tumor necrosis factor (TNF)-alpha failed to induce TARC mRNA
      expression in NHEK. However, stimulation with IFN-gamma and TNF-alpha together
      enhanced expression slightly. ELISA analysis failed to detect TARC protein in
      NHEK culture supernatant, even following stimulation with IFN-gamma and TNF
      alpha. In contrast, HaCaT cells produced TARC protein even without stimulation of
      cytokines. CONCLUSION: these results indicate that production of TARC by HaCaT
      cells is a phenomenon specific to the cell line and the observation on TARC in
      HaCaT cells can not be generalized. NHEK do not produce TARC protein in vitro.

PMID- 12615363
TI  - Gene expression of Sh3d19, a novel adaptor protein with five Src homology 3
      domains, in anagen mouse hair follicles.
AB  - BACKGROUND: Sh3yl1, which contains one Src homology (SH) 3 domain, has been
      previously identified from mouse skin and considered to play an important role in
      hair follicle formation by interacting with other proteins. OBJECTIVE: We
      performed this study to identify proteins capable of associating with Sh3yl1.
      METHODS: We screened a mouse skin cDNA library using the SH3 domain of Sh3yl1 as
      bait in the yeast two-hybrid system. RESULTS: We identified a 420-amino acid-long
      protein containing a proline-rich stretch and five carboxyl-terminal SH3 domains,
      which we have termed Sh3d19. We confirmed the interactions between Sh3yl1 and
      Sh3d19 by in vitro binding assays. Northern blot analysis showed that Sh3d19
      transcripts in mouse skin were expressed in accordance with the hair cycle.
      Furthermore, RNA in situ hybridization studies demonstrated that its transcripts
      were detected predominantly in the medulla cells at the level corresponding to
      the keratogenous zone of the hair follicles during the mid and late anagen
      phases. CONCLUSION: Sh3d19 is a novel adaptor protein that may be involved in the
      development of medulla cells during the anagen phase.

PMID- 12615364
TI  - TGF-beta/Smad signaling inhibits IFN-gamma and TNF-alpha-induced TARC (CCL17)
      production in HaCaT cells.
AB  - BACKGROUND: A Th2 chemokine, thymus and activation regulated chemokine
      (TARC/CCL17), produced by keratinocytes, is implicated in the development of
      atopic dermatitis by recruiting CLA(+)CCR4(+) lymphocytes into lesional skin and
      its expression was induced by proinflammatory cytokines such as interferon-gamma
      (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). However, it remains
      unknown how TARC expression is negatively regulated in keratinocytes. OBJECTIVE:
      We sought to determine whether transforming growth factor-beta 1 (TGF-beta 1)
      regulated TARC expression in keratinocytes. METHODS: The effect of TGF-beta 1 on
      mRNA and protein expression of IFN-gamma and TNF-alpha-induced TARC in a human
      keratinocyte cell line, HaCaT cells, was evaluated by using RT-PCR and ELISA.
      Adenovector-mediated gene transfer was used to determine the effect of Smad
      proteins on TARC expression in HaCaT cells. RESULTS: TGF-beta 1 inhibited mRNA
      and protein expression of IFN-gamma and TNF-alpha-induced TARC in HaCaT cells.
      The inhibitory effect of TGF-beta 1 on the TARC expression was suppressed by
      overexpression of Smad7, a major inhibitory regulator of Smad pathway for
      transforming growth factor-beta (TGF-beta) signaling, but not by PD98059, an
      inhibitor for ERK/mitogen-activated protein kinase (MAPK) pathway. In addition,
      overexpression of Smad2 or Smad3, major signal transducing Smads, was sufficient
      to inhibite the IFN-gamma and TNF-alpha-induced TARC production in HaCaT cells.
      CONCLUSION: TGF-beta1 inhibited IFN-gamma and TNF-alpha-induced TARC production
      in HaCaT cells via Smad2/3, suggesting that modulation of TGF-beta/Smad signaling
      pathway may be beneficial for the treatment of atopic dermatitis.

PMID- 12615365
TI  - A survey of psoriasis patients in Japan from 1982 to 2001.
AB  - BACKGROUND: The Japanese Society for Psoriasis Research has conducted an annual
      survey of psoriasis patients in Japan from 1982 to 2001. OBJECTIVE: To perform
      the epidemiological study about a survey of psoriasis patients conducted in Japan
      for twenty years. METHODS: A sample of 28628 cases was collected from 148
      dermatology centers throughout Japan. The reports from each center were analyzed.
      RESULTS: Males (65.8%) were predominant over females (34.2%) in number. The vast
      majority of cases (86.0%) had plaque-form of psoriasis vulgaris, and 812 cases
      (2.8%) showed guttate psoriasis. Psoriatic erythroderma (0.8%), generalized
      pustular psoriasis (0.9%), and localized pustular psoriasis (0.5%) were rare.
      Three hundred of the patients (1.0%) manifested psoriatic arthritis. Local
      corticosteroids (67.8%) were the most used modalities, whereas local vitamin D(3)
      preparations (2.4%) were rarely used. For photo-therapeutic treatments, topical
      (12.1%) and systemic (7.5%) PUVA were predominant over UVB therapy (0.5%). In
      systemic treatments, drugs from the herbal medicine was the first (14.2%),
      followed by etretinate (7.6%), nonsteroidal anti-inflammatory drugs (4.4%), oral
      corticosteroids (4.1%), methotrexate (2.8%), cyclosporine (1.6%), and anti-cancer
      drugs (1.4%). CONCLUSION: This survey was the first epidemiological study
      throughout Japan.

PMID- 12615366
TI  - Differential and bi-directional regulation between TR2/TR4 orphan nuclear
      receptors and a specific ligand mediated-peroxisome proliferator-activated
      receptor alpha in human HaCaT keratinocytes.
AB  - BACKGROUND: We have reported that human TR2 orphan nuclear receptor (TR2) can
      modulate the transcriptional activity of the reporter gene containing an AGGTCA
      direct repeat-hormone response element. OBJECTIVE: The aim of this study is to
      investigate the potential role and regulation of TR2 in human HaCaT
      keratinocytes. METHODS: We performed mainly chloramphenicol acetyltransferase
      reporter gene assays (CAT assays), and Western blot analysis. RESULTS: From CAT
      assays, TR2 can suppress retinoic acid (RA)-induced transactivation by 44.7% in
      HaCaT keratinocytes. This suppression is similar to our previous report showing
      TR4 orphan nuclear receptor (TR4) can suppress RA-induced transactivation.
      However, TR4 but not TR2 can significantly repress Wy-14643-mediated peroxisome
      proliferator-activated receptor alpha (PPAR alpha) transactivation by 95%.
      Western blot analysis suggested that Wy-14643 can differentially regulate the
      expression of TR2 and TR4 (by increasing the expression of TR4 protein and
      decreasing that of TR2) in HaCaT keratinocytes. CONCLUSION: Our data not only
      provides the first evidence to demonstrate that close members of orphan nuclear
      receptors group, such as TR2 and TR4, can have distinct functions, but also
      suggests the existence of differential and bi-directional regulation between PPAR
      alpha and TR2/TR4, that may play some important roles in the PPAR alpha signaling
      pathway in human keratinocytes.

PMID- 12615367
TI  - Increased interleukin-6 and granulocyte-macrophage colony stimulating factor
      levels in the sera of patients with non-segmental vitiligo.
AB  - BACKGROUND: Although the cause of vitiligo is unknown, an autoimmune theory has
      been proposed, and there is now convincing evidence that cytokines have an
      important role in pathogenesis of autoimmunity. OBJECTIVE: To study the possible
      role of interleukin-1, beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL
      8), tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony
      stimulating factor (GM-CSF) in the pathogenesis of vitiligo. METHODS: The authors
      measured the serum levels of the above-mentioned cytokines from 50 patients with
      the vitiligo compared with 20 healthy volunteers, employing the method of
      radioimmunoassay. RESULTS: The results showed that the serum levels of both IL-6
      and GM-CSF of the patients with both focal type and generalized type of vitiligo,
      and the serum level of IL-1 beta of the generalized type,were significantly,
      higher than those of normal controls in the patients with segmental vitiligo, the
      serum levels of all the cytokines tested were not significantly different from
      those of the normal controls. The GM-CSF levels of both focal type and
      generalized type, and the IL-6 level of the generalized type in progressive stage
      were significantly higher than those in stable state. CONCLUSION: It is
      speculated that IL-6 and GM-CSF may be involved in the autoimmune mechanism of
      non-segmental vitiligo. However, more evidence is required before a definite
      conclusion can be drawn.

PMID- 12615368
TI  - Travel epidemiology: WHO perspective.
AB  - International travel is undertaken by increasing, numbers of people for
      professional, social, recreational and humanitarian purposes, and this trend
      looks set to continue. Travellers are exposed to a variety of health risks of the
      unfamiliar environment of the area visited. Most such risks can be minimized by
      suitable precautions taken before, during and after travel. Furthermore
      travellers can introduce any infectious agents they may harbour to the visited
      area. Because of rapid air travel, no country is safe from infectious diseases
      and an outbreak in one country can easily and rapidly be transmitted across long
      distances to affect other countries through travel and trade. The main WHO
      strategies for minimizing the negative effects of expanding travel on global
      health security include developing the necessary strategies, rules and
      regulations, strengthening global communicable diseases surveillance and
      response, dissemination of related information throughout the world and
      strengthening national capacity for communicable diseases surveillance and
      response.

PMID- 12615369
TI  - Travel epidemiology--a global perspective.
AB  - In order to have a rational approach to necessary preventive measures it is
      essential to know the health risks. The 80 million travellers each year with
      destinations in Africa, Asia, Latin America, Pacific Islands and remote areas in
      Eastern Europe are exposed to a broad range of pathogens that are rarely
      encountered at home. The risk depends on the degree of endemicity in the area
      visited, the duration of stay, the individual behaviour and the preventive
      measures taken. Travellers' diarrhoea (TD) is the most frequent ailment of
      visitors to countries with poor hygiene. The incidence rate is 25-90% in the
      first 2 weeks abroad. The risk of TD is far less in travellers originating in a
      high risk country, as some immunity develops. Malaria is an important risk for
      travellers going to endemic areas. Without chemoprophylaxis, the monthly
      incidence is high in some destinations, among them frequently visited tropical
      Africa where 80-95% of the infections are due to Plasmodium falciparum. The
      incidence rates are lower in most endemic areas of Asia and Latin America where
      Plasmodium vivax predominates. The risk is nil in all capital cities of South
      America and SE Asia, as well as in many frequently visited tourist destinations.
      The diseases preventable by immunization will be discussed in a separate paper
      (Vaccination priorities; page 175). Sexually transmitted diseases occur
      frequently, as some travellers (5% of Europeans) engage in casual sex,
      approximately half of them without being protected by a condom. The prevalence
      for HIV-infection, syphilis, gonorrhoea, etc. often exceeds 50% in prostitutes.
      In some European countries, a major proportion of heterosexuals with newly
      acquired HIV-infection have acquired it while abroad.

PMID- 12615370
TI  - Travel epidemiology: the Saudi perspective.
AB  - The Kingdom of Saudi Arabia occupies four-fifths of the Arabian Peninsula, with a
      land area of 2 million square kilometres. Saudi Arabia holds a unique position in
      the Islamic world, as the custodian of the two holiest places of Islam, in Mecca
      and Medina. Annually, some 2 million Muslims from over 140 countries embark on
      Hajj. This extraordinary en masse migration is a unique forum for the study of
      travel epidemiology since the Hajj carries various health risks, both
      communicable and non-communicable, often on a colossal scale. Non-communicable
      hazards of the Hajj include stampede and motor vehicle trauma, fire-related burn
      injuries and accidental hand injury during animal slaughter. Communicable hazards
      in the form of outbreaks of multiple infectious diseases have been reported
      repeatedly, during and following the Hajj. Meningococcal meningitis,
      gastroenteritis, hepatitis A, B and C, and various zoonotic diseases comprise
      some of the possible infectious hazards at the Hajj. Many of these infectious and
      non-infectious hazards can be avoided or averted by adopting appropriate
      prophylactic measures. Physicians and health personnel must be aware of these
      risks to appropriately educate, immunize and prepare these travellers facing the
      unique epidemiological challenges of Hajj in an effort to minimize untoward
      effects. Travel epidemiology related to the Hajj is a new and exciting area,
      which offers valuable insights to the travel specialist. The sheer scale of
      numbers affords a rare view of migration medicine in action. As data is
      continually gathered and both national and international policy making is
      tailored to vital insights gained through travel epidemiology, the Hajj will be
      continually safeguarded. Practitioners will gain from findings of travel related
      epidemiological changes in evolution at the Hajj: the impact of vaccinating
      policies, infection control policies and public health are afforded a real-world
      laboratory setting at each annual Hajj, allowing us to learn from this unique
      phenomenon of migration medicine.

PMID- 12615371
TI  - Meningococcal disease and travel.
AB  - Meningococcal disease continues to be a worldwide problem. This review examines
      the impact meningococcal disease has on international travel and vice versa the
      impact international travel has on the intercontinental spread of meningococci.
      The risk of meningococcal disease to the endemic population differs from that of
      travellers. The best documented risk of meningococcal disease among travellers
      has been in Hajj pilgrims for Mecca and Madina in Saudi Arabia. In response to
      the recent Hajj associated outbreak of W135 meningococcal disease, quadrivalent
      meningococcal vaccine (against serogroups A/C/Y/W135) became a visa requirement.
      In view of increasing worldwide reports of Y and W135 meningococcal disease,
      there should be a switch in recommendation from the bivalent (against A& C) to
      the quadrivalent vaccine for all travellers.

PMID- 12615372
TI  - Meningococcal carriage among local inhabitants during the pilgrimage 2000-2001.
AB  - The first international outbreak of Neisseria meningitidis serogroup W135
      occurred in 2000, in direct association with the annual Hajj in Saudi Arabia. In
      anticipation of the following Hajj, we conducted a survey of oropharyngeal
      carriage rates of N. meningitidis both pre- and post-pilgrimage in the King
      Khalid National Guard Hospital (KKNGH) employees preparing to attend the Hajj.
      These KKNGH employees were native to the Mecca-Jeddah area. Pre-Hajj throat
      cultures were obtained 1 week prior to Hajj, and post-Hajj cultures within 10
      days after completing the Hajj pilgrimage. A total of 327 throat culture samples
      were collected from 218 persons. Overall meningococcal carriage rate was found to
      be 4.7%. Serogroup W135 accounted for 40% of all recovered pre-Hajj strains of N.
      meningitidis. Only one post-Hajj sample was positive for N. meningitidis W135.
      This high rate of colonization with N. meningitidis serogroup W135 indicates this
      strain predominates amongst the population indigenous to the Mecca-Jeddah area.
      This 'nidus' of N. meningitidis W135 is a potential reservoir for future
      outbreaks. More worrying, there is real risk of future W135 endemicity in this
      vulnerable local population. These preliminary findings warrant larger
      surveillance studies examining both transmission and carrier rate acquisition of
      N. meningitidis in the Mecca-Jeddah area. These vital data are needed to curb
      further epidemic outbreaks during future Hajj pilgrimages.

PMID- 12615373
TI  - W135 meningococcal carriage in association with the Hajj pilgrimage 2001: the
      Singapore experience.
AB  - An international outbreak among pilgrims returning from the Hajj (pilgrimage to
      Mecca) and their close contacts was caused by W135 Neisseria meningitidis. In
      Singapore, this strain is a new emerging problem, clearly associated with this
      outbreak. We investigated the extent of transmission of N. meningitidis in Hajj
      pilgrims and their contacts, in order to provide evidence for developing a
      rational public health policy. We found a high acquisition rate of W135 N.
      meningitidis in Singaporean pilgrims during the Hajj with substantial
      transmission to their household contacts. These findings would support a policy
      of eradication of pharyngeal carriage in returning pilgrims to prevent
      introduction and dissemination of meningococci.

PMID- 12615375
TI  - Tuberculosis in association with travel.
AB  - Throughout history, tuberculosis has been spread by the movement of human
      populations. Modern travel continues to be associated with risk of tuberculosis
      infection and disease. TB transmission has been documented on commercial
      aircraft, from personnel or passengers to other personnel and passengers, but the
      risk of transmission is low. As in other settings, the likelihood of transmission
      is proportional to duration and proximity of contact. Travellers from low
      incidence to high incidence countries have an appreciable risk of acquiring TB
      infection similar to that of the general populations in the countries they visit,
      but the risk is higher if they work in health care. Two-step tuberculin skin
      testing prior to departure, followed by single-step tuberculin testing after
      return, is recommended for all such travellers. For travellers from high
      incidence to low incidence countries the risk of acquiring new TB infection is
      low. Tuberculin screening is not beneficial and not recommended. Chest X-ray
      screening is expensive and complex but may be beneficial for long-term migrants.
      For short-term travellers, such as the pilgrims to Mecca in Saudi Arabia, there
      is no practical or feasible intervention to detect or prevent TB. Emphasis should
      be placed on public awareness and education campaigns to facilitate passive
      diagnosis of symptomatic cases. Mycobacterium tuberculosis (MTB) continues to be
      a common concern for the global traveller.

PMID- 12615374
TI  - Travellers' diarrhoea.
AB  - Risk of travellers' diarrhoea is about 7% in developed countries and 20-50% in
      the developing world. Options for prevention include education and
      chemoprophylaxis. Vaccination is a promising but incomplete option. Achieving
      behaviour modification of food and water choices among tourists is difficult.
      Bismuth subsalicylate (BSS)-containing compounds are about 62% effective in the
      prevention of travellers' diarrhoea. Antibiotics are about 84% effective in
      preventing travellers' diarrhoea. Routine prophylaxis of travellers' diarrhoea,
      especially with antibiotics, should be discouraged. Oral rehydration is generally
      important in the treatment of diarrhoea, but travellers' diarrhoea is only
      infrequently dehydrating in adults. The addition of oral rehydration solutions
      confers no additional benefit to loperamide in the treatment of travellers'
      diarrhoea in adults. Presently, the most active of the antibiotics routinely
      available for treatment are members of the fluoroquinolone group. Antibiotics
      that are not absorbed such as aztreonam and a rifampicin-like agent, rifaximin,
      are both effective. The latter might become a therapy of choice once it is
      routinely available, due to predictably less adverse reactions with a non
      absorbed antibiotic. Preliminary results with azithromycin look very promising.
      Less severe disease can be treated with a variety of non-antibiotic agents (e.g.
      BSS-containing compounds, loperamide and a calmodulin inhibitor, zaldaride). The
      combination of an antibiotic and loperamide is superior to treatment with either
      agent alone in a several studies and is arguably the treatment of choice for
      distressing travellers' diarrhoea.

PMID- 12615376
TI  - Sexually transmitted diseases and travel.
AB  - Sexually transmitted diseases (STDs) are infections and resulting clinical
      syndromes caused by more than 25 infectious organisms transmitted through sexual
      activity. International travellers are at great risk of contracting any of these
      STDs, including HIV, if they have been sexually exposed to persons with any of
      these diseases. Population movement has been shown to be a major contributing
      factor in the global spread of STDs. Increased sexual promiscuity and casual
      sexual relationships tend to occur during travel abroad to foreign countries.
      Travellers should be aware that the risk of STDs is high especially in the
      developing countries and sexual encounter with casual partners or commercial sex
      workers (CSWs) carries a high risk of infection. Prevention of STDs during travel
      can be achieved by complete abstinence from sexual exposure or adopting safe
      sexual practices such as consistently and correctly using a latex condom during
      sexual contact.

PMID- 12615378
TI  - Viral hepatitis in international travellers: risks and prevention.
AB  - Viral hepatitis is caused by a number of unrelated hepatotrophic viruses, known
      and unknown. Five hepatitis viruses namely HAV, HBV, HCV, HDV and HEV have been
      well characterized and the epidemiology and disease pattern of each agent has
      been defined. In the West, HAV, HBV and HCV are major causes of viral hepatitis.
      In the East, HEV is the most common cause of viral hepatitis. HAV is ubiquitous
      in childhood in such countries and accounts for less than 4% of disease in
      adults. Viral hepatitis becomes a problem to an international traveller when he
      envisages a journey from low endemic to high endemic area and is susceptible to
      the infection endemic at his destination. Millions of such potentially
      susceptible travellers from Europe, the USA, Canada, Japan, Australia, and New
      Zealand visit endemic areas every year for various reasons. Viral hepatitis is
      the most common reported immunization-preventable disease among travellers to
      developing countries. Imported viral hepatitis incapacitates the incumbents for
      an average of 4-10 weeks. Considering the magnitude of the travel, the number of
      cases of viral hepatitis and case fatality of around 2%, the disease causes
      significant morbidity and mortality in such communities. It has been estimated
      that viral hepatitis occurs 100 times more frequently than typhoid fever and
      1,000 times more often than cholera in travellers to developing countries.
      Hepatitis A is the most common form of viral hepatitis in travellers and
      cumulative data have shown a risk of 3-6 cases/1,000 persons/month of stay
      whereas the risk of acquiring hepatitis B is 10 times lower.

PMID- 12615377
TI  - Impact of travel on international spread of antimicrobial resistance.
AB  - Antimicrobial resistance, an escalating problem worldwide, affects a broad range
      of human diseases. Excessive and inappropriate drug usage is the key driver for
      the emergence of resistant organisms. Travel, trade and mass migration form an
      important mode for their spread. The use of molecular biology provides the means
      of understanding the genesis and spread of the genes for drug resistance.
      Antimicrobial use in veterinary practice as food additives causes selection of
      resistant zoonotic pathogens that may spread to humans. Comprehensive
      surveillance systems should be designed and implemented at local and national
      levels and a national resistance surveillance database operationalized. There is
      also need for better regulation of the use of antibiotics and education of the
      medical fraternity, veterinarians and the public in the appropriate use of
      antimicrobials.

PMID- 12615379
TI  - Rift Valley fever: an uninvited zoonosis in the Arabian peninsula.
AB  - Rift Valley fever (RVF) is an acute viral disease, affecting mainly livestock but
      also humans. The virus is transmitted to humans through mosquito bites or by
      exposure to blood and bodily fluids. Drinking raw, unpasteurized milk from
      infected animals can also transmit RVF. Routine vaccination of livestock in
      Africa has been prohibitively expensive, leading to endemicity of RVF in most
      African countries. Reports in September 2000 first documented RVF occurring
      outside of Africa in the Kingdom of Saudi Arabia and Yemen. Prior to this
      outbreak, the potential for RVF spread into the Arabian Peninsula had already
      been exemplified by a 1977 Egyptian epidemic. This appearance of RVF outside the
      African Continent might be related to importation of infected animals from
      Africa. In the most recent outbreak patients presented with a febrile
      haemorrhagic syndrome accompanied by liver and renal dysfunction. By the end of
      the outbreak, April 2001 statistics from the Saudi Ministry of Health documented
      a total of 882 confirmed cases with 124 deaths. Both the severity of disease and
      the relatively high 14% death rate might be a consequence of underreporting of
      less severe disease. Travellers to endemic areas may be at risk of acquiring the
      disease if exposed to animals or their body fluids directly or through mosquito
      bites. Special education regarding both modes of transmission and the
      geographical distribution of this disease needs to be given to travellers at
      risk.

PMID- 12615380
TI  - Malaria: still a threat to travellers.
AB  - Each year, some 25-30 million international travellers from non-tropical regions
      visit malaria endemic countries. Up to 10,000 cases of malaria are imported into
      industrialised countries with an average case fatality rate of around 1%. Malaria
      still poses a real threat to travellers, particularly in areas with high
      transmission such as sub-Saharan Africa, Papua New Guinea and the South Pacific
      islands. The spread of malaria resistant to an increasing number of drugs forces
      us to adjust chemoprophylaxis regimens. Although new drugs are available and can
      protect travellers effectively, the number of imported cases to Europe and North
      America remains substantial. An increasing proportion of imported cases is seen
      in migrants and foreign-born residents visiting friends and relatives (VFR) in
      endemic countries. New easy-to-use drugs, better understanding of risk perception
      of travellers, finding new and innovative ways to reach at risk travellers such
      as VFRs are among the new challenges to improve malaria prevention for
      international travellers.

PMID- 12615381
TI  - Venomous snakes of Saudi Arabia and the Middle East: a keynote for travellers.
AB  - Geographically Saudi Arabia and the Middle East include Asian Turkey, Syria,
      Lebanon, Jordan, Israel, Palestine, the Arabian Peninsula, Iraq, Iran and the
      previous Southern Asiatic Soviet Republics. The snake fauna contains species in
      common with northern Africa, Europe and central Asia and towards the east there
      is infiltration of species characteristic of tropical Asia. A classification of
      the venomous snakes of this area together with their distribution in the
      different countries is presented. The epidemiology of snake bites,
      pathophysiology of toxicity and the clinical features of envenoming by the
      different species of snakes are discussed. Management of snake bite victims
      including first aid, treatment at the hospital, clues from signs and symptoms
      that can help in the identification of the causative snake and antivenom
      treatment is stressed. Traditional manipulations like local incision and suction,
      use of caustics, oxidizing agents and cryotherapy and the injudicious use of
      tourniquets are evaluated and criticized. Finally the preventive control of snake
      bites for travellers in areas infested with venomous snakes is presented and
      discussed.

PMID- 12615382
TI  - Treatment of the scorpion envenoming syndrome: 12-years experience with
      serotherapy.
AB  - The pathophysiology of the scorpion envenoming syndrome is described with
      emphasis on the body systems commonly affected. Concepts of the mechanisms
      underlying venom action, as can be explained by the recently discovered effects
      on ionic channels, are discussed. A protocol for the treatment of scorpion stings
      based mainly on antivenom therapy was applied nationwide in Saudi Arabia. A list
      of drugs with alternatives was specified to be used in adjunctive therapy, when
      required. Analysis of the outcome from 1,033 cases at Al-Baha region, 791 cases
      at Al-Qassim region and more than 2,000 cases from 12 central and specialist
      hospitals in the Central Province, Saudi Arabia gave impressive results. The
      incidence of severe venom toxicity following antivenom administration was almost
      negligible. The period of stay in the hospital was reduced. The early reaction to
      antivenom administration was lower than expected the severity of the reaction
      consisting mainly of skin rashes, urticaria, wheezing and bronchial
      hypersensitivity, but no anaphylaxis. About 13.8% of the victims had been
      previously treated with antivenom but only 1.7% of the patients showed positive
      skin tests. This might be due to the low protein content of the antivenom and the
      action of the venom in releasing massive amounts of catecholamines.

PMID- 12615383
TI  - Vaccination priorities.
AB  - Selection of immunizations should be based on requirements and on risk of
      infection. According to the International Health Regulations, many countries
      require yellow fever vaccination and proof thereof as the International
      Certificate of vaccination. Additionally selected countries require proof of
      vaccination against cholera and meningococcal disease. A consultation for travel
      health advice is always an opportunity to ascertain that routine immunizations
      have been performed. Recommended immunizations often are more important for
      traveller's health than the required or routine ones. The most frequent vaccine
      preventable infection in non-immune travellers to developing countries is
      hepatitis A with an average incidence rate of 0.3% per month; in high risk
      backpackers or foreign-aid-volunteers this rate is 2.0%. Many immunizations are
      recommended for special risk groups only: there is a growing tendency in many
      countries to immunize all young travellers to developing countries against
      hepatitis B, as it is uncertain who will voluntarily or involuntarily get
      exposed. The attack rate of influenza in intercontinental travel is estimated to
      be 1%. Immunity against poliomyelitis remains essential for travel to Africa and
      parts of Asia. Many of the 0.2-0.4% who experience an animal bite are at risk of
      rabies. Typhoid fever is diagnosed with an incidence rate of 0.03% per month
      among travellers to the Indian subcontinent, North and West Africa (except
      Tunisia), and Peru, elsewhere this rate is 10-fold lower. Meningococcal disease,
      Japanese encephalitis, cholera and tuberculosis have been reported in travellers,
      but these infections are rare in this population. Although no travel health
      vaccine is cost beneficial, most professionals will offer protection against the
      frequent risks, while most would find it ridiculous to use all available vaccines
      in every traveller. It is essentially an arbitrary decision made on the risk
      level one wishes to recommend protection--but the priorities need to be set
      correctly.

PMID- 12615384
TI  - Travellers with pre-existing medical conditions.
AB  - Medical conditions that influence travel include those that compromise the
      immunity of the traveller and chronic underlying diseases or infirmities. The
      former includes HIV, transplantation, malignancy and its treatment, IgA
      deficiency, asplenia and use of immunocompromising drugs like corticosteroids.
      Chronic conditions include diabetes mellitus, end stage renal disease, diseases
      associated with compromised cardiac or pulmonary function and certain
      gastrointestinal diseases including cirrhosis. This review includes practical
      approaches to each of these conditions with attention to risk assessment and
      avoidance, vaccination when appropriate and not a risk to the compromised host,
      and arming the traveller with self-therapy and chemoprophylaxis. Since travellers
      with underlying conditions are often taking various medications the travel health
      practitioner must be alert for possible drug/drug interactions and must adjust
      dosages depending on the level of compromised renal or hepatic function. Finally,
      education of such travellers is paramount; they must understand that risk
      avoidance is critical and preventative modalities such as vaccination and
      chemoprophylaxis are never 100% efficacious.

PMID- 12615385
TI  - Neurological disorders and travel.
AB  - Travel is associated with a number of neurological disorders that can be divided
      into two categories: (1) Neurological infections including encephalitides,
      neurotuberculosis, neurobrucellosis, cysticercosis and trichinosis. Some of these
      disorders can be prevented by vaccinations, such as Japanese B encephalitis and
      rabies, some by the use of insect repellents and some by avoiding raw milk
      products and undercooked meat. (2) Non-infective neurological disorders, such as
      acute mountain sickness and high altitude cerebral oedema, problems occurring
      during air travel such as syncope, seizures, strokes, nerve compression,
      barotrauma and vertigo, motion sickness and foodborne neurotoxic disorders such
      as ciguatera, shellfish poisoning and intoxication by cassava. This group of
      diseases and disorders could be prevented if the traveller knows about them,
      applies simple physiological rules, takes some specific medications and knows how
      to avoid intoxications in certain geographical areas. Meningococcal meningitis,
      malaria and jet lag syndrome are extensively discussed in other articles of this
      issue. The discussion in this paper will be limited to the other disorders.

PMID- 12615386
TI  - Travelling with children.
AB  - Today children are more frequently travelling worldwide, thus increasing their
      exposure to exotic pathogens and unexpected environmental hazards. In order to
      ensure the safety of their health while travelling, children should see the
      person in charge of their medical care well in advance of their journey to assess
      the status of their routine immunizations and to evaluate their need for any
      travel-specific vaccines. In this review we touch on some of the most critical
      pre-travel vaccines and precautions needed for travelling children.

PMID- 12615387
TI  - Bioterrorism--a new challenge for public health.
AB  - The opening years of the new millennium have presented a new and worrisome
      possibility to the public, including travellers: the threat of deadly infectious
      diseases from biological agents being deliberately released. The possibility of
      bioterrorism had always seemed remote but the recent anthrax attacks by mail have
      made this threat of immediate relevance. The deliberate use of Bacillus anthracis
      with the intent to harm civilian populations has raised public health concerns
      about potential exposure to intentionally released Variola virus and other
      biological agents. There is an urgent need for countries to examine their
      preparedness to respond to biological weapons attacks. Given the emotional shock
      of even an alleged threat of a biological release, it will be wise for
      governments to consider how to address such dangers as an integral part of the
      national response to other threats to public health and well being. Physicians
      and other health professionals, including those providing guidance to
      international and domestic travellers, need to have a clear understanding of the
      possible agents and the appropriate therapy or prophylaxis. This paper attempts
      to give a perspective on the threat of bioterrorism, the consequences of its use,
      the likely biological agents that may be used, and the clinical presentation and
      management of diseases caused by some agents most likely to be used.

PMID- 12615388
TI  - The revised International Health Regulations: a framework for global health
      security.
AB  - The origins of the International Health Regulations (IHR) date back to the mid
      19th century when epidemics of cholera resulted in intensive infectious disease
      diplomacy. Many agreements were set in place both in Europe and in the American
      States before being eventually replaced in 1951 by the International Sanitary
      Regulations, later renamed the IHR. The present IHR oblige WHO Member States to
      notify outbreaks of cholera, plague and yellow fever and list the maximum
      measures applicable during such outbreaks. A number of permanent, routine
      measures relating to hygiene and sanitation at ports and airports are specified
      along with general provisions for the transport of persons and goods. The revised
      IHR will provide an opportunity to change from three diseases to a system for all
      public health emergencies of international concern. The core capacities required
      at national level to detect and respond to such emergencies will be clearly
      defined as will the linkage between notification under the revised IHR and
      international response and action in support of affected countries. Other
      existing IHR provisions and technical guidance will be updated to meet the
      demands of contemporary global surveillance and control of international
      outbreaks.

PMID- 12615389
TI  - Epilogue: regional development of travel medicine--the Saudi challenge.
AB  - To outline a plan for the expansion of travel medicine programmes and discipline
      in the mid eastern region, a panel of travel medicine experts convened at the
      First International Conference on Travel Medicine in Riyadh, Saudi Arabia to
      present and discuss the risks, prevention strategies, and treatment methods for
      the myriad of travel-related health issues. During some formal and informal
      discussions, suggestions were put forth and strategies outlined on how to expand
      programmes for travel medicine and promote its discipline in the region.
      Expanding and/or developing programmes of any nature is not without its
      challenges. In this light, the cooperation and commitment of the appropriate
      government sectors and significant others must be established to ensure success.

PMID- 12615390
TI  - Assessing gene expression variation in normal human tissues using GeneTag, a
      novel, global, sensitive profiling method.
AB  - GeneTag is a novel expression profiling method that allows the visualization,
      quantification and identification of expressed genes-whether known or novel-in
      any species, tissue or cell type, independent of knowledge of the underlying
      sequence. Here we describe the application of this method to determine variation
      of gene expression in individual human liver samples and the identification of
      tissue-specific genes by comparing expression patterns across several human
      organs. Expression data are stored in a database for future reference and data
      analysis relies on proprietary software, which allows complex comparisons to be
      performed. Differentially expressed genes are quickly identified through a link
      to a sequence database. The results from our study underscore the importance of
      knowledge of individual variation of gene expression for the design and
      interpretation of transcript profiling experiments in the context of any
      biological question.

PMID- 12615392
TI  - A modified Escherichia coli protein production strain expressing staphylococcal
      nuclease, capable of auto-hydrolysing host nucleic acid.
AB  - The large-scale production of recombinant biotherapeutics, particularly
      recombinant proteins, provides significant process and regulatory challenges to
      the biotechnology industry in order to meet the regulatory agencies stringent
      requirements in a cost-effective manner. Host cell derived nucleic acid causes
      problems from both a process and a regulatory perspective, as high molecular
      weight chromosomal DNA is responsible both for the viscosity of cell lysates, and
      it is a source of heterologous DNA sequences whose inclusion in the final product
      must be prevented. We have constructed a modified Escherichia coli JM107
      expression host (JMN), containing a staphylococcal nuclease expression cassette,
      integrated into the host chromosome at the dif locus. The nuclease is expressed
      as a fusion to the ompA signal peptide, and is translocated to the periplasm of
      the cell, protecting the cytoplasmic nucleic acid from any toxic activity. The
      nuclease is released during cell lysis, where it subsequently acts to hydrolyse
      host nucleic acid present in the lysate. Results with this strain show that
      sufficient levels of nuclease activity are produced to completely auto-hydrolyse
      the host's chromosomal DNA to a size non-visible on 1% agarose gel, generating a
      markedly lower lysate viscosity. This provides a suitable methodology to remove
      heterologous DNA sequences early in the product stream and decrease lysate
      viscosity, improving the efficiency of downstream processing and product yield,
      whilst avoiding the addition of exogenous nuclease and its prohibitive costs at
      large-scale.

PMID- 12615391
TI  - DNA extraction using bacterial magnetic particles modified with hyperbranched
      polyamidoamine dendrimer.
AB  - A cascading hyperbranched polyamidoamine dendrimer was synthesized on the surface
      of bacterial magnetite from Magnetospirillum magneticum AMB-1 to allow enhanced
      extraction of DNA from fluid suspensions. Characterization of the synthesis
      revealed linear doubling of the surface amine charge from generations one through
      five starting with an amino silane initiator. Furthermore, transmission electron
      microscopy revealed clear dispersion of the single domain magnetite in aqueous
      solution. The dendrimer modified magnetic particles have been used to carry out
      magnetic separation of DNA. Binding and release efficiencies increased with the
      number of generations and those of bacterial magnetite modified with six
      generation dendrimer were 7 and 11 times respectively as many as those of
      bacterial magnetite modified with only amino silane.

PMID- 12615393
TI  - Decolorization of azo dye using PVA-immobilized microorganisms.
AB  - A microbial consortium having a high capacity for rapid decolorization of azo dye
      (RED RBN) was immobilized by a phosphorylated polyvinyl alcohol (PVA) gel. The
      immobilized-cell beads exhibited a color removal capability of 75%, even at a
      high concentration of RED RBN (500 mg l(-1)) within 12 h using flask culture. The
      continuous operation was conducted at a hydraulic retention time (HRT) of 5-20 h
      in which the dye loading rate ranged from 240 to 60 mg dye h(-1). A removal
      efficiency exceeding 90% was obtained at the HRT higher than 10 h. No
      recognizable destruction of bead appearance was observed in the 6-month
      operation. Examination of the mechanism of the decolorization process by cell
      beads indicated that it proceeded primarily by biological decolorization
      associated with partial adsorption of the dye onto the entrapped cells and gel
      matrix. Microscopic observation revealed that the microbial consortium contained
      in the gel beads was at least made up of three kinds of bacterial species. From
      the economical viewpoint, alternative cheaper nitrogen sources such as fish meal,
      soybean meal, pharmamedia and vita yeast powder were examined.

PMID- 12615394
TI  - Catalytic properties of endoxylanase fusion proteins from Neocallimastix
      frontalis and effect of immobilization onto metal-chelate matrix.
AB  - The production of hybrid enzymes with novel properties and the research for new
      methods for enzyme immobilization in bioreactors are of major interest in
      biotechnology. We report here the second part of a study concerning the
      improvement of the properties of the endoxylanase XYN3A4 from the anaerobic fungi
      Neocallimastix frontalis. The effects of gene fusion and immobilization on metal
      chelate matrix are also compared for the reference enzymes XYN3, XYN3A, XYN4 used
      for the construction of the fusion protein XYN3A4. The influence of the metal ion
      in the immobilization process was first investigated and best immobilization
      yields were obtained with the Cu(II) ion whereas best coupling efficiencies were
      reached with the Ni(II) ion. It was also observed that XYN3, XYN3A and XYN34 had
      a lower rate of hydrolysis when immobilized on Ni(II)-IDA and more difficulties
      to accomodate small substrates than the soluble enzymes. Nevertheless, a major
      difference was noted during the hydrolysis of birchwood xylan and it appears that
      the reaction using the immobilized XYN3A4 chimeric enzyme leads to the
      accumulation of a specific product.

PMID- 12615395
TI  - Thermokinetic description of anaerobic growth of Halomonas halodenitrificans
      using a static microcalorimetric ampoule technique.
AB  - Efficiency and velocity of growth are key variables to consider when designing
      any microbial biotechnological process. Selection of the optimal strain and
      description of environmental effects on growth patterns require rapid information
      about relevant parameters. Calorimetry is particularly suitable for providing
      such data, provided it can simultaneously perform many measurements and the
      apparatus is as simple as possible. The simplest experimental set-up measures the
      heat flux of microorganisms growing in a static, sealed ampoule. But, how
      reliable and reproducible are the growth rates and growth yield coefficients
      obtained from such a system? To answer this question, the strain Halomonas
      halodenitrificans CCM 286(T) was grown on glycerol with nitrate as the terminal
      electron acceptor in a multi-channel isothermal heat conduction calorimeter in
      such a way that growth was predominantly influenced by availability of the
      oxidant. The time course of the heat fluxes up to the maximum attained was
      successfully modelled using integrated Monod kinetics. The reproducibility of the
      specific growth rate obtained was excellent (standard deviation less than 1% for
      a single measurement and less than 3% for a couple of measurements) and agreed
      well with figures reported in the literature. An Arrhenius-type model, consisting
      of one term for the activation and one for the inactivation of the microbial
      catalyst, was found to fit the whole specific growth rate versus temperature
      curve.

PMID- 12615396
TI  - Evaluation of phenylboronate agarose for industrial-scale purification of
      erythropoietin from mammalian cell cultures.
AB  - The search for novel, cost-effective ways to produce erythropoietin (Epo), the
      world top-selling biopharmaceutical, is a major challenge for today's
      biotechnology industry. However, Epo's high glycosylation content (almost 40% of
      total mass) and the requirement for sialic acid for optimal in vivo activity
      still make mammalian cells the expression system of choice. In contrast to the
      abundance of reports on Epo production, robust, cost-effective methods for large
      scale Epo purification can hardly be found in literature. To fill this gap, we
      describe here a process specifically studied for industrial-scale purification of
      the protein. Our method is based on the ability of phenylboronate agarose (PBA)
      to form reversible complexes with 1,2-cis-diol-containing molecules, like sugars
      in glycoproteins. Finding that additional factors (i.e., ionic and hydrophobic
      interactions) contribute to the Epo-PBA binding reaction, chromatography
      conditions have been optimized in scale-down experiments to improve selectivity
      and yield. As a result, the high performance of affinity chromatography has been
      achieved using a support possessing the robustness, chemical stability and low
      cost of a small synthetic ligand. By adding an anion exchange chromatography step
      and gel filtration for polishing, a pure and active product can easily be
      obtained by an integrated, start-to-end process optimized for industrial-scale
      operations.

PMID- 12615397
TI  - Extracting and purifying R-phycoerythrin from Mediterranean red algae Corallina
      elongata Ellis & Solander.
AB  - R-Phycoerythrin (R-PE) is a protein acting as a photosynthetic accessory pigment
      in red algae (Rodophyta). This protein has gained importance in many
      biotechnological applications in food science, immunodiagnostic, therapy,
      cosmetics, protein and cell labelling, and analytical processes. In this paper we
      report on a new, one step procedure for the extraction and purification of R-PE
      from a new source: the Mediterranean red algae Corallina elongata Ellis &
      Solander. This red algae contains mainly R-PE and is suitable for the production
      in culture. No other contaminating phycobiliproteins could be detected in the
      extracts. The method we propose for the purification is based on the use of
      hydroxyapatite, a chromatographic resin that can be produced in the laboratory at
      very low cost and can be used batch-wise with large amounts of extracts,
      alternative to chromatography, and therefore can be scaled up. Both the yield and
      the purity of R-PE are very good.

PMID- 12615399
TI  - Plasma protein adsorption patterns on surfaces of Amphotericin B-containing fat
      emulsions.
AB  - Nephrotoxicity of the conventional Amphotericin B formulation Fungizone is the
      most common side effect in treatment of systemic fungal infections. Lipid
      formulations of Amphotericin B including fat emulsions showed a reduced
      nephrotoxicity. In vivo distribution studies of lipid formulations have shown an
      accumulation of Amphotericin B in liver and spleen, while concentration in the
      kidneys is reduced. Blood proteins adsorbed onto particles after intravenous
      administration are regarded as the key factors determining their in vivo fate.
      Two-dimensional polyacrylamid gel electrophoresis is a powerful tool for analysis
      of protein adsorption patterns. This paper deals with the question if there is
      any correlation between proteins adsorbed on surfaces of AmB fat emulsions
      produced with a new production technique and the potentially organ distribution
      of this formulation.

PMID- 12615401
TI  - Some properties of extruded non-ionic surfactant micro-tubes.
AB  - Polyhedral non-ionic surfactant vesicles (niosomes) undergo complex shape
      transitions as a result of mechanical stress. When extruded under pressure from
      capillaries with exit diameters smaller than the diameter of the vesicles, a
      series of novel structures comprising mostly of tubules, vesicles inside tubules
      and concentric structures can be formed. The microtubules (up to 80 microm in
      length) form as a result of the pressure exerted on polyhedral niosomes, this
      leading to the fusion of many vesicles, the relative shear giving movement of the
      vesicles giving rise to the formation of three distinctive structures, namely
      tubules, vesicle within tubule and concentric ("whorl") morphologies. The
      entrapment efficiency of the tubules has been studied using a model solute 5(6)
      carboxyfluorescein (CF), as has the effect of shear stress this and compaction
      pressure on the release of the entrapped solute. Deformation of the structures
      affects their ability to retain entrapped solute. Tubular structures heated above
      their transition temperatures reversibly transform into discrete vesicular
      structures.

PMID- 12615400
TI  - Secondary structure alterations in insulin and growth hormone water-in-oil
      emulsions.
AB  - Water-in-oil (w/o) emulsions have shown a promising release profile of small drug
      molecules and proteins. However, the major concerns are the structural stability,
      the retention of the activity and to avoid unwanted immunological reactions
      caused by the changes in protein structure. In the present study, the secondary
      structure of insulin and growth hormone is investigated after manufacture of w/o
      emulsions, using Fourier transform infrared (FTIR) spectroscopy. Initial
      investigations indicate an altered distribution in the secondary structure
      elements, e.g. alpha-helix and beta-sheet, measured by area overlap calculations.
      The changes are more pronounced for growth hormone than for insulin. The
      overlapping area is 0.93 +/- 0.01 for the emulsion containing insulin
      manufactured at 0 degrees C and homogenised for 3 min, the corresponding value
      for growth hormone is 0.83 +/- 0.01. The droplet size changes from 0.27 +/- 0.04
      microm in the blank w/o emulsion to 0.79 +/- 0.13 and 0.66 +/- 0.21 microm when
      insulin or growth hormone is incorporated into the w/o emulsions, respectively.

PMID- 12615402
TI  - Dendriplexes and their characterisation.
AB  - The interaction of DNA with partial dendrimers (dendritic polylysine containing
      seven lysines and eight terminal amino groups with or without a lipidic core) was
      studied. Compact complexes were formed which we term "dendriplexes". Agarose gel
      electrophoresis and exclusion of ethidium bromide confirmed the interaction. All
      the dendrons formed compact complexes above a 2:1 (+/-) charge ratio in water and
      HBSS. Photon correlation spectroscopy, electron microscopy and zeta potential
      measurements were used to determine, respectively, the particle size, shape and
      surface charge of the dendriplexes. The z-average diameter of the dendriplexes
      were found to be 60-70 nm irrespective of the dendron used and the zeta potential
      varied from 10 to 35 mV at a 3:1 (+/-) charge ratio depending on the dendron. The
      protection of the DNA component of these dendriplexes from nuclease degradation
      was confirmed by DNase protection assays.

PMID- 12615403
TI  - Adsorption of amphipathic dendrons on polystyrene nanoparticles.
AB  - Adsorption of dendrons onto nanoparticles may provide new model structures which
      may be useful in drug and gene delivery. Tritiated amphipathic dendrons having
      three lipidic (C(14)) chains coupled to branched (dendritic) lysine head groups
      with 8, 16 or 32 free terminal amino groups have been synthesised by solid phase
      peptide techniques. The interaction between these tritiated dendrons and 200 nm
      polystyrene latex nanoparticles was investigated in phosphate buffered saline.
      The amount of dendron adsorbed increased with increasing concentration of
      dendrons and then decreased. Maximum adsorption of dendrons per gram of
      nanoparticles was found to be between 8.2 and 84 x 10(-6)M, the amounts adsorbed
      being inversely proportional to the number of amino groups present in the
      molecule. The number of dendron molecules adsorbed per nanoparticle was found to
      be between 430 and 4421. The degree of adsorption was found to be slightly
      altered by the temperature.

PMID- 12615404
TI  - Formulation and stability of surface-tethered DNA-gold-dendron nanoparticles.
AB  - The formulation of plasmid DNA on 100 nm gold nanoparticles surface-tethered via
      cationic dendrons, and the behaviour of the complex in cell culture media, is
      described in this communication. Adsorption of dendrons onto gold nanoparticles
      in water resulted in the generation of positively charged nanoparticles with a
      corresponding small increase in particle size. Addition of plasmid DNA did not
      markedly reduce the surface potential but resulted in a approximately 10-20%
      increase in hydrodynamic diameter. More dramatic effects were seen in the
      presence of cell culture media that, overall, drastically increased the apparent
      size of the gold-dendron-DNA nanoparticles and reduced the surface potential of
      the colloids, the presence of serum components partially ameliorating these
      effects possibly due to steric stabilisation. Release of the surface-tethered DNA
      was reduced in cell culture media compared to water. This reduced detachment of
      DNA coupled with the flocculation of the carrier which would likely inhibit
      endocytosis, demonstrates the importance of testing drug delivery systems with
      relevant physiologically based fluids prior to their use in vivo studies.

PMID- 12615405
TI  - Dendrisomes: cationic lipidic dendron vesicular assemblies.
AB  - A new lipidic cationic polylysine dendron was prepared by solid-phase peptide
      synthesis. Its behaviour in aqueous media and its ability, with and without
      cholesterol, to form higher order structures, "dendrisomes", was studied to
      further our understanding of how dendrons interact with drug molecules and may be
      utilised as drug carriers. Dynamics simulations of the dendron show their
      flexibility. Incorporation of cholesterol increases the hydrodynamic diameter of
      the aggregates from 311 to 556 nm but does not affect their positive zeta
      potential (of the order of +50 mV). The dendrisomes encapsulated penicillin G
      (6.15% w/w) compared to only 1.4% w/w entrapment in REV liposomes of 1:1
      distearoyl phosphatidylcholine:cholesterol. Cholesterol, however, decreases the
      entrapment efficiency. Electrostatic forces and H-bonding between the negatively
      charged drug and dendron amino groups are likely to be key in determining these
      interactions.

PMID- 12615406
TI  - The interaction of cationic dendrons with albumin and their diffusion through
      cellulose membranes.
AB  - Amphipathic dendrons (partial dendrimers) having three lipidic (C(14)) chains
      coupled to dendritic lysine head groups with 8, 16 or 32 free terminal amino
      groups have been synthesised by solid phase peptide synthesis. Their interaction
      with albumin was studied in the presence of NaCl using dynamic dialysis, the
      diffusion of the dendrons through regenerated cellulose membranes also being
      studied. The stoichiometry of dendron: albumin interactions was found to be
      1:1.5, 1:4 and 1:5 for the dendrons with 8, 16 and 32 amino groups, respectively.
      Membrane permeability P, membrane diffusion coefficient D and the membrane
      partition coefficient K values were calculated for each dendron. P and D values
      were low but highest for the 8 amino group dendron. The membrane partition
      coefficient K was greatest for the 8 amino group dendron. This was also the case
      with octanol/water partition coefficient studies. Considerable adsorption of the
      dendrons to the cellulose membrane occurred but NaCl decreased adsorption and
      improved diffusion of the dendrons through the cellulose membrane.

PMID- 12615407
TI  - Pulmonary administration of IgG loaded liposomes for passive immunoprophylaxy.
AB  - Local passive immunoprophylaxy has been used in pulmonary infectious diseases
      successfully. However, the short immunoglobulins half-life in the lungs limits
      the duration of their action. The aim of the present study was to evaluate the
      efficiency of human polyvalent intravenous immunoglobulins (IVIG) when protected
      after encapsulation within EPC: DPPG liposomes by dehydration/rehydration. Two
      IVIG concentrations were chosen: 10 and 1 mg/ml for further studies in mice
      infected by influenza A. For the highest concentration (10 mg/ml), IVIG loaded
      liposomes did not significantly differ from IVIG/unloaded liposomes mixture with
      around 45% association yield. For the lowest concentration (1 mg/ml), two thirds
      of the IVIG associated were found inside the vesicles. In vivo, IVIG administered
      intranasally at 10 mg/ml (500 microg per mouse) 4 days before the infection led
      to 100% survival whatever the formulation. When administered at a lower dose (1
      mg/ml-50 microg per mouse) 2 days before the challenge, loaded liposomes were
      found less efficient than free IVIG while unloaded liposomes showed a slight
      aspecific immunoprotection. Gastrointestinal clearance must be responsible for a
      major loss of liposomes compared to IVIG solution because of a higher viscosity
      of the formulation. Discrepancies with the literature are discussed.

PMID- 12615408
TI  - In vitro and in vivo aspects of N-acyl-phosphatidylethanolamine-containing
      liposomes.
AB  - Incorporation of the phospholipid, N-acyl-phosphatidylethanolamine (NAPE), has
      shown to increase the liposomal stability towards plasma components in vitro.
      Besides increasing the circulation-time, NAPE has been shown to contain
      fusiogenic properties. Hence, fusion between NAPE-liposomes and target cells may
      be expected, resulting in a favorable delivery of drug to the target cell. In
      this study, NAPE has been tested as a potential liposomal component of
      phosphatidylcholine-liposomes. The liposomes were characterized by size, long
      term stability and phase transition temperature (T(m)). In vivo behavior of NAPE
      liposomes was determined by the blood-circulation half-life in mice. A
      characterization of the liposomes revealed that high content of NAPE resulted in
      liposomes of increased size compared to pure phosphatidylcholine-liposomes.
      However, the liposomes showed only a slight increase in size during storage for 5
      weeks. Determination of T(m) for NAPE-liposomes showed increasing values of T(m)
      by increasing percentage of NAPE in the liposomal bilayer, due to the higher T(m)
      of NAPE compared to phosphatidylcholine. Blood-clearance studies showed an
      initial increase in blood-circulation of liposomes containing high amounts of
      NAPE. Thus, these results suggest that liposomes containing high percentage of
      NAPE may be a promising candidate for long-circulating liposomes, possibly in
      combination with other stabilizing components, e.g. cholesterol.

PMID- 12615409
TI  - Peptide-targeted PEG-liposomes in anti-angiogenic therapy.
AB  - Peptides with the RGD amino acid sequence show affinity for the alpha(v)beta(3)
      integrin, an integrin which is over-expressed on angiogenic endothelium and
      involved in cell adhesion. A peptide with the sequence ATWLPPR has been
      demonstrated to show affinity for the vascular endothelial growth factor (VEGF)
      receptor, a receptor involved in the proliferation of endothelial cells. By
      coupling these peptides to liposomes, these liposomes can serve as a site
      specific drug delivery system to tumor endothelial cells in order to inhibit
      angiogenesis. In the present study we demonstrate that the coupling of cyclic RGD
      peptides or ATWLPPR-peptides to the surface of PEG-liposomes results in binding
      of these liposomes to endothelial cells in vitro. Subsequent studies with RGD
      peptide targeted liposomes in vivo also demonstrate specific binding to the tumor
      endothelium.

PMID- 12615410
TI  - Influence of methyl-beta-cyclodextrin and liposomes on rheological properties of
      Carbopol 974P NF gels.
AB  - The influence of positively-charged and sterically stabilized liposomes and/or
      methyl-beta-cyclodextrin on rheological properties of Carbopol 974P NF hydrogels
      was investigated. All formulations have displayed a shear-thinning behavior of
      Carbopol gels, and the rate stress as a function of the shear rate was fitted
      using the Cross equation. An important loss of viscosity was observed when 1.5%
      Carbopol gels were formed in Hepes/NaCl buffer or in a 5% aqueous solution of
      methyl-beta-cyclodextrin. Nevertheless, when methyl-beta-cyclodextrin was
      dissolved in buffer at 5% there was no additional effect on gel viscosity
      reduction. The incorporation of positively-charged and sterically stabilized
      liposomes at 2 mM of lipid concentration had no incidence on rheological
      properties of the Carbopol gels, whereas gel viscosity was significantly
      increased in the presence of positively-charged liposomes at 10 mM of lipid
      concentration. Finally, the viscosity of hydrogels containing both liposomes and
      methyl-beta-cyclodextrin tended to be close to control gels, remaining high and
      relevant for a topical delivery.

PMID- 12615411
TI  - Cosmetic applications for solid lipid nanoparticles (SLN).
AB  - Solid lipid nanoparticles (SLN) are novel delivery systems for pharmaceutical and
      cosmetic active ingredients. This paper highlights advantages of SLN for cosmetic
      applications. The dependence of the occlusive effect on the particle size of SLN
      due to film formation is presented by in vitro data. An in vivo study showed that
      addition of 4% SLN to a conventional o/w cream lead to an increase of skin
      hydration of 31% after 4 weeks. The application of SLN as physical sunscreens and
      as active carriers for molecular sunscreens has also been investigated. The
      amount of molecular sunscreen could be decreased by 50% while maintaining the
      protection level compared to a conventional emulsion.

PMID- 12615412
TI  - Cell interaction studies of PLA-MePEG nanoparticles.
AB  - Poly(D,L-lactic acid)-methoxypoly(ethylene glycol) (PLA-MePEG) copolymers were
      synthesized by ring-opening polymerization of D,L-lactide in the presence of
      MePEG of different molecular weights and stannous octoate as the catalyst. The
      chemical composition of the diblock-copolymer PLA-MePEG was confirmed by 1H-NMR
      and the molecular weight and distribution were assessed by gel permeation
      chromatography. Nanoparticles containing Nile red as a fluorescent dye were
      prepared using poly(D,L-lactic acid) (PLA), blends of PLA and PLA-MePEG or PLA
      MePEG alone. Incubation of nanoparticles with human blood monocytes was performed
      in serum or in PBS and the cell-associated fluorescence was analyzed by flow
      cytometry. In serum, a protective effect was obtained and the interaction of
      particles with mononuclear leukocytes decreased to 40%.

PMID- 12615413
TI  - Formulation of amphotericin B as nanosuspension for oral administration.
AB  - Amphotherin B was formulated in a nanosuspension as a new oral drug delivery
      system for the treatment of experimental visceral leishmaniasis. Amphotericin B
      (AmB) nanosuspensions were produced by high pressure homogenisation obtaining
      particles with a PCS diameter of 528 nm. Environmental stability was determined
      in artificial gastrointestinal fluids at different pH and electrolyte
      concentrations. In vivo efficacy was determined in a mouse model of visceral
      leishmaniasis. Following oral administration (5 mg kg(-1)), micronised
      amphotericin B did not show any curative effect. However, administrations of
      amphotericin B nanosuspension, reduced liver parasite load by 28.6% compared to
      untreated controls.

PMID- 12615414
TI  - Study of emulsion stabilization by graft copolymers using the optical analyzer
      Turbiscan.
AB  - Oil-in-water nanoemulsions were prepared using a series of synthetic graft
      copolymers with a backbone of dextran (DEX) and a number of side chains of poly
      epsilon-caprolactone (PCL). In this paper, we focus on the o/w emulsion
      stabilizing abilities of these novel PCL-DEX copolymers, using a recently
      developed optical analyzer (Turbiscan). The main advantage of Turbiscan is to
      detect the destabilization phenomena in non-diluted emulsion, much earlier than
      the naked eye's operator, especially in the case of an opaque and concentrated
      system. This study shows that PCL-DEX copolymers successfully stabilized ethyl
      acetate-in-water emulsions, even in the absence of additional surfactants,
      whereas they were not efficient in stabilizing methylene chloride-in-water
      emulsions which coalesced fast and irreversibly. The ethyl acetate-in-water
      emulsion stabilizing ability of PCL-DEX seemed to be related to the localization
      of their blocks with regard to the oil-water interface.

PMID- 12615415
TI  - Preparation and purification of cationic solid lipid nanospheres--effects on
      particle size, physical stability and cell toxicity.
AB  - Cationic solid lipid nanospheres (SLN) were prepared by the microemulsion
      technique with polysorbate 80 (Tween 80) and butanol as surfactants. The SLN
      (diameter 100-500 nm, zetapotential around +15 mV) consisted mainly of
      stearylamine (SA) and different triglycerides. Three different purification
      methods, ultrafiltration, ultracentrifugation and dialysis, were investigated and
      compared with the cellular toxicity and physical stability of the dispersions.
      The cell toxicity was dependent on both the SLN composition and the purification
      method. Dialysis was found to easily and efficiently remove excessive surfactant
      determined by dynamic light scattering (DLS), leading to reduced cell toxicity
      and increased physical stability of the SLN on storage. The cationic SLN might
      constitute a promising DNA delivery system.

PMID- 12615416
TI  - A new delivery system for antisense therapy: PLGA microspheres encapsulating
      oligonucleotide/polyethyleneimine solid complexes.
AB  - Microspheres for the controlled release of an antisense oligonucleotide against
      the Transforming growth factor beta(1) were designed. Free oligonucleotide or its
      solid complexes with polyethylenimine (PEI) at different nitrogen/phosphate (N/P)
      ratios, were encapsulated within poly(lactide-co-glycolide) (PLGA) microspheres
      prepared by the multiple emulsion-solvent evaporation technique. The
      encapsulation of the oligonucleotide in form of solid complexes, the N/P ratio,
      as well as the PLGA type affected microspheres characteristics in term of
      loading, morphology, oligonucleotide distribution inside matrix and in vitro
      release profile. The designed microspheres allow the encapsulation and slow
      release of oligonucleotide/PEI solid complexes that should be effectively
      internalized inside cells.

PMID- 12615417
TI  - A copepod life-cycle test and growth model for interpreting the effects of
      lindane.
AB  - A full life-cycle test was performed to measure the effects of lindane (3.2-3,200
      microg l(-1)) on the survival, development and reproduction of the freshwater
      copepod Bryocamptus zschokkei. This copepod survived at relatively high
      concentrations of lindane compared with other freshwater crustaceans with a 10
      day LC50 of 241 microg l(-1) (95% CL of 141-440). 'Equiproportional development',
      which assumes that each moult stage represents a specific proportion of the total
      development time, and is not affected by processes that influence metabolism such
      as temperature and food quality, was used to determine the mode of action of
      lindane on development in B. zschokkei. Development to adult was significantly
      longer at 100 microg l(-1) lindane compared with the controls, however,
      development remained equiproportional regardless of lindane exposure. Increased
      development times, therefore, are not due to a direct effect of lindane on the
      moulting process but are due probably to reduced food intake or increased
      metabolism through the stress imposed by toxicant exposure. Although the survival
      data suggest that B. zschokkei is relatively tolerant of lindane exposure,
      reproduction was affected at low lindane concentrations. At 32 microg l(-1)
      lindane, significantly fewer eggs and viable offspring were produced per female
      compared with the solvent control. At very low lindane concentrations (3.2 and 10
      microg l(-1)), there was a significant increase in the numbers of offspring
      produced per female compared with the controls and this is interpreted as a
      hormesis effect. In conclusion, a full life-cycle test demonstrated B. zschokkei
      is relatively sensitive to lindane compared with other freshwater crustaceans.
      Incorporating a copepod growth model (equiproportional development) into the life
      cycle test design, provided information on the dominant mode of action of the
      toxicant.

PMID- 12615418
TI  - Comparative bioavailability of selenium to aquatic organisms after biological
      treatment of agricultural drainage water.
AB  - Selenium (Se) is naturally abundant in the soils of the western San Joaquin
      Valley, California, USA. Intense agricultural activity in this region requires
      irrigation which leaches Se into surface waters draining to the San Joaquin
      River. Se water contamination and subsequent accumulation in wildlife is a
      serious problem in the Central Valley of California, and the subject of
      increasingly intensive regulatory action. Algal-bacterial selenium reduction
      (ABSR) is a potential new treatment approach to reduce Se in agricultural
      drainage, and an ABSR demonstration facility was examined with respect to its Se
      removal efficiency and effect on Se bioavailability and bioaccumulation. Water
      samples were taken to study treatment effects on Se speciation. Invertebrate
      tissue Se concentrations in the ABSR ponds were monitored for 2 years. Laboratory
      based algal bioaccumulation tests and in situ microcosms with a variety of
      invertebrates were also used to address differences in Se bioavailability before
      and after ABSR treatment. The ABSR system removed about 80% of the total influent
      Se; however, microbial and algal activity produced selenite and organic Se, the
      combined concentration of which increased 8-fold during treatment. As a result of
      the greater bioavailability of selenite and organic Se, relative to the selenate
      of the influent, treatment contributed to greater Se concentrations in effluent
      exposed organisms. ABSR-treated water produced Se concentrations in biota 2-4
      times greater than organisms exposed to untreated water. The bioavailability of
      Se in the treated water was 2-10 times greater than Se in the influent. The shift
      to more bioavailable Se forms due to biological treatment is inherent in system
      design, and makes it difficult to weigh the ecological benefits of a reduction in
      total Se loadings from a regional perspective against the greater toxicological
      risk to biota in the vicinity of the effluent.

PMID- 12615419
TI  - Ecotoxicological study of Lithuanian and Estonian wastewaters: selection of the
      biotests, and correspondence between toxicity and chemical-based indices.
AB  - The toxicity of industrial and urban wastewater (WW) samples collected in
      Lithuania and Estonia was evaluated by using a suite of biological tests
      comprising the Algaltoxkit F with Selenastrum capricornutum, the Charatox with
      Nitellopsis obtusa, Daphtoxkit F with Daphnia magna, Thamnotoxkit F with
      Thamnocephalus platyurus, Protoxkit F with Tetrahymena thermophila and the
      Microtox with Vibrio fischeri. The Charatox and Thamnotoxkit F tests showed
      highest relative sensitivity, responding to 80-90% of samples, respectively, and
      both expressed good discrimination capacity between samples. Principal Component
      and pairwise correlation analysis allowed to select test-battery consisting of
      Charatox, Thamnotoxkit and Microtox. The WW toxicity was evaluated by means of
      cumulative indices such as average toxicity (AvTx) and two indices derived from
      the PEEP-index (Environ. Toxicol. Water Qual. 8 (1993) 115). In addition to these
      integrated evaluations of test-battery response, WW toxicity was evaluated
      according to the most sensitive test (MST) in the battery. The linear regression
      analysis between cumulative toxicity indices and chemical-based indices (derived
      from comparison of WW chemical concentrations and their respective maximum
      allowable concentration) revealed positive linear relationships (r(2)=0.7-0.8),
      while toxicity evaluation based on the MST was less positively related with
      chemical analysis data (r(2)=0.5-0.6). Although better coincidence between the
      toxicity and chemical-based assessments was achieved when information from all
      tests in the battery was assembled, the prediction of toxicity from chemical data
      was still limited. In search of suitable test-battery for the screening of
      certain type of WWs, a preliminary study comprising excessive suite of tests
      might be useful.

PMID- 12615420
TI  - Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the
      concept of independent action.
AB  - For a predictive assessment of the aquatic toxicity of chemical mixtures, two
      competing concepts are available: concentration addition and independent action.
      Concentration addition is generally regarded as a reasonable expectation for the
      joint toxicity of similarly acting substances. In the opposite case of
      dissimilarly acting toxicants the choice of the most appropriate concept is a
      controversial issue. In tests with freshwater algae we therefore studied the
      extreme situation of multiple exposure to chemicals with strictly different
      specific mechanisms of action. Concentration response analyses were performed for
      16 different biocides, and for mixtures containing all 16 substances in two
      different concentration ratios. Observed mixture toxicity was compared with
      predictions, calculated from the concentration response functions of individual
      toxicants by alternatively applying both concepts. The assumption of independent
      action yielded accurate predictions, irrespective of the mixture ratio or the
      effect level under consideration. Moreover, results even demonstrate that
      dissimilarly acting chemicals can show significant joint effects, predictable by
      independent action, when combined in concentrations below individual NOEC values,
      statistically estimated to elicit insignificant individual effects of only 1%.
      The alternative hypothesis of concentration addition resulted in overestimation
      of mixture toxicity, but differences between observed and predicted effect
      concentrations did not exceed a factor of 3.2. This finding complies with
      previous studies, which indicated near concentration-additive action of mixtures
      of dissimilarly acting substances. Nevertheless, with the scientific objective to
      predict multi-component mixture toxicity with the highest possible accuracy,
      concentration addition obviously is no universal solution. Independent action
      proves to be superior where components are well known to interact specifically
      with different molecular target sites, and provided that reliable statistical
      estimates of low toxic effects of individual mixture constituents can be given.
      With a regulatory perspective, however, fulfilment of both conditions may be
      regarded as an extraordinary situation, and hence concentration addition may be
      defendable as a pragmatic and precautionary default assumption.

PMID- 12615421
TI  - Acute waterborne nickel toxicity in the rainbow trout (Oncorhynchus mykiss)
      occurs by a respiratory rather than ionoregulatory mechanism.
AB  - The acute mechanism of toxicity of waterborne nickel (Ni) was investigated in the
      rainbow trout (Oncorhynchus mykiss) in moderately hard ( approximately 140 mg l(
      1) as CaCO(3)) Lake Ontario water, where the 96-h LC(50) for juvenile trout (1.5
      3.5 g) was 15.3 mg (12.7-19.0, 95% C.L.) dissolved Ni l(-1). No marked impact of
      Ni exposure on average unidirectional or net fluxes of Na(+), Cl(-), or Ca(2+)
      was observed in juvenile trout exposed for 48-60 h to 15.6 mg Ni l(-1) as
      NiSO(4). Furthermore, when adult rainbow trout (200-340 g) were fitted with
      indwelling dorsal aortic catheters and exposed for 117 h to 11.6 mg Ni l(-1) as
      NiSO(4), plasma ions (Na(+), Cl(-), Ca(2+), and Mg(2+)) were all well conserved.
      However, mean arterial oxygen tension dropped gradually to approximately 35% of
      control values. This drop in P(aO(2)) was accompanied by an acidosis primarily of
      respiratory origin. P(aCO(2)) rose to more than double control values with a
      concomitant drop in arterial pH of 0.15 units. Acute respiratory toxicity was
      further evidenced by a significant increase in hematocrit (Ht), and plasma
      lactate, and a significant decrease in spleen hemoglobin (Hb). Following 117 h of
      exposure to 11.6 mg Ni l(-1), the gill, intestine, plasma, kidney, stomach, and
      heart accumulated Ni significantly, with increases of 60, 34, 28, 11, 8, and 3
      fold, respectively. Brain, white muscle, liver, and bile did not significantly
      accumulate Ni. Plasma Ni exhibited a remarkable linear increase with time to
      levels approximately 30-fold higher than controls. We conclude that in contrast
      to most other metals, Ni is primarily a respiratory, rather than an
      ionoregulatory, toxicant at exposure levels close to the 96-h LC(50). The
      implications of a waterborne metal as an acute respiratory toxicant (as opposed
      to ionoregulatory toxicants such as Cu, Ag, Cd, or Zn) with respect to toxicity
      modeling are discussed.

PMID- 12615422
TI  - Fractal analysis of vascular complexity in cadmium-treated zebrafish embryos.

PMID- 12615423
TI  - Author response to letter to the editor by Marciani et al.

PMID- 12615424
TI  - Introduction of a HIV vaccine in developing countries: social and cultural
      dimensions.
AB  - Using insights from studies on social and cultural aspects of immunization in
      Africa and Asia the paper discusses the introduction of a HIV vaccine from three
      perspectives. Firstly, it shows how at the side of public health programs local
      differences will impact on the introduction of a new vaccine. Secondly, it
      elaborates how at the side of the users of vaccinations acceptance, non
      acceptance and demand of and for a new vaccine are related to local vaccination
      cultures, images of the HIV/AIDS epidemic, and perceptions of vaccine potency and
      efficacy. Thirdly, it points out socio-cultural aspects of the introductory
      process. Tailoring health education and social marketing to local conditions and
      local interpretations of globally provided information will be decisive for a
      successful introduction. Strong public health programs with highly motivated and
      appropriately supported staff are another necessary condition.

PMID- 12615425
TI  - Combined hepatitis B vaccines.
AB  - The status and likely impact of existing and potential new combined hepatitis B
      vaccines were broadly considered at the Viral Hepatitis Prevention Board (VHPB)
      meeting in Malta, October 2001. The currently available and/or licensed combined
      hepatitis B vaccines in Europe and the prospects for further such vaccines were
      reviewed. Data on the safety, immunogenicity, and European licensing status and
      availability of haxavalent vaccines combining hepatitis B (HepB), Haemophilus
      influenza type b (Hib), diphtheria, tetanus, and pertussis (acellular) (DTPa),
      and inactivated poliovirus (IPV) antigens were presented. Finally, the impact of
      the availability of combined hepatitis B vaccines on hepatitis B immunisation
      programmes in Europe were examined and the added value of combined hepatitis B
      vaccines globally was estimated.

PMID- 12615426
TI  - Protein vaccination with the HER2/neu extracellular domain plus anti-HER2/neu
      antibody-cytokine fusion proteins induces a protective anti-HER2/neu immune
      response in mice.
AB  - Previously protein vaccines consisting of the extracellular domain of HER2/neu
      (ECD(HER2)) were shown to elicit an immune response that does not provide
      protection against transplantable tumors expressing HER2/neu. Here, we showed
      that when mice were vaccinated with a mixture of human ECD(HER2) and anti-human
      HER2/neu IL-12, IL-2 or GM-CSF fusion proteins, significant retardation of the
      growth of a syngeneic carcinoma expressing rat HER2/neu, and long-term survivors
      were observed. Immune sera inhibited the in vitro growth of SK-BR-3, a human
      breast cancer overexpressing HER2/neu. Transfer of immune sera into mice
      challenged with TUBO also led to partial inhibition of tumor growth. Splenocytes
      from mice vaccinated with ECD(HER2) plus IgG3-(GM-CSF) incubated with ECD(HER2)
      demonstrated significant proliferation and IFN-gamma secretion. Taken together
      these results suggest that vaccines including ECD(HER2) and Ab-cytokine fusion
      proteins may be used to elicit both humoral and cell-mediated responses against
      HER2/neu.

PMID- 12615427
TI  - Protective effect of a naked DNA vaccine cocktail against lethal toxoplasmosis in
      mice.
AB  - BALB/c mice were intramuscularly immunized with low doses (25-50microg) of DNA
      cocktail containing plasmids encoding the full-length SAG1/P30 and the 196-561
      terminal sequence of ROP2 genes. This immunization resulted in a Th1-type
      response with predominance of IgG2a and a specific T-cell proliferation with high
      levels of interferon-gamma (IFN-gamma) secretion, whereas no IL-4 was detected.
      Moreover, DNA cocktail immunization induced a long-lasting protection against a
      lethal challenge with the highly virulent Toxoplasma gondii RH strain, whereas
      low doses of single genes were not protective. These results support further
      investigations to achieve a multigene anti-T. gondii DNA vaccine.

PMID- 12615428
TI  - Longevity of antibody and cytokine responses following vaccination with high
      potency emergency FMD vaccines.
AB  - The ability of high potency emergency foot-and-mouth disease (FMD) vaccines to
      promote sustainable immune responses in sheep and pigs following a single
      application was examined. All vaccine formulations induced a rapid seroconversion
      in both species, as expected, which was maintained at near peak titres for up to
      6 months in sheep and 7 months in pigs. The Montanide ISA 206 formulation gave
      the best results in sheep. Vaccinated pigs challenged with homologous FMDV were
      protected from disease at 7 months post vaccination. Systemic levels of cytokines
      IL-6, IL-8, and in some pigs IL-12, increased following vaccination and were
      often maintained at an increased level for the duration of the trials. These
      initial results suggest that high potency vaccines may promote longer lasting
      immunity than the conventional lower potency vaccines in ruminants and a
      comparable response in pigs. Results indicate that in an outbreak situation,
      should emergency vaccination be done with these high potency vaccines, protection
      should be conferred for a long enough period for the outbreak to be brought under
      control without the need to revaccinate. Given the increased interval for re
      vaccination the use of high potency vaccines for routine prophylactic campaigns
      could provide a more cost-effective and efficient means of maintaining herd
      immunity and is an area thus worthy of further examination.

PMID- 12615429
TI  - Adverse medical events in British service personnel following anthrax
      vaccination.
AB  - The safety of the UK anthrax vaccine in British service personnel was evaluated
      by a retrospective cohort study of randomly selected personnel from five Royal
      Air Force bases by investigating adverse medical events and consultation rates
      for a period before and after vaccination. Vaccination acceptance rate varied
      from 27 to 89% (P=0.0001). In the vaccinated cohort 11.1% (n=368) reported side
      effects. The number of consultations in the year prior to vaccination (P=0.04)
      and RAF base (P=0.0085) were associated with side-effects. Only the RAF base
      remained a statistically significant factor (P=0.007) after adjusting for other
      factors. The anthrax vaccine resulted in mild side-effects in 11%, and no serious
      side-effects were observed. Acceptors of vaccine did not have significantly more
      medical consultations following vaccination than their unvaccinated counterparts.

PMID- 12615430
TI  - Immunity to avian pneumovirus infection in turkeys following in ovo vaccination
      with an attenuated vaccine.
AB  - Fertile turkey eggs after 24 days of incubation were vaccinated in ovo with a
      commercial live attenuated subtype A avian pneumovirus (APV) vaccine.
      Hatchability was not adversely affected. When a high dose (10 times maximum
      commercial dose) of vaccine was tested in maternal antibody negative (MA-) eggs,
      mild clinical signs developed in a small proportion of the poults for 1-4 days
      only. Post-vaccination antibody titres at 3 weeks of age were significantly
      higher than those seen when the same dose was administered by eyedrop or spray at
      day-old. A low dose (end of shelf-life titre) of vaccine given to MA- eggs did
      not cause disease and vaccinated poults were 100% protected against virulent APV
      challenge at 3 or 5 weeks of age. Post-vaccination antibody titres reached
      significant levels at 3 weeks of age, whereas those from MA- poults vaccinated by
      spray at day-old with a similar low dose did not. In a 'worst-case' scenario,
      maternal antibody positive (MA+) poults vaccinated in ovo with the low dose were
      still 77% protected against clinical disease, despite lack of seroconversion. The
      recommended commercial dose of vaccine given to MA- eggs in ovo induced 100%
      protection against virulent APV challenge for up to 14 weeks of age, even though
      post-vaccination antibody titres had dropped to insignificant levels at this age.
      In ovo vaccination with a mixture of the recommended commercial doses of live APV
      and Newcastle disease (ND) vaccines had no detrimental affect on the efficacy of
      the APV vaccine. This is the first report of the successful use of an APV vaccine
      being given in ovo. The results indicate that for turkeys, in ovo vaccination
      with a live attenuated APV vaccine is safe and effective against virulent
      challenge and comparable with vaccination by conventional methods.

PMID- 12615431
TI  - Super-activated interferon-regulatory factors can enhance plasmid immunization.
AB  - We have been investigating the adjuvant properties of two super-activated
      interferon-regulatory factors (IRFs), IRF-3(5D) and IRF7/3A, identified in our
      previous studies of structure-function relationships, for enhancing plasmid
      vaccines. Intramuscular injection of plasmid cocktails encoding IRF-3(5D) and
      IRF7/3A molecules elicited cytotoxic T cell responses in over 80% of mice
      following a single immunization compared to a 20% response-rate using a control
      cocktail. Most interestingly, greater than 60% of mice immunized with the super
      activated IRFs developed antigen-specific antibodies compared to 0% of the mice
      in the control group. Finally, vaccines which incorporated the super-activated
      IRFs provided greater protection against challenge with a recombinant vaccinia
      virus. These results support further investigation of the potential of these
      agents as adjuvants for genetic immunization.

PMID- 12615432
TI  - Cold adapted avian pneumovirus for use as live, attenuated vaccine in turkeys.
AB  - We report the development of a cold adapted strain of avian pneumovirus (APV) and
      its evaluation as a live vaccine candidate in 2-week-old turkey poults. A US
      isolate of APV (APV/MN/turkey/1-a/97) was serially passaged in Vero cells for 41
      passages and then adapted to grow at sub-optimal temperatures by growing
      successively at 35, 33 and 31 degrees C for eight passages at each temperature.
      The virus thus adapted to grow at 31 degrees C was used as a candidate vaccine.
      The birds were vaccinated with two different doses of cold adapted virus and
      challenged with virulent virus 2 weeks after vaccination. No clinical signs were
      observed post-vaccination. Upon challenge, no clinical signs were seen in
      vaccinated birds but severe clinical signs were seen in non-vaccinated,
      challenged birds. The signs included unilateral or bilateral mucoid nasal
      discharge, watery eyes and swelling of infraorbital sinuses. The antibody levels
      in vaccinated birds were not very high. None of the vaccinated birds were found
      to shed virus after challenge in their choanal secretions whereas all of the non
      vaccinated, challenged birds shed the virus. The absence of clinical signs and
      virus shedding in vaccinated birds as compared to that in non-vaccinated birds
      suggests that the cold adapted strain of APV is a viable candidate for use as a
      live, attenuated vaccine in turkeys.

PMID- 12615434
TI  - Smallpox vaccination techniques. 2. Accessories and aftercare.
AB  - The various accessories used for smallpox vaccination are surveyed. These
      included modified vaccination instruments and various other items which
      facilitated the procedure, containers for preservation and transport of vaccine,
      sterilising equipment, aids to interpretation and recording, and a variety of
      skin preparations and dressings. Three phases can be discerned in the development
      and use of such items and procedures. Initially, in the pre-bacteriological era,
      there was little need for accessory equipment apart from the means of preserving
      and transporting vaccine. Later, particularly by the end of the 19th century, the
      importance of aseptic and antiseptic procedures was realised, use was made of
      more traumatic vaccination techniques and glass capillaries became the standard
      method for preservation and transport. All this led to the increasing
      availability of a wide range of accessories, particularly of skin preparations
      and dressings. Finally, from about 1930, it was appreciated that skin preparation
      and dressings were often unnecessary, and could be counter-productive. So,
      although accessories for this were still available their use was very much
      reduced. In some respects the use of accessories during this last phase, based on
      scientific analysis was a return to the earliest, 'pre-scientific', era.

PMID- 12615435
TI  - Improvement of the systemic prime/oral boost strategy for systemic and local
      responses.
AB  - This paper describes oral boost immunisations of primed animals as an alternative
      oral vaccination strategy. Mice were primed orally (PO), intranasally (IN),
      subcutaneously (SC), or intraperitoneally (IP) with ovalbumin (OVA) with or
      without adjuvant. Boost immunisations were given orally with or without cholera
      toxin (CT) as adjuvant. Prime immunisations induced variable IgA and IgG(1)
      titres in serum depending on the route. A subsequent oral boost increased these
      titres. Use of an adjuvant in the priming significantly increased serum IgA and,
      to a lesser extend, IgG(1). Oral boost immunisation induced significantly higher
      serum IgA titres in animals primed via the SC, IP and the IN route compared to
      the PO route. This was independent of the use of CT. Three oral boosts with OVA
      plus 5 microg CT given in 5 days to primed mice revealed higher IgA titres
      compared to single oral boosts and anti-OVA IgA titres in faeces were also
      detected. Finally, we put together our findings and propose a systemic
      priming/oral boost strategy in which mice were primed via the SC route with 100
      microg OVA plus 50 microg Butyl16-p(AA), and subsequently orally boosted with
      three doses of 300 microg OVA plus 5 microg CT each. We concluded that oral
      immunisation is more effective in IN, SC, or IP primed mice than in PO primed
      mice, and that the IgA antibody response in serum and faeces can be improved by
      increasing the immunisation frequency and the use of appropriate adjuvants in
      primary and boost immunisation. The here-formulated strategy improves the
      probability of success of oral vaccination. The results are discussed in the
      light of the development of edible vaccines.

PMID- 12615433
TI  - Protection against a European H1N2 swine influenza virus in pigs previously
      infected with H1N1 and/or H3N2 subtypes.
AB  - A novel swine influenza virus, H1N2, circulates in European swine populations
      together with H1N1 and H3N2 viruses. This study examines whether post-infection
      immunity to H1N1 and/or H3N2 viruses provides cross-protection against H1N2
      infection. Pigs (n=51) were inoculated intranasally with either Sw/Belgium/1/98
      (H1N1) or Sw/Flanders/1/98 (H3N2), or with both viruses at a 5-week interval.
      Control groups were left uninoculated or inoculated with Sw/Gent/7625/99 (H1N2).
      Four weeks later, all the pigs were challenged intranasally and intratracheally
      with a high H1N2 virus dose. The challenge control pigs showed typical influenza
      symptoms, and all had high H1N2 virus titres in the lungs and nasal virus
      excretion during 6 or 7 days. The H1N2-immune pigs showed total clinical and
      virological protection. Pigs immune against H1N1 or H3N2 only were not protected
      against disease and virus replication in the lungs, but virus excretion was 2
      days shorter. By contrast, pigs immune against both H1N1 and H3N2 did not show
      disease and H1N2 virus replication was either undetectable or markedly reduced.
      Haemagglutination inhibition (HI) and virus neutralisation (VN) tests indicated
      that cross-protection against H1N2 was probably not mediated by antibodies
      against the haemagglutinin (HA). Antibodies inhibiting the neuraminidase (NA) of
      H1N2 were at minimal levels in H3N2 only-immune pigs, but they were consistently
      found in (H1N1+H3N2)-immune pigs. The immune response against the internal
      proteins, which are relatively conserved in H1N1, H3N2 and H1N2 viruses, may play
      a significant role in protection against H1N2. Given the severe challenge model
      used here, cross-protection against H1N2 could be more pronounced under natural
      conditions of infection.

PMID- 12615436
TI  - Chitosan microparticles for mucosal vaccination against diphtheria: oral and
      nasal efficacy studies in mice.
AB  - In this study, the ability of chitosan microparticles to enhance both the
      systemic and local immune responses against diphtheria toxoid (DT) after oral and
      nasal administration in mice was investigated.Firstly, DT was associated to
      chitosan microparticles to determine antigen loading and release. Then DT loaded
      chitosan microparticles, DT in phosphate buffered saline (PBS) and empty chitosan
      microparticles (as controls) were fed intragastrically and administered nasally
      to mice. Mice were also subcutaneously immunised with DT associated with alum.
      All mice were vaccinated in week 1 and boosted in week 3. Sera were analysed for
      anti-DT IgG and nasal washings and faeces for anti-DT IgA titres using an enzyme
      linked immunosorbent assay. Loading capacities of about 25% and loading
      efficacies of about 100% were obtained after loading the chitosan microparticles
      with DT. No DT was released at 37 degrees C in PBS. Compared to intragastrical
      feeding with DT in PBS, a strong enhancement of the systemic and local immune
      responses against DT were found in mice fed with DT loaded chitosan
      microparticles. In addition, a dose-dependent immune reaction was observed for
      mice vaccinated with different doses of DT associated to chitosan microparticles.
      Significant systemic humoral immune responses were also found after nasal
      vaccination with DT associated to chitosan microparticles.DT associated to
      chitosan microparticles results in protective systemic and local immune response
      against DT after oral vaccination, and in significant enhancement of IgG
      production after nasal administration. Hence, these in vivo experiments
      demonstrate that chitosan microparticles are very promising mucosal vaccine
      delivery systems.

PMID- 12615437
TI  - Development of a foot-and-mouth disease NSP ELISA and its comparison with
      differential diagnostic methods.
AB  - The gene encoding the nonstructural protein (NSP) of O/SKR/2000 foot-and-mouth
      disease virus (FMDV) was constructed to express under the polyhedron promoter of
      baculovirus. The expression of NSP was confirmed by indirect immunofluorescence
      assay (IFA) and Western blotting. The expressed NSP was applied as a diagnostic
      antigen for indirect-trapping ELISA (I-ELISA). An I-ELISA using monoclonal
      antibody (Mab) against 3A as trapping antibody was developed to differentiate
      infected from vaccinated cattle. The diagnostic efficiency of Mab linked I-ELISA
      was compared and evaluated with baculovirus expressed 3ABC I-ELISA from USDA and
      Mab (3A) linked E. coli expressed 3ABC I-ELISA from IZSLE through retrospective
      sero-surveillance. Compared with the two different I-ELISA methods, Mab (3A)
      linked I-ELISA using baculovirus expressed NSP showed the same level of
      sensitivity and specificity, indicating that this method is suitable for a
      differential diagnostic method in cattle.

PMID- 12615438
TI  - Protective immunity against pasteurellosis in cattle, induced by Pasteurella
      haemolytica ghosts.
AB  - Pasteurella haemolytica is a cattle pathogen of significant economic impact. An
      effective vaccine against bovine pneumonic pasteurellosis is therefore of high
      importance. Apart from economic concerns, pasteurellosis caused by P. haemolytica
      is a serious disease leading to death in cattle if it remains untreated. In this
      study P. haemolytica-ghosts are presented as a promising vaccine candidate in
      cattle. To obtain sufficient vaccination material a fermentation protocol for P.
      haemolytica-ghost production was established. With the obtained experimental P.
      haemolytica-ghost vaccine, cattle immunization studies were performed based on a
      Pasteurella cattle challenge model developed specifically for vaccine validation.
      It was shown that protective immunization of cattle against homologous challenge
      was induced by adjuvanted P. haemolytica-ghosts. The level of protection was
      similar to a commercially available vaccine.

PMID- 12615439
TI  - Vaccines for children: policies, politics and poverty.
AB  - The dawn of the 21st century ushered in spectacular advances in vaccine
      production technology. However, the benefits of these developments have been
      largely confined to the world's most affluent and least afflicted. Of the 14
      million deaths that occur world-wide in children aged less than 5 years, over 95%
      of these occur in developing countries and at least 70% are caused by infections
      for which vaccines are already available in other countries. While impoverished
      countries do not have a right to be assisted with the provision of funds or
      vaccines by affluent developed countries, an initiative for the global
      eradication of a vaccine preventable disease, requires a global effort. Assisting
      developing countries to achieve such goals should be a high priority for wealthy
      nations, even if only to protect their own populations. With improved
      international travel, not only can newly emerging diseases spread across the
      globe, but pathogens eliminated from one population can be re-imported by
      travellers or immigrants. In contrast, the recent decline in acceptance of
      immunisation programmes in developed countries are secondary to strong anti
      vaccine movements attributing unproven adverse reactions to vaccines, placing
      these life-saving vaccines into disrepute. A fertile ground for propagation of
      these ideologies is created by parents who in their lifetime may not have seen a
      child killed or maimed from bacterial meningitis or measles and therefore have
      little understanding of the risk-benefit of vaccination. The development and
      deployment of vaccines must be a global effort as are the treaties for global
      disarmament for weapons of mass destruction.

PMID- 12615440
TI  - Gene gun-based co-immunization of merozoite surface protein-1 cDNA with IL-12
      expression plasmid confers protection against lethal Plasmodium yoelii in A/J
      mice.
AB  - The carboxyl-terminal region of the merozoite surface protein-1 (MSP1) is a
      leading candidate for a vaccine against malaria in the erythrocytic stage. In
      this study, we investigated the utility of interleukin-12 (IL-12) cDNA as an
      adjuvant for malaria DNA vaccine in a mouse challenge model. We found that co
      immunization of expression plasmids encoding a C-terminal 15-kDa fragment of MSP1
      (MSP1-15) with the IL-12 gene using a gene gun significantly increased the
      protective immunity against malaria as compared with MSP1-15 DNA immunization
      alone. Co-immunization of IL-12 DNA potentiated MSP1-15-specific T helper (Th)1
      type immune responses as evaluated by in vivo antibody (Ab) responses and in
      vitro cytokine profiles. After the Plasmodium yoelii challenge, mice immunized
      with MSP1-15 plus IL-12 DNA showed a higher level of interferon gamma (IFN-gamma)
      production than did other groups of mice. In vivo neutralization of IFN-gamma or
      depletion of CD4(+) T cells completely abolished this protective immunity.
      Macrophages, but not nitric oxide (NO), were found to play an important role in
      this effector mechanism. The sera from mice in which the infection had been
      cleared by the vaccination showed strong protection against P. yoelii infection.
      Thus, in addition to cellular immune responses, Abs against parasites induced in
      the course of infection are essential for protection against P. yoelii. The
      results indicate that combined vaccination with DNA encoding antigenic peptides
      plus IL-12 DNA provides a strategy for improving the prophylactic efficacy of a
      vaccine for malaria infection.

PMID- 12615441
TI  - Modulation of dendritic cell endocytosis and antigen processing pathways by
      Escherichia coli heat-labile enterotoxin and mutant derivatives.
AB  - Escherichia coli heat-labile enterotoxin (LT) is known to be a potent adjuvant of
      both the mucosal and systemic immune systems but the mechanism of action leading
      to adjuvant activity remains incompletely understood. This study investigates the
      action of LT and LT mutants with impaired enzymatic activity, on the function of
      dendritic cells. Wild-type LT and LTR72, which retains some ADP
      ribosyltransferase activity, induced a selective increase in cell surface
      expression of B7.1, and a selective decrease of CD40 expression on mouse bone
      marrow derived dendritic cells. LTK63 and LT-B had no obvious effect on the
      expression of these antigens on similar dendritic cells. LT-treated dendritic
      cells also showed a profoundly impaired ability to present protein antigen
      (ovalbumin) to cognate T cells, although this effect was not observed with non
      toxic LT mutants. LT and LTR72-treated cells showed a slower rate of receptor
      mediated endocytosis as measured by flow cytometric analysis of uptake of
      fluorescently labelled dextran. Furthermore, confocal microscopy showed changes
      in the intracellular distribution of endocytosed molecules, and of the class II
      containing acidic antigen processing compartments. This response of dendritic
      cells to toxin is likely to play an important role in determining the adjuvant
      activity of these molecules.

PMID- 12615442
TI  - Immunization with the Chlamydia trachomatis major outer membrane protein, using
      the outer surface protein A of Borrelia burgdorferi as an adjuvant, can induce
      protection against a chlamydial genital challenge.
AB  - Two strains of mice C3H/HeN (H-2(k)) and BALB/c (H-2(d)) were immunized with the
      Chlamydia trachomatis mouse pneumonitis (MoPn) major outer membrane protein
      (MOMP) using the Borrelia burgdorferi outer surface protein A (OspA) as an
      adjuvant. As a control, groups of mice were inoculated with ovalbumin instead of
      MOMP. Female mice were immunized using three different routes: intramuscular
      (i.m.) plus subcutaneous (s.c.), intranasal (i.n.) and perivaginal and perisacral
      (p.vag.+p.sac.). Significant humoral and cell mediated immune responses developed
      particularly in mice inoculated by the i.m.+s.c. routes as determined by the
      levels of chlamydial specific antibody in the serum and genital secretions and a
      T-cell proliferative assay. Following immunization the animals were challenged in
      the genital tract with C. trachomatis MoPn and the course of the infection
      followed by vaginal cultures. Significant protection against infection was
      achieved in the C3H/HeN mice inoculated i.m.+s.c. with MOMP+OspA, as shown by the
      intensity and duration of vaginal cultures, and by the number of mice with
      positive cultures. On the other hand in BALB/c mice there was only a decrease in
      the number of animals with positive vaginal cultures. Six weeks after the
      challenge the mice were mated and the outcome of the pregnancy evaluated. In both
      the C3H/HeN and the BALB/c mice immunized i.m.+s.c. with MOMP+OspA there was
      significant protection against infertility as shown by the number of animals with
      bilateral fertility and number of embryos per uterine horn. In conclusion,
      immunization using C. trachomatis MOMP, and B. burgdorferi OspA as an adjuvant,
      can induce significant protection against a chlamydial genital challenge.

PMID- 12615443
TI  - Innate immune responses following emergency vaccination against foot-and-mouth
      disease virus in pigs.
AB  - Inactivated "emergency" foot-and-mouth disease virus (FMDV) vaccine of high
      potency will induce early protection against the disease, implying a critical
      role for innate immune defences. At 3 and 6 days post-vaccination (dpv), there
      was no evidence of vaccine-induced specific anti-FMDV antibodies (Abs), nor
      enhanced uptake and destruction of opsonised virus by macrophages. Sera from
      vaccinates and control animals showed similar capacity to neutralise the virus,
      and were not different from the pre-vaccination sera. There were also no
      distinguishable changes in the distribution of the different peripheral blood
      leucocyte (PBL) subpopulations. Nor was any vaccine-induced increase in
      production of acute phase proteins noted. In contrast, chemotaxis assays
      identified an increase in PBL migratory activity which was vaccine-related.
      Furthermore, sera from 3 days post-vaccination contained elevated chemotactic
      potential. These results demonstrate that enhanced chemotaxis of cells of the
      innate immune defences, could play an important role during the early protection
      induced by emergency FMDV vaccines.

PMID- 12615444
TI  - Nasal delivery of chitosan-DNA plasmid expressing epitopes of respiratory
      syncytial virus (RSV) induces protective CTL responses in BALB/c mice.
AB  - Respiratory syncytial virus (RSV), an important pathogen of the lower respiratory
      tract, is responsible for severe illness both in new born and young children and
      in elderly people. Due to complications associated with the use of the early
      developed vaccines, there is still a need for an effective vaccine against RSV.
      Most pathogens enter the body via mucosal surfaces and therefore vaccine delivery
      via routes such as the nasal, may well prove to be superior in inducing
      protective immune responses against respiratory viruses, since both local and
      systemic immunity can be induced by nasal immunisation. Previously we have shown
      that intradermal immunisation of a plasmid DNA encoding the CTL epitope from the
      M2 protein of RSV induced protective CTL responses. In the present study, the
      mucosal delivery of plasmid DNA formulated with chitosan has been investigated.
      Chitosan is a polysachharide consisting of copolymers of N-acetylglucosamine and
      glucosamine that is derived from chitin, a material found in the shells of
      crustacea. Intranasal immunisation with plasmid DNA formulated with chitosan
      induced peptide- and virus-specific CTL responses in BALB/c mice that were
      comparable to those induced via intradermal immunisation. Following RSV challenge
      of chitosan/DNA immunised mice, a significant reduction (P<0.001) in the virus
      load was observed in the lungs of immunised mice compared to that in the control
      group. These results indicate the potential of immunisation with chitosan
      formulated epitope-based vaccines via the intranasal route.

PMID- 12615445
TI  - Sensitivity and specificity of patient self-report of influenza and pneumococcal
      polysaccharide vaccinations among elderly outpatients in diverse patient care
      strata.
AB  - National surveys of adult vaccination indicate moderate self-reported
      immunization rates in the US, with limited validity data. We compared self-report
      with medical record abstraction for 820 persons aged > or =66 years from inner
      city health centers, Veterans Affairs (VA) outpatient clinics, rural and suburban
      practices. For influenza vaccine, sensitivity was 98% (95% CI: 96-99%);
      specificity was 38% (95% CI: 33-43%). For pneumococcal polysaccharide vaccine,
      sensitivity was 85% (95% CI: 82-89%) and specificity was 46% (95% CI: 42-50%).
      The VA had the highest sensitivity and lowest specificity for both vaccines while
      the converse was true in inner-city centers. High negative predictive values
      indicate that clinicians can confidently vaccinate based on negative patient self
      report.

PMID- 12615446
TI  - Identification of protective antigens for the control of Ixodes scapularis
      infestations using cDNA expression library immunization.
AB  - Identification of antigens that induce an immune response against tick
      infestations is required for the development of vaccines against these
      economically important ectoparasites. In order to identify protective antigens,
      we constructed a cDNA expression library from a continuous Ixodes scapularis cell
      line (IDE8) that was initially derived from tick embryos. cDNA clones were
      subjected to several rounds of screening in which mice were immunized with
      individual pools and then challenge-exposed by allowing I. scapularis larvae to
      feed on the immunized and control mice. Immunity against tick infestation was
      determined by the reduction in the ability of the larvae to feed to repletion and
      molt to the nymphal stage. Individual clones in pools that induced immunity to
      larval infestations were partially sequenced and grouped according to their
      putative protein function by comparison with sequence databases. The screening
      identified several individual antigens that induced a protective immune response
      against I. scapularis infestations. Our studies demonstrated for the first time
      that cDNA expression library immunization (ELI) combined with sequence analysis
      is a powerful and efficient tool for identification of candidate antigens for use
      in vaccines against ticks.

PMID- 12615447
TI  - Induction of specific T-helper and cytolytic responses to epitopes displayed on a
      virus-like protein scaffold derived from the pyruvate dehydrogenase multienzyme
      complex.
AB  - The icosahedral protein scaffold (1.5MDa) generated by self-assembly of the
      catalytic domains of the dihydrolipoyl acetyltransferase core of the pyruvate
      dehydrogenase multienzyme complex from Bacillus stearothermophilus has been
      engineered to display 60 copies of one or more peptide epitopes on a single
      molecule (E2DISP). An E2DISP scaffold displaying pep23, a 15-residue B- and T
      helper epitope from the reverse transcriptase of HIV-1, was able to induce a
      pep23-specific T-helper response in cell lines in vitro. The same scaffold
      displaying both pep23 and peptide RT2, a nine-residue CTL epitope from HIV-1
      reverse transcriptase, was able to prime an RT2-specific CD8(+) T-cell response
      in human cell lines in vitro and in HLA-A2 transgenic mice in vivo. This was
      accompanied by a humoral antibody response specific for E2DISP-presented
      epitopes. Thus, the icosahedral acetyltransferase core constitutes a simple and
      flexible scaffold for multiple epitope display with access to both cellular and
      humoral immune response pathways.

PMID- 12615448
TI  - Barriers and facilitators of pneumococcal vaccination among the elderly.
AB  - Despite the burden of disease caused by pneumococcus, adult immunization rates
      are modest. To understand barriers in diverse settings, we surveyed patients age
      > or =66 years at: (1) inner-city health centers; (2) Veterans Affairs (VA)
      outpatient clinics; (3) rural practices; and (4) suburban practices. Among the
      1007 respondents, self-reported pneumococcal vaccination rates were: 85% VA; 62%
      rural; 66% suburban; and 57% inner-city with substantial variability among
      practices. Half of the unvaccinated (50%) did not know they needed vaccination.
      Most vaccinees (90%) thought that their doctor believed they should be
      vaccinated, compared with 23% of the unvaccinated (P<0.0001). More of the
      vaccinees (75%) believed that the vaccine "keeps a person from getting pneumonia"
      than the unvaccinated (54%; P=0.0001). In regression analysis, predictors of
      vaccination included: belief that doctor recommends vaccine, feeling that
      vaccination is wise, recommendation by someone in the physician's office, and
      receipt of influenza vaccine.

PMID- 12615449
TI  - Immune responses of elk to Mycobacterium bovis bacillus Calmette Guerin
      vaccination.
AB  - Although rare, detection of Mycobacterium bovis infection of captive or free
      ranging elk (Cervus elaphus) elicits serious concern due to regulatory and
      zoonotic implications. Few studies, however, have evaluated the immune response
      of elk to M. bovis or other pathogens. To model natural infection, elk were
      vaccinated with live M. bovis bacillus Calmette Guerin (BCG, Pasteur strain) for
      evaluation of immune responsiveness to this attenuated live vaccine. Peripheral
      blood mononuclear cells (PBMC) of vaccinated elk proliferated in response to
      stimulation with a soluble mycobacterial antigen preparation (i.e. M. bovis
      purified protein derivative, PPDb). Greater numbers of sIgM(+) cells (i.e. B
      cells) proliferated in this response than did either CD4(+), gammadeltaTCR(+) or
      CD8(+) cells. The in vivo response (i.e. delayed type hypersensitivity, DTH) to
      PPDb by vaccinated elk exceeded both the response by non-vaccinated elk and BCG
      vaccinated cattle at 24, 48, and 72h post-administration of PPD. In vivo
      responses to PPDb by vaccinated elk diminished after 72h as compared to responses
      at 24 and 48h. Serum was also collected periodically and evaluated by ELISA for
      immunoglobulin (i.e. IgG heavy and light chains) reactivity to crude
      mycobacterial antigens. Two weeks post-vaccination and throughout the duration of
      the study, serum immunoglobulin reactivity to PPDb and to a proteinase K-digested
      whole cell sonicate of BCG exceeded that of serum from non-vaccinated elk.
      Intradermal administration of PPD for measurement of hypersensitive responses
      boosted the serum antibody response. These findings demonstrate that BCG
      vaccination of elk induces a serum antibody response to crude M. bovis antigens,
      a B cell in vitro proliferative response, and in vivo trafficking of mononuclear
      cells to sites of mycobacterial antigen administration (i.e. delayed type
      hypersensitivity). A predominant B cell in vitro proliferative response by elk
      PBMC to crude mycobacterial test antigens will likely impact the development of
      improved diagnostic tests of tuberculosis infection for this species.

PMID- 12615450
TI  - Rectal immunization of mice with hepatitis A vaccine induces stronger systemic
      and local immune responses than parenteral immunization.
AB  - Systemic (spleen cell (SPLC), serum antibodies) and intestinal mucosal (Peyer's
      patch cells (PPC), lamina propria lymphocytes (LPLs), coproantibodies) immune
      responses were compared in mice immunized with varying doses (144, 72, 36, 18
      ELISA units [EU]) of HAVRIX, an alum-adsorbed killed hepatitis A virus (HAV)
      vaccine, delivered either intrarectally (i.r.) or intraperitoneally (i.p.) in
      three doses at weekly intervals. HAV-specific IgG, IgM, and IgA antibody
      responses were evaluated by ELISPOT and EIA and HAV-responsive lymphocytes by
      lymphocyte stimulation assays. Systemic IgG responses were greater in mice
      immunized intraperitoneally with 144, 72, and 36EU of HAVRIX, while IgM and IgA
      responses were greater in PPC and LPL cell populations, serum and coproantibodies
      of rectally immunized mice, particularly at HAVRIX doses of 36 and 18EU. Rectal
      immunization at lower doses (36, 18EU) also elicited strong cellular responses in
      all cell populations while parenteral (i.p.) vaccination, did not. Results
      suggest that rectal immunization may be a highly effective way of inducing both
      local and systemic immunity to HAV.

PMID- 12615451
TI  - Effect of vaccine delivery system on the induction of HPV16L1-specific humoral
      and cell-mediated immune responses in immunized rhesus macaques.
AB  - There have been numerous studies to assess the immunogenicity of candidate
      therapeutic and prophylactic vaccines for human papillomavirus (HPV), but few of
      them have directly compared different vaccines in an immunologically relevant
      animal system. In the present study, several vaccine delivery systems (VLPs,
      chimeric VLPs, plasmid DNA, and a replication incompetent adenoviral vector)
      expressing HPV16L1 were evaluated for their ability to induce HPV16L1 VLP
      specific humoral immune responses, including neutralizing antibodies, and cell
      mediated immune responses in rhesus macaques. Monkeys immunized with HPV16L1 VLPs
      mounted a potent humoral response with strongly neutralizing antibodies and a
      strong L1-specific Th2 response as measured by IL-4 production by CD4+ T cells.
      Monkeys immunized with plasmid DNA or an adenoviral vector expressing HPV16L1
      showed strong Th1/Tc1 responses as measured by IFN-gamma production by CD4+
      and/or CD8+ T cells and potent humoral responses, but only weakly neutralizing
      antibodies. These data demonstrate that the nature of the immune response against
      HPV16L1 is dramatically different when it is introduced via different delivery
      systems. Additionally, these findings support the notion that an HPV16L1 VLP
      based vaccine will induce the strongly neutralizing antibodies necessary for
      effective prophylaxis.

PMID- 12615452
TI  - The role of lipopolysaccharide in T-cell responses following DNA vaccination.
AB  - Bacterial products, including lipopolysaccharide (LPS), are potential impurities
      in plasmid DNA vaccines. LPS has immunostimulatory properties even at exceedingly
      low concentrations through activation of Toll-like receptor 4 (TLR4). The potency
      of T-cell responses after vaccination was tested with DNA containing high LPS or
      depleted of LPS in TLR4-competent and TLR4-deficient mice. CD8(+) T-cell
      responses were readily induced in TLR4-deficient mice immunized with DNA depleted
      of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses.

PMID- 12615453
TI  - Non-interference between two protein carriers when used with the same
      polysaccharide for pneumococcal conjugate vaccines in 2-year-old children.
AB  - The carriers tetanus toxoid (T) and diphtheria CRM-197 (C) were compared in
      conjugate vaccines using identical coupling chemistry and polysaccharide (PS)
      loading, for safety and immunogenicity in 2-year-old children. Also tested were a
      mixture of halved doses of both carriers bearing the same PS serotypes. For this
      study, PS types 6A, 14, 19F, and 23F (separately) were coupled to T or C by
      reductive amination at PS/protein ratios of 0.50+/-0.18. With each carrier the
      four PS types were combined, giving the tetravalent vaccines "T-6, -14, -19, -23"
      or "C-6, -14, -19, -23" containing 50 microg of the carrier and roughly 20 microg
      total PS per ml of saline (no adjuvant). The children received primary (1')
      injections of 50 microg (protein) of either vaccine or a mixture of 25 microg of
      both; identical secondary (2') injections were given 2 months afterwards. Sera
      were taken before the 1' and 2' and 1 month post-2', and serum IgG responses to
      the four PS were determined by ELISA. For geometric mean (GM) post-1' antibody,
      "C-6, -14, -19, -23" exceeded "T-6, -14, -19, -23" for type 19F; for 2' antibody,
      "T-6, -14, -19, -23" exceeded "C-6, -14, -19, -23" for type 14, but "C-6, -14, 
      19, -23" and the T/C mixture exceeded "T-6, -14, -19, -23" for the type 23F
      response. No other differences were significant. Analyzed by individual fold
      rises, "C-6, -14, -19, -23" and the T/C mixture exceeded "T-6, -14, -19, -23" for
      types 19F and 23F. Thus, there was no consistent difference between the T and C
      carriers; rather, the results differed by serotype. When a mixture of halved
      doses of "T-6, -14, -19, -23" and "C-6, -14, -19, -23" was injected, neither
      negative nor positive interference with the PS antibody responses was found.
      Anticipating multivalent PS conjugate vaccines of the future to be used in
      infancy, this strategy would have two hypothetical advantages worth further
      investigation-avoiding "carrier epitopic overload" by reducing each carrier
      dosage and recruiting T-helper activity by both carriers for each PS.

PMID- 12615454
TI  - Prognostic indicators and burns.

PMID- 12615455
TI  - The effect of burn plasma on skeletal muscle proteolysis in rats.
AB  - We studied the effects of plasma from burned rats on skeletal muscle proteolysis.
      Major burn injury (40% total body surface area (TBSA)) was produced in male
      Sprague-Dawley rats. Fluid resuscitation was given with intraperitoneal Ringer's
      solution (4cm(3)/(kg%) TBSA). Plasma was harvested daily for 5 days after burn
      injury from the tail blood vessel. This plasma was added in vitro to incubated
      soleus muscles from healthy animals. The incubation medium was assayed for amino
      acids by HPLC. Glutamine, glutamate, leucine and alanine were tested to monitor
      the amino acid profile in the medium. Results showed there was no significant
      change during the initial 4 days after injury, except that glutamine and alanine
      increased significantly on the first day. However, all of them had a tendency to
      increase on the fifth day after injury. Present results suggest that the humoral
      effect on muscle proteolysis did not exist during the initial days after burning.
      The humoral effect on skeletal muscle proteolysis may have been present 5 days
      post-burn.

PMID- 12615456
TI  - Dissociation between gene expression and protein contents of tissue superoxide
      dismutase in a rat model of lethal burns.
AB  - The aim of this study was to examine the changes in the tissue Cu/Zn- and the Mn
      SOD contents and gene expression following mild and severe burns in a rodent burn
      model. Thirty-eight male Wistar rats, weighing 208-278g, were divided into a sham
      burn group and two burn groups, with one receiving burns to 35% of the body
      surface and the other to 60%. Twenty animals of the burn groups were monitored
      daily for 7 days after injuries to examine survival. Six animals in the sham, 35
      or 60% burn group were sacrificed at 3h postburn, and the blood, lungs and
      kidneys were collected for a biological analysis. The Cu/Zn- and Mn-SOD contents
      of the tissue and plasma specimens were measured using ELISA. The mRNA
      expressions of Cu/Zn- and Mn-SOD were determined by a Northern blot analysis. The
      survival rate of the 60% burn group for 7 days was 30%, whereas the survival rate
      of the 35% burn group was 100%. The mRNA expressions of Mn-SODs in the lung and
      the kidney were significantly higher in the 60% burn group than in 35% burn or
      sham burn group, as was the mRNA expression of lung Cu/Zn-SOD. Nevertheless, the
      tissue SOD contents in the 60% burn group (mortality 70%) did not exceed those in
      the 35% group. Based on these findings, tissue SOD synthesis is thus suggested to
      be inhibited in lethal burns in spite of a strong mRNA expression of SOD.

PMID- 12615457
TI  - Peripheral blood lymphocytes immunophenotype and serum concentration of soluble
      HLA class I in burn patients.
AB  - The level of the soluble form of histocompatibility class I antigens, associated
      with beta(2)-microglobulin (sHLA-I) has been determined by an ELISA sandwich
      method in serum from burned patients (n=42) and healthy volunteers (n=30). The
      sHLA-I level was insignificantly increased in burn patients at the stage of burn
      shock (1284+/-324U/ml, mean+/-S.E.M.) and after day 28 postburn (1368+/-258U/ml)
      compared to volunteers (1150+/-90U/ml). At the same time a decrease of sHLA-I
      levels between 4 and 14 days (638+/-178U/ml) was determined (P<0.05). Increased
      levels of sHLA, though not significant, were detected in patients with TBSAB >70%
      in comparison to patients with TBSAB from 30 to 70% during burn shock (1493+/-528
      and 1075+/-339U/ml, respectively). Expression of membranous HLA class I antigens
      (mHLA-I) in peripheral blood lymphocytes (PBLs) was assayed simultaneously by
      indirect immunofluorescence. The number of CD3(+), CD4(+), CD8(+), CD25(+),
      CD71(+) and CD26(+) lymphocytes was also evaluated. The expression of mHLA-I in
      PBLs was increased significantly in patients with TBSAB <70% at early postburn
      period. Daily monitoring showed that the relative numbers of CD25(+) and CD71(+)
      lymphocytes in patients varied greatly within short intervals of time during burn
      shock. The data obtained suggest that mHLA-I expression can reflect postburn
      lymphocyte activation. The serum content of sHLA-I does not depend on lymphocyte
      number or activated lymphocyte number in peripheral blood at burned patients.

PMID- 12615458
TI  - Changing trends in bacteriology of burns in the burns unit, Delhi, India.
AB  - A retrospective study of bacterial isolates from the wounds of patients admitted
      to burns unit, was undertaken at Guru Tegh Bahadur Hospital, University College
      of Medical Sciences, Delhi, India, over a period of 5 years between July 1997 and
      April 2002. The study compared the results obtained with the previous 5 years
      data (June 1993-June 1997) from the same unit to determine the changing patterns
      and emerging trends of bacterial isolates and their antimicrobial
      susceptibilities. Pseudomonas species (31%) and Staphylococcus aureus (22%) were
      the most common pathogens followed by Klebsiella species (19%). Multi-drug
      resistant (MDR) Acinetobacter species (9%) have emerged as an important
      nosocomial pathogen in our burn unit. Most of the gram-negative isolates obtained
      were found to be multi-drug resistant and 61% of the tested isolates were
      extended spectrum beta-lactamase (ESBL) producers. Concomitant resistance to
      penicillin and aminoglycosides was observed in 61% of Enterococcus fecalis
      isolates. When compared with the results of previous 5 years (June 1993-June
      1997) Pseudomonas spp. was still the commonest pathogen in the burns unit.
      However, isolation of this organism and other gram-negative organisms has
      decreased in comparison to previous years. The incidence of antimicrobial
      resistance has markedly increased over the past years resulting in limitation of
      therapeutic options.

PMID- 12615459
TI  - Escherichia coli endotoxin enhances acute renal failure in rats after thermal
      injury.
AB  - This study was designed to evaluate the burned rat model to determine whether
      there are any differences in endotoxin-sensitive kidney functions between an
      infant rat (10-day-old pup) and an adult rat (10-week-old rat). Renal failure was
      observed in the infant burned rat and histological changes showed the adhesion of
      inflammatory cells in the glomerular capillaries and vacuolar changes in the
      renal proximal tubular cell. A horseradish peroxidase (HRP) tracer experiment
      suggested that the intestinal barrier damage of the infant burned rat was more
      severe than that of the adult burned rat. Therefore, more bacterial translocation
      of the intestinal flora, rich in endotoxin, might be expected in the infant
      versus the adult rats. Renal failure was not observed in the adult burned rat, so
      we investigated to determine the effects of endotoxin on the kidney function of
      the adult burned rat with low lethal lipopolysaccharide (LPS) or carrageenan
      (CAR). CAR is known to increase sensitivity to the lethal effects of endotoxin in
      rodents. Our present data demonstrated that renal failure was observed in the LPS
      or CAR-treated adult burned rat and LPS- and CAR-treated adult rat (non-burned).
      These results show the possibility that endotoxin enhances renal failure in a
      burned rat model and provide additional support for the hypothesis that postburn
      renal failure is mediated, in part, by endotoxin associated with bacterial
      translocation.

PMID- 12615460
TI  - Phantom limb pain in pediatric burn survivors.
AB  - Phantom limb sensation and pain are reported by youth following amputations.
      While youth survivors of severe burns may require amputation as a part of their
      treatment, the authors are unaware of any descriptions as to the rates and
      features of phantom limb sensation and pain in this population. A retrospective
      chart review of all youth that were admitted to a burn care unit over the past 30
      years and received amputations as part of their treatment was conducted to
      describe the rate of phantom sensation and pain. In the 34 patients with major
      limb amputations, phantom limb pain occurred at a rate similar to that reported
      in other studies and was an important issue in their care. Patients with
      amputations following electrical burn injury had a significantly higher rate of
      phantom limb pain than those with amputations following flame burn injury.

PMID- 12615461
TI  - Psychosocial adjustments 5 years after burn injury.
AB  - The present study investigates factors influencing the quality of life and social
      reintegration of burn victims. A study concept was developed to assess the
      functional and aesthetic long-term outcomes of burn victims. Objective data from
      a clinical examination was correlated with subjective data from completed
      questionnaires. The success of social rehabilitation was documented and an
      indicative profile of life quality evaluated. This profile could prompt early
      intervention if found necessary. Ninety-two patients were examined 5.4+/-1.1
      years after trauma in relation to three factors: physical functions, localization
      of the burn injuries and extent of the body surface area burned. Physical
      functioning allows the best predictions for successful rehabilitation, because
      all areas of life quality are affected by it. Localization of burns in the face
      and hands creates disadvantages in social reintegration. Of less value in
      prediction is the extent of the body surface area burned, which is only closely
      linked to occupational rehabilitation and directly correlates to physical
      functional limitations. Our correlation showed, that even slight functional
      limitations were linked to severe depressions, similar to the values found with
      patients with serious functional impairment. Interdisciplinary cooperation
      between plastic surgeons and psychosomatic specialists will optimize early
      intervention with patients exposed to social maladaptation.

PMID- 12615462
TI  - An evaluation of functional improvement following surgical corrections of severe
      burn scar contracture in the axilla.
AB  - This report present an evaluation 13 consecutive cases of severe burn scar
      contracture of the axilla and investigates the factors that influence functional
      improvement. The operation was performed at various times during the period from
      3 months to 63 years after the initial burn wound healed. The active range of
      shoulder abduction before the operation in these patients was restricted to 30-90
      degrees. The scar contractures in the axilla were released in all cases and the
      defects of the axillary region were covered with musculocutaneous flaps or
      fasciocutaneous flaps. Following operation rehabilitation was performed with the
      range of shoulder abduction had reached a plateau. The relations between the
      improved range of shoulder abduction, time to reach a stable range of abduction,
      patient age and duration of illness in each patient are discussed. Patient with
      long post-injury periods required a longer time to reach a stable range of
      abduction. Furthermore, the patients with an extremely long period before
      operation had difficulties such as nerve injury or stiff joint which restricted
      improvement. In conclusion, adequate surgical treatment in early period after
      occurrence of contracture is desirable for burn scar contracture of the axilla.

PMID- 12615463
TI  - Incidence of vomiting in burns and implications for mass burn casualty
      management.
AB  - When faced with large numbers of burn patients and limited resources such as in
      war or disaster, oral fluids may be used as an alternative to intravenous
      resuscitation. Vomiting during the first 48 h can limit the usefulness of this
      method; yet its incidence has not been documented. This study aimed to identify
      those patients at risk of vomiting following burn injury and who therefore might
      be suitable for oral resuscitation. A retrospective review of case notes from
      burn patients between 1990 and 2001 was undertaken. Burns requiring intravenous
      resuscitation (>10% total body surface area (TBSA) in children, >15% TBSA in
      adults) were included (n=110). Documentation of vomiting during the first 48 h
      following burn injury to an extent that prevented commencement of feeding was
      regarded as significant. Patients that vomited were significantly older (28.3
      years compared with 18.5 years, P=0.03), and had sustained significantly larger
      burns (29.8% compared with 22.9%, P=0.047). Administration of opiates and anti
      emetics was similar in both groups and not significant. Although the number of
      patients in this study excludes a logistic regression analysis, it would seem
      reasonable to attempt oral resuscitation in patients under 25 years of age and
      with burns up to 25% TBSA given limited resources.

PMID- 12615464
TI  - Potent inhibition of burn pain without use of opiates.

PMID- 12615465
TI  - A collagen based dermal substitute and the modified Meek technique in extensive
      burns. Report of three cases.

PMID- 12615466
TI  - Accidental burns caused by domestic infra-red muscle massaging device.

PMID- 12615467
TI  - An interesting case of chemical burn injury of the genital perianal region caused
      by hydrochloric acid exposure.

PMID- 12615468
TI  - Major burn injury caused by helium vapour.

PMID- 12615469
TI  - Debridement of a mixed partial and full thickness burn with an erbium:YAG laser.

PMID- 12615470
TI  - Facial contact burn caused by air bag deployment.

PMID- 12615471
TI  - An unusual self inflicted burn in an asthmatic patient.

PMID- 12615472
TI  - An unusual complication of asthma--the exploding inhaler.

PMID- 12615473
TI  - Tissue engineering--a shifting paradigm.

PMID- 12615474
TI  - In situ imaging and impedance measurements of titanium surfaces using AFM and
      SPIS.
AB  - Surfaces of commercially pure titanium and titanium, 6-aluminum, 4-vanadium were
      subjected to simultaneous polarization/impedance testing and in situ
      electrochemical atomic force microscopy imaging to evaluate how the structure and
      properties of the passive oxide film is affected by varying potential and
      hydration. Current transients were acquired via a step polarization impedance
      spectroscopy technique: the voltage was stepped between -1 and 1 V in 50 mV
      increments, while current transients and surface morphology were digitally
      recorded. Numerical Laplace transformation applied to the current transient data
      provided frequency-dependent admittance (impedance(-1)). Simultaneous AFM imaging
      of dry surfaces, initially hydrated surfaces, and surfaces immersed and changing
      with potential revealed that all sample surfaces were covered with protective
      titanium oxide domes that grew in area and coalesced due to hydration and as a
      function of increasing applied voltage and time. Reversal of dome growth did not
      occur upon voltage reduction, while impedance behavior was quasi-reversible,
      suggesting independence between structural and electrical properties. Oxide
      growth appeared to occur in part by lateral spreading and overgrowth of domes at
      the oxide-solution interface. Interfacial impedance data reflect oxide passivity
      and n-type semiconductor behavior. Non-linear Mott-Schottky fits specified multi
      layer donor concentrations between 10(18) and 10(19)cm(-3), depending on the
      surface.

PMID- 12615475
TI  - Observations on the effect of BMP-2 on rat bone marrow cells cultured on titanium
      substrates of different roughness.
AB  - The objective of this study was to examine the osteoinductive capacity of
      different concentrations of BMP-2 on bone marrow stromal cells in vitro. Further,
      we intended to determine whether titanium provided with an increased surface
      roughness is more efficient in osteoblast differentiation than machined titanium.
      Therefore, 20,000 cells/ml were seeded and cultured on machined and grit-blasted
      titanium discs for 4, 8 and 16 days. Different concentrations of rhBMP-2 (0, 10,
      100, 1000 ng/ml) were supplemented to the medium for 8 days of culturing. To
      evaluate cellular proliferation and differentiation, specimens were examined for
      DNA, alkaline phosphatase activity, and calcium content. Morphological appearance
      of the specimens at 8 and 16 days of incubation was evaluated using scanning
      electron microscopy. Two separate experimental runs were performed. Evaluation of
      the DNA and alkaline phosphatase data revealed that a significant difference
      existed for these data between both experimental runs. Further analysis of the
      DNA figures learned that roughening of the titanium surface and addition of BMP-2
      had no effect on cell proliferation. The alkaline phosphatase analysis and
      calcium measurements revealed that BMP-2 stimulated the early differentiation of
      osteogenic cells on machined titanium substrates in a dose-dependent manner.
      After 16 days of culture, no significant differences in calcium content could be
      observed anymore between machined and roughened titanium surfaces. Further, the
      data revealed that the machined surfaces showed a significant increase in calcium
      deposition when 100 and 1000 ng/ml BMP-2 were supplemented to the medium.
      However, the roughened surfaces showed this significant enhancement in calcium
      content only with 1000 ng/ml BMP-2. In addition, SEM evaluation revealed a dose
      dependent response to BMP-2. Increasing BMP-2 concentrations resulted in more
      calcified globular accretions on bone surfaces than when no BMP-2 was added. On
      the basis of our results, we conclude that (1) due to the heterogeneous nature of
      bone marrow, experimental results with primary rat bone marrow cells are
      difficult to reproduce from one experiment to the other, and (2) addition of
      rhBMP-2 in the medium stimulates the early differentiation and matrix
      mineralization of osteogenic cells on machined titanium surfaces in a dose
      responsive manner. Further, we concluded that our roughened titanium surfaces had
      no effect on proliferation and differentiation of primary derived rate bone
      marrow cells.

PMID- 12615476
TI  - Bonding efficacy of polyalkenoic acids to hydroxyapatite, enamel and dentin.
AB  - Previously, we introduced a methodology to determine the chemical bonding
      potential of polyalkenoic acids to mineralized tissues through quantification of
      the degree of ionic bond formation between the carboxyl groups of a polyalkenoic
      acid with calcium of hydroxyapatite. In a continuation of that study, we now
      investigated in how far the chemical bonding potential to synthetic
      hydroxyapatite is influenced by the molecular structure of the polyalkenoic acid
      and if this also may affect the self-adhesiveness to enamel and dentin. X-ray
      photoelectron spectroscopy and inductively coupled plasma atomic emission
      spectrometry were used to quantitatively analyze the chemical bonding efficacy of
      a polyalkenoic acid consisting of acrylic acid units (PAA) to synthetic
      hydroxyapatite (HAp) in comparison to the chemical bonding potential of the
      previously investigated synthesized polyalkenoic acid (s-PA) co-polymer
      consisting of 90w/w% acrylic and 10w/w% maleic acid units. In addition, the
      analysis was carried out for enamel and dentin samples. PAA revealed a
      significantly lower bonding effectiveness with only half of its carboxyl groups
      bonded to HAp versus about two-third of the carboxyl groups of s-PA. The
      difference in bonding potential was confirmed by the considerably lower
      adhesiveness of PAA to enamel and dentin as compared to that of s-PA The present
      findings indicate that the molecular structure of the polyalkenoic acid
      significantly influences the chemical bonding efficacy to Hap-based substrates.

PMID- 12615477
TI  - Induction of cyclooxygenase-2 mRNA and protein expression by epoxy resin and zinc
      oxide-eugenol based root canal sealers in human osteoblastic cells.
AB  - An ideal root canal sealer should be nonirritating to the surrounding tissues.
      Unfortunately, all histological investigation demonstrated that all types of root
      canal sealer can induce mild to severe inflammatory alternations. However, there
      is little information on the precise mechanisms about root canal sealers-induced
      inflammatory reaction. Cyclooxygenase-2 (COX-2) is an inducible enzyme believed
      to be responsible for prostaglandin synthesis at site of inflammation. The aim of
      the present study was to investigate the effects of epoxy resin (AH26) and zinc
      oxide-eugenol based (Endomethansone and N2) root canal sealers on the expression
      of COX-2 mRNA gene and protein in cultured human osteoblastic cells.
      Investigations of the time dependence of COX-2 mRNA expression in root canal
      sealer-treated human osteoblastic cells revealed a rapid accumulation of the
      transcript, a significant signal first detectable within 2h and diminished to
      control level after 24h. In addition, all root canal sealers also induced COX-2
      protein expression in human osteoblastic cells. Furthermore, to elucidate whether
      induction of COX-2 is associated with cytotoxicity, NS-398 (a selective COX-2
      inhibitor), was added to test its protective effects. NS-398 at non-cytotoxic
      dose is not able to prevent root canal sealers-induced cytotoxicity. Taken
      together, the activation of COX-2 expression may be one of the pathogenesis of
      root canal sealers-induced periapical inflammation. In addition, root canal
      sealers-induced cytotoxicity is not directly via the induction of COX-2
      expression.

PMID- 12615478
TI  - Selective bone cell adhesion on formulations containing carbon nanofibers.
AB  - Bone cell adhesion on novel carbon nanofibers and polycarbonate urethane/carbon
      nanofiber (PCU/CNF) composites is investigated in the present in vitro study.
      Carbon nanofibers have exceptional theoretical mechanical properties (such as
      high strength to weight ratios) that, along with possessing nanoscale fiber
      dimensions similar to crystalline hydroxyapatite found in physiological bone,
      suggest strong possibilities for use as an orthopedic/dental implant material.
      The effects of select properties of carbon fibers (specifically, dimension,
      surface energy, and chemistry) on osteoblast, fibroblast, chondrocyte, and smooth
      muscle cell adhesion were determined in the present in vitro study. Results
      provided evidence that smaller-scale (i.e., nanometer dimension) carbon fibers
      promoted osteoblast adhesion. Adhesion of other cells was not influenced by
      carbon fiber dimensions. Also, smooth muscle cell, fibroblast, and chondrocyte
      adhesion decreased with an increase in either carbon nanofiber surface energy or
      simultaneous change in carbon nanofiber chemistry. Moreover, greater weight
      percentages of high surface energy carbon nanofibers in the PCU/CNF composite
      increased osteoblast adhesion while at the same time decreased fibroblast
      adhesion.

PMID- 12615479
TI  - Wear performance of ultrahigh molecular weight polyethylene/quartz composites.
AB  - Ultrahigh molecular weight polyethylene (UHMWPE)/quartz composites were
      compression molded in the presence of organosiloxane, and then hydrolyzed. The
      used organosiloxane is vinyl tri-ethyloxyl silane. The gelation, the melting
      behavior, the crystallinity, the mechanical properties and the wear resistance of
      UHMWPE/quartz composites were investigated. The results showed that
      organosiloxane can act as a cross-linking agent for UHMWPE matrix and serve as a
      coupling agent for improving the bonding between the quartz particles and the
      UHMWPE matrix. The correlation between the various properties and the morphology
      of the composites has been discussed. At about 0.5phr organsiloxane while the
      degree of crystallinity of the composite is at the peak value of 57%, the
      mechanical properties and the wear resistance of UHMWPE/quartz composites reaches
      their maximum.

PMID- 12615480
TI  - Characterizing multicomponent adsorbed protein films using electron spectroscopy
      for chemical analysis, time-of-flight secondary ion mass spectrometry, and
      radiolabeling: capabilities and limitations.
AB  - Characterization of complex adsorbed protein films is a critical aspect of
      biomaterials science, particularly in understanding the in vivo response to
      biomaterials. The surface analysis techniques electron spectroscopy for chemical
      analysis (ESCA) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) are
      particularly suited to the analysis of complex adsorbed protein films due to
      their wide applicability to a variety of materials. We have investigated the
      applicability of ESCA for studying the structure of adsorbed serum and plasma
      protein layers. ESCA was able to monitor the thickness of the adsorbed protein
      film. Due to its chemical specificity, ToF-SIMS was used to estimate the
      composition of the plasma and serum protein layers by comparison of their spectra
      with the spectra of single protein films. The limit of detection of ToF-SIMS for
      the plasma protein fibrinogen was determined by comparison with independent
      radiolabeled fibrinogen adsorption measurements. While ToF-SIMS was able to
      determine some qualitative trends in the composition of the plasma protein films
      as a function of adsorption time, the detection limit of the minor components in
      multicomponent adsorbed protein films ultimately limits the ability of ToF-SIMS
      to quantify the composition of these films. However, both ESCA and ToF-SIMS can
      provide useful information on adsorbed plasma protein films without further
      sample treatment. This study outlines the strengths and weaknesses of ESCA and
      ToF-SIMS for studying multicomponent adsorbed plasma protein films.

PMID- 12615481
TI  - Synergistic effects of H2O2 with components of dental restorative materials on
      gluconeogenesis in rat kidney tubules.
AB  - No data are available about (toxic) effects of dental materials administered in
      combination with H(2)O(2) from dental bleaching compounds. The effect of dental
      composite components triethyleneglycoldimethacrylate (TEGDMA) and
      hydroxyethylmethacrylate (HEMA) as well as mercuric chloride (HgCl(2)) and
      methylmercury chloride (MeHgCl), each in combination with H(2)O(2), was
      investigated on gluconeogenesis in kidney cells. From rats kidney tubules were
      prepared. Every 10 min up to 60 min 1-ml samples were drawn from the cell
      suspension for quantitating the glucose content. Glucose formation in controls
      was 3.5+/-0.3 nmol/mg.per min (mean+/-SEM, n=21). Relative rates of glucose
      formation were obtained by expressing individual rates as percentage of the
      corresponding control. X-Y concentration curves (effective concentration, EC) of
      the substances were calculated by fitting a four-parametric sigmoid function to
      the relative rates of the glucose formation at various test concentrations. At
      the end of the incubation period cell viability was assessed by trypan blue
      exclusion. Cell viability decreased within the 60 min interval from 90% to
      approx. 80% (controls), <25 (HEMA), <20 (TEGDMA), <20 (H(2)O(2)) <10 (MeHgCl),
      and <10 (HgCl(2)). Values of 50% effective concentration (EC(50)) were calculated
      from fitted curves. EC(50) values were (mmol/l; mean+/-SEM; n=4): HEMA, 17.2+/
      2.8; TEGDMA, 1.9+/-0.2; H(2)O(2) 0.22+/-0.03, MeHgCl, 0.016+/-0.0005; and
      HgCl(2), 0.0017+/-0.0005. No significant decrease of the EC(50) values was found
      when kidney cells were exposed to HEMA, HgCl(2), or MeHgCl in addition with
      H(2)O(2) (1-100 microM), compared to those EC(50) values of each compound without
      H(2)O(2) addition. A significant decrease of the TEGDMA EC(50) values to about
      0.25 or 0.04 (mmol/l) was found when cells were exposed to TEGDMA in combination
      with H(2)O(2) (75 or 100 microM), compared to that TEGDMA EC(50) value without
      H(2)O(2) addition. The addition of H(2)O(2) (75 and 100 microM) resulted in a
      synergistic toxic effect of TEGDMA.

PMID- 12615483
TI  - The relative influence of five variables on the in vitro wear rate of
      uncrosslinked UHMWPE acetabular cup liners.
AB  - The wear factors, k(exp)(in 10(-6)mm(3)N(-1)m(-1)), of two sets of hemispherical
      uncrosslinked ultra-high-molecular-weight polyethylene UHMWPE acetabular cup
      liners, when articulated against 28-mm-diameter Co-Cr alloy femoral heads, were
      determined in a hip joint wear simulator. All test conditions used were the same
      for both sets, with the exception that in one set (comprising six liners), the
      bovine serum concentration in the test lubricant (P) was 25vol%, while it was
      90vol% for the other set (comprising seven liners). For each liner in each set,
      the values of the following independent or explanatory variables were determined:
      the tensile toughness (U, in MJm(-3)) of the UHMWPE; the degree of crystallinity
      (%C) of the UHMWPE; the mean surface roughness (R(a), in microm) of the liner;
      and the radial clearance between the femoral head and the liner (DeltaL, in mm).
      All the results in both sets were combined and correlational analyses were
      performed between k(exp), on the one hand, and various combinations of U,
      %C,R(a),DeltaL, and P, on the other hand. It was found that the strongest
      correlations were obtained when P was included, but that %C and U are also
      important variables. Within the range of values of the independent variables
      used, the recommended relationship isk(exp)=460U(0.72)%C(-5.29)P(
      0.66)(adjustedr(2)=0.858). This relationship has many potential uses, such as for
      screening uncrosslinked UHMWPEs that are being considered as candidates for
      fabricating acetabular cup liners, and for conducting studies of the sensitivity
      of k(exp) to a change in a value of a specified independent variable (with the
      values of all the other independent variables held constant). These uses, as well
      as the study limitations, are discussed in detail.

PMID- 12615482
TI  - Thrombogenicity of polysaccharide-coated surfaces.
AB  - Heparinization of artificial surfaces has been proven to reduce the intrinsic
      thrombogenicity of such surfaces. The mechanism by which immobilized heparin
      reduces thrombogenicity is not completely understood. In the present study
      heparin-, alginic acid- and chondroitin-6-sulphate-coated surfaces were examined
      for protein adsorption, platelet adhesion and thrombin generation. The protein
      binding capacity from solutions of purified proteins was significantly higher for
      heparin-coated surfaces when compared with alginic acid- and chondroitin sulphate
      coated surfaces. Yet, when the surfaces were exposed to flowing plasma, only the
      heparinized surface adsorbed significant amounts of antithrombin. None of the
      surfaces adsorbed fibrinogen under these conditions, and as a result no platelets
      adhered from flowing whole blood. Our results indicate that protein adsorption
      and platelet adhesion from anticoagulated blood cannot be used to assess the
      thrombogenicity of (coated) artificial surfaces. Indeed, the thrombin generation
      potentials of the different surfaces varied remarkable: while non-coated surface
      readily produced thrombin, alginic acid- and chondroitin sulphate-coated surfaces
      showed a marked reduction and virtually no thrombin was generated in flowing
      whole blood passing by heparinized surfaces.

PMID- 12615484
TI  - Porous polymeric structures for tissue engineering prepared by a coagulation,
      compression moulding and salt leaching technique.
AB  - A technique for the preparation of porous polymeric structures involving
      coagulation, compression moulding and particulate leaching has been developed.
      The technique combines the advantages of thermal processing methods and
      particulate leaching. A high molecular weight polymer solution in an organic
      solvent containing dispersed water-soluble salt particles is precipitated into an
      excess of non-solvent. The polymer-salt composite is then processed by thermal
      processing methods into devices of varying shapes and sizes, which can
      subsequently be extracted to give the desired porous structures. The porosities
      of the scaffolds could be varied between 70% and 95% by adjusting the polymer to
      salt ratio and the pore size could be controlled independently by varying the
      leachable particle size. This versatility provides for the optimisation of
      scaffolds used in medicine and in tissue engineering. Compared with commonly used
      porosifying methods such as sintering, compression moulding combined with salt
      leaching, and freeze-drying, this process allows excellent control over pore size
      and porosity and yields scaffolds with a much more homogeneous pore morphology.
      We have prepared porous structures from several relevant polymers in the
      biomedical field: poly(D,L-lactide), poly(epsilon-caprolactone) and
      1000PEOT70PBT30, a segmented poly(ether ester) based on polyethylene oxide and
      polybutylene terephthalate.

PMID- 12615485
TI  - Macroporous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) matrices for bone tissue
      engineering.
AB  - Macroporous poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) matrices
      were prepared after solvent evaporation and solute leaching. PHBV solutions with
      different concentrations were prepared in chloroform: dichloromethane (1:2, v/v).
      In order to create a matrix with high porosity and uniform pore sizes, sieved
      sucrose crystals (75-300 or 300-500 microm) were used. PHBV foams were treated
      with rf-oxygen plasma to modify their surface chemistry and hydrophilicity with
      the aim of increasing the reattachment of osteoblasts. Surface characteristics,
      pore sizes and their distribution on PHBV surface were studied by scanning
      electron microscopy (SEM) and Scion Image Analysis Program. Void volume, pore
      sizes and density of foams were found to be significantly affected by foam
      preparation conditions. Stability of PHBV foams in aqueous media was studied.
      Their weight and density were unchanged for a period of 120 days and then a
      significant decrease was observed for the rest of the study (60 days).
      Osteoblasts were seeded onto the foams and their proliferation inside the
      matrices was also determined by SEM. After 29 and 60 days of incubation, growth
      of osteoblasts on matrices was observed.

PMID- 12615486
TI  - Biocompatibility and biofouling of MEMS drug delivery devices.
AB  - The biocompatibility and biofouling of the microfabrication materials for a MEMS
      drug delivery device have been evaluated. The in vivo inflammatory and wound
      healing response of MEMS drug delivery component materials, metallic gold,
      silicon nitride, silicon dioxide, silicon, and SU-8(TM) photoresist, were
      evaluated using the cage implant system. Materials, placed into stainless-steel
      cages, were implanted subcutaneously in a rodent model. Exudates within the cage
      were sampled at 4, 7, 14, and 21 days, representative of the stages of the
      inflammatory response, and leukocyte concentrations (leukocytes/microl) were
      measured. Overall, the inflammatory responses elicited by these materials were
      not significantly different than those for the empty cage controls over the
      duration of the study. The material surface cell density (macrophages or foreign
      body giant cells, FBGCs), an indicator of in vivo biofouling, was determined by
      scanning electron microscopy of materials explanted at 4, 7, 14, and 21 days. The
      adherent cellular density of gold, silicon nitride, silicon dioxide, and SU-8(TM)
      were comparable and statistically less (p<0.05) than silicon. These analyses
      identified the MEMS component materials, gold, silicon nitride, silicon dioxide,
      SU-8(TM), and silicon as biocompatible, with gold, silicon nitride, silicon
      dioxide, and SU-8(TM) showing reduced biofouling.

PMID- 12615487
TI  - Antinociceptive effects of hydromorphone, bupivacaine and biphalin released from
      PLGA polymer after intrathecal implantation in rats.
AB  - Intraspinal drug delivery, based on the concept of controlling pain by delivering
      drug to a nociceptive target rich in opioid and other relevant receptors is
      increasingly used clinically. The therapeutic ratio for opioids or other
      centrally acting agents is potentially greater if they are administered
      intrathecally (i.t.) than outside the central nervous system (CNS). The present
      study was designed with the ultimate goal of formulating a controlled release
      system for intrathecal analgesia characterized by effectiveness, rapid onset and
      few side effects for chronic pain control. A biodegradable copolymer poly(L
      lactide-co-glycolide) (PLGA) was used to prepare a rod-shaped drug delivery
      system containing hydromorphone (HM), bupivacaine (BP), both HM and BP, or
      biphalin (BI). In vitro drug release kinetics of these systems showed a zero
      order release rate for HM and BP from PLGA (85:15) rods. Drug-loaded rods were
      implanted i.t. Control groups received only placebo implants. Measurement of
      analgesic efficacy was carried out with tail flick and paw-withdrawal tests. In
      vivo studies showed potent, prolonged analgesia in comparison to controls for all
      active treatments. Analgesic synergy was observed with HM and BP. With further
      refinements of drug release rate, these rods may offer a clinically relevant
      alternative for intrathecal analgesia.

PMID- 12615488
TI  - Sustained release system for highly water-soluble radiosensitizer drug
      etanidazole: irradiation and degradation studies.
AB  - Etanidazole (one nitro-imidazole hypoxic radiosensitizer) is formulated as
      polymer matrix type controlled release devices in this study. A novel double
      polymer drug carrier, unlike the double wall microparticles, is fabricated for
      the purpose of drug delivery, with the following objectives in mind: (1) to have
      a high encapsulation efficiency, (2) to achieve a pusatile release profile
      suitable for the radiation schedule of radiotherapy, (3) to elucidate the
      degradation profile of these microparticles. Irradiation of the microparticles
      were also studied to investigate effects on release and degradation. At a dosage
      of 50 Gy (total dosage during a radiotherapy treatment period) showed no apparent
      effects on the tri-phase release profile. It consists of an initial burst in the
      first 72 h, followed by a slow and steady drug release phase, and finally a
      faster degradation controlled phase corresponding to the degradation state of the
      different microparticles. At 25 kGy (sterilization dosage), the release profiles
      of the drug carrier were drastically modified. The faster erosion of the polymer
      with high dosage irradiation hastened the drug release and shortened the release
      time span, accompanied by decreases in the polymer molecular weight and glass
      transition temperatures, which was not apparent from SEM imaging. Degradation
      studies suggested a heterogeneous degradation process, with the outer layer and
      inner matrix degrading at different rates. The modifiable tri-phase release
      profile using microparticles of different polymer blends implies that the release
      properties of the drug carriers can be modified for different treatment regimes.

PMID- 12615489
TI  - Urea permeation and hydrolysis through hollow fiber dialyzer immobilized with
      urease: storage and operation properties.
AB  - The surface of polyacrylonitrile hollow fibers was hydrolyzed and covalently
      bonded with urease via glutaraldehyde. Immobilized urease retained higher
      relative activity than native urease when storing at various pHs. The stabilities
      of immobilized urease to pH were higher than those of native enzyme. Immobilized
      urease retained 86% of initial activity after reusing 15 times at pH 7. After
      storing for 42d at 4 degrees C and pH 7, the immobilized urease can hydrolyze 15%
      of initial concentration of urea at pH 7 and 37 degrees C after 4h, while native
      urease lost almost its catalytic ability. The removal of urea using urease
      immobilized dialyzer was demonstrated with in vitro dialysis and showed faster
      removing rate of urea than a regular dialyzer by 2 times. Furthermore, the
      improvement in the urea clearance by the urease immobilization to a dialyzer
      increased with the dialysate velocity.

PMID- 12615490
TI  - Surface roughening of glass ionomer cements by neutral NaF solutions.
AB  - The objective of this study was to investigate the effect of repeated
      applications of a neutral NaF solution on the surface roughness of four
      conventional glass ionomer cements (GIC) (ChemFil Superior encapsulated, Fuji Cap
      II, Ketac-Fil and Hi Dense), three resin-modified (RM-) GIC (Fuji II LC
      encapsulated, Photac-Fil and Vitremer) and one polyacid-modified composite resin
      (PAM-C) (Dyract). Matured specimens were four times alternately eluted in water
      and exposed to 2% neutral NaF aqueous solutions for 1h. Control specimens were
      only subjected to elution in water for the same time period. After the treatment
      the surface roughness R(a) was determined using non-contact surface profilometry
      and selected samples were examined with SEM. Except for the PAM-C, R(a) increased
      drastically for the fluoride-treated samples compared to water-stored samples,
      the effect being most pronounced for the GIC. Surface roughening apparently is
      caused by a progressive disintegration or chemical erosion of the polysalt matrix
      of (RM-)GIC.

PMID- 12615491
TI  - A simulated annealing algorithm for maximum likelihood pedigree reconstruction.
AB  - The calculation of maximum likelihood pedigrees for related organisms using
      genotypic data is considered. The problem is formulated so that the domain of
      optimization is a permutation space. This is a feature shared by the travelling
      salesman problem, for which simulated annealing is known to be effective. Using
      this technique it is found that pedigrees can be reconstructed with minimal error
      using genotypic data of a quality currently realizable. In complex pedigrees
      accurate reconstruction can be done with no a priori age or sex information. For
      smaller numbers of individuals a method of efficiently enumerating all admissible
      pedigrees of nonzero likelihood is given.

PMID- 12615492
TI  - Competing populations in flows with chaotic mixing.
AB  - We investigate the effects of spatial heterogeneity on the coexistence of
      competing species in the case when the heterogeneity is dynamically generated by
      environmental flows with chaotic mixing properties. We show that one effect of
      chaotic advection on the passively advected species (such as phytoplankton, or
      self-replicating macro-molecules) is the possibility of coexistence of more
      species than that limited by the number of niches they occupy. We derive a novel
      set of dynamical equations for competing populations.

PMID- 12615493
TI  - Maximum likelihood and Bayesian methods for estimating the distribution of
      selective effects among classes of mutations using DNA polymorphism data.
AB  - Maximum likelihood and Bayesian approaches are presented for analyzing
      hierarchical statistical models of natural selection operating on DNA
      polymorphism within a panmictic population. For analyzing Bayesian models, we
      present Markov chain Monte-Carlo (MCMC) methods for sampling from the joint
      posterior distribution of parameters. For frequentist analysis, an Expectation
      Maximization (EM) algorithm is presented for finding the maximum likelihood
      estimate of the genome wide mean and variance in selection intensity among
      classes of mutations. The framework presented here provides an ideal setting for
      modeling mutations dispersed through the genome and, in particular, for the
      analysis of how natural selection operates on different classes of single
      nucleotide polymorphisms (SNPs).

PMID- 12615494
TI  - The balance between pleiotropic mutation and selection, when alleles have
      discrete effects.
AB  - The theory of pleiotropic mutation and selection is investigated and developed
      for a large population of asexual organisms. Members of the population are
      subject to stabilising selection on Omega phenotypic characters, which each
      independently affect fitness. Pleiotropy is incorporated into the model by
      allowing each mutation to simultaneously affect all characters. To expose
      differences with continuous-allele models, the characters are taken to originate
      from discrete-effect alleles and thus have discrete genotypic effects. Each
      character can take the values nxDelta where n=0,+/-1,+/-2, em leader, and the
      splitting in character effects, Delta, is a parameter of the model. When the
      distribution of mutant effects is normally distributed around the parental value,
      and Delta is large, a "stepwise" model of mutation arises, where only adjacent
      trait effects are accessible from a single mutation. The present work is
      primarily concerned with the opposite limit, where Delta is small and many
      different trait effects are accessible from a single mutation. In contrast to
      what has been established for continuous-effect models, discrete-effect models do
      not yield a singular equilibrium distribution of genotypic effects for any value
      of Omega. Instead, for different values of Omega, the equilibrium frequencies of
      trait values have very different dependencies on Delta. For Omega=1 and 2,
      decreasing Delta broadens the width of the frequency distribution and hence
      increases the equilibrium level of polymorphism. For all sufficiently large
      values of Omega, however, decreasing Delta decreases the width of the frequency
      distribution and the equilibrium level of polymorphism. The connection with
      continuous trait models follows when the limit Delta-->0 is considered, and a
      singular probability density of trait values is obtained for all sufficiently
      large Omega.

PMID- 12615495
TI  - Ancestral processes for non-neutral models of complex diseases.
AB  - We consider non-neutral models for unlinked loci, where the fitness of a
      chromosome or individual is not multiplicative across loci. Such models are
      suitable for many complex diseases, where there are gene-interactions. We derive
      a genealogical process for such models, called the complex selection graph (CSG).
      This coalescent-type process is related to the ancestral selection graph, and is
      derived from the ancestral influence graph by considering the limit as the
      recombination rate between loci gets large. We analyse the CSG both theoretically
      and via simulation. The main results are that the gene-interactions do not
      produce linkage disequilibrium, but do produce dependencies in allele frequencies
      between loci. For small selection rates, the distributions of the genealogy and
      the allele frequencies at a single locus are well-approximated by their
      distributions under a single locus model, where the fitness of each allele is the
      average of the true fitnesses of that allele with respect to the distribution of
      alleles at other loci.

PMID- 12615496
TI  - Emergence of a complex and stable network in a model ecosystem with extinction
      and mutation.
AB  - We propose a minimal model of the dynamics of diversity-replicator equations with
      extinction, invasion and mutation. We numerically study the behavior of this
      simple model and show that it displays completely different behavior from the
      conventional replicator equation and the generalized Lotka-Volterra equation. We
      reach several significant conclusions as follows: (1) a complex ecosystem can
      emerge when mutants with respect to species-specific interaction are introduced;
      (2) such an ecosystem possesses strong resistance to invasion; (3) a typical
      fixation process of mutants is realized through the rapid growth of a group of
      mutualistic mutants with higher fitness than majority species; (4) a hierarchical
      taxonomic structure (like family-genus-species) emerges; and (5) the relative
      abundance of species exhibits a typical pattern widely observed in nature.
      Several implications of these results are discussed in connection with the
      relationship of the present model to the generalized Lotka-Volterra equation.

PMID- 12615497
TI  - Mother's mitochondria and optimal offspring sex ratio.
AB  - In certain cases, predicted by evolutionary theory of sex-allocation and
      confirmed by empirical evidence, animals adaptively change their progeny sex
      ratio according to individual circumstances. Here we argue that a similar
      response of offspring sex-ratio must exist in relation to genetic variation of
      mothers' mitochondria, as a consequence of maternal inheritance of these
      organelles and of their influence on fitness resulting from their crucial role in
      metabolism. In fact, a mathematical analysis of evolutionary dynamics of sex
      allocation mutants demonstrates that natural selection promotes an evolutionarily
      stable allocation policy where mothers with defective mitochondria generate only
      sons, while those with optimal mitochondria have female biased progenies.

PMID- 12615498
TI  - Moment closure and the stochastic logistic model.
AB  - The quasi-stationary distribution of the stochastic logistic model is studied in
      the parameter region where its body is approximately normal. Improved asymptotic
      approximations of its first three cumulants are derived. It is shown that the
      same results can be derived with the aid of the moment closure method. This
      indicates that the moment closure method leads to expressions for the cumulants
      that are asymptotic approximations of the cumulants of the quasi-stationary
      distribution.

PMID- 12615499
TI  - Multiple equilibria: tuberculosis transmission require unrealistic assumptions.

PMID- 12615500
TI  - Bone development in neurofibromatosis 1.
AB  - Bony abnormalities are common findings in cases of neurofibromatosis 1. We might
      hypothesize that neurofibromin, the protein encoded by the neurofibromatosis 1
      gene, plays important roles in bone development. Loss of function of
      oligodendrocyte-myelin glycoprotein gene and increased activity of ras p21 might
      increase the level of c-fos proto-oncogene in bones with formation of fibrous
      dysplasia-like tissue. Also, increased ras p21 might disturb collagen I synthesis
      by osteoblasts. Moreover, increased ras activity might increase the mitogenic
      signals to the nucleus through mitogen-activated protein kinase (MAPK) and
      disturb the level of the transcription factor core-binding factor alpha(1)
      (Cbfa1). Abnormal fibrous tissue and neurofibromas formed at the site of
      pseudarthrosis might represent abnormal response of periosteal fibroblasts for
      injury, an effect simulating the response of skin fibroblasts in
      neurofibromatosis 1 to injury.

PMID- 12615501
TI  - Ionic channels and long-range electrical signals: a probabilistic interaction.
AB  - The synchronized activation of ionic channels generates long-range electrical
      signals that can be detected on the surface using EEG and MEG. We propose that
      the spatial and temporal properties of these signals during rhythmic activity are
      associated with the probabilistic attributes of the ionic channels. Specifically:
      (1) The EEG-signals present a phase relationship with the open probability of the
      channels that drives the rhythm, (2) The oscillatory preferences of the signals-
      the 'EEG spectral profile'--are determined by the location probability
      (concentration) of the channels. In order to test and apply the hypothesis, it is
      suggested to correlate open and location probabilities with changes in the
      structure and dynamic of water molecules, water protons and pH using novel MRI
      techniques.

PMID- 12615502
TI  - The origin of brain asymmetry and its psychotic reversal.
AB  - Ontogenetic brain-asymmetry and its reversal in schizophrenia constitute special
      cases of a more fundamental principle of sensory-motor integration. Transmitted
      through an immature optical system, asymmetric inputs from the left visual field
      induce the infant's right hemispheric preference for lower spatial frequencies
      during early mother-child interaction. The emerging classical features of
      hemispheric specialisation later in life can be accounted for by a transformation
      law of the neuronal reference frames based on relativistic non-linear information
      processing. Accordingly, the asymmetric distributions of the cannabinoid receptor
      CB1 in the right basal ganglia and the left area of Wernicke reflect the
      preferences for lateralised posture, positioning, and speech. Epigenetic
      development of brain asymmetry thus unifies the different aspects related to
      cradling and breast-feeding, speech- and visuospatial processing, the dimensional
      conversion of spatiotemporal information and, in the case of a dysbalanced
      cannabinoid system, its psychotic reversal. The predicted right hemispheric shift
      and the inverse relationship between Kolmogorov entropy and its dimensional
      embedding (Shannon entropy) has ultimately been confirmed by non-linear EEG
      analysis of a fluoro-methyl-anadamide induced model psychosis splitting conscious
      from unconscious mental processes.

PMID- 12615503
TI  - The Australian paralysis tick may be the missing link in the transmission of
      Hendra virus from bats to horses to humans.
AB  - Hendra virus is a new virus of the family Paramyxoviridae. This virus was first
      detected in Queensland, Australia, in 1994; although, it seems that the virus has
      infected fruit-eating bats (flying-foxes) for a very long time. At least 2 humans
      and 15 horses have been killed by this virus since it first emerged as a virus
      that may infect mammals other than flying-foxes. Hendra virus is thought to have
      moved from flying-foxes to horses, and then from horses to people. There is a
      reasonably strong hypothesis for horse-to-human transmission: transmission of
      virus via nasal discharge, saliva and/or urine. In contrast, there is no strong
      hypothesis for flying-fox-to-human transmission. I present evidence that the
      Australian paralysis tick, Ixodes holocyclus, which has apparently only recently
      become a parasite of flying-foxes, may transmit Hendra virus and perhaps related
      viruses from flying-foxes to horses and other mammals.

PMID- 12615504
TI  - Bacterial multicellularity as a possible source of antibiotic resistance.
AB  - Knowledge about survival of micro-organisms in stressful situations not only
      influences the evolutionary theory in a fundamental way, but bears an
      extraordinary importance in finding a global solution to a very concrete urgent
      problem of mankind, namely bacterial resistance to antibiotics. Recent in vitro
      experiments demonstrate that the adaptive mutation process involving transient
      hypermutators could be one of the most important mechanisms whereby bacterial
      cells achieve the antibiotic resistance. An effective response of the mutation
      rates to specific selective conditions and an increasing number of conclusive
      evidence that bacterial cells are indeed communicative and co-operative organisms
      lead us to a hypothesis that the emergence of the antibiotic resistant mutants
      through the so-called adaptive mutation is deeply connected with the
      multicellular organisation of bacterial cells.

PMID- 12615505
TI  - Proposition of treatment of cancer cells by nuclear protein mixtures from
      embryonic cells.
AB  - Several kinds of cancer cells are shown to revert to normal state by action of
      chemical or biochemical differentiation agents. The analogy between cancer and
      embryonic cells, with regard to the expression of oncogenes, and the presence, in
      young embryos, of regulating factors, lead to the proposition of treatment of
      cancer cells by extracts of nuclei from embryo cells. Preliminary experiments
      with these extracts, on hepatoma cells in culture, have shown growth and DNA
      synthesis inhibitions, without cell toxicity, and a prolongation of survival of
      rats injected with the treated cancer cells.

PMID- 12615506
TI  - Multilevel callus distraction: a novel idea to shorten the lengthening time.
AB  - Lower extremity inequality is a common problem in everyday orthopaedic practice.
      The leg discrepancy can lead to variety of other problems, i.e., spinal problems.
      Surgical intervention is very demanding and requires patient compliance. Wagner's
      and Ilizarov's elongation technique are most commonly used worldwide, but it
      gives satisfactory results only in a long period of time and as we know there
      could be several inconvenient outcomes. Our idea aims at shortening this time
      period, and avoiding some of the inconvenient outcomes. Unfortunately we do not
      have the opportunity to go further in our investigations, but we hope that
      someone interested in this field will have an idea which would make continuation
      possible.

PMID- 12615507
TI  - Predicting the concentration level of an anti-cancer drug during treatment of a
      living organism.
AB  - For many drugs used in chemotherapy the difference between the therapeutic
      concentration and the toxic concentration is small. During treatment of a living
      organism from cancer by using chemotherapy, it is therefore important to foresee
      the therapeutic concentration in the organism as a function of the injected
      therapeutic drug dose. This article provides a mathematical dynamic description
      of the interaction between the organism and the drug, and analyses the dynamics
      by using ordinary differential equations. The model is tested in a clinical
      situation where digitoxin is used as the therapeutic drug. The agreement with
      this experiment is good.

PMID- 12615508
TI  - Dynamics of subcellular compartmentalization of steroid receptors in living cells
      as a strategic screening method to determine the biological impact of suspected
      endocrine disruptors.
AB  - Although a number of screening methods being used for identifying potential
      endocrine disruptors have generated a wealth of information, a search for
      alternative combination of methods is still needed to overcome experimental
      artefacts. There are no generally accepted or validated screening methods for
      monitoring and studying impact of environmental endocrine disruptors. Also, no
      single assay can accurately predict all the deleterious effects of endocrine
      disruptors. For this reason various environmental protection agencies, mainly
      European and US, have urged that a battery of tests in current use need to be
      designed to assess their adequacy in detecting the effects of endocrine
      disruptors. Some details about endocrine disruptors and screening programs can be
      found at http://www.epa.gov/scipoly/oscpendo/whatis.htm. Several studies in
      recent years have used fusion proteins between steroid receptors (estrogen,
      androgen, progesterone, etc.) and green fluorescent protein (GFP) that can serve
      as an alternative potent screening method to study intracellular dynamics of
      receptors in living cells. An approach employing nucleocytoplasmic trafficking of
      steroid receptors as a parameter in response to potential xenobiotic chemicals in
      living cells may prove to be promising in terms of being direct, fast, reliable,
      simple and inexpensive.

PMID- 12615510
TI  - Sleepiness as a state-trait phenomenon, comprising both a sleep drive and a wake
      drive.
AB  - In this paper it is proposed to extend the classical models of sleepiness in two
      ways. Firstly, the role of a wake drive, besides a sleep drive, in determining
      sleepiness is emphasised. Although this has already been suggested in literature
      and convincing arguments can be found, it is not generally accepted. Secondly, we
      argue to incorporate trait aspects of sleepiness or a long-term person-specific
      level of sleepiness, besides short-term changes of sleepiness or 'state
      sleepiness'. Shortly, a conceptualisation of sleepiness in which situational wake
      drive and sleep drive modify a basal level of both wake drive and sleep drive, is
      proposed. It implies that sleepiness can result from essentially different
      factors involved: a chronic condition or an acute state of either a high level of
      sleep drive, a low level of arousal or a combination of both. This is illustrated
      in a working model and potential assessment tools for the wake drive and state
      versus trait sleepiness are discussed.

PMID- 12615509
TI  - Schematic illustration of some of the mechanisms for maintenance of homeostasis
      in organism.
AB  - The aim of the present paper is to illustrate schematically by a non-equal arm
      lever system the mechanisms that maintain the homeostasis of reactive oxygen
      species, glucose, mean arterial pressure and electrolytes. All regulating factors
      that increase the values of each physiological parameter are placed on the same
      arm of the lever system. The regulating factors that decrease this value are
      placed on the other arm of the lever. In this way the two types of factors
      interact with one another and maintain the lever system in a dynamic equilibrium,
      i.e., contribute to keeping the homeostasis. Illustrating the maintenance of
      homeostasis by a non-equal arm lever system gives the opportunity to express the
      quickness, flexibility, stability and effectiveness of physiological regulations.

PMID- 12615511
TI  - The potential efficacy of thalidomide in the treatment of recalcitrant alopecia
      areata.
AB  - Thalidomide has been used in the treatment of many dermatological disorders. This
      drug is a potent suppressor of IL-12 production which plays a critical role in
      the development of cellular immune responses mediated by helper T-cells. It
      induces a drop in helper T-cell counts and a corresponding, though relatively
      small, rise in suppressor T-cells. It seems that cellular, not humoral, immune
      mechanisms are involved in the pathogenesis of alopecia areata. Also, decreased
      suppressor T-cell numbers in the active disease have been reported. Therefore, it
      could be postulated that thalidomide, especially in combination with other
      agents, could be of help in the treatment of resistant cases of alopecia areata.

PMID- 12615512
TI  - A model of dual circulation in liver acini with hypoxia regulated adenosine
      secretion.
AB  - It was postulated by W.W. Lautt that the hepatic artery flow compensation for
      changes in portal vein flow (the 'hepatic arterial buffer response') is regulated
      through the portal blood washout of adenosine from the small fluid compartment
      that surrounds the hepatic arterial resistance vessels. It is presumed that the
      adenosine secretion there is constant and independent of oxygen supply or liver
      demand. It was reported by others that liver secretes variable quantities of
      adenosine and that secretion is related to the level of liver hypoxia. This paper
      is an attempt to describe a model of acinar circulation without sources of
      constant adenosine secretion. The presented model is based on the fact that
      portal blood enters acinar space near the vascular stalk in the zone 1, while
      most of the arterial branches empty one-third from the interlobular septa, at the
      beginning of the zone 2, just downstream from the zone 1. Another important
      characteristic of liver architecture is that near 5/9 of lobular volume is in the
      zone 1. Liver cells in zone 1 are well oxygenated by the portal blood and they
      have low adenosine secretion that might seem almost constant. Since most arterial
      branches empty more peripherally, the zone 1 normally does not depend on the
      arterial circuit and most of arterial branches are governed by the adenosine
      secretion from the upstream zone 1. Low portal flow, would increase adenosine
      secretion from the zone 1 and thus dilate numerous downstream arterial resistance
      vessels. An increased flow from these arterial vessels would compensate any
      decrease in the portal flow. Zones 2 and 3 probably have higher adenosine
      secretion rates since the oxygenation depends on the amount of added arterial
      blood and on the liver cell metabolism. Some of the arterial branches in those
      zones are probably open all the time, preserving them zones from hypoxic injury.
      Since the main point for arterial inflow is concentrated downstream from the zone
      1, in cases of low portal pressures, or elevated upstream resistance, some of the
      arterial blood might leave the acinus in retrograde direction via the portal
      branch and enter some other acinus as a part of portal blood. These arterio
      portal communications might be important in cases of low or none portal flow when
      zone 1 is in hypoxia. In the 3D liver space with tightly packed acini, very
      complex and ever-changing patterns of combined antegrade and retrograde flows can
      be expected.

PMID- 12615513
TI  - Induction of thymic tolerance as possibility in prevention of recurrent
      spontaneous abortion.
AB  - A major process through which the immune system becomes tolerant to self-proteins
      involves the deletion of self-reactive cells in the thymus and/or inhibition of
      specific Th(1) cells clones. Deletion process includes two selection mechanisms
      in which the thymus eliminates unwanted thymocytes are known as positive
      selection and negative selection. The thymus is an antigenically privileged site,
      mainly for it is discrete by blood-thymus barrier. Many researches were shown
      that intrathymic inoculation of any antigen resulted in specific tolerance
      induction. The embryo/fetus and placenta are an allograft to which the mother
      must remain immunologically tolerant in order for the fetus to survive. Today,
      there is much interest focused on the immunology of recurrent spontaneous
      abortion (RSA). Up to 50% of RSA may be mediated by the immune system via
      inadequate maternal anti-paternal response. Nature of this maternal-fetal
      disturbance represents disbalance in Th(1)/Th(2) activity. Contra-shift in
      Th(1)/Th(2) activity is the basis for immunotherapy with paternal leukocyte
      immunization (PLI). PLI induce some kind of peripheral tolerance on
      embryonic/fetal/trophoblast antigens, but problems of central tolerance are still
      open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic
      dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause
      central specific tolerance and may be a new possibility for immunotherapy in RSA
      patients.

PMID- 12615514
TI  - Platelets play an essential role in the aetiology of cerebral vasospasm after
      subarachnoid haemorrhage.
AB  - Platelets have long been implicated in the aetiology of cerebral vasospasm (CV)
      after subarachnoid haemorrhage (SAH). It was noticed that vasospastic CSF
      (CSF(V)) could be formed in vitro by the mixing of control blood (with platelets)
      and non-SAH CSF. We also propose a hypothesis for the aetiology of CV after SAH
      based on this and previous research. This study also aims to determine which
      blood fraction is responsible for the stimulation of O(2) consumption and
      vasospasm of blood vessels. Control blood was separated into various fractions
      and mixed with non-SAH CSF. The activity of the resulting mixture and the blood
      fraction alone were assessed. Only the fractions containing platelets mixed with
      CSF showed vasoactivity. These data suggest that platelets plus some component in
      the CSF produce vasoactive factors with actions similar to CSF(V). This study may
      help to elucidate the aetiology of CV after SAH.

PMID- 12615515
TI  - Neopterin as a potential modulator of tumor cell growth and proliferation.
AB  - The present article proposes tumor-promoting biochemical effects of the
      immunologically active pteridine-compound neopterin. Based on previous findings
      of interactions between neopterin and the cellular redox state, two major
      pathways of tumor progression are presented: (1) the inhibition of nitric oxide
      induced apoptotic death of tumor cells via suppression of nitric oxide synthesis
      in the presence of neopterin; (2) the stimulatory effects of neopterin on the
      production and release of angiogenic growth factors. High serum neopterin
      concentrations are a common finding in tumor patients and correlate well with the
      fatal outcome of the disease. Affection of tumor tissue growth as well as
      formation of metastases by neopterin may provide an explanation for these
      clinical observations.

PMID- 12615516
TI  - Stapedoplasty in patients with small air-bone gap: why not?
AB  - Otosclerosis is a primary osteodystrophy which affects a localized area within
      the human temporal bone. Hearing loss is the most functional deficit caused by
      otosclerosis. However, tinnitus and vestibular disorders are frequently reported
      by otosclerotic patients, especially in those patients with inner ear
      involvement. The best therapy in achieving a significant improvement is surgery
      (stapedoplasty). In most patients if the operation is not carried out for pure
      middle ear type, the hearing impairment can progress to high-degree hearing loss.
      Recently, guidelines for the treatment of otosclerosis reported the 20 dbHL
      threshold as the minimum air-bone gap in performing stapedoplasty. We believe
      that stapedoplasty is an effective procedure for selected patients affected by
      otosclerosis with an air-bone gap which is smaller than 20 dbHL. An operation in
      the earlier phases of the disease can arrest the progression of otosclerosis,
      preserve inner ear structures and provide a complete auditory recovery, with
      increased satisfaction of the patient.

PMID- 12615517
TI  - Speaking with a mirror: engagement of mirror neurons via choral speech and its
      derivatives induces stuttering inhibition.
AB  - 'Choral speech', 'unison speech', or 'imitation speech' has long been known to
      immediately induce reflexive, spontaneous, and natural sounding fluency, even the
      most severe cases of stuttering. Unlike typical post-therapeutic speech, a
      hallmark characteristic of choral speech is the sense of 'invulnerability' to
      stuttering, regardless of phonetic context, situational environment, or audience
      size. We suggest that choral speech immediately inhibits stuttering by engaging
      mirror systems of neurons, innate primitive neuronal substrates that dominate the
      initial phases of language development due to their predisposition to reflexively
      imitate gestural action sequences in a fluent manner. Since mirror systems are
      primordial in nature, they take precedence over the much later developing
      stuttering pathology. We suggest that stuttering may best be ameliorated by
      reengaging mirror neurons via choral speech or one of its derivatives (using
      digital signal processing technology) to provide gestural mirrors, that are
      nature's way of immediately overriding the central stuttering block.

PMID- 12615519
TI  - Cold adaptation as a life style strategy.
AB  - Humans evolved in Africa, where climate would have required cold adaptation.
      Modern humans have housing which separates them from the environment. Metabolic
      disorders are prevalent in populations with excess Western diet and lack of
      exercise. A thrifty genotype has been proposed as an explanation for
      susceptibility. An alternative explanation is that cold adaptation is absent. But
      the human genome is complex, and there are many variations possible in the
      metabolic pathways. Behaviour which uses the circadian rhythms of metabolism may
      be helpful for fitness.

PMID- 12615518
TI  - Nicotinamide-containing sunscreens for use in Australasian countries and cancer
      provoking conditions.
AB  - Nicotinamide has been employed to stimulate the repair of DNA damaged by chemical
      and physical means. It has also been used to promote the antitumor
      characteristics of keratinocytes and the suppression of UVB photocarcinogenesis.
      Therefore, I recommend the addition of this substance to sunscreens in order to
      develop a new generation of sunscreens for use in Australasian countries and
      cancer-provoking conditions. The anti-acne, skin lightening, and epidermal
      barrier improving effects of nicotinamide will afford another unique advantages
      to these new sunscreens.

PMID- 12615520
TI  - Polymorphisms of sorbitol dehydrogenase (SDH) gene and susceptibility to diabetic
      retinopathy.
AB  - The polyol pathway consists of two enzymes aldose reductase (AR) and sorbitol
      dehydrogenase (SDH); the former is the first enzyme in the polyol pathway, that
      catalyzes the reduction of glucose to sorbitol, the latter is the second one,
      that converts sorbitol to fructose using by NAD(+) as a cofactor. We along with
      others have recently found that SDH activity, the second step in the polyol
      pathway, might make a greater contribution to the etiology of diabetic
      retinopathy than does the first step involving AR. In this paper, we propose a
      novel hypothesis that polymorphisms of SDH gene may be correlated with SDH gene
      expression levels in diabetic retinas, thus being a valuable genetic marker for
      diabetic retinopathy.

PMID- 12615521
TI  - Work, salt intake and the development of stomach cancer.
AB  - An excess of stomach cancer among workers has been observed and it could be
      argued that men whose occupation involves heavy work eat more and are
      consequently exposed to a greater quantity of carcinogens in their food. Working
      under conditions of heat stress greatly increases a worker's salt excretion by as
      much as 0.1-15.0 g through sweating during one shift of work. Workers exposed to
      heat stress had consumed daily as much as from 13.0 to 38.0 g of salt, which is
      much higher than the safe level of 6 g/person/day recommended by the WHO, to keep
      a balance of salt in the body. Because salt strongly enhances and promotes
      chemical gastric carcinogenesis and Helicobacter pylori infection in both humans
      and animals, there is an association between work, salt intake, and the
      development of stomach cancer among workers in particular and in humans in
      general.

PMID- 12615522
TI  - An analysis associating the presence of Claviceps purpurea in grassland with the
      incidence of type 1 diabetes.
AB  - We introduce our paper by briefly outlining how we came to the conclusion that
      neurons in the brain and cells in other tissues can be killed by high
      intracellular concentrations of calcium ions (Ca(2+)). The life cycle of
      Claviceps purpurea is then described before theoretical information is drawn upon
      which indicates that ergot alkaloids can inactivate alpha adrenergic receptors
      for noradrenaline released from sympathetic nerve terminals. We deduce that
      inhibition of these receptors by ergot alkaloids leads to an increase in
      intracellular Ca(2+) concentration which can cause the death of the insulin
      producing cells of the pancreas.

PMID- 12615523
TI  - The radiographic diagnostic value of low intensity reduction of the lung
      compliance in malignant neoplasms.
AB  - The evaluation of low-intensity reduction in the compliance of the lung
      parenchyma (LIRCLP) can, we believe, give early diagnostic signs from a few
      months to two or more years before the time at which diagnosis can be made today
      from chest radiograms or CT scan of the chest in a significant number of cases of
      secondary lung neoplasm. Moreover, it can provide valuable information on small
      improvements or deteriorations in the great majority of patients with malignant
      neoplasms of the lung during the course of the illness. In general, the
      evaluation of LIRCLP improves the diagnostic capabilities not only of chest
      radiograms but also to some degree of CT scans of the chest. We consider that,
      apart from malignant neoplasms of the lung, it may also be of use in a large
      number of pathological conditions of the lung. We propose that the term
      hypoatelectasis be used for LIRCLP.

PMID- 12615524
TI  - The physiology and pharmacology of singlet oxygen.
AB  - Reactive oxygen species (ROS) are generated by many different cells. Singlet
      oxygen (1O(2)) and a reaction product of it, excited carbonyls (C=O*), are
      important ROS. 1O(2) and C=O* are nonradicalic and emit light (one
      photon/molecule) when returning to ground state oxygen. Especially activated
      polymorphonuclear neutrophil granulocytes (PMN) produce large amounts of 1O(2).
      Via activation of the respiratory burst (NADPH oxidase and myeloperoxidase) they
      synthesize hypochlorite (NaOCl) and chloramines (in particular N-chlorotaurine).
      Chloramines are selective and stable chemical generators of 1O(2). In the human
      organism, 1O(2) is both a signal and a weapon with therapeutic potency against
      very different pathogens, such as microbes, virus, cancer cells and thrombi.
      Chloramines at blood concentrations between 1 and 2 mmol/L inactivate lipid
      enveloped virus and chloramines at blood concentrations below 0.5 mmol/L, i.e. at
      oxidant concentrations that do not affect thrombocytes or hemostasis factors, act
      antithrombotically by activation of the physiologic PMN mediated fibrinolysis;
      this thrombolysis is of selective nature, i.e. it does not impair the hemostasis
      system of the patient allowing the antithrombotic treatment in patients where the
      current risky thrombolytic treatment is contraindicated. The action of 1O(2)
      might be compared to the signaling and destroying gunfire of soldiers directed
      against bandits at night, resulting in an autorecruitment of the physiological
      inflammatory response. Chloramines (such as the mild and untoxic oxidant
      chloramine T (N-chloro-p-toluene-sulfonamide)) and their signaling and destroying
      reaction product 1O(2) might be promising new therapeutic agents against a
      multitude of up to now refractory diseases.

PMID- 12615525
TI  - The earlier age of onset of malignancy in developing world is related to overall
      infection burden and could be due to the effect on telomere length.
AB  - It is a common observation that many common cancers occur at a younger age in
      developing countries, like India. The cancer registry data provide incidence rate
      of different cancers, which suggest the same. Telomere shortening is involved in
      ageing of cells. Inflammation and infection result in telomere shortening in
      immune cells. The higher infection burden in developing countries might mean an
      earlier ageing of immune cells, resulting in decreased efficiency of immune
      surveillance and thus predisposing to cancer at an earlier age than seen in
      developed countries with lesser infection burden.

PMID- 12615526
TI  - Singlet oxygen (1O2)-oxidazable lipids in the HIV membrane, new targets for AIDS
      therapy?
AB  - Human immunodeficiency virus (HIV) is a lipid enveloped virus. The lipid envelope
      differs significantly from the lipid membrane of normal human cells: it contains
      high amounts of cholesterol, that is of importance for the virus-cell interaction
      (for entry and exit of the virus) at so-called lipid rafts. Cholesterol, as a R
      C=C-R compound possesses an oxidazable carbenic bond. The present work suggests
      the inactivation of HIV by oxidation of viral cholesterol and/or unsaturated
      fatty acids. For oxidation, the relatively mild oxidant singlet oxygen (1O(2))
      might be used. 1O(2) is generated by redoxcyclers (e.g., of the quinone type,
      such as vitamin K) or by chloramines (e.g., taurine-chloramine). At the 1O(2)
      concentrations necessary to inactivate lipid enveloped virus in human blood the
      oxidation-sensible critical hemostasis parameters such as thrombocytes and
      fibrinogen are only partly inactivated. Therefore, it is proposed to consider
      generators of 1O(2) as a new form of AIDS therapy.

PMID- 12615527
TI  - Gene silencing--a new theory of aging.
AB  - The aging process involves silencing of the genes through methylation of promoter
      sequences and the acetylation of histones. This process contributes not only to
      aging, but also cancer when silencing affects tumor suppressor genes.
      Antineoplastons work as molecular switches, turning inactive tumor suppressor
      genes back on through demethylation of the DNA and acetylation of the histones.
      While they activate tumor suppressor genes, antineoplastons also activate some
      additional genes silenced during the aging process. Evidence of activation of
      silenced genes can be pursued by documenting the relationship between 'molecular
      switches' - DNA-demethylating agents and histone deacetylation inhibitors, genes
      which are turned on by them, and clinical anti-aging changes.

PMID- 12615528
TI  - The metabolic syndrome as a vicious cycle: does obesity beget obesity?
AB  - Most attempts at weight loss are frustrated by the body's propensity to maintain
      fat mass. There are genetic and environmental mechanisms behind this phenomenon,
      such as thrifty genes, sedentary lifestyle and abundant food resources. We will
      outline a physiologic mechanism that may perpetuate obesity once it develops.
      Specifically, we suggest that obesity-induced hyperinsulinemia facilitates fuel
      storage as fat. This can be exacerbated by high glucocorticoid activity, low
      growth hormone (GH) activity and the paradoxical increase in free fatty acid
      (FFA) flux resulting from basal lipolysis in an expanded fat mass. We also
      outline mechanisms by which obesity may perpetuate low GH and increased
      glucocorticoid activity in the metabolic syndrome.

PMID- 12615529
TI  - Why are sperm cells phagocytosed by leukocytes in the female genital tract?
AB  - When mammalian sperm cells enter the female genital tract, many of them are
      attacked and phagocytosed by leukocytes and epithelial cells. Although this
      intriguing phenomenon is known for almost five decades, there is no satisfactory
      explanation for it. Here, on the basis of recent information on the nature of the
      capacitated stage of mammalian sperm cells, that is, the sperm's stage of
      readiness for fertilizing the egg, I put forward the hypothesis that the
      phagocytosed sperm cells are post-capacitated cells. These cells, which lost
      their fertilizing ability and became functionless, apparently recruit leukocytes
      and then undergo apoptosis and phagocytosis and, thereby, are removed from the
      female genital tract. This fast removal probably prevents severe inflammation
      that could have been caused by necrotic products of sperm cells that remain
      functionless in the tract.

PMID- 12615530
TI  - Is ATP-sensitive K+ channel (K+ATP) recruitment a common mechanism for ECG-ST
      segment depression and elevation?
AB  - ATP sensitive (K(+)(ATP)) potassium cardiac channels are recruited when ATP
      levels are low as in ischemic injury and acute trauma. Such activation results in
      ECG-ST elevation and cardiac arrhythmias. K(+)(ATP) channel recruitment may be
      blocked by the sulfonylurea glibenclamide, permitting a wide variety of animal
      experimentation designed to test the genesis of ECG-ST segment elevations and
      depressions in diverse conditions including digitalis effect, acute arterial
      occlusion, tachycardias, and acute pericarditis. A specific series of animal
      experiments designed to test this hypothesis is proposed. Clinical implications
      are discussed.

PMID- 12615531
TI  - Can CK-MB and cTn-I be detected in the peripheral circulation within the first 10
      min of acute coronary ischemia?
AB  - There are approximately 4 million patients hospitalized with suspected acute
      coronary syndromes (ACS) annually. However, the current standard tools for
      assessing ACS in the Emergency Department are felt to have insufficient
      sensitivity and specificity. Animal studies have demonstrated that CK-MB and
      troponin-I are released in a biphasic pattern with an initial transient release
      which peaks and falls within the first 10 min of ischemia. We hypothesize that
      transient elevations of CK-MB and troponin-I can be detected in the peripheral
      circulation within the first 10 min of ischemia in a human model of brief
      coronary ischemia. We also present results from our pilot study that failed to
      confirm this hypothesis; however, this pilot studied was insufficiently powered
      to detect potentially clinically important results.

PMID- 12615532
TI  - Plato, Sun Tsu, and the Art of War (on cancer). Can we learn from history?
AB  - Cancer, in all its guises is on the rise along with the population growth. While
      not the leading cause of death in the world, it may soon garner that unfortunate
      honor. In the US, it is second only to heart disease. The 'war on cancer'
      declared in the US by Richard Milhouse Nixon is not being won. At present,
      treatment modalities are limited to resection, immunotoxins, radiation,
      chemotherapy, genomeceuticals, and variations on those themes. It is anticipated
      that with the emerging human genome data, most of these areas will be expanded,
      with the possible exception of radiation. However, all these approaches have two
      things in common. First, they have met with limited success. Second, they all
      work around the similar idea of containment and eradication in situ of the
      disease. This paper presents an alternative and novel way of looking at the
      research and treatment options for cancer taking two lessons from history. First,
      is Plato's dialectic where 'truth' is uncovered by examining a situation from two
      opposite directions at once. Second, from Sun Tsu's treaty on the Art of War,
      where he recommends that when faced with a superior opponent, one method of
      dealing with the situation is to provoke them, anger them, cause them to move.
      The second tactic wears out the opponent and presents them in a more favorable
      situation for assault. It is suggested herein that perhaps cancer can be attacked
      by first assisting its growth, and causing metastasis to a location more
      favorable to attack with the common mechanisms cited above.

PMID- 12615533
TI  - Is sickling trait associated with an increased risk for multiple myeloma?
AB  - In the US, multiple myeloma (MM) rates have been disproportionately higher in
      states with high proportions of African Americans. Understanding this disparity
      may assist in developing new control/prevention strategies for MM. Most of the
      known associated risk factors for MM are occupational and/or environmental. A
      possible chromosomal link between sickle cell disease and leukemia, a hematologic
      malignancy like MM, has been described. Interleukin-6 (IL-6) has been reported to
      be central to the pathogenesis of MM, inducing proliferation and inhibiting
      apoptosis in neoplastic plasma cells. IL-6 levels are also increased in healthy
      sickle cell disease patients. This role of IL-6 in the pathophysiology of MM and
      sickle cell disease makes it pertinent to ask whether persons with abnormal
      sickling erythrocytes are more at risk of developing MM than persons with no
      abnormal sickling erythrocytes. Abrogating the IL-6 signaling pathway will be of
      therapeutic interest for both MM and sickle cell disease.

PMID- 12615534
TI  - Why HIV-1 has diffused so much more rapidly in Sub-Saharan Africa than in North
      America.
AB  - AIDS was first identified in Sub-Saharan Africa and North America in the early
      1980s. Over the past twenty years, however, HIV-1 has diffused much more rapidly
      in the former continent than in latter. This appears to be because the virus
      cannot diffuse well in local populations that have an adequate dietary intake of
      selenium.

PMID- 12615535
TI  - Increasing the diffraction limit and internal order of a membrane protein crystal
      by dehydration.
AB  - It is notoriously difficult to produce crystals of membrane proteins that
      diffract to sufficient resolution for structural studies by X-ray
      crystallography. Crystals of a prokaryotic CLC chloride channel that were
      initially unacceptable for structural analysis improved in both quality and
      diffraction limit by a process of dehydration. The loss of water decreased the
      dimensions of the unit cell axes by up to 25 A, improved the diffraction limit
      from 8.0 to 4.0 A, and decreased the mosaicity to values of approximately 1
      degrees. Dehydration of integral membrane protein crystals should be one of the
      procedures included in the initial screening for appropriate crystals and as a
      method of improving the diffraction limits of existing crystals.

PMID- 12615536
TI  - A comparative three-dimensional model of the carboxy-terminal domain of the
      lambda repressor and its use to build intact repressor tetramer models bound to
      adjacent operator sites.
AB  - A model for residues 93-236 of the lambda repressor (1gfx) was predicted, based
      on the UmuD(') crystal structure, as part of four intact repressor molecules
      bound to two adjacent operator sites. The structure of region 136-230 in 1gfx was
      found to be nearly identical to the independently determined crystal structure of
      the 132-236 fragment, 1f39, released later by the PDB. Later, two more tetrameric
      models of the lambda repressor tetramer bound to two adjacent operator sites were
      constructed by us; in one of these, 1j5g, the N-domain and C-domain coordinates
      and hence monomer-monomer and dimer-dimer interactions are almost the same as in
      1gfx, but the structure of the linker region is partly based on the linker region
      of the LexA dimer in 1jhe; in the other, 1lwq, the crystalline tetramer for
      region 140-236 has been coopted from the crystal structure deposited in 1kca, the
      operator DNA and N-domain coordinates of which are same as those in 1gfx and
      1j5g, but the linker region is partly based on the LexA dimer structures 1jhe and
      1jhh. Monomer-monomer interactions at the same operator site are stabilized by
      exposed hydrophobic side chains in beta-strands while cooperative interactions
      are mostly confined to beta(6) and some adjacent residues in both 1gfx and 1j5g.
      Mutational data, existence of a twofold axis relating two C-domains within a
      dimer, and minimization of DNA distortion between adjacent operator sites allow
      us to roughly position the C-domain with respect to the N-domain for both 1gfx
      and 1j5g. The study correlates these models with functional, biochemical,
      biophysical, and immunological data on the repressor in the literature. The
      oligomerization mode observed in the crystal structure of 132-236 may not exist
      in the intact repressor bound to the operator since it is shown to contradict
      several published biochemical data on the intact repressor.

PMID- 12615537
TI  - Analysis of a Plasmodium falciparum EBA-175 peptide with high binding capacity to
      erythrocytes and their analogues using 1H NMR.
AB  - A 175-erythrocyte-binding protein (EBA-175) conserved high-activity binding
      peptide (HABP), called 1783 (nonimmunogenic, nonprotective against Plasmodium
      falciparum malaria), was analyzed for antigenic and protective activity in Aotus
      monkeys, together with several of its analogues. 1H NMR studies of peptides
      17912, 14016, and 22814 allowed their structure to be related to their biological
      function. These peptides showed helical regions having differences in their
      position and length. Nonimmunogenic, nonprotective peptides 1783 and 17912 showed
      an extensive helical region, while the 22814 immunogenic protective peptide's
      alpha-helix was found in the N-terminal region. This suggests that the more
      flexible C-terminal region will allow better interaction between these peptides
      and immune system molecules as well as relating these peptides' three-dimensional
      structure to their immunogenicity and protective activity, thus leading to a more
      rational development of the new malaria multicomponent vaccine.

PMID- 12615538
TI  - Detergent organisation in crystals of monomeric outer membrane phospholipase A.
AB  - The structure of the detergent in crystals of outer membrane phospholipase A
      (OMPLA) has been determined using neutron diffraction contrast variation. Large
      crystals were soaked in stabilising solutions, each containing a different
      H(2)O/D(2)O contrast. From the neutron diffraction at five contrasts, the 12 A
      resolution structure of the detergent micelle around the protein molecule was
      determined. The hydrophobic beta-barrel surfaces of the protein molecules are
      covered by rings of detergent. These detergent belts are fused to neighbouring
      detergent rings forming a continuous three-dimensional network throughout the
      crystal. The thickness of the detergent layer around the protein varies from 7-20
      A. The enzyme's active site is positioned just outside the hydrophobic detergent
      zone and is thus in a proper location to catalyse the hydrolysis of phospholipids
      in a natural membrane. Although the dimerisation face of OMPLA is covered with
      detergent, the detergent density is weak near the exposed polar patch, suggesting
      that burying this patch in the enzyme's dimer interface may be energetically
      favourable. Furthermore, these results indicate a crucial role for detergent
      coalescence during crystal formation and contribute to the understanding of
      membrane protein crystallisation.

PMID- 12615539
TI  - The native-like conformation of Ure2p in fibrils assembled under physiologically
      relevant conditions switches to an amyloid-like conformation upon heat-treatment
      of the fibrils.
AB  - The [URE3] phenotype in the yeast Saccharomyces cerevisiae is inherited by a
      prion mechanism involving self-propagating Ure2p aggregates. It is believed that
      assembly of intact Ure2p into fibrillar polymers that bind Congo Red and show
      yellow-green birefringence upon staining and are resistant to proteolysis is the
      consequence of a major change in the conformation of the protein. We recently
      dissected the assembly process of Ure2p and showed the protein to retain its
      native alpha-helical structure upon assembly into protein fibrils that are
      similar to amyloids in that they are straight, bind Congo red and show green
      yellow birefringence and have an increased resistance to proteolysis (). Here we
      further show using specific ligand binding, FTIR spectroscopy and X-ray fiber
      diffraction that Ure2p fibrils assembled under physiologically relevant
      conditions are devoid of a cross-beta core. The X-ray fiber diffraction pattern
      of these fibrils reveals their well-defined axial supramolecular order. By
      analyzing the effect of heat-treatment on Ure2p fibrils we bring evidences for a
      large conformational change that occurs within the fibrils with the loss of the
      ligand binding capacity, decrease of the alpha helicity, the formation of a cross
      beta core and the disappearance of the axial supramolecular order. The extent of
      the conformational change suggests that it is not limited to the N-terminal part
      of Ure2p polypeptide chain. We show that the heat-treated fibrils that possess a
      cross-beta core are unable to propagate their structural characteristic while
      native-like fibrils are. Finally, the potential evolution of native-like fibrils
      into amyloid fibrils is discussed.

PMID- 12615540
TI  - Crystallization and preliminary crystallographic analysis of San Miguel sea lion
      virus: an animal calicivirus.
AB  - The Caliciviridae is a family of nonenveloped, icosahedral, positive-sense single
      stranded RNA viruses. This family of viruses consists of both animal and human
      pathogens. Adapting human caliciviruses to cell culture has not been successful,
      whereas some animal caliciviruses, including San Miguel sea lion virus, have been
      successfully propagated in vitro. Here we report the crystallization of San
      Miguel sea lion virus serotype 4 (SMSV4) and the preliminary X-ray
      crystallographic analysis of the crystals. SMSV4 have been crystallized using the
      hanging-drop method. These crystals diffracted to approximately 3A resolution
      using a synchrotron radiation source. A single crystal under cryo-conditions
      yielded a complete set of diffraction data. Data processing of the diffraction
      patterns showed that SMSV crystals belong to I23 space group with cell dimensions
      a=b=c=457 A. The crystallographic asymmetric unit includes five icosahedral
      asymmetric units, each consisting of three capsid protein subunits. In the space
      group I23, given the icosahedral symmetry and the size of the virus particle, the
      location of the particle is constrained to be at the point where the
      crystallographic 2- and 3-fold axes intersect. The orientation of the virus
      particle in the unit cell was ascertained by self-rotation function calculations.

PMID- 12615541
TI  - The 1.45 A three-dimensional structure of C-phycocyanin from the thermophilic
      cyanobacterium Synechococcus elongatus.
AB  - The conversion of solar radiation to chemical energy by photosynthetic organisms
      provides the primary driving force for life on earth. Light energy is captured by
      a variety of pigments, usually bound to proteins, which vary with different types
      of organisms. We report here the 1.45 A resolution three-dimensional structure of
      one such pigment protein, C-phycocyanin, from Synechococcus elongatus. The
      structure is at the highest resolution achieved for any such phycobiliprotein.
      This level of resolution was made possible by implementing a novel
      crystallization method whereby nucleation is decoupled from subsequent growth, by
      incubating crystallizing drops for 7h under nucleation conditions and then
      transferring them to metastable conditions for growth. This is done without
      touching the crystallization drops throughout the process.

PMID- 12615542
TI  - Assemblies of Alzheimer's peptides A beta 25-35 and A beta 31-35: reverse-turn
      conformation and side-chain interactions revealed by X-ray diffraction.
AB  - Alzheimer's beta amyloid protein (A beta) is a 39 to 43 amino acid peptide that
      is a major component in the neuritic plaques of Alzheimer's disease (AD). The
      assemblies constituted from residues 25-35 (A beta 25-35), which is a sequence
      homologous to the tachykinin or neurokinin class of neuropeptides, are
      neurotoxic. We used X-ray diffraction and electron microscopy to investigate the
      structure of the assemblies formed by A beta 25-35 peptides and of various length
      sequences therein, and of tachykinin-like analogues. Most solubilized peptides
      after subsequent drying produced diffraction patterns characteristic of beta
      sheet structure. Moreover, the peptides A beta 31-35 (Ile-Ile-Gly-Leu-Met) and
      tachykinin analogue A beta(Phe(31))31-35 (Phe-Ile-Gly-Leu-Met) gave powder
      diffraction patterns to 2.8A Bragg spacing. The observed reflections were indexed
      by an orthogonal unit cell having dimensions of a=9.36 A, b=15.83 A, and c=20.10
      A for the native A beta 31-35 peptide, and a=9.46 A, b=16.22 A, and c=11.06 A for
      the peptide having the Ile31Phe substitution. The initial model was a beta strand
      where the hydrogen bonding, chain, and intersheet directions were placed along
      the a, b, and c axes. An atomic model was fit to the electron density
      distribution, and subsequent refinement resulted in R factors of 0.27 and 0.26,
      respectively. Both peptides showed a reverse turn at Gly33 which results in
      intramolecular hydrogen bonding between the antiparallel chains. Based on
      previous reports that antagonists for the tachykinin substance P require a
      reverse turn, and that A beta is cytotoxic when it is oligomeric or fibrillar, we
      propose that the tachykinin-like A beta 31-35 domain is a turn exposed at the A
      beta oligomer surface where it could interact with the ligand-binding site of the
      tachykinin G-protein-coupled receptor.

PMID- 12615543
TI  - Crystal structure of pokeweed antiviral protein with well-defined sugars from
      seeds at 1.8A resolution.
AB  - The crystal structure of pokeweed antiviral protein from seeds of Phytolacca
      americana (PAP-S) was solved at 1.8A. PAP-S is a one-chain ribosome-inactivating
      protein (RIP) and distinctively contains three well-defined N-acetylglucosamines,
      each covalently linked to an asparagine residue at positions, 10, 44, and 255,
      respectively. The high-resolution structure clearly shows the three mono-sugars
      to have either an alpha- or a beta-conformation. Two of sugars are located on the
      same side of the molecule with the active pocket. Except one hydrogen bond, there
      are no intermolecular interactions between the polypeptide chain and the sugars.
      Instead the sugar conformations appear to be stabilized by intermolecular
      interactions. The sugar structure defined at high resolution provides a
      structural basis for understanding their possible biological activity. The
      structural comparisons of PAP-S with other PAPs reveal that the major disparity
      of these homologous molecules is the different charge distribution on the upper
      right side of the front side near the active pocket. Based on the available
      structure of the 50S ribosomal subunit, the possible interactions between PAPs
      and the ribosome are discussed.

PMID- 12615544
TI  - A biochemical model of photosynthesis for mango leaves: evidence for the effect
      of fruit on photosynthetic capacity of nearby leaves.
AB  - Variations in leaf nitrogen concentration per unit mass (Nm) and per unit area
      (Na), mass-to-area ratio (Ma), total nonstructural carbohydrates (Ta), and
      photosynthetic capacity (maximum carboxylation rate, electron transport capacity,
      rate of phosphate release in triose phosphate utilization and dark respiration
      rate) were studied within the digitized crowns of two 3-year-old mango trees
      (Mangifera indica L.) on La Reunion Island. Additional measurements of Nm, Na,
      Ma, Ta and photosynthetic capacities were performed on young, fully expanded
      leaves of 11-year-old mango trees. Leaves of similar gap fractions were taken far
      from and close to developing fruits. Unlike Nm, both Na and Ta were linearly
      correlated to gap fraction. Similar relationships were found for all leaves
      whatever their age and origin, except for Ta, for which we found a significant
      tree effect. Photosynthetic capacity was nonlinearly correlated to Na, and a
      unique relationship was obtained for all types of leaves. Photosynthetic
      acclimation to light was mainly driven by changes in Ma, but allocation of total
      leaf N between the different photosynthetic functions also played a substantial
      role in acclimation to the lowest irradiances. Leaves close to developing fruits
      exhibited a higher photosynthetic capacity than other leaves, but similar Ta. Our
      data suggest that Ta does not control photosynthetic capacity in mango leaves. We
      used the data to parameterize a biochemically based model of photosynthesis and
      an empirical stomatal conductance model, allowing accurate predictions of net
      photosynthesis of leaves in field-grown mango trees.

PMID- 12615545
TI  - Characterizing the frost sensitivity of black spruce photosynthesis during cold
      acclimation.
AB  - We used photosynthetic light response curves to measure and model the responses
      of two provenances of 3-year-old black spruce (Picea mariana (Mill.) BSP)
      seedlings to severe artificial frost treatments applied at 2-week intervals
      during cold acclimation. Black spruce seedlings responded to cold acclimation
      with long-term suppression of photosynthetic capacity (Amax) and apparent quantum
      use efficiency (alpha'). Short-term reductions in both photosynthetic parameters
      following frost treatments were dependent on the extent of cold acclimation of
      the seedlings and the severity of the frost treatments. Large reductions in Amax
      in response to the frost treatments were observed in seedlings that had undergone
      little cold acclimation and these reductions were associated with an irreversible
      reduction in alpha'. Such seedlings recovered only partially during the
      subsequent 23 days, whereas seedlings in most other treatments showed complete
      recovery of Amax after 13 days. The impact of frost treatments on Amax and alpha'
      did not vary with seedling provenance. We propose an algorithm that predicts the
      combined effects of cold acclimation and severe freezing temperatures on the
      extent of the suppression of A(max) during autumn. The algorithm is based on (1)
      the maximum Amax observed during the growing season, (2) the accumulation of cold
      degree-days, based on a minimum nocturnal temperature < 5 degrees C, and (3) the
      severity of freezing temperatures during autumn. The parameters developed in the
      algorithm showed that cold acclimation of black spruce seedlings had a greater
      impact on the reduction of Amax in autumn than did the severe frost treatments.
      Mean Amax of seedlings subjected to artificial frosts showed a strong correlation
      with values predicted by the algorithm (r2 = 0.91).

PMID- 12615546
TI  - Influence of branch autonomy on fruit, scaffold, trunk and root growth during
      stage III of peach fruit development.
AB  - We studied the influence of branch autonomy on the growth of reproductive and
      vegetative organs by establishing different patterns of fruit distribution within
      and between large branch units (scaffolds) in mature peach trees (Prunus persica
      (L.) Batsch cv. 'Elegant Lady'). Different patterns of fruit distribution were
      established by defruiting either whole scaffolds (uneven fruit distribution
      between scaffolds; US) or several selected hangers (small fruiting branches) per
      tree (uneven fruit distribution between hangers; UH). The effects of these
      patterns were compared with the effects of an even fruit distribution treatment
      (EVEN) in which fruits were thinned to achieve maximum uniformity of fruit
      distribution within the canopy. The desired fruit loads were obtained by
      differentially thinning the remaining bearing parts. On a tree basis, the
      response of mean fruit mass to fruit load was strongly affected by fruit
      distribution. The steepest mean fruit mass to fruit load relationship was found
      in US trees, whereas the relationship in UH trees was intermediate between the US
      and EVEN trees. On a scaffold basis, differences in fruit size between EVEN and
      US trees with similar fruit loads, though statistically significant, were
      relatively small, indicating that scaffolds were almost totally autonomous with
      respect to dry matter partitioning to fruit during the final stage of peach fruit
      growth. Hangers also appeared to exhibit significant autonomy with respect to the
      distribution of dry matter during the final phase of fruit growth. Branch
      autonomy was evident in scaffold growth: defruited scaffolds in the US treatment
      grew more than fruited scaffolds, and fruit distribution treatments had little
      impact on scaffold cross-sectional area on a tree basis. On the other hand, as
      observed for fruit growth, branch autonomy did not appear to be complete because
      the fruited scaffolds grew more in US trees than in EVEN trees under heavy
      cropping conditions. However, the effect of fruit distribution occurred only over
      short distances, and was negligible on organs located farther away from the
      source of heterogeneity (fruits), such as the trunk and roots.

PMID- 12615547
TI  - Factors influencing red expression in autumn foliage of sugar maple trees.
AB  - We evaluated factors influencing the development of autumn red coloration in
      leaves of sugar maple (Acer saccharum Marsh.) by measuring mineral nutrient and
      carbohydrate concentrations, water content, and phenology of color development of
      leaves from 16 mature open-grown trees on 12 dates from June through October
      1999. Mean foliar nutrient and carbohydrate concentrations and water content were
      generally within the range published for healthy sugar maple trees. However,
      foliar nitrogen (N) concentrations were near deficiency values for some trees.
      The timing and extent of red leaf coloration was consistently correlated with
      both foliar N concentrations and starch or sugar concentrations, which also
      varied with N status. Leaves of trees with low foliar N concentrations turned red
      earlier and more completely than those of trees with high foliar N
      concentrations. Low-N trees also had higher foliar starch concentrations than
      high-N trees. During the autumn development of red leaf coloration, foliar
      starch, glucose and fructose concentrations were positively correlated with red
      leaf color expression. At peak red expression, the concentrations of glucose,
      fructose, sucrose and stachyose were all positively correlated with red color
      expressed as a percent of total leaf area.

PMID- 12615548
TI  - Leaf water relations of Eucalyptus cloeziana and Eucalyptus argophloia in
      response to water deficit.
AB  - Leaf water relations responses to limited water supply were determined in 7-month
      old plants of a dry inland provenance of Eucalyptus argophloia Blakely and in a
      humid coastal provenance (Gympie) and a dry inland provenance (Hungry Hills) of
      Eucalyptus cloeziana F. Muell. Each provenance of E. cloeziana exhibited a lower
      relative water content at the turgor loss point, a lower apoplastic water
      content, a smaller ratio of dry mass to turgid mass and a lower bulk modulus of
      elasticity than the single provenance of E. argophloia. Osmotic potential at full
      turgor and water potential at the turgor loss point were significantly lower in
      E. argophloia and the inland provenance of E. cloeziana than in the coastal
      provenance of E. cloeziana. There was limited osmotic adjustment in response to
      soil drying in E. cloeziana, but not in E. argophloia. Between-species
      differences in water relations parameters were larger than those between the E.
      cloeziana provenances. Both E. cloeziana provenances maintained turgor under
      moderate water stress through a combination of osmotic and elastic adjustments.
      Eucalyptus argophloia had more rigid cell walls and reached lower water
      potentials with less reduction in relative water content than either of the E.
      cloeziana provenances, thereby enabling it to extract water from dryer soils.

PMID- 12615549
TI  - Boron influences pollen germination and pollen tube growth in Picea meyeri.
AB  - To study the role of boron in pollen germination and pollen tube growth of Picea
      meyeri Rehd. et Wils., pollen grains were cultured in standard medium or boron
      deficient medium. Effects of boron on the localization of pectins and callose in
      the walls of pollen tubes were observed by laser scanning confocal microscopy
      after staining with aniline blue or immunolabeling with antibodies JIM5 and JIM7.
      Changes in the structures of pectins and phenolics were investigated by fourier
      transform infrared (FTIR) microspectroscopy. Pollen germination in boron
      deficient medium ranged from 18 to 24%, whereas pollen germination in standard
      medium reached 61%. Callose accumulated in the tip-regions of pollen tubes
      cultured in boron-deficient medium, but not in standard medium. Immunolabeling
      with antibody JIM5 revealed that acidic pectin preferentially accumulated in the
      tip regions of pollen tubes cultured in boron-deficient medium, whereas acidic
      pectin was weakly distributed along the entire lengths of pollen tubes cultured
      in standard medium. Esterified pectin, detected by immunolabeling with antibody
      JIM7, showed a similar distribution pattern in pollen tubes in both the boron
      deficient and standard treatments. The FTIR spectra indicated slight increases in
      contents of phenolics and carboxylic acids and a substantial decrease in the
      content of saturated esters in boron-deficient pollen tubes compared with normal
      pollen tubes. The FTIR spectra confirmed that boron deficiency enhanced acidic
      pectin accumulation in pollen tubes, which may be associated with the increased
      content of carboxylic acid. We conclude that boron has a regulatory role in
      pollen germination and pollen tube growth.

PMID- 12615550
TI  - Hydraulic redistribution by deep roots of a Chihuahuan Desert phreatophyte.
AB  - Downward redistribution of soil water through plant roots has important
      consequences for water and nutrient balance of arid and semi-arid ecosystems.
      Nevertheless, information on the seasonal patterns and magnitudes of
      redistribution is lacking for all but a few plant species. We measured sap flow
      in the taproot and three main lateral roots of a 10-year-old Juglans major Torr.
      tree, on an ephemeral catchment in southeastern Arizona, to determine how
      patterns of redistribution respond to pulses of summer precipitation. Groundwater
      was beyond rooting depth and a hardpan prevented recharge of surface water to
      deep soil layers. Reverse flow (hydraulic descent) commenced in the taproot and
      deep lateral roots in early August after a series of moderate precipitation
      events, and abruptly ceased after all shallow roots were experimentally severed
      in mid-August. On some days, hydraulic descent continued in the deep lateral
      roots during periods of daytime transpiration, and the daily volume of hydraulic
      descent (deep lateral roots plus taproot) ranged from 10 to nearly 60% of daily
      transpiration. The persistent pattern of reverse flow demonstrates that, in some
      plants, water potential gradients from soil to leaf during transpiration are
      often smaller than those between soil layers within the rooting zone. Hydraulic
      descent may be an important component of the water balance of phreatophytic trees
      by facilitating root growth in deep soil layers and by transferring water away
      from shallow-rooted competitors.

PMID- 12615551
TI  - The right medicine.

PMID- 12615552
TI  - Single-factor theories of insomnia--handle with care.

PMID- 12615553
TI  - Are older people still grateful?

PMID- 12615554
TI  - "Abuse of the elderly": a chapter in the World Report on Violence and Health.
      Edited by E. G. Krug et al. Geneva: World Health Organization, 2002.

PMID- 12615555
TI  - Age-related differences in walking stability.
AB  - BACKGROUND: a large proportion of falls in older people occur when walking;
      however the mechanisms underlying impaired balance during gait are poorly
      understood. OBJECTIVE: to evaluate acceleration patterns at the head and pelvis
      in young and older subjects when walking on a level and an irregular walking
      surface, in order to develop an understanding of how ageing affects postural
      responses to challenging walking conditions. METHODS: temporo-spatial gait
      parameters and variables derived from acceleration signals were recorded in 30
      young people aged 22-39 years (mean 29.0, SD 4.3), and 30 older people with a low
      risk of falling aged 75-85 years (mean 79.0, SD 3.0) while walking on a level and
      an irregular walking surface. Subjects also underwent tests of vision, sensation,
      strength, reaction time and balance. RESULTS: older subjects exhibited a more
      conservative gait pattern, characterised by reduced velocity, shorter step length
      and increased step timing variability. These differences were particularly
      pronounced when walking on the irregular surface. The magnitude of accelerations
      at the head and pelvis were generally smaller in older subjects; however the
      smoothness of the acceleration signals did not differ between the two groups.
      Older subjects performed worse on tests of vision, peripheral sensation,
      strength, reaction time and balance. CONCLUSION: the adoption of a more
      conservative basic gait pattern by older people with a low risk of falling
      reduces the magnitude of accelerations experienced by the head and pelvis when
      walking, which is likely to be a compensatory strategy to maintain balance in the
      presence of age-related deficits in physiological function, particularly reduced
      lower limb strength.

PMID- 12615556
TI  - Where now with Do Not Attempt Resuscitation decisions?
AB  - Geriatricians are often asked to make decisions about withholding cardiopulmonary
      resuscitation. This seems to be becoming more difficult and more controversial.
      There has been increased public concern about this subject recently and a
      recognition within the profession of the need for more openness and transparency
      in decision making. The implementation of The Human Rights Act led to updated
      guidelines from professional bodies, but these are likely to need careful
      interpretation in light of local circumstances before they can become a practical
      tool for decision making.

PMID- 12615557
TI  - Older people included in a venous thrombo-embolism clinical trial: a patients'
      viewpoint.
AB  - BACKGROUND AND OBJECTIVES: despite the numerous publications debating ethical
      rules of clinical research, older patients' opinions are rarely taken into
      account. We report on the feelings and memories related by older patients
      included in a randomised controlled trial. DESIGN AND SETTINGS: a closed
      questionnaire was submitted to patients, aged >65 years, who had been included in
      the randomised trial "PREPIC". PREPIC was a multicentre open trial performed in
      France, that included 400 patients over 42 months. The aim of PREPIC was to
      evaluate the benefits and risks of prophylactic filter placement in patients with
      proximal deep-vein thrombosis who were considered to be at risk for pulmonary
      embolism. RESULTS: 104 patients (mean age: 74 years) were interviewed. At the
      time the trial was proposed to them, 45% of patients felt surprised or shocked
      and 30% feared incurring additional risks. While 85% of patients did not remember
      the trial methods (including the randomisation), most older patients (77%) not
      only judged that they received clear medical information but also well remembered
      (95%) the aim of the study and the treatment they received (67%). Finally, most
      older patients not only did not regret their participation (91%), but would also
      recommend their close relations to participate in a clinical trial (62%).
      CONCLUSIONS: this study demonstrates that medical scientific information can be
      understood and remembered by older people.

PMID- 12615558
TI  - The problems of sleep for older women: changes in health outcomes.
AB  - OBJECTIVE: to identify the continuance of sleeping difficulty and medication use
      in a cohort of older Australian women from baseline to 3-year follow-up and to
      explore the relationship between these factors and health-related quality of life
      scores, falls and other health care use. METHOD: a 3-year longitudinal survey of
      10,430 Australian women aged 70-75 years at baseline. These women were
      participants in the Australian Longitudinal Study on Women's Health randomly
      selected from the Australian Medicare database. RESULTS: a majority of women
      (63%) endorsed one or more items related to sleeping difficulty at 3-year follow
      up: 33% reported one item only, 16% reported two or three items, and 14% reported
      more than three items; 4,194 (42.4%) reporting "waking in the early hours", 2,592
      (26.0%) "taking a long time to get to sleep", 2,078 (21.0%) "sleeping badly at
      night", 1,072 (10.8%) "lying awake most of the night" and 1,087 (11.0%) "worry
      keeping you awake". Total scores on the Nottingham Health Profile sleep sub-scale
      ranged from 0-100 and were skewed to the right. The median score was 12.57. There
      was a strong statistical association between reporting sleeping difficulty at
      baseline and at follow-up. A total of 1,532 (15%) women reported use of sleeping
      medication at follow-up and women were 6.5 times more likely to report use if
      they also reported any item of sleep difficulty. There was a moderate level of
      agreement (88%, kappa=0.56) between taking sleeping medication within 4 weeks
      before the baseline survey and within 4 weeks before follow-up. On multivariate
      analysis, sleeping difficulty at baseline was negatively associated with general
      health perceptions, emotional role limitations and general mental health sub
      scales of the Short-Form-36 Health Survey at follow-up; the use of sleep
      medication at baseline was negatively associated with physical functioning,
      bodily pain, vitality, social functioning and general mental health Short-Form-36
      sub-scale scores. The use of sleep medication was also significantly associated
      with falls, accidents, and health care utilisation. CONCLUSION: sleeping
      difficulty is a common and persistent complaint among older women and is strongly
      associated with use of sleeping medications. Both behaviours are negatively
      associated with health status.

PMID- 12615559
TI  - Does melatonin improve sleep in older people? A randomised crossover trial.
AB  - STUDY OBJECTIVE: to determine whether melatonin will improve quality of sleep in
      healthy older people with age-related sleep maintenance problems. DESIGN: a
      double blind randomised placebo controlled crossover trial in healthy older
      volunteers. SETTING: a largely urban population, Auckland, New Zealand.
      PARTICIPANTS: participants were part of the larger Possible Role of Melatonin in
      Sleep of Elders study. People 65 years or more of age were recruited through
      widespread advertising. We screened 414 potential participants by mail using the
      Pittsburgh Sleep Quality Index, and selected 194 for clinic interview. Exclusions
      included depression, cognitive impairment, hypnosedative medications, sleep phase
      abnormalities, medical and/or environmental problems that might impair sleep.
      Twenty normal and 20 problem sleepers were randomly allocated for this study from
      a larger sample of 60 normal and 60 problem sleepers. MEASUREMENTS AND RESULTS:
      24-hour urine 6-sulphatoxymelatonin was measured to estimate melatonin secretion
      in each participant. Five milligrams of melatonin, or matching placebo were each
      taken at bedtime for 4 weeks, separated by a 4-week washout period. Sleep quality
      was measured using sleep diaries, the Leeds Sleep Evaluation Questionnaire, and
      actigraphy. There was a significant difference between the groups in self
      reported sleep quality indicators at entry, but no difference in melatonin
      secretion. Melatonin did not significantly improve any sleep parameter measured
      in either group. CONCLUSION: 5 mg of fast release melatonin taken at bedtime does
      not improve the quality of sleep in older people with age-related sleep
      maintenance problems.

PMID- 12615560
TI  - Ageism in the management of lung cancer.
AB  - BACKGROUND: age-related differences in the treatment of lung cancer patients have
      been reported in the past, but most previous studies have not recorded case-mix
      factors, nor have they studied the impact of such ageism on survival. METHODS: a
      questionnaire-based study of diagnostic and case-mix factors was carried out
      across 48 hospital Trusts in the UK between 1997 and 1998. We identified 1,652
      patients and followed through with regard to their treatment and survival for 6
      months after diagnosis. RESULTS: the median age of the population was 69 years,
      and for this analysis, was divided into three age groups: under 65 years, 65-74
      and 75 years and over. There were significant inverse correlations between age
      and histological diagnosis, any active treatment and survival, even when
      corrected for case-mix factors and non-cancer causes of death. For example, the
      surgical resection rate in patients with confirmed non-small cell lung cancer
      with good performance status, no chronic obstructive pulmonary disease and
      limited disease was 37% in the younger patients compared with 15% in those 75 and
      over. The overall mortality rates at 6 months ranged from 42% in patients under
      65 to 58% in the over 75s. CONCLUSIONS: this national study of lung cancer care
      in the UK has shown large age-related differences in management and survival in
      patients with lung cancer, largely independent of case-mix factors. The reasons
      for this are complex but such under-treatment in the elderly may be one factor
      underlying the poor outcomes in lung cancer patients in the UK.

PMID- 12615561
TI  - Intimations of mortality: perceived age of leaving middle age as a predictor of
      future health outcomes within the Whitehall II study.
AB  - OBJECTIVES: to determine the association between the subjective rate of ageing
      and future health outcomes. DESIGN: prospective cohort study (Whitehall II
      study). At the third phase of the study (1991-1993), participants were asked at
      what age they think most people leave middle age. Participants were followed
      until the end of phase 5 (1997-2000), so that mean length of follow-up was 7
      years. SETTING: London based office staff in 20 civil service departments.
      SUBJECTS: 5,262 male and 2,277 female civil servants aged 40-60. MEASURES:
      validated new cases of coronary heart disease and health function, measured by
      the SF-36 General Health Survey, at phase 5. RESULTS: perceived age of leaving
      middle age increased with age, self-rated health and grade of employment, and was
      higher in women. Adjusting for age and sex, people who believed middle age ends <
      or =60 years, compared to > or =70 years, were at higher risk for coronary heart
      disease (HR=1.43, 95% CI=1.05-1.94), fatal coronary heart disease and non-fatal
      myocardial infarction (HR=1.52, 0.95-2.42), and poor physical (OR=1.29, 1.10
      1.50) and mental (OR=1.25, 1.07-1.45) functioning during follow-up. Adjustment
      for self-rated health, employment grade, health behaviours, social networks,
      control and baseline health status, respectively, did not eliminate these
      associations. CONCLUSIONS: the reported age at which middle age ends predicts
      future health outcomes. We hypothesise that perceived end of middle age acts as a
      general summary of the subjective rate of ageing.

PMID- 12615562
TI  - The use of an implantable loop recorder in the investigation of unexplained
      syncope in older people.
AB  - INTRODUCTION: Reveal is a patient activated implantable loop recorder device with
      an 18 month battery life now available to assist in the diagnosis of suspected
      syncope or arrhythmias. We present our experience using this device in older
      subjects referred to a dedicated falls and syncope clinic in whom usual clinical
      assessment had not satisfactorily identified an attributable diagnosis but where
      we still suspected a cardiovascular cause for syncope or falls. METHODS AND
      RESULTS: during the past 3 years 15 subjects (mean age 73 years, range 61-89
      years) had Reveal implanted for symptoms of syncope alone (n=6; 40%) and
      unexplained falls (n=3; 20%) or symptoms of syncope and unexplained falls (n=6;
      40%). Symptom duration was long (mean 48 months; range 4-200 months). Subjects
      had experienced significant morbidity, 6 subjects (40%) required A&E attendance
      or hospital admission and 4 (27%) experienced a fracture. Despite extensive and
      repeated investigations, which included 12-lead ECG, echocardiogram, 24-h
      ambulatory heart rate monitor, 24-h ambulatory blood pressure monitor,
      orthostatic blood pressure measurement, supine and erect carotid sinus massage,
      electroencephalogram, and passive and GTN head up tilt testing, the attributable
      diagnosis remained unexplained. Of the 15 subjects, 7 have activated the device
      at 4 (range 0-14) months after implantation. Bradycardia was identified in 3 and
      ventricular tachycardia in 1 subject. Two subjects did not activate the device
      during the 18 months it was in-situ. Four people had problems with device
      activation. This is comparable to rates noted using Reveal in younger subjects.
      CONCLUSION: Reveal offers additional diagnostic yield in complex elderly subjects
      with suspected cardiovascular causes of syncope or unexplained falls which have
      not been previously satisfactorily diagnosed despite extensive investigations.

PMID- 12615563
TI  - The effects of improving hearing in dementia.
AB  - BACKGROUND: audiological function is impaired in people with dementia and poor
      hearing is known to exaggerate the effects of cognitive deficits. OBJECTIVE: the
      objective of this study was to assess the effects of increasing auditory acuity
      by providing hearing aids to subjects with dementia who have mild hearing loss.
      METHOD: subjects were screened for hearing impairment and fitted with a hearing
      aid according to standard clinical practice. Measures of cognition and
      psychiatric symptoms, activities of daily living, and burden on carers were made
      over 6 months. Hearing aid diaries were kept to record the acceptability of the
      hearing aids to the subjects. RESULTS: more than 10% of eligible subjects were
      excluded as removal of wax restored hearing. Subjects showed a decline in
      cognitive function, no change in behavioural or psychiatric symptoms over the
      study period. Forty-two percent of subjects showed an improvement on an
      independently rated measure of change. The hearing aids were well accepted. Both
      carers and subjects reported overall reduction in disability from hearing
      impairment. CONCLUSIONS: all patients with hearing impairment require thorough
      examination. The presence of dementia should not preclude assessment for a
      hearing aid as they are well tolerated and reduce disability caused by hearing
      impairment. Hearing aids do not improve cognitive function or reduce behavioural
      or psychiatric symptoms. There is evidence that patients improved on global
      measures of change.

PMID- 12615564
TI  - Potentially reversible risk factors and urinary incontinence in frail older
      people living in community.
AB  - BACKGROUND: urinary incontinence is a common problem among older people living in
      different community settings. The multifactorial origin of urinary incontinence
      has been largely addressed and many previous studies have identified several
      reversible factors associated with incontinence. However, few data exist
      concerning the potentially reversible causes of this condition among frail
      community-dwelling older individuals. OBJECTIVE: the aim of the present study is
      to estimate, in a large population of frail elderly people living in the
      community, the prevalence of urinary incontinence and to determine physical,
      social, and psychological factors associated with it. DESIGN: observational
      study. SUBJECTS AND METHODS: we analysed data from a large collaborative
      observational study group, the Italian Silver Network Home Care project, that
      collected data on patients admitted to home care programmes (n=5418). A total of
      22 Home Health Agencies participated in this project evaluating the
      implementation of the Minimum Data Set for Home Care instrument. The main outcome
      measures were the prevalence and factors associated with urinary incontinence.
      RESULTS: urinary incontinence was recorded in 51% of patients, and it was more
      common in women than men (52% versus 49%, respectively; P=0.01). After adjustment
      for each of the variables considered in this study, three potentially reversible
      factors were strongly associated with urinary incontinence: urinary tract
      infection (adjusted odds ratio, 3.46; 95% confidence interval, 2.65-4.51), use of
      physical restraints (adjusted odds ratio, 3.20; 95% confidence interval, 2.19
      4.68), environmental barriers (adjusted odds ratio, 1.53; 95% confidence
      interval, 1.15-2.02). These associations were consistent in both men and women.
      CONCLUSIONS: the major finding of our study is that potentially reversible
      factors were strongly and independently associated with urinary incontinence.
      Failure to make all reasonable efforts to assess and to treat all these factors
      among frail elderly people should be considered one of the most important
      indicators of poor quality of care.

PMID- 12615565
TI  - Long-term cognitive and functional decline in late onset Alzheimer's disease:
      therapeutic implications.
AB  - BACKGROUND: National Institute of Clinical Excellence guidelines advocate the use
      of the Mini-Mental Test Examination and a functional assessment as a means of
      measuring treatment response. However, there is little knowledge of the change
      expected in those with Alzheimer's disease in clinical practice. OBJECTIVE: to
      describe the long-term variability of the Mini-Mental Test Examination and
      Blessed Dementia Rating Scale. METHOD: 374 Alzheimer's disease patients referred
      to psychiatric services in southeast London were followed annually over a 3-year
      period. RESULTS: the mean Mini-Mental Test Examination score for the total group
      at baseline was 9.9 points. Individual variability in the rate of cognitive and
      functional decline is large and around 40% of patients after 1 year, and up to
      one-quarter of patients after 3 years who survived, show no change or an
      improvement in scores compared with baseline measures. CONCLUSIONS: in the
      evaluation of individual treatment response the rate of change, as measured by
      the Mini-Mental Test Examination and Blessed Dementia Rating Scale, is of limited
      value.

PMID- 12615566
TI  - Study of the relationship between cigarette smoking, alcohol drinking and
      cognitive impairment among elderly people in China.
AB  - OBJECTIVE: the incidence of cognitive impairment is increasing; however, little
      is known about the prevalence and risk factors for cognitive impairment of
      elderly people in China. This report focuses on investigating the relationship
      between cigarette smoking, alcohol drinking and cognitive impairment in elderly
      people. METHODS: 3012 participants aged 60 years old and over were enrolled from
      six communities of Chongqing. Cognitive function was measured by the Mini-Mental
      State Examination and Activities of Daily Living. The chi(2) test and logistic
      regression was used to find the relationship between cigarette smoking, alcohol
      drinking and cognitive impairment. RESULT: the rate of abnormal cognitive
      function in elderly people was 11.95%. Smoking was closely related to cognitive
      impairment (chi(2)=6.59, P=0.027). Alcohol drinking was also associated with
      cognitive impairment (chi(2)=6.31, P=0.025). In all smokers, current smoking was
      associated with a significantly increased risk of cognitive impairment (RR 2.33;
      95% CI=1.37-5.82). In all people who drink every day, there was a significantly
      increased risk of cognitive impairment (RR 3.47; 95% CI=1.79-6.71). CONCLUSION:
      smoking and drinking are risk factors for cognitive impairment among elderly
      people. Cessation of smoking and reduction of drinking could be considered as
      part of a strategy to reduce the incidence of cognitive impairment.

PMID- 12615567
TI  - British Association of Stroke Physicians: benchmarking survey of stroke services.
AB  - BACKGROUND: the National Service Framework for Older People requires every
      general hospital which cares for stroke patients to introduce a specialist stroke
      service by 2004. OBJECTIVE: to describe the organisation and staffing of
      specialist hospital-based stroke services in the UK. DESIGN: a national postal
      survey of consultant members of the British Association of Stroke Physicians
      (BASP) seeking details of the provision of neurovascular clinics, acute stroke
      units (ASUs), stroke rehabilitation units (SRUs), and the organisation and
      staffing of these services. RESULTS: the response rate was 91/126 (72%). Fifty
      four neurovascular clinics, 40 ASUs and 68 SRUs were identified. Neurovascular
      clinics used a number of strategies to maintain rapid access and 30 (56%) were
      run by a single consultant. Only 50% ASUs usually admitted patients within 24 h
      of stroke. As the number of beds available on ASUs and SRUs did not reflect the
      total number of stroke in-patients, 21 (53%) ASUs and 45 (79%) SRUs had admission
      criteria. Training opportunities were limited: 37% ASUs and 82% SRUs had no
      specialist registrar. The therapy sessions (1 session=half a day) available per
      bed per week on a SRU were: physiotherapy 0.8; occupational therapy 0.6; speech
      and language therapy 0.25. CONCLUSIONS: significant development is needed to
      achieve the NSF target for hospital-based stroke services as few Trusts currently
      have all components in place and even when available not all stroke patients have
      access to specialist care. Stroke specialists will be required to run these
      services but training opportunities are currently limited. Stroke unit therapy
      staffing levels were lower than was available in randomised controlled trials.

PMID- 12615568
TI  - Caregiver burden and health-related quality of life among Japanese stroke
      caregivers.
AB  - OBJECTIVE: the present study had two main purposes: 1. To examine the
      relationship between caregiver burden and health-related quality of life in
      family caregivers of older stroke patients in Japan; and 2. To examine which
      characteristics of the caregiving situation significantly relate to increased
      burden. METHODS: subjects (n=100) were recruited from seven randomly selected
      neurological hospitals with out-patient rehabilitation clinics in western Japan
      and interviewed using the Zarit Burden Interview, the Modified Barthel Index, the
      Geriatric Depression Scale and the SF-12 Health Survey for health-related quality
      of life. RESULTS: increased caregiver burden was significantly related to
      worsening health-related quality of life, particularly worsening mental health
      (Geriatric Depression Scale and SF-12 items), even after controlling for
      caregiver age, sex, chronic illness, average caregiving hours/day, and functional
      dependence of the care-recipient. DISCUSSION: findings indicate that increased
      burden significantly relates to decreased health-related quality of life among
      stroke caregivers. In addition, the prevalence of depressive symptoms among
      caregivers was twice that of community dwelling older people. Roughly 52% of
      caregivers had Geriatric Depression Scale scores that warranted further
      evaluation. Despite the prevalence of depressive symptoms only one caregiver had
      received any psychiatric care during their caregiving tenure.

PMID- 12615569
TI  - Low dose amiodarone causing pseudo-alcoholic cirrhosis.
AB  - Amiodarone is a commonly used anti-arrhythmic in elderly patients. Abnormal liver
      function is frequently reported with its use but clinically symptomatic disease
      is rare. Hepatomegaly, cholestasis, acute hepatitis and rarely fulminant liver
      failure have been recorded [1, 2], however amiodarone toxicity presenting with
      cirrhosis is exceedingly rare. Toxic effects of amiodarone are well described
      with higher dosage but severe hepatic toxicity and cirrhosis with low dose
      amiodarone has not been reported in the English language literature. We present a
      report on a patient with pseudo-alcoholic cirrhosis with low dose amiodarone.

PMID- 12615571
TI  - Alzheimer's disease and edentulism.

PMID- 12615570
TI  - Warfarin sensitivity: be aware of genetic influence.
AB  - BACKGROUND: avoidance of over anticoagulation in response to warfarin therapy
      would reduce risk of associated bleeding. SUBJECTS: two elderly patients with
      venous thromboembolism exhibited extreme anticoagulant response to warfarin. Both
      were noted to have variant CYP2C9 alleles, which reduce the metabolic capacity of
      cytochrome P450 2C9. DISCUSSION: adverse outcomes with warfarin therapy could be
      explained and possibly avoided by identifying patients with variant alleles for
      CYP2C9 before initiation of therapy.

PMID- 12615572
TI  - Physiotherapists may not practice what is implied from treatment "labels".

PMID- 12615573
TI  - The investigation of occult malignancies in patients with venous thromboembolism.

PMID- 12615574
TI  - Does a single item question identify elderly medical inpatients who report
      significant depressive symptoms?

PMID- 12615575
TI  - Change in general practitioner prescribing.

PMID- 12615576
TI  - Pragmatic measures of outcome in trials of exercise training.

PMID- 12615577
TI  - Restless legs syndrome as a presenting symptom in malignant disease.

PMID- 12615579
TI  - Changing trends of antithrombotic therapy in atrial fibrillation.

PMID- 12615578
TI  - Is there rationale for vitamin D prescribing in the elderly population?

PMID- 12615580
TI  - Amiodarone and bretylium in the treatment of hypothermic ventricular fibrillation
      in a canine model.
AB  - Refractory ventricular fibrillation (VF) is a complication of severe hypothermia.
      Despite mixed experimental data, some authors view bretylium as the drug of
      choice in hypothermic VF. Bretylium was removed from Advanced Cardiac Life
      Support guidelines, and, to date, efficacy of amiodarone in hypothermia is
      unknown. OBJECTIVES: To compare defibrillation rates from hypothermic VF after
      drug therapy with amiodarone, bretylium, and placebo. METHODS: This was a
      randomized, blinded, and placebo-controlled laboratory experiment. Thirty
      anesthetized dogs were mechanically ventilated and instrumented to monitor
      coronary perfusion pressure (CPP), rectal core temperature, and electrocardiogram
      (ECG). Animals were cooled to 22 degrees C or the onset of spontaneous VF.
      Ventricular fibrillation was induced as needed with a transthoracic AC current.
      Cardiopulmonary resuscitation (CPR) was initiated and animals were randomized (n
      = 10 each group) to receive amiodarone 10 mg/kg (A), bretylium 5 mg/kg (B), or
      placebo (P) intravenously. CPR was continued while monitoring for chemical
      defibrillation. Rewarming was limited to removal from the cold environment. After
      10 minutes, up to three escalating defibrillatory shocks were administered.
      Hemodynamic monitoring continued after resuscitation. Return of spontaneous
      circulation (ROSC) was defined as a sustainable ECG rhythm generating a
      corresponding arterial pressure tracing lasting a minimum of 15 minutes. Sample
      size permitted 80% power to detect a 60% difference in conversion rate between
      groups. RESULTS: CPR was adequate based on CPP > 15 mm Hg in all animals. Mean
      (+/-SD) CPP was 35.3 +/- 18.8 mm Hg with an overall lower trend in the amiodarone
      group (p = 0.06). Baseline variables were similar between groups. No instance of
      chemical defibrillation was noted. There was no significant difference in ROSC
      rates between groups. Resuscitation rates were: amiodarone = 1/10, bretylium =
      4/10, and placebo = 3/10 (p = 0.45). CONCLUSIONS: In this model of severe
      hypothermic VF, neither amiodarone nor bretylium was significantly better than
      placebo in improving the resuscitation rate.

PMID- 12615581
TI  - A randomized controlled trial of intravenous aminophylline for atropine-resistant
      out-of-hospital asystolic cardiac arrest.
AB  - OBJECTIVES: Myocardial ischemia, during cardiopulmonary arrest, can lead to
      atropine-resistant bradyasystole from interstitial accumulation of endogenous
      adenosine. Aminophylline is a nonspecific adenosine receptor antagonist capable
      of reversing ischemia-induced bradyasystole in a variety of settings. The
      hypothesis of this study was that aminophylline improves the rate of return of
      spontaneous circulation (ROSC) in atropine-resistant asystolic out-of-hospital
      cardiac arrest when used early in the resuscitation effort. METHODS: This was a
      prospective, randomized, double-blinded, placebo-controlled trial set in an urban
      emergency medical services system serving a population of 250,000. All non
      pregnant, normothermic adults suffering nontraumatic out-of-hospital cardiac
      arrest (February 1999 to August 2000) with asystole were eligible. Patients
      remaining in asystole after initial doses of epinephrine and atropine received
      either aminophylline 250 mg or matching placebo as a bolus injection through a
      peripheral intravenous line. All other aspects of the attempted resuscitation
      proceeded in accordance with standard Advanced Cardiac Life Support (ACLS)
      guidelines. A sample size of 102 patients was calculated to yield a power of 80%
      to show an absolute improvement of 25% in ROSC. The aminophylline and control
      groups were compared by calculating 95% confidence intervals (95% CIs) and the
      data were modeled using logistic regression. RESULTS: The investigators enrolled
      112 consecutive patients. One subject was dropped prior to analysis because of
      missing data. Data for 111 patients were analyzed on an intention-to-treat basis.
      Baseline characteristics were similar for the two groups. Comparing the control
      and aminophylline groups, ROSC was achieved in 15.6% (95% CI = 6% to 29%) and
      22.7% (95% CI = 13% to 35%), while reversal of asystole occurred in 26.7% (95% CI
      = 15% to 42%) and 40.9% (95% CI = 29% to 54%), respectively. Group allocation had
      an odds ratio of 1.8 (95% CI = 0.6 to 5.3) for ROSC. Witnessed arrest was an
      independent predictor of outcome with an odds ratio of 3.8 (95% CI = 1.3 to
      11.2). CONCLUSIONS: Addition of aminophylline appears to be a promising new
      intervention in the ACLS treatment of atropine-resistant asystolic out-of
      hospital cardiac arrest.

PMID- 12615583
TI  - Can electrocardiographic criteria predict adverse cardiac events and positive
      cardiac markers?
AB  - OBJECTIVES: To determine electrocardiogram (ECG) predictors of positive cardiac
      markers and short-term adverse cardiac events in an undifferentiated chest pain
      population presenting to emergency departments (EDs). The authors hypothesized
      that specific ECG findings, other than those previously identified in higher-risk
      populations, would be predictive of cardiac outcomes and positive cardiac
      markers. METHODS: This study used data from a prospectively collected,
      retrospectively analyzed Internet-based data registry of undifferentiated chest
      pain patients (i*trACS). Logistic regression modeling was performed to determine
      the ECG findings that were predictive of 1) positive cardiac markers and 2) short
      term adverse cardiac events. RESULTS: ST-segment elevation (STE), ST-segment
      depression (STD), pathological Q-waves (PQW), and T-wave inversion were
      associated with increased odds of percutaneous coronary intervention or
      catheterization, myocardial infarction, or coronary artery bypass grafting. The
      odds of creatine kinase-MB (CK-MB) measuring positive were increased if STE, STD,
      or PQW were present [odds ratio (OR) 2.495, 2.582, and 1.295, respectively]. A
      right bundle branch block tended to decrease the odds of CK-MB measuring positive
      (OR 0.658). A similar pattern of results was observed for troponin I (OR 3.608
      for STE, 3.72 for STD, 1.538 for PQW). Troponin T showed an increased odds of
      measuring positive if any of STE, STD, left bundle branch block, or T-wave
      inversion were evident (OR 2.313, 2.816, 1.80, and 1.449, respectively).
      CONCLUSIONS: Initial ECG criteria can be used to predict short-term cardiac
      outcomes and positive cardiac markers. These findings can be important aids in
      the risk-stratification and aggressive treatment regimens of chest pain patients
      presenting to EDs.

PMID- 12615582
TI  - Uncovering heart failure in patients with a history of pulmonary disease:
      rationale for the early use of B-type natriuretic peptide in the emergency
      department.
AB  - Plasma B-type natriuretic peptide (BNP) can reliably identify acute congestive
      heart failure (CHF) in patients presenting to the emergency department (ED) with
      acute dyspnea. Heart failure, asthma, and chronic obstructive pulmonary disease
      (COPD) are syndromes where dyspnea and wheezing are overlapping signs, and hence,
      these syndromes are often difficult to differentiate. OBJECTIVE: To determine
      whether BNP can distinguish new-onset heart failure in patients with COPD or
      asthma presenting with dyspnea to the ED. METHODS: The BNP Multinational Study
      was a seven-center prospective study of 1,586 adult patients presenting to the ED
      with acute dyspnea who had blinded BNP levels measured on arrival with a rapid,
      point-of-care device. This study evaluated the 417 patients with no previous
      history of heart failure and a history of asthma or COPD as a subgroup from the
      1,586 adult patients in the BNP Multinational Study. The reference standard for
      CHF was adjudicated by two independent cardiologists, also blinded to BNP
      results, who reviewed all clinical data and standardized CHF scores. RESULTS: A
      total of 417 subjects (mean age 62.2 years, 64.4% male) had a history of asthma
      or COPD without a history of CHF. Of these, 87/417 (20.9%, 95% CI = 17.1% to
      25.1%) were found to have CHF as the final adjudicated diagnosis. The emergency
      physicians identified a minority, 32/87 (36.8%), of these patients with CHF. The
      mean BNP values (+/- SD) were 587.0 +/- 426.4 and 108.8 +/- 221.3 pg/mL for those
      with and without CHF (p < 0.0001). At a cutpoint of 100 pg/mL, BNP had the
      following decision statistics: sensitivity 93.1%, specificity 77.3%, positive
      predictive value 51.9%, negative predictive value 97.7%, accuracy 80.6%, positive
      likelihood ratio 4.10, and negative likelihood ratio 0.09. If BNP would have been
      added to clinical judgment (high > or = 80% probability of CHF), at a cutpoint of
      100 pg/mL, 83/87 (95.4%) of the CHF subjects would have been correctly diagnosed.
      Multivariate analysis found BNP to be the most important predictor of CHF (OR =
      12.1, 95% CI = 5.4 to 27.0, p < 0.0001). In the 87 subjects found to have CHF,
      39.0%, 22.2%, and 54.8% were taking angiotensin-converting enzyme inhibitors
      (ACEIs), beta-blockers (BBs), and diuretics on a chronic basis, respectively.
      CONCLUSIONS: The yield of adding routine BNP testing in patients with a history
      of asthma or COPD in picking up newly diagnosed CHF is approximately 20%. This
      group of patients presents a substantial therapeutic opportunity for the
      initiation and chronic administration of ACEI and BB therapy, as well as other
      CHF management strategies.

PMID- 12615584
TI  - Visual analog pain scores do not define desire for analgesia in patients with
      acute pain.
AB  - Increased attention to improving the provision of analgesia has led to calls for
      increased use of pain measurement systems, including visual analog scales, which
      have not been validated for use in clinical care. OBJECTIVE: To evaluate the
      ability of the visual analog scale to differentiate between patients with acute,
      painful conditions requiring pain medication, and those not requiring analgesia.
      METHODS: This was a prospective, observational study of a convenience sample of
      patients with acute pain. Subjects were asked about their desire for medication.
      Visual analog scale pain scores were determined. RESULTS: One hundred four
      patients participated. Patients requesting pain medication had a mean visual
      analog scale score of 66. The mean score for those not requesting medication was
      45. The difference between the means was 21 [95% confidence interval (95% CI) for
      difference between the means was 10.7]. The area under the receiver operating
      characteristic curve for the visual analog scale was 0.72 (95% CI = 0.61 to
      0.82). CONCLUSIONS: The visual analog scale cannot adequately discriminate
      between those patients who do and do not desire analgesia.

PMID- 12615585
TI  - Nebulized fentanyl for relief of abdominal pain.
AB  - OBJECTIVE: To compare the efficacies of nebulized vs. intravenous fentanyl for
      the relief of abdominal pain. METHODS: This randomized, double-blind, double
      placebo-controlled study compared nebulized and intravenous fentanyl (1.5 micro
      g/kg). Group I received intravenous fentanyl and nebulized saline. Group II
      received nebulized fentanyl and intravenous saline. Pain scores were measured at
      baseline and at 15 and 30 minutes after the study drug, using a 100-mm visual
      analog scale. Thirty minutes after the study drug, the subjects were offered
      rescue medication. The groups were compared for changes in pain scores at 30
      minutes (primary outcome, t-test), changes in pain scores at 15 minutes (t-test),
      and need for rescue medication (Fisher's exact test). Significance was defined as
      p < 0.05. RESULTS: Fifty subjects (24 group I, 26 group II) were enrolled. The
      groups were similar with respect to mean baseline pain (72 mm group I, 74 mm
      group II) and demographics. A statistically significant difference in changes in
      pain scores at 15 minutes favoring group I (25 mm vs. 10 mm, p = 0.005) was not
      evident by 30 minutes (25 mm vs. 16 mm, p = 0.24). The groups were not different
      with respect to need for rescue medication (50% in group I compared with 69% in
      group II, p = 0.25). CONCLUSIONS: Nebulized fentanyl provides comparable
      analgesia to that of intravenous fentanyl.

PMID- 12615586
TI  - Evaluation of emergency medicine resident death notification skills by direct
      observation.
AB  - Emergency physicians commonly perform death notifications. Physician training in
      death notification has been limited. Resident physicians are rarely evaluated in
      their performance of death notifications. OBJECTIVE: To evaluate death
      notification skills by direct observation of actual notifications performed by
      trained emergency medicine (EM) residents. METHODS: This was a prospective,
      observational study of EM resident death notification performance. EM residents
      received training and then were directly observed and evaluated by trained
      evaluators during actual death notifications in a 64,000-visit community teaching
      hospital emergency department. RESULTS: There were 327 evaluations of 70
      different EM residents. Overall performance evaluations were 55% excellent, 40%
      satisfactory, and 5% unsatisfactory. Third-year EM residents and female EM
      residents were more likely to be rated excellent. CONCLUSIONS: Death notification
      is a skill that can be evaluated like other EM skills. Trained EM residents
      performed well in actual death notifications when directly observed and
      evaluated. Senior residents and female residents were more likely to be rated
      excellent.

PMID- 12615588
TI  - A brief risk-stratification tool to predict repeat emergency department visits
      and hospitalizations in older patients discharged from the emergency department.
AB  - OBJECTIVES: To evaluate the predictive ability of a simple six-item triage risk
      screening tool (TRST) to identify elder emergency department (ED) patients at
      risk for ED revisits, hospitalization, or nursing home (NH) placement within 30
      and 120 days following ED discharge. METHODS: Prospective cohort study of 650
      community-dwelling elders (age 65 years or older) presenting to two urban
      academic EDs. Subjects were prospectively evaluated with a simple six-item ED
      nursing TRST. Participants were interviewed 30 and 120 days post-ED index visit
      and the utilization of EDs, hospitals, or NHs was recorded. Main outcome
      measurement was the ability of the TRST to predict the composite endpoint of
      subsequent ED use, hospital admission, or NH admission at 30 and 120 days.
      Individual outcomes of ED use, hospitalization, and NH admissions were also
      examined. RESULTS: Increasing cumulative TRST scores were associated with
      significant trends for ED use, hospital admission, and composite outcome at both
      30 and 120 days (p < 0.0001 for all, except 30-day ED use, p = 0.002). A simple,
      unweighted five-item TRST ("lives alone" item removed after logistic regression
      modeling) with a cut-off score of 2 was the most parsimonious model for
      predicting composite outcome (AUC = 0.64) and hospitalization at 30 days (AUC =
      0.72). Patients defined as high-risk by the TRST (score > or = 2) were
      significantly more likely to require subsequent ED use (RR = 1.7; 95% CI = 1.2 to
      2.3), hospital admission (RR = 3.3; 95% CI = 2.2 to 5.1), or the composite
      outcome (RR = 1.9; 95% CI 1.7 to 2.9) at both 30 days and 120 days than the low
      risk cohort. CONCLUSIONS: Older ED patients with two or more risk factors on a
      simple triage screening tool were found to be at significantly increased risk for
      subsequent ED use, hospitalization, and nursing home admission.

PMID- 12615589
TI  - Rapid two-stage emergency department intervention for seniors: impact on
      continuity of care.
AB  - OBJECTIVES: A two-stage intervention comprising screening and a brief
      standardized nursing assessment and referral, for emergency department (ED)
      patients aged 65 years and over, reduced the rate of functional decline four
      months after the visit, without increasing societal costs. In this study, the
      authors investigated the effects of the intervention on the process of care at,
      and during the month after, the ED visit. METHODS: Patients at four Montreal
      hospital EDs were randomized by day of visit to the intervention or to usual
      care. Patients admitted to the hospital were excluded. Measures of process of
      care included: referrals and visits to the primary physician and to the local
      community health center, for home care or other services, and return ED visits.
      Data sources included hospital charts, patient questionnaires, and provincial
      administrative databases. RESULTS: The study sample included 166 intervention and
      179 control group patients ready for discharge from the ED. Intervention group
      patients were more likely to have a chart-documented referral to their local
      community health center [adjusted odds ratio (OR) 4.0, 95% confidence interval
      (95% CI) = 1.7 to 9.5] and their primary physician [adjusted OR 1.9, 95% CI = 1.0
      to 3.4], and to have received home care services one month after the ED visit
      [adjusted OR 2.3, 95% CI = 1.1 to 5.1]. Unexpectedly, they were also more likely
      to make a return visit to the ED [adjusted OR 1.6, 95% CI = 1.0 to 2.6].
      CONCLUSIONS: The beneficial outcomes of the intervention appear to result
      primarily from the early provision of home care rather than early contact with
      the primary physician.

PMID- 12615590
TI  - Geriatric trauma patients-are they receiving trauma center care?
AB  - OBJECTIVES: The primary purpose of this study was to evaluate whether severely
      injured geriatric patients were as likely to be treated at designated trauma
      centers (TCs) within the statewide trauma system. The secondary objective was to
      compare the demographic and injury characteristics of severely injured older and
      young patients who received care in TCs with the characteristics of those
      patients cared for in non-TCs. METHODS: The authors reviewed files for all acute
      injury discharges in Pennsylvania for 1997. Injury diagnoses were mapped to
      Abbreviated Injury Scale (AIS) scores using ICDMAP software; the Injury Severity
      Score (ISS) was computed. The frequency of hospital discharges for injury from TC
      and non-TC hospitals in both the older (E) (>/=65 years) and younger (Y) (<65
      years) groups were computed, and compared using chi-square testing for
      significance. Logistic regression was performed to assess the influence of
      various factors. Severity of injury was controlled for with both ISS and Maximum
      AIS (MAIS). RESULTS: 107,358 patients were admitted to hospitals in the state
      because of injury; 8,980 had an ISS > 15; 5,855 were Y and 3,125 were E. Forty
      seven percent of the Y patients received TC care compared with only 36.6% of the
      E patients (p < 0.001). Logistic regression analysis showed that age was a
      strongly negative predictor for TC care when injury severity was controlled.
      CONCLUSIONS: Seriously injured older patients were less likely to receive care in
      a trauma center than younger patients.

PMID- 12615591
TI  - A research agenda for geriatric emergency medicine.
AB  - OBJECTIVES: The Research Agenda Setting Process (RASP), part of the American
      Geriatric Society's (AGS's) project "Increasing Geriatric Expertise in Surgical
      and Related Medical Specialties," was designed to define a research agenda for
      the geriatrics aspects of participating specialties. This paper presents a
      summary of the research agenda for emergency medicine. METHODS: The RASP was
      developed by the AGS in conjunction with experts from the participating specialty
      organizations. A "content expert" (CE) for each specialty developed a Medline
      search strategy in conjunction with RAND Health librarians. The CE reviewed the
      search to identify papers that were germane to research in the emergency care of
      older patients. The CE and a senior writing group member drafted a paper that
      synthesized the current literature and suggested areas for further research. A
      panel consisting of AGS members and emergency physicians with geriatrics
      expertise reviewed this paper. The research agenda was further refined at a two
      day retreat. Two senior geriatricians reviewed the resulting paper. RESULTS: The
      Medline search for emergency medicine resulted in a list of 3,348 articles; 299
      articles were pertinent and reviewed. The search for trauma resulted in a list of
      1,838 articles; 133 were reviewed. Research agenda items were defined for
      multiple topics within geriatric emergency medicine and trauma. CONCLUSION: A
      research agenda for geriatric emergency medicine has been developed, using a
      combination of review of current literature and expert opinion.

PMID- 12615592
TI  - Patient satisfaction data as a quality indicator: a tale of two emergency
      departments.
AB  - OBJECTIVE: Patient satisfaction is a commonly measured indicator of quality
      emergency care. However, the existing empirical literature on emergency
      department (ED) patient satisfaction provides little guidance on how to analyze,
      interpret, and use data obtained in the clinical setting. Using two EDs as
      examples, the authors describe practical strategies designed to identify priority
      areas for potential improvement. METHODS: The authors used a cross-sectional,
      observational design. All patients who presented for emergency care during the
      designated time periods were eligible. Patients were randomly selected, contacted
      by telephone, and surveyed using three measures of global satisfaction, 23
      perceived quality-of-care indicators, and six perceived wait times. Descriptive
      statistics were calculated. Comparisons were made of each of the perceived care
      and wait time indicators against explicitly defined acceptability criteria to
      determine satisfiers/dissatisfiers. Each indicator was correlated with the three
      global satisfaction indices. The authors integrated results obtained from
      applying the acceptability criteria with those obtained from the correlations to
      yield priority indicators for remediation and maintenance strategies. RESULTS:
      For hospitals A and B, respectively, 15 (52%) and 16 (55%) of perceived care and
      wait time indicators failed to meet acceptability criteria. Using the
      correlations with overall satisfaction, the authors further narrowed the priority
      areas for remediation to six indicators for hospital A and three indicators for
      hospital B. One maintenance indicator was revealed for hospital A and four for
      hospital B. CONCLUSIONS: A combination of applying explicit acceptability
      criteria to descriptive statistics and using correlation coefficients with
      overall satisfaction can help to maximize the usefulness of patient satisfaction
      data by uncovering priority areas. These priority areas were broken down into
      maintenance and remediation indicators and were found to vary considerably
      depending on the hospital in question. Such strategies can help to refine
      performance improvement efforts by targeting those domains with the greatest
      impact on overall satisfaction.

PMID- 12615593
TI  - Clinical pearls: neonatal breast mass.

PMID- 12615594
TI  - A new model for emergency care of geriatric patients.

PMID- 12615595
TI  - The use of B-type natriuretic peptide (BNP) to distinguish heart failure from
      lung disease in patients presenting with dyspnea to the emergency department.

PMID- 12615596
TI  - Preventive care in the emergency department: should emergency departments conduct
      routine HIV screening? a systematic review.
AB  - OBJECTIVE: To perform a systematic review of the emergency medicine literature to
      assess the appropriateness of offering routine HIV screening to patients in the
      emergency department (ED). METHODS: The systematic review was conducted with the
      aid of a structured template, a companion explanatory guide, and a grading and
      methodological scoring system based on published criteria for critical appraisal.
      Two reviewers conducted independent searches using OvidR, PubMed, MD Consult, and
      Grateful Med. Relevant abstracts were reviewed; those most pertinent to the
      stated objective were selected for complete evaluation using the structured
      template. RESULTS: Fifty-two relevant abstracts were reviewed; of these, nine
      were selected for detailed evaluation. Seven ED-based prospective cross-sectional
      seroprevalence studies found HIV rates of 2-17%. Highest rates of infection were
      seen among patients with behavioral risks such as male homosexual activity and
      intravenous drug use. Two studies demonstrated feasibility of both standard and
      rapid HIV testing in the ED, with more than half of the patients approached
      consenting to testing by either method, consistent with voluntary testing
      acceptance rates described in other settings. Several cost-benefit analyses lend
      indirect support for HIV screening in the ED. CONCLUSIONS: Multiple ED-based
      studies meeting the Centers for Disease Control and Prevention Guideline
      threshold to recommend routine screening, in conjunction with limited feasibility
      trials and extrapolation from cost-benefit studies, provide evidence to recommend
      that EDs offer HIV screening to high-risk patients (i.e., those with identifiable
      risk factors) or high-risk populations (i.e., those where HIV seroprevelance is
      at least 1%).

PMID- 12615598
TI  - Oral treatment of organophosphate poisoning in mice.
AB  - OBJECTIVE: Organophosphates are used as pesticides, herbicides, and chemical
      warfare agents. Treatment of organophosphate poisoning is with intravenous
      atropine and pralidoxime in addition to supportive care. This study determined
      the efficacy of oral agents in preventing death from organophosphate poisoning.
      METHODS: The organophosphate paraoxon (8 mg/kg) was used in a murine model with
      lethality at four and 24 hours as an end point. For oral treatment, 15 male Balbc
      mice were given either atropine sulfate (4 mg/kg), or a combination of atropine
      sulfate (4 mg/kg) with pralidoxime (100 mg/kg), by oral gavage. A control group
      of 22 mice received water by oral gavage. Chi-square analysis was used to compare
      results in the different groups. RESULTS: Of the control group, six of 22
      survived to four hours after paraoxon exposure. Of the exposed animals treated
      with oral atropine, eight of 15 survived to four hours. Of the exposed animals
      treated with a combination of atropine and pralidoxime, 13 of 15 survived to four
      hours. All animals surviving to four hours survived to 24 hours. The increased
      survival of animals in the atropine group relative to the control group was not
      significant (p = 0.09). Survival was significant in the group treated with
      atropine and pralidoxime relative to atropine alone (p = 0.02) and to the control
      group (p = 0.0002). All treated mice surviving at four hours were alive at 24
      hours. CONCLUSIONS: Both oral atropine and a combination of oral atropine and
      pralidoxime improved survival, and combination therapy achieved statistical
      significance. Generalization of this result to other organophosphate pesticides,
      other doses of paraoxon, and other species cannot be made without further
      investigations.

PMID- 12615599
TI  - The Westley croup score.

PMID- 12615600
TI  - A role for ipratropium in chemical terrorism preparedness.

PMID- 12615602
TI  - Design and interpretation of studies of differential exposure measurement error.
AB  - Differential exposure measurement error can have more adverse effects on
      estimates of exposure-disease associations than nondifferential measurement
      error, yet relatively little has been written about the design and interpretation
      of validity and reliability studies to assess differential measurement error. In
      this paper, a simple approximate equation is given for the effect of differential
      measurement error in a continuous exposure measure on the bias in the odds ratio.
      From this, it is shown that two parameters need to be estimated in
      validity/reliability studies in order to interpret the results in terms of the
      bias in the odds ratio in an epidemiologic study that will use the measure. The
      first is the correlation between the mismeasured and true exposure. The second is
      the differential bias (difference between cases and controls in the difference
      between mean measured and true exposure) relative to the true difference in
      exposure between cases and controls. It is shown that this latter parameter can
      be estimated in a method comparison study if one has a comparison measure that is
      unbiased or has nondifferential bias, so a perfect criterion measure is not
      needed. Researchers should consider measuring and reporting this parameter in
      validity/reliability studies when feasible.

PMID- 12615603
TI  - HLA-DPB1 and chronic beryllium disease: a HuGE review.
AB  - The human leukocyte antigen (HLA) complex is a series of genes located on
      chromosome 6 that are important in normal immune function. Susceptibility to
      chronic beryllium disease, a granulomatous lung disease that appears in workers
      exposed to beryllium, is modified by genetic variants of the HLA-DP subregion.
      Evaluation of HLA-DPB1 sequence motifs in current and former beryllium workers
      implicated a glutamic acid residue at position 69 (HLA-DPB1(Glu69)) in chronic
      beryllium disease. This finding has since been extended to specific HLA
      DPB1(Glu69) alleles. Specific job tasks have also been implicated in degree of
      risk, and in this paper the authors explore gene-environment interaction. The
      utility of this genetic information for prospective, current, and former
      beryllium workers must be weighed against the potential for employment and
      insurance discrimination. Continued research in the beryllium-exposed population
      will be important for improving personal risk assessment and identifying high
      risk genes associated with disease progression.

PMID- 12615604
TI  - Use of epidemiology in clinical medical publications, 1983-1999: a citation
      analysis.
AB  - Epidemiologists respond to the information needs of health professionals.
      Although medical professionals are routine users of epidemiologic information,
      use within medical specialties varies remarkably. To explore the variation in use
      of epidemiologic information across clinical medical specialties, the authors
      examined the scientific literature by analyzing patterns of citation of specific
      journal articles to and by the American Journal of Epidemiology (AJE). A total of
      178,396 journal citations to and 126,478 citations by AJE were made from 1983
      through 1999; citations were classified according to the subject category of the
      referencing or referenced journal. Clinical medical journals accounted for 50.6%
      of all citations combined (both referenced to and referenced by AJE);
      general/internal medicine (17.9%), cancer (10.4%), and cardiovascular (4.9%)
      journals had the highest number of citations. Few citations to and by AJE were
      found in publications specializing in dermatology, gastroenterology, orthopedics,
      allergy, anesthesiology, surgery, rheumatology, and other areas. Trend patterns
      of citations between clinical and epidemiologic literature indicated that
      citations to the fields of cardiovascular disease and cancer are increasing,
      whereas citations regarding pediatrics have remained stable. This analysis
      suggests an increasing interchange of information between epidemiologists and
      clinicians specializing in certain fields, uncovering potential research
      opportunities for epidemiologists.

PMID- 12615605
TI  - Neurodegenerative diseases and exposure to pesticides in the elderly.
AB  - The authors investigated the hypothesis that exposure to pesticides could be
      related to central nervous system disorders in a prospective cohort study of
      1,507 French elderly (1992-1998). Lower cognitive performance was observed in
      subjects who had been occupationally exposed to pesticides. In men, the relative
      risks of developing Parkinson's disease and Alzheimer's disease for occupational
      exposure assessed by a job exposure matrix were 5.63 (95% confidence interval:
      1.47, 21.58) and 2.39 (95% confidence interval: 1.02, 5.63), respectively, after
      confounding factors were taken into account. No association was found with having
      a primary job in agriculture or with environmental pesticide exposure, nor was an
      association found in women. These results suggest the presence of neurologic
      impairments in elderly persons who were exposed occupationally to pesticides.

PMID- 12615607
TI  - Height, weight, weight change, and ovarian cancer risk in the Netherlands cohort
      study on diet and cancer.
AB  - Although many studies have been conducted to investigate the relation between
      anthropometry and the risk of ovarian cancer, their results have been
      inconsistent. The Netherlands Cohort Study on Diet and Cancer was initiated in
      1986. A self-administered questionnaire on dietary habits and other risk factors
      for cancer was completed by 62,573 women. Follow-up for cancer was implemented by
      annual record linkages with the Netherlands Cancer Registry. After 7.3 years of
      follow-up, 172 incident cases of invasive epithelial ovarian cancer were
      available for analysis. Multivariate analysis yielded a rate ratio of ovarian
      cancer for women with adult height of more than 175 cm, compared with those with
      height of less than or equal to 160 cm, of 2.17 (95% confidence interval: 1.14,
      4.13; p trend = 0.01). The rate ratio for women with a body mass index of more
      than 30 kg/m(2) was 1.69 (95% confidence interval: 1.00, 2.86), compared with
      women with a Quetelet index of less than 25 kg/m(2), with p trend = 0.06. Rate
      ratios for weight and body mass index at age 20 years were nonsignificantly
      increased in the intermediate categories. These data support a positive
      association between height (and to a lesser extent body mass) and ovarian cancer
      risk in this population of postmenopausal women.

PMID- 12615606
TI  - Stressful life events and risk of breast cancer in 10,808 women: a cohort study.
AB  - The authors prospectively investigated the relation between stressful life events
      and risk of breast cancer among 10,808 women from the Finnish Twin Cohort. Life
      events and breast cancer risk factors were assessed by self-administered
      questionnaire in 1981. A national modification of a standardized life event
      inventory was used, examining accumulation of life events and individual life
      events and placing emphasis on the 5 years preceding completion of the
      questionnaire. Through record linkage with the Finnish Cancer Registry, 180
      incident cases of breast cancer were identified in the cohort between 1982 and
      1996. The multivariable adjusted hazard ratio for breast cancer per one-event
      increase in the total number of life events was 1.07 (95% confidence interval
      (CI): 1.00, 1.15). This risk estimate rose to 1.35 (95% CI: 1.09, 1.67) when only
      major life events were taken into account. Independently of total life events,
      divorce/separation (hazard ratio (HR) = 2.26, 95% CI: 1.25, 4.07), death of a
      husband (HR = 2.00, 95% CI: 1.03, 3.88), and death of a close relative or friend
      (HR = 1.36, 95% CI: 1.00, 1.86) were all associated with increased risk of breast
      cancer. The findings suggest a role for life events in breast cancer etiology
      through hormonal or other mechanisms.

PMID- 12615608
TI  - Heterocyclic amines, meat intake, and association with colon cancer in a
      population-based study.
AB  - The authors examined the association between colon cancer and meat intake
      categorized by level of doneness, cooking method, and estimated levels of
      heterocyclic amines (HCAs), benzo[a]pyrene, and mutagenicity. Data were collected
      as part of a population-based, case-control study of colon cancer in North
      Carolina between 1996 and 2000 that included 701 African-American (274 cases, 427
      controls) and 957 White (346 cases, 611 controls) participants. Odds ratios were
      calculated by using unconditional logistic regression, comparing the fifth to the
      first quintile levels of intake or exposure. Intake of red meat was positively
      associated with colon cancer (odds ratio (OR) = 2.0, 95% confidence interval
      (CI): 1.3, 3.2). Associations with meat intake by cooking method were strongest
      for pan-fried red meat (OR = 2.0, 95% CI: 1.4, 3.0). Associations with meat
      intake by doneness were strongest for well-/very well done red meat (OR = 1.7,
      95% CI: 1.2, 2.5). The strongest association for individual HCAs was reported for
      2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) across all levels of
      exposure, with odds ratios of 1.8-2.0. Overall, sophisticated exposure measures
      were used to report modest, positive associations between red meat intake and
      colon cancer consistent with the hypothesis that HCAs may be among the
      etiologically relevant compounds in red meat.

PMID- 12615609
TI  - Infant sleeping position and the risk of sudden infant death syndrome in
      California, 1997-2000.
AB  - To assess the association between infant sleeping position and risk of sudden
      infant death syndrome (SIDS) in an ethnically diverse US population, the authors
      conducted a population-based case-control study in 11 counties in California from
      May 1997 through April 2000. The authors conducted in-person interviews with the
      mothers of 185 SIDS cases and 312 randomly selected race/ethnicity- and age
      matched controls to collect information on sleeping positions. Infants who had
      last been put down to sleep in the prone or side position were at greater risk of
      SIDS than were infants who had last been put down on their backs (adjusted odds
      ratio (AOR) = 2.6 (95% confidence interval (CI): 1.5, 4.5) and AOR = 2.0 (95% CI:
      1.2, 3.4) for the prone and side positions, respectively). The risk of SIDS was
      especially high for an unstable side position in which an infant was placed on
      its side and found prone (AOR = 8.7, 95% CI: 3.3, 22.7). Infants who were usually
      placed on their backs to sleep but had last been put down in the prone or side
      position (an unaccustomed position) had a significantly high risk of SIDS (AOR =
      8.2 (95% CI: 2.6, 26.0) and AOR = 6.9 (95% CI: 2.3, 20.6) for the prone and side
      positions, respectively). Infants placed in an unaccustomed prone or side
      sleeping position had a higher risk of SIDS than infants who were always placed
      prone or on the side.

PMID- 12615610
TI  - Association of maternal caffeine consumption with decrements in fetal growth.
AB  - Whether caffeine consumption during pregnancy represents a fetal hazard remains
      uncertain. The authors report on a large prospective study designed to examine
      this question. In 1996-2000, 2,291 mothers with singleton livebirths in
      Connecticut and Massachusetts were evaluated after their first prenatal visit and
      were questioned about caffeine consumption and important confounding factors.
      Urine samples were provided to analyze urinary caffeine, cotinine, and creatinine
      levels. Mothers were followed throughout pregnancy to monitor changes in
      consumption. Pregnancy outcomes were obtained from medical records. Self-reports
      of caffeine consumption in the first and third trimesters were not associated
      with intrauterine growth retardation, low birth weight, or preterm delivery. For
      every 1 mg/g creatinine increase in urinary caffeine, risk of intrauterine growth
      retardation was essentially unchanged (odds ratio (OR) = 0.96, 95% confidence
      interval (CI): 0.85, 1.08). In contrast, a 0.005 mg/g creatinine increase in
      urinary cotinine significantly increased risk (OR = 1.003, 95% CI: 1.001, 1.005).
      Mean birth weight was reduced by reported caffeine consumption (-28 g per 100 mg
      of caffeine consumed daily, 95% CI: -0.10, -0.46, p = 0.001) but not mean
      gestational age. Decaffeinated coffee did not increase risk for any perinatal
      outcome. This small decrease in birth weight, observed for maternal caffeine
      consumption, is unlikely to be clinically important except for women consuming
      >/=600 mg of caffeine daily (approximately six 10-ounce (1 ounce = 28.3 g) cups
      of coffee).

PMID- 12615611
TI  - Variability in the incidence of human immunodeficiency virus, hepatitis B virus,
      and hepatitis C virus infection among young injecting drug users in New York
      City.
AB  - Cohort studies of young (aged 18-30 years) injecting drug users recruited in 1997
      1999 in the Harlem and Lower East Side areas of New York City, New York, were
      used to assess the incidence of human immunodeficiency virus (HIV), hepatitis B
      virus (HBV), and hepatitis C virus (HCV). The authors found that HIV incidence
      was low at both sites: 0.8/100 person-years at the Harlem site and 0/100 person
      years at the Lower East Side site. In contrast, HBV incidence was moderate
      (12.2/100 person-years) at the Harlem site and high (30.7/100 person-years) at
      the Lower East Side site. Similarly, HCV incidence was moderate (9.3/100 person
      years) at the Harlem site and high (34.0/100 person-years) at the Lower East Side
      site. Results show that high rates of HBV and HCV transmission do not imply high
      rates of HIV transmission, even within an area of high HIV seroprevalence.

PMID- 12615612
TI  - Re: "Neighborhood environment and loss of physical function in older adults:
      evidence from the Alameda County Study".

PMID- 12615613
TI  - Persistent hyperreactivity and reactive airway dysfunction in firefighters at the
      World Trade Center.
AB  - New York City Fire Department rescue workers experienced massive exposure to
      airborne particulates at the World Trade Center site. Aims of this longitudinal
      study were to (1) determine if bronchial hyperreactivity was present, persistent,
      and independently associated with exposure intensity, (2) identify objective
      measures shortly after the collapse that would predict persistent hyperreactivity
      and a diagnosis of reactive airways dysfunction 6 months post-collapse. A
      representative sample of 179 rescue workers stratified by exposure intensity
      (high, moderate, and control) without current smoking or prior respiratory
      disease was enrolled. Highly exposed workers arrived within 2 hours of collapse,
      moderately exposed workers arrived later on Days 1-2; control subjects were not
      exposed. Hyperreactivity at 1, 3, and 6 months post-collapse was associated with
      exposure intensity, independent of ex-smoking and airflow obstruction. Six months
      post-collapse, highly exposed workers were 6.8 times more likely than moderately
      exposed workers and control subjects to be hyperreactive (95% confidence
      interval, 1.8-25.2; p = 0.004), and hyperreactivity persisted in 55% of those
      hyperreactive at 1 and/or 3 months. In highly exposed subjects, hyperreactivity 1
      or 3 months post-collapse was the sole predictor for reactive airways dysfunction
      (p = 0.021). In conclusion, development and persistence of hyperreactivity and
      reactive airways dysfunction were strongly and independently associated with
      exposure intensity. Hyperreactivity shortly post-collapse predicted reactive
      airways dysfunction at 6 months in highly exposed workers; this has important
      implications for disaster management.

PMID- 12615614
TI  - Detection of telomerase expression in mediastinal lymph nodes of patients with
      lung cancer.
AB  - Mediastinal lymph nodes are the most common site of tumor spread in non-small
      cell lung cancer (NSCLC). We hypothesized that micrometastatic disease could be
      detected by reverse transcription-polymerase chain reaction (RT-PCR) for
      expression of human telomerase reverse transcriptase (hTERT) in mediastinal lymph
      nodes and that a minimally invasive technique (endoscopic ultrasound-guided fine
      needle aspiration [EUS-FNA]) is capable of sampling lymph nodes for PCR analysis
      without surgery. Mediastinal lymph nodes were sampled with EUS-FNA in patients
      with NSCLC and negative control subjects undergoing EUS for benign disease. Total
      RNA was harvested from samples, and RT-PCR was performed to detect telomerase
      gene expression. RNA was available from 87 of 100 lymph node aspirates from 39
      patients with NSCLC and from 12 negative control patients. hTERT was expressed in
      0 of 14 negative control lymph nodes in 18 of 57 pathologically negative lymph
      nodes from cancer patients and in 10 of 16 pathologically positive lymph nodes (p
      < 0.05). Five of 18 (28%) patients with no pathologically evident mediastinal
      disease expressed telomerase in at least one lymph node. Minimally invasive EUS
      FNA with RT-PCR is capable of detecting expression of cancer specific mRNA in
      lymph nodes. Approximately one-third of pathologically negative mediastinal lymph
      nodes in NSCLC patients express hTERT mRNA. The clinical significance of this
      observation is yet to be determined.

PMID- 12615615
TI  - Enhanced expression of vascular endothelial growth factor in pulmonary arteries
      of smokers and patients with moderate chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is associated with structural and
      functional changes in the pulmonary circulation that commence at an early stage.
      To investigate whether vascular endothelial growth factor (VEGF) might be
      implicated as a mediator in COPD-associated pulmonary vascular changes, we
      studied surgical specimens obtained from 19 nonsmokers, 21 smokers with normal
      lung function, 28 patients with moderate COPD, and 10 patients with severe
      emphysema. The expression of VEGF in pulmonary muscular arteries was evaluated by
      immunohistochemistry, its protein content in lung tissue by Western blot
      analysis, and VEGF mRNA and its isoforms were analyzed by reverse transcription
      polymerase chain reaction. The immunohistochemical expression of VEGF was
      increased in pulmonary arteries of smokers (median, 68% [interquartile range, 60
      88]) and patients with moderate COPD (77% [63-82]), compared with nonsmokers (53%
      [40-63]) (p < 0.05 each). The expression of VEGF in smooth muscle cells
      correlated with the thickness of the vessel wall (r = 0.38, p < 0.01). VEGF
      protein content in lung tissue was reduced in severe emphysema, where reverse
      transcription-polymerase chain reaction demonstrated a lower proportion of the
      VEGF189 isoform. In conclusion, the expression of VEGF varies according to the
      severity of COPD and might be involved in the pathogenesis of pulmonary vascular
      remodeling at early stages of the disease.

PMID- 12615616
TI  - Acute respiratory distress syndrome after bacteremic sepsis does not increase
      mortality.
AB  - To determine whether acute respiratory distress syndrome (ARDS) complicating
      bacteremic sepsis independently affects mortality in critically ill patients, we
      conducted a 3-year retrospective cohort study in a surgical intensive care unit.
      We included all consecutive patients with blood culture-positive sepsis and
      measured organ dysfunctions and mortality. Among 4,530 admissions, 196 cases of
      bacteremic sepsis were recorded. ARDS occurred in 31 (16%) of these patients. The
      case fatality rate was 58% in patients with ARDS compared with 31% in patients
      without ARDS. Using Cox proportional hazards regression with time-dependent
      variables, the unadjusted hazard ratio for death was 1.8 (95% confidence interval
      [CI], 1.0-3.2). After adjusting for comorbid factors that were present before the
      onset of sepsis, the hazard ratio was 2.2 (95% CI, 1.2-3.9). After further
      adjustment was made for nonpulmonary organ dysfunctions and microbiologic factors
      that were independently associated with mortality, the adjusted hazard ratio for
      ARDS was 0.6 (95% CI, 0.3-1.2). Among critically ill surgical patients, ARDS
      complicating bacteremic sepsis remains common, but it is not independently
      associated with short-term mortality, after adjusting for severity of illness and
      nonpulmonary organ dysfunctions evolving after the onset of sepsis.

PMID- 12615617
TI  - The feasibility of conducting clinical trials in infants and children with acute
      respiratory failure.
AB  - Designing robust clinical trials in critically ill, mechanically ventilated
      children requires an understanding of the epidemiology and course of pediatric
      respiratory failure. As part of a clinical trial, we screened all mechanically
      ventilated children in nine large pediatric intensive care units (ICUs) across
      North America for 6 consecutive months. Of 6,403 total ICU admissions, 1,096
      (17.1%) required mechanical ventilator support for a minimum of 24 hours. Of
      these, 701 (64%) met one or more exclusion criteria for trial enrollment. Common
      reasons for exclusion were upper airway obstruction (13.5%) and cyanotic
      congenital heart disease (11.5%). Life support interventions were restricted for
      9.7% of patients, and 5.5% were chronically ventilator dependent. In the patients
      who were eligible for respiratory failure studies, 62.4% had an acute primary
      diagnosis of pulmonary disease, 14.2% neurologic disease, and 8.9% cardiac
      disease. Chronic underlying conditions were present in 43.2% of the patients. The
      most common acute diagnosis was bronchiolitis in infants (43.6%) and pneumonia in
      children 1 year old and older (24.5%). Mortality was rare (1.6%), and the median
      duration of ventilation was 7 days. The design of clinical trials in critically
      ill children is feasible but must account for the diverse population, infrequent
      mortality, and short duration of mechanical ventilation.

PMID- 12615618
TI  - Targeted delivery of antiprotease to the epithelial surface of human tracheal
      xenografts.
AB  - The cystic fibrosis (CF) lung is uniquely susceptible to Pseudomonas aeruginosa,
      and infection with this organism incites an intense, compartmentalized
      inflammatory response that leads to chronic airway obstruction and
      bronchiectasis. Neutrophils migrate into the airway, and released neutrophil
      elastase contributes to the progression of the lung disease characteristic of CF.
      We have developed a strategy that permits the delivery of antiproteases to the
      inaccessible CF airways by targeting the respiratory epithelium via the human
      polymeric immunoglobulin receptor (hpIgR). A fusion protein consisting of a
      single-chain Fv directed against secretory component, the extracellular portion
      of the pIgR, linked to human alpha1-antitrypsin is effectively ferried across
      human tracheal xenografts and delivers the antiprotease to the apical surface to
      a much greater extent than occurs by passive diffusion of human alpha1
      antitrypsin alone. Targeted antiprotease delivery paralleled hpIgR expression in
      the respiratory epithelium in vivo and was not increased by escalating dose, so
      airway penetration was receptor-dependent, not dose-dependent. Thus, this
      approach provides us with the ability to deliver therapeutics, like
      antiproteases, specifically to the lumenal surface of the respiratory epithelium,
      within the airway surface fluid, where it will be in highest concentration at
      this site.

PMID- 12615619
TI  - Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans.
AB  - Sarcoidosis, in the United States, more commonly and severely affects African
      Americans. HLA associations with sarcoidosis have been reported, but most studies
      used case-control designs, which may produce biased results because of population
      stratification. We examined transmission of HLA-DQB1 alleles in 225 African
      American families with at least one offspring with sarcoidosis. Of five low
      resolution HLA-DQB1 alleles, *02 and *06 showed significant deviation in
      transmission patterns to affected offspring. High-resolution typing of these
      allelic subsets revealed that HLA-DQB1*0201 was transmitted to affected offspring
      half as often as expected (p = 0.001), whereas DQB1*0602 was transmitted to
      affected offspring about 20% more often than expected (p = 0.029). Examining
      interactions between *0201 and *0602 alleles and environmental exposures showed
      that *0602 varied little with respect to exposure, but sarcoidosis risk
      associated with *0201 often depended on exposure status. Alternatively, the *0602
      allele in affected probands was associated with radiographic disease progression,
      but the *0201 allele showed no significant correlation with phenotype. Major
      differences in the amino acid sequences encoded by *0201 and *0602 alleles exist,
      which may explain the differential effects these alleles have on sarcoidosis
      susceptibility and progression in African Americans.

PMID- 12615620
TI  - Characterization of a single nucleotide polymorphism in the lipopolysaccharide
      binding protein and its association with sepsis.
AB  - We sought to characterize polymorphisms in the proximal coding region of the
      lipopolysaccharide binding protein gene and to determine whether a previously
      reported variant was associated with sepsis complicated by organ failure or shock
      after trauma. We used multiple analytical methods, including pyrosequencing,
      restriction fragment length polymorphism, and sequencing to characterize the
      proximal coding region. We also reexamined a prospective cohort of severely
      injured patients and healthy control individuals. The single nucleotide
      polymorphism at nucleotide 292 does not exist as previously reported. Instead,
      the adjacent nucleotide (291) was observed to be polymorphic. In 151 trauma
      patients, 37 (25%) developed severe sepsis, and 19 (13%) died. Thirteen of 50
      (26%) C-allele carriers and 24 of 101 (24%) TT homozygotes developed severe
      sepsis. Unadjusted and adjusted analyses did not demonstrate any associations
      between genotype and severe sepsis, septic shock, or death. In conclusion, a
      single nucleotide polymorphism in the lipopolysaccharide binding protein coding
      region that was reported to exist at the 292 position and to result in an amino
      acid substitution actually exists at the adjacent 291 position and does not
      result in an amino acid substitution. Furthermore, this polymorphism does not
      appear to be associated with complicated sepsis after trauma.

PMID- 12615621
TI  - Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort
      Study.
AB  - Menopause is considered to be a risk factor for sleep-disordered breathing, but
      this hypothesis has not been adequately tested. The association of premenopause,
      perimenopause, and postmenopause with sleep-disordered breathing was investigated
      with a population-based sample of 589 women enrolled in the Wisconsin Sleep
      Cohort Study. Menopausal status was determined from menstrual history,
      gynecologic surgery, hormone replacement therapy, follicle-stimulating hormone,
      and vasomotor symptoms. Sleep-disordered breathing was indicated by the frequency
      of apnea and hypopnea events per hour of sleep, measured by in-laboratory
      polysomnography. Multivariable logistic regression was used to estimate odds
      ratios for having 5 or more and 15 or more apnea and hypopnea events per hour.
      Odds ratios (95% confidence interval), adjusted for age, body habitus, smoking,
      and other potential confounding factors, for 5 or more apnea and hypopnea events
      per hour were 1.2 (0.7, 2.2) with perimenopause and 2.6 (1.4, 4.8) with
      postmenopause; odds ratios for 15 or more apnea and hypopnea events per hour were
      1.1 (0.5, 2.2) with perimenopause and 3.5 (1.4, 8.8) with postmenopause. The
      menopausal transition is significantly associated with an increased likelihood of
      having sleep-disordered breathing, independent of known confounding factors.
      Evaluation for sleep-disordered breathing should be a priority for menopausal
      women with complaints of snoring, daytime sleepiness, or unsatisfactory sleep.

PMID- 12615622
TI  - Intermittent hypoxia is associated with oxidative stress and spatial learning
      deficits in the rat.
AB  - In the adult rat, exposure to intermittent hypoxia (IH), such as occurs in sleep
      disordered breathing, is associated with neurobehavioral impairments and
      increased apoptosis in the hippocampal CA1 region and cortex. We hypothesized
      that the episodic hypoxic-reoxygenation cycles of IH would induce oxidant stress,
      and the latter may underlie the IH-associated spatial learning and retention
      deficits. Adult male rats were therefore exposed to IH (90-second alternations of
      10% oxygen and 21% oxygen) or room air (RA) for 7 days, and received twice-daily
      injections of either 3 mg/kg of the antioxidant PNU-101033E (PNU) or vehicle (V).
      Rats were then trained in a standard place-training task in the water maze. V-IH
      displayed significant impairments of spatial learning in the water maze, which
      were attenuated by PNU-101033E. Post hoc analyses further revealed that V-IH had
      significantly longer latencies and pathlengths to locate the hidden platform than
      PNU-IH, V-RA, or PNU-RA, indicating that PNU-101033E treatment reduced the
      behavioral impairments associated with IH. In addition, treatment with PNU
      101033E markedly attenuated the increase in lipid peroxidation, and isoprostane
      concentrations associated with exposure to IH. Collectively, these findings
      indicate that the IH exposure is associated with increased oxidative stress,
      which is likely to play an important role in the behavioral impairments observed
      in a rodent model of sleep-disordered breathing.

PMID- 12615623
TI  - Characterization of a mouse model of allergy to a major occupational latex glove
      allergen Hev b 5.
AB  - Allergen-specific immunotherapy is a clinically proven effective treatment for
      many allergic diseases, including asthma; however, it is not currently available
      for latex allergy because of the high risk of anaphylaxis. There is, therefore, a
      crucial need for an animal model of latex allergy in which to develop effective
      immunotherapy. Previous mouse models of latex allergy either did not characterize
      the allergic pulmonary immune response or used crude latex extracts, making it
      difficult to quantify the contribution of individual proteins and limiting their
      usefulness for developing specific immunotherapy. We immunized mice with
      recombinant Hev b 5, a defined major latex allergen, or latex glove protein
      extract, representing the range of occupationally encountered processed latex
      allergens. The immune response was compared with that seen in ovalbumin-immunized
      mice. Immunization with Hev b 5 or glove extract elicits hallmarks of allergic
      pulmonary Th2-type immune responses, comparable to those for ovalbumin, including
      (1) serum antigen-specific IgE, (2) an eosinophilic inflammatory infiltrate in
      the lung, (3) increased interleukin-5 in lung bronchoalveolar lavage fluid, and
      (4) mucus hypersecretion by epithelial cells in the lung airways. This mouse
      model will aid the development of potentially curative treatments for latex
      sensitized individuals, including those with occupational asthma.

PMID- 12615624
TI  - Thrombin-activatable fibrinolysis inhibitor and protein C inhibitor in
      interstitial lung disease.
AB  - Intraalveolar activation of the coagulation system due to reduced fibrinolytic
      function plays a critical role in the pathogenesis of interstitial lung disease.
      Recently, a new potent inhibitor of fibrinolysis, thrombin-activatable
      fibrinolysis inhibitor, has been isolated and characterized from human plasma.
      This study evaluated the levels of thrombin-activatable fibrinolysis inhibitor
      and protein C inhibitor, another suppressor of fibrinolysis, in the
      bronchoalveolar lavage fluid from patients with interstitial lung disease. There
      were 82 patients with interstitial lung disease and 8 normal subjects. The
      bronchoalveolar lavage fluid levels of thrombin-activatable fibrinolysis
      inhibitor and protein C inhibitor were significantly higher in all patients with
      interstitial lung disease than in normal subjects. Both inhibitors of
      fibrinolysis were significantly and inversely correlated with fibrinolytic
      activity in all patients. The levels of thrombin-activatable fibrinolysis
      inhibitor were significantly correlated with those of protein C inhibitor,
      thrombin-antithrombin complex, and monocyte chemoattractant protein-1. Reverse
      transcriptase-polymerase chain reaction showed that alveolar macrophages isolated
      from patients with interstitial lung disease as well as immortalized lung
      epithelial cell lines express thrombin-activatable fibrinolysis inhibitor
      antigen. Overall, these findings suggest that thrombin-activatable fibrinolysis
      inhibitor and protein C inhibitor may play important roles in the mechanism of
      intraalveolar hypofibrinolysis associated with interstitial lung diseases.

PMID- 12615626
TI  - Altered clearance of gadolinium diethylenetriaminepentaacetic acid aerosol from
      bleomycin-injured dog lungs: initial observations.
AB  - To characterize altered alveolar transfer to solute in bleomycin (BLM)-injured
      lungs, eight dogs underwent a gadolinium diethylenetriaminepentaacetic acid
      aerosol (Gd-AS) magnetic resonance imaging study before and on Days 7 and 40
      after tracheal instillation of BLM (0.75 mg) in the left lungs. Consecutive fast
      gradient echo magnetic resonance imaging was acquired during and after
      spontaneous inhalation of 200-mM Gd-AS. The slope (Kep) and clearance half-time
      (T1/2) of logarithmic regression lines for clearance curves were estimated.
      Histology on Day 40 was compared with that on Day 7 in another three dogs. On
      Days 7 and 40, Gd-AS deposition was heterogeneously reduced in the affected
      lungs. On Day 7 with multifocal intraalveolar exudative changes, Kep in affected
      areas was significantly increased compared with baseline (2.5 x 10(-3) minutes(
      1) +/- 0.3 versus 1.7 x 10(-3) minutes(-1) +/- 0.2, p < 0.0001), with significant
      decrease in T1/2 (121.6 +/- 19.7 minutes vs. 170.4 +/- 15.8 minutes, p < 0.001).
      However, on Day 40 with multifocal interstitial fibrosis, Kep and T1/2 were
      recovered toward baseline. BLM-injured lungs can be characterized by accelerated
      Gd-AS clearance during the acute exudative phase and their recovery during the
      chronic fibrotic phase. This technique is acceptable for monitoring alveolar
      transfer changes in BLM-injured lungs.

PMID- 12615625
TI  - Parenteral nutrition with fish oil modulates cytokine response in patients with
      sepsis.
AB  - Infusion of fish oil-based (n-3) lipids may influence leukocyte function and
      plasma lipids in critical care patients. Twenty-one patients with sepsis
      requiring parenteral nutrition were randomized to receive an n-3 lipid emulsion
      rich in eicosapentaenoic acid and docosahexaenoic acid or a conventional (n-6)
      lipid emulsion (index fatty acid: arachidonic acid) for 5 days. The impact on
      plasma-free fatty acids, mononuclear leukocyte cytokine generation, and membrane
      fatty acid composition was examined. Cytokine synthesis by isolated mononuclear
      leukocyte was elicited by endotoxin. Before the onset of lipid infusion therapy,
      plasma-free fatty acid concentrations were greatly increased in septic patients,
      with arachidonic acid by far surpassing eicosapentaenoic acid and docosahexaenoic
      acid, a feature maintained during conventional lipid infusion. Within 2 days of
      fish oil infusion, free n-3 fatty acids increased, and the n-3/n-6 ratio was
      reversed, with rapid incorporation of n-3 fatty acids into mononuclear leukocyte
      membranes. Generation of proinflammatory cytokines by mononuclear leukocytes was
      markedly amplified during n-6 and was suppressed during n-3 lipid application.
      After termination of lipid administration, free n-3 fatty acid concentrations and
      mononuclear leukocyte cytokine synthesis returned to preinfusion values. Use of
      lipid infusions might allow us to combine intravenous alimentation with
      differential impact on inflammatory events and immunologic functions in patients
      with sepsis.

PMID- 12615627
TI  - Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy.
AB  - Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies are frequently used to
      treat inflammatory diseases. However, these drugs also have immunosuppressive
      effects. We report on three patients who developed disseminated histoplasmosis on
      therapy with TNF-alpha inhibitors. In vitro assays were used to characterize the
      role of these agents in host defense against Histoplasma capsulatum.
      Intracellular proliferation of H. capsulatum was measured in alveolar macrophages
      and peripheral monocytes of normal volunteers in the presence and absence of the
      TNF-alpha antibody, infliximab. Both infliximab and control antibody enhanced
      fungal growth in monocytes and alveolar macrophages, suggesting this was a
      nonspecific antibody response. Despite similar intracellular fungal loads in the
      presence of both antibodies, lymphocyte proliferation in response to blood
      monocytes and alveolar macrophages infected with H. capsulatum was inhibited by
      the addition of physiologic doses of infliximab, whereas control antibody had no
      effect. The production of H. capsulatum-induced interferon-gamma and TNF-alpha
      was assessed in 5-day cultures containing lymphocytes and alveolar macrophages or
      monocytes. Interferon-gamma secretion was significantly reduced in the presence
      of infliximab. In summary, patients receiving anti-TNF-alpha therapy are at risk
      for developing disseminated histoplasmosis. This may be due to a defect in the
      TH1 arm of cellular immunity.

PMID- 12615628
TI  - Positive end-expiratory pressure after a recruitment maneuver prevents both
      alveolar collapse and recruitment/derecruitment.
AB  - We tested the hypothesis that collapsed alveoli opened by a recruitment maneuver
      would be unstable or recollapse without adequate positive end-expiratory pressure
      (PEEP) after recruitment. Surfactant deactivation was induced in pigs by Tween
      instillation. An in vivo microscope was placed on a lung area with significant
      atelectasis and the following parameters measured: (1) the number of alveoli per
      field and (2) alveolar stability (i.e., the change in alveolar size from peak
      inspiration to end expiration). We previously demonstrated that unstable alveoli
      cause lung injury. A recruitment maneuver (peak pressure = 45 cm H2O, PEEP = 35
      cm H2O for 1 minute) was applied and alveolar number and stability were measured.
      Pigs were then separated into two groups with standard ventilation plus (1) 5
      PEEP or (2) 10 PEEP and alveolar number and stability were again measured. The
      recruitment maneuver opened a significant number of alveoli, which were stable
      during the recruitment maneuver. Although both 5 PEEP and 10 PEEP after
      recruitment demonstrated improved oxygenation, alveoli ventilated with 10 PEEP
      were stable, whereas alveoli ventilated with 5 PEEP showed significant
      instability. This suggests recruitment followed by inadequate PEEP permits
      unstable alveoli and may result in ventilator-induced lung injury despite
      improved oxygenation.

PMID- 12615629
TI  - Statin use is associated with improved function and survival of lung allografts.
AB  - 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are widely
      used antilipidemic agents that are also immunomodulatory. We evaluated possible
      effects of these agents after lung transplantation by comparing outcomes of 39
      allograft recipients, who were prescribed statins for hyperlipidemia, with those
      of 161 contemporaneous control recipients who did not receive these drugs. Acute
      rejection (>or= Grade II) was less frequently found in the statin group (15.1
      versus 25.6% of biopsies, p < 0.01). None of 15 recipients started on statins
      during postoperative Year 1 developed obliterative bronchiolitis, whereas the
      cumulative incidence of this complication among control subjects was 37% (p <
      0.01). Total cellularity, as well as proportions of inflammatory neutrophils and
      lymphocytes, were significantly lower in bronchoalveolar lavages of statin
      recipients. Among double lung recipients, those taking statins had significantly
      better spirometry: FVC (80 +/- 2 versus 70 +/- 1%) and FEV1 (87 +/- 2 versus 70
      +/- 1%), as percentages of predicted values, and absolute FEV1/FVC (83.4 +/- 1.2
      versus 78.6 +/- 0.5) (all p < 0.01). The 6-year survival of recipients taking
      statins (91%) was much greater than that of control subjects (54%) (p < 0.01).
      These data suggest statin use may have substantial clinical benefits after
      pulmonary transplantation.

PMID- 12615630
TI  - Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen
      vascular disease.
AB  - A histologic feature of usual interstitial pneumonia is the presence of
      fibroblastic foci. As some patients with usual interstitial pneumonia and an
      underlying collagen vascular disease have a better prognosis, we hypothesized
      that they would have fewer fibroblastic foci. Pathologists reviewed surgical lung
      biopsies from 108 patients with usual interstitial pneumonia (nine with collagen
      vascular disease) and assigned a score (absent 0, mild 1, moderate 2, and marked
      3) for fibroblastic foci. Patients with idiopathic usual interstitial pneumonia
      had a higher median profusion of fibroblastic foci (1.75 vs. 1.0, p = 0.003).
      Baseline characteristics were similar, although patients with a collagen vascular
      disease were younger, had a shorter duration of symptoms, and had a higher
      percentage of predicted total lung capacity. Profusion of fibroblastic foci was
      the most discriminative feature for separating idiopathic from collagen vascular
      disease-associated usual interstitial pneumonia (odds ratio 8.31; 95% confidence
      interval, 1.98, 59.42; p = 0.002 for a one-unit increase in fibroblastic foci
      score). No deaths were noted in the collagen vascular disease-associated usual
      interstitial pneumonia group; 52 deaths occurred in the idiopathic usual
      interstitial pneumonia group (log rank; p = 0.005). We conclude that patients
      with collagen vascular disease-associated usual interstitial pneumonia have fewer
      fibroblastic foci and improved survival.

PMID- 12615631
TI  - Sensitivity of spirometric measurements to detect airway obstruction in infants.
AB  - We evaluated the ability of forced expiratory flow volume curves from raised lung
      volumes to assess airway function among infants with differing severities of
      respiratory symptoms. Group 1 (n = 33) had previous respiratory symptoms but were
      currently asymptomatic; group 2 (n = 36) was symptomatic at the time of
      evaluation. As a control group, we used our previously published sample of 155
      healthy infants. Flow volume curves were quantified by FVC, FEF50, FEF75, FEF25
      75, FEV0.5, and FEV0.5/FVC, which were expressed as Z scores. All variables
      except FVC had Z scores that were significantly less than zero and distinguished
      groups 1 and 2 with progressively lower Z scores. The mean Z scores of the flow
      variables (FEF50%, FEF75%, and FEF25-75%) were more negative than the Z scores
      for the timed expired volumes (FEV0.5 or FEV0.5/FVC) for both groups. In general,
      measures of flow identified a greater number of infants with abnormal lung
      function than measures of timed volume; FEF50 had the highest performance in
      detecting abnormal lung function. In summary, forced expiratory maneuvers
      obtained by the raised volume rapid compression technique can discriminate among
      groups of infants with differing severity of respiratory symptoms, and measures
      of forced expiratory flows were better than timed expiratory volume in detecting
      abnormal airway function.

PMID- 12615632
TI  - Prognostic factors for survival in human immunodeficiency virus-associated
      pulmonary arterial hypertension.
AB  - We report a large monocentric case series of 82 patients with human
      immunodeficiency virus-associated pulmonary arterial hypertension (PAH). No
      germline mutations of the PPH1 gene (bone morphogenetic protein receptor-II) were
      found in any of the 19 patients tested. PAH was the direct cause of death in 72%
      of cases. Survival rates of the overall population at 1, 2, and 3 years were 73,
      60, and 47%, respectively. Survival was significantly poorer in patients in New
      York Heart Association functional class III-IV at the time of diagnosis, as
      compared with those in functional class I-II with respective rates of 60, 45, and
      28% versus 100, 90, 84% at 1, 2, and 3 years (p < 0.0001). Subsequently, we
      analyzed prognostic factors in patients in functional class III-IV. Univariate
      analysis indicated that CD4 lymphocyte count of more than 212 cells mm(-3), the
      use of combination antiretroviral therapy (CART), and epoprostenol infusion were
      related with a better survival. On multivariate analysis only CD4 lymphocyte
      count was an independent predictor of survival, presumably because CART and
      epoprostenol infusion were strongly linked in our patient population. These
      results suggest that patients with severe human immunodeficiency virus-associated
      PAH should be considered for long-term epoprostenol infusion in association with
      CART.

PMID- 12615633
TI  - Prevention of endotracheal suctioning-induced alveolar derecruitment in acute
      lung injury.
AB  - We studied endotracheal suctioning-induced alveolar derecruitment and its
      prevention in nine patients with acute lung injury. Changes in end-expiratory
      lung volume measured by inductive plethysmography, positive end-expiratory
      pressure-induced alveolar recruitment assessed by pressure-volume curves, oxygen
      saturation, and respiratory mechanics were recorded. Suctioning was performed
      after disconnection from the ventilator, through the swivel adapter of the
      catheter mount, with a closed system, and with the two latter techniques while
      performing recruitment maneuvers during suctioning (40 cm H2O pressure-supported
      breaths). End-expiratory lung volume after disconnection fell more than with all
      other techniques (-1,466 +/- 586, -733 +/- 406, -531 +/- 228, -168 +/- 176, and 
      284 +/- 317 ml after disconnection, through the swivel adapter, with the closed
      system, and with the two latter techniques with pressure-supported breaths,
      respectively, p < 0.001), and was not fully recovered 1 minute after suctioning.
      Recruitment decreased after disconnection and using the swivel adapter (-104 +/-
      31 and -63 +/- 25 ml, respectively), was unchanged with the closed system (-1 +/-
      10 ml), and increased when performing recruitment maneuvers during suctioning (71
      +/- 37 and 60 +/- 30 ml) (p < 0.001). Changes in alveolar recruitment correlated
      with changes in lung volume (rho = 0.88, p < 0.001) and compliance (rho = 0.9, p
      < 0.001). Oxygenation paralleled lung volume changes. Suctioning-induced lung
      derecruitment in acute lung injury can be prevented by performing recruitment
      maneuvers during suctioning and minimized by avoiding disconnection.

PMID- 12615635
TI  - A function of myelin is to protect axons from subsequent injury: implications for
      deficits in multiple sclerosis.

PMID- 12615634
TI  - Six-minute walk distance in chronic obstructive pulmonary disease:
      reproducibility and effect of walking course layout and length.
AB  - The 6-minute walk test is used in clinical practice and clinical trials of lung
      diseases; however, it is not clear whether replicate tests need to be performed
      to assess performance. Furthermore, little is known about the impact of walking
      course layout on test performance. We conducted 6-minute walks on 761 patients
      with severe emphysema (mean +/- SD FEV1% predicted = 26.3 +/- 7.2) who were
      participants in the National Emphysema Treatment Trial. Four hundred seventy
      participants had repeated walks on a separate day. The second test was improved
      by an average of 7.0 +/- 15.2% (66.1 +/- 146 feet, p < 0.0001, by paired t test),
      with an intraclass correlation coefficient of 0.88 between days. The course
      layout had an effect on the distance walked. Participants tested on continuous
      (circular or oval) courses had a 92.2-foot longer walking distance than those
      tested on straight (out and back) courses. Course length had no significant
      effect on walking distance. The training effect found in these patients with
      severe emphysema is less than in previous reports of patients with chronic
      obstructive pulmonary disease. Furthermore, the layout of the track may influence
      the 6-minute walk performance.

PMID- 12615636
TI  - Occipital epilepsies: identification of specific and newly recognized syndromes.
AB  - Occipital epilepsies often elude diagnosis as they frequently masquerade as other
      seizure syndromes. Visual hallucinations are the key clinical symptoms indicating
      an occipital focus, but may be difficult to elicit on history, especially from
      children, and are not always present. When visual symptoms are not prominent, the
      seizure semiology and scalp EEG may lead the clinician away from considering an
      occipital focus, as they often reflect seizure propagation rather than seizure
      origin. Clinical and neuroimaging advances have led to the recognition of many
      new occipital epilepsy syndromes, which generally present in childhood or
      adolescence. Major groups include malformations of cortical development [focal
      cortical dysplasia, periventricular heterotopia (PVH), subcortical band
      heterotopia (SBH), polymicrogyria], vascular (including epilepsy with bilateral
      occipital calcifications often associated with coeliac disease), metabolic and
      the emerging idiopathic occipital epilepsies. The idiopathic occipital epilepsies
      now comprise three identifiable electroclinical syndromes of childhood and
      adolescence, the biological inter-relationships and overlap with idiopathic
      generalized epilepsies of which are discussed here. We emphasize the clues to
      recognition of specific occipital epilepsies, some of which now have specific
      treatments. Where medical therapy is ineffective, occipital corticectomy should
      be considered. Emerging evidence suggests that some syndromes have a good
      surgical outcome, and the consequences to visual function may be less severe than
      anticipated.

PMID- 12615637
TI  - Early clinical predictors and progression of irreversible disability in multiple
      sclerosis: an amnesic process.
AB  - Prognosis of multiple sclerosis is highly variable. Clinical variables have been
      identified that are assessable early in the disease and are predictors of the
      time from the disease onset to the onset of irreversible disability. Our
      objective was to determine if these clinical variables still have an effect after
      the first stages of disability have been reached. We determined the dates of
      disease onset and assignment of scores of irreversible disability in 1844
      patients with multiple sclerosis. We used three scores on the Kurtzke Disability
      Status Scale as benchmarks of disability accumulation: 4 (limited walking but
      without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used
      Kaplan-Meier analyses and Cox regression models to determine the influence of the
      clinical variables on the time to disability onset. Median times from onset of
      multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly
      influenced by gender, age, symptoms and course (relapsing-remitting or
      progressive) at onset of the disease, degree of recovery from the first relapse,
      time to a second neurological episode, and the number of relapses in the first 5
      years of the disease. Similarly, times from onset of multiple sclerosis to a
      score of 6 and 7 were influenced by time to a score of 4. In contrast, none of
      the variables substantially affected the time from a score of 4 to a score of 6
      or 7, or from a score of 6 to a score of 7. Early assessable clinical variables
      significantly influence the time from the onset of multiple sclerosis to the
      assignment of a disability score of 4, but not the subsequent progression of
      irreversible disability.

PMID- 12615638
TI  - Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two
      pedigrees with PS-1 exon 9 deletions.
AB  - Several pedigrees have recently been reported in which dominantly inherited
      familial Alzheimer's disease is associated in some family members with spastic
      paraparesis and non-neuritic 'cotton wool' plaques. Here we report clinical,
      genetic and neuropathological findings in two further large pedigrees in which
      this combination of phenotypes is associated with a deletion of exon 9 of the
      presenilin-1 (PS-1) gene caused by mutations at the splice acceptor site. In both
      pedigrees, individuals with paraparesis at presentation had a later than average
      age at onset of symptoms. In addition, one subject with paraparesis had a much
      less prominent dementia syndrome than his dementia-affected siblings. As PS-1
      mutations are almost always associated with a particularly aggressive form of
      presenile dementia, these findings suggest the existence of a protective or
      delaying factor in individuals with spastic paraparesis.

PMID- 12615639
TI  - Slowly progressive defect in recognition of familiar people in a patient with
      right anterior temporal atrophy.
AB  - We report the case of a patient (C.O.) who showed a selective defect in the
      recognition of familiar people, with very mild disease progression during a
      period of 30 months resulting from focal atrophy of the right temporal lobe. On
      formal neuropsychological testing, C.O. obtained high scores on tests of general
      intelligence, episodic memory, language, executive functions, selective
      attention, visual recognition and visual-spatial abilities. On more specific
      tasks of familiar and unfamiliar face recognition, C.O. scored above the
      controls' means on perceptual tests, but obtained highly pathological results on
      amnesic-associative tests. His disorder of recognition of familiar people was not
      due to loss of person-specific information, since he obtained highly abnormal
      naming scores when presented with photographs of famous people but borderline or
      mildly abnormal scores in a tasks in which he had to name celebrities from verbal
      definitions. On the other hand, C.O.'s recognition disorder could not be
      considered to be a form of 'associative prosopagnosia' since a similar defect was
      observed when he was requested to access information about famous persons through
      their voice rather than their face. Two alternative interpretations are advanced
      to explain C.O.'s inability to access his relatively spared person-specific
      knowledge not only through the person's face but also through the person's voice.
      The first hypothesis is that, before accessing the person-specific information,
      unimodal recognition channels must converge into a multimodal, non-verbal person
      recognition system and that the right anterior temporal cortices play a crucial
      role in this integrative activity. The second hypothesis is that the face
      recognition units have privileged access to person-specific semantic knowledge
      and that other recognition subsystems require coactivation of the face
      recognition units in order to access person-specific semantic information.

PMID- 12615641
TI  - Mutations in the tau gene that cause an increase in three repeat tau and
      frontotemporal dementia.
AB  - The majority of cases with frontotemporal dementia (FTD) have no tau deposition
      in the brain, yet mutations in the tau gene lead to a similar clinical phenotype
      with insoluble tau depositing in neuropathological lesions. We report two tau
      gene mutations at positions +19 and +29, in the intronic sequences immediately
      following the stem loop structure in exon 10, which segregate with FTD. Exon
      trapping experiments showed that these gene mutations alter the splicing out of
      exon 10 and produce an increase in tau isoforms with three microtubule binding
      domains (three repeat tau). Mutagenesis experiments demonstrated that the +19
      mutation was responsible for the increase in three repeat tau, possibly by
      altering an intron silencer modulator sequence element found at this region of
      the gene. Microtubule binding experiments revealed a significant decrease in
      microtubule assembly with increasing amounts of three and decreasing amounts of
      four repeat tau. Brain autopsy was available in one case. Analysis of the type of
      soluble tau isoforms revealed an increase in three repeat tau and an absence of
      tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue
      fractions, consistent with the absence of tau-positive histopathology. There was
      also an increase in tau degradation products suggestive of increased proteolysis.
      This increase in tau breakdown products was associated with TUNEL- and activated
      caspase-3-positive neurons identified histologically. These studies show that
      increases in soluble three repeat tau can be responsible for FTD in cases with
      tau gene mutations in the intronic region immediately adjacent to the stem loop
      in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do
      not form abnormal aggregates and appear more prone to proteolysis. The increase
      in tau proteolysis was associated with increased evidence of apoptosis. This
      mechanism of neurodegeneration may be more applicable to the majority of FTD
      cases, which do not accumulate insoluble tau deposits.

PMID- 12615640
TI  - Preserved myelin integrity and reduced axonopathy in connexin32-deficient mice
      lacking the recombination activating gene-1.
AB  - Mice heterozygously deficient for myelin protein zero (P0) mimicking human
      Charcot-Marie-Tooth (CMT) disease 1B show T-lymphocyte and macrophage
      upregulation in peripheral nerves, which aggravates and modulates the genetically
      mediated demyelinating neuropathy. In connexin32 (cx32)-deficient (cx32(def))
      mice, which mimic the X-linked dominant form of CMT (CMTX), T-lymphocyte and
      macrophage numbers are also significantly elevated in peripheral nerves. To test
      the hypothesis that immune cells are indeed pathogenic in this model, we cross
      bred cx32(def) mice with recombination activating gene-1 (RAG-1)-deficient mice,
      which lack mature T- and B-lymphocytes. In these immunoincompetent double
      mutants, the number of endoneurial macrophages was reduced. Furthermore, features
      indicative of myelin degeneration and axonopathic changes were mitigated in the
      RAG-1-deficient double mutants, whereas enlarged periaxonal Schwann cell collars,
      a hallmark specific for cx32-mutants, were not reduced. Since both cx32- and P0
      deficiency lead to similar immunopathogenic processes, we conclude that immune
      mediated demyelination may be a feature common to many CMT-like neuropathies
      independent of the genetic origin.

PMID- 12615642
TI  - Severity of gliosis in Pick's disease and frontotemporal lobar degeneration: tau
      positive glia differentiate these disorders.
AB  - Frontotemporal dementia is a term used to characterize diverse neuropathological
      conditions that can present with the same clinical phenotype. Five different
      neuropathologies underlie this disorder. However, consistent frontal and/or
      temporal neuronal loss and gliosis characterize all cases, the majority having no
      obvious pathological inclusions. Because neuronal loss and gliosis are consistent
      features across all cases, the present study aimed to determine the relationship
      between neuronal loss, gliosis and, for cases with abnormal tau inclusions,
      intracellular tau deposition. Formalin-fixed brain specimens from sporadic cases
      with frontotemporal dementia (eight with tau-positive Pick bodies, five with
      frontotemporal lobar degeneration without inclusions) were compared with those
      from non-diseased controls (n = 5). Brain specimens were cut into 3 mm coronal
      slices for evaluation and tissue samples from the superior frontal gyrus were
      taken for microscopic analysis. Immuno histochemistry for glia-specific proteins
      (astrocytic glial fibrillary acidic protein and microglial major
      histocompatibility complex II) and different tau epitopes was performed on 50
      microm free-floating sections. Gross patterns of brain atrophy were analysed and
      upper and lower layer pyramidal neurons and glial cell numbers were quantified. A
      disease severity scheme was devised using the degree of gross macroscopic frontal
      and temporal atrophy to establish the relationship between the gliosis and
      neurodegeneration. In this small sample, the patterns of gross atrophy could be
      grouped reliably into four stages of severity. These stages were the same across
      disease groups and correlated with volume- corrected pyramidal neuron densities.
      In cases with Pick bodies, disease stage also correlated with duration, providing
      further evidence that these stages represent the progression of degeneration in
      this limited sample. Whereas there were, on average, many more reactive
      astrocytes in the cases with Pick bodies than in those with frontotemporal lobar
      atrophy, there was significant overlap between cases in the degree of
      astrocytosis. However, a large proportion of the astrocytes in Pick's disease
      displayed phosphorylated tau immunoreactivity, whereas no tau-positive astrocytes
      were found in frontotemporal lobar degeneration. The pattern and degree of
      microglia activation were similar in all the dementia cases analysed, with
      considerably more activated microglia accumulating in white matter. In this small
      sample, the abundance of white matter microglia at early disease stages suggests
      a prominent role for this cell type in the neurodegenerative process. In
      frontotemporal lobar degeneration, a significant proportion of the activated
      white matter microglia were tau-2-immunoreactive, suggesting direct involvement
      in axonal degeneration, possibly via immune processes.

PMID- 12615643
TI  - Theories of developmental dyslexia: insights from a multiple case study of
      dyslexic adults.
AB  - A multiple case study was conducted in order to assess three leading theories of
      developmental dyslexia: (i) the phonological theory, (ii) the magnocellular
      (auditory and visual) theory and (iii) the cerebellar theory. Sixteen dyslexic
      and 16 control university students were administered a full battery of
      psychometric, phonological, auditory, visual and cerebellar tests. Individual
      data reveal that all 16 dyslexics suffer from a phonological deficit, 10 from an
      auditory deficit, four from a motor deficit and two from a visual magnocellular
      deficit. Results suggest that a phonological deficit can appear in the absence of
      any other sensory or motor disorder, and is sufficient to cause a literacy
      impairment, as demonstrated by five of the dyslexics. Auditory disorders, when
      present, aggravate the phonological deficit, hence the literacy impairment.
      However, auditory deficits cannot be characterized simply as rapid auditory
      processing problems, as would be predicted by the magnocellular theory. Nor are
      they restricted to speech. Contrary to the cerebellar theory, we find little
      support for the notion that motor impairments, when found, have a cerebellar
      origin or reflect an automaticity deficit. Overall, the present data support the
      phonological theory of dyslexia, while acknowledging the presence of additional
      sensory and motor disorders in certain individuals.

PMID- 12615644
TI  - Motor learning elicited by voluntary drive.
AB  - Motor training consisting of voluntary movements leads to performance
      improvements and results in characteristic reorganizational changes in the motor
      cortex. It has been proposed that repetition of passively elicited movements
      could also lead to improvements in motor performance. In this study, we compared
      behavioural gains, changes in functional MRI (fMRI) activation in the
      contralateral primary motor cortex (cM1) and in motor cortex excitability
      measured with transcranial magnetic stimulation (TMS) after a 30 min training
      period of either voluntarily (active) or passively (passive) induced wrist
      movements, when alertness and kinematic aspects of training were controlled.
      During active training, subjects were instructed to perform voluntary wrist
      flexion-extension movements of a specified duration (target window 174-186 ms) in
      an articulated splint. Passive training consisted of wrist flexion- extension
      movements elicited by a torque motor, of the same amplitude and duration range as
      in the active task. fMRI activation and TMS parameters of motor cortex
      excitability were measured before and after each training type. Motor
      performance, measured as the number of movements that hit the target window
      duration, was significantly better after active than after passive training. Both
      active and passive movements performed during fMRI measurements activated cM1.
      Active training led to more prominent increases in (i) fMRI activation of cM1;
      (ii) recruitment curves (TMS); and (iii) intracortical facilitation (TMS) than
      passive training. Therefore, a short period of active motor training is more
      effective than passive motor training in eliciting performance improvements and
      cortical reorganization. This result is consistent with the concept of a pivotal
      role for voluntary drive in motor learning and neurorehabilitation.

PMID- 12615646
TI  - Hyperfamiliarity for unknown faces after left lateral temporo-occipital venous
      infarction: a double dissociation with prosopagnosia.
AB  - Right hemisphere dominance in face processing is well established and unilateral
      right inferior temporo-occipital damage can result in prosopagnosia. Here, we
      describe a 21-year-old right-handed woman with acute impairment in face
      recognition that selectively concerned unfamiliar faces, following a focal left
      lateral temporo-occipital venous infarct. She was severely impaired in discerning
      that unknown people seen in everyday life were unfamiliar, although she had no
      difficulty recognizing familiar people. Thus, she had no prosopagnosia, but
      abnormal 'hyperfamiliarity' for unknown faces. Her difficulty was not accompanied
      by delusions or deficits in discrimination, identification or memory for faces.
      Standard neuropsychological testing showed that her recognition of familiar faces
      was entirely normal. By contrast, her sense of personally knowing faces was
      severely impaired when unknown faces evoked weak signals of familiarity based on
      spurious cues, to the extent that she would misattribute fame to faces that were
      unknown but to which she had been incidentally exposed on a prior occasion.
      Priming experiments also revealed that, unlike normal subjects, she made
      familiarity judgements without accessing semantic identity representations.
      Moreover, in face recognition tests, she generally showed bias in that she relied
      more on right-hemisphere strategies to identify global traits and less on left
      hemisphere processes compared with healthy subjects. This case provides novel
      evidence for a differential contribution of the two hemispheres to face
      recognition. Hyperfamiliarity for unknown faces might arise from an imbalance
      between reciprocal hemispheric functions in face recognition, with relative
      hypoactivation of left hemisphere processes but hyperactivation of right
      hemisphere processes for retrieving stored associations about people, linking
      seen faces to representations of affective and personal relevance. Hence,
      abnormal bias in attributing some personal meaning to unknown faces could be
      evoked by spurious signals of familiarity based on irrelevant affective
      associations in the right hemisphere.

PMID- 12615647
TI  - Pure agnosia for mirror stimuli after right inferior parietal lesion.
AB  - This study reports the experimental investigation of G.R., a patient suffering
      from a highly specific disorder in discriminating mirror stimuli following a
      right temporoparietal cerebrovascular accident. G.R. showed intact perceptual,
      attentional, mnestic, linguistic and executive abilities. Object recognition was
      accurate even under unusual viewing conditions. He was highly accurate in
      defining the canonical orientation of common objects and in discriminating
      misoriented objects among identical distracters. However, he was severely
      impaired in tasks requiring mirror-stimulus discrimination, a deficit that
      persisted even when the object's coordinates were systematically misaligned with
      respect to his body. The disorder was also dependent upon the frame of reference
      (allocentric versus egocentric) activated on the basis of task demands. These
      results demonstrate the existence of a highly specific disorder in discriminating
      mirror stimuli defined in object-based coordinates, suggesting a failure in
      processing the directionality of an object's intrinsic x-axis.

PMID- 12615645
TI  - Age-related changes in the neural correlates of motor performance.
AB  - Age-related neurodegenerative and neurochemical changes are thought to underlie
      decline in motor and cognitive functions, but compensatory processes in cortical
      and subcortical function may allow maintenance of performance level in some
      people. Our objective was to investigate age-related changes in the motor system
      of the human brain using functional MRI. Twenty six right handed volunteers were
      scanned whilst performing an isometric, dynamic, visually paced hand grip task,
      using dominant (right) and non-dominant (left) hands in separate sessions. Hand
      grip with visual feedback activated a network of cortical and subcortical regions
      known to be involved in the generation of simple motor acts. In addition,
      activation was seen in a putative human 'grasping circuit', involving rostral
      ventral premotor cortex (Brodmann area 44) and intraparietal sulcus. Within this
      network, a number of regions were more likely to be activated the older the
      subject. In particular, age-related changes in task- specific activations were
      demonstrated in left deep anterior central sulcus when using the dominant or non
      dominant hand. Additional age-related increases were seen in caudal dorsal
      premotor cortex, caudal cingulate sulcus, intraparietal sulcus, insula, frontal
      operculum and cerebellar vermis. We have demonstrated a clear age-related effect
      in the neural correlates of motor performance, and furthermore suggest that these
      changes are non-linear. These results support the notion that an adaptable and
      plastic motor network is able to respond to age-related degenerative changes in
      order to maintain performance levels.

PMID- 12615648
TI  - A novel nonsense mutation in the ABC1 gene causes a severe syringomyelia-like
      phenotype of Tangier disease.
AB  - Tangier disease is a rare autosomal recessive disorder caused by mutations in the
      recently identified ATP-binding cassette transporter 1 gene (ABC1). A typical
      clinical manifestation of Tangier disease is peripheral neuropathy. Former
      studies differentiated between two manifestations: the more frequent mono- or
      polyneuropathic form and a syringomyelia-like type. It is unknown whether
      specific mutations in the ABC1 gene or a particular genetic background are
      responsible for either of these forms. A family is presented comprising a case
      with a severe syringomyelia-like phenotype of Tangier disease and absence of
      cardiovascular disease. Sequencing analysis of the ABC1 gene was performed. A new
      homozygous C-->T transition in exon 18 was found in the index patient. This
      mutation results in a stop codon at position 909 (R909X) leading to premature
      termination of translation. Her clinically asymptomatic daughters, her sister and
      one of her nieces were heterozygous. Sural nerve biopsies were studied in the
      index patient at the age of 45 and 54 years; both revealed a severe neuropathy,
      characterized by a subtotal and finally complete loss of nerve fibres. The entire
      loss of Schwann cells resulted in an extraordinary form of endoneurial sclerosis.
      Only rare capillaries, lipid-laden macrophages and fibroblasts had survived in
      the endoneurium. This case appears to be unique in respect to the underlying
      novel mutation in the ABC1 gene and its association with complete endoneurial
      sclerosis of all fascicles in the sural nerve and absence of cardiovascular
      disease.

PMID- 12615649
TI  - Neural resources for processing language and environmental sounds: evidence from
      aphasia.
AB  - Although aphasia is often characterized as a selective impairment in language
      function, left hemisphere lesions may cause impairments in semantic processing of
      auditory information, not only in verbal but also in nonverbal domains. We
      assessed the 'online' relationship between verbal and nonverbal auditory
      processing by examining the ability of 30 left hemisphere-damaged aphasic
      patients to match environmental sounds and linguistic phrases to corresponding
      pictures. The verbal and nonverbal task components were matched carefully through
      a norming study; 21 age-matched controls and five right hemisphere-damaged
      patients were also tested to provide further reference points. We found that,
      while the aphasic groups were impaired relative to normal controls, they were
      impaired to the same extent in both domains, with accuracy and reaction time for
      verbal and nonverbal trials revealing unusually high correlations (r = 0.74 for
      accuracy, r = 0.95 for reaction time). Severely aphasic patients tended to
      perform worse in both domains, but lesion size did not correlate with
      performance. Lesion overlay analysis indicated that damage to posterior regions
      in the left middle and superior temporal gyri and to the inferior parietal lobe
      was a predictor of deficits in processing for both speech and environmental
      sounds. The lesion mapping and further statistical assessments reliably revealed
      a posterior superior temporal region (Wernicke's area, traditionally considered a
      language-specific region) as being differentially more important for processing
      nonverbal sounds compared with verbal sounds. These results suggest that, in most
      cases, processing of meaningful verbal and nonverbal auditory information break
      down together in stroke and that subsequent recovery of function applies to both
      domains. This suggests that language shares neural resources with those used for
      processing information in other domains.

PMID- 12615650
TI  - Homozygosity for CAG mutation in Huntington disease is associated with a more
      severe clinical course.
AB  - Huntington disease is caused by a dominantly transmitted CAG repeat expansion
      mutation that is believed to confer a toxic gain of function on the mutant
      protein. Huntington disease patients with two mutant alleles are very rare. In
      other poly(CAG) diseases such as the dominant ataxias, inheritance of two mutant
      alleles causes a phenotype more severe than in heterozygotes. In this multicentre
      study, we sought differences in the disease features between eight homozygotes
      and 75 heterozygotes for the Huntington disease mutation. We identified subjects
      homozygous for the Huntington disease mutation by DNA testing and compared their
      clinical features (age at onset, symptom presentation, disease severity and
      disease progression) with those of a group of heterozygotes, who were assessed
      longitudinally. The age at onset of symptoms in the homozygote cases was within
      the range expected for heterozygotes with the same CAG repeat lengths, whereas
      homozygotes had a more severe clinical course. The observation of a more rapid
      decline in motor, cognitive and behavioural symptoms in homozygotes was
      consistent with the extent of neurodegeneration as available at imaging in three
      patients, and at the post-mortem neuropathological report in one case. Our
      analysis suggests that although homozygosity for the Huntington disease mutation
      does not lower the age at onset of symptoms, it affects the phenotype and the
      rate of disease progression. These data, once confirmed in a larger series of
      patients, point to the possibility that the mechanisms underlying age at onset
      and disease progression in Huntington disease may differ.

PMID- 12615651
TI  - Vibration-induced ocular torsion and nystagmus after unilateral vestibular
      deafferentation.
AB  - Vibration is an excitatory stimulus for both vestibular and proprioceptive
      afferents. Vibration applied either to the skull or to the neck muscles of
      subjects after unilateral vestibular deafferentation induces nystagmus and a
      shift of the subjective visual horizontal. Previous studies have ascribed these
      effects to vibratory stimulation of neck muscle proprioceptors. Using scleral
      search coils, we recorded three-dimensional eye movements during unilateral 92 Hz
      vibration of the mastoid bone or of the sternocleidomastoid (SCM) muscle in 18
      subjects with chronic unilateral vestibular deficits after vestibular neurectomy
      or neuro-labyrinthitis. Nine subjects had lost function of all three semicircular
      canals (SSCs) on one side, and the other nine had lost function of only the
      anterior and lateral SSCs. Vibration of the mastoid bone or of the SCM muscle on
      either side induced an ipsilesional tonic shift of torsional eye position of up
      to 6.5 degrees during visual fixation, as well as a nystagmus with horizontal,
      vertical and torsional components in darkness. Subjects who had lost function of
      all three SSCs on one side showed a larger shift in ocular torsion in response to
      SCM vibration than did subjects who had lost function of only two SSCs. The
      difference between ocular torsion produced by ipsilesional muscle or bone
      vibration was not significantly different from that produced by contralesional
      bone or muscle vibration. The vibration-induced nystagmus rotation axis tended to
      align with the pitch (y) axis of the head in subjects who had lost only anterior
      and lateral SSC function, and with the roll (x) axis of the head in subjects who
      had lost function of all three SSCs. We propose that the previously described
      vibration-induced shift of the subjective visual horizontal can be explained by
      the vibration-induced ocular torsion, and that the magnitude of ocular torsion is
      related to the extent of the unilateral vestibular deficit. While altered
      proprioceptive inputs from neck muscles might be important in the mechanism of
      vibration-induced ocular torsion and nystagmus after unilateral vestibular
      deafferentation, vibratory stimulation of vestibular receptors in the intact
      labyrinth also appears to have an important role.

PMID- 12615652
TI  - Muscle cramp in Machado-Joseph disease: altered motor axonal excitability
      properties and mexiletine treatment.
AB  - Machado-Joseph disease is one of the most common hereditary spinocerebellar
      degenerative disorders with a wide range of clinical manifestations. Pathology
      studies have shown mild to moderate loss of anterior horn cells and, in terms of
      spinal pathology, Machado-Joseph disease is regarded as a type of lower
      motoneuron disease. Muscle cramps are often associated with lower motoneuron
      disorders, but features of cramps in Machado-Joseph disease patients have never
      been studied. We investigated the incidence and nature of muscle cramps in
      Machado-Joseph disease patients, the excitability properties of motor axons
      [strength-duration time constant (tau(SD)), threshold electrotonus,
      refractoriness and supernormality] using threshold tracking and the effects of
      mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%)
      had frequent, severe muscle cramps in the legs, trunk or arms that disturbed
      their daily activities. The frequency of pathological muscle cramps was similar
      to that for patients with amyotrophic lateral sclerosis (68%) and higher than
      those for patients with spinal muscular atrophy (33%) or peripheral axonal
      neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part
      reflects Na(+) conductance at the resting membrane potential, was significantly
      greater in the Machado-Joseph disease patients than in normal subjects; severe
      muscle cramps were associated with a longer tau(SD). Threshold electrotonus,
      refractoriness and supernormality were not significantly different between
      Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease
      patients with severe cramps, who received mexiletine treatment, experienced
      nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle
      cramps are a very frequent and disabling factor in Machado-Joseph disease.
      Pathological muscle cramps responded well to mexiletine treatment, and this is
      consistent with the hypothesis that they are caused by an increase in persistent
      Na(+) conductance, possibly associated with axonal regeneration or collateral
      sprouting.

PMID- 12615653
TI  - Central nervous system inflammation is a hallmark of pathogenesis in mouse models
      of GM1 and GM2 gangliosidosis.
AB  - Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS),
      Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is
      a common neuro-inflammatory component to these disorders. During the disease
      course, we have: (i) examined the expression of a number of inflammatory markers
      in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine,
      CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF
      alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1
      beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of
      apoptosis and the expression of Fas and TNF-R1 were also assessed. In all
      symptomatic mouse models, a progressive increase in local microglial
      activation/expansion and infiltration of inflammatory cells was noted. Altered
      BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice.
      Progressive CNS inflammation coincided with the onset of clinical signs in these
      mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the
      rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of
      the inflammatory process and disease pathogenesis. These data suggest that
      inflammation may play an important role in the pathogenesis of the
      gangliosidoses.

PMID- 12615654
TI  - Changes in propriospinally mediated excitation of upper limb motoneurons in
      stroke patients.
AB  - It has been argued that, in humans, a part of the descending command to upper
      limb motoneurons is transmitted through cervical propriospinal pre-motoneurons.
      We explored whether excitation of these putative propriospinal neurons projecting
      onto extensor carpi radialis (ECR) motoneurons was modified in patients
      recovering from stroke. Suppression of the voluntary on-going ECR EMG activity by
      stimulation of cutaneous afferents in the superficial radial nerve was used to
      estimate the component of the descending command passing through the
      propriospinal relay. The degree of suppression was assessed on both sides of 30
      stroke patients (divided into two groups, whether recovery of wrist extension was
      poor or good by the time of the investigation) and of 34 age-matched controls.
      Single cutaneous volleys elicited a suppression which was symmetrical and of the
      same degree in patients and controls. In contrast, the amount of on-going EMG
      suppression produced by a train, which was symmetrical in normal subjects, was
      asymmetrical in most stroke patients: it indeed was significantly greater on the
      affected side of stroke patients with poor recovery of wrist extension than (i)
      in their non-affected side; (ii) in controls; and (iii) in the affected side of
      patients with good recovery. Cutaneous suppression of the H reflex, the motor
      evoked potential (MEP) and the on-going EMG was compared in three patients with
      poor recovery by the time of the first test; there was a small suppression of the
      H reflex on the affected side, but the asymmetry was much less than that of the
      on-going EMG and the MEP. In patients explored twice during the course of
      recovery, the asymmetry in the suppression of the on-going EMG tended to
      disappear, while recovery of wrist extension improved. This suggests that, when
      patients have not yet recovered, a relatively greater component of the descending
      command is mediated through the propriospinal relay. The findings are consistent
      with transiently increased efficacy of descending (possibly reticulospinal)
      projections onto propriospinal neurons, due to hyperexcitability of these neurons
      or unmasking and/or reorganization of the projections to them.

PMID- 12615655
TI  - Activity-dependent hyperpolarization and impulse conduction in motor axons in
      patients with carpal tunnel syndrome.
AB  - The differing contributions of axonal attenuation, ischaemia, demyelination and
      remyelination to the pathophysiology of carpal tunnel syndrome remain unresolved.
      Previous studies indicate that the hyperpolarization of motor axons produced by
      voluntary contractions may precipitate conduction block in chronic acquired
      demyelinating polyneuropathies. The present study investigated whether this
      axonal hyperpolarization can produce or accentuate conduction block in carpal
      tunnel syndrome, thereby implicating demyelination as a significant factor in its
      pathogenesis. Studies were performed in 12 patients with mild to moderate carpal
      tunnel syndrome and compared with 12 healthy control subjects. Using the
      technique of threshold tracking, the compound muscle action potential (CMAP) of
      abductor pollicis brevis (APB) was recorded in response to supramaximal stimuli
      to the median nerve at the wrist, alternating with measurements of axonal
      excitability. After a voluntary contraction of APB for 60 s, there was a lesser
      hyperpolarizing threshold increase in the patients (approximately 18%), than in
      controls (approximately 37%). The changes in strength-duration time constant and
      supernormality were appropriately smaller in the patients. The amplitude and area
      of the maximal CMAP was not significantly altered in either group. Activity
      dependent conduction block was not precipitated in the carpal tunnel syndrome
      patients even though this degree of axonal hyperpolarization was sufficient to
      produce conduction block in chronic inflammatory demyelinating polyneuropathy.
      These studies support the view that demyelination may not be a critical factor in
      the slowing of impulse conduction in mild to moderate carpal tunnel syndrome.

PMID- 12615656
TI  - Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase
      3 activity is decreased under oxidative stress.
AB  - OBJECTIVE: To determine whether paraoxonases (PONs) are expressed in macrophages
      and to analyze the oxidative stress effect on their expression and activities.
      METHODS AND RESULTS: We demonstrated the presence (mRNA, protein, activity) of
      PON2 and PON3 but not PON1 in murine macrophages, whereas in human macrophages,
      only PON2 was expressed. Under oxidative stress as present in mouse peritoneal
      macrophages (MPMs) from apoE-deficient (E0) mice as well as in C57BL6 mice, MPMs
      that were incubated with buthionine sulfoximine, with angiotensin II, with 7
      ketocholesterol, or with oxidized phosphatidylcholine, PON2 mRNA levels and
      lactonase activity toward dihydrocoumarin significantly increased (by 50% to
      130%). In contrast, PON3 lactonase activity toward lovastatin was markedly
      reduced (by 29% to 57%) compared with control cells. The supplementation of E0
      mice with dietary antioxidants (vitamin E, pomegranate juice) significantly
      increased macrophage PON3 activity (by 23% to 40%), suggesting that oxidative
      stress was the cause for the reduced macrophage PON3 activity. Incubation of
      purified PON2 or PON3 with E0 mice MPMs resulted in reduced cellular lipid
      peroxides content by 14% to 19% and inhibition of cell-mediated LDL oxidation by
      32% to 39%. CONCLUSIONS: Increased macrophage PON2 expression under oxidative
      stress could represent a selective cellular response to reduce oxidative burden,
      which may lead to attenuation of macrophage foam cell formation.

PMID- 12615657
TI  - GATA-6 is involved in PPARgamma-mediated activation of differentiated phenotype
      in human vascular smooth muscle cells.
AB  - OBJECTIVE: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a
      member of the nuclear receptor superfamily involved in the growth and
      differentiation of many cell types. Although the activation of PPARgamma in human
      vascular smooth muscle cells (VSMCs) inhibits the growth of these cells, the
      precise mechanism of this effect is unknown. PPARgamma-mediated growth inhibition
      of VSMCs is associated with the induction of the differentiated phenotype. A zinc
      finger transcription factor, GATA-6, has been implicated in the maintenance of
      the differentiated phenotype in VSMCs. METHODS AND RESULTS: The administration of
      15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a naturally occurring PPARgamma
      ligand, and troglitazone, a thiazolidinedione derivative, induced the expression
      of smooth muscle myosin heavy chain and smooth muscle alpha-actin, highly
      specific markers for differentiated VSMCs. Stimulation of proliferative VSMCs
      with PPARgamma ligands also increased the activity of the transfected wild-type
      smooth muscle myosin heavy chain promoter but not that of the mutant promoter, in
      which a GATA-6 binding site was mutated. Compatible with the role of GATA-6, both
      15d-PGJ2 and troglitazone upregulated the DNA binding activity of GATA-6 in
      proliferative VSMCs. CONCLUSIONS: The activation of PPARgamma-dependent pathways
      induces the differentiated phenotype in proliferative VSMCs, and this induction
      is mediated, in part, through a GATA-6-dependent transcriptional mechanism.

PMID- 12615658
TI  - Osteo/chondrocytic transcription factors and their target genes exhibit distinct
      patterns of expression in human arterial calcification.
AB  - OBJECTIVE: Mineralization-regulating proteins are found deposited at sites of
      vascular calcification. However, the relationship between the onset of
      calcification in vivo and the expression of genes encoding mineralization
      regulating proteins is unknown. This study aimed to determine the temporal and
      spatial pattern of expression of key bone and cartilage proteins as
      atherosclerotic calcification progresses. METHODS AND RESULTS: Using reverse
      transcription-polymerase chain reaction on a panel of noncalcified and calcified
      human arterial samples, two classes of proteins could be identified: (1) Matrix
      Gla protein, osteonectin, osteoprotegerin, and aggrecan were constitutively
      expressed by vascular smooth muscle cells (VSMCs) in the normal vessel media but
      downregulated in calcified arteries whereas (2) alkaline phosphatase, bone
      sialoprotein, osteocalcin, and collagen II were expressed predominantly in the
      calcified vessel together with Cbfa1, Msx2, and Sox9, transcription factors that
      regulate expression of these genes. In the calcified plaque in situ hybridization
      identified subsets of VSMCs expressing osteoblast and chondrocyte-like gene
      expression profiles whereas osteoclast-like macrophages were present around sites
      of calcification. CONCLUSIONS: These observations suggest a sequence of molecular
      events in vascular calcification beginning with the loss of expression by VSMCs,
      of constitutive inhibitory proteins, and ending with expression by VSMCs and
      macrophages of chondrocytic, osteoblastic, and osteoclastic-associated proteins
      that orchestrate the calcification process.

PMID- 12615659
TI  - Influence of interferon-gamma on the extent and phenotype of diet-induced
      atherosclerosis in the LDLR-deficient mouse.
AB  - OBJECTIVE: The aim of this study was to investigate the influence of interferon
      gamma (IFN-gamma) on atherosclerosis in low density lipoprotein receptor (LDLR)
      null mice. METHODS AND RESULTS: We cross-bred IFN-gamma-deficient mice with LDLR
      null mice and analyzed lipoprotein profiles and atherosclerosis in the compound
      mutant progeny after 8 and 20 weeks on a cholesterol-enriched diet. IFN-gamma
      deficiency did not affect serum cholesterol levels or lipoprotein profiles, but
      it did affect the extent and phenotype of atherosclerosis. Atherosclerotic
      lesions in IFN-gamma-deficient mice were reduced by 75% in the aortic arch and by
      46% in the descending aorta compared with control mice after 8 weeks on the diet.
      After 20 weeks, arch lesions were reduced by 43%, and descending aorta lesions
      were reduced by 65% in IFN-gamma-deficient mice compared with controls. At 8
      weeks, percent lesional macrophage and smooth muscle content was significantly
      less in the IFN-gamma-deficient mice, but not at 20 weeks. Although there were
      fewer class II major histocompatibility complex-positive cells in the lesions of
      IFN-gamma-deficient animals compared with controls, class II major
      histocompatibility complex expression on endothelial cells overlying lesions
      persisted in the absence of IFN-gamma. CONCLUSIONS: These data provide direct
      evidence that IFN-gamma influences atherosclerosis development and phenotype in
      the LDLR-deficient mouse, independent of changes in blood lipoprotein profiles.

PMID- 12615661
TI  - Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.
AB  - Investigation of arterial stiffness, especially of the large arteries, has
      gathered pace in recent years with the development of readily available
      noninvasive assessment techniques. These include the measurement of pulse wave
      velocity, the use of ultrasound to relate the change in diameter or area of an
      artery to distending pressure, and analysis of arterial waveforms obtained by
      applanation tonometry. Here, we describe each of these techniques and their
      limitations and discuss how the measured parameters relate to established
      cardiovascular risk factors and clinical outcome. We also consider which
      techniques might be most appropriate for wider clinical application. Finally, the
      effects of current and future cardiovascular drugs on arterial stiffness are also
      discussed, as is the relationship between arterial elasticity and endothelial
      function.

PMID- 12615660
TI  - Rupture of the atherosclerotic plaque: does a good animal model exist?
AB  - By its very nature, rupture of the atherosclerotic plaque is difficult to study
      directly in humans. A good animal model would help us not only to understand how
      rupture occurs but also to design and test treatments to prevent it from
      happening. However, several difficulties surround existing models of plaque
      rupture, including the need for radical interventions to produce the rupture,
      lack of direct evidence of rupture per se, and absence of convincing evidence of
      platelet- and fibrin-rich thrombus at the rupture site. At the present time,
      attention should therefore focus on the processes of plaque breakdown and
      thrombus formation in humans, whereas the use of animal models should probably be
      reserved for studying the function of particular genes and for investigating
      isolated features of plaques, such as the relationship between cap thickness and
      plaque stability.

PMID- 12615662
TI  - Pitavastatin-induced thrombomodulin expression by endothelial cells acts via
      inhibition of small G proteins of the Rho family.
AB  - OBJECTIVE: 3-hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can
      function to protect the vasculature in a manner that is independent of their
      lipid-lowering activity. The main feature of the antithrombotic properties of
      endothelial cells is an increase in the expression of thrombomodulin (TM) without
      induction of tissue factor (TF) expression. We investigated the effect of statins
      on the expression of TM and TF by endothelial cells. METHODS AND RESULTS: The
      incubation of endothelial cells with pitavastatin led to a concentration- and
      time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the
      expression of TF mRNA was not induced under the same conditions. A nuclear run-on
      study revealed that pitavastatin accelerates TM transcription rate. The
      stimulation of TM expression by pitavastatin was prevented by either mevalonate
      or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase
      I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively,
      enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3
      exoenzyme was ineffective. CONCLUSIONS: Statins regulate TM expression via
      inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated
      increase in TM expression by endothelial cells may contribute to the beneficial
      effects of statins on endothelial function.

PMID- 12615663
TI  - Human serum paraoxonase 1 decreases macrophage cholesterol biosynthesis: possible
      role for its phospholipase-A2-like activity and lysophosphatidylcholine
      formation.
AB  - OBJECTIVE: Human serum paraoxonase 1 (PON1) activity is inversely related to the
      risk of developing an atherosclerotic lesion, which contains cholesterol-loaded
      macrophage foam cells. To assess a possible mechanism for this relationship, we
      analyzed the effect of PON1 on cellular cholesterol biosynthesis. METHODS AND
      RESULTS: Mouse peritoneal macrophages (MPMs) were harvested from PON1-deficient
      mice (PON1o and PON1o/Eo mice on the genetic background of C57BL/6J and Eo mice,
      respectively). PON1o/Eo mice exhibited a significantly 51% increased
      atherosclerotic lesion area and 35% increased macrophage cholesterol content
      compared with control E degrees mice. In parallel, macrophage cholesterol
      biosynthesis rates were increased in PON1-deficient mice MPMs by 50% compared
      with their controls. Incubation of macrophages with human PON1 revealed a dose
      dependent inhibitory effect (up to 84%) on macrophage cholesterol biosynthesis.
      We demonstrated a PON1 phospholipase-A2-like activity on MPMs, evidenced by
      release of polyunsaturated fatty acids and formation of lysophosphatidylcholine.
      On incubation of macrophages with lysophosphatidylcholine, a dose-dependent
      inhibition (up to 40%) of cellular cholesterol biosynthesis was noted. The
      inhibitory effect of PON1 on macrophage cholesterol biosynthesis was shown to be
      downstream to mevalonate, probably at the lanosterol metabolic point.
      CONCLUSIONS: PON1 inhibits macrophage cholesterol biosynthesis and atherogenesis
      probably through its phospholipase-A2-like activity.

PMID- 12615664
TI  - Oncostatin M, an interleukin-6 family cytokine, upregulates matrix
      metalloproteinase-9 through the mitogen-activated protein kinase kinase
      extracellular signal-regulated kinase pathway in cultured smooth muscle cells.
AB  - OBJECTIVE: Matrix metalloproteinase (MMP)-9 is implicated in extracellular matrix
      (ECM) degradation of atherosclerotic lesions. Oncostatin M (OSM) regulates ECM
      metabolism in various kinds of cells. Thus, we sought to investigate whether OSM
      regulates MMP-9 expression in cultured rat aortic smooth muscle cells (SMCs) and,
      if so, to determine the signaling pathway for MMP-9 induction by OSM. METHODS AND
      RESULTS: Competitive reverse transcriptase polymerase chain reaction showed that
      OSM upregulated MMP-9 mRNA expression, peaking at 4 hours and returning to
      unstimulated levels by 24 hours. Gelatin zymography revealed that MMP-9 activity
      was increased in the conditioned medium after the 24-hour OSM treatment.
      Immunoblot analysis demonstrated that OSM transiently induced extracellular
      signal-regulated kinase (ERK)1/2 and STAT3 phosphorylations with a peak at 15 and
      5 minutes, respectively. A MEK1 inhibitor, PD98059, not only blocked ERK1/2
      phosphorylation but also abolished the OSM-induced MMP-9 upregulation, whereas
      the MMP-9 induction was not affected by overexpressing dominant-negative STAT3.
      In addition, OSM slightly upregulated MMP-2 and downregulated tissue inhibitors
      of MMP-1 and -3 through different mechanisms from that in case of MMP-9.
      CONCLUSIONS: OSM upregulates MMP-9 expression in SMCs through the MEK-ERK but not
      STAT3 pathway.

PMID- 12615665
TI  - Notch signaling in vascular development.
AB  - Notch signaling is an extremely conserved and widely used mechanism regulating
      cell fate in metazoans. Interaction of Notch receptors (Notch) with their ligands
      (Delta-like or Jagged) leads to cleavage of the Notch intracellular domain (NICD)
      that migrates into the nucleus. In the nucleus, NICD associates with a
      transcription factor, RBP-Jk. The NICD-RBP-Jk complex, in turn, upregulates
      expression of primary target genes of Notch signaling, such as hairy and enhancer
      of split (HES) and HES-related repressor protein (HERP) transcriptional
      repressors. Recent evidence has demonstrated that the Notch pathway is involved
      in multiple aspects of vascular development, including proliferation, migration,
      smooth muscle differentiation, angiogenic processes, and arterial-venous
      differentiation. In this brief review, we focus on ligands, receptors, and target
      genes of Notch signaling in the vascular system and discuss (1) tissue
      distribution; (2) gain- and loss-of-function studies; and (3) the role of Notch
      components in human diseases involving the vascular system.

PMID- 12615666
TI  - Increased superoxide production in coronary arteries in hyperhomocysteinemia:
      role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide
      synthase.
AB  - OBJECTIVE: In coronary arteries, hyperhomocysteinemia (HHcy, a known risk factor
      for coronary heart disease) impairs flow-induced dilations, which can be reversed
      by superoxide dismutase (SOD). To evidence increased O2*- generation and
      elucidate its source, we characterized changes in activity (lucigenin
      chemiluminescence, hydroethidine staining) and expression of arterial pro- and
      antioxidant systems (Western blotting, immunohistochemistry, cDNA microarray,
      reverse-transcription polymerase chain reaction) in the coronary arteries of rats
      by using methionine diet-induced HHcy. METHODS AND RESULTS: The increased
      generation of O2*- by HHcy coronary arteries was inhibited by SOD,
      diphenyleneiodonium, apocynin, and apocynin plus amino guanidine but was
      unaffected by allopurinol and rotenone. Also, diphenyleneiodonium-sensitive NADPH
      driven O2*- generation was increased in HHcy vessels. In HHcy arteries expression
      of the smooth muscle-confined NAD(P)H oxidase subunit nox1 and that of iNOS was
      increased. Expression of p67phox, p22phox, and p47phox subunits and that of
      endothelial nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, extracellular SOD (mRNA),
      and xanthine oxidase was unchanged. Microarray analysis showed increased
      expression of tumor necrosis factor (TNF)-alpha (confirmed by reverse
      transcription polymerase chain reaction, Western blotting, and
      immunohistochemistry) that was localized in smooth muscle. In vitro incubation
      (18 hours) of HHcy arteries with anti-TNF-alpha antibody decreased O2*-
      production, whereas incubation of control vessels with TNF-alpha increased O2*-
      generation and nox1 expression. CONCLUSIONS: In coronary arteries, HHcy increases
      TNF-alpha expression, which enhances oxidative stress through upregulating a nox1
      based NAD(P)H oxidase and inducible nitric oxide synthase. Thus, TNF-alpha
      induces a proinflammatory vascular phenotype in HHcy that potentially contributes
      to the development of coronary atherosclerosis.

PMID- 12615667
TI  - Amino terminal 38.9% of apolipoprotein B-100 is sufficient to support cholesterol
      rich lipoprotein production and atherosclerosis.
AB  - OBJECTIVE: Carboxyl terminal truncation of apolipoprotein (apo)B-100 and apoB-48
      impairs their capacity for triglyceride transport, but the ability of the
      resultant truncated apoB to transport cholesterol and to support atherosclerosis
      has not been adequately studied. The atherogenicity of apoB-38.9 was determined
      in this study by using our apoB-38.9-only (Apob38.9/38.9) mice. METHODS AND
      RESULTS: ApoB-38.9-lipoproteins (Lp-B38.9) circulate at very low levels in
      Apob38.9/38.9 mice as small LDLs or HDLs. Disruption of apoE gene in these mice
      caused accumulation of large amounts of betaVLDL-like LpB-38.9 in plasma. These
      betaVLDL particles were more enriched with cholesteryl esters but poor in
      triglycerides compared with the apoB-48-betaVLDL of the apoB-wild-type/apoE-null
      (Apob+/+/Apoe-/-) mice. Likewise, apoB-38.9-VLDL secreted by cultured
      Apob38.9/38.9 mouse hepatocytes also had higher ratios of total cholesterol to
      triglycerides than apoB-48-VLDL secreted by the apoB-48-only hepatocytes. Thus,
      despite its impaired triglyceride-transporting capacity, apoB-38.9 has a
      relatively intact capacity for cholesterol transport. Spontaneous aortic
      atherosclerotic lesions were examined in apoB-38.9-only/apoE-null
      (Apob38.9/38.9/Apoe-/-) mice at ages 9 and 13 months. Extensive lesions were
      found in the Apob38.9/38.9/Apoe-/- mice as well as in their Apob+/38.9/Apoe-/-
      and Apob+/+/Apoe-/- littermates. CONCLUSIONS: Deleting the C-terminal 20% from
      apoB-48 does not impair its ability to transport cholesterol and to support
      atherosclerosis, thus narrowing the "atherogenic region" of apoB.

PMID- 12615668
TI  - TWEAK is an endothelial cell growth and chemotactic factor that also potentiates
      FGF-2 and VEGF-A mitogenic activity.
AB  - OBJECTIVE: TWEAK, a member of the tumor necrosis factor superfamily, binds to the
      Fn14 receptor and stimulates angiogenesis in vivo. In this study, we investigated
      Fn14 gene expression in human endothelial cells (ECs) and examined the effect of
      TWEAK, added either alone or in combination with fibroblast growth factor-2 (FGF
      2) or vascular endothelial growth factor-A (VEGF-A), on EC proliferation,
      migration, and survival in vitro. We also determined whether a soluble Fn14-Fc
      fusion protein could inhibit TWEAK biologic activity on ECs and investigated
      TWEAK signal transduction in ECs. METHODS AND RESULTS: We found that both FGF-2
      and VEGF-A could induce Fn14 mRNA expression in ECs. TWEAK was a mitogen for ECs,
      and this proliferative activity could be inhibited by an Fn14-Fc decoy receptor.
      Furthermore, TWEAK treatment activated several intracellular signaling pathways
      in ECs and potentiated FGF-2--and VEGF-A--stimulated EC proliferation. TWEAK also
      had EC chemotactic activity, but it did not promote EC survival. CONCLUSIONS:
      These results indicate that TWEAK is an EC growth and migration factor but not a
      survival factor. TWEAK can also enhance both FGF-2 and VEGF-A mitogenic activity
      on ECs. Thus, TWEAK may act alone as well as in combination with FGF-2 or VEGF-A
      to regulate pathological angiogenesis.

PMID- 12615669
TI  - Olive oil and red wine antioxidant polyphenols inhibit endothelial activation:
      antiatherogenic properties of Mediterranean diet phytochemicals.
AB  - OBJECTIVE: Epidemiology suggests that Mediterranean diets are associated with
      reduced risk of cardiovascular disease. Because monocyte adhesion to the
      endothelium is crucial in early atherogenesis, we evaluated whether typical olive
      oil and red wine polyphenols affect endothelial-leukocyte adhesion molecule
      expression and monocyte adhesion. METHODS AND RESULTS: Phytochemicals in olive
      oil and red wine, including oleuropein, hydroxytyrosol, tyrosol, elenolic acid,
      and resveratrol, with or without antioxidant activity, were incubated with human
      umbilical vein endothelial cells for 30 minutes, followed by co-incubation with
      bacterial lipopolysaccharide or cytokines to trigger adhesion molecule
      expression. At nutritionally relevant concentrations, only oleuropein,
      hydroxytyrosol, and resveratrol, possessing a marked antioxidant activity,
      reduced monocytoid cell adhesion to stimulated endothelium, as well as vascular
      cell adhesion molecule-1 (VCAM-1) mRNA and protein by Northern analysis and cell
      surface enzyme immunoassay. Reporter gene assays with deletional VCAM-1 promoter
      constructs indicated the relevance of nuclear factor-kappaB, activator protein-1,
      and possibly GATA binding sites in mediating VCAM-1 transcriptional inhibition.
      The involvement of nuclear factor-kappaB and activator protein-1 was finally
      demonstrated at electrophoretic mobility shift assays. CONCLUSIONS: Olive oil and
      red wine antioxidant polyphenols at nutritionally relevant concentrations
      transcriptionally inhibit endothelial adhesion molecule expression, thus
      partially explaining atheroprotection from Mediterranean diets.

PMID- 12615670
TI  - Regulation of plasma PAI-1 concentrations in HAART-associated lipodystrophy
      during rosiglitazone therapy.
AB  - OBJECTIVE: Patients with highly active antiretroviral therapy-associated
      lipodystrophy (HAART+LD+) have high plasminogen activator inhibitor-1 (PAI-1)
      concentrations for unknown reasons. We determined whether (1). plasma PAI-1
      antigen concentrations are related to liver fat content (LFAT) independently of
      the size of other fat depots and (2) rosiglitazone decreases PAI-1 and LFAT in
      these patients. METHODS AND RESULTS: In the cross-sectional study, 3 groups were
      investigated: 30 HIV-positive patients with HAART+LD+, 13 HIV-positive patients
      without lipodystrophy (HAART+LD-), and 15 HIV-negative subjects (HIV-). In the
      treatment study, the HAART+LD+ group received either rosiglitazone (8 mg, n=15)
      or placebo (n=15) for 24 weeks. Plasma PAI-1 was increased in HAART+LD+ (28+/-2
      ng/mL) compared with the HAART+LD- (18+/-3, P<0.02) and HIV- (10+/-3, P<0.001)
      groups. LFAT was higher in HAART+LD+ (7.6+/-1.7%) than in the HAART+LD- (2.1+/
      1.1%, P<0.001) and HIV- (3.6+/-1.2%, P<0.05) groups. Within the HAART+LD+ group,
      plasma PAI-1 was correlated with LFAT (r=0.49, P<0.01) but not with subcutaneous
      or intra-abdominal fat or serum insulin or triglycerides. In subcutaneous adipose
      tissue, PAI-1 mRNA was 2- to 3-fold higher in the HAART+LD+ group than in either
      the HAART+LD- or HIV- group. Rosiglitazone decreased LFAT, serum insulin, and
      plasma PAI-1 and increased serum triglycerides but had no effect on intra
      abdominal or subcutaneous fat mass or PAI-1 mRNA. CONCLUSIONS: Plasma PAI-1
      concentrations are increased in direct proportion to LFAT in HAART+LD+ patients.
      Rosiglitazone decreases LFAT, serum insulin, and plasma PAI-1 without changing
      the size of other fat depots or PAI-1 mRNA in subcutaneous fat. These data
      suggest that liver fat contributes to plasma PAI-1 concentrations in these
      patients.

PMID- 12615671
TI  - Changes in perlecan expression during vascular injury: role in the inhibition of
      smooth muscle cell proliferation in the late lesion.
AB  - OBJECTIVE: Vascular smooth muscle cells (SMCs), activated by growth factors after
      arterial injury, migrate and proliferate to expand the intima of the blood
      vessel. During intimal expansion, proliferation is suppressed and an increasingly
      large proportion of the neointimal mass is composed of newly synthesized
      extracellular matrix (ECM). We sough to determine whether the ECM heparan sulfate
      proteoglycan (HSPG) perlecan, which inhibits SMC proliferation in vitro, also
      accumulates and limits SMC proliferation during neointimal expansion. METHODS AND
      RESULTS: Perlecan expression and accumulation were analyzed by
      immunohistochemistry and in situ hybridization during neointima formation after
      balloon catheter injury to the rat carotid artery. Perlecan expression was low in
      uninjured vessels and up to 7 days after injury, during maximal SMC
      proliferation. By 14 days after injury, perlecan was dramatically increased, and
      immunostaining remained heavy throughout the advanced lesion, 35 to 42 days after
      injury. Finally, explants of intimal tissue from 35- to 42-day neointimal lesions
      were digested with glycosaminoglycanases to determine whether endogenous HSPGs
      inhibit intimal SMC proliferation. SMCs within HS-depleted, but not
      chondroitinase ABC-treated or mock-incubated, explants were found to proliferate
      in response to platelet-derived growth factor BB. CONCLUSIONS: HSPGs, such as
      perlecan, may inhibit the proliferative response of SMCs after vascular injury.

PMID- 12615672
TI  - Endothelium-dependent effects of statins.
AB  - The vascular endothelium is a dynamic endocrine organ that regulates contractile,
      secretory, and mitogenic activities in the vessel wall and hemostatic processes
      within the vascular lumen. Risk factors for cardiovascular disease, such as
      cigarette smoking, hypertension, and elevated serum lipid levels, impair
      endothelial function and lead to the development of atherosclerotic vessels.
      Recent studies suggest that statins reduce cardiovascular events in part by
      improving endothelial function. Statins reduce plasma cholesterol levels, thereby
      decreasing the uptake of modified lipoproteins by vascular wall cells. There is
      increasing evidence, however, that statins may also exert effects beyond
      cholesterol lowering. Indeed, many of these cholesterol-independent or
      "pleiotropic" vascular effects of statins appear to involve restoring or
      improving endothelial function through increasing the bioavailability of nitric
      oxide, promoting re-endothelialization, reducing oxidative stress, and inhibiting
      inflammatory responses. Thus, the endothelium-dependent effects of statins are
      thought to contribute to many of the beneficial effects of statin therapy in
      cardiovascular disease.

PMID- 12615673
TI  - Enzymatically modified LDL induces cathepsin H in human monocytes: potential
      relevance in early atherogenesis.
AB  - OBJECTIVE: Modification with proteases and cholesterylesterase transforms LDL to
      a moiety that resembles lipoproteins isolated from atherosclerotic lesions and
      possesses atherogenic properties. To identify changes in monocyte-derived foam
      cells laden with enzymatically modified LDL (E-LDL), we compared patterns of the
      most abundant transcripts in these cells after incubation with LDL or E-LDL.
      METHODS AND RESULTS: Serial analyses of gene expression (SAGE) libraries were
      constructed from human monocytes after treatment with LDL or E-LDL. Several tags
      were differentially expressed in LDL-treated versus E-LDL-treated cells, whereby
      marked selective induction by E-LDL of cathepsin H was conspicuous. We show that
      cathepsin H is expressed in atherosclerotic lesions in colocalization with E-LDL.
      Furthermore, we demonstrate that LDL modified with cathepsin H and
      cholesterylesterase can confer onto LDL the capacity to induce macrophage foam
      cell formation and to induce cathepsin H. CONCLUSIONS: Cathepsin H could
      contribute to the transformation of LDL to an atherogenic moiety; the process
      might involve a self-sustaining amplifying circle.

PMID- 12615674
TI  - Elastogenesis in human arterial disease: a role for macrophages in disordered
      elastin synthesis.
AB  - OBJECTIVE: Elastin, an extracellular matrix protein, constitutes about 30% of the
      dry weight of the arteries. Elastolysis induced by inflammatory processes is
      active in chronic arterial diseases. However, elastogenesis in arterial diseases
      has received little attention. In this work we hypothesized that disordered
      elastogenesis is active in matrix remodeling in atheroma and abdominal aortic
      aneurysm (AAA). METHODS AND RESULTS: Human AAA and atheroma have 4- to 6-fold
      more tropoelastin protein than nondiseased arteries. The smooth muscle cell
      containing media and fibrous cap of atherosclerotic arteries contain ordered
      mature elastin, whereas macrophage (MPhi)-rich regions often have disorganized
      elastic fibers. Surprisingly, in addition to smooth muscle cells, MPhis in
      diseased arteries also produce the elastin precursor tropoelastin, as shown by
      double immunostaining, in situ hybridization, and reverse transcription
      polymerase chain reaction for tropoelastin mRNA. Cultured monocyte-derived MPhis
      can express the elastin gene. AAA have 9-fold but atheroma only 1.6-fold lower
      levels of desmosine, a marker for mature cross-linked elastin, than normal
      arteries. CONCLUSIONS: This study demonstrates ongoing but often ineffective
      elastogenesis in arterial disease and establishes human macrophages as a novel
      source for this important matrix protein. These results have considerable import
      for understanding mechanisms of extracellular matrix remodeling in arterial
      diseases.

PMID- 12615675
TI  - Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE
      deficient mice.
AB  - OBJECTIVE: Atherosclerosis is considered to be a chronic inflammatory disease and
      many cytokines participate in the development of atherosclerosis. We focused on
      the role of interleukin-1beta (IL-1beta), one of the proinflammatory cytokines
      secreted by monocytes/macrophages, in the progression of atherosclerosis. METHODS
      AND RESULTS: We generated mice lacking both apoE and IL-1beta. The sizes of
      atherosclerotic lesions at the aortic sinus in apoE-/-/IL-1beta-/-mice at 12 and
      24 weeks of age showed a significant decrease of approximately 30% compared with
      apoE-/-/IL-1beta+/+ mice, and the percentage of the atherosclerotic area to total
      area of apoE-/-/IL-1beta-/- at 24 weeks of age also showed a significant decrease
      of about 30% compared with apoE-/-/IL-1beta+/+. The mRNA levels of vascular cell
      adhesion molecule (VCAM)-1 and monocyte chemotactic protein-1 in the apoE-/-/IL
      1beta-/- aorta were significantly reduced compared with the apoE-/-/IL-1beta+/+.
      Furthermore, VCAM-1 was also reduced at the protein level in apoE-/-/IL-1beta-/-
      aorta compared with apoE-/-/IL-1beta+/+. CONCLUSIONS: The lack of IL-1beta
      decreases the severity of atherosclerosis in apoE deficient mice, possibly
      through increased expressions of VCAM-1 and monocyte chemotactic protein-1 in the
      aorta.

PMID- 12615676
TI  - Evidence that peroxisome proliferator-activated receptor delta influences
      cholesterol metabolism in men.
AB  - OBJECTIVE: The objective of this work was to explore the role of peroxisome
      proliferator-activated receptor delta (PPARD) in lipid metabolism in humans.
      METHODS AND RESULTS: PPARD is a nuclear receptor involved in lipid metabolism in
      primates and mice. We screened the 5'-region of the human gene for polymorphisms
      to be used as tools in association studies. Four polymorphisms were detected: 
      409C/T in the promoter region, +73C/T in exon 1, +255A/G in exon 3, and +294T/C
      in exon 4. The frequencies of the rare alleles were 4.2%, 4.2%, 1.2% and 15.6%,
      respectively, in a population-based group of 543 healthy men. Only the +294T/C
      polymorphism showed significant association with a metabolic trait. Homozygotes
      for the rare C allele had a higher plasma LDL-cholesterol concentration than
      homozygotes for the common T allele, which was verified in an independent cohort
      consisting of 282 healthy men. Transfection studies showed that the rare C allele
      had higher transcriptional activity than the common T allele. Electrophoretic
      mobility shift assays demonstrated that the +294T/C polymorphism influenced
      binding of Sp-1. An interaction with the PPAR alpha L162V polymorphism was also
      detected for several lipid parameters. CONCLUSIONS: These findings suggest that
      PPARD plays a role in cholesterol metabolism in humans.

PMID- 12615678
TI  - Apolipoprotein A5, a newly identified gene that affects plasma triglyceride
      levels in humans and mice.
AB  - Apolipoprotein A5 (APOA5) is a newly described member of the apolipoprotein gene
      family whose initial discovery arose from comparative sequence analysis of the
      mammalian APOA1/C3/A4 gene cluster. Functional studies in mice indicated that
      alteration in the level of APOA5 significantly affected plasma triglyceride
      concentrations. Mice that overexpressed human APOA5 displayed significantly
      reduced triglycerides, whereas mice that lacked apoa5 had a large increase in
      this lipid parameter. Studies in humans have also suggested an important role for
      APOA5 in determining plasma triglyceride concentrations. In these experiments,
      polymorphisms in the human gene were found to define several common haplotypes
      that were associated with significant changes in triglyceride concentrations in
      multiple populations. Several separate clinical studies have provided consistent
      and strong support for the effect with 24% of whites, 35% of blacks, and 53% of
      Hispanics who carry APOA5 haplotypes associated with increased plasma
      triglyceride levels. In summary, APOA5 represents a newly discovered gene
      involved in triglyceride metabolism in both humans and mice whose mechanism of
      action remains to be deciphered.

PMID- 12615677
TI  - Simvastatin reduces the expression of adhesion molecules in circulating monocytes
      from hypercholesterolemic patients.
AB  - OBJECTIVE: The intercellular adhesion molecule-1 (ICAM-1/CD54) and its ligand,
      CD11a/CD18, mediate endothelial adhesion of leukocytes and their consecutive
      transmigration. Anti-inflammatory effects of statins are considered to be exerted
      in part through inhibition of leukocyte-endothelial interactions. We investigated
      the in vivo effects of simvastatin treatment in hypercholesterolemic patients and
      the influence of various statins on expression of cellular adhesion molecules in
      vitro. METHODS AND RESULTS: A total number of 107 hypercholesterolemic patients
      were treated with 20 mg (n=52) or 40 mg (n=55) of simvastatin daily. After 6
      weeks of treatment, peripheral blood mononuclear cells (PBMCs) expressed lower
      amounts of CD54-, CD18-, and CD11a-mRNA compared with pretreatment values.
      Surface expression of CD54 and CD18/CD11a on CD14+-monocytes also decreased
      significantly in both groups of patients. Moreover, simvastatin, atorvastatin,
      and cerivastatin were found to downregulate tumor necrosis factor (TNF)-alpha
      induced expression of CD54 and CD18/CD11a in isolated PBMCs obtained from normal
      donors as well as TNF-alpha-dependent expression of these CAMs in cultured human
      umbilical vein endothelial cells (HUVECs). Furthermore, all three statins were
      found to reduce the binding of PBMCs to TNF-alpha-stimulated HUVECs in vitro.
      CONCLUSIONS: Statin-induced inhibition of expression of CD54 and CD18/CD11a in
      PBMCs and HUVECs with consecutive loss of adhesive function may contribute to the
      anti-inflammatory effects of these drugs and some of their beneficial clinical
      activities.

PMID- 12615679
TI  - ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL
      formation and inflammation.
AB  - Studies with ATP-binding cassette transporter (ABCA1)-deficient mice have been
      critical in demonstrating the relation between ABCA1 expression, cellular lipid
      efflux, and HDL metabolism. The phenotype of the ABCA1-deficient mouse parallels
      the phenotype observed in human Tangier disease, including substantial reductions
      in both apolipoprotein B and apolipoprotein AI with confounding affects on
      atherosclerosis.

PMID- 12615680
TI  - HDL apolipoproteins and ABCA1: partners in the removal of excess cellular
      cholesterol.
AB  - It is widely believed that HDL protects against atherosclerosis by removing
      excess cholesterol from arterial cells. Lipid-poor HDL apolipoproteins promote
      efflux of cholesterol, phospholipids, and other lipophilic molecules from cells
      by an active process mediated by a cell-membrane transporter called the ATP
      binding cassette transporter A-1 (ABCA1). ABCA1 either directly or indirectly
      translocates phospholipids and cholesterol to the cell surface, where they appear
      to form lipid domains that interact with amphipathic alpha-helixes in
      apolipoproteins. This interaction solubilizes these lipids and generates nascent
      HDL particles that dissociate from the cell. Binding of apolipoproteins to ABCA1
      may also enhance the activity of this lipid-transport pathway. Thus, the
      apolipoprotein/ABCA1 pathway efficiently clears cells of excess cholesterol that
      would otherwise accumulate as intracellular lipid droplets. ABCA1 expression is
      highly induced by cholesterol loading of cells and is also modulated by sterol
      independent mechanisms at both the transcriptional and posttranslational level.
      Studies of human disease and animal models have shown that both an increased
      availability of apolipoproteins and an enhanced macrophage ABCA1 activity are
      atheroprotective. These findings implicate the apolipoprotein/ABCA1 pathway as an
      important therapeutic target for treating cardiovascular disease.

PMID- 12615681
TI  - Study of ABCA1 function in transgenic mice.
AB  - The ATP-binding cassette transporter A1 (ABCA1), identified in 1999 as the gene
      defective in Tangier disease, promotes efflux of cellular cholesterol from
      macrophages and other peripheral tissues to apolipoprotein acceptors. These ABCA1
      mediated processes are anticipated to have antiatherogenic properties, prompting
      the development of pharmacological agents that increase ABCA1 gene expression as
      well as the establishment of ABCA1-transgenic mouse lines. Preliminary studies of
      ABCA1-Tg mice seem to validate the selection of this transporter as a therapeutic
      target for the treatment of low HDL syndromes and cardiovascular disease but have
      also raised new questions regarding the function of ABCA1. In particular, the
      relative contribution of hepatic and peripheral ABCA1 to plasma HDL levels and to
      reverse cholesterol transport, as well as the potential role of ABCA1 in
      modulating the plasma concentrations of the apolipoprotein B-containing
      lipoproteins and protecting against atherosclerosis, seem to be promising areas
      of investigation. The present review summarizes the most recent studies and
      discusses insights provided by these transgenic mouse models.

PMID- 12615682
TI  - A quantitative trait locus influencing free plasma protein S levels on human
      chromosome 1q: results from the Genetic Analysis of Idiopathic Thrombophilia
      (GAIT) project.
AB  - OBJECTIVE: Protein S (PS) is a component of the protein C anticoagulant system.
      PS deficiency is associated with myocardial infarction and venous
      thromboembolism, two highly prevalent causes of death in industrialized nations.
      As part of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, we
      conducted a genome-wide linkage screen to localize genes influencing variation in
      free PS (fPS) plasma levels. METHODS AND RESULTS: fPS levels were measured in 397
      individuals in 21 Spanish families. A total of 363 highly informative
      microsatellite markers were genotyped to provide a 10-cM genetic map, and
      variance component linkage methods were used. A region on chromosome 1q32,
      flanked by markers D1S425 and D1S213, showed strong evidence of linkage with fPS
      levels (LOD score, 4.07; nominal P=7.5x10(-6); genome-wide P=0.0024). This region
      contains two positional candidate genes, the complement component 4-binding
      protein alpha and beta chains, which encode the principal binding protein for PS.
      Suggestive evidence for linkage was also observed on chromosomes 11p and 19p.
      CONCLUSIONS: These results represent one of the first genomic screens for
      quantitative variation in a component of the hemostatic pathway and provide
      strong evidence for a locus on chromosome 1q influencing fPS levels.

PMID- 12615683
TI  - A synthetic peptide that inhibits lipoprotein(a) assembly.
AB  - OBJECTIVE: We previously reported that human apolipoprotein B100 (apoB) amino
      acids 4330-4397 were important for the initial noncovalent binding to
      apolipoprotein(a) [apo(a)] that facilitates lipoprotein(a) [Lp(a)] assembly. In
      this study, we aimed to further define the apoB sequences within the 4330-4397
      region that were important for the noncovalent binding to apo(a). METHODS AND
      RESULTS: Alignment of the human apoB4330-4397 sequence with mouse apoB, which
      also noncovalently binds apo(a), revealed stretches of similar sequence,
      including a lysine-rich sequence spanning apoB amino acids 4372-4392. Structural
      analysis of the apoB4372-4392 sequence using the WHEEL program predicted an
      amphipathic alpha-helix. Circular dichroism studies of a synthetic peptide
      spanning human apoB amino acids 4372-4392, both in the absence and presence of
      dimyristoylphosphatidylcholine, confirmed the alpha-helical nature of the
      sequence. We tested the ability of the apoB4372-4392 peptide to bind to apo(a)
      and found that the peptide bound to apo(a) with high affinity but not to Lp(a).
      The apoB4372-4392 peptide inhibited Lp(a) assembly in Lp(a) formation assays far
      more effectively than the lysine analogue, epsilon-amino-n-caproic acid (IC50=40
      micromol/L versus 10 mmol/L, respectively). Incorporation of the apoB4372-4392
      peptide onto dimyristoylphosphatidylcholine vesicles yielded an even more
      effective inhibitor (IC50=4 micromol/L). CONCLUSIONS: Our study shows that the
      apoB4372-4392 sequence mediates the initial noncovalent binding to apo(a) and has
      demonstrated that the apoB4372-4392 peptide is a novel and effective inhibitor of
      Lp(a) assembly.

PMID- 12615684
TI  - Hypercholesterolemia promotes P-selectin-dependent platelet-endothelial cell
      adhesion in postcapillary venules.
AB  - OBJECTIVE: The objectives of this study were to determine whether
      hypercholesterolemia promotes platelet-endothelial cell (P/E) adhesion in murine
      postcapillary venules and define the contributions of endothelial or platelet
      associated P-selection to hypercholesterolemia-induced P/E interactions. METHODS
      AND RESULTS: Wild-type (WT) or P-selectin deficient (P-sel-/-) platelets were
      isolated and labeled with the fluorochrome CFSE and administered to either WT or
      P-sel-/- mice placed on a normal diet (ND) or high cholesterol diet (HCD).
      Intravital videomicroscopy was used to quantify platelet saltation and firm
      adhesion. HCD-WT mice exhibited a time-dependent increase in P/E cell
      interactions (relative to ND-WT). Flow cytometry revealed an increased expression
      of P-selectin on circulating platelets of HCD-WT mice at 2 weeks compared with ND
      WT mice. When WT platelets were monitored in HCD-P-sel-/- mice, P/E adhesion was
      dramatically reduced. However, when P-sel-/- platelets were monitored in HCD-WT
      recipients, P/E adhesive interactions were reduced even further, comparable to ND
      WT mice. CONCLUSIONS: These results indicate that elevated cholesterol levels
      promote P/E adhesion in postcapillary venules and that whereas both endothelial
      and platelet P-selectin contribute to hypercholesterolemia-induced recruitment of
      platelets, platelet-associated P-selectin seems to play a more important role in
      producing the prothrombogenic phenotype in venules.

PMID- 12615685
TI  - Liver X receptor agonists as potential therapeutic agents for dyslipidemia and
      atherosclerosis.
AB  - The recent identification of liver X receptors (LXR) as regulators of the
      cholesterol and phospholipid export pump ABCA1 has raised the possibility that
      LXR agonists could be developed as HDL-raising agents, possibly also acting on
      the artery wall to stimulate cholesterol efflux from lipid-laden macrophages.
      Presently several pharmaceutical companies are working to develop such compounds,
      which will require finding a path for separating these beneficial effects from
      the detrimental stimulation of triglyceride synthesis also inherent to LXR
      agonists. Other challenges to the drug development process include species
      differences, which makes prediction of in vivo effects of LXR agonists in humans
      difficult. This review summarizes the present state of knowledge on LXR as a drug
      target and discusses possible solutions for dissociating the favorable effects of
      LXR agonists from their unwanted effects.

PMID- 12615686
TI  - Glucose-6-phosphate dehydrogenase overexpression decreases endothelial cell
      oxidant stress and increases bioavailable nitric oxide.
AB  - OBJECTIVE: Glucose-6-phosphate dehydrogenase (G6PD), the principal source of
      NADPH, serves as an antioxidant enzyme to modulate the redox milieu and nitric
      oxide synthase activity. Deficient G6PD activity is associated with increased
      endothelial cell oxidant stress and diminished bioavailable nitric oxide (NO.).
      Therefore, we examined whether overexpression of G6PD would decrease reactive
      oxygen species accumulation and increase bioavailable NO. in endothelial cells.
      METHODS AND RESULTS: Adenoviral-mediated gene transfer of G6PD increased G6PD
      expression, activity, and NADPH levels in bovine aortic endothelial cells
      (BAECs). BAECs overexpressing G6PD demonstrated a significant reduction in
      reactive oxygen species accumulation when exposed to hydrogen peroxide, xanthine
      xanthine oxidase, or tumor necrosis factor-alpha compared with BAECs with basal
      levels of G6PD. BAECs overexpressing G6PD maintained intracellular glutathione
      stores when exposed to oxidants because of increased activity of glutathione
      reductase, an effect that was not observed in endothelial cells with normal G6PD
      activity. Overexpression of G6PD was also associated with enhanced nitric oxide
      synthase activity, resulting in elevated levels of cGMP, nitrate, and nitrite,
      and this response was increased after stimulation with bradykinin. CONCLUSIONS:
      Overexpression of G6PD in vascular endothelial cells decreases reactive oxygen
      species accumulation in response to exogenous and endogenous oxidant stress and
      improves levels of bioavailable NO.

PMID- 12615687
TI  - Prognostic value of abnormal vasoreactivity of epicardial coronary arteries to
      sympathetic stimulation in patients with normal coronary angiograms.
AB  - OBJECTIVE: We aimed to evaluate prospectively whether patients with normal
      coronary angiogram but abnormal epicardial vasoreactivity to cold pressor test
      (CPT) are at increased risk for cardiovascular events. METHODS AND RESULTS:
      Vasoreactivity in response to CPT and dilation of epicardial arteries to
      intracoronary application of nitroglycerin were assessed quantitatively (percent
      change of luminal area, DeltaLA%) in 130 patients with normal coronary
      angiograms. Cardiovascular events (cardiovascular death, acute coronary syndrome,
      myocardial infarction, percutaneous transluminal coronary angioplasty, coronary
      bypass grafting, ischemic stroke, or peripheral revascularization) were assessed
      as clinical outcome parameters over a mean follow-up period of 45+/-9 months.
      Based on their vascular responses to CPT, patients were assigned into the
      following 3 groups: group 1, patients with normal vasodilator response (DeltaLA
      >0%; n=37); group 2, patients with moderate vasoconstrictor response (DeltaLA
      between 0% and -15%; n=42); and group 3, patients with severe vasoconstrictor
      response (DeltaLA < or =-15%; n=51). Although patients from groups 2 and 3 had
      significantly increased vasoconstrictor response to CPT (group 2, DeltaLA -6+/-3%
      and group 3, DeltaLA -24+/-6% versus group 1, DeltaLA 11+/-9%; P< or =0.0001),
      they showed normal endothelial-independent epicardial vasodilation to
      intracoronary application of nitroglycerin similar to patients from group 1
      (DeltaLA 39+/-16% and 34+/-14% versus 41+/-14%; P=NS, respectively). During
      follow-up, none of the patients from group 1 developed cardiac events. However, 7
      cardiovascular events occurred in group 2 and 30 occurred in group 3 in 4 and 22
      patients, respectively (P< or =0.0001, univariate by log-rank test). After
      adjustment for known risk factors for coronary artery disease, impaired
      epicardial coronary vasoreactivity to CPT remained significantly associated with
      the risk of developing cardiovascular events (P=0.040, multivariate by Cox
      regression model). CONCLUSIONS: In patients with normal coronary angiogram,
      abnormal vasoreactivity of epicardial coronary arteries in response to
      sympathetic stimulation is associated with the risk of developing cardiovascular
      events.

PMID- 12615688
TI  - Importance of different pathways of cellular cholesterol efflux.
AB  - The removal of excess free cholesterol from cells by HDL or its apolipoproteins
      is important for maintaining cellular cholesterol homeostasis. This process is
      most likely compromised in the atherosclerotic lesion because the development of
      atherosclerosis is associated with low HDL cholesterol. Multiple mechanisms for
      efflux of cell cholesterol exist. Efflux of free cholesterol via aqueous
      diffusion occurs with all cell types but is inefficient. Efflux of cholesterol is
      accelerated when scavenger receptor class-B type I (SR-BI) is present in the cell
      plasma membrane. Both diffusion-mediated and SR-BI-mediated efflux occur to
      phospholipid-containing acceptors (ie, HDL and lipidated apolipoproteins); in
      both cases, the flux of cholesterol is bidirectional, with the direction of net
      flux depending on the cholesterol gradient. The ATP-binding cassette transporter
      AI (ABCA1) mediates efflux of both cellular cholesterol and phospholipid. In
      contrast to SR-BI-mediated flux, efflux via ABCA1 is unidirectional, occurring to
      lipid-poor apolipoproteins. The relative importance of the SR-BI and ABCA1 efflux
      pathways in preventing the development of atherosclerotic plaque is not known but
      will depend on the expression levels of the two proteins and on the type of
      cholesterol acceptors available.

PMID- 12615689
TI  - Phagocytosis and macrophage activation associated with hemorrhagic microvessels
      in human atherosclerosis.
AB  - OBJECTIVE: Previously, we demonstrated that activated inducible NO synthase
      (iNOS)-expressing foam cells in human carotid plaques often produce
      autofluorescent (per)oxidized lipids (ceroid). Here, we investigate whether
      intraplaque microvessels can provide foam cells with lipids and trigger
      macrophage activation. METHODS AND RESULTS: Microvessels (von Willebrand factor
      [vWf] immunoreactivity), activated macrophages (iNOS immunoreactivity), and
      ceroid were systematically mapped in longitudinal sections of 15 human carotid
      endarterectomy specimens. An unbiased hierarchical cluster analysis classified
      vascular regions into 2 categories. One type with normal vWf expression and
      without inflammatory cells was seen, and another type with cuboidal endothelial
      cells, perivascular vWf deposits, and iNOS and ceroid-containing foam cells was
      seen in 4 (27%) of 15 plaques. The perivascular foam cells frequently contained
      platelets (glycoprotein Ibalpha) and erythrocytes (hemoglobin, iron), pointing to
      microhemorrhage/thrombosis and subsequent phagocytosis. Similar lipid-containing
      cells, expressing both ceroid and iNOS, were generated in atherosclerosis-free
      settings by incubating murine J774 macrophages with platelets or oxidized
      erythrocytes and also in vivo in organizing thrombi in normocholesterolemic
      rabbits. CONCLUSIONS: Focal intraplaque microhemorrhages initiate platelet and
      erythrocyte phagocytosis, leading to iron deposition, macrophage activation,
      ceroid production, and foam cell formation. Neovascularization, besides supplying
      plaques with leukocytes and lipoproteins, can thus promote focal plaque expansion
      when microvessels become thrombotic or rupture prone.

PMID- 12615690
TI  - Association between complement factor H and proteoglycans in early human coronary
      atherosclerotic lesions: implications for local regulation of complement
      activation.
AB  - OBJECTIVE: Complement activation has been suggested to play a role in
      atherogenesis. To study the regulation of complement activation in human coronary
      atherosclerotic lesions, we examined the spatial relationships between the major
      complement inhibitor, factor H, and the complement activation products C3d and
      C5b-9. METHODS AND RESULTS: In early lesions (American Heart Association types II
      and III), factor H was immunohistochemically found in the superficial
      proteoglycan-rich layer in association with numerous macrophages and C3d, whereas
      C5b-9 was found deeper in the intima, where factor H was virtually absent. In
      vitro experiments involving surface plasmon resonance and affinity chromatography
      analyses demonstrated that isolated human arterial proteoglycans bind factor H,
      and functional complement assays showed that glycosaminoglycans inhibit the
      complement activation induced by modified low density lipoprotein or by a foreign
      surface. CONCLUSIONS: The present observations raise the possibility that
      proteoglycans, because of their ability to bind the major complement inhibitor
      factor H, may inhibit complement activation in the superficial layer of the
      arterial intima. In contrast, deeper in the intima, where factor H and
      proteoglycans are absent, complement may be activated and proceed to C5b-9. Thus,
      the superficial and the deep layers of the human coronary artery appear to differ
      in their ability to regulate complement activation.

PMID- 12615691
TI  - In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus
      formation but not thrombus stability.
AB  - OBJECTIVE: ADP is a key platelet agonist in thromboembolism. One of the receptors
      involved in ADP-induced platelet activation is the P2Y12 receptor, which is a
      target for antithrombotic drugs. METHODS AND RESULTS: Here, we present first
      evidence for a differential role of this receptor in thrombus and embolus
      formation in vivo. Anesthetized rabbits were treated with the selective P2Y12
      antagonists AR-C69931 MX (3 microg x kg x min(-1) IV) or clopidogrel (25 mg/kg
      orally). Efficacy of these treatments was monitored by aggregation and thrombin
      generation measurements in blood samples ex vivo. Mesenteric arterioles were
      mechanically injured; thrombus growth and subsequent embolus formation were
      visualized by real-time intravital microscopy. AR-C69931 MX and clopidogrel
      significantly (P<0.05) reduced the total duration of embolization (by 52% and
      36%, respectively), and fewer and smaller emboli were produced. The size of the
      initial thrombus was significantly reduced (P<0.005), but its stability was
      unaffected: plug formation was still effective. CONCLUSIONS: These findings
      demonstrate that ADP and its P2Y12 receptor are involved in thrombus growth and
      especially in the formation of emboli on the downstream side of the initial
      thrombus. This may explain the beneficial effects of P2Y12 receptor antagonists
      in secondary prevention of ischemic events in patients with arterial thrombosis.

PMID- 12615692
TI  - Platelet activation and the formation of the platelet plug: deficiency of
      ADAMTS13 causes thrombotic thrombocytopenic purpura.
AB  - In the circulation, a plasma metalloprotease, ADAMTS13, cleaves von Willebrand
      factor (vWF) in a shear-dependent manner. This article reviews the role of this
      cleavage in regulating vWF-platelet interaction and proposes a scheme for
      understanding how a deficiency of ADAMTS13 results in the development of
      microthrombi in patients with thrombotic thrombocytopenic purpura.

PMID- 12615693
TI  - Obesity and systemic oxidative stress: clinical correlates of oxidative stress in
      the Framingham Study.
AB  - OBJECTIVE: To determine the clinical conditions associated with systemic
      oxidative stress in a community-based cohort. Information regarding
      cardiovascular risk factors associated with systemic oxidative stress has largely
      been derived from highly selected samples with advanced stages of vascular
      disease. Thus, it has been difficult to evaluate the relative contribution of
      each cardiovascular risk factor to systemic oxidative stress and to determine
      whether such risk factors act independently and are applicable to the general
      population. METHODS AND RESULTS: We examined 2828 subjects from the Framingham
      Heart Study and measured urinary creatinine-indexed levels of 8-epi-PGF2alpha as
      a marker of systemic oxidative stress. Age- and sex-adjusted multivariable
      regression models were used to assess clinical correlates of oxidative stress. In
      age- and sex-adjusted models, increased urinary creatinine-indexed 8-epi
      PGF2alpha levels were positively associated with female sex, hypertension
      treatment, smoking, diabetes, blood glucose, body mass index, and a history of
      cardiovascular disease. In contrast, age and total cholesterol were negatively
      correlated with urinary creatinine-indexed 8-epi-PGF2alpha levels. After
      adjustment for several covariates, decreasing age and total/HDL cholesterol
      ratio, sex, smoking, body mass index, blood glucose, and cardiovascular disease
      remained associated with urinary 8-epi-PGF2alpha levels. CONCLUSIONS: Smoking,
      diabetes, and body mass index were highly associated with systemic oxidative
      stress as determined by creatinine-indexed urinary 8-epi-PGF2alpha levels. The
      effect of body mass index was minimally affected by blood glucose, and diabetes
      and may suggest an important role of oxidative stress in the deleterious impact
      of obesity on cardiovascular disease.

PMID- 12615694
TI  - Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase
      inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic
      aneurysms.
AB  - OBJECTIVE: Angiotensin II (AngII) infusion into hyperlipidemic mice leads to the
      rapid formation of atherosclerotic lesions and abdominal aortic aneurysms (AAAs).
      To define the role of matrix metalloproteinases (MMPs) in the development of
      these vascular pathologies, we administered the broad-spectrum MMP inhibitor
      doxycycline to saline- and AngII-infused LDL receptor-/- mice. METHODS AND
      RESULTS: Mice were placed on a high-fat diet for 1 week before infusion with
      either saline or AngII (1000 ng x kg(-1) x min(-1)) via osmotic pumps for 28
      days. Doxycycline (30 mg x kg(-1) x d(-1)) was administered in the drinking water
      to both saline- and AngII-infused mice. Administration of doxycycline did not
      significantly influence systolic blood pressure, serum cholesterol
      concentrations, or lipoprotein-cholesterol distribution. Doxycycline had no
      effect on the extent of atherosclerosis in saline- or AngII-infused mice. In
      contrast, doxycycline markedly reduced the incidence of AAA formation (86% vs
      35%, AngII vs AngII+doxycycline, respectively; P<0.05), in addition to reducing
      aneurysm severity. CONCLUSIONS: These data do not imply a role for MMPs in AngII
      induced atherosclerosis but provide evidence consistent with a role in AngII
      induced AAA formation.

PMID- 12615695
TI  - Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into
      ApoE3-Leiden mice inhibits atherogenesis.
AB  - OBJECTIVE: To determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in
      the early development of atherosclerosis METHODS AND RESULTS: Bone marrow cells
      harvested from CCR2 (-/-) and CCR2 (+/+) mice were transplanted into ApoE3-Leiden
      mice, a mouse strain susceptible for diet-induced atherosclerosis. Eight weeks
      after bone marrow transplantation, the diet of regular chow was switched to a
      high-cholesterol diet (1% cholesterol, 15% fat, 0.5% cholate) for another 8 weeks
      to induce atherosclerosis. No significant differences in serum cholesterol and
      triglyceride levels were observed between the CCR2 (+/+) --> ApoE3-Leiden and
      CCR2 (-/-) --> ApoE3-Leiden mice. However, the mean cross-sectional aortic root
      lesion area of CCR2 (-/-) --> ApoE3-Leiden mice was only 2.94+/-1.94x10(4)
      microm2 compared with 20.94+/-12.71x10(4) microm2, for CCR2 (+/+) --> ApoE3
      Leiden mice. Thus, the absence of CCR2 on leukocytes induces an 86% reduction of
      aortic lesion area as compared with controls (n=10, P<0.01). CONCLUSIONS: These
      results provide direct evidence that CCR2 expressed by leukocytes plays a
      critical role in the initiation of early atherosclerosis and that pharmacological
      intervention in CCR2 function represents an attractive target to inhibit
      atherogenesis.

PMID- 12615696
TI  - Activation of peroxisome proliferator-activated receptor gamma and retinoid X
      receptor results in net depletion of cellular cholesteryl esters in macrophages
      exposed to oxidized lipoproteins.
AB  - OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand
      activated transcription factor, has pleiotropic effects, including regulation of
      macrophage differentiation and lipid homeostasis. The PPARgamma ligands,
      thiazolidinediones (TZDs), attenuate atherosclerosis in mice by uncertain
      mechanisms. The objective of this study was to determine whether activation of
      PPARgamma or its obligate heterodimer, retinoid X receptor (RXR), modulates
      macrophage foam cell formation induced by oxidized (ox) lipoproteins. METHODS AND
      RESULTS: Incubation of THP-1 macrophages with oxHTG-VLDL, oxREM, or oxLDL
      increased cellular cholesteryl ester over 6-fold. Preincubation with the TZD,
      ciglitazone, the RXR-specific ligand, 9-cis retinoic acid (9cRA) or the
      combination reduced CE mass accumulation by up to 65%. Ciglitazone and 9cRA
      increased CD36 mRNA (up to 4-fold); however, uptake of [125I]oxLDL was only
      modestly enhanced (up to 1.8-fold) becaues of a concomitant PPARgamma:RXR-induced
      decrease in SRAI/II activity (up to 40%). This suggested that PPARgamma:RXR
      activation inhibited cholesteryl ester accumulation by enhancing cholesterol
      efflux. Ciglitazone and 9cRA were found to increase the expression of ATP-binding
      cassette proteins A1 and G1, resulting in enhanced cholesterol efflux to
      lipoprotein-deficient serum, apoAI and HDL3. CONCLUSIONS: PPARgamma and/or RXR
      activation inhibit foam cell formation through enhanced cholesterol efflux
      despite increased oxLDL uptake. These observations explain the reduced
      atherosclerosis in TZD-treated mice and may extend the therapeutic implications
      of these ligands.

PMID- 12615698
TI  - Origin of vascular smooth muscle cells and the role of circulating stem cells in
      transplant arteriosclerosis.
AB  - To date, clinical solid-organ transplantation has not achieved its goals as a
      long-term treatment for patients with end-stage organ failure. Development of so
      called chronic transplant dysfunction (CTD) is now recognized as the predominant
      cause of allograft loss long term (after the first postoperative year) after
      transplantation. CTD has the remarkable histological feature that the luminal
      areas of intragraft arteries become obliterated, predominantly with vascular
      smooth muscle cells (VSMCs) intermingled with some inflammatory cells (transplant
      arteriosclerosis, or TA). The development of TA is a multifactorial process, and
      many risk factors have been identified. However, the precise pathogenetic
      mechanisms leading to TA are largely unknown and, as a result, adequate
      prevention and treatment protocols are still lacking. This review discusses the
      origin (donor versus recipient, bone marrow versus nonbone marrow) of the VSMCs
      in TA lesions. Poorly controlled influx and subsequent proliferative behavior of
      these VSMCs are considered to be critical elements in the development of TA.
      Available data show heterogeneity when analyzing the origin of neointimal VSMCs
      in various transplant models and species, indicating the existence of multiple
      sites of origin. Based on these findings, a model considering plasticity of VSMC
      origin in TA in relation to severity and extent of graft damage is proposed.

PMID- 12615699
TI  - Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.
AB  - Aberrant transactivation of a certain set of target genes by the beta-catenin and
      T-cell factor/lymphoid enhancer factor complex has been considered crucial for
      the initiation of intestinal tumorigenesis. The human multidrug resistance (MDR)1
      (ABCB1) gene contains multiple beta-catenin-T-cell factor4-binding elements in
      its promoter and is one of the immediate targets of the complex. In the current
      study, we have further substantiated the biological involvement of MDR1 in
      intestinal tumorigenesis based on the following evidence: (a) aberrant induction
      of the Mdr1a (Abcb1a) gene product, P-glycoprotein, associated with nuclear
      accumulation of the beta-catenin protein, was observed even in nascent
      microscopic adenomas of Min mice; (b) Mdr1-deficient Min (Apc(Min/+)Mdr1a/b(-/-))
      mice developed significantly fewer intestinal polyps than did
      Apc(Min/+)Mdr1a/b(+/+) mice; and (c) Inhibitors of P-glycoprotein, verapamil, and
      cyclosporin A had a suppressive effect on the in vitro polypoid growth of IEC6
      expressing stabilized (DeltaN89) beta-catenin protein. Inhibitors of P
      glycoprotein may be included in a novel class of chemopreventive agents against
      colorectal carcinogenesis.

PMID- 12615697
TI  - Suppression subtractive hybridization identifies distinctive expression markers
      for coronary and internal mammary arteries.
AB  - OBJECTIVE: We sought to identify differentially expressed genes in the athero
      prone coronary artery and athero-resistant internal mammary arteries. METHODS AND
      RESULTS: Using suppressive subtraction hybridization, we generated reciprocal
      cDNA collections of representative mRNAs specific to porcine coronary arteries
      versus porcine mammary arteries. We screened 1000 suppressive subtraction
      hybridization cDNA clones by dot blot array and sequenced 600 of those showing
      the most marked expression differences. Northern blot, in situ hybridization, and
      immunostaining confirmed the differential gene expression patterns identified by
      the dot blot arrays. Genes associated with mammary arteries included claudin-10
      and h-cadherin, which are genes associated with tight junctions and intermediate
      junctions. In contrast, genes associated with proatherosclerotic processes, such
      as lipid retention and metabolism, inflammation, and cell growth, were
      preferentially expressed in coronary arteries. CONCLUSIONS: Normal coronary
      arteries have gene expression program that is significantly different than
      internal mammary arteries. These differences may partly explain the resistance of
      coronary arteries and internal mammary arteries to atherosclerosis.

PMID- 12615700
TI  - Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene
      disruption.
AB  - Using Mth1 and Ogg1 knockout mice, we evaluated the roles of these enzymes to
      prevent tumorigenesis and the accumulation of 8-oxoguanine (8-oxoG) in DNA. We
      found that lung adenoma/carcinoma spontaneously developed in Ogg1 knockout mice
      approximately 1.5 years after birth in which 8-oxoG was found to accumulate in
      their genomes. The mean number of tumors/mouse was 0.71 for the Ogg1 knockout
      mice, which was five times higher than that observed in wild-type mice (0.14).
      Although the accumulation of 8-oxoG was also confirmed in the Ogg1, Mth1 double
      knockout mice, we found no tumor in the lungs of these mice. This observation
      suggests that Mth1 gene disruption resulted in a suppression of the tumorigenesis
      caused by an Ogg1 deficiency.

PMID- 12615701
TI  - Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor
      production in ovarian cancer.
AB  - Inhibition of cyclooygenase-2 (COX-2) catalytic activity has proven successful in
      restricting the growth of epithelial-derived cancers in vivo. Whether COX-2
      inhibitor therapy would be beneficial in the prevention and/or treatment of
      ovarian cancer, the most lethal gynecological malignancy worldwide, is not known.
      Most patients with ovarian cancer undergo cytoreductive therapy. Because many of
      the cytotoxic drugs used to treat ovarian cancer induce COX-2 expression, samples
      from patients that had not undergone cytoreductive therapy were specifically
      chosen for COX isoform expression analysis. A majority of specimens exhibited
      elevated levels of COX-1, not COX-2, mRNA, and protein compared with normal
      ovarian tissue. Focal regions within the tumor expressing high COX-1 also had
      elevated levels of pro-angiogenic proteins. Selective inhibition of COX-1, not
      COX-2, inhibited arachidonic acid-stimulated vascular endothelial growth factor
      production, which could be reversed by cotreatment with prostaglandin E(2). Thus,
      COX-1 may contribute to carcinoma development in the ovary through stimulation of
      neovascularization. Clinical studies testing the efficacy of COX inhibition as
      adjuvant therapy for ovarian cancer may see more beneficial effects with adjuvant
      therapy with either a COX-1 selective or nonselective cyclooxygenase inhibitor as
      compared with a COX-2 selective drug.

PMID- 12615703
TI  - Expression of the hypoxia marker carbonic anhydrase IX is critically dependent on
      SP1 activity. Identification of a novel type of hypoxia-responsive enhancer.
AB  - In the present study, we further studied mechanisms of transcriptional regulation
      of the tumor-associated carbonic anhydrase IX (CAIX). We identified PR5 in the
      CA9 promoter as another SP1/SP3-binding site. As shown by electromobility shift
      assays and block-replacement mutagenesis, PR5 is functionally equivalent to the
      SP1/SP3-binding PR1 identified previously. However, there is a strong requirement
      for SP1/SP3 activity in the PR1 position, and SP1/SP3 activity from the PR5
      position cannot compensate for this. In various cell lines, the expression of
      endogenous CAIX and activity of CA9 promoter constructs depend on SP1/SP3
      activity as demonstrated by the dose-dependent inhibitory effect of the SP1
      inhibitor mithramycin A. The two conditions of the induction of CAIX expression
      described previously differ in their sensitivity to mithramycin A inhibition; the
      hypoxia-mimic-induced expression is less sensitive than the cell density (mild
      hypoxia)-induced expression. Our present study highlights the importance of
      SP1/SP3 activity for CAIX expression and provides additional evidence for
      distinct mechanisms responsible for true and mild hypoxia-induced CAIX
      expression. The presence of a SP1/SP3-binding element in the PR1 position is
      absolutely required for mild hypoxia-induced activity, and it significantly up
      regulates the true hypoxic induction. The SP1/SP3 and hypoxia-response element in
      the CA9 promoter thus may represent a novel type of enhancer capable of mounting
      responses to a wider range of hypoxic conditions.

PMID- 12615702
TI  - Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related
      apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival
      factor for human myeloma cells.
AB  - Myeloma cells grow only in the bone marrow closely associated with
      bone,suggesting that this microenvironment provides critical signals for their
      growth and survival. Osteoprotegerin (OPG) is a member of the tumor necrosis
      factor (TNF) receptor family, which binds to the ligand for receptor activator of
      nuclear factor kappa B and inhibits bone resorption. However, it is unclear
      whether OPG can also bind to other TNF family members, such as TNF-related
      apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L), and, by inhibiting their
      activity, function as a survival factor for myeloma cells. In the present study
      MG63 osteoblast-like cells and primary bone marrow stromal cells were both shown
      to produce OPG, whereas human myeloma cells did not produce OPG but down
      regulated release of OPG from MG63 cells. TRAIL/Apo2L induced apoptosis in
      myeloma cells, and this could be prevented with the addition of recombinant OPG.
      Medium conditioned by MG63 cells was also shown to inhibit TRAIL/Apo2L-induced
      apoptosis, an effect that was reversed by the addition of soluble receptor
      activator of nuclear factor kappa B ligand. Medium conditioned by cocultures of
      MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2L-induced
      apoptosis, reflecting the decreased concentrations of OPG in cocultures of
      myeloma cells with bone cells. These observations suggest that OPG may function
      as a paracrine survival factor in the bone marrow microenvironment in multiple
      myeloma.

PMID- 12615704
TI  - Evidence for lack of enhanced hedgehog target gene expression in common
      extracutaneous tumors.
AB  - Abnormal hedgehog signaling, most commonly caused by loss of PTCH1 inhibitor
      activity,drives tumorigenesis of basal cell carcinomas (BCCs). To assess whether
      other tumors also have abnormal hedgehog signaling, we have assayed RNA from
      common cancers at nine different sites for levels of expression of hedgehog
      target genes that are up-regulated uniformly in BCCs. We report here that such
      dysregulation appears not to be common in the types of non-BCC cancers studied,
      indicating that the molecular pathogenesis of BCCs, like their frequency and
      behavior, differs markedly from that of most other cancers.

PMID- 12615705
TI  - Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone
      oxidoreductase-1.
AB  - Enzymes that activate and detoxify benzene are likely genetic determinants of
      benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies
      benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans
      is associated with an increased risk of leukemia, specifically acute myelogenous
      leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene
      induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more
      sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background
      strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene
      (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated
      peripheral blood cells were counted to assess genotoxicity. Peripheral blood
      counts and bone marrow histology were used to assess hematotoxicity and
      myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of
      DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene
      induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9
      fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a
      3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic
      response in male mice was similar between the two genotypes (> or = 10-fold
      increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater
      hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in
      male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which
      indicates an activated DNA damage response. These results indicate that NQO1
      deficiency results in substantially greater benzene-induced toxicity. However,
      the specific patterns of toxicity differed between the male and female mice.

PMID- 12615706
TI  - Delayed reactivation of p53 in the progeny of cells surviving ionizing radiation.
AB  - Ionizing radiation induces genomic instability, which is transmitted through many
      generations after irradiation in the progeny of surviving cells. To detect
      delayed activation of p53, we constructed a reporter plasmid containing the p53
      responsible promoter and the bacterial beta-galactosidase (beta-gal) gene and
      introduced it into human fibrosarcoma (HT1080) cells, which retain wild-type p53
      function. The resultant clones induce beta-gal protein after X-irradiation, and
      the induction kinetics were similar to those of p21(WAF1/CIP1) protein. More than
      90% of the cells were stained blue when the cells were incubated with X-gal 4 h
      after 6 Gy of X-rays, whereas very few control cells were beta-gal positive. The
      primary colonies formed after 6 Gy of X-rays were collected, and they were
      subjected to secondary colony formation. We observed that a significant number of
      surviving colonies contained beta-gal-positive cells, suggesting that delayed
      activation of p53 occurred in the progeny of irradiated cells. We also found
      higher frequency of phosphorylation of p53, NBS1, and CHK2/Cds1 in the progeny of
      surviving cells. Furthermore, foci formation of phosphorylated histone H2AX was
      detected in the progeny of surviving cells. These findings provide the
      possibility that the observed instability results from these DNA breaks, i.e.,
      the breaks lead to delayed chromosome rearrangements, delayed cell death, and so
      forth, many generations after irradiation and that activation of p53 function may
      eliminate cells that have potentially accumulated genomic alterations.

PMID- 12615707
TI  - Helicobacter pylori-associated gastric cancer in INS-GAS mice is gender specific.
AB  - Previous studies from our group have shown that hypergastrinemia in mice can
      synergize with Helicobacter felis infection to induce gastric carcinoma. In
      addition, epidemiological evidence and a recent study with C57BL/6 mice have
      strongly suggested a link between a high-salt diet during Helicobacter pylori
      infection and the development of hypergastrinemia and preneoplastic gastric
      lesions. To address the possible relationship between the two cofactors (gastrin
      and salt) and whether H. pylori can also lead to gastric cancer in this model, we
      undertook a longitudinal study involving 86 INS-GAS mice. The mice were fed
      either a high-salt (7.5%) or basal (0.25%) diet, and half were infected with H.
      pylori. Necropsies at 5 and 7 months postinfection included histopathological
      examination, quantitative culturing for bacterial colonization levels, and
      serology to estimate the magnitude of the Th1 and Th2 systemic inflammatory
      responses. Lesions consistent with in situ and intramucosal carcinoma were seen
      in H. pylori-infected male mice only. There was a highly significant main effect
      for Helicobacter infection status for all fundic and antral lesion parameters (P
      < 0.0001), as well as significant interactions of infection status with diet for
      all of the fundic parameters (all P < 0.03), except intestinal metaplasia. In
      subsequent ANOVAs in which the data were limited to that from infected animals,
      there was a highly significant main effect for time, diet, and gender (all P <
      0.02) on all of the corpus lesion parameters scored (inflammation, atrophy,
      hyperplasia, metaplasia, and dysplasia/neoplasia). In addition, gender interacted
      significantly with time (all P < 0.03), and. H. pylori colonization increased
      quantitatively over the course of the experiment but were independent of either
      diet or gender. The Th1-associated serum IgG2a responses to H. pylori increased
      from the time of experimental infection to necropsy at 5 or 7 months and were
      similar among all experimentally infected mice with no influence of gender (P >
      0.10) or dietary salt (P > 0.27). In contrast, the Th2-associated serum IgG1
      response to H. pylori was significantly increased in infected male INS-GAS mice
      on the high-salt diet at 7 months postinfection (P < 0.012). These results show
      that H. pylori can also accelerate the development of gastric cancer in the INS
      GAS mouse model, and the results suggest that salt has less of a procarcinogenic
      effect in the setting of endogenous hypergastrinemia. The increased Th2
      associated humoral response of the infected male mice on the high-salt diet
      correlated with less severe gastric lesions. In the INS-GAS mouse model, male
      gastric tissue responded more rapidly and aggressively to H. pylori infection,
      high-salt diet, and the combination when compared with females; a finding that
      appears consistent with the greater incidence of gastric carcinoma in men. This
      study highlights the importance of using both genders to investigate the
      pathogenesis of H. pylori.

PMID- 12615708
TI  - Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating
      cytotoxin.
AB  - Chronic gastritis induced by Helicobacter pylori is a strong risk factor for the
      development of distal gastric adenocarcinoma. A specific host response to H.
      pylori that may contribute to gastric carcinogenesis is epithelial cell
      apoptosis. The aim of this study was to investigate the capacity of H. pylori
      vacuolating toxin (VacA) to induce gastric epithelial cell apoptosis. When
      cocultured with AGS gastric epithelial cells, H. pylori strain 60190, which
      expresses a type s1/m1 VacA toxin, induced significantly higher levels of
      apoptosis than did an isogenic vacA null mutant strain. VacA purified from strain
      60190 induced apoptosis in a dose-dependent manner, which required acid
      activation of the purified toxin and the presence of ammonium chloride. In
      contrast, apoptosis was not induced after incubation with a chimeric s2/m1 toxin
      (in which the s1 sequence at the NH(2) terminus of VacA from strain 60190 was
      replaced with the s2 sequence from the nontoxigenic strain Tx30a) or a VacA
      mutant protein (VacA Delta 6-27) that lacks a unique strongly hydrophobic region
      near the VacA NH(2) terminus. Moreover, when an equimolar mixture of purified
      VacA Delta 6-27 and purified wild-type VacA were added simultaneously to AGS
      cells, the mutant toxin exhibited a dominant negative effect, completely
      inhibiting the apoptosis-inducing activity of wild-type VacA. These results
      indicate that VacA induces gastric epithelial cell apoptosis and suggest that
      differences in levels of gastric mucosal epithelial apoptosis among H. pylori
      infected persons may result from strain-dependent variations in VacA structure.

PMID- 12615709
TI  - Peroxisome proliferator-activated receptor gamma agonists induce proteasome
      dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast
      cancer cells.
AB  - Treatment of MCF-7 cells with the peroxisome proliferator-activated receptor
      (PPAR) gamma agonists ciglitazone or 15-deoxy-Delta 12,14-prostaglandin J2
      resulted in a concentration- and time-dependent decrease of cyclin D1 and
      estrogen receptor (ER) alpha proteins, and this was accompanied by decreased cell
      proliferation and G(1)-G(0)-->S-phase progression. Down-regulation of cyclin D1
      and ER alpha by PPARgamma agonists was inhibited in cells cotreated with the
      proteasome inhibitors MG132 and PSII, but not in cells cotreated with the
      protease inhibitors calpain II and calpeptin. Moreover, after treatment of MCF-7
      cells with 15-deoxy-Delta 12,14-prostaglandin J2 and immunoprecipitation with
      cyclin D1 or ER alpha antibodies, there was enhanced formation of ubiquitinated
      cyclin D1 and ER alpha bands. Thus, PPARgamma-induced inhibition of breast cancer
      cell growth is due, in part, to proteasome-dependent degradation of cyclin D1
      (and ER alpha), and this pathway may be important for other cancer cell lines.

PMID- 12615710
TI  - Experimental treatment of Epstein-Barr virus-associated primary central nervous
      system lymphoma.
AB  - Primary central nervous system lymphoma (PCNSL) that arises in immune-deficient
      patients is an aggressive B-cell neoplasm that is universally associated with the
      EBV. Patients with EBV(+) PCNSL face a particularly poor prognosis with median
      survival times of 2-12 months despite aggressive management with radiation
      therapy. We have developed a preclinical model of EBV(+) PCNSL to explore
      strategies that specifically target EBV-infected B lymphoblasts in vivo.
      Stereotactic implantation of EBV-transformed human lymphoblastoid B-cell lines
      into the caudate nucleus of the nude rat resulted in lethal CNS tumor burden
      manifested by the onset of focal neurological symptoms within 21 days.
      Histological evaluation at autopsy revealed a multifocal, perivascular human
      EBV(+) lymphoblastic B-cell infiltrate that displayed a latency type III EBV gene
      expression profile similar to PCNSL that develops in some immune-deficient
      patients. Radiation (1600 cGy) of lymphoblastoid B-cell lines resulted in up
      regulation of the EBV thymidine kinase (EBV-TK) transcript and sensitization of
      these cells to drug-induced apoptosis using nucleoside analogs. Enhanced
      expression of EBV-TK mRNA in EBV(+) PCNSL tumors by radiation therapy occurred in
      a dose-dependent fashion. In vivo trials using the nude rat PCNSL model
      demonstrated significantly improved mean survival time (MST) with single fraction
      whole-brain radiotherapy (WBRT) and antiviral therapy consisting of zidovudine
      (AZT) and ganciclovir (GCV; MST 41.3 +/- 3.3 days; P = 0.05), compared with
      either antiviral therapy (MST 32.1 +/- 1.1 days) or WBRT alone (MST 22 +/- 0.8
      days). We found constitutive and abundant EBV-TK mRNA expression in a
      stereotactic core biopsy specimen from a solid organ transplant patient with
      EBV(+) PCNSL. Withdrawal of immunosuppression did not result in disease
      regression. This patient achieved a complete response after therapy with high
      dose AZT and GCV in the absence of WBRT, and remains in remission on oral
      maintenance AZT/GCV therapy 3 years after diagnosis. These results suggest that
      antiviral therapies can be effectively explored in vivo using a preclinical
      animal model of human EBV(+) PCNSL with subsequent translation to patients with
      EBV(+) PCNSL.

PMID- 12615711
TI  - Modulation of inducible nitric oxide synthase and related proinflammatory genes
      by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells.
AB  - Epidemiological and preclinical studies demonstrate that consumption of diets
      high in omega-3 polyunsaturated fatty acids reduces the risk of colon cancer.
      Inhibition of colon carcinogenesis by omega-3 polyunsaturated fatty acids is
      mediated through modulation of more than one signaling pathway that alters the
      expression of genes involved in colon cancer growth. In our earlier studies on
      global gene expression with cDNA microarrays, we have shown that treatment of
      CaCo-2 colon cancer cells with docosahexaenoic acid (DHA) down-regulated the
      prostaglandin family of genes, as well as cyclooxygenase 2 expression and several
      cell cycle-related genes, whereas it up-regulated caspases 5, 8, 9, and 10 that
      are associated with apoptosis. It is known that nitric oxide activates the
      cyclooxygenase 2 enzyme, which plays a pivotal role in the progression of colon
      cancer via prostaglandin synthesis and angiogenesis. The present study was
      undertaken to examine the multifaceted role of DHA in the expression of inducible
      nitric oxide synthase (iNOS) and of related proinflammatory genes, as those have
      been shown to play a role in tumor progression. In addition, we aimed to identify
      associated target genes by DNA microarray, reverse transcription-PCR analysis,
      and cellular localization of iNOS expression in CaCo-2 cells. Results of this
      study demonstrate that treatment with DHA down-regulates iNOS in parallel with a
      differential expression and down-regulation of IFNs, cyclic GMP, and nuclear
      factor kappa B isoforms. More importantly, our findings clearly demonstrate the
      up-regulation of cyclin-dependent kinase inhibitors p21((Waf1/Cip1)) and p27,
      differentiation-associated genes such as alkaline phosphatases, and neuronal
      differentiation factors. These finding strongly suggest that the antitumor
      activity of DHA may be attributed, at least in part, to an effect on iNOS
      regulatory genes. In addition, our results indicate the presence of specific gene
      expression profiles in human colon cancer that can be used as molecular targets
      for chemopreventive agents.

PMID- 12615712
TI  - Wild-type p53 regulates human ribonucleotide reductase by protein-protein
      interaction with p53R2 as well as hRRM2 subunits.
AB  - Ribonucleotide reductase (RR) plays a key role in the synthesis of DNA and is the
      only enzyme responsible for the reduction of ribonucleotides to their
      corresponding deoxyribonucleotides, providing a balanced supply of precursors for
      DNA synthesis and repair. There are three known human RR subunits, hRRM1, hRRM2,
      and p53R2, which is encoded by a p53 target gene. It is not clear whether p53 and
      RR can directly interact at the protein level to regulate DNA repair. It is also
      not known where deoxyribonucleotides are synthesized in the cell. In
      coimmunoprecipitation experiments, we found that hRRM2 and p53R2, but not hRRM1,
      bound to p53 in KB cells, which express wild-type p53. Moreover, in response to
      UV irradiation, both p53R2 and hRRM2 were released from p53 and shifted to bind
      hRRM1. Confocal microscopy confirmed the colocalization of p53 with p53R2 and
      hRRM2 and the translocation of hRRM1, p53R2 and hRRM2 from the cytoplasm to the
      nucleus after UV treatment. An in vivo RR activity assay showed that the kinetic
      profile of increased RR activity was consistent with the accumulation of RR
      subunits in the nucleus. The ability of p53R2 and hRRM2 to shift from binding p53
      to hRRM1 in response to UV irradiation was deficient in the presence of mutant
      p53. Moreover, in cells overexpressing hRRM2, binding of p53R2 to p53 decreased,
      whereas binding to hRRM1 increased. Our results suggest that wild-type p53
      directly interacts with both p53R2 and hRRM2. In response to UV irradiation,
      p53R2 and hRRM2 dissociate from p53 and p53R2, and hRRM2 and hRRM1 transfer to
      the nucleus and form an active RR complex to provide dNDPs for DNA repair.
      Therefore, the direct interaction of p53 with p53R2 and hRRM2 and the nuclear
      accumulation of RR subunits after UV exposure might play a pivotal role in DNA
      repair.

PMID- 12615713
TI  - Immunity to the alpha(1,3)galactosyl epitope provides protection in mice
      challenged with colon cancer cells expressing alpha(1,3)galactosyl-transferase: a
      novel suicide gene for cancer gene therapy.
AB  - Human immunity to alpha(1,3)Galactosyl epitopes (alpha Gal) may provide the means
      for a successful cancer gene therapy that uses the immune system to identify and
      to destroy tumor cells expressing the suicide gene
      alpha(1,3)Galactosyltransferase (alpha GT). Innate antibody specific for cell
      surface alpha Gal constitutes a high percentage of circulating IgG and IgM
      immunoglobulins in humans and is the basis for complement-mediated hyperacute
      xenograft rejection and antibody-dependent cell-mediated cytotoxicity. In humans,
      the gene for alpha GT is mutated, and cells do not express the alpha Gal moiety.
      We hypothesized that human tumor cells induced to express the alpha Gal epitope
      would be killed by the hosts' innate immunity. Previous in vitro work by our
      group has demonstrated complement-mediated lysis of alpha Gal-transduced human
      tumor cells in culture by human serum. To induce antibodies to alpha Gal in this
      in vivo study, alpha GT knockout mice were used to determine whether immunization
      with alpha Gal could provide protection from challenge with alpha Gal-expressing
      murine MC38 colon cancer cells. Knockout mice were immunized either a single
      time, or twice, with rabbit RBC. Antibody titers to alpha Gal measured by
      indirect ELISA were significantly higher in mice immunized twice and approached
      the titers observed in human serum. Anti-alpha Gal antibodies were predominantly
      of the IgG1 and IgG3 subtype. Immunized knockout mice were challenged i.p. with
      varying doses of alpha Gal(+) MC38 colon carcinoma cells. Nonimmunized control
      groups consisting of alpha GT knockout mice, and wild-type C57BL/6 mice were
      challenged as well with MC38 cells. Immunized mice survived and exhibited slower
      tumor development in comparison to nonimmunized knockout and control mice. This
      study demonstrates, in vivo, the protective benefit of an immune response to the
      alpha Gal epitope. Our results provide a basis to pursue additional development
      of this cancer gene therapy strategy.

PMID- 12615714
TI  - Evidence of selection for clones having genetic inactivation of the activin A
      type II receptor (ACVR2) gene in gastrointestinal cancers.
AB  - The activin signaling pathway parallels the transforming growth factor (TGF)-beta
      pathway. Both use extracellular ligands and cell surface receptors that are
      structurally and functionally related, as well as the same intracellular
      mediators (SMADs 2-4) to transmit these signals. Members of both pathways have
      been characterized previously as tumor suppressor genes on the demonstration of
      inactivating mutations in human neoplasms, e.g., genetic inactivation of the
      activin type I receptor was reported recently in pancreatic cancer. Here, we
      present evidence of selection for mutations of the activin A type II receptor
      (ACVR2) gene during human gastrointestinal carcinogenesis. Two 8-bp polyadenine
      tracts of the ACVR2 gene are targets for inactivating frameshift mutations in
      gastrointestinal neoplasms having microsatellite instability (MSI). These
      mutations are similar to those of the 10-bp polyadenine tract within the TGF-beta
      type II receptor (TGFBR2), a well-characterized target of frameshift mutations in
      the same neoplasms. We identified biallelic mutations of ACVR2 in 25 of 28 MSI
      colorectal and pancreatic cancers. In addition, a mutation in the ACVR2 gene
      combined with loss of the wild-type allele was found in a non-MSI pancreatic
      cancer. This evidence is compatible with a high degree of selection for
      inactivation of the ACVR2 gene in tumorigenesis, supporting ACVR2 as a candidate
      tumor suppressor gene in gastrointestinal cancers.

PMID- 12615716
TI  - Irradiation-induced angiogenesis through the up-regulation of the nitric oxide
      pathway: implications for tumor radiotherapy.
AB  - The combination of radiotherapy and antiangiogenic strategies has been shown to
      increase the tumor response in various experimental models. The rationale for
      this cotherapy was initially related to the expected gain in efficacy by acting
      on two different targets, e.g., tumor cells and endothelial cells (ECs). However,
      recent studies have documented more than additive effects due to apparent mutual
      potentiation of these approaches. In this study, we tested the hypothesis that
      these synergistic effects could stem from the stimulatory effects of ionizing
      radiations on angiogenesis, which would then need to be restrained to avoid tumor
      regrowth after irradiation. We found that irradiation dose-dependently induced
      the activation of the proangiogenic NO pathway in ECs through increases in
      endothelial nitric oxide synthase abundance and phosphorylation. Using 2- and 3
      dimensional cultures of ECs and isolated mouse tumor arterioles, we documented
      that the irradiation-induced enhanced production of NO accounted for EC migration
      and sprouting. Irradiation was also shown to stimulate the colonization of
      Matrigel plugs implanted in mouse by ECs, where they formed capillary-like
      structures in a NO-dependent manner. These findings were confirmed by documenting
      the NO-mediated infiltration of CD31-positive ECs after local irradiation of
      Lewis lung carcinoma tumor-bearing mice. Finally, we measured a consistent
      increase in endothelial nitric oxide synthase mRNA by real-time PCR experiments
      in human biopsies of head and neck squamous cell carcinoma after low-dose
      irradiation. In conclusion, we have demonstrated that the potentiation of the NO
      signaling pathway after irradiation induces profound alterations in the EC
      phenotype leading to tumor angiogenesis. Moreover, our demonstration that the
      inhibition of NO production suppresses these provascular effects of irradiation
      highlights new potentials for the coordinated use of antiangiogenic strategies
      and radiotherapy in clinical practice.

PMID- 12615715
TI  - Apoptotic susceptibility of cancer cells selected for camptothecin resistance:
      gene expression profiling, functional analysis, and molecular interaction
      mapping.
AB  - To study the molecular mechanisms by which drug resistance develops, we compared
      DU145 humanprostate cancer cells with a subline selected for resistance to
      camptothecin. Differences in gene expression level were assessed by hybridizing
      the two cell types against each other using quadruplicate "Oncochip" cDNA
      microarrays that included 1648 cancer-related genes. Expression levels differing
      by a factor of >1.5 were detected for 181 of the genes. These differences were
      judged statistically reliable on the basis of a stratum-adjusted Kruskal-Wallis
      test, after taking into account a dye-dependent variable. The 181 expression
      altered genes included a larger than expected number of the "apoptosis-related"
      genes (P = 0.04). To assess whether this observation reflected a generalized
      resistance of RCO.1 to apoptosis, we exposed the cells to a range of stresses
      (cisplatin, staurosporine, UV, ionizing radiation, and serum starvation) and
      found greatly reduced apoptotic responses for RC0.1 (relative to DU145) using
      flow cytometric Annexin V and terminal deoxynucleotidyl transferase-mediated nick
      end labeling assays. We next examined the apoptosis-related genes in the context
      of a molecular interaction map and found expression differences in the direction
      "expected" on the basis of the apoptosis-resistance of RC0.1 for BAD, caspase-6,
      and genes that signal via the Akt pathway. Exposure of the cells to wortmannin,
      an inhibitor of the Akt effector phosphatidylinositol 3-kinase, provided
      functional support for involvement of the Akt pathway. However, closer
      examination of the molecular interaction map revealed a paradox: many of the
      expression differences observed for apoptosis-related genes were in the direction
      "contrary" to that expected given the resistance of RC0.1. The map indicated that
      most of these unexpected expression differences were associated with genes
      involved in the nuclear factor kappa B and transforming growth factor beta
      pathways. Overall, the patterns that emerged suggested a two-step model for the
      selection process that led to resistance in RC0.1 cells. The first hypothesized
      step would involve a decrease in apoptotic susceptibility through changes in the
      apoptosis-control machinery associated with the Bcl-2 and caspase gene families,
      and also in antiapoptotic pathways operating through Akt/PKB. The second step
      would involve changes in multifunctional upstream genes (including some genes in
      the nuclear factor kappa B and transforming growth factor beta pathways) that can
      facilitate apoptosis but that would also tend to contribute to cell proliferation
      in the presence of drug. Thus, we propose that a downstream blockade of apoptosis
      was "permissive" for the selection of upstream pathway changes that would
      otherwise have induced apoptosis. This model is analogous to one suggested
      previously for the relationship between oncogene function and apoptosis in
      carcinogenesis.

PMID- 12615717
TI  - Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP
      site inhibitors block tumor growth.
AB  - A central function of the tumor suppressor retinoblastoma (Rb) is its ability to
      repress E2F transcriptional activity. Many cancers harbor inactivated Rb and
      consequently deregulated E2F. RXL peptides inhibit E2F recruitment and
      phosphorylation by CDK2/cyclin A. Here we report that RXL peptides selectively
      kill tumor cells with deregulated Rb/cyclin D pathways. We extend these
      observations to tumor models and demonstrate inhibition of tumor growth in SV40
      large T transformed Balb/c 3T3 grafts and in HER2 transgenic tumors. Moreover,
      our observations reveal that RXL peptide-treated tumors undergo apoptosis. Our
      results indicate that RXL motif-based inhibitors will provide selective
      antiproliferative agents with in vivo efficacy in tumors with deregulated
      Rb/cyclin D pathways.

PMID- 12615718
TI  - Photodynamic therapy with verteporfin in the radiation-induced fibrosarcoma-1
      tumor causes enhanced radiation sensitivity.
AB  - Photodynamic therapy (PDT) with verteporfin (lipid form of benzoporphyrin
      derivative,benzoporphyrin derivative monoacid ring A) was used to treat radiation
      induced fibrosarcoma tumors before X-ray treatment. When verteporfin was injected
      3 h before light irradiation, the tumor partial pressure of oxygen (pO(2)) rose
      from a pretreatment value of 2.8 +/- 1 to 15.2 +/- 6.9 mm Hg immediately after
      light application was complete (P = 0.048). When the optical irradiation was
      given 15 min after verteporfin injection, the tumor pO(2) decreased slightly
      after treatment [i.e., 6.8 +/- 1.6 mm Hg (pretreatment) versus 4.1 +/- 0.3 mm Hg
      (posttreatment)], whereas control tumor pO(2) did not change significantly. In
      vitro study of the cellular oxygen consumption rate before and after PDT
      treatment indicated that the consumption rate decreased linearly with delivered
      optical dose and quantitatively matched the loss of cell viability as measured by
      a mitochondrial tetrazolium assay. Doppler measurements show that red cell flux
      is still patent immediately after treatment, indicating that oxygen should still
      be delivered to the tumor. Computational simulations of the oxygen supply from
      the vessels and the consumption from mitochondrial activity confirmed that if
      oxygen consumption is decreased in the presence of unhindered blood flow, the
      tumor oxygenation should rise, and the hypoxic fraction of the tumor should
      decrease. Combination treatments with PDT delivered (100 J/cm(2) optical dose,
      with 1 mg/kg benzoporphyrin derivative monoacid ring A injected 3 h before
      treatment) after radiation treatment (10 Gy from 300 keV source) were compared
      with PDT delivered simultaneously with radiation. Tumor regrowth assay showed
      that the delays to reach double the tumor volume for PDT alone and radiation
      alone were 2.7 +/- 1.6 and 3.2 +/- 1.7 days, respectively. When radiation was
      given before PDT, the delay was 5.4 +/- 1.4 days, and when PDT was given at the
      same time as radiation, the delay was 8.1 +/- 1.5 days. This observation
      indicates that the combined effect in the latter case was greater than additive
      (P = 0.049).

PMID- 12615719
TI  - Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells
      to cisplatin-induced death.
AB  - Cytokine growth factors regulate the normal proliferation of hematopoietic cells
      but can also override irradiation-induced growth arrest checkpoints through
      activation of a phosphoinositide 3-kinase (PI3K) signaling pathway. In the
      present study, we assessed the effect that erythropoietin and interleukin-3 have
      on cisplatin-treated hematopoietic cells. When cultured in the presence of
      cytokine, cisplatin-treated 32D cells transiently accumulated in a G(2)-M phase
      arrest and ultimately died by a nonapoptotic mechanism. By comparison, reduction
      of cytokine-induced PI3K activity, either through cytokine receptor mutation or
      direct inhibition with LY294002, caused cisplatin-treated cells to enter a
      biphasic G(1) and G(2)-M arrest. The arrest of these cells coincided with an
      absence of cyclin-dependent kinase (Cdk)1 and Cdk2 activity and significantly
      reduced cell death during cisplatin treatment. Indeed, LY294002 treatment during
      cisplatin exposure allowed the recovery of a viable, proliferating cell
      population after removal of cisplatin. In contrast, Cdks remained active in the
      G(2)-M-arrested population of cisplatin-treated cells with continuous cytokine
      activation of PI3K, and even transient exposure to cisplatin resulted in death of
      the entire population. These data suggest that cytokine activation of PI3K
      signaling pathways overrides cisplatin-induced growth arrest checkpoints, thereby
      sensitizing hematopoietic cells to DNA damage-induced death.

PMID- 12615720
TI  - CD4+ T lymphocytes play a critical role in antibody production and tumor immunity
      against simian virus 40 large tumor antigen.
AB  - The role of CD4+ T lymphocytes in antitumor immunity has been largely attributed
      to providing signals required for the priming of MHC class I-restricted CD8+
      cytotoxic T lymphocytes, and CD8+ cytotoxic T lymphocytes are thought to serve as
      the predominant mediators of tumor killing in vivo. We decided to evaluate the
      role of T lymphocyte subsets in tumor immunity induced by recombinant SV40 large
      tumor antigen (Tag) within an experimental murine pulmonary metastasis model of
      SV40 Tag-expressing tumors. Studies in BALB/c mice used in vivo depletion of
      either CD4+ or CD8+ T cells in the induction phase of the immune response to SV40
      Tag. These studies indicate that CD4+ T cells but not CD8+ T cells were critical
      in the production of antibodies to SV40 Tag and in tumor immunity as the result
      of recombinant SV40 Tag immunization. On the basis of the predominance of the
      IgG1 isotype in the antibody response to SV40 Tag immunization, Th2 type CD4+ T
      cells appeared to be involved. SV40 Tag immunization was not as effective in the
      induction of tumor immunity in therapeutic modalities when compared with the
      prophylactic setting. Our results suggest that CD4+ T cells, along with antibody
      responses, play a role in the induction of tumor immunity to a viral-encoded
      tumor antigen.

PMID- 12615721
TI  - Arf induces p53-dependent and -independent antiproliferative genes.
AB  - The tumor suppressor p19(Arf) (p14(ARF) in humans), encoded by the Ink4a/Arf
      locus, is mutated, deleted, or silenced in many forms of cancer. p19(Arf) induces
      growth arrest by antagonizing the activity of the p53-negative regulator, Mdm2,
      thereby inducing a p53 transcriptional response. p19(Arf) can also inhibit cell
      cycle progression of mouse embryo fibroblasts lacking Cip1 or lacking both Mdm2
      and p53, although in the absence of p53, arrest occurs more slowly. Profiling
      with high-density oligonucleotide GeneChips and cDNA microarrays was used to
      interrogate mouse genes, the expression of which was induced or suppressed by a
      conditionally regulated Arf gene. Cluster analysis of temporal gene expression
      patterns and validation of the results by RNA analysis identified Arf-responsive
      genes whose induction was both p53-dependent and -independent. The latter
      included four members of the B-cell translocation gene family (Btg1, Btg2, Btg3,
      and Tob1) that were demonstrated to inhibit cell proliferation in primary mouse
      embryo fibroblasts expressing or lacking functional p53. Together, the results
      indicate that p19(Arf) induces a broad spectrum of proteins that likely act in
      concert to arrest cell proliferation.

PMID- 12615722
TI  - SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and
      suppresses growth of colorectal carcinoma cells.
AB  - We have shown recently that SLIT2 has tumor suppressor activity and that it is
      epigenetically silenced in >40% of lung and breast tumors. In this study, we have
      analyzed the methylation status of SLIT2 in primary colorectal cancers and
      matching normal colorectal mucosa. SLIT2 promoter region methylation was found in
      23 (72%) of 32 primary colorectal cancers. In contrast, normal colorectal mucosa
      from the same patients exhibited significantly lower levels of SLIT2 promoter
      region hypermethylation. SLIT2 methylation was reversed and expression restored
      by treating colorectal tumor cell lines with the demethylating agent 5-aza-2
      deoxycytidine. Loss of heterozygosity at D4S1546 marker, which maps within 100 kb
      of the SLIT2 gene, was observed in 39% of the methylated tumors. Furthermore,
      SLIT2 epigenetic silencing was independent of ROBO1/p16/RASSF1A hypermethylation.
      The presence of SLIT2 methylation was also independent of the presence of K-RAS
      mutations. Ectopic expression of SLIT2 diminished the ability to form colonies in
      two colorectal tumor cell lines. In addition, conditioned medium from SLIT2
      transfected COS-7 cells reduced cell growth and induced apoptosis in SW48
      colorectal tumor cell line. In conclusion, SLIT2 is an excellent candidate tumor
      suppressor gene for colorectal cancer.

PMID- 12615723
TI  - Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in
      tumor necrosis factor-related apoptosis-inducing ligand signaling.
AB  - Apo-2L/TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand) is a
      member of the tumor necrosis factor superfamily and has recently been shown to
      induce apoptosis through engagement of the death receptors TRAIL-R1 (DR4) and
      TRAIL-R2 (DR5). The transcription factor nuclear factor (NF)-kappa B regulates
      the expression of genes involved in cancer cell invasion, metastasis, and
      resistance to chemotherapy. In normal unstimulated cells, NF-kappa B is
      maintained in the cytoplasm with its inhibitor protein I kappa B, whereas in
      cancer cells, NF-kappa B is in the nucleus and constitutively activates target
      genes. To understand the function of NF-kappa B in TRAIL-induced apoptosis, we
      have analyzed the specific roles of NF-kappa B subunits. Overexpression of a
      transdominant-negative mutant of the inhibitory protein I kappa B alpha results
      in down-regulation of constitutively active NF-kappa B, induction of DR5, and
      tumor necrosis factor receptor (TNFR) 1-associated death domain expression and
      enhancement of TRAIL sensitivity. Overexpression of RelA or a transcriptional
      deficient mutant of c-Rel inhibits TRAIL-induced apoptosis. Depletion of RelA in
      mouse embryonic fibroblasts increases cytokine-induced apoptosis, whereas
      depletion of c-Rel blocks this process. Overexpression of RelA subunit inhibits
      caspase-8 and DR4 and DR5 expression and enhances expression of cIAP1 and c-IAP2
      after TRAIL treatment. By comparison, overexpression of c-Rel enhances DR4, DR5,
      and Bcl-X(s) and inhibits cIAP1, cIAP2, and survivin after TRAIL treatment. These
      results suggest that the RelA subunit acts as a survival factor by inhibiting
      expression of DR4/DR5 and caspase-8 and up-regulating cIAP1 and cIAP2. The dual
      function of NF-kappa B, as an inhibitor or activator of apoptosis, depends on the
      relative levels of RelA and c-Rel subunits. Thus, NF-kappa B activity may play an
      important role in tumor progression, and down-regulation of RelA or up-regulation
      of c-Rel represents a possible therapeutic target for the treatment of cancer.

PMID- 12615724
TI  - Hormone dependence in premalignant mammary progression.
AB  - Human breast cancers that are estrogen receptor (ER) negative convey a poor
      prognosis for patient survival. A mouse model that mimics essential biological
      and genetic attributes of a subset of human breast cancer is the BALB/c p53-null
      mammary epithelium, in which deletion of the tumor suppressor gene p53 results in
      enhanced tumorigenic risk. The experiments reported herein examine the hormone
      dependence of premalignant mammary progression in this model. The p53-null normal
      mammary epithelium exhibits the same dependence as p53 wild-type mammary
      epithelium on ovarian hormones for growth. However, in contrast to p53 wild-type
      epithelium, estrogen and progesterone, singly or in combination, strongly enhance
      tumorigenesis in p53-null mammary epithelium. The removal of progesterone
      signaling by deletion of the progesterone receptor eliminates progesterone
      enhancement of tumorigenesis. The immortalized premalignant outgrowth lines,
      termed PN, possess different tumorigenic capabilities, but the majority of these
      lines showed a strong dependence on ovarian hormones for growth and
      tumorigenesis. Although these lines are highly ER positive, a large number of
      tumors arising from these lines were ER negative and grew when implanted in
      ovariectomized mice. As was the case for p53-null normal mammary cells, hormonal
      stimulation was a strong promoter for tumorigenesis in the premalignant outgrowth
      lines and, surprisingly, was much stronger than the chemical carcinogen 7,12
      dimethylbenzanthracene. In summary, these results demonstrate that p53-null
      mammary cells, which generate a significant percentage of ER-negative tumors, are
      highly responsive to the absence or presence of ovarian hormones during the
      normal and premalignant stages. This model would appear an excellent one to test
      the effects of chemopreventive agents on the development of both ER-negative and
      ER-positive mammary tumors.

PMID- 12615725
TI  - The human lipid phosphate phosphatase-3 decreases the growth, survival, and
      tumorigenesis of ovarian cancer cells: validation of the lysophosphatidic acid
      signaling cascade as a target for therapy in ovarian cancer.
AB  - Lysophosphatidic acid (LPA) is present at elevated concentrations in the ascites
      and plasma of ovarian cancer patients. Ovarian cancer cells produce and release
      LPA both constitutively and after stimulation. LPA can induce proliferation,
      survival, invasiveness, and resistance to chemotherapy of ovarian cancer cells.
      This suggests that LPA may be critically important for the development or
      progression of ovarian cancer and is thus a potential target for therapy. In this
      study, we demonstrate that introduction of the integral membrane protein, human
      lipid phosphate phosphohydrolase-3 (hLPP-3) enzyme, which hydrolyzes phosphatidic
      acid, LPA, sphingosine, and ceramide phosphate in vitro with selectivity for LPA,
      into SKOV3 and OVCAR-3 ovarian cancer cells decreases colony-forming activity,
      increases apoptosis, and decreases tumor growth in vitro and in vivo. Strikingly,
      coculture of hLPP-3-expressing cells with nontransfected parental cells decreased
      the colony-forming activity of the parental cells, compatible with hLPP-3
      decreasing levels of an extracellular mediator, likely LPA. Compatible with this
      contention, the expression of hLPP-3 was associated with increased rates of
      extracellular LPA hydrolysis. The effects of hLPP-3 on colony-forming activity
      were substantially reversed by the LPP-resistant LPA analogue, O
      methylphosphothionate. The ability of O-methylphosphothionate to ameliorate the
      effects of hLPP-3, combined with the inability of an enzymatically inactive hLPP
      3 to alter cellular function, suggests that the major effect of hLPP-3 was to
      increase the hydrolysis of extracellular LPA. Thus genetic or pharmacological
      manipulation of LPA metabolism, receptor activation, or downstream signaling is
      an attractive approach for therapy of ovarian cancer.

PMID- 12615726
TI  - Transforming growth factor beta 1 stimulates vascular endothelial growth factor
      gene transcription in human cholangiocellular carcinoma cells.
AB  - The expression pattern and functional interaction of proangiogenic factors in
      human cholangiocellular carcinoma (CCC) have not been fully defined. We therefore
      investigated the expression of vascular endothelial growth factor (VEGF) and
      transforming growth factor (TGF)-beta 1 as well as their respective receptors in
      human CCC tumor samples and further analyzed their functional interaction in
      vitro. Expression of VEGF, TGF-beta 1, and their receptors was examined by
      immunohistochemistry, in situ hybridization, quantitative competitive reverse
      transcription-PCR, and ELISA. VEGF promoter analysis and identification of
      transcription factors involved in promoter regulation were investigated using
      transient transfection and electrophoretic mobility shift assays. We observed
      strong expression of VEGF in CCC tumor cells and localization of VEGF receptors 1
      and 2 in endothelial cells; in addition, coexpression of TGF-beta 1 and its
      receptors in tumor cells suggests a possible functional interaction between both
      cytokines. In vitro studies confirmed a paracrine/autocrine stimulation of VEGF
      by TGF-beta 1 at a transcriptional level. Additional molecular studies using 5'
      deletion and mutational analysis of the human VEGF promoter revealed that TGF
      beta 1 stimulates VEGF through Sp1-dependent transcriptional activation. These
      data suggest that overexpression and functional interaction of TGF-beta 1 and
      VEGF might contribute to the "angiogenic switch" and the malignant phenotype in
      human CCC.

PMID- 12615727
TI  - Bcl-w is expressed in a majority of infiltrative gastric adenocarcinomas and
      suppresses the cancer cell death by blocking stress-activated protein kinase/c
      Jun NH2-terminal kinase activation.
AB  - To determine a cellular factor supporting the survival of gastric cancer cells, a
      comparative study was performed using two human adenocarcinoma cell lines, SNU-16
      and SNU-620. The latter cells were significantly less susceptible to various
      lethal stimuli including anti-Fas, H(2)O(2), etoposide, and serum withdrawal than
      the former. These stimuli were found to kill the SNU-16 cells by activating
      stress-activated protein kinase (SAPK)/c-Jun NH(2)-terminal kinase (JNK), whereas
      SAPK/JNK activation was not efficiently induced in the SNU-620 cells. Western
      blot analysis revealed that Bcl-w, but not the other tested members of the Bcl-2
      family, was expressed in the SNU-620 cells to levels higher than that observed in
      SNU-16 cells. An elevation of the Bcl-w levels in the SNU-16 cells by its stable
      transfection attenuated both the SAPK/JNK activation and the cell death induced
      by all of the tested stimuli. These results suggest that the susceptibility of
      gastric cancer cells to death stimuli is determined, at least in part, by the
      levels of Bcl-w that suppress the cell death by blocking SAPK/JNK activation. To
      examine whether Bcl-w was expressed in patients, tumor specimens were obtained
      from 50 consecutive advanced gastric adenocarcinoma cases. An immunohistochemical
      analysis showed that Bcl-w was expressed in cancer cells but not in the
      neighboring normal mucosa of the 23 cases (46%). Interestingly, Bcl-w expression
      was associated significantly with certain histopathological characteristics of
      the cancer, notably with the infiltrative morphotypes (P < 0.001). Therefore, Bcl
      w appears to be important for gastric cancer cell survival, particularly in
      infiltrative tumors.

PMID- 12615728
TI  - Tissue microarray analysis of hepatocyte growth factor/Met pathway components
      reveals a role for Met, matriptase, and hepatocyte growth factor activator
      inhibitor 1 in the progression of node-negative breast cancer.
AB  - Numerous studies have demonstrated that overexpression of Met, the hepatocyte
      growth factor(HGF) receptor, plays an important role in tumorigenesis. Met
      activation can either occur through ligand-independent or -dependent mechanisms,
      both of which are mediated by a series of proteases and modulators. We studied
      the protein expression of several components of the HGF/Met pathway on a cohort
      of 330 node-negative breast carcinomas using a tissue microarray annotated with
      30-year, disease-specific patient follow-up data. We examined HGF, matriptase (an
      activator of HGF expressed on mammary epithelial cell surfaces), HAI-I (the
      cognate inhibitor of matriptase), and the Met receptor itself. Our studies
      demonstrate tight correlation between the expression of HGF, matriptase, and Met
      in breast carcinoma. High-level expression of Met, matriptase, and HAI-I were
      associated with poor patient outcome. Met and HAI-I showed independent prognostic
      value when compared with traditional breast markers in a multivariate analysis.
      Intriguingly, antibodies against the intracellular but not the extracellular
      domain of Met were prognostic, suggesting that overexpression of the cytoplasmic
      tail of Met, perhaps through cleavage or truncating mutation, may play an
      important role in breast cancer progression.

PMID- 12615729
TI  - Oligodendrogliomas result from the expression of an activated mutant epidermal
      growth factor receptor in a RAS transgenic mouse astrocytoma model.
AB  - A significant proportion of human malignant gliomas exhibit amplification,
      overexpression, or mutations of the epidermal growth factor receptor (EGFR). To
      define the functional role(s) of the EGFR in the pathogenesis of gliomas, we
      established transgenic mice that express both wild-type (wt) and mutant
      (EGFRvIII) EGFR molecules using the human glial fibrillary acidic protein (GFAP)
      promoter. Both GFAP-EGFR(wt) and GFAP-EGFRvIII transgenic mice demonstrated
      increased numbers of astrocytes compared with control littermates, however,
      developed normally without formation of gliomas. To determine whether EGFR
      overexpression could modify the tumor phenotype in our previously reported GFAP
      V(12)Ha-ras transgenic mouse astrocytoma model, mice expressing both activated
      RAS and EGFR were developed. GFAP-V(12)Ha-ras;GFAP-EGFRvIII, but not GFAP-V(12)Ha
      ras;GFAP-EGFR(wt) double transgenic mice, had decreased survival with fifty
      percent of the mice dead at 2-4 weeks from gliomas, compared with 12-16 weeks for
      the GFAP-V(12)Ha-ras mice. Furthermore, GFAP-V(12)Ha-ras;GFAP-EGFRvIII mice
      developed oligodendrogliomas and mixed oligoastrocytoma tumors, instead of the
      fibrillary astrocytomas observed in GFAP-V(12)Ha-ras mice. In addition to
      yielding a spontaneous model of infiltrating oligodendroglioma, this study
      demonstrates that astrocyte-specific expression of EGFRvIII alone is insufficient
      for gliomagenesis but rather contributes to glioma progression in the context of
      existing predisposing genetic changes.

PMID- 12615730
TI  - A systematic profile of DNA methylation in human cancer cell lines.
AB  - Human cancer cell lines are commonly used in basic cancer research to understand
      the behavior of primary tumors. Aberrations in the DNA methylation patterns are
      nowadays recognized as a hallmark of the cancer cell. However, no comprehensive
      study defines the DNA methylation environment present in the established cancer
      cell lines used in everyday laboratory-based research. To address this matter, we
      have analyzed 70 widely used human cancer cell lines of 12 different tumor types
      for CpG island promoter hypermethylation of 15 tumor suppressor genes, global 5
      methylcytosine genomic content, chemical response to the demethylating agent 5
      aza-2'-deoxycytidine, and their genetic haplotype for methyl-group metabolism
      genes. Several conclusions arise from our study: (a) a specific profile of CpG
      island hypermethylation exists for each tumor type, allowing its classification
      within hierarchical clusters according to the originating tissue; (b) cancer cell
      lines generally have higher levels of CpG island hypermethylation than primary
      tumors, because of the contribution of particular CpG islands and tumor types;
      and (c) there are no major differences between cell lines in their 5
      methylcytosine DNA content, efficacy of 5-aza-2'-deoxycytidine treatment, and
      distribution of allelotypes of methyl-group metabolism genes. Our data provide a
      basis for a better use of human cancer cell lines in basic and translational
      research with respect to their DNA methylation environment.

PMID- 12615731
TI  - Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells
      sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but
      reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in
      NB.
AB  - The resistance of neuroblastoma (NB) cells to tumor necrosis factor-related
      apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack
      of caspase 8 expression. Here we demonstrate a clinically applicable molecular
      targeting strategy that not only increases caspase 8 expression ex vivo in NB
      cell lines but also in the tumor tissues of NB patients receiving IFN-gamma
      treatment. We identify the functional caspase 8 promoter, which is different from
      the methylated region reported previously, and show promoter activity is up
      regulated by IFN-gamma through a IFN-gamma activation site-containing region. IFN
      gamma also induces TRAIL expression in NB cell lines. However, the IFN-gamma
      restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in
      most NB cell lines examined. This additional lesion in the TRAIL path is because
      of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but
      in most of the NB tumor tissues evaluated. Restoration of TR2 expression by
      transfection enhances IFN-gamma-induced TRAIL sensitivity. Furthermore, we have
      found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8
      with IFN-gamma and TR2 with chemotherapeutic agents.

PMID- 12615732
TI  - Coregulation of epidermal growth factor receptor/human epidermal growth factor
      receptor 2 (HER2) levels and locations: quantitative analysis of HER2
      overexpression effects.
AB  - Elevated expression of human epidermal growth factor receptor 2 (HER2) is known
      to alter cell signaling and behavioral responses implicated in tumor progression.
      However, multiple diverse mechanisms may be involved in these overall effects,
      including signaling by HER2 itself, modulation of signaling by epidermal growth
      factor receptor (EGFR), and modification of trafficking dynamics for both EGFR
      and HER2. Because these processes are so tightly interrelated, the net effect of
      HER2 overexpression is difficult to reliably attribute to any single particular
      mechanism. To take an important first step toward dissecting the effects of HER2
      overexpression on cell responses in terms of the various specific underlying
      mechanisms, we have developed and validated a quantitative model of the relevant
      trafficking processes. We then use our model for successful prediction of EGFR
      and HER2 level and location changes attributable to HER2 overexpression in 184A1
      human mammary epithelial cells expressing a series of HER2 levels by retroviral
      infection. Model predictions are based on our independent experimental
      measurement of key trafficking parameters for both EGFR and HER2. In terms of
      trafficking processes, HER2 overexpression reduces the EGFR internalization rate
      constant and increases the fraction of EGFR recycled. Consequently, our model
      successfully predicts that HER2 increases the overall level of activated EGFR by
      both enhancing its recycling and reducing its internalization, but it increases
      activated EGFR localization at the cell surface almost solely by its reduction of
      internalization. Furthermore, the model also successfully predicts the effects of
      monoclonal antibody 2C4, which interferes with HER2/EGFR heterodimerization, on
      EGFR and HER2 levels and compartmental locations. We anticipate that this model
      should ultimately be useful in parsing the relative contributions of direct
      effects of HER2 via signaling vis-a-vis indirect effects of HER2 via modification
      of EGFR signaling.

PMID- 12615733
TI  - Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1.
AB  - Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which
      mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1
      alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has
      been demonstrated in common human cancers and is correlated with tumor
      angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1
      alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma
      cells, whereas this process is inhibited by a small interfering RNA directed
      against HIF-1 alpha. We show that HIF-1 regulates the expression of genes
      encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator
      receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming
      growth factor alpha; and autocrine motility factor, which are proteins that play
      established roles in the pathophysiology of invasion. Neutralizing antibodies
      against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha
      overexpression. These results provide a molecular basis for promotion of the
      invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.

PMID- 12615735
TI  - Correspondence re: A. Muller et al., Exclusion of breast cancer as an integral
      tumor of hereditary nonpolyposis colorectal cancer. Cancer Res., 62: 1014-1019,
      2002.

PMID- 12615734
TI  - The first international conference on vascular targeting: meeting overview.
AB  - The First International Conference on Vascular Targeting focused on vascular
      targeting agents (VTAs) that occlude or destroy the pre-existing blood vessels of
      solid tumors. The VTAs cause a rapid shutdown in the blood supply to the tumor
      that kills tumor cells by depriving them of oxygen and nutrients. The VTAs are
      distinct from antiangiogenic agents, which prevent new blood vessel formation.
      Two major types of VTAs are being developed for cancer: the ligand-directed VTAs
      that use antibodies, peptides, and growth factors to deliver toxins,
      procoagulants, and proapoptotic effectors to tumor endothelium, and the small
      molecule VTAs that do not specifically localize to tumor endothelium but exploit
      pathophysiological differences between tumor and normal tissue endothelia to
      induce acute vascular shutdown in tumors. Both approaches were described at the
      meeting and highlighted the variety of VTAs in preclinical development, their
      selectivity for tumor endothelium, their rapid antitumor effects, and the
      improved activity seen when combined with other anticancer approaches
      (antiproliferative chemotherapeutic drugs, radiation, radiolabeled antibodies,
      nitric oxide synthetase inhibitors, and antiangiogenic agents). Early clinical
      studies were summarized for the small molecule VTAs: the antitubulin drugs,
      combretastatin A4 phosphate (CA4P) and ZD6126, and the flavonoid, 5,6
      dimethylxanthenone-4-acetic acid (DMXAA). The agents lacked the bone marrow and
      gastrointestinal toxicities associated with antiproliferative chemotherapy. As a
      marker of biological effect, blood flow reductions in tumors were measured using
      magnetic resonance imaging or positron emission tomography for all of the agents
      tested, and single-agent clinical activity was seen. These agents are now being
      evaluated in combined modality studies to see whether the impressive results
      obtained in experimental models can be translated into humans.

PMID- 12615736
TI  - A patchwork policy: vaccination in Canada.

PMID- 12615740
TI  - Studying delirium.

PMID- 12615741
TI  - Medical women in academia: silenced by the system.

PMID- 12615742
TI  - Medical women in academia: silenced by the system.

PMID- 12615743
TI  - Medical women in academia: silenced by the system.

PMID- 12615744
TI  - Viral genomes.

PMID- 12615746
TI  - Depression and prognosis following hospital admission because of acute myocardial
      infarction.
AB  - BACKGROUND: Whether there is an association between depression at the time of
      acute myocardial infarction and subsequent risk of cardiac complications and
      death remains controversial. Most studies of this risk factor have been limited
      to patients of single institutions, and this might account for the varying
      results. We prospectively evaluated patients admitted to 5 tertiary care and 5
      community hospitals and followed them for 1 year to measure the prevalence and
      prognostic impact of depressive symptoms after acute myocardial infarction.
      METHODS: Patients were recruited for the study by trained nurse interviewers who
      had documented acute myocardial infarction within 2-3 days of admission. The
      nurses collected information from the medical records and asked study subjects to
      complete the Beck Depression Inventory questionnaire during their stay in
      hospital and using a mailed questionnaire 30 days, 6 months and 1 year later. We
      obtained information on vital status for patients lost to follow-up from a
      central death registry. RESULTS: Of the 587 study subjects, 550 (94%) completed
      the Beck Depression Inventory at baseline and 191 (35%) had a score of 10 or
      more, indicating at least mild depression. Rates of depression did not vary over
      the follow-up period and were similar among patients admitted to tertiary care or
      community hospitals. Depressed patients were more likely to undergo
      catheterization (57% v. 47%, 95% confidence interval [CI] around the difference
      0.1%-19.6%) and were more likely to undergo percutaneous coronary intervention
      (32% v. 24%, 95% CI around the difference 0.1%-16.2%) within 30 days of first
      admission to hospital. Patients with depression on admission had higher rates of
      a composite of cardiac complications, including recurrent ischemia, infarction or
      congestive heart failure during their first stay in hospital or readmission for
      angina, recurrent acute myocardial infarction, congestive heart failure or
      arrhythmia (adjusted hazard ratio 1.4, 95% CI 1.05-1.86), compared with patients
      who were not depressed on admission. After 1 year, death rates were higher among
      patients who were depressed at admission (30 patients, 16%) compared with
      nondepressed patients (28 patients, 8%), although the difference was not
      statistically significant (hazard ratio 1.3, 95% CI 0.59-3.05). INTERPRETATION:
      Depressive symptoms are common after acute myocardial infarction and are
      associated with a slight increase in risk of in-hospital catheterization and
      angiography and readmission because of cardiac complications. Death was
      infrequent, with no statistically significant difference between the 2 groups.

PMID- 12615748
TI  - Severe hydrocephalus associated with congenital varicella syndrome.
AB  - Congenital varicella syndrome refers to the spectrum of fetal anomalies
      associated with maternal varicella zoster virus (VZV) infection during the first
      trimester of pregnancy. The syndrome is rare and the risk to the fetus uncertain.
      We describe an unusual case of congenital varicella syndrome in which
      hydrocephalus was the main consequence and likely represented VZV reactivation in
      utero.

PMID- 12615747
TI  - The striking effect of the Heart Outcomes Prevention Evaluation (HOPE) on
      ramipril prescribing in Ontario.
AB  - BACKGROUND: The Heart Outcomes Prevention Evaluation (HOPE), a Canadian-led,
      multicentre, randomized controlled trial, demonstrated the effectiveness of the
      ACE inhibitor ramipril in the secondary prevention of cardiovascular disease in
      patients who were at high risk for cardiovascular events but did not have left
      ventricular dysfunction or heart failure. We studied whether HOPE affected the
      prescribing of ACE inhibitors generally, and ramipril specifically, in Ontario,
      where the trial was coordinated. METHODS: We used linked administrative databases
      to examine prescribing patterns for ACE inhibitors in the 1.29 million to 1.54
      million elderly (aged 66 and over) residents of Ontario during the study period
      and specifically those with diabetes or congestive heart failure. For all new
      prescriptions for these drugs filled between Jan. 1, 1993, and Mar. 31, 2001, we
      conducted time-series analyses to measure any association with the release of the
      HOPE results. RESULTS: The monthly number of new prescriptions for ramipril from
      the time it was introduced in 1995 until HOPE's early termination, in April 1999,
      peaked at 58 per 100,000 elderly Ontario residents. The rate increased to
      92/100,000 in May, coincident with newspaper coverage of the trial's early
      termination, then fell back to 63/100,000 in August. After HOPE's results were
      formally released, starting Aug. 31, the rate increased significantly; it peaked
      at 304/100,000 in May 2000 (p < 0.01). The market share of ramipril among ACE
      inhibitors also increased significantly (p < 0.01), both overall and among
      patients with diabetes or congestive heart failure. INTERPRETATION: HOPE led to a
      striking and unprecedented increase, over 400%, in ramipril prescribing to
      elderly Ontario residents, including those not eligible for the trial. Many
      physicians are now prescribing ramipril for patients with diabetes or congestive
      heart failure.

PMID- 12615749
TI  - Drinking, cannabis use and driving among Ontario students.
AB  - Little is known about the risk of injury among adolescents who drive after the
      use of alcohol or cannabis or ride in cars driven by drunk drivers. We examined
      data from self-administered interviews with 1846 students in grades 7 to 13 who
      participated in the 2001 Ontario Student Drug Use Survey about their experiences
      related to alcohol, cannabis and driving during the 12 months preceding the
      survey. In all, 31.9% of the students reported being a passenger in a car driven
      by a drunk driver; of the students in grades 10 to 13 who had a driver's licence,
      15.1% reported driving within an hour after consuming 2 or more drinks, and 19.7%
      reported driving within an hour after using cannabis. Our study shows that a
      sizeable proportion of adolescents are exposed to alcohol- and drug-related
      driving risks.

PMID- 12615750
TI  - Canada needs a national immunization program: an open letter to the Honourable
      Anne McLellan, federal minister of health.

PMID- 12615751
TI  - Ramipril use in Canada: HOPE or HYPE?

PMID- 12615752
TI  - Depression and coronary artery disease: time to move from observation to trials.

PMID- 12615753
TI  - Rhythm versus rate control for atrial fibrillation management: what recent
      randomized clinical trials allow us to affirm.

PMID- 12615755
TI  - Was it something she ate? Case report and discussion of scombroid poisoning.
AB  - We report the case of a 51-year old woman who developed headache, nausea,
      palpitations, tachycardia and hypertension 30 minutes after eating a tuna fish
      salad. Elevated histamine levels in the salad helped to confirm a suspected
      diagnosis of scombroid poisoning. The signs, symptoms, pathophysiology and
      management of poisoning from spoiled scombroid fish are discussed.

PMID- 12615756
TI  - Varicella vaccine update: need for a booster?

PMID- 12615754
TI  - Diagnosis and management of Graves' disease.
AB  - Graves' disease is characterized by hyperthyroidism, diffuse goitre,
      ophthalmopathy and, rarely, dermopathy. Although diagnostic testing is
      straightforward once Graves' disease is suspected, physicians need to be aware of
      heterogeneous and even atypical presentations of the disease, particularly in
      elderly patients. Because morbidity may be associated with even subtle forms of
      hyperthyroidism, treatment promoting long-term euthyroidism is necessary.
      Although all of the available treatments are effective, compliance is best
      assured by a full discussion of the risks and benefits of each approach. This
      review focuses on issues of diagnosis and management that will allow the primary
      care physician to identify patients with Graves' disease and guide them to
      recovery.

PMID- 12615757
TI  - Cutaneous ulcer in a man returning from Central America.

PMID- 12615764
TI  - U Sask dean vows to get his medical school off probation.

PMID- 12615758
TI  - Long-term management of atrial fibrillation: rhythm or rate control?

PMID- 12615765
TI  - One country, 13 immunization programs.

PMID- 12615768
TI  - Changing face of Canada is changing the face of medicine.

PMID- 12615772
TI  - Life span can be boosted by more than a decade for many, WHO says.

PMID- 12615775
TI  - "Shore up the core," CMA tells Ottawa.

PMID- 12615777
TI  - Health Canada's food-irradiation proposal sets off debate.

PMID- 12615771
TI  - HIV testing now compulsory for new NHS staff.

PMID- 12615778
TI  - RNs: demand up, supply down.

PMID- 12615779
TI  - Quebec specialists demand wage parity, better working conditions.

PMID- 12615783
TI  - Contemporary management of paroxysmal supraventricular tachycardia.

PMID- 12615782
TI  - Nanotechnology for molecular imaging and targeted therapy.

PMID- 12615784
TI  - Antiadrenergic therapy of chronic heart failure: surprises and new opportunities.

PMID- 12615785
TI  - Serum C-reactive protein level is associated with abdominal aortic aneurysm size
      and may be produced by aneurysmal tissue.
AB  - BACKGROUND: Abdominal aortic aneurysms (AAA) are characterized by extensive
      transmural inflammation and C-reactive protein (CRP) has emerged as an
      independent risk factor for the development of cardiovascular disease. Therefore,
      we evaluated a possible association between serum CRP and aneurysm dimension in
      patients with asymptomatic AAA. Furthermore, the possibility of CRP production by
      aneurysmal tissue has been examined. METHODS AND RESULTS: Serum CRP was
      determined highly sensitive (hsCRP) and aneurysmal size was measured in 39
      patients with AAA. The presence of CRP mRNA was assessed in the aneurysmal tissue
      of 16 patients. Mean (SD) hsCRP was 3.23 (2.96) mg/L. After log-transformation,
      hsCRP correlated significantly with aneurysmal size (r=0.477, P=0.002). When the
      patients were divided into 3 equally sized groups according to hsCRP level,
      aortic diameter increased from lowest to upper hsCRP-tertile (49 mm, 61 mm, and
      67 mm, respectively; P<0.05 for 3rd versus 1st tertile). This association
      persisted after correction for risk factors. CRP mRNA was found in 25% of
      aneurysmal aortic tissues. CONCLUSIONS: This is the first report showing that
      serum hsCRP is associated with aneurysmal size and that-in at least some patients
      CRP may be produced by aneurysmal tissue. These data underscore the inflammatory
      nature of AAA formation, suggesting that serum hsCRP may serve as a marker of AAA
      disease and that CRP produced in vascular tissue might contribute to aneurysm
      formation.

PMID- 12615786
TI  - Expression and function of a biological pacemaker in canine heart.
AB  - BACKGROUND: We hypothesized that localized overexpression of the
      hyperpolarization-activated, cyclic nucleotide-gated (HCN2) pacemaker current
      isoform in canine left atrium (LA) would constitute a novel biological pacemaker.
      METHODS AND RESULTS: Adenoviral constructs of mouse HCN2 and green fluorescent
      protein (GFP) or GFP alone were injected into LA, terminal studies performed 3 to
      4 days later, hearts removed, and myocytes examined for native and expressed
      pacemaker current (I(f)). Spontaneous LA rhythms occurred after vagal stimulation
      induced sinus arrest in 4 of 4 HCN2+GFP dogs and 0 of 3 GFP dogs (P<0.05). Native
      I(f) in nonexpressed atrial myocytes was 7+/-4 pA at -130 mV (n=5), whereas
      HCN2+GFP LA had expressed pacemaker current (I(HCN2)) of 3823+/-713 pA at -125 mV
      (n=10) and 768+/-365 pA at -85 mV. CONCLUSIONS: HCN2 overexpression provides an
      I(f)-based pacemaker sufficient to drive the heart when injected into a localized
      region of atrium, offering a promising gene therapy for pacemaker disease.

PMID- 12615787
TI  - Relative intensity of physical activity and risk of coronary heart disease.
AB  - BACKGROUND: Current recommendations prescribe at least moderate-intensity
      physical activity, requiring >or=3 METs (metabolic equivalents) for >or=30
      minutes almost daily, generating approximately 1000 kcal/wk. Defining intensity
      using an absolute scale in METs may be limited because it neglects variations in
      physical fitness: an activity requiring a particular MET value commands greater
      physical effort among less fit than more fit persons. It is unknown whether
      moderate-intensity exercise, relative to an individual's capacity, is associated
      with reduced coronary heart disease (CHD) rates. METHODS AND RESULTS: We followed
      7337 men (mean age, 66 years) from 1988 to 1995. At baseline, men reported their
      actual activities and, using the Borg Scale, the perceived level of exertion when
      exercising (relative intensity). During follow-up, 551 men developed CHD. After
      multivariate adjustment, the relative risks of CHD among men who perceived their
      exercise exertion as "moderate," "somewhat strong," and "strong" or more intense
      were 0.86 (95% confidence interval, 0.66 to 1.13), 0.69 (0.51 to 0.94), and 0.72
      (0.52 to 1.00), respectively (P(trend)=0.02), compared with "weak" or less
      intense. This inverse association extended to men not fulfilling current
      recommendations, ie, expending <1000 kcal/wk in physical activity or not engaging
      in activities of >or=3 METs (P(trend)=0.03 and 0.007, respectively). CONCLUSIONS:
      There is an inverse association between relative intensity of physical activity
      (an individual's perceived level of exertion) and risk of CHD, even among men not
      satisfying current activity recommendations. Recommendations for "moderate"
      intensity physical activity may need to consider individual fitness levels
      instead of globally prescribing activities of >or=3 METs.

PMID- 12615788
TI  - No evidence of association between prothrombotic gene polymorphisms and the
      development of acute myocardial infarction at a young age.
AB  - BACKGROUND: We investigated the association between 9 polymorphisms of genes
      encoding hemostasis factors and myocardial infarction in a large sample of young
      patients chosen because they have less coronary atherosclerosis than older
      patients, and thus their disease is more likely to be related to a genetic
      predisposition to a prothrombotic state. METHODS AND RESULTS: This nationwide
      case-control study involved 1210 patients who had survived a first myocardial
      infarction at an age of <45 years who underwent coronary arteriography in 125
      coronary care units and 1210 healthy subjects matched for age, sex, and
      geographical origin. None of the 9 polymorphisms of genes encoding proteins
      involved in coagulation (G-455A beta-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A
      factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9;
      and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T
      glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: OR, 0.9;
      CI, 0.8 to 1.2), fibrinolysis (G185T factor XIII: OR, 1.2; CI, 0.9 to 1.6; and
      4G/5G plasminogen activator inhibitor type 1: OR, 0.9; CI, 0.7 to 1.2), or
      homocysteine metabolism (C677T methylenetetrahydrofolate reductase: OR, 0.9; CI,
      0.8 to 1.1) were associated with an increased or decreased risk of myocardial
      infarction. CONCLUSIONS: This study provides no evidence supporting an
      association between 9 polymorphisms of genes encoding proteins involved in
      hemostasis and the occurrence of premature myocardial infarction or protection
      against it.

PMID- 12615789
TI  - Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the
      release of soluble CD40 ligand during platelet stimulation.
AB  - BACKGROUND: Glycoprotein (GP) IIb/IIIa antagonists inhibit platelet aggregation,
      an activity attributed to the clinical benefits of these drugs in settings that
      involve acute coronary thrombosis. However, platelet activation and subsequent
      aggregation are now known to cause the release of a soluble form of CD40 ligand
      (sCD40L), a prothrombotic and proinflammatory protein with GP IIb/IIIa binding
      activity and an established role in atherosclerotic lesion progression. The
      present study was designed to determine what effect GP IIb/IIIa antagonists have
      on the release of sCD40L. METHODS AND RESULTS: Doses of eptifibatide, abciximab,
      and tirofiban that inhibited platelet aggregation by at least 80% also inhibited
      sCD40L release in vitro (by 85%, 57%, and 80%, respectively). When platelets were
      stimulated with a thrombin receptor agonist, inhibition by GP IIb/IIIa
      antagonists occurred without affecting the release of betaTG, an alpha-granule
      protein. Unexpectedly, concentrations of the 3 antagonists that blocked
      aggregation by only 20% to 50% potentiated the release of sCD40L (by 19% to 26%).
      Platelets from aspirin-treated individuals were partially protected from sCD40L
      release, but only when the agonist was collagen, an affect augmented by the
      addition of GP IIb/IIIa antagonists. CONCLUSIONS: These studies suggest that the
      mechanisms responsible for the clinical benefits of GP IIb/IIIa antagonists (at
      doses that optimally inhibit aggregation) and of aspirin may not be limited to
      the inhibition of thrombosis through their blockade of platelet aggregation but
      may also involve the inhibition of inflammation and thrombosis through their
      blockade of sCD40L release. These studies also provide a mechanism by which
      suboptimal doses of GP IIb/IIIa antagonists may be proinflammatory.

PMID- 12615790
TI  - Elevated levels of C-reactive protein and interleukin-6 in patients with
      obstructive sleep apnea syndrome are decreased by nasal continuous positive
      airway pressure.
AB  - BACKGROUND: C-reactive protein (CRP) and interleukin (IL)-6 are important risk
      factors for atherosclerosis and coronary heart disease. In the present study, we
      examined serum levels of CRP and IL-6, IL-6 production by monocytes, and the
      effect of nasal continuous positive airway pressure (nCPAP) in patients with
      obstructive sleep apnea syndrome (OSAS). METHODS AND RESULTS: After
      polysomnography, venous blood was collected at 5 AM from 30 patients with OSAS
      and 14 obese control subjects. Serum levels of CRP and IL-6 and spontaneous
      production of IL-6 by monocytes were investigated. In addition, the effects of 1
      month of nCPAP were studied in patients with moderate to severe OSAS. Levels of
      CRP and IL-6 were significantly higher in patients with OSAS than in obese
      control subjects (CRP P<0.001, IL-6 P<0.05). IL-6 production by monocytes was
      also higher in patients with OSAS than in obese control subjects (P<0.01). In
      patients with OSAS, the primary factors influencing levels of CRP were severity
      of OSAS and body mass index and those influencing levels of IL-6 were body mass
      index and nocturnal hypoxia. nCPAP significantly decreased levels of both CRP
      (P<0.0001) and IL-6 (P<0.001) and spontaneous IL-6 production by monocytes
      (P<0.01). CONCLUSIONS: Levels of CRP and IL-6 and spontaneous production of IL-6
      by monocytes are elevated in patients with OSAS but are decreased by nCPAP.
      Therefore, OSAS is associated with increased risks for cardiovascular morbidity
      and mortality, and nCPAP may be useful for decreasing these risks.

PMID- 12615791
TI  - Geometric differences of the mitral apparatus between ischemic and dilated
      cardiomyopathy with significant mitral regurgitation: real-time three-dimensional
      echocardiography study.
AB  - BACKGROUND: This study was conducted to elucidate the geometric differences of
      the mitral apparatus in patients with significant mitral regurgitation caused by
      ischemic cardiomyopathy (ICM-MR) and by idiopathic dilated cardiomyopathy (DCM
      MR) by use of real-time 3D echocardiography (RT3DE). METHODS AND RESULTS: Twenty
      six patients with ICM-MR caused by posterior infarction, 18 patients with DCM-MR,
      and 8 control subjects were studied. With the 3D software, commissure-commissure
      plane and 3 perpendicular anteroposterior (AP) planes were generated for imaging
      the medial, central, and lateral sides of the mitral valve (MV) during mid
      systole. In 3 AP planes, the angles between the annular plane and each leaflet
      (anterior, Aalpha; posterior, Palpha) were measured. In ICM-MR, Aalpha measured
      in the medial and central planes was significantly larger than that in the
      lateral plane (39+/-5 degrees, 34+/-6 degrees, and 27+/-5 degrees, respectively;
      P<0.01), whereas Palpha showed no significant difference in any of the 3 AP
      planes (61+/-7 degrees, 57+/-7 degrees, and 56+/-7 degrees, P>0.05). In DCM-MR,
      both Aalpha (38+/-8 degrees, 37+/-9 degrees, and 36+/-7 degrees, P>0.05) and
      Palpha (59+/-6 degrees, 58+/-5 degrees, and 57+/-6 degrees, P>0.05) revealed no
      significant differences in the 3 planes. CONCLUSIONS: The pattern of MV
      deformation from the medial to the lateral side was asymmetrical in ICM-MR,
      whereas it was symmetrical in DCM-MR. RT3DE is a helpful tool for differentiating
      the geometry of the mitral apparatus between these 2 different types of
      functional mitral regurgitation.

PMID- 12615792
TI  - Asymptomatic or "silent" atrial fibrillation: frequency in untreated patients and
      patients receiving azimilide.
AB  - BACKGROUND: Asymptomatic, or "silent" atrial fibrillation could increase the risk
      of stroke. Little is known about the frequency of asymptomatic atrial
      fibrillation in patients who also have symptomatic atrial fibrillation;
      similarly, little is known about the effect of antiarrhythmic drug therapy on
      asymptomatic atrial fibrillation. METHODS AND RESULTS: Patients in sinus rhythm
      with a history of symptomatic atrial fibrillation or atrial flutter received
      placebo or azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar
      double-blind trials. The end point was the first recurrence of a symptomatic ECG
      documented supraventricular arrhythmia. Routine transtelephonic
      electrocardiograms, in the absence of symptoms, were recorded for 30 seconds
      every 2 weeks until patients completed follow-up or documented a symptomatic
      supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among
      these patients receiving placebo, 303 transmitted at least one routine ECG while
      asymptomatic. Asymptomatic atrial fibrillation was recorded in 50 (17%) within 6
      months and before recurrence of symptomatic supraventricular arrhythmia. In the 3
      trials evaluating azimilide in therapeutic doses (100 and 125 mg), asymptomatic
      atrial fibrillation occurred in 49 of 382 (13%) receiving azimilide and 43 of 233
      (18%) receiving placebo. Although drug effect on time to first asymptomatic event
      was not statistically significant (hazard ratio, 0.70; P=0.09), there was a 40%
      reduction in asymptomatic atrial fibrillation on azimilide compared with placebo
      (P=0.03) when repeated observations were considered. CONCLUSIONS: Asymptomatic
      atrial fibrillation is common in untreated patients with a history of symptomatic
      atrial fibrillation (and is likely underestimated by this analysis). Azimilide
      may reduce the occurrence of this silent arrhythmia.

PMID- 12615793
TI  - Carotid arterial structure in patients with documented coronary artery disease
      and disease-free control subjects.
AB  - BACKGROUND: Although atherosclerosis often leads to lumen narrowing and
      symptomatic cardiovascular disease, it is now recognized that arteries have the
      potential to compensate by enlarging in response to atherosclerosis. We tested
      the hypotheses that carotid arterial interadventitial (IA) and lumen diameters
      were related to wall thickness and that carotid arterial diameters of individuals
      with coronary artery disease (CAD) differed from those of CAD-free controls.
      METHODS AND RESULTS: We measured lumen diameter, IA diameter, and intima-media
      thickness (IMT) using B-mode ultrasound in the common and internal carotid
      arteries of 141 CAD case patients and 139 disease-free control subjects. Common
      carotid IA diameter was greater in CAD cases than controls after adjustment for
      age, height, and sex (P<0.01). Common carotid lumen diameter was marginally
      larger in individuals with greater IMT (P=0.06) but was not associated with case
      status. Conversely, mean internal carotid IA and lumen diameters were smaller in
      CAD cases than controls in both univariable and multivariable models (both
      P<0.001), and lumina were smaller in individuals with greater IMT. Despite these
      cross-sectional differences in carotid artery dimensions, we were unable to
      detect any statistically significant interactive effects of CAD case status on
      the association of IMT with arterial dimensions. CONCLUSIONS: Internal carotid
      artery lumen and IA diameters are both smaller in CAD cases than controls. The
      association of increased IMT with arterial dimensions varies in a manner that is
      segment-specific for the common and internal carotid arteries.

PMID- 12615794
TI  - Oral health and peripheral arterial disease.
AB  - BACKGROUND: Many studies have reported the association between poor oral health
      and coronary heart disease or stroke, but few of them evaluated peripheral
      arterial disease (PAD). Hence, in this study we examined the associations between
      oral health and PAD. METHODS AND RESULTS: In the prospective study of 45,136
      eligible male health professionals free of cardiovascular diseases at baseline,
      we identified 342 cases of PAD during a 12-year follow-up period. We evaluated
      the association between different measures of oral diseases and the occurrence of
      PAD. Baseline number of teeth was not related to the risk of PAD, but cumulative
      incident tooth loss was significantly associated with elevated risk of subsequent
      occurrence of PAD. The relative risk for history of periodontal disease was 1.41
      (95% CI, 1.12 to 1.77) and for any tooth loss during the follow-up period was
      1.39 (95% CI, 1.07 to 1.82), controlling for traditional risk factors of
      cardiovascular disease. Among men with a history of periodontal diseases, the
      relative risk of tooth loss increased to 1.88 (95% CI, 1.27 to 2.77), whereas no
      association was found between tooth loss and PAD among those without periodontal
      diseases (RR, 0.92; 95% CI, 0.61 to 1.38). We further explored the potential
      induction period of tooth loss and found that tooth loss in the previous 2 to 6
      years was most strongly associated with PAD. CONCLUSIONS: We found that incident
      tooth loss was significantly associated with PAD, especially among men with
      periodontal diseases. The results support a potential oral infection-inflammation
      pathway.

PMID- 12615795
TI  - Intramural hematoma of the aorta: predictors of progression to dissection and
      rupture.
AB  - BACKGROUND: Aortic intramural hematoma (IMH) is a variant of overt aortic
      dissection. The predictors of progression of IMH to dissection and rupture are
      still unknown, and strategies for management are not established. METHODS AND
      RESULTS: A multicenter study was conducted comprising 66 patients with IMH and
      hospital admission <or=48 hours after onset of initial symptoms. Among these,
      progression to aortic dissection or rupture occurred in 30 (45%) and death
      occurred in 13 (20%) patients within 30 days. Late progression was noted in 14
      (21%) and death in 11 (17%) patients, yielding a 1-, 2-, and 5-year survival of
      76%, 73%, and 43%, respectively. In a set of 9 variables, multivariate analysis
      identified IMH location in the ascending aorta (type A; P=0.02) and moderately
      ectatic aortic diameters (49+/-13 mm with progression versus 57+/-16 mm without
      progression; P=0.03) as independent predictors of early progression. In type A
      IMH, early mortality was 8% with swift surgery versus 55% without surgery
      (P=0.004). The risk of late progression of IMH was independently associated with
      age at index diagnosis (P=0.01) and absence of beta-blocker therapy during follow
      up (P=0.03). Kaplan-Meier analysis confirmed improved 1-year survival of IMH with
      beta-blocker therapy (95% versus 67% without beta-blockers; P=0.004).
      CONCLUSIONS: Regardless of aortic diameter, IMH of the ascending aorta (type A)
      is at high risk for early progression, and, thus, undelayed surgical repair
      should be performed. Moreover, oral beta-blocker therapy may improve long-term
      prognosis of IMH independent of anatomical location.

PMID- 12615796
TI  - Peripheral blood "endothelial progenitor cells" are derived from
      monocyte/macrophages and secrete angiogenic growth factors.
AB  - BACKGROUND: Endothelial progenitor cells (EPCs) have been isolated from
      peripheral blood and can enhance angiogenesis after infusion into host animals.
      It is not known whether the proangiogenic effects are a result of such events as
      endothelial differentiation and subsequent proliferation of EPCs or secondary to
      secretion of angiogenic growth factors. METHODS AND RESULTS: Human EPCs were
      isolated as previously described, and their phenotypes were confirmed by uptake
      of acetylated LDL and binding of ulex-lectin. EPC proliferation and surface
      marker expression were analyzed by flow cytometry, and conditioned medium was
      assayed for growth factors. The majority of EPCs expressed monocyte/macrophage
      markers such as CD14 (95.7+/-0.3%), Mac-1 (57.6+/-13.5%), and CD11c (90.8+/
      4.9%). A much lower percentage of cells expressed the specific endothelial marker
      VE-cadherin (5.2+/-0.7%) or stem/progenitor-cell markers AC133 (0.16+/-0.05%) and
      c-kit (1.3+/-0.7%). Compared with circulating monocytes, cultured EPCs showed
      upregulation of monocyte activation and macrophage differentiation markers. EPCs
      did not demonstrate any significant proliferation but did secrete the angiogenic
      growth factors vascular endothelial growth factor, hepatocyte growth factor,
      granulocyte colony-stimulating factor, and granulocyte-macrophage colony
      stimulating factor. CONCLUSIONS: Our findings suggest that acetylated LDL(+)ulex
      lectin(+) cells, commonly referred to as EPCs, do not proliferate but release
      potent proangiogenic growth factors. The majority of acetylated LDL(+)ulex
      lectin(+) cells are derived from monocyte/macrophages. The findings of low
      proliferation and endothelial differentiation suggest that their angiogenic
      effects are most likely mediated by growth factor secretion. These findings may
      allow for development of novel angiogenic therapies relying on secreted growth
      factors or on recruitment of endogenous monocytes/macrophages to sites of
      ischemia.

PMID- 12615797
TI  - Decreased efficiency of adenovirus-mediated gene transfer in aging
      cardiomyocytes.
AB  - BACKGROUND: Aging is an independent risk factor for the development of
      cardiovascular disease. Clinical application of myocardial gene transfer may be
      best suited in the elderly. In vivo gene transfer by adenovirus is less efficient
      in aging myocardium. METHODS AND RESULTS: When infected with adenovirus
      containing beta-galactosidase (beta-gal) and green fluorescent protein (GFP)
      driven by cytomegalovirus promoters in vitro, aging rat cardiac myocytes exhibit
      significantly lower infectivity and delayed transgene expression compared with
      adult controls. Abnormalities of viral internalization may be one mechanism
      accounting for this difference. To investigate this, we studied expression levels
      of the coxsackievirus and adenovirus receptor (CAR) as well as other potential
      integrins involved in the internalization of adenoviruses. CAR expression tended
      to be upregulated whereas among potential integrins, alpha(3)beta(1) was
      downregulated in aging cardiac myocytes. Blocking the beta(1) component of
      alpha(3)beta(1) further decreased infectivity, suggesting that the interaction
      between the penton base of the adenovirus and beta(1) maybe a crucial component
      of the viral entry mechanism. CONCLUSIONS: These results suggest that it is
      integrin-stimulated internalization rather than the adenovirus-CAR interaction
      that plays a vital role in adenoviral entry. The downregulation of integrins
      observed in senescent cells may be a key mechanism accounting for the decrease in
      viral infectivity seen in these cells. These findings have implications for the
      gene therapy treatment of myocardial failure in the elderly.

PMID- 12615798
TI  - Contractile reserve and calcium regulation are depressed in myocytes from
      chronically unloaded hearts.
AB  - BACKGROUND: Chronic cardiac unloading of the normal heart results in the
      reduction of left ventricular (LV) mass, but effects on myocyte contractile
      function are not known. METHODS AND RESULTS: Cardiac unloading and reduction in
      LV mass were induced by heterotopic heart transplantation to the abdominal aorta
      in isogenic rats. Contractility and [Ca(2+)](i) regulation in LV myocytes were
      studied at both 2 and 5 weeks after transplantation. Native in situ hearts from
      recipient animals were used as the controls for all experiments. Contractile
      function indices in myocytes from 2-week unloaded and native (control) hearts
      were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca(2+)](o), and 36
      degrees C) and in response to stimulation with high [Ca(2+)](o) (range 2.5 to 4.0
      mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in
      fractional cell shortening and peak-systolic [Ca(2+)](i) at baseline; however,
      time to 50% relengthening and time to 50% decline in [Ca(2+)](i) were prolonged
      compared with controls. Severe defects in fractional cell shortening and peak
      systolic [Ca(2+)](i) were elicited in myocytes from 5-week unloaded hearts in
      response to high [Ca(2+)](o). However, there were no differences in the
      contractile response to isoproterenol between myocytes from unloaded and native
      hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein
      levels of phospholamban were increased (345% of native heart values). Protein
      levels of sarcoplasmic reticulum Ca(2+) ATPase and the Na(+)/Ca(2+) exchanger
      were not changed. CONCLUSIONS: Chronic unloading of the normal heart caused a
      time-dependent depression of myocyte contractile function, suggesting the
      potential for impaired performance in states associated with prolonged cardiac
      atrophy.

PMID- 12615800
TI  - Efferent vagal fibre stimulation blunts nuclear factor-kappaB activation and
      protects against hypovolemic hemorrhagic shock.
AB  - BACKGROUND: We investigated whether electrical stimulation (STIM) of efferent
      vagus nerves may suppress nuclear factor (NF)-kappaB activation and the
      inflammatory cascade in hemorrhagic (Hem) shock. METHODS AND RESULTS: Rats were
      subjected to bilateral cervical vagotomy (VGX) or sham surgical procedures. Hem
      shock was induced by intermittent withdrawing of blood until mean arterial
      pressure stabilized within the range of 35 to 40 mm Hg. Application of constant
      voltage pulses to the caudal vagus ends (STIM; 5 V, 2 ms, 1 Hz for 12 minutes, 5
      minutes after mean arterial pressure stabilization) increased survival time
      (VGX+Hem+Sham STIM=38+/-3 minutes; VGX+Hem+STIM >180 minutes), reverted the
      marked hypotension (VGX+Hem+Sham STIM=33+/-3 mm Hg; VGX+Hem+STIM=66+/-5 mm Hg),
      inhibited IkappaBalpha liver loss, and blunted the augmented NF-kappaB activity,
      decreased hepatic tumor necrosis factor (TNF)-alpha mRNA (VGX+Hem+Sham
      STIM=1.42+/-0.5 amount of TNF-alpha m-RNA; VGX+Hem+STIM=0.51+/-0.2 amount of TNF
      alpha mRNA), and reduced plasma TNF-alpha (VGX+Hem+Sham STIM=190+/-24 pg/mL;
      VGX+Hem+STIM=87+/-15 pg/mL). Chlorisondamine, a nicotinic receptor antagonist,
      abated the effects of vagal stimulation. CONCLUSIONS: Our results show a
      parasympathetic inhibition of NF-kappaB by which the brain opposes NF-kappaB
      activation in the liver and modulates the inflammatory response during acute
      hypovolemic hemorrhagic shock.

PMID- 12615799
TI  - MCC-134, a single pharmacophore, opens surface ATP-sensitive potassium channels,
      blocks mitochondrial ATP-sensitive potassium channels, and suppresses
      preconditioning.
AB  - BACKGROUND: MCC-134 (1-[4-(H-imidazol-1-yl)benzoyl]-N-methylcyclobutane
      carbothioamide), a newly developed analog of aprikalim, opens surface smooth
      muscle-type ATP-sensitive potassium (K(ATP)) channels but inhibits pancreatic
      K(ATP) channels. However, the effects of MCC-134 on cardiac surface K(ATP)
      channels and mitochondrial K(ATP) (mitoK(ATP)) channels are unknown. A mixed
      agonist/blocker with differential effects on the two channel types would help to
      clarify the role of K(ATP) channels in cardioprotection. METHODS AND RESULTS: To
      index mitoK(ATP) channels, we measured mitochondrial flavoprotein fluorescence in
      rabbit ventricular myocytes. MCC-134 alone had little effect on basal
      flavoprotein fluorescence. However, MCC-134 inhibited diazoxide-induced
      flavoprotein oxidation in a dose-dependent manner (EC(50)=27 micro mol/L). When
      ATP was included in the pipette solution, MCC-134 slowly activated surface K(ATP)
      currents with some delay (>10 minutes). These results indicate that MCC-134 is a
      mitoK(ATP) channel inhibitor and a surface K(ATP) channel opener in native
      cardiac cells. In cell-pelleting ischemia assays, coapplication of MCC-134 with
      diazoxide abolished the cardioprotective effect of diazoxide, whereas MCC-134
      alone did not alter cell death. These results were reproducible in both rabbit
      and mouse myocytes. MCC-134 also attenuated the effect of ischemic
      preconditioning against myocardial infarction in mice, consistent with the
      results of cell-pelleting ischemia assays. CONCLUSIONS: A single drug, MCC-134,
      opens surface K(ATP) channels but blocks mitoK(ATP) channels; the fact that this
      drug inhibits preconditioning reaffirms the primacy of mitoK(ATP) rather than
      surface K(ATP), channels in the mechanism of cardioprotection.

PMID- 12615801
TI  - Metabolism of asymmetric dimethylarginines is regulated in the lung
      developmentally and with pulmonary hypertension induced by hypobaric hypoxia.
AB  - BACKGROUND: Nitric oxide (NO) plays an important part in lowering pulmonary
      vascular resistance after birth, and in persistent pulmonary hypertension of the
      newborn (PPHN), NO-mediated dilation is dysfunctional. The endogenous NO synthase
      inhibitor asymmetric dimethylarginine (ADMA) circulates in plasma, and its
      concentrations are elevated in certain cardiovascular diseases, including
      pulmonary hypertension. ADMA is metabolized by the enzyme dimethylarginine
      dimethylaminohydrolase (DDAH), the activity of which regulates ADMA
      concentrations and provides a mechanism for modulating NO synthase in vivo. We
      investigated the changes in expression and activity of the 2 isoforms of DDAH in
      lungs from newborn piglets both during normal development and in PPHN. METHODS
      AND RESULTS: Using Western blotting, we showed that DDAHI expression did not
      change in the normal developing lung; however, DDAHII increased after birth and
      reached a peak at 1 day. This was reflected in an increase in total DDAH activity
      according to an L-citrulline assay. With pulmonary hypertension, no changes in
      DDAHI expression were observed, but DDAHII expression was markedly decreased
      compared with age-matched controls. Total DDAH activity was similarly reduced.
      CONCLUSIONS: These results indicate that each DDAH isoform is differentially
      regulated during both lung development and PPHN. Suppression of DDAHII isoform
      expression may be a mechanism underlying PPHN.

PMID- 12615802
TI  - Diesel exhaust particles in lung acutely enhance experimental peripheral
      thrombosis.
AB  - BACKGROUND: Pollution by particulates has consistently been associated with
      increased cardiovascular morbidity and mortality, but a plausible biological
      basis for this association is lacking. METHODS AND RESULTS: Diesel exhaust
      particles (DEPs) were instilled into the trachea of hamsters, and blood platelet
      activation, experimental thrombosis, and lung inflammation were studied. Doses of
      5 to 500 micro g of DEPs per animal induced neutrophil influx into the
      bronchoalveolar lavage fluid with elevation of protein and histamine but without
      lactate dehydrogenase release. The same doses enhanced experimental arterial and
      venous platelet rich-thrombus formation in vivo. Blood samples taken from
      hamsters 30 and 60 minutes after instillation of 50 micro g of DEPs yielded
      accelerated aperture closure (ie, platelet activation) ex vivo, when analyzed in
      the Platelet Function Analyser (PFA-100). The direct addition of as little as 0.5
      micro g/mL DEPs to untreated hamster blood significantly shortened closure time
      in vitro. CONCLUSIONS: The intratracheal instillation of DEPs leads to lung
      inflammation as well as a rapid activation of circulating blood platelets. The
      kinetics of platelet activation are consistent with the reported clinical
      occurrence of thrombotic complications after exposure to pollutants. Our
      findings, therefore, provide a plausible explanation for the increase in
      cardiovascular morbidity and mortality accompanying urban air pollution.

PMID- 12615803
TI  - Image in cardiovascular medicine. Coronary artery imaging with flat-panel
      computed tomography.

PMID- 12615804
TI  - Exercise and heart failure: A statement from the American Heart Association
      Committee on exercise, rehabilitation, and prevention.

PMID- 12615805
TI  - Image in cardiovascular medicine. Needle in the heart.

PMID- 12615807
TI  - Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues
      in new uses of preimplantation genetic diagnosis.
AB  - The use of preimplantation genetic diagnosis (PGD) to screen embryos for
      aneuploidy and genetic disease is growing. New uses of PGD have been reported in
      the past year for screening embryos for susceptibility to cancer, for late-onset
      diseases, for HLA-matching for existing children, and for gender. These
      extensions have raised questions about their ethical acceptability and the
      adequacy of regulatory structures to review new uses. This article describes
      current and likely future uses of PGD, and then analyses the ethical issues posed
      by new uses of PGD to screen embryos for susceptibility and late-onset
      conditions, for HLA-matching for tissue donation to an existing child, and for
      gender selection. It also addresses ethical issues that would arise in more
      speculative scenarios of selecting embryos for hearing ability or sexual
      orientation. The article concludes that except for sex selection of the first
      child, most current extensions of PGD are ethically acceptable, and provides a
      framework for evaluating future extensions for nonmedical purposes that are still
      speculative.

PMID- 12615808
TI  - Reproductive semi-cloning respecting biparental origin. A biologically unsound
      principle.
AB  - The original debate article proposed the use of "semi-cloning" as a viable method
      for assisted reproduction. This debate counters the proposal as being
      biologically unsound. Given the fundamental limitations of chromosomal
      segregation and genomic imprinting, the notion of using the MII oocyte to drive
      haploidization of a somatic cell genome and thereby obtain a substitute for
      authentic gametes is ill-conceived and untenable.

PMID- 12615809
TI  - Reproductive semi-cloning respecting biparental origin. Reconstitution of gametes
      for assisted reproduction.
AB  - There are basically two major problems in the genesis of "cloned" gametes in
      mammals, which have not been addressed in the original debate article. There is
      no adequate discussion on the mechanisms providing for high fidelity of
      chromosome segregation in mitosis and meiosis, and for proper imprinting in
      construction of "reconstituted gametes". The original debate article is
      uncritical with respect to the currently insufficient database and the incomplete
      documentation of results.

PMID- 12615810
TI  - Bye-bye urinary gonadotrophins? Recombinant FSH: a real progress in ovulation
      induction and IVF?
AB  - Whether recombinant gonadotrophin products do, indeed, represent progress for
      routine ovulation induction and IVF cycles, in comparison with urinary products,
      has remained controversial. Here we review published data with regard to
      respective risks, outcomes and cost for both medication options. Safety
      considerations favour recombinant products, while overall outcome and cost
      considerations favour urinary gonadotrophins. Outcome, however, appears to
      differ, based on age and ovarian function, with younger patients benefiting from
      the FSH/LH combination offered by urinary products, while older women and young
      women with ovarian resistance, apparently benefiting from pure FSH stimulation.
      Young women with poor ovarian reserve may be best stimulated with a pure
      FSH/antagonist protocol. We conclude that under current pricing structures in the
      United States, recombinant gonadotrophins do not represent a major progress for
      the treatments of ovulation induction and IVF. They, however, allow for an
      improved selectivity of stimulation protocols. The creation of recombinant FSH/LH
      products and cost adjustments for recombinant products, may affect these
      conclusions in favour of recombinant products.

PMID- 12615811
TI  - The IVF league tables: time for a reality check.
AB  - In many countries the reported results of the different IVF clinics are published
      nationally by the relevant regulatory bodies, such as the Human Fertilisation and
      Embryology Authority in the UK. The published format suggests that clinics are
      being compared on a valid basis, and the involvement of the regulatory bodies
      apparently gives this comparison the official seal of authenticity. However,
      clinics can control many factors in patient selection, management and reporting,
      and these can inflate the reported results. Consequently, patients, instead of
      being appropriately guided, can be misled by these so-called "IVF league tables".
      The IVF community, including users, providers and regulatory bodies, need to
      recognize these factors and to develop a way forward for comparing clinics
      results on an equal and a valid basis. In this paper we discuss the factors that
      could affect the reported IVF results, and suggest possible options for valid
      comparison.

PMID- 12615812
TI  - Phytoestrogens inhibit aromatase but not 17beta-hydroxysteroid dehydrogenase
      (HSD) type 1 in human granulosa-luteal cells: evidence for FSH induction of
      17beta-HSD.
AB  - BACKGROUND: Studies using purified enzyme preparations, placental microsomes or
      cell lines have shown that certain phytoestrogens can inhibit the enzymes that
      convert androgens to estrogens, namely aromatase and 17beta-hydroxysteroid
      dehydrogenase (HSD) type 1 and type 5. The study aim was to investigate the
      effects of selected phytoestrogens on aromatase and 17beta-HSD type 1 activity in
      primary cultures of human granulosa-luteal (GL) cells. METHODS AND RESULTS: GL
      cells, cultured for 48 h in medium containing 5% fetal calf serum and for a
      further 24 h in serum-free medium with or without hFSH or hCG, were exposed to
      steroid substrates during the last 1-4 h of the experiment. The production of
      progesterone in the presence of pregnenolone or estradiol synthesis from
      androstenedione, estrone or testosterone showed dose- and time-dependent
      increases. Whilst hCG priming had no effect on progesterone production, FSH
      priming induced mean 68 and 56% increases in the production of estradiol from
      androstenedione (A-dione) and estrone respectively, but had no significant effect
      on the metabolism of testosterone to estradiol. None of the phytoestrogens
      investigated had any acute effects on enzyme activity. In contrast, when GL cells
      were exposed to the compounds for 24 h prior to exposure to steroid substrates
      for 4 h, 10 micro mol/l apigenin and zearalenone significantly inhibited
      aromatase activity, whilst biochanin A and quercetin had no effect. None of the
      phytoestrogens inhibited FSH-induced 17beta-HSD type 1 activity, and only
      quercetin significantly inhibited progesterone production. CONCLUSIONS: The
      inability of phytoestrogens to acutely inhibit steroidogenic enzymes in human GL
      cells (as has been shown in cell-free models) suggests that they are either
      rapidly metabolized to relatively inactive compounds or that the high enzyme
      activity in human GL cells masks any inhibitory effects of the compounds at the
      concentration tested.

PMID- 12615813
TI  - Do cycle disturbances explain the age-related decline of female fertility? Cycle
      characteristics of women aged over 40 years compared with a reference population
      of young women.
AB  - BACKGROUND: The cause of declining fertility with age, in women who still have
      regular menstrual cycles, is not clear. METHODS: Follicle development,
      endometrial growth and hormonal patterns were evaluated in cycles of older women
      (aged 41-46 years; n = 26) who previously were normally fertile, and these cycles
      were compared with a reference group of relatively young fertile women (aged 22
      34 years; n = 35). RESULTS: Clearly abnormal cycles were found in only two women
      in the older age group, and in one woman in the younger group. The main
      differences between the age groups were a shorter follicular phase and cycle
      length in the older group, in combination with higher FSH levels in the late
      luteal and early follicular phase. In contrast to published data which suggest an
      "accelerated" follicle development in older women, sonographical and hormonal
      evidence was found of an "advanced" follicle growth, with an earlier start
      already during the luteal phase of the preceding cycle, and an advanced selection
      and ovulation of the dominant follicle. CONCLUSIONS: Such an earlier start of
      follicle growth in a possibly less favourable hormonal environment, as well as a
      limited oocyte pool, may contribute to a decreased follicle and oocyte quality,
      resulting in diminished fertility in ageing women.

PMID- 12615814
TI  - Pseudo-isolated FSH deficiency caused by an inhibin B-secreting granulosa cell
      tumour: case report.
AB  - Isolated FSH deficiency due to a mutation in the FSHbeta subunit is characterized
      by an extremely low serum FSH concentration. We report a patient who presented
      with an FSH of 0.8 mIU/ml and infertility associated with anovulation.
      Endocrinological assessment and immunohistochemistry revealed that a granulosa
      cell tumour was secreting inhibin B and suppressing FSH; however, LH and
      estradiol were within their normal ranges. Upon removal of the tumour, inhibin B
      decreased and FSH levels rose to normal values. The patient subsequently
      conceived and delivered successfully. Based on this case and on those previously
      described in the literature, we suggest that inhibin B levels should be evaluated
      in anovulatory patients having a clinical presentation consistent with functional
      hypothalamic amenorrhoea and very low to normal values of FSH.

PMID- 12615815
TI  - Acquired haemophilia due to factor VIII inhibitors in ovarian hyperstimulation
      syndrome: case report.
AB  - A 31-year-old nulligravida woman developed an acquired factor VIII inhibitor
      associated with severe ovarian hyperstimulation syndrome (OHSS). She developed
      haematouria, ecchymosis, and intramuscular bleeding following the severe OHSS.
      Laboratory examinations showed a markedly prolonged activated partial
      thromboplastin time and a low level of factor VIII activity. Treatment with
      prothrombin complex concentrate and factor VIII inhibitor bypassing agent was
      successful in reducing the inhibitor so that she delivered a healthy baby via
      spontaneous vaginal delivery. Acquired haemophilia is a life-threatening
      disorder. This is the first case report of acquired haemophilia in OHSS.

PMID- 12615816
TI  - Preimplantation genetic diagnosis for achondroplasia: genetics and gynaecological
      limits and difficulties.
AB  - BACKGROUND: We report the first attempts at preimplantation genetic diagnosis
      (PGD) and IVF and their accompanying difficulties for achondroplasia (ACH)
      patients. METHODS: A PGD test was developed using fluorescent single cell PCR on
      lymphoblasts from patients and controls and from blastomeres from surplus IVF
      embryos. A specific digestion control based on the use of two fluorochromes was
      elaborated. Ovarian stimulation and oocyte retrieval were carried out using
      conventional protocols. RESULTS: We performed 88 single cell tests for which
      amplification was obtained in 86 (97.7%) single lymphoblasts. Allele drop out
      (ADO) was observed in two out of 53 (3.7%) heterozygous lymphoblasts. If we
      combine the results from the blastomere testing from surplus embryos with those
      from PGD cycles and re-analysis after PGD, we obtained a PCR signal in 84% of
      cases of which 91% were correctly diagnosed at the G380 locus. A total of six
      cycles were performed resulting in three embryo transfers. We observed
      difficulties in ovarian stimulation and oocyte retrieval with affected female
      patients. No pregnancy was obtained. CONCLUSION: A PGD test for ACH is now
      available at our centre but our initial practice raises questions on the
      feasibility of such a test, specially with affected female patients.

PMID- 12615817
TI  - Differences in the use of combined oral contraceptives amongst women with and
      without acne.
AB  - BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) provides
      a treatment option for women with acne, hirsutism or polycystic ovary syndrome
      (PCOS). CPA/EE may be prescribed as an oral contraceptive (OC), but is not
      licensed as such in the UK. The use of CPA/EE steadily increased after its
      introduction to the UK market in 1987, but there was a marked increase in its
      share of the OC market after 1995. METHODS: Using the General Practice Research
      Database, utilization patterns of CPA/EE and conventional oral contraceptives
      were compared in women aged 15-39 years, with or without acne or PCOS. RESULTS:
      Between 1994 and 1998, CPA/EE accounted for an increasing proportion of all OC
      use. The proportion of CPA/EE prescribed to women with acne declined between 1994
      and 1998, whereas that prescribed to women with PCOS remained constant. The age
      specific use of CPA/EE by women with acne or PCOS almost doubled. After 1995,
      there was a marked increase in the use of products containing levonorgestrel by
      women with acne or PCOS. CONCLUSIONS: A large proportion of CPA/EE is prescribed
      to women with acne and/or PCOS, although this proportion decreased between 1992
      and 1998. This has important implications in CPA/EE risk assessment studies.

PMID- 12615818
TI  - The risk of venous thromboembolism in women prescribed cyproterone acetate in
      combination with ethinyl estradiol: a nested cohort analysis and case-control
      study.
AB  - BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) is
      licensed in the UK for the treatment of women with acne and hirsutism and is also
      a treatment option for polycystic ovary syndrome (PCOS). Previous studies have
      demonstrated an increased risk of venous thromboembolism (VTE) associated with
      CPA/EE compared with conventional combined oral contraceptives (COCs). We believe
      the results of those studies may have been affected by residual confounding.
      METHODS: Using the General Practice Research Database we conducted a cohort
      analysis and case-control study nested within a population of women aged between
      15 and 39 years with acne, hirsutism or PCOS to estimate the risk of VTE
      associated with CPA/EE. RESULTS: The age-adjusted incidence rate ratio for CPA/EE
      versus conventional COCs was 2.20 [95% confidence interval (CI) 1.35-3.58]. Using
      as the reference group women who were not using oral contraception, had no recent
      pregnancy or menopausal symptoms, the case-control analysis gave an adjusted odds
      ratio (OR(adj)) of 7.44 (95% CI 3.67-15.08) for CPA/EE use compared with an
      OR(adj) of 2.58 (95% CI 1.60-4.18) for use of conventional COCs. CONCLUSIONS: We
      have demonstrated an increased risk of VTE associated with the use of CPA/EE in
      women with acne, hirsutism or PCOS although residual confounding by indication
      cannot be excluded.

PMID- 12615819
TI  - Poor response to ovulation induction is a stronger predictor of early menopause
      than elevated basal FSH: a life table analysis.
AB  - BACKGROUND: During the course of assisted reproduction treatment, a number of
      women exhibit a "poor response" to ovulation induction, or demonstrate an
      elevated basal FSH level (> or =10 IU/l) at a young age. We sought to determine
      whether these women are at increased risk of early menopause and poor
      reproductive performance. METHODS: A retrospective cohort study included 118
      "poor responders" with normal basal FSH level (<10 IU/l), 164 women with raised
      basal FSH (> or =10 IU/l), and 265 controls, who underwent assisted reproduction
      treatment between 1987 and 1998. All women were < 40 years of age at the time of
      treatment and had normal menstrual cycles. Participants were sent a postal
      questionnaire in 2000-2001, seeking information on ovarian function and
      reproductive performance following cessation of treatment. RESULTS: After
      adjusting for age and smoking habits, women with poor response and raised basal
      FSH levels were more likely to experience symptoms of the peri-menopause [hazard
      ratios 2.4, 95% confidence interval (CI) 1.52-3.78, and 2.76, 95% CI 1.78-4.29
      respectively, P = 0.0001]. Poor responders were six times and 23 times more
      likely to experience the menopause within 10 years of treatment than those with
      raised basal FSH levels and controls respectively (hazard ratio 5.97 and 23.9, P
      = 0.015 and 0.002 respectively). Poor responders and those with raised basal FSH
      levels have half the chance of spontaneous conception after discontinuation of
      treatment compared with controls (P < 0.007). CONCLUSIONS: Both poor response to
      ovarian stimulation and raised basal FSH are markers of reduced ovarian reserve
      and predict an increased risk of early menopause.

PMID- 12615820
TI  - The significance of the ionophore-challenged acrosome reaction in the prediction
      of successful outcome of controlled ovarian stimulation and intrauterine
      insemination.
AB  - BACKGROUND: This prospective study compared the acrosome reaction following
      ionophore challenge (ARIC) versus conventional sperm parameters and sperm
      velocities in predicting successful outcome following ovarian stimulation and
      intrauterine insemination. METHODS: All patients were offered a maximum of three
      treatment cycles. Conventional semen analysis was performed and sperm velocities
      were measured using computer-aided sperm analysis. Acrosome-reacted sperm were
      stained using chlortetracycline after ionophore challenge. Multiple logistic
      regression analysis and the receiver-operator characteristic curve analysis were
      applied to determine the best predictive variables and their cut-off values.
      RESULTS: ARIC score was the most significant variable in predicting pregnancy,
      followed by the percentage of induced acrosome-reacted sperm, serum estradiol
      levels on the day of hCG and sperm morphology by strict criteria. Higher
      spontaneous acrosome reaction had a negative relationship with pregnancy. ARIC
      score of 10% had a sensitivity of 85.3% and a specificity of 85.5%. The positive
      and negative predictive values were 64.2 and 96.6% respectively and the false
      positive and negative rates were 14.7 and 14.5% respectively. CONCLUSION: ARIC
      score was a better predictor of pregnancy than conventional sperm parameters and
      sperm velocities.

PMID- 12615821
TI  - Polymorphism in the peroxisome proliferator-activated receptor-gamma gene in
      women with polycystic ovary syndrome.
AB  - BACKGROUND: In view of the strong evidence implicating peroxisome proliferator
      activated receptor-gamma (PPARgamma) in adiposity and insulin resistance a study
      was carried out to investigate PPARgamma genotype frequencies in women with
      polycystic ovary syndrome (PCOS) and to elucidate its role in the pathogenesis of
      the syndrome. METHODS: The study involved 135 women with PCOS and 115 healthy
      control women who were genotyped for a known functional variant of the PPARgamma
      gene using single strand conformation polymorphism (SSCP) analysis. RESULTS: A
      significantly different allele distribution of the Pro12 Ala polymorphism of the
      PPARgamma gene was observed between the two groups, with the frequency of the
      variant Ala isoform being significantly reduced in the PCOS group (12.6%) when
      compared with the control group (19.1%) (P = 0.045), at an odds ratio of 0.609
      (95% confidence interval: 0.374-0.991). The genotype distributions of the Pro12
      Ala polymorphism in the PCOS and control groups were different with borderline
      significance (P = 0.051). CONCLUSIONS: Our data support a role for PPARgamma gene
      polymorphism in the pathogenesis of PCOS, the presence of the Ala isoform being
      protective against the development of PCOS.

PMID- 12615822
TI  - An association of IgG anti-laminin-1 autoantibodies with endometriosis in
      infertile patients.
AB  - BACKGROUND: Laminin-1, a multifunctional glycoprotein of the basement membrane,
      is thought to be important in embryogenesis, embryonic implantation, and
      placentation. We recently showed that serum IgG anti-laminin-1 autoantibodies
      (auto-Abs) are associated with recurrent first-trimester miscarriages. The
      present study assessed the clinical significance of anti-laminin-1 Abs with
      infertility, accompanied with or without endometriosis. METHODS: Sixty-eight
      infertile patients who underwent laparoscopy or laparotomy and 39 healthy non
      pregnant women were tested for IgG anti-laminin-1 Abs. The association between
      the Abs and endometriosis was analysed. The presence of laminin-1 mRNA was
      detected in endometriotic lesions. RESULTS: Twenty infertile patients were
      positive for anti-laminin-1 Abs. The Ab levels in those patients were
      significantly higher than those in healthy non-pregnant women (P = 0.0005). The
      presence of the Abs was significantly associated with endometriosis in those
      patients (P = 0.0096). The Abs recognized a particular domain, i.e., the laminin
      alpha1 chain G domain. mRNA encoding laminin-alpha1, -beta1, and -gamma1 chains
      was expressed in 90% of endometriotic lesions. CONCLUSIONS: IgG anti-laminin-1
      Abs were significantly associated with endometriosis in infertile patients. The
      Abs might be clinically important in the development of autoimmune-mediated
      reproductive failures and the assessment of the Abs may provide a novel non
      invasive diagnosis of endometriosis.

PMID- 12615823
TI  - Increased sperm mitochondrial DNA content in male infertility.
AB  - BACKGROUND: There is increasing evidence that mitochondrial DNA (mtDNA) anomalies
      in sperm may lead to infertility. Point mutations, deletions and the presence of
      a specific mtDNA haplogroup have been associated with poor sperm quality, but
      little attention has been paid to the role of mtDNA content. METHODS: Using
      density gradient separation and swim-up methods, we selected motile sperm from 32
      normal and 35 abnormal sperm samples. The mtDNA/beta-globin gene ratio was
      determined by real-time quantitative PCR. RESULTS: The average mtDNA/beta-globin
      ratio of sperm collected from 100% density layers was 1.4 for normal sperm, 6.1
      for sperm samples presenting at least one abnormal criterion [among the three
      criteria established by World Health Organization (1999), i.e. sperm count,
      motility and morphology], and 9.1 for sperm samples presenting two or more of
      these abnormal criteria. These differences are very highly significant (P <
      0.0001). The mtDNA numbers were also much greater in sperm collected from the 40%
      density gradient layers (mean: 17.1, P < 0.001), known to contain the most
      abnormal sperm of the sperm samples, than in those collected from the 100% layers
      known to contain sperm with the best fertilizing ability. CONCLUSION: Our results
      showed significant mtDNA amplification in sperm collected from abnormal sperm
      samples.

PMID- 12615824
TI  - Specialized medical search-engines are no better than general search-engines in
      sourcing consumer information about androgen deficiency.
AB  - BACKGROUND: The Internet provides consumers with access to online health
      information; however, identifying relevant and valid information can be
      problematic. Our objectives were firstly to investigate the efficiency of search
      engines, and then to assess the quality of online information pertaining to
      androgen deficiency in the ageing male (ADAM). METHODS: Keyword searches were
      performed on nine search-engines (four general and five medical) to identify
      website information regarding ADAM. Search-engine efficiency was compared by
      percentage of relevant websites obtained via each search-engine. The quality of
      information published on each website was assessed using the DISCERN rating tool.
      RESULTS: Of 4927 websites searched, 47 (1.44%) and 10 (0.60%) relevant websites
      were identified by general and medical search-engines respectively. The overall
      quality of online information on ADAM was poor. The quality of websites retrieved
      using medical search-engines did not differ significantly from those retrieved by
      general search-engines. CONCLUSION: Despite the poor quality of online
      information relating to ADAM, it is evident that medical search-engines are no
      better than general search-engines in sourcing consumer information relevant to
      ADAM.

PMID- 12615826
TI  - A modified cryopreservation method increases the survival of human biopsied
      cleavage stage embryos.
AB  - BACKGROUND: The relatively poor survival rate of human biopsied cleavage stage
      embryos following cryopreservation is a significant obstacle in the application
      of preimplantation genetic diagnosis (PGD). We have attempted to improve
      cryosurvival of biopsied embryos by modifying the standard embryo
      cryopreservation technique. METHODS: Biopsied embryos were cryopreserved in 1.5
      mol/l 1,2-propanediol in the presence of an elevated concentration of sucrose
      (0.2 mol/l) and human serum albumin was replaced by maternal serum (20% vol:vol).
      An additional initial thawing step in the presence of 0.3 mol/l sucrose was also
      included. RESULTS: The proportion of biopsied embryos which survived
      cryopreservation with > or =50% of their blastomeres intact was significantly
      higher using the modified method (138/185; 75%) than that observed using the
      standard propanediol method (20/46; 43%; P = 0.022). Total blastomere survival
      was also significantly increased as a result of the modifications (1010/1513; 67%
      versus 177/385; 46%; P < 0.001). Six fetal hearts have been detected to date
      following replacement of biopsied embryos cryopreserved with the modified method.
      CONCLUSIONS: Survival of human biopsied cleavage stage embryos can be restored to
      a level similar to that of non-biopsied controls by modification of the
      cryopreservation procedure. Embryos which have been cryopreserved using the
      modified method can implant following replacement in utero.

PMID- 12615825
TI  - Pregnancies after ICSI using sperm with abnormal head-tail junction from two
      brothers: case report.
AB  - We report ICSI pregnancies in two couples with a history of long standing primary
      infertility in which the sperm of the male partner were either acephalic or had
      abnormal head-midpiece attachments. The two couples, in which the men are
      brothers, underwent ICSI. Sperm were analysed by transmission electron microscopy
      and immunocytochemistry with an anti-MPM2 monoclonal antibody. The first couple
      underwent two ICSI cycles, each consisting of the injection of two mature oocytes
      and the transfer of two embryos. A successful pregnancy occurred after the second
      transfer and led to the birth to a healthy girl. The second couple underwent
      three ICSI cycles, each consisting of the injection of 18 oocytes and the
      transfer of two embryos; the last of these led to a triple ongoing pregnancy
      which included two identical twins. Caesarean section led to the birth of three
      fetal-growth restricted children. This case report demonstrates that ongoing
      pregnancies can be achieved in cases of abnormal development of the head-neck
      attachment. The genetic origin of this syndrome is generally accepted, but the
      phenotypic heterogeneity observed by light and electron microscopy among
      published cases suggests that there are a variety of genetic causes of this
      syndrome.

PMID- 12615827
TI  - Maternal serum hCG and alpha-fetoprotein levels in pregnancies conceived after
      IVF or ICSI with fresh and frozen-thawed embryos.
AB  - BACKGROUND: Studies have shown that levels of serum markers of Down's syndrome
      were altered in pregnancies conceived after IVF, though the reason for this
      remains unknown. METHODS: Second-trimester maternal serum levels of hCG and alpha
      fetoprotein (AFP) in pregnancies conceived with fresh and frozen-thawed embryos
      after assisted reproduction were compared with those conceived spontaneously.
      RESULTS: There were 203 pregnancies with fresh embryo transfers (130 IVF cases,
      73 ICSI cases) and 98 pregnancies with frozen-thawed embryo transfers (61 IVF
      cases, 37 ICSI cases). The controls consisted of 17 145 spontaneous pregnancies.
      The median hCG multiples of the median (MoM) was significantly increased to 1.24
      in 98 pregnancies conceived after frozen embryo transfer. This elevation was
      observed only in the IVF-frozen embryo transfer subgroup (P < 0.001), but not in
      the ICSI-frozen embryo transfer subgroup. The median AFP MoM for 203 pregnancies
      after fresh embryo transfer was 0.90. Among the subgroups, the median AFP MoM was
      significantly reduced to 0.90 and 0.86 in IVF-embryo transfer (P = 0.04) and ICSI
      embryo transfer (P = 0.001) pregnancies respectively, and significantly raised to
      1.20 in the IVF-frozen embryo transfer subgroup. CONCLUSIONS: The degree of
      alterations in maternal serum hCG and AFP levels varied between fresh and frozen
      thawed embryos, and also between the mode of fertilization. Pregnancies resulting
      from ICSI or frozen embryo transfer should be regarded as distinct entities from
      those of IVF-embryo transfer.

PMID- 12615828
TI  - Abnormal assembly of annulate lamellae and nuclear pore complexes coincides with
      fertilization arrest at the pronuclear stage of human zygotic development.
AB  - BACKGROUND: The assembly of nuclear pore complexes (NPC) and their cytoplasmic
      stacks, annulate lamellae (AL), promote normal nucleocytoplasmic trafficking and
      accompany pronuclear development within the mammalian zygote. Previous studies
      showed that a percentage of human oocytes fertilized in vitro failed to develop
      normal pronuclei and cleave within 40-48 h post insemination. We hypothesized
      that an aberrant recruitment of NPC proteins, nucleoporins and/or NPC
      preassembled into AL, might accompany human fertilization arrest. METHODS AND
      RESULTS: We explored NPC and AL assembly in unfertilized human oocytes, and
      fertilized and arrested zygotes by immunofluorescence with an NPC- and AL
      specific antibody, mAb 414, and by transmission electron microscopy. Major NPC or
      AL assembly was not observed in the unfertilized human oocytes. Once
      fertilization took place, the formation of AL was observed throughout the
      cytoplasm and near the developing pronuclei with NPC. On the contrary, NPC
      assembly was disrupted in the arrested zygotes, whereas AL were clustered into
      large sheaths. This was accompanied by the lack of NPC incorporation into the
      nuclear envelopes. CONCLUSIONS: We conclude that the aberrant assembly of NPC and
      AL coincides with early developmental failure in humans.

PMID- 12615829
TI  - Economic evaluation of three surgical interventions for menorrhagia.
AB  - BACKGROUND: The study was carried out to compare the overall effectiveness and
      direct economic costs of vaginal hysterectomy (VH), endometrial ablation (EA) and
      thermo-coagulation (TC) for the treatment menorrhagia. METHODS: We treated 50, 50
      and 47 women with menorrhagia (>150 points on the Higham pictorial chart) by VH,
      EA and TC respectively. The patients were treated consecutively by the same
      surgeon and the choice between the three procedures depended on the desire of the
      patients. Resource utilization for the interventions was collected
      retrospectively from the hospital charts. A study questionnaire was mailed to the
      patients 24-36 months after the primary surgery. Patients who reported that they
      had undergone a second procedure or who were still menorrhagic were considered as
      treatment failures. RESULTS: As expected, the failure rate was lowest for VH. The
      total cost (without re-intervention for persistent menorrhagia) was 5315 Euros
      for VH, 1098 Euros for EA and 921 Euros for TC. The total cost with re
      intervention was calculated based on therapeutic strategies used in 2001 and
      estimated at 5321 Euros for VH, 1263 Euros for EA and 1320 Euros for TC.
      CONCLUSIONS: The two out-patient procedures are very comparable in terms of
      success rates and costs. Choices will depend on budgeting considerations, surgeon
      skill and patient preference. The results may give guidance to investment
      decisions.

PMID- 12615830
TI  - Laparoscopic presacral neurolysis for endometriosis-related pelvic pain.
AB  - BACKGROUND: Some patients with endometriosis are candidates for sympathectomy of
      the superior hypogastric plexus. The objective of this paper is to describe our
      technique of laparoscopic presacral neurolysis for sympathectomy and to report 1
      year results of the first 15 cases. METHODS: To achieve this objective in a
      prospective observational study of 1 year follow-up; we performed laparoscopic
      presacral chemical neurolysis with phenol in 15 patients with pelvic pain and
      minimal-moderate endometriosis. The main outcome measures were: the impact of
      treatment on pelvic symptom resolution, non-opioid analgesic consumption during
      menses, sexual performance and observed complications and side effects during 1
      year follow-up. RESULTS: We noted a significant reduction in total pelvic symptom
      score as compared with baseline mean (SD) of 9.04 (1.2). The mean difference [95%
      confidence interval (CI)] of reduction was 5.7 (4.9-6.5), 5.8 (5.0-6.6) and 5.8
      (4.9-6.6) from the baseline at the 3rd, 6th and 12th postoperative month (P <
      0.001). We observed a significant improvement in Sabbatberg Sexual Rating Scale
      as compared with baseline mean (SD) of 30.9 (4.3). The mean difference (95% CI)
      of increase was 33.4 (30.3-36.4), 33.2 (30.1-36.2) and 33.2 (30.1-36.3) from the
      baseline at the 3rd, 6th and 12th postoperative month. We observed a significant
      reduction in analgesic consumption during menses in terms of total naproxen
      sodium tablets as compared with baseline mean (SD) of 8.9 (1.1). The mean
      difference (95% CI) of reduction in the total number of naproxen sodium 250 mg
      tablets was 6.5 (5.5-7.5), 6.7 (5.7-7.7) and 6.6 (5.6-7.6) from the baseline at
      the 3rd, 6th and 12th postoperative month. The most common side effect was
      constipation. CONCLUSION: Laparoscopic presacral neurolysis is feasible and
      simple. More data is needed to support its efficacy and safety.

PMID- 12615831
TI  - Peritoneal fluid concentrations of interleukin-8 in patients with endometriosis
      depend on the severity of the disorder and are higher in the luteal phase.
AB  - BACKGROUND: Previous evaluations of the relationship between the concentrations
      of interleukin-8 (IL-8) in the peritoneal fluid and endometriosis led to non
      consistent results. Our purpose was to investigate the correlation of the
      concentrations of IL-8 in the peritoneal fluid with the stage of endometriosis,
      the presence of red lesions and the phase of the menstrual cycle. METHODS: Ninety
      two patients with infertility (n = 87) or undergoing sterilization (n = 5) had
      peritoneal fluid samples collected at laparoscopy. IL-8 determinations were
      performed using an enzyme-linked immunosorbent assay. RESULTS: The concentrations
      of IL-8 in the peritoneal fluid of the 68 women with endometriosis were not
      significantly different from those of the 24 controls. Patients with
      moderate/severe stages had IL-8 significantly higher than controls (P = 0.008)
      and marginally higher than patients with minimal/mild endometriosis (P = 0.053).
      Concentrations of IL-8 were significantly higher in patients than in controls in
      the luteal phase. Red lesions were associated with significantly increased levels
      of peritoneal fluid IL-8 only in the luteal phase. CONCLUSIONS: Our findings
      reinforce the importance of IL-8 in the pathogenesis of endometriosis.

PMID- 12615832
TI  - Ultrasound examination of polycystic ovaries: is it worth counting the follicles?
AB  - BACKGROUND: This study revisited the ultrasonographic diagnostic criteria of
      polycystic ovary syndrome (PCOS) and studied the relationship between the major
      hormonal and metabolic features of PCOS and the follicle number per ovary (FNPO).
      METHODS: This prospective study included 214 women with PCOS compared with 112
      women with normal ovaries. Main clinical, biological and ultrasonographic markers
      of PCOS were assessed during the early follicular phase. RESULTS: The mean FNPO
      of follicles 2-5 mm in size was significantly higher in polycystic ovaries than
      in controls, while it was similar within the 6-9 mm range. Setting the threshold
      at 12 for the 2-9 mm FNPO offered the best compromise between specificity (99%)
      and sensitivity (75%). Within the 2-5 mm follicular range, we found significant
      positive relationships between the FNPO and androgens. The FNPO within the 6-9 mm
      range was significantly and negatively related to body mass index and fasting
      insulin serum level. CONCLUSIONS: We propose to modify the definition of
      polycystic ovaries by adding the presence of > or =12 follicles measuring 2-9 mm
      in diameter (mean of both ovaries). Also, our findings strengthen the hypothesis
      that the intra-ovarian hyperandrogenism promotes excessive early follicular
      growth and that further progression cannot proceed normally because of
      hyperinsulinism and/or other metabolic influence linked to obesity.

PMID- 12615833
TI  - Use of autologous buccal mucosa for vaginoplasty: a study of eight cases.
AB  - BACKGROUND: Vaginal agenesis is a rare condition and treatment methods are
      varied. The difference between most of the surgical techniques is the graft
      material used. The purpose of this study was to describe the procedure and
      outcome of creating a neovaginal pouch lined with autologous buccal mucosa.
      METHODS AND RESULTS: Between August 2000 and February 2002, eight patients with
      Mayer-Rokitansky-Kuster-Hauser syndrome were admitted to our hospital. All of the
      patients successfully underwent neovaginoplasty with autologous buccal mucosa as
      graft material. The buccal mucosal wound completely healed 2 weeks after the
      operation and the neovaginal length and calibre were well formed. Follow-up
      ranged from 0.5 to 1.5 years. One patient encountered post-operative vaginal
      bleeding and another patient suffered from urinary bladder injury. CONCLUSION:
      This is the first reported procedure of vaginoplasty with autologous buccal
      mucosa as graft material. Our method is ideal in its simplicity, provides good
      cosmetic results, and improves the vaginal length of the patient.

PMID- 12615835
TI  - Decreased serum levels of macrophage migration inhibition factor in miscarriages
      with normal chromosome karyotype.
AB  - BACKGROUND: The aim of this study was to determine serum concentrations of
      macrophage migration inhibition factor (MIF) during normal pregnancies, and to
      assess whether serum MIF concentrations early in pregnancies predict the
      subsequent outcome in women with recurrent miscarriage (RM). METHODS: Serum MIF
      concentrations were measured by ELISA. Sera were collected from normal women in
      the first (Group I, n = 29), second (Group II, n = 25) and third trimester (Group
      III, n = 26) and from 78 RM women at 4-6 weeks gestation. Eleven of these 78
      pregnancies subsequently ended in first trimester miscarriage with normal fetal
      chromosome karyotype (MsNK), seven ended in first trimester miscarriage with
      abnormal karyotype (MsAK), and three ended in biochemical pregnancy. The other 57
      pregnancies ended in live birth (LB) between 32-41 weeks gestation, and only one
      woman developed preeclampsia. RESULTS: Median MIF concentrations in Group I, II
      and III were similar at 17.6, 16.4 and 15.1 ng/ml respectively. MIF
      concentrations during early gestation in RM women with subsequent MsNK, MsAK and
      LB were 8.1, 11.4 and 16.4 ng/ml respectively. MIF concentrations in RM women
      with MsNK were significantly lower than those in RM women with LB (P < 0.01) and
      than those in Group I (P < 0.01), II (P < 0.05) and III (P < 0.05). CONCLUSIONS:
      Decreased serum MIF concentrations during early gestation were found in RM women
      with MsNK, and might be related to the aetiology of miscarriage.

PMID- 12615834
TI  - Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase
      activity in women with recurrent failed embryo transfer.
AB  - BACKGROUND: In all IVF programmes, some patients fail to achieve an ongoing
      pregnancy, even after numerous embryo transfer procedures. An unfavourable
      environment within the uterus might be a contributory factor to such recurrent
      implantation failure. This question was addressed by measuring cytokine
      concentrations and matrix metalloproteinase activities in fluid derived from
      uterine irrigation of such patients. METHODS AND RESULTS: The uterine cavities of
      22 patients who had previously undergone embryo transfer of at least 10 embryos
      without ongoing pregnancy were irrigated during the luteal phase. The resultant
      fluid was assayed for the concentration of interleukin (IL)-1beta, tumour
      necrosis factor (TNF)-alpha, interferon (IFN)-gamma, leukaemia inhibitory factor
      (LIF), IL-10 and matrix metalloproteinase (MMP) -2 and -9 activity. The results
      were compared with those of a control population of women known to be previously
      fertile (n = 16) and also with women with recurrent spontaneous abortion (n =
      13). In the recurrent implantation failure group, the MMP score and IL-1beta
      concentration were significantly higher than those in the control group, whereas
      concentrations of IFN-gamma and IL-10 were significantly lower. CONCLUSIONS: In
      IVF patients with recurrent implantation failure, an altered pattern of intra
      uterine cytokine concentration and MMP activity was observed.

PMID- 12615836
TI  - Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer.
AB  - BACKGROUND: Our aim was to study attitudes towards twins and single embryo
      transfer (SET) among IVF/ICSI-twin mothers with 3 to 4-year old children.
      METHODS: A national survey was conducted by questionnaire (n = 1769). The study
      population consisted of IVF/ICSI-twin mothers (n = 266), and the two control
      groups of IVF/ICSI-singleton mothers (n = 764) and non-IVF/ICSI-twin mothers (n =
      739), all giving birth in Denmark in 1997. The overall response rate was 81%.
      RESULTS: More IVF/ICSI-twin mothers (84.7%) preferred twins as their first child
      compared with IVF/ICSI-singleton mothers (62.3%) and non-IVF twin mothers
      (60.0%). The IVF/ICSI-twin mothers had a significantly higher wish for twins (OR
      = 4.4, 95% CI 2.8-6.9) compared with the non-IVF/ICSI-twin mothers. Though
      relatively few IVF/ICSI-twin mothers (23.4%) and IVF/ICSI-singleton mothers
      (17.3%) agreed to SET, delivery of a child with very low birth weight (VLBW)
      (<1500 g) was predictive of high acceptance of SET (OR = 2.9, 95% CI 1.2-6.9).
      CONCLUSION: Our study suggests that IVF/ICSI-twin mothers have a greater wish for
      twins compared with non-IVF/ICSI-twin mothers. Despite the fact that only a
      quarter of IVF/ICSI mothers agreed to SET, delivery of a child with VLBW and
      hence high morbidity was predictive of high acceptance of SET. The implementation
      of elective SET requires extensive counselling of the infertile couples and
      legislation including strict selection criteria may also be used to facilitate
      this process.

PMID- 12615837
TI  - Patients' attitudes to medical and psychosocial aspects of care in fertility
      clinics: findings from the Copenhagen Multi-centre Psychosocial Infertility
      (COMPI) Research Programme.
AB  - BACKGROUND: The aims were (i) to identify gender differences in motivations to
      seek assisted reproduction and gender differences in expectations about medical
      and psychosocial services and (ii) to examine factors that predict the perceived
      importance of, and intention to use, psychosocial services among infertile
      people. METHODS: We conducted an epidemiological study based on questionnaires
      among all new couples attending five fertility clinics with a response rate of
      80.0% and a total of 2250 patients. RESULTS: The vast majority of both men and
      women considered a high level of medical information and patient-centred care as
      important. Fewer respondents (women 10.0-20.8%, men 4.1-8.9%) felt that
      professional psychosocial services were important and/or had the intention to use
      these services. The main predictor of perceived importance of patient-centred
      care and professional psychosocial services for both men and women was high
      infertility-related stress in the marital, personal and social domain.
      CONCLUSIONS: A supportive attitude from medical staff and the provision of both
      medical and psychosocial information and support should be integral aspects of
      medical care in fertility clinics. Although only a minority of the participants
      perceived professional psychosocial services as important, they should be
      available for patients whose infertility causes them much strain, especially for
      patients whose marital relationship suffered much because of infertility.

PMID- 12615838
TI  - Exposure to air pollution during different gestational phases contributes to
      risks of low birth weight.
AB  - BACKGROUND: Although there have been growing concerns about the adverse effects
      of air pollution on birth outcomes, little is known about which specific exposure
      times of specific pollutants contribute to low birth weight (LBW). METHODS: We
      evaluated the relationships between LBW and air pollution exposure levels in
      Seoul, Korea. Using the air pollution data, we estimated the exposure during each
      trimester and also during each month of pregnancy on the basis of the gestational
      age and birth date of each newborn. Generalized additive logistic regression
      analyses were conducted considering infant sex, birth order, maternal age,
      parental education level, time trend, and gestational age. RESULTS: The monthly
      analyses suggested that the risks for LBW tended to increase with carbon monoxide
      (CO) exposure between months 2-5 of pregnancy, with exposure to particles <10
      micro m (PM(10)) in months 2 and 4, and for sulphur dioxide (SO(2)) and nitrogen
      dioxide (NO(2)) exposure between months 3-5. CONCLUSIONS: This study suggests
      that exposure to CO, PM(10,) SO(2) and NO(2) during early to mid pregnancy
      contribute to risks for LBW.

PMID- 12615839
TI  - Subfertility reflects accelerated ovarian ageing.
AB  - BACKGROUND: The aim of the study was to explore the extent to which accelerated
      ovarian ageing may lead to subfertility early in reproductive life and eventually
      cause early menopause. METHODS: The population studied (n = 2393) never used oral
      contraceptives, hormone replacement therapy or an intrauterine device. Logistic
      regression analyses were performed using age at menopause as proxy for
      accelerated ovarian ageing. Measures of ovarian ageing and subfertility were
      menstrual cycle irregularity, ever consulted a physician for fertility problems,
      nulliparity, uniparity, miscarriage(s) and time interval >5 years between birth
      of first and second child. RESULTS: For every 5 years later menopause, the
      probability of reporting menstrual cycle irregularity was reduced by 26% (OR =
      0.74, 95% CI: 0.63-0.86); the probability of ever consulting a physician for
      fertility problems was reduced by 18% (OR = 0.82, 95% CI: 0.71-0.95); the
      probability of staying nulliparous was reduced by 22% (OR = 0.78, 95% CI: 0.64
      0.96); the probability of being uniparous was reduced by 22% (OR = 0.78, 95% CI:
      0.66-0.91); the probability of having a miscarriage was reduced by 11% (OR =
      0.89, 95% CI: 0.79-1.01); the probability of a large time interval between birth
      of first two children was reduced by 27% (OR = 0.73, 95% CI: 0.61-0.89).
      CONCLUSIONS: Fertility problems are frequently followed by early menopause. The
      findings support the view that both are an expression of accelerated ovarian
      ageing.

PMID- 12615840
TI  - Taskforce 5: preimplantation genetic diagnosis.
AB  - The European Society of Human Reproduction and Embryology (ESHRE) Ethics Task
      Force sets out a recommended multidisciplinary approach to the application of
      preimplantation genetic diagnosis (PGD). The statement includes consideration of
      fundamental ethical principles, specific problems in cases of high genetic risk,
      and PGD for aneuploidy screening, HLA typing and sex selection for non-medical
      reasons.

PMID- 12615841
TI  - What role does decreased ovarian reserve play in the aetiology of infertility
      related to endometriosis?

PMID- 12615843
TI  - The causes of the excess males among pre-term and post-term births.

PMID- 12615845
TI  - Meta-analysis on luteal phase support.

PMID- 12615847
TI  - Current and future antiviral agents for chronic hepatitis B.

PMID- 12615848
TI  - Predicting antiviral treatment response in chronic hepatitis C: how accurate and
      how soon?

PMID- 12615849
TI  - The mechanisms that control intracellular penetration of the HIV protease
      inhibitors.

PMID- 12615850
TI  - Drugs of the 21st century: telithromycin (HMR 3647)--the first ketolide.
AB  - Telithromycin (HMR 3647) is the first ketolide introduced into clinical practice.
      Ketolides are semisynthetic derivates of erythromycin A that carry novel
      biological properties on the erythronolide A ring. This new class of
      antimicrobials was designed to overcome current resistance mechanisms against
      erythromycin A within Gram-positive cocci. Ketolides do not induce macrolide
      lincosamide-streptogramin B (MLS(B)) resistance and are active against
      erythromycin resistance methylase gene (erm)-carrying Gram-positive cocci. This
      review summarizes published data on telithromycin and intends to define the
      challenge that a new antimicrobial brings to medical practice.

PMID- 12615851
TI  - Caspofungin: the first representative of a new antifungal class.
AB  - Caspofungin (MK-0991; L-743,872) belongs to the echinocandin family, a new class
      of antifungal agents that act on the fungal cell wall by inhibiting glucan
      synthesis. Data in vitro, and experimental studies, have demonstrated that
      caspofungin has antifungal activity against yeasts of the genus Candida
      (including isolates resistant to azoles and amphotericin B), several species of
      filamentous fungi, including Aspergillus, and certain dimorphic fungi, such as
      Histoplasma, Blastomyces and Coccidioides. In vitro and in animals, caspofungin
      shows additive or synergic antifungal activity with amphotericin B and triazoles.
      It also possesses activity against Pneumocystis carinii. Clinical trials have
      shown caspofungin to be well tolerated and effective in invasive aspergillosis in
      patients refractory or intolerant to standard treatment (45% favourable
      responses), in oropharyngeal and oesophageal candidiasis (67-93% favourable
      responses with an efficacy similar to those of amphotericin B and fluconazole),
      and in invasive candidiasis with efficacy equivalent to that of amphotericin B,
      and better tolerability. The results of these first clinical trials were
      promising, and led to the approval of caspofungin for invasive aspergillosis
      after failure of, or intolerance to, standard therapy. Further studies are
      required to define the exact role of caspofungin in the antifungal armamentarium.

PMID- 12615852
TI  - Cefuroxime resistance in non-beta-lactamase Haemophilus influenzae is linked to
      mutations in ftsI.
AB  - The penicillin binding protein (PBP) genes dacA, dacB and ftsI from 14 cefuroxime
      resistant (CXM(R)) isolates and three clinical isolates with low CXM MIC for non
      beta-lactamase-producing Haemophilus influenzae type b were molecularly
      characterized. One strain, 5788, was used to transform H. influenzae Rd to CXM(R)
      for direct comparison of the pbps in the same genetic background. No obvious
      mutations in the dacA and dacB gene products could be associated with CXM(R). One
      amino acid substitution in the ftsI gene product in particular, S357N, could give
      rise to CXM(R). Sequence analysis from the CXM(R) transformants also implicated
      FtsI; in this case, the substitutions were V511A and R517H. To verify S357N
      substitution, the protein sequence of H. influenzae FtsI was threaded through the
      S. pneumoniae PBP 2X structure giving an average root mean square deviation of
      the alpha-carbon chains of 0.5 A. The S357N substitution alters both the residue
      size and charge. One explanation for the contribution of S357N to CXM(R) is that
      the asparagine side-chain produces unfavourable steric hindrance with the side
      chain of Val-362 changing the torsion angles of the asparagine residue, which in
      turn may influence the position of the loop V362-P366 adjacent to the active
      site. Whilst other groups have examined the contribution of H. influenzae PBPs in
      ampicillin resistance, this is the first report analysing their role in CXM(R).

PMID- 12615853
TI  - Identification of novel inhibitors of Pseudomonas aeruginosa MurC enzyme derived
      from phage-displayed peptide libraries.
AB  - OBJECTIVES: The machinery of peptidoglycan biosynthesis is an ideal site at which
      to look for novel antimicrobial targets. Phage display was used to develop novel
      peptide inhibitors for MurC, an essential enzyme involved in the early steps of
      biosynthesis of peptidoglycan monomer. METHODS: We cloned and overexpressed the
      murA, -B and -C genes from Pseudomonas aeruginosa in the pET expression vector,
      adding a His-tag to their C termini. The three proteins were overproduced in
      Escherichia coli and purified to homogeneity in milligram quantities. MurA and -B
      were combinatorially used to synthesize the MurC substrate UDP-N-acetylmuramate,
      the identity of which was confirmed by mass spectrometry and nuclear magnetic
      resonance analysis. Two phage-display libraries were screened against MurC in
      order to identify peptide ligands to the enzyme. RESULTS: Three rounds of
      biopanning were carried out, successively increasing elution specificity from
      round 1 to 3. The third round was accomplished with both non-specific elution and
      competitive elution with each of the three MurC substrates, UDP-N-acetylmuramic
      acid (UNAM), ATP and L-alanine. The DNA of 10 phage, selected randomly from each
      group, was extracted and sequenced, and consensus peptide sequences were
      elucidated. Peptides were synthesized and tested for inhibition of the MurC
      catalysed reaction, and two peptides were shown to be inhibitors of MurC activity
      with IC(50)s of 1.5 and 0.9 mM, respectively. CONCLUSION: The powerful selection
      technique of phage display allowed us to identify two peptide inhibitors of the
      essential bacterial enzyme MurC. The peptide sequences represent the basis for
      the synthesis of inhibitory peptidomimetic molecules.

PMID- 12615854
TI  - Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone
      resistance in Escherichia coli.
AB  - Quinolones are widely used, broad-spectrum antimicrobial agents. In screens for
      genes that, when overexpressed, allow Escherichia coli to grow on otherwise
      lethal concentrations of the fluoroquinolone norfloxacin, the ydhE gene was
      identified. We have shown that ydhE encodes a multidrug efflux pump with a
      narrower substrate range than that of its closest homologue, encoded by norM, and
      named the gene norE. The relative contributions to drug resistance of NorE
      compared with the two other known E. coli quinolone pumps, AcrAB and MdfA, have
      been defined. Overexpression of each of the three pumps separately resulted in
      roughly similar levels of quinolone resistance, whereas simultaneous
      overexpression of norE or mdfA in combination with acrAB gave synergic increases
      in quinolone resistance. The level of quinolone resistance mediated by efflux
      pumps seems to be constrained to an approximately 10-fold maximum, even with
      increased production of the pumps. We measured the drug resistance of an isogenic
      set of strains containing the various permutations of single, double and triple
      drug efflux pump mutants. The DeltanorE and DeltamdfA mutants were somewhat more
      susceptible to fluoroquinolones than the parent strain, and acrAB mutants were
      four- to six-fold more susceptible. Mutants lacking two or all three efflux pumps
      were not significantly more susceptible to fluoroquinolones than those lacking
      only one of the three pumps.

PMID- 12615855
TI  - Role of the transmembrane domain of the VanT serine racemase in resistance to
      vancomycin in Enterococcus gallinarum BM4174.
AB  - Enterococcus gallinarum BM4175 (a vancomycin-susceptible derivative of BM4174
      obtained by insertional inactivation of vanC-1) was transformed with plasmid
      constructs pCA10 (containing the genes necessary for resistance, vanC-1-XYc-T),
      pJP1 (with a fragment lacking the DNA encoding the transmembrane region of VanT, 
      vanC-1-XYc-T((Delta))(2-322)-) and with plasmids containing fragments encoding
      either the transmembrane (mvanT(1-322)) or racemase (svanT(323-698)) domains of
      VanT under the control of a constitutive promoter. Accumulated peptidoglycan
      precursors were measured in all strains in the presence of L-Ser, D-Ser (50 mM)
      or in the absence of any growth supplement. Uptake of 0.1 mM L-[(14)C]serine was
      also determined in BM4174, BM4175 and BM4175/pCA10. Vancomycin resistance was
      restored in BM4175 transformed with pCA10(C-1-XYc-T), and the profile of
      peptidoglycan precursors was similar to wild-type E. gallinarum BM4174.
      Transformation of E. gallinarum BM4175 with plasmid pJP1(vanC-1-XYc-T((Delta))(2
      322)) resulted in: (i) vancomycin MICs remaining within susceptible levels (< or
      =4 mg/L) in the absence of any growth supplement, but increasing to 8 mg/L when
      either L-Ser or D-Ser was added to the medium; and (ii) the relative amounts of
      accumulated UDP-MurNAc-pentapeptide[D-Ser] and tetrapeptide precursors decreasing
      substantially compared with BM4175/pCA10 and BM4174. The effect on the appearance
      of tetrapeptide appeared to be host dependent, since a substantial amount was
      present when the same plasmid construct pJP1(vanC-1-XYc-T((Delta))(2-322)) was
      electroporated into Enterococcus faecalis JH2-2. The uptake of L-[(14)C]Ser at
      240 s was decreased by approximately 40% in BM4175 compared with BM4174. Plasmid
      pCA10(C-1-XY(C)-T) restored uptake of L-[(14)C]Ser at 180 and 240 s in BM4175.
      The results suggest that the transmembrane domain of VanT is likely to be
      involved in the transport of L-Ser, and that in its absence the resistance
      phenotype is compromised.

PMID- 12615856
TI  - Relationship between beta-lactamase production, outer membrane protein and
      penicillin-binding protein profiles on the activity of carbapenems against
      clinical isolates of Acinetobacter baumannii.
AB  - Twenty blood isolates of Acinetobacter baumannii were studied, representing eight
      pulsed-field gel electrophoresis patterns and all different antimicrobial
      susceptibility patterns observed during 1995-97 at the University Hospital Virgen
      Macarena, Seville, Spain. The MIC(90)s (mg/L) of imipenem and meropenem decreased
      from 16 to 0.5 and from 8 to 4, respectively, in the presence of BRL 42715 (BRL)
      but not clavulanic acid. Hydrolysing activity (nmol/min/mg) of bacterial
      supernatants against cefaloridine ranged from 8.8 to 552.3 for A. baumannii type
      I (imipenem MICs < or = 2), which expressed only a beta-lactamase of pI > or = 9,
      and from 12.3 to 1543.5 for A. baumannii type II (imipenem MICs > or = 4), which
      expressed a beta-lactamase of pI > or = 9 and two others of pI 6.3 and 7. The
      hydrolysing activities of A. baumannii type II against imipenem, meropenem and
      oxacillin were higher than those observed for A. baumannii type I. Ten outer
      membrane protein (OMP) profiles (A. baumannii types I and II) were visualized on
      10% SDS-PAGE gels with 6 M urea, whereas only five OMP profiles (A. baumannii
      types I and II) were differentiated in 12% SDS-PAGE gels. Five A. baumannii with
      OMP profile type B, characterized by the absence of a 22.5 kDa OMP, were
      resistant to meropenem and/or imipenem. Twelve penicillin-binding protein (PBP)
      patterns were observed. PBP patterns of A. baumannii type II were characterized
      by the absence of a 73.2 kDa band (PBP 2). We concluded that production of beta
      lactamases of pI 6.3 and 7.0 and reduced expression of PBP 2 are the most
      frequently observed mechanisms of resistance to carbapenems. In some isolates,
      loss of a 22.5 kDa OMP is also related to resistance to carbapenems.

PMID- 12615857
TI  - Effects of ortho-phthalaldehyde, glutaraldehyde and chlorhexidine diacetate on
      Mycobacterium chelonae and Mycobacterium abscessus strains with modified
      permeability.
AB  - The mechanisms of the mycobactericidal action of ortho-phthalaldehyde (OPA),
      glutaraldehyde (GTA) and chlorhexidine diacetate (CHA) were investigated using
      mycobacterial spheroplasts of two reference strains, Mycobacterium chelonae NCTC
      946, Mycobacterium abscessus NCTC 10882 and two GTA-resistant strains, M.
      chelonae Epping and M. chelonae Harefield. Transmission electron microscopy of
      the spheroplasts revealed an altered cell wall structure compared with the parent
      cells. Structural alterations resulting from the spheroplasting process were in
      part correlated to a loss of lipid content. Low concentrations of CHA induced
      protein coagulation in M. chelonae NCTC 946 spheroplasts, which also exhibited
      the highest loss of free non-polar lipids. Higher concentrations of CHA were
      required to produce similar results to the other spheroplasts investigated in
      which there was a less substantial decrease in lipid content. OPA (0.5% w/v)
      readily penetrated the residual cell wall and cytoplasmic membrane, producing
      significant protein coagulation in M. chelonae NCTC 946. GTA (0.5% v/v) induced a
      similar effect but to a lesser extent. Pre-treatment of the spheroplasts with OPA
      and GTA and their subsequent suspension in water demonstrated that GTA was a more
      potent cross-linking agent. This protective effect of GTA results from extensive
      cross-linking of amino and/or sulphydryl side-chain groups of proteins. The rapid
      mycobactericidal effect of OPA probably arises from its more efficient
      penetration across biological membranes. Mycobacterial spheroplasts represented a
      useful cellular model with an altered cell wall permeability. This study also
      showed the importance of the mycobacterial cell wall in conferring intrinsic
      resistance to CHA.

PMID- 12615858
TI  - Antibacterial poly(D,L-lactic acid) coating of medical implants using a
      biodegradable drug delivery technology.
AB  - OBJECTIVES: Biomaterial-associated bacterial infections present common and
      challenging complications with medical implants. The purpose of this study was to
      determine the antibacterial properties of a low molecular weight biodegradable
      poly(D,L-lactic acid) coating with integrated antibiotics gentamicin and
      teicoplanin. METHODS: Coating of Kirschner-wires was carried out by a solvent
      casting technique under aseptic conditions with and without incorporated
      antibiotics. Release kinetics of gentamicin and teicoplanin were studied in
      phosphate-buffered saline. Initial bacterial adhesion of Staphylococcus
      epidermidis on coated and bare implants was determined by radiolabelling and
      counts of detached viable organisms. RESULTS: The incorporated antibiotics showed
      a continuous release over a period of at least 96 h with an initial peak of
      release in the first 6 h. Attachment of non-viable microorganisms, detected by
      radiolabelled bacteria, was increased significantly by the polymer coatings (P <
      0.05). In contrast, the number of viable bacteria was reduced by the pure polymer
      (P < 0.01) and further by the polymer-antibiotic combinations (P < 0.05).
      CONCLUSIONS: Poly(D,L-lactic acid) coating of implants could offer new
      perspectives in preventing biomaterial-associated infections. Combinations with
      other drugs to formulate custom-tailored implant surfaces are feasible.

PMID- 12615859
TI  - The in vitro susceptibility of Scedosporium prolificans to ajoene, allitridium
      and a raw extract of garlic (Allium sativum).
AB  - The in vitro susceptibility of 20 medical isolates of Scedosporium prolificans to
      ajoene, allitridium and raw garlic extract derived from cloves of garlic (Allium
      sativum) was tested using the NCCLS reference method (with minor modifications)
      for broth microdilution. The results demonstrate that both garlic derivatives and
      raw garlic extract appear to have in vitro activity against S. prolificans.

PMID- 12615860
TI  - Prevalence and association of macrolide-lincosamide-streptogramin B (MLS(B))
      resistance with resistance to moxifloxacin in Clostridium difficile.
AB  - Clostridium difficile remains the leading cause of nosocomially acquired
      diarrhoea. C. difficile usually exhibits resistance against beta-lactam
      antibiotics, whereas susceptibility to other drugs may vary. This study
      investigated the antimicrobial susceptibility of C. difficile to different
      antibiotics over a period of time and characterizes molecular mechanisms for
      resistance. One hundred and seventy-three toxigenic and 19 non-toxigenic C.
      difficile strains, recovered from patients in two university hospitals in Germany
      between 1986 and 2001, were investigated for their susceptibility to
      erythromycin, clindamycin, moxifloxacin, vancomycin and metronidazole employing
      the Etest. The genetic background for resistance was analysed using PCR and DNA
      sequencing. All strains were susceptible to vancomycin and metronidazole.
      Resistance to erythromycin, clindamycin and moxifloxacin was found in 27%, 36%
      and 12% of the tested strains, respectively. High-level resistance (MIC > 128
      mg/L) against erythromycin and clindamycin was detected in 25% of the strains
      tested. Thirty-four of the macrolide-lincosamide-streptogramin B (MLS(B))
      resistant strains carried the erythromycin resistance methylase gene. The results
      indicate an increase in the prevalence of resistance to MLS(B) and
      fluoroquinolone antibiotics in C. difficile. Fluoroquinolone resistance is
      associated with resistance to MLS(B) antimicrobials.

PMID- 12615862
TI  - Mupirocin and Staphylococcus aureus: a recent paradigm of emerging antibiotic
      resistance.
AB  - OBJECTIVES: To describe trends in mupirocin resistance among Staphylococcus
      aureus in New Zealand (NZ), following the availability of mupirocin in 1986.
      PATIENTS AND METHODS: Data from a variety of sources were used for this study:
      susceptibility data collected annually from diagnostic laboratories throughout
      NZ; a local survey of mupirocin-resistant S. aureus in the Auckland area in 1997;
      a national survey of S. aureus antimicrobial susceptibility in 1999; and the
      national methicillin-resistant S. aureus (MRSA) surveillance programme. RESULTS:
      All data sources show that there was a steady increase in mupirocin resistance
      among S. aureus throughout the 1990s, and rates in NZ are now markedly higher
      than those reported in most other comparable countries. By 1999, resistance
      averaged 28%, with higher rates among community-acquired compared with hospital
      acquired isolates, and with a wide geographical variation in resistance.
      Resistance was more common among S. aureus generally than MRSA. CONCLUSION: We
      postulate that the steady rise in mupirocin resistance among S. aureus in NZ
      throughout the 1990s may be due, at least in part, to the over the counter
      availability of mupirocin from 1991 to 2000. The current patterns of mupirocin
      consumption need to be reviewed and its use rationalized to maximize the chances
      of this antibiotic retaining beneficial antistaphylococcal activity.

PMID- 12615861
TI  - Variable susceptibility to piperacillin/tazobactam amongst Klebsiella spp. with
      extended-spectrum beta-lactamases.
AB  - MICs of piperacillin/tazobactam are conventionally determined by varying the
      concentration of piperacillin in the presence of a fixed 4 mg/L tazobactam. When
      tested in this way, the MIC distribution for Klebsiella isolates with extended
      spectrum beta-lactamases (ESBLs) is strongly bimodal, such that many producers
      are inhibited at 16 + 4 mg/L whilst others require MICs of > or =512 + 4 mg/L.
      When, however, piperacillin/tazobactam was tested as a fixed 8:1 ratio, the MIC
      distribution became unimodal. If clavulanate 4 mg/L was combined with
      piperacillin, a unimodal MIC distribution was seen for ESBL-producing Klebsiella
      spp. but a bimodal distribution arose if the clavulanate concentration was
      reduced to 0.25 mg/L. These data for alternative combinations suggested that the
      bimodal MIC distribution seen for piperacillin + tazobactam 4 mg/L was a
      titration effect, not a reflection of some ESBLs being resistant to tazobactam.
      Even within single strains, as defined by serotype and DNA fingerprints, there
      was considerable variation in susceptibility to piperacillin + tazobactam 4 mg/L,
      with some representatives highly susceptible and others highly resistant. Some of
      the more resistant representatives produced more of their ESBL, or had a greater
      number of beta-lactamase types, but these associations were not universal.
      Elevated resistance to piperacillin + tazobactam was not associated with porin
      change in any ESBL producer examined, but has been found by others.

PMID- 12615863
TI  - Prevalence and mechanisms of low- and high-level mupirocin resistance in
      staphylococci isolated from a Korean hospital.
AB  - Mupirocin has been used against Gram-positive pathogenic bacteria, and is a
      specific inhibitor of bacterial isoleucyl-tRNA synthetase. In this work, we have
      determined the prevalence of mupirocin resistance among staphylococci isolated
      from a Korean hospital, and have investigated the characteristics of the
      resistance. In Staphylococcus aureus, the prevalence of high-level mupirocin
      resistance was 5% (16 of 319), whereas low-level mupirocin resistance was not
      detected. In coagulase-negative staphylococci (CoNS) the rates of high- and low
      level mupirocin resistance were 16.7% (34 of 204) and 10.3% (21 of 204),
      respectively. The high-level resistant strains contained the ileS-2 gene, which
      encodes a novel staphylococcal isoleucyl-tRNA synthetase. In contrast, all of the
      low-level mupirocin-resistant CoNS contained the mutation V588F, which is located
      near the conserved motif KMSKS, within the chromosomal staphylococcal isoleucyl
      tRNA synthetase gene (ileS). In conclusion, this work describes the recent, but
      rapid, emergence of two different types of mupirocin-resistant staphylococci in
      Korea, and the sequence and mutant characterization of the isoleucyl-tRNA
      synthetase of CoNS.

PMID- 12615864
TI  - Antimicrobial resistance in Cairo, Egypt 1999-2000: a survey of five hospitals.
AB  - Antimicrobial resistance among bacterial pathogens is a global problem, but in
      Egypt data are sparse. We reviewed the antimicrobial susceptibility patterns of
      bloodstream isolates of Gram-positive cocci and Gram-negative bacilli in five
      hospitals in Cairo, Egypt, from 1999 to 2000. In addition, susceptibilities of
      non-bloodstream isolates of Streptococcus pneumoniae and Enterococcus spp. were
      analysed. High rates of resistance were found in most of the bacteria studied. In
      the hospitals, a variety of methods were used for identification and
      susceptibility testing, but in the laboratories quality controlled strains were
      utilized routinely, to ensure accurate performance of the assays. Only 29% of
      Staphylococcus aureus isolates and 23% of coagulase-negative staphylococcal
      isolates were oxacillin susceptible. Both groups of staphylococci were also
      highly resistant to erythromycin, co-trimoxazole, clindamycin and doxycycline;
      all isolates were susceptible to vancomycin. Susceptibility of S. pneumoniae
      isolates to penicillin, ceftriaxone and fluoroquinolones was 63%, 84% and 82%,
      respectively. Vancomycin susceptibility of the enterococci was 96%;
      susceptibility to high-level gentamicin and streptomycin was 54% and 48%,
      respectively. Resistance to most relevant antimicrobials was commonplace among
      the Gram-negative bacilli; however, most remained susceptible to imipenem. The
      percentage of bloodstream isolates of Escherichia coli susceptible to common
      antimicrobial agents was as follows: ampicillin (6%), ampicillin-sulbactam (38%),
      co-trimoxazole (38%) and aminoglycosides (52%). The susceptibility of isolates of
      E. coli, Klebsiella and Enterobacter spp. to ceftazidime was 62%, 40% and 46%,
      respectively. This suggests a potentially high rate of extended-spectrum beta
      lactamase (ESBL) and/or Amp-C enzyme production. These results call for a
      nationwide surveillance programme to monitor microbial trends and antimicrobial
      resistance patterns in Egypt.

PMID- 12615865
TI  - Production of CTX-M-3 extended-spectrum beta-lactamase and IMP-1 metallo beta
      lactamase by five Gram-negative bacilli: survey of clinical isolates from seven
      laboratories collected in 1998 and 2000, in the Kinki region of Japan.
AB  - The aim of this study was to research the distribution in the Kinki region of
      Japan of Enterobacteriaceae and Pseudomonas aeruginosa that produce extended
      spectrum beta-lactamase (ESBL) and metallo beta-lactamase (MBL). One thousand
      isolates, 200 of each of four enterobacterial species (i.e. Escherichia coli,
      Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens) and 200 of
      P. aeruginosa, were collected from seven different laboratories during two 2
      month periods, one in 1998 and one in 2000. A double-disc synergy test (DDST) and
      2-mercaptopropionic acid inhibition test (2-MPAT) were used to confirm beta
      lactamase-producing isolates. The DDST was positive for one isolate of E. coli,
      five of K. pneumoniae, two of E. cloacae and 14 of S. marcescens. The 2-MPAT was
      positive for five isolates of S. marcescens and two of P. aeruginosa. We
      identified the beta-lactamase type of each isolate by molecular confirmatory
      tests (isoelectric focusing, PCR and DNA sequencing): CTX-M-3 ESBLs (three
      isolates of K. pneumoniae, two of E. cloacae and 13 of S. marcescens), CTX-M-2
      ESBL (one isolate of K. pneumoniae), SHV-12 ESBLs (one isolate of E. coli and one
      of S. marcescens), CTX-M-3 and SHV-12 combination ESBL (one isolate of K.
      pneumoniae) and IMP-1 MBLs (five isolates of S. marcescens and two of P.
      aeruginosa). In conclusion, many species of Gram-negative bacilli that produce
      CTX-M-3 ESBLs and IMP-1 MBLs were disseminated widely in different hospitals of
      the Kinki region of Japan. Therefore, monitoring of laboratory bacterial ecology
      seems important to stop the spread of these strains through nosocomial outbreaks.

PMID- 12615866
TI  - Activity of daptomycin against susceptible and multidrug-resistant Gram-positive
      pathogens collected in the SECURE study (Europe) during 2000-2001.
AB  - Antibiotic resistance was prevalent in Gram-positive pathogens collected from 40
      sites in 15 European countries during 2000-2001. Among Staphylococcus aureus,
      27.3% of all isolates submitted were resistant to oxacillin and ranged from 0% of
      isolates from the Netherlands to 36.9% of isolates from Portugal. The overall
      prevalence of vancomycin-resistant Enterococcus faecium was 25.1%, with Italy
      submitting the largest percentage of resistant isolates (60.6%). For
      Streptococcus pneumoniae, 9.4% of all isolates collected were resistant to
      penicillin with variation by country from 0% in the Netherlands to 20.7% in
      Portugal. Multidrug resistance (MDR), defined as concurrent resistance to three
      or more antimicrobials of different chemical classes, was observed in 24.6% of S.
      aureus, 19.6% of E. faecium and 3.6% of S. pneumoniae. The directed spectrum
      agents daptomycin, linezolid and quinupristin-dalfopristin were active in vitro
      against all isolates regardless of their resistance to other agents. Daptomycin
      and quinupristin-dalfopristin (MIC(90)s 0.5 mg/L) were equally active against
      oxacillin-resistant S. aureus compared with linezolid (MIC(90) 2 mg/L). The
      activities of daptomycin, quinupristin-dalfopristin and linezolid were not
      affected by resistance to vancomycin in E. faecium (MIC(90)s of 4, 2 and 2 mg/L,
      respectively). Daptomycin was more active against penicillin-resistant S.
      pneumoniae (MIC(90) 0.25 mg/L) than was quinupristin-dalfopristin (MIC(90) 0.5
      mg/L) or linezolid (MIC(90) 2 mg/L). Daptomycin was highly active against
      clinically important Gram-positive pathogens, including those that were multiply
      resistant to currently available agents. The results of this study provide a
      benchmark of the activity of daptomycin against contemporary European isolates
      and will serve as a baseline to monitor future changes in the susceptibility of
      these organisms to daptomycin.

PMID- 12615867
TI  - Stability and compatibility study of cefepime in comparison with ceftazidime for
      potential administration by continuous infusion under conditions pertinent to
      ambulatory treatment of cystic fibrosis patients and to administration in
      intensive care units.
AB  - Cefepime has been examined for stability, potential liberation of degradation
      products and compatibility with other drugs under conditions mimicking its
      potential use by continuous infusion in cystic fibrosis and intensive care
      patients (5-12% w/v solutions; temperatures from 20 to 37 degrees C; 1 h contact
      at 25 degrees C with other drugs frequently co-administered by intravenous route
      to these types of patients). Ceftazidime was used as a comparator based on a
      previous normative study with this antibiotic for the same indications. Based on
      a limit of max. 10% degradation, cefepime can be considered stable for a maximum
      of 24 h at 25 degrees C, but for only approximately 14 h at 30 degrees C, and for
      <10 h at 37 degrees C. Cefepime released so far unidentified degradation products
      if maintained at >30 degrees C for >12 h as shown from a marked increase in pH
      and from the development of a strong red-purple colour. Incompatibilities were
      observed with erythromycin, propofol, midazolam, phenytoin, piritramide,
      theophylline, nicardipine, N-acetylcysteine and a concentrated solution of
      dobutamine. We conclude that: (i) cefepime cannot be used safely by continuous
      infusion if containers are kept for more than a few hours at 37 degrees C (as
      will be the case for cystic fibrosis patients if using portable pumps carried
      under clothes); (ii) caution must be exercised in intensive care patients if the
      temperature and co-administration of other drugs is not kept under tight control.
      The nature and safety of the cefepime degradation products need to be studied
      further.

PMID- 12615868
TI  - Optimizing ceftazidime pharmacodynamics in patients with acute exacerbation of
      severe chronic bronchitis.
AB  - OBJECTIVES: Implementation of current pharmacodynamic knowledge could enhance
      clinical results, avoid resistance development and reduce treatment costs. In
      this open, randomized, multicentre study, we evaluated the clinical and
      bacteriological outcome and pharmacokinetic as well as pharmacodynamic parameters
      of two ceftazidime therapy regimens in patients with acute exacerbation of severe
      chronic bronchitis (AECB). METHODS: Eighty-one patients (56 males, 25 females,
      age 65.3 +/- 10.1 years) with AECB were included. A subgroup of 21 patients
      underwent pharmacokinetic and pharmacodynamic examination. The patients received
      either ceftazidime 2 g every 8 h (C3 x 2) or ceftazidime 2 g as a loading dose,
      followed by ceftazidime 2 g over 7 h every 12 h (C2 x 2) for 8-14 days. Clinical
      and bacteriological responses were monitored at day 8 or 9, and 72 h after the
      end of therapy (EOT). RESULTS: At EOT, clinical success was recorded in 90% and
      90.2% of clinically evaluable patients receiving C3 x 2 and C2 x 2, respectively.
      Bacteriological success at EOT was achieved in 87.5% and 90.2% of evaluable
      patients treated with C3 x 2 and C2 x 2, respectively. C(max) (mg/L) varied
      between 168.9 +/- 34.1 and 144.0 +/- 9.8 in the C3 x 2 group, and between 60.1 +/
      34.1 and 54.2 +/- 30.4 at steady-state in the C2 x 2 group. Minimal
      concentrations were between 9.1 and 13.4 mg/L in the C3 x 2 group, and between
      16.6 and 17.7 mg/L in the C2 x 2 group. Concentrations >4-5 x MIC were seen in
      all pathogens, except Staphylococcus aureus, during 100% of infusion time.
      CONCLUSION: The 2 x 7 h infusion of ceftazidime 2 g (C2 x 2) was clinically and
      bacteriologically as effective as the usual 3 x 2 g ceftazidime short-term
      infusion in the treatment of AECB, and demonstrated advantages in terms of
      pharmacodynamic parameters compared with the C3 x 2 regimen.

PMID- 12615869
TI  - Experimental pneumococcal pleural empyema model: the effect of moxifloxacin.
AB  - OBJECTIVES: Pleural empyema is a serious complication of pneumonia, the optimal
      therapy of which is still unknown. The objective of this study was to evaluate
      the use of moxifloxacin in this condition. METHODS: Pleural empyema was induced
      in rabbits by intrapleural administration of Pasteurella multocida (10(5-6) cfu)
      or turpentine (0.3 mL) followed 3 h later by instillation of Streptococcus
      pneumoniae (ATCC 49619) (10(6) cfu) into the pleural cavity. The MICs of
      moxifloxacin for S. pneumoniae and P. multocida were 0.4 and 0.05 mg/L,
      respectively. Starting 30 h following S. pneumoniae challenge intramuscular
      moxifloxacin 12.5 and 25 mg/kg was administered x 4 (every 12 h). Pleural empyema
      fluid samples were obtained for bacterial count at 12 h intervals following the
      first three moxifloxacin administrations. Moxifloxacin levels in pleural empyema
      and serum samples were obtained at 0, 30, 60, 120, 240, 360 and 480 min and 12 h
      after the 4th dose and determined by bioassay. RESULTS: In control animals, S.
      pneumoniae (and P. multocida) persisted in the pleural empyema. S. pneumoniae
      also persisted in the pleural empyema fluid when moxifloxacin was administered at
      12.5 mg/kg (x4 administrations). Mean serum and pleural empyema peak moxifloxacin
      levels (following the 25 mg/kg dose) were 7.6 (+/-3.2) and 4.8 (+/-2.5) mg/L,
      respectively. Pleural empyema peak moxifloxacin concentration lagged 1 h after
      serum moxifloxacin. Serum and pleural empyema half-lives were approximately 1.5
      and approximately 6 h, respectively. Serum AUC(1-12) was 29.4 (+/-6.8) mg.h/L and
      serum area under the inhibitory concentration curve (AUIC) was 73.5 mg.h/L.
      Pleural empyema AUC(1-12) was 34.3 (+/-11.7) mg/L and pleural empyema AUIC was
      85.8 mg.h/L. S. pneumoniae was eradicated from pleural empyema following a single
      dose of moxifloxacin 25 mg/kg in 52% of the animals and in 96% following four
      doses. Moxifloxacin was also effective in eradication of P. multocida. The rate
      of pleural empyema sterilization was related to moxifloxacin serum AUIC (r =
      0.82) as well as serum peak moxifloxacin level (r = 0.84), but not to pleural
      empyema AUIC (r = 0.19) or pleural empyema peak levels. The results were similar
      for both methods of induction of pleural empyema. CONCLUSIONS: Moxifloxacin
      appears to penetrate well into experimental pleural empyema and effectively
      sterilize it from S. pneumoniae. Sterilization of S. pneumoniae is related to
      serum AUIC rather than to moxifloxacin pharmacokinetics in pleural empyema.

PMID- 12615870
TI  - Amphotericin B lipid formulations in critically ill patients on continuous veno
      venous haemofiltration.
AB  - OBJECTIVES: The pharmacokinetics of lipid-formulated amphotericin B (AMB), and of
      AMB that has dissociated from its lipid moiety and bound to lipoproteins in
      plasma, were separately determined in critically ill patients. PATIENTS AND
      METHODS: Eleven patients required continuous veno-venous haemofiltration (CVVH).
      Five of them were treated with liposomal AMB (AmBisome) and seven with AMB
      colloidal dispersion (Amphocil). Six of the critically ill were not undergoing
      CVVH (three of them treated with liposomal AMB and three with AMB colloidal
      dispersion). RESULTS: Significant amounts of AMB are liberated from liposomes or
      colloidal dispersion during circulation in plasma, where pharmacokinetics mimic
      that of AMB deoxycholate. Elimination of the remaining lipid-formulated fraction
      is different and differentially affected by CVVH. Plasma levels of lipid
      formulated AMB were significantly higher in patients treated with liposomal AMB
      than in those treated with AMB colloidal dispersion; clearance of liposomal AMB
      is enhanced by haemofiltration, whereas elimination of AMB colloidal dispersion
      is not significantly affected. CONCLUSIONS: The pharmacokinetics of AMB that has
      been liberated from its lipid moiety is similar under treatment with either
      liposomal AMB or AMB colloidal dispersion. Since no significant influence of
      haemofiltration on the pharmacokinetics of liberated AMB has been found, a
      standard dose of lipid-formulated AMB can be recommended for patients on
      haemofiltration.

PMID- 12615871
TI  - Socioeconomic factors and prescription of antibiotics in 0- to 2-year-old Danish
      children.
AB  - OBJECTIVES: The aim was to examine the impact of socioeconomic factors on the use
      of systemic antibiotics during the first 2 years of life. METHODS: This was a
      population-based cohort study of 5024 Danish children born in 1997. The study was
      conducted by linking records drawn from public administrative registries. The
      main predictor variables were mother's education level, household income and
      cohabitation status. The outcome was the number of antibiotic courses (0, 1-5, >
      or =6) during the first 2 years of life. RESULTS: A total of 3273 children
      (65.1%) received 1-5 antibiotic courses, and 337 (6.7%) received > or =6 courses
      of antibiotics during the first 2 years of life. The risk of receiving > or =6
      courses of antibiotics was increased in children of mothers with a low
      educational level (< or =10 years) compared with vocational education [OR 1.3
      (95% CI 1.0-1.7)]. Children of mothers with a higher education >4 years had a
      reduced risk of receiving > or =6 courses [OR 0.3 (95% CI 0.1-0.7)]. Children
      from high-income families had a reduced risk (not statistically significant) of
      receiving antibiotics, compared with children from middle-income families [1-5
      and > or =6 courses: adjusted OR 0.6 (95% CI 0.3-1.2)]. Children of single
      mothers had an increased risk of receiving antibiotics, particularly if the child
      did not attend day care. CONCLUSIONS: Socioeconomic factors have some impact on
      antibiotic prescription in young children. Children of mothers with only basic
      schooling were at highest risk of receiving multiple prescriptions, whereas
      children of mothers with a high education, and/or high household income, had the
      lowest risk.

PMID- 12615872
TI  - Breakthrough pneumococcal bacteraemia in patients treated with clarithromycin or
      oral beta-lactams.
AB  - The incidence of penicillin- and erythromycin-resistant strains of Streptococcus
      pneumoniae has increased considerably in Belgium. The medical charts of all
      patients with pneumococcal bacteraemia who were admitted to hospital over a
      period of 3 years (n = 136) were reviewed to identify treatment failure of
      outpatient antibiotic therapy. Twelve patients had received antibiotics for at
      least 48 h prior to admission. Four treatment failures received clarithromycin as
      pre-hospitalization therapy, and S. pneumoniae from all four patients were highly
      resistant to macrolides. Five patients failed on co-amoxiclav, whereas their S.
      pneumoniae were susceptible to penicillin and amoxicillin. This observation
      suggests that macrolide resistance is clinically relevant and leads to treatment
      failure, whereas suboptimal dosing may explain breakthrough pneumococcal
      bacteraemia in beta-lactam-treated patients.

PMID- 12615873
TI  - Clostridium difficile-associated diarrhoea in patients with community-acquired
      lower respiratory infection being treated with levofloxacin compared with beta
      lactam-based therapy.
AB  - The aim of the study was to compare the incidence of Clostridium difficile
      associated diarrhoea (CDAD) following treatment of community-acquired lower
      respiratory tract infection (LRTI) in hospitalized patients with levofloxacin or
      a beta-lactam-based therapy. Nine hundred and thirty-eight patients were included
      in the prospective open-labelled "randomized" trial. This included 490 patients
      treated with levofloxacin and 448 patients treated with beta-lactams such as
      cefuroxime or amoxicillin. The overall incidence of CDAD was 3.8%. There was a
      lower incidence of CDAD (P < 0.01) in the patients treated with levofloxacin
      (levofloxacin group) (11/490; 2.2%) compared with patients treated with beta
      lactams (beta-lactam group) (25/448; 5.6%), particularly with cefuroxime
      (cefuroxime group) (21/229; 9.2%; P < 0.0001). There was no significant
      difference (P = 0.6) in the incidence of CDAD between patients treated with
      levofloxacin or amoxicillin (amoxicillin group) (4/219; 1.8%). Patients in the
      cefuroxime and amoxicillin groups had a significantly longer duration of
      treatment than patients in the levofloxacin group. Although previous antibiotic
      therapy was a significant risk factor for CDAD in each of the groups, previous
      antibiotic therapy or admission to specific wards in the hospital were not
      confounding factors when comparing the groups. The levofloxacin group had a
      significantly shorter duration of hospitalization (mean 11.7 days; P < 0.01)
      compared with the beta-lactam group (mean 13.3 days), especially compared with
      the cefuroxime group (mean 16 days; P < 0.0000001). The amoxicillin group (mean
      10.5 days) had a shorter duration of stay compared with the levofloxacin group,
      but this was not found to be statistically significant. Patients with CDAD had a
      longer duration of hospital stay than those without CDAD (CDAD +ve 25.8 days;
      CDAD -ve 11.9 days; P < 0.0000001). In conclusion, levofloxacin is less likely to
      be the cause of CDAD and is associated with a shorter duration of hospital stay
      compared with beta-lactam-based therapy for LRTI.

PMID- 12615874
TI  - The vanC-3 vancomycin resistance gene cluster of Enterococcus flavescens CCM 439.
AB  - Enterococcus flavescens CCM 439 is phenotypically similar to Enterococcus
      casseliflavus; it possesses intrinsic low-level resistance to vancomycin and has
      the VanC phenotype. The complete vanC-3 vancomycin resistance gene cluster was
      cloned and sequenced, and found to contain five open reading frames. These
      encoded five proteins that displayed a high degree of amino acid identity to the
      proteins of the vanC-2 cluster of E. casseliflavus. The serine racemases
      displayed the lowest degree of identity (97%), whereas the response regulators
      VanR(C-2) and VanR(C-3) were 100% identical. Long-PCR-RFLP analysis of the vanC-3
      and vanC-2 gene clusters distinguished E. flavescens CCM 439 from E.
      casseliflavus ATCC 25788 due to the absence of a single EcoRV restriction
      endonuclease site from the E. flavescens gene cluster. However, the lack of
      nucleotide divergence between the sequences of the vanC-2 and vanC-3 clusters
      casts doubt on the validity of E. flavescens and E. casseliflavus being classed
      as distinct species.

PMID- 12615875
TI  - A multidrug efflux phenotype mutant of Streptococcus pyogenes.
AB  - We describe a mutant of Streptococcus pyogenes NCTC 8198 with a multidrug efflux
      phenotype. A mutant selected with ethidium bromide showed a four-fold rise in MIC
      of norfloxacin, a 16-fold rise in MIC of ethidium bromide and an eight-fold rise
      in MIC of acriflavine when compared with the parent strain. The MICs were
      unaffected by the efflux pump inhibitors reserpine, rescinnamine and verapamil.
      The mutant's ethidium bromide MIC was reduced two-fold by norfloxacin. Ethidium
      bromide accumulation after 10 min was 58% lower in the mutant compared with the
      parent. This difference was not affected by carbonyl cyanide m
      chlorophenylhydrazone.

PMID- 12615876
TI  - Plasmid-mediated, carbapenem-hydrolysing beta-lactamase, KPC-2, in Klebsiella
      pneumoniae isolates.
AB  - Four isolates of Klebsiella pneumoniae obtained from patients at a Maryland
      medical centre exhibited reduced susceptibility to carbapenems and were found to
      produce the novel, class A, plasmid-mediated, carbapenem-hydrolysing enzyme, KPC
      2. This enzyme has 99% identity with the plasmid-mediated, carbapenem-hydrolysing
      enzyme KPC-1, reported previously in a North Carolina K. pneumoniae isolate. The
      KPC-2-producing isolates were either susceptible or intermediate to imipenem and
      meropenem, unlike the KPC-1-producing isolate, which was resistant to these
      agents. Detection of KPC-2 may be a problem for clinical laboratories because in
      this study it was associated with positive extended-spectrum beta-lactamase
      (ESBL) confirmation tests (clavulanate-potentiated activities of ceftriaxone,
      ceftazidime, cefepime and aztreonam). Therefore, a failure to recognize the
      significance of reduced carbapenem susceptibility in the isolates that remained
      susceptible to imipenem or meropenem could have resulted in the isolates being
      incorrectly identified as ESBL producers.

PMID- 12615877
TI  - Spain14-5 international multiresistant Streptococcus pneumoniae clone resistant
      to fluoroquinolones and other families of antibiotics.
AB  - The Spain(14)-5 international multiresistant clone was initially described as
      resistant to penicillin, tetracycline, chloramphenicol and
      trimethoprim/sulfamethoxazole. In Gipuzkoa, Spain, Streptococcus pneumoniae
      isolated from 16 patients, and determined by PFGE and multilocus sequence typing
      to belong to the Spain(14)-5 clone, showed further resistance to fluoroquinolones
      (all strains had point mutations in the parC and gyrA genes). In addition, most
      strains showed resistance to amoxicillin (MIC > or = 8 mg/L), cefotaxime (MIC >
      or = 2 mg/L), macrolides and lincosamides. Two strains were resistant to
      rifampicin (MIC 8 mg/L). The multiresistance observed in these isolates converts
      the Spain(14)-5 clone into one of the most, if not the most, multiresistant of
      the international clones described.

PMID- 12615878
TI  - Faropenem, a new oral penem: antibacterial activity against selected anaerobic
      and fastidious periodontal isolates.
AB  - The in vitro activity of faropenem, an oral penem, was compared with those of
      penicillin, co-amoxiclav, cefoxitin, clindamycin, erythromycin and metronidazole
      against 106 isolates of anaerobic pathogens involved in systemic infections. The
      organisms tested comprised Porphyromonas gingivalis (29), Prevotella spp.
      (eight), Prevotella melaninogenica (seven), Prevotella intermedia (five),
      Actinomyces spp. (25), Fusobacterium nucleatum (14), Peptostreptococcus spp.
      (11), Bacteroides ureolyticus (five) and Bacteroides forsythus (two). The
      antimicrobial properties of faropenem were investigated by studying MICs, MBCs,
      time-kill kinetics and post-antibiotic effect (PAE). Faropenem was highly active
      against all the anaerobes tested (MIC(90) < or = 0.5 mg/L) and was bactericidal
      against both beta-lactamase-positive and -negative anaerobes, with a maximum
      bactericidal effect at 10 x MIC at between 12 and 24 h. In addition, faropenem
      had an in vitro PAE on all the tested isolates and this was not influenced by
      beta-lactamase production. Faropenem may be useful for treating infections caused
      by periodontal bacteria or oral flora.

PMID- 12615879
TI  - Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages
      and epithelial lining fluid following a single oral 600 mg dose in healthy adult
      subjects.
AB  - A microbiological assay was used to measure concentrations of garenoxacin (BMS
      284756) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and
      epithelial lining fluid (ELF), following a single 600 mg oral dose. Twenty-four
      healthy subjects were allocated into four nominal time intervals after the dose,
      2.5-3.5, 4.5-5.5, 10.5-11.5 and 23.5-24.5 h. Mean concentrations in plasma, BM,
      AM and ELF, respectively, for the four nominal time windows were for 2.5-3.5 h
      10.0 mg/L (S.D. 2.8), 7.0 mg/kg (S.D. 1.3), 106.1 mg/L (S.D. 60.3) and 9.2 mg/L
      (S.D. 3.6); 4.5-5.5 h 8.7 mg/L (S.D. 2.2), 6.0 mg/kg (S.D. 1.9), 158.6 mg/L (S.D.
      137.4) and 14.3 mg/L (S.D. 8.2); 10.5-11.5 h 6.1 mg/L (S.D. 1.9), 4.0 mg/kg (S.D.
      1.4), 76.0 mg/L (S.D. 47.7) and 7.9 mg/L (S.D. 4.6); and 23.5-24.5 h 2.1 mg/L
      (S.D. 0.5), 1.7 mg/kg (S.D. 0.7), 30.7 mg/L (S.D. 12.9) and 3.3 mg/L (S.D. 2.3).
      Concentrations at all sites exceeded MIC(90)s for the common respiratory
      pathogens Haemophilus influenzae (0.03 mg/L), Moraxella catarrhalis (0.015 mg/L)
      and Streptococcus pneumoniae (0.06 mg/L). These data suggest that garenoxacin
      should be effective in the treatment of community-acquired pneumonia and chronic
      obstructive pulmonary disease.

PMID- 12615880
TI  - Oral streptogramins in the management of patients with methicillin-resistant
      Staphylococcus aureus (MRSA) infections.
AB  - OBJECTIVES: Chronic methicillin-resistant Staphylococcus aureus (MRSA) infections
      in debilitated patients are difficult to treat. We studied the clinical efficacy
      and safety of an oral streptogramin, pristinamycin, for these patients. PATIENTS
      AND METHODS: Patients were admitted consecutively to receive pristinamycin,
      usually with doxycycline, for 7-21 days. Fifty-six patients (average age 75
      years) from hospital and community were treated for skin, soft tissue, chest and
      other infections. RESULTS: The overall clinical response rate was 39 of 53
      patients (74%; 95% CI: 60%, 85%) cured or substantially improved, from 53 of 56
      (95%) patients clinically and 49 of 56 (87.5%) patients bacteriologically
      evaluable. Toxic effects comprised gastrointestinal disturbances in eight
      patients (14%) and one (2%) possible skin rash. CONCLUSION: This study suggests
      that oral streptogramins may be useful in the management of debilitated patients
      with MRSA infections.

PMID- 12615881
TI  - Extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae: activity
      of single versus combination agents.

PMID- 12615882
TI  - Mu50 glycopeptide-resistant Staphylococcus aureus: the case of the missing
      penicillinase.

PMID- 12615883
TI  - Quinolone resistance in Campylobacter.

PMID- 12615884
TI  - In vitro activity of fluoroquinolones against erythromycin-susceptible and 
      resistant Bordetella pertussis.

PMID- 12615885
TI  - In vitro activity of linezolid against Clostridium difficile.

PMID- 12615886
TI  - Activity of the oxazolidinones AZD2563 and linezolid against Corynebacterium
      jeikeium and other Corynebacterium spp.

PMID- 12615887
TI  - Spontaneous Achilles tendon rupture in patients treated with levofloxacin.

PMID- 12615888
TI  - IL-13 effector functions.
AB  - IL-13 was first recognized for its effects on B cells and monocytes, where it
      upregulated class II expression, promoted IgE class switching and inhibited
      inflammatory cytokine production. It was also thought to be functionally
      redundant with IL-4. However, studies conducted with knockout mice, neutralizing
      antibodies, and novel antagonists demonstrate that IL-13 possesses several unique
      effector functions that distinguish it from IL-4. Resistance to most
      gastrointestinal nematodes is mediated by type-2 cytokine responses, in which IL
      13 plays a dominant role. By regulating cell-mediated immunity, IL-13 modulates
      resistance to intracellular organisms including Leishmania major, Leishmania
      mexicana, and Listeria monocytogenes. In the lung, IL-13 is the central mediator
      of allergic asthma, where it regulates eosinophilic inflammation, mucus
      secretion, and airway hyperresponsiveness. Manipulation of IL-13 effector
      function may also prove useful in the treatment of some cancers like B-cell
      chronic lymphocytic leukemia and Hodgkin's disease, where IL-13 modulates
      apoptosis or tumor cell growth. IL-13 can also inhibit tumor immunosurveillance.
      As such, inhibitors of IL-13 might be effective as cancer immunotherapeutics by
      boosting type-1-associated anti-tumor defenses. Finally, IL-13 was revealed as a
      potent mediator of tissue fibrosis in both schistosomiasis and asthma, which
      indicates that it is a key regulator of the extracellular matrix. The mechanisms
      that regulate IL-13 production and/or function have also been investigated, and
      IL-4, IL-12, IL-18, IFN-gamma, IL-10, TGF-beta, TNF-alpha, and the IL-4/IL-13
      receptor complex play important roles. This review highlights the effector
      functions of IL-13 and describes multiple pathways for modulating its activity in
      vivo.

PMID- 12615889
TI  - Location is everything: lipid rafts and immune cell signaling.
AB  - The cells of both the adaptive and innate immune systems express a dizzying array
      of receptors that transduce and integrate an enormous amount of information about
      the environment that allows the cells to mount effective immune responses. Over
      the past several years, significant advances have been made in elucidating the
      molecular details of signal cascades initiated by the engagement of immune cell
      receptors by their ligands. Recent evidence indicates that immune receptors and
      components of their signaling cascades are spatially organized and that this
      spatial organization plays a central role in the initiation and regulation of
      signaling. A key organizing element for signaling receptors appears to be
      cholesterol- and sphingolipid-rich plasma membrane microdomains termed lipid
      rafts. Research into the molecular basis of the spatial segregation and
      organization of signaling receptors provided by rafts is adding fundamentally to
      our understanding of the initiation and prolongation of signals in the immune
      system.

PMID- 12615890
TI  - Molecular interactions mediating T cell antigen recognition.
AB  - Over the past decade, key protein interactions contributing to T cell antigen
      recognition have been characterized in molecular detail. These have included
      interactions involving the T cell antigen receptor (TCR) itself, its coreceptors
      CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and
      CTLA-4. A clear view is emerging of how these molecules interact with their
      ligands at the cell-cell interface. Structural and binding studies have confirmed
      that the proteins span small but comparable distances and that, overall, they
      interact very weakly. However, there have been important surprises as well: that
      TCR interactions with peptide-MHC are topologically constrained and characterized
      by considerable conformational flexibility at the binding interface; that
      coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles
      apparently precluding direct interactions with the TCR bound to the same peptide
      MHC; that the structural mechanisms allowing recognition by costimulatory and
      accessory molecules to be weak and yet specific are very heterogeneous; and that
      because of differences in both binding affinity and stoichiometry, there is
      enormous variation in the stability of the various costimulatory receptor/ligand
      complexes. These studies provide the necessary framework for exploring how these
      molecular interactions initiate T cell activation.

PMID- 12615891
TI  - Tolerogenic dendritic cells.
AB  - Dendritic cells (DCs) have several functions in innate and adaptive immunity. In
      addition, there is increasing evidence that DCs in situ induce antigen-specific
      unresponsiveness or tolerance in central lymphoid organs and in the periphery. In
      the thymus DCs generate tolerance by deleting self-reactive T cells. In
      peripheral lymphoid organs DCs also induce tolerance to antigens captured by
      receptors that mediate efficient uptake of proteins and dying cells. Uptake by
      these receptors leads to the constitutive presentation of antigens on major
      histocompatibility complex (MHC) class I and II products. In the steady state the
      targeting of DC antigen capture receptors with low doses of antigens leads to
      deletion of the corresponding T cells and unresponsiveness to antigenic
      rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation
      is coadministered with the antigen, the mice develop immunity, including
      interferon-gamma-secreting effector T cells and memory T cells. There is also new
      evidence that DCs can contribute to the expansion and differentiation of T cells
      that regulate or suppress other immune T cells. One possibility is that distinct
      developmental stages and subsets of DCs and T cells can account for the different
      pathways to peripheral tolerance, such as deletion or suppression. We suggest
      that several clinical situations, including autoimmunity and certain infectious
      diseases, can be influenced by the antigen-specific tolerogenic role of DCs.

PMID- 12615892
TI  - Biology of hematopoietic stem cells and progenitors: implications for clinical
      application.
AB  - Stem cell biology is scientifically, clinically, and politically a current topic.
      The hematopoietic stem cell, the common ancestor of all types of blood cells, is
      one of the best-characterized stem cells in the body and the only stem cell that
      is clinically applied in the treatment of diseases such as breast cancer,
      leukemias, and congenital immunodeficiencies. Multicolor cell sorting enables the
      purification not only of hematopoietic stem cells, but also of their downstream
      progenitors such as common lymphoid progenitors and common myeloid progenitors.
      Recent genetic approaches including gene chip technology have been used to
      elucidate the gene expression profile of hematopoietic stem cells and other
      progenitors. Although the mechanisms that control self-renewal and lineage
      commitment of hematopoietic stem cells are still ambiguous, recent rapid advances
      in understanding the biological nature of hematopoietic stem and progenitor cells
      have broadened the potential application of these cells in the treatment of
      diseases.

PMID- 12615893
TI  - Does the immune system see tumors as foreign or self?
AB  - Given the vast number of genetic and epigenetic changes associated with
      carcinogenesis, it is clear that tumors express many neoantigens. A central
      question in cancer immunology is whether recognition of tumor antigens by the
      immune system leads to activation (i.e., surveillance) or tolerance.
      Paradoxically, while strong evidence exists that specific immune surveillance
      systems operate at early stages of tumorigenesis, established tumors primarily
      induce immune tolerance. A unifying hypothesis posits that the fundamental
      processes of cancer progression, namely tissue invasion and metastasis, are
      inherently proinflammatory and thus activating for innate and adaptive antitumor
      immunity. To elude immune surveillance, tumors must develop mechanisms that block
      the elaboration and sensing of proinflammatory danger signals, thereby shifting
      the balance from activation to tolerance induction. Elucidation of these
      mechanisms provides new strategies for cancer immunotherapy.

PMID- 12615894
TI  - B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell
      antigen receptor.
AB  - B cell chronic lymphocytic leukemia (B-CLL) is an accumulative disease of slowly
      proliferating CD5(+) B lymphocytes that develops in the aging population. Whereas
      some patients with B-CLL have an indolent course and die after many years from
      unrelated causes, others progress very rapidly and succumb within a few years
      from this currently incurable leukemia. Over the past decade studies of the
      structure and function of the B cell antigen receptor (BCR) used by these
      leukemic cells have helped redefine the nature of this disease. In this review we
      summarize and reinterpret several aspects of these BCR-related studies and how
      they might relate to the disease. In particular, we address the ability of
      antigens to select out and drive B cell clones from the normal state to overt
      leukemic cells by binding to BCRs that are relatively unique and characteristic
      of B-CLL cells. The differential capacity of some B-CLL cases to continue to
      transduce signals through the BCR during the leukemic phase and the consequences
      for the in vivo biology of the leukemic clone is also considered. Finally, we
      discuss current and emerging views of the cellular origin of B-CLL cells and the
      differentiation pathways down which we believe these cells progress.

PMID- 12615895
TI  - VDJ recombination: Artemis and its in vivo role in hairpin opening.

PMID- 12615896
TI  - Metal-derivatized major histocompatibility complex: zeroing in on contact
      hypersensitivity.

PMID- 12615898
TI  - Components of the ligand for a Ni++ reactive human T cell clone.
AB  - The major histocompatibility complex (MHC) restriction element for a human Ni(2+)
      reactive T cell, ANi-2.3, was identified as DR52c. A series of experiments
      established that the functional ligand for this T cell was a preformed complex of
      Ni(2+) bound to the combination of DR52c and a specific peptide that was
      generated in human and mouse B cells, but not in fibroblasts nor other antigen
      processing-deficient cells. In addition, ANi-2.3 recognition of this complex was
      dependent on His81 of the MHC beta chain, suggesting a role for this amino acid
      in Ni(2+) binding to MHC. We propose a general model for Ni(2+) recognition in
      which betaHis81 and two amino acids from the NH(2)-terminal part of the MHC bound
      peptide coordinate Ni(2+) which then interacts with some portion of the Valpha
      CDR1 or CDR2 region.

PMID- 12615897
TI  - Defective DNA repair and increased genomic instability in Artemis-deficient
      murine cells.
AB  - In developing lymphocytes, the recombination activating gene endonuclease cleaves
      DNA between V, D, or J coding and recombination signal (RS) sequences to form
      hairpin coding and blunt RS ends, which are fused to form coding and RS joins.
      Nonhomologous end joining (NHEJ) factors repair DNA double strand breaks
      including those induced during VDJ recombination. Human radiosensitive severe
      combined immunodeficiency results from lack of Artemis function, an NHEJ factor
      with in vitro endonuclease/exonuclease activities. We inactivated Artemis in
      murine embryonic stem (ES) cells by targeted mutation. Artemis deficiency results
      in impaired VDJ coding, but not RS, end joining. In addition, Artemis-deficient
      ES cells are sensitive to a radiomimetic drug, but less sensitive to ionizing
      radiation. VDJ coding joins from Artemis-deficient ES cells, which surprisingly
      are distinct from the highly deleted joins consistently obtained from DNA
      dependent protein kinase catalytic subunit-deficient ES cells, frequently lack
      deletions and often display large junctional palindromes, consistent with a
      hairpin coding end opening defect. Strikingly, Artemis-deficient ES cells have
      increased chromosomal instability including telomeric fusions. Thus, Artemis
      appears to be required for a subset of NHEJ reactions that require end
      processing. Moreover, Artemis functions as a genomic caretaker, most notably in
      prevention of translocations and telomeric fusions. As Artemis deficiency is
      compatible with human life, Artemis may also suppress genomic instability in
      humans.

PMID- 12615899
TI  - Flt3 ligand-treated neonatal mice have increased innate immunity against
      intracellular pathogens and efficiently control virus infections.
AB  - Flt-3 ligand (FL), a hematopoetic growth factor, increases the number of
      dendritic cells (DCs), B cells, and natural killer cells in adult mice but the
      effect in neonates was unknown. We show that FL treatment of newborn mice induced
      a >100-fold increase in the innate resistance against infection with herpes
      simplex virus type 1 and Listeria monocytogenes. This resistance required
      interferon (IFN)-alpha/beta for viral and interleukin (IL)-12 for bacterial
      infections. Long-term survival after viral but not bacterial infection was
      increased approximately 100-fold by FL treatment. After treatment, CD11c(+)/major
      histocompatibility complex type II(+) and CD11c(+)/B220(+) DC lineage cells were
      the only cell populations increased in the spleen, liver, peritoneum, and skin.
      DC induction was independent of IFNs, IL-2, -4, -7, -9, -15, and mature T and B
      cells. The data suggest that FL increases the number of DCs in neonates and
      possibly in other immune-compromised individuals, which in turn improves IFN
      alpha/beta- and IL-12-associated immune responses.

PMID- 12615901
TI  - T cell receptor gene rearrangement lineage analysis reveals clues for the origin
      of highly restricted antigen-specific repertoires.
AB  - Due to ordered, stage-specific T cell receptor (TCR)-beta and -alpha locus gene
      rearrangements and cell division during T cell development, a given, ancestral
      TCR-beta locus VDJ rearrangement might be selected into the mature T cell
      repertoire as a small cohort of "half-sibling" progeny expressing identical TCR
      beta chains paired with different TCR-alpha chains. The low frequency of such a
      cohort relative to the total alphabeta TCR repertoire precludes their direct
      identification and characterization in normal mice. We considered it possible
      that positive selection constraints might limit the diversity of TCR-alpha chains
      selected to pair with beta chains encoded by an ancestral VDJ-beta rearrangement.
      If so, half-sibling T cells expressing structurally similar, but different TCR
      alpha chains might recognize the same foreign antigen. By single cell polymerase
      chain reaction analysis of antigen-specific TCRs selected during a model anti
      tumor response, we were able to identify clusters of T cells sharing identical
      VDJ-beta rearrangements but expressing different TCR-alpha chains. The
      amplification of residual DJ-beta rearrangements as clonal markers allowed us to
      track T cells expressing different TCR-alpha chains back to a common ancestral
      VDJ-beta rearrangement. Thus, the diversity of TCR-alpha's selected as partners
      for a given VDJ-beta rearrangement into the mature TCR repertoire may indeed be
      very limited.

PMID- 12615900
TI  - Compartmentalized production of CCL17 in vivo: strong inducibility in peripheral
      dendritic cells contrasts selective absence from the spleen.
AB  - Dendritic cells (DCs)(*) fulfill an important regulatory function at the
      interface of the innate and adaptive immune system. The thymus and activation
      regulated chemokine (TARC/CCL17) is produced by DCs and facilitates the
      attraction of activated T cells. Using a fluorescence-based in vivo reporter
      system, we show that CCL17 expression in mice is found in activated Langerhans
      cells and mature DCs located in various lymphoid and nonlymphoid organs, and is
      up-regulated after stimulation with Toll-like receptor ligands. DCs expressing
      CCL17 belong to the CD11b(+)CD8(-)Dec205(+) DC subset, including the myeloid
      related DCs located in the subepithelial dome of Peyer's patches. CCL17-deficient
      mice mount diminished T cell-dependent contact hypersensitivity responses and
      display a deficiency in rejection of allogeneic organ transplants. In contrast to
      lymphoid organs located at external barriers of the skin and mucosa, CCL17 is not
      expressed in the spleen, even after systemic microbial challenge or after in
      vitro stimulation. These findings indicate that CCL17 production is a hallmark of
      local DC stimulation in peripheral organs but is absent from the spleen as a
      filter of blood-borne antigens.

PMID- 12615902
TI  - Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in
      ventricular remodeling after myocardial infarction.
AB  - Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV
      dilation, a major cause of congestive heart failure and sudden cardiac death.
      Ischemic injury and the ensuing inflammatory response participate in LV
      remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO),
      which accumulates in the infarct zone, is released from neutrophils and monocytes
      leading to the formation of reactive chlorinating species capable of oxidizing
      proteins and altering biological function. We studied acute myocardial infarction
      (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO(-/-)).
      MPO(-/-) demonstrated decreased leukocyte infiltration, significant reduction in
      LV dilation, and marked preservation of LV function. The mechanism appears to be
      due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI
      1) in the MPO(-/-), leading to decreased tissue plasmin activity. MPO and PAI-1
      are shown to have a critical role in the LV response immediately after MI, as
      demonstrated by markedly delayed myocardial rupture in the MPO(-/-) and
      accelerated rupture in the PAI-1(-/-). These data offer a mechanistic link
      between inflammation and LV remodeling by demonstrating a heretofore unrecognized
      role for MPO and PAI-1 in orchestrating the myocardial response to AMI.

PMID- 12615904
TI  - Infectious hepatitis C virus pseudo-particles containing functional E1-E2
      envelope protein complexes.
AB  - The study of hepatitis C virus (HCV), a major cause of chronic liver disease, has
      been hampered by the lack of a cell culture system supporting its replication.
      Here, we have successfully generated infectious pseudo-particles that were
      assembled by displaying unmodified and functional HCV glycoproteins onto
      retroviral and lentiviral core particles. The presence of a green fluorescent
      protein marker gene packaged within these HCV pseudo-particles allowed reliable
      and fast determination of infectivity mediated by the HCV glycoproteins. Primary
      hepatocytes as well as hepato-carcinoma cells were found to be the major targets
      of infection in vitro. High infectivity of the pseudo-particles required both E1
      and E2 HCV glycoproteins, and was neutralized by sera from HCV-infected patients
      and by some anti-E2 monoclonal antibodies. In addition, these pseudo-particles
      allowed investigation of the role of putative HCV receptors. Although our results
      tend to confirm their involvement, they provide evidence that neither LDLr nor
      CD81 is sufficient to mediate HCV cell entry. Altogether, these studies indicate
      that these pseudo-particles may mimic the early infection steps of parental HCV
      and will be suitable for the development of much needed new antiviral therapies.

PMID- 12615903
TI  - The apoptosome pathway to caspase activation in primary human neutrophils
      exhibits dramatically reduced requirements for cytochrome C.
AB  - Caspase activation is a central event in numerous forms of apoptosis and results
      in the proteolytic degradation of multiple substrate proteins that contribute to
      the apoptotic phenotype. An important route to caspase activation proceeds via
      assembly of the "apoptosome" as a result of the cell stress-associated release of
      mitochondrial cytochrome c. Previous studies have shown that primary neutrophils
      are largely incapable of mitochondrial respiration, suggesting that these cells
      either lack functional mitochondria or possess a defective respiratory chain.
      This prompted us to examine whether neutrophils retain an intact cytochrome
      c/apoptotic protease-activating factor 1 (Apaf-1) pathway to caspase activation
      and apoptosis. We show that primary human neutrophils contain barely detectable
      levels of cytochrome c as well as other mitochondrial proteins. Surprisingly,
      neutrophil cell-free extracts readily supported Apaf-1-dependent caspase
      activation, suggesting that these cells may assemble cytochrome c-independent
      apoptosomes. However, further analysis revealed that the trace amount of
      cytochrome c present in neutrophils is both necessary and sufficient for Apaf-1
      dependent caspase activation in these cells. Thus, neutrophils have a lowered
      threshold requirement for cytochrome c in the Apaf-1-dependent cell death
      pathway. These observations suggest that neutrophils retain cytochrome c for the
      purpose of assembling functional apoptosomes rather than for oxidative
      phosphorylation.

PMID- 12615905
TI  - Presentation of antigen by endothelial cells and chemoattraction are required for
      homing of insulin-specific CD8+ T cells.
AB  - Activated insulin-specific CD8(+) T cells (IS-CD8(+) cells) home to the pancreas,
      destroy beta cells, and cause rapid diabetes upon transfer into diabetes-prone
      NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free
      of preexistent inflammation. Thus, we hypothesized that islet-specific homing may
      be in part dependent on IS-CD8(+) cells' recognition of the cognate major
      histocompatibility complex (MHC)/peptide complexes presented by pancreatic
      endothelial cells, which acquire the antigen (insulin) from beta cells. In fact,
      islet-specific homing was abrogated in mice that lack MHC class I expression, or
      presentation of the specific peptide, or have impaired insulin secretion.
      Moreover, we found that IS-CD8(+) cells directly recognized pancreatic
      endothelial cells in islet organ cultures. Triggering of IS-CD8(+) cells' T cell
      receptor (TCR) led to activation of integrins expressed by these cells. In
      addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8(+)
      cells' adhesion to endothelial monolayers and for successful homing in vivo.
      Thus, signaling through TCR and chemokine receptors work in concert to assure
      firm adhesion of T cells to the pancreatic endothelium. The antigen cross
      presentation ability of endothelia may therefore contribute to the specificity of
      homing of activated T lymphocytes to the tissues where antigens are generated by
      other cell types.

PMID- 12615906
TI  - Critical roles of Pten in B cell homeostasis and immunoglobulin class switch
      recombination.
AB  - Pten is a tumor suppressor gene mutated in human cancers. We used the Cre-loxP
      system to generate a B cell-specific mutation of Pten in mice
      (bPten(flox/flox)mice). bPten(flox/flox) mice showed elevated numbers of B1a
      cells and increased serum autoantibodies. Among B2 cells in bPten(flox/flox)
      spleens, numbers of marginal zone B (MZB) cells were significantly increased
      while those of follicular B (FOB) cells were correspondingly decreased. Pten
      deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and
      showed enhanced migration. The survival kinase PKB/Akt was highly activated in
      Pten-deficient splenic B cells. In addition, immunoglobulin class switch
      recombination was defective and induction of activation-induced cytidine
      deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate
      determination of B cells and is an indispensable regulator of B cell homeostasis.

PMID- 12615907
TI  - Increased susceptibility to LPS-induced endotoxin shock in secretory
      leukoprotease inhibitor (SLPI)-deficient mice.
AB  - Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive
      action of neutrophil elastase at the site of inflammation. Recent studies on new
      functions of SLPI have demonstrated that SLPI may play a larger role in innate
      immunity than merely as a protease inhibitor. To clarify the functions of SLPI in
      bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) and
      analyzed their response to experimental endotoxin shock induced by
      lipopolysaccharide (LPS). SLPI(-/-) mice showed a higher mortality from endotoxin
      shock than did wild type mice. This may be explained in part by our observation
      that SLPI(-/-) macro-phages show higher interleukin 6 and high-mobility group
      (HMG)-1 production and nuclear factor kappaB activities after LPS treatment than
      do SLPI(+/+) macrophages. SLPI also affects B cell function. SLPI(-/-) B cells
      show more proliferation and IgM production after LPS treatment than SLPI(+/+) B
      cells. Our results suggest that SLPI attenuates excessive inflammatory responses
      and thus assures balanced functioning of innate immunity.

PMID- 12615908
TI  - Fluorescence resonance energy transfer (FRET) microscopy imaging of live cell
      protein localizations.
AB  - The current advances in fluorescence microscopy, coupled with the development of
      new fluorescent probes, make fluorescence resonance energy transfer (FRET) a
      powerful technique for studying molecular interactions inside living cells with
      improved spatial (angstrom) and temporal (nanosecond) resolution, distance range,
      and sensitivity and a broader range of biological applications.

PMID- 12615909
TI  - Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes
      before cohesins SMC1beta and SMC3.
AB  - In meiotic prophase, the sister chromatids of each chromosome develop a common
      axial element (AE) that is integrated into the synaptonemal complex (SC). We
      analyzed the incorporation of sister chromatid cohesion proteins (cohesins) and
      other AE components into AEs. Meiotic cohesin REC8 appeared shortly before
      premeiotic S phase in the nucleus and formed AE-like structures (REC8-AEs) from
      premeiotic S phase on. Subsequently, meiotic cohesin SMC1beta, cohesin SMC3, and
      AE proteins SCP2 and SCP3 formed dots along REC8-AEs, which extended and fused
      until they lined REC8-AEs along their length. In metaphase I, SMC1beta, SMC3,
      SCP2, and SCP3 disappeared from the chromosome arms and accumulated around the
      centromeres, where they stayed until anaphase II. In striking contrast, REC8
      persisted along the chromosome arms until anaphase I and near the centromeres
      until anaphase II. We propose that REC8 provides a basis for AE formation and
      that the first steps in AE assembly do not require SMC1beta, SMC3, SCP2, and
      SCP3. Furthermore, SMC1beta, SMC3, SCP2, and SCP3 cannot provide arm cohesion
      during metaphase I. We propose that REC8 then provides cohesion. RAD51 and/or
      DMC1 coimmunoprecipitates with REC8, suggesting that REC8 may also provide a
      basis for assembly of recombination complexes.

PMID- 12615910
TI  - Regulation of cytochrome c oxidase activity by c-Src in osteoclasts.
AB  - The function of the nonreceptor tyrosine kinase c-Src as a plasma membrane
      associated molecular effector of a variety of extracellular stimuli is well
      known. Here, we show that c-Src is also present within mitochondria, where it
      phosphorylates cytochrome c oxidase (Cox). Deleting the c-src gene reduces Cox
      activity, and this inhibitory effect is restored by expressing exogenous c-Src.
      Furthermore, reducing endogenous Src kinase activity down-regulates Cox activity,
      whereas activating Src has the opposite effect. Src-induced Cox activity is
      required for normal function of cells that require high levels of ATP, such as
      mitochondria-rich osteoclasts. The peptide hormone calcitonin, which inhibits
      osteoclast function, also down-regulates Cox activity. Increasing Src kinase
      activity prevented the inhibitory effect of calcitonin on Cox activity and
      osteoclast function. These results suggest that c-Src plays a previously
      unrecognized role in maintaining cellular energy stores by activating Cox in
      mitochondria.

PMID- 12615914
TI  - Conformational changes in the integrin beta A domain provide a mechanism for
      signal transduction via hybrid domain movement.
AB  - The ligand-binding head region of integrin beta subunits contains a von
      Willebrand factor type A domain (betaA). Ligand binding activity is regulated
      through conformational changes in betaA, and ligand recognition also causes
      conformational changes that are transduced from this domain. The molecular basis
      of signal transduction to and from betaA is uncertain. The epitopes of mAbs 15/7
      and HUTS-4 lie in the beta(1) subunit hybrid domain, which is connected to the
      lower face of betaA. Changes in the expression of these epitopes are induced by
      conformational changes in betaA caused by divalent cations, function perturbing
      mAbs, or ligand recognition. Recombinant truncated alpha(5)beta(1) with a
      mutation L358A in the alpha7 helix of betaA has constitutively high expression of
      the 15/7 and HUTS-4 epitopes, mimics the conformation of the ligand-occupied
      receptor, and has high constitutive ligand binding activity. The epitopes of 15/7
      and HUTS-4 map to a region of the hybrid domain that lies close to an interface
      with the alpha subunit. Taken together, these data suggest that the transduction
      of conformational changes through betaA involves shape shifting in the alpha7
      helix region, which is linked to a swing of the hybrid domain away from the alpha
      subunit.

PMID- 12615913
TI  - Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by
      inactivating integrins.
AB  - The binding of urokinase plaminogen activator (uPA) to its cell surface receptor
      (uPAR; CD87) promotes cell adhesion by increasing the affinity of the receptor
      for both vitronectin (VN) and integrins. We provide evidence that plasminogen
      activator inhibitor (PAI)-1 can detach cells by disrupting uPAR-VN and integrin
      VN interactions and that it does so by binding to the uPA present in uPA-uPAR
      integrin complexes on the cell surface. The detached cells cannot reattach to VN
      unless their surface integrins are first activated by treatment with MnCl2.
      Immunoprecipitation and subcellular fractionation experiments reveal that PAI-1
      treatment triggers deactivation and disengagement of uPA-uPAR-integrin complexes
      and their endocytic clearance by the low density lipoprotein receptor-related
      protein. Transfection experiments demonstrate that efficient cell detachment by
      PAI-1 requires an excess of matrix-engaged uPA-uPAR-integrin complexes over free
      engaged integrins and that changes in this ratio alter the efficacy of PAI-1.
      Together, these results suggest a VN-independent, uPA-uPAR-dependent mechanism by
      which PAI-1 induces cell detachment. This pathway may represent a general
      mechanism, since PAI-1 also can detach cells from fibronectin and type-1
      collagen. This novel "deadhesive" activity of PAI-1 toward a variety of cells
      growing on different extracellular matrices may begin to explain why high PAI-1
      levels often are associated with a poor prognosis in human metastatic disease.

PMID- 12615912
TI  - Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on
      collagen through activation of Src kinases and PLCgamma2.
AB  - Collagen plays a critical role in hemostasis by promoting adhesion and activation
      of platelets at sites of vessel injury. In the present model of platelet-collagen
      interaction, adhesion is mediated via the inside-out regulation of integrin
      alpha2beta1 and activation through the glycoprotein VI (GPVI)-Fc receptor (FcR)
      gamma-chain complex. The present study extends this model by demonstrating that
      engagement of alpha2beta1 by an integrin-specific sequence from within collagen
      or by collagen itself generates tyrosine kinase-based intracellular signals that
      lead to formation of filopodia and lamellipodia in the absence of the GPVI-FcR
      gamma-chain complex. The same events do not occur in platelet suspensions.
      alpha2beta1 activation of adherent platelets stimulates tyrosine phosphorylation
      of many of the proteins in the GPVI-FcR gamma-chain cascade, including Src, Syk,
      SLP-76, and PLCgamma2 as well as plasma membrane calcium ATPase and focal
      adhesion kinase. alpha2beta1-mediated spreading is dramatically inhibited in the
      presence of the Src kinase inhibitor PP2 and in PLCgamma2-deficient platelets.
      Spreading is abolished by chelation of intracellular Ca2+. Demonstration that
      adhesion of platelets to collagen via alpha2beta1 generates intracellular signals
      provides a new insight into the mechanisms that control thrombus formation and
      may explain the unstable nature of beta1-deficient thrombi and why loss of the
      GPVI-FcR gamma-chain complex has a relatively minor effect on bleeding.

PMID- 12615911
TI  - Differential regulation of cell motility and invasion by FAK.
AB  - Cell migration and invasion are fundamental components of tumor cell metastasis.
      Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are
      connected with elevated tumorigenesis. Null mutation of FAK results in embryonic
      lethality, and FAK-/- fibroblasts exhibit cell migration defects in culture. Here
      we show that viral Src (v-Src) transformation of FAK-/- cells promotes integrin
      stimulated motility equal to stable FAK reexpression. However, FAK-/- v-Src cells
      were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase
      activity were required for the generation of an invasive cell phenotype. Cell
      invasion was linked to transient FAK accumulation at lamellipodia, formation of a
      FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal
      kinase activation, and increased matrix metalloproteinase expression and
      activity. Our studies support a dual role for FAK in promoting cell motility and
      invasion through the activation of distinct signaling pathways.

PMID- 12615915
TI  - Dual functional roles of dentin matrix protein 1. Implications in
      biomineralization and gene transcription by activation of intracellular Ca2+
      store.
AB  - Dentin matrix protein 1 (DMP1) is a bone- and teeth-specific protein initially
      identified from mineralized dentin. Here we report that DMP1 is primarily
      localized in the nuclear compartment of undifferentiated osteoblasts. In the
      nucleus, DMP1 acts as a transcriptional component for activation of osteoblast
      specific genes like osteocalcin. During the early phase of osteoblast maturation,
      Ca(2+) surges into the nucleus from the cytoplasm, triggering the phosphorylation
      of DMP1 by a nuclear isoform of casein kinase II. This phosphorylated DMP1 is
      then exported out into the extracellular matrix, where it regulates nucleation of
      hydroxyapatite. Thus, DMP1 is a unique molecule that initiates osteoblast
      differentiation by transcription in the nucleus and orchestrates mineralized
      matrix formation extracellularly, at later stages of osteoblast maturation. The
      data presented here represent a paradigm shift in the understanding of DMP1
      function. This information is crucial in understanding normal bone formation,
      remodeling, fracture healing, and skeletal tissue repair.

PMID- 12615917
TI  - Tumor necrosis factor-alpha-induced targeted proteolysis of cystathionine beta
      synthase modulates redox homeostasis.
AB  - Cystathionine beta-synthase (CBS) catalyzes the first of two steps in the
      transsulfuration pathway that converts homocysteine to cysteine, a precursor of
      glutathione, a major intracellular antioxidant. Tumor necrosis factor-alpha
      (TNFalpha), which is known to enhance production of reactive oxygen species,
      increased CBS activity and glutathione levels in HepG2 cells. Western blot
      analysis revealed that the higher CBS activity correlated with cleavage of the
      enzyme to a truncated form. This cleavage was suppressed by inhibitors of
      superoxide production or by transfection with an expression vector for manganese
      superoxide dismutase. The commonly used proteasome inhibitors, MG132 and
      lactacystin but not N-acetyl-Leu-Leu-norleucinal, suppressed the TNFalpha-induced
      response. Targeted proteolysis of CBS was also observed in livers of mice
      injected with lipopolysaccharide, which is known to induce TNFalpha. Together,
      these data reveal a novel and previously unknown mechanism of regulation for
      homocysteine-linked glutathione homeostasis in cells challenged by oxidative
      stress.

PMID- 12615916
TI  - Characterization of human constitutive photomorphogenesis protein 1, a RING
      finger ubiquitin ligase that interacts with Jun transcription factors and
      modulates their transcriptional activity.
AB  - RING finger proteins have been implicated in many fundamental cellular processes,
      including the control of gene expression. A key regulator of light-dependent
      development in Arabidopsis thaliana is the constitutive photomorphogenesis
      protein 1 (atCOP1), a RING finger protein that plays an essential role in
      translating light/dark signals into specific changes in gene transcription.
      atCOP1 binds the basic leucine zipper factor HY5 and suppresses its
      transcriptional activity through a yet undefined mechanism that results in HY5
      degradation in response to darkness. Furthermore, the pleiotropic phenotype of
      atCOP1 mutants indicates that atCOP1 may be a central regulator of several
      transcriptional pathways. Here we report the cloning and characterization of the
      human orthologue of atCOP1. Human COP1 (huCOP1) distributes both to the cytoplasm
      and the nucleus of cells and shows a striking degree of sequence conservation
      with atCOP1, suggesting the possibility of a functional conservation as well. In
      co-immunoprecipitation assays huCOP1 specifically binds basic leucine zipper
      factors of the Jun family. As a functional consequence of this interaction,
      expression of huCOP1 in mammalian cells down-regulates c-Jun-dependent
      transcription and the expression of the AP-1 target genes, urokinase and matrix
      metalloproteinase 1. The RING domain of huCOP1 displays ubiquitin ligase activity
      in an autoubiquitination assay in vitro; however, suppression of AP-1-dependent
      transcription by huCOP1 occurs in the absence of changes in c-Jun protein levels,
      suggesting that this inhibitory effect is independent of c-Jun degradation. Our
      findings indicate that huCOP1 is a novel regulator of AP-1-dependent
      transcription sharing the important properties of Arabidopsis COP1 in the control
      of gene expression.

PMID- 12615918
TI  - Kinetics control preferential heterodimer formation of platelet-derived growth
      factor from unfolded A- and B-chains.
AB  - The folding and assembly of platelet-derived growth factor (PDGF), a potent
      mitogen involved in wound-healing processes and member of the cystine knot growth
      factor family, was studied. The kinetics of the formation of disulfide-bonded
      dimers were investigated under redox reshuffling conditions starting either from
      unfolded and reduced PDGF-A- or B-chains or an equimolar mixture of both chains.
      It is shown that in all cases the formation of disulfide-bonded dimers is a very
      slow process occurring in the time scale of hours with a first-order rate
      determining step. The formation of disulfide-bonded PDGF-AA or PDGF-BB homodimers
      displayed identical kinetics, indicating that both monomeric forms as well as the
      dimerized homodimer have similar folding and assembly pathways. In contrast, the
      formation of the heterodimer occurred three times more rapidly compared with the
      formation of the homodimers. As both monomeric forms revealed similar
      renaturation kinetics, it can be concluded that the first-order rate-determining
      folding step does not occur during monomer folding but must be attributed to
      conformational rearrangements of the dimerized, not yet disulfide-bonded protein.
      These structural rearrangements allow a more rapid formation of intermolecular
      disulfide bonds between the two different monomers of a heterodimer compared with
      the formation of the disulfide bonds between two identical monomers. The
      preferential formation of disulfide-bonded heterodimers from an equimolar mixture
      of unfolded A- and B-chains is thus a kinetically controlled process. Moreover,
      similar activation enthalpies for the formation of all different isoforms suggest
      that faster heterodimerization is controlled by entropic factors.

PMID- 12615919
TI  - Calcineurin/nuclear factors of activated T cells (NFAT)-activating and
      immunoreceptor tyrosine-based activation motif (ITAM)-containing protein (CNAIP),
      a novel ITAM-containing protein that activates the calcineurin/NFAT-signaling
      pathway.
AB  - We report in this study the identification and characterization of a novel
      protein that we designated as calcineurin/NFAT-activating and immunoreceptor
      tyrosine-based activation motif (ITAM)-containing protein (CNAIP). The predicted
      270-amino acid sequence contains an N-terminal signal peptide, an immunoglobin
      domain in the extracellular region, a transmembrane domain and an ITAM in the
      cytoplasmic tail. Quantitative reverse transcription-PCR showed that CNAIP was
      preferentially expressed in neutrophils, monocytes, mast cells, and other immune
      related cells. Co-transfection of CNAIP expression constructs with luciferase
      reporter plasmids in HMC-1 cells resulted in activation of interleukin-13 and
      tumor necrosis factor-alpha promoters, which was mediated through the
      calcineurin/NFAT-signaling pathway. Mutation of either or both tyrosines in the
      ITAM abolished transcriptional activation induced by CNAIP, indicating that the
      ITAM is indispensable for CNAIP function in activating cytokine gene promoters.
      Thus, it is concluded that CNAIP is a novel ITAM-containing protein that
      activates the calcineurin/NFAT-signaling pathway and the downstream cytokine gene
      promoters.

PMID- 12615920
TI  - Dimerization and DNA binding properties of the Bacillus licheniformis 749/I BlaI
      repressor.
AB  - In the absence of penicillin, the beta-lactamase encoding gene blaP of Bacillus
      licheniformis 749/I is negatively regulated by the transcriptional repressor
      BlaI. Three palindromic operator regions are recognized by BlaI: two in the blaP
      promoter (OP1 and OP2) and one (OP3) in the promoter of the blaI-blaR1 operon. In
      this study, the dissociation constant of the purified BlaI dimer was estimated at
      25 microm by equilibrium ultracentrifugation. Quantitative Western blot analysis
      indicates that the intracellular concentrations of BlaI in B. licheniformis 749/I
      and Bacillus subtilis transformed by a multicopy plasmid harboring the beta
      lactamase locus (blaP-blaI-blaR1) were lower than (1.9 microm) or in the same
      range as (75 microm) the dissociation constant, respectively. This suggests that
      BlaI is partially dimeric in the cytoplasm of these strains and interacts in vivo
      with its operators as a preformed dimer. This hypothesis is supported by band
      shift assays on an operator containing a randomized half-operator sequence. The
      global dissociation constants of the operator-BlaI dimer complexes were measured
      by band shift assays and estimated as K(d)(OP1) = 1.7 +/- 0.5 10(-15) m(2),
      K(d)(OP2) = 3.3 +/- 0.9 10(-15) m(2), and K(d)(OP3) = 10.5 +/- 2.5 10(-15) m(2).
      The role of the DNA binding properties of BlaI on the beta-lactamase regulation
      is discussed.

PMID- 12615922
TI  - Constitutive STAT3 activation in intestinal T cells from patients with Crohn's
      disease.
AB  - Via cytoplasmic signal transduction pathways, cytokines induce a variety of
      biological responses and modulate the outcome of inflammatory diseases and
      malignancies. Crohn's disease is a chronic inflammatory bowel disease of unknown
      etiology. Perturbation of the intestinal cytokine homeostasis is believed to play
      a pivotal role, but the pathogenesis of Crohn's disease is not fully understood.
      Here, we study intestinal T cells from Crohn's disease and healthy volunteers. We
      show that STAT3 and STAT4 are constitutively activated in Crohn's patients but
      not in healthy volunteers. The activation is specific, because other STAT
      proteins are not constitutively activated. Furthermore, the STAT3 regulated
      protein, SOCS3, is also constitutively expressed in Crohn's patients but not in
      healthy volunteers. Taken together, these data provide evidence of abnormal
      STAT/SOCS signaling in Crohn's disease. This aberrant activation, so far noted
      only in malignant cells, establish a new critical approach for better
      understanding the immunopathogenesis of Crohn's disease.

PMID- 12615921
TI  - Identification of Shp-2 as a Stat5A phosphatase.
AB  - Stat5A, a member of the signal transducers and activators of transcription (Stat)
      family, is activated upon a single tyrosine phosphorylation. Although much is
      known about the activation process, the mechanism by which the tyrosine
      phosphorylated Stat5A proteins are inactivated is largely unknown. In this
      report, we demonstrate that down-regulation of the tyrosine-phosphorylated Stat5A
      was via dephosphorylation. Using tyrosine-phosphorylated peptides derived from
      Stat5A, we were able to purify protein-tyrosine phosphatase Shp-2 from cell
      lysates. Shp-2, but not Shp-1, specifically interacted with Stat5A in vivo, and
      the interaction was tyrosine phosphorylation-dependent. Moreover, Shp-2 was able
      to accelerate Stat5A dephosphorylation, and dephosphorylation of Stat5A was
      dramatically delayed in Shp-2-deficient cells. Therefore, we conclude that Shp-2
      is a Stat5A phosphatase, which down-regulates the active Stat5A in vivo.

PMID- 12615923
TI  - 37-kDa laminin receptor precursor modulates cytotoxic necrotizing factor 1
      mediated RhoA activation and bacterial uptake.
AB  - Cytotoxic necrotizing factor 1 (CNF1) is a bacterial toxin known to activate Rho
      GTPases and induce host cell cytoskeleton rearrangements. The constitutive
      activation of Rho GTPases by CNF1 is shown to enhance bacterial uptake in
      epithelial cells and human brain microvascular endothelial cells. However, it is
      unknown how exogenous CNF1 exhibits such phenotypes in eukaryotic cells. Here, we
      identified 37-kDa laminin receptor precursor (LRP) as the receptor for CNF1 from
      screening the cDNA library of human brain microvascular endothelial cells by the
      yeast two-hybrid system using the N-terminal domain of CNF1 as bait. CNF1
      mediated RhoA activation and bacterial uptake were inhibited by exogenous LRP or
      LRP antisense oligodeoxynucleotides, whereas they were increased in LRP
      overexpressing cells. These findings indicate that the CNF1 interaction with LRP
      is the initial step required for CNF1-mediated RhoA activation and bacterial
      uptake in eukaryotic cells.

PMID- 12615924
TI  - Protein kinase C inhibits ROMK1 channel activity via a phosphatidylinositol 4,5
      bisphosphate-dependent mechanism.
AB  - The activity of apical K(+) channels in cortical collecting duct (CCD) is
      stimulated and inhibited by protein kinase A (PKA) and C (PKC), respectively.
      Direct interaction between phosphatidylinositol 4,5-bisphosphate (PIP(2)) and the
      cloned CCD K(+) channel, ROMK1, is critical for channel opening. We have found
      previously that phosphorylation of ROMK1 by PKA increases affinity of the channel
      for PIP(2) and mutation of PKA sites reduces the affinity of ROMK1 for PIP(2). In
      this study we investigate the molecular mechanism for PKC regulation of ROMK and
      report that mutants of ROMK1 with reduced PIP(2) affinity exhibit an increased
      sensitivity to inhibition by phorbol myristate acetate (PMA). The effect of PMA
      can be prevented by pretreatment with calphostin-C. Activation of PKC by
      carbachol in Xenopus oocytes co-expressing M1 muscarinic receptors also causes
      inhibition of the channels. Calphostin-C prevents carbachol-induced inhibition,
      suggesting that activation of PKC is necessary for inhibition of the channels.
      PMA reduces open probability of the channel in cell-attached patch clamp
      recordings. After inhibition by PMA in cell-attached recordings, application of
      PIP(2) to the cytoplasmic face of excised inside-out membranes restores channel
      activity. PMA reduces PIP(2) content in oocyte membrane and calphostin-C prevents
      the reduction. These results suggest that reduction of membrane PIP(2) content
      contributes to the inhibition of ROMK1 channels by PKC. This mechanism may
      underscore the inhibition of K(+) secretion in CCD by hormones that activate PKC.

PMID- 12615925
TI  - The adaptor protein fish associates with members of the ADAMs family and
      localizes to podosomes of Src-transformed cells.
AB  - Fish is a scaffolding protein and Src substrate. It contains an amino-terminal
      Phox homology (PX) domain and five Src homology 3 (SH3) domains, as well as
      multiple motifs for binding both SH2 and SH3 domain-containing proteins. We have
      determined that the PX domain of Fish binds 3-phosphorylated
      phosphatidylinositols (including phosphatidylinositol 3-phosphate and
      phosphatidylinositol 3,4-bisphosphate). Consistent with this, a fusion protein of
      green fluorescent protein and the Fish PX domain localized to punctate structures
      similar to endosomes in normal fibroblasts. However, the full-length Fish protein
      was largely cytoplasmic, suggesting that its PX domain may not be able to make
      intermolecular interactions in unstimulated cells. In Src-transformed cells, we
      observed a dramatic re-localization of some Fish molecules to actin-rich
      structures called podosomes; the PX domain was both necessary and sufficient to
      effect this translocation. We used a phage display screen with the fifth SH3
      domain of Fish and isolated ADAM19 as a binding partner. Subsequent analyses in
      mammalian cells demonstrated that Fish interacts with several members of the
      ADAMs family, including ADAMs 12, 15, and 19. In Src-transformed cells, ADAM12 co
      localized with Fish in podosomes. Because members of the ADAMs family have been
      implicated in growth factor processing, as well as cell adhesion and motility,
      Fish could be acting as an adaptor molecule that allows Src to impinge on these
      processes.

PMID- 12615926
TI  - Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells.
AB  - Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth
      muscle cells (PASMC) and plays an important role in the development of pulmonary
      hypertension. Signal transduction initiated by 5-HT involves serotonin
      transporter-dependent generation of reactive oxygen species and activation of the
      MEK-ERK pathway. However, the downstream transcriptional regulatory components
      have not been identified. In systemic smooth muscle cells, GATA-6 has been shown
      to regulate mitogenesis by driving cells into a quiescent state, and the down
      regulation of GATA-6 induces mitogenesis. Thus, the present study tested the
      hypothesis that 5-HT induces mitogenesis of PASMC by down-regulating GATA-6.
      Quiescent bovine PASMC were treated with 5-HT, and the binding activity of
      nuclear extracts toward GATA DNA sequence was monitored. Surprisingly, PASMC
      express GATA-4, and 5-HT up-regulates the GATA DNA binding activity. Pretreatment
      of cells with inhibitors of serotonin transporter, reactive oxygen species, and
      MEK blocks GATA-4 activation by 5-HT. GATA-4 is not activated when the ERK
      phosphorylation site is mutated, indicating that 5-HT phosphorylates GATA-4 via
      the MEK/ERK pathway. GATA up-regulation is also induced by other mitogens of
      PASMC such as endothelin-1 and platelet-derived growth factor. Dominant negative
      mutants of GATA-4 suppress cyclin D2 expression and cell growth, indicating that
      GATA-4 activation regulates PASMC proliferation. Thus, GATA-4 mediates 5-HT
      induced growth of PASMC and may be an important therapeutic target for the
      prevention of pulmonary hypertension.

PMID- 12615927
TI  - Interaction of the anaphase-promoting complex/cyclosome and proteasome protein
      complexes with multiubiquitin chain-binding proteins.
AB  - Fission yeast Rhp23 and Pus1 represent two families of multiubiquitin chain
      binding proteins that associate with the proteasome. We show that both proteins
      bind to different regions of the proteasome subunit Mts4. The binding site for
      Pus1 was mapped to a cluster of repetitive sequences also found in the proteasome
      subunit SpRpn2 and the anaphase-promoting complex/cyclosome (APC/C) subunit Cut4.
      The putative role of Pus1 as a factor involved in allocation of ubiquitinylated
      substrates for the proteasome is discussed.

PMID- 12615928
TI  - Claudin-8 expression in Madin-Darby canine kidney cells augments the paracellular
      barrier to cation permeation.
AB  - Claudins are a family of integral membrane proteins of the tight junction that
      are thought to participate in the permeation of solutes across epithelia via the
      paracellular pathway. Claudin-8 is expressed in the distal renal tubule, which
      has a characteristically low passive permeability to monovalent cations. To test
      the hypothesis that claudin-8 plays a role in forming a tight paracellular
      barrier to cations, stably transfected Madin-Darby canine kidney II cell lines
      with inducible expression of claudin-8 were generated. Induction of claudin-8
      expression was associated with down-regulation of endogenous claudin-2 protein.
      Other tight junction proteins were expressed and targeted normally, and the
      number of junctional strands was minimally altered. By Ussing chamber and
      radiotracer flux studies, claudin-8 expression was found to reduce paracellular
      permeability to monovalent inorganic and organic cations and to divalent cations
      but not to anions or neutral solutes. The size selectivity, charge dependence,
      and activation energy of paracellular cation permeation were all unchanged. These
      observations are consistent with a model in which claudin-2 encodes a highly
      cation-permeable channel, whereas claudin-8 acts primarily as a cation barrier.
      When exogenous claudin-8 is expressed, it replaces endogenous claudin-2,
      inserting in its place into existing tight junction strands, thereby reducing the
      apparent number of functional cation pores. Our findings suggest that claudin-8
      plays an important role in the paracellular cation barrier of the distal renal
      tubule.

PMID- 12615929
TI  - Sterol regulatory element-binding proteins are negatively regulated through SUMO
      1 modification independent of the ubiquitin/26 S proteasome pathway.
AB  - Sterol regulatory element-binding proteins (SREBPs) are major transcription
      factors that activate the genes involved in cholesterol and fatty acid
      biosynthesis. We here report that the nuclear forms of SREBPs are modified by the
      small ubiquitin-related modifier (SUMO)-1. Mutational analyses identified two
      major sumoylation sites (Lys(123) and Lys(418)) in SREBP-1a and a single site
      (Lys(464)) in SREBP-2. Mutant SREBPs lacking one or two sumoylation sites
      exhibited increased transactivation capacity on an SREBP-responsive promoter.
      Overexpression of SUMO-1 reduced whereas its dominant negative form increased
      mRNA levels of SREBP-responsive genes. Nuclear SREBPs interacted with the SUMO-1
      conjugating enzyme Ubc9, and overexpression of a dominant negative form of Ubc9
      increased the mRNA levels of SREBP-responsive genes. Pulse-chase experiments
      revealed that sumoylation did not affect the degradation of SREBPs through the
      ubiquitin-proteasome pathway. In vitro ubiquitylation assay showed no competition
      between ubiquitin and SUMO-1 for the same lysine. Considered together, our
      results indicate that SUMO-1 modification suppresses the transactivation capacity
      of nuclear SREBPs in a manner different from the negative regulatory mechanism
      mediated by proteolysis.

PMID- 12615930
TI  - Phosphorylation-dependent regulation of Kv2.1 Channel activity at tyrosine 124 by
      Src and by protein-tyrosine phosphatase epsilon.
AB  - Voltage-gated potassium (Kv) channels are a complex and heterogeneous family of
      proteins that play major roles in brain and cardiac excitability. Although Kv
      channels are activated by changes in cell membrane potential, tyrosine
      phosphorylation of channel subunits can modulate the extent of channel activation
      by depolarization. We have previously shown that dephosphorylation of Kv2.1 by
      the nonreceptor-type tyrosine phosphatase PTPepsilon (cyt-PTPepsilon) down
      regulates channel activity and counters its phosphorylation and up-regulation by
      Src or Fyn. In the present study, we identify tyrosine 124 within the T1
      cytosolic domain of Kv2.1 as a target site for the activities of Src and cyt
      PTPepsilon. Tyr(124) is phosphorylated by Src in vitro; in whole cells, Y124F
      Kv2.1 is significantly less phosphorylated by Src and loses most of its ability
      to bind the D245A substrate-trapping mutant of cyt-PTPepsilon. Phosphorylation of
      Tyr(124) is critical for Src-mediated up-regulation of Kv2.1 channel activity,
      since Y124F Kv2.1-mediated K(+) currents are only marginally up-regulated by Src,
      in contrast with a 3-fold up-regulation of wild-type Kv2.1 channels by the
      kinase. Other properties of Kv2.1, such as expression levels, subcellular
      localization, and voltage dependence of channel activation, are unchanged in
      Y124F Kv2.1, indicating that the effects of the Y124F mutation are specific.
      Together, these results indicate that Tyr(124) is a significant site at which the
      mutually antagonistic activities of Src and cyt-PTPepsilon affect Kv2.1
      phosphorylation and activity.

PMID- 12615931
TI  - Identification of a key determinant of hepatitis C virus cell culture adaptation
      in domain II of NS3 helicase.
AB  - Efficient replication of hepatitis C virus (HCV) replicons in cell culture is
      associated with specific sequences not generally observed in vivo. These cell
      culture adaptive mutations dramatically increase the frequency with which
      replication is established in vitro. However, replicons derived from HCV isolates
      that have been shown to replicate in chimpanzees do not replicate in cell culture
      even when these adaptive mutations are introduced. To better understand this
      apparent paradox, we performed a gain-of-function screen to identify sequences
      that could confer cell culture replication competence to replicons derived from
      chimpanzee infectious HCV isolates. We found that residue 470 in domain II of the
      NS3 helicase is a critical determinant in cell culture adaptation. Substitutions
      in residue 470 when combined with the NS5A-S232I adaptive mutation are both
      necessary and sufficient to confer cell culture replication to otherwise inactive
      replicons, including those derived from genotype 1b HCV-BK and genotype 1a HCV
      H77 isolates. The specific substitution at residue 470 required for replication
      is context-dependent, with R470M and P470L being optimal for the activity of HCV
      BK and HCV-H77 replicons, respectively. Together these data indicate that
      mutations in the NS3 helicase domain II act in concert with previously identified
      adaptive mutations and predict that introduction of compatible residues at these
      positions can confer cell culture replication activity to diverse HCV isolates.

PMID- 12615933
TI  - Characterization of the last subunit of the Arabidopsis COP9 signalosome.

PMID- 12615934
TI  - Laser-capture microdissection, a tool for the global analysis of gene expression
      in specific plant cell types: identification of genes expressed differentially in
      epidermal cells or vascular tissues of maize.
AB  - Laser-capture microdissection (LCM) allows for the one-step procurement of large
      homogeneous populations of cells from tissue sections. In mammals, LCM has been
      used to conduct cDNA microarray and proteomics studies on specific cell types.
      However, LCM has not been applied to plant cells, most likely because plant cell
      walls make it difficult to separate target cells from surrounding cells and
      because ice crystals can form in the air spaces between cells when preparing
      frozen sections. By fixing tissues, using a cryoprotectant before freezing, and
      using an adhesive-coated slide system, it was possible to capture large numbers
      (>10,000) of epidermal cells and vascular tissues (vascular bundles and bundle
      sheath cells) from ethanol:acetic acid-fixed coleoptiles of maize. RNA extracted
      from these cells was amplified with T7 RNA polymerase and used to hybridize a
      microarray containing approximately 8800 maize cDNAs. Approximately 250 of these
      were expressed preferentially in epidermal cells or vascular tissues. These
      results demonstrate that the combination of LCM and microarrays makes it feasible
      to conduct high-resolution global gene expression analyses of plants. This
      approach has the potential to enhance our understanding of diverse plant cell
      type-specific biological processes.

PMID- 12615935
TI  - Alteration of microtubule dynamic instability during preprophase band formation
      revealed by yellow fluorescent protein-CLIP170 microtubule plus-end labeling.
AB  - At the onset of mitosis, plant cells form a microtubular preprophase band that
      defines the plane of cell division, but the mechanism of its formation remains a
      mystery. Here, we describe the use of mammalian yellow fluorescent protein-tagged
      CLIP170 to visualize the dynamic plus ends of plant microtubules in transfected
      cowpea protoplasts and in stably transformed and dividing tobacco Bright Yellow 2
      cells. Using plus-end labeling, we observed dynamic instability in different
      microtubular conformations in live plant cells. The interphase plant microtubules
      grow at 5 micro m/min, shrink at 20 micro m/min, and display catastrophe and
      rescue frequencies of 0.02 and 0.08 events/s, respectively, exhibiting faster
      turnover than their mammalian counterparts. Strikingly, during preprophase band
      formation, the growth rate and catastrophe frequency of plant microtubules
      double, whereas the shrinkage rate and rescue frequency remain unchanged, making
      microtubules shorter and more dynamic. Using these novel insights and four
      dimensional time-lapse imaging data, we propose a model that can explain the
      mechanism by which changes in microtubule dynamic instability drive the dramatic
      rearrangements of microtubules during preprophase band and spindle formation in
      plant cells.

PMID- 12615936
TI  - Cell polarity and PIN protein positioning in Arabidopsis require STEROL
      METHYLTRANSFERASE1 function.
AB  - Plants have many polarized cell types, but relatively little is known about the
      mechanisms that establish polarity. The orc mutant was identified originally by
      defects in root patterning, and positional cloning revealed that the affected
      gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate
      synthesis and composition of major membrane sterols. smt1(orc) mutants displayed
      several conspicuous cell polarity defects. Columella root cap cells revealed
      perturbed polar positioning of different organelles, and in the smt1(orc) root
      epidermis, polar initiation of root hairs was more randomized. Polar auxin
      transport and expression of the auxin reporter DR5-beta-glucuronidase were
      aberrant in smt1(orc). Patterning defects in smt1(orc) resembled those observed
      in mutants of the PIN gene family of putative auxin efflux transporters.
      Consistently, the membrane localization of the PIN1 and PIN3 proteins was
      disturbed in smt1(orc), whereas polar positioning of the influx carrier AUX1
      appeared normal. Our results suggest that balanced sterol composition is a major
      requirement for cell polarity and auxin efflux in Arabidopsis.

PMID- 12615937
TI  - Disruption mutations of ADA2b and GCN5 transcriptional adaptor genes dramatically
      affect Arabidopsis growth, development, and gene expression.
AB  - We previously identified Arabidopsis genes homologous with the yeast ADA2 and
      GCN5 genes that encode components of the ADA and SAGA histone acetyltransferase
      complexes. In this report, we explore the biological roles of the Arabidopsis
      ADA2b and GCN5 genes. T-DNA insertion mutations in ADA2b and GCN5 were found to
      have pleiotropic effects on plant growth and development, including dwarf size,
      aberrant root development, and short petals and stamens in flowers. Approximately
      5% of the 8200 genes assayed by DNA microarray analysis showed changes of
      expression in the mutants, three-fourths of which were upregulated and only half
      of which were altered similarly in the two mutant strains. In cold acclimation
      experiments, C-repeat binding factors (CBFs) were induced in the mutants as in
      wild-type plants, but subsequent transcription of cold-regulated (COR) genes was
      reduced in both mutants. Remarkably, nonacclimated ada2b-1 (but not gcn5-1)
      mutant plants were more freezing tolerant than nonacclimated wild-type plants,
      suggesting that ADA2b may directly or indirectly repress a freezing tolerance
      mechanism that does not require the expression of CBF or COR genes. We conclude
      that the Arabidopsis ADA2b and GCN5 proteins have both similar and distinct
      functions in plant growth, development, and gene expression and may be components
      of both a common coactivator complex and separate complexes with distinct
      biological activities.

PMID- 12615938
TI  - DRL1, a homolog of the yeast TOT4/KTI12 protein, has a function in meristem
      activity and organ growth in plants.
AB  - The DEFORMED ROOTS AND LEAVES1 (DRL1) gene is single copy in the Arabidopsis
      genome, and based on overall amino acid similarity and conservation of functional
      domains, the DRL1 protein is homologous with yeast TOT4/KTI12. TOT4/KTI12
      associates with Elongator, a multisubunit complex that binds the RNA polymerase
      II transcription elongation complex. Recessive mutations at the DRL1 locus caused
      defective organ formation indicative of disorganized shoot, inflorescence,
      flower, and root meristems. DRL1 is a putative ATP/GTP binding protein; in
      addition, calmodulin binding activity was demonstrated in vitro for the C
      terminus of the DRL1 protein. Phenotypic and genetic data position DRL1 relative
      to regulatory loci for leaf development, in which it acts early. We identified
      Arabidopsis homologs for the six Elongator components and hypothesize that DRL1
      regulates transcription elongation through a putative plant Elongator.
      Upregulation of the ANGUSTIFOLIA transcript in the strong drl1-2 allele supports
      this model.

PMID- 12615939
TI  - A plant-specific dynamin-related protein forms a ring at the chloroplast division
      site.
AB  - Chloroplasts have retained the bacterial FtsZ for division, whereas mitochondria
      lack FtsZ except in some lower eukaryotes. Instead, mitochondrial division
      involves a dynamin-related protein, suggesting that chloroplasts retained the
      bacterial division system, whereas a dynamin-based system replaced the bacterial
      system in mitochondria during evolution. In this study, we identified a novel
      plant-specific group of dynamins from the primitive red alga Cyanidioschyzon
      merolae. Synchronization of chloroplast division and immunoblot analyses showed
      that the protein (CmDnm2) associates with the chloroplast only during division.
      Immunocytochemical analyses showed that CmDnm2 appears in cytoplasmic patches
      just before chloroplast division and is recruited to the cytosolic side of the
      chloroplast division site to form a ring in the late stage of division. The ring
      constricts until division is complete, after which it disappears. These results
      show that a dynamin-related protein also participates in chloroplast division and
      that its behavior differs from that of FtsZ and plastid-dividing rings that form
      before constriction at the site of division. Combined with the results of a
      recent study of mitochondrial division in Cyanidioschyzon, our findings led us to
      hypothesize that when first established in lower eukaryotes, mitochondria and
      chloroplasts divided using a very similar system that included the FtsZ ring, the
      plastid-dividing/mitochondrion-dividing ring, and the dynamin ring.

PMID- 12615940
TI  - Mutational analysis of the pullulanase-type debranching enzyme of maize indicates
      multiple functions in starch metabolism.
AB  - Plants contain two types of alpha(1-->6) glucan hydrolase (starch-debranching
      enzyme [DBE]). Mutations that affect the pullulanase-type DBE have not been
      described, although defects in isoamylase-type DBE, known in many plant species,
      indicate a function in starch biosynthesis. We describe a null mutation of a
      pullulanase-type DBE gene, a Mutator insertion in maize Zpu1. Plants homozygous
      for the zpu1-204 mutation are impaired in transient and storage starch
      degradation. Thus, hydrolytic activity of pullulanase-type DBE contributes to
      starch catabolism. Developing zpu1-204 endosperm accumulates branched
      maltooligosaccharides not found in the wild type and is deficient in linear
      maltooligosaccharides, indicating that the pullulanase-type DBE functions in
      glucan hydrolysis during kernel starch formation. Furthermore, in a background
      deficient in isoamylase-type DBE, zpu1-204 conditions a significant accumulation
      of phytoglycogen in the kernel that is not seen in the wild type. Therefore,
      pullulanase-type DBE partially compensates for the defect in isoamylase-type DBE,
      suggesting a function during starch synthesis as well as degradation.

PMID- 12615941
TI  - EMF genes maintain vegetative development by repressing the flower program in
      Arabidopsis.
AB  - The EMBRYONIC FLOWER (EMF) genes EMF1 and EMF2 are required to maintain
      vegetative development and repress flower development. EMF1 encodes a putative
      transcriptional regulator, and EMF2 encodes a Polycomb group protein homolog. We
      examined expression profiles of emf mutants using GeneChip technology. The high
      degree of overlap in expression changes from the wild type among the emf1 and
      emf2 mutants was consistent with the functional similarity between the two genes.
      Expression profiles of emf seedlings before flower development were similar to
      that of Arabidopsis flowers, indicating the commitment of germinating emf
      seedlings to the reproductive fate. The germinating emf seedlings ectopically
      expressed flower organ genes, suggesting that vegetative development in wild-type
      plants results from EMF repression of the flower program, directly or indirectly.
      In addition, the seed development program is derepressed in the emf1 mutants.
      Gene expression analysis showed no clear regulation of CONSTANS (CO), FLOWERING
      LOCUS T (FT), LEAFY (LFY), and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 by EMF1.
      Consistent with epistasis results that co, lfy, or ft cannot rescue rosette
      development in emf mutants, these data show that the mechanism of EMF-mediated
      repression of flower organ genes is independent of these flowering genes. Based
      on these findings, a new mechanism of EMF-mediated floral repression is proposed.

PMID- 12615942
TI  - The DORNROSCHEN/ENHANCER OF SHOOT REGENERATION1 gene of Arabidopsis acts in the
      control of meristem ccll fate and lateral organ development.
AB  - The two main tasks of a meristem, self-perpetuation and organ initiation, are
      separated spatially. Slowly dividing cells in the meristem center act as
      pluripotent stem cells, and only their derivatives in the meristem periphery
      specify new organs. Meristem integrity and cellular proliferation are controlled
      in part by regulatory interactions between genes that are expressed in specific
      subdomains of the meristem. Using transposon-mediated activation tagging, we have
      identified Dornroschen (drn-D) mutants of Arabidopsis that prematurely arrest
      shoot meristem activity with the formation of radialized lateral organs. The
      mutated gene (DRN/ESR1), which encodes an AP2/ERF protein, is expressed in a
      subdomain of meristem stem cells, in lateral organ anlagen, and transiently in
      the distal domain of organ primordia. During the development of drn-D mutants,
      expression of the homeobox gene SHOOTMERISTEMLESS is downregulated and later
      reactivated in an altered domain. In addition, we found increased expression of
      CLAVATA3 and WUSCHEL, two genes that antagonistically regulate stem cell fate in
      meristems. These findings suggest that the DRN/ESR1 gene product is involved in
      the regulation of gene expression patterns in meristems. Furthermore, specific
      misexpression of DRN in meristem stem cells affects organ polarity and outgrowth
      in the meristem periphery, indicating that DRN/ESR1 itself, or a process
      regulated by DRN/ESR1, can act non-cell-autonomously. We elaborate on the role of
      DRN/ESR1 in meristem and organ development and discuss its possible role in the
      process of shoot regeneration.

PMID- 12615943
TI  - Nicotiana benthamiana gp91phox homologs NbrbohA and NbrbohB participate in H2O2
      accumulation and resistance to Phytophthora infestans.
AB  - Active oxygen species (AOS) are responsible for triggering defense responses in
      plants. Respiratory burst oxidase homologs (rboh genes) have been implicated in
      AOS generation. We have isolated two rboh cDNAs, NbrbohA and NbrbohB, from
      Nicotiana benthamiana leaves. NbrbohA was expressed constitutively at a low level
      and the transcripts were increased after mechanical stress of control leaf
      infiltration, whereas NbrbohB was induced specifically by the protein elicitor
      INF1 from the potato pathogen Phytophthora infestans. We examined the function of
      the Nbrboh genes in AOS generation and in the hypersensitive response (HR) using
      virus-induced gene silencing (VIGS). VIGS indicated that both genes are required
      for H2O2 accumulation and for resistance to Phytophthora. VIGS of Nbrboh genes
      also led to a reduction and delay of HR cell death caused by INF1. We further
      demonstrate that the induction of HR-like cell death by overexpression of a
      constitutively active mutant of a mitogen-activated protein kinase kinase,
      MEK(DD), is compromised by VIGS of NBRBOHB: We found that MEK(DD) induced NbrbohB
      but not NBRBOHA: This work provides genetic evidence for the involvement of a
      mitogen-activated protein kinase cascade in the regulation of rboh genes.

PMID- 12615944
TI  - Characterization of the last subunit of the Arabidopsis COP9 signalosome:
      implications for the overall structure and origin of the complex.
AB  - The COP9 signalosome (CSN) is an evolutionarily conserved protein complex that
      resembles the lid subcomplex of proteasomes. Through its ability to regulate
      specific proteasome-mediated protein degradation events, CSN controls multiple
      aspects of development. Here, we report the cloning and characterization of
      AtCSN2, the last uncharacterized CSN subunit from Arabidopsis. We show that the
      AtCSN2 gene corresponds to the previously identified FUS12 locus and that AtCSN2
      copurifies with CSN, confirming that AtCSN2 is an integral component of CSN.
      AtCSN2 is not only able to interact with the SCF(TIR1) subunit AtCUL1, which is
      partially responsible for the regulatory interaction between CSN and SCF(TIR1),
      but also interacts with AtCUL3, suggesting that CSN is able to regulate the
      activity of other cullin-based E3 ligases through conserved interactions.
      Phylogenetic analysis indicated that the duplication and subsequent divergence
      events that led to the genes that encode CSN and lid subunits occurred before the
      divergence of unicellular and multicellular eukaryotic organisms and that the CSN
      subunits were more conserved than the lid subunits during evolution. Comparative
      analyses of the subunit interaction of CSN revealed a set of conserved subunit
      contacts and resulted in a model of CSN subunit topology, some aspects of which
      were substantiated by in vivo cross-link tests.

PMID- 12615945
TI  - Recognition specificity and RAR1/SGT1 dependence in barley Mla disease resistance
      genes to the powdery mildew fungus.
AB  - A large number of resistance specificities to the powdery mildew fungus Blumeria
      graminis f. sp. hordei map to the barley Mla locus. This complex locus harbors
      multiple members of three distantly related gene families that encode proteins
      that contain an N-terminal coiled-coil (CC) structure, a central nucleotide
      binding (NB) site, a Leu-rich repeat (LRR) region, and a C-terminal non-LRR (CT)
      region. We identified Mla12, which encodes a CC-NB-LRR-CT protein that shares 89
      and 92% identical residues with the known proteins MLA1 and MLA6. Slow Mla12
      triggered resistance was altered dramatically to a rapid response by
      overexpression of Mla12. A series of reciprocal domains swaps between MLA1 and
      MLA6 identified in each protein recognition domain for cognate powdery mildew
      fungus avirulence genes (AvrMla1 and AvrMla6). These domains were within
      different but overlapping LRR regions and the CT part. Unexpectedly, MLA chimeras
      that confer AvrMla6 recognition exhibited markedly different dependence on Rar1,
      a gene required for the function of some but not all Mla resistance
      specificities. Furthermore, uncoupling of MLA6-specific function from RAR1 also
      uncoupled the response from SGT1, a protein known to associate physically with
      RAR1. Our findings suggest that differences in the degree of RAR1 dependence of
      different MLA immunity responses are determined by intrinsic properties of MLA
      variants and place RAR1/SGT1 activity downstream of and/or coincident with the
      action of resistance protein-containing recognition complexes.

PMID- 12615946
TI  - Disease resistance and abiotic stress tolerance in rice are inversely modulated
      by an abscisic acid-inducible mitogen-activated protein kinase.
AB  - Mitogen-activated protein kinase (MAPK) cascades play an important role in
      mediating stress responses in eukaryotic organisms. However, little is known
      about the role of MAPKs in modulating the interaction of defense pathways
      activated by biotic and abiotic factors. In this study, we have isolated and
      functionally characterized a stress-responsive MAPK gene (OsMAPK5) from rice.
      OsMAPK5 is a single-copy gene but can generate at least two differentially
      spliced transcripts. The OsMAPK5 gene, its protein, and kinase activity were
      inducible by abscisic acid as well as various biotic (pathogen infection) and
      abiotic (wounding, drought, salt, and cold) stresses. To determine its biological
      function, we generated and analyzed transgenic rice plants with overexpression
      (using the 35S promoter of Cauliflower mosaic virus) or suppression (using double
      stranded RNA interference [dsRNAi]) of OsMAPK5. Interestingly, suppression of
      OsMAPK5 expression and its kinase activity resulted in the constitutive
      expression of pathogenesis-related (PR) genes such as PR1 and PR10 in the dsRNAi
      transgenic plants and significantly enhanced resistance to fungal (Magnaporthe
      grisea) and bacterial (Burkholderia glumae) pathogens. However, these same dsRNAi
      lines had significant reductions in drought, salt, and cold tolerance. By
      contrast, overexpression lines exhibited increased OsMAPK5 kinase activity and
      increased tolerance to drought, salt, and cold stresses. These results strongly
      suggest that OsMAPK5 can positively regulate drought, salt, and cold tolerance
      and negatively modulate PR gene expression and broad-spectrum disease resistance.

PMID- 12615947
TI  - NPR1 modulates cross-talk between salicylate- and jasmonate-dependent defense
      pathways through a novel function in the cytosol.
AB  - Plant defenses against pathogens and insects are regulated differentially by
      cross-communicating signal transduction pathways in which salicylic acid (SA) and
      jasmonic acid (JA) play key roles. In this study, we investigated the molecular
      mechanism of the antagonistic effect of SA on JA signaling. Arabidopsis plants
      unable to accumulate SA produced 25-fold higher levels of JA and showed enhanced
      expression of the JA-responsive genes LOX2, PDF1.2, and VSP in response to
      infection by Pseudomonas syringae pv tomato DC3000, indicating that in wild-type
      plants, pathogen-induced SA accumulation is associated with the suppression of JA
      signaling. Analysis of the Arabidopsis mutant npr1, which is impaired in SA
      signal transduction, revealed that the antagonistic effect of SA on JA signaling
      requires the regulatory protein NPR1. Nuclear localization of NPR1, which is
      essential for SA-mediated defense gene expression, is not required for the
      suppression of JA signaling, indicating that cross-talk between SA and JA is
      modulated through a novel function of NPR1 in the cytosol.

PMID- 12615948
TI  - Structural and transcriptional analysis of the self-incompatibility locus of
      almond: identification of a pollen-expressed F-box gene with haplotype-specific
      polymorphism.
AB  - Gametophytic self-incompatibility in Rosaceae, Solanaceae, and Scrophulariaceae
      is controlled by the S locus, which consists of an S-RNase gene and an
      unidentified "pollen S" gene. An approximately 70-kb segment of the S locus of
      the rosaceous species almond, the S haplotype-specific region containing the S
      RNase gene, was sequenced completely. This region was found to contain two pollen
      expressed F-box genes that are likely candidates for pollen S genes. One of them,
      named SFB (S haplotype-specific F-box protein), was expressed specifically in
      pollen and showed a high level of S haplotype-specific sequence polymorphism,
      comparable to that of the S-RNases. The other is unlikely to determine the S
      specificity of pollen because it showed little allelic sequence polymorphism and
      was expressed also in pistil. Three other S haplotypes were cloned, and the
      pollen-expressed genes were physically mapped. In all four cases, SFBs were
      linked physically to the S-RNase genes and were located at the S haplotype
      specific region, where recombination is believed to be suppressed, suggesting
      that the two genes are inherited as a unit. These features are consistent with
      the hypothesis that SFB is the pollen S gene. This hypothesis predicts the
      involvement of the ubiquitin/26S proteasome proteolytic pathway in the RNase
      based gametophytic self-incompatibility system.

PMID- 12615949
TI  - Telomerase dependence of telomere lengthening in Ku80 mutant Arabidopsis.
AB  - We have identified a ku80 mutant of Arabidopsis and show that telomerase is
      needed to generate the longer telomeres observed in this mutant. Telomeres are
      specialized nucleoprotein structures at the ends of chromosomes that permit cells
      to distinguish chromosome ends from double-strand breaks, thus preventing
      chromosome fusion events. Ku80 deficiency results in the lengthening of
      telomeres, a phenotype also seen in an Arabidopsis ku70 mutant. Furthermore,
      homogeneous populations of ku80 mutant cells show a steady increase in the length
      of telomere tracts, which reach an equilibrium length and then stabilize. In
      contrast to that in mammals, Ku80 deficiency in Arabidopsis cells does not cause
      end-to-end fusion of chromosomes. This telomere lengthening is dependent on the
      presence of telomerase, although it is not attributable to a significant increase
      in telomerase activity per se. These results demonstrate the essential role of
      the Ku80 protein as a negative regulator of telomerase function in plant cells.

PMID- 12615950
TI  - AtDUR3 encodes a new type of high-affinity urea/H+ symporter in Arabidopsis.
AB  - Urea is the major nitrogen form supplied as fertilizer in agricultural plant
      production but also an important nitrogen metabolite in plants. We report the
      cloning and functional characterization of AtDUR3, a high-affinity urea
      transporter in plants. AtDUR3 contains 14 putative transmembrane-spanning domains
      and represents an individual member in Arabidopsis that belongs to a superfamily
      of sodium-solute symporters. Heterologous expression in urea uptake-defective
      yeast as well as two-electrode voltage clamp and uptake studies using (14)C
      labeled urea in AtDUR3-expressing oocytes demonstrated that AtDUR3 mediates urea
      transport. In both heterologous systems, urea transport was stimulated at low pH.
      In oocytes, inward currents indicated that urea is cotransported with protons. By
      contrast, a supply of Na(+) ions could not stimulate urea transport. Transport of
      (14)C-labeled urea by AtDUR3 in oocytes exhibited saturation kinetics with a K(m)
      of approximately 3 micro M. AtDUR3 was expressed in shoots and roots and
      upregulated during early germination and under nitrogen deficiency in roots. We
      propose a role of AtDUR3 in urea uptake by plant cells at low external urea
      concentrations.

PMID- 12615951
TI  - Topical and peripherally acting analgesics.
AB  - Acute nociceptive, inflammatory, and neuropathic pain all depend to some degree
      on the peripheral activation of primary sensory afferent neurons. The localized
      peripheral administration of drugs, such as by topical application, can
      potentially optimize drug concentrations at the site of origin of the pain, while
      leading to lower systemic levels and fewer adverse systemic effects, fewer drug
      interactions, and no need to titrate doses into a therapeutic range compared with
      systemic administration. Primary sensory afferent neurons can be activated by a
      range of inflammatory mediators such as prostanoids, bradykinin, ATP, histamine,
      and serotonin, and inhibiting their actions represents a strategy for the
      development of analgesics. Peripheral nerve endings also express a variety of
      inhibitory neuroreceptors such as opioid, alpha-adrenergic, cholinergic,
      adenosine and cannabinoid receptors, and agonists for these receptors also
      represent viable targets for drug development. At present, topical and other
      forms of peripheral administration of nonsteroidal anti-inflammatory drugs,
      opioids, capsaicin, local anesthetics, and alpha-adrenoceptor agonists are being
      used in a variety of clinical states. There also are some clinical data on the
      use of topical antidepressants and glutamate receptor antagonists. There are
      preclinical data supporting the potential for development of local formulations
      of adenosine agonists, cannabinoid agonists, cholinergic ligands, cytokine
      antagonists, bradykinin antagonists, ATP antagonists, biogenic amine antagonists,
      neuropeptide antagonists, and agents that alter the availability of nerve growth
      factor. Given that activation of sensory neurons involves multiple mediators,
      combinations of agents targeting different mechanisms may be particularly useful.
      Topical analgesics represent a promising area for future drug development.

PMID- 12615952
TI  - International Union of Pharmacology. XXXVI. Current status of the nomenclature
      for receptors for corticotropin-releasing factor and their ligands.
AB  - Receptors for corticotropin-releasing factor (CRF) are members of a family of G
      protein-coupled receptors ("Family B") that respond to a variety of structurally
      dissimilar releasing factors, neuropeptides, and hormones (including secretin,
      growth hormone-releasing factor, calcitonin, parathyroid hormone, pituitary
      adenylate cyclase-activating polypeptide, and vasoactive intestinal polypeptide)
      and signal through the cyclic AMP and/or calcium pathways. To date, three genes
      encoding additional CRF-like peptides (urocortins) have been identified in
      mammals. The urocortins and CRF bind with differential ligand selectivity at the
      two mammalian CRF receptors. This report was prepared by the International Union
      of Pharmacology Subcommittee on CRF Receptors, to summarize the current state of
      CRF receptor biology and to propose changes in the classification and
      nomenclature of CRF ligands and receptors.

PMID- 12615953
TI  - Mechanisms of antimicrobial peptide action and resistance.
AB  - Antimicrobial peptides have been isolated and characterized from tissues and
      organisms representing virtually every kingdom and phylum, ranging from
      prokaryotes to humans. Yet, recurrent structural and functional themes in
      mechanisms of action and resistance are observed among peptides of widely diverse
      source and composition. Biochemical distinctions among the peptides themselves,
      target versus host cells, and the microenvironments in which these counterparts
      convene, likely provide for varying degrees of selective toxicity among diverse
      antimicrobial peptide types. Moreover, many antimicrobial peptides employ
      sophisticated and dynamic mechanisms of action to effect rapid and potent
      activities consistent with their likely roles in antimicrobial host defense. In
      balance, successful microbial pathogens have evolved multifaceted and effective
      countermeasures to avoid exposure to and subvert mechanisms of antimicrobial
      peptides. A clearer recognition of these opposing themes will significantly
      advance our understanding of how antimicrobial peptides function in defense
      against infection. Furthermore, this understanding may provide new models and
      strategies for developing novel antimicrobial agents, that may also augment
      immunity, restore potency or amplify the mechanisms of conventional antibiotics,
      and minimize antimicrobial resistance mechanisms among pathogens. From these
      perspectives, the intention of this review is to illustrate the contemporary
      structural and functional themes among mechanisms of antimicrobial peptide action
      and resistance.

PMID- 12615954
TI  - Pharmacogenetics of anticancer drug sensitivity in non-small cell lung cancer.
AB  - In mammalian cells, the process of malignant transformation is characterized by
      the loss or down-regulation of tumor-suppressor genes and/or the mutation or
      overexpression of proto-oncogenes, whose products promote dysregulated
      proliferation of cells and extend their life span. Deregulation in intracellular
      transduction pathways generates mitogenic signals that promote abnormal cell
      growth and the acquisition of an undifferentiated phenotype. Genetic
      abnormalities in cancer have been widely studied to identify those factors
      predictive of tumor progression, survival, and response to chemotherapeutic
      agents. Pharmacogenetics has been founded as a science to examine the genetic
      basis of interindividual variation in drug metabolism, drug targets, and
      transporters, which result in differences in the efficacy and safety of many
      therapeutic agents. The traditional pharmacogenetic approach relies on studying
      sequence variations in candidate genes suspected of affecting drug response.
      However, these studies have yielded contradictory results because of the small
      number of molecular determinants of drug response examined, and in several cases
      this approach was revealed to be reductionistic. This limitation is now being
      overcome by the use of novel techniques, i.e., high-density DNA and protein
      arrays, which allow genome- and proteome-wide tumor profiling. Pharmacogenomics
      represents the natural evolution of pharmacogenetics since it addresses, on a
      genome-wide basis, the effect of the sum of genetic variants on drug responses of
      individuals. Development of pharmacogenomics as a new field has accelerated the
      progress in drug discovery by the identification of novel therapeutic targets by
      expression profiling at the genomic or proteomic levels. In addition to this,
      pharmacogenetics and pharmacogenomics provide an important opportunity to select
      patients who may benefit from the administration of specific agents that best
      match the genetic profile of the disease, thus allowing maximum activity.

PMID- 12615956
TI  - Interleukins in atherosclerosis: molecular pathways and therapeutic potential.
AB  - Interleukins are considered to be key players in the chronic vascular
      inflammatory response that is typical of atherosclerosis. Thus, the expression of
      proinflammatory interleukins and their receptors has been demonstrated in
      atheromatous tissue, and the serum levels of several of these cytokines have been
      found to be positively correlated with (coronary) arterial disease and its
      sequelae. In vitro studies have confirmed the involvement of various interleukins
      in pro-atherogenic processes, such as the up-regulation of adhesion molecules on
      endothelial cells, the activation of macrophages, and smooth muscle cell
      proliferation. Furthermore, studies in mice deficient or transgenic for specific
      interleukins have demonstrated that, whereas some interleukins are indeed
      intrinsically pro-atherogenic, others may have anti-atherogenic qualities. As the
      roles of individual interleukins in atherosclerosis are being uncovered, novel
      anti-atherogenic therapies, aimed at the modulation of interleukin function, are
      being explored. Several approaches have produced promising results in this
      respect, including the transfer of anti-inflammatory interleukins and the
      administration of decoys and antibodies directed against proinflammatory
      interleukins. The chronic nature of the disease and the generally pleiotropic
      effects of interleukins, however, will demand high specificity of action and/or
      effective targeting to prevent the emergence of adverse side effects with such
      treatments. This may prove to be the real challenge for the development of
      interleukin-based anti-atherosclerotic therapies, once the mediators and their
      targets have been delineated.

PMID- 12615955
TI  - Pharmacological agents that directly modulate insulin secretion.
AB  - Blood glucose levels are sensed and controlled by the release of hormones from
      the islets of Langerhans in the pancreas. The beta-cell, the insulin-secreting
      cell in the islet, can detect subtle increases in circulating glucose levels and
      a cascade of molecular events spanning the initial depolarization of the beta
      cell membrane culminates in exocytosis and optimal insulin secretion. Here we
      review these processes in the context of pharmacological agents that have been
      shown to directly interact with any stage of insulin secretion. Drugs that
      modulate insulin secretion do so by opening the K(ATP) channels, by interacting
      with cell-surface receptors, by altering second-messenger responses, by
      disrupting the beta-cell cytoskeletal framework, by influencing the molecular
      reactions at the stages of transcription and translation of insulin, and/or by
      perturbing exocytosis of the insulin secretory vesicles. Drugs acting primarily
      at the K(ATP) channels are the sulfonylureas, the benzoic acid derivatives, the
      imidazolines, and the quinolines, which are channel openers, and finally
      diazoxide, which closes these channels. Methylxanthines also work at the cell
      membrane level by antagonizing the purinergic receptors and thus increase insulin
      secretion. Other drugs have effects at multiple levels, such as the calcineurin
      inhibitors and somatostatin. Some drugs used extensively in research, e.g.,
      colchicine, which is used to study vesicular transport, have no effect at the
      pharmacological doses used in clinical practice. We also briefly discuss those
      drugs that have been shown to disrupt beta-cell function in a clinical setting
      but for which there is scant information on their mechanism of action.

PMID- 12615957
TI  - International Union of Pharmacology. XXXV. The glucagon receptor family.
AB  - Peptide hormones within the secretin-glucagon family are expressed in endocrine
      cells of the pancreas and gastrointestinal epithelium and in specialized neurons
      in the brain, and subserve multiple biological functions, including regulation of
      growth, nutrient intake, and transit within the gut, and digestion, energy
      absorption, and energy assimilation. Glucagon, glucagon-like peptide-1, glucagon
      like peptide-2, glucose-dependent insulinotropic peptide, growth hormone
      releasing hormone and secretin are structurally related peptides that exert their
      actions through unique members of a structurally related G protein-coupled
      receptor class 2 family. This review discusses advances in our understanding of
      how these peptides exert their biological activities, with a focus on the
      biological actions and structural features of the cognate receptors. The
      receptors have been named after their parent and only physiologically relevant
      ligand, in line with the recommendations of the International Union of
      Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC
      IUPHAR).

PMID- 12615958
TI  - International Union of Pharmacology XXXVII. Nomenclature for leukotriene and
      lipoxin receptors.
AB  - The leukotrienes and lipoxins are biologically active metabolites derived from
      arachidonic acid. Their diverse and potent actions are associated with specific
      receptors. Recent molecular techniques have established the nucleotide and amino
      acid sequences and confirmed the evidence that suggested the existence of
      different G-protein-coupled receptors for these lipid mediators. The nomenclature
      for these receptors has now been established for the leukotrienes. BLT receptors
      are activated by leukotriene B(4) and related hydroxyacids and this class of
      receptors can be subdivided into BLT(1) and BLT(2). The cysteinyl-leukotrienes
      (LT) activate another group called CysLT receptors, which are referred to as
      CysLT(1) and CysLT(2). A provisional nomenclature for the lipoxin receptor has
      also been proposed. LXA(4) and LXB(4) activate the ALX receptor and LXB(4) may
      also activate another putative receptor. However this latter receptor has not
      been cloned. The aim of this review is to provide the molecular evidence as well
      as the properties and significance of the leukotriene and lipoxin receptors,
      which has lead to the present nomenclature.

PMID- 12615960
TI  - Tensegrity I. Cell structure and hierarchical systems biology.
AB  - In 1993, a Commentary in this journal described how a simple mechanical model of
      cell structure based on tensegrity architecture can help to explain how cell
      shape, movement and cytoskeletal mechanics are controlled, as well as how cells
      sense and respond to mechanical forces (J. Cell Sci. 104, 613-627). The cellular
      tensegrity model can now be revisited and placed in context of new advances in
      our understanding of cell structure, biological networks and mechanoregulation
      that have been made over the past decade. Recent work provides strong evidence to
      support the use of tensegrity by cells, and mathematical formulations of the
      model predict many aspects of cell behavior. In addition, development of the
      tensegrity theory and its translation into mathematical terms are beginning to
      allow us to define the relationship between mechanics and biochemistry at the
      molecular level and to attack the larger problem of biological complexity. Part I
      of this two-part article covers the evidence for cellular tensegrity at the
      molecular level and describes how this building system may provide a structural
      basis for the hierarchical organization of living systems--from molecule to
      organism. Part II, which focuses on how these structural networks influence
      information processing networks, appears in the next issue.

PMID- 12615962
TI  - Adherens junctions and tight junctions are regulated via different pathways by
      progastrin in epithelial cells.
AB  - Adhesion between neighbouring epithelial cells is a crucial and tightly
      controlled process. In the gastrointestinal tract, the integrity of cell-cell
      contacts is essential for the regulation of electrolyte absorption and for the
      prevention of tumour metastasis. We recently showed that migration of the gastric
      epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone
      gastrin(17). Here, we examine the effect on cell-cell adhesion of the prohormone
      progastrin, the concentration of which is increased in the plasma of patients
      with colorectal carcinoma. Progastrin induced the dissociation of both tight
      junction (TJ) and adherens junction (AJ) complexes in IMGE-5 cells. In progastrin
      secreting DLD-1 human colorectal carcinoma cells, expression of an antisense
      gastrin construct restored membrane localisation of zonula occludens-1 (ZO-1),
      occludin, beta-catenin and E-cadherin. This restoration was reversed by treatment
      with exogenous progastrin. Endogenous or exogenous progastrin also increased the
      paracellular flux of mannitol, and induced cell migration of several
      gastrointestinal cell lines. In addition, progastrin enhanced Src tyrosine kinase
      activity and induced a spatial delocalisation of protein kinase C alpha. Using
      dominant-negative mutants and pharmacological inhibitors, we showed that the
      stimulation of Src kinase activity was essential for the regulation of TJs. By
      contrast, the dissociation of AJs involved phosphatidylinositol 3-kinase, partly
      through the formation of a complex with protein kinase C alpha. We conclude that
      separate pathways mediate the disruption of AJs and TJs by progastrin. Either
      pathway may contribute to the co-carcinogenic role of this prohormone in
      colorectal carcinoma.

PMID- 12615963
TI  - Drosophila miniature and dusky encode ZP proteins required for cytoskeletal
      reorganisation during wing morphogenesis.
AB  - We have characterised the function of two Drosophila genes, miniature and dusky,
      that are required for the morphological reorganisation of the apical membrane
      during wing epidermis differentiation. These genes encode transmembrane proteins
      containing a ZP (zona pellucida) domain and are homologous to several vertebrate
      and invertebrate apical matrix components. miniature and dusky are only expressed
      in tissues secreting a cuticle, and the Min protein localises to the apical
      membrane during the early stages of cuticle formation. We propose that Min and
      Dusky form a novel subfamily within the ZP domain proteins and are specifically
      involved in the interactions between the apical membrane, the cytoskeleton and
      the forming cuticle.

PMID- 12615961
TI  - GSK-3: tricks of the trade for a multi-tasking kinase.
AB  - Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase
      found in all eukaryotes. The enzyme is a key regulator of numerous signalling
      pathways, including cellular responses to Wnt, receptor tyrosine kinases and G
      protein-coupled receptors and is involved in a wide range of cellular processes,
      ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK
      3 is unusual in that it is normally active in cells and is primarily regulated
      through inhibition of its activity. Another peculiarity compared with other
      protein kinases is its preference for primed substrates, that is, substrates
      previously phosphorylated by another kinase. Several recent advances have
      improved our understanding of GSK-3 regulation in multiple pathways. These
      include the solution of the crystal structure of GSK-3, which has provided
      insight into GSK-3's penchant for primed substrates and the regulation of GSK-3
      by serine phosphorylation, and findings related to the involvement of GSK-3 in
      the Wnt/beta-catenin and Hedgehog pathways. Finally, since increased GSK-3
      activity may be linked to pathology in diseases such as Alzheimer's disease and
      non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as
      the aloisines, the paullones and the maleimides, have been developed. Although
      they are just starting to be characterized in cell culture experiments, these new
      inhibitors hold promise as therapeutic agents.

PMID- 12615964
TI  - Regulation of membrane expansion at the nerve growth cone.
AB  - Exocytotic incorporation of plasmalemmal precursor vesicles (PPVs) into the cell
      surface is necessary for neurite extension and is known to occur mainly at the
      growth cone. This report examines whether this is a regulated event controlled by
      growth factors. The Golgi complex and nascent PPVs of hippocampal neurons in
      culture were pulse-labeled with fluorescent ceramide. We studied the dynamics of
      labeled PPVs upon arrival at the axonal growth cone. In controls and cultures
      stimulated with brain-derived neurotrophic factor (BDNF), PPV clusters persisted
      in growth cones with a half-life (t(1/2)) of >14 minutes. Upon challenge with IGF
      1, however, fluorescent elements cleared from the growth cones with a t(1/2) of
      only 6 minutes. Plasmalemmal expansion was measured directly as externalization
      of membrane glycoconjugates in resealed growth cone particles (GCPs) isolated
      from fetal forebrain. These assays demonstrated that membrane expansion could be
      stimulated by IGF-1 in a dose-dependent manner but not by BDNF, even though
      intact, functional BDNF receptor was present on GCPs. Because both BDNF and IGF-1
      are known to enhance neurite growth, but BDNF did not stimulate membrane
      expansion at the growth cone, we studied the effect of BDNF on the IGF-1
      receptor. BDNF was found to cause the translocation of the growth-cone-specific
      IGF-1 receptor subunit beta(gc) to the distal axon, in a KIF2-dependent manner.
      We conclude that IGF-1 stimulates axonal assembly at the growth cone, and that
      this occurs via regulated exocytosis of PPVs. This mechanism is affected by BDNF
      only indirectly, by regulation of the beta(gc) level at the growth cone.

PMID- 12615965
TI  - Targeting of p0071 to desmosomes and adherens junctions is mediated by different
      protein domains.
AB  - p0071, a member of the armadillo protein family, is most closely related to
      p120(ctn) and the plakophilins 1-3. Whereas plakophilins are desmosomal plaque
      proteins, p120(ctn) localizes to adherens junctions and interacts with classical
      cadherins. In contrast, p0071 has been described as a protein with dual
      localization in adherens junctions and desmosomes depending on the cell type
      examined. Here we have analyzed the localization of p0071 and its domains in
      detail. Although by sequence analysis, p0071 is more closely related to the
      adherens junction proteins p120(ctn), ARVCF and delta-catenin, endogenous p0071
      associated preferentially with desmosomes in MCF-7 epithelial cells.
      Overexpressed p0071 localized along cell borders and overlapped only partially
      with desmosomal markers but colocalized with non-desmosomal cadherins and
      recruited cadherins to the membrane. The head domain of p0071 was sufficient for
      desmosomal targeting, whereas the arm repeat domain associated with adherens
      junctions and enhanced membrane association of classical cadherins. The tail
      domain localized preferentially to the nucleus and associated with desmosomes. To
      examine the mechanism underlying this dual localization more closely we
      determined binding partners of p0071 by using yeast-two-hybrid and mom-targeting
      assays. These approaches show that the head domain interacted with desmosomal
      proteins desmocollin 3a and desmoplakin, whereas the armadillo repeat domain
      binds to non-desmosomal cadherins. Head and armadillo repeat domains both
      interacted with plakoglobin by binding to different sites. Our data suggest that,
      in addition to plakoglobin, p0071 is the second armadillo protein present in both
      types of adhesive junctions and may play a role in regulating crosstalk between
      adherens junctions and desmosomes.

PMID- 12615966
TI  - Microtubule distribution during meiosis I in flea-beetle [Alagoasa (Oedionychus)]
      spermatocytes: evidence for direct connections between unpaired sex chromosomes.
AB  - The meiosis-I spindle in flea-beetle spermatocytes is unusual in that the
      autosomes and univalent sex chromosomes are separated by a mitochondrial sheath
      and move polewards at different times. To help understand the basis for this
      interesting chromosome behaviour, and to gather more detailed information about
      it, we studied microtubule distributions throughout meiosis I using
      immunofluorescence and confocal microscopy, and took careful measurements of pole
      and kinetochore positions at all stages of division. Our results show that, by
      late prophase, there is a spindle-shaped cytoplasmic array of microtubules in the
      central part of the cell, with the nucleus at the periphery. Following nuclear
      envelope breakdown, both autosomes and sex chromosomes become associated with
      cytoplasmic microtubules, although only the autosomes move centrally to the
      'cytoplasmic spindle'. The two unpaired sex chromosomes remain at the cell
      periphery and appear to be connected to each other by a microtubule bundle
      extending between their kinetochores. These bundles often persist into anaphase.
      Analysis of measurements taken from fixed/stained cells supports previous
      observations that sex chromosomes move part way to the pole in early prometaphase
      and then stop. The measurements also suggest that during autosomal anaphase,
      spindle elongation precedes autosome movement to the poles and polewards movement
      of sex chromosomes is limited or absent when autosomes are moving polewards.

PMID- 12615967
TI  - Control of morphogenesis and actin localization by the Penicillium marneffei RAC
      homolog.
AB  - Rac proteins control polarized growth in many organisms but the specific function
      of these proteins remains undefined. In this study, we describe the cloning and
      functional characterization of a RAC homolog, cflB, from the dimorphic fungus
      Penicillium marneffei. P. marneffei produces asexual spores on complex structures
      (conidiophores) and switches between hyphal and yeast growth. CflB colocalizes
      with actin at the tips of vegetative hyphal cells and at sites of cell division.
      Deletion of cflB results in cell division (septation) and growth defects in both
      vegetative hyphal and conidiophore cell types such that cells become depolarized,
      exhibit inappropriate septation and the actin cytoskeleton is severely disrupted.
      This data suggests that Rac proteins play a crucial role in actin dependent
      polarized growth and division. The CDC42 ortholog in P. marneffei, cflA, controls
      vegetative hyphal and yeast growth polarization but does not affect asexual
      development. By contrast, CflB affects cellular polarization during asexual
      development and hyphal growth but not during yeast growth. This shows that these
      two GTPases have both overlapping and distinct roles during growth and
      development. RAC orthologs are not found in less morphologically complex
      eukaryotes such as Saccharomyces cerevisiae, suggesting that RAC genes might have
      evolved with increasing cellular complexity.

PMID- 12615969
TI  - Microtubule-dependent redistribution of the type-1 inositol 1,4,5-trisphosphate
      receptor in A7r5 smooth muscle cells.
AB  - In A7r5 vascular smooth muscle cells, the two expressed inositol 1,4,5
      trisphosphate receptor (IP(3)R) isoforms were differentially localized. IP(3)R1
      was predominantly localized in the perinuclear region, whereas IP(3)R3 was
      homogeneously distributed over the cytoplasm. Prolonged stimulation (1-5 hours)
      of cells with 3 microM arginine-vasopressin induced a redistribution of IP(3)R1
      from the perinuclear region to the entire cytoplasm, whereas the localization of
      IP(3)R3 appeared to be unaffected. The redistribution process occurred
      independently of IP(3)R downregulation. No structural changes of the endoplasmic
      reticulum were observed, but SERCA-type Ca(2+) pumps redistributed similarly to
      IP(3)R1. The change in IP(3)R1 localization induced by arginine-vasopressin could
      be blocked by the simultaneous addition of nocodazole or taxol and depended on
      Ca(2+) release from intracellular stores since Ca(2+)-mobilizing agents such as
      thapsigargin and cyclopiazonic acid could induce the redistribution. Furthermore,
      various protein kinase C inhibitors could inhibit the redistribution of IP(3)R1,
      whereas the protein kinase C activator 1-oleoyl-2-acetyl-sn-glycerol induced the
      redistribution. Activation of protein kinase C also induced an outgrowth of the
      microtubules from the perinuclear region into the cytoplasm, similar to what was
      seen for the redistribution of IP(3)R1. Finally, blocking vesicular transport at
      the level of the intermediate compartment inhibited the redistribution. Taken
      together, these findings suggest a role for protein kinase C and microtubuli in
      the redistribution of IP(3)R1, which probably occurs via a mechanism of vesicular
      trafficking.

PMID- 12615968
TI  - Intracellular calcium measurements of single human skin cells after stimulation
      with corticotropin-releasing factor and urocortin using confocal laser scanning
      microscopy.
AB  - Using confocal laser scanning microscopy we investigated the Ca(2+) distribution
      in single corticotropin releasing factor- and urocortin-stimulated human skin
      cells. The models tested included melanoma cells, neonatal melanocytes and
      keratinocytes, and immortalized HaCaT keratinocytes. The changes in intracellular
      Ca(2+) signal intensities observed after stimulation of different cell types with
      corticotropin releasing factor and urocortin showed that: (1) the increase of
      intracellular Ca(2+) concentration was caused by a Ca(2+) influx (inhibition by
      EGTA); (2) this Ca(2+) influx took place through voltage-activated Ca(2+) ion
      channels (inhibition by d-cis-diltiazem, verapamil) and (3) cyclic nucleotide
      gated ion channels were not involved in this process (no effect of Mg(2+)). The
      effects were also observed at very low peptide concentrations (10(-13) M) with no
      apparent linear correlation between peptide dosage and increase of fluorescence
      intensity, which implied co-expression of different corticotropin releasing
      factor receptor forms in the same cell. Immortalized (HaCaT) keratinocytes
      exhibited the strongest differential increases of a Ca(2+) fluorescence after
      peptide-stimulation. Corticotropin releasing factor induced Ca(2+) flux into the
      cytoplasm, while urocortin Ca(2+) flux into the nucleus with a remarkable
      oscillatory effect. The latter indicated the presence of an intracellular
      urocortin-induced signal transduction pathway that is unique to keratinocytes.

PMID- 12615970
TI  - Junctional protein MAGI-3 interacts with receptor tyrosine phosphatase beta (RPTP
      beta) and tyrosine-phosphorylated proteins.
AB  - Receptor protein tyrosine phosphatase beta (RPTP beta) mediates cell-cell and
      cell-matrix interactions. By searching for intracellular proteins that interact
      with the cytoplasmic region of this phosphatase using the two-hybrid method, we
      identified several proteins containing PDZ domains. One of these proteins, MAGI
      3, contains a guanylate-kinase-like region, six PDZ and two WW domains. The
      interaction between RPTP beta and MAGI-3 was confirmed by co-immunoprecipitation
      and pulldown experiments in transfected cells. Immunofluorescence and
      immunoelectron microscopy revealed that MAGI-3 is concentrated in specific sites
      at the plasma membrane and in the nucleus. In epithelial cells, MAGI-3 was
      localized with ZO-1 and cingulin at tight junctions, whereas in primary cultured
      astrocytes it was found in E-cadherin-based cell-cell contacts and in focal
      adhesion sites. Although MAGI-3 itself was not phosphorylated on tyrosine
      residues, it became associated with tyrosine-phosphorylated proteins following a
      short treatment of the cells with vanadate. In glioblastoma SF763T cells MAGI-3
      was associated with a tyrosine-phosphorylated protein with the apparent molecular
      weight of 130 kDa, whereas in Caco2 cells it was associated with a 90 kDa
      protein. Finally, we show that p130 served as a substrate for RPTP beta and that
      its dephosphorylation required the C-terminal sequence of the phosphatase, which
      mediated the interaction with MAGI-3. These findings suggest a possible role for
      MAGI-3 as a scaffolding molecule that links receptor tyrosine phosphatase with
      its substrates at the plasma membrane.

PMID- 12615971
TI  - Cytoskeletal proteins with N-terminal signal peptides: plateins in the ciliate
      Euplotes define a new family of articulins.
AB  - Protistan cells employ a wide variety of strategies to reinforce and give pattern
      to their outermost cortical layers. Whereas some use common cytoskeletal elements
      such as microtubules, others are based on novel cytoskeletal proteins that are as
      yet-unknown in higher eukaryotes. The hypotrich ciliate Euplotes possesses a
      continuous monolayer of scales or plates, located within flattened membranous
      sacs ('alveoli') just below the plasma membrane, and this provides rigidity and
      form to the cell. Using immunological techniques, the major proteins comprising
      these 'alveolar plates' have been identified and termed alpha-, beta-, and gamma
      plateins. The present report describes work leading to the molecular
      characterization of three plateins, alpha 1 and alpha 2 (predicted M(r)s of 61
      and 56 kDa) and a beta/gamma form (M(r)=73 kDa). All three proteins have features
      that are hallmarks of articulins, a class of cytoskeletal proteins that has been
      identified in the cortex of a wide variety of protistan cells, including certain
      flagellates, ciliates, dinoflagellates and PLASMODIUM: Chief among these common
      features are a prominent primary domain of tandem 12-amino acid repeats, rich in
      valine and proline, and a secondary domain of fewer, shorter repeating units.
      However, variations in amino acid use within both primary and secondary
      repetitive domains, and a much more acidic character (predicted pIs of 4.7-4.9),
      indicate that the plateins represent the first proteins in a new subclass or
      family of articulins. This conclusion is supported by another novel feature of
      the plateins, the presence of a canonical hydrophobic signal peptide at the N
      terminus of each derived platein sequence. This correlates well with the final
      cellular location of the plateins, which are assembled into plates within the
      membrane-limited alveolar sacs. To our knowledge, this is the first report in any
      eukaryote of cytoskeletal proteins with such start-transfer sequences. Confocal
      immunofluorescence microscopy, using antibodies to the plateins as probes,
      reveals that new alveolar plates (enlarging in cortical zones undergoing
      morphogenesis) label more faintly than mature parental plates. During plate
      assembly (or polymerization), the plateins thus appear to exist in a more soluble
      form.

PMID- 12615972
TI  - The cancer antigen CA125 represents a novel counter receptor for galectin-1.
AB  - CA125 is an ovarian cancer antigen whose recently elucidated primary structure
      suggests that CA125 is a giant mucin-like glycoprotein present on the cell
      surface of tumor cells. Here, we establish a functional link between CA125 and
      beta-galactoside-binding, cell-surface lectins, which are components of the
      extracellular matrix implicated in the regulation of cell adhesion, apoptosis,
      cell proliferation and tumor progression. On the basis of mass spectrometry and
      immunological analyses, we find that CA125 is a counter receptor for galectin-1,
      as both soluble and membrane-associated fragments of CA125 derived from HeLa cell
      lysates are shown to bind specifically to human galectin-1 with high efficiency.
      This interaction is demonstrated (1) to depend on beta-galactose-terminated, O
      linked oligosaccharide chains of CA125, (2) to be preferential for galectin-1
      versus galectin-3 and (3) to be regulated by the cellular background in which
      CA125 is expressed. Despite lacking a conventional signal peptide, a CA125 C
      terminal fragment of 1148 amino acids, representing less than 10% of the full
      length protein, retains the ability to integrate into secretory membranes such as
      the endoplasmic reticulum (ER) and the Golgi, and is targeted to the plasma
      membrane by conventional secretory transport. As demonstrated by a novel assay
      that reconstitutes non-conventional secretion of galectin-1 based on fluorescence
      activated cell sorting (FACS), we find that tumor-derived HeLa cells expressing
      endogenous CA125 present more than ten times as much galectin-1 on their surface
      compared with non-tumor-derived, CA125-deficient CHO cells. Intriguingly, both
      the galectin-1 expression level and the cell-surface binding capacity for
      galectin-1 are shown to be similar in CHO and HeLa cells, suggesting that CA125
      might be a factor involved in the regulation of galectin-1 export to the cell
      surface.

PMID- 12615973
TI  - Intracellular localisation of human HIF-1 alpha hydroxylases: implications for
      oxygen sensing.
AB  - Hypoxia-inducible factor1 (HIF-1) is an essential transcription factor for
      cellular adaptation to decreased oxygen availability. In normoxia the oxygen
      sensitive alpha-subunit of HIF-1 is hydroxylated on Pro564 and Pro402 and thus
      targeted for proteasomal degradation. Three human oxygen-dependent HIF-1 alpha
      prolyl hydroxylases (PHD1, PHD2, and PHD3) function as oxygen sensors in vivo.
      Furthermore, the asparagine hydroxylase FIH-1 (factor inhibiting HIF) has been
      found to hydroxylate Asp803 of the HIF-1 C-terminal transactivation domain, which
      results in the decreased ability of HIF-1 to bind to the transcriptional
      coactivator p300/CBP. We have fused these enzymes to the N-terminus of
      fluorescent proteins and transiently transfected the fusion proteins into human
      osteosarcoma cells (U2OS). Three-dimensional 2-photon confocal fluorescence
      microscopy showed that PHD1 was exclusively present in the nucleus, PHD2 and FIH
      1 were mainly located in the cytoplasm and PHD3 was homogeneously distributed in
      cytoplasm and nucleus. Hypoxia did not influence the localisation of any enzyme
      under investigation. In contrast to FIH-1, each PHD inhibited nuclear HIF-1 alpha
      accumulation in hypoxia. All hydroxylases suppressed activation of a
      cotransfected hypoxia-responsive luciferase reporter gene. Endogenous PHD2mRNA
      and PHD3mRNA were hypoxia-inducible, whereas expression of PHD1mRNA and FIH-1mRNA
      was oxygen independent. We propose that PHDs and FIH-1 form an oxygen sensor
      cascade of distinct subcellular localisation.

PMID- 12615974
TI  - Internalization signals in synaptotagmin VII utilizing two independent pathways
      are masked by intramolecular inhibitions.
AB  - The synaptotagmin family of membrane proteins has been implicated in both
      exocytosis and endocytosis. Synaptotagmin I, a protein containing two tandem C2
      domains (the C2A and the C2B) in its cytoplasmic tail, is involved in regulated
      exocytosis of synaptic vesicles as well as compensatory endocytosis. A related
      family member, synaptotagmin VII, is involved in multiple forms of regulated
      exocytosis of lysosomes and secretory granules. In this study we show that the
      cytoplasmic C2 domains in synaptotagmin VII contain unique internalization
      signals and regulators of these signals. The C-terminal portion of the C2B is
      internalized in much the same way as the corresponding region of synaptotagmin I.
      This signal is tryptophan-based and dynamin and eps15 dependent. In contrast, the
      C2A contains an unusual internalization signal that is not seen in the C2A of
      synaptotagmin I. This signal is not based on the homologous tryptophan in its C
      terminus. Moreover, internalization of the C2A domain is both dynamin and eps15
      independent. Finally, the C2B domain of synaptotagmin VII contains an inhibitory
      motif that prevents internalization. Endocytic trafficking of synaptotagmin VII
      is thus governed by these two latent internalization signals, which are concealed
      by intramolecular inhibition. We propose that endocytosis of synaptotagmin VII is
      regulated in this way to allow it to couple the processes of regulated exocytosis
      and compensatory endocytosis.

PMID- 12615975
TI  - Myosin Va facilitates the distribution of secretory granules in the F-actin rich
      cortex of PC12 cells.
AB  - Neuroendocrine secretory granules, the storage organelles for neuropeptides and
      hormones, are formed at the trans-Golgi network, stored inside the cell and
      exocytosed upon stimulation. Previously, we have reported that newly formed
      secretory granules of PC12 cells are transported in a microtubule-dependent
      manner from the trans-Golgi network to the F-actin-rich cell cortex, where they
      undergo short directed movements and exhibit a homogeneous distribution. Here we
      provide morphological and biochemical evidence that myosin Va is associated with
      secretory granules. Expression of a dominant-negative tail domain of myosin Va in
      PC12 cells led to an extensive clustering of secretory granules close to the cell
      periphery, a loss of their cortical restriction and a strong reduction in their
      motility in the actin cortex. Based on this data we propose a model that implies
      a dual transport system for secretory granules: after microtubule-dependent
      delivery to the cell periphery, secretory granules exhibit a myosin Va-dependent
      transport leading to their restriction and even dispersal in the F-actin-rich
      cortex of PC12 cells.

PMID- 12615976
TI  - Telomere-based proliferative lifespan barriers in Werner-syndrome fibroblasts
      involve both p53-dependent and p53-independent mechanisms.
AB  - Werner-syndrome fibroblasts have a reduced in vitro life span before entering
      replicative senescence. Although this has been thought to be causal in the
      accelerated ageing of this disease, controversy remains as to whether Werner
      syndrome is showing the acceleration of a normal cellular ageing mechanism or the
      occurrence of a novel Werner-syndrome-specific process. Here, we analyse the
      signalling pathways responsible for senescence in Werner-syndrome fibroblasts.
      Cultured Werner-syndrome (AG05229) fibroblasts senesced after approximately 20
      population doublings with most of the cells having a 2N content of DNA. This was
      associated with hypophosphorylated pRb and high levels of p16(Ink4a) and
      p21(Waf1). Senescent AG05229 cells re-entered the cell cycle following
      microinjection of a p53-neutralizing antibody. Similarly, production of the human
      papilloma virus 16 E6 oncoprotein in presenescent AG05229 cells resulted in
      senescence being bypassed and extended cellular life span. Werner-syndrome
      fibroblasts expressing E6 did not proliferate indefinitely but reached a second
      proliferative lifespan barrier, termed M(int), that could be bypassed by forced
      production of telomerase in post-M1 E6-producing cells. The conclusions from
      these studies are that: (1) replicative senescence in Werner-syndrome fibroblasts
      is a telomere-induced p53-dependent event; and (2) the intermediate lifespan
      barrier M(int) is also a telomere-induced event, although it appears to be
      independent of p53. Werner-syndrome fibroblasts resemble normal human fibroblasts
      for both these proliferative lifespan barriers, with the strong similarity
      between the signalling pathway linking telomeres to cell-cycle arrest in Werner
      syndrome and normal fibroblasts providing further support for the defect in
      Werner syndrome causing the acceleration of a normal ageing mechanism.

PMID- 12615977
TI  - The lipoma preferred partner LPP interacts with alpha-actinin.
AB  - The lipoma preferred partner LPP is a member of the zyxin family of proteins. In
      this paper, we demonstrate that the structural similarities observed between
      zyxin and LPP also extend to their interaction capabilities. Similar to zyxin,
      LPP was found to bind to alpha-actinin in vitro. This interaction was confirmed
      in yeast and mammalian cells. Studies utilizing the three-hybrid system further
      indicated that zyxin and LPP compete for the same binding site in alpha-actinin.
      This site was mapped to the central rod of alpha-actinin, which contains spectrin
      like repeats 2 and 3. In the case of LPP, a conserved motif present at the N
      terminus was shown to be responsible for the interaction. Constructs lacking this
      motif did not bind to alpha-actinin in the yeast two-hybrid system and were not
      able to recruit alpha-actinin to an ectopic site in mammalian cells. Quantitative
      data obtained with the two-hybrid and the three-hybrid system suggest that LPP
      has a lower affinity for alpha-actinin than zyxin. It is likely that this
      difference leads to slightly different roles played by LPP and zyxin during the
      assembly and disassembly of focal adhesions.

PMID- 12615978
TI  - EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via
      the Rac/PAK pathway.
AB  - Interactions between the Eph receptor tyrosine kinase and ephrin ligands
      transduce short-range signals regulating axon pathfinding, development of the
      cardiovascular system, as well as migration and spreading of neuronal and non
      neuronal cells. Some of these effects are believed to be mediated by alterations
      in actin dynamics. The members of the small Rho GTPase family elicit various
      effects on actin structures and are probably involved in Eph receptor-induced
      actin modulation. EphrinA1 is proposed to contribute to angiogenesis as it is
      strongly expressed at sites of neovascularization. Moreover, angiogenic factors
      induce the expression of ephrinA1 in endothelial cells. In this study, using rat
      vascular smooth muscle cells (VSMCs), we investigated the contribution of the
      small Rho GTPases in ephrinA1-induced integrin inactivation. EphrinA1 did not
      significantly affect early adhesion of VSMCs on purified laminin or fibronectin,
      but strongly impaired cell spreading. The Rho kinase inhibitor Y-27632 partly
      reversed the ephrinA1 effect, suggesting involvement of Rho in this model.
      However, inhibition of RhoA synthesis with short interfering (si)RNA had a modest
      effect, suggesting that RhoA plays a limited role in ephrinA1-mediated inhibition
      of spreading in VSMCs. The ephrinA1-mediated morphological alterations correlated
      with inhibition of Rac1 and p21-activated kinase 1 (PAK1) activity, and were
      antagonized by the expression of a constitutively active Rac mutant. Moreover,
      repression of Rac1 synthesis with siRNA amplifies the ephrinA1-induced inhibition
      of spreading. Finally, sphingosine-1-phosphate (S1P), a lipid mediator known to
      inhibit Rac activation in VSMCs amplifies the ephrinA1 effect. In conclusion, our
      results emphasize the role of the Rac/PAK pathway in ephrinA1-mediated inhibition
      of spreading. In this way, ephrinA1, alone or in synergy with S1P, can
      participate in blood vessel destabilization, a prerequisite for angiogenesis.

PMID- 12615979
TI  - Polo boxes form a single functional domain that mediates interactions with
      multiple proteins in fission yeast polo kinase.
AB  - Polo kinases play multiple roles in cell cycle regulation in eukaryotic cells. In
      addition to the kinase domain, conservation at the primary sequence level is also
      found in the non-catalytic region mainly in three blocks, namely the polo boxes.
      Although several studies have implicated the polo boxes in protein localisation,
      no systematic study to elucidate the roles of individual polo boxes has been
      carried out. Here we show, by using fission yeast, that the polo boxes form a
      single functional unit that is essential for both cellular function and cell
      cycle-regulated localisation to the spindle pole bodies. Various polo box
      mutations abolish the mitotic arrest seen upon overexpression of plo1 but do not
      prevent the untimely septation seen under these conditions, showing that the
      functions of Plo1 may be separated. Plo1 interacts with multiple proteins
      including cell cycle regulators in a polo-box-dependent manner. Isolation of
      mutants that differentially disrupt these interactions revealed a role for the
      polo boxes in mediating protein-protein interactions.

PMID- 12615981
TI  - Stroke: beyond thrombolysis and back to basics.

PMID- 12615982
TI  - Autoimmunity and the basal ganglia: new insights into old diseases.
AB  - Sydenham's chorea (SC) occurs weeks or months after Group A streptococcal
      infection, and is characterized by involuntary, purposeless movements of the
      limbs, in addition to behavioural alteration. There is a body of evidence which
      suggests that SC is an immune-mediated brain disorder with regional localization
      to the basal ganglia. Recent reports have suggested that the spectrum of post
      streptococcal CNS disease is broader than chorea alone, and includes other
      hyperkinetic movement disorders (tics, dystonia and myoclonus). In addition,
      there are high rates of behavioural sequelae, particularly emotional disorders
      such as obsessive-compulsive disorder, anxiety and depression. These findings
      have lead to the hypothesis that similar immune-mediated basal ganglia processes
      may be operating in common neuropsychiatric disease such as tic disorders,
      Tourette syndrome and obsessive-compulsive disorder. This review analyses the
      historical aspects of post-streptococcal CNS disease, and the recent
      immunological studies which have addressed the hypothesis that common
      neuropsychiatric disorders may be secondary to basal ganglia autoimmunity.

PMID- 12615983
TI  - Vasoactive mediators and renal haemodynamics in exertional heat stroke
      complicated by acute renal failure.
AB  - BACKGROUND: Although vasoactive substances may be important in the pathogenesis
      of some types of acute renal failure (ARF), their potential role in exertional
      heat stroke (ExHS) with ARF has not been explored. AIM: To evaluate whether
      changes in concentration of individual vasoactive mediators correlated with
      alterations in renal function and haemodynamics in patients with ExHS and ARF.
      DESIGN: Prospective case-control study. METHODS: Systemic and renal
      haemodynamics, circulating vasoactive hormones and urinary vasodilator
      metabolites were determined in 12 military recruits who developed ExHS with ARF
      but without other organ failure during a three-year period. The control group
      consisted of 12 recruits who performed similar exercise under the same conditions
      without developing ExHS. RESULTS: There were significant elevations in
      circulating pressor hormones (catecholamines, renin, aldosterone and endothelin-1
      (ET-1)) and significant decreases in the vasodilatory hormone prostaglandin E(2)
      (PGE(2)) in the acute phase of ExHS with ARF when compared to ExC. There was also
      a significant rise in nitric oxide metabolites (NOx) in the acute phase of ExHS.
      All of these abnormalities in circulating hormones returned to normal range
      during the recovery phase of ExHS. The ERPF correlated positively with GFR and
      urinary PGE(2) and negatively with plasma catecholamines, renin, ET-1 and NOx.
      DISCUSSION: The changes in the plasma levels of these hormones, together with
      enhanced NO production, may both contribute to the pathophysiology of ARF in
      ExHS.

PMID- 12615984
TI  - Identifying acute myocardial infarction: effects on treatment and mortality, and
      implications for National Service Framework audit.
AB  - BACKGROUND: The National Service Framework (NSF) for Coronary Heart Disease
      requires annual clinical audit of the care of patients with myocardial
      infarction, with little guidance on how to achieve these standards and monitor
      practice. AIM: To assess which method of identification of acute myocardial
      infarction (AMI) cases is most suitable for NSF audit, and to determine the
      effect of the definition of AMI on the assessment of quality of care. DESIGN:
      Observational study. METHODS: Over a 3-month period, 2153 consecutive patients
      from 20 hospitals across the Yorkshire region, with confirmed AMI, were
      identified from coronary care registers, biochemistry records and hospital coding
      systems. The sensitivity and positive predictive value of AMI patient
      identification using clinical coding, biochemistry and coronary care registers
      were compared to a 'gold standard' (the combination of all three methods).
      RESULTS: Of 3685 possible cases of AMI singled out by one or more methods, 2153
      patients were identified as having a final diagnosis of AMI. Hospital coding
      revealed 1668 (77.5%) cases, with a demographic profile similar to that of the
      total cohort. Secondary preventative measures required for inclusion in NSF were
      also of broadly similar distribution. The sensitivities and positive predictive
      values for patient identification were substantially less in the cohorts
      identified through biochemistry and coronary care unit register. Patients
      fulfilling WHO criteria (n=1391) had a 30-day mortality of 15.9%, vs. 24.2% for
      the total cohort. DISCUSSION: Hospital coding misses a substantial proportion
      (22.5%) of AMI cases, but without any apparent systematic bias, and thus provides
      a suitably representative and robust basis for NSF-related audit. Better still
      would be the routine use of multiple methods of case identification.

PMID- 12615985
TI  - Clinical experience and pre-test probability scores in the diagnosis of pulmonary
      embolism.
AB  - BACKGROUND: The Geneva and Wells pre-test probability scores are intended to
      replace empirical assessment of patients with suspected pulmonary embolism (PE).
      The effect of clinical experience on the inter-rater variability of these scores,
      and on empirical judgement, is unknown. AIM: To determine whether medical staff
      appointment grade affects the inter-rater variability of these pre-test
      probability scores, or empirical assessment, in patients with suspected PE.
      DESIGN: Questionnaire survey. METHODS: Doctors were grouped by grade (mean number
      of years since graduation+/-SEM): house officers 0.7+/-0.2, registrars 6.3+/-0.6,
      consultants 25+/-4 and applied pre-test probability scores to actual case
      scenarios. RESULTS: The Geneva score was the most consistent method of
      determining pre-test probability and was unaffected by clinical experience
      (Geneva kappa=0.73, Wells kappa=0.38, empirical kappa=0.23, p<0.001 ). With
      empirical judgement, inter-rater variability was inversely proportional to
      clinical experience (house officers kappa=0.37, registrars kappa=0.24,
      consultants kappa= 0.16, p<0.05). DISCUSSION: The Geneva score was the least
      variable method and can be applied by junior or senior doctors. Using empirical
      judgement, junior doctors were more likely to agree on the pre-test probability
      of PE than were their more senior colleagues. This may imply that as physicians
      gain experience, they recognize that the diagnosis of PE can be difficult to
      assess and are reluctant to exclude it on clinical grounds.

PMID- 12615986
TI  - Infective endocarditis in the Western Cape Province of South Africa: a three-year
      prospective study.
AB  - BACKGROUND: The last 50 years have seen major changes in the epidemiology of
      infective endocarditis (IE). AIM: To evaluate local patient characteristics, risk
      factors, clinical sequelae, microbiology, morbidity and mortality in patients
      with definite IE. DESIGN: Prospective observational study. METHODS: Over a three
      year period, patients referred with probable IE were prospectively enrolled. All
      received a standardized diagnostic evaluation. Epidemiological data were
      documented; underlying risk factors for IE were sought. Initial evaluation and
      follow-up (to 6 months) included the documentation of vascular or immunological
      phenomena, morbidity and mortality. RESULTS: Of 92 patients referred with
      probable IE, 47 had definite IE. These patients had a mean age of 37.7 years with
      a male predominance (1.6:1). Rheumatic heart disease was present in 36 (76.6%).
      Eight had prosthetic valves. Three had congenital heart disease, mitral valve
      prolapse or multiple central intravascular catheters, respectively. All denied
      the use of intravenous recreational drugs and only one tested seropositive for
      HIV. Renal involvement (59.6%) and clubbing (29.8%) were commonly observed. The 6
      month mortality rate was 35.6%, while 44.7% needed valvular replacement. An
      aetiological diagnosis was made in 21, with viridans streptococci the most common
      isolate. DISCUSSION: Infective endocarditis in the Western Cape of South Africa
      is a disease of younger adults, with a male predominance. Rheumatic heart disease
      is the major predisposing factor. Degenerative heart disease and intravenous drug
      abuse are not important risk factors. Our data do not support the notion that HIV
      infection is an independent risk factor for IE. Local mortality rates are much
      higher than recent international figures, as is the proportion of 'culture
      negative' IE.

PMID- 12615989
TI  - Me and my heart.

PMID- 12615987
TI  - Bacteraemia in adults due to glucose non-fermentative Gram-negative bacilli other
      than P. aeruginosa.
AB  - BACKGROUND: Glucose non-fermentative Gram-negative bacilli other than P.
      aeruginosa (NF) are emerging pathogens. AIM: To evaluate the epidemiology,
      clinical characteristics, predictors of acquisition, and outcome of bacteraemia
      due to NF. DESIGN: Retrospective analysis of prospectively recorded data.
      METHODS: We reviewed episodes of NF bacteraemia in patients older than 14 years,
      recorded through a blood culture surveillance program. Patients were identified
      at the time of their bacteraemia and prospectively followed. RESULTS: Between
      January 1991 and December 2000, 296 episodes of NF bacteraemia were detected: 87%
      were due to Acinetobacter sp., Pseudomonas sp. other than P. aeruginosa, or
      Stenotrophomonas maltophilia. The global incidence (0.87 cases per 1000
      discharges) remained stable during the study period. Patients were of all ages
      and both sexes, and 282/296 (95.3%) had some predisposing underlying disease or
      condition, the most common being haematological malignancies without
      transplantation (85/296, 28.7%), treatment with steroids (78/296, 26.3%), and
      transplantation (bone marrow or solid organ) (70/296, 23.6%). Fifty (16.9%) were
      neutropenic. The most common sources of bacteraemia were central venous catheter
      infection (117/296, 39.5%) and unknown primary site (97/296, 32.8%). Sixty-one
      episodes (20.6%) were community-acquired and 235 (79.4%) were nosocomial. Forty
      three patients (14.5%) died. Pneumonia (RR 1.5, 95%CI 1.1-14.2), age<65 (RR 3.1,
      95%CI 1.4-10.3), hospitalization in the intensive care unit (ICU) (RR 3.2, 95%CI
      1.3-9.8), rapidly fatal disease (RR 4.9, 95%CI 3.1-12.6), and severe sepsis (RR
      9.8, 95%CI 1.6-19.7) were independent predictors of death. Factors predicting the
      probability that an episode of nosocomial bacteraemia was due to NF included:
      rapidly fatal disease (RR 1.23, 95%CI 1.02-4.1), age<65 (RR 2.05, 95%CI 1.4-3),
      hospitalization in the ICU (RR 2.06, 95%CI 1.4-3, and pneumonia (RR 2.1, 95%CI
      1.05-4.8). DISCUSSION: NF bacteraemia mainly affects patients with malignant
      haematological disease, with and without transplantation, and patients in the
      ICU. The most common known source is a central venous catheter, though many
      sources are unknown. Mortality is relatively low, and depends on the severity of
      the underlying disease.

PMID- 12615991
TI  - Nuclear georeactor origin of oceanic basalt 3He/4He, evidence, and implications.
AB  - Nuclear georeactor numerical simulation results yield substantial (3)He and (4)He
      production and (3)He(4)He ratios relative to air (R(A)) that encompass the entire
      2-SD (2sigma) confidence level range of tabulated measured (3)He(4)He ratios of
      basalts from along the global spreading ridge system. Georeactor-produced
      (3)He(4)He ratios are related to the extent of actinide fuel consumption at time
      of production and are high near the end of the georeactor lifetime. Georeactor
      numerical simulation results and the observed high (3)He(4)He ratios measured in
      Icelandic and Hawaiian oceanic basalts indicate that the demise of the georeactor
      is approaching. Within the present level of uncertainty, one cannot say precisely
      when georeactor demise will occur, whether in the next century, in a million
      years, or in a billion years from now.

PMID- 12615992
TI  - Metabolic incorporation of unnatural sialic acids into Haemophilus ducreyi
      lipooligosaccharides.
AB  - The lipooligosaccharides (LOS) of Haemophilus ducreyi are highly sialylated, a
      modification that has been implicated in resistance to host defense and in
      virulence. In previous work, we demonstrated that H. ducreyi scavenges sialic
      acid from the extracellular milieu and incorporates those residues into LOS. Here
      we report that H. ducreyi can use unnatural sialic acids bearing elongated N-acyl
      groups from three to seven carbon atoms in length, resulting in outer membrane
      presentation of unnatural sialyl-LOS. The unnatural variant comprises
      approximately 90% of cell surface sialosides when exogenous substrates are added
      to the media at micromolar concentrations, despite the availability of natural
      sialic acid in the growth media. Although they represent the majority of cell
      surface sialosides, analogs with longer N-acyl groups diminish the overall level
      of LOS sialylation, culminating in complete inhibition of LOS sialylation by N
      octanoyl sialic acid. Thus, sialylation of H. ducreyi LOS can be modulated with
      respect to the structure of the terminal sialic acid residue and the extent to
      which the LOS acceptor is modified by supplying the bacteria with various sialic
      acid analogs.

PMID- 12615995
TI  - On the pattern of discovery of introduced species.
AB  - Introductions of nonindigenous species can have significant effects. It is
      commonly claimed that the rate of species introductions to the United States has
      increased over time. This claim is based in part on the increasing rate of
      discoveries of introduced species. This discovery rate is influenced by factors
      other than the introduction rate. These include the sampling rate and population
      growth in the introduced species. In this article, we show that the discovery
      rate can increase even when there is no increase in either the introduction rate
      or the sampling rate. This suggests that the basis for some claims regarding an
      increasing rate of introductions may be invalid.

PMID- 12615994
TI  - Novel functions of the phosphatidylinositol metabolic pathway discovered by a
      chemical genomics screen with wortmannin.
AB  - We report a novel connection between the phosphatidylinositol (PI) metabolic
      pathway and the DNA replication and damage checkpoint pathway discovered from an
      unbiased chemical genomics screen. Substrates and products of PI kinases are
      important signaling molecules that affect a wide range of biological processes.
      The full collection of yeast deletion strains was screened to identify genes that
      confer altered sensitivity to the natural product wortmannin, a PI kinase
      inhibitor. These experiments have allowed us to explore metabolomic and proteomic
      implications of PI synthesis and turnover. This study also uncovers other
      biological processes affected by wortmannin treatment, including proteasome
      mediated degradation and chromatin remodeling. Bioinformatic analyses were used
      to reveal the relative distances among cellular processes affected by wortmannin
      and protein-protein interactions in the wortmannin-sensitive proteomic
      subnetwork. These results illustrate the great utility of using a whole-genome
      approach in annotating the biological effects of small molecules and have clear
      implications for pharmacogenomics. Furthermore, our discovery points to a route
      to overcoming genome instability, a result of defective DNA damage
      signaling/repair and a hallmark of cancer.

PMID- 12615996
TI  - Functional-morphologic MR imaging with ultrasmall superparamagnetic particles of
      iron oxide in acute and chronic soft-tissue infection: study in rats.
AB  - PURPOSE: To investigate the use of magnetic resonance (MR) imaging enhanced with
      ultrasmall superparamagnetic particles of iron oxide (USPIO) to identify acute,
      early chronic, and late chronic abscess formation in an experimental model of
      soft-tissue abscess. MATERIALS AND METHODS: Experimental soft-tissue infection in
      15 rats was imaged with an MR imaging unit on days 1 and 2 (acute), days 5 and 6
      (early chronic), and days 8 and 9 (late chronic) after inoculation of the
      infectious agent. All animals were imaged without contrast enhancement and
      immediately and 24 hours after USPIO administration. MR and histopathologic
      findings were compared. The changes in relative signal intensity (SI) and in the
      extent and pattern of contrast enhancement (macrophage distribution) between the
      animal groups were analyzed. Statistical testing was performed with Kruskal
      Wallis analysis of variance and the chi2 test. RESULTS: At 24 hours after USPIO
      administration, the relative SI of the abscess wall and the relative macrophage
      extent were 0.50 (0.33-0.73) and 1.03 (0.90-1.08), respectively, for acute
      infection; 0.11 (0.10-0.18) and 0.94 (0.93-1.01) for early chronic infection; and
      0.53 (0.44-0.58) and 0.80 (0.77-0.83) for late chronic infection. The changes in
      enhancement pattern (P <.001), relative SI (P <.001), and relative macrophage
      extent (P <.05) with time were significant. CONCLUSION: The macrophage
      distribution pattern increases the specificity of MR findings in chronic
      infection and allows differentiation between areas with active inflammation and
      areas of reparative granulation tissue.

PMID- 12615997
TI  - Differentiation of perforated from nonperforated appendicitis at CT.
AB  - PURPOSE: To evaluate the sensitivity and specificity of five computed tomographic
      (CT) criteria in the differentiation of perforated from nonperforated
      appendicitis. MATERIALS AND METHODS: CT scans of 94 patients with surgically
      proven appendicitis were classified on review as showing perforation if one of
      five CT findings was present. The authors calculated the sensitivity and
      specificity for each finding by comparing the predicted outcome to the surgical
      and pathologic outcome. RESULTS: The perforated group comprised 39 patients and
      the nonperforated group comprised 55 patients. Sensitivity for abscess, phlegmon,
      extraluminal air, extraluminal appendicolith, and focal defect in enhancing
      appendiceal wall individually were 36%, 46%, 36%, 21%, and 64%, respectively.
      Sensitivity for any one of the five findings was 94.9%. Specificities were 100%
      for all findings except for phlegmon (95%). Groups differed with respect to age:
      47 years +/- 19 (mean +/- SD) for perforated appendicitis and 30 years +/- 13 for
      nonperforated appendicitis (P <.001). Groups also differed with respect to
      appendiceal diameter: 15 mm +/- 4.9 for perforated appendicitis and 12 mm +/- 3.3
      for nonperforated appendicitis (P =.049). CONCLUSION: A dedicated search for five
      specific CT findings allowed an overall sensitivity of 94.9% for perforated
      appendicitis. Among findings with 100% specificity, a focal defect in the
      enhancing appendiceal wall achieved the highest sensitivity.

PMID- 12615993
TI  - Heat shock protein coinducers with no effect on protein denaturation specifically
      modulate the membrane lipid phase.
AB  - The hydroxylamine derivative bimoclomol (BM) has been shown to activate natural
      cytoprotective homeostatic responses by enhancing the capability of cells to cope
      with various pathophysiological conditions. It exerts its effect in synergy with
      low levels of stress to induce the synthesis of members of major stress protein
      families. We show here that the presence of BM does not influence protein
      denaturation in the cells. BM and its derivatives selectively interact with
      acidic lipids and modulate their thermal and dynamic properties. BM acts as a
      membrane fluidizer at normal temperature, but it is a highly efficient membrane
      stabilizer, inhibiting the bilayer-nonbilayer phase transitions during severe
      heat shock. We suggest that BM and the related compounds modify those domains of
      membrane lipids where the thermally or chemically induced perturbation of lipid
      phase is sensed and transduced into a cellular signal, leading to enhanced
      activation of heat shock genes. BM may be a prototype for clinically safe
      membrane-interacting drug candidates that rebalance the level and composition of
      heat shock proteins.

PMID- 12615998
TI  - Dynamic three-dimensional MR renography for the measurement of single kidney
      function: initial experience.
AB  - A three-dimensional magnetic resonance (MR) renographic method to measure single
      kidney glomerular filtration rate (GFR) and split renal function was developed
      that is based on renal signal intensity measurements during 2-3 minutes after
      intravenous injection of a low dose (2 mL or 0.01 mmol/kg) of gadopentetate
      dimeglumine. In nine subjects, single kidney MR GFR indices correlated well with
      technetium 99m (99mTc) diethylenetriaminepentaacetic acid (DTPA) clearance (r =
      0.7-0.8) for GFR values of 7-48 mL/min. MR right kidney split renal function
      values (range, 32%-59%) also correlated well with 99mTc-DTPA radionuclide
      measurements (r = 0.76); differences between the two methods averaged 0.8% +/- 8.
      MR renography was performed along with contrast material-enhanced MR imaging of
      the kidneys and renal arteries and added 8 minutes or less to the total
      examination time.

PMID- 12616000
TI  - Dynamic US of the anterior band of the ulnar collateral ligament of the elbow in
      asymptomatic major league baseball pitchers.
AB  - PURPOSE: To determine whether dynamic ultrasonography (US) can reveal
      abnormalities of the anterior band of the ulnar collateral ligament (UCL) of the
      elbow in asymptomatic major league professional baseball players. MATERIALS AND
      METHODS: US was performed in 26 asymptomatic major league professional baseball
      pitchers before spring training. Images were obtained in both pitching and
      nonpitching arms with a multifrequency 13-MHz linear-array transducer. The
      thickness of the anterior band of the UCL and the width of the joint it spans
      (the ulnohumeral joint) were measured with the elbow at 30 degrees of flexion,
      both at rest and with valgus stress. The thickness of the anterior band of the
      UCL and the width of the joint space were compared for pitching and nonpitching
      arms by using the Student t test. The prevalence of hypoechoic areas and
      calcifications within the anterior band of the UCL in pitching and nonpitching
      arms was compared by using the McNemar test. The average time of the US
      examinations was recorded. RESULTS: At rest, the mean thickness (+/- 1 SD) of the
      anterior band of the UCL was 6.3 mm +/- 1.1 in pitching arms and 5.3 mm +/- 1.0
      in nonpitching arms. This difference was statistically significant (P <.01). With
      stress, the anterior band thickness was 6.3 mm +/- 1.4 in the pitching arms and
      4.8 mm +/- 0.9 in the nonpitching arms (P <.001). The joint space width at rest
      was 2.8 mm +/- 1.0 in the pitching arms and 2.5 mm +/- 0.7 in the nonpitching
      arms (not statistically significant). When stress was applied, however, the joint
      space width was significantly greater in the pitching arms than in the
      nonpitching arms (4.2 mm +/- 1.5 vs 3 mm +/- 1.0, respectively; P <.01).
      Hypoechoic foci within the anterior band of the UCL were seen in 18 of 26 (69%)
      pitching arms and three of 26 (12%) nonpitching arms (P <.001). Calcifications
      were detected in nine of 26 (35%) pitching arms but in none of the nonpitching
      arms (P <.001). The average time for bilateral US was 10.4 minutes. CONCLUSION:
      Dynamic US provides a rapid means for evaluating the anterior band of the UCL in
      professional baseball pitchers. In pitching arms, this band is thicker, is more
      likely to have hypoechoic foci and/or calcifications, and demonstrates more
      laxity with valgus stress.

PMID- 12615999
TI  - Detection of subtle undisplaced rib fractures in a porcine model: radiation dose
      requirement--digital flat-panel versus screen-film and storage-phosphor systems.
AB  - PURPOSE: To compare a large-area direct read-out flat-panel detector radiography
      system with screen-film and storage-phosphor systems with regard to detection of
      subtle undisplaced rib fractures and to assess the diagnostic performance of the
      flat-panel system with decreasing exposure level. MATERIALS AND METHODS: Subtle
      fractures were created artificially in 100 of 200 porcine rib specimens.
      Specimens were enclosed in containers of water to generate absorption and scatter
      radiation conditions similar to those of a human chest wall. Imaging was
      performed with flat-panel, screen-film, and storage-phosphor systems with
      conditions that were exactly matched. Different exposure levels equivalent to
      speed classes (S) of 400, 800, 1,600, and 6,400 were used. All images were
      independently assessed for the presence of fracture by three radiologists with a
      five-level confidence scale. Receiver operating characteristic (ROC) analysis was
      performed for a total of 4,200 observations (600 for each imaging system and
      exposure level). Diagnostic performance was estimated with area under the ROC
      curve (Az). Significance of differences in diagnostic performance was tested with
      analysis of variance. RESULTS: ROC analysis yielded mean Az values for the flat
      panel system of 0.879 (S = 400), 0.833 (S = 800), 0.765 (S = 1,600), and 0.576 (S
      = 6,400). Az values were 0.834 (S = 400) for the screen-film system and 0.789 (S
      = 400) and 0.729 (S = 800) for the storage-phosphor system. Analysis of variance
      revealed significant differences in diagnostic performance between various
      combinations of imaging system and exposure levels (P <.05). CONCLUSION: The flat
      panel system is superior to the screen-film and storage-phosphor systems for
      detection of subtle undisplaced rib fractures at clinical exposure settings (eg,
      S = 400). With the flat-panel system, radiation dose can be reduced by 50% to
      achieve diagnostic performance comparable to that of a speed class 400 screen
      film system.

PMID- 12616001
TI  - Upper airway motion depicted at cine MR imaging performed during sleep:
      comparison between young Patients with and those without obstructive sleep apnea.
AB  - PURPOSE: To compare the patterns of dynamic airway motion depicted on cine
      magnetic resonance (MR) images obtained during sleep between young patients with
      and those without obstructive sleep apnea (OSA). MATERIALS AND METHODS: Fast
      gradient-echo sequences were performed in the sagittal midline by using a 1.5-T
      unit to create cine MR images. Cine MR images obtained during sleep in 16 young
      patients with OSA were compared with those obtained in 16 young patients with no
      airway symptoms of airway disease. The nasopharynx, oropharynx, and hypopharynx
      were characterized in terms of airway motion as static patent (SP), dynamic
      patent, intermittent collapsed (IC), or static collapsed (SC); and the maximal
      diameter and greatest change in diameter (in millimeters) of these airways were
      calculated. Adenoid tonsil size and mouth position (ie, opened or closed) were
      determined. Differences in the frequency of MR imaging parameters in the
      different anatomic regions were evaluated by using Fisher exact, chi 2, and
      sample t tests. RESULTS: There were statistically significant differences in the
      following parameters between the two groups: nasopharynx SP (P <.001) and IC (P
      <.001); hypopharynx SP (P <.001) and IC (P <.001); and mean change in airway
      diameter of the nasopharynx (P <.001) and hypopharynx (P <.001). The mean adenoid
      tonsil size in the patients with OSA was larger (P =.006). CONCLUSION: There are
      significant differences in the patterns of dynamic airway motion between young
      patients with and those without OSA.

PMID- 12616002
TI  - Blunt abdominal trauma: should US be used to detect both free fluid and organ
      injuries?
AB  - PURPOSE: To evaluate abdominal ultrasonography (US) for indirect (with free fluid
      analysis only) and direct (with free fluid and parenchymal analysis) detection of
      organ injury in patients with blunt abdominal trauma, with findings at computed
      tomography (CT) and/or surgery as the standard of diagnosis. MATERIALS AND
      METHODS: Abdominal US was performed at hospital admission in consecutive patients
      with blunt abdominal trauma. The presence of free peritoneal fluid and organ
      injury were recorded and compared with results of abdominal CT in all
      hemodynamically stable patients. When US results were considered false-negative
      for free fluid or organ injury compared with CT results, repeat US was performed
      within 6 hours. Admission and second US results were compared with CT and/or
      surgical results to determine sensitivity, specificity, negative predictive
      value, and positive predictive value of US with regard to the presence of free
      intraperitoneal fluid and/or organ injury. RESULTS: Two hundred five
      hemodynamically stable patients underwent abdominal US and CT. CT revealed free
      fluid in 83 patients and organ injury in 99. Thirty-one (31%) of 99 patients with
      organ injury did not have free fluid at CT. Three (10%) of the 31 patients
      required surgery or angiographic embolization. The sensitivity of admission US
      was 93% (77 of 83 cases) for the diagnosis of free fluid, 41% (39 of 99) for
      directly demonstrating organ injury, and 72% (71 of 99) for suggesting organ
      injury by means of both free fluid and organ analysis. At second US, these
      sensitivities were 96% (80 of 83 cases), 55% (54 of 99) and 84% (83 of 99),
      respectively. CONCLUSION: US is highly sensitive for the detection of free
      intraperitoneal fluid but not sensitive for the identification of organ injuries.
      In hemodynamically stable patients, the value of US is mainly limited by the
      large percentage of organ injuries that are not associated with free fluid.

PMID- 12616003
TI  - Hypothesis testing II: means.
AB  - Whenever means are reported in the literature, they are likely accompanied by
      tests to determine statistical significance. The t test is a common method for
      statistical evaluation of the difference between two sample means. It provides
      information on whether the means from two samples are likely to be different in
      the two populations from which the data originated. Similarly, paired t tests are
      common when comparing means from the same set of patients before and after an
      intervention. Analysis of variance techniques are used when a comparison involves
      more than two means. Each method serves a particular purpose, has its own
      computational formula, and uses a different sampling distribution to determine
      statistical significance. In this article, the authors discuss the basis behind
      analysis of continuous data with use of paired and unpaired t tests, the
      Bonferroni correction, and multivariate analysis of variance for readers of the
      radiology literature.

PMID- 12616004
TI  - CT depiction of portal vein thrombi after creation of ileal pouch-anal
      anastomosis.
AB  - PURPOSE: To determine the presence and location of portal vein thrombi in
      patients who have undergone ileal pouch-anal anastomosis (IPAA) and who were
      scanned with computed tomography (CT). MATERIALS AND METHODS: During a 4-year
      period, 92 of 702 patients underwent contrast medium-enhanced CT after a total
      proctocolectomy with an IPAA. These CT scans were retrospectively reviewed for
      portal vein thrombus presence, location, and occlusive nature, as well as any
      accompanying enhancement abnormalities of the hepatic parenchyma. Only 13
      patients who had initial CT scans that were positive for thrombi underwent follow
      up examinations, and these were reviewed for resolution or progression of the
      original findings. RESULTS: Portal vein thrombi were present in 41 (45%) of the
      92 patients; 24 (59%) of the 41 were isolated, often multiple, segmental right
      lobe thrombi. Five patients had both right and left segmental vein involvement.
      Eleven patients had various combinations of main portal vein, right and left
      portal vein, or segmental vein thrombi. One patient had an isolated superior
      mesenteric vein thrombus. Twenty-two of 25 superior mesenteric vein, main portal
      vein, and right and left portal vein thrombi were nonocclusive, while most (63 of
      86) of the segmental vein thrombi were occlusive. Wedge-shaped, peripheral areas
      of hepatic parenchymal hyperenhancement that were distal to the thrombi were
      present in 30 (73%) of the 41 patients. Follow-up scans obtained in the 13
      patients with portal vein thrombi showed thrombi resolved in five patients,
      progression to cavernous transformation occurred in one patient, and parenchymal
      enhancement changes persisted in seven patients. In the seven patients with
      persistent enhancement changes, four had complete resolution of thrombi.
      CONCLUSION: Portal vein thrombi appear to be relatively common after IPAA surgery
      and are most likely segmental, multiple, and occlusive. Peripheral wedge-shaped
      areas of hepatic parenchymal hyperenhancement commonly accompany these thrombi.

PMID- 12616006
TI  - Portal vein embolization with polyvinyl alcohol particles and coils in
      preparation for major liver resection for hepatobiliary malignancy: safety and
      effectiveness--study in 26 patients.
AB  - PURPOSE: To evaluate whether preoperative portal vein embolization (PVE) with
      polyvinyl alcohol (PVA) particles and coils is safe and effective for inducing
      lobar hypertrophy in patients with hepatobiliary malignancy. MATERIALS AND
      METHODS: PVE was performed in 26 patients. All patients had malignancy:
      metastases (n = 11), cholangiocarcinoma (n = 9), hepatocellular carcinoma (n =
      5), and gallbladder carcinoma (n = 1). One patient had underlying liver disease
      caused by hepatitis. PVE was performed if the future liver remnant (FLR) was
      estimated to be less than 25% of the total liver volume. PVE was performed with a
      percutaneous transhepatic approach (right, 25 patients; left, one patient). PVA
      particles and coils were used to occlude the right portal system and veins
      supplying segment IV to promote FLR hypertrophy (segments I-III +/- IV). FLR
      hypertrophy was assessed with comparison of computed tomographic scans obtained
      before and 2-4 weeks after PVE. Effectiveness evaluation was based on changes in
      absolute FLR size and ratio of FLR to total estimated liver volume (TELV). Safety
      of PVE and hepatic resection was determined with postprocedure complication rate
      and median hospital stay. RESULTS: Sixteen patients underwent hepatic resection
      (right trisegmentectomy [n = 13], right lobectomy [n = 3]) without mortality. Ten
      patients did not undergo resection (complete remission after medical therapy [n =
      1], lack of regeneration [n = 2], extrahepatic disease undetected prior to PVE [n
      = 7]). Six patients had biliary obstruction; five were treated percutaneously
      before PVE. No patient developed postembolization syndrome or signs of fulminant
      hepatic insufficiency after PVE or resection. Two patients had complications
      after PVE that did not preclude successful resection. Median hospital stays were
      1 day (PVE) and 7 days (liver resection). Mean absolute FLR increased from 325.0
      to 458.6 cm3 (increase, 41.1%). Mean TELV was 1,784.8 cm3. FLR/TELV ratio
      increase was 8%. CONCLUSION: Preoperative PVE with PVA particles and coils is
      safe and effective for inducing lobar hypertrophy in patients with advanced
      hepatobiliary malignancy.

PMID- 12616007
TI  - Prospective blinded evaluation of Gd-DOTA- versus Gd-BOPTA-enhanced peripheral MR
      angiography, as compared with digital subtraction angiography.
AB  - PURPOSE: To compare the diagnostic accuracy of gadobenate dimeglumine (Gd-BOPTA)
      enhanced versus gadoterate meglumine (Gd-DOTA)-enhanced magnetic resonance (MR)
      angiography in patients with peripheral arterial occlusive disease (PAOD).
      MATERIALS AND METHODS: Fifty-six patients underwent MR angiography enhanced with
      either Gd-DOTA (28 patients) or Gd-BOPTA (28 patients). All arterial segments
      from the renal arteries to the distal run-off vessels were evaluated for disease
      severity. The sensitivity, specificity, and accuracy of MR angiography enhanced
      with both agents separately were evaluated with a paired t test; digital
      subtraction angiography was the reference standard. Interobserver variability was
      assessed by using the Cohen test. RESULTS: Diagnostic MR angiograms were obtained
      in all 56 patients. Overall, sensitivity and specificity of Gd-DOTA-enhanced MR
      angiography were 96% and 93%, respectively, for observer 1 and 96% and 85%,
      respectively, for observer 2 (kappa = 0.82). Corresponding values for Gd-BOPTA
      enhanced MR angiography were 94% and 93%, respectively, for observer 1 and 94%
      and 89%, respectively, for observer 2 (kappa = 0.78). No consistent differences
      between the two contrast materials in assessment of PAOD in the renal to
      popliteal arteries were observed. For assessment below the knee, specificity was
      slightly higher in the Gd-BOPTA group-91% and 84% for observers 1 and 2,
      respectively-than in the Gd-DOTA group-89% and 77%, respectively (P <.01). The
      number of nonassessable below-the-knee segments was significantly lower in the Gd
      BOPTA group: nine of 299 segments versus 25 of 312 segments in the Gd-DOTA group
      (P <.01). CONCLUSION: At MR angiography of the distal run-off vessels, Gd-BOPTA
      yielded higher specificity and a significantly smaller number of nonassessable
      segments than Gd-DOTA. The diagnostic accuracy of the two gadolinium chelates at
      peripheral MR angiography was comparable in the renal to popliteal arteries.

PMID- 12616005
TI  - Dietary caffeine consumption and withdrawal: confounding variables in
      quantitative cerebral perfusion studies?
AB  - PURPOSE: To evaluate the effects of dietary caffeine intake and withdrawal on
      cerebral blood flow (CBF), as determined from a randomized, blinded, placebo
      controlled study. MATERIALS AND METHODS: Twenty adults (16 men, four women; age
      range, 24-64 years) categorized as low (mean, 41 mg/d) or high (mean, 648 mg/d)
      caffeine users underwent quantitative flow-sensitive alternating inversion
      recovery perfusion magnetic resonance (MR) imaging twice: 90 minutes after a dose
      of caffeine (250 mg) on one day and after a dose of placebo on another day
      (randomized counterbalanced design). Doses were preceded by 30 hours of caffeine
      abstinence to induce withdrawal in high caffeine users. Quantitative CBF maps
      were gray matter (GM)-white matter (WM) segmented and subjected to region-of
      interest analysis to obtain mean CBF in WM, anterior circulation GM (AGM), and
      posterior circulation GM (PGM). By using two-way repeated-measures analysis of
      variance, regional CBF data were tested for within-subject differences between
      caffeine and placebo and for between-subject differences related to dietary
      caffeine habits. Linear regression was used to determine whether dietary caffeine
      use predicts CBF or CBF response to caffeine. RESULTS: Caffeine reduced CBF (P <
      or =.05) by 23% (AGM, PGM) and 18% (WM) in all subjects. Postplacebo (withdrawal)
      CBF in high caffeine users exceeded that in low users (P < or =.05) by 31% (AGM)
      and 32% (WM) (PGM, not significant). Mean postcaffeine CBF reduction in AGM was
      26% in high users versus 19% in low users (P < or =.05; PGM and WM, not
      significant). Increasing caffeine consumption predicted higher CBF (P < or =.05)
      in all regions: r = 0.79 (AGM), 0.57 (PGM), and 0.76 (WM). Dietary caffeine use
      did not predict CBF response to caffeine. CONCLUSION: Dietary caffeine
      consumption and withdrawal are potential confounding variables in cerebral
      perfusion and functional MR imaging.

PMID- 12616008
TI  - Computer-aided detection versus independent double reading of masses on
      mammograms.
AB  - PURPOSE: To evaluate the use of a computer-aided detection (CAD) system (designed
      for mammographic mass detection) to help improve mass interpretation and to
      compare CAD results with independent double-reading results. MATERIALS AND
      METHODS: Screening mammograms from 500 cases were collected; 125 of these cases
      were screening-detected cancers, and 125 were interval cancers. Previously
      obtained screening mammograms (ie, prior mammograms) were available in all cases.
      All mammograms were analyzed by a CAD system, which detected mass regions and
      assigned a level of (cancer) suspicion to each mass. Ten experienced screening
      radiologists read the prior mammograms. For independent interpretation with CAD,
      the suspicion rating assigned to each finding by the radiologist was weighted
      with the CAD output at the area of the finding. CAD markers on areas that were
      not reported by the radiologist were not used. Independent double reading was
      implemented by using a rule to combine the levels of suspicion assigned to
      findings by two radiologists. Results were evaluated by using localized-response
      receiver operating characteristic analysis. RESULTS: In a total of 141 cases,
      there was a visible abnormality at the location of the cancer on the prior
      mammogram, and 115 of these were classified as mass cases. For prior mammograms
      that depicted masses, the mean sensitivity of the radiologists, as averaged among
      the false-positive rates lower than 10%, was 39.4%; this increased by 7.0% with
      CAD and by 10.5% with double reading. Differences among single, double, and CAD
      readings were statistically significant (P <.001). CONCLUSION: Although
      independent double reading yields the best detection performance, the presence
      and probability of CAD mass markers can improve mammogram interpretation.

PMID- 12616009
TI  - Injury of the tibiofibular syndesmosis: value of MR imaging for diagnosis.
AB  - PURPOSE: To compare the use of magnetic resonance (MR) imaging with the use of
      arthroscopy for the diagnosis of tibiofibular syndesmotic injury. MATERIALS AND
      METHODS: This study involved 58 patients who had ankle sprains or distal fibular
      fractures and underwent surgery. All patients were examined with MR imaging for
      diagnosis of tibiofibular syndesmotic injury. When MR imaging revealed ligament
      discontinuity (criterion 1) or either a wavy or curved ligament contour or
      nonvisualization of the ligament (criterion 2), the injury was considered to be a
      ligament disruption. After MR imaging, ankle arthroscopy was performed in all
      patients for a definitive diagnosis of ligament disruption. RESULTS: Arthroscopic
      findings showed anteroinferior tibiofibular ligament (AITFL) disruption in 28
      patients and posteroinferior tibiofibular ligament (PITFL) disruption in five
      patients. When an MR imaging diagnosis was based on criterion 1 only, the
      diagnosis of AITFL disruption was made with a sensitivity of 100%, a specificity
      of 70%, and an accuracy of 84%, and the diagnosis of PITFL disruption was made
      with a sensitivity of 100%, a specificity of 94%, and an accuracy of 95%. When an
      MR imaging diagnosis was based on criteria 1 and 2, the diagnosis of AITFL
      disruption was made with a sensitivity of 100%, a specificity of 93%, and an
      accuracy of 97%, whereas the diagnosis of PITFL disruption was made with a
      sensitivity of 100%, a specificity of 100%, and an accuracy of 100%. CONCLUSION:
      MR imaging with use of both criteria is highly accurate for the diagnosis of
      tibiofibular syndesmotic disruption.

PMID- 12616010
TI  - Obstruction of the lacrimal system: treatment with a covered, retrievable,
      expandable nitinol stent versus a lacrimal polyurethane stent.
AB  - PURPOSE: To compare the clinical effectiveness of a covered nitinol stent with
      that of a polyurethane stent for treatment of lacrimal system obstructions.
      MATERIALS AND METHODS: A nitinol stent was knit from a single thread of 0.1-mm
      nitinol wire in a tubular configuration and was covered by dipping the stent into
      a polyurethane solution. The stent was 4 mm in diameter and 30 or 35 mm long.
      With fluoroscopic guidance, a covered nitinol stent (n = 33, group A) or a
      polyurethane stent (n = 35, group B) was placed in 68 patients. The following
      items were evaluated retrospectively: technical success, procedure time,
      cumulative patency rate, and complications. An unpaired Student t test was used
      to analyze the difference between the procedure times. Kaplan-Meier survival
      curves and a log-rank test were used to compare the cumulative patency rates.
      RESULTS: Stent placement was technically successful in 31 (94%) of 33 patients in
      group A and in all 35 (100%) patients in group B. After stent placement, all
      patients showed resolution of epiphora. Average procedure time was 400 seconds
      (range, 270-900 seconds) in group A and 260 seconds (range, 150-900 seconds) in
      group B. The difference between the procedure times was statistically significant
      (P =.0003). During the mean follow-up period of 40 months, there was recurrence
      of epiphora in 30 of 31 patients in group A and 26 of 35 patients in group B. The
      difference of the cumulative patency rates was statistically insignificant (P
      =.2). CONCLUSION: Although the polyurethane stent used for treatment seemed to be
      more effective than the nitinol stent, selection of these stents for placement
      should be made with caution, because the long-term patency rates are not
      encouraging.

PMID- 12616011
TI  - Coronary MR angiography: true FISP imaging improved by prolonging breath holds
      with preoxygenation in healthy volunteers.
AB  - In 15 healthy volunteers undergoing coronary magnetic resonance (MR) angiography,
      the breath-hold duration with and without preoxygenation was measured. The effect
      of preoxygenation on coronary artery imaging was also evaluated. A three
      dimensional magnetization-prepared true fast imaging with steady-state precession
      sequence was employed for coronary MR angiography. All subjects showed an
      increase in comfortable breath-hold duration with preoxygenation. This extra
      imaging time allowed coronary artery imaging with increased spatial resolution.

PMID- 12616012
TI  - Sonography of the scrotum.
AB  - Ultrasonography (US) with a high-frequency (7.5-10-MHz) transducer has become the
      imaging modality of choice for examination of the scrotum. US examination can
      provide information valuable for the differential diagnosis of a variety of
      disease processes involving the scrotum that have similar clinical manifestations
      (eg, pain, swelling, or presence of mass). The pathologic condition that may be
      at the origin of such symptoms can vary from testicular torsion to infection to
      malignancy. The ability of color and power Doppler US to demonstrate testicular
      perfusion aids in reaching a specific diagnosis in patients with acute scrotal
      pain. This review covers the anatomy of the scrotum and the scanning protocol for
      scrotal US, as well as detailed descriptions of disease processes and their US
      appearances. Newly described conditions such as intratesticular varicoceles and
      other benign intratesticular cystic lesions are also discussed.

PMID- 12616013
TI  - MR venography: unsung and underutilized.

PMID- 12616014
TI  - Respecting patient autonomy: screening at CT and informed consent.

PMID- 12616015
TI  - The sandwich sign.

PMID- 12616016
TI  - MR imaging features of primary sclerosing cholangitis: patterns of cirrhosis in
      relationship to clinical severity of disease.
AB  - PURPOSE: To evaluate the spectrum of magnetic resonance (MR) imaging appearances
      of the liver in primary sclerosing cholangitis (PSC) and to examine their
      correlation with clinical stage of disease. MATERIALS AND METHODS: Fifty-two
      patients (25 female, 27 male; mean age, 43 years; age range, 11-87 years) with
      PSC underwent nonenhanced and gadolinium-enhanced MR imaging. Two abdominal
      radiologists retrospectively reviewed all images (independently and then in
      consensus) for the imaging pattern of the liver parenchyma, presence and grade of
      intrahepatic biliary ductal dilatation, and presence of areas of parenchymal
      atrophy or abnormal signal intensity and/or gadolinium enhancement. Imaging
      findings were correlated with Child class, Child-Turcotte-Pugh score, and Mayo
      end-stage liver disease (MELD) score. Statistical analyses (kappa scoring for
      interobserver agreement, McNemar test, Mann-Whitney U test, multiple regression
      analysis, Spearman correlation) were performed. RESULTS: Of 52 patients, seven
      (13%) had no imaging findings of cirrhosis, 17 (33%) had a diffuse pattern of
      cirrhosis, and 28 (54%) had a large macronodular pattern (with nodules >or=3 cm)
      (kappa = 0.84). Intrahepatic biliary ductal dilatation was observed in 44 (85%)
      patients and was general in 18 (35%) and segmental in 26 (50%). Peripheral wedge
      shaped areas of parenchyma were observed with atrophy in 23 (44%) and 25 (48%)
      patients by the two readers (kappa = 0.76) and without atrophy in 18 (35%)
      patients by both readers (kappa = 1.00). No correlation was found between imaging
      findings and clinical scores (P >.05, multiple regression analysis; P =.25-.75,
      Mann-Whitney U test; Spearman correlation coefficients between -0.33 and 0.33).
      CONCLUSION: The spectrum of MR imaging appearances of PSC is diverse and
      comprises distinct patterns that do not appear to correlate with severity of
      disease. Large regenerative nodules are a frequent finding and may help to
      establish the diagnosis.

PMID- 12616018
TI  - Case 56: cor triatriatum dexter.

PMID- 12616019
TI  - Stunned, infarcted, and normal myocardium in dogs: simultaneous differentiation
      by using gadolinium-enhanced cine MR imaging with magnetization transfer
      contrast.
AB  - PURPOSE: To simultaneously differentiate stunned, infarcted, and normal
      myocardial regions by using gadolinium-enhanced cine magnetic resonance (MR)
      imaging with magnetization transfer contrast. MATERIALS AND METHODS: Twelve dogs
      were imaged on days 1 and 8 after transient 90-minute coronary artery occlusion.
      A magnetization transfer contrast with echo-train readout (MTET) MR sequence was
      performed before and 30 minutes after gadolinium contrast enhancement. Ex vivo
      analysis consisted of MR imaging, microsphere blood flow analysis, and
      triphenyltetrazolium chloride (TTC) staining. A paired two-tailed t test was used
      to compare wall thickening from day 1 to day 8. Linear regression and Bland
      Altman analyses were used to compare infarct size depicted with MTET imaging with
      that seen on TTC-stained tissue. RESULTS: Severe wall motion abnormalities were
      detected in all dogs. At TTC analysis, seven dogs had evidence of myocardial
      infarction and five had evidence of stunned myocardium. The mean percentages of
      left ventricular wall thickening in infarcted, stunned, and remote myocardial
      regions were 2% +/- 4 (SD), 4% +/- 8, and 33% +/- 5, respectively. Wall
      thickening did not improve in the infarcted zones, but it improved to nearly
      normal levels in the stunned region 1 week after induced occlusion (mean, 40% +/-
      8; P <.02). MTET images clearly depicted infarcted myocardium as brighter than
      both the normal and stunned myocardial regions but darker than the blood pool. In
      vivo MTET infarct volume correlated with ex vivo TTC analysis data (y = 1.01x +
      0.00, R = 0.98, standard error of the estimate = 0.019). CONCLUSION: One day
      after myocardial ischemia, MTET during one MR imaging examination enabled
      simultaneous differentiation of infarcted, stunned, and normal myocardial regions
      on the basis of gadolinium enhancement and regional function.

PMID- 12616020
TI  - Multi-detector row CT: radiation dose characteristics.
AB  - PURPOSE: To determine the dose characteristics of multi-detector row computed
      tomography (CT) and to provide tabulated dose values and rules of thumb that
      assist in minimizing the radiation dose at multi-detector row CT. MATERIALS AND
      METHODS: Weighted CT dose index (CTDI100w) values were obtained from three multi
      detector row CT scanners (LightSpeed; GE Medical Systems, Milwaukee, Wis) for
      both head and body CT modes by using standard CT-dose phantoms. The CTDI100w was
      determined as a function of x-ray tube voltage (80, 100, 120, 140 kVp), tube
      current (range, 50-380 mA), tube rotation time (0.5-4.0 seconds), radiation
      profile width (RPW) (5, 10, 15, 20 mm), and acquisition mode (helical high
      quality and high-speed modes and axial one-, two-, and four-section modes).
      Statistical regression was performed to characterize the relationships between
      CTDI100w and various technique factors. RESULTS: The CTDI100w (milligray)
      increased linearly with tube current: in head mode, CTDI100w = (0.391 mGy/mA +/-
      0.004) x tube current (milliampere) (r2 = 0.999); in body mode, CTDI100w = (0.162
      mGy/mA +/- 0.002) x tube current (milliampere) (r2 = 0.999). The CTDI100w
      increased linearly with rotation time: in head mode, CTDI100w = (34.7 mGy/sec +/-
      0.2) x rotation time (seconds) (r2 = 1.0); in body mode, CTDI100w = (13.957
      mGy/sec +/- 0.005) x rotation time (seconds) (r2 = 1.0). The relationship of
      normalized CTDI100w (milligrays per 100 mAs) with tube voltage followed a power
      law: in head mode, CTDI100w = (0.00016 mGy/100 mAs. kVp +/- 0.00007) x (tube
      voltage)(2.5+/-0.1) (r2 = 0.997); in body mode, CTDI100w = (0.000012 mGy/100 mAs.
      kVp +/- 0.000007) x (tube voltage)(2.8+/-0.1) (r2 = 0.996). In all scanning
      modes, CTDI100w decreased when RPW increased. CTDI100w was 10% higher in head
      mode and 13% lower in body mode compared with the value suggested by the
      manufacturer, which is displayed at the scanner console. When deposited power
      exceeded 24 kW, CTDI100w increased by 10% as a result of use of the large focal
      spot. CONCLUSION: The authors provide a set of tables of radiation dose as a
      function of imaging protocol to facilitate implementation of radiation dose
      efficient studies.

PMID- 12616021
TI  - Benign breast lesions: minimally invasive vacuum-assisted biopsy with 11-gauge
      needles patient acceptance and effect on follow-up imaging findings.
AB  - PURPOSE: To evaluate patient acceptance of stereotactic or ultrasonographically
      (US) guided directional vacuum-assisted 11-gauge needle biopsy of breast lesions
      and short- and long-term changes at mammography and US resulting from the
      procedure. MATERIALS AND METHODS: For 91 benign lesions that had been sampled at
      either stereotactic or US-guided directional vacuum-assisted breast biopsy
      performed with 11-gauge needles, clinical, mammographic, and US changes were
      evaluated 1 week after biopsy; 6-month follow-up findings were available for 74
      lesions. The subjective outcome of the procedure and patient satisfaction were
      assessed on the basis of a patient-completed questionnaire that incorporated a
      multistage scoring system. Statistical analysis of scores for condition for both
      biopsy methods was performed with the chi2 test. RESULTS: Adverse events occurred
      during the procedure in four patients. Clinically visible hematomas were observed
      at 1-week follow-up in 79% of patients. Densities were observed on mammograms in
      46% of patients 1 week after biopsy; hematomas with a maximum diameter of 2 cm
      were seen on sonograms in 74%. Six months after biopsy, mammography revealed
      discrete architectural changes in one case. No abnormalities were found at 6
      month follow-up US. Fifteen patients had various complaints during the procedure;
      six reported feeling constrained during the first few days after biopsy, and one
      patient was not satisfied with the cosmetic result. No patient reported a
      retrospective preference for surgical biopsy instead of directional vacuum
      assisted biopsy. Analysis of scores for the stereotactic and US-guided methods
      revealed a significant difference (P <.001) in favor of the stereotactic method
      for condition during biopsy, while scores for condition in the first days after
      biopsy were more equally distributed between the two methods (P =.386).
      CONCLUSION: Directional vacuum-assisted 11-gauge needle biopsy of the breast is
      well accepted by patients and rarely produces changes that may alter the
      mammographic or sonographic appearance of the breast at 6-month follow-up.

PMID- 12616022
TI  - Fractures of proximal portion of fifth metatarsal bone: anatomic and imaging
      evidence of a pathogenesis of avulsion of the plantar aponeurosis and the short
      peroneal muscle tendon.
AB  - PURPOSE: To evaluate the normal anatomy of the structures supporting the proximal
      portion of the fifth metatarsal bone and investigate the pathogenesis of
      fractures in this region. MATERIALS AND METHODS: In two cadaveric feet, the
      region of the lateral component of the plantar aponeurosis (PAL), short peroneal
      muscle (SPM) tendon, and third peroneal muscle (TPM) tendon was dissected. These
      two foot specimens and four nondissected foot specimens were studied at magnetic
      resonance (MR) imaging. Two of the six specimens were studied at computed
      tomography (CT). Sectioning the nondissected foot specimens enabled anatomic
      correlation. In two additional specimens, simulation of the presumed mechanism of
      fifth metatarsal bone fracture was attempted. The radiographic, CT, and MR images
      obtained in 13 patients with fractures of the proximal portion of the fifth
      metatarsal bone were evaluated. RESULTS: Anatomic, CT, and MR imaging studies
      revealed broad insertion of the PAL into the plantar aspect of the proximal
      portion of the fifth metatarsal bone in all specimens. The SPM tendon was
      consistently attached more distally and to the lateral side of the tuberosity,
      blending with the PAL fibers. The TPM tendon was inconsistently identified
      inserting anteriorly to the SPM tendon. No fracture was created in the specimens
      subjected to attempted injury. Frequent attachment of the PAL and the SPM tendon
      to the avulsed fragment was confirmed in clinical cases. CONCLUSION: The
      pathogenesis of fractures of the proximal portion of the fifth metatarsal bone
      appears to be related to avulsion injury of PAL and SPM tendon fibers.

PMID- 12616023
TI  - MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility
      study.
AB  - The feasibility and safety of magnetic resonance (MR) imaging-guided focused
      ultrasound surgery for uterine leiomyomas is reported. Sequential sonications
      were delivered to nine targets. Temperature-sensitive phase-difference MR imaging
      monitored the location of the focus and measured tissue temperature elevations,
      ensuring therapeutic dose. MR images and hysterectomy specimens were evaluated.
      Six leiomyomas received full therapeutic doses, and 98.5% of the sonications were
      visualized. MR thermometry was successful in all sonications and cases. Focal
      necrotic lesions were seen in all cases at MR, and five were pathologically
      confirmed. MR imaging-guided focused ultrasound causes thermocoagulation and
      necrosis in uterine leiomyomas and is feasible and safe, without serious
      consequences.

PMID- 12616024
TI  - Respiration-induced attenuation artifact at PET/CT: technical considerations.
AB  - Combined positron emission tomographic (PET)/computed tomographic (CT) scanners
      allow the use of CT data for attenuation correction of PET images. Eight patients
      with cancer underwent PET/CT scanning. Transmission scanning was performed with
      conventional attenuation correction and with CT scanning during maximum
      inspiration and normal expiration. Image quality was visually compared and
      fluorine 18 activities were measured in volumes of interest in the lung and
      myocardium. Analysis of variance for repeated measures revealed a significant
      decrease (P =.0001) in measured activities between PET images corrected with CT
      data acquired during maximum inspiration and those corrected with the
      conventional attenuation correction method or with CT data acquired during normal
      expiration. Deep inspiration during CT can result in severe deterioration in the
      final PET image.

PMID- 12616025
TI  - Anatomy of the trochanteric bursae.

PMID- 12616026
TI  - The nature of MR signal changes.

PMID- 12616027
TI  - Underestimated drawbacks of combined simple dilation and thrombolytics for
      restoration of thrombosed brescia-cimino dialysis fistulas.

PMID- 12616028
TI  - Academic radiology: sustaining the mission.

PMID- 12616029
TI  - Treating IgA Nephropathy - Who, When and How?.

PMID- 12616030
TI  - Another Marker of Cardiac Dysfunction in Dialysis Patients?

PMID- 12616031
TI  - The importance of associated extra-renal vascular disease on the outcome of
      patients with atherosclerotic renovascular disease.
AB  - Atherosclerotic renovascular disease (ARVD) is a disease of ageing. It is usually
      a manifestation of widespread vascular disease and although it may be
      symptomless, many patients with ARVD present with the effects of extra-renal
      vascular disease, such as peripheral vascular (PVD), coronary heart (CHD) and
      cerebrovascular disease. ARVD is a common cause of hypertension and chronic renal
      failure (CRF), and it is one of the most common renal diagnoses in elderly
      patients accepted on to dialysis programmes with end-stage renal failure (ESRF).
      The cause of renal impairment in these patients is still a matter of debate.
      Patients with ARVD have a high mortality, especially those with renal failure. In
      this review we examine the relationships between ARVD and co-morbid extra-renal
      vascular disease, and the impact of these associated vascular pathologies upon
      renal functional and mortality outcomes is considered. The latest evidence
      concerning the likely pathogenesis of renal dysfunction in patients with ARVD is
      also reviewed.

PMID- 12616032
TI  - Prednisolone and azathioprine in IgA nephropathy - a ten-year follow-up study.
AB  - BACKGROUND: Immunoglobulin A nephropathy (IgAN) is one of the most common primary
      glomerular diseases. Although its clinical course is usually benign, some
      patients develop end-stage renal failure (ESRF). The role of immunosuppressive
      drugs in the treatment of IgAN remains controversial. The effect of treatment
      with prednisolone and azathioprine and the clinical and histological parameters
      related to a poor outcome are examined retrospectively in this analysis. METHODS:
      Seventy-four patients with IgAN and a follow-up period of 10 years were included
      in this study. Forty-one were treated with prednisolone (initially 60 mg/day) and
      azathioprine (initially 2 mg/kg BW/day) in gradually reduced doses for 24 +/- 9
      months, whereas 33 patients received no immunosuppressive drugs. The clinical
      course was estimated using the end-points of doubling of baseline serum
      creatinine and/or ESRF. The contribution of clinical and histological parameters
      in the clinical outcome was estimated by univariate and multivariate analyses.
      RESULTS: The overall clinical courses of both groups of patients showed a rather
      similar pattern. Doubling of serum baseline creatinine was observed in 9 of 41
      treated (22%) and in 10 of 33 untreated (30%), whereas ESRF developed in 6
      treated (15%) and 6 untreated patients (18%) (p = NS). However, treated patients
      with heavy proteinuria (>3 g/24 h) had a significantly better outcome compared to
      untreated (doubling of serum creatinine in 29 vs. 78% and ESRF in 17 vs. 55%, p <
      0.05). Proteinuria (p < 0.01), mean blood pressure (p < 0.02), baseline serum
      creatinine (p = 0.02) and severity of interstitial myofibroblast expression (p =
      0.02) were identified as independent risk factors related to a poor outcome by
      multivariate analysis. Side effects of treatment were not uncommon and observed
      in 10 (24%) patients. CONCLUSION: Treatment with prednisolone and azathioprine is
      beneficial in ameliorating the clinical course of a subset of IgAN patients with
      heavy proteinuria or impaired renal function. Patients with advanced renal
      failure and severe chronic histological lesions should not be treated by this
      regimen as no benefit is expected and there is a risk of side effects.

PMID- 12616033
TI  - Serum ratio of heart-type fatty acid-binding protein to myoglobin. A novel marker
      of cardiac damage and volume overload in hemodialysis patients.
AB  - BACKGROUND: The concentration of heart-type fatty acid-binding protein (hFABP), a
      promising novel marker for detection of acute or persistent myocardial damage, is
      significantly influenced by renal clearance and thus has limitations to its
      usefulness in patients with renal dysfunction. We evaluated whether the serum
      ratio of hFABP to myoglobin (F/M) might be a useful marker for assessing cardiac
      damage in hemodialysis patients. METHODS: Serum hFABP and myoglobin were
      measured, and the value of F/M was calculated in 21 hemodialysis patients.
      Cardiac markers (cardiac troponin T [cTnT], atrial natriuretic peptide [ANP], and
      brain natriuretic peptide [BNP]) and echocardiographic indices (left ventricular
      end-diastolic dimension [LVDd], left ventricular mass index [LVMI], and inferior
      vena cava [IVC] dimension) were examined and compared with hFABP, myoglobin, and
      F/M ratios. RESULTS: Serum hFABP and myoglobin levels were significantly elevated
      in hemodialysis patients and reduced by 30-40% during hemodialysis. The value of
      F/M after hemodialysis, but not the concentration of hFABP or myoglobin, had
      significant linear correlations with ANP, BNP, cTnT, LVDd, LVMI, and IVC.
      CONCLUSION: The value of F/M after hemodialysis, but not the concentration of
      hFABP itself, might be a newly useful marker for estimation of cardiac damage and
      volume overload in hemodialysis patients.

PMID- 12616036
TI  - Pathology and therapeutics, in fifty lectures. 1871.

PMID- 12616034
TI  - One-year growth hormone therapy improves granulocyte function without major
      effects on nutritional and anthropometric parameters in malnourished hemodialysis
      patients.
AB  - BACKGROUND/AIMS: Growth hormone (GH) resistance leads to enhanced protein
      catabolism and contributes to the malnutrition of patients with chronic renal
      failure (CRF). In short-term trials anabolic effects of rhGH therapy have been
      demonstrated in patients on chronic hemodialysis. METHODS: This study was
      initiated to determine the effects of 12 months of rhGH therapy on
      polymorphonuclear leukocyte (PMNL) function as well as on nutritional and
      anthropometric parameters. 0.125 IU/kg rhGH was given 3 times a week during the
      first 4 weeks and 0.25 IU/kg thereafter to 19 malnourished hemodialysis patients
      with a mean age of 59.3 +/- 13.4 years. RESULTS: Insulin-like growth factor I
      (IGF-I) concentrations rose significantly from 169.2 +/- 95.6 to 262.9 +/- 144.4
      ng/ml (p < 0.01) in the first 3 months, but declined thereafter. Phagocytic
      activity of PMNLs also increased significantly in response to rhGH therapy and
      this activation remained stable over the whole 12-month period. Other parameters
      of PMNL function were not influenced by rhGH therapy. In addition, nutritional
      parameters such as albumin, prealbumin, transferrin, cholesterol, HDL
      cholesterol, cholinesterase, predialytic creatinine and blood urea nitrogen were
      not affected by rhGH therapy. A decline of total body fat (TBF) was observed
      after 3 and 9 months of rhGH therapy (17.5 +/- 10 vs. 16.7 +/- 10% after 3
      months, p < 0.017 and 16.8 +/- 8.7% after 9 months, p < 0.049), whereas lean body
      mass remained stable. CONCLUSIONS: Twelve months of rhGH therapy caused a
      significant increase in IGF-I levels, stimulated phagocytic activity of PMNLs and
      induced a decline of TBF. Other anthropometric and nutritional parameters were
      not affected, which might be related to the persistence of GH resistance.

PMID- 12616037
TI  - A synopsis of urban firearm ballistics: Washington, DC model.
AB  - Although current statistics are available pertaining to weapon retrieval rates,
      the evolution of ballistics in most metropolitan areas has not been critically
      examined and correlated with the resultant impact on public health. Of special
      concern to law enforcement agencies and urban Level 1 trauma centers is the
      unabated increase in the availability of firearms with accelerated firepower
      capable of increased kinetic energy and reduced time to exhaust the weapon's
      magazine. The firearms statistics from the Washington, DC area were examined
      retrospectively by review of the records of the Firearms and Toolmark Examination
      section of the Metropolitan Police Department. The data from 1999 indicate that
      57% of the firearms confiscated during criminal apprehension and prosecution were
      semiautomatic weapons. However, 51% of the firearms recovered during amnesty
      programs were revolvers and 23% were semiautomatic weapons. In the District of
      Columbia, during a 4.5-month period in 1999, the cost of medical treatment of
      patients with gunshot wound injuries averaged 15,000.00 US dollars per patient
      with costs of rehabilitation reaching an estimated 40,000.00 US dollars per
      patient.

PMID- 12616038
TI  - Gun control in the United States: ethical perspectives for the twenty-first
      century.
AB  - The current author will explore the way we should think about the ethical
      implications of gun control in the United States today. The generating pedagogy
      will be: (1) an explication of worldview perspectives, personal and community as
      per the author's recently published writings; (2) a discussion of the worldviews
      of both sides of the gun control debate; (3) a critical appraisal of the
      positions of each side; and (4) some suggestions about a future that is without
      ordinary citizen ownership of guns. The author argues that based on an ethical
      rights model of analysis, an ordinary citizen's right to bear arms is outweighed
      by other competing rights claims.

PMID- 12616039
TI  - Clinical update: gunshot wound ballistics.
AB  - Although firearm related injury and mortality actually may be declining, gunshot
      trauma remains a significant cause of morbidity and socioeconomic cost with
      115,000 missile injuries annually and as many as 40,000 deaths. Wounds typically
      are classified as low-velocity (< 2000 feet/second) or high-velocity (> 2000
      feet/second). However, these terms can be misleading. More important is the
      efficiency of energy transfer, which is dependent on the projectile's physical
      characteristics including deformation and fragmentation, kinetic energy,
      stability, entrance profile, path traveled through the body, and the biologic
      characteristics of the tissues. Therefore, the decision whether to explore the
      wound should not be based solely on the involvement of a high-velocity or low
      velocity weapon. The majority of low-velocity gunshot wounds can be treated
      safely nonoperatively with local wound care and outpatient treatment. Treatment
      of associated fractures generally is dictated by the bony injuries, which have
      similar personalities to closed fractures. Because contamination is not always
      apparent, routine antibiotic prophylaxis still is recommended. The soft tissues
      assume a more crucial role in high-velocity and shotgun fractures, whereas high
      energy injuries and grossly contaminated wounds mandate irrigation, appropriate
      debridement, and the use of open fracture protocols. However, a patient with a
      high-velocity wound with limited soft tissue disruption, no significant
      functional deficits, no evidence of bullet fragmentation, and minimal bony
      involvement can be a candidate for simple wound care. When exploration is
      indicated, decompression and excision of necrotic tissue is the rule with color,
      consistency, contractility, and capacity to bleed providing valuable information
      regarding muscle viability.

PMID- 12616040
TI  - Current concepts of gunshot wound treatment: a trauma surgeon's perspective.
AB  - Trauma remains a significant and persistent public health problem, accounting for
      90,000 deaths and 20 million people disabled annually. Current concepts of
      appropriate triage and emergency treatment of gunshot wounds are addressed from a
      trauma surgeon's perspective. Recent studies regarding prehospital transport
      policy, and acute diagnostic studies allow optimal treatment guidelines to be
      formulated. Specifically, rapid transport rather than prolonged on-scene
      treatment (including maneuvers such as formal thoracolumbar immobilization)
      should be given the highest priority. Also, routine arteriography (another time
      consuming and invasive procedure) in the treatment of gunshot wounds to the
      extremity is no longer the standard of care.

PMID- 12616041
TI  - Classification of gunshot injuries in civilians.
AB  - Gunshot injuries have become extremely prevalent among the United States civilian
      population because of increasing urban violence and the availability of handguns.
      However, the increasing prevalence of gunshot injuries in civilians dramatically
      contrasts with the paucity of scientific literature pertaining to the diagnosis,
      classification, and treatment of these injuries. The objective of the current
      study was to delineate the principal factors associated with gunshot injury
      severity in civilians, designate their importance in various injury patterns, and
      propose a new comprehensive classification system that may establish more uniform
      treatment approaches. The authors critically review existing gunshot injury
      classification systems with emphasis on the ballistic and clinical parameters
      that compose each system. The authors propose a new classification system based
      on five gunshot injury parameters: energy, vital structures involved, wound
      characteristics, fracture, and degree of contamination. This new classification
      scheme is applicable to all firearm injuries in civilians and assists with proper
      treatment selection. The proposed classification system is based on the authors'
      clinical experience in a Level I urban trauma center, and will require validation
      in a prospective clinical setting.

PMID- 12616042
TI  - Antibiotic therapy in gunshot wound injuries.
AB  - Protocols for antibiotic prophylaxis in the treatment of fractures caused by
      gunshots have not been delineated clearly in the literature to date. The current
      review of the literature reveals that antibiotic therapy for treatment of these
      fractures is predicated on the muzzle velocity of the weapon used to inflict the
      fracture. General consensus has been reached regarding the requirement of at
      least 24 hours of intravenous antibiotic treatment in fractures caused by high
      velocity weapons in conjunction with the appropriate wound and fracture care.
      Similarly, in fractures caused by shotguns, thorough wound debridement and 24- to
      48-hour administration of intravenous antibiotics is necessary. However, in
      fractures caused by low-velocity weapons, there is not a preponderance of the
      evidence showing that there is a distinct advantage to using antibiotic
      prophylaxis in these injuries. Special clinical consideration must be given
      regarding the use of antibiotics in fractures caused by gunshots that are
      intraarticular and those about the hand, foot, and ankle.

PMID- 12616043
TI  - Gunshot wounds of the foot.
AB  - It is imperative that the physician participating in the care and treatment of
      foot and ankle trauma appreciate the epidemiology, the unique characteristics,
      and principles of treatment of gunshot injuries involving the foot and ankle. The
      current author will provide the reader with knowledge of how the bullet velocity,
      its mass, and its area are important in determining the energy transmitted to the
      tissues struck by the bullet. These forces imparted by the projectile interact
      with the specific characteristics of the tissues to determine the nature and
      extent of the trauma sustained by the foot and ankle. An understanding of the
      appropriate grading of the injury will allow for a rationale approach to the
      treatment of these injuries. The hallmark of treatment includes rigid skeletal
      fixation, revascularization, and treatment of soft tissues including appropriate
      wound coverage techniques.

PMID- 12616044
TI  - Grading system for gunshot injuries to the femoral diaphysis in civilians.
AB  - One hundred patients had surgical treatment for a gunshot injury to the femur at
      the authors' hospital. Each injury was classified (Grade 1-3) based on clinical
      and radiographic signs of deep soft tissue necrosis. All patients were followed
      up for a minimum of 6 months (average, 18 months; range, 6 months-72 months).
      Grade 1 injuries are defined by small entry and exit wounds (< 2 cm) and the
      absence of high-energy characteristics on plain radiographs. Grade 2 gunshot
      injuries have small wounds (< 5 cm) and radiographic evidence of a high-energy
      injury. Grade 3 gunshot injuries are diagnosed by physical examination whenever
      necrotic muscle is present at the fracture site. Radiographs show extensive
      superficial and deep soft tissue disruption and segmental bone destruction.
      Seventy-nine patients with Grade 1 fractures had intramedullary nailing without
      wound exploration; all fractures united without infection. Seven patients with
      Grade 2 injuries had wound exploration; a necrotic cavity was discovered in five
      patients and three (43%) patients had deep infection develop. Fourteen patients
      with Grade 3 injuries had one or more debridements followed by skeletal
      stabilization, and seven patients (50%) had deep infection develop. Important
      decisions regarding wound debridement and fracture stabilization are determined
      by examination of the wound and radiographs, and not by determining muzzle
      velocity.

PMID- 12616045
TI  - Gunshot femoral shaft fractures: is the current classification system reliable?
AB  - The reliability of the AO/Orthopaedic Trauma Association classification system
      has not been evaluated for diaphyseal fractures or fractures attributable to
      gunshot injuries. Therefore, the current authors assessed its reliability for
      diaphyseal femur fractures and investigated the effect of a gunshot mechanism of
      injury. Forty-seven diaphyseal femur fractures, 23 caused by gunshots and 24
      caused by blunt trauma, were classified by four observers on two occasions. The
      interobserver and intraobserver reliability of each level of the AO/Orthopaedic
      Trauma Association classification was assessed with kappa statistics.
      Determination of fracture type had substantial interobserver and intraobserver
      reliability for gunshot and blunt injuries. Reliability decreased at the
      subsequent levels of the classification. Fractures caused by gunshots compared
      with those caused by blunt trauma were characterized by significantly lower
      interobserver agreement on fracture group (k = 0.26 versus 0.45) and subgroup (k
      = 0.21 versus 0.38). The AO/Orthopaedic Trauma Association classification system
      has substantial interobserver and intraobserver reliability when evaluating the
      type of diaphyseal femur fractures. Determination of fracture group and subgroup,
      however, progressively reduces the reliability of the classification, especially
      for fractures caused by a gunshot. Diaphyseal femur fractures caused by gunshots,
      by means of their fracture patterns, cannot be classified reliably with the
      AO/Orthopaedic Trauma Association classification system.

PMID- 12616046
TI  - Current treatment of gunshot wounds to the hip and pelvis.
AB  - Gunshot wounds to the pelvis can result in injuries to various organ systems.
      These injuries require the care of a multispecialty trauma team at a trauma
      center. Orthopaedic care includes wound treatment, fracture stabilization, and
      infection prophylaxis. Wound care is determined by the personality of the injury,
      and not solely based on the velocity of the missile. Antibiotic treatment usually
      is indicated for patients with gunshot wounds to the pelvis, but is controversial
      in patients with low-energy wounds. Fractures are treated based on their
      stability. Regional consideration of pelvic gunshot wounds includes injuries with
      associated abdominal viscus injury, intraarticular bullets, and retained bullets
      in the spinal canal.

PMID- 12616047
TI  - Current treatment of gunshot wounds to the spine.
AB  - The incidence of spinal cord injury from gunshot wounds in penetrating trauma
      continues to increase with the violent nature of society. This particularly is
      true in urban areas, as is found with other violent crime. Either the direct path
      of the bullet or the concussive effects cause injury to the spine and spinal
      column. Thorough patient evaluation and appropriate radiographic studies will
      provide the keys to treatment of these patients. Criteria are given for treatment
      related to neurologic findings and progressive neurologic evaluation. Infection
      related to missiles penetrating through the alimentary tract and then lodging in
      the spine is a relatively rare complication and appropriate standards for
      debridement and fragment removal are discussed. Principles of treatment in all
      missile injuries to the spine evolve around spine stability, aggressive
      rehabilitation, and preservation of neurologic function.

PMID- 12616048
TI  - Spinal cord injuries from gunshot wounds to the spine.
AB  - Although vehicular trauma traditionally has accounted for the majority of spinal
      cord injuries, gunshot wounds are the second most common cause. Furthermore, the
      proportion of spinal cord injuries caused by gunshot wounds are increasing
      although the proportion of injuries caused by high-speed vehicular trauma is
      decreasing. Gunshot wounds to the spine commonly are thought to be stable
      injuries. There is, however, a potential for instability if the bullet passes
      transversely through the spinal canal and fractures pedicles and facets. Injuries
      to the thoracic region of the spine are the most common, followed by the
      thoracolumbar area and the cervical spine. Completeness of injury is related to
      the anatomic region. Patients with incomplete injuries and patients with injuries
      in the thoracolumbar region have the greatest improvement in motor function.
      Approximately (1/4) of individuals are able to ambulate 1 year after injury.
      Surgical decompression of bullets from the spinal canal has been shown to improve
      neurologic recovery below the T12 level. Improvement of neurologic recovery after
      bullet removal has not been shown in other regions of the spine. Rare instances
      of late neurologic decline because of retained bullet fragments have been
      documented.

PMID- 12616049
TI  - Recent advances in the treatment of gunshot fractures of the humeral shaft.
AB  - The increase in violent crime has lead to an increase in gunshot-induced
      fractures in the United States. Injuries to the upper extremity are common. The
      treatment of gunshot injuries depends on the extent of soft tissue disruption and
      the type and location of fracture. Most of these injuries are a result of low
      energy gunshot wounds that may be treated conservatively under the appropriate
      conditions. Low-energy fractures that require operative stabilization may be done
      with predictable results for achieving union with intramedullary fixation or
      compression plating. Complex open fractures from gunshot wounds associated with
      neurovascular injuries present a therapeutic challenge to the orthopaedic
      surgeon. The fractures associated with these injuries often are comminuted and
      unstable. Bone loss is common. Soft tissue disruption plays a more important role
      in high-energy gunshot-induced fractures. In these cases, external fixation is
      the treatment of choice for stabilization. Recent advances in the use of external
      fixation have led to quick fracture stabilization, stability for vascular repair,
      and access to the wound for debridement and subsequent soft tissue surgery.

PMID- 12616050
TI  - Gunshots to the hand and upper extremity.
AB  - Gunshot injuries to the hand and upper extremity have been studied during
      military conflicts and in urban settings. Treatment concepts include
      identification of injured structures, aggressive surgical wound care, and
      reconstruction of important functional structures. There are various types of
      missile injuries. For simplicity, low-energy injuries imply limited damage, and
      require only conservative approaches. High-energy injuries are complicated by
      significant tissue destruction, rehabilitation dilemmas, and uncertain outcomes.
      The surgeon must recognize the anatomic complexity of the hand and proceed with
      caution. Most gunshot injuries to the hand involve a combination of tissue types.
      Bone injury is dramatic and is seen radiographically. However, injury to the soft
      tissue including skin, tendon, blood vessel, and nerve also must be appreciated.
      Individually, the tissues have varied function and properties of healing.
      Therefore, the challenge is to prioritize the injury, select an aggressive
      surgical approach, and integrate a suitable rehabilitation plan.

PMID- 12616051
TI  - Spinal cord injury caused by gunshot wounds: the cost of rehabilitation.
AB  - The current authors did a retrospective review of the medical records of 47
      patients with spinal cord injury secondary to gunshot wounds who were admitted to
      National Rehabilitation Hospital between 1993 and 1999. There were 44 male
      patients and three female patients; the mean age of the patients was 24.7 years
      (range, 15-56 years). Thirty-seven patients had paraplegia (27 had complete
      paraplegia, 10 had incomplete paraplegia) as a result of their gunshot wounds,
      and 10 had quadriplegia (eight had complete quadriplegia, two had incomplete
      quadriplegia). None of the weapons were identified. The most common firearm types
      were low-velocity weapons. The length of acute hospitalization increased with the
      number of associated injuries. Rehabilitation total length of stay was
      proportional to the injury classification (paraplegia, quadriplegia). The daily
      occupancy fee in the National Rehabilitation Hospital was approximately 1900 US
      dollars. Patients were admitted to the hospital when acute medical and surgical
      problems had been cleared and when they were ready to participate in
      rehabilitation and therapy.

PMID- 12616052
TI  - Anatomy of the posterior rotator interval: implications for cuff mobilization.
AB  - Release of the posterior rotator interval between the supraspinatus and
      infraspinatus tendons may be necessary to obtain appropriate mobilization for an
      anatomic rotator cuff repair. Ten cadaver shoulders were dissected to expose the
      region between the infraspinatus and supraspinatus from the spinoglenoid notch to
      the greater tuberosity. Measurements were made from the spinoglenoid notch to the
      glenoid rim, the glenoid rim to the confluence of the supraspinatus and
      infraspinatus musculotendinous junction, and from the confluence of the tendons
      to the insertion on the humerus. The histologic features of the posterior rotator
      interval were examined. The posterior rotator interval is a clear structure,
      consisting of the glenohumeral capsule medially, which fuses with the
      supraspinatus and infraspinatus tendons laterally. The average length of the
      posterior rotator interval was 77.8 mm which includes the distance from the
      spinoglenoid notch to the glenoid rim (25 mm; standard deviation, 2.89 mm; range,
      21-28 mm), from the glenoid to the tendon confluence (25 mm; standard deviation,
      1.95 mm; range, 21-28 mm), and from the tendon confluence to insertion (28 mm;
      standard deviation, 2.36 mm; range, 24-31 mm). Release of the posterior rotator
      interval can be important to realign the supraspinatus tendon if it is retracted
      and scarred at its posterior edge.

PMID- 12616053
TI  - A neurovascular complication after scapulothoracic arthrodesis.
AB  - Facioscapulohumeral muscular dystrophy is a progressive disorder characterized by
      weakness in the muscles of the face, shoulder girdle and upper limbs, and
      variable lower extremity weakness. The muscles that stabilize the scapula are
      significantly weak, although the deltoid usually is preserved. With attempted
      shoulder abduction, the unstable scapula protrudes, elevates, and internally
      rotates. Scapulothoracic arthrodesis stabilizes the scapula and improves active
      range of motion and function of the shoulder. Appropriate scapular positioning on
      the chest wall has been described previously. The current authors review a
      neurovascular complication after scapulothoracic arthrodesis in which the scapula
      was positioned as described in the literature. Immediate repositioning resulted
      in an excellent long-term outcome. Previous recommendations as to scapular
      position must be taken simply as guidelines. Intraoperative monitoring of
      neurovascular function in the upper extremity should prevent this complication.

PMID- 12616054
TI  - Anatomic study of the axis for surgical planning of transarticular screw
      fixation.
AB  - Transarticular screw fixation has shown increased stability compared with other
      posterior stabilization techniques. However, there have been few reports on
      vertebral artery injury related to the screw insertion. The current study
      measured the parameters of the pedicle and vertebral artery groove of the axis
      and clarified the accuracy and safety of the transarticular screw fixation.
      Direct measurements were taken from 98 dry axis vertebrae. The width and height
      of the pedicle were measured. The mediolateral and anteroposterior dimensions of
      the vertebral artery groove also were measured. Forty-one percent had asymmetry.
      In 20% of the specimens, the pedicle was smaller than the diameter of the screw
      (3.5 mm). The pedicle of the axis has large anatomic variability and asymmetry.
      Some pedicles were not suitable for atlantoaxial transarticular screw fixation.
      The risks associated with screw fixation should be prevented by preoperative
      computed tomography with three-dimensional reconstruction. Screw trajectory
      reconstruction with coronal and sagittal reconstruction is useful to evaluate the
      pedicle width and height.

PMID- 12616055
TI  - Nitric oxide induced ectopic firing in a lumbar nerve root with cauda equina
      compression.
AB  - Nitric oxide is thought to be involved in the pathophysiology of radiculopathy
      attributable to herniated intervertebral disc, but its effect on ectopic firing,
      which is the main source of sciatica, has not been investigated. The authors
      investigated whether ectopic firing is elicited when the lumbar nerve root is
      exposed to nitric oxide using rats with and without cauda equina compression. A
      group of animals had partial L3 laminectomy, and a silicone tube was inserted in
      the epidural space to compress the cauda equina. A sham operation group and
      nontreated control group also were prepared. Seven days later, ectopic firing of
      the nerve root was recorded from the sural nerve. The animals with cauda equina
      compression showed significantly higher spontaneous firing rates than other
      groups. After a lumbar epidural administration of sodium nitroprusside, only the
      animals with cauda equina compression showed a marked increase in the firing
      rate. These results showed that the nerve roots became hyperexcitable under
      compression as indicated by increased spontaneous firing and marked sensitivity
      to nitric oxide. This mechanism may play an important role in the development of
      sciatica.

PMID- 12616056
TI  - Load sharing and kinematics of threaded cages for lumbar interbody fusion.
AB  - The load-sharing characteristics of threaded interbody cages before and after
      cyclic loading are poorly understood. In the current study, lumbar interbody
      cages were filled with epoxy, sectioned longitudinally, and pressure sensors were
      placed between halves of the cages to measure the distribution of loads between
      and within the cages. Human lumbar spine segments were instrumented anteriorly
      with bilateral cages and subjected to cyclic compression loads combined with
      flexion and extension moments. Sagittal plane motion between vertebrae on either
      side of the cages also was measured during application of cyclic compression and
      flexion loads. A small but statistically significant asymmetry was found in the
      distribution of load between the left and right cages, and the extent of
      asymmetry varied during compression and flexion loading. With ligament tension
      only, 66% of the load was supported by the posterior regions of the cages,
      whereas during peaks in the combined compression and flexion loading, only 33% of
      the load was supported by the posterior regions. The cages reduced intervertebral
      motion 78% during forward flexion, whereas extension resulted in a 100% increase
      in motion. Surgeons should recognize that bilateral cages may not share loads
      equally, and the results of this study suggest that early extension should be
      restricted after the placement of anterior lumbar interbody cages.

PMID- 12616057
TI  - Femoral fracture risk in hip arthroplasty: smooth versus toothed instruments.
AB  - Compaction of cancellous bone with smooth tamps in total hip arthroplasty has
      been shown to improve initial implant fixation. It is not known, however, whether
      this improved fixation occurs at the expense of an increased risk of
      intraoperative femoral fracture. The current authors explore this issue by
      comparing the risk of fracture in 10 pairs of femurs prepared with either smooth
      tamps or conventional toothed broaches. Using one pass for each size, smooth
      tamps were advanced incrementally into one femur of each pair and toothed
      broaches were advanced incrementally into the contralateral femur. A controlled
      impulse, representative of a typical impact during surgery, was applied to the
      instruments by a drop tower (mean starting force, 3017 N). When the instruments
      no longer advanced distally, the applied force was increased incrementally.
      Instrument sizes were increased until a femoral fracture was observed or the
      impact exceeded 8000 N without causing a femoral fracture. At preoperative
      templated size, significantly more femurs that had tamps had fractured (eight of
      10), compared with femurs that had broaches (two of 10). Smooth tamps therefore
      increased the risk of intraoperative femoral fracture in vitro in this particular
      implant design developed for cemented fixation of the femoral component.

PMID- 12616058
TI  - Recurrent anterior hip instability after a simple hip dislocation: a case report.
AB  - A 35-year-old woman sustained a simple anterior hip dislocation after a fall.
      Initial treatment involved a closed reduction under sedation with brace
      immobilization. Nine months after the initial dislocation, she began having
      recurrent anterior hip instability (four events) requiring closed reduction under
      anesthesia. Secondary to the recurrent dislocations, she had a derotational
      subtrochanteric femoral osteotomy at an outside hospital for the anterior
      instability. After this procedure she sustained five additional anterior
      dislocations requiring closed reduction under anesthesia. After nine anterior
      dislocations, she had periacetabular osteotomy retroverting her acetabulum with
      repair of the anterior hip capsule which has successfully solved the recurrent
      instability. To the author's knowledge this is the first reported case of
      recurrent anterior hip instability treated successfully with a periacetabular
      osteotomy.

PMID- 12616059
TI  - Exercise improves early functional recovery after total hip arthroplasty.
AB  - The purpose of this prospective, randomized study was to apply an 8-week
      customized exercise program to patients (Group E) scheduled for total hip
      arthroplasty, followed by a postsurgery exercise program, and show the effect on
      functional recovery compared with control subjects (Group C) who received no
      additional exercise apart from routine in-hospital physical therapy. Strength,
      range of motion, and physical function tests were completed by 57 patients at
      Week 8 and Week 1 before surgery and at Weeks 3, 12, and 24 postoperatively. No
      differences between the exercise and control groups were observed at baseline. By
      1 week before surgery, patients in Group E had shown significant improvements for
      Western Ontario and McMaster Universities Osteoarthritis Index (total score,
      stiffness, and physical function components), and combined hip strength. Patients
      in Group E had improved hip flexion range of motion in the diseased hip compared
      with patients in Group C. Significant differences in outcome measures between
      Group E and Group C were observed throughout the postoperative phase from Weeks 3
      to 24. The current study showed that customized perioperative exercise programs
      are well tolerated by patients with end-stage hip arthritis, and are effective in
      improving early recovery of physical function after total hip arthroplasty.

PMID- 12616060
TI  - Osteointegration and implant position after cementless total knee replacement.
AB  - Osteointegration and implant position are regions of interest after cementless
      total knee replacement. The radiographic and functional status of 101 implants in
      101 patients were evaluated 3, 12, and 24 months after implantation. To obtain
      satisfactory radiographs, a fluoroscopically assisted technique was used. In 92%
      of tibia interfaces, at least one wedge-shaped radiolucent area was visible
      without measurable changes of component position. The width of the gap increased
      from the central tibial area to the periphery. The shape was determined 3 months
      postoperatively. The femur could not be assessed for radiolucency because of the
      central metal crest design. In the current study, regularly appearing wedge
      shaped radiolucent areas at the tibia interface, with the maximal width at the
      periphery, did not indicate aseptic loosening but showed that the forces of
      displacement had overcome initial mechanical stability, inducing micromotion of
      the implant. Osteointegration was seen only in central regions of the implant
      with minimal micromotion. Within the first year, partial bone ingrowth, fibrous
      fixation, and the surrounding bone gave satisfactory stability to provide secure
      fixation of the implant.

PMID- 12616061
TI  - Use of a lateral offset short-leg walking cast before high tibial osteotomy.
AB  - The clinical results after high tibial osteotomy for the treatment of symptomatic
      varus gonarthrosis are unpredictable. Although preoperative gait analysis has
      been shown to be useful in predicting successful outcome after high tibial
      osteotomy, there are no readily available preoperative clinical tests for
      predicting success. The authors did a study to determine the effects of an offset
      short-leg walking cast as a potential predictor of clinical success after high
      tibial osteotomy. Specifically, the authors evaluated the effect of an offset
      short-leg walking cast on pain relief and changes in the peak external adduction
      moments in patients with symptomatic varus gonarthrosis indicated for high tibial
      osteotomy. Nineteen consecutive patients indicated for high tibial osteotomy were
      enrolled and completed the study. All patients had precast gait analysis to
      determine baseline parameters. Immediately after gait analysis, a short-leg
      lateral offset walking cast was applied and worn for 3 days to allow time for
      adaptation. Gait analysis then was repeated. Western Ontario and McMaster
      Universities Osteoarthritis Index pain scores were obtained before and after the
      cast was applied. The cast resulted in a mean reduction in pain of 53%, and a
      mean reduction in the peak external adduction moment of 36% in the 17 of 19
      patients who tolerated the cast. The reduction in pain was correlated with the
      reduction in the peak adduction moment (r = 0.63). The authors conclude that an
      offset short-leg walking cast results in pain reduction that correlates with
      changes in external adduction moments about the knee. Therefore, an offset short
      leg walking cast may prove to be an effective tool for predicting patients who
      ultimately will benefit from valgus high tibial osteotomy.

PMID- 12616062
TI  - Medial torsion of the tibia in Japanese patients with osteoarthritis of the knee.
AB  - To assess the reliability of the landmarks for the rotationally neutral alignment
      of the tibial component in total knee arthroplasty for Japanese patients, the
      rotational position of the medial (1/3) of the tibial tuberosity relative to the
      femoral epicondylar line (Angle TT) and that relative to the center of the ankle
      (Angle TT-AA) were measured in 24 knees with medial femorotibial osteoarthritis
      and in 28 normal knees by computed tomography. Angle TT-AA shows the degree of
      medial torsion of the tibia. The range of Angle TT and that of Angle TT-AA each
      was greater than 40 degrees. The position of the tibial tuberosity and degree of
      medial torsion of the tibia varied by individual. In patients with severe medial
      torsion, the internal rotation of the foot is extreme if the medial (1/3) of the
      tibial tuberosity is used for the rotationally neutral alignment of the partially
      constrained tibial component. In the treatment specifically of patients from East
      Asian countries, medial torsion of the tibia should be taken into account in
      total knee arthroplasty to ensure proper patellar tracking and proper rotation of
      the foot in knees with medial femorotibial osteoarthritis.

PMID- 12616064
TI  - Posteromedial dislocation of the elbow with lateral condyle fracture in children.
AB  - Posteromedial dislocation of the elbow in children is an extremely rare injury.
      The current study describes four boys with posteromedial dislocation of the elbow
      associated with a displaced fracture of the lateral humeral condyle. The patients
      ranged in age from 6 to 12 years (average age, 9 years 6 months). Closed
      reduction of the elbow dislocation and open reduction of the lateral humeral
      condyle fracture with fixation by Kirschner wires by a lateral approach was done
      in each patient. This was followed by 4 weeks immobilization wearing a long-arm
      cast. There were three excellent results and one good result. Healing and return
      of normal function occurred in all but one patient who had minor loss of full
      extension. Average duration of followup was 7 years 6 months (range, 3-13 years).
      Dislocation of the elbow associated with a displaced fracture of the lateral
      humeral condyle can be treated by closed reduction of the elbow dislocation and
      open anatomic reduction and fixation of the lateral condyle fracture with good
      results.

PMID- 12616063
TI  - Ultrasound, magnetic resonance imaging, and posterior tibialis dysfunction.
AB  - The authors studied posterior tibialis tendons in 31 subjects with posterior
      tibialis tendon pain to compare clinical findings with those of magnetic
      resonance imaging and ultrasound images. All subjects received clinical,
      ultrasound, and magnetic resonance imaging examinations using T1-weighted, T2
      weighted, and enhanced magnetic resonance imaging, and high resolution ultrasound
      using power Doppler. Forty-four tendons in 25 women and six men with a mean age
      43.3 years (range, 20-73 years) were studied. Magnetic resonance imaging tendon
      and peritendon enhancement are associated statistically with increasing pain
      intensity on resistance to testing. Ultrasound tendon and peritendon flow were
      associated with increasing pain intensity on resistance to testing. There is no
      statistically significant association between magnetic resonance imaging
      inhomogeneity and pain intensity on resistance to testing. Clinical and
      ultrasound examinations positively identify peritendinitis and tendonitis but not
      inhomogeneity (partial tear) of the posterior tibialis tendon. The magnetic
      resonance imaging is a more sensitive test for posterior tibialis tendon tear
      than either clinical or ultrasound evaluation.

PMID- 12616065
TI  - Pediatric Kienbock's disease: case report and review of the literature.
AB  - A 13-year-old boy with symptomatic Stage III Kienbock's disease was treated
      successfully with a radial shortening procedure. A comparison of the preoperative
      and postoperative radiographs and magnetic resonance imaging studies showed
      evidence of lunate revascularization and remodeling after a radial shortening
      osteotomy.

PMID- 12616066
TI  - Prevention of ankle valgus after vascularized fibular grafts in children.
AB  - Ankle valgus after the use of vascularized fibular grafts is a specific
      complication of the donor site ankle in the growing child. Incidence of this
      deformity and prevention strategy are documented poorly. The goal of the current
      study was to evaluate the rate of such deformities and to analyze efficiency of
      two prevention methods. Charts of 20 children surgically treated for sarcomas of
      long bones with a mean followup of 4.1 years were studied retrospectively. Ankle
      valgus was considered if the tibiotalar angle on radiographs with the patient
      standing was 5 degrees or greater in valgus than that of the opposite ankle, and
      deformity was considered severe if it required surgical treatment. Prevention was
      done in some patients with a tibiofibular syndesmotic screw or with
      reconstruction of the fibula using a tibial autograft. Valgus occurred in nine
      patients (45%) and was severe in five (25%). Valgus prevention with a syndesmotic
      screw was efficient and lacking in complications, whereas patients with fibula
      reconstruction had a high incidence of deformity and relevant complications. The
      authors recommend using a tibiofibular screw in all patients whose growth plates
      are open in the lower limbs at the time of surgery.

PMID- 12616067
TI  - Percutaneous computed tomographic stabilization of the pathologic sacroiliac
      joint.
AB  - Metastases to the sacroiliac joint region can be a source of significant pain in
      many patients who are terminally ill. Six patients with metastatic lesions in the
      sacroiliac region who presented with significant posterior pelvic pain were
      treated with computed tomography-guided insertion of iliosacral screws. All
      patients reported excellent pain control in the early postoperative period.
      Computed tomography-guided insertion of iliosacral screws in an area of
      relatively preserved bone stock provides good purchase of the screws. It is a
      safe percutaneous procedure and it helps alleviate pain in patients with
      sacroiliac metastases.

PMID- 12616068
TI  - CD99 positive adamantinoma of the ulna with ipsilateral discrete osteofibrous
      dysplasia.
AB  - An adamantinoma is a rare, low-grade malignant, osteolytic bone tumor occurring
      predominantly in the diaphysis of the tibia. Osteofibrous dysplasia has been
      suggested as a precursor lesion to adamantinoma. Evidence for the relationship
      between these two tumors is based on their similar histologic features,
      immunohistochemistry, shared clonal abnormalities, overlapping skeletal
      distribution, and simultaneous occurrence in the tibia and fibula. The ulna is an
      unusual site of involvement by adamantinoma and osteofibrous dysplasia.
      Simultaneous involvement of the ulna by adamantinoma and ossifying fibroma has
      not been previously reported. A case is presented of an adamantinoma of the
      distal ulna with unique pathologic features occurring with an ipsilateral
      discrete focus of osteofibrous dysplasia as additional evidence of the
      relationship between these two lesions.

PMID- 12616069
TI  - Plate fixation with hydroxyapatite-coated screws: a comparative loaded study.
AB  - The authors evaluated whether AO/ASIF screws coated with hydroxyapatite are
      better fixed than standard screws in a highly loaded plate fixation animal study.
      Twelve sheep were divided into two groups. The medial tibial middiaphysis was
      exposed and a 5-mm long bone cylinder was removed. The tibiae were fixed with six
      hole dynamic compression plates. Six sheep received standard AO/ASIF stainless
      steel cortical screws (Group A), and six sheep received AO/ASIF stainless steel
      cortical screws coated with hydroxyapatite (Group B). Three months after surgery,
      the sheep were euthanized. The mean screw insertion torque was 4800 +/- 768 N/mm
      in Group A and 4847 +/- 450 N/mm in Group B. The mean screw extraction torque was
      530 +/- 374 N/mm in Group A and 3733 +/- 849 N/mm in Group B. Extraction torque
      of Group A was significantly lower compared with the corresponding insertion
      torque. In Group B, there were no differences between extraction and insertion
      torque. Morphologic analyses showed marked fibrous tissue encapsulation in Group
      A and bone to screw direct contact in Group B. The results confirm that
      hydroxyapatite-coated AO/ASIF screws prevent deterioration of screw anchorage,
      even under highly loaded conditions. By using hydroxyapatite-coated screws,
      complications resulting from inadequate fixation could be avoided.

PMID- 12616070
TI  - Long-term administration of clodronate does not prevent fracture healing in rats.
AB  - Clinicians have been concerned that fractures do not heal properly in individuals
      exposed to bisphosphonate treatment, a treatment that strongly affects bone
      metabolism. The current study attempted to clarify the long-term effects of
      clodronate (dichloromethylene bisphosphonate) treatment on fracture healing in
      growing rats. Clodronate was administered subcutaneously twice a week in a dose
      of 2 mg/kg or 10 mg/kg. Physiologic saline served as a control. After 24 weeks of
      treatment, the tibiae were fractured, and the treatment was continued for another
      4 weeks and 8 weeks. At both end points the cross-sectional areas of the callus,
      measured by peripheral quantitative computed tomography, were greater in the
      clodronate-treated rats than in controls, but there were no significant
      differences in bone mineral density. There were no significant differences
      between treatments in radiologic healing, histomorphometry, or in mechanical
      failure load of the callus with the exception of increased tensile stiffness at a
      dose of 2 mg/kg at 4 weeks. Clodronate treatment does not seem to prolong the
      fracture healing process, even when administered on a long-term basis before the
      fracture. Clodronate increases the size of the callus, but has only a minor
      effect on its biomechanical properties. The current results suggest that long
      term clodronate treatment does not inhibit fracture healing.

PMID- 12616071
TI  - Elastic stable intramedullary nailing of midclavicular fractures with a titanium
      nail.
AB  - This study presents the results of a minimally invasive operative treatment for
      markedly displaced midclavicular fractures. In all patients a flexible titanium
      nail was inserted in an unreamed technique from the sternal end of the clavicle.
      The result of surgery was determined with clinical and radiographic controls. The
      clinical outcome was evaluated 12 months after hardware removal using the scoring
      system of Constant and Murley. Fifty-eight fractures in 55 patients were treated
      with intramedullary fixation. Postoperatively on Day 3, the mean subjective pain
      was significantly lower and range of motion was improved compared with the day
      before surgery. One nonunion occurred. There was no infection and no implant
      displacement or refracture. Intramedullary nailing of midclavicular fractures
      with a flexible titanium nail is a safe minimally invasive surgical technique
      with excellent functional and cosmetic results compared with plate fixation or
      conservative treatment. Marked pain reduction along with early restoration of
      shoulder function and early mobilization are advantageous for patients. This
      technique can be used as an alternative treatment to conservative procedures or
      plate fixation in patients with markedly displaced midclavicular fractures,
      multiple trauma, fractures of the lower extremities, or associated shoulder
      girdle injuries.

PMID- 12616072
TI  - Distal tibia metaphyseal fractures treated by percutaneous plate osteosynthesis.
AB  - Twenty-one patients with fractures of the distal tibial metaphysis, some with
      minimal displacement in the ankle, were treated by percutaneous plate
      osteosynthesis with a narrow limited contact-dynamic compression plate. Using the
      classification by the Arbeitsgemeinschaft fur Osteosynthesefragen and Orthopaedic
      Trauma Association, 17 fractures had no articular involvement, whereas four
      included intraarticular extension. At final followup (mean, 20 months), all the
      fractures healed without second procedures and the mean union time was 15.2
      weeks. One patient had malalignment of the limb with 10 degrees internal
      rotation, but there were no angular deformities greater than 5 degrees or any
      shortening greater than 1 cm. All patients had excellent or satisfactory ankle
      function. There were no infections or any soft tissue compromise. Percutaneous
      plate osteosynthesis is a safe and worthwhile method of managing such fractures,
      which avoids some of the complications associated with conventional open plating
      methods.

PMID- 12616073
TI  - Brodie's abscess of the cuboid bone: a case report.
AB  - The case of a patient with Brodie's abscess of the cuboid bone and who presented
      with a painful and swollen right foot is described. The patient was treated
      successfully by surgical evacuation of the abscess and with antibiotics. To the
      authors' knowledge, Brodie's abscess of the cuboid bone has not been reported
      previously. The clinical presentation and diagnostic difficulties which may be
      encountered are discussed.

PMID- 12616074
TI  - Serum markers of bone metabolism show bone loss in hibernating bears.
AB  - Disuse osteopenia was studied in hibernating black bears (Ursus americanus) using
      serum markers of bone metabolism. Blood samples were collected from male and
      female, wild black bears during winter denning and active summer periods.
      Radioimmunoassays were done to determine serum concentrations of cortisol, the
      carboxy-terminal cross-linked telopeptide, and the carboxy-terminal propeptide of
      Type I procollagen, which are markers of bone resorption and formation,
      respectively. The bone resorption marker was significantly higher during winter
      hibernation than it was in the active summer months, but the bone formation
      marker was unchanged, suggesting an imbalance in bone remodeling and a net bone
      loss during disuse. Serum cortisol was significantly correlated with the bone
      resorption marker, but not with the bone formation marker. The bone formation
      marker was four- to fivefold higher in an adolescent and a 17-year-old bear early
      in the remobilization period compared with the later summer months. These
      findings raise the possibility that hibernating black bears may minimize bone
      loss during disuse by maintaining osteoblastic function and have a more efficient
      compensatory mechanism for recovering immobilization-induced bone loss than that
      of humans or other animals.

PMID- 12616075
TI  - Rinsing morselized allografts improves bone and tissue ingrowth.
AB  - Bone defects in revision hip surgery can be reconstructed with impacted
      morselized bone grafts. Rinsing these trabecular allografts may enhance graft
      incorporation by washing out immunogenic factors present in blood, marrow, and
      fat. However, it has been proposed that impaction of the graft releases
      biologically active factors, which can provide sufficient activity to stimulate
      new bone formation. Rinsing before impaction could enhance bone allograft
      incorporation, but rinsing after impaction could diminish the incorporation
      process of impacted bone graft. To study the effect of rinsing and impaction of
      morselized bone grafts on bone ingrowth, a bone chamber study was done in goats.
      Autografts and allografts were divided into three treatment groups: (A) impacted;
      (B) rinsed and impacted; and (C) rinsed, impacted, rinsed, and impacted again.
      Ten goats received three bone chambers in each proximal tibia. The chambers were
      filled with either allograft or autograft, yielding six different implants per
      goat. After 6 weeks, histologic analyses were done and bone and tissue ingrowth
      were measured. New bone and total tissue ingrowth were higher in autografts than
      in allografts, especially in the nonrinsed group. With rinsing, total tissue
      ingrowth increased in the allograft group to approach that of autografts. Rinsing
      after impaction did not additionally alter bone ingrowth. The current findings
      show that incorporation of allografts can be improved by rinsing the grafts
      before impaction.

PMID- 12616076
TI  - Failure characteristics of various arthroscopically tied knots.
AB  - The current study evaluated multiple arthroscopic knot configurations and
      compared their properties with open, hand-tied square knots. This is an
      experimental study done on a material testing system. Number 2 Ethibond Extra and
      Number 1 Polydioxanone sutures were used. Four types of sliding knot
      configurations were tested: the Duncan loop, the Tennessee Slider, the Savoie
      Modified Roeder, and the Lieurance-Modified Roeder. Two types of nonsliding knots
      were tested: the Revo knot and a knot consisting of alternating half-hitches tied
      with the Sixth Finger Knot Pusher. Ten knots were tied of each configuration,
      using strict arthroscopic technique. Each knot was backed-up with four half
      hitches using post switching technique. Knots were tied around two rings and then
      transferred wet to a materials testing machine. The knots were tested until
      ultimate failure, with note of clinical failure at 3 mm. Ethibond suture using
      the Revo knot, the Lieurance-Modified Roeder knot, and the Savoie-Modified Roeder
      knot were similar in strength to the square knot with comparable failure modes.
      Polydioxanone suture was more variable; the Revo knot, the Savoie-Modified
      Roeder, the Tennessee Slider, and the Duncan loop were comparable with hand-tied
      square knots. All of the open and arthroscopic suture loops tested in this study
      failed by the suture loops expanding to greater than 3 mm before ultimate failure
      occurred. The surgeon choosing arthroscopic repair techniques should be aware of
      the differences in suture material and the variation in knot strength afforded by
      different knot configurations.

PMID- 12616077
TI  - Decreased platelet derived growth factor expression during fracture healing in
      diabetic animals.
AB  - Animal model experiments have suggested that diabetes inhibits cell proliferation
      during fracture healing. Immunohistochemical analysis of proliferating cell
      nuclear antigen revealed significant reductions in cellular proliferation rates
      in the fracture callus of spontaneously diabetic BB Wistar rats as compared with
      healthy BB Wistar rats. Because platelet derived growth factor is associated with
      the early stage of fracture healing, it was hypothesized that diabetes causes
      decreased platelet derived growth factor expression during the early phase of
      fracture healing with a concomitant decrease in cell proliferation. Midshaft
      femur fractures were created in healthy and spontaneously diabetic BB Wistar rats
      and analyzed at Days 2, 4, and 7 after fracture for expression of platelet
      derived growth factor. Immunohistochemistry showed decreased localization of
      platelet derived growth factor in early diabetic fracture callus compared with
      healthy controls. Platelet derived growth factor messenger ribonucleic acid
      levels, as determined by reverse transcription and polymerase chain reaction,
      also were decreased in early diabetic fractures compared with healthy controls.
      Therefore the decreased cell proliferation rates associated with diabetic
      fracture healing are consistent with decreased platelet derived growth factor
      levels and suggest a causal relationship. These results suggest that diabetes is
      affecting the early phase of fracture healing by inhibiting cell proliferation
      through decreasing expression of platelet derived growth factor.

PMID- 12616078
TI  - Bone morphogenetic protein-4 regulation in fibrodysplasia ossificans progressiva.
AB  - Fibrodysplasia ossificans progressiva is a rare genetic disorder in which
      connective tissues are replaced with heterotopic bone through an endochondral
      process. Bone morphogenetic protein-4 messenger ribonucleic acid and protein
      levels are elevated in the cells of patients with fibrodysplasia ossificans
      progressiva, but the molecular mechanism of this steady-state elevation is
      unknown. Nuclear run-on assays and messenger ribonucleic acid stability assays
      were done to examine the molecular mechanisms of increased bone morphogenetic
      protein-4 messenger ribonucleic acid. The bone morphogenetic protein-4
      transcription rate in patient cells was found to be enhanced fivefold to
      sevenfold over normal control cells, suggesting that elevated steady-state levels
      of this transcript were attributable at least in part to an enhancement in
      transcription initiation. The stability of bone morphogenetic protein-4 messenger
      ribonucleic acid was found to be similar for patient and control cells and to
      have an extremely brief half-life, with bone morphogenetic protein-4 messenger
      ribonucleic acid almost completely decayed (75%) by 40 minutes. This unusually
      brief half-life suggests that a high fidelity control over temporal expression of
      the bone morphogenetic protein 4-message can be maintained. The data document
      that enhanced transcription rather than increased messenger ribonucleic acid
      stability is responsible for the elevation in steady-state levels of bone
      morphogenetic protein-4 messenger ribonucleic acid, and suggest that an
      inappropriate enhancement of the rate of bone morphogenetic protein-4
      transcription plays a critical role in the molecular pathophysiology of
      fibrodysplasia ossificans progressiva.

PMID- 12616079
TI  - A long finger mass in a 43-year-old woman.

PMID- 12616080
TI  - Management of suprasellar meningiomas.

PMID- 12616081
TI  - Visual outcome in surgically treated suprasellar meningiomas.
AB  - OBJECTIVE To determine long-term (>10 years) visual outcome in patients with
      suprasellar meningiomas. METHODS Retrospective case series.RESULTS Among 18
      patients who underwent surgery for suprasellar meningioma (1 patient died
      postoperatively), 1 experienced initial improvement in vision in both eyes, 8
      experienced improvement in vision in one eye and maintained stable vision in the
      other eye, 2 experienced improvement in vision in one eye and worsening of vision
      in the other, 3 experienced worsening of vision in one eye and stable vision in
      one eye, and 4 maintained stable visual acuity in both eyes. No patient
      experienced postoperative worsening of vision in both eyes. During 10 years or
      more of follow-up, 10 of the patients (56%) maintained stable vision in both
      eyes, 6 patients (33%) experienced loss of vision in one eye while maintaining
      stable vision in the other, and 2 patients (11%) experienced loss of vision in
      both eyes. During this period, 7 of the 18 patients (39%) developed neuroimaging
      evidence of tumor growth or recurrence, with a mean time of 10.7 years. Four of
      these patients were thought to have had gross total resection of their tumor.
      Patients who experienced worsening of vision during the follow-up period were
      more likely to have developed neuroimaging evidence of growth or recurrence (five
      patients) than patients without such evidence (two patients), and such patients
      did not regain vision following subsequent surgery or radiation therapy.
      Nevertheless, at final examination, 13 patients (72%) had visual acuity of 20/40
      or better in at least one eye. CONCLUSIONS The long-term visual prognosis for
      patients who undergo surgery for suprasellar meningioma is excellent, although
      tumor recurrence is common, even in patients thought to have undergone gross
      total removal of their tumor, and often occurs more than 10 years after surgery.
      Patients who develop tumor recurrence are likely to lose vision in at least one
      eye and are unlikely to achieve improvement in vision with subsequent surgery or
      radiation therapy. Thus, patients with suprasellar meningiomas believed to have
      been completely resected should undergo long-term, serial postoperative clinical
      examinations and neuroimaging to allow detection and further treatment of
      recurrences as early as possible. Postoperative radiation therapy should be
      considered for patients whose suprasellar meningiomas have been incompletely
      resected.

PMID- 12616083
TI  - Magnetic resonance imaging abnormalities in cat-scratch disease encephalopathy.
AB  - A 23-year-old woman who presented with a branch retinal artery occlusion followed
      by encephalopathy showed, by brain magnetic resonance imaging, a nonenhancing
      lesion in the right parietal gray matter with normal diffusion-weighted imaging.
      Of 64 reported cases of cat-scratch encephalopathy with documented neuroimaging
      findings, only 12 (18.8%) have had abnormal imaging findings. The abnormalities
      have included cerebral white matter lesions, basal ganglia and thalamic lesions,
      and multifocal lesions in immunocompromised patients, but no gray matter lesions
      similar to those in this patient. The variety of neuroimaging findings supports
      multiple pathophysiologic mechanisms of central nervous system involvement in
      this disorder.

PMID- 12616082
TI  - A functional magnetic resonance imaging study in patients with benign essential
      blepharospasm.
AB  - OBJECTIVE To identify blinking-induced functional magnetic resonance imaging
      (fMRI) activation patterns in five benign essential blepharospasm (BEB) patients
      and five age-matched control subjects. METHODS fMRI brain activation maps were
      obtained during repeated conditions of spontaneous and voluntary blinking in BEB
      and control groups. Blood oxygen level-dependent intensity images were collected
      from two separate runs as 16 axial and 16 coronal, 8 mm thick slices using a T2
      star weighted gradient echo EPI sequence, coregistered with anatomic images.
      Spatially normalized and isotropically blurred activation maps for each subject
      were combined within groups of BEB patients and control subjects to generate maps
      of the intersubject mean fractional signal change.RESULTS Substantially greater
      activation during spontaneous and voluntary blinking was seen in BEB patients
      compared with control subjects in the anterior visual cortex, anterior cingulate
      cortex, primary motor cortex, central region of the thalamus, and superior
      cerebellum. In both groups, activations were generally greater for voluntary than
      for spontaneous blinking. CONCLUSIONS The activations observed might represent a
      hyperactive cortical circuit linking visual cortex, limbic system, supplementary
      motor cortex, cerebellum, and supranuclear motor pathways innervating the
      periorbital muscles.

PMID- 12616085
TI  - Simultaneous occurrence of neuroretinitis and optic perineuritis in a single eye.
AB  - A 52-year-old woman presented with pain, decreased visual acuity, decreased color
      vision, and visual field loss in the OD. Fundus examination revealed optic disc
      edema and later a macular star figure consistent with neuroretinitis. Magnetic
      resonance imaging showed enhancement of the orbital optic nerve sheath and
      perineural fat suggestive of optic perineuritis. The patient was not treated. At
      11 months, visual function and fundus examination had returned to normal. This
      unusual simultaneous occurrence of neuroretinitis and optic perineuritis suggests
      that these two entities may have a similar pathogenesis.

PMID- 12616084
TI  - False negative hydroxyamphetamine test in horner syndrome caused by acute
      internal carotid artery dissection.
AB  - A patient with Horner syndrome from internal carotid artery dissection initially
      had a false negative hydroxyamphetamine test. Two months later, the ophthalmic
      signs had disappeared but the hydroxyamphetamine test was positive. This case
      illustrates that hydroxyamphetamine testing may be falsely negative in acute
      Horner syndrome because norepinephrine stores in oculosympathetic postganglionic
      terminals have not yet been depleted. However, the hydroxyamphetamine test may be
      positive even after the ophthalmic signs of Horner syndrome have disappeared.

PMID- 12616086
TI  - Chiasmal high signal on magnetic resonance imaging in the atrophic phase of leber
      hereditary optic neuropathy.
AB  - A 30-year-old man with Leber hereditary optic neuropathy mutation 11778 displayed
      no magnetic resonance imaging abnormalities during the acute phase of visual loss
      in the right eye. Three months later, during the acute phase of visual loss in
      the left eye, magnetic resonance imaging showed T2 hyperintense signal changes on
      the right half of the optic chiasm. Six months later, magnetic resonance imaging
      revealed T2 hyperintense signal changes on both sides of the optic chiasm. This
      is the first reported case of optic chiasmal involvement on magnetic resonance
      imaging in the atrophic phase of Leber hereditary optic neuropathy.

PMID- 12616087
TI  - Progressive visual failure in an eye with optic disc drusen and an orbital mass.
AB  - A 44-year-old woman with progressive monocular visual loss was found to have
      ipsilateral optic disc drusen and an ipsilateral orbital apex mass compressing
      the optic nerve. The mass, not the drusen, was considered responsible for the
      worsening vision. Visual loss should not be glibly attributed to drusen,
      particularly if the visual loss is rapidly progressive. Retrobulbar imaging
      should be considered in such cases.

PMID- 12616089
TI  - Clinical applications of pupillography.
AB  - The development of personal computer-based infrared video instruments has allowed
      pupillography to enter the clinical arena. Measuring pupil diameter for
      refractive surgery, distinguishing Horner syndrome from physiologic anisocoria,
      quantifying the relative afferent pupillary defect, and plotting visual fields by
      means of graded pupil constriction to focal light stimuli are recent applications
      in ophthalmology. Pupillography has also been used to determine sleepiness and
      autonomic effects of new pharmaceuticals.

PMID- 12616088
TI  - Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography
      (SPECT): Clinical Applications.
AB  - Positron emission tomography and single-photon emission computed tomography are
      nuclear imaging modalities that excel in depicting the biological function of
      tissue. Unlike structural imaging methods, they provide functional diagnostic
      information about brain neoplasms, stroke, neurodegenerative disorders, epilepsy,
      cortical visual loss, and migraine.

PMID- 12616090
TI  - The coagulation system.
AB  - Congenital and acquired hypercoagulable states arise from an imbalance between
      procoagulant and anticoagulant activity. Although these imbalances are present
      throughout the entire vascular tree, thrombotic lesions are usually localized in
      discrete segments of the veins or arteries and in certain organ systems. Thus,
      hypercoagulable states are likely to be associated with focal defects in the
      vascular wall to produce thrombosis. Many recently described factors are
      associated with hypercoagulability. Because thrombosis is a disease in which
      genetic and acquired risk factors interact dynamically, a thorough history,
      family history, and physical examination should be performed before ordering an
      extensive and costly coagulation panel.

PMID- 12616092
TI  - Management of traumatic optic neuropathy.

PMID- 12616091
TI  - Coagulopathies and arterial stroke.
AB  - Although hypercoagulable states are most often associated with venous thrombosis,
      arterial thromboses are reported in protein S, protein C, and antithrombin III
      deficiencies, factor V Leiden and prothrombin gene mutations,
      hyperhomocysteinemia, dysfibrinogenemia, plasminogen deficiency, sickle cell
      disease, and antiphospholipid antibody syndrome.

PMID- 12616094
TI  - Annual Meeting of the Association for Research in Vision and Ophthalmology
      (ARVO), Fort Lauderdale, Florida, May 5-10, 2002.

PMID- 12616095
TI  - 54th annual meeting of the American Academy of Neurology, Denver, Colorado, April
      13-20, 2002.

PMID- 12616096
TI  - Optic nerve and chiasmal enhancement in leber hereditary optic neuropathy.

PMID- 12616097
TI  - Photophobia in anterior visual pathway lesions.

PMID- 12616098
TI  - Micropsia and dissociative disorders.

PMID- 12616099
TI  - Guillain-Barre syndrome.

PMID- 12616100
TI  - Immunotherapy With Low-Dose IL-2 in Combination With GM-CSF.

PMID- 12616101
TI  - Generating potent Th1/Tc1 T cell adoptive immunotherapy doses using human IL-12:
      Harnessing the immunomodulatory potential of IL-12 without the in vivo-associated
      toxicity.
AB  - Interleukin (IL)-12 is a cytokine originally identified from medium conditioned
      by an Epstein-Barr virus transformed cell line. IL-12 has been shown to increase
      IFN-gamma secretion from NK and T cells, significantly enhance cytolytic activity
      in both of these cell types, and promote the development of Th1/Tc1 immune
      responses. These properties make IL-12 an attractive candidate for the
      development of various clinical protocols ranging from the treatment of viral
      diseases to tumor immunotherapy. The initial attempts to use IL-12 in the
      treatment of tumors demonstrated toxicity at potentially therapeutic doses. To
      circumvent the toxicity associated with IL-12 administration, the authors have
      developed an adoptive immunotherapy protocol that uses IL-12 for a brief period
      during ex vivo T cell activation. They show that IL-12 conditioning may be
      achieved without altering the growth characteristics of the in vitro expanding T
      cells. T cells generated in the presence of IL-12 show a shift to a Th1/Tc1
      dominant phenotype. The resultant cells are more potent killers in vitro and in
      vivo as assessed by CTL assays and tumor regression. The ability to harness the
      potent Th1/Tc1 generating potential of IL-12 while avoiding its associated in
      vivo toxicity has the potential to benefit a large number of clinical trial
      protocols using adoptive transfer of T cells specific for tumors, viruses, or
      intracellular pathogens.

PMID- 12616102
TI  - Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity
      against malignant glioma in rats.
AB  - Dendritic cells (DC) are attractive candidates for innovative cancer
      immunotherapy by virtue of their ability to function as powerful antigen
      presenting cells and elicit potent antitumor cytotoxic immune responses. With the
      aim of generating antitumor immunity, the authors sought to enhance in vivo tumor
      antigen presentation by using an intratumoral DC vaccination strategy in the
      setting of partially irradiated intracranial brain tumors. Fisher rats, implanted
      with 9L gliomas in the right corpus striatum, were treated with freshly cultured,
      unpulsed syngeneic DC inoculated directly into the tumor bed. Intracranially
      inoculated DCs were found to drain to ipsilateral deep cervical lymph nodes. This
      was associated with increased local and systemic antitumor cytoxicity, as
      evidenced by robust infiltration of treated tumors with CD4 and CD8 T cells as
      well as by increased IFN-gamma protein and message levels in in vitro
      restimulated splenic lymphocytes. DC therapy resulted in prolonged survival and
      immunity to subsequent intracranial tumor re-challenge. These results demonstrate
      the viability of intratumoral DC vaccination as an effective therapeutic strategy
      for intracranial glioma.

PMID- 12616103
TI  - Intratumoral expression of macrophage-derived chemokine induces CD4+ T cell
      independent antitumor immunity in mice.
AB  - Macrophage-derived chemokine is chemotactic for a variety of leukocytes, and has
      been shown to be involved in T 2-mediated cellular immunity. To evaluate the role
      of this chemokine in tumor immunity in vivo, an adenovirus vector encoding the
      human macrophage-derived chemokine cDNA (AdMDC) was administered to established
      murine tumors. Gene transfer with AdMDC significantly inhibited tumor growth and
      prolonged animal survival. AdMDC was not directly cytotoxic to tumor cells, but
      splenocytes from animals that received intratumoral AdMDC were able to lyse
      syngeneic tumor cells, and purified splenic CD8 cells secreted interferon-gamma
      in a tumor-specific manner. The antitumor activity of AdMDC was lost in mice
      lacking CD8 T lymphocytes, but surprisingly, it was preserved in animals lacking
      CD4 cells, as was the systemic cytotoxic T lymphocyte response. Systemic NK cells
      did not play a role in the antitumor immune response induced by AdMDC.
      Experiments using knockout mice demonstrated that host expression of MHC Class I,
      but not Class II, IL-4, or IL-12, was necessary for AdMDC to exert its antitumor
      effect, and immunohistochemistry demonstrated infiltrates of CD8 and CD86 cells,
      but not CD4 cells in treated tumors. These studies highlight a new function for
      macrophage-derived chemokine by demonstrating that it possesses in vivo antitumor
      activity with CD8 T cells as the effector cells, and interestingly, that the CD4
      cell/MHC II pathway of CD8 cell activation is not required for the antitumor
      effects of this chemokine.(H)

PMID- 12616104
TI  - Immune effects of escalating doses of granulocyte-macrophage colony-stimulating
      factor added to a fixed, low-dose, inpatient interleukin-2 regimen: a randomized
      phase I trial in patients with metastatic melanoma and renal cell carcinoma.
AB  - Previous studies in cancer patients demonstrated that granulocyte-macrophage
      colony-stimulating factor (GM-CSF) upregulated the interleukin (IL)-2 receptor on
      T lymphocytes and monocytes suggesting that subsequently administered IL-2 would
      produce greater immune effects. The authors treated 21 patients with metastatic
      renal cell carcinoma and melanoma on a randomized phase I study to test this
      hypothesis. All 21 patients received a fixed dose of IL-2 (72,000 IU/kg every 8
      hours for 5 days) administered intravenously as an inpatient. Patients were
      randomized to receive IL-2 alone or in combination with GM-CSF at a dose of 125
      or 250 mcg/m /d (Sargramostim; Immunex Corporation, WA, U.S.A.) daily for 7 days
      by subcutaneous injection starting on day 1, the day before IL-2 treatment. The
      results from this study demonstrated that GM-CSF did not worsen the toxicities
      produced by IL-2 alone. Grade 3 confusion occurred in four patients, three who
      received IL-2 alone. No partial or complete tumor responses were seen. Assays of
      serum soluble IL-2 receptor (sIL2R) and neopterin, measures of T cell and
      monocyte activation, respectively, demonstrated a significant increase in sIL2R
      but not neopterin, 24 hours after the first dose of GM-CSF. In combination with
      IL-2, the higher dose of GM-CSF (250 mcg/m ) produced higher sIL2R levels on days
      3 and 7 than the 125-mcg/m dose of GM-CSF or IL-2 alone. Although neopterin
      levels did not increase after 1 day of GM-CSF, the addition of IL-2 resulted in a
      significantly increased neopterin level on day 3 at the higher dose of GM-CSF. On
      day 7, neopterin levels in all three groups were similarly increased over
      baseline. Ten days after treatment, neopterin levels had returned to normal, but
      sIL2R levels remained markedly increased (12 fold) over baseline in the higher GM
      CSF dose group. The authors conclude that 1) monocyte activation was not
      significantly enhanced by 1 day of GM-CSF treatment; 2) the 250-mcg/m GM-CSF dose
      plus IL-2 produced superior T cell activation compared with a lower dose of GM
      CSF plus IL-2 or to IL-2 alone; and 3) the combination of GM-CSF and IL-2 was
      safe and tolerable but was not associated with any clinical responses.

PMID- 12616105
TI  - Pharmacological evaluation of humanized anti-epidermal growth factor receptor,
      monoclonal antibody h-R3, in patients with advanced epithelial-derived cancer.
AB  - Epidermal growth factor receptor (EGFR) overexpression has been detected in many
      tumors of epithelial origin, and it is often associated with tumor growth
      advantages and poor prognosis. h-R3 is a genetically engineered humanized
      antibody (mAb) that recognizes an epitope located in the extracellular domain of
      human EGFR. The antibody exhibited potent in vitro and in vivo antitumor effect
      on EGFR overexpressing cell lines. To study safety, pharmacokinetics, and
      biodistribution, 12 patients with advanced epithelial-derived tumors received
      single intravenous infusion of h-R3 at four dose levels. Safety evaluation was
      made according to World Health Organization toxicity criteria. For
      biodistribution, 3 mg of the total dose were labeled with Technetium and then
      pooled with the rest of the dose. Anterior and posterior whole-body images were
      acquired using a gamma camera. Blood samples were taken for pharmacokinetics,
      antiidiotypic response, and for soluble EGFR detection. After hR3 administration,
      no evidence of severe toxicity was observed. Secondary reactions were mild and
      moderate and mainly consisted of tremors, fever, and vomiting. No anaphylactic or
      skin reactions were detected. Qualitative analysis of whole-body images showed
      that the liver had the highest mAb uptake. Pharmacokinetic analysis revealed that
      elimination half-lives and the AUC increased linearly with dose, while total body
      clearance decreased when increasing doses of h-R3. No relation between shed EGFR
      and mAb clearance was found. No antiidiotypic response against h-R3 was detected.
      Several phase II trials are now underway to evaluate the efficacy of h-R3 in the
      treatment of advanced cancer patients.

PMID- 12616106
TI  - Significance of perivascular lymphocytic infiltrates on survival of patients with
      invasive cervical cancer.
AB  - The authors retrospectively reviewed the medical records of 129 patients with
      stage IB and II cervical cancer (93 squamous cell carcinomas, 30 adenocarcinomas,
      and 6 adenosquamous carcinomas) who underwent primary surgery between 1989 and
      2000. Vascular invasion is the predictor of recurrence, and lymphocytic
      infiltrates within the tumor is associated with favorable outcome in cervical
      cancer. Hence, 129 patients were divided into three groups according to the
      presence or absence of vascular invasion (VI) and perivascular lymphocytic
      infiltrates (PLI); VI- (n = 77), VI+PLI- (n = 26), and VI+PLI+ (n = 26), to
      evaluate the significance of PLI. Age, clinical stage, histology, tumor grade,
      depth of stromal invasion, VI and PLI, tumor size, ovarian metastasis, pelvic
      lymph node metastasis, postoperative irradiation, and chemotherapy were assessed
      statistically for recurrence of the disease by Cox regression analysis. Disease
      free survival was analyzed using Kaplan-Meier survival analysis. Recurrence was
      observed in 32 (25%) of all 129 cases. In a multivariate analysis, VI ( = 0.003)
      and histology ( = 0.006) remained significantly associated with recurrence. When
      divided into three groups, the hazard ratio for recurrence was higher in the
      absence of PLI (2.95 in VI+PLI- group versus 2.07 in VI+PLI+ group), and value
      became significant in the absence of PLI (0.008 in VI+PLI- group versus 0.106 in
      VI+PLI+ group). In Kaplan-Meier survival analysis, only the VI+PLI- group ( =
      0.006) was significantly associated with worse survival compared with the VI-
      group. These results suggest that the coexistence of perivascular lymphocytic
      infiltrates is associated with a better prognosis in cases with vascular
      invasion.

PMID- 12616107
TI  - Adjuvant immunotherapy with tumor infiltrating lymphocytes and interleukin-2 in
      patients with resected stage III and IV melanoma.
AB  - Adoptive immunotherapy with tumor infiltrating lymphocytes (TIL) and interleukin
      (IL)-2 is reasonably effective in the treatment of patients with advanced
      melanoma. However, theoretically it should be of greater benefit as adjuvant
      therapy, especially in high-risk stages (resected stages III and IV). In a
      preliminary study, 25 patients (aged 23-72 years) with stage III-IV melanoma who
      underwent resection of metachronous metastases were reinfused with TIL cultivated
      and expanded in vitro with IL-2 from surgically removed metastases. IL-2
      (starting dose 12 x 10 IU/m ) was co-administered as a continuous infusion
      according to West's scheme. A total of 8/22 (36.3%) evaluable patients were
      disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall
      survival (OS) rates were 44% and 37%, respectively, at 2 years, and 52% and 45%
      at 3 years. The CNS was the only site of disease recurrence in 57% of patients
      who relapsed. DF patients received a higher median dose of IL-2 than those who
      progressed (total dose 110 x 10 versus 86 x 10 IU/m, respectively). The
      progressive reduction in IL-2 dosage allowed all patients to complete treatment
      without permanent grade 4 toxicity. Analysis of tumor immunosuppression factors
      in lymphocytes inside the tumor (TCR zeta and epsilon chains, p56, FAS, and FAS
      ligand) confirmed that the immunologic potential of TIL, depressed at the time of
      metastasectomy, was significantly restored after in vitro culture with IL-2.
      Adoptive immunotherapy with TIL and IL-2 could improve DFS and OS, although
      further work is required to determine its role in the treatment of patients with
      high-risk melanoma.

PMID- 12616109
TI  - Phase I trial of granulocyte macrophage-colony stimulating factor and interleukin
      4 as a combined immunotherapy for patients with cancer.
AB  - Antigen-presenting cells (APC), such as dendritic cells (DC), are the key
      component of many cancer immunotherapy strategies. However, DCs comprise a rare
      population of clinically obtainable cells and are compromised in function in
      cancer-bearing hosts. Clinical trials therefore rely upon DC generated ex vivo.
      The authors hypothesized that systemic administration of granulocyte-macrophage
      colony-stimulating factor (GM-CSF) plus interleukin (IL)-4 might lead to the
      differentiation of DC from their precursors and enhance their number and function
      in vivo, as it does in vitro. Subjects with advanced malignancies were treated in
      this phase I, multiple cohort, dose-escalation trial combining GM-CSF (2.5
      microgram/kg/d) plus IL-4 (0-6.0 microgram/kg/d). A cycle consisted of 14 days of
      cytokine therapy and 14 days of observation (cohorts A-D), or alternating 7-day
      treatment and observation periods (cohort E). Subjects were followed clinically
      to determine a maximally tolerated dose (MTD), and complimentary in vitro studies
      were performed to determine a biologically active dose (BAD). Twenty-one subjects
      received treatment on this outpatient-based protocol. Treatment was well
      tolerated and generally characterized by Grade 1 and 2 cytokine related
      toxicities. The MTD was determined to be GM-CSF 2.5 microgram/kg/d plus IL-4 6.0
      microgram/kg/d (cohort E). Treatment in cohort D (GM-CSF 2.5 microgram/kg/d plus
      IL-4 4.0 microgram/kg/d) was well tolerated and resulted in a BAD. Systemic GM
      CSF plus IL-4 provides a mechanism for increasing the number and function of APC
      in cancer patients. Future clinical applications of this strategy are numerous
      and include the potential as a strong vaccine adjuvant.

PMID- 12616108
TI  - Identification of tumor-specific antibodies in patients with breast cancer
      vaccinated with gene-modified allogeneic tumor cells.
AB  - Thirty HLA-A2 women with metastatic breast cancer received up to 14 vaccinations
      with MDA-MB-231-CD80, an HLA-A2 allogeneic breast cancer cell line, which had
      been lipofected with the cDNA for the CD80 costimulatory molecule. Tumor cells
      were administered with BCG or GM-CSF as an adjuvant. Sera obtained before and
      after vaccination were analyzed for antibodies to tumor cell lysate, MUC1,
      HER2/neu and p53. Since the cell line was grown in fetal bovine serum (FBS), sera
      were also analyzed for antibodies to FBS. Eighteen of 24 patients for whom sera
      were available exhibited anti-FBS activity at baseline. Eleven of these 18
      patients and all six patients without baseline anti-FBS activity showed an
      increased titer after vaccination. The anti-FBS activity required that serum
      samples be absorbed in excess FBS to detect specific antibodies to tumor cell
      lysate. A two-fold increase in the titer of IgG specific to tumor cell lysate was
      observed in 6 patients. Eight of 24 patients made an antibody response to HER
      2/neu, four of 24 to MUC1 and one of 24 to p53. Although antibody production to a
      variety of tumor cell-associated antigens was detected our results suggest that a
      whole cell vaccine comprising a CD80-transfected allogeneic breast cancer cell
      line with adjuvant BCG or GM-CSF was not a reliable method to induce significant
      antibody responses in women with advanced breast cancer.

PMID- 12616110
TI  - Continuous intravenous administration of live genetically modified salmonella
      typhimurium in patients with metastatic melanoma.

PMID- 12616111
TI  - Long-term results of a randomized prospective study comparing medical and
      surgical treatment of Barrett's esophagus.
AB  - OBJECTIVE: To compare the results of medical treatment and antireflux surgery in
      patients with Barrett's esophagus (BE). SUMMARY BACKGROUND DATA: The treatment of
      choice in BE is still controversial. Some clinical studies suggest that surgery
      could be more effective than medical treatment in preventing BE from progressing
      to dysplasia and adenocarcinoma. However, data from prospective comparative
      studies are necessary to answer this question. METHODS: One hundred one patients
      were included in a randomized prospective study, 43 with medical treatment and 58
      with antireflux surgery. All patients underwent clinical, endoscopic, and
      histologic assessment. Functional studies were performed in all the operated
      patients and in a subgroup of patients receiving medical treatment. The median
      follow-up was 5 years (range 1-18) in the medical treatment group and 6 years
      (range 1-18) in the surgical treatment group. RESULTS: Satisfactory clinical
      results (excellent to good) were achieved in 39 of the 43 patients (91%)
      undergoing medical treatment and in 53 of the 58 patients (91%) following
      antireflux surgery. The persistence of added inflammatory lesions was
      significantly higher in the medical treatment group. The metaplastic segment did
      not disappear in any case. Postoperative functional studies showed a significant
      decrease in the median percentage of total time with pH below 4, although 9 of
      the 58 patients (15%) showed pathologic rates of acid reflux. High-grade
      dysplasia appeared in 2 of the 43 patients (5%) in the medical treatment group
      and in 2 of the 58 patients (3%) in the surgical treatment group. In the latter,
      both patients presented with clinical and pH-metric recurrence. There was no case
      of malignancy after successful antireflux surgery. CONCLUSIONS: These results
      show that there are no differences between the two types of treatment with
      respect to preventing BE from progressing to dysplasia and adenocarcinoma.
      However, successful antireflux surgery proved to be more efficient than medical
      treatment in this sense, perhaps because it completely controls acid and
      biliopancreatic reflux to the esophagus.

PMID- 12616112
TI  - Barrett's esophagus: now what?

PMID- 12616113
TI  - Intra-abdominal activation of a local inflammatory response within the human
      muscularis externa during laparotomy.
AB  - OBJECTIVE: To investigate the initiation of a complex inflammatory response
      within the human intestinal muscularis intraoperatively so as to determine the
      clinical applicability of the inflammatory hypothesis of postoperative ileus.
      SUMMARY BACKGROUND DATA: Mild intestinal manipulation in rodents initiates the
      activation of transcription factors, upregulates proinflammatory cytokines, and
      increases the release of kinetically active mediators (nitric oxide and
      prostaglandins), all of which results in the recruitment of leukocytes and a
      suppression in motility (i.e., postoperative ileus). METHODS: Human small bowel
      specimens were harvested during abdominal procedures at various times after
      laparotomy. Histochemical and immunohistochemical techniques were applied to
      intestinal muscularis whole-mounts. Reverse transcriptase-polymerase chain
      reaction (RT-PCR) was performed for interleukin (IL)-6, IL-1beta, tumor necrosis
      factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2
      (COX-2). Signal transducers and activators of transcription (STAT) protein
      phosphorylation was determined by electromobility shift assay. Organ bath
      experiments were performed on jejunal circular smooth muscle strips. GW274150C
      and DFU were used in vitro as iNOS and COX-2 inhibitors. RESULTS: Normal human
      muscularis externa contained numerous macrophages that expressed increased
      lymphocyte function associated antigen-1 (LFA-1) immunoreactivity as a function
      of intraoperative time. RT-PCR demonstrated a time-dependent induction of IL-6,
      IL-1beta, TNF-alpha, iNOS, and COX-2 mRNAs within muscularis extracts after
      incision. Mediators were localized to macrophages with STAT protein activation in
      protein extracts demonstrating local IL-6 functional activity. DFU alone or in
      combination with GW274150C increased circular muscle contractility. Specimens
      harvested after reoperation developed leukocytic infiltrates and displayed
      diminished in vitro muscle contractility. CONCLUSIONS: These human data
      demonstrate that surgical trauma is followed by resident muscularis macrophage
      activation and the upregulation, release, and functional activity of
      proinflammatory cytokines and kinetically active mediators.

PMID- 12616114
TI  - Ileus and the macrophage.

PMID- 12616115
TI  - Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta
      analysis of cohort studies and controlled trials.
AB  - OBJECTIVE: To determine whether hypoalbuminemia is an independent risk factor for
      poor outcome in the acutely ill, and to assess the potential of exogenous albumin
      administration for improving outcomes in hypoalbuminemic patients. SUMMARY
      BACKGROUND DATA: Hypoalbuminemia is associated with poor outcomes in acutely ill
      patients, but whether this association is causal has remained unclear. Trials
      investigating albumin therapy to correct hypoalbuminemia have proven
      inconclusive. METHODS: A meta-analysis was conducted of 90 cohort studies with
      291,433 total patients evaluating hypoalbuminemia as an outcome predictor by
      multivariate analysis and, separately, of nine prospective controlled trials with
      535 total patients on correcting hypoalbuminemia. RESULTS: Hypoalbuminemia was a
      potent, dose-dependent independent predictor of poor outcome. Each 10-g/L decline
      in serum albumin concentration significantly raised the odds of mortality by
      137%, morbidity by 89%, prolonged intensive care unit and hospital stay
      respectively by 28% and 71%, and increased resource utilization by 66%. The
      association between hypoalbuminemia and poor outcome appeared to be independent
      of both nutritional status and inflammation. Analysis of dose-dependency in
      controlled trials of albumin therapy suggested that complication rates may be
      reduced when the serum albumin level attained during albumin administration
      exceeds 30 g/L. CONCLUSIONS: Hypoalbuminemia is strongly associated with poor
      clinical outcomes. Further well-designed trials are needed to characterize the
      effects of albumin therapy in hypoalbuminemic patients. In the interim, there is
      no compelling basis to withhold albumin therapy if it is judged clinically
      appropriate.

PMID- 12616116
TI  - Laparoscopic total mesorectal excision: a consecutive series of 100 patients.
AB  - OBJECTIVE: To analyze total mesorectal excision (TME) for rectal cancer by the
      laparoscopic approach during a prospective nonrandomized trial. SUMMARY
      BACKGROUND DATA: Improved local control and survival rates in the treatment of
      rectal cancer have been reported after TME. METHODS: The authors conducted a
      prospective consecutive series of 100 laparoscopic TMEs for low and mid-rectal
      tumors. All patients had a sphincter-saving procedure. Case selection, surgical
      technique, and clinical and oncologic results were reviewed. RESULTS: The distal
      limit of rectal neoplasm was on average 6.1 (range 3-12) cm from the anal verge.
      The mean operative time was 250 (range 110-540) minutes. The conversion rate was
      12%. Excluding the patient who stayed 104 days after a severe fistula and
      reoperation, the mean postoperative stay was 12.05 (range 5-53) days. The 30-day
      mortality was 2% and the overall postoperative morbidity was 36%, including 17
      anastomotic leaks. Of 87 malignant cases, 70 (80.4%) had a minimum follow-up of
      12 months, with a median follow-up of 45.7 (range 12-72) months. During this
      period 18.5% (13/70) died of cancer and 8.5% (6/70) are alive with metastatic
      disease. The port-site metastasis rate was 1.4% (1/70): a rectal cancer stage IV
      presented with a parietal recurrence at 17 months after surgery. The locoregional
      pelvic recurrence rate was 4.2% (3/70): three rectal cancers stage III at 19, 13,
      and 7 postoperative months. CONCLUSIONS: Laparoscopic TME is a feasible but
      technically demanding procedure (12% conversion rate). This series confirms the
      safety of the procedure, while oncologic results are at present comparable to the
      open published series with the limitation of a short follow-up period. Further
      studies and possibly randomized series will be necessary to evaluate long-term
      clinical outcome in cancer patients.

PMID- 12616117
TI  - CO2 Pneumoperitoneum modifies the inflammatory response to sepsis.
AB  - OBJECTIVE: To analyze the effect of CO2 pneumoperitoneum on the inflammatory
      response induced by sepsis during laparoscopy. SUMMARY BACKGROUND DATA: A growing
      body of evidence challenges the once generally accepted notion that smaller
      incisions alone account for the observed benefits of the laparoscopic approach.
      Furthermore, laparoscopic surgery is now being applied to a broad spectrum of
      patients, including those in whom the inflammatory response is ignited.
      Delineation of the effects of CO2 pneumoperitoneum on the inflammatory response
      induced by sepsis is needed. METHODS: Sepsis was induced in rats by cecal
      ligation and puncture (CLP) performed either open or laparoscopically using CO2
      or helium as insufflation gases. Animals were killed 24 hours postoperatively, at
      which time whole blood was collected for complete blood cell counts and livers
      were harvested for analysis of hepatic expression of the rat acute phase genes
      alpha2-macroglobulin and beta-fibrinogen. RESULTS: Laparoscopic CLP using CO2
      resulted in significantly reduced hepatic expression of the rat acute phase gene
      alpha2-macroglobulin compared to both laparoscopic CLP using helium and open CLP.
      Hepatic expression of another rat acute phase gene, beta-fibrinogen, paralleled
      that of alpha2-macroglobulin and was significantly reduced following laparoscopic
      CLP using CO2 compared to laparoscopic CLP using helium. Total white blood cell
      and neutrophil counts following CLP were both significantly higher when CLP was
      performed laparoscopically using CO2 than when CLP was performed open or
      laparoscopically using helium. CONCLUSIONS: Intra-abdominal CO2 present during
      laparoscopy attenuates the acute phase inflammatory response associated with
      perioperative sepsis.

PMID- 12616118
TI  - Long-term impact of pneumoperitoneum used for laparoscopic donor nephrectomy on
      renal function and histomorphology in donor and recipient rats.
AB  - OBJECTIVE: To investigate the long-term impact of pneumoperitoneum used for
      laparoscopic donor nephrectomy on renal function and histomorphology in donor and
      recipient. SUMMARY BACKGROUND DATA: Laparoscopic donor nephrectomy has the
      potential to increase the number of living kidney donations by reducing donor
      morbidity. However, function of laparoscopically procured kidneys might be at
      risk due to ischemia as a consequence of elevated intra-abdominal pressure during
      laparoscopy. METHODS: In experiment 1, 30 Brown Norway rats were randomized to
      three procedures: 2 hours of CO2 insufflation, 2 hours of helium insufflation,
      and 2 hours of gasless laparoscopy. After this, a unilateral nephrectomy was
      performed in all animals. Another six rats were used as controls. In experiment
      2, 36 donor Brown Norway rats were subjected to a similar insufflation protocol,
      but after nephrectomy a syngeneic renal transplantation was performed. All rats
      had a follow-up period of 12 months. Urine and blood samples were collected each
      month for determination of renal function. After 1 year, donor and recipient
      kidneys were removed for histomorphologic and immunohistochemical analysis.
      RESULTS: In donors as well as in recipients, no significant changes in serum
      creatinine, proteinuria, or glomerular filtration rate were detected between the
      CO2, the helium, and the gasless control group after 1 year. No histologic
      abnormalities due to abdominal gas insufflation were found. Immunohistochemical
      analysis did not show significant differences in the number of infiltrating cells
      (CD4, CD8, ED1, OX62, and OX6) and adhesion molecule expression (ICAM-1) between
      the three groups. CONCLUSIONS: Abdominal gas insufflation does not impair renal
      function in the donor 1 year after LDN. One year after transplantation, no
      differences in renal function or histomorphology were detected between kidney
      grafts exposed to either pneumoperitoneum or a gasless procedure.

PMID- 12616119
TI  - Does using a laparoscopic approach to cholecystectomy decrease the risk of
      surgical site infection?
AB  - OBJECTIVE: To assess the impact of laparoscopy on surgical site infections (SSIs)
      following cholecystectomy in a large population of patients. SUMMARY BACKGROUND
      DATA: Previous investigations have demonstrated that laparoscopic cholecystectomy
      is associated with a shorter postoperative stay and fewer overall complications.
      Less is known about the impact of laparoscopy on the risk for SSIs. METHODS:
      Epidemiologic analysis was performed on data collected during a 7-year period
      (1992-1999) by participating hospitals in the National Nosocomial Infections
      Surveillance (NNIS) System in the United States. RESULTS: For 54,504 inpatient
      cholecystectomy procedures reported, use of the laparoscopic technique increased
      from 59% in 1992 to 79% in 1999. The overall rate of SSI was significantly lower
      for laparoscopic cholecystectomy than for open cholecystectomy. Overall,
      infecting organisms were similar for both approaches. Even after controlling for
      other significant factors, the risk for SSI was lower in patients undergoing the
      laparoscopic technique than the open technique. CONCLUSIONS: Laparoscopic
      cholecystectomy is associated with a lower risk for SSI than open
      cholecystectomy, even after adjusting for other risk factors. For interhospital
      comparisons, SSI rates following cholecystectomy should be stratified by the type
      of technique.

PMID- 12616120
TI  - Colon and rectal surgery without mechanical bowel preparation: a randomized
      prospective trial.
AB  - OBJECTIVE: To assess whether elective colon and rectal surgery can be safely
      performed without preoperative mechanical bowel preparation. SUMMARY BACKGROUND
      DATA: Mechanical bowel preparation is routinely done before colon and rectal
      surgery, aimed at reducing the risk of postoperative infectious complications.
      However, in cases of penetrating colon trauma, primary colonic anastomosis has
      proven to be safe even though the bowel is not prepared. METHODS: Patients
      undergoing elective colon and rectal resections with primary anastomosis were
      prospectively randomized into two groups. Group A had mechanical bowel
      preparation with polyethylene glycol before surgery, and group B had their
      surgery without preoperative mechanical bowel preparation. Patients were followed
      up for 30 days for wound, anastomotic, and intra-abdominal infectious
      complications. RESULTS: Three hundred eighty patients were included in the study,
      187 in group A and 193 in group B. Demographic characteristics, indications for
      surgery, and type of surgical procedure did not significantly differ between the
      two groups. Colo-colonic or colorectal anastomosis was performed in 63% of the
      patients in group A and 66% in group B. There was no difference in the rate of
      surgical infectious complications between the two groups. The overall infectious
      complications rate was 10.2% in group A and 8.8% in group B. Wound infection,
      anastomotic leak, and intra-abdominal abscess occurred in 6.4%, 3.7%, and 1.1%
      versus 5.7%, 2.1%, and 1%, respectively. CONCLUSIONS: These results suggest that
      elective colon and rectal surgery may be safely performed without mechanical
      preparation.

PMID- 12616122
TI  - Prognosis after hepatic resection for stage IVA hepatocellular carcinoma: a need
      for reclassification.
AB  - OBJECTIVE: To evaluate whether the prognosis of the four categories of patients
      with hepatocellular carcinoma (HCC) classified as stage IVA in the tumor-node
      metastasis (TNM) classification of the International Union Against Cancer (UICC)
      is homogeneous. SUMMARY BACKGROUND DATA: Hepatic resection has been proposed as
      the treatment of choice for patients with TNM stage IVA HCC, which consists of
      four different categories. It is unknown whether the prognosis of the four
      categories of patients is homogeneous. METHODS: Clinicopathologic and follow-up
      data of 106 patients with resection of stage IVA HCC from 1989 to 2000 were
      prospectively collected. Survival results of the four categories of stage IVA
      patients were compared. RESULTS: Among stage IVA patients, survival was
      significantly worse in those with tumors involving a major branch of the portal
      or hepatic veins than in those with tumors invading adjacent organs, bilobar
      multiple tumors, or perforated visceral peritoneum. There were no significant
      differences in survival among the latter three groups. By Cox regression
      analysis, invasion of the portal or hepatic veins and presence of cirrhosis were
      independent adverse prognostic factors of overall survival among stage IVA
      patients, and invasion of the portal or hepatic veins was the only significant
      adverse prognostic factor of disease-free survival. CONCLUSIONS: The prognosis of
      the four categories of patients with stage IVA HCC under the current UICC TNM
      staging was not homogeneous. A refined classification of stage IV HCC is needed
      to take into consideration the worse prognosis associated with tumor invasion of
      a major branch of the portal or hepatic veins.

PMID- 12616121
TI  - Prognostic value of postoperative detection of blood circulating tumor cells in
      patients with colorectal cancer operated on for cure.
AB  - OBJECTIVE: To assess whether postoperative detection of circulating tumor cells
      in peripheral blood influenced the prognosis of patients with colorectal cancer
      after radical surgery. SUMMARY BACKGROUND DATA: In a previous study, the authors
      demonstrated that baseline detection of blood circulating tumor cells does not
      have prognostic significance in patients with colorectal cancer. However,
      surgical procedures may increase tumor cell detachment and mobilization. METHODS:
      Sixty-six patients with histologically confirmed colorectal cancer operated on
      for cure were included in this study. Circulating tumor cells were detected by
      means of reverse transcriptase-polymerase chain reaction targeting to
      carcinoembryonic antigen messenger RNA in peripheral blood samples obtained 24
      hours after surgery. Endpoints of the study were tumor recurrence, overall
      survival, and cancer-related survival. Univariate (Kaplan-Meier method) and
      multivariate (Cox regression model) analyses were performed. RESULTS: After a
      median follow-up of 36 months, 15 patients (23%) had tumor relapse and 14 had
      died (21%), 8 of them from a cancer-related cause. Cox regression analysis
      identified lymph node metastases and gender as independent predictors of tumor
      recurrence and cancer-related survival, whereas overall survival was dependent on
      the degree of differentiation of the primary tumor. More importantly, the
      presence of circulating tumor cells after surgery had no prognostic influence on
      tumor recurrence, overall survival, or cancer-related survival. CONCLUSIONS:
      Postoperative detection of blood circulating tumor cells had no prognostic
      significance in patients with colorectal cancer operated on for cure.

PMID- 12616123
TI  - Increased muscle proteasome activity correlates with disease severity in gastric
      cancer patients.
AB  - OBJECTIVE: To investigate the state of activation of the ATP-ubiquitin-dependent
      proteolytic system in the skeletal muscle of gastric cancer patients. SUMMARY
      BACKGROUND DATA: Muscle wasting in experimental cancer cachexia is frequently
      associated with hyperactivation of the ATP-dependent ubiquitin-proteasome
      proteolytic system. Increased muscle ubiquitin mRNA levels have been previously
      shown in gastric cancer patients, suggesting that this proteolytic system might
      be modulated also in human cancer. METHODS: Biopsies of the rectus abdominis
      muscle were obtained intraoperatively from 23 gastric cancer patients and 14
      subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin
      mRNA expression and proteasome proteolytic activities were assessed. RESULTS:
      Muscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to
      controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin
      like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased
      in gastric cancer patients with respect to controls. Advanced tumor stage, poor
      nutritional status, and age more than 50 years were associated with significantly
      higher CTL activity but had no influence on TL and PGP activity. CONCLUSIONS:
      These results confirm the involvement of the ubiquitin-proteasome proteolytic
      system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia.
      The observation that perturbations of this pathway in gastric cancer patients
      occur even before clinical evidence of body wasting supports the thinking that
      specific pharmacologic and metabolic approaches aimed at counteracting the
      upregulation of this pathway should be undertaken as early as cancer is
      diagnosed.

PMID- 12616124
TI  - Lymphoscintigraphic visualization of internal mammary nodes with subtumoral
      injection of radiocolloid in patients with breast cancer.
AB  - OBJECTIVE: To determine whether subtumoral injection of radiocolloid is useful
      for lymphoscintigraphic visualization of the internal mammary node and in
      sentinel lymph node (SLN) biopsy of the axilla in breast cancer patients. SUMMARY
      BACKGROUND DATA: The presence of retromammary lymphatics connecting to the
      axillary and internal mammary basins has been demonstrated by early anatomic
      studies. Thus, it is hypothesized that some lymph, especially that from the
      parenchyma under the tumor, may drain into both the axillary and internal mammary
      basins. METHODS: Patients (n = 196) with T1-2, N0 breast cancer underwent
      preoperative lymphoscintigraphy with radiocolloid (technetium 99m tin colloid)
      injection into various sites of the breast, followed by SLN biopsy using the
      combined method with blue dye. Patients were divided into four groups: group A (n
      = 41), peritumoral injection of both radiocolloid and blue dye; group B (n = 70),
      periareolar radiocolloid and peritumoral blue dye; group C (n = 45), intradermal
      radiocolloid and periareolar blue dye; and group D (n = 40), subtumoral
      radiocolloid and intradermal blue dye. A retrospective analysis of 1,297 breast
      cancer patients who underwent extended radical mastectomy with internal mammary
      node dissection was also conducted to determine the relationship between vertical
      tumor location (superficial or deep) and frequency of axillary and internal
      mammary node metastases. RESULTS: One patient (2%) in group A, 3 (4%) in group B,
      0 (0%) in group C, and 15 (38%) in group D exhibited hot spots in the internal
      mammary region on lymphoscintigraphy (P <.001, group D vs. the other groups). The
      concordance rate of radiocolloid and blue dye methods in detection of SLNs in the
      axillary basin was significantly lower in group D than in the other groups. In
      contrast, the mismatch rate (some SLNs were identified by radiocolloid and other
      SLNs were identified by blue dye, but no SLN was identified by both in the same
      patient) was significantly higher in group D than in the other groups. In
      patients treated with extended radical mastectomy, positivity of axillary and
      internal mammary metastases was significantly higher in patients (n = 215) with
      deep tumors than those (n = 368) with superficial tumors. CONCLUSIONS: These
      results suggest the presence of a retromammary lymphatic pathway from the deep
      portion of the breast to both axillary and internal mammary basins, which is
      distinct from the superficial pathway. Therefore, SLN biopsy with a combination
      of subtumoral and other (peritumoral, dermal, or areolar) injections of
      radiocolloid will improve both axillary and internal mammary nodal staging.

PMID- 12616125
TI  - Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency,
      pattern of occurrence and recurrence, and optimal strategy for neck dissection.
AB  - OBJECTIVE: To determine the frequency and pattern of lymph node metastasis (LNM)
      from papillary thyroid microcarcinoma (PTMC) and the results of node dissection,
      and to establish the optimal strategy for neck dissection in these patients.
      SUMMARY BACKGROUND DATA: Most PTMCs carry a favorable prognosis, but a few
      present with palpable lymphadenopathy. Patients with LNM are at risk for nodal
      recurrence, although they do not have higher mortality. The frequency and pattern
      of LNM from PTMC and the results of node dissection are not well established.
      METHODS: The frequency and pattern of LNM from 259 PTMCs were analyzed according
      to the size and location of the primary tumor. Of the 259, 24 with palpable nodes
      underwent therapeutic node dissection and the other 235 patients without palpable
      nodes underwent prophylactic node dissection. The authors compared the results of
      node dissection between the therapeutic group and the prophylactic group, and
      between PTMCs 5 mm or smaller and PTMCs larger than 5 mm. The authors also
      compared nodal recurrence between the prophylactic group and a no-lymph-node
      dissection group (155 PTMCs). RESULTS: Overall, 64.1% (166/259) and 44.5%
      (93/209) had node involvement of the central and ipsilateral lateral compartment,
      respectively. Pretracheal (43.2%), ipsilateral central (36.3%), and ipsilateral
      mid-lower (37.8%) jugular were more commonly involved. LNM was more frequent in
      the therapeutic group than in the prophylactic group (95.8% vs. 60.9% for central
      compartment, 83.3% vs. 39.5% for ipsilateral lateral compartment). Nodal
      recurrence was more common in the therapeutic group than in the prophylactic
      group (16.7% vs. 0.43%), but did not differ between the prophylactic group and
      the no-dissection group (0.43% vs. 0.65%). The tumor size did not influence nodal
      recurrence. Nodal recurrence preferentially occurred in ipsilateral mid-lower
      jugular nodes. CONCLUSIONS: Patients who have PTMC presenting with palpable
      lymphadenopathy should have therapeutic node dissection. Prophylactic node
      dissection is not beneficial in those without palpable lymphadenopathy.

PMID- 12616126
TI  - Regional and systemic cytokine responses to acute inflammation of the vermiform
      appendix.
AB  - OBJECTIVE: To measure local (peritoneal fluid) and systemic (plasma) cytokine
      profiles in patients with infection-inflammation of the vermiform appendix, a
      relatively mild, localized inflammatory process. SUMMARY BACKGROUND DATA: The
      systemic host response to invading microorganisms, often termed the systemic
      inflammatory response syndrome (SIRS), includes changes in heart rate,
      respiratory rate, body temperature, and circulating white blood cell numbers.
      Although these changes can be induced experimentally by administering
      proinflammatory cytokines, the mediators that appear in the bloodstream during
      early, localized infection in humans have not been defined. METHODS: The authors
      studied 56 patients with pathologically proven appendicitis. Blood was obtained
      before the induction of anesthesia, when 82% of the patients met the criteria for
      SIRS. Peritoneal fluid (PF) was obtained by intraoperative lavage. Cytokines were
      measured by immunoassay. To assess the net impact of the mediators within plasma,
      the authors studied the ability of patient plasma to augment or suppress
      bacterial lipopolysaccharide (LPS) stimulation of monocytes in vitro. RESULTS: Of
      the proinflammatory cytokines, tumor necrosis factor-alpha was present in PF but
      not in plasma, interleukin (IL)-1beta and interferon-gamma were found in low
      concentrations in both PF and plasma, and IL-12 (p70) was detectable in plasma
      but not PF. In contrast, IL-6 and IL-1 receptor antagonist (IL-1ra) were the most
      abundant cytokines in the PF and plasma, and the concentrations of IL-4 and IL-10
      were also elevated in both compartments. Patients with more severe appendicitis
      had higher plasma levels of IL-6 and IL-10 and lower plasma levels of IL-12 and
      interferon-gamma than did those with uncomplicated disease. Patient plasma
      inhibited LPS-induced stimulation of a monocyte cell line, and this inhibition
      was accentuated by complicated disease. CONCLUSIONS: As judged from the pattern
      of soluble cytokines in plasma and the effect of the plasma on monocyte
      activation by LPS, mild, localized infection can induce a systemic response that
      is predominantly anti-inflammatory.

PMID- 12616127
TI  - Perioperative erythropoietin administration in patients with gastrointestinal
      tract cancer: prospective randomized double-blind study.
AB  - OBJECTIVE: To investigate the effect of recombinant human erythropoietin (r
      HuEPO) administration on perioperative hemoglobin concentrations and on the
      number of blood transfusions in patients undergoing surgery for gastrointestinal
      tract malignancies. SUMMARY BACKGROUND DATA: Erythropoietin has been shown to
      improve the yield of autologously predonated blood and to reduce the subsequent
      requirements for homologous blood transfusions in cancer patients. METHODS: In
      this double-blind placebo-controlled study, 31 cancer patients received
      subcutaneous r-HuEPO in a dose of 300 IU/kg body weight plus 100 mg iron
      intravenously (study group) and 32 patients received placebo medication and iron
      (control group). All patients received the medications daily for at least 7 days
      before and 7 days after the operation. RESULTS: Patients who received
      erythropoietin received significantly fewer transfusions intraoperatively and
      postoperatively. Postoperatively, the study group had significantly higher
      hematocrit, hemoglobin, and reticulocyte count values compared to the control
      group. The use of erythropoietin was also associated with a reduced number of
      postoperative complications and improved 1-year survival. CONCLUSIONS: Patients
      with gastrointestinal tract cancer and mild anemia benefit from perioperative
      erythropoietin administration in terms of stimulated erythropoiesis, reduction in
      the number of blood transfusions, and a favorable outcome.

PMID- 12616129
TI  - Modulation of portal graft inflow: a necessity in adult living-donor liver
      transplantation?
AB  - OBJECTIVE: To evaluate the clinical significance of modulating the recipient
      portal inflow (rPVF) through perioperative ligation of the splenic artery in
      adult living-donor liver transplantation (ALDLTx) by focusing on vascular
      complications, intractable ascites production, and the prevention of small-for
      size syndrome (SFSS). SUMMARY BACKGROUND DATA: In ALDLTx, portal graft flow is
      enhanced to at least twice the donor value, raising the total liver inflow.
      Recipient hepatic arterial flow (rHAF) is lower than expected. Portal
      hyperperfusion of small grafts in larger recipients is thought to be one of the
      main causes of posttransplant graft dysfunction/SFSS. METHODS: Seventeen ALDLTx
      were reviewed for a minimum of 2 months. Patients were divided retrospectively
      into two groups: G1 (n = 7), without modulation of rPVF, and G2 (n = 10), with
      splenic artery ligation to decrease rPVF perioperatively. Donor and recipient
      hepatic hemodynamics were evaluated against graft function and outcome, including
      correlations between rPVF, graft weight, graft:recipient body weight ratio, and
      recipient weight. RESULTS: Following portal and arterial reperfusion, mean rPVF
      and rPVF/graft weight were much higher than in the donors, whereas mean rHAF and
      rHAF/graft weight were much lower. No differences were found between groups,
      except for rPVF and rHAF, which were much more higher and lower, respectively,
      before splenic artery ligation. In G1 patients, SFSS was seen in two patients and
      vascular complications occurred in two others. In G2 patients, splenic artery
      ligation permitted a significant decrease in rPVF, an improvement in rHAF, and
      the resolution of refractory ascites. Neither SFSS nor vascular complications
      were seen in G2 patients. CONCLUSIONS: When a suboptimal graft:recipient body
      weight ratio is accompanied by high rPVF in ALDLTx, the portal flow should be
      modulated perioperatively; splenic artery ligation is a simple and safe method
      that is sufficient to allow this modulation in most patients.

PMID- 12616130
TI  - Definitive surgical treatment of infected or exposed ventral hernia mesh.
AB  - OBJECTIVE: To discuss the difficulties in dealing with infected or exposed
      ventral hernia mesh, and to illustrate one solution using an autogenous abdominal
      wall reconstruction technique. SUMMARY BACKGROUND DATA: The definitive treatment
      for any infected prosthetic material in the body is removal and substitution.
      When ventral hernia mesh becomes exposed or infected, its removal requires a
      solution to prevent a subsequent hernia or evisceration. METHODS: Eleven patients
      with ventral hernia mesh that was exposed, nonincorporated, with chronic
      drainage, or associated with a spontaneous enterocutaneous fistula were referred
      by their initial surgeons after failed local wound care for definitive
      management. The patients were treated with radical en bloc excision of mesh and
      scarred fascia followed by immediate abdominal wall reconstruction using
      bilateral sliding rectus abdominis myofascial advancement flaps. RESULTS: Four of
      the 11 patients treated for infected mesh additionally required a bowel
      resection. Transverse defect size ranged from 8 to 18 cm (average 13 cm). Average
      procedure duration was 3 hours without bowel repair and 5 hours with bowel
      repair. Postoperative length of stay was 5 to 7 days without bowel repair and 7
      to 9 days with bowel repair. Complications included hernia recurrence in one case
      and stitch abscesses in two cases. Follow-up ranges from 6 to 54 months (average
      24 months). CONCLUSIONS: Removal of infected mesh and autogenous flap
      reconstruction is a safe, reliable, and one-step surgical solution to the problem
      of infected abdominal wall mesh.

PMID- 12616128
TI  - Gene expression patterns in skeletal muscle of thermally injured children treated
      with oxandrolone.
AB  - OBJECTIVE: To analyze gene expression patterns in skeletal muscle from burned
      children. SUMMARY BACKGROUND DATA: Analysis of gene expression patterns in
      skeletal muscle from burned children can help provide a fundamental understanding
      of muscle wasting at the molecular level. This study is the first to use such an
      approach in burned children receiving anabolic treatment. METHODS: Children who
      received 0.1 mg/kg oxandrolone twice a day (n = 7) were compared to placebo (n =
      7). Net protein balance was determined before and after treatment with
      oxandrolone. Total RNA, extracted from muscle biopsies obtained from burned
      children age 3 to 18 years, was purified, reverse transcribed, and biotinylated
      cRNA hybridized to the human high-density oligonucleotide array (U95Av2). Western
      blot analysis verified the mRNA changes at their protein level. RESULTS: DNA
      microarray analysis showed two genes significantly changed in muscle from burned
      children receiving placebo, while the expression of 21 genes was altered with
      oxandrolone. Muscle net protein balance increased with oxandrolone treatment
      compared to placebo. CONCLUSIONS: DNA microarray technology will help identify
      molecular changes that can serve as targets for new therapies to attenuate muscle
      wasting in severely burned children and thus improve recovery and early
      rehabilitation.

PMID- 12616131
TI  - Virtual reality applied to procedural testing: the next era.
AB  - OBJECTIVE: To establish the construct validity of a virtual reality-based upper
      gastrointestinal endoscopy simulator as a tool for the skills training of
      residents. SUMMARY BACKGROUND DATA: Previous studies have demonstrated the
      relevance of virtual reality training as an adjunct to traditional operating room
      learning for residents. The use of specific task trainers, which have the ability
      to objectively analyze and track user performance, has been shown to demonstrate
      improvements in performance over time. Using this off-line technology can lessen
      the financial and ethical concerns of using operative time to teach basic skills.
      METHODS: Thirty-five residents and fellows from General Surgery and
      Gastrointestinal Medicine were recruited for this study. Their performance on
      virtual reality upper endoscopy tasks was analyzed by computer. Assessments were
      made on parameters such as time needed to finish the examination, completeness of
      the examination, and number of wall collisions. Subjective experiences were
      queried through questionnaires. Users were grouped according to their prior level
      of experience performing endoscopy. RESULTS: Construct validation of this
      simulator was demonstrated. Performance on visualization and biopsy tasks varied
      directly with the subjects' prior experience level. Subjective responses
      indicated that novice and intermediate users felt the simulation to be a useful
      experience, and that they would use the equipment in their off time if it were
      available. CONCLUSIONS: Virtual reality simulation may be a useful adjunct to
      traditional operating room experiences. Construct validity testing demonstrates
      the efficacy of this device. Similar objective methods of skills evaluation may
      be useful as part of a residency skills curriculum and as a means of procedural
      skills testing.

PMID- 12616132
TI  - Herpes simplex virus type 2 infection among bar and hotel workers in northern
      Tanzania: prevalence and risk factors.
AB  - BACKGROUND: Type-specific serological tests have allowed for a better
      understanding of the epidemiology of herpes simplex virus type 2 (HSV-2)
      infection in Africa. GOAL: The goal was to determine risk factors for HSV-2 among
      bar and hotel workers in Moshi, Tanzania. STUDY DESIGN: A cross-sectional study
      was conducted involving 515 workers in randomly selected bars and hotels in
      Moshi. RESULTS: The seroprevalence of HSV-2 was 43.5%. Women were more likely to
      be HSV-2-seropositive than men (age-adjusted OR = 3.8; 95% CI = 2.5-5.8). In
      multivariate analyses, age was positively associated with HSV-2 in both women and
      men. HIV-1-seropositive women had a significantly increased risk of HSV-2
      infection (adjusted OR = 2.8; 95% CI = 1.5-5.1). Other predictors of HSV-2 were
      religion and sexual behavior for women and level of education, frequency of
      alcohol use, and concurrent partners for men. CONCLUSION: The most common genital
      infection was that with HSV-2. Control of HSV-2 might be an important strategy
      for HIV-1 infection prevention in this population.

PMID- 12616133
TI  - Answering frequently asked questions about HPV.

PMID- 12616134
TI  - Prevalence of Chlamydia trachomatis infection in registered female sex workers in
      northern Mexico.
AB  - BACKGROUND: Little is known about the epidemiology of Chlamydia trachomatis
      infection in female sex workers (FSWs) in Mexico. GOAL: The goal of the study was
      to determine the prevalence of C trachomatis infection in registered FSWs from
      northern Mexico and to determine the sociodemographic characteristics associated
      with the infection. STUDY DESIGN: An enzyme immunoassay was used to test 354 FSWs
      in three northern Mexican cities for cervical C trachomatis infection. All
      participants were registered in a government health office. Recruitment was
      consecutive and voluntary. The association between clinical and sociodemographic
      characteristics of FSWs and infection was evaluated. RESULTS: The overall
      prevalence of C trachomatis infection among participants in the three cities was
      12.4%. Women of low socioeconomic level and those younger than 25 years were the
      most frequently infected. Among FSWs in Durango, a higher frequency of C
      trachomatis infection was found for those who did not use condoms. CONCLUSION: C
      trachomatis is an important pathogen in the sexually transmitted diseases of
      registered FSWs in northern Mexico.

PMID- 12616135
TI  - Factors associated with human herpesvirus type 8 infection in an injecting drug
      user cohort.
AB  - BACKGROUND: Human herpesvirus type 8 (HHV-8) has been infrequently studied in
      injecting drug user (IDU) populations. GOAL: To estimate the seroprevalence of
      HHV-8 and risk factors for infection in a cohort of 2,946 IDUs. STUDY DESIGN: In
      this nested cross-sectional study of 390 IDUs, lytic HHV-8 indirect
      immunofluorescence assay (IFA) was utilized to estimate the HHV-8 seroprevalence.
      Multivariate logistic regression was used to assess risk factors for infection.
      RESULTS: The HHV-8 seroprevalence among the IDUs examined in 1988 was 11.5% (95%
      confidence interval, 8.5-15.13). HHV-8 seroprevalence in this population was
      associated with being female (OR = 2.2; = 0.080), having a larger body mass index
      (OR = 3.0; = 0.053), and history of genital warts (OR = 4.0; = 0.023). Injection
      of any drug more than daily exhibited an inverse effect on HHV-8 seropositivity
      (OR = 0.5; = 0.085). CONCLUSION: The seroprevalence of HHV-8 in this population
      is similar to that seen in the general population, with risk factors being more
      consistent with sexual behaviors than injection drug use.

PMID- 12616136
TI  - Genotyping of Chlamydia trachomatis would improve contact tracing.
AB  - BACKGROUND: The reported number of Chlamydia trachomatis genital infections has
      increased 15% annually since 1997 in Sweden. Inaccurate partner notification
      might be one reason. GOAL: The goals were to determine if genotyping of C
      trachomatis would improve partner notification and to study the duration of
      infection. STUDY DESIGN: Sexual networks were constructed. C trachomatis isolates
      from 231 individuals attending the Orebro STD clinic during 1 year were typed by
      sequencing of the omp1 gene. RESULTS: All individuals were traced and diagnoses
      were established in 30 of 161 networks. More than one genotype was seen in seven
      networks. The mean duration of C trachomatis infection in each network was
      calculated to be 23 weeks. CONCLUSION: Genotyping could be a useful tool in
      partner notification when there are discrepant or uncommon genotypes. Limited
      clinic catchment areas create information difficulties that obstruct accurate
      contact tracing.

PMID- 12616137
TI  - Older partners and STD prevalence among pregnant African American teens.
AB  - BACKGROUND: Several recent studies have addressed the question of whether
      adolescent females who have sex with older partners have a greater risk of
      sexually transmitted disease (STD) acquisition. GOAL: The goal was to identify
      differences in STD prevalence and selected measures of behavioral risk between
      unmarried pregnant African American adolescent females reporting sex with older
      partners and those reporting sex with similar-age partners. STUDY DESIGN:
      Adolescents (n = 169) were recruited during their first prenatal visit.
      Adolescents completed a self-administered survey and a face-to-face interview and
      provided urine specimens for nucleic acid amplification assays. RESULTS:
      Approximately 65% of adolescents reported that their male sex partners were >/=2
      years older, while 35% reported having similar-age male sex partners. In age
      adjusted analyses, adolescents with older partners were four times more likely to
      test positive for chlamydia (P < 0.04) and were more than twice as likely to
      report that their partner was also having sex with other women (P < 0.04). With
      use of a 30-day recall period, the mean number of unprotected vaginal sexual
      encounters among adolescents with older partners was 4.1, as compared to a mean
      of 6.9 among those reporting similar-age partners; this difference approached
      significance (P = 0.051). Prevalence of trichomoniasis as well as scale measures
      of adolescents' self-efficacy for condom negotiation and frequency of sexual
      communication with partners did not differ between those adolescents with older
      or similar-age male sex partners. CONCLUSION: In resource-constrained clinical
      settings, one implication of these findings is that pregnant adolescents
      reporting older partners may be a priority for targeted delivery of partner
      services. More frequent screening for chlamydia may also be cost-effective for
      pregnant adolescents with older partners.

PMID- 12616138
TI  - Do older partners place adolescent girls at higher risk for STDs?

PMID- 12616139
TI  - Sexual behavior of older women: results of a random-digit-dialing survey of 2,000
      women in the United States.
AB  - BACKGROUND: There are few reports describing sexual activity among women older
      than 50 years of age. GOAL: The goal of the study was to describe sexual
      practices and health behaviors of women aged 18-94 years, highlighting
      characteristics of older women (aged 60-94 years). STUDY DESIGN: The study
      involved a random-digit-dialing survey (N = 2,000) of women aged 18-94 years
      living in the continental United States. RESULTS: Frequency and occurrence of
      sexual activity decreased with age. Married women in every age group were more
      likely to have engaged in recent sexual activity. Condom use decreased with age
      and lubricant use increased with age. Over one-third of all women reported
      douching in a typical month, and there was no trend with age. CONCLUSION: Women
      in older age groups vary greatly in terms of sexual practices and health
      behaviors.

PMID- 12616140
TI  - Gap length: an important factor in sexually transmitted disease transmission.
AB  - BACKGROUND: Sexually transmitted disease (STD) transmission may occur if the time
      between dissolution and formation of sex partnerships, the gap, is shorter than
      mean duration of infectivity of STDs. GOAL: The goal was to examine gaps reported
      by a nationally representative sample of reproductive-age women. STUDY DESIGN:
      Data on women's sex partnership dynamics were collected from the 1995 National
      Survey of Family Growth (NSFG). Gap was defined as the time between first sex
      with current/most recent partner and last sex with previous partner. RESULTS: One
      third of women reported negative gaps (concurrent partnerships). Among the women
      who reported positive gaps (serial monogamy), more than half switched partners in
      time periods shorter than the mean infectivity periods of some bacterial STDs.
      Adolescents and women with past STD diagnoses reported shorter gaps than any
      other group. CONCLUSION: Given that many STDs are often asymptomatic, short gaps
      may present a problem if women and their partners are not routinely screened for
      STDs.

PMID- 12616142
TI  - Genital herpes simplex infections: some therapeutic dilemmas.

PMID- 12616141
TI  - Patients' preference of valacyclovir once-daily suppressive therapy versus twice
      daily episodic therapy for recurrent genital herpes: a randomized study.
AB  - BACKGROUND: Valacyclovir is effective for suppressive and episodic treatment of
      recurrent genital herpes. Few data on patients' treatment strategy preferences
      are available. GOAL: The goal was to assess patients' preference, satisfaction,
      and quality of life with suppressive versus episodic treatment of recurrent
      genital herpes. STUDY DESIGN: This was a multicenter, open-label, randomized, two
      arm, crossover 48-week study involving 225 patients with genital herpes. RESULTS:
      Suppressive valacyclovir therapy was preferred to episodic valacyclovir treatment
      by 72% of patients (P < 0.001). Overall treatment satisfaction and quality of
      life were significantly greater during suppressive therapy (P < 0.001 and P =
      0.002, respectively). The risk of recurrence during the first 24 weeks was
      reduced by 78% with suppressive therapy (P < 0.001). Significantly fewer patients
      experienced recurrences during suppressive treatment than with episodic treatment
      (P < 0.001). Valacyclovir was well tolerated. CONCLUSIONS: Suppressive
      valacyclovir was preferred to episodic therapy by most patients. Suppressive
      therapy was associated with increased treatment satisfaction, and decreased risk
      and lower frequency of recurrences.

PMID- 12616143
TI  - Discordant sexual partnering: a study of high-risk adolescents in San Francisco.
AB  - BACKGROUND: In sexual networks, bridge members engaging in discordant partnering
      play key roles in maintaining and transmitting sexually transmitted infections
      (STIs) within a population. GOAL: The goal was to characterize adolescents likely
      to engage in discordant sexual relationships with main and casual sex partners.
      STUDY DESIGN: Egocentric data about adolescents and their most recent sex
      partner(s) collected over 6 months were analyzed with use of logistic regression.
      RESULTS: History of STI, drug use, and meeting venue were significantly
      associated with discordant sexual partnering among high-risk adolescents.
      Participants with histories of high-risk behavior, e.g., hard drug use or STI,
      were more likely to have had a recent, dissimilar partner than those with lower
      risk profiles. Particular meeting venues, such as clubs and street locations,
      were more likely to be associated with age-discordant, race-discordant, and drug
      use-discordant partnerships for females. CONCLUSION: Bridge members of adolescent
      sexual networks were more likely to have a history of STI, hard drug use, or
      meeting their sex partner through particular venues.

PMID- 12616144
TI  - Association between HIV-1 infection, the etiology of genital ulcer disease, and
      response to syndromic management.
AB  - BACKGROUND: Reports on the effect of HIV-1 infection on healing rates of ulcers
      are conflicting. GOAL: The goal was to determine the etiology and response to
      treatment of genital ulcer disease (GUD) in relation to HIV-1 infection. STUDY
      DESIGN: This was a cohort study of patients with GUD treated with local syndromic
      management protocols. RESULTS: Among the 587 recruited, the prevalences of
      infections due to HSV, Treponema pallidum, Chlamydia trachomatis (lymphogranuloma
      venereum [LGV]), Haemophilus ducreyi, Calymmatobacterium granulomatis, and HIV-1
      were 48%, 14%, 11%, 10%, 1%, and 75%, respectively. The prevalence T. pallidum of
      was higher among men (P = 0.03), and an association was seen among HIV-1
      seronegatives on univariate and multivariate analyses (P < 0.001; = 0.01). The
      prevalence of C trachomatis (LGV) was higher among females (P = 0.004), and an
      association was seen among HIV-1-seropositives on univariate analysis (P = 0.04).
      At follow-up, 40/407 (10%) showed a decreased healing tendency, not associated
      with ulcer etiology or HIV-1 seropositivity. CONCLUSION: Response to syndromic
      management of GUD was acceptable and not associated with HIV-1 coinfection.

PMID- 12616145
TI  - Poor sensitivity of polymerase chain reaction assays of genital skin swabs and
      urine to detect HPV 6 and 11 DNA in men.
AB  - BACKGROUND: A possible reason for the failure to detect human papillomavirus
      (HPV) DNA in asymptomatic men who are likely to be infected is the sensitivity of
      the detection methods. GOAL: The goal of this study was to identify a method for
      sampling the anogenital skin of men that was simple and well tolerated and that
      would permit the detection of asymptomatic or subclinical HPV infection, which is
      thought to occur commonly in sexually active men. STUDY DESIGN: Swabs of genital
      skin and urine from men at high and low risk of infection with types 6 and 11
      were tested for HPV by polymerase chain reaction. RESULTS: These specimens had a
      low sensitivity for HPV detection, often because inadequate material was
      collected on the swab. CONCLUSION: Noninvasive sampling of genital skin to
      identify individuals with subclinical HPV infection remains a challenge. Future
      studies should involve the use of more abrasive sampling devices (such as
      cytobrushes), perhaps combined with some type of soap to dislodge more epithelial
      cells.

PMID- 12616146
TI  - The molecular epidemiology of genital Chlamydia trachomatis in the greater
      Reykjavik area, Iceland.
AB  - BACKGROUND: The diversity in MOMP (major outer membrane protein) of Chlamydia
      trachomatis is thought to be necessary for the bacteria to survive in its
      environment. The rate of change in the omp1 gene (coding for MOMP) is not known.
      Iceland offers a good opportunity to study the epidemiology of chlamydial
      infections because the population is small (280,000) and geographically well
      defined. GOAL: The goal was to determine the number and distribution of genotypes
      in a population attending the STD clinic in Reykjavik and to assess changes in
      omp1 sequences over a period of 2 years. STUDY DESIGN: Three-hundred thirty
      isolates of C trachomatis collected periodically from January 1999 to January
      2001 were omp1 genotyped with nested PCR and sequencing. RESULTS: The serotypes
      found, in descending order of prevalence, were E, D, J, F, K, G, H, and I.
      Eighteen distinctive genotypes were found. During the study period no significant
      changes in frequency of genotypes were noted, and introduction of new or changed
      genotypes was not observed. CONCLUSION: The results indicate a relatively stable
      situation of genotypes and suggest an ecological advantage of serotype E.

PMID- 12616147
TI  - Glycosidase and proteinase activity of anaerobic gram-negative bacteria isolated
      from women with bacterial vaginosis.
AB  - BACKGROUND: It is known that glycosidases and proteases are produced by the
      anaerobic gram-negative bacteria associated with bacterial vaginosis (BV). We
      hypothesized that these enzymes enzymatically degrade mucins, thereby destroying
      the mucus gel that otherwise helps protect against sexually transmitted
      pathogens, including HIV. GOAL: The goal was to determine glycosidase and
      protease production by vaginal bacteria associated with BV and to compare these
      with symptoms and signs of abnormal discharge and to test vaginal fluid
      viscosity. STUDY DESIGN: The anaerobic gram-negative rods recovered from the
      vaginas of 153 women with normal flora, intermediate flora, or BV were tested for
      production of sialidase, fucosidase, galactosidase, glucosaminidase, and glycine
      and arginine aminopeptidases. RESULTS: Women with BV had higher frequencies and
      concentrations of bacteria producing mucin-degrading enzymes than did women with
      intermediate and normal flora (P < 0.001). Women with higher concentrations of
      bacteria producing mucin-degrading enzymes were more likely to have a thin
      discharge associated with BV (P < 0.001). The viscosity of diluted vaginal fluid
      samples from women with BV was significantly lower than those from women with
      normal flora (P = 0.001). CONCLUSION: These data support the hypothesis that BV
      organisms degrade the protective mucus gel.

PMID- 12616148
TI  - Sexual behavior and sexually transmitted infections in men living in rural
      Madagascar: implications for HIV transmission.
AB  - BACKGROUND: Madagascar is in the midst of a large HIV epidemic. Therefore, it is
      important to obtain relevant epidemiologic data that can be used to develop a
      preventive strategy. GOAL: The goal of the study was to assess sexual behavior
      and sexually transmitted infections (STIs) among men living in two coastal
      villages and one highland village with different levels of endemicity of
      urogenital schistosomiasis. STUDY DESIGN: Data were obtained from cross-sectional
      studies on male reproductive health. All men aged 15 to 49 years were offered
      enrollment. RESULTS: Of 401 men evaluated, 6.5% had used a condom and 45.6%
      reported having multiple partners in the previous 3 months. Symptoms of
      urethritis during the previous 7 days were reported by 128 men (31.9%).
      Urethritis was associated with the youngest age group (15-19 years) and the
      coastal villages, in which HIV antibodies were found in 0.9% and 2.5%,
      respectively. The prevalence of Schistosoma hematobium was 31.0% and 55.0% in
      these two villages, whereas none of the men in the highland village were
      infected. In bivariate analyses, urogenital schistosomiasis was associated with
      reported symptoms of urethritis, but it acted as a confounder in multivariate
      analyses. CONCLUSION: Several risk factors for HIV propagation exist in these
      rural areas in Madagascar. Young men in particular should be targeted for HIV/STI
      prevention. Treatment of urogenital schistosomiasis could be considered part of
      the syndromic STI treatment in areas where S hematobium is endemic, for patients
      seeking primary care for urethritis.

PMID- 12616149
TI  - Sociodemographic dynamics and sexually transmitted infections in female sex
      workers at the Mexican-Guatemalan border.
AB  - BACKGROUND: If the predominant means of HIV transmission is heterosexual in the
      Soconusco region of Mexico, then the female sex workers (FSWs) from Central
      America who work in this region may be playing a significant role in the
      heterosexual transmission of HIV. GOAL: The goal was to estimate the prevalence
      of several sexually transmitted infections (STIs), including HIV infection, and
      to evaluate the population mobility of Mexican and Central American FSWs in the
      Soconusco region in Chiapas State, Mexico. METHODS: A cross-sectional study was
      conducted upon the construction of a sampling frame of sex work-related bars in
      the municipalities of the Soconusco region. Consenting participants answered a
      questionnaire that recorded sociodemographic characteristics, previous and
      current experience in commercial sex, and risk indicators for STI. Women also
      provided blood and endocervical swab specimens to be analyzed. RESULTS: A sample
      of 484 women were enrolled, who were characterized as follows: the average age
      was 25.6 years, and a high proportion had children, were single, had started
      sexual activity at an early age, and had a low level of education and low
      earnings. The global prevalences of infections with Treponema pallidum, HSV-2,
      HIV, Neisseria gonorrhoeae, and Chlamydia trachomatis were 9.4%, 85.7%, 0.6%,
      11.6%, and 14.4%, respectively. Frequencies of HBcAb and HBsAg hepatitis B
      markers were 17.7% and 1.3%. The cumulative prevalence of treatable gonorrhea,
      chlamydia, and syphilis was 27.4%. CONCLUSION: The data on women's mobility
      illustrate that the Soconusco region attracts Central American women to enter the
      commercial sex trade. The women's sociodemographic characteristics were
      consistent with high prevalences of STI, except HIV infection. The low frequency
      of HIV infection suggests that this population may have had little contact with
      HIV core groups in Central America and in the Soconusco and no history of blood
      transfusion or intravenous drug use.

PMID- 12616150
TI  - An anatomic study of the lumbar plexus with respect to retroperitoneal endoscopic
      surgery.
AB  - STUDY DESIGN: The distribution of the lumbar plexus was analyzed using cadavers.
      OBJECTIVE: To clarify the safety zone to prevent nerve injuries with respect to
      retroperitoneal endoscopic surgery. SUMMARY OF BACKGROUND DATA: Surgical
      approaches to the retroperitoneal space vary among surgeons. Recently,
      retroperitoneal endoscopic surgery has been applied to various spinal disorders.
      When the psoas major muscle is separated during retroperitoneal endoscopic
      surgery, there is a potential risk of injury to the lumbar plexus or nerve roots.
      However, there is sparse knowledge regarding the relationship between the greater
      psoas muscle and the lumbar plexus. METHODS: A total of 30 cadavers were
      analyzed. Six lumbar spines of the cadavers were cut in parallel with the lumbar
      disc space. Each axial section was photographed and captured into a computer. The
      distribution of the lumbar plexus was analyzed using computer images. The
      positions where the genitofemoral nerve emerged on the abdominal surface of the
      psoas major muscle were analyzed using 24 cadavers. RESULTS: L2/3 and above, all
      parts of the lumbar plexus, and nerve roots were located from the dorsal fourth
      of the vertebral body and dorsally. The genitofemoral nerve descends obliquely
      forward through the psoas major muscle, emerging on the abdominal surface between
      the cranial third of the L3 vertebra and the caudal third of the L4 vertebra. The
      safety zone of the psoas major muscle to prevent nerve injuries, excluding the
      genitofemoral nerve, is at L4/L5 and above. CONCLUSIONS: The safety zone,
      excluding the genitofemoral nerve, is at L4-L5 and above.

PMID- 12616152
TI  - Simple carrier matrix modifications can enhance delivery of recombinant human
      bone morphogenetic protein-2 for posterolateral spine fusion.
AB  - STUDY DESIGN: A nonhuman primate lumbar intertransverse process arthrodesis model
      was used to evaluate modifications to a plain collagen sponge to deliver
      recombinant human bone morphogenetic protein-2 (rhBMP-2). OBJECTIVES: To evaluate
      the feasibility of enhancing the delivery of rhBMP-2 with the established
      collagen sponge carrier by adding biphasic ceramic phosphate (BCP) granules (15%
      hydroxyapatite, 85% tricalcium phosphate) or allograft chips to provide
      compression resistance for posterolateral spine arthrodesis. SUMMARY OF
      BACKGROUND DATA: Recombinant human bone morphogenetic protein-2 was successfully
      delivered with a resorbable collagen sponge in a rabbit intertransverse process
      fusion model. Success in nonhuman primates required a higher dose (6-9 mg) of
      rhBMP-2 and a more compression-resistant matrix (ceramic) than plain collagen.
      The limitation of the ceramic carrier was its radiopacity, which made
      radiographic detection of new bone formation difficult. METHODS: Nine adult
      rhesus monkeys underwent bilateral posterolateral intertransverse process
      arthrodesis at L4-L5. The animals were divided into three groups (n = 3 each)
      based on the graft material implanted: 1) autogenous iliac crest bone (5
      cm3/side); 2) collagen sponge and 15:85 BCP granules loaded with rhBMP-2 (3
      mg/side); and, 3) collagen sponge and allograft chips loaded with rhBMP-2 (3
      mg/side). The monkeys were killed 24 weeks after surgery. Inspection, manual
      palpation, radiography, computed tomographic scans, and histology were used to
      assess fusion. RESULTS: All six monkeys with rhBMP-2 delivered in the
      collagen/15:85 BCP carrier and the collagen/allograft chips carrier achieved
      solid spine fusions, whereas only one of three animals fused with autogenous bone
      graft. Histologic analysis of the bone induced by rhBMP-2 showed normal
      trabecular bone and bone marrow elements. CONCLUSIONS: The addition of either
      15:85 BCP granules or allograft bone chips to the existing resorbable collagen
      sponge matrix enhanced delivery of rhBMP-2 in the posterolateral spine. The
      combination matrices were more compression resistant and had improved
      radiographic resorption properties that permitted easy radiographic visualization
      of new bone. In addition, a lower dose of rhBMP-2 (3 mg/side) was successful
      compared with the dose previously used with the plain collagen sponge (6
      mg/side).

PMID- 12616153
TI  - Pathomechanisms of nerve root injury caused by disc herniation: an experimental
      study of mechanical compression and chemical irritation.
AB  - STUDY DESIGN: An electrophysiologic and histologic study on nerve roots after
      mechanical compression and/or local application of nucleus pulposus (NP) was
      performed. OBJECTIVE: To assess the effects of mechanical compression and/or
      chemical irritation caused by NP. SUMMARY OF BACKGROUND DATA: It has been shown
      that application of NP to nerve roots without compression induces histologic and
      functional changes in nerve roots and the dorsal root ganglia. In clinical
      situations, however, mechanical compression has also been considered an important
      factor in disc herniation. METHODS: Eighteen dogs (9-15 kg) were used in this
      study. Four groups were used to assess the effect of each factor: 1) sham group
      (n = 3); 2) NP group (NP applied under the S1 lamina) (n = 5); 3) comp group (a
      plastic balloon placed under the S1 lamina) (n = 5); and 4) comp+NP group (a
      balloon and NP placed under the S1 lamina) (n = 5). Ascending cauda equina action
      potentials (CEAPs) and cauda equina-sensory nerve conduction velocity (SCV) were
      recorded before, immediately after, and 1 week after treatment. Histologic
      changes were also assessed by light microscopy. RESULTS: There were no
      significant differences in CEAP and SCV among the four groups immediately after
      the treatment. However, 1 week after treatment, the amplitudes in the NP group,
      comp group, and comp+NP group were statistically significantly lower compared
      with those in the sham group. The comp+NP group showed significantly lower
      amplitude than did the NP group and comp group. Immediately after treatment, SCV
      in the NP group and comp group did not show significant differences compared with
      that in the sham group. However, 1 week after treatment, SCV in the comp+NP group
      was significantly lower compared with that in the sham group. Histologic changes
      such as intraneural edema, Schwann cell edema, and nerve fiber injury seemed to
      be more pronounced in the comp+NP group than in the other groups. CONCLUSIONS: It
      was shown that each of the assessed factors induces nerve dysfunction. However,
      the combination of mechanical compression (mass effect of herniated NP) and
      chemical irritation (inflammation around nerve root) may induce more nerve root
      injury than each factor per se.

PMID- 12616154
TI  - The effects of folic acid in the prevention of neural tube development defects
      caused by phenytoin in early chick embryos.
AB  - STUDY DESIGN: The effects of phenytoin and folic acid on the development of
      neural tube defects in early chick embryos were studies. OBJECTIVE: To
      investigate the effects of folic acid in the prevention of neural tube
      development defects. SUMMARY OF BACKGROUND DATA: Several studies have shown that
      phenytoin selectively inhibits neural tube closure. Folic acid supplementation
      has been reported to decrease the occurrence of neural tube defects. METHODS:
      This study shows the effects of folic acid in preventing neural tube development
      defects caused by phenytoin in chicks based on light microscopy, transmission
      electron microscopy, and histopathological examination. Forty-five fertile
      Hubbard Broil eggs, all at Stage 8 (four somite) of development, were divided
      into three equal groups: Group 1 embryos (n = 15), the control group, were
      explanted and grown for 18 hours in a nutrient medium (thin albumin). Group 2
      embryos (n = 15) were explanted and grown for 18 hours in a nutrient medium
      containing 500 microg/mL of phenytoin. Group 3 embryos (n = 15) were explanted
      and grown for 18 hours in a nutrient medium containing 500 microg/mL of phenytoin
      and 0.4 microg/mL of folic acid. RESULTS: After the incubation period, 86.6% of
      the control embryos (Group 1) had intact neural tubes; 80% of Group 2 and 46.6%
      of Group 3 embryos showed neural tube defects. CONCLUSIONS: The results of this
      study suggest that phenytoin causes neural tube defects, whereas folic acid
      decreases the incidence of neural tube development defects caused by phenytoin in
      early chick embryos.

PMID- 12616155
TI  - The potential and limitations of a cell-seeded collagen/hyaluronan scaffold to
      engineer an intervertebral disc-like matrix.
AB  - STUDY DESIGN: The use of a cell-seeded biomatrix for tissue engineering of the
      intervertebral disc. OBJECTIVE: To evaluate the ability of a biomatrix to support
      the viability of intervertebral disc cells and to accumulate the extracellular
      matrix that they produce. SUMMARY OF BACKGROUND DATA: Intervertebral disc
      degeneration is a common occurrence during adult life that has adverse economic
      consequences on the health care system. Current surgical treatments are aimed at
      removing or replacing the degenerate tissue, which can alter the biomechanics of
      the spine and result in degeneration at adjacent disc levels. The ideal treatment
      of the degenerate disc would involve biologic repair, and tissue-engineering
      techniques offer a means to achieve this goal. METHODS: Scaffolds of type I
      collagen and hyaluronan were seeded with bovine nucleus pulposus or anulus
      fibrosus cells and maintained in culture for up to 60 days in the presence of
      fetal calf serum or a variety of growth factors to try to generate a tissue whose
      properties could mimic those of the nucleus pulposus with respect to proteoglycan
      content. RESULTS: During the culture period, various proteoglycans (aggrecan,
      decorin, biglycan, fibromodulin, and lumican) and collagens (types I and II)
      accumulated in the scaffold. Proteoglycan accumulation in the scaffold was
      greatest under conditions in which transforming growth factor-beta1 was present,
      but under all conditions, more proteoglycan was lost into the culture medium than
      retained in the scaffold. Both the nucleus and anulus cells behaved in a similar
      manner with respect to their ability to synthesize matrix macromolecules and have
      them retained in the scaffold. By day 60 of culture, the proteoglycan content of
      the scaffolds never exceeded 10% of that present in the mature nucleus pulposus,
      although this figure could have been considerably increased if most of the
      proteoglycan being synthesized could have been retained. Furthermore,
      proteoglycan retention was not uniform within the scaffold, but increased near
      its periphery. CONCLUSIONS: This work demonstrates that although it is possible
      to maintain functional disc cells in a biomatrix, it will be necessary to
      optimize proteoglycan synthesis and retention if any resulting tissue is to be of
      value in the biologic repair of the degenerate disc. The ability of the anulus
      cells to replicate the matrix production of the nucleus cells, at least in the
      collagen/hyaluronan scaffold, suggests that repair may not be limited to the
      availability of authentic nucleus cells.

PMID- 12616157
TI  - Prediction of osteoporotic spinal deformity.
AB  - STUDY DESIGN: A biomechanical model was developed from full-spine lateral
      radiographs to predict osteoporotic spinal deformity in elderly subjects.
      OBJECTIVE: To investigate the biomechanics of age-related spinal deformity and
      concomitant height loss associated with vertebral osteoporosis. SUMMARY OF
      BACKGROUND DATA: Vertebral bone loss and disc degeneration associated with aging
      causes bone and disc structures to weaken and deform as a result of gravity and
      postural stresses. METHODS: An anatomically accurate sagittal-plane, upright
      posture biomechanical model of the anterior spinal column (C2-S1) was created by
      digitizing lateral full-spine radiographs of 20 human subjects with a mean height
      of 176.8 cm and a mean body weight of 76.6 kg. Body weight loads were applied to
      the model, after which intervertebral disc and vertebral body forces and
      deformation were computed and the new spine geometry was calculated. The strength
      and stiffness of the vertebral bodies were reduced according to an osteopenic
      aging model and modulus reduction algorithm, respectively. RESULTS: The most
      osteopenic model (L3 F(ult) = 750 N) produced gross deformities of the spine,
      including anterior wedge-like fracture deformities at T7 and T8. In this model,
      increases in thoracic kyphosis and decreases in vertebral body height resulted in
      a 25.2% decrease in spinal height (C2-S1), an 8.6% decrease in total body height,
      and a 15.1-cm anterior translation of the C2 spine segment centroid. The
      resulting deformity qualitatively resembled deformities observed in elderly
      individuals with osteoporotic compression fractures. CONCLUSIONS: These
      predictions suggest that postural forces are responsible for initiation of
      osteoporotic spinal deformity in elderly subjects. Vertebral deformities are
      exacerbated by anterior translation of the upper spinal column, which increases
      compressive loads in the thoracolumbar region of the spine.

PMID- 12616158
TI  - Do alterations in vertebral and disc dimensions affect an elliptical model of
      thoracic kyphosis?
AB  - STUDY DESIGN: Mathematical modeling, using least squares method, of thoracic
      kyphosis was constructed as digitized points from radiographs of 50 healthy
      patients. OBJECTIVE: To determine a simple geometric model of the thoracic
      kyphosis. SUMMARY OF BACKGROUND DATA: Thoracic kyphosis is an important parameter
      of health, but geometric models of kyphosis are rare. Few papers report vertebral
      body and disc height data. METHODS: Thoracic vertebral bodies were digitized on
      lateral radiographs of 50 healthy patients. The average path of the posterior
      vertebral body corners of T1 through T12 was modeled, in the least squares sense,
      with a portion of an ellipse. The best-fit ellipse was sectioned with different
      model partitions using four sets of vertebral body heights and disc heights.
      Segmental and global angles derived from these four models were compared with
      reported values in the literature. RESULTS: A 72 degrees portion of an ellipse,
      with a minor-to-major axis ratio of 0.69, can closely approximate the path of the
      posterior body corners from the inferior of T1 to the superior of T12. The
      posterior vertebral body heights and disc heights have an average ratio of
      approximately 5:1. Segmental angles from T3-T4 through T11-T12 for all four
      models are close to other reported values. The thoracic spine has a height-to
      length ratio of approximately 0.96. CONCLUSIONS: Thoracic kyphosis from inferior
      posterior T1 to superior-posterior T12 can be closely modeled (least squares
      error per point < 1 mm) with a 72 degrees piece of an ellipse with a minor-to
      major axis ratio of 0.69. The major axis is parallel to the posterior body margin
      of T12, whereas the minor axis passes through the superior endplate of T12.
      Segmental angles derived from this elliptical modeling are in the range of values
      from healthy patients.

PMID- 12616159
TI  - Physical characteristics of polyaxial-headed pedicle screws and biomechanical
      comparison of load with their failure.
AB  - STUDY DESIGN: Pedicle screw strength or load to failure was biomechanically
      evaluated, and the geometric characteristics of pedicle screw instrumentation
      systems were compared. OBJECTIVES: To compare the features of pedicle screw
      systems, and to demonstrate the failure point of the polyaxial pedicle screw
      head. SUMMARY OF BACKGROUND DATA: Many pedicle screw instrumentation systems are
      currently available to the spine surgeon. Each system has its unique
      characteristics. It is important for the surgeon to understand the differences in
      these pedicle screw systems. Pedicle screw load to failure has not been subjected
      to a comparison study. METHODS: The physical characteristics of each pedicle
      screw instrumentation system were determined. Features of rods, instruments, and
      pedicle screws were cataloged. Biomechanical testing of the pedicle screw
      construct was performed to determine the site and force of the load to failure.
      Nine pedicle screw systems were evaluated. Testing was performed with a pneumatic
      testing system under load control. Three polyaxial screws were used for each test
      at a load rate of 100 N/second. The load failure value was the force at which the
      pedicle screw or polyaxial head-screw interface initially deflected. RESULTS:
      Biomechanical testing demonstrated in all instances that the polyaxial head
      coupling to the screw was the first failure point. Although there have been
      subtle design differences in the instruments over time, the features of the
      pedicle screw instrument sets have become remarkably similar. CONCLUSIONS:
      Biomechanical pedicle screw load-to-failure data demonstrated that the polyaxial
      head coupling to the screw is the first to fail and may be a protective feature
      of the pedicle screw, preventing pedicle screw breakage. Knowing the physical
      characteristics of the available pedicle screw instrumentation systems may allow
      the choice of pedicle screw best suited for a given clinical situation.

PMID- 12616160
TI  - The role of anterior spinal instrumentation and allograft fibula for the
      treatment of pott disease.
AB  - STUDY DESIGN: The authors retrospectively reviewed 28 patients with multilevel
      Pott disease who underwent anterior radical debridement, decompression, and
      fusion with anterior spinal instrumentation and fibular allograft replacement.
      OBJECTIVES: To assess the efficacy of allograft fibular fusion and anterior
      spinal stabilization as an alternative treatment of spinal tuberculosis. SUMMARY
      OF BACKGROUND DATA: The results of anterior surgery in preventing late or early
      spinal deformity from Pott disease have been closely related to the status of the
      segmental stability and graft materials, especially in cases of multisegmental
      involvement. The use of allograft and anterior spinal instrumentation in
      tuberculous spondylitis remains controversial because of the risk of persistence
      and recurrence of infection in the presence of devitalized bone graft, which may
      also be prone to poor incorporation. METHODS: Between 1993 and 1998, a total of
      28 patients with Pott disease (two or more segments involved) underwent anterior
      debridement, allograft fusion, and stabilization. The patients were given
      antituberculosis treatment in the postoperative period according to a
      standardized protocol. The authors retrospectively analyzed their experience in
      tuberculous spondylitis, with particular attention to method, allograft
      incorporation, and anterior spinal instrumentation. Incorporation of the
      allograft was evaluated by either static or dynamic (flexion/extension)
      radiographs. RESULTS: None of the patients used external support in the
      postoperative period. A minimum of 3 years' follow-up was achieved in 26
      patients. The overall fusion rate was 96%. There were no graft problems. Two
      patients died in the early postoperative period as a result of multiorgan
      failure. One patient suffered from an instrumentation failure. No other
      complications were observed. The segmental correction was maintained successfully
      in all of the patients. The mean correction loss was 6 degrees. CONCLUSION: The
      use of anterior spinal stabilization accompanied with a structural allograft
      fibula is effective after proper radical debridement for interbody fusion,
      deformity correction, and maintenance in cases of multisegment-involved Pott
      disease.

PMID- 12616161
TI  - Preserving ambulatory potential in pediatric patients with cerebral palsy who
      undergo spinal fusion using unit rod instrumentation.
AB  - STUDY DESIGN: A retrospective study investigated 24 ambulatory pediatric patients
      with spastic cerebral palsy and neuromuscular scoliosis. OBJECTIVE: To evaluate
      the effect of spinal fusion from T1-T2 to the sacrum with pelvic fixation using
      unit rod instrumentation on the ambulatory potential of these patients. SUMMARY
      OF BACKGROUND DATA: Spinal deformities in patients with cerebral palsy and good
      ambulatory capacity are infrequently associated with pelvic obliquity, so
      instrumented spinal fusions traditionally do not extend to the pelvis. METHODS:
      The medical charts and radiographs were reviewed, and the patients' ambulatory
      ability was assessed clinically with videotape or complete gait analysis. A
      questionnaire assessing patients' functional improvement was given to the
      caretakers. RESULTS: The study group included 17 female and 7 male patients,
      among whom were 19 quadriplegics and 5 diplegics. The mean age at surgery was
      15.4 years. Of the 24 patients, 20 underwent posterior spinal fusion and 4 had
      combined anteroposterior procedures. The patients were evaluated clinically
      before surgery and after surgery. Follow-up evaluations of ambulatory function
      occurred at a mean of 2.86 years after surgery. No alteration in the ambulatory
      status of the patients was found, except in one patient who experienced bilateral
      hip heterotopic ossification and gradually lost her ability to ambulate.
      Preoperative and postoperative gait analysis was performed for 12 patients,
      showing no change in their ambulatory function. The surgical outcome survey
      demonstrated significant improvement in the patients' physical appearance, head
      and trunk balance, sitting ability, and respiration, with no change in ambulatory
      capacity. CONCLUSIONS: Spine surgery with fusion extending to the pelvis in
      ambulatory patients with cerebral palsy provided excellent deformity correction
      and preserved their ambulatory function.

PMID- 12616162
TI  - Determination of distal fusion level with segmental pedicle screw fixation in
      single thoracic idiopathic scoliosis.
AB  - STUDY DESIGN: A retrospective study was conducted. OBJECTIVE: To determine the
      exact distal fusion level in the treatment of single thoracic idiopathic
      scoliosis (King Types 3 and 4) with segmental pedicle screw fixation. SUMMARY OF
      BACKGROUND DATA: Pedicle screw fixation effectively shortens the distal fusion
      extent by improved three-dimensional deformity correction. However, the selection
      of distal fusion extent remains controversial in single thoracic idiopathic
      scoliosis. METHODS: This study analyzed 42 patients with single thoracic
      adolescent idiopathic scoliosis (32 King 3 patients and 10 King 4 patients) who
      underwent segmental pedicle screw fixation and had a minimum follow-up period of
      2 years (range, 2-6 years). The patients were grouped according to the distal
      fusion level with reference to the standing neutral rotated vertebra (NV) for
      comparison of deformity correction and spinal balance using standing radiographs.
      Failure to restore an adequate trunk balance and progression or extension of the
      primary curve (adding on) was considered unsatisfactory. RESULTS: Preoperative 50
      degrees +/- 11 degrees of thoracic deformity was corrected to 13 degrees +/- 5
      degrees, for a curve correction of 74%. Preoperative 23 degrees +/- 7 degrees of
      lumbar deformity was corrected to 2 degrees +/- 8 degrees, for a curve correction
      of 93%. Curve correction was not significantly affected by King type or distal
      fusion level (P > 0.05). Postoperative unsatisfactory results were obtained in 14
      patients. When the preoperative NV was the same or one level distal to end
      vertebra (EV), fusion down to NV was satisfactory (14/14). When the preoperative
      NV was more than two levels distal to EV, fusion down to one level shorter than
      NV (NV-1) also was satisfactory (9/9). However, when fusion down to NV-2 or
      shorter was performed, the chances of adding on were higher (14/19; P < 0.01).
      Preoperative 17 degrees +/- 8 degrees of thoracic kyphosis was improved to 24
      degrees +/- 7 degrees. CONCLUSIONS: In single thoracic idiopathic scoliosis, NV
      is an important factor for the determination of fusion level. When preoperative
      NV and EV show no more than two-level gap differences, the curve should be fused
      down to NV. When the gap is more than two levels, fusion down to NV-1 is
      satisfactory, saving one or two motion segments, as compared with fusion
      extending to the stable vertebra.

PMID- 12616163
TI  - Inverse relation between osteoporosis and spondylosis in postmenopausal women as
      evaluated by bone mineral density and semiquantitative scoring of spinal
      degeneration.
AB  - STUDY DESIGN: The relation between bone mineral density and severity of
      spondylosis was evaluated in postmenopausal women. OBJECTIVE: To examine the
      possible inverse relation between osteoporosis and spondylosis by evaluating the
      association between bone mineral density and osteophyte formation or
      intervertebral disc narrowing using a semiquantitative scoring system. SUMMARY OF
      BACKGROUND DATA: The literature contains studies demonstrating an inverse
      relation between osteoporosis and spondylosis as well as those documenting
      insufficient support for such a relation. However, in these studies, only limited
      range grading systems (e.g., Grades 1-4) were used to evaluate the severity of
      spondylosis. METHODS: In this study, 104 postmenopausal women older than 60 years
      underwent bone mineral density measurement of the lumbar spine (anteroposterior,
      lateral, and midlateral) and proximal femur (femoral neck, trochanter, and Ward's
      triangle) using dual-energy x-ray absorptiometry. Raw data representing the
      semiquantitative osteophyte score and disc score as well as the number of
      vertebral fractures were obtained using spinal radiograph. Correlations between
      bone mineral density and the radiographic variable were then analyzed. RESULTS:
      Significant negative correlations were found between all bone mineral density
      data and the number of vertebral fractures (-0.524 < or r= r < or = -0.347; P <
      0.05). Marginal/moderate positive correlations were observed between the
      osteophyte score and the bone mineral density data (0.263 < or = r < or = 0.580,
      P < 0.05), and between the disc score and the bone mineral density data (0.233 <
      or = r < or = 0.570, P < 0.05).CONCLUSIONS On the basis of the finding that
      spondylotic changes in postmenopausal women exhibit positive correlations not
      only with the lumbar bone mineral density, but also with the remote-site bone
      mineral density, this study supports the view that osteoporosis has an inverse
      relation with spondylosis.

PMID- 12616164
TI  - Evaluation of lumbosacral nerve root lesions using evoked potentials recorded by
      a surface electrode technique.
AB  - STUDY DESIGN: Patients with lumbar disc herniation were studied with lumbosacral
      evoked potentials (EPs). OBJECTIVES: To evaluate lumbosacral EPs for the
      functional diagnosis of nerve root lesions in patients with lumbar disc
      herniation. SUMMARY OF BACKGROUND DATA: No clinical studies have been conducted
      using lumbosacral EPs elicited by body surface leads. METHODS: Lumbosacral EPs
      elicited by stimulating the posterior tibial nerve were recorded using surface
      electrodes placed over the interspinous processes of T12-S1. By subtracting the
      waveform recorded at NT12 (T12/L1 potential) from that at NL3 (L3/L4 potential),
      NL3' (residual potential) potentials were clearly identified. NT12 and NL3'
      potentials were classified into four groups based on the degree of the reduction
      of amplitude and/or the prolongation of latency. RESULTS: Significant
      correlations were found between the NL3' score and the straight-leg raising test
      score (r = 0.36, P < 0.05) and between the NT12 amplitude and sensory disturbance
      (r = 0.37, P < 0.02). The NL3' score was 1.2 +/- 0.5 points before surgery, and
      it significantly improved to 2.5 +/- 0.5 points 2 months after surgery (P <
      0.05). Short-term, the NT12 amplitude did not change significantly. Twelve months
      after surgery, the NT12 amplitude improved significantly to 1.1 +/- 0.5 microV (P
      < 0.05). CONCLUSIONS: The results of this study indicated that the NL3' score may
      reflect impairment of the impulse traversing the nerve root in the acute clinical
      stage, whereas the NT12 amplitude reflects a neurologic deficit. The
      postoperative clinical course can be estimated by observing recovery of the NL3'
      score and NT12 amplitude.

PMID- 12616165
TI  - Procedural coding of spinal surgeries (CPT-4 versus ICD-9-CM) and decisions
      regarding standards: a multicenter study.
AB  - STUDY DESIGN: A comparison of procedural coding systems ( [ICD-9-CM] [CPT-4])
      applied to lumbar spine surgery patients from six teaching institutions.
      OBJECTIVE: To compare the detail reflected by coding systems used to describe
      spinal procedures. SUMMARY OF BACKGROUND DATA: Administrative databases contain
      ICD-9-CM procedural codes, which are derived from hospital discharge abstracts.
      These databases are used, in part, to establish health care utilization patterns
      and set health care policy. Previous studies have demonstrated inaccuracies in
      ICD diagnosis coding. However, the literature is void of information regarding
      the accuracy of ICD procedural coding of spine procedures. METHODS: Data were
      complete in 143 of 150 lumbar spine surgery patients (aged 17-84 years). Surgeons
      assigned CPT-4 procedural codes. These codes were compared with ICD procedure
      codes assigned by hospital medical records staff. RESULTS: On average, in four of
      six hospitals, there were more CPT codes assigned to patient records by the
      surgeon than ICD codes assigned by hospital medical records staff. Overall, CPT
      codes reflected a greater level of detail than ICD codes. CONCLUSIONS: These
      findings illustrate the increased detail of CPT coding over ICD coding in the
      spinal surgery cases reviewed. The ICD procedural codes contained in
      administrative databases tend to underrepresent the complexity of the surgical
      procedures actually performed.

PMID- 12616166
TI  - Quality of life in surgical treatment of metastatic spine disease.
AB  - STUDY DESIGN: Overall quality of life after surgical management of metastatic
      disease of the spine was prospectively assessed using a validated global health
      status quality-of-life instrument-the Edmonton Symptom Assessment Scale.
      OBJECTIVES: To prospectively evaluate the efficacy of surgery in patients with
      metastatic spinal disease with respect to quality of life. SUMMARY OF BACKGROUND
      DATA: Management of spinal metastases is palliative and is aimed at improving
      quality of life at an acceptable risk. Although previous studies have evaluated
      physical outcomes, improvements in pain, and neurologic function after surgery, a
      multidimensional assessment of quality of life is more relevant in the palliative
      patient. METHODS: Twenty-five consecutive patients undergoing surgery for spinal
      metastases were prospectively evaluated. Pre- and postoperative assessments were
      performed using the Edmonton Symptom Assessment Scale. The surgical procedure
      consisted of decompression and instrumented stabilization. RESULTS: After
      surgery, the largest improvement was noted in the domain of pain (P < 0.00001).
      There were also significant improvements noted in the domains of tiredness (P =
      0.004), nausea (P = 0.01), anxiety (P = 0.006), drowsiness (P = 0.044), appetite
      (P = 0.02), and well-being (P = 0.004). CONCLUSIONS: The current study
      demonstrates that in the appropriate patient, surgical management brings about a
      positive effect on the overall quality of life in patients with spinal
      metastases. The greatest benefit occurred in the reduction of a patient's level
      of pain.

PMID- 12616168
TI  - Re: Rozenberg S, Delval C, Rezvani Y, et al. Bed rest or normal activity for
      patients with acute low back pain. Spine 2002;27:1487-1493.

PMID- 12616169
TI  - Re: Hagen KB, Hilde G, Jamtvedt G, et al. The Cochrane review of advice do stay
      active as a single treatment for low back pain and sciatica. Spine 2002;27:1736
      41.

PMID- 12616167
TI  - Reposition sense of lumbar curvature with flexed and asymmetric lifting postures.
AB  - STUDY DESIGN: Reposition sense of lumbar curvature was assessed as a function of
      trunk flexion, trunk asymmetry, and target lumbar curvature using a repeated
      measures design and an active-active proprioception paradigm. OBJECTIVE: The
      objectives of the research were to measure the ability of the subjects to sense
      and control the lumbar curvature in different lifting postures and to see if
      error in the lumbar curvature would increase in high-risk postures. SUMMARY OF
      BACKGROUND DATA: The risk of low back disorders (LBDs) is related to trunk
      posture, with greater risk reported in flexed and asymmetric trunk positions.
      Spinal posture, including trunk position and lumbar lordosis, influences spinal
      stability. Hence, the ability to accurately sense and control spinal curvature
      may be an important factor in the control of LBD risk. METHODS: Eleven subjects
      were trained to assume specified lumbar curvatures using visual feedback. The
      ability of the subjects to reproduce this curvature without feedback was then
      assessed. This procedure was repeated for different trunk postures, including
      flexion and asymmetry, and with different target lumbar curvatures. RESULTS:
      These measurements demonstrated reposition error was increased in flexed trunk
      positions but was unchanged with trunk asymmetry. This increase in reposition
      error with flexion was diminished when the target posture and lumbar curvature
      were highly flexed and kyphotic. CONCLUSIONS: This research suggests that it may
      be difficult to control spinal curvature in flexed positions, leading to an
      increased risk of injury. For jobs in which flexed working postures are
      unavoidable, therefore, it is important to minimize potentially unstable events
      such as slipping or shifting loads to avoid injury.

PMID- 12616170
TI  - Re: Pellise F, Puig O, Rivas A, et al. Low fusion rate after L5-S1 laparoscopic
      anterior lumbar interbody fusion using twin stand-alone carbon fiber cages. Spine
      2002;27:1665-1669.

PMID- 12616171
TI  - Paraspinous muscle flaps for the treatment and prevention of cerebrospinal fluid
      fistulas in neurosurgery.
AB  - STUDY DESIGN: A prospective clinical study was conducted to evaluate the efficacy
      of paraspinous muscle flaps in preventing and managing cerebrospinal fluid
      fistulas in high-risk neurosurgery patients. OBJECTIVES: To evaluate the efficacy
      of paraspinous muscle flap coverage using a "vest-over-pants" closure in the
      prevention and treatment of cerebrospinal fluid fistulas. SUMMARY OF BACKGROUND
      DATA: Previous studies have described paraspinous muscle flaps for the closure of
      complex spinal wounds, but none has addressed their use for the prevention and
      treatment of cerebrospinal fluid fistulas. METHODS: This prospective clinical
      study evaluated nine consecutive patients with either refractory cerebrospinal
      fluid fistulas or high risk for cerebrospinal fluid leaks after spinal surgery.
      Bilateral paraspinous muscle flaps were used as primary flaps and closed using an
      overlapping vest-over-pants technique in eight of nine cases. The latissimus
      dorsi and trapezius muscles were recruited as additional muscle flaps for closure
      of thoracolumbar and high thoracic deficits, respectively. RESULTS: Paraspinous
      muscle flaps provided immediate wound coverage in seven high-risk patients
      undergoing spinal surgery and two patients with recurrent cerebrospinal fluid
      fistulas. Postoperative hospitalization averaged 14.4 days. There was no evidence
      of a cerebrospinal fluid fistula after an average follow-up of 176.7 days. No
      wound infections occurred. The only complications were a superficial hematoma,
      which was drained percutaneously on postoperative day 6, and a seroma, which was
      drained during the follow-up period and eventually resolved. CONCLUSIONS:
      Paraspinous muscle flaps allow effective treatment and prevention of
      cerebrospinal fluid fistulas in selected high-risk patients and provide simple
      durable coverage of complex spinal wounds with minimal morbidity.

PMID- 12616172
TI  - Mild cervical spine trauma showing symptomatic calcified cervical disc herniation
      in a child: a case report.
AB  - STUDY DESIGN: A case study was conducted. OBJECTIVE: A child with a previously
      unknown calcified cervical disc herniation experienced acute myelopathy after
      minor cervical trauma. SUMMARY AND BACKGROUND DATA: Calcified cervical
      intervertebral disc herniations are rare in children. Although these herniations
      typically pursue a benign course and respond to conservative treatment, surgical
      removal of the disc may become necessary if spinal cord compression becomes
      symptomatic. METHODS: After a minor traumatic event, a 12-year-old boy with an
      underlying calcified cervical disc herniation at C3-C4 experienced progressive
      myelopathy requiring anterior discectomy and intervertebral fusion. RESULTS:
      After the progression of myelopathy over a 3-week period, an anterior discectomy
      and fusion with autologous tricortical iliac bone graft was performed at C3-C4.
      Histologic analysis showed a calcified disc herniation. CONCLUSION: In the
      presence of a large, calcified cervical disc herniation, mild cervical trauma may
      result in the onset of severe spastic myelopathy warranting surgical correction.

PMID- 12616173
TI  - Atlantooccipital distraction: a diagnostic and therapeutic dilemma: report of two
      cases.
AB  - STUDY DESIGN: Two cases of severe atlantooccipital distraction, one with a fatal
      outcome and one with survival and 2 years of follow-up evaluation, are reported.
      OBJECTIVE: To show the problems in diagnosing and the dilemma in treating
      patients with severe atlantooccipital distraction in two cases with different
      outcomes. SUMMARY OF BACKGROUND DATA: Isolated severe traumatic atlantooccipital
      distraction without bony injuries is rarely seen in clinical practice. Because of
      high neurologic morbidity, most patients with the disorder are dead after the
      accident and before medical attention has arrived. However, because of improved
      immediate medical care for victims of motor vehicle accidents, an increased
      number of survivors are reported in the last years. METHODS: Two cases of
      isolated atlantooccipital distraction are described. The first case involved a 13
      year-old cyclist hit by a car. In the second case, a 40-year-old woman sustained
      a severe accident as a motorcycle driver. Both patients were found to have severe
      atlantooccipital distraction on the lateral topogram of the computed tomography.
      In both cases, the initial MRI of the craniocervical junction failed to show
      medullary contusion. The diagnosis of severe medullary contusion was made by
      follow-up MRI performed 48 hours later. RESULTS: Both patients were treated
      initially with halo vest. Patient 1 survived the injury with tetraplegia and was
      referred to a spinal center for rehabilitation. At this writing, he is improving
      neurologically. Patient 2 did not recover and died 4 days after delivery to the
      neurosurgical intensive care unit because of circulatory failure. CONCLUSIONS:
      Because of high neurologic morbidity and mortality, atlantooccipital distraction
      represents a diagnostic and therapeutic problem. The therapy should be
      symptomatic, with life supporting measures, allowing the recovery of
      consciousness and then further neurologic evaluation.

PMID- 12616175
TI  - A clinical case of endoscopically assisted anterior screw fixation for the type
      II odontoid fracture.
AB  - STUDY DESIGN: A clinical case using a new surgical technique is reported.
      OBJECTIVE: To report for the first time an endoscopically assisted anterior screw
      fixation for the Type II odontoid fracture. SUMMARY OF BACKGROUND DATA: Recently,
      many endoscopically assisted surgeries have been performed for various spinal
      surgery because of its minimally invasive character. However, the anterior
      retropharyngeal approach to the upper cervical spine using endoscopy has not been
      reported. METHODS: A 76-year-old man was operatively managed for a Type II
      odontoid fracture. The operation was performed under immobilization of cervical
      spine using a halo vest apparatus. A skin incision 2 cm long was made on the
      medial border of the right sternocleidomastoid muscle at the C5-C6 intervertebral
      level. Blunt dissection between the neurovascular bundle laterally and the
      trachea and esophagus medially was performed. A processed polyethylene syringe
      (volume, 10 mL) was used as the tubular retractor. This retractor kept the
      minimum but sufficient space for the screw fixation and avoided esophageal
      complication. Using a cannulated screw system, a cancellous screw was inserted
      from the anteroinferior edge of the C2 vertebral body to the tip of the odontoid
      process. The drilling and the screwing process was monitored by a two-dimensional
      image intensifier. The entry point was monitored by endoscopy to avoid soft
      tissue involvement as well. RESULTS: The operation was completed without any soft
      tissue complications such as esophageal injury. The blood loss was 30 mL. The
      procedure resulted in nonunion, partially because of patient's old age or an
      entry point 2 mm above the anterior caudal margin of the C2 body retrospectively.
      CONCLUSIONS: Although the reported odontoid fracture ended in nonunion, the
      authors believe their modification of the approach using an endoscope made
      anterior screw fixation for the odontoid fracture safer and less invasive than
      the original anterior retropharyngeal approach.

PMID- 12616174
TI  - Arterial-esophageal fistula: a complication of nasogastric tube placement after
      lumbar spine surgery: a case report.
AB  - STUDY DESIGN: A case of arterial-esophageal fistula related to nasogastric tube
      placement in a 13-year-old girl after surgical correction of her progressive
      congenital lumbar kyphosis is presented. OBJECTIVES: This case report illustrates
      the importance of early recognition of "sentinel" hematemesis before massive
      hemorrhage, as this may allow for timely surgical intervention to prevent fatal
      exsanguination. The proposed pathogenesis of the arterial-esophageal fistula in
      the reported patient is discussed. SUMMARY OF BACKGROUND DATA: Although arterial
      esophageal fistula formation has been recognized as an unusual complication of
      prolonged nasogastric intubation, to the authors' knowledge, this is the only
      case that illustrates an association of this complication with short-term
      nasogastric tube placement. METHODS: A 13-year-old girl was evaluated for
      progressive congenital lumbar kyphosis. Failure of segmentation and an anterior
      bar at L4-L5 was diagnosed when the patient was 7 years of age. At that time, she
      showed 28 degrees of kyphosis from L3 to L5. Because of her cardiopulmonary
      status at the time, she was deemed not to be a candidate for a corrective
      surgical procedure and followed conservatively until the age of 13 years. At that
      time, her gibbus deformity was 56 degrees from L3 to L5. She had significant
      ventral sagittal imbalance, which in combination with her cardiopulmonary
      abnormalities created difficulty with ambulation. Her preoperative neurologic
      examination was within normal limits. The patient had an extensive history of
      congenital cyanotic cardiopulmonary disease. She was born with pulmonary atresia,
      right-sided aortic arch with mirror image branching, a large coronary sinus type
      atrial septal defect, and a large ventricular septal defect. She had history of
      multiple surgical procedures for correction of her congenital cardiopulmonary
      abnormalities. The patient underwent posterior L3 and L5 wedge pedicle reduction
      osteotomies with posterior instrumentation and fusion from L2 to S1 using pedicle
      screw segmental fixation. A nasogastric tube was placed after surgery. On
      postoperative day 7, profuse bleeding from the patient's mouth and nose
      developed, which subsequently ceased. Shortly afterward, she became hypotensive
      and tachycardic. Upper gastrointestinal endoscopy showed a large amount of blood
      in her stomach without an active source. Cardiac arrest then developed, and she
      could not be resuscitated. The autopsy findings were consistent with an arterial
      esophageal fistula. RESULTS: In the reported patient, the anomalous aortic arch
      system provided direct contact between the aorta and the esophagus. Dense fibrous
      adhesions between the aorta and esophagus resulting from multiple previous
      thoracic surgeries also may have facilitated the development of the fistula by
      the nasogastric tube in this patient. CONCLUSIONS: Patients with congenital
      cardiac abnormalities frequently also have congenital spinal deformities. These
      patients may undergo spinal correction procedures requiring nasogastric
      intubation. Increased awareness of arterial-esophageal fistula among the spine
      surgery community may enhance early recognition and treatment of this potentially
      lethal condition.

PMID- 12616177
TI  - Early identification of patients at risk of developing a persistent back problem:
      the predictive validity of the Orebro Musculoskeletal Pain Questionnaire.
AB  - OBJECTIVE: To test the predictive utility of the Orebro Musculoskeletal Pain
      Screening Questionnaire in identifying patients at risk for developing persistent
      back pain problems. DESIGN: Prospective, where participants completed the
      questionnaire and their cases were followed for 6 months to assess outcome with
      regard to pain, function, and absenteeism due to sickness. PARTICIPANTS: One
      hundred seven patients, recruited from seven primary care units. RESULTS:
      Discriminant analyses showed that the items on the questionnaire were
      significantly related to future problems. For absenteeism due to sickness, 68% of
      the patients were correctly classified into one of three groups, whereas an even
      distribution would have produced 33%. The analyses for function correctly
      classified 81%, and for pain 71%, into one of two groups, compared with a chance
      level of 50%. A total score analysis demonstrated that a cutoff score of 90
      points had a sensitivity of 89% and a specificity of 65% for absenteeism due to
      sickness, and a sensitivity of 74% and a specificity of 79% for functional
      ability. CONCLUSIONS: The results underscore that psychological variables are
      related to outcome 6 months later, and they replicate and extend earlier findings
      indicating that the Orebro Screening Questionnaire is a clinically reliable and
      valid instrument. The total score was a relatively good predictor of future
      absenteeism due to sickness as well as function, but not of pain. The results
      suggest that the instrument could be of value in isolating patients in need of
      early interventions and may promote the use of appropriate interventions for
      patients with psychological risk factors.

PMID- 12616178
TI  - Secondary prevention of work-related disability in nonspecific low back pain:
      does problem-solving therapy help? A randomized clinical trial.
AB  - OBJECTIVES: Given the individual and economic burden of chronic work disability
      in low back pain patients, there is a need for effective preventive
      interventions. The aim of the present study was to investigate whether problem
      solving therapy had a supplemental value when added to behavioral graded
      activity, regarding days of sick leave and work status. DESIGN: Randomized
      controlled trial. PATIENTS AND SETTING: Employees who were recently on sick leave
      as a result of nonspecific low back pain were referred to the rehabilitation
      center by general practitioner, occupational physician, or rehabilitation
      physician. Forty-five employees had been randomly assigned to the experimental
      treatment condition that included behavioral graded activity and problem-solving
      therapy (GAPS), and 39 employees had been randomly assigned to behavioral graded
      activity and group education (GAGE). OUTCOME MEASURES: Days of sick leave and
      work status. Data were retrieved from occupational health services. RESULTS: Data
      analyses showed that employees in the GAPS group had significantly fewer days of
      sick leave in the second half-year after the intervention. Moreover, work status
      was more favorable for employees in this condition, in that more employees had a
      100% return-to-work and fewer patients ended up receiving disability pensions one
      year after the intervention. Sensitivity analyses confirmed these results.
      CONCLUSIONS: The addition of problem-solving therapy to behavioral graded
      activity had supplemental value in employees with nonspecific low back pain.

PMID- 12616179
TI  - Psychologically based occupational rehabilitation: the Pain-Disability Prevention
      Program.
AB  - OBJECTIVES: To describe the development, implementation, and preliminary outcome
      of the Pain-Disability Prevention (PDP) Program. The PDP Program is a 10-week
      cognitive-behavioral intervention program that aims to increase daily involvement
      in goal-directed activity and minimize psychological barriers to activity
      involvement after occupational injury. Workers' Compensation Board claimants with
      soft tissue injuries to the back, who were still off work 6 weeks after injury
      and showed evidence of at least one "yellow flag," were offered participation in
      the PDP Program. DESIGN: A single-group, prospective treatment outcome analysis.
      PARTICIPANTS: Data from the first 104 claimants who participated in the PDP
      Program are summarized. RESULTS: Participation in the PDP Program was associated
      with a 60% success rate, where success was defined as return to work (45%) or
      readiness to return to work (15%). Initial scores on measures of catastrophizing,
      fear of movement/reinjury, and depression afforded 92% correct classification of
      treatment outcome. Early treatment changes in catastrophizing and fear of
      movement/reinjury were also predictive of treatment outcome. CONCLUSIONS: The
      findings suggest that a psychologically based activity mobilization program can
      be an effective means of yielding reductions in psychological risk factors for
      occupational disability. Challenges to program implementation, fidelity to
      protocol, and issues related to cost efficacy are discussed.

PMID- 12616180
TI  - From evidence to community practice in work rehabilitation: the Quebec
      experience.
AB  - BACKGROUND: The causes of prolonged disability due to back pain are multiply
      determined, involving medical, social, and environmental factors. Possible
      solutions to the problem of prolonged back pain disability have emerged from
      recent research but few efforts have been made to transfer evidence-based
      programs to large community settings. OBJECTIVE: This article describes three
      phases of the process of transfer of evidence from rehabilitation research to
      community practice in the province of Quebec. METHODS AND RESULTS: Phase A: Based
      on literature review and expert knowledge, the Sherbrooke model was developed and
      assessed through a population-based, randomized clinical trial. Results at 1-year
      follow-up showed quicker return to regular work and improvement of quality of
      life; the 6-year follow-up showed the cost-effectiveness of the method. Phase B:
      Based on the Sherbrooke model experience and recent evidence, a new program
      addressing the disability paradigm was developed and implemented in the province
      of Quebec (Canada). Results at 1- and 3-year follow-ups showed that only 24% of
      workers were not working owing to their musculoskeletal disorder. The program is
      presently being tested through a population-based, randomized clinical trial in a
      population of construction workers. Phase C: To implement the program at a
      provincial level, a network for management, research and education in work
      rehabilitation was developed. An external assessment is presently planned to
      evaluate return to work and economic outcomes and quality of implementation of
      the program in various settings.

PMID- 12616181
TI  - Challenges to early prevention and intervention: personal experiences with
      adherence.
AB  - OBJECTIVE: To describe potential adherence-related difficulties encountered in
      the implementation of a secondary prevention, early intervention study with acute
      low back pain patients. An additional goal is to provide recommendations, based
      on the authors' experience, on how best to overcome these potential obstacles for
      future research. DESIGN: The study used a predictive algorithm, identified
      through previous research, to identify which patients presenting with acute low
      back pain were at risk for developing chronic problems. These subjects were then
      treated prophylactically with an interdisciplinary intervention. Specific
      difficulties initially encountered during the pilot stage of implementation of
      this intervention included securing adequate physician referrals to the study and
      helping patients to progress through treatment in the most efficient manner.
      CONCLUSIONS: Potential difficulties are discussed in the contextual framework of
      treatment adherence and factors affecting it, including the impact of personality
      factors, satisfaction, comprehension, side effects, financial issues, length of
      treatment, type of regimen, social issues, patient beliefs, and biologic factors.
      It is hoped that the present authors' experience will enable future investigators
      to anticipate these common problems, and structure their research endeavors
      accordingly.

PMID- 12616182
TI  - Pain on injection of propofol: the effect of granisetron pretreatment.
AB  - OBJECTIVE: To assess the effect of granisetron pretreatment in alleviating
      propofol injection pain. STUDY DESIGN: A randomized, controlled, double-blind
      study, using venous retention with a tourniquet. MATERIALS AND METHODS: One
      hundred fifty adult patients were randomly assigned to one of three groups: group
      1 (who received 5 mL of 0.9% saline pretreatment), group 2 (who received 5 mL
      lidocaine [40 mg in 0.9% saline] pretreatment), and group 3 (who received 5 mL
      granisetron [2 mg in 0.9% saline] pretreatment). Injections were given in the
      largest vein on the dorsum of the hand. After 2 minutes, the tourniquet was
      released and one fourth of the total calculated dose of propofol (2.5 mg/kg body
      weight) was administered and pain assessment was made. RESULTS: Lidocaine and
      granisetron significantly reduced the incidence and severity of propofol
      injection pain more than placebo (P < 0.001). The efficacy of granisetron in
      alleviating the pain on injection of propofol was no different from lidocaine.
      CONCLUSIONS: Granisetron pretreatment may be used to reduce the incidence of pain
      on injection of propofol, an advantage added to the useful prevention of
      postoperative nausea and vomiting.

PMID- 12616183
TI  - Pain catastrophizing and symptom severity during upper respiratory tract illness.
AB  - OBJECTIVES: The present study examined the relation of pain catastrophizing to
      the severity of upper respiratory tract illness. MATERIALS AND METHODS:
      Participants included 50 adults (35 female subjects, 15 male) who were self
      diagnosed with upper respiratory tract illness and who agreed to complete a diary
      of symptoms for 7 days. Illness symptoms were grouped into three categories: pain
      related, constitutional, and respiratory symptoms. RESULTS: Results showed that
      pain catastrophizing was associated with symptom number and symptom severity in
      all three categories of symptoms. The rumination subscale of the Pain
      Catastrophizing Scale showed the strongest relations with illness severity. The
      relation between pain catastrophizing and illness severity remained significant
      even when controlling for initial symptom severity, duration of the symptoms
      before the study period, and depression. DISCUSSION: The results provide the
      preliminary evidence that the influence of pain catastrophizing may not be
      restricted to pain-specific domains. The data also provide some support for the
      view that the excessive focus on bodily sensations may account for more severe
      symptoms.

PMID- 12616184
TI  - Single needle approach for multiple medial branch blocks: a new technique.
AB  - BACKGROUND AND OBJECTIVES: Medial branch blocks are an important tool for the
      diagnosis of facet joint arthropathy. The most commonly used technique involves
      multiple needle placements, one for each nerve blocked. This multiple needle
      technique may require a large amount of local anesthetic for anesthetizing the
      skin, thereby increasing the rate of false-positive blocks. TECHNIQUE: Diagnostic
      lumbar medial branch blocks are usually performed using multiple needles, one for
      each branch. The authors describe a different technique using a single needle for
      all levels. Initially, the needle is directed toward the medial branch located at
      the level of the affected facet joint in the antero-posterior view. After
      anesthetizing this nerve with local anesthetic, the same needle is withdrawn to
      the skin with the tip still in the subcutaneous tissue and repositioned to block
      the medial branch above, and thereafter below, while continuing to use only the
      antero-posterior view, thereby using only one entry site. CONCLUSIONS: When
      performed correctly, the single needle technique provides accuracy similar to the
      more conventional multiple needle approach during the performance of diagnostic
      facet joint nerve blocks. Because only one skin entry point is needed, however,
      this technique may afford several advantages over the multiple needle approach.
      These may include less patient discomfort, less time required and less radiation
      exposure since only one C-arm position is used, a smaller volume of local
      anesthetic, and possibly a lower incidence of false-positive blocks.

PMID- 12616186
TI  - Subglottic laryngeal paraganglioma.
AB  - OBJECTIVES: To review the clinical and pathological picture of laryngeal
      paragangliomas and compare laryngeal paragangliomas with the three other types of
      laryngeal neuroendocrine neoplasms. STUDY DESIGN: The study presents a case
      review of a patient with a subglottic laryngeal paraganglioma treated at our
      institution, with a literature review of the laryngeal neuroendocrine neoplasms.
      Included is a review of all four neuroendocrine neoplasms, taking a close look at
      a comparison between laryngeal paragangliomas and atypical carcinoids tumors. All
      cases of subglottic laryngeal paragangliomas reported in the literature were also
      compiled and tabulated. METHODS: The patient's record was reviewed for age,
      symptomatology, workup, and surgical procedures performed. RESULTS: The patient
      was disease free 36 months after undergoing a tracheostomy for airway control,
      followed by a cricoid split for complete excision of the tumor. CONCLUSIONS: It
      is important to differentiate among the four laryngeal neuroendocrine neoplasms,
      especially between atypical carcinoids and paragangliomas. Each tumor requires
      different treatments, with the former requiring a more aggressive approach.
      Paragangliomas must be completely excised to prevent their recurrence, and this
      approach should be considered a curative treatment. In addition, the
      immunohistochemical battery is of paramount importance in obtaining the correct
      pathological diagnosis.

PMID- 12616185
TI  - Potential biomarkers for head and neck squamous cell carcinoma.
AB  - OBJECTIVE: The purpose of the study was twofold: 1) to search for potential
      biomarkers that were overexpressed in cell lines that could represent both a
      clinical premalignant (immortalized) and a malignant state, and 2) to attempt to
      correlate metallothionein gene expression with clinical outcome in laryngeal
      carcinoma. STUDY DESIGN: A series of in vitro experiments were used to unearth
      differentially expressed genes among normal, immortalized and tumorigenic cell
      lines. Secondarily, a retrospective analysis was undertaken. METHODS:
      Differential display analysis was conducted to identify differentially expressed
      genes between human papillomavirus-infected immortalized HOK16B and benzo[
      ]pyrene-derived tumorigenic cell line, HOK16B-BaP-T. The cell-specific
      expressions were examined by Northern blot analysis and compared with other known
      immortalized and cancer cell lines. Immunohistochemical staining was also
      conducted to localize metallothionein (MT I/II) protein expression among the
      different cell lines studied. A retrospective analysis of laryngeal specimens
      from archival tissues of 29 cancer patients who underwent primary surgical
      resection was also undertaken after immunohistochemical staining. RESULTS: Twenty
      one differentially expressed complementary cDNA clones, both novel and known,
      were identified using the differential display analysis. Northern blot analysis
      confirmed that clone 6 hybridized to a 1.6-kb RNA in HOK16B-Bap-T cell line.
      Clone 4 showed decreased expression in immortalized and cancer cell compared with
      NHOK. MT I/II transcript was observed in HOK16B, which was further elevated in
      HOK16B-Bap-T. Retrospective analysis showed that high immunoreactivity to MT I/II
      in surgically resected laryngeal cancer specimen correlated with increased
      frequency of recurrence within 2 years of surgery. CONCLUSION: These findings
      suggest that clone 4 may potentially function as a tumor suppressor gene, which
      may be significant in tumor progression and invasion. Clone 6 may participate in
      viral-mediated oncogenic transformation of normal cells. Clone 6 may also have
      potential as a tumor maker differentiating normal from malignant tissue, as in
      the determination of surgical resection margins. MT I/II gene product may serve
      as a prognostic biomarker for laryngeal squamous cell carcinoma. The
      differentially expressed genes and gene products may serve as sensitive
      biomarkers for improved early detection, diagnosis, and prognosis of head and
      neck squamous cell carcinoma.

PMID- 12616187
TI  - Local administration of nitric oxide donor significantly impacts microvascular
      thrombosis.
AB  - OBJECTIVES/HYPOTHESIS: Clinical pharmacotherapy has demonstrated a role in
      preventing microvascular thrombosis in both experimental and clinical settings.
      Previous studies in the rabbit model have noted an increased rate of thrombosis
      with intravenous infusion of nitric oxide antagonists. The study assessed the
      effects of local application of nitric oxide agonists and antagonists on
      microvascular anastomotic patency rates. STUDY DESIGN: A randomized, prospective
      analysis. METHODS: An arterial inversion graft microvascular thrombosis model was
      used in New Zealand white rabbits. The rabbits were randomly assigned to nitric
      oxide agonist, antagonist, and control groups. In each rabbit, the common femoral
      artery was surgically exposed and a 2-mm arterial inversion graft was harvested.
      The anastomosis of the graft to the common femoral artery was performed in
      solutions of either 100 micromol/L spermine NONOate (nitric oxide donor), 100
      micromol/L nitro-L-arginine-methyl ester (L-NAME) (nitric oxide synthase
      inhibitor), or 0.9% sodium chloride (control) solution. The contralateral common
      femoral artery also underwent arterial inversion graft testing with the use of
      the same solution. Arterial patency was assessed 1 hour after anastomosis.
      RESULTS: Sixteen of 22 arterial inversion grafts performed in the spermine
      NONOate solution remained patent, and 6 of 22 clotted. Eleven of 21 arterial
      inversion grafts performed in the control solution remained patent, and 10
      clotted. Seven of 21 arterial inversion grafts performed in the L-NAME solution
      remained patent, and 14 clotted. These results were found to be statistically
      significant using the chi test with a value of less than.05. CONCLUSIONS: In the
      rabbit model, local application of nitric oxide agonists and antagonists can
      significantly impact anastomotic patency rates. Further studies may demonstrate a
      role for the clinical use of nitric oxide in microvascular surgery.

PMID- 12616188
TI  - Inflammation and remodeling of the sinus mucosa in children and adults with
      chronic sinusitis.
AB  - OBJECTIVES/HYPOTHESIS: The sinus mucosal inflammatory response in adult patients
      with chronic sinusitis is well documented in the literature. In contrast, little
      is known about the pathogenesis of this condition in children. The objective of
      the study was to compare the inflammatory cell profile and the extent of tissue
      remodeling in the sinus mucosa of children and adults with chronic sinusitis.
      STUDY DESIGN: Prospective design. METHODS: Children (n = 7) and adult patients (n
      = 7) with chronic sinusitis undergoing functional endoscopic sinus surgery were
      recruited for the study. Patients with no evidence of sinus disease (n = 6) were
      used as control subjects. Using immunohistochemical analysis, sinus mucosal
      specimens were assessed for the presence of T lymphocytes, eosinophils,
      basophils, mast cells, and neutrophils. The extent of submucosal collagen
      deposition was evaluated in histological sections using van Gieson stain.
      RESULTS: The number of T lymphocytes, eosinophils, and basophils and the amount
      of subepithelial collagen deposition are significantly higher in the mucosa of
      both adults and children with chronic sinusitis compared with normal control
      subjects (P <.01). The number of mast cells is significantly higher in the mucosa
      of children with chronic sinusitis compared with normal control subjects (P
      <.01). The number of eosinophils and neutrophils and the amount of subepithelial
      collagen deposition are significantly greater in adults compared with children
      with chronic sinusitis (P <.01). CONCLUSIONS: The sinus mucosal inflammatory
      profile is similar in adults and children with chronic sinusitis. However, the
      degree of tissue eosinophilia and remodeling is significantly greater in adult
      sinus specimens when compared with those of children with chronic sinusitis.

PMID- 12616189
TI  - Comparative study of cochlear damage with three perimodiolar electrode designs.
AB  - OBJECTIVE: To describe intracochlear insertion trauma caused by three
      perimodiolar cochlear implant electrodes. STUDY DESIGN: Descriptive histological
      study of 15 human cadaver temporal bones. METHODS: Fifteen cadaver temporal bones
      underwent surface preparation and were implanted with one of the following
      perimodiolar electrode arrays: Combi 40+PM (MedEl Corporation), HiFocus II
      (Advanced Bionics Corporation), or Contour (Cochlear Corporation). A
      cryosectioning technique was used to study horizontal sections at 200 microm
      intervals with the electrode in place. Image-enhanced videofluoroscopy and
      computer-assisted morphometrics were used to assess the mechanism of insertion
      trauma and to determine electrode position within the modiolus. RESULTS:
      Histological examination revealed varying degrees of damage to the spiral
      ligament, basilar membrane, and osseous spiral lamina. Using a novel grading
      system for electrode trauma, there was no statistically significant difference
      among the three electrodes. A literature search of histological studies of a
      commonly used "standard" electrode showed damage equal to or greater than that
      seen in the current study. CONCLUSIONS: Insertion trauma caused by periomodiolar
      electrodes occurs to an acceptable degree. Refinement of electrodes based on
      mechanisms of trauma may be able to further reduce damage.

PMID- 12616190
TI  - Postoperative magnetic resonance imaging findings after transtemporal and
      translabyrinthine vestibular schwannoma resection.
AB  - OBJECTIVES/HYPOTHESIS: Magnetic resonance imaging (MRI) has become the
      investigation of choice to follow up patients after vestibular schwannoma
      resection. STUDY DESIGN: Retrospective. METHODS: Postoperative MRI findings of 70
      patients after vestibular schwannoma resection through a transtemporal (n = 48)
      and a translabyrinthine (n = 22) approach were reviewed. Time-dependent changes
      in intensity, size, and shape of enhancement in the internal auditory canal
      before and after contrast administration, postoperative temporal lobe gliosis,
      and changes of fat grafts were evaluated. RESULTS: After vestibular schwannoma
      resection, all patients showed signal enhancements in the internal auditory canal
      ranging from a faint to high signal intensity in the first postoperative MRI, 3
      to 6 months after surgery. In the next MRI at 12 to 24 months after surgery, 30
      patients (43%) showed a decreased signal, 35 patients (50%) a stable enhancement,
      and 5 patients (7%) an increased enhancement in the internal auditory canal
      depicted as an intense nodular or mass-like pattern. In patients with decreased
      or stable enhancement, a residual tumor could be excluded in the following MRI
      scans, whereas in all patients with increased enhancements after 12 to 24 months,
      signal enhancement further increased and residual tumors were detected. Different
      degrees of temporal lobe gliosis were found in 15 of 48 cases (31%) after
      transtemporal tumor removal. Enhancement of fat grafts used in 22 cases decreased
      to different degrees in 14 cases (64%). CONCLUSIONS: Differentiation of residual
      tumor from scar tissue in the internal auditory canal after vestibular schwannoma
      resection requires close, long-term follow-up. Nodular and progressive
      enhancements in the internal auditory canal indicate residual tumor. Linear
      enhancement in the internal auditory canal has been found to be a common finding
      after vestibular schwannoma resection not associated with residual tumor.

PMID- 12616191
TI  - Hearing impairment and tinnitus pitch in patients with unilateral tinnitus:
      comparison of sudden hearing loss and chronic tinnitus.
AB  - OBJECTIVES: The objectives were to analyze the results of pitch-matching and
      loudness-balance testing in patients with unilateral tinnitus and to evaluate the
      relationship between audiological findings based on the tinnitus-affected and
      tinnitus-unaffected threshold differences and tinnitus pitch by using linear
      interpolation methods. In addition, the effects of the duration of the tinnitus
      on this relationship were investigated. Sudden sensorineural hearing loss with
      tinnitus was selected for the "acute tinnitus" group, and unilateral tinnitus
      with unknown disease and a duration of more than 3 months was selected for the
      "chronic tinnitus" group. STUDY DESIGN: Retrospective study of the clinical
      records of patients. METHODS: One hundred thirty-two patients with unilateral
      tinnitus (comprising 68 female [51.5%] and 64 male [48.5%] patients) were
      investigated as subjects. Their mean age was 50.4 years (SD = 15.8 y). All
      patients underwent otoneurological testing, including the pure-tone audiogram and
      pitch-matching and loudness-balance tests. RESULTS: The mean difference in the
      hearing threshold between the tinnitus-affected ear and the tinnitus-unaffected
      ear was largest near the tinnitus pitch in both the acute and the chronic
      tinnitus groups. However, the relationship between hearing impairments and
      tinnitus pitch was somewhat different in the two groups: It exhibited a single
      smooth peak in the acute tinnitus group but a bimodal peak in the chronic
      tinnitus group. CONCLUSION: The results suggest that tinnitus is related to
      hearing impairment in the same frequency region in patients with sudden
      sensorineural hearing loss with tinnitus or in patients with chronic tinnitus,
      whereas some instances of chronic tinnitus are caused by reorganization in
      cortical cells.

PMID- 12616192
TI  - Expression of a cathelicidin antimicrobial peptide is augmented in cholesteatoma.
AB  - OBJECTIVES/HYPOTHESIS: Antimicrobial peptides are active defense components of
      innate immunity. Their importance was confirmed at epithelial surfaces as
      immediate barrier effectors in preventing infection. Cathelicidins are peptide
      antibiotics that are receiving increasing attention. Several studies have shown
      that overexpression of cathelicidin results in augmented protection against
      bacterial infection and prevention of local infection and systemic invasion of
      microbes. The goal of the study was to investigate whether cathelicidin is
      upregulated in cholesteatoma epithelium compared with normal skin. STUDY DESIGN:
      Twenty patients from a prospective study of cholesteatoma tissues and normal
      skins were enrolled in the study. The specimens were divided into two portions.
      One portion was used for subsequent RNA studies; the other was used for
      immunohistochemical staining. METHODS: Reverse transcriptase-polymerase chain
      reaction was used to assess the expression levels of cathelicidin messenger RNA
      (mRNA) both in cholesteatoma and in normal skin. Presumptive concentration of
      cathelicidin mRNA and beta2-microglobulin mRNA was evaluated. Ratio of beta2
      microglobulin to cathelicidin was analyzed in each group. The expressions of
      cathelicidin in cholesteatoma and normal skin epithelium were investigated by an
      immunohistochemical technique. RESULTS: Cathelicidin mRNA in cholesteatoma
      epithelium was increased 5.5-fold compared with normal skin of the ear canal. In
      cholesteatoma epithelium, cathelicidin was located in all the layers, but in the
      normal skin it was expressed only in the granular and prickle cell layers.
      CONCLUSIONS: Cathelicidin is augmented in cholesteatoma epithelium, and the data
      in the present study are in agreement with the hypothesis that cathelicidin is
      likely to act as a key component in the first line of defense at the surface
      epithelium.

PMID- 12616194
TI  - Management of cholesteatoma: status of the canal wall.
AB  - OBJECTIVE/HYPOTHESIS: Management of chronic otitis media with cholesteatoma
      remains controversial. The purpose of the study is to examine factors associated
      with the surgical approach to manage cholesteatoma. STUDY DESIGN: A retrospective
      review. METHODS: A retrospective review was made of all primary cases of mastoid
      surgery for cholesteatoma performed at an otological center between 1995 and
      2000. During the study period, 486 ears underwent surgery for cholesteatoma. Data
      included procedures performed, location and extent of the disease, residual and
      recurrent disease, complications, reasons for staging the surgery, and duration
      of follow-up. RESULTS: The canal wall remained intact in 68.5% of ears. The
      majority of the remainder of the patients underwent a canal wall down technique
      with mastoid obliteration. Residual cholesteatoma was found in 26.9% of second
      procedures and in 2.7% of third procedures. CONCLUSIONS: The majority of patients
      with cholesteatoma can be adequately managed with a canal intact
      tympanomastoidectomy with staging. Otolaryngologists should consider a two-staged
      procedure as a viable management approach for chronic otitis media with
      cholesteatoma.

PMID- 12616193
TI  - Osteoclast stimulating and differentiating factors in human cholesteatoma.
AB  - OBJECTIVES: To investigate the expression of osteoclast-activating and
      differentiating factors and to study the occurrence of osteoclast precursor cells
      and osteoclasts in acquired human cholesteatoma tissue. METHODS: We examined 21
      cholesteatoma samples versus 18 normal auditory canal skin specimens for the
      expression of osteoprotegerin ligand (OPGL), osteoprotegerin (OPG), and
      macrophage-colony stimulating factor (M-CSF) using reverse transcriptase
      polymerase chain reaction (RT-PCR) and immunohistochemistry. Immunohistochemistry
      and computer-assisted microscopy using markers CD4, CD11a, CD11b, CD14, CD51,
      CD68, and TRAP obtained the detection of osteoclast cell lineage. RESULTS: An
      increased expression of the investigated cytokines M-CSF, OPG, and OPGL was
      demonstrated by immunohistochemistry and RT-PCR in cholesteatoma tissue compared
      with normal external meatal skin. Several CD4-positive cells exhibited a co
      expression for OPGL within the perimatrix of cholesteatoma. The presence of
      osteoclast precursor cells was confirmed in all samples of cholesteatoma tissue.
      CONCLUSIONS: This study reveals that the number of osteoclast precursor cells is
      markedly increased in the perimatrix of cholesteatoma tissue. Our results support
      a concept described for inflammatory arthritis: the inflammation related to
      cholesteatoma induces bone resorption by release of OPGL from activated T-cells
      and triggers osteoclastogenesis. This could be a major target for drugs to
      inhibit osteoclast formation and bone resorption and may be an adjunct in
      cholesteatoma management.

PMID- 12616195
TI  - Evidence against neonatal aspiration of keratinizing epithelium as a cause of
      congenital cholesteatoma.
AB  - OBJECTIVES/HYPOTHESIS: It has been suggested that congenital cholesteatoma may be
      caused by perinatal aspiration of squamous epithelium. STUDY DESIGN: Microscopic
      study of fetal temporal bones. METHODS: Thirty-one temporal bones from infants
      who died of sudden infant death syndrome before 1 year of age and 27 temporal
      bones obtained from preterm fetal deaths aged 4 to 8 months of fetal development
      were studied to assess signs of aspiration of squamous epithelium in the middle
      ear. RESULTS: None of the prenatal or postnatal temporal bones showed
      keratinizing epithelial cells or lanugo. A certain number of specimens displayed
      a nonspecific inflammatory lymphocytic infiltration. CONCLUSION: The data in the
      present study do not support the theory of amniotic fluid and squamous epithelial
      aspiration as an origin of congenital cholesteatoma.

PMID- 12616196
TI  - Gentamicin-induced hair cell death is not dependent on the apoptosis receptor
      Fas.
AB  - OBJECTIVES/HYPOTHESIS: The hair cells are the most vulnerable elements in the
      cochlea, and damage to them is the most common cause of sensorineural hearing
      loss. Understanding the intracellular events that lead to the death of hair cells
      is a key to developing protective strategies. The Fas death receptor-mediated
      apoptotic pathway is well studied and plays an important role in the elimination
      of damaged cells in a number of different cellular systems. We have studied the
      role of the Fas receptor in aminoglycoside-mediated toxicity in vitro. We
      employed the MRL/MpJ-Fas mouse, which does not express a functional Fas receptor.
      STUDY DESIGN: Response of Fas-deficient hair cells to gentamicin was compared
      with the response of normal hair cells in vitro. METHODS: Basal turn organ of
      Corti explants from p3-5 mice were maintained in tissue culture and treated with
      gentamicin for 72 hours. The explants were fixed and were stained with
      phalloidin, and counting was performed. RESULTS: There was no difference in hair
      cell loss between Fas mutant mice and control MRL/MpJ mice with a functional Fas
      receptor. CONCLUSION: The gentamicin-mediated hair cell death is not dependent on
      a functional Fas receptor.

PMID- 12616197
TI  - Intratympanic gentamicin for intractable Meniere's disease.
AB  - OBJECTIVE: The study aimed to analyze the results of the intratympanic injection
      of gentamicin as a treatment option for patients with unilateral Meniere's
      disease who were refractory to medical treatment. STUDY DESIGN: Prospective study
      in the setting of a tertiary care medical center. METHODS: Seventy-one patients
      with unilateral Meniere's disease according to 1995 American Academy of
      Otolaryngology-Head and Neck Surgery 1995 guidelines who had been unresponsive to
      medical therapy for at least 1 year were studied. Intratympanic injections of a
      prepared concentration of 27 mg/mL gentamicin were performed at weekly intervals
      until the development of symptoms and signs indicative of vestibular hypofunction
      in the treated ear. As the main outcome measure, the 1995 American Academy of
      Otolaryngology-Head and Neck Surgery criteria for reporting treatment outcome in
      Meniere's disease were used. The results of treatment were expressed in terms of
      control of vertigo, disability status (functional level and degree of overall
      impairment evaluated by the Dizziness Handicap Inventory and the University of
      California Los Angeles Dizziness Questionnaire), hearing level, and quantitative
      measurement of vestibular function. RESULTS: Vertigo was controlled in 83.1% of
      the 71 patients. Recurrence of vertigo spells after initially complete control
      was noted in 17 patients. In 13 of these patients, this was cured by another
      course of intratympanic injections of gentamicin. Functional level and measures
      of self-reported handicap were significantly and promptly lowered after treatment
      in the patients who attained control of vertigo. Hearing level as pure-tone
      average was unchanged 2 years after treatment, but hearing loss as a result of
      gentamicin injections occurred in 23 patients at the end of treatment and in 9
      and 11 patients at 3 months and 2 years after the treatment, respectively.
      Vestibular function was kept normal or reduced in 49.3% of the patients, whereas
      in the rest of the patients vestibular areflexia was observed. Control of vertigo
      did not depend on the amount of vestibular damage. CONCLUSIONS: Ending weekly
      intratympanic injections when clinical signs of vestibular deafferentation appear
      can control vertigo in the majority of patients, and it is a useful alternative,
      together with other surgical options, for the treatment of patients with
      Meniere's disease who do not respond to medical treatment.

PMID- 12616198
TI  - Development of the first force-controlled robot for otoneurosurgery.
AB  - OBJECTIVE: In some surgical specialties (eg, orthopedics), robots are already
      used in the operating room for bony milling work. Otological surgery and
      otoneurosurgery may also greatly benefit from the enhanced precision of robotics.
      STUDY DESIGN: Experimental study on robotic milling of oak wood and human
      temporal bone specimen. METHODS: A standard industrial robot with a six-degrees
      of-freedom serial kinematics was used, with force feedback to proportionally
      control the robot speed. Different milling modes and characteristic path
      parameters were evaluated to generate milling paths based on computer-aided
      design (CAD) geometry data of a cochlear implant and an implantable hearing
      system. RESULTS: The best-suited strategy proved to be the spiral horizontal
      milling mode with the burr held perpendicular to the temporal bone surface. To
      reduce groove height, the distance between paths should equal half the radius of
      the cutting burr head. Because of the vibration of the robot's own motors, a high
      oscillation of the SD of forces was encountered. This oscillation dropped
      drastically to nearly 0 Newton (N) when the burr head made contact with the dura
      mater, because of its damping characteristics. The cutting burr could be kept in
      contact with the dura mater for an extended period without damaging it, because
      of the burr's blunt head form. The robot moved the burr smoothly according to the
      encountered resistances. CONCLUSION: The study reports the first development of a
      functional robotic milling procedure for otoneurosurgery with force-based speed
      control. Future plans include implementation of ultrasound-based local navigation
      and performance of robotic mastoidectomy.

PMID- 12616199
TI  - Cochlear implantation concurrent with translabyrinthine acoustic neuroma
      resection.
AB  - OBJECTIVES/HYPOTHESIS: Cochlear implants provide successful auditory
      rehabilitation for patients with profound sensorineural hearing loss who do not
      derive at least marginal benefit from conventional hearing aids. Patients with
      neurofibromatosis type 2 can present with bilateral profound sensorineural
      hearing loss caused by bilateral vestibular schwannomas. Auditory rehabilitation
      in these patients can be challenging. We present the case of one such patient who
      underwent a concurrent translabyrinthine vestibular schwannoma resection and
      cochlear implantation in the same ear. STUDY DESIGN: A case report and review of
      the literature. METHODS: Review the patient's medical record and MEDLINE
      literature search. RESULTS: The patient presented with a relatively small tumor
      that was situated in the fundus of the internal auditory canal with
      intralabyrinthine extension. Postoperative performance with implant stimulation
      was in the higher range of that for other cochlear implant patients. CONCLUSIONS:
      To the best of our knowledge, this is the first case reported of simultaneous
      cochlear implant and translabyrinthine acoustic neuroma resection in the same ear
      of a patient with neurofibromatosis type 2.

PMID- 12616200
TI  - Tutorials in clinical research, part VIII: Creating a journal club.
AB  - OBJECTIVE: The present report is the eighth in a series of sequential tutorials
      entitled "Tutorials in Clinical Research." The objective of the report is to
      provide the reader with information to create or refine a journal club. STUDY
      DESIGN: Tutorial. METHODS: The authors met weekly for 3 months and discussed the
      features of a journal club that would be of interest to otolaryngologists. A
      Medline search provided a number of relevant articles for review. RESULTS: The
      report is organized into the following sections: Introduction, History of Journal
      Club, Goals of Journal Club, Basic Organization, Factors Associated With
      Successful Journal Clubs, Design of Journal Club, Selecting Literature,
      Evaluation of Journal Club, and Summary. CONCLUSIONS: There is a paucity of
      information within the otolaryngology literature regarding the journal club and
      the significant role it can play in physician education. The flexible nature of
      the journal club gives it the potential to address many educational needs. Its
      relevance has never been greater.

PMID- 12616201
TI  - Single cell analysis of adenoid CD5+ B cells and their protective contributions
      to nasopharyngeal immunity.
AB  - OBJECTIVES: CD5+ B cells are phenotypically and functionally distinct from the
      conventional (CD5-) B cells, and the function of CD5+ B cells in the upper
      respiratory tract remains unknown. A previous study showed that immunoglobulin A
      producing cells in the adenoid play a protective role in the nasopharynx. In the
      present study, the contribution of adenoid CD5+ B cells to nasopharyngeal
      immunity at the single cell level was investigated. STUDY DESIGN: In vitro
      laboratory study. METHODS: Mononuclear cells were isolated from adenoids of
      children aged 1 to 12 years, and the frequency of CD5+ B cells was determined by
      flow cytometry. The numbers of cells producing immunoglobulin M, immunoglobulin
      G, and immunoglobulin A in sorted adenoid CD5+ B cells were determined by enzyme
      linked immunospot assay. Further, to characterize adenoid CD5+ B cells, the
      expression of various surface molecules was analyzed by flow cytometry. RESULTS:
      The results showed that adenoids of young children contain a relatively large
      number of CD5+ B cells, which have a greater capacity for antibody production
      than do CD5- B cells. CD5+ B cells also differed from CD5- B cells in the
      expression of interleukin receptors Il-4R, IL-5R, and IL-10R as well as CD27, B7
      1, B7-2, Fas, and Bcl-2. CONCLUSIONS: These findings suggest that adenoid CD5+ B
      cells contribute to protective immunity by forming a first line of defense in the
      upper respiratory tract of young children and that they are probably regulated in
      a manner that differs from that of CD5- B cells.

PMID- 12616202
TI  - Dog bites of the scalp, face, and neck in children.
AB  - OBJECTIVE: To update the surgical management of injuries from dog bites of the
      scalp, face, and neck in children. STUDY DESIGN: Retrospective case review.
      METHODS: A retrospective review of 44 children with dog bites of the scalp, face,
      and neck was carried out at the University of New Mexico Health Sciences Center
      (Albuquerque, NM) between January 1, 1995, and December 31, 2000. Data on
      demographics, hospitalization, surgery, and outcome were collected and entered
      into an Access 2000 database. RESULTS: The children ranged in age from 1.0 to
      12.1 years. The mean age of the study population was 5.2 years (+/-2.9 y standard
      deviation). Sixteen severely injured children (36%) were hospitalized to repair
      damage to the airway and blood vessels of the neck or to treat hemodynamic
      compromise. The length of stay in hospital ranged from 1 to 16 days. The most
      common injury in these children was a scalp laceration (57%). Twenty-six less
      severely injured children (64%) were not hospitalized. The most common surgery in
      these children (88%) was repair of multiple facial lacerations. Attention deficit
      hyperactivity disorder was noted in the medical records of 12 children (29%).
      Complications occurred in five children (31%) who were hospitalized and nine
      children (35%) who were not hospitalized. CONCLUSIONS: The injured child is
      typically a 5-year-old boy attacked by a familiar dog at home or in the local
      neighborhood. Children with the diagnosis of attention deficit hyperactivity
      disorder appear to be at a higher risk of dog bite injuries and should be
      monitored during interactions with dogs. The goal of surgical management for
      severely injured children is to avoid immediate mortality and to establish a
      schedule of multiple-staged procedures for revision surgeries. An optimal
      cosmetic result is the principal goal for less severely injured children.

PMID- 12616203
TI  - Endoscopic reconstruction of anterior and middle cranial fossa defects using
      acellular dermal allograft.
AB  - OBJECTIVE: To report our experience in reconstructing defects of the anterior and
      middle cranial fossa skull base using endoscopic placement of acellular dermal
      allograft (AlloDerm, LifeCell Corp., The Woodlands, TX). STUDY DESIGN:
      Retrospective chart review. METHODS: In all cases, the skull base repair was
      completed with a similar technique. After identification of the defect
      boundaries, endoscopic transnasal repair was performed through placement of a
      layered reconstruction of acellular dermal allograft, septal bone/cartilage, and
      acellular dermal allograft, which were all placed on the intracranial side of the
      defect. A mucosal free graft was draped over the reconstruction. Fibrin glue was
      used to hold the mucosal graft in place, and the reconstruction was supported by
      both absorbable and nonabsorbable nasal packing. RESULTS: Eight patients with
      nine skull base defects underwent the procedure for repair of cerebrospinal fluid
      rhinorrhea. All defects were successfully repaired. One patient underwent
      successful reconstruction of bilateral ethmoid roof defects that resulted from
      endoscopic resection of ethmoid adenocarcinoma. Twenty-four patients underwent
      primary resection of hypophyseal adenomas. Twenty-three patients had
      macroadenomas, and intraoperative cerebrospinal fluid leaks were noted in 11
      patients. Sellar repairs after trans-sphenoidal hypophysectomy were successful in
      22 of 24 patients. One patient with hypophysectomy required reoperation (1 of 24
      [4%]) for secondary closure of a cerebrospinal fluid leak. Serious complications
      were avoided in all patients. Patients were followed for a period ranging from 5
      to 57 months (mean period, 34 mo). CONCLUSIONS: Acellular dermal allograft can be
      successfully used for the reconstruction of anterior and middle cranial fossa
      skull base defects. This allograft, which is easy to manipulate endoscopically,
      provides an effective seal and barrier in skull base reconstruction and avoids
      the need for a donor site.

PMID- 12616204
TI  - Olfactory neuroblastoma: past, present, and future?
AB  - OBJECTIVE: To consider the long-term survival and outcomes in patients with
      olfactory neuroblastoma undergoing craniofacial resection. STUDY DESIGN: A single
      center prospective cohort study. METHODS: All patients with olfactory
      neuroblastoma treated in a 23-year period with craniofacial resection (with or
      without radiotherapy) were analyzed; a multivariate analysis was included.
      RESULTS: Forty-two patients aged 12 to 70 years were assessed, 83% of whom had
      received no preceding treatment. Craniofacial resection was used in all cases,
      combined with radiotherapy in 24 patients (57%). Duration of follow-up ranged
      from 2 to 206 months (mean follow-up period, 57 mo). The disease-free actuarial
      survival and overall survival were 77% and 61% at 5 years and 53% and 42% at 10
      years, respectively. A Cox regression analysis identified intracranial extension
      and orbital involvement as independent factors affecting outcome. CONCLUSION:
      Craniofacial resection combined with radiotherapy offers the gold standard of
      care against which other approaches such as endoscopic resection must be judged.

PMID- 12616205
TI  - Endoscopic and transconjunctival orbital decompression for thyroid-related
      orbital apex compression.
AB  - OBJECTIVE: To evaluate the efficacy and safety of a combined endoscopic and
      transconjunctival orbital decompression in patients with thyroid-related
      orbitopathy with orbital apex compression. STUDY DESIGN: Retrospective review.
      METHODS: A sequential series of patients with thyroid-related orbitopathy
      presenting with orbital apex compressive myopathy with and without optic
      neuropathy who were undergoing combined endoscopic and transconjunctival
      decompression by the same surgeons from 1992 to 2001 was reviewed. Patients were
      regularly evaluated preoperatively and postoperatively over a 3- to 55-month
      period to record the effects of this approach on visual acuity, Hertel
      exophthalmometry, and diplopia. Complications and secondary ophthalmological
      procedures were reviewed. RESULTS: Between 1992 and 2001, 72 combined endoscopic
      and transconjunctival decompressions were performed on 41 patients with orbital
      apex compression. Visual acuity improved in 89.3% of the patients with
      compressive optic neuropathy (P <.0005) and in 34.1% of those without neuropathy.
      Proptosis was reduced by 3.65 mm, on average. There was one case of transient
      intraoperative cerebrospinal fluid extravasation at the site of the optic nerve
      decompression, and one patient developed epistaxis. CONCLUSIONS: The study
      supports the treatment of thyroid-related orbital apex compression with and
      without compressive optic neuropathy by a combined transconjunctival and
      endoscopic approach. This approach offers short hospital stays, excellent visual
      recovery, and minimal complications in patients with thyroid-related orbital apex
      compressive myopathy and related compressive optic neuropathy. The beneficial
      effects observed in the patients with visual loss continued to improve over time
      and were significant (P <.001).

PMID- 12616207
TI  - Distribution of respiratory mucin proteins in human nasal mucosa.
AB  - OBJECTIVES/HYPOTHESIS: The upper respiratory tract is involved in many acute and
      chronic respiratory tract diseases that present with the symptom of mucus
      hypersecretion. Mucin genes that encode for the backbone of glycoproteins
      contribute to the viscoelastic property of airway mucus. We examined the cellular
      expression and distribution of two major respiratory mucus-forming glycoproteins,
      MUC5AC and MUC5B, in normal human nasal tissues. METHODS: Immunohistochemical
      analysis using polyclonal antibodies against the mucins MUC5AC and MUC5B was
      performed in normal human nasal tissues. RESULTS: An abundant staining of
      submucosal mucus gland and epithelial goblet cells for MUC5B was found.
      Immunohistochemical analysis of MUC5AC showed staining of surface epithelium
      goblet cells, whereas there was no staining of glandular cells. Comparison of the
      expression to lower airways revealed a similar pattern of expression of both
      mucins. CONCLUSIONS: The data in the present study demonstrated the localization
      of the two major respiratory mucin proteins in human nasal mucosa with a similar
      distribution of expression of MUC5AC and MUC5B in normal upper and lower airways.
      Mucin protein expression parallels that of mucin messenger RNA expression.

PMID- 12616206
TI  - Comparison of the effects of radiofrequency tissue ablation, CO2 laser ablation,
      and partial turbinectomy applications on nasal mucociliary functions.
AB  - OBJECTIVES: One of the major causes of chronic nasal airway obstruction is
      disease of the inferior turbinate. However, there is no agreement on how to deal
      with this problem. Comparison was made of the nasal functions after treatment by
      radiofrequency tissue ablation, laser ablation, and partial turbinectomy using
      subjective symptom scores and objective tests. STUDY DESIGN: Prospective,
      randomized clinical trial. METHODS: The study was conducted on three groups of 45
      adult volunteer patients with symptoms and signs of nasal obstruction and
      stuffiness related to enlarged turbinates. In group A, laser ablation was applied
      to the inferior turbinate on one side and partial turbinectomy to the inferior
      turbinate on the other side. In group B, radiofrequency tissue ablation was
      applied to the inferior turbinate on one side and partial turbinectomy to the
      inferior turbinate on the other side. In group C, patients who were not treated
      by any surgical techniques were the control subjects. Clinical examinations,
      visual analogue scales, rhinomanometry, and isotopic study of nasal mucociliary
      transport time were used to assess treatment outcomes. RESULTS: At 12 weeks after
      surgery, the nasal mucociliary transport time results were compared in the same
      patients. The average time was 25.60 minutes on the side where laser ablation was
      applied and 11.40 minutes on the side where partial turbinectomy (PT) was
      applied. In the patients on whom radiofrequency tissue ablation and partial
      turbinectomy were applied, the average nasal mucociliary transport time was 10.33
      minutes on the radiofrequency tissue ablation side, whereas it was 11.33 minutes
      on the partial turbinectomy side. Rhinomanometric measurements demonstrated a
      significant decrease in nasal resistances at 12 weeks in both sides in groups A
      and B. CONCLUSIONS: In the study it was demonstrated that radiofrequency tissue
      ablation to the turbinate is effective in improving nasal obstruction objectively
      and in preserving nasal mucociliary function. Laser ablation of the turbinate is
      effective in improving the nasal obstruction; however, it disturbs the
      mucociliary function significantly. With the partial turbinectomy technique,
      results obtained were similar to the results with the radiofrequency tissue
      ablation technique.

PMID- 12616208
TI  - Is the external laryngeal nerve an exclusively motor nerve? The cricothyroid
      connection branch.
AB  - OBJECTIVES: To obtain an accurate morphological description of the nerve that
      provides communication between the external laryngeal nerve and the recurrent
      laryngeal nerve in a large sample of human larynges. STUDY DESIGN: Morphological
      study of human larynges. METHODS: Microdissection of 103 human larynges obtained
      from necropsies was performed. Both the external laryngeal nerve and the
      recurrent laryngeal nerve were identified and dissected. The existence of a
      communication between the two nerves was evaluated. RESULTS: A neural
      communication between the external laryngeal nerve and the recurrent laryngeal
      nerve was found in 85% of the larynges studied (bilaterally in 44% and
      unilaterally in 41%). Two patterns of communication (with single or double
      branches) were found. The communication between the nerves can appear at
      different levels, giving off collateral branches to the cricothyroid muscle
      (23%), the cricothyroid joint capsule (49%), and the subglottic mucosa (50%).
      CONCLUSIONS: The nerve supply of the human larynx is more complex than
      classically considered. Our study does not support the classic neuroanatomical
      belief that the external laryngeal nerve is purely a motor nerve to the
      cricothyroid muscle. Our results reveal that it carries sensory and motor fibers
      on to other muscles (thyroarytenoid) or regions (subglottis mucosa and
      cricothyroid joint), as has been demonstrated in experimental studies in cats and
      dogs.

PMID- 12616209
TI  - Translaryngeal tracheostomy: experience of 340 cases.
AB  - OBJECTIVE: To describe the authors' initial experience with a new and innovative
      dilational translaryngeal tracheostomy bedside technique. STUDY DESIGN: A
      prospective documentation of 340 patients who received an elective translaryngeal
      tracheostomy in a multidisciplinary, tertiary care intensive care unit during a
      45-month period. RESULTS: All translaryngeal tracheostomy procedures but one were
      completed successfully; one was aborted because of bleeding from a thyroid vein.
      Minor perioperative complications occurred in 42% of patients, which caused no
      adverse effects. The most common complication was arterial desaturation occurring
      in 17% of patients; this was short-lived, and the lowest saturation was 79%.
      Blood loss was minimal (<5 mL) in all but one case, despite an elevated
      international normalized ratio (INR) and partial thromboplastin time in 42% and
      41% of patients, respectively, and a low platelet count in 13% of patients.
      CONCLUSIONS: Translaryngeal tracheostomy is a safe and reliable technique and can
      also be used in patients with unstable cervical spines and bleeding diathesis. It
      has become the authors' procedure of choice for an elective bedside tracheostomy
      in the intensive care unit.

PMID- 12616210
TI  - Vocal cord palsy resulting from spontaneous carotid dissection.
AB  - OBJECTIVES/HYPOTHESIS: Vocal cord palsy has a variety of causes, such as
      malignant tumors of the thyroid, lung, or upper mediastinum, aortic aneurysm,
      surgery of the thyroid, and infectious diseases. STUDY DESIGN: Case report.
      METHODS: A 43-year-old biologist had a holocephalic headache and right-sided neck
      pain for 1 day. Five days later, he developed paralysis of the right-side vocal
      cord. In addition, an angiotensin converting enzyme (ACE) inhibitor was
      administered because the patient had high systolic and diastolic blood pressures,
      which were formerly not known to the patient. Five days after admission, a
      temporary sensorimotor hemiparesis occurred. RESULTS: Neurological examination
      revealed, in addition to the known paralysis of the right-side vocal cord, right
      side palatoplegia, right-side hypoglossal nerve palsy, and mild dysphagia. Duplex
      sonography showed evidence of lumen narrowing of the right-side internal carotid
      artery caused by an hypoechogenic mural hematoma. Magnetic resonance imaging (0.5
      T, Philips Gyroscan) revealed a circumscribed dissection of the right-side
      internal carotid artery from the carotid bifurcation to the petrosal segment. The
      diffusion-weighted magnetic resonance imaging scan of the brain also demonstrated
      multiple embolic ischemic lesions in the right hemisphere. CONCLUSION: Internal
      carotid artery dissection must be included in the differential diagnosis of lower
      cranial nerve palsy and should be assessed by duplex ultrasonography and magnetic
      resonance imaging.

PMID- 12616211
TI  - Intracordal injection of autologous fat in patients with unilateral laryngeal
      nerve paralysis: long-term results from the patient's perspective.
AB  - OBJECTIVE: Based on 80 patients with a previously nonsurgically treated
      unilateral laryngeal nerve paralysis (ULNP) and according to the patient's self
      assessment, the authors document the long-term results achieved with the
      intracordal injection of autologous fat. STUDY DESIGN: Retrospective series,
      inception cohort. METHODS: Kaplan-Meier actuarial life table method and
      univariate analysis. RESULTS: None of the 80 patients died in the immediate
      postoperative period. Morbidity included hematoma at the donor site (in three
      patients), development of an intracordal cyst at the injection site (in three
      patients), fat extrusion at the injection site (in one patient), and temporary
      tracheotomy (in one patient). The initial and ultimate overall success rates were
      96.2% and 77.2%, respectively. In univariate analysis, none of the variables
      under analysis (gender, age, associated neurological lesions, associated
      pneumonectomy, associated neoplasia, cause of the ULNP, side of the ULNP, nerve
      involved, delay between the onset of the ULNP and the intracordal injection,
      severity of the symptoms, mode of harvesting the autologous fat, and surgeon who
      performed the injection) was statistically related to the ultimate outcome after
      the intracordal injection of autologous fat. Among the group of 45 patients in
      whom the intracordal injection was initially considered to be successful with no
      further recovery of motion of the true vocal cord and a minimum survival of 12
      months, the ultimate overall success rate was 62.2%, and the 3-month, 6-month,
      and 12-month Kaplan-Meier actuarial estimates for success were 91.1%, 72.8%, and
      63.1%, respectively. CONCLUSIONS: In the present study, data confirm that the
      intracordal injection of autologous fat is a useful and safe procedure in
      patients with ULNP. However, the impossibility of exactly predicting the amount
      of resorption of the injected fat and the lack of predictability of the duration
      of the results, together with the good and stable results achieved at the
      authors' department with the medialization thyroplasty led the authors to reduce
      its current use.

PMID- 12616212
TI  - Altered fractionation and/or adjuvant chemotherapy in definitive irradiation of
      squamous cell carcinoma of the head and neck.
AB  - OBJECTIVE: To review the roles of altered fractionation and adjuvant chemotherapy
      in the treatment of patients with squamous cell carcinomas of the head and neck.
      STUDY DESIGN: Review of the pertinent literature. METHODS: The literature
      pertaining to altered fractionation and/or adjuvant chemotherapy for patients
      with squamous cell carcinomas of the head and neck was reviewed to define the
      optimal combination of radiotherapy and adjuvant chemotherapy. RESULTS: The
      efficacy of altered fractionation compared with conventional fractionation
      depends on the fractionation schedule employed. Some hyperfractionated and
      accelerated fractionation schedules have resulted in improved locoregional
      control but no significant improvement in overall survival. In contrast to
      induction and maintenance chemotherapy, concomitant chemotherapy appears to
      result in improved locoregional control and survival. CONCLUSIONS: Altered
      fractionation and/or concomitant chemotherapy results in improved locoregional
      control and, in some instances, survival for patients with advanced head and neck
      cancer. Depending on primary site, the applicability of these aggressive
      treatment regimens is limited by an enhanced probability of severe complications
      as tumor volume increases. The optimal combination of these modalities is unclear
      and will be defined by future prospective trials.

PMID- 12616213
TI  - Genetically engineered tumor cell vaccine in a head and neck cancer model.
AB  - OBJECTIVES: Using a murine model, a novel tumor vaccine for head and neck
      squamous cell carcinoma expressing the granulocyte-macrophage colony stimulating
      factor (GM-CSF) gene was evaluated for its ability to protect against tumor
      challenge. STUDY DESIGN: Mice vaccinated in the floor of the mouth with the GM
      CSF tumor cell vaccine were challenged with parental tumor cells, and subsequent
      tumor development was monitored. Specificity of the antitumor response was
      demonstrated by vaccinating the mice and then challenging them with an unrelated
      but syngeneic radiation-induced fibrosarcoma tumor cell line, RIF. Irradiated
      (only) tumor cells were used as a control to see whether an augmented antitumor
      response was attributable to possible increased immunogenicity that could
      theoretically be induced by the irradiation. METHODS: The GM-CSF gene was
      transduced into tumor cells via a retroviral vector. The tumor cells were
      irradiated to prevent replication in vivo. GM-CSF concentrations were determined
      using ELISA, and physiological activity was confirmed using a biological assay
      with a GM-CSF-dependent cell line. RESULTS: Vaccination with genetically
      engineered tumor cells significantly protected against subsequent tumor challenge
      (5% level) when compared to control groups. Mice were not protected when
      vaccinated and challenged with the unrelated tumor cell line, RIF. Mice
      vaccinated with irradiated (only) tumor cells were not protected, either.
      CONCLUSIONS: Vaccination with genetically engineered tumor cells offers
      significant protection from later tumor challenge. The response is systemic and
      tumor specific, not due to an inflammatory response. Irradiation of the tumor
      cells does not account for the augmented antitumor response. This work supports
      the continued investigation of the GM-CSF tumor vaccine for the treatment of head
      and neck squamous cell carcinoma.

PMID- 12616215
TI  - Frozen section in a cytological diagnosis of thyroid follicular neoplasm.
AB  - OBJECTIVE/HYPOTHESIS: Fine-needle aspiration biopsy is the most accurate
      diagnostic test for thyroid nodules, its only limitation being the diagnosis of
      follicular neoplasm that does not distinguish between benign and malignant
      follicular lesions. STUDY DESIGN: To determine the utility of intraoperative
      frozen-section analysis in cases of a cytological diagnosis of follicular
      neoplasm, a retrospective review of 66 patients with a solitary thyroid nodule
      and follicular neoplasm who underwent thyroid surgery was carried out. METHODS:
      Fine-needle aspiration was classified following the Papanicolaou Society of
      Cytopathology Classification, and frozen section was defined as malignant or
      "deferred." If a malignant diagnosis was made by frozen-section analysis, a total
      thyroidectomy was carried out. The extension of thyroid surgery in the deferred
      cases was based on the definitive histological diagnosis. RESULTS: Sixty-four
      cases were classified as deferred, and two as suspect for malignancy. Among the
      64 deferred cases, 15 were malignant in the final pathological findings, and 49
      were benign. The two suspect cases were papillary carcinoma. Frozen-section
      analysis classified 2 of 17 (11.7%) cases as follicular variant of papillary
      carcinoma that could not be diagnosed by cytological study. However, these two
      cases had a strong clinical evidence of malignancy. CONCLUSION: The routine use
      of frozen-section analysis is useless in cases of cytological diagnosis of
      follicular neoplasm on fine-needle aspiration biopsy, because of the low
      probability of achieving the diagnosis of follicular carcinoma and the inability
      to provide additional information apart from the clinical and the cytological
      data.

PMID- 12616214
TI  - Highlights in the evolution of diagnosis and treatment of laryngeal cancer.
AB  - OBJECTIVES: To present selected highlights from the evolution of diagnosis of
      laryngeal disease and treatment of laryngeal cancer from ancient Greece until the
      20th century. STUDY DESIGN: Historical study of diagnosis of laryngeal disease
      and treatment of laryngeal cancer from the ancient Greek medical scriptures until
      the most recent evolutional steps in the 20th century. METHODS: Original Greek
      language texts of ancient and Byzantine medical writers were studied and
      literature on history of medicine was investigated to reveal early knowledge of
      diagnostic and therapeutic techniques for laryngeal disease and cancer of the
      larynx. RESULTS: Diseases of the upper aerodigestive tract were known and treated
      by ancient Greek physicians, and, later, Byzantine doctors, apart from preserving
      ancient medical concepts, contributed their own ideas, mainly about surgery and
      postoperative care. The initial therapeutic approach for the disorders caused by
      laryngeal tumors was either tracheotomy or endotracheal intubation in an attempt
      to prevent suffocation. In more recent times, construction of the laryngoscope
      and other modern examination instruments, as well as the final acceptance of
      histological diagnosis based on tissue biopsy, has allowed for accurate diagnosis
      and successful treatment of laryngeal lesions. Preoperational biopsy, application
      of pharyngoesophageal speech and advanced vocal devices for the laryngectomees,
      and invention of antibiotic and anesthetic agents had led, by the middle of the
      20th century, to the establishment of extended and radical surgical techniques as
      optional treatment for laryngeal cancer. In addition, the discovery of x-rays and
      radium introduced radiotherapy as an alternative in the treatment procedure for
      cancer of the larynx. CONCLUSION: Progress in the evolution of laryngological
      diagnosis and practice demanded efforts by many daring and courageous
      investigators and surgeons, contributing new ideas and techniques in the
      development of modern laryngology.

PMID- 12616216
TI  - Preoperative parathyroid localization: correlating false-negative technetium 99m
      sestamibi scans with parathyroid disease.
AB  - OBJECTIVE/HYPOTHESIS: The recent trend toward minimally invasive directed
      parathyroid surgery has increased the surgeon's reliance on preoperative
      parathyroid localization. Technetium Tc 99m sestamibi scanning is generally
      viewed as the gold standard for preoperative localization, with reported
      sensitivities of 75% to 100% and specificities of 75% to 90%. However, in each
      reported series there exists a group of patients in whom preoperative
      localization is either equivocal or negative. STUDY DESIGN: We focused on a
      subset of patients from our parathyroid database with false-negative sestamibi
      (MIBI) scans, in an attempt to elucidate features that could affect these
      studies. We identified 20 patients with negative preoperative scans and confirmed
      parathyroid disease. We compared them with 22 consecutive patients with positive
      scans, correlating the following variables: patient age, gender, concomitant
      thyroid disease (Hashimoto's thyroiditis, papillary thyroid carcinoma, thyroid
      adenoma), preoperative parathyroid hormone values, location and number of
      enlarged parathyroid glands, parathyroid weight, and the relative proportion of
      chief cells, clear cells, oxyphil cells, and adipose tissue. METHODS:
      Retrospective chart review of clinicopathological and radiological findings.
      RESULTS: We found that patients with false-negative scans were more likely to
      have an enlarged parathyroid containing a high proportion of clear cells (P
      =.01). A trend was seen (P =.1) correlating increased parathyroid fat content and
      false-negative scans. Conversely, positive preoperative scans were more likely to
      be associated with a higher percentage of oxyphil cells (P =.02). Univariate
      analysis for other variables, as well as logistic regression analysis, did not
      achieve statistical significance. CONCLUSIONS: To date, the present study is the
      largest clinicopathological review of patients with false-negative sestamibi
      scans. Technetium Tc 99m uptake correlates with parathyroid oxyphil cell content,
      and false-negative scans can occur with parathyroid glands containing
      predominantly clear cells.

PMID- 12616217
TI  - Swallow function in patients before and after intra-arterial chemoradiation.
AB  - OBJECTIVES/HYPOTHESIS: To prospectively evaluate swallow function in patients
      with advanced head and neck cancer before and after completion of intra-arterial
      chemoradiation therapy and planned neck dissection. STUDY DESIGN: Prospective
      nonrandomized study. METHODS Swallow function was evaluated in 11 patients with
      resectable T4 and selected T3 head and neck cancer before and, on average, 19
      weeks after completion of treatment. RESULTS: The Performance Status Scale
      demonstrated worse scores for both eating in public (P =.004) and normalcy of
      diet (P =.004) after treatment. Patients who underwent neck dissections had
      significantly worse scores (P =.02) in normalcy of diet. A significant decline
      was noted in swallowing functional measures at the time of the repeat evaluation
      (P =.02). Videofluoroscopic swallow studies revealed altered swallow function in
      9 of 11 patients before treatment, with aspiration seen in 3 patients. Following
      treatment, the incidence of aspiration increased to seven patients. Tongue base
      retraction, reduced laryngeal elevation, and increased laryngeal vestibule
      penetration of thick liquid were all statistically significantly worse after
      treatment. The overall score on the quality of life instrument was not
      significantly changed from before to after treatment. CONCLUSIONS: The majority
      of patients demonstrated significantly worse swallow function on all three
      methods of analysis at 19 weeks after completion of treatment. Continued detailed
      monitoring of patients' swallow function is critical in determining long-term
      effects of intra-arterial chemoradiation therapy and neck dissection.

PMID- 12616218
TI  - Management of the high jugular bulb in translabyrinthine surgery.

PMID- 12616219
TI  - [Hypertension and stress].
AB  - Stress and adjustment to stress involve pathophysiological processes operating in
      the cardiovascular system, particularly concerning high blood pressure. Stress
      and high blood pressure are closely linked. Stress induces transient
      psychosomatic-related increases in blood pressure, but can also induce more
      permanent rise in blood pressure when associated with other environmental,
      psychological, or genetic risk factors. Symptomatic treatment of high blood
      pressure requires medicinal antihypertensive therapy; anti-stress therapy is an
      effective but not sufficient complement.

PMID- 12616220
TI  - [Per and early postoperative use of low molecular weight heparin in carotid
      surgery].
AB  - The goal of this study was to evaluate per and postoperative use of nadroparin
      during carotid surgery with mortality and neurologic morbidity as primary end
      points. From January 1995 to December 1999, 237 procedures were performed on 215
      patients for isolated carotid surgery; 57% were symptomatic. Surgery was
      performed under general anesthesia. Before clamping, patients received an
      intravenous bolus of 70 UI/kg of nadroparin. Shunting was used in 40% of
      patients. Postoperatively, from the 6(th) hour, nadroparin was given
      subcutaneously, 2,850 UI or 3,800 UI every 12 hours depending on the patient
      weight (less or more than 70 kg). The only biologic surveillance was platelet
      count twice a week. Antiplatelet drugs were given at day 2. Completion Duplex
      scan was performed before day 30. Seven postoperative ischemic strokes (3 non
      disabling) occurred including one fatal stroke. Another patient died at day 25
      from inaugural duodenal bleeding due to pancreas cancer. The 30 days stroke or
      death rate was 3.37% (5.92% in symptomatic; 0% in asymptomatic). No hemorrhagic
      stroke occurred. Four patients were reoperated for cervical hematoma (1.68%). No
      thrombocytopenia occurred. Duplex scan, performed on 235 operated carotid
      arteries, showed 2 asymptomatic carotid thromboses. No other cardiovascular
      complication was found on clinical data. These results are comparable to
      published literature data in prospective as well as retrospective studies. Per
      and postoperative use of nadroparin in carotid surgery gave results similar to
      previously published reports in terms of mortality, neurologic morbidity and
      hematoma. Its easy use, needing only 2 injections a day and platelet count, with
      a reduction of the risk of heparin-induced thrombocytopenia make the use of
      nadroparin very attractive during the perioperative period.

PMID- 12616221
TI  - [Mycotic aneurysm of the subrenal abdominal aorta: extra anatomical
      reconstruction in five patients].
AB  - Between 1988 and 2001, five patients with mycotic aneurysm of the abdominal aorta
      underwent surgery. Extra-anatomical reconstruction with axillo-bifemoral bypass
      grafting was performed in all patients. The hospital mortality rate was 20%.
      During the follow-up period two patients presented thrombosis of the axillo
      bifemoral bypass, descending aorto-bifemoral bypass was performed in one. Extra
      anatomic revascularization is a satisfactory procedure in the treatment of
      mycotic abdominal aortic aneurysm. The results are acceptable and the prognosis
      is mainly related to the underlying pathology and the severity of the infection.

PMID- 12616222
TI  - [Effect of elastic stockings on edema related to chronic venous insufficiency.
      Videocapillaroscopic assessment].
AB  - AIM: To evaluate the effect of class II (23-32 mm Hg) compression stockings on
      the edema of the ankle in patients with chronic venous insufficiency (CVI), and
      to assess the relationship between the microvascular phenomenon and the volume of
      the leg. MATERIAL AND METHOD: 11 patients (19 limbs, 5 women and 6 men, mean age
      57 years) with CVI, CEAP 2-3 were studied through physical examination, Doppler
      color ultrasound test, measurement of leg volume and videocapillaroscopy.
      Patients were evaluated before (T0), after 7 days (T1) and 14 days (T2) of daily
      compression therapy with elastic stockings. Statistical comparisons used the Mac
      Nemar test for binomial variables and Wilcoxon test for paired quantitative data.
      RESULTS: All patients experienced significant improvement of symptoms, the volume
      of the limbs on the average decreased in the first week T0-T1=284.8 cm(3) +/-
      307.5 cm(3) (6.27%, p<0.001). During the second week a small increase in volume
      was observed T2-T1=+ 12.23 cm(3), NS, 0.29%). The width of the capillary halo of
      edema decreased during the first week by an average of T0-T1=5.77 microm +/-
      10.99 microm. During the second week the width of the edema halo continued
      diminishing, although in smaller proportion (T0-T2=7.89 microm +/- 11.77 microm).
      CONCLUSION: Daily use of grade II compression stockings induces a reduction in
      leg volume in patients with CEAP grades 2-3. This improvement of edema is
      paralleled by a decrease in the size of the pericapillary halo.

PMID- 12616223
TI  - [Vascular dysplasia in vascular surgery in an African area: 28 cases at the Dakar
      teaching hospital].
AB  - This retrospective study was conducted to analyze the anatomic and clinical data
      concerning vascular dysplasia in vascular surgery patients seen in an African
      hospital and to assess its role in treatment. Twenty-eight patients (14 women and
      14 men) were treated for vascular dysplasia between 1994 and 1998. There were 8
      cases of hemangioma and 20 cases of vascular malformation. Average age of
      patients with hemangioma was 3.23 years, with a sex ratio of 0.33. There were 4
      cases of mixed hemangioma, 3 of cutaneous hemangioma, and 1 of subcutaneous
      hemangioma. Cervicocephalic (n=4) and limb (n=3) localizations were the most
      frequent. Duplex Doppler did not reveal any signs of muscle disease. Four
      patients underwent surgery, for an early indication in 3 and a late indication in
      1. Resection suture was performed in 3 cases and resection graft in one. Mean
      follow-up was 85.90 days. There was one case of early suppuration. There were no
      cases of recurrence or late complications and the operative wounds healed well.
      Vascular malformations concerned 20 patients (sex ratio 1.5, average age 15.55
      years) with 16 cases of venous malformation including 4 patients with Klippel
      Trenaunay syndrome, three with arteriovenous malformation and one with capillary
      angioma. CT and arteriography were obtained in all cases. Limb localizations
      predominated (14 patients). In-depth extension was found in 6 cases of venous
      malformation. Sixteen patients underwent surgery for functional indications in 7.
      Resection suture was performed in 11 cases. Mean follow-up was 85.90 days. There
      were 4 early and 2 late postoperative complications. There has been no
      recurrence. Anatomic and clinical polymorphism of vascular dysplasia requires
      multidisciplinary collaboration in which vascular surgery plays an important role
      in complex or complicated forms of the disease in patients attending facilities
      with limited resources.

PMID- 12616225
TI  - [Duplex sonography and ankle-brachial index in lower limb arterial disease:
      practical approach].
AB  - OBJECTIVE: The Societe Francaise de Medecine Vasculaire and Societe Francaise
      d'Imagerie Cardio-Vasculaire requested that ANAES perform an Health Technology
      Assessment (HTA) report entitled "Duplex Sonography in Lower Limb Arterial
      Disease". This report showed a wide variability of practices as well as for
      diagnostic criteria. The HTA Working Group wished to express that there was a
      consensual opinion to promote clinical practice harmonization. METHOD: A working
      document was sent to the HTA Working Group and to a specifically selected Reading
      Group. A direct draft report was transcribed during the last Working Group
      meeting. This document was then sent to both Working Group and Reading Group for
      review and recommendations. The final version takes into account these comments.
      RESULTS: The consensual practical approach concerns the minimal equipment
      required to carry out a lower limb arterial Duplex Sonography, examination
      proceeding and its place according to the clinical situations (asymptomatic
      patient, claudication, critical ischemia, therapeutic situations support,
      clinical situations where Duplex Sonography is not justified). CONCLUSION: The
      document represents a special initiative of the Working Group implemented in the
      context of an ANAES HTA report. This document should not be considered as ANAES
      professional guidelines since its working method was not compliant with the ANAES
      method used to elaborate guidelines. Importantly, it represents the first
      consensual finalised document regarding this topic in France. It should be
      considered as a practical guide for professional use, and serve as a basis for
      the development of recommendations.

PMID- 12616224
TI  - [Quantitative evaluation and qualitative results of surgical lymphovenous
      anastomosis in lower limb lymphedema].
AB  - PURPOSE: Treatment of lymphedema (LE) includes complex decongestive physiotherapy
      (manual lymphatic drainage, bandaging, exercises, skin care, elastic stockings).
      Surgical therapy is rarely useful. However, lymphovenous anastomosis (LVA) is the
      most used surgery in LE. We have assessed LVA in lower limb LE. METHODS: Thirteen
      patients (5 women, 8 men) with primary (n=10) or secondary LE (n=3) were
      included. Primary LE started at a mean age (+/- SD) of 28.9 +/- 14.5 years. LE
      was located in left lower limb (n=7), right (n=4) or both (n=2). LVA was
      performed 7.1 +/- 4.9 years after the onset of LE by the same surgeon. Two to
      five lymphatic vessels were used for LVA. Assessment of LVA was based upon
      objective criteria (volumetry, erysipelas) and subjective criteria (global
      discomfort, heaviness, cutaneous tenderness, difficulties for doing significant
      effort or walking more than 1 km). Global assessement of LVA was collected for
      each patient. RESULTS: Before LVA, excess of volume (+/- SD) of LE was 1906 +/-
      1277 ml or 28.5 +/- 18% in comparison with the controlateral limb. After LVA,
      excess of volume (+/- SD) remained stable with 1863 +/- 1468 ml or 24.4 +/-
      18.9%. Volumetry was appreciated with a mean (+/- SD) follow-up of 52 +/- 3
      months. Frequency of erysipelas was unchanged for the 6 patients with recurrent
      episodes. Only heaviness and cutaneous tenderness were significantly reduced
      after LVA. But global discomfort (+/- SD) decreased from 6.7 +/- 2.7 to 5 +/- 3.2
      on visual analogic scale (NS). No differences were observed for significant
      effort or walking more than 1 km. Global assessment of LVA by the patient was
      very good (n=3), good (n=2), intermediate (n=5) and bad (n=3). CONCLUSION: LVA
      failed to improve the volume of lower limb LE and reduce the frequency of
      erysipelas. LVA improves few subjectives criteria but not global discomfort.
      Further studies are needed to evaluate LVA and to select patients to obtain best
      results.

PMID- 12616227
TI  - Maxillofacial rehabilitation of a large facial defect resulting from an
      arteriovenous malformation utilizing a two-piece prosthesis.
AB  - Large facial defects involving the oral cavity can be difficult to restore
      prosthetically because of a lack of anatomic undercuts, limited means of
      retention, mobility of soft tissue margins, and the weight of the prosthesis. Use
      of skin adhesives may be precluded because of the presence of persistent moisture
      and saliva. The maxillofacial rehabilitation, including the design and
      fabrication of a 2-piece silicone prosthesis retained by the teeth, of a patient
      with a large facial defect as a result of treatment for an arteriovenous
      malformation is described. The pathogenesis and therapeutic alternatives for
      arteriovenous malformations is also discussed.

PMID- 12616226
TI  - [An odd red leg].

PMID- 12616228
TI  - Occlusal rehabilitation of a patient with hereditary multicentric osteolysis.
AB  - This article describes the fixed prosthodontic rehabilitation of a 53-year-old
      male patient with multicentric osteolysis. Before treatment, the patient
      exhibited signs and symptoms of temporomandibular disorder and had recurrent
      tension-type headaches and pain in the neck and shoulder area. One of his chief
      complaints was frequent fracture of restorations. After extensive occlusal
      rehabilitation, occurrence of headache and pain ceased, and other signs and
      symptoms of TMD diminished. The long-term prognosis depends on the stage of the
      genetic disorder, which cannot be determined.

PMID- 12616229
TI  - Prosthetic management of a total glossectomy defect after free flap
      reconstruction in an edentulous patient: a clinical report.
AB  - Total glossectomy with surgical reconstruction can result in a significantly
      altered mandibular arch anatomy. In edentulous patients, lingual vestibules along
      with the mandibular alveolar ridge can be obliterated. With the absence of lower
      anterior dentition, support of the lower lip is lost and traction from surgical
      closure can cause the lower lip to collapse into the oral cavity. This report
      describes the prosthetic treatment of an edentulous total glossectomy patient
      with an unconventional custom impression procedure to develop and record proper
      lower lip and cheek support. It also discusses some issues involved in the
      prosthetic management of the total glossectomy patient.

PMID- 12616230
TI  - A positioning device for computed tomography: a clinical report.
AB  - This clinical report describes a device (Centrascan) used to assist in the
      correct alignment of the patient's head during computed tomography (CT)
      assessment of a proposed implant site. To obtain the desired anatomic detail, CT
      requires precise alignment of the axial images at right angles to the long axis
      of the proposed implant. This clinical report compared the anatomic morphology of
      a projected implant site derived from axial images provided by DentaScan software
      analysis of the CT scan acquisition. Images from a conventional scan, with the
      patient's head aligned along the frontal plane (perpendicular to the Frankfort
      plane) and along the sagittal plane (coinciding with either the cortical bone of
      the hard palate or the inferior border of the mandible), were compared with
      images acquired by use of the Centrascan device. The two scans differed
      substantially. In particular, the cross-sectional images obtained by the
      conventional procedure showed a distorted anatomy; conversely, the images
      obtained by the Centrascan procedure showed a better reproduction of the examined
      area. The Centrascan device seemed to help the radiologist achieve a more correct
      alignment of the patient's head during CT scan acquisition. Further studies are
      necessary to fully explore the relative technical merits of the Centrascan
      device.

PMID- 12616231
TI  - Mechanical and physical properties of contemporary dental luting agents.
AB  - STATEMENT OF PROBLEM: New luting agents, particularly with adhesive capability,
      are being introduced in an attempt to improve clinical success. Independent
      studies of basic comparative data are necessary to characterize these materials
      in relation to mechanical and physical properties. PURPOSE: The purpose of this
      study was to compare the flexural strength, modulus of elasticity, and
      radiopacity and pH of representatives of 5 types (categories) of luting agents.
      MATERIAL AND METHODS: The luting agents included a zinc phosphate, a conventional
      and a resin-modified glass ionomer, 2 dual-polymerizing resins
      ("photopolymerized" after mixing and "unphotopolymerized" conditions), and an
      auto-polymerizing resin. The specimens were prepared and the testing was
      conducted by 1 person to maximize standardization. Flexural strength (MPa) and
      modulus of elasticity (GPa) were determined on bar-shaped specimens (2 x 2 x 20
      mm) at 24 hours and 3 months (n = 8). Radiopacity (mm Al) was measured by
      exposing 1 mm thick specimens along with an aluminum step wedge (n = 4). pH was
      measured using a pH electrode immediately after mixing; at 1, 5, 15, 30 minutes;
      and at 1, 2, 4, 6, and 24 hours (n = 4). The data were subjected to statistical
      analyses with analysis of variance and Duncan's multiple range test (P<.05).
      RESULTS: The resin luting agents (64 to 97 MPa) showed higher flexural strength
      than all other materials tested (7 to 27 MPa), with the "photopolymerized" (83 to
      97 MPa) conditions higher than "unphotopolymerized" (64 to 81 MPa) (P<.0005).
      Zinc phosphate was the most radiopaque (6.4 mm Al) (P<.0001) and provided the
      highest rigidity (9.2 GPa) (P<.05). The autopolymerization resin cement was the
      most radiolucent (1.1 mm Al) (P<.0001). Zinc phosphate and conventional glass
      ionomer cements were the most acidic immediately after mixing (pH 1.5 to 2.2) but
      were the least acidic after 24 hours (pH 6.4 to 6.8) (P<.0001). CONCLUSIONS:
      Within the limitations of this study the data showed a wide variation of material
      properties. The dual-polymerization resin luting agents tested showed the best
      combination of mechanical and physical properties combined with the highest
      setting pH. Photopolymerization of these resin-based materials was necessary to
      maximize strength and rigidity.

PMID- 12616232
TI  - Different methods of finishing and polishing enamel.
AB  - STATEMENT OF PROBLEM: Highly polished enamel surfaces are recommended for axial
      tooth surfaces that will serve as guiding planes and be contacted by component
      parts of a removable partial denture. There is little evidence to support the
      assumption that this tooth modification will provide accurate adaptation of the
      framework and prevent build-up of plaque. PURPOSE: The aim of this investigation
      was to evaluate the surface roughness of the tooth enamel, prepared to serve as
      guiding planes, with different polishing systems. MATERIAL AND METHODS: Four
      different methods (designated A, B, C, and D) for finishing and polishing the
      prepared enamel surfaces of 20 freshly extracted third molar teeth were studied.
      Each method involved 3, 4, or 5 different steps. The roughness of each specimen
      was measured at the start of each method before recontouring, after recontouring,
      and after each step of the 4 finishing and polishing procedures. The 4
      experimental finishing methods were applied after recontouring the axial surfaces
      (buccal, lingual, and proximal) of each tooth. Thus the 20 teeth (60 surfaces)
      were finished and polished by use of 1 of the experimental methods. Surface
      roughness was measured with a profilometer (microm); the readings of the
      unpolished enamel surfaces were recorded as control measurements. Results were
      statistically analyzed with one-way analysis of variance followed by Tukey's test
      at the 95% level of confidence. RESULTS: The highest roughness mean values (14.41
      microm to 16.44 microm) were found when the diamond bur was used at a high speed
      for tooth preparation. A significant decrease in roughness values was observed
      with the diamond bur at a low speed (P<.05). Analysis of the roughness values
      revealed that all polishing methods produced surface roughness similar to that of
      the corresponding control teeth. CONCLUSION: Within the limitations of this
      study, all finishing procedures tested effectively promoted an enamel surface
      similar to the original unpolished enamel.

PMID- 12616233
TI  - A clinical trial to compare double-arch and complete-arch impression techniques
      in the provision of indirect restorations.
AB  - STATEMENT OF PROBLEM: Anecdotal reports of use of double-arch impressions for
      indirect restorations suggest time and materials savings, but there is little
      clinical evidence to support their use. PURPOSE: To establish whether a double
      arch impression technique could produce restorations comparable with those
      produced by use of the complete-arch technique and to investigate reported time
      and material savings. MATERIAL AND METHODS: Five practitioners each recruited 10
      adult patients requiring a single complete veneer crown into the study. Two sets
      of impressions, 1 complete-arch in a stock metal tray, and 1 double-arch in a
      plastic double-arch tray were made for each patient in addition-polymerized
      silicones in a random order. The time taken for each impression was recorded
      along with patient's assessment of comfort, taste, and overall acceptability. One
      technician, who selected the impressions for the fabrication of each crown
      according to a predetermined scheme of randomization, fabricated all crowns.
      Equal numbers of crowns were made from the complete and double-arch impressions.
      At the time of crown placement, the accuracy of fit, occlusal harmony, and the
      time taken for try-in were also recorded. The weight of impression material used
      was measured for each impression. Data were analyzed by use of computerized
      statistical software (t test for equality of means) at a significance level of
      95%. RESULTS: The double-arch technique was faster (222 seconds [SD, 57 seconds]
      vs 445 seconds [SD, 87 seconds], P=.000), more comfortable (P=.025), better
      tasting (P=.001), and preferred by 80% of the patients (P=.000). No significant
      differences were found between the 2 groups for accuracy of fit, occlusion, or
      time taken for try-in of the restorations. The mean weight of impression material
      used was 39 g (SD, 10 g) for complete-arch and 20 g (SD, 7 g) for double-arch
      impressions, a mean difference of 19 g (P=.000). CONCLUSION: Within the
      limitations of this study, double-arch impressions were found to take less time,
      to use less material, and to be preferred by patients. Under the conditions of
      this study, the resulting restorations were no less accurate than those made from
      complete-arch impressions.

PMID- 12616234
TI  - In vitro study of endodontic post cementation protocols that use resin cements.
AB  - STATEMENT OF PROBLEM: Sodium hypochlorite (NaOCl) may alter resin bond strength
      by deproteination of demineralized dentin collagen. PURPOSE: To analyze the
      effect of NaOCl treatment on bond adhesion and tensile strength of different post
      cementation protocols in vitro. MATERIAL AND METHODS: The periconductual dentin
      of 120 single-rooted, caries-free, unrestored human teeth was etched with 37%
      orthophosphoric acid. The teeth in Group I (60) were left untreated, and the
      teeth in Group II (60) were treated with 10% NaOCl. Four post-cementation
      protocols were examined (15 teeth in each) for Groups I and II: ED Primer dentin
      adhesive + Panavia 21 Ex; ED Primer dentin adhesive + Dual Cement; Panavia 21 Ex;
      and Dual Cement. For each condition, resin tags, hybrid layers over the
      periconductual dentin and post surface, were analyzed by scanning electron
      microscopy (SEM). Specimens were loaded with a uniaxial tensile force using an
      electromechanical testing machine until cement failure. Bond adhesion and tensile
      strength with different protocols were examined statistically using multiple
      analysis of variance at a significance level of alpha<.05. RESULTS: SEM revealed
      morphologic differences; Group II exhibited cylindrical, solid tags and Group I,
      tapered, hollow tags. Uniaxial tensile strength tests showed that in Group I,
      Panavia 21 Ex cement was strongest, whereas in Group II, this protocol was the
      weakest and Dual Cement with adhesive was the strongest. In Group II, Panavia 21
      Ex diminished the tensile bond strength; however, combination with dentin
      adhesive increased it. CONCLUSION: Within the limitations of this study, NaOCl
      treatment did not significantly alter tensile bond strength, but when combined
      with the dentin adhesive ED Primer, a significant rise in strength resulted. A
      positive relationship existed between increased tag numbers and higher tensile
      bond strength.

PMID- 12616235
TI  - An in vitro study of the compressive load at fracture of Procera AllCeram crowns
      with varying thickness of veneer porcelain.
AB  - STATEMENT OF PROBLEM: When designing and cutting a crown preparation, a balance
      must be achieved between the amount of tooth structure conserved and the space
      created for the restoration. All-ceramic crowns, which contain a core, are
      usually veneered with porcelain to produce the desired aesthetics and contour.
      The effect of veneer porcelain on the strength of the restoration has been a
      cause of debate. PURPOSE: The purpose of this study was to investigate the effect
      of different thickness of veneer porcelain on the compressive load at fracture of
      Procera AllCeram crowns. MATERIAL AND METHODS: Sixty brass dies were fabricated
      with a crown-like preparation and a chamfer margin. Sixty crowns were fabricated
      with a 0.6-mm-thick core: Procera crowns with either a 0.4-mm- or 0.9-mm-thick
      veneer of AllCeram (Groups 1 and 2 respectively) and In-Ceram crowns with a 0.9
      mm-thick veneer of Vitadur Alpha porcelain (Group 3). Each group consisted of 20
      crowns. In-Ceram crowns were used as the control group. All crowns were measured
      at 4 axial and 1 occlusal random locations before autoglazing. They were air
      abraded and adhesively bonded onto the appropriate brass die using Clearfil
      Newbond Bonding Agent, Clearfil Porcelain Bond Activator, and Panavia 21 TC
      Dental Adhesive as the luting agent. After storage in distilled water at 37
      degrees C for 24 hours, the specimens were placed in a compressive test rig
      within an Instron universal testing machine and loaded in the center of the
      occlusal surface with a 4-mm diameter stainless steel ball. An axial preload of
      20 N was applied before compressive testing at a crosshead speed of 0.1 mm/minute
      until fracture occurred. An analysis of variance revealed no significant
      difference in the load at fracture between the 3 groups (P=.3). Using a
      Bonferroni correction, independent t tests revealed no significant difference in
      load at fracture for any of the pair-wise comparisons between the 3 test groups
      (P < .05). RESULTS: The mean load at fracture for Group 1 was 2197.6 N (SD =
      776.4); Group 2, 2401.4 N (SD = 699.1); and Group 3, 2581.0 N (SD = 715.6).
      CONCLUSION: Within the parameters of this study, the axial thickness of veneer
      porcelain did not have a significant effect on the compressive load at fracture
      of Procera AllCeram crowns.

PMID- 12616236
TI  - Comparison of microleakage on one composite etched with phosphoric acid or a
      combination of phosphoric and hydrofluoric acids and bonded with several
      different systems.
AB  - STATEMENT OF PROBLEM: There are no data available on whether or to what extent
      hydrofluoric acid affects the marginal integrity of dentin-bonded composite
      restorations when it is used instead of phosphoric acid in the total-etch
      technique. PURPOSE: This in vitro study examined the etching effects of
      phosphoric acid versus a combination of phosphoric and hydrofluoric acid by
      evaluation of microleakage in a composite restoration bonded with different
      dentin adhesive systems. MATERIAL AND METHODS: Extracted teeth (n = 90)
      containing 2 class II preparations, mesial occlusal (MO) and distal occlusal (DO)
      standarized (cervical margins in dentin) were perfused with Ringer solution and
      etched in 1 of 2 ways: with phosphoric acid only or with phosphoric combined with
      hydrofluoric acid. Different dentin bonding agents were then applied (Etch &
      Prime 3.0, Optibond Solo, Prime & Bond NT, Scotchbond 1, Syntac Single Component,
      or Syntac Sprint; (n = 15 for each etching material)). The preparations were
      restored with a hybrid composite (Herculite XRV) and submitted to 5000
      thermocycles (5 degrees C to 55 degrees C) to simulate the in vivo situation.
      Microleakage was assessed with 2% methylene blue diffusion for 24 hours. Dye
      penetration was calculated as a percentage of the total length of the gingival
      margins of the preparation with light microscopy at original magnification x 32.
      The results were analyzed with the Kruskal-Wallis multiple comparison z-value
      assay (alpha = .05). RESULTS: Differences in dye penetration were significant,
      both as a function of the dentin adhesive and the conditioning mode applied. In
      the specimen groups conditioned with phosphoric acid, Optibond Solo (54% +/- 44%)
      and Syntac Sprint (74% +/- 39%) demonstrated the lowest penetration values.
      Higher values were obtained for Prime & Bond NT (81% +/- 34%), Scotchbond 1 (83%
      +/- 31%), Etch & Prime 3.0 (85% +/- 33%), and Syntac Single Component (95% +/-
      16%), with no significant differences (alpha=.05) between specimen groups. The
      best results were obtained for Syntac Sprint (24% +/- 26% dye penetration) after
      conditioning with a mixture of phosphoric and hydrofluoric acid. The least
      favorable result was obtained for Optibond Solo (65% +/- 31%). It was
      significantly different from Prime & Bond NT (76% +/- 37%), Scotchbond 1 (85% +/-
      29%), and Etch & Prime 3.0 (88% +/- 24%). Syntac Single Component (75% +/- 32%)
      was significantly different from Syntac Sprint. Syntac Single Component and
      Syntac Sprint exhibited significantly better results when conditioned with a
      combination of phosphoric acid and hydrofluoric acid than with phosphoric acid
      only. CONCLUSION: Within the limitations of this in vitro study, total-etching
      water-based (Syntac Single Component) and acetone-based (Syntac Sprint) bonding
      agents with a combination of phosphoric acid and hydrofluoric acid led to
      significant reductions (alpha=.05) in dye penetration compared to phosphoric acid
      conditioning only. Ethanol-based dentin bonding agents (Etch & Prime 3.0,
      Optibond Solo, and Scotchbond 1) were not significantly influenced by the type of
      conditioner used.

PMID- 12616237
TI  - In vitro resistance of reinforced interim fixed partial dentures.
AB  - STATEMENT OF PROBLEM: Comprehensive restorative dental treatment often
      necessitates the use of interim fixed partial dentures (FPDs) with high
      stiffness, especially in long-span restorations or areas of heavy occlusal
      stress. PURPOSE: This in vitro study evaluated the fracture load of interim FPDs
      made with various materials and span lengths. MATERIAL AND METHODS: Groups (n =
      3) of interim FPDs were fabricated with prosthodontic resin materials on 2
      abutments with 3 different pontic widths of 3 units (12 mm), 4 units (19 mm), and
      5 units (30 mm). The following materials were tested: (1) a thermoplastic polymer
      (Promysan Star), (2) Promysan Star with a veneering composite (Vita Zeta), (3) a
      nonimpregnated polyethylene fiber reinforced resin (Ribbond) with a veneering
      composite (Sinfony), (4) an impregnated fiber reinforced composite system
      (Targis/Vectris), and (5) a conventional polymethyl methacrylate, Biodent K+B,
      (control group). After 5000 thermocycles in 2 water baths at 5 degrees and 55
      degrees C, the FPDs were temporarily fixed with a provisional cement on the
      corresponding abutments and subjected to 3-point bending until fracture by a
      universal testing machine. Statistical analysis consisted of an analysis of
      variance (ANOVA, 1-way, 2-way) and Bonferroni-Dunn's multiple comparisons post
      hoc analysis for test groups (alpha = .05). RESULTS: Fracture resistance (N)
      differed significantly for 3 (mean: 640 +/- 146 N), 4 (626 +/- 229 N), and 5 unit
      (658 +/- 98 N) Targis/Vectris FPDs compared with the corresponding Promysan (284
      +/- 21 N to 125 +/- 73 N), Biodent K+B (247 +/- 91 N to 218 +/- 85 N), and
      Promysan/Vita Zeta (95 +/- 15 N to 82 +/- 6 N) groups (P < .05). Significant
      differences were obtained for the 4 and 5 unit Targis/Vectris FPDs compared with
      the Sinfony/Ribbond FPDs (281 +/- 25 N - 252 +/- 74 N) for the corresponding
      pontic spans. CONCLUSION: Within the limitations of this in vitro study the
      impregnated fiber reinforcement may considerably enhanced the fracture resistance
      of interim FPDs of different span lengths.

PMID- 12616238
TI  - Comparative tests of arbitrary and kinematic transverse horizontal axis
      recordings of mandibular movements.
AB  - STATEMENT OF PROBLEM: The reliability of recording maxillomandibular
      relationships for articulator programming with a transverse horizontal axis
      determined arbitrarily with an arbitrary face-bow has not been verified against a
      kinematically determined and recorded transverse horizontal axis in an in vivo
      study. PURPOSE: The goal of this study was to determine the measuring accuracy of
      the Cadiax Compact system in a clinical series of tests and to determine whether
      there is a clinically significant difference between the 3-dimensional
      measurements recorded from kinematically and arbitrarily determined transverse
      horizontal axes. MATERIAL AND METHODS: Thirty subjects (11 women, 19 men; ages 21
      to 26) participated in this study. Mandibular movement, the sagittal condylar
      inclination (SCI) angle, and the transversal condylar inclination (TCI) angle
      were recorded in each subject with the Cadiax Compact system, by use of first an
      arbitrarily and second a kinematically determined transverse horizontal axis. A
      subset of 10 subjects was examined with another computerized axiograph, the Gamma
      Cadiax system. Measurements were made and recorded twice, on different days under
      similar circumstances. To compare the systems and measurement methods, the SCI
      measurements taken at 3- and 5-mm sagittal protrusion and the TCI taken at 3- and
      5-mm mediotrusion were used. The lengths and characteristic curvatures of
      protrusion, opening, and mediotrusion tracings were determined for the evaluation
      as follows: tracing lengths (<8 mm, 8 to 12 mm, and >12 mm); degree of overlap of
      the excursive and incursive tracing; and tracing curvature. The intraclass
      correlation was used to compare angle values at the 95% confidence interval. To
      assess the track progression, kappa values were calculated. RESULTS: Repetition
      of the mandibular track inclination angles and the condylar movement pattern was
      highly reliable (intraclass correlation of >0.8) with the Cadiax Compact system.
      When the mandibular track inclinations determined kinematically and arbitrarily
      by the Gamma Cadiax and Cadiax Compact systems were compared, both systems
      demonstrated high reliability (ICC>0.8). The congruence results of the protrusion
      tracings from kinematic and arbitrary measurements with the Cadiax Compact system
      were as follows: strong congruence in quantity, characteristics, and horizontal
      tracing; only the quality diminished slightly (Kappa 0.46 in the first
      measurement, which still represented a clear congruence). The opening and
      mediotrusion tracings demonstrated fair to almost complete congruence in all
      parameters. CONCLUSION: Within the limitations of this study, the kinematic and
      arbitrary measurements of the Cadiax Compact system could be reliably used for
      articulator programming. The results suggest that arbitrarily determined
      posterior reference points may be comparable to a kinematically determined
      transverse horizontal axis.

PMID- 12616239
TI  - Unilateral temporomandibular disorder and asymmetry of occlusal contacts.
AB  - STATEMENT OF PROBLEM: The relationship between temporomandibular disorders and
      occlusal tooth contacts is unclear and controversial. PURPOSE: This study
      assessed whether unilateral temporomandibular disorders were associated with the
      absence of bilateral symmetry in the number of occlusal contacts. MATERIAL AND
      METHODS: Fifteen university dental students who had complete natural dentition
      and normal occlusion and exhibited unilateral signs and symptoms of
      temporomandibular disorders were compared to 15 age- and sex-matched healthy
      control subjects. All participants met specific inclusion and exclusion criteria.
      Occlusal contacts were recorded in the intercuspal position with wax
      registrations. Dental impressions were made and poured in type I stone. Contacts
      were classified according to location and intensity. Four experienced dentists
      using an established protocol made all measurements. Assessment of the
      reliability of the occlusal registration procedure showed a small (<4%) within
      subject variability. Statistical analysis was based on the binomial distribution
      and nonparametric tests (P < .05). RESULTS: Subjects with unilateral
      temporomandibular disorders had greater bilateral difference in the number of
      contacts than controls. The median (95% confidence interval) difference was 3 (2
      to 4) and 2 (1 to 2), respectively. In unilateral temporomandibular disorder
      subjects, the number of occlusal contacts was greater on the side with, rather
      than without, disorder (median number 20 vs. 16). The median (95% confidence
      interval) difference between sides with and without unilateral temporomandibular
      disorders was 3 (2 to 4) for all contacts and 2 (1 to 3) for contacts on the
      posterior teeth. CONCLUSION: Within the population of this study, a weak
      association was found between unilateral temporomandibular disorders and
      asymmetry in the number of occlusal contacts.

PMID- 12616240
TI  - Evaluation of the accuracy of three techniques used for multiple implant abutment
      impressions.
AB  - STATEMENT OF PROBLEM: Movement of pick-up type impression copings inside the
      impression material during clinical and laboratory phases may cause inaccuracy in
      transferring the spatial position of implants from the oral cavity to the master
      cast. As a consequence, the laboratory technician may fabricate a restoration
      that requires corrective procedures. PURPOSE: This in vitro study evaluated the
      accuracy of 3 different impression techniques using polyether impression material
      to obtain a master cast for the fabrication of a prosthesis that would fit
      passively on multiple implants. MATERIAL AND METHODS: A machined metal model with
      6 implants and abutments and a corresponding, passively fitting, matching metal
      template were fabricated. A total of 45 medium-consistency polyether impressions
      (Impregum Penta) of this model were made with pick-up type square impression
      copings. Three groups of 15 each were made with different impression techniques:
      in group 1, nonmodified square impression copings were used; in group 2, square
      impression copings were used and joined together with autopolymerizing acrylic
      resin before the impression procedure; and in group 3, square impression copings
      previously airborne particle-abraded and coated with the manufacturer-recommended
      impression adhesive were used. The matching metal template, which had been
      passively fit to the metal model so that it encountered no visually perceptible
      resistance or rocking on the abutments, was used as the control for evaluation of
      the accuracy of passive fit. A single calibrated and blinded examiner visually
      evaluated each cast. Positional accuracy of the abutments was numerically
      assessed with an optical scanner at original magnification x 10, which provided
      measurements to within 2 microm of the variations of the casts with respect to
      the horizontal distances between the 2 most posterior abutments and the 2 most
      anterior abutments. Data were analyzed with a 1-way analysis of variance at
      alpha=.05, followed by the Student Newman-Keuls method (P=.05). RESULTS: Visual
      examination of the casts from group 1 revealed discrepancies between 1 or more
      abutments and the metal template. Visual analysis of the master casts from groups
      2 and 3 revealed close alignment of the metal template on all 6 abutments. One
      way analysis of variance analyzed the numerical data obtained with the optical
      scanner and revealed significant differences among the 3 impression techniques
      (P<.001). The Newman-Keuls procedure disclosed significant differences between
      the groups, with group 2 and 3 casts being significantly more accurate than group
      1 casts (P=.05). The distance between abutments 1 and 6 compared to the standard
      metal model was 33.83 microm (SD +/- 5.4) greater on group 2 casts, 31.72 microm
      (SD +/- 4.6) greater on group 3 casts, and 78.16 microm (SD +/- 22.14) greater on
      group 1 casts. Distances between the most anterior abutments were also greater
      than those recorded on the metal model. The distance was 31.42 microm (SD +/-
      7.6) greater on group 2 casts, 30.34 microm (SD +/- 6.4) greater on group 3
      casts, and 67.91 microm (SD +/- 15.34) greater on group 1 casts. CONCLUSION:
      Within the limitations of this study, improved accuracy of the master cast was
      achieved when the impression technique involved square impression copings joined
      together with autopolymerizing acrylic resin or square impression copings that
      had been airborne particle-abraded and adhesive-coated.

PMID- 12616242
TI  - Scientific composition and review of manuscripts for publication in peer-reviewed
      dental journals.
AB  - This article provides an extensive tutorial for writers and reviewers involved
      with the preparation and evaluation of manuscripts submitted for publication in
      dental journals. The contents were compiled from the Instructions for Authors
      printed in various peer-reviewed dental journals and from feedback from 10
      workshops conducted for the Editorial Review Board of the Journal of Prosthetic
      Dentistry. The 10 major sections of a scientific manuscript are reviewed in
      detail in terms of content, format, and common errors; examples of good content
      are provided. The review process is described, and instructions on conducting
      fair and expeditious manuscript evaluations are provided for reviewers. In
      addition, a number of special topics are addressed, including potential conflicts
      of interest for an author, institutional review of experiments that involve human
      subjects or animals, and the reproduction of photographs and other images in
      color versus black and white. In summary, this article presents key guidelines to
      ensure compliance with the principles of sound scientific writing and the
      expeditious review of manuscripts prepared for publication in peer-reviewed
      dental journals.

PMID- 12616241
TI  - Dimensional changes of one-piece frameworks cast from titanium, base metal, or
      noble metal alloys and supported on telescopic crowns.
AB  - STATEMENT OF PROBLEM: The dimensional accuracy of 1-piece frameworks cast from
      commercially pure titanium and used to accommodate supporting telescopic crowns
      has not been demonstrated. PURPOSE: To compare dimensional changes incurred in
      frameworks cast from commercially pure titanium, a cobalt-chromium alloy, and a
      noble metal (gold) alloy. MATERIAL AND METHODS: This study was based on 2
      different models, both prepared to receive telescopic crowns: 1 with 4 dies,
      designed to measure dimensional changes of the castings in the horizontal plane;
      and another with 2 dies, designed to measure dimensional changes in the vertical
      plane. As variables for the 2-die models, the palatal shape (16- and 20-mm
      radius) as well as the palatal depth (20-mm radius with the smallest palatal
      depth of 8 mm, 16-mm radius with flat palate and palatal depth of 10 mm, 16-mm
      radius with greatest palatal depth of 16 mm) were studied. Ten specimens each
      were fabricated from a commercially pure titanium, a cobalt-chromium alloy, and a
      gold alloy. All castings were fabricated under standardized conditions. All
      measurements were taken with a computer-controlled measuring microscope at the
      margins of the simulated telescopic crowns; these served to calculate the ideal
      midpoint from which the distances between the telescopic crowns were measured.
      The positional relation of the telescopic crowns was determined in horizontal and
      vertical directions. The measurements of the cast models were compared with
      measurements of the original model. The distances between the dies and the angles
      of the chosen telescopic crowns were calculated in fractions of millimeters and
      the angles were measured in degrees. The Kruskal-Wallis test and the Mann-Whitney
      U test were used for statistical analysis. The level of significance was
      alpha=5%. RESULTS: With the following exceptions, none of the 3 alloy types
      showed significantly different results. With the 4-die model, all 3 alloys showed
      significant variations from the original model for chosen lengths (P=.001). For
      those lengths, the dimensional accuracy of the noble metal alloy was
      approximately 99.9% of the length of the original; for the 2 other alloys, an
      average value of 99.4% was determined. With the 2-die models the calculated angle
      was significantly different from the original model for all alloys (P=.001
      or.000), independent from the palatal vault and depth. Significant differences
      from the original model were also found for the distance between the 2 telescopic
      crowns with all alloys for the 2-die model with a 16-mm depth palatal vault and a
      16-mm radius (P=.001,.006, or.009). CONCLUSIONS: Within the limitations of this
      study, the significant different dimensional changes both for the 4-die models
      and the 2-die models did not depend on the type of alloy. The 2-die models
      demonstrated significant dimensional changes resulting from the palatal geometry
      of the corresponding test models; the 4-die models demonstrated a tendency to
      contract toward the geometric center.

PMID- 12616243
TI  - A technique for cast duplication.
AB  - A simple, effective, and inexpensive method of cast duplication used for models
      and working casts is described.

PMID- 12616244
TI  - A conservative technique for restoring a tooth affected by interproximal root
      caries.
AB  - The insertion of amalgam through an opening in a matrix band facilitates amalgam
      condensation, aids moisture control, reduces overhangs, and enables the dentist
      to achieve an acceptable restoration.

PMID- 12616245
TI  - Preventing aspiration or ingestion of fixed restorations.

PMID- 12616248
TI  - Lifelong learning goals: individual steps that propel the profession of
      dietetics.

PMID- 12616249
TI  - ADA consumer education message to appear on Hunt's tomato products.

PMID- 12616250
TI  - Homocysteine and Alzheimer's disease.

PMID- 12616251
TI  - Expanding medical nutrition therapy: an argument for evidence-based practices.

PMID- 12616252
TI  - Family meal patterns: associations with sociodemographic characteristics and
      improved dietary intake among adolescents.
AB  - OBJECTIVE: To examine family meal patterns and associations with sociodemographic
      characteristics and dietary intake in adolescents. DESIGN: A population-based
      cross-sectional study design was employed. Adolescents completed the Project EAT
      (Eating Among Teens) survey and the Youth and Adolescent Food Frequency
      Questionnaire within their schools. Subjects/setting The study population
      included 4,746 middle and high school students from Minneapolis/St. Paul public
      schools with diverse racial and socioeconomic backgrounds. Statistical analyses
      Associations were examined using cross tabulations, log-linear modeling, and
      linear regressions. RESULTS: There was a wide distribution in the frequency of
      family meals during the previous week: never (14.0%), 1 or 2 times (19.1%), 3 to
      6 times (40.1%), and 7 or more times (24.8%). Sociodemographic characteristics
      associated with more frequent family meals included gender (boys), school level
      (middle school), race (Asian American), mother's employment status (not
      employed), and socioeconomic status (high). Frequency of family meals was
      positively associated with intake of fruits, vegetables, grains, and calcium-rich
      foods and negatively associated with soft drink consumption. Positive
      associations were also seen between frequency of family meals and energy; protein
      (percentage of total calories); calcium; iron; folate; fiber; and vitamins A, C,
      E, and B-6. CONCLUSIONS: Family meals appear to play an important role in
      promoting positive dietary intake among adolescents. Feasible ways to increase
      the frequency of family meals should be explored with adolescents and their
      families.

PMID- 12616253
TI  - Changes in diet, physical activity, and supplement use among adults diagnosed
      with cancer.
AB  - OBJECTIVE: To investigate the prevalence and predictors of changes in diet,
      physical activity, and dietary supplement use among cancer patients.
      Design/subjects Telephone interviews of a population-based sample of 126 breast,
      114 prostate, and 116 colorectal cancer patients from the state of Washington.
      ANALYSIS: Logistic regression was used to estimate the odds ratio as a measure of
      the association of participant characteristics with lifestyle changes in the 12
      months before the interview. RESULTS: Overall, 66.3% of patients reported making
      lifestyle changes: 40.4% made one or more dietary changes, 20.8% added new
      physical activity, and 48.0% started taking new dietary supplements. Compared
      with men, women were 2.2 times more likely to take new dietary supplements (P
      <.01). Compared with patients aged 35 to 59, those aged 60 to 69 and 70 or older
      were statistically significantly less likely to make dietary changes (odds ratio
      = 0.39 and 0.54, respectively) or to take new supplements (odds ratio = 0.42 and
      0.69, respectively). Compared with patients who received only one medical
      treatment, those receiving three or more treatments were more likely to make
      dietary changes (odds ratio = 2.6) or to start new physical activity (odds ratio
      = 3.0). Patients diagnosed 12 to 24 months before the interview were as likely to
      report making lifestyle changes as those diagnosed within one year of the
      interview. Having a stronger desire for personal control or internal locus of
      control predicted use of new dietary supplements (P for trend <.05 for both).
      Applications/conclusions Cancer survivors are likely to be making lifestyle
      changes and represent a group that could benefit from counseling on diet and
      physical activity.

PMID- 12616254
TI  - Effects of two models of nutritional intervention on homebound older adults at
      nutritional risk.
AB  - OBJECTIVE: To test the feasibility of two models of home meal delivery with Meals
      on-Wheels (MOW) applicants who were identified as being malnourished or "at-risk"
      as determined by the validated Mini Nutritional Assessment (MNA). DESIGN: A 6
      month, prospective comparative study of two nutrition intervention models with
      data collection at baseline, 3 months, and 6 months. Randomized treatment
      assignment was followed, with a few exceptions linked to particular client
      circumstances. SUBJECTS: A total of 203 older adults (age range = 60 to 90 years)
      newly applying for homebound meal service were enrolled. At baseline, the body
      mass index (BMI) was 26.3+/-7.2 (mean+/-SD) in the "Traditional" MOW model (101
      subjects including 30 malnourished), and the BMI was 27.6+/-9.0 in the "New" MOW
      model (102 subjects including 26 malnourished) (P = ns). INTERVENTION: Study
      participants received either the Traditional MOW program of five hot meals per
      week, meeting 33% of the Daily Reference Intake (DRI) or the restorative,
      comprehensive New MOW program of three meals and two snacks per day, 7 days a
      week, meeting 100% of the DRI. Assessments were conducted in the home of the
      participants. Main outcome measures The MNA was used to evaluate nutritional risk
      and status of participants at baseline, 3 months, and 6 months. Standardized
      functional impairment scales, Activities of Daily Living (ADL), and Instrumental
      Activities of Daily Living (IADL) evaluated limitations in activities of daily
      living and life management skills. Statistical analysis Comparisons between
      treatment groups were calculated with t tests or Wilcoxon rank-sum tests when
      appropriate. Comparisons among time periods between treatment groups were
      conducted with repeated measures analysis of variance. A general linear model was
      used to evaluate the relationship between change in functional status and BMI,
      controlling for sex. RESULTS: The New MOW group gained significantly more weight
      between baseline and 3 months than did the Traditional MOW group (2.78 lb vs 
      1.46 lb, respectively, P =.0120) and again between baseline and 6 months (4.30 lb
      vs -1.72 lb, respectively, P =.0004). MNA improved faster in the New MOW group.
      Functional change appeared to be related more to BMI and age than to treatment
      intervention. The malnourished participants in both groups took longer to affect
      positive change in nutrition measurements, with the New MOW group showing the
      most improvement over the 6-month measurement period. Both delivery models were
      well accepted. CONCLUSIONS: Applicants for home meal delivery have varying
      nutrition needs. By addressing nutritional risk, interventions can be targeted to
      meet these needs. A new, restorative, comprehensive meal program improved
      nutritional status and decreased nutritional risk and can possibly impact
      independence and functionality.

PMID- 12616255
TI  - Strengthening the role of nutrition and improving the health of the elderly
      population.

PMID- 12616256
TI  - The Eating Behavior Patterns Questionnaire predicts dietary fat intake in African
      American women.
AB  - OBJECTIVE: To develop a behavioral assessment of eating that would be predictive
      of fat intake in African American women. DESIGN: Questionnaires were developed
      using a three-stage design, involving item generation, item refinement, and
      questionnaire validation. SUBJECTS: Focus groups sessions were conducted with 40
      African American women, initial questionnaire development employed 80 African
      American women, and questionnaire validation involved 310 African American women
      from diverse socioeconomic backgrounds. Statistical analyses Transcripts of focus
      groups were used to generate 113 behavioral questionnaire items. The initial
      questionnaire was administered along with a food frequency questionnaire, and the
      item pool was reduced to 51 items. Factor analysis was used to create subscales.
      Correlation (r) and multiple regression analysis (R) were used to evaluate
      construct validity. RESULTS: Factor analysis revealed six subscales: low-fat
      eating, emotional eating, snacking on sweets, cultural/ethnic, haphazard
      planning, and meal skipping. The scales are significant predictors of
      micronutrient (R values from 0.22 to 0.47) and macronutrient intakes (R values
      from 0.33 to 0.58) assessed using a food frequency questionnaire and show
      construct validity in relationship to other measures of eating behavior (r values
      from 0.22 to 0.65). APPLICATIONS: The Eating Behavior Patterns Questionnaire
      (EBPQ) may be a useful tool for clinical assessment, clinical and community
      nutrition intervention studies, and epidemiologic research with African American
      women.

PMID- 12616257
TI  - Soy-enhanced lunch acceptance by preschoolers.
AB  - OBJECTIVE: To evaluate acceptance of soy-enhanced compared with traditional menus
      by preschool children. Soy-enhanced foods were substituted on a traditional cycle
      menu, and the amount eaten, energy, and nutrient values for traditional and soy
      enhanced lunches were compared. DESIGN: A traditional three-week cycle menu,
      using the Child and Adult Care Food Program (CACFP) meal pattern guidelines, was
      used to develop a comparable soy-enhanced menu. Traditional and soy-enhanced
      lunches were randomly assigned to respective days. Foods were portioned onto
      individual plates using standardized measuring utensils. Individual plate waste
      techniques were used to collect food waste. Subjects/setting Participants were
      preschool children, three to six years of age and of white and Hispanic origin,
      attending a part-day Head Start program. Statistical analyses performed Analysis
      of covariance was used to adjust lunch and food intakes for differences in
      average amounts of foods served. The Nutrient Data System was used to calculate
      energy and nutrient content of lunches. Analysis of variance was used to
      calculate differences in amounts eaten, energy values, and nutrient values of
      traditional and soy-enhanced lunches and foods. Data analyses were performed with
      the Statistical Analysis Software (version 8.0, 1999, SAS Institute, Cary, NC).
      RESULTS: Soy-enhanced foods were successfully substituted for 23 traditional
      foods included in the cycle menus. Soy-enhanced foods tended to be higher in
      energy, protein, and iron. Traditional lunches tended to be higher in fat,
      saturated fat, and vitamin A. Consumption was significantly less for energy,
      protein, fiber, and iron from foods eaten from traditional compared with soy
      enhanced lunch menus. Applications/conclusions Acceptance of soy-enhanced lunches
      was shown because there were no significant differences in the average amount
      eaten (grams per meal) between traditional and soy-enhanced lunches. Preschool
      programs can substitute soy-enhanced for traditional foods, which will add
      variety to the diet without sacrificing taste, energy, or nutrient value. The fat
      and energy content of the lunches was higher than recommended, and soy-enhanced
      foods were not always lower in fat. There is a need for the food industry and
      foodservice personnel to address the energy and fat content of all foods served
      in lunches to preschool children because a few extra calories added to the daily
      intakes can contribute to weight gain.

PMID- 12616258
TI  - Will taking the amino acid supplement lysine prevent or treat the herpes simplex
      virus?

PMID- 12616259
TI  - Medical nutrition therapy for the prevention and treatment of unintentional
      weight loss in residential healthcare facilities.
AB  - OBJECTIVES: To identify the rate of unintentional weight loss (UWL) in adults
      following their admission into residential healthcare facilities, assess the
      effectiveness of a new medical nutrition therapy (MNT) protocol for the
      prevention and treatment of UWL, and describe nutrition assessment and
      intervention activities of dietitians. DESIGN: Prospective intervention study in
      which volunteer dietitians were randomly assigned to usual nutrition care (UC) or
      MNT protocol care (MNT-PC) groups. Dietitians recruited newly admitted residents
      and tracked their weights for up to 6 months using standardized weighing
      procedures. Data on weight outcomes and nutrition care activities were abstracted
      from medical records and compared between study groups. Subjects/settings Thirty
      one dietitians from 29 facilities completed the field test (16 MNT-PC, 13 UC).
      Medical record data were available for 394 residents (223 MNT-PC, 171 UC), and
      complete weight trend data were available for 364 residents (200 MNT-PC, 164 UC).
      INTERVENTION: The new MNT protocol for UWL in residential facilities emphasized
      assessment; intervention (including weighing frequency); communication with
      staff, medical doctor, family, and resident; and reassessment. Main outcome
      measures Rate of UWL and weight status 90 days after admission and weight status
      90 days after identification of UWL. Statistical analyses Chi;(2), Independent t
      test, analysis of variance, and multiple regression using the general linear
      model. RESULTS: Fourteen of 364 residents (4%) were admitted with significant
      preexisting weight loss, which was successfully treated in eight residents during
      the first 90 days. Substantial unintentional weight loss (>or=5% in any 30 days)
      developed in 78 residents (21%). MNT-PC dietitians were more likely to identify
      UWL. When UWL was identified, and, after providing nutrition care to these
      residents for an additional 90 days, 32 of 61 residents (52%) maintained or
      gained weight. Dietitians in UC and MNT-PC groups were equally successful in
      treating preexisting or postadmission unintentional weight loss when it was
      identified. Differences were found in nutrition care activities. MNT-PC
      dietitians reported more nutrition assessment activities, whereas UC dietitians
      reported more intervention activities. Conclusions/applications Nutrition care
      protocols with standardized weighing procedures can increase the identification
      of UWL in the residential healthcare environment. Improved identification
      supports the additional assessment activities used by MNT-PC dietitians. Similar
      outcomes for UC and MNT-PC groups when UWL was identified indicate that usual
      nutrition care was already a high standard of care for intervention.

PMID- 12616260
TI  - The key to curbing unintentional weight loss lies in identifying the problem.

PMID- 12616261
TI  - A blueprint-based case study analysis of nutrition services provided in a midterm
      care facility for the elderly.
AB  - Ensuring nutritionally adequate food intake in institutions is a complex and
      important challenge for dietitians. To tackle this problem, we argue that
      dietitians need to adopt a systematic, integrative, and patient-centered approach
      to identify and manage more effectively organizational determinants of the
      quality of food intake under their control. In this study, we introduce such an
      approach, the blueprint-based case study, that we applied in the context of a
      midterm care facility for elderly patients. Data gathered through interviews and
      field observations were used to develop, from the perspective of key patient
      encounters, detailed representations of the food, nutrition, and nursing
      activities necessary to ensure adequate food intake. These service "blueprints"
      were developed to illustrate all activities that might potentially impact on the
      nutritional, sensory, functional, and social quality of patients' meals. They
      were also used as roadmaps to develop a case study analysis in which critical
      areas were identified and opportunities for improvement put forth, while
      considering services' resources and priorities. By providing a precise,
      objective, yet comprehensive mapping of the service operations and management,
      the blueprint-based case study approach represents a valuable tool to determine
      the optimal allocation of resources to insure nutritionally adequate food intake
      to patients.

PMID- 12616262
TI  - Effect of weight change on bone mass in female adolescents.
AB  - The purpose of this study was to examine changes in bone mineral density/bone
      mineral content (BMD/BMC) in obese female adolescents (Tanner stages 2 to 4)
      pursuing a weight reduction program. This was a prospective pilot clinical
      investigation involving 92 obese females screened to meet inclusion criteria and
      required to participate in a 6-month weight loss intervention. Baseline, 6
      months, and 12 months measurements were taken for total body/lumbar spine BMD/BMC
      and percentage body fat. Survey instrumentation included the following: calcium
      food frequency/24-hour dietary recall, physical activity, and psychological
      assessments for anxiety/self-esteem. Changes in bone measurements were compared
      with changes in body weight measurements using multiple linear regression. Other
      potentially confounding variables analyzed included bone area, calcium intake,
      baseline Tanner stage, activity level, and height. Total body/lumbar spine
      BMD/BMC changes were found to be most significantly correlated with weight
      changes in the subject population. Although mean weight increased, the rate of
      increase per a given height velocity slowed to an appropriate height for weight
      ratio. Individuals who lost weight did not lose BMD/BMC; however, the rate of
      growth declined when compared with all study subjects whose bone growth rate was
      consistent with normal weight female adolescents. In this study, weight changes
      were strongly related to bone measurement changes in an obese adolescent female
      population. Dietitians counseling obese young girls are encouraged to emphasize
      the importance of a healthy weight loss program with optimal calcium intake and
      inclusive of weight-bearing exercises.

PMID- 12616263
TI  - Galactose content of baby food meats: considerations for infants with
      galactosemia.
AB  - Treatment of galactosemia requires a galactose-restricted diet. Although meats
      are not traditionally thought of as a dietary carbohydrate source, small amounts
      may be present in free form and/or bound to proteins or lipids. The purpose of
      this study was to determine the free and bound galactose contents of baby food
      meats. Galactose was assayed using high-performance liquid chromatography. The
      free galactose content of baby food meats ranged from 0 to 0.031 mg/100 g. No
      statistically significant differences in free galactose content were found among
      the meats. Bound galactose was found in all analyzed baby food meats, ranging
      from 0.065 to 0.148 mg/100 g. The mean galactose content of BeechNut chicken (St.
      Louis, MO) was significantly less than that found in Gerber (Fremont, MI) and
      Heinz (Pittsburgh, PA) brands of chicken, beef, and turkey, and Gerber lamb and
      veal. Based on current recommendations, all examined baby food meats would be
      acceptable for infants with galactosemia.

PMID- 12616265
TI  - Professional boundary issues in practice.

PMID- 12616264
TI  - Oats and the gluten-free diet.
AB  - Whether oats should be included in a gluten-free diet has been debated for half a
      century. In 1995, the largest and most scientifically rigorous study on the
      safety of oats was published. Investigators concluded that the consumption of
      oats was safe for adults with celiac disease. Since 1995, several additional
      studies have been published. Without exception, these investigations found no
      adverse effects associated with the regular consumption of moderate amounts of
      oats. However, there are concerns among some authorities on celiac disease that
      even if oats themselves are safe, they nonetheless may be contaminated with
      wheat, rye, or barley. Unfortunately, the extent to which contamination of
      commercial oat products occurs is not known. Ideally, if a patient appears likely
      to use oats, they should be advised to consume only those products tested and
      found to be free of contamination.

PMID- 12616267
TI  - ?

PMID- 12616266
TI  - The National Dysphagia Diet: implementation at a regional rehabilitation center
      and hospital system.

PMID- 12616268
TI  - [Health status description of populations living in three areas of Tuscany
      (Livorno, Orbetello and Piombino) through causes of death distribution]
AB  - By assessing mortality causes, the authors have described the health status of
      people living in 3 areas of Tuscany around Livorno, Orbetello and Piombino
      municipalities. Direct standard mortality and local standard mortality ratios
      were assessed as regards the years 1988?1997. Total mortality turned out to be
      equal or lower than the Italian average, with the exception of the women from
      Livorno municipality. Cancer mortality is higher in Livorno area, among females
      in Orbetello area and males in both Orbetello and Piombino municipalities. As
      regards regional mortality, the situation in Livorno seems to be the worst,
      followed by Orbetello and Piombino.

PMID- 12616269
TI  - [The health staff's exposure to biological materials in a Hospital in the Marches
      Region, Italy: epidemiological analysis (1995-2001)]
AB  - The authors have analyzed some epidemiological events caused by the exposure to
      biological material amongst health workers at the Mazzoni Hospital in Ascoli
      Piceno (the Marches Region). According to a tailor-made questionnaire, 704
      accidents occurred in the years 1995-2001. Data showed that nurses are the most
      frequently exposed (67%). As regards the premises, operating rooms account for
      16.5 % of the accidents, ERs 9.2 % and Nephrology/Haemodialysis Units 8.8%. The
      highest rate of accidents occurred during injections procedures (67%) and
      precautions were observed only by 65% of the health care workers. The source
      patient was known in 86% of the cases and all workers were submitted to HBC, HCV
      and HIV tests. 95 subjects (16%) showed not less than one marker and 80% of them
      were HCV-positive. No anti-HIV/HCV/HBV seroconversions were registered.

PMID- 12616270
TI  - ?

PMID- 12616271
TI  - [Presence and meaning of aeromonas in drinkable water]
AB  - Many species of Aeromonas are thought to be the cause of diarrhoeal syndromes,
      bactaeremia and eye infections. Recent studies have shown that the presence of
      aeromonas in drinkable water is not associated with that of feacal indicators.
      The authors have tested 62 samples of drinkable water from various wells, as well
      as 14 samples of two mineral waters collected in Eastern Sicily from 1996 to
      1999. Aeromonas were found in 14 (18%) out of 76 samples. Also, biochemical
      detection of the strains showed the presence of A. Salmoncida and A. hydrophila.
      According to the survey's data, there is a need to check aeromonas in drinkable
      water as a constant practice.

PMID- 12616272
TI  - [Perinatal infections of B19 Parvoviruses]
AB  - This study is aimed at detecting perinatal infections of Parvovirus B19 (PV B19).
      The authors have analyzed specific antibodies (IgM and IgG) in the cord serum of
      647 babies, born consecutively at the St. Eugenio Hospital in Rome. 156 of them
      (24%) were positive to IgG. The analysis of viral genome by PCR methods showed
      three positive subjects (2%). The three newborn babies did not develop any
      pathologies during a two-year follow-up and PCR became negative within the first
      6 months. Data show that a mass pregnancy test is not useful for PV B19
      detection, and that specific antibody analysis should be limited to pregnancies
      at risk. However healthy the infected patients may appear at birth, though, it is
      advisable to have them monitored for at least one year so as to avoid the risk of
      chronic infections.

PMID- 12616273
TI  - [The 1817 outbreak of louse-borne typhus in the Leghorn area (Tuscany):
      relationship between Authorities, public Health and medical doctrine]
AB  - The authors recall the louse-borne typhus that took place in Leghorn in 1817.
      They analyse its causes and the health measures adopted to face it. Out of the
      historical reconstruction, there arise some issues on both the coming up again of
      such risk and the role played by health measures. Data concern the chronicles and
      the medical literature of those days. The method adopted implies comparison
      between historical circumstances, medical debate and provisions: in 1817 an
      epidemic of typhus exanthematicus caused hundreds of deaths and gave rise to much
      medical controversy incapable, however, of improving the existing knowledge. The
      analysis show a lack of health protection programs and a fallacious medical
      approach which did not help understand the relationship between pediculosis and
      disease. Following the health risks posed by migration pressures, this study
      stresses the importance of keeping the health agents' freedom of judgment away
      from political and administrative authority.

PMID- 12616274
TI  - [The health professions for prevention]

PMID- 12616284
TI  - NTP Toxicology and Carcinogenesis Studies of Pentachloroanisole (CAS No. 1825-21
      4) in F344 Rats and B6C3F1 Mice (Feed Studies).
AB  - Pentachloroanisole is a chlorinated aromatic compound which is widely distributed
      at low levels in the environment and in food products. Formation of
      pentachloroanisole in the environment may result from the degradation of
      structurally related, commercially important, ubiquitous chlorinated aromatic
      compounds such as pentachlorophenol and pentachloronitrobenzene which are known
      rodent toxins or carcinogens. Toxicology and carcinogenesis studies were
      conducted by administering pentachloroanisole (>99% pure) in corn oil by gavage
      to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks,
      or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium
      strains, mouse lymphoma cells, and Chinese hamster ovary cells. 16-DAY STUDIES IN
      RATS: Groups of five male and five female F344/N rats were administered
      pentachloroanisole in corn oil by gavage once per day, 5 days per week, for 16
      days at doses of 0, 100, 125, 150, 175, or 200 mg/kg body weight. Deaths occurred
      during days 2 and 3 in rats receiving doses of 125 mg/kg or greater; these deaths
      were considered directly related to pentachloroanisole administration. No
      biologically significant changes in mean body weight gains or final body weights
      were noted in the 100 mg/kg groups of rats. Because of the high early mortality
      rate, valid comparisons of body weight differences in other dose groups could not
      be made. Inactivity was noted in all dose groups. Rats administered doses of 125
      mg/kg or greater also exhibited dyspnea. 16-DAY STUDIES IN MICE: Groups of five
      male and five female B6C3F1 mice were administered pentachloroanisole in corn oil
      by gavage once per day, 5 days per week, for 16 days at doses of 0, 100, 175,
      250, 325, or 400 mg/kg. Deaths occurred during days 2 and 3 in mice receiving
      doses of 175 mg/kg or greater; these deaths were considered directly related to
      chemical administration. No biologically significant changes in mean body weight
      gains or final body weights were noted in 100 mg/kg males or 100 or 175 mg/kg
      females. Because of the high early mortality rate, valid comparisons of body
      weight differences in other dose groups could not be made. Inactivity was noted
      in dosed mice. 13-WEEK STUDIES IN RATS: Groups of 10 male and 10 female rats were
      administered pentachloroanisole in corn oil by gavage once per day, 5 days per
      week, for 13 weeks at doses of 0, 40, 80, 120, 140, or 180 mg/kg body weight.
      Most rats receiving doses of 120 mg/kg or greater died during the first week of
      the study as a direct result of pentachloroanisole administration. Mean body
      weight gains of males administered 40 or 80 mg/kg and of females administered 40,
      80, or 120 mg/kg pentachloroanisole were significantly lower than those of the
      controls. Most dosed rats exhibited temporary inactivity for several hours after
      dosing. Relative liver and kidney weights of males administered 40 or 80 mg/kg
      and absolute and/or relative liver and kidney weights of females administered 40
      to 120 mg/kg were significantly greater than those of the controls. Lesions
      observed in males administered 80 mg/kg or more and in females administered 120
      mg/kg or more included pulmonary congestion, hemorrhage, and/or edema, meningeal
      congestion, and hepatocellular necrosis, glycogen depletion, and degeneration of
      biliary epithelium in the liver. 13-WEEK STUDIES IN MICE: Groups of 10 male and
      10 female mice were administered pentachloroanisole in corn oil by gavage once
      per day, 5 days per week, for 13 weeks at doses of 0, 40, 80, 120, 140, or 180
      mg/kg body weight. Most mice administered doses of 120 mg/kg or higher died
      during the first week of the study as a direct result of pentachloroanisole
      administration. Mean body weight gains of females administered 40 to 140 mg/kg
      were significantly greater than that of the controls, but those of dosed males
      were similar to that of the controls. Most dosed mice exhibited temporary
      inactivity for several hours after dosing. Absolute and relative liver weights of
      males administered 80 mg/kg, absolute and relative liver weights of femats of
      females administered 40 to 180 mg/kg, and absolute and relative kidney weights of
      females administered 80 to 180 mg/kg pentachloroanisole were also significantly
      greater than those of the controls. Lesions observed in males administered 40
      mg/kg or more and in females administered 80 mg/kg or more included pulmonary
      congestion and/or edema, adrenal congestion, lymphoid depletion of lymph nodes
      and thymus, hepatocellular cytomegaly and karyomegaly, and pigment accumulation
      in hepatocytes and Kupffer cells. 2-YEAR STUDIES IN RATS: Based on the chemical
      related mortality and liver lesions seen in the 16-day and 13-week studies, doses
      selected for the 2-year studies were 0, 10, 20, and 40 mg/kg for males and 0, 20,
      and 40 mg/kg for females. Groups of 70 male and 70 female rats were administered
      pentachloroanisole in corn oil by gavage 5 days per week for up to 2 years. At 9
      and 15 months, up to 10 animals per group were selected for interim evaluations.
      Survival, Body Weights, and Clinical Findings: The survival of high-dose males
      was significantly decreased (vehicle control, 24/50; low-dose, 20/50; mid-dose,
      24/50; high-dose, 14/50); most deaths in the high-dose group occurred at or
      before week 16. The majority of deaths in the mid- and high-dose groups may have
      been due to pentachloroanisole-related hyperthermia. The survival of dosed
      females was greater than that of the controls (29/50, 35/50, 44/50). Final mean
      body weights of mid- and high-dose males were 7&percnt; and 10&percnt; lower than
      that of the controls; final mean body weight of high-dose females was 11&percnt;
      lower than that of the controls. Final mean body weights of other dose groups
      were similar to those of the vehicle controls. At the 9-month interim evaluation,
      mean rectal temperature of males administered 40 mg/kg was significantly greater
      than that of the controls. Relative liver and kidney weights of males and females
      administered 20 or 40 mg/kg were significantly greater than those of controls. At
      the 15-month interim evaluation, relative liver weights of dosed females and
      absolute liver weights of 40 mg/kg females were significantly greater than those
      of the controls, as were relative liver and kidney weights of 40 mg/kg males.
      Pathology Findings: In the 2-year studies, administration of pentachloroanisole
      to males was associated with significant increases in the incidences of benign
      adrenal medulla pheochromocytomas. The incidence of benign adrenal medulla
      pheochromocytomas was marginally increased in high-dose females and slightly
      exceeded the range of the historical controls. Incidences of adrenal medulla
      hyperplasia were increased in dosed female rats, but not in dosed males. The
      incidences of pancreatic adenomas and focal hyperplasia were decreased in dosed
      males. The incidences of mammary gland fibroadenomas and uterine stromal polyps
      and sarcomas (combined) were decreased in high-dose females. Treatment-related
      increased incidences of intracytoplasmic pigmentation occurred in renal tubule
      epithelium, olfactory epithelium, and hepatocytes of males and females.
      Congestion and hemorrhage of the lungs, lymph nodes, thymus, adrenal cortex, and
      meninges, as well as hepatocellular centrilobular necrosis occurred almost
      exclusively in mid- and high-dose males that died or were killed moribund before
      the end of the studies. 2-YEAR STUDIES IN MICE: Based on the chemical-related
      mortality and liver lesions seen in the 16-day and 13-week studies, doses
      selected for the 2-year studies were 0, 20, and 40 mg/kg. Groups of 70 male and
      70 female mice were administered pentachloroanisole in corn oil by gavage 5 days
      per week for up to 2 years. At 9 and 15 months, up to 10 animals per group were
      selected for interim evaluations. Survival, Body Weights, and Clinical Findings:
      The survival of dosed males was similar to that of the controls; survival of high
      dose females was lower than that of the controls (24/50, 25/50, 16/50). The
      decreased survival of the high-dose females was attributed primarily to ovarian
      abscesses which were observed after moribund sacrifice. At the 9-month interim
      evaluation, the mean body weight of males administered 40 mg/kg was significantly
      lower than that of the vehicle controls. Absolute and relative liver weights of
      females and the relative liver weight of males administered 40 mg/kg were
      significantly greater than those of the controls. Final mean body weights of low-
      and high-dose males were 11&percnt; and 17&percnt; lower than that of the
      controls. Final mean body weights of dosed females were similar to that of the
      controls. There were no clinical findings attributed to pentachloroanisole
      administration. Pathology Findings: Centrilobular hepatocyte cytomegaly and
      pigment accumulation in hepatocytes and Kupffer cells were seen in dosed mice,
      but not in controls at the 9- and 15-month interim evaluations. In the 2-year
      studies, the incidence of benign pheochromocytomas was significantly increased in
      high-dose males. Dosed males also exhibited increased incidences of adrenal
      medulla hyperplasia and hypertrophy. The incidences of hemangiosarcomas of the
      liver were significantly increased in dosed males. Increased incidences of
      hepatocellular cytologic alteration, biliary tract hyperplasia, and Kupffer cell
      pigmentation occurred in dosed males and females; the incidences of mixed cell
      foci were also increased in dosed males. Cytologic alteration encompassed
      hepatocellular cytomegaly, karyomegaly, hepatocyte degeneration and necrosis, and
      multinucleated giant cell formation, and was considered an advanced stage of the
      pathologic process observed at 13 weeks. GENETIC TOXICOLOGY: Pentachloroanisole
      was mutagenic in Salmonella typhimurium strains TA98 and TA1537 in the absence
      but not in the presence of exogenous metabolic activation (S9). No clear
      mutagenic activity was observed in TA100 with hamster S9, without S9, or in
      TA1535 with or without S9. An equivocal response was observed in TA100 with rat
      S9. Pentachloroanisole was positive for induction of trifluorothymidine
      resistance in mouse lymphoma L5178Y cells with S9; the response observed without
      S9 was weak and inconsistent. In cytogenetic tests with Chinese hamster ovary
      cells, pentachloroanisole induced sister chromatid exchanges, but not chromosomal
      aberrations, with and without S9. TOXICOKINETICS: Male and female F344/N rats and
      B6C3F1 mice were administered 10, 20, or 40 mg/kg pentachloroanisole by gavage or
      10 mg/kg pentachloroanisole intravenously (Appendix H). A rapid elimination of
      pentachloroanisole and a rapid formation of its main metabolite,
      pentachlorophenol, were seen in both species after an intravenous or an oral dose
      of pentachloroanisole. The area under the concentration-versus-time curve of
      pentachloroanisole increased with dosage in each species but the dose
      proportionality was lost above 20 mg/kg. No sex-related differences were found in
      the rate of absorption of pentachloroanisole from the GI tract, in the area under
      the concentration-versus-time curve, or in the overall rate elimination of
      pentachloroanisole. However, in female rats the area under the concentration
      versus-time curve of pentachlorophenol was significantly larger than in male
      rats. No such difference was observed in mice. CONCLUSIONS: Under the conditions
      of these 2-year gavage studies, there was some evidence of carcinogenic activity
      of pentachloroanisole in male F344/N rats based on increased incidences of benign
      pheochromocytomas of the adrenal medulla. There was equivocal evidence of
      carcinogenic activity of pentachloroanisole in female F344/N rats based on
      marginally increased incidences of benign pheochromocytomas of the adrenal
      medulla. There was some evidence of carcinogenic activity of pentachloroanisole
      in male B6C3F1 mice based on increased incidences of benign pheochromocytomas of
      the adrenal medulla and hemangiosarcomas of the liver. There was no evidence of
      carcinogenic activity of pentachloroanisole in female B6C3F1 mice given doses of
      20 or 40 mg/kg. Pentachloroanisole administration was associated with increased
      incidences of adrenal medulla hyperplasia in female rats and increased incidences
      of pigmentation in the renal tubule epithelium, olfactory epithelium, and
      hepatocytes of male and female rats. In addition, decreased incidences of
      pancreatic adenomas and focal hyperplasia in male rats and decreased incidences
      of mammary gland fibroadenomas and uterine stromal polyps and sarcomas (combined)
      in female rats were observed. Hyperthermia-related lesions in male rats receiving
      20 or 40 mg/kg were considered indirectly related to pentachloroanisole
      administration. Pentachloroanisole administration was associated with increased
      incidences of adrenal medulla hyperplasia and hypertrophy and hepatocellular
      mixed cell foci in male mice. In male and female mice, nonneoplastic liver
      lesions associated with pentachloroanisole administration included hepatocellular
      cytologic alteration, Kupffer cell pigmentation, biliary tract hyperplasia, and
      subacute inflammation. Synonyms: 2,3,4,5,6-pentachloroanisole; methyl
      pentachlorophenate; methyl pentachlorophenyl ether; o-methylpentachlorophenol;
      pentachloromethoxybenzene; pentachlorophenyl methyl ether

PMID- 12616285
TI  - NTP Toxicology and Carcinogenesis Studies of Ethylene Glycol (CAS No. 107-21-1)
      in B6C3F1 Mice (Feed Studies).
AB  - Ethylene glycol is a major constituent of motor vehicle antifreeze-coolant fluids
      and is also found in other commercial products including hydraulic brake fluids,
      adhesives, printer's inks, and wood stains. It is used in the manufacture of
      polyester films and fibers, polyethylene terephthalate (PET) solid state resins,
      plasticizers, elastomers, cellophane, and other products. Previous 13-week and 2
      year studies of ethylene glycol in F344 rats were considered adequate to evaluate
      the toxicology and carcinogenicity of ethylene glycol in this species and strain;
      therefore, the present studies were conducted in mice only. Toxicology and
      carcinogenesis studies were conducted by administering ethylene glycol (greater
      than 99% pure) in feed to male and female B6C3F1 mice for 13 weeks and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium, mouse
      lymphoma L5178Y cells, and Chinese hamster ovary cells. 13-Week Studies: Groups
      of 10 male and 10 female mice received feed containing 0, 3,200, 6,300, 12,500,
      25,000 or 50,000 ppm ethylene glycol. All mice survived to the end of the
      studies. Final mean body weights of dosed male and female mice and feed
      consumption of dosed males were similar to those of the controls. Feed
      consumption of dosed females was significantly greater than that of controls.
      Absolute and relative organ weights of mice administered ethylene glycol were
      generally similar to those of controls throughout the study. No chemical-related
      clinical findings were observed. Chemical-related kidney and liver lesions, seen
      only in 25,000 and 50,000 ppm male mice, consisted of nephropathy and
      centrilobular hepatocellular hyaline degeneration (cytoplasmic accumulation of
      non-birefringent, eosinophilic, globular, or crystalline material resembling
      erythrocyte fragments). 2-Year Studies: Groups of 60 mice received diets
      containing ethylene glycol for up to 103 weeks (males: 0, 6,250, 12,500, or
      25,000 ppm; females: 0, 12,500, 25,000, or 50,000 ppm). These concentrations
      correspond to daily doses of approximately 1,500, 3,000, or 6,000 mg/kg body
      weight for male mice and 3,000, 6,000, or 12,000 mg/kg for females. Dietary
      concentrations greater than 50,000 ppm have the potential to affect the
      nutritional value of the feed. Interim evaluations were performed on six males
      and nine or ten females from each dose group at 15 months. Survival, Body
      Weights, Feed Consumption, and Clinical Findings in the 2-Year Studies: At the
      end of the 2-year studies, survival rates of male and female mice exposed to
      ethylene glycol were similar to those of controls. Mean body weights and feed
      consumption of exposed male and female groups were also similar to those of
      controls. No clinical findings associated with the administration of ethylene
      glycol were observed. Pathology Findings: No chemical-related neoplasms were
      observed in male or female mice in these studies. Hepatocellular hyaline
      degeneration was seen in mid- and high-dose male and high-dose female mice.
      Pulmonary arterial medial hyperplasia was observed at an increased incidence in
      exposed females but not in exposed males. Incidence and severity of nephropathy
      were not affected by treatment in either sex. Small numbers of oxalate-like
      crystals, calculi, or both were noted in renal tubules, urethrae, and/or urinary
      bladders in a few high-dose male mice. Genetic Toxicology: Ethylene glycol did
      not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535,
      and TA1537, trifluorothymidine resistance in mouse L5178Y lymphoma cells, or
      sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary
      cells. All tests were conducted with and without exogenous metabolic activation
      (S9). Conclusions: Under the conditions of these 2-year feed studies, there was
      no evidence of carcinogenic activity of ethylene glycol in male B6C3F1 mice
      receiving 6,250, 12,500, or 25,000 ppm, or in female B6C3F1 mice receiving
      12,500, 25,000, or 50,000 ppm. Administration of ethylene glycol resulted in
      hepatocellular hyaline degeneration in male mice fed diets diets containing
      12,500 or 25,000 ppm and in female mice fed diets containing 50,000 ppm. An
      increased incidence of medial hyperplasia of small pulmonary arteries and
      arterioles occurred in female mice fed diets containing 12,500, 25,000, or 50,000
      ppm ethylene glycol. Synonyms: 1,2-dihydroxyethane; ethane-1,2-diol; 1,2
      ethanediol; ethylene alcohol; ethylene dihydrate; glycol; glycol alcohol; 2
      hydroxyethanol; monoethylene glycol

PMID- 12616286
TI  - NTP Toxicology and Carcinogenesis Studies of Promethazine Hydrochloride (CAS No.
      58-33-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
AB  - Promethazine hydrochloride is a drug used for the management of allergic
      conditions, motion sickness and nausea, and as a sedative to (treat psychiatric
      disorders. This drug was nominated for testing by the Food and Drug
      Administration because of its widespread use in human medicine and because of
      lack of data on its potential carcinogenicity. Oral administration is the most
      common route of human exposure. Toxicology and carcinogenicity studies were
      conducted by administering promethazine hydrochloride (>99% pure) in distilled
      water by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16
      days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in
      Salmonella typhimurium, in cultured Chinese hamster ovary cells, and in
      Drosophila melanogaster. 16-DAY STUDY IN RATS: Groups of five male and five
      female rats received 0, 18.5, 55.5, 166.5, 500, or 1,500 mg promethazine
      hydrochloride/kg body weight once daily, 5 days per week for a total of 12 doses
      in a 16-day period. All rats receiving 1,500 mg/kg, four males and four females
      receiving 500 mg/kg, and one male and one female receiving 166.5 mg/kg died
      during the study. No deaths occurred in the remaining dose groups. Final mean
      body weights of rats receiving 166.5 mg/kg were significantly lower (12% to 25%)
      than those of the controls. Clinical findings included decreased activity, ocular
      discharge, and labored breathing in males and females receiving 166.5, 500, and
      1,500 mg/kg as well as tremors in females receiving 166.5 and 500 mg/kg. There
      were dose-related increases in the absolute and relative liver weights of rats.
      Focal suppurative inflammation occurred in the nose of some male and female rats
      receiving 55 or 166.5 mg/kg and in the trachea of some male and female rats
      receiving 166.5 mg/kg. 16-DAY STUDY IN MICE: Groups of five male and five female
      mice received 0, 18.8, 37.5, 75, 150, or 300 mg promethazine hydrochloride/kg
      body weight once daily, 5 days per week for a total of 12 doses in a 16-day
      period. Two females receiving 75 mg/kg, one male and one female receiving 150
      mg/kg, and four females receiving 300 mg/kg died during the study. No deaths
      occurred in the remaining dose groups. Final mean body weights of mice receiving
      promethazine hydrochloride were similar to those of the controls. However, in
      male and female controls, the final mean body weights were 11% to 12% lower than
      the initial mean body weights. Clinical findings occurred as early as the first
      day of the study and included decreased activity in male and female mice
      receiving 150 and 300 mg/kg. Tremors occurred in one male and five females in the
      300 mg/kg group on day 1 and in one male in the 150 mg/kg group and five males
      and one female in the 300 mg/kg group on day 2. Absolute and relative liver
      weights of male mice receiving 75, 150, or 300 mg/kg were significantly greater
      than those of the controls. No chemical related lesions were present in male or
      female mice. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received
      0, 3.7, 11.1, 33.3, 100, or 300 mg promethazine hydrochloride/kg body weight once
      daily, 5 days per week for 13 weeks. One female receiving 100 mg/kg and six males
      and nine females receiving 300 mg/kg died during the study. No deaths occurred in
      the remaining dose groups. Final mean body weights of male rats receiving 100 or
      300 mg/kg were significantly lower (19% to 22%) than those of the controls. Mean
      body weight gain of females receiving 100 mg/kg was significantly lower (14%)
      than that of the controls. Clinical findings in rats included hunched posture and
      labored breathing. Absolute and relative liver weights of males receiving 11.1,
      33.3, 100, or 300 mg/kg and females receiving 33.3 or 100 mg/kg were
      significantly greater than those of the controls. Focal suppurative inflammation
      of the nose and trachea occurred with an increased incidence in rats receiving
      100 and 300 mg/kg. A dose-related increased incidence of vacuolar degeneration of
      the nasal olfactory epithelium occurred in male and female rats that received
      11.1, 33.3, or urred in male and female rats that received 11.1, 33.3, or 100
      mg/kg. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5,
      15, 45, 135, or 405 mg promethazine hydrochloride/kg body weight once daily, 5
      days per week for 13 weeks. One control female, one female receiving 5 mg/kg, two
      females receiving 45 mg/kg, four females receiving 135 mg/kg, and all mice
      receiving 405 mg/kg died during the study. No deaths occurred in the remaining
      dose group. Final mean body weights of mice receiving 135 mg/kg were
      significantly lower (8&percnt; to 9&percnt;) than those of the controls. Clinical
      findings of toxicity included labored breathing and decreased activity in one 135
      mg/kg female. Absolute and relative liver weights increased in a dose-related
      trend in both sexes. No chemical-related lesions were observed in mice. 2-YEAR
      STUDY IN RATS: Based on mortality and body weight differences observed at higher
      levels, doses of promethazine hydrochloride selected for the 2-year study in rats
      were 0, 8.3, 16.6, and 33.3 mg/kg. Groups of 60 male or 60 female rats were
      administered promethazine hydrochloride in deionized water by gavage once daily,
      5 days per week for up to 103 weeks. Up to ten male and ten female rats per dose
      group were evaluated at 15 months. Survival, Body Weights, and Clinical Findings:
      There was a significant dose-related decrease in survival of rats. The survival
      rates in the 16.6 and 33.3 mg/kg male groups and in the 33.3 mg/kg female group
      were significantly lower than those of the controls. The final mean body weight
      of male rats receiving 33.3 mg/kg promethazine hydrochloride was 10&percnt; lower
      than that of the controls. Final mean body weights of female rats in the 16.6 and
      33.3 mg/kg groups were 9&percnt; and 11&percnt; lower than that of the controls,
      respectively. No chemical-related clinical findings were noted in any dose group.
      Significant increases in the absolute and relative liver weights of mid- and high
      dose female rats and the relative liver weights of mid- and high-dose male rats
      were observed at the 15-month interim evaluation. There were no biologically
      significant differences in the hematology or clinical chemistry parameters
      measured at 15 months. Pathology Findings: No neoplasms that could be attributed
      to promethazine hydrochloride administration were found in male or female rats.
      Several neoplasms occurred with a significantly decreased incidence in rats
      receiving promethazine hydrochloride. These included adrenal medullary
      pheochromocytoma (benign or malignant) and pituitary gland adenoma in the 33.3
      mg/kg males and uterine stromal polyp in the 33.3 mg/kg females. The decreased
      incidences of adrenal medullary pheochromocytoma were chemical related. The
      decreased incidences of pituitary gland adenoma and uterine stromal polyp may
      have been related to chemical administration. Diffuse fatty change of the liver
      of male rats increased with dose and was attributed to chemical administration. 2
      YEAR STUDY IN MICE: Based on mortality and body weight differences observed at
      higher levels, the doses of promethazine hydrochloride selected for the 2-year
      study were 0, 11.25, 22.5, and 45 mg/kg for male mice and 0, 3.75, 7.5, and 15
      mg/kg for female mice. Groups of 60 male or 60 female mice were administered
      promethazine hydrochloride in deionized water by gavage once daily, 5 days per
      week for up to 103 weeks. Up to 10 male and 10 female mice per dose group were
      evaluated at 15 months. Survival, Body Weights, and Clinical Findings: Survival
      of mice receiving promethazine hydrochloride was similar to that of the controls.
      Mean body weights of mice were within 7&percnt; of those of the controls
      throughout the study. There were no chemical-related clinical findings in male or
      female mice. There were no differences in hematology or clinical chemistry
      parameters measured at 15 months that were attributed to the administration of
      promethazine hydrochloride. Pathology Findings: There were no neoplasms or
      nonneoplastic lesions that were attributed to the administration of promethazine
      hydrochloride. GENETIC TOXICOLOGY: Promethazine hydrochloride did not induce gene
      mutations in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537,
      or a significant increase in chromosomal aberrations in cultured Chinese hamster
      ovary cells; both of these tests were conducted with and without exogenous
      metabolic activation (S9). A small dose-related increase in sister chromatid
      exchanges was observed in cultured Chinese hamster ovary cells in the presence of
      S9; this response was considered to be equivocal. No increase in sister chromatid
      exchanges was observed in the absence of S9. Promethazine hydrochloride did not
      induce sex-linked recessive lethal mutations in germ cells of male Drosophila
      melanogaster administered the chemical by feeding or injection. CONCLUSIONS:
      Under the conditions of these 2-year gavage studies, there was no evidence of
      carcinogenic activity of promethazine hydrochloride in male or female F344/N rats
      receiving 8.3, 16.6, or 33.3 mg/kg. There was no evidence of carcinogenic
      activity of promethazine hydrochloride in male B6C3F1 mice receiving 11.25, 22.5,
      or 45 mg/kg. There was no evidence of carcinogenic activity of promethazine
      hydrochloride in female B6C3F1 mice receiving 3.75, 7.5, or 15 mg/kg. The
      decrease in the incidences of adrenal medullary pheochromocytoma in male rats was
      considered to be related to promethazine hydrochloride administration. The
      decrease in the incidences of pituitary gland adenoma in male rats and uterine
      stromal polyp in female rats may have been related to promethazine
      administration. Synonyms: Phenothiazine,10-(2-(dimethylamino)propyl)
      ,monochlorohydrate; 10H-phenothiazine-10-ethanamine;10-(2-dimethylamino-2
      methylethyl)phenothiazine hydrochloride; N-(2 -dimethylamino-2 
      methyl)ethylphenothiazine hydrochloride Trade names: Diprazi; Kinetosin;
      Phenergan; Phenergan hydrochloride; Promine; Pipolfen; Plletia; Prorex;
      Promantine; Pyrethia; Romergan hydrochlonde

PMID- 12616287
TI  - NTP Toxicology and Carcinogenesis Studies of o-Benzyl-p-Chlorophenol (CAS No. 120
      32-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
AB  - o-Benzyl-p-chlorophenol is an aryl halide biocide with widespread use in
      hospitals and households as a broad-spectrum germicide in disinfectant solutions
      and soap formulations for general cleaning and disinfecting. Human exposure to o
      benzyl-p-chlorophenol occurs by absorption through the skin and mucous membranes
      and by ingestion. Toxicity and carcinogenicity studies were conducted by
      administering o-benzyl-p-chlorophenol (approximately 97% pure) in corn oil by
      gavage to male and female F344/N rats and B6C3F1 mice for 16-days, 13-weeks, and
      2-years. Clinical pathology parameters were evaluated during the 2-year rat
      study. Genetic toxicity studies were conducted in Salmonella typhimurium,
      cultured Chinese hamster ovary cells, L5178Y mouse lymphoma cells, and cultured
      human lymphoblast cells. 16-DAY STUDY IN RATS: Groups of five male and five
      female rats were administered o-benzyl-p-chlorophenol in corn oil by gavage at
      doses of 0, 62.5, 125, 250, 500, or 1,000 mg/kg body weight 5 days a week over a
      16-day period. Two 1,000 mg/kg female rats died and these deaths were attributed
      to chemical administration. The mean body weight gains of 1,000 mg/kg males and
      females were significantly lower than those of the controls. Clinical findings in
      1,000 mg/kg males and females included diarrhea and rough hair coat. Absolute and
      relative kidney and liver weights of 250, 500, and 1,000 mg/kg males and 1,000
      mg/kg females were significantly greater than those of the controls. Absolute and
      relative thymus weights of 500 and 1,000 mg/kg males and 250, 500, and 1,000
      mg/kg females were significantly lower than those of the controls. At necropsy,
      dilatation of the cecum was observed in male and female rats; the incidence
      generally increased with dose. The dilated cecum of some dosed rats had necrosis
      of the mucosal epithelium. Mild to moderate nephropathy was observed in all 1,000
      mg/kg male and female rats. Minimal nephropathy occurred in one rat receiving
      62.5 mg/kg, two rats each from the 125 and 250 mg/kg groups, and seven rats in
      the 500 mg/kg groups. The incidence and severity of nephropathy increased with
      dose. 16-DAY STUDY IN MICE: Groups of five male and five female mice were
      administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 62.5,
      125, 250, 500, or 1,000 mg/kg body weight 5 days a week over a 16-day period.
      Deaths occurred only in the 1,000 mg/kg groups, in which three males and all
      females died. Mean body weight gains of dosed male and female mice were generally
      similar to those of the controls. Clinical findings in male and female high-dose
      mice included rough hair coat and postural changes. Absolute and relative liver
      weights of 500 and 1,000 mg/kg males and 500 mg/kg females (the highest dose
      group of females surviving) were significantly greater than those of the
      controls. Necropsy findings included dilatation of the cecum. Nephropathy
      occurred in 500 and 1,000 mg/kg mice (500 mg/kg, 2/10; 1,000 mg/kg, 6/10). 13
      WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered o
      benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 30, 60, 120, 240, or
      480 mg/kg body weight 5 days a week for 13 weeks. No deaths were attributed to o
      benzyl-p-chlorophenol administration; however, the deaths of five male rats were
      attributed to gavage trauma. Mean body weight gains of all dosed rats were
      generally similar to those of the controls. Clinical findings included yellow-red
      staining of the urogenital region hair coat of all dosed females. The
      albumin/globulin ratios in 120, 240, and 480 mg/kg male rats increased with dose
      and were the result of net decreases in total globulin. Administration of o
      benzyl-p-chlorophenol caused no significant alterations in hematologic or
      urinalysis parameters. Absolute and relative kidney weights were significantly
      greater and the absolute and relative thymus weights were significantly lower in
      480 mg/kg male and female rats and in 240 mg/kg female rats. No gross lesions
      related to compound administration were observed at necropsy. Nephropathy of mild
      to moderate derate severity occurred in 480 mg/kg male and female rats and in 240
      mg/kg male rats. Few or no lesions occurred in other dosed rats and none occurred
      in controls. 13-WEEK STUDIES IN MICE: In the first 13-week study, groups of 10
      male and 10 female mice were administered o-benzyl-p-chlorophenol in corn oil by
      gavage at doses of 0, 30, 60, 120, 240, or 480 mg/kg body weight 5 days a week
      for 13 weeks. Survival, mean body weight gains, and clinical findings of dosed
      animals were similar to those of the controls throughout the study. The Pathology
      Working Group confirmed that no microscopic lesions were observed that could
      definitively be associated with o-benzyl-p-chlorophenol administration. On the
      basis of these findings, a second 13-week study was performed using higher doses.
      In the second 13-week study, groups of 15 male and 15 female mice were
      administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 500,
      650, 800, or 1,000 mg/kg body weight 5 days a week for up to 13 weeks. Five male
      and five female mice from each group were evaluated after 2 weeks, with the
      remainder (up to 10 per sex) evaluated at the end of the study. One 500 mg/kg
      mouse, three 650 mg/kg mice, 14 mice receiving 800 mg/kg, and 19 mice
      administered 1,000 mg/kg died before the end of the study. Mean body weight gains
      of dosed male and female mice that received 500 or 800 mg/kg were lower than
      those of the controls. Absolute and relative liver weights of 800 mg/kg males and
      all surviving dosed females were significantly greater than those of the
      controls. Absolute and relative kidney weights of 500, 650, and 800 mg/kg male
      mice were slightly lower than those of the controls, and those of female mice
      were similar to those of the controls. The incidence and severity of nephropathy
      increased with time and with increasing dose of o-benzyl-p-chlorophenol.
      Significant nephropathy was present at all doses, with mild nephropathy present
      at the 500 mg/kg dose. Acute necrotizing, suppurative inflammation of the
      olfactory epithelium was noted in all dose groups, with severity increasing with
      dose. These lesions were considered to be directly related to the caustic nature
      of o-benzyl-p-chlorophenol following retrograde exposure after gavage, with the
      presence of foreign material likely due to retrograde migration of the chemical.
      2-YEAR STUDY IN RATS: Groups of 80 male and 80 female rats were administered o
      benzyl-p-chlorophenol in corn oil by gavage 5 days a week for 103 weeks. The
      doses were 0, 30, 60, or 120 mg/kg body weight for male rats and 0, 60, 120, or
      240 mg/kg body weight for female rats. After 3 and 15 months, 7 to 10 male and 8
      to 10 female rats were evaluated for organ weights and clinical pathology, and
      control and high-dose rats were evaluated for histopathology. Survival, Body
      Weights, and Clinical Findings: Survival of dosed male and female rats was
      similar to that of the controls. Mean body weights of dosed rats were generally
      similar to those of the controls. No chemical-related clinical findings were
      observed except yellow staining of the urogenital area hair coat in dosed female
      rats; staining was observed earlier in high-dose female rats. Pathology Findings:
      Severe, time- and dose-related nephropathy was observed in male and female rats,
      occurring as early as 3 months after the beginning of chemical administration
      (females). In male rats dosed for as long as 2 years, secondary
      hyperparathyroidism developed, with parathyroid gland hyperplasia, mineralization
      of the kidney and glandular stomach, and fibrous osteodystrophy occurring in the
      high-dose group. The severity of these lesions was greater in males. The kidney
      was the only organ in which chemical related increased incidences of neoplasms
      may have occurred. One renal tubule adenoma occurred in a control male rat, one
      renal tubule adenoma and one transitional cell carcinoma occurred in high-dose
      female rats, and one transitional cell carcinoma occurred in a mid-dose female.
      One renal tubule carcinoma was observed in a high-dose male rat. 2-YEAR STUDY IN
      MICE: Groups of 70 male and 70 female mice were administered o-benzyl-p
      chlorophenol in corn oil by gavage at doses of 0, 120, 240, or 480 mg/kg body
      weight 5 days a week for 103 weeks. Ten male and 9 or 10 female mice were
      evaluated after 3 and 15 months for organ weights and histopathology; the
      remaining 50 male and 50 female mice were evaluated at the end of the study.
      Survival, Body Weights, and Clinical Findings: Survival of high-dose male and
      female mice was lower than that of the controls, which was associated in part
      with dose-related increases in the incidence and severity of nephropathy. The
      final mean body weights of all dosed males and mid- and high-dose females were
      lower than those of the controls. Chemical-related clinical findings included
      emaciation, abnormal posture, rough hair coat, and hypoactivity. Pathology
      Findings: Nephropathy occurred in most dosed males and females, and the incidence
      and severity increased with time and dose. Fibrous osteodystrophy of bone,
      mineralization of the glandular stomach, and squamous hyperplasia of the
      forestomach occurred in male and female mice. In the standard evaluation, the
      combined incidence of renal tubule adenoma and carcinoma was increased in 240
      mg/kg male mice. Six renal tubule adenomas and three renal tubule carcinomas
      occurred in dosed male mice. No renal neoplasms occurred in female mice. Due to
      the marginal increase in renal neoplasia, and the small size of renal neoplasms,
      an extended evaluation of the kidney was conducted. No significant alteration in
      the neoplasm incidences were observed in female mice. However, a dose-related
      increased trend of renal tubule adenoma was observed in male mice. Combination of
      the extended evaluation with the original evaluation resulted in an increased
      incidence of renal tubule adenomas in the 480 mg/kg males and an increased
      incidence of renal tubule adenomas or carcinomas in both the 240 and 480 mg/kg
      males. GENETIC TOXICOLOGY: o-Benzyl-p-chlorophenol did not induce gene mutations
      in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 and did not
      induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese
      hamster ovary cells. These tests were performed with and without exogenous
      metabolic activation (S9). Positive results were obtained, however, in gene
      mutation tests conducted with LS178Y mouse Lymphoma cells and TK6 human
      lymphoblast cells in the absence of S9. CONCLUSIONS: Under the conditions of
      these 2-year gavage studies, there was no evidence of carcinogenic activity of o
      benzyl-p-chlorophenol in male F344/N rats receiving 30, 60, or 120 mg/kg body
      weight. There was equivocal evidence of carcinogenic activity of o-benzyl-p
      chlorophenol in female F344/N rats based on the occurrence of two rare renal
      transitional cell carcinomas. There was some evidence of carcinogenic activity of
      o-benzyl-p-chlorophenol in male B6C3F1 mice based on increased incidences of
      renal tubule adenoma and renal tubule adenoma or carcinoma (combined). There was
      no evidence of carcinogenic activity of o-benzyl-p-chlorophenol in female B6C3F1,
      mice receiving 120, 240, or 480 mg/kg. o-Benzyl-p-chlorophenol was nephrotoxic
      for male and female F344/N rats and B6C3F1 mice. The severity of nephropathy was
      increased in male and female rats and the incidence and severity of nephropathy
      was increased in male and female mice. The incidence and severity of nephropathy
      increased with length of treatment. Other lesions considered to be associated
      with the nephropathy and the secondary hyperparathyroidism in male rats and in
      male and female mice included fibrous osteodystrophy and soft tissue
      mineralization. Increased incidences of squamous cell hyperplasia of the
      forestomach were observed in mice. Synonyms: 2-benzyl-4-chlorophenol, 4-chloro-2
      benzylphenol, 4-chloro-2-(phenylmethyl)phenol, 4-chloro-alpha-phenol o-cresol, p
      chloro-o-benzylphenol, 2-hydroxy-5-chlorodiphenylmethane Trade names: Bio-Clave,
      Chlorophene, Clorofene, Clorophene, Ketolin H, Nipacide BCPR, Preventol BPR,
      Santophen 1, Septiphene

PMID- 12616288
TI  - NTP Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin (CAS No. 119-84
      6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
AB  - 3,4-Dihydrocoumarin was nominated by the Food and Drug Administration and the
      National Cancer Institute for study because of its widespread use as a flavoring
      agent in beverages, gelatins, puddings, candy, and other food items; as a
      fragrance in perfumes, creams, and cosmetics; and because of interest in the
      structure-activity relationships of the coumarin derivatives. Toxicity and
      carcinogenicity studies were conducted by administering 3,4-dihydrocoumarin (99%
      pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1
      mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and
      peripheral blood cells of mice. 16-DAY STUDY IN RATS: Groups of five male and
      five female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of
      0, 190, 375, 750, 1,500, or 3,000 mg/kg body weight 5 days per week for a total
      of 12 doses in a 16-day period. All male and female rats given 3,000 mg/kg, and
      four male rats and five female rats given 1,500 mg/kg died. Body weight gains and
      final mean body weights of rats receiving 190, 375, or 750 mg/kg were similar to
      those of the controls. There were no clinical findings of organ-specific toxicity
      or evidence of impaired blood coagulation. 16-DAY STUDY IN MICE: Groups of five
      male and five female mice received 3,4-dihydrocoumarin in corn oil by gavage at
      doses of 0, 140, 280, 560, 1,125, or 2,250 mg/kg body weight 5 days per week for
      a total of 12 doses in a 16-day period. All mice given 2,250 mg/kg died. Body
      weight gains and final mean body weights of mice receiving 140, 280, 560, and
      1,125 mg/kg were similar to those of the controls. There were no clinical
      findings of organ-specific toxicity or evidence of impaired blood coagulation. 13
      WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 3,4
      dihydrocoumarin in corn oil by gavage at doses of 0, 75, 150, 300, 600, or 1,200
      mg/kg body weight 5 days per week for 13 weeks. Two male rats and five female
      rats given 1,200 mg/kg died. The body weight gain and final mean body weight of
      male rats that received 1,200 mg/kg were significantly lower than those of the
      controls, but the final mean body weights of other dosed groups of male rats and
      all dosed groups of female rats were similar to or slightly greater than those of
      the controls. Platelet counts were significantly lower in males and females
      receiving 600 and 1,200 mg/kg and in females receiving 300 mg/kg. Hemoglobin and
      hematocrit values and erythrocyte counts were significantly lower in males that
      received 300 mg/kg or more. The absolute and relative liver and kidney weights of
      males and females receiving 600 and 1,200 mg/kg were significantly greater than
      those of the controls. Hepatocellular hypertrophy was observed in rats given 300,
      600, and 1,200 mg/kg. The high dose selected for the 2-year study was 600 mg/kg,
      which was below the level at which mortality, lower final mean body weights, and
      treatment-related liver lesions were observed. 13-WEEK STUDY IN MICE: Groups of
      10 male and 10 female mice received 3,4-dihydrocoumarin in corn oil by gavage at
      doses of 0, 100, 200, 400, 800, or 1,600 mg/kg body weight 5 days per week for 13
      weeks. Eight male and five female mice receiving 1,600 mg/kg died. Deaths in
      other groups were attributed to dosing accidents. Final mean body weights of
      dosed male and female mice were similar to those of the controls, and there were
      no treatment-related changes in any hematologic parameters. The absolute and
      relative liver weights of males and females that received 1,600 mg/kg and the
      relative kidney weight of males that received 1,600 mg/kg were significantly
      greater than those of the controls. No treatment-related lesions were noted. The
      high dose selected for the 2-year study was 600 mg/kg, which was below the level
      at which mortality, lower final mean body weights, and treatment-related liver
      lesions were observed. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats
      received 3,4-dihydrocoumarin in corn oil by gavage at age at doses of 0, 150,
      300, or 600 mg/kg body weight. After 15 months, up to 10 animals from each group
      were evaluated. Survival, Body Weights, and Clinical Findings: Survival rates of
      dosed male rats were lower than that of the controls (O mg/kg, 28/51; 150 mg/kg,
      12/50; 300 mg/kg, 8/50; 600 mg/kg, 2/50) but survival rates of dosed female rats
      were similar to that of the controls (31/50, 21/51, 26/50, 23/51). The decreased
      survival in dosed male rats was attributed to a chemical-related increase in the
      severity of nephropathy. The final mean body weight of male rats receiving 600
      mg/kg was lower than that of the controls, but the final mean body weights of
      other dosed groups of male rats and all dosed groups of female rats were similar
      to those of the controls. No clinical findings related to chemical administration
      were observed. Hematology and Clinical Chemistry: At the 15-month interim
      evaluation, the hemoglobin concentrations, mean erythrocyte volumes, or mean
      erythrocyte hemoglobin concentrations in the 300 and 600 mg/kg female rats were
      slightly, but significantly, lower than those of the controls. In males, only the
      hemoglobin concentration in the 600 mg/kg group was significantly lower. Serum
      levels of alkaline phosphatase, alanine aminotransferase, sorbitol dehydrogenase,
      or g-glutamyltransferase in the 300 and 600 mg/kg male rats were significantly
      higher than those in the controls. In females, alkaline phosphatase and g
      glutamyltransferase levels were significantly higher in the 600 mg/kg group.
      Pathology Findings: The principal lesions associated with the administration of
      3,4-dihydrocoumarin to rats occurred in the kidney and forestomach. There was a
      chemical related increase in the severity of nephropathy in all dosed male rats
      and in 300 and 600 mg/kg female rats. There was a corresponding increased
      incidence of parathyroid gland hyperplasia, probably as a result of compromised
      renal function. In the standard evaluation of single kidney sections, renal
      tubule adenomas were observed in one 150 and two 600 mg/kg males and one each in
      the control, 150, and 300 mg/kg females. Transitional cell carcinomas were also
      observed in two 600 mg/kg male rats. However, an extended evaluation of step
      sections identified significantly higher incidences of focal hyperplasia and
      adenoma in the 600 mg/kg males than in controls (hyperplasia: 0/50, 5/48, 6/47,
      8/50; adenoma: 1/50,1/48, 3/47, 6/50). The incidence of forestomach ulcers in all
      groups of dosed male rats was significantly greater than that of the controls
      (4/47, 14/48, 20/50, 16/46). STOP-EXPOSURE EVALUATION: A group of 40 male rats
      received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 9 months, when
      20 of the animals were necropsied and evaluated. The remainder of the male rats
      received only the corn oil vehicle until they died or until the end of the study.
      Similarly, a group of 30 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn
      oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated.
      The remaining 20 rats received only corn oil until the end of the study. A group
      of 20 vehicle control male rats was necropsied at 9 months, and another 10
      vehicle control male rats were necropsied at 15 months. The severity of
      nephropathy in male rats of the stop-exposure groups was significantly greater
      than that of males examined at the 9- and 15-month interim evaluations. This was
      expected because nephropathy is a progressive degenerative disease that naturally
      increases in severity with age. 2-YEAR STUDY IN MICE: Groups of 70 male and 70
      female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0,
      200, 400, or 800 mg/kg body weight. After 15 months, five to 10 animals from each
      group were evaluated. Additional groups of 8 to 10 animals were evaluated for
      clinical pathology after 15 months. Survival, Body Weights, and Clinical Findings
      Survival rates of dosed male and female mice were similar to those of the
      controls (males: O mg/kg, 42/50; 200 mg/kg, 39/51; 400 mg/kg, 34/51; 800 mg/kg,
      38/50; females: 36/51, 39/50, 41/50, 28/52). Final mean body weights of dosed
      male and female mice were similar to those of the controls. No clinical findings
      were noted that were related to chemical administration. Hematology and Clinical
      Chemistry: There were no differences in hematology or clinical chemistry
      parameters that were considered to be chemical related. Pathology Findings: The
      principal neoplasms associated with the administration of 3,4-dihydrocoumarin to
      mice occurred in the liver. There were significantly increased incidences of
      hepatocellular adenomas in all groups of dosed female mice. Further, the
      incidences of multiple hepatocellular adenomas in dosed female mice were greater
      than that of the controls (control, 0/51; 200 mg/kg, 6/50; 400 mg/kg, 9/50; 800
      mg/kg, 9/52). However, there was no corresponding increased incidence of
      hepatocellular carcinoma in dosed female mice (3/51, 2/50, 4/50, 6/52), and the
      incidences of hepatocellular adenoma or carcinoma were similar between dosed and
      control male groups (adenoma: 29/50, 23/51, 36/51, 31/50; carcinoma: 11/50,
      11/51, 11/51, 6/50). The incidence of alveolar/bronchiolar adenoma in the 200 and
      400 mg/kg male mice was marginally greater than that of the controls
      (8/50,15/50,15/51,10/50). However, these neoplasms were not considered chemical
      related because the increased incidence was slight and there was no corresponding
      increased incidence in the 800 mg/kg group. The incidence of alveolar/bronchiolar
      neoplasms in female mice was similar between the dosed and control groups
      (adenoma: 2/51, 5/50, 1/48, 3/51; carcinoma: 0/51, 1/50, 0/48, 0/51). In the
      standard evaluation of single sections of kidney, focal hyperplasia and adenoma
      or carcinoma of the renal tubule were identified in several dosed male mice, but
      not in controls [adenoma or carcinoma (combined): 0/50,1/51, 2/51,1/49;
      hyperplasia: 2/50, 2/51, 5/51, 2/49]. In an extended evaluation of step sections,
      a few additional males with focal hyperplasia or renal tubule adenomas were
      identified in the dosed groups. However, the incidences of these lesions in dosed
      groups of male mice were not significantly greater than those of the controls,
      and did not increase with dose (hyperplasia: 0/50,1/51, 3/51, 1/49; renal tubule
      adenoma: 0/50, 0/51, 2/51, 1/49). Therefore, the low number of renal tubule
      neoplasms in male mice was not considered to be chemical related. GENETIC
      TOXICOLOGY: 3,4-Dihydrocoumarin did not induce gene mutations in Salmonella
      typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous
      metabolic activation (S9). It induced sister chromatid exchanges but not
      chromosomal aberrations in cultured Chinese hamster ovary cells, with and without
      S9. No induction of micronuclei was noted in peripheral blood erythrocyte samples
      obtained from male and female B6C3F1 mice at the end of the 13-week toxicology
      study. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there
      was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N
      rats based on increased incidences of renal tubule adenomas and focal
      hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also
      have been chemical related. There was no evidence of carcinogenic activity of 3,4
      dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was
      no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3F1 mice
      receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic
      activity in female B6C3F1 mice based on increased incidences of hepatocellular
      adenoma and hepatocellular adenoma or carcinoma (combined). 3,4-Dihydrocoumarin
      caused ulcers, hyperplasia, and inflammation of the forestomach, parathyroid
      gland hyperplasia, and increased severity of nephropathy in male rats. Synonyms:
      1,2-benzodihydropyrone, 2H-1-benzopyran-2-one, 2-chromanone, 3,4-dihydro-2H-1
      benzopyran-2-one, dihydrocoumarin, hydrocoumarin, o-hydroycinnamic acid, delta
      lactone-hydrocinnamic acid, melilotin, melilotine, melilotol, 2-oxochroman

PMID- 12616289
TI  - NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N
      Rats and B6C3F1 Mice (Gavage Studies).
AB  - Coumarin is the basic structure of numerous naturally occurring compounds with
      important and diverse physiological activities. More than a thousand coumarin
      derivatives have been described, varying from simple coumarins containing alkyl
      and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl,
      or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were
      nominated by the Food and Drug Administration and the National Cancer Institute
      for study because of the widespread use of coumarin in perfumes, cosmetics, and
      other products as a fragrance, continued interest in coumarin compounds as flavor
      enhancing agents for foods, and the interest in structure-activity relationships
      of this important group of compounds. Coumarin is believed to be metabolized to a
      3,4-epoxide intermediate, which may be responsible for its toxic effects, while
      3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to
      form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted
      by administering coumarin (97% pure) in corn oil by gavage to groups of male and
      female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic
      toxicology studies were conducted in Salmonella typhimurium, cultured Chinese
      hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN
      RATS: Groups of five male and five female rats received coumarin in corn oil by
      gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a
      week for a total of 12 doses in a 16-day period. All female rats and four male
      rats receiving 400 mg/kg died. The mean body weight gains and final mean body
      weights of surviving dosed male and female rats were similar to those of the
      controls. There were no clinical signs of organ-specific toxicity, and there was
      no evidence of impaired blood coagulation from measurements of capillary clotting
      time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN
      MICE: Groups of five male and five female mice received coumarin in corn oil by
      gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a
      week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg,
      two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died.
      The mean body weight gains and final mean body weights of surviving dosed male
      and female mice were similar to those of the controls. Clinical findings of
      inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia
      were observed in some mice from the 300 and 600 mg/kg groups within the first
      several hours after dosing. Capillary clotting time and platelet counts of dosed
      mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male
      and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38,
      75,150, or 300 mg per kg body weight. Three male and three female rats receiving
      300 mg/kg died. The mean body weight gains and final mean body weights of male
      rats that received 150 and 300 mg/kg were significantly lower than those of the
      controls. There were no clinical signs related to specific organ toxicity. Male
      and female rats receiving coumarin exhibited dose-related decreases in mean
      erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in
      erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic
      enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine
      carbamoyltransferase, and/or sorbitol dehydrogenase in males and females
      receiving 300 mg/kg were higher than those of controls. The absolute and relative
      liver weights of male and female rats that received 150 and 300 mg/kg were
      significantly greater than those of the controls. Centrilobular hepatocellular
      degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia
      were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose
      selected for the 2-year study was 100 mg/kg, which was just below the level at
      which mortality, lower final mean body weiody weights, and treatment-related
      liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups
      of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of
      0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300
      mg/kg died. The mean body weight gain and final mean body weight of surviving
      male mice that received 300 mg/kg were significantly lower than those of the
      controls. No clinical signs of toxicity were observed. Male and female mice
      receiving coumarin exhibited dose-related decreases in mean erythrocyte volume
      and mean erythrocyte hemoglobin. The absolute and relative liver weights of males
      and females that received 150 and 300 mg/kg were significantly greater than those
      of the controls. Centrilobular hepatocellular hypertrophy was observed in male
      and female mice receiving 300 mg/kg. The high dose selected for the 2-year study
      was 200 mg/kg, which was just below the level at which mortality and liver
      lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60
      male and 60 female rats were administered coumarin in corn oil by gavage at doses
      of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each
      group were evaluated. Survival, Body Weights, and Clinical Findings: None of the
      male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived
      until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg,
      2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the
      controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats
      was primarily attributed to chemical-related exacerbation of spontaneously
      occurring renal disease. Final mean body weights of female rats that received 100
      mg/kg and all dosed groups of male rats were lower than those of the controls.
      There were no clinical signs of toxicity in rats, other than nonspecific signs
      relating to debilitation as a result of renal or other spontaneous disease.
      Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values
      for one or more hematologic parameters including mean erythrocyte volume, mean
      erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in
      100 mg/kg rats were significantly lower than those of controls. Activated partial
      thromboplastin times were also significantly lower in 50 and 100 mg/kg males,
      while platelet counts were significantly higher. Activities of alanine
      aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100
      mg/kg male and 100 mg/kg female rats were significantly higher than those of the
      controls at the 15-month interim evaluation. Pathology Findings: The principal
      lesions associated with the administration of coumarin to rats for up to 2 years
      occurred in the liver, kidney, and forestomach. While the hepatic lesions were
      seen in all groups of males, they occurred only in the 50 and 100 mg/kg females.
      The lesions consisted of a spectrum of changes including hepatocellular necrosis,
      fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia.
      The incidences of hepatocellular neoplasms were not increased in dosed rats.
      There was a chemical-related increase in the average severity of nephropathy in
      all groups of dosed male and female rats. There were corresponding increased
      incidences of parathyroid gland hyperplasia in all groups of dosed males,
      probably as a result of compromised renal function. In the standard evaluation of
      single kidney sections, a low incidence of renal adenomas was seen in all groups
      of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50;
      50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation
      of step sections identified additional individuals with renal tubule focal
      hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49)
      and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in
      the dosed groups. The incidences of forestomach ulcers in all groups of dosed
      male rats and in 100 mg/kg female rats were significantly greater than those of
      the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48).
      STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in
      corn oil by gavage for 9 months, when 20 of the animals were necropsied and
      evaluated. The remainder of the male rats received only the corn oil vehicle
      during the 15-month recovery period. Similarly, a group of 30 male rats received
      100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were
      necropsied and evaluated. The remaining 20 rats received only corn oil during the
      9-month recovery period. A group of 20 vehicle control male rats were necropsied
      at 9 months, and another 10 vehicle control male rats were necropsied at 15
      months. While chemical-related hepatic lesions were seen at both the 9- and 15
      month interim evaluations, the incidences and severities of these lesions
      following the recovery period were generally similar to controls. Thus, the
      hepatic lesions produced by 9 or 15 months of exposure were reversible. In
      contrast to the liver lesions, the severity of nephropathy in male rats following
      the recovery period was significantly greater than that of males examined at the
      9- and 15-month interim evaluations. This is not unexpected, since nephropathy is
      a progressive degenerative disease that naturally increases in severity with age.
      The incidence of renal tubule hyperplasia in the 15-month stop-exposure group
      (dosed for 15 months followed by the recovery period) and the incidence of renal
      tubule adenoma in the 9-month stop-exposure group were significantly greater than
      those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female
      mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or
      200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from
      each group were evaluated. Survival, Body Weights, and Clinical Findings:
      Survival of dosed male and female mice was similar to that of the controls
      (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg,
      37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg
      male and female mice were lower than those of controls throughout much of the
      study. There were no clinical findings related to chemical administration.
      Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte
      hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200
      mg/kg females were significantly lower than those of the controls. Blood platelet
      counts of 200 mg/kg males and females were significantly higher than those of
      controls. There were no biologically significant differences in enzyme activities
      between dosed and control mice. Pathology Findings: The principal toxic lesions
      associated with the administration of coumarin to mice occurred in the liver. The
      incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg
      females were significantly greater than those of controls. The incidences of
      syncytial alteration in all male dose groups and in 200 mg/kg females were also
      significantly greater than controls. The incidences of eosinophilic foci, a
      putative preneoplastic lesion, and of hepatocellular adenoma were significantly
      greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with
      low incidences in the dosed females, but none occurred in the controls. The
      overall incidence of hepatocellular neoplasms (benign and malignant combined) in
      the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51;
      200 mg/kg, 13/50) exceeds the range in historical controls (range 2&percnt;
      34&percnt;; 129/898, 14.4&percnt;) from recent NTP studies. The reason for a lack
      of liver response in 200 mg/kg female mice is not known, but may be due in part
      to the decrease in body weight. While the incidences of eosinophilic foci were
      marginally greater in dosed male mice, the incidences of hepatocellular neoplasms
      were similar among the dosed and control groups. The incidences of
      alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and
      female mice than in the controls. Further, the incidence of alveolar/bronchiolar
      carcinoma in 200 mg/kg females was also significantly greater than in controls.
      The overall incidence of pulmonary neoplasms (benign and malignant combined) in
      the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49,
      27/51) exceeds the range in historical controls (males: range 6&percnt;
      28&percnt;; 166/900, 18.4&percnt;; females: range 0&percnt;-14&percnt;; 58/899,
      6.5&percnt;) from recent NTP studies. The incidence of squamous cell papilloma of
      the forestomach in 50 mg/kg males was greater than that of the controls (2/50,
      8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male
      mice from recent NTP studies (range 0&percnt;-14&percnt;; 27/902, 3.0&percnt;).
      The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female
      mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence
      did not exceed the NTP historical range (27/901, 3&percnt;; range, 0&percnt;
      10&percnt;). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella
      typhimurium strain TA100 in the presence, but not in the absence, of exogenous
      metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or
      TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced
      sister chromatid exchanges in the absence of S9, and chromosomal aberrations in
      the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations
      in germ cells of male Drosophila melanogaster treated either as adults by feeding
      or injection, or as larvae by feeding. No increase in the frequency of
      micronucleated erythrocytes was observed in peripheral blood of male and female
      B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the
      conditions of these 2-year gavage studies there was some evidence of carcinogenic
      activity of coumarin in male F344/N rats based on increased incidences of renal
      tubule adenomas. There was equivocal evidence of carcinogenic activity of
      coumarin in female F344/N rats based on a marginally increased incidence of renal
      tubule adenomas. There was some evidence of carcinogenic activity of coumarin in
      male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar
      adenomas. There was clear evidence of carcinogenic activity of coumarin in female
      B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas,
      alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally
      increased incidences of squamous cell papillomas of the forestomach in male and
      female mice receiving 50 mg/kg may have been related to coumarin administration.
      The administration of coumarin to rats was also associated with an increased
      severity of nephropathy in the kidney and of bile duct hyperplasia in the liver,
      increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and
      cytologic alteration of the liver. Administration of coumarin to mice was also
      associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic
      focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H
      benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic
      acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone,
      kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka
      bean camphor

PMID- 12616290
TI  - NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non
      Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
AB  - Talc ore may contain several other minerals including calcite, dolomite,
      magnesite, tremolite, anthophyllite, antigorite, quartz, pyrophyllite, micas, or
      chlorites. Talc products are sold in a multitude of grades which have physical or
      functional characteristics especially suited for particular applications, so
      occupational and consumer exposures to talc are complex. Epidemiology studies
      have suggested an association between non-fibrous talc and lung cancer risk. Talc
      was nominated by the National Institute of Occupational Safety and Health (NIOSH)
      for study by the NTP because of widespread human exposure and because of the lack
      of adequate information on its chronic toxicity and potential carcinogenicity.
      Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade),
      a finely powdered hydrous magnesium silicate, were conducted by exposing groups
      of F344/N rats to aerosols for 6 hours per day, 5 days per week for up to 113
      weeks (males) or 122 weeks (females). Groups of B6C3F1 mice were exposed
      similarly for up to 104 weeks. LIFETIME STUDY IN RATS: Groups of 49 or 50 male
      and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/m(3) talc until
      mortality in any exposure group reached 80% (113 weeks for males and 122 weeks
      for females). These exposures were selected based on 4-week inhalation studies of
      the terminal lung talc burden in F344/N rats; concentrations greater than 18
      mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung
      function. These exposure concentrations provided a dose equivalent of 0, 2.8, or
      8.4 mg/kg per day for male rats and 0, 3.2, or 9.6 mg/kg per day for female rats.
      In a special study, additional groups of 22 male and 22 female rats were
      similarly exposed and examined for interim pathology evaluations or pulmonary
      function tests after 6, 11, 18, and 24 months and lung biochemistry and cytology
      studies after 24 months. The talc aerosols had a median mass aerodynamic diameter
      of 2.7 mm in the 6 mg/m(3) chamber and a median diameter of 3.2 mm in the 18
      mg/m(3) chamber, with geometric standard deviations of 1.9 mm. However, there was
      a 7-week period beginning at study week 11 during which the chamber concentration
      for the 18 mg/m(3) rats varied from approximately 30 to 40 mg/m(3) because of
      difficulties with the aerosol concentration monitoring system. Further, there was
      a 12-week period beginning at approximately week 70 during which there were
      difficulties in generating the talc aerosol, and the chamber concentrations for
      rats and mice were substantially lower than the target concentrations. Survival,
      Body Weights, and Clinical Findings: The survival of male and female rats exposed
      to talc was similar to that of the controls. Mean body weights of rats exposed to
      18 mg/m(3) were slightly lower than those of controls after week 65. No clinical
      findings were attributed to talc exposure. Pathology Findings: Absolute and
      relative lung weights of male rats exposed to 18 mg/m(3) were significantly
      greater than those of controls at the 6-, 11-, and 18-month interim evaluations
      and at the end of the lifetime study, while those of female rats exposed to 18
      mg/m(3) were significantly greater at the 11-, 18-, and 24-month interim
      evaluations and at the end of the lifetime study. Inhalation exposure of rats to
      talc produced a spectrum of inflammatory, reparative, and proliferative processes
      in the lungs. Granulomatous inflammation occurred in nearly all exposed rats and
      the severity increased with exposure duration and concentration. Hyperplasia of
      the alveolar epithelium and interstitial fibrosis occurred in or near foci of
      inflammation in many exposed rats, while squamous metaplasia of the alveolar
      epithelium and squamous cysts were also occasionally seen. Accumulations of
      macrophages (histiocytes), most containing talc particles, were found in the
      peribronchial lymphoid tissue of the lung and in the bronchial and mediastinal
      Iymph nodes. In female rats, the incidences of alveolar/bronchiolar adenoma,
      carcinoma, and adenoma or carcinoma (combined) in the 18 mg/m(8 mg/m(3) group
      were significantly greater than those of controls. The incidences of pulmonary
      neoplasms in exposed male rats were similar to those in controls. Minor
      alterations attributed to talc exposure were also observed in the upper
      respiratory tract. Hyperplasia of the respiratory epithelium of the nasal mucosa
      in males and accumulation of cytoplasmic, eosinophilic droplets in the nasal
      mucosal epithelium in male and female rats occurred with a concentration-related
      increased incidence in the exposed groups. Adrenal medulla pheochromocytomas
      [benign, malignant, or complex (combined)] occurred with a significant positive
      trend in male and female rats, and the incidences in the 18 mg/m(3) groups were
      significantly greater than those of controls. Although adrenal medulla
      hyperplasia occurred with similar frequency among exposed and control females,
      the incidences of hyperplasia in exposed males were significantly lower than in
      controls. Lung Talc Burden: Lung talc burdens of male and female rats exposed to
      6 mg/m(3) were similar and increased progressively from 6 to 24 months. Lung talc
      burdens of females exposed to 18 mg/m(3) also increased progressively from 6 to
      24 months, while those of males exposed to 18 mg/m(3) remained about the same
      after 18 months. Lung burdens were generally proportional to exposure
      concentration at each interim evaluation. Pulmonary Function, Bronchoalveolar
      Lavage, and Lung Biochemistry: In exposed male and female rats there was a
      concentration-related impairment of respiratory function which increased in
      severity with increasing exposure duration. The impairment was characterized by
      reductions in lung volume (total lung capacity, vital capacity, and forced vital
      capacity), lung compliance, gas exchange efficiency (carbon monoxide diffusing
      capacity), and nonuniform intrapulmonary gas distribution. After 24 months, males
      exposed to 6 mg/m(3) talc had a significant increase in beta-glucuronidase and
      polymorphonuclear leukocytes; males exposed 18 mg/m(3) had significant increases
      in b -glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total
      protein in bronchoalveolar lavage fluid. All exposed females had significantly
      increased a-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total
      protein, and polymorphonuclear leukocytes; 18 mg/m(3) females also had
      significantly increased glutathione reductase. Viability and phagocytic activity
      of macrophages recovered from lavage fluid were not affected by talc exposure.
      Total lung collagen was significantly increased in rats at both exposure
      concentrations after 24 months, while collagenous peptides in lavage fluid and
      the percentages of newly synthesized protein from females, but not males, were
      also significantly increased at the 6 or 18 mg/m(3) levels. In addition, lung
      proteinase activity, primarily cathepsin D-like activity, was significantly
      greater in exposed males and females. Rats exposed to talc also had significant
      increases in collagenous peptides and acid proteinase in lung homogenates. 2-YEAR
      STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to
      aerosols containing 0, 6, or 18 mg/m(3) talc for up to 104 weeks. These exposures
      were selected based on 4-week inhalation studies of the terminal lung talc burden
      in B6C3F1 mice; concentrations greater than 18 mg/m(3) were expected to overwhelm
      lung clearance mechanisms and impair lung function. These exposure concentrations
      provide a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3,
      or 3.9 mg/kg per day for female mice. In a special study, additional groups of 39
      or 40 male and 39 or 40 female mice similarly exposed were examined for interim
      pathology evaluations, lung biochemistry, and cytology studies after 6, 12, and
      18 months of exposure. The talc aerosols had a median mass aerodynamic diameter
      of 3.3 mm with a geometric standard deviation of 1.9 mm in the 6 mg/m(3) chamber,
      and a median diameter of 3.6 mm with a geometric standard deviation of 2.0 mm in
      the 18 mg/m(3) chamber. Further, there was a 12-week period beginning at
      approximately week 70 during which there were difficulties in generating the talc
      aerosol, and the chamber concentrations for rats and mice were substantially
      lower than the target concentrations. Survival, Body Weights, and Clinical
      Findings: Survival and final mean body weights of male and female mice exposed to
      talc were similar to those of the controls. There were no clinical findings
      attributed to talc exposure. Pathology Findings: Inhalation exposure of mice to
      talc was associated with chronic active inflammation and the accumulation of
      macrophages in the lung. In contrast to rats, hyperplasia of the alveolar
      epithelium, squamous metaplasia, or interstitial fibrosis were not associated
      with the inflammatory response in mice, and the incidences of pulmonary neoplasms
      in exposed and control groups of mice were similar. Accumulations of macrophages
      (histiocytes) containing talc particles were also present in the bronchial Iymph
      node. In the upper respiratory tract, cytoplasmic alteration, consisting of the
      accumulation of cytoplasmic eosinophilic droplets in the nasal mucosal
      epithelium, occurred with a concentration-related increased incidence in exposed
      male and female mice. Lung Talc Burden: Lung talc burdens of mice exposed to 6
      mg/m(3) were similar between males and females and increased progressively from 6
      to 24 months, except for males at 18 months. The lung talc burdens of mice
      exposed to 18 mg/m(3) were also similar between the sexes at each interim
      evaluation. Although the talc burdens of males and females increased
      substantially from 6 to 24 months, the values at 12 and 18 months were similar.
      Generally, lung burdens of mice exposed to 18 mg/m(3) were disproportionately
      greater than those of mice exposed to 6 mg/m(3), suggesting that clearance of
      talc from the lung was impaired, or impaired to a greater extent, in mice exposed
      to 18 mg/m(3) than in mice exposed to 6 mg/m(3). Bronchoalveolar Lavage and Lung
      Biochemistry: Increases in total protein, beta-glucuronidase, lactate
      dehydrogenase, glutathione reductase, total nucleated cells, and
      polymorphonuclear leukocytes in bronchoalveolar lavage fluid were observed
      primarily in mice exposed to 18 mg/m(3), although some parameters were also
      increased in mice exposed to 6 mg/m(3). The amount of collagenous peptides in
      lavage fluid and total lung collagen were increased in male and female mice
      exposed to 18 mg/m(3). Acid proteinase activity, principally cathepsin D-like
      activity, of lung homogenate supernatant fluid was also significantly increased
      in mice at the 18 mg/m(3) exposure concentration. CONCLUSIONS: Under the
      conditions of these inhalation studies, there was some evidence of carcinogenic
      activity of talc in male F344/N rats based on an increased incidence of benign or
      malignant pheochromocytomas of the adrenal gland. There was clear evidence of
      carcinogenic activity of talc in female F344/N rats based on increased incidences
      of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or
      malignant pheochromocytomas of the adrenal gland. There was no evidence of
      carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18
      mg/m(3). The principal toxic lesions associated with inhalation exposure to the
      same concentrations of talc in rats included chronic granulomatous inflammation,
      alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and
      interstitial fibrosis of the lung. These lesions were accompanied by impaired
      pulmonary function characterized primarily by reduced lung volumes, reduced
      dynamic and/or quasistatic lung compliance, reduced gas exchange efficiency, and
      nonuniform intrapulmonary gas distribution. In mice, inhalation exposure to talc
      produced chronic inflammation of the lung with the accumulation of alveolar
      macrophages. Synonyms: talcum; agalite; emtal 596; non-asbestiform talc; non
      fibrous talc; steatite; hydrous magnesium silicate

PMID- 12616291
TI  - NTP Toxicology and Carcinogenesis Studies of Triamterene (CAS No. 396-01-0) in
      F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - Triamterene is a potassium-sparing diuretic used in the treatment of edema
      associated with congestive heart failure, cirrhosis of the liver, and other
      diseases in which edema may occur. Toxicity and carcinogenicity studies were
      conducted by administering triamterene (greater than 99% pure) in feed to groups
      of male and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, or 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese
      hamster ovary cells. 15-day Studies: Groups of five male and five female rats
      were fed diets containing 0, 1,000, 3,000, 10,000, 30,000, or 60,000 ppm
      triamterene. The diets containing 10,000 ppm or more were unpalatable, and feed
      consumption by the 3,000 ppm groups was reduced. Rats exposed to 1,000 or 3,000
      ppm triamterene received approximate doses of 80 or 60 mg/kg body weight per day
      (males) or 70 or 50 mg/kg per day (females). One male rat and two female rats
      receiving 3,000 ppm died during the second week of the study. The final mean body
      weights of 3,000 ppm male and female rats were significantly lower than those of
      controls. Rats in the 3,000 ppm groups had renal tubule regeneration and
      cytoplasmic vacuolization of the zona glomerulosa of the adrenal gland. Groups of
      five male and five female mice were fed diets containing 0, 300, 1,000, 3,000,
      10,000, or 30,000 ppm triamterene, but the diets containing 10,000 or 30,000 ppm
      were unpalatable. All mice receiving 3,000 ppm died by day 6. Mice exposed to 300
      or 1,000 ppm triamterene received approximate doses of 40 or 155 mg/kg body
      weight per day (males) or 45 or 170 mg/kg body weight per day (females). The
      final mean body weights of mice in the 300 and 1,000 ppm groups were similar to
      those of the controls. Renal tubule degeneration and necrosis were observed in
      the kidney of 3,000 ppm mice. 13-Week Studies: Groups of 10 male and 10 female
      rats were fed diets containing 0, 150, 300, 600, 1,200, or 2,400 ppm triamterene.
      All rats receiving 2,400 ppm died before the end of the study; all other rats
      survived to the end of the study. Rats exposed to 150, 300, 600, or 1,200 ppm
      triamterene received approximate doses of 10, 20, 40, or 70 mg/kg body weight per
      day (males) or 10, 20, 40, or 80 mg/kg per day (females). Body weight gains and
      final mean body weights of rats in the 1,200 ppm groups were significantly lower
      than those of controls. There were no biologically significant differences in
      hematologic, clinical chemistry, or urinalysis parameters among exposed and
      control rats. Calculi were observed in the renal pelvis of four male rats in the
      1,200 ppm group. Chemical-related lesions were observed in the kidney and adrenal
      gland of rats in the 1,200 and 2,400 ppm groups. These consisted of degeneration
      and regeneration of the renal tubule epithelium and cytoplasmic vacuolization of
      cells of the zona glomerulosa of the adrenal cortex. Depletion of hematopoietic
      cells from the bone marrow and of lymphocytes from the spleen and thymus of rats
      in the 2,400 ppm groups may have been related to debilitation and reduced feed
      consumption rather than chemical exposure. Groups of 10 male and 10 female mice
      were fed diets containing 0, 100, 200, 400, 800, or 1,600 ppm triamterene. All
      mice receiving 1,600 ppm, one 800 ppm female, one 200 ppm male, and four 100 ppm
      males died before the end of the study. Mice exposed to 100, 200, 400, or 800 ppm
      triamterene received approximate doses of 15, 25, 50, or 90 mg/kg body weight per
      day (males) or 15, 25, 50, or 115 mg/kg per day (females). The body weight gain
      and final mean body weight of male mice receiving 800 ppm were significantly
      lower than those of the controls. The total leukocyte and lymphocyte counts of
      males receiving 800 ppm and of females receiving 100, 400, or 800 ppm were
      significantly lower than those of controls. No other differences in hematologic,
      clinical chemistry, or urinalysis parameters were considered to be biologically
      significant. Necrosis of Lymphocytes was observed in the lymph node, spleen, and
      thymus of mice in the 800 and 1,600 ppm groups groups. 2-Year Studies: The doses
      selected for the 2-year studies were based on lower body weights, mortality, and
      chemical-related lesions observed in exposed animals during the 13-week studies.
      Groups of 70 male and 70 female rats were fed diets containing 0, 150, 300, or
      600 ppm triamterene and groups of 70 male and 70 female mice were fed diets
      containing 0, 100, 200, or 400 ppm. Ten animals from each group were included for
      interim evaluations at 3 and 15 months. Because of a dosing error involving the
      high-dose mice at week 40, a second study was conducted with groups of 60 male
      and 60 female mice fed diets containing 0 or 400 ppm triamterene. In the 2-year
      studies, rats exposed to 150, 300, or 600 ppm triamterene received approximately
      5,10, or 25 mg/kg body weight per day (males) and 5, 15, or 30 mg/kg (females)
      and mice exposed to 100, 200, or 400 ppm received approximately 10, 25, or 45
      mg/kg (males) and 15, 30, or 60 mg/kg (females) per day. 3-Month and 15-Month
      Interim Evaluations in the 2-Year Studies: There were no biologically significant
      differences in hematologic, clinical chemistry, or urinalysis parameters between
      exposed and control rats or mice at the 3- or 15-month interim evaluations. At
      necropsy, the mean body weights of exposed rats and mice were similar to those of
      the controls. There were no chemical-related lesions in exposed rats at 3 months
      or in exposed mice at 3 or 15 months. At the 15-month evaluation, basophilic,
      clear cell, and mixed cell foci of the liver occurred in exposed male rats. No
      chemical-related lesions were observed in female rats at 15 months. Survival,
      Body Weights, Clinical Findings, and Feed Consumption in the 2-Year Studies:
      Survival of exposed rats was similar to that of controls (males: 0 ppm, 25/47;
      150 ppm, 25/50; 300 ppm, 19/50; 600 ppm, 27/50; females: 29/50, 34/50, 34/50,
      29/50). The mean body weights of 600 ppm rats were consistently lower than, but
      within 5&percnt; of, those of controls after week 49. Feed consumption by male
      and female rats was similar among exposed and control groups throughout the
      studies. There were no clinical findings of toxicity. Survival of 400 ppm male
      mice in the first study was lower than that of controls because of the dosing
      accident at week 40. Survival of 100 and 200 ppm male mice and of all exposed
      groups of female mice in the first study and of exposed males and females in the
      second study was similar to controls (males: first study, 0 ppm, 47/50; 100 ppm,
      45/50; 200 ppm, 46/50; 400 ppm, 46/60; second study, 0 ppm, 43/50; 400 ppm,
      39/50; females: first study, 38/50; 43/50; 43/50; 43/60; second study, 40/50;
      38/51). Mean body weights of exposed mice were similar to those of controls
      throughout the first study with one exception; in the week following the dosing
      error, the mean body weight of 400 ppm males was 16&percnt; lower than that of
      controls. In the second study, mean body weights of 400 ppm mice were slightly
      lower than those of controls during the final 8 weeks. Feed consumption by
      exposed mice was similar to that by controls throughout the studies. There were
      no clinical findings of toxicity in exposed mice. Neoplasms and Nonneoplastic
      Lesions in the 2-Year Studies: The incidences of mixed cell foci and focal
      hyperplasia of the liver were significantly increased in 300 and 600 ppm male
      rats, and the incidences of clear cell and mixed cell foci were significantly
      increased in 300 and 600 ppm female rats. Hepatocellular adenomas occurred in all
      groups of exposed male rats, but none occurred in controls; the incidence of
      hepatocellular adenoma in the 150 ppm males was significantly higher than that of
      controls (O ppm, 0/50; 150 ppm, 6/50; 300 ppm, 4/50; 600 ppm, 3/49).
      Hepatocellular adenomas were observed in two 600 ppm female rats, but not in the
      lower exposure groups or in controls. No hepatocellular carcinomas were seen in
      exposed or control rats. The incidences of nephropathy in exposed rats were
      similar to those of controls, but the average severity of the lesion was
      marginally increased in male rats receiving 300 ppm and in female rats receiving
      600 ppm (males: 47/50, 2.4; 49/50, 2.7; 50/50, 3.0; 49/50, 2.8; females: 38/50,
      1.1; 45/50, 1.2; 45/50, 1.3; 45/50, 1.4). Although in the first study the
      incidences of hepatocellular adenoma in exposed male mice were similar to that of
      controls, the incidences of multiple adenomas were greater in the exposed groups,
      and the incidence of hepatocellular carcinoma in the 400 ppm group was marginally
      greater (hepatocellular adenoma: 0 ppm, 17/50; 100 ppm, 22/50; 200 ppm, 19/50;
      400 ppm, 20/60; hepatocellular carcinoma: 5/50; 7/50; 3/50; 13/60). In the second
      study, the incidence of hepatocellular adenoma in the 400 ppm males was
      significantly higher than that of controls (hepatocellular adenoma: 0 ppm, 21/50;
      400 ppm, 36/50; hepatocellular carcinoma: 9/50; 11/50). The incidences of
      hepatocellular adenoma in exposed female mice in the first and second studies
      were significantly greater than those of controls (hepatocellular adenoma, first
      study: 10/50; 22/50; 23/50; 36/60; second study: 7/50; 28/51). The incidences of
      multiple adenoma were also increased in the exposed groups. Although the
      incidences of hepatocellular carcinoma were similar among exposed and control
      female mice in the first study, the incidence of hepatocellular carcinoma in the
      400 ppm females in the second study was marginally greater than that of controls
      (hepatocellular carcinoma, first study: 4/50; 4/50; 3/50; 8/60; second study:
      5/50; 11/50). In both studies, hepatocellular foci (basophilic, eosinophilic,
      clear cell, or mixed cell) also occurred more frequently in exposed female mice
      than in controls. The incidences of thyroid gland follicular cell hyperplasia in
      the 200 and 400 ppm males and in all exposed groups of females were significantly
      greater than those of controls in the first study. These findings were confirmed
      in the second study (follicular cell hyperplasia: males, first study, 3/50, 8/50,
      16/50, 20/60; second study, 0/50,16/50; females, first study, 4/49,17/49,18/50,
      28/60; second study, 9/50, 32/51). The incidences of follicular cell neoplasms
      were similar among exposed and control mice in both studies. The incidences
      (28/50, 36/50, 43/50, 49/60) and average severity (0.56, 0.80, 1.00, 1.07) of
      nephropathy were marginally higher in exposed female mice than in controls in the
      first study. In the second study, the differences in incidence (15/50, 21/50) and
      severity (0.38, 0.55) were not as great. It is uncertain if these increases were
      related to the ingestion of triamterene. The incidences and severity of
      nephropathy were similar among exposed and control male mice in both studies.
      Genetic Toxicology: Triamterene was not mutagenic in Salmonella typhimurium
      strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic
      activation (S9). It did not induce chromosomal aberrations in Chinese hamster
      ovary cells, with or without S9. Positive results were obtained for induction of
      sister chromatid exchanges in Chinese hamster ovary cells with and without S9.
      Conclusions: Under the conditions of these 2-year feed studies, there was
      equivocal evidence of carcinogenic activity of triamterene in male F344/N rats
      based on a marginal increase in the incidence of hepatocellular adenoma. There
      was no evidence of carcinogenic activity of triamterene in female F344/N rats
      administered 150, 300, or 600 ppm. There was some evidence of carcinogenic
      activity of triamterene in male B6C3F1 mice based on a marginal increase in the
      incidence of hepatocellular carcinoma in the first study and a significantly
      increased incidence of hepatocellular adenoma in the second study. There was some
      evidence of carcinogenic activity of triamterene in female B6C3F1 mice based on
      significantly increased incidences of hepatocellular adenoma and of adenoma and
      carcinoma (combined). Exposure to triamterene was associated with an increased
      incidence of hepatocellular foci, primarily mixed cell type, and an increase in
      the severity of nephropathy in female rats. In mice, exposure to triamterene was
      associated with an increased incidence of hepatocellular foci in females and an
      increased incidence of thyroid gland follicular cell hyperplasia in males and
      females. Synonyms: 6-Phenyl-2,4,7-pteridinetnamine; 6-phenyl-2,4,7
      triaminopteridine; 2,4,7-triamino-6-phenypteridine; ademin; pterofen; pterophane;
      NSC-77625; SKF 8542 Trade names: Dyrenium, Dyazide, Dyren, Dytac, Jatropur,
      Maxzide, Noridyl, Triteren, Teriam, Urocaudal

PMID- 12616292
TI  - NTP Toxicology and Carcinogenesis Studies of HC Yellow 4 (CAS No. 59820-43-8) in
      F344 Rats and B6C3F1 Mice (Feed Studies).
AB  - HC Yellow 4 is used in semipermanent hair dyes. Toxicology and carcinogenesis
      studies were conducted by administering HC Yellow 4 (greater than 93% pure) in
      feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks,
      and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,
      cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-Day
      Studies: Groups of five rats of each sex were given 0, 5,000, 10,000, 20,000,
      40,000, or 80,000 ppm and groups of five mice of each sex were given 0, 1,250,
      2,500, 5,000, 10,000, or 20,000 ppm HC Yellow 4 in feed for 14 days. All animals
      survived to the end of the studies. Final mean body weights of male rats that
      received 20,000 ppm or more, female rats that received 10,000 ppm or more, and
      female mice that received 20,000 ppm were significantly lower than those of the
      controls. The mean body weights of exposed and control groups of male mice were
      similar. No chemical-related decrease in feed consumption was observed. No
      chemical-related clinical findings or changes in absolute or relative organ
      weights occurred in rats or mice. No gross or microscopic changes were related to
      HC Yellow 4 administration in rats or mice. 13-Week Studies: Groups of 10 rats of
      each sex were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm
      and groups of 10 mice of each sex were fed diets containing 0, 5,000, 10,000,
      20,000, 40,000, or 80,000 ppm HC Yellow 4 for 13 weeks. All rats survived to
      study termination. Chemical-related deaths occurred at the two highest dose
      levels in male and female mice. Final mean body weights of male rats that
      received 10,000 ppm or greater, female rats that received 20,000 or 40,000 ppm,
      and mice that received 10,000 ppm or greater were significantly lower than those
      of the controls. There were no biologically significant changes in absolute or
      relative organ weights. Mineralization of the renal papilla occurred in all male
      rats in the 40,000 ppm group. Thyroid pigmentation occurred in rats receiving
      40,000 ppm and in mice at all dose levels. Uterine atrophy occurred in female
      rats in the 20,000 and 40,000 ppm groups and female mice in the 40,000 and 80,000
      ppm groups. Lymphoid depletion and atrophy of the spleen occurred in male mice
      that received 40,000 or 80,000 ppm and female mice that received 80,000 ppm.
      Atrophy of the thymus occurred in male and female mice that received 40,000 or
      80,000 ppm. 2-Year Studies: Groups of 70 male rats were fed diets containing 0,
      2,500, or 5,000 ppm and groups of 70 female rats and 70 mice of each sex were fed
      diets containing 0, 5,000, or 10,000 ppm HC Yellow 4 for up to 2 years. Interim
      evaluations were performed on 10 rats and 10 mice from each dose group at 6 and
      15 months. No biologically significant changes in absolute or relative organ
      weight or hematology or clinical chemistry values were found in these rats or
      mice. No compound-related lesions were seen in exposed rats. In exposed mice,
      pigmentation of the thyroid gland was observed at the 6-month interim
      evaluations; pigmentation and hyperplasia of the thyroid gland were seen at the
      15-month interim evaluations. Body Weight, Survival, and Feed Consumption in the
      2-Year Studies: The mean body weight of female rats that received 10,000 ppm was
      significantly lower than that of the controls. The mean body weights of mice
      receiving 10,000 ppm were 20% to 30% lower than those of the controls during the
      second year of the studies. The survival of exposed rats and mice was similar to
      that of the controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies:
      Pituitary gland pars distalis adenomas were marginally increased in exposed male
      rats (0 ppm, 17/45; 2,500 ppm, 20/49; 5,000 ppm, 28/49), and there was a
      concomitant dose-related increase in the incidence of hyperplasia (8/45, 13/49,
      18/49). There was no increase in the incidence of pituitary gland adenomas or
      carcinomas in female rats (34/49, 35/48, 30/49). In mice, no neoplasms were
      considered related to chemical administration. However, a dose-related incr, a
      dose-related increased incidence of thyroid gland pigmentation and follicular
      cell hyperplasia occurred in both sexes of mice. Genetic Toxicology: HC Yellow 4
      was mutagenic in Salmonella typhimurium strains TA100, TA1537, and TA98 with and
      without exogenous metabolic activation (S9); the response in strain TA1535
      without S9 was equivocal. HC Yellow 4 induced sister chromatid exchanges in
      Chinese hamster ovary cells in the absence but not the presence of S9 activation;
      no induction of chromosomal aberrations occurred in Chinese hamster ovary cells,
      with or without S9. HC Yellow 4 induced sex-linked recessive lethal mutations in
      germ cells of adult male Drosophila melanogaster when administered by injection;
      results of a reciprocal translocation test in D. melanogaster were negative.
      Conclusions: Under the conditions of these 2-year feed studies, there was
      equivocal evidence of carcinogenic activity of HC Yellow 4 in male F344/N rats
      based on the increased incidence of pituitary gland adenomas and hyperplasia. The
      male rats may have been able to tolerate a slightly higher dose of the chemical.
      There was no evidence of carcinogenic activity of HC Yellow 4 in female F344/N
      rats given 5,000 or 10,000 ppm. There was no evidence of carcinogenic activity of
      HC Yellow 4 in male or female B6C3F1 mice given 5,000 or 10,000 ppm. There was a
      chemical-related increase in the incidence of thyroid gland pigmentation and
      follicular cell hyperplasia in mice. Synonym: N,O-di(2-hydroxyethyl)-2-amino-5
      nitrophenol

PMID- 12616293
TI  - NTP Toxicology and Carcinogenesis Studies of p-Nitroaniline (CAS No. 100-01-6) in
      B6C3F1 Mice (Gavage Studies).
AB  - p-Nitroaniline is an intermediate in the preparation of several azo dyes used for
      coloring consumer products. Toxicology and carcinogenicity studies were conducted
      by administering p-nitroaniline (>99% pure) in corn oil by gavage to groups of
      male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic
      toxicology studies were conducted in Salmonella typhimurium, Chinese hamster
      ovary cells, mouse Iymphoma cells, and Drosophila melanogaster. 14-DAY STUDIES:
      Groups of five male and five female B6C3F1 mice received p-nitroaniline in corn
      oil by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg body weight 5 days
      per week for 2 weeks. All mice that received 1,000 mg/kg died from chemical
      related toxicity by day 4 of the studies. Final mean body weights of mice
      receiving 300 mg/kg or less were similar to those of the controls. Hematology
      results were consistent with chemical-related methemoglobinemia and regenerative
      anemia. Met hemoglobin concentrations in all groups of dosed mice were
      significantly higher than those in controls. Hematocrit values in mice that
      received 300 mg/kg and total erythrocyte counts in mice that received 100 or 300
      mg/kg were significantly lower than those in controls. Reticulocyte counts in 300
      mg/kg male mice and in 100 or 300 mg/kg females were significantly higher than
      controls. Heinz bodies were observed in erythrocytes of all 300 mg/kg mice and in
      two 100 mg/kg male mice. The absolute and relative spleen weights of 100 and 300
      mg/kg mice were significantly greater than those of the controls. Hematopoiesis
      and pigment (hemosiderin) accumulation were observed in the splenic red pulp of
      males and females receiving 300 mg/kg; pigment (hemosiderin) accumulation in
      Kupffer cells of the liver was also seen in male mice at this dose level. 13-WEEK
      STUDIES: Groups of 20 male and 20 female B6C3F1 mice received p-nitroaniline in
      corn oil by gavage at doses of 0, 1, 3, 10, 30, or 100 mg/kg body weight 5 days
      per week for up to 13 weeks. Eight or nine mice in each group were evaluated at 7
      weeks. There were no deaths associated with exposure to p-nitroaniline, and final
      mean body weights of dosed mice were similar to those of the controls.
      Hematologic and pathologic findings at 7 and 13 weeks were similar to those seen
      in the 14-day studies and occurred primarily in the 30 and 100 mg/kg groups. Met
      hemoglobin concentrations were increased and hematocrit levels and erythrocyte
      counts were decreased relative to those of the controls. Heinz bodies were
      observed in erythrocytes and nucleated erythrocytes and reticulocytes were
      increased in number. Absolute and relative spleen weights of male and female mice
      receiving 30 and 100 mg/kg were significantly greater than those of controls at 7
      and 13 weeks. Absolute and relative liver weights of female mice necropsied at 7
      weeks were significantly greater in the 30 and 100 mg/kg groups; by 13 weeks,
      both absolute and relative liver weights were similar to control values. The
      incidence or severity of splenic hematopoiesis and pigmentation (hemosiderin)
      increased with dose at the 7-week interim evaluations and at the end of the
      studies. Pigment (hemosiderin) was also present in Kupffer cells of the liver in
      dosed male mice. 2-YEAR STUDIES: Groups of 70 male and 70 female B6C3F1 mice
      received p-nitroaniline in corn oil by gavage at doses of 0, 3, 30, or 100 mg/kg
      body weight for 5 days per week for up to 103 weeks. The dose selection was based
      on the hematologic and pathologic findings of the 13-week studies. Nine or ten
      mice from each group were evaluated at 9 and 15 months for the presence of
      chemical-related lesions. Body Weights, Clinical Findings, Survival, and
      Hematology: Mean body weights of male and female mice that received p
      nitroaniline were similar to those of control mice throughout the 2-year studies.
      There were no clinical findings associated with chemical exposure, and survival
      of dosed mice was similar to that of controls. The hematology findings at the 9
      and 15-month interim evaluations were similar to those in the 14-day and 13-week
      s 13-week studies. The methemoglobin concentrations were significantly higher in
      all 30 or 100 mg/kg mice; sulfhemoglobin concentrations were significantly higher
      at 9 months in all 30 or 100 mg/kg female mice and at 15 months in 100 mg/kg
      females. Hematocrit and erythrocyte counts in 100 mg/kg mice were significantly
      lower than those in controls. By 9 months, reticulocyte counts were significantly
      higher in all 30 or 100 mg/kg mice. At 15 months, only the 100 mg/kg mice
      exhibited significantly higher reticulocyte counts. Neoplasms and Nonneoplastic
      Lesions: Lesions related to the administration of p-nitroaniline occurred in the
      spleen, liver, and bone marrow, primarily in mice receiving 30 or 100 mg/kg;
      these were observed at the 9- and 15-month interim evaluations and at the end of
      the studies. There were increases in the incidence or severity of splenic
      congestion, hematopoiesis, pigment (hemosiderin) accumulation, Kupffer cell
      pigmentation in the liver, and bone marrow hypercellularity (hyperplasia). The
      incidences of hemangiosarcoma of the liver (0 ppm, 0/50; 3 ppm, 1/50; 30 ppm,
      2/50; 100 ppm, 4/50) and hemangioma or hemangiosarcoma (combined) at all sites
      (5/50, 3/50, 4/50, 10/50) were marginally increased in 100 mg/kg male mice. The
      incidence of hepatocellular adenoma or carcinoma (combined) was significantly
      decreased (25/50, 26/50, 25/50, 13/50) in 100 mg/kg male mice. GENETIC
      TOXICOLOGY: p-Nitroaniline is mutagenic in vitro. It was tested in two
      laboratories for induction of gene mutations in several strains of Salmonella
      typhimurium. Both studies showed positive results in strain TA98, with and
      without S9 activation; results were negative for all other strains. p
      Nitroaniline was tested in two laboratories for induction of sister cremated
      exchanges and chromosomal aberrations in Chinese hamster ovary cells. In the
      sister cremated exchange study, one laboratory reported negative results without
      S9 and positive results with S9; the second laboratory reported equivocal results
      without S9 and negative results with S9. In the chromosomal aberrations study,
      both laboratories found positive results with S9. Without S9, one laboratory
      reported weakly positive results while the other reported negative results. p
      Nitroaniline induced trifluorothymidine resistance in L5178Y mouse Iymphoma cells
      in the absence of S9; no induction of trifluorothymidine resistance was noted
      with S9. In contrast to the positive results in the previous tests, p
      nitroaniline did not induce sex-linked recessive lethal mutations in germ cells
      of male Drosophila melanogaster when administered by feeding or injection to
      adult males or by feeding to larvae. CONCLUSIONS: Under the conditions of these 2
      year gavage studies there was equivocal evidence of carcinogenic activity of p
      nitroaniline in male B6C3F1 mice based on the increased incidences of
      hemangiosarcoma of the liver and hemangioma or hemangiosarcoma (combined) at all
      sites. There was no evidence of carcinogenic activity of p-nitroaniline in female
      B6C3F1 mice receiving doses of 3, 30, or 100 mg/kg.

PMID- 12616294
TI  - NTP Toxicology and Carcinogenesis Studies of p-Nitrophenol (CAS No. 100-02-7) in
      Swiss Webster Mice (Dermal Studies).
AB  - p-Nitrophenol is used in the production of acetaminophen, methyl and ethyl
      parathion insecticides, fungicides, and dyestuffs. Toxicology and carcinogenesis
      studies of p-nitrophenol (greater than 97% pure) were conducted by dermal
      application to male and female Swiss-Webster mice for 18 months. Dermal
      application was selected as the route of chemical administration because of
      possible skin absorption from p-nitrophenol-treated leather footwear. Genetic
      toxicology studies were conducted in Salmonella typhimurium, Chinese hamster
      ovary cells, and Drosophila melanogaster. 18-MONTH STUDIES: Groups of 60 Swiss
      Webster mice of each sex received p-nitrophenol in acetone applied to the
      interscapular skin. Doses of 0, 40, 80, or 160 mg/kg p-nitrophenol were
      administered to mice 3 days per week for 78 weeks. At the end of the study,
      survival rates of mice receiving 0, 40, 80, or 160 mg/kg p-nitrophenol were
      29/60, 17/60, 26/60, and 24/60 for males and 35/60, 26/60, 33/60, and 27/60 for
      females. Deaths after 60 weeks were caused by generalized amyloidosis and
      secondary kidney failure. The severity of amyloidosis was similar among dosed and
      control animals. At the end of the study, the final mean body weights of the
      dosed groups of each sex were similar to those of the controls. No biologically
      significant lesions were observed that were related to the dermal administration
      of p-nitrophenol. GENETIC TOXICOLOGY: p-Nitrophenol was not mutagenic in
      Salmonella typhimurium (strains TA100, TA1535, TA1537, and TA98) with or without
      exogenous metabolic (S9) activation, or in germ cells of male Drosophila
      melanogaster administered p-nitrophenol in feed or by injection. In Chinese
      hamster ovary cells, no induction of sister chromatid exchanges was observed with
      or without S9, but a significant increase in chromosomal aberrations occurred in
      trials conducted with S9. CONCLUSIONS: Under the conditions of these 18-month
      dermal studies there was no evidence of carcinogenic activity in male or female
      Swiss-Webster mice receiving 40, 80, or 160 mg/kg p-nitrophenol. Synonyms: 4
      hydroxynitrobenzene, p-hydroxynitrobenzene, 4-nitrophenol, paranitrophenol, PNP,
      Niphen

PMID- 12616295
TI  - NTP Toxicology and Carcinogenesis Studies of o-Nitroanisole (CAS No. 91-23-6) in
      F344 Rats and B6C3F1 Mice (Feed Studies).
AB  - o-Nitroanisole is used as an intermediate for the preparation of o-anisidine and
      in the manufacture of azo dyes. Toxicology and carcinogenesis studies were
      conducted by administering o-nitroanisole (>99% pure) in the diet to groups of
      male and female F344 rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese
      hamster ovary cells, and mouse lymphoma cells. 14-DAY STUDIES: Groups of five
      male and five female F344 rats received diets containing 0, 583, 1,166, 2,332,
      4,665, or 9,330 ppm o-nitroanisole. Mean body weight gains and final mean body
      weights of males in the 4,665 and 9,330 ppm groups were lower than those of the
      controls. Absolute liver weights were significantly increased in males receiving
      1,166 ppm or more and in females receiving 583 ppm or more. Groups of five male
      and five female B6C3F1 mice received diets containing 0, 250, 500, 1,000, 2,000,
      or 4,000 ppm o-nitroanisole. Mean body weight gains and final mean body weights
      of males that received 250 ppm and females that received 4,000 ppm were
      significantly lower than those of the controls. No other chemical-associated
      effects were observed. 13-WEEK STUDIES: Groups of 10 male and 10 female F344 rats
      received diets containing 0, 200, 600, 2,000, 6,000, or 18,000 ppm o
      nitroanisole. Final mean body weights and feed consumption by male and female
      rats receiving 6,000 and 18,000 ppm were lower than those of the controls.
      Hemoglobin and hematocrit values were significantly lower and methemoglobin
      levels significantly higher in males in the 6,000 and 18,000 ppm groups than in
      controls. Absolute liver weights were significantly increased in females that
      received 200, 600, 2,000, and 6,000 ppm, absolute kidney weights were
      significantly increased in males that received 600, 2,000, and 6,000 ppm, and
      absolute spleen weights were significantly increased in males and females that
      received 6,000 and 18,000 ppm. Groups of 10 male and 10 female B6C3F1 mice
      received diets containing 0, 60, 200, 600, 2,000, or 6,000 ppm o-nitroanisole.
      Final mean body weight gains, final mean body weights, and feed consumption by
      male and female mice receiving 6,000 ppm were lower than those of the controls.
      Hemoglobin and hematocrit values in males and females that received 2,000 or
      6,000 ppm were significantly lower than those in the controls. The absolute and
      relative liver weights of females in the 600 ppm group and relative liver weights
      of males and females in the 2,000 and 6,000 ppm groups were significantly greater
      than those of controls. Lesions associated with exposure to o-nitroanisole were
      present in the urinary bladder, spleen, kidney, liver, testis, and uterus of
      rats. Diffuse hyperplasia of the transitional epithelium of the urinary bladder
      occurred in all male and female rats that received 6,000 and 18,000 ppm. A
      transitional cell papilloma occurred in one male and transitional cell carcinomas
      occurred in two males and three females receiving 18,000 ppm. Congestion of the
      red pulp and capsular hyperplasia of the spleen and hepatocellular hypertrophy of
      the liver were present in males and females from the 18,000 ppm groups.
      Multifocal degeneration and necrosis of the renal tubule epithelium with
      infiltration of mononuclear inflammatory cells were present in male rats that
      received 600, 2,000, and 6,000 ppm. At the 18,000 ppm level, degeneration of the
      seminiferous epithelium accompanied by loss of spermatogenic cells and decreased
      numbers of spermatozoa were observed in the testes of male rats, while uterine
      atrophy was observed in female rats. Hepatocyte hypertrophy of the centrilobular
      and midzonal regions of liver lobules was present in mice that received 200 ppm
      and increased in severity at higher exposure levels. 2-YEAR STUDIES: The doses
      selected for the 2-year study of o-nitroanisole in rats were based on lower mean
      body weights, reduced feed consumption, and increased severity of regenerative
      anemia in male and female rats receiving 6,000 and 18,000 ppm during the 13-week
      study. Groups of 6roups of 60 male and 60 female F344 rats received diets
      containing 0, 222, 666, or 2,000 ppm o-nitroanisole. Groups of 60 male and 60
      female B6C3F1 mice received diets containing 0, 666, 2,000, or 6,000 ppm o
      nitroanisole. After 15 months, up to 10 animals from each group were evaluated
      for chemical-related lesions. Survival, Body Weights, Feed Consumption, and
      Clinical Findings: Survival of male rats receiving 2,000 ppm was significantly
      lower than that of the controls due to increased severity of nephropathy.
      Survival of 222 and 666 ppm male rats and all exposed female rats was similar to
      that of the controls. Survival of groups of exposed male and female mice was
      similar to that of the controls. The final mean body weight of male rats
      receiving 2,000 ppm was lower than that of the controls. Final mean body weights
      of male and female mice that received 2,000 and 6,000 ppm were lower than those
      of the controls. Feed consumption by male and female rats was similar to that by
      the controls. The only clinical finding in male or female mice attributable to
      chemical administration was discolored urine. Neoplasms and Nonneoplastic
      Lesions: The incidence of mononuclear cell leukemia was significantly increased
      in male rats that received 666 and 2,000 ppm and in female rats that received
      2,000 ppm (males: 0 ppm, 26/50; 222 ppm, 25/50; 666 ppm, 42/50; 2,000 ppm, 34/50;
      females: 14/50, 11/50, 14/50, 26/50). Nephropathy occurred in all male rats; the
      severity increased with exposure level. Focal hyperplasia of the renal tubule
      epithelium was present in three males receiving 222 ppm and two males receiving
      2,000 ppm. Renal tubule adenomas occurred in one male from each of the 222, 666,
      and 2,000 ppm groups, and renal tubule carcinomas occurred in two males from the
      2,000 ppm group. Focal hyperplasia of the transitional epithelium of the urinary
      bladder was present in one female rat that received 222 ppm and two male rats and
      six female rats that received 2,000 ppm. A transitional cell papilloma occurred
      in the urinary bladder of one female rat from the 2,000 ppm group, and a
      transitional cell carcinoma occurred in another female from the 2,000 ppm group.
      The incidence of forestomach ulcers increased in male rats that received 2,000
      ppm, and the incidence of focal hyperplasia of the forestomach increased with
      exposure level in male and female rats. In addition, squamous cell papillomas of
      the forestomach were present in one female receiving 222 ppm, one male receiving
      666 ppm, and one male and one female receiving 2,000 ppm, while squamous cell
      carcinomas were present in one male receiving 666 ppm and one male and one female
      receiving 2,000 ppm. The incidences of pituitary gland adenomas in male rats and
      mammary gland fibroadenomas in female rats decreased with exposure level. The
      incidence of cellular alteration in the liver was significantly increased in
      exposed groups of male and female mice. The incidences of hepatocellular adenoma,
      hepatocellular adenoma or carcinoma (combined), and hepatocellular carcinoma or
      hepatoblastoma (combined) were significantly increased in male mice receiving
      2,000 and 6,000 ppm. The incidences of hepatocellular adenoma or carcinoma were
      significantly increased in female mice that received 2,000 ppm. STOP-EXPOSURE
      STUDY: Groups of 60 male and 60 female F344 rats received diets containing 0,
      6,000, or 18,000 ppm o-nitroanisole for 27 weeks and were then maintained on
      control feed without further chemical exposure for up to an additional 77 weeks.
      Up to 10 rats from each group were evaluated for the presence of chemical-related
      lesions at 3, 6, 9, and 15 months. Survival and Body Weights: Survival of exposed
      male and female rats was significantly lower than that of the controls as a
      result of moribund deaths associated with significantly increased incidences of
      urinary bladder neoplasms, primarily transitional cell carcinomas. All male rats
      that received 18,000 ppm were dead by week 48 and all females that received
      18,000 ppm were dead by week 61. Mean body weights of exposed male and female
      rats were lower than those of the controls throughout the study. Neoplasms and
      Nonneoplastic Lesions: Hyperplasia of the transitional epithelium of the urinary
      bladder was present in nearly all exposed male and female rats examined at the
      interim evaluations. A transitional cell carcinoma was first observed at the 3
      month interim evaluation in a male rat that received 18,000 ppm. At the 6- and 9
      month interim evaluations, transitional cell papillomas or carcinomas were
      observed in both exposed groups of male rats. Transitional cell carcinomas were
      observed at the 6-month interim evaluation in females receiving 18,000 ppm and at
      the 9-month interim evaluation in females receiving 6,000 and 18,000 ppm.
      Adenomatous polyps of the large intestine were observed in a small number of
      exposed rats at the 6-, 9-, and 15-month interim evaluations. At the end of the
      study, the incidence of adenomatous polyps of the large intestine was
      significantly increased in all exposed groups and carcinomas of the large
      intestine were present in four males and two females from the 18,000 ppm groups.
      The incidence of hyperplasia of the transitional epithelium of the kidney pelvis
      was significantly increased in exposed male and female rats and transitional cell
      papillomas were present in three males and one female that received 18,000 ppm.
      Transitional cell carcinomas of the kidney were present in one male receiving
      6,000 ppm and six males and one female receiving 18,000 ppm. Transitional cell
      carcinomas of the urinary bladder were seen in nearly all exposed male and female
      rats. Of the males and females receiving 6,000 ppm which were without carcinomas,
      three males and one female had transitional cell papillomas. Generalized
      centrilobular hypertrophy, focal hepatocellular necrosis, multifocal
      hepatocellular cytoplasmic vacuolation, and Kupffer cell pigmentation were
      observed in the livers of male and female rats at the 3- and 6-month interim
      evaluations; however, only Kupffer cell pigmentation was observed at the end of
      the study. Congestion of the red pulp of the spleen was observed in nearly all
      exposed male and female rats at the 3-, 6-, and 9-month interim evaluations but
      the incidence was only slightly increased in the 18,000 ppm groups at the end of
      the study. Degeneration and atrophy of the seminiferous tubule epithelium of the
      testes were observed at the 3- and 6-month interim evaluations in all male rats
      receiving 18,000 ppm. GENETIC TOXICOLOGY: o-Nitroanisole was tested in two
      laboratories for mutagenicity in Salmonella typhimurium strains TA97, TA98,
      TA100, TA1535, and TA1537 with and without exogenous metabolic activation (S9).
      Positive responses were observed at both laboratories in TA100 with and without
      S9 activation. One laboratory found no increase in mutations, while the second
      laboratory detected a weakly positive response in TA1535 without S9. No mutagenic
      activity was observed in the other tester strains. o-Nitroanisole was positive in
      the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y
      cells without S9 activation. In cytogenetic tests with Chinese hamster ovary
      cells, o-nitroanisole induced a significant increase in chromosomal aberrations
      at the highest dose tested in the presence of S9 activation; sister chromatid
      exchanges were induced both with and without S9. CONCLUSIONS: Under the
      conditions of these feed studies there was clear evidence of carcinogenic
      activity of o-nitroanisole in male and female F344 rats that received diets
      containing 6,000 or 18,000 ppm for 6 months based on overall increased incidences
      of benign and malignant neoplasms of the urinary bladder, transitional cell
      neoplasms of the kidney, and benign and malignant neoplasms of the large
      intestine. There was a chemical-related increased incidence of mononuclear cell
      leukemia in male and female rats receiving diets containing 222, 666, or 2,000
      ppm o-nitroanisole for 2 years. Marginally increased incidences of uncommon renal
      tubule neoplasms in male rats and forestomach neoplasms in male and female rats
      were considered uncertain findings. There was clear evidence of carcinogenic
      activity of o-nitroanisole in male B6C3F1 mice based on increased incidences of
      benign and malignant hepatocellular neoplasms. There was some evidence of
      carcinogenic activity of o-nitroanisole in female B6C3F1 mice based on increased
      incidences of hepatocellular adenomas. Increased severity of nephropathy in male
      rats, and increased incidences of focal hyperplasia of the renal tubule
      epithelium and forestomach ulcers in male rats, and of transitional cell
      hyperplasia of the urinary bladder, focal hyperplasia of the forestomach, and
      hyperplasia of transitional epithelium of the kidney pelvis in male and female
      rats were associated with exposure to o-nitroanisole. Synonyms:
      Methoxynitrobenzene, nitrophenyl methyl ether

PMID- 12616296
TI  - NTP Toxicology and Carcinogenesis Studies of Polysorbate 80 (CAS No. 9005-65-6)
      in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - Polysorbate 80 is a nonionic surfactant used widely as an additive in foods,
      pharmaceutical preparations, and cosmetics as an emulsifier, dispersant, or
      stabilizer. Toxicity and carcinogenicity studies were conducted by administering
      polysorbate 80 (which met all compendial specifications) in feed to groups of
      F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium. 14-Day
      Studies: Groups of five rats and five mice of each sex received diets containing
      0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm polysorbate 80. All animals
      survived to the end of the studies. The mean body weight change of male rats that
      received 50,000 ppm was significantly lower than that of the controls. The mean
      body weight changes in all other groups of dosed rats and in all groups of dosed
      mice were similar to those of the respective controls. No clinical findings or
      changes in absolute or relative organ weights in rats or mice were related to
      polysorbate 80 administration. 13-Week Studies: Groups of 10 rats and 10 mice of
      each sex received diets containing 0, 3,100, 6,200, 12,500, 25,000, or 50,000 ppm
      polysorbate 80. All animals survived to the end of the studies. The final mean
      body weights of dosed rats and mice were similar to those of the controls. No
      clinical findings, changes in absolute or relative organ weights, or gross or
      microscopic lesions in rats or mice were related to polysorbate 80
      administration. 2-Year Studies: Doses for the 2-year studies were selected based
      on the lack of observed compound-related effects at the dose levels used in the
      13-week studies. Groups of 60 rats and 60 mice of each sex received diets
      containing 0, 25,000, or 50,000 ppm polysorbate 80 for up to 103 weeks. 15-Month
      Interim Evaluations: Interim evaluations were performed on 7 to 10 rats and mice
      from each dose group at 15 months. There were no significant changes in absolute
      or relative organ weights. Incidences of hyperplasia and inflammation of the
      forestomach were increased in female mice that received 50,000 ppm. No other
      chemical-related lesions occurred in rats or male mice evaluated at 15 months.
      Body Weights, Clinical Findings, and Survival in the 2-Year Studies: The mean
      body weights in male and female rats and male mice administered polysorbate 80
      were similar to those of the controls throughout the studies. The final mean body
      weight of female mice receiving 50,000 ppm was 11%lower than that of the
      controls. No clinical findings were associated with administration of polysorbate
      80. The survival of dosed male rats was lower than that of the controls (0 ppm,
      29/50; 25,000 ppm, 18/50; 50,000 ppm, 18/50); the survival of dosed female rats
      and male and female mice was similar to that of the respective controls (female
      rats: 23/50, 25/50, 25/50; male mice: 33/49, 34/50, 32/50; female mice: 30/50,
      28/50, 26/50). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: The
      incidence of adrenal medulla pheochromocytoma was marginally increased in high
      dose male rats (21/50, 19/50, 29/50). The incidence of hyperplasia of the adrenal
      medulla was increased in low-dose male rats but not in high-dose male rats
      (11/50, 22/50, 12/50). No chemical-related increases in the incidences of
      neoplasms occurred in male or female mice. The incidences of squamous hyperplasia
      and inflammation of the forestomach were significantly increased in high-dose
      male and female mice; forestomach ulcers were significantly increased in high
      dose females. Genetic Toxicology: Polysorbate 80 was not mutagenic in Salmonella
      typhimurium strains TA100, TA1535, TA1537, and TA98 with or without exogenous
      metabolic activation (S9). Conclusions: Under the conditions of these 2-year feed
      studies, there was equivocal evidence of carcinogenic activity for polysorbate 80
      in male F344/N rats based on an increased incidence of pheochromocytomas of the
      adrenal medulla. There was no evidence of carcinogenic activity for polysorbate
      80 in female F344/N rats or in male or female B6C3F1 mice given 25,000 or 50, or
      50,000 ppm. Administration of polysorbate 80 was associated with inflammation and
      squamous hyperplasia of the forestomach in male and female mice, and with ulcers
      of the forestomach in female mice. Synonyms: Glycol; sorbitan mono-9
      octadecenoate poly(oxy-1,2-ethanediyl) derivatives; polyoxyethylene (20) sorbitan
      mono-oleate; sorethytan (20) mono-oleate; polyethylene oxide sorbitan mono-oleate
      Trade names: Alkamuls PSMO-20; Armotan PMO-20; Capmul POE-O; Drewmulse POE-SMO;
      Emsorb 2722; Glycosperse O-20; Glycosperse O20 Veg; Glycosperse O20X; Hetsorb
      O20; Industrol O20S; Laxan ESO; Liposorb O-20; Lonzest SMO-20; Montanox 80;
      Nikkol TO-10;Protasorb O-20; Sorbitan mono-oleate polyoxyethylene; Sorlate; Tween
      80; Monitan; Olothorb; Sorbimacrogol Oleate 300; T-Maz 80

PMID- 12616297
TI  - NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in
      B6C3F1 Mice (Inhalation Studies).
AB  - 1,3-Butadiene is produced in large volumes for use in the manufacture of
      synthetic rubber and of thermoplastic resins. In previous inhalation studies
      conducted by the NTP (NTP, 1984) there was clear evidence of multiple organ
      carcinogenicity in male and female mice exposed to 625 or 1,250 ppm 1,3-butadiene
      for 60 or 61 weeks. To better characterize exposure-response relationships for
      neoplasms and nonneoplastic lesions, toxicology and carcinogenesis studies were
      conducted by exposing groups of male and female B6C3F1 mice to air containing 1,3
      butadiene (greater than 99% pure) for up to 2 years. An additional study in male
      B6C3F1 mice, in which exposure to 1,3-butadiene was stopped after limited
      exposure periods (13, 26, 40, or 52 weeks), was performed to assess the effects
      of varying concentration and duration of exposure on the incidences of 1,3
      butadiene-induced neoplasms. In vitro genetic toxicology studies were conducted
      in Salmonella typhimurium and mouse lymphoma cells. In vivo genetic effects were
      assayed in germ cells of male Drosophila melanogaster and in bone marrow and
      peripheral blood cells of B6C3F1 mice. 2-Year Studies: Groups of 70 male and 70
      female mice were exposed to air containing 0, 6.25, 20, 62.5, or 200 ppm 1,3
      butadiene for 6 hours per day, 5 days per week for up to 2 years; groups of 90
      male and 90 female mice were exposed to 625 ppm 1,3-butadiene on the same
      schedule. Up to 10 animals from each group were examined after 9 and 15 months of
      exposure. Survival and Body Weight in the 2-Year Studies: Two-year survival was
      decreased for males and females exposed to concentrations of 20 ppm or above,
      primarily due to the development of chemical-related malignant neoplasms. No
      female mice exposed to 200 or 625 ppm or males exposed to 625 ppm survived to the
      end of the studies (males: 35/50, 39/50, 24/50, 22/50, 4/50, 0/70; females:
      37/50, 33/50, 24/50, 11/50, 0/50, 0/70). Mean body weights of exposed male and
      female mice were similar to those of the controls. Hematologic Effects in the 2
      Year Studies: Hematologic parameters were evaluated after 9 and 15 months of
      exposure. At 9 months, decreases in erythrocyte counts, hemoglobin concentration,
      and packed red cell volume were observed in male mice exposed to 62.5 ppm or
      above and in female mice exposed to 200 or 625 ppm. Mean erythrocyte volume was
      increased in male mice exposed to 625 ppm and in females exposed to 200 or 625
      ppm. At 15 months, decreases in erythrocyte counts, hemoglobin concentration, and
      packed red cell volume and increases in mean erythrocyte volume were observed in
      male and female mice exposed to 625 ppm. Neoplasms and Nonneoplastic Lesions in
      the 2-Year Studies: Exposure of mice to 1,3-butadiene induced benign and
      malignant neoplasms at multiple sites. Statistically significant increases in the
      incidences of neoplasms at one or more sites were seen at concentrations of 20
      ppm and higher in males and 6.25 ppm and higher in females. There was no exposure
      level in this study at which a significant carcinogenic response was not
      observed. Statistically significant increases occurred in the incidences of
      malignant lymphoma; histiocytic sarcoma; cardiac hemangiosarcoma; harderian gland
      adenoma; hepatocellular adenoma and carcinoma; alveolar/bronchiolar adenoma and
      carcinoma; mammary gland carcinoma, adenoacanthoma, and malignant mixed tumor
      (females only); benign and malignant ovarian granulosa cell tumor; and
      forestomach squamous cell papilloma and carcinoma. Low incidences of uncommon
      neoplasms also occurred in exposed male and female mice, including intestinal
      carcinomas in males, renal tubule adenomas in males and females, skin sarcomas
      (all types combined) in females, and Zymbal's gland adenomas and carcinomas in
      females. Lymphocytic lymphomas appeared as early as week 23 and were the
      principal cause of death of male and female mice exposed to 625 ppm 1,3
      butadiene. The early and extensive development of lethal lymphocytic lymphomas in
      mice exposed to 625 ppm resulted in a reduced number of mice at risk for
      neoplasms developing laterg later at other sites. Exposure-response relationships
      for 1,3-butadiene-induced neoplasms were more clearly characterized at
      concentrations below 625 ppm and after adjustment for intercurrent mortality.
      Increased incidences of nonneoplastic lesions in exposed mice included bone
      marrow atrophy; testicular atrophy; ovarian atrophy, angiectasis, germinal
      epithelial hyperplasia, and granulosa cell hyperplasia; uterine atrophy; cardiac
      endothelial hyperplasia and mineralization; alveolar epithelial hyperplasia;
      forestomach epithelial hyperplasia; and harderian gland hyperplasia. Stop
      Exposure Study: The stop-exposure study consisted of groups of 50 male mice
      exposed to 1,3-butadiene at concentrations of 200 ppm for 40 weeks, 625 ppm for
      13 weeks, 312 ppm for 52 weeks, or 625 ppm for 26 weeks. After the exposures were
      completed, these groups were placed in control chambers for the remainder of the
      2-year study. The total exposure of 1,3-butadiene (concentration times duration
      of exposure) of the 13- and 40-week stop-exposure groups was approximately 8,000
      ppm-weeks, while that of the 26- and 52-week stop-exposure groups was
      approximately 16,000 ppm-weeks. The survival of all stop-exposure groups was
      markedly lower than that of the controls. The incidences of lymphocytic lymphoma,
      histiocytic sarcoma, cardiac hemangiosarcoma, alveolar/bronchiolar adenoma and
      carcinoma, forestomach squamous cell papilloma and carcinoma, hepatocellular
      adenoma, harderian gland adenoma and adenocarcinoma, and preputial gland
      carcinoma were significantly increased. Neoplasms were induced at most of these
      sites after only 13 weeks of exposure to 1,3-butadiene. Additionally, low numbers
      of malignant gliomas and neuroblastomas of the brain and Zymbal's gland
      carcinomas occurred in one or more stop-exposure groups. At similar total
      exposures, the incidence of lymphocytic lymphoma was greater with exposure to a
      higher concentration of 1,3-butadiene for a short time compared with exposure to
      a lower concentration for an extended period (34&percnt; at 625 ppm for 13 weeks
      versus 12&percnt; at 200 ppm for 40 weeks; 60&percnt; at 625 ppm for 26 weeks
      versus 8&percnt; at 312 ppm for 52 weeks). Genetic Toxicology: 1,3-Butadiene has
      been tested both in vitro and in vivo for mutagenic activity. In vitro, positive
      results were obtained in the Salmonella typhimurium gene mutation assay with
      strain TA1535; mutagenic activity was not observed in other S. typhimurium
      strains (TA100, TA97, and TA98). 1,3-Butadiene was negative in the mouse lymphoma
      assay for induction of trifluorothymidine resistance in L5178Y cells with and
      without S9. In vivo, 1,3-butadiene did not induce sex-linked recessive lethal
      mutations in germ cells of male Drosophila melanogaster; however, it did induce
      significant increases in chromosomal aberrations and sister chromatid exchanges
      in bone marrow cells of mice exposed for 2 weeks by inhalation. In addition,
      significant increases in micronucleated erythrocytes were observed in peripheral
      blood samples obtained from male and female mice exposed to 1,3-butadiene for 2
      or 13 weeks or 15 months by inhalation. Conclusions: The previous inhalation
      studies of 1,3-butadiene (TR-288) in male and female B6C3F1 mice provided clear
      evidence of carcinogenicity at exposure concentrations of 625 or 1,250 ppm. The
      present inhalation studies - 2-year exposures of 6.25, 20, 62.5, 200, or 625 ppm
      or shorter duration exposures of 200, 312, or 625 ppm - provide a better
      characterization of the concentration-dependent responses for 1,3-butadiene
      induced neoplasms and nonneoplastic lesions. The present studies confirmed the
      clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on
      increased incidences of neoplasms in the hematopoietic system, heart, lung,
      forestomach, liver, harderian gland, preputial gland, brain, and kidney. There
      was clear evidence of carcinogenicity of 1,3-butadiene in female B6C3F1 mice
      based on increased incidences of neoplasms in the hematopoietic system, heart,
      lung, forestomach, liver, harderian gland, ovary, and mammary gland. Low
      incidences of intestinal carcinomas in male mice, Zymbal's gland carcinomas in
      male and female mice, and renal tubule adenomas and skin sarcomas in female mice
      may also have been related to administration of 1,3-butadiene. Synonyms:
      alpha,gamma-Butadiene; bivinyl; divinyl; erythrene; vinylethylene; biethylene;
      pyrrolylene

PMID- 12616298
TI  - NTP Toxicology and Carcinogenesis Studies of Tricresyl Phosphate (CAS No. 1330-78
      5) in F344/N Rats and B6C3F1 Mice (Gavage and Feed Studies).
AB  - Tricresyl phosphate is an organophosphate plasticizer widely used in vinyl
      plastics and as a fire retardant additive for hydraulic fluids. Toxicology and
      carcinogenesis studies were conducted by administering a mixed isomer preparation
      of 79% tricresyl phosphate esters (consisting of 21% tri- m-cresyl phosphate, 4%
      tri- p-cresyl phosphate, less than 1% tri- o-cresyl phosphate, and other
      unidentified tricresyl phosphate esters) by gavage to groups of F344/N rats and
      B6C3F1 mice for 16 days and 13 weeks, and in feed to groups of F344/N rats and
      B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted
      in Salmonella typhimurium and cultured Chinese hamster ovary cells. 16-DAY GAVAGE
      STUDY IN RATS: Groups of 10 male and 10 female rats received tricresyl phosphate
      in corn oil by gavage at doses of 0, 360, 730, 1,450, 2,900, or 5,800 mg/kg body
      weight, 5 days per week, for a total of 13 or 14 doses in a 16-day period. One
      female receiving 1,450 mg/kg and five males and eight females receiving 2,900
      mg/kg died before the end of the study. Final mean body weights of male and
      female rats that received 1,450, 2,900, or 5,800 mg/kg were significantly lower
      than those of the controls. Necrosis of the mandibular lymph node, spleen, and
      thymus occurred primarily in rats receiving 2,900 and 5,800 mg/kg. Diffuse
      aspermatogenesis occurred in the testes of male rats that received 2,900 and
      5,800 mg/kg. Changes in neurobehavioral parameters in groups that received 1,450,
      2,900, or 5,800 mg/kg were confounded by mortality and reduced body weights and
      were not attributed to a direct neurotoxic response. 16-DAY GAVAGE STUDY IN MICE:
      Groups of 10 male and 10 female mice received tricresyl phosphate in corn oil by
      gavage at doses of 0, 360, 730, 1,450, 2,900, or 5,800 mg/kg body weight, 5 days
      per week, for a total of 13 or 14 doses in a 16-day period. Five males and all
      females that received 1,450 mg/kg, all mice that received 2,900 mg/kg, and four
      males and one female that received 5,800 mg/kg died before the end of the study.
      Final mean body weights of male mice that received 1,450 and 5,800 mg/kg were
      significantly lower than that of the controls. Final mean body weights of female
      mice that received 360, 730, or 5,800 mg/kg were significantly greater than that
      of the controls. Necrosis of the mandibular lymph node, thymus, and spleen
      occurred primarily in mice receiving 2,900 and 5,800 mg/kg. Hindlimb grip
      strengths of male mice that received 360 and 1,450 mg/kg and male and female mice
      that received 730 and 5,800 mg/kg were significantly lower than those of the
      controls at the end of the study. 13-WEEK GAVAGE STUDY IN RATS: Groups of 10 male
      and 10 female rats received tricresyl phosphate in corn oil by gavage at doses of
      0, 50, 100, 200, 400, or 800 mg/kg body weight. All rats survived to the end of
      the study. Final mean body weights of male rats receiving 200, 400, and 800 mg/kg
      were significantly lower than that of the controls. Cytoplasmic vacuolization of
      the adrenal cortex occurred in all dosed groups and the severity increased with
      dose. Ovarian interstitial cell hypertrophy occurred in all dosed groups of
      females. Atrophy of the seminiferous tubules occurred in male rats that received
      400 and 800 mg/kg. There were no biologically significant changes in
      neurobehavioral parameters in rats. 13-WEEK GAVAGE STUDY IN MICE: Groups of 10
      male and 10 female mice received tricresyl phosphate in corn oil by gavage at
      doses of 0, 50, 100, 200, 400, or 800 mg/kg body weight. All mice survived to the
      end of the study. Final mean body weights of male mice receiving 200 mg/kg and of
      male and female mice receiving 400 and 800 mg/kg were significantly lower than
      those of the controls. Cytoplasmic vacuolization of the adrenal cortex occurred
      in all dosed groups of mice and the severity increased with dose. Ovarian
      interstitial cell hypertrophy was present in all dosed groups of female mice.
      Multifocal degeneration of the spinal cord occurred in males and females that
      received 100, 200, 400, and 800 mg/kg, and multifocal degenerg/kg, and multifocal
      degeneration of the sciatic nerve occurred in males that received 200, 400, and
      800 mg/kg and females that received 100, 200, 400, and 800 mg/kg. Hindlimb grip
      strengths of male mice that received 200, 400, or 800 mg/kg were significantly
      lower than that of the controls at the end of the study. 13-WEEK FEED STUDY IN
      RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 900,
      1,700, 3,300, 6,600, or 13,000 ppm of tricresyl phosphate. All rats survived to
      the end of the study. Final mean body weights of males and females exposed to
      6,600 and 13,000 ppm and females exposed to 3,300 ppm were significantly lower
      than those of controls. Feed consumption by male and female rats exposed to
      13,000 ppm was lower than that by controls during the first week of the study.
      Dietary levels of 900, 1,700, 3,300, 6,600 or 13,000 ppm tricresyl phosphate were
      estimated to deliver daily doses of 55, 120, 220, 430, or 750 mg/kg body weight
      (males) and 65, 120, 230, 430, or 770 mg/kg (females). There were no biologically
      significant changes in neurobehavioral parameters in rats. Cytoplasmic
      vacuolization of the adrenal cortex occurred in all exposed groups of rats.
      Hyperplasia of ovarian interstitial cells and inflammation of the ovarian
      interstitium occurred in all exposed groups of females. Renal papillary edema and
      renal papillary necrosis occurred in 13,000 ppm males and females and in 6,600
      ppm females. Basophilic hypertrophy of the pituitary gland pars distalis and
      atrophy of the seminiferous tubules occurred in 6,600 and 13,000 ppm males. Dose
      selection for the 2-year study in rats was based on lower mean body weights;
      toxic responses observed in the kidney, pituitary gland, and testis of males and
      the kidney of females exposed to 6,600 and 13,000 ppm; the presence of
      cytoplasmic vacuolization of the adrenal cortex in exposed males and females; and
      the occurrence of ovarian interstitial cell hyperplasia in females exposed to 900
      and 1,700 ppm. 13-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female mice
      were fed diets containing 0, 250, 500, 1,000, 2,100, or 4,200 ppm of tricresyl
      phosphate. All mice survived to the end of the study. Mean body weights of 4,200
      ppm males and of females exposed to 2,100 and 4,200 ppm were lower than those of
      controls throughout the study. Feed consumption by females exposed to 1,000,
      2,100, or 4,200 ppm was lower than that by controls during week 12. Dietary
      levels of 250, 500, 1,000, 2,100, or 4,200 ppm tricresyl phosphate were estimated
      to deliver average daily doses of 45, 110, 180, 380, or 900 mg/kg body weight
      (males) and 65, 130, 230, 530, or 1,050 mg/kg (females). Interpretation of grip
      strength changes observed in groups receiving 2,100 or 4,200 ppm were confounded
      by the reduced body weights of these groups. Cytoplasmic vacuolization of the
      adrenal cortex occurred in all exposed groups of male and female mice with the
      exception of 250 ppm males. Papillary hyperplasia of the gallbladder mucosa
      occurred in male mice exposed to 500 ppm or more and in female mice exposed to
      1,000 ppm or more. Axonal degeneration occurred in males and females exposed to
      2,100 and 4,200 ppm and females exposed to 1,000 ppm. Renal tubule regeneration
      occurred in all 4,200 ppm male mice. Dose selection for the 2-year study in mice
      was based on the presence of axonal degeneration at concentrations of 1,000 ppm
      or more and cytoplasmic vacuolization of the adrenal cortex at concentrations of
      500 ppm or more in males and in all exposed groups of females. 2-YEAR FEED STUDY
      IN RATS: Groups of 95 male and 95 female rats were fed diets containing 0, 75,
      150, or 300 ppm of tricresyl phosphate. An additional group of 95 male and 95
      female rats were fed diets containing 600 ppm of tricresyl phosphate for 22 weeks
      and then received only control feed. After 3, 9, and 15 months of chemical
      exposure, up to 15 males and 15 females per group were evaluated for forelimb and
      hindlimb grip strength, then necropsied and evaluated for histopathologic
      lesions. Survival, Mean Body Weights, and Feed Consumption: Survival of exposed
      rats was similar to that of controls. The final mean body weights of all exposed
      groups of males and females were similar to those of the controls. Feed
      consumption by exposed groups of male and female rats was similar to that by the
      controls. Dietary levels of 75, 150, or 300 ppm tricresyl phosphate were
      estimated to deliver average daily doses of 3, 6, or 13 mg/kg body weight (males)
      and 4, 7, or 15 mg/kg (females). Pathology Findings: There were no chemical
      related increased incidences of neoplasms in rats. Cytoplasmic vacuolization of
      the adrenal cortex occurred in 600 ppm males and 150, 300, and 600 ppm females at
      the 3-month interim evaluation. At 9 and 15 months, cytoplasmic vacuolization
      occurred only in female rats, primarily in the 300 ppm group. Cytoplasmic
      vacuolization of the adrenal cortex and ovarian interstitial cell hyperplasia
      occurred in female rats exposed to 300 ppm throughout the 2-year study and the
      incidence and severity were significantly increased at the end of the study. 2
      YEAR FEED STUDY IN MICE: Groups of 95 male and 95 female mice were fed diets
      containing 0, 60, 125, or 250 ppm of tricresyl phosphate. After 3, 9, and 15
      months of chemical exposure, up to 15 males and 15 females per group were
      evaluated for forelimb and hindlimb grip strength, then necropsied and evaluated
      for histopathologic lesions. Survival, Mean Body Weights, and Feed Consumption:
      Survival of exposed groups of male and female mice was similar to that of the
      controls. The final mean body weights of males and females receiving tricresyl
      phosphate were similar to those of controls. Feed consumption by exposed groups
      of male and female mice was similar to that by the controls. Dietary levels of
      60, 125, or 250 ppm tricresyl phosphate were estimated to deliver average daily
      doses of 7, 13, or 27 mg/kg body weight (males) and 8, 18, or 37 mg/kg (females).
      Pathology Findings: There were no chemical-related increased incidences of
      neoplasms in mice. Ceroid pigmentation of the adrenal cortex occurred in all
      groups of mice throughout most of the 2-year study, with the exception of 60 and
      125 ppm females at the 3-month interim evaluation; however, the severity was
      markedly increased in female mice receiving 250 ppm. Incidences of clear cell
      foci, fatty change, and ceroid pigmentation of the liver were significantly
      increased in male mice that received 125 or 250 ppm. GENETIC TOXICOLOGY:
      Tricresyl phosphate was not mutagenic in Salmonella typhimurium strains TA98,
      TA100, TA1535, or TA1537, nor did it induce chromosomal aberrations or sister
      chromatid exchanges in cultured Chinese hamster ovary cells. These in vitro
      assays were all conducted with and without exogenous metabolic activation (S9).
      CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no
      evidence of carcinogenic activity of tricresyl phosphate in male or female F344/N
      rats that received 75, 150, or 300 ppm. There was no evidence of carcinogenic
      activity of tricresyl phosphate in male or female B6C3F1 mice that received 60,
      125, or 250 ppm. Nonneoplastic lesions associated with exposure to tricresyl
      phosphate included cytoplasmic vacuolization of the adrenal cortex and ovarian
      interstitial cell hyperplasia in female rats, increased incidences of clear cell
      focus, fatty change, and ceroid pigmentation of the liver in male mice, and
      increased severity of ceroid pigmentation of the adrenal cortex in female mice.

PMID- 12616299
TI  - NTP Toxicology and Carcinogenesis Studies of Barium Chloride Dihydrate (CAS No.
      10326-27-9) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).
AB  - Barium chloride dihydrate, a white crystalline granule or powder, is used in
      pigments, aluminum refining, leather tanning and coloring, the manufacture of
      magnesium metal, ceramics, glass, and paper products, as a pesticide, and in
      medicine as a cardiac stimulant. Toxicology and carcinogenicity studies were
      conducted by administering barium chloride dihydrate (99% pure) in drinking water
      to F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic
      toxicology studies were conducted in Salmonella typhimurium, cultured Chinese
      hamster ovary cells, and mouse lymphoma cells. 15-DAY STUDY IN RATS: Groups of
      five males and five females received barium chloride dihydrate in the drinking
      water at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm for 15 days,
      corresponding to average daily doses of 10, 15, 35, 60, or 110 mg barium/kg body
      weight to males and females. No chemical-related deaths, differences in final
      mean body weights, or clinical findings of toxicity were observed. Water
      consumption by male and female rats exposed to 2,000 ppm was slightly less (S16%)
      than controls during week 2. There were no significant differences in absolute or
      relative organ weights between exposed and control rats. No biologically
      significant differences in hematology, clinical chemistry, or neurobehavioral
      parameters occurred in rats. 15-DAY STUDY IN MICE: Groups of five males and five
      females received barium chloride dihydrate in the drinking water at
      concentrations of 0, 40, 80,173, 346, or 692 ppm for 15 days, corresponding to
      average daily doses of 5,10, 20, 40, or 70 mg barium/kg body weight to males and
      5, 10, 15, 40, or 85 mg barium/kg body weight to females. No chemical-related
      deaths, differences in mean body weights or in water consumption, or clinical
      findings of toxicity were observed in mice. The relative liver weight of males
      receiving 692 ppm was significantly greater than that of the controls. The
      absolute and relative liver weights of females that received 692 ppm were
      significantly greater than those of the controls. No histopathologic evidence of
      toxicity was observed in mice. 13-WEEK STUDY IN RATS: Groups of 10 males and 10
      females received barium chloride dihydrate in the drinking water at
      concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for 13 weeks,
      corresponding to average daily doses of 10, 30, 65, 110, or 200 mg barium/kg body
      weight to males and 10, 35, 65, 115, or 180 mg barium/kg body weight to females.
      Three males and one female in the 4,000 ppm groups died during the last week of
      the study. The final mean body weights of male and female rats receiving 4,000
      ppm were significantly lower (13% and 8%) than those of the controls. Water
      consumption by male and female rats in the 4,000 ppm groups was approximately 30%
      lower than that by the controls. No clearly chemical-related clinical findings of
      toxicity or neurobehavioral or cardiovascular effects were noted. Serum
      phosphorus levels in 2,000 and 4,000 ppm male and female rats were significantly
      higher than those in controls, but there were no biologically significant
      differences in hematology parameters or in serum sodium, potassium, or calcium
      levels. Renal tubule dilatation in the outer stripe of the outer medulla and
      cortex occurred in male and female rats receiving 4,000 ppm. 13-WEEK STUDY IN
      MICE: Groups of 10 males and 10 females received barium chloride dihydrate in the
      drinking water at concentrations of 0, 125, 500, 1,000, 2,000, or 4,000 ppm for
      13 weeks, corresponding to average daily doses of 15, 55, 100, 205, or 450 mg
      barium/kg body weight to males and 15, 60, 110, 200, or 495 mg barium/kg body
      weight to females. Six males and seven females that received 4,000 ppm and one
      male that received 125 ppm died during the study. Final mean body weights of male
      and female mice receiving 4,000 ppm were significantly lower (>30%) than those of
      controls. Water consumption by male mice in the 4,000 ppm group was 18% lower
      than that by the controls; water consumption by other exposed groups of male and
      female mice was similar to thatd groups of male and female mice was similar to
      that by the controls. Clinical findings of toxicity were limited to debilitation
      in the surviving male and female mice receiving 4,000 ppm. The absolute and/or
      relative liver weights of mice receiving 1,000, 2,000, and 4,000 ppm were
      significantly lower than those of the controls. Multifocal to diffuse nephropathy
      characterized by tubule dilatation, regeneration, and atrophy occurred in 4,000
      ppm male and female mice. 2-YEAR STUDY IN RATS: Groups of 60 males and 60 females
      received barium chloride dihydrate in the drinking water at concentrations of 0,
      500, 1,250, or 2,500 ppm for 104 (males) or 105 weeks (females), corresponding to
      average daily doses of 15, 30, or 60 mg barium/kg body weight for males and 15,
      45, or 75 mg barium/kg body weight for females. The high dose of 2,500 ppm was
      selected based on decreased final mean body weights, mortality, decreased water
      consumption, and chemical-related kidney lesions observed in the 4,000 ppm groups
      in the 13-week study. Survival, Body Weights, Water Consumption, and Clinical
      Findings: Two-year survival of exposed male and female rats was similar to that
      of the controls. The final mean body weights of male and female rats that
      received 2,500 ppm were (5&percnt; and 11&percnt;) lower than those of controls.
      Beginning as early as week 5, water consumption by male and female rats receiving
      2,500 ppm was substantially lower than that by controls (male: 11&percnt; to
      30&percnt;; female: 19&percnt; to 33&percnt;). There were no chemical-related
      clinical findings. Hematology and Clinical Chemistry: There were no chemical
      related differences in hematology or clinical chemistry parameters in male or
      female rats. Special Studies: At the 15-month interim evaluation, the plasma
      barium concentrations (mg/ml) were significantly increased in males receiving
      1,250 and 2,500 ppm and in all exposed groups of females (male: 0 ppm, 0.98; 500
      ppm, 1.00; 1,250 ppm, 1.23; 2,500 ppm, 1.68; female: 0 ppm, 0.74; 500 ppm, 0.99;
      1,250 ppm, 0.97; 2,500 ppm, 1.43). Barium levels in bone in rats from the 2,500
      ppm groups were about 400 times greater than those in the controls. Pathology
      Findings: At the end of 2 years, there were no increased incidences of neoplasms
      or nonneoplastic lesions that could be attributed to barium chloride dihydrate.
      However, there were dose-related decreased incidences of adrenal medulla
      pheochromocytomas and mononuclear cell leukemia in male rats. 2-YEAR STUDY IN
      MICE: Groups of 60 males and 60 females received barium chloride dihydrate in the
      drinking water at concentrations of 0, 500, 1,250, or 2,500 ppm for 103 (males)
      or 104 weeks (females), corresponding to average daily doses of 30, 75, or 160 mg
      barium/kg body weight for males and 40, 90, or 200 mg barium/kg body weight for
      females. The high dose of 2,500 ppm was selected based on decreased final mean
      body weights, mortality, decreased water consumption, and chemical-related kidney
      lesions observed in the 4,000 ppm groups in the 13-week study. Survival, Body
      Weights, Water Consumption, and Clinical Findings: Two-year survival of male and
      female mice receiving 2,500 ppm was significantly lower than that of the controls
      due to renal toxicity. Final mean body weights of 2,500 ppm males and females
      were 9% and 12% lower than those of controls. Water consumption by male and
      female mice receiving barium chloride was similar to that by the controls. There
      were no chemical-related clinical findings. Hematology and Clinical Chemistry:
      There were no differences in hematology or clinical chemistry parameters measured
      at the 15-month interim evaluation. Special Studies: At the 15-month interim
      evaluation, plasma barium concentrations (mg/mL) were significantly increased in
      all exposed groups of mice (male: 0 ppm, 0.62; 500 ppm, 0.77; 1,250 ppm, 0.89;
      2,500 ppm, 1.49; female: 0 ppm, 0.52; 500 ppm, 0.74; 1,250 ppm, 1.01; 2,500 ppm,
      1.35). Pathology Findings: At the end of the 2-year study, there were increased
      incidences of nephropathy in male and female mice (male: 1/50, 0/50, 2/48, 19/50;
      female: 0/50, 2/53, 1/50, 37/54). There were no chemical-related increased
      incidences of neoplasms in male or female mice. The incidence of hepatocellular
      adenoma was significantly decreased in male mice receiving 2,500 ppm. GENETIC
      TOXICOLOGY: Barium chloride dihydrate was not mutagenic in Salmonella typhimurium
      strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic
      activation (S9). It was mutagenic in L5178Y mouse lymphoma cells in the presence
      of S9, but it did not induce sister chromatid exchanges or chromosomal
      aberrations in cultured Chinese hamster ovary cells, with or without S9.
      CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there
      was no evidence of carcinogenic activity of barium chloride dihydrate in male or
      female F344/N rats that received 500, 1,250, or 2,500 ppm. There was no evidence
      of carcinogenic activity of barium chloride dihydrate in male or female B6C3F1
      mice that received 500, 1,250, or 2,500 ppm. There were chemical-related
      increased incidences of nephropathy in male and female mice.

PMID- 12616300
TI  - NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in
      F344/N Rats and B6C3F1 Mice Feed Studies).
AB  - Benzyl acetate is used as a flavoring agent in foods, as a fragrance in soaps and
      perfumes, as a solvent for cellulose acetate and nitrate, and as a component of
      printing inks and varnish removers. The NTP previously studied the toxicology and
      carcinogenicity of this chemical in F344/N rats and B6C3F1 mice using the gavage
      route of administration and corn oil as a vehicle. Benzyl acetate increased the
      incidences of pancreatic acinar cell adenomas in male rats and the incidences of
      hepatocellular adenomas and forestomach neoplasms in male and female mice.
      Because of the confounding effect of corn oil on the incidences of pancreatic
      neoplasms and because of controversy over the use of the gavage route of
      administration, the NTP decided to restudy benzyl acetate using the dosed feed
      route of administration. In these repeat studies, male and female F344/N rats and
      B6C3F1 mice received benzyl acetate (at least 98% pure) in feed for 13 weeks and
      2 years. Genetic toxicology studies were conducted in Salmonella typhimurium
      nunnery, cultured Chinese hamster ovary cells, LS178Y mouse lymphoma cells,
      Drosophila melanogaster, and mouse bone marrow and peripheral blood cells. 13
      WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets
      containing 0, 3,130, 6,250,12,500, 25,000, or 50,000 ppm (0, 230, 460, 900,1,750,
      or 3,900 mg/kg body weight for males and 0, 240, 480, 930,1,870, or 4,500 mg/kg
      for females) benzyl acetate for 13 weeks. Nine male and nine female rats
      receiving 50,000 ppm benzyl acetate died or were killed moribund between weeks 2
      and 8 of the study. The mean body weight gain and the final mean body weight of
      25,000 ppm males were significantly lower (P</=0.01) than those of the control
      group. Feed consumption by exposed rats, except the 25,000 and S0,000 ppm males
      and 50,000 ppm females, was similar to that by the controls. The reduced feed
      consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been
      due to toxicity or decreased palatability. Tremors and ataxia occurred only in
      the 50,000 ppm rats. These findings were first observed on day 15 in nine males
      and six females and continued until the end of the study. Cholesterol levels in
      12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were
      lower than those in the controls. Chemical-related lesions occurred in the brain,
      kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain
      involving the cerebellum and/or hippocampus, degeneration and regeneration of the
      renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of
      the tongue and skeletal muscles occurred in most male and female 50,000 ppm rats.
      This effect was observed in the 1,000 mg/kg group in the previous gavage study
      (NTP, 1986). 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice
      were fed diets containing 0, 3, 130, 6,250, 12,500, 25,000, or 50,000 ppm (0,
      425, 1,000, 2,000, 3,700, or 7,900 mg/kg body weight for males and 0, 650, 1,280,
      2,980, 4,300, or 9,400 mg/kg for females) benzyl acetate. One 50,000 ppm male
      mouse died and one 50,000 ppm female mouse was killed moribund before the end of
      the study. Mean body weight gains and final mean body weights of all exposed male
      and female mice were significantly lower than those of the controls and the mean
      body weight gains decreased with increased exposure level. Feed consumption by
      3,130 ppm males and all exposed females was lower than that by the controls.
      Tremors occurred only in females and were first observed on day 16 in three
      females receiving 50,000 ppm, day 94 in one female receiving 25,000 ppm, and day
      93 in one female receiving 12,500 ppm. The tremors continued until the end of the
      study. Necrosis of the brain involving the hippocampus occurred in four 50,000
      ppm mice, one male and three females. Hepatocellular necrosis also occurred in
      the male with brain lesions. On reexamination of the previous 13-week gavage
      study (NTP, 1986), a similar lesion was seen in the brain of one 1,000 mg/kg
      female mouse; none were seen in 1,000 mg/kg male mi male mice. The lesion was
      less severe than that described in the present dosed feed study. The highest dose
      used in the gavage study was 1,000 mg/kg compared to an estimated high dose of
      7,200 mg/kg for the feed study. 2-YEAR STUDY IN RATS: The doses selected for the
      2-year feed study of benzyl acetate in F344/N rats were based on lower survival,
      mean body weights, and feed consumption, and on increased incidences of
      histopathologic brain lesions in 50,000 ppm male and female rats in the 13-week
      study. Groups of 60 male and 60 female F344/N rats were fed diets containing 0,
      3,000, 6,000, or 12,000 ppm benzyl acetate for 2 years. Survival, Body Weights,
      Feed and Compound Consumption, and Clinical Pathology: Survival of exposed rats
      was similar to that of the controls. The mean body weights of the 12,000 ppm
      males and exposed females were approximately 5&percnt; lower than those of the
      controls throughout most of the study. The feed consumption by 12,000 ppm males
      was slightly lower than that by the controls. Dietary levels of 3,000, 6,000, and
      12,000 ppm benzyl acetate were estimated to result in average daily consumption
      levels of 130, 260, and 510 mg/kg body weight (males) and 145, 290, and 575 mg/kg
      (females). No biologically significant changes in hematology or clinical
      chemistry parameters were found that could be attributed to benzyl acetate
      administration. Pathology Findings: No compound-related increased incidences of
      neoplasms or nonneoplastic lesions occurred in male or female F344/N rats
      receiving benzyl acetate for as long as 2 years. 2-YEAR STUDY IN MICE: The doses
      selected for the 2-year feed study of benzyl acetate in B6C3F1 mice were based
      primarily on lower body weight gains and lower final mean body weights of exposed
      mice in the 13-week study. Groups of 60 male and 60 female B6C3F1 mice were fed
      diets containing 0, 330, 1,000, or 3,000 ppm benzyl acetate for 2 years.
      Survival, Body Weights, Feed and Compound Consumption, and Clinical Pathology:
      Survival of all exposed mice, except the 3,000 ppm females, was similar to that
      of the control groups. Survival of 3,000 ppm females was significantly higher
      than that of the control group. Throughout the 2-year study, the mean body
      weights of 1,000 and 3,000 ppm males and females were 2&percnt; to 14&percnt;
      lower than those of the control groups. Dietary levels of 330, 1,000, and 3,000
      ppm benzyl acetate were estimated to result in average daily consumption levels
      of 35, 110, and 345 mg/kg (males) and 40, 130, and 375 mg/kg (females). No
      biologically significant changes in hematology or clinical chemistry parameters
      were observed in mice receiving 330,1,000, or 3,000 ppm benzyl acetate. Pathology
      Findings: No increase in neoplasm incidence in mice could be attributed to benzyl
      acetate administration in feed. This contrasts with the previous finding that
      administration of benzyl acetate in corn oil by gavage once daily 5 days a week
      for as long as 2 years was carcinogenic to mice, causing increased incidences of
      hepatocellular neoplasms and forestomach neoplasms. The contrast in results
      between the two studies may be due to differences in the dose levels used
      (highest dose: gavage, 1,000 mg/kg a day; feed, 360 mg/kg a day). Dose-related
      increased incidences or severities of nonneoplastic nasal lesions occurred in the
      most posterior portions of the nasal cavity in all exposed groups. The lesions
      occurred in the majority of the exposed mice and consisted of atrophy and
      degeneration, primarily of the olfactory epithelium, cystic hyperplasia of the
      nasal submucosal glands, pigmentation of the mucosal epithelium, and exudate
      accumulation. GENETIC TOXICOLOGY: Benzyl acetate was not mutagenic in Salmonella
      typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous
      metabolic activation (S9). However, a positive response was observed for benzyl
      acetate, with and without S9, in the mouse lymphoma assay for induction of
      trifluorothymidine resistance in L5178Y cells. No significant increases in the
      frequencies of sister chromatid exchanges or chromosomal aberrations occurred in
      cultured Chinese hamster ovary cells treated with benzyl acetate in vitro, with
      or without S9, and no increases in either sister chromatid exchanges or
      chromosomal aberrations occurred in bone marrow cells of male mice treated in
      vivo by intraperitoneal injection. No increase in sex-linked recessive lethal
      germ cell mutations occurred in male Drosophila melanogaster administered benzyl
      acetate in feed or by injection. Tests of benzyl acetate for induction of
      micronucleated erythrocytes in bone marrow and peripheral blood of mice were also
      negative. CONCLUSIONS: Under the conditions of these 2-year feed studies, there
      was no evidence of carcinogenic activity of benzyl acetate in male or female
      F344/N rats receiving 3,000, 6,000, or 12,000 ppm; however, rats may have
      tolerated higher doses. There was no evidence of carcinogenic activity of benzyl
      acetate in male or female B6C3F1 mice receiving 330, 1,000, or 3,000 ppm. Nasal
      lesions associated with benzyl acetate exposure in male and female mice included
      nasal mucosa atrophy and degeneration (primarily of the olfactory epithelium),
      cystic hyperplasia of the nasal submucosal gland, and luminal exudate and
      pigmentation of the nasal mucosal epithelium. In previous 2-year gavage studies
      (TR-250), benzyl acetate increased the incidence of acinar cell adenomas of the
      exocrine pancreas in male F344/N rats; the gavage vehicle may have been a
      contributing factor. There was no evidence of carcinogenic activity in female
      F344/N rats receiving 250 or 500 mg/kg a day. There was some evidence of
      carcinogenic activity in male and female B6C3F1 mice, indicated by the increased
      incidences of hepatocellular adenomas and squamous cell neoplasms of the
      forestomach. Synonyms: acetic acid benzyl ester, acetic acid phenyl methyl ester,
      (acetoxymethyl)benzene, acetoxytoluene, benzyl ethanoate, phenylmethyl acetate

PMID- 12616301
TI  - NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 218 (CAS No. 28407
      37-6) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - C.I. Direct Blue 218 is a copper chelated dye used for cellulose, acetate, nylon,
      silk, wool, tissue, papers, and textile goods with a urea-formaldehyde finish.
      C.I. Direct Blue 218 is one of five chemicals/dyes that are part of the National
      Toxicology Program's Benzidine Dye Initiative, established to determine the
      toxicity and carcinogenicity of representative benzidine congeners, congener
      derived dyes, and benzidine-derived dyes. Industrial grade C.I. Direct Blue 218
      was selected for study because of its widespread use. Because of the high salt
      content, the dye was desalted prior to use. Toxicology and carcinogenesis studies
      were conducted by administering C.I. Direct Blue 218 in feed to groups of male
      and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium, cultured
      Chinese hamster ovary cells, and Drosophila melanogaster. 14-DAY STUDY IN RATS:
      Groups of five male and five female F344/N rats were fed diets containing 0,
      1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All rats
      survived until the end of the study. Rats receiving 30,000 ppm lost weight, and
      the mean body weight gain of males receiving 15,000 ppm was significantly lower
      than that of the controls. Feed consumption by rats receiving 30,000 ppm was
      lower than that by the controls. Decreased organ weights at the 30,000 ppm level
      were related to the decreased body weights at this exposure level. 14-DAY STUDY
      IN MICE: Groups of five male and five female mice were fed diets containing 0,
      1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All mice
      survived until the end of the study. The final mean body weight of males
      receiving 30,000 ppm was 25% lower than that of controls and that of 30,000 ppm
      females was 20% lower than that of controls. Feed consumption by exposed and
      control groups was similar except for the 15,000 and 30,000 ppm groups. Feed
      spillage, due to reduced palatability, precluded the accurate determination of
      feed consumption by these two groups. Male and female mice receiving 30,000 ppm
      appeared hyperactive and emaciated during the last week of the study. Decreased
      organ weights were noted at 30,000 ppm and were attributed to the decreased mean
      body weights at this exposure level. 13-WEEK STUDY IN RATS: Groups of 10 male and
      10 female rats were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I.
      Direct Blue 218. All male and female rats survived until the end of the study.
      Rats exposed to 3,000,10,000, or 20,000 ppm C.I. Direct Blue 218 received
      approximate daily doses of 200, 600 or 1,300 mg dye/kg body weight (males) and
      200, 800, or 1,400 mg/kg (females). The final mean body weight of male rats
      receiving 20,000 ppm was 24% lower than that of the controls and the final mean
      body weight of female rats receiving 20,000 ppm was 15% lower than that of the
      controls. Feed consumption by exposed and control groups was similar except in
      the 20,000 ppm groups where feed spillage was noted. Absolute and relative kidney
      weights of rats receiving 10,000 or 20,000 ppm were significantly greater than
      those of controls. Significantly decreased organ weights were noted, particularly
      in the 20,000 ppm groups, and were attributed to the lower mean body weights at
      this exposure level. The hematocrit, hemoglobin, mean erythrocyte volume, and
      mean erythrocyte hemoglobin values in male and female rats receiving 10,000 and
      20,000 ppm were significantly lower than those of controls. Serum levels of
      alanine aminotransferase and sorbitol dehydrogenase in male and female rats
      receiving 20,000 ppm were significantly higher than those of controls, which is
      consistent with hepatocellular injury. Male rats receiving 10,000 ppm and male
      and female rats receiving 20,000 ppm had hepatic lesions consisting of
      intracytoplasmic pigment in periportal Kupffer cells, minimal to mild individual
      hepatocyte necrosis, increased numbers of binucleated and multinucleated
      hepatocytes, and minimal bile duct hyperplasia. Male and female rats receiving
      20,000 ppm had ys receiving 20,000 ppm had yellow-green pigment within the
      cytoplasm of proximal convoluted tubules of the kidney. Microconcretions of
      mineral were observed along the corticomedullary junction of the kidney in most
      female rats, but the numbers of microconcretions in kidney sections were
      increased in females that received 20,000 ppm. 13-WEEK STUDY IN MICE: Groups of
      10 male and 10 female B6C3F1 mice were fed diets containing 0, 3,000, 10,000, or
      20,000 ppm C.I. Direct Blue 218. There were no deaths attributed to C.I. Direct
      Blue 218. Mice exposed to 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218
      received approximate daily doses of 400, 1,500, or 3,600 mg dye/kg body weight
      (males) and 400, 1,800, or 4,000 mg/kg (females). The final mean body weight of
      males that received 20,000 ppm was 24&percnt; lower than that of the controls,
      and the final mean body weight of females that received 20,000 ppm was 14&percnt;
      lower than that of controls. Feed consumption by exposed mice was similar to that
      by controls except in the 20,000 ppm groups where feed spillage was noted.
      Significant differences in organ weights were noted at 20,000 ppm which were
      attributed primarily to the lower mean body weights in these exposure groups. The
      hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte volume, and
      mean erythrocyte hemoglobin values were significantly lower in males and females
      receiving 10,000 and 20,000 ppm. Serum levels of alanine aminotransferase and
      sorbitol dehydrogenase in male and female mice receiving 10,000 and 20,000 ppm
      were significantly higher than those of controls, indicating hepatic injury. Male
      and female mice receiving 20,000 ppm had hepatic lesions consisting of
      centrilobular hepatocyte hypertrophy and karyomegaly, multifocal individual
      hepatocyte necrosis, oval cell proliferation, and periportal Kupffer cells with
      intracytoplasmic pigment. Males and females receiving 20,000 ppm also had
      increased numbers of pigmented macrophages within the red pulp of the spleen. 2
      YEAR STUDY IN RATS: The doses selected for the 2-year study of C.I. Direct Blue
      218 were based on the lower final mean body weights and the occurrence of hepatic
      lesions in the 20,000 ppm groups in the 13-week study. Groups of 60 male and 60
      female rats were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct
      Blue 218 for 103 weeks. Nine or 10 rats from each group were evaluated after 15
      months. Survival, Body Weights, Feed and Compound Consumption, and Clinical
      Findings: Survival of female rats receiving 10,000 ppm was slightly, but not
      significantly, lower than that of the controls. Mean body weights of male and
      female rats in the 10,000 ppm groups were approximately 5&percnt; to 14&percnt;
      lower than those of the controls after week 15, and the final mean body weights
      of male and female rats at this level were 11&percnt; and 9&percnt; lower than
      those of the controls, respectively. Feed consumption by exposed male and female
      rats was similar to that by the controls and was estimated to deliver daily doses
      of 40, 120, and 440 mg dye/kg body weight to males and 50, 140, and 470 mg/kg to
      females. No chemical-related clinical signs of toxicity were noted. Hematology
      and Clinical Chemistry: The hematocrit, hemoglobin, mean erythrocyte volume, and
      mean erythrocyte hemoglobin values in 10,000 ppm female rats were significantly
      lower than those of controls, while in males only the mean erythrocyte hemoglobin
      value was significantly lower. Serum levels of alanine aminotransferase and
      sorbitol dehydrogenase in male and female rats receiving 10,000 ppm were
      significantly higher than those of the controls at the 15-month interim
      evaluation. Pathology Findings: Squamous cell papillomas of the oral mucosa
      (pharynx) occurred in five males receiving 10,000 ppm but not in the lower
      exposure groups or in controls. A squamous cell carcinoma occurred in one 10,000
      ppm male and a benign basosquamous tumor was observed in another. The incidence
      of oral mucosal neoplasms in the 10,000 ppm males was significantly greater than
      that in controls and exceeded the range observed in untreated historical controls
      (lO/l,253, 0.8&percnt;; range 0&percnt;-4&percnt;). These neoplasms were
      considered chemical related. Administration of C.I. Direct Blue 218 to rats
      produced significantly increased incidences of forestomach basal cell hyperplasia
      in males receiving 3,000 or 10,000 ppm (0 ppm, 0/50; 1,000 ppm, 2/50; 3,000 ppm,
      10/50;10,000 ppm, 19/50) and in females receiving 10,000 ppm (1/50, 1/49, 5/50,
      11/49). Further, there were marginal increased incidences of focal squamous
      hyperplasia in the 3,000 and 10,000 ppm males (1/50,1/50, 6/50, 4/50). Squamous
      cell papillomas of the forestomach were seen in two 3,000 ppm males and in one
      10,000 ppm male; no papillomas were observed in the controls. A squamous cell
      carcinoma was also seen in one 3,000 ppm male. Because of the uncommon occurrence
      of forestomach neoplasms in untreated control male rats (4/1,253, 0.3&percnt;;
      range 0&percnt;-2&percnt;) and the slight increase in the incidence of focal
      hyperplasia, these neoplasms may have been chemical related. The incidence of
      uterine endometrial stromal polyps in each exposed group of female rats was
      significantly greater than that of the controls (1/50,12/50,10/50, 10/50).
      Because the incidences in the exposed groups did not increase in a dose-related
      manner and the incidence in the controls was unusually low (historical incidence:
      205/1,251,16.4&percnt;; range 2&percnt;-30&percnt;), the higher incidence of
      stromal polyps in the exposed groups was not considered chemical related. 2-YEAR
      STUDY IN MICE: The dose selection for the 2-year study was based on the lower
      final mean body weights and the liver lesions observed at the 20,000 ppm level in
      the 13-week study. Groups of 60 male and 60 female mice were fed diets containing
      0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10
      mice from each exposure group were evaluated after 15 months. Survival, Body
      Weights, Feed and Compound Consumption, and Clinical Findings: Survival of
      exposed male and female mice was similar to that of the controls. Mean body
      weights of male and female mice receiving 10,000 ppm were 10&percnt; to
      29&percnt; lower than those of the controls during most of the study, and the
      final mean body weights in these groups were 19&percnt; lower than that of the
      controls for males and 27&percnt; lower than that of the controls for females.
      Feed consumption by exposed mice was similar to that by controls and the diets
      were estimated to deliver daily doses of approximately 120, 360, and 1,520 mg of
      dye/kg body weight to males and 140, 470, and 2,050 mg/kg to females. No chemical
      related clinical signs of toxicity were noted. Hematology and Clinical Chemistry:
      Hematocrit, hemoglobin, and mean erythrocyte volume values in males and females
      receiving 10,000 ppm were significantly lower than those of the controls. Serum
      levels of alanine aminotransferase and/or sorbitol dehydrogenase values in male
      and female mice that received 10,000 ppm were significantly higher than those of
      controls, which is consistent with hepatocellular damage. Pathology Findings: The
      administration of C.I. Direct Blue 218 to mice produced significantly increased
      incidences of hepatocellular adenoma (0 ppm, 16/50; 1,000 ppm, 19/50; 3,000 ppm,
      17/50; 10,000 ppm, 40/50) and hepatocellular carcinoma (7/50, 3/50, 8/50,17/50)
      in males receiving 10,000 ppm, and a significantly increased incidence of
      hepatocellular adenoma in females receiving 3,000 or 10,000 ppm (7/49, 12/50,
      17/49, 41/49). In females that received 10,000 ppm, the incidence of
      hepatocellular carcinoma was marginally increased. Consistent with these
      findings, the incidence of hepatocellular foci of cytologic alteration, a
      preneoplastic lesion, was also increased in males and females in the 10,000 ppm
      groups. The increased incidences of hepatocellular foci, adenomas, and carcinomas
      were considered chemical related. Uncommon renal tubule neoplasms also occurred
      at low incidences in male mice receiving C.I. Direct Blue 218, but not in
      controls. Renal tubule adenomas were seen in two males receiving 1,000 ppm, one
      male receiving 3,000 ppm, and one male receiving 10,000 ppm. A renal tubule
      carcinoma was also seen in one male that received 1,000 ppm. Because renal tubule
      neoplasms are uncommon in male mice (4/1,366, 0.3&percnt;; range 0&percnt;
      2&percnt;), these neoplasms may have been chemical related. Carcinomas of the
      small intestine occurred in four male mice receiving 10,000 ppm. One was observed
      at the 15-month interim evaluation, while the other three were observed in mice
      at the end of the study. One control male mouse also had a carcinoma of the small
      intestine. Because of the uncommon occurrence of small intestine neoplasms in
      untreated male mice (12/1,374, 0.9&percnt;; range 0&percnt;-4&percnt;), the
      slightly higher incidence of these neoplasms in males receiving 10,000 ppm may
      have been chemical related. Carcinomas of the small intestine also occurred in
      one 3,000 ppm and one 10,000 ppm female, but the low incidences precluded drawing
      an association with chemical administration. GENETIC TOXICOLOGY: C.I Direct Blue
      218 was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or
      TA1537 tested with and without exogenous metabolic activation (S9). It was also
      tested in a modified Salmonella test protocol which employed reductive metabolism
      supplied by flavin mononucleotide or rat cecal bacteria, followed by oxidative
      metabolism; results of this test using strain TA1538 were also negative. C.I.
      Direct Blue 218 induced a small but significant increase in sister chromatid
      exchanges in Chinese hamster ovary cells at the highest dose tested without S9.
      No increase in chromosomal aberrations were observed in Chinese hamster ovary
      cells with or without S9. C.I. Direct Blue 218 did not induce sex-linked
      recessive lethal mutations in germ cells of male Drosophila melanogaster.
      CONCLUSIONS: Under the conditions of these 2-year feed studies, there was some
      evidence of carcinogenic activity of C.I. Direct Blue 218 in male F344/N rats
      based on the occurrence of pharyngeal neoplasms. Squamous cell neoplasms of the
      forestomach may have been chemical related. There was no evidence of carcinogenic
      activity of C.I Direct Blue 218 in female F344/N rats given 1,000, 3,000, or
      10,000 ppm. There was clear evidence of carcinogenic activity of C.I. Direct Blue
      218 in male and female B6C3F1 mice based on increased incidences of
      hepatocellular adenomas and carcinomas. The occurrence of a few neoplasms of the
      kidney and small intestine in male mice may have been related to C.I. Direct Blue
      218 treatment. The administration of C.I. Direct Blue 218 produced an increased
      incidence of forestomach basal cell hyperplasia in rats and hepatocellular foci
      of cytologic alteration in mice. Synonyms: cuprate(4-), [mu-[(3,3'-dihydroxy[1,1'
      biphenyl]-4,4'-diyl)bis[5-amino-4-hydroxy- 2,7-naphthalnedisulfonato]](8-)]]di-,
      tetrasodium; copper, [tetrahydrogen-3,3'-[(3,3'-dihydroxy-4,4'
      biphenylylene)bis(azo)]bis [5-amino-4-hdroxy-2,7-naphthalenedisulfonato](4-)]di-,
      tetrasodium salt; 1-naphthol-3,6-disulfonic acid, 2,2'-(3,3'-dihydroxy-4,4'
      biphenylylenebisazo)bis [8-amino-, dicopper deriv., tetrasodium salt

PMID- 12616302
TI  - NTP Toxicology and Carcinogenesis Studies of Diethylphthalate (CAS No. 84-66-2)
      in F344/N Rats and B6C3F1 Mice (Dermal Studies) with Dermal Initiation/ Promotion
      Study of Diethylphthalate and Dimethylphthalate (CAS No. 131-11-3) in Male Swiss
      (CD-1(R)) Mice.
AB  - Diethylphthalate and dimethylphthalate are used as phthalate plasticizers, in an
      extensive array of products. The chronic dermal toxicity of diethylphthalate was
      evaluated in male and female F344/N rats and B6C3F1 mice in 2-year studies. In a
      series of special studies, the tumor initiation or promotion potential of
      diethylphthalate or dimethylphthalate was evaluated in male Swiss (CD-1(R)) mice
      by an initiation/promotion model of skin carcinogenesis. The genetic toxicity of
      diethylphthalate and dimethylphthalate in Salmonella typhimurium and cultured
      Chinese hamster ovary cells was also evaluated. 4-WEEK STUDY IN F344/N RATS:
      Groups of 10 male and 10 female rats were dermally administered diethylphthalate
      at volumes of 0, 37.5, 75, 150, or 300 &mgr;L (0, 46, 92, 184, or 369 &mgr;g)
      applied neat, 5 days per week for 4 weeks. All male and female rats survived to
      the end of the study. No evidence of dermatotoxicity was observed, with no
      adverse clinical signs observed and no effects on weight gain or feed
      consumption. Relative liver weights of 300 &mgr;L males and females and 150
      &mgr;L females were greater than those of controls. Relative kidney weights of
      150 and 300 &mgr;L males and 150 &mgr;L females were greater than those of
      controls. No other adverse effects were observed in this study. 4-WEEK STUDY IN
      B6C3F1 MICE: Groups of 10 male and 10 female mice were dermally administered
      diethylphthalate at volumes of 0, 12.5, 25, 50, or 100 &mgr;L (0, 15, 31, 62, or
      123 &mgr;) applied neat, five days per week for 4 weeks. One control female died
      before the end of the study; all other mice survived. No evidence of
      dermatotoxicity or other adverse clinical signs were observed, and no clear
      adverse effects on weight gain or feed consumption were seen. Absolute and
      relative liver weights of 25 and 100 &mgr;L females were greater than those of
      the controls. Based on these 4-week study results, doses of 0, 35, and 100 &mgr;L
      diethylphthalate were recommended for the 2-year mouse studies. A chronic study
      in male and female B6C3F1 mice at 0, 35, and 100 &mgr;L (applied neat, once per
      day, 5 days per week) was started and subsequently stopped after 32 weeks when
      significant body weight reductions were noted in treated animals (males and
      females, 100 &mgr;L groups: 19% lower; males, 35 &mgr;L group: 12% lower;
      females, 35 &mgr;L group: 10% lower than controls). Based on these body weight
      reductions, doses of 0, 7.5, 15, and 30 &mgr;L in 100 &mgr;L acetone were
      recommended for the restart of the 2-year mouse study. 2-YEAR STUDY IN F344/N
      RATS: Based upon the results of the 4-week study, doses of 0, 100, or 300 &mgr;L
      diethylphthalate (0, 123, or 369 &mgr;) were chosen for the 2-year rat study.
      Groups of 60 male and 60 female rats received the doses applied neat 5 days per
      week for 103 weeks and up to 10 animals per group were evaluated after 15 months.
      Survival, Body Weights, and Clinical Findings: Survival of dosed rats during the
      first 15 months was similar to that of controls. However, 2-year survival was
      significantly reduced in all groups of male rats (survival probabilities, males:
      0 &mgr;L, 8%; 100 &mgr;L, 12%; and 300 &mgr;L, 12%). The mean body weights of 300
      &mgr;L males were slightly less than those of the controls throughout the study.
      No adverse clinical signs were observed, including no evidence of
      dermatotoxicity. Pathology Findings: No morphological evidence of dermal or
      systemic toxicity was observed in male or female rats. Skin neoplasms were not
      observed in female rats and were only rarely observed in male rats. A high
      incidence of anterior pituitary adenoma occurred in all groups of male and female
      rats. The incidence of anterior pituitary adenomas in the 0, 100, and 300 &mgr;L
      groups were: males, 39/44, 41/49, 41/49; females, 38/50, 33/49, 33/48. The
      incidence of this benign tumor in control males (84%) exceeded the historical
      control mean incidence [feed controls, (28.7%)] and range (12% to 60%). Anterior
      pituitary adenomas were considered a primary contributing factor in the increased
      mortality observed in all grtor in the increased mortality observed in all
      groups, regardless of treatment. A dose-related decreasing trend in the incidence
      of mammary gland fibroadenomas was observed in female rats (21/50, 12/48, 7/50).
      The incidence of mononuclear cell leukemia in male rats in this study was lower
      than the historical incidence and may be attributable to the shortened life span
      of male rats. Similarly, the incidence of interstitial cell tumors of the testes
      was markedly decreased in all groups of males (4/50, 3/50, 8/50), relative to
      historical control rates (90.1&percnt;; range 74&percnt;-98&percnt;). The
      incidence of fatty liver degeneration was notably lower in dosed rats than in
      controls (males: 26/50, 8/50, 4/51; females: 23/50, 11/50, 3/50). 2-YEAR STUDY IN
      B6C3F1 MICE: Groups of 60 male and 60 female mice received doses of 0, 7.5, 15,
      or 30 &mu;L diethylphthalate (0, 9, 18, or 37 &mu;) in 100 &mu;L acetone 5 days
      per week for 103 weeks with a 1 week recovery period, and up to 10 animals per
      group were evaluated after 15 months. Survival, Body Weights, and Clinical
      Findings: Two-year survival of dosed mice was similar to that of controls: 43/50,
      41/48, 46/50, and 43/50 (males), and 41/50, 38/51, 37/49, and 36/49 (females).
      Mean body weights of dosed male and female mice were similar to those of the
      controls throughout the study. No adverse clinical signs were observed in mice,
      including no gross evidence of dermatotoxicity. Feed consumption by male and
      female mice was similar to or up to 13% greater than that by controls. Pathology
      Findings: No morphological evidence of dermal toxicity was observed in male or
      female mice. No skin neoplasms were observed in dosed male mice. In female mice
      receiving 30 &mu;L, one squamous cell carcinoma and one basal cell carcinoma were
      seen at the site of application. An increased incidence of liver neoplasms was
      observed in dosed male and female mice. The incidence of hepatocellular adenoma
      or carcinoma (combined) in B6C3F1 mice in the 0, 7.5, 15, and 30 &mu;L groups
      were: (males) 9/50, 14/50, 14/50, and 18/50; (females) 7/50, 16/51, 19/50, and
      12/50. The incidence of adenoma or carcinoma (combined) was increased in 30 &mu;L
      male mice and the incidences of adenoma and of adenoma or carcinoma (combined)
      were increased in 7.5 and 15 &mu;L females. A positive dose-related trend in the
      incidence of adenoma or carcinoma (combined) was also observed in male mice. The
      incidence of basophilic hepatic foci was increased in 15 &mu;L male mice (0/50,
      1/50, 9/50, 3/50). The increased incidence of liver neoplasms in this study was
      considered equivocal because the incidence of hepatocellular neoplasms in control
      and dosed males was within the historical range and because there was no clear
      dose-response relationship in females. No other treatment-related findings were
      observed in this study. 1-YEAR INITIATION/PROMOTION STUDY IN MALE SWISS (CD
      1&reg;) MICE: Groups of 50 male mice were dosed dermally with diethylphthalate or
      dimethylphthalate to study their effect as initiators and promoters.
      Diethylphthalate and dimethylphthalate were tested as initiators with and without
      the known skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diethyl
      phthalate and dimethylphthalate were tested as promoters with and without the
      known skin tumor initiator 7,12-dimethylbenzanthrancene (DMBA). Comparative
      control groups used during the study of diethylphthalate and dimethylphthalate
      included: vehicle control (acetone/acetone); initiation/promotion control
      (DMBA/TPA); initiator control (DMBA/acetone); and promoter control (acetone/TPA).
      Based on the incidence of skin neoplasms diagnosed histologically and the
      multiplicity of skin neoplasms, there was no suggestion that either
      diethylphthalate or dimethylphthalate was able to initiate skin carcinogenesis
      when chronically promoted by TPA. Further, there was no evidence that either
      diethylphthalate or dimethylphthalate was able to promote skin carcinogenesis in
      skin previously initiated with DMBA. High incidences of both squamous cell
      papillomas and squamous cell carcinomas occurred among the initiation/promotion
      control animals initiated with DMBA and promoted with TPA. All TPA-dosed groups
      had significantly greater incidences of dermal acanthosis, ulceration, exudation,
      and hyperkeratosis than controls. GENETIC TOXICOLOGY: Neither diethylphthalate
      (10-10,000 &mu;/plate) nor dimethylphthalate (33-6,666 &mu;/plate) induced gene
      mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with
      or without rat and hamster liver S9. In cultured Chinese hamster ovary cells,
      both diethylphthalate and dimethylphthalate induced sister chromatid exchanges in
      the presence of S9. Neither induced sister chromatid exchanges in the absence of
      S9. Neither chemical induced chromosomal aberrations, with or without S9, in
      cultured Chinese hamster ovary cells. CONCLUSIONS: Under the conditions of these
      2-year dermal studies, there was no evidence of carcinogenic activity of
      diethylphthalate in male or female F344/N rats receiving 100 or 300 &mu;L. The
      sensitivity of the male rat study was reduced due to low survival in all groups.
      There was equivocal evidence of carcinogenic activity of diethylphthalate in male
      and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms,
      primarily adenomas. In an initiation/promotion model of skin carcinogenesis,
      there was no evidence of initiating activity of diethylphthalate or
      dimethylphthalate in male Swiss (CD-1&reg;) mice. Further, there was no evidence
      of promotion activity of diethylphthalate or dimethylphthalate in male Swiss (CD
      1&reg;) mice. The promoting activity of TPA following DMBA initiation was
      confirmed in these studies. Minor dermal acanthosis was observed following dermal
      application of diethylphthalate in male and female F344/N rats dosed for 2 years
      and in male Swiss (CD-1&reg;) mice dosed for 1 year. Synonyms: Diethylphthalate
      (CAS No. 84-66-2): 1,2-benzenedicarboxylic acid, diethyl ester; DEP; diethyl 1,2
      benzenedicarboxylate; diethyl o-phthalate; diethyl phthalate; ethyl phthalate; o
      benzenedicarboxylic acid diethyl ester; phthalic acid, diethyl ester; RCRA U088
      Dimethylphthalate (CAS No. 131-11-3): 1,2-benzenedicarboxylic acid, dimethyl
      ester; dimethyl 1,2-benzenedicarboxylate; dimethyl benzene-o-dicarboxylate;
      dimethyl benzeneorthodicarboxylate; dimethyl o-phthalate; dimethyl phthalate;
      DMP; FIFRA 028002; methyl phthalate; go-dimethyl phthalate; phthalic acid,
      dimethyl ester; phthalic acid methyl ester; RCRA U102

PMID- 12616303
TI  - NTP Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate
      (CAS No. 10034-96-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - Manganese is the 12th most abundant element in the earth's crust. The base metal
      does not occur naturally, but is a component of more than 100 minerals, including
      sulfides, oxides, carbonates, silicates, phosphates, and borates. In addition to
      occurring in foods and drinking water, manganese occurs in the atmosphere from
      dust, volcanic activity, forest fires, and industrial emissions. Manganese (II)
      sulfate monohydrate was chosen for study because of its stability, solubility,
      and availability. Toxicology and carcinogenesis studies were conducted by
      administering manganese (II) sulfate monohydrate (97% pure) in feed to groups of
      male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years.
      Genetic toxicology studies were conducted in Salmonella typhimurium, germ cells
      of Drosophila melanogaster, and cultured Chinese hamster ovary cells. 14-DAY
      STUDY IN RATS: Groups of five male and five female rats received diets containing
      0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate
      monohydrate. All rats survived to the end of the study. Male rats exposed to
      50,000 ppm had a mean body weight gain 57% lower and a final mean body weight 13%
      lower than those of the controls. The mean body weight gain of 50,000 ppm females
      was 20% lower and the final mean body weight was 7% lower than those of the
      controls. During the second week, 50,000 ppm males and females exhibited
      diarrhea. 14-DAY STUDY IN MICE: Groups of five male and five female mice received
      diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II)
      sulfate monohydrate. One female mouse in the 25,000 ppm group died on day 1 of
      unknown causes; all other mice survived to the end of the study. Differences in
      body weights between exposed and control mice could not be attributed to chemical
      administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats
      received diets containing 0, 1,600, 3,130, 6,250, 12,500, or 25,000 ppm manganese
      (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate
      monohydrate ranged from 110 to 1,700 mg/kg body weight in males and 115 to 2,000
      mg/kg in females. All rats survived to the end of the study. Mean body weight
      gains were marginally lower than that of controls in males exposed to 3,130 ppm
      or more; mean body weight gains were significantly lower than that of the
      controls in females exposed to 6,250,12,500, or 25,000 ppm. At the end of the
      study, absolute and relative liver weights of all exposed male rats and of 25,000
      ppm female rats were significantly lower than those of controls. The total
      leukocyte count in males was similar between exposed and control rats; however,
      neutrophil counts of all exposed groups were greater than those of the controls,
      whereas lymphocyte counts of the 6,250, 12,500, and 25,000 ppm groups were
      significantly lower than those of the controls. Total leukocyte counts in
      6,250,12,500, and 25,000 ppm females were significantly decreased because of a
      decrease in lymphocytes. Male rats also demonstrated marginal but significant
      increases in percent hematocrit and erythrocyte count in the 6,250,12,500, and
      25,000 ppm groups. No clinical or histopathologic findings in rats were chemical
      related. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received
      diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II)
      sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate
      ranged from 330 to 7,400 mg/kg body weight in males and 390 to 6,900 mg/kg body
      weight in females. No deaths were chemical related. The mean body weight gains of
      exposed male mice and of 50,000 ppm female mice were significantly lower than
      those of controls. The absolute and relative liver weights of 50,000 ppm males
      were significantly lower than those of controls. The percent hematocrit and
      hemoglobin concentration of males and females exposed to 50,000 ppm were lower
      than those of the controls, and the mean erythrocyte volumes were significantly
      lower than those of the controls. The total leukocyte counts of males in the
      25,eukocyte counts of males in the 25,000 and 50,000 ppm groups were
      significantly lower than that of the controls. No clinical findings were
      attributed to manganese (II) sulfate monohydrate ingestion. Epithelial
      hyperplasia and hyperkeratosis of the forestomach occurred in three 50,000 ppm
      males. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were fed diets
      containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate.
      Based on average daily feed consumption, these doses resulted in the daily
      ingestion of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg
      (females). Eight to 10 rats from each group were evaluated at 9 and 15 months.
      Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of
      15,000 ppm male rats in the 2-year study was significantly lower than that of the
      control group. The deaths of males in the control and exposure groups were
      attributed to a variety of spontaneous neoplastic and nonneoplastic lesions;
      however, the greater number of deaths in the 15,000 ppm group resulted from
      increased incidences of advanced renal disease related to ingestion of manganese
      (II) sulfate monohydrate. The decreased survival of the 15,000 ppm males did not
      occur until approximately week 93 of the study; before week 93, survival was
      similar in all groups. Survival of exposed females was similar to that of the
      controls. The mean body weight of 15,000 ppm male rats was within 5&percnt; of
      the control group until week 89, by week 104, the mean body weight of 15,000 ppm
      males was 10&percnt; lower than that of the control group. The mean body weights
      of 1,500 and 5,000 ppm male rats and all exposed female groups were similar to
      those of the controls throughout the study. Feed consumption by all exposure
      groups was similar to that by the control groups. No clinical findings were
      attributed to manganese (II) sulfate monohydrate ingestion. Hematology, Clinical
      Chemistry, and Tissue Metal Concentration Analyses No differences in hematology
      and clinical chemistry parameters attributable to the ingestion of manganese (II)
      sulfate monohydrate occurred between exposed and control groups. At both the 9-
      and 15-month interim evaluations, tissue concentrations of manganese were
      significantly elevated in the livers of 5,000 and 15,000 ppm male and female
      rats, with an accompanying depression of hepatic iron. Pathology Findings: The
      ingestion of diets containing 15,000 ppm manganese (II) sulfate monohydrate was
      associated with a marginal increase in the average severity of nephropathy in
      male rats (0 ppm, 2.9; 1,500 ppm, 3.0; 5,000 ppm, 3.0; 15,000 ppm, 3.2). The
      increased severity of nephropathy in the 15,000 ppm male rats was accompanied by
      significantly increased incidences of mineralization of the blood vessels (4/52,
      10/51, 6/51,17/52) and glandular stomach (8/52,13/51, 9/51, 23/52), parathyroid
      gland hyperplasia (14/51, 14/46, 12/49, 23/50), and fibrous osteodystrophy of the
      femur (12/52,14/51,12/51, 24/52). These lesions are manifestations of renal
      failure, uremia, and secondary hyperparathyroidism. The increased incidence of
      advanced renal disease caused reduced survival of the high-dose male rats. No
      increase in the incidence of neoplasms in male or female rats was attributed to
      the ingestion of diets containing manganese (II) sulfate monohydrate. 2-YEAR
      STUDY IN MICE: Groups of 70 male and 70 female mice received diets containing 0,
      1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. These levels
      resulted in an average daily ingestion of 160, 540, or 1,800 mg/kg body weight
      (males) or 200, 700, or 2,250 mg/kg (females). Nine or 10 mice from each group
      were evaluated at the 9-month and 15-month interim evaluations. Survival, Body
      Weights, Feed Consumption, and Clinical Findings: Survival rates of exposed male
      and female mice in the 2-year study were similar to those of the control groups.
      The mean body weights of exposed male mice were similar to that of the control
      group. Compared to controls, female mice had exposure related lower mean body
      weights after week 37, and the final mean body weights for the 1,500, 5,000, and
      15,000 ppm groups were 6&percnt;, 9&percnt;, and 13&percnt; lower than that of
      the control group. Feed consumption by all exposure groups was similar to that by
      the control groups. No clinical findings were attributed to the administration of
      manganese (II) sulfate monohydrate. Hematology, Clinical Chemistry, and Tissue
      Metal Concentration Analyses No chemical-related differences between exposed and
      control groups occurred in hematology or clinical chemistry parameters. At the 9-
      and 15-month interim evaluations, tissue concentrations of manganese were
      significantly elevated in the livers of the 5,000 and 15,000 ppm groups. Hepatic
      iron levels were significantly lower in exposed females at the 9-month interim
      evaluation and in 5,000 and 15,000 males and all exposed females at the 15-month
      interim evaluation. Pathology Findings: Incidences of thyroid follicular
      dilatation and hyperplasia were significantly greater in 15,000 ppm male and
      female mice than in controls. Follicular cell adenomas occurred in one 15,000 ppm
      male at the 15-month interim evaluation and in three 15,000 ppm males at the end
      of the study but not in the lower exposure groups or the control group.
      Follicular cell adenomas also occurred in two control, one 1,500, and five 15,000
      ppm female mice at the end of the study. It is uncertain if the slightly
      increased incidence of follicular cell adenoma is related to the ingestion of
      manganese (II) sulfate monohydrate. The incidences of focal hyperplasia of the
      forestomach epithelium were significantly greater in the 15,000 ppm male and
      exposed female groups. The hyperplasia was associated with ulcers and
      inflammation in some mice, particularly males. GENETIC TOXICOLOGY: Manganese (II)
      sulfate monohydrate was not mutagenic in Salmonella typhimurium strains TA97,
      TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation
      (S9), and did not induce sex-linked recessive lethal mutations in germ cells of
      male Drosophila melanogaster. Tests for induction of sister chromatid exchanges
      and chromosomal aberrations in cultured Chinese hamster ovary cells treated
      without S9 were positive; with S9, only the sister chromatid exchange test with
      manganese (11) sulfate monohydrate was positive. CONCLUSIONS: Under the
      conditions of these 2-year feed studies, there was no evidence of carcinogenic
      activity of manganese (II) sulfate monohydrate in male or female F344/N rats
      receiving 1,500, 5,000, or 15,000 ppm. There was equivocal evidence of
      carcinogenic activity of manganese (II) sulfate monohydrate in male and female
      B6C3F1 mice, based on the marginally increased incidences of thyroid gland
      follicular cell adenoma and the significantly increased incidences of follicular
      cell hyperplasia. The ingestion of diets containing manganese (II) sulfate
      monohydrate was associated with an increased severity of nephropathy in male
      rats, focal squamous hyperplasia of the forestomach in male and female mice, and
      ulcers and inflammation of the forestomach in male mice. These studies were not
      designed to assess any neurotoxicity that might have been expected with chronic
      exposure to sufficiently high doses of manganese. Synonyms: Manganese sulfate;
      manganous sulfate; sulfuric acid. manganese2+ salt (1:1), monohydrate

PMID- 12616304
TI  - NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37
      1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1
      Mice (Feed Studies).
AB  - Turmeric oleoresin is the organic extract of turmeric, a ground powder from the
      root of the Curcuma plant, and is added to food items as a spice and coloring
      agent. Turmeric oleoresin, turmeric, and curcumin (the major component found in
      turmeric) were nominated by the National Cancer Institute and the Food and Drug
      Administration for study because these chemicals are used in food items and curry
      powders, and there was little information on their toxic or carcinogenic
      properties. Pure curcumin was not available in sufficient quantities for study,
      and a turmeric oleoresin with a high curcumin content (79% to 85%) was selected
      for evaluation. Toxicity and carcinogenicity studies were conducted by
      administering turmeric oleoresin in feed to groups of male and female F344/N rats
      and B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were
      conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 13
      WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets
      containing 0, 1,000, 5,000, 10,000, 25,000, or 50,000 ppm turmeric oleoresin. All
      rats survived until the end of the study. The final mean body weight of males
      receiving 50,000 ppm was 5% lower than that of the controls. Feed consumption by
      exposed male and female rats was similar to that by the controls. Dietary levels
      of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated
      to deliver average daily doses of 50, 250, 480, 1,300, or 2,600 mg/kg body weight
      to males and 60, 300, 550, 1,450, or 2,800 mg/kg to females. The absolute and
      relative liver weights of female rats and the relative liver weights of male rats
      receiving 5,000, 10,000, 25,000, and 50,000 ppm were significantly greater than
      those of the controls. There were no biologically significant differences in
      hematologic, clinical chemistry, or urinalysis parameters. Clinical findings
      included stained fur, and discolored feces and urine of exposed animals,
      presumably due to the parent compound or its metabolites. Hyperplasia of the
      mucosal epithelium was observed in the cecum and colon of male and female rats
      that received 50,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female
      B6C3F1 mice were fed diets containing 0,1,000, 5,000,10,000, 25,000, or 50,000
      ppm turmeric oleoresin. There were no deaths attributed to turmeric oleoresin and
      the final mean body weight gains and final mean body weights of all exposed
      groups of male and female mice were similar to those of the controls. Feed
      consumption by exposed male and female mice was similar to that by the controls.
      Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin
      were estimated to deliver average daily doses of 150, 750, 1,700, 3,850, or 7,700
      mg/kg body weight to males and 200, 1,000, 1,800, 4,700 or 9,300 mg/kg to
      females. Absolute and relative liver weights of male mice that received 5,000 ppm
      and male and female mice that received 10,000, 25,000 and 50,000 ppm were
      significantly greater than those of the controls. Clinical findings in mice
      included stained fur, and discolored feces and urine. There were no biologically
      significant differences in hematologic, clinical chemistry, or urinalysis
      parameters, and there were no chemical related histopathologic lesions. 2-YEAR
      STUDY IN RATS: The exposure level selection for the 2-year study was based on the
      13-week study, which showed that rats could tolerate diets containing up to
      50,000 ppm. Groups of 60 male and 60 female F344/N rats were fed diets containing
      2,000, 10,000, or 50,000 ppm turmeric oleoresin for 104 (males) or 103 (females)
      weeks, which were estimated to deliver average daily doses of 80, 460, or 2,000
      mg/kg to males and 90, 440, or 2,400 mg/kg to females. Nine or 10 rats from each
      exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed
      Consumption, and Clinical Findings: Survival of exposed male and female rats was
      similar to that of the controls (male: O ppm, 18/50; 2,000 ppm, 17/50; 10,000
      ppm, 15/50; 50,000 ppm, 17/50; female: 33/50, 27/50, 28/50, 34/50). Th50, 28/50,
      34/50). The final mean body weights of all exposed male rats and female rats
      receiving 2,000 and 10,000 ppm were similar to those of the controls. The final
      mean body weights of male and female rats that received 50,000 ppm were slightly
      lower (up to 10&percnt;) than those of the controls throughout much of the study.
      Feed consumption by exposed male and female rats was similar to that by controls
      throughout the study. The absolute and relative liver weights of female rats
      receiving 10,000 or 50,000 ppm were significantly greater than those of controls
      at the 15-month interim evaluation. There were no clinical findings related to
      toxicity. Hematology and Clinical Chemistry: In male and female rats receiving
      50,000 ppm the hematocrit values, hemoglobin concentrations, and erythrocyte
      counts at the 15-month interim evaluation were significantly lower than those in
      the controls. In addition, platelet counts in male and female rats that received
      50,000 ppm and reticulocyte counts in male rats that received 50,000 ppm were
      significantly higher than those in the controls. No biologically significant
      differences were observed in clinical chemistry parameters. Pathology Findings:
      Chemical-related nonneoplastic lesions occurred in the gastrointestinal tract of
      rats that received 50,000 ppm. Males receiving 50,000 ppm had increased
      incidences of ulcers, hyperplasia, and hyperkeratosis of the forestomach. Male
      and female rats that received 50,000 ppm had ulcers, chronic active inflammation,
      and hyperplasia of the cecum. Similar lesions also occurred in the colon of males
      receiving 50,000 ppm. Male and female rats that received 50,000 ppm and male rats
      that received 10,000 ppm had significantly increased incidences of sinus ectasia
      of the mesenteric Iymph node. The incidences of clitoral gland adenoma in all
      exposed groups of female rats were significantly increased. Clitoral gland
      carcinomas occurred in one control female and in four 2,000 ppm females, but not
      in females that received 10,000 or 50,000 ppm. The incidences of clitoral gland
      adenoma or carcinoma (combined) in all exposed groups of female rats were similar
      (6/50, 16/48, 15/47, 16/49) and did not increase with exposure level. The
      incidence of clitoral gland hyperplasia was similar among exposed and control
      groups of female rats (7/50, 5/48, 4/47, 7149). 2-YEAR STUDY IN MICE: The
      exposure level selection for the 2-year study was based on the 13-week study,
      which showed that mice could tolerate diets containing up to 50,000 ppm. Groups
      of 60 male and 60 female B6C3F1 mice were fed diets containing 2,000, 10,000, or
      50,000 ppm turmeric oleoresin for 103 weeks, which were estimated to deliver
      average daily doses of 220, 520, or 6,000 mg/kg to males and 320,1,620, or 8,400
      mg/kg to females. Nine or 10 mice from each exposure group were evaluated after
      15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings:
      Survival of exposed male and female mice was similar to that of the controls
      (male: O ppm, 43/50; 2,000 ppm, 43/50; 10,000 ppm, 37/50; 50,000 ppm 42/50;
      female: 39/50, 41/50, 34/50, 42/50). The mean body weight of female mice
      receiving 50,000 ppm was slightly lower (up to 12&percnt;) than that of the
      controls from about week 25. The final mean body weights of males that received
      50,000 ppm and females that received 10,000 and 50,000 ppm were significantly
      lower than those of controls. The final mean body weights of other exposed groups
      of male and female mice were similar to those of the controls. Feed consumption
      by exposed male and female mice was similar to that by the controls throughout
      the study. The absolute and relative liver weights of male and female mice
      receiving 10,000 and 50,000 ppm were significantly greater than those of the
      controls at the l5-month interim evaluation. There were no clinical findings
      related to toxicity. Hematology and Clinical Chemistry: No biologically
      significant differences were observed in hematologic parameters. The alkaline
      phosphatase values of male and female mice that received 10,000 and 50,000 ppm
      were significantly higher than those of controls at the 15-month interim
      evaluation. Pathology Findings: The incidences of hepatocellular adenoma in male
      and female mice receiving 10,000 ppm, but not those in mice receiving 2,000 or
      50,000 ppm, were significantly increased (male: 25/50, 28/50, 35/50, 30/50;
      female: 7/50, 8/50, 19/51, 14/50). The number of male and female mice in the
      10,000 and 50,000 ppm groups with multiple hepatocellular neoplasms was
      significantly greater than that in the controls. The incidences of hepatocellular
      carcinoma were similar among exposed and control groups. In contrast to rats,
      there were no chemical-related nonneoplastic lesions of the gastrointestinal
      tract in mice. Three males that received 2,000 ppm and three males that received
      10,000 ppm had carcinomas of the small intestine; neoplasms of the small
      intestine were not observed in control males or in males that received 50,000
      ppm. Female mice receiving 50,000 ppm had a significantly increased incidence of
      thyroid gland follicular cell hyperplasia. GENETIC TOXICOLOGY: Turmeric oleoresin
      was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or
      TA98 with or without exogenous metabolic activation (S9). It induced small but
      significant increases in sister chromatid exchanges and chromosomal aberrations
      in cultured Chinese hamster ovary cells. The positive response in the sister
      chromatid exchange test occurred in the presence of S9, whereas the aberrations
      response occurred without S9. CONCLUSIONS: Under the conditions of these 2-year
      feed studies, there was no evidence of carcinogenic activity of turmeric
      oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There
      was equivocal evidence of carcinogenic activity of turmeric oleoresin in female
      F344/N rats based on increased incidences of clitoral gland adenomas in the
      exposed groups. There was equivocal evidence of carcinogenic activity of turmeric
      oleoresin in male B6C3F1 mice based on a marginally increased incidence of
      hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas
      of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal
      evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice
      based on an increased incidence of hepatocellular adenomas in the 10,000 ppm
      group. Turmeric oleoresin ingestion was also associated with increased incidences
      of ulcers, hyperplasia, and inflammation of the forestomach, cecum, and colon in
      male rats and of the cecum in female rats. In female mice, ingestion of diets
      containing turmeric oleoresin was also associated with an increased incidence of
      thyroid gland follicular cell hyperplasia. Synonyms for Turmeric Oleoresin:
      curcuma oil; oil of turmeric; turmeric oil; curcuma longa oils; curcuma long oil;
      Curcumin Synonyms for Curcumin: 1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene
      3,5-dione; C.I. Natural Yellow 3; C.I. 75300; Curcuma; diferuloylmethane; E 100;
      Haidr; Halad; Haldar; Halud; HSDB 4334; Indian Saffron; kacha haldi; Kurkumin;
      merita earth; Souchet; Turmeric Yellow; yellow ginger; yellow root; Yo-kin; Zlut
      Prirodni 3; NCI-C613253

PMID- 12616305
TI  - NTP Comparative Toxicology Studies of Corn Oil, Safflower Oil, and Tricaprylin
      (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as Vehicles for
      Gavage.
AB  - The types and levels of fats in the diet are known to affect the incidence of
      certain neoplasms in humans and rodents. In long-term toxicity and
      carcinogenicity studies in rodents, the level of dietary fat is altered by using
      oil as a vehicle to administer unpalatable or volatile chemicals. Control male
      rats receiving a corn oil vehicle have a higher incidence of pancreatic
      proliferative lesions and a lower incidence of mononuclear cell leukemia than
      untreated control males. Therefore, the National Toxicology Program (NTP)
      designed studies to evaluate the role of several oils in altering cancer rates in
      male rats. The NTP study reported here was part of a larger program that included
      cooperative agreements with Dartmouth Medical School, Northwestern Medical
      School, and the University of Missouri. The program was designed to study the
      mechanisms by which corn oil induces pancreatic cancer. To evaluate corn oil as
      well as two other gavage vehicles for potential toxicity, corn oil, safflower
      oil, and tricaprylin were administered by gavage to male F344/N rats for 2 years.
      The rats that received corn oil were also made available to the university
      investigators for study of the corn oil-induced pancreatic lesions. Each vehicle
      was administered by gavage at volumes of 2.5, 5, or 10 mL/kg body weight once
      daily for 5 days per week. In the corn oil study, a control of 10 mL saline/kg
      was also included. To evaluate the potential role of corn oil in promoting a
      pancreatic proliferative effect, 500 mg dichloromethane/kg body weight was
      administered in 2.5, 5, or 10 mL corn oil/kg body weight for 2 years to male
      F344/N rats. Dichloromethane was chosen because the chemical appeared to cause
      pancreatic proliferative lesions when administered by gavage in a corn oil
      vehicle but not when the exposure was by inhalation. In each of these studies,
      the term "dose" refers to the volume of gavage vehicle administered. 2-YEAR
      STUDIES OF CORN OIL, SAFFLOWER OIL, AND TRICAPRYLIN: Survival and Body Weights:
      Two-year survival was increased in male rats receiving corn oil (untreated
      control, 26/50; saline control, 32/50; 2.5 mL/kg, 33/50; 5 mL/kg, 38/50; 10
      mL/kg, 40/50) primarily due to a dose-related decreased incidence of mononuclear
      cell leukemia. The mean body weights of all dosed groups were at least 5% higher
      than those of the untreated and saline controls by week 48, but the mean body
      weights of groups receiving 2.5 or 5 mL corn oil/kg decreased during the final
      weeks of the study (after week 89) and were similar to those of the controls at
      the end of the study. Two-year survival was slightly increased in male rats
      receiving safflower oil relative to that of the controls (untreated control,
      30/50; 2.5 mL/kg, 33/50; 5 mL/kg, 40/50; 10 mL/kg, 36/50). The mean body weight
      of male rats receiving 10 mL safflower oil/kg was at least 5% greater than that
      of the controls after week 45 and was 16% greater by the end of the study. Two
      year survival of high-dose tricaprylin males was lower than that of the controls
      (untreated control, 31/50; 2.5 mL/kg, 30/50; 5 mL/kg, 31/50; 10 mL/kg, 23/53) due
      to moribund kills and deaths that appeared to be related to toxicity. The mean
      body weight of the high-dose group was lower than that of the controls throughout
      the study, although the difference was less than 5% after week 61. Pathology
      Findings: In the corn oil study, there were significant dose-related increased
      incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/50,
      28/47, 28/50, 35/50; adenoma: 1/50, 8/47, 10/50, 23/50; carcinoma: 0/50, 0/47,
      1/50, 0/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively).
      The incidence and severity of nephropathy decreased with dose (incidence [mean
      severity grade]: 47/50 [2.1], 43/48 [1.8], 45/50 [1.4], 40/49 [1.2]). The
      incidences of pheochromocytomas (benign, malignant, or complex) of the adrenal
      medulla were also decreased in dosed rats (23/49, 21/50, 5/50, 9/50). The
      incidence of mononuclear cell leukemia was significantly decreased in rats dosed
      with corn oil (27/50, 16/50, 11h corn oil (27/50, 16/50, 11/50, 7/50). In rats
      receiving safflower oil, the incidences of pancreatic exocrine hyperplasia and
      adenoma increased significantly with dose (hyperplasia: 8/50, 14/50, 29/49,
      30/50; adenoma: 1/50, 7/50,15/49, 28/50; carcinoma: 0/50, 0/50, 0/49, 1/50 in the
      untreated control, 2.5, 5, and 10 mL/kg groups, respectively). There was a
      decrease in the severity, but not in the incidence, of nephropathy, a common
      lesion in aging F344/N rats (incidence [mean severity grade]: 49/50 [2.0], 50/50
      [1.8], 47/50 [1.1], 49/49 [1.1]). There were decreased incidences of mononuclear
      cell leukemia (33/50, 19/50, 18/50, 7/51). In the tricaprylin study, there were
      significant dose-related increased incidences of pancreatic exocrine hyperplasia
      and adenoma (hyperplasia: 8/49, 9/49, 18/49, 28/50; adenoma: 2/49,
      6/49,13/49,18/50 in the untreated control, 2.5, 5, and 10 mL/kg groups,
      respectively). The incidence of proliferative lesions of the forestomach
      increased significantly with dose (basal cell hyperplasia: 4/50, 7/50, 12/49,
      21/52; squamous cell papilloma: 0/50, 0/50, 3/50, 10/53). The incidence of
      nephropathy was significantly decreased in high-dose rats, and the severity of
      nephropathy decreased with dose (incidence [mean severity grade]: 46/50 [2.0],
      42/50 [1.5], 45/50 [1.7], 27/49 [0.9]). In high-dose rats, the incidence of
      mononuclear cell leukemia was decreased (23/50, 28/50, 22/50, 9/53). 2-YEAR STUDY
      OF DICHLOROMETHANE IN CORN OIL: Survival and Body Weights: Two-year survival
      increased slightly with dose in the three groups receiving 500 mg
      dichloromethane/kg in 2.5, 5, or 10 mL corn oil/kg (23/50, 28/50, 31/50) due to a
      dose-related decrease in the incidence of mononuclear cell leukemia. The rats
      receiving 500 mg dichloromethane/kg without corn oil were sacrificed within the
      first 3 weeks of the study due to the severe toxicity of dichloromethane. The
      final mean body weight of the high-dose rats was greater than the final mean body
      weights of groups receiving dichloromethane in 2.5 or 5 mL corn oil/kg. Pathology
      Findings: There was a dose-related increase in the incidence of pancreatic
      proliferative exocrine lesions in rats receiving dichloromethane in 2.5, 5, and
      10 mL corn oil/kg (hyperplasia: 28/50, 38/50, 44/50; adenoma: 9/50,19/50, 41/50;
      carcinoma: 0/50,1/50, 3/50). The incidences of pancreatic exocrine hyperplasia
      and adenoma in rats receiving dichloromethane in 5 or 10 mL, but not 2.5 mL, corn
      oil were increased compared to the incidences in rats receiving comparable
      volumes of corn oil alone (hyperplasia: 2.5 mL, 28/47; 5 mL, 28/50;10 mL, 35/50;
      adenoma: 8/47,10/50, 23/50; carcinoma: 0/47,1/50, 0/50). There were significantly
      increased incidences of pituitary gland pars distalis adenoma in rats receiving
      dichloromethane in corn oil (20/50, 18/49, 16/49) when compared to those in rats
      receiving comparable volumes of corn oil alone (10/50, 6/49, 7/50). The incidence
      of mammary gland adenoma and fibroadenoma (combined) was significantly increased
      in rats receiving dichloromethane in 10 mL corn oil/kg (7/50) when compared to
      rats receiving dichloromethane in 2.5 mL corn oil/kg (1/50), but was not
      significantly increased when compared to the group receiving 10 mL of corn oil
      alone (3/50). The incidences of mammary gland adenoma and fibroadenoma (combined)
      were 7/50 for the untreated safflower oil controls and 6/50 for the untreated
      tricaprylin controls. The incidence of mononuclear cell leukemia decreased in the
      group receiving dichloromethane in 10 mL corn oil/kg (13/50,14/50, 5/50). GENETIC
      TOXICOLOGY: Neither safflower oil nor corn oil was mutagenic in Salmonella
      typhimurium strains TA97, TA98, TA100, or TA1535, with or without S9.
      Tricaprylin, in contrast, was mutagenic in strain TA1535 with, but not without,
      S9. Tricaprylin did not induce mutations in strains TA97, TA98, or TA100, with or
      without S9. SUMMARY: These studies were designed to evaluate the effects of
      various concentrations of an oil very high in polyunsaturated fat (safflower
      oil), an oil containing high levels of polyunsaturated and monounsaturated fats
      (corn oil), and an oil containing saturated medium-chain fatty acids
      (tricaprylin) on the incidence and pattern of neoplasms in the F344/N rat. In
      addition, safflower oil and tricaprylin were evaluated as replacements for the
      corn oil vehicle. These studies demonstrate that safflower oil and tricaprylin do
      not offer significant advantages over corn oil as a gavage vehicle in long-term
      rodent studies. Corn oil, safflower oil, and tricaprylin each caused hyperplasia
      and adenoma of the exocrine pancreas, decreased incidences of mononuclear cell
      leukemia, and reduced incidences or severity of nephropathy in male F344/N rats.
      There was an increased incidence of squamous cell papillomas of the forestomach
      in F344/N rats receiving 10 mL tricaprylin/kg. Further, the use of corn oil as a
      gavage vehicle may have a confounding effect on the interpretation of chemical
      induced proliferative lesions of the exocrine pancreas and mononuclear cell
      leukemia in male F344/N rats. Synonyms: Corn Oil - Maize oil, Maydol Tricaprylin 
      Trioctanoin; 1,2,3-trioctanoyl glycerol; Glycerol trioctanoate

PMID- 12616306
TI  - Childhood social and early developmental factors associated with mental health
      service use.
AB  - BACKGROUND: The aim of this study was to determine the influence of family and
      child variables on the pathway to mental health care in children. METHODS: A
      blinded, matched case control study was conducted, involving a retrospective
      analysis of prospectively collected data from routine examinations at the Youth
      Health Care Division from the Municipal Health Centre Maastricht (YHCD), where
      all children in a geographically defined area from foetal life through to age 19
      years are periodically screened. The sample included 400 children, 80 referred to
      the Community Mental Health Centre in Maastricht and 320 matched controls, aged 6
      13 years. RESULTS: The most potent risk factors associated with mental health
      service use were: being small at birth, having a younger mother at delivery,
      living in a one-parent family, having a divorced mother and/or unemployed father,
      observations of externalising behaviour and/or motor developmental problems,
      speech problems and experiencing several adverse family circumstances. The group
      of variables pertaining to the family (e. g. one-parent family, parental mental
      health problems, etc.) influenced mental health service independently of the
      group of variables pertaining to the child (e. g. birth length, speech problems,
      etc.) and vice versa. Several combinations of risk factors, under realistic
      prevalence estimates, had positive predictive values of up to 26 %. CONCLUSION:
      Pathways to child psychiatric care are heavily influenced by the child's family
      environment as well as by deviance in social, motor and speech development.
      Independence of child developmental effects suggests these are not merely on the
      causal pathway between adverse family environment and psychiatric service use
      outcome. Combinations of risk factors may be useful to develop a screening
      approach with the possibility of early prevention.

PMID- 12616307
TI  - Aftercare of depressed inpatients--service delivery and unmet needs.
AB  - BACKGROUND: In contrast to acute treatment, delivery of aftercare to depressed
      patients has not been well studied. Poor care may contribute to poor outcomes for
      treated depression. METHODS: One hundred and two patients discharged from
      hospital with unipolar depression were followed up 18 months later and were
      interviewed in detail regarding aftercare and treatment received. Unmet needs
      were assessed on the community version of the MRC Needs for Care Assessment.
      RESULTS: In the first month after discharge approximately 70 % of subjects
      received contacts with mental health services and in the first 3 months over 80 %
      received at least one contact. About 40 % were in contact with mental health
      services at 18 months. Needs assessment found comparatively low unmet needs,
      reaching highest levels (around 25 % in any 6-month period) for medication. Two
      thirds of unmet needs for medication and psychotherapy were due to patient
      refusal or non-compliance. Aftercare levels were higher in those with more
      previous admissions and were unrelated to presence of personality disorder.
      CONCLUSIONS: There were some deficiencies in service aftercare for depressed
      patients in a British NHS setting, although unmet need was not high. Some
      aftercare failures reflect patient reluctance to receive further treatment,
      representing a challenge to overcome in patients entitled to autonomous choices.

PMID- 12616308
TI  - Family intervention in schizophrenia--impact on family burden and attitude.
AB  - BACKGROUND: This study focuses on the effect of psycho-educative family therapy
      on the self-assessed burden in families in which one member has suffered from
      relapse of schizophrenia or a schizoaffective syndrome. The impact on the
      family's self-assessed attitude towards continuing to take care of the patient
      was also evaluated. Burden and attitude were assessed continuously during a
      period that contained no further relapse episodes. METHODS: Included were 31
      families in which one family member suffered from schizophrenia or a
      schizoaffective syndrome. Of these, 14 families underwent a psycho-educative
      intervention programme called BFT (Behavioural Family Therapy). The remaining 17
      families, i. e. the contrast group, received conventional family support. The
      intervention was initiated within 24 h after the patient/family member was
      admitted to a psychiatric ward due to relapse of the psychotic disorder. The
      intervention continued until the patient was discharged from hospital. Falloon's
      Distress Scale and Attitude Scale were used in the families' self-assessments of
      burden and attitude towards continuing to take care of the patient, respectively.
      The self-assessments were performed on three occasions: 1) on the day of
      admission to the ward, or the day after; 2) 4-5 weeks after admission; and 3) on
      the day of discharge, or the day after. Medication doses were registered upon
      admission and at the time of discharge. Finally, the rates of re-occurring
      relapses within 1 year after discharge from hospital were determined, i. e. 1
      year after the completion of the family treatment programme. The BFT families had
      access to the therapist for questions after the programme had been completed,
      when needed. The patients and families in the contrast group had access to
      physicians and therapists in the outpatient care. RESULTS: The self-assessed
      family burden was significantly lower for the BFT families at the time of
      discharge, compared to the contrast group, and the self-assessed attitude towards
      continuing to take care of the patient was significantly more positive for the
      BFT families at the time of discharge, compared to the contrast families. One
      patient in the BFT group relapsed within 1 year, whereas 13 patients relapsed in
      the contrast group. The dosages of neuroleptics were significantly lower on
      discharge than on admission for the patients in the BFT group. CONCLUSIONS: The
      results suggest that BFT, when provided to schizophrenic patients and their
      families during a hospitalisation period caused by a psychotic relapse, reduces
      the feeling of burden in these families. Likewise, the families' attitude towards
      continuing to take care of the patients was influenced in a positive way.

PMID- 12616310
TI  - Coping strategies in civilians during air attacks.
AB  - BACKGROUND: Coping strategies may influence the psychological outcome after a
      stressful event, both as coping at the time of the event and as strategies of
      dealing with its consequences after the event. The aim of the study was to
      investigate coping strategies used by civilians during the air attacks in
      Yugoslavia in 1999, and their association with the level of exposure, gender and
      psychological symptoms 1 year later. METHOD: The sample is a non-selective group
      of 139 medical students from the University of Belgrade, Yugoslavia. Open
      questions and content analysis were used to assess coping strategies. Symptoms of
      intrusion and avoidance were assessed, as well as general psychological symptoms.
      RESULTS: Content analysis of answers to open questions revealed nine categories
      of coping strategies (sport and walks, leisure activities, talking and gathering,
      humor, avoidance, philosophical approach, getting information, work, and
      substance abuse). A cluster analysis identified three groups of students with
      different styles of coping. Students that used dominantly 'talking and gathering'
      had the highest, and the ones that mostly used 'leisure activities' the lowest
      scores on intrusion. There were significant gender differences in how coping
      strategies were associated with intrusive symptoms. CONCLUSION: The type of
      coping strategies used during the air attacks may contribute to the level of
      intrusive symptoms 1 year after the event. Different coping strategies might be
      effective in men and women to reduce intrusive symptoms. Longitudinal and
      prospective studies are needed to draw definite conclusions on causal
      relationships between coping strategies and levels of posttraumatic stress.

PMID- 12616309
TI  - Beliefs about alcohol among UK Jews and Protestants: do they fit the alcohol
      depression hypothesis?
AB  - BACKGROUND: Some research has suggested that Jews drink less alcohol than other
      cultural groups, and may have different beliefs about its use. Differences in
      beliefs about alcohol, and different patterns of use, may play a role in
      accounting for cultural and gender variations in depression prevalence. Alcohol
      may act as an escape route from depression, thus deflating depression rates in
      certain groups of people, in particular, men from Protestant backgrounds.
      METHODS: Self-reported use and beliefs about alcohol were assessed in a UK sample
      of 70 Jews and 91 Protestants, including non-practising people of Jewish and
      Protestant background. The effects of religious group and of gender on measures
      of alcohol behaviour and beliefs were examined. RESULTS: Some differences were
      found between Jews and Protestants. Jews had less favourable beliefs about
      alcohol and drank less than Protestants. More importantly, and in line with our
      hypotheses, there were gender differences in Protestants but not Jews with
      respect to some beliefs about alcohol and actual use of alcohol. CONCLUSIONS: The
      study goes some way in supporting the notion that religious-cultural and gender
      differences in beliefs and behaviour towards alcohol may contribute to religious
      cultural and gender differences in rates of depression.

PMID- 12616311
TI  - Predictors of life satisfaction in retired physicians and spouses.
AB  - BACKGROUND: With the current demographic changes, adjustment to retirement has
      become a major concern for physicians. Yet information on adjustment to
      retirement gathered from retired physicians is sparse. Information on physician
      spouses following retirement is currently not available. Therefore, we conducted
      a survey of a multi-disciplinary group of retired physicians and their spouses on
      adjustment to retirement. METHODS: A mail survey was sent to 1834 alumni who
      graduated from medical school prior to 1965. Responses were received from 795 (43
      %) physicians and 455 spouses. Of the physicians, 678 indicated that they were
      retired or semi-retired. Life satisfaction was measured on a 9-point Likert
      scale. RESULTS: Levels of life satisfaction were high for both physicians and
      spouses. Approximately 88 % of both groups reported being mostly satisfied or
      better with their lives. Factors associated with better life satisfaction for
      physicians included better health, optimism, feelings of financial security,
      participation in activities and hobbies and a good sexual relationship. For
      spouses, good health, having a husband willing to help with chores, quality of
      relationships including sexual relationship and attending theatre or sporting
      events were associated with higher levels of life satisfaction. Spouses who had
      never worked reported higher levels of life satisfaction than spouses who had
      worked and were now retired. For changes in life satisfaction since physician
      retirement, predictors for both physicians and spouses were similar to those for
      life satisfaction. However, for physicians, both younger age and more years in
      retirement were independently associated with improved life satisfaction. Issues
      regarding loss of role and methods and reasons for retirement influenced
      satisfaction in the early retirees. For spouses, major challenges involved coping
      with changes in the marital relationship. CONCLUSIONS: Physicians and their
      spouses reported high levels of life satisfaction. The factors predicting life
      satisfaction and change in life satisfaction following retirement differed for
      physicians and spouses. For physicians, life satisfaction and change in life
      satisfaction were affected by time since retirement.

PMID- 12616312
TI  - Cross-cultural differences in the conceptualisation of patients' satisfaction
      with psychiatric services--content validity of the English version of the Verona
      Service Satisfaction Scale.
AB  - BACKGROUND: The VSSS is a multi-dimensional questionnaire developed to address
      methodological concerns about measurement of satisfaction with services on the
      part of psychiatric patients. The acceptability, sensitivity, content validity
      and test-retest reliability of the original version of the VSSS, in Italian, have
      already been demonstrated [1, 2]. The internal consistency [3] and test-retest
      reliability [4] of the English translation have been shown to be within
      acceptable ranges. The content validity of the original 82-item and the 54-item
      English version has not yet been assessed. AIMS: The aims of this study were to
      assess the content validity of the English translation of the VSSS and to compare
      it with that of the original version in Italian. METHOD: We used data collected
      as part of the first wave (T1) of the PRiSM Psychosis Study [5] and repeated the
      methods used to assess the content validity of the original Italian version of
      the VSSS [1, 2]. Content elements derived from answers to four open questions
      were rated independently by CH and HH in terms of their equivalence to VSSS items
      or dimensions. RESULTS: were compared to those from the content validity study of
      the Italian version. Results Inter-rater agreement was very high. The largest
      proportion of the content elements of the answers were rated as equivalent or
      related to a questionnaire item or a dimension of the VSSS. The dimension
      'Professionals' Skills and Behaviour' appears the most significant contributor to
      satisfaction, as it was most often related to content elements in answers to all
      four key questions (39.1 %). The second most frequently mentioned dimension was
      that of 'Types of Intervention' for three out of four open questions, while
      'Access' was second most frequent for the fourth. Of the content elements, 17.2 %
      did not include items or dimensions covered by the VSSS; the three most
      frequently mentioned were other patients, food and security. CONCLUSIONS: The 82
      item English version of the VSSS captures sharply most contents relevant to
      patients' satisfaction. Consideration of contributors to satisfaction so far
      neglected may refine the conceptualisation of satisfaction.

PMID- 12616314
TI  - Patients' and their relatives' causal explanations of schizophrenia.
AB  - BACKGROUND: Previous studies with schizophrenia patients and their relatives
      which have been carried out in the western part of Germany and in Austria have
      demonstrated a strong tendency towards assuming psychosocial stress as a cause of
      schizophrenia. The question arises as to whether patients with schizophrenia and
      their relatives in the eastern part of Germany (former German Democratic
      Republic) share these beliefs. METHODS: Problem-centered interviews were
      conducted with 100 schizophrenia patients living in the catchment area of the
      university hospital who were in psychiatric outpatient treatment. Thirty-six
      relatives were also interviewed at the same time. RESULTS: Both patients and
      relatives most frequently reported psychosocial stress as a cause of the illness.
      Sixty-two per cent of the patients and 86 % of the relatives reported more than
      one cause. However, the majority of them did not explicitly link these causes to
      one another. DISCUSSION: Similarities between the results of this study and those
      of previous studies prevail. However, there are some differences with regard to
      the role attributed to socialisation and society. Whereas there is a stronger
      tendency to hold the family responsible for the illness in the West, in the East
      the social conditions are more frequently considered to be of etiological
      relevance. Inconsistencies between patients' and relatives' beliefs and the
      results of psychiatric research on the causes of schizophrenia suggest a need to
      provide specific psychoeducation for both.

PMID- 12616313
TI  - How psychotic are individuals with non-psychotic disorders?
AB  - BACKGROUND: The objective of this study was to compare, using a self-report
      questionnaire, the dimensions of psychosis across different patient groups in a
      community mental health service (CMHS) and in non-patients in the general
      population. METHODS: The Community Assessment of Psychic Experiences (CAPE) is a
      40-item self-report instrument with positive, negative and depressive symptom
      dimensions. Seven hundred and sixty-two patients and 647 subjects in the general
      population filled in the CAPE. In 555 of the 762 patients, a DSM-IV diagnosis was
      made. The following DSM-IV categories were used in the analyses: 1. Schizophrenia
      and Other Psychotic Disorders (n = 72), 2. Mood Disorders (n = 214), 3. Anxiety
      Disorders (n = 129). The patient and non-patient groups were compared on the
      three dimensions of the CAPE using multivariate regression analysis. RESULTS: The
      patient groups scored significantly higher on the positive, negative and
      depressive dimensions than the non-patients. Patients with psychotic disorders
      had the greatest difference in positive psychosis items compared to non-patients
      (beta = 0.94, 95 % CI: 0.7-1.18), whereas patients with mood and anxiety
      disorders had the highest depressive symptom scores, and positive symptom scores
      that were intermediate to that of non-patients and patients with psychotic
      disorders (mood disorders: beta = 0.53, 95 % CI: 0.39-0.68; anxiety disorders:
      beta = 0.22, 95 % CI: 0.04-0.39). The CAPE distress score adjusted for the
      corresponding frequency score was not significantly different between the patient
      groups, but compared to the general population, patient status did contribute
      significantly to the level of distress. DISCUSSION: Patients with anxiety and
      mood disorders had elevated scores on positive psychosis items, indicating that
      expression of psychosis in non-psychotic disorders is common. The finding of
      elevated scores of the patient groups on all three dimensions compared to non
      patients suggests that the psychopathology associated with psychotic disorders
      varies quantitatively across DSM-IV categories.

PMID- 12616315
TI  - Patient dose in cardiac computed tomography.
AB  - BACKGROUND: Computed tomographic (CT) imaging of the heart is becoming more
      widely available, and the quality of and interest in these examinations continues
      to increase. Yet, many physicians who perform or order these exams may be
      unfamiliar with the radiation doses that are delivered to the patient during
      specific cardiac CT examinations. OBJECTIVE: The purpose of this article is to
      describe several fundamental radiation dose quantities that are used to either
      measure or report the dose associated with a particular CT examination. In
      addition, radiation dose estimates are given for coronary artery calcium imaging
      and coronary angiography performed using either electron beam CT (EBCT) or multi
      detector row CT (MDCT) systems.

PMID- 12616316
TI  - Performance evaluation of a multi-slice CT system with 16-slice detector and
      increased gantry rotation speed for isotropic submillimeter imaging of the heart.
AB  - BACKGROUND: 4-slice CT scanners have shown limitations in clinical application
      for noninvasive coronary CT angiography (CTA). We evaluate advances in ECG-gated
      scanning of the heart and the coronary arteries with recently introduced 16-slice
      CT equipment (SOMATOM Sensation 16, Siemens, Forchheim, Germany). MATERIALS AND
      METHODS: The technical principles of ECG-gated cardiac scanning, scan parameters,
      and detector design of the new scanner are presented. ECG-gated scan and image
      reconstruction techniques and ECG-controlled dose modulation ("ECG pulsing") for
      a reduction of the patient dose are described, key parameters for image quality
      and simulation results presented, and phantom studies and initial patient
      experience discussed. The impact of reduced gantry rotation time (0.42 s) on
      temporal resolution and initial estimations of the patient dose are presented.
      RESULTS: Extensions of ECG-gated reconstruction algorithms used for 4-slice CT
      provide adequate image quality for up to 16 slices. For each detector collimation
      different slice widths are available for retrospective reconstruction with well
      defined slice sensitivity profiles (SSPs). For coronary CTA the heart can be
      covered with 0.75 mm collimation within a 20-s breathhold. The best possible
      spatial resolution is 0.5 x 0.5 x 0.6 mm. For 0.42 s gantry rotation time,
      temporal resolution reaches its optimum (105 ms) at a heart rate of 81 bpm.
      Effective patient dose for coronary CTA is 4-5 mSv using ECG-pulsed acquisition.
      CONCLUSION: The clinical performance of coronary CTA by means of spatial
      resolution, temporal resolution and scan time is substantially improved with the
      evaluated 16-slice CT scanner. Also, display of smaller coronary segments and
      instent visualization are substantially improved.

PMID- 12616318
TI  - [Combined approach of contrast and non contrast CT for the assessment of coronary
      atherosclerosis].
AB  - BACKGROUND: The newest generation multi-detector-row CT scanner is allowed for
      investigation of the entire heart within a breathhold period of approximately 20
      s. Within this time 250 slices with a thickness of 1 mm each are acquired. In
      conjunction with the ECG signal the images are acquired with a temporal
      resolution of 210 ms in the mid diastolic phase of the heart. TECHNICAL
      INNOVATIONS: In patients with a heart rate < 60 beats per minute images free of
      motion artefacts can be reconstructed, that allow for assessment of the coronary
      artery lumen as well as calcified and non-calcified lesions in the coronary
      artery wall. Such lesions may be differentiated into thrombus, atheroma and
      fibrocalcified plaques on the base of characteristic morphologic criteria.
      CORONARY HEART DISEASE IN CT: The absence of coronary artery lesions in
      symptomatic patients with atypical chest pain allows for reliable exclusion for
      coronary heart disease. In asymptomatic patients with cardiovascular risk factors
      we first perform an investigation without contrast media to detect coronary
      calcifications as a marker of atherosclerosis. To assess the complete extent of
      coronary atherosclerosis in high risk patients, we then consider a contrast
      enhanced CT study.

PMID- 12616317
TI  - Do segmented reconstruction algorithms for cardiac multi-slice computed
      tomography improve image quality?
AB  - PURPOSE: To evaluate segmented reconstruction algorithms for spiral multi-slice
      computed tomography (MSCT) that use data from two cardiac cycles to improve
      temporal resolution (tau) for imaging of the heart. MATERIALS AND METHODS: An
      initial group of 78 cardiac patients (heart rates [HR] = 63-167 beats per minute
      [bpm]) were imaged on a 4-slice, 500 ms gantry rotation time scanner (scanner 1).
      Images were reconstructed with a single-segment algorithm using data from one
      cardiac cycle with a reconstruction window of fixed length (tau = 250 ms). Images
      were also reconstructed with two variants of a multi-segment algorithm using data
      from two cardiac cycles where only one end of the reconstruction window was fixed
      and the other end was freely moveable to allow adjustment of tau according to HR:
      (1) "2-segment fixed start" with fixed start of reconstruction, (2) "2-segment
      fixed end" with fixed end of reconstruction (for both, tau = 125-250 ms). The
      resulting image sets were ranked from best to worst (1-3, respectively) in a side
      by-side, blinded comparison by two independent readers. A second group of 26
      patients (HR = 74-90 bpm) were imaged on a 12-slice, 420 ms gantry rotation time
      scanner (scanner 2). Data were reconstructed with a single-segment algorithm (tau
      = 210 ms) and a "2-segment fixed start" algorithm (tau = 105-210 ms) and image
      sets were ranked from best to worst (1-2, respectively). RESULTS: There was no
      clear evidence that any one technique is superior for imaging on scanner 1.
      Reader 1 ranked single-segment images the highest for all HRs, but statistically
      significant differences among the three algorithms were only found for the lowest
      HRs (< 80 bpm), where reader 1 preferred single-segment over "2-segment fixed
      end" techniques (p = 0.048). The highest rankings given by reader 2 varied
      according to HR: single-segment images were superior for lowest HRs, while "2
      segment fixed start" images were superior for HRs > 80 bpm; none of these
      comparisons reached statistical significance. Improved performance of 2-segment
      reconstruction was found with scanner 2. Both readers ranked "2-segment fixed
      start" images the highest (p < 0.01). CONCLUSIONS: The added value of 2-segment
      cardiac reconstruction algorithms for spiral MSCT was not demonstrated for a 4
      slice, 500 ms gantry rotation time scanner but shown to be beneficial for a 12
      slice, 420 ms gantry rotation time scanner in the crucial HR range of 74-90 bpm.

PMID- 12616319
TI  - [Invasive versus noninvasive (MSCT) coronary angiography. Importance of cardiac
      diagnostics with multislice computed tomography].
AB  - Cardiac imaging with fast computed tomography (CT) is a quickly evolving field
      starting to become established in the cardiac routine work-up. The exclusion of
      coronary calcification is the most accurate noninvasive method to exclude
      significant coronary stenosis whereas the detection of calcification identifies
      coronary arteriosclerosis. The total calcium load correlates with the risk of
      coronary stenosis, but there is not a 1 : 1 relationship. CT angiography with
      contrast enhancement offers promises to increase diagnostic accuracy. 4-slice
      scanners acquire data with a slide width down to 1 mm. The spatial resolution of
      invasive coronary angiography cannot be achieved yet. Severe coronary stenosis
      may be excluded with 90% specificity if image quality is not impaired by
      artifacts, severe calcification, arrhythmia, and a heart rate > 70 beats/min.
      With present technology, about 26% of segments may not be adequately assessed.
      Despite these limitations CT angiography is a useful tool to reduce the number of
      invasive diagnostic angiography. In patients with known coronary artery disease
      (CAD), progression as well as stent occlusion can be assessed. Instent stenosis
      can only be diagnosed indirectly. The patency of arterial and venous grafts can
      be assessed very well including also the bypass insertion site. Actual studies on
      the significance of noncalcified plaques are in progress.A CT angiography should
      take place in order to avoid further exposure to radiation. Therefore, patients
      with typical angina or significant signs of coronary ischemia have to be
      investigated by invasive methods and do not profit from a CT scan. Preparation
      and implementation of this method should only be applied in cooperation with
      radiologists and cardiologists in an experienced center.

PMID- 12616320
TI  - General utilities of multislice tomography in the cardiac field.
AB  - OBJECTS: To show all cardiac evaluations multislice computed tomography (MSCT)
      can perform. METHODS: MSCTs were performed on an MSCT scanner (Mx8000; Philips
      Medical Systems) with enhanced contrast acquisition. The reconstructed images
      were sent to a workstation for multiplanar reconstruction, volume rendering, and
      3-D reconstruction. A total of 140 patients were studied with MSCT and
      conventional angiography (CA) to assess coronary artery stenosis. 30 of these
      patients were also evaluated by intravascular ultrasound (IVUS) for plaque
      characterization. A group of 20 patients were studied with MSCT, gated single
      photon emission computed tomography (SPECT), and echocardiography for myocardial
      perfusion test and volumetric analysis. RESULTS: The results of MSCT versus CA
      showed a sensitivity of 79.2% and a specificity of 93.7%, whereas for MSCT versus
      IVUS the sensitivity was 84.4% and the specificity 91.6%. A total of 156 plaques
      were detected by both methods. 105 (67%) were soft, 14 (24%) were fibrous and 37
      (9%) were calcified. In the evaluation of myocardial perfusion, the cardiac
      software showed a sensitivity of 55% and a specificity of 80%. However, general
      evaluation disclosed a sensitivity of 88.5% and a specificity of 96.4%. The
      volumetric analysis showed a good correlation between MSCT and echocardiography
      for end-systolic volume (ESV), rS = 0.874, and end-diastolic volume (EDV), rS =
      0.828. There was also a good correlation for the evaluation of the left
      ventricular anatomy: septal wall rS = 0.96, posterior wall rS = 0.81, and
      diameter of left ventricle rS = 0.69. CONCLUSION: Nowadays, MSCT allows different
      cardiologic evaluations with the same acquisition as that for the coronary
      arteries. These data show a general view of the patient providing information
      that is obtained by the hand of multiple cardiologic methods such as DA, IVUS,
      gated SPECT, and echocardiography.

PMID- 12616321
TI  - Noninvasive serial evaluation of myocardial mechanics in pressure overload
      hypertrophy of rabbit myocardium.
AB  - BACKGROUND: The determination of progression from afterload mismatch to
      myocardial failure in small animals requires invasive monitoring to assess
      ventricular pressure. OBJECTIVE: We sought to (1) validate the noninvasive
      determination of blood pressure using optical plethysmography, and (2) determine
      the time course and progression from afterload mismatch to myocyte failure in
      neonatal rabbits with coarctation (aortic banding at 7-10 days of life) compared
      to normal rabbits. METHODS AND RESULTS: Comparison of continuous arterial
      pressure determined by optical plethysmography with high-fidelity intraarterial
      recording was performed in nine animals. An accuracy of 5.9 +/- 4.7 and 9.2 +/-
      6.9 mm Hg for systolic and diastolic blood pressure was noted. Fourier analysis
      confirmed similar frequency components. Simultaneous transthoracic
      echocardiography and optical plethysmography were serially performed in 33 banded
      and 13 control animals. Load-dependent and -independent measures of myocardial
      function were obtained. Midwall contractility, initially normal, showed a gradual
      significant deterioration (0.22 +/- 1.68 [week 3] to -1.36 +/- 1.24 [week 6]; Z
      scores). CONCLUSIONS: This novel noninvasive method for determination of
      myocardial mechanics allows for serial evaluation of cardiac function and the
      determination of the time course from compensated hypertrophy to myocyte failure.

PMID- 12616322
TI  - The value of (18)FDG-PET for the detection of infected hip prosthesis.
AB  - We compared the accuracy of fluorine-18 labelled 2-fluoro-2-deoxy- d-glucose
      positron emission tomography ((18)FDG PET) with that of technetium-99m
      hexamethylpropylene amine oxime leucocyte scintigraphy (LS) in the detection of
      infected hip prosthesis. Seventeen patients with a hip prosthesis suspected for
      infection were prospectively included and underwent (99m)Tc-methylene
      diphosphonate bone scintigraphy (BS), LS and an (18)FDG-PET scan within a 2-week
      period. Seven volunteers with ten asymptomatic hip prostheses were used as a
      control group and underwent BS and an (18)FDG-PET scan. Bacteriology of samples
      obtained by surgery or by needle aspiration and/or clinical follow-up for up to 6
      months were used as the gold standard. Planar images of BS and LS (4 and 24 h
      p.i.) were acquired, followed by single-photon emission tomography (SPET) LS
      images (after 4 h). These images were scored as positive or negative by two
      experienced readers. The (18)FDG-PET scans of the patients were compared with the
      tracer distribution pattern in the asymptomatic control group and with BS. A
      phantom study was performed in order to identify artefacts. For this purpose,
      three different attenuation correction methods were tested. The combined analysis
      of the planar BS and LS resulted in a 75% sensitivity and a 78% specificity. The
      SPET LS images showed a better lesion contrast, resulting in an 88% sensitivity
      and a 100% specificity, while 24-h planar images were of no additional value. The
      analysis of PET images alone resulted in an 88% sensitivity and a 78%
      specificity. The combination of (18)FDG-PET and BS images resulted in an 88%
      sensitivity and a 67% specificity. Given the presence of small errors near the
      edge of the metal, which can induce significant artefacts in the corrected
      emission image, we decided to use the data without attenuation correction. In
      this preliminary study, (18)FDG-PET scans alone showed the same sensitivity as
      combined BS and LS, although the specificity was slightly lower.

PMID- 12616323
TI  - 99mTc-sestamibi uptake and histological malignancy grade in invasive breast
      carcinoma.
AB  - The aim of this study was to investigate whether there is a correlation between
      (99m)Tc-sestamibi uptake and histological malignancy grade in breast carcinoma.
      Such a correlation could, prior to surgery and histopathological analysis,
      facilitate selection of patients who need adjuvant therapy. Ninety-six patients
      with mammographically determined lesions and/or a palpable tumour suspected for
      malignancy underwent (99m)Tc-sestamibi scintimammography prior to surgery. The
      final diagnosis was determined by histopathological examination. Benign lesions,
      cancer in situ and tumours located medially in the breast were excluded. Fifty
      three invasive cancer lesions in 53 patients were finally included in the study.
      Planar scintigraphic breast imaging included two prone lateral projections and
      one anterior supine projection taken 10 min after injection of 700 MBq (99m)Tc
      sestamibi. Focal (99m)Tc-sestamibi uptake in breast lesions was used as the
      scintigraphic criterion of abnormality. Tumour to background ratios were
      calculated with partial volume compensation, and histological malignancy grading
      was performed according to the Elston classification. A correlation was found
      between (99m)Tc-sestamibi uptake and histological malignancy grade in invasive
      breast carcinomas ( P<or=0.037).

PMID- 12616327
TI  - Scanning electron microscopic analysis of the mineralization of type I collagen
      via a polymer-induced liquid-precursor (PILP) process.
AB  - We have put forth the hypothesis that collagen is mineralized during bone
      formation by means of a polymer-induced liquid-precursor (PILP) process, in which
      a liquid-phase mineral precursor could be drawn into the gaps and grooves of the
      collagen fibrils by capillary action, and upon solidification, leave the
      collagenous matrix embedded with nanoscopic crystallites of hydroxyapatite. This
      hypothesis is based upon our observations of capillarity seen for liquid-phase
      mineral precursors generated with calcium carbonate. Here, we demonstrate proof
      of-concept of this mechanism by mineralizing Cellagen sponges (type I
      reconstituted bovine collagen) in the presence of a liquid-precursor phase to
      calcium carbonate. Scanning electron microscopy (SEM) was used to examine the
      mineralized collagen, which in combination with selective etching studies,
      revealed the extent to which the mineral phase infiltrated the collagenous
      matrix. A roughly periodic array of disk-like crystals was found to be embedded
      within the collagen fibers, demonstrating that the mineral phase spans across the
      diameter of the fibers. Some of the morphological features of the mineralized
      fibers in our in vitro model system are similar to those seen in natural bone
      (albeit of a different mineral phase), lending support to our hypothesis that
      these non-equilibrium morphologies might be generated by a PILP process. SEM
      provides a different perspective on the morphology of bone, and has been useful
      here for examining the extent of mineralization in composite structures generated
      via the PILP process. However, further investigation is needed to examine the
      nanostructural arrangement of the crystallites embedded within the collagenous
      matrix.

PMID- 12616324
TI  - Should high hTg levels in the absence of iodine uptake be treated?

PMID- 12616334
TI  - Subjective effects of the nicotine lozenge: assessment of abuse liability.
AB  - RATIONALE: A nicotine lozenge was developed as a novel smoking cessation aid.
      Abuse liability, which in this context refers to use by novices not addicted to
      tobacco, may be expected to be low for the lozenge due to the relatively slow
      route of nicotine absorption. However, its resemblance to commercially marketed
      lozenges and its palatability, intended to increase medication compliance, may
      increase its abuse liability, especially among younger individuals. OBJECTIVES:
      The present study evaluated the abuse liability of the nicotine lozenge. Effects
      of the lozenge on cigarette craving were also measured. METHODS: Subjective and
      physiological effects of the nicotine lozenge were tested in healthy adult
      smokers ( n=12, 22-55 years old); a group of younger subjects ( n=12, 18-21
      years) was also included to allow for assessment of abuse liability of the
      lozenge in young adults specifically. Amphetamine and a confectionery lozenge
      were included in the study conditions as positive controls for abuse liability
      and palatability, respectively, and nicotine gum was included to allow for
      comparison with a marketed oral nicotine replacement product with low abuse
      liability. RESULTS: The nicotine lozenge did not increase ratings of traditional
      abuse liability predictors (good effect, like effect, MBG scale of the ARCI),
      while amphetamine significantly increased ratings on these measures. The lozenge
      dose dependently decreased craving for cigarettes after 70 min of abstinence, but
      only in the older group. Palatability of the lozenge was rated lower than a
      confectionery lozenge, but not lower than nicotine mint gum. CONCLUSIONS: Results
      suggest that the nicotine lozenge has low abuse liability, both in adults and
      young adults. The lozenge reduces craving to smoke, although craving reduction
      may not apply to young adults (18-21 years). Subjective effects of the lozenge
      are consistent with utility as a smoking cessation aid and are comparable to
      those of nicotine gum.

PMID- 12616335
TI  - Functional characterisation of the putative somatostatin sst2 receptor antagonist
      CYN 154806.
AB  - The two forms (DTyr8 and LTyr8) of the putative somatostatin sst2 receptor
      antagonist CYN 154806 (Ac-4NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-D/LTyr-NH2) were
      investigated on recombinant human somatostatin receptors and endogenous guinea
      pig ileum receptors. In radioligand binding studies using the agonist
      radioligands [125I]LTT-SRIF-28, [125I][Tyr10]cortistatin-14, [125I]CGP 23996 and
      [125I][Tyr3]octreotide in Chinese hamster lung fibroblast (CCL39) and Chinese
      hamster ovary (CHO) cells expressing human somatostatin receptors (hsst1-5), CYN
      154806 binds to sst2 receptors with nanomolar affinity (pKD=8.14-8.89), 40- to
      4500-fold higher than for sst1, sst3 or sst4. High affinity was also demonstrated
      for sst5 receptors, particularly for LTyr8CYN 154806 where the sst5 affinity was
      higher than for sst2 receptors when using [125I]CGP 23996 and
      [125I][Tyr3]octreotide. Functional properties of the compounds were examined in
      Chinese hamster ovary (CHO) cells expressing human sst2 receptors, in (1)
      inhibition of forskolin-stimulated adenylate cyclase, (2) stimulation of serum
      response element-driven luciferase expression and (3) [35S]guanosine 5'-O-(3
      thiotriphosphate) ([35S]GTPS) binding. L- and DTyr8CYN 154806 showed full agonism
      at inhibition of forskolin-stimulated cAMP accumulation (pEC50=7.73 for both,
      Emax 104% and 78%, respectively), partial agonism at luciferase expression
      (pEC50=7.85 and 8.16, Emax=50% and 29%, respectively) and behaved as apparently
      silent antagonists at [35S]GTPS binding (no agonism observed, pKB=6.88 and 7.50,
      respectively). The agonist potential was confirmed in isolated guinea-pig ileum
      preparations via measurement of SRIF-induced inhibition of neurotransmission,
      where the L-isoform had marked agonism (pEC50=8.23, Emax=32%) whereas the D
      isoform was apparently devoid of agonism. The present data suggest that CYN
      154806 should be used with caution as an sst2 receptor antagonist tool, since it
      possesses intrinsic activity at sst2, and high affinity for both sst2 and sst5
      receptors. The DTyr form, having lower intrinsic activity, especially in natural
      tissues, and greater selectivity for sst2 receptors, may be more reliable than
      LTyr CYN 154806.

PMID- 12616336
TI  - (-)-CGP 12177 increases contractile force and hastens relaxation of human
      myocardial preparations through a propranolol-resistant state of the beta 1
      adrenoceptor.
AB  - Two forms of the activated beta1-adrenoceptor exist, one that is stabilized by (
      )-noradrenaline and is sensitive to blockade by (-)-propranolol and another which
      is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is
      relatively insensitive to (-)-propranolol. We investigated the effects of
      stimulation of the propranolol-resistant beta1-adrenoceptor in the human heart.
      Myocardium from non-failing and failing human hearts were set up to contract at 1
      Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)
      propranolol, (-)-CGP 12177 caused concentration-dependent increases in
      contractile force (-logEC50[M] 7.3+/-0.1, E(max) 23+/-1% relative to maximal (-)
      isoprenaline stimulation of beta1- and beta2-adrenoceptors, n=86 patients),
      shortening of the time to reach peak force (-logEC50[M] 7.4+/-0.1, E(max) 37+/
      5%, n=61 patients) and shortening of the time to reach 50% relaxation ( t(50%), 
      logEC50[M] 7.3+/-0.1, E(max) 33+/-2%, n=61 patients). The potency and maxima of
      the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta1
      adrenoceptor polymorphisms but were potentiated by the phosphodiesterase
      inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7+/-0.1, E(max) 68+/-6%, n=6
      patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1
      methylxanthine, the potency (-logEC50[M] 7.4+/-0.1, P=0.0013, n=9 patients) but
      not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing
      hearts, which was associated with 64% and 52% reductions in the densities of low
      affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (
      )-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial
      cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right
      atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP
      12177 increased contractile force (-logEC50[M] 7.4+/-0.1, E(max) 34+/-3%, n=13
      patients) and hastened the time to peak force (-logEC50[M] 7.6+/-0.1) and time to
      reach 50% relaxation (-logEC50[M] 7.4+/-0.1) in the presence of (-)-propranolol
      and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases
      contractility and hastens relaxation through a cyclic AMP pathway in human
      myocardium, consistent with mediation through a (-)-propranolol-resistant state
      of the beta1-adrenoceptor. The reduction in heart failure of atrial inotropic
      potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity
      binding sites for (-)-[3H]CGP 12177, is consistent with the beta1-adrenoceptor
      nature of these sites.

PMID- 12616337
TI  - Interleukin 1 beta-induced inhibition of gastric acid secretion involves
      glutamate, NO and cGMP synthesis in the brain.
AB  - This study examines the role of a central pathway involving glutamate receptors,
      nitric oxide (NO) and cGMP in the acute inhibitory effects of central interleukin
      1beta on pentagastrin-stimulated acid production.The acid-inhibitory effect of
      central interleukin 1beta was prevented by intracisternal (i.c.) microinjections
      of interleukin 1beta together with the NMDA receptor antagonist, dizocilpine
      maleate (MK-801). Intracisternal co-administration of the nitric oxide synthase
      inhibitor, N(G)-nitro- L-arginine methyl esther ( L-NAME) or 1H
      [1,2,4]oxazodiolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC)
      blocker, both reversed the hyposecretory effect of central interleukin 1beta.
      Peripheral administration of endotoxin significantly reduced pentagastrin
      stimulated gastric acid secretion. I.c. pre-treatment with the interleukin 1
      receptor antagonist, IL-1ra, failed to restore acid secretory responses in these
      rats. In addition, endotoxin did not modify the levels of endogenous mRNA for IL
      1beta in the brainstem. We conclude that central glutamate receptors are involved
      in the acid inhibitory effect of centrally administered interleukin 1beta. This
      central pathway involves synthesis of NO, which acts on the enzyme sGC. However,
      endogenous interleukin 1beta does not seem to be involved in the inhibition of
      gastric acid secretion elicited by peripheral endotoxin.

PMID- 12616338
TI  - Nociceptive reaction and thermal hyperalgesia induced by local ET-1 in mice: a
      behavioral and Fos study.
AB  - The peptide endothelin-1 (ET-1) has been involved in nociception independently of
      its vasoconstrictor effects. We have studied the direct nociceptive behavior
      produced by this peptide as well as its ability to induce thermal sensitisation
      (as measured by the unilateral hot plate method, UHP) when intraplantarly (i.pl.)
      administered in mice. These behavioural measures were complemented by the
      quantification of Fos-protein immunoreactivity in the superficial laminae of the
      dorsal horn spinal neurons located ipsilateral to the injected paw.ET-1 induces
      licking (60-600 pmol, i.pl.) and thermal hyperalgesia (20-200 pmol, i.pl.) in the
      injected paw, both effects being inhibited by the coadministration of ET-1 with
      endothelin type A (ET(A)) receptor antagonist, BQ-123 (0.3-10 nmol), but not with
      endothelin type B (ET(B)) receptor antagonist, BQ-788 (10 nmol). Moreover, the
      licking behavior induced by ET-1 was dose-dependently inhibited by the
      prototypical micro -opioid agonist, morphine. The prior i.pl. administration of
      ET-1 (200 pmol) to mice subjected to thermal heat stimulus (55+/-1 degrees C, 10
      s) increases the number of Fos-immunoreactive dorsal horn spinal neurons compared
      with the application of noxious heat alone. This effect is inhibited by BQ-123
      (10 nmol) but not by BQ-788 (10 nmol).Thus, local ET-1 induces nocifensive
      behavior and thermal hyperalgesia acting through ET(A) receptors. These same
      receptors seem to be also involved in the amplification of Fos immunoreactivity
      induced by ET-1 under heat stimulus in the dorsal horn neurons. These results
      could help to characterize the role of ET-1 in nociceptive processing, a topic of
      special interest due to the pathophysiological involvement of this peptide in
      painful states such as cancer.

PMID- 12616340
TI  - Replacement of imidazole by a piperidine moiety differentially affects the
      potency of histamine H3-receptor antagonists.
AB  - We examined whether replacement of imidazole by a piperidine or pyrrolidine
      moiety will affect the potency and affinity of six H3-receptor antagonists.
      Potencies were determined in superfused mouse brain cortex slices preincubated
      with [3H]noradrenaline, in which the interaction of the antagonists with
      histamine with respect to its inhibitory effect on the electrically evoked
      tritium overflow was studied. Affinities were determined in mouse brain cortex
      membranes, using the radioligand [3H] N(alpha)-methylhistamine. The concentration
      response curve of histamine for its effect on the evoked overflow from mouse
      brain cortex slices was shifted to the right by the 13 compounds under study.
      Replacement of the imidazole by a piperidine ring affected the p A2 value as
      follows: thioperamide, -2.7 log units; clobenpropit, -1.9; proxyfan, -1.3; FUB
      138, -1.2. Potency hardly changed (< or =0.4 log units) when imidazole was
      replaced by piperidine in FUB 181 and by piperidine or pyrrolidine in FUB 153.
      Binding of [3H] N (alpha)-methylhistamine to mouse brain cortex membranes was
      inhibited monophasically by all compounds. The p K(i) values closely matched
      their p A2 values with three exceptions. The p K(i) values of proxyfan, FUB 138,
      and FUB 153 exceeded their respective p A(2) values by about 1 log unit. To
      reveal a potential partial agonism, the effect of the three drugs on (1) the
      electrically evoked tritium overflow and (2) [35S]GTPgammaS binding in mouse
      cortex preparations was determined. Proxyfan proved to be a partial agonist in
      both models (with intrinsic activities of 0.2 and 0.3, respectively) whereas FUB
      138 and FUB 153 were devoid of agonistic effects. In conclusion, replacement of
      imidazole by piperidine or pyrrolidine affects the antagonist potencies of six H3
      receptor antagonists in a very different manner. The piperidine analogue of FUB
      181 (with a p A2 value as high as 7.7) may represent a lead for the development
      of non-imidazole H3-receptor antagonists. The discrepancy between the p K(i) and
      p A2 values may be accounted for by partial agonism in the case of proxyfan but
      can, at present, not be satisfactorily explained with respect to FUB 138 and FUB
      153.

PMID- 12616339
TI  - Pharmacological evidence that tetraethylammonium-sensitive, iberiotoxin
      insensitive K+ channels function as a negative feedback element for sympathetic
      neurotransmission by suppressing omega-conotoxin-GVIA-insensitive Ca2+ channels
      in the relaxation of rabbit facial vein.
AB  - The facial vein isolated from various species relaxes in response to electrical
      field stimulation (EFS). EFS-elicited relaxation of the facial vein is mediated
      through the release of noradrenaline (NA) from sympathetic nerve endings and the
      subsequent activation of smooth muscle beta-adrenoceptors. The release of NA from
      sympathetic nerve endings in arterial tissues requires transmembrane Ca2+ influx,
      mediated predominantly by voltage-gated N-type Ca2+ channels. The present
      pharmaco-mechanical study was undertaken to determine whether the N-type channel
      is the exclusive pre-junctional Ca2+ channel mediating NA release from
      sympathetic nerve endings in the rabbit facial vein. Possible roles of K+
      channels in the sympathetic neurotransmission were also examined, especially
      focusing on the contribution of voltage-dependent, Ca2+-activated K+ (BKCa)
      channels. An isolated ring preparation of the rabbit facial vein exhibited
      intrinsic myogenic tone which lasted for several hours when stretched. EFS
      produced frequency-dependent (0.25-2 Hz) relaxation in this preparation. EFS
      elicited relaxation was abolished by tetrodotoxin (TTX, 1 microM), guanethidine
      (5 microM) or propranolol (1 microM), indicating that NA released from
      sympathetic nerve endings was mediating the relaxant response. NA-mediated
      neurogenic relaxation was almost eliminated by omega-conotoxin-GVIA (1 microM),
      an N-type Ca2+ channel blocker. On the other hand, tetraethylammonium (TEA, 2 mM)
      strongly potentiated EFS-elicited relaxation without affecting the relaxation
      induced by exogenously applied NA. This potentiation by TEA was not profoundly
      diminished by omega-conotoxin-GVIA (1 microM) alone or omega-conotoxin-GVIA (1
      microM) plus omega-agatoxin IVA (10 nM, P-type channel blocker), but was almost
      abolished by omega-conotoxin-GVIA (1 microM) plus omega-agatoxin IVA (10 nM) plus
      omega-conotoxin-MVIIC (3 microM, N-, P- and Q-type channel blocker). The
      potentiating effect of TEA was not mimicked by iberiotoxin (100 nM) or
      charybdotoxin (3 microM), both of which block BKCa channels. These findings
      suggest that pre-junctional N-type Ca2+ channels play the predominant role in the
      sympathetic nerve transmission in the rabbit facial vein, as in peripheral
      arterial vascular beds. In addition, Ca2+ channels resistant to 1 microM omega
      conotoxin-GVIA, most probably Q-type channels, appear to be present at the
      sympathetic nerve endings in the rabbit facial vein and contribute substantially
      to the regulation of NA release from the nerve endings. Prejunctional K+
      channels, sensitive to TEA but pharmacologically distinct from iberiotoxin
      sensitive BKCa channels, seem to be functionally coupled intimately with the
      omega-conotoxin-GVIA-resistant Ca2+ channels, and thus function as a negative
      feedback element in sympathetic neurotransmission in the rabbit facial vein.

PMID- 12616341
TI  - Endotoxin stimulates fecal pellet output in rats through a neural mechanism.
AB  - The effects of endotoxin on fecal pellet output and the neural mechanisms
      involved in this response were investigated in conscious rats. E. coli endotoxin
      (40 micro g/kg i.p.) significantly increased fecal excretion for 3 h after the
      injection. Water content in feces was not modified by endotoxin. Ablation of
      primary afferent neurons by systemic administration of high doses of capsaicin
      (20+30+50 mg/kg s.c.) to adult rats prevented the stimulatory effect of endotoxin
      and so did abdominal vagotomy. Adrenoceptor blockade with phentolamine (5 mg/kg
      i.p.) + propranolol (3 mg/kg i.p.) did not modify pellet output in endotoxin
      treated rats while muscarinic receptor blockade with atropine (1 mg/kg i.p.)
      abolished the stimulatory effect of endotoxin. Finally, the increase in pellet
      output induced by endotoxin was prevented in animals receiving the substance P
      receptor antagonist D-Pro2, D-Trp7,9-substance P (2 mg/kg i.p.) or the NO
      synthase inhibitor L-NAME (10 mg/kg i.p.). None of the above treatments modified
      pellet output in saline-treated rats. These observations indicate that endotoxin
      increases fecal pellet output through a nervous reflex in which capsaicin
      sensitive afferent neurons and the release of excitatory (acetylcholine and
      substance P) and inhibitory (NO) neurotransmitters in the colonic wall are
      involved.

PMID- 12616342
TI  - Molecular modes of action of cephalotaxine and homoharringtonine from the
      coniferous tree Cephalotaxus hainanensis in human tumor cell lines.
AB  - Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive
      from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor
      cell growth at molar ranges comparable to established cytostatic drugs, whereas
      CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50)
      values of CET and HHT were significantly correlated to doxorubicin, vincristine,
      methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental
      Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA).
      We tested both drugs for resistance of cell lines which selectively overexpress
      the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1
      (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance
      protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and
      CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines
      did not show cross-resistance compared to their drug-sensitive counterparts. As
      the tumor suppressor p53 is another important factor of chemoresistance, we also
      analyzed the possibility that p53 affects the response of tumor cells to CET and
      HHT. Comparing the p53 mutational status of the 55 NCI cell lines
      (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation.
      Thus, CET and HHT were more active in cell lines without p53 mutation. We
      correlated the IC50 values of CET and HHT with the cell doubling times of the 55
      NCI cell lines as proliferation parameter and observed that rapidly growing cells
      were more susceptible than slowly growing cell lines. We conducted a search
      mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines
      and correlated the data with the IC50 values for CET and HHT. Of these genes 61
      (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50
      values for HHT indicating the multifactorial mode of action of these drugs in
      cancer cells. We have chosen one example from these genes to test a causative
      role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal
      growth factor receptor ( EGFR) gene truncated in its extracellular domain through
      a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than
      control cells transfected with mock expression vector or non-transfected cells.
      The present investigation presents a starting point to dissect the genes and
      molecular pathways involved in the tumor cells' response to CET and HHT in
      greater detail.

PMID- 12616343
TI  - IL-18 initiates release of matrix metalloproteinase-9 from peripheral blood
      mononuclear cells without affecting tissue inhibitor of matrix metalloproteinases
      1: suppression by TNF alpha blockage and modulation by IL-10.
AB  - The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the
      etiology of a variety of pathological conditions, among them rheumatoid arthritis
      and atherosclerosis as well as tumor growth and metastasis. As biological
      activity of matrix metalloproteinase-9 (MMP-9) has been identified as a hallmark
      in the pathogenesis of these diseases, effects of IL-18 on MMP-9 production by
      human peripheral blood mononuclear cells (PBMC) were investigated. Moreover,
      effects of immunopharmacological intervention by anti-tumor necrosis factor-alpha
      (TNFalpha) or IL-10 were evaluated. Here we report that IL-18 augmented
      production of MMP-9 by PBMC. The potency of IL-18 to induce release of MMP-9 from
      PBMC was comparable with that of TNFalpha. MMP-9 production was dependent on
      endogenous production of TNFalpha, as detected by use of neutralizing monoclonal
      antibodies. Whereas IL-18 and TNFalpha induced the protease, MMP-9 release was
      not mediated by IFNgamma. IL-18 also induced secretion of MMP-9 from human whole
      blood cultures. Antiinflammatory IL-10 efficiently downregulated release of MMP-9
      from unstimulated and IL-18-activated PBMC. In contrast to MMP-9, secretion of
      tissue inhibitor of metalloproteinases-1 (TIMP-1) was not augmented by IL-18.
      Addition of IL-10 enhanced release of TIMP-1 from PBMC. The present study
      broadens the current pattern of IL-18 proinflammatory actions on PBMC, emphasizes
      the pivotal role of intermediate TNFalpha production in these responses, and
      relates IL-18 biological functions to the pathological role of MMP-9.

PMID- 12616344
TI  - Role of the M2 muscarinic receptor pathway in lidocaine-induced potentiation of
      the relaxant response to atrial natriuretic peptide in bovine tracheal smooth
      muscle.
AB  - We earlier reported that lidocaine augments the relaxation and accumulation of
      guanosine 3',5'-cyclic monophosphate produced by atrial natriuretic peptide (ANP)
      in bovine tracheal smooth muscle contracted with methacholine. However, the
      mechanism of that augmentation remains to be elucidated. In this study, we
      examined the role of muscarinic receptor-mediated signalling in the potentiation
      of ANP-induced relaxation by lidocaine. Lidocaine (100 micro M) augmented the
      relaxant responses to ANP in methacholine (0.3 microM)-contracted bovine tracheal
      smooth muscle but had no effect on the relaxant effects of ANP in preparations
      contracted with 100 micro M histamine. Treatment of tracheal preparations with
      methoctramine (0.03 microM), an M2 muscarinic receptor antagonist, enhanced ANP
      induced relaxation and this treatment abolished the synergistic action of
      lidocaine on ANP. In radioligand-binding experiments, lidocaine concentration
      dependently displaced the specific binding of [3H]- N-methyl scopolamine to
      cloned human M2 and M3 muscarinic receptors expressed in Chinese hamster ovary
      cells. These results suggest that lidocaine acts as an M2 muscarinic receptor
      antagonist, thereby potentiating the relaxant responses to ANP in the bovine
      tracheal smooth muscle contracted with muscarinic receptor agonists.

PMID- 12616345
TI  - Inhibition of cromakalim-activated K+ current by ethanol in follicle-enclosed
      Xenopus oocytes.
AB  - Ethanol has been reported to modulate arterial dilation and insulin secretion.
      ATP-inhibited K+ channels (K(ATP)) are reported to have regulatory roles during
      these events. In the present study, the effect of ethanol on K+ currents
      activated by the K(ATP) channel opener cromakalim was investigated in follicular
      cells of Xenopus oocytes. The results indicate that ethanol in the concentration
      range of 10-300 mM (approximately 0.06%-2% v/v) reversibly inhibits the
      cromakalim-induced K+ currents. The 50% of maximal ethanol effect was obtained at
      53 mM. Inhibition of cromakalim-activated K+ current by ethanol was non
      competitive. In oocytes treated with the Ca2+-chelator BAPTA, inhibition of
      cromakalim-induced K+ currents by ethanol was not altered, suggesting that Ca2+
      activated second messenger pathways were not involved in the actions of ethanol.
      Similarly, currents activated by 8-Br-cAMP were also inhibited by ethanol, but
      the ethanol inhibition of 8-Br-cAMP-activated currents was significantly less
      than inhibition of cromakalim-activated currents by ethanol. These results
      indicate that cromakalim-activated K+ currents in follicular cells of Xenopus
      oocytes were modulated by ethanol.

PMID- 12616348
TI  - Rupture of a previously thrombosed thoracoabdominal aneurysm.
AB  - Spontaneous thrombosis of abdominal aortic aneurysms is rare. A patient with a 12
      cm thoracoabdominal aneurysm developed sudden thrombosis of his aneurysm. He was
      treated with axillobifemoral bypass. He went on to rupture 7 months later. While
      spontaneous thromboses of abdominal aortic aneurysms have been previously
      reported, we did not find any reports of a thrombosed thoracoabdominal aneurysm
      or a subsequent rupture of this type of aneurysm. The literature on thrombosis of
      aneurysms is reviewed as well as proposed etiologies for thrombosis and
      subsequent rupture. We believe that resectional therapy may be warranted even in
      high-risk patients.

PMID- 12616349
TI  - Postoperative complications of carotid patching: pseudoaneurysm and infection.
AB  - Patch angioplasty after carotid endarterectomy has been advocated to improve
      results by decreasing the incidence of recurrent stenosis and postoperative
      carotid thrombosis. Aneurysmal and infectious complications may be secondary to
      use of prosthetic materials in arterial reconstruction. We report four patients
      who developed late operative site complications related to carotid patching. All
      four of our patients had delayed pseudoaneurysms and three had infection related
      to the Dacron patch. In a typical case, a 57-year-old who had a right carotid
      endarterectomy in 1994 presented with a 1-month history of an enlarging right
      neck mass 7 years later. Imaging revealed a 6 x 4 cm pseudoaneurysm originating
      from an opening between the patch graft and the old endarterectomized carotid
      wall. Analysis of the literature disclosed an additional 45 patients who had
      pseudoaneurysms and/or infection related to carotid patching, most frequently
      with Dacron. We postulate that a low-grade Staphylococcus epidermidis infection
      of the foreign body patch may be the etiology. Autogenous saphenous vein
      interposition graft and antimicrobials effective against gram-positive organisms
      corrected the pseudoaneurysm. Although the benefits of routine carotid patching
      may include a decrease in restenosis, this advantage must be weighed against the
      risk of late pseudoaneurysm and/or infection when a prosthetic patch is used to
      closed the endarterectomy site.

PMID- 12616350
TI  - Distal aortic arch replacement for aneurysmal disease: the value of preparatory
      carotid subclavian reconstruction.
AB  - Between November 2000 and January 2002, two patients with aneurysms that involved
      the distal part of the aortic arch including the left subclavian artery were
      treated at our institution. Patient 1 had an aneurysm of 5.8 cm extending to the
      proximal descending aorta. Patient 2 had a 6.8 cm type II thoracoabdominal
      aneurysm extending proximal to the aortic bifurcation. Both patients had left
      subclavian-to-carotid transposition in preparation for distal aortic arch
      replacement. Complete replacement of the descending thoracic and abdominal aorta
      was carried out in patient 2. Both cases were done with distal aortic perfusion,
      spinal catheter drainage, and dual lumen endotracheal anesthesia. There was no
      mortality. There were no cerebrovascular complications in spite of the fact that
      patient 1 required aortic cross-clamping between the innominate and left carotid
      artery. There was no paraplegia, renal failure, or mesenteric or lower extremity
      complications. Patient 1 had postoperative vocal cord palsy, eventually requiring
      medialization procedure. He recovered normal voice. Both patients remain alive
      and well at the time of last follow-up (7 to 20 months). Carotid subclavian
      reconstruction in preparation for distal aortic arch replacement facilitates the
      performance of the proximal anastomosis and attempts to maintain flow through the
      left vertebral system during aortic cross-clamping. This may reduce the risk of
      stroke during distal aortic arch replacement.

PMID- 12616351
TI  - Accuracy of three-dimensional simulation in the sizing of aortic endoluminal
      devices.
AB  - The purpose of this study is to examine the accuracy of a 3D simulation generated
      by inclusion of various intensity-selected portions of spiral CT data into a
      proprietary software program (Preview, Medical Media Systems, MMS) in
      preoperative and postoperative assessment of the anatomical features of abdominal
      aortic aneurysm (AAA). The accuracy of this software was measured against two
      other modalities-intravascular ultrasound (IVUS) and axial CT scan-using the IVUS
      as the reference. Eighty-five patients were included; 43 underwent AAA
      endovascular exclusion with Talent devices, and 42 with Aneurx devices.
      Measurement of proximal neck diameter was performed using IVUS, Preview software,
      and axial CT scan with manual calipers. Measurement of the AAA maximum diameter
      was performed using Preview software and axial CT scan; 253 measurements in the
      85 patients were included. These measurements were compared by means of both
      linear regression and Bland-Altman agreement analysis. Our results showed that
      the 95% confidence interval between the Preview software and mean IVUS
      measurement of proximal AAA neck (3.1 and 2.5) is narrow enough for the software
      to be used in sizing AAA. This would be especially important for having the
      properly sized devices available preoperatively. The Preview software tended to
      be more accurate than CT scans although it was not statistically significant.

PMID- 12616353
TI  - Anterior retroperitoneal lumbosacral spine exposure: operative technique and
      results.
AB  - We review our two-team operative technique and results of anterior
      retroperitoneal lumbosacral spine exposure for diskectomy, partial corpectomy,
      and spinal instrumentation. Seventy-two patients with lumbar spondylosis and
      associated symptomatic radiculopathy had this exposure between January 1, 2000
      and January 1, 2002. A single disc space was isolated in 54 patients. Multilevel
      exposure was achieved in 18 patients. Main outcome measures included intra- and
      postoperative complications, blood transfusion requirements, duration of ileus,
      incidence of erectile/sexual dysfunction, and length of hospital stay. A single
      small bowel enterotomy and iliac vein laceration, both repaired primarily, were
      the only intraoperative complications. Perioperative blood transfusions were
      required in 13 patients (18%). Mean length of postoperative ileus was 3.5 days
      and average length of hospital stay was 5 days. Postoperative complications
      occurred in 7 patients (9.7%). These included erectile dysfunction (2), transient
      unilateral lower extremity paresis (1), acute acalculous cholecystitis (1),
      femoral vein thrombosis (1), pneumonia (1), and acute myocardial infarction (1).
      There were no genitourinary or other major vascular injuries. A two-team approach
      for lumbosacral spine instrumentation via anterior retroperitoneal exposure
      capitalizes on unique specialty-specific surgical skills. This paradigm
      facilitates safe lumbosacral spine surgery and major perioperative complications
      are rare.

PMID- 12616352
TI  - Aortoenteric fistula development following endovascular abdominal aortic aneurysm
      repair: a case report.
AB  - Aortoenteric fistulae (AEF) are now known to occur following endovascular repair
      of abdominal aortic aneurysms (AAA), presumably because of mechanical forces of
      dislodged or migrating devices. We present an unusual case of fistula development
      between the ileum and an AAA presenting as a graft infection following
      endovascular AAA repair in the absence of direct mechanical strain. Continued
      pressurization of the aneurysm sac due to endoleak may predispose to this event,
      especially in large aneurysms. Aggressive surveillance and early interventions
      are necessary following all endovascular AAA repairs.

PMID- 12616354
TI  - Treatment of type III endoleak with an aortouniiliac stent graft.
AB  - The purpose of this study was to present a novel treatment method for repair of a
      type III endoleak due to separation of modular components of an AneuRx (Medtronic
      AVE, Sunnyvalle, CA) stent graft as a result of graft kinking. A 73-year-old male
      had undergone endovascular repair of a 8.2-cm abdominal aortic aneurysm (AAA) 2
      years previously. An aortic extender cuff was required to secure the proximal
      graft. Computed tomographic (CT) follow-up revealed a type III endoleak at 6
      month follow-up. Plain radiographs showed separation between the main graft body
      and the aortic extender cuff. A second custom-made 28 mm x 5.5 cm aortic extender
      cuff was placed to seal the type III endoleak. Follow-up CT showed a persistent
      endoleak with an increase in AAA size to 10.5 cm. The patient underwent remedial
      AAA repair with an aortouniiliac endograft placed within the previous stent graft
      and a femorofemoral bypass. At 3-month follow-up there was no detectable
      endoleak. This constitutes an alternative endovascular therapy for modular device
      separation (type-III endoleak) after endoluminal AAA repair in patients who
      cannot undergo repair with a second bifurcated graft.

PMID- 12616355
TI  - Combined off-pump coronary artery bypass and abdominal aortic surgery is
      associated with low morbidity and mortality.
AB  - Patients with abdominal aortic aneurysms (AAAs) often have concomitant coronary
      artery disease. In patients with large or symptomatic AAAs and symptomatic
      coronary artery disease, it may be necessary to address both problems
      simultaneously. We report a case series of five patients undergoing simultaneous
      off-pump coronary artery bypass and abdominal aortic reconstruction. Our series
      and a literature review indicate that simultaneous coronary artery bypass
      grafting on the beating heart and abdominal aortic surgery is safe and effective
      and has a low perioperative morbidity rate.

PMID- 12616356
TI  - Angiographic improvement after rapid intermittent compression treatment
      [ArtAssist] for small vessel obstruction.
AB  - A case is presented of a female ex-smoker who underwent bypass or exploration of
      all three below-knee arteries with failed results. Three separate arteriograms,
      performed at other academic institutions, demonstrated progressive, severe
      involvement of the pedal arteries. Therefore, the patient was prepared to undergo
      below-knee amputation surgery for uncontrollable rest pain and progressive
      necrosis of the forefoot; instead, the patient underwent 4 months of intermittent
      compression treatment. A fourth arteriogram, performed after 4 months of
      intermittent compression treatment (using rapid inflation/deflation and high
      pressure cycle; ArtAssist demonstrated marked improvement of the posterior tibial
      artery runoff and development of more extensive collateral arteries in the calf.
      The patient's rest pain subsided and successful limb salvage was accomplished
      with a modified transmetatarsal amputation. This case could encourage other
      practitioners to repeat arteriography after compression treatments, which may
      redirect the treatment plan for selected patients with critical limb ischemia and
      nonreconstructable peripheral vascular disease.

PMID- 12616357
TI  - Hepatic artery aneurysm.
AB  - Hepatic artery aneurysms are rare. It is also very uncommon to diagnose a hepatic
      artery aneurysm prior to rupture. We report a 53-year-old woman who presented
      with symptoms of gallstones, and was later diagnosed as having hepatic artery
      aneurysm. Abdominal ultrasound and computed tomography showed two cystic lesions
      located at the hepatoduodenal ligament. Color Doppler and arteriography
      identified two aneurysms situated at the common hepatic artery and at the
      bifurcation of gastroduodenal artery, respectively. A saphenous vein graft was
      interposed between the origin of the common hepatic artery and the bifurcation of
      the right and left hepatic arteries. The postoperative course was uneventful and
      the patient was discharged on the seventh postoperative day.

PMID- 12616358
TI  - Complication registration in patients after peripheral arterial bypass surgery.
AB  - The objective of this study was to describe the kinds of complications and their
      incidence after peripheral vascular surgery of the lower limb, coding for causes
      and effect on the patient. In this prospective study, a standardized complication
      registration system was used at the Red Cross Hospital, The Hague. All patients
      (n = 373) receiving an infrainguinal bypass graft during the period January 1,
      1996 to December 31, 1999 were included. All postoperative complications
      occurring during admission were coded. In 29% of the patients 153 complications
      were coded. Early occlusions of the graft occurred 36 times, wound infections 21
      times and postoperative hemorrhages 20 times. Postoperative retention of urine
      was seen most frequently of all nonspecific complications (n = 22). In 43 cases
      the patient needed medication or a blood transfusion for his complication. In 42
      cases a re-intervention was necessary. Complications led to a prolonged stay in
      the hospital in 20 cases. Six patients died during admittance (mortality 1.6%).
      An error in surgical therapy and error in nonsurgical therapy were the cause of
      the complication in 108 cases (out of 153). The advantage of this complication
      registration is that it describes all complications, not just the specific ones.
      Furthermore, by categorizing all complications we force ourselves to look for
      errors in nonsurgical therapy and surgical technique and to describe the effect
      of the complication.

PMID- 12616359
TI  - Aortic and iliac reconstruction after kidney transplantation: experience with an
      algorithm for renal protection.
AB  - Advances in renal transplantation have allowed for improved survival and an
      increased age of recipients. This has resulted in more aortoiliac lesions
      requiring intervention. The optimal approach for renal protection during
      aortoiliac surgery remains unknown. A retrospective review of transplant patients
      admitted to Toronto General Hospital for aortoiliac reconstruction between 1990
      and 2000 was performed. A total of 20 aortic reconstructions were carried out in
      18 patients: 5 patients with ascending aortic repairs and 15 patients with
      aortoiliac reconstructions. Of the five ascending repairs, all had
      cardiopulmonary bypass and four were performed under hypothermic arrest. There
      was one allograft loss in the postoperative period and one mortality. Of the 15
      aortoiliac reconstructions 12 had protection: 10 temporary axillofemoral artery
      bypasses and 2 renal cold perfusion. In the 10 patients with temporary bypass
      protection, there were no graft losses. There was no graft loss in the
      hypothermic perfusion group. Of the three patients without protection, there was
      one graft loss. The postoperative rise in serum creatinine was significantly
      higher (p <0.05) in the no-protection group than in those receiving temporary
      bypass protection. Our algorithm of (1). temporary axillofemoral bypass, (2).
      cold perfusion if temporary bypass cannot be performed, and (3). clamp and sew if
      the patient is too unstable allows for surgery with excellent graft survival.

PMID- 12616360
TI  - Infrainguinal bypass graft patency and limb salvage rates in critical limb
      ischemia: influence of the mode of presentation.
AB  - Rest pain, ulceration, and gangrene are often considered together in studies
      describing outcomes in patients with critical limb ischemia. A retrospective
      analysis of prospectively collected data of 152 infrainguinal bypass grafts
      performed on 128 patients with chronic critical limb ischemia over a 6-year
      period was carried out. Grafts were classified according to the mode of
      presentation and were followed up by regular clinical and duplex examinations.
      Mean follow-up period was 29 months (range 12 to 60 months). Patients'
      demographics, risk factors, and graft characteristics were not statistically
      different between the groups. The 5-year cumulative primary patency rates were
      33%, 52%, and 51% for gangrene, ulceration, and rest pain, respectively (p =
      0.04). The 5-year cumulative primary assisted patency rates were 46%, 70%, and
      72% for gangrene, ulceration, and rest pain, respectively (p = 0.01). The 5-year
      cumulative secondary patency rates were 48%, 76%, and 75% for gangrene,
      ulceration, and rest pain, respectively (p = 0.003). The 5-year cumulative limb
      salvage rates were 59%, 87%, and 83%, for gangrene, ulceration, and rest pain,
      respectively (p = 0.01). Gangrene is a distinct subcategory of critical limb
      ischemia with a worse prognosis than ulceration and rest pain and should be
      classified as such when reporting results of infrainguinal bypass grafts.

PMID- 12616361
TI  - Tumor embolus: a case report and review of the literature.
AB  - Peripheral embolization of macroscopic tumor fragments is an uncommon occurrence.
      A patient with a previously undiagnosed primary lung adenocarcinoma who presented
      with an acutely ischemic limb is described. Following review of the literature,
      the characteristics of tumor embolization are discussed.

PMID- 12616362
TI  - Mortality, morbidity, and costs of ruptured and elective abdominal aortic
      aneurysm repairs in Nova Scotia, Canada.
AB  - Ruptured abdominal aortic aneurysms (RAAA) have a 78-94% mortality rate. If cost
      effectiveness of screening programs for abdominal aortic aneurysms (AAA) are to
      be assessed, direct costs for RAAA repairs and elective AAA (EAAA) repairs are
      required. This study reports mortality, morbidity, and direct costs for RAAA and
      EAAA repairs in Nova Scotia in 1997-1998 and also compares Nova Scotia and U.S.
      costs. We performed a retrospective study of 41 consecutive RAAA and 48 randomly
      selected EAAA patients. Average total costs for RAAA repair were significantly
      greater than those for EAAA repair (direct costs: $15,854 vs. $9673; direct plus
      overhead costs: $18,899 vs. $12,324 [pricing in 1998 Canadian dollars]).
      Intensive care unit length of stay and blood product usage were the most
      substantial direct cost differentials ($3593 and $2106). Direct cost for
      preoperative testing and surveillance was greater in the EAAA group ($839 vs.
      $33). Estimates of U.S. in-hospital RAAA and EAAA repair costs are more than 1.5
      times Nova Scotia costs. Direct in-hospital RAAA repair costs are $6181 more than
      EAAA repair costs. These in-hospital cost data are key cost elements required to
      assess the cost-effectiveness of various screening strategies for earlier
      detection and monitoring of AAA within high-risk populations in Canada. Further
      studies are required to estimate cost per quality-adjusted-life-year gained for
      various AAA screening and monitoring strategies in Canada.

PMID- 12616363
TI  - Thoracic aorta endoprosthesis: the final countdown for open surgery after
      traumatic aortic rupture?
AB  - From December 1998 through May 2001, seven patients with thoracic aortic isthmus
      rupture underwent endovascular stent graft repair. Diagnosis was made by chest X
      ray, transesophageal echography, CT scan, and aortography. The endoprosthesis was
      ordered and/or custom made on an urgent basis. During the delay period blood
      pressure was kept low and the tear closely monitored by means of transesophageal
      echography and CT scan. The mean delay period was 94 days: three patients were
      treated within 24 hr, two patients had their treatment postponed because of
      multiple organ failure, and two patients were diagnosed late. Complete exclusion
      of the pseudoaneurysmal sac was successful in all patients. One patient underwent
      a preliminary carotidosubclavian bypass because of a short proximal neck, one
      subclavian artery was unintentionally partially covered, and a second one was
      deliberately overstented. None of these patients developed arm ischemia or
      claudication. One patient died 3 weeks after the procedure because of the
      severity of associated lesions and comorbidity. Our preliminary results prove
      that endografting for aortic isthmic rupture is technically feasible and that it
      represents a safe and potentially valuable alternative to the mortality and
      morbidity of open surgery. Further evaluation is needed to assess the full
      therapeutic potential and determine the mid and long-term follow-up.

PMID- 12616364
TI  - Psuedoaneurysm of the superficial femoral artery resulting from stingray
      envenomation.
AB  - Stingray envenomations usually result in minor injuries with localized symptoms.
      In some cases the injury incurred is more serious, resulting in significant
      morbidity if not adequately treated. We report a case of pseudoaneurysm of the
      superficial femoral artery resulting from a stingray envenomation in a young
      female. Stingray venom is known to have necrosing properties in human tissues and
      in this case this led to graft failure requiring surgical repair. This case
      emphasizes the insidious nature of stingray venom and the necessity of extensive
      surgical debridement for more significant envenomations.

PMID- 12616365
TI  - Prosthetic femorocrural bypass surgery and adjuvant arteriovenous fistulae.
AB  - The use of an adjuvant arteriovenous fistula (AVF) in vascular procedures is
      controversial. The purpose of this study was to evaluate our experience with this
      adjunct in femorodistal bypass surgery. Patients who received a prosthetic
      femorocrural bypass with or without an AVF were studied (n = 56). Risk factors,
      Doppler and plethysmographic characteristics, and preoperative angiograms were
      analyzed. Of all prosthetic bypasses anastomosed to a single crural vessel, 75%
      received an AVF (AVF+, n = 44) whereas 25% did not (AVF-, n = 12). Preoperative
      ankle/brachial pressures and angiographic outflow scores in both groups were
      comparable. Successful revascularization doubled ankle/brachial pressure indices
      and tripled toe pressures. Bypasses with a maximum angiographic outflow score
      performed better than those with low scores (p <0.05). The overall patency rates
      after 1, 12, and 24 months were 87%, 62%, and 47%, respectively; an AVF did not
      influence these numbers although a trend favoring the use of a fistula was
      present at 1 year (AVF-, 54% vs. AVF+, 64%; p = 0.11). Moreover, 2-year limb
      salvage was not different between groups (AVF-, 75% vs. AVF+, 68%). The use of an
      AVF in prosthetic femorodistal bypass surgery does not improve rates of patency
      and limb salvage in the long term.

PMID- 12616366
TI  - Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA levels in thymoma.
AB  - PURPOSE: Thymoma is one of the most common solid tumors in the mediastinum.
      However, there is no definitive consensus regarding the optimal adjuvant
      chemotherapy for advanced thymoma. METHODS: To predict tumor sensitivity to 5
      fluorouracil (5-FU) in thymoma, we investigated the mRNA levels of thymidylate
      synthase (TS), the key enzyme that catalyzes the methylation of deoxyuridine
      monophosphate, and correlates with the resistance of 5-FU and dihydropyrimidine
      dehydrogenase (DPD), which degrades 5-FU in thymoma. We used real-time
      quantitative reverse transcription-polymerase chain reaction (RT-PCR) using the
      LightCycler to monitor the TS and DPD gene expression levels in thymoma tissue
      specimens from patients, coamplified with glyceraldehyde-3-phosphate
      dehydrogenase (GAPDH) as an internal standard. RESULTS: In the resected tumor
      specimens, TS and DPD mRNA levels were 3.876 and 14.651, respectively. Both the
      TS and DPD mRNA levels were significantly higher in the tumor tissue specimens
      than in the normal adjacent thymus tissue specimens. No significant correlations
      were observed between the TS or DPD levels and other clinicopathological factors.
      CONCLUSIONS: The combined use of measurements of TS and DPD mRNA levels using
      real-time RT-PCR analyses may provide an indication of the selective cytoxicity
      of 5-FU on thymoma. In general, 5-FU itself is not considered to be a useful
      treatment for thymoma. The usufulness of DPD-inhibiting fluoropyrimidine (DIF)
      drugs for thymoma should therefore be further considered.

PMID- 12616367
TI  - Pathophysiological measurement and results after laparoscopic fundoplication for
      gastroesophageal reflux disease.
AB  - PURPOSE: Both surgical and conservative treatments for gastroesophageal reflux
      disorder (GERD) are controversial. The aim of this prosepective study was to
      examine outcomes after laparoscopic antireflux surgery. METHODS: The subjects
      were 143 patients who underwent laparoscopic antireflux surgery. Following
      diagnostic procedures 126 patients were allocated to a total fundoplication group
      (360 degrees C, Nissen-DeMeester) and 17, to a posterior semifundoplication group
      (250-270 degrees, Toupet). All complications were registered, and
      pathophysiological and outcome data were examined 3, 6, and 9 months after
      surgery. RESULTS: By 6 months after surgery the mean lower esophageal sphincter
      (LES) pressure had improved significantly, to 14.8 mmHg in the Nissen-DeMeester
      group, and to 12.1 mmHg in the Toupet group, corresponding to successful
      prevention of esophageal reflux in both groups. Dysphagia was more common in the
      early postoperative period after total fundic wrap (17% vs12%), but this
      difference disappeared in time. All patients reported complete relief of reflux
      symptoms, although two of those who underwent the Nissen-DeMeester fundoplication
      experienced relapse of GERD and required open reconstruction (1.4%). The
      laparoscopic procedure was converted to open surgery in three patients (2%).
      There were no associated deaths and the perioperative complication rate was 4.2%.
      CONCLUSION: Laparoscopic antireflux surgery is an effective treatment for GERD.
      More than 93% of the patients in this series rated their outcome as good to
      excellent following the operation.

PMID- 12616368
TI  - The significance of perineural invasion as a prognostic factor in patients with
      gastric carcinoma.
AB  - PURPOSE: Few studies have investigated the prognostic significance of perineural
      invasion (PNI) in gastric cancer. Therefore, we examined the association between
      PNI and clinicopathological factors and the effect of PNI on overall survival in
      patients with gastric carcinoma. METHODS: Paraffin sections of surgical specimens
      from 354 patients who underwent gastric resection were stained with hematoxylin
      and eosin. PNI was assessed histologically as positive when cancer cells were
      seen in the perineurium or neural fascicles. Survival analysis was done in 219
      patients with T(2,3,4) tumors who underwent potentially curative resection. Data
      were collected prospectively. RESULTS: PNI was positive in 211 of the 354
      patients (59.6%). The ratio of undifferentiated tumors, tumors with vascular
      invasion, and lymph node metastasis was significantly higher in the PNI-positive
      patients than in the PNI-negative patients ( P < 0.0001 for all three
      associations). As the depth of mural invasion increased, so did PNI positivity (
      P < 0.0001). The overall survival of the PNI-positive patients was significantly
      worse than that of the PNI-negative patients in the univariate analysis ( P =
      0.0009). However, PNI had no independent prognostic significance in the
      multivariate Cox proportional hazards model analysis. When the patients were
      separated into subgroups, PNI had prognostic value in patients with T(3) tumors (
      P = 0.036) and no lymph node metastasis ( P = 0.005) in the univariate analysis,
      but no prognostic significance in the multivariate analysis. CONCLUSIONS:
      Although the incidence of PNI is high in gastric carcinoma and increases with the
      progression of disease, it does not provide any additional information to the
      classical prognostic parameters.

PMID- 12616369
TI  - Assessment of effective hepatic blood flow in critically ill patients by
      noninvasive pulse dye-densitometry.
AB  - PURPOSE: Effective hepatic blood flow (EHBF) is thought to reflect splanchnic
      perfusion and the metabolic state of the liver. This study was conducted to
      examine the relationship between cardiac output (CO) and EHBF using pulse dye
      densitometry (PDD) in nonseptic and septic patients, and to assess the prognostic
      value of this relationship. METHODS: The subjects were 33 critically ill
      patients, 16 of whom met the criteria for sepsis. Indocyanine green (ICG) was
      given via a central venous catheter to each patient. CO (l/min) and EHBF (l/min)
      were assessed with PDD. RESULTS: CO and EHBF were significantly correlated in the
      nonseptic patients ( r = 0.92, P < 0.001), but not in the septic patients ( r =
      0.38, P = 0.15). The ratio of EHBF to CO (EHBF/CO) in the septic patients was
      significantly lower than that in the nonseptic patients (0.08 +/- 0.04 vs 0.22 +/
      0.05; P < 0.001). Moreover, in the septic patients, the EHBF/CO ratios of
      nonsurvivors were significantly lower than those of survivors (0.06 +/- 0.04 vs
      010 +/- 0.02; P < 0.01). CONCLUSIONS: In nonseptic patients, the EHBF decreased
      in relation to the CO. However, the EHBF/CO ratio of septic patients was lower
      than that of nonseptic patients, suggesting that inadequate splanchnic perfusion
      or metabolic change occurs in septic patients. Furthermore, the lower EHBF/CO
      ratio was related with a fatal outcome in septic patients. PDD could be a
      clinically useful method of assessing splanchnic conditions in critically ill
      patients.

PMID- 12616370
TI  - Effectiveness of collagenase in the treatment of sacrococcygeal pilonidal sinus
      disease.
AB  - PURPOSE: Sacrococcygeal pilonidal sinus disease (SPSD) is a disease affecting
      young patients, which results in a long-term loss of productive power, and also
      tends to have high rates of morbidity since it has no ideal treatment. The main
      purpose of this study was to investigate the effectiveness of topical collagenase
      in the treatment of SPSD. METHODS: In the present study, 40 patients admitted to
      our department were separated into two groups. Excision and marsupialization with
      dressing by bacterial collagenase was performed in the first group, while the
      treatment was excision and marsupialization without dressing by bacterial
      collagenase in the second group. RESULTS: We determined that the healing in terms
      of the width and depth of the wound in the first week and in depth of wound in
      the second week was better in group 1 than in group 2 ( P = 0.040, P = 0.020, P =
      0.048, respectively). The duration of wound healing was 21.9 +/- 1.3 days in
      group 1, and 28.1 +/- 1.3 days in group 2 ( P = 0.0001). The recurrence rate in
      the intergluteal area, which heals by granulation and has no hair follicles,
      tends to decrease when a partial closure is obtained. CONCLUSION: We therefore
      recommend an excision, marsupialization, and dressing with bacterial collagenase,
      in cases with noncomplicated SPSD.

PMID- 12616371
TI  - Secretory carcinoma of the breast with a cystically dilated intraductal
      component: report of a case.
AB  - A case of secretory carcinoma of the breast in a 61-year-old woman is described.
      She came to our hospital complaining of a bloody nipple discharge. The physical
      examination revealed a 2.8 x 2.1-cm, firm, irregular lump with bloody nipple
      discharge in her left breast. Mammography demonstrated an irregular mass and
      ultrasonography showed an irregular hypoechoic mass accompanied with a cyst.
      Ductgraphy was done. It showed a dilated mammary duct leading to the cyst which
      was partially occupied with carcinoma. A cytologic smear of the nipple discharge
      and fine-needle aspiration cytology revealed similar findings, and both findings
      were malignant. A modified radical mastectomy was performed. A pathological
      examination revealed secretory carcinoma of the breast which had spread inward
      and outward from the cyst. In addition, the nipple discharge flowed from the cyst
      through the dilated mammary duct. The patient is presently alive and well 2 years
      after the operation. Secretory carcinoma is an extremely rare tumor of the breast
      and 48 cases have been reported in Japan. The present case is the first known
      case of secretory carcinoma demonstrating a bloody nipple discharge to come from
      a cyst which has been invaded by carcinoma.

PMID- 12616372
TI  - Stanford type A aortic dissection which ruptured into the left atrium: report of
      a case.
AB  - A Stanford type A aortic dissection ruptures usually into the pericardial space
      or the mediastinal space. We herein report the rare surgical case of a Stanford
      type A aortic dissection which ruptured into the left atrium. The patient had a
      previous history of mitral valve replacement. The time and the cause of the
      aortic dissection was unclear. At operation, adhesions around the proximal aorta
      and between the aortic root and the left atrial roof were confirmed to be one of
      the causes for this rare form. A fistula to the cardiac cavity following an
      aortic dissection may occur in any patient, especially in those with a history of
      previous cardiac surgery.

PMID- 12616373
TI  - Renal preservation in low ectopic right renal artery reconstruction during
      abdominal aortic aneurysm repair: report of a case.
AB  - Renal hypothermia achieved using cold (4 degrees C) heparinized Ringer's lactate
      is an effective method of preventing renal compromise during abdominal aortic
      surgery. We present the case of a 62-year-old man with an abdominal aortic
      aneurysm (AAA), complicated by involvement of an ectopic right renal artery with
      a low abdominal aortic origin and passage across the ventral side of the inferior
      vena cava. The patient underwent AAA repair and right renal artery reconstruction
      using renal perfusion with cold heparinized Ringer's lactate, and no
      deterioration of renal function occurred.

PMID- 12616374
TI  - Giant chylolymphatic cyst of the jejunal mesentry in a child: report of a case.
AB  - A giant chylolymphatic cyst from the jejunal mesentery in a 4-year-old boy is
      herein described. The child presented with an acute intestinal obstruction and
      the etiology of the obstruction was only discovered at surgery, even though
      preoperative abdominal sonography had hinted at the presence of a mesenteric
      lesion. An excision of the cyst, along with part of the involved bowel, was
      performed and was curative. The literature regarding the origin, presentation,
      complications, and particularly, the diagnosis of this rare lesion is also
      reviewed.

PMID- 12616375
TI  - Small bowel obstruction caused by anisakiasis of the small intestine: report of a
      case.
AB  - Enteric anisakiasis is a relatively rare disease that is difficult to diagnose
      preoperatively. We report a case of small bowel obstruction caused by enteric
      anisakiasis in a 59-year-old Japanese man who presented with abdominal pain a few
      hours after eating sliced, raw fish. Because of signs of an intestinal
      obstruction, a laparotomy was performed. Focal thickening and stenosis of the
      ileocecal region were seen about 100 cm from the end of the ileum and the lesion
      was excised. We found a moving anisakis thrusting its head into the mucosa of the
      excised small intestine. Histopathological examination revealed the infiltration
      of eosinophils in all layers of the intestinal wall and severe edema. Enteric
      anisakiasis is very rare, and its diagnosis is usually only made after
      laparotomy. Nevertheless, when signs of acute abdomen develop after the ingestion
      of raw fish, such as sushi or sashimi, the possibility of enteric anisakiasis
      should be borne in mind.

PMID- 12616376
TI  - Adrenal metastasis from rectal cancer: report of a case.
AB  - We report a case of heterochronic adrenal metastasis from colorectal carcinoma in
      a 51-year-old woman. A left adrenal metastasis was found by computed tomography
      and magnetic resonance imaging 8 months after an anterior resection for advanced
      rectal carcinoma, and a left hepatectomy for a solitary liver metastasis. The
      level of serum carcinoembryonic antigen was still within the normal range. A left
      adrenalectomy was performed, and histopathological examination revealed
      adenocarcinoma, compatible with the rectal carcinoma resected 8 months earlier.
      The patient died of lung metastases 6 months after the adrenalectomy. A review of
      autopsy series in the world literature revealed that adrenal metastasis from
      colorectal cancer is not rare. Therefore, the possibility of adrenal metastasis
      should be considered in the follow-up of patients after primary surgery for
      colorectal cancer, even though the liver and lung are the main metastatic sites.

PMID- 12616377
TI  - Jejunal varix with extrahepatic portal obstruction treated by embolization using
      interventional radiology: report of a case.
AB  - We report a case of relapsing jejunal varix with extrahepatic portal obstruction,
      which was successfully treated by embolization using interventional radiology. A
      79-year-old woman suffered repeated episodes of tarry stools 2 years after
      undergoing jejunal resection for a jejunal varix. The bleeding point was inferred
      to be in the small intestine, and abdominal angiography revealed extrahepatic
      portal obstruction and the development of a jejunal varix around the
      hepaticojejunostomy. Because surgical obliteration of the varices or a shunt
      operation for portal decompression may have been very invasive due to severe
      adhesions, the jejunal varix was embolized with anhydrous ethanol and
      interlocking detachable coils. There were no changes in liver enzymes, the
      clearance rate of indocyanine green, or portal pressure, and there has been no
      sign of rebleeding for 13 months. Our experience shows that hemostasis can last,
      as long as the embolization can be done without aggravating portal hypertension.
      In conclusion, embolization using interventional radiology is a safe and useful
      method of treating intestinal varices.

PMID- 12616378
TI  - Metastatic melanoma in the gallbladder: report of a case.
AB  - Both primary and secondary gallbladder melanomas are rare and, when a solitary
      melanoma is found in the gallbladder, it is difficult to determine if it is
      primary or metastatic disease. We report the case of a young woman found to have
      a single metastatic gallbladder melanoma. Surgical removal of a solitary
      metastatic focus remains the treatment of choice for isolated metastasis of a
      malignant melanoma; however, the effectiveness of complementary chemotherapy and
      immunotherapy is still being examined.

PMID- 12616379
TI  - Intraductal papillary mucinous tumor of the pancreas in a young man: report of a
      case.
AB  - We report the rare case of an intraductal papillary mucinous tumor (IPMT) in a
      man younger than 30 years of age. The patient was admitted with upper abdominal
      pain and an elevated amylase level of 662 IU/l. Ultrasonography showed a cystic
      mass in the pancreatic body and endoscopic retrograde cholangiopancreatography
      (ERCP) revealed a dilated pancreatic duct with a filling defect communicating
      with the tumor. He was successfully treated by segmental resection, which seems
      to be the best surgical option for pancreatic body tumors since it results in
      long-term survival and preserves as much pancreatic parenchyma as possible.
      Nevertheless, it can only be done in the absence of additional nodules along the
      pancreatic duct. A pathological diagnosis of intraductal papillary adenocarcinoma
      of the noninvasive type was confirmed, and both stumps were free of tumor.

PMID- 12616380
TI  - Laparoscopic excision of a retroperitoneal cystic lymphangioma: report of a case.
AB  - A 36-year-old woman without any relevant medical history was admitted to our
      hospital with an abdominal tumor that had caused recurrent right hypochondral and
      back pain for 3 months. Retroperitoneal cystic lymphangioma was diagnosed by
      abdominal ultrasonography and computed tomography. We suc-cessfully excised the
      tumor laparoscopically. Retroperitoneal cystic lymphangiomas are rare lesions
      that usually present in infancy, rather than in adulthood. Most patients
      experience chronic symptoms, necessitating therapeutic intervention. Excision is
      the treatment of choice, and can be performed laparoscopically in selected
      patients.

PMID- 12616381
TI  - Isolated traumatic vertebral pseudoaneurysm: report of a case.
AB  - We report a case of isolated traumatic pseudoaneurysm of the vertebral artery in
      a 20-year-old man who suffered blunt injury to the left foreneck and arm in a
      traffic accident. A chest computed tomography (CT) scan on admission showed an
      upper mediastinal hematoma, but the patient's vital signs were stable. A CT scan
      of the head and neck showed a cerebral mass, and an elective cerebral four-vessel
      angiography was performed, which revealed a pseudoaneurysm in the proximal
      portion of the left vertebral artery. At surgery, about 2 cm of the left
      vertebral artery was found to be lacerated, and suture ligation was done on each
      side of the laceration. Postoperative intravenous digital subtraction angiography
      showed an intact right vertebral artery with no residual pseudoaneurysm. There
      were no neurological complications and the patient was discharged on the 16th
      postoperative day.

PMID- 12616382
TI  - False aneurysm in the palmar segment of the ulnar artery: report of a case.
AB  - A case demonstrating a false aneurysm in the palmar segment of the ulnar artery
      caused by a Fogarty's catheter, which had been inserted during a thrombectomy, is
      described. The diagnosis was suspected based on a clinical examination, and
      duplex ultrasonography and computed tomography (CT) confirmed an aneurysm in the
      palmar segment of the ulnar artery. The patient underwent a successful
      aneurysmectomy with end-to-end reanastomosis.

PMID- 12616383
TI  - Prognostic significance of the combination of biological parameters in breast
      cancer.
AB  - To evaluate whether the combination of biological parameters increases their
      prognostic value, the expression of epidermal growth factor receptor (EGFR), DNA
      ploidy, and estrogen receptor (ER) status were analyzed on 998 patients with
      breast cancer. Poor findings for each biological parameter were positive for
      EGFR, aneuploid for DNA ploidy, and negative for ER. According to the number of
      poor findings in these three parameters, the groups with none (309 cases), one
      (377 cases), two (161 cases), and three (151 cases) poor findings were
      classified. A significant ( P < 0.0001) difference was found in the disease-free
      survival (DFS) among the four groups. A multivariate analysis indicated the
      combination of three biological parameters to be an independently significant
      factor for DFS, while the relative risk gradually increased as the number of poor
      findings increased. In conclusion, the present study indicated a gradual increase
      in the prognostic significance as the number of combined biological parameters
      increased.

PMID- 12616384
TI  - Current practices in adult groin hernias: a survey of Japanese general surgeons.
AB  - The tendency to perform abdominal wall reinforcement using various types of mesh
      (tension-free repair) is increasing. A questionnaire to poll Japanese surgeons on
      their current surgical modalities for groin hernias was sent to 105 hospitals and
      was returned by 83 hospitals. The majority (83%) of responders to this survey
      supported the tension-free repair as a standard operation for adult groin
      hernias. Of these 69 tension-free repairs, the mesh-plug repair was the most
      frequent standard operation ( n = 53, 64%) and was performed by all responders.
      Ten (12%) opted for the prolene hernia system (PHS) repair as a standard
      operation and 52% of responders had experience of the PHS repair. Laparoscopic
      repair was performed as a standard operation by only one responder and was
      performed by only 34% of responders.

PMID- 12616388
TI  - Laparoscopic cholecystectomy in octogenarians.
AB  - BACKGROUND: This study aimed to assess the outcome of laparoscopic
      cholecystectomy (LC) in patients 80 years old or older. METHODS: All consecutive
      patients 80 years old or older who underwent LC for symptomatic gallstone disease
      were evaluated. Data analysis included patients' age, gender, indication for
      surgery, comorbid condition, American Society of Anesthesiology (ASA) score,
      preoperative endoscopic retrograde cholangio pancreatography (ERCP),
      intraoperative cholangiogram, operative time, conversion to open surgery,
      morbidity, mortality, and length of stay. RESULTS: In this study, 67 patients (31
      men and 36 women) with a mean age of 84 years (range, 80-90 years) were
      evaluated. Of these 67 patients, 38 (57%) underwent surgery for complicated
      diseases including acute cholecystitis in 15 patients (22%), gallstone
      pancreatitis in 17 patients (25%), cholangitis in 3 patients (4.5%), and
      obstructive jaundice in 3 patients (4.5%). A total of 38 patients (57%) had a
      preoperative ASA of 3 or 4; 23 (34%) had a preoperative ERCP; and 6 (9%) had
      intraoperative cholangiogram. The mean operative time was 94 +/- 20 min. Five
      patients (7.4%) underwent conversion to open surgery because of unclear anatomy.
      Complications occurred in 12 patients (18%) including pulmonary edema in 3
      patients, myocardial infarction in 1 patient, atelectasis in 2 patients, common
      bile duct injury in 1 patient, urinary tract infection in 2 patients, wound
      infection in 2 patients, and intraabdominal infected hematoma in 1 patient. The
      mean length of stay was 5.3 days. There was no mortality. CONCLUSIONS: In
      octogenarians LC is safe and associated with acceptable morbidity and mortality.
      Therefore, it should be considered for this age group. The relatively high
      incidence of complicated gallstone disease in this age group may be decreased if
      surgery is offered to them at earlier stage of the disease, leading to further
      decrease in perioperative morbidity.

PMID- 12616390
TI  - Evaluation of scar formation after botulinum toxin injection or forced balloon
      dilation to the lower esophageal sphincter.
AB  - BACKGROUND: It has been postulated that nonsurgical treatments for achalasia
      cause fibrosis, increasing the risk of surgical Heller myotomy. The goal of this
      study was to evaluate fibrosis, muscle fracture, and esophageal inflammation
      after these treatments. METHODS: Eighteen female swine were divided into three
      groups: 6 were euthanized and their lower esophageal sphincters were harvested
      (group 1); 6 underwent botulinum toxin injection (group 2); and 6 underwent
      forced balloon dilatation (group 3). Groups 2 and 3 were euthanized 30 days later
      and LESs harvested. LESs, were evaluated with trichrome and hematoxylin and eosin
      (H&E) preparations. RESULTS: Results for both trichrome and H&E slides were the
      same: severe inflammation in groups 2 and 3 but only minimal inflammation in
      group 1 (p <0.05) and mild fibrosis in groups 2 and 3 and none in group 1 (p
      <0.05). CONCLUSIONS: Botulinum toxin injection and forced balloon dilatation
      caused significant inflammation in the esophagus of the swine, which would be
      consistent with the injury caused by reflux. Forced balloon dilatation and
      botulinum toxin caused fibrosis and may increase surgical risk.

PMID- 12616391
TI  - Can current technology be integrated to facilitate laparoscopic living donor
      hepatectomy?
AB  - BACKGROUND: Living donor hepatectomy (LDH) is a technically demanding procedure
      that is an alternative for providing livers for transplantation. Unlike liver
      resections for other pathology, LDH requires preservation of the major vessels
      and biliary tree. This study was performed to determine if current technology can
      be integrated to perform laparoscopic LDH. METHODS: Six adult sheep underwent
      laparoscopic LDH of the left lateral segment under general anesthesia.
      Instruments utilized included standard dissecting instruments, ultrasound,
      ultrasonic dissectors, CUSA, the TissueLink Floating Ball, and endoscopic
      staplers. RESULTS: LDH-harvested liver grafts were 44% of whole liver weight.
      Estimated blood loss was 300 cc. Warm ischemia time was 5-7 min. Grafts were
      delivered through 18-cm abdominal wounds. Major vessels and biliary anatomy were
      positively identified in the grafts. CONCLUSIONS: Laparoscopic LDH can be
      performed with available technology. Theoretical advantages include reduced liver
      manipulation and smaller wound size.

PMID- 12616389
TI  - Benign rectal ulcer: an underground cause of inpatient lower gastrointestinal
      bleeding.
AB  - BACKGROUND: Although it is uncommon, significant bleeding per rectum presents one
      of the most difficult emergency problems. Bleeding from a rectal ulcer is not
      well recognized as a cause of such bleeding. METHODS: From July 2000 through
      December 2000, 195 consecutive patients with significant blood loss per rectum
      were reviewed. RESULTS: Forty-eight cases in whom significant gastrointestinal
      (GI) bleeding occurred following prior hospitalization were identified. Sources
      of bleeding were gastroduodenal in 38 cases (79%) and colorectal in 10 cases
      (21%). The causes of inpatient colorectal bleeding were benign rectal ulcer (n =
      4), ischemic colitis (n = 3), neoplasia (n = 2), and diversion colitis (n = 1).
      CONCLUSION: The differential diagnosis for inpatients who develop new inpatient
      GI bleeding differs from that of patients who develop outpatient GI bleeding.
      Careful examination of the rectum following rectal instrumentation is critical.
      In addition to the standard resuscitative measures, the identification and
      treatment of rectal ulcers in this group of patients is of paramount importance.
      The treatment options for bleeding rectal ulcer include conservative therapy,
      cauterization, embolization, banding, and local excision.

PMID- 12616392
TI  - Warm ischemia time does not correlate with recipient graft function in
      laparoscopic donor nephrectomy.
AB  - BACKGROUND: Laparoscopic donor nephrectomy (LDN) has been shown to be a safe and
      effective option for renal procurement. Studies comparing open nephrectomy and
      hand-assisted laparoscopy have emphasized decreased warm ischemia time when
      compared with "pure" laparoscopic retrieval. However, no data exist that define
      exactly what constitutes a prolonged warm ischemia time in terms of recipient
      graft function. The aim of this study was to use a large, single-institution
      experience with LDN to determine if warm ischemia time correlates with recipient
      graft function as measured by serum creatinine levels. METHODS: A total of 640
      LDNs were performed from March 1996 to August 2001. Warm ischemia times were
      prospectively collected and were defined as the time from renal artery occlusion
      to immersion in iced saline. Serial recipient creatinine levels were measured at
      1 week and 1, 3, 6, and 12 months (when possible) from the transplant. Data were
      analyzed using Pearson correlation analysis at a confidence interval of 95%.
      RESULTS: Mean warm ischemia time was 151 s with a standard error of 3.4 s and
      ranged from 35 to 720 s. Recipient creatinine mean at 1 week was 1.94 mg/dl with
      a standard error of 0.06 mg/dl and ranged from 0.5 to 10.5 mg/dl. Recipient
      creatinine mean at 1 month was 1.68 mg/dl with a standard error of 0.06 mg/dl and
      ranged from 0.6 to 8.5 mg/dl. Recipient creatinine mean at 3 months was 1.60
      mg/dl with a standard error of 0.04 mg/dl and ranged from 0.6 to 8.8 mg/dl.
      Recipient creatinine mean at 6 months was 1.63 mg/dl with a standard error of
      0.06 mg/dl and ranged from 0.7 to 13.5 mg/dl. Recipient creatinine mean at 12
      months was 1.70 mg/dl with a standard error of 0.07 mg/dl and ranged from 0.5 to
      14.5 mg/dl. No correlation was found between warm ischemia time and recipient
      creatinine levels at 1 week (p = 0.4737), 1 month (p = 0.9180), 3 months (p =
      0.6227), 6 months (p = 0.8349), or 12 months (p = 0.2835). CONCLUSIONS: Warm
      ischemia time does not correlate with recipient graft function in LDN within the
      range of times studied. Shorter warm ischemia time associated with open donor
      nephrectomy and hand-assisted LDN does not necessarily offer a measurable
      advantage in recipient graft function. During extraction of the kidney,
      expediency to minimize warm ischemia time should not supersede controlled and
      safe maneuvers in renal vessel division and extraction of the kidney.

PMID- 12616393
TI  - Laparoscopic versus open appendectomy: a prospective comparative study of 227
      patients.
AB  - BACKGROUND: Although laparoscopic appendectomy is widely practiced in developed
      countries, still there are many questions regarding the advantages and
      disadvantages of this approach in the treatment of acute appendicitis. Several
      controlled trials have been conducted, some in favor of laparoscopic appendectomy
      others not. The aim of this study was to evaluate laparoscopic appendectomy in
      comparison with open appendectomy, with special emphasis on postoperative septic
      complications. METHODS: For this study, 227 consecutive patients (159 males and
      68 females) with a diagnosis of suspected appendicitis between 1995 and 1999 were
      assigned either to laparoscopic appendectomy (n = 108) or open appendectomy (n =
      119). The patients were assigned according to insurance company approval and
      patient preference. There were no exclusion criteria and no age limits in this
      study. RESULTS: Wound infection was significantly higher in the open group
      (incidence, 7.6%) than in the laparoscopic group (incidence, 0%; p <0.003).
      Intraabdominal infections were equal in both groups. Hospital stay was
      significantly shorter in the laparoscopic group (p <0.046), but operative time
      was little longer than in the open group (p <0.002). Conversion to open surgery
      was necessary in one case. CONCLUSIONS: Laparoscopic appendectomy is as safe and
      effective as the open procedure. It significantly reduces the rate of
      postoperative wound infection. However, it is still acceptable to perform the
      open procedure, especially in hospitals without a large amount of laparoscopic
      experience.

PMID- 12616394
TI  - Laparoscopically assisted colectomy and ileoanal pouch procedure with and without
      protective ileostomy.
AB  - BACKGROUND: Apart from an obviously better cosmetic situation, there is
      controversy on the actual benefit of laparoscopic and laparoscopically assisted
      techniques in restorative proctocolectomy. The need for a protective ileostomy
      remains unclear. METHODS: Fifty-nine consecutive patients with ulcerative colitis
      and familial polyposis were included in this prospective cohort study. The colon
      was mobilized laparoscopically with a four-trocar technique, facilitating
      vascular dissection, rectal resection, and ileoanal pouch construction to be done
      through a Pfannenstiel incision. A protective ileostomy was constructed only in
      patients where the operation was difficult or where the anastomosis was under
      tension. Intra- and postoperative data were recorded; statistical analyses were
      performed by exact logistic regression. RESULTS: Laparoscopic mobilisation was
      successful in 54 patients (91.2%). Two patients had to be primarily converted
      because of exceeding the set time limit; 3 other patients had to have an
      additional median laparotomy. These 5 patients all had an increased body mass
      index (BMI), which was a statistically significant risk factor for failure of the
      laparoscopic technique. 18.6% of patients developed major complications (n = 11).
      Nine patients required secondary ileostomies; all of them either were under high
      dose immunosuppressants (n = 5) or had an increased BMI (average 28.42 kg/m2).
      Failure of the laparoscopic technique was associated with major complications.
      CONCLUSION: Laparoscopically assisted restorative proctocolectomy is technically
      feasible; an increased BMI is a relevant risk factor for failure. The minimally
      invasive approach probably does not reduce the need for a protective ileostomy in
      selected patients. The selection criteria for the addition or omission of a
      protective ileostomy in minimally invasive restorative proctocolectomy remain to
      be clearly defined.

PMID- 12616395
TI  - Matched-pair comparison of three different approaches for thymectomy in
      myasthenia gravis.
AB  - BACKGROUND: Because of the lack of evidence-based data comparing different
      techniques for thymectomy (Thx), a matched-pair study was conducted to evaluate
      the role of thoracoscopic Thx (tThx) more objectively. METHODS: Of 182 patients
      who underwent Thx, 3 groups according to the operation technique were matched for
      myasthenia gravis (MG) without thymoma, age, gender, and severity of MG. Twenty
      patients each who had Thx through anterolateral thoracotomy (aThx), extended
      median sternotomy (sThx), and tThx were compared for length of operation,
      postoperative morbidity, complete remission, quantification of improvement of MG,
      and cosmetic results. RESULTS: Complete tThx required 197 +/- 35 min as compared
      to 113 +/- 43 min for sThx and 82 +/- 27 min for aThx (P <0.001). With zero
      mortality the overall postoperative morbidity rate was 25% for sThx versus 15%
      for aThx and 5% for tThx (P <0.05). There was no difference in complete remission
      of MG. The median activities of daily living (ADL) scores improved by 6.0 (1-19)
      after tThx, 5.5 (2-4) after sThx, and 7.5 (0-12) after aThx. Best cosmetic
      results were achieved after tThx. CONCLUSIONS: There was adequate cumulative
      medium-term improvement of MG and less postoperative morbidity after tThx, which
      may become the preferred technique for Thx.

PMID- 12616396
TI  - Risks and benefits of surgical management of gastroesophageal reflux in
      neurologically impaired children.
AB  - BACKGROUND: The aim of this study was to investigate the feasibility and results
      of laparoscopic antireflux procedure in neurologically impaired children.
      METHODS: Over a 5-yr period, 259 children affected by gastroesophageal reflux
      disease underwent laparoscopic antireflux procedure. Eighty of them (30.8%) were
      neurologically impaired. In 58 children we performed an anterior fundoplication
      according to Thal and in 22 patients a 360 degrees fundoplication according to
      Nissen. Forty-eight children underwent an associated gastrostomy placement at the
      same time as the laparoscopic antireflux procedure. RESULTS: We recorded 4/80
      intraoperative complications; in all cases the complication was managed
      laparoscopically and no conversion was needed. Follow-up ranged from 6 months to
      6 yrs (median 3 yrs). We recorded 24/80 postoperative complications, 5 of which
      required a redo procedure. We have a mortality rate of 17.5% but in only one case
      was the event related to the antireflux procedure. CONCLUSIONS: Laparoscopic
      fundoplication can be performed safely and with acceptable results in
      neurologically impaired children. The indication to add a gastrostomy should be
      tailored to the needs of the individual patient. Mortality rate in neurologically
      impaired children patients with gastroesophageal reflux disease is high but in
      most cases unrelated to the antireflux procedure.

PMID- 12616397
TI  - Improvement of the laparoscopic needle holder based on new ergonomic guidelines.
AB  - BACKGROUND: The aim of this study is to create new ergonomic guidelines for the
      design of laparoscopic needle holders. METHODS: An ergonomic literature study,
      observations in the operating room, handle-shaft angle measurements, and
      anthropometric data were used to compile new ergonomic criteria, specified to the
      function of a laparoscopic needle holder. Based on these guidelines a new needle
      holder was designed. The prototype and three currently available needle holders
      were evaluated according to the new guidelines. In addition, a pelvi-trainer test
      was done to measure the extreme wrist excursions. RESULTS: The ergonomic
      evaluation of three commonly used handles and the new prototype indicate that the
      new handle is an ergonomic improvement in the field of laparoscopic needle
      holders: only the new handle satisfies all criteria. This is validated by the
      results of the pelvi-trainer test, which showed that the new prototype
      significantly (p <0.001) reduced the extreme wrist excursions. CONCLUSION: The
      new design guidelines for a laparoscopic needle holder result in an ergonomic
      improvement of the instrument.

PMID- 12616398
TI  - Genotyping microsatellite DNA markers at putative disease loci in
      inbred/multiplex families with respiratory chain complex I deficiency allows
      rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene
      in Leigh syndrome.
AB  - Complex I deficiency, the most common cause of mitochondrial disorders, accounts
      for a variety of clinical symptoms and its genetic heterogeneity makes
      identification of the disease genes particularly tedious. Indeed, most of the 43
      complex I subunits are encoded by nuclear genes, only seven of them being
      mitochondrially encoded. In order to offer urgent prenatal diagnosis, we have
      studied an inbred/multiplex family with complex I deficiency by using
      microsatellite DNA markers flanking the putative disease loci. Microsatellite DNA
      markers have allowed us to exclude the NDUFS7, NDUFS8, NDUFV1 and NDUFS1 genes
      and to find homozygosity at the NDUFS4 locus. Direct sequencing has led to
      identification of a homozygous splice acceptor site mutation in intron 1 of the
      NDUFS4 gene (IVS1nt -1, G-->A); this was not found in chorion villi of the
      ongoing pregnancy. We suggest that genotyping microsatellite DNA markers at
      putative disease loci in inbred/multiplex families helps to identify the disease
      causing mutation. More generally, we suggest giving consideration to a more
      systematic microsatellite analysis of putative disease loci for identification of
      disease genes in inbred/multiplex families affected with genetically
      heterogeneous conditions.

PMID- 12616401
TI  - Syncope in the elderly.
AB  - Syncope is defined as a self-limited loss of consciousness, usually combined with
      falling due to the inability to maintain postural tone. The underlying mechanism
      is a transient global cerebral hypoperfusion. The aetiology essentially includes
      cardiac disorders (structured heart disease or arrhythmias), neurally-mediated
      reflex syndromes, orthostatic hypotension and carotid sinus syndrome. History and
      physical examination will lead to the diagnosis in up to 50%. The most important
      step is to differentiate patients with heart disease from others, since the
      mortality of these patients is doubled. Echocardiography, Holter-monitoring and
      electrophysiological study are useful to approach this population. In patients
      with suspected neurally-mediated syncope (vasovagal syncope) tilt testing is
      indicated. Treatment depends on the aetiology. The diagnostic work-up and the
      therapeutic approach of patients with syncope are outlined. For patients with
      vasovagal syncope conventional therapeutic strategies include an increased
      salt/fluid intake, moderate exercise training, tilt-sleeping or tilt-training.
      Beta-blockers failed to show efficacy in a number of randomised trials. Recently,
      pacemaker implantation in selected patients with recurrent vasovagal syncopical
      episodes showed a significant increase in syncope-free survival, compared to no
      therapy and compared to beta-blocker therapy. In contrast to the increased
      mortality risk for patients with cardiac syncope, patients with vasovagal syncope
      have a benign prognosis.

PMID- 12616402
TI  - Management of chronic dizziness in elderly people.
AB  - Dizziness is a frequent complaint in elderly people, and is a broad term used to
      explain various abnormal sensations related to the perception of the body's
      relationship to space. Classically, four subtypes are described: vertigo, pre
      syncopal lightheadedness, disequilibrium, and other dizziness. Dizziness is often
      a chronic complaint in elderly people and may lead to dramatic worsened
      functional and psychosocial outcomes. Dizziness should be approached as a symptom
      and as a syndrome. In fact, physicians should exclude potential curable causes of
      dizziness, considering dizziness as a symptom of specific diseases. As dizziness
      is often multifactorial, it should also be treated as a geriatric syndrome.
      Physicians should, thus, identify risk factors of recurrent dizziness. The
      "Dizziness Handicap Inventory Scale" may assist the clinician to establish the
      extent of the "dizziness" problem. Specific causes of dizziness should be
      addressed as well as contributive factors (i.e., medications). Vestibular and
      balance rehabilitation with an interdisciplinary collaboration should start
      rapidly to avoid psycho-social complications, such as fear of falling.

PMID- 12616399
TI  - A genome-wide scan for primary open-angle glaucoma (POAG): the Barbados Family
      Study of Open-Angle Glaucoma.
AB  - Primary open-angle glaucoma (POAG) is characterized by damage to the optic nerve
      with associated loss of vision. Six named genetic loci have been identified as
      contributing to POAG susceptibility by genetic linkage analysis of mostly
      Caucasian families, and two of the six causative genes have been identified. The
      Barbados Family Study of Open-Angle Glaucoma (BFSG) was designed to evaluate the
      genetic component of POAG in a population of African descent. A genome-wide scan
      was performed on 1327 individuals from 146 families in Barbados, West Indies.
      Linkage results were based on models and parameter estimates derived from a
      segregation analysis of these families, and on model-free analyses. Two-point LOD
      scores >1.0 were identified on chromosomes 1, 2, 9, 10, 11, and 14, with
      increased multipoint LOD scores being found on chromosomes 2, 10, and 14. Fine
      mapping was subsequently carried out and indicated that POAG may be linked to
      intervals on chromosome 2q between D2S2188 and D2S2178 and chromosome 10p between
      D10S1477 and D10S601. Heterogeneity testing strongly supports linkage for
      glaucoma to at least one of these regions and suggests possible linkages to both.
      Although TIGR/myocilin and optineurin mutations have been shown to be causally
      linked to POAG in other populations, findings from this study do not support
      either of these as causative genes in an Afro-Caribbean population known to have
      relatively high rates of POAG.

PMID- 12616403
TI  - Predictors of falls in elderly people during rehabilitation after hip fracture-
      who is at risk of a second one?
AB  - BACKGROUND: A fall in old age is known as a common consequence of frailty and
      decline as well as a risk factor for further falls. Studies identifying hip
      fracture patients who are at risk of a further fall are lacking. Therefore it was
      of interest to evaluate the risk factors for falling in a high-risk population,
      i.e., patients during rehabilitation after recent proximal femur fracture.
      METHODS: 935 consecutive patients who had surgical intervention after acute
      fracture of the proximal femur underwent a multidimensional assessment within the
      first two days after admission to the rehabilitation ward. Falls during the stay
      on the rehabilitation ward were registered. The baseline data were compared
      between fallers and non-fallers. FINDINGS: 11.8% of the patients fell during
      rehabilitation. Risk factors associated with a fall were increasing age, male
      gender, type of surgery, the use of a rollator and nocturnal urinary
      incontinence. The risk of falling increased in the middle of the second week of
      rehabilitation, when frailer patients gained mobility and ability to walk by
      themselves, while they were not yet safe enough. INTERPRETATION: It was possible
      to compose a risk profile for future falls. Those identified as 'at risk of a
      further fall' should be selectively offered protective devices and special
      training programs in order to prevent future fractures. As for the surgical
      intervention, the type of surgery in relation to age and long-term outcome is of
      particular interest since the use of the more expensive total hip arthroplasty
      procedure may be more cost effective in the long term.

PMID- 12616404
TI  - Daily physical activity and the use of a walking aid in relation to falls in
      elderly people in a residential care setting.
AB  - Physical activity is usually considered as an important component of a healthy
      lifestyle, including a preventive effect on the risk of falls in the elderly. The
      relationship between physical activity and falls is complex: physical activity is
      a prerequisite to maintain neuromuscular functioning, necessary to keep balance
      and to react to a fall, but a higher level of physical activity also implies a
      greater exposure to environmental threats, possibly leading to a fall. Related to
      this greater exposure to threats, the use of a walking aid may protect against
      falls in those who have impaired mobility. In this cross-sectional study we
      investigated the relationship between daily physical activity and falls and the
      use of a walking aid in elderly subjects. Participants were 131 men and 563
      women, aged 70 years and over (mean age and standard deviation: 82+/-6 years),
      living in homes for the elderly (n=335) and apartment houses for elderly (n=359).
      Data on baseline characteristics and falls in the previous year were obtained
      using a questionnaire. The level of daily physical activity in the previous year
      was obtained by means of a questionnaire regarding household and leisure
      activities. Subjects with a lower extremity fracture in the previous year were
      excluded from the analyses. Data were analysed using multiple logistic
      regression, adjusted for age, gender, and residence. In the past year, 40% of the
      participants fell at least one time, and 19% of the participants fell two times
      or more. Since falls and recurrent falls were nonlinearly related to the level of
      daily physical activity, the physical activity score was grouped into quartiles:
      the highest quartile corresponding to the highest activity level. Odds ratios
      (and 95% confidence intervals) for falls and recurrent falls for subjects in the
      highest quartile contrasted with those in the lowest quartile were 0.5 (0.3-0.9)
      and 0.3 (0.2-0.6), respectively. The risk of falls and recurrent falls was not
      lower for those with intermediate levels of daily physical activity. The use of a
      walking aid protected against falls in those with intermediate high activity
      levels (third quartile). It was suggested that the exposure to environmental
      hazards, due to some degree of physical activity may have been responsible for
      the nonlinear relationship between daily physical activity and falling. We
      conclude that a high activity level and the use of a walking aid may protect
      against falls.

PMID- 12616405
TI  - Elevated heels and adaptation to new shoes in frail elderly women.
AB  - Footwear is supposed to have influence on postural control and is a potential
      aspect to address in the prevention of falls in the elderly. This study aimed to
      show whether measurements of static balance and gait are different with habitual
      shoes compared to new special senior shoes with different heel height and whether
      these results change after adaptation. In a randomized controlled intervention
      study, 26 subjects (median age 87 years) were recruited from two nursing homes
      and one facility of assisted living. Measurements of static balance and gait were
      performed with habitual shoes and two types of new special senior shoes differing
      in heel height. Measurements were repeated after five weeks. There was no
      difference in static balance and gait with habitual shoes compared to either of
      the new footwear offered. Results of performance with higher heels were not
      different compared to lower heels. No further effect of adaptation after wearing
      a new shoe over five weeks could be demonstrated. With respect to static and
      dynamic balance, there seems to be a wide range of acceptable footwear as long as
      the heel height is below a critical value. A standardized shoe can be used in the
      assessment of balance because the effect of adaptation can be neglected.

PMID- 12616406
TI  - [Executive functions and prospective memory performance in old age: an analysis
      of event-based and time-based prospective memory].
AB  - The goal of the present study was to examine the role of executive functions in
      age-related differences in prospective memory. Therefore, in a sample of 40 young
      ( M=24.8; SD=2.0) and 40 old adults ( M=69.3; SD=5.6), event- and time-based
      prospective memory as well as five executive functions were assessed. Results
      show that age differences in prospective memory performance depend largely on age
      related individual differences in executive functions. Furthermore, the results
      indicate several executive functions to differentially predict prospective memory
      performance. The event-based prospective memory task requires inhibition to avoid
      distraction from irrelevant items. The time-based prospective memory task
      requires the flexible shifting of cognitive sets. Overall, the data support the
      assumption that age differences in prospective memory performance are closely
      related to executive functioning. In addition, time- and event-based prospective
      memory seem to rely on different executive processes.

PMID- 12616407
TI  - [Age as a predictor of everyday environmental demands in old age].
AB  - Across the lifespan, different environmental contexts may, in the long term,
      affect health and well-being. Exactly which contextual demands translate into
      different aspects of self-reported everyday demands has hardly been examined. In
      this telephone-based study with 365 adults between 51 and 80 years, we assessed
      (a) age differences in the existing everyday demands, (b) relations between
      different measures of everyday demands, and (c) the correlational patterns
      between measures of everyday contexts and everyday demands. Results demonstrate
      age effects in all measures of everyday demands, and differences between
      measures. The findings suggest age-related differences in the correlational
      patterns between specific everyday contexts and the levels of everyday demands.

PMID- 12616408
TI  - [Nursing in the framework of long-term care insurance as a basic principle of a
      specific nursing approach of rehabilitation?].
AB  - Activating nursing based on the criteria of the long-term care insurance may be
      understood as a second specific and nursing approach of rehabilitation beneath
      medical rehabilitation. Activating nursing is unspecific, characterized by the
      norms and guidelines of the long-term care insurance, but defined as the general
      norm of practical nursing. A professional nursing definition for a specific
      concept is lacking just as funding of nursing science. Adhering to activating
      nursing as a nursing complement to medical rehabilitation in the framework of
      long-term care insurance requires professional development and funding.
      Furthermore, more support of social law is necessary, which depends on
      professional nursing and nursing science-based indication and the intervention
      approach. The article develops an approach--based on a study about rehabilitation
      of people in need for care--and reflects on implementation and acceptance by
      people in the need of care.

PMID- 12616409
TI  - [Is age an independent predictor of mortality in cardiac surgery as postulated in
      EuroScore?].
AB  - The number of "older" patients undergoing cardiac surgery is steadily increasing.
      In the year 2000, 37% of all patients who underwent a cardiac operation in
      Germany were 70 years of age or older. Looking at data form our institution, we
      focused on the topic, whether age on its own is an independent determinant for
      mortality in cardiac surgery. Data from 8769 patients who underwent cardiac
      surgery in our institution from January 1996 until January 2002 were analyzed.
      For all patients, EuroScore and the corresponding age-stripped value was
      calculated. All recorded postoperative complications and 30-day mortality were
      statistically analyzed. EuroScore as well as the age-stripped EuroScore showed a
      significant rise with increasing age in the total number of patients as well as
      in the patients, who did not die during the first 30 days after the operation.
      The 30 day mortality and the incidence of postoperative complications increased
      significantly with age. While the EuroScore showed a significant age-dependent
      increase in patients who died within 30 days after the operation, the age
      stripped EuroScore did not reveal a significant discrepancy in mortality with
      respect to age. Arterial hypertension, diabetes mellitus and atrial fibrillation,
      parameters not mentioned in EuroScore, showed significant differences among age
      groups. According to univariate analysis, arterial hypertension and diabetes
      mellitus were significant predictors of mortality. Entered into a multivariate
      logistic regression analysis, only diabetes mellitus achieved statistical
      significance. Our data and the known age-associated functional and structural
      changes of different organ systems show that age integrates risk factors
      together. In order to limit mortality in the steadily growing number of older and
      multi-morbid patients undergoing cardiac surgery, exceptional emphasis has to be
      put on patient selection and therapeutic measures to improve preoperative status.

PMID- 12616411
TI  - Deep vein thrombosis due to spontaneous nontraumatic myositis ossificans:
      treatment with a venous stent.

PMID- 12616410
TI  - Renal stenting from the radial artery: a novel approach.
AB  - PURPOSE: To describe the technique and feasibility of renal artery angioplasty
      and stenting from the radial artery. METHODS: A series of 19 patients were
      evaluated for transradial renal artery intervention. Procedures were performed
      using carbon dioxide gas (CO2) as the preferred angiographic contrast agent.
      Intervention was performed through a 5 Fr radial artery sheath using low-profile
      balloons and balloon-expandable stents. RESULTS: Nineteen patients with 26
      stenosed renal arteries were considered for treatment via the radial route. A
      negative Allen's test precluded radial puncture in two (11%). In one patient the
      descending aorta could not be catheterized. Stenting from the radial route was
      successful in 22 renal arteries in 16 patients. On an intention-to-treat basis 16
      of the 19 (84%) were treatable from the radial route. In the 17 patients with
      radial access technical success was 94% (16 of 17) patients and 91% (21 of 23) of
      renal arteries. One patient experienced a cerebrovascular event during
      intervention. CONCLUSION: Transradial renal artery intervention is technically
      feasible using low-profile angioplasty balloons and stents. This route offers
      advantages in renal arteries with a caudal angulation and in patients with
      diseases or tortuous iliac arteries.

PMID- 12616412
TI  - Post-kidney transplantation iliac artery stenosis due to iatrogenic injury: case
      report.
AB  - We report a case of left external iliac artery lesions as a complication of post
      kidney transplantation due to vascular clamp application injury. The lesions were
      proximal stenosis and distal occlusion just near the graft anastomosis site and
      they were diagnosed incidentally during the embolization for arteriovenous
      fistula. Angiography confirmed the diagnosis and it was managed successfully by
      percutaneous interventional techniques.

PMID- 12616413
TI  - Right subclavian artery aneurysm: yin-yang sign on CT.

PMID- 12616414
TI  - Transcatheter arterial chemoembolization of liver tumors: effects of embolization
      protocol on injectable volume of chemotherapy and subsequent arterial patency.
AB  - The purpose of this study was to determine whether transcatheter arterial
      chemoembolization (TACE) protocol affects the total volume of chemotherapy
      injected into the liver as well as subsequent arterial patency. A total of 160
      patients with primary or secondary liver cancer were treated with 3 different
      chemoembolization protocols at a single institution. Data were analyzed
      retrospectively. Group 1 (n = 36) consisted of slurry of chemotherapy, oil and
      polyvinyl alcohol particles (PVA), group 2 (n = 91), chemotherapy and oil
      followed by PVA, and group 3 (n = 33), chemotherapy and oil followed by Gelfoam
      pledgets. The total volume of chemotherapy injected into the liver was recorded.
      Arterial patency was determined during subsequent chemoembolizations. The mean
      percentage of total intended chemotherapy dose administered was 54.6% for group
      1, 75.3% for group 2, and 80.6% for group 3. Arterial patency at follow-up
      angiography was 56% for group 1, 74% for group 2, and 81% for group 3. The slurry
      protocol (group 1) significantly reduced arterial patency and injectable volume
      of chemotherapy during TACE.

PMID- 12616415
TI  - Preliminary experience with locoregional intraarterial chemotherapy of uterine
      cervical or endometrial cancer using the peripheral implantable port system
      (PIPS): a feasibility study.
AB  - The purpose of this study was to assess the suitability of a percutaneously
      implantable catheter port system (PIPS) for repeated intraarterial locoregional
      chemotherapy (ILC) for cervical and endometrial carcinoma. In 30 patients with
      advanced, recurrent, or high-risk cervical (n = 23) or endometrial (n = 7)
      carcinoma, PIPS for ILC was implanted via a femoral access, the catheter
      localized in the infrarenal abdominal aorta. Chemotherapy was performed
      adjuvantly after surgery (n = 14) or neo-adjuvantly to enable surgery, or for
      palliation (n = 16). Port implantation, catheter placement, and repeated port
      puncture was uneventful in all patients. Complications included catheter
      dislocation (n = 1), catheter thrombosis (n = 2), subcutaneous infection (n = 1),
      port-bed skin atrophy (n = 1), requiring port explantation in 3 patients. At 2
      years follow-up, complete remission was observed in 7/14 patients with adjuvant
      chemotherapy, partial remission in 3/14. Successful down-staging could be
      achieved in 4/8 patients with neo-adjuvant chemotherapy. The PIPS is suitable for
      repeated ILC which may be a valuable method for pre- and post-surgical therapy of
      advanced or high-risk cervical and endometrial cancer, for adjuvant chemotherapy
      as well as neo-adjuvantly for down-staging, or for palliation.

PMID- 12616416
TI  - Intense inflammatory reaction to heparin polymer coated intravascular Palmaz
      stents in porcine arteries compared to uncoated Palmaz stents.
AB  - The objective of this study was to evaluate the efficacy of heparin-polymer
      coated intravascular stents in the reduction of vessel stenosis. Three types of
      coatings for Palmaz stents were tested: 1) heparin covalently bound to a
      polyethylene oxide (Hp-PEO) tether; 2) heparin copolymerized with ethylene vinyl
      acetate (Hp-Elvax) and 3) Elvax alone. Polymer-coated stents and uncoated
      controls were deployed in the external iliac arteries following endothelial
      injury in 18 swine. The animals were maintained on an atherogenic diet and
      examined by angiography at 6 and 12 weeks. The stented segments were then
      harvested for histopathologic analysis. Both types of heparin-coated stents
      resulted in increased luminal narrowing as compared to the contralateral uncoated
      stents. At 6 weeks, average luminal stenosis was 48% for Hp-PEO stents vs 35% for
      uncoated stents (p <0.05). At 12 weeks, average luminal stenosis was 36% for Hp
      PEO stents vs 26% for uncoated stents (p = NS). For Hp-Elvax stents, the average
      stenosis was 58% vs 33% for uncoated controls (p < 0.05) at 6 weeks and 47% vs
      19% for uncoated controls (p <0.05) at 12 weeks. There was no significant
      difference between Hp-Elvax stents and Elvax stents (p = NS). Increased luminal
      narrowing in coated stents was primarily secondary to a marked inflammatory
      response. Heparin-polyethylene oxide and heparin-ethylene vinyl acetate-coated
      stents resulted in increased luminal narrowing as compared with uncoated stents,
      due to a marked inflammatory response.

PMID- 12616417
TI  - An animal model of abdominal aortic aneurysm created with peritoneal patch:
      technique and initial results.
AB  - The purpose of this study was to develop an abdominal aortic aneurysm model that
      more closely resembles the morphology of human aneurysms with potential for
      further growth of the sac. An infrarenal abdominal aortic aneurysm (AAA) model
      was created with a double-layered peritoneal patch in 27 domestic swine. The
      patch, measuring in average from 6 to 12 cm in length and from 2 to 3 cm in
      width, was sutured to the edge of an aortotomy. Pre- and postsurgical digital
      subtraction aortograms (DSA) were obtained to document the appearance and
      dimensions of the aneurysm. All animals were followed with DSA for up to 5
      months. Laparoscopic examination enhanced by the use of laparoscopic ultrasound
      was also carried out in 2 animals to assess the aneurysm at 30 and 60 days
      following surgery. Histological examination was performed on 4 animals. All the
      animals that underwent the surgical creation of the AAA survived the surgical
      procedure. Postsurgical DSA demonstrated the presence of the AAA in all animals,
      defined as more than 50% increase in diameter. The aneurysmal mean diameter
      increased from the baseline of 10.27 +/- 1.24 to 16.69 +/- 2.29 mm immediately
      after surgery, to 27.6 +/- 6.59 mm at 14 days, 32.45 +/- 8.76 mm at 30 days (p <
      0.01), and subsequently decreased to 25.98 +/- 3.75 mm at 60 days. A total of 15
      animals died of aneurysmal rupture that occurred more frequently in the long
      aneurysms (> or =6 cm in length) than the short aneurysms (<6 cm in length)
      during the first 2 weeks after surgery (p <0.05). No rupture occurred beyond 16
      days after surgery. Four animals survived and underwent 60-day angiographic
      follow-up. Laparoscopic follow-up showed strong pulses, a reddish external
      appearance and undetectable suture lines on the aneurysmal wall. On pathology,
      the patches were well incorporated into the aortic wall, the luminal wall
      appeared almost completely endothelialized, and cellular and matrix proliferation
      were noted in the aneurysmal wall. A reproducible technique for the creation of
      an infrarenal AAA model was developed using a peritoneal patch in swine. The
      aneurysm model proved to have potential for further growth of the sac and a
      tendency to rupture. Because of the growth potential, this might be a better
      model than those with a noncompliant aneurysmal wall for the preclinical
      evaluation of stent-graft devices.

PMID- 12616419
TI  - Incidence of central vein stenosis and occlusion following upper extremity PICC
      and port placement.
AB  - The purpose of this study was to determine the incidence of central vein stenosis
      and occlusion following upper extremity placement of peripherally inserted
      central venous catheters (PICCs) and venous ports. One hundred fifty-four
      patients who underwent venography of the ipsilateral central veins prior to
      initial and subsequent venous access device insertion were retrospectively
      identified. All follow-up venograms were interpreted at the time of catheter
      placement by one interventional radiologist over a 5-year period and compared to
      the findings on initial venography. For patients with central vein abnormalities,
      hospital and home infusion service records and radiology reports were reviewed to
      determine catheter dwell time and potential alternative etiologies of central
      vein stenosis or occlusion. The effect of catheter caliber and dwell time on
      development of central vein abnormalities was evaluated. Venography performed
      prior to initial catheter placement showed that 150 patients had normal central
      veins. Three patients had central vein stenosis, and one had central vein
      occlusion. Subsequent venograms (n = 154) at the time of additional venous access
      device placement demonstrated 8 patients with occlusions and 10 with stenoses.
      Three of the 18 patients with abnormal follow-up venograms were found to have
      potential alternative causes of central vein abnormalities. Excluding these 3
      patients and the 4 patients with abnormal initial venograms, a 7% incidence of
      central vein stenosis or occlusion was found in patients with prior indwelling
      catheters and normal initial venograms. Catheter caliber showed no effect on the
      subsequent development of central vein abnormalities. Patients who developed new
      or worsened central vein stenosis or occlusion had significantly (p = 0.03)
      longer catheter dwell times than patients without central vein abnormalities. New
      central vein stenosis or occlusion occurred in 7% of patients following upper arm
      placement of venous access devices. Patients with longer catheter dwell time were
      more likely to develop central vein abnormalities. In order to preserve vascular
      access for dialysis fistulae and grafts and adhere to Dialysis Outcomes Quality
      Initiative guidelines, alternative venous access sites should be considered for
      patients with chronic renal insufficiency and end-stage renal disease.

PMID- 12616418
TI  - Carbon dioxide in the aortic arch: coronary effects and implications in a swine
      study.
AB  - PURPOSE: CO2 angiography is considered dangerous in the aortic arch where bubbles
      may cause critical cerebral and cardiac ischemia. We investigated CO2
      distribution, physiologic effects in the heart, methods of detection and
      treatments. METHODS: Eight pigs had CO2 and iodinated contrast arch angiograms in
      supine and both lateral decubitus positions. An electrocardiogram, physiologic
      data and cardiac ultrasound were obtained. Therapies included precordial thumps
      and rolls to lateral decubitus positions. RESULTS: Supine high descending aorta
      CO2 injections floated retrograde up the arch during diastole and preferentially
      filled the right coronary artery (RCA): mean score 3.5 (of 4), innominate artery
      2.4, left coronary artery 1.2; n = 17; p = 0.0001. Aortic root injections
      preferentially filled the RCA when the animal was supine, left coronary in the
      right decubitus position, and showed a diffuse pattern in the left decubitus
      position. Right decubitus rolls filled both coronaries causing several lethal
      arrhythmias. Precordial thumps successfully cleared CO2. Ultrasound is a
      sensitive detector of myocardial CO2. CONCLUSION: Arch distribution of CO2
      primarily involves the RCA. Diagnostic ultrasound detects cardiac CO2 well.
      Precordial thumps are an effective treatment.

PMID- 12616422
TI  - Limited surgery and tamoxifen in the treatment of elderly breast cancer patients.
AB  - A conservative approach to treating breast cancer patients was adopted for those
      more than 70 years of age with T1-3 and small localized T4b N0-1 lesions. It
      consists of tumor excision or simple mastectomy with adjuvant tamoxifen. From the
      prospective breast cancer database, patients 70 years or older at the time of
      diagnosis were identified for the period January 1990 to December 1996.
      Demographic, clinical, pathological, and oncologic data were retrieved. A total
      of 236 patients were identified. Ninety-seven patients (41%) were treated
      according to the conservative protocol. Of these, 74 had a tumor excision and 23
      had a simple mastectomy. Their mean age was 79 years. TNM staging was stage I in
      18 patients, stage II in 66 patients, and stage III in 13 patients. There was no
      30-day mortality. Eleven patients were not compliant with tamoxifen use. Two
      patients were lost to follow-up. The mean follow-up is 51 months (range 4 to 109
      months). The cumulative incidence of local and regional recurrence at 8 years is
      5% and 7%, respectively. Locoregional recurrences were controlled with excision,
      mastectomy, or axillary dissection. The cumulative disease-specific, overall, and
      disease-free survival at 5 years is 86%, 64% and 46%, respectively. Tumor
      excision or simple mastectomy with tamoxifen offers sufficient tumor control for
      elderly patients. Axillary dissection and breast or chest wall radiotherapy can
      safely be omitted, thereby greatly reducing health care resource utilization.

PMID- 12616421
TI  - Malignant esophagogastric junction obstruction: efficacy of balloon dilation
      combined with chemotherapy and/or radiation therapy.
AB  - PURPOSE: To assess the efficacy of balloon dilation combined with chemotherapy
      and/or radiation therapy for palliation of dysphagia due to malignant
      esophagogastric junction strictures. METHODS: Fluoroscopically guided balloon
      dilation was attempted in 20 patients. The causes of strictures were gastric
      adenocarcinoma (n = 10) and esophageal squamous cell carcinoma (n = 10).
      Scheduled chemotherapy and/or radiation therapy followed balloon dilation in all
      patients. RESULTS: There were no technical failures or major complications. After
      balloon dilation, 15 (75%) patients showed improvement of dysphagia. No patient
      complained of reflux esophagitis during the follow-up period. Among the 15
      patients, seven needed no further treatment for palliation of dysphagia until
      their deaths. The remaining eight patients underwent repeat balloon dilation (n =
      4) or stent placement (n = 4) 3-43 weeks (mean 15 weeks) after the initial
      balloon dilation because of recurrent dysphagia. CONCLUSION: Balloon dilation
      combined with chemotherapy and/or radiation therapy seems to be an easy and
      reasonably effective palliative treatment for malignant esophagogastric
      strictures.

PMID- 12616423
TI  - Breast abscesses in lactating women.
AB  - We designed a prospective study to assess the contributing factors in puerperal
      breast abscess and to evaluate the treatment options. During the 4-year study
      period, 128 nursing women with breast infection were followed. Of these, 102 had
      mastitis (80%) and 26 had breast abscess (20%). Ultrasonographic examination was
      performed in all cases. Patient age, parity, localization of infection, cracked
      nipples, duration of lactation, duration of symptoms, milk culture results,
      breast infections during previous lactation period, treatment options, healing
      time, and recurrence were recorded prospectively. All mastitis patients were
      treated with antibiotics and none developed an abscess. Ten abscesses were
      aspirated, and 16 abscesses were treated by incision and drainage. Healing times
      were similar. There was no significant difference between mastitis and abscess
      groups regarding age, parity, localization of breast infection, cracked nipples,
      positive milk cultures, or mean lactation time. Duration of symptoms and healing
      were longer in cases of abscess. Multivariate analyses showed that duration of
      symptoms was the only independent variable for abscess development. Recurrent
      mastitis developed in 13 patients (10.2%) within a median of 24 weeks of follow
      up. Delayed treatment of mastitis can lead to abscess formation, and it can be
      prevented by early antibiotic therapy. Ultrasonography is helpful for detecting
      abscess formation. In selected cases the abscess can be drained with needle
      aspiration with excellent cosmesis.

PMID- 12616424
TI  - War injuries of major extremity arteries.
AB  - During the period 1991-1994, 99 patients (all males, median age 35 years) with
      combat-related injuries of major limb arteries were managed. Mechanism: mine
      fragments (40%), high-velocity projectiles (35%), and shotgun pellets (25%).
      Patients were admitted 1 hour to 16 hours (median 8 hours) after injury; 39% were
      in severe hemorrhagic shock. Arterial injury was diagnosed by clinical findings.
      Preoperative angiography was usually not necessary. Of 99 injured patients, 50
      (51%) showed signs of distal ischemia and required arterial reconstruction. No
      primary amputation was performed. Reconstruction was always necessary in cases of
      injury of axillary or popliteal arteries, but not of superficial femoral or
      brachial arteries. Ligation of injured single forearm or crural arteries was well
      tolerated. End-to-end anastomosis by reconstruction was possible only in 38% of
      cases. In 56% of patients, autologous venous bypass was performed. Uncontrolled
      wound infection developed in 22% of cases, leading to a secondary hemorrhage
      compelling arterial ligature (8%), and thrombosis (6%). The secondary amputation
      rate after arterial reconstruction was 10%. Injury of major vessels was
      associated with limb bone fractures, nerve damage, or major vein injuries in 68%
      of cases, frequently on the forearm, the popliteal region, and the crural region.
      When limb ischemia was present, vascular reconstruction had priority over
      orthopedic immobilization. Arterial injury was almost always associated with the
      venous damage in the forearm, the popliteal region, and the crural region.
      Injured veins of the upper limb were ligated; venous repair was more often
      indicated in lower limb injury (52%). The method of choice was lateral
      suture/patch. Gunshot damage to peripheral nerves was rarely treated with primary
      repair.

PMID- 12616425
TI  - Soluble adhesion molecules and myocardial injury during coronary artery bypass
      grafting.
AB  - Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex
      systemic inflammatory response after cardiac surgery. Leukocyte-endothelial
      binding followed by neutrophil migration appears to play a central role. These
      interactions are mediated by adhesion molecules on the surface of activated
      cells. The present study compared the perioperative levels of soluble adhesion
      molecules after coronary artery bypass grafting (CABG) in patients with or
      without cardiopulmonary bypass (CPB). Altogether, 9 patients underwent off-pump
      revascularization and 11 did so with CPB. Plasma levels of soluble adhesion
      molecules sE-selectin and sP-selectin and soluble intercellular adhesion molecule
      1 (sICAM-1) were measured before anesthesia induction and 1, 4, and 20 hours
      after reperfusion to the myocardium. The baseline plasma levels of the adhesion
      molecules were similar in the two groups. Perioperative levels of sE-selectin
      remained the same and did not differ between groups. Plasma sP-selectin increased
      in both groups, the change being significantly greater in the CPB group than that
      in the off-pump group (p = 0.001). Plasma sICAM-1 decreased during an early stage
      after CABG with CPB, recovering at 4 hours after reperfusion; and a significant
      increase in ICAM-1 was observed 20 hours later. In the off-pump group, sICAM-1
      levels did not change at 1 and 4 hours after reperfusion but increased 20 hours
      later. Postoperative creatine kinase-muscle bound (CK-MB) levels were
      significantly higher in the CPB group than in the off-pump group (p = 0.001). The
      change in sP-selectin levels also showed a correlation with CK-MB values (r =
      0.676, p = 0.001). The results indicated that off-pump revascularization is
      associated with reduced endothelial activation and myocardial injury.

PMID- 12616426
TI  - Expression of cyclooxygenases in Helicobacter pylori gastritis and residual
      gastritis after distal gastrectomy.
AB  - It has long been thought that duodenal reflux induces residual gastritis after
      distal gastrectomy. H. pylori infection appears to be another factor in residual
      gastritis; and H. pylori induced gastritis may exist preoperatively or may have
      been introduced postoperatively. Up until now, the surgical effect itself and H.
      pylori infection have not been well differentiated as causes of residual
      gastritis. Our aim in this study was to clarify the relationship between the
      surgical effect and H. pylori infection in residual gastritis. A residual
      gastritis model using the Mongolian gerbil has been established with
      microsurgical technique. Residual gastritis with and without H. pylori infection
      has been studied by histopathological examination and quantitated by Rauws'
      score. The expression of cyclooxygenase (both COX-1 and COX-2) has also been
      examined immunohistologically. Elevation of pH in gastric juice after surgery was
      confirmed. H. pylori infection led to deterioration after surgery. The
      postoperative Rauws' score with infection is higher than without infection.
      Levels of COX-1 were higher after surgery in both animals. COX-2 was not
      expressed in the animals without infection and only a little was expressed in the
      animals with infection. COX-2 was strongly expressed in the operated animals with
      infection, but the surgical effect was minute in the animals without infection.
      Residual gastritis consisted of both surgical gastritis and H. pylori gastritis.
      H. pylori gastritis is curable with eradication of the organism, but surgical
      gastritis is not. The COX inhibitor can be a good candidate in preventing
      residual gastritis after eradication of the H. pylori organism. The clinical
      implications of COX expression for patients with residual gastritis might deserve
      further study in the point of treatment of surgical and H. pylori gastritis.

PMID- 12616427
TI  - Pathologic features and long-term results in early gastric cancer: report of 116
      cases 8-13 years after surgery.
AB  - One hundred sixteen patients who underwent surgery for early gastric cancer (EGC)
      at Careggi General Hospital in Florence between 1987 and 1992 were studied with
      regard to clinicopathologic features, incidence, and recurrence of the disease.
      The overall 5-year cumulative survival rate was 87.5%, and the disease-specific 5
      year survival rate was 88.2%. EGC was limited to the mucosa in 43 patients (37%),
      while it infiltrated the submucosa in 73 others (63%). At the time of surgery,
      9.5% of patients were found to have lymph node metastasis, always concomitant
      with submucosal invasion. There was 1 postoperative death (0.8%); 16 patients
      (13.7%) died of tumor recurrence, and 20 (17.2%) died of unrelated causes.
      Analysis of recurrence showed an intestinal histotype in 13 patients (81.2%),
      submucosal infiltration in 14 patients (87.5%), a Pen-A growth pattern in 8
      patients (50%), and lymph node involvement in 3 patients (18.7%). The Cox
      proportional hazard model indicated that age and depth of wall invasion were
      statistically significant. The best predictor of survival appears to be the depth
      of invasion within the gastric wall. The claim by several investigators that
      prognosis for EGC is also associated with the presence of lymph node involvement
      is not supported by the present study. The postoperative 5-year survival rate in
      node-negative patients was 88.8% compared to 81.8% in node-positive patients (p =
      0.296).

PMID- 12616428
TI  - Incidence and factors associated with recurrence patterns after intended curative
      surgery for gastric cancer.
AB  - Recurrence after curative resection for gastric cancer remains high. We examined
      its incidence and factors related to recurrence pattern, while trying to avoid
      the interaction of various factors. A total of 611 gastric cancer patients after
      resection for curative intent (1988-1995) were analyzed. The result showed that
      245 patients had recurrence (40.1%). Cumulative recurrence rates were 53.5%, 80%,
      89.0%, 94.7%, 96.3%, 98%, and 99.5% at 1, 2, 3, 4, 5, 6, and 7 years,
      respectively. Over half of patients with recurrence (123; 50.2%) had an initial
      single recurrence. Taking single and multiple recurrence together, most
      recurrences (213; 86.9%) were distant metastases, 110 recurrences (44.9%) were
      local relapses, and 78 recurrences (49.8%) were both local and distant. Among the
      distant metastases, 131 patients (53.5%) had peritoneal dissemination, 106
      patients (43.3%) had hematogenous metastases, and 70 patients (28.6%) had distant
      lymphatic spread. Scirrhous-type stromal reaction, serosa invasion, and female
      gender were factors negatively related to peritoneal recurrence. Medullary-type
      stromal reaction and male gender showed a preference for locoregional recurrence,
      and expanding growth tumor commonly led to hematogenous metastasis. Patients who
      had paraaortic lymph node metastasis were at high risk of developing distant
      lymphatic recurrence. It is conceivable that the patterns of recurrence and the
      times to recurrence provide a biological basis for clinical monitoring of
      patients with the aim of modifying therapeutic modalities.

PMID- 12616429
TI  - Relationship between jejunal interdigestive migrating motor complex and quality
      of life after total gastrectomy with Roux-en-Y reconstruction for early gastric
      cancer.
AB  - A total of 22 patients (16 men, 6 women; age 33 to 70 years, m mean, 60.2 years)
      1.0 to 1.5 years (mean 1 year and 2 months) after total gastrectomy with Roux-en-
      Y reconstruction for early gastric cancer (D2 lymph node dissection, curability
      A) were divided into two groups based on the occurrence of interdigestive
      migrating motor complex, phase III (IMMC-pIII) from the Roux-en- Y loop, and
      postoperative quality of life (QOL) was compared. Results were as follows: (1)
      Patients in the IMMC- pIII positive group (n = 12) had more appetite and ate more
      food with less decrease in body weight than those in the IMMC-pIII negative group
      (n = 10). (2) Patients in the IMMC-pIII positive group clearly had fewer
      symptoms, such as early dumping symptoms (systemic symptoms), symptoms of reflux
      esophagitis (e.g., heartburn, feeling of regurgitation, difficult swallowing),
      nausea, abdominal pain, diarrhea, abdominal fullness, and borborygmus, than those
      in the IMMC-pIII negative group. These results showed a more satisfactory
      condition in regard to abdominal symptoms in the IMMC-pIII positive group than in
      the IMMC-pIII negative group.

PMID- 12616430
TI  - Diaphragm myoplasty in the prevention of complications after surgery of hydatid
      disease of the liver.
AB  - A variety of techniques have been used for surgical treatment of hepatic hydatid
      cysts. The objective of this study is to describe the technique of diaphragm
      myoplasty, and to present our experience in the treatment of selected patients
      with hydatid disease of the liver by means of this alternative surgical
      technique. The technique combines a diaphragm myoplasty with a wide partial
      cystectomy performed through a right thoracophrenotomy incision. The medical
      records of the patients with hydatid disease of the liver who were submitted to
      surgical treatment with this technique were reviewed. The clinical
      manifestations, laboratory examinations, operative notes, and postoperative
      results were analyzed. Eight consecutive patients with hepatic hydatid cyst were
      operated on. The cyst was located in the posterior-superior aspect of the right
      hepatic lobe in all patients. Five patients suffered from recurrence of a
      previously operated hepatic hydatid cyst, and two patients suffered from
      complications of their disease. There was no in-hospital mortality or morbidity.
      The early and late postoperative results compare favorably with the results of
      other investigators. The alternative surgical technique for treatment of selected
      patients with hepatic hydatid disease is indicated for patients with a cyst
      located in the posterior-superior aspect of the right hepatic lobe, especially if
      there is a recurrence of the disease after a previous surgery or involvement of
      the diaphragm and/or the intrathoracic organs. The technique provides easy and
      safe access to the cyst and carries most of the advantages of omentoplasty.

PMID- 12616431
TI  - Adenosquamous carcinoma of the liver: clinicopathologic study of 10 surgically
      treated cases.
AB  - This investigation presents the clinical features and outcomes of 10 surgically
      treated primary adenosquamous carcinomas of the liver (ADS-CCC). Peripheral
      cholangiocarcinoma (CCC) occurs less frequently than hepatocellular carcinoma in
      most parts of the world. Reports of surgically treated cases of ADS-CCC are
      sporadic owing to the low resectability rate, difficulty of making an early
      diagnosis, and its poor prognosis. Furthermore, clinicopathologic studies based
      on a limited number of surgically treated cases are still lacking. From 1988 to
      1999 the clinical features of 10 surgically treated cases of ADS-CCC were
      reviewed, including clinical features, operative findings, the pathologic
      picture, and long-term results. The clinical features and outcomes of 171
      patients with CCC were also summarized for comparison. Of 181 surgically treated
      CCC patients, 10 (5.3%) had ADS-CCC. Low bilirubin values and high resectability
      were prominent in the patients in the ADS-CCC group compared with those in the
      CCC group. The prognosis for ADS-CCC is dismal, although overall survival did not
      differ significantly between these two groups. Hepatic resection and curative
      hepatic resection had significant benefit on the overall survival in the CCC
      group but only hepatic overall survival in the ADS-CCC group. The 1- and 3-year
      survival rates of ADS-CCC and CCC patients were 22.2%/0% and 33.7/9.4%,
      respectively. This investigation presents the clinical features and outcomes of
      10 surgically treated ADS-CCC patients. ADS-CCC exhibited higher resectability
      than CCC. Although hepatic resection might benefit the treatment and prolong the
      survival of ADS-CCC patients, the prognosis is still dismal because of the
      specific biologic behavior of the tumor.

PMID- 12616432
TI  - Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma.
AB  - The aim of this study was to assess the value of radiotherapy, and especially
      intraluminal brachytherapy, after resection of hilar cholangiocarcinoma by
      analyzing long-term complications and survival. Between 1983 and 1998, 112
      patients underwent resection of a hilar cholangiocarcinoma. Of the 91 patients
      who survived the postoperative period, 20 patients had no additional
      radiotherapy, 30 patients had only external radiotherapy (46 +/- 11 Gy), and 41
      patients had a combination of external (42 +/- 5 Gy) and intraluminal
      brachytherapy (10 +/- 2 Gy). Overall, 88% of the patients had late complications,
      with a significantly higher rate of complications occurring among patients
      receiving external beam irradiation and brachytherapy. Second to abdominal pain
      (56%), cholangitis (49%) was the most frequent complication and occurred
      significantly more often in patients who had received brachytherapy. Retrograde
      bile leakage after closure of the temporary jejunostomy was a troublesome
      complication in 24% of patients treated with brachytherapy. Overall median
      survival after treatment with adjuvant radiotherapy was longer than after
      resection without additional radiation (24 months versus 8 months, respectively).
      There was, however, no significant benefit from the use of intraluminal
      brachytherapy. In conclusion, additional radiotherapy after resection of hilar
      cholangiocarcinoma significantly improved survival and is recommended by giving
      external beam irradiation but not intraluminal brachytherapy.

PMID- 12616433
TI  - Preoperative endoscopic sphincterotomy and laparoscopic cholecystectomy for the
      management of cholecystocholedocholithiasis: 10-year experience.
AB  - No procedure has yet been identified as the "gold standard" for the detection and
      treatment of common bile duct stones (CBDS) in patients undergoing laparoscopic
      cholecystectomy (LC). This prospective study involves 2137 patients undergoing
      elective laparoscopic cholecystectomy. The algorithm for diagnostic management in
      place until July 1997 involved routine intravenous cholangiography and selective
      endoscopic retrograde cholangiography (ERC). Subsequently, assessment of the bile
      duct was not routinely performed, but a scoring system was applied to single out
      those patients at risk of CBDS who should undergo intravenous cholangiography
      and/or ERC (see Fig. 2). Whenever bile duct stones were found, endoscopic
      sphincterotomy (ES) was performed, and LC was performed with a standardized four
      cannula technique after endoscopic bile duct stone clearance. Common bile duct
      stones were suspected in 340 patients who were referred for preoperative ERC; 250
      patients were referred for ES; 21 patients were referred for open surgery because
      of failure of ERC or sphincterotomy. Common bile duct stones, detected in 283
      cases (13.2%), were removed before surgery in 250 cases (88.3%) and during
      surgery in 28 cases (9.9%). Self-limited pancreatitis occurred in 4.2% of the
      patients after sphincterotomy. Laparoscopic cholecystectomy was performed in
      98.4% of the cases. The conversion rate was 8.3% if sphincterotomy had been
      performed previously and 3.4% after standard laparoscopic cholecystectomy (p <
      0.001). The morbidity rate was 4.5%; mortality, 0.09%. During follow-up five
      patients (0.2%) had retained stones endoscopically treated. Future trials of
      novel strategies for detecting and treating CBDS should compare the results of
      novel strategies with those of the strategy employed in this study, which
      includes selective ERC, preoperative ES, and LC.

PMID- 12616434
TI  - Spontaneous pancreatic bleeding.
AB  - A condition of massive pancreatic hemorrhage without relation to injury,
      inflammation, or aneurysm is described. Seven patients treated between 1972 and
      2001 with spontaneous pancreatic bleeding were reviewed. Follow-up examinations
      were performed in 1999. At the time of presentation, all patients had abdominal
      pain, upper abdominal tenderness, and shock, findings that led laparotomy, where
      the diagnosis was made. The treatment was suture ligation in every case. The
      postoperative course was uncomplicated for five of the seven patients. The other
      two patients died. In conclusion, spontaneous pancreatic bleeding is rare and,
      because of shock and the need for urgent surgery, the diagnosis cannot be made
      preoperatively. The immediate mortality seems to be high.

PMID- 12616435
TI  - Comparison of medial-to-lateral versus traditional lateral-to-medial laparoscopic
      dissection sequences for resection of rectosigmoid cancers: randomized controlled
      clinical trial.
AB  - This study aimed to compare medial-to-lateral versus lateral-to-medial
      laparoscopic dissection sequences for resecting rectosigmoid cancers. We
      hypothesized that the medial-to-lateral approach was a more efficient procedure
      and with potentially better oncologic results. Between January 1997 and June
      1999, a total of 67 patients of rectosigmoid cancer treated by one surgeon using
      the laparoscopic approach were recruited for this prospective, randomized, double
      blind clinical trial. Using the blocked randomization method, 36 patients were
      allocated to a medial-to-lateral (M) group and the other 31 to a lateral-to
      medial (L) group; the groups were well matched in age, gender, symptoms, body
      mass index, American Society of Anesthesiology (ASA) class, tumor location, tumor
      distance above the anal verge, tumor gross morphology, TNM stage of the tumor,
      and accuracy of preoperative TNM staging (p > 0.05). All patients were followed
      up until June 2001. We found that the M group had a significantly shorter
      operating time and lower overall costs than the L group (p < 0.05). There was no
      significant difference between these two groups in terms of intraoperative
      complications, conversion rate, postoperative ileus, hospitalization,
      postoperative pain, postoperative complications, wound length, or disability (p >
      0.05). The postoperative proinflammatory response, evaluated by the C-reactive
      protein level and the erythrocyte sedimentation rate, was significantly lower in
      the M group (p < 0.05). There was no significant difference between these two
      groups regarding postoperative immunosuppression, as evaluated by the alterations
      of total lymphocyte counts and the CD4(+)/CD8(+) ratio (p > 0.05). The extent of
      dissection of these two dissection approaches was similar, as the harvested lymph
      nodes were equivalent (p > 0.05). During the whole follow-up period (median 32
      months, range 24-54 months), the tumor recurrence rate was similar for these two
      groups of patients (5.6% in the M group vs. 6.5% in the L group; p > 0.05). These
      findings indicated that the medial-to-lateral approach was quicker, less
      expensive and possibly less invasive; moreover, it gave oncologic results similar
      to those achieved with the traditional lateral-to-medial dissection sequence. We
      thus concluded that the medial-to-lateral dissection sequence may currently be
      the most appropriate procedure for laparoscopic resection of rectosigmoid
      cancers.

PMID- 12616436
TI  - Local rectal tumor resection results: gasless, video-endoscopic transanal
      excision versus the conventional posterior approach.
AB  - This study compares surgical outcomes for local resection of rectal tumors by two
      approaches: (1) gasless, video-endoscopic transanal-rectal tumor excision
      (gasless VTEM); and (2) a conventional posterior approach. Gasless VTEM involves
      a modification of transanal endoscopic microsurgery (TEM) that incorporates a
      standard laparoscopic video camera without a CO(2) insufflation system. A series
      of 42 patients with 45 rectal tumors (9 adenomas, 36 adenocarcinomas) who
      underwent gasless VTEM between 1993 and 2000 were studied prospectively. The
      control group consisted of 26 similar patients who underwent conventional surgery
      (transsacral or transsphincteric approach) between 1985 and 1993. Age, gender
      ratio, tumor localization, maximum tumor diameter, and histology for the cases
      and the controls were similar, whereas operating time and blood loss were
      significantly greater in the control group (p < 0.001 and p < 0.001,
      respectively). The postoperative intervals until able to walk, urinary catheter
      removal, solid food intake, and discharge from hospital were significantly
      shorter in the gasless VTEM group (p < 0.001, p = 0.002, p < 0.001, and p <
      0.001, respectively); analgesic requirements were significantly less (p < 0.001).
      There was no operative mortality in either group. Postoperative complications
      developed significantly less frequently in the gasless VTEM group than in the
      control group (7.1% vs. 38.5%; p = 0.003). During the median follow-up length of
      73.3 months, no patient developed tumor recurrence in the gasless VTEM group,
      whereas one patient did in the control group. In conclusion, gasless VTEM is less
      invasive and allows shorter hospitalizations and reduced complications than the
      conventional posterior approach, thereby providing an attractive alternative for
      selected patients.

PMID- 12616437
TI  - Stapled and open hemorrhoidectomy: randomized controlled trial of early results.
AB  - The aim of the study was to compare the early results in 52 patients randomly
      allocated to undergo either stapled or open hemorrhoidectomy. Seventy-four
      patients with grade III and IV hemorrhoids were randomly allocated to undergo
      either stapled (37 patients) or open (37 patients) hemorrhoidectomy. Stapled
      hemorrhoidectomy was performed with the use of a circular stapling device. Open
      hemorrhoidectomy was accomplished according to the Milligan-Morgan technique.
      Postoperative pain was assessed by means of a visual analogue scale (V.A.S.).
      Recovery evaluation included return to pain-free defecation and normal
      activities. A 6-month clinical follow-up and a 17.5 (10 to 27)-month median
      telephone follow-up was obtained in all patients. Operation time for stapled
      hemorrhoidectomy was shorter (median 25 [range 15 to 49] minutes versus 30 [range
      20 to 44] minutes, p = 0.041). Median (range) V.A.S. scores in the stapled group
      were significantly lower (V.A.S. score after 4 hours: 4 [2 to 6] versus 5 [2 to
      8], p = 0.001; V.A.S. score after 24 hours: 3 [1 to 6] versus 5 [3 to 7], p =
      0.000; V.A.S. score after first defecation: 5 [3 to 8] versus 7 [3 to 9], p =
      0.000). Resumption of pain-free defecation was significantly faster in the
      stapled group (10 [6 to 14] days vs 12 [9 to 19] days, p = 0.001). At follow-up 4
      weeks and 6 months postoperatively the median (range) symptom severity score was
      similar in both groups (1 [0 to 2] versus 0 [0 to 3], p = 0.150 and 0 [0 to 2]
      versus 0 [0 to 2], p = 0.731). At long-term follow-up occasional pain was present
      in 6/37 (16.2) patients in the stapled group and 7/37 (18.9%) in the Milligan
      Morgan group (p = 1.000); episodes of bleeding were reported by 8/37 (21.6%)
      patients in the stapled group and 5/37 (13.5%) patients in the Milligan-Morgan
      group (p = 0.542). No problems related to continence and defecation were reported
      in either group. Patients were satisfied with the operation in 33/37 (89.2%)
      cases in the stapled group and 31/37 (83.8%) cases in the Milligan-Morgan group
      (p = 0.735). Hemorrhoidectomy with a circular staple device is easy to perform
      and achieves better results than the Milligan-Morgan technique in terms of
      postoperative pain and recovery. Comparable results are obtained at long-term
      follow-up.

PMID- 12616438
TI  - Utilization of fine-needle aspiration in patients undergoing thyroidectomy at two
      academic centers across the Atlantic.
AB  - Although fine-needle aspiration (FNA) has been accepted as a first-line test in
      patients with thyroid masses, the utilization of FNA varies even among
      experienced surgeons. To determine its utility we compared FNA results,
      pathology, and clinical results in patients who underwent thyroidectomy in two
      major endocrine centers on both sides of the Atlantic: one in the United States
      (US) and another in the United Kingdom (UK). Between January 1997 and March 1998
      a total of 84 patients underwent thyroid surgery at the UK center, and 143
      underwent thyroidectomy at the US center. The most common indication for
      thyroidectomy at the UK center was compressive goiter (CG), whereas follicular
      neoplasm (FN) was the most common indication at the US center. Bilateral thyroid
      resections, frozen section utilization, and thyroid cancer surgery were more
      common at the US center. Thyroidectomy for symptomatic multinodular goiter and
      Graves' disease was more prevalent at the UK center. Thyroid gland weights were
      also significantly greater in the UK, indicating a higher incidence of endemic
      goiter. FNA was more commonly employed in the US center (84% vs. 52%; p < 0.001).
      Despite the differing utilization of FNA at these major endocrine centers, only
      one thyroid cancer at each institution was not detected preoperatively (both
      patients had a benign FNA result). Therefore there were no clinically significant
      thyroid cancers found in patients who did not undergo preoperative FNA. In
      conclusion, FNA appears to be differentially utilized depending on the incidence
      of endemic goiter, Graves' disease, and thyroid cancer. In this series no
      clinically significant thyroid cancers were found in patients who did not undergo
      preoperative FNA. Therefore in the hands of experienced thyroid surgeons, FNA can
      be utilized selectively based on the clinical presentation.

PMID- 12616439
TI  - Patients with elevated serum parathyroid hormone levels after parathyroidectomy:
      showing signs of decreased peripheral parathyroid hormone sensitivity.
AB  - We have previously shown that patients with elevated levels of parathyroid
      hormone (PTH) after surgery for parathyroid adenoma have normal parathyroid and
      renal function but demonstrate signs of remineralization of cortical bone,
      decreased calcium absorption, and low levels of vitamin D. We hypothesized that
      decreased peripheral PTH sensitivity could also be of importance for this
      condition. Thirteen patients operated on for a solitary parathyroid adenoma, with
      a mean +/- SD preoperative serum level of calcium of 2.72 +/- 0.12 mmol/L, were
      investigated 6 weeks after surgery with a standardized PTH (1-34) infusion test
      for 6 hours. The eight patients with elevated PTH levels had less increase in
      serum levels of ionized calcium (0.02 +/- 0.03 mmol/L) than did the five patients
      with normal PTH levels (0.06 +/- 0.02 mmol/L) (p < 0.05). Patients with elevated
      PTH also showed less decrease in serum phosphate levels (p < 0.05) and a trend to
      a larger decrease in the excretion of urinary calcium (p = 0.08). The increase in
      1,25-dihydroxyvitamin D(3) did not differ between the two groups of patients.
      Thus patients operated on for parathyroid adenoma with postoperatively elevated
      serum PTH levels showed decreased peripheral sensitivity to PTH.

PMID- 12616441
TI  - Expectations and outcomes when moving from open to laparoscopic adrenalectomy:
      multivariate analysis.
AB  - Various authors have suggested that laparoscopic adrenalectomy (LA) leads to
      better surgical outcomes than open surgery. The debate is still open, however,
      and indications and limitations of minimally invasive surgery have not been
      completely established. The objective of our study was to compare surgical
      outcomes of LA and open adrenalectomy (OA), using multivariate analysis to adjust
      for potential confounding factors (e.g., size of the lesion, histology). Between
      1995 and June 2000 at "Careggi" Hospital in Florence, Italy patients with an
      indication for adrenalectomy were treated laparoscopically if the lesion was < 10
      cm and there was no clinical evidence of malignancy. All 79 patients who
      underwent LA have been included in this study. Among 152 patients who underwent
      OA at "La Sapienza" University in Rome, 93 had an adrenal lesion < 10 cm and no
      clinical evidence of malignancy; they were selected for comparison. Multivariate
      analysis has been used to analyze the effect of the surgical approach (OA vs. LA)
      on the surgical outcome, controlling for potential confounders. Multiple logistic
      regression showed that there is no significant difference in intraoperative
      outcomes (i.e., surgical time > 2 hours, blood loss > or = 500 ml) between
      patients operated on through a traditional approach and those who underwent LA.
      On the other hand, patients operated on laparoscopically have a significantly
      higher probability than the OA group of experiencing a better recovery from
      surgery (i.e., require less postoperative analgesics and return to normal
      activities earlier). The results of the present study show that, although LA does
      not add much benefit in terms of expected intraoperative outcomes, it
      dramatically speeds patients' recovery from surgery. The two approaches are
      complementary and should both be integrated into the technical background of all
      endocrine surgeons.

PMID- 12616440
TI  - Cardiovascular events before and after surgery for primary hyperparathyroidism.
AB  - Cardiovascular disease [atherosclerosis and subsequent myocardial infarction
      (MI)] has been associated with primary hyperparathyroidism. We aimed at studying
      cardiovascular events before and after surgery and mortality after surgery for
      primary hyperparathyroidism using a historical follow-up design. A total of 674
      patients who underwent surgery at three Danish centers between January 1, 1979
      and December 31, 1997 were compared with 2021 age- and gender-matched controls.
      There was an increased incidence of acute MI up to 10 years prior to surgery
      [relative risk (RR) 2.5, 95% confidence interval (95% CI) 1.5-4.2] and within the
      first year following surgery (RR 3.6, 95% CI 1.7-7.6). The risk of MI
      subsequently declined to a normal level more than 1 year after surgery. Patients
      with MI prior to diagnosis also had a higher postoperative risk of new infarction
      than did patients without [odds ratio (OR) 6.0, 95% CI 1.2-30.0]. The risk of
      hypertension, stroke, congestive heart failure, and diabetes was increased before
      surgery. More than 1 year after surgery only hypertension and congestive heart
      failure were more frequent in patients than controls. Preoperative cardiovascular
      disease was associated with an increased risk of death (RR 1.8, 95% CI 1.1-2.8).
      Mortality following surgery was higher than in the general population between
      1979 and 1990 but not between 1991 and 1997. We concluded that there was an
      increase in acute MI up to 10 years prior to surgery. The risk of MI decreased to
      a normal level after surgery, which may be important for preventing
      cardiovascular disease in patients with primary hyperparathyroidism.

PMID- 12616442
TI  - Methodologic requirements for assessing surgical procedures in current medical
      literature.
AB  - Even though, in theory, a new surgical technique should traverse all the stages
      established for drugs before being introduced into medical practice, it is
      suspected that many surgical procedures are utilized without having rigorously
      evaluated their efficacy and safety. With the aim of identifying the methodologic
      aspects currently employed for assessing new surgical procedures, a descriptive
      bibliographic study was carried out. Altogether, 75 journal articles published
      from 1996 to 1998 were reviewed. The papers must have come from studies carried
      out with the expressed objective of evaluating a surgical procedure and were
      selected through MEDLINE or directly from six prestigious medical journals (three
      specifically surgical and three general). Of the reviewed articles, 47% were
      retrospective studies, and the rest were prospective studies. More than 40% of
      the retrospective studies omitted some basic methodologic features, namely a
      description of the patients' source or a definition of the inclusion criteria.
      Among the 41 prospective articles, only 35 used a control group and 15 did not
      employ random allocation. Other basic issues, such as the sample size or
      inclusion of prognostic factors in the analysis, were present in fewer than 50%
      of the articles. It seems there is consensus about admitting that rigorous
      assessment of new surgical treatments should be an unavoidable condition before
      introducing such treatment into practice. The facts demonstrate that this
      principle is not being followed.

PMID- 12616443
TI  - Snakebites in the rainforests of Ecuador.
AB  - Epidemiologic information about snakebites in Ecuador is scarce. Snakebites are
      more common in the lowlands east of the Andes, in the Amazon basin. In the
      present study, a retrospective review of all ( n = 142) snakebite admissions to
      Hospital Pio XII, a regional health center/hospital in the canton of Sucua,
      Morona Santiago, Ecuador was carried out between the years of 1996 and 2000.
      Bites occurred more frequently during the months of March to May. The largest
      group of patients were in the 15- to 49-year-old range (52.5%), and agricultural
      workers were the most affected of all patients by occupation (> 40%). In most
      cases of snakebite, patients could not identify the type of snake that had bitten
      them. A small number of patients ( n = 60, 42.3%) received some type of treatment
      prior to arrival at the hospital. Bites occurred most frequently on the left
      lower extremity (31.7%). Typical symptoms included pain and local edema at the
      snakebite site; generalized symptoms such as fever, nausea, and vomiting were
      less frequent. Most patients (almost 90%) received antivenin during
      hospitalization in addition to supportive care. The mean hospital stay was 4.3
      days. More than 90% of all 142 patients recovered, about 8% with local abscesses.
      Mortality was 2.9% and occurred as a result of complications, including renal
      failure, respiratory failure, and disseminated intravascular coagulation.

PMID- 12616444
TI  - Epidemiology and outcome of aortic aneurysms in Hong Kong.
AB  - The objective of this study was to determine epidemiology and mortality
      statistics for abdominal aortic aneurysms (AAAs) in Hong Kong. Data from three
      sources were obtained and analyzed: (1) Hong Kong Hospital Authority discharge
      statistics for 1999 and 2000; (2) a survey on aortic aneurysms in public
      hospitals conducted by the Working Group of Vascular Surgery; and (3) the
      Department of Surgery, University of Hong Kong Medical Center aortic aneurysm
      database. The disease pattern, distribution, and operative mortality were
      determined. The annual incidence of AAA in Hong Kong is 13.7 per 100,000
      population and 105 per 100,000 for those aged 65 and above. About 10% of the AAAs
      that presented were ruptured. The mean age of the AAA patients was 74 years, with
      84% of them over age 65. The operative repair rate for AAAs was low, being only
      8% for intact aneurysms and 54% for ruptured ones. Overall, 45% of all aneurysm
      repairs were performed for a ruptured AAA. There is diverse practice between
      major vascular centers and smaller regional hospitals. The territory-wide
      operative mortality rates for intact and ruptured aneurysms were 10% (range 4
      24%) and 70% (range 38--100%), respectively. There was no gender bias in the
      rupture and operative rates. The overall mortality was 17% for intact AAAs and
      78% for ruptured AAAs. The average length of hospital stay was 19 days for
      elective AAA surgery and 13 days for ruptured AAAs. The number of operations in
      high-volume centers is increasing with a concomitant decrease in operative
      mortality. There are no definitive data to indicate that the incidence of AAAs is
      rising, but a trend toward an increasing number of operations in referral centers
      is noted. The low repair rates for intact AAAs and the high proportion of repairs
      for ruptured aneurysms suggest that AAAs are undertreated in Hong Kong.

PMID- 12616445
TI  - Reflections on the 50th anniversary of the first abdominal aortic aneurysm
      resection.
AB  - Fifty years ago, on March 29, 1951, Charles Dubost in France performed the first
      successful resection of an abdominal aortic aneurysm and replaced it with a
      cadaver homograft, thereby initiating the modern era of surgical correction of a
      common entity. This article offers a summary of the events leading to that
      milestone in vascular surgery.

PMID- 12616446
TI  - Hepatitis B: progress in the last decade.

PMID- 12616447
TI  - The hepatitis B virus and common mutants.
AB  - Most biological systems have developed complex mechanisms to maintain the
      stability of their genetic information. Exceptions to this include viruses that
      can undergo rapid and substantial genetic sequence changes and alterations. The
      hepatitis B virus (HBV) has evolved a unique life cycle resulting in the
      production of enormous viral loads during active replication without actually
      directly killing the infected cell. Because the virus uses reverse transcription
      to copy its DNA genome, mutant viral genomes are frequently found. Particular
      selection pressures, both endogenous (host immune clearance) and exogenous
      (vaccines and antivirals), readily select out these escape mutants. It is still
      not known which particular viral mutations or combination of mutations directly
      affects the clinical presentation of the liver disease, the nature of the viral
      persistence, or the course and outcome of chronic infection. Further studies are
      needed to identify the pathogenic basis for the selection of these mutants. Such
      research should help improve the basic understanding of this unique virus-host
      relationship and provide new strategies for complete control of HBV infections.

PMID- 12616448
TI  - Immune responses in hepatitis B virus infection.
AB  - Hepatitis B virus infection is one of the most frequent causes of chronic liver
      disease worldwide. Even though a preventive vaccine is available, the search for
      a cure for chronically infected patients remains a high priority to reduce the
      morbidity and mortality from liver cirrhosis and hepatocellular carcinoma. This
      review summarizes the immune response in acute, self-limited and chronic
      hepatitis B; its differential effects on viral replication and liver injury; and
      prospects for immunotherapy.

PMID- 12616449
TI  - Epidemiology and prevention of hepatitis B.
AB  - The primary goal of hepatitis B prevention programs is reduction of chronic
      hepatitis B virus (HBV) infection and HBV-related chronic liver disease. Although
      donor screening, risk-reduction counseling and services, and effective infection
      control practices can reduce or eliminate the potential risk for HBV
      transmission, immunization is by far the single most effective prevention
      measure. Worldwide, the integration of hepatitis B vaccine into existing
      childhood vaccination schedules has the greatest likelihood of long-term success.
      However, by 2000, only 116 of 215 countries had such a policy, representing 31%
      of the global birth cohort. In addition, efforts must be strengthened to
      vaccinate older adolescents and adults with high-risk behaviors or occupations in
      countries where most HBV transmission and the morbidity associated with acute
      hepatitis B occur among persons in these age groups. Although continued
      immunization of successive birth cohorts should achieve the eventual elimination
      of HBV transmission, this will not occur for decades without successful
      vaccination of adults at increased risk for infection.

PMID- 12616450
TI  - Natural history and prognosis of hepatitis B.
AB  - The natural history of hepatitis B virus (HBV) infection is complex and variable
      and is greatly influenced by the age at infection, the level of HBV replication,
      and host immune status. Chronic HBV infection generally consists of an early
      replicative phase with active liver disease (hepatitis B e antigen [HBeAg]
      positive chronic hepatitis) and a late low or nonreplicative phase with HBeAg
      seroconversion and remission of liver disease (inactive carrier state). After
      HBeAg seroconversion, some patients may have active hepatitis due to HBV variants
      not expressing HBeAg (HBeAg-negative chronic hepatitis). Morbidity and mortality
      are linked to development of cirrhosis and hepatocellular carcinoma. Survival is
      reasonably good (about 85% probability at 5 years) in compensated cirrhosis but
      very poor in decompensated cirrhosis. Both cirrhotic and noncirrhotic patients
      with sustained reduction of HBV replication and normalization of aminotransferase
      after interferon alfa therapy have a reduced risk for liver-related
      complications.

PMID- 12616451
TI  - Hepatitis B in children.
AB  - Childhood hepatitis B virus (HBV) infection presents both medical and public
      health challenges. Infants who acquire HBV perinatally have up to 90% risk of
      developing chronic HBV infection. Many HBV-infected children have normal alanine
      aminotransferase values and minimal chronic hepatitis. Children with chronic HBV
      infection are usually asymptomatic but may develop chronic liver disease or
      hepatocellular carcinoma. Both interferon-alfa and lamivudine are available for
      the treatment of chronic hepatitis B in children, but the optimal treatment of
      children with chronic HBV infection is evolving as the indications, timing,
      efficacy, and side effects of the treatments are better understood. Universal
      infant vaccination has been shown to decrease the frequency of HBV infection and
      its sequelae. This article addresses aspects of HBV infection that are either
      unique to or different in children.

PMID- 12616452
TI  - Treatment of HBe antigen-positive chronic hepatitis B.
AB  - Spontaneous loss of hepatitis B e antigen (HBeAg) followed by seroconversion to
      anti-HBe usually coincides with normalization of serum alanine aminotransferase
      (ALT) levels, reduction in HBV DNA in serum (< 1 x 10(6) copies/mL), and a marked
      reduction in hepatic inflammation. Licensed antiviral therapies are the
      interferon (IFN) alphas and the nucleoside analogue lamivudine. Both drugs
      enhance the rate at which HBeAg seroconversion takes place and thus reduce
      progression of disease. These therapeutic agents are ineffective if given when
      there is no ongoing hepatitis (i.e., normal ALT), and their efficacy is greatest
      in individuals with the most active disease. The effectiveness of these two
      classes of drugs is similar, and it is possible that the two therapies combined
      are more effective than monotherapy with either drug. A high side-effect profile
      and the high risk of further morbidity when given to patients with decompensated
      disease limit the use of IFN-alpha. When prescribing lamivudine, drug resistance
      that increases with duration of therapy and the potential risk of a severe flare
      of hepatitis with sudden cessation of therapy, probably greatest in patients with
      cirrhosis, are realistic concerns. Both patient and physician need to recognize
      the need for close monitoring both during and after cessation of any antiviral
      therapy for hepatitis B.

PMID- 12616453
TI  - Treatment of HBeAg-negative chronic hepatitis B.
AB  - The goals of therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis
      B (CHB) are to abolish or efficiently suppress viral replication, which
      represents the main determinant of underlying liver necroinflammation and
      fibrosis. Currently available agents include interferon-alfa (IFN-alpha),
      lamivudine, and soon adefovir dipivoxil. A > or = 12-month course of IFN-alpha
      treatment or retreatment achieves sustained biochemical responses in 15 to 25% of
      patients with eventual hepatitis B surface antigen (HBsAg) loss and anti-HBs
      development in a proportion of them. Lamivudine induces initial virologic and
      biochemical responses in 70 to 90%, but breakthroughs due to lamivudine-resistant
      mutants accumulate with continuation of therapy and thus only one third of
      patients may remain in remission after the third year of therapy. Adefovir
      dipivoxil also achieves on-therapy responses in the majority of cases. Adefovir
      dipivoxil and entecavir appear to be effective against lamivudine-resistant
      strains. Many other antiviral agents and immunomodulatory approaches are
      currently evaluated for CHB, but, besides IFN-alpha, none has yet been
      convincingly shown to induce sustained off-therapy responses.

PMID- 12616455
TI  - Xanthogranulomatous choledochitis: a previously undescribed mass lesion of the
      hepatobiliary and ampullary region.
AB  - Solid liver and pancreatic masses are commonly neoplastic in nature; however,
      inflammatory lesions mimicking carcinoma are at times encountered in these sites.
      We report two cases of previously undescribed inflammatory mass lesions of the
      liver and pancreas that originated in the biliary tract. Detailed clinical and
      histologic evaluations were performed in two patients who underwent right partial
      hepatic lobectomy and Whipple's resection for presumed hepatic and pancreatic
      neoplasms. In case 1, with a remote history of cholecystectomy and recent
      extraction of a stone from the common bile duct, a liver mass in segment 6 was
      discovered incidentally. In case 2, a periampullary pancreatic mass was diagnosed
      radiographically following papillotomy and stent insertion for stricture and
      biliary calculous disease. The histologic findings in both cases were similar,
      localized around a part of the biliary tract, and consisted of inspissated bile,
      acute and chronic inflammation, abundant lipid-laden macrophages, fibrosis, and
      giant cell reaction. No neoplasm was identified. On the basis of the close
      resemblance of these features to those seen in xanthogranulomatous cholecystitis,
      the lesions seen here were termed xanthogranulomatous choledochitis. In
      conclusion, xanthogranulomatous choledochitis is a benign inflammatory process
      involving the biliary tract that can form a mass lesion within the liver or
      pancreas and thus mimic a neoplasm. Extensive sampling of the lesion is required
      to rule out an underlying neoplastic process. In our patients a propensity to
      form lithogenic bile and a prior history of biliary tract operative procedure
      were present.

PMID- 12616454
TI  - Management of patients with decompensated HBV cirrhosis.
AB  - Patients with decompensated hepatitis B virus (HBV) cirrhosis have a poor
      prognosis due to the development of progressive liver failure and hepatocellular
      carcinoma. Lamivudine appears to be a safe and effective antiviral agent, which
      may improve or stabilize liver disease in selected patients with advanced
      cirrhosis and active HBV replication. However, viral resistance can develop with
      prolonged treatment and some patients with advanced cirrhosis may not experience
      any discernible benefit. The use of hepatitis B immunoglobulin prophylaxis with
      or without lamivudine has resulted in excellent survival and a low rate of graft
      reinfection in patients who undergo liver transplantation for decompensated HBV
      cirrhosis. Adefovir and entecavir are newer antiviral agents that have activity
      against both wild-type and lamivudine-resistant HBV. Additional studies of
      individual or combination antiviral agents are urgently needed to improve further
      the prospects for the large number of patients worldwide with decompensated HBV
      cirrhosis.

PMID- 12616457
TI  - Introduction: gender and kidney disease.

PMID- 12616458
TI  - The role of gender in the progression of renal disease.
AB  - The rate of progression of certain renal diseases in animals is greater in men
      than in women. In various animal models of renal disease, investigators have
      concluded that the presence of testosterone explains the worse course in men
      compared with women, whereas in other diseases, estrogen seems to confer
      protection for women. The gender disparity in renal disease progression found in
      animals is seen in certain human renal diseases, including chronic renal disease,
      membranous nephropathy, immunoglobin A nephropathy, and polycystic kidney
      disease. In humans, the differences between the genders in renal disease
      progression cannot be fully explained by differences in blood pressure or serum
      cholesterol levels. The underlying mechanisms for this gender disparity are
      potentially related to differences between the sexes in glomerular structure,
      glomerular hemodynamics, diet, variations in the production and activity of local
      cytokines and hormones, and/or the direct effect of sex hormones on kidney cells.
      Further investigation into the contribution of gender to renal disease
      progression may aid us in developing strategies for slowing this pathological
      process.

PMID- 12616459
TI  - Sex and the renin angiotensin system: implications for gender differences in the
      progression of kidney disease.
AB  - Two recognized risk factors implicated in the pathogenesis of progressive renal
      disease are overactivation of the renin angiotensin system and male gender. The
      peptide hormone, angiotensin II, produced by the renin angiotensin system
      cascade, plays a crucial role in maintaining blood pressure and electrolyte
      homeostasis. Medications that block the action of angiotensin II by either
      inhibiting its synthesis or by blocking its ability to bind its receptor are in
      wide clinical use because of their ability to significantly retard the
      progression of kidney disease. Analysis of data from national end-stage renal
      disease registries, clinical trials, and experimental animal models suggest that
      the progression of chronic kidney disease from several etiologies is more rapid
      in men than in women. In this review, we examine the data supporting the
      hypothesis that modulation of the activity of the renin angiotensin system by sex
      steroids markedly contributes to the gender differences observed in the
      pathophysiology of progressive kidney disease.

PMID- 12616460
TI  - Cystic disease in women: clinical characteristics and medical management.
AB  - Autosomal dominant polycystic kidney disease (ADPKD) is a dominantly inherited
      systemic disorder equally inherited in men and women characterized by renal cyst
      development and expansion ultimately leading to renal failure. ADPKD women have a
      slower rate of progression to renal failure, with a later age of entry into end
      stage renal disease (ESRD) as compared with men. Renal cyst growth and renal
      expansion are the hallmarks of ADPKD, and women will develop renal insufficiency
      with smaller renal volume than their male counterparts. As well, women have
      different rates of occurrence of renal and extrarenal complications in ADPKD.
      Renal complications related to ADPKD, including hypertension and gross hematuria,
      occur more frequently in men than in women, whereas liver cystic disease occurs
      earlier and more frequently in women than in men. The presence of polycystic
      liver disease is related to pregnancy number and oral contraceptive pill use in
      ADPKD women. Importantly, massive polycystic liver disease requiring surgical
      intervention occurs primarily in ADPKD women. ADKPD women have a highly
      successful reproductive course. The chance of a successful pregnancy is excellent
      in ADPKD women and comparable to healthy unaffected women as long as prepregnancy
      blood pressure and renal function are normal. Fetal complication rates are no
      greater than in the general population; however, maternal complication rates in
      ADPKD women are high with an increased frequency of new or worsening hypertension
      as well as an increased occurrence of preeclampsia and preterm deliveries.
      Finally, increasing pregnancy number has minimal or no effect on renal outcome in
      ADPKD women.

PMID- 12616461
TI  - Impact of pregnancy on underlying renal disease.
AB  - Normal pregnancy involves marked renal vasodilation and large increases in
      glomerular filtration rate (GFR). Studies in rats reveal that the gestational
      renal vasodilation is achieved by parallel reductions in tone in afferent and
      efferent arterioles so GFR rises without a change in glomerular blood pressure.
      There is some evidence from animal studies that increased renal generation of
      nitric oxide (NO) may be involved. Although chronic renal vasodilation has been
      implicated in causing progression of renal disease in nonpregnant states by
      glomerular hypertension, there are no long-term deleterious effects of
      pregnancies on the kidney when maternal renal function is normal because
      glomerular blood pressure remains normal. When maternal renal function is
      compromised before conception, there are no long-term adverse effects on renal
      function in most types of renal disease, providing that the GFR is well
      maintained before conception. When serum creatinine exceeds approximately 1.4
      mg/dL, pregnancy may accelerate the renal disease increases and when serum
      creatinine >2 mg/dL, the chances are greater than 1 in 3 that pregnancy will
      hasten the progression of the renal disease. The available animal studies suggest
      that glomerular hypertension does not occur despite diverse injuries. Thus, the
      mechanisms of the adverse interaction between pregnancy and underlying renal
      disease remain unknown.

PMID- 12616462
TI  - Pregnancy in renal transplant recipients.
AB  - Most women of childbearing age who receive a renal transplant have a return of
      normal menses and have the ability to become pregnant. Most studies indicate that
      pregnancy does not adversely affect the transplant kidney's survival as long as
      renal function is good and serum creatinine is stable before pregnancy. The
      experience with immunosuppressive drugs has been surprisingly reassuring with no
      increase in congenital anomalies with cyclosporine, prednisone, and azathioprine.
      There is little experience with newer drugs. Pregnant transplant recipients need
      to be monitored for opportunistic infections, which may adversely affect the
      fetus, including herpes, toxoplasmosis, and CMV. Hypertension, urinary tract
      infections, and anemia are other common problems in pregnant transplant
      recipients. Despite a high frequency of premature births, over 80% of pregnancies
      result in surviving infants.

PMID- 12616463
TI  - Sexual dysfunction in men and women with chronic kidney disease and end-stage
      kidney disease.
AB  - Sexual dysfunction is a common finding in both men and women with chronic kidney
      failure. Common disturbances include erectile dysfunction in men, menstrual
      abnormalities in women, and decreased libido and fertility in both sexes. These
      abnormalities are primarily organic in nature and are related to uremia as well
      as the other comorbid conditions that frequently occur in the chronic kidney
      failure patient. Fatigue and psychosocial factors related to the presence of a
      chronic disease are also contributory factors. Disturbances in the hypothalamic
      pituitary-gonadal axis can be detected before the need for dialysis but continue
      to worsen once dialytic therapy is initiated. Impaired gonadal function is
      prominent in uremic men, whereas the disturbances in the hypothalamic-pituitary
      axis are more subtle. By contrast, central disturbances are more prominent in
      uremic women. Therapy is initially directed toward optimizing the delivery of
      dialysis, correcting anemia with recombinant erythropoietin, and controlling the
      degree of secondary hyperparathyroidism with vitamin D. For many practicing
      nephrologists, sildenafil has become the first line therapy in the treatment of
      impotence. In the hypogonadal man whose only complaint is decreased libido,
      testosterone may be of benefit. Regular gynecologic follow-up is required in
      uremic women to guard against potential complications of unopposed estrogen
      effect. Uremic women should be advised against pregnancy while on dialysis.
      Successful transplantation is the most effective means of restoring normal sexual
      function in both men and women with chronic kidney failure.

PMID- 12616464
TI  - Psychosocial issues in women with renal disease.
AB  - In this article, we review data on the epidemiology and outcomes of women in the
      US End-Stage Renal Disease (ESRD) Program. The complexity of the psychosocial
      milieu of patients is described, and levels of analysis are delineated. The
      relationships between age, marital status and satisfaction, and perception of
      quality of life and depressive affect level and diagnosis of depression, and
      medical outcomes have not been determined in large studies of women with renal
      disease. We present data from our cross-sectional and longitudinal studies of
      psychosocial outcomes in a population comprised primarily of black patients with
      ESRD and review some differences between relationships of parameters in the
      groups of men and women in the study. Women are more likely to be kidney donors
      rather than recipients in national programs. Women with ESRD treated with
      hemodialysis appear to be more immunologically responsive to the psychosocial
      milieu than men. These differences in access to and utilization of health care
      and relationships between perceptions and immunochemical mediators may have
      important ramifications for outcomes in women with chronic renal disease.

PMID- 12616466
TI  - Multidisciplinary contributions to rehabilitation: a National Kidney Foundation
      survey of the dialysis health care team.
AB  - Rehabilitation of patients on dialysis encompasses vocational, physical,
      psychological, and social domains. Rehabilitation efforts in each of these areas
      require not only a team approach but also performance of specific roles and
      responsibilities by each member of that team. This National Kidney Foundation
      survey will show that nephrology professionals do not routinely associate their
      main professional activities with the rehabilitation of their patients and that
      all too frequently dialysis patients do not see rehabilitation as within their
      realm.

PMID- 12616465
TI  - Prescribing hemodialysis: the role of gender.
AB  - Mortality rates remain high in the United States for people who depend on
      artificial kidney replacement for their existence, and the mortality rates are
      similar in men and women. However, women differ from men in many respects; some
      of these ways may have an impact on the response to dialysis through mechanisms
      that need to be further explored. Observational studies have shown that women
      respond more readily to a higher dose of dialysis, and recent data from the HEMO
      clinical trial suggest that women respond to an increase in clearance of low
      molecular-weight uremic toxins, whereas men do not. If the findings of these
      studies prove to be accurate, then we may conclude not only that women require a
      higher dose of dialysis as currently measured, but we might also expect women to
      require dialysis sooner during the course of a progressive decline in renal
      function. The reason for this gender-dependent difference in susceptibility
      escapes definition at the present time, but size is an obvious confound that can
      be explored by using current data and in future studies. More detailed analyses
      of the HEMO data are forthcoming and may shed further light on this question.

PMID- 12616467
TI  - Immunohistochemical expression of angiogenic cytokines and their receptors in
      reactive benign lymph nodes and non-Hodgkin lymphoma.
AB  - Angiogenic cytokines regulate B-cell lymphopoiesis and are related to prognosis
      in B-cell lymphoproliferative disorders. Transforming growth factor-beta (TGF
      beta) inhibits mature B-cell proliferation and immunoglobulin production.
      Increased levels of serum vascular endothelial growth factor (VEGF) and basic
      fibroblast growth factor (bFGF) are associated with poor prognosis in non-Hodgkin
      lymphoma (NHL). To understand the expression of angiogenic cytokines at different
      stages of B-cell differentiation in lymph nodes, we examined the
      immunohistochemical expression of TGF-beta, VEGF, bFGF, and their receptors in
      five patients with reactive benign lymphadenopathy and 12 patients with B-cell
      NHL (mantle cell lymphoma, 4; small cleaved cell follicular lymphoma, 5;
      lymphoplasmacytic lymphoma, 3). In benign lymph nodes, TGF-beta1, TGF-beta2, and
      TGFbetaRII were positive in prefollicular mantle cells, follicular center cells,
      and postfollicular plasma cells. Basic FGF, FGF-R1, and FGF-R4 were positive in
      large follicular center cells and postfollicular plasma cells. Vascular
      endothelial growth factor was positive in large follicular center cells and
      postfollicular plasma cells. In NHL, TGF-beta and its receptors were weakly
      positive in small cleaved cell follicular lymphoma; VEGF was strongly positive in
      lymphoplasmacytic lymphoma and weakly positive in mantle cell lymphoma. Basic FGF
      and its receptors were negative in NHL; however, FGF-R4 was positive in some
      cases of small cleaved cell follicular lymphoma. Our findings suggest that TGF
      beta, bFGF, and their receptors have opposite roles in B-cell differentiation and
      maturation in benign lymph nodes. Transforming growth factor-beta and its
      receptors have an important role in germinal center development; loss of their
      activity could be associated with abnormal clonal proliferation of NHL.

PMID- 12616468
TI  - Interobserver variability in determining MIB-1 labeling indices in
      oligodendrogliomas.
AB  - Several studies have shown that MIB-1 labeling indices correlate well with tumor
      grade and prognosis in a variety of tumor types. Several factors are responsible
      for some degree of variability in the determination of labeling indices.
      Interobserver variability is one of the factors often cited as responsible for
      this variability. A slide from each of 30 oligodendrogliomas, stained with MIB-1
      antibody, was distributed to six pathologists. The same set of slides was
      reviewed by each individual. Each pathologist was instructed to determine a MIB-1
      labeling index by evaluating 1,000 tumor cell nuclei from the area of the slide
      with the most staining. The labeling index record reflected a percentage of
      positive-staining tumor cells. Interobserver agreement was compared. MIB-1
      labeling indices ranged from 0 to 45.7. Overall agreement was good (> or =0.75)
      with a concordance coefficient of 0.832 (confidence interval, 0.700 to 0.909).
      Variability was greater among tumors with higher labeling indices as compared
      with tumors with labeling indices closer to 0. The overall agreement of MIB-1
      labeling indices, while not perfect, was good. The generally minor variability
      among observers may be related to differences in the area of the slide evaluated
      and in differing lower thresholds for interpreting positivity. Further
      improvement of concordance may theoretically be attainable by further training
      and discussion among observers.

PMID- 12616469
TI  - Colonic histoplasmosis in acquired immunodeficiency syndrome mimicking carcinoma.
AB  - Four cases of colonic histoplasmosis in patients with acquired immunodeficiency
      syndrome mimicking other diseases, primarily colonic adenocarcinoma, are
      presented. This topic has been extensively discussed from the medical and
      radiologic standpoint, but very few publications are found in the pathology
      literature. Emphasis is made on the discussion of the clinical manifestations;
      endoscopic, radiologic, and pathologic characteristics; differential diagnosis;
      and treatment.

PMID- 12616470
TI  - Interpretation of tissue artifacts in transbronchial lung biopsy specimens.
AB  - Proper interpretation of transbronchial biopsies is critical for appropriate
      patient management. Artifacts in lung tissue acquired during the biopsy procedure
      or subsequent processing may mimic "true" disease and potentially lead to
      incorrect diagnoses. In this study the interpretation of various artifacts in
      transbronchial biopsies will be correlated with the level of pathologist training
      and experience. Minced 1 to 2 mm fragments of normal lung tissue were processed
      to produce various tissue artifacts (atelectasis, sponge artifact, or bubble
      artifact). Seven hematoxylin-eosin-stained slides of various artifacts and three
      similar-appearing slides from "true" pulmonary diseases (lipoid pneumonia, usual
      interstitial pneumonia, and foreign body reaction) were evaluated by eight
      pathologists of different levels of training and experience. Most pathologists
      were unaware of the various artifacts in transbronchial biopsies and were
      occasionally able to differentiate them from true disease. Senior faculty
      frequently identified and correctly diagnosed the true pathology slides; however,
      they often failed to recognize artifacts. Junior faculty performed the best by
      correctly identifying the majority of true pathology and dismissed most
      artifacts. Junior and senior residents described the microscopic changes, but had
      more difficulty determining the significance of both true pathology and
      artifacts. Various artifacts in transbronchial biopsy specimens can create
      diagnostic dilemmas for all pathologists regardless of level of training. The
      elimination of these artifacts should reduce the possibility of biopsy
      misinterpretation.

PMID- 12616472
TI  - Mucoepidermoid carcinoma of the lacrimal sac.
AB  - Mucoepidermoid carcinoma of the lacrimal sac is a rare entity. We report a case
      of mucoepidermoid carcinoma arising in the lacrimal sac of a 30-year-old man who
      presented with an inner canthal mass. To our knowledge this is the first example
      of the cytopathology of this neoplasm in this anatomic site.

PMID- 12616471
TI  - Chronic sclerosing sialadenitis (Kuttner's tumor): unusual presentation with
      bilateral involvement of major and minor salivary glands.
AB  - In 1896 Kuttner reported four cases which he described as induration of the
      submandibular gland. Histologically, they showed chronic inflammation and
      fibrosis. Sporadic cases of this entity that have come to be known as Kuttner's
      tumor or chronic sclerosing sialadenitis of the submandibular gland and have been
      reported throughout the 20th century. This inflammatory tumor has been under
      recognized, and awareness of its importance and probable immunologic background
      have recently become evident. We report an unusual case of chronic sclerosing
      sialadenitis, affecting both parotid glands, both submandibular glands, and minor
      salivary glands of the oral cavity, and explore the immunohistochemical profile
      of this entity.

PMID- 12616473
TI  - Prosthetic implant associated sarcomas: a case report emphasizing surface
      evaluation and spectroscopic trace metal analysis.
AB  - Advances with implantation of synthetic biomaterials in the setting of orthopedic
      surgery have clearly resulted in improvements in patient outcomes. However, all
      implants have been shown to have associated risks. For example, ionic and
      particulate debris from implants have been shown to engage in biological
      interactions with the native tissue, and have been associated with a wide range
      of metabolic, bacteriologic, immunologic, and oncogenic effects. The propensity
      of synthetic biomaterials to undergo degradation, producing an inflammatory
      reaction or other sequelae, has been well recognized. The use of porous implants,
      which allow for a greater interface area between native tissue and the
      prosthesis, may magnify the interaction between biologically active tissue and
      synthetic devices in some situations, giving rise to new and intriguing issues
      concerning biocorrosion and biocompatibility. In this article, we report the case
      of a high-grade conventional osteosarcoma occurring at the site of a modular
      porous-surfaced titanium and cobalt alloy total hip prosthesis 3 years after
      device implantation. Detailed spectroscopic trace metal analysis was performed
      and elevated levels of both vanadium and chromium, but not aluminum, nickel, or
      titanium were identified in the tumor.

PMID- 12616474
TI  - Pulmonary crystal-storing histiocytosis and extranodal marginal zone B-cell
      lymphoma associated with a fibroleiomyomatous hamartoma.
AB  - Crystal-storing histiocytosis (CSH) is a rare disorder occurring in patients with
      lymphoproliferative diseases, predominantly in cases of multiple myeloma and low
      grade B-cell lymphoma. To the best of our knowledge, only three cases of
      pulmonary CSH have been reported in the English literature and one of them was
      associated with a low-grade B-cell lymphoma (immunocytoma). We document a case of
      a 59-year-old man with bilateral lung masses in which a right middle lobe
      pulmonary lobectomy specimen showed CSH associated with an extranodal marginal
      zone B-cell lymphoma. A single nodule showing features of fibroleiomyomatous
      hamartoma was present in a wedge biopsy specimen from the left lung. Two nodules
      within the right middle lobe were composed of sheets of histiocytic cells with
      abundant eosinophilic cytoplasm resembling striated muscle cells. In addition,
      there were nodular aggregates and a more diffuse infiltrate of small slightly
      atypical centrocyte-like lymphocytes, as well as bronchial lymphoepithelial
      lesions. Immunohistochemistry performed on paraffin-embedded sections
      demonstrated that the histiocytic cells were immunoreactive with the KP-1 (CD68)
      antibody while the lymphocytic infiltrate was CD20 positive, co-expressed for
      CD43, and was negative for CD3, CD5, and CD10. Genotypic analysis demonstrated
      the presence of an immunoglobulin heavy-chain gene rearrangement, indicating the
      presence of a monoclonal B-cell population. These features were consistent with
      pulmonary CSH associated with extranodal marginal-zone lymphoma of baltoma type.

PMID- 12616475
TI  - Littoral cell angiomatosis with poorly differentiated adenocarcinoma of the lung.
AB  - We report on a 64-year-old male United States Navy Veteran of World War II, one
      of two identical twins, diagnosed with littoral cell angiomatosis of the spleen,
      liver, and lymph nodes, later found to have a massive poorly differentiated
      adenocarcinoma involving the mediastinum, adjoining lung, and sternum with
      widespread metastases. Herein we include our findings at autopsy, pertinent
      immunohistochemical studies, and a review of the literature pertaining to
      littoral cell angiomatosis with comment on its association with visceral
      malignancies.

PMID- 12616476
TI  - Criteria for malignancy in nonvisceral smooth muscle tumors.
AB  - Reliable prediction of the behavior of smooth muscle tumors is notoriously
      problematic at many anatomic locations. Relatively few studies have addressed the
      minimal histologic criteria for malignancy in smooth muscle tumors of soft tissue
      and the presently available criteria are not only inconsistently applied but also
      vary at different anatomic sites. It has been widely believed that the presence
      of any mitotic activity in a deep-seated smooth muscle tumor should lead to a
      diagnosis of leiomyosarcoma. Until very recently, the existence of leiomyomas in
      deep soft tissue has been disputed. Using presently available data, this review
      examines criteria for malignancy in smooth muscle tumors in each of the following
      anatomic compartments: deep soft tissue, including retroperitoneum/abdominal
      cavity; skin; subcutis; and external genitalia. Distinct criteria for assessing
      malignancy should be applied to smooth muscle tumors at each of these locations.

PMID- 12616477
TI  - Use of virtual microscopy for didactic live-audience presentation in anatomic
      pathology.
AB  - Didactic presentations on the topic of anatomic pathology in front of a live
      audience have been largely dependent on the use of standard 2 x 2 inch projection
      slides (Kodachromes) of selected still images from the topic at hand. Because of
      the highly visual nature of the specialty of anatomic pathology, this method has
      had some serious limitations. With the advent of digital imaging techniques and
      the availability of new electronic software for the projection of images, new
      possibilities have become available for didactic presentations in anatomic
      pathology in front of a large, live audience. We describe a method whereby large
      digital images or "virtual slides" were produced from digitally scanned whole
      mount sections of histologic glass slides and projected using a combination of
      PowerPoint (Microsoft Corp, Redmond, WA) and virtual microscopy in front of a
      live audience. To provide a seamless transition between the two presentation
      formats, the personal computer-based PowerPoint slides were hyperlinked to a
      browser-based virtual microscope viewer. The presenter, with the use of a mouse,
      was able to "move" the image of the scanned slide on the screen, to transition
      seamlessly among various magnifications, and to rapidly select from the whole
      mount scanned slide among any areas of interest pertinent to the topic. Thus, the
      visual experience obtained by the audience simulated that of viewing a glass
      slide at a multi-headed microscope during a glass slide tutorial. Because this
      most closely approximates the experience of reviewing glass slides under the
      microscope for practicing pathologists, the educational experience of the
      presentation is greatly enhanced by the use of this technique. Also, this method
      permits making this type of presentation available to a much larger group of
      individuals in a live audience.

PMID- 12616478
TI  - CD4 T cell activation by myelin oligodendrocyte glycoprotein is suppressed by
      adult but not cord blood CD25+ T cells.
AB  - Regulatory T cells expressing CD25 have been shown to protect rodents from organ
      specific autoimmune diseases. Similar CD25+ cells with a memory phenotype
      exerting suppressive function after polyclonal or allogeneic stimulation are also
      present in adult human blood. We demonstrate that adult human CD25+ cells
      regulate the response to myelin oligodendrocyte glycoprotein (MOG), as depletion
      of CD25(+) cells increases responses of PBMC and the addition of purified CD25+
      cells suppresses MOG-specific proliferation and IFN-gamma production of
      CD4(+)CD25(-) T cells. In contrast, cord blood CD25+ cells do not inhibit
      responses to self antigens, and only a small subpopulation of cord CD25+ cells
      expresses the typical phenotype of adult regulatory T cells (CD45RA(-) and
      GITR(+)) enabling suppression of polyclonal responses. We conclude that
      activation of self-reactive T cells in normal healthy individuals is prevented by
      the presence of self-antigen-specific CD25+ regulatory T cells and that the
      majority of these cells mature after birth.

PMID- 12616479
TI  - Dominant effector memory characteristics, capacity for dynamic adaptive
      expansion, and sex bias in the innate Valpha24 NKT cell compartment.
AB  - Valpha24 natural killer T (NKT) cells are innate immune cells that recognize self
      and nonself glycolipids presented by CD1d molecules, and play immunoregulatory
      roles in autoimmunity and tumor immunity. We have investigated the circulating
      Valpha24 NKT cells in a large cohort of human subjects. CCR7(-) CD45RO(+)
      effector memory cells dominated both CD4(+) and CD4() NKT subsets, while a
      minority displayed a central memory phenotype. CD4(-) central memory NKT cells,
      however, were atypical in that they largely lacked CD62L expression. Overall,
      CD4(-) NKT cells displayed a functional phenotype with effector characteristics,
      while the CD4(+) subset appeared immunoregulatory. Interestingly, NKT cell
      numbers in blood varied widely between subjects, and elevated numbers of these
      cells were much more common in women than in men. The CD4(+) subset dominated the
      NKT cell compartment in both sexes, while circulating NKT cell numbers above 0.1%
      were associated with an expanded CD4(-) subset. Although NKT cell numbers were
      generally stable over time, we describe a dynamic fivefold expansion that was
      associated with a skewing of the NKT CD4(+):CD4(-) ratio that persisted after
      numbers returned to base line. Thus, the two NKT cell subsets display different
      properties and dynamics that will influence their function as innate
      immunoregulatory and effector cells.

PMID- 12616480
TI  - Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated
      cytokine expression in mouse macrophages.
AB  - Recent evidence suggests a role for phosphatidylinositol (PI) 3-kinase in various
      inflammatory responses. In this study, the consequences of LPS-induced PI 3
      kinase activation on cytokine and chemokine expression and the intracellular
      mechanisms of inflammatory activation were examined in mouse macrophages. LPS
      stimulation induced a complex formation between PI 3-kinase and myeloid
      differentiation factor 88 (MyD88), which was followed by an induction of IL
      1beta, tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory
      protein (MIP)-2. The induction of IL-1beta, but not of MIP-2 or TNF-alpha, was
      blocked by the PI 3-kinase inhibitors LY294002 and wortmannin. The nuclear factor
      kappaB (NF-kappaB) inhibitor pyrrolidinedithiocarbamate (PDTC) blocked the
      induction of IL-1beta and TNF-alpha, but had no effect on MIP-2 expression.
      Inhibition of PI 3-kinase decreased the LPS-induced transcriptional activity of
      NF-kappaB, but it had no effect on the nuclear DNA binding activity of NF-kappaB.
      These findings suggest that, while NF-kappaB nuclear localization and DNA binding
      are necessary, they are not sufficient for transcriptional activation of the IL
      1beta gene in the absence of PI 3-kinase activity. Taken together, our results
      demonstrate that activation of Toll-like receptor (TLR)-4 results in PI 3-kinase
      MyD88 complex formation, and that PI 3-kinase activity selectively leads to
      cytokine induction downstream of TLR4.

PMID- 12616481
TI  - Extensive proliferation of T cell lineage-restricted progenitors in the thymus:
      an essential process for clonal expression of diverse T cell receptor beta
      chains.
AB  - For clonal diversification of TCR, a large number of T cell progenitors are
      required in which highly diverse TCRbeta chains are accommodated individually. In
      the present study, we examined the proliferative potential of thymic progenitors
      that have been defined to be T cell lineage restricted. We show that the earliest
      fetal thymus (FT) cells from Rag2(-/-) mice, when cultured individually in a
      thymic organ culture system, produced 150-1,800 CD25(+) cells. Since
      differentiation and proliferation of Rag2(-/-) thymocytes are arrested at the
      stage of TCRbeta chain gene rearrangement, the observed proliferation was
      considered to represent the proliferative potential of progenitors prior to the
      TCRbeta rearrangement. A comparable level of proliferation was revealed to occur
      by analyzing the Dbeta-Jbeta rearrangement profiles of T cells generated from
      single progenitors in the earliest population of FT from normal mice. The
      proliferative potential of progenitors declined along with the progression of
      developmental stages. Such an extensive proliferation of progenitors after the
      restriction to the T cell lineage may be an essential process ensuring the clonal
      diversification of TCRbeta chains.

PMID- 12616482
TI  - All-trans retinoic acid down-regulates expression and function of beta2 integrins
      by human monocytes: opposite effects on monocytic cell lines.
AB  - All-trans retinoic acid (ATRA) plays an important role in the differentiation of
      malignant myeloid cells but its effects on primary leukocytes have been poorly
      investigated. We report here that ATRA negatively affects expression and function
      of leukocyte integrins that play a key role in monocyte adhesive interactions. As
      evidenced by flow cytometry, ATRA (at 1 microM) clearly and donor-independently
      suppressed the expression of all integrin chains investigated (CD11a, CD11b,
      CD11c, and CD18), most strikingly of CD11a. Down-regulation was detectable after
      24 and maximal after 72-96 h. Reverse transcription-PCR analysis revealed
      diminished steady-state concentrations of alpha specific transcripts but not of
      the common beta chain, suggesting that heterodimer expression was predominantly
      regulated through alpha chains. Results obtained with blood-derived monocytes
      were in sharp contrast to those for the leukemic cell lines THP-1 and U937, both
      of which showed marked increase in all integrin subunits in response to ATRA.
      ATRA-pretreated monocytes displayed significantly diminished beta(2) integrin
      dependent homotypic aggregation, and adhesion to stimulated endothelial cells
      (EC), while ATRA-pretreated monocytic cell lines showed the opposite behavior
      displaying markedly enhanced aggregation and CD18-mediated adhesion to EC.
      Therefore, the level of leukocyte integrins was obviously a decisive factor for
      these adhesive interactions irrespective of the cellular source. Collectively,
      our data indicate a striking difference between leukemic cell lines and normal
      hematopoietic cells with regard to ATRA responsiveness. By acting on key adhesive
      structures of normal leukocytes, ATRA mediates processes that may be of
      substantially broad range applying to inflammation and immunity in addition to
      differentiation and proliferation.

PMID- 12616483
TI  - Efficient expansion of regulatory T cells in vitro and in vivo with a CD28
      superagonist.
AB  - CD4(+)CD25(+) T cells play a central role in the suppression of autoimmunity and
      inflammation, making their in vivo expansion a highly attractive therapeutic
      target. By phenotyping with a novel rat CTL antigen-4 (CTLA-4)-specific
      monoclonal antibody (mAb) and functional in vitro assays, we here first establish
      that rat CD4(+)CD25(+) T cells correspond to the regulatory T cells (Treg cells)
      described in mice and humans: they constitutively express CTLA-4, produce IL-10
      but not IL-2, and are able to suppress the proliferation of costimulated CD25
      negative indicator cells. Furthermore, we show that rat Treg cells respond less
      well than CD25(-) T cells to conventional costimulation, but are readily expanded
      in vitro with "superagonistic" CD28-specific mAb which are potent mitogens for
      all T cells without the need for TCR engagement. In vivo, functional Treg cells
      are preferentially expanded by CD28 stimulation over other T cell subsets,
      leading to a 20-fold increase within 3 days in response to a single antibody
      dose. These data suggest that CD28-driven activation of Treg cells may be highly
      effective in the treatment of inflammatory and autoimmune diseases.

PMID- 12616484
TI  - Recognition of HLA-G by the NK cell receptor KIR2DL4 is not essential for human
      reproduction.
AB  - A central issue of reproductive immunology in mammals is why a semi-allogeneic
      embryo is not rejected by the pregnant mother. This is particularly intriguing
      since, in different species, the early pregnant uterus is infiltrated by numerous
      maternal lymphocytes, predominantly NK cells. The human NK cell receptor KIR2DL4
      has been implicated in the maternal tolerance to the embryo due to its
      recognition of HLA-G, a non-classical MHC molecule expressed preferentially in
      the placenta. Killer cell Ig-like receptors (KIR) are believed to participate in
      the natural immunity to infection and tumors, but KIR2DL4 has unique structural,
      functional and genetic features that could confer it a different role. However,
      we demonstrate here that the KIR2DL4:HLA-G interaction is not essential for human
      reproduction by showing that a multiparous woman lacks a KIR2DL4 gene.

PMID- 12616486
TI  - Heterozygous null mutation of myelin P0 protein enhances susceptibility to
      autoimmune neuritis targeting P0 peptide.
AB  - Mice with a heterozygous null mutation in myelin protein zero (P0(+/-)) develop
      late-onset clinical paralysis associated with inflammatory pathology in the
      peripheral nerves. Although the development of this illness is known to require T
      cells and macrophages, little is understood regarding the immunological defect in
      the mice. Here we report that young P0(+/-) mice, free from clinical
      manifestations, have a defect in central tolerance to P0, and are more prone to
      induction of experimental autoimmune neuritis (EAN) by sensitization against
      P0(180-199 )peptide. Notably, we found that the P0 gene is transcribed in the
      thymus of wild-type and the P0(+/-) mice in an amount proportional to the gene
      dosage. We then replaced the thymus of wild-type mice with that of the P0
      deficient mice and vice versa. Immunization of these mice with P0(180-199
      )revealed that a lower thymic P0 transcript would be associated with the higher
      recall T cell response to P0(180-199), thus accounting for the higher
      susceptibility of the P0(+/-) mice to P0-induced EAN. These results imply that a
      heterozygous mutation in an autoantigen could cause defective central tolerance
      to the autoantigen. As such, autoimmune T cells may play some role in "genetic"
      diseases caused by a heterozygous gene defect.

PMID- 12616485
TI  - Superoxide activates very late antigen-4 on an eosinophil cell line and increases
      cellular binding to vascular cell adhesion molecule-1.
AB  - The recruitment of eosinophils to the airway is a key event in the pathogenesis
      of allergy. Very late antigen-4 (VLA-4), an integrin ligand for vascular cell
      adhesion molecule-1 (VCAM-1), is expressed on eosinophils. VLA-4-mediated
      adhesion of eosinophils to VCAM-1 may contribute to their selective recruitment
      to tissues in allergy. Reactive oxygen species (ROS), including nitric oxide
      (NO), are abundant in the airway of allergic patients, but their role in
      pathogenesis of allergy is unclear. In this investigation, we studied the effects
      of ROS on integrin-mediated eosinophil adhesion. Recombinant soluble VCAM-1 and
      ICAM-1 were used to test the effects of ROS on the integrin-mediated adhesion of
      an eosinophil cell line. We used phorbol 12-myristate 13-acetate-stimulated
      neutrophils and hypoxanthine to generate superoxide, NO donors as sources of NO,
      and a static cell-to-protein adhesion assay to analyze cellular adhesion.
      Stimulated neutrophils significantly increased eosinophil binding to VCAM-1,
      which was reversed in the presence of superoxide dismutase. Neutrophils from a
      chronic granulomatous disease patient lacked this activity in enhancing
      eosinophil adhesion. Our results suggest that the balance between ROS molecules
      in different tissue microenvironments may change the integrin-mediated leukocyte
      adhesion and is likely to be a key factor in leukocyte recruitment in allergic
      inflammation.

PMID- 12616487
TI  - Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T
      cells.
AB  - Modulation of the immune response using immunoglobulin fusion proteins has shown
      great promise for clinical immunotherapy of autoimmune diseases. Alefacept is an
      immunoglobulin fusion protein composed of the first extracellular domain of human
      LFA-3 fused to the hinge, C(H)2 and C(H)3 domains of human IgG(1). Alefacept has
      previously been reported to inhibit T cell proliferation. Here, we analyzed the
      effects of alefacept on lymphocytes in vitro and characterized the role of
      autologous NK cells in its mechanism of action. Alefacept, but not a C(H)2
      binding mutant of Alefacept, inhibited CD3-induced T cell proliferation only in
      the presence of live NK cells, consistent with an important role for FcgammaR
      engagement. Alefacept caused preferential depletion of CD69+CD45R0+CD25+ T cell
      subsets. Cytotoxicity assays revealed that alefacept, but not the C(H)2 binding
      mutant, induced NK cell-mediated death of activated T cells and sorting into
      CD45R0+ and CD45RA+ subpopulations showed that lymphocyte deletion occurred
      preferentially in the CD45R0+ subset. Activated CD45R0+ cells expressed higher
      levels of CD2 than CD45R0- cells, providing a possible explanation for the
      selective targeting of this subset. Our results suggest that selective targeting
      of CD45R0+ T cells by NK cells represents a potential therapeutic mechanism of
      action of alefacept.

PMID- 12616488
TI  - Requirement for Q226, but not multiple charged residues, in the class I MHC CD
      loop/D strand for TCR-activated CD8 accessory function.
AB  - Activation of CD8+ cytotoxic T lymphocytes typically begins with recognition of
      class I MHC-peptide complexes by the TCR and CD8 as a coreceptor. In its
      coreceptor role, CD8 binds thesame class I-peptide antigen complex as the TCR,
      enhancing the strength of TCR-class I interaction. Subsequent to initial TCR
      engagement, CD8 acts as an accessory molecule by binding any properly conformed
      class I molecules on the target cell surface, leading to CD8-mediated adhesion
      and cosignaling functions. We expressed and isolated a number of mutant class I
      molecules in which one or moreacidic or polar residues in the class I alpha3
      domain CD loop and D strand region, or alpha2 domain were altered. Using solid
      phase CTL adhesion and degranulation assays with isolated class I molecules, we
      demonstrate that multiple acidic residues in the alpha3 domain, although involved
      in CD8 coreceptor interaction, are not required for TCR-activated CD8 accessory
      interactions. Instead, we show that Q226, a polar group on the end of the CD
      loop, is required for TCR-activated CD8 accessory functions. These results
      indicate that CD8 coreceptor and accessory interactions differ substantially and
      suggest that TCR activation results in changes that alter the structural
      constraints for CD8 accessory interactions.

PMID- 12616490
TI  - Immune evasion of Borrelia burgdorferi: mapping of a complement-inhibitor factor
      H-binding site of BbCRASP-3, a novel member of the Erp protein family.
AB  - The causative agents of Lyme disease, Borrelia burgdorferi s.s., B. garinii, and
      B. afzelii, differ in their susceptibility to complement-mediated lysis. This
      phenomenon apparently depends on the expression of proteins termed complement
      regulator-acquiring surface proteins (CRASP) and their binding to the inhibitory
      plasma proteins factor H and FHL-1. To characterize these bacterial proteins in
      more detail we have now isolated from a B. burgdorferi expression library a novel
      factor H-binding protein. In accordance with our previous studies this protein
      was termed BbCRASP-3 and represents a novel member of the polymorphic Erp (OspE/F
      related) protein family. On the basis of protease accessibility assays using
      intact spirochetes, BbCRASP-3 is identified as a surface-exposed protein and
      binds the C-terminal short consensus repeats of factor H. Applying deletion
      mutants of BbCRASP-3, the factor H-binding site was mapped to the nine-amino-acid
      motif LEVLKKNLK localized at the C-terminal end of BbCRASP-3. Factor H bound to
      BbCRASP-3 maintains its cofactor activity in factor I-mediated C3b inactivation.
      Binding of BbCRASP-3 to factor H can be inhibited by heparin, a physiological
      ligand of the complement regulator factor H. Blocking of factor-H-binding by
      soluble BbCRASP-3 leads to an increase of complement deposition on intermediate
      serum-resistant strain ZS7. In conclusion, BbCRASP-3 has been identified as a
      novel factor H-binding protein on B. burgdorferi which by conferring complement
      resistance to the pathogen may contribute to its persistence in the mammalian
      host.

PMID- 12616489
TI  - Weak agonist self-peptides promote selection and tuning of virus-specific T
      cells.
AB  - Recent progress has begun to define the interactions and signaling pathways that
      are triggered during positive selection. To identify and further examine self
      peptides that can mediate positive selection, we searched a protein-database to
      find peptides that have minimal homology with the viral peptide (p33) that
      activates a defined P14 transgenic TCR. We identified four peptides that could
      bind the restriction element H-2D(b) and induce proliferation of P14 transgenic
      splenocytes at high concentration. Two of the four peptides (DBM and RPP) were
      able to positively select the virus-specific TCR in fetal thymic organ culture
      but were unable to induce clonal deletion. Reverse-phase HPLC and mass
      spectrometry demonstrated that these peptides were presented by H-2D(b) molecules
      on thymic epithelial cell lines. We also examined whether the selecting ligands
      altered T cell responsiveness in vitro. DBM-selected T cells lost their ability
      to respond to the positively selecting ligand DBM, whereas RPP-selected T cells
      only retained their ability to respond to high concentrations of RPP. These
      results demonstrate that self-peptides that mediate positive selection can
      differentially "tune" the activation threshold of T cells and alter the
      functional repertoire of T cells.

PMID- 12616491
TI  - Artificial-infection protocols allow immunodetection of novel Borrelia
      burgdorferi antigens suitable as vaccine candidates against Lyme disease.
AB  - Vaccination with recombinant outer surface protein A (OspA) from Borrelia
      burgdorferi provides excellent antibody-mediated protection against challenge
      with the pathogen in animal models and in humans. However, the bactericidal
      antibodies are ineffective in the reservoir host, since OspA is expressed by
      spirochetes only in the vector, but rarely, if at all, in mammals. Using an
      artificially generated immune serum (anti-10(8) spirochetes) with high protective
      potential for prophylactic and therapeutic treatment, we have now isolated from
      an expression library of B. burgdorferi (strain ZS7) three novel genes, zs7.a36,
      zs7.a66 and zs7.a68. All three genes are located, together with ospA/B, on the
      linear plasmid lp54, and are expressed in vitro and in ticks. At least
      temporarily two of them, ZS7.A36 and ZS7.A66, are also expressed during
      infection. The respective natural antigens are poorly immunogenic ininfected
      normal mice but elicited antibodies in Lyme disease patients. We show that
      recombinant preparations of ZS7.A36, ZS7.A66 and ZS7.A68 induce functional
      antibodies in rabbits capable of protecting immunodeficient mice against
      subsequent experimental infection. These findings suggest that all three
      recombinant antigens represent potential candidates for a "second generation"
      vaccine to prevent and/or cure Lyme disease.

PMID- 12616492
TI  - Role of T cell help and endoplasmic reticulum targeting in protective CTL
      response against influenza virus.
AB  - We report on the induction of primary and long-term memory cytotoxic T lymphocyte
      (CTL) responses against the nucleoprotein of the influenza virus A/PR8/34 in mice
      immunized with plasmid DNA targeted to B lymphocytes in the spleen. We found that
      the magnitude of the CTL response and the size of the pool of memory CTL was
      greater when the CTL response was induced in presence of T cell help.
      Interestingly, immunization with a signal sequence-competent transgene was
      markedly superior to immunization with a transgene lacking the endoplasmic
      reticulum (ER) targeting sequence, in inducing CTL. We also found a correlation
      between in vivo protection from lethal virus challenge and (1) the availability
      of T cell help and (2) ER targeting. Immunization of dendritic cell-deficient
      mice suggests that B lymphocytes function as antigen-presenting cells in this
      model of immunization. Collectively, the results suggest that somatic transgene
      immunization is a conceptually new approach to induce effective anti-viral CTL
      responses and to assess the parameters critical for long-lasting and protective
      CTL responses in vivo.

PMID- 12616493
TI  - Human fractalkine mediates leukocyte adhesion but not capture under physiological
      shear conditions; a mechanism for selective monocyte recruitment.
AB  - Fractalkine is a unique chemokine possessing a long mucin-like stalk and a
      transmembrane region that has been proposed to act as an adhesion molecule. We
      investigated the ability of fractalkine to recruit leukocytes from whole blood,
      using an immobilized fractalkine fusion protein in the parallel-plate flow
      chamber assay. Significant adhesion of leukocytes to fractalkine peaked at 2
      dynes/cm(2) but was minimal at 10 dynes/cm(2). In contrast, VCAM-1 could recruit
      cells from whole blood at 10 dynes/cm(2). Co-immobilization of fractalkine and
      VCAM-1 at 10 dynes/cm(2) resulted in a twofold increase in adherent cells
      compared with VCAM-1 alone, suggesting that fractalkine can mediate adhesion at
      high shear if combined with a molecule that can mediate leukocyte tethering.
      Pretreatment of blood with pertussis toxin eliminated this increase in adhesion,
      implicating intracellular signaling in fractalkine-mediated mechanisms of
      adhesion to co-immobilized fractalkine/VCAM-1. Analysis of the cell types
      recruited to fractalkine alone at low shear, or to fractalkine and VCAM-1 at 10
      dynes/cm(2), revealed that monocytes were recruited to fractalkine with the
      highest specificity. In conclusion, fractalkine is unlikely to act alone at shear
      forces found in most vascular beds where it most likely co-operates with
      tethering molecules, e.g. VCAM-1, in the recruitment of monocytes.

PMID- 12616494
TI  - Toll-like receptor-mediated tyrosine phosphorylation of paxillin via MyD88
      dependent and -independent pathways.
AB  - Toll-like receptor (TLR)-mediated recognition of pathogens represents one of the
      most important mechanisms of innate immunity. A proximal signaling event of TLR
      is the direct binding of an adaptor protein MyD88 to TLR and recruitment of the
      IL-1R-associated kinase (IRAK). In the present study, we examined the effect of
      several TLR ligands on protein tyrosine phosphorylation in rat macrophages.
      Macrophage-activating lipopeptide-2 kDa (MALP2) and lipoarabinomannan were used
      as activators of TLR2, while lipopolysaccharides (LPS) and lipoteichoic acid were
      used as TLR4 ligands. All these ligands induced tyrosine phosphorylation of
      proline-rich tyrosine kinase 2 (Pyk2) and its substrate paxillin, an integrin
      associated focal adhesion adaptor protein, in the macrophages. PP2, an inhibitor
      of Src family tyrosine kinases, prevented the TLR-induced phosphorylation of
      paxillin and Pyk2 without affecting TLR-induced IRAK activation. MALP2 failed to
      induce paxillin phosphorylation in the macrophages from MyD88-knockout mice. In
      contrast, the effect of LPS weakened, but was still observed even in the MyD88
      deficient cells. Thus, TLR regulate the function of paxillin in an Src family
      dependent mechanism through both MyD88-dependent and MyD88-independent pathways.

PMID- 12616495
TI  - Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the
      cell surface following endosomal recycling.
AB  - The MHC class I allele HLA-B27 is very strongly associated with development of
      autoimmune spondyloarthritis, although the disease mechanism remains unknown.
      Class I molecules classically associate in the endoplasmic reticulum (ER) with
      beta2-microglobulin (beta(2)m) and antigenic peptides for cell surface expression
      and presentation to T cells. We have previously shown that HLA-B27 is capable of
      forming beta(2)m-free disulfide-bonded homodimers in vitro. Here we show that HLA
      B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27
      homodimers form in the ER but appear unable to egress to the cell surface in
      human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a
      variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27
      homodimers can arise from cell-surface heterodimers via an endosome-dependent
      recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is
      dependent on the unpaired cysteine(67) and is inhibited by restoration of tapasin
      function or by incubation with peptides that bind strongly to HLA-B27
      heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be
      immunologically reactive ligands for NK family immunoreceptors and, hence, could
      play a pathogenic role in spondyloarthritis.

PMID- 12616496
TI  - Characterization of antigen-specific repertoire diversity following in vitro
      restimulation by a recombinant adenovirus expressing human cytomegalovirus pp65.
AB  - Human cytomegalovirus (HCMV) and adenovirus cause significant morbidity and
      mortality in immunocompromised hosts undergoing allogeneic stem cell
      transplantation. We have previously established a procedure for the generation of
      polyclonal CTL with specificity against adenovirus and HCMV using a recombinant
      adenovirus encoding the HCMV pp65 protein (RAdpp65). However, specific CTL
      expanded after in vitro culture steps were subjected to several in vitro
      restimulations and, depending on the protocol adopted, this could lead to a
      selection bias, compromising the clinical benefit. To determine which part of the
      memory repertoire is selected after in vitro restimulation, we have followed the
      specificity and clonal composition of pp65-peptide-specific CD8(+) T cells in HLA
      A*201 individuals before and after repeated in vitro restimulation of cells with
      RAdpp65, combining HLA tetrameric complexes and immunoscope analysis. Tetramer
      staining showed that, after in vitro restimulation, up to 60% of CD8(+) T cells
      were virus-specific. Immunoscope analysis showed that the predominant TCRBV
      diversity of pp65-specific clones was conserved, demonstrating that the memory
      repertoire was preserved all along the procedure. Altogether, these results
      suggest that the use of RAdpp65 to induce CMV- and adenovirus-specific CTL maybe
      appropriate for immunotherapy.

PMID- 12616497
TI  - Perforin-dependent activation-induced cell death acts through caspase 3 but not
      through caspases 8 or 9.
AB  - Activation-induced cell death (AICD) is a phenomenon in which activated T cells
      undergo apoptosis upon restimulation. We are studying a form of AICD that can
      occur before cells become competent to die by Fas (hence "early" AICD) and which
      depends on the presence of perforin. Previous studies indicate that it does not
      occur through granule exocytosis but via some endogenous pathway. We here
      investigate a possible role for caspases. Caspase 3(-/-) cells were protected,
      suggesting a role for caspase 3 in early AICD. After recrosslinking, caspase 3
      activity could be detected in cell lysates between 3 and 12 h, and CD8(+) T cells
      became annexin V-positive between 15 and 18 h. Blocking anti-Fas ligand antibody
      failed to inhibit death, and no processing of either caspase 8 or caspase 9 was
      detected in recrosslinked cells. Furthermore, T cells lacking functional caspase
      9 continued to die in early AICD. Thus, perforin-dependent early AICD appears to
      require activation of caspase 3, but not caspases 8 or 9. As perforin has no
      intrinsic catalytic abilities, we propose that it releases some endogenous
      activity that can activate caspase 3.

PMID- 12616498
TI  - Distinct contributions of different CD40 TRAF binding sites to CD154-induced
      dendritic cell maturation and IL-12 secretion.
AB  - The mechanisms by which CD40 controls the maturation and antigen presentation
      functions of dendritic cells (DC) remains largely undefined in this critical cell
      type. To examine this question, we have employed retroviral transduction of
      primary bone marrow-derived mouse DC. Mutation of the distinct binding sites for
      TNF receptor-associated factor 6 (TRAF6) and for TRAF 2, 3, and 5 in the CD40
      cytoplasmic domain revealed their independent contributions to DC maturation and
      activation of NF-kappaB. In contrast, disruption of the TRAF6 but not the TRAF
      2,3,5 binding site markedly decreased IL-12 p40 secretion along with p38 and JNK
      activation in response to CD154 stimulation. These data document a clear
      bifurcation of the CD40 signaling cascade in primary DC at the level of the
      receptor's two distinct and autonomous TRAF binding sites, and reveal the
      predominant role of the TRAF6 binding site in CD40-induced pro-inflammatory
      cytokine production by these cells.

PMID- 12616499
TI  - Vav1 transduces TCR signals required for LFA-1 function and cell polarization at
      the immunological synapse.
AB  - Activation of T lineage cells through the TCR by peptide-MHC complexes on APC is
      critically dependent on rearrangement of the actin cytoskeleton. Vav1 is a
      guanine nucleotide exchange factor for members of the Rho/Rac family of GTPases
      which is activated following TCR stimulation, suggesting that it may transduce
      TCR signals to the activation of some or all actin-controlled processes. We show
      that Vav1-deficient double-positive thymocytes are less efficient at forming
      conjugates with APC presenting agonist peptide than wild-type cells are.
      Furthermore we demonstrate that Vav1 is required for TCR-induced activation of
      the integrin LFA-1, which is likely to explain the defect in conjugate formation.
      However, once Vav1-deficient cells form a conjugate, the assembly of proteins
      into an immunological synapse at the conjugate interface is normal. In contrast,
      thymocyte polarization is defective in the absence of Vav1, as judged by the
      relocalization of the microtubule-organizing center. These data demonstrate that
      Vav1 transduces signals to only a subset of cytoskeleton-dependent events at the
      immunological synapse.

PMID- 12616500
TI  - Toll-like receptor 4 expression levels determine the degree of LPS-susceptibility
      in mice.
AB  - C57BL/10ScCr (Cr) mice carry a deletion of the Toll-like receptor 4 (tlr4) gene
      (i.e. they are tlr4(0/0)) and are thus refractory to LPS effects. Insertion of
      wild-type tlr4 transgene into the tlr4(0/0) Cr germ line endowed LPS
      susceptibility in the two transgenic lines created, indicating that TLR4 is the
      only limiting factor for LPS responsiveness in Cr mice. The absolute levels of
      tlr4 mRNA expressed by the heterozygous transgenic (tlr4(Tr/0)), wild-type
      C57BL/10ScSn (Sn) (tlr4(+/+)) and heterozygous F1 (Sn x Cr) (tlr4(+/0)) mice
      varied markedly. However, the pattern of distribution of expression in the
      different organs was the same in all strains. In different biological assays (B
      cell mitogenicity, cytokine induction and lethal toxicity) the degree of LPS
      response obtained in the different strains of mice correlated with the levels of
      tlr4 mRNA expression. In macrophages, investigation of the LPS-induced cytokine
      (IL-6) response revealed a linear relationship between the response and the
      logarithm of TLR4-MD-2 levels.

PMID- 12616501
TI  - Visualizing the course of antigen-specific CD8 and CD4 T cell responses to a
      growing tumor.
AB  - Spontaneous tumors frequently express antigens that can be recognized by the
      immune system but nevertheless manage to evade immune surveillance. To better
      understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting
      against a subcutaneously growing tumor, modified to express influenza
      hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen
      specific CD8 T cells was sufficient to protect against challenge with 1x10(6)
      tumor cells, while larger numbers of T cells rejected established tumors. HA
      specific CD4 T cells could not reject tumors on their own but helped rejection by
      CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded
      antigen-specific CD8 and CD4 T cells, while a failing anti-tumor response was
      accompanied by transient expansion followed by rapid elimination of antigen
      specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance
      because of an insufficient number of tumor-specific T cells and antigen overload,
      resulting in exhaustion of the immune response. In this scenario, adoptive
      immunotherapy rather than vaccination promises successful treatment.

PMID- 12616510
TI  - Recovery of touch after median nerve lesion and subsequent repair.
AB  - Many techniques have been developed for the evaluation of peripheral nerve
      function. Consequently, physicians use different techniques in the clinic. This
      study describes the evaluation of touch after median nerve lesions in the forearm
      and repair. In order to evaluate touch, 25 patients, aged 11-51 years (mean, 29
      years), were evaluated 3-10.5 years (mean, 5 years) after median nerve repair.
      The evaluation included the moving two-point discrimination test and Semmes
      Weinstein monofilaments. We showed that 32% good-excellent results can be
      obtained with difficult nerve lesions. The results could have been improved if a
      sensory reeducation regime had been applied.

PMID- 12616502
TI  - The same endothelial receptor controls lymphocyte traffic both in vascular and
      lymphatic vessels.
AB  - The mechanisms controlling the exit of lymphocytes from tissues via lymphatics
      are practically unknown. We have now identified a 270-300-kDa molecule designated
      common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) on
      human lymphatic endothelium and high endothelial venules. We show that it
      mediates binding of lymphocytes both to high endothelial venules and to lymphatic
      vessels. Moreover, blocking of the function of CLEVER-1 results in significant
      reduction of lymphocyte traffic in vivo. Notably, CLEVER-1 is also an inducible
      vascular adhesion molecule for other classes of leukocytes at sites of
      inflammation in peripheral tissues. These findings suggest that CLEVER-1 is
      involved in regulation of lymphocyte recirculation and migration of leukocytes to
      sites of inflammation and is a potential new target to control inflammation.

PMID- 12616512
TI  - One-fascicle median nerve transfer to biceps muscle in C5 and C6 root avulsions
      of brachial plexus injury.
AB  - Five male patients with avulsions of the C5 and C6 roots of the brachial plexus
      underwent transfer of one fascicle of the median nerve to the motor branch of the
      biceps muscle. The mean period of follow-up was 32 months. The average
      reinnervation time of the biceps was 3.4 months. Four patients achieved biceps
      strength of Medical Research Council (MRC) grade 4, and one patient had strength
      of the biceps of MRC grade 3. The mean period of time from surgery to MRC grade 3
      was 9 months. At the last follow-up examination, grip strength, pinch strength,
      moving two-point discrimination, and strength of wrist volar flexion on the
      affected side were not worse than before the operation in any patient.

PMID- 12616511
TI  - Incidence and significance of microscopic pathological lesions found in pedicle
      and recipient vessels used in microsurgical breast reconstruction.
AB  - The purpose of this study was to assess the incidence of abnormal vascular
      histology and to determine whether or not this was correlated with the incidence
      of postoperative microvascular problems. The microvascular histology of both
      donor and recipient vessels was studied in 38 patients (40 flaps) undergoing
      breast reconstruction with free TRAM flaps. Preoperative risk factors were
      assessed and correlated with histological changes in vessels, and both were
      tested against anastomotic complications. Thrombosis of either the artery or the
      vein of the flap was seen in 6 cases (15%), and of these, two flaps failed
      completely and one suffered partial necrosis. The occlusion affected the arterial
      anastomosis in 3 patients, and the venous anastomosis in 2 patients, while both
      the artery and the vein were thrombosed in one case. Preoperative risk factors
      such as smoking, obesity, radiotherapy, and chemotherapy were not associated with
      a significantly higher incidence of thrombosis or with significant histological
      abnormalities in vessels (P value varied between 0.3-0.06). Microvascular
      histology showed variable degrees of pathological changes in six flaps (15%);
      nevertheless, in this group, only one flap suffered a venous thrombosis, which
      ended in total flap loss. Among those with one or more risk factors (24
      patients), only 2 had some evidence of histological abnormality of the blood
      vessels used for the microvascular anastomosis (P = 0.2).

PMID- 12616513
TI  - Surgical treatment of brachial plexus traction injuries in children, excluding
      obstetric palsy.
AB  - Traumatic brachial plexus injuries in children, excluding birth palsy, are seldom
      reported. In this study, we report on 11 cases operated upon between 1995-1998,
      and followed for at least 30 months. All patients were males with an average age
      of 11 years (range, 3-16 years). The denervation time averaged 3.8 months (range,
      1-8 months). Eight patients had two or more root avulsions; two had additional
      severe infraclavicular injuries. In total, 6 grafting and 25 extraplexal
      neurotization procedures were used. Donor nerves included the intercostal nerves,
      phrenic nerve, spinal accessory nerve, and contralateral C7 root. Elbow flexion
      was restored in all but 2 cases. Shoulder abduction varied from 30-90 degrees,
      according to the method of reconstruction. Triceps recovered in 2 cases and
      finger and wrist extensors in 1 case. Wrist and finger flexion was obtained in 1
      case. Sensory recovery in the palm reached S2/S2+. Harvesting the phrenic nerve
      and the contralateral C7 root resulted in no residual morbidity. Compared to
      adults, children have a higher incidence of root avulsion, no deafferentiation
      pain, a higher incidence of associated skeletal injuries, and the same recovery
      rate of elbow and shoulder functions following plexus reconstruction, but
      recovery is faster. Given the frequency of root avulsions, neurotization is often
      required.

PMID- 12616514
TI  - Transoral reconstruction of the mobile tongue, using radial forearm free flap.
AB  - Tongue resection has significant influence on the patient's quality of life,
      because it interferes with masticatory and speech functions and affects facial
      aesthetics. To avoid the disadvantages of the traditional lip-splitting used to
      approach partial tongue reconstruction for resection (40% of the tongue or more),
      we recommend a completely transoral approach, with the radial forearm free flap
      as a donor flap. Between 1999-2001, the suggested technique was applied in 11
      patients with squamous-cell carcinoma of the mobile tongue. A follow-up of 6-30
      months showed good to excellent oral function, with preservation of tongue
      volume, motion, and facial aesthetics. This approach seems to be preferable over
      the lip-split approach for the reconstruction of mobile tongue defects.

PMID- 12616515
TI  - Follow-up study of upper limb lymphedema patients treated by microsurgical
      lymphaticovenous implantation (MLVI) combined with compression therapy.
AB  - We present a follow-up study of 18 patients with upper limb lymphedema treated by
      microsurgical lymphaticovenous implantation (MLVI) combined with compression
      therapy. This combined technique provides increased lymphatic flow through newly
      created lymphaticovenous bypasses by the MLVI surgery, with assistance for
      pumping function in the lymphatics by compression therapy. Preoperative
      assessment of the affected limb was performed by the average enlargement of edema
      circumference (AEEC), comparing the lymphedema limb and normal limb
      circumferences. Objective improvement was analyzed by the percent reduction of
      edema circumference (%REC) at two levels of the lymphedema limb. With an average
      follow-up of 24 months, 77.8% of patients presented excellent or good results,
      with %REC >50% at either the distal or proximal site of the treated limb. This
      combined treatment can be expected to provide favorable long-term results, even
      for patients with AEEC >8 cm.

PMID- 12616516
TI  - Microsurgical treatment of Mooren's corneal ulcer.
AB  - This study evaluated the effect of microsurgery of lamellar keratoplasty (LKP) on
      Mooren's corneal ulcer. The surgical effect, postoperative astigmatism,
      postoperative vision, postoperative ulcer recurrence, and surgical complications
      of 2 groups of consecutive Mooren's ulcer inpatients treated respectively by non
      microsurgery of LKP and microsurgery of LKP were analyzed. There were significant
      differences of the effect, postoperative astigmatism, postoperative vision,
      postoperative ulcer recurrence, and surgical complications between the 2 groups.
      The effect and postoperative vision of the microsurgery-treated group were better
      than those of the non-microsurgery-treated group. The postoperative astigmatism,
      postoperative ulcer recurrence, and surgical complications of the microsurgery
      treated group were less than those of the non-microsurgery-treated group.
      Microsurgery of LKP of Mooren's corneal ulcer can greatly improve the cure rate
      of the disease and postoperative vision, and reduce surgical complication and
      postoperative ulcer recurrence.

PMID- 12616517
TI  - Flap coverage of dorsum of hand associated with extensor tendons injuries: A
      completely vascularized single-stage reconstruction.
AB  - This study reports results in 12 patients treated with "completely vascularized
      single-stage approaches," so defined because skin, tendon, and nerve are
      transferred as a compound flap, and all are vascularized. A free dorsalis pedis
      cutaneotendinous flap was used in 7 patients, while a radial forearm
      cutaneotendinous island flap was transposed in 5 patients. A dorsalis pedis flap
      provides four vascularized extensor tendons (extensor digitorum comunis tendons),
      and the radial artery flap permits the inclusion of one completely vascularized
      tendon (palmaris longus) and two "strips" of vascularized tendons (flexor carpi
      radialis and brachioradialis). The flaps survived in all cases, and the
      transferred tendons were functioning well. The dorsalis pedis flap can be
      employed in the reconstruction of cutaneotendinous defects of the dorsum of the
      hand which require the use of three or four tendons grafts. We suggest the use of
      forearm cutaneotendinous flaps in cases of reconstruction of one or two extensor
      tendons. The "completely vascularized single-stage reconstruction" avoids
      prolonged hospitalization and results in a rapid restoration of near-normal
      function and appearance of the hand.

PMID- 12616518
TI  - Comparison of functional results of nerve graft, vein graft, and vein filled with
      muscle graft in end-to-side neurorrhaphy.
AB  - End-to-side neurorrhaphy is an alternative method in the situation where the
      proximal part of the nerve cannot be found. When the intact nerve is not close
      enough to perform end-to-side neurorrhaphy, it will be necessary to use a graft
      for transporting the regenerating axons. In this study, we tried to find out
      whether it is possible to use a graft in an end-to-side neurorrhaphy, and
      compared the nerve graft with possible alternative grafts, i.e., vein and muscle
      filled vein grafts. Thirty male Sprague Dawley rats were used, with an average
      weight of 293 g (range, 250-350 g). All experiments were done on the right side.
      A 2-cm nerve graft, beginning 1 cm distal to the branching level, was sectioned
      from the peroneal nerve. A 1-mm epineural window was opened in the tibial nerve.
      In the first group, the proximal side of this graft was sutured to the tibial
      nerve side in an end-to-side fashion, and the distal side was sutured to the
      distal peroneal nerve stump in an end-to-end fashion. In the second group, the
      right 2-cm jugular vein was harvested, and was used to bridge the defect instead
      of the nerve graft used in the first group. In the third group, a 2-cm jugular
      vein filled with fresh skeletal muscle was used to bridge the defect. At 2, 4, 8,
      12, 20, and 28 weeks, functional assessment of nerve regeneration was performed,
      using walking-track analysis. The numbers of myelinated fibers and fiber
      diameters were measured, and an electron microscopic evaluation was carried out.
      Based on walking-track analysis and fiber diameters, the differences of all three
      groups were statistically significant (P < 0.05). While the differences of
      myelinated fibers between the first and second groups were not significant, the
      differences between the rest (group 1-group 3 and group 2-group 3) were
      significant (P < 0.05). Our study showed that, in end-to-side neurorrhaphy, the
      use of a nerve graft is possible, and a vein graft is also a good alternative,
      but a muscle-filled vein graft is not.

PMID- 12616519
TI  - Effect of subepineurial dehydroepiandrosterone treatment on healing of transected
      nerves repaired with the epineurial sleeve technique.
AB  - The epineurial sleeve technique for nerve repair is designed in part to protect a
      healing nerve from external humoral influences, but research suggests that the
      external factor dehydroepiandrosterone (DHEA) may actually improve nerve healing
      in crush injuries. To test the effect of DHEA, we injected it into the epineurial
      chambers created to repair transected rat sciatic nerves. In 18 control rats, the
      nerve was transected and repaired without DHEA treatment. Eighteen animals
      received subepineurial injections of propylene glycol vehicle, and 18 received
      subepineurial injections of about 0.2 ml DHEA. Walking-track analysis and toe
      contracture measurements showed no significant differences among the three
      groups. At 12 weeks, the gastrocnemius muscles in the DHEA group were
      significantly heavier than those of untreated controls. At 6 and 12 weeks, DHEA
      treated nerves had significantly more myelinated axons, larger average fiber
      diameter, and greater axonal cross-sectional areas in the proximal, middle, and
      distal sections. Myelin thickness did not differ between groups, except at 6
      weeks between the DHEA and vehicle-treated groups. We conclude that subepineurial
      dehydroepiandrosterone treatment reduced the extent of denervation atrophy and
      induced an earlier onset of axonal regeneration.

PMID- 12616520
TI  - Effect of torsion on microarterial anastomosis patency.
AB  - All kinds of technical faults must be prevented in microvascular anastomosis for
      successful reconstructive microsurgery. Torsion at the anastomosis site is one of
      the most basic technical errors. In this study, we investigate the effect of
      different degrees of microarterial torsion on patency and its physical changes on
      anastomosis in a rat model. A total of 144 microanastomosis were performed in 72
      Sprague-Dawley rats. They were divided into 9 groups. The anastomosis was
      performed at 0 degrees, 45 degrees, 90 degrees, 135 degrees, 180 degrees, 225
      degrees, 270 degrees, 315 degrees, and 360 degrees of torsion randomly. Patency
      rates and the narrowest point of the artery after the anastomosis were recorded
      after 1 hour for each group. In the second stage of the study, the 9 groups were
      divided into 2 groups for patency rates and histopathological sampling at the
      second and seventh days postoperatively. The femoral arteries in all groups were
      all patent at the end of 1 hour. Only 5 microanastomosis were thrombosed (one in
      the 45 degrees group, one in the 225 degrees group, one in the 270 degrees group,
      and two in the 315 degrees group) at the second day of exploration. Only two
      arteries were thrombosed (one in the 45 degrees group and one in the 315 degrees
      group) at the seventh day of exploration. The patency rate was 96.8% in
      experimental groups excluding the control group. Different degrees of torsion had
      no statistically significant effect on the patency rates of microvascular
      anastomosis. Torsional repair of the femoral artery in the rat has no significant
      histopathologic changes, but alternately, endothelial integrity was affected by
      excessive degrees of torsion. Different degrees of torsion at the anastomosis
      site do not affect patency rates and cross sectional histology of rat femoral
      arteries. In clinical practice, minor torsion can be tolerated, however, factors
      affecting patency such as tension, diameter disproportion, and tight closure can
      affect the final result of anastomosis. We observed that torsional force of the
      vessel is distributed along the artery to the weakest point.

PMID- 12616521
TI  - Primary nerve grafting: A study of revascularization.
AB  - It was the purpose of this study to evaluate the revascularization of primary
      nerve repair and grafts using orthogonal polarization spectral (OPS) (Cytometrix,
      Inc.) imaging, a novel method for real-time evaluation of microcirculatory blood
      flow. Twenty male Sprague Dawley rats (250 g) were anesthetized with vaporized
      halothane and surgically prepared for common peroneal nerve resection. Group I
      animals (n = 10) underwent primary neurorraphy following transection, utilizing a
      microsurgical technique with 10-0 nylon suture. Group II (n = 10) animals had a 7
      mm segment of nerve excised, reversed, and subsequently replaced as a nerve graft
      under similar techniques. All animals were evaluated using the OPS imaging system
      on three portions (proximal, transection site/graft, and distal) of the nerve
      following repair or grafting. Reevaluation of 5 animals randomly selected from
      each group using the OPS imaging system was again performed on days 14 and 28
      following microsurgical repair/grafting. Values were determined by percent change
      in vascularity of the common peroneal nerve at 0 hr following surgery. Real-time
      evaluation of blood flow was utilized as an additional objective criterion.
      Percent vascularity in group I and II animals increased from baseline in all
      segments at day 14. By day 28, vascularity in nerves of group I rats decreased in
      all segments to values below baseline, with the exception of the transection
      site, which remained at a higher value than obtained directly after surgical
      repair. In group II animals, vascularity remained above baseline in all segments
      except the distal segment, which returned to vascularity levels similar to those
      at 0 hr. Further, occlusion of the vessels demonstrated in the graft and distal
      segments following initial transection appeared to be corrected. This study
      suggests that revascularization may occur via bidirectional inosculation with
      favored proximal vascular growth advancement. The use of real-time imaging offers
      a unique evaluation of tissues through emerging technologies.

PMID- 12616522
TI  - Inside-out vein graft and inside-out artery graft in rat sciatic nerve repair.
AB  - Although veins and arteries present similar wall structures, there are
      differences which may be relevant in peripheral nerve reconstruction. Inside-out
      vein grafts (IOVG) have been satisfactorily used to repair both motor and
      sensitive nerves. However, the inside-out artery graft (IOAG) is a new technique
      and not fully investigated. Our study presents comparative morphological data on
      nerve regeneration achieved with IOVG and IOAG in the repair of Wistar rat
      sciatic nerves. Jugular veins and aorta arteries were harvested from donor
      animals and used "inside-out" to bridge a 10-mm gap. Animals were sacrificed at
      10 weeks to evaluate nerve regeneration. Both techniques presented great
      variability in nervous tissue, though some animals showed satisfactory results.
      Different intensities of scarring processes might have interfered with nerve
      regeneration. Although IOVG and IOAG techniques showed similar morphometric
      results, in general, IOVG presented a closer-to-normal nerve organization than
      IOAG.

PMID- 12616523
TI  - Tissue engineering of peripheral nerves: Epineurial grafts with application of
      cultured Schwann cells.
AB  - After a simple nerve lesion, primary microsurgical suture is the treatment of
      choice. A nerve gap has to be bridged, with a nerve graft sacrificing a
      functioning nerve. Alternatively, tissue engineering of nerve grafts has become a
      subject of experimental research. It is evident that nerve regeneration requires
      not only an autologous, allogenous, or biodegradable scaffold, but additional
      interactions with regeneration-promoting Schwann cells. In this study, we
      compared epineurial and acellularized epineurial tubes with and without
      application of cultured Schwann cells as alternative grafts in a rat sciatic
      nerve model. Autologous nerve grafts served as controls. Evaluation was performed
      after 6 weeks; afterwards, sections of the graft and distal nerve were harvested
      for histological and morphometrical analysis. Compared to controls, all groups
      showed a significantly lower number of axons, less well-shaped remyelinizated
      axons, and a delay in clinical recovery (e.g., toe spread). The presented
      technique with application of Schwann cells into epineurial tubes did not offer
      any major advantages for nerve regeneration. Thus, in this applied model, neither
      the implantation of untreated nor the implantation of acellularized epineurial
      tubes with cultured Schwann cells to bridge nerve defects was capable of
      presenting a serious alternative to the present gold standard of conventional
      nerve grafts for bridging nerve defects in this model.

PMID- 12616524
TI  - Dextrans in microsurgery: A review.
AB  - This articles reviews the use of dextrans in free tissue transfer. Current
      recommended regimes, indications, and complications are discussed. In conclusion,
      dextrans cannot be used as a substitute for good surgical technique, and should
      be utilized cautiously, especially in the elderly.

PMID- 12616525
TI  - Biochemical fractionation reveals association of DNA methyltransferase (Dnmt) 3b
      with Dnmt1 and that of Dnmt 3a with a histone H3 methyltransferase and Hdac1.
AB  - De novo DNA methyltransferases, Dnmt3a and 3b, were purified by fractionation of
      S-100 extract from mouse lymphosarcoma cells through several chromatographic
      matrices followed by glycerol density gradient centrifugation. Dnmt3a was
      separated from Dnmt3b and Dnmt1 in the first column, Q-Sepharose whereas Dnmt3b
      co-purified with Dnmt1 after further fractionation through Mono-S and Mono-Q
      columns and glycerol density gradient centrifugation. Following purification, the
      majority of de novo DNA methyltransfearse activity was associated with
      Dnmt3b/Dnmt1 fractions. By contrast, the fractions containing Dnmt3a alone
      exhibited markedly reduced activity, which correlated with diminished expression
      of this isoform in these cells. Histone deacetylase 1(Hdac1) cofractionated with
      Dnmt3a throughout purification whereas Hdac1 was separated from Dnmt3b/Dnmt1
      following chromatography on Mono-Q column. Dnmt3a purified through glycerol
      gradient centrifugation was also associated with a histone H3 methyltransferase
      (HMTase) activity whereas purified Dnmt3b/Dnmt1 was devoid of any HMTase
      activity. The activity of this HMTase was abolished when lysine 9 of N-terminal
      histone H3 peptide was replaced by leucine whereas mutation of lysine 4 to
      leucine inhibited this activity only partially. This is the first report on the
      identification of a few key co-repressors associated with endogenous Dnmt3a and
      of a complex containing Dnmt3b and a minor form of Dnmt1 following extensive
      biochemical fractionation.

PMID- 12616526
TI  - Human melanoma TrkC: its association with a purine-analog-sensitive kinase
      activity.
AB  - The various members of the Trk tyrosine kinase family and p75 neurotrophin
      receptor (p75(NTR)) have been identified as signaling receptors for the
      structurally related members of the neurotrophins (NT) family. We have previously
      reported that NT treatment of murine and human brain-metastatic melanoma cells
      affects their invasive capacities and increases the production of extracellular
      matrix degradative enzymes. These cells express aberrant levels of functional
      p75(NTR) and TrkC, the putative high-affinity receptor for the neurotrophin NT-3.
      Here we demonstrate that, by using sensitive immune-complex kinase assays in
      human brain-metastatic (70W) melanoma cells, TrkC receptors associate with a
      kinase activity exhibiting a dose-dependent susceptibility to inhibition by the
      purine-analogs 6-thioguanine and 2-aminopurine. The activity of this purine
      analog-sensitive kinase (PASK) was induced by NT-3 in a time-dependent fashion,
      phosphorylating exogenous myelin basic protein (MBP) but not denatured enolase.
      It is similar to the one reported to relate with p75(NTR) and TrkA receptors and
      stimulated by the prototypic NT, nerve growth factor. Thus, PASKs may represent
      unique signaling components common to NT receptors that could engage joint
      downstream signaling effectors in brain-metastatic melanoma.

PMID- 12616527
TI  - Fracture healing as a post-natal developmental process: molecular, spatial, and
      temporal aspects of its regulation.
AB  - Fracture healing is a specialized post-natal repair process that recapitulates
      aspects of embryological skeletal development. While many of the molecular
      mechanisms that control cellular differentiation and growth during embryogenesis
      recur during fracture healing, these processes take place in a post-natal
      environment that is unique and distinct from those which exist during
      embryogenesis. This Prospect Article will highlight a number of central
      biological processes that are believed to be crucial in the embryonic
      differentiation and growth of skeletal tissues and review the functional role of
      these processes during fracture healing. Specific aspects of fracture healing
      that will be considered in relation to embryological development are: (1) the
      anatomic structure of the fracture callus as it evolves during healing; (2) the
      origins of stem cells and morphogenetic signals that facilitate the repair
      process; (3) the role of the biomechanical environment in controlling cellular
      differentiation during repair; (4) the role of three key groups of soluble
      factors, pro-inflammatory cytokines, the TGF-beta superfamily, and angiogenic
      factors, during repair; and (5) the relationship of the genetic components that
      control bone mass and remodeling to the mechanisms that control skeletal tissue
      repair in response to fracture.

PMID- 12616528
TI  - Apoptosis and lung cancer: a review.
AB  - It is important to understand the molecular events that contribute to drug
      induced apoptosis, and how tumors evade apoptotic death. Defects in apoptosis are
      implicated in both tumorigenesis and drug resistance, and these defects are cause
      of chemotherapy failures. These studies should explain the relationship between
      cancer genetics and treatment sensitivity, and should enable a more rational
      approach to anticancer drug design and therapy. Lung cancer is a major cause of
      cancer deaths throughout the world. Small cell lung carcinoma (SCLC) and non
      small cell lung carcinoma (NSCLC) represent the two major categories of lung
      cancer that differ in their sensitivity to undergo apoptosis. The role of
      apoptosis regulation in lung cancer with major focus on the differential
      sensitivities of the major subtypes is reviewed.

PMID- 12616529
TI  - Expression of various genes is controlled by DNA methylation during mammalian
      development.
AB  - Despite thousands of articles about 5-methylcytosine (m(5)C) residues in
      vertebrate DNA, there is still controversy concerning the role of genomic m(5)C
      in normal vertebrate development. Inverse correlations between expression and
      methylation are seen for many gene regulatory regions [Heard et al., 1997;
      Attwood et al., 2002; Plass and Soloway, 2002] although much vertebrate DNA
      methylation is in repeated sequences [Ehrlich et al., 1982]. At the heart of this
      debate is whether vertebrate DNA methylation has mainly a protective role in
      limiting expression of foreign DNA elements and endogenous transposons [Walsh and
      Bestor, 1999] or also is important in the regulation of the expression of diverse
      vertebrate genes involved in differentiation [Attwood et al., 2002]. Enough
      thorough studies have now been reported to show that many tissue- or development
      specific changes in methylation at vertebrate promoters, enhancers, or insulators
      regulate expression and are not simply inconsequential byproducts of expression
      differences. One line of evidence comes from mutants with inherited alterations
      in genes encoding DNA methyltransferases and from rodents or humans with
      somatically acquired changes in DNA methylation that illustrate the disease
      producing effects of abnormal methylation. Another type of evidence derives from
      studies of in vivo correlations between tissue-specific changes in DNA
      methylation and gene expression coupled with experiments demonstrating cause-and
      effect associations between DNA hyper- or hypomethylation and gene expression. In
      this review, I summarize some of the strong evidence from both types of studies.
      Taken together, these studies demonstrate that DNA methylation in mammals
      modulates expression of many genes during development, causing major changes in
      or important fine-tuning of expression. Also, I discuss previously established
      and newly hypothesized mechanisms for this epigenetic control.

PMID- 12616530
TI  - Regulation by glucocorticoids of cell differentiation and insulin-like growth
      factor binding protein production in cultured fetal rat nasal chondrocytes.
AB  - Glucocorticoids (GCs) modulate insulin-like growth factor action in cartilage
      through mechanisms that are complex and insufficiently defined, especially in the
      context of cranio-facial growth. Because the family of IGF-binding proteins
      (IGFBP-1 to -6) is important in the regulation of IGF availability and
      bioactivity, we examined the effect of GCs on chondrocyte differentiation in
      correlation with IGFBP production in cultured fetal rat chondrocytes isolated
      from nasal septum cartilage of fetal rat. Dexamethasone (DEX) effects were tested
      before and at the onset of extracellular matrix maturation. DEX induced a dose
      dependent increase in the size of cartilage nodule formed, (45)Ca incorporation
      into extracellular matrix, alkaline phosphatase activity, and sulfatation of
      glycosaminoglycans, maximal effects being obtained with a 10-mM DEX
      concentration. The IGFBPs produced by cultured chondrocytes were characterized in
      culture medium which had been conditioned for 24 h under serum-free conditions by
      these cells. Western ligand blotting with a mixture of [(125)I]IGF-I and -II
      revealed bands of 20, 24, 29, a 31-32 kDa doublet and a 39-41 kDa triplet which
      were differently regulated by DEX. Immunoblotting showed that following DEX
      exposure, IGFBP-3 and -6 were up-regulated whereas IGFBP-2, -5, and the 24 kDa
      band were down-regulated. The effect of DEX on both differentiation and IGFBP
      production showed a same dependence, and developed when extracellular matrix
      maturation had been just induced. The results obtained in this chondrocyte
      culture system show that production of IGFBPs is modulated by DEX at
      physiological concentrations thus regulating IGF availability and action, a
      control which could promote the primordial role of the rat nasal septum in
      craniofacial growth.

PMID- 12616531
TI  - Same origins of DNA replication function on the active and inactive human X
      chromosomes.
AB  - We previously characterized a functional origin of DNA replication at the
      transcriptional promoter of the human hypoxanthine-guanine
      phosphoribosyltransferase (HPRT) gene (Cohen et al. [2002] J. Cell. Biochem.
      85:346-356). This origin was mapped using a quantitative PCR assay to evaluate
      the relative abundance of HPRT markers in short nascent DNA strands isolated from
      asynchronous cultures of male fibroblasts. The HPRT gene on the X chromosome is
      transcriptionally active in male human fibroblasts. It is known that on the
      heterochromatic X chromosome in female cells the HPRT gene is transcriptionally
      silenced and its replication timing changes from early to late in S phase. This
      change in replication timing could indicate that replication of the HPRT gene is
      under the control of different origins of DNA replication in the active
      (euchromatic, early replicating) and the inactive (heterochromatic, late
      replicating) X chromosomes. In the present study, we identified the location of
      the origin of replication of a second X chromosome gene, glucose-6-phosphate
      dehydrogenase (G6PD), which we mapped to its transcriptional promoter, in normal
      male human fibroblasts. Then, we determined the activity of the previously
      identified HPRT and the G6PD human origins in hybrid hamster cells carrying
      either the active or the inactive human X chromosome. The results of these
      studies clearly demonstrated that the human HPRT and G6PD origins of replication
      were utilized to the same extent in the active and the inactive X chromosomes.
      Therefore, transcription activity at the HPRT and G6PD genes is not necessary for
      initiation of DNA replication at the origins mapped to these chromosomal loci.

PMID- 12616532
TI  - Cloning and functional characterization of GNPI2, a novel human homolog of
      glucosamine-6-phosphate isomerase/oscillin.
AB  - The enzyme, glucosamine-6-phosphate isomerase (GNPI) or deaminase (GNPDA) (EC
      5.3.1.10), catalyzes the conversion of GNP to fructose-6-phosphate and ammonia,
      with an aldo/keto isomerization and an amination/deamination. A hamster sperm
      derived protein (Oscillin) with high similarity to bacterial GNPI has been proved
      to be capable of inducing calcium oscillation in eggs at fertilization.
      GNPI/Oscillin was supposed to be an important factor in starting embryonic
      development. From the cDNA library of human dendritic cells (DC), we isolated a
      novel full-length cDNA encoding a 276-amino acid-residue protein that shares high
      homology with human GNPI/Oscillin. So, the novel molecule is named as GNPI2. The
      GNPI2 gene consists of seven exons and six introns. It is mapped to chromosome 4.
      Northern blot analysis indicated that the tissue distribution of GNPI2 mRNA is
      different from that of human GNPI or Oscillin mRNA. GNPI2 is ubiquitously
      expressed in most of human tissues with high expression in testis, ovary,
      placenta, and heart. Like GNPI, the recombinant GNPI2 has been proved to have the
      enzymatic activity to catalyze the conversion of GNP to fructose-6-phosphate. Our
      results indicated that GNPI2 is a novel protein with definite function as a GNPI.

PMID- 12616533
TI  - Coordinate down-regulation of cartilage matrix gene expression in Bcl-2 deficient
      chondrocytes is associated with decreased SOX9 expression and decreased mRNA
      stability.
AB  - The anti-apoptotic protein Bcl-2 has been shown to function in roles unrelated to
      apoptosis in a variety of cell types. We have previously reported that loss of
      Bcl-2 expression alters chondrocyte morphology and modulates aggrecan expression
      via an apoptosis-independent pathway. Here we show that Bcl-2 is required for
      chondrocytes to maintain expression of a variety of cartilage-specific matrix
      proteins. Using quantitative, real-time PCR, we demonstrate that Bcl-2-deficient
      chondrocytes coordinately down-regulate genes coding for hyaline cartilage matrix
      proteins including collagen II, collagen IX, aggrecan, and link protein. The
      decrease in steady-state level of these mRNA transcripts results, in part, from
      decreased mRNA stability in Bcl-2-deficient chondrocytes. Transcriptional
      regulation is also likely involved because chondrocytes with decreased Bcl-2
      levels show decreased expression of SOX9, a transcription factor necessary for
      expressing the major cartilage matrix proteins. In contrast, chondrocytes
      constitutively expressing Bcl-2 have a stable phenotype when subjected to loss of
      serum factor signaling. These cells maintain high levels of SOX9, as well as the
      SOX9 targets collagen II and aggrecan. These results suggest that Bcl-2 is
      involved in a pathway important for maintaining a stable chondrocyte phenotype.

PMID- 12616534
TI  - Intracellular zinc fluxes associated with apoptosis in growth plate chondrocytes.
AB  - Matrix vesicles released by epiphyseal growth plate chondrocytes are known to
      contain a significant quantity of labile Zn(2+). Zonal analysis of chicken
      metatarsal bones showed that the resting/proliferative region of the growth plate
      contained high levels of Zn(2+) with significantly lower levels in the
      hypertrophic cartilage suggesting a loss of cellular Zn(2+) as the chondrocytes
      mature. Intracellular labile Zn(2+) was measured in primary cultures of growth
      plate chondrocytes by assay with the fluorescent Zn-chelator
      toluenesulfonamidoquinoline (TSQ) and imaged by multi-photon laser scanning
      microscopy (MPLSM) with the TSQ derivative zinquin. Short-term exposure to
      Zn(2+), both in the presence and absence of pyrithione resulted in significant
      increases in cytosolic Zn(2+). Treatment with the membrane-permeant Zn(2+)
      chelator TPEN rapidly reduced the levels of labile Zn(2+) and triggered
      apoptosis. Cytosolic Zn(2+) levels were significantly reduced following 24-h
      incubations with known inducers of chondrocyte apoptosis. The loss of
      intracellular Zn(2+) was accompanied by a significant reduction in the cytosolic
      metal-binding protein metallothionein. Examination of Zn(2+)-treated cells with
      MPLSM showed uniformly higher zinquin fluorescence. Treatment of Zn(2+)-loaded
      cells with TPEN quenched zinquin fluorescence confirming that the observed
      fluorescence in chondrocytes is due to the presence of intracellular Zn(2+). A
      dose-dependent increase in zinquin fluorescence was observed in cells treated
      with a range of Zn(2+) concentrations. Short-term treatment of cultured
      chondrocytes with apoptosis-inducing chemicals resulted in transient increases in
      intracellular labile Zn(2+). These results indicate that Zn(2+) is mobilized from
      intracellular binding sites in the early stages of chondrocyte apoptosis and is
      subsequently lost from the cells. The early mobilization of Zn(2+) provides a
      mechanism for its movement to matrix vesicles and the extracellular matrix.

PMID- 12616535
TI  - Identification of reciprocally regulated gene modules in regenerating dorsal root
      ganglion neurons and activated peripheral or central nervous system glia.
AB  - Differential gene expression in the rat after injury of dorsal root ganglion
      neurons in vivo, and simulation injury of Schwann cells and oligodendrocytes in
      vitro was analyzed using high-density cDNA microarrays. The analyses were carried
      out to study the genetic basis of peripheral nerve regeneration, and to compare
      gene regulation in glia of the central (oligodendrocyte) and peripheral (Schwann
      cell) nervous systems. The genes showing significant differential regulation in
      the three study groups represented all aspects of cellular metabolism. However,
      two unexpected observations were made. Firstly, a number of identical genes were
      differentially regulated in activated Schwann cells, activated oligodendrocytes
      and regenerating DRG neurons. Specifically, a group of 113 out of 210 genes that
      were down-regulated in Schwann cells upon lipopolysaccharide (LPS) treatment,
      were identical to genes up-regulated in the injured, regenerating DRG.
      Furthermore, a group of 53 out of 71 genes that were down-regulated in interferon
      gamma (IFN-gamma)/LPS-activated oligodendrocytes, were identical to genes up
      regulated in the DRG neurons. Finally, 22 genes were common to these three
      groups, i.e., down-regulated in activated oligodendrocytes, down-regulated in
      activated Schwann cells, and up-regulated in regenerating DRG neurons. Secondly,
      a group of 16 cell-cycle and proliferation-related genes were up-regulated in the
      DRG following sciatic nerve crush, despite the absence of cells undergoing
      mitosis in the DRG, or any significant presence of apoptosis-related gene
      expression. Therefore, it appears that in these three cell types, large sets of
      genes are reciprocally regulated upon injury and/or activation. This suggests
      that the activation of the injury-related gene expression program in cell
      derivatives of the neuroectoderm involves, in part, highly conserved genetic
      elements.

PMID- 12616536
TI  - Modulation of TNF-alpha expression in bone marrow macrophages: involvement of
      vitamin D response element.
AB  - The calcium-regulating hormone, 1,25(OH)(2)D(3), induces tumor necrosis factor
      alpha (TNF-alpha) synthesis and release from bone marrow macrophages (BMMs). To
      investigate the mechanism of this regulation, we have examined the effects of
      1,25(OH)(2)D(3) on the cytokine message. 1,25(OH)(2)D(3) increased TNF-alpha mRNA
      abundance in a dose- and time-dependent manner. The combined treatment of BMMs
      with LPS and 1,25(OH)(2)D(3) resulted in a synergistic increase of TNF-alpha. The
      steroid also increased the expression of CD14 (LPS receptor). Vitamin D receptors
      (VDRs) mediate 1,25(OH)(2)D(3) genomic effects by forming homodimers or
      heterodimers with retinoic acid receptors (RARs) or retinoic X receptors (RXRs).
      The RXR ligand, 9-cis retinoic acid (9cRA), reduced TNF-alpha mRNA abundance in
      BMMs, but increased CD14 mRNA levels. 1,25(OH)(2)D(3) or LPS did not affect TNF
      alpha transcript stability. 9cRA, however, caused TNF-alpha mRNA destabilization.
      Next, we searched for potential vitamin D response elements (VDREs) in the
      promoter region (1.2 kb) of the TNF-alpha gene, and identified six such
      sequences. Using electrophoresis mobility shift assay (EMSA) we identified one of
      those sequences (-1008 to -994) as a likely candidate to be a VDRE (tnfVDRE). The
      binding of tnfVDRE to BMM-derived nuclear extract was increased following cell
      treatment with 1,25(OH)(2)D(3). No induction was observed with 9cRA treatment,
      but the retinoid enhanced the activity of 1,25(OH)(2)D(3) when added together.
      Previously characterized VDREs (mouse osteopontin and rat osteocalcin) competed
      effectively with tnfVDRE, demonstrating the nature of the TNF-alpha-derived
      sequence as a VDRE. We observed super-shift and block-shift of the complex in the
      presence of either anti-VDR or anti-RXR antibodies. Our data suggest that
      1,25(OH)(2)D(3) increases TNF-alpha transcript abundance in BMMs via a
      transcriptional mechanism; 9cRA decreases TNF-alpha mRNA by destabilizing the
      transcript, and possibly also by forming transcriptionally inactive complex with
      1,25(OH)(2)D(3) on the tnfVDRE. The receptor complex interacting with tnfVDRE
      found in the promoter of the cytokine gene is probably composed of VDR-RXR
      heterodimer.

PMID- 12616538
TI  - Modulation of PECAM-1 expression and alternative splicing during differentiation
      and activation of hematopoietic cells.
AB  - PECAM-1 (CD31) is a member of immunoglobulin gene superfamily, which is highly
      expressed on the surface of endothelial cells and at moderate levels on
      hematopoietic cells. Hematopoietic cells and platelets, like endothelial cells,
      express multiple isoforms of PECAM-1. However, the identity and physiological
      role of these isoforms during hematopoiesis remains largely unknown. Here we
      demonstrate that PECAM-1 expression is dramatically up regulated upon phorbol
      myristate acetate (PMA) or transforming growth factor (TGF)-beta1-mediated
      differentiation of leukemic HEL and U937 cells. The level of PECAM-1 expression
      did not significantly change during activation of Jurkat T cells by PMA or
      phytohaemagglutinin (PHA). Utilizing RT-PCR and DNA sequencing analysis, we show
      that the expression of PECAM-1 isoforms changes in a cell-type and lineage
      specific manner during cellular differentiation and activation. We identified a
      number of novel PECAM-1 isoforms previously not detected in the endothelium.
      These results demonstrate that regulated expression of PECAM-1 and its exonic
      inclusion/exclusion occurs during differentiation and/or activation of
      hematopoietic cells. Thus, different PECAM-1 isoforms may play important roles in
      generation of hematopoietic cells and their potential interactions with vascular
      endothelium.

PMID- 12616537
TI  - Mouse PSP94 expression is prostate tissue-specific as demonstrated by a
      comparison of multiple antibodies against recombinant proteins.
AB  - Prostate tissue-specific gene expression is crucial for driving potentially
      therapeutic genes to target specifically to the prostate. Prostate secretory
      protein of 94 amino acids (PSP94), also known as beta-MSP (microseminoprotein),
      is one of the three most abundant secretory proteins of the prostate gland, and
      is generally considered to be prostate tissue-specific. We have previously
      demonstrated that the expression of the rat PSP94 gene is strictly prostate
      tissue-specific by an antibody against a recombinant rat PSP94. In order to study
      prostate targeting utilizing the PSP94 gene in a mouse pre-clinical experimental
      model, we need to establish antibodies against mouse PSP94 to confirm if it is
      prostate tissue-specific as well. In this study, firstly we raised a polyclonal
      antibody against a recombinant glutathione-S-transferase- (GST-) mouse mature
      form of PSP94. However, it showed very poor immunoreactivity against prostate
      tissue PSP94 as tested in Western blotting experiments. Neither antibodies
      against rat PSP94 nor mouse PSP94 showed significant cross-reactivity. Thus a
      second antibody was established against a recombinant mouse mature PSP94
      containing N-terminal polyhistidines, and stronger immunoreactivity against mouse
      prostate tissue PSP94 was identified in Western blotting experiments. Both of
      these antibodies showed immunohistochemical reactivity, while the latter showed
      stronger reactivity in IHC when tested with different fixatives. By studying
      tissue distribution, we demonstrated that, as with rat PSP94, mouse PSP94 is
      strictly prostate tissue-specific in experiments of both Western blotting and
      immunohistochemistry (IHC). This conclusion was also derived from a comparison
      among antibodies against human, rat, and mouse PSP94, showing very different
      immunoreactivities in Western blotting and IHC. Finally, a competitive assay
      between different species was performed. We demonstrated that antibodies against
      PSP94 from different species (human, primate, rodents) have poor cross
      reactivities. These observations also indicate that the PSP94 gene is a rapidly
      evolving gene in all species. Results from this study have led to the possibility
      of utilizing PSP94 as a targeting agent specifically to the prostate in a mouse
      experimental model.

PMID- 12616540
TI  - Alpha 4 integrin increases anoikis of human osteosarcoma cells.
AB  - Cell motility, growth, and proliferation are regulated by adhesion to the
      extracellular matrix. Detachment of adherent cells from extracellular matrix
      results in induction of apoptosis ("anoikis"). Transformed cells often show an
      anchorage-independent growth that enables them to acquire a motile, invasive
      phenotype. This phenotype has been associated with the altered expression and
      function of the integrin family of transmembrane proteins that mediate cell
      adhesion to the extracellular matrix. Although alpha4 integrin is normally
      expressed on leukocyte subpopulations, a number of metastatic melanomas and
      sarcomas express it as well. In this study, we demonstrated the expression of
      alpha4 integrins on the human osteosarcoma cell line SAOS and on metastatic
      osteosarcoma lesions from the lung and pericardium. We further demonstrated that
      alpha4 integrin is coupled to the beta1 subunit by biochemical analysis and by
      using a mAb directed against a combinatorial epitope unique to the alpha4beta1
      molecule. SAOS cells undergo anoikis when adherence is denied. Anoikis involved
      the activation of caspase 3 and the release of cytochrome c from mitochondria.
      Treatment of non-adherent SAOS with an anti-alpha4 mAb increased anoikis while
      anti-beta1 integrin mAbs did not alter anoikis, thus indicating a novel function
      for the alpha4 subunit in the control of cell death. Since integrins can control
      cell migration, proliferation, and apoptosis these results demonstrate a
      potential role for alpha4 integrin during multiple aspects of osteosarcoma
      metastasis.

PMID- 12616539
TI  - Proprotein interaction with the GPI transamidase.
AB  - For characterizing how the glycosylphosphatidylinositol (GPI) transamidase
      complex functions, we exploited a two-step miniPLAP (placental alkaline
      phosphatase) in vitro translation system. With this system, rough microsomal
      membranes (RM) containing either [(35)S]-labeled Gaa1p or epitope-tagged Gpi8p,
      alternative components of the enzymatic complex, were first prepared. In a second
      translation, unmodified or mutant miniPLAP mRNA was used such that [(35)S]
      labeled native or variant miniPLAP nascent protein was introduced. Following
      this, the RM were solubilized and anti-PLAP or anti-epitope immunoprecipitates
      were analyzed. With transamidase competent HeLa cell RM, anti-PLAP or anti
      epitope antibody coprecipitated both Gaa1p and Gpi8p consistent with the assembly
      of the proprotein into a Gaa1p:Gpi8p-containing complex. When RM from K562 mutant
      K cells which lack Gpi8p were used, anti-PLAP antibody coprecipitated Gaa1p. The
      proprotein coprecipitation of Gaa1p increased with a nonpermissive GPI anchor
      addition (omega) site. In contrast, if a miniPLAP mutant devoid of its C-terminal
      signal was used, no coprecipitation occurred. During the transamidation reaction,
      a transient high Mr band forms. To definitively characterize this product, RM
      from K cells transfected with FLAG-tagged GPI8 were employed. Western blots of
      anti-FLAG bead isolates of solubilized RM from the cells showed that the high Mr
      band corresponded to Gpi8p covalently bound to miniPLAP. Loss of the band
      following hydrazinolysis demonstrated that the two components were associated in
      a thioester linkage. The data indicate that recognition of the proprotein
      involves Gaa1p, that the interaction with the complex does not depend on a
      permissive omega site, and that Gpi8p forms a thioester intermediate with the
      proprotein. The method could be useful for rapid analysis of nascent protein
      interactions with transamidase components, and possibly for helping to prepare a
      functional in vitro transamidase system.

PMID- 12616541
TI  - Soluble glucocorticoid-induced tumor necrosis factor receptor (sGITR) increased
      MMP-9 activity in murine macrophage.
AB  - Glucocorticoid induced tumor necrosis factor receptor (GITR), a new TNFR family,
      increased production of matrix matalloproteinase (MMP-9) in murine macrophages.
      Murine macrophages produced a band of gelatinolytic activity at 100 kDa when
      stimulated for 18 h with soluble GITR. MMP-9 was identified by gelatin zymography
      and Western blot. Previous results demonstrated that murine macrophages express
      GITR and GITR ligand constitutively. Induction of MMP-9 was synergistic with co
      treatment of INF-gamma. MMPs could play a critical role in progression and
      promotion of tissue injury after inflammation stimulated by GITR/ligand system.

PMID- 12616542
TI  - Low temperature-induced dimerization of the bovine sperm serine protease, BSp66.
AB  - BSp120 and BSp66 are trypsin-like serine proteases from bovine spermatozoa. The
      former is active in cryopreserved sperm samples while the latter shows
      proteolytic activity in recently obtained fresh sperm. Both proteases are
      immunologically related and co-localize in the apical portion of the sperm head.
      In Western blots with specific antibodies, sperm samples incubated with reducing
      agents showed a decrease in the amount of BSp120, while BSp66 was detected with
      both anti-BSp120 and anti-BSp66 antibodies. BSp120 was evident in frozen intact
      spermatozoa after 60 days of semen cryopreservation and the kinetic of appearance
      of this protein was coincident with the decrease in the amount of BSp66.
      Identical results were obtained by freezing sperm extracts from fresh semen at 
      20 degrees C. Our results suggest that BSp120 results from disulfide bond
      dimerization of BSp66 and that this process may be induced by temperatures below
      zero in both intact spermatozoa and in sperm extracts.

PMID- 12616546
TI  - Mobius strips of NbSe3: morphology design and solid-state chemistry.

PMID- 12616543
TI  - Inhibition of actin polymerization enhances commitment to and execution of
      apoptosis induced by withdrawal of trophic support.
AB  - We have previously shown, using jasplakinolide, that stabilization of the actin
      cytoskeleton enhanced apoptosis induced upon cytokine withdrawal (Posey and
      Bierer [1999] J. Biol. Chem. 274:4259-4265). It remained possible, however, that
      a disruption in the regulation of actin dynamics, and not simply F-actin
      stabilization, was required to affect the transduction of an apoptotic signal. We
      have now tested the effects of cytochalasin D, a well-characterized agent that
      promoted actin depolymerization. Actin depolymerization did not affect CD95 (Fas)
      induced death of Jurkat T cells in the time course studied but did enhance the
      commitment to cytokine withdrawal-induced apoptosis of factor-dependent cell
      lines. The induction of cell death was not the result of direct cytoskeletal
      collapse, since treatment of the cells with cytochalasin D in the presence of IL
      2 did not promote death. As with jasplakinolide, the enhancement of commitment to
      apoptosis could be delayed by overexpression of the anti-apoptotic protein Bcl
      x(L), but, unlike jasplakinolide, cytochalasin D modestly affected the
      "execution" stage of apoptosis as well. Taken together, these results suggest
      that changes in actin dynamics, i.e., the rate of actin polymerization and
      depolymerization, modulate the transduction of the apoptotic signal committing
      lymphocytes, withdrawn from required growth factors, to the death pathway.

PMID- 12616547
TI  - Proline-catalyzed asymmetric alpha-amination of aldehydes and ketones--an
      astonishingly simple access to optically active alpha-hydrazino carbonyl
      compounds.

PMID- 12616548
TI  - Organic templates for the generation of inorganic materials.
AB  - Mankind's fascination with shapes and patterns, many examples of which come from
      nature, has greatly influenced areas such as art and architecture. Science too
      has long since been interested in the origin of shapes and structures found in
      nature. Whereas organic chemistry in general, and supramolecular chemistry
      especially, has been very successful in creating large superstructures of often
      stunning morphology, inorganic chemistry has lagged behind. Over the last decade,
      however, researchers in various fields of chemistry have been studying novel
      methods through which the shape of inorganic materials can be controlled at the
      micro- or even nanoscopic level. A method that has proven very successful is the
      formation of inorganic structures under the influence of (bio)organic templates,
      which has resulted in the generation of a large variety of structured inorganic
      structures that are currently unattainable through any other method.

PMID- 12616549
TI  - Metallacarborane-based nanostructures: a carbon-wired planar octagon.

PMID- 12616550
TI  - Preparation of artificial metalloenzymes by insertion of chromium(III) Schiff
      base complexes into apomyoglobin mutants.

PMID- 12616551
TI  - Oligonucleotide-templated self-assembly of nucleotide bolaamphiphiles: DNA-like
      nanofibers edged by a double-helical arrangement of A-T base pairs.

PMID- 12616552
TI  - Molecular mousetraps: gas-phase studies of the covalent coupling of noncovalent
      complexes initiated by reactive carbenes formed by controlled activation of diazo
      precursors.

PMID- 12616553
TI  - A rare-earth metal TCNQ magnet: synthesis, structure, and magnetic properties of
      [[Gd2(TCNQ)5(H2O)9][Gd(TCNQ)4-(H2O)3]].4 H2O.

PMID- 12616554
TI  - Direct liquid-phase sulfonation of methane to methanesulfonic acid by SO3 in the
      presence of a metal peroxide.

PMID- 12616555
TI  - Control of alpha/beta stereoselectivity in Lewis acid promoted C-glycosidations
      using a controlling anomeric effect based on the conformational restriction
      strategy.

PMID- 12616556
TI  - An unexpected, sterically driven, methyl halide elimination in pentacoordinate
      siliconium halide salts: silicon complexes with equatorial nitrogen coordination.

PMID- 12616557
TI  - Oxidation of unactivated primary aliphatic amines catalyzed by an
      electrogenerated 3,4-azaquinone species: a small-molecule mimic of amine
      oxidases.

PMID- 12616558
TI  - Efficient degradation of organic pollutants by using dioxygen activated by resin
      exchanged iron(II) bipyridine under visible irradiation.

PMID- 12616559
TI  - A highly enantioselective catalyst for the asymmetric Nozaki-Hiyama-Kishi
      reaction of allylic and vinylic halides.

PMID- 12616560
TI  - A catalytic carbon-phosphorus ylide reaction: phosphane-catalyzed annulation of
      allylic compounds with electron-deficient alkenes.

PMID- 12616562
TI  - Chiral-Mn(salen)-complex-catalyzed kinetic resolution of secondary alcohols in
      water.

PMID- 12616561
TI  - Stabilization of low-oxidation-state early transition-metal complexes bearing
      1,2,4-triphosphacyclopentadienyl ligands: structure of [[Sc(P3C2tBu2)2]2]; ScII
      or mixed oxidation state?

PMID- 12616563
TI  - Protonation of cubane in the gas phase: a high-level Ab initio and DFT study.

PMID- 12616565
TI  - Topomerization of a distorted diamond-shaped tetraborane(4) and its hydroboration
      to a closo-pentaborane(7) with a nido structure.

PMID- 12616564
TI  - Synthesis and structure of cyclic gold(I) phosphanyl complexes [[Au(PR2)]n].

PMID- 12616566
TI  - The fluoroacyltris(trifluoromethyl)borate ion, [(CF3)3BC(O)F]-, a fluoroacylboron
      complex.

PMID- 12616567
TI  - A versatile catalyst for the Sonogashira coupling of aryl chlorides.

PMID- 12616570
TI  - Modeling the jaw mechanism of Pleuronichthys verticalis: The morphological basis
      of asymmetrical jaw movements in a flatfish.
AB  - Several flatfish species exhibit the unusual feature of bilateral asymmetry in
      prey capture kinematics. One species, Pleuronichthys verticalis, produces lateral
      flexion of the jaws during prey capture. This raises two questions: 1) How are
      asymmetrical movements generated, and 2) How could this unusual jaw mechanism
      have evolved? In this study, specimens were dissected to determine which cephalic
      structures might produce asymmetrical jaw movements, hypotheses were formulated
      about the specific function of these structures, physical models were built to
      test these hypotheses, and models were compared with prey capture kinematics to
      assess their accuracy. The results suggest that when the neurocranium rotates
      dorsally the premaxillae slide off the smooth, rounded surface of the vomer
      (which is angled toward the blind, or eyeless, side) and are "launched"
      anteriorly and laterally. The bilaterally asymmetrical trajectory of the upper
      jaw is determined by the orientation of the "launch pad," the vomer. During lower
      jaw depression, the mandibles rotate about their articulations with the quadrate
      bones of the suspensoria. The quadrato-mandibular joint is positioned farther
      anteriorly on the eye side than on the blind side, and this asymmetry deflects
      the lower jaw toward the blind side. Asymmetry in the articular surfaces of the
      lower jaw augments this effect. Thus, it appears that fish with intermediate
      forms of this asymmetrical movement could have evolved from symmetrical ancestors
      via a few key morphological changes. In addition, similar morphological
      modifications have been observed in other fish taxa that also produce jaw flexion
      during feeding, which suggests that there may be convergence in the basic
      mechanism of asymmetry.

PMID- 12616568
TI  - Hydrogen-bonded sugar-alcohol trimers as hexadentate silicon chelators in aqueous
      solution.

PMID- 12616571
TI  - Keratinization of the epidermis of the Australian lungfish Neoceratodus forsteri
      (dipnoi).
AB  - The differentiation of the epidermis in sarcopterigian fish may reveal some trend
      of keratinization followed by amphibian ancestors to adapt their epidermis to
      land. Therefore, the process of keratinization of the epidermis of the Australian
      lungfish Neoceratodus forsteri was studied by histochemistry, electron
      microscopy, and keratin immunocytochemistry. The epidermis is tri-stratified in a
      2-3-month-old tadpole but becomes 6-8 stratified in young adults. Keratin
      filaments increase from basal to external cells where loose tonofilament bundles
      are present. This is shown also by the comparison of positivity to sulfhydryl
      groups and increasing immunoreactivity to alpha-keratins in more external layers
      of the epidermis. Two broad-spectrum anti alpha-keratin monoclonal antibodies
      (AE1 and AE3) stain all epidermal layers as they do in actinopterigian fish. In
      the adult epidermis, but not in that of the larva, the AE2 antibody (a marker of
      keratinization in mammalian epidermis) often immunolabels more heavily the
      external keratinized layers where sulfhydryl groups are more abundant. Mucous
      granules are numerous and concentrate on the external surface of the epidermis to
      be discharged and contribute to cuticle formation. Keratin is therefore embedded
      in a mucus matrix, but neither compact keratin masses nor cell corneous envelope
      were seen in external cells. It is not known whether specific matrix proteins are
      associated with mucus. There was no immunolocalization of the keratin-associated
      proteins, filaggrin and loricrin, which suggests that the epidermis of this
      species lacks the matrix and cell corneus envelope proteins characteristic of
      that of amniotes. In conclusion, while specific keratins (AE2 positive) are
      probably produced in the uppermost layers as in amphibian epidermis, no
      interkeratin, matrix proteins seem to be present in external keratinocytes of the
      lungfish other than mucus.

PMID- 12616572
TI  - Autapomorphies of the endophragmal system in trichodactylid freshwater crabs
      (Crustacea: Decapoda: Eubrachyura).
AB  - An examination of the thoracic endophragmal system in trichodactylid freshwater
      crabs revealed several derived features that appear restricted to this family.
      Trichodactylids have a highly reduced sella turcica with a rim-like overall
      configuration; as a consequence of sella turcica reduction the median septum is
      dorsoventrally diminished and exposed along its length. In addition,
      interosternite 7/8 is medially erased with the remnants restricted to the lateral
      regions of the sternum. The configurations of the sella turcica and
      interosternite 7/8 in trichodactylids underscore the monophyly of this family.
      The Dilocarcininae is characterized by having interosternites 5/6 through 7/8
      restricted to the lateral sectors of the sternum, the lateral remnants of
      interosternite 4/5 forming prominent, rib-like ridges oriented diagonally to the
      longitudinal axis of the crab, and the median septum forming with interosternite
      4/5 a Y-shaped pattern. These autapomorphies of the endophragmal system separate
      the trichodactylids from all other eubrachyurans and emphasize the morphological
      distinctness of the group. A description of the trichodactylid endophragmal
      junction plate is also provided.

PMID- 12616573
TI  - Epidermal differentiation during ontogeny and after hatching in the snake Liasis
      fuscus (Pythonidae, Serpentes, Reptilia), with emphasis on the formation of the
      shedding complex.
AB  - Differentiation and localization of keratin in the epidermis during embryonic
      development and up to 3 months posthatching in the Australian water python,
      Liasis fuscus, was studied by ultrastructural and immunocytochemical methods.
      Scales arise from dome-like folds in the skin that produce tightly imbricating
      scales. The dermis of these scales is completely differentiated before any
      epidermal differentiation begins, with a loose dermis made of mesenchymal cells
      beneath the differentiating outer scale surface. At this stage (33) the embryo is
      still unpigmented and two layers of suprabasal cells contain abundant glycogen.
      At Stage 34 (beginning of pigmentation) the first layers of cells beneath the
      bilayered periderm (presumptive clear and oberhautchen layers) have not yet
      formed a shedding complex, within which prehatching shedding takes place. At
      Stage 35 the shedding complex, consisting of the clear and oberhautchen layers,
      is discernible. The clear layer contains a fine fibrous network that faces the
      underlying oberhautchen, where the spinulae initially contain a core of fibrous
      material and small beta-keratin packets. Differentiation continues at Stage 36
      when the beta-layer forms and beta-keratin packets are deposited both on the
      fibrous core of the oberhautchen and within beta-cells. Mesos cells are produced
      from the germinal layer but remain undifferentiated. At Stage 37, before
      hatching, the beta-layer is compact, the mesos layer contains mesos granules, and
      cells of the alpha-layer are present but are not yet keratinized. They are still
      only partially differentiated a few hours after hatching, when a new shedding
      complex is forming underneath. Using antibodies against chick scale beta-keratin
      resolved at high magnification with immunofluorescent or immunogold conjugates,
      we offer the first molecular confirmation that in snakes only the oberhautchen
      component of the shedding complex and the underlying beta cells contain beta
      keratin. Initially, there is little immunoreactivity in the small beta-packets of
      the oberhautchen, but it increases after fusion with the underlying cells to
      produce the syncytial beta layer. The beta-keratin packets coalesce with the
      tonofilaments, including those attached to desmosomes, which rapidly disappear in
      both oberhautchen and beta-cells as differentiation progresses. The labeling is
      low to absent in forming mesos-cells beneath the beta-layer. This study further
      supports the hypothesis that the shedding complex in lepidosaurian reptiles
      evolved after there was a segregation between alpha-keratogenic cells from beta
      keratogenic cells during epidermal renewal.

PMID- 12616574
TI  - Osteology and skeletal development of Apalone spinifera (Reptilia: Testudines:
      Trionychidae).
AB  - Despite considerable attention that other groups of reptiles have received, few
      descriptions of the development and sequences of chondrification and ossification
      of the entire skeleton of turtles exist. Herein, the adult skeleton of the spiny
      softshell turtle, Apalone spinifera (Testudines: Trionychidae), is described;
      this description forms a basis of comparison for the embryonic skeleton and its
      ontogenesis. Descriptions are made on the basis of cleared and double-stained
      embryos and dry skeletal postembryonic specimens. The embryonic chondrocranium of
      A. spinifera is described and compared to those of Emys orbicularis and Caretta
      caretta, the sequence of chondrification of fore- and hindlimbs are compared with
      published descriptions of Chelydra serpentina and Chrysemys picta, and the
      sequence of ossification of elements is compared with those of C. serpentina,
      Lacerta vivipara, and Alligator mississippiensis. In A. spinifera, the first
      elements that ossify (Stage 17) are associated with the dermatocranium and
      mandible, followed by elements of the dermal skull table, lower jaw, and dermal
      elements of the plastron. In A. spinifera, the sequence of chondrification of
      limb elements is similar to that of C. serpentina; however, the sequence of
      ossification varies greatly among Apalone, Chelydra, Lacerta, and Alligator.

PMID- 12616575
TI  - Diaphragm muscle development in bottlenose dolphins (Tursiops truncatus).
AB  - Being born directly into the aquatic environment creates unique challenges for
      the breathing muscles of neonatal cetaceans. Not only must these muscles be
      active at the instant of birth to ventilate the lungs, but their activities must
      also be coordinated with those of the locomotor muscles such that breathing takes
      place only at the water's surface. At least one major locomotory muscle of
      bottlenose dolphins (Tursiops truncatus) has been demonstrated to be well
      developed and, therefore, able to power the neonatal dolphin's early movements
      (Dearolf et al. [2000] J Morphol 244:203-215). Thus, because of the demands for
      coordinated behavior with the locomotor muscles, it is hypothesized that the
      breathing muscles of bottlenose dolphins, represented in this study by the
      diaphragm, will also demonstrate adult morphology at birth. However,
      histochemical and biochemical analyses demonstrate that neonatal dolphins have
      immature diaphragms, with only 52% of the adult slow fiber-type profile
      (neonates: 34% slow-twitch fibers; adults: 66% slow-twitch fibers). The
      developmental state of the dolphin diaphragm is compared to those of other
      neonatal mammals, using a muscle development index (% slow-twitch fibers in
      neonatal muscle / % slow-twitch fibers in adult muscle). Fiber-type profiles
      reported in the literature are used to calculate index values for the diaphragms
      of altricial rats, rabbits, and cats, intermediate baboons and humans, and
      precocial sheep and horses. The dolphin is not unique in having an immature
      diaphragm at birth; however, there is a positive relationship between the
      developmental state of the diaphragm and the overall developmental state of the
      neonate. The presence of type IIc ("undifferentiated") fibers in the diaphragms
      of altricial developers (e.g., rats, rabbits, and cats) is correlated with the
      slow contraction speeds recorded from their diaphragms. The diaphragms of
      neonatal horses and dolphins express little to no type IIc fibers and, thus, may
      have the ability to contract at the speeds required for their increased
      ventilation rates. These results lead to the modification of the criterion for
      evaluating the developmental state of a muscle at birth. Thus, the developmental
      state of a neonatal muscle should be based on both its value of Dearolf et al.'s
      (2000) developmental index, as well as the percentage of type IIc fibers found in
      that muscle.

PMID- 12616576
TI  - Inter- and intraspecific variation in the distribution and number of pit organs
      (free neuromasts) of sharks and rays.
AB  - The distribution of pit organs (free neuromasts) has previously been documented
      for several species of pelagic sharks, but is relatively poorly known for rays
      and bottom-dwelling (demersal) sharks. In the present study, the complete
      distribution of pit organs was mapped in the demersal sharks Heterodontus
      portusjacksoni, Orectolobus maculatus, Hemiscyllium ocellatum, Chiloscyllium
      punctatum, and Asymbolus analis, and the rays Rhinobatos typus, Aptychotrema
      rostrata, Trygonorrhina sp. A, Raja sp. A, and Myliobatis australis. All of these
      species had pit organs scattered over the dorsolateral surface. The sharks also
      had "mandibular" pit organs (and "umbilical" pit organs in C. punctatum and A.
      analis) on the ventral surface, while pit organs were sparse or absent on the
      ventral surface of rays. All of the species examined here, except for M.
      australis, also had a "spiracular" group of pit organs adjacent to the eye and/or
      spiracle. Spiracular pit organs were also recorded for the sawshark Pristiophorus
      sp. A and the skate Pavoraja nitida, although the remainder of pit organs were
      not mapped in these species. The distribution and number of pit organs varied
      both within and among species. Pit organ distribution was asymmetrical in each
      individual examined, but no particular trend towards left or right "handedness"
      was observed in any species. Although rays have been thought to have fewer pit
      organs than sharks in general, this was not the case in the present study. All of
      the species examined here had few pit organs compared to the pelagic sharks
      previously documented, but it is not clear whether this is due to ecological or
      phylogenetic causes.

PMID- 12616577
TI  - Osteoporosis in anorexia nervosa: prevention and treatment.
AB  - BACKGROUND: Osteoporosis is a very prevalent complication of anorexia nervosa. In
      contrast to the many other medical complications of anorexia, osteoporosis and
      its sequelae of fractures, kyphosis, and pain may persist regardless of the
      overall treatment outcome. DISCUSSION: Traditional well-proven therapies for
      postmenopausal osteoporosis are not as effective against osteoporosis in anorexia
      nervosa. Therefore, clinicians who treat these patients must become increasingly
      vigilant about osteoporosis in regards to preventive, diagnostic, and treatment
      strategies.

PMID- 12616578
TI  - Role of exposure with response prevention in cognitive-behavioral therapy for
      bulimia nervosa: three-year follow-up results.
AB  - BACKGROUND: Previous studies have not reported the longer-term outcome of
      exposure-based treatments for bulimia nervosa. The current study evaluated the 3
      year outcome of a randomized clinical trial that compared the additive efficacy
      of exposure-based versus nonexposure-based behavioral treatments (BT) with a core
      of cognitive-behavior therapy (CBT). METHODS: One hundred thirteen women
      participated in the original treatment trial and attended a 3-year follow-up
      assessment. Eating disorder diagnoses and primary, secondary, and tertiary
      outcome measures were assessed. The impact of treatment completion on
      symptomatology and the stability of treatment effects over time were evaluated.
      RESULTS: At the 3-year follow-up, 85% of the sample had no current diagnosis of
      bulimia nervosa and 69% had no current eating disorder diagnoses of any sort.
      Failure to complete CBT was associated with inferior outcome. No clear advantages
      were evident for participants who completed BT in addition to CBT. For subjects
      who did complete both CBT and BT, outcome was mostly stable from posttreatment to
      follow-up. No differential effects were found for exposure versus nonexposure
      based treatments at 3-year follow-up. DISCUSSION: The results of the current
      study compare favorably with other treatment outcome studies for bulimia nervosa
      and suggest that treatment gains are maintained after 3 years.

PMID- 12616579
TI  - Brain dopamine is associated with eating behaviors in humans.
AB  - OBJECTIVE: Eating behavior in humans is influenced by variables other than just
      hunger-satiety including cognitive restraint, emotional distress, and sensitivity
      to food stimuli. We investigate the role of dopamine (DA), a neurotransmitter
      involved with food motivation, in these variables. METHODS: We used the Dutch
      Eating Behavior Questionnaire (DEBQ) to measure Restraint, Emotionality, and
      Externality in 10 subjects. We correlated DEBQ scores with brain DA levels.
      Positron emission tomography and [(11)C]raclopride uptake were used to measure
      baseline D(2) receptors (neutral stimulation) and to assess changes in
      extracellular DA to food stimulation (display of food). RESULTS: Restraint was
      correlated with DA changes with food stimulation (higher restraint, greater
      responsivity), emotionality was negatively correlated with baseline D(2)
      receptors (higher emotionality, lower D(2) receptors), whereas externality was
      not. These correlations were significant in the dorsal but not in the ventral
      striatum. DISCUSSION: These results provide evidence that DA in the dorsal
      striatum is involved with the restraint and emotionality components regulating
      eating behavior and that these two dimensions reflect different neurobiologic
      processes.

PMID- 12616580
TI  - Causes and recovery in anorexia nervosa: the patient's perspective.
AB  - OBJECTIVE: We explored anorexic patients' subjective accounts of the causes of
      their anorexia and of the factors that fostered recovery. Subjective accounts
      could assist in understanding this complicated and often intractable disorder.
      METHOD: All female new referrals to an eating disorders service underwent
      extensive interviews including open-ended questions about their beliefs
      concerning the causes of their anorexia nervosa and factors that led to recovery.
      Responses were categorized by two independent raters. RESULTS: The most commonly
      mentioned perceived causes were dysfunctional families, weight loss and dieting,
      and stressful experiences and perceived pressure. The three most commonly cited
      factors contributing to recovery were supportive nonfamilial relationships,
      therapy, and maturation. DISCUSSION: Individuals with anorexia nervosa perceive
      both external (family environment) and personal factors (dieting and stress) as
      contributory to their disorders. The results underscore the importance of
      interpersonal factors in recovery from anorexia nervosa and suggest that
      attention to this area in treatment may be beneficial.

PMID- 12616581
TI  - Do eating disorders co-occur with personality disorders? Comparison groups
      matter.
AB  - OBJECTIVE: To assess and compare lifetime rates of occurrence of eating disorders
      (ED) with four Axis II personality disorders (PD) and with major depressive
      disorder (MDD) without PD. The eating disorders met criteria outlined in the 4th
      edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
      METHOD: Six hundred sixty-eight patients recruited for the Collaborative
      Longitudinal Personality Disorders Study (CLPS) were reliably assessed with the
      Structured Clinical Interview for DSM-IV Axis I Disorders and the Diagnostic
      Interview for DSM-IV Personality Disorders. The distribution of ED diagnoses was
      compared among four PD study groups (schizotypal, borderline, avoidant, obsessive
      compulsive) and a fifth study group with MDD without any PD. RESULTS: The
      distribution of lifetime diagnoses of anorexia nervosa (N = 40), bulimia nervosa
      (N = 56), and eating disorder not otherwise specified (N = 118) did not differ
      significantly across the five study groups, between the MDD group versus all PD
      groups, and among the four PD study groups. CONCLUSIONS: ED diagnoses did not
      differentially co-occur significantly across common Axis I and II disorders. The
      pattern of ED lifetime co-occurrence rates demonstrates the powerful influence of
      base rates and highlights that declarations of comorbidity demand significant
      variations from base-rate patterns.

PMID- 12616582
TI  - Conformity and dietary disinhibition: a test of the ego-strength model of self
      regulation.
AB  - OBJECTIVE: Ego-strength depletion was examined as an explanation for dietary
      disinhibition in restrained eaters. We predicted that the depletion of ego
      strength resulting from having to choose whether to conform would undermine
      dietary restraint. METHOD: Participants completed an Asch-type conformity task,
      after which they completed a taste-rating task in which food intake was measured.
      RESULTS: As predicted, restrained eaters who repeatedly exercised choice ate
      significantly more than did restrained eaters who did not exercise choice.
      DISCUSSION: An ego-strength model of dietary restraint is discussed.

PMID- 12616583
TI  - Six-month open trial of haloperidol as an adjunctive treatment for anorexia
      nervosa: a preliminary report.
AB  - OBJECTIVE: To evaluate the effectiveness of haloperidoll as an adjunctive
      treatment for resistant anorexia nervosa restricting subtype (AN-R). METHOD:
      Thirteen outpatients with treatment-resistant AN-R were treated for 6 months with
      haloperidol in addition to standard treatment. Treatment resistance was defined
      as persistent and resistant anorectic symptoms despite multiple standard
      therapies. Assessments were carried out at baseline and after 1, 3, and 6 months
      with the Eating Disorder Inventory (EAT), the Eating Attitude Test (EAT), and the
      Clinical Global Impression and Improvement Scale (CGI-I). RESULTS: Significant
      change from baseline to end point was observed on EDI total score (p =.02) and on
      the subscales Drive for Thinness (p =.009), Bulimia (p =.01), and Interoceptive
      Awareness (p =.02), as well as on the EAT (p =.009) and CGI scores (p =.001).
      Body mass index changed significantly from baseline (15.7 +/- 1.9) to end point
      (18.1 +/- 2.5; p =.03). DISCUSSION: These preliminary data suggest that low doses
      of haloperidol might be effective as an adjunctive treatment for patients with
      severe AN-R. Larger controlled studies are warranted to confirm these data.

PMID- 12616584
TI  - Eating behaviors and attitudes in women with infertility: a controlled study.
AB  - OBJECTIVE: Infertility arises from a complex pathogenic process in which it is
      often difficult to identify etiology. Psychological and behavioral factors may
      play a role in some cases of infertility. The extent to which eating behaviors
      and attitudes contribute to infertility is unknown. METHOD: In this study, 120
      subjects with infertility, 80 fertile women, and 90 patients suffering from
      anorexia nervosa, restricting subtype (AN-R), were assessed with the Eating
      Disorder Inventory (EDI-2). RESULTS: The EDI-2 highlights differences among
      patients with AN-R and fertile and infertile subjects. Infertile patients had
      higher scores on the Interpersonal Distrust, Interoceptive Awareness, and
      Maturity Fears EDI-2 subscales than fertile subjects. Logistic regression
      identifies the independent variables of interpersonal distrust, interoceptive
      awareness, maturity fears, and asceticism as predictors of infertility.
      DISCUSSION: Infertile patients without eating disorders share some psychological
      features of women with AN. These features do not include disturbed eating
      attitudes and behaviors, but rather feelings of inadequacy, insecurity, and
      maturity fears.

PMID- 12616585
TI  - Preoccupation, food, and failure: an investigation of cognitive performance
      deficits in dieters.
AB  - OBJECTIVE: This study tested two explanations of the cognitive performance
      deficits of dieters. First, these deficits are due to the metabolic consequences
      of food deprivation. Second, they are psychological in origin (i.e.,
      preoccupation with dieting-related thoughts during dieting depletes the cognitive
      resources available for nondieting tasks). METHOD: Dieters and nondieters
      performed a battery of cognitive tasks before and after consumption of a high
      energy chocolate bar. Eating the chocolate bar was expected to reverse the
      effects of food deprivation but, as a "diet-threatening" food, it could increase
      dieting-related preoccupation. RESULTS AND CONCLUSIONS: The results supported the
      latter prediction. Performance on a memory task was further impaired, rather than
      improved, after food consumption in dieters. In addition, dieters experienced a
      significant increase in the number of food and dieting-related thoughts. Some
      dieters attributed their poorer performance to distraction by these thoughts.
      Marked individual differences in thought content accounted for some of the
      variability in the effects on performance.

PMID- 12616586
TI  - Internalization of ideal body shapes in 9-12-year-old girls.
AB  - OBJECTIVE: Body dissatisfaction is reported in girls as young as 9 years old in
      Western countries. In the current study, internalization of the "thin ideal" was
      predicted to be a critical influence on the development of body dissatisfaction.
      METHOD: Participants (n = 356) were weighed and completed measures of body
      dissatisfaction, awareness and internalization of the thin ideal, and peer and
      maternal attitudes and behavior. Exposure to relevant print media was also
      assessed. RESULTS: Body dissatisfaction was associated with a higher body mass
      index, although it was not restricted to overweight girls. Internalization
      mediated the relationship between awareness of the sociocultural standard of
      appearance and body dissatisfaction. Media exposure and peer and maternal weight
      related attitudes and behavior were, in turn, related to awareness, supporting
      the hypothesized sociocultural processes. DISCUSSION: Internalization operates as
      a central component in the development of body dissatisfaction, occurring at a
      young age in some girls. Internalization may be a suitable target for preventive
      strategies.

PMID- 12616587
TI  - Ethnicity and differential access to care for eating disorder symptoms.
AB  - OBJECTIVE: The impact of ethnicity on access to health care for eating disorder
      symptoms among participants in the 1996 National Eating Disorders Screening
      Program (NEDSP) was examined in two studies. METHOD: Self-report and clinician
      assessed data were analyzed from 9,069 participants in an educational and two
      stage screening program for eating disorders in Study I. In Study II, both cross
      sectional and prospective data from a randomly selected sample of 289
      participants from the same program were analyzed to investigate the impact of
      ethnic minority status on both help-seeking patterns and clinician referral
      patterns for eating disorder symptoms. RESULTS: Even after controlling for
      severity of self-reported eating disorder symptoms, both Latino and Native
      American participants in the NEDSP were significantly less likely than Whites to
      receive a recommendation or referral for further evaluation or care. Ethnic
      minority subjects with self-acknowledged eating and weight concerns were also
      significantly less likely than non-minority participants to have been asked by a
      doctor about eating disorder symptoms. Only one marginally significant difference
      was found between ethnic minority and non-minority respondents with respect to
      their help-seeking behaviors, namely, ethnic minority subjects were less likely
      (at the level of a trend) to seek eating disorders treatment within 1(1/2)-2
      years following the NEDSP. DISCUSSION: These data suggest that clinician bias may
      be an important barrier to access to care for eating disorder symptoms in ethnic
      minority populations.

PMID- 12616588
TI  - Comparison of assessments of children's eating-disordered behaviors by interview
      and questionnaire.
AB  - OBJECTIVE: In adults, interview methods may detect eating-disordered behaviors
      more accurately than self-report methods. However, no studies have investigated
      the relationships between interview and self-report assessments in children. We
      compared results from the Eating Disorder Examination adapted for Children
      (ChEDE) with the Adolescent version of the Questionnaire on Eating and Weight
      Patterns (QEWP-A) and with the Children's Eating Attitude Test (ChEAT) in a
      nontreatment sample of overweight and normal weight children. METHOD: The ChEDE,
      QEWP-A, and ChEAT were administered to 46 overweight (body mass index [BMI] at or
      above the 85th percentile) and 42 normal weight (BMI at the 15th-85th percentile)
      children, 10 +/- 1.8 years, recruited from the community. RESULTS: The ChEDE and
      QEWP-A were not concordant for the number or type of eating episodes that
      occurred in the past month. Compared with the ChEDE, the QEWP-A was reasonably
      specific, but it was not sensitive for the presence of objective (17 %
      sensitivity, 91% specificity) or subjective bulimic episodes (0 % sensitivity, 89
      % specificity) during the past month. ChEDE and ChEAT global scores were
      significantly related (Kendall's tau = 0.286, p <.001), but specific items
      assessing guilt in relation to eating and preoccupation with food were not.
      DISCUSSION: Although self-report methods of eating disorder assessment in
      children may provide some general information regarding eating psychopathology in
      non-treatment-seeking children, they do not accurately reflect the results of a
      structured interview.

PMID- 12616589
TI  - Perfectionism in anorexia nervosa: a 6-24-month follow-up study.
AB  - OBJECTIVE: This study examined the relationship between perfectionism and outcome
      in anorexia nervosa (AN). METHOD: Seventy-three patients received inpatient
      treatment for AN. Participants completed the Eating Disorder Inventory (EDI) at
      admission to (n = 55), at discharge (n = 27), and at a median of 15.9 months (n =
      49) after inpatient treatment. At follow-up, participants also completed the
      Multidimensional Perfectionism Scale (MPS) and their scores were compared with
      those of healthy controls. RESULTS: EDI Perfectionism was associated with illness
      status. A lower EDI Perfectionism score at admission was associated with a better
      response to treatment, which was subsequently associated with better outcome at
      follow-up. Both the good and poor outcome groups had significantly higher MPS
      total perfectionism scores than healthy controls. DISCUSSION: The EDI measures an
      aspect of perfectionism that is sensitive to illness status, whereas the MPS is
      less dependent on clinical state and may reflect a common personality trait that
      persists with remission of disease.

PMID- 12616590
TI  - Respiratory muscle weakness and anorexia nervosa.
AB  - BACKGROUND: Nutritional recovery in anorexia nervosa (AN) is associated with
      improved exercise tolerance. METHOD: We describe the investigation of a male with
      AN. Despite nutritional recovery, he complained of impaired exercise tolerance.
      RESULTS: Respiratory muscle weakness was demonstrated as the cause of the
      impaired exercise tolerance. DISCUSSION: Weakness of the muscles of respiration
      results from prolonged malnutrition. The diaphragmatic muscle may be slower to
      recover than other muscles. This can cause impaired exercise tolerance due to
      shortness of breath on exertion, despite nutritional recovery.

PMID- 12616591
TI  - Olanzapine treatment of anorexia nervosa: a retrospective study.
AB  - BACKGROUND: Recent reports raise the possibility that olanzapine, which commonly
      causes weight gain in non-eating-disordered subjects, assisted weight gain and
      mood during refeeding in anorexia nervosa (AN) patients. METHODS: Eighteen AN
      subjects who engaged in open treatment with olanzapine were retrospectively
      questioned about their response. RESULTS: Subjects reported a significant
      reduction in anxiety, difficulty eating, and core eating disorder symptoms after
      taking olanzapine. DISCUSSION: These data lend support to the possibility that
      olanzapine may be useful in AN patients. CONCLUSION: A controlled trial is
      necessary to prove that olanzapine is efficacious.

PMID- 12616592
TI  - Differential toxic effect of cis-platinum(II) and palladium(II) chlorides
      complexed with methyl 3,4-diamine-2,3,4,6-tetradeoxy-alpha-L-lyxo-hexopyranoside
      in mouse lymphoma cell lines differing in DSB and NER repair ability.
AB  - The aim of this work was to test the cytotoxicity of newly synthesized cis-type
      complexes of platinum(II) and palladium(II) dichloride with methyl 3,4-diamine
      2,3,4,6-tetradeoxy-alpha-L-lyxohexopyranoside, [M(C(7)H(16)N(2)O(2))Cl(2)].H(2)O,
      against two mouse lymphoma cell lines (L5178Y) differing in their double strand
      breaks and nucleotide excision repair ability. cis- Diaminedichloroplatinum
      (CDDP) was used as a reference compound. The toxicity of
      Pt(C(7)H(16)N(2)O(2))Cl(2) appeared to be similar for both cell lines: IC(50) is
      8 microM for L5178Y-R cells and 12 microM for L5178Y-S cells, respectively. In
      contrast, the palladium complex was found to be more toxic for the LY-R cells
      than for the LY-S cells. The cytotoxicity of both compounds was compared with
      their ability to induce DNA crosslinks, as measured by the modified comet assay.
      CDDP caused retardation of the DNA migration induced by 2 Gy of the X-irradiation
      in a dose-dependent manner. The ability of Pd(C(7)H(16)N(2)O(2))Cl(2) to retard X
      ray induced DNA migration was more pronounced than its platinum analogue and CDDP
      (see Fig. 6). However, this was not reflected in the toxicity of the compound.
      Such results indicate that these two compounds may cause a different type of DNA
      damage and/or that the DNA damage caused by the palladium(II) compound was dealt
      with in a different manner from that induced by the platinum(II) complex.

PMID- 12616593
TI  - Differential role of hydrogen peroxide and organic hydroperoxides in augmenting
      ferric nitrilotriacetate (Fe-NTA)-mediated DNA damage: implications for
      carcinogenesis.
AB  - An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent nephrotoxic
      agent, and induces acute and subacute renal proximal tubular necrosis, a
      consequence of the Fenton-like reaction that eventually leads to a high incidence
      of renal adenocarcinoma in rodents. In order to examine the possible mechanism
      for carcinogenic activity, we investigated the DNA damage with Fe-NTA in the
      presence of various peroxides/organic hydroperoxides. S1 nuclease hydrolysis and
      deoxyribose degradation assays were performed. Incubation of calf thymus DNA with
      ferric nitrilotriacetate (0.1 mM) in the presence of peroxides/organic
      hydroperoxides at a final concentration of 40 mM of each in phosphate buffer (0.1
      M, pH 7.4) augmented DNA damage severalfold as compared to the damage caused by
      individual treatments. Fe-NTA in the presence of hydrogen peroxide caused DNA
      single-strand breaks and damage to its deoxyribose sugar moiety as measured,
      respectively, by S1 nuclease hydrolysis and deoxyribose degradation using calf
      thymus DNA. However, only deoxyribose degradation could be recorded in the
      presence of other peroxide/organic hydroperoxides. No DNA single-strand break was
      observed by this treatment. The observed differences in DNA damage by hydrogen
      peroxide and organic hydroperoxides/peroxide have been ascribed to the
      differential reactivity of DNA with hydroxyl and alkoxy/aryloxy free radicals
      produced, respectively, from these inorganic and organic peroxides. These studies
      suggest that Fe-NTA not only mediated the production of reactive oxygen species,
      but also catalysed the decomposition of these peroxides and organic
      hydroperoxides, which may cause a clastogenic change in DNA. This reactivity
      enhances the clastogenic activity in DNA. These changes in the DNA structure may
      ultimately be responsible, at least in part, for the induction of carcinogenesis
      in Fe-NTA-exposed animals.

PMID- 12616594
TI  - Inhibitory effect of Eucommia ulmoides Oliv. on oxidative DNA damage in
      lymphocytes induced by H2O2.
AB  - This study used the alkaline single cell gel electrophoresis assay (comet assay)
      to investigate the effect of water extracts of roasted cortex and leaves from Du
      zhong on DNA damage in lymphocytes induced by H(2)O(2). The results showed that
      the DNA damage in human lymphocytes increased with an increase in the
      concentration of H(2)O(2) (0-200 micro;M), but that the water extracts from Du
      zhong (0-2 g l(-1)) only slightly affected DNA damage. The inhibitory effect of
      leaf extract on DNA damage induced by H(2)O(2) in lymphocytes was more
      significant (P<0.05) than that of roasted cortex. Leaf extract showed a rather
      significant inhibitory effect in a concentration-dependent manner. At a
      concentration of 2 g l(-1), the leaf extract inhibited 37.9% DNA oxidative damage
      in human lymphocytes. In order to elucidate the mechanism of the leaf extract
      suppression effect on DNA damage induced by H(2)O(2) in lymphocytes, an
      experiment was divided with six groups (A-F). Group A was used to evaluate the
      repair ability of the leaf extract for DNA damage; Group B was employed to
      determine the scavenging ability on H(2)O(2); and Group C was studied to assess
      the ability of leaf extract to increase the defense capability. Groups D-F were
      negative controls and blank. The results showed that group B had the best
      inhibitory effect. Also, leaf extract had significant ability to scavenge
      H(2)O(2) in an in vitro HRP-phenol red test. Thus, it appears that H(2)O(2)
      scavenging potency may be the major mechanism whereby leaf extract inhibits
      oxidative DNA damage induced by H(2)O(2).

PMID- 12616595
TI  - Expression of aphidicolin-induced fragile sites and their relationship between
      genetic susceptibility in breast cancer, ovarian cancer, and non-small-cell lung
      cancer patients.
AB  - Fragile sites are nonrandomly located gaps and/or breaks and their expres-sion
      can be induced by specific culture conditions. There are many reports in the
      literature that indicate that these sites can act as factors that predispose to
      specific chromosome aberrations and other complex rearrangement in the chromosome
      and their association with cancers. In the present study, the expression of the
      fragile sites induced by aphidicolin was evaluated on prometaphase chromosomes
      from peripheral blood lymphocytes of 55 patients with breast cancer patients
      belonging to different stages of the cancer, 25 patients with epithelial ovarian
      cancer, and 13 with non-small-cell lung cancer, 100 of their first-degree
      clinically healthy female relatives, and 100 normal age-matched healthy persons
      without a familial history of cancer. The frequency of expression of the fragile
      sites in cancer patients and their first-degree relatives was found to be
      statistically significant (P<0.05) than those of the controls. In different
      stages of breast cancer patients, 6q26 is the best-defined fragile site whereas
      13q13 is confined to stage II and stage III patients only. The chromosomal
      aberration rate/cell in breast cancer patients was found to be 0.29+/-0.13, in
      epithelial ovarian cancer patients 0.38+/-0.14, and in non-small-cell lung cancer
      0.29+/-0.11 as compared to 0.07+/-0.03 in controls, and was found to be
      statistically significant. Therefore, our results indicate that these fragile
      sites may be the unstable sites in the genome and, hence, can be used as suitable
      and reliable markers for genetic predisposition to breast cancer, epithelial
      ovarian cancer, and in non-small-cell lung cancer.

PMID- 12616596
TI  - Mutant spectra analysis at hisG46 in Salmonella typhimurium strain YG1029 induced
      by mammalian S9- and plant-activated aromatic amines.
AB  - Mutant spectra analysis was conducted with spontaneous hisG46 revertants of
      Salmonella typhimurium strain YG1029 and revertants induced by the plant- and
      mammalian S9-activation of benzidine and 4-aminobiphenyl (4-ABP). Under
      preincubation conditions, YG1029 cells were exposed to benizidine or 4-ABP with
      mammalian S9 activation or to a high molecular weight fraction that contained the
      plant-activated products. The induced revertants were isolated at mutagen
      concentrations that caused an increased mutant frequency of approximately 4- to
      10-fold above background. Genomic DNA from each revertant was isolated and the
      hisG region was amplified using polymerase chain reaction (PCR). Using a series
      of specific probes and a modified version of the ECL3's-oligolabelling and
      detection system, each of the six possible base-pair substitution mutations at
      hisG46 that leads to a reversion event was determined. Of the YG1029 spontaneous
      revertants, transition mutations were 31.8% and transversion mutations were
      68.2%. The YG1029 spontaneous mutant spectrum differed significantly from the
      spontaneous spectrum of TA1535 but did not significantly differ from the
      spontaneous TA100 mutant spectrum. The differences of the spontaneous mutant
      spectra among these highly related strains illustrate that the introduction of
      the plasmid pKM101 into S. typhimurium increased the frequency of transversions
      (CCC-->ACC; CCC-->CAC) and reduced site 2 (CCC-->CTC) transitions. With plant
      activated benzidine, 21.1% of recovered revertants resulted from transitions and
      78.9% from transversions while S9 activated-benzidine induced revertants were
      recovered as 14.2% from transition and 85.8% from transversion mutations. Plant
      activated 4-ABP recovered 20.0% transitions and 80.0% transversions. S9-activated
      4-ABP-induced 21.4% transitions and 78.6% transversions. Chi-square analysis of
      mutant spectra indicated that the DNA lesions that resulted in reversion at the
      hisG46 allele induced by plant-activated benzidine or 4-ABP were different from
      those generated after mammalian S9 activation of these promutagens. The plant
      activated benzidine and 4-ABP induced statistically identical mutant spectra.
      Also, the mammalian-activated benzidine and 4-ABP induced statistically similar
      mutant spectra. These data show that the plant-activated and mammalian-activated
      aromatic amine products inflicted different types or distributions of DNA lesions
      that were reflected in the resulting induced mutant spectra.

PMID- 12616597
TI  - Rat breast microsomal biotransformation of ethanol to acetaldehyde but not to
      free radicals: its potential role in the association between alcohol drinking and
      breast tumor promotion.
AB  - We recently showed that mammary cytosolic xanthineoxidoreductase had the ability
      to bioactivate ethanol (EtOH) to acetaldehyde (AC) and free radicals. In the
      present study, we report that the microsomal fraction also biotransforms EtOH to
      AC. One pathway requires NADPH and the others do not. Both need oxygen. The NADPH
      dependent pathway is not inhibited by CO:O(2) (80:20) or SKF 525A and that
      excludes the participation of cytochrome P450. It is inhibited by
      diethyldithiocarbamate (DDTC), sodium azide, and diphenyleneiodonium (DPI) but
      not by desferrioxamine, which suggests a possible role of a non-iron copper
      requiring flavoenzyme. The process was partially inhibited by thiobenzamide
      (TBA), methylmercaptoimidazole (MMI), and nordihydroguaiaretic acid (NDG) but not
      by dapsone, aminotriazole, or indomethacin. These results suggest the potential
      participation of flavine monooxygenase and of lipooxygenase or of
      peroxidases/oxidases having similar characteristics but not of lactoperoxidase or
      cyclooxygenase. The pathway not requiring NADPH could also be partially inhibited
      by DDTC, NDG, azide, DPI, and TBA or MMI but not by the other chemicals. Little
      activity proceeds under nitrogen. Oxidases or peroxidases might be involved. No
      formation of 1-hydroxyethyl radicals was detected either in the presence or
      absence of NADPH. The nature of the EtOH bioactivating enzymes involved remains
      to be established. However, the fact remains that an activation of EtOH to AC was
      found in mammary tissue and could have a significant effect in some stages of the
      process of breast tumor promotion by EtOH.

PMID- 12616598
TI  - Natural dietary agents can protect against DMBA genotoxicity in lymphocytes as
      revealed by single cell gel electrophoresis assay.
AB  - Many natural agents including fruits and vegetables are known to provide
      protection from different degenerative diseases including cancer, by preventing
      damage to the cellular components. The effect of two important dietary agents,
      alpha tocopherol, and the flavonoid quercetin, along with two commonly consumed
      vegetables, bitter gourd and tomato, were investigated on spontaneous and
      dimethylbenz(a)anthracene (DMBA)-induced DNA damage in murine lymphocytes in
      vitro. DNA damage was determined by single cell gel electrophoresis (comet
      assay). The rationale for such an approach for this study is that DNA damage can
      lead to genetic disorders that occur at different stages of carcinogenesis and
      protection from such damages may in the long run help to prevent development of
      cancer. Both alpha tocopherol and quercetin as single agents were found to be
      potent inhibitors of DNA damage (spontaneous and carcinogen induced) in a dose
      dependent manner. Fresh juices of bitter gourd and tomato could also protect from
      DMBA-induced DNA damage but not as effectively as the single agents. The
      anticarcinogenic role of nutrients as well as non-nutrient dietary components
      need to be explored more extensively. The Comet assay is a simple, fast, and
      reliable method to determine the protective effect against DNA damage, one of the
      prerequisites for carcinogenesis.

PMID- 12616599
TI  - Induction of DNA damage in human lymphocytes treated with a soluble factor
      secreted by Taenia solium metacestodes.
AB  - We have previously reported that a factor secreted by the metacestode of Taenia
      solium (MF) is able to transform Syrian hamster embryo cells. The aim of this
      study was to analyze the genotoxicity of MF in cultured human lymphocytes using
      the micronucleus assay. Results show a significantly high frequency of
      micronucleated cells in lymphocyte cultures treated with MF. Although further
      experiments are needed to determine whether this factor is also secreted by T.
      solium metacestodes in humans, analysis of the frequency of micronucleus induced
      in cultured human lymphocytes indicates that DNA instability induced by MF could
      represent a risk for malignant transformation.

PMID- 12616600
TI  - Antiperoxidative, anti-inflammatory, and antimutagenic activities of ethanol
      extract of the mycelium of Ganoderma lucidum occurring in South India.
AB  - Free radical mediated genetic instability is widely thought to be a major
      etiological factor for initiation of carcinogenesis. Mushrooms represent a
      largely untapped source of powerful new pharmaceutical products. In the present
      study, we examined the antiperoxidative, anti-inflammatory, and antimutagenic
      activities of the ethanol extract of the mycelium of a medicinal mushroom,
      Ganoderma lucidum, occurring in south India. Antiperoxidative activity was
      evaluated using Fe(2+)-ascorbate-induced lipid peroxidation in rat liver
      homogenate and a phorbol ester (croton oil)-induced lipid peroxidation in mouse
      skin. Antiinflammatory activity was evaluated against carrageenan-induced acute
      and formalin-induced chronic inflammatory paw edema in mouse and phorbol ester
      induced mouse skin inflammation. Antimutagenic activity was determined by the
      Ames mutagenicity assay using histidine mutant of Salmonella typhimurium strains
      TA 98, TA100, and TA102. Sodium azide (NaN(3)), N-methyl-N-nitro-N
      nitrosoguanidine (MNNG), 4-nitro-o-phenylenediamine (NPD), and benzo[a]pyrene
      (B[a]P) were used as the mutagens. The extract showed significant inhibition of
      Fe(2+)-induced peroxidation of lipid in rat liver (IC(50) 510 +/- 22 microg/ml)
      and 37% inhibition of croton oil-induced peroxidation on the mouse skin at 20
      mg/0.1 ml/skin. Carrageenan-induced acute and formalin-induced chronic
      inflammatory edema were inhibited by 56 and 60%, respectively, by the extract at
      1,000 mg/kg body wt (i.p). The extract at a concentration of 5 mg/plate showed
      inhibition of mutagenicity elicited by direct acting mutagens, NaN(3) (55.5 and
      75.7%) and MNNG (50.0 and 57.5%) for S. typhymurium strains TA100 and TA102,
      respectively. The extract at the same concentration also inhibited mutagenicity
      elicited by NPD (52.4 and 64.2%) and B[a]P (60.7 and 59.6%) for TA98 and TA100
      strains, respectively. The B[a]P was activated in the presence of rat liver
      microsomal (S9) fraction. The results of our study revealed that ethanol extract
      of Ganoderma lucidum mycelium possessed significant antiperoxidative,
      antiinflammatory, and antimutagenic activities. The findings suggest a medicinal
      use for the ethanol extract of the mycelium of G. lucidum occurring in South
      India.

PMID- 12616601
TI  - Ascorbic acid potentiates mitomycin C-induced micronuclei and sister chromatid
      exchanges in human peripheral blood lymphocytes in vitro.
AB  - Vitamin C (l-ascorbic acid), an effective free radical scavenger present as
      ascorbate in most biological systems, is one of the most extensively studied
      antioxidant vitamins. Vitamin C acts as either a free radical scavenger or a pro
      oxidant producing hydrogen peroxide and free radicals. The modulatory effect of L
      ascorbic acid (AA) on Mitomycin C (MMC) induced chromosome damage has been
      evaluated in human peripheral blood lymphocytes in vitro. The effect of L
      ascorbic acid, 200 microg/ml as 1- and 2-h pretreatment on the frequencies of the
      biomarkers micronuclei (MN), sister chromatid exchanges (SCEs), and chromosome
      aberrations (CA) induced by mitomycin C 0.1 and 0.2 microg/ml has been studied.
      AA pretreatment caused a statistically significant increase in MMC-induced MN and
      SCE frequencies for all treatment groups, but did not show an increase in induced
      chromosome aberrations compared to MMC treatment alone. Cell division delays
      caused by MMC was reversed in the presence of AA. Interindividual variability in
      MMC as well as AA plus MMC-induced MN, SCE, and CA frequencies were evident.
      Ascorbic acid potentiated MMC-induced chromosome damage in human lymphocytes in
      vitro. The potentiation observed has to be viewed in the light of metal ion
      catalysed autooxidation of AA in oxygenated media and the existence of an
      antioxidant system in vivo that inactivates oxyradicals before their interaction
      with DNA.

PMID- 12616602
TI  - Repair of 8 oxoguanine in mammalian cells expressing the Drosophila S3
      ribosomal/repair protein.
AB  - 8-oxo-7,8-dihydroguanine (8-oxoG) is a potent mutagenic lesion that forms at
      elevated levels in cellular DNA and is repaired with low efficiency in human
      cells. Unlike its human counterpart, the Drosophila S3 ribosomal/repair protein
      is endowed with a vigorous 8 oxoG repair activity that is associated to
      beta,delta-elimination AP lyase activity. We have recently observed that pure GST
      tagged Drosophila S3 protein can significantly accelerate the in vitro repair of
      8 oxoG performed by human and mouse cell extracts [Cappelli et al., unpublished
      data]. In this work, we have transfected Chinese hamster cells with mammalian
      expression vectors containing the Drosophila S3 cDNA. The cells synthesized both
      S3 mRNA and protein but no improved repair of 8 oxoguanine was observed. Factors
      important for the proper expression of Drosophila genes in mammalian cells are
      discussed.

PMID- 12616603
TI  - Developmental toxicity evaluation of the new fluoroquinolone antibacterial DW-116
      in rats.
AB  - We have recently reported that the fluoroquinolone antibacterial DW-116 induces a
      significant developmental toxicity in rat. The present study was conducted to
      better understand the teratogenic effects of DW-116 at several developmental
      toxic doses in rats. DW-116 was orally administered to pregnant rats from
      gestational day (GD) 6 through 16 at dose levels of 0, 320, 400, and 500
      mg/kg/day. All dams were subjected to caesarean section on GD 20 and their
      fetuses were examined for external, visceral, and skeletal abnormalities. At
      above 400 mg/kg, severe decreases in maternal body weight gain, food consumption,
      litter size, fetal weight and placental weight, and severe increases in
      resorption rate and fetal morphological alterations were observed. At 320 mg/kg,
      mild decreases in maternal body weight gain, food consumption, fetal weight and
      placental weight, and mild increases in fetal variations and retardations were
      observed. These results suggest that DW-116 is embryotoxic at above 320 mg/kg/day
      and is embryolethal and teratogenic at above 400 mg/kg in pregnant rats and that
      DW-116 is a selective developmental toxicant in rat conceptuses.

PMID- 12616604
TI  - Genetic toxicology of remifentanil, an opiate analgesic.
AB  - Compounds that interact with opioid receptors are commonly used as analgesics.
      Opioid agonists vary in their potency and pharmacokinetic properties as well as
      in their affinity for distinct opioid receptors. The fentanyl opiate analogues
      are an important group of analgesics that interact with the mu opioid receptor.
      Remifentanil (GI87084) is a particularly interesting member of this group of
      opioids because its action is especially short in duration. This report examines
      the genetic toxicology of remifentanil. Remifentanil was not genotoxic in an Ames
      test, an in vitro chromosome aberration assay in Chinese hamster ovary cells, an
      in vivo micronucleus assay in rat erythrocytes, or an in vivo/in vitro
      unscheduled DNA synthesis assay in rat hepatocytes. In the in vitro L5178Y tk(+/
      ) mouse lymphoma assay, remifentanil produced a genotoxic response at dose levels
      >or=308 microg/mL only in the presence of rat liver S9 metabolic activation;
      primarily tiny and small mutant colonies were produced. This pattern of activity
      in a battery of genetic toxicology assays is not unique to remifentanil, but has
      also been observed for other pharmaceuticals, including the opioid fentanyl. A
      weight-of-evidence analysis, taking into consideration genotoxic mechanisms, in
      vivo results, and the conditions of clinical use, suggests remifentanil does not
      pose a genotoxic risk to patients.

PMID- 12616605
TI  - In vitro curcumin modulates ferric nitrilotriacetate (Fe-NTA) and hydrogen
      peroxide (H2O2)-induced peroxidation of microsomal membrane lipids and DNA
      damage.
AB  - A number of investigations have implicated the involvement of free radicals in
      various pathogenic process including initiation/promotion stages of
      carcinogenesis and antioxidants have been considered to be a protective agent for
      this reason. An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent
      nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis
      by catalyzing the decomposition of hydrogen peroxide-derived production of
      hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage.
      The latter is associated with a high incidence of renal adenocarcinoma in
      rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe
      NTA-induced toxicity, which could be mitigated by antioxidants. In this study, we
      therefore investigated the effect of curcumin, a polyphenolic compound from
      Curcuma longa for a possible protection against lipid peroxidation and DNA damage
      induced by Fe-NTA and hydrogen peroxide in vitro. Incubation of renal microsomal
      membrane/and or calf thymus DNA with hydrogen peroxide (40 mM) in the presence of
      Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to
      about 2.2-and 5.6-fold, respectively, as compared to saline treated control
      (P<0.001). Induction of renal microsomal lipid peroxidation and DNA damage was
      modulated by curcumin dose dependently. In lipid peroxidation protection studies,
      curcumin treatment showed a dose-dependent strong inhibition (18-80% inhibition,
      P<0.05-0.001) of Fe-NTA and hydrogen peroxide-induced lipid peroxidation as
      measured by MDA formation in renal microsomes. Similarly, in DNA-sugar damage
      protection studies, curcumin treatment also showed a dose dependent inhibition
      (22-57% inhibition, P<0.05-0.001) of DNA-sugar damage. From these studies, it was
      concluded that curcumin modulates Fe-NTA and hydrogen peroxide-induced
      peroxidation of microsomal membrane lipids and DNA damage. Curcumin might,
      therefore, be a suitable candidate for the chemoprevention of Fe-NTA-associated
      cancer.

PMID- 12616606
TI  - Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by
      bleomycin and 1-nitropyrene in A/J mice.
AB  - Bleomycin is a radiomimetic antitumor agent with unique genotoxic properties. 1
      nitropyrene is an environmental mutagen and carcinogen that undergoes both
      oxidative and reductive metabolism. In the present study, hepatocellular
      carcinomas were induced in male A/J mice by the intraperitoneal injection of
      bleomycin (120 mg/kg) followed by the intraperitoneal administration of 1
      nitropyrene (total dose: 1,575 mg/kg). In order to understand the mechanism by
      which these two compounds induce hepatocellular carcinomas, the incidence and
      spectrum of mutations in the K-ras proto-oncogene in these hepatocellular
      carcinomas were analyzed. The hepatocellular carcinomas were induced by the
      administration of bleomycin and 1-nitropyrene were evaluated for point mutations
      in exon 1 and exon 2 of the K-ras gene by the polymerase chain reaction and a
      sequencing analysis. No mutation was found in the hotspots regions of the K-ras
      gene codon 12, 13, or 61. However, the codon 64 of the K-ras gene mutation was
      identified in 10 of 10 (100%) hepatocellular carcinomas. All mutations showed the
      same pattern, which was TAC-CAC transition. Codon 64 of the K-ras gene mutation
      may thus play an important role in the induction of hepatocellular carcinomas by
      bleomycin in the existence of 1-nitropyrene. As far as we know, this is the first
      report of a codon 64 mutation in the K-ras gene in a chemically induced tumor.

PMID- 12616607
TI  - Chromosomal aberrations induced by 5-azacytidine combined with VP-16 (etoposide)
      in CHO-K1 and XRS-5 cell lines.
AB  - A cytogenetic study was carried out with 5-azacytidine (5-azaC) and etoposide (VP
      16) in CHO-K1 and XRS-5 (mutant cells deficient for double-strand break
      rejoining) cell lines to verify the interaction effects of the drugs in terms of
      induction of chromosomal aberrations. 5-azaC is incorporated into DNA causing DNA
      hypomethylation, and VP-16 (inhibitor of topoisomerase II enzyme) is a potent
      clastogenic agent. Cells in exponential growth were treated with 5-azaC for 1 h,
      following incubation for 7 h, and posttreatment with VP16 for the last 3 h. In K1
      cells, the combined treatments induced a significant reduction in the aberrations
      induced in the X and "A" (autosome) chromosomes, which are the main target for 5
      azaC. However, in XRS-5 cells, the drug combination caused a significant increase
      in the aberrations induced in those chromosomes, but with a concomitant reduction
      in the randomly induced-aberrations. In addition, each cell line presented
      characteristic cell cycle kinetics; while the combined treatment induced an S
      arrest in K1 cells, alterations in cell cycle progression were not found for XRS
      5, although each drug alone caused a G2-arrest. The different cell responses
      presented by the cell lines may be explained on the basis of the evidence that
      alterations in chromatin structure caused by 5-aza-C probably occur to a
      different extent in K1 and XRS-5 cells, since the mutant cells present a typical
      hyper-condensed chromosome structure (especially the X- and "A" chromosomes),
      but, alternatively, 5-aza-C could induce reactivation of DNA repair genes in XRS
      5 cells.

PMID- 12616608
TI  - A quantitative structure-activity relationship (QSAR) study of mutagenicity in
      several series of organic chemicals likely to be activated by cytochrome P450
      enzymes.
AB  - The results of quantitative structure-activity relationship (QSAR) studies on six
      series of compounds exhibiting indirect mutagenic activity are reported. These
      findings demonstrate the importance of frontier orbital energies and, in some
      cases, frontier orbital electronic populations to overall mutagenicity in diverse
      polyaromatic hydrocarbons, benzidines and aminobiphenyls, benzonitrofurans,
      nitrogenous cooked-food mutagens, benzanthracenes, and chrysenes. The
      correlations between structural parameters and mutagenic potency vary from R=0.81
      to R=0.97, and these findings are discussed in the context of possible molecular
      mechanisms of mutagenicity. In particular, it is generally regarded that
      cytochrome P450-mediated activation of polyaromatic hydrocarbons and their amino
      derivatives plays an important role in mutagenic activity. In this respect, it is
      apparent that enzymes of the cytochrome P4501 (CYP1) family are closely
      associated with the metabolic activation of polyaromatic mutagens and carcinogens
      via the generation of reactive intermediates (usually electrophilic in nature)
      that attack DNA. The findings presented in this study indicate that QSAR analyses
      on several series of compounds are consistent with the known evidence of
      procarcinogen activation mechanisms, particularly for polyaromatic hydrocarbons
      and their heterocyclic/amino derivatives, pointing to the importance of frontier
      orbital energy values in particular.

PMID- 12616609
TI  - Inhibitory effect of local ischaemic preconditioning in total body irradiated
      rats.
AB  - The aim of this study was to explore the relationship between local ischaemic
      preconditioning and the effectiveness of fractionated radiotherapy. The rat
      serum, bone marrow, and small intestine were examined for oxidative changes
      induced by total body irradiation with gamma rays with applied local ischaemic
      preconditioning immediately before irradiation. Serum concentrations of TBA-RS
      examined 12 hours after the last irradiation did not reveal any differences among
      the groups of animals analyzed. Twenty-four hours after the last dose of
      irradiation, the serum concentrations of TBA-RS varied in particular groups
      (P<0.0001). The concentration of triglycerides in the serum of local
      preconditioned ischaemia and irradiated animals showed a reversed shape similar
      to the TBA-RS fluctuation (P<0.003). The level of uric acid in the serum of
      animals treated only with radiation is slightly higher than the level of this
      acid in the serum of the local preconditioned ischaemia radiation group (P<0.58).
      The number of bone marrow polychromatic erythrocytes did not appear to differ
      substantially in both irradiated groups. At the first 12 hours after irradiation,
      the frequency of micronucleated polychromatic erythrocytes is significantly
      different in the bone marrow of both groups either in combination with ischaemic
      preconditioned radiation or with radiation alone (P<0.0002). In irradiated
      animals without ischaemic preconditioning, on the 3rd day after irradiation the
      number of crypts increased and in the next days decreased achieving the level of
      the control group on the 7th day. Irradiated rats with local ischaemic
      preconditioning did not reveal an increase in the number of crypts. The
      difference was statistically significant (P<0.05). These data indicate that the
      local ischaemic preconditioning modifies the radiation peroxidising effects
      through inhibition of free radical-dependent lipid peroxidation and, probably,
      other unrecognized mechanisms.

PMID- 12616610
TI  - Factors secreted by peritoneal macrophages are cytotoxic for transformed rat
      pleural mesothelium and mesothelioma cells.
AB  - The report is devoted to the investigation of cytotoxic action of macrophages and
      asbestos on transformed mesothelium and mesothelioma cells, the characterization
      of its specificity, and the nature of the factors mediating it. The viability of
      different cells after asbestos exposure was studied in co-culture with
      macrophages. Mesothelioma cell lines obtained from tumors developed in vivo were
      the most sensitive to the cytotoxic action of macrophages and asbestos.
      Mesothelium cells of late passages and ras-transformed cell lines IAR2 and Rat1
      were somewhat less sensitive, whereas untransformed cells of IAR2 and Rat1 lines
      and early passage mesothelium were low sensitive to that cytotoxic action. In
      experiments performed on Petri dishes with inserts that allowed treatment with
      asbestos of only one of two cell populations, it was shown that asbestos
      treatment of mesothelioma cells was necessary and sufficient for manifestation of
      cytotoxic effect (in the absence of macrophages asbestos caused very low
      cytotoxicity). The medium conditioned by macrophages was not cytototoxic by
      itself but it strongly enhanced cytotoxic action of asbestos on transformed
      mesothelium and mesothelioma cells but not on normal mesothelial cells and IAR2
      and Rat1 cells (both normal and ras-transformed). The specificity of this
      augmenting effect for different toxicants was also investigated. It was shown
      that medium conditioned by macrophages enhanced cytotoxicity of hydrogen peroxide
      and sodium azide but not that of nonfibrous silicon dioxide,
      ethylmethanesulfonate, and sodium dodecylsulfate. The factor mediating this
      effect is thermolabile, non-dialyzable and protease-sensitive. Its m.w. is
      approximately 3-5 kD.

PMID- 12616611
TI  - Oncocalyxone A from Auxemma oncocalyx lacks genotoxic activity in
      phytohemagglutinin-stimulated lymphocytes.
AB  - Inadequate doses or prolonged chemotherapy can be cytotoxic or genotoxic to
      cancer patients, increasing the risk for the development of a second cancer,
      particularly acute leukemia. The association between therapeutic and genotoxic
      properties of oncocalyxone A (Onco A), make cytotoxic tests (mitotic index and
      chromosomal aberrations) fundamental in the accompaniment of the effects of this
      active compound. Therefore, the aim of the present study was to determine the
      genotoxic action of Onco A in vitro, during different phases of the cell cycle,
      utilizing primary cultures of lymphocytes of healthy individuals. The results
      showed that Onco A is cytotoxic during the cell cycle phases G1, G1/S, and S,
      however, not in G2. Onco A did not demonstrate a genotoxic effect in any of the
      cell cycle phases at the concentration studied. It is concluded that during the
      period of exposure, this active substance inhibits DNA synthesis and consequently
      cell division. Therefore, the absence of such genotoxicity for Onco A in the
      tests performed in this study provides important information in regard to the
      therapeutic use of this agent. Further studies are necessary to better understand
      the molecular mechanism of action of Onco A.

PMID- 12616612
TI  - Proceedings of the XXVII Annual Conference of the Environmental Mutagen Society
      of India (EMSI) Symposium on Environmental Genomics and Health Sciences. March 19
      21, 2002, Lucknow, India.

PMID- 12616613
TI  - Human molecular cytogenetics: diagnosis, prognosis, and disease management.
AB  - The year 2001 witnessed the sequencing of 90% of the euchromatic region in the
      human genome but the ultimate goal to delineate the positions of all genes is yet
      to be achieved. Fluorescence In Situ Hybridization (FISH) is one of the methods
      for localizing genes on chromosomes. In the present study, diagnostic utility of
      single-, dual-, and multicolor FISH was evaluated for prenatal diagnosis, cancer
      genetics, and screening of various congenital anomalies (sex chromosomal and
      autosomal). Centromeric probes for chromosomes X and Y were used for screening
      minor aneuploid cell lines (XXY, XO, and XXX) in the cases of primary amenorrhea
      and suspected Klinefelter syndrome. The cases with ambiguous genitalia were
      analyzed using a probe specific for the sex-determining region (SRY). Suspected
      cases of Down syndrome were subjected to FISH using probe specific for chromosome
      21. FISH was also used to study gene alterations in retinoblastoma and myeloid
      leukemias. Prenatal diagnosis was done to screen for aneuploidies of chromosomes
      13, 18, 21, X, and Y using FISH on uncultured cells from amniotic fluid and
      chorionic villi sampling. The screening for common aneuploidies was extended to
      abortuses from spontaneous abortions. Using FISH, low-level mosaicism could be
      identified in some cases of primary amenorrhea and suspected Klinefelter
      syndrome. Submicroscopic gene rearrangements could be detected using FISH in
      cases of ambiguous genitalia and cancers. Further interphase FISH could provide
      results within 24 hours. To conclude, FISH adds to the diagnostic utility of
      routine cytogenetics and its use on interphase nuclei overcomes the difficulty of
      conventional cytogenetics, thereby reducing the time between sampling and
      diagnosis to 24 hr.

PMID- 12616614
TI  - Spermatogenic arrest in men with testicular hyperthermia.
AB  - Sperm is produced by a highly complex and poorly understood differentiation
      process known as spermatogenesis. Occupational exposure to high temperatures
      adversely affect testicular function, causing partial or complete spermatogenic
      arrest. Dyers, cooks, blast furnace workers, and men with varicocele are known to
      develop testicular hyperthermia, which leads to oligoasthenoteratozoospermia
      (OAT) and azoospermia. Semen analysis of 122 infertile men (and 25 fertile
      controls), following the WHO guidelines, 1999, showed azoospermia in 106 men and
      oligozoospermia in 16 men. Twenty azoospermic and fourteen oligozoospermic men
      had high testiculoepididymal temperatures, either due to occupational exposure to
      high temperature or varicocele. All the 14 oligozoospermic men showed a very high
      percentage of sperm with abnormal morphology, impaired motility and they were
      subclassified as OAT group. Observations made in this study reiterates that high
      intratesticular temperature causes partial or complete spermatogenic arrest and
      may lead to increased production of morphologically abnormal sperm with impaired
      motility. This inverse relationship of sperm function with elevated temperature
      has implications in clinical medicine both in understanding pathological states
      and for therapeutic measures.

PMID- 12616615
TI  - X chromosomal abnormalities in Indian adolescent girls.
AB  - In girls of adolescent age, primary amenorrhea is a major problem and it is often
      suspected as Turner syndrome (TS), with complete or partial absence of one of the
      two X chromosomes. The girls who are unable to menstruate are primarily
      investigated by the gynecologists with the help of a physical examination,
      sonogram of the pelvis, endocrinologic tests, and ultimately cytogenetic
      analysis. Chromosomal analyses have been carried out in 280 such cases that were
      referred from different parts of the country. The standard protocol for
      peripheral blood lymphocyte culture was followed for metaphase chromosome
      preparation and conventional analysis of G-banded chromosomes. A total of 29%
      cases were found to have some chromosomal abnormality, including TS and
      testicular feminization syndrome involving sex chromosomes. Amongst those with
      sex chromosomal anomaly, 34% had evidence of a 46,XY karyotype in phenotypic
      females and 51% had pure line 45,X or mosaic with normal XX or other aberrations
      in X. The classification of the TS group further showed the spectrum of variant
      TS in Indian adolescent girls who suffered from absence or delayed menarche to
      correspond well with the Belgian, Danish, or Russian population. However, it has
      been reported that only 1% of the pure line 45,X conception is viable, indicating
      the necessity of mosaicism with X or Y chromosome. It has been understood that
      conventional banding analysis is absolutely necessary for segregating the variant
      nature of TS. In addition, molecular genetic or molecular cytogenetic
      investigations can determine the nature of mosaicism. The present study further
      indicated the involvement of autosomes in causing improper sexual development in
      girls of adolescent age.

PMID- 12616616
TI  - Assessment of microsatellite instability in bladder and thyroid malignancies.
AB  - Microsatellite instability (MSI) is an indicator of a defective DNA mismatch
      repair system (MMR) that results from somatic mutations. The present work has
      been planned to investigate MSI and its clinical significance in human urinary
      bladder and thyroid cancers in Indian patients. Tumor tissues of histologically
      confirmed cases of urinary bladder and thyroid cancers, respectively, were
      obtained. Clinical data on tumor stage and histopathological grades were
      recorded. Corresponding matched peripheral blood was taken as a control. Genomic
      DNA was isolated from the tumor tissues and blood using a standard phenol
      chloroform extraction method. Polymerase chain reaction was done to amplify
      mononucleotide microsatellite markers, BAT-26, BAT-40, TGFbetaRII, IGFIIR, hMSH3,
      and Bax by using specific primer sequences. For analysis of allelic patterns, the
      PCR products were run on 8% denaturing Polyacrylamide gel and sizing was done
      using a pUC18 sequencing ladder. The instability with BAT-26 and BAT-40 was found
      to be 20% and 45% in urinary bladder and 33% and 19% in thyroid cancers,
      respectively. However, no instability was observed with the other four
      mononucleotide markers in either of the cancers studied. Eighty-three percent of
      the unstable urinary bladder cancers were found to have a high grade in a
      superficial group, whereas only 27% MSI+ve were muscle invasive cancers. Forty
      percent of unstable thyroid lesions were found to be at high risk of developing
      metastasis. Association of BAT-26 and BAT-40 instabilities with high grade tumors
      as well as risk tumors may help in choosing a more definite therapy at the
      outset.

PMID- 12616617
TI  - Effect of oxymetholone on SCE frequency in human lymphocyte chromosomes in vitro.
AB  - Genotoxicity evaluation of a commonly used synthetic androgen, Oxymetholone, was
      carried out in human peripheral blood lymphocytes in vitro. Sister chromatid
      exchange (SCE) was used as genetic end point. The concentrations of the drug were
      determined after observing its effects on the mitotic index. A wide range of
      concentrations, i.e., 25, 50, and 100 micro g/ml of the drug, were used to
      determine the genotoxic effects in the absence as well as in the presence of rat
      liver microsomal activation system (S9 mix). The drug did not induce any
      significant increase in the SCE frequency at any of the concentrations either in
      the presence or in the absence of S9 mix. The maximum value of SCE was observed
      in the absence of S9 mix at 100 microg/ml concentration (i.e., 1.38+/
      0.080/cell), which was not significant statistically. Moreover, the drug was not
      effective in increasing the SCE frequency even in the presence of S9 mix. The
      maximum value of SCE (i.e., 1.78+/-0.103/cell) was observed at 50 microg/ml of
      concentration in the presence of S9 mix. A dose relationship was also not
      observed. It was concluded that Oxymetholone does not affect the genetic material
      in human lymphocytes at a wide range of concentrations in the SCE assay.

PMID- 12616618
TI  - Effects of mustard sprouts and allylisothiocyanate on benzo(a)pyrene-induced DNA
      damage in human-derived cells: a model study with the single cell gel
      electrophoresis/Hep G2 assay.
AB  - The aim of this study was to investigate the chemoprotective effects of mustard
      sprouts on benzo(a)pyrene [B(a)P]-induced DNA damage in the single cell gel
      electrophoresis (SCGE)/Hep G2 assay. This model combines the advantages of the
      SCGE assay with that of human-derived cells that possess inducible phase I and
      phase II enzymes. Treatment of the cells with small amounts of mustard juice (0.1
      1.25 microl/ml) and B(a)P reduced the genotoxic effect of the carcinogen in a
      dose-dependent manner. Contrary to the results with the juice, unexpected
      synergistic effects were observed with allyl isothiocyanate (AITC, 0.3 microM), a
      breakdown product of sinigrin, which is contained in black mustard and many other
      cruciferous vegetables. Although these concentrations of AITC did not cause DNA
      damage per se, pronounced dose-dependent DNA damage was seen with higher
      concentrations of AITC (>or= 25 microM). In parallel with the comet assays, also
      enzyme measurements were carried out which showed that exposure of the cells to
      mustard juice (2.0 microl/ml) causes a moderate induction of ethoxyresorufin-O
      deethylase, and more pronounced (approximately 2-fold) increase of the activity
      of glutathione-S-transferase. In conclusion, our findings indicate that i)
      mustard juice is highly protective against B(a)P-induced DNA damage in human
      derived cells and ii) that induction of detoxifying enzymes may account for its
      chemoprotective properties. iii) Furthermore, our findings show that the effects
      of crude juice can not be explained by its allyl isothiocyanate contents.

PMID- 12616619
TI  - Customized cDNA microarray for expression profiling of environmentally important
      genes of Pseudomonas stutzeri strain KC.
AB  - DNA microarray is a powerful tool for parallel detection of multiple target genes
      in biological systems. In this study, a low-density DNA microarray has been
      custom designed by using Pseudomonas stutzeri strain KC ORFs that are implicated
      in carbon tetrachloride degradation. PCR amplified strain KC probes of varying
      lengths were obtained using ORF-specific primers. Purified short probes (80-120
      bp) and full-length amplicons were directly immobilized on gamma-aminosilane
      coated and superaldehyde trade mark glass substrates without any chemical
      modification. The full-length amplicons exhibited a much higher signal compared
      to the shorter probes upon hybridization with the Cy5/Cy3-labeled unfragmented
      cDNA targets. The meager signal with the shorter probes limits the advantage of
      using the multiple probes of the same genes for enhancing the specificity of
      hybridization with environmental samples. Nevertheless, expression analysis of
      strain KC genome, under controlled laboratory conditions, revealed the
      constitutive expression of at least 11 putative ORFs of the pdt operon.
      Comparatively weaker hybridization signals with the cDNA from mutant cells
      suggested a low abundance of mRNA transcripts in the KC 1896 mutant. Similar
      expression levels of the pdt ORFs I, J, K, M, N, O, P, and fur gene both under
      iron-limiting conditions and in presence of iron (20 micro M Fe(3+)) suggested
      metal ion-independent regulation of the pdt operon. The tailor-made array with
      strain KC gene-specific probes served as a model for demonstrating the utility of
      cDNA microarray technology in monitoring the expression of environmentally
      important genes in bacteria.

PMID- 12616620
TI  - Indian medicinal plants as a reservoir of protective phytochemicals.
AB  - India is one of the 12 mega diversity countries in the world so it has a vital
      stake in conservation and sustainable utilization of its biodiversity resources.
      Plant secondary metabolites have been of interest to man for a long time due to
      their pharmacological relevance. With this in view, the bark powder of Acacia
      auriculiformis, A. nilotica, Juglans regia, and the fruit powder of Terminalia
      bellerica, T. chebula, Emblica officinalis, and a combination drug "Triphala,"
      which are known to be rich in polyphenols, were tested for their antimutagenic
      activities. Antimutagenic activities of the extracts were estimated by employing
      the plate incorporation Ames Salmonella histidine reversion assay by using the
      frame shift mutagen tester strain TA98 and base pair substitution strain TA100
      against direct acting mutagens (NPD, sodium azide), and the S9-dependent mutagen
      2-aminofluorene(2AF). Acetone extracts of all the plants exhibited significant
      antimutagenic activities among the other extracts tested, but an acetone extract
      of Acacia nilotica showed a marked anti-mutagent effect. Furthermore, it was more
      effective against indirect acting mutagen, 2AF, in both TA98 and TA100 tester
      strains of Salmonella typhimurium than against the direct acting mutagens. The
      results indicate that an acetone extract of bark and fruit of the medicinal
      plants under study harbors constituents with promising
      antimutagenic/anticarcinogenic potential that could be investigated further.

PMID- 12616621
TI  - Tumor promotion by metanil yellow and malachite green during rat
      hepatocarcinogenesis is associated with dysregulated expression of cell cycle
      regulatory proteins.
AB  - Metanil yellow (MY) and malachite green (MG) are textile dyes, which, despite a
      ban, are used as food-coloring agents. MY and MG have promoter effects on the
      development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine
      (DEN). Tumor-promoting agents are not mutagenic but may alter the expression of
      genes whose products are associated with hyper-proliferation, tissue remodeling,
      and inflammation. Cell cycle controls normally function to ensure the integrity
      of the genome and arrest of cells at G1/S or G2/M checkpoints until all the
      prerequisite events are completed. In order to understand the mechanism(s) of
      tumor promotion by MY and MG, we have studied the levels of PCNA, a marker of
      cell proliferation and cell cycle regulatory proteins, cyclin D1, and its
      associated kinase, cdk4, cyclin B1, and associated kinase, cdc2.
      Immunohistochemical staining showed an elevated level of PCNA in animals
      administered MY and MG subsequent to DEN treatment. Western and Northern blot
      hybridization showed an increased expression of both cyclin D1 and its associated
      kinase cdk4, and cyclin B1 and its associated kinase cdc2, in livers of rats
      administered MY and MG after administration of DEN as compared to untreated or
      DEN controls. The increased level of mRNA was due to the increased rate of
      transcription of these genes as studied by run-on transcription assay. These data
      obtained by the in vivo model of liver tumor development provide strong evidence
      for a link between dysregulation of the two critical checkpoints of the cell
      cycle as one of the possible mechanism(s) during tumor promotion by malachite
      green and metanil yellow.

PMID- 12616623
TI  - Antigenotoxic potential of certain dietary constituents.
AB  - The human diet contains a variety of compounds that exhibit chemopreventive
      effects towards an array of xenobiotics. In the present study, the antigenotoxic
      potential of selected dietary constituents including Diallyl sulfide (DAS),
      Indole-3-carbinol (I3C), Curcumin (CUR), and Black tea polyphenols (BTP) has been
      evaluated in the Salmonella typhimurium reverse mutation and mammalian in vivo
      cytogenetic assays. In addition, the anticlastogenic effect of the above dietary
      constituents was identified towards Benzo(a)pyrene (BaP) and cyclophosphamide-
      (CP) induced cytogenetic damage in mouse bone marrow cells. The induction of BaP
      and CP induced chromosomal aberrations, micronuclei formation, and sister
      chromatid exchanges (SCEs) were found to be inhibited in a dose-dependent manner
      by DAS, I3C, CUR, and BTP. Thus the study reveals the antimutagenic potential of
      these dietary compounds towards BaP- and CP-induced genotoxicity in microbial and
      mammalian test systems.

PMID- 12616622
TI  - Regulation of hazardous exposure by protective exposure: modulation of phase II
      detoxification and lipid peroxidation by Camellia sinensis and Swertia chirata.
AB  - Many natural compounds are now known to have a modulatory role on physiological
      functions and biotransformation reactions involved in the detoxification process,
      thereby affording protection from cytotoxic, genotoxic, and metabolic actions of
      environmental toxicants. As part of a programme on evaluation of food, beverage,
      and traditional medicinal plants for their anticarcinogenic activity, their
      effects on detoxification enzymes were also studied. The present report deals
      with Camellia sinensis and Swertia chirata. The effect of water infusions as well
      as crude and purified components of these plants on glutathione-S-transferase
      (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase
      (CAT) was analyzed in mice that were exposed to the chemical carcinogen DMBA. All
      the four enzymes were found to be activated in different degrees following
      treatment. The effect of Theaflavin, a component of black tea, was highly
      significant. The activation of the enzymes was accompanied by significant
      reduction in lipid peroxidation. The observation suggest the chemopreventive
      potential of both Camellia sinensis and Swertia chirata.

PMID- 12616625
TI  - Kurt Wuthrich, the ETH Zurich, and the development of NMR spectroscopy for the
      investigation of structure, dynamics, and folding of proteins.

PMID- 12616626
TI  - Modulated nucleoside kinases as tools to improve the activation of therapeutic
      nucleoside analogues.
AB  - The use of nucleoside analogues in anticancer and antiviral treatments is often
      impaired by the slow intracellular activation of these drugs. This problem can be
      addressed by the modulation of rate-limiting enzymes in the activation pathways
      of the nucleoside analogues. Therapeutic strategies based on the combination of
      optimized activating enzymes and established nucleoside drugs promise significant
      improvements to traditional chemotherapy.

PMID- 12616627
TI  - Polyglycine II nanosheets: supramolecular antivirals?
AB  - Tetraantennary peptides [glycine(n)-NHCH(2)](4)C can form stable noncovalent
      structures by self-assembly through intermolecular hydrogen bonding. The
      oligopeptide chains assemble as polyglycine II to yield submicron-sized, flat,
      one-molecule-thick sheets. Attachment of alpha-N-acetylneuraminic acid
      (Neu5Acalpha) to the terminal glycine residues gives rise to water-soluble
      assembled glycopeptides that are able to bind influenza virus multivalently and
      inhibit adhesion of the virus to cells 10(3)-fold more effectively than a
      monomeric glycoside of Neu5Acalpha. Another antiviral strategy based on virus
      promoted assembly of the glycopeptides was also demonstrated. Consequently, the
      self-assembly principle offers new perspectives on the design of multivalent
      antivirals.

PMID- 12616628
TI  - The binding mode of progesterone to its receptor deduced from molecular dynamics
      simulations.
AB  - An unambiguous understanding of the binding mode of human progesterone to its
      receptor still eludes experimental search. According to the X-ray structure of
      the ligand-binding domain, only one (O3) of the two keto groups at the ligand
      ends (O3 and O20) should play a role. This result is in conflict with chemical
      intuition and the results of site-directed mutagenesis experiments. Herein, we
      report classical molecular dynamics simulations that reveal the dynamic nature of
      the binding in solution, elucidate the reasons why X-ray studies failed to
      determine the role of O20, and clarify the effects of the mutations. The
      predictive power of the force field is ensured by the consistent introduction of
      a first-principles representation of the ligand.

PMID- 12616629
TI  - DMACM-caged adenosine nucleotides: ultrafast phototriggers for ATP, ADP, and AMP
      activated by long-wavelength irradiation.
AB  - The development of new photocleavable adenosine nucleotides based on the
      photochemistry of [7-(dimethylamino)coumarin-4-yl]methyl (DMACM) esters is
      described. The phototriggers liberate adenosine triphosphate (ATP), diphosphate,
      and monophosphate upon UV/Vis irradiation between 334 and 405 nm. The efficiency
      of photocleavage at long wavelengths is high as a result of a combination of
      appropriate quantum yields and intensive absorptivities. By using time-resolved
      fluorescence spectroscopy, we determined a lower limit of 1.6 x 10(9) s(-1) for
      the rate constant of the release of ATP from DMACM-caged ATP. The favorable
      properties of DMACM-caged ATP were confirmed in physiological studies by confocal
      laser scanning microscopy. We were able to uncage DMACM-caged ATP in cultures of
      mouse astrocytes and in brain tissue slices from mice and were also able to
      measure the effect of photoreleased ATP on the cellular response of astrocytes,
      namely the ability of the ATP to evoke Ca(2+) ion waves.

PMID- 12616631
TI  - D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic
      secretory phospholipase A2 (IIa) with antiinflammatory activity.
AB  - Few reported inhibitors of secretory phospholipase A(2) enzymes truly inhibit the
      IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations.
      Herein, the simple chiral precursor D-tyrosine was derivatised to give a series
      of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-A crystal structure shows an
      inhibitor bound in the active site of the enzyme, chelated to a Ca(2+) ion
      through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to
      His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6
      interaction. Antiinflammatory activity is also demonstrated for two compounds
      administered orally to rats.

PMID- 12616630
TI  - NMR structure of the single QALGGH zinc finger domain from the Arabidopsis
      thaliana SUPERMAN protein.
AB  - Zinc finger domains of the classical type represent the most abundant DNA binding
      domains in eukaryotic transcription factors. Plant proteins contain from one to
      four zinc finger domains, which are characterized by high conservation of the
      sequence QALGGH, shown to be critical for DNA-binding activity. The Arabidopsis
      thaliana SUPERMAN protein, which contains a single QALGGH zinc finger, is
      necessary for proper spatial development of reproductive floral tissues and has
      been shown to specifically bind to DNA. Here, we report the synthesis and UV and
      NMR spectroscopic structural characterization of a 37 amino acid SUPERMAN region
      complexed to a Zn(2+) ion (Zn-SUP37) and present the first high-resolution
      structure of a classical zinc finger domain from a plant protein. The NMR
      structure of the SUPERMAN zinc finger domain consists of a very well-defined
      betabetaalpha motif, typical of all other Cys(2)-His(2) zinc fingers structurally
      characterized. As a consequence, the highly conserved QALGGH sequence is located
      at the N terminus of the alpha helix. This region of the domain of animal zinc
      finger proteins consists of hypervariable residues that are responsible for
      recognizing the DNA bases. Therefore, we propose a peculiar DNA recognition code
      for the QALGGH zinc finger domain that includes all or some of the amino acid
      residues at positions -1, 2, and 3 (numbered relative to the N terminus of the
      helix) and possibly others at the C-terminal end of the recognition helix. This
      study further confirms that the zinc finger domain, though very simple, is an
      extremely versatile DNA binding motif.

PMID- 12616632
TI  - Solid-phase synthesis and biological activity of a thioether analogue of
      conotoxin G1.
AB  - A bicyclic thioether analogue of alpha-conotoxin G1, a neurotoxin found in the
      venom of cone snails, was synthesized on solid phase. Two successive
      intramolecular on-bead cyclizations between a cysteine residue and a
      chloroacetylated reduced peptide bond are the key steps in the synthesis. The
      first reduced peptide bond was introduced by a reductive alkylation with a 9
      fluorenylmethoxycarbonyl protected amino aldehyde, and the second by coupling of
      a dipeptide building block containing an allyloxycarbonyl protected reduced
      peptide bond. The desired bicyclic product was obtained as a mixture of two
      isomers, which were evaluated for their ability to inhibit the muscular nicotinic
      acetylcholine receptor expressed in Xenopus oocytes. The two isomers were found
      to have IC(50) values (inhibitory activities) of 144 microM and 48 microM,
      compared to 0.18 microM for native conotoxin G1.

PMID- 12616633
TI  - Photocrosslinking in ruthenium-labelled duplex oligonucleotides.
AB  - The formation of a photoadduct between a [Ru(1,4,5,8-tetraazaphenanthrene)(2)4,7
      diphenylphenanthroline](2+) complex chemically attached to a synthetic
      oligonucleotide, and a guanine moiety in a complementary targeted single-stranded
      DNA molecule was studied for ten 17-mer duplexes by denaturing gel
      electrophoresis. This photoadduct formation leads to photocrosslinking of the two
      strands. The percentage quenching of luminescence of the complex by electron
      transfer was compared to the resulting yield of photocrosslinked product. This
      yield does not only depend on the ionisation potential of the guanine bases,
      which are electron donors, but also on other factors, such as the position of the
      guanine bases as compared to the site of attachment of the complex. The
      photocrosslinking yield is higher when the guanine moieties are towards the 3'
      end on the complementary strand as compared to the tethering site. Computer
      modelling results are in agreement with this preference for the 3' side for the
      photoreaction. Interestingly, the photocrosslink is not alkali labile. Moreover,
      a type III exonuclease enzyme is blocked at the position of photocrosslinking.

PMID- 12616634
TI  - Behavior of silica aerogel networks as highly porous solid solvent media for
      lipases in a model transesterification reaction.
AB  - Highly porous silica aerogels with differing balances of hydrophobic and
      hydrophilic functionalities were studied as a new immobilization medium for
      enzymes. Two types of lipases from Candida rugosa and Burkholderia cepacia were
      homogeneously dispersed in wet gel precursors before gelation. The materials
      obtained were compared in a simple model reaction: transesterification of vinyl
      laurate by 1-octanol. To allow a better comparison of the hydrophobic/hydrophilic
      action of the solid, very open aerogel networks with traditional organic
      hydrophobic/hydrophilic liquid solvents, this reaction was studied in mixtures
      containing different proportions of 2-methyl-2-butanol, isooctane, and water. The
      results are discussed in relation to the porous and hydrophobic nature of
      aerogels, characterized by nitrogen adsorption. It was found that silica aerogels
      can be considered as "solid" solvents for the enzymes, able to provide
      hydrophobic/hydrophilic characteristics different from those prevailing in the
      liquid surrounding the aerogels. A simple mechanism of action for these aerogel
      networks is proposed.

PMID- 12616635
TI  - Substrate specificity of mutants of the hydroxynitrile lyase from Manihot
      esculenta.
AB  - Several tryptophan128-substituted mutants of the hydroxynitrile lyase from
      Manihot esculenta (MeHNL) are constructed and applied in the MeHNL-catalyzed
      addition of HCN to various aromatic and aliphatic aldehydes as well as to methyl
      and ethyl ketones to yield the corresponding cyanohydrins. The mutants
      (especially MeHNL-W128A) are in most cases superior to the wild-type (wt) enzyme
      when diisopropyl ether is used as the solvent. Substitution of tryptophan128 by
      an alanine residue enlarges the entrance channel to the active site of MeHNL and
      thus facilitates access of sterically demanding substrates to the active site, as
      clearly demonstrated for aromatic aldehydes, especially 3-phenoxybenzaldehyde.
      These experimental results are in accordance with the X-ray crystal structure of
      MeHNL-W128A. Aliphatic aldehydes, surprisingly, do not demonstrate this
      reactivity dependence of mutants on substrate bulkiness. Comparative reactions of
      3-phenoxybenzaldehyde with wtMeHNL and MeHNL-W128A in both aqueous citrate buffer
      and a two-phase system of water/methyl tert-butyl ether again reveal the
      superiority of the mutant enzyme: 3-phenoxybenzaldehyde was converted
      quantitatively into a cyanohydrin nearly independently of the amount of enzyme
      present, with a space-time yield of 57 g L(-1) h(-1).

PMID- 12616636
TI  - In vitro selection of N-peptide-binding RNA on a quartz-crystal microbalance to
      study a sequence-specific interaction between the peptide and loop RNA.

PMID- 12616637
TI  - External regulation of hairpin ribozyme activity by an oligonucleotide effector.

PMID- 12616638
TI  - Synthesis of thioether-linked analogues of the 2,3-sialyl-TF and MECA-79
      antigens: mucin-type glycopeptides associated with cancer and inflammation.

PMID- 12616640
TI  - DNA with gamma-aminopropyltriethoxysilane switches between B- and C-form
      structures under thermal control.

PMID- 12616639
TI  - Modelling of photointermediates suggests a mechanism of the flip of the beta
      ionone moiety of the retinylidene chromophore in the rhodopsin photocascade.

PMID- 12616642
TI  - Isolation, sequencing, and expression of a cDNA for the HXM-A form of
      xenobiotic/medium-chain fatty acid:CoA ligase from human liver mitochondria.
AB  - The purification of xenobiotic/medium-chain fatty acid:CoA ligases (XM-ligases)
      from human liver mitochondria resulted in the isolation of two
      chromatographically separable forms (HXM-A and HXM-B). These two forms were
      purified to near homogeneity, cleaved with cyanogen bromide, the resulting
      peptides separated, and the N-terminus of two of the peptides partially
      sequenced. Identical sequences were obtained for HXM-A and HXM-B for the two
      peptides. These sequences were used to design probes for screening a human liver
      cDNA library. This resulted in the isolation of two overlapping cDNAs. Using
      these sequences we were able to design PCR primers that resulted in the isolation
      of a full-length cDNA from a human cDNA library. The cDNA contained 1731 bp of
      open reading frame and coded for a 64230-Da protein. This protein bears 56.2%
      amino acid homology to the MACS1 (medium-chain acyl-CoA synthetase) enzyme, 58.7%
      homology to the bovine XL-III XM-ligase, and 81.5% homology to the bovine XL-I XM
      ligase. The cDNA could be expressed in COS cells, and the expressed enzyme had
      greater benzoate activity than phenylacetate activity, which is consistent with
      the known substrate specificity of HXM-A.

PMID- 12616643
TI  - Human aldehyde dehydrogenases: potential pathological, pharmacological, and
      toxicological impact.
AB  - Aldehyde dehydrogenases catalyze the pyridine nucleotide-dependent oxidation of
      aldehydes to acids. Seventeen enzymes are currently viewed as belonging to the
      human aldehyde dehydrogenase superfamily. Summarized herein, insofar as the
      information is available, are the structural composition, physical properties,
      tissue distribution, subcellular location, substrate specificity, and cofactor
      preference of each member of this superfamily. Also summarized are the
      chromosomal locations and organization of the genes that encode these enzymes and
      the biological consequences when enzyme activity is lost or substantially
      diminished. Broadly, aldehyde dehydrogenases can be categorized as critical for
      normal development and/or physiological homeostasis (1). even when the organism
      is in a friendly environment or (2). only when the organism finds itself in a
      hostile environment. The primary, if not sole, evolved raison d'etre of first
      category aldehyde dehydrogenases appears to be to catalyze the biotransformation
      of a single endobiotic for which they are relatively specific and of which the
      resultant metabolite is essential to the organism. Most of the human aldehyde
      dehydrogenases for which the relevant information is available fall into this
      category. Second category aldehyde dehydrogenases are relatively substrate
      nonspecific and their evolved raison d'etre seems to be to protect the organism
      from potentially harmful xenobiotics, specifically aldehydes or xenobiotics that
      give rise to aldehydes, by catalyzing their detoxification. Thus, the lack of a
      fully functional first category aldehyde dehydrogenase results in a gross
      pathological phenotype in the absence of any insult, whereas the lack of a
      functional second category aldehyde dehydrogenase is ordinarily of no consequence
      with respect to gross phenotype, but is of consequence in that regard when the
      organism is subjected to a relevant insult.

PMID- 12616644
TI  - Diabetes, oxidative stress, and antioxidants: a review.
AB  - Increasing evidence in both experimental and clinical studies suggests that
      oxidative stress plays a major role in the pathogenesis of both types of diabetes
      mellitus. Free radicals are formed disproportionately in diabetes by glucose
      oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative
      degradation of glycated proteins. Abnormally high levels of free radicals and the
      simultaneous decline of antioxidant defense mechanisms can lead to damage of
      cellular organelles and enzymes, increased lipid peroxidation, and development of
      insulin resistance. These consequences of oxidative stress can promote the
      development of complications of diabetes mellitus. Changes in oxidative stress
      biomarkers, including superoxide dismutase, catalase, glutathione reductase,
      glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite
      concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes,
      and their consequences, are discussed in this review. In vivo studies of the
      effects of various conventional and alternative drugs on these biomarkers are
      surveyed. There is a need to continue to explore the relationship between free
      radicals, diabetes, and its complications, and to elucidate the mechanisms by
      which increased oxidative stress accelerates the development of diabetic
      complications, in an effort to expand treatment options.

PMID- 12616646
TI  - A quantitative structure-activity relationship analysis on a series of alkyl
      benzenes metabolized by human cytochrome p450 2E1.
AB  - The results of quantitative structure-activity relationships for eight alkyl
      benzenes undergoing oxidative metabolism via human CYP2E1 are reported. Molecular
      orbital calculations via the AM1 method were employed for the generation of
      electronic structural descriptors against experimentally generated kinetic data
      for CYP2E1-mediated metabolism. The findings point to the importance of
      electronic structural properties of the molecules themselves, particularly the
      role of frontier orbitals, in determining rates of metabolism. Other factors
      appear to be responsible for the affinity of these substrates for the CYP2E1
      enzyme however, such as its lipophilic character. The results are consistent with
      the interactive molecular modeling of these compounds within the putative active
      site of human CYP2E1 constructed from the CYP2C5 template, where it was found
      that pi-pi stacking interactions between aromatic rings are important for the
      binding of substrates to the CYP2E1 active site, together with contributions from
      desolvation entropy changes accompanying substrate binding.

PMID- 12616645
TI  - Increase of lipid peroxidation by cisplatin in WI38 cells but not in SV40
      transformed WI38 cells.
AB  - Cisplatin (CPT) is an effective anticancer drug that causes cumulative toxicity
      to normal tissues. It has been suggested that CPT damages normal cells by causing
      oxidative stress, but it is not known whether it can induce similar oxidative
      damage to tumor cells. In this study, by using normal human lung fibroblast
      (W138) cells and SV40-transformed WI38 (VA13) cells as a model, we compared the
      effect of CPT on cytotoxicity, apoptosis, lipid peroxidation, and mitochondrial
      gene expression, which could be regulated by oxidative stress, between normal and
      tumor cells. CPT induced greater growth inhibition and percentage of apoptotic
      cells in VA13 cells. However, levels of esterified F(2)-isoprostanes and 4
      hydroxy-2-nonenal, two specific products of lipid peroxidation, were increased by
      CPT in WI38 cells, but not in VA13 cells. Furthermore, the transcript level of
      mitochondrial 12S rRNA was augmented by CPT in both cells, but to a higher degree
      in WI38 cells. The data suggest a correlation between lipid peroxidation and
      cytotoxicity or increased mitochondrial transcript levels in WI38 cells but not
      in VA13 cells. The results also indicate an altered response of oxidative damage
      and mitochondrial gene regulation to CPT in the transformed phenotype of WI38
      cells.

PMID- 12616647
TI  - Purification and activity of two phospholipase enzymes from Naja nigricolis
      nigricolis Reinhardt venom.
AB  - Two phospholipase enzymes NN1 and NN2 were purified from the venom of Naja
      nigricolis nigricolis Reinhardt to apparent homogeneity. NN1 was purified by a
      two-step anion-exchange chromatography on DEAE-cellulose column while NN2 was
      purified by a combination of anion-exchange chromatography and gel filtration on
      Sephadex G-150. The enzyme NN1 moved homogenously on acrylamide gel as a monomer
      with a molecular weight of 65 kDa while NN2 was a dimer of 71 kDa. Both enzymes
      were clearly separated. Both enzymes hydrolyzed L-alpha-phosphatidyl choline with
      activities of 345.5 for NN1 and 727.8 micromol min(-1) x mg(-1) for NN2. The
      dimeric 71-kDa enzyme has a higher haemolytic and anticoagulant activity than the
      monomeric 65-kDa enzyme. It is apparent that the dimeric enzyme has a more
      pronounced activity than the monomer has, thus toxic activity may be related to
      the hydrolysis of phospholipids.

PMID- 12616649
TI  - [Skull base surgery for frontobasal meningioma].

PMID- 12616648
TI  - Aryl sulfatase from Naja nigricolis venom: characterization and possible
      contribution in the pathology of snake poisoning.
AB  - The venom of Naja nigricolis was found to contain a high level of the enzyme aryl
      sulfatase. The enzyme was isolated from the venom of N. nigriclois and purified
      to electrophoretic homogeneity by gel chromatography on Sephadex G-100, DEAE
      cellulose, and phenyl-sepharose columns. The enzyme was optimally active at pH 5
      and 40 degrees C. Arrhenius plot for the determination of the activation energy
      (E(a)) gave the value 25 kJ/mol with a half-life (t(1/2)) of 5 min at 50 degrees
      C. It was highly activated by Fe(2+) and Ca(2+) and inhibited by Co(2+) and
      Mn(2+). The enzyme catalyzed the hydrolysis of the fluorescent compound
      methylumbelliferyl-sulfate (MU-SO(4)). Double reciprocal plots of initial
      velocity data, using MU-SO(4) as substrate, gave a K(M) value of 110 microM and
      V(max) of 225 micromol min(-1) x mg(-1). N. nigricolis Aryl sulphatase also
      hydrolyzed chondroitin-4-sulphate. It was inhibited competitively by N-acetyl
      glucosamine sulfate (GlcNAc-SO(4)), glucose-6-sulfate (Glc-6-SO(4)), and glucose
      1-sulfate (Glc-1-SO(4)). Extrapolated inhibition binding constants (K(i)) gave
      the values of 3, 25, and 315 microM for GlcNAc-SO(4), Glc-6-SO(4), and Glc-1
      SO(4) respectively.

PMID- 12616650
TI  - [Current treatment strategy with gamma knife surgery for mesial temporal lobe
      epilepsy].

PMID- 12616651
TI  - [Relationship between the natural history of chronic subdural hematoma and
      enhancement of the inner membrane on post-contrast CT scan].
AB  - The purpose of this study was to determine the features and natural history of
      the inner membrane in CSDH (chronic subdural hemotoma) patients using pre- and
      post-contrast CT scans. Twenty-four patients with CSDH (28 hematomas) who
      underwent pre- and post-contrast CT scanning prior to surgery were studied. CSDH
      was classified according to the internal architecture as the homogeneous (HM)
      type, the laminar (LM) type, the separated (SP) type, and the trabecular (TR)
      type. For each type, the enhancement of the inner membrane, the outer membrane,
      and trabeculae was evaluated. Enhancement of the inner membrane develops as the
      stage of CSDH progresses. Although the inner membrane was not enhanced in the HM
      type, it was enhanced in almost all of the patients with the other types (p <
      0.0001). In 13% of patients with the LM type, 29% with the SP type, and 40% with
      the TR type, the inner membrane was moderately or markedly enhanced. The outer
      membrane was not thickened in any patient. In 88% of the patients who had
      contralateral hemiparesis on admission and 42% of those who did not have
      hemiparesis, the inner membrane was clearly enhanced (p = 0.0166). This indicated
      that blood flow to the inner membrane from the pia matter induced hypoperfusion
      of the brain parenchyma beneath the hematoma in addition to the effect of direct
      compression. Contrast CT scanning may be useful for diagnosing the extent of
      enlargement of the inner membrane, predicting the risk of local brain damage, and
      evaluating the stage in the natural history of CSDH.

PMID- 12616652
TI  - [Changes in 1H-MRS in glioma patients before and after irradiation: the
      significance of quantitative analysis of choline-containing compounds].
AB  - The evaluation of the response to radiation therapy in brain tumor patients is a
      major and an important issue. Although CT and MRI can measure changes in tumor
      size, it is difficult to use these imaging methods to evaluate the viability or
      the proliferation activity of a tumor. In this study, we investigated the
      metabolite changes in glioma patients using 1H-MRS from before to after radiation
      therapy, to see whether or not early metabolic changes occur during therapy.
      Seven patients with histologically proven glioma (1 astrocytoma, 1 anaplastic
      astrocytoma, 2 oligoastrocytoma, 1 oligodendroglioma, 2 glioblastoma) were
      examined by means of 1H-MRS using a point-resolved spectroscopy (PRESS) sequence
      with a repetition time of 2,000 ms and echo times of 68 ms, 136 ms and 272 ms.
      The 1H-MRS was evaluated by both the spectrum pattern and the quantification of
      the metabolites. As to radiation therapy, each patient received a total dose of
      64.8 Gy (1.8 Gy/fraction) with a 10-MeV linear accelerator. The results revealed
      that the concentration of choline-containing compounds (Cho) was 4.55 +/- 1.08
      mmol/kg wet weight before radiation therapy and was reduced to 2.69 +/- 0.56
      mmol/kg wet weight (p < 0.01) after radiation therapy. Moreover, both the N
      acetylaspartate (NAA) peak and creatine/phosphocreatine (t-Cr) peak were lower
      after radiation therapy than before. The peaks of both the lipids (Lip) and
      lactate (Lac) were higher after radiation therapy than before. In conclusion, Cho
      concentration is thought to be a useful marker for the evaluation of early post
      radiation response. The effect of radiation therapy can be evaluated according to
      the value of Cho. Further long-term MRS study is needed to prove whether or not
      the decrease of the Cho value in the present study will change before recurrence
      at later stages.

PMID- 12616654
TI  - [Early recurrent meningioma with malignant transformation: case report].
AB  - It has been reported that the incidence of malignant transformation of meningioma
      is 10 to 38%. However, it is rare for a benign meningioma to recur with malignant
      transformation shortly after surgery. We reported a case of recurrent meningioma
      with malignant transformation 4 months after the initial surgery. A 64-year-old
      female was admitted for meningioma in the right parietal convexity on July 1,
      1999. The tumor was totally resected on August 31st. There were no surgically nor
      histologically detected malignancies. The tumor was diagnosed as a psammomatous
      meningioma, but there was a co-exsisting transitional meningioma-like area. There
      were no postoperative neurological deficits, but, left hemiparesis and numbness
      on the left side of the body appeared around the end of December, and the patient
      was re-hospitalized on January 11, 2000. The CT scan and MRI showed that a cystic
      tumor had formed at the site of the previous tumor. Using Gd-DTPA, this new tumor
      showed ring enhancement. The tumor was extirpated again on February 3, 2000. It
      was histologically diagnosed as a malignant transformation of the meningioma. The
      Patient died of tumor recurrence on December 17, 2000. We speculated that the
      mechanism of recurrence as follows: Tumor cells with the possibility of becoming
      malignant, remained in the brain after the initial surgery. Postoperatively,
      these cells underwent malignant transformation and the tumor recurred.

PMID- 12616653
TI  - [Clinical evaluation of patients with isolated, traumatic, localized subarachnoid
      hemorrhage].
AB  - Three hundred and fifty cases of patients with head injury were admitted to our
      hospital from 1998 to 2000. Among these cases, 10 cases manifested isolated,
      localized subarachnoid hemorrhage on the first computed tomographic image after
      the trauma. Traumatic subarachnoid hemorrhage was found in the ambient,
      suprasellar, and sylvian fissure, Bleeding was seen in the ambient cistern or
      suprasellar cistern at the site of the blow on the frontal or occipital area of
      the head. The bleeding was seen in the sylvian fissure at the site of the
      temporal head blow. The bleeding was washed out after one day. None of the
      patients had symptomatic spasms, and all of the patients had a good prognosis.
      The mechanism of isolated, traumatic, localized subarachnoid hemorrhage was
      considered as shear strain or coup and contre-coup injury.

PMID- 12616656
TI  - [Successful local thrombolytic therapy for atherosclerotic middle cerebral artery
      occlusion 24 hours after onset: case report].
AB  - We describe success with local thrombolytic therapy given to a patient 24 hours
      after onset of left middle cerebral artery (MCA) occlusion. A 53-year-old man was
      admitted 18 hours after onset of disorientation, motor aphasia, and right upper
      and lower limb weakness. Computed tomography (CT) showed an area of slightly
      decreased density in the deep left frontal white matter. A stable Xenon CT
      cerebral blood flow study revealed mildly decreased perfusion in the left MCA
      territory, which showed negative cerebrovascular reactivity. FLAIR method
      magnetic resonance images demonstrated an area of slight hyperintensity in the
      left frontal white matter. Angiography showed atherothrombotic left MCA
      occlusion. 24 hours after clinical onset of occlusion, we successfully performed
      local thrombolytic therapy with urokinase. The patient's neurological status
      improved immediately. While indications for local thrombolysis in cerebral
      infarction presenting more than 6 hours after onset have not been established, we
      experienced success in the present patient who presented 18 hours after onset.

PMID- 12616655
TI  - [Spontaneous thrombosis of a fusiform aneurysm arising from the distal posterior
      cerebral artery: case report].
AB  - A 58-year-old woman complaining of a mild headache was admitted to our hospital.
      MRI 3 months before admission revealed a round lesion at the right quadrigeminal
      cistern. Cerebral angiograms demonstrated a fusiform aneurysm arising from the
      parietooccipital artery, which is the distal branch of the right posterior
      cerebral artery. Repeated MRI and cerebral angiograms performed on admission
      demonstrated complete thrombosis of an aneurysm and the parent artery without any
      clinical symptoms. This is the first case of complete spontaneous thrombosis of
      an aneurysm of the distal posterior cerebral artery. The mechanism of its
      development and spontaneous thrombosis in a fusiform aneurysm is discussed.

PMID- 12616657
TI  - [A case of the traumatic hydrocephalus after large craniectomy for acute subdural
      hematoma].
AB  - Decompressive craniectomy sometimes causes neurological deficits known as 'the
      syndrome of the sinking skin flap' or 'the symptom of the trephined'. These
      disorders can be corrected with cranioplasty, but there is no consensus on
      appropriate treatments. We report a case of successful correction of traumatic
      hydrocephalus following craniotomy. A 50-year-old man was admitted to our
      hospital with disturbance of consciousness after a head injury. Decompressive
      craniectomy was performed for a right acute subdural hematoma. His consciousness
      recovered after the operation, but then deteriorated gradually and left
      hemiparesis occurred. CT scan revealed midline shift from right to left. These
      symptoms and CT findings were not improved after cranioplasty, but were improved
      with removal of the CSF from the adhered subarachnoid space. The diagnosis was
      traumatic hydrocephalus, and a cisternoperitoneal shunt was subsequently placed.
      We report this case to emphasize the necessity for study of CSF circulation, as
      well as the importance of examination of CBF and ICP after craniectomy.

PMID- 12616658
TI  - [The improvement in regional cerebral blood flow in the anterior cranial fossa
      which was affected by a dural arteriovenous fistula: case report].
AB  - We report a case of dural arteriovenous fistula of the anterior cranial fossa
      with venous ischemia. A 55-year-old man presented with headache and visual
      disturbance. Neurological examination showed no abnormality. MR images
      demonstrated flow void at the right anterior cranial fossa. Right internal
      carotid angiograms showed a dural arteriovenous fistula of the anterior cranial
      fossa, fed by the anterior ethmoidal artery. The draining vein was the
      leptomeningeal vein draining into the basal vein, the straight sinus, and the
      left transverse sinus. 123I-IMP SPECT revealed a low perfusion area in the left
      occipital region. We interrupted the draining vein at the anterior cranial fossa.
      Angiographic cure was obtained and venous circulation was improved. 123I-IMP
      SPECT revealed improvement in the low perfusion area in the left occipital
      region. The postoperative course was uneventful. We discuss the clinical
      features, the hemodynamic findings and the management of this case.

PMID- 12616659
TI  - [Neurodegenerative disorders (2), System degeneration, no. 8 in series of
      articles: basic knowledge of neuropathology for neurosurgeons].

PMID- 12616660
TI  - [Progressing crisis of domestic medical insurance system in Japan, problems and
      proposals from neurosurgical practice, no. 12, in series of articles: controversy
      and reform proposals concerning insured medical care in neurosurgery].

PMID- 12616661
TI  - Safety and tolerability of the lidocaine patch 5%, a targeted peripheral
      analgesic: a review of the literature.
AB  - The safety, tolerability, and efficacy of the lidocaine patch 5% (Lidoderm), a
      targeted peripheral analgesic with an FDA-approved indication for the treatment
      of postherpetic neuralgia, has been well established. Recent case reports and
      studies have suggested potential efficacy in other neuropathic and nonneuropathic
      pain conditions. Several pharmacokinetic studies have demonstrated minimal
      systemic absorption with 12-, 18-, and 24-hour/day dosing. Mean maximum plasma
      concentrations have shown the lidocaine patch to possess a minimal risk for
      systemic toxicities or drug-drug interactions. The most common adverse events
      generally involve mild skin reactions. There have been no drug-drug interactions
      noted in clinical trials. Recent evidence suggests that extended application does
      not result in A-beta-mediated sensory loss at the application site, which is
      particularly important in patients who already have a degree of sensory loss due
      to their underlying condition. The lidocaine patch provides a treatment option
      that carries a relatively low systemic adverse event and drug-drug interaction
      risk burden, even with continuous application of up to four patches per day.

PMID- 12616662
TI  - Are coagulation times biomarkers? Data from a phase I study of the oral thrombin
      inhibitor LB-30057 (CI-1028).
AB  - Ecarin clotting time and activated partial thromboplastin time are coagulation
      tests that meet the definition of a biomarker. Prolongation of these coagulation
      times closely correlated with blood concentrations of the oral thrombin inhibitor
      LB-30057 (CI-1028) during a phase 1 study. But this simply reflects their
      functioning as enzyme inhibition assays of drug concentration. Directly adding
      the drug to blood results in the same concentration-response relationship.
      Changes in coagulation tests only demonstrate that ex vivo clot formation has
      been altered, not that an in vivo process has been affected. To be most
      informative in drug development, biomarker assays should measure in vivo drug
      effects, not drug concentrations.

PMID- 12616663
TI  - Effects of CYP2D6 genotypes on plasma concentrations of risperidone and
      enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia.
AB  - It has been shown that risperidone (+)-9-hydroxylation is enantioselectively
      catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine
      the effect of CYP2D6 genotype on (+)-9-hydroxylation of risperidone in
      schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients
      receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)-
      and (-)-9-hydroxyrisperidone at steady state were quantified using LC/MS/MS and
      HPLC with alpha 1 acid-AGP chiral column, respectively. The CYP2D6*5(*5) and *10
      alleles were identified using polymerase chain reaction (PCR) methods. Twenty
      patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated
      alleles. There were significant differences in the steady-state plasma
      concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype
      groups, while the CYP2D6 genotype did not affect the steady-state plasma
      concentrations of (+)-9-hydroxyrisperidone (p = 0.314) or (-)-9
      hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9
      hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study
      suggests that CYP2D6 activity strongly influences the steady-state plasma
      concentrations of risperidone and risperidone/9-hydroxyrisperidone concentration
      ratios but is unlikely to determine enantio-selectivity in the steady-state
      plasma concentrations of 9-hydroxyrisperidone in the clinical situation.

PMID- 12616664
TI  - Pharmacokinetics of quinapril in children: assessment during substitution for
      chronic angiotensin-converting enzyme inhibitor treatment.
AB  - Quinapril pharmacokinetics were studied in infants and children using a novel
      study design that allowed substitution of quinapril for one dose of the current
      chronic angiotensin-converting enzyme (ACE) inhibitor treatment. A total of 24
      patients ranging in age from 2.5 to 82 months who were receiving an ACE inhibitor
      held their usual treatment on the study day and received a 0.2-mg/kg dose of
      quinapril syrup. Blood samples were collected through 24 hours postdose, and
      plasma was analyzed for quinapril and its active metabolite, quinaprilat.
      Quinapril was rapidly converted to quinaprilat. Quinaprilat concentrations
      generally peaked 1 to 2 hours postdose and declined with a mean half-life of 2.30
      hours. Dosing on a mg/kg basis resulted in quinaprilat AUC and Cmax values that
      were generally comparable across the age range of patients in this study. The
      overall mean AUC0-infinity was 993 ng.h/mL (range: 533-1523), and mean Cmax was
      260 ng/mL (range: 70.0-445.5). Quinaprilat CL/F correlated well with body size
      (body surface area or weight) and creatinine clearance (mL/min). Pharmacokinetic
      results after a 0.2-mg/kg dose in infants and children are comparable to those
      observed following a 10-mg dose in adults.

PMID- 12616665
TI  - Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected
      infants and children.
AB  - The purpose of this study was to assess the population pharmacokinetics (PK) and
      pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This
      evaluation includes 394 subjects who participated in Pediatric AIDS Clinical
      Trials Group (PACTG) Study 152 and received either ZDV alone or in combination
      with didanosine. The most significant PK covariate was age, with infants < 2
      years of age having reduced size-adjusted clearance. ZDV exposure was weakly
      related to maximal reduction in immune complex-dissociated (ICD) p24 antigen but
      not to reduction at 6 months. Mild chronic anemia occurred in 7.6% of subjects
      with ZDV average concentration < 1.3 microM (350 ng/mL) versus in 23.4% subjects
      with higher ZDV concentrations (p < 0.001). There was a direct linear
      relationship between hemoglobin and ZDV levels. It was concluded that ZDV oral
      clearance is reduced in infants compared to older children. This lower clearance
      leads to higher ZDV exposure in infants and contributes to increased hematologic
      toxicity.

PMID- 12616666
TI  - Clinical development of an everolimus pediatric formulation: relative
      bioavailability, food effect, and steady-state pharmacokinetics.
AB  - The immunosuppressant everolimus used in organ transplantation is formulated as a
      conventional tablet for adults and a dispersible tablet that can be administered
      in water for pediatric use. As part of the pediatric clinical development
      program, the relative bioavailability and food effect for the dispersible tablet
      were evaluated in healthy adult subjects as a prelude to characterizing the
      steady-state pharmacokinetics in pediatric kidney allograft recipients. In a
      randomized, open-label, three-way crossover study, 24 healthy adults received
      single 1.5-mg oral doses of everolimus as (1) six 0.25-mg dispersible tablets in
      water, (2) two 0.75-mg conventional tablets, and (3) six 0.25-mg dispersible
      tablets in water after a high-fat breakfast. Cmax and AUC were evaluated by
      standard bioequivalence testing to determine relative bioavailability and to
      quantify the effect of food. In a multicenter open-label efficacy/safety trial,
      pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid
      everolimus as dispersible tablets in water. Serial trough concentrations over the
      first week and a steady-state pharmacokinetic profile on day 7 posttransplant
      were collected in 19 patients ranging from ages 2 to 16 years old. The
      bioavailability of everolimus from the dispersible tablet was 10% lower relative
      to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76
      1.07). After a high-fat meal, tmax was delayed by a median 2.5 hours, and Cmax
      was reduced by 50%. Overall absorption, however, was not affected by food
      inasmuch as the fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric
      patients, steady state was reached between days 3 and 5. The corresponding steady
      state parameters were as follows: Cmin, 4.4 +/- 1.7 ng/ml; Cmax, 13.6 +/- 4.2
      ng/ml; and AUC, 87 +/- 27 ng.h/ml. Steady-state concentration-time profiles in
      pediatric transplant patients receiving the dispersible tablet were comparable to
      those of adult patients receiving the conventional tablet when both were dosed to
      yield similar trough concentrations. If a pediatric patient is converted from the
      everolimus dispersible tablet to the conventional tablet, this should be based on
      a 1:1 milligram switch with subsequent therapeutic drug monitoring to further
      individualize the dose as needed. The dispersible tablet formulation should be
      taken consistently either with or without food to minimize fluctuations in
      exposure over time.

PMID- 12616667
TI  - The bioequivalence of nizatidine (Axid) in two extemporaneously and one
      commercially prepared oral liquid formulations compared with capsule.
AB  - Nizatidine (Axid) is an H2-receptor antagonist used for the treatment of acid
      related gastrointestinal disorders. Given the frequency of these conditions in
      children and the potential for pediatric use of nizatidine, an oral liquid dosage
      formulation would provide an alternative treatment option for patients unable to
      swallow solid oral dosage forms. This study was designed as an open-label, single
      dose, four-way crossover trial to investigate the bioequivalence of 150 mg
      nizatidine administered in three oral liquid formulations (a commercially
      prepared oral syrup, an extemporaneous solution in apple juice, and an
      extemporaneous suspension in infant formula) relative to the marketed capsule
      formulation. Twenty-four adult subjects (ages 31.2 +/- 7.5 years; weight 71.1 +/-
      11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine
      concentrations were collected prior to drug administration and at 19 discrete
      intervals over a 24-hour postdose interval. Nizatidine was quantitated from
      plasma using a validated HPLC-MS assay, and a noncompartmental approach was used
      to describe nizatidine biodisposition in all subjects. Significant treatment
      effects were observed for log-normalized Cmax, AUC0-n, and AUC0-infinity (p <
      0.001). Further evaluation revealed that nizatidine prepared in apple juice was
      markedly less bioavailable than the reference capsule, with 90% confidence
      intervals (CIs) of 0.518-0.626, 0.682-0.751, and 0.696-0.763 for Cmax, AUC0-n,
      and AUC0-infinity, respectively. The remaining two oral formulations demonstrated
      90% CI within the guidelines established by the Food and Drug Administration
      (e.g., 0.80-1.25). Thus, nizatidine in infant formula and the commercially
      prepared oral syrup can be considered bioequivalent to the reference capsule.

PMID- 12616669
TI  - Pharmacokinetics of nateglinide in renally impaired diabetic patients.
AB  - Treatment of hyperglycemia in patients with diabetes mellitus and renal
      insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents.
      This study evaluated the pharmacokinetic profile and safety of nateglinide, an
      amino acid derivative that improves early phase insulin secretion and reduces
      mealtime glucose excursions. This open-label, single-dose, two-center study
      included patients (mean age = 57 +/- 10 years) with type 1 or 2 diabetes with
      impaired renal function (IRF) (n = 10) or with renal failure undergoing
      hemodialysis (n = 10). Both groups were compared with age-, sex-, height-, and
      weight-matched healthy controls (n = 20). All participants received a single 120
      mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety
      evaluations were undertaken up to 48 hours postdose. All 40 subjects completed
      the study. Plasma nateglinide concentrations increased rapidly in patients
      undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h,
      respectively) and was comparable with patients with IRF and matched healthy
      subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically
      significant differences for Cmax or AUC0-t between the groups. Nateglinide was
      eliminated rapidly in all groups (t1/2 = 1.9-2.8 h). There was no correlation
      between the level of renal function and systemic exposure. There was a low extent
      of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients
      with IRF (3%). Nateglinide was well tolerated. These data suggest that
      nateglinide is suitable for use in diabetic patients with IRF or with renal
      failure undergoing dialysis. Given the comparable absorption and elimination
      profiles of nateglinide in renally impaired and healthy subjects, no dose
      adjustment appears necessary in the renally impaired.

PMID- 12616668
TI  - The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients
      with varying degrees of renal function.
AB  - An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid
      (Zometa) was performed in 19 cancer patients with bone metastases and known,
      varying levels of renal function. Patients were stratified according to
      creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min),
      mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50
      mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were
      administered at 1-month intervals between doses. Plasma concentrations and
      amounts excreted in urine were determined in all subjects, and 4 patients were
      administered 14C-labeled zoledronic acid to assess excretion and distribution of
      drug in whole blood. In general, the drug was well tolerated by the patients.
      Mean area under the plasma concentration versus time curve and mean concentration
      immediately after cessation of drug infusion were lower, and mean amounts
      excreted in urine over 24 hours from start of infusion were higher in normal
      subjects than in those with impaired renal function (36% vs. 28% of excreted
      dose), although the differences were not significant. Furthermore, with repeated
      doses, there was no evidence of drug accumulation in plasma or changes in drug
      exposure in any of the groups, nor was there any evidence of changes in renal
      function status. Serum levels of markers of bone resorption (serum C-telopeptide
      and N-telopeptide) were noticeably reduced after each dose of zoledronic acid
      across all three renal groups. It was concluded that in patients with mildly to
      moderately reduced renal function, dosage adjustment of zoledronic acid is likely
      not necessary.

PMID- 12616670
TI  - Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric
      hypoacidity.
AB  - To determine the impact of gastric hypoacidity and acidic beverages on
      delavirdine mesylate pharmacokinetics in HIV-infected subjects, matched subjects
      with (n = 11) and without (n = 10) gastric hypoacidity received delavirdine 400
      mg tid with either water or an acidic beverage (usually orange juice). The
      pharmacokinetics of delavirdine and its N-desalkyl metabolite were determined
      over 8 hours after 14 days of each treatment. Gastric pH was measured at baseline
      and during each pharmacokinetic evaluation. Delavirdine exposure (Cmax, AUC0-->8
      h, and Cmin) was approximately 50% lower and the extent of delavirdine metabolism
      was higher in subjects with gastric hypoacidity. Orange juice produced a lower
      mean gastric pH compared to water and increased delavirdine absorption by 50% to
      70% in subjects with gastric hypoacidity. However, orange juice had a marginal
      impact on delavirdine exposure in subjects without gastric hypoacidity. HIV
      infected subjects with gastric hypoacidity significantly malabsorb delavirdine.
      Delavirdine administration with acidic beverages improves, but dose not
      normalize, absorption in these subjects.

PMID- 12616671
TI  - Pharmacokinetic and safety assessments of concurrent administration of
      risperidone and donepezil.
AB  - Treatment of Alzheimer's disease sometimes uses combinations of drugs because
      dementia is frequently associated with behavioral symptoms. Risperidone and
      donepezil are both metabolized through cytochrome P450 2D6 and 3A4, raising the
      possibility of drug interactions with combination therapy. The objective of this
      study was to determine whether significant drug interactions occur with
      concomitant administration of donepezil and risperidone. In an open-label, three
      way crossover study, 24 healthy men were randomly assigned to receive 0.5 mg of
      risperidone twice daily, 5 mg of donepezil once daily, or both drugs for 14
      consecutive days, followed by a 21-day washout period. The treatment ratios of
      AUC and associated 90% confidence intervals (CIs) for risperidone active moiety,
      defined as risperidone plus 9-hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7
      117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0-103.6) were within the
      80% to 125% of bioequivalence range. The treatment ratios of Cmax and associated
      90% CIs for risperidone active moiety (ratio = 114.6%; 90% CI = 107.0-122.8) and
      for donepezil (ratio = 96.1%; 90% CI = 90.0-102.6) were also within the
      bioequivalence range. Therefore, no significant pharmacokinetic differences
      occurred in either risperidone active moiety or donepezil when given alone or in
      combination. Adverse events (predominantly headache, nervousness, and somnolence)
      were minor and comparable for all treatment groups. The results indicate that no
      clinically meaningful drug interactions occurred between risperidone 1 mg daily
      and donepezil 5 mg daily at steady state, and therefore no dosage adjustment is
      required when both drugs are combined with the dosage regimen studied. Additional
      investigations are warranted to determine the potential for interactions in
      elderly patients with dementia who may eliminate risperidone and donepezil more
      slowly and thus be more vulnerable to clinical drug interactions than the young
      healthy subjects examined in this study.

PMID- 12616672
TI  - Effect of rofecoxib on prednisolone and prednisone pharmacokinetics in healthy
      subjects.
AB  - Patients receiving nonsteroidal anti-inflammatory drug therapy may also require
      administration of corticosteroids, particularly patients with rheumatoid
      arthritis. To investigate the effect of rofecoxib on the single-dose
      pharmacokinetics of oral prednisone and intravenous prednisolone, the authors
      conducted a randomized, double-blind, placebo-controlled crossover study in 12
      healthy subjects. Oral rofecoxib (250.0 mg/day for 14 days) failed to influence
      prednisone or prednisolone pharmacokinetics after intravenous prednisolone or
      oral prednisone administration. The geometric mean ratio (GMR) (90% confidence
      interval) of prednisolone AUC infinity (rofecoxib/placebo) following intravenous
      and oral corticosteroid was 0.97 (0.94, 1.01) and 0.99 (0.91, 1.08),
      respectively. Similarly, the prednisone AUC infinity GMRs (rofecoxib/placebo)
      after intravenous and oral corticosteroid were 1.03 (0.95, 1.11) and 1.08 (0.92,
      1.28), respectively. The absence of an effect of rofecoxib on the
      pharmacokinetics of oral prednisone or intravenous prednisolone indicates that no
      adjustment in dose of this corticosteroid is necessary when administered
      concurrently with rofecoxib.

PMID- 12616673
TI  - Effect of inhaled steroids on bone mineral density: a meta-analysis.
AB  - Inhaled corticosteroids are currently considered first-line agents for the
      treatment of asthma. Medium- to long-term administration of inhaled steroids may
      be associated with bone loss. Various studies have evaluated their effect on bone
      mineral density (BMD); some have shown loss of BMD with steroid treatment, but
      others have failed to do so. The present meta-analysis was undertaken to
      determine the possible effect of inhaled steroids on bone density. Literature was
      collected using computerized (MEDLINE) and manual searches using index medicus
      and checking cross-references of the published articles. The studies identified
      were screened for inclusion/exclusion criteria. Grouped means (XT/XC) and pooled
      standard deviations (SDT/SDC) for the treatment group (XT[95% CI] = 1.144 [1.019
      1.269]; SDT = 0.163, g/cm2) and control group (XC [95% CI] = 1.193 [1.073-1.313];
      SDC = 0.157, g/cm2) were worked out respectively for the selected studies.
      Finally, a comparison between grouped means of steroid-treated and control groups
      was done by two-sample t-test at the 5% level of significance. The results of the
      meta-analysis showed that although the mean BMD of the steroid-treated group was
      reduced by 4.1% as compared to the control group, this failed to achieve
      statistical significance (p = 0.8; 95% CI for the mean difference between two
      groups = 0.028-0.070 g/cm2). It is concluded that inhaled steroids for the
      treatment of asthma can be considered safe with respect to their effect on bone
      loss.

PMID- 12616674
TI  - Pediatric neurology, Part I. Preface.

PMID- 12616675
TI  - Brain development and the genetics of brain development.
AB  - The progress made in the understanding of the genetics of human brain
      malformations has lead to insight into the formation of brain and into mechanisms
      of disease affecting brain. It bears upon neurologists and geneticists to
      recognize the patterns of diseases of brain formation, to properly diagnose such
      disorders, to assess the recurrence risk of these malformations, and to guide
      families with appropriate expectations for outcomes. This article may serve as a
      guide to neurologists in their approach to these disorders. Because this area is
      one of rapid progress, the clinician is advised to seek more current information
      that may be available through on-line databases and other sources.

PMID- 12616676
TI  - Tuberous sclerosis complex and neurofibromatosis type 1: the two most common
      neurocutaneous diseases.
AB  - TSC and NF1 are the most common of the neurocutaneous diseases, and both are
      autosomal dominant with a high spontaneous mutation rate. For diagnosis, two
      features are necessary for each disease. Skin findings for each are especially
      helpful for diagnosis, as is neuroimaging in TSC. For NF1, neuroimaging is not
      yet reliable for diagnosis. In children, brain symptoms cause most of the
      morbidity in TSC, and nerve sheath and nervous system tumors as well as learning
      disabilities cause major morbidity in NF1. Renal disease becomes a serious
      problem for adults with TSC. The TSC1, TSC2, and NF1 genes function as tumor
      suppressor genes and have other functions that are being investigated. Blood
      tests for diagnosis have a high false-negative rate. Therapies for TSC and for
      NF1 are both medical and surgical.

PMID- 12616677
TI  - Neuroradiology of the central nervous system in childhood.
AB  - The purpose of this article is to familiarize readers with new imaging
      applications, identify the relative strengths of imaging modalities, and
      emphasize practical applications of imaging the child's nervous system. Because
      of recent advances in MRI, the article emphasizes the expanding role of MRI in
      evaluating children with neurologic disease.

PMID- 12616678
TI  - HIV-1 infection and AIDS.
AB  - Since the initial descriptions of AIDS in the late 1970s, much has been learned
      about the biology of HIV-1 and the cells it infects. Much has also been learned
      about mother-to-infant viral transmission and the natural history of HIV-1
      infection. Key studies led to strategies for interrupting mother-to-infant
      transmission, resulting in a significant decline in neonatal HIV-1 infection.
      More proficient diagnostic techniques made early diagnosis of HIV-1-infected
      neonates and infants possible during asymptomatic or mildly symptomatic disease
      stages. Major advances in treatment led to the control of viral replication and
      thereby altered the course of disease progression. HIV-1/AIDS-associated
      neurologic disorders declined in parallel. In countries where these therapies are
      readily available, a dramatic decline in the number of infants born HIV-1
      infected has been realized as has a markedly improved survival rate of those
      infected. Many questions remain, however. The long-term effects of prenatal
      exposure to antiretroviral agents are not yet known and continue to be studied.
      Just exactly how HAART therapy may affect early signs of pediatric HIV-1/AIDS
      associated CNS disease, should they develop, is unclear. As new anti-retroviral
      agents are developed and new combination drug regimens are instituted, the
      potential for neurologic complications, toxicities, and adverse drug interactions
      (e.g., with antiepileptic drugs (AEDS)) exists and needs to be identified and
      monitored.

PMID- 12616679
TI  - Meningitis and encephalitis in children. An update.
AB  - Over the course of the past decade, much has changed on the landscape of
      meningitis and encephalitis in children. West Nile virus has emerged in the
      United States as a new etiologic pathogen causing encephalitis. Human herpesvirus
      6 has been identified as a cause of encephalitis and febrile seizures.
      Lymphocytic choriomeningitis virus has been identified as an underrecognized
      neuroteratogen. The emergence of penicillin-resistant Streptococcus pneumoniae
      has complicated the treatment of bacterial meningitis, whereas the Haemophilus
      influenzae vaccine has fundamentally altered the disease's epidemiology. The
      recognition that much of the neuropathologic change induced by bacterial
      meningitis is inflammation mediated has paved the way to the demonstration that
      dexamethasone can substantially improve the outcome of bacterial meningitis in
      children. Although much progress has been made toward understanding, treating,
      and preventing these important infections, much remains to be learned.

PMID- 12616680
TI  - Congenital infections.
AB  - Despite major medical advances, such as the introduction of the rubella vaccine
      and prolonged postnatal therapy of infants with congenital toxoplasmosis,
      intrauterine infections remain important causes of deafness, vision loss, and
      behavioral or neurologic disorders among children worldwide. This article
      describes the common pathogens causing intrauterine infections and summarizes the
      current status of diagnosis, treatment, and prevention.

PMID- 12616681
TI  - Cerebral venous thrombosis and venous malformations in children.
AB  - Venous strokes are not as common as arterial strokes in the pediatric population,
      but may be associated with significant mortality and morbidity. Cerebral vein
      thrombosis and venous sinus thrombosis are responsible for most venous strokes.
      Vein of Galen malformation is a rare but important cause of mortality in neonates
      and infants. Awareness of these potential causes of stroke in the pediatric
      population, early diagnosis, and appropriate therapeutic strategies are paramount
      to reduce mortality and improve neurologic outcome.

PMID- 12616682
TI  - Arterial strokes in children.
AB  - Pediatric stroke has received special attention in the recent literature. It is
      now recognized as an important cause of mortality and morbidity in pediatric
      population. Varied and poorly specific symptomatology as well as overlapping risk
      factors makes the diagnosis of stroke in childhood challenging. Therapy remains
      controversial. The use of anticoagulation and thrombolysis in the management of
      acute stroke in children has not been systematically studied. In this article, we
      discuss the natural history, investigation, and treatment of pediatric arterial
      hemorrhagic and ischemic strokes.

PMID- 12616683
TI  - Movement disorders in children and adolescents.
AB  - Tourette syndrome (TS), Sydenham chorea, and drug-induced dyskinesias are
      prototypical movement disorders affecting children. Underlying involvement of
      basal ganglia has been apparent for several decades, but new neuroimaging studies
      are adding detail to this mechanism. Genetic studies of TS and tardive dyskinesia
      may further reveal the underlying pathophysiology. Most provocative is the new
      conceptual model of poststreptococcal autoimmune neuropsychiatric disorder.
      Although unproven, substantial support for this model comes from immunologic,
      family, neuroimaging, and treatment studies.

PMID- 12616684
TI  - Rett syndrome. Current status and new vistas.
AB  - RS, the most common cause of profound cognitive impairment in girls and women, is
      composed of characteristic clinical features, including communication
      dysfunction, stereotypic movements, and pervasive growth failure. Neuropathologic
      findings indicate a failure of neuronal maturation with too small neurons and too
      few dendritic arbors and no evidence of a progressive neurodegenerative process.
      The combination of clinical and neuropathologic characteristics presents the
      profile of a neurodevelopmental disorder. Mutations in the gene MECP2, which
      encodes MeCP2, have been identified in 80% to 85% of girls and women with RS.
      Furthermore, the panorama of phenotypes with MECP2 mutations now extends far
      beyond RS to include normal girls and women, mild learning disability, autistic
      spectrum disorders, and X-linked mental retardation. These rapid advances in our
      understanding of RS over the past three decades have opened new avenues of study
      in developmental neurobiology.

PMID- 12616685
TI  - Diagnosis and treatment of neurotransmitter-related disorders.
AB  - Neurotransmitter disorders constitute a spectrum of neurologic conditions that
      share several clinical features depending on the severity and pattern of
      neurotransmitter deficiency or excess. These uncommon conditions can be suspected
      based on their clinical features, and several can be confirmed by cerebrospinal
      fluid analysis of neurotransmitters and their metabolites. Certain disorders,
      such as autosomal dominant dopa-responsive dystonia caused by GTP cyclohydrolase
      deficiency, or Segawa syndrome, respond dramatically to medical therapy. This
      article summarizes current knowledge regarding the clinical manifestations,
      diagnosis, and treatment of these important disorders.

PMID- 12616687
TI  - Intractable pediatric epilepsy: vagal nerve stimulation and the ketogenic diet.
AB  - The KD has been proven an effective alternative epilepsy treatment in children
      refractory to standard anticonvulsants. Children to be placed on the diet must be
      carefully selected, monitored, and followed. The diet is to be regarded as a
      strict medical regimen and requires a comprehensive medical team approach in
      concert with intensive parental involvement. With better understanding of the
      scientific principles underlying brain ketosis, we should be able to optimize the
      KD to achieve even better results.

PMID- 12616688
TI  - Epilepsy surgery. Presurgical evaluation.
AB  - The presurgical evaluation should result in a clear understanding of whether
      surgery can be undertaken and its associated risks and potential for benefit. The
      results of surgery are best when there is congruence in the seizure semiology,
      the irritative zone on interictal EEG, and the ictal onset zone with the
      epileptogenic lesion as defined on MRI and PET, and when there is a clear
      understanding of the ictal onset zone's relationship to eloquent cortex as
      defined by neuropsychologic evaluation, the intracarotid amobarbital test, and
      cortical functional mapping.

PMID- 12616686
TI  - New antiepileptic drug therapies.
AB  - The introduction of these new antiepileptic drugs, from felbamate to
      levetiracetam, raised hope of control of epilepsy with fewer adverse effects and
      improved quality of life. Unfortunately, many patients continue to experience
      refractory epilepsy despite the use of these new agents, and dose-related adverse
      effects and idiosyncratic reactions continue to be problematic. A recent report
      describes six new compounds in preclinical development, and five in clinical
      trials [131]. As the number of available, effective, but imperfect antiepileptic
      drugs increases, many challenges remain. These include: choosing the drug
      appropriate for the epileptic syndrome, assessing accurately the range of a
      drug's adverse effects in an individual patient, and considering carefully the
      drug's interactions in combination drug therapy. In considering drug
      combinations, differing mechanisms of drug action and favorable pharmacodynamic
      interactions (an area requiring additional studies) are of importance. Clinicians
      caring for children who have epilepsy anticipate further advances in the
      pharmacogenetics and molecular pathophysiology of epilepsy, leading to
      individually tailored, effective, and safe therapy.

PMID- 12616689
TI  - Amplification of HMG-CoA reductase production enhances carotenoid accumulation in
      Neurospora crassa.
AB  - Neurospora crassa, a filamentous fungus, naturally produces the carotenoids
      lycopene and neurosporaxanthin. To increase the carbon flux through the
      carotenoid biosynthetic pathway, the 1658-bp region of the HMG1 gene encoding the
      catalytic domain (cHMG1) of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase of Saccharomyces cerevisiae was expressed in N. crassa under control of
      the strong, constitutive glyceraldehyde-3-phosphate dehydrogenase (GPD) promoter
      and the inducible alcohol dehydrogenase (alcA) promoter. Overexpressing cHMG1
      under control of the GPD promoter increased lycopene and neurosporaxanthin
      production 6- and 1.5-fold, respectively, relative to the wild-type strain. Over
      expression of cHMG1 under control of the alcA promoter increased production of
      lycopene and neurosporaxanthin 3- and 2-fold, respectively.

PMID- 12616690
TI  - Metabolic flux analysis in Synechocystis using isotope distribution from 13C
      labeled glucose.
AB  - Using the carbon isotope labeling technique, the response of cyanobacterial
      central carbon metabolism to the change in environmental conditions was
      investigated. Synechocystis was grown in the heterotrophic and mixotrophic
      cultures fed with 13C-labeled glucose. The labeling patterns of the amino acids
      in biomass hydrolysates for both cultures were detected by the two-dimensional 1H
      13C correlation nuclear magnetic resonance (2D 1H-13C COSY NMR) spectroscopy and
      gas chromatography-mass spectrometry (GC-MS) technique. The in vivo intracellular
      flux distributions were then quantitated from the labeling measurements and
      metabolite balances using a parameters fitting approach. From the estimated flux
      distributions, it was found that the pentose phosphate pathway was the major
      pathway of glucose catabolism in the heterotrophic culture, while in the
      mixotrophic culture, the flux of CO2 fixation through the Calvin cycle was about
      two-fold of the glucose input flux. The relative flux through the
      phosphoenolpyruvate carboxylase was very high in both cultures, and this reaction
      represented about 25% of the assimilated CO2 in the mixotrophic culture. More
      importantly, we found a substantial outflow from the tricarboxylic acid cycle to
      glycolysis pathway carried by the malic enzyme, demonstrating the operation of a
      C4 pathway in cyanobacterial cells through the PEP carboxylase and malic enzyme.
      The estimated flux distributions also revealed that the NADPH synthesis was in
      excess relative to its requirement, and the excess NADPH might be reoxidized in
      cyanobacterial respiration to provide the energy for cellular requirement.
      Moreover, the analyzed result also suggested that the activity of the respiratory
      electron transport chain in cyanobacterial cells was not inhibited by light.

PMID- 12616691
TI  - Metabolic engineering of Escherichia coli: increase of NADH availability by
      overexpressing an NAD(+)-dependent formate dehydrogenase.
AB  - Metabolic engineering studies have generally focused on manipulating enzyme
      levels through either the amplification, addition, or deletion of a particular
      pathway. However, with cofactor-dependent production systems, once the enzyme
      levels are no longer limiting, cofactor availability and the ratio of the reduced
      to oxidized form of the cofactor can become limiting. Under these situations,
      cofactor manipulation may become crucial in order to further increase system
      productivity. Although it is generally known that cofactors play a major role in
      the production of different fermentation products, their role has not been
      thoroughly and systematically studied. However, cofactor manipulations can
      potentially become a powerful tool for metabolic engineering. Nicotinamide
      adenine dinucleotide (NAD) functions as a cofactor in over 300 oxidation
      reduction reactions and regulates various enzymes and genetic processes. The
      NADH/NAD+ cofactor pair plays a major role in microbial catabolism, in which a
      carbon source, such as glucose, is oxidized using NAD+ producing reducing
      equivalents in the form of NADH. It is crucially important for continued cell
      growth that NADH be oxidized to NAD+ and a redox balance be achieved. Under
      aerobic growth, oxygen is used as the final electron acceptor. While under
      anaerobic growth, and in the absence of an alternate oxidizing agent, the
      regeneration of NAD+ is achieved through fermentation by using NADH to reduce
      metabolic intermediates. Therefore, an increase in the availability of NADH is
      expected to have an effect on the metabolic distribution. This paper investigates
      a genetic means of manipulating the availability of intracellular NADH in vivo by
      regenerating NADH through the heterologous expression of an NAD(+)-dependent
      formate dehydrogenase. More specifically, it explores the effect on the metabolic
      patterns in Escherichia coli under anaerobic and aerobic conditions of
      substituting the native cofactor-independent formate dehydrogenase (FDH) by and
      NAD(+)-dependent FDH from Candida boidinii. The over-expression of the NAD(+)
      dependent FDH doubled the maximum yield of NADH from 2 to 4 mol NADH/mol glucose
      consumed, increased the final cell density, and provoked a significant change in
      the final metabolite concentration pattern both anaerobically and aerobically.
      Under anaerobic conditions, the production of more reduced metabolites was
      favored, as evidenced by a dramatic increase in the ethanol-to-acetate ratio.
      Even more interesting is the observation that during aerobic growth, the
      increased availability of NADH induced a shift to fermentation even in the
      presence of oxygen by stimulating pathways that are normally inactive under these
      conditions.

PMID- 12616692
TI  - The effect of increasing NADH availability on the redistribution of metabolic
      fluxes in Escherichia coli chemostat cultures.
AB  - It is generally known that cofactors play a major role in the production of
      different fermentation products. This paper is part of a systematic study that
      investigates the potential of cofactor manipulations as a new tool for metabolic
      engineering. The NADH/NAD+ cofactor pair plays a major role in microbial
      catabolism, in which a carbon source, such as glucose, is oxidized using NAD+ and
      producing reducing equivalents in the form of NADH. It is crucially important for
      continued cell growth that NADH be oxidized to NAD+ and a redox balance be
      achieved. Under aerobic growth, oxygen is used as the final electron acceptor.
      While under anaerobic growth, and in the absence of an alternate oxidizing agent,
      the regeneration of NAD+ is achieved through fermentation by using NADH to reduce
      metabolic intermediates. Therefore, an increase in the availability of NADH is
      expected to have an effect on the metabolic distribution. We have previously
      investigated a genetic means of increasing the availability of intracellular NADH
      in vivo by regenerating NADH through the heterologous expression of an NAD(+)
      dependent formate dehydrogenase and have demonstrated that this manipulation
      provoked a significant change in the final metabolite concentration pattern both
      anaerobically and aerobically (Berrios-Rivera et al., 2002, Metabolic engineering
      of Escherichia coli: increase of NADH availability by overexpressing an NAD(+)
      dependent formate dehydrogenase, Metabolic Eng. 4, 217-229). The current work
      explores further the effect of substituting the native cofactor-independent
      formate dehydrogenase (FDH) by an NAD(+)-dependent FDH from Candida boidinii on
      the NAD(H/+) levels, NADH/NAD+ ratio, metabolic fluxes and carbon-mole yields in
      Escherichia coli under anaerobic chemostat conditions. Overexpression of the
      NAD(+)-dependent FDH provoked a significant redistribution of both metabolic
      fluxes and carbon-mole yields. Under anaerobic chemostat conditions, NADH
      availability increased from 2 to 3 mol NADH/mol glucose consumed and the
      production of more reduced metabolites was favored, as evidenced by a dramatic
      increase in the ethanol to acetate ratio and a decrease in the flux to lactate.
      It was also found that the NADH/NAD+ ratio should not be used as a sole indicator
      of the oxidation state of the cell. Instead, the metabolic distribution, like the
      Et/Ac ratio, should also be considered because the turnover of NADH can be fast
      in an effort to achieve a redox balance.

PMID- 12616693
TI  - The effect of NAPRTase overexpression on the total levels of NAD, the NADH/NAD+
      ratio, and the distribution of metabolites in Escherichia coli.
AB  - Escherichia coli (E. coli) maintains its total NADH/NAD+ intracellular pool by
      synthesizing NAD through the de novo pathway and the pyridine nucleotide salvage
      pathway. The salvage pathway recycles intracellular NAD breakdown products and
      preformed pyridine compounds from the environment, such as nicotinic acid (NA).
      The enzyme nicotinic acid phosphoribosyltransferase (NAPRTase; EC 2.4.2.11),
      encoded by the pncB gene, catalyzes the formation of nicotinate mononucleotide
      (NAMN), a direct precursor of NAD, from NA. This reaction is believed to be the
      rate-limiting step in the NAD salvage pathway. The current study investigates the
      effect of overexpressing the pncB gene from Salmonella typhimurium on the total
      levels of NAD, the NADH/NAD+ ratio, and the production of different metabolites
      in E. coli under anaerobic chemostat conditions and anaerobic tube experiments.
      In addition, this paper studies the effect of combining the overexpression of the
      pncB gene with an NADH regeneration strategy that increases intracellular NADH
      availability, as we have previously shown. (The effect of increasing NADH
      availability on the redistribution of metabolic fluxes in Escherichia coli
      chemostat cultures, Metabolic Eng. 4, 230-237; Metabolic engineering of
      Escherichia coli: Increase of NADH availability by overexpressing an NAD(+)
      dependent formate dehydrogenase, Metabolic Eng. 4, 217-229.) Overexpression of
      the pncB gene in chemostat experiments increased the total NAD levels, decreased
      the NADH/NAD+ ratio, and did not significantly redistribute the metabolic fluxes.
      However, under anaerobic tube conditions, overexpression of the pncB gene led to
      a significant shift in the metabolic patterns as evidenced by a decrease in
      lactate production and an increase as high as two-fold in the ethanol-to-acetate
      (Et/Ac) ratio. These results suggest that under chemostat conditions the total
      level of NAD is not limiting and the metabolic rates are fixed by the system at
      steady state. On the other hand, under transient conditions (such as those in
      batch cultivation) the increase in the total level of NAD can increase the rate
      of NADH-dependent pathways (ethanol) and therefore change the final distribution
      of metabolites. The effect of combining overexpression of the pncB gene with the
      substitution of the native cofactor-independent formate dehydrogenase (FDH) with
      an NAD(+)-dependent FDH was also investigated under anaerobic tube conditions.
      This manipulation produced a metabolic pattern that combines a high Et/Ac ratio
      similar to that obtained with the new FDH with an intermediate lactate level
      similar to that obtained with the overexpression of the pncB gene. It was found
      that addition of the pncB gene to the FDH system does not increase further the
      production of reduced metabolites because the system for NADH regeneration
      already reached the maximum theoretical yield of approximately 4 mol NADH/mol of
      glucose.

PMID- 12616694
TI  - Metabolic flux analysis of Candida tropicalis growing on xylose in an oxygen
      limited chemostat.
AB  - We have studied the metabolism of xylose by Candida tropicalis in oxygen-limited
      chemostat. In vitro enzyme assays indicated that glycolytic and gluconeogenetic
      enzymes are expressed simultaneously facilitating substrate cycling. Enhancing
      the redox imbalance by cofeeding of formate increased xylose and oxygen
      consumption rates and ethanol, xylitol, glycerol and CO2 production rates at
      steady state. Metabolic flux analysis (MFA) indicated that fructose 6-phosphate
      is replenished from the pentose phosphate pathway in sufficient amounts without
      contribution of the gluconeogenetic pathway. Substrate cycling between pyruvate
      kinase, pyruvate carboxylase and phospho-enol-pyruvate kinase increased ATP
      turnover. Cofeeding of formate increased the ATP yield. The ATP yields of xylose
      and xylose-formate cultivation were 6.9 and 8.7 mol ATP/C-mol CDW, respectively,
      as calculated from the MFA.

PMID- 12616695
TI  - Quantification of metabolic flux in plant secondary metabolism by a biogenetic
      organizational approach.
AB  - Metabolic engineering represents a promising approach to enhance the yield of
      valuable natural products from plants. A method to quantify flux through
      metabolite measurements is necessary for the analysis of native and modified
      pathways. Rather than focusing only on the accumulation of the final products,
      analyzing a wide range of secondary metabolites has significant advantages. We
      propose a model that organizes the flux analysis by grouping metabolites of
      similar biosynthetic origin. To this end, we have quantified temporal profiles of
      metabolites from several branches of the indole alkaloid pathway in Catharanthus
      roseus hairy root cultures. By analyzing these data, we are able to examine the
      distribution of flux around key branchpoints. Furthermore, this analysis provides
      crucial information such as an estimate of total flux to secondary metabolism.

PMID- 12616696
TI  - Allogeneic stem cell transplantation for multiple myeloma.
AB  - The sensitivity of myeloma cells to high dose chemotherapy has led to the use of
      allogeneic hematopoietic stem cell transplantation (HSCT) as a therapeutic
      modality in this disease. In addition to providing more effective chemotherapy,
      the transplantation of allogeneic stem cells also initiates the development of an
      allogeneic immune response directed against residual myeloma cells. Direct
      evidence for a graft vs. myeloma (GVM) effect is provided by the ability of donor
      lymphocyte infusion (DLI) to induce significant responses in 30-50% of patients
      with myeloma who have relapsed after allogeneic HSCT. Nevertheless, allogeneic
      stem cell transplantation is also associated with a high incidence of transplant
      related toxicities, including regimen-related toxicities, graft vs. host disease
      (GVHD) and opportunistic infections. DLI has been shown to enhance immune
      reconstitution after allogeneic HSCT in addition to inducing a GVM response.
      Current efforts are directed at reducing the toxicities associated with
      allogeneic HSCT, identification of the target antigens of GVM and the development
      of new strategies to selectively enhance the immune response to myeloma cells.

PMID- 12616697
TI  - Monoclonal gammopathies of undetermined significance.
AB  - The term 'monoclonal gammopathy of undetermined significance' denotes the
      presence of a monoclonal protein in patients without evidence of multiple
      myeloma, macroglobulinemia, amyloidosis or related plasma cell proliferative
      disorders. The disorder has been found in approximately 3% of persons older than
      70 years and in approximately 1% of persons older than 50 years. A population
      based study included 1384 patients from south-eastern Minnesota who had the
      disorder diagnosed at the Mayo Clinic from 1960 through 1994. Risk of progression
      was about 1% per year, but patients were at risk of progression even after 25
      years or more of stable monoclonal gammopathy of undetermined significance. The
      risk for development of multiple myeloma was increased 25-fold; the risk of
      macroglobulinemia, 46-fold; and the risk of primary amyloidosis, 8.4-fold.
      Concentration and type of monoclonal protein were the only independent predictors
      of progression. The presence of a urine monoclonal protein and the reduction of
      one or more uninvolved immunoglobulins were not risk factors for progression.
      Monoclonal gammopathy of undetermined significance may be associated with various
      disorders, including lymphoproliferative diseases, leukemia, von Willebrand
      disease, connective tissue diseases and neurologic disorders.

PMID- 12616698
TI  - Management of multiple myeloma.
AB  - There has been no improvement in the treatment of multiple myeloma (MM) during
      the last decades and two meta-analyses of randomized trials recorded no
      significant survival benefit for combination chemotherapy compared to the classic
      melphalan-prednisone combination. However the past 15 years has seen several
      innovative strategies which have dramatically modified the management of MM. In
      younger patients, high-dose therapy with autologous stem cell transplantation is
      considered to be superior to conventional chemotherapy and is used as part of
      front-line therapy. A number of issues have been addressed in recent trials in
      order to improve the results of autologous transplantation (source of stem cells,
      conditioning regimen, impact of double transplants, maintenance therapy).
      Bisphosphonates reduce the incidence of skeletal-related events and improve the
      quality of life. Recombinant erythropoietin reduces red blood cell transfusion
      need and improves the quality of life. Thalidomide has been introduced more
      recently. Phase II studies with thalidomide alone or combined with dexamethasone
      have shown impressive response rates and this drug is currently being evaluated
      as part of front-line therapy. Finally, analysis of prognostic factors such as
      beta 2 microglobulin and cytogenetics define subgroups of patients with a
      completely different outcome and help the process of selecting therapeutics
      strategies.

PMID- 12616699
TI  - The biology and cytogenetics of multiple myeloma.
AB  - Despite the advances in our knowledge of myeloma cell biology, our understanding
      of myeloma pathogenesis is still incomplete. In this review, we present a summary
      of the cellular and molecular aspects of B-cell development and immunoglobulin
      (lg) gene rearrangement which have been important in defining the characteristics
      of the myeloma plasma cell (MPC). The PMC has undergone variable gene
      recombination, somatic hypermutation and isotype switching, and is therefore at a
      postgerminal center stage of development. The finding of preswitch clonal cells
      and isotype variants have raised interesting questions about the cell of origin
      of myeloma, for which no conclusive data is as yet available. However much
      information has been obtained about the chromosomal and genetic aberrations in
      myeloma, including monosomy 13, Ig heavy chain (IgH) switch region
      translocations, numerical abnormalities and a multitude of heterogeneous changes.
      A variety of techniques have been developed to overcome the insensitivity of
      conventional karyotyping, utilizing molecular cytogenetic strategies ranging from
      the delineation of precise loci by fluorescent in situ hybridization, a more
      "global" assessment of the genome by multicolor spectral karyotyping, to the
      quantitation of chromosomal material of specific origin by comparative genomic
      hybridization. Whether the abnormalities detected represent oncogenic insults,
      are involved in disease progression or are simply "by-products" of genetic
      instability is still unclear. For IgH translocations, the role of candidate genes
      such as Cyclin D1 and FGFR3 has been studied extensively by quantitating their
      expression and assessment of their oncogenicity (e.g. for FGFR3) in animal
      models. The significance of other aberrations such as c-myc, ras and p53 has also
      been investigated. With the advent of oligonucleotide microarrays, the expression
      of thousands of genes can be efficiently examined. So far, this approach seems
      promising in defining subgroups of different disease behavior, and may highlight
      specific genes and molecular mechanisms which are important in myeloma
      pathogenesis.

PMID- 12616700
TI  - Novel biologically based therapeutic strategies in myeloma.
AB  - Multiple myeloma remains incurable despite advances in conventional chemotherapy
      and wider applicability of high dose chemotherapy with single and/or tandem
      autologous peripheral blood stem cell transplantation. Although a complete
      remission rate of 41% and an event-free survival of 43 months have been reported
      after tandem transplantation, it is highly unlikely that further improvements in
      the outcome of multiple myeloma will be achieved by escalating cytotoxic
      chemotherapy alone. Novel biologically based therapies are therefore urgently
      required. Targeted therapeutic approaches based on: identification of genetic
      abnormalities in malignant plasma cells; interrupting growth of myeloma cells;
      triggering apoptotic signaling cascades in tumor cells; modulating growth and
      survival of multiple myeloma cells in the bone marrow microenvironment, i.e.
      angiogenesis and cytokine networks; enhancing allogeneic and autologous
      antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy
      are under development. These therapies offer great promise, used alone/or in
      combination with conventional treatment approaches, to improve the outcome in
      this disease in newly diagnosed/refractory or relapsed patients with multiple
      myeloma.

PMID- 12616701
TI  - Laser-Doppler imaging of activation-flow coupling in the somatosensory cortex:
      normalization of signal when the baseline changes significantly.
AB  - This study describes two approaches used to normalize the laser-Doppler flowmetry
      (LDF) signal, corresponding to the regional cerebral blood flow (rCBF) response
      after electrical hind-paw stimulation. The first approach divides the LDF signal
      to the baseline and subsequently integrates the response curve from the rise
      point to the termination point (defined formally as "normalized rCBF response",
      and the second subtracts the baseline from the LDF signal and subsequently
      integrates the response curve from the rise point to the termination point
      (defined as "absolute rCBF response"). Both parameters are given in arbitrary
      units. A comparative analysis of the changes in the "normalized" and "absolute"
      LDrCBF response is presented both for when the baseline does not change
      significantly, and for when the baseline changes significantly under the
      influence of different factors. In summary, when the baseline changes
      significantly it is preferable to normalize the LDrCBF response towards the
      baseline by subtraction, not by division.

PMID- 12616702
TI  - The pyridoindole antioxidant stobadine attenuates albuminuria, enzymuria, kidney
      lipid peroxidation and matrix collagen cross-linking in streptozotocin-induced
      diabetic rats.
AB  - The aim of the present study was to investigate the effect of dietary
      supplementation with the pyridoindole antioxidant stobadine on kidney status and
      function in streptozotocin-induced diabetic rats. Diabetic male Wistar rats were
      fed a standard diet for 32 weeks or a diet supplemented with stobadine (0.05%
      w/w). The diabetic state was characterized by significantly elevated plasma
      levels of glucose, HbA1c and urea, severe reduction of total body weight and
      relatively enlarged kidneys. Elevated levels of conjugated dienes were recorded
      in the diabetic kidney confirming the presence of oxidative stress in diabetic
      animals. All diabetic rats showed marked proteinuria and albuminuria along with
      elevated excretion of the enzyme N-acetyl-beta-D-glucosaminidase. Long-term
      treatment of diabetic animals with stobadine significantly reduced total
      proteinuria, albuminuria and enzymuria, yet left the overall physical and
      glycemic status unaffected. It reduced oxidative damage of kidney tissue as shown
      by decreased conjugated diene level, and decreased matrix collagen cross-linking,
      as indicated by decreased breaking time values of rat tail tendons. These
      beneficial effects of stobadine, supported also by histological findings, may be
      brought about by virtue of the combination of its antioxidant potential with
      other effects, e.g., the postulated cholesterol-lowering ability or its ability
      to alter vascular reactivity and reduce the vascular tone.

PMID- 12616703
TI  - Enhancement in immune function and growth using E-JUR-94013 supplementation.
AB  - Animal studies suggest that fish oils are capable of modulating the cell
      functions of immune system and there is some evidence that the effects of fish
      oils on immune function are due to fatty acids rather than trace elements or
      antioxidants. The major objectives of this study were: i) to identify a fish
      species with high nutritional value able to improve pig feeding conditions; ii)
      to utilize diets that modulate the immune system early in life in pigs and; iii)
      to enhance growth rate on a physiological basis. With the aim of maximizing
      feeding intake after weaning in order to reduce stress and increase growth rate,
      a study was carried out on 300 pigs supplemented with different fish extracts
      obtained by advanced biotechnological methods. The results of this work suggest
      that the lipoproteins obtained from the Trachurus trachurus (E-JUR-94013) species
      may have a great effect as both an immunomodulating compound (acting mainly on
      the regulation of IgA synthesis and/or release) and as a hypocholesterolemic
      compound, reducing the total cholesterol level in the serum of treated pigs. Both
      effects resulted in better pig growth, demonstrating that E-JUR-94013 can also be
      used as a natural growth promoter and an immune enhancer.

PMID- 12616704
TI  - Rationale and design of TeraViC-4 study: a phase III, randomized clinical trial
      to evaluate the effects of treatment duration with peginterferon alfa-2a (40-kDa)
      and ribavirin in naive patients with chronic hepatitis C virus infection without
      early virological response at week 4.
AB  - Several studies are available on the efficacy and safety of 40 kDa branched
      peginterferon alfa-2a (40-kDa) combined with ribavirin in the treatment of
      chronic hepatitis C patients. The TeraViC-4 study is a phase III, randomized,
      parallel group, multicenter study that includes two additional open arms. The
      main objective is to investigate if extended therapy over 72 weeks increases the
      rate of sustained virological response induced by a standard 48-week treatment
      period in naive patients with chronic hepatitis C who do not show an early
      virological response. All patients will be treated with peginterferon alfa-2a (40
      kDa), 180 micrograms subcutaneous (s.c.) once-weekly, and ribavirin, 400 mg
      b.i.d. Virological response will be assessed by a hepatitis C virus ribonucleic
      acid (HCV-RNA) qualitative polymerase chain reaction (PCR) test. Non-early
      responders (HCV-RNA still detectable after 4 weeks of therapy) will be randomly
      separated to receive combination therapy for 44 or 68 additional weeks. Early
      responders (undetectable HCV-RNA at week 4) will be allocated into two open arms
      according to HCV genotype and basal viral load, and they will be treated for 20
      or 44 additional weeks. All patients will be followed for 24 weeks on no therapy.
      A total of 504 patients are planned to be included in the study in order to reach
      the required sample size in the two randomized groups. Efficacy of treatment will
      be assessed by determination of HCV-RNA and the primary efficacy variable is the
      rate of sustained virological response (after 24 weeks of treatment-free follow
      up) in patients without early virological response. Secondary efficacy variables
      are the rate of sustained biochemical response, the rate of response in function
      of HCV genotype, viral load and treatment duration. Safety data will also be
      recorded and analyzed.

PMID- 12616705
TI  - Clinical findings with the oral contraceptive combination
      ethinylestradiol/dienogest in Poland.
AB  - The efficacy and safety of the low dose monophasic oral contraceptive (OC)
      combination containing 30 micrograms of ethinylestradiol (EE) and 2.0 mg of
      dienogest (DNG) (EE/DNG) was evaluated in a prospective, open-label, multicenter,
      uncontrolled, phase III trial. The trial was carried out in five hospitals in
      Poland, and included 431 healthy women (aged 18-35 years), over 12 cycles, with a
      total of 4608 cycles. EE/DNG provided reliable ovulation inhibition. No women
      became pregnant during the trial. The unadjusted Pearl index was 0. EE/DNG
      provided good cycle control and reduced the incidence of intermenstrual
      bleedings, the intensity of menstrual bleeding and frequency of dysmenorrhea. Due
      to the antiandrogenic properties of the progestogen component DNG, EE/DNG
      improved androgen-related conditions, such as skin blemishes, hair greasiness and
      acne vulgaris. Of 50 women with acne, 80% improved after the 6th cycle and 1 was
      healed. After 12 cycles, 54% were improved and 37% were healed. Breast tenderness
      and gastric complaints were the most frequent of the common complaints due to
      treatment with EE/DNG. The frequency of all complaints decreased steadily over
      time. Only 5.6% of subjects discontinued due to adverse reactions. No
      thrombophlebitic events were noticed.

PMID- 12616706
TI  - Preclinical pharmacokinetics of statins.
AB  - This review summarizes the pharmacokinetic properties of HMG-CoA reductase
      inhibitors (or statins) reported in animals. Lovastatin and simvastatin are
      administered as lactone prodrugs in contrast to other statins, which are
      generally formulated in the pharmacological active hydroxy acid form.
      Pharmacokinetics vary with the statin and animal species considered. Oral
      absorption is rapid and the bioavailability low due to an extensive first-pass
      metabolism. Pitavastatin is the exception, with high bioavailability in all
      species except monkeys (80% vs. 18%). Plasma protein binding is high for all
      statins (> 95%) except pravastatin (60%). Regardless of the dosing schedule
      (single or multiple), animal species and statin, the highest tissue levels are
      found in the liver--the target organ. Elimination is rapid with metabolism being
      the main elimination route for all statins, except for pitavastatin, which is
      only slightly metabolized, and pravastatin, which aside from metabolism is also
      eliminated by renal excretion. Statins undergo enterohepatic circulation and are
      recovered mainly in feces via bile, the extent of which is species-dependent.
      Metabolism varies with the statin and animal species, particularly the beta
      oxidation of the dihydroxy heptanoic side chain that occurs primarily in rodents.

PMID- 12616707
TI  - Gateways to clinical trials.
AB  - Gateways to Clinical Trials is a guide to the most recent clinical trials in
      current literature and congresses. The data in the following tables has been
      retrieved from the Clinical Studies knowledge area of Prous Science Integrity,
      the drug discovery and development portal, http://integrity.prous.com. This issue
      focuses on the following selection of drugs: Abacavir sulfate, abarelix,
      adalimumab, adefovir dipivoxil, AdGVVEGF121.10, anastrozole, anecortave acetate,
      aripiprazole, asulacrine isethionate, atazanavir, ATL-962, 16-Aza-epothilone B;
      Bevacizumab, bicalutamide, blonanserin, BMS-188667, bosentan; Celecoxib,
      celmoleukin, cetuximab, cilomilast, cinacalcet hydrochloride, CNTF(Ax15),
      colesevelam hydrochloride; Daclizumab, delavirdine mesilate, desogestrel,
      desoxyepothilone B, dexmethylphenidate hydrochloride, duloxetine hydrochloride;
      Ecogramostim, emtricitabine, epalrestat, escitalopram oxalate, examorelin,
      exendin-4, ezetimibe; Fidarestat, frovatriptan; HIV-1 Immunogen; Iloperidone,
      insulin detemir, insulin lispro, irinotecan hydrochloride; Keratinocyte growth
      factor; Lasofoxifene tartrate, levetiracetam, levormeloxifene, levosimendan,
      lumiracoxib, LY-307161 SR; Memantine hydrochloride, MEN-10755, metformin
      hydrochloride, metreleptin, motexafin gadolinium; Naratriptan hydrochloride,
      natalizumab, nesiritide, nicotine, NN-2211, NN-414; Olanzapine, omalizumab;
      Pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegvisomant,
      pimecrolimus, pirfenidone, pramlintide acetate prasterone, pregabalin; Quetiapine
      fumarate; Rabeprazole sodium, raloxifene hydrochloride, raltitrexed, rDNA
      insulin, rFGF-2, risedronate sodium, rofecoxib, roflumilast, rosiglitazone
      maleate; SN-22995; Tacrolimus, tadalafil, tegaserod maleate, tiotropium bromide,
      tomoxetine hydrochloride, trastuzumab, trimegestone; Voglibose, Voriconazole;
      Ziprasidone hydrochloride.

PMID- 12616708
TI  - Functional analysis of the antimitogenic activity of tumor suppressors.
AB  - Loss of tumor suppressors contributes to numerous cancer types. Many, but not
      all, proteins encoded by tumor suppressor genes have antiproliferative activity
      and halt cell-cycle progression. In this chapter, we present three methods that
      have been utilized to monitor the antimitogenic action exerted by tumor
      suppressors. Tumor suppressor function can be demonstrated by colony formation
      assays and acquisition of the flat-cell phenotype. Because of the anti
      proliferative action of these agents, we also present two transient assays that
      monitor the effect of tumor suppressors on cell-cycle progression. One is based
      on BrdU incorporation (i.e., DNA replication) and the other on flow cytometry.
      Together, this triad of techniques is sufficient to determine the action of tumor
      suppressors and other antiproliferative agents.

PMID- 12616710
TI  - Signal transduction study using gene-targeted embryonic stem cells.
AB  - Gene targeting is one of the most powerful tools to define the role of signaling
      molecules in animal development and disease etiology. By using this technique,
      nearly 1000 knockout mice have been produced over the last two decades.
      Generating knockout mice, however, is a time-consuming procedure. Also, an
      unexpected embryonic lethality sometimes prevents us from examining the function
      of the gene in specific tissues. Here, we describe a convenient method to
      directly disrupt genes at both alleles in murine embryonic stem (ES) cells. These
      homozygous knockout ES cells have been shown useful to determine the role of the
      genes in the mediation of various cellular activities such as proliferation,
      differentiation, apoptosis, survival, transformation, and so on. Furthermore,
      with the recent advance of in vitro differentiation techniques, it is now
      feasible to rapidly determine the role of specific molecules in particular
      tissues.

PMID- 12616709
TI  - Rescue and isolation of Rb-deficient prostate epithelium by tissue recombination.
AB  - The ability to rescue viable prostate precursor tissue from Rb-/-fetal mice has
      allowed for the generation of Rb-/-prostate tissue and Rb-/-prostate epithelial
      cell lines. Herein, we provide a protocol for the rescue of urogenital precursor
      tissue from mouse embryos harboring the lethal Rb-/-mutation. The rescued
      precursors can matured as subrenal capsule grafts in athymic mice. Subsequently
      prostatic tissue can be used as a source for Rb-/-epithelium in a tissue
      recombination protocol for the generation of chimeric prostate grafts in athymic
      male mouse hosts. We have also provided a detailed description for isolating and
      propagating the Rb-/-epithelium from such tissue recombinants as established cell
      lines. Methods for characterizing the grafts and cell lines by determining the
      retention of prostate-specific epithelial expression markers, including
      cytokeratins, the androgen receptor, estrogen receptor beta and the dorsolateral
      prostatic secretory protein (mDLP) are given.

PMID- 12616711
TI  - The use of the yeast two-hybrid system to measure protein-protein interactions
      that occur following oxidative stress.
AB  - Oxidative stress has been shown to have a myriad of effects on cells. Treatment
      of cells with oxidants, such as hydrogen peroxide or agents that induce reactive
      oxygen intermediates, has been shown to induce many cellular signaling pathways
      and, in some cases, cell apoptosis. Many chemotherapeutic treatments used to
      induce cell death do so via the induction of oxygen radicals. It is thought that
      oxidative stress can create, or modify the strength of, protein-protein
      interactions in cells that do not typically occur, or are weaker, under normal
      redox conditions. In this chapter, I describe a method to measure the strength of
      protein-protein interactions that may be enhanced during oxidative stress using
      the yeast two-hybrid system.

PMID- 12616712
TI  - Differential screening of cDNA libraries for analysis of gene expression during
      tumor progression.
AB  - The ability to examine gene expression differences during cancer progression is
      crucial to our understanding of the biological events that lead to uncontrolled
      growth of malignant cells. Differential expression screening of complementary DNA
      libraries is described in detail here as a valuable method for monitoring gene
      expression changes in a prostate cancer xenograft model. Using Southern blot
      analysis of complementary DNA clones and Northern blot analysis to confirm
      differential expression, several androgen-regulated transcripts have been
      identified that may be important in prostate cancer progression.

PMID- 12616714
TI  - TUNEL and immunofluorescence double-labeling assay for apoptotic cells with
      specific antigen(s).
AB  - A double-labeling assay for detecting apoptotic cells, using the terminal deoxy
      nucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and
      antigens of interest, using immunofluorescence, is described. The assay has been
      used successfully on fixed, cultured cells and formalin-fixed paraffin-embedded
      tissue sections. This in situ detection system can be used to correlate apoptosis
      with specific antigen expression to identify factors involved in the induction
      and execution of the apoptotic pathway of cell death in a wide variety of
      experimental systems.

PMID- 12616713
TI  - Mitogen-activated protein kinase signaling in drug-resistant neuroblastoma cells.
AB  - Widespread inherent or acquired resistance to cytotoxic drugs is a major
      limitation to chemotherapy. There are many mechanisms that contribute to such
      resistance. In neuroblastomas there is evidence that acquired drug resistance may
      be associated with altered response to growth factor signals. The ubiquitous
      mitogen-activated protein kinase (MAPk) cascade, which transmits growth factor
      signals from the cell membrane to the nucleus, provides a principal mechanism for
      regulation of cell cycle progression and proliferation. We have shown that there
      is a relationship between acquired drug resistance in human neuroblastoma cells
      to doxorubicin, a topoisomerase-2 inhibitor, and to MDL-28842, an inhibitor of S
      adenosylhomocysteine hydrolase, and reductions in the activation and nuclear
      translocation of MAPk.

PMID- 12616715
TI  - Kinetworks protein kinase multiblot analysis.
AB  - The proteomics analysis of protein kinases and other cell-signaling proteins in
      tumor samples by traditional two-dimensional (2-D) gel electrophoresis is
      complicated by the low abundance of these regulatory proteins relative to
      metabolic enzymes and structural proteins. We present an antibody-based method
      called Kinetworks that relies on sodium dodecyl sulfate (SDS)-poly-acrylamide
      minigel electrophoresis and multilane immunoblotters to permit the specific and
      quantitative detection of 45 or more protein kinases or other signal transduction
      proteins at once. The technique can also permit the resolution of these proteins
      based on differences in their phosphorylation state and other forms of covalent
      modification. Kinetworks profiling of protein kinases in solid human tumors and
      cell lines can reveal profound differences in their expression and
      phosphorylation states, which can serve for the identification of cancer
      diagnostic markers and therapeutic targets for drug discovery.

PMID- 12616716
TI  - Protein tyrosine kinase and phosphatase expression profiling in human cancers.
AB  - Alterations of protein tyrosine kinase and tyrosine phosphatase are often
      associated with uncontrolled cell growth and cellular transformation. Because of
      the large number of tyrosine kinase/phosphatase genes in such gene family, it is
      essential to use an efficient and simple approach to obtain comprehensive protein
      tyrosine kinase and protein tyrosine phosphatase expression profiles. Knowledge
      of such an overall expression pattern of tyrosine kinases/phosphatases in a given
      cancer cell represents the first step in understanding key components involved in
      the sequential events of tumor progression. In this article, we described a novel
      approach by using degenerate PCR primers according to the consensus catalytic
      motifs in order to amplify protein tyrosin kinase/phosphatase molecules from
      cancer cells by reverse-transcription polymerase-chain-reaction. An improved
      profiling approach (RAGE) was also described by utilizing restriction enzyme
      digestion and electrophoresis for quick and efficient kinase/phosphatase
      profiling.

PMID- 12616717
TI  - Association of nonreceptor tyrosine kinase c-yes with tight junction protein
      occludin by coimmunoprecipitation assay.
AB  - Immunoprecipitation is one of the most commonly used techniques to study protein
      protein interaction in vivo. There are three major steps involved in an
      immunoprecipitation procedure: 1) lysis of the cells to make the antigen of
      interest available; 2) formation of the antibody-antigen complex by adding
      specific antibody; 3) separation and detection of the immune complex by sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting.
      Both polyclonal and monoclonal antibodies can be used to immunoprecipitate the
      antigen. Polyclonal antibodies usually bind to multiple sites on the antigen and,
      therefore, are more efficient than monoclonal antibodies. The advantage of using
      monoclonal antibodies for immunoprecipitations is the specificity of the antibody
      antigen interaction because monoclonal antibodies bind to only one epitope of the
      antigen. If the antigen of interest is tyrosine phosphorylated, and this tyrosine
      phosphorylation is under investigation, each step has to be handled with extra
      care to ensure success of the procedure. The buffer used to lyse the cells
      depends on the nature of the antigen, with more stringent conditions required for
      integral membrane proteins than for soluble cytosolic proteins. In either case,
      it is very important to add the protease inhibitors to the lysis buffer in order
      to prevent degradation of the antigen.

PMID- 12616718
TI  - Isolation of novel substrates using a tyrosine kinase overlay/in situ assay.
AB  - Identifying substrates of receptor and non-receptor protein tyrosine kinases
      (PTK), and how phosphorylation of these substrates affects signaling and
      cytoskeletal pathways, has been a key step in understanding the role of PTK in
      differentiation, mitogenesis and oncogenesis. However, it has been difficult to
      distinguish substrates phosphorylated directly by PTK vs those phosphorylated by
      PTK-activated kinases. The following describes an in situ/overlay technique in
      which purified PTK (in our case, FAK) can be used to identify potential
      substrates from filter lifts of protein produced from a cDNA expression library.

PMID- 12616719
TI  - Manipulating expression of endogenous oncogenic proteins using an antisense
      oligonucleotide approach in prostate cancer cells.
AB  - It has been shown that antisense oligodeoxynucleotide (ODN) treatments provide an
      effective, specific approach to inhibiting the function of target proteins. Using
      this method, we have acquired additional evidence that protein kinase C-epsilon
      functions as an oncogenic protein in the progression of recurrent human prostate
      cancer. This chapter describes the use of antisense ODN to directly target
      cellular protein kinase C-epsilon as a potential chemotherapeutic agent for
      blocking the advance of prostatic adenocarcinoma to androgen-independence. Using
      Lipofectin as the carrier, phosphorothioate-modified antisense ODNs were
      transferred into prostate cancer cells with high efficiency, effectively
      inhibiting the expression of endogenous protein kinase C-epsilon and the androgen
      independent (AI) proliferation of several independent human prostate cancer cell
      lines.

PMID- 12616721
TI  - Detection of the content and activity of the transcription factor AP-1 in a
      multistage skin carcinogenesis model.
AB  - Investigation of transcription factor activity in animal tissue during the early
      stage of cancer development can be difficult because of a low number of affected
      cells in a background of a large number of normal cells. We have used a well
      established multistage skin carcinogenesis model to study the effect of manganese
      superoxide dismutase on the activity of AP-1 during an early stage of mouse skin
      carcinogenesis. The DNA binding activity of AP-1 proteins to a concensus DNA
      regulatory binding element known as TRE (TPA Responsive Element) is used as an in
      vitro assay for AP-1 activity in the nucleus of skin cells. This activity is
      detected by electrophoretic mobility shift assay (EMSA) which is based on the
      ability of specific proteins to bind and retard the migration of radioactive
      labeled oligonucleotides on a native gel. The presence of a specific protein in
      the complex can be identified by adding to EMSA an antibody specific for that
      protein, which will result in supershift complexes on the gel. The presence of
      the proteins in question can be further verified by standard Western analysis of
      the nuclear proteins.

PMID- 12616720
TI  - Measurements of phospholipases A2, C, and D (PLA2, PLC, and PLD). In vitro
      microassays, analysis of enzyme isoforms, and intact-cell assays.
AB  - In order to be properly divisible, the cell membrane has to be remodeled and
      intracellular membranes must be converted into a vesiculated state prior to
      mitosis. Phospholipases A2, C, and D (PLA2, PLC, and PLD) are involved in
      regulatory events of intracellular mitogen signaling pathways. We describe here
      three methods for comprehensively assaying those phospholipases: 1) in vitro
      microassays, in which a radiolabeled substrate is exogenously added to cell
      lysates to measure the enzyme activity(ies); 2) immunocomplex assays, in which
      immunoprecipitation with a specific antibody is performed in order to study the
      contribution of a particular isoform within a family of enzymes; and 3) intact
      cell or in vivo assays, in which cells are labeled with a radioactive substrate
      until steady state is reached. The uniqueness of the in vitro microassay method
      described here for the first time is that it allows the measurement of, in
      parallel, the activities of three phospholipases utilizing aliquots derived from
      the same biological sample. The approach for immunoprecipitation described in
      this chapter can be extrapolated to the study of a large array of enzyme
      isoforms. Finally, the intact-cell assays allow for the accurate measurement of
      receptor-mediated activation in vivo.

PMID- 12616722
TI  - Fibroblastic, hematopoietic, and hormone responsive epithelial cell lines and
      culture conditions for elucidation of signal transduction and drug resistance
      pathways by gene transfer.
AB  - Elucidation of signal transduction pathways involved in proliferation, cell cycle
      progression and the regulation of apoptosis has shown great promise in the
      treatment of various diseases including neoplastic, inflammatory, autoimmune,
      immunodeficiency, arthritic and neurodegenerative disorders. By understanding how
      these signal transduction pathways function, chemotherapeutic targets may be
      identified which will suppress or eliminate the disease. This information may
      eventually be translated into therapy, which would either eliminate or safely
      contain the patient's disease. This chapter will focus on basic tissue culture
      techniques which are used to elucidate signal transduction pathways. Furthermore,
      this chapter will provide a general background for understanding how gene
      transfer techniques can be used to elucidate signal transduction pathways as well
      as various pitfalls commonly encountered with their usage.

PMID- 12616723
TI  - Elucidation of signal transduction pathways by transfection of cells with
      modified oncogenes.
AB  - This chapter will focus on introduction of various wild type (WT) and mutant
      genes into cells by DNA transfection. Techniques for analysis of the inheritance,
      expression, and biological effects of the introduced genes will be described.
      Various strong and weak points about three different techniques of stable gene
      transfer, including calcium-phosphate DNA precipitation, transfection via
      liposomes, and transfection via electroporation, will be discussed.

PMID- 12616724
TI  - Elucidation of signal transduction pathways by retroviral infection of cells with
      modified oncogenes.
AB  - This chapter will focus on understanding how various wild type (WT), dominant
      negative (DN), constitutively active (CA), and conditionally active (COND)
      oncogenes, as well as antisense (AS) genes contained in retroviral vectors may be
      used to elucidate signal transduction pathways. We will describe methods to
      introduce these genes into cells and subsequent analysis of inheritance,
      expression, and biological effects of the genes introduced. Furthermore, we will
      discuss various strong points about each of these different types of constructs,
      how they can be used to elucidate signal transduction, apoptotic, and drug
      resistance pathways as well as various pitfalls commonly encountered with their
      usage.

PMID- 12616725
TI  - Methods for the study of protein-protein interactions in cancer cell biology.
AB  - Development of sensitive methods to monitor and quantitatively assess the
      expression levels of endogenous genes and the association-interaction of proteins
      in living cells and whole organisms is a complex and challenging problem. In this
      chapter, we have described basic methods for investigating protein-protein
      interactions which include immunoprecipitation, GST pull-down assays, peptide
      bead pull-down assays, chemical crosslinking and photoaffinity labeling. These
      methods should provide important tools to dissect crosstalk between proteins and
      the direct implications of this crosstalk in signaling pathways and cancer
      biology.

PMID- 12616726
TI  - Production of ligand-specific mutants using a yeast two-hybrid mating assay.
AB  - Acquiring functional knowledge from protein-protein interaction studies often
      necessitates the production of binding-impaired mutants and the study of their
      effects in biological systems. In many cases, multiple ligands compete for
      binding to the same protein domain and it becomes useful to produce specific
      mutations that prevent binding to one ligand but not to the others. We have
      combined PCR mutagenesis and a two hybrid mating assay to produce a screening
      strategy that has already proven useful in isolating ligand-specific mutants of
      the Grb10 and Raf-1 signaling proteins.

PMID- 12616727
TI  - Coimmunoprecipitation assay for the detection of kinase-substrate interactions.
AB  - Coimmunoprecipitation is a powerful tool to study protein-protein interactions
      and can be used to test for the physical association between a known protein
      kinase and its substrate. In this chapter, the author describes a protocol for
      the preparation of a cell lysate, the immunoprecipitation of the antigen, and the
      analysis of the immune complex by gel electrophoresis and immunoblotting with
      antibodies that recognize the putative associated protein.

PMID- 12616728
TI  - Mutational analysis of the androgen receptor using laser capture microdissection
      and direct sequencing.
AB  - Molecular analysis of prostate cancer specimens is complicated by tumor
      heterogeneity and admixture of malignant cells with benign epithelium, stroma and
      inflammatory cells. Laser Capture Microdissection allows procurement of selected
      groups of cells from specific areas of tissue sections. We have used Laser
      Capture Microdissection to obtain pure samples of malignant prostate epithelial
      cells from frozen radical prostatectomy specimens. Methods for DNA extraction,
      androgen receptor amplification and exon sequencing have been optimized. These
      methods should be adaptable for molecular analysis of DNA, RNA and protein from
      other complex tissues.

PMID- 12616729
TI  - Clonality analysis by T-cell receptor gamma PCR and high-resolution
      electrophoresis in the diagnosis of cutaneous T-cell lymphoma (CTCL).
AB  - During T-cell maturation, T-cell receptor (TCR) gene segments rearrange,
      resulting in a new, unique DNA configuration. The recombined TCR gene loci
      display a high degree of nucleotide sequence variability. Molecular biological
      clonality assays focus on this cell-specific DNA pattern. The finding of an
      identical TCR rearrangement in a large number of T lymphocytes signals a
      malignant proliferation, although clonality is not always equivalent to
      malignancy. Thus, detection of clonal TCR gamma rearrangements by polymerase
      chain reaction (PCR), followed by high-resolution electrophoresis is a valuable
      tool in the diagnosis of cutaneous and other T-cell lymphomas. For the clonality
      assay described here, all rearrangements of T cells present in a given sample are
      amplified by a set of only three TCR gamma-PCRs. The products are investigated by
      either heteroduplex temperature gradient gel electrophoresis (HD-TGGE) or
      fluorescent fragment analysis (FFA) on a capillary DNA sequencer (or by both
      methods), for clonality. Both electrophoresis techniques show highly reproducible
      results and are comparatively easy to conduct, however, specific instruments are
      required. Concerning lower detection thresholds, the methods need a minimum of
      about 1% of clonal T-cells in mixtures with polyclonal T-cells for revealing
      clonality.

PMID- 12616730
TI  - [Slow-progressive schizophrenia (actual problems of clinical appearance and
      systematics)].
AB  - Slow-progressive schizophrenia is a slow-progredient endogenous process
      characterized by a prevalence of either negative disorders which do not reach
      final stages as in a case of psychotic types, or positive symptom complexes
      showing affinity to psychopathological appearances of "borderline" level
      (obsessions, somatoform, dissociate, nonpsychotic affective disorders, over-value
      formations). The clinical systematics of slow-progressive schizophrenia is built
      on a model implying a prevalence of either negative or positive disorders.
      Respectively, in the terms of "negative" schizophrenia, there are disease
      variants featured by a predominance of basic manifestations of an endogenous
      process: slow-progredient simple, asthenic, and senestopathic schizophrenia.
      Positive schizophrenia following the pattern of pseudoneurosis is represented by
      the following variants: neurotic-like, hysteric, depersonalization, visceral
      neurotic, hypohondriac as well as reactive schizophrenia.

PMID- 12616731
TI  - [Gelastic seizures: etiology, semiology, therapeutic perspectives].
AB  - Gelastic seizures (laughing seizures) are a rare type of epileptic seizure in
      which laugh in a main and dominating manifestation of the seizure. As a rule, the
      seizures are caused by organic cerebral pathology and are often reported as a
      specific epilepsy marker related to hypothalamic hamartoma. The interictal EEG
      frequently shows a focal activity. Based on examination of 2 patients with
      gelastic seizures and hypothalamic hamartoma, clinical features, EEG
      characteristics and therapeutic perspectives for the disorder are discussed.

PMID- 12616732
TI  - [Clinical course of autonomic nervous system disorders in veterans with
      consequences of combat mild brain injury].
AB  - Twenty-two veterans with combat mild brain injury (BI) were studied 7 and 14.9
      years after BI. Along with evaluation of clinical symptoms, the authors
      investigated the autonomic tonus, autonomic background, regulatory brain systems
      function (cardiointervalography), emotional and personality state measured by
      Scmiscek-Litman (MMPI-modification) and Spilberger tests. Initial examination
      identified clinical syndromes, such as autonomic dystonia (70% of the patients),
      psychopathological syndromes represented by asthenic, affective, neurotic and
      neurotic-like states (90%), cochleo-vestibular (30%), insomniac (20%) states.
      Follow-up revealed these syndromes in 100, 100, 45, 20% of the cases,
      respectively. There was an increase in the dysfunction of nonspecific brain
      systems, which emerged clinically as a psychoautonomic syndrome in the form of
      autonomic dystonia with an elevation of sympathetic activity and emotional shift
      to depressive and hypochondriac disorders.

PMID- 12616733
TI  - [Aspects of depressive states in repatriated female refugees].
AB  - Nine hundred and eight repatriated women--refugees from Tadjikistan, who spent
      1.5-5 years in the refugee's camps in the Islamic State of Afghanistan during the
      1992 military conflict have been examined. A broad spectrum of depressive states
      was found: subdepressive psychogenic states (42.5% of the cases), lingering
      psychogenic depressions (28.8%), and endogenous depressions (28.6%). Among
      lingering psychogenic depressions, there were most frequently anxious-depressive,
      depressive-hypochondriac, and depressive-obsessive types. A 1.5-year follow-up
      revealed subdepressive states to have the most favourable outcome. Lingering
      depressive states, specifically when transformed to endogenous ones, their
      prognosis was less favourable. However, in some of these cases, a favourable
      outcome may be detected in the follow-up period when adequate complex medical and
      social rehabilitation care was used.

PMID- 12616734
TI  - [Comparative efficacy and tolerance of fluvoxamine and amitriptyline in the
      treatment of moderate and severe depression in mental hospital].
AB  - The aim of the study was to compare the efficacy and tolerance of fluvoxamine
      (FL) and amitriptyline (AM) in the treatment of patients hospitalized for
      moderate and severe depression and to evaluate the spectrum of antidepressive
      activity in FL. The study was open, randomized and comparative. Sixty patients
      (mean age 41 +/- 2.9 years) diagnosed as having recurrent depressive disorder, a
      moderate or severe depressive episode (ICD-10 F33.1, F33.2) were divided into two
      equal groups treated with FL or AM. The efficacies of FL and AM were comparable,
      with AM exhibiting an earlier clinical effect and FL having a better tolerance.
      FL was defined as an antidepressant with the predominantly sedative effect
      comparable to that of AM, but being better tolerated.

PMID- 12616735
TI  - [Experience with lamictal in the treatment of outpatients with resistant
      epilepsy].
AB  - The article summarizes the results of lamictal treatment in 93 patients with
      resistant epilepsy. Lamictal was used in a dose of 50-200 mg a day as an
      auxiliary drug in the treatment with other anticonvulsants. Its therapeutic
      efficacy was analyzed in relation to the form of epilepsy, the type of seizures,
      dosage of lamictal duration of therapy, and as patients' sex, age, and social
      activity. In the total group, 17.2% of the patients have remissions, in 48.4% the
      frequency of seizures frequency was reduced (> 50%) and 34.4% of the patients
      exhibited a less pronounced effect (< 50%). When combining lamictal and
      valproates, the best results were obtained in generalized seizures, especially in
      idiopathic generalized epilepsy, and in young and middle-age female patients with
      active social functioning.

PMID- 12616736
TI  - [Adhesive molecules as immunologic markers of activity of multiple sclerosis].
AB  - The correlations between concentrations of the adhesive circulating molecules
      cICAM-1 and cVCAM-1 in the peripheral blood of patients with relapses-remitting
      multiple sclerosis (RRMS) in different clinical phases and magnetic resonance
      imaging (MRI) activity are presented. The patients in clinically active phase
      with Gd-enhancing lesions had elevated blood levels of cICAM-1. However, 5
      patients without Gd-enhancing lesions exhibited elevated cICAM-1 and cVCAM-1
      levels in active phase comparing to those in remission stage that indicate a high
      level of sensibility of these immunologic parameters.

PMID- 12616737
TI  - [Catecholamine metabolism in Parkinson's disease with depression].
AB  - Daily urinary catecholamine excretion (DOPA, DA, DOPAC, NA, A) was studied in 66
      patients with Parkinson's disease, 38 of them with differently expressed
      depression. Depression severity correlated with rigid form of disorders (p <
      0.001). Biochemical profile of the depressive patients was characterized by
      noradrenaline (NA) to adrenaline (A) ratio reduction (p < 0.01) and dopamine to
      NA (p < 0.01) ratio increase on the background of total catecholamines deficit.
      Changes of NA/A and DOPA and correlation between DOPA and depression severity
      imply a role of dopamine neuromediator deficit in depression development.

PMID- 12616738
TI  - [Clinical significance of adrenoreactivity in patients with some paroxysmal
      disorders (panic attacks and migraine)].

PMID- 12616740
TI  - [A familial case of Hallervorden-Spatz disease].

PMID- 12616739
TI  - [Age-dependent monoamine oxidase activity and lipid peroxidation products in
      human brain].

PMID- 12616741
TI  - [Hypnotics: achievements of modern psychopharmacology].

PMID- 12616742
TI  - [Conformational diseases (neurological aspects)].

PMID- 12616744
TI  - [Catastrophies].

PMID- 12616743
TI  - [Transcranial magnetic stimulation in the study of epilepsy].

PMID- 12616745
TI  - [Role of androgens in externalizing behavior problems in adolescents].
AB  - OBJECTIVE: While an association between androgens and different types of
      aggression has been well documented in male offenders, the influence of androgens
      on externalizing behavior in adolescents at risk for antisocial behavior has not
      been investigated so far. METHODS: Plasma levels of the main androgen metabolites
      testosterone (T) and 5a-dihydrotestosterone (DHT) were measured in N = 119 14
      year-olds (51 boys, 68 girls) from a prospective longitudinal study of children
      at risk. The Achenbach Child Behavior Checklist (CBCL) and the Youth Self Report
      Form (YSR) were used to assess externalizing behavior at age 14. RESULTS: The
      CBCL revealed significant positive correlations between DHT levels and the
      subscales "externalizing problems" and the problem scales "aggressive behavior"
      and "delinquent behavior" in male adolescents. Only the YSR subscale "delinquent
      behavior" exhibited a marginally significant association with DHT. Neither scale
      showed any significant correlations between androgen levels and externalizing
      behavior in female adolescents. CONCLUSIONS: Earlier findings of androgen effects
      on aggressive and antisocial behavior in male offenders were confirmed for male
      adolescents from a general population sample. The results stress the importance
      of the androgen metabolite DHT.

PMID- 12616746
TI  - [Value of telephone interview for quality assurance and therapy evaluation in
      child and adolescent psychiatry. Review of the literature and empirical results
      of participation quota and possible sampling bias].
AB  - OBJECTIVE: The incurred costs of telephone interviews are lower than those of
      other methods. Thus the question arises whether this method affords the necessary
      quality for therapy evaluation in child and adolescent psychiatry and
      psychopathology. A review of the literature shows higher rates of participation
      for telephone and personal interviews as opposed to those for questionnaires sent
      by mail. Results of investigations within the social sciences are inconsistent
      with regard to the quality of the data collected in telephone interviews. The few
      results available from samples from psychiatry permit no clear-cut conclusions as
      to the quality of such data. METHOD: The results of two follow-up studies of
      former inpatients of a hospital for child and adolescent psychiatry are presented
      with regard to the rate of participation and the sample bias. RESULTS: The
      empirical data show a higher rate of participation for telephone interviews (85%)
      than for either personal interviews or questionnaires sent by mail. Sample bias
      in telephone interviews is smaller than in the other assessment approaches.
      CONCLUSIONS: Since the advantages of telephone interviews outweigh those of other
      methods, this method of interviewing should be used as a matter of routine for
      quality assurance and therapy evaluation.

PMID- 12616747
TI  - [Reliability and validity of evaluation data collected by telephone].
AB  - OBJECTIVES: Follow-up telephone interviewing is an increasingly popular method of
      quality assurance and therapy evaluation in child and adolescent psychiatry.
      However, the reliability and validity of data gathered in telephone interviews
      has not been investigated sufficiently. The current article examines the quality
      of the information gathered from the parents of former inpatients of a hospital
      for child and adolescent psychiatry. METHODS: In a sample of n = 32 cases a
      telephone interview was carried out, followed by a personal interview two weeks
      later. Data from both interviews were analyzed for correlations between the
      ratings by parents and experts. RESULTS: The results from the telephone
      interviews indicate sufficient, respectively good reliability and underscore the
      validity of these data. CONCLUSIONS: On the basis of these results, the
      standardized telephone interview developed in our group and used in the study can
      be applied as a reliable and valid method of controlling for treatment success in
      follow-up investigations. As the interview does not entail any great
      expenditures, it can be used in routine quality assurance.

PMID- 12616748
TI  - [Psychological education as a group process for parents of adolescents with
      eating disorders].
AB  - Psychoeducation is a well-established component of cognitive-behavioral therapy
      in adult patients with eating disorders. This paper describes a group model of
      psychoeducation that has been offered by our department for the past two years to
      parents of adolescent patients with anorexia and bulimia nervosa. According to
      their own reports, parents appreciate this means of support to help them cope
      with their child's illness.

PMID- 12616749
TI  - [Day care treatment of 2 siblings with elective mutism].
AB  - OBJECTIVES: This case report deals with the day care treatment of two seven- and
      eight-year-old siblings with elective mutism. Their treatment entails a
      combination of psychopharmacological and intensive behavior therapy. The
      multimodal therapeutic process is presented together with continuing psychosocial
      steps. Behavioral intervention focuses on building verbal expressive capacity,
      reducing speech anxiety in social situations and generalization to non
      therapeutic situations. The case report is discussed in the context of the
      current literature on elective mutism.

PMID- 12616750
TI  - Survey reveals that some providers reuse needles.

PMID- 12616751
TI  - CDC: alcohol-based handrubs are better than soap & water.

PMID- 12616752
TI  - New therapy may reduce risk of hospitalization and death for patients with severe
      CHF.

PMID- 12616753
TI  - Women, more than men, report stroke symptoms that are "nontraditional".

PMID- 12616754
TI  - Acute care decisions. Ethics in action.

PMID- 12616755
TI  - How to improve in-office collections .

PMID- 12616756
TI  - Coronary stenting--with a twist.

PMID- 12616757
TI  - New meaning for safe sex.

PMID- 12616758
TI  - Nurse, heal thyself.

PMID- 12616759
TI  - Medication errors. The bigger picture.

PMID- 12616760
TI  - Complementary therapies--they're not without risk.

PMID- 12616762
TI  - Support for safe medication guidelines. Parent education information on potential
      poisons.

PMID- 12616764
TI  - Health insurance for all.
AB  - It's a pleasure to report that when school nurses in a part of western
      Massachusetts were asked to identify barriers to healthcare for children, they
      did not mention health insurance. This was not always the case. Thanks to an
      innovative collaboration between a community hospital and a regional school
      district, almost all school children in the three-town area have health
      insurance. Fewer children are without healthcare, allowing them access to
      healthcare more freely and minimizing acute and primary care in the local
      emergency department, which is typically an outcome for the uninsured.

PMID- 12616763
TI  - The nutritional challenges of genetic enzyme-deficiency syndromes.

PMID- 12616765
TI  - Childhood obesity--a public health problem.

PMID- 12616767
TI  - Beneath the surface of eating disorders.

PMID- 12616766
TI  - Obesity: the widening issue we can't ignore.

PMID- 12616768
TI  - Aesthetic considerations in cranial neurosurgery. Preface.

PMID- 12616769
TI  - The cosmetic aspects of neurosurgery.
AB  - The cosmetic aspects of neurosurgery are important and make a considerable
      difference to the patient's quality of life. In general, the saying is true that
      "at a cocktail party, the patient should not be recognized as having had
      neurosurgery, or, even better, the patient's own neurosurgeon should not be able
      to detect which side the patient was operated on when the patient is seen in the
      office 6 months later without looking at the chart."

PMID- 12616771
TI  - Hair sparing techniques and scalp flap design.
AB  - Individualizing each patient in deciding on flap selection, flap design, hair
      sparing or shaving, and method of closure ensures proper treatment outcome with
      the goal of achieving a good cosmetic result.

PMID- 12616770
TI  - Cosmetic considerations in cranial surgery: plastic surgical perspective.
AB  - This article is an overview of the recent advances and cosmetic implications of
      various aspects of craniofacial surgery from a plastic surgical viewpoint.

PMID- 12616772
TI  - Cosmetic considerations in cranial base surgery.
AB  - Recent advances in the surgical techniques for the resection of cranial base
      tumors have allowed for improved degrees of tumor resection, functional outcomes,
      and esthetic results. If the resection and functional results are not compromised
      by procedures providing excellent cosmetic outcomes, there is no reason to ignore
      or compromise the esthetic aspect with regard to technical execution and
      planning. A thorough assessment of the patient's preoperative deficits and tumor
      anatomy and a working knowledge of the available cranial base approaches and
      their combinations permit the surgeon to design an approach that allows for
      optimal tumor resection with the best possible cosmetic result. In a time when
      alternative treatment options like radiosurgery exist for cranial base tumors,
      esthetic outcome is a significant quality-of-life issue that patients consider in
      their decision to choose surgery versus an alternative treatment.

PMID- 12616774
TI  - Cosmetic concerns in posterior fossa skull base surgery.
AB  - Although cosmetic defects produced by posterior fossa surgery may not seem
      obvious, a poor cosmetic result can overshadow an otherwise successful operation.
      It is important to approach the operation with knowledge that each phase of a
      surgical procedure either directly or indirectly influences the eventual cosmetic
      result. The careful use of anatomic dissection and repair and attempts to
      reconstitute bony defects to their native contour as well as avoidance of
      complications all contribute to excellent cosmetic outcomes.

PMID- 12616773
TI  - Osteotomy design and execution.
AB  - Craniofacial osteotomies are an integral part of contemporary neurosurgery
      because of their ability to provide substantially more exposure to deepseated
      lesions with reduced brain retraction. A systematic approach to the performance
      of these osteotomies coupled with meticulous bone work capitalizes on their
      advantages without producing any significant cosmetic defects. As their
      indications are progressively more clearly defined and familiarity and facility
      are gained by the surgeons performing them, operative time and morbidity should
      decrease. Lowering operative time and morbidity with excellent esthetic results
      is likely to be increasingly important when considering operative versus
      nonoperative management, particularly as nonsurgical modalities continue to
      develop.

PMID- 12616775
TI  - Cosmetic aspects of cranial reconstruction.
AB  - Cranial reconstruction has evolved to achieve both functional coverage and
      esthetic appearance. Hair preservation/reconstruction and free flaps have
      markedly improved the soft tissue esthetic outcome. Restoration of bony contour
      has been facilitated by advanced craniofacial techniques and three-dimensional
      alloplast.

PMID- 12616776
TI  - Cosmetic concerns in pediatric craniofacial surgery.
AB  - This article highlights the technical details of the authors' techniques in the
      surgical management of craniosynostosis. The role of orthotic devices vis-a vis
      positional plagiocephaly and postsurgical molding is discussed. A method of
      avoiding temporal hollowing in cranioplasty is presented.

PMID- 12616777
TI  - Transcultural communication: the cornerstone of culturally competent care.
AB  - Cultural diversity will continue to expand in the "great melting pot"--the United
      States of America. The ability of the nurse to foster transcultural communication
      will remain a very real challenge in rendering culturally competent health care.
      Accepting differences in people and displaying a nonjudgmental attitude are
      essential for the nurse to communicate successfully across different cultural
      groups. In conclusion, nurses must be engaged in a dynamic dialogue to ameliorate
      transcultural communication, avoid language barriers, and employ approaches to
      enhance nurse-patient rapport.

PMID- 12616778
TI  - Presidential address. Enlighten, empower, envision: action strategies for SCI
      nursing practice.

PMID- 12616779
TI  - Don't underestimate the power of culture.
AB  - Integrating a client's health care beliefs into the plan of care is the first
      step in providing culturally congruent care. Since caring is largely defined
      within a cultural context, knowing how clients wish to be cared for, and knowing
      about their culture, is paramount for the nursing profession. Transcultural
      nursing, a specialized area within nursing, embraces the power of culture.
      Transcultural nurses recognize and utilize the role of culture in the provision
      of culturally congruent care. By the year 2060, non-Hispanic whites are projected
      to comprise about half of the U.S. population (49.4%). In the year 2000, an
      estimated 12% of registered nurses were from an identified minority group.
      Therefore, it is not surprising that the culture of nursing in the United States
      continues to reflect the predominant values of the non-Hispanic white or Anglo
      American culture. Ethnocentrism and cultural imposition must be avoided. Three
      major health belief systems (biomedical, naturalistic, and magico-religious) are
      presented with emphasis on their influential power with respect to health care
      practices. Underestimating the power of culture may be harmful to the health of
      the client.

PMID- 12616780
TI  - The importance of cultural assessment.
AB  - This article presents the importance of cultural assessment to care of patients
      in general, with a description of the background development of the Sharma
      Cultural Assessment Instrument and its potential application to care of persons
      with spinal cord impairment (SCI). A description is presented of the research
      questions, methods, and results of the doctoral study in which the instrument was
      originally developed, as well as the explanation of why particular parts of the
      instrument are significant to care of the patient. A description of how cultural
      assessment data had an impact on care of a particular geriatric patient is used
      as an example of the importance of this additional information. The significance
      of cultural data for care of the person with an SCI concerns such areas as
      explanatory models, fears and concerns, and the relationship of the nurse with
      the culturally diverse patient.

PMID- 12616781
TI  - Diversity is our strength!
AB  - Valuing and appreciating diversity are key requirements for health care
      organizations faced with increasingly diverse workforces and patient populations.
      Diversity issues are central to effectively functioning teams, patient outcomes,
      staff satisfaction, recruitment, and retention. Shands HealthCare, a health care
      system containing a large teaching medical center and several community hospitals
      and clinics centered around Gainesville, Florida, made a commitment to take the
      necessary steps to make diversity a priority and strategic initiative. A
      systemwide diversity initiative was launched in 1998. Diversity was defined, and
      organizational leaders were developed as "Ambassadors for Diversity." The
      Ambassadors developed an extensive training program that all staff and managers
      attend upon hiring. The primary goal of the program is to create a culture of
      respect and appreciation for diversity. Over 2,500 employees and managers have
      attended the training.

PMID- 12616782
TI  - From a diverse culture to an integrated culture.

PMID- 12616783
TI  - Technology assessment.

PMID- 12616784
TI  - Online resources for spinal cord injury nursing research.
AB  - Selected online resources for nursing research related to SCI were explored.
      Online resources cited here provide a tremendous amount of information at your
      fingertips. These resources are not meant to be all-inclusive, but may serve as a
      good starting point to find valuable research information for a future research
      project related to SCI.

PMID- 12616785
TI  - Working toward cultural competence in the workplace.
AB  - Once personal cultural characteristics are identified by the nurse, he/she can
      begin to hold in abeyance those preconceived beliefs and opinions that may impact
      a situation. By doing this, the participant deals with the situation in its
      purest form, and is open to people, ideas, and perspectives of a broader
      spectrum. These personal cultural characteristics contribute to delivering
      culturally competent care to a diverse society.

PMID- 12616786
TI  - Bracing for success.

PMID- 12616787
TI  - Il Dissoluto Punito: medicine in the age of blame.

PMID- 12616788
TI  - The culture of the accident.

PMID- 12616789
TI  - Consent and the chain of causation and quantum.

PMID- 12616790
TI  - The triumph of logic over common sense? A commentary on Chester v Afshar.

PMID- 12616791
TI  - Patient confidentiality.

PMID- 12616792
TI  - Parental alienation and the courts.

PMID- 12616793
TI  - Loss of earnings: a lifetime of opportunity.

PMID- 12616794
TI  - Values in the role of the family therapist: self determination and justice.
AB  - Recently, there has been renewed interest in the role of values in family
      therapy. A number of theorists agree that there is an inherent ethical dimension
      in all forms of therapy, because therapy necessarily involves influencing others
      in accord with a set of values. In cultures that value self determination, a
      potential conflict arises between the therapist's inherent moral influence and
      protecting the client's self determination. This article identifies that dilemma
      and investigates how different treatment approaches resolve it as they attempt to
      promote justice in the family.

PMID- 12616795
TI  - Motivational, ethical, and epistemological foundations in the treatment of
      unwanted homoerotic attraction.
AB  - A recent special section of the Journal of Marital and Family Therapy (October,
      2000) focusing on the mental health needs of gay, lesbian, and bisexual
      individuals neglected to address the clinical needs of homosexual persons who
      desire to increase their heterosexual potential. This article attempts to correct
      this omission by outlining common motivations for pursuing change, updating the
      current state of knowledge regarding the effectiveness of change efforts, and
      providing some ethical guidelines when therapists encounter clients who present
      with unwanted homoerotic attraction. Finally, to assist marriage and family
      therapists (MFTs) in more deeply understanding divergent perspectives about
      reorientation treatments, an examination of the role of moral epistemology is
      presented and some examples of its potential influence are described. MFTs are
      encouraged to recognize and accept, rather than ignore or deny the valid needs of
      clients who seek to modify their same-sex attraction.

PMID- 12616796
TI  - When therapists do not want their clients to be homosexual: a response to Rosik's
      article.
AB  - This commentary is a response to Rosik's "Motivational, Ethical, and
      Epistemological Foundations in the Treatment of Unwanted Homoerotic Attraction"
      (this issue). Such treatment raises complex questions that cannot be resolved by
      focusing on the therapist's conservative versus liberal values. Most such clients
      are deeply ambivalent about their homosexual attractions. The degree to which
      their homosexuality is "unwanted" is highly variable among them and sometimes
      within them over time. Clients who are exclusively homosexual are very unlikely
      to be able to change their sexual attractions, whereas some clients who are
      bisexual may be more able to "manage" their homoerotic attractions (acting only
      on their heterosexual feelings). Marriage and family therapists should be able to
      support a client along whatever sexual orientation path the client ultimately
      takes, and the client's sense of integrity and interpersonal relatedness are the
      most important goals of all.

PMID- 12616797
TI  - When therapists do not acknowledge their moral values: Green's response as a case
      study.
AB  - In this rejoinder to Green's (this issue) commentary on my article, I clarify
      several points of agreement and divergence with his critique. The failure of
      Green to be forthcoming about the sociopolitical and moral framework that infuses
      his response is unfortunately all too common in this literature. This places a
      limitation on the degree to which his comments can be contextually evaluated,
      though they remain didactically useful. Marriage and family therapists (MFTs)
      must realize that their underlying belief systems exact a profound influence on
      their conceptions about what constitutes mental health, valid treatment goals,
      and the best means to achieve these aims. These value frameworks may or may not
      be shared by religiously conservative and other clients who seek to develop their
      heterosexual potential. This has important, but often unrecognized, implications
      for clinical practice.

PMID- 12616799
TI  - Incorporating sexual orientation into MFT training programs: infusion and
      inclusion.
AB  - Many authors have questioned the preparedness of family therapists to deal with
      sexual minority clients. Even though the Commission on Accreditation for Marriage
      and Family Therapy Education (COAMFTE) has called for the integration of sexual
      orientation into the curriculum of marriage and family therapy training programs,
      the subject continues to be marginalized. The purpose of this article is to
      encourage trainers to examine their programs' curricula for evidence of
      heterosexist bias and introduce ways that they might integrate issues related to
      same-sex affectional and sexual orientations into their programs via the
      classroom and the clinic.

PMID- 12616798
TI  - Protecting persons in family therapy research: an overview of ethical and
      regulatory standards.
AB  - Family therapists are expected to engage in ethical and responsible research,
      while maintaining rigorous ethical standards and adhering to federal regulations
      that require protection for research participants. We present a short historical
      overview of the significant events and ethical controversies leading to the
      formulation of current regulations in human subject research and review. Federal
      regulations and guidelines, including issues of informed consent, special
      populations, and conflict of interest are reviewed. A short list of
      recommendations to assist family therapists in staying abreast of contemporary
      research protocol is provided.

PMID- 12616801
TI  - Effectiveness research in marriage and family therapy: introduction.
AB  - The papers in this volume offer compelling evidence that MFT is making
      significant progress toward becoming an evidenced based discipline. Nonetheless,
      a large gap persists between research and practice, which perpetuates a false
      dichotomy between the art and science of treatment and has other deleterious
      consequences for the field. The methodological strengths of the investigations
      reported, which focus on clinical trials, are discussed along with concerns
      raised about this type of research. Several important challenges facing MFT
      research in the decades ahead are described. Finally, MFT education must be
      changed substantially to give more emphasis to the science of the discipline.

PMID- 12616800
TI  - Assessing nontraditional couples: validity of the marital satisfaction inventory-
      revised with gay, lesbian, and cohabiting heterosexual couples.
AB  - Thirty-one gay male couples and 28 lesbian couples were compared with 36
      cohabiting heterosexual couples using the Marital Satisfaction Inventory-Revised
      (MSI-R), a multidimensional measure of relationship functioning intended for use
      with both traditional and nontraditional couples. Analyses of scales' internal
      consistency and factor structure supported the construct validity of this measure
      with nontraditional couples. Analyses of mean profiles on the MSI-R indicated
      that cohabiting opposite-gender and same-gender couples were more alike than
      different, and were more similar to nondistressed samples of married heterosexual
      couples from the general community than to couples in therapy. Implications of
      current findings for clinical assessment and intervention are considered, and
      directions for future research are proposed.

PMID- 12616802
TI  - Substance abuse.
AB  - Liddle and Dakof's (1995) comprehensive review of the status of family-based
      treatment for drug abuse concluded that this modality offered a "promising, but
      not definitive" approach to treating drug abuse among adolescents and adults.
      Less than a decade later, significant progress can be seen in the treatment of
      drug abuse problems using family-based approaches, particularly with adolescents.
      Family-based treatments are currently recognized as among the most effective
      approaches for adolescent drug abuse. Family-based treatment of adult drug abuse
      problems has also advanced in important ways with the recent systematic
      application and testing of engagement techniques and behavioral couples therapy
      approaches. The current review characterizes and discusses the developmental
      status of this subspecialty and outlines areas in which continued research
      attention is needed.

PMID- 12616803
TI  - Alcohol abuse.
AB  - We reviewed 38 controlled studies of marital and family therapy (MFT) in
      alcoholism treatment. We conclude that, when the alcoholic is unwilling to seek
      help, MFT is effective in helping the family cope better and motivating
      alcoholics to enter treatment. Specifically, (a) Al-Anon facilitation and
      referral help family members cope better; (b) Community Reinforcement and Family
      Training promotes treatment entry; and (c) the popular Johnson intervention
      apparently does not effectively promote treatment entry. Once the alcoholic
      enters treatment. MFT, particularly behavioral couples therapy (BCT), is clearly
      more effective than individual treatment at increasing abstinence and improving
      relationship functioning. BCT also reduces social costs, domestic violence, and
      emotional problems of the couple's children. Future studies need to specifically
      evaluate: MFT with women and with minority patients, mechanisms and processes of
      change, and transportability of evidence-based MFT approaches to clinical
      practice settings.

PMID- 12616804
TI  - STOP-NIDDM: a new paradigm for diabetes prevention?

PMID- 12616805
TI  - Minimal and best linear combination of oxidative stress and antioxidant
      biomarkers to discriminate cardiovascular disease.
AB  - BACKGROUND AND AIM: Free radicals have been implicated in the atherosclerotic
      process of coronary heart disease (CHD). Well-developed laboratory methods may
      make available a large number of biomarkers of individual oxidative stress and
      antioxidant status. Such markers are able to quantify different phases of the
      oxidative stress and antioxidant status of an individual. However, limited
      knowledge is available on how to combine these biomarkers to best discriminate
      between individuals with and without CHD. METHODS AND RESULTS: We evaluated
      combined discrimination properties of six biomarkers of oxidative stress and
      antioxidant status, as indicators of CHD, in a cross-sectional random sample of
      968 white men and women from Buffalo, New York. Individuals with CHD had
      significantly higher levels of thiobarbuturic acid reacting substances (TBARS)
      and uric acid, and significantly lower levels of high-density lipoproteins (HDL)
      after adjusting for age and gender, when compared to healthy subjects. There were
      no significant differences in erythrocyte glutathione (GSH), trolox equivalent
      antioxidant capacity (TEAC), and glutathione peroxidase (GSHPx) levels. TBARS
      were found to be the best discriminating of the biomarkers when it was
      individually evaluated. TBARS discriminate 76.2% (95% C.I. 0.66-0.82) of the CHD
      cases from healthy controls. When combining TBARS, GSH, TEAC, HDL, uric acid and
      GSHPx, they discriminate 81.5% (95% C.I.: 0.67-0.90) of the area under the curve.
      CONCLUSIONS: These preliminary findings suggest that the combination of multiple
      markers of oxidative stress does not greatly improve ability to differentiate
      between individuals with and without CHD compared to the use of TBARS alone.

PMID- 12616806
TI  - Distribution of risk factors, plasma lipids, lipoproteins and dyslipidemias in a
      small Mediterranean island: the Ustica Project.
AB  - BACKGROUND AND AIM: The populations of the Mediterranean area have a low
      incidence of cardiovascular disease (CHD). The aims of this paper are: 1) to
      present demographic data of the population of Ustica, a small island in the
      southern part of the Tyrrhenian sea that has reduced communications with the
      mainland and a diet presumably rich in fish; and 2) to evaluate the distribution
      of risk factors, plasma lipids, lipoproteins and dyslipidemias in this
      population. METHODS AND RESULTS: We invited all of the free-living resident
      population aged more than 14 years (about 800 individuals) to participate in the
      study; 576 responded, for a participation rate of about 73%. The distribution of
      cardiovascular risk factors, plasma lipids, lipoproteins and dyslipidemias were
      evaluated in all of the subjects. More than 60% of the population was out of the
      normal weight range. Total and low-density lipoprotein cholesterol levels were
      respectively 207.4 +/- 46.7 and 141.7 +/- 42.4 mg/dL, and similar in males and
      females. Lipoprotein (a) (Lp[a]) levels presented the classical "skewed"
      distribution and, among the apolipoprotein(a) isoforms, there was a clear
      predominance of intermediate-sized kringle IV repeats. Overall, 43% of the
      subjects had a lipid disorder: the prevalence of hypercholesterolemia was 22.8%
      (3.2% with severe hypercholesterolemia terolemia > or = 300 mg/dL); low high
      density lipoprotein cholesterol levels were found in 22.5%; the so-called lipid
      triad in 2.1%; and high Lp(a) levels in 6.2%. Large familial clusters were found
      for some lipid disorders. CONCLUSIONS: A large prevalence of body weight
      disturbances and high frequency of dyslipidemias are the main characteristics of
      this population. Ongoing data and future longitudinal studies will better clarify
      the relative influence of each parameter on CHD risk and total mortality.

PMID- 12616807
TI  - Relationship of visceral fat distribution to angiographically assessed coronary
      artery disease: results in subjects with or without diabetes or impaired glucose
      tolerance.
AB  - BACKGROUND AND AIM: To evaluate the relationship between the degree of coronary
      artery disease (CAD) and the amount of visceral fat deposition in a mixed
      population of CAD patients with or without diabetes or impaired glucose tolerance
      (IGT), and with different body weights. METHODS AND RESULTS: A total of 55
      patients undergoing coronary angiography (43 men and 12 women with a mean age of
      58.9 +/- 1.1 years, range 37-70, and a mean body mass index [BMI] of 27.9 +/-
      0.4, range 21.3-38.7) were studied in order to establish whether the coronary
      damage exclusively depends on intra-abdominal adipose tissue per se, or may be
      influenced by the coexistence of diabetes or IGT. Twenty-one subjects were non
      diabetic, 13 had type 2 diabetes, and 21 IGT. Hypertension was found in 47% and
      dyslipidemia in 55%; 69% were smokers. The angiographic evaluation of CAD was
      made using the method of Gensini, and computed tomography (CT) was used to
      estimate the amount of visceral adipose tissue (VAT) based on a single scan at L4
      level. Clinical, anthropometric, biochemical and hormonal variables, as well as
      smoking and alcohol consumption were determined. In the study population as a
      whole, the coronary score did not correlate with VAT, but only with smoking.
      However, both univariate and multivariate regression analysis showed that CAD
      significantly correlated with VAT in the non-diabetic patients, particularly in
      those with VAT of > 130 cm2. This correlation did not appear in the diabetic or
      IGT patients, nor when the group of patients with VAT > 130 cm2 was extended to
      include diabetic or IGT patients. No relationship was found between CAD and BMI
      or the other considered variables. CONCLUSIONS: In a mixed population of CAD
      patients with or without diabetes, CAD correlates with VAT only in the absence of
      diabetes or IGT, and especially when VAT exceeds 130 cm2 at an L4 CT scan,
      regardless of weight or obesity. Diabetes or IGT therefore seem to contribute
      towards the development of CAD regardless of the amount of VAT.

PMID- 12616808
TI  - Body iron stores and coronary atherosclerosis assessed by coronary angiography.
AB  - BACKGROUND AND AIM: Epidemiological studies have suggested an association between
      higher body iron stores and coronary artery disease (CAD), but recent trials have
      reported conflicting data on the role of ferritin in CAD. To assess these
      findings, we examined the association between serum ferritin and the angiographic
      extent of coronary atherosclerosis in consecutive patients referred for coronary
      angiography. METHODS AND RESULTS: We studied 100 consecutive white subjects (41
      women and 59 men; mean age 63.7 +/- 11.0 years) who underwent coronary
      angiography. The data collected at baseline included conventional risk factors
      for coronary artery disease (CAD), lipid and fasting total homocysteine levels,
      serum ferritin levels and transferrin saturation, and clinical characteristics.
      Serum ferritin levels and transferrin saturation (serum iron concentration
      divided by total iron-binding capacity) were used as measures of the amount of
      circulating iron available to tissues. Two experienced cardiologists blinded to
      the clinical and laboratory data reviewed the angiographic cinefilms, and defined
      the angiographic severity of CAD on the basis of the sum of three vessel scorring
      systems. The risk of CAD assessed by coronary angiography was not related to
      ferritin concentrations or transferrin saturation levels. The estimated relative
      risk of CAD for the fifth vs the first quintile of serum ferritin was 0.83 (95%
      CI: 0.63-1.24). Forty of the 100 patients had no or minimal CAD (group A; score 0
      3), 33 moderate CAD (group B; score 4-8) and 27 severe CAD (group C; score > 8):
      the serum ferritin levels in the three groups were respectively 165 +/- 126, 167
      +/- 121 and 164 +/- 110 ng/ml, and did not represent an independent risk factor
      for CAD (p = 0.98). Transferrin saturation in the three groups was 22.9 +/- 10%,
      21 +/- 9% and 19.9 +/- 10%, with no significant relationship to the severity of
      CAD (p = 0.23). The presence of angiographic CAD was associated with patient age
      (p = 0.048), male gender (p < 0.01), high lowdensity lipoprotein cholesterol
      levels (p = 0.02), low high-density lipoprotein cholesterol levels (p = 0.02),
      high plasma fibrinogen levels (p < 0.01) and high fasting total homocysteine
      levels (p = 0.04). CONCLUSION: In patients referred for coronary angiography,
      higher ferritin concentrations and transferrin saturation levels were not
      associated with an increased extent of coronary atherosclerosis.

PMID- 12616809
TI  - Maximal response to a plasma cholesterol-lowering diet is achieved within two
      weeks.
AB  - BACKGROUND AND AIM: Replacing saturated fat with polyunsaturated fat reduces
      plasma cholesterol concentrations; however, it has not been well documented how
      rapidly the decline occurs nor how long is required to reach the maximum
      cholesterol-lowering effect. The aim of the present study was to determine the
      time course of change in plasma cholesterol concentrations when participants
      adopt a lipid-lowering diet. METHODS AND RESULTS: Participants (n = 19) were
      asked to follow for 19 days a diet high in saturated fat and then crossed over-
      without washout--for 19 days to a diet high in n-6 polyunsaturated fat.
      Participants were asked to maintain a total fat intake of 30-33% of total energy
      on both diets. Energy and nutrient intakes were assessed by self-reported food
      records covering 3 days. Plasma total cholesterol concentrations were measured on
      days 0, 1, 2, 5, 8, 12, and 19 of the n-6 polyunsaturated fat rich diet. Mean
      (95% CI) plasma total cholesterol concentration declined from 5.10 mmol/L (4.77,
      5.46) at day 0 to 4.25 mmol/L (3.83, 4.67) on day 12 and remained unchanged at
      4.23 mmol/L (3.85, 4.61) on day 19. A statistically significant decrease in
      plasma cholesterol concentration was achieved on day 2 of the intervention; by
      day 5, 59% (0.51 mmol/L) of the maximum reduction (0.87 mmol/L) had been reached.
      CONCLUSIONS: Adopting a lipid lowering diet initiates an immediate decline in
      plasma cholesterol concentration, the full effect of which is achieved within two
      weeks.

PMID- 12616810
TI  - Apoptosis and proliferation of endothelial cells in early atherosclerotic
      lesions: possible role of oxidised LDL.
AB  - BACKGROUND AND AIM: Evidence for apoptosis has been found in advanced
      atherosclerotic lesions, but the factors triggering it are poorly understood.
      Oxidised low-density lipoproteins (LDLs) are cytotoxic to a variety of cells and
      induce the apoptosis of smooth muscle cells (SMC), fibroblast, macrophages and
      endothelial cells in vitro. The aim of this study was to investigate apoptotic
      cell death in the early phases of aortic atherosclerosis in rabbits, and whether
      oxidised LDLs colocalize ex vivo with apoptotic cells in atherosclerotic lesions
      in cholesterol-fed rabbits. METHODS AND RESULTS: Male albino New Zealand rabbits
      were fed a standard diet or a diet containing 1.2% cholesterol for 60 days. The
      aortic arch of each animal was sectioned and stained with antibodies against SMC,
      endothelial cells, macrophages and oxidised LDLs or for proteins involved in
      apoptotic pathways such as Fas, Bax, Bcl2, and caspase 3. The nuclei in adjacent
      sections were stained with Hoechst 33258, TUNEL and for the proliferating cell
      nuclear antigen (PCNA). Early atherosclerotic lesions were characterised by
      intimal thickening and the presence of SMC and macrophages. The percentage of
      apoptotic cells, calculated as the ratio of TUNEL-positive nuclei to total nuclei
      was 32.6 +/- 3.73% in the lesions and 55.9 +/- 2.36% in the endothelium. As it
      has been reported that nuclei undergoing active gene transcription can be TUNEL
      positive, we evaluated the percentage of PCNA-positive cells, which proved to be
      45.2 +/- 4.68% along the endothelium and 22.3 +/- 2.7% in the intima. The true
      percentage of apoptotic cells was therefore about 10% in both cases. Fas, Bax and
      caspase3 signals were mainly located in the endothelium and SMC proximal to the
      lumen, whereas Bcl2 colocalized with macrophages and SMC deeper in the lesions.
      Abundant oxidised LDL epitopes were detected in areas of lipid accumulation and
      along the endothelium, mainly in the areas in which TUNEL and PCNA-positive cells
      were localised. CONCLUSIONS: Our findings may be taken as ex vivo indications of
      an apoptotic and proliferating role of oxidised LDLs as previously shown in
      vitro, and may at least partially account for the endothelial dysfunction that
      can be rapidly induced by hypercholesterolemia.

PMID- 12616811
TI  - High-altitude pulmonary edema: potential protection by red wine.
AB  - High-altitude pulmonary edema (HAPE) is the predominant cause of death due to
      high-altitude illness. At first sight, the observation that mountaineers
      regularly consume red wine in order to "feel better" seems to be paradoxical
      because, especially at higher altitudes, alcohol consumption could be
      detrimental. In this article, we review the potential mechanisms by which the
      components of red wine may beneficially affect the development of HAPE. DATA
      SYNTHESIS: The underlying cause of HAPE is the altitude-related reduction in
      barometric pressure, which leads to a decrease in partial pressure of oxygen in
      the alveolae and subsequently in the pulmonary capillaries and arterial system.
      Two cellular mechanisms have been described, both of which increase pulmonary
      vascular tone: enhanced endothelin 1 production and the increased generation of
      reactive oxygen species. Recent evidence has indicated that some of the compounds
      of red wine suppress endothelin 1 gene expression, and the anti-oxidative
      properties of red wine have been previously reported. CONCLUSION: This article
      briefly summarises the pathophysiological cellular events leading to HAPE and
      describes the potential mechanisms by which the ingredients of red wine may have
      a beneficial effect.

PMID- 12616812
TI  - A boycott by passport.

PMID- 12616813
TI  - Embracing the impossible profession.

PMID- 12616814
TI  - Who is Anna Wenne? Gender play within art's potential space.

PMID- 12616815
TI  - Craving, longing, denial, and the dangers of change: clinical manifestations of
      greed.
AB  - Greed is the unrelenting and unrealistic search for all the good an object has to
      offer and, via identification, all the good one can produce and provide. In
      phantasy, and sometimes in the patient's early developmental environment, the
      object and the ego demand more from each other than either have to give. Some
      patients cannot contain their urge to possess all and to be all, so it becomes a
      part of the interpersonal and psychological relationship with the analyst rather
      quickly. These patients feel something is owed to them, and they demand to be fed
      immediately. Other patients try and hide these greedy phantasies by being the
      opposite of greedy. They strive to be independent and charitable, while having
      great conflict over deeper desires to be dependent and in possession of an
      idealized giving object, an all-providing breast. Case material was used to
      explore these ideas.

PMID- 12616816
TI  - The curse of empire: grandiosity and guilt in the stories of Arthur Conan Doyle.

PMID- 12616817
TI  - Depression and its relation to light deprivation.
AB  - The absence or diminution of light is potentially an anxiety-arousing situation
      for, perhaps, all of us. Even a cursory look at the origin myths of many cultures
      reveals the chaotic, destructive, and dangerous aspects of darkness.
      Additionally, language reflects the same qualities metaphorically and
      symbolically. Developmentally, the arrival of the darkness of evening potentially
      signals object loss and ego regression. But factors other than ubiquitous
      references to a consideration of light and darkness are relevant. Can it be that
      we are all at least prone to depression due in part to this factor? Questions
      regarding possible biological causes of depression are perhaps unanswerable at
      this time. Is the seratonin level really associated with depression and light
      deprivation? Research is as yet inconclusive. If a relationship exists, another
      question must be asked: Will certain psychological situations affect a person's
      seratonin production? The answer to this question of how depression is associated
      with biological causes is certainly beyond the scope of this paper. Yet the
      preceding case history reveals at least some psychological causes of depression
      that were initially seen as biologically based. The SAD proponents would have
      treated Mr. B with light therapy. The quick solution of light therapy, based on a
      shaky theoretical base and lacking sturdy research, has too often replaced the
      psychoanalytic approach. In all too many situations psychoanalysts are being
      replaced by lightbulbs.

PMID- 12616818
TI  - [Role of extra-anatomical bypasses in the treatment of aorto-iliac occlusion].
AB  - In the last six years we have performed 468 operations because of aortoiliac
      occlusion or septic complications of these arteries. 410 (87.6%) of these
      operations were anatomical reconstructions, in 58 (12.4%) patients we performed
      extra anatomical bypasses. The distribution of the operations was the following;
      12 obturator, 23 femoro-femoral crossover, 13 axillofemoral and 10
      axillobifemoral bypasses. The indication for extra-anatomical reconstruction in
      24 (41.4%) patients was septic complication (EABS), and in 34 cases (58.6%) poor
      general condition or difficulties during surgery. The average age of the patients
      with non-septic indication (EABNS) was significantly higher than the average age
      of the patients treated with anatomical reconstruction (AR) (66.3 vs. 60.9 year,
      p < 0.01). There were more REDO operations in the group EABNS then in the AR
      group (35.3%/11.7% p < 0.02). Despite of the high operative risk, the rate of
      early complications (EABNS 13.8%, AR 10%) and postoperative mortality (EABNS
      3.7%, AR 4.0%) was not statistically different between the two groups. If the
      indication was aorto-duodenal fistula (6 patients) or acute limb ischaemia (7
      patients), the mortality was significantly higher compared to other extra
      anatomical operations (46.2% vs. 4.4%, p < 0.01). The postoperative mortality
      after EABNS and EABS operations was similar (11.7% vs. 16.6%), but we performed
      more reoperations after EABS operations (10/24 vs. 2/34, p < 0.05). According to
      our early postoperative results elective extra-anatomical bypasses are suitable
      for the treatment of aortoiliac occlusion in high risk patients, with poor life
      expectancy. Extra-anatomical bypasses are performed because of acute ischemia or
      septic complications which are life or limb threatening complications, so early
      results must be validated concerning this fact.

PMID- 12616820
TI  - [Hungarian surgeons and surgical treatment of stomach cancer at the turn of the
      Millennium. II. Regional extension of the resection].
AB  - Authors interviewed the most considerable Hungarian surgical clinics and
      departments about the operative treatment of gastric cancer using a question
      form. Forty-seven of 51 clinics and departments sent the questionnaires back.
      68.5 per cent of the gastric resections were performed in these clinics and
      departments in 1999. The main purpose of this paper was to show how the Hungarian
      surgeons decide the extension of the resection outside of the stomach. Extended
      lymphadenectomy is performed in 43 clinics and departments. Twenty-three
      institutes described splenectomy to be necessary in case of cardiac or upper
      third tumors and 21 clinics and departments perform it in case of suspicious
      hilar lymph nodes. Combined, extended operation is performed if the tumorous
      infiltrates surrounding organs in 38 institutes if radical resection is feasible,
      and 8 clinics and departments perform it as palliation as well. Showing the
      results of prospective randomised studies we analyse the answers of the
      questionnaires. Our opinion is not described here. In addition to demonstrating
      the Hungarian situation we would like our readers to compare their own practice
      with the principles of other authors.

PMID- 12616819
TI  - [Hungarian surgeons and surgical treatment of stomach cancer at the turn of the
      Millennium. I. Extent of stomach resection].
AB  - Authors interviewed the most prestigeous Hungarian surgical clinics and
      departments about the operative treatment of gastric cancer using question form.
      Forty-seven of the involved 51 clinics and departments filled out and sent the
      questionnaires back. 68.5 per cent of the gastric resections were performed by
      these clinics and departments in 1999. The main purpose of this paper was to show
      how the Hungarian surgeons decide the extension of the resection on the organ.
      Only 5 out of 47 clinics and departments are satisfied with 2-3 cm long resection
      distance proximally from the tumor, 25 of 47 answering institutes aimed to 4-6 cm
      and 15 of them think that more than 6 cm is necessary. In case of antral tumor 2
      departments perform total gastrectomy. Seventeen clinics and departments perform
      subtotal resection in case of antral tumor. Seventeen institutes decide to
      perform subtotal or total gastrectomy depending on the preoperative histology.
      Thirty-two departments perform total gastrectomy in case of mid-third tumors, and
      15 of them perform subtotal gastrectomy if the resection distance is adequate.
      The necessity of total gastrectomy is generally accepted in case of tumors in the
      proximal third. Only two departments perform proximal resections regularly and 8
      departments perform that in selected cases. Describing the results of prospective
      randomised studies we analyse the answers of the questionnaires. Our opinion is
      not described here. In addition to demonstrating the Hungarian situation we would
      like our readers to compare their own practice with the principles of other
      authors.

PMID- 12616821
TI  - [Effect of extending the resection on postoperative complications of total
      gastrectomies: experience with 161 operations].
AB  - Authors operated on 416 patients for gastric cancer between 1st of June 1991 and
      31st of May 2001. Among them 305 lesions were resectable. So the resection rate
      was 73.3 per cent. Gastrectomy was performed in 161 patients (52.8 per cent of
      resections). Total gastrectomy with omentectomy was performed in 44 patients. In
      96 patients splenectomy, in 19 patients splenectomy with the resection of the
      left side of the pancreas, in 33 patients distal esophageal resection and in 8
      patients other organ resection was performed with total gastrectomy. Standard,
      two field lymphadenectomy has been performed only in the past few years.
      Uneventful recovery followed in 100 cases (62 per cent), 61 patients (38 per
      cent) suffered complications in the postoperative period. The most frequent
      surgical complication was anastomotic leak, which was observed in 8 patients (5
      per cent). Septic complications, intraluminal bleeding, postoperative
      pancreatitis, intraabdominal bleeding, pancreatic fistula and small bowel
      obstruction were the most frequent surgical complications. Most general
      complications occurred in the cardiorespiratory system. In 9 patients reoperation
      was necessary. Eight patients (5 per cent) died in the postoperative period. In
      patients with extended gastrectomy significantly more complications occurred-
      compared with gastrectomy + omentectomy only. This could also be observed in
      patients with only splenectomy. If more organs were removed or resected with
      total gastrectomy and splenectomy, the complication rate increased only if
      pancreatic resection was performed. Mortality rate increased in these patients as
      well. The esophageal or other neighbouring organ (colon, small-bowel, liver,
      diaphragm etc.) resection had no influence on the postoperative morbidity or
      mortality. Extended operations should be performed, as the risk is acceptable, if
      there is hope for tumour clearance.

PMID- 12616822
TI  - [Effect of prophylactic N-acetylcysteine on postoperative organ dysfunction and
      inflammatory markers after major abdominal surgery for cancer. Prospective,
      randomized, double-blind, placebo-controlled clinical trial].
AB  - OBJECTIVES: To investigate whether short-term N-acetylcysteine (NAC) infusion
      administered before and during extensive abdominal surgery could modify the
      progression of early postoperative organ dysfunction and systemic inflammatory
      response. METHODS: After randomisation the treatment group (n = 47) received NAC
      (150 mg kg-1 bolus followed by a continuous infusion of 12 mg kg-1 h-1) and the
      placebo group (n = 46) received the same volume of 5% dextrose during surgery.
      Clinical progress was monitored by the Multiple organ dysfunction score, systemic
      inflammatory response by serum procalcitonin (PCT), C-reactive protein (CRP) and
      microalbuminuria during the first 3 postoperative days. Mann-Whitney and chi 2
      tests were used for statistical analysis. RESULTS: There was no significant
      difference between the two groups regarding the MODS, organ dysfunction, length
      of intensive care stay, days of mechanical ventilation and mortality. PCT and
      microalbuminuria did not differ significantly. Significantly lower CRP levels
      were found in the NAC group on day one and two [t24: median: 84.5 interquartile
      range: (62.48-120.25) vs. 118 (86-137) mg/l; p = 0.020; t48: 136 (103-232) vs.
      195 (154.5-252) mg/l p = 0.013, NAC vs. placebo]. CONCLUSION: The results of this
      study do not support the routine use of NAC as a prophylactic drug during
      surgery, and reinforce previous evidence which challenge the indication of NAC in
      the critically ill patient.

PMID- 12616823
TI  - [Sentinel lymph node mapping in colorectal cancer].
AB  - Sentinel lymph node mapping has already been accepted as part of the treatment
      for malignant melanomas of the skin and in breast carcinomas. The status of lymph
      nodes is an important prognostic marker in colorectal carcinoma as well. The
      authors tried the feasibility of this technique in colorectal carcinomas. The
      technique is analogous to the one used in breast cancer and melanoma: 2 ml of
      2.5% Patentblau dye was given subserosally around the tumor. After resection the
      specimen was immediately sent to pathology where the lymph nodes were removed.
      This technique has been tried on 31 patients, 22 with colonic and 9 with rectal
      tumors. Of these patients, 15 were Dukes stage C, 14 were Dukes stage B and 2
      were Dukes stage A. An average 4.3 blue lymph nodes were found in colon tumors
      and 5.4 in rectal tumors and an average 14 unstained lymph nodes were found in
      colon tumors, and 7 in rectal tumors. The blue nodes were predictive of the nodal
      status in 9 of the 15 Dukes stage C patients. In these cases the blue lymph nodes
      contained metastases and there were 2 cases where metastases were limited to the
      blue lymph nodes. SUMMARY: The authors found a high false negative rate for
      lymphatic mapping with the vital dye technique, therefore they try to change the
      method according to that used by Saha et al. The aim of sentinel node
      identification in colorectal carcinomas would be improved staging rather than
      reducing of the extent of lymphadenectomy. The role of lymphatic mapping in large
      bowel cancers needs further investigations. Until the results are reliable, as
      many lymph nodes as possible have to be excited and sent for histology.

PMID- 12616824
TI  - [Late reconstructive surgery for cloaca malformations].
AB  - The rarity of cloacal anomalies, the wide range of anatomical variants, and the
      number of different operations mean that successful management of a patient
      (neonate or child) with this condition is one of the greatest challenges for
      paediatric surgeons. The authors describe the complex corrections of 3 patients
      with cloacal malformation (age 10-13 years). The cloacal malformations were not
      diagnosed at neonatal age and therefore only the anorectal agenesis was corrected
      at the first stage. The authors strongly recommend that all components of this
      anomaly (urethra, vagina and anorectum) should be managed in one step. Because of
      the rarity and complexity of cloacal malformations, the anomaly should be
      operated on only in specialised centres.

PMID- 12616825
TI  - [Intramural esophageal metastasis of diffuse, infiltrative gastric
      adenocarcinoma].
AB  - Authors report a patient with a gastric carcinoma that developed an intramural
      metastasis to the oesophagus. The diagnosis of the metastasis was suggested on
      endoscopy and was verified by pathohistology. Preoperative investigations
      suggested advanced cancer. During the operation an inoperable tumour was found.
      Authors describe the methods to diagnose oesophageal metastasis.

PMID- 12616826
TI  - Personality disorders at the crossroads.
AB  - Personality disorders are now at a crossroads with respect to theory, research,
      and conceptualization. In this article, we review relevant and current issues
      within the personality disorder field. After reviewing changes in the conception
      of personality disorders across the past half century (1952 to 2002), we focus on
      the issue of continuity versus discontinuity methodologies for assessing
      personality, interactionism, treatments, resolved and unresolved issues, and
      future directions. The issue of continuity versus discontinuity is a theme in
      this article. We conclude that the evidence is in favor of a reapprochment
      between a categorical classification system and a dimensional system and we also
      outline the difficulties in achieving this change.

PMID- 12616827
TI  - Defining disordered personality functioning.
AB  - Current definitions of the PDs commonly combine descriptors of personality style
      and disordered personality functioning. This leads to artefactual comorbidity of
      formally separate disorders and compromising of diagnostic precision. We suggest
      that measurement of disordered functioning alone might provide a more efficient
      and precise first-level measure of PD. We review candidate constructs for the
      definition of disordered functioning and consider how constructs might be refined
      in subsequent research and lead to applied measures.

PMID- 12616828
TI  - The relation between depressive symptoms and borderline personality disorder
      features over time in dysthymic disorder.
AB  - Dysthymic Disorder (DD) and Borderline Personality Disorder (BPD) frequently co
      occur. To understand this association better, we tested four competing models of
      the relationship between depressive and BPD symptoms over time in DD: (a) no
      association between depression and BPD over time; (b) contemporaneous direct
      effects in which BPD features and depressive symptoms influence one another over
      a relatively short time period; (c) lagged direct effects in which one condition
      influences the other condition over a longer period; and (d) a fixed common
      factor underlies both depression and BPD, along with influences that are unique
      to each condition. We assessed 84 outpatients with DD three times over 5 years
      using semistructured interviews. Data were analyzed using structural equation
      modeling techniques. The fixed common factor model was the best fitting of the
      models, providing an excellent fit to the data. These results suggest that
      depressive symptoms and BPD features in DD arise from partially overlapping
      processes.

PMID- 12616829
TI  - Perceived dysfunction of male-typed and female-typed DSM-IV personality disorder
      criteria.
AB  - To determine whether female-typed personality disorders are associated with a
      different pattern of dysfunction than male-typed disorders, lay judges (N = 216)
      estimated the amount of social impairment, occupational impairment, and personal
      distress related to symptoms of personality disorders. Results for both the
      subset of six disorders originally rated by clinician judges in the research of
      Funtowicz and Widiger (1999) and for a larger set of nine disorders revealed a
      pattern originally reported by Funtowicz and Widiger where female-typed disorders
      were associated with relatively higher ratings of personal distress, whereas male
      typed disorders were associated with relatively higher ratings of social (and
      sometimes occupational) impairment. Findings are discussed with respect to the
      emphasis of different forms of dysfunction for male- and female-typed disorders,
      lay versus clinician judgments, and directions for future research.

PMID- 12616831
TI  - High-risk situations associated with parasuicide and drug use in borderline
      personality disorder.
AB  - Both parasuicide and drug use continue to be difficult problems to treat in
      borderline personality disorder (BPD). One useful approach that has not yet been
      applied to BPD is to develop a taxonomy of triggering situations for these
      problems. Once these high-risk precipitants are identified, then the behaviors
      can be targeted with skills training. This model has been applied by Marlatt
      (1996) with very influential results. To examine high-risk situations for
      parasuicide and drug use in BPD, the current study examined women with BPD who
      came to treatment for two different primary problems: parasuicide (N = 75) and
      drug dependence (N = 47). Participants identified the situation associated with
      highest risk for relapse in either the parasuicide or drug category. A taxonomy
      is presented, which divides results into six main categories. Differences between
      high-risk situations for drugs and parasuicide were also explored. Parasuicide
      was significantly more likely to be linked to interpersonal problems, whereas
      drug use was more likely to be preceded by addiction cues (i.e., being near drugs
      or people who use drugs).

PMID- 12616830
TI  - Sociotropy, autonomy, and personality disorder criteria in psychiatric patients.
AB  - Sociotropy and autonomy (Beck, 1983) are sets of beliefs, concerns, and
      behavioral tendencies that are proposed to create vulnerability to depression and
      other psychopathology and to influence its manifestation and treatment response.
      Other theoretical frameworks (Blatt, 1974) have made similar suggestions. We
      investigated the differential relations of sociotropy and autonomy to dimensional
      scores for each DSM-III-R personality disorder (PD) in a sample of 188
      psychiatric patients, controlling for the other set of characteristics and for
      the other PDs. Histrionic and dependent PD traits were related specifically to
      sociotropy. Paranoid, schizoid, schizotypal, and passive-aggressive PD traits
      were related specifically to autonomy. Borderline, narcissistic, avoidant, and
      self-defeating PD traits were related significantly and about equally to both
      sociotropy and autonomy. Obsessive-compulsive PD traits were not related
      consistently to either. Results were mostly as predicted and suggest that
      sociotropy and autonomy may be useful constructs for understanding and treating
      PDs.

PMID- 12616832
TI  - Avian cardiology.
AB  - The field of avian cardiology is continually expanding. Although a great deal of
      the current knowledge base has been derived from poultry data, research and
      clinical reports involving companion avian species have been published. This
      article will present avian cardiovascular anatomy and physiology, history and
      physical examination considerations in the avian cardiac disease patient,
      specific diagnostic tools, cardiovascular disease processes, and current
      therapeutic modalities.

PMID- 12616833
TI  - Avian renal disease: pathogenesis, diagnosis, and therapy.
AB  - Avian renal diseases are common in practice but are often undetected or
      misdiagnosed. Polyuria can be interpreted as diarrhea leading to inappropriate
      investigation and therapy. The avian urinary system differs from the mammalian.
      This article explains the anatomy and physiology of the avian kidney and focuses
      on the diagnosis of renal disorders. In particular, blood chemistry, urinalysis,
      radiography, urography, ultrasonography, computed tomography, and endoscopy
      (including biopsy) are explained and illustrated. Specific avian renal disorders
      and treatment possibilities are discussed.

PMID- 12616834
TI  - Physiology, diagnosis, and diseases of the avian reproductive tract.
AB  - Disorders of the reproductive system represent a large portion of both large and
      small domestic animal medicine. Although some disorders of this system have been
      extensively studied in birds, this science is still in its infancy, when compared
      to mammalian reproductive medicine. This may be due to several reasons, but the
      simple fact that birds are oviparous renders knowledge of mammalian reproductive
      anatomy, histology, physiology, and disease process, inapplicable to avian
      patients. Nevertheless, several specific diseases or conditions affecting the
      reproductive system of birds have been described. By integrating information
      about the comparative anatomy and physiology of birds, reports of the most common
      reproductive diseases of birds and utilizing the latest diagnostic techniques,
      especially videoendoscopy, the avian practitioner should be able to diagnose and
      properly treat a high percentage of the avian reproductive diseases.

PMID- 12616835
TI  - The anatomy, physiology, and diseases of the avian proventriculus and
      ventriculus.
AB  - Diseases affecting the proventriculus and ventriculus often present with similar
      clinical signs. It is important for the avian practitioner to be familiar with
      these diseases, their prevalence, and the species most commonly affected to
      judiciously prioritize the appropriate diagnostic techniques. A basic
      understanding of the anatomy and physiology of the proventriculus and ventriculus
      is useful in integrating the pathophysiology and clinical signs associated with
      variable disease processes. It is also essential to evaluate radiographs and
      endoscopic images, perform diagnostic techniques, make a diagnosis, and provide
      appropriate therapy.

PMID- 12616836
TI  - Ferret urogenital diseases.
AB  - Improved nutrition and client education have decreased the incidence of certain
      urinary tract diseases in ferrets. Early neutering programs at commercial
      breeding farms in the United States have also led to a marked decrease in the
      incidence of reproductive tract disease, especially estrogen-induced bone marrow
      suppression. However, the increased incidence of adrenal disease and its
      secondary effects on reproductive and associated urinary tract tissue presents an
      ongoing challenge for the clinician working with pet ferrets. Acute and chronic
      renal failure remain important, though less common, disease entities. It is
      imperative that the veterinarian working with pet ferrets be aware of the
      clinical presentation and clinicopathologic abnormalities associated with these
      syndromes.

PMID- 12616837
TI  - Rabbit gastrointestinal physiology.
AB  - The rabbit's gastrointestinal physiology is a complex system that centers around
      the separation of digestible and indigestible components of the diet in the
      proximal colon. The clinical importance of this system is the need for a
      consistent diet high in long particle length (> 0.5 mm) indigestible fiber to
      maintain the motility of the cecum and colon. Most of the common gastrointestinal
      problems seen in captive rabbits are related to inappropriate diets (low fiber;
      high protein; high carbohydrate) and infrequent feeding of treats to which the
      rabbit is not accustomed. Many of these problems can be avoided if captive
      rabbits are fed a diet consisting primarily of fibrous vegetation, such as grass,
      hay, and fibrous weeds. Feeding of fruits, grains, and carbohydrate or fat-based
      treats should be avoided. Pelleted feeds, although convenient, should be kept to
      a minimum, and where pellets are used those manufactured by an extrusion process,
      which retains the long particle length of the indigestible fiber, should be
      chosen.

PMID- 12616838
TI  - Cholesterol, corneal lipidosis, and xanthomatosis in amphibians.
AB  - Many captive amphibians have high serum or plasma cholesterol and concomittant
      lesions such as corneal lipidosis and xanthomas. The underlying cause of this
      disorder is unknown, but it is likely that a diet high in cholesterol plays a
      role. The metabolism of lipids in healthy amphibians remains poorly documented,
      which makes it challenging to interpret the findings in affected specimens.
      Affected amphibians should be maintained on a low-cholesterol diet and fed
      sparingly, and their captive environment modified to provide an optimal
      temperature gradient for thermoregulation.

PMID- 12616839
TI  - Osmoregulation in fish. Mechanisms and clinical implications.
AB  - Fish have developed remarkable mechanisms for coping with life in water. The
      salinity/osmolarity of aquatic habitats can be quite variable. Fish have evolved
      mechanisms for maintaining fluid and electrolyte homeostasis across a wide range
      of salinities. Marine teleosts, freshwater teleosts, and marine elasmobranchs all
      utilize different physiologic strategies for osmoregulation. Kidneys do play a
      role in osmoregulation, but overall, extrarenal mechanisms are equally if not
      more important sites for maintaining osmotic homeostasis. Extrarenal sites
      include the gill tissue, the alimentary tract, the rectal gland (elasmobranchs),
      and the urinary bladder. Through an understanding of osmoregulatory physiology in
      these three groups of fishes, the effects of injury and disease on fluid and
      electrolyte balance can be elucidated. Armed with this knowledge and the results
      of diagnostic testing, safe and effective fluid/electrolyte support can then be
      instituted.

PMID- 12616840
TI  - Diseases of the reptile pancreas.
AB  - A great deal of research is still needed to better understand the reptile
      pancreas especially with regard to diagnosis and treatment. However, vigilant
      clinicians and pathologists have important roles to play in expanding our
      knowledge base in this field, and are encouraged to share their findings through
      publications and presentations.

PMID- 12616841
TI  - Reptile respiratory medicine.
AB  - Respiratory tract disease is commonly diagnosed in captive collections of
      reptiles and associated with high morbidity and mortality. Improper environmental
      conditions are often contributing factors for the development of respiratory
      disease in reptiles. A detailed knowledge of the unique reptilian respiratory
      morphology and function is essential to successfully diagnose and treat
      respiratory disease. A variety of noninfectious and infectious causes have been
      identified in the etiology of reptile respiratory disease. Knowledge of the
      pathophysiology of reptilian diseases is increasing, and with the availability of
      new therapeutic agents and advanced diagnostic techniques, the diagnosis and
      treatment of reptile respiratory tract disease has become more successful.

PMID- 12616842
TI  - Green iguana nephrology: a review of diagnostic techniques.
AB  - There is still much to learn about renal physiology and pathophysiology in
      reptiles. In the case of the green iguana, initiating causes are often inferred
      from poor husbandry and nutrition, or extrapolated from histopathologic
      interpretations made late in the course of the disease, or at postmortem. The
      link between parathyroid hormone and renal disease in humans has been well
      documented and, given the high prevalence of clinical (and subclinical) secondary
      nutritional hyperparathyroidism in iguanas, this certainly warrants further
      investigation in saurians [31,32,34,35]. Apart from hyperparathyroidism, chronic
      water deprivation also appears to be a common historic factor. As a foliovore
      originating from the high humidity rain forests of central and South America,
      water recovery is not considered to be an adaptive stress in Iguana iguana, and
      therefore, renal anatomy and physiology are considered to be non-specialized
      compared to more arid or aquatic reptiles [21]. These arboreal lizards do not
      voluntarily drink from open water but instead imbibe rain or dew droplets from
      foliage [2]. Maintaining such a species in low relative humidity with a water
      bowl from which to drink is likely to both increase insensible water losses and
      interfere with normal water intake. Appropriate therapeutic decisions (including
      euthanasia) can only be made following an accurate diagnosis. To date, our
      diagnoses are based largely upon the structural evaluations of renal
      histopathology, and renal biopsy remains our most useful tool. However, in the
      future it may become possible to evaluate renal function by quantifying
      glomerular filtration rate, proximal tubular secretion, or functional renal mass.
      Glomerular filtration rate may be estimated by measuring the rate of glomerular
      clearance of substances from the blood (e.g., iohexol). Phenolsulphonphthalein
      assays may offer an insight into proximal tubule secretion and renal blood flow.

PMID- 12616843
TI  - Neoplasia of reptiles with an emphasis on lizards.
AB  - Neoplasia is an important form of disease in saurians. According to previous
      reviews, the organs most commonly affected by neoplastic disease are the
      hematopoeitic system, the hepatic system, and the skin. However, our own review
      suggests that tumors of the musculoskeletal system are also prevalent. Neoplasia
      should be considered as a significant differential diagnosis when presented with
      a lizard that has nonspecific clinical signs. The previously described diagnostic
      techniques should be applied to obtain a rapid and accurate definitive diagnosis.
      As more cases of neoplastic disease in saurians are reported, a comprehensive
      study of the data, including detailed examination of environmental factors, may
      bring forth causative agents. According to Withrow, cancer is one of the leading
      killers of pet animals, and thus has become a real concern for dog and cat owners
      [67]. Given that most people will either know someone with cancer or experience
      cancer first hand, the general public is more educated than ever on neoplastic
      disorders. As veterinarians, it is important to become familiar with the
      neoplastic diseases in all species, and to be educated in tumor pathophysiology
      and treatment. The public expects veterinarians to be dependable sources of
      knowledge and compassion.

PMID- 12616844
TI  - A model for the future conduct of pharmacovigilance.
AB  - A scientific model to support excellence in pharmacovigilance has been developed
      from first principles by brainstorming sessions and discussions with experts in
      the field. The model represents a long-term vision of how pharmacovigilance could
      be conducted in the future. So far it has been developed without any
      consideration of constraints such as resources or the need for legislative
      change. Although the vision is holistic, it would be possible to test and
      implement parts of the model in a piecemeal fashion.

PMID- 12616845
TI  - Prolongation of the QT interval and cardiac arrhythmias associated with
      cisapride: limitations of the pharmacoepidemiological studies conducted and
      proposals for the future.
AB  - Not all hazards can be identified from clinical studies prior to marketing of
      medicinal products. Pre-marketing large-scale trials for cisapride did not report
      any serious cardiac arrhythmias. After a long period of availability in several
      countries it was withdrawn in 2000 because of reports of serious, and in many
      cases fatal, cardiac events. Whilst spontaneous reporting systems for adverse
      drug reactions (ADRs) have limitations such as under-reporting, they are an
      effective system for signal generation, particularly of rare ADRs.
      Pharmacoepidemiological studies aim to identify and calculate the incidence of
      adverse reactions, with increased sensitivity to less common ADRs compared to
      randomised controlled trials, yet cohort sizes may be insufficient to detect very
      rare ADRs such as drug-induced Torsade de Pointes, with an estimated incidence of
      the order of 1 per 12,000 to 1 per 120,000 patients. Several
      pharmacoepidemiological studies investigated adverse events associated with
      cisapride, one of which specifically examined the association between serious
      cardiac arrhythmias and cisapride. These observational studies were conducted
      using large population databases, but each failed to identify sufficient cases to
      establish a causal relationship. Explanations include that the cohort sample
      sizes were too small, and either under-, or mis-reporting of events of interest
      may have occurred. To estimate the risk of very rare adverse events,
      pharmacoepidemiological studies require very large numbers. Furthermore, the
      events in question need to be clinically recognisable by doctors and adequately
      documented in patients' notes, computer records, or on study questionnaires. The
      establishment of a national registry for drug-induced QT prolongation to identify
      cases and correlate clinical information may help to better identify these rare
      ADRs earlier. Such proactive surveillance could avoid unnecessary delays for
      other drugs where QT prolongation and serious cardiac arrhythmias may be an
      issue.

PMID- 12616846
TI  - Antipsychotic medication coprescribing in a large state hospital system.
AB  - PURPOSE: To systematically characterize antipsychotic medication coprescribing
      ('polypharmacy') in a large state hospital system. METHODS: All antipsychotic
      prescriptions written for all adult in-patients (N = 8212) in New York state-run
      civil facilities for the year 1999 were identified using the Integrated Research
      Database (IRDB) created by the Information Systems Division of the Nathan Kline
      Institute for Psychiatric Research. Antipsychotics were considered to be
      intentionally coprescribed only when both were prescribed for an overlapping
      period of 28 days. RESULTS: Coprescribing of typical, atypical, and depot
      antipsychotics comprised 31% of antipsychotic prescribing episodes. Medications
      were usually coprescribed with medications from outside their own antipsychotic
      class. Patient factors, such as age, diagnosis, and history of prior
      hospitalization, affected coprescribing rates (p < 0.001 for all indicated
      variables). Atypical antipsychotic medications were less likely to be given with
      another antipsychotic than were oral or depot typical medications. CONCLUSIONS:
      Coprescribing of antipsychotic drugs is a common practice in the New York State
      hospital system. The analysis of large clinical databases can yield valuable
      information about the kinds of complex pharmacotherapy regimens actually utilized
      in the treatment of the most severely ill patients.

PMID- 12616847
TI  - Comparing patterns of long-term benzodiazepine use between a Dutch and a Swedish
      community.
AB  - BACKGROUND: There is much concern about the widespread long-term use of
      benzodiazepines. Utilisation data can give a foundation for interventions for
      appropriate use. OBJECTIVE: To compare long-term usage patterns of
      benzodiazepines in a Dutch and a Swedish community in different periods. METHODS:
      Eight-year follow-up patterns of use were investigated with respect to the
      characteristics of those who continued use over the whole follow-up period. In
      the Dutch community of 13,500, the data of a cohort of 1358 benzodiazepine users
      were analysed during the years 1984-1991; in the Swedish community of 20,000
      people, a cohort of 2038 benzodiazepine users was followed from 1976. RESULTS: At
      the end of the follow-up period, 32.9% of the Dutch cohort and 33% of the Swedish
      cohort had continued use of benzodiazepines. The two overall survival curves
      showed similar patterns. Stratification for age, gender, previous versus initial
      use and heavy versus non-heavy use showed comparable proportions of patients
      continuing benzodiazepine use over time. CONCLUSION: The parallels in the results
      of two cohorts in different countries and different periods are striking and give
      support to the idea to stimulate interventions to reduce long-term benzodiazepine
      use.

PMID- 12616848
TI  - Patient information leaflets--helpful guidance or a source of confusion?
AB  - BACKGROUND: According to the European Community Directive 92/27, pharmaceutical
      companies are responsible for working out patient information leaflets (PILs) for
      all products marketed, and every PIL should comply with the Summary of Product
      Characteristics (SPC) and be phrased so that it is easily understandable by the
      patient. However, the volume of information included in the PIL may differ for
      different brands, and furthermore, the same drug may be registered for different
      indications. Patients may therefore receive different drug information when they
      renew prescriptions for the same generic drug. OBJECTIVES: To examine if PILs on
      different brands of generically identical drugs contain inconsistent and
      diverging information that may lead to confusion. DESIGN: Case-finding among
      patients who contacted a pharmacy because of problems related to the information
      retrieved from the PIL. SETTING: Inquiries to a Danish pharmacy during one year
      (1 June 2000-31 May 2001). RESULTS: Different brands of generically identical
      products included PILs with substantial inconsistencies. Diverging information
      about indications for drug use, adverse effects, drug-drug interactions and
      precautions and considerations concerning pregnancy and breastfeeding resulted in
      inquiries to the pharmacy. CONCLUSION: Patients may be confused by inconsistent
      information in PILs from different brands of generically identical drugs.
      Confusion about drug treatment may lead to reduced compliance and initiatives
      should be taken to coordinate information in PILs covering the same generic
      product.

PMID- 12616849
TI  - Safety and patient tolerance of standard and slow-release formulations of NSAIDs.
AB  - OBJECTIVE: To examine the rates of co-prescribing of gastro-protective drugs
      (GPDs) and the frequency of gastrointestinal (GI) investigations associated with
      standard and slow-release (SR) formulations of nonsteroidal antiinflammatory
      drugs (NSAIDs). METHODS: Patients were identified from the MediPlus database,
      which contains the medical records of some 2 million patients throughout the
      United Kingdom. We selected all new NSAID users who received at least one
      prescription between 1 July 1997 and 31 December 1997. Patients were classified
      as starting SR or standard formulations by their first prescription and followed
      for 12 months. Events specified as of interest included GPDs prescribed and GI
      investigations. GPDs included prescriptions for all proton pump inhibitors, H2
      antagonists and misoprostol. GI investigations included endoscopies and barium
      contrast studies. RESULTS: Taken overall, patients prescribed SR formulations of
      NSAIDs were significantly more likely to receive GPDs than those prescribed
      standard formulations, odds ratio (OR) 1.34, 95% confidence intervals (CI) 1.21
      1.47. They also tended to be more likely to need GI investigations (OR 1.25, CI
      0.91-1.71). Differences were not explained by prior predisposition to GI damage
      as judged by the previous need for GPDs, and were evident whether the NSAID
      prescription was the first, the second, or the third or later in the series (OR
      1.40, CI 1.21-1.62; 1.33, 1.08-1.62; and 1.17, 1.00-1.38 respectively).
      CONCLUSION: This study found that patients prescribed SR formulations of NSAIDs
      were significantly more likely to receive GPDs, and may be more likely to need GI
      investigations than those receiving standard formulations. In addition, switching
      away from SR formulations was far more common than switching to them.

PMID- 12616851
TI  - Letter to the ISPE commentary editor.

PMID- 12616850
TI  - COX-2 selective non-steroidal anti-inflammatory drugs and cardiovascular disease.

PMID- 12616852
TI  - Pharmacoepidemiology and drug safety.

PMID- 12616853
TI  - [Recent advances in the study of endothelium-dependent hyperpolarizing factor
      (EDHF)].
AB  - Recent advances in the properties and physiological functions of endothelium
      dependent hyperpolarizing factor (EDHF) in vascular tissues were reviewed
      briefly. The EDHF-induced hyperpolarization is inhibited by charybdotoxin,
      indicating that the potential is produced mainly by activation of intermediate
      conductance Ca-sensitive K-channels. During generation of EDHF responses,
      endothelial Ca2+ concentration was elevated, suggesting that the activated K
      channels were distributed on the endothelial membrane. This was confirmed by
      direct recording of membrane potentials from endothelial and smooth muscle cells
      using double patch electrodes. Measurement of the propagation of potentials
      applied to endothelial or smooth muscle cells to surrounding cells revealed that
      there were tight electrical connections between endothelial cells much more than
      between endothelial and smooth muscle cells or between smooth muscle cells, and
      these observations yielded a possible spread of electrical signal along the
      endothelial layer first, and then the signals would be conducted to smooth muscle
      cell layers. These properties of vascular tissues allow speculating that EDHF is
      an electrical signal propagated from endothelial cells electrotonically through
      myoendothelial gap junctions. Several candidates have been proposed as EDHF, and
      possibilities of individual substances for EDHF were discussed. The cellular
      mechanism of the hyperpolarization-induced vasodilatation remains unclear, and
      this should be clarified in the future for further understanding of the EDHF
      induced vasodilatation.

PMID- 12616854
TI  - [New expansion of endothelin research: perspectives for clinical application of
      endothelin-receptor antagonists].
AB  - Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through
      stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial
      cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1
      has direct mitogenic actions on cardiovascular tissues, as well as comitogennic
      actions with a wide variety of growth factors and vasoactive substances. ET-1
      also promotes the synthesis and secretion of growth factors and various
      substances, including extracellular constituents. These effects of endogenous ET
      1 would naturally be thought to be concerned with the development and/or
      aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary
      hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and
      heart failure. A large number of peptide and orally active non-peptide endothelin
      receptor antagonists have been developed, and utilized to analyze physiological
      and pathophysiological roles of endogenous ET-1. These antagonists have been
      shown to exert excellent therapeutic effects in animal models of various kinds of
      diseases by either acute or chronic treatment. Therapeutic treatment of patients
      suffering from the above-mentioned cardiovascular diseases with ET-receptor
      antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was
      recently approved by the FDA as a formal therapeutic drug for pulmonary
      hypertension. In this review, perspectives for therapeutic applicability of ET
      receptor antagonists will be explored.

PMID- 12616856
TI  - [Detections of matrix metalloproteinases activities and localization by film in
      situ zymography (FIZ)].
AB  - Extracellular proteolysis is an essential process for cell migration in several
      diseases such as tumor invasion, metastasis, and angiogenesis. In an invasive
      process, matrix metalloproteinases (MMPs) play a central role as degradation
      enzymes of extracellular matrix. Immunohistochemical staining (IHC) or ELISA
      methods have been carried out for the detection of tissue MMP proteins, and MMP
      activities have been mainly measured by gelatin zymography. Recently, film in
      situ zymography (FIZ) was developed for the regional detection of tissue MMP
      activities. FIZ uses a polyester film coated with gelatin uniformly and thinly.
      Frozen sections are incubated on the film at 37 degrees for optimal time. After
      gelatin staining with Biebrich Scarlet, the unstained area corresponds to MMP
      activities. The regional detection of tissue MMP activities by FIZ is simple and
      quantitative, and it is a useful tool for the studies of many diseases involving
      MMP. The detection of precise localization of MMP activity in tissues by FIZ may
      contribute the new classification of diseases involving MMP.

PMID- 12616855
TI  - [Regulatory role of mechanical stress response in cellular function: development
      of new drugs and tissue engineering].
AB  - The investigation of mechanotransduction in the cardiovascular system is
      essentially important for elucidating the cellular and molecular mechanisms
      involved in not only the maintenance of hemodynamic homeostasis but also etiology
      of cardiovascular diseases including arteriosclerosis. The present review
      summarizes the latest research performed by six academic groups, and presented at
      the 75th Annual Meeting of the Japanese Pharmacological Society. Technology of
      cellular biomechanics is also required for research and clinical application of a
      vascular hybrid tissue responding to pulsatile stress. 1) Vascular tissue
      engineering: Design of pulsatile stress-responsive scaffold and in vivo vascular
      wall reconstruction (T. Matsuda); 2) Cellular mechanisms of mechanosensitive
      calcium transients in vascular endothelium (M. Oike et al.); 3) Cross-talk of
      stimulation with fluid flow and lysophosphatidic acid in vascular endothelial
      cells (K. Momose et al.); 4) Mechanotransduction of vascular smooth muscles: Rate
      dependent stretch-induced protein phosphorylations and contractile activation (K.
      Obara et al.); 5) Lipid mediators in vascular myogenic tone (I. Laher et al.);
      and 6) Caldiomyocyte regulates its mechanical output in response to mechanical
      load (S. Sugiura et al.).

PMID- 12616858
TI  - The relentless storm.

PMID- 12616857
TI  - [Preclinical and clinical profile of imatinib mesilate, a potent protein-tyrosine
      kinase inhibitor for CML therapy].
AB  - Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently
      inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet
      derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and
      cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in
      chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate
      that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic
      approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl
      positive cell lines and suppress the formation of bcr-abl-positive colonies in
      cells derived from bone marrow of CML patients. This compound induced apoptosis
      in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that
      imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in
      mice. As the profile expected from the preclinical studies, imatinib mesilate
      showed impressive hematological and cytogenic responses in the clinical trials,
      including interferon-alpha-resistant or intolerant patients.

PMID- 12616859
TI  - The search for dark matter.

PMID- 12616860
TI  - Dismantling nuclear reactors.

PMID- 12616862
TI  - Digital entertainment jumps the border.

PMID- 12616861
TI  - Restoring aging bones.

PMID- 12616863
TI  - Which came first,  the feather or the bird?

PMID- 12616865
TI  - No two alike.

PMID- 12616866
TI  - Theory and practice: intimate partnership or false connection?

PMID- 12616864
TI  - Bugs in the brain.

PMID- 12616867
TI  - Some complexities in the relationship of psychoanalytic theory to technique.
AB  - This paper considers the current fragmentation of psychoanalytic theory as a
      result of the illusorily close association of practice and theory. The author
      argues that the politically motivated assertion of a direct connection between
      theory and practice should be set aside and that practice should be liberated
      from theory, permitting theory to evolve in the context of radically modified
      patterns of practice. If theory were decoupled from practice, technique might
      progress on purely pragmatic grounds, on the basis of what is seen to work.
      Psychoanalytic theory of mental function could then follow practice, integrating
      what is newly discovered through innovative methods of clinical work. Such a
      pragmatic, principally action-oriented use of theory would bring psychoanalysis
      more in line with modern, postempirical views of science.

PMID- 12616869
TI  - Spatial metaphors of the mind.
AB  - A case in which the author began to understand her patient as "collapsing the
      space between them," rather than as continuing only to free associate, is the
      occasion for a contemplation of the way psychoanalytic theory effects a
      transition between what is inner, or lived, and outer, or experienced. Metaphor
      is seen as the agent of this transition. The author discusses metaphor in
      relation to the case described, while also examining spatial metaphors of mind in
      classical analysis and in Kleinian theory. It is suggested that both may be
      integrated in a third metaphorical-spatial construct, Green's analytic space.

PMID- 12616868
TI  - Conceptions of conflict in psychoanalytic theory and practice.
AB  - There are many different views of conflict in contemporary psychoanalysis, each
      with its own technical implications. After reviewing the psychoanalytic origins
      of the concept of conflict, the author discusses the diverse positions of four
      North American conflict theorists, each of whom offers a different view of the
      location of conflict both in the mind of the patient and in the material of the
      clinical hour. The role of conflict in the work of several relational
      psychoanalysts is then examined. A tentative approach toward integration is
      proposed.

PMID- 12616870
TI  - In search of the elusive nature of clinical psychoanalytic theory.
AB  - Two case vignettes illustrating different ways of listening to clinical material
      are presented. The author discusses some limitations of clinical psychoanalytic
      theory that stem from the fact that primary unconscious processes are, by their
      very nature, impossible to describe in a language regulated by secondary
      processes. Hegelian dialectics, first addressed in psychoanalysis by Lacan and
      later elaborated in the work of Green, as well as the use of paradox by Winnicott
      and the formalistic approaches of Matte Blanco and Bion, are briefly reviewed as
      alternative formulas. As psychoanalysts, we are condemned to live with doubt, and
      neither clinical theories nor metapsychology offer escape from this reality.

PMID- 12616871
TI  - The function of theory in psychoanalysis: a self psychological perspective.
AB  - Although aware of a lack of consensus in the literature about the exact nature of
      the relationship between psychoanalytic theory and the clinical process, the
      authors contend that the analyst's theory(ies) are inextricably intertwined with
      the treatment process. Two clinical case examples are presented to illustrate
      this and to highlight the authors' discussion of the empathic mode of listening
      and its role in self psychology, as well as the self-object transferences and the
      interpretive process in self psychology.

PMID- 12616872
TI  - Marcella: the transition from explosive sensoriality to the ability to think.
AB  - The author discusses an analytic case in which it was necessary to first address
      the patient's need for containment of her protoemotions--her sensoriality--before
      the analysis could proceed along more standard lines, with interpretation of the
      transference, work on displacement and aspects of her childhood history, and so
      forth. Prior to treatment, the patient had resorted to a sort of affective autism
      in order not to experience dangerously overwhelming emotions, and her emotional
      lethargy in sessions at first engendered similar feelings in the analyst, making
      progress impossible until a container was established for her projective
      identifications.

PMID- 12616874
TI  - Analysts' observing-participation with theory.
AB  - The author summarizes some of the literature's critiques of psychoanalytic
      theory, which have noted its constrictive quality and failure to take into
      account the vicissitudes of treatment within each analytic dyad. Such postmodern
      reactions have given rise to a countertheoretical trend toward psychoanalytic
      pluralism, leading the author to suggest that a single, standard psychoanalytic
      technique no longer exists. The interpersonal tradition, which tends to
      prioritize praxis over theory, is discussed in the light of its emphasis on an
      intersubjective model of participant-observation, and two clinical vignettes are
      presented to illustrate the author's way of utilizing this model.

PMID- 12616873
TI  - Back to the future.
AB  - Significant components of psychoanalytic technique, and the theory that underlies
      it, seem to remain buried in our past, but are central to the growth of
      psychoanalysis as a treatment method based on understanding a patient's mind. By
      updating technique based on a theory of mind with structure, the author views the
      increasing freedom of the patient's mind as central to the curative process, and
      takes the position that in interpretive work, the analyst needs to pay more
      attention to the patient's capacity to meaningfully receive and integrate the
      analyst's interventions.

PMID- 12616875
TI  - The jouissance of the other and the prohibition of incest: a Lacanian
      perspective.
AB  - The authors describe how Lacan diverged from classical Freudian concepts to
      arrive at an alternative model of psychoanalysis. In a discussion that also
      addresses the concept of the mirror stage and Lacan's use of language, the
      authors show how the Lacanian concepts of jouissance and the prohibition of
      incest contribute to this model, which can be successfully applied to the
      psychoanalytic treatment of more seriously disturbed patients. A clinical
      vignette is presented to illustrate the latter point.

PMID- 12616876
TI  - Does the cure come as a byproduct of psychoanalytic treatment?
AB  - Successful psychoanalytic treatment accomplishes more than symptom relief; it
      involves a psychic restructuring that is facilitated by the process of working
      through. The author reviews Freud's original description of this process and
      traces its evolution since then. Application of the psychoanalytic method as an
      appropriate therapeutic modality for non-neurotic patients is illustrated through
      the presentation of a clinical vignette.

PMID- 12616877
TI  - The several relationships of theory and practice.

PMID- 12616878
TI  - What is the future of continuing education in dentistry?

PMID- 12616879
TI  - Why do we do veneers in easy ortho cases?

PMID- 12616880
TI  - The total patient.

PMID- 12616881
TI  - Study reveals Periostat lowers C-reactive protein in patients suffering from
      acute coronary syndromes.

PMID- 12616882
TI  - FDA approves rapid-result HIV test kit.

PMID- 12616883
TI  - Nonsurgical periodontal therapy reviewed.

PMID- 12616884
TI  - The potential for suck-back with saliva ejectors.

PMID- 12616885
TI  - Oral healthcare of the overweight or obese patient.

PMID- 12616887
TI  - "Straight-line" access. A must for faster and better endodontics.

PMID- 12616886
TI  - Professional standards, personal responsibility.

PMID- 12616888
TI  - Capping carious exposed pulps with potassium nitrate, dimethyl isosorbide,
      polycarboxylate cement.

PMID- 12616889
TI  - Dentistry for the long-term care patient.

PMID- 12616890
TI  - Aesthetic restoration for single-tooth implants. Multidisciplinary approach.

PMID- 12616892
TI  - High-quality panoramic radiographs. Tips and tricks.

PMID- 12616891
TI  - Managing risk factors in successful nonsurgical treatment of periodontal disease.

PMID- 12616893
TI  - A big issue about a little tissue.

PMID- 12616894
TI  - Technique for achieving general field isolation during dental procedures.

PMID- 12616895
TI  - Office design. Communicating service quality.

PMID- 12616896
TI  - A review of the ADA mercury hygiene recommendations.

PMID- 12616897
TI  - Bridging the diagnostic void. A case study in early detection and modern
      conservative care.

PMID- 12616899
TI  - Dentists can protect their incomes with business interruption insurance.

PMID- 12616898
TI  - Dental fear. Aren't you tired of it?

PMID- 12616900
TI  - [The next patient is a sick fish, what to do? (Part II)].
AB  - In the first article the clinical history, water testing and clinical examination
      were described. In this article the therapy and surgery procedures of fish will
      be discussed. The risk for prescribing drugs for consumption fish will be
      underlined. A reference list is enclosed for interested veterinarians.

PMID- 12616901
TI  - [ACE inhibitors in dogs with subclinical chronic mitral insufficiency].

PMID- 12616902
TI  - [Use of vitamin E in swine feed].

PMID- 12616903
TI  - [Interview with Professor of Animals and Law Dirk Boon. Interview by Pauline
      Hoefer-van Dongen].

PMID- 12616904
TI  - [The field awaits the start sign from the government].

PMID- 12616905
TI  - ['Udder health panel' discusses mastitis treatment in Norway and United States].

PMID- 12616906
TI  - [Dog castration abroad].

PMID- 12616908
TI  - Respirator problems misstated in 'breathe' article.

PMID- 12616907
TI  - [The eye looks away...].

PMID- 12616909
TI  - Getting results from safety meetings. Try the 'POP' model to make your sessions
      productive.

PMID- 12616910
TI  - Online training for on-site testing.

PMID- 12616911
TI  - A report on confined space retrieval....
AB  - The client should be proactive with the CS program strategy. By continually re
      evaluating its program and its spaces, the client can refine its program with the
      dual goals of preparedness and compliance that keep worker safety in mind. It is
      the Consultant's experience that when a compliance officer assesses an employer's
      program, the efforts made by the employer prior to any potential or actual
      incident are deemed crucial to the success of the program. The Consultant finds
      it a pleasure to work with an organization that strives for the highest standards
      of safety rather than the minimum standards of compliance.

PMID- 12616912
TI  - Coping with the new TLV for diesel fuel.

PMID- 12616913
TI  - Was this a permit-required CS?

PMID- 12616914
TI  - The challenge of compliance in an uncertain world.

PMID- 12616915
TI  - Winter woes.

PMID- 12616916
TI  - Installed fire protection: alarm systems.

PMID- 12616917
TI  - A unique approach to industrial fire protection.

PMID- 12616918
TI  - Heading for the exits. Photoluminescent egress markings increase the safety and
      efficiency of emergency plant evacuations.

PMID- 12616919
TI  - Life-saving reminder.

PMID- 12616920
TI  - Paying for quality improvement: compliance with tobacco cessation guidelines.
AB  - BACKGROUND: Identification and treatment of routine tobacco use in medical
      practice is an effective intervention but is not used consistently. A study was
      conducted at HealthPartners, a large network-model health plan in Minnesota, to
      determine the effect of an outcomes recognition strategy that involved bonus
      funds and the rates at which network physicians document that tobacco users are
      identified and advised to quit. METHODS: Audits of 14,489 ambulatory patient
      records from 19-20 medical groups were conducted to determine the proportion of
      charts from each medical group that demonstrated identification of smoking status
      and counseling to encourage quitting at the most recent office visit in each
      year. RESULTS: Overall mean tobacco use identification increased from 49% +/- 7%
      (95% confidence interval [CI]) in 1996 to 73% +/- 7% in 1999 (p < .001), while
      advice to quit increased from 32% +/- 10% in 1996 to 53% +/- 10% CI in 1999 (p <
      .005). The number of medical groups with tobacco status identified at > 80% of
      visits and > 80% of tobacco users advised to quit increased from 0 in 1996 to 8
      in 1999. DISCUSSION: Data feedback combined with a financial incentive appear to
      be an effective way for a health plan to improve physician compliance with the
      tobacco treatment guideline. Other health plans might consider similar reporting
      and incentive approaches to effectively engage medical group leadership and to
      improve the health of their members who use tobacco.

PMID- 12616921
TI  - Centralized oversight for clinical performance improvement: a pilot initiative at
      the Lexington VAMC.
AB  - BACKGROUND: In July 2000 the Lexington Veterans Affairs Medical Center
      (Lexington, Ky) centralized oversight of clinical performance improvement (CPI)
      activities by creating an office of clinical operations (OCO) to improve patient
      care and operational efficiency. The OCO was designed to eliminate redundancy of
      effort, correct resource underuse and overuse, and improve the communication of
      change initiatives and successes. Before 2000 no formal process existed for
      creating interdisciplinary CPI teams. Lack of organizational oversight for CPI
      activities had also led to duplication of effort, mixed accountability, and
      difficulty in remaining focused on organizational goals. CREATING THE OCO: OCO
      staff have led and facilitated numerous projects, all of which involved
      interdisciplinary teams consisting of physician and nurse leaders, users, and
      support staff. The OCO has also developed a utilization management plan for the
      entire medical center. The OCO formally interfaces with three major arenas of
      medical center operation: clinical processes, patient safety, and cost
      efficiency. CHALLENGES AND LESSONS LEARNED: A major effort of OCO staff has been
      to learn about data availability and access and to determine how data can be used
      in a meaningful way to benefit CPI project teams. The creation of the OCO
      precipitated the typical cultural integration problems that are often encountered
      with the introduction of new organizational entities that lack existing turf.

PMID- 12616922
TI  - Peer review in obstetrics and gynecology by a national medical specialty society.
AB  - BACKGROUND: Since 1986 the American College of Obstetricians and Gynecologists
      (ACOG) has offered a voluntary consultation service (Voluntary Review of Quality
      of Care [VRQC] program) to assist departments of obstetrics and gynecology in
      assessing their quality of care. HOW THE VQRC PROGRAM WORKS: The VRQC program
      review team selects three to five topics for on-site medical record review to
      further investigate the care processes that may contribute to the perceived
      problems. Each chart is evaluated by a single reviewer with the use of worksheets
      with explicit, objective criteria that represent practice guidelines. In
      addition, key departmental and hospital personnel are interviewed on site to
      provide insight into the issues that prompted the request. EVALUATION OF THE VRQC
      PROGRAM: The first 100 site visits took place in 29 states and represented a
      diverse geographic cohort of hospital departments of obstetrics and gynecology.
      Overall departmental and systemic deficiencies were significantly more common
      than clinical concerns. Obstetric issues were more prevalent than gynecologic
      issues. Induction and augmentation of labor was the most common deficiency, and
      the availability and quality of obstetric anesthesia was the second. CONCLUSION:
      The VRQC program, as a voluntary consultative peer review program, addresses
      hospital-specific quality problems and also identifies common deficiencies across
      a diverse group of hospitals, which may warrant continuing education.

PMID- 12616923
TI  - What do collaborative improvement projects do? Experience from seven countries.
AB  - BACKGROUND: Health care organizations are increasingly adopting
      multiorganizational collaborative approaches to quality improvement.
      Collaboratives have been conducted in many countries. There are large variations
      in the way collaboratives are structured and run, but there is no widely accepted
      framework for describing the components of collaboratives. Thus, it is difficult
      to study which approaches are most effective. METHOD: The authors conducted
      semistructured interviews with 15 leaders of collaboratives to ascertain the
      common components of collaboratives and identify variations in the ways these
      components are implemented. RESULTS: The study identified seven features of
      collaboratives that the leaders interviewed thought were critical determinants of
      how effective the collaboratives were: sponsorship, topic, ideas for
      improvements, participants, senior leadership support, preliminary work and
      learning, and strategies for learning about and making improvements. For example,
      every interviewee mentioned that having participants collect data, perform audit
      work, or analyze the system they were in before the collaboration started was
      important to understanding their organization and the nature of the problems they
      had and to developing baseline data for later comparison. The authors describe
      variations in how these features have been implemented and possible functions of
      these features. CONCLUSION: Systematically studying the impact of variations in
      the seven key features of collaboratives could yield important information about
      their role and impact.

PMID- 12616924
TI  - Improving care of patients with alcohol withdrawal syndrome in a community
      hospital.
AB  - The authors report how they developed a protocol for nurses to identify and
      provide care for patients with alcohol withdrawal syndrome.

PMID- 12616925
TI  - Childhood attachment, childhood sexual abuse, and onset of masturbation among
      adult sexual offenders.
AB  - Written autobiographies of 48 incarcerated adult male sexual offenders (22
      rapists, 13 intrafamilial child molesters, and 13 extrafamilial child molesters)
      were used to generate retrospective self-report measures of their childhood
      maternal and paternal attachment, childhood sexual abuse experiences, and onset
      of masturbation. Contrary to expectation, the offenders as a combined group more
      often reported secure than they did insecure childhood maternal and paternal
      attachment. There were no differences between the three offender subgroups with
      respect to maternal attachment; however the rapists and the intrafamilial child
      molesters were more likely to report insecure paternal attachment than were the
      extrafamilial child molesters. There were no differences between these offender
      subgroups in the frequency with which childhood sexual abuse was reported.
      However, offenders with insecure paternal attachment were more likely to report
      having been sexually abused than were those with secure paternal attachment.
      Sexually abused offenders in turn reported earlier onset of masturbation than did
      those who were not sexually abused. These results are consistent with
      contemporary attachment models linking insecure childhood attachment to childhood
      sexual abuse, and with traditional conditioning models linking childhood sexual
      abuse, early masturbation, and sexual offending.

PMID- 12616926
TI  - Victim empathy, social self-esteem, and psychopathy in rapists.
AB  - The purpose of the present study was to compare the responses of 27 incarcerated
      rapists and 27 incarcerated nonsexual offenders using the Rapist Empathy Measure
      (targeting victim specific empathy deficits) and to examine the relationship
      between empathy with self-esteem and psychopathy for both groups. The Social Self
      Esteem Inventory was used as a measure of perceived social competence and the
      Psychopathy Checklist-Revised (PCL-R; Hare, 1991) was used as a measure of
      psychopathy. All participants completed the two self-report questionnaires on
      empathy and self-esteem; in addition, the rapists were required to complete an
      extra section of the empathy measure that assessed their empathic responses to
      their own victims. Demographic information and psychopathy scores were obtained
      by reviewing institutional files. When psychopathy scores were not available,
      subjects participated in a semi-structured interview and were scored on the
      Psychopathy Checklist-Revised by the researcher. Rapists demonstrated more
      empathy than the nonsexual offenders toward women in general and the same degree
      of empathy as the nonsexual offenders toward a woman who had been a victim of a
      sexual assault by another male. Of particular importance were the within-group
      comparisons across victim type for the rapists which revealed significant empathy
      deficits toward their own victim(s). Interestingly, no differences were found
      between the rapists and nonsexual offenders in terms of self-esteem and
      psychopathy, and neither self-esteem nor psychopathy significantly predicted
      empathy for either group. It was concluded from the present study that rapists
      may suppress empathy primarily toward their own victim rather than suffer from a
      generalized empathy deficit. It is suggested that empathy deficits in rapists
      might better be construed as cognitive distortions specific to their victims and
      should be addressed in that manner in treatment.

PMID- 12616927
TI  - Juvenile sex offenders: toward the development of a typology.
AB  - Adolescent males who sexually offended against prepubescent children were
      contrasted with those who targeted pubescent and postpubescent females. As
      hypothesized, path analyses revealed that the former group had greater deficits
      in psychosocial functioning, used less aggression in their sexual offending, and
      were more likely to offend against relatives. Theorized relationships between
      developmental risk factors, personality mediators, and sexual and nonsexual
      offense characteristics were assessed in both groups of juvenile sex offenders.
      Deficits in psychosocial functioning were found to mediate the influence of
      childhood exposure to violence against females on adolescent perpetration of
      sexual and nonsexual offenses. Additional univariate analyses were conducted to
      further explore some associations among early risk factors, personality
      mediators, and outcomes. Childhood physical abuse by a father or stepfather and
      exposure to violence against females were found to be associated with higher
      levels of comorbid anxiety and depression. Noncoercive childhood sexual
      victimization by a male nonrelative was found to be associated with sexual
      offending against a male child. Clinical and theoretical implications of the
      findings are discussed.

PMID- 12616928
TI  - Trait empathy and criminal versatility in sexual offenders.
AB  - Associations between trait empathy and criminal versatility were examined in a
      sample of 88 incarcerated adult sexual offenders (29 extrafamilial child
      molesters, 26 intrafamilial child molesters, and 33 rapists). Considerable
      criminal versatility was observed, with 60% of the whole sample and 88% of
      recidivist offenders having previous convictions for nonsexual offenses.
      Regression analyses showed significant associations between trait empathy and
      nonsexual offense convictions, but not between trait empathy and sexual offense
      convictions. More specifically, greater involvement in violent offending (e.g.,
      assault, robbery) was associated with lower levels of empathic concern and higher
      levels of fantasy. Greater involvement in miscellaneous (e.g., traffic, drug,
      public order) offending was associated with lower levels of empathic concern. We
      argue that insufficient theoretical and empirical attention has historically been
      given to criminal versatility among sexual offenders, especially among child
      molesters. In particular, we suggest that developments in empathy training for
      sexual offenders may benefit from distinguishing needs of criminally versatile
      and non-versatile sexual offenders. More knowledge about trait empathy in sexual
      offenders, and about situational factors that may override otherwise normal
      empathic responsiveness, is needed.

PMID- 12616929
TI  - Multiplex versus multiple taxonomy of paraphilia: case example.
AB  - Several different paraphilias are presently diagnosed in some individuals whereas
      a more parsimonious taxonomy would be that of one multiplex paraphilia. A
      multiplex paraphilia may be expressed by variations of content at different times
      in an individual's life or in different situations. The present case example
      shows the unfolding of a multiplex paraphilia over a lifetime. At age 7 the
      subject was dressed in public as a girl wearing a diaper as a humiliation for bed
      wetting. This experience had 3 paraphilic components that were separately
      manifested at different times in his life: fetishistic transvestism, pedophilic
      incest, and infantilism. A multiplex paraphilia taxonomy may lead to improved
      identification of etiology, prognosis, and treatment of paraphilia.

PMID- 12616930
TI  - A nine-year-old girl with new-onset tics.

PMID- 12616931
TI  - Terrorism: its impact on primary pediatrics, Part I.

PMID- 12616932
TI  - Pediatric health professionals and public health response.

PMID- 12616933
TI  - Mass casualty management in a changing world.

PMID- 12616935
TI  - [Unknown parents!].

PMID- 12616934
TI  - Military family support.

PMID- 12616936
TI  - [The Mycobacterium leprae genome: from sequence analysis to therapeutic
      implications].
AB  - The genome of Mycobacterium leprae, the causative agent of leprosy, was analyzed
      by rapid sequencing of cosmids and plasmids prepared from DNA isolated from one
      patient's strain. Results showed that the bacillus possesses a single circular
      chromosome that differs from other known mycobacterium chromosomes with regard to
      size (3.2 Mb) and G + C content (57.8%). Computer analysis demonstrated that only
      half of the sequence contains protein-coding genes. The other half contains
      pseudogenes and non-coding sequences. These findings indicate that M. leprae has
      undergone a major reductive evolution leaving a minimal set of functional genes
      for survival. Study of the coding region of the sequence provides evidence
      accounting for the particular pathogenic properties of M. leprae which is an
      obligate intracellular parasite. Disappearance of numerous enzymatic pathways in
      comparison with M. tuberculosis, an intracellular pathogen comparable to M.
      leprae, could explain the differences observed between the two organisms. Genomic
      analysis of the leprosy bacillus also provided insight into the molecular basis
      for resistance to various antibiotics and allowed identification of several
      potential targets for new drug treatments.

PMID- 12616937
TI  - [Cryptococcosis].

PMID- 12616939
TI  - [Image ... of Borrelia].

PMID- 12616938
TI  - [Riamet: a new antimalarial for curative treatment of malaria].

PMID- 12616940
TI  - [Health care services in the Kingdom of Morocco].
AB  - Kingdom of Morocco is located in Northwestern Africa on the Atlantic Ocean and
      the Mediterranean Sea. Its surface area is 710,850 km2. In 2001 the estimated
      population of Morocco was 29,800,000 people who are not equally distributed over
      the territory. Population growth rate is changing with a tendency toward levels
      similar to those in developed countries. The health care system created in 1959
      has undergone several reorganizations including the most recent reform now in
      progress. At the present time the health care system is organized into
      approximately 60 medical districts. It is subdivided into two networks, i.e., an
      ambulatory action network and a hospital action network. The ambulatory action
      network provides basic health care services. It includes 2128 basic care units.
      Most of these units have medical equipment designed mainly for preventive
      medicine. The hospital action network comprises 112 hospitals classified as zone
      hospitals, provincial hospitals, regional hospitals, and university hospitals.
      Both networks receive technical and scientific support from a network of
      institutes, laboratories, and specialized centers. Training for health care
      professionals in Morocco is provided by four medical schools and two health care
      institutes for paramedical care specialists. Morocco is in a period of
      epidemiological transition characterized by the coexistence of patients with
      developed and developing country diseases.

PMID- 12616941
TI  - [A cholera epidemic in Dijibouti (May 2000-January 2001)].
AB  - The purpose of this report is to describe a cholera outbreak that occurred in the
      Republic of Djibouti from May 2000 to January 2001. Because the Somalian index
      cases involved were identified, this outbreak can be used as a model for imported
      epidemics. Development of the disease in the Djibouti City is promoted by a
      combination of poor living conditions and inadequate water supply. Unlike in
      previous epidemics in Djibouti, bacteriological study demonstrated the emergence
      of Vibrio cholerae strains presenting antibiotic resistance similar to that
      observed in Somalia. At the only facility available for cholera treatment in the
      country, 1920 patients were admitted and 36(1.9%) died. An epidemiological study
      of these patients demonstrated that females accounted for most cases in the 15-to
      44-year age group (p < 0.0001) whereas males accounted for most cases in the age
      groups ranging from 0 to 1 year (p = 0.003) and 5 to 14 years (p = 0.002). These
      findings suggest that the mode of contamination and access to care vary according
      to sex and age.

PMID- 12616942
TI  - [Systematic search for parasites among leprosy patients in Mali].
AB  - Practice of multidrug therapy in leprosy (combination Dapsone + Rifampicine +
      Clofazimine) established since 1981, has significantly reduced the incidence of
      the disease. However, immunosuppression due to treatment of multi-drugs therapy
      induced adverse reactions with glucocorticoid and the change in host immune
      response due to the leprosy itself, might increase the risk of parasitic
      infections. To test this hypothesis, we carried out a case-control study at the
      "Institut Marchoux" in Bamako. Stool and urine samples from all patients included
      in the study were examined for parasites identification. In addition, we
      performed thick and thin blood film to identify malaria infection and skin biopsy
      (snip) to detect onchocerciasis. A total of 121 cases of leprosy and 219 controls
      aged 10-84 years old were included in the study from March 1999 to February 2000.
      Sixty two percent (n = 121) of cases were treated with glucocorticoid. The
      prevalence of infection due to Entamoeba coli and Entamoeba histolytica were
      higher in cases than in controls (p = 0.02). The prevalence of infection due to
      hookworms was higher in cases than in controls. There was no difference of the
      infections to the other intestinal parasites. Three cases of cryptosporidiosis
      and one case of isosporosis were observed in leprosy group vs none in the control
      group. There was no significant difference between cases and controls with regard
      to prevalence of Schistosoma haematobium, Trichomonas vaginalis and Onchocera
      volvulus. The prevalence of Plasmodium falciparum was 4.9% (6/121) in the leprosy
      case and 7.8% (17/219) in the control group. In conclusion, despite the
      corticotherapy and immunosuppression due to leprosy, there was no difference in
      prevalence of pathogenic parasites. Entomoeba coli, Entamoeba histolytica which
      have significantly higher prevalence among the cases were not pathogen therefore
      there was no higher risk of severe intestinal parasitosis among the cases of
      leprosy. Treatment with glycocorticoid in patients with leprosy did not suggest
      any impact on the prevalence of this parasitic infections. In addition, multidrug
      therapy did not show any effect on the carriage of Plasmodium falciparum.

PMID- 12616943
TI  - [Evaluation of eight diagnostic tests for HIV infection in Lome (Togo)].
AB  - This study to evaluate the performance of eight diagnostic tests for HIV/AIDS
      infection was conducted at the National Reference Center for HIV/AIDS/STD in
      Lome, Togo. The tests were as follows: Enzymum test anti HIV Combi, Enzymum tests
      anti-HIV1 + 2 + subtype O, Genscreen HIV 1/2, Ice 1.0.2, Vironostika HIV Uni-Form
      II Plus O, Genie II HIV 1/2, SFD HIV 1/2 PA and DETERMINE HIV 1/2. A total of 238
      serum specimens collected consecutively between January and April 1999 were
      studied. They were from 161 occasional blood donors and 77 patients. New Lav-Blot
      I and Ii (western blot) were used as reference tests. Test sensitivity ranged
      from 90 to 100%. Specificity ranged from 96 to 100%. The Enzymum test anti HIV
      Combi used only on serum samples from blood donors demonstrated a sensitivity and
      specificity of 100%. Tests based on Elisa (Emzymum Combi, Enzymum HIV 1 + 2 +
      subtype O, Genscreen, Ice 1.0.2 and Vironostika) allowed acceptable diagnosis of
      HIV/AIDS as alternatives to western blot. Two of the three rapid assays tested
      provided acceptable results, i.e., Genie II HIV 1/2 and SFD HIV 1/2. They are
      suitable for screening to prevent HIV transmission by blood transfusion in areas
      where Elisa is unfeasible.

PMID- 12616944
TI  - [Evaluation of cocoa oil for individual protection against Simulium damnosum
      s.i].
AB  - Thanks to larviciding and distribution of ivermectine, transmission of
      onchocerciasis was virtually halted in all countries covered by the WHO
      Onchocerciasis Control Program (OCP). However as a result of this success vector
      control has been stopped in most areas covered by the program and a recrudescence
      of files is an increasing problem. In some rural communities fly biting hinders
      normal agricultural activity. Since local farmers cannot afford ground
      larviciding, many rely on topical repellents. For this reason, development of an
      inexpensive method of individual protection is a major priority. The purpose of
      this study carried out in the savannah area of the Cote d'Ivoire was to assess
      the repellent properties of cocoa oil, which is frequently used in some rural
      areas of the Cote d'Ivoire to prevent fly biting. Results showed that cocoa oil
      provides excellent protection against Simulium damnosum s.l.

PMID- 12616945
TI  - [Uterine rupture in the maternity ward of the Bangui Community Hospital (Central
      Africa)].
AB  - Although now uncommon in developed countries, uterine rupture is among the major
      obstetrical emergencies dealt on a daily bases in the maternity ward of the
      Bangui Community Hospital in Central African Republic, which is the national
      reference facility. Uterine rupture is life-threatening for both the fetus and
      mother. In view of the relatively high rate of rupture observed in our department
      in previous years, this cross-sectional study was undertaken in order to
      determine incidence, identify predisposing factors, evaluate prognosis for the
      mother and newborn, and propose solutions. From January 1997 to December 1997,
      all deliveries by the vaginal route or cesarean section including cases involving
      uterine rupture were recorded. The length of time elapsed between the decision to
      perform cesarean section and actual performance of the procedure was determined.
      Risk factors associated with uterine rupture in our department were noted. The
      outcome of uterine rupture was evaluated in both the mother and fetus. Of a total
      of 5763 deliveries during the study period, 299 required cesarean section (5.9%).
      Uterine rupture occurred in 35 cases of the 299 women (11.7%). In 10 cases of
      uterine rupture, the time lapse for performance of cesarean section was at least
      2 hours. The main cause of delay was the lack of funding for cesarean section.
      Six women died due to irreversible shock (0.1% of deliveries, 2% of cesarean
      sections and 17.1% of uterine ruptures). The perinatal mortality rate was 80%. In
      our department, uterine rupture is a common emergency causing high mortality in
      mothers and newborns. Most of these patients could have been saved.

PMID- 12616947
TI  - [Sickle cell disease and vertigo: a possible diagnosis in metropolitan France.
      Review of the literature and case report].
AB  - Sickle cell anemia is frequently associated with auditory dysfunction. However
      peripheral vestibulopathy is uncommon. The purpose of this report is to describe
      a patient who presented repeated episodes of severe vertigo attributable to
      sickle cell disease. Discussion of this case includes a review of the literature.

PMID- 12616946
TI  - [Fetal ultrasound biometry in a Cameroonian population: study of femur length].
AB  - The length of the fetal femur was measured by fetal ultrasonography in
      Cameroonian population as a preliminary step in constructing local curves for
      fetal growth. This prospective cross-sectional study was conducted in 3 centers
      in Yaounde, Cameroon over a period of one year. A total of 803 pregnant women
      (mean age, 27.15 years) knowing the exact date of the last menstrual period (LMP)
      were included. Based on ultrasound findings demonstrating a single fetus with
      normal development. Gestational age ranged from 12 to 42 weeks of amenorrhea
      (WOA). The mean length of the femur increased from 16.61 +/- 2.25 mm at 13 WOA to
      75.36 +/- 4.85 mm at 42 WOA. There was a good correlation with gestational age
      and findings reported in the literature. Curves obtained using these data were
      compared with those in the literature. In most cases femur lengths measured in
      Cameroonian fetuses were slightly longer than European standards throughout
      pregnancy.

PMID- 12616948
TI  - [A case report of testicular leiomyosarcoma].
AB  - This report describes a case of primary leiomyosarcoma of the testis in a 70-year
      old man. Treatment consisted in orchidectomy by the inguinal route with no
      adjuvant treatment. The patient developed pulmonary metastasis 14 months after
      surgical treatment. Few reports have been published on primary leiomyosarcoma of
      the testis. Most reported cases have been in small series in association with
      germ cell tumors. Surgical treatment is the most effective therapeutic modality.
      The standard surgical technique is orchidectomy by the inguinal route.
      Retroperitoneal lymph node dissection is not always performed. The prognosis of
      isolated testicular sarcoma is better than that of sarcoma associated with germ
      cell components.

PMID- 12616949
TI  - [Epidemiologic surveillance of cutaneous leishmaniasis in Guiana. Summary of
      military data collected over 10 years].
AB  - This report describes the results of epidemiological surveillance of cutaneous
      leishmaniasis in French military personnel in French Guiana. Data was collected
      regarding microscopic diagnosis, clinical manifestations, and lesion location as
      well as compliance with vector control measures. Year-to-year variations in the
      incidence in the general population have been attributed to changes in climatic
      conditions. Monitoring incidence and density curves, correlation of findings with
      local epidemiological data, and analysis of the most recent epidemic in 1998/99
      (326 cases, attack rate 3.2% men years) highlight the importance of behavioral
      factors. The proportion of total cases involving military personnel varied widely
      from 20 to 85%. Investigation consistently showed that failure to apply
      elementary protective measures against sandfly bites was the most determinant
      factor in this proportion. Strict compliance with these measures appears to
      reduce the risk of infection considerably.

PMID- 12616950
TI  - [Treatment of malaria in children: 1. Uncomplicated malaria].
AB  - Malaria is a worldwide epidemic causing high morbidity and mortality especially
      in children younger than 5 years. In France the incidence of pediatric malaria
      has constantly increased up to 1500 cases in the last two years, due to
      Plasmodium falciparum in more than 80% of cases. According to current
      recommendations, any patient with clinical suspicion or confirmed diagnosis of
      malaria must be hospitalized for treatment. Halofantrine is the most widely used
      antimalarial for treatment of uncomplicated P. falciparum malaria in children.
      However due to halofontrine-related cardiotoxicity some teams recommend
      mefloquine as the first-line drug despite disadvantages related to its poorly
      adapted formulation and adverse gastrointestinal effects in young children.
      Treatment of malaria involving other plasmodium species is still based on
      chloroquine. Likewise the World Health Organization continues to recommend
      chloroquine as the first-line agent for uncomplicated malaria in endemic zones
      with moderate chloroquine resistance. Amodiaquin or sulfadoxine-pyrimethamine
      combination may be used either in case of failure or as first-line agents in
      zones with high chloroquine resistance. In case of multiple resistance, quinine
      may be used alone or in association with an antimicrobial. Other drug therapies
      such as combinations using artemisinine derivatives have been shown to be highly
      effective for control of clinical symptoms and parasitemia. Widespread use of
      these therapies to prevent the appearance and extension of resistance is now
      undergoing evaluation.

PMID- 12616951
TI  - [Statistical tests: value, principle and interpretation].
AB  - Comparison of data groups requires the use of statistical tests. This article
      utilizes an example taken from the Revue Medicine Tropicale to illustrate the
      value of statistical testing as well as an interpretation of the probability
      value "p" associated with test results.

PMID- 12616952
TI  - [Prognostic value of WHO criteria defining severe malaria in expatriates treated
      in an intensive care unit in the Ivory Coast].

PMID- 12616953
TI  - [Tuberculous osteitis of the malar bone].

PMID- 12616955
TI  - [A case report of a donkey bite injury with avulsion of the eyelid].

PMID- 12616954
TI  - [Bilateral aural myiasis caused by Lucilia sericata].

PMID- 12616956
TI  - Backbone modification alters the efficacy of antisense oligonucleotides directed
      against mRNA encoding either TGF-alpha or EGFR in the treatment of prostate
      cancer cell lines.
AB  - Antisense oligonucleotides (oligos) directed against mRNA-encoding, transforming
      growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR),
      have been shown to significantly inhibit in vitro and in vivo growth of prostate
      tumor models. Recently, second generation oligos have been employed with
      identical base sequences, but containing backbome modifications that enhance
      stability, solubility and circulatory patterns. Using relatively low
      concentrations of oligos, we compared the efficacy of the first generation
      phosphorothioated oligos against TGF-alpha (MR1) and EGFR (MR2) with second
      generation oligos containing completely phosphorothioated backbones and different
      patterns of 2'-methoxyethyl (2'-MOE) backbone modifications, while retaining the
      original designated base sequence using, the LNCaP and PC-3 prostate cancer cell
      lines, respectively. All experiments were conducted in vitro with lipofectin to
      enhance oligo entry. Under these conditions, using oligo concentrations between
      0.83 and 3.32 microM for LNCaP cells treated with oligos directed against TGF
      alpha only the first generation MR1 had inhibitory activity. When treated with
      oligos directed against EGFR, none of the oligos had inhibitory activity and they
      behaved similarly. Using the PC-3 cell line and treatment directed against TGF
      alpha with oligo concentrations between 0.42 and 3.32 microM, first generation
      MR1 and second generation 5005 behaved similarly with no notable effect, while
      second generation 5007 produced dramatic growth stimulation. When PC-3 cells were
      treated with oligos directed against EGFR, second generation 5006 and 5008 had
      similar and apparently dose-dependent inhibition. We conclude that backbone
      modifications influence oligo efficacy and may result in either enhanced or
      diminished activity. Because of their activity against the hormone insensitive PC
      3 cells, the 5006 and 5008 compounds warrant additional study at greater
      concentrations and also merit in vivo testing.

PMID- 12616957
TI  - Preparation and comparative evaluation of 99mTc-labeled 2-iminothiolane modified
      antibodies and CITC-DTPA immunoconjugates of anti-EGF-receptor antibodies.
AB  - The use of antibodies as targeting agents for the delivery of radioisotopes to
      tumors is a promising concept that has received widespread attention since the
      advent of monoclonal antibody (mAb) technology. The following studies are
      described in this article: the 99mTc-randiolabeling of 2-iminothiolane (2-IT)
      modified antibodies and 6-p-isothiocyanatobenzyl- diethylene-triamine penta
      acetic acid (CITC-DTPA) immunoconjugates of anti-EGF-receptor antibodies murine
      ior egf/r3 and humanized h-R3; the analytical methods for quality control of the
      radiopharmaceutical such as instant thin layer chromatography-silica gel (ITLC
      SG); the biological assessment of the radiolabeled molecule using flow cytometry
      analysis; in vitro stability studies with cysteine and DTPA challenge and the
      biodistribution studies in 4NMRI xenografted nude mice with U-87 human
      glioblastoma multiforme and MDA-MB-468 breast cancer cell lines. Labeling
      efficency of (96.48 +/- 0.70%) (98.42 +/- 0.38%), (94.8 +/- 1.25%) and (96.41 +/-
      0.89%) was achieved for 99mTC-2-IT ior efg/r3, 99mTc-CITC-DTPA- ior egf/r3, 99mTc
      CITC-DTPA- h-R3 and 99mTc-DIACIM h-R3, respectively. Radiocolloids were less than
      2.0% in all cases. The biological activity measured by flow cytometry analysis
      using the MDA-MB-468 breast cancer cell line showed an immunoreactivity fraction
      greater than 85% in all concentrations of each immunoconjugate. Challenge studies
      demonstrated no evidence of transcomplexation of 99mTc to 1.0 mM DTPA for 2-IT
      modified antibody ior egf/r3 and CITC-DTPA immunoconjugates and only 8.7%, 4.9%
      and 5.0% of the 99mTc-radiolabeled was transcomplexed to 1.0 mM cysteine after 1
      h incubation at 37 degrees C for 2-IT modified antibody ior egf/r3, CITC-DTPA ior
      egf/r3 and CITC-DTPA h-R3, respectively. Biodistribution studies with 2-IT
      modified antibodies and CITC-DTPA immunoconjugates indicated high tumor uptake in
      both cell lines with both immunoconjugates and no accumulation of the
      radiolabeled antibodies in normal organs.

PMID- 12616959
TI  - Structures and pathways of the central nervous system are potentially involved in
      the serotonergic modulation of gastrointestinal activity.
AB  - The supposed involvement of rat brain regions in the modulation of rat small
      intestine serotonergic activity was investigated. Small electrolytic lesions were
      placed in the areas of medulla oblongata and pons Varoli; one week later, changes
      in the serotonergic response of the intestine were detected. The contractions
      mediated by the activation of 5-HT2 receptors in the proximal ileum were
      investigated. The whole ileum segments were cut and placed into the bath. The
      preparations were contracted by adding increasing concentrations of 5
      hydroxytryptamine (5-HT) (10 nM-1 microM) and noncumulative concentration
      response curves (CRCs) were established. The differences between 5-HT responses
      of preparations from either sham-operated or experimental rats suggest the
      existence of brainstem regions (dorsal vagal and solitary nuclei, parvocellular
      reticular nuclei and serotonergic A1,2,5 groups) that either stimulate or inhibit
      5-HT modulatory action in the rat gastrointestinal tract.

PMID- 12616958
TI  - A pharmacological analysis of the contractile effects of glutamate on rat and
      human isolated gut smooth muscle strips.
AB  - Although the contractile effects of glutamate and related excitatory amino acids
      on gut smooth muscle strips have been demonstrated, the mechanisms, and
      particularly the physiological importance of that action, remain unknown. In this
      study, glutamate, aspartate, AMPA, quisqualate, cis-ACPD and (2R,4R)-APDC evoked
      concentration-dependent contraction of isolated adult rat gastric fundus, with
      EC50 values of 210 microM, 150 microM, 20 microM, 33 microM, and 2.7 microM and
      7.9 microM, respectively. L-SOP (0.1 microM-1.9 mM) did not change the basal tone
      of the preparations. The maximal contractions evoked by glutamate (20 mM) were
      38.83% compared with those elicited by acetylcholine (20 microM). The glutamate
      evoked contractions were not affected by atropine, verapamil and nicardipine,
      blocked by CNQX (0.01 microM), or potentiated by Mg2+ (0.01-100 microM), ketamine
      (0.01-100 microM) and DL-AP5 (0.1-100 microM), as well as L-trans-2,4-PDC (1-100
      microM). Analysis of glutamate's action on rat rectum (EC50 = 44 microM) could
      only be carried out at the early stages, as half of the preparations were not
      affected by glutamate. Only 5 out of 26 human longitudinal and circular smooth
      muscle preparations taken from the stomach and three segments of the large
      intestine were very slightly contracted by glutamate, excluding further analysis.
      The contractile effects of glutamate on rat gut smooth muscles were mediated by
      multiple GluR (non-NMDA > NMDA > group I/II mGluRs) located primarily on smooth
      muscle cells but functional GluRs on neurons and/or nerve fibers of myenteric
      nervous plexuses could not be excluded. To fully understand the physiological
      significance of glutamate-evoked contractions in the gut, more research is
      required, most likely using many different methodological approaches.

PMID- 12616960
TI  - Pharmacological studies on Myristica fragrans--antidiarrheal, hypnotic, analgesic
      and hemodynamic (blood pressure) parameters.
AB  - Recurrent diarrhea is prevalent in developing countries, particularly in tropical
      regions. A natural based antidiarrheal home remedy can serve as an ideal health
      tool to limit diarrhea-related morbidity and mortality. In the traditional Indian
      medical science of Ayurveda, nutmeg is one such plant said to possess
      antidiarrheal activity. A study was therefore planned to assess the various
      pharmacological effects (antidiarrheal, sedative, analgesic and blood pressure)
      of nutmeg. Both Nutmeg crude suspension (NMC) and petroleum ether (PE), but not
      aqueous extract (Aq), decreased the mean number of loose stools or increased the
      latency period. NMC increased intestinal tone while PE had no such effect. PE had
      no effect on guinea pig ileum, but inhibited the contraction produced by
      acetylcholine, histamine and prostaglandin. NMC but not PE extract showed a
      significant but weak analgesic effect. While PE effectively potentiated both
      phenobarbitone and pentobarbitone-induced sleeping time, NMC was considerably
      less effective. NMC administered intraduodenally did not produce much effect on
      blood pressure (BP), but potentiated the action of exogenously administered
      adrenaline and nor-adrenaline. On the other hand, PE in higher, but not lower,
      doses caused a precipitous fall in BP not blocked by atropine. Thus, overall
      extracts of nutmeg showed a good antidiarrheal effect, with a significant
      sedative property. The extracts possessed only a weak analgesic effect, with no
      harmful effects on blood pressure and ECG.

PMID- 12616961
TI  - The effects of the benzodiazepine receptor ligand 3-(methoxycarbonyl) amino-beta
      carboline on food and water intake in rats.
AB  - The effects of the benzodiazepine receptor ligand 3-(methoxycarbonyl) amino-beta
      carboline (beta-CMC) were investigated on food intake in rats that had been
      fasted for 22 h, and on water intake in rats that had been deprived of water for
      16 h. beta-CMC (2-8 mg/kg i.p.) produced a dose-related inhibition of food
      intake. Significant hyperphagia (p < 0.01) was observed with the 8 mg/kg dose. By
      contrast, the 8 mg/kg dose did not affect water intake in thirsty rats. The data
      suggests that beta-CMC has properties on food intake similar to those of a
      benzodiazepine receptor inverse agonist.

PMID- 12616962
TI  - Antiinflammatory properties of Hypoxis hemerocallidea corm (African potato)
      extracts in rats.
AB  - The effects of aqueous and methanolic extracts of Hypoxis hemerocallidea corm,
      locally known as 'African potato' in South Africa, were examined on rat paw edema
      induced by subplantar injections of fresh egg albumin (0.5 ml/kg). Acetyl
      salicylic acid (100 mg/kg p.o.) was used as the reference antiinflammatory agent
      for comparison. Both the aqueous and methanolic extracts of H. hemerocallidea
      corm (500 mg/kg p.o.) progressively reduced rat paw edema induced by the
      subplantar injections of fresh egg albumin. The methanolic extract produced
      relatively greater and more pronounced antiinflammatory effect than the aqueous
      extract in the experimental animal model used. However, the two extracts of
      African potato examined in this study were found to be less potent than acetyl
      salicylic acid (ASA) as an antiinflammatory agent.

PMID- 12616963
TI  - Clinical findings with the oral contraceptive combination
      ethinylestradiol/dienogest in the Czech Republic.
AB  - The efficacy and safety of the low dose monophasic oral contraceptive (OC)
      combination containing 30 micrograms of ethinylestradiol (EE) and 2.0 mg of
      dienogest (DNG) (EE/DNG) was evaluated in a prospective, open-label, multicenter,
      uncontrolled, phase III trial. The trial was carried out in six hospitals by 36
      investigators in the Czech Republic, and included 557 healthy women (aged 18-35
      years), over 12 cycles, with a total of 6051 cycles. EE/DNG provided a reliable
      ovulation inhibition. The contraceptive efficacy study showed an adjusted Pearl
      index of 0.198 on the basis of three pregnancies occurring during 6051 cycles.
      EE/DNG provided good cycle control, reduced the incidence of intermenstrual
      bleedings, the intensity of menstrual bleeding and frequency of dysmenorrhea. Due
      to the antiandrogenic properties of the progestogen component DNG, EE/DNG
      improved androgen-related conditions, such as skin blemishes, hair greasiness and
      acne vulgaris. From 108 women with acne, 62 (57%) improved after the 6th cycle,
      and 16 (15%) were healed. Similar changes were found after cycle 12. Breast
      tenderness and headache were the most frequent of the common complaints due to
      treatment with EE/DNG. The frequency of all complaints decreased steadily over
      time. Only 7.7% of subjects discontinued due to adverse reactions. No
      thrombophlebitic events were noticed.

PMID- 12616964
TI  - Effect of intravenous infusion of NIK-716 in anesthetized pediatric patients.
AB  - NIK-716 is a maintenance fluid based on the new concept of containing acetate as
      a base source and 5% glucose as an energy source. It was administered to
      pediatric patients under general anesthesia for less invasive surgical
      operations, and its efficacy was investigated by performing blood chemistry
      examination and urinalysis before and after administration. For efficacy
      assessment, the three items selected as efficacy parameters, i) the replacement
      and maintenance of water (assessment of hydration and urine output); ii) the
      maintenance of serum electrolytes (Na and K); and iii) the utilization of glucose
      (blood glucose and urinary glucose), were evaluated based on the results of
      laboratory examination (hematology, blood chemistry and urinalysis), and overall
      improvement was rated on the basis of total scores of these assessment items. No
      adverse events or abnormal laboratory values attributable to the maintenance
      fluid were observed in any of the 25 children administered NIK-716. In an overall
      improvement rating, NIK-716 proved markedly effective or effective in 79.2% of
      the 24 children evaluated. The overall safety rating was judged as 'no problem'
      in all 25 children. These findings suggest that NIK-716 is a useful and safe
      maintenance fluid that can be administered to pediatric patients during the
      course of surgery.

PMID- 12616965
TI  - Gateways to clinical trials.
AB  - Gateways to Clinical Trials is a guide to the most recent clinical trials in
      current literature and congresses. The data in the following tables has been
      retrieved from the Clinical Studies knowledge area of Prous Science Integrity,
      the drug discovery and development portal, http://integrity.prous.com. This issue
      focuses on the following selection of drugs: Abacavir sulfate, adalimumab, AERx
      morphine sulphate, alefacept, alemtuzumab, alendronic acid sodium salt,
      alicaforsen sodium, almotriptan, amprenavir, aripiprazole, atenolol, atorvastatin
      calcium; BSYX-A110; Cantuzumab mertansine, capravirine, CDP-571, CDP-870,
      celecoxib; Delavirdine mesilate, docetaxel, dofetilide, donepezil hydrochloride,
      duloxetine hydrochloride, dutasteride, dydrogesterone; Efavirenz, emtricitabine,
      enjuvia, enteryx, epristeride, erlotinib hydrochloride, escitalopram oxalate,
      etanercept, etonogestrel, etoricoxib; Fesoterodine, finasteride, flt3ligand;
      Galantamine hydrobromide, gemtuzumab ozogamicin, genistein, gepirone
      hydrochloride; Indinavir sulfate, infliximab; Lamivudine,
      lamivudine/zidovudine/abacavir sulfate, leteprinim potassium, levetiracetam,
      liposomal doxorubicin, lopinavir, lopinavir/ritonavir, losartan potassium; MCC
      465, MRA; Nebivolol, nesiritide, nevirapine; Olanzapine, OROS(R)-Methylphenidate
      hydrochloride; Peginterferon alfa-2a, peginterferon alfa-2b, Pimecrolimus,
      polyethylene glycol 3350, pramlintide acetate, pregabalin, PRO-2000; Risedronate
      sodium, risperidone, ritonavir, rituximab, rivastigmine tartrate, rofecoxib,
      rosuvastatin calcium; Saquinavir mesilate, Stavudine; Tacrolimus, tadalafil,
      tamsulosin hydrochloride, telmisartan, tomoxetine hydrochloride, treprostinil
      sodium, trimegestone, trimetrexate; Valdecoxib, venlafaxine hydrochloride;
      Zoledronic acid monohydrate.

PMID- 12616966
TI  - Flight related deep vein thrombosis.

PMID- 12616967
TI  - Time to train all doctors to look after seriously ill patients--CCRISP and
      IMPACT.

PMID- 12616968
TI  - Outcomes of permanent pacemaker implantation for carotid sinus hypersensitivity
      in a district general hospital with a Falls Fits Faints and Funny Turns Clinic.
AB  - Permanent pacemaker implantation is considered for carotid sinus hypersensitivity
      with asystolic pause of > 3 seconds during carotid sinus massage, with or without
      associated systolic blood pressure drop of > 50 mmHg. AIMS: To assess the outcome
      of treatment with dual chamber permanent pacemaker implantation for carotid sinus
      hypersensitivity in a district general hospital and to compare our practice with
      available national data. METHODS: Patients presenting with syncope, dizziness or
      unexplained falls were initially assessed as outpatient and investigations,
      commonly cardiovascular were performed including tilt table test with carotid
      sinus massage to look for carotid sinus hypersensitivity, vasovagal syncope and
      postural hypotension. A retrospective analysis was performed on patients who had
      pacemaker implantations for carotid sinus hypersensitivity. RESULTS: Fifty
      pacemaker implantations were performed, 14 (28%) were for carotid sinus
      hypersensitivity. Mean follow-up period was 10 months. Age range was 56-88 (mean
      = 71.9) years. In the eighteen months prior to pacemaker implantation, 71.4% of
      patients had syncope, 64% dizziness and 50% had unexplained falls. Following
      pacemaker implantations, only 2 (14.3%) had symptoms. Scottish national figures
      show 13.6% of all new pacemaker implants were for carotid sinus hypersensitivity,
      and in district general hospitals this was 16%. CONCLUSIONS: Health benefits for
      patients presenting with syncope dizziness and falls can be achieved by
      cardiovascular investigations including tilt table testing. We have shown carotid
      sinus hypersensitivity is successfully treated with pacemaker implantation in a
      district general hospital setting and this type of clinic has an impact on the
      rate and type of new pacemaker implantation.

PMID- 12616970
TI  - Outcome, functional recovery and unmet needs following acute stroke. Experience
      of patient follow up at 6 to 9 months in a newly established stroke service.
AB  - OBJECTIVE: To assess outcome at six months post stroke and the unmet needs and
      adherence to the secondary prevention advice among survivors living at home.
      SETTING: Stroke Rehabilitation Unit (SRU), Hairmyres Hospital and patients homes.
      SUBJECTS: Survivors living at home who had been managed in the SRU. RESULTS: Of
      572 consecutive patients with confirmed acute stroke, 301 were managed in the SRU
      and 179 of these were reviewed at home between 6 and 9 months post acute stroke
      incident. One hundred and thirty seven (76%) survivors at home were living with a
      carer. Sixty-eight (38%) had had no personal contact with their General
      Practitioner since discharge from hospital, although 83 (46%) had attended or
      were attending day hospital. Thirty-two individuals (18%) had resumed smoking.
      One hundred and forty nine survivors (83%) still required assistance with daily
      living tasks. One hundred and fifteen patients (64%) required medication advice.
      One hundred and forty one (79%) had health concerns. Eight subjects had returned
      to paid employment. Issues raised by survivors included a feeling of being
      abandoned by the healthcare system, poor access to professional psychological
      support and a fear of further stroke. CONCLUSION: There is a need for continuing
      patient education, improved support for stroke survivors and more active
      involvement of Primary Care Services in the care of stroke patients following
      hospital discharge.

PMID- 12616969
TI  - A limited epidemiological study of seropositive myasthenia gravis in Tayside.
AB  - Myasthenia gravis is an acquired disorder of the neuromuscular junction
      characterised by fatiguable weakness of the limbs, bulbar and facial muscles and
      may be complicated by respiratory muscle weakness and failure. One often confirms
      the diagnosis by a simple serological test looking for the presence of the
      nicotinic acetylcholine receptor antibody. However, seronegative myasthenia
      constitutes about 20% of cases and in the case of ocular myasthenia, only 50%
      will have the antibody. Therefore, the diagnosis can be less than straightforward
      especially if the patient presents with vague symptoms such as fatigue or
      presents to specialities other than neurology or ophthalmology. The fact that the
      diagnosis may prove to be challenging, compounded by the fact that the condition
      is relatively rare and that the antibody to the acetylcholine receptor is not
      always present, epidemiological data is often less than precise and indeed
      difficult to acquire. We felt it was necessary to try to establish the
      epidemiological data on seropositive myasthenia gravis in Tayside, (this has
      never been carried out) bearing in mind the above pitfalls, and see how the
      incidence compares with similar and previous studies.

PMID- 12616971
TI  - As time goes by.
AB  - The timing of birth-related events may influence neonatal outcome and is often
      pivotal in medicolegal cases. This prospective observational study determined the
      variation in displayed time on timepieces in a regional maternity unit which
      could result in inaccuracies of time documentation. The mean (95% CI) difference
      between time displayed and true time was sec (+/- 2 min 4 sec) for delivery room
      clocks and +1 m 8 s (+/- 7 m 12 s) for resuscitation room clocks. The maximum
      discrepancy between delivery room and resuscitation room clocks was 7 m 52 s. The
      abilities of staff to estimate the duration of time passed was also assessed. The
      mean (95% CI) five-minute estimate was 4 m 52 s (+/- 3 m 12 s). These disparities
      could have considerable medicolegal significance, and should be taken into
      consideration in risk management studies. Maternity units should move towards
      synchronising all timepieces. Meanwhile, statements about the precise timing of
      events should be regarded with suspicion.

PMID- 12616972
TI  - John Cleland 1835-1925.
AB  - John Cleland, a surgeon-anatomist, trained at Edinburgh and Glasgow before
      gaining the Chair of Anatomy at Queens College Galway, Ireland when that
      institution was of a mere 14 years standing. This outline of his life, career and
      contemporaries provides some insight into the Scottish tradition of teaching and
      research in the anatomical sciences of the late 19th and early 20th centuries.

PMID- 12616973
TI  - Sensitive markers of inflammation make it possible to study the chronic process:
      the rise of interest in low levels of C-reactive protein.
AB  - Increases in baseline levels of C-reactive protein (CRP) have been consistently
      identified as an independent risk indicator of cardiovascular events. The
      measurement of the low level is robust and well established. Increases in low
      levels of CRP can mark low-grade continuous inflammation and hyperresponse in
      acute situations. In addition, CRP can exert various actions on vascular cells
      and activates complement thus participating in infarction pathogenesis. Various
      cardiovascular drugs, notably statins, can induce a marked decrease in low levels
      of CRP, which is indicative of their beneficial effect on inflammation. Future
      studies need to demonstrate whether increases in baseline levels of CRP can
      become a useful practical addition to risk recognition strategies and possibly
      may also serve as an additional surrogate endpoint in cardiovascular disease
      treatments.

PMID- 12616975
TI  - Levels of haemostatic factors, arteriosclerosis and cardiovascular disease.
AB  - Plasma levels of haemostasis factors (HFs) such as fibrinogen, tissue-type
      plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and D
      dimer may be markers of arteriosclerosis for the following reasons: There seems
      to be no difference in levels of HFs between patients with longstanding stable
      angina and those with an isolated myocardial infarction. HF levels are generally
      positively associated with subclinical arteriosclerosis as determined by ankle
      arm index and carotid ultrasonography in asymptomatic individuals. Levels of most
      HFs are positively associated with inflammation, which is an essential part of
      the initiation and progression of the disease. A rough classification is assigned
      to the associations found in under (2) and (3). Fibrinogen is strongly associated
      with subclinical arteriosclerosis and with inflammation; Factor VII is not, while
      an intermediate group is formed by, for instance, von Willebrand Factor (vWF),
      Factor VIII (F VIII), t-PA, PAI-1, and D-dimer. Also, the associations of HFs
      with cardiovascular events follow a similar pattern. Fibrinogen is a strong and
      consistent risk factor in several studies, Factor VII is not, and a similar
      intermediate group as mentioned under (2) and (3) exists. It suggests that the
      risk of cardiovascular events in relation to HF levels is explained by their
      identity as markers of arteriosclerosis. A causal association between HF levels
      and the disease is not proven. Out of the HF, the markers of coagulation such as
      thrombin-antithrombin complex and of fibrinolysis such as D-dimer are more likely
      to act causally. Increased levels indicate that they are markers of
      arteriosclerosis, but in addition, they may reflect a low-grade, continuous
      formation and subsequent lysis of fibrin in the disease. As the latter reflects
      an increased tendency to thrombosis, a causal association of levels of markers of
      coagulation and fibrinolysis with arteriosclerosis, although not yet proven,
      seems likely.

PMID- 12616974
TI  - The biological functions of C-reactive protein.
AB  - We have obtained data from various investigations that firmly establishes an
      important host defense function for human C-reactive protein (CRP). In transgenic
      mice, the beneficial effect of CRP depends largely on its ability to recruit
      complement, Fc gamma receptors and the adaptive immune system; but this function
      is not limited to the blood-borne protein nor does it require a substantial rise
      in blood CRP levels. Moreover, in clinical studies, we have observed that
      differences in baseline levels of CRP among individuals correlate with a
      polymorphism in the CRP gene. The relevance of this finding is underlined by the
      observation that subtle elevation of blood CRP is associated with significantly
      increased risk of cardiac disease.

PMID- 12616976
TI  - Relationship between CRP and clinical course of unstable angina depends on assay
      method.
AB  - BACKGROUND: The CRP concentration has been identified as a cardiovascular risk
      factor in healthy volunteers and in patients with stable and unstable angina
      pectoris. There is little information about the comparability of the results of
      different CRP assays and it has also not been evaluated whether different assays
      give different associations with risk. METHODS: We studied this in the APRAIS
      study, a study on 211 patients with unstable angina pectoris who were admitted to
      hospital and in whom we studied the association between the CRP concentration on
      admission and the in-hospital clinical course (refractiviness to medication). We
      used two different immunological methods: an in-house ELISA using polyclonal
      rabbit anti-human CRP antibodies as catching and tagging antibody and a
      commercial nephelometric method (Dade-Behring). RESULTS: The analytical variation
      was much smaller for the nephelometric method than for the in-house ELISA. Both
      methods gave higher levels in the refractory group than in the stabilized group,
      but only for the nephelometric method was this difference significant. Also, when
      the relative risk is calculated, it is clear that the more accurate nephelometric
      method can better discriminate between the two groups [RR 2.19 (95% CI 0.94-5.11)
      for the nephelometric method and RR 1.30 (95% CI 0.56-3.03) for the ELISA].
      CONCLUSIONS: In conclusion, the nephelometric method measures the CRP
      concentration with a smaller intra- and interassay variation. The nephelometric
      method can also better discriminate between unstable angina patients who will be
      stabilized and those who are refractory during hospitalization.

PMID- 12616977
TI  - Yellow fever vaccination as a model to study the response to stimulation of the
      inflammation system.
AB  - BACKGROUND: High basal plasma levels of inflammatory molecules are associated
      with a higher risk of cardiovascular events. It has been suggested that also the
      dynamic response to an inflammatory trigger is important in determining
      cardiovascular risk. The aim of the present study was to evaluate the use of
      vaccination against yellow fever as an in vivo model to study the interindividual
      variation in the response to inflammatory triggers. METHODS: Ten healthy
      volunteers were vaccinated with 17D yellow fever vaccine. Blood samples were
      drawn each day, until Day 8 after vaccination. Automated blood cell counting was
      performed, and the plasma concentrations of C-reactive protein (CRP), interleukin
      6 (IL-6) and fibrinogen were determined. RESULTS: In most individuals, CRP levels
      peaked slightly (45% increase from basal values) around Day 7 after vaccination,
      preceded by an IL-6 (30%) peak around Day 5. Fibrinogen levels showed a
      significant increase (10%) from Day 2 after vaccination, with a further rise
      (17%) around Day 5. The monocyte fraction showed a significant 2-fold increase on
      Day 7 after vaccination. The lymphocyte fraction increased slightly towards Day 7
      (not significant). CONCLUSION: Our findings show that yellow fever vaccination
      can be used as a model to study the response to mild stimulation of the
      inflammatory system.

PMID- 12616978
TI  - Blood sample stability at room temperature for counting red and white blood cells
      and platelets.
AB  - Blood handling required for different cellular variables is different. In a
      practical setting of blood sampling approximately 4 h separated from the first
      analysis, we compared the analysis of blood cell variables at this 4-h point with
      analysis of blood stored for approximately 48 h (over the weekend) at room
      temperature. Blood was collected from 304 apparently healthy individuals aged
      between 17 and 70 years, with a female/male ratio of 1.8, in K3EDTA. Measurement
      was performed with a Beckman Coulter Counter Maxm. In addition to the comparison
      of the data and their correlation on the two time points, we investigated
      agreement between the data using analysis according to Bland and Altman. Counts
      of white and red blood cells and platelets were found stable over time and
      agreement of data was excellent. Platelet mean volume increased as expected
      between the two time points from 8.8 to 10.3 fl. The white blood cell
      subpopulations, however, changed over time with a decrease in neutrophils and
      monocytes and increases in lymphocytes and eosinophils. Apparently, ageing of the
      sample resulted in the alteration of certain cell characteristics leading to a
      change in automated cell classification without changing the total number of
      cells. Among the preanalytical variables recorded, only the time of the year and
      gender were found to be minor determinants (r < .25) of some of the differences
      between approximately 4 and approximately 48 h analysis delay. It is concluded
      that after storage at room temperature over approximately 48 h counts of red,
      total white cells, platelets and analysis of platelet volume can be combined in
      one assay session.

PMID- 12616979
TI  - Internal quality control of PCR-based genotyping methods: practical experiences.
AB  - Internal quality control programmes for genetic analyses are needed. We have
      focused on quality control aspects of selected polymorphism analyses used in
      thrombosis research. DNA was isolated from EDTA-blood (n = 500) and analysed for
      18 polymorphisms by polymerase chain reaction (PCR), i.e. restriction fragment
      length polymorphisms, allele specific amplification, or amplification of
      insertion/deletion fragments. We evaluated the following aspects in the
      analytical procedures: sample handling and DNA-isolation (pre-analytical
      factors), DNA-amplification, digestion with restriction enzymes, electrophoresis
      (analytical factors), result reading and entry into a database (post-analytical
      factors). Furthermore, we evaluated a procedure for result confirmation. Isolated
      DNA was of good quality (42 micrograms/ml blood, A260/A280 ratio > 1.75, negative
      DNAsis tests). Occasionally, results were reanalysed because of positive reagent
      blanks (< 1%) or because of problems with the controls (< 5%). On confirmation,
      we observed four genotyping discrepancies. Control of data handling revealed 0.1%
      reading mistakes and 0.5% entry mistakes. Based on our experiences, we propose an
      internal quality control programme for widely used PCR-based haemostasis
      polymorphism analyses.

PMID- 12616980
TI  - Genetic polymorphisms modify the response of factor VII to oral contraceptive
      use: an example of gene-environment interaction.
AB  - Elevated plasma levels of factor VII and fibrinogen are risk factors for
      cardiovascular disease, especially arterial thrombosis. Oral contraceptive use
      increases factor VII and fibrinogen plasma levels. It has been described that DNA
      polymorphisms are associated with the plasma levels of hemostatic variables and
      their regulation. The R/Q353 polymorphism in the factor VII gene and the -455G/A
      polymorphism in the fibrinogen beta-gene are associated with plasma levels of
      factor VII and fibrinogen, respectively. We analysed data of a randomised study
      (n = 95) in which two types of oral contraceptives were compared with regard to
      their effect on factor VII and fibrinogen, in which we also determined R/Q353 and
      -455G/A polymorphisms. Women were allocated randomly to either receiving a
      monophasic oral contraceptive containing 75 micrograms of gestodene and 20
      micrograms of ethinyl estradiol, or 150 micrograms of desogestrel and 20
      micrograms of ethinyl estradiol. Blood was taken before treatment and after 3 and
      6 months of oral contraceptive use. Factor VII and fibrinogen increased
      significantly after 3 and 6 months of oral contraceptive use; the increase in
      factor VII was higher in the desogestrel group than in the gestodene group at 3
      and 6 months. For fibrinogen, there were no intergroup differences at 3 and 6
      months. At baseline, an association between genotype and plasma factor VII and
      fibrinogen levels was observed. In multivariate analysis, the R/Q353 polymorphism
      and the type of oral contraceptive were determinants of the effect on the change
      in factor VII, with the highest increase in women carrying the Q allele and using
      the desogestrel-containing oral contraceptive, and the lowest increase in women
      with the RR genotype who use the gestodene-containing oral contraceptive. For
      fibrinogen, no interaction among type of oral contraceptive, -455G/A
      polymorphism, and change in plasma levels was observed. We conclude that an
      individual's genetic variation may contribute to the response of plasma factor
      VII to oral contraceptive use.

PMID- 12616981
TI  - The association between inflammation markers, coronary artery disease and
      smoking.
AB  - Inflammation and smoking are associated with risk of cardiovascular disease, but
      not much is known yet about their relationship. We studied in 15 smoking and 15
      nonsmoking patients with coronary artery disease (CAD) and in 15 smoking and 15
      nonsmoking healthy subjects the relationships with the inflammatory markers C
      reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and
      tumour necrosis factor-alpha (TNF-alpha). IL-6 and TNF-alpha were significantly
      higher in patients than in controls, both in smokers and in nonsmokers. Smoking
      only had a significant effect on IL-6, and mainly in the controls. In conclusion,
      inflammation is affected by both smoking and cardiovascular disease.

PMID- 12616982
TI  - The effect of 17 beta-oestradiol on variables of coagulation and fibrinolysis in
      postmenopausal women with type 2 diabetes mellitus.
AB  - Type 2 diabetes mellitus is frequently accompanied by hypercoagulability and
      hypofibrinolysis. Both are related to increased cardiovascular risk, but possibly
      with endothelial injury as well. Studies with nondiabetic persons indicate that
      unopposed oestrogen replacement therapy (oERT) decreases cardiovascular risk,
      possibly mediated in part by effects on coagulation and fibrinolysis. In a double
      blind, randomised placebo-controlled trial, we assessed the effect of oral 17
      beta-oestradiol daily during 6 weeks on indicators of coagulation and of
      fibrinolysis in postmenopausal women with type 2 diabetes mellitus. We observed
      significant increases of Factor VII (FVII) and von Willebrand factor (vWF) after
      oERT and no change in the already high fibrinogen. Prothrombin fragment 1 + 2 (F1
      + 2) increased after oERT, whereas thrombin-antithrombin (TAT) complexes was
      unchanged, but increments of F1 + 2 and TAT correlated. Soluble fibrin (SF)
      levels remained stable. In fibrinolysis, a clear reduction in plasminogen
      activator inhibitor 1 (PAI-1) was observed, but no significant change in tissue
      type plasminogen activator antigen (t-PA-Ag) or activity was found, although
      fibrinolytic activity assessed as t-PA activity (t-PA-Act) tended to increase
      after oERT. Indicators of fibrinolytic activity (plasmin-antiplasmin complexes
      and fibrin degradation products) however did not change. oERT increased C
      reactive protein (CRP) but none of the coagulation or fibrinolysis changes
      significantly associated with the CRP changes. It is concluded that oERT
      increases the coagulation potency as well as the fibrinolytic potency raising the
      question of the net effect in their balance. Increase in F1 + 2 suggests that in
      diabetic women oERT effectively increases the chronic, continuous activation of
      coagulation, which appears to be compensated for or not effective in the blood
      compartment as judged from the unchanged levels of SF. Suspected increased fibrin
      formation in the vascular wall is at least not followed by increases in
      fibrinogen degradation products (TDP), which suggests the possibility of
      accumulation and increased cardiovascular risk. The results indicate that
      specific attention should be paid to fibrin turnover in studying other categories
      of women and the effects of the addition of progesterone.

PMID- 12616983
TI  - Pro-inflammatory effects of oestrogens during use of oral contraceptives and
      hormone replacement treatment.
AB  - The effects of two third-generation monophasic combined oral contraceptives (COC)
      and a postmenopausal hormone replacement therapy (HRT) consisting of 2 mg 17 beta
      oestradiol on the plasma level of the acute-phase indicator C-reactive protein
      (CRP) and other acute-phase reactants were analysed. Two studies were conducted:
      (1) a randomised, open-label study with two different oral contraceptive
      preparations with an equal dose of ethinylestradiol (30 micrograms) and a
      different progestogen, either 75 micrograms gestodene (GSD-EE) or 150 micrograms
      desogestrel (DSG-EE); blood samples of 39 young women were analysed before and
      after 3, 6, 12 treatment cycles; (2) a randomised, blinded placebo-controlled
      study with 2 mg 17 beta-oestradiol in postmenopausal women with non-insulin
      dependent diabetes mellitus without signs of cardiac involvement; blood samples
      of 38 women were analysed before and after 6 weeks of treatment. The plasma
      concentration of CRP increased strongly during oral contraceptive use for both
      preparations; the increase persisted over 12 cycles. The already elevated CRP in
      postmenopausal diabetic women showed a moderate increase after 6 weeks of
      treatment with 17 beta-oestradiol. CRP increases during oral contraceptive use
      were associated with changes in some other acute-phase proteins (fibrinogen,
      ceruloplasmin, von Willebrand factor [vWF]) originating from the liver and vessel
      wall, but not in others (interleukin-6 [IL-6], serum amyloid A [SAA]). The
      results demonstrate an increase in a specific set of acute-phase reactants caused
      by oestrogen-containing preparations. It is proposed that the pro-inflammatory
      effect of oestrogens should be checked for a relationship with the increased risk
      of thromboembolism for both oral contraceptive and HRT.

PMID- 12616984
TI  - Pharmacokinetics of intraarterial mitomycin C in hypoxic hepatic infusion with
      embolization in the treatment of liver metastases.
AB  - 1. The pharmacokinetics of mitomycin C (MMC) was evaluated during hypoxic hepatic
      infusion (HHMI) with arterial embolization for the treatment of unresectable
      liver metastases. 2. Ten patients with hepatic metastases from colorectal cancer
      were considered. Antiblastic infusion with MMC (20 mg/m2 at 30 ml/min) was
      initiated after 10 min of hepatic arterial occlusion. Peripheral venous blood
      samples were collected at different time intervals. MMC was assayed by high
      pressure liquid chromatography (HPLC), and pharmacokinetic parameters were
      determined using an open, two-compartment model and linear kinetics. 3. Cmax of
      MMC during HHMI was 708 +/- 336.6 ng/ml, and tmax was 9.3 +/- 1.1 min. The plasma
      concentration-time curve showed a t1/2 alpha ranging from 1.5 to 9 min, followed
      by a t1/2 beta ranging from 31 to 93 min. The Cltot was 35.5 l/h/m2 with an area
      under the plasma concentration-time curve (AUC) ranging from 251 to 850
      micrograms h/l. The same AUC parameter standardized for the amount of MMC was
      15.5 mg-1. The HHMI model that we used revealed a significant increase in Cltot
      and a reduction in AUC when compared to the locoregional intraarterial and
      peripheral intravenous models (p < .001). 4. The reduction in AUC following HHMI
      explains the limited systemic toxicity in treated patients, with a greater total
      tumor exposure to the drug and improved drug activation.

PMID- 12616985
TI  - Low 4-aminopyridine concentration-induced contraction is mediated by neuronal
      noradrenaline in canine saphenous vein.
AB  - 4-Aminopyridine (4-AP), a known inhibitor of the voltage-dependent potassium
      channels, is able to increase the basal tone of different types of blood vessel
      preparations. In order to determine the efficiency of 4-AP in veins and to
      clarify its possible mechanism of action, the aim of the present study was to
      determine the basal tone and release of radio-labelled tissue noradrenaline (NA)
      after administration of low 4-AP concentrations. Experiments were performed in
      canine saphenous vein in the absence and presence of functional endothelium. 4-AP
      (0.012-5 microM) enhanced the basal tone of venous rings without and with
      endothelium (maximum tone at 5 microM 4-AP: 2.20 +/- 1.29 and 1.3 +/- 0.57 mN,
      respectively). NA stores of the venous tissue were loaded by adding 1 mM NA to
      the tissue for 10 min and then washed out. After loading the NA-stores of venous
      tissue, 4-AP-induced contractions were significantly increased both in the
      absence and presence of endothelium (maximum tone at 5 microM 4-AP after loading
      with NA: 10.51 +/- 3.64 and 10.52 +/- 4.69 mN, respectively). Following NA
      loading, chemical denervation of the endothelium denuded venous preparations by
      0.5 mM 6-hydroxydopamine (6-OHDA) completely abolished the contractions evoked by
      4-AP. After incubation of the saphenous preparations with 3H-NA, 5 microM 4-AP
      significantly increased tritium-efflux from the tissue. These results provide
      evidence for the efficiency of 4-AP on the basal tone of isolated canine
      saphenous vein when applied in low concentrations. Furthermore, it is suggested
      that this action of 4-AP may considerably depend on the release of NA from the
      perivascular nerve endings.

PMID- 12616986
TI  - Binding and uptake of transferrin-bound liposomes targeted to transferrin
      receptors of endothelial cells.
AB  - The use of liposomes as carriers for site-specific delivery is an attractive
      strategy, especially for the vascular endothelium that by position is an
      accessible target for drug and gene delivery via the blood circulation. The aim
      of this study was to detect whether liposomes coupled to transferrin (Tf)-bound
      and are taken up by aortic endothelial cells (EC) following the pathway of Tf
      interaction with transferrin receptors, reportedly expressed on their cell
      membrane. To this purpose, small unilamellar liposomes of different compositions,
      either classical (C) or sterically stabilized (SS), have been prepared,
      characterized and coupled with transferrin (Tf-liposomes). To assess the binding
      and uptake, cultured EC were incubated with fluorescently labelled Tf-liposomes
      for various times intervals (from 5 min to 24 h) at 4 and 37 degrees C, and
      further investigated by flow cytometry, fluorimetry and fluorescence microscopy.
      The results showed that: (i) binding of Tf-liposomes to EC was specific; (ii) the
      EC binding of SS-Tf-liposomes was lower than that of C-Tf-liposomes; and (iii)
      after 30 min of incubation, both C- and SS-Tf-liposomes appeared localized in the
      acidic compartments of the cells. Together, the data indicate that transferrin
      bound liposomes are specifically taken up by EC by a receptor-mediated mechanism
      employing the pathway of surface-exposed Tf receptors.

PMID- 12616987
TI  - The effect of Sacoglottis gabonensis stem bark extract, a Nigerian alcoholic
      beverage additive, on the natural antioxidant defences during 2,4-dinitrophenyl
      hydrazine-induced membrane peroxidation in vivo.
AB  - This study was designed to ascertain/verify whether Sacoglottis gabonensis stem
      bark extract has biological antioxidant activity in membrane lipid peroxidation
      using male weanling rats as the experimental animals and, if so, to attempt to
      establish/deduce the possible mechanism(s) of the antioxidant action of the bark
      extract. Lipid peroxidation was induced experimentally with a single
      intraperitoneal 2,4-dinitrophenyl hydrazine (2,4-DNPH) at the end of a 3-day
      administration with the bark extract in drinking water. Three hours later, the
      liver and red blood cells were analysed for the three primary antioxidant
      enzymes, namely catalase, superoxide dismutase (SOD) and glutathione peroxidase,
      and two nonenzymic antioxidants, namely vitamin E (alpha-tocopherol) and vitamin
      C (ascorbic acid) levels. Results showed that pretreatment with the bark extract
      exhibited divergent effects on natural antioxidant enzymes: It impaired the
      enzyme-inducing action of 2,4-DNPH (and of ethanol) on liver and red blood cell
      catalase but reduced the SOD depressing effect of the experimental oxidant (2,4
      DNPH) and ethanol. Neither 2,4-DNPH nor the extract had any measurable effect on
      glutathione peroxidase. The bark extract also exerted a sparing effect on tissue
      antioxidant vitamins, ascorbic acid and vitamin E, effectively inhibiting their
      depletion by 2,4-DNPH or ethanol in the liver, red blood cells and brain. It is
      being concluded that the mechanism of antioxidant action of the bark extract
      against membrane peroxidation is multifactorial/multisystem, involving inhibition
      of catalase, enhancing the SOD capability of the liver and red blood cells and
      sparing tissue depletion/utilization of vitamins C (ascorbic acid) and E (alpha
      tocopherol).

PMID- 12616989
TI  - Antibodies to advanced glycation end products in children with diabetes mellitus.
AB  - The tissue accumulation of advanced glycation end products (AGE) alters the
      structure and function of long-lived proteins. A number of studies have shown
      that tissue accumulation of AGE correlates with the severity of diabetic
      complications. Proteins containing AGE are highly immunogenic and anti-AGE
      antibodies were found in sera of diabetic rats and human. Considering the
      potential use of anti-AGE antibodies as a marker of AGE deposition during
      diabetes, we have investigated, by competitive ELISA, the presence of anti-AGE
      antibodies in sera of 58 children with Type 1 diabetes mellitus. The patients
      were studied for the period of 5 years. Positive for anti-AGE antibodies were 19
      children with diabetes. Fourteen of them showed initial data for vascular
      complications. Anti-AGE antibodies were related to age (r = .25, P = .024),
      duration of diabetes (r = .41, P = .0001), HbA1c (r = .27, P = .016),
      microalbuminuria (r = .41, P = .0001), retinopathy (r = .35, P = .001),
      triglycerides (r = .27, P = .016), and total cholesterol (r = .19, P = .05). In
      conclusion, our study showed that the investigation of the levels and dynamics of
      anti-AGE antibodies might give the possibility for early diagnosis and prognosis
      of the severity of diabetic late complications.

PMID- 12616988
TI  - Inhibitory effects of volatile anesthetics on currents produced on heterologous
      expression of KvLQT1 and minK in Xenopus oocytes.
AB  - The slowly activating component of delayed rectifier K+ current (IKs) in the
      heart modulates the repolarization of cardiac action potential. We investigated
      the effects of the volatile anesthetics isoflurane and sevoflurane on cloned IKs
      coexpressed by KvLQT1 and minK. Currents were induced following injection into
      oocytes of KvLQT1 mRNA (10 ng) with or without minK mRNA (1 ng), which were
      transcribed in vitro from cDNAs of normal rats hearts. A two-electrode voltage
      clamp recording technique was used to investigate the effects of isoflurane (0
      1.5 minimum alveolar concentration, MAC) and sevoflurane (0-1.5 MAC) on IKs
      (KvLQT1 with minK) and KvLQT1 alone currents. Currents were activated by step
      depolarizations to a series of potentials from a holding potential of -80 mV and
      measured as the deactivating tail current on repolarization to -60 mV. Following
      a 2-s depolarization to 40 mV, isoflurane and sevoflurane caused potency
      dependent reductions in IKs and KvLQT1 currents. Both of the volatile anesthetics
      tested accelerated the deactivation of IKs and KvLQT1 currents. We conclude that
      the significant inhibitory effect of volatile anesthetics on the cloned IKs may
      partly contribute to the clinical observations of the prolongation of the
      ventricular repolarization (Q-T interval) by the anesthetics.

PMID- 12616990
TI  - Protein kinase C isoforms and A1 adenosine receptors in porcine coronary smooth
      muscle cells.
AB  - We have previously reported that prolonged exposure of porcine coronary arteries
      to adenosine agonists upregulates protein kinase C (PKC) through the activation
      of adenosine A1 receptor-coupled to pertussis toxin sensitive G-protein(s) [Am.
      J. Physiol. 264 (1993) H1465; Am. J. Physiol. 269 (1995) H1619]. The mechanism(s)
      by which A1 adenosine receptor upregulates PKC (isoforms) are not yet clearly
      understood. In the present study, we identified the alpha, beta 1, beta 2, gamma,
      epsilon, and zeta PKC isoforms that were upregulated by adenosine A1 receptor
      agonist as a possible mechanism(s) involved for this upregulation. Incubation of
      porcine coronary smooth muscle cells (PCSMC) with adenosine A1 receptor agonist
      (2s)-N6-[2-endo-norbornyl]adenosine (ENBA) caused an upregulation of PKC
      (isoforms), which were blocked by adenosine A1 receptor antagonist 1,3-dipropyl-8
      cyclopentylxanthine (DPCPX). Western blot analysis using specific antibodies to
      PKC isoforms indicated that all the isoforms tested (alpha, beta I, beta II, mu,
      gamma, delta, epsilon, and zeta) were present in the primary cultured smooth
      muscle cells from porcine coronary artery. Western blot studies indicated that
      PKC alpha, beta I, beta II, gamma, epsilon, and zeta isoforms were upregulated in
      a dose dependent manner by adenosine agonist (ENBA) and PKC delta and mu were not
      altered.

PMID- 12616991
TI  - Modulation by nicotine of the ionic currents in guinea pig ventricular
      cardiomyocytes. Relatively higher sensitivity to IKr and IKl.
AB  - The effects of nicotine on the ionic currents in guinea pig cardiomyocytes were
      investigated using a whole-cell voltage-clamp technique. Nicotine (30 microM to 1
      mM) inhibited the ionic currents in a concentration-dependent manner. Nicotine at
      30 microM did not affect the Ca2+ current (ICa), but at 300 microM inhibited ICa
      at 10 mV by 29.3 +/- 2.4% (n = 6, P < .01) and at 1 mM almost blocked the ICa (by
      approximately 90%, n = 5, P < .001). After 5- to 10-min washout, these responses
      had 50-70% recovery. The fast time constant (tau f) of the inactivation phase for
      ICa at 10 mV was not affected, but the slow one (tau s) increased from 35.7 +/-
      2.8 to 39.5 +/- 2.4 ms (n = 7) at 300 microM nicotine. Nicotine at 100 microM
      also inhibited the delayed rectifier K+ current (IK) at 60 mV by 42.7 +/- 3.0% (n
      = 7, P < .01), and at 30 microM inhibited the inwardly rectifying K+ current
      (IKl) at -110 mV by 43.0 +/- 2.5% (n = 7, P < .01). The responses to nicotine
      were not significantly modified by atropine, hexamethonium, and nicotine receptor
      antagonists (d-tubocurarine and benzoquinonium). The IK is composed of two
      components for rapidly and slowly activated currents (IKr and IKs). Nicotine
      markedly decreased the tail current of IKr, but had less or no effect on that of
      IKs. However, the activation and inactivation kinetics (d infinity and f
      infinity) for ICa and its activation kinetics (P infinity) for IKr and IKs were
      not modified. These results suggest that nicotine inhibits the ionic currents
      with relatively higher sensitivity to IKl and IKr, resulting in modulation of the
      cardiac functions.

PMID- 12616992
TI  - Yangkyuk-Sanhwa-Tang induces changes in serum cytokines and improves outcome in
      focal stroke patients.
AB  - Yangkyuk-Sanhwa-Tang (YS-Tang), a specific prescription composed of nine herbal
      mixtures, has been developed as a formula for the Soyangin cerebral infarction
      (CI) patients according to Sasang constitutional philosophy. However, the
      mechanisms by which this formula affects CI remain unknown. This study revealed
      changes in cytokine production in the acute stage of Soyangin constitution CI
      patients after YS-Tang administration. Clinical signs (vertigo, headache and
      slurred speech) of CI disappeared significantly in about 2 weeks after oral
      administration of YS-Tang (P < .05). The mean interleukin (IL)-2 plasma levels
      were lower by 15% in the patients with CI than in the normal groups, whereas the
      mean TNF-alpha, IL-4, IL-6 and IgE levels were significantly higher in the
      patients (P < .01). There were no significant differences in interferon-gamma
      (IFN-gamma) levels between the groups. Serum IFN-gamma and IL-2 levels were
      elevated significantly (P < .01) in the patients with CI by YS-Tang
      administration. Significant reduced plasma levels (P < .01) of TNF-alpha, IL-4,
      IL-6 and IgE were observed in the patients treated with YS-Tang. During the
      period of YS-Tang administration, there were no other adverse effects. The data
      indicate that YS-Tang has an enhancing effect on antiinflammatory cytokines and
      an inhibitory effect on inflammatory cytokines. These results may implicate a
      good CI treatment effect of YS-tang and that its action may be due to regulation
      of cytokine production.

PMID- 12616993
TI  - Reduction of cardiac functional reserve and elevation of aortic stiffness in
      hyperlipidemic Yucatan minipigs with systemic and coronary atherosclerosis.
AB  - To test the hypothesis that cardiac functional reserve is reduced in animals with
      severe atherosclerosis, Yucatan minipigs were fed a high-cholesterol diet (Chol)
      for 8 months. Half of them was made diabetic, an additional risk factor for
      atherosclerosis, with streptozotocin (STZ). Another group of age-matched minipigs
      were fed a normal diet as controls. At the end of the treatment period, animals
      were instrumented for the measurement of cardiovascular hemodynamic parameters
      under isoflurane anesthesia. Cardiac functional reserve was measured by the
      magnitude of the inotropic response to isoproterenol stress. Hyperlipidemic
      minipigs developed severe atherosclerotic plaques in the aorta, coronary and
      iliac artery, accompanied by an increase in the aortic stiffness indexed by
      increases in pulse wave velocity and augmentation index. These vascular changes
      were more severe in STZ-induced insulin-dependent diabetes mellitus. The
      isoproterenol-induced increase in left ventricular contractility (dP/dt) and
      relaxation (-dP/dt) and, consequently, cardiac output were also significantly
      reduced in both the Chol groups with or without STZ, compared to control group.
      Thus, cardiac functional reserve measured by isoproterenol-stimulated responses
      was reduced in atherosclerotic minipigs, which was further diminished in
      diabetes.

PMID- 12616994
TI  - Endothelin-1-induced contraction is impaired in the tail artery of renal
      hypertensive rats.
AB  - The contraction induced by endothelin-1 (ET-1) was evaluated in tail arteries
      from normotensive two-kidney (2K) and hypertensive two-kidney-one-clip (2K-1C)
      rats. Since the maximal effect induced by ET-1 (0.1-30 or 100 nmol/l) was lower
      in 2K-1C (1.11 +/- 0.10 g) than in 2K (1.46 +/- 0.14 g) tail arteries, we
      evaluated the possible mechanisms involved in this blunted response. The
      sensitivity and efficacy of ET-1 were not affected by endothelium removal in
      either group. ET-1 failed to induce contraction of 2K and 2K-1C arteries in
      Ca(2+)-free medium. The contractile response induced by 10 nmol/l ET-1 was
      similarly inhibited by 0.1 microM nifedipine in arteries from 2K (81.6 +/- 3.3%)
      and 2K-1C (81.3 +/- 3.8%) rats. The effect of nifedipine was not potentiated by
      10 mumol/l SK&F 96365. The cytosolic Ca2+ concentration ([Ca2+]c) was similarly
      increased by 30 nmol/l ET-1 in smooth muscle cells isolated from tail arteries of
      2K (30.80 +/- 11.94 nmol/l) and 2K-1C (54.06 +/- 10.98 nmol/l) rats. In
      conclusion, the blunted contraction induced by ET-1 in 2K-1C tail arteries was
      not dependent on the endothelium or on decreased Ca2+ influx through channels
      sensitive to nifedipine or SK&F 96365. Since the increase of [Ca2+]c upon
      stimulation with ET-1 was similar in 2K and 2K-1C tail artery cells, probably the
      sensitivity to Ca2+ is decreased in 2K-1C tail arteries.

PMID- 12616995
TI  - Pharmacological characterization of a UTP-sensitive P2Y nucleotide receptor in
      organ cultured coronary arteries.
AB  - Our lab has previously demonstrated that organ cultured coronary smooth muscle
      cells express a nucleotide receptor that is dramatically more responsive to UTP
      than non-organ cultured cells. Thus, the purpose of this study was to
      pharmacologically characterize this UTP-sensitive nucleotide receptor. Porcine
      coronary arteries were organ cultured (serum-free media, 37 degrees C) for 4
      days, and fura-2 imaging of single cells was used to measure myoplasmic Ca2+
      (Cam) in response to several nucleotide agonists. A concentration-response
      relationship (0.01-100 microM) was generated to the nucleotide receptor agonists,
      UTP, UDP, ATP, ADP, and 2-MeSATP. The potency order was UTP >> UDP = ATP = ADP =
      2-MeSATP, thus, this nucleotide receptor is predominantly UTP-sensitive. The Cam
      response to 10 microM UTP was attenuated approximately 50% by the nucleotide
      receptor antagonists (10 and 100 microM), suramin, reactive blue 2, and
      pyridoxalphosphate-6-azophenyl-2',4'-disulphonoic acid (PPADS). Depletion of the
      sarcoplasmic reticulum Ca2+ store with thapsigargin completely abolished the UTP
      induced Cam response. In addition, the peak UTP-induced Cam increase was almost
      two-fold higher in a 2-mM Ca2+ solution than a 0-mM Ca2+ solution. This suggests
      that the UTP-induced Cam response is comprised of both Ca2+ influx and the
      mobilization of intracellular Ca2+ stores. Pertussis toxin reduced the UTP
      induced Cam response 50%, thus, the UTP-induced increase in Cam is mediated, in
      part, via Gi/o. These data suggest this UTP-sensitive receptor belongs to the P2Y
      nucleotide receptor family; however, it does not possess pharmacological
      characteristics associated with any known P2Y receptor subtype.

PMID- 12616996
TI  - Effects of adenosine analogs on inositol 1,4,5-trisphosphate production in
      porcine coronary artery.
AB  - Using various pharmacological methods, we previously demonstrated that the smooth
      muscle and endothelium of porcine coronary artery contain vasorelaxant adenosine
      A2 receptors, which are predominantly the A2A subtype. The present study was
      intended to investigate the effect of adenosine receptor stimulation on agonist
      induced inositol 1,4,5-trisphosphate (IP3) generation in porcine coronary artery
      using the nonselective adenosine analogs, 2-chloroadenosine (CAD) and 5'-(N
      ethylcarboxamido)adenosine (NECA), and the A2A selective analog 2-p-(2
      carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS). In both
      endothelium-intact and denuded coronary artery rings, CAD, NECA and CGS elicited
      a dose-dependent inhibition of prostaglandin F2 alpha (PG)-induced IP3
      production. However, the inhibitory effect of NECA was relatively less in
      endothelium-denuded preparations. The nonselective xanthine adenosine receptor
      antagonist, 8-sulfophenyltheophylline (8-SPT), significantly attenuated the IP3
      inhibitory effect of CAD and, to a lesser extent, that of NECA. Further, the A2A
      selective nonxanthine antagonist, 5-amino-7-(2-phenylethyl)-2-(furyl)
      pyrazolo[4,3]-1,2,4-triazolo[1,5-c] pyrimidine (SCH), markedly decreased the
      effects of all CAD, NECA and CGS on PG-induced IP3 generation. These results
      provide evidence that activation of adenosine A2 receptors by CAD, NECA and CGS
      in porcine coronary artery causes inhibition of agonist-induced IP3 production,
      and these receptors involve at least the A2A subtype.

PMID- 12616997
TI  - The "best practice" approach.

PMID- 12616998
TI  - Obstructive sleep apnea in head and neck cancer patients post treatment ...
      something to consider?
AB  - Obstructive sleep apnea (OSA) occurs due to enlarged tissue such as tonsils, base
      of tongue or palate, pharyngeal space narrowing, or decreased muscle tone of the
      pharyngeal dilator muscles. Treatments for head and neck cancer may cause
      physical changes resulting in OSA. Based on recent anecdotal experience and
      limited research available looking at the incidence of OSA in post treatment head
      and neck cancer patients, assessment for signs and symptoms of OSA by
      otorhinolaryngology nurses seems warranted. Prompt diagnosis and treatment of OSA
      in the patient with head and neck cancer may significantly improve the person's
      health and quality of life.

PMID- 12617000
TI  - Of speciality interest: steps to successfully produce an educational videotape.

PMID- 12616999
TI  - Efficacy of video education for patients and caregivers.
AB  - Videotapes are valuable resources for assistance in educating patients and
      caregivers in today's changing health care environment. Videotapes can be
      effective teaching tools for patients by facilitating knowledge acquisition,
      reducing anxiety, improving coping skills, and enhancing self care behaviors.
      They incorporate visual and auditory information into a teaching modality that is
      often easy for individuals to understand and retain. Research on videotaped
      patient education will be presented with application of findings to the practice
      of otolaryngologic nursing.

PMID- 12617001
TI  - Patient education: tips for smoking cessation.

PMID- 12617002
TI  - Practice management: telephone triage in an otolaryngology practice.
AB  - Telephone triage is not a new healthcare concept, but it is an idea that is
      gaining momentum as Americans move into today's "e-technology, e-health" world.
      In fact, many companies are creating systems and protocols to improve efficiency
      and increase access to "triage" personnel.

PMID- 12617003
TI  - Next regulation wrangle on the way.

PMID- 12617004
TI  - NMC must retain safeguards for nurses.

PMID- 12617005
TI  - Can nurse practitioners replace junior doctors?

PMID- 12617006
TI  - Breaking the error chain.

PMID- 12617008
TI  - What you need to know about.. acute appendicitis.

PMID- 12617007
TI  - A nurse-led outpatient service for patients with DVT.
AB  - The traditional management of patients with suspected deep vein thrombosis
      required hospital admission for diagnostic investigation and anti-coagulation
      therapy. Since November 2001 all patients with suspected DVT at Tameside and
      Glossop Acute Services NHS Trust have been managed as outpatients via the
      vascular studies unit according to agreed protocols. Audit results have shown
      that the service has resulted in a reduction in bed occupancy for patients with a
      sole diagnosis of DVT, and a reduction in the cost of managing and treating
      patients with a suspected DVT.

PMID- 12617009
TI  - Wound VACs.

PMID- 12617010
TI  - Diabetes: new treatments and guidance.
AB  - It is recommended today that care for people with diabetes should be given in the
      community. New initiatives are being set up to deliver that care, and new
      treatments are constantly being developed, such as insulin analogues that provide
      an opportunity for patients to adjust their insulin regimen to suit their
      lifestyle. National initiatives in diabetes care are aiming to reduce
      inequalities in care.

PMID- 12617011
TI  - Multidisciplinary patient records in a palliative care setting.
AB  - Multidisciplinary team working is essential to the delivery of specialist
      palliative care. Recent government initiatives have focused on improving the
      quality of patient care through a collaborative approach. The palliative care
      directorate of the Thames Gateway NHS Trust developed a patient record system
      that could be utilised by all health care professionals. An audit was carried out
      and showed that the new documentation, which provides only one set of records,
      improves the clarity of information, enhances communication, avoids duplication
      and helps to maintain the continuity of the patient's journey.

PMID- 12617012
TI  - Money to learn. Interview by Rebecca Coombes.

PMID- 12617013
TI  - Identifying food allergies in children.

PMID- 12617014
TI  - Benchmarking and nutrition.

PMID- 12617015
TI  - Management of intestinal failure.

PMID- 12617016
TI  - Living with intestinal failure.

PMID- 12617017
TI  - Update on access to nutritional support.

PMID- 12617018
TI  - New light on Dr Thomas Moffet: the triple roles of an early modern physician,
      client, and patronage broker.

PMID- 12617019
TI  - "Russian nervousness": neurasthenia and national identity in nineteenth-century
      Russia.

PMID- 12617020
TI  - The government of Israel and the health care of the Negev Bedouin under military
      government, 1948-1966.

PMID- 12617021
TI  - The medical activities of the London Jews' Society in nineteenth-century
      Palestine.

PMID- 12617022
TI  - Surgical instruments in the Taxila Museum.

PMID- 12617023
TI  - Spanish toxic oil syndrome.

PMID- 12617024
TI  - Owsei Temkin 1902-2002.

PMID- 12617025
TI  - Reconstructing history.

PMID- 12617027
TI  - How can primary concerns of school district superintendents guide school health
      efforts?
AB  - School-based research and health promotion interventions typically require upper
      administration support and acceptance to succeed. This paper focuses on a
      recently completed Delphi survey of the majority of school district
      superintendents in a frontier state. The survey examined superintendent district
      level concerns at the elementary, middle/junior high, and high school levels.
      Primary concerns revolved around school funding, classroom education and student
      achievement, and teacher-centered issues. Implications for this research are
      discussed as are the importance of these data to those interested in working with
      schools to improve student health. The importance of this information for
      implementation of coordinated school health programs also is discussed.

PMID- 12617026
TI  - Using technology to teach health: a collaborative pilot project in Alabama.
AB  - The Centers for Disease Control and Prevention (CDC) identified six adolescent
      risk behaviors that contribute to chronic diseases and disorders, including poor
      dietary habits, sedentary lifestyle, and abuse of alcohol, tabacco, and other
      drugs. This project pilot-tested a "train-the-trainer" model to diffuse an
      interactive health education software program into Alabama middle schools during
      a school year. Developmentally appropriate content included nutrition, physical
      activity, and prevention of substance use. Twenty-four site facilitators selected
      from 18 public school systems trained 364 colleagues and 2,249 students to use
      the software. During a school year, facilitators created 150 student assignments;
      they reported increased interest among students in health instruction. An
      essential feature of the project involved an active partnership among the funder,
      state department of education, university, and public schools. Planners provided
      technical assistance through face-to-face interaction, distance learning,
      telephone and e-mail communications, and a Web site. Planners and facilitators
      worked together to overcome barriers to the use of technology for health
      instruction.

PMID- 12617028
TI  - Television viewing and its associations with overweight, sedentary lifestyle, and
      insufficient consumption of fruits and vegetables among US high school students:
      differences by race, ethnicity, and gender.
AB  - Television (TV) viewing has been associated with overweight, decreased physical
      activity, and unhealthy dietary behavior among children and adolescents, and may
      represent a modifiable cause of childhood obesity. This study examined race,
      ethnic, and gender-specific differences in these associations among high school
      students in the United States. The study analyzed data from the 1999 national
      Youth Risk Behavior Survey, a representative sample (N = 15,349) of US high
      school students. Logistic regression tested for significant associations. TV
      viewing on an average school day exceeded 2 hours/day among 43% of students; it
      was greater among Black (74%) and Hispanic (52%) than White (34%) students.
      Overall, 11% of students were overweight, 31% of students were sedentary (i.e.,
      did not participate in moderate or vigorous physical activity at recommended
      levels), and 76% ate less than five servings/day of fruits and vegetables.
      Watching TV more than 2 hours/day was associated with being overweight, being
      sedentary, and eating insufficient fruits and vegetables among White females, and
      with being overweight among Hispanic females. No significant associations were
      found among Black females. TV viewing was associated with being overweight and
      eating insufficient fruits and vegetables among White males. No significant
      associations were found among Hispanic males. Among Black males, TV viewing was
      associated with greater participation in physical activity. These findings
      suggest the presence of cultural factors to consider when developing
      interventions to promote physical activity, healthy eating, and healthy weight
      through reduced TV viewing among adolescents.

PMID- 12617030
TI  - Our proud heritage in school health.

PMID- 12617029
TI  - The influence of preservice instruction in health education methods on the health
      content taught by elementary teachers in Indiana.
AB  - This study examined whether receiving preservice instruction in health education
      methods affects the health instruction provided by elementary classroom teachers.
      Using a researcher-constructed self-report questionnaire, 800 third-, fourth-,
      and fifth-grade teachers in Indiana were randomly selected to complete the
      questionnaire. Returns included 366 usable responses from an effective sample of
      772, for an overall response rate of 48.06%. Analysis of variance indicated a
      statistically significant difference among respondents in the mean number of 10
      health content areas taught, the depth of coverage of all content areas except
      Community and Environmental Health, the mean number of health lessons taught per
      week, and the minutes spent teaching health per week. Pairwise comparisons
      indicated respondents who completed both a health education methods course and a
      physical education methods course taught a greater number of health content
      areas, and taught more topics in eight of the 10 health content areas, than did
      respondents who did not complete preservice instruction in health education
      methods.

PMID- 12617031
TI  - On dental erosion and associated factors.
AB  - The aim of this thesis was to explore aspects of dental erosion by investigating
      its prevalence among young Saudi men and young children, develop a system for its
      assessment and to evaluate various tentative background factors that may be
      associated with its occurrence. Saudi military inductees (n = 95) were subjected
      to questionnaire and clinical examination, including recordings of severity of
      dental erosion and a number of other oral health parameters. The system applied
      for grading the severity of dental erosion showed an intraexaminer agreement of
      78%. Around one-fourth of the maxillary anterior tooth surfaces exhibited
      pronounced dental erosion and the average soft drink consumption was 247
      liters/year. High level of soft drink consumption and long retention time of the
      drink in the mouth before swallowing, intensified oral hygiene, mouth breathing
      and low gingival bleeding index were found to have significant correlations with
      the presence of dental erosion. Furthermore, less plaque on maxillary palatal
      tooth surfaces, increased numbers of buccal cervical defects, first permanent
      molar "cuppings", missing teeth, and lower salivary urea content had significant
      correlations with the severity of dental erosion. High intake of acidic drinks
      and fruits, upper respiratory tract problems and frequent taking of medication
      were common findings in young Saudi children (n = 16) with severe dental erosion.
      The clinical diagnosis of erosion in deciduous teeth was confirmed by SEM. Enamel
      from various healthy teeth were subjected to microhardness measurements before
      and after in vitro exposure to citric acid. Deciduous enamel was found to be
      softer and relatively more prone to erosion than permanent enamel but the
      potential for erosion was about the same regardless of the origin of the teeth.
      Six methods of drinking a sugar-free cola-type drink were assessed in two groups
      of healthy volunteers. Intraoral pH was measured at specific locations and at
      predetermined time points using the microtouch method (n = 12), and continuously
      by using telemetric measurement (n = 6). Of the six methods tested, those in
      which the drink was in contact with the tooth surface for a prolonged period of
      time were found to strongly affect intraoral pH. It may be concluded from this
      thesis that dental erosion is common among young Saudi men and that erosion is
      associated with many etiological, aggravating and modifying factors. Consumption
      of soft drinks, amount of palatal plaque on maxillary anterior teeth and salivary
      urea concentration are some factors related to erosion. The presence of dental
      erosion in children is likely to be associated with a number of general health
      and dietary factors but is also aggravated by the relatively more rapid
      progression of erosion in the deciduous teeth. Drinking method seems to be an
      important factor in the risk of developing dental erosion.

PMID- 12617033
TI  - [Molecular chaperone inducers in medicine and diseases].
AB  - In response to stresses, mammalian cells induce heat shock proteins (HSP).
      Overproduction of a stress-inducible 70-kDa protein (Hsp70) results in the
      acquisition of tolerance against various types of stresses. An acyclic
      isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a
      non-toxic Hsp 70 inducer, which selectively and safely induced Hsp70 in cultured
      guinea pig gastric mucosal cells and rat gastric mucosa. GGA also primed other
      types of cells for enhanced induction of Hsp70, when exposed to stress.
      Pretreatment of rats with GGA markedly suppressed ischemia-reperfusion injury of
      the liver, small intestine, or heart, and improved survival after 95% hepatectomy
      as well as liver transplantation. GGA can block insult-induced apoptosis at
      multiple levels; it inhibited activation of c-Jun N-terminal kinases, decline of
      mitochondrial membrane potential, and formation of apoptosome by binding with
      Apaf-1. Recently, GGA has been shown to induce thioredoxin and anti-viral genes,
      suggesting that GGA may exhibit protective actions independently of Hsp70
      induction. HSP are members of molecular chaperones that are essential for the
      quality control of intracellular proteins. New compounds specifically targeting
      molecular chaperones that function to prevent the accumulation of misfolded
      proteins may be useful for the treatment of neurodegenerative disorders in the
      near future.

PMID- 12617032
TI  - [Therapeutic strategy for fibrotic diseases by regulating the expression of
      collagen-specific molecular chaperone HSP47].
AB  - Through disruption of the hsp47 gene in mice, we found that HSP47, a collagen
      specific molecular chaperone residing in the endoplasmic reticulum, is essential
      for mouse development. Improper triple helix formation was observed in hsp47-null
      embryos, and no collagen fibrils in the mesenchyme or basement membranes between
      the mesenchyme and epithelial cell layers were seen in those mice, which resulted
      in embryonic lethality. Interestingly, constitutive expression of HSP47 is always
      correlated with that of collagens in various cells or tissues. HSP47 is markedly
      up-regulated during the progression of fibrosis in the liver, kidney, lung, and
      so on. A preliminary experiment showed that down-regulation of HSP47 caused the
      reduction in the progression of fibrosis by down-regulating the accumulation of
      collagens in the tissues, which suggests a novel strategy for the therapy of
      fibrotic diseases including liver cirrhosis.

PMID- 12617034
TI  - [Novel physiological roles of low molecular weight HSPs].
AB  - Some low molecular mass heat shock proteins (HSPs) appear to act as molecular
      chaperones, but their exact physiological roles have not been fully elucidated.
      We reported the physiological roles of HSP20, HSP27, and alpha B-crystallin in
      platelet function in vitro and ex vivo. HSP20 and alpha B-crystallin dose
      dependently inhibited the aggregation of human platelets induced by thrombin or
      botrocetin. On the other hand, HSP27, the other type of low molecular mass HSP,
      did not affect platelet aggregation. When HSP20 or alpha B-crystallin was
      injected intravenously as a bolus in hamsters, the development of thrombus after
      endothelial injury was prevented. Moreover, 9 amino acid sequences isolated from
      HSP20 or alpha B-crystallin significantly reduced platelet aggregation induced by
      TRAP, but not a PAR-4 agonist. These findings strongly suggest that HSP20 or
      alpha B-crystallin can act intercellularly to regulate platelet functions. Our
      results may provide the basis for a novel defense system against thrombus
      formation in vivo.

PMID- 12617035
TI  - [Small heat shock proteins participate in the regulation of cellular aggregates
      of misfolded protein].
AB  - Molecular chaperones participate in folding of many proteins and several families
      are known to exist in mammalian cells including the small heat shock protein
      (sHSP) family. sHSPs have a molecular mass of 15-30 kDa and are known to be
      induced and phosphorylated in response to various stimuli. There are several
      reports describing the correlation between sHSPs and degenerative diseases. We
      have been reported that Hsp27 and alpha B-crystallin were recruited to aggresome
      when cells were treated with proteasome inhibitors. Expression of Hsp27
      suppresses the cell death induced by expression of expanded polyglutamine via
      down regulation of the oxidative stress pathway. Recently, a missense mutation in
      alpha B-crystallin, R120G, has been found in a French family suffering from
      desmin-related myopathy. Moreover, transgenic mice expressing R120G alpha B
      crystallin exhibit symptoms similar to desmin-related myopathy. We recently
      examined the interaction of R120G alpha B-crystallin and Hsp27 in mammalian cells
      and found that expression of R120G alpha B-crystallin caused formation of
      inclusion bodies and co-expression of Hsp27 inhibited this formation of inclusion
      bodies. Clarification of physiological roles of sHSPs in degenerative diseases
      may lead to the development of new therapy.

PMID- 12617036
TI  - [Molecular chaperone HSP90 as a novel target for cancer chemotherapy].
AB  - HSP90 is one of the major molecular chaperones whose expression level increases
      by environmental stresses. Even under normal conditions, HSP90 is a highly
      abundant cytosolic protein and is essential for cell viability. HSP90 is involved
      in the maintenance of appropriate folding and conformation of many cellular
      functional proteins. These "HSP90 client proteins" are associated with HSP90 and
      they include a wide variety of signal-transducing proteins that regulate cell
      growth and differentiation, such as protein kinases and steroid hormone
      receptors. HSP90 functions in an ATP-dependent manner with other molecular
      chaperones such as Cdc37 and FKBP52. An HSP90 inhibitor, geldanamycin, binds the
      ATP-binding pocket of HSP90 and specifically inhibits the essential ATPase
      activity of HSP90. Thus, treatment of cells with geldanamycin results in
      inactivation, destabilization, and degradation of HSP90 client proteins. Because
      HSP90 client proteins play important roles in the regulation of the cell cycle,
      cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs
      the proliferation of cultured cancer cells and shows anti-cancer activity in
      experimental animals. Although the precise mechanism of the effect of HSP90
      inhibitors on cancer cells remains to be clarified, HSP90 inhibitors will be
      potential and effective cancer chemotherapeutic drugs with a unique profile. In
      fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17
      AAG), has been examined in phase I clinic trials with encouraging results.

PMID- 12617037
TI  - [ORP150 (150 kDa oxygen regulated protein) suppressed neuronal cell death].
AB  - Cells subject to environmental change express stress proteins, which contribute
      importantly to maintenance of metabolic homeostasis and viability. As the most
      abundant cell type in the central nervous system, astrocytes show a phenotype
      resistant to environmental alterations. Based upon this ability of astrocytes, we
      have purified and cloned a novel stress protein, ORP150, a 150-kDa oxygen
      regulated protein. We have shown that ORP150 is an inducible chaperone present in
      endoplasmic reticulum (ER), which regulates cytosolic free calcium and activation
      of proteolytic pathways causing cell death in neurons subject to excitatory
      stress. Using mice heterozygous for ORP150 deficiency, exposure to excitatory
      stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic
      calcium accompanied by an increased vulnerability to glutamate-induced cell death
      in vitro and decreased survival to kainate in vivo. In contrast, targeted
      neuronal overexpression of ORP150 suppressed each of these events and enhanced
      neuronal and animal survival in parallel with diminished seizure intensity. Our
      data underscore a pivotal role for ER stress in glutamate toxicity and pinpoint a
      key ER chaperone, ORP150, which orchestrates the protective stress response
      critical for neuronal survival.

PMID- 12617038
TI  - [Possible participation of advanced glycation endproducts and their receptor
      system in the development of diabetic vascular complications].
AB  - Diabetes causes vascular injuries in various organs and tissues, among which the
      lesions in retina and kidney are called retinopathy and nephropathy,
      respectively. As the number of diabetic patients is increasing in Japan, the
      population with the vascular complications is also elevating. For preventing
      diabetic complications, it is necessary to develop new drugs that target for key
      molecules in the development of this disease and useful animal models for the
      evaluation of their therapeutic potentials. We have focused on the non-enzymatic
      glycation reaction under prolonged hyperglycemia, which results in the formation
      and accumulation of advanced glycation endproducts (AGE). The interaction of AGE
      with the receptor for AGE (RAGE) has been implicated in the development of the
      vascular complications. AGE elicited vascular cell changes typical of diabetes,
      including angiogenic and thrombogenic responses of endothelial cells (EC), and a
      decrease in pericytes, the hallmarks of diabetic retinopathy. Our recent in vivo
      study revealed that transgenic mice overexpressing human RAGE in vascular EC
      developed advanced nephropathy when they were made diabetic. This mouse is thus
      regarded as a useful animal model of diabetic vascular disease. These results
      suggest that the AGE-RAGE system plays an active role in the development of
      diabetic vasculopathy and is a promising target in the prophylaxis and therapy of
      this disease. Recently, we identified three RAGE variants: novel C-terminally and
      N-terminally truncated forms and the known full-length form. The C-terminally
      truncated variant was found to be a soluble form and actually detected in human
      sera, and it was found to have neutralizing activities against AGE-induced EC
      injury. The endogenous soluble decoy against the AGE-RAGE system may contribute
      to the individual resistance to the development of diabetic vascular
      complications. The stimulation of secretion of this protein can be a new means
      for the prevention of chronic vascular disease in diabetes.

PMID- 12617039
TI  - [Pharmacological profile of anti-human TNF alpha monoclonal antibody, infliximab
      (Remicade)].
AB  - TNF alpha (tumor necrosis factor-alpha) plays an important role in the
      pathogenesis of inflammatory diseases including Crohn's disease and rheumatoid
      arthritis. Infliximab (Remicade) is a chimeric monoclonal antibody that
      recognizes human TNF alpha. Clinical trials trials have been persuasive that
      infliximab is effective in both Crohn's disease and rheumatoid arthritis.
      Infliximab is an important treatment option in patients with active Crohn's
      disease who have not responded to conventional therapy and in patients with
      Crohn's disease who have fistulae. Moreover, infliximab plus methotrexate is
      effective in patients with active rheumatoid arthritis who have not responded
      adequately to traditional disease-modifying anti-rheumatic drugs, in terms of
      reducing symptoms and signs, inhibiting the progression of structural damage and
      improving physical function.

PMID- 12617040
TI  - [Maxacalcitol, a medicine for secondary hyperparathyroidism (2 degrees HPT)].
AB  - Maxacalcitol (Oxarol) is a derivative of vitamin D compounds applied for the
      secondary hyperparathyroidism (2 degrees HPT) of hemodialysis (HD) patients as an
      injection and psoriasis as an ointment. 2 degrees HPT is one of the complications
      in HD patients with hyperplasia of parathyroid glands and elevated serum
      parathyroid hormone (PTH) levels. On the other hand, vitamin D compounds are
      known to have multiple actions in many organs (promotion of calcium absorption
      from the small intestine, induction of differentiation of leukemia cells,
      differentiation and proliferation of the chondrocyte, muscle cells and epidermal
      cells, immunosuppressive activities) and their activities on parathyroid glands
      seem to be mediated by the vitamin D receptor (genomic action). It was reported
      that both serum PTH and PTH mRNA levels were suppressed by Maxacalcitol with less
      calcemic action and also Maxacalcitol could ameliorate high-turnover bone and
      marked osteitis fibrosa in uremic rats. Here I review many reports focused on the
      effects of Maxacalcitol on the 2 degrees HPT.

PMID- 12617041
TI  - [Mitochondrial diseases].

PMID- 12617042
TI  - [Mitochondrial diseases. Clinical features, investigation and genetics].
AB  - The aim of this article is to give an overview of mitochondrial disorders.
      Mitochondria are responsible for the generation of energy in the cells. The term,
      mitochondrial disorders, usually refers to disorders of the respiratory chain.
      These disorders can be caused by mutations in the DNA of the mitochondria or in
      the nuclear DNA. A characteristic feature is that all tissues can be affected,
      and a defect is expressed differently in different tissues. Highly differentiated
      energy-demanding tissues, such as neurons and muscle cells, are often affected.
      Mitochondrial disorders are difficult to diagnose. The investigations comprise
      metabolic screening, respiratory chain enzyme analysis in muscle tissue, muscle
      histology, and mutation analysis. The focus of this article is on diagnostic
      evaluation of childhood disorders, because investigation and diagnosis are
      particularly difficult in children.

PMID- 12617043
TI  - [The systematic inflammatory response after major trauma].
AB  - Few investigations have elucidated the acute inflammatory response after
      accidental trauma before the patients were anesthetized and treated with
      analgetics and intravenous fluid. The cellular immunological response seems to be
      characterized by an initial activation followed by suppression. In major tissue
      trauma, the granulocytes are the major effector cells. Activated granulocytes are
      redistributed from the peripheral blood into the tissues, where release of
      proteolytic enzymes and oxygen-free radicals participate in the development of
      systemic inflammation and organ dysfunction. The antigen presentation capacity of
      monocytes and the cytotoxicity of NK-cells are reduced following major trauma.
      High concentrations of proinflammatory and antiinflammatory cytokines can be
      measured locally in the injured tissue. In uncomplicated cases, elevated cytokine
      concentrations are measured in the blood for a few days, whereas a sustained high
      cytokine production seems to correlate with organ dysfunction and mortality.

PMID- 12617044
TI  - [Ventral herniotomy. Development of surgical technique and effect on the
      frequency of recurrence].
AB  - The surgical journal, Repair of Ventral Hernias, was reviewed with regard to
      recurrence of hernia. Ventral hernias must be operated on with a tension-free
      technique. It is recommended that hernias larger than 4 cm are repaired with
      mesh. A randomised, controlled trial has yet to be carried out to determine
      whether even small hernias should be repaired with mesh. Controlled and
      uncontrolled studies have shown that the use of mesh to repair larger hernias
      results in a lower recurrence rate. The operative technique with the mesh placed
      to bridge the wall defect gives a higher rate of recurrence than does an overlap
      technique. The overlap of the mesh and its placement in relation to the different
      layers of abdominal wall are not defined. The laparoscopic operation using the
      overlap technique and intraperitoneal mesh has shown a lower recurrence rate than
      the open technique. However, a randomised, controlled study comparing the
      laparoscopic and open overlap technique over a long follow-up period still needs
      to be conducted.

PMID- 12617045
TI  - [Elective mutism--a disorder of social functioning or an emotional disorder?].
AB  - Elective mutism is a relatively uncommon disorder characterized by consistent
      failure to speak in specific social settings, such as in school, despite speaking
      fluently in a variety of other situations. Elective mutism is a very debilitating
      disorder for the affected child, as well as for their families, with detrimental
      implications for the development of social skills and learning if not offered
      appropriate support and treatment. The most promising treatment results have thus
      by far been achieved through a combination of cognitive behaviour therapy and
      supportive cooperation between parents, the school, and the treating child
      psychiatrist, occasionally supplemented with pharmacological treatments such as
      selective serotonin reuptake inhibitors. The available literature on this
      disorder is still very limited and consists predominantly of case reports. In
      recent years, however, there has been a growing focus on the etiology and general
      understanding of the disorder. While still disputed, it has been suggested that
      elective mutism might be understood as an emotional disorder on a par with e.g.
      separation anxiety and social phobia. Studies looking at the long-term course of
      the disorder are urgently required to elucidate whether children presenting
      elective mutism will be more likely to suffer from emotional disorders in
      adulthood, and may also ultimately lead to improved treatments for this disabling
      psychiatric disorder of childhood.

PMID- 12617046
TI  - [Reconstruction of anterior cruciate ligament using bone-patellar tendon-borne
      graft or fascia lata graft. A retrospective study of functional results].
AB  - INTRODUCTION: The purpose of this study was to compare the functional results
      using two different types of reconstruction of the anterior cruciate ligament.
      MATERIAL AND METHODS: A retrospective comparison of 34 patients operated with a
      fascia lata graft and 26 patients operated with a bone-patellar tendon-bone
      graft. The patients were evaluated twice with a postoperative Lysholm score, a
      preoperative and postoperative Tegner score, and a postoperative knee-laxity
      test. RESULTS: The Lysholm scores after the first (P = 0.07) and second (P =
      0.29) postoperative control showed no difference between the two groups. There
      was no difference between the preoperative and postoperative Tegner scores of the
      two groups (P = 0.42). A total of 27 patients out of 60 practiced sports or had
      knee-straining work postoperatively at the same level as preoperatively. No
      difference was found between the two groups when comparing the knee-laxity tests
      (P = 0.12). DISCUSSION: This study did not find any difference in the final
      functional results when comparing the two operation techniques. Almost half of
      the patients can expect a return to sports at a preinjury level.

PMID- 12617047
TI  - [Establishment of a nurse-led heart failure clinic. Design and baseline data from
      the first two years].
AB  - INTRODUCTION: Previous studies on the effect of heart failure clinics have shown
      a reduction in hospitalizations, reduced cost and improved quality of life.
      MATERIAL AND METHODS: We report on the establishment of a heart failure clinic
      and its impact on heart failure hospitalizations. Since September 1, 1999, a
      heart failure clinic has been operated at the Frederiksberg University Hospital.
      The clinic was designed with both a diagnostic and a therapeutic unit. The
      diagnostic unit offers open access to all patients with suspected heart failure,
      either through referral from general practitioners or from the medical
      departments of the hospital. In case of confirmed systolic heart failure, the
      patient is referred to the therapeutic unit. RESULTS: During the two years of
      operation, a total of 510 patients were registered in a newly established
      database (HJERTER+). Of these, 352 (69%) were found to have clinical evidence of
      heart failure, and 304 (86% of the heart failure patients) had left ventricular
      (LV) systolic dysfunction (ejection fraction < or = 0.45). Before referral, most
      patients with LV dysfunction had been treated with no or insufficient dose of ACE
      inhibitor (55%), and one third received beta-blockers (32%). During the two years
      of operation of the clinic, there was a 23% decline in heart failure related
      hospital admissions to the department of cardiology. DISCUSSION: Patients with
      systolic heart failure are not always optimally treated. The establishment of a
      heart failure clinic offering the combination of diagnosing and managing
      congestive heart failure appears to be effective both in terms of therapy
      optimization and with respect to a concomitant decline in hospitalization for
      heart failure.

PMID- 12617048
TI  - [Etiology and diagnostic methods in vocal cord paralysis].
AB  - INTRODUCTION: The etiology of vocal cord paralysis (VCP) is varied. There is lack
      of consensus regarding the choice of investigations to be used in the evaluation
      of VCP. The aim of this study was to establish the etiology, assess the
      diagnostic methods used in the evaluation, and outline an algorithm for future
      evaluation of unilateral vocal cord paralysis (UVCP). MATERIAL AND METHODS:
      Charts of all patients (n = 94) with the diagnostic code of VCP were reviewed,
      and reexaminations were performed of patients in whom no etiology was found after
      the initial symptoms. RESULTS: The etiology of UVCP was neoplasm in 34%, surgical
      trauma in 12%, and miscellaneous causes in 54%. The etiology of bilateral vocal
      cord paralysis (BVCP) was neoplasm in 24%, surgical trauma in 24%, and
      miscellaneous causes in 52%. The reexaminations did not reveal any cancer
      diseases in the patients concerned. The most effective diagnostic method was CT
      scanning while the least effective was thyroid scanning. DISCUSSION: Because
      cancer is a common cause of VCP a thorough evaluation is necessary. For UVCP we
      recommend history and physical examination, X-ray of the chest, ultrasonography
      of the neck, and CT-scanning of the superior mediastinum. If these prove
      negative, panendoscopy should be performed. Workup of patients with idiopathic
      VCP should include examination, X-ray of the chest at 6-month intervals, and
      annual CT-scanning for two years.

PMID- 12617049
TI  - [Retained fetal bones in uterus].
AB  - We report a case of menorrhagia caused by retained fetal bones after a missed
      abortion in the second trimester. By hysteroscopy several bone fragments were
      removed. The patient got pregnant two months later.

PMID- 12617050
TI  - [Posttraumatic osteolysis of the distal clavicle].
AB  - Posttraumatic osteolysis of the distal clavicle (ODC) is a very rare condition
      that occurs after acute injury or repetitive microtrauma of the shoulder and
      which is characterized by persistent shoulder pain, restricted shoulder motion,
      and progressive osteolytic changes at the outer end of the clavicle. A case of
      posttraumatic osteolysis of the distal clavicleis presented and the aetiology,
      diagnosis and treatment are discussed.

PMID- 12617051
TI  - [Cyclocaprone prevents early rebleeding after subarachnoid hemorrhage and should
      be administered already prior to transfer to the department of neurology].

PMID- 12617052
TI  - [Excessive mortality related to antibiotic resistant Salmonella typhimurium].

PMID- 12617053
TI  - [Should lesbian women have access to artificial fertilization?].

PMID- 12617054
TI  - [A new critical report on coxiber].

PMID- 12617055
TI  - [Minutes of the Directing Council of the Italian Society of Anesthesia,
      Analgesia, Resuscitation, and Intensive Care. Rome, 27 April 2002].

PMID- 12617056
TI  - Waiting for the doctor: gender differences in the timing of an intervention by
      the occupational physician.
AB  - This study aims to answer the question whether the relatively high inflow risk
      into disability for women, compared to that for men, is related to a lower chance
      of being called by the occupational physician during sickness absence. This
      chance is influenced by sociodemographic, health-related, and work-related
      factors, as well as by the duration of sickness absence. Using a proportional
      hazards model, the "risk" of being called by the physician within a certain time
      period (the so-called hazard rate) is estimated. Kaplan-Meier curves show a
      gender difference in the hazard rate. Women appear to have a higher chance of
      being called by the occupational physician (i.e., a shorter waiting time). The
      influence of the covariates on the hazard rate is estimated using a Weibull
      model. The Weibull estimations show a negative duration dependence for women,
      while for men there is no duration dependence. It is concluded that the higher
      chance for women to be called by the occupational physician is not associated
      with a gender difference in treatment. Rather, it is the result of a difference
      in underlying characteristics. Underlying characteristics that significantly
      predict the waiting time for the occupational physician are in particular related
      to the labor market position of the employee: educational qualifications, firm
      size, industry, occupational workload, and job tenure. Other significant
      predictors are duration and diagnosis.

PMID- 12617057
TI  - [Nutrients intake in elderly people living in Providence, Santiago de Chile].
AB  - BACKGROUND: The information available on food intake in the elderly in Chile is
      restricted to individuals of low socioeconomic groups, but there is no data
      available on food intake in elderly of higher income groups. AIM: To assess food
      intake in a group of elderly people from Providencia County in Santiago, a middle
      income community. SUBJECTS AND METHODS: Forty one subjects (20 male), aged 60 to
      73 years, were studied. Trained volunteers applied a 3 days food registry, to
      determine food intake. Intake was assessed using 1985 FAO/OMS/UNU recommendations
      for energy intake and USA Food and Nutrition Board recommendations for
      micronutrient intake. RESULTS: The studied subjects had an adequate macronutrient
      intake, when compared with current recommendations. There was a relatively low
      intake of calories from fat (24.6% in males and 26.1% in females). Also, vitamin
      and mineral intake was adequate with the exception of calcium (64.5% and 57.9% of
      recommendation in males and in females respectively), zinc and folic acid (74.2%
      and 62.4% in males and females respectively). The intake of legumes and cereals
      was relatively low. CONCLUSIONS: Food intake in this group of individuals was
      substantially higher than that reported previously for poor elderly Chileans and
      similar to that of industrialized countries. Food intake of the elderly is
      probably related to socioeconomic level.

PMID- 12617058
TI  - Hypoglycemic effect of several substituted amides and acylhydrazides of succinic
      acid.

PMID- 12617059
TI  - An application of reversible-jump Markov chain Monte Carlo to spike
      classification of multi-unit extracellular recordings.
AB  - Multi-electrode recordings in neural tissue contain the action potential
      waveforms of many closely spaced neurons. While we can observe the action
      potential waveforms, we cannot observe which neuron is the source for which
      waveform nor how many source neurons are being recorded. Current spike-sorting
      algorithms solve this problem by assuming a fixed number of source neurons and
      assigning the action potentials given this fixed number. We model the spike
      waveforms as an anisotropic Gaussian mixture model and present, as an
      alternative, a reversible-jump Markov chain Monte Carlo (MCMC) algorithm to
      simultaneously estimate the number of source neurons and to assign each action
      potential to a source. We derive this MCMC algorithm and illustrate its
      application using simulated three-dimensional data and real four-dimensional
      feature vectors extracted from tetrode recordings of rat entorhinal cortex
      neurons. In the analysis of the simulated data our algorithm finds the correct
      number of mixture components (sources) and classifies the action potential
      waveforms with minimal error. In the analysis of real data, our algorithm
      identifies clusters closely resembling those previously identified by a user
      dependent graphical clustering procedure. Our findings suggest that a reversible
      jump MCMC algorithm could offer a new strategy for designing automated spike
      sorting algorithms.

PMID- 12617060
TI  - Environmental and occupational medicine and injury prevention: education and
      impact, classroom and community.
AB  - The core value guiding the work of physicians and health workers, including those
      in Environmental and Occupational Epidemiology and Medicine and Injury
      Prevention, is to protect the health of the public, especially its most
      vulnerable individuals. In these fields, we emphasize teaching the use of
      epidemiology, the core discipline of public health, as a tool for early detection
      and prevention of disease and injury, as well as an instrument for hypothesis
      testing. The classic core topics are toxic and physical exposures and their
      effects, and strategies for their prevention; emerging issues are child labor,
      mass violence, and democide. In environmental health, students need to be
      prepared for the reality that the most important and severe problems are often
      the most difficult to investigate, solve, and evaluate. The following are some
      recommendations for producing graduates who are effective in protecting
      communities from environmental hazards and risks: (1) Teach the precautionary
      principle and its application; (2) Evaluate programs for teaching environmental
      and occupational health, medicine and epidemiology in schools of public health by
      their impact on the WHO health indicators and their impact on measures of
      ecosystem sustainability; (3) Develop problem-oriented projects and give academic
      credit for projects with definable public health impact and redefine the role of
      the health officer as the chief resident for Schools of Public Health and
      Community Medicine; (4) Teach the abuses of child labor and working conditions of
      women in the workplace and how to prevent the hazards and risks from the more
      common types of child work; (5) Upgrade teaching of injury prevention and
      prevention of deaths from external causes; (6) Teach students to recognize the
      insensitivity of epidemiology as a tool for early detection of true risk; (7)
      Teach the importance of context in the use of tests of statistical significance;
      (8) Teach the epidemiologic importance of short latency periods from high
      exposures as sentinel events for later group risk for cancer and stating the case
      for action; (9) Protect students and colleagues who are whistleblowers in
      environmental health from harassment and punishment; (10) Develop curricula and
      workshops that promote the use of epidemiologic tools for preventing genocide,
      democide, and their precursors. Schools of Public Health and Community Medicine
      are at the interface between the resources of academic power and the major
      problems of community health. Implementing the above recommendations will
      strengthen academic investigation and impact.

PMID- 12617061
TI  - New approach to the simultaneous analysis of catecholamines and tyrosines in
      biological fluids.
AB  - New high-performance liquid chromatographic (HPLC) methods with amperometric
      CoulArray detection were developed for simultaneous analyses of norepinephrine,
      epinephrine, L-DOPA, dopamine, 3-nitrotyrosine, m-, o-, and p-tyrosines. Overall,
      detection limit was in the low pmol range with amperometry, and in the low fmol
      range for the CoulArray method. Linear (r2 = 0.99) detector performances were
      observed in the ranges of 2-200 pmol with amperometry, and 0.2-20 pmol for the
      CoulArray method. Analytical precision values were better than 80 and 95% for
      HPLC-amperometry and HPLC-CoulArray method, respectively. These methods offer
      sensitivity, specificity, minimal sample requirement, and especially the HPLC
      CoulArray method allows simultaneous assessment of various similar biomolecules.

PMID- 12617063
TI  - Criteria for practice guideline development and evaluation.

PMID- 12617064
TI  - Criteria for evaluating treatment guidelines.

PMID- 12617062
TI  - Correlates of low bone density in females with anorexia nervosa.
AB  - The objectives were to delineate those factors which correlate with low bone
      density in patients with anorexia nervosa and in turn to predict those at
      greatest risk for osteopenia. DESIGN: Bone density was evaluated by dual energy x
      ray absorptiometry in 28 postmenarchal females with anorexia nervosa who had
      never received hormonal therapy. Bone density results were correlated with
      specific historical and physical factors utilizing descriptive statistics,
      scatter plots, and the Spearman correlation coefficient. RESULTS: Mean age was
      18.6 years, mean age at menarche was 12.9 yrs, mean length of illness was 19.8
      months and mean duration of amenorrhea was 13.4 months. Mean % ideal body weight
      was 84% at the time of bone density, 75% at minimum weight and 100% at maximum
      weight. Mean lumbar spine bone density was -1.69 standard deviations from the
      norm; mean lateral spine bone density was -1.45 standard deviations from the
      norm; mean femoral neck of the hip bone density was -1.18 standard deviations
      from the norm. There was a strong negative correlation between duration of
      amenorrhea and bone density at the lumbar spine (r = -0.50, p < .01) and a mild
      correlation at the lateral spine (r = -0.49, p < 0.05) and femoral neck (r = 
      0.41, p < 0.05). There was also a strong negative correlation between length of
      illness and bone density at the lumbar spine (r = -0.53, p < 0.01) and lateral
      spine (r = -0.77, p < 0.0001), and a mild correlation with the femoral neck (r = 
      0.48, p < 0.05). Scatter plots of lumbar bone density versus duration of
      amenorrhea, and versus length of illness clearly showed not only that longer
      duration of amenorrhea and longer length illness correlated to bone loss, but
      also strikingly that within a short time of being ill and amenorrheic,
      significant bone loss was seen. Age, and age at menarche correlated mildly with
      osteopenia at the lateral spine; age correlated mildly with osteopenia at the
      femoral neck as well. There was a trend for minimum BMI to correlate with
      osteopenia at the lateral spine. There were no correlations of bone density with
      % IBW at bone density, minimum % IBW, maximum % IBW, change in % IBW, BMI at the
      time of the bone density, maximum BMI or change in BMI. CONCLUSIONS: Low bone
      density, especially in the lumbar spine, correlated with both a longer duration
      of amenorrhea and longer length of illness, but not with other factors, in our
      patients with anorexia nervosa. As many of these patients, even those with a
      short duration of illness and amenorrhea, were osteopenic, it is advisable to
      continue to perform bone density studies in all patients with anorexia nervosa,
      on both a clinical and research basis.

PMID- 12617066
TI  - [Nasopharyngeal rhinosporidosis mimicking angiofibroma in a Cambodian
      adolescent].

PMID- 12617065
TI  - Multifactorial screening design and analysis of SELDI-TOF ProteinChip array
      optimization experiments.
AB  - Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry is
      a powerful tool for rapidly generating protein expression data (peptide and
      protein profiles) from a large number of samples. However, as with any
      technology, it must be optimized and reproducible for one to have confidence in
      the results. Using a classical statistical method called the fractional factorial
      design of experiments, we assessed the effects of 11 different experimental
      factors. We also developed several metrics that reflect trace quality and
      reproducibility. These were used to measure the effect of each individual factor,
      and the interactions between factors, to determine optimal factor settings and
      thus ultimately produce the best possible traces. Significant improvements to
      output traces were seen by simultaneously altering several parameters, either in
      the sample preparation procedure or during the matrix preparation and application
      procedure. This has led to the implementation of an improved method that gives a
      better quality, reproducible, and robust output.

PMID- 12617067
TI  - [An inaugural generalized tonic-clonic convulsive crisis following ingestion of
      Japanese star anise].

PMID- 12617069
TI  - Bibliography. Current world literature. Neuro-ophthalmology and neuro-otology.

PMID- 12617068
TI  - [Pulmonary neoplastic-like multiple coin lesions of good prognosis].

PMID- 12617070
TI  - Bibliography. Current world literature. Cerebrovascular disease.

PMID- 12617071
TI  - Media influence on suicide. Media influence behaviour.

PMID- 12617072
TI  - Media influence on suicide. Media's role is double edged.

PMID- 12617073
TI  - Low dosage tricyclic antidepressants in depression. Evidence to change current
      guidelines is insufficient.

PMID- 12617074
TI  - Low dosage tricyclic antidepressants in depression. Non-superiority does not
      equal equivalence.

PMID- 12617075
TI  - Mortality from methicillin resistant Staphylococcus aureus. Is death by disease
      or treatment?

PMID- 12617076
TI  - Managing acute renal colic. Perpetuating a urological myth.

PMID- 12617077
TI  - From the Centers for Disease Control and Prevention. HIV/STD risks in young men
      who have sex with men who do not disclose their sexual orientation--six U.S.
      cities, 1994-2000.

PMID- 12617078
TI  - From the Centers for Disease Control and Prevention. Accelerated measles control-
      Cambodia, 1999-2002.

PMID- 12617079
TI  - From the Centers for Disease Control and Prevention. Neurologic impairment in
      children associated with maternal dietary deficiency of cobalamin--Georgia, 2001.

PMID- 12617080
TI  - Master index, volumes 510-532 (2002).

PMID- 12617081
TI  - Abstracts of the 103rd Annual Meeting of the American Roentgen Ray Society. San
      Diego, California, USA. May 4-9, 2003.

PMID- 12617082
TI  - [Two cultures in medicine: reduction or construction?].
AB  - Medicine is not only a science but also belongs to the humanities. Being a
      science means that it has the objective and universally applicable methodology.
      Science, because of its stringent methodologies (determinism, reductionism and
      mechanism), cannot grasp the fruitful context of human life. Although the
      humanities can give us flexible wisdom of life, nobody can insist on its
      objective and universal applicability. We have two different cultures in medicine
      -those of science and the humanities. If you examine the ways how people choose
      health services, however, you can find that they do not have any conflict between
      the two cultures. They simply do not care whether the service they are going to
      buy is orthodox or alternative if they have have high expectations of it. The two
      cultures already have been resolved in their lives. I suggest that we should
      learn from ordinary people and not from logic of science and philosophy to
      resolve the conflict between the two cultures. We can probably begin with the
      fact that the ultimate goal of medicine is to serve the people and not to find
      abstract truth in the material body.

PMID- 12617083
TI  - Age, antioxidants, and atherogenesis.

PMID- 12617084
TI  - [Comment requested by the editorial staff].

PMID- 12617085
TI  - Medical Devices; hematology and pathology devices; reclassification of automated
      blood cell separator device operating by filtration principle from class III to
      class II. Final rule.
AB  - The Food and Drug Administration (FDA) is reclassifying the automated blood cell
      separator (ABCS) device operating by filtration principle, intended for routine
      collection of blood and blood components, from class III to class II (special
      controls). The special control requirement for this device is an annual report
      with emphasis on adverse reactions to be filed by the manufacturer for a minimum
      of 3 years. The agency is taking this action in response to a petition submitted
      under the Federal Food, Drug, and Cosmetic Act (the act) as amended by the
      Medical Device Amendments of 1976 (the 1976 amendments), the Safe Medical Devices
      Act of 1990 (the SMDA), and the Food and Drug Administration Modernization Act of
      1997 (FDAMA). The agency is reclassifying the automated blood cell separator
      devices operating by filtration principle into class II (special controls)
      because special controls, in addition to general controls, are capable of
      providing a reasonable assurance of safety and effectiveness of the device.

PMID- 12617086
TI  - Medicare program; physician fee schedule update for calendar year 2003. Final
      rule.
AB  - This final rule revises the estimates used to establish the sustainable growth
      rates (SGRs) for fiscal years 1998 and 1999 for the purposes of determining
      future updates to the physician fee schedule and announces a 1.6 percent increase
      in the calendar year (CY) 2003 physician fee schedule conversion factor (CF) for
      March 1 to December 31, 2003. The physician fee schedule CF from March 1 to
      December 31, 2003, will be $36.7856. The anesthesia CF for this period will be
      $17.05. Any information contained in this final rule related to the CY 2003
      physician or anesthesia CFs takes the place of the information contained in the
      December 31, 2002, final rule. All other provisions of the December 31, 2002,
      final rule are unchanged by this final rule.

PMID- 12617087
TI  - TEFRA Medicaid option for children with mental illness.

PMID- 12617089
TI  - Health centers and the President's growth initiative.

PMID- 12617088
TI  - Insurance mandates for childhood immunizations.

PMID- 12617090
TI  - A job with prospects. Interview by Nick Edwards.

PMID- 12617091
TI  - Pharmacologic alternatives to transfusion.

PMID- 12617092
TI  - Indications for red cell transfusion.

PMID- 12617093
TI  - The efficacy, safety and acceptance of autologous blood donation as a blood
      conservation strategy.

PMID- 12617094
TI  - Haemovigilance--closing the loop.

PMID- 12617095
TI  - The impact of ISO 15189 and ISO 9001 quality management systems on reducing
      errors.

PMID- 12617096
TI  - The medical event reporting system for transfusion medicine.

PMID- 12617097
TI  - Structure-based design of AIDS drugs and the development of resistance.
AB  - AIDS is a major worldwide epidemic spread primarily through contact with infected
      blood during sexual activity, drug injection, birth, and, rarely now, blood
      transfusion. More than a dozen drugs for the treatment of AIDS have been
      introduced in the last 15 years and the process leading to their development
      offers an excellent example of the progress made in the field of rational drug
      design. The principal targets of the approved drugs are reverse transcriptase and
      protease enzymes encoded by the human immunodeficiency virus. In particular,
      introduction of protease inhibitors has led to a significant decrease of the
      mortality and morbidity associated with AIDS. My presentation will discuss
      methods utilized for the development of selected AIDS drugs, primarily protease
      inhibitors, and the emergence of drug resistance which is presently the greatest
      challenge in fighting this disease in developed countries.

PMID- 12617098
TI  - Hepatitis C virus envelope glycoproteins and potential for vaccine development.
AB  - HCV envelope glycoproteins play an important role in the initiation of viral
      infection. The functional dichotomy of the individual HCV glycoproteins was
      investigated using VSV/HCV pseudotype virus. Surprisingly, VSV/HCV pseudotype
      virus generated from either E1 or E2 displayed infectivity of a number of
      mammalian cells. The use of pseudotyped virus has allowed us to better understand
      the similar and divergent properties of E1 and E2 glycoproteins decorating the
      envelope of HCV. The serum pseudotype virus neutralizing activity in patient sera
      did not exhibit a correlation with the infecting HCV genotype or virus load. HCV
      E2 glycoprotein induces a weak neutralizing antibody response, however the
      neutralization function was augmented by complement. Taken together, these
      observations suggest a role for both the glycoproteins in HCV attachment and
      entry into susceptible host cells. An understanding of HCV entry and strategies
      appropriate for mimicking cell surface molecules may help in the development of
      new therapeutic modalities against HCV infection. Furthermore, incorporation of
      the HCV glycoproteins in a candidate vaccine may offer protection, although
      additional work is necessary to enhance their immunogenicity.

PMID- 12617100
TI  - Cellular therapy.

PMID- 12617099
TI  - Molecular basis for invasive and immune modulating functions of pathogenic
      Yersinia spp.

PMID- 12617101
TI  - Specialized therapeutic hemapheresis: present and future.

PMID- 12617102
TI  - Apheresis: four decades of practice.

PMID- 12617103
TI  - Immunomodulation of autoimmunity by intravenous immunoglobulin through
      interaction with immune networks.

PMID- 12617104
TI  - Mechanism of action of IVIG in ITP.
AB  - IVIG is prepared from large pools of plasma from healthy donors and the IgG is
      present predominantly in monomeric form. It was first reported in 1981 by Dr.
      Paul Imbach that high doses of IVIG promote fast recovery of ITP in children.
      Despite extensive clinical use in a variety of autoimmune and inflammatory
      states, the mechanism of action of IVIG remains as yet incompletely understood.
      Several theories have been proposed to explain how administration of IVIG to
      individuals with ITP increases the platelet count. Following is an overview of
      some of the major theories.

PMID- 12617105
TI  - Mechanisms of action of IVIg: physiology of Fc receptors.

PMID- 12617106
TI  - Using haemovigilance data to set blood safety priorities.

PMID- 12617107
TI  - Haemovigilance around the world.

PMID- 12617108
TI  - Gene expression: overview and clinical implications.

PMID- 12617109
TI  - Molecular basis of erythrocyte blood group antigens and applications in
      transfusion medicine.

PMID- 12617110
TI  - The influence of platelet glycoprotein polymorphisms on receptor function and
      risk for thrombosis.
AB  - With regard to hemostasis and thrombosis, collagens are among the most important
      physiologic components of the extracellular matrix in their role as platelet
      activators. Differences in the rate of platelet activation markedly influence
      normal hemostasis and the pathological outcome of thrombosis. Thus, collagen
      receptors, such as the integrin alpha2beta1 and indirectly, GPIb alpha, represent
      a relatively unexploited target of pharmacological control and are only recently
      becoming appreciated as potential factors in the generic risk for thrombosis. In
      general, the importance platelet glycoprotein polymorphisms as genetic risk
      factors for arterial thrombosis is a new area of human genomics that needs to be
      carefully addressed. Discrepancies in the degree to which they are reported to
      contribute to risk for clinical thrombosis will only be resolved once there is a
      universal standard for clinical study design. Most of the clinical studies differ
      by patient population size, ethnicity, bias in the selection of patients and
      controls, plurality in clinical endpoints and variation of environmental factors.
      Despite these differences, there is substantial evidence that the integrin beta3
      PlA2 haplotype, the GPIb alpha Met145 haplotype, the GPIb alpha -5C haplotype and
      the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and
      morbidity of thrombotic disease. There may remain dispute as to the extent of
      their contribution. However, well-designed, large, prospective, genetic and
      epidemiologic studies are needed to clarify the role of these and other platelet
      receptor polymorphisms. Most importantly, the cumulative effects of multiple
      platelet and plasma glycoproteins SNPs to thrombotic risk must be evaluated
      concurrently. Additional in vitro studies of the functional relevance underlying
      these polymorphisms are needed to provide a sound biological explanation for the
      results of clinical correlations. The opportunity now exists to make significant
      inroads into the development of strategies for the prevention of thrombotic
      disease.

PMID- 12617111
TI  - DNA analysis to find rare blood donors when antisera is not available.
AB  - In order to screen for antigen-negative blood donors, it is necessary to have
      appropriate, potent antisera in sufficient volume. Anti-Do(a) and anti-Do(b) are
      notoriously weakly reactive antibodies, available only in small volumes, usually
      in sera containing other alloantibodies, and often deteriorate on storage. Thus,
      it has not been possible to test large numbers of blood samples to find Do (a-)
      or Do (b-) blood donors. At the NYBC, we now type selected donors for DOA and DOB
      by DNA analysis. Initially, we tested DNA prepared from donors who had been typed
      by hemagglutination for one or both antigens. We found that four donors, whose
      RBCs previously typed as Do (a+b-), had both DOA and DOB alleles, and when
      retested, the RBCs were Do (a+b+w). We have now tested over 300 donors for DO by
      PCR-RFLP using either Eam1105 I or BseRI restriction enzymes. Blood from DOA/DOA
      donors has survived better than "crossmatch compatible" blood for patients with
      anti-Do(b) and such results suggest that anti-Do(b) is a more frequent cause of
      transfusion reactions than reported. Furthermore, we have demonstrated that PCR
      RFLP can be used to screen for antigen-negative donors in other blood group
      systems when appropriate antisera are not available. When interpreting the
      results, it is important to remember that the genotype may not reflect the
      phenotype. Our strategy has been to perform DNA analysis for the DO alleles on
      those donors who have been shown by hemagglutination to lack antigens
      corresponding to multiple alloantibodies in patients' plasma. In this way, we
      have been able to supply rare blood to numerous patients, whose serum contained
      at least 5 additional alloantibodies of clinical significance.

PMID- 12617112
TI  - Rare blood donors: the past and the future.
AB  - For many years, there has been a clinical requirement for the provision of units
      of rare blood for patients with either single or multiple blood group antibodies
      present. To co-ordinate this need, the Rare Blood Donor Working Party of the
      International Society of Blood Transfusion was established in 1985. Since then,
      the Working Party has been active in promoting information on the procedures and
      methods for testing, packaging, transport and delivery of rare blood
      internationally. The Working Party has a close relationship with the Blood Group
      Reference Laboratory in the United Kingdom. The availability of the World Health
      Organization International Donor Panel permits the rapid and accurate locating of
      rare blood units. The Rare Blood Donor Working Party conducts surveys, attends to
      technical queries and is active in education. This can assist countries that are
      upgrading their blood services and give them a greater understanding of the
      international help available when confronted with a difficult-to-transfuse
      patient. In the future, it is anticipated that a wider range of countries will
      contribute to the International Donor Panel. It is likely that with the many
      major population movements throughout the world and the potential consequent
      development of rare antibodies or mixtures of antibodies, the need for the
      availability of rare blood donations will remain for the foreseeable future.

PMID- 12617113
TI  - The screening, identification and use of rare blood.

PMID- 12617114
TI  - Will stealth RBCs replace blood donors of rare types?

PMID- 12617115
TI  - Computerization in the transfusion service.

PMID- 12617116
TI  - In silico analysis in transfusion medicine.

PMID- 12617117
TI  - National contributions to transfusion medicine; Canada and the world.

PMID- 12617118
TI  - Norman Bethune and transfusion in the Spanish Civil War.

PMID- 12617119
TI  - A personal perception of the history of blood and transfusion.

PMID- 12617120
TI  - Challenges in developing a bacterial detection system.

PMID- 12617121
TI  - Novel methods for detection of platelet bacterial contamination.

PMID- 12617122
TI  - Scarce resources in an affluent society. Striving for zero risk?

PMID- 12617123
TI  - Management of scarce resources in blood services in developing countries.

PMID- 12617124
TI  - Plasma exchange in the management of thrombotic thrombocytopenic purpura.

PMID- 12617125
TI  - Cardinal signs of reactions: hypotension following blood transfusion.

PMID- 12617126
TI  - Breathlessness and blood: a combustible combination.
AB  - Pulmonary complications are increasingly recognized as serous hazards of
      transfusion. The evidence suggests that transfusion-related acute lung injury
      (TRALI) and transfusion-associated circulatory overload (TACO) are
      underrecognized. Both present with dyspnea but other signs and symptoms assist in
      determining the proper diagnosis. Males and females are equally affected.
      Morbidity is significant with both complications and in the case of TRALI, the
      mortality is in the range of 6-10%. Although the clinical descriptions of both
      entities are well established, the clinical profile of the at-risk population for
      both TRALI and TACO is not well understood. Because early intervention can reduce
      morbidity, it is important that clinicians recognize these disorders and apply
      appropriate treatment.

PMID- 12617127
TI  - Immunologic tolerance maintained by regulatory T cells: implications for
      autoimmunity, tumor immunity and transplantation tolerance.

PMID- 12617128
TI  - Two signal models of lymphocyte activation incorporate a mechanism of peripheral
      tolerance, and have implications for achieving immunological unresponsiveness and
      effective transplantation.

PMID- 12617129
TI  - Tolerance induction: historical and scientific background and recent development
      in clinical practice.

PMID- 12617130
TI  - Risk management strategies for HIV in blood transfusion in developing countries.

PMID- 12617131
TI  - Blood safety in the developing world and WHO initiatives.

PMID- 12617132
TI  - Rh proteins: a family of structural membrane proteins with putative transport
      activity.

PMID- 12617133
TI  - Understanding the Knops blood group and its role in malaria.
AB  - The antibodies that once were referred to as "HTLAs" have now help to define an
      entire blood group system with a well characterized genetic basis. Although not
      "clinically significant" in transfusion medicine, the Knops blood group has
      gained importance in the field of infectious disease. Its further role in protein
      (CR1) function and autoimmune diseases remains unknown but may provide
      interesting work for years to come.

PMID- 12617134
TI  - The molecular basis of the Lutheran blood group antigens.

PMID- 12617135
TI  - Status report on the quality of liquid and frozen red blood cells.

PMID- 12617136
TI  - Regionalization of the blood transfusion service in Egypt.

PMID- 12617137
TI  - Kuwait experience with the ISBT 128 code labeling system.

PMID- 12617138
TI  - Progress towards a blood test for vCJD?

PMID- 12617140
TI  - Acute normovolemic hemodilution.

PMID- 12617139
TI  - Evaluation of a universal leukoreduction program in Canada.

PMID- 12617141
TI  - Transfusion triggers in the UK.

PMID- 12617142
TI  - Web-based educational resources: an overview.

PMID- 12617143
TI  - Overview of a blood center web based educational resource.

PMID- 12617144
TI  - How to rejuvenate a tired blood drive.

PMID- 12617145
TI  - Challenges facing donor recruitment in South Africa.

PMID- 12617146
TI  - Success factors in donor recruitment and retention in Denmark.

PMID- 12617147
TI  - Clinical research designs: quantitative studies.

PMID- 12617148
TI  - Qualitative research: what is it and how can it be applied to transfusion
      medicine research?

PMID- 12617149
TI  - Confounding variables and co-interventions in the design of clinical trials: real
      life experience.

PMID- 12617151
TI  - Pathogen inactivation in cellular blood components: clinical trials and
      implications of introduction to transfusion medicine.

PMID- 12617150
TI  - Pathogen inactivation: mechanisms of action and in vitro efficacy of various
      agents.

PMID- 12617152
TI  - Residual risk of transfusion-transmitted diseases in Japan and pathogen
      inactivation.

PMID- 12617153
TI  - Artificial oxygen carriers: status 2002.

PMID- 12617154
TI  - Platelet substitutes: the reality and the potential.

PMID- 12617156
TI  - Alloimmunity to human red blood cell antigens.

PMID- 12617155
TI  - Platelet alloimmunity: the fetal/neonatal alloimmune thrombocytopenia.

PMID- 12617157
TI  - Transfusion-associated acute lung injury (TRALI): an evolving understanding of
      the role of anti-leukocyte antibodies.

PMID- 12617158
TI  - Horizontal transfer of DNA by the uptake of apoptotic bodies.

PMID- 12617159
TI  - Molecular and cellular mechanisms of erythrocyte programmed cell death: impact on
      blood transfusion.

PMID- 12617160
TI  - Apoptosis in platelets during ex vivo storage.

PMID- 12617161
TI  - Beyond expansion: structural studies on the transport roles of human serum
      albumin.

PMID- 12617162
TI  - Function and therapeutic development of apotransferrin.

PMID- 12617163
TI  - The major factors and weak links that must be considered to achieve safety in
      compatability testing.

PMID- 12617164
TI  - Medical laboratories--requirements for quality and competence: an ISO
      perspective.

PMID- 12617165
TI  - Event reporting, mindfulness and the high reliability organization: is the glass
      half empty?

PMID- 12617166
TI  - Mad cows and Englishmen: an update on blood and vCJD.

PMID- 12617167
TI  - Research, monitoring, and policy issues related to emerging pathogens.

PMID- 12617168
TI  - Activation of leukocyte beta2-integrins.

PMID- 12617170
TI  - September eleventh.

PMID- 12617169
TI  - Neutrophil-specific antigen HNA-2a (NB1, CD177): serology, biochemistry, and
      molecular biology.

PMID- 12617171
TI  - Transportation and other blood system issues related to disasters: Washington, DC
      experience of September 11, 2002.

PMID- 12617172
TI  - An overview of apoptosis in blood transfusion.

PMID- 12617173
TI  - New insights into fibrin (ogen) structure and function.

PMID- 12617174
TI  - The TRICC trial: a focus on the sub-group analysis.

PMID- 12617175
TI  - Assessment of the quality of clinical research.

PMID- 12617176
TI  - Molecular characterization of the immune response to factor VIII.
AB  - Inhibitory antibodies to factor VIII arise from an alloimmune response in
      patients with hemophilia A infused with factor VIII and as an autoimmune response
      in a variety of settings. The immune response to factor VIII is T-cell dependent.
      Helper T cells recognize numerous epitopes in the factor VIII molecule. B cell
      epitopes in both the alloimmune and autoimmune responses are much more
      restricted, usually involving two major epitopes in the A2 and C2 domains and
      apparently minor epitopes in the light chain activation peptide (ap) region and
      the A3 domain. Anti-C2 antibodies inhibit the binding of factor VIII to
      phospholipid and may also interfere with the binding of factor VIII to von
      Willebrand factor. Anti-A2 and anti-A3 antibodies block the binding of factor
      VIII to factor X and factor IXa, respectively, in the intrinsic pathway factor X
      activation complex. The mechanism of inhibition of anti-ap antibodies is unknown.
      A murine hemophilia A model has been developed to study the immunogenicity of
      factor VIII. This model may lead to improved approaches to prevent development of
      inhibitory antibodies and to reverse the immune response if it develops.

PMID- 12617177
TI  - Antenatal screening for fetomaternal alloimmune thrombocytopenia: should we be
      doing it?

PMID- 12617178
TI  - An alternative mechanism for the immunosuppressive effect of transfusion.

PMID- 12617179
TI  - Understanding the effects of different types of white cells on patient's
      responses to transfusion: immunization versus tolerization.

PMID- 12617180
TI  - Leukoreduction just doesn't "take away" immunogenic leukcocytes, it creates an
      immunosuppressive leukocyte dose.

PMID- 12617181
TI  - Pathogen inactivated transfusion plasma: existing and emerging methods.

PMID- 12617182
TI  - Choice of human plasma preparations for transfusion.

PMID- 12617183
TI  - Alternatives to intravenous immunoglobulins in the treatment of immune
      thrombocytopenic purpura.

PMID- 12617184
TI  - Intravenous immunoglobulin in Australia. Supply and demand.

PMID- 12617185
TI  - A multi-center prospective randomized trial of buffy coat depleted- and leukocyte
      filtered erythrocyte transfusions in vascular- and gastrointestinal oncologic
      surgery.

PMID- 12617186
TI  - Leucocyte-depleted blood in prevention of post-operative infections following
      elective orthopaedic and cardiac procedures.

PMID- 12617187
TI  - Large-cell medulloblastoma with arrestin-like protein expression.
AB  - We report a case of a cerebellar large-cell medulloblastoma in a 12-year-old
      patient. Despite a gross-total resection followed by a radiation therapy and then
      a chemotherapy, the death occurred 6 months later. The cyogenetic analysis showed
      an isochromosome 17q. Immunoreactivity for synaptophysin, neurofilaments,
      chromogranin and arrestin-like proteins was detected, whereas rhodopsin,
      vimentin, EMA and PAX-6 were negative. In this study, we demonstrate that large
      cell medulloblastoma with translocation in chromosome 17q is a neuronal
      differentiated medulloblastoma with non-photoreceptor characterization. By
      reverse transcription and polymerase chain reaction (RT-PCR) method, using
      primers for beta1, beta2 and visual arrestin, we demonstrate corresponding mRNA
      for beta1, beta2 arrestin but not for visual arrestin. These results suggest that
      arrestin immunoreactivity in this tumor corresponds to non-visual arrestin. This
      case corresponds to a new entity of large-cell medulloblastoma. The potential
      role of a new marker linked to a beta2 adrenergic receptor needs further
      molecular characterization to be useful.

PMID- 12617188
TI  - Leukemic dissemination within a glioblastoma in a patient with chronic lymphoid
      leukemia.
AB  - Metastasis from an extracranial tumor to a primary central nervous system tumor
      is a rare event, and most reported cases concern metastases to meningiomas. The
      authors describe the first case of leukemic cell dissemination within a
      glioblastoma. The patient likely presented a genetic predisposition to multiple
      neoplasms, and the unusual localization of leukemic cells might be partly related
      to the characteristic microvascular proliferation in glioblastoma.

PMID- 12617189
TI  - Gliofibroma with extensive calcified deposits.
AB  - Gliofibroma is a rare astrocytic neoplasm of young people that shows abundant
      deposition of collagenous matrix around glial cells. It shares some clinical and
      pathologic features with desmoplastic cerebral astrocytoma of infancy or
      desmoplastic infantile ganglioglioma. However, histogenesis or clinical behavior
      of these tumors is not fully known. Here, we report a case of gliofibroma with
      unusual extensive calcification which complicated radiologic as well as
      pathologic diagnosis.

PMID- 12617190
TI  - Unusual case of multiple cellular and malignant schwannomas of the cranial and
      spinal nerves.
AB  - Schwannomas from cranial nerves and spinal roots are most often benign, malignant
      schwannomas being uncommon in this location. This report describes a unique case
      of multiple cellular and malignant schwannomas of the cranial and spinal nerves
      in a patient with features of neurofibromatosis 2. The tumors were arising from
      left optic, bilateral oculomotor, trochlear, abducent and vestibular nerves, the
      left facial and the spinal lumbar nerve roots. The tumor arising from the right
      trochlear nerve was seen excavating into the hippocampus and the left vestibular
      nerve into the medulla. In addition, the patient had nodular schwannomas adherent
      to the inferior surface of the optic chiasm and the cerebellum away from the
      cranial nerves. Hyperplastic schwannosis was noted in perivascular spaces of
      thalamus, cerebellum and hippocampus on both sides away from the main lesions.
      The immunohistochemical and ultrastructural profiles of the tumors suggest that
      neurofibromas and schwannomas are probably not distinct tumors but lie within a
      spectrum that differs histologically depending on the predominant cell type.

PMID- 12617191
TI  - Expression of Ki-67 antigen and vascular endothelial growth factor in sporadic
      and neurofibromatosis type 2-associated schwannomas.
AB  - Neurofibromatosis type 2 (NF2) is a formidable disease with considerable
      morbidity. Among tumors associated with NF2, schwannomas are the most difficult
      to treat because they are multiple and tend to recur. Vascular endothelial growth
      factor (VEGF) has been reported to act as a survival factor for Schwann cells.
      We, therefore, investigated VEGF expression in NF2-associated and sporadic
      schwannomas. We also evaluated the proliferative potential of these tumors by Ki
      67 staining (MIB-1 labeling index) and microvascular density by CD34 staining.
      Immunohistochemistry was performed in 8 schwannomas from 6 NF2 patients, 2
      schwannomas from 2 probable NF2 patients and 10 sporadic schwannomas. VEGF
      immunostaining was present in most schwannomas: all sporadic schwannomas and 8 of
      10 schwannomas from NF2 or probable NF2 patients (NF2 group). No difference was
      evident in VEGF staining between the 2 groups. MIB-1 labeling index was
      significantly higher in the NF2 group (3.8 +/- 1.7) than the sporadic group (2.0
      +/- 1.0, p < 0.01). Microvascular density was higher in the NF2 group (12.9 +/-
      6.0) than the sporadic group (9.4 +/- 3.5), but not significantly (p = 0.06).
      Although VEGF alone cannot explain the higher proliferative potential in NF2
      associated schwannomas, VEGF could be a factor influencing the proliferative
      potential of schwannomas.

PMID- 12617193
TI  - Intracalvarial cholesterol granulomas--clinicopathologic correlates of three
      cases.
AB  - Cholesterol granulomas (CGs) are tumor-like lesions seldom encountered by
      neuropathologists. CGs develop in reaction to localized hemorrhage, often
      occurring in bony sites with possible impaired drainage of blood and blood
      products. The most common bony location is the petrous apex, although orbital,
      frontal sinus, and maxillary sinus sites have been reported. We compare and
      contrast three recent cases seen at our institution that illustrate the spectrum
      of clinical, radiographic, and pathologic features that can be seen with these
      mass lesions. One case demonstrated the unique pathological features of Gamma
      Gandy body formation, epithelioid histiocytes heavily encrusted with iron
      pigments, and extensive tophi. The latter most likely represented aggregates of
      calcium pyrophosphate crystals associated with extensive iron deposition.

PMID- 12617192
TI  - Cellular expression of tumor necrosis factor a and its receptors in human
      ischemic stroke.
AB  - We evaluated by immunocytochemistry cellular localization and time-dependent
      expression of tumor necrosis factor a (TNF-alpha) and its receptors p55 (TNF-RI)
      and p75 (TNF-R2) in human ischemic brains. We observed them in microglia,
      neurons, astrocytes, macrophages and blood vessels. Since TNF-alpha expression
      was very intense and prolonged in microglia, it probably constitutes the main
      cellular source of the cytokine following cerebral ischemia in humans.
      Constitutive expression of TNF-alpha receptors was observed in neurons and blood
      vessels while in other cells it was induced by ischemia. In macrophages, dominant
      immunolabeling for TNF-R2 was seen. In other cells, immunoreactions for both
      types of TNF-alpha receptors were similar but the pattern of immunostaining was
      different: homogenous for TNF-R1 and granular for TNF-R2. Beneficial and
      detrimental role of TNF-alpha in cerebral ischemia and supposed mechanisms of
      action are discussed.

PMID- 12617195
TI  - Delivering consumer health information digitally: a comparison between the web
      and touchscreen kiosk.
AB  - Employing survey and web log data the study presented here compares the use and
      users of two digital health information platforms geared toward consumers-web
      sites and touchscreen information kiosks. The kiosks featured are those supplied
      by InTouch With Health and the web-site is surgerydoor (some analysis of
      NHSDirect Online is also supplied). Problems of making direct comparisons between
      the two platforms are discussed and comparative figures provided. The two
      platforms were compared using the following metrics: page view time, session
      duration, number of sessions conducted, pages viewed per session, and
      topic/subject of pages viewed. Possible reasons for the differences between the
      two platforms are discussed, including the environment in which they are housed,
      the proximity of the platform to the user, the specific purpose of the individual
      platform, the different audiences served, the extent of delegation, the computer
      literacy of the audiences served, the quantity and comprehensiveness of the
      platform's information, and user's perceptions of authority. The research reminds
      and informs web-site and kiosk designers of the different audiences that they
      serve. The work reported here forms part of a Department of Health funded study
      which is evaluating digital health information provision to the consumer, in
      particular the use and impact of more than seventy heath kiosks located in all
      kinds of locations throughout the United Kingdom.

PMID- 12617194
TI  - An e-learning caregiving program for prostate cancer patients and family members.
AB  - e-health interventions have the potential to augment caregiving training for
      management of chronic disease. Instruction on caregiving functions often key to
      patients and families' well being is time consuming but not reimbursable in our
      current health care system. A theoretically defined interactive multimedia
      program is described which would assess patient and family member's level of
      preparedness for specific caregiving functions for prostate cancer and provide
      tailored skill building vignettes on caregiving techniques. Maximizing today's
      technology, this program is best designed for a hybrid delivery utilizing both
      web-based resources and a CD-ROM. Feedback from 45 prostate patients and family
      members from a Midwest cancer center on perceived needs for caregiving training
      underscores the potential value of a computer supported intervention for some
      patients and families. Implementation of the software, marketing, and
      distribution will be guided in part by recent e-health experiences that leave
      many health professionals appropriately skeptical about the utility of such
      products.

PMID- 12617196
TI  - The journey to e-Health: VA Healthcare Network Upstate New York (VISN 2).
AB  - e-Health offers the rich potential of supplementing traditional delivery of
      services and channels of communication in ways that extend the healthcare
      organization's ability to meet the needs of its patients. Benefits include
      enhanced access to information and resources, empowerment of patients to make
      informed healthcare decisions, streamlined organizational processes and
      transactions, and improved quality, value, and patient satisfaction. A diverse
      array of factors affects the development and implementation of e-Health
      initiatives and applications. Crafting a strategic approach is critical to
      success, especially in this era of rapidly changing technology. The journey to
      implementing e-Health at this VA Network is discussed and a model described for
      assessing the environment, identifying critical success factors, and selecting
      areas of focus. Recommendations are offered for defining a strategic approach to
      e-Health for healthcare organizations.

PMID- 12617197
TI  - The power of collaboration: using internet-based tools to facilitate networking
      and benchmarking within a consortium of academic health centers.
AB  - The University HealthSystem Consortium (UHC) represents a strategic alliance of
      169 academic health centers and associated institutions engaged in knowledge
      sharing and idea-generation. The use of the Internet as a tool in the delivery of
      UHC's products and services has increased dramatically over the past year and
      will continue to increase during the foreseeable future. This paper examines the
      current state of UHC-member institution driven tools and services that utilize
      the Web as a fundamental component in their delivery. The evolution of knowledge
      management at UHC, its management information and reporting tools, and expansion
      of e-commerce provide real world examples of Internet use in health care delivery
      and management. Health care workers are using these Web-based tools to help
      manage rising costs and optimize patient outcomes. Policy, technical, and
      organizational issues must be resolved to facilitate rapid adoption of Internet
      applications.

PMID- 12617198
TI  - Internet pharmacy: issues of access, quality, costs, and regulation.
AB  - Internet pharmacy has been the focus of heightened interest over the past 3 years
      since the first major Web site was introduced in the United States. This paper
      addresses issues pertaining to Internet pharmacies that sell prescriptions and
      other products to consumers at the retail level. The Internet pharmacy industry
      has shifted rapidly in the short time span. This paper begins with a summary of
      historical considerations and the shifting organization of Internet pharmacy. The
      advantages and disadvantages of online pharmacy practice are listed. Issues of
      access, quality, and cost are described. The challenges in regulation at the
      state and federal levels are presented. Advice to consumers is offered regarding
      the use of Internet pharmacy sites for purchasing prescription drug products.

PMID- 12617199
TI  - The impact of CyberHealthcare on the physician-patient relationship.
AB  - It is estimated that 70 million Americans have used the Internet to acquire
      health-related information. Multiple factors provide the driving force behind
      this demand for online health information. Information technology is beginning to
      change the exclusive focus of medicine from curing disease to prevention of
      disease and enhancing health status. A critical feature of this change is the
      development of information and services that assist consumers to assume more
      responsibility for their own health and to actively participate in health care
      decisions. At the same time, physicians remain skeptical about the advantages of
      using the Internet for patient education. Some of the issues that this paper
      addresses include the following: What are the major factors that are leading to
      the increased use of the Internet by consumers to obtain health-related
      information? How do physicians view the use of the Internet by patients to obtain
      health-related information and services? How is the use of the Internet by
      consumers affecting physician-patient communications? What are the implications
      of the Internet for the future of physician-patient relationships?

PMID- 12617200
TI  - Virtual integrated practice: integrating teams and technology to manage chronic
      disease in primary care.
AB  - The use of teams in health care has generally relied on the notion that teams
      must physically meet and function in person in the same location, on a regular,
      scheduled basis, in order to maximize the value of the interdisciplinary process.
      This article examines the concept of creating a different kind of team in primary
      care, out-patient settings--one which relies upon communications technology to
      link together clinicians from different locations to coordinate and manage the
      care of patients, particularly those with chronic disease. This approach-
      referred to as Virtual Integrated Practice--is designed to overcome the barriers
      of traditional in-person teams by creating a "virtual team" with the potential to
      function more efficiently, productively, and satisfactorily for clinicians and
      patients alike.

PMID- 12617201
TI  - What it will take to create new Internet initiatives in health care.
AB  - Today's Internet cannot fulfill the anticipated future needs of health care
      organizations. To address growing administrative, clinical, and research
      communication networking requirements and to serve as a test bed for future
      technology, two separate initiatives, the Next Generation Internet (NGI-
      federally funded by the NIH/NLM) and Internet2 (a consortium of academic
      partners), are establishing project partnerships that will create new and
      improved opportunities for health care applications and interactions such as
      telemedicine, medical imaging, virtual medicine, home health care, public health,
      consumer medicine, medical education, and medical research, among other uses. In
      addition to creating and improving large-scale health care networking, it is also
      expected that much of the technology developed and tested for NGI/Internet2 will
      filter down to improve the mainstream Internet.

PMID- 12617203
TI  - Atmospheric correction of SeaWiFS imagery for turbid coastal and inland waters:
      comment.
AB  - Ruddick et al. [Appl. Opt. 39, 897 (2000)] extended the standard SeaWiFS
      atmospheric-correction algorithm for use over turbid coastal and inland waters.
      However, Ruddick's method is based on the assumption of a spatially homogeneous
      constant ratio for the water-leaving reflectances normalized by the sun-sea
      atmospheric transmittance at 765 and 865 nm. Such first-order b(b)/a model-based
      assumption can result in an inaccuracy for highly turbid water. Using the first-
      and second-order b(b)/(a + b(b)) models as well as the second-order b(b)/a model
      (which, more realistically, do not assume spatial homogeneity ratio), we suggest
      using the modified assumption, R(8)(-1) = alpha0 R(7)(-1) + (l1Q)(-1) (1 -
      alpha0), instead of Ruddick's assumption, in SeaWiFS atmospheric-correction
      algorithms for highly turbid waters.

PMID- 12617202
TI  - Parameterization and analysis of the optical absorption and scattering
      coefficients in a western Norwegian fjord: a case II water study.
AB  - Based on statistical analyses of optical properties measured during a whole year
      of monthly cruises in a Norwegian fjord, we constructed a two-component model for
      the absorption and scattering coefficients for visible light. The input to the
      model is the concentrations of yellow substance and chlorophyll a. Because of the
      presence of a significant amount of nonalgal particles in coastal water, we
      assume that the absorption and scattering coefficients approach constant
      background values when the concentration of chlorophyll a approaches zero. The
      model works reasonably for a variety of optical conditions encountered throughout
      the year, with a possible exception during a bloom of the Emiliania huxleyi algae
      in June.

PMID- 12617204
TI  - Sky-radiance measurements for ocean-color calibration-validation.
AB  - The calibration of an ocean-color sensor or validation of water products is
      generally based on ground-based extinct measurements from which the aerosol
      products (optical thickness tau(a) and aerosol type) are deduced. Sky-radiance
      measurements complement the extinction measurements mainly in the aerosol-model
      characterization. Our basic goal is to promote calibration-validation activities
      based on the radiative properties of the aerosols rather than their chemical or
      physical properties. A simple method is proposed (and evaluated) to convert sky
      radiances measured in the principal plane into atmospheric phase functions P.
      Indeed tau(a) and P are the required inputs to a radiative-transfer code for
      predicting the top-of-the-atmosphere radiances. The overall error in this
      prediction is a few percent. This method can operate on a worldwide network on
      ground-based sun radiometers and then be used to achieve a statistical analysis
      for validating satellite products.

PMID- 12617206
TI  - Complex refractive index of ammonium nitrate in the 2-20-microm spectral range.
AB  - Using high-resolution Fourier-transform infrared absorbance and transmittance
      spectral data for ammonium sulfate (AMS), calcium carbonate (CAC), and ammonium
      nitrate (AMN), we made comparisons with previously published complex reactive
      index data for AMS and CAC to infer experimental parameters to determine the
      imaginary refractive index for AMN in the infrared wavelength range from 2 to 20
      microm. Subtractive Kramers-Kronig mathematical relations were applied to
      calculate the real refractive index for the three compositions. Excellent
      agreement for AMS and CAC with the published values was found, validating the
      complex refractive index obtained for AMN. We performed backscatter calculations
      using a log-normal size distribution for AMS, AMN, and CAC aerosols to show
      differences in their backscattered spectra.

PMID- 12617205
TI  - Experimental estimation of the spatial statistics of turbulence-induced index of
      refraction fluctuations in the upper atmosphere.
AB  - We present results from an experiment to estimate the parameters of homogeneous,
      isotropic optical turbulence in the upper atmosphere. The balloon-borne
      experiment made high-resolution temperature measurements at seven points on a
      hexagonal grid for altitudes from 12,000 to 18,000 m. From the temperature data,
      we obtained index of refraction fluctuations that can be used to compute a sample
      based estimate for a parameterized description of the spatial autocorrelation of
      the turbulence. The three parameters of interest were a proportionality constant
      Pc, the power-law parameter alpha, and the outer scale L0. The results obtained
      for Pc are within the expected range and agree well with independent measurements
      made from a standard rising thermosonde measurement made approximately
      simultaneously with the data collection. Values for a were in the range 1.52 < or
      = alpha < or = 1.73 were observed, which are significantly less than the power
      law used in the Kolmogorov and von Karman models, alpha = 1.833. Values observed
      for L0 were in the range 5 < or = L0 < or = 19 m. Evidence that alpha may be
      consistently less than that used in the Kolmogorov and von Karman models likely
      has the most significant implications for systems that must work in or through
      the tropopause.

PMID- 12617207
TI  - Ocean optics estimation for absorption, backscattering, and phase function
      parameters.
AB  - We propose and test an inverse ocean optics procedure with numerically simulated
      data for the determination of inherent optical properties using in-water radiance
      measurements. If data are available at only one depth within a deep homogeneous
      water layer, then the single-scattering albedo and the single parameter that
      characterizes the Henyey-Greenstein phase function can be estimated. If data are
      available at two depths, then these two parameters can be determined along with
      the optical thickness so that the absorption and scattering coefficients, and
      also the backscattering coefficient, can be estimated. With a knowledge of these
      parameters, the albedo and Lambertian fraction of reflected radiance of the
      bottom can be determined if measurements are made close to the bottom. A
      simplified method for determining the optical properties of the water also is
      developed for only three irradiance-type measurements if the radiance is
      approximately in the asymptotic regime.

PMID- 12617208
TI  - Accurate and self-consistent ocean color algorithm: simultaneous retrieval of
      aerosol optical properties and chlorophyll concentrations.
AB  - A new algorithm has been developed for simultaneous retrieval of aerosol optical
      properties and chlorophyll concentrations in case I waters. This algorithm is
      based on an improved complete model for the inherent optical properties and
      accurate simulations of the radiative transfer process in the coupled atmosphere
      ocean system. It has been tested against synthetic radiances generated for the
      Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) channels and has been shown to be
      robust and accurate. A unique feature of this algorithm is that it uses the
      measured radiances in both near-IR and visible channels to find that combination
      of chlorophyll concentration and aerosol optical properties that minimizes the
      error across the spectrum. Thus the error in the retrieved quantities can be
      quantified.

PMID- 12617209
TI  - Temperature field measurements of small, nonpremixed flames with use of an Abel
      inversion of holographic interferograms.
AB  - Interferometry has been used for many years as a semi-quantitative image-based
      diagnostic for combustion research. In this paper, we use image-plane, double
      pulse holographic interferograms of axisymmetric flames to infer their radial
      temperature distribution. An Abel inversion is performed on the fringe data to
      account for line-of-sight integration through the flame. The sensitivity of
      nonresonant refractive diagnostics decreases inversely with temperature, and the
      accuracy of the technique is discussed in this context. A small, nonpremixed
      capillary flame is investigated, and the temperatures inferred from
      interferometry are compared with those obtained with N2 coherent anti-Stokes
      Raman spectroscopy thermometry. Additionally, the thermal field of a burning
      monodisperse methanol droplet stream is investigated interferometrically. Because
      of their small size, both of these flames challenge the performance limit of
      temperature interferometery.

PMID- 12617210
TI  - Optimized metrology for laser-damage measurement: application to multiparameter
      study.
AB  - An automatic test apparatus for refined testing of laser damage is presented that
      permits an in situ analysis of the tested area before, during, and after pulsed
      irradiation. Spatial and temporal beam profiling are performed in real time and
      give access to the localized fluence for each shot. Furthermore, an optimization
      of the initiation of damage detection is undertaken by use of image processing
      and yields a resolution better than 1 microm. Through several examples, these
      conditions are demonstrated to be useful for reaching an understanding of the
      laser-damage process. A complete study is undertaken of different kinds of glass
      that permits the main influence of test parameters (shot frequency, shot number,
      beam profile variation, temporal and spatial meshing, ...) on the damage procees
      to be shown. The study was made for different test procedures (1:1, S:1, R:1) and
      completed by atomic-force microscope analysis. Evidence indicates that the
      upgrading of metrology associated with an automatic process offers new
      opportunities for understanding laser-induced damage mechanisms and for
      emphasizing specific effects such as damage initiation, damage growth, and
      conditioning for repetitive shots.

PMID- 12617211
TI  - Single-camera method to determine the optical axis position of ellipsoidal drops.
AB  - The sizing of droplets by optical imaging typically requires a small depth of
      field so that variations in the magnification ratio are minimized. However, if
      the location of the drop along the optical axis can be determined, a variable
      magnification ratio can be imposed on each imaged drop, and the depth of field
      can be increased. Previous research suggested that droplet location can be
      determined with a characteristic of droplet images that is obtained when the
      droplet is illuminated from behind. In this prior research, the method was
      demonstrated with spherical glass objects to simulate raindrops. Raindrop are
      known to deviate significantly from a spherical shape, especially when the drop
      size is large. We demonstrate the ability to locate the position of objects that
      deviate from sphericity. Deformed water drops and glass ellipsoids are tested,
      along with glass spheres. The role of refractive index is also discussed.

PMID- 12617212
TI  - Hydrocarbon absorption coefficients at the 3.39-microm He-Ne laser transition.
AB  - In view of the application of light-extinction techniques for fuel-specie
      concentration measurements in combustion systems, the vapor-absorption
      coefficient of several hydrocarbon species at the 3.39-microm He-Ne laser
      transition has been measured. The hydrocarbon species include paraffins, olefins,
      and aromatics. Result are included for total pressure over the range of
      approximately 200-650 Torr at 295 K with air as the buffer gas. Observations are
      made regarding the difference in the absorption coefficient within and between
      hydrocarbon classifications.

PMID- 12617213
TI  - Comparison of adaptive optics and phase-conjugate mirrors for correction of
      aberrations in double-pass amplifiers.
AB  - Correction of birefringence-induced effects (depolarization and bipolar focusing)
      were achieved in double-pass amplifiers by use of a Faraday rotator between the
      laser rod and the retroreflecting optic. A necessary condition was ray retrace.
      Retrace was limited by imperfect conjugate-beam fidelity and by nonreciprocal
      refractive indices. We compared various retroreflectors: stimulated-Brillouin
      scatter phase-conjugate mirrors (PCMs), PCMs with rod-to-PCM relay imaging
      (IPCM), IPCMs with astigmatism-correcting adaptive optics, and all-adaptive-optic
      imaging variable-radius mirrors. Results with flash-lamp-pumped, Nd:Cr:GSGG
      double-pass amplifiers showed the superiority of adaptive optics over nonlinear
      optic retroreflectors in terms of maximum average power, improved beam quality,
      and broader oscillator pulse duration/bandwidth operating range. Hybrid PCM
      adaptive optics retroreflectors yielded intermediate power/beam-quality results.

PMID- 12617214
TI  - Laser-generated spark morphology and temperature records from emission and
      Rayleigh scattering studies.
AB  - Using both Rayleigh scattering and time-resolved emission spectroscopy, we have
      recorded the spatial and temporal evolution of laser-generated sparks in argon
      from changes during the first ten of nano-seconds to complete dissipation, which
      occurs in a time span of approximately 5 ms. Maps of either emission intensity or
      argon density spanning the entire region affected by the energy deposited by the
      laser show the dissipation of the spark in detail. Immediately after ignition,
      the argon plasma occupies an ellipsoidal volume of roughly 3-mm vertical (axial)
      length. After approximately 20-40 micros, the spark region has transformed into a
      toroidal shape in a plane perpendicular to the vertical axis, with a radius of
      approximately 1.5 mm. The torus rises slowly up and expands noticeably in the
      radial direction. A record of peak temperatures of the spark ranging from
      approximately 10,000 K at 60-micros delay time to approximately 450 K at 4-ms
      delay time indicate cooling rates from approximately 100 to 1 K/micros at these
      times.

PMID- 12617215
TI  - Dependence of bending losses on cladding thickness in plastic optical fibers.
AB  - Our main goal is to provide a comprehensive explanation of the existing
      differences in bending losses arising from having step-index multimode plastic
      optical fibers with different cladding thickness and under different types of
      conditions, namely, the variable bend radius R, the number of fiber turns, or the
      fiber diameter. For this purpose, both experimental and numerical result of
      bending losses are presented for different cladding thicknesses and conditions.
      For the measurements, two cladding thicknesses have been considered: one finite
      and another infinite. A fiber in air has a finite cladding thickness, and rays
      are reflected at the cladding-air interface, whereas a fiber covered by oil is
      equivalent to having an infinite cladding, since the very similar refractive
      index of oil prevents reflections from occurring at the cladding-oil interface.
      For the sake of comparison, numerical simulations based on ray tracing have been
      performed for finite-cladding step-index multimode waveguides. The numerical
      results reinforce the experimental data, and both the experimental measurements
      and the computational simulations turn out to be very useful to explain the
      behavior of refracting and tunneling rays along bent multimode waveguides and
      along finite-cladding fibers.

PMID- 12617216
TI  - Interferometric fiber-optic sensor embedded in a spark plug for in-cylinder
      pressure measurement in engines.
AB  - Pressure sensing in an internal combustion engine with an intrinsic fiber Fabry
      Perot interferometer (FFPI) integrated with a spark plug is demonstrated for the
      first time. The spark plug was used for the ignition of the cylinder in which it
      was mounted. The FFPI element, protected with a copper/gold coating, was embedded
      in a groove in the spark-plug housing. Gas pressure inthe engine induced
      longitudinal strain in this housing, which was also experienced by the fiber
      optic sensing element. The sensor was monitored with a signal conditioning unit
      containing a chirped distributed-feedback laser. Pressure sensitivities as high
      as 0.00339 radians round-trip phase shift per pounds per square inch of pressure
      were observed. Measured pressure versus time traces showed good agreement with
      those from a piezoelectric reference sensor mounted in the same engine cylinder.

PMID- 12617217
TI  - Fringe pattern analysis with a parametric method for measurement of absolute
      distance by a frequency-modulated continuous optical wave technique.
AB  - Interferometry associated with an external cavity laser of long coherence length
      and broad wavelength tuning range shows promising features for use in measurement
      of absolute distance. As far as we know, the processing of the interferometric
      signals has until now been performed by Fourier analysis or fringe counting. Here
      we report on the use of an autoregressive model to determine fringe pattern
      frequencies. This concept was applied to an interferometric device fed by a
      continuously tunable external-cavity laser diode operating at a central
      wavelength near 1.5 microm. A standard uncertainty of 4 x 10(-5) without
      averaging at a distance of 4.7 m was obtained.

PMID- 12617218
TI  - Pressure dependence of the small-signal gain and saturation intensity of a copper
      vapor laser.
AB  - The small-signal gain coefficient and the saturation intensity of a copper vapor
      laser have been measured for both 510.6- and 578.2-nm transitions through the
      implementation of a discharge driven oscillator-amplifier configuration. Pressure
      dependence of the gain and saturation property of the laser has been
      investigated.

PMID- 12617219
TI  - Comparison of 127I2-stabilized frequency-doubled Nd:YAG lasers at the Bureau
      International des Poids et Mesures.
AB  - A frequency comparison was carried out between iodine-stabilized Nd:YAG lasers at
      532 nm from the Bureau International des Poids et Mesures, the Centre for
      Metrology and Accreditation, the Czech Metrology Institute, and the Bureau
      National de Metrologie-Institut National de Metrologie. The frequency differences
      between lasers, as well as the frequency reproducibility of each system,were
      investigated. Pressure-, modulation-, and power-induced shifts were studied. A
      frequency dispersion (1 sigma) of 3.5 kHz (6.2 x 10(-12) in relative terms) with
      an average reproducibility for each laser of the order of 0.4 kHz (7.1 x 10(-13)
      in relative terms) was observed over the duration of the comparison. Relative
      stabilities better than 1 x 10(13) at 1 s were demonstrated for the third
      harmonic systems.

PMID- 12617220
TI  - Efficient frequency doubling of 1-W continuous-wave Ti:sapphire laser with a
      robust high-finesse external cavity.
AB  - We demonstrated an intrinsic conversion efficiency of 56% from the input
      fundamental power to the generated second-harmonic power. The second-harmonic
      power of 581 mW was obtained from the external cavity with a LiB3O5 crystal
      through the frequency doubling of a 1.17-W Ti:sapphire laser at 746 nm, when the
      finesse of the robust external cavity was 260.

PMID- 12617221
TI  - High-performance diode-pumped Nd:YLF amplifier.
AB  - We report on the performance of a multipass diode-pumped amplifier design to
      provide a combination of high gain and efficiency with high stability. A simple
      rod-cavity design and the establishment of quasi-steady-state operation resulted
      in a saturated gain of over 6000 at an average output intensity during the pulse
      train of 7 kW/cm2. The amplifier showed an output stability of 0.2% rms in the
      short-term and 0.7% rms in the long-term and an output intensity insensitive to
      input power changes. Zernike analysis of the measurements of pump distortion
      showed an almost pure astigmatic phase error that can be compensated up to high
      average power levels.

PMID- 12617222
TI  - Nearly diffraction-limited signal generated by a lower beam-quality pump in an
      optical parametric oscillator.
AB  - The beam quality of an optical parametric oscillator (OPO) within a singly
      resonant, confocal-positive branch unstable resonator is investigated. Resonator
      configurations have been found in which the beam quality of the outgoing signal
      exceeds the beam quality of the pump. Cavity magnification and pump-pulse
      duration are found to determine the signal beam quality. It is shown that signal
      M2 decreases with increasing pump-pulse duration for a given cavity
      magnification. In an experimental demonstration of a LiNbO3 OPO within an
      unstable resonator, pumped by a multitransversal mode beam, a signal beam with an
      almost-single transversal mode has been generated, whereas the multitransversal
      mode behavior of the pump beam is projected on the idler beam.

PMID- 12617223
TI  - Analysis of electro-optic crystal-based Fabry-Perot etalons for high-speed
      spatial light modulators.
AB  - The use of electro-optic (EO) crystal-based Fabry-Perot modulators (FPMs) as high
      speed spatial light modulators is proposed. The FPMs operate with an extremely
      low drive voltage and a high extinction ratio. It is revealed by analysis of both
      the linear EO effect and the inverse piezoelectric effect of various EO crystals
      that three kinds of crystal configuration are suitable as FPMs. One of these is
      applicable to isotropic crystals, point groups 23 and (-)43m, and the others are
      better suited for uniaxial EO crystals, point groups (-)42m and 3m. Typical EO
      crystals suitable as FPMs are ferroelectric crystals such as LiNbO3, LiTaO3, and
      LiIO3 and sillenite compounds such as Bi12SiO20 and Bi12GeO20 as well as compound
      semiconductors such as GaAs and GaP.

PMID- 12617224
TI  - Suppression of intensity noise of a laser-diode-pumped single-frequency Nd:YVO4
      laser by optoelectronic control.
AB  - The intensity-noise reduction of a laser-diode-pumped single-frequency ring
      Nd:YVO4 laser when different optoelectronic control systems are used is
      theoretically and experimentally investigated. It has been demonstrated that
      combining two techniques, optoelectronic feedback control of the drive current of
      the pump laser diode and feed-forward control of the output laser beam, is a good
      way to significantly suppress the intensity noise of a laser at low frequency.

PMID- 12617225
TI  - Analytical modeling of Raman lidar return, including multiple scattering.
AB  - An analytical approach to modeling Raman lidar return with multiple scattering in
      presented. This approach is based on a small-angle quasi-single-scattering
      approximation developed earlier for elastic lidar sounding. An approximation of
      isotropic backscattering for the Raman-scattering case is proposed and tested.
      The computed results are presented and compared with known data. The
      approximation was found to be quite simple and provided a high accuracy of Raman
      lidar return calculations.

PMID- 12617226
TI  - Method for high-accuracy reflectance measurements in the 2.5-microm region.
AB  - Reflectance measurement with spectroradiometers in the solar wavelength region
      (0.4-2.5 microm) are frequently conducted in the laboratory or in the field to
      characterize surface materials of artificial and natural targets. The spectral
      surface reflectance is calculated as the ratio of the signals obtained over the
      target surface and a reference panel, yielding a relative reflectance value. If
      the reflectance of the reference panel is known, the absolute target reflectance
      can be computed. This standard measurement technique assumes that the signal at
      the radiometer is due completely to reflected target and reference radiation.
      However, for field measurements in the 2.4-2.5-microm region with the Sun as the
      illumination source, the emitted thermal radiation is not a negligible part of
      the signal even at ambient temperatures, because the atmospheric transmittance,
      and thus the solar illumination level, is small in the atmospheric absorption
      regions. A new method is proposed that calculates reflectance values in the 2.4
      2.5-microm region while it accounts for the reference panel reflectance and the
      emitted radiation. This technique needs instruments with noise-equivalent
      radiances of 2 orders of magnitude below currently commercially available
      instruments and requires measurement of the surface temperatures of target and
      reference. If the reference panel reflectance and temperature effects are
      neglected, the standard method yields reflectance errors up to 0.08 and 0.15
      units for 7- and 2-nm bandwidth instruments, respectively. For the new method the
      corresponding errors can be reduced to approximately 0.01 units for the surface
      temperature range of 20-35 degrees C.

PMID- 12617227
TI  - Lidar frequency modulation vibrometry in the presence of speckle.
AB  - We report laboratory target vibration measurements that use an easily aligned and
      adjusted fiber-based 1.5-microm heterodyne lidar. The targets are simple
      spherically curved retroreflectors with well-controlled vibration frequencies and
      amplitudes. A rotating ground-glass screen creates Gaussian speckle. We wish to
      understand the modulated and fast-fading lidar returns seen from real target. We
      frequency demodulated the recorded laboratory data by phase differencing to
      provide estimates of dphi/dt, where phi is the phase of the received carrier-plus
      noise phasor. Experimental results for signal strength and signal-to-noise ratio,
      for specific target modulation parameters, agree well with our recently developed
      dphi/dt correlation-function theory.

PMID- 12617228
TI  - Simultaneous measurements of particle backscattering and extinction coefficients
      and wind velocity by lidar with a Mach-Zehnder interferometer: principle of
      operation and performance assessment.
AB  - The development of remote-sensing instruments that can be used to monitor several
      parameters at the same time is important for the study of complex processes such
      as those that control climate and environment. In this paper the performance of a
      new concept of lidar receiver that allows for the direct measurement of aerosol
      and cloud optical properties simultaneously with wind velocity is investigated.
      This receiver uses a Mach-Zehnder interferometer. Two different configurations,
      either with four photometric output channels or with fringe imaging on a
      multichannel detector, are studied. Analytical expressions of the statistical
      errors are given under the assumption of Gaussian signal spectra. It is shown
      that similar accuracies can be achieved for both configurations. Performance
      modeling of the retrieval of semitransparent cloud optical scattering properties
      and wind velocity was done at different operation wavelengths for a Nd:YAG laser
      source. Results for such a lidar system onboard an aircraft flying at an altitude
      of 12 km show that for semitransparent clouds the best results were obtained at
      355 nm, with relative standard deviations of 0.5% and 5% for the backscatter and
      extinction coefficients, respectively, together with a velocity accuracy of 0.2
      ms(-1). The accuracy of optical properties retrieved for boundary layer aerosols
      are comparable, whereas the velocity accuracy is decreased to 1 ms(-1). Finally,
      an extrapolation to a large 355-nm spaceborne lidar shows accuracies in the range
      from 2.5% to 5% for the backscatter coefficient and from 10% to 15% for the
      extinction coefficient together with a vertical wind speed accuracy of better
      than 0.5 ms(-1) for semitransparent clouds and boundary layer, with a vertical
      resolution of 500 m and a 100 shot averaging.

PMID- 12617229
TI  - Infrared 7.6-microm lead-salt diode laser heterodyne radiometry of water vapor in
      a CH4-air premixed flat flame.
AB  - We deal with the design of a diode laser heterodyne radiometer and its
      application in a combustion process. We present some experimental results
      obtained with a CH4-air premised flat flame as the optical source. The goal is to
      prove that heterodyne detection techniques are relevant in remote detection and
      diagnostics of combustion and can have important applications in both civil and
      military fields. To the best of our knowledge, it is the first time that this
      demonstration is made. The radiometer, in spite of the low-power lead-salt diode
      laser used as a local oscillator, enables us to record high-temperature water
      vapor emission spectra in the region of 1315 cm(-1).

PMID- 12617230
TI  - Application of a nonuniform spectral resampling transform in Fourier-transform
      spectrometry.
AB  - We describe a nonuniform spectral resampling transform (NUSRT) that resamples a
      frequency-scaled spectrum that has been measured by a Fourier-transform
      spectrometer (FTS). Frequency scaling of a spectrum can arise from measurements
      made with off-axis detectors and Doppler shift induced by motion of a spaceborne
      FTS relative to an input radiation source. In addition, a spectrum may need to be
      rescaled in frequency to match spectral lines for applications such as the
      retrieval of atmospheric state parameters. The NUSRT is cast as a linear
      algebraic expression that relates a nonuniformly sampled interferogram to an
      input spectrum. A polynomial approximation is applied to this expression that
      reduces the inverse of the NUSRT to a series of Fourier transforms that can be
      implemented as fast Fourier transforms (FFTs). We show that this NUSRT algorithm
      requires on the order of 6N log N flops, which reduces the computational cost of
      rescaling by more than 1 order of magnitude compared with conventional FFT-based
      Shannon interpolation techniques while comparable accuracy is maintained.

PMID- 12617231
TI  - Nonlinear and bistable reflection minima at lambda = 10.6 microm in an attenuated
      total reflection configuration with a highly doped n-GaAs film.
AB  - n-GaAs can be so highly doped that its plasma frequency is larger than the
      associated frequency of a CO2 laser emission line, leading to a negative real
      part of the dielectric permittivity. We studied linear and nonlinear reflection
      properties of structures composed of such thin highly doped n-GaAs film in an
      attenuated total reflection (ATR) configuration. We show that deep reflection
      minima coincide with the excitation of Brewster-type modes of the multilayer
      structure. These minima feature strong nonlinear and bistable behavior and are
      sensitive to geometrical and material parameters. The proposed ATR configuration
      can be used to determine doping concentrations with an accuracy of better than 1
      partper thousand and different deformation potentials of the higher-conduction
      bands in n-GaAs.

PMID- 12617232
TI  - Real-time inversion of polarization gate frequency-resolved optical gating
      spectrograms.
AB  - Frequency-resolved optical gating (FROG) is a technique used to measure the
      intensity and phase of ultrashort laser pulses through the optical construction
      of a spectrogram of the pulse. To obtain quantitative information about the pulse
      from its spectrogram, an iterative two-dimensional phase retrieval algorithm must
      be used. Current algorithms are quite robust but retrieval of all the pulse
      information can be slow. Previous real-time FROG trace inversion work focused on
      second-harmonic-generation FROG, which has an ambiguity in the direction of time,
      and required digital signal processors (DSPs). We develop a simplified real-time
      FROG device based on a single-shot geometry that no longer requires DSPs. We use
      it and apply the principal component generalized projections algorithm to invert
      polarization gate FROG traces at rates as high as 20 Hz.

PMID- 12617233
TI  - The hitch stitch: an obsolete neurosurgical technique?
AB  - The objective was to assess the efficacy of dural tenting sutures as a
      prophylactic measure against extradural haemorrhage following craniotomy. A
      comparison was made of postoperative extradural haemorrhage between a surgeon
      always using tenting sutures and a surgeon who never uses them. The subjects
      consisted of 130 adult patients, 44 with postoperative scans, with normal blood
      coagulation who underwent elective supratentorial craniotomy (September 1998 to
      December 2000). Outcome measures were haematoma volume and midline shift as
      measured on CT and reoperation due to extradural haematoma. The group using
      tenting sutures had larger median extradural haematoma (2.5 vs 2.0 ml) and
      midline shift (3 vs 0 mm) than the omitting group. These differences were not
      significant (P = 0.74 and 0.84). Reoperation due to extradural haemorrhage
      occurred in 3.6% of the group using tenting sutures and in 0% of the group
      omitting them. Prophylactic dural tenting sutures do not reduce the size of
      extradural haematomas in this study. A prospective, randomized trial is needed to
      eliminate surgeon bias.

PMID- 12617234
TI  - Measurement of outcome in patients with cervical spondylotic myelopathy treated
      surgically.
AB  - The objective was to establish the role of the Short Form 36 (SF 36) as an
      objective measure of clinical outcome in cervical spondylotic myelopathy (CSM),
      and took the form of a prospective observational study. Seventy patients with
      symptomatic CSM were treated by surgical decompression. Health status was
      measured pre- and 3 months postoperation using objective, validated patient
      completed measures. These were the SF 36, neck disability index, myelopathy
      disability index and analogue scores for neck pain and arm symptoms. SF 36 scores
      were compared with age matched control data. Twelve-month postoperative data are
      available in a proportion of the cohort. CSM patients have lower preoperative SF
      36 scores than age-matched population controls. Comparing pre- and postoperative
      SF36 scores for the physical functioning domain 64% of patients improve, 23% show
      no change and 14% of patients continue to deteriorate (Wilcoxon P< 0.0001). These
      changes are replicated in other domains of the SF36 and by the other measures of
      outcome. The SF36 is responsive, valid, and practical. Its use for determining
      outcome in the surgical treatment of CSM is recommended.

PMID- 12617235
TI  - Investigation of prevalence of MRSA in referrals to neurosurgery: implications
      for antibiotic prophylaxis.
AB  - In order to establish the appropriateness of our current prophylactic antibiotic
      regimen we analysed the prevalence of MRSA in emergency referrals to our unit.
      MRSA screening records for all emergency admissions for a 3-month period were
      analysed. One-hundred-and-seventy-five patients were admitted as transfers from
      another hospital. Evidence of screening was found in 61% (107 patients). Of the
      screened patients, 15% (16) were MRSA positive. Source of referral or length of
      inpatient stay after referral to the time of transfer were not predictive for
      MRSA status. Gentamicin is active against more than 95% of MRSA strains cultured
      in our hospital and against 87% of MRSA strains cultured in the neurosurgery
      unit. A number-needed-to-treat (NNT) analysis showed that, with MRSA prevalence
      at 15%, cefuroxime plus gentamicin at induction could prevent one MRSA infection
      per 421 treated patients compared with cefuroxime alone. Vancomycin had minimal
      additional benefit over cefuroxime plus gentamicin (NNT: 1684). We conclude that
      MRSA carriage is common in patients referred as emergencies from other hospitals.
      Cefuroxime plus gentamicin can be used as antibiotic prophylaxis in this group.
      Vancomycin can be reserved for patients known to be colonized with MRSA (NNT:
      51).

PMID- 12617236
TI  - Low pressure hydrocephalus and ventriculomegaly: hysteresis, non-linear dynamics,
      and the benefits of CSF diversion.
AB  - Low pressure hydrocephalus (LPH) is a rare clinical condition. We report our
      experience with 10 patients treated at the Johns Hopkins Hospital. We reviewed
      the records of 10 patients (five men, five women; mean age 43 years) treated
      between 1996 and 2000. All underwent intracranial pressure (ICP) monitoring and
      subatmospheric cerebrospinal fluid (CSF) drainage with an intraventricular or
      lumbar catheter. All patients developed ventriculomegaly: five following
      aneurysmal subarachnoid haemorrhage; one after meningitis; one after
      intraventricular haemorrhage. Three patients presented with chronic aqueductal
      stenosis. Ventriculomegaly was clinically detected on average 12 days after
      presentation. Mean ICP was 4.8 mmHg (range 0-10). All patients improved only in
      the setting of negative pressure CSF drainage, and were subsequently treated with
      low pressure ventriculo- or lumboperitoneal shunts. At 1 year, eight patients
      (80%) showed good recovery to minimal disability; seven patients (70%) had
      resolving ventriculomegaly. The mechanism of low pressure hydrocephalus remains
      unclear. In our cohort, different aetiologies were responsible for the change in
      compliance/elastance of the brain parenchyma and subsequent development of
      ventriculomegaly. We propose that while ventriculomegaly (and therefore neuronal
      dysfunction) can be initiated in the setting of high ICP, the maintenance of
      ventriculomegaly at normal or low ICP is a physiological example of hysteresis.
      This behaviour, which has been characterized by the chaos theory of non-linear
      dynamics as a Hopf bifurcation, explains how a system can exhibit two different
      states (ventricular size) at a single parameter value (ICP). Most importantly, it
      helps to explain how lowering ICP in the setting of LPH can resolve
      ventriculomegaly and its neurologic sequelae.

PMID- 12617237
TI  - Racial differences in the incidence of gliomas: a retrospective study from
      Memphis, Tennessee.
AB  - This study records the incidence of glioblastoma multiforme, astrocytoma and
      oligodendroglioma in the white and Black patients in the Memphis Statistical
      Metropolitan Area (MSMA) during a 10.5-year period from 1 January 1984 through 30
      June 1994. During this time, only six hospitals performed craniotomy and computer
      tomography (CT) scanning was routine in each of the hospitals. A total of 824
      histologically confirmed first diagnoses were made at these six area hospitals.
      Based on the zip code listed as the home address, we determined patient's locale
      and identified 373 patients (232 glioblastoma multiforme, 106 astrocytomas and 35
      oligodendroglioma) who resided in the area during the study interval. There were
      50 black and 323 white patients. The background population for the area was
      obtained from the US Census Bureau's statistics for the year 1990. These
      statistics indicated that 40.5% of the population identified themselves as black
      and 57.9% as white. Age adjusted incidence rates were 1.550 (p < 0.001) for other
      astrocytomas, and 0.106 and 0.461 (p = 0.003) in the black and white populations,
      respectively. There was no significant difference in survival between the two
      populations. This study confirms a significant disparity in incidence rates for
      the three most common gliomas between the black and white populations and this
      disparity is higher than predicted by previous reports.

PMID- 12617238
TI  - Glioma tumourgenicity is decreased by iNOS knockout: experimental studies using
      the C6 striatal implantation glioma model.
AB  - Nitric oxide synthase (NOS) has recently been shown to be an important
      pathophysiological regulator in experimental implantation glioma since
      manipulation of NOS can significantly alter tumoural blood flow and inhibit
      tumour growth. In this study we investigated the role of iNOS (inducible NOS) in
      glioma tumourogenisis using the rodent C6 striatal implantation model. We
      produced genetically engineered C6 clones that do not express iNOS activity even
      after stimulation with a mixture of lipopolysaccaride (LPS) and tumour necrosis
      factor (TNF)-alpha. These iNOS knockout cells showed a similar growth rate to
      control cells in vivo at 5 days. We then performed an in vivo implantation glioma
      study using either the iNOS knockout clone or two genetically engineered control
      C6 clones. There was a significant reduction (p < 0.01) of tumour mass with the
      iNOS knockout clone 28 days after the implantation. Immunocytochemistry indicated
      infiltrates of CD3 positive T cells and macrophages in the controls and the iNOS
      knockout group. These studies indicate that iNOS expression by tumour parenchymal
      cells is a critical factor for tumour growth with this model. The mechanisms that
      cause failure of tumour growth need clarification prior to considering that
      specific iNOS inhibitors might be candidates for adjuvant treatment of malignant
      glioma.

PMID- 12617239
TI  - How well do radiologists diagnose intracerebral tumour histology on CT? Findings
      from a prospective multicentre study.
AB  - The management of patients with intracranial tumours relies on accurate diagnosis
      of tumour type. To assess the accuracy with which tumour histology could be
      diagnosed from brain CT we reviewed data from a prospective, population-based
      study from three Scottish neuroscience centres. Between October 1997 and April
      1999 all patients from the Edinburgh, Aberdeen and Dundee Neuroscience Centres
      with a CT-diagnosis of a solitary, supratentorial intra-cerebral tumour were
      recruited. General and neuroradiologists were asked to give their best guess
      tumour diagnosis. Biopsy confirmed neuropathological tumour type was available
      for comparison with best guess CT-diagnosis in 221 of 324 patients. Histological
      diagnosis was either malignant glioma, low grade glioma or metastasis in 199
      cases. The accuracy of CT lesional diagnosis for these three categories was 60%
      (95% confidence interval 54-67%), 85% (80-89%) and 82% (77-88%), respectively.
      The diagnostic accuracy of an intra-cerebral tumour was 0.81 with a positive
      predictive value of 0.93. There was no significant difference between
      histological diagnostic accuracy of neuroradiologists and general radiologists.
      In 10% of patients the initial CT scan was reported as negative for intracranial
      tumour, with 62% of these scans having been carried out without contrast. Based
      on CT alone radiologists are good at identifying an intra-cerebral tumour, but
      not so good at distinguishing between different tumour types. The implications of
      the findings for patient management are discussed.

PMID- 12617240
TI  - Failure testing cerebral arteries: are branch points weaker than unbranched
      vessels?
AB  - The bursting pressure of samples of cerebral arteries was measured. Eighty-five
      samples of cerebral arteries were taken from 11 fresh cadavers. These samples
      were filled with saline under pressure to the point of bursting. The bursting
      pressures were recorded. The mean bursting pressure of all samples was 1.8 bar
      (1370 mmHg). The range was 0.7-4.6 (530-3190 mmHg). The mean bursting pressures
      of samples containing branch points was 1.6 and that of those without branch
      points was 2.2. This difference was significant with p < 0.001. Samples taken
      from persons dying from subarachnoid haemorrhage were weaker (mean 1.45 bar) than
      those taken from persons dying from other causes (mean 1.971 bar). This
      difference was significant with p < 0.001. Bursting pressure was found to decline
      at 2% per year of age. This figure was different from 0 with p = 0.003.

PMID- 12617241
TI  - How to write a neurosurgical website.
AB  - Most neurosurgical departments have access to networks including intranets and
      the internet, yet few have developed their own pages. This article reviews the
      benefits and describes how to develop an intranet and internet website.

PMID- 12617242
TI  - Spontaneous thrombosis of a giant internal carotid aneurysm in a patient who
      presented with hypopituitarism.
AB  - This case report describes a 66-year-old woman who initially presented with
      features of hypopituitarism secondary to a giant intra-cavernous internal carotid
      aneurysm. She represented a year later with features suggestive of a subarachnoid
      haemorrhage, but repeat CT showed no change from the one performed previously. A
      repeat angiogram, however, showed complete spontaneous thrombosis of the aneurysm
      including the parent artery.

PMID- 12617244
TI  - Bilateral sensorineural hearing loss complicating basal skull fracture.
AB  - Otological damage is well-recognized following head injury. The commonest
      complication is hearing loss. We present a case of bilateral sensorineural
      hearing loss due to bilateral temporal bone fractures following an epileptic
      seizure, which is unique in the literature and illustrates the importance of this
      complication of head injury.

PMID- 12617243
TI  - Grisel's syndrome: a case of potentially lethal spinal cord injury in the adult.
AB  - A 22-year-old woman presented with respiratory difficulty and quadriparesis two
      weeks after an upper respiratory tract infection. CT showed mild (Type I)
      rotatory atiantoaxial subluxation, but MRI demonstrated a severely contused and
      oedematous spinal cord at C2-3. The case was managed conservatively with collar,
      steroid and antibiotics. The outcome was excellent.

PMID- 12617245
TI  - Trochlear nerve schwannoma removed by combined petrosal approach.
AB  - Trochlear nerve schwannoma is an extremely rare intracranial tumour. It is a
      benign tumour often presenting late with the involvement of neighbouring
      structures and potentially life threatening complications. We report a case of
      this condition, which is the first to be treated by surgery via a presigmoid
      'combined petrosal approach' with follow-up by magnetic resonance imaging (MRI)
      for 6 years. The advantages of the presigmoid combined petrosal approach for this
      type of tumour are described. Early investigation of patients with unexplained
      trochlear nerve palsy by MRI will facilitate the management of these rare
      tumours.

PMID- 12617247
TI  - Lateral thoracic meningocele presenting as a retromediastinal mass.

PMID- 12617246
TI  - Posterior mediastinal paravertebral hydatid cyst causing severe paraparesis.

PMID- 12617248
TI  - Spontaneous resolution of an acute subdural haematoma.

PMID- 12617250
TI  - Cytokeratins in epithelia of odontogenic neoplasms.
AB  - Neoplasms and tumours related to the odontogenic apparatus may be composed only
      of epithelial tissue or epithelial tissue associated with odontogenic
      ectomesenchyme. The immunohistochemical detection of different cytokeratins (CKs)
      polypeptides and vimentin has made it easier to explain the histogenesis of many
      epithelial diseases. The present study aimed to describe the immunohistochemical
      expression of cytokeratins 7, 8, 10, 13, 14, 18, 19 and vimentin in the
      epithelial components of the dental germ and of five types of odontogenic
      tumours. The results were compared and histogenesis discussed. All cells of the
      dental germ were positive for CK14, except for the preameloblasts and secreting
      ameloblasts, in which CK14 was gradually replaced by CK19. CK7 was especially
      expressed in the cells of the Hertwig root sheath and the stellate reticulum. The
      dental lamina was the only structure to express CK13. The reduced epithelium of
      the enamel organ contained CK14 and occasionally CK13. Cells similar to the
      stellate reticulum, present in the ameloblastoma and in the ameloblastic fibroma,
      were positive for CK13, which indicates a nature other than that of the stellate
      reticulum of the normal dental germ. The expression of CK14 and the
      ultrastructural aspects of the adenomatoid odontogenic tumour probably indicated
      its origin in the reduced dental epithelium. Calcifying odontogenic epithelial
      tumour is thought to be composed of primordial cells due to the expression of
      vimentin. Odontomas exhibited an immunohistochemical profile similar to that of
      the dental germ. In conclusion, the typical IF of odontogenic epithelium was
      CK14, while CK8, 10 and 18 were absent. Cytokeratins 13 and 19 labelled squamous
      differentiation or epithelial cells near the surface epithelium, and CK7 had
      variable expression.

PMID- 12617251
TI  - IGF-1 and insulin receptor expression in the minor salivary gland tissues of
      Sjogren's syndrome and mucoceles--immunohistochemical study.
AB  - OBJECTIVE: To investigate the expression of IGF-1 receptors and insulin receptors
      on the minor salivary gland (MSG) tissues of patients diagnosed with Sjogren's
      syndrome (SS) and normal salivary gland tissue surrounding mucoceles. SUBJECTS
      AND METHODS: Five MSG tissue sections from SS and seven from mucocele patients
      were stained immunohistochemically using antibody to IGF-1 receptor and insulin
      receptor in a horse radish peroxidase and DAB system. RESULTS: The expression of
      the insulin receptor was increased in the SS sections compared with controls,
      while the insulin-like growth factor-1 receptor was more intensely expressed in
      the controls. CONCLUSION: The presence of differential expression of receptors
      for IGF and insulin might suggest a possible role of these growth factors in the
      pathogenesis of SS.

PMID- 12617252
TI  - Oral non-Hodgkin lymphomas: studies of EBV and p53 expression.
AB  - OBJECTIVES: The aims of the study were to assess sociodemographic and
      clinicopathologic characteristics of patients with oral non-Hodgkin lymphomas
      (NHLs) and the expression of Epstein-Barr virus (EBV) and p53. MATERIALS AND
      METHODS: The clinical and pathologic features of 11 patients with oral NHLs were
      studied. The expression of EBV mRNA and p53 protein were studied by means of in
      situ hybridization and immunohistochemical methods in 11 formalin-fixed, paraffin
      embedded specimens from these patients. RESULTS: The patients' age ranged from 13
      to 70 years with the mean of 42 years. Human immuno-deficiency virus (HIV) status
      was documented in five of the 11 patients and three were known to be HIV
      positive. The most common locations were gingiva and alveolar mucosa. Pain and
      tenderness were major symptoms of the patients. The most common histologic
      subtype was diffuse large-cell, intermediate-grade NHL. Eight of 11 cases (72.7%)
      showed positive expression of p53 protein. Four of 10 cases (40%) expressed EBV
      encoded RNA (EBER) transcripts. All known HIV-positive cases were EBV-positive.
      CONCLUSIONS: The findings suggest that appropriately expressed p53 protein may
      play a role in tumorigenesis of oral NHLs. In addition, EBV may be involved with
      the pathogenesis of oral NHLs particularly in patients with HIV infection.

PMID- 12617253
TI  - Amelogenesis imperfecta: a classification and catalogue for the 21st century.
AB  - Amelogenesis imperfecta (AI) is a collective term for a number of conditions with
      abnormal enamel formation. Many cases are inherited, either as an X-linked,
      autosomal dominant or autosomal recessive trait. Several classifications have
      evolved since 1945, based primarily on phenotype with the mode of inheritance
      being used in some systems as a secondary factor in allocating a case into a
      particular category. The benefits and shortcomings of these systems are reviewed.
      As we move into an era of establishing the molecular basis of AI we propose a
      robust mechanism for classification and cataloguing of the disorder which
      parallels systems used in medical genetics. This system is applicable to
      individuals and families irrespective of current or future knowledge of the
      molecular defect involved. We argue that this system is of more benefit to these
      individuals and families than previous classifications.

PMID- 12617254
TI  - Bone mineral density of the mandible in ovariectomized rats: analyses using dual
      energy X-ray absorptiometry and peripheral quantitative computed tomography.
AB  - INTRODUCTION: Although previous studies have shown that maxillary molar
      extraction in ovariectomized (OVX) animals causes mandibular loss of bone, it is
      still questionable as to whether estrogen deficiency affects mandibles with
      functional occlusion. MATERIALS AND METHODS: To answer this question, 13-week-old
      female Sprague-Dawley rats were bilaterally OVX or sham-operated. After 109 days,
      the bone mineral density (BMD) of the femurs and mandibles was measured using
      dual-energy X-ray absorptiometry (DEXA) and peripheral quantitative computed
      tomography (pQCT). RESULTS: In DEXA analysis, although the BMD of the total
      mandible of the OVX rats was similar to that of the sham-operated rats, the BMD
      of the condylar region in the OVX rats had decreased by 12.5%. In pQCT analysis,
      decrease in trabecular BMD of the mandibular bone was detectable but low in the
      molar region (maximal 13%), whereas no difference was seen in cortical BMD. In
      the femurs, the trabecular bone prominently decreased in OVX rats (30% decrease
      in pQCT analysis) as previously reported. CONCLUSION: This study revealed
      regional differences in the mandibular bone decrease in OVX rats. Although the
      mechanism of low susceptibility of the mandible to estrogen-deficient conditions
      remains unknown, it is likely that mechanical stress derived from functional
      occlusion is preventing bone loss in this pathological condition. Furthermore,
      this study demonstrated the advantage of pQCT in analyzing rat mandibular bone.

PMID- 12617255
TI  - Dento-osseous changes as diagnostic markers in familial adenomatous polyposis
      families.
AB  - BACKGROUND: We have previously described a weighted index for determining the
      diagnostic significance of dento-osseous changes observed on dental panoramic
      radiographs (DPRs) in individuals at 50% risk of inheriting Familial Adenomatous
      Polyposis (FAP). A diagnostic test based on this index (Dental Panoramic
      Radiograph Score, DPRS) was shown to have a sensitivity of 69% and specificity of
      100%. OBJECTIVES: To evaluate the validity of the diagnostic test in an
      independent sample of individuals at 50% risk of inheriting FAP. DESIGN: A
      retrospective assessment of DPRs in individuals at 50% risk of inheriting FAP.
      SUBJECTS AND METHODS: A final year dental student assessed blindly and
      independently, DPRs from an independent sample (n = 119) of affected (n = 26),
      unaffected (n = 78) and clinically low risk individuals (n = 15). This revealed a
      sensitivity and specificity of 62 and 97% respectively which is in close
      agreement with results of the previous study. The dental student's training in
      assessing DPRs was previously tested using radiographs from 81 individuals from
      our original study. Weighted Kappa statistics were used to test for agreement. A
      kappa score of 0.82 (95% confidence interval 0.70-0.93) indicated almost perfect
      agreement. MAIN OUTCOME: The DPRS is a reproducible and valid index for assessing
      the diagnostic significance of dentoosseous changes, in individuals at 50% risk
      of FAP, even in relatively inexperienced hands.

PMID- 12617256
TI  - Oral signs and symptoms in relation to disease activity and site of involvement
      in patients with inflammatory bowel disease.
AB  - OBJECTIVE: An assessment of oral symptoms and signs in patients with inflammatory
      bowel disease (IBD). METHODS: Fifty-four patients with IBD, 34 with Crohn's
      disease (CD) and 20 with ulcerative colitis (UC) participated in the study. Forty
      two patients without gastrointestinal disease or complaints attending the
      orthopedic clinic served as controls. Each patient completed a written
      questionnaire and was subjected to an oral examination. RESULTS: The main
      findings of this study were the higher prevalence of halitosis (50% vs 10% P <
      0.0008), nausea (30% vs 7%, P < 0.017) and reflux (regurgitation) (45% vs 17%, P
      < 0.017) in patients with UC, and nausea (50% vs 7%, P < 0.026), dry mouth and
      halitosis (29% vs 10%, P < 0.026) and vomiting (41% vs 5%, P = 0.01) in patients
      with CD, compared with controls. Patients with active CD had a higher prevalence
      of dry mouth, nausea and vomiting compared with controls (46, 69 and 54% vs 10, 7
      and 5%, respectively, P < 0.001) and of reflux compared with non-active CD (46%
      vs 5%, P < 0.001). Patients with active UC had a higher prevalence of halitosis
      and regurgitation (50 and 60% vs 10 and 17%, P < 0.001) compared with controls.
      CONCLUSIONS: The present study demonstrates increased frequency of oral signs and
      symptoms in patients with IBD. Patients with active CD had more oral signs
      compared with non-active CD patients. Manifestations such as nausea, vomiting,
      regurgitation and dry mouth may have detrimental effects on teeth and soft
      tissues of the oral cavity. Communication between gastroenterologists and
      dentists is imperative for success of the overall treatment of their patients.

PMID- 12617257
TI  - Opinions about oral cancer prevention and early detection among dentists
      practising along the Texas-Mexico border.
AB  - OBJECTIVES: The purpose of this study was to assess dentists' opinions about oral
      cancer (OC) prevention and early detection. METHODS: Data were collected by a
      self-administered mail questionnaire sent to all 398 registered dentists
      practising along the Texas-Mexico border. RESULTS: The effective response rate to
      the survey was 40%. While 90% of respondents agreed that oral cancer examinations
      (OCE) should be provided annually for patients 40 years of age and older, only
      59% of respondents believed their OC knowledge was current. While 99% agreed that
      dentists were qualified to perform OCE, only 54 and 68% respectively, agreed that
      dental hygienists and physicians were similarly qualified. Dentists who rated
      their undergraduate OC training favorably (OR = 2.68, 1.23-5.81, P = 0.011), had
      attended their last oral cancer continuing education (OCCE) course within the
      past 5 years (OR = 2.46, 1.25-4.86, P = 0.009), and those who performed OCE on
      all patients 40 years and older (OR = 2.64, 1.32-5.26, P = 0.005), were more
      likely to agree their OC knowledge was current. CONCLUSIONS: Respondents
      expressed diverse opinions about OC prevention and early detection. Positive
      opinion on currency of OC knowledge was associated with performance of OCE.
      Results indicate a need for OCCE targeting the study population as well as
      increased emphasis on OC curriculum in dental schools.

PMID- 12617258
TI  - Primary oral tuberculosis: a report of a case diagnosed by polymerase chain
      reaction.
AB  - We present a case of primary oral tuberculosis, affecting the maxillary gingiva
      and causing alveolar bone loss in a 34-year-old Colombian female patient.
      Definitive diagnosis was facilitated by polymerase chain reaction analysis, a
      useful modern tool for the diagnosis of infectious diseases. The location and
      clinical presentation of this lesion is unusual and underlines the importance of
      considering tuberculosis in the differential diagnosis of oral lesions that
      affect the gingiva and alveolar bone.

PMID- 12617259
TI  - Primary aspergillosis affecting the tongue of a leukemic patient.
AB  - We describe a case of primary aspergillosis involving the tongue of a patient
      with acute myeloid leukemia. Intraoral aspergillosis is very rare and we found
      only 23 cases reported in the English literature. Clinically it was a 2-cm,
      ulcerated, grayish lesion on the dorsum of the tongue. Microscopically there was
      invasion of the epithelium, connective tissue and muscle of the tongue by fungal
      hyphae branching at 45 degrees angle. The large hyphae were easily seen by H & E
      stain, and were strongly positive for periodic acid-Schiff and Grocott
      methenamine. The patient was successfully treated with intravenous amphotericin
      B. Based on clinical, microscopic and culture data, the diagnosis of primary
      aspergillosis of the tongue was established. Invasive oral aspergillosis is a
      potentially lethal disease and it should be considered in immunosuppressed
      patients.

PMID- 12617260
TI  - Factors that predict health-related quality of life in patients with relapsing
      remitting multiple sclerosis.
AB  - Health-Related Quality of Life (HRQoL) research is gaining acceptance in the
      field of multiple sclerosis (MS). Little is known about what precipitates quality
      of life change. It was hypothesized that physical aspects of quality of life
      decline with worsening objective disease measures and psychosocial aspects remain
      relatively stable regardless of change in objective measures. These assumptions
      are tested using data from a Phase 3 study of relapsing-remitting MS patients
      treated with interferon beta-1a and reassessed approximately eight years after
      study initiation. The Sickness Impact Profile (SIP) questionnaire is the generic
      quality of life measure used in this study. Three summary scores of the SIP
      (Physical, Psychosocial, and Total scores), Expanded Disability Status Scores,
      Multiple Sclerosis Functional Composite, and Brain Parenchymal Fraction were
      determined at baseline, year 2, and after an average of 8.1 years from study
      entry. SIP data collected during a clinic visit were available from 137 of the
      original 172 participants. All objective indicators worsened by follow-up. SIP
      Physical and Total scores significantly worsened from baseline to follow-up. SIP
      Psychosocial showed nonsignificant worsening. Regression analysis indicated that
      final measures of SIP Physical and Total scores were most strongly associated
      with change in objective measures and follow-up SIP Psychosocial was most
      strongly related to earlier scores on the same measure.

PMID- 12617261
TI  - Antibodies against a human endogenous retrovirus and the preponderance of env
      splice variants in multiple sclerosis patients.
AB  - The human endogenous retrovirus HERV-H is associated with multiple sclerosis
      (MS). Previously performed reverse transcriptase-polymerase chain reactions (RT
      PCR) on virion-RNA demonstrated sequence variants of the HERV-H family located in
      the particulate fraction of MS patient plasma samples and not in controls. In
      this study a significantly elevated level of antibodies towards peptides derived
      from HERV-H/RGH-2 DNA sequences in serum and cerebrospinal fluid (CSF) from MS
      patients is demonstrated. Further, Wistar rats immunized with purified virions
      develop a specific serologic response, indicating that some virion proteins are
      encoded by HERV-H-related sequences. Also shown is that in RNA from blood cells,
      a HERV-H protease-env splice variant can be found together with an env splice
      variant in about 40% of MS patients but only in 10% of controls. The results
      substantiate the association between activated HERV-H and MS, but a causal
      relationship is yet to be demonstrated. HERV-H could represent a causal factor
      either by eliciting an autoimmune response or through the pathogenic potential of
      the retrovirus itself.

PMID- 12617262
TI  - Effect of immunomodulatory drugs on in vitro production of brain-derived
      neurotrophic factor.
AB  - Multiple sclerosis (MS), a disease of presumably autoimmune aetiology, is
      characterized by inflammation, demyelination and axonal degeneration in the
      central nervous system. Current treatment concepts target the inflammatory
      activity, reducing the number of relapses and inflammatory lesions on magnetic
      resonance imaging as well as the proinflammatory cytokine production in blood
      lymphocytes. Recently, the neuroprotective aspect of inflammation has been
      documented and is thought to be mediated by neurotrophins, like brain-derived
      neurotrophic factor (BDNF). The question whether the in vitro BDNF production in
      MS patients and healthy controls is influenced by the immunomodulatory agents
      interferon beta (IFN-beta) and immunoglobulin G (Ig) is addressed. A
      significantly increased BDNF production in MS patients was found compared with
      normal controls (mean +/- SD: 492 +/- 172 pg/mL versus 217 +/- 55 pg/mL, P <
      0.001). IFN-beta and low-dose Ig had no effect on BDNF production, whereas high
      dose Ig reduced in vitro BDNF production in MS patients significantly (to 409 +/-
      125 pg/mL, P = 0.001). These in vitro findings might indicate that Igs in high
      doses potentially interfere with neuroprotective mechanisms despite their potent
      anti-inflammatory properties.

PMID- 12617263
TI  - Cerebral atrophy and disability in relapsing-remitting and secondary progressive
      multiple sclerosis over four years.
AB  - Pathology and magnetic resonance imaging (MRI) studies have provided evidence of
      widespread axonal loss and reductions of cerebral and spinal cord volume in
      multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker
      of worsening disability in MS, but the published studies are of relatively short
      duration. Change in brain volume (atrophy) was measured over a four-year period
      in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive
      (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of
      interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume
      changes were determined and correlated with clinical measures. Over four years,
      brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P =
      0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes
      increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS
      patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = 
      0.47, P = 0.037) were related to disability change, as measured by the Expanded
      Disability Status Scale. Even though a small study and despite the possible
      confounding effects of interferon treatment, this study demonstrated an
      association between measures of cerebral atrophy and worsening disability. The
      data also provides evidence that brain atrophy can be detected early in the
      disease course and central white matter atrophy as reflected by ventricle
      enlargement appears to be a continuous process.

PMID- 12617264
TI  - Effects of combination therapy of beta-interferon 1a and prednisone on serum
      immunologic markers in patients with multiple sclerosis.
AB  - Beta-interferon (beta-IFN) has a proven treatment effect on relapsing-remitting
      multiple sclerosis (MS), presumably through its regulatory properties on T-cell
      activation and cytokine production. This paper examines whether combination
      therapy of beta-IFN with prednisone would enhance immunoregulatory effects of
      beta-IFN by measuring serum levels of selected proinflammatory cytokines and
      soluble T-cell activation markers associated with MS. The selected markers were
      analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN
      combined with a low daily dose of prednisone (n = 33), as compared with those in
      27 healthy controls at baseline and at a three-month interval for one year. The
      study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis
      factor-alpha (TNFalpha) and intracellular adhesion molecule-1 (ICAM-1) in
      patients with MS. However, combination therapy did not significantly enhance the
      inhibitory effect of beta-IFN treatment on the production of TNFalpha,
      interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone
      antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No
      difference in the occurrence of binding antibodies to beta-IFN was found between
      the two treatment groups. The findings are important for the understanding of the
      role of combination therapy in the treatment of MS.

PMID- 12617265
TI  - A novel and rapid assay for the detection of neutralizing antibodies against
      interferon-beta.
AB  - There is evidence that neutralizing antibodies (NAB) have a negative influence on
      the clinical and magnetic resonance imaging effects of interferon-beta (IFNbeta)
      in multiple sclerosis (MS) patients. The current methods for NAB detection are
      restricted to specialized laboratories because they require a cell culture and
      sometimes a viral culture. Results are typically obtained after several weeks.
      Therefore, the development of a simple and rapid assay for the detection of NAB
      was sought. Whole blood samples from 28 NAB-positive patients and 110 NAB
      negative patients (52 with IFNbeta and 58 without IFNbeta therapy) were incubated
      with IFNbeta 976 IU/mL for 24 hours. MxA protein levels--a specific marker of
      class I IFN bioactivity--were measured in paired samples with and without IFNbeta
      incubation and the difference in MxA levels was calculated. The mean increase of
      MxA levels after stimulation with IFNbeta in the NAB-positive group was 8 ng/mL
      (range 0-44 ng/mL) and in the NAB-negative group was 84 ng/mL (range 0-302
      ng/mL). Using an increase of 22.5 ng/mL as cut-off) the specificity of the MxA
      stimulation assay was 81.2% and the sensitivity was 96.4%. The whole blood MxA
      stimulation assay is virtually as sensitive as the conventional NAB assay but
      somewhat less specific. However, this is outweighed by the procedural advantage
      of the assay, which is simpler, quicker and much less expensive.

PMID- 12617266
TI  - Multiple sclerosis: report on 200 cases from Iran.
AB  - Clinical findings of 200 patients in Iran with definite multiple sclerosis (MS)
      according to Poser et al.'s criteria and positive findings on magnetic resonance
      imaging (MRI) have been reviewed. The clinical course was relapsing-remitting
      (RR) for 88%, primary progressive (PP) for 7% and secondary progressive (SP) for
      5% of cases. The mean age of onset was 27 +/- 7.4 years for the whole group and
      37.1 +/- 8.8 years for PPMS. The gender ratio was 2.5:1 female:male. Involvement
      of the pyramidal system was the most common mode of presentation. Five per cent
      of patients had positive family history for the disease, 14% of patients had
      benign MS and 12% with disease duration longer than five years had an Expanded
      Disability Status Scale < or = 2. The optico-spinal form was not a common form of
      presentation in the group.

PMID- 12617267
TI  - Conversion to multiple sclerosis after a clinically isolated syndrome of the
      brainstem: cranial magnetic resonance imaging, cerebrospinal fluid and
      neurophysiological findings.
AB  - BACKGROUND AND AIM: Conversion to multiple sclerosis (MS) after optic neuritis
      and myelitis has been thoroughly studied; however, limited data are available
      regarding conversion to MS after a clinically isolated syndrome of the brainstem
      (CISB). The aim of this study was to investigate conversion to MS in patients
      with CISB. METHODS: Fifty-one patients with CISB were prospectively studied.
      Cranial magnetic resonance imaging (MRI), determination of oligoclonal bands
      (OBs) in the cerebrospinal fluid (CSF) and evoked potentials (EPs) were
      performed. Based on conversion to MS at follow-up, the sensitivity, specificity,
      accuracy and positive and negative predictive values of these tests were
      calculated. RESULTS: Clinically definite MS developed in 18 (35%) patients after
      a mean follow-up of 37 months. Paty's MRI criteria showed a sensitivity of 89%, a
      specificity of 52% and an accuracy of 65%; Fazekas' criteria showed a sensitivity
      of 89%, a specificity of 48% and an accuracy of 63%; Barkhof's criteria showed a
      sensitivity of 78%, a specificity of 61% and an accuracy of 67%. The presence of
      OBs in the CSF showed a sensitivity of 100%, a specificity of 42% and an accuracy
      of 63%. No differences for neurophysiological parameters were found between
      patients who did and those who did not convert to MS. CONCLUSION: Fulfilling
      Paty's, Fazekas' or Barkhof's MRI criteria and the presence of OBs in the CSF are
      associated with a higher risk of conversion to MS in patients with CISB.
      Determination of OBs in the CSF has the greatest sensitivity of all tests.
      Barkhof's MRI criteria have greater specificity (although less than previously
      published for mixed cohorts of clinically isolated syndromes) in predicting
      conversion to MS for CISB than either Paty's or Fazekas' criteria.

PMID- 12617268
TI  - Intention tremor during manual aiming: a study of eye and hand movements.
AB  - Accurate goal-directed movements toward a visual target require a precise
      coordination of both the oculomotor and limb motor systems. Intention tremor and
      eye movement deficits are frequently observed in multiple sclerosis (MS). The
      goal of this study was to examine the characteristics of intention tremor and
      simultaneously produced eye movements during rapid goal-directed movements. Eye
      and hand movements were synchronously measured in 16 MS patients with intention
      tremor and 16 control subjects. Manual performances of the patient group were
      characterized by a delayed onset, slower execution and aiming inaccuracies. In
      line with the clinically defined picture of intention tremor differences between
      patients and control subjects were most pronounced toward the end of the
      movement. Dependent variables were obviously greater in MS patients compared with
      control subjects, and correlated well with clinical outcome measures. The
      application of an inertial load to the limb did not show any effect on intention
      tremor. In addition to impaired limb coordination, evidence has been found that
      eye movements, too, were abnormal in patients compared with control subjects.
      Moreover, eye and hand movement deficits seemed to be closely related, suggesting
      a common underlying command structure. Inaccurate eye movements were likely to
      hamper an accurate motor performance of the hand.

PMID- 12617269
TI  - Horizontal monocular saccadic failure: an unusual clinically isolated syndrome
      progressing to multiple sclerosis.
AB  - This paper describes an unusual clinically isolated syndrome of inflammatory
      demyelination that was characterized by a right VI nerve palsy and right
      internuclear ophthalmoparesis (INO), along with an unusual form of dissociated
      nystagmus. Magnetic resonance imaging (MRI) revealed an isolated lesion within
      the right dorsomediolateral pontine tegmentum. Four years later, the subject
      developed a partial sensory transverse myelitis, confirming clinically definite
      multiple sclerosis (MS). This paper extends the range of isolated syndromes
      associated with MS.

PMID- 12617270
TI  - Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple
      sclerosis.
AB  - Mitoxantrone is a recently approved drug for patients with secondary progressive
      multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use
      in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2.
      Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a
      baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of
      this study was to monitor LVEF more frequently than ordinarily recommended since
      experience with Mitoxantrone use in SPMS patients is limited. An unexpected
      decline in LVEF in one of the SPMS patients being treated with Mitoxantrone
      prompted further investigation into this finding. In our clinic, 47 patients on
      Mitoxantrone were followed prospectively; 28 of 47 patients had received a
      minimum of three doses and underwent a repeat LVEF evaluation prior to their
      fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a
      significant decline in LVEF from baseline. It is suggested that more stringent
      cardiac monitoring guidelines than current Food and Drug Administration (FDA)
      recommendations be used to avert potential cardiac complications in SPMS patients
      on Mitoxantrone.

PMID- 12617271
TI  - The use of quality of life measures in multiple sclerosis research.
AB  - Quality of life research contributes knowledge essential to the health and
      healthcare of multiple sclerosis (MS) patients. This article reviews 83 MS
      studies in English that have presented data on quality of life. The studies may
      be classified into three categories, according to the application and the main
      focus: 1) evaluating the development and validity of quality of life
      questionnaires and clinical scales (n = 27); 2) evaluating factors that might
      influence the quality of life or comparing the quality of life among various
      groups (n = 37); and 3) using quality of life questionnaires as outcome measures
      in medical trials and other interventions (n = 19). The studies have shown that
      quality of life questionnaires more broadly measure the impact of MS than do the
      most frequently used measures of disease activity and effects. Using quality of
      life measures provides additional information in evaluating the effects of
      treatment and in studying the development of the disease. Such information is
      crucial in planning interventions for MS patients. A challenge in this field is
      to improve the study designs, including reaching some agreement on how to measure
      the quality of life.

PMID- 12617272
TI  - Development and validation of a self-efficacy measure for people with multiple
      sclerosis: the Multiple Sclerosis Self-efficacy Scale.
AB  - The aim of this study is to develop and validate a brief measure of self-efficacy
      specifically for use with people with multiple sclerosis (MS). Self-efficacy is
      the subjective belief that one can overcome challenges that one is faced with. In
      order to incorporate the subjective experiences of individuals with MS, a
      'patient-focused' methodology has been adopted. Open-ended interviews were used
      to generate potential scale items. Items were piloted on an initial sample of
      individuals with MS and reduced to 14 items on the basis of their perceived
      relevance to this patient group. The final 14-item scale was then used with a
      further 142 individuals in order to assess its psychometric properties. The scale
      demonstrated high internal consistency (Cronbach's alpha = 0.81) and test-retest
      reliability (r = 0.81, P < 0.001) and acceptable validity. Issues concerning the
      assessment of validity are discussed in terms of the scale's relevancy to
      individuals with MS and the theoretical issues around the construct of self
      efficacy. The scale has shown sensitivity to detect change following a brief
      therapeutic intervention, with an effect size of 0.502. This MS Self-efficacy
      Scale could, therefore, be a useful tool in the assessment of psychological
      adjustment and quality-of-life of individuals with MS.

PMID- 12617273
TI  - On receiving the diagnosis of multiple sclerosis: managing the transition.
AB  - This article reports on one aspect of a wider study into multiple sclerosis (MS)
      specialist nurse roles in the UK. Insights gained from in-depth patient
      interviews are discussed in relation to literature regarding the meaning of
      health-related events, such as diagnosis. The findings of this project indicated
      that for many people, intense feelings of abandonment and isolation were
      generated at the time of diagnosis and stayed with the person for many months or
      years. Differing expectations between patient and neurologist following
      confirmation of diagnosis could contribute to these findings. It is suggested
      that imparting a diagnosis of MS should be seen as the start of a transition that
      needs to be made explicit to the patient and closely linked to the provision of
      sources of information, advice and ongoing support as people learn to live with
      and manage the disease.

PMID- 12617274
TI  - The role of helplessness as mediator between neurological disability, emotional
      instability, experienced fatigue and depression in patients with multiple
      sclerosis.
AB  - The aim of this study was to test, in patients with multiple sclerosis (MS),
      whether the concept of helplessness might improve the understanding of the
      relationship between disease severity (neurological impairment) and personality
      characteristics (emotional instability) on one hand, and depressive mood and
      fatigue severity on the other hand. Data pertain to 89 patients with a definite
      diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8).
      Helplessness, fatigue severity, depressive mood and emotional instability were
      rated with validated questionnaires. Model testing revealed that more
      neurological impairment and more emotional instability were associated with more
      helplessness, while higher levels of helplessness were associated with more
      fatigue and depressive mood. The initially observed direct relationship between
      EDSS and fatigue disappeared. Emotional instability also had a direct significant
      relationship with depressive mood, and depressive mood had only a small
      relationship with fatigue severity. The results indicated that helplessness
      affected both depressive mood and fatigue severity and that fatigue was not
      merely a symptom of depressive mood. The correlation between neurological
      impairment and fatigue severity was largely explained by the mediating effect of
      helplessness. These findings suggest that MS patients troubled by disabling
      fatigue might benefit from a psychological intervention targeting unfavourable
      illness cognitions.

PMID- 12617275
TI  - Screening for multiple sclerosis cognitive impairment using a self-administered
      15-item questionnaire.
AB  - Since there is a need for cost-effective screening techniques to identify
      neuropsychological impairment in multiple sclerosis (MS) patients, and because
      existing methods require cognitive testing with subsequent interpretation by a
      neuropsychologist, a brief self-report procedure was developed to screen for
      neuropsychological impairment in MS. In the first phase of the study, a pool of
      80 items was generated based on a literature review and consultation with
      healthcare professionals. The set was reduced to 15 via Rasch analysis. Using
      these items, a brief (five minute) MS Neuropsychological Screening Questionnaire
      (MSNQ), including patient- and informant-report forms, was composed. In phase II,
      50 MS patients and their caregivers completed the MSNQ. A comprehensive
      neuropsychological test battery was also administered. Analyses covered the
      reliability of the MSNQ and correlations between both patient- and informant
      report scores and objective neuropsychological testing. Cronbach's alpha
      coefficients were 0.93 and 0.94 for the patient- and informant-report forms,
      respectively, and both forms of the test were strongly correlated with a more
      general cognitive complaints questionnaire. The patient MSNQ form correlated
      significantly with measures of depression but not with objective tests of
      cognitive function. In contrast, the informant form was correlated with patient
      cognitive performance but not depression. A cut-off score of 27 on the informant
      form of the MSNQ optimally separated patients based on a neuropsychological
      summary score encompassing measures of processing speed and memory. There were
      two false-negatives and one false-positive, giving the test a sensitivity of 0.83
      and a specificity of 0.97. It is concluded, therefore, that this self
      administered neuropsychological screening test is reliable and predicts
      neuropsychological impairment in MS patients with a reasonable degree of
      accuracy.

PMID- 12617276
TI  - Gadolinium-enhanced magnetic resonance imaging predicts response to
      methylprednisolone in multiple sclerosis.
AB  - Oral high-dose methylprednisolone treatment is efficacious in acute optic
      neuritis (ON) and attacks of multiple sclerosis (MS). The responses to treatment
      in subgroups of patients participating in two randomized, controlled trials were
      assessed. Fifty-eight patients with ON and 51 patients with attacks of MS were
      treated with placebo or oral methylprednisolone (500 mg daily for five days with
      a 10-day tapering period). A gadolinium (Gd)-enhanced magnetic resonance imaging
      (MRI) scan was obtained at baseline in 66 patients, and 29 patients underwent
      repeated MRI studies. Seventy-four patients underwent lumbar puncture before
      treatment. The odds ratio (OR) of improvement after methylprednisolone treatment
      (a one point change in the visual function system score of the Kurtzke Expanded
      Disability Status Scale (EDSS) in ON or in the EDSS score in attacks of MS) was
      higher in patients with enhancing lesions on baseline MRI (one week: OR 15, P =
      0.02; eight weeks: OR 4.6, P = 0.02). Methylprednisolone treatment suppressed Gd
      enhancement after one week (P < 0.001) and three weeks (P = 0.001). Cerebrospinal
      fluid measures of intrathecal inflammation correlated with the area of Gd
      enhancement but did not correlate as closely with the treatment response as did
      the results of Gd-enhanced MRI. These findings suggest that the resolution of
      intrathecal inflammation as assessed by Gd-enhanced MRI is a major effect of oral
      high-dose methylprednisolone.

PMID- 12617277
TI  - Correlation of sexual dysfunction and brain magnetic resonance imaging in
      multiple sclerosis.
AB  - Sixty-two patients (40 women and 22 men) with multiple sclerosis (MS) were
      examined with 1.5 tesla magnetic resonance imaging (MRI) of the brain.
      Information on sexual and sphincteric disturbances has been collected, and data
      on disability, independence, cognitive performances and psychological functioning
      have been assessed. Calculations of T1- and T2-lesion load (LL) of total brain,
      frontal lobes and pons have been performed using a reproducible semiautomated
      technique. Whole brain, frontal and pontine atrophies were estimated using a
      normalized measure, the brain parenchymal fraction (BPF), obtained with a
      computerized interactive program. When comparing patients with and without sexual
      dysfunction (SD), there were no differences in total brain, frontal and pontine
      T1- and T2-LL, as well as in measures of whole brain and frontal atrophy. The
      only significant difference was in the pontine BPF (P = 0.026). In linear
      multiple regression analysis, SD was associated with depression (R = 0.56, P <
      0.001) and, after adjusting for depression and anxiety, with bladder dysfunction
      (R = 0.43, P = 0.003) and pontine BPF (R = 0.56, P < 0.001). No association
      between SD and any of the measures of T1- and T2-LL was found. The findings
      showed a relationship between SD and pontine atrophy, confirmed the correlation
      of SD with bladder dysfunction and highlighted the role of psychological factors
      in determining SD.

PMID- 12617278
TI  - Health and nutrition in a Philippine highland community.
AB  - The article deals with the nutritional habits of the people of Bauko, an upland
      community in the northern Philippine island of Luzon, and its implications for
      health preservation and disease management. Data on dietary behavior were
      collected through a 24-hour-recall survey administered to a representative sample
      of students and adults. This method provided researchers with the information
      needed to infer the people's concept of food, to explore differences and
      similarities in the dietary behavior of young and adult individuals, to describe
      strategies utilized in food preparation, and to establish the nutritional content
      of the diet's main components.

PMID- 12617279
TI  - Wading for food the driving force of the evolution of bipedalism?
AB  - Evidence is accumulating that suggests that the large human brain is most likely
      to have evolved in littoral and estuarine habitats rich in naturally occurring
      essential fatty acids. This paper adds further weight to this view, suggesting
      that another key human trait, our bipedality might also be best explained as an
      adaptation to a water-side niche. Evidence is provided here that extant apes,
      although preferring to keep dry, go into water when driven to do so by hunger.
      The anecdotal evidence has suggested that they tend to do this bipedally. Here, a
      new empirical study of captive bonobos found them to exhibit 2% or less
      bipedality on the ground or in trees but over 90% when wading in water to collect
      food. The skeletal morphology of AL 288-1 ("Lucy") is shown to indicate a strong
      ability to abduct and adduct the femur. These traits, together with a remarkably
      platypelloid pelvis, have not yet been adequately explained by terrestrial or
      arboreal models for early bipedalism but are consistent with those expected in an
      ape that adopted a specialist side-to-side 'ice-skating' or sideways wading mode.
      It is argued that this explanation of A. afarensis locomotor morphology is more
      parsimonious than others which have plainly failed to produce a consensus.
      Microwear evidence of Australopithecus dentition is also presented as evidence
      that the drive for such a wading form of locomotion might well have been
      waterside foods. This model obtains further support from the paleo-habitats of
      the earliest known bipeds, which are consistent with the hypothesis that wading
      contributed to the adaptive pressure towards bipedality.

PMID- 12617280
TI  - Decreased serum magnesium and zinc levels: atherogenic implications in type-2
      diabetes mellitus in Nigerians.
AB  - Serum magnesium, zinc and total cholesterol were evaluated in 40 Nigerian
      patients suffering from type-2 diabetes mellitus (21M, 19F) and 20 (14M, 6F)
      apparently normal non diabetic control subjects. The mean age of the diabetic
      patients was similar to that of controls (p > 0.05). The mean duration of the
      disease was (4.7 + 0.7 SEM) in these patients. Fasting blood glucose and total
      cholesterol were significantly higher in diabetics than in non diabetic control
      subjects (p > 0.001). The serum total cholesterol showed inter-group variation
      when the patients were classified into four different age groups. In contrast,
      the serum level of magnesium (Mg) and zinc (Zn) were significantly lower in
      diabetics than in controls (p > 0.001). There were no significant correlation
      between glucose and the minerals, Mg. and Zn. Serum total cholesterol showed a
      significant positive correlation with magnesium (r = 0.6: p > 0.001), while the
      correlation with zinc was not significant. In type-2 diabetic mellitus the
      concentration of both Mg and Zn levels were significantly reduced, probably
      suggesting lower antioxidant status in this condition. The implication is the
      greater susceptibility to LDL-cholesterol oxidation. The attendant risk of
      development of premature Coronary Heart Disease is discussed. Magnesium and zinc
      are nutritional minerals that play crucial roles in the regulation of
      carbohydrate and lipid metabolism.

PMID- 12617281
TI  - Growth pattern of exclusively breast-fed infants during the first six months of
      life in Ile-Ife, Osun State, Nigeria.
AB  - Several studies to determine the growth pattern of exclusively breast fed infants
      have provided varying conclusions as to the sufficiency of breast milk alone to
      support adequate growth for the first six months of life. Disagreement exists
      concerning the optimal timing of introduction of complementary foods to
      exclusively breast fed infants. This prospective study thus examined the adequacy
      of breast milk alone to support normal growth during the first six months of life
      in our environment. The overall objective was to propose a scientifically sound
      national recommendation on the appropriate timing for the introduction of
      complementary feeding in Nigeria. Three hundred and fifty-two mother/infant pairs
      were serially recruited into the study; all babies were aged 14 days or less and
      weighed 2.5 kg and above. Three hundred and forty-five (98%) were successfully
      followed up till the infants were six months old. By six months, 264 (76.5%) were
      exclusively breast-fed, while 81 (23.5%) had commenced complementary feeding.
      Growth curves of exclusively breast-fed infants showed increasing weight from
      birth to six months. Although the 50th percentile birth weight for both boys and
      girls were the same (3.2 kg), boys gained weight faster than the girls from the
      age of one month to six months and were heavier at six months. Additionally, the
      50th percentile curves of these infants (both genders) for the first six months
      were above the 50th percentile curve of the World Health Organisation and
      National Centre for Health Statistics (WHO/NCHS) reference currently used on our
      national "road to health" (growth monitoring) cards. It was concluded that
      exclusive breast-feeding supported adequate growth during the first six months of
      life for most of the children studied and that our national recommendation that
      infants be introduced to complementary feeding at six months is appropriate.

PMID- 12617283
TI  - Note: the role of dry heat treatment in improving the shelf life of pearl millet
      flour.

PMID- 12617282
TI  - Effect of supplementation on physicochemical, sensory and nutritional
      characteristics of bread.
AB  - Supplementation of wheat flour with soy flour (full fat and defatted) at 5, 10,
      15 and 20% levels was carried out to test the effect on physico-chemical,
      sensory, nutritional evaluation and shelf life of breads. Adding 10% of soy flour
      (full fat and defatted) produced breads with good baking and organoleptic
      characteristics. However, at 15 and 20% levels they were less acceptable. The
      better breads were further investigated for various nutritional parameters and
      shelf life. Full fat and defatted soy flour (10%) supplemented bread exhibited
      13.66 and 13.81% protein, and 3.02 and 3.05 g/100 g protein total lysine contents
      as compared to control (wheat) bread (11.47% protein and 2.36 g/100 g protein
      total lysine). Other nutrients are also increased in supplemented breads as
      compared to wheat bread. However, for storage, defatted soy supplemented bread
      exhibited better shelf life than the full fat version.

PMID- 12617284
TI  - Note: storage practices, salt intake and iodine content of salt consumed in rural
      households of Haryana State, North India.
AB  - A survey of 180 rural families from different zones of Haryana State was carried
      out to know the type and intake of salt used and the domestic storage practices
      followed by rural households using a questionnaire method. Salt samples from
      rural households were analyzed for their iodine content. Results indicated that
      most of the people in rural Haryana consume powdered salt and stored it in
      airtight containers. Daily intake per person ranged from 9.91 to 11.42 g. In the
      wet zone a higher percentage of families consume iodized salt. Analysis of iodine
      in salt samples showed that of samples from three zones, 39% contained no iodine;
      with 9% < 15 ppm; 14% 15-29 ppm and 37% > or = 30 ppm.

PMID- 12617285
TI  - PUFA supply.

PMID- 12617286
TI  - Marine fat and human health.

PMID- 12617287
TI  - Worshippers' exposure to particulate matter in two temples in Taiwan.
AB  - Worshippers in temples may be exposed to high concentrations of pollutants
      emitted from incense burning. This work assessed the PM2.5 and PM10 exposures of
      temple worshippers in Taiwan and explored the important exposure determinants
      such as numbers of passing visitors and joss sticks in censers, worshipping
      dates, and temple characteristics. Sampling was conducted on the 1st, 2nd, 15th,
      and 16th of the lunar month in two temples in Taichung, Taiwan. Research staff
      took samples by wearing one PM2.5 and one PM10 sampler and imitating worshipping
      activity. Personal environmental monitors connected to personal pumps with 2
      L/min flow rates were used for sampling. PM10 samples were also simultaneously
      taken outside the temples. The results suggested that burning joss sticks in
      temples is a significant PM exposure source. The geometric mean of personal
      exposure was 444 microg/m3 PM2.5 [geometric standard deviation (GSD) = 1.8] and
      583 microg/m3 PM10 (GSD = 1.4). The latter was approximately 4-6 times that of
      roadside concentrations. Exposures on the 1st and 15th (with more visitors and
      more joss sticks) were about 130 microg/m3 PM2.5 and 249 microg/m3 PM10 higher
      than those on the 2nd and the 16th. Furthermore, each joss stick in the censer
      contributed about 0.40 microg/m3 of particles to the worshippers' exposure. In
      the worst case, PM exposure during one temple visit would account for 11% of the
      personal exposure in one day.

PMID- 12617288
TI  - Waste burning and heat recovery characteristics of a mass burn incineration
      system.
AB  - An experimental investigation on waste combustion characteristics of a mass burn
      incinerator is conducted in this study. Three different charging modes, including
      operator manipulation, periodic feeding, and temperature control, are taken into
      consideration. The results indicate that the burning characteristics in the
      combustion chambers are closely related to the operating modes. For the operator
      manipulation where the wastes are sent into the incinerator in two short periods,
      the entire temperature distribution of the primary combustion chamber can be
      partitioned into two parts, thereby yielding waste group combustion. Temperature
      oscillations in both the primary and secondary combustion chambers are
      characterized for the periodic feeding. However, because of the shorter charging
      period and smaller amount of waste, the burning interaction between the two
      chambers is initially weak and becomes notable in the final stage. When
      temperature control is performed, the burning oscillation of the primary
      combustion chamber is further amplified so the combustion interaction is drastic.
      These exhibitions are mainly caused by the competition between endothermic and
      exothermic reactions. The instantaneous heat exchange efficiency of the cyclone
      heat recovery system (CHRS) installed in the incineration system is also
      evaluated to obtain details of energy recovery behaviors. As a result, the
      efficiency tends to decrease linearly with increasing temperature of hot flue
      gas. This arises from the fact that heat loss from the gas to the environment is
      increased when the temperature of the former is higher, even though the
      temperature gradient across the cyclone is enlarged.

PMID- 12617289
TI  - Release of mercury from broken fluorescent bulbs.
AB  - Mercury is a persistent, bioaccumulative toxin. Although the primary human
      exposure is from ingestion of fish contaminated with methyl mercury (HgCH3),
      exposures to elemental mercury vapor and mercury compounds via inhalation and
      dermal contact may also occur. Fluorescent bulbs contain mercury. Estimates of
      the amount of this mercury released when the bulbs are discarded and broken have
      varied widely. A new method was developed for measuring mercury released from
      broken bulbs. With the assumption that all mercury released is elemental vapor,
      it was found that between 17 and 40% of the mercury in broken low-mercury
      fluorescent bulbs is released to the air during a two-week period immediately
      following breakage, with higher temperatures contributing to higher release
      rates. One-third of the mercury release occurs during the first 8 hr after
      breakage. Many bulbs contain more mercury than the low-mercury bulbs tested. A
      typical discarded bulb releases between 3 and 8 mg of elemental mercury vapor
      over two weeks. Approximately 620 million fluorescent bulbs are discarded
      annually in the United States, and many are broken during disposal. Based on the
      estimated release rate of 3-8 mg per broken bulb developed in this study,
      discarded bulbs release approximately 2-4 tons of mercury per year in the United
      States. Waste management systems that minimize breakage before final disposal
      could reduce this total, as would the reduction of mercury content of bulbs.
      Elevated airborne levels of mercury could exist in the vicinity of recently
      broken bulbs, and under certain conditions, mercury concentrations could exceed
      occupational exposure limits.

PMID- 12617290
TI  - Real-world vehicle emissions: a summary of the twelfth Coordinating Research
      Council On-Road Vehicle Emissions Workshop.
AB  - The Coordinating Research Council (CRC) held its 12th workshop in April 2002,
      with nearly 90 presentations on the most recent on-road vehicle emissions
      research. This paper summarizes the presentations from researchers who are
      engaged in improving understanding of the contribution of mobile sources to air
      quality. Participants in the workshop discussed mobile source emission models and
      emission inventories, results from gas- and particle-phase emissions studies from
      spark-ignition and diesel-powered vehicles (with an emphasis in this workshop on
      particle emissions), effects of fuels on emissions, evaluation of in-use
      emissions control programs, and efforts to improve our capabilities in performing
      on-board emissions measurements, as well as topics for future research.

PMID- 12617291
TI  - Seasonal aerosol sulfate trends for selected regions of the United States.
AB  - Site and regional trends in seasonally averaged particle SO4(2-) concentrations
      were examined for a large portion of the United States using data collected by
      the CASTNet air monitoring network. Trends were analyzed for overlapping periods
      of 1988-1999 and 1992-1999. The largest absolute SO4(2-) decreases--approximately
      -0.4 microg/m3/yr--between 1988 and 1999 occurred in summer for sites in the Ohio
      River Valley and areas to the east. Generally, the largest SO4(2-) reductions
      were found for summer, but larger relative reductions often occurred for spring
      and autumn. Sulfate changes during 1992-1999 were quite different from those
      found for 1988-1999 and were not entirely consistent with changes in SO2
      emissions. In some locations, the 1992-1999 period saw smaller declines in SO4(2
      ), while in other places seasonal SO4(2-) actually increased. Increases were
      mostly confined to summer and autumn across the southern and southwestern states.
      Multivariate analysis of ambient sulfur levels, by region, versus SO2 emissions
      reveals that annual emissions are associated with more than 80% of the variance
      in seasonal sulfur (SO2 and SO4(2-)) in more than three-quarters of the cases
      examined. The weakest associations were found for the southeastern United States.

PMID- 12617292
TI  - Emissions from charbroiling and grilling of chicken and beef.
AB  - Emission rates for fine particle (<2.5 microm) mass (PM2.5), carbon
      (organic/elemental), inorganic ions (SO4(2-), NO3-, NH4+), elements (primarily
      metals), and speciated organic compounds are reported for charbroiling hamburger,
      steak, and chicken. The PM2.5 rates for charbroiling meats ranged from 4.4 to
      11.6 g/kg of uncooked meat in this study. No mass-emission rates are available
      from grilling, but the speciated organic data are available for these samples.
      Emission rates varied by type of appliance, meat, meat-fat content, and cooking
      conditions. High-fat hamburger cooked on an underfired charbroiler emitted the
      highest amount of PM2.5. The emissions were almost exclusively composed of
      organic carbon, with small amounts of elements and inorganic ions. Water-soluble
      K+ and Cl-, which are used as indicators of wood smoke in source apportionment
      studies, were also present in meat-cooking emissions. The speciated organic
      compounds that were measured include polycyclic aromatic hydrocarbons (PAHs),
      cholesterol, and the long-chain gamma-lactones. Charbroiling emissions yielded an
      average of approximately 3-5 times more PAHs, approximately 20 times more
      cholesterol, and approximately 10 times more lactones than grilling. These data
      were utilized in the ambient source apportionment analysis for the 1997 Northern
      Front Range Air Quality Study source apportionment.

PMID- 12617293
TI  - Understanding the effectiveness of precursor reductions in lowering 8-hr ozone
      concentrations.
AB  - Analyses of ambient measured ozone data were used in conjunction with the
      application of photochemical modeling to determine the technical feasibility of
      attaining the federal 8-hr ozone standard in central California. Various
      combinations of volatile organic compound (VOC) and oxides of nitrogen (NOx)
      emission reductions were effective in lowering modeled peak 1-hr ozone
      concentrations. However, VOC emissions reductions were found to have only a
      modest impact on modeled peak 8-hr ozone concentrations. NOx emission reductions
      generally lowered 8-hr ozone concentrations, but their effectiveness was
      partially or, in some cases, wholly offset by the increase in the number of NO
      cycles and, hence, in the ozone produced per NO. As a result, substantial NOx
      emission reductions--70 to 90%--were required to reduce peak 8-hr ozone
      concentrations to the level of the standard throughout the modeling domain. These
      modeling results provide a possible physical explanation for recent analyses that
      have reported more prominent trends in peak 1-hr ozone levels than in peak 8-hr
      ozone concentrations or in occurrences of mid-level (60-90 parts per billion by
      volume) ozone concentrations. The findings also have serious implications for the
      feasibility of attaining the 8-hr ozone standard in central California. Further
      efforts are needed to clarify the applicability of the modeling results to the
      full set of days with ozone levels exceeding the 8-hr ozone standard, as well as
      their applicability to other geographical areas.

PMID- 12617294
TI  - Entrainment of radio frequency chaff by wind as a function of surface aerodynamic
      roughness.
AB  - Radio frequency (RF) chaff (approximately 2-cm x 25-microm diameter aluminum
      coated glass silicate cylinders) released by military aircraft during testing and
      training activities has the potential to become entrained by wind upon settling
      to the Earth's surface. Once entrained from the surface there is the potential
      for RF chaff to be abraded and produce PM10 and PM2.5, which are regulated
      pollutants and pose health concerns. A series of portable wind tunnel tests were
      carried out to examine the propensity of RF chaff to become entrained by wind by
      defining the relationship between the threshold friction velocity of RF chaff
      (u(*t RF chaff)) and aerodynamic roughness (z(o)) of surfaces onto which it may
      deposit. The test surfaces were of varying roughness including types near the
      Naval Air Station (NAS), Fallon, NV, where RF chaff is released. The u(*t) of
      this fibrous material ranged from 0.14 m/sec for a smooth playa to 0.82 m/sec for
      a rough crusted playa surface with larger cobble-sized (approximately 6-26-cm
      diameter) rocks rising above the surface. The u(*t RF chaff) is dependent on the
      z(o) of the surface onto which it falls as well as the physical characteristics
      of the roughness. The wind regime of Fallon would allow for chaff suspension
      events to occur should it settle on typical surfaces in the area. However, the
      wind climatology of this area makes the probability of such events relatively
      low.

PMID- 12617295
TI  - Degradation of toluene, xylene, and trimethylbenzene vapors by biofiltration: a
      comparison.
AB  - This paper presents a comparative study of the biodegradation of three aromatic
      volatile compounds in a compost-based biofilter: toluene, xylene, and 1,2,4
      trimethylbenzene, used in the course of this work for the first time in the field
      of biofiltration. Hence, three identical biofiltration units have been operated
      at the laboratory scale. During the experiments, nitrogen (as urea) was supplied
      at various concentrations to each reactor, via irrigated nutrient solutions. A
      comparative analysis of the results showed that the biodegradability scale
      followed the degree of substitution around the aromatic ring: toluene > xylene >
      trimethylbenzene, with 95, 80, and 70% maximum conversions, respectively. In
      addition, and despite the different removal levels achieved in the three
      bioreactors, it was established that from a reaction viewpoint, the degradation
      of the three compounds seemed to follow similar metabolic pathways involving
      methylcatechol isomers. Finally, by varying the nitrogen input concentrations in
      the three reactors, three degradation regimes have been highlighted: an N
      limitation regime and an N-optimum regime, common to the three solvents, and an N
      excess regime, favorable to the colonization of the filter beds by nitrifying
      species, which particularly affected the xylene and trimethylbenzene
      biodegradation.

PMID- 12617296
TI  - Utilization of selected area electron diffraction patterns for characterization
      of air submicron particulate matter collected by a thermophoretic precipitator.
AB  - A thermophoretic precipitator (TP) that uses a novelty of direct sampling of
      ambient air particulate matter (PM) onto transmission electron microscopy (TEM)
      grids was designed and utilized to determine its potential applicability for the
      collection and consequent qualitative analyses of representative PM in the air,
      especially those with aerodynamic diameter less than 1 microm (PM1.0). After a
      calibration process, preliminary field tests were performed under different
      weather conditions, locations, and time frames. TEM, selected area electron
      diffraction (SAED), and electron energy-dispersive X-ray spectrometry (EDS)
      analyses were performed on individual samples, and chemical species were
      analyzed. During this investigation, individual air PM with different sizes
      ranging from 10 microm to 10 nm for TEM analysis was collected. Two observations
      were made: (1) a large fraction of collected particulates were aggregates of very
      small particles of both organic and inorganic origin, and (2) a large fraction of
      the collected particulates were crystalline or polycrystalline. This study has
      demonstrated, by utilization of SAED patterns from TEM on air particles collected
      by a TP, the potential to analyze and identify individual air PM in a nanometer
      regime qualitatively by combining SAED and EDS data.

PMID- 12617297
TI  - Daily surface UV exposure and its relationship to surface pollutant measurements.
AB  - For the past 30 years, the stratospheric ozone layer has decreased in the
      Northern Hemisphere. The main effect of this ozone decrease was an expected
      increase in the UV radiation at the Earth's surface, but there has been no clear
      evidence of an increasing urban trend in surface UV. This study shows that
      specific air pollutants can reduce the increased surface levels of UV radiation
      and offers an explanation for why the expected surface UV increases have not been
      observed, especially in urban regions. A U.S. Environmental Protection Agency
      (EPA) UV monitoring site at the University of California at Riverside combined
      with air pollution data from a site operated by the California Air Resources
      Board in Rubidoux, CA, provided the basis of this study. The 1997 South Coast
      Ozone Study (SCOS-97) provided three key ingredients: black carbon, PM10
      concentrations, and collocated radiometric measurements. The Total Ozone Mapping
      Spectrometer (TOMS) satellite data were used to provide the stratospheric ozone
      levels that were included in the statistical model. All of these input parameters
      would be used to test this study's hypothesis: the expected increase of surface
      UV radiation, caused by decreases in stratospheric ozone, can be masked by
      increases in anthropogenic emissions. The values for the pollutants were 7:00
      a.m.-5:00 p.m. averages of the instrument's values taken during summer 1997. A
      statistical linear regression model was employed using the stratospheric ozone,
      black carbon, PM10, and surface ozone concentrations, and the sin (theta) and cos
      (theta). The angle theta is defined by theta = 2pi (Julian date/365). This model
      obtained a coefficient of determination of 0.94 with an uncertainty level (p
      value) of less than 0.3% for all of the variables in the model except ground
      level ozone. The final model, regressed against a data set from a remote, western
      North Carolina site, resulted in a coefficient of determination of 0.92. The
      model shows that black carbon can reduce the Diffey-weighted UV levels that reach
      the surface by as much as 35%, depending on the season.

PMID- 12617298
TI  - Absorption and reaction kinetics of amines and ammonia solutions with carbon
      dioxide in flue gas.
AB  - The removal system for the absorption of CO2 with amines and NH3 is an advanced
      air pollution control device to reduce greenhouse gas emissions. Absorption of
      CO2 by amines and NH3 solutions was performed in this study to derive the
      reaction kinetics. The absorption of CO2 as encountered in flue gases into
      aqueous solutions of monoethanolamine (MEA), diethanolamine (DEA), and NH3 was
      carried out using a stirred vessel with a plane gas-liquid interface at 50
      degrees C. Various operating parameters were tested to determine the effect of
      these variables on the absorption kinetics of the reactants in both gas and
      liquid phases and the effect of competitions between various reactants on the
      mass-transfer rate. The observed absorption rate increases with increasing gas
      liquid concentration, solvent concentration, temperature, and gas flow rate, but
      changes with the O2 concentration and pH value. The absorption efficiency of MEA
      is better than that of NH3 and DEA, but the absorption capacity of NH3 is the
      best. The active energies of the MEA and NH3 with CO2 are 33.19 and 40.09 kJ/mol,
      respectively.

PMID- 12617299
TI  - The adaptive effects of hypoxic preconditioning of brain neurons.
AB  - Prophylactic transient hypoxia (preconditioning) increased neuron resistance to
      subsequent induction of severe hypoxia. Published data and results obtained by
      the authors on the molecular-cellular mechanisms of hypoxic preconditioning are
      presented. The roles of intracellular signal transduction, genome function,
      stress proteins, and neuromodulatory peptides in this process are discussed. The
      roles of glutamatergic as well as calcium and phosphoinositide regulatory systems
      and neuromodulatory factors as components of "volume" signal transmission are
      analyzed in hypoxic preconditioning-associated induction of functional tolerance
      mechanisms against the acute harmful effects of hypoxia on neurons in olfactory
      slices.

PMID- 12617301
TI  - Heterochronous involvement of neurotrophic factors in the neurochemical
      organization of learning and memory processes in adult organisms.
AB  - Studies were performed on the involvement of neurotrophic factors in the
      neurochemical mechanisms of the integrative functions of the brain. The effects
      of various intrahippocampal doses of antibodies to neurotrophic factors--protein
      S100 and lectin CSL--were studied on the formation, retention, and reproduction
      of a habituated acoustic startle response and conditioned fear in adult rats.
      S100b contents in the hippocampus, hypothalamus, frontal cortex, and cerebellar
      hemispheres and vermis, and in the basal nuclei were measured in rat brains 0.5,
      1, 2, 4, 6, 8, 24, and 48 h after long-term habituation to the startle response.
      Antibodies to neurotrophic factors had selective and dose-dependent effects on
      the different memory and learning processes underlying these types of behavior.
      Changes in S100b in brain structures were seen, which were specific in terms of
      quantitative levels and dynamics, after acquisition of the behavioral habit. The
      results obtained here, along with previously reported data on the effects of
      antibodies to S100b and CSL given into the cerebellum, are discussed as
      experimental support for the hypothesis of the heterochronous neurochemical
      organization of integrative brain activity.

PMID- 12617300
TI  - Influence of postweaning social isolation in the rat on brain development,
      conditioned behavior, and neurotransmission.
AB  - There is substantial evidence that early life events influence brain development
      and subsequent adult behavior and play an important role in the causation of
      certain psychiatric disorders including schizophrenia and depression. The
      underlying mechanism of the effects of these early environmental factors is still
      not understood. It is a challenge to attempt to model early environmental factors
      in animals to gain understanding of the basic mechanisms that underlie the long
      term effects. This paper reviews the effects of rearing rats from weaning in
      social isolation and reports some recent results indicating hippocampal
      dysfunction. Isolation rearing in rats from weaning produces a range of
      persistent behavioral changes in the young adult, including hyperactivity in
      response to novelty and amphetamine and altered responses to conditioning. These
      are associated with alterations in the central aminergic neurotransmitter
      functions in the mesolimbic areas and other brain regions. Isolation-reared rats
      have enhanced presynaptic dopamine (DA) and 5-HT function in the nucleus
      accumbens (NAC) associated with decreased presynaptic 5-HT function in the
      frontal cortex and hippocampus. Isolation-reared rats have reduced presynaptic
      noradrenergic function in the hippocampus, but have enhanced presynaptic DA
      function in the amygdala. These neurochemical imbalances may contribute to the
      exaggerated response of the isolated rat to a novel stimulus or to stimuli
      predictive of danger, and isolation-induced behavioral changes. These changes
      have neuroanatomical correlates, changes which seem to parallel to a certain
      degree those seen in human schizophrenia. A greater understanding of the
      processes that underlie these changes should improve our knowledge of how
      environmental events may alter brain development and function, and play a role in
      the development of neuropsychiatric disorders.

PMID- 12617302
TI  - Formation of AP-1 transcription factors during learning in Helix.
AB  - Gel shift assays were used to study the formation of transcription factors of the
      AP-1 family in the CNS of Helix during the acquisition of a conditioned defensive
      reflex based on food aversion. Increases in the DNA-binding activity of AP-1
      factors were seen 1-3 h after training. Modeling of "learning" in an in situ
      system (incubation of the CNS in the presence of serotonin and the Ca2+ ionophore
      A23187 or the protein kinase C activator phorbol ester (TPA)) also increased the
      DNA-binding activity of this transcription complex. The DNA-binding activity
      induced by serotonin acting alone was significantly less than that in controls,
      while that in the presence of A23187 and TPA was the same as or less than that in
      controls. The calcium/calmodulin-dependent protein kinase inhibitor KN62 produced
      significant suppression of the effects of simultaneous exposure to serotonin and
      calcium on the activation of transcription factors of the AP-1, while greater
      suppression was obtained with the mitogen-activated protein kinase (ERK)
      inhibitor PD98059. Cooperative induction of the activation of AP-1 transcription
      factors in the CNS of the common snail by the serotonin-induced and calcium
      dependent regulatory systems may be a mechanism underlying the formation of
      conditioned defensive reflexes in these animals. Lesions of the formation of
      transcription factors of the AP-1 family in animals unable to learn defensive
      forms of behavioral plasticity may be explained in terms of the presence of
      inhibitory forms of transcription factors interacting with the SRE element.

PMID- 12617303
TI  - Studies of the Rf = 0.58 protein in common snail command neurons during learning.
AB  - Levels of the acidic brain-specific Rf = 0.58 protein in neurons of the
      subglottal complex of ganglia were studied in the common snail during the process
      of acquisition of defensive food aversion. Levels were significantly increased in
      neurons LPa3 and RPa3 at both the early and late stages of learning. There was a
      tendency to increased protein levels in neurons LP11 and RP12, while there were
      no changes in levels in neuron RPa5 and pool D. The level of involvement of
      defensive behavior command neurons appears to be determined by the specific
      involvement of their receptor and effector fields.

PMID- 12617305
TI  - The ability of Drosophila mutants with defects in the central complex and
      mushroom bodies to learn and form memories.
AB  - One of the most important questions in the genetics of behavior is that of
      studies of the mechanisms of learning and memory. A convenient system for this is
      provided by Drosophila melanogaster, in which a whole series of mutations
      affecting the formation of different types of memory and learning have been
      obtained. The brain formations involved in these processes have been studied in
      parallel. Attention is currently focused on two main structures: the central
      complex and the mushroom bodies. These mediate the integration and storage of
      information accumulating during the process of learning. Mutants with defects in
      individual parts of the central complex and mushroom bodies have been obtained.
      Mutants simultaneously affecting the operation, development, or structure of the
      central part of the cerebral neural ganglion and the ability to learn and form
      memory traces are of particular interest. We have evaluated the learning ability
      of mutants with defects in the central complex (cexKS181 and ccbKS127) and
      mutants with defects in the mushroom bodies (mud1, mbm1, and cxbN71), using a
      method based on the conditioned reflex suppression of courtship. Memory defects
      were seen in cexKS181 and mud1 mutants.

PMID- 12617304
TI  - The role of central parts of the brain in the control of sound production during
      courtship in Drosophila melanogaster.
AB  - The question of the roles of the two main parts of the insect brain, the mushroom
      bodies and the central complex, in controlling motor coordination and triggering
      a variety of behavioral programs, including sound production, remains
      controversial. With the aim of improving our understanding of this question, we
      studied the parameters of songs used by five-day-old males during courtship for
      fertilized wild-type females (Canton-S, C-S) over 5-min periods at 25 degrees C;
      males were of two wild-type Drosophila melanogaster lines (Berlin and C-S).
      Berlin males lacking mushroom bodies because of treatment with hydroxyurea during
      development (chemical removal of the mushroom bodies) were used, along with two
      mutants with defects in the mushroom bodies (mbm1 and mud1), two mutants with
      defects in the central complex (ccbKS127 and cexKS181), and mutant cxbN71 with
      defects in both the mushroom bodies and the central complex. The experiments
      reported here showed that courtship songs in males lacking mushroom bodies were
      virtually identical to those of wild-type males. The main parameters of pulsatile
      song in mutants mbm1 and mud1 (interpulse interval and train duration) were
      insignificantly different from those of the songs of wild-type flies, though the
      stability of the pulse oscillator was the same. Flies of these lines were no
      different from wild-type flies in terms of courtship success (percentage of
      copulating pairs in 10-min tests). Conversely, the songs of mutants with defects
      in the central complex differed from those of wild-type males. Firstly, there was
      degradation of the stability of the pulse oscillator and interpulse intervals
      were very variable. In addition, pulses were often significantly longer and
      appeared multicyclic, as in the well-known cacophony mutant, while the mean train
      duration was significantly shorter. Males of the line cexKS181 usually courted
      very intensely, though abnormal sounds were generally emitted. Mutants cexKS181
      and ccbKS127 were significantly less successful in courtship than wild-type
      flies. These data show that the central complex appears to play a very important
      role in controlling song, while the mushroom bodies are not related to this
      function.

PMID- 12617306
TI  - Comparative studies of four Drosophila P-insertion mutants with memory defects.
AB  - Studies of conditioned reflex courtship suppression in mutant Drosophila males in
      two tests--a memory retention test (with a virgin female) and a repeat training
      test (with a fertilized female)--yielded experimental support for a previously
      suggested physiological model of the acquisition of this reflex. Mutations
      altered both types of conditioned association suggested in the model, i.e., the
      association between the conditioned and unconditioned stimuli (lat, rut, dnc,
      amn, and P153) and the association between the conditioned stimulus and the
      aversive motivational system mediating the action of the unconditioned stimulus
      (P171). A third category of mutants appeared to have a disturbance to the
      function of the aversive motivational system (P95 and P124).

PMID- 12617307
TI  - Expression of early genes in the rat brain after administration of corticoliberin
      into the neostriatum.
AB  - In situ hybridization using oligonucleotide probes was used to study the effects
      of intrastriatal microinjection of corticoliberin on the expression of the early
      genes c-fos, jun B, c-jun, and NGFIA in the rat brain. Administration of
      corticoliberin (0.25 microg) into the neostriatum induced the expression of mRNA
      encoded by the early genes c-fos, jun B, and NGFIA in both the neostriatum itself
      and in its efferent structures, particularly the nucleus accumbens and various
      parts of the cortex. Intrastriatal microinjection of corticoliberin had no effect
      on the expression of mRNA for the oncogene c-jun in the brain. These results
      suggest that neuronal activation in the neostriatum and its projection targets
      manifest as the expression of early genes is one of the mechanisms underlying the
      adaptive effects of corticoliberin in stress.

PMID- 12617308
TI  - The neurite-stimulating influence of components of medicinal leech salivary gland
      secretions in organotypic culture of spinal ganglia.
AB  - The effects of components from medicinal leech (Hirudo medicinalis) salivary
      gland secretions and the therapeutic agent Piyavit on the growth of chick embryo
      neurites in organotypic culture were studied. Native destabilase and bdellin A at
      concentrations of 0.01, 0.02, 0.05, and 0.1 ng/ml, bdellin B at a concentration
      of 0.05 ng/ml, and eglin at a concentration of 0.1 ng/ml had neurite-stimulating
      activity, evident on the third day of organotypic culture of spinal ganglia. The
      stimulatory activity of destabilase was lost after revere-phase chromatography.
      The neurite-stimulating activity of the extract of the therapeutic agent Piyavit
      (200 ng/ml) in organotypic ganglion culture appeared to result from the neurite
      stimulating salivary gland components within this agent, suggesting that Piyavit
      could be used for the treatment of neurodegenerative disorders.

PMID- 12617311
TI  - Effects of Hg and Cu on hemocytes-mediated functions in the prawn, Macrobrachium
      malcolmsonii.
AB  - Sublethal effects of Hg (9.6, 14.5 and 24.1 microg/l) and Cu (60.5, 90.8 and
      150.5 microg/l) on the hemocytes-mediated functions in the juveniles of the
      economically important freshwater prawns, Macrobrachium malcolmsonii were
      investigated. The population of total hemocytes, percentile phagocytosis and
      superoxide anion production were found to be increased in test prawns exposed to
      the lowest sublethal concentration of these two metals in comparison to controls.
      This indicates the fact that a mechanism of host-defence was in an active state
      to encounter metal toxicity. The total hemocytes population, percentile
      phagocytosis and superoxide anion production were found to be decreased in test
      prawns exposed to intermediate as well as the highest sublethal concentrations of
      Hg and Cu when compared with controls. This suggests that high concentrations of
      both Hg and Cu have inhibitory effects on the immune functions of the hemocytes
      in the prawn, M. malcolmsonii.

PMID- 12617310
TI  - Effect of trichloroethylene (TCE) inhalation on biotransformation enzymes of rat
      lung and liver.
AB  - Trichloroethylene (TCE) is widely used as an industrial solvent and cleaning
      fluid. In the present study the toxic effects of TCE inhalation on pulmonary and
      hepatic biotransformation enzymes in rats have been investigated by assay of
      aniline hydroxylase (AH), aminopyrine-N-demethylase (APD), benzo-a-pyrene
      hydroxylase (BH) and glutathione-s-transferase (GST) activities and glutathione
      (GSH) contents in liver as well as lungs of exposed animals. In both organs phase
      I and phase II drug metabolizing enzymes have been found to be increased along
      with decrease in GSH contents following TCE inhalation. Pulmonary as well as
      hepatic MFO's seem to be activated by inhaled TCE probably in an attempt for its
      rapid detoxification and reduced glutathione is used during its
      biotransformation.

PMID- 12617312
TI  - Evaluation of the pesticidal potential of the congress grass, Parthenium
      hysterophorus Linn. on the mustard aphid, Lipaphis erysimi (Kalt.).
AB  - Petroleum ether extracts of leaves, stem and inflorescence of Parthenium
      hysterophorus Linn. at 500, 1000, 2000 and 5000 ppm concentrations were tested in
      the laboratory for their toxic effects on the mean life span and progeny
      production of adults of the mustard aphid, Lipaphis erysimi (Kalt.). The
      investigations revealed a significant decrease in life span and progeny
      production with treatment. Among the three plant parts tested for their efficacy,
      the leaf extract showed the most significant effect in causing a dose dependent
      decline in both the life span and progeny production.

PMID- 12617309
TI  - Components of the intracellular cAMP system supporting the olfactory reception of
      amyl alcohol.
AB  - Experiments on isolated frog olfactory epithelium, using vital luminescent
      microscopy showed that the olfactory transduction of amyl alcohol is mediated by
      the intracellular cAMP signaling system. Increases in intracellular cAMP levels
      resulted from activation of adenylate cyclase type III via odorant-induced
      stimulation of G protein linked to it.

PMID- 12617313
TI  - Effect of weed extracts on seedling growth of some varieties of wheat.
AB  - Allelopathic effect ofAvena fatua L., Cyperus rotundus L., Polygonum hydropiper
      L., and Solanum nigrum L. were examined on seedling growth of certain commonly
      used varieties of wheat (Triticum aestivum L.) in the Tarai region of U.P. state.
      The weed extracts inhibited the length of plumule in all the varieties (100%)
      with Solanum and it was in 12 (92%), 10 (77%) and 06 (46%) varieties with
      Polygonum, Avena and Cyperus, respectively. In radicle length, it was in 92% with
      both Polygonum and Solanum; and 85% and 69% of the varieties with Avena and
      Cyperus, respectively. However, all the four weed extracts reduced the dry weight
      of plumule, radicle and total seedling in all the varieties (100%) of wheat
      except in HD--2329 with Cyperus, in which it was positive. The percent reduction
      (percentage of control) was more than 50% in 92%, 77%, 54% and 39% of the
      varieties, respectively with Solanum, Polygonum, Avena and Cyperus. Among the
      weed extracts, the inhibitory effect on seedling growth in different varieties
      followed the order: Solanum > Polygonum > Avena and > Cyperus. On the basis of
      the present results, UP--2003 and WH--542 followed by PBW--226, Sangam and HD-
      248 were more susceptible to all the four weed extracts compared to the rest of
      the varieties of wheat.

PMID- 12617314
TI  - Lead exposure: health effects, prevention and treatment.
AB  - This article focuses on the risk to human health associated with exposure to
      lead. Various human health effects associated with lead are discussed--based
      human and experimental data. Another important information provided in the
      article is regarding recent developments in the area of treatment i.e. chelation
      therapy against lead poisoning. Emphasis has been given to data, which have
      become available in the last decade.

PMID- 12617315
TI  - Effect of FSH and LH on testis during nonbreeding season in Calotes versicolor
      (Daud.).
AB  - Histological and biochemical studies carried out on the male reproductive organs
      of the Indian garden lizard, Calotes versicolor after the treatment with
      pituitary gonadotrophins (FSH and LH), showed a significant increase in the
      weight, protein content and diameter of testis, but decrease in its cholesterol.
      The spermatogonia, spermatocytes and spermatids increased significantly in the
      germinal epithelium of seminiferous tubule, and spermatozoa appeared in its
      lumen. The Leydig and Sertoli cells were hypertrophied with increase in their
      nuclear diameter. The epidymal weight, diameter and protein content also
      increased after gonadotrophins treatment. There was a significant decrease in the
      testicular cholesterol indicating the utilization of cholesterol for steroid
      hormone synthesis. The combined gonadotrophin (FSH + LH) treatment was more
      effective than the individual gonadotrophin treatment.

PMID- 12617316
TI  - Season-dependent mineral accumulation in fruits of Okra (Abelmoschus esculentus)
      and Tomato (Lycopersicon esculentum).
AB  - Season-dependent mineral accumulation was recorded in fruits of Okra and Tomato.
      The highest concentration was in summer in Okra and in winter in Tomato. Lowest
      concentrations were in winter in Okra and rainy in Tomato. Both crop plants
      indicated that the mineral contents were in the order of P > K > Ca > Mg > Na >
      Fe which also signify their relative functional importance in growth and
      metabolism.

PMID- 12617317
TI  - Environmental impact of noise levels in and around opencast bauxite mine.
AB  - Until recently, noise pollution has not been paid adequate attention as air,
      water and land pollution. In order to assess (predict) the impact of bauxite mine
      noise on employees health and in and around bauxite mine environment, general
      noise sources and equipment noise were monitored. All these noise sources were
      compared with prescribed standard noise levels laid down by Central Pollution
      Control Board (CPCB). Data has also been compared with reference site, north
      block hill top which is barren and virgin plateau/top covered with grass only and
      free from human interference. Equipment noise levels were much higher than the
      other zone of the mine which does not have the corresponding standards. Rock
      breaker recorded the highest noise level with 73.1 +/- 14.2 to 89.5 +/- 10.1 dB
      (A) while from ripper dozer it was least with 61.0 +/- 17.3 to 76.2 +/- 6.2 dB
      (A). Meteorological parameters did not have much influence upon equipment noise
      up to 100 feet from the source.

PMID- 12617318
TI  - Uptake of nickel (II) by Serratia marcescens.
AB  - Bioaccumulation and biosorption of various nickel salts by Serratia marcescens
      (NCIM 2078) were investigated Biosorption of nickel was found maximum for the
      nickel nitrate and nickel chloride as 28.08 and 25.51 mg-1 nickel was obtained in
      dry biomass of S. marcescens, respectively. The possible role of pigment
      prodigiosin in uptake of nickel is discussed.

PMID- 12617319
TI  - Effect of mercury and methyl parathion on the ovaries of Labeo rohita (Ham).
AB  - Adult pre-spawning fish Labeo rohita were sublethally (1/5th 96h LC50) exposed to
      mercuric chloride and metacid-50 (methyl parathion). Accumulation of mercury and
      methyl parathion was studied and it was found that pre-spawning ovary appears as
      a potent organ for deposition of both the pollutants. RNA/DNA ratio of the
      control and treated fish were studied. It was found that the signifcant decrease
      in RNA/DNA ratio occurs after 9 and 30 days of exposure for mercury and 30 days
      for methyl parathion. Fluorescence microscopic studies by acridine orange
      staining method were also performed to show how much it is related to biochemical
      alterations. In some cases loss of metachromasia is correlated with the fall in
      RNA/DNA ratio. Some other abnormalities like fall in stage II: stage I oocyte
      ratio and necrosis was also observed.

PMID- 12617320
TI  - Effect of harvesting operations on fungal spore populations of air.
AB  - Agricultural practices such as harvesting of crops cause the pathogens to
      disseminate in abundance and may cause diseases, like skin and respiratory
      allergies in an epidemic form. Also the farm workers were likely to be exposed
      repeatedly to high doses of fungal spore allergens from crop harvesting
      operations. At Srikakulam, located in North Coastal Andhra Pradesh, India, the
      major crops grown include rice and sugarcane. As part of a major study on the
      airspora of Srikakulam the effect of harvesting of these two crops on aerial
      spore concentrations was studied through rotorod trappings. The results showed an
      enormous increase in the spore load not only of the fungi pathogenic to the crop
      but also saprophytic fungi while the crop was harvested. The increase in the
      pathogenic fungal spores was large as evidenced by the increase of the rice crop
      pathogens as Trichoconis padwickii, Ustilaginoidea virens, Cochilobolus oryzae
      etc.

PMID- 12617321
TI  - Minimum effective release rate of antifoulants. 2. Effects of TBTCI, 2-furyl-n
      pentyl ketone and coumaric acid at Snug harbor, Hawaii.
AB  - Minimum effective release rate (MERR) of three antifoulants was examined at Snug
      harbor, Hawaii using a dynamic diffusion system. Among the three antifoulants
      tested TBTCI was found to be effective in preventing the settlement of Hydroides
      elegans and Crisea sp at 0.5 microg cm(-2) d(-1) flux rate. At a maximum flux
      rate of 10 microg cm(-2) d(-1) of 2-furyl-n-pentyl ketone larval settlement of
      both the test species were 32-36% reduced. More or less similar effect was seen
      at 10 microg cm(-2) d(-1) of coumaric acid. Non-toxic antifoulants, 2-furyl-n
      pentyl ketone and coumaric acid exhibit specific activity against target species.
      MERR obtainedfor the three antifoulants is discussed.

PMID- 12617322
TI  - Distillery effluent effect on seed germination, early seedling growth and pigment
      content of sugarbeet (Beta vulgaris Linn. var. mezzanau-poly).
AB  - Bioassay studies were carried out to assess the toxicity of distillery effluent
      on seed germination, seedling growth and pigment contents. Higher concentrations
      (> 5%) of effluent were found to be toxic but however, can be used for
      irrigational purpose after proper dilution.

PMID- 12617323
TI  - Implications of fluoride--an endless uncertainty.
AB  - Fluorosis has become pandemic and it has assumed global status in the public
      health point of view. The paper deals with the health issues pertaining to
      fluorosis with special emphasis in the Indian context. It explains the equivocal
      evidences of fluoride-related problems and discusses the control measures of
      fluorosis. In general, it reveals how fluoride is useful at very low
      concentrations and at the same time brings forth manifestation of clinical
      abnormalities at higher concentrations that are the basis of the principles of
      toxicology.

PMID- 12617324
TI  - A comparative study of effects of cigarette and bidi smoking on respiratory
      function tests.
AB  - The effects of cigarette and bidi smoking on pulmonary function tests have been
      studied in 90 healthy males from North India Forced vital capacity (FVC), peak
      expiratory flow rate (PEFR), forced expiratory volume in 1 sec (FEV) were
      determined in 30 nonsmokers (as control group), 30 cigarette smokers and 30 bidi
      smokers. All the above pulmonary function parameters were found to be lower among
      smokers as compared to nonsmokers. Moreover, the decrease in the pulmonary
      function tests was greater in cigarette smokers as compared to bidi smokers.

PMID- 12617325
TI  - Physico-chemical characteristics of breeding habitats of Anopheles dirus
      (Diptera:Culicidae) in Assam, India.
AB  - Larval ecology of Anopheles dirus, the main vector of forest malaria in north
      eastern region of India, was studied in relation to physico-chemical
      characteristics of its breeding habitats in a rain forest area of Assam, India.
      Shady stream side pools, positive for the breeding of An. dirus, had
      significantly higher amounts of total hardness (P < 0.024) in comparison to
      negative pools of similar type. When compared with An. dirus negative breeding
      habitats, in hot-wet as well as in cool-dry seasons, An. dirus positive shady
      ground pools showed higher mean values of total alkalinity, hardness and chloride
      content, whereas lower pH, dissolved oxygen along with higher total alkalinity
      and hardness were possessed by An. dirus positive stream side pools. Specificity
      of breeding habitats of An. dirus in relation to its ecology has been discussed.

PMID- 12617326
TI  - Haematotoxic effect of linear alkyl benzene sulphonate (LAS) in fish,
      Heteropneustes fossilis.
AB  - It was observed that clotting time decreased with the increased concentrations of
      LAS. However, the decrease was more pronounced at LC50 for 24 h and at the end of
      96 h LC50, it was very close to control values.

PMID- 12617327
TI  - Effects of gentamicin on mouse immortalized mesangial cells (MIMC).

PMID- 12617328
TI  - Effects of Helichrysum ceres extracts on renal function and blood pressure in the
      rat.
AB  - OBJECTIVE: To evaluate the effects of Helicrysum ceres root and leaf extracts on
      mean arterial blood pressure and renal fluid and electrolyte handling in
      anesthetized male Sprague-Dawley rats. DESIGN: Cross sectional study. SETTING:
      Departments of Physiology and Pharmacy, University of Zimbabwe. SUBJECTS: Eight
      separate groups comprising of control and treated Male Sprague-Dawley rats (n =6
      in each group) were anesthetized and placed on a continuous jugular infusion of
      0.077 M NaCl at 150 microL min(-1). The left carotid artery was cannulated with
      polythene tubing and then connected to a pressure transducer for blood pressure
      measurements. After 3 h equilibration period, consecutive 20 min urine
      collections and blood pressure measurements were made over the subsequent 4 h of
      1 h 20 min control, 1 h treatment and I h 40 min post-equilibration periods for
      measurements of urine flow and Na+ and K+ excretion rates. Helichrysum ceres leaf
      extracts at 0.3, 0.6 and 1.2 microg min(-1) roots 0.3, 3 and 6 microg min(-1)
      were added to the infusate during the treatment period. To establish whether the
      extracts had activities comparable to drugs already in use, a separate group of
      animals was administered furosemide (0.12 microg min(-1)) during the treatment
      period. MAIN OUTCOME MEASURES: Hypotension, Natriuresis and Diuresis. RESULTS:
      Infusion of graded doses of aqueous leaf extracts of Helicrysum ceres provoked an
      increase in urine flow rates but did not achieve statistical significance.
      However, the extracts produced dose dependent decrease in potassium excretion as
      well as increases in urinary Na+ outputs and diuresis. Administration of the
      various doses of aqueous root extracts of Helicrysum ceres significantly
      increased urine flow rate and urinary Na+ excretion in all groups. The
      intravenous (i.v.) administration of the aqueous root or leaf extracts of
      Helichrysum ceres significantly depressed mean arterial blood pressure (MAP). The
      diuretic and natriuretic effects of plant extracts were not significantly
      different to that of furosemide. CONCLUSION: The results suggest that oral
      administration to rats of aqueous crude Helicrysum ceres root or leaves extracts
      induce hypotension and natriuresis.

PMID- 12617329
TI  - The effect of treatment with gum Arabic on gentamicin nephrotoxicity in rats: a
      preliminary study.
AB  - In the present work we assessed the effect of treatment of rats with gum Arabic
      on acute renal failure induced by gentamicin (GM) nephrotoxicity. Rats were
      treated with the vehicle (2 mL/kg of distilled water and 5% w/v cellulose, 10
      days), gum Arabic (2 mL/kg of a 10% w/v aqueous suspension of gum Arabic powder,
      orally for 10 days), or gum Arabic concomitantly with GM (80mg/kg/day
      intramuscularly, during the last six days of the treatment period).
      Nephrotoxicity was assessed by measuring the concentrations of creatinine and
      urea in the plasma and reduced glutathione (GSH) in the kidney cortex, and by
      light microscopic examination of kidney sections. The results indicated that
      concomitant treatment with gum Arabic and GM significantly increased creatinine
      and urea by about 183 and 239%, respectively (compared to 432 and 346%,
      respectively, in rats treated with cellulose and GM), and decreased that of
      cortical GSH by 21% (compared to 27% in the cellulose plus GM group) The GM
      induced proximal tubular necrosis appeared to be slightly less severe in rats
      given GM together with gum Arabic than in those given GM and cellulose. It could
      be inferred that gum Arabic treatment has induced a modest amelioration of some
      of the histological and biochemical indices of GM nephrotoxicity. Further work is
      warranted on the effect of the treatments on renal functional aspects in models
      of chronic renal failure, and on the mechanism(s) involved.

PMID- 12617330
TI  - Thrombotic thrombocytopenic purpura (TTP): initial treatment with plasma exchange
      plus steroids and immunosuppressive agents for relapsing cases.
AB  - BACKGROUND: The thrombotic thrombocytopenic purpura (TTP) is a rare disorder with
      a high mortality rate if untreated or delayed therapy. Whether immediate
      diagnosis and promptly treated with plasma exchange can change the grave
      prognosis? METHOD: Retrospective analysis was performed on clinical
      characteristics and treatment outcome of 13 patients diagnosed and treated during
      a 6-year period, from August 1994 to August 2000, in a tertiary care university
      hospital in Taiwan. RESULTS: Among the patients, 8 were males and 5 were females,
      10 were idiopathic, 2 were ticlopidine, and 1 was SLE-induced; 12 (92.3%) had
      neurological abnormalities, 11 (84.6%) had ecchymosis, 8 (61.5%) had fever, and 6
      (46.2%) had renal impairment (creatinine > or = 1.5 mg/dL) at initial
      presentation of the syndrome. Excluding the SLE patient, 6 of 10 (60%) had shown
      antinuclear antibody (ANA) non-specific positive (titer > or = 1:40). All
      patients were initially treated with plasma exchange plus steroids. Of these 13
      patients, 11 (84.6%) achieved complete remission, one had partial remission, and
      one, which was ticlopidine-induced, had no response and died of a progressive
      disease complicated with pneumonia. Within a median follow-up period of 31
      months, 4 of 11 patients who achieved complete remission relapsed after one week,
      two weeks, three weeks, and three months, respectively. In the four relapsing
      patients, three late relapsing patients received FFP infusion, increased steroid
      dosages, added cyclophosphamide plus vincristine; and one early relapsing
      patient, relapsing twice, received an additional two courses of plasma exchange
      and added cyclophosphamide plus vincristine. All of the four patients achieved
      complete remission again. The patient who had partial remission relapsed early
      and responded promptly to another course of plasma exchange plus cyclophosphamide
      and vincristine and achieved complete remission. CONCLUSION: Based on the results
      in this study, we conclude that plasma exchange plus steroids can effectively
      treat TTP. For patients with a refractory or relapsing disease, immunosuppressive
      therapy with cyclophosphamide plus vincristine should be administered as well.

PMID- 12617332
TI  - Influence of fluid volume variations on the calculated value of the left
      ventricular mass measured by echocardiogram in patients submitted to
      hemodialysis.
AB  - The left ventricular mass (LVM) measurement is of major importance for renal
      patients, as ventricular hypertrophy is an important prognostic index. The
      echocardiogram of the ventricular mass is larger before than it is after
      hemodialysis, which can confuse data interpretation. The aim of this work is to
      study the influence of alterations in fluid volume on the variations in
      measurements of ventricular mass observed during the course of a hemodialysis.
      Sixteen patients with chronic renal insufficiency in hemodialysis were evaluated
      at the Dialysis Unit of the University Hospital-UNESP, Botucatu, Sao Paulo State.
      The left ventricular mass was calculated from echocardiograms taken before and
      after hemodialysis and simultaneous ultra-filtration (12 patients: UF GROUP) and
      before and after hemodialysis isovolemic phase with sequential ultra-filtration
      (10 patients: ISO GROUP). Six of these patients were submitted to measurements of
      left ventricular mass before and after hemodialysis in both isovolemic and
      simultaneous ultra-filtration procedures. In the UF group, there was significant
      reduction in the following parameters before and after dialysis: diastolic
      diameter from 54.0 +/- 6.0mm to 45.6 +/- 7.6mm; left ventricular mass from 342 +/
      114 g to 265 +/- 117 g; and its respective index (IMVE) from 214 +/- 68 g/m2 to
      168 +/- 71 g/m2. The ISO group showed no statistically significant variation. The
      behavior of the variables of six patients submitted to both observations confirm
      these results. In conclusion, the variations in echocardiogram measurements of
      the left ventricula mass relating to hemodialysis appear to be induced by
      alterations of the volemic condition.

PMID- 12617333
TI  - Relationship between elevated serum troponin values in end-stage renal disease
      patients and abnormal isotopic cardiac scans following stress.
AB  - One hundred asymptomatic high-risk renal transplant candidates were screened for
      asymptomatic coronary artery disease using stress cardiac isotopic imaging. The
      cardiac markers, serum cTnT, cTnI, and CKMB, were collected pre and post stress
      testing. Of the 99 patients whose cardiac scans were technically satisfactory, 32
      were normal, 49 had a definite imaging abnormality and the scan was indeterminate
      in the remaining 18 patients. Based on these results, patients were stratified
      into either normal, indeterminate or abnormal scan groups. They then were
      analyzed to detect any correlations between cardiac perfusion defects and either
      elevated pre-stress cardiac markers or consistent changes 24h after stress
      testing. While the mean pre-stress serum values for both cardiac troponin T
      (0.117 +/- 0.12 microgram/L) and cardiac troponin I (0.235 +/- 0.89 microgram/L)
      were increased in the abnormal cardiac scan group, only the cTnT value proved to
      differ significantly from the normal group (p < 0.01). For the indeterminate
      group neither marker was different from the normal scan group. Only an elevated
      serum cTnT > 0.1 microgram/L (OR 3.042, p = 0.030) proved to discriminate an
      abnormal scan in this population. It is concluded that the increase in pre-stress
      serum cTnT encountered in patients with chronic renal failure, with or without
      evidence of overt, symptomatic coronary artery disease, may represent a
      combination of subclinical myocardial damage and a prolonged half-life of the
      marker in the serum. Because of the frequency of elevated serum concentrations of
      cTnT and, to a lesser degree cTnI, the physician should exercise caution when
      interpreting a single elevated Troponin value during the evaluation of chest pain
      in patients with end-stage renal disease. A cTnT > 0.1 microgram/L increases the
      likelihood of finding significant coronary artery disease three fold in high-risk
      ESRD patients being evaluated for renal transplantation.

PMID- 12617331
TI  - Echography of left ventricular end-diastolic diameter as a reliable tool for
      estimating "dry weight" in hemodialysis patients.
AB  - PURPOSE: It is hard to decide an accurate value for the so-called dry weight (DW)
      in hemodialysis patients with cardiac disease. Our objective is to evaluate the
      efficacy of echocardiography to decide DW. PATIENTS AND METHODS: 115 patients on
      hemodialysis were divided into 2 groups: the cardiac disease group and non
      cardiac disease group. The relationship between atrial natriuretic peptide (ANP)
      and left ventricular end-diastolic diameter (LVDd) measured by echocardiography
      was examined. RESULTS: There was a significant positive relationship between ANP
      and LVDd in the noncardiac disease group, but no significant relationship was
      noted in the cardiac disease group. The DW was re-evaluated and transferred into
      more suitable criteria for the patients who often became unconscious with
      decreased blood pressure during dialysis. When LVDd slightly increased beyond the
      new criteria of dry weight, unconsciousness was disappeared and blood pressure
      became stable. CONCLUSIONS: Echocardiography examination is very beneficial for
      screening to determine DW for the patients with cardiac disease.

PMID- 12617334
TI  - Molecular investigation of GB virus C RNA in hemodialysis and thalassemics
      patients from Brazil.
AB  - The GB virus C (GBV-C)/hepatitis G virus (HGV) is a member of the Flaviviridae
      family. Based on the clinical and epidemiological profiles, this virus could be
      acquired mainly by parenteral transmission through contaminated blood. We
      therefore investigated the presence of GBV-C/HGV and its relation with the other
      blood borne viruses as hepatitis B and C viruses (HBV, HCV) in hemodialysis and
      thalassemic individuals and blood donors from Ribeirao Preto-Brazil. Detection of
      blood borne virus markers including HBV surface antigen (HbsAg), HBV core
      antibody (anti-Hbc) and HCV antibody was carried out. HIV-1, HIV-2, HTLV-1 and
      HTLV-2 were also investigated. GBV-C/HGV RNA was detected by reverse
      transcriptase and polymerase chain reaction (RT-PCR). Ninety-four serum samples
      from patients with chronic renal failure were analyzed. GBV-C/HGV RNA was
      identified in 12 (12.8%) patients, anti-HCV antibodies in 28 (29.8%), anti-Hbc in
      9 (9.6%), anti-HIV in 1 (1%), HBsAg in 33 (35.1%), and HBsAg/ anti-HBc was
      observed in 2 (2.1%) patients. Thirty-six (38.3%) samples were non-reactive.
      Seven of the 12 GBV-C/HGV RNA infected samples were co-infected with other
      viruses: 3 (25%) with HBsAg, 2 (16.7%) with anti-HCV and 2 (16.7%) with anti
      HBc/anti-HCV/HBsAg. Among the 42 thalassemic patients GBV-C/HGV RNA was detected
      in 6/42 patients (14.2 %). Three patients presented GBV-C/HGV, with other blood
      borne markers. We also detected GBV-C/ HGV in 6/50 (12%) blood donors. In these
      GBV-C/HGV positive thalassemics patients, 50% (3/6) were young individuals
      (lesser 15 years old) and 67% (4/6) were female patients. The presence of GBV-C
      RNA in the absence of hepatitis B and C infection in the young patients and
      healthy donors could be indicate that this virus is capable of independent
      transmission and does not contribute to liver disease.

PMID- 12617336
TI  - Analysis of mutations in alpha-actinin 4 and podocin genes of patients with
      chronic renal failure due to sporadic focal segmental glomerulosclerosis.
AB  - Although the pathogenesis of idiopathic focal segmental glomerulosclerosis (FSGS)
      may be heterogeneous, autosomal dominant and recessive forms of FSGS are
      recognized. Recently, mutations in alpha-actinin 4 (ACTN4) and podocin genes were
      reported in patients with such familial FSGS. However, whether mutations in ACTN4
      and podocin genes are associated with sporadic FSGS has not been determined. In
      the present study, we clarified the relation between mutations in ACTN4 and
      podocin genes and sporadic FSGS. We analyzed these reported mutations in ACTN4
      and podocin in five patients with chronic renal failure due to therapy-resistant
      FSGS by direct sequencing of polymerase chain reaction products of ACTN4 and
      podocin. We found a C to T transition at nucleotide 465 in the ACTN4 gene in all
      of patients, and a T to C transition at nucleotide 954 in exon eight of podocin
      gene in two of five patients, resulting in no amino acid substitutions. Other
      mutations were not found in ACTN4 and podocin genes. Our findings suggest that
      sporadic FSGS is a heterogeneous disease, since ACTN4 and podocin genes are not
      found in our patients with sporadic FSGS.

PMID- 12617335
TI  - A prospective, randomized, open labeled crossover trial of fosinopril and
      theophylline in post renal transplant erythrocytosis.
AB  - Angiotensin converting enzyme inhibitors (ACEI) and theophylline have been
      reported to decrease the elevated hemoglobin (Hgb) and hematocrit (Hct) levels in
      the renal transplant recipients with erythrocytosis. We conducted a prospective
      randomized, open labeled, crossover trial with theophylline, and an ACEI,
      fosinopril in nine stable renal transplant recipients with erythrocytosis. Aim of
      the study was to determine and compare the efficacy of these medications in
      stable renal transplant patients. At three months, compared to baseline,
      fosinopril significantly reduced the elevated hemoglobin (Hgb 17.2 +/- 0.6 vs.
      14.9 +/- 1.4 gm/dL, p = 0.0023), and hematocrit levels (Hct 51.3 +/- 2.4 vs. 43.7
      +/- 4.6%, p = 0.003). In contrast theophylline therapy was associated with a non
      significant rise in hemoglobin (17.4 +/- 0.7 vs. 18.1 +/- 0.9gm/dL, p > 0.05) and
      hematocrit (52.4 +/- 2.7 vs. 54.7 +/- 3.9%, p > 0.05). With fosinopril compared
      to theophylline, there was a significant difference in the change in hemoglobin
      (baseline to three months 2.8 +/- 1.7 vs. -0.7 +/- 0.69 gm/dL respectively, p =
      0.017), and the change in hematocrit (baseline to three months 9 +/- 6 vs. -2.3
      +/- 2.7% respectively, p = 0.027). Four patients (44.4%) did not tolerate
      theophylline and did not complete the theophylline arm. To conclude, in our
      study, fosinopril effectively decreased the elevated hemoglobin and hematocrit in
      patients with post transplant erythrocytosis, and was superior to theophylline,
      while theophylline was ineffective and poorly tolerated in this condition.

PMID- 12617337
TI  - General or disease specific questionnaire? A comparative study in hemodialysis
      patients.
AB  - OBJECTIVE: Today questionnaires developed to assess important outcome measures
      such as health-related quality of life are widely used. In this study we
      evaluated the construct validity of the Nottingham Health Profile (NHP) and the
      reliability of its Turkish version in hemodialysis patients. METHODS: In a sample
      of patients on renal dialysis (n = 94) the quality of life is measured by the
      NHP. The validity of this questionnaire is evaluated by using the Kidney Disease
      Questionnaire (KDQ) in the same patient group. The NHP is administered twice to
      each patient, at dialysis intervals two weeks apart. RESULTS: NHP scores at both
      administrations are similar in both assessments. Pearson's correlation
      coefficients range from 0.61 to 0.84. Cronbach's alpha coefficients for the NHP
      sections range between 0.64 and 0.79. The alpha coefficients for three of the NHP
      scales (energy, sleep and social isolation) are well below 0.7. In the KDQ the
      mean values obtained for the five dimensions are: 4.2 +/- 1.5 for physical
      symptoms, 4.8 +/- 1.7 for fatigue, 4.9 +/- 1.9 for depression, 4.2 +/- 1.2 for
      relationship with others, and 4.8 +/- 1.5 for frustration. In general the
      correlation between the dimensions of the NHP and KDQ is good and the correlation
      coefficients varies from 0.18 to 0.73. Clinical validity is assessed by examining
      the correlation between the results obtained for the two questionnaires
      (components of the NHP and KDQ) and hemoglobin level, number of the co-morbid
      conditions and educational level. CONCLUSIONS: The NHP is shown to have construct
      validity when used in patients with end-stage renal disease (ESRD) in Turkey. The
      application of the NHP in patients with ESRD is easy, fast and the questions are
      not difficult to understand. The multiple-degree scoring in the KDQ causes a
      complexity in answering. The correlation between the dimensions of the NHP and
      KDQ is good. Our results show better correlations between disease specific
      questionnaires and clinical parameters.

PMID- 12617339
TI  - Relationship between serum N-carbamoyl-beta-D-glucopyranosylamine level and renal
      failure.
AB  - A statistical investigation was carried out on the distribution of serum N
      carbamoyl-beta-D-glucopyranosylamine (NCG) among various patient groups. The
      serum NCG levels of patients treated in the departments of hemodialysis (131 +/-
      microM), nephritic syndrome (47 +/- 54 microM), and diabetes mellitus (55 +/- 70
      microM) were significantly higher (p < 0.01) than those in other internal disease
      patients (18 +/- 22 microM) and healthy volunteers (6 +/- 22 microM). The serum
      NCG level was greatly reduced by hemodialysis therapy, however a return to
      initial NCG levels was observed within about one week. These results indicate
      that a high serum NCG level is a feature of renal failure patients, and a
      relationship was demonstrated between hyperuremia and NCG formation and
      accumulation in blood.

PMID- 12617338
TI  - Acute renal failure in medical and surgical intensive care units--a one year
      prospective study.
AB  - The spectrum of acute renal failure is different in intensive care unit (ICU) vs.
      non-ICU population. This one year prospective study carried out in medical and
      surgical intensive care units showed an incidence of 8.6% of acute renal failure.
      The incidence of acute renal failure was highest in medical ICU (17.2%) followed
      by burns ICU (5.3%), pulmonary ICU (5.2%), stroke ICU (4.4%), surgical ICU (3.1%)
      and least in coronary ICU (1.3%). The acute renal failure was attributable to
      medical causes in 68% followed by surgery and trauma in 21.2%, burns in 5.6% and
      pregnancy related in 5.1%. In majority, acute renal failure was multifactorial.
      Septicemia was the commonest cause in both medical (50%) and surgical (86%) ICUs.
      Multi organ system failure was present in 77.3% of patients with acute renal
      failure. Approximately 40% required dialysis. The mortality of acute renal
      failure was 62% and the mortality was correlated with the number of organ system
      failures, presence of oliguria and septicemia. The mean ICU stay was
      significantly shorter in the non-survivors.

PMID- 12617340
TI  - Serum cystatin C and beta2-microglobulin as markers of glomerular filtration
      rate.
AB  - Continuous efforts have been made to find out precise and simple method for
      determination of glomerular filtration rate (GFR). Cystatin C (cysteine
      proteinase inhibitor = CyC) is a low molecular weight (LMW) protein which is
      produced constantly by all nucleated cells independently of different
      pathological conditions and eliminated from the blood exclusively by glomeruli.
      So, CyC closely reflects the GFR. In the present study 75 patients aged between
      18 and 74 (44.3 +/- 12.2) years were analyzed, with the aim to compare the
      reciprocal values of serum level of LMW proteins CyC and beta2-microglobulin
      (beta2-MG) with creatinine clearance (Ccr) as a measure of GFR. Patients were
      divided into groups according to sex, age (<60; >60 years) and renal diseases:
      patients with glomerulonephritis (GN) with and without nephrotic proteinuria,
      pyelonephritis (PyN), and renal transplant (Tx). High correlation between Ccr and
      1/CyC (r = 0.81; p < 0.01) and Ccr and 1/beta2-MG (r = 0.80; p < 0.01) in all
      examined patients was found. There was significant correlation between Ccr and
      1/CyC (0.82 vs. 0.79) and Ccr and 1/beta2-MG (0.85 vs. 0.76) in men as well in
      women, and also in two groups of patients formed according to the age (0.82 vs.
      0.77; p < 0.01; 0.80 vs. 0.81; p < 0.01), without any statistical significant
      difference between the groups. In studied groups with different renal diseases,
      there were no differences in correlation coefficients between Ccr and 1/CyC and
      Ccr and 1/beta2-MG (p1 = 0.29; p2 = 0.21; p3 = 0.79; p4 = 0.43), without
      statistical differences between the groups, except significant difference in
      correlation coefficients for Ccr and 1/beta2-MG between patients with GN with and
      without nephrotic proteinuria (p < 0.032). LMW proteins, serum CyC and beta2-MG,
      are as good markers of GFR as Ccr, regardless sex and age. Both of these LMW
      proteins are good markers of GFR in patients with GN without nephrotic
      proteinuria, PyN and Tx patients. In patients with GN and nephrotic proteinuria
      serum CyC is a better marker of GFR than beta2-MG.

PMID- 12617341
TI  - Encephalopathy caused by isoniazid in a patient with end stage renal disease with
      extrapulmonary tuberculosis.
AB  - Tuberculosis infection is common in patients on maintenance hemodialysis, and the
      extrapulmonary presentations, which is usually asymptomatic, and only mild
      clinical presentation, are not uncommon. These hemodialysis patients were always
      prescribed multiple antituberculosis agents, including isoniazid, rifampin,
      ethambutol, and pyrazinamide, alongside their usual medication. Conscious
      disturbance was also frequently observed in these patients, with different
      paramount etiologies in the pre- and post-hemodialysis phases. We report a case
      undergoing maintenance hemodialysis, showing disturbed consciousness ten days
      following antituberculosis treatment for his established extrapulmonary
      tuberculosis infection. Consciousness was regained seven days later, after
      discontinuation of isoniazid.

PMID- 12617343
TI  - Extra-renal erythropoietin secretion after bilateral nephrectomy.
AB  - Serum concentrations of erythropoietin and soluble transferrin receptor were
      examined immediately after removal of the remaining kidney in a patient with a
      history of unilateral radical nephrectomy. Unexpectedly, the erythropoietin
      concentration increased from 18.2 U/L to 42.5 within 6 h after the operation.
      Soluble transferrin receptor (TfR) concentration rapidly decreased from 2,725
      microgram/L to 1,548 during the 12-h postoperative period. Extra-renal
      erythropoietin secretion could increase to more than twice as much as the renal
      secretion of erythropoietin immediately after the loss of renal tissue, and the
      rise in erythropoietin could accelerate the recycling of TfR, thus causing a
      decrease in its serum concentration.

PMID- 12617342
TI  - Acute rhabdomyolysis after gemfibrozil therapy in a pregnant patient complicated
      with acute pancreatitis and hypertriglycerdemia while receiving continuous veno
      venous hemofiltration therapy.
AB  - Gemfibrozil therapy alone can induce severe myopathy and rhabdomyolysis. This
      catastrophic complication had been frequently reported in renal failure patients.
      Dosage reduction is therefore compulsory in patients with compromised renal
      function, no matter which type of renal replacement therapy they receive. This
      study's patient clearly demonstrates that gemfibrozil can induce severe
      rhabdomyolysis, even in patients receiving CVVH, if the dosage is not properly
      adjusted.

PMID- 12617344
TI  - Sociocultural influences on body image and body changes among adolescent boys and
      girls.
AB  - In 2 studies, the authors evaluated the role of parents, peers, and the media in
      body image and body-change strategies among adolescent boys and girls. The
      respondents for Study 1 (423 boys and 377 girls) completed the Body Image and
      Body Change Inventory (L. A. Ricciardelli & M. P. McCabe, 2002) and the Perceived
      Sociocultural Influences on Body Image and Body Change Questionnaire (M. P.
      McCabe & L. A. Ricciardelli, 2001b). Body mass index and age were also included
      in the analyses. Regression analyses demonstrated that sociocultural influences
      and feedback from the participant's best male friend were important predictors
      for all body-change strategies among boys. For girls, sociocultural influences
      and feedback from the participant's best female friend and mother were important
      predictors for body-change strategies. The most consistent predictor of weight
      loss, weight gain, and strategies to increase muscles was body-image importance.
      In Study 2, the authors examined the influence of the same sociocultural
      variables, as well as negative affect and puberty on body image and body-change
      strategies among a second group of 199 boys and 267 girls. The results
      demonstrated that a broad range of sociocultural influences predicted body-change
      strategies for boys and girls, with negative affect also having a unique
      influence for boys but not for girls. Puberty played a minor role, once other
      sociocultural variables were entered into the regression equation. The
      implications of these findings are discussed.

PMID- 12617345
TI  - Taiwanese employees' justice perceptions of co-workers' punitive events.
AB  - The authors examined justice perceptions of Taiwanese employees in response to co
      workers' punitive events (punishment by a superior). They developed a hypothesis
      based on Chinese indigenous wu-lun principles and the concept of empathy. Results
      of the study showed that perceived vertical (between superior and subordinate)
      and horizontal (between subordinates) relationships jointly affected justice
      perceptions. Respondents who perceived low (negative) leader-member exchange with
      the superior and high (positive) liking of the punished person showed the lowest
      justice perceptions. In conclusion, the authors note that comparative analysis of
      organizational justice is a promising direction for future research.

PMID- 12617346
TI  - The horizontal and vertical attributes of individualism and collectivism in a
      Spanish population.
AB  - The authors examined the dimensionality and factorial structure of individualism
      and collectivism in Spanish participants (N = 526). A series of confirmatory
      factor analyses were performed on responses to the 32-item individualism
      collectivism measure reported by T. M. Singelis, H. C. Triandis, D. S. Bhawuk,
      and M. Gelfand (1995). Consistent with earlier data, the best fitting model was
      multidimensional: a vertical versus a horizontal attribute crossed with
      individualism and collectivism dimensions. Whereas the overall fit of the data to
      a LISREL model was moderate, additional self-report data on respondents'
      interpersonal experiences supported the construct validity of the 4 factors. The
      authors suggest that the additional complexity is useful in explaining Spanish
      social behavior.

PMID- 12617347
TI  - Learned helplessness, therapy, and personality traits: an experimental study.
AB  - The authors investigated 3 aspects of the learned helplessness (LH) phenomenon:
      the induction of helplessness in humans by a new instrumental task, the effects
      of a therapy technique that relies on direct retroactive reevaluation of the
      helplessness experience, and the role of personality characteristics in both
      helplessness induction and therapy. The sample consisted of 92 Turkish Bogazici
      University undergraduates, 42 men and 50 women. The authors exposed 2
      experimental groups to an LH induction by presenting them with an unsolvable maze
      task; 1 group received therapy afterward, and the other group did not. There were
      also 2 control groups: a group that received only a solvable version of the maze
      and another group that received no treatment. Before the experimental procedure,
      all participants completed the Turkish version of the NEO-Five Factor Inventory
      (FFI). The authors evaluated picture-rating and anagram-solving performances to
      differentiate the cognitive and emotional deficits of LH. Results of the
      factorial analyses of variance and the Wilcoxon signed ranks test supported the
      success of both the helplessness induction and the therapy technique. Although no
      significant gender differences were found in the effects of the helplessness
      induction and therapy procedures, correlation analyses revealed that individual
      differences, particularly in the interaction between gender and personality
      characteristics, can have an important impact on LH and on the capacity to
      benefit from therapy.

PMID- 12617348
TI  - Zulu mothers' beliefs about their own and their children's intelligence.
AB  - Zulu women (N = 133) were given a structural interview concerning their own and
      their children's multiple intelligences. The best predictor of their own self
      estimated overall intelligence rating was mathematical and spatial intelligence.
      Mothers showed few significant differences in their estimates of their sons and
      daughters' overall or multiple intelligences. However, they rated their
      daughters' interpersonal intelligence higher than those of their sons, and their
      sons' bodily-kinesthetic intelligence higher than those of their daughters. The
      mothers believed that overall their children were about 6 IQ points more
      intelligent than themselves. Although mothers estimated their own spatial, inter
      , and intrapersonal intelligence to be higher than those of their children, they
      also believed that their children had higher mathematical intelligence.

PMID- 12617349
TI  - Intelligence and family marital structure: the case of adolescents from
      monogamous and polygamous families among Bedouin Arabs in Israel.
AB  - The levels of intelligence among Bedouin Arab adolescents from monogamous and
      polygamous families living in the Negev region of Israel were examined. A
      shortened version of the Raven's Progressive Matrices (RPM) test (S. Elbedour, T.
      J. Bouchard, & Y. Hur, 1997; J. Raven, J. C. Raven, & J. H. Court, 1998) was used
      to assess intelligence. There were no significant test score differences between
      adolescents from monogamous families and adolescents from polygamous families. In
      addition, participants with 2 mothers tended to have lower RPM scores than those
      with 3 or 4 mothers, and participants with related parents tended to have lower
      RPM scores than participants with unrelated parents. One major finding of this
      study is that polygamous family marital structures tended not to have deleterious
      effects on the Bedouin Arab adolescents' RPM test scores.

PMID- 12617350
TI  - Applying a social identity paradigm to examine the relationship between men's
      self-esteem and their attitudes toward men and women.
AB  - The authors used a psychometrically robust measure of attitudes toward men in
      applying a social identity framework to obtain a better understanding of the
      previous finding of a significant positive relationship, among men, between self
      esteem and attitudes toward men. Two studies of that issue are reported. Northern
      Irish university students (N = 106 men) participated in the 1st study, and 56
      English university students participated in a replication. In both studies,
      participants completed measures of attitudes toward men and women before and
      after an experimental intervention that was designed to produce a threat to self
      esteem regarding their identity as men. The findings suggested that, following
      such a threat, men with a high positive regard toward men will have enhanced self
      regard toward men and will tend to view women more negatively. The present
      findings also suggested that the application of social identity theory and the
      method used in the present research in investigating that theory are very
      relevant to the understanding of the relationship between men's self-esteem and
      their attitudes toward men and women.

PMID- 12617351
TI  - Value priorities in American and British female and male university students.
AB  - Value priorities were analyzed as they relate to nationality (American vs.
      British) and gender in a study involving 207 university students from the 2
      countries. Participants responded anonymously to S. H. Schwartz's Value Survey
      (1992, 1994), consisting of various individualistic and collectivistic values.
      American students assigned greater importance to the individualistic values of
      achievement, hedonism, self-direction, and stimulation than British students did;
      students from the 2 countries assigned equal importance to the power value type.
      Compared with men, women from both countries assigned greater value priorities to
      the collectivistic values of benevolence, universalism, security, and
      subordination of self to others. Women and men, however, did not differ on the
      individualistic values, and, in fact, women placed greater importance on
      achievement than men did. The results for the individualistic values are
      discussed primarily within the context of major changes in the career and work
      opportunities afforded women by society in the past 30 years.

PMID- 12617352
TI  - Dimensionality of the women as managers scale: factor congruency among three
      samples.

PMID- 12617353
TI  - Determination of stenosis and occlusion in arteries with the application of FFT,
      AR, and ARMA methods.
AB  - Doppler ultrasound is a noninvasive technique that allows the examination of the
      direction, velocity, and volume of blood flow. Therefore, Doppler ultrasonography
      is known as reliable technique, which demonstrates the flow characteristics and
      resistance of arteries in various vascular disease. In this study, arterial
      Doppler signals recorded from 105 subjects were processed by PC-computer using
      fast Fourier transform, Burg autoregressive, and least squares modified Yule
      Walker autoregressive moving average methods. Doppler power spectrums of arterial
      Doppler signals were obtained by using these spectrum analysis techniques. The
      variations in the shape of the Doppler power spectrums as a function of time were
      presented in the form of sonograms in order to obtain medical information. These
      sonograms were then used to compare the applied methods in terms of their
      frequency resolution and the effects in determination of stenosis and occlusion
      in arteries. Reliable information on hemodynamic alterations in arteries can be
      obtained by evaluation of these sonograms.

PMID- 12617354
TI  - Determination of coronary failure with the application of FFT and AR methods.
AB  - In this study, Doppler signals recorded from the output of carotid artery of 30
      patients were transferred to a personal computer (PC) by using a 16-bit sound
      card. Doppler difference frequencies were recorded from each of the patients, and
      then analyzed using fast Fourier transform (FFT) and least squares autoregressive
      (AR) methods to obtain their sonograms. These sonograms are then used to compare
      with the applied methods in terms of medical evaluation.

PMID- 12617355
TI  - Development of an emergency medical video multiplexing transport system. Aiming
      at the nation wide prehospital care on ambulance.
AB  - The Emergency Medical Video Multiplexing Transport System (EMTS) is designed to
      support prehospital cares by delivering high quality live video streams of
      patients in an ambulance to emergency doctors in a remote hospital via satellite
      communications. The important feature is that EMTS divides a patient's live video
      scene into four pieces and transports the four video streams on four separate
      network channels. By multiplexing four video streams, EMTS is able to transport
      high quality videos through low data transmission rate networks such as satellite
      communications and cellular phone networks. In order to transport live video
      streams constantly, EMTS adopts Real-time Transport Protocol/Real-time Control
      Protocol as a network protocol and video stream data are compressed by Moving
      Picture Experts Group 4 format. As EMTS combines four video streams with checking
      video frame numbers, it uses a refresh packet that initializes server's frame
      numbers to synchronize the four video streams.

PMID- 12617356
TI  - Evaluation of a semiautomatic 3D fusion technique applied to molecular imaging
      and MRI brain/frame volume data sets.
AB  - A generally applicable 3D fusion method was evaluated using molecular imaging and
      MRI volumetric data sets from 15 brain tumor patients with stereotactic frames
      attached to their skull. Point pairs, placed on the frame only, were chosen,
      polynomial warping coefficients were generated to map voxels from one coordinate
      space to the other. The MRI frame was considered the reference structure and the
      standard for "correct" registration. An ANOVA test (p > 0.05) confirmed the point
      pair choice to be consistent. The 95% confidence interval for the t-test showed
      the measured distance difference between the registered volumes was within one
      MRI voxel. A further experiment was conducted to independently evaluate the brain
      registration based on testing for consistency of randomly selected
      interior/exterior points. A t-test result (p < 0.05) showed that the consistency
      (i.e., both interior or both exterior) before and after volume registration were
      significantly different. This fusion method may be a viable alternative when
      other methods fail.

PMID- 12617357
TI  - Low-cost instrumentation for the diagnosis of Hirschsprung's disease.
AB  - In Hirschsprung's disease, the internal anorectal sphincter fails to relax in
      response to rectal distension, which strongly indicates the absence of rectoanal
      inhibitory reflex (RAIR). Hirschsprung's disease is a very common case
      particularly encountered in the newborns in our region. Development of a
      manometric system targeted specifically for the diagnosis of this disease at a
      reasonable cost is an urgent need identified by our regional colorectal surgeons.
      These surgeons indicated that commercially available anorectal manometers are too
      expensive to acquire. Therefore, in our research we tried to develop a low-cost
      single balloon-transducer system, which only provides information about RAIR, and
      hence diagnoses the Hirschsprung's disease. The hardware part of our
      instrumentation is made of a latex balloon, pressure transducer, amplifier, and
      A/D converter circuits, which all collects the pressure readings and sends the
      data to the computer. The manometer system software, programmed based on Delphi,
      displays these readings and patient information on a computer screen. This
      designed system was successful enough to perform manometric recording of RAIR in
      the anorectal ampulla of rabbits and rats.

PMID- 12617358
TI  - Data security issues arising from integration of wireless access into healthcare
      networks.
AB  - The versatility of having Ethernet speed connectivity without wires is rapidly
      driving adoption of wireless data networking by end users across all types of
      industry. Designed to be easy to configure and work among diverse platforms,
      wireless brings online data to mobile users. This functionality is particularly
      useful in modern clinical medicine. Wireless presents operators of networks
      containing or transmitting sensitive and confidential data with several new types
      of security vulnerabilities, and potentially opens previously protected core
      network resources to outside attack. Herein, we review the types of
      vulnerabilities, the tools necessary to exploit them, and strategies to thwart a
      successful attack.

PMID- 12617359
TI  - Aggregate Health Status: a benchmark index for community health.
AB  - A qualitative review of population health assessment models used throughout the
      United States and Canada indicate both individual and community-level domains of
      health. Individual-level domains of health include health habits, education,
      public safety, environment, social, government, culture, and mobility. Community
      level domains include the same general health domains but aggregated to the
      community level Aggregate Health Status (AHS). In the development of the AHS
      portion of our model, the dependent variable was the general health question from
      the Medical Outcomes Study. The remainder of the survey was partitioned into
      mutually exclusive individual measure subsets. A linear combination of these
      global variables then produces a single estimate relating the multiple domains of
      the broader determinants of health to health status. This global variable
      uniquely discriminates between the five categories of general health. This model
      serves as a framework and benchmark indicator that (1) provides a summary
      indicator of the overall health status of the population, (2) is broadly
      representative of populations rather than individuals, (3) is a population
      perspective rather than a provider perspective, and (4) emphasizes outcomes
      versus inputs and processes.

PMID- 12617361
TI  - Classification of transcranial Doppler signals using artificial neural network.
AB  - Transcranial Doppler signals, recorded from the temporal region of brain on 110
      patients were transferred to a personal computer by using a 16-bit sound card.
      The fast Fourier transform (FFT) method was applied to the recorded signal from
      each patient. Since FFT method inherently can not offer a good spectral
      resolution at jet blood flows, it sometimes causes wrong interpretation of
      transcranial Doppler signals. To do a correct and rapid diagnosis, transcranial
      Doppler blood flow signals were statistically arranged so that they were
      classified in artificial neural network. Back propagation neural network and self
      organization map algorithms of artificial neural network were used for training,
      whereas momentum and delta-bar-delta algorithms were used for learning. The
      results of these algorithms were compared in the case of classification and
      learning.

PMID- 12617360
TI  - The effects of preparatory sensory information on ICU patients.
AB  - Preparatory sensory information (PSI) has been found to have significant effects
      in reducing distress, tension, restlessness, negative moods, and anxiety, and
      also in reducing length of postoperative hospitalization during various
      threatening medical events, but no evidence has demonstrated the effect of PSI on
      a patient during ICU hospitalization. On the basis of Lazarus' theory, a
      structural equation model was developed to examine the role of the nursing
      intervention, PSI, as a significant factor influencing patients' processes of
      cognitive appraisals and coping, adaptational responses, and patient care
      outcomes during ICU hospitalization. The analytical model examined the net effect
      of PSI on outcomes, controlling for the effects of mastery, interpersonal trust,
      social support, socioeconomic status, severity of illness, age, and gender. A
      quasi-experiment was executed in four large acute care hospitals. Data were
      collected from 41 subjects in the control group and from 42 in the treatment
      group receiving PSI before ICU admission. Structural equation modeling was
      employed to test the proposed analytic model. The initial tests of model fit
      indicate that the original model did not fit the data well with GFI = 0.85, AGFI
      = 0.76, RMSEA = 0.059, p_close = 0.28, and critical N = 78. A revised model was
      developed, and the fit indices suggested an adequate fit with GFI = 0.90, AGFI =
      0.84, RMSEA = 0.00, p_close = 0.89, and critical N = 109. These findings provide
      empirical support for Lazarus' theory on stress, appraisal, and coping. The
      findings also verify the beneficial effects of the nursing intervention of PSI on
      ICU patients.

PMID- 12617362
TI  - Survey of fuzzy logic applications in brain-related researches.
AB  - The aim of this study was to survey fuzzy logic (FL) applications in brain
      researches. In general, these applications are related to pattern recognition for
      localization in brain structures or tumor detection, image segmentation, and
      simulations. In recent years, neural networks and FL are gaining popularity. FL
      is based on the observation of people. The enormous amount of information
      representation by the brain suggests that FL principles can be useful, especially
      for complex brain functions. Causal models based on functional neuroanatomy can
      be then implemented in computer simulations to reflect the dynamical intersection
      of brain structures. FL is considered as an appropriate tool for modelling and
      control. FL has been applied in different ways to brain researches. This paper
      surveys the utilization of FL in brain researches.

PMID- 12617363
TI  - What happened to the magician?

PMID- 12617364
TI  - Evaluation of periodontal regeneration following grafting intrabony defects with
      bio-oss collagen: a human histologic report.
AB  - This study evaluated the clinical, radiographic, and histologic response to Bio
      Oss Collagen when used alone or in combination with Bio-Gide bilayer collagen
      membrane for the treatment of four intrabony defects (5 to 7 mm) around single
      rooted teeth. After reflecting a full-thickness flap, thorough degranulation and
      root planing were accomplished. In all cases, Bio-Oss Collagen was then used to
      fill the defects, and in two cases, a Bio-Gide membrane was placed over the
      filled defect. Radiographs, clinical probing depths, and attachment levels were
      obtained before treatment and immediately preceding en bloc resection of teeth
      and surrounding tissues 9 months later. Reduction in pocket depth and gain in
      clinical attachment level were observed for both treatment protocols. The
      histologic evaluation demonstrated the formation of a complete new attachment
      apparatus, evidencing periodontal regeneration that varied with defect
      morphology. This human histologic study demonstrated that Bio-Oss Collagen has
      the capacity to induce regeneration of the periodontal attachment apparatus when
      placed in intrabony defects.

PMID- 12617365
TI  - Predictability of soft tissue form around single-tooth implant restorations.
AB  - The objective of this study was to answer important questions about gingival
      responses to single-tooth implants: (1) Are papilla regeneration and sulcular
      recession expected results? (2) Do soft tissue profiles retain their sulcular
      form over an extended period? and (3) Do single-implant replacements require
      special restorative handling to achieve predictable soft tissue form? A
      retrospective, photographic examination was used to follow 55 single-implant
      restorations in 51 patients for a period from 1 to 9 years (mean 3.5 years).
      Papillae regenerated in 83.9% of implants for a mean growth of 0.65 mm mesially
      and 0.62 mm distally. The sulcular apex receded in 59% of patients for a mean of
      0.06 mm. Complete papilla fill was noted in 75% of patients examined. Short- to
      long-term measurements revealed that papilla regrowth continued slightly and that
      sulcular recession abated. Papilla regeneration around single implants was a
      predictable outcome in this population; sulcular recession was not a predictable
      finding. Papilla levels demonstrated a tendency toward increasing height, and
      sulcular levels remained fairly constant over the long term. Predictable soft
      tissue profiles were achieved with a simplified implant prosthetic protocol,
      progressing directly from healing abutments to definitive crowns in most cases.

PMID- 12617366
TI  - Clinical and histologic evaluation of bone-replacement grafts in the treatment of
      localized alveolar ridge defects. Part 1: Mineralized freeze-dried bone
      allograft.
AB  - The purpose of this study was to evaluate the use of mineralized freeze-dried
      bone allograft (FDBA) in conjunction with a titanium-reinforced expanded
      polytetrafluoroethylene (TR e-PTFE) barrier in the treatment of localized
      alveolar ridge deficiencies prior to endosseous dental implant placement. Twelve
      patients (aged 23 to 65 years) requiring tooth replacement with ridge
      augmentation were recruited to participate in this study. During ridge
      augmentation surgery, measurements were made prior to grafting with FDBA plus a
      TR e-PTFE barrier. Six months later, ridge measurements were repeated, and
      suitability for implant placement was assessed. At each implant site, a biopsy
      was taken from the grafted site. The implants were placed and allowed to
      osseointegrate for 13 weeks prior to phase-two surgery. Clinical data analyzed
      were horizontal ridge width changes and vertical ridge height changes. Histologic
      evaluation revealed the formation of new bone and residual particles in each
      graft site at the time of implant placement Ten patients completed the study. The
      mean alveolar ridge width increased by 3.2 +/- 1.0 mm (P < .0005).
      Histomorphometric analysis revealed a range of new bone from 42.9% to 70.5%, with
      a mean of 47.6%. Graft particles remaining ranged from 29.5% to 57.1%, with a
      mean of 52.4%. The clinical and histologic findings of this study demonstrate
      that sites grafted with FDBA in conjunction with an e-PTFE barrier can provide a
      predictable way to augment deficient alveolar ridges prior to implant placement.

PMID- 12617367
TI  - Immediate loading of dental implants in the edentulous maxilla: case study of a
      unique protocol.
AB  - Although immediate loading of dental implants is increasingly gaining recognition
      as an important option for certain categories of implant patients, the maxillary
      arch has historically posed difficulties that have limited the number of
      immediate loading applications. To address the needs of patients who cannot
      tolerate maxillary removable complete dentures, an immediate loading protocol we
      call "Teeth in a Day" uses a conversion prosthesis that has been expanded to
      include complete-arch maxillary reconstruction. Use of a large number of implants
      to prevent micromotion at the bone-to-implant interface is a critical element in
      this protocol. A patient treatment is reported.

PMID- 12617368
TI  - Clinical and histologic evaluation of human intrabony defects treated with an
      enamel matrix protein derivative combined with a bovine-derived xenograft.
AB  - The purpose of the present case report study was to clinically and histologically
      evaluate the healing of deep intrabony defects following treatment with either a
      combination of an enamel matrix protein derivative (EMD) and a bovine-derived
      xenograft (BDX) or with BDX alone. Three female patients with generalized
      marginal periodontitis and presenting one advanced intrabony defect each were
      treated with either a combination of EMD + BDX (two defects) or with BDX alone
      (one defect). The postoperative healing was uneventful in all three cases. Six
      months after surgery, a gain of clinical attachment was measured at all treated
      sites. The histologic examination revealed that all three defects healed with a
      new connective tissue attachment (ie, new cellular cementum with inserting
      collagen fibers) and new bone. Most of the BDX particles were surrounded by a
      bone-like tissue. No direct contact between BDX particles and the root surface
      (cementum or dentin) was observed. Within their limits, the present data indicate
      that treatment with either EMD + BDX or with BDX alone may enhance the formation
      of new connective tissue attachment and new bone in human intrabony defects.

PMID- 12617369
TI  - Clinical considerations and rationale for the use of simplified instrumentation
      in occlusal rehabilitation. Part 1: Mounting of the models on the articulator.
AB  - The development of an occlusal scheme with an appropriate number and location of
      occlusal contacts is of the utmost importance for the long-term success of any
      prosthetic rehabilitation. This, however, can be a time-consuming procedure. To
      avoid undue mistakes, a high degree of competence must be demonstrated by both
      the clinician and the technician. Especially when performing extensive
      rehabilitations, many operators believe that to have optimum control of the
      occlusal variables, it is necessary to employ rather sophisticated instruments
      and complicated procedures. This article presents a rationale for an approach
      that uses a simplified but sound instrumentation in the clinical and laboratory
      steps necessary to produce a successful prosthesis. In part 1, the registration
      of the spatial position of a patient's maxillary and mandibular arches is
      described.

PMID- 12617370
TI  - Histologic effect of pure-phase beta-tricalcium phosphate on bone regeneration in
      human artificial jawbone defects.
AB  - The effect of the pure-phase beta-tricalcium phosphate (beta-TCP) Cerasorb on
      bone regeneration was evaluated in hollow titanium cylinders implanted in the
      posterior jaws of five volunteers. Beta-TCP particles were inserted inside the
      cylinders and harvested 6 months after placement. The density of the newly formed
      bone inside the bone-growing chambers measured 27.84% +/- 24.67% in test and
      17.90% +/- 4.28% in control subjects, without a statistically significant
      difference. Analysis of the histologic specimens revealed that the density of the
      regenerated bone was related to the density of the surrounding bone. The present
      study demonstrates the spontaneous healing of infrabony artificial defects, 2.5
      mm diameter, in the jaw. The pure beta-TCP was resorbed simultaneously with new
      bone formation, without interference with the bone matrix formation.

PMID- 12617371
TI  - Clinical repair of an osseous defect associated with a cemental tear: a case
      report.
AB  - Cemental tears have been described as detachment of cementum caused by trauma or
      aging. They often result in severe periodontal lesions that may necessitate the
      extraction of the affected tooth. This case report describes the clinical
      resolution of a periodontal lesion associated with a cemental tear. A maxillary
      central incisor was subjected to endodontic treatment twice with no resolution of
      a deep distobuccal pocket and a palatal sinus tract from its apical region. The
      preoperative differential diagnosis for the condition present on the tooth
      included a vertical fracture and a combined periodontal-endodontic lesion.
      Surgical exploration of the area revealed a cemental tear on the apical third of
      the tooth. The cementum fragments were removed, root-end resection was performed,
      and the osseous lesion was treated with an osseous graft and guided tissue
      regeneration. Clinical examination of the area 1 year after surgery revealed
      resolution of both the prior pocket and sinus tract. Radiographic examination of
      the area showed increased radiopacity in the area of the original lesion,
      suggesting bone fill.

PMID- 12617372
TI  - Soft tissue ridge augmentation with an acellular dermal matrix.
AB  - The goal of this case report was to evaluate the use of an acellular dermal
      matrix for soft tissue ridge augmentation. The technique used was a modification
      of the procedure proposed by Langer and Calagna and involved reflecting a partial
      thickness pedicle, placing an acellular dermal matrix, and covering the acellular
      dermal matrix with the pedicle. The increases in the quantity of tissue obtained
      were adequate to permit placing an esthetic fixed restoration in four of the five
      cases treated. In one of the five cases, the acellular dermal matrix became
      exposed and partially sloughed. This resulted in less of an increase in tissue
      than in the other cases. Histologic evaluation of this case showed that the
      entire acellular dermal matrix did not slough; part of the acellular dermal
      matrix was incorporated into the result. The use of an acellular dermal matrix
      for soft tissue ridge augmentation is a clinically valuable technique.

PMID- 12617373
TI  - Barriers to rehabilitation research, and overcoming them.
AB  - Although rehabilitation is thought to be underresearched, some data suggest that
      evaluative randomized controlled trials (RCTs) form a greater proportion of
      studies in rehabilitation research than in the general medical literature.
      Various obstacles to more evaluative research are sometimes put forward. These
      include suggestions that it is unethical, that the personalized nature of
      rehabilitation coupled with the unique problems of each patient make it
      impossible to study groups, that patients will not agree to enter trials, and
      that the funding mechanisms for both service and research are not available. In
      practice these arguments probably reflect low self-confidence within the
      profession. Education of the profession, public and purchasers should help in the
      long term. Meanwhile rehabilitation research would benefit from the development
      of stable research units of adequate size conjoined with clinical units.

PMID- 12617374
TI  - A systematic review of exercise trials post stroke.
AB  - OBJECTIVE: To perform a systematic review of exercise trials post stroke. DESIGN:
      A systematic review of controlled clinical trials. SEARCH STRATEGY: MEDLINE,
      EMBASE, CINAHL, Amed, Sports Discus, Cochrane controlled trials register and
      PEDro were searched for relevant trials. INCLUSION CRITERIA: Studies--randomized
      or quasi-randomized controlled clinical trials. Participants--Adults of any age
      with a clinical diagnosis of stroke. Interventions--Any cardiovascular exercise
      intervention aimed at improving cardiovascular fitness and/or function. OUTCOMES:
      Impairment: gait speed, strength, endurance, balance, flexibility, tonus and
      exercise capacity. Disability: global dependency, functional independence.
      Extended activities of daily living. Quality of life. Death. DATA COLLECTION AND
      ANALYSIS: Two independent reviewers categorized selected trials, documented the
      methodological quality and extracted the relevant data. Comparisons of
      cardiovascular exercise interventions versus no cardiovascular intervention were
      made. Statistical comparisons were carried out using a random effects model to
      calculate standardized mean differences. RESULTS: We identified three eligible
      trials. Small numbers and heterogeneous outcomes limited the analyses and
      comparisons. Based on the limited data available, we found that cardiovascular
      exercise post stroke was no better than no exercise with respect to disability,
      impairment, extended activities of daily living, quality of life and death.
      CONCLUSION: Insufficient evidence was identified to establish if cardiovascular
      exercise has a positive effect on disability, impairment, extended activities of
      daily living, quality of life and case fatality post stroke.

PMID- 12617376
TI  - A preliminary controlled study to determine whether whole-plant cannabis extracts
      can improve intractable neurogenic symptoms.
AB  - OBJECTIVES: To determine whether plant-derived cannabis medicinal extracts (CME)
      can alleviate neurogenic symptoms unresponsive to standard treatment, and to
      quantify adverse effects. DESIGN: A consecutive series of double-blind,
      randomized, placebo-controlled single-patient cross-over trials with two-week
      treatment periods. SETTING: Patients attended as outpatients, but took the CME at
      home. SUBJECTS: Twenty-four patients with multiple sclerosis (18), spinal cord
      injury (4), brachial plexus damage (1), and limb amputation due to
      neurofibromatosis (1). INTERVENTION: Whole-plant extracts of delta-9
      tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo
      were self-administered by sublingual spray at doses determined by titration
      against symptom relief or unwanted effects within the range of 2.5-120 mg/24
      hours. Measures used: Patients recorded symptom, well-being and intoxication
      scores on a daily basis using visual analogue scales. At the end of each two-week
      period an observer rated severity and frequency of symptoms on numerical rating
      scales, administered standard measures of disability (Barthel Index), mood and
      cognition, and recorded adverse events. RESULTS: Pain relief associated with both
      THC and CBD was significantly superior to placebo. Impaired bladder control,
      muscle spasms and spasticity were improved by CME in some patients with these
      symptoms. Three patients had transient hypotension and intoxication with rapid
      initial dosing of THC-containing CME. CONCLUSIONS: Cannabis medicinal extracts
      can improve neurogenic symptoms unresponsive to standard treatments. Unwanted
      effects are predictable and generally well tolerated. Larger scale studies are
      warranted to confirm these findings.

PMID- 12617375
TI  - Treating sensory impairments in the post-stroke upper limb with intermittent
      pneumatic compression. Results of a preliminary trial.
AB  - OBJECTIVE: To evaluate the efficacy of intermittent pneumatic compression (IPC)
      in treating sensory impairments in the hemiplegic upper limb in stroke patients.
      DESIGN: Twenty-three stroke patients were enrolled in a randomized, controlled
      preliminary trial that compared the application of intermittent pneumatic
      compression with a passive treatment strategy. SETTING: Four Belgian day centres
      for treatment of neurological disabilities. Four acute and rehabilitation care
      wards specialized in neurological treatment. SUBJECTS: Twenty-three stroke
      patients. INTERVENTIONS: The experimental group (n = 11) received standard
      physiotherapy combined with intermittent pneumatic compression treatment (10
      cycles of 3 minutes with a peak of 40 mmHg) for their hemiplegic upper limb. The
      control group (n = 12) received supplementary to their conventional physiotherapy
      a placebo treatment, namely sham short-wave therapy on the hemiplegic shoulder
      for 30 minutes. MAIN OUTCOME MEASURES: Sensory impairments were clinically
      assessed at three occasions over a period of four weeks using the Nottingham
      Sensory Assessment scale. RESULTS: Both groups improved in somatosensation over
      time, but the experimental group improved more than the control group (p= 0.036)
      or 81.1% improvement versus 30.9%. CONCLUSIONS: The use of intermittent pneumatic
      compression in the rehabilitation of stroke patients may be of clinical
      importance for the restoration of sensory function.

PMID- 12617377
TI  - Effects of multisensory stimulation in people with Huntington's disease: a
      randomized controlled pilot study.
AB  - OBJECTIVE: To investigate whether behavioural, motor and physiological responses
      of individuals with Huntington's disease (HD) to a controlled multisensory
      environment (MSE) are effective as a therapeutic (sustained effects) or leisure
      (immediate effects) activity. DESIGN: Pilot study--a randomized, controlled, two
      group design. SETTING: Specialist residential unit for people with mid-late stage
      HD. SUBJECTS: Twelve patients with HD (one subject from each group dropped out
      during the study after week 8 due to medical complications). INTERVENTIONS:
      Patients attended eight, 30-minute sessions over a four-week period, of
      multisensory stimulation (MSE, treatment group) or relaxation activities (control
      group). MAIN OUTCOME MEASURES: Between-group comparisons for changes between
      assessment sessions for two behavioural assessments: Rehabilitation Evaluation-
      Hall and Baker (REHAB), Behaviour and Mood Disturbance Scale (BMD); a motor
      assessment: the dyskinesia section of the St Hans Rating Scale (SHRS);
      physiological measures: blood pressure, heart rate and respiratory rate.
      Secondary measures during intervention sessions included behavioural assessment
      using the Interact. RESULTS: There were no significant differences found between
      the groups for any main outcome measures made between sessions. The MSE group
      showed some positive effects within-sessions, with the Interact showing
      significant between-group differences in immediate effects on mood (p = 0.028).
      There was also a significantly different change over time for within-session
      changes in stimulation levels (p = 0.0002) and mood (p = 0.0001) between the
      groups. No physiological effects were observed in relation to sessions in either
      group. Two MSE subjects underwent changes in medication during the study period.
      CONCLUSIONS: There was no therapeutic effect of MSEs over the four-week study
      period. MSEs appear to be more effective thanconventional relaxation techniques
      as a leisure activity.

PMID- 12617378
TI  - Lower abdominal pressure versus external bladder stimulation to aid bladder
      emptying in multiple sclerosis: a randomized controlled study.
AB  - OBJECTIVE: To investigate the change in post-void residual bladder volumes (PVR)
      with 'abdominal vibration' using a percutaneous bladder stimulator in multiple
      sclerosis (MS) patients compared with either 'no treatment' or 'abdominal
      pressure'. DESIGN: Randomized controlled cross-over study. SETTING: Regional
      neurorehabilitation clinics. SUBJECTS: Twenty-eight MS patients with urinary
      symptoms and PVR > 100 ml. Twelve patients had urinary incontinence. METHODS: MS
      patients with voiding dysfunction and elevated PVR of 100-500 ml on BVI-3000
      Ultrasound Scanner were randomized to either 'abdominal pressure' or 'vibration'
      by a portable, percutaneous, vibrating device (Queen Square Bladder Stimulator;
      Malem Medical) or to 'no treatment'. PVR was assessed at the end of each two-week
      phase. OUTCOME MEASURE: PVR reduction by greater than 100 ml. RESULTS: The 28
      patients ranged in age from 29 to 71 years with a mean age of 49 years and a mean
      duration of MS of 12 years (range 1-37 years). The PVR decreased from 231 (SD
      119) ml during no treatment to 191 (SD 132) ml with abdominal pressure (p =
      0.242). Using suprapubic vibration the PVR reduced further to 126 (SD 121) ml,
      which was highly significant (p = 0.002) compared with no treatment. The
      difference between abdominal pressure and vibration just failed to reach
      significance (p = 0.059). There was no significant reduction in either the
      frequency of micturition or episodes of incontinence. The device was well
      tolerated by patients. CONCLUSION: Abdominal vibration is an effective method of
      reducing PVR in MS patients and appears more effective than abdominal pressure
      alone.

PMID- 12617379
TI  - Functional strength training in cerebral palsy: a pilot study of a group circuit
      training class for children aged 4-8 years.
AB  - OBJECTIVE: To determine the effects of intensive task-specific strength training
      on lower limb strength and functional performance in children with cerebral
      palsy. DESIGN: A nonrandomized ABA trial. SETTING: Sydney school. SUBJECTS: Eight
      children with cerebral palsy, aged 4-8 years, seven with diagnosis of spastic
      diplegia, one of spastic/ataxic quadriplegia. INTERVENTION: Four weeks of after
      school exercise class, conducted for one hour twice weekly as group circuit
      training. Each work station was set up for intensive repetitive practice of an
      exercise. Children moved between stations, practising functionally based
      exercises including treadmill walking, step-ups, sit-to-stands and leg presses.
      MAIN OUTCOME MEASURES: Baseline test obtained two weeks before training, a pre
      test immediately before and a post-test following training, with follow-up eight
      weeks later. Lower limb muscle strength was tested by dynamometry and Lateral
      Step-up Test; functional performance by Motor Assessment Scale (Sit-to-Stand),
      minimum chair height test, timed 10-m test, and 2-minute walk test. RESULTS:
      Isometric strength improved pre- to post-training by a mean of 47% (SD 16) and
      functional strength, on Lateral Step-up Test, by 150% (SD 15). Children walked
      faster over 10 m, with longer strides, improvements of 22% and 38% respectively.
      Sit-to-stand performance had improved, with a reduction of seat height from 27
      (SD 15) to 17 (SD 11) cm. Eight weeks following cessation of training all
      improvements had been maintained. CONCLUSIONS: A short programme of task-specific
      strengthening exercise and training for children with cerebral palsy, run as a
      group circuit class, resulted in improved strength and functional performance
      that was maintained over time.

PMID- 12617381
TI  - Intensive, time-series measurement of upper limb recovery in the subacute phase
      following stroke.
AB  - OBJECTIVES: To discover if intensive monitoring of wrist extension would produce
      consistent recovery curves during the subacute period, and whether any impact of
      additional physiotherapy could be detected. We also investigated improved
      approaches to statistical analysis in single-case experiments. DESIGN: A
      randomized multiple-baseline experiment with very frequent assessment. SETTING:
      Stroke rehabilitation unit. SUBJECTS: Four patients with some active wrist
      movement less than seven weeks after stroke. INTERVENTIONS: Wrist extension was
      measured twice daily with an electrogoniometer for 3-4 weeks. Additional upper
      limb physiotherapy 115 minutes, twice per day) commenced after a randomly
      determined period. MAIN OUTCOME MEASURES: Speed and range of wrist movement.
      RESULTS: A logarithmic function was fitted to the data to produce recovery
      curves. In all cases, active range and maximum velocity of wrist extension rose
      gradually over time. Mean variability in range was <5%, but with occasional
      outliers. Range of passive movement decreased in two cases in association with
      pain and increased tone. There were no large improvements coinciding with
      additional physiotherapy but autoregression analysis indicated statistically
      significant changes in three cases. A randomization test confirmed an increase in
      active range associated with additional physiotherapy. CONCLUSIONS: Intensive
      electrogoniometry provided a detailed recovery pattern for each of these
      patients. The data were surprisingly consistent over time, showing that it is
      feasible to use a time-series approach to investigate subacute recovery. Changes
      associated with additional physiotherapy were observed on some measures,
      demonstrating the potential of this approach for exploratory evaluation of
      interventions.

PMID- 12617380
TI  - Can the repetition effect maximize learning in multiple sclerosis?
AB  - OBJECTIVE: The 'repetition effect' stipulates that recall ability improves as the
      number of learning trials that a person receives increases. While the repetition
      effect has been supported through many empirical investigations in healthy
      individuals, it has not yet been applied to clinical populations. The present
      study tested the hypothesis that an increased number of learning trials improves
      recall ability in persons with a neurological disorder, namely multiple sclerosis
      (MS). DESIGN: Prospective between-group design with 30-minute, 90-minute and one
      week assessments. SETTING: Private, nonprofit, research facility. SUBJECTS: Sixty
      four MS subjects; 20 healthy control subjects (HC). INTERVENTIONS: Subjects were
      given a modified Selective Reminding Test (SRT), a list of 10 words to remember
      in a selective reminding format. To control for the amount of information
      initially learned, the learning trials were repeated until the subject recalled
      all 10 words on two consecutive trials. MAIN OUTCOME MEASURES: SRT word recall
      and recognition was tested 30 minutes, 90 minutes and one week subsequent to
      initial acquisition. RESULTS: Interestingly, the antithesis of our hypothesis was
      found. That is, persons with MS who required more learning trials to reach the
      perfect learning criterion performed significantly worse on the recall trials.
      However, this was not the case in a sample of healthy individuals undergoing the
      same protocol. CONCLUSIONS: These results indicate that individuals with MS may
      not benefit from repetition in isolation, but rather require the use of more
      intensive cognitive rehabilitation strategies (i.e., increased organization) to
      help improve their depth of encoding of new information.

PMID- 12617382
TI  - The effect of physical exercise following acute disease exacerbation in patients
      with dermato/polymyositis.
AB  - OBJECTIVE: To study the effect of physical exercise shortly after an acute
      episode of dermato/polymyositis (DM/PM). DESIGN: Pilot study of a descriptive
      nature. SETTING: Rehabilitation unit of a large general hospital. SUBJECTS: Ten
      patients 2-3 weeks after an acute phase of DM/PM (early recovery group) and 11
      patients in the inactive stage of DM/PM for at least three months (chronic stage
      group). INTERVENTIONS: Isotonic muscle training consisted of several series of
      different repeated movements at 65-70% of individual maximal repetition limit.
      Special training was applied for the respiratory muscles. Relaxing baths, mud
      packs and massages were also applied. OUTCOME MEASURES: Dynamometer and
      spirometer were used for measuring the changes in muscle strength and respiratory
      function. Disability tests were done before and after therapy. RESULTS: No
      disease relapses or decreases in muscle function were seen. In the early recovery
      group, the average muscle strength improvement was 17 +/- 31 % (p > 0.05) in the
      proximal muscles and 37 +/- 23% (p < 0.05) in the distal muscles, while the vital
      capacity also increased by 17 +/- 21% (p < 0.05). In the chronic stage group the
      average improvement in muscle strength was 46 +/- 34% (p < 0.05) in the proximal
      muscles and 37 +/- 29% (p < 0.05) in the distal muscles. By the end of the
      therapy both groups showed improvements in disability tests (p < 0.05).
      CONCLUSIONS: Physical training started 2-3 weeks following an acute exacerbation
      of the disease seems to be useful and safe. Some improvement in muscle strength
      and respiratory function can be obtained, muscle atrophy due to inactivity may be
      partially prevented and the level of disability can be decreased.

PMID- 12617383
TI  - Contractures in the post-stroke wrist: a pilot study of its time course of
      development and its association with upper limb recovery.
AB  - BACKGROUND: Contractures are common in a stroke population, yet there is little
      information on the time course of development. OBJECTIVES: Investigate
      quantitatively changes associated with contracture formation in an acute stroke
      population. STUDY DESIGN: Longitudinal study on 22 subjects who were 2-4 weeks
      post stroke. OUTCOME MEASURES: Contractures were assessed by quantifying the
      resting posture, resistance to passive movement and passive range of movement.
      Upper limb function was measured using the Action Research Arm Test and the Nine
      Hole Peg Test. Active range of extension, wrist extension strength (isometric),
      grip strength and neglect were also measured. REPEATED MEASURES: Following an
      initial assessment, repeated measurements were taken at 4, 8, 20 and 32 weeks
      after recruitment. RESULTS: Two distinct subgroups, one capable of some
      functional movement (F group; 8 subjects) and another which was not (NF group; 14
      subjects), were identified at the start of the study. The NF group showed changes
      associated with contracture formation at the wrist, i.e., reduction in the
      passive range of movement, an increase in resistance to passive movement and a
      worsening of the flexion posture. Changes were observed from the time of
      recruitment even though neglect improved. The F group showed improvements in
      upper limb function and there was no evidence to support contracture formation.
      CONCLUSIONS: Subjects most prone to contracture formation were those who showed
      no signs of early functional recovery (2-4 weeks after the stroke). Changes
      consistent with adaptive shortening were seen from week 4 of the study period.

PMID- 12617384
TI  - Comparison of effects of phonophoresis and iontophoresis of naproxen in the
      treatment of lateral epicondylitis.
AB  - OBJECTIVE: The aim of this study was to compare the effectiveness of naproxen
      (10%) applied by topical iontophoresis or by phonophoresis in the treatment of
      lateral epicondylitis. DESIGN: Randomized controlled trial. SETTING: Dokuz Eylul
      University School of Physical Therapy and Rehabilitation. SUBJECTS: This study
      was carried out with 61 patients who had lateral epicondylitis. They were
      randomized into two groups. INTERVENTIONS: Naproxen was applied to the first
      group using phonophoresis (29 patients--33 extremities) and to the second group
      using iontophoresis (32 patients--34 extremities). Patients in both groups were
      treated by other physiotherapy methods (cold pack, progressive strengthening and
      stretching exercises). OUTCOMES: Pain scores (at rest, during motion, with
      pressure, weight lifting), grip strength and Nirschl-Petterone Grading System
      were evaluated before and after treatment. RESULTS: Pain scores decreased, grip
      strength and Nirsch-Petterone Grading System statistically significantly
      increased in both groups after treatment (p < 0.05), but there were no
      statistical differences between groups before or after treatment (p > 0.05).
      CONCLUSION: The results suggest that iontophoresis and phonophoresis of naproxen
      are equally effective electrotherapy methods in the treatment of lateral
      epicondylitis.

PMID- 12617386
TI  - Predictors of a nursing home placement from a non-acute geriatric hospital.
AB  - BACKGROUND: Identifying patients who need Nursing Home (NH) care following a
      hospital admission is important. OBJECTIVE: To identify the factors that
      predispose to an NH discharge. DESIGN: Prospective observational study with
      blinded end-point evaluation. SETTING: A non-acute geriatric hospital. SUBJECTS:
      Two hundred consecutive elderly patients who were admitted for rehabilitation
      following treatment for an acute illness. MAIN OUTCOME MEASURES: Discharge to an
      NH or home. RESULTS: Thirty-five out of the 150 live discharges (23.3%) were to
      an NH. NH discharges had a longer length of stay (38.5 versus 19.8 days; p <
      0001). They were more likely to have visual impairment (p = 0.0009), confusion (p
      < 0.0001), wandering behaviour (p = 0.003), incontinence (p < 0.0001 or unsafe
      gait (p = 0.0005), to be on tranquillizers (p = 0.003), to be at risk of falls (p
      = 0.02) and to have sustained a fall while in hospital (p = 0.001). Multiple
      logistic regression identified confusion (p = 0.001), incontinence (p = 0.02),
      falls in hospital (p = 0.01), gait abnormalities (p < 0.001), tranquillizers (p <
      0.001), impaired distant vision (p = 0.01) and living alone (p < 0.001) as
      independently associated with the risk of an NH discharge. This risk
      proportionately increased with the number of risk factors present: 4.28% for 0-2
      factors, 25.8% for 3-4 factors and 81.8% for 5-6 factors (p < 0.0001).
      CONCLUSION: These factors should be the target of specific rehabilitation in an
      attempt to reduce the risk of discharge to a nursing home and improve patient
      outcome.

PMID- 12617387
TI  - Use of ultrasonography to estimate cistern size and milk storage at different
      milking intervals in the udder of dairy cows.
AB  - Four lactating Holstein cows (average milk yield: 20 +/- 3 l/d) were used to
      develop and validate a method for estimating the size of udder cisterns (Sinus
      lactiferi) using ultrasonography. A sectorial transducer probe of 5 MHz, placed
      in contact with the teat in a parallel cranial position, was used to obtain
      vertical scans of the udder in two perpendicular planes with the teat canal axis
      as reference. Udder scans for each udder quarter were taken randomly at intervals
      of 4, 8, 12, 16, 20 and 24 h after milking. Glandular parenchyma (echogenic) and
      lumen of the cisterns full of milk (anechogenic) were evident in the scans, the
      calculated area of the anechogenic portion being defined as cistern area. Cistern
      areas measured in perpendicular scans were highly correlated. Immediately after
      each measurement, cisternal milk was removed from each quarter using a teat
      cannula after i.v. injection of an oxytocin-receptor blocking agent. Alveolar
      milk from each quarter was then obtained by machine milking after i.m. injection
      of oxytocin. Cistern area and cisternal milk volume increased with length of
      milking interval showing a curvi-linear pattern with a plateau after 16 h.
      Correlations between cistern area and cisternal milk volume were positive and
      significant (P<0.001) at all intervals but showed the highest values with the
      smallest residual standard deviations at 8 h (r=0.88) and 12 h (r=0.84). Since 8
      h has previously been identified as a suitable time at which to determine
      cisternal milk volume for the purposes of defining suitability for different
      milking strategies, we conclude that ultrasonography provides a satisfactory, non
      invasive method for determination of milk storage characteristics in dairy cows.

PMID- 12617385
TI  - Whiplash-associated disorders--predicting disability from a process-oriented
      perspective of coping.
AB  - OBJECTIVE: To describe the coping process over time for patients with whiplash
      associated disorders (WAD). DESIGN: The study was conducted by following patients
      prospectively for 12 months. SETTINGS: The orthopaedic clinic at a university
      hospital. SUBJECTS: Fifty-three patients out of 59 had complete data-sets. MAIN
      OUTCOME MEASURES: Two measures were used: the Pain Disability Index (PDI) and the
      Coping Strategies Questionnaire (CSQ). RESULTS: The results showed that the
      proportion of variance in disability shared with coping increased over time.
      CONCLUSION: The importance of coping as an explanatory factor for disability
      increased during the one year follow-up. Thus, coping has a crucial role for
      disability. The possibility of a positive long-term outcome could therefore be
      improved by teaching patients to use active and adaptive coping strategies
      shortly after an accident.

PMID- 12617388
TI  - Effects of dietary supplements of zinc-methionine on milk production, udder
      health and zinc metabolism in dairy goats.
AB  - Twenty-two Murciano-Granadina dairy goats were used to investigate the effects of
      organic Zn supplementation of a diet containing a high level of inorganic Zn.
      Goats were kept in pens, machine milked once a day throughout lactation and fed a
      diet based on a dehydrated mixture of whole-plant maize and alfalfa ad libitum,
      alfalfa pellets, barley grain and a concentrate mixture. Treatments were: (1)
      control, and (2) supplemented with 1 g/d Zn-Methionine (Zn-Met) included in the
      concentrate mixture. After parturition, goats were blocked in week 3 and dietary
      treatments were applied until week 23. From weeks 3-20, feed intake, milk yield,
      milk composition, milk somatic cell count (SCC), and udder health were measured.
      In week 21, all goats were injected intraperitoneally with 1 g/d DL-methionine
      for 5 d to establish the effects of methionine under the conditions of udder
      stress induced by hand milking on the second day. During weeks 22 and 23, diet
      digestibility, and N and Zn balance were determined. Dry matter intake, milk
      yield, and milk contents of total solids, fat, total and true protein, and casein
      did not differ between treatments, but whey protein and non-protein nitrogen
      contents were significantly lower for the Zn-Met group. Milk SCC tended to
      decrease as a result of Zn-Met supplementation but differences between treatments
      were not significant when halves with persistent infection were excluded. Hand
      milking increased SCC in both groups, but udders of supplemented goats showed a
      lower reaction. Apparent absorption of N significantly increased and Zn retention
      tended to increase in Zn-Met supplemented goats. We conclude that Zn-Met
      supplementation can enhance resistance to udder stress in dairy goats. Effects
      were attributed to the organic Zn and not to the methionine component. Zn
      retention and protein utilization were also improved by the Zn-Met supplement.

PMID- 12617389
TI  - Basement membrane integrity and keratinization in healthy and ulcerated bovine
      hoof tissue.
AB  - Damage to, or deterioration of, the keratinized horn tissue of the bovine hoof
      claw culminates ultimately in the development of solear ulceration. We have
      observed abnormal keratin distribution at the site of solear ulceration in the
      bovine claw that may be due to alteration of the positional cues of the
      keratinocytes. In this study we have characterized key cell biological changes
      associated with ulceration in the claw that may precipitate abnormal
      keratinization. Loss of basement membrane at sites of ulceration was found by
      immunofluorescent detection of laminin and integrins. In other tissues, basement
      membrane breakdown results from degradation by matrix metalloproteinases (MMPs).
      Similarly, elevated levels of MMPs 2 and 9 were observed in ulcerated bovine claw
      tissue both by zymography and, quantitatively, by assay of enzyme activity. In
      the sole of claws that contained an ulcer, tissue distal to the ulcer site also
      had elevated MMP 2 when compared with healthy sole tissue from the same animals,
      as did sole tissue of claws recovering from ulceration. Tissue inhibitor of
      metalloproteinase 2 (TIMP 2) was detected by ELISA in healthy tissue. TIMP 2
      tended to be lower in diseased tissue distal to ulcer sites, and was
      significantly lower in ulcerated tissue. MMP 2 was located by immunofluorescence
      in the dermal and basal epidermal region of sole tissue, in the region of the
      basement membrane. Increased punctate staining of material in the dermis was
      associated with ulcerated material. ELISA of TIMP 2 in tissue extracts enriched
      for dermis or epidermis confirmed that the inhibitor was located predominantly in
      the dermis. To investigate a possible causal relationship between basement
      membrane anchorage and epidermal keratinization, the effect of function-blocking
      antibodies to laminins and integrins was tested in tissue explant cultures
      prepared from healthy sole tissue. Anti-integrin antibody treatment had no effect
      on either protein or DNA synthesis. In contrast, in the presence of anti-laminin
      antibody, protein synthesis was decreased in a concentration-dependent manner, a
      significant effect being observed at the highest concentration after treatment
      for 24 h. At this concentration, DNA synthesis was also decreased after 48 h of
      culture, an effect that may be relevant to a hibernal reduction in claw cell
      turnover, and the associated seasonal vulnerability of cows to claw damage. The
      results provide evidence for basement membrane disruption at ulcer sites, and an
      increased potential for disruption in the diseased claw, and a causal link
      between this and abnormal epidermal keratinization. Basement membrane disruption
      is in turn associated with reciprocal changes in MMPs and their inhibitors,
      favouring extracellular proteolysis. Whether MMP activation is the primary cause
      of dermal-epidermal deterioration and, if so, how MMP activation is triggered,
      remains to be determined.

PMID- 12617390
TI  - Characterization of equine cDNA sequences for alphaS1-, beta- and kappa-casein.
AB  - Here we report the entire cDNA sequences for equine alphaS1-, beta- and kappa
      casein. Based on interspecies comparison, nine exons were found in equine beta
      casein and five in kappa-casein. In equine alphaS1-casein cDNA the exon 5 was
      missing, which resulted in the total of 18 exons instead of 19 theoretically
      possible exons in alphaS1-casein cDNA. Comparison of DNA sequences representing
      exon 5 in other species with corresponding equine genomic region confirmed the
      presence of cryptic exon in horse genomic DNA. Equine alphaS1-casein mRNA was
      present in three forms in the lactating mammary gland and we showed that the two
      shorter forms were produced by skipping either the exon 8 or exon 15. In horse,
      as in some other mammals, beta- and kappa-casein are considerably more conserved
      (sequence identity 53% to 59% and 57% to 67%, respectively) than alphaS1-casein
      which appears as the most variable casein among species (sequence identity 40% to
      54%). Interestingly, horse caseins resemble human much more than bovine caseins
      which may also explain the high dietetic value of mares' milk.

PMID- 12617391
TI  - Isolation, purification and characterization of chymosin from riverine buffalo
      (Bubalos bubalis).
AB  - Chymosin, an aspartyl proteinase, is used for curdling of milk and manufacture of
      cheese. We report the purification and the physicochemical properties of chymosin
      isolated from the abomasal tissue of buffalo calves. The enzyme preparation
      extracted from buffalo abomasal tissues could be purified 29-fold using anion
      exchange and gel filtration chromatography. The molecular weight of the purified
      enzyme was 35.6 kDa on SDS-PAGE. Partial N-terminal amino acid sequence of the
      first eight amino acid sequences of buffalo chymosin was identical to the first
      eight amino acid sequences of cattle chymosin. Buffalo chymosin exhibited a
      skewed bell-shaped stability profile as a function of temperature with maximum
      activity near 55 degrees C. Milk clotting activity decreased gradually as pH
      increased. The enzyme became completely inactive, however, above pH 7.0. The
      ratio of milk clotting to proteolytic activity was 3.03. When compared with
      cattle chymosin, there were subtle differences in the stability and relative
      proteolytic activity of buffalo chymosin.

PMID- 12617392
TI  - Heterogeneity of proteolytic enzyme activities in milk samples of different
      somatic cell count.
AB  - Milk contains the alkaline proteinase plasmin and lysosomal proteinases; the
      significance of the latter is ill-defined. The objective of this study was to
      investigate composition and activities of several different proteolytic enzymes
      in milk samples of varying somatic cell count (SCC). Increasing milk SCC was
      correlated with increased plasmin, cathepsin D and cysteine protease activities,
      with concomitant increases in proteolysis in milk. Addition of plasmin inhibitors
      confirmed the heterogeneity of proteinase activities in milk, as urea-PAGE
      analysis of milk samples showed casein hydrolysis in milk after 7 d storage even
      in samples with inhibitors added; extent and heterogeneity of proteolysis was
      correlated with milk SCC. Rennet coagulation properties were not significantly
      correlated with SCC, or activities of measured enzymes. Milk of increasing SCC
      also exhibited decreased physical stability during incubation of milk at 37
      degrees C. Pasteurized milk was more stable than raw milk, suggesting that the
      enzyme(s) or mechanisms leading to such instability are impaired by
      pasteurization. Overall, milk has a very heterogeneous proteolytic enzyme
      population, with a higher significance of non-plasmin enzymes, such as cathepsin
      D and cysteine proteinases, than perhaps previously recognised.

PMID- 12617393
TI  - Reduction of immunoreactivity of bovine beta-lactoglobulin upon combined physical
      and proteolytic treatment.
AB  - Bovine beta-lactoglobulin was hydrolyzed with trypsin or chymotrypsin before,
      during and after treatment at 600 MPa and pH 6.8 for 10 min at 30, 37 and 44
      degrees C. The extent of beta-lactoglobulin hydrolysis under pressure was
      noticeably higher than at atmospheric pressure, particularly when chymotrypsin
      was used. Addition of proteases at ambient pressure to previously pressure
      treated beta-lactoglobulin gave only a modest increase in proteolysis with
      respect to the untreated protein. Products of enzyme hydrolysis under pressure
      were separated by reverse-phase HPLC, and were found to be different from those
      obtained at atmospheric pressure when chymotrypsin was used. The residual
      immunochemical reactivity of the products of combined pressure-enzyme treatment
      was assessed on the unresolved hydrolysates by ELISA tests using polyclonal and
      monoclonal antibodies, and on individual hydrolytic fractions by Western Blotting
      using sera of paediatric patients allergic to whey proteins in cow milk. The
      immunoreactivity of the whole hydrolysates was related to their content of
      residual intact beta-lactoglobulin, and no immunochemical reactivity was found
      for all the products of chymotrypsin hydrolysis under pressure. The results
      indicate that chymotrypsin effectively hydrolysed hydrophobic regions of beta
      lactoglobulin that were transiently exposed during the pressure treatments and
      that were not accessible in the native protein or in the protein that had been
      previously pressure treated.

PMID- 12617394
TI  - Heat-induced interactions of beta-lactoglobulin A and kappa-casein B in a model
      system.
AB  - The interaction of kappa-casein and beta-lactoglobulin is fundamental to all heat
      induced modifications of milk product functionality, such as the heat stability
      of concentrated milks. Purified native kappa-casein B and beta-Ig A solutions
      were heated at 80 degrees C at pH 6.7 separately and in a mixture. The circular
      dichroism spectra in the near UV indicated irreversible changes in the disulphide
      bonding patterns involving both proteins. Alkaline- and SDS-PAGE of heated
      samples showed that, in the presence of kappa-casein, less beta-Ig was converted
      into beta-Ig polymers and the rate of loss of native beta-Ig was greater. When
      kappa-casein was added to previously heated beta-Ig and the mixture was heated,
      the kappa-casein reacted with the heat-induced beta-Ig polymers more readily than
      with the beta-Ig native monomers. The formation of beta-Ig dimers, trimers etc.
      was diminished. It was concluded that, when beta-Ig and kappa-casein were heated
      together, beta-Ig formed thiol-exposed monomers, which reacted with each other or
      with the native kappa-casein depending on the relative concentrations of beta-Ig
      and kappa-casein. The products of these reactions included some disulphide-bonded
      1:1 beta-Ig:kappa-casein complexes, some monomer kappa-casein and a range of
      large aggregates held together by either or both disulphide bonds and hydrophobic
      association.

PMID- 12617395
TI  - Association of denatured whey proteins with casein micelles in heated
      reconstituted skim milk and its effect on casein micelle size.
AB  - When skim milk at pH 6.55 was heated (75 to 100 degrees C for up to 60 min), the
      casein micelle size, as monitored by photon correlation spectroscopy, was found
      to increase during the initial stages of heating and tended to plateau on
      prolonged heating. At any particular temperature, the casein micelle size
      increased with longer holding times, and, at any particular holding time, the
      casein micelle size increased with increasing temperature. The maximum increase
      in casein micelle size was about 30-35 nm. The changes in casein micelle size
      were poorly correlated with the level of whey protein denaturation. However, the
      changes in casein micelle size were highly correlated with the levels of
      denatured whey proteins that were associated with the casein micelles. The rate
      of association of the denatured whey proteins with the casein micelles was
      considerably slower than the rate of denaturation of the whey proteins. Removal
      of the whey proteins from the skim milk resulted in only small changes in casein
      micelle size during heating. Re-addition of beta-lactoglobulin to the whey
      protein-depleted milk caused the casein micelle size to increase markedly on heat
      treatment. The changes in casein micelle size induced by the heat treatment of
      skim milk may be a consequence of the whey proteins associating with the casein
      micelles. However, these associated whey proteins would need to occlude a large
      amount of serum to account for the particle size changes. Separate experiments
      showed that the viscosity changes of heated milk and the estimated volume
      fraction changes were consistent with the particle size changes observed. Further
      studies are needed to determine whether the changes in size are due to the
      specific association of whey proteins with the micelles or whether a low level of
      aggregation of the casein micelles accompanies this association behaviour.
      Preliminary studies indicated lower levels of denatured whey proteins associated
      with the casein micelles and smaller changes in casein micelle size occurred as
      the pH of the milk was increased from pH 6.5 to pH 6.7.

PMID- 12617396
TI  - Kinetics of hydroxymethylfurfural, lactulose and furosine formation in milk with
      different fat content.
AB  - In the context of the general applicability of hydroxymethylfurfural (HMF),
      lactulose and furosine as time-temperature integrators (TTIs) for thermal
      processing of milk, the influence of milk fat content was studied. Formation
      kinetics were analysed for milk with fat content of 4.0 +/- <0.1%. In previous
      experiments, it was observed that, under isothermal and non-isothermal heating
      conditions, formation of the three chemical compounds could be described by
      pseudo-zero order kinetics. Since the kinetic model was known, the experimental
      design could be simplified. Data were analysed by a non-linear regression
      procedure and results were evaluated by construction of joint confidence regions
      and temperature time tolerance (TTT-) diagrams. Formation kinetics of HMF and
      lactulose was not affected by milk fat content. Regarding furosine, significant
      differences were observed between kinetic parameters in whole, semi-skimmed and
      skimmed milk. The observed differences however were negligible in the context of
      process impact evaluation.

PMID- 12617397
TI  - Repeatability estimates for milk coagulation traits and non-coagulation of milk
      in Finnish Ayrshire cows.
AB  - Effects of systematic environmental factors and milk production and quality
      traits on milk coagulation properties (MCP), and on repeatability of those traits
      were estimated from 979 milk samples collected once a month over a period of 2
      years from 83 Finnish Ayrshire cows. Estimation was based on a multitrait animal
      model and REML methodology. In addition, persistence of non-coagulation of milk
      in individual cows, and factors associated with it were established from a sub
      sample of 24 cows producing non-coagulating (NC) milk at least once. MCP were at
      their best during the first lactation, at the beginning and at the end of
      lactation, and during grazing seasons. Variation in MCP with systematic
      environmental factors was partly due to variation in composition and quality of
      milk, especially in pH and ln (somatic cell count, SCC). Coefficients of
      repeatability for milk coagulation time and curd firmness were 0.65 and 0.68.
      These estimates were of the same magnitude as those for protein content, but were
      higher than those for daily milk yield, fat content, pH, and SCC. Based on the
      repeatability estimates for the milk coagulation traits and effects of the
      environmental factors, cows should be sampled at least three times during a
      lactation to estimate reliably breeding values for the milk coagulation traits. A
      total of 10% of the milk samples did not coagulate in 30 min after addition of
      rennet. Cows that produced NC milk at least once (30% of the cows) could be
      classified into those that produced NC milk only a few times during a lactation
      and those that produced NC milk at almost every sampling. Based on logistic
      regression analyses, peak and mid-lactation, high milk yield, low protein and fat
      content and high pH increased the risk of non-coagulation of milk.

PMID- 12617398
TI  - A preliminary study on the effect of adding yeast extract to cheese curd on
      proteolysis and flavour development of reduced-fat Cheddar.
AB  - Yeast extract was used as a nutrient for growing lactobacilli in reduced-fat
      Cheddar cheese as early growth of non-starter lactic acid bacteria (NSLAB) in
      Cheddar cheese is suppressed by pasteurization of milk and the hostile
      environment of the cheese. Reduced-fat Cheddar cheese was manufactured from 100
      kg standardized milk on two occasions. After milling, the curd was divided into
      two portions, C and E. To control portion, C, salt was added at normal levels. A
      mixture of salt and yeast extract was added to the experimental, E. The cheeses
      were ripened for 7 months at 8 degrees C and assessed for proteolysis and NSLAB
      growth during ripening. Mean % moisture, fat, protein, salt and pH were 40.6,
      20.5, 31.1, 1.72 and 5.22 respectively, in E cheeses, and 39.5, 20.5, 30.9, 1.68
      and 5.22, respectively, in C cheese. NSLAB counts in E cheeses were 10(1), 10(3),
      10(5) cfu/g compared with 0, 10(1), 10(4) cfu/g in C respectively, after 1, 7 and
      30 d of ripening. After 60 d, cell densities of NSLAB were similar (approximately
      10(6) cfu/g) in C and E cheese. Addition of yeast extract to curd affected
      neither the electrophoretic patterns of cheese nor its water-soluble N content
      during ripening. However, the total free amino acids were significantly higher in
      E cheese than C cheese throughout ripening, suggesting faster secondary
      proteolysis in the former cheeses. A 6-member trained descriptive panel evaluated
      the cheese at 7 months and found that the E cheeses had higher intensities of
      whey, fruity, sulphur, nutty, sweet and sour flavours, but had lower intensities
      of brothy flavours as compared to C cheeses. Also, the E cheeses were perceived
      to be more mature than corresponding C cheese. Results show that addition of
      yeast extract to cheese curd is a promising method of enhancing flavour
      development in ripened cheeses.

PMID- 12617399
TI  - Evidence of a relationship between autolysis of starter bacteria and lipolysis in
      cheddar cheese during ripening.
AB  - Cell viability, autolysis and lipolysis were studied in Cheddar cheese made using
      Lactococcus lactis subsp. cremoris AM2 or Lactococcus lactis subsp. cremoris HP.
      Cheddar cheese was made in triplicate over a 3 month period and ripened for 238
      days at 8 degrees C. Cell viability in cheese was lower for AM2 (a non-bitter
      strain) than for strain HP (a bitter strain). Autolysis, monitored by the level
      of the intracellular marker enzyme, lactate dehydrogenase (EC 1.1.1.27) in cheese
      'juice' extracted by hydraulic pressure, was much greater in the cheese made
      using AM2 than that made with HP. Lipolysis was determined by the increase during
      ripening of individual free fatty acids (FFA) from butyric (C4:0) to linolenic
      acid (C18:3) measured using a high performance liquid chromatographic technique.
      Levels of individual FFA from butyric (C4:0) to linolenic (C18:3) acids increased
      significantly (P<0.05) during ripening in cheeses made with either starter
      culture. Palmitic (C16:0) and oleic (C18:1) acids were the most abundant FFA
      throughout ripening in all cheeses. Levels of caprylic (C8:0), myristic (C14:0),
      palmitic (C16:0) and stearic (C18:0) acids were significantly higher (P<0.05) in
      cheeses manufactured with Lc. lactis subsp. cremoris AM2 than in cheeses
      manufactured with Lc. lactis subsp. cremoris HP. Differences in levels of
      lipolysis between strains was not due to differences in the specific lipolytic or
      esterolytic activities in cell free extracts of the strains as measured by
      activity on triolein (lipase) and p-nitrophenylbutyrate (esterase) substrates.
      Therefore, evidence is provided for a relationship between the extent of starter
      cell autolysis and the level of lipolysis during Cheddar cheese ripening.

PMID- 12617400
TI  - Proteolysis in rennet-coagulated spanish hard cheeses made from milk preserved by
      refrigeration and addition of carbon dioxide.

PMID- 12617401
TI  - Chronic oxytocin treatment causes reduced milk ejection in dairy cows.

PMID- 12617402
TI  - Estimation of inbreeding in cattle using RAPD markers.

PMID- 12617403
TI  - Changing perceptions of disease.

PMID- 12617404
TI  - Physicians in a foreign land?

PMID- 12617405
TI  - Medical aspects of intermediate care.

PMID- 12617406
TI  - Thyrotoxicosis.

PMID- 12617407
TI  - Adult growth hormone deficiency.

PMID- 12617408
TI  - Hypercalcaemia.

PMID- 12617409
TI  - Obesity.

PMID- 12617410
TI  - Disorders of water balance.

PMID- 12617411
TI  - The status of nurse practitioners in gastroenterology.
AB  - The role of the nurse practitioner in the UK is new. It extends the traditional
      role of the nurse and may help overcome some of the difficulties in communication
      that have bedevilled clinical practice in recent years. This paper reviews the
      emergence of nurse practitioners in the USA and considers their status in the UK.
      The philosophical basis for clinical interventions by nurses is assessed and the
      training needs and legal consequences explored. The future role of nurses in
      prescribing drugs is uncertain, but likely to be significant.

PMID- 12617412
TI  - The national clinical assessment authority: a healthy sign of the times.
AB  - The National Clinical Assessment Authority (NCAA) is a special health authority
      established on the 1 April 2001 following recommendations made in the Chief
      Medical Officer's reports, Supporting doctors, protecting patients (November
      1999) and Assuring the quality of medical practice (January 2001). The aim of the
      Authority is to provide a support service to NHS primary care, hospital and
      community trusts, and to the Prison and Defence Medical Services when they are
      faced with concerns at the performance of an individual doctor or dentist. The
      Authority provides advice, takes referrals and carries out targeted assessments
      where necessary, using trained medical and lay assessors. Once an assessment has
      been completed, the Authority will advise on appropriate courses of action and
      will facilitate a local plan of action. The NCAA does not take over the role of
      an employer, nor does it function as a regulator: its function is purely advisory
      and the NHS employer remains responsible for resolving the problem.

PMID- 12617413
TI  - The evolution of the doctrine of consent.
AB  - The doctrine of informed consent is evolving. It has taken different routes in
      different jurisdictions. However, these different paths are converging to a
      general consensus. The Bolam test, which has been the primary exposition of this
      doctrine in this country, sets the standard of care as a matter of medical
      judgement. However, recent cases, particularly Rogers v Whitaker, shift the
      perspective in favour of warning the patient of material risks inherent to
      proposed treatment. Whether this information is sufficient to give consent is not
      a question the answer to which depends upon standards of medical practice. There
      is no doubt that this is the evolving global trend. Whilst this might seem more
      onerous the doctrine is of constructive use in securing public awareness in organ
      donation and in the effectiveness of public health policies.

PMID- 12617414
TI  - Bowel care in older people.
AB  - Bowel dysfunction not only causes considerable hardship for many older people and
      their carers, it is also financially costly to the health service and to the
      individuals affected. Despite the prevalence of constipation and faecal
      incontinence amongst, for example, older people in institutionalised settings,
      both conditions are often iatrogenic and entirely preventable. One reason why
      these conditions are generally not well managed is that the research base is
      poor: there are few robust data because of methodological weaknesses in existing
      studies, so clinicians and care staff are left to rely on anecdote and personal
      experience. Secondly, the costs to the NHS involved in providing proper bowel
      care for the elderly would be considerable, although recent government documents
      have set out a specific commitment to improve standards of care in this area. In
      order to address some of these issues, the College has recently published a book
      which gathers together and assesses research on faecal incontinence and
      constipation, and provides informed guidance on current best practice. The
      contents of the publication, including comments from older people suffering from
      bowel dysfunction, are outlined in this article.

PMID- 12617415
TI  - Cultural differences: practising medicine in an Islamic country.
AB  - Islam and Muslims have been in the headlines recently for one reason or another.
      But the practice of medicine in an Islamic conservative country such as Saudi
      Arabia has not been adequately reported. Many questions about cultural
      differences in the practice of medicine have been directed at me by non-Muslim
      colleagues. Below, I have tried to answer some of them after practising at a
      university hospital in Saudi Arabia for the last 25 years.

PMID- 12617416
TI  - Recognising severe pneumonia with simple clinical and biochemical measurements.
AB  - Community-acquired pneumonia (CAP) is the most common reason for acute admission
      to hospital and the fourth most common cause of death in the UK. It is important
      to identify patients with severe pneumonia and the worst prognosis. We conducted
      this study to validate a rule designed to do this devised in New Zealand. CAP was
      defined by evidence of new shadowing on the chest X-ray and clinical features of
      pneumonia. A standardised proforma was completed documenting clinical features
      and investigation results. Severe pneumonia was identified by two or more of the
      following: confusion; respiratory rate > or = 30/min; diastolic blood pressure <
      or = 60 mmHg; urea >7 mmol/l. One hundred patients (mean age 58.8 years) were
      included; 32 satisfied the rule. Seven died, all of whom satisfied the rule. Ten
      patients received intensive care, including six who died. Of 11 patients who died
      and/or received intensive care, nine satisfied the rule. The sensitivity and
      specificity of the rule for predicting death and/or intensive care were 82% and
      73% respectively.

PMID- 12617418
TI  - Advances in rehabilitation: an overview and an odyssey.

PMID- 12617417
TI  - The management of pulmonary and lymph node tuberculosis notified in England and
      Wales in 1998.
AB  - The management of 1,337 cases of pulmonary tuberculosis and 422 cases of lymph
      node tuberculosis reported to the 1998 national notification survey was compared
      with the recommended standards of treatment. Most patients (84%) were under the
      care of thoracic physicians. Culture confirmation was obtained in 67.5% of
      pulmonary cases and 52% of lymph node cases. Drug resistance was reported in 7%,
      ranging from 3.3% in white patients to 7.9-8.2% in other ethnic groups. Only a
      minority of non-white ethnic patients received the recommended four-drug initial
      phase of therapy. Non-standard durations of initial and/or continuation therapy
      were used in 35% of cases on recommended drug combinations. Thirty-nine (2.9%)
      pulmonary cases were diagnosed only at post-mortem and a further 96 died before
      the end of the survey period, 55 (4.3%) due to tuberculosis. The outcome for
      pulmonary disease, with 80% cured or completing treatment, compare favourably
      with European outcome data. Although overall outcome data were satisfactory, more
      patients should have received a four-drug initial phase, with more combination
      tablet use and better compliance monitoring. Outcome monitoring will henceforth
      be based mainly on the continuous enhanced surveillance system introduced since
      1999.

PMID- 12617419
TI  - Safety and quality in healthcare: what can England and Australia learn from each
      other?
AB  - Australia and England have similar healthcare systems. They are affordable and
      accessible to all; both are blessed with health professionals of great skill.
      Anybody who falls ill in either country can expect a high standard of care. And
      yet, all is not well. The care we give our patients is not as safe as it should
      be and the community is becoming well aware of this. Our public healthcare
      systems never seem to have enough resources; our public hospitals show varying
      degrees of dilapidation. Access to care, while universal, is too often delayed.
      The medical workforce is understaffed, maldistributed (or both) and the shortage
      of nurses is of great concern. In both professions, morale is fragile. What,
      then, can be done to improve the safety and quality of healthcare in Australia
      and England?

PMID- 12617420
TI  - Forensic entomology.
AB  - Forensic entomology is the application of insect biology to the investigation of
      crime. The subject covers all aspects of insect evidence, but for the purpose of
      this article the discussion will be restricted to insect evidence from the bodies
      of persons thought to have been the victims of murder or other unlawful killing.

PMID- 12617422
TI  - AIDS and CFS/ME: a tale of two syndromes.
AB  - Both HIV/AIDS and chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
      presented major challenges for medicine, science and society. This article
      explores what could have impeded investigation of--and specifically
      pharmaceutical engagement with--CFS/ME, in contrast to the impressive
      achievements seen in HIV/AIDS. It explores the obstruction of mind-body dualism
      in a historical context, and examines some of the possible obstacles to
      pharmaceutical enquiry. Nothing of real substance is identified that would
      justify the lack of investment and interest in solutions for patients with
      CFS/ME.

PMID- 12617421
TI  - Treatment in art. Portrait of Sir Alexander Morison.

PMID- 12617423
TI  - 'Trust me--I'm a philosopher...

PMID- 12617424
TI  - Are preventive drugs preventive enough.

PMID- 12617426
TI  - Sir Douglas Black (1913-2002).

PMID- 12617427
TI  - Senior house officers in medicine are still not getting adequate appraisals.

PMID- 12617425
TI  - Diagnosis and management of gastrointestinal causes of chest pain of uncertain
      origin--'oesophageal angina'.

PMID- 12617428
TI  - Driving restrictions after stroke: doctors' awareness of DVLA guidelines and
      advice given to patients.

PMID- 12617430
TI  - Scientific conservatism.

PMID- 12617431
TI  - Sub-Saharan Africa.

PMID- 12617429
TI  - Serious hyperkalaemia after short use of low molecular weight heparin in a
      diabetic patient.

PMID- 12617432
TI  - The Doolin Memorial Lecture: December 2002. The fight against diseases of the
      poor; the moral imperative for development assistance.

PMID- 12617433
TI  - Haemoglobinopathy in Ireland: the changing face of Irish medicine.

PMID- 12617434
TI  - Treatment of anaemia in the polytrauma Jehovah's Witness.
AB  - The management of Jehovah's Witnesses can prove quite challenging to the surgeon
      who routinely uses blood and blood products in the treatment of anaemia and
      hypovolaemia. The medical and legal dilemmas are exacerbated when the patient has
      a critically low haemoglobin level or has suffered life-threatening blood loss
      following polytrauma. It is essential that the treating physician should have
      some knowledge and understanding of the beliefs of the Jehovah's Witness in order
      to effectively minimise and treat blood loss. This paper reviews the ethical and
      medicolegal aspects involved, as well as alternatives to allogenic blood products
      in the treatment of anaemia in the polytrauma Jehovah's Witness patient.

PMID- 12617435
TI  - A national census of Irish general practice training programme graduates 1990
      1996.
AB  - We followed the career pathways of all graduates of Irish general practice
      training schemes between 1990 and 1996 inclusive, with specific reference to
      their current positions, ten year aspirations, perceived barriers to their ideal
      career and attitudes to out of hours work. A postal survey using a structured
      questionnaire was performed. Addresses were identified for 253 of the 266
      graduates (95%). A total of two hundred and nine responses were received (84% of
      those with an identifiable address). 173 (83%) have remained in general practice;
      90% in Ireland and 60% in the same health board of their training programme. The
      preferred career option for 79% was to be a general practice principal; this
      differed significantly between males (89%) and females (74%) (p=0.016). Being a
      single-handed general practitioner was the preferred option for 2%; 43%
      considered this unacceptable. A half would prefer to work in a country town; one
      third considered a rural location as unacceptable. 'Out of hours' commitment and
      availability of local posts were the most commonly perceived barriers to career
      progress (53% and 45% respectively). 26% were not prepared to do any out of hours
      work; this differed significantly between males (10%) and females (30%) (p<.001).
      17% have permanently left a career in general practice. Female general
      practitioners were not significantly more likely than male general practitioners
      to have left (19% vs. 14%, p=0.3). The most common reason given for leaving
      general practice was other career interest (78%). The significant increase in
      female general practice graduates over the past twenty years is highlighted. The
      vast majority of these female graduates wished to be a principal in a group
      practice and were prepared to undertake out of hours work. There is also a
      mismatch between career aspirations and the present structure of general practice
      in Ireland. The urgent need for changes in health system organisation to ensure
      that these intentions can be fulfilled is emphasised.

PMID- 12617436
TI  - Helicobacter Pylori eradication therapy: getting research into practice.
AB  - Helicobacter Pylori (H. Pylori) is the primary cause of duodenal ulcer (DU).
      Guidelines recommend that all patients with DU be considered for Helicobacter
      Pylori Eradication Therapy (HPET). However, the proportion of patients with DU on
      long term anti-ulcer medication receiving HPET is small. This study examined the
      effectiveness of the continuing medical education (CME) network of the Irish
      College of General Practitioners (ICGP) in promoting best practice in DU
      treatment among GPs in an eastern region of Ireland. Ninty eight GPs recruited
      from the CME network of the ICGP were randomised in two cohorts. Cohort 1
      received an (early) intervention; GPs were asked to identify their patients with
      DU receiving long term anti-ulcer medication and prescribe HPET according to
      defined criteria. Cohort 2 received the intervention later. Prescribing of HPET
      was monitored using routine prescribing data. Twenty per cent (286/1,422) of
      patients in cohort 1 and 19.2% (127/661) in cohort 2 had a DU. After exclusions,
      53% (152/286) in cohort 1 and 30.7% (39/127) in cohort 2, were eligible for HPET.
      A significantly higher proportion of patients in cohort 1 received HPET compared
      with cohort 2 during the early intervention period (13.8% vs 0.0%, p<0.05).
      Reasons for not prescribing HPET included concurrent illness in patients, failure
      to comply with treatment. Best practice guidelines on HPET treatment of DU can be
      successfully applied using CME networks. This model could be repeated in another
      therapeutic area where established research is not yet current practice.

PMID- 12617437
TI  - The incidence of incomplete excision in surgically treated basal cell carcinoma:
      a retrospective clinical audit.
AB  - BCC is the commonest of the malignant skin tumours and the complete resection is
      the key to successful outcome with the cure rate of the order of 95%. Incomplete
      excisions are associated with high rate of recurrence. We designed our study to
      quantify the incidence of incomplete excision and its association with the
      subsequent recurrence of the tumour and also to identify any variables that might
      affect it. Case notes of 118 patients who had 126 BCCs excised between January
      1995 and December 1995 in the Mater Hospital were studied retrospectively. 10
      lesions showed incomplete excision on histology.

PMID- 12617438
TI  - Prescription monitoring in an Irish hospital.
AB  - The prescribing of medicines is an integral part of the provision of healthcare
      and represents a relatively safe, effective and inexpensive mode of treatment.
      Hospital prescribing is of importance not alone for patients but also for the
      impact that it has on the prescribing of drugs in the community. We conducted a
      'snap-shot' study of 1,488 hospital prescriptions and assessed such areas as
      legibility, generic prescribing and drug dosage. The average number of active
      prescriptions per patient was 5.47 for medical in-patients and 5.05 for surgical
      in-patients. 5% of prescriptions were deemed illegible and the rate of generic
      prescribing was relatively low. However the rate of compliance with the hospital
      formulary was good. The spectrum of drugs prescribed changed significantly from a
      previous study performed in 1987. Continuous review of doctors' prescribing
      habits will ensure the safe and economic use of medications.

PMID- 12617439
TI  - A survey of Irish consultants regarding awareness of sperm freezing and assisted
      reproduction.
AB  - Chemotherapy and radiotherapy decrease male fertility. Pretreatment semen
      cryopreservation offers a chance for future fatherhood. However many eligible
      patients are not referred. One potential reason for the reduced uptake is lack of
      awareness by referring consultants. We sent a questionnaire to all 41 consultant
      oncologists, haematologists and urologists listed in the Irish Medical Directory.
      The questionnaire surveyed the current knowledge, opinions and clinical practices
      of this key group regarding semen cryopreservation for male cancer patients. 63%
      responded. 73% routinely discuss semen freezing with their male cancer patients
      (mostly testicular carcinomas and lymphomas). 100% believe semen cryopreservation
      helps the patient psychologically. 12% do not know where facilities exist. 92%
      will only refer men aged between 20 and 40 years. 92% are unaware that semen
      freezing does not delay cancer treatment. 54% have heard of intracytoplasmic
      sperm injection (ICSI) but 88% are unaware of its benefits for patients with low
      sperm counts. Consultants dealing with male cancer patients do not prioritise
      future fertility. Most of the consultants surveyed were unaware of the advances
      in reproductive technology and this may be contributing to underutilization of
      sperm cryopreservation by male cancer patients. Units offering this service need
      to increase awareness of its potential benefits.

PMID- 12617440
TI  - Deep vein thrombosis in a tiler wearing tight knee pads.
AB  - Venous compression is a rare but accepted cause of Deep Venous Thrombosis. We
      report a case of DVT caused by extrinsic compression of the popliteal vein by
      constricting elasticated knee pads. The knee pads were worn at work by a Tiler
      who did not have any hypercoagulability disorder.

PMID- 12617441
TI  - Generic drug packaging leading to a critical incident.

PMID- 12617442
TI  - Wilson's disease--a diagnostic dilemma?

PMID- 12617443
TI  - Evaluation of diagnostic parameters of Wilson's disease in childhood.
AB  - BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder with
      variable clinical presentation. Its diagnosis depends on a combination of
      clinical and laboratory findings. We evaluated the sensitivity of various
      diagnostic tests in children with WD and high liver copper concentrations.
      METHODS: Thirty-three children (6-15 years old, 19 male) with confirmed WD
      (hepatic copper >250 mcirog/g dry weight) were evaluated retrospectively. Eyes
      were examined with biomicroscope for Kayser-Fleischer rings and urinary copper
      content was determined in 30 patients. Serum ceruloplasmin levels were measured
      and liver tissue samples were stained with orcein in all. RESULTS: All patients
      presented with hepatic disease. Four patients also had neurological involvement.
      Hepatic copper concentration was between 250 and 1200 microg/g. Eighteen patients
      had liver cirrhosis, 9 chronic hepatitis, and 6 had massive hepatic necrosis on
      liver biopsy or necropsy. The sensitivity of various tests evaluated was: 100%
      (30/30) for urinary copper excretion, 88% (29/33) for orcein staining on liver
      tissues, 82% (27/33) for ceruloplasmin levels, and 63% (19/30) for presence of
      Kayser-Fleischer ring. Kayser-Fleischer ring was present in all patients with
      neurological manifestations and in 58% of patients with only hepatic
      presentation. CONCLUSIONS: 24-hour urinary copper excretion seems to be the most
      sensitive test for diagnosis of WD, particularly when liver biopsy cannot be
      performed due to coagulation abnormalities.

PMID- 12617444
TI  - Infected necrosis complicating acute pancreatitis: experience with 131 cases.
AB  - OBJECTIVE: Despite advances in its management, the mortality of infected
      pancreatic necrosis (IPN) remains high. We report our observations on
      complications and treatment of IPN. METHODS: We studied 131 patients with IPN
      seen over a 20-year period. Infection, suspected clinically, was proved by
      presence of extraluminal air on CT scan (23 cases), or by guided percutaneous
      aspiration of fluid or solid necrotic tissue, and bacteriological studies of the
      aspirate. Apart from organ support, vigorous nutritional support and appropriate
      antibiotic therapy were instituted. Evacuation of pus and surgical necrosectomy
      was done. Feeding jejunostomy was done in the majority of patients. RESULTS:
      Postoperative complications included multiple organ dysfunction syndrome (MODS;
      n=40, in addition to 65 with pre-operative MODS), pancreatic fistula (69),
      gastrointestinal fistula (24), and severe extra-intestinal bleeding (8 patients).
      Pancreatic fistula developed in 30 of 63 patients who received octreotide and in
      39 of 68 patients who did not (p=ns). Forty-five patients died. Of 35 patients
      who underwent surgery within 15 days of the onset of acute necrotizing
      pancreatitis, 21 (60%) died; in comparison, of the 96 patients who underwent
      surgery more than 15 days after onset, 24 (25%) died (p<0.002). Mortality was
      higher among those with serum albumin less than 2.5 g/dL than in those with
      albumin above 2.5 g/dL (20/36 versus 25/95; p=0.002), and in those with MODS
      (43/105) than in those without (2/26; p=0.001). CONCLUSIONS: Complications of IPN
      include MODS (pre- or post-operative), gastrointestinal and pancreatic fistula,
      and extra-intestinal bleeding. Serum albumin below 2.5 g/dL, development of MODS
      and need for early surgery appear to be unfavorable features associated with
      higher mortality.

PMID- 12617446
TI  - Bile cultures and sensitivity patterns in malignant obstructive jaundice.
AB  - BACKGROUND: Bactibilia is one of the important factors in the development of
      postoperative septic complications. We undertook this retrospective analysis to
      identify the organisms present in bile and their antibiotic susceptibility
      patterns in patients with malignant obstructive jaundice. METHODS: Bile specimens
      were obtained during endoscopic cholangiography (ERC; n=65), by flushing biliary
      stents (n=15), intra-operatively before incising the common bile duct (n=7) or
      during percutaneous transhepatic biliary drainage (PTBD; n=1). Eighty-eight
      samples from 65 consecutive patients were analyzed for their bacterial spectrum
      and sensitivity to antibiotics. Concomitant septic complications such as wound
      infection and cholangitis were also assessed. RESULTS: Of 65 patients (hilar
      block 39, distal block 26), 17 (26.1%) had bactibilia at initial ERCP; in
      addition, 3 of 7 bile specimens obtained during surgery, one collected during
      PTBD, and 13 of 15 stent flushings grew bacterial organisms. Cholangitis
      developed in 15 patients (12 with hilar block, 3 with distal block). Blood
      cultures were positive in 3 cases, and initial bile culture was positive in four
      patients with cholangitis. The most commonly found organisms were Escherichia
      coli (36.6%), Klebsiella pneumonia (18.3%), Pseudomonas aeruginosa (8.3%),
      Proteus vulgaris (8.3%) and coagulase-negative staphylococci (8.3%). The
      organisms found on ERC were similar to those found at wound cultures in 3 of the
      4 cases who developed wound infection. Amikacin, gentamicin, cefotaxime,
      ceftazidime, and cefoperazone-sulbactam combination showed good activity against
      E. coli and K. pneumonia. CONCLUSION: Approximately one-fourth of patients with
      malignant obstructive jaundice have positive bile cultures at initial ERC. Post
      ERC cholangitis is common in hilar blocks.

PMID- 12617445
TI  - Comparison of etiology of sporadic acute and fulminant viral hepatitis in
      hospitalized patients in Pune, India during 1978-81 and 1994-97.
AB  - OBJECTIVE: To determine and compare the etiology of sporadic acute and fulminant
      viral hepatitis in two groups of patients 16 years apart. METHODS: Serologic
      diagnostic tests for hepatitis A, B, C, D and E, and cytomegalovirus infection
      were carried out in 276 patients during 1994-1997 (Group A) and 206 patients
      during 1978-1981 (Group B). RESULTS: Among children, hepatitis A virus was the
      major etiologic agent (81.6% in Group A and 51.4% in Group B), followed by
      hepatitis E virus (12.2%, 46.4%) and hepatitis B virus (5.4%, none). Among
      adults, hepatitis E virus was the main causative agent (42.4% in Group A and
      71.2% in Group B) followed by HBV (28%, 25.5%) and hepatitis A virus (10.6%,
      3.5%). Delta hepatitis was found only in Group A. No viral cause was found in 25%
      of patients in Group A and 13.5% patients in Group B. CONCLUSIONS: Hepatitis E
      virus is a major cause of sporadic acute and fulminant hepatitis. There has been
      an increase in hepatitis A in adults who developed fulminant hepatic failure. Our
      data points to the emergence of hepatitis A in adults and emergence of delta
      virus infection. Hepatitis C virus was unimportant in causing sporadic hepatitis.

PMID- 12617447
TI  - Multidrug resistance 1 gene expression in Indian patients with gastric carcinoma.
AB  - BACKGROUND: Gastric carcinoma is frequently refractory to chemotherapy. The
      multidrug resistance 1 gene (MDR1) encodes for a protein (p-glycoprotein) that
      functions as a drug efflux pump and thus contributes to resistance to
      chemotherapeutic agents. METHODS: We studied gastric tissues from 28 patients
      with gastric cancer for MDR1 expression, using immunohistochemistry. RESULTS:
      Sixteen (57%) of 28 cases showed MDR1 expression. Sections of normal mucosa away
      from the tumor showed perinuclear staining for MDR1 in surface epithelial cells,
      whereas tumor cells showed diffuse cytoplasmic positivity. CONCLUSIONS: Over one
      half of gastric carcinoma specimens at our center show MDR1 gene expression.

PMID- 12617448
TI  - Familial clustering of hepatitis B infection: study of a family.
AB  - Familial clustering of hepatitis B virus infection has been reported
      infrequently. We report a family of 27 members, where 13 members were HBsAg
      positive. This included 7 of 10 members in one linear family across four
      generations. Nine subjects who were tested were HBeAg-negative. Of these nine,
      three subjects had elevated ALT; histology in one of them showed activity index
      <3. One subject received lamivudine therapy elsewhere; ALT levels returned to
      normal in two months.

PMID- 12617449
TI  - Obstructing enterolith as presenting feature in Crohn's disease.
AB  - We report a 54-year-old woman with Crohn's disease presenting with intestinal
      obstruction due to an enterolith impacted at the site of a small bowel stricture.
      The diseased bowel was successfully resected by laparoscopy-assisted surgery.

PMID- 12617450
TI  - Mycobacterium avium-intracellulare in stool in HIV-seropositive man.
AB  - Mycobacterium tuberculosis is the predominant acid-fast bacillus causing diarrhea
      in HIV-seropositive patients in India. We report a 27-year-old HIV-seropositive
      man with diarrhea in whom M. avium-intracellulare was isolated on stool culture.

PMID- 12617451
TI  - Non-parasitic hepatic cysts causing obstructive jaundice: two cases.
AB  - Non-parasitic hepatic cysts rarely cause jaundice. We report two patients with
      such lesions treated by percutaneous drainage.

PMID- 12617452
TI  - Sacrococcygeal teratoma with anorectal malformation.
AB  - A 7-month-old child presented with imperforate anus, penoscrotal hypospadias and
      transposition, and a midline mucosa-lined perineal mass. At surgery the mass was
      found to be supplied by the median sacral artery. It was excised and the
      anorectal malformation was repaired by posterior sagittal anorectoplasty.
      Histologically the mass revealed well-differentiated colonic tissue. The final
      diagnosis was well-differentiated sacrococcygeal teratoma in association with
      anorectal malformation.

PMID- 12617453
TI  - Acute mesenteric venous thrombosis complicating endoscopic variceal sclerotherapy
      with absolute alcohol.
AB  - We report two patients, one with liver cirrhosis and another with extrahepatic
      portal vein obstruction, who developed acute mesenteric vein thrombosis following
      endoscopic variceal sclerotherapy with absolute alcohol. Both patients recovered
      after emergency laparotomy and resection of gangrenous bowel loop.

PMID- 12617454
TI  - Endoscopic management of anal protrusion of ventriculo-peritoneal shunt.
AB  - A 2-year-old male child, who was operated on 18 months earlier for tuberculous
      meningitis with hydrocephalus by placement of a ventriculo-peritoneal shunt,
      presented with the lower end of the shunt tube coming out through the anus.
      Colonoscopy showed the shunt tube coming out through the colon 22 cm from the
      anal opening. The cranial end, along with a malfunctioning valve, were
      disconnected surgically, and the shunt was removed endoscopically using a
      pediatric flexible colonoscope.

PMID- 12617455
TI  - Liver adenomatosis.
AB  - A 27-year-old man presented with 2 months' history of right hypochondrial pain,
      fever and mild transient pruritus. On examination, he had firm, nontender and
      nodular hepatomegaly. Imaging modalities showed multiple heterogeneous lesions of
      varying size in the liver. Liver biopsy was consistent with hepatocellular
      adenoma.

PMID- 12617456
TI  - Jejunogastric intussusception presenting with outlet obstruction.
AB  - A 77-year-old man presented with sudden-onset epigastric pain and bilious
      vomiting following a light breakfast. Vagotomy and gastrojejunostomy for bleeding
      duodenal ulcer had been done 22 years ago. Barium meal study suggested
      jejunogastric intussusception. At laparotomy, a retrograde type II jejunogastric
      intussusception was confirmed and managed by reduction of the intussusception,
      disconnection of gastrojejunostomy and resection of the jejunum. Postoperative
      recovery was uneventful.

PMID- 12617457
TI  - Transfixation of neck of hernial sac--a needless step in adults?

PMID- 12617458
TI  - Community-based study of hepatitis B markers in women of reproductive age.

PMID- 12617459
TI  - Magnitude of hepatitis C virus infection in upper Assam.

PMID- 12617460
TI  - Treatment of typhoid ileal perforation by resection and temporary ileostomy.

PMID- 12617461
TI  - Recurrent trichobezoar in a woman.

PMID- 12617462
TI  - Clinical significance of fading infraumbilical abdominal veins.

PMID- 12617464
TI  - The effects of vitamin E and selenium intake on oxidative stress and plasma
      lipids in hamsters fed fish oil.
AB  - The aim of the present work was to test the effects of large-dose supplementation
      of vitamin E (Vit E) and selenium (Se), either singly or in combination, on fish
      oil (FO)-induced tissue lipid peroxidation and hyperlipidemia. The
      supplementation of Se has been shown to lower blood cholesterol and increase
      tissue concentrations of the antioxidant glutathione (GSH); however, the effects
      of Se supplementation, either alone or in combination with supplemental Vit E, on
      FO-induced oxidative stress and hyperlipidemia have not been studied. Male Syrian
      hamsters received FO-based diets that contained 14.3 wt% fat and 0.46 wt%
      cholesterol supplemented with Vit E (129 IU D-alpha-tocopheryl acetate/kg diet)
      and/or Se (3.4 ppm as sodium selenate) or that contained basal requirements of
      both nutrients. The cardiac tissue of hamsters fed supplemental Se showed
      increased concentrations of lipid hydroperoxides (LPO) but decreased oxidized
      glutathione (GSSG) concentrations. The higher concentrations of LPO in the hearts
      of Se-supplemented hamsters were not lowered with concurrent Vit E
      supplementation. In the liver, Se supplementation was associated with higher Se
      dependent glutathione peroxidase activity and an increase in the GSH/GSSG ratio,
      whereas a lower hepatic non-Se-dependent glutathione peroxidase activity was seen
      with Vit E supplementation. Supplemental intake of Se was associated with lower
      plasma concentrations of total cholesterol and low density lipoprotein
      cholesterol plus very low density lipoprotein cholesterol. In view of the pro
      oxidative effects of Se supplementation on cardiac tissue, a cautionary approach
      needs to be taken regarding the plasma lipid-lowering properties of supplemental
      Se.

PMID- 12617465
TI  - Endothelial vasodilatory function is predicted by circulating apolipoprotein B
      and HDL in healthy humans.
AB  - Endothelium-dependent vasodilation (EDV), LDL particle size, and antibodies
      against oxidized LDL (oxLDLab) have been shown to be related to the development
      of atherosclerosis and cardiovascular disease. In this study, we investigated
      whether LDL particle size, oxLDLab, apolipoproteins, and lipoproteins are related
      to endothelial vasodilatory function in a population sample of 58 apparently
      healthy subjects aged 20 to 69 yr. EDV and endothelium-independent vasodilation
      (EIDV) were studied in the forearm during local administration of methacholine
      chloride (2 and 4 microg/min) or sodium nitroprusside (5 and 10 microg/min).
      Forearm blood flow was determined with venous occlusion plethysmography. In
      multiple stepwise regression analyses, neither oxLDLab nor small LDL particles
      were significantly predictive of endothelial vasodilatory function. Instead, a
      high level of apolipoprotein B (apoB) was an independent predictor of both
      attenuated EDV and EIDV (r = -0.43, P < 0.01, and r = -0.34, P < 0.05,
      respectively). HDL cholesterol, on the other hand, was the only lipid variable
      that was significantly related to the EDV to EIDV ratio, an index of endothelial
      vasodilatory function (r = 0.35, P < 0.01). The inverse associations between apoB
      and both EDV and EIDV indicate that apoB might be an early marker of structural
      vascular changes in healthy subjects, whereas HDL seems to be more specifically
      related to endothelial vasodilatory function.

PMID- 12617466
TI  - The types of circulating fatty acids influence vascular reactivity.
AB  - The objective of this study was to investigate the relationship between the
      composition of FA in serum lipids, a marker of dietary fat intake, and vascular
      reactivity using a combination of cross-sectional and intervention approaches.
      Fifty-six middle-aged subjects were evaluated in a cross-sectional protocol
      regarding the relationship between the proportion of FA in serum cholesterol
      esters and vascular reactivity using measurements of forearm blood flow (FBF)
      with venous occlusion plethysmography during hyperemia. Another 19 middle-aged
      subjects were given a rapeseed oil-based diet rich in mono- and polyunsaturated
      FA or a control diet rich in saturated FA during two consecutive 4-wk periods
      separated by a 4-wk washout period. In the cross-sectional protocol, the FA 18:0
      and 20:3 were positively related to resting FBF, whereas an inverse relationship
      was seen for the FA 20:5 and 22:6 (P < 0.05-0.01). Opposite relationships were
      seen between these four FA and the relative increase in maximal FBF during
      hyperemia (P < 0.05-0.01). In the intervention protocol, the saturated diet
      increased resting FBF, as well as the relative increase in maximal FBF during
      reactive hyperemia, compared to the diet rich in unsaturated FA (P < 0.05). Both
      the cross-sectional and intervention data support the view that the composition
      of serum FA, which at least partly reflects the quality of dietary fat, plays a
      role in determinations of vascular reactivity.

PMID- 12617467
TI  - Are trans isomers of alpha-linolenic acid of nutritional significance for certain
      populations?

PMID- 12617463
TI  - What is the role of alpha-linolenic acid for mammals?
AB  - This review examines the data pertaining to an important and often underrated
      EFA, alpha-linolenic acid (ALA). It examines its sources, metabolism, and
      biological effects in various population studies, in vitro, animal, and human
      intervention studies. The main role of ALA was assumed to be as a precursor to
      the longer-chain n-3 PUFA, EPA and DHA, and particularly for supplying DHA for
      neural tissue. This paper reveals that the major metabolic route of ALA
      metabolism is beta-oxidation. Furthermore, ALA accumulates in specific sites in
      the body of mammals (carcass, adipose, and skin), and only a small proportion of
      the fed ALA is converted to DHA. There is some evidence that ALA may be involved
      with skin and fur function. There is continuing debate regarding whether ALA has
      actions of its own in relation to the cardiovascular system and neural function.
      Cardiovascular disease and cancer are two of the major burdens of disease in the
      21st century, and emerging evidence suggests that diets containing ALA are
      associated with reductions in total deaths and sudden cardiac death. There may be
      aspects of the action and, more importantly, the metabolism of ALA that need to
      be elucidated, and these will help us understand the biological effects of this
      compound better. Additionally, we must not forget that ALA is part of the whole
      diet and should be seen in this context, not in isolation.

PMID- 12617468
TI  - Reassessment of the contribution of bovine milk fats to the trans-18:1 isomeric
      acid consumption by European populations. Additional data for rumenic (cis
      9,trans-11 18:2) acid.

PMID- 12617469
TI  - From gallstones to genes: two hundred years of sterol research. A tribute to
      George J. Schroepfer Jr.
AB  - The origins of cholesterol research can be traced to prerevolutionary France. The
      discovery of cholesterol as a single substance, present in human gallstones, owes
      much to the scientists of l'Academie Francaise, including Lavoisier, who
      contributed so much to the emergence of chemistry as a modern scientific
      discipline. Since that time, cholesterol probably has been the most intensively
      scrutinized natural product of all time, and it has been the subject of Nobel
      Prizes for several who have studied its structure, biosynthesis, and regulation.
      The pace of research into cholesterol shows no sign of diminishing, and recent
      discoveries have led to the recognition that the regulation of cholesterol
      metabolism is intimately linked with that of other metabolic pathways. Details of
      these interactions are only just emerging, but it is becoming apparent that under
      some circumstances it is difficult to reconcile, in a conventional manner,
      changes in regulatory gene expression with corresponding changes in pathway
      carbon flux. The present review includes some of our studies on the roles of the
      transcription factors sterol regulatory element-binding protein, liver X-receptor
      alpha, and peroxisome proliferator activated receptor a in the coordination of
      cholesterol and fatty acid synthesis and describes how some of the results
      obtained can best be interpreted from a Metabolic Control Analysis perspective of
      the regulation of pathway carbon fluxes.

PMID- 12617470
TI  - The role of cytochrome P450 in the regulation of cholesterol biosynthesis.
AB  - A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51,
      encodes lanosterol 14alpha-demethylase, the first step in the conversion of
      lanosterol into cholesterol in mammals. The biosynthetic intermediates of
      lanosterol 14alpha-demethylation are oxysterols, which inhibit HMG-CoA reductase
      and sterol synthesis in mammalian cells in vitro. These oxysterols (5alpha-lanost
      8-en-3beta,32-diol and 3beta-hydroxy-5alpha-lanost-8-en-32-al) are efficiently
      converted into cholesterol in vitro and are generally considered to be natural
      cholesterol precursors. When added to hepatocytes in high concentrations, besides
      their conversion into cholesterol, they are also rapidly metabolized into more
      polar sterols and into steryl esters. The 15alpha- and 15beta-hydroxy epimers of
      5alpha-lanost-8-en-3beta-ol are also rapidly metabolized into more polar sterols
      and steryl esters but are not converted efficiently into cholesterol. Polar
      sterol formation from all these oxysterols is dependent on an active form of
      cytochrome P450. Oxysterols are potent regulators of the activities of
      transcription factors of the sterol regulatory element-binding protein family and
      of liver X-receptor alpha. It is proposed that the rapid, cytochrome P450
      dependent metabolism of naturally occurring regulatory oxysterols provides a
      route for their deactivation so that they become incapable of affecting gene
      transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents
      the inactivation of such oxysterols, leading to a prolonged suppression of
      hepatic HMG-CoA reductase in vivo and in vitro.

PMID- 12617472
TI  - Evidence for multiple sterol methyl transferase pathways in Pneumocystis carinii.
AB  - The sterol composition of Pneumocystis carinii, an opportunistic pathogen
      responsible for life-threatening pneumonia in immunocompromised patients, was
      determined. Our purpose was to identify pathway-specific enzymes to impair using
      sterol biosynthesis inhibitors. Prior to this study, cholesterol 15 (ca. 80% of
      total sterols), lanosterol 1, and several phytosterols common to plants
      (sitosterol 31, 24alpha-ethyl and campesterol, 24alpha-methyl 30) were
      demonstrated in the fungus. In this investigation, we isolated all the previous
      sterols and many new compounds from P. carinii by culturing the microorganism in
      steroid-immunosuppressed rats. Thirty-one sterols were identified from the fungus
      (total sterol = 100 fg/cell), and seven sterols were identified from rat chow.
      Unusual sterols in the fungus not present in the diet included, 24(28)
      methylenelanosterol 2; 24(28)E-ethylidene lanosterol 3; 24(28)Z-ethylidene
      lanosterol 4; 24beta-ethyllanosta-25(27)-dienol 5; 24beta-ethylcholest-7-enol 6;
      24beta-ethylcholesterol 7; 24beta,-ethylcholesta-5,25(27)-dienol 8; 24
      methyllanosta-7-enol 9; 24-methyldesmosterol 10; 24(28)-methylenecholest-7-enol
      11; 24beta-methylcholest-7-enol 12; and 24beta-methylcholesterol 13. The
      structural relationships of the 24-alkyl groups in the sterol side chain were
      demonstrated chromatographically relative to authentic specimens, by MS and high
      resolution 1H NMR. The hypothetical order of these compounds poses multiple
      phytosterol pathways that diverge from a common intermediate to generate 24beta
      methyl sterols: route 1, 1 --> 2 --> 11 --> 12 --> 13; route 2, 1 --> 2 --> 9 -->
      10 --> 13; or 24beta-ethyl sterols: route 3, 1 --> 2 --> 4 --> 6 --> 7; route 4,
      1 --> 2 --> 5 --> 8 --> 7. Formation of 3 is considered to form an interrupted
      sterol pathway. Taken together, operation of distinct sterol methyl transferase
      (SMT) pathways that generate 24beta-alkyl sterols in P. carinii with no
      counterpart in human biochemistry suggests a close taxonomic affinity with fungi
      and provides a basis for mechanism-based inactivation of SMT enzyme to treat
      Pneumocystis pneumonia.

PMID- 12617473
TI  - Transformations of DHEA and its metabolites by rat liver.
AB  - Because dehydroepiandrosterone (DHEA) has a wide variety of weak beneficial
      effects in experimental animals and humans, we searched for metabolites of this
      steroid in the hope of finding more active compounds that might qualify for the
      title "steroid hormone." Incubation of DHEA with rat liver homogenate fortified
      with energy-yielding substrates resulted in rapid hydroxylation at the 7alpha
      position of the molecule and subsequent conversion to other 7-oxygenated steroids
      in the sequence DHEA --> 7alpha-hydroxyDHEA --> 7-oxoDHEA --> 7beta-hydroxyDHEA,
      with branching to diols, triols, and sulfate esters. The ability of these
      metabolites to induce the formation of liver thermogenic enzyme activity
      increased from left to right in that sequence. A total of 25 different steroids
      were characterized, and at least six additional structures that are currently
      under study were produced from DHEA. 7-OxoDHEA is more effective than DHEA in
      enhancing memory performance in old mice and in reversing the amnesic effects of
      scopolamine.

PMID- 12617471
TI  - Subcellular localization of oxidosqualene cyclases from Arabidopsis thaliana,
      Trypanosoma cruzi, and Pneumocystis carinii expressed in yeast.
AB  - Cycloartenol synthase from Arabidopsis thaliana and lanosterol synthase from
      Trypanosoma cruzi and Pneumocystis carinii were expressed in yeast, and their
      subcellular distribution in the expressing cells was compared. Determination of
      enzymatic (oxidosqualene cyclase, OSC) activity and SDS-PAGE analysis of
      subcellular fractions proved that enzymes from T. cruzi and A. thaliana have high
      affinity for lipid particles, a subcellular compartment rich in triacylglycerols,
      and steryl esters, harboring several enzymes of lipid metabolism. In lipid
      particles of strains expressing the P. carinii enzyme, neither OSC activity nor
      the electrophoretic band at the appropriate M.W. were detected. Microsomes from
      the three expressing strains retained some OSC activity. Affinity of enzymes from
      A. thaliana and T. cruzi for lipid particles is similar to that of OSC of
      Saccharomyces cerevisiae, which is mainly located in this compartment. A
      different distribution of OSC in yeast cells suggests that they differ in some
      structural features critical for the interaction with the surface of lipid
      particles. Computer analysis supports the hypothesis of the structural difference
      since OSC from S. cerevisiae, A. thaliana, and T. cruzi lack or contain only one
      transmembrane spanning domain (a structural feature that makes a protein poorly
      inclined to associate with lipid particles), whereas OSC from P. carinii
      possesses six transmembrane domains. In the strain expressing cycloartenol
      synthase from A. thaliana, the accumulation of lipid particles largely exceeded
      that of the other strains.

PMID- 12617474
TI  - Studies toward the synthesis of the shark repellent pavoninin-5.
AB  - Sharks are the most dangerous predators of people in the sea, resulting in people
      being mauled and killed each year. A shark repellent could help to diminish this
      danger. The aglycone of the shark repellent pavoninin-5, (25R)-cholest-5-en
      3beta,15alpha,26-triol (5a), was synthesized from diosgenin (9). Removing mercury
      from the Clemmensen reduction of 9 gave a higher yield of (25R)-cholest-5-en
      3beta,16beta,26-triol, 10a, and was also more environmentally friendly. Attempted
      methods for the transposition of the C-16beta hydroxyl to the 15alpha position
      are described. A successful method for this transposition via the 15alpha-hydroxy
      16-ketone, 8a, using the Barton deoxygenation reaction on the 16-alcohol 14b, is
      reported.

PMID- 12617475
TI  - New chemical syntheses of cholest-4,6-dien-3-one.
AB  - Steroidal dienones represent a significant class of compounds that are useful
      intermediates in the further functionalization of the steroid nucleus. Their
      chemical synthesis can be problematic owing to the lack of a simplified method of
      preparation and the occurrence of impurities that can be difficult to remove. We
      have endeavored to develop new methods of chemical synthesis of cholest-4,6-dien
      3-one that would yield a product of high purity.

PMID- 12617476
TI  - Temperature-enhanced alumina HPLC method for the analysis of wax esters, sterol
      esters, and methyl esters.
AB  - Previous attempts at separating nonpolar lipid esters (including wax esters,
      sterol esters, and methyl esters) have achieved only limited success. Among the
      several normal-phase methods tested, a single recent report of a method employing
      an alumina column at 30 degrees C with a binary gradient system was the most
      promising. In the current study, modification of the alumina method by increasing
      the column temperature to 75 degrees C improved the separation of standards of
      wax esters and sterol esters. Elevated column temperature also enhanced the
      separation of FAME with differing degrees of unsaturation. Evidence was also
      presented to indicate that the method similarly separated phytosterol esters,
      based on their levels of unsaturation. With the increased interest in phytosterol
      and phytostanol-ester enriched functional foods, this method should provide a
      technique to characterize and compare these products.

PMID- 12617477
TI  - On the birth of a suicide prevention strategy and the death of suicidology.

PMID- 12617479
TI  - A description of a psychosocial/psychoeducational intervention for persons with
      recurrent suicide attempts.
AB  - This paper gives a description of a psychosocial/psychoeducational group
      intervention for individuals with a history of recurrent suicide attempts. The
      intervention was conceived to reduce the risk of future suicidal behavior and to
      modify the client's psychopathology. Three features are felt to make the
      intervention unique from others described in the literature. First, the
      intervention is targeted at both men and women from an inner-city population who
      are often underhoused, underemployed, and undereducated. 24 of 48 clients (50%)
      lived alone, and 24 of those (92%) were living in subsidized housing; 33% lived
      in supportive housing, and one lived on the street at the time of assessment. 48%
      had a high-school education or less. Second, the principles of our approach
      stressed client validation and participation in the development and delivery of
      the therapy. Our frame of reference was to name ourselves as professionals with a
      set of skills and access to some kinds of information and clients as the experts
      on the experience in their lives. Third, the group content incorporated a
      multimodal approach to meet the varied needs of the clients. Future reports will
      discuss the empirical evaluation of this intervention; however, the development
      of specific, targeted approaches for unique individuals with recurrent suicide
      attempts is clearly needed.

PMID- 12617478
TI  - The communicative aspect of nonfatal suicidal behavior--are there gender
      differences?
AB  - Data from the Norwegian part of the WHO/EURO Multicenter Study on Suicidal
      Behavior were used to investigate gender differences in the communicative aspect
      of nonfatal suicidal behavior by means of analyzing precipitating factors,
      intentions involved in and effects of the suicidal act within the frame of
      Qvortrup's interpretation of speech-act theory. Eighty-nine patients (48 women
      and 41 men) were included in the analyses, virtually no gender differences were
      found. Thus, in general, the results did not support the view that persons
      engaging in nonfatal suicidal behavior should receive different treatment or
      follow-up as a group based on their gender. The results gave some support to
      Qvortrup's speech-act theory and his four categories of suicidal behavior,
      emotional toward others, regulative toward others, emotional toward oneself and
      regulative toward oneself.

PMID- 12617480
TI  - Is the time of suicide a random choice? A new statistical perspective.
AB  - The problem of the time distribution of suicide has aroused the interest of many
      authors, but their findings often appear uncertain and contradictory. These
      inconsistencies can be partially explained by both the choice of the sample and
      the statistical method used for the analysis. In this study, in order to reveal
      expected and unexpected periodicities in the time distribution of suicides, we
      analyzed a small but complete and very homogeneous sample of suicides which
      occurred in the Mountain District of the Metauro River Valley in Italy in the
      period 1960-1994. A recent circular statistics technique, the "maximization of
      mean vector length" was used. We found no significant weekly and lunar patterns,
      but significant seasonal and intraseasonal cycles, with peaks in March and at the
      beginning of each season. The superposition of these two significant cyclic
      trends was also studied.

PMID- 12617482
TI  - Successful model of suicide prevention in the Ukraine military environment.
AB  - The article deals with the problem of suicidal behavior in the Ukraine military
      environment and gives an example of the successful prevention approach. The model
      of prevention is based on (1) education of the responsible officers, (2) training
      of the representatives of the most vulnerable risk groups, and (3) follow-up
      procedures based on distribution of pocket books for soldiers, educational
      booklets, and sets of helpful materials for officers. One of the main conclusions
      is that the prevention activity must be organized as a continuum of actions,
      seminars, consultations, and materials distribution.

PMID- 12617481
TI  - Psychological analysis of the Sri Lankan conflict culture with special reference
      to the high suicide rate.
AB  - The extremely high suicide rate in Sri Lanka is explained by a psychological
      analysis of the way in which Sri Lankans deal with conflicts. This "conflict
      culture" includes psychological factors, such as high rates in collectivism and
      power distance, repressive education, influence of foreign cultures, religion,
      and posttraumatic stress symptoms. Structural changes toward another "conflict
      culture," including conflict prevention and conflict solution in families and
      communities, are proposed.

PMID- 12617484
TI  - In the land of the lotos eaters. Letter across the Pacific.

PMID- 12617483
TI  - A Marxist perspective on assisted suicide.

PMID- 12617485
TI  - Nodus informis leti--"The most infamous death" (Virgil).

PMID- 12617486
TI  - Gabriel Ward Lasker--an appreciation.

PMID- 12617487
TI  - Genetic evidence for the phylogenetic relationship between Na-Dene and Yeniseian
      speakers.
AB  - Ruhlen's hypothesis, based on linguistic evidence, for a common phylogenetic
      origin of Na-Dene and Yeniseian speakers is tested using genetic data. Gene
      frequency data for the Kets, the only surviving Yeniseian speakers, were
      collected during a field study in 1993. Data for several Na-Dene groups, as well
      as other New World and Siberian populations, were compiled from the literature.
      These data were analyzed using R-matrix, principal components analysis, and
      Mantel tests. In a comparison of 10 New World and Siberian populations using
      eight alleles, 55.8% of the variation was accounted for by the first principal
      component, and 22.1% of the variation was subsumed by the second principal
      component. Contrary to Ruhlen's interpretation of the linguistic data, analysis
      of the genetic data shows that the Na-Dene cluster with other Native American
      populations, while the Kets genetically resemble the surrounding Siberian groups.
      This conclusion is further supported by correlations that are higher when the
      Kets are considered unrelated to Na-Dene speakers, and an insignificant partial
      correlation between genes and language when geography is held constant,
      indicating that spatial patterning accounts for most of the variation present in
      these populations.

PMID- 12617488
TI  - High levels of Y-chromosome differentiation among native Siberian populations and
      the genetic signature of a boreal hunter-gatherer way of life.
AB  - We examined genetic variation on the nonrecombining portion of the Y chromosome
      (NRY) to investigate the paternal population structure of indigenous Siberian
      groups and to reconstruct the historical events leading to the peopling of
      Siberia. A set of 62 biallelic markers on the NRY were genotyped in 1432 males
      representing 18 Siberian populations, as well as nine populations from Central
      and East Asia and one from European Russia. A subset of these markers defines the
      18 major NRY haplogroups (A-R) recently described by the Y Chromosome Consortium
      (YCC 2002). While only four of these 18 major NRY haplogroups accounted for -95%
      of Siberian Y-chromosome variation, native Siberian populations differed greatly
      in their haplogroup composition and exhibited the highest phiST value for any
      region of the world. When we divided our Siberian sample into four geographic
      regions versus five major linguistic groupings, analyses of molecular variance
      (AMOVA) indicated higher phiST and phiCT values for linguistic groups than for
      geographic groups. Mantel tests also supported the existence of NRY genetic
      patterns that were correlated with language, indicating that language affiliation
      might be a better predictor of the genetic affinity among Siberians than their
      present geographic position. The combined results, including those from a nested
      cladistic analysis, underscored the important role of directed dispersals, range
      expansions, and long-distance colonizations bound by common ethnic and linguistic
      affiliation in shaping the genetic landscape of Siberia. The Siberian pattern of
      reduced haplogroup diversity within populations combined with high levels of
      differentiation among populations may be a general feature characteristic of
      indigenous groups that have small effective population sizes and that have been
      isolated for long periods of time.

PMID- 12617489
TI  - Low levels of STRP variability are not universal in American Indians.
AB  - Data related to 15 short tandem repeat polymorphisms (STRPs) are reported for
      five Brazilian Indian populations, and a set of them compared with results
      previously reported for Asian, neo-Brazilian, North American, Iberian, and
      African populations. The low variability observed for these markers among the
      Surui Indians is confirmed, but the other populations show variability levels
      that are similar to those found elsewhere. Previous suggestions of population
      bottlenecks in the prehistorical colonization of the New World were not
      confirmed. On the other hand, STRPs again showed to be good markers for the
      establishment of population relationships.

PMID- 12617491
TI  - Genomic diversities and affinities among four endogamous groups of Punjab (India)
      based on autosomal and mitochondrial DNA polymorphisms.
AB  - Nineteen insertion/deletion and restriction site polymorphisms on autosomal and
      mitochondrial genomes and mitochondrial DNA hypervariable segment 1 sequences
      were used to study genetic diversities and affinities among four endogamous
      groups of Punjab, India. High values of heterozygosity were noted in all four
      groups, both in the autosomal and mitochondrial genomes. The coefficient of gene
      differentiation among the groups, however, was found to be low. Genetic distance
      and phylogenetic analyses based on these data indicated that inferences on
      affinities among the populations were different when the two sets of loci
      (autosomal and mitochondrial) were considered separately. We have interpreted
      these results on the basis of some known historical data on migrations into this
      region. The results of this study when compared with the findings of some
      previous studies indicate that there are regional differences in the patterns of
      correlation between genomic and sociocultural affinities within India.

PMID- 12617490
TI  - Craniometric variation in the Americas.
AB  - Craniofacial variation is investigated in Latin America and the Caribbean. The
      samples included in this study are two historic and one prehistoric sample from
      Ecuador; prehistoric and modern Cuban samples; a prehistoric Peruvian sample; two
      prehistoric Mexican samples and one contemporary admixed Mexican sample; a
      16th/17th-century Spanish sample; and Terry blacks. Biological distance is
      investigated using traditional craniometrics by computing size and shape
      variables according to Mosimann and colleagues. This study shows that there is
      much biological variation within the Americas.

PMID- 12617492
TI  - Origin and history of the IVS-I-110 and codon 39 beta-thalassemia mutations in
      the Lebanese population.
AB  - Using restriction fragment length polymorphisms (RFLPs) and sequence haplotype
      analysis, we studied the chromosomal background of the beta-globin gene in 31
      unrelated Lebanese IVS-I-110 or codon 39 (Cd39) subjects, and five normal
      betaAbeta/A individuals. Our results are compared with those from similar studies
      in other parts of the Mediterranean in an attempt to provide insights into
      historical patterns of selection and disease. The great majority of the Lebanese
      chromosomes with the IVS-I-110 mutation are associated with the RFLP haplotype I
      and sequence haplotype HT1, which is probably the ancestral structure on which
      the mutation first emerged. The remainder of the IVS-I-110 alleles are linked to
      the 5'-subhaplotype 12 RFLP haplotype and/or HTR sequence haplotype. In contrast,
      in Turkey, IVS-I-110 is associated with six distinct sequence haplotypes and four
      distinct RFLP haplotypes, suggesting that the mutation probably emerged there.
      The diversity of sequence haplotypes described in Turkey was probably generated
      through recombination or gene conversion events with the most frequent betaA
      autochthonous structures. Our data on Lebanese betaA chromosomes and Algerian
      betaA chromosomes, along with previously described Turkish betaA chromosomes,
      strengthen this hypothesis. Following its emergence in Turkey, the IVS-1-110
      mutation was probably introduced to Lebanon later, by migration or settlements.
      Cd39 demonstrates a remarkable level of sequence and RFLP haplotype heterogeneity
      in Algeria, in contrast to its relative homogeneity in Turkish samples. However,
      its rarity in the Near East, and more specifically in Lebanon, does not allow us
      to draw any conclusions concerning its origin and gene flow.

PMID- 12617493
TI  - Mode of inheritance of hand osteoarthritis in ethnically homogeneous pedigrees.
AB  - The aim of the present study was to investigate the extent and mode of
      inheritance of hand osteoarthritis (OA) using a large sample of ethnically
      homogeneous pedigrees. Two types of segregation analysis (SA) models were
      examined. Type I models used the data adjusted for potential significant
      covariates, particularly age and sex, prior to genetic analysis. Type 11 models
      incorporated effects of the potential covariates into major gene penetrance
      functions, permitting an account of the genotype covariate-specific effect on
      study variables. The results of this study strongly supported the hypothesis of a
      major gene effect and additional multifactorial component. The best-fitting model
      was the Mendelian one with an additive type of inheritance. The estimates
      obtained using the standard three-factor variance decomposition analysis suggest
      that age (72.8%) and major gene (14.5%) are the main sources of interindividual
      differences in the development of hand OA. The contribution of the putative major
      gene on age- and sex-adjusted OA phenotype variation was 55% in the present
      study.

PMID- 12617494
TI  - Evidence against a relationship between dermatoglyphic asymmetry and male sexual
      orientation.
AB  - Hall and Kimura (1994) studied the relation between dermatoglyphic asymmetry and
      male sexual orientation in a sample of 66 homosexual and 182 heterosexual men.
      They found that more homosexual men possessed a leftward dermatoglyphic asymmetry
      than did heterosexual men. In this paper, we report a comparative study about the
      relationship between sexual orientation and dermatoglyphic characteristics,
      including 60 homosexual men, 76 heterosexual men, and 60 heterosexual women,
      recruited from the general population, and also from a gay-rights nongovernmental
      organization, in Salvador, Brazil. Ulnar loops were the most frequent
      dermatoglyphic pattern in all groups, followed by whorls, arches, and radial
      loops. A chi-square analysis comparing the frequencies of the patterns in the
      three groups only showed an excess of ulnar loops in women (p < 0.05) and arches
      in men (p < 0.01), but did not reveal significant differences between homosexuals
      and the other groups studied. There was no significant difference between gay and
      straight men on total ridge count. We found a preponderance of rightward
      asymmetry in homosexual and heterosexual men, as well as in heterosexual women.
      Our results do not agree with Hall and Kimura's data indicating that more gay men
      possessed the minority leftward asymmetry than did straight men. There was no
      significant difference in leftward asymmetry in the sample studied. The results
      reported in this paper do not support any relation between dermatoglyphic
      asymmetry and male sexual orientation, and, thus, any hypothesis concerning a
      biological intrauterine contribution to adult sexual orientation somehow
      associated with dermatoglyphic development.

PMID- 12617495
TI  - Interpopulation relationship by isonymy: application to ethnosocial groups and
      illegitimacy.
AB  - The application of the isonymic method to establish interpopulation relationships
      is made difficult by such factors as: (1) a small population size; (2) the
      subdivision of the population into ethnosocial groups; and (3) the existence of
      individuals born extramaritally. The present study analyzes the validity of the
      isonymy method in populations where such difficulties exist. Lasker's R(ij)
      relationship coefficients were calculated in base to marital records from six
      Pocho parishes (Argentina) for the period 1766 to 1840. Three endogamous
      ethnosocial groups were considered-Spanish, American Indians, "Mestizos"--and a
      fourth group combining mates of the three previous groups. For each ethnosocial
      category, and taking into account paternal surnames, maternal surnames (both for
      legitimate and illegitimate mates), and whole surnames merged, R(i) interparish
      relationship matrices were obtained. All these matrices were correlated by means
      of the Mantel test. Maternal surnames of illegitimate mates show a similar
      pattern to the maternal surnames of legitimate mates and to all surnames of each
      category. Groups with larger sample size in every parish intercorrelate
      regardless of ethnosocial category. Results suggest the convenience of maximizing
      the sample size and using maternal surnames in populations with high
      illegitimacy.

PMID- 12617496
TI  - Sex differential patterns in perinatal deaths in Italy.
AB  - In industrialized countries, male excess is generally found in early deaths,
      despite the overall decrease in mortality. We studied the association between sex
      and some factors generally considered crucial for babies' survival, such as
      mother's age and education, birth order, and gestational age, in order to gain
      insight into the causes underlying the persisting higher vulnerability of male
      sex in early life. The analysis was performed on babies dying during the
      perinatal period. These were subdivided into those who were stillborn and those
      who died during the first week of extrauterine life. A higher male excess among
      babies dying during the neonatal period than among those who were stillborn was
      always found in all classes of all factors. The finding of such generalized male
      overmortality in the early extrauterine period of life, together with the
      patterns shown by the temporal sex ratio in stillbirths and in early deaths,
      supports the hypothesis of a postponement of male risk from late fetal into
      neonatal life.

PMID- 12617497
TI  - Sex ratios at birth in African populations: a review of survey data.
AB  - This study analyzes the distribution of sex ratio at birth in African populations
      using data collected in birth histories in sample demographic surveys
      (Demographic and Health Surveys and World Fertility Surveys). The average sex
      ratio from 56 surveys, totaling 1.130 million births, was 1.033 (95% CI, 1.029
      1.037), significantly different from the world average of 1.055. The distribution
      of sex ratios across surveys was found to be heterogeneous, and different from
      what could have been expected from random fluctuations due to sample size. Three
      subsets were identified: a subset with lower sex ratios, primarily in countries
      of eastern and southern Africa of Bantu populations (1.010), a subset with
      average sex ratios (1.035), and a subset of countries with higher sex ratios, in
      particular Nigeria and Ethiopia (1.070). Further analysis revealed that African
      populations are as diverse as other populations, with sex ratios ranging from low
      values (below 1.00) to high values (above 1.08). Results are discussed in light
      of independent data sources and in comparison with other human populations.

PMID- 12617499
TI  - Deteriorative changes of maize, groundnut and soybean seeds by fungi in storage.
AB  - This paper deals with investigations on fungal infection, moisture content,
      germinability and deterioration of three seeds, viz., maize (starchy), groundnut
      (oily) and soybean (proteinaceous) in storage at the locality of Santiniketan,
      West Bengal, India, under natural condition for 1 year. The airspora of storage
      environment was trapped using culture plate method. Different species of
      Aspergillus (A. candidus, A. flavus, A. niger, A. terreus, and A. ruber) were
      dominant followed by Rhizopus, Penicillium, Curvularia, Fusarium, Alternaria,
      etc. Seed moisture was maximum in the rainy season followed by a gradual decrease
      during longer storage. A gradual decrease in field fungi with simultaneous
      increase in storage fungi accompanied by a reduction in germinability occurred in
      all seeds as storage proceeded. A gradual loss of carbohydrate (both soluble and
      insoluble) content in all the seeds were recorded. A loss of protein content was
      recorded followed by a small increase. Oil content decreased in prolonged storage
      with simultaneous increase in fatty acid.

PMID- 12617498
TI  - Multicenter evaluation of an enzyme immunoassay (Platelia Aspergillus) for the
      detection of Aspergillus antigen in serum.
AB  - Invasive aspergillosis is a serious problem for immunocompromised patients,
      especially if neutropenic. The diagnosis of this infection is complicated, since
      clinical symptoms are often similar to those of other fungal diseases. The chance
      of detecting the presence of a specific antigen in the serum could confirm the
      suspected clinical diagnosis and. perhaps, be useful for the follow-up of the
      patient. The Medical Mycology Committee of the Associazione Microbiologi Clinici
      Italiani (AMCLI) decided to evaluate in a multicenter prospective study (from I
      November 1998 to 28 February 1999) the performance of the Platelia Aspergillus
      Kit (Bio-Rad) for the detection of Aspergillus galactomannan in human serum. The
      enrolled patients included various groups of immunosuppressed patients (mostly
      neutropenic). Blood samples were drawn at the time of enrollment. This decision
      was based upon a clinical diagnosis of probable aspergillosis (antibiotic non
      responsive fever for at least 96 hours, cough, hemophthosis and positive chest X
      ray). Additional blood samples were drawn on days 3, 6, 9, 12, 15 and 21. Culture
      and histopathologic examinations were performed according to the individual
      laboratory workflow. For each patient the laboratory filled a form with all the
      available clinical information, to create a database on which to evaluate the
      results of the test. During the study, 187 patients with various kinds of
      immunosuppression were enrolled. A total of 256 sera were tested: for 117
      patients (62.6%) only the basal sample was tested, whereas for the 70 symptomatic
      patients (37.4%) multiple specimens (range: 1-6) were tested. The results allowed
      the laboratories to exclude (68.6%) or confirm (31.5%: confirmed and/or probable)
      the clinical diagnosis of invasive aspergillosis; 4 cases remained undetermined.
      Based on the results of this study, it seems that the use of this test should be
      limited to those patients with clinical symptoms of aspergillosis.

PMID- 12617500
TI  - Cocoa-based media for culturing Phytophthora palmivora (Butl.) Butl., causal
      agent of black pod disease of cocoa.
AB  - Green cocoa pod husk agar (GCPA), ripe cocoa pod husk agar (RCPA), green cocoa
      bean agar (GCBA), ripe cocoa bean agar (RCBA), green cocoa mucilage agar (GCMA)
      and ripe cocoa mucilage agar (RCMA) were prepared and assessd for their clarity
      and for potential to support mycelial growth and sporulation of P. palmivora.
      Oatmeal agar (OMA), potato-dextrose agar (PDA), vegetable 8 juice agar (V8JA) and
      pineapple crown agar (PCA) were included for comparison. The highest radial
      growth rates of 8.3 and 7.2 mm/day were recorded, respectively, on OMA and GCPA
      but these were not significantly different (P < 0.05) from each other. The two
      media also supported good aerial mycelial growth but were not clear. Radial
      mycelial growth rates of 6.5, 7.0 and 6.6 mm/day were obtained on GCMA, RCPA and
      V8JA, respectively, and these rates were also not significantly different from
      each other. Of the three media, only the GCMA was clear and supported the best
      aerial mycelial growth. In comparison, the RCMA supported a significantly lower
      radial growth (4.6 mm/day) of P. palmivora than the three media. Growth rates
      were least on RCBA, PCA and PDA but sporulation was poorest on PDA, PCA and V8JA.
      GCMA was found to be the best medium based on all the growth parameters and media
      characteristics. GCMA has been used effectively to isolate/detect P. palmivora
      from infected cocoa pod tissues. Apart from differences in radial growth rate,
      both the GCMA and RCMA were similar in all other respects and are recommended for
      culturing P. palmivora.

PMID- 12617501
TI  - Morphological, cultural and pathogenic characteristics of Coniothyrium zuluense
      isolates from different plantation regions in South Africa.
AB  - Coniothyrium canker caused by Coniothyrium zuluense, is a serious stem canker
      disease of Eucalyptus species in sub-tropical regions of South Africa. This
      disease is typified by necrotic bark lesions that coalesce to form large kino
      impregnated cankers along the stems of trees. The strategy currently used to
      manage Coniothyrium canker in plantations is to deploy Eucalyptus species or
      clones that are resistant to the disease. Considerable success has already been
      achieved in this regard, but the long-term durability of resistance is of
      concern. Thus, forest managers are interested in the genetic diversity of the
      pathogen and its potential to overcome disease resistance in planting stock. In
      this study, 344 isolates of C. zuluense from different plantation regions in
      South Africa were compared on the basis of colony colour, conidial morphology,
      growth characteristics on agar and pathogenicity to a susceptible E. grandis
      clone. Conidia of all C. zuluense isolates measured were similar in size and
      shape. The fungus is slow growing in culture, which is indicative of its apparent
      biotrophic habit, with optimum growth observed at 30 degrees C. Isolates of C.
      zuluense displayed considerable variation in colony colour and pathogenicity in
      inoculation trials. Variation in morphology and pathogenicity amongst isolates
      suggests that C. zuluense has been present in South Africa for an extended period
      of time, or that it is changing rapidly due to strong directional selection
      pressures.

PMID- 12617503
TI  - Aspergillus on tree nuts: incidence and associations.
AB  - California exports tree nuts to countries where they face stringent standards for
      aflatoxin contamination. Trade concerns have stimulated efforts to eliminate
      aflatoxins and Aspergillus flavus from almonds, pistachios and walnuts. Incidence
      of fungi on tree nuts and associations among fungi on tree nuts were studied.
      Eleven hundred pistachios, almonds, walnuts and brazil nuts without visible
      insect damage were plated on salt agar and observed for growth of fungi. Samples
      came both from California nut orchards and from supermarkets. To distinguish
      internal fungal colonization of nuts from superficial colonization, half the nuts
      were surface-sterilized before plating. The most common genera found were
      Aspergillus, Rhizopus and Penicillium. Each species of nut had a distinct
      mycoflora. Populations of most fungi were reduced by surface sterilization in all
      except brazil nuts, suggesting that they were present as superficial inoculum on
      (rather than in) the nuts. In general, strongly positive associations were
      observed among species of Aspergillus; nuts infected by one species were likely
      to be colonized by other species as well. Presence of Penicillium was negatively
      associated with A. niger and Rhizopus in some cases. Results suggest that harvest
      or postharvest handling has a major influence on nut mycoflora, and that nuts
      with fungi are usually colonized by several fungi rather than by single species.

PMID- 12617502
TI  - Fungi and aflatoxins associated with spices in the Sultanate of Oman.
AB  - One hundred and five samples of seven spices (cumin, cinnamon, clove, black
      pepper, cardamom, ginger, and coriander) were purchased from five popular
      companies in the Sultanate of Oman. The spices were surveyed for the mycoflora
      and aflatoxins. Twenty fungal species were isolated in which Aspergillus flavus,
      A. niger. Penicillium, Rhizopus, and Syncephalastrum racemosum were the most
      dominant. When colony forming units per gm (cfu/gm) of fungi were compared,
      significant differences were found among spices and companies. Of the seven
      spices studied, clove was found to be the least contaminated, while cumin was the
      most contaminated. None of the 15 selected samples of the spices contaminated by
      A. flavus were found to contain aflatoxins. Nevertheless, nine isolates (45%) of
      the twenty A. flavus strains screened for aflatoxins were aflatoxigenic. The
      moisture content of most of the spices was below the maximum standard limit. The
      results showed that the spices were contaminated by some fungi that might
      constitute health hazards for humans.

PMID- 12617505
TI  - Dealing with discreteness: making 'exact' confidence intervals for proportions,
      differences of proportions, and odds ratios more exact.
AB  - 'Exact' methods for categorical data are exact in terms of using probability
      distributions that do not depend on unknown parameters. However, they are
      conservative inferentially. The actual error probabilities for tests and
      confidence intervals are bounded above by the nominal level. This article
      examines the conservatism for interval estimation and describes ways of reducing
      it. We illustrate for confidence intervals for several basic parameters,
      including the binomial parameter, the difference between two binomial parameters
      for independent samples, and the odds ratio and relative risk. Less conservative
      behavior results from devices such as (1) inverting tests using statistics that
      are 'less discrete', (2) inverting a single two-sided test rather than two
      separate one-sided tests each having size at least half the nominal level, (3)
      using unconditional rather than conditional methods (where appropriate) and (4)
      inverting tests using alternative p-values. The article concludes with
      recommendations for selecting an interval in three situations-when one needs to
      guarantee a lower bound on a coverage probability, when it is sufficient to have
      actual coverage probability near the nominal level, and when teaching in a
      classroom or consulting environment.

PMID- 12617504
TI  - Genetic variability of Fusarium wilt pathogen isolates of chickpea (Cicer
      arietinum L.) assessed by molecular markers.
AB  - Genetic variability among 43 isolates of Fusarium oxysporum f.sp. ciceri, the
      chickpea wilt pathogen, collected from nine states of India including the four
      well-characterized races of the pathogen were assessed using the molecular
      markers, RAPDs and AFLP. Principal coordinate analysis of the similarity index
      data generated from the molecular marker studies mostly gave three different
      clusters: Of these two clusters represented race-1 and race-2, and the third
      cluster consisted of race-3 and race-4 pathogen isolates. In RAPDs a fourth
      cluster was seen which did not go with any of the four races of the pathogen. The
      molecular markers established the distinctness of race-1 and race-2 pathogen
      isolates and the close similarity of pathogen isolates of race-3 with that of
      race-4. AFLP was found to be more informative as it differentiated more number of
      the pathogen isolates with the known races with minimum of outliers. The high
      levels of DNA polymorphism observed with the molecular markers suggest the rapid
      evolution of new recombinants of the pathogen in the chickpea growing fields.

PMID- 12617508
TI  - Saddlepoint distribution function approximations in biostatistical inference.
AB  - Applications of saddlepoint approximations to distribution functions are
      reviewed. Calculations are provided for marginal distributions and conditional
      distributions. These approximations are applied to problems of testing and
      generating confidence intervals, particularly in canonical exponential families.

PMID- 12617507
TI  - Proving non-inferiority or equivalence of two treatments with dichotomous
      endpoints using exact methods.
AB  - Since the early work of RA Fisher, exact methods have been recognized as
      important tools in data analysis because they provide valid statistical inference
      even with small sample sizes, or with sparse or skewed data. With the recent
      advance of computational power and the availability of commercial software
      packages, exact methods have gained substantial popularity over the past two
      decades. However, most of these exact methods have been devoted to testing
      classical null hypotheses of no differences, and until recently little was known
      about exact methods dealing with non-inferiority or equivalence hypotheses. The
      presence of nuisance parameters in testing non-inferiority/equivalence hypotheses
      presents a special challenge for exact methods because of the intense
      computational requirement. In this paper, we review exact methods available for
      proving non-inferiority or equivalence of two treatments with a dichotomous
      endpoint. First, we present the general methodology for conducting exact tests
      for non-inferiority or equivalence; we then discuss several unconditional and
      conditional methods available for constructing hypothesis tests and confidence
      intervals based on three commonly used measures, namely, the difference, relative
      risk, and odds ratio of two independent proportions or rates. Finally, we
      illustrate with several examples the application of these exact methods in
      analysing and planning non-inferiority or equivalence trials.

PMID- 12617509
TI  - Power and sample size for ordered categorical data.
AB  - We propose a new method for computing power and sample size for linear rank tests
      of differences between two ordered multinomial populations. The method is
      flexible in that it is applicable to any general alternative hypothesis and for
      any choice of rank scores. We show that the method, though asymptotic, closely
      approximates existing exact methods. At the same time it overcomes the
      computational limitations of the exact methods. This advantage makes our
      asymptotic approach more practical for sample size computations at the planning
      stages of a large study. We illustrate the method with data arising from both
      proportional and non-proportional odds models in the two ordered multinomial
      setting.

PMID- 12617506
TI  - Methods of reducing loss of efficiency due to discreteness of distributions.
AB  - All models of this paper involve R x C contingency tables in which the total
      frequency is fixed (full multinomial model), or in which the row totals are fixed
      (product multinomial model). For the most part, we assume that the column
      categories are ordered. For the full multinomial model the null hypothesis of
      interest is independence, i.e., the (ij)th cell probability is the product of the
      marginal probabilities of the ith row and jth column. In the product multinomial
      model the null hypothesis is that the R multinomial distributions have the same
      vector of cell probabilities. Our review includes (1) a careful listing of two
      sided and one-sided alternatives, and (2) methodology to reduce the loss of
      efficiency of tests because of the discreteness of the model (The methodologies
      discussed are efficient in several senses. Tests are exact. Tests have very
      favorable and robust power properties. Tests make use of back-up statistics,
      thereby providing a finer grid of p-values. In some special cases, e.g., a 2 x C
      table and a one-sided alternative, conditional p-values are found, within
      seconds, simply by entering row frequencies into a given website. Thus,
      computational efficiency is exceptional.), and (3) a critique of some exact
      linear permutation tests (that are conditional on row and column margins) for
      both two-sided and some one-sided alternatives. Furthermore, recommendations as
      to which tests to use for specific alternatives are made.

PMID- 12617512
TI  - YM-202204, a new antifungal antibiotic produced by marine fungus Phoma sp.
AB  - A new antifungal antibiotic, YM-202204 (1), was found in the culture broth of
      marine fungus Phoma sp. Q60596. The structure of 1 was determined by several
      spectroscopic experiments as a new lactone compound. This antibiotic exhibited
      potent antifungal activities against Candida albicans, Cryptococcus neoformans
      and Aspergillus fumigatus, and also inhibited glycosyl-phosphatidyl-inositol
      (GPI)-anchoring in yeast cells.

PMID- 12617513
TI  - A novel potent cell cycle inhibitor dehydrophenylahistin--enzymatic synthesis and
      inhibitory activity toward sea urchin embryo.
AB  - A novel dehydrogenated cyclic dipeptide named as dehydrophenylahistin (deltaPLH)
      was effectively prepared from a fungal metabolite (-)-phenylahistin by the
      enzymatic conversion catalyzed by the cell-free extract of Streptomyces albulus
      KO-23, an albonoursin-producing actinomycete. deltaPLH exhibited more than 1,000
      times as high potent inhibitory activity toward the first cleavage of sea urchin
      embryos as (-)-phenylahisitn which has been reported to be a cell cycle inhibitor
      and more than 10,000 as high as albonoursin, indicating that deltaPLH is a
      promising leading compound for anticancer drugs.

PMID- 12617511
TI  - Parimycin: isolation and structure elucidation of a novel cytotoxic 2,3
      dihydroquinizarin analogue of gamma-indomycinone from a marine streptomycete
      isolate.
AB  - In our screening of actinomycetes from the marine environment for bioactive
      components, a new antibiotic with a novel structure designated as parimycin was
      obtained from the culture broth of Streptomyces sp. isolate B8652. The structure
      of the new antibiotic was determined by spectroscopic methods and by comparison
      of the NMR data with those of the structurally related gamma-indomycinone.

PMID- 12617514
TI  - Selective production of fungal beauveriolide I or III by fermentation in amino
      acid-supplemented media.
AB  - Beauveriolides I and III, cyclic depsipeptides composed of L-Phe, L-Ala, D-Leu
      and (3S,4S)-3-hydroxy-4-methyloctanoic acid, and L-Phe, L-Ala, L-allo-Ile and
      (3S,4S)-3-hydroxy-4-methyloctanoic acid, respectively, were previously isolated
      from the culture broth of fungal Beauveria sp. FO-6979 as inhibitors of
      macrophage foam cell formation. To improve the production of these compounds by
      fermentation, the culture conditions were studied. The production of both
      beauveriolides was increased five to ten folds by fermentation in the culture
      media containing tryptone. Further study revealed that addition of L-Leu/L-Ile,
      but not D-Leu/D-allo-Ile, to the culture medium yielded a high and selective
      production of beauveriolide I or III. As a result, regardless of their separation
      difficulty due to the similar physico-chemical properties, a large amount of
      beauveriolide I or III was prepared from the culture broth obtained from L-Leu-
      or L-Ile-supplemented fermentation, respectively, by one step purification using
      silica gel column chromatography.

PMID- 12617510
TI  - Smallpox vaccination and adverse reactions. Guidance for clinicians.
AB  - The guidance in this report is for evaluation and treatment of patients with
      complications from smallpox vaccination in the preoutbreak setting. Information
      is also included related to reporting adverse events and seeking specialized
      consultation and therapies for these events. The frequencies of smallpox vaccine
      associated adverse events were identified in studies of the 1960s. Because of the
      unknown prevalence of risk factors among today's population, precise predictions
      of adverse reaction rates after smallpox vaccination are unavailable. The
      majority of adverse events are minor, but the less-frequent serious adverse
      reactions require immediate evaluation for diagnosis and treatment. Agents for
      treatment of certain vaccine-associated severe adverse reactions are vaccinia
      immune globulin (VIG), the first-line therapy, and cidofovir, the second-line
      therapy. These agents will be available under Investigational New Drug (IND)
      protocols from CDC and the U.S. Department of Defense (DoD). Smallpox vaccination
      in the preoutbreak setting is contraindicated for persons who have the following
      conditions or have a close contact with the following conditions: 1) a history of
      atopic dermatitis (commonly referred to as eczema), irrespective of disease
      severity or activity; 2) active acute, chronic, or exfoliative skin conditions
      that disrupt the epidermis; 3) pregnant women or women who desire to become
      pregnant in the 28 days after vaccination; and 4) persons who are
      immunocompromised as a result of human immunodeficiency virus or acquired
      immunodeficiency syndrome, autoimmune conditions, cancer, radiation treatment,
      immunosuppressive medications, or other immunodeficiencies. Additional
      contraindications that apply only to vaccination candidates but do not include
      their close contacts are persons with smallpox vaccine-component allergies, women
      who are breastfeeding, those taking topical ocular steroid medications, those
      with moderate-to-severe intercurrent illness, and persons aged < 18 years. In
      addition, history of Darier disease is a contraindication in a potential vaccinee
      and a contraindication if a household contact has active disease. In the event of
      a smallpox outbreak, outbreak-specific guidance will be disseminated by CDC
      regarding populations to be vaccinated and specific contraindications to
      vaccination. Vaccinia can be transmitted from a vaccinee's unhealed vaccination
      site to other persons by close contact and can lead to the same adverse events as
      in the vaccinee. To avoid transmission of vaccinia virus (found in the smallpox
      vaccine) from vaccinees to their close contacts, vaccinees should wash their
      hands with warm soapy water or hand rubs containing > or = 60% alcohol
      immediately after they touch their vaccination site or change their vaccination
      site bandages. Used bandages should be placed in sealed plastic bags and can be
      disposed of in household trash. Smallpox vaccine adverse reactions are diagnosed
      on the basis of clinical examination and history, and certain reactions can be
      managed by observation and supportive care. Adverse reactions that are usually
      self-limited include fever, headache, fatigue, myalgia, chills, local skin
      reactions, nonspecific rashes, erythema multiforme, lymphadenopathy, and pain at
      the vaccination site. Other reactions are most often diagnosed through a complete
      history and physical and might require additional therapies (e.g., VIG, a first
      line therapy and cidofovir, a second-line therapy). Adverse reactions that might
      require further evaluation or therapy include inadvertent inoculation,
      generalized vaccinia (GV), eczema vaccinatum (EV), progressive vaccinia (PV),
      postvaccinial central nervous system disease, and fetal vaccinia. Inadvertent
      inoculation occurs when vaccinia virus is transferred from a vaccination site to
      a second location on the vaccinee or to a close contact. Usually, this condition
      is self-limited and no additional care is needed. Inoculations of the eye and
      eyelid require evaluation by an ophthalmologist and might require therapy with
      topical antiviral or antibacterial medications, VIG, or topical steroids. GV is
      characterized by a disseminated maculopapular or vesicular rash, frequently on an
      erythematous base, which usually occurs 6-9 days after first-time vaccination.
      This condition is usually self-limited and benign, although treatment with VIG
      might be required when the patient is systemically ill or found to have an
      underlying immunocompromising condition. Infection-control precautions should be
      used to prevent secondary transmission and nosocomial infection. EV occurs among
      persons with a history of atopic dermatitis (eczema), irrespective of disease
      severity or activity, and is a localized or generalized papular, vesicular, or
      pustular rash, which can occur anywhere on the body, with a predilection for
      areas of previous atopic dermatitis lesions. Patients with EV are often
      systemically ill and usually require VIG. Infection-control precautions should be
      used to prevent secondary transmission and nosocomial infection. PV is a rare,
      severe, and often fatal complication among persons with immunodeficiencies,
      characterized by painless progressive necrosis at the vaccination site with or
      without metastases to distant sites (e.g., skin, bones, and other viscera). This
      disease carries a high mortality rate, and management of PV should include
      aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive
      care. Anecdotal experience suggests that, despite treatment with VIG, persons
      with cell-mediated immune deficits have a poorer prognosis than those with
      humoral deficits. Infection-control precautions should be used to prevent
      secondary transmission and nosocomial infection. Central nervous system disease,
      which includes postvaccinial encephalopathy (PVE) and postvaccinial
      encephalomyelitis (or encephalitis) (PVEM), occur after smallpox vaccination. PVE
      is most common among infants aged < 12 months. Clinical symptoms of central
      nervous system disease indicate cerebral or cerebellar dysfunction with headache,
      fever, vomiting, altered mental status, lethargy, seizures, and coma. PVE and
      PVEM are not believed to be a result of replicating vaccinia virus and are
      diagnoses of exclusion. Although no specific therapy exists for PVE or PVEM,
      supportive care, anticonvulsants, and intensive care might be required. Fetal
      vaccinia, resulting from vaccinial transmission from mother to fetus, is a rare,
      but serious, complication of smallpox vaccination during pregnancy or shortly
      before conception. It is manifested by skin lesions and organ involvement, and
      often results in fetal or neonatal death. No known reliable intrauterine
      diagnostic test is available to confirm fetal infection. Given the rarity of
      congenital vaccinia among live-born infants, vaccination during pregnancy should
      not ordinarily be a reason to consider termination of pregnancy. No known
      indication exists for routine, prophylactic use of VIG in an unintentionally
      vaccinated pregnant woman; however, VIG should not be withheld if a pregnant
      woman develops a condition where VIG is needed. Other less-common adverse events
      after smallpox vaccination have been reported to occur in temporal association
      with smallpox vaccination, but causality has not been established. Prophylactic
      treatment with VIG is not recommended for persons or close contacts with
      contraindications to smallpox vaccination who are inadvertently inoculated or
      exposed. These persons should be followed closely for early recognition of
      adverse reactions that might develop, and clinicians are encouraged to enroll
      these persons in the CDC registry by calling the Clinician Information Line at
      877-554-4625. To request clinical consultation and IND therapies for vaccinia
      related adverse reactions for civilians, contact your state health department or
      CDC's Clinician Information Line (877-554-4625). Clinical evaluation tools are
      available at http.//www.bt.cdc.gov/agent/smallpox/vaccination/clineval. Clinical
      specimen-collection guidance is available at
      http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen
      collection.asp. Physicians at military medical facilities can request VIG or
      cidofovir by calling the U.S. Army Medical Research Institute of Infectious
      Diseases (USAMRIID) at 301-619-2257 or 888-USA-RIID.

PMID- 12617515
TI  - kasT gene of Streptomyces kasugaensis M338-M1 encodes a DNA-binding protein which
      binds to intergenic region of kasU-kasJ in the kasugamycin biosynthesis gene
      cluster.
AB  - We previously reported that a 4.2 kb SacI-EcoRI DNA region from Streptomyces
      kasugaensis M338-M1, a kasugamycin (KSM) producer, included KSM transporter genes
      (kasKLM). As an extension of that study, a 3.7 kb Psti-SacI DNA region, located
      at 1.5 approximately 5.2 kb upstream of kasK, was cloned and sequenced, revealing
      three complete open reading frames, designated kasT, kasU and kasJ. The kasJ gene
      encodes a protein (KasJ) with a conserved dinucleotide (FAD)-binding motif
      Homology search for KasJ showed its similarity to NADH: N-amidino-scyllo
      inosamine oxidoreductase (StsB) which is involved in biosynthesis of the
      streptidine moiety of streptomycin (SM) in S. griseus. The kasT gene encodes a
      DNA-binding protein (KasT), including a helix-turn-helix motif near the center of
      the sequence. This protein is similar in structure to a pathway-specific
      activator protein (StrR) that plays a role in regulating the SM biosynthesis gene
      cluster of S. griseus. A fusion protein (Trx-KasT) clearly showed DNA binding
      activity with the intergenic region of kasU-kasJ, suggesting that KasT is a
      pathway-specific regulator of the KSM biosynthesis gene cluster.

PMID- 12617516
TI  - Cloning of the staurosporine biosynthetic gene cluster from Streptomyces sp. TP
      A0274 and its heterologous expression in Streptomyces lividans.
AB  - Staurosporine is a representative member of indolocarbazole antibiotics. The
      entire staurosporine biosynthetic and regulatory gene cluster spanning 20-kb was
      cloned from Streptomyces sp. TP-A0274 and sequenced. The gene cluster consists of
      14 ORFs and the amino acid sequence homology search revealed that it contains
      three genes, staO, staD, and staP, coding for the enzymes involved in the
      indolocarbazole aglycone biosynthesis, two genes, staG and staN, for the bond
      formation between the aglycone and deoxysugar, eight genes, staA, staB, staE,
      staJ, staI, staK, staMA, and staMB, for the deoxysugar biosynthesis and one gene,
      staR is a transcriptional regulator. Heterologous gene expression of a 38-kb
      fragment containing a complete set of the biosynthetic genes for staurosporine
      cloned into pTOYAMAcos confirmed its role in staurosporine biosynthesis.
      Moreover, the distribution of the gene for chromopyrrolic acid synthase, the key
      enzyme for the biosynthesis of indolocarbazole aglycone, in actinomycetes was
      investigated, and rebD homologs were shown to exist only in the strains producing
      indolocarbazole antibiotics.

PMID- 12617517
TI  - Chloroquinocin, a novel chlorinated naphthoquinone antibiotic from Streptomyces
      sp., LL-A9227.

PMID- 12617518
TI  - Total synthesis of a tetracyclic anti-tumor, UCE6.

PMID- 12617519
TI  - Modeling and measurement of flow effects on tracheal sounds.
AB  - The analysis of breathing sounds measured over the extrathoracic trachea offers a
      noninvasive technique to monitor obstructions of the respiratory tract. Essential
      to development of this technique is a quantitative understanding of how such
      tracheal sounds are related to the underlying tract anatomy, airflow, and disease
      induced obstructions. In this study, the first dynamic acoustic model of the
      respiratory tract was developed that takes into consideration such factors as
      turbulent sound sources and varying glottal aperture. Model predictions were
      compared to tracheal sounds measured on four healthy subjects at target flow
      rates of 0.5, 1.0, 1.5, and 2.0 L/s, and also during nontargeted breathing. Both
      the simulation and measurement spectra depicted increasing sound power with
      increasing flow, with smaller incremental increases at the higher flow rates. A
      sound power increase of approximately 30 dB between a flow rate of 0.5 and 2.0
      L/s was observed in both the simulated and measured spectra. Variations of as
      much as 15 dB over the 300-600 Hz frequency band were noted in the sound power
      produced during targeted and nontargeted breathing maneuvers at the same flow
      rates. We propose that this variability was in part due to changes in glottal
      aperture area, which is known to vary during normal respiration and has been
      observed as a method of flow control. Model simulations incorporating a turbulent
      source at the glottis with respiratory cycle variations in glottal aperture from
      0.64 cm2 to 1.4 cm2 explained approximately 10 dB of the measured variation. This
      study provides the first links between spatially distributed sound sources due to
      turbulent flow in the respiratory tract and noninvasive tracheal sounds
      measurements.

PMID- 12617520
TI  - Comparison of potential- and activation-based formulations for the inverse
      problem of electrocardiology.
AB  - Two predominant source formulations for the inverse problem of electrocardiology
      currently exist. They involve the reconstruction of epicardial potentials or
      myocardial activation times from noninvasively recorded torso surface potentials.
      Each of these formulations have their advantages, however, they have not been
      systematically compared against each other. We present results from a simulation
      study which compared a number of epicardial potential (Tikhonov, Truncated
      singular value decomposition (TSVD), Greensite-Tikhonov and Greensite-TSVD), and
      a myocardial activation time formulation for the inverse problem of
      electrocardiology. A number of different methods were also used to determine the
      appropriate level of regularization (optimal, L-curve, zero-crossing, and
      composite residual and smoothing operator) to apply to each formulation. The
      simulation study was conducted using an anatomically based boundary element
      porcine model with a variety of cardiac sources. Varying levels of geometric
      error were introduced to the system and solutions were computed using each of the
      inverse algorithms. Results show that under pure Gaussian noise potential-based
      methods performed best at low noise levels while the activation-based method was
      less effected by higher noise levels. In the presence of correlated geometric
      error, the activation-based method out performed the potential methods, with the
      Greensite-Tikhonov method being the most favored potential-based method when
      using the L-curve or zero-crossing method to determine the regularization
      parameter.

PMID- 12617521
TI  - Effects of experimental and modeling errors on electrocardiographic inverse
      formulations.
AB  - The inverse problem of electrocardiology aims to reconstruct the electrical
      activity occurring within the heart using information obtained noninvasively on
      the body surface. Potentials obtained on the torso surface can be used as input
      for the inverse problem and an electrical image of the heart obtained. There are
      a number of different inverse algorithms currently used to produce electrical
      images of the heart. The relative performances of these inverse algorithms at
      this stage is largely unknown. Although there have been many simulation studies
      investigating the accuracy of each of these algorithms, to date, there has been
      no comprehensive study which compares a wide variety of inverse methods. By
      performing a detailed simulation study, we compare the performances of epicardial
      potential [Tikhonov, Truncated singular value decomposition (TSVD), and
      Greensite] and myocardial activation-based (critical point) inverse simulations
      along with different methods of choosing the appropriate level of regularization
      (optimal, L-curve, composite residual and smoothing operator, zero-crossing) to
      apply to each of these inverse methods. We also examine the effects of a variety
      of signal error, material property error, geometric error and a combination of
      these errors on each of the electrocardiographic inverse algorithms. Results from
      the simulation study show that the activation-based method is able to produce
      solutions which are more accurate and stable than potential-based methods
      especially in the presence of correlated errors such as geometric uncertainty. In
      general, the Greensite-Tikhonov method produced the most realistic potential
      based solutions while the zero-crossing and L-curve were the preferred method for
      determining the regularization parameter. The presence of signal or material
      property error has little effect on the inverse solutions when compared with the
      large errors which resulted from the presence of any geometric error. In the
      presence of combined Gaussian and correlated errors representing conditions which
      may be encountered in an experimental or clinical environment, there was less
      variability between potential-based solutions produced by each of the inverse
      algorithms.

PMID- 12617522
TI  - Field stimulation of cardiac fibers with random spatial structure.
AB  - Polarization of individual cells ("sawtooth") has been proposed as a mechanism
      for field stimulation and defibrillation. To date, the modeling work has
      concentrated on the myocardium with periodic spatial structure; this paper
      investigates potentials arising in cardiac fibers with random spatial structure.
      Ten different random fibers consisting of cells with varying length (l(c) = 100
      +/- 50 microm), diameter (d(c) = 20 +/- 10 microm), thickness of extracellular
      space (t(e) = 1.18 +/- 0.59 microm), and junctional resistance (R(j) = 2 +/- 1
      M(omega)) are studied. Simulations demonstrate that randomizing spatial structure
      introduces to the field-induced potential (V(m)) a randomly varying baseline,
      which arises due to polarization of groups of cells. This polarization appears
      primarily in response to randomizing t(e); R(j), l(c), and d(c) have less
      influence. The maximum V(m) increases from 3.5 mV in a periodic fiber to 20.5+/
      4.7 mV in random fibers (1 V/cm field applied for 5 ms). Field stimulation
      threshold E(th) decreases from 6.9 to 1.59 +/- 0.43 V/cm, which is within the
      range of experimental measurements. Thresholds for normal and reversed field
      polarities are statistically equivalent: 1.59 +/- 0.43 versus 1.44 +/- 0.41 V/cm
      (p value = 0.453). Thus, V(m) arising due to random structure of the myocardium
      may play an important role in field stimulation and defibrillation.

PMID- 12617523
TI  - Analysis of raw microneurographic recordings based on wavelet de-noising
      technique and classification algorithm: wavelet analysis in microneurography.
AB  - We propose a new technique for analyzing the raw neurogram which enables the
      study of the discharge behavior of individual and group neurons. It utilizes an
      ideal bandpass filter, a modified wavelet de-noising procedure, an action
      potential detector, and a waveform classifier. We validated our approach with
      both simulated data generated from muscle sympathetic neurograms sampled at high
      rates in five healthy subjects and data recorded from seven healthy subjects
      during lower body negative pressure suction. The modified wavelet method was
      superior to the classical discriminator method and the regular wavelet de-noising
      procedure when applied to simulated neuronal signals. The detected spike rate and
      spike amplitude rate of the action potentials correlated strongly with number of
      bursts detected in the integrated neurogram (r = 0.79 and 0.89, respectively, p <
      0.001). Eight major action potential waveform classes were found to describe more
      than 81% of all detected action potentials in all subjects. One class had
      characteristics similar in shape and in average discharge frequency (27.4 +/- 5.1
      spikes/min during resting supine position) to those of reported single
      vasoconstrictor units. The newly proposed technique allows a precise estimate of
      sympathetic nerve activity and characterization of individual action potentials
      in multiunit records.

PMID- 12617524
TI  - Noise reduction in directional signals using multiple morse wavelets illustrated
      on quadrature Doppler ultrasound.
AB  - The use of multiple complex-valued Morse wavelets for the scalogram study of
      signals which are unidirectional at any time, but are bidirectional overall is
      considered. These wavelets are well-suited to identifying the forward and reverse
      components. Scalogram averaging which is possible due to the multiplicity of the
      complex-valued wavelets leads to a scalogram with reduced noise. Information from
      positive and negative scales can then be used to estimate a final "cleaned"
      scalogram. Quadrature Doppler ultrasound blood flow in the femoral artery is
      taken as an example to clearly illustrate the noise reduction.

PMID- 12617525
TI  - A software package for the decomposition of long-term multichannel EMG signals
      using wavelet coefficients.
AB  - This paper presents a method to decompose multichannel long-term intramuscular
      electromyogram (EMG) signals. In contrast to existing decomposition methods which
      only support short registration periods or single-channel recordings of signals
      of constant muscle effort, the decomposition software EMG-LODEC (ElectroMyoGram
      LOng-term DEComposition) is especially designed for multichannel long-term
      recordings of signals of slight muscle movements. A wavelet-based, hierarchical
      cluster analysis algorithm estimates the number of classes [motor units (MUs)],
      distinguishes single MUAPs from superpositions, and sets up the shape of the
      template for each class. Using three channels and a weighted averaging method to
      track action potential (AP) shape changes improve the analysis. In the last step,
      nonclassified segments, i.e., segments containing superimposed APs, are
      decomposed into their units using class-mean signals. Based on experiments on
      simulated and long-term recorded EMG signals, our software is capable of
      providing reliable decompositions with satisfying accuracy. EMG-LODEC is suitable
      for the study of MU discharge patterns and recruitment order in healthy subjects
      and patients during long-term measurements.

PMID- 12617527
TI  - A coaxial antenna with miniaturized choke for minimally invasive interstitial
      heating.
AB  - We present a new coaxial antenna for microwave interstitial coagulative therapy,
      working at 2450 MHz and endowed with a miniaturized sleeve choke in order to
      reduce back heating effects and make the system response less dependent on the
      antenna insertion depth into the tissue; the way the choke is implemented makes
      the overall transversal size minimum and allows small adjustments of the choke
      section length even during operation. We describe the main technical features of
      the antenna and show experimental results clearly proving the choke
      effectiveness. Numerical simulations well agree with experimental data,
      confirming the suitability of the proposed device for minimally invasive medical
      applications.

PMID- 12617526
TI  - NARMAX representation and identification of ankle dynamics.
AB  - Representation and identification of a parallel pathway description of ankle
      dynamics as a model of the nonlinear autoregressive, moving average exogenous
      (NARMAX) class is considered. A nonlinear difference equation describing this
      ankle model is derived theoretically and shown to be of the NARMAX form.
      Identification methods for NARMAX models are applied to ankle dynamics and its
      properties investigated via continuous-time simulations of experimental
      conditions. Simulation results show that 1) the outputs of the NARMAX model match
      closely those generated using continuous-time methods and 2) NARMAX
      identification methods applied to ankle dynamics provide accurate discrete-time
      parameter estimates. Application of NARMAX identification to experimental human
      ankle data models with high cross-validation variance accounted for.

PMID- 12617528
TI  - Estimation of anomaly location and size using electrical impedance tomography.
AB  - We developed a new algorithm that estimates locations and sizes of anomalies in
      electrically conducting medium based on electrical impedance tomography (EIT)
      technique. When only the boundary current and voltage measurements are available,
      it is not practically feasible to reconstruct accurate high-resolution cross
      sectional conductivity or resistivity images of a subject. In this paper, we
      focus our attention on the estimation of locations and sizes of anomalies with
      different conductivity values compared with the background tissues. We showed the
      performance of the algorithm from experimental results using a 32-channel EIT
      system and saline phantom. With about 1.73% measurement error in boundary current
      voltage data, we found that the minimal size (area) of the detectable anomaly is
      about 0.72% of the size (area) of the phantom. Potential applications include the
      monitoring of impedance related physiological events and bubble detection in two
      phase flow. Since this new algorithm requires neither any forward solver nor time
      consuming minimization process, it is fast enough for various real-time
      applications in medicine and nondestructive testing.

PMID- 12617530
TI  - Comparison of various safety guidelines for electronic article surveillance
      devices with pulsed magnetic fields.
AB  - The paper uses the two methods suggested in both the ICNIRP and proposed IEEE
      safety guidelines for compliance testing of security systems based on time
      varying magnetic fields being introduced for electronic article surveillance
      (EAS), radiofrequency identification, and other applications. For nonsinusoidal
      pulses that are often used, the two procedures are to treat the exposure as a
      multifrequency exposure with various frequency components or to calculate the
      peak induced current densities or electric fields treating the highest of the
      pulses of duration t(p) as a single frequency, half sinusoid of the same duration
      and frequency 1/(2t(p)). Using either of the procedures, the induced current
      densities (J) or electric fields (E) are compared to the basic restrictions on J
      or E for compliance testing. Using a heterogeneous, tissue-classified anatomic
      model of the human body, we calculate the induced J and E for the various tissues
      for a realistic, EAS system for two typical nonsinusoidal pulses to show that the
      two methods give substantially different results. While the approximate but
      simpler method of treating the pulse as a half sinusoid results in peak induced J
      or E that may be compliant with safety guidelines, the rigorous method of
      treating such exposures as multifrequency exposures gives induced current
      densities or electric fields that may be up to twice as large, thus making such
      systems potentially noncompliant with the safety guidelines. Since it is more
      accurate, it is suggested that safety assessment based on the Fourier analysis
      leading to multifrequency components be used for compliance testing of such
      devices.

PMID- 12617529
TI  - Syllectometry: the effect of aggregometer geometry in the assessment of red blood
      cell shape recovery and aggregation.
AB  - Syllectometry is a measuring method that is commonly used to assess red blood
      cell (RBC) aggregability. In syllectometry, light is incident on a layer of whole
      blood initially exposed to shear flow. The backscattered light is measured after
      abruptly stopping the driving mechanism. The resultant time-dependent intensity
      plot is called the syllectogram. Parameters that quantify RBC aggregability are
      obtained by analyzing the syllectogram. As we will show in this paper, the
      upstroke in the initial part of the syllectogram contains the information for
      measurement of RBC-shape recovery in whole blood as well. To estimate RBC-shape
      recovery, we extended the existing two-exponential mathematical representation of
      the syllectogram by a third exponent that describes the upstroke. To investigate
      the feasibility of RBC-shape recovery measurement from the upstroke, we derived
      an analytical model of the flow decay that follows after abruptly stopping the
      driving mechanism. The model reveals that for large gaps the flow decay may
      interfere with the true RBC-shape recovery process. These theoretical findings
      were confirmed by velocity measurements in a Couette-type aggregometer.
      Syllectograms obtained using large gaps differ in many respects from those
      obtained using small gaps. As predicted by our model large gaps show a prolonged
      apparent shape-recovery time-constant. Moreover, a delayed intensity peak, a
      reduced upstroke of the intensity peak and a considerable increase of the half
      life parameter are observed. The aggregation indices for large gaps are lower
      than for small gaps. This paper yields a better understanding of the velocity and
      shear-rate decay following upon abruptly stopping the driving mechanism. A better
      mathematical representation of the syllectogram and recommendations for a maximum
      gap width enables both RBC-shape recovery and aggregation measurements in whole
      blood using syllectometry.

PMID- 12617531
TI  - Authors reply to comments on "Line patterns in the mosaic electric properties of
      human skin--a cross correlation study.".

PMID- 12617532
TI  - Reduction of electromyographic noise in the signal-averaged electrocardiogram by
      spectral decomposition.
AB  - This paper proposes a technique to improve the quality of high-resolution
      electrocardiogram by weighting the coherent average of beats by a function of the
      energy of the corrupting myoelectric noise, prior to subsequent detection of
      ventricular late potentials. The results obtained with 20 patients indicate the
      method requires fewer beats than conventional nonweighted average to achieve the
      same noise level.

PMID- 12617533
TI  - An improved morphological approach to background normalization of ECG signals.
AB  - This paper describes an improved morphological approach to remove baseline wander
      from neonatal electrocardiogram (ECG) signals, with particular emphasis on
      preserving the ST segment of the original signal. The algorithm consists of two
      stages of morphological processing. First, the QRS complex and impulsive noise
      component due to skeletal muscle contractions etc., are detected and removed from
      the input signal. Second, the corrected QT interval (QTc) and RR interval are
      used to determine a structuring element. With this structuring element, the same
      morphological operation as in the first stage is then applied to the QRS-removed
      signal to obtain and remove the baseline wander. The performance of the algorithm
      is evaluated with simulated and real ECGs. Compared with an existing
      morphological method, there is a substantial improvement, especially in reducing
      distortion of the baseline waveform within the PR and QT intervals.

PMID- 12617534
TI  - Advanced optical tweezers for the study of cellular and molecular biomechanics.
AB  - Optical tweezers are an important tool for studying cellular and molecular
      biomechanics. We present a robust optical tweezers device with advanced features
      including: multiple optical traps, acousto-optic trap steering, and back focal
      plane interferometry position detection. We integrate these features into an
      upright microscope, with no compromise to its capabilities (differential
      interference contrast microscopy, fluorescence microscopy, etc.). Acousto-optic
      deflectors (AODs) steer each beam and can create multiple time-shared traps.
      Position detection, force calibrations and AOD performance are presented. The
      system can detect subnanometer displacements and forces below 0.1 pN.

PMID- 12617537
TI  - Atrial fibrillation as a contributing cause of death and Medicare hospitalization
      -United States, 1999.
AB  - Stroke is the leading cause in the United States of serious long-term disability
      and the third leading cause of death. One of the major risk factors for stroke is
      atrial fibrillation (AF), a common cardiac disorder characterized by cardiac
      arrhythmia and the absence of coordinated contractions, which increases the risk
      for blood stasis, clot formation, and embolic stroke. AF affects approximately
      2.2 million adults in the United States and is the most common sustained heart
      rhythm disturbance observed in clinical practice. The rate of AF increases with
      age, from < 1% among persons aged < 60 years to approximately 10% among persons
      aged > or = 80 years. The frequency with which AF is reported on death
      certificates as a contributing cause of death has increased since 1980. To assess
      the burden of AF-related deaths and hospitalizations among U.S. residents, CDC
      analyzed national and state multiple-cause mortality statistics and Medicare
      hospital claims for persons with AF in 1999 (the latest year for which data were
      available) for the 50 states and the District of Columbia. The findings indicate
      that AF as a contributing cause of death and hospitalization affects primarily
      persons aged > or = 75 years and that death and hospitalization rates vary by
      state. Public and medical education are needed to prevent and reduce AF-related
      disability and death.

PMID- 12617538
TI  - Potential exposures to airborne and settled surface dust in residential areas of
      lower Manhattan following the collapse of the World Trade Center--New York City,
      November 4-December 11, 2001.
AB  - Following the terrorist attacks of September 11, 2001, which destroyed the World
      Trade Center (WTC) in lower Manhattan, the New York City (NYC) Department of
      Health and Mental Hygiene (DOHMH) and the Agency for Toxic Substances and Disease
      Registry (ATSDR), with assistance from the U.S. Public Health Service (PHS)
      Commissioned Corps Readiness Force and the WTC Environmental Assessment Working
      Group, assessed the composition of outdoor and indoor settled surface and
      airborne dust in residential areas around the WTC and in comparison areas. This
      report summarizes the results of the investigation, which found 1) similar levels
      of airborne total fibers in lower and in upper Manhattan, 2) greater percentage
      levels of synthetic vitreous fibers (SVF) and mineral components of concrete and
      building wallboard in settled dust of residential areas in lower Manhattan than
      in upper Manhattan, and 3) low levels of asbestos in some settled surface dust in
      lower Manhattan residential areas. Based in part on the results of this
      investigation, the U.S. Environmental Protection Agency (EPA) is cleaning and
      sampling residential areas as requested by lower Manhattan residents. In
      addition, to assess any short- or long-term health effects of smoke, dust, and
      airborne substances around the WTC site, DOHMH and ATSDR are developing a
      registry that will track the health of persons who were most highly exposed to
      these materials.

PMID- 12617539
TI  - Smallpox vaccine adverse events among civilians--United States, January 24
      February 18, 2003.
AB  - During the civilian smallpox vaccination program, CDC and state health
      departments are conducting surveillance for vaccine-associated adverse events. In
      the first stage of the program, active surveillance is being conducted for
      potentially life-threatening, moderate-to-severe, and other serious adverse
      events and for vaccinia transmission to contacts of vaccinees (Table). Nonserious
      events are reported via passive surveillance and are expected to be
      underreported. This report summarizes smallpox vaccine adverse events reported
      among civilians vaccinated as of February 14, 2003, and received by CDC from the
      Vaccine Adverse Event Reporting System (VAERS) as of February 18.

PMID- 12617535
TI  - Laser-guided direct writing: a novel method to deposit biomolecules for
      biosensors arrays.
AB  - In this paper, we present a potential biomolecular patterning method, laser
      guided direct writing guidance (LGDW), which may be utilized to deposit organic
      and bioactive particles for biosensor arrays. The instrumentation and operation
      of the LGDW system is introduced and the system settings used to achieve
      deposition are reported. The biomolecule, avidin, was deposited onto a substrate
      using LGDW to evaluate the possible damage from the laser on the biomolecules.
      The functionality of avidin after laser-based guidance was examined by exposing
      the deposited avidin molecules to its ligand, biotin. The results show some
      avidin retained its affinity to biotin after LGDW demonstrating little damage to
      the biomolecules.

PMID- 12617536
TI  - Fatal degenerative neurologic illnesses in men who participated in wild game
      feasts--Wisconsin, 2002.
AB  - Creutzfeldt-Jakob disease (CJD) is a fatal neurologic disorder in humans. CJD is
      one of a group of conditions known as transmissible spongiform encephalopathies
      (TSEs), or prion diseases, that are believed to be caused by abnormally
      configured, host-encoded prion proteins that accumulate in the central nervous
      tissue. CJD has an annual incidence of approximately 1 case per million
      population in the United States and occurs in three forms: sporadic, genetically
      determined, and acquired by infection. In the latter form, the incubation period
      is measured typically in years. Recent evidence that prion infection can cross
      the species barrier between humans and cattle has raised increasing public health
      concerns about the possible transmission to humans of a TSE among deer and elk
      known as chronic wasting disease (CWD). During 1993-1999, three men who
      participated in wild game feasts in northern Wisconsin died of degenerative
      neurologic illnesses. This report documents the investigation of these deaths,
      which was initiated in August 2002 and which confirmed the death of only one
      person from CJD. Although no association between CWD and CJD was found, continued
      surveillance of both diseases remains important to assess the possible risk for
      CWD transmission to humans.

PMID- 12617540
TI  - Report of the American Animal Hospital Association (AAHA) Canine Vaccine Task
      Force: executive summary and 2003 canine vaccine guidelines and recommendations.
AB  - The AAHA has undertaken the development of this document in an effort to inform
      veterinary practitioners, clarify misunderstandings held by veterinarians, and
      encourage practitioners to recognize that immunization of patients is a medical
      procedure. As such, it is bound by the same tenets that govern the recommendation
      of other medical procedures-principally, that it be tailored to the needs of the
      individual patient. Many diseases we immunize against are ubiquitous. Many are
      serious and some even life threatening. Some are of limited demographic concern
      given the exposure risk for each patient. These factors have all been considered
      in developing the AAHA Canine Vaccination Guidelines. In the end, each
      veterinarian must do what he or she determines to be in the best interest of the
      patient. Vaccination of individual animals produces not only individual immunity
      but also population or herd immunity. Since we have no readily available and
      reliable way to determine if each patient has developed an adequate immune
      response, we encourage the practice philosophy of vaccinating more patients while
      vaccinating each patient no more than needed.

PMID- 12617541
TI  - Hypothyroidism and myocardial failure in two Great Danes.
AB  - Two Great Danes were evaluated for signs of congestive heart failure. Dilated
      cardiomyopathy was diagnosed in each dog. Both dogs were diagnosed concurrently
      with primary hypothyroidism. Following appropriate supplementation with
      levothyroxine, both dogs showed significant improvement in myocardial
      contractility, as demonstrated by increased fractional shortening and reductions
      in left atrial size, and left ventricular end-systolic and diastolic diameters.
      These observations suggest that hypothyroidism may lead to myocardial failure in
      Great Danes that is partially or fully reversible following thyroid hormone
      replacement therapy, and that hypothyroidism should be considered in all Great
      Danes presenting with systolic failure.

PMID- 12617542
TI  - A retrospective study regarding the treatment of lupoid onychodystrophy in 30
      dogs and literature review.
AB  - The treatment records of 30 dogs with lupoid onychodystrophy were evaluated
      retrospectively. Dogs were treated with fatty acid supplementation (n=18),
      doxycycline and niacinamide (n=12), tetracycline and niacinamide (n=10),
      pentoxifylline (n=6), prednisolone (n=5), azathioprine (n=1), clofazimine (n=1),
      or with combinations thereof. An excellent response was seen in almost half of
      the patients treated with tetra- or doxycycline in combination with niacinamide.
      Six of the dogs were maintained successfully on fatty acid supplementation.
      Spontaneous remissions and recurrences made evaluation of success rates difficult
      and emphasized the varied and often unclear etiology and natural course of the
      syndrome.

PMID- 12617543
TI  - Ultrasound-guided percutaneous drainage as the primary treatment for prostatic
      abscesses and cysts in dogs.
AB  - Thirteen dogs with prostatic abscesses and cysts were treated using percutaneous
      ultrasound-guided drainage. Eight dogs were diagnosed with prostatic abscesses
      and five with cysts on the basis of cytopathological examination and bacterial
      culture of the prostatic fluid. Antibiotic therapy, based on culture and
      sensitivity results, was administered for a minimum of 4 weeks. Intact dogs were
      castrated after initial drainage. Repeat ultrasonography of the prostate was
      performed every 1 to 6 weeks, and any residual cavitary lesions were drained and
      fluid analysis repeated. The median number of drainage procedures required to
      completely resolve the lesions was two (range, one to four). No complications
      were observed after drainage, and clinical signs resolved in all dogs. None of
      the dogs developed clinical signs of recurrent abscesses or cysts in the follow
      up period (median, 36 months; range, 10 to 50 months). Ultrasound-guided,
      percutaneous drainage of prostatic abscesses and cysts appears to be a useful
      alternative to surgical treatment in select dogs.

PMID- 12617545
TI  - Portosystemic shunts: diagnosis, prognosis, and treatment of 64 cases (1993
      2001).
AB  - Cases diagnosed with portosystemic shunting between the years 1993 and 2001 were
      reviewed. Sensitivities of screening tests and abdominal ultrasonographic
      evaluation for the detection of portosystemic shunting were evaluated. Prognosis
      for surgically treated shunts was also evaluated. Results indicated that both
      paired serum bile acids and blood ammonia levels were useful screening tests for
      portosystemic shunting. However, paired bile acid tests were significantly more
      sensitive than blood ammonia levels. Overall postoperative mortality rates for
      extrahepatic shunts and intrahepatic shunts were 8.7% and 20%, respectively.
      Postoperative mortality rates were slightly higher for animals treated with
      partial ligation when compared to those treated with ameroid ring placement,
      although this did not reach statistical significance. Long-term complication
      rates for animals with single extrahepatic portosystemic shunts treated with
      complete ligation, ameroid ring placement, and partial ligation alone were 9%,
      15.4%, and 42%, respectively. Animals >2 years of age with extrahepatic shunts
      had almost identical postoperative mortality and long-term complication rates as
      animals < or = 2 years of age. No animal in this study had paired bile acid
      samples within the reference range postoperatively, indicating continued abnormal
      liver function after surgery.

PMID- 12617546
TI  - Protein-losing enteropathy associated with cystic mucoid changes in the
      intestinal crypts of two dogs.
AB  - Two dogs were emaciated and hypoalbuminemic due to protein-losing enteropathy
      associated with a severe, focal, mucoid, cryptal ectasia of the duodenum and
      marked villus atrophy. In one case, diseased portions of the duodenum were
      obvious endoscopically and were limited to discrete, focal areas in the small
      intestine, with apparently more undiseased tissue than diseased tissue being
      present. The signs and lesions in one dog resolved after initiating combination
      dietary and pharmacological therapy.

PMID- 12617548
TI  - Cerebellar infarcts in two dogs diagnosed with magnetic resonance imaging.
AB  - Two dogs presented with severe, peracute-onset, neurological signs.
      Neuroanatomical localization was cerebellovestibular. Magnetic resonance imaging
      (MRI) was performed and revealed focal, wedge-shaped lesions in the cerebellum.
      Diagnosis of cerebellar infarctions was made based on peracute-onset, clinical
      signs, MRI, and outcome as well as ancillary diagnostic information. Both dogs
      recovered completely. Cerebellar infarction should be included in the
      differential of any dog with peracute-onset, central cerebellovestibular signs
      regardless of severity of clinical signs. Outcome was excellent in these dogs.

PMID- 12617544
TI  - Feline esophagitis secondary to gastroesophageal reflux disease: clinical signs
      and radiographic, endoscopic, and histopathological findings.
AB  - Chronic esophagitis due to gastroesophageal reflux (GER) is rarely reported in
      the cat. This paper describes the clinical signs and diagnostic findings,
      including radiographic, endoscopic, and histopathological abnormalities, in three
      young, purebred, male cats with esophagitis presumed to be secondary to GER.
      Clinical signs included regurgitation, dysphagia, and weight loss. Contrast
      radiography revealed GER, esophageal dilatation, and decreased motility.
      Endoscopy showed hyperemia, increased vascularity, ulcers, erosion, and an
      abnormal lower esophageal sphincter. Histopathological lesions included squamous
      hyperplasia and dysplasia, erosions, ulcers, and an inflammatory infiltrate of
      lymphocytes, plasma cells, and neutrophils. Long-term follow-up demonstrated
      progression of the disease in two of the cats.

PMID- 12617547
TI  - Effect of anticonvulsant dosages of potassium bromide on thyroid function and
      morphology in dogs.
AB  - A placebo-controlled experiment was performed to evaluate the effect of potassium
      bromide on the canine thyroid gland. Basal total thyroxine, free thyroxine, and
      basal thyrotropin serum concentrations were evaluated over a 6-month period in
      potassium bromide-treated and control dogs. A thyrotropin-releasing hormone
      stimulation test was also performed in all dogs at the beginning and conclusion
      of the study. Thyroid histopathology was compared between treated and control
      dogs at the end of the study. No difference was detected in any parameter between
      the two groups at the end of the study. A decline in thyroid hormone
      concentrations over the course of the study did occur in both groups of dogs.
      Potassium bromide does not appear to have a significant effect on canine thyroid
      function or morphology.

PMID- 12617549
TI  - Effects of bandage configuration on paw pad pressure in dogs: a preliminary
      study.
AB  - Seven bandage configurations were placed on the right forepaw of six English
      pointer dogs to evaluate the effects that configurations have on reducing pad
      pressure. The "clam shell" configuration resulted in less pressure being applied
      to all palmar pad surfaces. For the major weight-bearing pad, a basic paw bandage
      with an intermediate compressible foam sponge that had a hole under the major
      weight-bearing pad, combined with a metal splint paw cup under the sponge,
      resulted in a significantly lower pressure recording than for other bandage
      configurations. Digital pads 3 and 5 had the greatest pressure in a basic bandage
      configuration. Based on pressures on these pads, a basic paw bandage with an
      intermediate compressible foam sponge under the major weight-bearing pad, with or
      without a metal splint paw cup under the sponge, helped elevate the digits to
      relieve pressure on them. Placing a foam sponge pad, with or without a splint paw
      cup under the palmar paw surface, also provided less pressure on these pads.

PMID- 12617552
TI  - Dissipation and mobility of permethrin in the field with repeated applications
      under tropical conditions.
AB  - Studies on persistence, mobility and the effect of repeated application of
      permethrin on its half-life were carried out under field conditions. The half
      life of permethrin in the top 20 cm of the soil increased from 11.5 to 23.6 days
      as the application rates increased from 35 to 140 g ha(-1). Induced by heavier
      rainfall, more residues moved downward in trial 2 than in trial 1. Repeated
      applications enhanced degradation rates and mobility of permethrin in the soil.
      The residue level in the 0-5-cm layer was reduced at day 28 after 17 consecutive
      applications to a level lower than after 5 applications. The half-life of
      permethrin was reduced from 15.9 days to 11.2 days after 5 and 17 applications,
      respectively. The residue reached the 15-20 cm layer much earlier (approximately
      3 days after treatment) in soil that received 17 applications as compared to
      those with two applications.

PMID- 12617550
TI  - Comparison of gas chromatography and immunoassay methods for analysis of total
      DDT in calcareous soils.
AB  - Three different calcareous soil samples from Lebanon were analyzed for total DDT
      pesticide residue using GC and ELISA methods. Two experiments were conducted on
      three different calcareous soil samples. In each experiment, triplicates of 5 gm
      soil samples were each fortified with standard solutions of DDE to reach
      concentrations of 0, 5, 25, 50, 100 and 200 ng g(-1) and allowed to equilibrate
      at room temperature for 6 hours. Each sample was then extracted with 25 mL of 90%
      methanol by shaking in glass bottles on a mechanical shaker for 16 hours. The
      bottles were allowed to stand for 30 minutes and aliquots were taken from the
      clear supernatant for analyses without further cleanup. The total DDT in the
      extract was measured in triplicate by GC and ELISA. The results indicated that
      the two methods were highly correlated (R = 0.955-0.994). Differences in soil
      properties did not affect the accuracy of the detection limits of ELISA.
      Immunoassay technique can be used for rapid and accurate measurement of total DDT
      residues in mineral calcareous soils in Lebanon.

PMID- 12617553
TI  - Interactions between algae (Selenastrum capricornutum) and pesticides:
      implications for managing constructed wetlands for pesticide removal.
AB  - This laboratory study examined the interactions between an algal species found in
      wetlands (Selenastrum capricornutum) and two agricultural pesticides (atrazine
      and lindane). Pesticide additions had a positive effect on the chlorophyll a
      concentrations of the treatments. The presence of algae decreased the aqueous
      persistence of both pesticides. It is speculated that the algae either provided
      sites for pesticide sorption or facilitated pesticide degradation.

PMID- 12617551
TI  - Degradation of 3,4-dichloro- and 3,4-difluoroaniline by Pseudomonas fluorescens
      26-K.
AB  - 3,4-Dichloro- and 3,4-difluoroanilines were degraded by Pseudomonas fluorescens
      26-K under aerobic conditions. In the presence of glucose strain degraded 170
      mg/L of 3,4-dichloroaniline (3,4-DCA) during 2-3 days. Increasing of toxicant
      concentration up to 250 mg/L led to degradation of 3,4-DCA during 4 days and its
      intermediates during 5-7 days. Without cosubstrate and nitrogen source
      degradation of 3,4-DCA took place too, but more slowly--about 40% of toxicant at
      initial concentration 75 mg/L was degraded during 15 days. 3,4-Difluoroaniline
      (3,4-DFA) (initial concentration 170 mg/L) was degraded by Pseudomonas
      fluorescens 26-K during 5-7 days. The strain was able to completely degrade up to
      90 mg/L of 3,4-DFA, without addition of cosubstrate and nitrogen during 15 days.
      Degradation of fluorinated aniline was accompanied by intensive defluorination.
      Activity of catechol 2,3-dioxygenase (C2,3DO) (0.230 micromol/min/mg of protein)
      was found in the culture liquid of the strain, grown with 3,4-DCA and glucose.
      This fact, as well as, the presence of 3-chloro-4-hydroxyaniline as a metabolite
      suggested that 3,4-DCA degradation pathway includes dehalogenation and
      hydroxylation of aromatic ring followed by its subsequent cleaving by C2,3DO. On
      the contrary, activity of catechol 1,2-dioxygenase (C1,2DO) (0.08 micromol/min/mg
      of protein) was found in the cell-free extract of biomass grown on 3,4-DFA. 3
      Fluoro-4-hydroxyaniline as intermediate was found in this cell-free extract.

PMID- 12617554
TI  - Adsorption of pesticides on resins.
AB  - The objective of this work was to assess the capability of organic hydrophobic
      polymeric resins Amberlite XAD-4 and XAD-7 to remove the pesticides alachlor and
      amitrole from water. The pesticides adsorption on the two different adsorbents
      was measured by batch equilibrium technique and isotherm types and parameters
      were estimated. Two theoretical models were applied based on a Freundlich and a
      Langmuir isotherms. The effect of pesticides chemical composition and structure
      as well as the nature of solid surface on the efficiency of adsorption was
      evaluated. The influence of pH also was studied. In low pH solutions adsorption
      of amitrole was higher upon the nonionic aliphatic acrylic ester copolymer XAD-7
      in comparison to the nonionic, crosslinked macroreticular copolymer of styrene
      divinylbenzene XAD-4. In neutral and intermediate pH solutions the polar acrylic
      ester copolymer XAD-7 was more effective to the retention of alachlor. The
      acrylic ester copolymer showed at pH 3 the lower effectiveness in alachlor
      removal from water. The data of the adsorption isotherms of pesticides upon the
      examined polymeric resins seemed to conform to both the Freundlich and the
      Langmuir isotherm models.

PMID- 12617555
TI  - Acute toxicity assessment of azadirachtin-based pesticides using murine hybridoma
      and oyster cells.
AB  - In vitro acute toxicities of azadirachtin-containing pesticides (Neemix and
      Bioneem), formulated with neem tree extracts, and pure azadirachtin (AZA), the
      believed active ingredient, were studied using hybridoma and oyster cells and
      were compared to results obtained using the standard in vivo Daphnia pulex
      toxicity assay. Neem-based pesticides showed relatively high toxicity to both
      hybridoma and oyster cells at concentrations of 1 microg AZA/mL and higher. The
      IC50 values for hybridoma cells were 2.15 microg AZA/mL for Neemix and 1.67 pg
      AZA/mL for Bioneem. Oyster cells had IC50 values of 2.18 microg AZA/mL for Neemix
      and 9.46 pg AZA/mL for Bioneem. Purified AZA, however, did not appear to be as
      toxic as the formulations. D. pulex was also more sensitive to neem-based
      pesticide exposure than that of pure AZA. The applications and limits of these
      two in vitro models for testing the acute toxicity of AZA-based pesticides are
      discussed in comparison with the in vivo D. pulex test.

PMID- 12617556
TI  - Heavy and toxic metals in staple foodstuffs and agriproduct from contaminated
      soils.
AB  - This article presents basic data on the content of Cr, Fe, Ni, Cu, Zn, As, Cd,
      Sb, Hg, and Pb in staple foodstuffs and agriproduct grown in Russia (Astrakhan
      region and the town of Belovo) and Egypt (Helwan region). The dependence of the
      concentration of metals in agriproducts on the content and chemical form of
      existence in irrigation water and soils is indicated.

PMID- 12617557
TI  - Influence of ascorbic acid supplementation on the haematological and clinical
      biochemistry parameters of male rabbits exposed to aflatoxin B1.
AB  - This study was undertaken to evaluate the effectiveness of L-ascorbic acid (AA)
      in alleviating the toxicity of aflatoxin B1 (AFB1) in male New-Zealand white
      rabbits. Five rabbits (6 months of age and mean body weight 3.12 kg) per group
      were assigned to 1 of 6 treatment groups: 0 mg AA and 0 mg AFB1/kg BW (control);
      20 mg AA/kg BW; 15 microg AFB1/kg BW; 15 microg AFB1 plus 20 mg AA/kg BW; 30 pg
      AFB1/kg BW; 30 pg AFB1 plus 20 mg AA/kg BW. Rabbits were orally administered
      their respective doses every other day for 9 weeks, followed by a 9-week recovery
      period where all drugs were withdrawn. Evaluations were made for hemato
      biochemical parameters and enzymatic activities. Results showed that AFB1
      significantly (p < 0.05) decreased hemoglobin (Hb), total erythrocytic count
      (TEC) and packed cell volume (PCV), in a dose-dependent manner, and these effects
      were continued during the recovery period. Ascorbic acid caused an increase in
      these parameters, and alleviated the negative effect of AFB1 during the treatment
      period. Additionally, serum concentrations of total protein, albumin and glucose
      were significantly (P < 0.05) declined by treatment with the high dose of
      aflatoxin and these effects were continued during the recovery period. Ascorbic
      acid caused non-significant increases in these parameters and alleviated the
      harmful effect of AFB1. On the other hand, aflatoxin treatment caused significant
      increases (P < 0.05) in the activities of serum aspartate aminotransferase (AST),
      alanine aminotransferase (ALT) and alkaline phosphatase (AlP) during the
      treatment period in a dose dependent manner, and this effect was continued during
      the recovery period, especially with the high dose. Also, treatment with the high
      dose of aflatoxin caused significant increases (P<0.05) in cholesterol and total
      bilirubin. Ascorbic acid caused significant decreases in these parameters and
      alleviated the harmful effects of AFB1. Whereas, Total leukocyte count (TLC),
      urea and creatinine were not significantly affected by aflatoxin-treatment.
      Generally, it is interesting feature that the treatment with AA alone had no
      negative effects on most of the previous parameters. Also, the presence of AA
      could diminished the adverse effects of AFB1 on most of hematological and
      biochemical values, and enzymatic activities in rabbits.

PMID- 12617559
TI  - Investigation of appropriate initial composition and aeration method for co
      composting of yard waste and market wastes.
AB  - The purpose of this research was to shorten the composting period by speeding up
      the composting process and to obtain good quality compost that can be used in
      agriculture. In order to accomplish the acceleration of the process, different
      mixtures of feedstock were loaded to the composting containers to observe the
      effect of initial composition on the quality of the compost and the rate of
      composting. The first feedstock prepared was composed of grass, leaves and market
      waste whereas the second feedstock composed only of leaves and market wastes.
      Composting process was accomplished by applying different composting methods such
      as composting without manual stirring, with manual stirring, with aeration by
      air, with aeration by oxygen, with manual stirring and aeration by air and
      finally by with manual stirring and aeration by oxygen to achieve the purpose of
      the research. Aeration was found as a primary requirement for the acceleration of
      composting because it was observed that when the aeration was not applied the
      conversion of nutrients was very low. The high conversion efficiency of the
      nutrients in the feedstock with market and yard wastes-without grass-resulted in
      higher quality end product. The organic content of the composted yard and market
      wastes were monitored and the best operational parameters and methods were
      identified. Parameters such as temperature, moisture, pH and end-product metal
      contents were also monitored in the study. and the experiments were run in
      duplicates. Corrected C/N, (C/N)t/(C/N)initial, were used in the calculations
      which provided objectivity in comparison of the compost quality with respect to
      nutritional components. The C/N change was found to be higher in the container
      that was manually stirred and aerated with oxygen but with regard to the economic
      feasibility of the system aeration with air was preferred. Compost quality that
      was achieved in the study was compared to the standards of different countries
      with respect to the amount of metal contents in the end-product. The
      applicability of the end-product in agriculture depends on the level of
      contaminants in the compost, especially metals that have to be present only in
      trace amounts.

PMID- 12617558
TI  - Extractable soil lipids and microbial activity as affected by Bt and non Bt maize
      grown on a silty clay loam soil.
AB  - Pyrolysis-gas (Py-GC) chromatography was used to characterize extractable lipids
      from Bt and non-Bt maize shoots and soils collected at time of harvesting. Py-GC
      MS (mass spectrometry) showed that the concentrations of total alkenes identified
      in non-Bt shoots and soils were 47.9 and 21.3% higher than in Bt maize shoots and
      soils, respectively. N-alkanes identified were of similar orders of magnitude in
      Bt and non-Bt maize shoots, but were 28.6% higher in Bt than in non-Bt soils. Bt
      maize shoots contained 29.7% more n-fatty acids than non-Bt maize shoots, whereas
      the concentrations of n-fatty acids in Bt soils were twice as high as those in
      non-Bt soils. Concentrations of unsaturated fatty acids in Bt maize shoots were
      22.1% higher than those in non-Bt maize shoots, while concentrations of
      unsaturated fatty acids were 22.5% higher in non-Bt than in Bt soils. The
      cumulative CO2-C evolved from soils under Bt and non-Bt crops was 30.5% lower
      under Bt as compared to non-Bt crops, whereas when maize shoots were added to Bt
      and non-Bt soils, the decrease in CO2-C evolved were 16.5 and 23.6%,
      respectively. Our data showed that the cultivation of Bt maize significantly
      increased the saturated to unsaturated lipid ratios in soils which appeared to
      negatively affect microbial activity.

PMID- 12617560
TI  - Odor measurements for manure spreading using a subsurface deposition applicator.
AB  - Odor emissions during manure spreading events have become a source of concern,
      particularly where farms are located nearby urban areas. The objective of the
      present study was to compare odor concentrations and odor emission rates due to
      pig manure application using two different types of applicators, a sub-surface
      deposition system and a conventional splash-plate applicator. Air samples were
      collected using a Surface Isolation Flux Chamber and the "bag-in-vacuum chamber"
      techniques, at 0.5, 1.5 and 2.5 hours after manure application. A three-station
      forced-choice dynamic dilution olfactometer was used by an odor panel for
      determining odor concentration. Preliminary results indicated that with the sub
      surface deposition system applicator odor emission rate was reduced by 8% to 38%
      compared to that of the conventional splash-plate applicator. The highest
      reduction in odor strength and odor emission rate was observed in the most
      offensive period after manure application. The sub-surface deposition system may
      be a solution for hog producers who wish to reduce odor complaints from applying
      manure without the cost and problems associated with deep injection systems.

PMID- 12617561
TI  - Glial proinflammatory cytokines mediate exaggerated pain states: implications for
      clinical pain.
AB  - When you hurt yourself, you become consciously aware of the pain because a chain
      of neurons carries the pain message from the injury to the spinal cord, and then
      from the spinal cord up to consciousness in the brain. However, it has been known
      for more than two decades that neural circuits within the spinal cord can cause
      your conscious experience of pain to be amplified-that is, the pain you perceive
      is out of proportion to the injury that caused it. Until now, all research aimed
      at understanding how pain amplification occurs in the spinal cord and all drug
      therapies aimed at curing exaggerated pain have focused exclusively on neurons.
      This is because neurons were the only type of cell believed to be important in
      pain. The present review argues that neurons in fact are not the only cell type
      involved. Rather, that spinal cord cells called "glia" are also critically
      important. Indeed, when glia become activated, they begin releasing a variety of
      chemical substances that causes the pain message to become amplified, thus
      causing pain to hurt more. This review discusses evidence that glia cause pain to
      become amplified and describes how the glia cause this to happen. The take-home
      message is that drugs that target glia and the chemical substances that these
      glia release are predicted to be powerful remedies for pain problems in people.

PMID- 12617563
TI  - Cytokines and peripheral analgesia.
AB  - Tissue damage causes an inflammatory response in which cytokines contribute to a
      painful state. Local inflammation also leads to an enhanced expression of opioid
      peptides such as END within immune cells of inflamed tissue. These endogenous
      substances can be released by "releasing factors" such as CRF and IL-4 via
      activation of their receptors on the cell surface of inflammatory cells. Local
      application of CRE or IL-1 into inflamed tissue results in significant analgesia
      which is most likely mediated by a release of opioid peptides from immune cells
      within inflamed tissue. This mechanism of pain inhibition also seems to have a
      physiological role. Upon certain stressful stimuli analgesic effects seem to be
      mediated by a release of opioid peptides and a subsequent activation of
      peripheral opioid receptors. Locally expressed CRF but not IL-1 appear to trigger
      this release. Thus, inflammatory pain can be modulated both by exogenous CRF and
      IL-1 as well as endogenous CRF. These mechanisms are based on interaction between
      the immune and nervous systems. Both the initiation of pain and its control can
      be regarded as the body's response to prevent further injury, to support wound
      healing and to return to a normal function as quickly as possible.

PMID- 12617562
TI  - Peripheral hyperalgesic cytokines.

PMID- 12617564
TI  - Opioid peptides in immune cells.

PMID- 12617565
TI  - Opioid receptors on peripheral sensory neurons.

PMID- 12617569
TI  - Experimental evidence for immunomodulatory effects of opioids.

PMID- 12617567
TI  - Functional evidence of pain control by the immune system.

PMID- 12617566
TI  - Morphological correlates of immune-mediated peripheral opioid analgesia.
AB  - The immune system is a source of opioid peptides and plays an important role in
      the control of inflammatory pain. Inflammation not only increases the opioid
      receptor expression in DRG neurons but also enhances transport and accumulation
      of opioid receptors on the peripheral terminals of sensory neurons. Immune cells
      containing opioid peptides migrate to the inflamed tissue. This is orchestrated
      by adhesion molecules up-regulated on vessel endothelia and co-expressed by
      opioid-containing immunocytes. The peptides are secreted by stressful stimuli,
      CRF and cytokines and the corresponding receptors are present on opioid
      expressing leukocytes. The opioids bind to their receptors localized on
      peripheral sensory nerves leading to pain inhibion. In the more distant future,
      these findings might stimulate the development of novel analgesics based on
      enhancing the transport and release of immune-derived opioid peptides into
      injured tissue.

PMID- 12617568
TI  - Opioid receptor expression and intracellular signaling by cells involved in host
      defense and immunity.
AB  - More than two decades ago, Joseph Wybran reported his original insights on the
      expression of different opioid receptor types by T-cells. This was based on the
      differential effects that morphine and methionine enkephalin exerted on human T
      cell rosetting in the presence of sheep red blood cells. Since that time,
      numerous laboratories have shown that opiate alkyloids and opioid peptides have
      pleiotropic effects on immune function. In general, these compounds act as
      immunomodulators that modify the immune response to mitogens, antigens and
      antibodies that cross-link the T-cell receptor. In the past decade, it has become
      clear that cells involved in host defense and immunity express the various mRNAs
      encoding the same opioid receptors originally identified in neuronal tissues.
      Recently, indirect fluorescence and immunofluorescence have been utilized to
      demonstrate the regulated expression of both delta and kappa opioid receptors,
      predominantly on T-cells. In addition, immune cells express sites that show
      atypical opiate and opioid binding properties. In this review, we will distill
      the evidence for both classical and atypical opioid receptors and their effects
      on signaling within immune cells, focusing on the T-cell and emphasizing the
      delta opioid receptor.

PMID- 12617570
TI  - The immune-suppressive effects of pain.

PMID- 12617571
TI  - Invertebrate opiate immune and neural signaling.

PMID- 12617572
TI  - Anti-inflammatory effects of opioids.
AB  - In summary, therapy with opioids is an exciting new development for arthritis
      especially since there is the potential for fewer side effects from molecules
      which act outside the CNS. We found kappa-opioid drugs to be powerfully anti
      inflammatory, reducing disease severity by as much as 80%; attenuating arthritis
      in a dose-dependent, stereoselective, antagonist-reversible manner. By contrast
      opioids acting at other receptors were only therapeutic at near toxic doses. The
      HPA-axis was found to be only partially involved, thus we investigated other
      neural and immune mechanisms. Results showed that the kappa-opioid anti
      inflammatory actions were exerted via (i) reduced adhesion molecule expression;
      (ii) inhibition of cell trafficking; (iii) reduced TNF release and expression and
      (iv) alterations in mRNA expression and protein levels of SP and CGRP in joint
      tissue (Fig. 2). The ability of kappa-opioids to act at multiple sites in the
      inflammatory cascade, as suggested by the presence of opioid receptors at various
      locations throughout the cascade, may explain their powerful actions (Fig. 2). It
      is also relevant that during inflammatory states that enhanced peripherally
      directed axonal transport leads to receptor upregulation on peripheral nerve
      terminals in the joint. Neuropeptides (SP and CGRP) were found to be involved in
      the later phases of adjuvant arthritis suggesting that they are involved in the
      maintenance or persistence of the disease. The involvement of SP and the efficacy
      of neurokinin-1 (SP receptors) antagonists predicts that combined opioid-
      neurokinin-1 therapy has promise. Kappa-opioids are, however, powerfully
      therapeutic during disease onset. Thus, they most likely exert their anti
      inflammatory effects via changes in cellular activation and cytokine expression.
      The mechanisms involved are summarized in Fig. 2. The increased potency of kappa
      opioids in females is likely to be a significant advantage for treatment of
      inflammatory disease with these agents. Thus our work supports the findings of
      Stein's group, that opioids do indeed have powerful actions in the periphery via
      specific receptors at that site. Peripherally acting opioids may prove to be a
      potent new treatment for rheumatoid arthritis sufferers in the future.

PMID- 12617573
TI  - Guidelines for using antiretroviral agents among HIV-infected adults and
      adolescents.
AB  - The availability of an increasing number of antiretroviral agents and the rapid
      evolution of new information have introduced substantial complexity into
      treatment regimens for persons infected with human immunodeficiency virus (HIV).
      In 1996, the Department of Health and Human Services and the Henry J. Kaiser
      Family Foundation convened the Panel on Clinical Practices for the Treatment of
      HIV to develop guidelines for clinical management of HIV-infected adults and
      adolescents (CDC. Report of the NIH Panel To Define Principles of Therapy of HIV
      Infection and Guidelines for the use of antiretroviral agents in HIV-infected
      adults and adolescents. MMWR. 1998;47[RR-5]:1-41). This report, which updates the
      1998 guidelines, addresses 1) using testing for plasma HIV ribonucleic acid
      levels (i.e., viral load) and CD4+ T cell count; 2) using testing for
      antiretroviral drug resistance; 3) considerations for when to initiate therapy;
      4) adherence to antiretroviral therapy; 5) considerations for therapy among
      patients with advanced disease; 6) therapy-related adverse events; 7)
      interruption of therapy; 8) considerations for changing therapy and available
      therapeutic options; 9) treatment for acute HIV infection; 10) considerations for
      antiretroviral therapy among adolescents; 11) considerations for antiretroviral
      therapy among pregnant women; and 12) concerns related to transmission of HIV to
      others. Antiretroviral regimens are complex, have serious side effects, pose
      difficulty with adherence, and carry serious potential consequences from the
      development of viral resistance because of nonadherence to the drug regimen or
      suboptimal levels of antiretroviral agents. Patient education and involvement in
      therapeutic decisions are critical. Treatment should usually be offered to all
      patients with symptoms ascribed to HIV infection. Recommendations for offering
      antiretroviral therapy among asymptomatic patients require analysis of real and
      potential risks and benefits. In general, treatment should be offered to persons
      who have <350 CD4+ T cells/mm3 or plasma HIV ribonucleic acid (RNA) levels of
      >55,000 copies/mL (by b-deoxyribonucleic acid [bDNA] or reverse transcriptase
      polymerase chain reaction [RT-PCR] assays). The recommendation to treat
      asymptomatic patients should be based on the willingness and readiness of the
      person to begin therapy; the degree of existing immunodeficiency as determined by
      the CD4+ T cell count; the risk for disease progression as determined by the CD4+
      T cell count and level of plasma HIV RNA; the potential benefits and risks of
      initiating therapy in an asymptomatic person; and the likelihood, after
      counseling and education, of adherence to the prescribed treatment regimen.
      Treatment goals should be maximal and durable suppression of viral load,
      restoration and preservation of immunologic function, improvement of quality of
      life, and reduction of HIV-related morbidity and mortality. Results of therapy
      are evaluated through plasma HIV RNA levels, which are expected to indicate a 1.0
      log10 decrease at 2-8 weeks and no detectable virus (<50 copies/mL) at 4-6 months
      after treatment initiation. Failure of therapy at 4-6 months might be ascribed to
      nonadherence, inadequate potency of drugs or suboptimal levels of antiretroviral
      agents, viral resistance, and other factors that are poorly understood. Patients
      whose therapy fails in spite of a high level of adherence to the regimen should
      have their regimen changed; this change should be guided by a thorough drug
      treatment history and the results of drug-resistance testing. Because of
      limitations in the available alternative antiretroviral regimens that have
      documented efficacy, optimal changes in therapy might be difficult to achieve for
      patients in whom the preferred regimen has failed. These decisions are further
      confounded by problems with adherence, toxicity, and resistance. For certain
      patients, participating in a clinical trial with or without access to new drugs
      or using a regimen that might not achieve complete suppression of viral
      replicatioing a regimen that might not achieve complete suppression of viral
      replication might be preferable. Because concepts regarding HIV management are
      evolving rapidly, readers should check regularly for additional information and
      updates at the HIV/AIDS Treatment Information Service website (
      http://www.hivatis.org ).

PMID- 12617576
TI  - Supercritical extraction of essential oil from aniseed (Pimpinella anisum L)
      using CO2: solubility, kinetics, and composition data.
AB  - Supercritical fluid extraction (SFE) from aniseed using carbon dioxide was
      performed at 30 degrees C and pressures of 80-180 bar. The chemical composition
      of the SFE extract was determined by GC-MS; the quantitative analysis was done by
      GC-FID and TLC. The total amount of extractable substances or global yield (mass
      of extract/mass of feed) for the SFE process varied from 3.13 to 10.67% (mass).
      The solubilities of the anise essential oil in CO(2) were 0.0110, 0.0277, 0.0143,
      and 0.0182 kg of solute/kg of CO(2) at 80, 100, 140, and 180 bar, respectively.
      The major compounds identified and quantified in the extracts were anethole (
      approximately 90%), gamma-himachalene (2-4%), p-anisaldehyde (<1%),
      methylchavicol (0.9-1.5%), cis-pseudoisoeugenyl 2-methylbutyrate ( approximately
      3%), and trans-pseudoisoeugenyl 2-methylbutyrate ( approximately 1.3%). The
      Sovova model described quite well the experimental overall extraction curves.

PMID- 12617575
TI  - Sulfite analysis of fruits and vegetables by high-performance liquid
      chromatography (HPLC) with ultraviolet spectrophotometric detection.
AB  - Free and total sulfite were analyzed in acidified vegetable products, instant
      mashed potatoes, and dried apples. Sulfite was separated by HPLC and quantified
      with a UV-vis detector. Resolution from components of food samples was achieved
      by varying the acid concentration of the eluant solution and by appropriate
      choice of the analytical wavelength. The minimum detectable levels for sulfite
      were 0.5 mg/L for a 10-cm analytical column and 1.5 mg/L for a 30-cm column. For
      analyses done with a 30-cm column, the coefficient of variation was <2% for
      analysis of free sulfite and total sulfite in acidified vegetables. For dried
      apples and instant potatoes, it ranged from 1 to 6.5%. The corresponding
      analytical errors were <4% and 1.2-5.6%, respectively, for the 10-cm column.

PMID- 12617574
TI  - Guidelines for preventing opportunistic infections among HIV-infected persons-
      2002. Recommendations of the U.S. Public Health Service and the Infectious
      Diseases Society of America.
AB  - In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases
      Society of America (IDSA) developed guidelines for preventing opportunistic
      infections (OIs) among persons infected with human immunodeficiency virus (HIV);
      these guidelines were updated in 1997 and 1999. This fourth edition of the
      guidelines, made available on the Internet in 2001, is intended for clinicians
      and other health-care providers who care for HIV-infected persons. The goal of
      these guidelines is to provide evidence-based guidelines for preventing OIs among
      HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or
      infected children. Nineteen OIs, or groups of OIs, are addressed, and
      recommendations are included for preventing exposure to opportunistic pathogens,
      preventing first episodes of disease by chemoprophylaxis or vaccination (primary
      prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major
      changes since the last edition of the guidelines include 1) updated
      recommendations for discontinuing primary and secondary OI prophylaxis among
      persons whose CD4+ T lymphocyte counts have increased in response to
      antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for
      infection with hepatitis C virus; 3) new information regarding transmission of
      human herpesvirus 8 infection; 4) new information regarding drug interactions,
      chiefly related to rifamycins and antiretroviral drugs; and 5) revised
      recommendations for immunizing HIV-infected adults and adolescents and HIV
      exposed or infected children.

PMID- 12617578
TI  - A new approach to the characterization of volatile signatures of cork wine
      stoppers.
AB  - This work describes a new method for the rapid characterization of volatile
      compounds of cork wine stoppers by a dynamic headspace method coupled to mass
      spectrometry (DHS-MS). This technique does not require any pretreatment of the
      sample. The global volatile signature of the cork is evaluated without real
      chromatographic separation of its constituents. For data analysis, the mass
      fragments of each spectrum (50 < m/z <180 amu) were considered as potential
      descriptors of the composition of the cork sample headspace. Chemometrics methods
      (principal component analysis and partial least-squares regression) were applied
      to extract useful information by selecting the most significant mass fragments
      (m/z) that allowed a good classification of the cork samples studied. In the
      present work, geographical origin of cork samples could be successfully
      characterized and predicted.

PMID- 12617579
TI  - Liquid chromatography analysis of erythromycin A in salmon tissue by
      electrochemical detection with confirmation by electrospray ionization mass
      spectrometry.
AB  - A rapid and sensitive method is described for the quantitation of erythromycin A
      (EA) in edible salmon tissue by liquid chromatography (LC) analysis using either
      electrochemical detection (ED) or electrospray ionization mass spectrometric
      (ESI/MS) detection. The salmon tissue is extracted with 10 mM ammonium formate.
      The extract is then purified by solid phase extraction using a hydrophilic
      lipophilic balanced (HLB) polymeric-based C18 packing, followed by partitioning
      of EA into methylene chloride at alkaline pH, evaporation, and final dilution.
      The mean recoveries of EA at 50, 100, 200, and 400 ppb levels in fortified salmon
      tissue were 63.8 +/- 6.0 and 75.5 +/- 5.4% by LC-ED and LC-ESI/MS, respectively.
      There was no evidence of formation of the anhydro-EA (m/z 716) decomposition
      product of EA (m/z 734) that was reported to occur by other published methods.

PMID- 12617577
TI  - Identification of goose, mule duck, chicken, turkey, and swine in foie gras by
      species-specific polymerase chain reaction.
AB  - A specific Polymerase Chain Reaction (PCR) has been developed for the
      identification of goose (Anser anser), mule duck (Anas platyrhynchos x Cairina
      moschata), chicken (Gallus gallus), turkey (Meleagris gallopavo), and swine (Sus
      scrofa domesticus) in foie gras. A forward common primer was designed on a
      conserved DNA sequence in the mitochondrial 12S ribosomal RNA gene (rRNA), and
      reverse primers were designed to hybridize on species-specific DNA sequences of
      each species considered. The different sizes of the species-specific amplicons,
      separated by agarose gel electrophoresis, allowed clear identification of goose,
      mule duck, chicken, turkey, and swine in foie gras. Analysis of experimental
      mixtures demonstrated that the detection limit of the assay was approximately 1%
      for each species analyzed. This genetic marker can be very useful for the
      accurate identification of these species, avoiding mislabeling or fraudulent
      species substitution in foie gras.

PMID- 12617580
TI  - Microwave-assisted rapid determination of vitamins a and e in beverages.
AB  - A new rapid procedure for the determination of vitamins A and E in beverages has
      been developed and validated. Key steps include a microwave-assisted
      saponification of the sample and a single-step extraction of the vitamins prior
      to HPLC analysis. All sample preparation steps are carried out consecutively in
      the same vial. The vitamins are determined using normal-phase (Si-60) HPLC with
      fluorescence detection. The method is applicable to beverages with a content of
      all-trans-retinol >0.14 mg/L and/or a content of alpha-tocopherol >1 mg/L.
      Recoveries determined by spiking experiments ranged from 91.3 to 106.3%. The
      precision of the method is characterized by relative standard deviations of <2%
      for alpha-tocopherol and <5% for all-trans-retinol.

PMID- 12617581
TI  - Analysis of wine components in Cynthiana and Syrah wines.
AB  - Red wine is composed of a complex matrix of compounds that can interfere with
      analysis. A high-performance liquid chromatography (HPLC) procedure was developed
      to efficiently analyze organic acids, sugars, glycerol, and ethanol in Cynthiana
      (Vitis aestivalis) wine. Standard laboratory procedures (pH, titratable acidity,
      and color attributes) and HPLC were found reproducible for Cynthiana wine. HPLC
      recovery efficiency was determined by analysis of spiked and unspiked samples
      (model, Cynthiana, and Syrah (Vitis vinifera) wines). Although recovery of
      components was greater in the model wine, recovery in Cynthiana and Syrah wine
      was comparable. The HPLC procedure was further compared to commercial rapid
      enzyme analysis tests using model, Cynthiana, and Syrah wines. HPLC analyses were
      more accurate than enzymatic tests for determining components in the model,
      Cynthiana, and Syrah wines. Considering the complexity of the wines analyzed,
      reproducibility and recovery of the HPLC procedure was demonstrated and showed
      improvement and precision when compared to existing methods.

PMID- 12617582
TI  - Determination of free phenolic acids in wort and beer by coulometric array
      detection.
AB  - The simultaneous determination of 19 phenolic compounds was performed directly in
      wort and beer by a combination of reverse-phase high-performance liquid
      chromatography coupled with coulometric array detection. Chromatographic
      separation was achieved with an appropriate gradient of flow and a binary solvent
      based on phosphate buffer, methanol, and acetonitrile in a 45-min run. Eight
      serial coulometric detectors were used for on-line generation of voltammetric
      data to resolve coeluting compounds. The method was reliable and sensitive, the
      regression coefficient of standard calibration curves is 0.972 < or = r < or =
      1.000, and the standard deviation value ranges from 0.010 to 0.129 mg/L for wort
      and from 0.002 to 0.332 mg/L for beer. The mean concentrations of phenolic acids
      were 22.1 and 33.8 mg/L, respectively, in worts and beers produced in Italy.
      These amounts represent 5 and 10% of the non-tannic, non-flavonoid phenols in
      wort and beer, respectively.

PMID- 12617584
TI  - Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on
      lipopolysaccharide/d-galactosamine-induced liver injury.
AB  - To evaluate the hepatoprotective activity of spices, 21 different spices were fed
      to rats with liver damage caused by lipopolysaccharide (LPS) plus d-galactosamine
      (D-GalN). As assessed by plasma aminotranferase activities, nutmeg showed the
      most potent hepatoprotective activity. Bioassay-guided isolation of the active
      compound from nutmeg was carried out in mice by a single oral administration of
      the respective fractions. Myristicin, one of the major essential oils of nutmeg,
      was found to possess extraordinarily potent hepatoprotective activity. Myristicin
      markedly suppressed LPS/D-GalN-induced enhancement of serum TNF-alpha
      concentrations and hepatic DNA fragmentation in mice. These findings suggest that
      the hepatoprotective activity of myristicin might be, at least in part, due to
      the inhibition of TNF-alpha release from macrophages. However, further studies
      are needed to elucidate the hepatoprotective mechanism(s) of myristicin.

PMID- 12617583
TI  - Antifeedant and growth inhibitory effects of some neo-clerodane diterpenoids
      isolated from Clerodendron species (Verbenaceae) on Earias vitella and Spodoptera
      litura.
AB  - Antifeedant and growth inhibitory effects of various neo-clerodane diterpenoids
      having a furofuran moiety, isolated from Clerodendron spp., were studied using
      Earias vitella and Spodoptera litura. The compounds clerodendrin B, 3
      epicaryoptin, 15-hydroxyepicaryoptin, and clerodin were effective antifeedants at
      10 microg/cm(3) (30 microg/g) of diet against E. vitella and at 10 microg/cm(2)
      of leaf against S. litura. All of the tested compounds, namely, clerodendrin B, 3
      epicaryoptin, clerodendrin C, 15-hydroxyepicaryoptin, clerodendrin B acetate, and
      clerodin, showed good insect growth inhibitory activity even at lower
      concentrations.

PMID- 12617585
TI  - Antioxidant properties of bran extracts from "Akron" wheat grown at different
      locations.
AB  - Bran extracts of Akron wheat grown at four nonirrigated and one irrigated testing
      locations were examined and compared for their free radical scavenging properties
      against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)) and the radical
      cation ABTS(*)(+), chelating capacities, and total phenolic content (TPC) to
      determine the potential effects of environmental factors on the antioxidant
      properties of hard winter wheat. The environmental factors included total solar
      radiation, average daily solar radiation, and number of hours exceeding 32
      degrees C. The results showed that bran samples from different growing locations
      may significantly differ in their radical scavenging activities against both
      DPPH(*) and ABTS(*)(+), chelating capacities, and TPC. A significant negative
      correlation was detected between the chelating activities of the bran samples
      from the four nonirrigated locations and total solar or daily average solar
      radiation (r = -0.999 and P = 0.001). These data suggest potential influences of
      growing conditions on the antioxidant properties of hard winter wheat and the
      possibility of producing wheat that is strong in a selected antioxidant property
      by optimizing the growing conditions of a selected wheat variety. More research
      is required to further investigate the relationship among antioxidant properties
      and environmental factors using different wheat varieties and larger sample
      sizes.

PMID- 12617586
TI  - Protective effects of fermented filtrate from Antrodia camphorata in submerged
      culture against CCl4-induced hepatic toxicity in rats.
AB  - The protective effects and the possible mechanisms of dry matter of fermented
      filtrate (DMF) from Antrodia camphorata in submerged culture (ACSC) on H(2)O(2)
      induced cytotoxicity in HepG2 and carbon tetrachloride (CCl(4))-induced
      hepatotoxicity in Sprague-Dawley rats were investigated. The results showed that
      the inhibitory effect of DMF and its crude triterpenoids on lipid peroxidation
      occurred in a dose-response manner in an AAPH/linoleic acid system. When HepG2
      cells were pretreated with DMF at the concentration of 0.10 mg/mL for 4 h and
      then induced by 1 h of treatment with H(2)O(2) (100 microM), lipid peroxidation
      was significantly (p < 0.05) decreased, as measured by the formation of
      malondialdehyde. The oral pretreatment with DMF [0.25 and 0.50 mg/kg of body
      weight (bw)] for 5 consecutive days prior to the administration of a single dose
      of 40% CCl(4) (0.10 mL/100 g of bw, ip) significantly prevented the increase in
      serum levels of hepatic enzyme markers (alanine and aspartate aminotransferase)
      and liver lipid peroxidation (p < 0.05). Histopathological evaluation of the rat
      liver revealed that DMF reduced the incidence of liver lesions, including
      neutrophil infiltration, hydropic swelling, and necrosis induced by CCl(4) in
      rats. Moreover, reduced glutathione (GSH)-dependent enzymes (glutathione
      peroxidase, glutathione reductase, and glutathione S-transferase) and the
      GSH/GSSG ratio were significantly improved in the oral pretreatment DMF of rats
      (p < 0.01). The results suggest that DMF may play a role in preventing oxidative
      damage in living systems by up-regulating hepatic GSH-dependent enzymes to
      preserve the normal GSH/GSSH ratio and scavenging free radicals formed during
      CCl(4) metabolism.

PMID- 12617587
TI  - Fungicidal property of Curcuma longa L. rhizome-derived curcumin against
      phytopathogenic fungi in a greenhouse.
AB  - Fungicidal activity of Curcuma longa rhizome-derived materials against Botrytis
      cineria, Erysiphe graminis, Phytophthora infestans, Puccinia recondita,
      Pyricularia oryzae, and Rhizoctonia solani was tested using a whole plant method
      in vivo. It was compared with synthetic fungicides and four commercially
      available compounds derived from C. longa. The response varied with the tested
      plant pathogen. At 1000 mg/L, the hexane extract of C. longa showed fungicidal
      activities against E.graminis, P. infestans, and R. solani, and the ethyl acetate
      extract of C. longa showed fungicidal activities against B. cineria, P.
      infestans, Pu. recondita, and R. solani. Curcumin was isolated from the ethyl
      acetate fraction using chromatographic techniques and showed fungicidal
      activities against P. infestans, Pu. recondita, and R. solani with 100, 100, and
      63% control values at 500 mg/L and 85, 76, and 45% control values at 250 mg/L,
      respectively. In the test with components derived from C. longa, turmerone
      exhibited weak activity against E. graminis, but no activity was observed from
      treatments with borneol, 1,8-cineole, sabinene, and turmerone. In comparison,
      potent fungicidal activity with chlorothalonil against P. infestans at 50 mg/L
      and dichlofluanid against B. cinerea at 50 mg/L was exhibited. These results may
      be an indication of at least one of the fungicidal actions of curcumin derived
      from C. longa.

PMID- 12617588
TI  - Comparative characterization of peanuts grown by aquatic floating cultivation and
      field cultivation for seed and resveratrol production.
AB  - Peanut pods (Tainan 12, a Spanish cultivar, Arachis hypogaea L.) have been
      obtained from peanuts grown in a newly developed aquatic floating cultivation
      system without artificial aeration or periodic renewal of the solution. The
      system provided a convenient status for examination of root and pod development.
      Compared to field-grown peanuts of the same cultivar, the aquatic-cultivated
      peanut pods and seeds were smaller, whereas seed/pod weight ratios, crude fat and
      protein contents, and SDS-PAGE protein patterns varied within similar ranges.
      During cultivation, the highest detected temperature of the aquatic solution was
      higher than the field-soil temperature. After gas chromatographic analysis of the
      fatty acid compositions, the oleic acid/linoleic acid ratio of the aquatic
      cultivated seeds was higher than that of field-cultivated ones. When the peanut
      roots were collected, cleaned, dried, weighed, pulverized, and subjected to
      resveratrol analysis, dry root weights were 4.2 +/- 0.1 and 2.2 +/- 1.1 g/plant
      and resveratrol contents were 0.074 +/- 0.009 and 0.114 +/- 0.212 mg/g for the
      aquatic- and field-cultivated peanut roots, respectively. This indicates that the
      aquatic-cultivated peanut roots could be a potent and consistent source of
      resveratrol.

PMID- 12617589
TI  - Protein glycation inhibitory and antioxidative activities of some plant extracts
      in vitro.
AB  - The protein glycation inhibitory activity of aqueous ethanolic extracts from 25
      plant tissues was evaluated in vitro using the model system of bovine serum
      albumin and fructose. The most bioactive plant tissue was Allium cepa (skin),
      followed by Illicium religiosum (bark and wood), Fagopyrum esculentum (hull),
      Origanum officinalis (leaf), Rosmarinus officinalis (leaf), Pyrus pyrifolia
      (bark),Acanthopanax senticosus (bark), Eugenia caryophllata (leaf), and Erigeron
      annuus (whole). The extracts with glycation inhibitory activity also showed
      antioxidative activity when a micellar linoleic acid peroxidation system was
      applied followed by 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical
      cation decolorization and 1,1-diphenyl-2-picrylhydrazyl free radical scavenging
      assays. The glycation inhibitory activity was significantly correlated with the
      antioxidative potency of the extracts. The positive glycation inhibitory and
      antioxidative activities of these plants might suggest a possible role in
      targeting aging and diabetic complications.

PMID- 12617590
TI  - Purification and characterization of a peroxidase from corn steep water.
AB  - Three cationic peroxidases have been detected in early, middle, and late corn
      steep water, with pI values of approximately 8.9, approximately 9.5, and >10.0.
      The major cationic corn steep water peroxidase (CSWP), with a pI >10, was
      purified 36400-fold with a 12% recovery from late steep water by a combination of
      acetone and ammonium sulfate precipitation and sequential chromatography on CM
      cellulose, phenyl-Sepharose, and Sephadex G-75. The UV-vis spectrum of purified
      CSWP is typical of other plant class III peroxidases. The RZ (A(403)/A(280)) of
      CSWP was between 2.6 and 2.9. It is not glycosylated and exhibited an M(r) of
      30662 +/- 7 by MALDI-TOF MS. The pH optimum of CSWP depends on the substrate, and
      it is active on 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), guaiacol,
      ferulic acid, o-dianisidine, o-phenylenediamine, and pyrogallol but is not active
      on either syringaldazine or ascorbate. At 75 degrees C and pH 4.5, the enzyme has
      half-lives of 22.7 min (0 mM Ca(2+)) and 248 min (1 mM Ca(2+)). The enzyme is
      stable at room temperature (22-25 degrees C), losing <3% of the activity at pH
      4.5 and <10% at pH 6.2 over 400 h in the presence of 1 mM Ca(2+).

PMID- 12617591
TI  - Pre- and post-mortem use of grape seed extract in dark poultry meat to inhibit
      development of thiobarbituric acid reactive substances.
AB  - Diets containing grape seed extract (GSE)-control, GSE [low GSE, low GSE +
      methionine, high GSE, and high GSE + methionine], or alpha-tocopherol-were fed to
      broiler chicks to estimate the antioxidative activity of GSE in processed meat.
      GSE was detrimental to the growth of chicks, and methionine did not reverse the
      detrimental effect. GSE with 85.4 g of gallic acid equiv/100 g (GAE 85.4) was
      added to ground dark turkey meat to obtain treatments with no GSE, 1.0% GSE, and
      2.0% GSE and then processed as unsalted or salted and unheated or heated.
      Processed treatments were analyzed for thiobarbituric acid reactive substances
      (TBARS) and percent expressible moisture (%EM). GSE at 1.0 and 2.0% decreased
      TBARS values nearly 10-fold as compared to the control. GSE (1.0%) had a %EM
      value significantly greater than that of the control. GAE 85.4 decreased TBARS
      values more than GAE 88.9.

PMID- 12617592
TI  - Effect of drying temperature on alkylamide and cichoric acid concentrations of
      Echinacea purpurea.
AB  - Root and aerial sections (flower, stem, and leaf) of Echinacea purpurea were
      dried with hot air at temperatures in the range of 40-70 degrees C, and the
      concentrations of alkylamides and cichoric acid were determined after drying.
      Increasing drying temperature decreased from 48 h at 40 degrees C to 9 h at 70
      degrees C but resulted in a decreased concentration of cichoric acid in all plant
      sections with a greater loss from aerial plant parts than from the root. There
      was, however, no significant difference in the concentration of the alkylamides
      at any drying temperature. Establishment of operational parameters for the drying
      of echinacea must therefore be structured around the more labile cichoric acid.

PMID- 12617594
TI  - Seasonal variations of fatty acid compositions in various Korean shellfish.
AB  - Seasonal variations of fatty acids in various Korean shellfish were investigated
      in relation to the changes in total fatty acids contents, the ratio of
      polyunsaturated fatty acids to saturated fatty acids (P/S), and that of n-3 fatty
      acids to n-6 fatty acids (n-3/n-6). A distinct seasonal pattern was found in
      total fatty acids contents with maximal values in early summer and minimal values
      in late summer. The percentage of monounsaturated fatty acids was lowest in most
      species throughout the year. In summer months, the proportion of polyunsaturated
      fatty acids decreased while that of saturated fatty acids increased. The major
      contributing factor to the seasonal variation of polyunsaturated fatty acids was
      n-3 fatty acids. These results led to the lowest levels of P/S and n-3/n-6 in
      summer. Nevertheless, the data suggest that bivalve shellfish would be excellent
      sources of n-3 fatty acids, especially eicosapentaenoic acid and docosahexaenoic
      acid.

PMID- 12617593
TI  - Juice components of a new pigmented citrus hybrid Citrus sinensis (L.) Osbeck x
      Citrus clementina Hort. ex Tan.
AB  - Fruit juice of a new pigmented citrus hybrid named Omo-31 and those of its
      parents clementine cv. Oroval (Citrus clementina Hort. ex Tan.) and Moro orange
      [Citrus sinensis (L.) Osbeck] were analyzed during fruit maturation to determine
      juice yield, total soluble solids (TSS), total acidity (TA), TSS/TA ratio
      (classical parameters of quality), and potential health beneficial components,
      such as vitamin C, flavanones, anthocyanins, and phenolic acids. Results showed
      that juice yield, TA, TSS, and TSS/TA ratio values of Omo-31 were similar to
      those of the Moro orange. Vitamin C content of the new hybrid was slightly higher
      than that of clementine and lower than that of the Moro orange, but at maturity
      stage no differences were observed among the three genotypes. The phenolic
      compounds content of the new hybrid and those of the parents and their evolution
      during maturation were studied. At maturity stage the amount of anthocyanins,
      flavanones, and hydroxycinnamic acids in Omo-31 was found to be notably higher
      than those of the parents. The high level of antioxidant substances makes this
      new fruit important for its nutritional benefits.

PMID- 12617595
TI  - High-performance liquid chromatography determination of phenolic constituents in
      17 varieties of cowpeas.
AB  - Seventeen varieties of cowpeas grown in Arkansas were analyzed for their phenolic
      constituents using high-performance liquid chromatography (HPLC). Protocatechuic
      acid was identified as the major phenolic acid present in esterified forms. The
      amount of protocatechuic acid increased from trace-3.6 to 9.3-92.7 mg/100 g of
      flour in the 17 varieties of cowpeas after hydrolysis. Six other phenolic acids,
      including, p-hydroxybenzoic acid, caffeic acid, p-coumaric acid, ferulic acid,
      2,4-dimethoxybenzoic acid, and cinnamic acid, were also identified. These
      phenolic acids were evenly distributed mainly in free acid forms at <7 mg/100 g
      of flour. Total phenolic contents determined using Folin-Ciocalteu's reagent were
      largely different among the 17 varieties, ranging from 34.6 to 376.6 mg/100 g of
      flour. A comparison of the HPLC chromatograms of the 17 cowpea phenolics before
      and after alkali hydrolysis indicated the conversion of a pattern with evenly
      distributed peaks to one with a single major peak for protocatechuic acid,
      suggesting that the chromatograms before hydrolysis better represent the
      identities of the cowpea varieties.

PMID- 12617596
TI  - High-fat diet enhances the accumulation of hexachlorobenzene (HCB) by pregnant
      rats during continuous exposure to HCB.
AB  - To investigate the influence of a high-fat diet on HCB distribution and
      accumulation, pregnant rats in study 1 were fed a high-fat or control diet
      containing HCB, and, in study 2, pregnant rats were given a single HCB dose by
      intragastric gavage and HCB-free high-fat or control diet. In study 1, the high
      fat diet group had higher HCB concentrations in fat tissues and liver than did
      the controls. In study 2, although the total amounts of HCB in the fat tissue and
      liver were greater in the high-fat diet group than in the controls, no
      significant differences in HCB concentration were observed between the two
      groups. The high-fat diet group also showed more fecal excretion of HCB.
      Therefore, HCB accumulation in rats fed a high-fat diet was enhanced more by
      continuous exposure to HCB than by administration of a single dose.

PMID- 12617597
TI  - Effect of harvesting and drying conditions on chlorophyll levels of soybean
      (Glycine max L. Merr).
AB  - Chlorophyll in soybean represents a downgrading factor for the crops. Five
      Brazilian cultivars were harvested between R(6) and R(8) stage of development
      (Fehr & Caviness scale) and dried at 25 degrees and 40 degrees C. The effect of
      maturity stages and two drying conditions after harvest were studied to achieve
      reduction of moisture and chlorophylls to acceptable levels. When seeds were
      dried at 25 degrees C, even harvesting at early stages of development such as
      R(6), the green pigments were almost degraded, and 16 ppm of chlorophyll were
      found at maximum, accompanied by loss of moisture. Moisture and chlorophyll
      declines as seed matures, but at intermediary stages (R(6)-R(7)), chlorophyll
      degrades first, so the rate of moisture loss should not be used to predict
      chlorophyll contents. At 40 degrees C, complete degradation of chlorophyll
      pigments is only achieved when seeds are swathed from R(7) stage up, otherwise
      the seed quality could be compromised. Slow drying allows almost complete removal
      of green pigments, even when seeds are swathed a few days before the
      physiological maturity stage.

PMID- 12617598
TI  - Effect of pH on the association of denatured whey proteins with casein micelles
      in heated reconstituted skim milk.
AB  - Skim milk was adjusted to pH values between 6.5 and 6.7 and heated (80, 90, and
      100 degrees C) for up to 60 min. Changes in casein micelle size, level of whey
      protein denaturation, and level of whey protein association with the micelles
      were monitored for each milk sample. Changes in casein micelle size were markedly
      affected by the pH at heating. At low pH (6.5-6.55), the casein micelle size
      increased markedly during the early stages of heating, and the size plateaued on
      prolonged heating. The maximum increase in size was approximately 30-35 nm. In
      contrast, at high pH (6.7), much smaller changes in size were observed on heating
      and the maximum increase in size was only approximately 10 nm. An intermediate
      behavior was observed at pH values between these two extremes. The rate of
      denaturation of the major whey proteins, alpha-lactalbumin and beta
      lactoglobulin, was essentially unaffected by the pH at heating for the small pH
      changes involved in this study, and the changes in casein micelle size were
      poorly related to the level of whey protein denaturation. In contrast, the level
      of denatured whey proteins associating with the micelles was markedly dependent
      on the pH at heating, with high levels of association at pH 6.5-6.55 and low
      levels of association at pH 6.7. Changes in casein micelle size were related to
      the levels of denatured whey proteins that were associated with the casein
      micelles, although there was a small deviation from linearity at low levels of
      association (<15%). Further studies on reconstituted and fresh milk samples at
      smaller pH steps confirmed that the association of whey proteins with the casein
      micelles was markedly affected by the pH at heating. These results indicate that
      the changes in casein micelle size induced by the heat treatment of skim milk
      were a consequence of the whey proteins associating with the casein micelles and
      that the level of association was markedly influenced by small pH changes of the
      milk. It was not possible to determine whether the association itself influenced
      the casein micelle size or whether parallel reactions involving micellar
      aggregation caused the increase in micelle size as whey protein association
      progressed.

PMID- 12617600
TI  - Oxidation of resveratrol catalyzed by soybean lipoxygenase.
AB  - In this work the oxidative degradation of resveratrol catalyzed by lipoxygenase-1
      (LOX-1) has been studied. The process has been characterized by spectroscopic and
      polarographic measurements. The oxidation of resveratrol was dependent on the
      concentration of resveratrol and the enzyme. When resveratrol was incubated in
      the presence of lipoxygenase at pH 9.0, the reaction displayed a k(M) value of
      18.6 x 10(-)(6) M and a catalytic efficiency (k(cat)/k(M)) of 4.3 x 10(4) s(-)(1)
      M(-)(1). These values are close to those shown by the enzyme when linoleic acid
      is used as the substrate. The effect of lipoxygenase inhibitors on the
      lipoxygenase-catalyzed resveratrol oxidation was also evaluated. The rate of
      resveratrol oxidation was markedly decreased by the presence of NDGA in the
      incubation mixture. From HPLC measurements, it can be deduced that resveratrol is
      oxidatively decomposed to a complex mixture of products similar to those obtained
      when the molecule is oxidized by hydrogen peroxide.

PMID- 12617599
TI  - Water mobility in multicomponent model media as studied by 2H and 17O NMR.
AB  - Molecular mobility of water was studied in a microbiological media containing
      complex and heterogeneous mixtures of cellulose, l-sorbose, and orange serum
      broth (OSB) using (2)H and (17)O high-resolution NMR. All mixtures showed
      Lorentian (17)O NMR spectra but complex (2)H NMR line shapes. Sorbose, when
      solubilized, caused line-narrowing where as cellulose-OSB mixtures showed wide
      peaks with flat plateaus. Presence of liquid or solvent water had a profound
      effect on a marked increase in T(2) relaxation time observed in sorbose
      containing samples. (17)O NMR data were not composition dependent, while (2)H NMR
      data were highly sorbose dependent.

PMID- 12617601
TI  - Dynamics of competitive adsorption of alphas-casein and beta-casein at planar
      triolein-water interface: evidence for incompatibility of mixing in the
      interfacial film.
AB  - Competitive adsorption of alpha(s)-casein and beta-casein from a bulk solution
      mixture to the triolein-water interface has been studied. Although the binding
      affinity of alpha(s)-casein to the triolein-water interface was lower than that
      of beta-casein in single-component systems, in a 1:1 mixture of alpha(s)-casein
      and beta-casein in the bulk solution the ratio of interfacial concentrations of
      alpha(s)-casein to beta-casein at equilibrium was about 2:1, indicating that
      alpha(s)-casein was preferentially adsorbed to the triolein-water interface.
      Furthermore, the equilibrium composition of alpha(s)-casein and beta-casein in
      the interfacial film at various bulk concentration ratios did not follow a simple
      Langmuir adsorption model. This deviation from ideal behavior was mainly due to
      thermodynamic incompatibility of mixing of these caseins in the interfacial
      region. The value of the incompatibility parameter, X(12), for these caseins at
      the triolein-water interface was much greater than that at the air-water
      interface. Displacement experiments showed that while alpha(s)-casein could
      dynamically displace beta-casein when the latter was in an unsaturated monolayer
      state at the interface, it could not do so when beta-casein was in a saturated
      monolayer film state. It is hypothesized that, because of thermodynamic
      incompatibility of mixing, the alpha(s)-casein and beta-casein mixed film at the
      oil-water interface may undergo two-dimensional phase separation.

PMID- 12617602
TI  - Novel antioxidative metabolites in rat liver with ingested sesamin.
AB  - Sesamin, a major lignan in sesame oil, is known to have many biological
      activities, especially protective effects against oxidative damage in the liver.
      As sesamin itself has no antioxidative properties in vitro, to elucidate the
      mechanism of its antioxidative effects, the reaction products of sesamin in rat
      liver homogenate were analyzed. The methylenedioxyphenyl moiety in the structure
      of sesamin was shown to be changed into a dihydrophenyl (catechol) moiety. The
      enzymatic reaction products in vitro were identified as (1R,2S,5R,6S)-6-(3,4
      dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo[3,3,0]octane and
      (1R,2S,5R,6S)-2,6-bis(3,4-dihydroxyphenyl)-3,7-dioxabicyclo[3,3,0]octane, which
      showed strong radical scavenging activities; the latter was a novel compound. The
      same metabolites were found as glucuronic acid and/or sulfic acid conjugates in
      substantial amounts in rat bile after oral administration of sesamin. It is
      suggested that sesamin is a prodrug and the metabolites containing the catechol
      moieties in their structures are responsible for the protective effects of
      sesamin against oxidative damage in the liver.

PMID- 12617603
TI  - Microencapsulation and modification of synthetic peptides of food proteins
      reduces the blood pressure of spontaneously hypertensive rats.
AB  - Synthetic peptides were microencapsulated into liposomes, cycled with a disulfide
      bond or modified with d-phenylglycine (d-phg) at the N-terminal, and their
      antihypertensive effects as orally administered (0.18 mM/kg body weight) to
      spontaneously hypertensive rats (SHR) were measured. The microencapsulated Leu
      Lys-Pro reduced significantly the systolic blood pressures of SHR by 45 mmHg and
      showed a prolonged duration, revealing the significant protective effect of
      encapsulation. d-phg-Leu-Arg-Pro showed a duration about 2 h shorter than that of
      the peptide without modification. In addition, cyclic Leu-Arg-Pro peptide with a
      disulfide bond between the N- and C-terminal amino acids reduced the systolic
      blood pressure of SHR by 35 mmHg and displayed a lengthy duration.

PMID- 12617604
TI  - Apple peels as a value-added food ingredient.
AB  - There is some evidence that chronic diseases, such as cancer and cardiovascular
      disease, may occur as a result of oxidative stress. Apple peels have high
      concentrations of phenolic compounds and may assist in the prevention of chronic
      diseases. Millions of pounds of waste apple peels are generated in the production
      of applesauce and canned apples in New York State each year. We proposed that a
      valuable food ingredient could be made using the peels of these apples if they
      could be dried and ground to a powder without large losses of phytochemicals.
      Rome Beauty apple peels were treated with citric acid dips, ascorbic acid dips,
      and blanches before being oven-dried at 60 degrees C. Only blanching treatments
      greatly preserved the phenolic compounds, and peels blanched for 10 s had the
      highest total phenolic content. Rome Beauty apple peels were then blanched for 10
      s and dried under various conditions (oven-dried at 40, 60, or 80 degrees C, air
      dried, or freeze-dried). The air-dried and freeze-dried apple peels had the
      highest total phenolic, flavonoid, and anthocyanin contents. On a fresh weight
      basis, the total phenolic and flavonoid contents of these samples were similar to
      those of the fresh apple peels. Freeze-dried peels had a lower water activity
      than air-dried peels on a fresh weight basis. The optimal processing conditions
      for the ingredient were blanching for 10s and freeze-drying. The process was
      scaled up, and the apple peel powder ingredient was characterized. The total
      phenolic content was 3342 +/- 12 mg gallic acid equivalents/100 g dried peels,
      the flavonoid content was 2299 +/- 52 mg catechin equivalents/100 g dried peels,
      and the anthocyanin content was 169.7 +/- 1.6 mg cyanidin 3-glucoside
      equivalents/100 g dried peels. These phytochemical contents were a significantly
      higher than those of the fresh apple peels if calculated on a fresh weight basis
      (p < 0.05). The apple peel powder had a total antioxidant activity of 1251 +/- 56
      micromol vitamin C equivalents/g, similar to fresh Rome Beauty peels on a fresh
      weight basis (p > 0.05). One gram of powder had an antioxidant activity
      equivalent to 220 mg of vitamin C. The freeze-dried apple peels also had a strong
      antiproliferative effect on HepG(2) liver cancer cells with a median effective
      dose (EC(50)) of 1.88 +/- 0.01 mg/mL. This was lower than the EC(50) exhibited by
      the fresh apple peels (p < 0.05). Apple peel powder may be used in a various food
      products to add phytochemicals and promote good health.

PMID- 12617605
TI  - Kinetic and stoichiometric assessment of the antioxidant activity of flavonoids
      by electron spin resonance spectroscopy.
AB  - There is current interest in the use of naturally occurring flavonoids as
      antioxidants for the preservation of foods and the prevention of diseases such as
      atherosclerosis and cancers. To establish the molecular characteristics required
      for maximum antioxidant activity, electron spin resonance (ESR) spectroscopy has
      been used to determine the stoichiometry and kinetics of the hydrogen-donating
      ability of 15 flavonoids and d-alpha-tocopherol to galvinoxyl, a resonance
      stabilized, sterically protected aryloxyl radical. The second-order reaction
      rates, which will be governed by O-H bond dissociation energies, were myricetin >
      morin > quercetin > fisetin approximately catechin > kaempferol approximately
      luteolin > rutin > d-alpha-tocopherol > taxifolin > tamarixetin > myricetin
      3',4',5'-trimethyl ether > datiscetin > galangin > hesperitin approximately
      apigenin. Reactivity is highly dependant on the configuration of OH groups on the
      flavonoid B and C rings, there being little contribution from the A ring to
      antioxidant effectiveness. Highest reaction rates and stoichiometries were
      observed with flavonols capable of being oxidized to orthoquinones or extended
      paraquinones. However, rates and stoichiometries did not always correlate and the
      data suggest that kinetic factors may be of greater importance within a
      biological context.

PMID- 12617606
TI  - Effect of glutathione on oxymyoglobin oxidation.
AB  - The oxidation of oxymyoglobin (OxyMb) to metmyoglobin (MetMb) is responsible for
      fresh meat discoloration. Glutathione (GSH) is an important tripeptide reductant
      that can protect lipid and protein from oxidation. The objective of this research
      was to investigate the effect of GSH on MetMb formation in vitro and in bovine
      skeletal muscle cytosol. Equine MetMb formation was greater in the presence of
      GSH than controls at pH 5.6 or 7.2 and 25 or 37 degrees C (p < 0.05); GSH
      addition to purified bovine OxyMb solution also resulted in more MetMb formation
      at pH 7.2 and 25 or 37 degrees C (p < 0.05). This effect on MetMb formation was
      partly or completely inhibited by EDTA or catalase in the GSH-equine OxyMb system
      (p < 0.05). The addition of GSH to bovine muscle cytosol inhibited MetMb
      formation at pH 5.6 or 7.2 and 4 or 25 degrees C (p < 0.05); the effect was
      concentration-dependent. The inhibitory effect was observed in a high molecular
      weight (HMW) but not low molecular weight fraction of cytosol at pH 7.2 and 25
      degrees C (p < 0.05); there was no effect when HMW was heated at 90 degrees C for
      15 min. These results suggest the antioxidant effect of GSH on bovine OxyMb is
      dependent on heat-sensitive HMW cytosolic component(s).

PMID- 12617607
TI  - Lipid oxidation in corn oil-in-water emulsions stabilized by casein, whey protein
      isolate, and soy protein isolate.
AB  - Proteins can be used to produce cationic oil-in-water emulsion droplets at pH 3.0
      that have high oxidative stability. This research investigated differences in the
      physical properties and oxidative stability of corn oil-in-water emulsions
      stabilized by casein, whey protein isolate (WPI), or soy protein isolate (SPI) at
      pH 3.0. Emulsions were prepared with 5% corn oil and 0.2-1.5% protein. Physically
      stable, monomodal emulsions were prepared with 1.5% casein, 1.0 or 1.5% SPI, and
      > or =0.5% WPI. The oxidative stability of the different protein-stabilized
      emulsions was in the order of casein > WPI > SPI as determined by monitoring both
      lipid hydroperoxide and headspace hexanal formation. The degree of positive
      charge on the protein-stabilized emulsion droplets was not the only factor
      involved in the inhibition of lipid oxidation because the charge of the emulsion
      droplets (WPI > casein > or = SPI) did not parallel oxidative stability. Other
      potential reasons for differences in oxidative stability of the protein
      stabilized emulsions include differences in interfacial film thickness, protein
      chelating properties, and differences in free radical scavenging amino acids.
      This research shows that differences can be seen in the oxidative stability of
      protein-stabilized emulsions; however, further research is needed to determine
      the mechanisms for these differences.

PMID- 12617608
TI  - Synthesis of new glycosides by transglycosylation of N-acetylhexosaminidase from
      Serratia marcescens YS-1.
AB  - Serratia marcescens YS-1, a chitin-degrading microorganism, produced mainly N
      acetylhexosaminidase. The purified enzyme had an optimal pH of approximately 8-9
      and remained stable at 40 degrees C for 60 min at pH 6-8. The optimum temperature
      was around 50 degrees C, and enzyme activity was relatively stable below 50
      degrees C. YS-1 N-acetylhexosaminidase hydrolyzed p-nitrophenyl beta-N
      acetylgalactosamide by 28.1% relative to p-nitrophenyl beta-N-acetylglucosamide.
      The N-acetylchitooligosaccharides were hydrolyzed more rapidly, but the
      cellobiose and chitobiose of disaccharides that had the same beta-1,4 glycosidic
      bond as di-N-acetylchitobiose were not hydrolyzed. YS-1 N-acetylhexosaminidase
      efficiently transferred the N-acetylglucosamine residue from di-N
      acetylchitobiose (substrate) to alcohols (acceptor). The ratio of transfer to
      methanol increased to 86% in a reaction with 32% methanol. N-Acetylglucosamine
      was transferred to the hydroxyl group at C1 of monoalcohols. A dialcohol was used
      as an acceptor when the carbon number was more than 4 and a hydroxyl group
      existed on each of the two outside carbons. Sugar alcohols with hydroxyl groups
      in all carbon positions were not proper acceptors.

PMID- 12617609
TI  - Antioxidant peptides with Angiotensin converting enzyme inhibitory activities and
      applications for Angiotensin converting enzyme purification.
AB  - Five commercial peptides, namely, reduced glutathione (GSH), oxidized glutathione
      (GSSG), carnosine, homocarnosine, and anserine, were used to test angiotensin
      converting enzyme inhibitory (ACEI) activities using N-[3-(2-furyl)acryloyl]-Phe
      Gly-Gly (FAPGG) as a substrate. All of these peptides showed dose-dependent ACEI
      activities. Using 50% inhibition (IC(50)) of captopril as 0.00781 microM for the
      reference, the IC(50) values of GSH, carnosine, homocarnosine, and anserine were
      determined to be 32.4 microM, 5.216 mM, 6.147 mM, and 6.967 mM, respectively. GSH
      or carnosine showed mixed noncompetitive inhibition against ACE. When 0.0164 mM
      GSH or 0.4098 mM carnosine was added, the apparent inhibition constant (K(i)) was
      49.7 microM or 3.899 mM, respectively. Commercial glutathione-Sepharose 4 fast
      flow, GSH-coupled CNBr-activated and GSH-coupled EAH-activated Sepharose gels
      were used for ACE purification. Commercial ACE could be adsorbed only by EAH
      coupled GSH gels and eluted off the gels by increasing salt concentrations. These
      EAH-coupled GSH gels might be developed as affinity aids for ACE purification.

PMID- 12617610
TI  - Purification and identification of barley (Hordeum vulgare L.) proteins that
      inhibit the alkaline serine proteinases of Fusarium culmorum.
AB  - It has been proposed that microbial proteinase inhibitors, which are present in
      abundance in cereal grains, protect the seed against plant pathogens. So far,
      however, very little is known about the interactions of those inhibitors with the
      proteinases of phytopathogenic microbes. The increased alkaline proteinase
      activities of Fusarium head blight (FHB) diseased wheat and barley grain imply
      that the Fusarium fungi synthesize those enzymes during the colonization of the
      kernel. To study which barley proteins can inhibit Fusarium proteinases, and
      hence, possibly protect the seed from FHB, the proteins of a grain extract have
      been separated and tested for their abilities to inhibit two alkaline serine
      proteinases that we previously isolated from F. culmorum. The proteins were
      separated by size exclusion, ion exchange, and reversed-phase-HPLC
      chromatographies. The purified inhibitors were identified by their molecular
      masses and N-terminal amino acid sequences. The proteins that inhibited the
      subtilisin-like Fusarium proteinase were the chymotrypsin/subtilisin (CI)
      inhibitors 1A, 1B, and 2A and the barley alpha-amylase/subtilisin inhibitor
      (BASI). Only one of the purified proteins inhibited the trypsin-like proteinase,
      the barley Bowman-Birk inhibitor (BBBI). No novel inhibitors were detected.

PMID- 12617611
TI  - Antiproliferative activity of apples is not due to phenolic-induced hydrogen
      peroxide formation.
AB  - Anticancer compound screening of natural products using tumor cell lines has been
      commonly used to identify anticancer drugs. Two highly significant anticancer
      drugs, paclitaxel (Taxol) and camptothecin, were discovered using tumor cell
      lines by the U.S. National Cancer Institute (NCI) screening program of plants. It
      has been recently reported that the inhibition of cancer cell proliferation by
      fruit extracts was indirectly caused by phenolic-induced H(2)O(2) production in
      the cell culture media, suggesting that many previously reported effects of
      flavonoids and phenolic compounds on cultured cells might be from an artifact of
      H(2)O(2)-induced oxidative stress. The objective of the present study was to
      determine if apple extracts induced H(2)O(2) formation in common cell culture
      media and to investigate if the antiproliferative activity of apple extracts was
      due to phenolic-induced H(2)O(2) formation. It is reported here that apple
      extracts did not induce H(2)O(2) formation in WME, DMEM, or DMEM/Ham F12 media
      with the cell culture conditions tested. These same extracts inhibited
      proliferation of HepG(2) and Caco-2 cells. Therefore, antiproliferative activity
      of apple extracts was not due to the phenolic-induced H(2)O(2) production in cell
      culture media. In addition, H(2)O(2) added to the culture medium at 100 microM
      did not cause inhibition of cell proliferation in either HepG(2) liver cancer
      cells or Caco-2 colon cancer cells in vitro.

PMID- 12617612
TI  - Pigment-lipoprotein complexes in table olives (Cv. Gordal) with green staining
      alteration.
AB  - In table olives showing the green staining alteration, extracts of pigment
      lipoprotein complexes were obtained from the zone altered and the rest of the
      fruit. In the altered zone of the olive, the surrounding components of pigments
      were affected, with the degeneration of proteins and phospholipids forming the
      pigment-lipoprotein complexes. There was also less interaction between the
      pigments and the membrane lipids. These results suggested a greater loss of cell
      integrity in the green-stained zone of the fruit, allowing the migration and
      local accumulation of Cu-metallochlorophyll complexes, macroscopically visible as
      the form of green staining alteration.

PMID- 12617613
TI  - Electrochemical study of the Maillard reaction.
AB  - Electrochemical properties of beta-alanine/carbohydrate Maillard reaction
      products were measured using a combination platinum/Ag-AgCl (Cl(-)) redox
      electrode. Changes toward more negative voltages were observed, which were
      consistent with reductone formation during the course of the Maillard reaction.
      Using voltage change as a guide, the propensity for reductone formation among
      various sugars was ribose > xylose approximately arabinose > glucose
      approximately rhamnose approximately mannose approximately lactose > fructose.
      Similar electrochemical behavior indicative of reductone formation was observed
      in the decomposition products of a model Amadori compound, N-(1-deoxyfructos-1
      yl)piperidine (1).

PMID- 12617614
TI  - Honey with high levels of antioxidants can provide protection to healthy human
      subjects.
AB  - Free radicals and reactive oxygen species (ROS) have been implicated in
      contributing to the processes of aging and disease. Humans protect themselves
      from these damaging compounds, in part, by absorbing antioxidants from high
      antioxidant foods. This report describes the effects of consuming 1.5 g/kg body
      weight of corn syrup or buckwheat honey on the antioxidant and reducing
      capacities of plasma in healthy human adults. The corn syrup treatment contained
      0.21 +/- 0.06 mg of phenolic antioxidants per gram, and the two buckwheat honey
      treatments contained 0.79 +/- 0.02 and 1.71 +/- 0.21 mg of phenolic antioxidants
      per gram. Following consumption of the two honey treatments, plasma total
      phenolic content increased (P < 0.05) as did plasma antioxidant and reducing
      capacities (P < 0.05). These data support the concept that phenolic antioxidants
      from processed honey are bioavailable, and that they increase antioxidant
      activity of plasma. It can be speculated that these compounds may augment
      defenses against oxidative stress and that they might be able to protect humans
      from oxidative stress. Given that the average sweetener intake by humans is
      estimated to be in excess of 70 kg per year, the substitution of honey in some
      foods for traditional sweeteners could result in an enhanced antioxidant defense
      system in healthy adults.

PMID- 12617615
TI  - Selenium supplementation can protect cultured rat cardiomyocytes from
      hypoxia/reoxygenation damage.
AB  - The possibility of enhancing glutathione peroxidase (GPx) activity and cytosolic
      total antioxidant activity (TAA) in normoxia and hypoxia/reoxygenation (H/R) by
      the supplementation of different concentrations of sodium selenite (SS) or
      selenomethionine (SM) was investigated in cultured rat cardiomyocytes. To assess
      the entity of oxidative stress due to H/R, levels of conjugated dienes containing
      lipids were determined. In normoxia, GPx activity and TAA increased in parallel
      with the increase in SS and SM supplementation. H/R did not influence GPx
      activity but lowered TAA; both SS and SM supplementations were effective in
      increasing GPx activity, the most effective concentration being 1 microM. At this
      SS and SM concentration, TAA returned to a normoxic value. Conjugated diene
      production, increased by H/R, was reduced by SS and SM supplementation, the 1
      microM concentration appearing to be the most effective one. According to these
      data Se supplementation represents another possibility to counteract oxidative
      damage in the myocardium.

PMID- 12617616
TI  - Angiotensin I-converting enzyme inhibitory peptides in a hydrolyzed chicken
      breast muscle extract.
AB  - The blood pressure of spontaneously hypertensive rats (SHRs) decreased after oral
      administration of an extract prepared from chicken breast muscle, falling
      maximally to 50 mmHg lower than before. This effect continued for at least 4 h
      after administration. The peptides possessing hypotensive activity in the chicken
      extract were examined by measuring the inhibitory activity (IC(50)) against
      angiotensin I-converting enzyme (ACE). The inhibitory activity of the chicken
      extract was 1060 mg%, whereas the activity of the extract treated with an
      Aspergillus protease and gastric proteases (trypsin, chymotrypsin, and intestinal
      juice) became stronger, reaching 1.1 mg%. Peptides in this hydrolysate of the
      extract were isolated by HPLC on a reversed-phase column, and their N-terminal
      sequences were analyzed. Three peptides possessed a common sequence, Gly-X-X-Gly
      X-X-Gly-X-X, which was homologous with that of collagen. The peptide Gly-Phe-Hyp
      Gly-Thr-Hyp-Gly-Leu-Hyp-Gly-Phe showed the strongest inhibitory activity (IC(50)
      = 42 microM).

PMID- 12617618
TI  - Source of arsenic in licorice confectionery products.
AB  - Spanish legislation sets a maximum level for total arsenic (As) in confectionery
      products at 0.1 microg g(-)(1). The U.S. Food and Drug Administration limitations
      for glycyrrhizic acid in hard and soft candies are 160 and 31 mg g(-)(1),
      respectively. Arsenic and glycyrrhizic acid were determined in 22 different
      confectionery products: 9 throat pearls, 4 hard candies, and 9 soft candies.
      Arsenic and glycyrrhizic acid were quantified by atomic absorption spectrometry
      with hydride generation and high-performance liquid chromatography, respectively.
      Levels of glycyrrhizic acid were always below the maximum limits established by
      the U.S. FDA; however, the As concentration in seven of nine throat pearls (0.55
      +/- 0.15 microg g(-)(1)) were above the Spanish maximum limit. A clear empirical
      relationship between the arsenic and glycyrrhizic acid concentrations was
      observed (R (2) = 0.9357), implying that to avoid high levels of potentially
      toxic arsenic in licorice confections high-quality licorice extract should be
      used.

PMID- 12617617
TI  - Heat stability of zearalenone in an aqueous buffered model system.
AB  - Zearalenone is an endocrine disruptor with estrogenic activity, produced
      primarily by Fusarium graminearum, a common cause of corn ear rot and Fusarium
      head blight or scab in wheat. Zearalenone can be a contaminant of both corn and
      wheat and may survive thermal food processes. This study was done to determine
      the heat stability of zearalenone. Reduction of zearalenone was measured during
      heating at different temperatures (100, 125, 150, 175, 200, and 225 degrees C) in
      an aqueous buffer solution at different pH values. The rate and extent of
      zearalenone reduction increased with processing temperature. Less than 23% of
      zearalenone was lost when heated to </=125 degrees C whereas 34-68% was lost at
      150 degrees C after 60 min, depending on the pH of the buffer. Greater than 92%
      of zearalenone was lost after 60 min when heated to >/=175 degrees C, and
      complete reduction of zearalenone was observed in less than 30 min at 225 degrees
      C, regardless of pH. Overall, zearalenone was most stable at pH 7 followed by
      that at pH 4 and 10, and the greatest losses occurred above 175 degrees C.

PMID- 12617619
TI  - Why asparagine needs carbohydrates to generate acrylamide.
AB  - Structural considerations dictate that asparagine alone may be converted
      thermally into acrylamide through decarboxylation and deamination reactions.
      However, the main product of the thermal decomposition of asparagine was
      maleimide, mainly due to the fast intramolecular cyclization reaction that
      prevents the formation of acrylamide. On the other hand, asparagine, in the
      presence of reducing sugars, was able to generate acrylamide in addition to
      maleimide. Model reactions were performed using FTIR analysis, and labeling
      studies were carried out using pyrolysis-GC/MS as an integrated reaction,
      separation, and identification system to investigate the role of reducing sugars.
      The data have indicated that a decarboxylated Amadori product of asparagine with
      reducing sugars is the key precursor of acrylamide. Furthermore, the
      decarboxylated Amadori product can be formed under mild conditions through the
      intramolecular cyclization of the initial Schiff base and formation of oxazolidin
      5-one. The low-energy decarboxylation of this intermediate makes it possible to
      bypass the cyclization reaction, which is in competition with thermally induced
      decarboxylation, and hence promote the formation of acrylamide in
      carbohydrate/asparagine mixtures. Although the decarboxylated Amadori compound
      can be formed under mild conditions, it requires elevated temperatures to cleave
      the carbon-nitrogen covalent bond and produce acrylamide.

PMID- 12617622
TI  - Multicolor luminescence patterning by photoactivation of semiconductor
      nanoparticle films.
AB  - Indiscriminate adsorption of nanoparticles (NPs) significantly complicates the
      preparation of mesoscale NP patterns considered as enabling technology for many
      devices and processes. Instead of selected chemical functionalization of the
      substrate surface prior to the assembly of nanocolloids, the required optical
      properties - in our case, high quantum yield luminescence - are imparted to the
      layer-by-layer assembled films by spatially selected photoactivation. The films
      are made by sequential adsorption of a positively charged polyelectrolyte and a
      negatively charged CdSe/CdS aqueous dispersion with an initial quantum yield of
      0.5-2%. The photoactivation process takes place in the presence of oxygen and may
      be accompanied by photoetching. A 50-500-fold increase in the luminescence
      intensity of CdSe/CdS citrate-stabilized particles (quantum yield 25-45%) after
      visible light illumination provides excellent pattern contrast. Micron scale
      luminescence patterns were produced from NPs of various CdSe core diameters with
      red, yellow, and green emission. It was also demonstrated that different emission
      colors such as orange and green can be combined in one image by taking advantage
      of spatially selective photoetching. The presented optical patterning technique
      significantly simplifies the preparation of luminescence patterns as compared to
      conventional methods. The high signal-to-noise ratio associated with it is
      essential for optical devices, information processing, and biophotonics. The most
      immediate use of this approach is expected in cryptography and cell monitoring.

PMID- 12617621
TI  - Multiple mixed-valence behavior in trans,trans-[(tpy)(Cl)2Os(III)(mu-1,3
      N3)Os(III)(Cl)2(tpy)]+. An azido bridge from the reaction between trans
      [Os(VI)(tpy)(Cl)2(N)]+ and NH3.
AB  - Reaction between the Os(VI)-nitrido complex, trans-[OsVI(tpy)(Cl)2(N)]PF6 (tpy =
      2,2':6',2' '-terpyridine), and ammonia (NH3) under N2 in dry CH3CN gives the mu
      1,3-azido bridged [OsII-N3-OsII]- dimer, trans,trans
      NH4[(tpy)(Cl)2OsII(N3)OsII(Cl)2(tpy)]. It undergoes air oxidation to give the
      [OsIII-N3-OsIII]+ analogue, trans,trans-[(tpy)(Cl)2OsIII(N3)OsIII(Cl)2(tpy)]PF6
      ([OsIII-N3-OsIII]PF6), which has been isolated and characterized. The structural
      formulation as a mu-1,3-N3 bridged complex has been established by infrared and
      15N NMR measurements on the 15N-labeled forms, [OsIII-14N=15N=14N-OsIII]+, [OsIII
      15N=14N=15N-OsIII]+, and [OsIII-15N=15N=15N-OsIII]+. Cyclic voltammetric
      measurements in 0.2 M Bu4NPF6/CH3CN reveal the existence of five chemically
      reversible waves from 1.40 to -0.12 V for couples ranging from OsV-OsIV/OsIV-OsIV
      to OsIII-OsII/OsII-OsII. DeltaE1/2 values for couples adjacent to the three mixed
      valence forms are 0.19 V for OsIII-OsII, 0.52 V for OsIV-OsIII, and >0.71 V for
      OsV-OsIV. In CH3CN at 60 degrees C, [OsIII-N3-OsIII]+ undergoes a [2 + 3]
      cycloaddition with CH3CN at the mu-N3- bridge followed by a solvolysis to give
      trans-[OsIII(tpy)(Cl)2(5-MeCN4)] and trans-[OsIII(tpy)(Cl)2(NCCH3)]PF6.

PMID- 12617623
TI  - The cyanoimido ligand as an oxo analogue. Novel approaches to the preparations of
      cyano(imino)-aza-phosphorus(V) and N-cyanoaziridine.
AB  - The known Os(IV)-cyanoimido complexes, mer-Et4N[OsIV(bpy)(Cl)3(NalphaCNbeta)]
      (mer-[OsIV=N-CN]-) (bpy = 2,2'-bipyridine) and trans
      [OsIV(tpy)(Cl)2(NalphaCNbeta)] (trans-[OsIV=N-CN]) (2,2':6',2' '-terpyridine),
      have formal electronic relationships with high oxidation state Ru and Os-oxo and 
      dioxo complexes. These include multiple bonding to the metal, the ability to
      undergo multiple electron transfer, and the availability of nonbonding electron
      pairs for donation. Thermodynamic, oxo-like behavior is observed for mer-[OsIV=N
      CN]- in the pH-dependence of its Os(VI/V) to Os(III/II) redox couples in 1:1
      (v/v) CH3CN:H2O. Oxo-like behavior is also observed in the reaction between mer
      [OsVI(bpy)(Cl)3(NalphaCNbeta)]PF6 and benzyl alcohol to give mer
      [OsIV(bpy)(Cl)3(NalphaCNbetaH2)]PF6 and benzaldehyde. The reaction is first order
      in each reactant with kbenzyl(CH3CN, 25.0 +/- 0.1 degrees C) = (8.6 +/- 0.2) x
      102 M-1 s-1. Formal NCN degrees transfer, analogous to O-atom transfer, occurs in
      reactions with tertiary phosphine and hexenes. In CH3CN under N2, a rapid
      reaction occurs between trans-[OsIV=N-CN] and PPh3 (kPPh3(DMF, 25.0 +/- 0.1
      degrees C) = 4.06 +/- 0.02 M-1 s-1) to form the nitrilic N-bound Os(II)-(N
      cyano)iminophosphorano product, trans-[OsII(tpy)(Cl)2(NalphaCNbetaPPh3)] (trans
      [OsII-NalphaC-Nbeta=PPh3]). It undergoes solvolysis at 45 degrees C after 24 h to
      give trans-[OsII(tpy)(Cl)2(NCCH3)] and (N-cyano)iminophosphorane (NalphaC
      Nbeta=PPh3). The analogue to epoxidation, N-cyanoaziridination of cyclohexene and
      1-hexene by mer-[OsIV=N-CN]- and trans-[OsIV=N-CN], occurs at Nbeta to give the
      Os(IV)-N-cyanoaziridino complexes, mer-Et4N[OsII(bpy)(Cl)3(NalphaCNbetaC6H10)]
      and trans-[OsII(tpy)(Cl)2(NalphaCNbetaC6H11)], respectively. Oxidation to mer
      [OsV(bpy)(Cl)3(NalphaCNbeta)]- greatly accelerates N-cyanoaziridination of
      cyclohexene, which is followed by slow solvolysis to give mer
      [OsIII(bpy)(Cl)3(NCCH3)] and N-cyanoaziridine (NC-NC6H10). The Os-(N
      cyano)aziridino complexes are the first well-characterized examples of
      coordinated cyanoaziridines.

PMID- 12617624
TI  - Synthesis, structure, and aromaticity of a hoop-shaped cyclic benzenoid
      [10]cyclophenacene.
AB  - The first hoop-shaped cyclic benzenoid compounds, [10]cyclophenacene derivatives
      that contain 40 pi electrons, have been synthesized in three or four steps from
      [60]fullerene by rationally designed chemical modification. The compounds thus
      synthesized are chemically stable, yellow-colored, luminescent, and EPR-silent. X
      ray crystallographic analysis provided high precision structural data sets. On
      the basis of these results and theoretical investigations, the new cyclic
      benzenoid molecules were proven to be aromatic.

PMID- 12617625
TI  - Stepwise formation of heterobimetallic macrocycles synthesized via the weak-link
      approach.
AB  - A new dissymmetric bis-hemilabile ligand with strong binding phosphorus moieties,
      weak binding thioether moieties, and weaker binding ether moieties has been
      synthesized to construct heterobimetallic Rh(I)- and Pd(II)-containing
      macrocycles. The metals are placed in either the phosphorus/thioether or the
      phosphorus/ether coordination pocket of the dissymmetric ligand by taking
      advantage of the stepwise synthetic control offered by the weak-link approach.
      The weak bonds of these isomeric intermediates are systematically broken through
      ligand substitution reactions to cleanly and selectively generate a variety of
      open, macrocyclic architectures.

PMID- 12617626
TI  - A non-covalent strategy for the assembly of supramolecular photocurrent
      generating systems.
AB  - Three photocurrent-generating thin films were assembled on gold surfaces. SAM I
      was constructed from molecules consisting of an alkyl disulfide group linked
      covalently to a 12-residue helical peptide and terminated with an alanine residue
      containing a pyrene chromophore. SAM I served as a benchmark for multilayered
      films II and III in photocurrent generation experiments. Films II and III were
      assembled from several components that were linked noncovalently by metal-ligand
      complexation. Cyclic voltammetry and contact angle measurements suggest that the
      films consist of ordered layers with relatively few defects. Photoexcitation of
      SAM I by the output of a 350 nm lamp ( approximately 0.2 mW power incident on the
      sample) results in current generation in the range 5-10 nA/cm2. Photoexcitation
      of II and III yields higher current in the range 10-30 nA/cm2, representing a
      quantum efficiency of approximately 1%. The observation of comparable or higher
      current from noncovalently assembled multicomponent films indicates that this
      method of assembly may obviate the problems associated with the covalent assembly
      of devices from large molecules.

PMID- 12617628
TI  - Novel eta 3 -1-silaallyl tungsten complexes via Si-H bond activation of
      hydrovinylsilanes: structure and reactivity toward methanol.
AB  - Reactions of cis-Cp*(CO)2W(MeCN)Me (1) with HSiMe2(CH=CR2) (R = H, Me) afford the
      novel eta3-1-silaallyl complexes Cp*(CO)2W(eta3-Me2SiCHCR2) [R = H (2), Me (3)]
      accompanied by liberation of MeCN and CH4 via thermal Si-H bond activation. eta3
      Coordination and exo conformation of the 1-silaallyl ligand in 3 are shown by X
      ray crystal analysis, which reveals the partial double bond character of the Si-C
      bond (1.800(4) A) in the silaallyl moiety. Complexes 2 and 3 show extremely high
      reactivity toward MeOH to give the hydrido-(methoxysilyl)alkene complex trans
      Cp*(CO)2WH(eta2-MeOMe2SiCH=CH2) (4) and the four-membered metallacycle
      Cp*(CO)2WCH(CHMe2)SiMe2OMe (6), respectively.

PMID- 12617627
TI  - Chloride transport across lipid bilayers and transmembrane potential induction by
      an oligophenoxyacetamide.
AB  - This contribution describes the discovery and properties of a synthetic, low
      molecular weight compound that transports Cl- across bilayer membranes. Such
      compounds have potential as therapeutics for cystic fibrosis and cancer. The
      H+/Cl- co-transport activities of acyclic tetrabutylamides 1-6 were compared by
      using a pH-stat assay with synthetic EYPC liposomes. The ion transport activity
      of the most active compound, trimer 3, was an order of magnitude greater than
      that of calix[4]arene tetrabutylamide C1 a macrocycle known to function as a
      synthetic ion channel. Trimer 3 has an unprecedented function for a synthetic
      compound, as it induces a stable potential in liposomes experiencing a
      transmembrane Cl-/SO42- gradient. Data from both pH-stat and 35Cl NMR experiments
      indicate that 3 co-transports H+/Cl-. Although 3 transports both Cl- and H+ the
      overall process is not electrically silent. Thus, trimer 3 induces a stable
      potential in LUVs due to a transmembrane anionic gradient. The ability of trimer
      3 to transport Cl-, to maintain a transmembrane potential, along with its high
      activity at uM concentrations, its low molecular weight, and its simple
      preparation, make this compound a valuable lead in drug development for diseases
      caused by Cl- transport malfunction.

PMID- 12617629
TI  - New cyclic peptide assemblies with hydrophobic cavities: the structural and
      thermodynamic basis of a new class of peptide nanotubes.
AB  - A new class of self-assembling peptides based on cyclic peptides made of
      alternating 3-aminocyclohexanecarboxylic acid (gamma-Acc) and alpha-amino acids
      is described. The studied cylindrical assemblies are models for a new class of
      self-assembling peptide nanotubes (SPN) that present the particular property of
      having the C2 methylene group pointing toward the lumen of the cavity, modifying
      the properties of the inner surface of the assembly.

PMID- 12617630
TI  - Migration of poly-L-lysine through a lipid bilayer.
AB  - When a giant vesicle, composed of neutral and anionic lipid (90:10 mol %), comes
      into contact with various poly-l-lysines (MW 500-29 300), ropelike structures
      form within the vesicle interior. By using fluorescence lipids and epi
      fluorescence microscopy, we have shown that both neutral and anionic lipids are
      constituents of the ropes. Evidence that the ropes are also comprised of poly-l
      lysine comes from two experiments: (a) direct microinjection of poly(acrylic
      acid) into rope-containing vesicles causes the ropes to contract into small
      particles, an observation consistent with a polycation/polyanion interaction; and
      (b) direct microinjection of fluorescein isothiocyanate (a compound that
      covalently labels poly-l-lysine with a fluorescent moiety) into rope-containing
      vesicles leads to fluorescent ropes. The results may be explained by a model in
      which poly-l-lysine binds to the vesicle exterior, forms a domain, and enters the
      vesicle through defects or at the domain boundary. The model helps explain the
      ability of poly-l-lysine to mediate the permeation of a cancer drug,
      doxorubicine, into the vesicle interior.

PMID- 12617631
TI  - Direct observation of key reaction intermediates on gold clusters.
AB  - Using ultraviolet photoelectron spectroscopy, we provide direct experimental
      evidence that di-oxygen species are stable on anionic gold dimer and tetramer
      clusters at room temperature. The stabilization of molecular oxygen is crucial
      for the high activities of the low-temperature reactions on gold catalysts.

PMID- 12617632
TI  - Measuring LCSTs by novel temperature gradient methods: evidence for
      intermolecular interactions in mixed polymer solutions.
AB  - Herein we describe studies of molecular interactions in thermoresponsive polymers
      as they go through phase transitions in aqueous solutions. By using our recently
      reported linear temperature gradient setup for studying the effects of
      temperature on chemical processes, we demonstrate the ability to probe lower
      critical solution temperature (LCST) behavior with excellent precision. This
      method also provides a simple and convenient way to assay the LCST of solutions
      containing more than one polymer and follow the clouding kinetics of polymer
      mixtures in real time.

PMID- 12617634
TI  - Adhesion between molecules and calcium oxalate crystals: critical interactions in
      kidney stone formation.
AB  - Kidney stones are crystal aggregates, most commonly containing calcium oxalate
      monohydrate (COM) crystals as the primary constituent. Notably, in vitro studies
      have suggested that anionic molecules or macromolecules with substantial anionic
      functionality (e.g., carboxylate) play an important role in crystal aggregation
      and crystal attachment to renal epithelial cells. Furthermore, kidney stones
      contain measurable amounts of carboxylate-rich proteins that may serve as
      adhesives and promote aggregation of COM crystals. Atomic force microscopy (AFM)
      measurements of adhesion forces between tip-immobilized molecules and the COM
      (100) surface in aqueous media, described herein, reveal the effect of functional
      groups on adhesion and support an important role for the carboxylate group in
      processes responsible for kidney stone formation, specifically macromolecule
      mediated adhesion of COM crystals to cells and crystal aggregation. The presence
      of poly(aspartic acid) during force measurements results in a reduction in the
      adhesion force measured for carboxylate-modified tips, consistent with the
      blocking of binding sites on the COM (100) surface by the carboxylate-rich
      polymer. This competitive binding behavior mimics the known reduction in
      attachment of COM crystals to renal epithelial cells in the presence of
      carboxylate-rich urinary macromolecules. These results suggest a feasible
      methodology for identifying the most important crystal surface-macromolecule
      combinations related to stone formation.

PMID- 12617633
TI  - An exceptionally mild catalytic thioester aldol reaction inspired by polyketide
      biosynthesis.
AB  - This report details our discovery of a new catalytic ester aldol reaction using
      malonic acid half thioesters (MAHTs) that directly affords beta
      hydroxythioesters. The reaction is catalyzed by combination of a Cu(II) salt and
      an amine base, and it can be performed under exceptionally mild conditions (23
      degrees C, open to the air, wet solvent). Methyl malonic acid half thioesters
      afforded syn aldol products with distereoselectivities greater than 6:1.

PMID- 12617635
TI  - Macromolecular effect: synthesis of a ferrocenylmethylphosphine-containing
      polymer as highly efficient ligands for room-temperature palladium(0)-catalyzed
      Suzuki cross-coupling reactions of aryl chlorides.
AB  - The design and synthesis of a ferrocenylmethylphosphine-containing polymer and
      its application as efficient ligands for the room-temperature Pd(0)-catalyzed
      cross-coupling reaction of aryl chlorides with arylboronic acids, for which
      corresponding monomeric monophosphines are totally inactive, are described. Our
      work demonstrated that rather small monophosphine moieties such as RPPh2 can be
      used as highly efficient ligands when appropriately incorporated into a rigid and
      sterically regular polymer network and using monophosphine-containing polymers as
      ligands is a feasible approach to access highly active (monophosphine)
      palladium(0) complexes. The macromolecular approach described here may open a new
      avenue to other coordinatively unsaturated (monoligand)-transition metal
      complexes which are potentially useful in organic synthesis.

PMID- 12617636
TI  - Electric field-induced cubic phase in 4'-n-docosyloxy-3'-nitrobiphenyl-4
      carboxylic acid.
AB  - We examine the influence of an alternating-current electric field on the lamellar
      smectic C (SmC) phase of 4'-n-docosyloxy-3'-nitrobiphenyl-4-carboxylic acid, and
      the formation of a field-induced cubic (Cub) phase with optical isotropy was
      observed for the first time. The induction was realized down to a temperature 10
      K below the zero-field SmC to Cub phase transition temperature (TSmC-Cub). The
      formation of the induced Cub phase gave rise to a gradual increase of the shear
      storage modulus, and the modulus recovered quickly in response to the removal of
      the field, which is of interest as future applications to the stress transferring
      device.

PMID- 12617637
TI  - Asymmetric catalysis on the intramolecular cyclopropanation of alpha-diazo-beta
      keto sulfones.
AB  - This work describes the development of a highly enantioselective asymmetric
      catalysis on the intramolecular cyclopropanation of alpha-diazo-beta-keto
      sulfones. We have found that the catalytic asymmetric intramolecular reactions of
      alpha-diazo-beta-keto sulfones generally proceed with high enantioselectivity
      when the alpha-diazo-beta-keto mesityl sulfone is used with the newly prepared
      ligand 2e. The absolute configuration of products has been determined by X-ray
      crystallographic analysis, and the outcome of the enantioselectivities is
      explained well by our proposed models A and B. The products possess great
      potential for natural product synthesis because (1) many different chemistries of
      cyclopropane, ketone, and sulfone are available, and (2) the products are
      generally highly crystalline, facilitating the supplies of enantiomerically pure
      synthetic intermediates.

PMID- 12617638
TI  - Sigma aromaticity of the bimetallic Au5Zn+ cluster.
AB  - Experimental and theoretical evidence for a "sigma aromatic" bimetallic cluster
      is presented. A mass spectrometric analysis of AuNZn+ (N = 2-44) photofragments
      shows Au5Zn+ to be very abundant, proving its high stability. Calculations
      predict that Au5Zn+ has a planar geometry and six valence s electrons occupying
      delocalized sigma-bonded molecular orbitals in a manner similar to that of
      aromatic organic compounds, except for their nodal properties in the molecular
      plane. The delocalized sigma electrons provide diamagnetic ring currents,
      suggesting Au5Zn+ is aromatic.

PMID- 12617639
TI  - Polarizability effects and dispersion interactions in alkene-Br2 pi-complexes.
AB  - Weakly bound molecular complexes play an important role in chemistry, physics,
      and biodisciplines. The preequilibrium pi-complexes of various alkenes with
      bromine have been examined quantitatively, and a direct relationship between
      association constants (KF) of these pi-complexes and polarizability of the
      olefins was found. The stability of the Br2-olefin pi complexes is affected by
      both the donor ionization potential and the polarizability of the olefin, and an
      equation able to take into account both effects is proposed.

PMID- 12617640
TI  - Conformer-specific photoconversion of 25-hydroxytachysterol to 25
      hydroxyprevitamin D3: role in the production of vitamin Ds.
AB  - The photochemical goal in the production of vitamin Ds (Vit Ds) is to maximize
      the conversion of the provitamins (Pros) to the previtamins (Pres) while
      minimizing stoichiometric losses to undesirable over-irradiation products. The
      last step in the syntheses, the [1,7]-sigmatropic rearrangement of the Pres to
      the Vits, is thermally induced. The competition between cis-trans
      photoisomerization and photocyclization of the Pres is known to be highly
      excitation-wavelength specific. It inspired Havinga's nonequilibration of excited
      rotamers (NEER) principle and more recent alternative explanations. In contrast,
      the photochemistry of tachysterol has been reported to be relatively
      unexceptional with Tachy --> Pre quantum yields in the 0.10-0.13 range,
      independent of lambdaexc. Examination of the spectrum of the 25-hydroxy
      derivative of tachysterol (HOTachy) reveals vibronic structure between 295 and
      260 nm and a broad structureless shoulder between 330 and 295 nm. These features
      are consistent with absorption by at least two Tachy conformers. We show that
      these conformers differ dramatically in their trans-to-cis photoisomerization
      efficiency. The Tachy --> Pre quantum yield at 313 nm (0.42) in degassed methanol
      solution is substantially higher than at 254 nm (0.12). On the basis of recent
      theoretical predictions, it is likely that 313 nm selectively excites the cEc
      HOTachy conformer which gives photoisomerization much more efficiently than do
      the other expected conformers (cEt, most abundant, and tEt). Efficient conversion
      of HOPro D3 to HOPre D3 is accomplished by a two-stage 254/313-nm irradiation
      sequence. Use of 313 nm in the second step is preferable to previously proposed
      much longer wavelengths that were hardly absorbed by HOTachy.

PMID- 12617641
TI  - Flavin catalyzed oxidations of sulfides and amines with molecular oxygen.
AB  - Novel biomimetic, aerobic oxidation with an organocatalyst was performed. The
      oxidations of organic substrates such as sulfides, secondary amines, N
      hydroxylamines, and tertiary amines with molecular oxygen (1 atm) or even in air
      in the presence of 5-ethyl-3-methyllumiflavinium perchlorate catalyst and
      hydrazine monohydrate in 2,2,2-trifluoroethanol occur highly efficiently to give
      the corresponding oxidized compounds in excellent yields along with water and
      molecular nitrogen, which are environmentally benign. The TON of the oxidation of
      sulfides amounts to 19 000.

PMID- 12617643
TI  - A new cine-substitution of alkenyl sulfones with aryltitanium reagents catalyzed
      by rhodium: mechanistic studies and catalytic asymmetric synthesis of
      allylarenes.
AB  - The reaction of alkenyl sulfones with aryltitanium triisopropoxide (ArTi(OPr-i
      )3) in the presence of 3 mol % of [Rh(OH)((S)-binap)]2 in THF at 40 degrees C
      gave high yield of cine-substitution products. The catalytic cycle was
      established by deuterium-labeling studies, and it was applied to catalytic
      asymmetric synthesis of allylarenes which proceeds with over 99%
      enantioselectivity.

PMID- 12617642
TI  - Multishell microspheres with integrated chromatographic and detection layers for
      use in array sensors.
AB  - The development of miniaturized chromatographic systems localized within
      individual polymer microspheres and their incorporation into a bead-based cross
      reactive sensor array platform is reported. The integrated chromatographic and
      detection concept is based on the creation of distinct functional layers within
      the microspheres. In this first example of the new methodology, complexing
      ligands have been selectively immobilized to create "separation" layers harboring
      an affinity for various metal cations. Additionally, a broadly responsive
      compleximetric dye is used to yield the "detection" layers that exhibit optical
      responses in the presence of a wide range of metal cations. Information
      concerning the identities and concentrations of solution-dissolved metal cations
      can be drawn from the temporal properties of the beads' optical responses.
      Varying the nature of the ligand in the separation shell yields a collection of
      cross-reactive sensing elements well-suited for use in array-based micrototal
      analysis systems. Accordingly, such beads have been incorporated into the
      "Electronic Taste Chip" platform and used for discriminating among aqueous metal
      cation solutions.

PMID- 12617644
TI  - Anomalous distance dependence of electron transfer across peptide bridges.
AB  - The first investigation on the distance dependence of a dissociative electron
      transfer process across peptide bridges is reported. This study was carried out
      by using a series of donor-peptide-acceptor systems in which the donor is a
      phthalimido moiety, the peptide bridges are provided by alpha-aminoisobutyric
      acid (Aib) homooligomers, and the acceptor is a peroxide functional group. The
      intramolecular electron transfer from the electrogenerated phthalimido radical
      anion to the peroxide was studied in comparison with the thermodynamic and
      kinetic information obtained with models of the acceptor and the donor. The
      intramolecular rate constants were determined in N,N-dimethylformamide by taking
      into account the corresponding intermolecular values. The experimental results
      point to an unusual non-exponential dependence of the intramolecular electron
      transfer rate on the number of bridge units. The same trend could be verified
      also by taking into account the actual donor-acceptor edge-to-edge distance. The
      peculiar distance dependence that was observed for the intramolecular electron
      transfer rate is attributed to the mediating effect of the intramolecular C=O...H
      N hydrogen bonds.

PMID- 12617645
TI  - Synthesis of polysiloxane stabilized palladium colloids and evidence of their
      participation in silaesterification reactions.
AB  - The role of "Pd" colloids in Pd(OAc)2 -catalyzed silaesterification reactions was
      investigated. The first example of the generation and utilizations of recyclable
      polysiloxane network stabilized palladium nanoparticles is described. We also
      provide the evidence that the silicon polymers play the role of stabilizing
      agents, preventing the generation of bulk palladium without compromising the
      activity of the catalyst.

PMID- 12617646
TI  - Enantiocontrolled synthesis of 2,6-disubstituted piperidines by desymmetrization
      of meso-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. application to the
      total synthesis of (-)-dihydropinidine and (-)-andrachcinidine.
AB  - A conceptually new approach to the enantiocontrolled synthesis of 2,6
      disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy
      eta-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the
      piperidine nitrogen as a urethane derived from (+)- or (-)-trans-2-(alpha
      cumyl)cyclohexyl (TCC), a sequential, one-pot methoxide abstraction/nucleophilic
      addition/methoxide abstraction/nucleophilic addition generated good yields of 2,6
      disubstituted-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. This sequence
      proceeds by way of a highly diastereoselective methoxide abstraction (>40:1).
      High yielding protodemetalation and N-deprotection provided a simple and
      enantiocontrolled synthetic entry to a variety of 2,6-disubstituted piperidines.
      This new method was used for the total synthesis of (-)-dihydropinidine and (-)
      andrachcinidine.

PMID- 12617647
TI  - A titanium-catalyzed three-component coupling to generate alpha,beta-unsaturated
      beta-iminoamines.
AB  - The three-component coupling of an amine, alkyne, and isonitrile is facilitated
      by a titanium complex bearing the N,N-di(pyrrolyl-alpha-methyl)-N-methylamine
      (dpma) ligand. From this methodology, alpha,beta-unsaturated beta-iminoamines are
      generated regioselectively with many substrates and are available on multigram
      scales.

PMID- 12617648
TI  - Synthesis of Unidirectional Alumina Nanostructures without Added Organic
      Solvents.
AB  - Alumina nanotubes, nanofibers, and nanorods were synthesized through a new method
      based on a surfactant-driven hydrothermal process, but without adding any organic
      solvent. Our procedure provides a single-step, low-temperature route to different
      alumina nanostructures with thermal stability by varying the nature of
      surfactants.

PMID- 12617649
TI  - A ratiometric fluorescent sensor for Ag(I) with high selectivity and sensitivity.
AB  - A bicyclic cycloadduct 1 bearing a pyrenyl moiety has been synthesized and
      investigated as a ratiometric fluorescent sensor for AgI. In an aqueous ethanol
      solution of 1, the presence of silver ion induces the formation of a 1:2 metal
      ligand complex, which exhibits a strong intensity enhancement of the pyrene
      excimer emission at the expense of the emission of monomeric pyrene.

PMID- 12617650
TI  - Chiral ligand-controlled asymmetric conjugate addition of lithium amides to
      enoates.
AB  - The external chiral ligand-controlled asymmetric conjugate addition reaction of
      lithium amides with alpha,beta-unsaturated esters provided beta-amino esters in
      high yields and high enantioselectivities.

PMID- 12617651
TI  - Photomechanical actuation and manipulation of the electronic properties of linear
      pi-conjugated systems.
AB  - A photodynamic molecular architecture has been synthesized by covalent fixation
      of a photoisomerizable azobenzene group at two fixed points of a conformationally
      flexible pi-conjugated quaterthiophene chain. The crystallographic structure
      shows that the two systems lie in parallel planes with a short interplane
      distance. Theoretical modelization and experimental analysis by 1H NMR and cyclic
      voltammetry unequivocally show that trans to cis photoisomerization of the
      azobenzene group induces dimensional and conformational changes in the underlying
      pi-conjugated system. These geometrical changes produce, in turn, an increase of
      the HOMO level and a narrowing of the HOMO-LUMO gap, thus providing a first
      example of photomechanical control of the electronic properties of the pi
      conjugated system.

PMID- 12617653
TI  - Use of selective Trp side chain labeling to characterize protein-protein and
      protein-ligand interactions by NMR spectroscopy.
AB  - Recent studies on amino acid occurrence in protein binding sites suggest that
      only a reduced number of residues are responsible for most interaction energy in
      protein-protein and protein-ligand interactions. Above all, tryptophan (Trp)
      seems to be the most frequent residue in protein's hot spots. Here we report a
      novel, efficient, and cost-effective method to selectively incorporate specific
      isotope labels into the side chains of Trp residues in recombinant proteins. We
      show that the method proposed allows selective NMR observation of Trp side chains
      that enables studies of ligand binding, protein-protein interactions, hydrogen
      binding, protein folding, and side chain dynamics. Examples with the protein BIR3
      will be given.

PMID- 12617652
TI  - Copper-catalyzed domino halide exchange-cyanation of aryl bromides.
AB  - An efficient copper-catalyzed domino halogen exchange-cyanation procedure for
      aryl bromides was developed utilizing 10 mol % CuI, 20 mol % KI, 1.0 equiv of the
      inexpensive N,N'-dimethylethylenediamine as ligand, and 1.2 equiv of NaCN in
      toluene at 110 degrees C. The new method represents a significant improvement
      over the traditional Rosenmund-von Braun reaction: the reaction conditions are
      much milder, and the use of stoichiometric amounts of copper(I) cyanide and polar
      solvents is avoided; therefore the isolation and purification of the aromatic
      nitrile products is greatly simplified. In addition, the new method exhibits
      excellent functional group compatibility comparable to that of the analogous Pd
      catalyzed cyanation methodology.

PMID- 12617654
TI  - A novel bis(imino)amine ligand as a result of acetonitrile coupling with the
      diiodides of Dy(II) and Tm(II).
AB  - Complexes of Dy(III) and Tm(III) with novel 1,1'-bis(iminoethyl)ethylamine
      ligands, [{(HN=CMe)2MeCNH2}Ln(MeCN)6]I3, were obtained by the reactions of LnI2
      (Ln = Dy(II), Tm(II)) with acetonitrile.

PMID- 12617655
TI  - Light-induced coherent interactions between silver nanoparticles in two
      dimensional arrays.
AB  - Silver nanoparticles arranged in two-dimensional arrays experience quadrupolar
      coupling of plasmon resonances when irradiated with visible light. This coupling
      leads to the formation of the coherent plasmon mode characterized by an intense
      narrow resonance in the blue spectral range in the extinction spectrum. The
      coupling and the intensity of this mode can be effectively controlled by varying
      the distance between particles. The interparticle distance was varied by biaxial
      stretching of the arrays prepared in transparent elastomeric film of
      poly(dimethylsiloxane). The observed phenomenon exemplifies a generic approach in
      which new optical properties of materials can be engineered by organizing metal
      nanoparticles in various one-, two-, and three-dimensional structures. Further
      development of this approach will result in the discovery of novel principles of
      both fundamental and practical importance.

PMID- 12617656
TI  - Complex target-oriented total synthesis in the drug discovery process: the
      discovery of a highly promising family of second generation epothilones.
AB  - The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D
      (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise
      and amenable to production of new congeners. Furthermore, the chemistry described
      herein constitutes a major simplification in the total synthesis of EpoD, which
      is in human clinical trials. This new family of epothilones shows major
      advantages in terms of their potency and pharmacostability relative to the wild
      type saturated analogues in the D series. From the perspective of compound
      availability through synthesis, potency, and pharmacokinetic properties, these
      compounds could well warrant advancement to clinical evaluation in humans.

PMID- 12617657
TI  - Docking of protein-protein complexes on the basis of highly ambiguous
      intermolecular distance restraints derived from 1H/15N chemical shift mapping and
      backbone 15N-1H residual dipolar couplings using conjoined rigid body/torsion
      angle dynamics.
AB  - A simple and reliable method for docking protein-protein complexes using
      (1)H(N)/(15)N chemical shift mapping and backbone (15)N-(1)H residual dipolar
      couplings is presented and illustrated with three complexes (EIN-HPr, IIA(Glc)
      HPr, and IIA(Mtl)-HPr) of known structure. The (1)H(N)/(15)N chemical shift
      mapping data are transformed into a set of highly ambiguous, intermolecular
      distance restraints (comprising between 400 and 3000 individual distances) with
      translational and some degree of orientational information content, while the
      dipolar couplings provide information on relative protein-protein orientation.
      The optimization protocol employs conjoined rigid body/torsion angle dynamics in
      simulated annealing calculations. The target function also comprises three
      nonbonded interactions terms: a van der Waals repulsion term to prevent atomic
      overlap, a radius of gyration term (E(rgyr)) to avoid expansion at the protein
      protein interface, and a torsion angle database potential of mean force to bias
      interfacial side chain conformations toward physically allowed rotamers. For the
      EIN-HPr and IIA(Glc)-HPr complexes, all structures satisfying the experimental
      restraints (i.e., both the ambiguous intermolecular distance restraints and the
      dipolar couplings) converge to a single cluster with mean backbone coordinate
      accuracies of 0.7-1.5 A. For the IIA(Mtl)-HPr complex, twofold degeneracy
      remains, and the structures cluster into two distinct solutions differing by a
      180 degrees rotation about the z axis of the alignment tensor. The correct and
      incorrect solutions which have mean backbone coordinate accuracies of
      approximately 0.5 and approximately 10.5 A, respectively, can readily be
      distinguished using a variety of criteria: (a) examination of the overall
      (1)H(N)/(15)N chemical shift perturbation map (because the incorrect cluster
      predicts the presence of residues at the interface that experience only minimal
      chemical shift perturbations; this information is readily incorporated into the
      calculations in the form of ambiguous intermolecular repulsion restraints); (b)
      back-calculation of dipolar couplings on the basis of molecular shape; or (c) the
      E(rgyr) distribution which, because of its global nature, directly reflects the
      interfacial packing quality. This methodology should be particularly useful for
      high throughput, NMR-based, structural proteomics.

PMID- 12617658
TI  - Structural model for an alkaline form of ferricytochrome C.
AB  - An (15)N-enriched sample of the yeast iso-1-ferricytochrome c triple variant
      (Lys72Ala/Lys79Ala/Cys102Thr) in an alkaline conformation was examined by NMR
      spectroscopy. The mutations were planned to produce a cytochrome c with a single
      conformer. Despite suboptimal conditions for the collection of spectra (i.e., pH
      approximately equal to 11), NMR remains a suitable investigation technique
      capable of taking advantage of paramagnetism. 76% of amino acids and 49% of
      protons were assigned successfully. The assignment was in part achieved through
      standard methods, in part through the identification of groups maintaining the
      same conformation as in the native protein at pH 7 and, for a few other residues,
      through a tentative analysis of internuclear distance predictions. Lys73 was
      assigned as the axial ligand together with His18. In this manner, 838 meaningful
      NOEs for 108 amino acids, 50 backbone angle constraints, and 203 pseudocontact
      shifts permitted the convergence of randomly generated structures to a family of
      conformers with a backbone RMSD of 1.5 +/- 0.2 A. Most of the native cytochrome c
      conformation is maintained at high pH. The NOE pattern that involves His18
      clearly indicates that the proximal side of the protein, including the 20s and
      40s loops, remains essentially intact. Structural differences are concentrated in
      the 70-80 loop, because of the replacement of Met80 by Lys73 as an axial ligand,
      and in the 50s helix facing that loop; as a consequence, there is increased
      exposure of the heme group to solvent. Based on several spectral features, we
      conclude that the folded polypeptide is highly fluxional.

PMID- 12617660
TI  - Conformational flexibility of the group B meningococcal polysaccharide in
      solution.
AB  - To elucidate the role of secondary structure in the immune response against
      alpha(2-->8)-linked polysialic acid, the capsular polysaccharide of Group B
      meningococci, we have investigated its solution dynamics by using specific models
      of molecular motion and hydrodynamic modeling to interpret experimental NMR data.
      (13)C-[(1)H] NMR relaxation times and steady-state NOE enhancements were measured
      for two aqueous solutions of alpha(2-->8)-linked sialic acid polysaccharides.
      Each contained a unique distribution of polysaccharide chain lengths, with
      average lengths estimated at 40 or 400 residues. Models for rigid molecule
      tumbling, including two based on helical conformations proposed for the
      polysaccharide,(31) could not explain the NMR measurements. In general for these
      helices, the correlation times for their overall tumbling that best account for
      the NMR data correspond to polysaccharide chains between 9 and 18 residues in
      length, far short of the average lengths estimated for either solution. The
      effects of internal motions incorporated into these helices was modeled with an
      effective correlation time representing helix tumbling as well as internal
      motion. This modeling demonstrated that even with extreme amounts of internal
      motion, "flexible helices" of 25 residues or more still could not produce the NMR
      measurements. All data are consistent with internal and segmental motions
      dominating the nuclear magnetic relaxation of the polysaccharide and not
      molecular tumbling. Statistical distributions of correlation times have been
      found specifically for the pyranose rings, linkage groups, and methoxy groups
      that can account for the measured relaxation times and NOE enhancements. The
      distributions suggest that considerable flexibility attends the polysaccharide in
      solution, and the ranges of motional frequencies for the linkage groups and
      pyranose rings are comparable. We conclude that the Group B meningococcal
      polysaccharide is a random coil chain in solution, and therefore, does not have
      antigenic epitopes dependent upon a rigid, ordered conformation.

PMID- 12617659
TI  - Effects of As(III) binding on alpha-helical structure.
AB  - As(III) displays a wide range of effects in cellular chemistry. Surprisingly, the
      structural consequences of arsenic binding to peptides and proteins are poorly
      understood. This study utilizes model alpha-helical peptides containing two
      cysteine (Cys) residues in various sequential arrangements and spatial locations
      to study the structural effects of arsenic binding. With i, and i + 1, i + 2, or
      i + 3 arrangements, CD spectroscopy shows that As(III) coordination causes
      helical destabilization when Cys residues are located at central or C-terminal
      regions of the helix. Interestingly, arsenic binding to i, i + 3 positions
      results in the elimination of helical structure and the formation of a relatively
      stable alternate fold. In contrast, helical stabilization is observed for
      peptides containing i, i + 4 Cys residues, with corresponding pseudo pairwise
      interaction energies (Delta G(pw) degrees) of -1.0 and -0.7 kcal/mol for C
      terminal and central placements, respectively. Binding affinities and association
      rate constants show that As(III) binding is comparatively insensitive to the
      location of the Cys residues within these moderately stable helices. These data
      demonstrate that As(III) binding can be a significant modulator of helical
      secondary structure.

PMID- 12617661
TI  - Cross-linked normal hexagonal and bicontinuous cubic assemblies via polymerizable
      gemini amphiphiles.
AB  - The synthesis and lyotropic liquid-crystalline (LLC) phase behavior of a
      homologous series of intrinsically cross-linkable gemini surfactants are
      described. These novel bis(alkyl-1,3-diene)-based phosphonium gemini amphiphiles
      exhibit "normal" hexagonal (H(I)), Type I bicontinuous cubic (Q(I)), and lamellar
      (L(alpha)) phases in water, and can be photocross-linked with retention of phase
      architecture in each case. On the basis of their locations on the phase diagram,
      their powder X-ray diffraction profiles, and the physical properties of the cross
      linked materials, the Q(I) phases formed by these gemini monomers are consistent
      with four possible bicontinuous cubic architectures with P or I space group
      symmetry that have been identified previously for small molecule amphiphiles. The
      extent of polymerization (i.e., the degree of diene conversion) achieved in the
      LLC phases was determined to be in the 23% to 71% range using UV-vis
      spectrometry, which is more than sufficient to extensively stabilize the systems.
      The resulting cross-linked H(I), L(alpha), and Q(I) phases are stable up to 300
      degrees C in air. To our knowledge, these reactive amphiphiles constitute the
      first example of a polymerizable gemini surfactant, and the first example of a
      cross-linkable amphiphile system that can be polymerized in both the H(I) and a
      Q(I) mesophase with retention of phase microstructure.

PMID- 12617662
TI  - Structural effects on the barrier properties of self-assembled monolayers formed
      from long-chain omega-alkoxy-n-alkanethiols on copper.
AB  - The adsorption of long-chain omega-alkoxy-n-alkanethiols [CH(3)(CH(2))(p
      1)O(CH(2))(m)SH; m = 11, 19, 22; p = 18, 22] onto copper produces self-assembled
      monolayers (SAMs) that can provide protection against corrosion of the underlying
      metal substrate. The resulting films are 40-60 A in thickness and are
      isostructural with SAMs formed on copper from unsubstituted n-alkanethiols. As
      evidenced by electrochemical impedance spectroscopy (EIS), the barrier properties
      of these ether-containing SAMs depend on the chain length of the adsorbate and
      the position of the ethereal unit along the hydrocarbon chain. For SAMs where the
      ether substitution is farther from the copper surface, the initial coating
      resistances are similar to those projected for unsubstituted n-alkanethiolate
      SAMs of similar thickness. For SAMs where the ether substitution is nearer to the
      copper surface (m = 11), the resistances are significantly less than those for
      unsubstituted n-alkanethiolate SAMs of similar thickness, reflecting the effect
      of the molecular structure on the barrier properties of the film. Upon exposure
      to 1 atm of O(2) at 100% RH, the SAMs become less densely packed as observed by
      infrared (IR) spectroscopy, and their barrier properties deteriorate as observed
      by EIS. The rate that the SAMs lose their barrier properties upon exposure to
      oxidizing conditions is correlated to the strength of intermolecular interactions
      within the bulk state of the adsorbate.

PMID- 12617663
TI  - Development of a highly alpha-regioselective metal-mediated allylation reaction
      in aqueous media: new mechanistic proposal for the origin of alpha-homoallylic
      alcohols.
AB  - This paper described a general method to obtain alpha-adduct homoallylic alcohols
      using indium, zinc, and tin in water. A new mechanism was proposed to account for
      the formation of these synthetically difficult-to-obtain molecules. Generally,
      this method can be performed with a wide range of aldehydes and allylic halides
      with just 6 equiv of water added, giving the alpha-adduct in high selectivities.
      To account for the origin of the alpha-homoallylic alcohol, the reaction
      mechanism was carefully studied using (1)H NMR, a crossover experiment, and the
      inversion stereochemical studies of 22 beta gamma-adduct homoallylic sterol to
      the 22 alpha alpha-adduct homoallylic sterol. From the results of mechanism
      studies, it is possible that two mechanism pathways coexisted in the metal
      mediated alpha-regioselective allylation. The metal salts formed from the metal
      mediated allylation can catalyze the gamma-adduct to undergo a bond cleavage to
      generate the parent aldehyde in situ followed by a concerted rearrangement,
      perhaps a retroene reaction followed by a 2-oxonia[3,3]-sigmatropic rearrangement
      to furnish the alpha-adduct. The alpha-adduct can also be synthesized via the
      formation of an oxonium ion intermediate between the gamma-adduct and the
      unreacted aldehyde. The proposed mechanisms were further supported by
      experimental findings from the addition of InBr(3) to gamma-adduct under similar
      conditions.

PMID- 12617664
TI  - Synthesis of azo-conjugated metalladithiolenes and their photo- and proton
      responsive isomerization reactions.
AB  - A versatile synthetic method of azo-conjugated metalladithiolenes was developed,
      and new complexes with various central metals and substituent groups were
      synthesized. Molecular structures of the azo-conjugated metalladithiolenes of
      Ni(II), Pd(II), and Pt(II) with diphenylphosphinoethane as a co-ligand were
      determined by X-ray crystallography. While the energy of the reversible trans-to
      cis photoisomerization is considerably lower than that of azobenzene, the thermal
      stability of the cis form is much higher than that of the organic azobenzene
      derivatives showing similar low-energy trans-to-cis photoisomerization. A novel
      proton response of the azo group occurs, and the combination of
      photoisomerization and protonation leads to a novel proton-catalyzed cis-to-trans
      isomerization, the rate of which correlates with the redox potential of the
      metalladithiolene moiety. The study including other azo-conjugated
      metalladithiolenes has indicated that the protonation is a common feature for the
      azo-conjugated metalladithiolenes, but trans-to-cis photoisomerization is
      strongly dependent on the electronic structure of the trans form or a steric
      effect in the cis form.

PMID- 12617665
TI  - Synthesis and photochromic properties of molecules containing [e]-annelated
      dihydropyrenes. Two and three way pi-switches based on the dimethyldihydropyrene
      metacyclophanediene valence isomerization.
AB  - The syntheses of several new simple negative, a simple positive, and multiple
      negative photochromes containing the dihydropyrene-cyclophanediene photochromic
      system are described. The photo-openings of the negative photochromes, the [e]
      annelated benzo (7), naphtho (9), anthro (11), furano (19), and triphenyleno (15)
      derivatives of the parent 2,7-di-tert-butyl-trans-10b,10c-dimethyl-dihydropyrene
      (5), as well as its 4,5-dibromo derivative (13), are described to give the
      corresponding cyclophanedienes, as well as their photoclosures and thermal
      closures back to the dihydropyrenes. These are compared to the results obtained
      for the positive photochrome dibenzo[e,l]dihydropyrene (21) and to the
      bis(dihydropyreno)chrysene (44) and the
      (dihydropyrenobenzo)(benzo)metacyclophanediene (47) photochromes, which have more
      than one photochromic switch present and thus have more than a simple "on-off"
      state. Thermodynamic data are obtained for the thermal closing reactions. The
      anthrodihydropyrene (12) has the fastest thermal closing (tau(1/2) = 20 min),
      while the furanodihydropyrene (19') has the slowest (tau(1/2) = 63 h) at 46
      degrees C. An electrochemical readout of the state of the switch is demonstrated
      for the benzodihydropyrene (7).

PMID- 12617666
TI  - Catalytic asymmetric aldol reactions in aqueous media using chiral bis-pyridino
      18-crown-6-rare earth metal triflate complexes.
AB  - Catalytic asymmetric aldol reactions in aqueous media have been developed using
      Pr(OTf)(3) and chiral bis-pyridino-18-crown-6 1. In the asymmetric aldol reaction
      using rare earth metal triflates (RE(OTf)(3)) and 1, slight changes in the ionic
      diameters of the metal cations greatly affected the diastereo- and
      enantioselectivities of the products. The substituents (MeO, Br) at the 4
      position of the pyridine rings of the crown ether did not significantly affect
      the selectivities in the asymmetric aldol reaction, although they affected the
      binding ability of the crown ether with RE cations and the catalytic activity of
      Pr(OTf)(3)-crown ether complexes. From X-ray structures of RE(NO(3))(3)-crown
      ether complexes, it was found that they had similar structures regardless of the
      RE cations and the crown ethers used. Accordingly, the binding ability of the
      crown ether with the RE cation and the catalytic activity of the complex are
      important for attaining high selectivity in the asymmetric aldol reaction.
      Various aromatic and alpha,beta-unsaturated aldehydes and silyl enol ethers
      derived from ketones and a thioester can be employed in the catalytic asymmetric
      aldol reactions using Pr(OTf)(3) and 1, to provide the aldol adducts in good to
      high yields and stereoselectivities. In the case using the silyl enol ether
      derived from the thioester, 2,6-di-tert-butylpyridine significantly improved the
      yields of the aldol adducts.

PMID- 12617667
TI  - Sensing and fixation of NO2/N2O4 by calix[4]arenes.
AB  - An approach toward visual detection and chemical utilization of NO(2)/N(2)O(4) is
      proposed, which employs simple calix[4]arenes. Exposure of tetra-O-alkylated
      calix[4]arenes 1 and 2, possessing either a cone or a 1,3-alternate conformation,
      to NO(2)/N(2)O(4), both in chloroform solution and in the solid state, results in
      deeply colored calixarene-nitrosonium (NO(+)) complexes. In the presence of a
      Lewis acid, such as SnCl(4), stable calixarene-NO(+) complexes 7 and 8 were
      isolated in a quantitative yield and characterized by UV-vis, FTIR, high
      resolution (1)H NMR spectroscopy and elemental analysis. NO(+) is found
      encapsulated within the calixarene cavity, and stable charge-transfer complexes
      result with K(ass) > 10(6) M(-1) (CDCl(3)). The NO(+) encapsulation was also
      demonstrated in titration experiments with calixarenes 1, 2, and 5 and
      commercially available NO(+)SbF(6)(-) salt in chloroform. The complexation
      process is reversible, and the complexes dissociate upon addition of water and
      alcohol, recovering the parent calixarenes. Attachment of functionalized
      calix[4]arenes to silica gel was demonstrated, which afforded a solid material 15
      capable of visual detection and entrapment of NO(2)/N(2)O(4). Calixarene-NO(+)
      complexes can be utilized for the NO(+) transfer processes and nitrosation
      reactions. The NO(+) guest transfer between two calixarene containers 2 and 5 was
      achieved and studied by UV-vis and (1)H NMR spectroscopy. Chemical fixation of
      NO(2)/N(2)O(4) was demonstrated through their quantitative transformation into
      the calixarene-NO(+) complex and its use as a nitrosonium transfer agent in the
      synthesis of N-nitrosoamides. These results may lead toward novel nitrogen oxides
      storing materials.

PMID- 12617668
TI  - Microenvironmental polarity control of electron-transfer photochirogenesis.
      Enantiodifferentiating polar addition of 1,1-diphenyl-1-alkenes photosensitized
      by saccharide naphthalenecarboxylates.
AB  - Enantiodifferentiating polar photoaddition of alcohol to 1,1-diphenylpropene and
      1,1-diphenyl-1-butene sensitized by saccharide naphthalene(di)carboxylates was
      performed in nonpolar to polar solvents containing methanol, ethanol, or 2
      propanol as the nucleophile to give the corresponding anti-Markovnikov alcohol
      adduct, that is, 1,1-diphenyl-2-alkoxy-propane and -butane in low-to-good
      chemical yields, depending on the sensitizer, chiral auxiliary, alcohol, solvent,
      and temperature employed. The excited state and intermediate involved, the
      reaction and enantiodifferentiation mechanism operating, and the factors
      controlling chemical and optical yields were elucidated from the photochemical
      and stereochemical outcomes under various conditions and also from the sensitizer
      and exciplex fluorescence quenching experiments and the molecular orbital
      calculations. A new strategy was developed to overcome the normally accepted
      tradeoff between the chemical and optical yields. This is made possible by
      employing protected saccharides as chiral auxiliaries and running the
      photoreactions not in a nonpolar but in a low-polarity solvent such as diethyl
      ether, which jointly enhance the "microenvironmental" polarity around the
      sensitizer to facilitate electron transfer, keeping the intimate interactions
      between the chiral sensitizer and substrate within the exciplex intermediate. By
      optimizing these factors, we obtained the photoadduct in enantiomeric excesses of
      up to 58%, which is the highest ever reported for a photosensitized bimolecular
      enantiodifferentiating reaction.

PMID- 12617669
TI  - Ultrafast UV-mid-IR investigation of the ring opening reaction of a photochromic
      spiropyran.
AB  - We present a femtosecond UV-mid-IR pump-probe study of the photochemical ring
      opening reaction of the spiropyran 1',3',3',-trimethylspiro-[-2H-1-benzopyran
      2,2'-indoline] (also known as BIPS) in tetrachloroethene, using 70 fs UV
      excitation pulses and probing with 100 fs mid-IR pulses. The time evolution of
      the transient IR absorption spectrum was monitored over the first 100 ps after UV
      excitation. We conclude that the merocyanine product is formed with a 28 ps time
      constant, contrasting with a 0.9 ps time constant obtained in previous
      investigations where the rise of absorption bands at visible wavelengths were
      associated with product formation. We deduce from the observed strong recovery of
      the spiropyran IR absorption bleaches that, in tetrachloroethene, the main decay
      channel for the S(1) excited state of the spiropyran BIPS, is internal conversion
      to the spiropyran S(0) state with a quantum yield of > or = 0.9. This puts an
      upper limit of 0.1 to the quantum yield of the photochemical ring-opening
      reaction.

PMID- 12617670
TI  - Solvent-induced polymorphism of three-dimensional hydrogen-bonded networks of
      hexakis(4-carbamoylphenyl)benzene.
AB  - The crystal structures for three types of three-dimensional (3-D) hydrogen-bonded
      networks of hexakis(4-carbamoylphenyl)benzene (1), the network morphologies of
      which depend greatly on crystallization conditions, have been determined. When
      this compound is crystallized from hot DMSO, the resulting crystals, 1.12DMSO
      (orthorhombic, Pca2(1)), showed a 3-D hydrogen-bonded porous network (type A) via
      1-D catemer chains as a hydrogen-bonding motif of six primary amide groups. The
      type A network creates chambers surrounded by six molecules of 1 and channels
      along the c axis to give the highest porosity among the network polymorphs of 1
      investigated here. Crystallization from a boiling mixture of n-PrOH and water
      gave 1.6n-PrOH (monoclinic, P2(1)/c), which exhibits another type of 3-D hydrogen
      bonded porous network (type B) via cyclic dimers as another hydrogen-bonding
      motif of six primary amide groups. The type B network leads to triangle-like
      channels along the a axis having a cross section of ca. 9.2 x 9.7 x 9.7 A
      (including van der Waals radii). The crystal structure of 1.H(2)O (monoclinic,
      P2(1)/c), which was produced under hydrothermal conditions, showed a nonporous 3
      D hydrogen-bonded network chain of amide groups (type C) composed of a mixed
      hydrogen bonding motif of helical catemer chains/cyclic dimer/catemer. Solvent
      induced topological isomerism of these 3-D hydrogen-bonded networks of 1 arises
      from (i) the guest inclusion ability based on a radially functionalized hexagonal
      structure of 1, (ii) the correlation between the hydrogen bond donor ability of
      the syn and anti protons of the primary amide group in host 1 and the hydrogen
      bond acceptor ability of the oxygen atoms of 1 and guest solvents, and (iii) the
      polarity of the bulk crystallization solvents.

PMID- 12617671
TI  - In situ generation of carbenes: a general and versatile platform for
      organocatalytic living polymerization.
AB  - A metal-free, organocatalytic approach to living polymerization using N
      heterocyclic carbenes as nucleophilic catalysts generated and used in situ in a
      single-pot process is detailed. The N-heterocyclic carbene catalyst platform is
      extremely versatile, as the nature of the substituents has a pronounced effect of
      catalyst stability and activity toward different substrates. The generation of
      imidazolium- and thiazaolium-based carbenes was accomplished from the reaction of
      the corresponding salts with the appropriate bases. This allowed the rapid
      screening of libraries of catalysts that provided a basic understanding of
      catalyst structure (sterics, electronics, etc.) with the polymerization rate,
      control, substrate, and range of molecular weights. The imidazole-based catalysts
      were significantly more active toward ROP than the thiazolium-based analogues. No
      appreciable differences between imidazol-2-ylidene and imidazolin-2-ylidene
      catalysts were observed. Less sterically demanding carbenes were found to be more
      active toward ring-opening polymerization (ROP) than their sterically encumbered
      analogues for lactone polymerization. These data prompted the investigation of
      ionic liquid as a precatalyst reservoir in a phase-transfer polymerization with
      an immiscible THF solution of monomer and initiator. In situ activation of the
      ionic liquid generates carbene that migrates to the organic phase effecting
      living ROP. Precatalyst (ionic liquid) regeneration terminates polymerization.
      This simple reaction/recycle protocol readily allows repetitive ROPs from the
      ionic liquid using commercially available materials.

PMID- 12617672
TI  - Structural transformation of fluorinated carbon nanotubes induced by in situ
      electron-beam irradiation.
AB  - We have investigated the structural transformation of fluorinated singlewalled
      nanotubes (SWNTs) induced by electron-beam irradiation during the transmission
      electron microscope observations. Heavily fluorinated SWNT bundles were
      systematically transformed into multiwall-like nanotubes by releasing fluorine
      atoms during electron-beam irradiation and even broken into two pieces of the
      capped graphitic structures. Such structural transformations at relatively low
      kinetic energy (< or = 300 keV) could be explained by the local strains induced
      by fluorination, where C-C bonds that were fluorine-attached became 1.53 A, a
      single bond similar to that of a diamond, from our density functional
      calculations. We propose a possible concerted pathway for the structural
      transformation of fluorinated SWNTs induced by electron-beam irradiation based on
      the experimental observations.

PMID- 12617673
TI  - Porous lanthanide-organic frameworks: synthesis, characterization, and
      unprecedented gas adsorption properties.
AB  - The reactions of Ln(NO(3))(3) (Ln = La, Er) with 1,4-phenylendiacetic acid
      (H(2)PDA) under hydrothermal conditions produce isostructural lanthanide
      coordination polymers with the empirical formula [Ln(2)(PDA)(3)(H(2)O)] x 2H(2)O.
      The extended structure of [Ln(2)(PDA)(3)(H(2)O)] x 2H(2)O consists of Ln-COO
      triple helices cross-linked through the [bond]CH(2)C(6)H(4)CH(2)[bond] spacers of
      the PDA anions, showing 1D open channels along the crystallographic c axis that
      accommodate the guest and coordinated water molecules. Evacuation of
      [Er(2)(PDA)(3)(H(2)O)] x 2H(2)O at room temperature and at 200 degrees C,
      respectively, generates [Er(2)(PDA)(3)(H(2)O)] and [Er(2)(PDA)(3)], both of which
      give powder X-ray diffraction patterns consistent with that of
      [Er(2)(PDA)(3)(H(2)O)] x 2H(2)O. The porosity of [Er(2)(PDA)(3)(H(2)O)] and
      [Er(2)(PDA)(3)] is further demonstrated by their ability to adsorb water vapor to
      form [Er(2)(PDA)(3)(H(2)O)] x 2H(2)O quantitatively. Thermogravimetric analyses
      show that [Er(2)(PDA)(3)] remains stable up to 450 degrees C. The effective pore
      window size in [Er(2)(PDA)(3)] is estimated at 3.4 A. Gas adsorption measurements
      indicate that [Er(2)(PDA)(3)] adsorbs CO(2) into its pores and shows nonporous
      behavior toward Ar or N(2). There is a general correlation between the pore size
      and the kinetic diameters of the adsorbates (CO(2) = 3.3 A, Ar = 3.40 A, and N(2)
      = 3.64 A). That the adsorption favors CO(2) over Ar is unprecedented and may
      arise from the combined differentiations on size and on host-guest interactions.

PMID- 12617674
TI  - Mechanistic studies of nickel(II) alkyl agostic cations and alkyl ethylene
      complexes: investigations of chain propagation and isomerization in (alpha
      diimine)Ni(II)-catalyzed ethylene polymerization.
AB  - The synthesis of a series of (alpha-diimine)NiR(2) (R = Et, (n)Pr) complexes via
      Grignard alkylation of the corresponding (alpha-diimine)NiBr(2) precursors is
      presented. Protonation of these species by the oxonium acid
      [H(OEt(2))(2)](+)[BAr'(4)](-) at low temperatures yields cationic Ni(II) beta
      agostic alkyl complexes which model relevant intermediates present in nickel
      catalyzed olefin polymerization reactions. The highly dynamic nature of these
      agostic alkyl cations is quantitatively addressed using NMR line broadening
      techniques. Trapping of these complexes with ethylene provides cationic Ni alkyl
      ethylene species, which are used to determine rates of ethylene insertion into
      primary and secondary carbon centers. The Ni agostic alkyl cations are also
      trapped by CH(3)CN and Me(2)S to yield Ni(R)(L)(+) (L = CH(3)CN, Me(2)S)
      complexes, and the dynamic behavior of these species in the presence of varied
      [L] is discussed. The kinetic data obtained from these experiments are used to
      present an overall picture of the ethylene polymerization mechanism for (alpha
      diimine)Ni catalysts, including effects of reaction temperature and ethylene
      pressure on catalyst activity, polyethylene branching, and polymer architecture.
      Detailed comparisons of these systems to the previously presented analogous
      palladium catalysts are made.

PMID- 12617675
TI  - Highly efficient water splitting into H2 and O2 over lanthanum-doped NaTaO3
      photocatalysts with high crystallinity and surface nanostructure.
AB  - NiO-loaded NaTaO(3) doped with lanthanum showed a high photocatalytic activity
      for water splitting into H(2) and O(2) in a stoichiometric amount under UV
      irradiation. The photocatalytic activity of NiO-loaded NaTaO(3) doped with
      lanthanum was 9 times higher than that of nondoped NiO-loaded NaTaO(3). The
      maximum apparent quantum yield of the NiO/NaTaO(3):La photocatalyst was 56% at
      270 nm. The factors affecting the highly efficient photocatalytic water splitting
      were examined by using various characterization techniques. Electron microscope
      observations revealed that the particle sizes of NaTaO(3):La crystals (0.1-0.7
      microm) were smaller than that of the nondoped NaTaO(3) crystal (2-3 microm) and
      that the ordered surface nanostructure with many characteristic steps was created
      by the lanthanum doping. The small particle size with a high crystallinity was
      advantageous to an increase in the probability of the reaction of photogenerated
      electrons and holes with water molecules toward the recombination. Transmission
      electron microscope observations and extended X-ray absorption fine structure
      analyses indicated that NiO cocatalysts were loaded on the edge of the nanostep
      structure of NaTaO(3):La photocatalysts as ultrafine particles. The H(2)
      evolution proceeded on the ultrafine NiO particles loaded on the edge while the
      O(2) evolution occurred at the groove of the nanostep structure. Thus, the
      reaction sites for H(2) evolution were separated from those of O(2) evolution
      over the ordered nanostep structure. The small particle size and the ordered
      surface nanostep structure of the NiO/NaTaO(3):La photocatalyst powder
      contributed to the highly efficient water splitting into H(2) and O(2).

PMID- 12617676
TI  - Palladium catalyzed kinetic and dynamic kinetic asymmetric transformations of
      gamma-acyloxybutenolides. Enantioselective total synthesis of (+)-Aflatoxin B1
      and B2a.
AB  - The reaction of gamma-tert-butoxycarbonyloxy-2-butenolide with phenol
      nucleophiles in the presence of a Pd(0) complex with chiral ligands may be
      performed under conditions that favor either a kinetic resolution or a kinetic
      asymmetric transformation (KAT) or dynamic kinetic asymmetric transformation
      (DYKAT). Performing the reaction at high concentration (0.5 M) in the presence of
      a carbonate base favors the former, i.e., KAT; whereas, running the reaction at
      0.1M in the presence of tetra-n-butylammonium chloride favors the DYKAT process.
      Syntheses of aflatoxin B(1) and B(2a) employs the DYKAT to introduce the
      stereochemistry. Starting with Pechmann condensation of the monomethyl ether of
      phloroglucinol, the requisite phenol nucleophile is constructed in two steps. The
      DYKAT proceeds with > 95% ee. A reductive Heck cyclization followed by a
      lanthanide catalyzed intramolecular acylation completes the synthesis of the
      pentacyclic nucleus in 3 steps. Reduction of the lactone provides aflatoxin B(2a)
      and its dehydration product B(1). This synthetic strategy creates an asymmetric
      synthesis of the former in only 7 steps and the latter in 9 steps. Thus, the
      ultimate synthetic sequence involves 3 + 5 --> 39 --> 40 --> 42 --> 43 --> 46 -->
      47 --> 48 (aflatoxin B(2a)) --> 49 (aflatoxin B(1)).

PMID- 12617677
TI  - 2D conformationally sampled pharmacophore: a ligand-based pharmacophore to
      differentiate delta opioid agonists from antagonists.
AB  - Pharmacophores are widely used for rational drug design and include those based
      on receptor binding sites or on known ligands. To date, ligand-based
      pharmacophores have typically used one or a small number of conformers of known
      receptor ligands. However, this method does not take into account the inherent
      dynamic nature of molecules, which sample a wide range of conformations, any of
      which could be the bound form. In the present study, molecular dynamics (MD)
      simulations were used as a means to sample the conformational space of ligands to
      include all accessible conformers at room temperature in the development of a
      pharmacophore. On the basis of these conformers, probability distributions of
      selected distances and angles in a series of delta specific opioid ligands were
      obtained and correlated with agonist versus antagonist activities. Individually,
      the distributions did not allow for unique agonist and antagonist pharmacophores
      to be identified. However, by extending the conformational analysis to two
      dimensions, a 2D conformationally sampled pharmacophore (CSP) for distinguishing
      delta receptor agonists and antagonists was developed. Application of this model
      to the compound DPI2505 suggests that it may have agonist activity. It is
      anticipated that the CSP method, which does not require alignment of compounds
      during pharmacophore development, will be a useful tool for obtaining structure
      function relationships of ligands particularly in systems where the receptor 3D
      structure is not known.

PMID- 12617678
TI  - Decisive role of electronic polarization of the protein environment in
      determining the absorption maximum of halorhodopsin.
AB  - It is known that the absorption maximum of halorhodopsin is red shifted by 10 nm
      with the uptake of a chloride ion Cl(-). According to the X-ray structure, the
      ion is located at the position of the counterion of the chromophore, protonated
      retinal Schiff base. Thus, the direction of the observed spectral change is
      opposite to that expected from the pi-electron redistribution (an increase in the
      bond alternation) induced by the counterion. The physical origin of this abnormal
      shift is never explained in terms of any simple chemical analogues. We
      successfully explain this phenomenon by a QM/MM type of excitation energy
      calculation. The three-dimensional structure of the protein is explicitly taken
      into account using the X-ray structure. We reveal that the electronic
      polarization of the protein environment plays an essential role in tuning the
      absorption maximum of halorhodopsin.

PMID- 12617679
TI  - Simulating the nucleation of water/ethanol and water/n-nonane mixtures: mutual
      enhancement and two-pathway mechanism.
AB  - A combination of the aggregation-volume-bias and configurational-bias Monte Carlo
      algorithms and the umbrella sampling technique was applied to investigate two
      different binary vapor-liquid nucleation systems: water/ethanol and water/n
      nonane. The simulations are able to reproduce the different nonideal nucleation
      behavior observed experimentally for these two systems, i.e., the mutual
      enhancement of nucleation rates for water/ethanol mixtures and the two-pathway
      nucleation for water/n-nonane mixtures. Structural analysis provides microscopic
      explanations for the observed nucleation behavior. In particular, the simulations
      show a large and size-dependent surface enrichment of ethanol in the
      water/ethanol droplets, which confirms the previous experimental interpretation
      for this system. The immiscibility observed even for small water/n-nonane
      clusters causes the two-pathway nucleation mechanism.

PMID- 12617680
TI  - Specific ethene surface activation on silver oxide covered Ag[111] from the
      interplay of STM experiment and theory.
AB  - High-resolution scanning tunneling microscopy (STM) images at 5 K, simultaneously
      resolving the molecular adsorbate and the honeycomb structure of the well-defined
      Ag[111]-p(4 x 4)+Ag(1.83)O substrate, assign the adsorption site for ethene on
      the silver oxide surface. Ethene molecules are exclusively adsorbed above a
      particular subset of Ag(delta)(+) sites in the hexagonal rings of the oxide.
      Extensive density functional theory (DFT) slab calculations confirm that this is
      the most stable site, with an adsorption energy of 0.4 eV (39 kJ mol(-1)).
      Adsorption is accompanied by a large deformation of the hexagonal oxide ring and
      a significant increase in the C-C bond length. STM image simulations provide
      qualitative agreement with the experimental images, and the molecular orientation
      is discussed with the help of simple molecular orbital arguments.

PMID- 12617681
TI  - Noble gas-actinide complexes of the CUO molecule with multiple Ar, Kr, and Xe
      atoms in noble-gas matrices.
AB  - Laser-ablated U atoms react with CO in excess argon to produce CUO, which is
      trapped in a triplet state in solid argon at 7 K, based on agreement between
      observed and relativistic density functional theory (DFT) calculated isotopic
      frequencies ((12)C(16)O, (13)C(16)O, (12)C(18)O). This observation contrasts a
      recent neon matrix investigation, which trapped CUO in a linear singlet state
      calculated to be about 1 kcal/mol lower in energy. Experiments with krypton and
      xenon give results analogous to those with argon. Similar work with dilute Kr and
      Xe in argon finds small frequency shifts in new four-band progressions for CUO in
      the same triplet states trapped in solid argon and provides evidence for four
      distinct CUO(Ar)(4-n)(Ng)(n) (Ng = Kr, Xe, n = 1, 2, 3, 4) complexes for each Ng.
      DFT calculations show that successively higher Ng complexes are responsible for
      the observed frequency progressions. This work provides the first evidence for
      noble gas-actinide complexes, and the first example of neutral complexes with
      four noble gas atoms bonded to one metal center.

PMID- 12617682
TI  - Protein-polyelectrolyte cluster formation and redissolution: a Monte Carlo study.
AB  - Aqueous solutions of proteins and oppositely charged polyelectrolytes were
      studied at different polyelectrolyte chain length, ionic strength, and protein
      protein interaction potential as a function of the polyelectrolyte concentration.
      One of the protein models used represented lysozyme in aqueous environment. The
      model systems were solved by Monte Carlo simulations, and their properties were
      analyzed in terms of radial distribution functions, structure factors, and
      cluster composition probabilities. In the system with the strongest electrostatic
      protein-polyelectrolyte interaction the largest clusters were formed near or at
      equivalent amount of net protein charge and polyelectrolyte charge, whereas in
      excess of polyelectrolyte a redissolution appeared. Shorter polyelectrolyte
      chains and increased ionic strength lead to weaker cluster formation. An
      inclusion of nonelectrostatic protein-protein attraction promoted the protein
      polyelectrolyte cluster formation.

PMID- 12617683
TI  - Molecular packing of lysozyme, fibrinogen, and bovine serum albumin on
      hydrophilic and hydrophobic surfaces studied by infrared-visible sum frequency
      generation and fluorescence microscopy.
AB  - Infrared-visible sum frequency generation (SFG) vibrational spectroscopy, in
      combination with fluorescence microscopy, was employed to investigate the surface
      structure of lysozyme, fibrinogen, and bovine serum albumin (BSA) adsorbed on
      hydrophilic silica and hydrophobic polystyrene as a function of protein
      concentration. Fluorescence microscopy shows that the relative amounts of protein
      adsorbed on hydrophilic and hydrophobic surfaces increase in proportion with the
      concentration of protein solutions. For a given bulk protein concentration, a
      larger amount of protein is adsorbed on hydrophobic polystyrene surfaces compared
      to hydrophilic silica surfaces. While lysozyme molecules adsorbed on silica
      surfaces yield relatively similar SFG spectra, regardless of the surface
      concentration, SFG spectra of fibrinogen and BSA adsorbed on silica surfaces
      exhibit concentration-dependent signal intensities and peak shapes. Quantitative
      SFG data analysis reveals that methyl groups in lysozyme adsorbed on hydrophilic
      surfaces show a concentration-independent orientation. However, methyl groups in
      BSA and fibrinogen become less tilted with respect to the surface normal with
      increasing protein concentration at the surface. On hydrophobic polystyrene
      surfaces, all proteins yield similar SFG spectra, which are different from those
      on hydrophilic surfaces. Although more protein molecules are present on
      hydrophobic surfaces, lower SFG signal intensity is observed, indicating that
      methyl groups in adsorbed proteins are more randomly oriented as compared to
      those on hydrophilic surfaces. SFG data also shows that the orientation and
      ordering of phenyl rings in the polystyrene surface is affected by protein
      adsorption, depending on the amount and type of proteins.

PMID- 12617684
TI  - Cyclic vinylogous TTF: a potential molecular clip triggered by electron transfer.
AB  - Cyclic vinylogous tetrathiafulvalenes (TTFs) where the two dithiole rings are
      linked through the outer sulfur atoms with an alkyl chain of various lengths were
      synthesized by oxidative intramolecular coupling of bis(dithiafulvenes). Upon
      oxidation, these systems exhibit large molecular movements associated with
      electron transfers. Their electrochemical behaviors were investigated together
      with the X-ray crystallographic structures of several derivatives and compared
      with molecular geometry calculations. Dependent on the length of the alkyl chain,
      either a stretch or a clip movement can be observed. These conformational
      modifications were found to be fast and fully reversible and required only low
      oxidation potentials. The movements seem to be almost insensitive to the nature
      of the substituents or its steric hindrance on the central conjugated spacer.

PMID- 12617685
TI  - First-second shell interactions in metal binding sites in proteins: a PDB survey
      and DFT/CDM calculations.
AB  - The role of the second shell in the process of metal binding and selectivity in
      metalloproteins has been elucidated by combining Protein Data Bank (PDB) surveys
      of Mg, Mn, Ca, and Zn binding sites with density functional theory/continuum
      dielectric methods (DFT/CDM). Peptide backbone groups were found to be the most
      common second-shell ligand in Mg, Mn, Ca, and Zn binding sites, followed (in
      decreasing order) by Asp/Glu, Lys/Arg, Asn/Gln, and Ser/Thr side chains. Aromatic
      oxygen- or nitrogen-containing side chains (Tyr, His, and Trp) and sulfur
      containing side chains (Cys and Met) are seldom found in the second coordination
      layer. The backbone and Asn/Gln side chain are ubiquitous in the metal second
      coordination layer as their carbonyl oxygen and amide hydrogen can act as a
      hydrogen-bond acceptor and donor, respectively, and can therefore partner
      practically every first-shell ligand. The second most common outer-shell ligand,
      Asp/Glu, predominantly hydrogen bonds to a metal-bound water or Zn-bound
      histidine and polarizes the H-O or H-N bond. In certain cases, a second-shell
      Asp/Glu could affect the protonation state of the metal ligand. It could also
      energetically stabilize a positively charged metal complex more than a neutral
      ligand such as the backbone and Asn/Gln side chain. As for the first shell, the
      second shell is predicted to contribute to the metal selectivity of the binding
      site by discriminating between metal cations of different ionic radii and
      coordination geometries. The first-shell-second-shell interaction energies decay
      rapidly with increasing solvent exposure of the metal binding site. They are less
      favorable but are of the same order of magnitude as compared to the respective
      metal-first-shell interaction energies. Altogether, the results indicate that the
      structure and properties of the second shell are dictated by those of the first
      layer. The outer shell is apparently designed to stabilize/protect the inner
      shell and complement/enhance its properties.

PMID- 12617686
TI  - Carbon dioxide-in-water microemulsions.
AB  - Liquid and supercritical carbon dioxide swell potassium carboxylate
      perfluoropolyether (PFPE-K) cylindrical micelles in water to produce novel CO(2)
      in-water (C/W) microemulsions. The swelling elongates the micelles significantly
      from 20 to 80 nm as the molar ratio of CO(2) in the micelles to surfactant
      (R(CO2)) reaches approximately 8. As the micelles swell to form microemulsions,
      the solubility of pyrene increases by a factor of ca. 10. Fluorescence spectra
      suggest that pyrene resides primarily in the low-polarity micelle core rather
      than in the palisade region. The results illustrate the ability of C/W
      microemulsions to solubilize both lipophilic and fluorophilic substances
      simultaneously.

PMID- 12617688
TI  - Biochemical aspects of overtraining in endurance sports : the metabolism
      alteration process syndrome.
AB  - Recent studies have shown that endurance overtraining could result from
      successive and cumulative alterations in metabolism, which become chronic during
      training. The onset of this process is a biochemical alteration in carbohydrate
      (saccharide) metabolism. During endurance exercises, the amount of saccharide
      chains from two blood glycoproteins (alpha(2)-macroglobulin and alpha(1)-acid
      glycoprotein) was found to have decreased, i.e. concentrations of these proteins
      remained unchanged but their quality changed. These saccharide chains were
      probably used for burning liver glycogen stores during exercise. This step was
      followed by alterations in lipid metabolism. The most relevant aspect of this
      step was that the mean chain length of blood fatty acids decreased, i.e. the same
      amount of fatty acids were found within the blood, but overtrained individuals
      presented shorter fatty acids than well-trained individuals. This suggests that
      alterations appeared in the liver synthesis of long-chain fatty acids or that
      higher peroxidation of blood lipoparticles occurred. For the final step of this
      overtraining process, it was found that these dysfunctions in carbohydrate/lipid
      metabolism led to the higher use of amino acids, which probably resulted from
      protein catabolism. The evolution of three protein concentrations (alpha(1)-acid
      glycoprotein, alpha(2)-macroglobulin and IgG(3)) correlated with this amino acid
      concentration increase, suggesting a specific catabolism of these proteins. At
      this time only, overtraining was clinically diagnosed through conventional
      symptoms. Therefore, this process described successive alterations in exercise
      metabolism that shifted from the main energetic stores of exercise (carbohydrates
      and lipids) towards molecular pools (proteins) normally not substantially used
      for the energetic supply of skeletal muscles. Now, a general biochemical model of
      the overtraining process may be proposed which includes most of the previously
      identified metabolic hypotheses.

PMID- 12617690
TI  - Asthma and recreational SCUBA diving: a systematic review.
AB  - Asthma has traditionally been a contraindication to recreational self-contained
      underwater breathing apparatus (SCUBA) diving, although large numbers of patients
      with asthma partake in diving. The purpose of this paper is to review all the
      research relevant to the issue of the safety of asthma in divers. MEDLINE and
      MDConsult were searched for papers between 1980-2002. Keywords used for the
      search were 'asthma', 'SCUBA' and 'diving'. Additional references were reviewed
      from the bibliographies of received articles.A total of fifteen studies were
      identified as relevant to the area. These included three surveys of divers with
      asthma, four case series and eight mechanistic investigations of the effect of
      diving on pulmonary function. The survey data showed a high prevalence of asthma
      among recreational SCUBA divers, similar to the prevalence of asthma among the
      general population. There was some weak evidence for an increase in rates of
      decompression illness among divers with asthma. In healthy participants, wet
      hyperbaric chamber and open-water diving led to a decrease in forced vital
      capacity, forced expired volume over 1.0 second and mid-expiratory flow rates. In
      participants with asymptomatic respiratory atopy, diving caused a decrease in
      airway conductivity.There is some indication that asthmatics may be at increased
      risk of pulmonary barotrauma, but more research is necessary. Decisions regarding
      diving participation among asthmatics must be made on an individual basis
      involving the patient through informed, shared decision making.

PMID- 12617689
TI  - A new direction for ultrasound therapy in sports medicine.
AB  - Ultrasound therapy is a widely available and frequently used electrophysical
      agent in sports medicine. However, systematic reviews and meta-analyses have
      repeatedly concluded that there is insufficient evidence to support a beneficial
      effect of ultrasound at dosages currently being introduced clinically.
      Consequently, the role of ultrasound in sports medicine is in question. This does
      not mean that ultrasound should be discarded as a therapeutic modality. However,
      it does mean that we may need to look in a new direction to explore potential
      benefits. A new direction for ultrasound therapy has been revealed by recent
      research demonstrating a beneficial effect of ultrasound on injured bone. During
      fresh fracture repair, ultrasound reduced healing times by between 30 and 38%.
      When applied to non-united fractures, it stimulated union in 86% of cases. These
      benefits were generated using low-intensity (<0.1 W/cm(2)) pulsed ultrasound
      (LIPUS), a dose alternative to that traditionally used in sports medicine.
      Although currently developed for the intervention of bone injuries, LIPUS has the
      potential to be used on tissues and conditions more commonly encountered in
      sports medicine. These include injuries to ligament, tendon, muscle and
      cartilage. This review discusses the effect of LIPUS on bone fractures, the
      dosages introduced and the postulated mechanisms of action. It concludes by
      discussing the relevance of these latest findings to sports medicine and how this
      evidence of a beneficial clinical effect may be implemented to intervene in
      sporting injuries to bone and other tissues. The aim of the paper is to highlight
      this latest direction in ultrasound therapy and stimulate new lines of research
      into the efficacy of ultrasound in sports medicine. In time this may lead to
      accelerated recovery from injury and subsequent earlier return to activity.

PMID- 12617693
TI  - Alpine ski injuries and their prevention.

PMID- 12617691
TI  - Determinants of post-exercise glycogen synthesis during short-term recovery.
AB  - The pattern of muscle glycogen synthesis following glycogen-depleting exercise
      occurs in two phases. Initially, there is a period of rapid synthesis of muscle
      glycogen that does not require the presence of insulin and lasts about 30-60
      minutes. This rapid phase of muscle glycogen synthesis is characterised by an
      exercise-induced translocation of glucose transporter carrier protein-4 to the
      cell surface, leading to an increased permeability of the muscle membrane to
      glucose. Following this rapid phase of glycogen synthesis, muscle glycogen
      synthesis occurs at a much slower rate and this phase can last for several hours.
      Both muscle contraction and insulin have been shown to increase the activity of
      glycogen synthase, the rate-limiting enzyme in glycogen synthesis. Furthermore,
      it has been shown that muscle glycogen concentration is a potent regulator of
      glycogen synthase. Low muscle glycogen concentrations following exercise are
      associated with an increased rate of glucose transport and an increased capacity
      to convert glucose into glycogen. The highest muscle glycogen synthesis rates
      have been reported when large amounts of carbohydrate (1.0-1.85 g/kg/h) are
      consumed immediately post-exercise and at 15-60 minute intervals thereafter, for
      up to 5 hours post-exercise. When carbohydrate ingestion is delayed by several
      hours, this may lead to ~50% lower rates of muscle glycogen synthesis. The
      addition of certain amino acids and/or proteins to a carbohydrate supplement can
      increase muscle glycogen synthesis rates, most probably because of an enhanced
      insulin response. However, when carbohydrate intake is high (> or =1.2 g/kg/h)
      and provided at regular intervals, a further increase in insulin concentrations
      by additional supplementation of protein and/or amino acids does not further
      increase the rate of muscle glycogen synthesis. Thus, when carbohydrate intake is
      insufficient (<1.2 g/kg/h), the addition of certain amino acids and/or proteins
      may be beneficial for muscle glycogen synthesis. Furthermore, ingestion of
      insulinotropic protein and/or amino acid mixtures might stimulate post-exercise
      net muscle protein anabolism. Suggestions have been made that carbohydrate
      availability is the main limiting factor for glycogen synthesis. A large part of
      the ingested glucose that enters the bloodstream appears to be extracted by
      tissues other than the exercise muscle (i.e. liver, other muscle groups or fat
      tissue) and may therefore limit the amount of glucose available to maximise
      muscle glycogen synthesis rates. Furthermore, intestinal glucose absorption may
      also be a rate-limiting factor for muscle glycogen synthesis when large
      quantities (>1 g/min) of glucose are ingested following exercise.

PMID- 12617692
TI  - Delayed onset muscle soreness : treatment strategies and performance factors.
AB  - Delayed onset muscle soreness (DOMS) is a familiar experience for the elite or
      novice athlete. Symptoms can range from muscle tenderness to severe debilitating
      pain. The mechanisms, treatment strategies, and impact on athletic performance
      remain uncertain, despite the high incidence of DOMS. DOMS is most prevalent at
      the beginning of the sporting season when athletes are returning to training
      following a period of reduced activity. DOMS is also common when athletes are
      first introduced to certain types of activities regardless of the time of year.
      Eccentric activities induce micro-injury at a greater frequency and severity than
      other types of muscle actions. The intensity and duration of exercise are also
      important factors in DOMS onset. Up to six hypothesised theories have been
      proposed for the mechanism of DOMS, namely: lactic acid, muscle spasm, connective
      tissue damage, muscle damage, inflammation and the enzyme efflux theories.
      However, an integration of two or more theories is likely to explain muscle
      soreness. DOMS can affect athletic performance by causing a reduction in joint
      range of motion, shock attenuation and peak torque. Alterations in muscle
      sequencing and recruitment patterns may also occur, causing unaccustomed stress
      to be placed on muscle ligaments and tendons. These compensatory mechanisms may
      increase the risk of further injury if a premature return to sport is attempted.A
      number of treatment strategies have been introduced to help alleviate the
      severity of DOMS and to restore the maximal function of the muscles as rapidly as
      possible. Nonsteroidal anti-inflammatory drugs have demonstrated dosage-dependent
      effects that may also be influenced by the time of administration. Similarly,
      massage has shown varying results that may be attributed to the time of massage
      application and the type of massage technique used. Cryotherapy, stretching,
      homeopathy, ultrasound and electrical current modalities have demonstrated no
      effect on the alleviation of muscle soreness or other DOMS symptoms. Exercise is
      the most effective means of alleviating pain during DOMS, however the analgesic
      effect is also temporary. Athletes who must train on a daily basis should be
      encouraged to reduce the intensity and duration of exercise for 1-2 days
      following intense DOMS-inducing exercise. Alternatively, exercises targeting less
      affected body parts should be encouraged in order to allow the most affected
      muscle groups to recover. Eccentric exercises or novel activities should be
      introduced progressively over a period of 1 or 2 weeks at the beginning of, or
      during, the sporting season in order to reduce the level of physical impairment
      and/or training disruption. There are still many unanswered questions relating to
      DOMS, and many potential areas for future research.

PMID- 12617694
TI  - Role of pharmacogenomics in individualising treatment with SSRIs.
AB  - The introduction of the SSRIs has significantly transformed the pharmacological
      treatment of a range of psychiatric disorders. In particular, individuals
      affected by depression, panic disorder, obsessive-compulsive disorder and social
      phobia have benefited substantially from their use. Compared with the previous
      generation of psychotropic drugs, SSRIs offer an improved tolerability to therapy
      while maintaining a high level of efficacy. Nevertheless, despite these
      advantages, not all patients benefit from treatment; an appreciable proportion do
      not respond adequately, while others may react adversely. This necessitates a
      review of the initial treatment choice, often involving extended periods of
      illness while a more suitable therapy is sought. Such a scenario could be avoided
      were it possible to determine the most suitable drug prior to treatment. Several
      factors are postulated to influence outcome of drug therapy; most recently,
      pharmacogenetic studies have demonstrated a significant influence of genetic
      mechanisms on the efficacy of clinically prescribed drugs. This contribution,
      which is primarily a reflection of alterations in genes that encode drug
      metabolising enzymes, drug receptors, transporters and second messengers, may be
      pertinent to the success of SSRI therapy. Attesting to this potential, studies to
      elucidate the influence of genetic processes on SSRI efficacy now represent a
      major focus of pharmacogenetics research. Current evidence emerging from the
      field suggests that gene variants within the serotonin transporter and cytochrome
      P450 drug-metabolising enzymes may bear a particular importance, though further
      corroboration of these findings is still warranted. At the same time, it appears
      likely that further key participating genes remain to be identified. By
      comprehensively delineating these genetic components, it is envisaged that this
      will eventually facilitate the development of highly sensitive protocols for
      individualising SSRI treatment.

PMID- 12617695
TI  - Cerebral malaria: optimising management.
AB  - Cerebral malaria is one of the most common nontraumatic encephalopathies in the
      world. Children living in sub-Saharan Africa bear the brunt of the disease, but
      cerebral malaria is being seen increasingly in adults throughout the world,
      including outside malarious areas. There are differences in the clinical
      presentation and pathophysiology between African children and nonimmune adults
      from any region. Mortality is high (10-20%). Parenteral antimalarials are the
      only interventions that have been shown to affect outcome. The cinchona alkaloids
      (quinine and quinidine) are the mainstay of antimalarial treatment, but the
      artemisinin derivatives are increasingly being used. Aggressive treatment and
      prevention of convulsions may be important, particularly in children. Other
      ancillary treatments that can be used to augment standard antimalarial drugs,
      such as exchange blood transfusions, osmotic diuretics and pentoxifylline, may
      improve outcome but have not been subjected to rigorous clinical trials. There is
      little support for corticosteroids or deferoxamine (desferrioxamine) in cerebral
      malaria. Other adjuncts have not been adequately tested. Further research is
      required on drugs that interfere with the pathophysiological processes to prevent
      neurological complications and death.

PMID- 12617696
TI  - Psychiatric disorders in Prader-Willi syndrome: epidemiology and management.
AB  - Although people with intellectual disabilities are at increased risk for
      psychiatric disorders, the type and rate of these problems differ between those
      with different causes for their retardation. In this paper, we review behavioural
      and psychiatric problems in persons with Prader-Willi syndrome, a disorder caused
      by a paternally derived deletion at chromosome 15(q11-q13) in about 70% of
      affected patients, and by maternal uniparental disomy in the majority of the
      remaining patients. In addition to the syndrome's characteristic hyperphagia and
      food seeking, individuals with Prader-Willi syndrome also have increased risks of
      nonfood, compulsive behaviours. These include skin picking, which is highly
      prevalent, as well as more variable rates of hoarding, redoing and concerns with
      symmetry, exactness, cleanliness, ordering and arranging. Relative to others with
      mental retardation, persons with Prader-Willi syndrome are at a marked increased
      risk for developing full-blown, obsessive-compulsive disorder. In addition, many
      people with Prader-Willi syndrome show increased rates of tantrums,
      oppositionality and aggression. Recent findings suggest that they also have an
      increased risk of psychotic disorder or affective illness with a psychotic
      component, especially young adult patients and those with the maternal
      uniparental disomy as opposed to paternal deletion. Dietary approaches include a
      reduced-calorie diet and increased physical activity, as well as close
      supervision around food and keeping food locked away. To date, neither CNS
      stimulants nor anorectic agents have been effective in treating hyperphagia, in
      part because hyperphagia in Prader-Willi syndrome is attributed to decreased
      satiation as opposed to increased hunger. Treatment for compulsivity and
      maladaptive behaviours include: behavioural programming; a structured,
      predictable routine; extra help with transitions; family support; and
      pharmacotherapy. Although formal drug studies have yet to be conducted, SSRIs
      have been effective in reducing skin picking, compulsivity and aggressive
      episodes in some individuals with Prader-Willi syndrome. Atypical antipsychotics
      have also proven helpful in persons with psychotic features or extreme aggression
      and impulsivity. Largely on the basis of case studies, the risks and benefits of
      these and other drugs in Prader-Willi syndrome are reviewed. Drug trials that
      move beyond case studies and that assess the relative efficacy of behavioural
      treatments alone or in combination with pharmacotherapy are sorely needed.

PMID- 12617699
TI  - Diplopia after refractive surgery: occurrence and prevention.
AB  - OBJECTIVES: To report the occurrence of persistent diplopia manifesting after
      refractive surgery, to describe the different causes of this complication, to
      provide risk stratification for its occurrence, and to outline minimal screening
      techniques for its prevention. METHODS: A retrospective medical record review of
      patients seen in 2 private strabismus practices who experienced persistent
      diplopia after refractive surgery. RESULTS: A total of 28 patients were
      identified who met the inclusion criteria. The causes of postoperative diplopia
      could be traced to 1 of 5 mechanisms. These included technical problems, prior
      need of prisms, aniseikonia, iatrogenic monovision, and improper control of
      accommodation in patients with strabismus. The recommended screening techniques
      would have identified all patients in this series as being at risk for
      postoperative diplopia with the exception of those in whom technical problems
      were responsible. CONCLUSIONS: Diplopia can become manifest after refractive
      surgery. With proper attention paid to risk stratification and recommended
      screening criteria, the incidence of this complication can be minimized.

PMID- 12617700
TI  - Management of post-LASIK corneal ectasia with Intacs inserts: one-year results.
AB  - OBJECTIVE: To prospectively study the effects of the use of Intacs microthin
      prescription inserts (Addition Technology Inc, Fremont, Calif) for the
      postoperative management of corneal ectasia resulting from laser in situ
      keratomileusis (LASIK). METHODS: In this prospective nonrandomized clinical
      trial, 10 eyes of 7 patients with post-LASIK corneal ectasia (2 men and 5 women)
      aged 33 to 46 years (mean +/- SD, 40.67 +/- 5.99 years) were included. The follow
      up ranged from 6 to 24 months (mean +/- SD, 15.0 +/- 6.5 months). Two Intacs
      segments of thickness depending on the residual refraction of the patients were
      inserted in each eye. MAIN OUTCOME MEASURES: Uncorrected visual acuity, best
      spectacle-corrected visual acuity, refractive outcome, and topographic findings
      after Intacs implantation. RESULTS: Intacs were successfully implanted in all
      eyes. Spherical equivalent error was statistically significantly reduced after
      Intacs implantation (pre-Intacs, mean +/- SD: -4.81 +/- 3.24 Diopters (D) (range,
      -13.75 to -2.50 D) to -0.96 +/- 2.93 D (range, -8.75 to 2.50 D) (P<.001). Pre
      Intacs uncorrected visual acuity was 20/100 or worse in all eyes (range, counting
      fingers to 20/100) while at the last follow-up examination, 9 (90%) of 10 eyes
      had uncorrected visual acuity of 20/40 or better (range, counting fingers to
      20/20). Three eyes maintained the pre-Intacs best spectacle-corrected visual
      acuity while the rest of the eyes (7) experienced a gain of 1 to 2 lines. The
      mean difference between pre-Intacs and last follow-up best spectacle-corrected
      visual acuity was a gain of 1.00 +/- 0.82 lines. CONCLUSIONS: Intracorneal ring
      segments implantation improved uncorrected visual acuity and best spectacle
      corrected visual acuity in patients with post-LASIK ectasia. Even though the
      results are encouraging, concern still exists regarding the long-term effect of
      such an approach for the management of post-LASIK ectasia.

PMID- 12617701
TI  - Kinetics of indocyanine green dye after intraocular surgeries using indocyanine
      green staining.
AB  - OBJECTIVE: To determine the elimination kinetics of indocyanine green (ICG) after
      intraocular operations using ICG staining. METHODS: Intraocular fluorescence of
      ICG was determined using the ICG angiographic mode of a scanning laser
      ophthalmoscope (in vivo) and fluorescence microscopy (in vitro) after circular
      curvilinear capsulorhexis with ICG staining during cataract surgery and internal
      limiting membrane (ILM) peeling with ICG staining during macular hole surgery.
      SUBJECTS: We studied 9 eyes of 7 patients with white cataracts and 14 eyes of 14
      patients with idiopathic macular holes. RESULTS: Scanning laser ophthalmoscopy
      revealed fluorescence in the anterior segment of patients with cataracts on the
      first postoperative day, and fluorescence remained for a mean +/- SD of 6.0 +/-
      2.2 days postoperatively. Scanning laser ophthalmoscopy also revealed
      fluorescence in the posterior pole of patients with macular holes, and it
      remained for a mean +/- SD of 2.7 +/- 1.4 months postoperatively. Fluorescence
      microscopy showed fluorescence of the entire tissues, suggesting that ICG had
      stained not only the surface of the membranes but had also entered them. In both
      operations, visual outcomes were not significantly different from the results
      obtained without ICG. CONCLUSIONS: Because entire tissues were stained, the
      differences in ICG kinetics might also be caused by factors other than
      differences in stainability, such as the environment surrounding the tissues or
      molecular structural differences between the lens capsule and the ILM. Although
      we found complete disappearance of fluorescence and good functional recovery, the
      longer resident time of the dye after macular hole surgery may suggest a
      potential risk to intraocular tissues.

PMID- 12617702
TI  - Retinochoroidal collateral veins protect against anterior segment
      neovascularization after central retinal vein occlusion.
AB  - OBJECTIVE: To test the hypothesis that retinochoroidal collateral veins (RCVs),
      or alternatively, retinociliary or optociliary shunts/collaterals/veins or
      opticociliary anastomoses, act protectively against the development of anterior
      segment neovascularization (ASN) following central retinal vein occlusion (CRVO).
      DESIGN: Case-control retrospective medical record review of patients with CRVO.
      PATIENTS: We identified 107 patients with CRVO, of whom 34 had developed ASN, by
      reviewing their medical records. After applying exclusion criteria, a case group
      and an age-, sex-, and visual acuity-matched control group were selected. We
      analyzed these groups for the presence or absence of RCVs and noted the time
      course involved in their development. MAIN OUTCOME MEASURES: Anterior segment
      neovascularization (including neovascularization of the iris and/or anterior
      chamber angle), neovascular glaucoma, and RCV development. RESULTS: Only 1 (5.4%)
      of 19 individuals who developed ASN did so in the presence of RCVs. In contrast,
      11 (57.9%) of 19 individuals in the control group developed RCVs. Statistical
      analysis revealed that patients who developed ASN were roughly 25 times less
      likely to have had RCVs than individuals who never developed ASN (odds ratio =
      24.74; P =.001). CONCLUSION: Retinochoroidal collateral veins are negatively
      associated with ASN post-CRVO and may function in a protective manner against
      such an outcome.

PMID- 12617697
TI  - Therapeutic potential of cannabinoids in CNS disease.
AB  - The major psychoactive constituent of Cannabis sativa, delta(9)
      tetrahydrocannabinol (delta(9)-THC), and endogenous cannabinoid ligands, such as
      anandamide, signal through G-protein-coupled cannabinoid receptors localised to
      regions of the brain associated with important neurological processes. Signalling
      is mostly inhibitory and suggests a role for cannabinoids as therapeutic agents
      in CNS disease where inhibition of neurotransmitter release would be beneficial.
      Anecdotal evidence suggests that patients with disorders such as multiple
      sclerosis smoke cannabis to relieve disease-related symptoms. Cannabinoids can
      alleviate tremor and spasticity in animal models of multiple sclerosis, and
      clinical trials of the use of these compounds for these symptoms are in progress.
      The cannabinoid nabilone is currently licensed for use as an antiemetic agent in
      chemotherapy-induced emesis. Evidence suggests that cannabinoids may prove useful
      in Parkinson's disease by inhibiting the excitotoxic neurotransmitter glutamate
      and counteracting oxidative damage to dopaminergic neurons. The inhibitory effect
      of cannabinoids on reactive oxygen species, glutamate and tumour necrosis factor
      suggests that they may be potent neuroprotective agents. Dexanabinol (HU-211), a
      synthetic cannabinoid, is currently being assessed in clinical trials for
      traumatic brain injury and stroke. Animal models of mechanical, thermal and
      noxious pain suggest that cannabinoids may be effective analgesics. Indeed, in
      clinical trials of postoperative and cancer pain and pain associated with spinal
      cord injury, cannabinoids have proven more effective than placebo but may be less
      effective than existing therapies. Dronabinol, a commercially available form of
      delta(9)-THC, has been used successfully for increasing appetite in patients with
      HIV wasting disease, and cannabinoid receptor antagonists may reduce obesity.
      Acute adverse effects following cannabis usage include sedation and anxiety.
      These effects are usually transient and may be less severe than those that occur
      with existing therapeutic agents. The use of nonpsychoactive cannabinoids such as
      cannabidiol and dexanabinol may allow the dissociation of unwanted psychoactive
      effects from potential therapeutic benefits. The existence of other cannabinoid
      receptors may provide novel therapeutic targets that are independent of CB(1)
      receptors (at which most currently available cannabinoids act) and the
      development of compounds that are not associated with CB(1) receptor-mediated
      adverse effects. Further understanding of the most appropriate route of delivery
      and the pharmacokinetics of agents that act via the endocannabinoid system may
      also reduce adverse effects and increase the efficacy of cannabinoid treatment.
      This review highlights recent advances in understanding of the endocannabinoid
      system and indicates CNS disorders that may benefit from the therapeutic effects
      of cannabinoid treatment. Where applicable, reference is made to ongoing clinical
      trials of cannabinoids to alleviate symptoms of these disorders.

PMID- 12617703
TI  - West African crystalline maculopathy.
AB  - OBJECTIVE: To describe the findings of a new crystalline maculopathy exclusively
      affecting elderly members of the Igbo tribe of southeast Nigeria. DESIGN:
      Retrospective, observational noncomparative case series. METHODS: Six patients
      referred over a 2-year period to the medical retina consultation service of the
      King/Drew Medical Center (Los Angeles, Calif) were identified as having a
      characteristic crystalline maculopathy. Each underwent detailed historical
      questioning and comprehensive ocular evaluation, including formal retinal
      examination. Color vision testing, fluorescein angiography, Humphrey visual field
      analysis, and electrophysiologic assessment were also performed. RESULTS: Each of
      the 6 patients was an elderly member of the Igbo tribe of southeast Nigeria and
      demonstrated a unique crystalline maculopathy. A central, superficial cluster of
      green or yellow, refractile, foveal crystals that were bilateral and asymmetric
      in distribution was noted in each case. The crystals were benign and unassociated
      with visual deficit. Retinal sequelae were notably absent and fluorescein
      angiography results were unremarkable. Additional ancillary testing was generally
      normal, although 1 patient demonstrated unexplained mild to moderate depression
      of the scotopic and photopic responses on electrophysiologic analysis.
      CONCLUSIONS: Elderly members of the Igbo tribe of southeast Nigeria may harbor
      characteristic bilateral but asymmetric foveal crystals, comprising a novel
      syndrome of crystalline maculopathy unassociated with obvious visual deficits or
      retinal sequelae. The etiology of this crystalline maculopathy remains unclear,
      although genetic, degenerative, and toxic causes are postulated.

PMID- 12617704
TI  - Vitreous and aqueous penetration of orally administered gatifloxacin in humans.
AB  - OBJECTIVE: To investigate the penetration of gatifloxacin, a novel extended
      spectrum fourth-generation fluoroquinolone antibiotic, into the vitreous and
      aqueous humor after oral administration. METHODS: A prospective, nonrandomized
      study of 24 consecutive patients scheduled for pars plana vitrectomy between
      September 2001 and May 2002 at the Cullen Eye Institute. Aqueous, vitreous, and
      serum samples were obtained and analyzed from 24 patients after administration of
      two 400-mg gatifloxacin tablets taken 12 hours apart before the operation. Assays
      were performed using high-performance liquid chromatography. RESULTS: Mean +/- SD
      gatifloxacin concentrations in serum (n = 23), vitreous (n = 23), and aqueous (n
      = 11) were 5.14 +/- 1.36 micro g/mL, 1.34 +/- 0.34 micro g/mL, and 1.08 +/- 0.54
      micro g/mL respectively. Mean +/- SD sampling times after oral administration of
      the second gatifloxacin tablet for serum, vitreous, and aqueous were 3.2 +/- 1.0
      hours, 4.0 +/- 1.0 hours, and 3.9 +/- 1.1 hours, respectively. The percentages of
      serum gatifloxacin concentration achieved in the vitreous and aqueous were 26.17%
      and 21.02%, respectively. Mean inhibitory vitreous and aqueous MIC(90 ) levels
      were achieved against many pathogens, including Staphylococcus epidermidis,
      Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes,
      Propionibacterium acnes, Haemophilus influenzae, Escherichia coli, Bacillus
      cereus, Proteus mirabilis, and other organisms. CONCLUSIONS: Orally administered
      gatifloxacin achieves therapeutic levels in the noninflamed human eye, and the
      activity spectrum appropriately encompass the bacterial species most frequently
      involved in the various causes of endophthalmitis. Because of its broad-spectrum
      coverage, low MIC(90) levels for the organisms of concern, and good tolerability,
      gatifloxacin represents a major advance in the prophylaxis or treatment of
      postoperative, posttraumatic, and bleb-associated bacterial endophthalmitis.

PMID- 12617705
TI  - Secondary glaucoma in patients with familial amyloidotic polyneuropathy.
AB  - OBJECTIVE: To elucidate the clinical features and surgical outcomes of the
      treatment of secondary glaucoma associated with transthyretin (TTR)-related
      familial amyloidotic polyneuropathy (FAP). DESIGN: Retrospective case study.
      PARTICIPANTS: Forty-nine Japanese patients with FAP. METHODS: For all patients,
      measurement of best-corrected visual acuity, intraocular pressure, and visual
      fields as well as slitlamp and ocular fundus examinations were conducted and
      compared. In addition, the exact mutation of the amyloidogenic TTR variants was
      analyzed for all 49 patients with FAP. The TTR mutations included amyloidogenic
      TTR (ATTR) Val30Met in 41 patients, ATTR Tyr114Cys in 6, ATTR Ser50Ile in 1, and
      a compound heterozygous mutation of ATTR Val30Met + Arg104His in 1. RESULTS: The
      onset of secondary glaucoma was defined as elevation of intraocular pressure and
      glaucomatous changes in visual field defects. Secondary glaucoma was detected in
      12 (24%) of the 49 patients. The incidence of secondary glaucoma in patients with
      the Val30Met mutation (17%) was lower than for the other FAP genotypes (P =.02
      using the chi(2) test). Of 20 glaucomatous eyes, amyloid deposition on the pupil
      and anterior surface of the lens was found in 18 eyes. Amyloid deposition was
      found prior to glaucoma in 11 eyes and at the first visit to our clinic in
      another 7 eyes. In the 11 eyes in which the onset of glaucoma occurred following
      amyloid deposition along the pupil, the mean +/- SD period between the onsets of
      pupillary amyloid deposition and glaucoma was 2.55 +/- 1.43 years (range, 0.2-4.0
      years). Further statistical analyses revealed significant relationships between
      the onset of secondary glaucoma and both amyloid deposition (P<.001) and vitreous
      opacity (P<.001). Surgical treatment was required in 15 (75%) of the 20
      glaucomatous eyes. In 9 (81%) of the 11 eyes that underwent trabeculectomy, the
      intraocular pressure was well controlled at or lower than 20 mm Hg during the
      follow-up period. In the eyes that underwent combined trabeculotomy and
      sinusotomy (2 eyes), nonpenetrating trabeculectomy (1 eye), or a cyclodestructive
      procedure (1 eye), the intraocular pressure was poorly controlled. CONCLUSIONS:
      Glaucoma is not a rare condition in patients with FAP, especially because liver
      transplantation now enables patients with FAP to live longer. Careful observation
      of amyloid deposition along the pupil allows the prediction of glaucoma onset.

PMID- 12617707
TI  - Axon-tracing properties of indocyanine green.
AB  - OBJECTIVE: It has been shown recently that the application of indocyanine green
      (ICG) over the retinal surface is followed by prolonged staining of the optic
      disc. This study was performed to analyze the diffusion of ICG in the optic
      tract. METHODS: Anterograde diffusion of ICG was evaluated after injection into
      the vitreous of rabbits. Retrograde diffusion was evaluated after microinjection
      into the lateral geniculate nucleus of rats. RESULTS: Anterograde and retrograde
      diffusion occurred along the axons at a rate of about 2 mm per hour when ICG was
      injected. Anterograde staining of the visual pathway persisted for several weeks.
      After injection into the lateral geniculate nucleus, fluorescent retinal ganglion
      cells could be visualized for at least 7 days in conscious rats by conventional
      infrared photography. Microscopic examination findings of retrograde-labeled
      retinas showed the presence of ICG vesicles inside the axons, cytoplasm, and
      dendrites of retinal ganglion cells. No evidence of toxic effects was detected by
      optical microscopy. CONCLUSIONS: Indocyanine green is a fast bidirectional axonal
      tracer. Injection into normal vitreous results in long-term staining of the
      visual pathway. In vivo counting of ICG-labeled retinal ganglion cells in rats
      can be performed for several days after injection. Indocyanine green is therefore
      potentially of interest for use in experimental neurophysiological studies.
      CLINICAL RELEVANCE: The present results suggest that in humans, epiretinal
      application of ICG results in prolonged staining of the visual pathway.
      Therefore, additional studies of long-term toxic effects of ICG on neural cells
      are warranted before recommending its use in humans as an intraoperative tool for
      vitreoretinal surgery.

PMID- 12617706
TI  - Treatment of experimental choroidal melanoma with an Nd:yttrium-lanthanum
      fluoride laser at 1047 nm.
AB  - OBJECTIVE: To evaluate the effect of a new infrared laser in the destruction of
      pigmented choroidal melanomas. METHODS: B16F10 melanomas were implanted in the
      subchoroidal space of 64 rabbits (tumor height, 2.0-4.0 mm). Laser radiation from
      an Nd:yttrium-lanthanum-fluoride laser (1047 nm) was delivered as a focused (beam
      waist, 25 micro m; irradiance, 100 kW/cm( 2)) raster-scanned transpupillary beam.
      To investigate melanin heating, treatment with focused light was compared with
      collimated light (beam waist, 2 mm; irradiance, 16 W/cm(2)). Fine-wire
      thermocouples were implanted at the base of 3 tumors for in vivo temperature
      measurements. Untreated animals were used as controls. RESULTS: Of 64 animals, 27
      received a single treatment with focused 1047-nm light. The rate of complete
      tumor eradication was 91% (10 of 11 animals) at a dosage of 125 J/cm(2) and 75%
      (9/12) at 63 J/cm(2) to 87 J/cm(2). The eradication rate dropped to 25% (1 of 4)
      at 38 J/cm(2) or less (P<.001). Continuous tumor growth was observed in all
      animals treated with collimated radiation and in untreated controls. Temperature
      measurements indicated that tissue heating at the tumor base was more rapid at
      1047 nm than at 805 nm. CONCLUSIONS: These data suggest that a single treatment
      with a focused, raster-scanned beam at 1047 nm may play a role in the destruction
      of pigmented choroidal melanoma. Focused irradiation at 1047 nm may provide more
      effective submillisecond heating of melanin than collimated irradiation,
      resulting in immediate photothermal disruption of tumor cells.

PMID- 12617708
TI  - A randomized trial of beta carotene and age-related cataract in US physicians.
AB  - OBJECTIVE: To examine the development of age-related cataract in a trial of beta
      carotene supplementation in men. DESIGN: Randomized, double-masked, placebo
      controlled trial. METHODS: Male US physicians aged 40 to 84 years (n = 22 071)
      were randomly assigned to receive either beta carotene (50 mg on alternate days)
      or placebo for 12 years. MAIN OUTCOME MEASURES: Age-related cataract and
      extraction of age-related cataract, defined as an incident, age-related lens
      opacity, responsible for a reduction in best-corrected visual acuity to 20/30 or
      worse, based on self-report confirmed by medical record review. RESULTS: There
      was no difference between the beta carotene and placebo groups in the overall
      incidence of cataract (998 cases vs 1017 cases; relative risk [RR], 1.00; 95%
      confidence interval [CI], 0.91-1.09) or cataract extraction (584 vs 593; RR,
      1.00; 95% CI, 0.89-1.12). In subgroup analyses, the effect of beta carotene
      supplementation appeared to be modified by smoking status at baseline (P =.02).
      Among current smokers, there were 108 cases of cataract in the beta carotene
      group and 133 in the placebo group (RR, 0.74; 95% CI, 0.57-0.95). Among current
      nonsmokers, there was no significant difference in the number of cases in the 2
      treatment groups (884 vs 881; RR, 1.03; 95% CI, 0.94-1.13). The results for
      cataract extraction appeared to be similarly modified by baseline smoking status
      (P =.05). CONCLUSIONS: Randomized trial data from a large population of healthy
      men indicate no overall benefit or harm of 12 years of beta carotene
      supplementation on cataract or cataract extraction. However, among current
      smokers at baseline, beta carotene appeared to attenuate their excess risk of
      cataract by about one fourth.

PMID- 12617709
TI  - The prevalence of age-related maculopathy in iceland: Reykjavik eye study.
AB  - OBJECTIVE: To examine the age- and sex-specific prevalence of age-related
      maculopathy (ARM) and age-related macular degeneration (AMD) in citizens of
      Reykjavik, Iceland, who were 50 years and older. DESIGN: Random sample, cross
      sectional. MATERIALS AND METHODS: Response rate was 75.8%. The presence and
      severity of various characteristics of drusen and pigmentary changes that are
      typical of ARM and AMD were determined by grading stereoscopic color fundus
      photographs, using the international classification and grading system for ARM
      and AMD. RESULTS: We were able to evaluate 1021 right-eye and 1020 left-eye
      macular photographs. There was no statistically significant difference between
      right and left eyes. In people aged 50 to 59 years, 4.8% of participants (95%
      confidence interval [CI], 2.6-7.0) were found to have intermediate soft drusen
      measuring 63 to 125 micro m in either eye; 1.2% (95% CI, 0.0-2.3) had large soft
      distinct drusen larger than 125 micro m; and 0.6% (95% CI, 0.0-1.4) had large
      soft, crystalline, or semisolid drusen. The same figures for those 80 years and
      older were 18.2% (95% CI, 9.8-26.6), 10.9% (95% CI, 4.0-17.8), and 25.5% (95% CI,
      18.4-32.6), respectively. Geographic atrophy was found in either eye in 9.2% of
      those participants 70 years and older (95% CI, 5.6-12.7), and exudative macular
      degeneration was found in 2.3% of participants 70 years and older (95% CI, 0.5
      4.1). CONCLUSION: Geographic atrophy was found to be more common in our study
      than in other population-based studies.

PMID- 12617710
TI  - Herpes zoster ophthalmicus in olmsted county, Minnesota: have systemic antivirals
      made a difference?
AB  - OBJECTIVE: To determine the frequency of complications and adverse outcomes due
      to herpes zoster ophthalmicus before and after the introduction of oral antiviral
      medications in a community-based setting. METHODS: We identified all Olmsted
      County, Minnesota, residents diagnosed with acute herpes zoster ophthalmicus from
      1976 through 1998. The frequencies of complications within 6 months of disease
      onset were compared between untreated patients vs those treated with antivirals.
      MAIN OUTCOME MEASURES: Defined complications were ocular sequelae due to herpes
      zoster ophthalmicus. Adverse outcomes included visual acuity of 20/200 or worse,
      trichiasis, or eyelid malposition requiring surgical treatment. RESULTS: A total
      of 202 patients had been treated with antivirals, and 121 had not. Neurotrophic
      keratitis was the only complication that was less likely in the treated group
      (3.3% vs 0%; P =.02). The probability of an adverse outcome at 5 and 10 years was
      8.9% among untreated patients and 2.1% among treated patients (P =.009). Among
      patients who had been treated, the mean time from symptom onset to initiation of
      therapy was 4.8 days in those who developed stromal keratitis, corneal edema,
      scleritis, uveitis, or glaucoma compared with 3.8 days in those who did not (P
      =.006). CONCLUSIONS: Neurotrophic keratitis was less frequent among patients who
      received antiviral therapy. However, among treated patients, development of a
      serious inflammatory complication was associated with a delay in therapy. Most
      important, adverse outcomes were less probable in the treated group. These data
      may support the early and routine use of systemic antiviral therapy for acute
      herpes zoster ophthalmicus.

PMID- 12617712
TI  - Clinicopathologic reports, case reports, and small case series: enucleation
      following transpupillary thermotherapy of choroidal melanoma: clinicopathologic
      correlations.

PMID- 12617711
TI  - Imaging a child's fundus without dilation using a handheld confocal scanning
      laser ophthalmoscope.
AB  - Images of the fundus were acquired in children without pupil dilation using a
      prototype handheld confocal scanning laser ophthalmoscope (SLO). A 780-nm laser
      beam imaged a 20 degrees x 20 degrees area of the fundus while a 645-nm beam
      scanned a fixation target. Scorable images of the optic nerve, macula, and
      vessels were obtained in 67 (72%) of 93 eyes from pediatric patients with
      nystagmus, amblyopia, media opacities, or optic nerve or macular abnormalities.
      Images were obtained in all eyes of pediatric and adult controls. Unsuccessful
      imaging was associated with media opacities, high refractive error, and poor
      cooperation. Disadvantages of the SLO were the inability to detect optic nerve
      pallor or consistently image the periphery. Advantages of the SLO were seen in
      children with nystagmus, photophobia, eccentric fixation, cone dystrophy, and
      mild papilledema.

PMID- 12617713
TI  - Clinicopathologic reports, case reports, and small case series:
      fibrovascularization of porous polyethylene orbital floor implants in humans.

PMID- 12617714
TI  - Clinicopathologic reports, case reports, and small case series: peripheral
      pigmented corneal ring: a new finding in hypercarotenemia.

PMID- 12617715
TI  - Clinicopathologic reports, case reports, and small case series: usher syndrome
      type 1 associated with primary ciliary aplasia.

PMID- 12617716
TI  - Clinicopathologic reports, case reports, and small case series: congenital
      anomalous retinal artery associated with a leaking macroaneurysm.

PMID- 12617717
TI  - Photo essay: bilateral sclerosing orbital pseudotumor with intracranial spread.

PMID- 12617718
TI  - Improvement after verteporfin therapy.

PMID- 12617719
TI  - AREDS misses on safety.

PMID- 12617720
TI  - Greater than predicted decrease in energy expenditure during exercise after body
      weight loss in obese men.
AB  - This study was performed retrospectively to investigate whether exercise energy
      expenditure (EE) measured during a standardized treadmill protocol (4.5 km/h at
      0% grade) falls below predicted values after body weight loss in obese men. A
      reference equation was established to predict net exercise EE in a control sample
      of 83 obese individuals (27 kg/m(2)< or = body mass index <45 kg/m(2)), using
      age, fat mass and fat-free mass as independent variables. This equation was then
      used to predict net exercise EE in another group of 11 obese men before and after
      a 15-week drug-based weight loss programme that was coupled with energy
      restriction [-2929 kJ/day (-700 kcal/day)]. Body weight and body composition were
      determined by hydrodensitometry. Net exercise EE, insulin, leptin, 3,3',5-tri
      iodothyronine and free thyroxine were measured after an overnight fast at
      baseline and 2-4 weeks after the end of the programme, when subjects were weight
      stable. Body weight was significantly reduced (-11%; P <0.01) at the end of the
      weight loss programme. At baseline, measured net exercise EE was similar to that
      predicted from the regression equation [19.6 and 19.8 kJ/min (4.69 and 4.74
      kcal/min) respectively; not significant]. However, after the end of the
      intervention, measured net exercise EE was significantly below the predicted
      value [15.5 and 17.3 kJ/min (3.71 and 4.14 kcal/min) respectively; P <0.01]. The
      difference between the predicted and the measured fall in net exercise EE was
      significantly associated with changes in leptin concentration ( r =0.79, P
      <0.01), even after correction for changes in fat mass and insulin. These
      observations suggest that net exercise EE falls below predicted values after body
      weight loss. In addition, this greater than predicted decrease in net exercise EE
      was associated with changes in leptin.

PMID- 12617721
TI  - The structure and regulation of the human and mouse matrix metalloproteinase-21
      gene and protein.
AB  - Matrix metalloproteinases (MMPs) play key roles in tissue remodelling under
      normal development and, especially, in diseases ranging from malignancies to
      stroke. We cloned and thoroughly characterized the novel human and mouse MMP gene
      encoding MMP-21. MMP-21 is the last uncharacterized MMP coded by the human
      genome. Human and mouse MMP-21 is the orthologue of Xenopus laevis X-MMP. The
      latent proenzyme of MMP-21 (569 amino acid residues) consists of the prodomain,
      the catalytic domain and the haemopexin-like domain, and is potentially capable
      of being activated in its secretory pathway to the extracellular milieu by furin
      like proprotein convertases. Human MMP-21 is the probable target gene of the Wnt
      pathway. In addition, the expression of MMP-21 is controlled uniquely by Pax and
      Notch transcription factors known to be critical for organogenesis. MMP-21 is
      expressed transiently in mouse embryogenesis and increased in embryonic neuronal
      tissues. Our observations clearly indicate that there is an important specific
      function for MMP-21 in embryogenesis, especially in neuronal cells.

PMID- 12617722
TI  - cGMP-dependent protein kinase protects cGMP from hydrolysis by phosphodiesterase
      5.
AB  - The physiological effects of cGMP are largely determined by the activities of
      intracellular receptors, including cGMP-dependent protein kinase (PKG) and cGMP
      binding cyclic nucleotide phosphodiesterases (PDEs), and the distribution of cGMP
      among these receptors dictates activity of the signalling pathway. In the present
      study, the effects of PKG-Ialpha or PKG-Ibeta on the rate of cGMP hydrolysis by
      the isolated PDE5 catalytic domain were examined. PKG-Ialpha strongly inhibited
      cGMP hydrolysis with an IC(50) value of 217 nM, which is similar to the
      physiological concentration of PKG in pig coronary artery reported previously. By
      contrast, PKG-Ibeta, which has lower affinity for cGMP than does PKG-Ialpha,
      inhibited cGMP hydrolysis with an IC(50) of approx. 1 microM. Inhibition by PKG
      Ialpha was more effective than that by PKG-Ibeta, consistent with their relative
      affinities for cGMP. Autophosphorylation of PKGs increased their cGMP-binding
      affinities and their inhibitory effects on PDE5 hydrolysis of cGMP.
      Autophosphorylation of PKG-Ibeta increased its inhibitory potency on PDE5
      hydrolysis of cGMP by 10-fold compared with a 2-fold increase upon
      autophosphorylation of PKG-Ialpha. The results indicate that cGMP bound to
      allosteric cGMP-binding sites of PKG is protected from hydrolysis by PDE5 and
      that persistent protection of cGMP by either non-phosphorylated or
      autophosphorylated PKGs may be a positive-feedback control to sustain cGMP
      signalling.

PMID- 12617723
TI  - Induction of ASABF (Ascaris suum antibacterial factor)-type antimicrobial
      peptides by bacterial injection: novel members of ASABF in the nematode Ascaris
      suum.
AB  - Recently, invertebrate models have been widely used for the study of innate
      immunity. Nematodes are novel potential candidates because of the experimental
      advantages of Caenorhabditis elegans. However, whether nematodes have active
      immune responses is still ambiguous. Previously, we reported ASABF (Ascaris suum
      antibacterial factor)-type antimicrobial peptides in the parasitic nematode
      Ascaris suum and the genetic model nematode C. elegans. Further screening of a
      cDNA library and an expressed-sequence-tag database search detected five novel
      members of ASABF (ASABF-beta, -gamma, -delta, - epsilon and -zeta) in A. suum.
      The transcripts for ASABF-alpha, -beta, -gamma, and -delta clearly increased in
      the body wall, and also in the intestine for ASABF-delta, 4 h after injection of
      heat-killed bacteria into the pseudocoelom (body cavity), suggesting that these
      peptides are inducible in the acute phase of immune response. These results also
      suggest that the nematodes can recognize bacteria in the pseudocoelomic fluid and
      evoke an active immune response.

PMID- 12617724
TI  - Structural analysis of xylanase inhibitor protein I (XIP-I), a proteinaceous
      xylanase inhibitor from wheat (Triticum aestivum, var. Soisson).
AB  - A novel class of proteinaceous inhibitors exhibiting specificity towards
      microbial xylanases has recently been discovered in cereals. The three
      dimensional structure of xylanase inhibitor protein I (XIP-I) from wheat
      (Triticum aestivum, var. Soisson) was determined by X-ray crystallography at 1.8
      A (1 A=0.1 nm) resolution. The inhibitor possesses a (beta/alpha)(8) barrel fold
      and has structural features typical of glycoside hydrolase family 18, namely two
      consensus regions, approximately corresponding to the third and fourth barrel
      strands, and two non-proline cis -peptide bonds, Ser(36)-Phe and Trp(256)-Asp (in
      XIP-I numbering). However, detailed structural analysis of XIP-I revealed several
      differences in the region homologous with the active site of chitinases. The
      catalytic glutamic acid residue of family 18 chitinases [Glu(127) in hevamine, a
      chitinase/lysozyme from the rubber tree (Hevea brasiliensis)] is conserved in the
      structure of the inhibitor (Glu(128)), but its side chain is fully engaged in
      salt bridges with two neighbouring arginine residues. Gly(81), located in subsite
      -1 of hevamine, where the reaction intermediate is formed, is replaced by Tyr(80)
      in XIP-I. The tyrosine side chain fills the subsite area and makes a strong
      hydrogen bond with the side chain of Glu(190) located at the opposite side of the
      cleft, preventing access of the substrate to the catalytic glutamic acid. The
      structural differences in the inhibitor cleft structure probably account for the
      lack of activity of XIP-I towards chitin.

PMID- 12617725
TI  - Partial characterization of cell-type X collagen interactions.
AB  - Type X collagen is a short-chain non-fibrillar collagen that is deposited
      exclusively at sites of new bone formation. Although this collagen has been
      implicated in chondrocyte hypertrophy and endochondral ossification, its precise
      function remains unclear. One possible function could be to regulate the
      processes of chondrocyte hypertrophy through direct cell-type X collagen
      interactions. Adhesions of embryonic chick chondrocytes, and cell lines with
      known expression of collagen-binding integrins (MG63 and HOS), were assayed on
      chick type X collagen substrates, including the native, heat-denatured and pepsin
      digested collagen, and the isolated C-terminal non-collagenous (NC1) domain. Type
      X collagen supported the greatest level of adhesion for all cell types tested.
      The involvement of the alpha2beta1 integrin in type X collagen-cell interaction
      was demonstrated by adhesion studies in the presence of Mg(2+) and Ca(2+) ions
      and integrin-function-blocking antibodies. Cells expressing alpha2beta1 integrin
      (chick chondrocytes and MG63 cells) also adhered to heat-denatured type X
      collagen and the isolated NC1 domain; however, removal of the non-collagenous
      domains by limited pepsinization of type X collagen resulted in very low levels
      of adhesion. Both focal contacts and actin stress-fibre formation were apparent
      in cells plated on type X collagen. The presence of alpha2 and beta1 integrin
      subunits in isolated chondrocytes and epiphyseal cartilage was also confirmed by
      immunolocalization. Our results demonstrate, for the first time, that type X
      collagen is capable of interacting directly with chondrocytes and other cells,
      primarily via alpha2beta1 integrin. These findings are atypical from the
      fibrillar collagen-cell interactions via collagen binding integrins in that: (1)
      the triple-helical conformation is not strictly required for cell adhesion; (2)
      the NC1 domain is also involved in the adhesion of alpha2beta1-expressing cells.
      These data form the basis for further studies into the mechanism and biological
      significance of type X collagen deposition in the growth plate.

PMID- 12617726
TI  - Mutagenesis of the HMGB (high-mobility group B) protein Cmb1 (cytosine-mismatch
      binding 1) of Schizosaccharomyces pombe: effects on recognition of DNA mismatches
      and damage.
AB  - Cmb1 (cytosine-mismatch binding 1) is a high-mobility group (HMG) protein of
      Schizosaccharomyces pombe, which consists of 223 amino acids and has a single HMG
      domain at the C-terminal end. We have created several mutant and deletion forms
      of the Cmb1 protein and studied the effects on general DNA binding and specific
      binding to DNA mismatches and damaged DNA. Cmb1Delta41 (i.e. Cmb1 from which the
      41 N-terminal amino acids have been deleted) bound specifically to cytosine
      containing mismatches, to the cisplatin-induced intrastrand cross-links cis -GG
      and cis -AG and to an O (6)-methylguanine lesion. DNA binding was not affected
      when the 45 N-terminal amino acids were deleted, but was abolished in the absence
      of the 50 N-terminal amino acids, and was reduced when Cmb1 was truncated by
      between five and eleven C-terminal amino acids. Cmb1, both with and without the C
      terminal truncations, retained its DNA binding affinity after heating at 95
      degrees C. The cmb1 gene was induced when S. pombe cells were treated with
      cisplatin. Mitotic mutation rates were increased in a S. pombe cmb1 null mutant
      and in a cmb1-(1-212) mutant, which encodes a Cmb1 protein lacking the 11 C
      terminal amino acids. We conclude that mutation avoidance by Cmb1 is distinct
      from Msh2-dependent mismatch repair, but related to nucleotide excision repair.

PMID- 12617727
TI  - The Surviving Sepsis Campaign: raising awareness to reduce mortality.

PMID- 12617728
TI  - The International Sepsis Forum's controversies in sepsis: my initial vasopressor
      agent in septic shock is norepinephrine rather than dopamine.

PMID- 12617729
TI  - The International Sepsis Forum's controversies in sepsis: my initial vasopressor
      agent in septic shock is dopamine rather than norepinephrine.

PMID- 12617731
TI  - Recruitment and retention of lung volume.

PMID- 12617732
TI  - Beyond ethical dilemmas: improving the quality of end-of-life care in the
      intensive care unit.

PMID- 12617733
TI  - Glucose-insulin-potassium infusion in sepsis and septic shock: no hard evidence
      yet.

PMID- 12617735
TI  - Recently published papers: a number of treatment controversies.

PMID- 12617736
TI  - The optimal endpoint of resuscitation in trauma patients.

PMID- 12617737
TI  - ICUs worldwide: a brief description of intensive care development in Argentina.

PMID- 12617739
TI  - Science review: key inflammatory and stress pathways in critical illness - the
      central role of the Toll-like receptors.
AB  - A pure reductionist approach can sometimes be used to solve an exceptionally
      complicated biologic problem, and sepsis is nothing if not complicated. A serious
      infection promptly leads to changes in many aspects of host physiology, including
      alterations in circulation, metabolism, renal, hepatic, and neuroendocrine
      function; all of these changes happen at once, and each influences one another.
      It is difficult to tease apart a problem of this sort, if only because the
      systems affected are so profoundly interactive. The key to understanding sepsis,
      insofar as we do understand it at present, was found in the use of genetic tools
      to study the very earliest events that take place at the interface of the
      pathogen and the host. The continued application of both forward and reverse
      genetic methods, in both mammals and insects, is steadily revealing the central
      biochemical events that occur during infection.

PMID- 12617741
TI  - Lung recruitment manoeuvres are effective in regaining lung volume and
      oxygenation after open endotracheal suctioning in acute respiratory distress
      syndrome.
AB  - INTRODUCTION: Lung collapse is a contributory factor in the hypoxaemia that is
      observed after open endotracheal suctioning (ETS) in patients with acute lung
      injury and acute respiratory distress syndrome. Lung recruitment (LR) manoeuvres
      may be effective in rapidly regaining lung volume and improving oxygenation after
      ETS. MATERIALS AND METHOD: A prospective, randomized, controlled study was
      conducted in a 15-bed general intensive care unit at a university hospital. Eight
      consecutive mechanically ventilated patients with acute lung injury or acute
      respiratory distress syndrome were included. One of two suctioning procedures was
      performed in each patient. In the first procedure, ETS was performed followed by
      LR manoeuvre and reconnection to the ventilator with positive end-expiratory
      pressure set at 1 cmH2O above the lower inflexion point, and after 60 min another
      ETS (but without LR manoeuvre) was performed followed by reconnection to the
      ventilator with similar positive end-expiratory pressure; the second procedure
      was the same as the first but conducted in reverse order. Before (baseline) and
      over 25 min following each ETS procedure, partial arterial oxygen tension (PaO2)
      and end-expiratory lung volume were measured. RESULTS: After ETS, PaO2 decreased
      by 4.3(0.9-9.7)kPa (median and range; P < 0.005). After LR manoeuvre, PaO2
      recovered to baseline. Without LR manoeuvre, PaO2 was reduced (P = 0.05) until 7
      min after ETS. With LR manoeuvre end-expiratory lung volume was unchanged after
      ETS, whereas without LR manoeuvre end-expiratory lung volume was still reduced
      (approximately 10%) at 5 and 15 min after ETS (P = 0.01). DISCUSSION: A LR
      manoeuvre immediately following ETS was, as an adjunct to positive end-expiratory
      pressure, effective in rapidly counteracting the deterioration in PaO2 and lung
      volume caused by open ETS in ventilator-treated patients with acute lung injury
      or acute respiratory distress syndrome.

PMID- 12617738
TI  - Bench-to-bedside review: functional relationships between coagulation and the
      innate immune response and their respective roles in the pathogenesis of sepsis.
AB  - The innate immune response system is designed to alert the host rapidly to the
      presence of an invasive microbial pathogen that has breached the integument of
      multicellular eukaryotic organisms. Microbial invasion poses an immediate threat
      to survival, and a vigorous defense response ensues in an effort to clear the
      pathogen from the internal milieu of the host. The innate immune system is able
      to eradicate many microbial pathogens directly, or innate immunity may indirectly
      facilitate the removal of pathogens by activation of specific elements of the
      adaptive immune response (cell-mediated and humoral immunity by T cells and B
      cells). The coagulation system has traditionally been viewed as an entirely
      separate system that has arisen to prevent or limit loss of blood volume and
      blood components following mechanical injury to the circulatory system. It is
      becoming increasingly clear that coagulation and innate immunity have coevolved
      from a common ancestral substrate early in eukaryotic development, and that these
      systems continue to function as a highly integrated unit for survival defense
      following tissue injury. The mechanisms by which these highly complex and
      coregulated defense strategies are linked together are the focus of the present
      review.

PMID- 12617740
TI  - Science review: redox and oxygen-sensitive transcription factors in the
      regulation of oxidant-mediated lung injury: role for hypoxia-inducible factor
      1alpha.
AB  - A progressive rise of oxidative stress due to altered reduction-oxidation (redox)
      homeostasis appears to be one of the hallmarks of the processes that regulate
      gene transcription in physiology and pathophysiology. Reactive oxygen species and
      reactive nitrogen species serve as signaling messengers for the evolution and
      perpetuation of the inflammatory process that is often associated with the
      condition of oxidative stress, which involves genetic regulation. Changes in the
      pattern of gene expression through reactive oxygen species/reactive nitrogen
      species-sensitive regulatory transcription factors are crucial components of the
      machinery that determines cellular responses to oxidative/redox conditions. The
      present review describes the basic components of the intracellular
      oxidative/redox control machinery and its crucial regulation of oxygen-sensitive
      and redox-sensitive transcription factors within the context of lung injury.
      Particularly, the review discusses mechanical ventilation and NF-kappaB-mediated
      lung injury, ischemia-reperfusion and transplantation, compromised host defense
      and inflammatory stimuli, and hypoxemia and the crucial role of hypoxia-inducible
      factor in mediating lung injury. Changes in the pattern of gene expression
      through regulatory transcription factors are therefore crucial components of the
      machinery that determines cellular responses to oxidative/redox stress.

PMID- 12617742
TI  - Effects of contrast material on computed tomographic measurements of lung volumes
      in patients with acute lung injury.
AB  - BACKGROUND: Intravenous injection of contrast material is routinely performed in
      order to differentiate nonaerated lung parenchyma from pleural effusion in
      critically ill patients undergoing thoracic computed tomography (CT). The aim of
      the present study was to evaluate the effects of contrast material on CT
      measurement of lung volumes in 14 patients with acute lung injury. METHOD: A
      spiral thoracic CT scan, consisting of contiguous axial sections of 10 mm
      thickness, was performed from the apex to the diaphragm at end-expiration both
      before and 30 s (group 1; n = 7) or 15 min (group 2; n = 7) after injection of 80
      ml contrast material. Volumes of gas and tissue, and volumic distribution of CT
      attenuations were measured before and after injection using specially designed
      software (Lungview; Institut National des Telecommunications, Evry, France). The
      maximal artifactual increase in lung tissue resulting from a hypothetical leakage
      within the lung of the 80 ml contrast material was calculated. RESULTS: Injection
      of contrast material significantly increased the apparent volume of lung tissue
      by 83 +/- 57 ml in group 1 and 102 +/- 80 ml in group 2, whereas the
      corresponding maximal artifactual increases in lung tissue were 42 +/- 52 ml and
      31 +/- 18 ml. CONCLUSION: Because systematic injection of contrast material
      increases the amount of extravascular lung water in patients with acute lung
      injury, it seems prudent to avoid this procedure in critically ill patients
      undergoing a thoracic CT scan and to reserve its use for specific indications.

PMID- 12617743
TI  - Cost of intensive care in a Norwegian University hospital 1997-1999.
AB  - AIM: The present study was performed in order to document costs of intensive care
      in a Norwegian university hospital and to perform an average cost-effectiveness
      study using the expected remaining life-years in survivors after 18 months.
      MATERIALS AND METHODS: Patients admitted to the general intensive care unit (ICU)
      at Haukeland University Hospital from 1997 to 1999 were followed up to 18 months
      post ICU using data from the Norwegian Peoples' registry. Our ICU patients have a
      further mortality equal to the average population in Norway from that time. By
      creating an age-matched and sex-matched sample of the general Norwegian
      population equal to survivors 18 months after ICU treatment, we could find the
      expected further survival time for each ICU survivor. Direct and indirect ICU
      expenses in the study period were retrieved using a 'top-down' method. Outcome
      assessment was performed using the total ICU expenses in the period divided by
      the sum of the life expectancy (years) in survivors after 18 months. RESULTS: The
      total ICU costs (converted to 2001 values) were 16,697,415, excluding the costs
      of radiology and the use of operating theatres, which were both impossible to
      retrieve. A total of 1051 patients were treated, of whom 60.9% survived up to 18
      months. Further total life expectancies were 24,428 years. The average costs of
      an ICU day and stay per patient were 2601 and 14,223, respectively, and the
      average cost per year of survival per patient was 684. DISCUSSION: The absolute
      costs were found to be higher than recent European ICU studies reporting on the
      cost of ICU treatment. However, the price of a further life-year in survivors was
      lower and was comparable with other medical treatment.

PMID- 12617744
TI  - Esophageal capnometry during hemorrhagic shock and after resuscitation in rats.
AB  - BACKGROUND: Splanchnic perfusion following hypovolemic shock is an important
      marker of adequate resuscitation. We tested whether the gap between esophageal
      partial carbon dioxide tension (PeCO2) and arterial partial carbon dioxide
      tension (PaCO2) is increased during graded hemorrhagic hypotension and reversed
      after blood reinfusion, using a fiberoptic carbon dioxide sensor. MATERIALS AND
      METHOD: Ten Sprague-Dawley rats were anesthetized, tracheotomized, and cannulated
      in one femoral artery and vein. A calibrated fiberoptic PCO2 probe was inserted
      into the distal third of the esophagus for determination of luminal PeCO2 during
      maintained anesthesia (pentobarbital 15 mg/kg per hour), normothermia (38 +/- 0.5
      degrees C), and fluid balance (saline 5 ml/kg per hour). Three out of 10 rats
      were used to determine the limits of hemodynamic stability during gradual
      hemorrhage. Seven of the 10 rats were then subjected to mild and severe
      hemorrhage (15 and 20-25 ml/kg, respectively). Thirty minutes after severe
      hemorrhage, these rats were resuscitated by reinfusion of the shed blood.
      Arterial gas exchange, hemodynamic variables, and PeCO2 were recorded at each
      steady-state level of hemorrhage (at 30 and 60 min) and after resuscitation.
      RESULTS: The PeCO2-PaCO2 gap was significantly increased after mild and severe
      hemorrhage and returned to baseline (prehemorrhagic) values following blood
      reinfusion. Base deficit increased significantly following severe hemorrhage and
      remained significantly elevated after blood reinfusion. Significant correlations
      were found between base deficit and PeCO2-PaCO2 (P < 0.002) and PeCO2 (P <
      0.022). Blood bicarbonate concentration decreased significantly following mild
      and severe hemorrhage, but its recovery was not complete at 60 min after blood
      reinfusion. CONCLUSION: Esophageal-arterial PCO2 gap increases during graded
      hemorrhagic hypotension and returns to baseline value after resuscitation without
      complete reversal of the base deficit. These data suggest that esophageal
      capnometry could be used as an alternative for gastric tonometry during
      management of hypovolemic shock.

PMID- 12617745
TI  - Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit.
AB  - INTRODUCTION: The diagnosis of sepsis in critically ill patients is challenging
      because traditional markers of infection are often misleading. The present study
      was conducted to determine the procalcitonin level at early diagnosis (and
      differentiation) in patients with systemic inflammatory response syndrome (SIRS)
      and sepsis, in comparison with C-reactive protein, IL-2, IL-6, IL-8 and tumour
      necrosis factor-alpha. METHOD: Thirty-three intensive care unit patients were
      diagnosed with SIRS, sepsis or septic shock, in accordance with the American
      College of Chest Physicians/Society of Critical Care Medicine consensus criteria.
      Blood samples were taken at the first and second day of hospitalization, and on
      the day of discharge or on the day of death. For multiple group comparisons one
      way analysis of variance was applied, with post hoc comparison. Sensitivity,
      specificity and predictive values of PCT and each cytokine studied were
      calculated. RESULTS: PCT, IL-2 and IL-8 levels increased in parallel with the
      severity of the clinical condition of the patient. PCT exhibited a greatest
      sensitivity (85%) and specificity (91%) in differentiating patients with SIRS
      from those with sepsis. With respect to positive and negative predictive values,
      PCT markedly exceeded other variables. DISCUSSION: In the present study PCT was
      found to be a more accurate diagnostic parameter for differentiating SIRS and
      sepsis, and therefore daily determinations of PCT may be helpful in the follow up
      of critically ill patients.

PMID- 12617746
TI  - 15th Annual Congress of the European Society of Intensive Care Medicine, 29
      September-2 October 2002, Barcelona, Spain: clinical research to improve outcome.

PMID- 12617748
TI  - Quantification of anandamide content in animal cells and tissues: the
      normalization makes the difference.
AB  - Anandamide (N-arachidonoylethanolamine, AEA) is an endogenous lipid that binds to
      cannabinoid receptors in the central nervous system and in peripheral cells.
      Quantitative analysis of AEA is generally based on the normalization to the fresh
      weight of the samples. Here, we show that the normalization procedure of AEA
      content is such a critical factor, that it might introduce per se significant
      discrepancies in the quantification of AEA even in the same sample. We suggest
      that a rapid, accurate and most reliable reference to quantify AEA and congeners
      from different sources is the protein content, a common parameter to cells and
      tissues.

PMID- 12617747
TI  - Epidermal anti-Inflammatory properties of 5,11,14 20:3: effects on mouse ear
      edema, PGE2 levels in cultured keratinocytes, and PPAR activation.
AB  - BACKGROUND: 5,11,14 20:3 is similar to 20:4n-6 but lacks the internal Delta8
      double bond essential for prostaglandin and eicosanoid synthesis. When previously
      fed to laboratory animals as a gymnosperm seed oil component it has shown anti
      inflammatory properties. RESULTS: Herein, topically applied Podocarpus nagi
      methyl esters (containing 26% 5,11,14 20:3) were incorporated into mouse ear
      phospholipids, reduced 20:4n-6, and reduced 20:4n-6- and TPA-induced mouse ear
      edema. Purified 5,11,14 20:3 was taken up by cultured human skin keratinocytes,
      reduced 20:4n-6, and reduced PGE2 levels dramatically. Purified 5,11,14 20:3 did
      not affect PPARalpha, PPARgamma, or PPARdelta transactivation. CONCLUSIONS:
      Topical application of 5,11,14 20:3 to skin surfaces can thus reduce inflammatory
      processes, most likely by displacing 20:4n-6 from phospholipid pools and reducing
      downstream inflammatory products derived from 20:4n-6 such as PGE2 and
      leukotrienes. It could have potential use in treating clinical skin disorders
      resulting from overproduction of 20:4n-6-derived eicosanoid products.

PMID- 12617749
TI  - Effects of dietary lipids on cell proliferation of murine oral mucosa.
AB  - BACKGROUND: The lack of certain essential polyunsaturated fatty acids (PUFAs)
      induces perturbation in cell proliferation, apoptosis and dedifferentiation that
      could be linked to an increased protumorigenic trend. Contrarily, n-3 essential
      fatty acids (EFAs) arrest cell proliferation in several tumor models. According
      to the concept of field cancerization, multiple patches of abnormal epithelial
      proliferation may coexist in the vicinity of oropharyngeal neoplasms. The purpose
      of the present study is to determine whether certain dietary PUFAs differentially
      modulate the patterns of cell proliferation and apoptosis at non-tumoral sites of
      the oral mucosa in mice bearing DMBA induced salivary tumors. After weaning,
      BALB/c mice were assigned to four diets: Control (C), Corn Oil (CO), Fish (FO)
      and Olein (O). Two weeks later, DMBA was injected into the submandibular area.
      The animals were sacrificed between 94 and 184 days at 4-6 PM. Fixed samples of
      lip, tongue and palate were stained using H-E and a silver technique. A
      quantification of AgNORs in the basal (BS) and suprabasal stratum (SBS) of the
      covering squamous epithelia as well as of mitosis and apoptosis was performed.
      RESULTS: Analysis of Variance showed greater proliferation in tongue than in
      palate or lip. According to the diet, a significant difference was found in the
      Fish Oil, in which palate exhibited fewer AgNOR particles than that of the
      control group, both for BS and SBS (p < 0.05 and 0.152, respectively), indicating
      a reduced cell proliferation. CONCLUSIONS: These results corroborate and reaffirm
      that the patterns of cell proliferation, apoptosis and differentiation of the
      oral stratified squamous epithelium may be differentially modulated by dietary
      lipids, and arrested by n-3 fatty acids, as shown in several other cell
      populations.

PMID- 12617751
TI  - Anandamide uptake by synaptosomes from human, mouse and rat brain: inhibition by
      glutamine and glutamate.
AB  - Anandamide (N-arachidonoylethanolamine, AEA) belongs to an emerging class of
      endogenous lipids, called "endocannabinoids". A specific AEA membrane transporter
      (AMT) allows the import of this lipid and its degradation by the intracellular
      enzyme AEA hydrolase. Here, we show that synaptosomes from human, mouse and rat
      brain might be an ideal ex vivo system for the study of: i) the accumulation of
      AEA in brain, and ii) the pharmacological properties of AMT inhibitors. Using
      this ex vivo system, we demonstrate for the first time that glutamine and
      glutamate act as non-competitive inhibitors of AEA uptake by human, mouse and rat
      brain AMT.

PMID- 12617750
TI  - Dietary effects of arachidonate-rich fungal oil and fish oil on murine hepatic
      and hippocampal gene expression.
AB  - BACKGROUND: The functions, actions, and regulation of tissue metabolism affected
      by the consumption of long chain polyunsaturated fatty acids (LC-PUFA) from fish
      oil and other sources remain poorly understood; particularly how LC-PUFAs affect
      transcription of genes involved in regulating metabolism. In the present work,
      mice were fed diets containing fish oil rich in eicosapentaenoic acid and
      docosahexaenoic acid, fungal oil rich in arachidonic acid, or the combination of
      both. Liver and hippocampus tissue were then analyzed through a combined gene
      expression- and lipid- profiling strategy in order to annotate the molecular
      functions and targets of dietary LC-PUFA. RESULTS: Using microarray technology,
      329 and 356 dietary regulated transcripts were identified in the liver and
      hippocampus, respectively. All genes selected as differentially expressed were
      grouped by expression patterns through a combined k-means/hierarchical clustering
      approach, and annotated using gene ontology classifications. In the liver, groups
      of genes were linked to the transcription factors PPARalpha, HNFalpha, and SREBP
      1; transcription factors known to control lipid metabolism. The pattern of
      differentially regulated genes, further supported with quantitative lipid
      profiling, suggested that the experimental diets increased hepatic beta-oxidation
      and gluconeogenesis while decreasing fatty acid synthesis. Lastly, novel
      hippocampal gene changes were identified. CONCLUSIONS: Examining the broad
      transcriptional effects of LC-PUFAs confirmed previously identified PUFA-mediated
      gene expression changes and identified novel gene targets. Gene expression
      profiling displayed a complex and diverse gene pattern underlying the biological
      response to dietary LC-PUFAs. The results of the studied dietary changes
      highlighted broad-spectrum effects on the major eukaryotic lipid metabolism
      transcription factors. Further focused studies, stemming from such transcriptomic
      data, will need to dissect the transcription factor signaling pathways to fully
      explain how fish oils and arachidonic acid achieve their specific effects on
      health.

PMID- 12617752
TI  - Comparison of the responses of the chorda tympani and glossopharyngeal nerves to
      taste stimuli in C57BL/6J mice.
AB  - BACKGROUND: Recent progress in discernment of molecular pathways of taste
      transduction underscores the need for comprehensive phenotypic information for
      the understanding of the influence of genetic factors in taste. To obtain
      information that can be used as a base line for assessment of effects of genetic
      manipulations in mice taste, we have recorded the whole-nerve integrated
      responses to a wide array of taste stimuli in the chorda tympani (CT) and
      glossopharyngeal (NG) nerves, the two major taste nerves from the tongue.
      RESULTS: In C57BL/6J mice the responses in the two nerves were not the same. In
      general sweeteners gave larger responses in the CT than in the NG, while
      responses to bitter taste in the NG were larger. Thus the CT responses to
      cyanosuosan, fructose, NC00174, D-phenylalanline and sucrose at all
      concentrations were significantly larger than in the NG, whereas for acesulfame
      K, L-proline, saccharin and SC45647 the differences were not significant. Among
      bitter compounds amiloride, atropine, cycloheximide, denatonium benzoate, L
      phenylalanine, 6-n-propyl-2-thiouracil (PROP) and tetraethyl ammonium chloride
      (TEA) gave larger responses in the NG, while the responses to brucine,
      chloroquine, quinacrine, quinine hydrochloride (QHCl), sparteine and strychnine,
      known to be very bitter to humans, were not significantly larger in the NG than
      in the CT. CONCLUSION: These data provide a comprehensive survey and comparison
      of the taste sensitivity of the normal C57BL/6J mouse against which the effects
      of manipulations of its gustatory system can be better assessed.

PMID- 12617754
TI  - Molecular cloning and characterization of Escherichia coli K12 ygjG gene.
AB  - BACKGROUND: Putrescine is the intermediate product of arginine decarboxylase
      pathway in Escherichia coli which can be used as an alternative nitrogen source.
      Transaminase and dehydrogenase enzymes seem to be implicated in the degradative
      pathway of putrescine, in which this compound is converted into gamma
      aminobutyrate. But genes coding for these enzymes have not been identified so
      far. RESULTS: The 1.8-kbp DNA fragment containing E. coli K12 ygjG gene with aer
      ygjG intergenic region was examined. It was found that the fragment contains
      sigma54-depended open reading frame (ORF) of 1,380 nucleotides encoding a 459
      amino acid polypeptide of approximately 49.6 kDa. The cytidine (C) residue
      localized 10 bp downstream of the sigma54 promoter sequence was identified as the
      first mRNA base. The UUG translation initiation codon is situated 36 nucleotides
      downstream of the mRNA start. The YgjG was expressed as a his6-tag fused protein
      and purified to homogeneity. The protein catalyzed putrescine:2-oxoglutaric acid
      (2-OG) aminotransferase reaction (PATase, EC 2.6.1.29). The Km values for
      putrescine and 2-OG were found to be 9.2 mM and 19.0 mM, respectively. The
      recombinant enzyme also was able to transaminate cadaverine and, in lower extent,
      spermidine, and gave maximum activity at pH 9.0. CONCLUSION: Expression of E.
      coli K12 ygjG coding region revealed sigma54-depended ORF which encodes a 459
      amino acid protein with putrescine:2-OG aminotransferase activity. The enzyme
      also was able to transaminate cadaverine and, in lower extent, spermidine.

PMID- 12617753
TI  - Mapping of neurokinin-like immunoreactivity in the human brainstem.
AB  - BACKGROUND: Using an indirect immunoperoxidase technique, we have studied the
      distribution of immunoreactive fibers and cell bodies containing neurokinin in
      the adult human brainstem with no prior history of neurological or psychiatric
      disease. RESULTS: Clusters of immunoreactive cell bodies and high densities of
      neurokinin-immunoreactive fibers were located in the periaqueductal gray, the
      dorsal motor nucleus of the vagus and in the reticular formation of the medulla,
      pons and mesencephalon. Moreover, immunoreactive cell bodies were found in the
      inferior colliculus, the raphe obscurus, the nucleus prepositus hypoglossi, and
      in the midline of the anterior medulla oblongata. In general, immunoreactive
      fibers containing neurokinin were observed throughout the whole brainstem. In
      addition to the nuclei mentioned above, the highest densities of such
      immunoreactive fibers were located in the spinal trigeminal nucleus, the lateral
      reticular nucleus, the nucleus of the solitary tract, the superior colliculus,
      the substantia nigra, the nucleus ambiguus, the gracile nucleus, the cuneate
      nucleus, the motor hypoglossal nucleus, the medial and superior vestibular
      nuclei, the nucleus prepositus hypoglossi and the interpeduncular nucleus.
      CONCLUSION: The widespread distribution of immunoreactive structures containing
      neurokinin in the human brainstem indicates that neurokinin might be involved in
      several physiological mechanisms, acting as a neurotransmitter and/or
      neuromodulator.

PMID- 12617756
TI  - KV2.1 K+ channels underlie major voltage-gated K+ outward current in H9c2
      myoblasts.
AB  - The H9c2 clonal cell line derived from embryonic rat ventricle is an in vitro
      model system for cardiac and skeletal myocytes. We used the whole-cell patch
      clamp technique to characterize the electrophysiological and pharmacological
      properties of an outward K+ current (IK(V)) and determined its molecular
      correlate in H9c2 myoblasts. IK(V) was activated by threshold depolarization to 
      30 mV, and its current amplitude and rate of activation increased with further
      depolarizations. IK(V) inactivated slowly with a time constant of 1-2 s, and the
      V(0.5) for steady-state inactivation was -37.9 +/- 4.6 mV (n = 10).
      Tetraethylammonium and quinidine suppressed IK(V) with IC(50)'s of 3.7 mM and
      11.6 microM, respectively. Using RT-PCR analysis we found that the K(V )2.1 gene
      is the most abundantly expressed among genes for K(V)1.2, 1.4, 1.5, 2.1, 4.2, and
      4.3, and by Western blotting we confirmed the synthesis of the K(V)2.1 alpha
      subunit protein. We conclude that IK(V), the predominant voltage-gated outward
      current in H9c2 myoblasts, flows through the channels comprised of the K(V)2.1
      subunit gene product.

PMID- 12617757
TI  - In vitro potassium transport in the mouse small intestine.
AB  - Ingested K+ is believed to be absorbed mainly in the small intestine by passive
      diffusion through the paracellular pathway. To further clarify K+ absorption in
      the small intestine, we determined the unidirectional flux values of Rb+ in vitro
      by atomic absorption spectroscopy in the mouse ileum mounted in Ussing chambers
      under short-circuit conditions. The mucosal-to-serosal Rb+ flux (J(ms)) was
      larger than the serosal-to-mucosal Rb+ flux (J(sm)), resulting in positive net
      Rb+ absorption (J(net)). The effect of changing the transmucosal potential (V(t))
      showed that J(ms) was composed of both a V(t)-dependent diffusion component and a
      V(t)-independent non-diffusion component, while J(sm) was composed mainly of a
      V(t)-dependent component. A forskolin treatment eliminated J(net) mainly due to
      the increase in J(sm). When animals were fed a low-Na diet, J(net) was mainly
      eliminated as a result of the increase in J(sm). These findings suggest that K+
      is absorbed not only by passive diffusion through the paracellular pathway, but
      also by an active transport mechanism operating through the cellular pathway. In
      addition, cAMP and aldosterone may be involved in regulating intestinal K+
      transport.

PMID- 12617755
TI  - Myosin heavy chain and physiological adaptation of the rat diaphragm in elastase
      induced emphysema.
AB  - BACKGROUND: Several physiological adaptations occur in the respiratory muscles in
      rodent models of elastase-induced emphysema. Although the contractile properties
      of the diaphragm are altered in a way that suggests expression of slower isoforms
      of myosin heavy chain (MHC), it has been difficult to demonstrate a shift in MHCs
      in an animal model that corresponds to the shift toward slower MHCs seen in human
      emphysema. METHODS: We sought to identify MHC and corresponding physiological
      changes in the diaphragms of rats with elastase-induced emphysema. Nine rats with
      emphysema and 11 control rats were studied 10 months after instillation with
      elastase. MHC isoform composition was determined by both reverse transcriptase
      polymerase chain reaction (RT-PCR) and immunocytochemistry by using specific
      probes able to identify all known adult isoforms. Physiological adaptation was
      studied on diaphragm strips stimulated in vitro. RESULTS: In addition to
      confirming that emphysematous diaphragm has a decreased fatigability, we
      identified a significantly longer time-to-peak-tension (63.9 +/- 2.7 ms versus
      53.9 +/- 2.4 ms). At both the RNA (RT-PCR) and protein (immunocytochemistry)
      levels, we found a significant decrease in the fastest, MHC isoform (IIb) in
      emphysema. CONCLUSION: This is the first demonstration of MHC shifts and
      corresponding physiological changes in the diaphragm in an animal model of
      emphysema. It is established that rodent emphysema, like human emphysema, does
      result in a physiologically significant shift toward slower diaphragmatic MHC
      isoforms. In the rat, this occurs at the faster end of the MHC spectrum than in
      humans.

PMID- 12617758
TI  - Effects of adrenoceptor antagonists on the cutaneous blood flow increase response
      to sympathetic nerve stimulation in rats with persistent inflammation.
AB  - There is some evidence that the sympathetic nervous system plays a role in the
      development and/or maintenance of painful states, and that sympathetic nervous
      function is altered in these conditions. Our previous experiments showed that
      electrical stimulation of the lumbar sympathetic trunk (sympathetic stimulation:
      SS), which normally induces a decrease in blood flow (BF) of plantar skin,
      induced its BF increase in about 50% of adjuvant-inflamed rats. To investigate
      the mechanism of this BF-increase response, we examined whether noradrenaline
      (NA) plays any role in this changed response to SS, and which receptor subtype is
      involved. We measured paw cutaneous BF response with a laser Doppler flowmeter in
      rats chronically inflamed with complete Freund's adjuvant. SS induced the BF
      increase response in 50-67% of measured sites. Close-arterially injected NA
      induced the BF-increase response at dosages between 10-100 ng/kg only at the
      sites with the BF-increase response to SS. The BF-increase and -decrease
      responses to NA was significantly reduced after the close-arterial injection of
      either alpha1- or alpha2-adrenoceptor antagonists (p lt; 0.05, respectively). In
      contrast, although the BF-decrease responses to SS were significantly reduced by
      administration of alpha1- and alpha2-adrenoceptor antagonist, BF-increase
      response was reduced only by alpha1-adrenoceptor antagonist, and that only at a
      higher dose. In addition, the beta-adrenoceptor antagonist had no effects on both
      responses. These results suggest that the BF-increase response to SS involves,
      additionally to NA, a non-adrenergic mechanism.

PMID- 12617759
TI  - The mechanism of increasing Ca2+ responsiveness by alpha1-adrenoceptor
      stimulation in rat ventricular myocytes.
AB  - We investigated the mechanism of alpha(1)-adrenoceptor stimulation on the
      myofibrillar Ca(2+) responsiveness at steady-state in intact rat ventricular
      myocytes. We produced tetanus, and an instantaneous plot of [Ca(2+)](i) vs. cell
      length (Ca-L trajectory) was constructed to estimate the Ca(2+) responsiveness.
      An alpha(1)-agonist, phenylephrine, dose-dependently shifted the Ca-L trajectory
      to the left, corresponding to sensitization of the myofilaments. An alpha(1)
      antagonist, prazosin, and inhibition of the Na/H exchange by
      ethylisopropylamiloride (EIPA) completely reversed the phenylephrine-induced
      shift. Phenylephrine increased pH(i) (DeltapH(i) = +0.1), which was reversed by
      prazosin and EIPA. Chelerythrine, an inhibitor of protein kinase C (PKC),
      completely blocked the effects of phenylephrine on Ca(2+) responsiveness and
      pH(i). When pH(i) was increased (DeltapH(i) = +0.1) without phenylephrine by
      changing pH(o), the Ca-L trajectory was shifted to the same extent as that
      observed with phenylephrine. We conclude that alpha(1)-adrenoceptor stimulation
      activates Na/H exchange through a PKC-mediated pathway and that an increase in
      pH(i) is mainly responsible for the increase in Ca(2+) responsiveness.

PMID- 12617760
TI  - Effects of membrane potential on Na+ -dependent Mg2+ extrusion from rat
      ventricular myocytes.
AB  - To study Mg2+ transport across the cell membrane, the cytoplasmic concentration
      of Mg2+ ([Mg2+](i)) in rat ventricular myocytes was measured with the fluorescent
      indicator furaptra (mag-fura-2) under Ca2+ -free conditions (0.1 mM EGTA) at 25
      degrees C. The fluorescence ratio signal of furaptra was converted to [Mg2+](i)
      using calibration parameters previously estimated in myocytes (Watanabe and
      Konishi, Pflugers Arch 442: 35-40, 2001). After [Mg2+](i) was raised by loading
      the cells with Mg2+ in a solution containing 93 mM Mg(2+), the cells were voltage
      clamped at a holding potential of -80 mV using the perforated patch-clamp
      technique with amphotericin B. At the holding potential of -80 mV, the reduction
      of extracellular Mg2+ to 1.0 mM caused a rapid decrease in [Mg2+](i) only in the
      presence of extracellular Na(+). The rate of the net Mg2+ efflux appeared to be
      dependent on the initial level of [Mg2+](i); the decrease in [Mg2+](i) was
      significantly faster in the myocytes markedly loaded with Mg2+. The rate of
      decrease in [Mg2+](i) was influenced little by membrane depolarization from -80
      to -40 mV, but the [Mg2+](i) decrease accelerated significantly at 0 mV by, on
      average, approximately 40%. Hyperpolarization from -80 to -120 mV slightly but
      significantly slowed the decrease in [Mg2+](i) by approximately 20%. The results
      clearly demonstrate an extracellular Na(+)- and intracellular Mg2+ -dependent
      Mg2+ efflux activity, which is consistent with the Na(+)-Mg2+ exchange, in rat
      ventricular myocytes. We found that the apparent rate of Mg2+ transport depends
      slightly on the membrane potential: facilitation by depolarization and inhibition
      by hyperpolarization with no sign of reversal between -120 and 0 mV.

PMID- 12617761
TI  - Modulating effects of the menstrual cycle on cardiorespiratory responses to
      exercise under acute hypobaric hypoxia.
AB  - The purpose of this study was to examine the hypothesis that the menstrual cycle
      induced modulation of the cardiorespiratory response to exercise might be altered
      by acute exposure to altitude. During both the luteal and follicular phases, 9
      moderately trained female subjects with normal menstrual cycles performed
      incremental exercise to maximal effort on a cycle ergometer at sea level (SL) and
      under hypobaric hypoxia (HH) at the equivalent of 3,000 m altitude. Both at rest
      and during exercise, minute ventilation (.VE) and oxygen uptake (.VO(2)) did not
      differ between the luteal and follicular phases (either at SL or HH). However,
      the ratio of .VE to .VO(2) (.VE /.VO(2)), both at rest and during peak exercise,
      was greater in the luteal phase than in the follicular phase under HH conditions.
      Furthermore, the partial pressure of end-tidal carbon dioxide (PETCO(2)) during
      exercise was lower in the luteal phase than in the follicular phase in HH. These
      results suggest that the menstrual cycle-induced modulation of the ventilatory
      response to exercise may be altered under acute hypobaric-hypoxic conditions.

PMID- 12617762
TI  - Terbutaline-induced triphasic changes in volume of rat alveolar type II cells:
      the role of cAMP.
AB  - Changes in the volume of rat alveolar type II cells (AT-II cells) induced by
      terbutaline, a beta(2)-agonist, were measured using video-enhanced contrast
      microscopy. The changes consisted of three phases: initial cell shrinkage, cell
      swelling, and gradual cell shrinkage. The initial cell shrinkage was Ca(2+)
      dependent and was inhibited by quinine (a K+ channel blocker). The subsequent
      cell swelling was cAMP-dependent and was inhibited by amiloride (a Na+ channel
      blocker). The final cell shrinkage was cAMP-dependent and was inhibited by 5
      nitro-2-(3-phenylpropylamino)-benzoate (NPPB, a Cl- channel blocker). Thus,
      terbutaline-induced cell volume changes were regulated by both Ca2+ and cAMP.
      Accumulation of cAMP alone, however, induced the Ca2+ -dependent cell shrinkage
      of AT-II cells and H-89 (a PKA inhibitor) inhibited terbutaline-induced cell
      volume changes. This suggests that cAMP accumulation stimulates the Ca2+ signal
      during terbutaline stimulation. In conclusion, terbutaline stimulates not only
      Na+ influx, but also K+ and Cl- release mediated via cAMP accumulation in rat AT
      II cells, which induces the triphasic cell volume changes.

PMID- 12617764
TI  - Intravascular inhomogeneous distribution of oxygen in arterioles of rat cremaster
      muscle.
AB  - Previously, cross-sectional oxygen distribution in microvessels was assumed to be
      homogeneous. The oxygen profile in the arterioles of rat cremaster muscle was
      measured using microspectrophotometry and a PO(2) microelectrode, showing a drop
      in SO(2) as well as PO(2) close to the vascular wall with a flat PO(2) profile in
      the perivascular tissue.

PMID- 12617763
TI  - Effects of diurnal bright/dim light intensity on circadian core temperature and
      activity rhythms in the Japanese macaque.
AB  - Circadian rhythms of core temperature and activity were studied using three
      Japanese macaques under influences of two different light intensities during the
      daytime. Nocturnal core temperature and activity onset time were lower and
      advanced, respectively, in bright as compared to dim light. These results suggest
      the possibility that diurnal bright light could influence the circadian
      organization.

PMID- 12617765
TI  - A striking correlation between lethal activity and apoptotic DNA fragmentation of
      liver in response of D-galactosamine-sensitized mice to a non-lethal amount of
      lipopolysaccharide.
AB  - AIM: To observe whether challenge of bacterial lipopolysaccharide (LPS) with D
      galactosamine (D-GalN) in mice will result in apoptotic characteristic of vital
      organs. METHODS: The experimental group of mice was challenged directly with
      bacterial LPS (0.05 microg) in the presence of D-GalN (20 mg), and the control
      group of mice was challenged either with bacterial LPS or with D-GalN alone. The
      organs including brain, kidney, heart, spleen, lung, and liver were removed at an
      indicated time point under ether anesthesia, and immediately homogenized, from
      which DNA was extracted. The DNA obtained from these organs was analyzed by
      agarose gel electrophoresis to determine whether the DNA laddering phenomenon
      existed. The amount of plasma LDH and GOT was detected in mice challenged with
      bacterial LPS in the presence of D-GalN, and either bacterial LPS or D-GalN
      alone. RESULTS: Apoptotic DNA fragmentation was initially seen at 4 h after
      challenge only in the livers of mice challenged with bacterial LPS and D-GalN,
      all mice in this group challenged with bacterial LPS and D-GalN died at 7 h after
      challenge; in contrast, the animals in the control group were all alive and the
      DNA was integral. CONCLUSION: The liver is the only specific target organ where
      apoptotic DNA fragmentation was present in mice treated with D-GalN and
      challenged with bacterial LPS and the liver impairment might be the critical
      cause of the lethality of mice elicited by bacterial LPS.

PMID- 12617766
TI  - Effects of lercanidipine on coronary reactivity and myocardial remodeling in
      transition to heart failure in cardiomyopathic hamsters.
AB  - AIM: Lercanidipine is a new vasoselective dihydropyridine calcium channel blocker
      with a short plasma half-life, long duration of action, and demonstrated
      cardioprotective properties. We hypothesized that it might be effective at
      attenuating the adverse impact observed on the coronary compartment and
      myocardium in the transition phase to heart failure in the UM-X7.1
      cardiomyopathic (CM) hamster. METHODS: The effects of 4-month exposure to
      lercanidipine 3 and 10 mg/kg (daily oral administration) were evaluated in 150
      day-old CM hamsters and in age-matched normal hamsters. Coronary reactivity
      (reactive hyperemia to 30-s coronary occlusion) and the response to the
      administration of acetylcholine (100 nmol/L) and sodium nitroprusside (1
      micromol/L) were assessed monthly, using the isolated perfused heart model. The
      left ventricular chamber dilatation index and wall thickness, myocardial fibrosis
      and myocardial capillary density (papillary muscle) were estimated in selected
      subgroups at monthly intervals. RESULTS: High-dose lercanidipine had beneficial
      effects on coronary dysfunctions: at month 4 of the treatment period, reactive
      hyperemia to short duration ischemia was improved, as was the endothelium
      dependent vasodilator response (acetylcholine=68 %+/-16 % vs 11 %+/-5 % in
      untreated CM hamsters, P<0.05) and endothelium-independent vasodilator response
      (sodium nitroprusside=36 %+/-5 % vs 22 %+/-12 % in untreated CM hamsters,
      P<0.05). Capillary density averaged 10,879+/-474 capillaries per mm2 in papillary
      muscle from normal hamsters; this value did not change over time in normal
      hamsters and was not affected during the transition phase to heart failure in CM
      hamsters. Lercanidipine preserved myocardial capillary density in these
      conditions. Chronic exposure to lercanidipine had no impact on myocardial
      remodeling observed in CM hamsters. CONCLUSION: Lercanidipine had a beneficial
      impact on the coronary compartment in the transition phase to heart failure in a
      model of dilated cardiomyopathy.

PMID- 12617767
TI  - Fructose diet and VEGF-induced plasma extravasation in hamster cheek pouch.
AB  - AIM: To determine in the hamster cheek pouch whether or not the changes in plasma
      extravasation induced by vascular endothelial growth factor (VEGF) could be
      affected by fructose diet. METHODS: Hamsters were subjected to control drinking
      water or to water containing fructose (10 %) for 18 weeks. RESULTS: The fructose
      diet induced a small but significant increase in glycemia (0.80+/-0.11 and 1.09+/
      0.15, n=8 and 9 for control and fructose- treated animals, respectively, P<0.05).
      Bradykinin-induced plasma extravasation was not affected by the fructose diet
      while the effects of VEGF were markedly increased (maximal number of leakage
      sites: 76+/-20 and 126+/-55, n = 8 and 9 for control and fructose-treated
      animals, respectively, P<0.01). CONCLUSION: Even moderate changes in glycemic
      levels can produce profound alteration in the VEGF response.

PMID- 12617768
TI  - Differentiation of endothelial progenitor cells from human umbilical cord blood
      CD 34+ cells in vitro.
AB  - AIM: To study the time course of the expression of stem cell marker and
      endothelial cell markers on human cord blood CD34+ cells during in vitro
      differentiation process of endothelial progenitor cells (EPC). METHODS: CD34+
      cells were selected and enriched from human cord blood by magnetically activated
      cell sorting (MACS), and cultured in dishes coated with or without fibronectin
      (Fn). Endothelial cells were identified by staining the cells with anti Flk-1 and
      vWF antibodies. The percentage of AC133+ cells in adherent CD34+ cell population
      was analyzed by fluorescence-activated cell sorting (FACS). RESULTS: The
      expression of Flk-1 and vWF on adherent CD34+ cells increased during the culture
      time, with 27.0 % positive for Flk-1 and negative for vWF at d 3, and 100 %
      positive for both Flk-1 and vWF at d 7. When cells were cultured in Fn-treated
      dishes, the percentages of Flk-1 and vWF positive cells increased to 34 % and 47
      %, respectively at d 3, and 100 % at d 7. In contrast, the percentages of AC133+
      cells among the adherent cell population decreased rapidly, and similar changes
      occurred in cells cultured in the presence of Fn. CONCLUSION: The gradual
      appearance of endothelial cell markers and the disappearance of stem cell marker
      characterized the in vitro differentiation of endothelial progenitor cells.
      Fibronectin accelerated the differentiation process of EPC.

PMID- 12617769
TI  - Effects of beta-adrenoceptor stimulation on endothelial nitric-oxide synthase
      phosphorylation of human umbilical vein endothelial cells.
AB  - AIM: To investigate the effects of isoprenaline on the phosphorylation level of
      endothelial nitric oxide synthase (eNOS) of human umbilical vein endothelial
      cells (HUVEC) and to elucidate the regulation mechanisms of beta-adrenoceptor
      (beta-AR) on eNOS activity. METHODS: HUVEC were exposed to isoprenaline (1
      micromol/L) for 30 min, in the absence or presence of selective beta1- or beta2 
      adrenoceptor antagonists. eNOS was then isolated by immunoprecipitation using a
      specific eNOS antibody. eNOS activity was determined by the conversion of L
      [3H]arginine to L-[3H]citrulline. The levels of eNOS expression and eNOS
      phosphorylation were measured by Western blotting. RESULTS: Treatment of HUVEC
      with isoprenaline (1 micromol/L) for 30 min caused no measureable change in eNOS
      expression. However, eNOS activity and serine phosphorylation level were
      significantly increased (P<0.01). This effect could be abolished by a selective
      beta2-adrenoceptor antagonist ICI 118551. CONCLUSION: Isoprenaline increases eNOS
      activity of HUVEC, this is mediated by beta2-adrenoceptor and associated with an
      increase of eNOS serine phosphorylation level.

PMID- 12617770
TI  - Expression of dopamine D1 receptor in Sf9 insect cells and agonism of l-12
      chloroscoulerine on recombinant D1 receptor.
AB  - AIM: To express dopamine D1 receptor in baculovirus-Sf9 cell system, and to
      investigate the effects of l-12-chloroscoulerine (l-CSL) on the recombinant D1
      receptor (D1R). METHODS: The recombinant baculovirus, Autographa californica
      nuclear polyhedrosis virus bearing D1R (AcNPV- D1R) was generated, and then was
      used to produce recombinant D1R in Sf9 insect cells. Expression of D1R in Sf9
      cells was monitored by [3H]SCH23390 binding assay. The effects of l-CSL on
      recombinant D1R were investigated by [3H]SCH23390 binding assay and cAMP assay.
      RESULTS: The recombinant baculovirus AcNPV bearing D1R cDNA was generated, and
      was successfully expressed in Sf9 insect cells. The expression level of (Bmax)
      was (0.94+/-0.06) nmol/g protein. The Kd value of [3H]SCH23390 was (1.9+/-0.3)
      nmol/L, which was consistent with the previous results from calf striatum
      tissues. l-CSL had a high affinity to recombinant D1R with Ki value of (6.3+/
      1.4) nmol/L, and increased the intracellular cAMP level in a concentration
      dependent manner with EC50 value of 0.72 micromol/L and 95 % confidence limit was
      0.67-0.77 micromol/L. Thus l-CSL has the D1 receptor agonism. CONCLUSION: An
      efficient baculovirus-Sf9 insect cell system for dopamine D1 receptor was
      constructed and l-CSL presented the D1 receptor agonism on cellular-molecular
      level directly.

PMID- 12617771
TI  - Anti-aging effect of astragalosides and its mechanism of action.
AB  - AIM: To study the anti-aging effect of astragalosides (AST) and its mechanism of
      action. METHODS: Rotating rod test and step-down type passive avoidance test were
      performed to determine the effects of AST on motor and memory of D-galactose (D
      gal)-induced senescent mice and the middle-aged mice. The proliferative response
      of splenocytes induced by Con A or LPS, IL-2 production of splenocytes induced by
      ConA of D-gal-treated mice and the middle-aged mice were also measured. RESULTS:
      AST (40 mg.kg(-1).d(-1), ig, for 10 weeks) was found to ameliorate age-related
      alternations in both motor response and memory, enhance the deteriorated cellular
      immunity in D-gal-treated mice and the pre-aged (17-month-old) mice. CONCLUSION:
      AST has an anti-aging effect on D-gal-induced senescent mice and has the effect
      of delaying senility of the middle-aged mice, which was related to its
      improvement of brain function and immunomodulatory effects.

PMID- 12617772
TI  - No association of antipsychotic agent-induced weight gain with a DA receptor gene
      polymorphism and therapeutic response.
AB  - AIM: To investigate whether there is an association of antipsychotic agent
      induced weight gain with the TaqI A polymorphism of dopamine D2 receptor (DRD2)
      gene and therapeutic response to antipsychotic treatment in schizophrenia.
      METHODS: Genotyping was performed using the PCR-RFLP techniques in a total of 117
      first-episode Chinese Han schizophrenic patients (mean age 26+/-8 a; 58 male, 59
      female). Moreover, the measurements were finished either for baseline weight and
      body mass index (BMI) or for changed weight and BMI 10 weeks after antipsychotic
      treatment. The Positive and Negative Symptom Scale (PANSS) was used for the
      evaluation of the improvement of clinical psychotic symptoms. RESULTS: There was
      an average increase in body weight of (3+/-3) kg or (6+/-6) % of baseline weight
      with a changed range of -7 kg - 12 kg or -7.8 % - 32.4 % 10 weeks after
      treatment, and the change in the BMI was associated with the baseline BMI and
      patients' age (P=0.0001; P=0.03; respectively). However, there was no significant
      difference in distribution of allelic frequencies (X2=0.65, v1, P>0.05) and
      genotype (x2=1.47, v2, P>0.05) between the subgroups, and the change in BMI was
      not associated with genotypes of DRD2. Furthermore, there was no relationship of
      the therapeutic response to antipsychotic treatment with changed BMI in the
      patients (P>0.05). CONCLUSION: The TaqI A polymorphism of DRD2 gene is therefore
      unlikely to play an important role in antipsychotic agent-induced weight gain, a
      side effect of antipsychotic treatment. Furthermore, increase in body weight is
      unlikely to be prediction of therapeutic response to antipsychotic treatment in
      schizophrenia.

PMID- 12617773
TI  - Antitumor effects of curcin from seeds of Jatropha curcas.
AB  - AIM: To study the antitumor effects of curcin from Jatropha curcas. METHODS:
      Antitumor activity of curcin was tested by MTT assay. The N-glycosidase activity
      of curcin was determined by characterization of R-fragment in gel. A cell-free
      system, rabbit reticulocyte lysate, was introduced to quantify the inhibitory
      activity of curcin on protein biosynthesis. RESULTS: The curcin had a powerful
      inhibitory action upon protein synthesis in reticulocyte lysate with an IC50 (95
      % confidence limits) value of 0.19 (0.11-0.27) nmol/L. The IC50 (95 % confidence
      limits) of curcin on SGC-7901, Sp2/0, and human hepatoma was 0.23 (0.15-0.32)
      mg/L, 0.66 (0.35-0.97) mg/L, 3.16 (2.74-3.58) mg/L, respectively. Curcin was
      found to have no toxic to Hela cells and normal cells (MRC). After the rRNA of
      ribosome was treated with curcin and aniline at acidic condition, a cleaved R
      fragment of approximately 450 nt appeared, but this fragment did not occur after
      treatment with curcin only. A comparison of the amino acid sequences of curcin,
      ricin A-chain and trichosanthin revealed that there were relatively high
      similarities among them. The percentages of homology between curcin and ricin A
      chain, between curcin and trichosanthin were found to be 54 % and 57 %
      respectively. Especially, the conserved residues forming the active sites of the
      A chain of ricin and trichosanthin occurred in curcin. CONCLUSION: Curcin has an
      obvious antitumor effect and its mechanisms are related to the N-glycosidase
      activity.

PMID- 12617775
TI  - Therapeutic effects of interleukin-1 receptor antagonist on allergic rhinitis of
      guinea pig.
AB  - AIM: To determine the effect of interleukin-1 receptor antagonist (IL-1ra) on
      allergic rhinitis. METHODS: Allergic rhinitis was induced by toluene-2,4
      diisocyanate (TDI). At the end of the treatment, the pathological changes in the
      nasal mucosa were observed. The concentrations of histamine in the nasal mucosa
      and IgE in the blood were determined as well. RESULT: Symptoms of allergic
      rhinitis were remarkably relieved after IL-1ra treatment. Hematoxylin and eosin
      staining demonstrated that less edema was found in the nasal mucosa and small
      vessel was normal after IL-1ra application, but edema,vasodilation, and
      inflammatory cell infiltration were discovered in the model group. The
      concentrations of histamine in the nasal mucosa and IgE in the blood were less
      than those in the control group. CONCLUSION: IL-1ra im administration selectively
      and non-traumatically alleviated nasal congestion, rhinorrhea, and sneezing.

PMID- 12617774
TI  - Acute effects of huperzine A and tacrine on rat liver.
AB  - AIM: To observe the acute effects of huperzine A and tacrine on rat liver.
      METHODS: Changes of liver coefficient, serum biochemistry, and histopathology
      were detected after single dose. In vitro cytotoxicity was assessed by
      determining extracellular and intracellular amount of lactate dehydrogenase in
      cultured hepatocytes. RESULTS: Both huperzine A and tacrine raised liver
      coefficient and increased serum aspartate aminotransferase and alanine
      aminotransferase. Tacrine induced liver histopathologic changes. The acute
      effects of huperzine A on liver could be redressed by atropine, while effects of
      tacrine on liver could not. Concentration-dependent in vitro cytotoxicity
      occurred with tacrine, but not with huperzine A. CONCLUSION: The acute effects of
      huperzine A on rat liver are not related to hepatotoxicity. The acute effects of
      tacrine on rat liver are related to hepatotoxicity.

PMID- 12617776
TI  - Pharmacokinetics of 9-nitro-20(S)-camptothecin in rats.
AB  - AIM: To study the pharmacokinetics and the excretion of 9-nitro-20(S)
      camptothecin (9-NC) in rats. METHODS: Each rat was given a single dose at random
      by iv or ig administration. Serial plasma and excreta samples were collected and
      the pharmacokinetic behavior of 9-NC in rats was characterized by specific liquid
      chromatographic assays. Individual 9-NC plasma-concentration data were analyzed
      by both noncompartmental and compartmental analysis. For dose proportionality,
      AUC- and Cmax-dose relationships were evaluated by linear regression, and t1/2
      and CLtot were compared by an analysis of variance model. Also, the excretion of
      the parent drug was estimated. RESULTS: After iv administration of 9-NC at the
      doses of 1.5, 3, and 6 mg/kg, the t1/2 values for 9-NC were estimated to be 0.5,
      0.5, and 0.7 h, respectively, and the mean AUC0-t values were 633, 1606, and 3011
      h.microg.L(-1), respectively. 9-NC was rapidly absorbed, reaching mean Cmax of
      203, 417, and 1150 microg/L at Tmax of 0.3, 0.2, and 0.3 h at the doses of 3, 6,
      and 12 mg/kg, respectively. The mean AUC0-t values were 269, 439, and 881
      h.microg.L(-1), and the mean t1/2 values were 1.7, 0.9, and 0.9 h, respectively.
      The absolute oral bioavailability of 9-NC was calculated to be 14.6 %, which was
      consistent with the ratio of the total cumulative excretion in the urine and bile
      by ig to that by iv injection. CONCLUSION: The kinetic process of 9-NC in rats in
      vivo was best fitted to a two-compartmental model. For iv administration, the
      pharmacokinetics are not dose-dependent. The oral bioavailability of 9-NC was
      low. Renal excretion was the primary elimination route of the parent drug after
      iv administration, however, after ig administration the unchanged drug was
      largely excreted in the feces because of the poor absorption.

PMID- 12617777
TI  - Metabolism and metabolic inhibition of cilnidipine in human liver microsomes.
AB  - AIM: To study the metabolism of cilnidipine and the effects of selective
      cytochrome P-450 (CYP450) inhibitors on the metabolism of cilnidipine in human
      liver microsomes in vitro. METHODS: Human liver microsomes were used to perform
      metabolism studies. Various selective CYP450 inhibitors were used to investigate
      their effects on the metabolism of cilnidipine and the principal CYP450 isoform
      involved in dehydrogenation of dihydropyridine ring of cilnidipine in human liver
      microsomes. RESULTS: Cilnidipine was rapidly metabolized to three metabolites.
      They are dehydrogenated metabolite of dihydropyridine ring of cilnidipine (M1),
      demethylation metabolite of lateral chain of dihydropyridine ring of cilnidipine
      (M2), and the dehydrogenation and demethylation metabolite of cilnidipine (M3).
      Ketoconazole (Ket) competitively inhibited the dehydrogenation of dihydropyridine
      ring of cilnidipine and lowered the metabolic rate of cilnidipine while alpha
      naphthoflavone (alpha-Naph), sulfaphenazole (Sul), quinidine (Qui),
      diethyldithiocarbamate (DDC), and tranylcypromine (Tra) had a little or no
      inhibitory effects on the dehydrogenation of cilnidipine. CONCLUSION: Cilnidipine
      was rapidly metabolized in human liver microsomes and dehydrogenation of
      dihydropyridine ring of cilnidipine is crucial for the elimination of
      cilnidipine. Cytochrome P-4503A(CYP3A) is the major human CYP involved in the
      dehydrogenation of dihydropyridine ring of cilnidipine.

PMID- 12617778
TI  - Antisense candidates against protein kinase C-alpha designed based on
      phylogenesis and simulant structure of mRNA.
AB  - AIM: To optimize the antisense drug design by the combined method of phylogenetic
      analysis and secondary structure prediction and to get ideal candidates. METHODS:
      The phylogenetic analysis and the secondary structure simulation were performed
      by computer. Oligodeoxynucleotides (ODN) were designed against the full-conserved
      blocks with low local reaction free energy of protein kinase C (PKC)-alpha mRNA.
      The in vitro effects of ODN were evaluated by human A549 lung carcinoma cells and
      mouse B16-BL6 melanoma cells, the expression of target mRNA was detected by in
      situ hybridization and RT-PCR. The in vivo effects of ODN were also evaluated by
      models of A549 xenografts in nude mice and B16 melanoma in mice. RESULTS: Three
      ODN had significantly lower IC50 values than that of ISIS3521, the positive
      control, on A549 cells in vitro. Five ODN inhibited the growth of B16-BL6 cells
      with IC50 <100 nmol/L, while IC50 of ISIS3521 was >200 nmol/L. In situ
      hybridization and RT-PCR showed that the best candidate AP1261 inhibited the
      expression of PKC-alpha at mRNA level in a dose-dependent manner. AP1261
      inhibited the growth of A549 and B16 tumors in vivo at 0.005-0.5 mg.kg(-1).d(-1).
      The inhibitory rate of AP1261 on A549 tumors was greater than that of ISIS3521 at
      the same dose. ISIS3521 did not affect the growth of B16 tumors. CONCLUSION:
      AP1261 may be of value as an antitumor agent or adjuvant and the combined method
      of phylogenetic analysis and secondary structure prediction is a potential
      helpful tool for antisense drug design.

PMID- 12617780
TI  - Effect of unsaturated fatty acid on muscarinic current in guinea pig gastric
      antral circular myocytes.
AB  - AIM: To investigate the effect of ectogenesis unsaturated fatty acid on carbachol
      induced muscarinic current (ICCh) and its mechanism. METHODS: Using the whole
      cell patch-clamp technique, ICCh was recorded in single smooth muscle cell
      isolated from the antral circular smooth muscles of guinea-pig stomach. RESULTS:
      Arachidonic acid (AA) was added in external perfusing solution and AA inhibited
      ICCh to 46 %+/-8 %, 23 %+/-5 %, and 3.8 %+/-0.9 % at 1, 3, and 5 micromol/L.
      Another unsaturated fatty acid, linoleic acid (LA) also inhibited ICCh in a dose
      dependant manner. LA inhibited ICCh to 69 %+/-10 %, 35 %+/-5 %, and 7.4 %+/-1.2 %
      at 1, 5, and 10 micromol/L, respectively. The same concentration (5 micromol/L)
      of AA, LA, and oleic acid (OA) suppressed ICCh to 3.8 %+/-0.9 %, 35 %+/-5 %, and
      67 %+/-9 %, respectively. The inhibitory potency sequence of these unsaturated
      fatty acids was AA>LA>OA. After 10-15 min of pretreatment with H-7 (a protein
      phosphorylation C inhibitor) 100 micromol/L or indomethacin (a cyclooxygenase
      inhibitor) 10 micromol/L, ICCh was inhibited by 5 micromol/L of AA to 5.5 %+/-0.7
      % and 3.0 %+/-1.0 %, respectively. CONCLUSION: The unsaturated fatty acids
      directly inhibited ICCh, and the inhibitory potency was related to the number of
      double bonds in fatty acid chain.

PMID- 12617779
TI  - Comparison of bronchodilating and antiinflammatory activities of oral formoterol
      and its (R,R)-enantiomers.
AB  - AIM: To compare the bronchodilating and antiinflammatory effects of oral racemic
      formoterol (rac-FMT) and (R,R)-formoterol (R,R-FMT). METHODS: The changes of lung
      resistance (RL), dynamic lung compliance (Cdyn), and the accumulation of
      inflammatory cells in bronchoalveolar lavage fluids (BALF) induced by ovalbumin
      aerosol in sensitized guinea pigs and mice were investigated in vivo. RESULTS:
      Mean value increase of RL and mean value reduction of Cdyn from 1 to 30 min after
      antigen challenge were up to 101 %+/-34 % and 42 %+/-7 %, respectively. rac-FMT
      0.5, 1.0, and 2.0 mg/kg, and R,R-FMT 0.25, 0.5, and 1.0 mg/kg ig, induced dose
      related inhibition of the bronchoconstrictive responses to aerosolised ovalbumin.
      ID50 (95% confidence limits, 95 % CL) value of rac-FMT on RL maximal increase and
      Cdyn maximal reduction at 5 min were 0.64 (0.54-0.76) and 1.02 (0.88-1.18) mg/kg,
      respectively. For R,R-FMT they were 0.46 (0.40-0.53) and 0.52 (0.45-0.61) mg/kg,
      respectively. ID50 (95 % CL) value of rac-FMT on RL mean increase and Cdyn mean
      reduction from 1 to 30 min were 0.96 (0.86-1.07) and 1.59 (1.32-1.92) mg/kg,
      respectively. For R,R-FMT they were 0.52 (0.45-0.59) and 0.43 (0.37-0.51) mg/kg,
      respectively. Ovalbumin-aerosol challenge induced an increase of inflammatory
      cells in BALF in sensitized mice. rac-FMT and RR-FMT caused a dose-dependent and
      almost complete inhibition at 2.0 mg/kg. ID50 (95 % CL) of rac-FMT on the number
      of total inflammatory cells and eosinophil in BALF were 1.48 (1.22-1.81) and 0.80
      (0.62-1.04) mg/kg, respectively. ID50 (95 % CL) of RR-FMT were 0.80 (0.57-1.13)
      and 0.60 (0.43-0.83) mg/kg, respectively. CONCLUSION: R,R-FMT protected lung
      against increase of RL and reduction of Cdyn induced by bronchial challenge of
      ovalbumin in the asthma model of guinea pigs, and inhibited airway inflammation
      in the sensitized mice. Efficacy of R,R-FMT was approximately 2-fold than that of
      rac-FMT.

PMID- 12617781
TI  - A chronic low dose infusion of insulin-like growth factor I alters placental
      function but does not affect fetal growth.
AB  - Knowledge of the anabolic effects of insulin-like growth factor I (IGF-I) on
      fetal growth and feto-placental metabolism are derived from studies using large
      doses of IGF-I. Low doses of enteral IGF-I have trophic effects on the fetal gut,
      but there are no data on the effects of systemic low doses of IGF-I on fetal
      growth and feto-placental metabolism. We therefore compared the effects of a
      chronic infusion of low dose IGF-I (50 microg day(-1), n = 7) with vehicle
      infused controls (n = 7) on fetal growth, metabolism and placental transfer
      capacity in the chronically instrumented late gestation ovine fetus (121-132 days
      of gestation; term = 145 days). Insulin-like growth factor I infusion did not
      affect fetal growth or the size of individual organs, including liver, spleen and
      bone. Placental morphology was altered, and placental clearances of 3-O-[methyl
      3H]D-glucose (a non-metabolizable glucose analogue) and
      [methyl(14C)]aminoisobutyric acid (a non-metabolizable analogue of amino acids
      utilizing the system A transporter), were reduced in IGF-I-treated fetuses (P <
      0.05 v. control). However, fetal and placental metabolite uptake was not
      significantly different between groups. We conclude that, despite altering
      placental transfer capacity and morphology, a chronic low dose infusion of IGF-I
      does not alter fetal growth or metabolism.

PMID- 12617782
TI  - Semen quality in captive Houbara bustard, Chlamydotis undulata undulata.
AB  - Semen quality in captive-bred Houbara bustards, Chlamydotis undulata undulata,
      was assessed during three consecutive breeding seasons. In any one season, sperm
      quality, in terms of the proportion of eosin-permeable spermatozoa and of
      spermatozoa with abnormally large nuclei, varied among individual males, but not
      among their ejaculates. Neither the proportion of spermatozoa with large nuclei,
      nor those permeable to eosin were related to the total sperm output of males. The
      fertilizing ability of males was related to their mean seasonal proportion of
      eosin-permeable spermatozoa, but not the proportion of spermatozoa with large
      nuclei. The ranking of males on the basis of the proportion of spermatozoa with
      large nuclei in their ejaculates was significantly positively correlated between
      seasons, although ranking on the basis of sperm eosin-permeability was not. The
      cause or consequence of producing spermatozoa with large nuclei (and excess DNA)
      remains to be elucidated, but appears to be a trait that is characteristic of
      houbara bustard males that is maintained between breeding seasons.

PMID- 12617783
TI  - Development of infertility at young adult age in a mouse model of human Sandhoff
      disease.
AB  - Sandhoff disease is a human lysosomal storage disease. In a knockout mouse model
      of Sandhoff disease, which lacks the beta-subunit of beta-hexosaminidase A (Hex
      A, alphabeta subunits) and B (Hex B, betabeta subunits), the mutant homozygous
      mice (Hexb(-/-)) are healthy until 15 weeks of age when they develop
      neurodegenerative symptoms. This study was designed to analyse the fertility
      profile of male and female Hexb(-/-) mice. Mating behaviour of Hexb(-/-) mice was
      assessed at different ages. The ovarian function of Hexb(-/-) females was
      determined by superovulation studies. The quality of spermatozoa and ova was
      assessed by an in vitro fertilization (IVF) procedure. Hexb(-/-) mice were
      fertile at a young age. Males were fertile up to the age of 69.3 +/- 6.3 days
      (mean +/- SD) and females were fertile up to the age of 56-63 days. Since both
      the Hexb (-/-) sexes showed fertility, the results indicate that Hex A and Hex B
      (major isozymes of beta-hexosaminidase) may not be required for sperm-ovum
      interactions, in contrast to the widely accepted belief. On the other hand, young
      adult Hexb(-/-) males showed a reduction in mating behaviour at the age of 84.8
      +/- 2.2 days and an absence of mating behaviour at 94.2 +/- 2.0 days. Spermatozoa
      from Hexb(-/-) mice (aged 109.2 +/- 1.8 days) showed a lower IVF rate. Among Hexb
      (-/-) females aged 85.6 +/- 2.1 days, no mice became pregnant although they were
      positive for a vaginal plug when caged with fertile males. The number of ova
      recovered from Hexb(-/-) females (aged 111.0 +/- 3.1 days) and the IVF rate of
      ova were lower than those of controls. In conclusion, Hex A and Hex B may not be
      required for sperm-ovum interactions. Mice lacking Hex A and Hex B activities
      develop infertility at a young adult age in an age-dependent manner.

PMID- 12617784
TI  - Developmental changes in pulmonary and renal angiotensin-converting enzyme
      concentration in fetal and neonatal horses.
AB  - Angiotensin-converting enzyme (ACE) has an active role in the control of blood
      pressure and body fluid homeostasis both before and after birth. This study
      investigated the ontogeny of pulmonary and renal ACE concentrations in fetal and
      neonatal horses. Fetal pulmonary ACE concentration increased from 250 days
      towards term (c. 335 days). Newborn foals showed significantly higher mean
      concentrations of pulmonary ACE (4.40 +/- 0.62 nmol min(-1) mg protein(-1)) than
      both fetuses during late gestation (1.23 +/- 0.51 nmol min(-1) mg protein(-1))
      and animals aged 1 day to 2 weeks of postnatal age (0.85 +/- 0.15 nmol min(-1) mg
      protein(-1)). Renal ACE was detected in fetal horses from 100 days of gestation
      but showed no developmental trend during the second half of gestation or in early
      postnatal life. Overall in the fetus, mean concentrations of renal ACE were also
      approximately 10 times lower than mean pulmonary values. Renal ACE concentration
      may be related to the functional immaturity of the equine kidneys. The increase
      in pulmonary ACE concentration seen towards term in the fetal horse may be
      induced by the prepartum cortisol surge that occurs very close to delivery in
      this species. Therefore, premature delivery in this species may interrupt the
      onset of ACE production in the fetal lungs and circumvent the normal maturation
      of the renin-angiotensin system.

PMID- 12617785
TI  - Patterns of fetal growth within Large White x Landrace and Chinese Meishan gilt
      litters at three stages of gestation.
AB  - Low birthweight piglets have an increased incidence of mortality and morbidity.
      As there are few opportunities to remedy the detrimental consequences of low
      birthweight after birth, it is important to understand the nature of fetal growth
      retardation and to identify when low birthweight fetuses deviate from the growth
      trajectory of their normally grown siblings. The aims of this study were to
      identify the nature, timing and possible causal factors influencing inadequate
      fetal growth in Large White x Landrace (LW) and Chinese Meishan (MS) gilts at
      three stages of pregnancy. Thirty-six per cent of litters contained inadequately
      grown fetuses. Both intrauterine-growth-restricted (IUGR) and small-for
      gestational-age (SGA) fetuses could be identified as early as Day 30 in MS and LW
      litters and the percentage of litters containing inadequately grown fetuses was
      similar throughout gestation. MS fetuses, placentas and piglets had less within
      litter variation in weight at all stages studied. Inverse relationships were
      observed between litter size and both minimum and mean weights of MS neonates. No
      other relationships between fetal size and either uterine position or litter size
      were observed.

PMID- 12617786
TI  - Concentration of calcium, zinc, magnesium, potassium and sodium in the bovine
      cervical mucus during normal oestrus and oestrus induced by progesterone and/or
      PGF(2alpha).
AB  - Ninety-two healthy Friesian cows were used to determine the concentration of
      calcium (Ca), zinc (Zn), magnesium (Mg), potassium (K) and sodium (Na) in bovine
      cervical mucus and to compare these concentrations in cervical mucus collected
      during spontaneous and induced oestrus. Cows were assigned to four groups: (1) no
      treatment (2) PRID for 12 days plus pregnant mare's serum gonadotrophin (PMSG;
      1000 IU, i.m.) at the removal of the PRID (3) PGF(2alpha), two doses (6 mg, i.m.)
      11 days apart, and (4) PRID for 7 days plus one dose of PGF(2alpha) (6 mg, i.m.)
      24 h before removal of the PRID. The cows of the three induced-oestrus groups
      received two artificial inseminations (AI), whereas those in the spontaneous
      oestrus group received only one. Cervical mucus samples were collected from all
      cows 5 to 30 min before the first AI. The results of this study can be summarized
      as follows: (1) viscosity was significantly lower (P<0.001) and crystallization
      was significantly (P<0.001) higher in the cervical mucus of cows in the
      spontaneous-oestrus group compared with cows in the induced-oestrus groups; (2)
      Na concentration was similar in all groups; (3) concentration of all the other
      elements in the spontaneous-oestrus group was significantly lower (P<0.05) than
      in the induced-oestrus groups; (4) there was significant positive correlation
      (P<0.001) between viscosity and all elements, and significant negative
      correlation (P<0.05-P<0.001) between crystallization and all elements.

PMID- 12617787
TI  - Synchronization of porcine oocyte meiosis using cycloheximide and its application
      to the study of regulation by cumulus cells.
AB  - This paper describes the use of the protein synthesis inhibitor cycloheximide
      (CHX) to synchronize nuclear progression during meiotic maturation in porcine
      oocytes, and also the time-dependence of nuclear maturation on exposure of the
      oocyte to cumulus cells. Prior to culture, the majority of oocytes were at the
      germinal vesicle (GV) stage (95-100%), but distributed from GVI to GVIV (GVI 56.1
      +/- 9.1%, GVII 15.3 +/- 1.4%, GVIII 21.5 +/- 7.1%, GVIV 7.1 +/- 3.5%). During
      culture of cumulus-enclosed oocytes (COCs) from 12 h to 48 h in a conventional
      culture system, all meiotic stages were represented at any time point examined,
      with 63.6 +/- 4.2% of oocytes maturing to metaphase II (MII). Cycloheximide
      blocked the progression of nuclear development in a dose-dependent manner.
      Treatment for 12 h with CHX at 1-25 microg mL(-1) resulted in 95-100% oocytes
      being arrested and synchronized at GVII. With >5 microg mL(-1) CHX, all oocytes
      were arrested before germinal vesicle breakdown (GVBD) (mostly at GVIII) by 24 h.
      A 12 h preincubation with 5 microg mL(-1) CHX followed by 24 h of further culture
      without CHX resulted in >80% of oocytes maturing to MII. The profile of nuclear
      progression during maturation revealed discrete peaks of occurrence of different
      meiotic stages, with GVBD at 6-12 h, metaphase I (MI) at 10-18 h and anaphase
      I/telophase I at 16-20 h. After 12 h preincubation with 5 microg mL(-1) CHX,
      denuded oocytes (DOs) matured to MI as COCs. However, DOs matured to MII as
      normal when denuded at MI. In conclusion, CHX not only efficiently blocks and
      synchronizes the meiotic progression of porcine oocytes at a specific GV stage,
      but it also effectively synchronizes subsequent meiotic progression to MII,
      resulting in discrete peaks of occurrence of different meiotic stages. Using this
      technique, the study showed that cumulus cells are essential for oocytes to
      mature from MI to MII but exposure to cumulus cells must occur before MI.

PMID- 12617788
TI  - The effect of extracellular matrix molecules on mouse preimplantation embryo
      development in vitro.
AB  - The extracellular matrix (ECM) molecules, laminin (LN), chondroitin sulfate (CS),
      fibronectin (FN), hyaluronic acid (HA), mucin (MUC) and heparan sulfate
      proteoglycan (HS), were investigated as supplements to culture medium to improve
      the in vitro development of mouse 1-cell zygotes to blastocysts. Development was
      also compared with that in medium supplemented with bovine serum albumin (BSA) to
      determine the potential for ECM molecules as suitable alternatives to serum
      albumin in culture medium. Supplementation of sequential culture media with LN at
      all concentrations examined failed to result in more than 70% of zygotes
      developing to blastocysts; therefore, LN was considered unsuitable as a
      replacement for BSA and was not examined further. The optimal concentration of
      the remaining ECM molecules was used to supplement sequential culture media and
      the effect on blastocyst quality was assessed by determining the differential
      cell numbers of blastocysts grown in BSA-supplemented medium. Development to
      blastocyst was similar, regardless of the macromolecule used. The number of inner
      cell mass cells was significantly higher in HS-supplemented medium compared with
      controls. Trophectoderm cell numbers were similar to control values for all ECM
      molecules examined except CS for which there were fewer trophectoderm cells. It
      is concluded that ECM molecules, FN, HA, MUC and HS may be used as substitutes
      for serum protein supplementation of culture media EG0/G2 for mouse
      preimplantation embryo development. Heparan sulfate proteoglycan increases inner
      cell mass numbers and this may be due to interactions with the growth factors
      fibroblast growth factor 4 (FGF-4) and granulocyte-macrophage colony-stimulating
      factor.

PMID- 12617789
TI  - Development of a porcine follicle-stimulating hormone and porcine luteinizing
      hormone induced ovulation protocol in the seasonally anoestrus brushtail possum
      (Trichosurus vulpecula).
AB  - Monovulatory brushtail possums (Trichosurus vulpecula) were stimulated with
      exogenous hormones during seasonal anoestrus to overcome ovarian insensitivity
      and induce ovulation. Seasonal ovarian insensitivity to pregnant mare serum
      gonadotrophin (PMSG) was overcome by a new porcine follicle-stimulating
      hormone/porcine luteinizing hormone (pFSH/pLH) protocol. This protocol was
      refined because the original treatment produced oocytes with abnormal morphology.
      Possums (n = 12 per group) received eight injections of pFSH of 1.5, 3.0 or 6.0
      mg per injection (at 12-h intervals for 4 consecutive days). Ovulation was
      induced 12 h after the final pFSH injection with a 4-mg injection of pLH. Control
      animals were treated with the established protocol of a single injection of 15 IU
      of PMSG, followed 48 h later with an injection of 4 mg of pLH. All females
      responded to pFSH/pLH treatment, although optimal stimulation occurred in those
      receiving 8 x 3 mg pFSH, with 13-14 ovulations and recovery of 11-12 oocytes per
      female (8 x 1.5 mg pFSH: 13 ovulations, 8-9 oocytes; 8 x 6 mg pFSH: 7-8
      ovulations, 4-5 oocytes). In contrast, only seven of 12 females responded to
      PMSG/pLH and, of those responding, only 2-3 ovulations occurred and only 1-2
      oocytes per female were recovered. However, around 80% of oocytes recovered after
      PMSG/pLH treatment had undergone nuclear maturation (metaphase II/1st polar body)
      compared with around 60% of oocytes from pFSH/pLH-treated animals. In possums
      killed from 27 to 39 h after pLH treatment, ovulation onset was first observed
      from 30 h and by 31.5 h, all animals had completed ovulation. Laparoscopic
      artificial insemination (LAI) was performed on pFSH/pLH-treated animals to
      determine whether the oocytes produced were capable of fertilization. Uterine LAI
      performed 27.5-28.5 h after pLH treatment yielded 11/26 fertilized oocytes (up to
      4-cell stage), whereas vaginal LAI performed 13-14 h after pLH treatment yielded
      21/53 fertilized oocytes. A proportion of oocytes generated from the refined
      pFSH/pLH protocol are thus properly mature and capable of fertilization. Further
      refinement of the protocol is now needed to improve the yield of fully matured
      oocytes.

PMID- 12617791
TI  - Effects of electrical stimulation and seminal plasma on the motility of mouse
      sperm.
AB  - The effects of electric current (in vivo and in vitro) and seminal plasma on
      epididymal and ejaculated sperm obtained from C57BL x CBA and C57BL/6J mice were
      investigated by studying motility parameters, fertilization and embryo
      development. Electroejaculates were obtained by applying a series of computer
      generated sinusoidal alternating currents (0.25-3.0 V at 50 Hz) delivered for 1,
      2 and 3 s with 1-s rest periods using a four-electrode rectal probe for 4 min.
      Epididymal sperm obtained from the same mice were either subjected to electric
      current in vitro in a Plexiglass chamber or incubated in a medium containing
      seminal plasma for 2 h. In vitro electric current application and incubation in a
      medium containing seminal plasma significantly (P < 0.01) decreased sperm
      motility. Neither electroejaculates nor epididymal spermatozoa incubated with
      seminal plasma could fertilize oocytes by conventional IVF (P < 0.001), whereas
      sperm subjected to in vitro electric current had lost little of their ability to
      fertilize oocytes. Following transfer of embryos generated by intracytoplasmic
      sperm injection (ICSI), the number of live pups obtained from electroejaculated
      sperm (10.2%; 6/59) was significantly (P < 0.01) lower than from epididymal sperm
      (50.0%; 22/42). Electroejaculation using a rectal probe had little effect on
      motility and fertilization capacity of mouse epididymal sperm, whereas the
      presence of seminal plasma decreased motility and prevented fertilization.

PMID- 12617790
TI  - Deviant peri-oestrual hormone patterns affect the epithelium of the uterine tube
      in repeat-breeder heifers.
AB  - In the bovine reproductive tract, the uterine tube is the critical site for a
      series of events required for fertilization and early embryonic development. In
      previous studies, a defined category of subfertile heifers, repeat-breeder
      heifers (RBH), has presented peri-oestrual disturbances (deviating hormone
      patterns and follicular dynamics) and uterine maternal-embryonic asynchrony. The
      present study aimed to investigate if tubal function was also affected, by
      determination of differences in the morphology of the tubal lining epithelium of
      RBH (n = 4) in comparison to controls (n = 6) during standing oestrus, studied by
      light and electron microscopy (SEM/TEM), and relate this to steroid hormone
      concentrations and receptor distribution in the target tissues. Tissue
      distribution of oestrogen receptor alpha (ERalpha) and progesterone receptor B
      (PRB) was quantified using immunohistochemistry. In particular, secretory cells
      differed in appearance between RBH and controls. The cells were less lumen
      protruding, microvilli were fewer and smaller and secretory granules in the
      apical cytoplasm were more numerous in RBH. Furthermore, the tubal epithelium was
      conspicuously coated with amorphous material. Morphological differences between
      categories were not explained hormonally or by steroid receptor distribution,
      except in two heifers from which uterine tubes were obtained after the
      luteinizing hormone (LH) surge. The isthmic PRB : ERalpha ratio was twice as high
      in the RBH than in the control. The deviating ultrastructure found in RBH, before
      and after the LH surge, might influence the tubal microenvironment with effects
      on gamete transport and final maturation and early embryonic development. The
      present study confirms that previously recorded perturbations in reproductive
      physiology in RBH are also manifested in the uterine tube, mainly by a deviating
      ultrastructure of the lining epithelium.

PMID- 12617792
TI  - Metalloproteinase 2 activity and modulation in uterus from neonatal
      streptozotocin-induced diabetic rats during embryo implantation.
AB  - Matrix metalloproteinases (MMPs) are responsible for the remodelling of the
      uterine extracellular matrix during embryo implantation. Nitric oxide (NO)
      production is increased at the time when implantation begins. Abnormal tissue
      levels of MMPs are present in diabetes; elevated NO levels in tissues and an
      increased oxidative stress are also found. The present work evaluates the uterine
      MMP2 activity and levels during embryo implantation, as well as the influence of
      nitridergic compounds and reactive oxygen species (ROS) on the MMP2 enzymatic
      activity in a model of neonatal streptozotocin-induced diabetic rat.
      Metalloproteinase 2 activity and levels are increased in diabetic tissues
      compared with controls (P < 0.05 and P < 0.002 respectively). The uterine
      enzymatic activity in diabetic animals decreases in the presence of the NOS
      inhibitor NG-nitro-L-arginine methyl ester (P < 0.01) and is enhanced (P < 0.005)
      when a generating ROS system (xanthine/xanthine oxidase) is added to the
      incubating medium. It was also found that uterine superoxide dismutase activity
      is higher in diabetic rats than in control rats on the day of implantation (P <
      0.001), suggesting a compensatory antioxidant ability. In conclusion, the results
      show that the uterine MMP2 activity, which is higher in diabetic animals than in
      control animals, is modulated positively by NO and ROS during embryo implantation
      in a model of streptozotocin-induced diabetic rats.

PMID- 12617794
TI  - Fertility of male and female emus (Dromaius novaehollandiae) as determined by
      spermatozoa trapped in eggs.
AB  - Changes in the fertility status of 10 pairs of emus were investigated using egg
      break-out and numbers of sperm in the perivitelline membrane of the germinal disc
      (GD) region. After the sexes were separated, sperm in consecutive eggs declined
      approximately logarithmically at a mean (+/-SEM, n = 10 females) rate of -0.148
      +/- 0.021 per log day. Sperm continued to be detected in eggs for 16.5 +/- 1.7
      days during which 5.6 +/- 0.6 fertilized eggs were laid. Fertilized eggs that did
      not contain detectable sperm were laid by five females for a further 2.2 +/- 0.9
      days. Based on break-out fertility, the fertile period continued for up to 18.7
      +/- 2.1 days, for which the mean number of laid eggs was 6.3 +/- 0.8. An egg with
      a 50:50 chance of being fertilized would contain 3.5 sperm mm(-2) of GD. Based on
      the sperm decline model, an egg containing that many sperm would be laid 21 days
      after the last copulation. In emus that were not separated and allowed to
      incubate their eggs (n = 3 pairs), the number of sperm in eggs laid before and
      during incubation declined in a manner similar to that after the last copulation
      and egg-laying stopped after the females had laid 3.3 +/- 0.3 eggs. After
      incubation was terminated, females resumed laying within 8.3 +/- 1.2 days and the
      number of sperm in eggs gradually increased but it did not return to pre
      incubation levels. In non-incubating emus (three pairs), the number of sperm in
      eggs declined as laying progressed, although lit was higher during the period
      when the first seven eggs were laid than during the period when the rest of eggs
      were laid (214 +/- 39 v.100 +/- 16 sperm mm(-2) of GD). Sperm numbers varied
      between successive eggs but a sharp increase followed by a decrease acted as an
      indicator of recent copulation. There were 8.7 +/- 0.3 such increases per laying
      period (one per 2.8 +/- 0.2 eggs), a frequency that suggests that emus copulate
      once weekly. In conclusion, as long as a female emu is supplied with sperm on a
      weekly basis, she will be fertile but, when copulations stop, she will stop
      laying soon after. Male fertility appears to fall towards the end of the laying
      season and it can be affected by egg incubation at any time of the season.

PMID- 12617793
TI  - Immunohistochemical distribution of oestrogen and progesterone receptors and
      tissue concentrations of oestrogens in the cervix of non-pregnant cows.
AB  - An immunohistochemical study of the expression of oestrogen (ER) and progesterone
      receptors (PR) in different regions along the longitudinal and vertical axes of
      the cervix of non-pregnant cows was performed. Animals were separated into two
      groups depending on the presence or absence of a functional corpus luteum in
      their ovaries, as indicated by blood progesterone concentrations. The high
      progesterone group (HP4) had serum progesterone concentrations > 2.0 ng mL(-1) (n
      = 6) and the low progesterone group (LP4) had serum progesterone concentrations <
      or = 0.5 ng mL(-1) (n = 4). Significantly higher concentrations of oestrogen were
      found in the cervical tissue of animals in the LP4 group than those in the HP4
      group (473 +/- 53 v.149 +/- 46 pg g(-1) wet weight; P < 0.01). Furthermore, there
      was a significant effect of tissue layer (epithelium to deep stroma) on the
      number of ER (P < 0.01) and PR (P < 0.05) immunoreactive nuclei per 1000 cells.
      For both ER and PR the proportion of cells expressing the receptor increased from
      epithelium to subepithelial stroma (P < 0.01) and from subepithelium to deep
      stroma (ER P < 0.05; PR P =0.061). When the number of receptor-positive cells
      were expressed per mm2 tissue, differences between the subepithelial stroma and
      the deep stroma became even more marked. In addition, the vaginal part of the
      cervix had significantly more (P < 0.01) ER and PR immunoreactive nuclei per 1000
      cells than the uterine part, but these differences were no longer apparent when a
      correction was made for cell density. There was no relationship between
      progesterone status of the animals, nor local tissue oestrogen concentrations and
      ER or PR immunoreactivity in the cervix of these non-pregnant cows. Instead, a
      strong relationship between both longitudinal and vertical positioning of tissue
      in the cervix and expression of both receptor types was shown. In addition, a
      strong correlation between ER and PR expression in the subepithelial stroma (R =
      0.85, P < 0.01) and the deep stroma (R = 0.83 P < 0.01) was evident. In
      conclusion, these results demonstrate that in studies of steroid hormone receptor
      expression in the cervix, careful description of sampling site and depth are
      necessary if the results are to be interpreted meaningfully.

PMID- 12617795
TI  - Production of lambs of predetermined sex after the insemination of ewes with low
      numbers of frozen-thawed sorted X- or Y-chromosome-bearing spermatozoa.
AB  - The fertilizing ability of sex-sorted frozen-thawed ram spermatozoa was assessed
      after insemination of mature Merino ewes at a synchronized oestrus. Ewes were
      inseminated into the uterus or utero-tubal junction (UTJ) with a total of 140 x
      10(6) unsorted (control) or 2-4 x 10(6) sorted (X or Y) frozen-thawed ram
      spermatozoa 54 to 57 hours after removal of progestagen-impregnated pessaries and
      an injection of 400 IU of pregnant mare serum gonadotrophin (Folligon, Intervet).
      The spermatozoa were separated into X- and Y-chromosome-bearing spermatozoa after
      analysis with a modified high-speed cell sorter (SX MoFlo). The number of ewes
      pregnant after insemination with unsorted frozen-thawed spermatozoa was
      significantly higher (26/48; 54.3%) than for ewes inseminated with either X-
      (12/48; 25.0%) or Y-sorted spermatozoa (7/48; 14.6%) (P<0.05). Seventeen of the
      eighteen lambs produced by ewes inseminated with X-sorted spermatozoa were female
      (94.4%) and 8/8 lambs from ewes inseminated with Y-sorted spermatozoa were male
      (100%). The sex ratio of the lambs born to ewes inseminated with sex-sorted
      spermatozoa was significantly skewed from the 51.3% male and 48.7% female ratio
      in the control group (P<0.05). This study showed, for the first time, that lambs
      of predicted sex can be produced after insemination with low numbers of sex
      sorted cryopreserved ram spermatozoa.

PMID- 12617796
TI  - Characterization of viability, mitochondrial activity, acrosomal integrity and
      capacitation status in boar sperm during in vitro storage at different ambient
      temperatures.
AB  - Extended storage of unfrozen boar semen becomes an alternative because the use of
      frozen-thawed boar sperm results in low fertility. Sperm viability, mitochondrial
      activity, capacitation and acrosome integrity of freshly ejaculated boar semen
      stored in vitro for up to 48 h at 4 degrees C, 15 degrees C, 20 degrees C and 39
      degrees C was characterized during the study. The viability of boar sperm was
      assessed by both Hoechst 33258 and SYBR-14/PI staining. Mitochondrial function
      was assessed by JC-1 staining. Capacitation status was determined by
      chlortetracycline (CTC)/Hoechst 33258 staining. The acrosome integrity was
      analysed with Coomassie blue staining. These data were derived from three
      ejaculates each from three crossbred boars. The viabilities assessed with SYBR
      14/PI, Hoechst 33258 and JC-1 staining correlated highly (r > 0.980). In freshly
      ejaculated boar semen, 96 +/- 1% of the sperm did not take up the Hoechst 33258,
      whereas 95 +/- 2% were stained by SYBR-14 and 96 +/- 2% of the sperm had
      mitochondria exhibiting positive JC-1 staining. Staining with CTC/Hoechst 33258
      suggested that a high percentage of sperm became capacitated after 24 h storage
      at 15 degrees C and 20 degrees C. There were 62 +/- 2% (15 degrees C) and 89 +/-
      2% (20 degrees C) capacitated sperm by 48 h. Moreover, most of the capacitated
      sperm were acrosome intact. These results suggest that SYBR-14/PI, Hoechst 33258
      or JC-1 staining can be used to effectively evaluate the quality of boar sperm
      during in vitro storage.

PMID- 12617797
TI  - The phosphatidylinositol signalling system in elongating bovine blastocysts;
      formation of phosphoinositides, inositol phosphates and stimulation by growth
      factors.
AB  - The uptake of myo-inositol and its incorporation into the phosphoinositides and
      inositol phosphates of the phosphatidylinositol (PtdIns) signal transduction
      system by in vivo elongating cattle blastocysts was investigated using [3H]myo
      inositol. Uptake was examined in 13-, 14- and 16-day-old blastocysts and was
      largely sodium-dependent throughout (P<0.001), indicating the presence of a
      sodium-dependent inositol transporter. Incorporation of inositol into the three
      phosphoinositides, PtdIns, PtdInsP and PtdInsP2, and the inositol phosphates of
      the phosphatidylinositol signal transduction system was examined at Days 14 and
      16; incorporation into the three phosphoinositides and into the inositol
      phosphate species, InsP1, InsP2, InsP3 (including the second messenger,
      Ins(1,4,5)P3) and InsP4 was detected in both blastocyst stages. The effects of
      the peptide growth factor, epidermal growth factor (EGF), and the lipid growth
      factors, lysophosphatidic acid (LPA) and platelet activating factor (PAF), on the
      activity of the phosphatidylinositol signalling system in 14- and 16-day-old
      blastocysts were examined. All growth factors significantly stimulated
      phosphatidylinositol signalling activity. Epidermal growth factor was stimulatory
      (P<0.001) only in 16-day-old blastocysts, whereas LPA and PAF were active in both
      14- (P<0.005 for LPA and P<0.001 for PAF) and 16-day-old blastocysts (P<0.001 for
      LPA and PAF). These results indicate that the phosphatidylinositol signalling
      system is present in cattle blastocysts at the elongation stage and is responsive
      to stimulation by growth factors.

PMID- 12617798
TI  - Expression of the FGF receptor 2 gene (fgfr2) during embryogenesis in the
      zebrafish Danio rerio.
AB  - We isolated a full-length cDNA clone for the zebrafish homologue of fibroblast
      growth factor receptor (FGFR) 2. The deduced protein sequence is typical of
      vertebrate FGFRs in that it has three Ig-like domains in the extracellular
      region. The expression of fgfr2 is initiated during epiboly in the paraxial
      mesoderm. During early somitogenesis, fgfr2 expression was noted in the anterior
      neural plate as well as in newly formed somites. Whereas fgfr2 expression in
      somites is transient, it increases in the central nervous system (CNS), i.e. in
      the ventral telencephalon, anterior diencephalon, midbrain, and respective
      rhombomeres of the hindbrain, from the mid-somitogenesis stage. The dorsal
      telencephalon and the region around the midbrain-hindbrain boundary are devoid of
      fgfr2 expression. Essentially the same expression pattern is observed until 48 h
      post-fertilization in the CNS, although rhombomeric expression in the hindbrain
      is progressively confined to narrower stripes. After somitogenesis, fgfr2
      expression was also observed in the lens, hypochord, endoderm, and fin
      mesenchyme. We compared the expression of the four fgfr genes (fgfr1-4) in the
      CNS of zebrafish embryos and show that fgfr1 is the only fgfr gene that is
      expressed in the dorsal telencephalon and isthmic region from which expression of
      fgfr2-4 is absent.

PMID- 12617799
TI  - Mouse Crossveinless-2 is the vertebrate homolog of a Drosophila extracellular
      regulator of BMP signaling.
AB  - The Dpp/BMP signaling pathway is highly conserved between vertebrates and
      invertebrates. The recent molecular characterization of the Drosophila
      crossveinless-2 (cv-2) mutation by Conley and colleagues introduced a novel
      regulatory step in the Dpp/BMP pathway (Development 127 (2000) 3945). The CV-2
      protein is secreted and contains five cysteine-rich (CR) domains similar to those
      observed in the BMP antagonist Short gastrulation (Sog) of Drosophila and Chordin
      (Chd) of vertebrates. The mutant phenotype in Drosophila suggests that CV-2 is
      required for the differentiation of crossvein structures in the wing which
      require high Dpp levels. Here we present the mouse and human homologs of the
      Drosophila cv-2 protein. The mouse gene is located on chromosome 9A3 while the
      human locus maps on chromosome 7p14. CV-2 is expressed dynamically during mouse
      development, in particular in regions of high BMP signaling such as the posterior
      primitive streak, ventral tail bud and prevertebral cartilages. We conclude that
      CV-2 is an evolutionarily conserved extracellular regulator of the Dpp/BMP
      signaling pathway.

PMID- 12617800
TI  - Characterization of DeY1, a novel Y-box gene specifically expressed in
      differentiating male germ cells of planarians.
AB  - Y-box proteins are conserved regulatory factors that play a key role in
      coordinating gene activity with protein synthesis by influencing both the
      transcription and translation of specific subsets of genes. We report the
      identification of a novel Y-box gene, DeY1, whose transcripts are found in the
      testes of sexual planarians. DeY1 is expressed in spermatogonia, spermatocytes
      and spermatids, while no expression is detected in spermatozoa. No DeY1
      transcripts are found in the blastema during regeneration. The subcellular
      distribution of DeY1 protein was analyzed by electron microscope
      immunocytochemistry. Immunolabelling was found in the nucleus of spermatogonia,
      in both the nucleus and the cytoplasm of spermatocytes, and in the cytoplasm of
      spermatids.

PMID- 12617801
TI  - Developmental expression of zebrafish emx1 during early embryogenesis.
AB  - Emx family homeobox genes, Emx1 and Emx2, play an essential role in rostral brain
      development in mammalian embryos. Here we report a zebrafish emx family gene,
      emx1, which is more similar to the mouse Emx1 gene than the previously reported
      zebrafish emx1 gene; we propose to rename that gene emx3. The expression of emx1
      is first detected around the 10-somite stage in the pineal gland (epiphysis)
      primodium in the developing anterior brain and in the pronephric primodium within
      the intermediate mesoderm. emx1 expression in the epiphysis has not been reported
      in other species. Expression in the epiphysis is suppressed at 23 h post
      fertilization (hpf) in the floating head (flh) mutant, in which development of
      the epiphysis is impaired. Subsequently, emx1 is expressed in the telencephalon,
      as reported in mammals, and can be detected in the olfactory placode and in a
      small group of cells in the forebrain at 25 hpf. In the mesoderm, emx1 expression
      is gradually concentrated in the posterior pronephric duct during somitogenesis,
      and becomes expressed predominantly in the urogenital opening at 25 hpf. Thus,
      emx1 displays a unique expression pattern that is distinct from the patterns of
      emx2 and emx3.

PMID- 12617803
TI  - Expression of gamma-adducin is associated with regions of morphogenetic cell
      movement in the chick embryo.
AB  - The adducin family of cytoskeletal proteins are known to mediate actin driven
      cell movements. Here we describe the cloning and expression pattern of a gene
      encoding gamma-adducin in the chick embryo. Expression of this gene is strikingly
      restricted to the epithelial cell layer (with a few exceptions including emerging
      notochord and lateral mesoderm). Gamma-adducin is detected at particularly high
      levels in cell populations undergoing important morphogenetic movements, such as
      epiblast approaching the primitive streak, regressing spinal cord primordia and
      closing neural tube.

PMID- 12617802
TI  - Dynamic expression and regulation by Fgf8 and Pou2 of the zebrafish LIM-only
      gene, lmo4.
AB  - We report the expression of zebrafish lmo4 during the first 48 h of development.
      Like its murine ortholog, lmo4 is expressed in somitic mesoderm, branchial
      arches, otic vesicles, and limb (pectoral fin) buds. In addition, however, we
      report zebrafish lmo4 expression in the developing eye, cardiovascular tissue,
      and the neural plate and telencephalon. We demonstrate that expression in the
      rostral hindbrain requires acerebellar (ace/fgf8) and spiel ohne grenzen
      (spg/pou2) activity.

PMID- 12617804
TI  - Expression of zebrafish cyp11a1 as a maternal transcript and in yolk syncytial
      layer.
AB  - Cyp11a1 (P450scc, cholesterol side-chain cleavage enzyme) is the first enzyme for
      the synthesis of all steroid hormones. The regulation of steroid synthesis has
      been extensively investigated, except during embryogenesis. To study
      steroidogenesis in embryos, we have isolated the zebrafish cyp11a1 gene, which
      consists of 11 exons. Reverse transcription-polymerase chain reaction analysis
      indicates that zebrafish cyp11a1 is expressed temporally in two waves during
      embryonic stages and when sexual differentiation begins. It is expressed in adult
      brain, testicular Leydig cells, and the granulosa/theca layer of the ovary. In
      addition, zebrafish cyp11a1 is expressed in oocytes, and is inherited as a
      maternal transcript in early embryos. Throughout zebrafish epiboly and
      segmentation stages, cyp11a1 is expressed in the yolk syncytial layer. At 36 h
      post fertilization, cyp11a1 transcript is located ventral to the third somite,
      where the primordial interrenal gland is located. In summary, zebrafish cyp11a1
      is expressed in the cytoplasm of oocytes, as a maternal transcript, and in yolk
      syncytial layer during early embryogenesis.

PMID- 12617805
TI  - Foxp4: a novel member of the Foxp subfamily of winged-helix genes co-expressed
      with Foxp1 and Foxp2 in pulmonary and gut tissues.
AB  - In this study, we describe the isolation and characterization of Foxp4, a new
      member of the Foxp subfamily of winged-helix transcription factors. The full
      length mouse Foxp4 cDNA encodes a 685-amino-acid protein that is similar to Foxp1
      and Foxp2. Foxp4 gene expression is observed primarily in pulmonary, neural, and
      gut tissues during embryonic development. To compare the protein expression
      patterns of Foxp4 to Foxp1 and Foxp2, specific polyclonal antisera to each of
      these proteins was used in immunohistochemical analysis of mouse embryonic
      tissues. All three proteins are expressed in lung epithelium with Foxp1 and Foxp4
      expressed in both proximal and distal airway epithelium while Foxp2 is expressed
      primarily in distal epithelium. Foxp1 protein expression is also observed in the
      mesenchyme and vascular endothelial cells of the lung. At embryonic day 12.5,
      Foxp1 and Foxp2 are expressed in both the mucosal and epithelial layers of the
      intestine. However, Foxp2 is expressed only in the outer mucosal layer of the
      intestine and stomach later in development. Finally, Foxp4 is expressed
      exclusively in the epithelial cells of the developing intestine, where, in late
      development, it is expressed in a gradient along the longitudinal axis of the
      villi.

PMID- 12617806
TI  - Differential gene expression in the distal tip endoderm of the embryonic mouse
      lung.
AB  - During the early development of the mouse lung a number of genes encoding
      signaling molecules are differentially expressed in the epithelium and mesenchyme
      of the distal buds. Evidence suggests they play a role in regulating the
      stereotypic processes of bud outgrowth and branching as well as proximal-distal
      patterning of both cell layers. To better understand the mechanisms underlying
      branching morphogenesis, a subtractive hybridization and differential screen was
      carried out for genes preferentially expressed in the epithelium at the tips of
      embryonic day 11.5 lung buds, versus more proximal regions. Twenty genes were
      identified, assigned to different categories based on sequence analysis, and
      their distal expression confirmed by whole-mount in situ hybridization.

PMID- 12617807
TI  - Gene expression markers for Caenorhabditis elegans vulval cells.
AB  - The analysis of cell fate patterning during the vulval development of
      Caenorhabditis elegans has relied mostly on the direct observation of cell
      divisions and cell movements (cell lineage analysis). However, reconstruction of
      the developing vulva from EM serial sections has suggested seven different cell
      types (vulA, vulB1, vulB2, vulC, vulD, vulE, and vulF), many of which cannot be
      distinguished based on such observations. Here we report the vulval expression of
      seven genes, egl-17, cdh-3, ceh-2, zmp-1, B0034.1, T04B2.6 and F47B8.6 based on
      gfp, cfp and yfp (green fluorescent protein and color variants) reporter fusions.
      Each gene expresses in a specific subset of vulval cells, and is therefore useful
      as a marker for vulval cell fates. Together, expressions of markers distinguish
      six cell types, and reveal a strict temporal control of gene expression in the
      developing vulva.

PMID- 12617808
TI  - Cloning, mapping, and developmental expression of a sixth zebrafish Na,K-ATPase
      alpha1 subunit gene (atp1a1a.5).
AB  - We have identified and characterized cDNAs encoding a novel zebrafish Na,K-ATPase
      alpha subunit. The full-length cDNA encodes a 1,023-amino-acid-long peptide which
      shows greatest homology to zebrafish alpha1 polypeptides. Radiation hybrid
      mapping localized the new gene (atp1a1a.5) to linkage group 1 in close proximity
      to the previously identified cluster of Na,K-ATPase alpha1 genes. The expression
      of atp1a1a.5 in zebrafish embryos was analyzed using whole-mount in situ
      hybridization. From mid-somitogenesis through 48 h post fertilization (hpf),
      atp1a1a.5 transcripts were detected in the pronephric duct, ear, and mucous
      cells. This expression pattern continues through 108 hpf, when high levels of
      expression were also detected in the intestinal bulb.

PMID- 12617809
TI  - Expression of Notch pathway components in fetal and adult mouse small intestine.
AB  - Cell-to-cell communication mediated by the evolutionary conserved Notch
      signalling pathway regulates cell fate decisions and patterning in various
      tissues in invertebrates and vertebrates (Science 284 (1999) 770). In mouse, four
      Notch receptors, five ligands of the delta and Serrate types, three fringe
      glycosyltransferases that modify Notch, and a growing number of direct
      transcriptional targets of Notch are known. Mutational analysis of Hes1 (Nat.
      Genet. 24 (2000) 36) and Math1 (Science 294 (2001) 2155) have implicated Notch
      signalling in the regulation of intestinal epithelium development and
      homeostasis. Here, we describe the expression of the genes encoding the murine
      Notch receptors (Notch1-4), the ligands (delta1, 3, 4 and Jagged1, 2), the
      modifying glycosyltransferases of the fringe family (Lfng, Mfng, Rfng) and four
      Hes genes (Hes1, 5, 6, 7) in the mouse small intestine during fetal (E13.5 and
      E18.5) and postnatal (P25) development. All analyzed Notch pathway components
      were expressed in the intestine, although at different levels and with varying
      spatial and temporal distribution, consistent with roles of Notch signalling at
      various stages of intestinal development and renewal.

PMID- 12617810
TI  - Cloning of two tryptophan hydroxylase genes expressed in the diencephalon of the
      developing zebrafish brain.
AB  - The monoamine serotonin (5-HT) exerts key neuromodulatory activities in all
      animal phyla, but the development and function of the serotonergic system is
      still incompletely understood. The zebrafish Danio rerio is an excellent model to
      approach this question since it is amenable to a combination of genetic,
      molecular and embryological studies. In order to characterize the organization of
      serotonergic neurons in the zebrafish we cloned two cDNAs encoding distinct forms
      of tryptophan hydroxylase (Tph), the rate-limiting enzyme in serotonin synthesis.
      We report here the pattern of expression of these two genes in relation with
      immunoreactive TH and 5-HT nuclei in the developing zebrafish embryo and early
      larva. tphD1 expression starts at 22 h post-fertilization (hpf) in the epiphysis
      and in basal spinal cells. Expression persists in the epiphysis until at least 4
      days (dpf). Between 48 hpf and 3 dpf, tphD1 expression is initiated in retinal
      amacrine cells and in restricted preoptic and posterior tubercular nuclei within
      the basal diencephalon. At 3 and 4 dpf, tphD1 expression is newly initiated in
      the caudal hypothalamus and in branchial arches-associated neurons. tphD2 mRNA is
      detected transiently (between 30 somites and 32 hpf) in a restricted preoptic
      nucleus. All sites of tphD1 or D2 expression within the anterior central nervous
      system are also immunoreactive for 5-HT, but are not positive for TH. However,
      neither tphD gene is expressed in raphe nuclei, suggesting that additional tph
      gene(s) exist in zebrafish to account for 5-HT synthesis in that location. The co
      expression of tphD1, tphD2 and 5-HT in the zebrafish diencephalon appears in
      striking contrast to the situation in mammals, where diencephalic serotonin
      results from re-uptake rather than from local production.

PMID- 12617811
TI  - Ziwi, the zebrafish homologue of the Drosophila piwi: co-localization with vasa
      at the embryonic genital ridge and gonad-specific expression in the adults.
AB  - PIWI regulates the proliferation and maintenance of germline stem cells in
      diverse organisms. The full-length 3.26 kb ziwi cDNA, the zebrafish homologue of
      piwi of Drosophila, encodes a putative protein of 858 amino acids. ZIWI is 65%
      homologous with the mouse and human PIWI, but only 38 and 33% with Caenorhabditis
      elegans and Drosophila PIWI, respectively. In adult zebrafish, ziwi is expressed
      exclusively in the gonads. In embryos and fry, its expression is detectable
      initially during segmentation and persisted for at least 4 weeks post hatching.
      During neurogenesis and organogenesis, its expression was detected in the CNS and
      fin buds. Starting from 24 hpf and later on, ziwi transcripts were found in the
      genital ridge.

PMID- 12617812
TI  - Compartmentalized Eph receptor and ephrin expression in the thymus.
AB  - The maturation of T cells is an intricate process involving the interaction of
      developing thymocytes with discrete microenvironments within the thymus. Numerous
      studies have indicated that distinct thymic compartments provide signals required
      for each stage of thymocyte maturation. In this study we performed a
      comprehensive analysis of the expression patterns of Eph-A receptors and ephrins
      A in the thymus using in situ hybridization and reverse transcription-polymerase
      chain reaction, and show that expression of these molecules is highly
      compartmentalized. Based on these expression patterns and the known mechanisms of
      action of Eph receptor/ephrin interactions in other organs, these data suggest
      that differential Eph receptor expression on discrete subsets of thymic stromal
      cells may be important in establishing compartment boundaries and preventing
      intermingling of stromal cell subtypes. Further, together with chemotactic
      signals such as those provided by chemokines, regulated Eph receptor/ephrin
      expression on thymocytes may play a role in thymocyte migration.

PMID- 12617813
TI  - Developmental expression of EphA4-tyrosine kinase receptor in the mouse brain and
      spinal cord.
AB  - Eph receptor tyrosine kinases and their ephrin ligands are involved in some of
      the most important steps during the development of the central nervous system,
      including cell migration, axon guidance, topographic mapping and synapse
      formation. Moreover, in the adult, they have been implicated in plasticity and
      regulation of neural stem cell function. One member of the Eph family, EphA4, can
      bind to both classes of ephrins and may have multiple functions in nervous system
      development. In order to look for potential sites of EphA4 action during central
      nervous system development, we conducted a spatio-temporal analysis of EphA4
      protein expression. We used immunohistochemistry in preference to in situ
      hybridization because of the high likelihood that EphA4 protein is expressed on
      axon tracts, long distances from EphA4 mRNA. In the telencephalon, EphA4 was
      expressed in the developing cortex from embryonic day 11 (E11) and, later, on
      major cortical tracts including the corpus callosum and cortico-spinal tract.
      Robust EphA4 expression was also found in the hippocampus and fornix, and cells
      and tracts in the striatum. In the diencephalon, the thalamus, the hypothalamus
      and thalamo-cortical projection were strongly positive. In the mesencephalon, a
      number of different nuclei were weakly positive, most prominently the red
      nucleus. In the rhombencephalon, many nuclei were strongly positive including the
      cerebellum and one of its afferent paths, the inferior cerebellar peduncle, as
      well as the olivary region. In the spinal cord, there was a dynamic pattern of
      expression through development, with persistent expression in the dorsal
      funiculus and ventral grey matter.

PMID- 12617815
TI  - Xdtx1, a Xenopus Deltex homologue expressed in differentiating neurons and in
      photoreceptive organs.
AB  - We report the isolation of Xdtx1, a Xenopus homologue of the Drosophila Deltex
      gene. Starting from tailbud stage, Xdtx1 transcripts are detected in the
      olfactory bulbs, pineal complex and along the neural tube according to an antero
      posterior gradient showing a gap at the midbrain-hindbrain boundary. At tadpole
      stage, Xdtx1 expression is activated in the differentiating retina, where it is
      also found in the neuronal fibres of the outer and inner plexiform layers, while
      its expression in the pineal complex becomes restricted to the photosensitive
      frontal organ. Differently from other vertebrate Deltex homologues, Xdtx1 is
      exclusively expressed in regions undergoing neuronal differentiation as shown by
      complementarity with X-Notch-1 expression.

PMID- 12617814
TI  - Characterisation and developmental expression of mouse Plu-1, a homologue of a
      human nuclear protein (PLU-1) which is specifically up-regulated in breast
      cancer.
AB  - PLU-1 is a novel breast cancer associated nuclear protein containing highly
      conserved domains including the PLU domain, putative DNA/chromatin binding
      motifs, and PHD/LAP domains. Here we report the cloning of the mouse homologue
      (Plu-1), and document its expression in adult tissues, mammary tumours and the
      embryo. The overall homology with human PLU-1 is 94% at the protein level, with
      almost 100% identity in the conserved domains, suggesting functional
      conservation. As with human PLU-1 the expression of Plu-1 in adult tissues is
      restricted, with high expression being seen only in testis, while expression in
      mammary tumours from c-neu transgenic mice is high. Plu-1 is also differentially
      expressed in the adult mammary gland. In the developing embryo Plu-1 is expressed
      in a temporally restricted fashion with tissue specific expression being limited
      to parts of the developing brain, whisker follicle, mammary bud, thymus, limbs,
      intervertebral disc, olfactory epithelium, teeth, eye, and stomach. The temporal
      and spatial expression patterns of the transcription factors Bf-1 and Pax9,
      recently found to bind to PLU-1 through the PLU domain overlap with Plu-1
      expression during development. Thus Plu-1 appears to play an important role in
      mouse embryonic development which may involve interaction with Pax9 and Bf-1.

PMID- 12617816
TI  - Identification and expression of Ima, a novel Ral-interacting Drosophila protein.
AB  - We report the identification of Ima, a novel Drosophila MAGUK-like protein, which
      contains two WW and four PDZ protein interaction domains and interacts with the
      small GTPase dRal in the yeast two-hybrid system and pull-down assays. The gene
      is expressed in distinct spatiotemporal patterns throughout embryonic
      development. Overexpression of Ima interferes with normal Drosophila development,
      indicating that the gene functions in a tissue specific manner.

PMID- 12617817
TI  - Developmentally regulated expression of mil-1 and mil-2, mouse interferon-induced
      transmembrane protein like genes, during formation and differentiation of
      primordial germ cells.
AB  - In all multicellular organisms, germ cells originating from a fertilized egg have
      the highly specialized role of transmitting genetic information to the next
      generation. In many animal species, the establishment of the germ cell lineage is
      regulated by the maternally inherited germplasm. In mammals, however, germline
      determination is not based on the unequal distribution of maternal determinants.
      In the processes of mammalian germ cell formation and subsequent differentiation,
      the molecular basis of the acquisition of germ cell status is not well
      understood. Since migrating primordial germ cells (PGCs) are lineage-restricted
      to the germline, they have already acquired a germ cell specific fate distinct
      from that of pluri/multi-potent stem cells. However, there have been no molecules
      known to be expressed in migrating PGCs but not in the inner cell mass of
      blastocysts. Such molecules should be involved in early germ cell development,
      and they should make good markers for following the process of PGC formation. To
      identify such molecules, we performed a subtracted cDNA screening with migrating
      PGCs and blastocysts in mice, and isolated 11 clones preferentially expressed in
      PGCs. Here, we report the identification of two genes with similarity to human
      interferon-induced transmembrane protein (Ifitm) genes, and expression patterns
      of these genes in forming and in differentiating PGCs. During germ cell
      formation, mouse Ifitm like (mil)-1 was expressed in putative PGC ancestors in
      embryos at 6.5-7.5 days post coitum. In migrating PGCs, mil-1 expression was
      continuously observed and mil-2 expression was first detected during germ cell
      differentiation.

PMID- 12617818
TI  - VITO-1, a novel vestigial related protein is predominantly expressed in the
      skeletal muscle lineage.
AB  - In order to identify novel genes expressed in skeletal muscle we performed a
      subtractive hybridization for genes expressed in human skeletal muscle but not in
      other tissues. We identified a novel scalloped interaction domain (SID)
      containing protein in humans and in the mouse, which we named VITO-1. Highest
      homology of VITO-1 was found with the Drosophila vestigial and the human TONDU
      proteins in the SID (54 and 40%, respectively). Using whole-mount hybridzation
      and Northern blot analysis, we showed that VITO-1 is expressed in the somitic
      myotome from E8.75 mouse embryos onwards and later on in skeletal muscle but not
      in the heart. Additional expression domains during development were detected in
      the pharyngeal pouches and clefts starting at E8.0 as well as in the cranial
      pharynx and in Rathkes pouch. By Northern blot analysis, we found VITO-1 to be up
      regulated in C2C12 myotubes although some expression can be detected in
      proliferating C2C12 myoblasts. No expression was spotted in other adult mouse
      tissues. Likewise, expression of human Vito-1 during fetal and adult human
      development was found exclusively in skeletal muscle preferentially in fast
      skeletal muscles. These data suggest a role of VITO-1 for the development of
      skeletal muscles and of pharyngeal clefts/Rathkes' pouch derived structures.

PMID- 12617819
TI  - Tissue and stage-specific expression of the Tolls in Drosophila embryos.
AB  - The Drosophila transmembrane receptor Toll plays a key role in specifying the
      dorsoventral axis of the embryo. At later stages of development, it controls the
      immune response of the fly to fungal and Gram-positive bacterial infections. The
      Drosophila genome has a total of nine Toll-like genes, including the previously
      characterized Toll (Toll-1) and 18-wheeler (Toll-2). Here we describe the
      embryonic expression patterns of the seven Toll-like genes Toll-3 through Toll-9.
      We find that these genes have distinct expression domains and that their
      expression is dynamically changing throughout embryonic development. This complex
      and tissue-specific regulation of Toll-like gene expression strongly suggests a
      role in embryonic development for most Drosophila Tolls. The evolving picture on
      the Toll family members in Drosophila contrasts with that of mammalian Toll-like
      receptors, which are predominantly expressed in immune responsive cells where
      their activation occurs via microbial structural determinants.

PMID- 12617820
TI  - Region specific gene expressions in the central nervous system of the ascidian
      embryo.
AB  - The vertebrate brain is regionalized during development into forebrain, midbrain
      and hindbrain. Fibroblast growth factor 8 (FGF8) is expressed in the
      midbrain/hindbrain boundary (MHB) and functions as an organizer molecule.
      Previous studies demonstrated that the brain of basal chordates or ascidians is
      also regionalized at least into fore/midbrain and hindbrain. To better understand
      the ascidian brain regionalization, the expression of the Ciona Fgf8/17/18 gene
      was compared with the expression of Otx, En and Pax2/5/8 genes. The expression
      pattern of these genes resembled that of the genes in the vertebrate forebrain,
      midbrain, MHB and hindbrain, each of those domains being characterized by sole or
      combined expression of Otx, Pax2/5/8, En and Fgf8/17/18. In addition, the
      putative forebrain and midbrain expressed Ci-FgfL and Ci-Fgf9/16/20,
      respectively. Therefore, the regionalization of the ascidian larval central
      nervous system was also marked by the expression of Fgf genes.

PMID- 12617821
TI  - tincar encodes a novel transmembrane protein expressed in the Tinman-expressing
      cardioblasts of Drosophila.
AB  - We cloned and characterized the Drosophila gene, tincar (tinc), which encodes a
      novel protein with eight putative transmembrane domains. The tinc mRNA was
      expressed specifically in four of the six pairs of cardioblasts in each segment,
      in a pattern identical to that of tinman (tin), a homeobox gene required for the
      specification of the dorsal vessel. In the non-Tin-expressing pairs of
      cardioblasts, tinc transcription seemed to be repressed by Seven-up.

PMID- 12617822
TI  - Exhaustive identification of human class II basic helix-loop-helix proteins by
      virtual library screening.
AB  - Cellular proliferation, specification and differentiation in developing tissues
      are tightly coordinated by groups of transcription factors in response to
      extrinsic and intrinsic signals. Furthermore, renewable pools of stem cells in
      adult tissues are subject to similar regulation. Basic helix-loop-helix (bHLH)
      proteins are a group of transcription factors that exert such a determinative
      influence on a variety of developmental pathways from C. elegans to humans, and
      we wished to exclusively identify novel members from within the whole human bHLH
      family. We have, therefore, developed an 'empirical custom fingerprint', to
      define the class II bHLH domain and exclusively identify these proteins in
      silico. We have identified nine previously uncharacterised human class II
      proteins, four of which were novel, by interrogating conceptual translations of
      the GenBank HTGS database. RT-PCR and mammalian 2-hybrid analysis of a subset of
      the factors demonstrated that they were indeed expressed, and were able to
      interact with an appropriate binding partner in vitro. Thus, we are now
      approaching an almost complete listing of human class II bHLH factors.

PMID- 12617823
TI  - Metabolism of sphingosine 1-phosphate and lysophosphatidic acid: a genome wide
      analysis of gene expression in Drosophila.
AB  - Lipids, in addition to being structural components of cell membranes, can act as
      signaling molecules. Bioactive lipids, such as sphingosine 1-phosphate (S1P) and
      lysophosphatidic acid (LPA), may act intracellularly as second messengers or be
      secreted and act as intercellular signaling molecules. Such molecules can affect
      a variety of cellular processes including apoptosis, proliferation,
      differentiation and motility. To investigate possible sources of bioactive lipids
      during development we have searched the Drosophila genome for homologs of genes
      involved in mammalian S1P and LPA metabolism. Here we report the developmental
      expression of 31 such genes by in situ hybridization to Drosophila embryos. Most
      show expression in specific tissues, with expression in the gut and nervous
      system being recurring patterns.

PMID- 12617824
TI  - Expression of Spred and Sprouty in developing rat lung.
AB  - Sproutys and Sprouty-related proteins, Spred-1 and -2, are known inhibitors of
      fibroblast growth factor (FGF) signaling, which plays key role in lung branching
      morphogenesis and the development of other tissues. The present study
      demonstrates that Spreds are expressed in a variety of rat embryonic tissues
      (brain, intestine, heart, skin) including the lung. In the embryonic lung, Spreds
      and Sproutys are expressed during the early stages of branching morphogenesis,
      but their expression profiles are both distinct and overlapping. Spreds are
      predominantly expressed in mesenchymal cells in contrast to Sproutys, which are
      abundantly expressed in epithelial cells. Spred expression is especially strong
      in the regions of new bud formation both in the peripheral mesenchyme as well as
      in the epithelium. The peripheral region also expresses FGF-10 in the mesenchymal
      cells and FGF-9 in the mesothelial cells. The expression profiles suggest that
      Spreds, Sproutys and FGF-9/FGF-10 are part of epithelial-mesenchymal
      interactions, which are essential for the development and maintenance of normal
      lung branching pattern.

PMID- 12617825
TI  - Expression of zisp, a DHHC zinc finger gene, in somites and lens during zebrafish
      embryogenesis.
AB  - The zebrafish zisp gene encodes a putative transmembrane protein with a DHHC zinc
      finger motif. At the segmentation period zisp is expressed in the adaxial cells
      and the somites in a striping pattern. The zisp transcripts are localized to the
      posterior parts within the individual somites. In fused somites mutants, zisp is
      expressed throughout the somitic mesoderm. These expression patterns are similar
      to those of myoD. In addition to the somitic expression, the zisp expression was
      observed in lens cells at the late segmentation period and the early pharyngula
      period.

PMID- 12617826
TI  - Sexually dimorphic gene expression in the developing mouse gonad.
AB  - Over the course of a few days, the bipotential embryonic mouse gonad
      differentiates into either a testis or an ovary. Though a few gene expression
      differences that underlie gonadal sex differentiation have been identified,
      additional components of the testicular and ovarian developmental pathways must
      be identified to understand this process. Here we report the use of a PCR-based
      cDNA subtraction to investigate expression differences that arise during gonadal
      sex differentiation. Subtraction of embryonic day 12.5 (E12.5) XY gonadal cDNA
      with E12.5 XX gonadal cDNA yielded 19 genes that are expressed at significantly
      higher levels in XY gonads. These genes display a variety of expression patterns
      within the embryonic testis and encode a broad range of proteins. A reciprocal
      subtraction (of E12.5 XX gonadal cDNA with E12.5 XY gonadal cDNA) yielded two
      genes, follistatin and Adamts19, that are expressed at higher levels in XX
      gonads. Follistatin is a well-known antagonist of TGFbeta family members while
      Adamts19 encodes a new member of the ADAMTS family of secreted metalloproteases.

PMID- 12617827
TI  - Expression of the Wnt inhibitor, sFRP5, in the gut endoderm of Xenopus.
AB  - Signaling by the Wnt family of secreted growth factors is involved in numerous
      different aspects of embryonic development and also for maintenance of cellular
      function in adult tissues. In addition to regulation at the transcriptional
      level, Wnt activity is modulated by a number of different Wnt-binding proteins.
      Here we report the cloning and developmental expression pattern of the Xenopus
      orthologue of secreted Frizzled-related protein 5 (sFRP5), an endogenous
      inhibitor of Wnt signaling. At early stages of endodermal differentiation, sFRP5
      is expressed in the developing liver. At later stages however, sFRP5 expression
      is down-regulated in the liver and becomes strongly expressed in the region
      corresponding to the junction between the posterior portion of the stomach and
      the anterior intestines.

PMID- 12617828
TI  - Lhx9 expression during gonadal morphogenesis as related to the state of cell
      differentiation.
AB  - Lhx9 (LIM/Homeobox gene 9) encodes a transcription factor implicated in various
      developmental processes, including gonadogenesis. Our observations in the rat
      show that Lhx9 expression present in undifferentiated gonads disappears as
      epithelial cells differentiate into Sertoli cells and begin to express AMH. In
      rat and in chick testes, Lhx9 expression present in interstitial cells decreases
      progressively to become undetectable after birth. In the female rat, Lhx9 is
      highly expressed in epithelial ovigerous cords of the fetal ovary. Its expression
      is down-regulated as epithelial cells differentiate into granulosa cells during
      the process of folliculogenesis occurring at birth. If this process is impaired
      by the lack of oocytes, ovigerous cord organization is maintained together with
      Lhx9 expression. In conclusion, Lhx9 expression can be inversely correlated with
      the commitment into a differentiation pathway of the different categories of
      mesothelium-derived cells of the gonad.

PMID- 12617829
TI  - Hoxc-8 expression shows left-right asymmetry in the posterior lateral plate
      mesoderm.
AB  - XHoxc-8 is the Xenopus homologue of the mouse Hoxc-8 gene, a homeodomain
      containing transcription factor that is expressed in the posterior neural tube
      and adjacent tissues. Although XHoxc-8 has a very similar expression pattern to
      the Hoxc-8 gene in other species, it also displays distinct left/right asymmetry
      at later stages of development, being expressed in the posterior lateral mesoderm
      only on the left-hand side of the embryo.

PMID- 12617831
TI  - Rac-1 and IQGAP are potential regulators of E-cadherin-catenin interactions
      during murine preimplantation development.
AB  - Adherens junction formation is fundamental for compaction and trophectoderm
      differentiation during mammalian preimplantation development. We recently
      isolated an IQGAP-2 cDNA from a differential display-polymerase chain reaction
      screen of bovine preimplantation developmental stages. IQGAP-1 and -2 proteins
      mediate E-cadherin-based cell-to-cell adhesion through interactions with beta
      catenin and the Rho GTPases, rac1 and cdc42. Our study demonstrates IQGAP-1,-2,
      rac-1 and cdc42 mRNAs are present throughout murine preimplantation development.
      IQGAP-1 and rac-1 protein distribution changes from predominantly plasma membrane
      associated to predominantly cytoplasmic as the embryo progresses through cleavage
      divisions and compaction to the blastocyst stage.

PMID- 12617830
TI  - Restricted neural epidermal growth factor-like like 2 (NELL2) expression during
      muscle and neuronal differentiation.
AB  - We have identified a secreted glycoprotein, neural epidermal growth factor-like
      like 2 (NELL2), in a screen designed to isolate molecules regulating sensory
      neuron genesis and differentiation in the dorsal root ganglia (DRG). In
      investigating NELL2 expression during embryogenesis, we demonstrate here that
      NELL2 is highly regulated spatially and temporally, being only transiently
      expressed in discrete regions of the central (CNS) and peripheral nervous systems
      (PNS) and in a subset of mesoderm derived structures during their peak periods of
      development. In the CNS and PNS, NELL2 is maximally expressed as motor and
      sensory neurons differentiate. Interestingly, its expression is restricted to
      sublineages of the neural crest, being strongly expressed throughout the immature
      DRG, but excluded from sympathetic ganglia. Similarly during muscle development,
      NELL2 is specifically expressed by hypaxial muscle precursor cells in the
      differentiating somite and derivatives in the forelimbs and body wall, but not by
      epaxial muscle precursors. Furthermore, NELL2 is differentially regulated in the
      CNS and PNS; in the CNS, NELL2 is only expressed by nascent, post-mitotic neurons
      as they commence their differentiation, yet in the PNS, NELL2 is expressed by
      subsets of progenitor cells in addition to nascent neurons. Based on this
      restricted spatial and temporal expression pattern, functional studies are in
      progress to determine NELL2's role during neuronal differentiation in both the
      PNS and CNS.

PMID- 12617832
TI  - Gene expression pattern analysis of the tight junction protein, Claudin, in the
      early morphogenesis of Xenopus embryos.
AB  - To study how epithelial layers are formed during early development in Xenopus
      embryos, we have focused on Claudin, the major component of the tight junction.
      So far, 19 claudin genes have been found in the mouse, expressed in different
      epithelial tissues. However, though a number of cytological studies have been
      done for the roles of Claudins, their expression patterns and functions during
      early embryogenesis are largely unknown. We found three novel Xenopus claudin
      genes, which are referred to as claudin-4L1, -4L2, and -7L1. At the early
      gastrula stage, claudin-4L1, -4L2, and -7L1 mRNAs were detected in the ectoderm
      and in the mesoderm. At the late gastrula stage, claudin mRNAs were detected in
      the ectoderm through the involuting archenteron roof. At the neurula stage,
      claudin-4L1/4L2 and -7L1 mRNAs were differentially expressed in the neural groove
      and the epidermal ectoderm. At the tailbud stage, the claudin mRNAs were found in
      the branchial arches, the otic vesicles, the sensorial layer of the epidermis,
      and along the dorsal midline of the neural tube. In addition, claudin-4L1/4L2
      mRNAs were detected in the pronephros and the endoderm, whereas claudin-7L1 mRNA
      was observed in the epithelial layer of the epidermis.

PMID- 12617833
TI  - Multiple developmental roles of Ahnak are suggested by localization to sites of
      placentation and neural plate fusion in the mouse conceptus.
AB  - Ahnak is a gigantic (700 kD) phosphoprotein with a unique structure whose
      expression and cellular localization are dynamically regulated during cell cycle
      progression. Here, we report that Ahnak is localized to sites of major
      morphogenesis during mouse placentation and neurulation. Ahnak was found in: (i)
      derivatives of trophectoderm, including chorionic ectoderm prior to and during
      union with the ectoplacental cone, presumptive syncytiotrophoblast cells in the
      chorionic labyrinth, and giant cells at the trophoblast-uterine interface; (ii)
      the allantois prior to, during, and after union with the chorion; and (iii) the
      tips of the neural plate during formation of the neural tube. On the basis of
      these observations, we suggest that Ahnak may play heretofore unrecognized roles
      in tissue union during normal mouse development.

PMID- 12617834
TI  - Coordinated expression of Rb gene family in the mammary gland.
AB  - We have previously demonstrated that the retinoblastoma gene family, Rb, p107 and
      p130, is differentially expressed during mouse embryogenesis. Here we show that
      this gene family is coordinately regulated in the mammary luminal epithelium.
      Expression of Rb, p107 and p130 in the epithelial compartment is low in
      nulliparous female mice and early stages of pregnancy but is induced at mid
      pregnancy and peaks at lactation. During involution p107 expression is lost
      whereas expression pRb and p130 persist. The induction of this gene family at mid
      pregnancy accompanies the expression of beta-casein. However, whereas beta-casein
      transcripts are confined to the lobuloalveolar compartment, the Rb gene family is
      expressed both in lobuloalveoli and ducts. The co-expression of the Rb family in
      the mammary gland may allow functional compensation among these family members.
      This in turn may explain the recent observations that loss of Rb alone in the
      mammary gland is inconsequential, whereas overexpression of cyclin D1 or SV40
      large T antigen, which can abrogate all members of the pRb protein family,
      induces mammary gland carcinogenesis.

PMID- 12617835
TI  - Expression of mOb1, a novel atypical 73 amino acid K50-homeodomain protein,
      during mouse development.
AB  - We report the initial characterization of mOb1 (Odd homeoBox 1), which encodes an
      atypical 73 amino acid K50-homeodomain protein localised in the cytoplasm and
      absent from nuclei during mouse development. Conserved orthologues were present
      in man, rat, cow, pig and chicken, but not in fish, amphibians or invertebrates.
      Temporo-spatial patterns of mOb1 transcript and mOb1 protein expression were
      coincident in developing mouse embryos. Cardiac expression was first observed at
      E8.25 in linear heart tube myocardium and briefly in both horns of the sinus
      venosus. Myocardial expression peaked at E13.5, where after it diminished and was
      not detectable above background by adulthood. At no stage was expression observed
      in endocardium, endocardial cushion tissue, the coronary arteries or great
      vessels. At E13.5 and E15.5, mOb1 expression broadened to include skeletal
      muscle, stratified epithelium (upper aerodigestive tract and skin), epithelium of
      developing airways, vibrissae, midbrain/hindbrain junction, meninges, mesenchymal
      cellular condensations that preceded cartilage formation and chondrocytes.

PMID- 12617836
TI  - Molecular cloning and expression analysis of dystroglycan during Xenopus laevis
      embryogenesis.
AB  - Dystroglycan is a transmembrane receptor protein that provides a structural
      linkage between extracellular matrix components and cytoskeletal proteins. It was
      originally characterized as a member of dystrophin associated protein complex in
      muscle but, unlike other proteins of this complex, mutations in the dystroglycan
      gene have not been implicated as a cause of muscular dystrophies. Indeed,
      dystroglycan is an essential gene, expressed early in development that, if
      removed in knockout mice, provokes lethal defects before the onset of myogenesis.
      Dystroglycan is synthesized as a precursor propeptide that is post
      translationally cleaved and glycosylated to yield alpha and beta subunits. We
      have cloned and characterized a cDNA clone, containing the complete coding region
      of the dystroglycan precursor, from a Xenopus laevis cDNA library. We have
      performed a spatial and temporal analysis of its expression in X. laevis embryos,
      using whole-mount in situ hybridization and reverse transcription-polymerase
      chain reaction analysis. Early expression of dystroglycan in a variety of tissues
      of different embryological derivation suggests a crucial role in morphogenetic
      events, especially during central nervous system differentiation.

PMID- 12617837
TI  - Evolutionarily conserved, DMRT1, encodes alternatively spliced transcripts and
      shows dimorphic expression during gonadal differentiation in the lizard, Calotes
      versicolor.
AB  - An orthologue of Dmrt1 has been cloned and characterized in the lizard, Calotes
      versicolor (CvDmrt1). CvDmrt1 encodes alternatively spliced transcripts in
      genital ridge during gonadal differentiation and in adult testis. Its expression
      in genital ridge initiates from day 3 and is restricted to mesenchymal cells,
      which differentiate into the Sertoli cells. Lack of expression in the coelomic
      epithelium of GR shows that CvDmrt1 expression occurs only in the testicular
      pathway, and that the Sertoli and granulosa cells in GR may originate from
      different primordia. From day 25 onwards, the expression shifts majorly towards
      the germ cells both in testis and ovary. Thus its role in sexual differentiation
      of C. versicolor, which lacks CSD and TSD, is well documented.

PMID- 12617838
TI  - A differential screen for putative targets of the bHLH transcription factor Hand1
      in cardiac morphogenesis.
AB  - The bHLH transcription factor, Hand1 has been implicated in cardiac looping in
      the mouse, however its function in the developing heart remains unknown. To
      investigate the mechanism(s) through which Hand1 might function, we screened for
      potential downstream target genes using representational difference analysis.
      Thymosin beta4 was found to be down-regulated whereas cystatin C and alphaCA were
      up-regulated in Hand1-null embryoid bodies. Whole-mount in situ hybridisation on
      wild type embryos (E8.0-E10.5) and Hand1 homozygous-mutant embryos (E8.0)
      confirmed co-expression of the putative targets with Hand1 in the heart and their
      aberrant expression in a Hand1-null background.

PMID- 12617839
TI  - Restricted expression of DMRT3 in chicken and mouse embryos.
AB  - Vertebrate DM domain genes encode a novel group of proteins related to the
      Drosophila doublesex and Caenorhabditis elegans mab-3 transcription factors. It
      is shown here that the recently identified gene, DMRT3, has a restricted
      embryonic expression profile that is conserved in chicken and mouse embryos.
      DMRT3 is expressed primarily in the forebrain, neural tube and nasal placode of
      both species. In the chicken, DMRT3 is also expressed in newly forming tail
      somites at early developmental stages and, later, in the Mullerian ducts of the
      urogenital system.

PMID- 12617840
TI  - Embryonic expression of three mouse genes with homology to the Drosophila
      melanogaster prickle gene.
AB  - The Drosophila melanogaster gene prickle-spiny-legs (pk) functions in an
      intercellular feedback loop that is central to the establishment of planar cell
      polarity in the eye and epidermis of the fly, by modulating Frizzled-Disheveled
      signalling. Here we identify three mouse prickle-related genes (dyxin, testin and
      prickle) and describe their expression pattern during murine embryogenesis (E7.5
      E15.5). We report that the three genes are expressed in restricted areas of the
      developing mouse brain: dyxin in the most ventral region of the neural tube and
      in some localized regions of the ventricular layer of the mesencephalon and
      rhombencephalon, prickle in the pons region, ventrolateral part of
      rhombencephalon and motoneurons in the spinal cord, and testin in differentiating
      neurons of the spinal cord and retina. At the stages analyzed, the main site of
      expression of testin is the migrating cranial neural crest, while the expression
      of dyxin is noticeable in myotomal cells and its derivatives, with prickle
      expression being reciprocally localized to some sclerotomal derivatives, like
      bone primordia. prickle is also expressed in the apical ectodermal ridge and the
      most distal mesenchyme of the forming limb buds.

PMID- 12617841
TI  - Cloning and expression of a novel armadillo motif containing gene in Xenopus.
AB  - We report an isolation of a cDNA containing armadillo motif (XAMP: Xenopus
      armadillo motif protein) and its expression during Xenopus development. The open
      reading frame of Xamp encodes a predicted protein of 275 amino acids including an
      armadillo motif, and a bipartite nuclear localization signal. Xamp shares
      significant homology with a putative mouse protein (GeneBank AK009402) in the
      database. It is expressed both maternally and zygotically. Xamp is localized to
      the animal region of an egg and in the ectoderm of a gastrula stage embryo. At
      the neurula stages, Xamp is expressed in the dorsal region of neural tube from
      which presumptive sensory neurons arise. In addition to its neural tissue
      specific expression, Xamp transcripts are found to be localized in the developing
      gut tube. At the early tadpole stage, Xamp is expressed predominantly in the
      pharyngeal endoderm. As further development proceeds, its expression domain
      expands to include the entire foregut region but excludes the midgut and hindgut
      regions. This polarized pattern of expression persists until stage 46 after
      which, anterior specific expression of Xamp sharply decreases. These results
      suggest that Xamp may have a role in the neural tissue specification and gut
      endoderm patterning during the Xenopus development.

PMID- 12617842
TI  - FET-1: a novel W-linked, female specific gene up-regulated in the embryonic
      chicken ovary.
AB  - A differential expression screen for sex-determining genes in the embryonic
      chicken gonad revealed a novel gene called Female Expressed Transcript 1 (FET-1).
      Fluorescent in situ hybridization analysis mapped FET-1 to the female specific W
      chromosome. Whole mount in situ hybridization showed that FET-1 expression was
      restricted to females and up-regulated in the cortex of the left gonad during the
      sex-determining period. Female specific expression was also observed in the
      embryonic caudal somites, neural tube and waste collection ducts.

PMID- 12617843
TI  - Stage- and sex-dependent expressions of Usp9x, an X-linked mouse ortholog of
      Drosophila Fat facets, during gonadal development and oogenesis in mice.
AB  - During the Drosophila oogenic processes, Fat facets (Faf), an ubiquitin-specific
      protease essential for normal development of oocyte and eye, becomes localized at
      the posterior pole and is incorporated into the pole cells. This is dependent on
      Oskar, a key factor for pole cell determination, and suggests a role for Faf in
      germ cell differentiation and development. Here we show that Usp9x, an X-linked
      ortholog of Faf, is predominantly expressed in both germ cell and supporting cell
      lineages during mouse gonadal development in stage- and sex-dependent manners.
      Usp9x was first detected in PGCs at 10.5 days post coitum (dpc), and thereafter
      its expression both at mRNA and protein levels was enhanced in PGCs of both sexes
      at 11.5-13.5 dpc. In testis, Usp9x expression rapidly decreased to an
      undetectable level by 15.5 dpc and after birth to adult, no expression was found
      in any spermatogenic cells, except for weak expression in Sertoli cells. In the
      ovary, Usp9x expression in embryonic oocytes was also reduced at the newborn
      stage, its expression reappeared in oocytes at secondary follicle stage, and its
      products were highly accumulated in the cytoplasm of Graaffian follicles in
      adults. Although follicular epithelial cells also expressed Usp9x at a moderate
      level during postnatal development, its expression was downregulated from early
      secondary follicle stage. Thus, the present study is not only the first to
      demonstrate a conserved expression of fat facets in PGCs between mouse and fly,
      but also sex- and stage-dependent changes of a specific component of the
      deubiquitylation system during mammalian gonadal development.

PMID- 12617845
TI  - Embryonic expression of Tbx1, a DiGeorge syndrome candidate gene, in the lamprey
      Lampetra fluviatilis.
AB  - We report the embryonic expression in the lamprey Lampetra fluviatilis of Tbx1,
      the main candidate gene involved in DiGeorge/velo-cardio-facial syndrome
      (DGS/VCFS). From the end of neurulation to stage 26, Tbx1 becomes progressively
      expressed in all developing pharyngeal arches, as they form. Transcripts are
      mainly restricted to the mesodermal core and to the posterior pharyngeal
      endoderm, excluding ingressing neural crest cells. They are also present in the
      otic vesicle, in a ventral and posterior location. From a later stage (stage 27)
      onwards, additional expression domains in the head mesenchyme, later contributing
      to labial muscle precursors, and in the cloacal region, become visible. The
      comparison of these data with those reported in the chick and the mouse indicates
      a high conservation of Tbx1 expression in the pharyngeal arches among
      vertebrates.

PMID- 12617844
TI  - Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse
      strain.
AB  - We have generated a transgenic line that expresses the Cre gene product under the
      regulation of a 12.5 kb upstream regulatory sequence from the Sox2 gene. Using a
      R26R reporter line, we show that this transgenic line induces recombination in
      all epiblast cells by embryonic day (E) 6.5 but little or no activity in other
      extraembryonic cell types at this time. When crossed to a conditional allele of
      the Sonic hedgehog gene (Shh(c)), all Sox2Cre;Shh(n)/Shh(c) embryos displayed a
      phenotype indistinguishable from that of the Shh null mutant. Sox2Cre functioned
      more efficiently in epiblast-mediated recombination than the Mox2Cre (MORE)
      transgenic line, which has also been shown to drive Cre-mediated recombination
      exclusively in the embryonic component of the early mouse embryo. Although most
      MORE; shh(h)/shh(c) embryos have a shh hull phenotype, 33% displayed a milder
      skeletal phenotype, most likely result of incomplete recombination at egg
      cylinder stages. In agreement with these findings, Sox2Cre was active earlier and
      Sox2Cre-mediated recombination was more advanced than MORE-mediated recombination
      at early gastrulation stages. The Sox2Cre line is likely to be more effective in
      generating complete, epiblast-specific removal of gene activity, and the mosaic
      activity of the MORE line will be helpful in generating partial loss-of-function
      phenotypes in the embryo-proper.

PMID- 12617846
TI  - Novel sites of expression of the bHLH gene NSCL1 in the developing nervous
      system.
AB  - We report on novel sites of expression of the bHLH transcription factor NSCL1 in
      the developing forebrain, hindbrain and spinal cord in chick and mouse. In the
      hindbrain in particular, NSCL1 is the first bHLH transcription factor detected so
      far in rhombomere boundaries and its expression is coincident with boundary
      formation and maintenance. Novel sites of expression of this gene include the
      hippocampus, septum, tectum and hypothalamic nuclei. NSCL1 is thus expressed in
      various neuronal populations that are either not actively proliferating or
      postmitotic.

PMID- 12617847
TI  - Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone
      development.
AB  - We describe the expression of three Runt-related RUNX genes (previously termed
      AML, Cbfa, or Pebp2alpha) Runx1 and Runx3 during the development of teeth and
      other craniofacial tissues and compare them to Runx2 expression reported earlier.
      All three genes were expressed in mesenchymal condensates. Runx1 was expressed in
      several cartilage primordia earlier than Runx3, and Runx2 was intense in all
      mesenchymal condensations of bones and teeth. Only Runx1 was expressed in
      epithelia, and in tooth germs transcripts were detected in outer dental
      epithelium. Runx1 was also intensely expressed in the midline epithelium of
      palatal shelves. In early tooth morphogenesis Runx3 was coexpressed with Runx2 in
      a thin layer of mesenchymal cells underlying dental epithelium. Unlike Runx2,
      Runx3 was expressed in odontoblasts. However, Runx3 mutant mice did not show
      obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in
      the tooth.

PMID- 12617848
TI  - Expression profiles of the connexin genes, Gjb1 and Gjb3, in the developing mouse
      cochlea.
AB  - Several connexin genes (GJB1, GJB2, GJB3, GJB6 and GJA1) have been found mutated
      in patients with non-syndromic and/or syndromic deafness indicating an important
      role of these proteins in the auditory system. In order to better understand the
      function of the connexins in the inner ear we have analyzed the gene expression
      profiles of two connexin genes, Gjb1 (connexin 32) and Gjb3 (connexin 31), by in
      situ hybridization during the mouse cochlea organogenesis, from early otocyst up
      to the mature organ in adult. In the developing otocyst epithelium, some
      restricted domains expressed Gjb3 and Gjb1 whilst high levels of both transcripts
      were present in the surrounding mesenchymal tissue. As development proceeds,
      expression of these two genes was found in various subtypes of fibrocytes, either
      within the spiral limbus or along the spiral ligament, as well as in the basilar
      membrane cells, in the Reissner's membrane cells, and in subsets of the cellular
      elements of the cochlear ganglion. Gjb3 and Gjb1 expression was spatiotemporally
      modulated within the sensory hair cells and the various supporting cells that
      compose the developing organ of Corti. A transitory expression of Gjb1 was found
      in the basal and intermediate cells of the stria vascularis. In the adult cochlea
      Gjb1 transcripts disappeared while Gjb3 expression remained present in fibrocytes
      with specific expression patterns.

PMID- 12617849
TI  - Expression of Trps1 during mouse embryonic development.
AB  - The Trps1 gene codes for an atypical member of the GATA type family of
      transcription factors. Mutations in human TRPS1 lead to the tricho-rhino
      phalangeal syndrome types I and III, which are characterized by craniofacial and
      skeletal abnormalities and disturbed hair development. Correspondingly, during
      mouse embryonic development strong Trps1 expression is found in the cartilage
      condensations, the developing joints, the hair follicles and in the developing
      snout. In addition, Trps1 is expressed surrounding the skeletal condensations, in
      the trachea, the intervertebral disks, and in lung and gut mesenchyme. A complex
      pattern of expression is also found in the developing brain.

PMID- 12617850
TI  - Widespread expression of an extended peptide sequence of GATA-6 during murine
      embryogenesis and non-equivalence of RNA and protein expression domains.
AB  - The transcription factor GATA-6 is known to be a critical determinant of early
      vertebrate development. We have shown previously that mammalian GATA-6 genes have
      the potential to encode two protein isoforms, resulting from alternative, in
      frame, initiator methionine codons. We have generated GATA-6 antibodies,
      including one specific to the longer form of GATA-6, and by immunohistochemical
      analysis we demonstrate here that the longer protein, which is the more potent
      transcriptional transactivator, is widely expressed in vivo. In accordance with
      previous RNA expression studies, GATA-6 protein was found to be abundant within
      regions of the gut and pulmonary systems, in addition to the heart myocardium. We
      also report novel GATA-6 expression within sites of chondrogenesis derived from
      cranial neural crest and sclerotomes. Surprisingly however, levels of GATA-6
      protein were substantially reduced within the endocardial cushions and outflow
      tract of the heart. These are regions which express the highest levels of GATA-6
      RNA within the heart.

PMID- 12617851
TI  - Integrin expression patterns during early limb muscle development in the mouse.
AB  - Cell-extracellular matrix interactions play crucial roles in limb muscle
      development but practically nothing is known on what integrins are involved
      before the differentiation of muscle precursor cells (MPCs) in the limb muscle
      masses. In this study we determine the expression patterns of integrins during
      early forelimb muscle development in the mouse. alpha6beta1 integrin is
      downregulated in the lateral dermomyotome when delamination of MPCs occurs. In
      late E9.5 embryos, alpha1beta1 and alpha5beta1 are expressed in a pattern very
      similar to pax3, which marks MPCs migrating to the limb bud. After myf5
      upregulation in the limb bud, alpha1beta1 and alpha5beta1 expression is
      maintained and the alpha4beta1 integrin starts being expressed.

PMID- 12617852
TI  - Expression of the zebrafish recognition molecule F3/F11/contactin in a subset of
      differentiating neurons is regulated by cofactors associated with LIM domains.
AB  - We have identified a zebrafish homolog of the F3/F11/contactin (F3) recognition
      molecule. The gene shares 55% amino acid identity with F3 molecules in other
      vertebrates. Expression of F3 mRNA is first detectable at 16 h post-fertilization
      (hpf) in trigeminal and Rohon-Beard neurons. At 18-24 hpf, additional weaker
      expression is present in discrete cell clusters in the hindbrain, in the anterior
      lateral line/acoustic ganglion and in spinal motor neurons. Transcription factors
      of the LIM homeodomain class (LIM-HD) and their associated cofactors CLIM/NLI/Ldb
      (CLIM) have been implicated in the development of peripheral axons of trigeminal
      and Rohon-Beard neurons. We demonstrate that ectopic overexpression of a dominant
      negative CLIM molecule early during zebrafish development strongly reduces
      expression of F3 mRNA in these neurons indicating regulation of F3 by the LIM-HD
      protein network. These results and the spatiotemporal correlation of F3
      expression with axonal differentiation in a subset of primary neurons suggest an
      important role of F3 for axon growth.

PMID- 12617853
TI  - Molecular cloning and developmental expression of Par-1/MARK homologues XPar-1A
      and XPar-1B from Xenopus laevis.
AB  - Par-1 encodes a serine/threonine kinase that is involved in asymmetric
      segregation of cell fate determinants in Caenorhabditis elegans and Drosophila
      embryos. Recent biochemical studies indicate an association of PAR-1 with the
      Dishevelled protein and suggest a role in so-called canonical Wnt signaling (Nat.
      Cell Biol. 3 (2001) 628). Here we describe two Xenopus laevis cDNAs, which encode
      PAR-1 homologues designated XPar-1A and XPar-1B. Structurally, XPar-1A and XPar
      1B are closely related to rat MARK proteins and human Par-1A and Par-1Balpha,
      respectively. XPar-1A and XPar-1B are expressed both maternally and zygotically
      in an indistinguishable pattern. In the egg and cleavage stage embryos their
      transcripts are enriched in the animal pole of the embryo. During blastula and
      gastrula stages, cells in the animal and marginal regions continue to express
      both genes uniformly. Expression progresses vegetally towards and then through
      the blastopore lip concomitantly with the movements of epiboly and gastrulation.
      With the onset of neurulation, XPar-1A and XPar-1B transcripts are restricted to
      the neurectoderm. At tailbud and tadpole stages they are detected in the head
      region, including brain, eyes, otic vesicles, cement gland, branchial arches as
      well as spinal cord and somites. Therefore, this analysis suggests that the
      Xenopus par-1 homologues XPar-1A and XPar-1B are expressed in frog embryos both
      maternally and zygotically in a restricted pattern and may play a role in
      establishing polarity in early embryos as well as in organogenesis during later
      stages of development.

PMID- 12617854
TI  - Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the
      kidney.
AB  - Semaphorins 3A and 3F are axon guidance proteins during nervous system
      development. Their expression pattern and function outside the nervous system are
      unknown. Neuropilin 1 and 2 (NP-1, NP-2) are natural ligands for semaphorins 3A
      and 3F, respectively. NP-1 is also a co-receptor for vascular endothelial growth
      factor (VEGF) required for normal vascular development. We showed that VEGF is a
      direct chemoattractant for glomerular endothelial cells towards developing
      nephrons. To examine whether semaphorins could modulate VEGF endothelial cell
      guidance cues in the developing kidney, we studied the expression of semaphorin
      3A and semaphorin 3F and their receptors NP-1 and NP-2 in the kidney during
      ontogeny using Northern blot analysis, in situ hybridization, Western blot
      analysis and immunohistochemistry. All four genes are developmentally regulated,
      with abundant expression during organogenesis and downregulation in the adult
      kidney. Semaphorin 3A and 3F are expressed by podocytes and tubules whereas their
      receptors NP-1 and NP-2 are localized to endothelial cells. In vitro, renal
      tubular epithelial cell lines (tsMPT, IRPT and MDCK) and glomerular endothelial
      cells express both semaphorins and their receptors, suggesting the presence of an
      autocrine system. The distribution of the receptors NP-1 and NP-2 in endothelial
      cells and developing vessels is complementary to that of the ligands in adjacent
      epithelial cells during kidney development. The sum of the guidance cues provided
      by VEGF and semaphorins 3A and 3F may be important determinants of the pattern of
      endothelial cell migration during kidney morphogenesis.

PMID- 12617855
TI  - Pax 2 expression in mesodermal segmentation and its relationship with EphA4 and
      Lunatic-fringe during chicken somitogenesis.
AB  - In the Pax gene family, which encodes DNA-binding proteins, Pax 2 has been known
      to play important roles in the formation of the midbrain/hindbrain boundary, eye,
      inner ear and kidney in vertebrates (Bioessays 19 (1997) 755). In this article,
      we report a segmentally regulated pattern of Pax 2 expression during chicken
      somitogenesis. Pax 2 mRNA is localized in the rostral end of the unsegmented
      presomitic mesoderm (PSM), abutting anteriorly on a prospective segmentation
      border. This pattern repeats every segmentation cycle (90 min) observed in ovo
      and also in the half embryo culture assay in which one half of PSM along the
      midline is fixed immediately while the other half is cultured for a given period.
      We also determined the sequence of changes in Pax 2 expression during a
      segmentation cycle by comparing the pattern of Pax 2 with that of Lunatic-fringe
      (L-fringe), known to cycle periodically in posterior PSM. A systematic comparison
      of the expression patterns between Pax 2, L-fringe and EphA4 further highlighted
      a close relationship between EphA4 and Pax 2 during a segmentation cycle. Lastly,
      Pax 2 is not segmentally expressed in mouse PSM, suggestive of species (avian)
      specific mechanisms underlying somitic segmentation.

PMID- 12617856
TI  - Isolation and expression of two zebrafish homologues of parvalbumin genes related
      to chicken CPV3 and mammalian oncomodulin.
AB  - Full-length cDNA clones coded for two beta-type homologues of parvalbumin genes,
      pvalb3a and pvalb3b, were isolated from zebrafish. The homology and phylogenetic
      analyses, based on the deduced amino acid sequences, revealed that PVALB3A and
      PVALB3B are co-orthologues to chicken CPV3 and mammalian oncomodulin (OCM) but
      are divergent from alpha-type PVALB of tetrapods and muscle-type PVALB of bony
      fish. Whole-mount in situ hybridization revealed that the spatio-temporal
      expression of pvalb3a and pvalb3b were distinct and highly development-regulated
      during early embryogenesis. Unlike their counterparts of CPV3 in chicken and OCM
      in mammals, zebrafish pvalb3a transcripts were widely expressed in mucous cells,
      the olfactory epithelium, anterior pituitary, pharyngeal teeth germ, macrophages,
      inner ear and lateral line neuromasts, whereas, pvalb3b transcripts were more
      restrictedly expressed in the yolk syncytial layer, inner ear and pronephric
      ducts.

PMID- 12617857
TI  - Planarian Gtsix3, a member of the Six/so gene family, is expressed in brain
      branches but not in eye cells.
AB  - Six/sine oculis (Six/so) class genes, with representatives in vertebrates and
      invertebrates, include members with key developmental roles in the anterior part
      of the central nervous system (CNS) and eye. Having characterized the role of the
      first planarian gene of the Six/so family in eye development, we attempted to
      identify novel genes of this family related to the platyhelminth eye genetic
      network. We isolated a new Six/so gene in the planarian Girardia tigrina, Gtsix
      3, which belongs to the Six3/6 class. Whole mount in situ hybridization revealed
      Gtsix3 expression in a stripe surrounding the cephalic ganglia in adults. This
      spatial pattern corresponds to the cephalic branches, the nerve cells that
      connect the CNS with the marginal sensory organs located continuously at the edge
      of the head. During head regeneration, Gtsix-3 shows delayed activation compared
      to other head genes, with an initial two spot pattern that later evolves to a
      continuous lateral expression in the new regenerated cephalic ganglia with a
      final reduction to the adult pattern. However, Gtsix-3 is not activated in tail
      regeneration and no eye expression is observed at any regenerative stage. These
      findings provide a new marker for the developing anterior nervous system and
      evidence the complexity of planarian brain.

PMID- 12617858
TI  - Investigating the encoding and retrieval of intentions with event-related
      potentials.
AB  - Strong evidence exists in the literature that remembering to complete intentions
      involves executive processing subserved by the frontal lobes. Event-related
      potentials were measured during the encoding of actions with the intention to
      perform versus more neutral material about which there was no such
      intentionality. Event-related potentials were also measured in a two-alternative
      discrimination task requiring identification of the to-be-performed actions and
      to-be-memorized actions. The results suggest that formation and retrieval of
      intentions differs from encoding and retrieval of similar material committed to
      memory. Additionally, the results suggest that right frontal areas may play an
      important role in the formation of prospective actions and that intentions are
      kept active in memory by processing mediated by the left frontal pole.

PMID- 12617862
TI  - Completeness and accuracy of morning reports after a recall cue: comparison of
      dream and film reports.
AB  - Our goal was to test the efficiency and accuracy of a complementary morning
      report, after recall cue, of an experience (having a dream or viewing a film)
      made and first described during the night. Twenty participants were awakened 10
      min after the onset of the second REM sleep. Upon awakening, on one night they
      described the dream they just had and on the other night they were presented a 4
      min video, then had to describe it. A new description requested in the morning
      after a recall cue yielded an important amount of new information both for the
      film and the dreams, and for the film, where the accuracy could be checked, 86%
      of this new information was accurate. Some aspects of the results pointed to an
      effect of hypermnesia. In conclusion, the morning additional information after
      recall cue stems from a good access to the memory of the night experience.

PMID- 12617861
TI  - Active hippocampus during nonconscious memories.
AB  - The hippocampal formation is known for its importance in conscious, declarative
      memory. Here, we report neuroimaging evidence in humans for an additional role of
      the hippocampal formation in nonconscious memory. We maskedly presented
      combinations of faces and written professions such that subjects were not aware
      of them. Nevertheless, the masked presentations activated many of the brain
      regions that unmasked presentations of these stimuli did. To induce a
      nonconscious retrieval of the faces and face-associated occupational information,
      subjects were instructed to view the previously masked faces and to guess the
      professional category of each person--academic, artist, and workman. Guessing the
      professional category of previously masked versus new faces activated the left
      and right hippocampal formation and right perirhinal cortex as well as bilateral
      fusiform areas and fronto-temporal areas known to mediate the retrieval of
      semantic information. These activations within the semantic processing system
      suggest that conceptual knowledge acquired during masking was nonconsciously
      retrieved. Our data provide clues to an analogous role of the hippocampus in
      conscious and nonconscious memory.

PMID- 12617863
TI  - Developmental aspects of consciousness: how much theory of mind do you need to be
      consciously aware?
AB  - When do children become consciously aware of events in the world? Five possible
      strategies are considered for their usefulness in determining the age in
      question. Three of these strategies ask when children show signs of engaging in
      activities for which conscious awareness seems necessary in adults (verbal
      communication, executive control, explicit memory), and two of the strategies
      consider when children have the ability to have the minimal form of higher-order
      thought necessary for access consciousness and phenomenal consciousness,
      respectively. The tentative answer to the guiding question is that children
      become consciously aware between 12 and 15 months (+/-3 months).

PMID- 12617864
TI  - Pre-frontal executive committee for perception, working memory, attention, long
      term memory, motor control, and thinking: a tutorial review.
AB  - As an explicit organizing metaphor, memory aid, and conceptual framework, the
      prefrontal cortex may be viewed as a five-member 'Executive Committee,' as the
      prefrontal-control extensions of five sub-and-posterior-cortical systems: (1) the
      'Perceiver' (dominant-right-hemisphere ventral-lateral prefrontal cortex--VL/PERC
      PFC) is the frontal extension of the ventral perceptual stream (the VL/PERC
      system) which represents the world and self in object coordinates; (2) the
      'Verbalizer' (dominant-left-hemisphere ventral-lateral prefrontal cortex system-
      VL/VERB-PFC) is the frontal extension of the language stream (the VL/VERB system)
      which represents the world and self in language coordinates; (3) the 'Motivator'
      (ventral/medial-orbital pre-frontal cortex--VMO-PFC) is the frontal cortical
      extension of a subcortical extended-amygdala stream (the VMO system) which
      represents the world and self in motivational/emotional coordinates; (4) the
      'Attender' (dorsal-medial/anterior cingulate--DM/AC-PFC) is the frontal cortical
      extension of a subcortical extended-hippocampal stream (the DM/AC system) which
      represents the world and self in spatiotemporal coordinates and directs attention
      to internal and external events; and (5) the 'Coordinator' (the dorsolateral
      prefrontal cortex--DL-PFC) is the frontal extension of the dorsal perceptual
      stream (the DL system) which represents the world and self in body- and eye
      coordinates and controls willed action and working memory. This tutorial review
      examines the interacting roles of these five systems in perception, working
      memory, attention, long-term memory, motor control, and thinking.

PMID- 12617866
TI  - Acute lymphoblastic leukaemia: diagnosis and classification.
AB  - Acute lymphoblastic leukaemia (ALL) is a heterogeneous disease with distinct
      biological and prognostic groupings. Diagnosis relies on traditional
      cytomorphological and immunohistochemical evaluation of the leukaemic blasts.
      Subsequently, cytogenetic analysis identifies clonal numeric and/or structural
      chromosomal abnormalities that may be present, thus confirming the subtype
      classification and providing important prognostic information for treatment
      planning. The major chromosomal abnormalities in ALL are t(9;22)(q34;q11),
      t(12;21)(p13;q22), t(4;11)(q21;q23), t(1;19)(q23;p13), 8q24 translocations and
      hyperdiploidy. Generally, hyperdiploidy, occurring most frequently in paediatric
      cases, is associated with a good prognosis, while hypodiploidy confers a poor
      prognosis. Among structural chromosomal abnormalities, the t(9;22)(q34;q11)
      resulting in the BCR/ABL fusion protein, and rearrangements of the MLL gene,
      confer a poor prognosis in both children and adults, while t(12;21)(p13;q22),
      resulting in the TEL/AML1 fusion protein, and del (12p) confer a good prognosis.
      More recently, additional diagnostic and prognostic information has been gained
      from fluorescence in situ hybridization (FISH) and DNA microarray techniques.

PMID- 12617865
TI  - Methodological note: erratum and comment on the use of the Revised
      Transliminality Scale.

PMID- 12617867
TI  - Results of minimal residual disease (MRD) evaluation and MRD-based treatment
      stratification in childhood ALL.
AB  - The study of minimal residual disease (MRD) as a 'surrogate' marker of molecular
      response to treatment has drawn great interest because of the potential of
      tailoring treatment and the possibility of gaining insight into the nature of a
      cure. Polymerase chain reaction-based (PCR-based) detection of MRD by
      immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements can be applied
      in more than 90-95% of cases of childhood acute lymphoblastic leukaemia (ALL).
      Accordingly, several retrospective studies of MRD in childhood ALL have used one
      of the different PCR approaches for the detection of antigen-receptor gene
      rearrangements. The promising results on the predictivity of MRD evaluation at
      the end of induction treatment has raised the need of a new definition of
      remission. Until now, most PCR-based MRD studies have used semiquantitative
      methods for the detection of Ig and TCR gene rearrangements. The introduction of
      real-time quantitative PCR (RQ-PCR) has resulted in the improvement of
      sensitivity and specificity and has given better quality control of the MRD data.
      There is an urgent need to incorporate MRD data in clinical studies, properly
      designed to address treatment questions. In this context several ongoing co
      operative study groups have adopted an MRD-based risk group classification to
      explore whether a better tailored treatment would result in further improvement
      in cure rates for children with ALL.

PMID- 12617868
TI  - Risk-adapted treatment according to minimal residual disease in adult ALL.
AB  - The evaluation of minimal residual disease (MRD) is a new diagnostic method which
      is applicable in various malignant disorders. Acute lymphoblastic leukaemia (ALL)
      is a somewhat ideal disease in this respect because >90% of the patients show
      individual clonal markers and because several methods for MRD evaluation are
      already established. Futhermore, it was demonstrated that level and course of MRD
      are significantly correlated with relapse risk in childhood and in adult ALL. In
      clinical practice MRD evaluation may serve for several purposes such as follow-up
      of individual course of disease, identification of new prognostic factors or
      evaluation of single treatment elements. We discuss these options as well as
      general considerations for MRD-based risk stratification and treatment options
      for risk groups. Practical applications are analysed because prospective MRD
      based clinical trials have been recently started. Finally, future options for
      application of MRD evaluation and also limitations and pitfalls of this method
      are reviewed.

PMID- 12617869
TI  - Stem cell transplantation in adult ALL patients.
AB  - Less than 40% of adult acute lymphocytic leukaemia (ALL) patients will still be
      alive at 5 years post-diagnosis. Ways to improve patients' outcome, using high
      dose therapy followed by autologous/allogeneic stem cell transplantation (SCT) in
      first complete remission (CR1) rather than consolidation/maintenance
      chemotherapy, have been investigated. However, prospective studies are small and
      results are inconclusive. The largest prospective trial ever being performed in
      adult ALL patients, the ongoing UKALL 12/ECOG 2993 trial, is assigning all
      patients who have a sibling donor to receive allogeneic SCT (alloSCT) in CR1,
      whereas all other patients are randomized to continue chemotherapy versus
      autologous SCT. An interim analysis of this trial seems to support an alloSCT in
      first CR in adult ALL patients (reflected by a significantly reduced relapse rate
      with an improved disease-free survival). However, less than 30% of the patients
      have a matched sibling donor, the majority of the patients are over 40 years old,
      which makes them less suitable for conventional allograft, and even in those who
      have a matched sibling donor and are young and fit enough to receive it the
      treatment-related mortality (TRM) is about 20%. Strategies for expanding donor
      availability, meanwhile, to reduce the TRM, remain challenges. Data regarding the
      efficacy of reduced-intensity regimens in ALL patients are still scanty. Another
      way of improving patient outcome is to select patients for allograft more
      carefully. There are enough data to suggest now that children who achieved a
      clinical remission but failed to obtain a molecular/immunological remission are
      more prone to relapse. Similar data have recently been published for adult ALL.
      However, data are still limited, and the significance of minimal residual disease
      (MRD) has never been studied prospectively in adult ALL patients. A reasonable
      approach is to assign all patients with a matched related donor who has failed to
      achieve a molecular/immunological remission to receive a conventional alloSCT,
      whereas all others might be randomized to receive alloSCT versus
      chemotherapy/autologousSCT. However, patients with Ph(+) ALL who have a donor
      should receive an alloSCT in CR1, regardless of their MRD results. It appears
      that alloSCT provides the best chance for cure. However, by improving our ability
      to select those who have the highest risk for relapse, unnecessary
      toxicity/mortality might be prevented and the general outcome might improve.

PMID- 12617870
TI  - Autologous stem cell transplantation and purging in adult acute lymphoblastic
      leukaemia.
AB  - The prognosis for adult acute lymphoblastic leukaemia (ALL) is poor. Only 20-30%
      of patients will be cured with conventional chemotherapy. Haematopoietic
      progenitor transplantation is thus an attractive option in these patients. Even
      if allogeneic transplantation allows a better control of the disease, autologous
      transplantation remains an important alternative for patients lacking a suitable
      donor or when allogeneic transplants imply excessive risk. Relapse is the main
      drawback of autologous transplants, but many strategies are being explored to
      overcome this problem. We focus here on transplant modality, the source of
      haematopoietic progenitors, and the best timing to apply the procedure. Also
      reviewed are the current situation and future strategies for improving results in
      this setting, such as ex vivo purging; immunotherapy and maintenance
      chemotherapy.

PMID- 12617871
TI  - Treatment of mature B-ALL and high grade B-NHL in children.
AB  - Burkitt Lymphoma and L3ALL are considered to be different forms of the same
      disease (B-cell disease). Tumour cells have similar cytological and immunological
      features and display the same non-random translocation involving c- myc on
      chromosome 8q24 and the gene of an immunoglobulin chain on chromosome 14, 2 or
      22. Treatment outcome has greatly improved over the past 15 years as a result of
      multicentric national trials, especially in Europe, so that the disease has
      become curable in the majority of patients. Treatment is based on intensive
      polychemotherapy of short duration and adapted to tumour burden. The major drugs
      are cyclophosphamide, high-dose methotrexate and cytosine-arabinosine. CNS
      directed therapy is essential. Supportive care is also important for the
      management of the acute treatment-related toxicity. A patient who remains for 1
      year in complete remission can be considered as cured, because all relapses occur
      early within the first year after diagnosis.

PMID- 12617872
TI  - Treatment of lymphoblastic lymphoma in adults.
AB  - Lymphoblastic lymphoma (LBL) is a rare subtype of non-Hodgkin's lymphoma (NHL)
      with biological features similar to those of acute lymphoblastic leukaemia. In
      the majority of cases LBL shows a T-cell phenotype, and mediastinal tumours are
      the most frequent manifestation. Outcomes of LBL patients treated according to
      NHL or ALL-type regimens are reviewed. Since prophylaxis of CNS relapse and local
      recurrence emerged as important issues in the treatment of LBL the different
      options are discussed. Several studies have used autologous stem cell
      transplantation (SCT) in the primary treatment of LBL and results are reviewed.
      The analysis of published prognostic factors and models in LBL demonstrates that,
      at present, no convincing risk model is available for LBL treated according to
      contemporary intensive chemotherapy protocols. Therefore indications for SCT in
      first complete remission (CR) cannot be defined. Future prospects for improvement
      of treatment results in LBL include intensification of chemotherapy, definition
      of prognostic factors, evaluation of minimal residual disease and SCT in high
      risk patients.

PMID- 12617873
TI  - New treatment strategies in childhood acute lymphoblastic leukaemia.
AB  - Today, 80% of paediatric patients with acute lymphoblastic leukaemia (ALL) can be
      cured. To reduce the rate of relapses, but also to limit treatment morbidity,
      risk-adapted treatment has been attempted after identifying the most specific
      prognostic factors. In addition to clinical factors (e.g. age, WBC), the
      immunophenotype and cytogenetic results, the early in vivo treatment response as
      determined by cytology had evolved as the most important predictor for relapse.
      The lack of specificity of most prognostic factors stimulated the search for more
      relevant parameters. Detection of minimal residual disease (MRD) at defined time
      points by identifying clone-specific T-cell receptor- (TCR) or immunoglobulin
      (Ig) gene rearrangements can provide new, highly specific prognostic information
      which allows definition of new risk groups. The high sensitivity of the method is
      a prerequisite for applying treatment reduction in patients with fast clearance
      of leukaemia. Persistent disease is an indication for treatment modification and
      intensification. Logistics and quality control are demanding but are essential
      for the introduction of this new technology into clinical practice.

PMID- 12617874
TI  - Role of pharmacogenomics and pharmacodynamics in the treatment of acute
      lymphoblastic leukaemia.
AB  - Pharmacodynamic studies have been used to establish the relationships between the
      administered dosage and the concentration of drugs and metabolites in the blood
      or tissues and that between these concentrations and pharmacological effects.
      Polymorphisms in the genes that encode drug-metabolizing enzymes, drug
      transporters and drug targets can affect a person's response to therapy and may
      affect the development of de novo or therapy-related leukaemias. The burgeoning
      field of pharmacogenomics elucidates inherited differences in drug metabolism and
      treatment response. Increasingly, pharmacodynamic and pharmacogenomic studies are
      being used to individualize therapy to enhance efficacy and reduce toxicity.

PMID- 12617875
TI  - Imatinib in the treatment of Philadelphia chromosome-positive acute lymphoblastic
      leukaemia: current status and evolving concepts.
AB  - Until recently, progress in the treatment of patients with Ph(+) acute
      lymphoblastic leukaemia (ALL) has been limited, and long-term survival, even with
      high-dose intensified chemotherapy, is rare. Allogeneic stem cell transplantation
      is potentially curative, but treatment-related mortality and rate of disease
      recurrence are substantial. With the advent of the ABL-selective tyrosine kinase
      inhibitor STI571 (imatinib mesylate, Glivec), it has become apparent that the
      understanding of crucial leukaemogenic pathways at the molecular level can lead
      to the development of specific and selective agents. In recent clinical trials,
      imatinib has demonstrated significant anti-leukaemic efficacy in patients with
      advanced Ph(+) ALL, in conjunction with a remarkably favourable safety profile.
      Clinical resistance to imatinib develops rapidly, highlighting the limitations of
      using imatinib as a single agent; however, the value of imatinib as an element of
      treatment has become apparent. Resistance mechanisms have already been identified
      that will enable the development of rational strategies to prevent or overcome
      resistance. On the basis of available clinical results, combinations of imatinib
      with established anti-leukaemic agents, as well as with novel, molecularly
      targeted treatment modalities, will need to be evaluated in advanced Ph(+) ALL.
      Incorporation of imatinib in the first-line treatment of de novo Ph(+) ALL and in
      the setting of minimal residual disease is a promising therapeutic approach which
      is currently being studied in clinical trials. Better understanding of targeted
      therapies, including strategies based on recruitment of host immune functions, as
      well as the prudent use of active chemotherapy agents, may eventually improve the
      outlook for patients with Ph(+) ALL.

PMID- 12617879
TI  - Genetics of inflammatory bowel disease: scientific and clinical implications.
AB  - Considerable progress has been made in the last decade in studies of the genetics
      of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis.
      Epidemiological data, notably concordance rates in twin pairs and sibling pairs,
      have provided strong evidence for the importance of the genetic contribution,
      particularly in Crohn's disease. These observations provided the catalyst for
      laboratory-based studies of the molecular genetics of Crohn's disease and
      ulcerative colitis around the world. The complementary strategies of genome-wide
      scanning and candidate gene-directed studies have led to the identification of a
      number of genetic markers which appear to predict disease susceptibility and
      behaviour. The identification of the IBD1 gene on chromosome 16 as NOD-2 is
      unquestionably an important scientific discovery. Although many issues with
      respect to gene function and expression remain to be resolved there is great
      optimism that important clinical applications will directly result.

PMID- 12617876
TI  - New agents in the treatment of acute lymphocytic leukaemia.
AB  - The overall prognosis of adult patients with acute lymphocytic leukaemia (ALL)
      has improved significantly over the past few decades. Combined modality
      strategies (e.g. chemotherapy used with targeted therapies such as monoclonal
      antibodies or tyrosine kinase inhibitors) may improve long-term disease-free
      survival. Still, most patients succumb to complications of disease progression,
      with current long-term disease-free survival rates of 30-45% overall. Thus,
      either new strategies or refinements of old ones are needed to improve the long
      term prognosis. An increasing number of unique active new chemotherapeutic and
      biological agents are available for study. This chapter reviews new agents with
      the potential to be incorporated into therapeutic strategies for the treatment of
      ALL.

PMID- 12617880
TI  - Serological markers in inflammatory bowel diseases.
AB  - This chapter is an overview of the literature on serological markers of
      inflammatory bowel diseases (IBD), focusing on anti-neutrophil cytoplasm
      autoantibodies (ANCA) and anti- Saccharomyces cerevisiae mannan antibodies
      (ASCA). The methodology for ANCA and ASCA testing is first introduced. The value
      of these markers as diagnostic tools is then discussed. Other chapters are
      devoted to the potential role of ANCA and ASCA in disease monitoring, disease
      stratification and as subclinical markers in families. Finally reviewed are other
      antibodies recently tested in clinical trials such as pancreatic antibodies and
      antibodies directed against bacterial antigens. The role of these antibodies in
      the pathophysiology of IBD still needs to be assessed. We also need to identify
      the ASCA immunogen(s) eliciting the antibody response.

PMID- 12617881
TI  - Optimizing treatment with thioguanine derivatives in inflammatory bowel disease.
AB  - Thioguanine derivatives, azathioprine and 6-mercaptopurine, represent major drugs
      in the treatment of chronic active inflammatory bowel disease. They are effective
      in two-thirds of the patients and safe over the long term in patients who can
      tolerate them (80-90%). Recent progress in understanding the metabolism of these
      drugs and its implication in clinical practice have brought up new tools and
      strategies that are proposed to optimize treatment. In particular, the
      measurement and characterization of key enzymes and metabolites may have clinical
      impact. Thus, thiopurine methyl transferase genotyping and activity measurement,
      as well as erythrocytes, 6-thioguanine nucleotides and 6-methyl mercaptopurine
      levels, may help in some situations of intolerance or inefficacy with these
      drugs. Indications for starting and stopping treatment with thioguanine
      derivatives are also discussed.

PMID- 12617882
TI  - Manipulation of the bacterial flora in inflammatory bowel disease.
AB  - In this chapter we summarize the clinical and experimental data which indicate
      that bacteria, especially from the endogenous microflora, play a role in the
      pathogenesis of Crohn's disease, ulcerative colitis and pouchitis. We review the
      clinical trials, focusing on randomized controlled trials which used antibiotics
      or probiotics to treat situations of IBD or prevent recurrence, and we discuss
      the future of this approach.

PMID- 12617883
TI  - Strategies in the prevention of post-operative recurrence in Crohn's disease.
AB  - The majority of patients with Crohn's disease require resectional surgery in the
      course of their disease. Most of them will suffer symptomatic recurrence in the
      years after their operation, leading to new complications and sometimes repeated
      surgery. Clinical risk factors for early and evolutive recurrence have not been
      well identified. Smoking, perforating behaviour of the disease and ileal or
      ileocolonic location seem to predispose to early and aggressive recurrence. No
      clear prophylactic drug regime has been identified. Sulfasalazine and 5-ASA are
      only mildly protective and meta-analysis of all studies does not show superiority
      over placebo. Glucocorticosteroids are not efficacious. Nitroimidazole
      antibiotics, metronidazole and ornidazole prevent early endoscopic recurrence and
      postpone symptomatic relapse but are not well tolerated. Immunosuppression with
      azathioprine or 6-MP is attractive but hard data concerning their efficacy are
      still lacking. No data are available on the use of biologicals for the prevention
      of post-operative Crohn's disease. We need well designed and well powered
      multicentre trials to investigate the efficacy of different drugs for recurrence
      prophylaxis.

PMID- 12617884
TI  - Diagnosis and treatment of pouchitis.
AB  - Total proctocolectomy with ileal pouch-anal anastomosis is the surgical procedure
      of choice for the management of ulcerative colitis. Pouchitis, a non-specific
      inflammation of the ileal reservoir, is the most frequent complication that
      patients experience in the long-term. Diagnosis should be made on the basis of
      clinical, endoscopic and histological aspects. The Pouchitis Disease Activity
      Index (PDAI) represents an objective and reproducible scoring system for
      pouchitis: active pouchitis is defined as a score > or = 7 and remission as a
      score < 7. About 15% of patients develop a chronic disease. Treatment of
      pouchitis is empirical, and very few controlled studies have been carried out.
      Antibiotics, particularly metronidazole and ciprofloxacin, are the treatment of
      choice. Chronic pouchitis may benefit from a prolonged course of a combination of
      antibiotics. Highly concentrated probiotics are effective for both prevention of
      relapses and prevention of pouchitis onset. There is no convincing evidence of
      the efficacy of other therapeutic agents.

PMID- 12617885
TI  - Management of acute severe colitis.
AB  - Early identification of patients with acute severe colitis is essential so that
      prompt treatment can be instigated. Corticosteroids have remained the mainstay of
      treatment since 1955. The introduction of ciclosporin into the pharmacological
      armamentarium has reduced early colectomy rates but even with modern medical
      management up to 30% of patients will still undergo colectomy on the same
      admission. The overall mortality is now less than 1% in specialist centres
      compared to 30% in the pre-steroid era. The future promises further advances in
      treatment through medications that are targeted directly at the underlying
      inflammatory process.

PMID- 12617886
TI  - Strategies for targeting tumour necrosis factor in IBD.
AB  - Tumour necrosis factor (TNF) plays an important role in mediating the
      inflammation of inflammatory bowel disease, in particular, Crohn's disease.
      Strategies aimed at reducing tumour necrosis factor in patients with inflammatory
      bowel disease include the mouse/human chimeric monoclonal antibody infliximab,
      the humanized monoclonal antibody CDP571, the human soluble TNF p55 receptor
      onercept, the human monoclonal antibody D2E7 (adalimumab), the anti-TNF human
      antibody Fab' fragment-polyethelene glycol (PEG) conjugate CDP870, and the small
      molecules thalidomide and CNI-1493 (MAP-kinase inhibitor). Infliximab is
      effective for treating active Crohn's disease, maintaining remission, closing
      fistulas, maintaining fistula closure, and treating ankylosing spondylitis.
      Infliximab is also being investigated for the treatment of ulcerative colitis.
      Side-effects occurring in patients treated with infliximab include human anti
      chimeric antibodies, infusion reactions, delayed hypersensitivity reactions,
      formation of autoantibodies, and, in rare circumstances, drug-induced lupus and
      serious infections, including tuberculosis. CDP571 is effective for treating
      active Crohn's disease, steroid sparing, and possibly for closing fistulas and
      maintaining remission. Side-effects occurring in patients treated with CDP571
      include anti-idiotype antibodies, infusion reactions and the formation of
      autoantibodies. A controlled trial of etanercept in patients with Crohn's disease
      was negative. Pilot studies with onercept, thalidomide, and CNI-1493 have
      suggested benefit for Crohn's disease. There are no published data on the
      efficacy of adalimumab (D2E7) or CDP870 for either Crohn's disease or ulcerative
      colitis. Anti-tumour necrosis factor therapies are effective for the treatment of
      Crohn's disease and are being investigated for ulcerative colitis.

PMID- 12617887
TI  - New biological therapies in inflammatory bowel disease.
AB  - Several biological therapies (monoclonal antibodies, designer molecules,
      recombinant cytokines) have been tested for clinical efficacy in inflammatory
      bowel disease, and some have been found to be effective. Anti-TNF-alpha (anti
      tumour necrosis factor-alpha) antibody therapy is an important treatment modality
      in the treatment of active and fistulating Crohn's disease and should be
      considered in patients who fail standard medical therapies. Treatment with TNF
      alpha-neutralizing antibodies is associated with immunosuppression that may lead
      to opportunistic infections and reactivation of tuberculosis, and patients should
      undergo Mantoux testing prior to treatment. Several other monoclonal antibodies,
      including anti-IL12 and anti-IFN-gamma, are currently in development for Crohn's
      disease. Other new approaches include ex vivo generation of regulatory T
      lymphocytes and antibodies that target and kill (subpopulations of) memory T
      lymphocytes.

PMID- 12617888
TI  - Crohn's disease: step up or top down therapy.
AB  - The concept of a 'step-up' or 'top-down' approach to the treatment of Crohn's
      disease has evolved from the impact of novel anti-TNF (anti-tumour necrosis
      factor) therapies that have been effective for patients who are refractory to
      other medical treatments. In addition, the potential to produce mucosal healing
      with anti-TNF treatments without the well-recognized systemic complications of
      glucocorticoid therapy has created debate as to whether earlier, more aggressive,
      therapies should be advocated. This controversy arises at a time when the concept
      of sequential therapy to induce and maintain remissions for Crohn's disease has
      begun to be accepted and precedes our ability to define the concept of disease
      modification or predict the natural history of Crohn's disease based upon
      clinical, pathological, molecular orgenetic criteria. Evidence for therapeutic
      efficacy in Crohn's disease is presented as a prologue to considerations
      necessary to determine the benefits and risks of early aggressive treatment
      versus sequential approaches based upon disease severity.

PMID- 12617890
TI  - Peptidyl aldehyde inhibitors of calpain incorporating P2-proline mimetics.
AB  - Four new peptidyl aldehydes bearing proline mimetics at the P(2)-position were
      synthesized and studied as inhibitors of calpain I, cathepsin B, and selected
      serine proteases. The ring size of the P(2)-constraining residue influenced the
      inhibitory potency and selectivity of the compounds for calpain I compared to the
      other proteases.

PMID- 12617891
TI  - Design and synthesis of bicyclic pyrimidinone-based HCV NS3 protease inhibitors.
AB  - A series of bicyclic pyrimidinone-based HCV NS3 protease inhibitors was
      synthesized via selective C8 position functionalization. Substituted phenylamides
      and phenylureas were preferred in the S2 binding pocket.

PMID- 12617892
TI  - Novel thrombin inhibitors incorporating non-basic partially saturated
      heterobicyclic P1-arginine mimetics.
AB  - The design, synthesis and biological activity of non-covalent thrombin inhibitors
      incorporating 4,5,6,7-tetrahydroindazole, 2-methyl-4,5,6,7-tetrahydroindazole,
      4,5,6,7-tetrahydroisoindole, 5,6,7,8-tetrahydroquinazoline and 5,6,7,8
      tetrahydroquinazolin-2-amine as novel, partially saturated, heterobicyclic P(1)
      arginine side-chain mimetics is described. The binding mode of the most potent
      candidate in the series co-crystallized with human alpha-thrombin, which
      exhibited an in vitro K(i) of 140nM and more that 478-fold selectivity against
      trypsin, is discussed.

PMID- 12617894
TI  - An adjustable release rate linking strategy for cytotoxin-peptide conjugates.
AB  - Peptide hormones are often rapidly internalized after binding to and activation
      of their receptors which are sometimes over-expressed on tumor cells. Thus,
      peptide ligands are increasingly being utilized for specific tumor cell targeting
      and internalization of radioactive isotopes for tumor imaging and for
      specifically delivering and internalizing cytotoxic moieties. Here, we describe a
      new carbamate linker system containing a series of built-in nucleophile assisted
      releasing (BINAR) groups which enable the 'fine-tuning' of intracellular cleavage
      rates of free cytotoxic agents containing reactive OH groups. Release rates were
      found to fit well with the chemical model and several conjugates of camptothecin
      and one of combretastatin were shown to have potent cytotoxic effects on cultures
      of human neuroblastoma IMR-32 cells which over-express somatostatin receptors.

PMID- 12617893
TI  - Azaindoles: moderately basic P1 groups for enhancing the selectivity of thrombin
      inhibitors.
AB  - Starting from a 2-amino-6-methylpyridine P1 group and following a strategy of
      enlarging it whilst reducing its polarity, we have developed a series of potent,
      moderately basic azaindoles which are intrinsically much more selective for
      thrombin versus trypsin. Certain pyrazinone acetamide azaindole derivatives have
      pharmacokinetic parameters after oral administration to dogs, or efficacy in
      vitro, comparable to an optimized pyrazinone acetamide 2-amino-6-methylpyridine
      derivative.

PMID- 12617896
TI  - Novel synthesis of 2-substituted 19-norvitamin D A-ring phosphine oxide from D
      glucose as a building block.
AB  - 19-norvitamin D A-ring phosphine oxide 5 was synthesized by a new sequence mode
      starting from D-glucose as a chiral template. Transformation of the pyranoside
      ring into the A-ring carbocycle was achieved by the Pd-catalyzed Ferrier
      rearrangement. The phosphine oxide 5 was obtained in an 18% overall yield by this
      novel cost-effective method.

PMID- 12617895
TI  - Dehydrophenylalanine derivatives as VLA-4 integrin antagonists.
AB  - We describe a series of dehydrophenylalanine derivatives where the Z isomers are
      potent VLA-4 antagonists but are subject to rapid biliary clearance and the E
      isomers have poor activity but have a slower rate of clearance. These
      configurationally constrained molecules have led to the design of a novel class
      of benzodiazepine VLA-4 antagonists.

PMID- 12617897
TI  - Design, synthesis, and evaluation of beta-galactosylceramide mimics promoting
      beta-glucocerebrosidase activity in keratinocytes.
AB  - We have established an efficient synthesis of mimics of beta-galactosylceramide
      (beta-GalCer) increasing a beta-glucocerebrosidase (beta-GlcCer'ase) activity
      that associates with the skin barrier function. Among the synthetic beta-GalCer
      analogues (6a-6e) described herein, compound 6e exhibited a potent effect on the
      activation of beta-GlcCer'ase function in vitro and reduced the transepidermal
      water loss (TEWL) level in a UVB-induced barrier disrupted mice model. These
      findings indicated that compound 6e could be useful for cosmetics and medicines
      to improve skin barrier function.

PMID- 12617898
TI  - Design, synthesis and binding affinity of 3'-fluoro analogues of Cl-IB-MECA as
      adenosine A3 receptor ligands.
AB  - Several 3'-fluoro analogues, 1a, 1b, and 1c of selective and potent adenosine
      A(3) receptor agonist, Cl-IB-MECA were synthesized from D-xylose via highly
      regioselective opening of lyxo-epoxides, 8a and 8b with fluoride anion. Compared
      to the high binding affinity of Cl-IB-MECA to the A(3) adenosine receptor, the
      corresponding 3'-fluoro derivative showed remarkably decreased binding affinity,
      indicating that 3'-hydroxyl group acts as hydrogen bonding acceptor, not hydrogen
      bonding donor like fluorine atom in binding to the A(3) adenosine receptor.

PMID- 12617899
TI  - Antiplatelet activity of synthetic pyrrolo-benzylisoquinolines.
AB  - Pyrrolo-benzylisoquinolines were prepared as target compounds and their
      antiplatelet aggregation activity, adreno-receptor affinity, and cytotoxicity
      were screened. Compounds 1d-9d showed specific antiplatelet aggregation activity
      induced by arachidonic acid and collagen. Among them, 8d and 9d exhibited better
      activity than the reference drug, aspirin and 9d also showed inhibition of
      platelet aggregation by all four inducers.

PMID- 12617900
TI  - Interaction of binuclear xylylthiolato(2,2',2"-terpyridine)platinum(II) complexes
      with DNA.
AB  - The new binuclear platinum(II) complexes, (1,3-benzenedimethanethiolate
      S)di(2,2',2"-terpyridine)diplatinum(II) chloride tetrahydrate, 5, and (1,4
      benzenedimethanethiolate-S)di(2,2',2"-terpyridine)diplatinum(II) chloride
      tetrahydrate, 6, were synthesized in order to investigate the binding of
      platinum(II) complex with calf thymus DNA, which was examined by UV and CD
      spectroscopies. Complex 5 interacted strongly with DNA by intercalation compared
      to 6.

PMID- 12617901
TI  - 2-(3,4-Dihydro-1H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype
      selective NMDA receptor antagonists.
AB  - Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype
      selective NMDA receptor antagonists. We would now like to report our findings on
      structurally related pyridine analogues. The SAR developed in this series
      resulted in the discovery of high affinity antagonists which are selective (vs
      alpha1 and M1 receptors) and active in vivo.

PMID- 12617902
TI  - Hydroporphyrins as tumour photosensitizers: synthesis and photophysical studies
      of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin.
AB  - The synthesis and characterization of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl)
      porphyrin is reported. The phototoxicity on C6 cell lines and the
      pharmacokinetics are also reported as preliminary results showing a very high
      tumor to skin ratio and short retention time in tissues, and thus promising
      activity in photodynamic therapy.

PMID- 12617903
TI  - Carbonic anhydrase inhibitors: inhibition of cytosolic isozymes I and II with
      sulfamide derivatives.
AB  - A novel class of effective CAIs has been identified, starting from a very weak
      carbonic anhydrase inhibitor (CAI), sulfamide, whose X-ray crystal structure in
      the adduct with hCA II has recently been reported. A series of N,N-disubstituted-
      and N-substituted-sulfamides were prepared from the corresponding amines and N
      (tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1
      ylsulfonyl]azanide or the unstable N-(tert-butoxycarbonyl)sulfamoyl chloride. The
      disubstituted compounds being too bulky, were ineffective as CAIs, whereas mono
      substituted derivatives (incorporating aliphatic, cyclic and aromatic moieties)
      as well as a bis-sulfamide, behaved as micro-nanomolar inhibitors of two
      cytosolic isozymes, hCA I and hCA II, responsible for critical physiological
      processes in higher vertebrates. Aryl-sulfamides were more effective than
      aliphatic derivatives. Low nanomolar inhibitors have been detected, which
      generally incorporated 4-substituted phenyl moieties in their molecule. This is
      the first example of CAIs in which low nanomolar inhibitors were generated
      starting from a very ineffective lead molecule.

PMID- 12617904
TI  - Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the
      interaction of sugar sulfamates/sulfamides with isozymes I, II and IV.
AB  - A series of sugar sulfamate/sulfamide derivatives were prepared and assayed as
      inhibitors of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV.
      Best inhibitory properties were observed for the clinically used antiepileptic
      drug topiramate, which is a low nanomolar CA II inhibitor, and possesses good
      inhibitory properties against the other two isozymes investigated here, similarly
      with acetazolamide, methazolamide or dichlorophenamide. The X-ray structure of
      the complex of topiramate with hCA II has been solved and it revealed a very
      tight association of the inhibitor, with a network of seven strong hydrogen bonds
      fixing topiramate within the active site, in addition to the Zn(II) coordination
      through the ionized sulfamate moiety. Structural changes in this series of sugar
      derivatives led to compounds with diminished CA inhibitory properties as compared
      to topiramate.

PMID- 12617905
TI  - Oligonucleotides containing a new type of acyclic, achiral nucleoside analogue: 1
      [3-hydroxy-2-(hydroxymethyl)prop-1-enyl]thymine.
AB  - An achiral, acyclic nucleoside analogue has been incorporated once or twice in
      oligodeoxyribonucleotides by the phosphoramidite method, and conditions found
      which allow deprotection of the oligonucleotides containing a sensitive modified
      allylic unit. The binding affinity of the modified oligonucleotides towards
      complementary DNA and RNA was reduced compared to unmodified DNA (DeltaT(m) -2 to
      -6.5 degrees C). An oligonucleotide with two modifications at the 3'-end showed
      considerable resistance towards cleavage with a 3'-exonuclease.

PMID- 12617906
TI  - Cyclic amidines as benzamide bioisosteres: EPC synthesis and SAR studies leading
      to the selective dopamine D4 receptor agonist FAUC 312.
AB  - Investigation of conformationally restricted benzamide bioisosteres led to the
      chiral phenyltetrahydropyrimidine derivative ent2a (FAUC 312) displaying strong
      and highly selective dopamine D4 receptor binding (K(i(high))=1.5 nM).
      Mitogenesis experiments indicated 83% ligand efficacy when compared to the
      unselective agonist quinpirole. The target compounds of type 2 and 3 were
      synthesized in enantiopure form starting from asparagine.

PMID- 12617907
TI  - Bis(acridinylthiourea)platinum(II) complexes: synthesis, DNA affinity, and
      biological activity in glioblastoma cells.
AB  - The preparation of two novel bis(acridine)platinum(II) complexes is reported. The
      4+ charged conjugates associate strongly with double-stranded native DNA
      (K(i)>10(6)), possibly through bisintercalation. A cell viability assay was used
      to demonstrate that both compounds are capable of mediating cytotoxicity at
      micromolar concentrations in SNB19 brain tumor cells.

PMID- 12617908
TI  - Synthesis of a new family of glycolipidic nitrones as potential antioxidant drugs
      for neurodegenerative disorders.
AB  - This paper deals with the synthesis of a novel series of amphiphilic glycosylated
      spin-traps derived from alpha-Phenyl-N-tert-butyl nitrone (PBN) and an initial
      characterization of their anti-caspase-3 activity. Preliminary investigation of
      their anti-apoptosis effect showed they dramatically inhibit the activity of
      caspase-3 in cultured neuronal cells following induction of apoptosis by hydrogen
      peroxide.

PMID- 12617909
TI  - Docking studies of sulphamate inhibitors of estrone sulphatase in human carbonic
      anhydrase II.
AB  - We describe the docking of selected steroidal and non-steroidal estrone
      sulphatase inhibitors, including the Phase I clinical trial candidate 667COUMATE
      (6), into the active site of human carbonic anhydrase II (hCA II). The docking
      scores are compared with the inhibition of hCA II and show good correlation with
      biological activity.

PMID- 12617911
TI  - Discovery of the first antibacterial small molecule inhibitors of MurB.
AB  - A series of imidazolinone analogues was synthesized and shown to possess potent
      MurB inhibitory as well as good antibacterial activity.

PMID- 12617910
TI  - Design and synthesis of the tumor-activated prodrug of dihydropyrimidine
      dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with
      capecitabine.
AB  - A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine
      dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been
      designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a
      known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues
      by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase
      and thymidine phosphorylase, the latter two of which are known to be highly
      expressed in various tumor tissues. When capecitabine (1), a tumor-activated
      prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was
      significantly increased with only a slight increase of 5-FU in plasma as compared
      with oral capecitabine alone.

PMID- 12617913
TI  - Synthesis and anticancer effect of chrysin derivatives.
AB  - A series of chrysin derivatives, prepared by alkylation, halogenation, nitration,
      methylation, acetylation and trifluoromethylation, were tested in vitro against
      human gastric adenocarcinoma cell line (SGC-7901) and colorectal adenocarcinoma
      (HT-29) cells. Among these derivatives of chrysin, 5,7-dimethoxy-8-iodochrysin 3
      and 8-bromo-5-hydroxy-7-methoxychrysin 11 have the strongest activities against
      SGC-7901 and HT-29 cells, respectively. 5,7-Dihydroxy-8-nitrochrysin 12 were
      found to have strong activities against both SGC-7901 and HT-29 cells.

PMID- 12617912
TI  - Cytotoxic activity of 6-alkynyl- and 6-alkenylpurines.
AB  - 6-Alkynyl- and 6-alkenylpurines have been screened for cytotoxic activity against
      a human chronic myelogenous leukemia cell line; K-562 cells using a [(3)H]
      thymidine incorporation assay. Most alkynes displayed cytotoxicity comparable to,
      or better than, the known anticancer drugs 6-mercaptopurine and fludarabine. The
      6-alkenylpurines, which are promising plant growth stimulators and 15
      lipoxygenase inhibitors, exhibited only low toxicity.

PMID- 12617914
TI  - N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent,
      selective VLA-4 antagonists.
AB  - The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4
      integrin, was investigated. This effort resulted in the identification of N-(3
      phenylsulfonyl-3-piperidinoyl)-(L)-4-(2',6'-dimethoxyphenyl)phenylalanine 52 as a
      potent, selective VLA-4 antagonist (IC(50)=90 pM). Expansion of the SAR
      demonstrated that this structural unit can be used to identify a diverse series
      of sub-nanomolar antagonists.

PMID- 12617915
TI  - Substituted quinolines induce inhibition of proliferation of HTLV-1 infected
      cells.
AB  - Several quinolines were synthesized and evaluated against HTLV-1 infected cells.
      Some of them were able to inhibit HTLV-1 cell-growth at 10 microM. Some structure
      activity relationships were observed.

PMID- 12617916
TI  - Structure-based design of thioether-bridged cyclic phosphopeptides binding to
      Grb2-SH2 domain.
AB  - A series of phosphotyrosine containing cyclic peptides was designed and
      synthesized based upon the phage library derived cyclopeptide, G1TE. Considering
      the type-I beta-turn feature of peptidic ligand binding to Grb2 SH2 domain, we
      introduce alpha,alpha-disubstituted cyclic amino acid, Ach, into the 4th position
      of the cyclic peptide to induce a local right handed 3(10) helical conformation.
      In order to stabilize the favorable binding conformation, the bulky and
      hydrophobic amino acids, neopentylglycine (NPG) and phenylalanine, were
      introduced into the 8th and 2nd positions of the peptide ligand, respectively. To
      facilitate the sidechain of pTyr3 reaching into the phosphotyrosine binding
      pocket, a less bulky alanine was preferred in position 1. Based upon these global
      modifications, a highly potent peptide ligand 12 was discovered with an
      IC(50)=1.68 nM, evaluated by ELISA binding essay. Ligand 12 is at least 10(5)
      more potent than the lead peptide, termed G1TE.

PMID- 12617917
TI  - Synthesis of (+),(-)-neamine and their positional isomers as potential
      antibiotics.
AB  - The syntheses of (+)-neamine 1, (-)-neamine ent-1 and their positional isomers 2,
      3, ent-2 and ent-3 are reported as potential new scaffolds for novel
      aminoglycoside antibiotics. These isomers exhibit similar inhibitory activities,
      as shown using an in vitro translation assay. A simple model is proposed to
      explain this lack of stereospecific binding to the ribosomal RNA.

PMID- 12617918
TI  - Design, synthesis and photochemical properties of caged bile acids.
AB  - Photolabile derivatives of bile acids (8-10 and 13) were synthesized via silver
      (I) oxide promoted selective etherification of 3alpha-hydroxyls. Quantitative
      production of the parent cholic acid was detected from the photolytic mixture of
      3-NB-CA (8) in Tris buffered solution. Interestingly, the unexpectedly stable
      nitroso-hemiacetal intermediate (14) was detected when the photolysis was
      conducted in methanol. The enzymatic analysis using 7alpha-HSDH showed 8 and 9
      could serve as caged bile acids that might be able to regulate certain biological
      processes upon UV irradiation.

PMID- 12617919
TI  - Why B-ring is the active center for genistein to scavenge peroxyl radical: a DFT
      study.
AB  - The structure-activity relationship for genistein to scavenge peroxyl radical was
      clarified by density functional theory (DFT) calculations using the B3LYP/6
      31G(d,p) method. It was revealed that the conjugation of an electron-withdrawing
      1,4-pyrone group with A-ring of genistein was not beneficial to enhance the
      radical-scavenging activities. Thus, hydroxyl in B-ring became the active center
      of genistein to scavenge peroxyl radical.

PMID- 12617921
TI  - Discovery of novel neuronal voltage-dependent calcium channel blockers based on
      emopamil left hand as a bioactive template.
AB  - A series of novel neuronal voltage-dependent calcium channel (VDCC) blockers,
      with inhibitory activity at low micromolar and moderate solubility in water, was
      discovered by constructing and screening a focused library based on emopamil (1)
      left hand (ELH) as a bioactive template.

PMID- 12617920
TI  - Discovery of novel and selective IKK-beta serine-threonine protein kinase
      inhibitors. Part 1.
AB  - IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically
      involved in the activation of the transcription factor Nuclear Factor kappa B (NF
      kappaB) in response to various inflammatory stimuli. We have identified a small
      molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in
      improvements in both in vitro and in vivo potency, and provided IKK-beta
      inhibitors exhibiting potent activity in an acute cytokine release model (LPS
      induced TNFalpha).

PMID- 12617922
TI  - Plasmid relaxation induced by copper metalated diglycine conjugates under
      heterogeneous reaction conditions.
AB  - This paper reports synthesis and plasmid modification activities of a new class
      of insoluble copper-metalated diglycine conjugates, containing aliphatic linkers
      of varying length. Besides providing significant rate enhancement for model
      phosphate ester cleavage, these constructs also displayed efficient supercoiled
      plasmid scission, in the absence of co-oxidants, under heterogeneous catalytic
      conditions.

PMID- 12617923
TI  - Acylcyclohexanedione derivatives as potential in vivo sequential inhibitors of 4
      hydroxyphenylpyruvate dioxygenase and GA(20) 3beta-hydroxylase.
AB  - Acylcyclohexanedione derivatives have been designed, synthesized, and evaluated
      for in vitro inhibition activity against the enzyme 4-hydroxyphenylpyruvate
      dioxygenase (4-HPPD). The biological data demonstrated that 7 is a potent
      inhibitor of 4-HPPD with an IC(50) value of 40 nM. After metabolism, compound 7
      has the potential to become a potent inhibitor of a second enzyme, GA(20) 3beta
      hydroxylase.

PMID- 12617924
TI  - Amphipathic 3-phenyl-7-propylbenzisoxazoles; human pPaR gamma, delta and alpha
      agonists.
AB  - A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists
      of human PPARalpha, gamma and delta. The optimization of acid proximal structure
      for in vitro and in vivo potency is described. Results of po dosed efficacy
      studies in the db/db mouse model of type 2 diabetes showed efficacy equal or
      superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
      Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can
      be obtained.

PMID- 12617925
TI  - Total synthesis and adjuvant activity of all stereoisomers of pinellic acid.
AB  - Pinellic acid is a novel and potentially useful oral adjuvant when used in
      conjunction with intranasal inoculation of influenza HA vaccines. All
      stereoisomers of pinellic acid have been synthesized via regioselective
      asymmetric dihydroxylation, regioselective inversion, and stereoselective
      reduction, and their adjuvant activities were characterized. Among this series of
      isomers, 9S, 12S, 13S compound has the most potent adjuvant activity. Structure
      activity relationships are discussed.

PMID- 12617926
TI  - Highly cytotoxic benzo[c]pyrido[2,3,4-kl]acridines.
AB  - Several benzo[c]pyrido[2,3,4-kl]acridines bearing different substituents on the A
      and E rings were synthesized and evaluated for their capacity to bind to DNA and
      to inhibit DNA topoisomerases. Potent cytotoxic compounds were discovered but no
      strict correlation with their DNA binding affinity and effects on topoisomerases
      were observed. DNA is one but not the unique target of these compounds.

PMID- 12617927
TI  - Cancer chemotherapy: a SN-38 (7-ethyl-10-hydroxycamptothecin) glucuronide prodrug
      for treatment by a PMT (Prodrug MonoTherapy) strategy.
AB  - A glucuronide-based prodrug of SN-38 (7-ethyl-10-hydroxycamptothecin) has been
      synthesized for use in a Prodrug MonoTherapy Strategy (PMT). Since this prodrug
      is significantly less cytotoxic than SN-38 itself and efficiently releases the
      drug in vitro in the presence of beta-D-glucuronidase, it can be considered as an
      appropriate candidate for cancer treatment by a PMT strategy.

PMID- 12617928
TI  - Bis-sulfonamides as endothelin receptor antagonists.
AB  - Modification of the structure of bosentan 1, the first marketed endothelin
      receptor antagonist (Tracleer), by introduction of a second sulfonamide function
      at the alkoxy side chain, led to bis-sulfonamides 2. This allowed to prepare dual
      ET(A)/ET(B) as well as ET(B) receptor selective antagonists, which could serve as
      tools to investigate the pharmacological consequences of selective ET(B) receptor
      blockade.

PMID- 12617929
TI  - The use of sulfonylamido pyrimidines incorporating an unsaturated side chain as
      endothelin receptor antagonists.
AB  - A series of compounds structurally related to bosentan 1 featuring an unsaturated
      side chain at position 6 of the core pyrimidine have been studied for their
      potential to block the ET(A) and ET(B) receptor. Incorporation of a 2-butyne-1,4
      diol linker bearing a pyridyl carbamoyl moiety led to in vitro highly potent
      endothelin receptor antagonists (e.g., 70 and 75). The propargyl derivative 26
      significantly reduced blood pressure in in vivo model studies with hypertensive
      salt-sensitive Dahl rats.

PMID- 12617930
TI  - Synthesis and thrombolytic activity of fibrinogen fragment related cyclopeptides.
AB  - In the modification of the fibrinogen fragment related sequences ARPAK, QRPAK
      GRPAK and KRPAK, the corresponding cyclo-ARPAK, cyclo-QRPAK, cyclo-GRPAK, and
      cyclo-KRPAK were prepared in the diluted solution. The bioassay in vivo indicated
      that the thrombolytic potencies of cyclo-ARPAK, cyclo-GRPAK, cyclo-QRPAK, and
      cyclo-KRPAK were significantly higher than that of ARPAK, QRPAK, GRPAK, and
      KRPAK. In water, the cyclopeptides were incubated with pepsin or trypsin at 37
      degrees C for 64 h. There was no degradation product observed, on the other hand,
      with the same condition, the peptides were completely hydrolyzed in 8 h. The
      relationships among the rigidity or the conformation and the thrombolytic
      activity in vivo and the stability to enzyme-induced hydrolysis in vitro of the
      cyclopeptides were discussed.

PMID- 12617931
TI  - Synthesis and photoreactivity of caged blockers for glutamate transporters.
AB  - L-TBOA (L-threo-beta-benzyloxyaspartate) is, so far, the most potent non
      transportable blocker for glutamate transporters. We synthesized alpha-CMCM-L
      TBOA (1a) possessing [7-(carboxymethoxy)coumarin-4-yl]methyl ester as a caging
      group. alpha-CMCM-L-TBOA (1a) is biologically inactive until UV irradiation and
      the photolysis of 1a immediately released L-TBOA to show glutamate uptake
      inhibition. The photoreactivity of the coumarin-type caging group was superior to
      that of the o-nitrobenzyl-type caging group.

PMID- 12617932
TI  - Modification of the N-terminus of peptidomimetic protein tyrosine phosphatase 1B
      (PTP1B) inhibitors: identification of analogues with cellular activity.
AB  - Low molecular weight peptidomimetic compounds based on O-malonyl tyrosine and O
      carboxymethyl salicylic acid are potent inhibitors of PTP1B. Modifications of the
      N-terminal Boc-Phe moiety were undertaken in an effort to improve physical
      chemical properties and to achieve cellular activity. Although Phe ultimately
      proved to be the optimal N-terminal amino acid, several viable replacements for
      the Boc group were identified, two of which afforded analogues that were
      effective at enhancing the insulin-stimulated uptake of 2-deoxyglucose by L6
      myocytes.

PMID- 12617933
TI  - Orexin A (hypocretin-1) application at the medial preoptic area potentiates male
      sexual behavior in rats.
AB  - The medial preoptic area plays an important role in the regulation of male sexual
      behavior in rats, and this area receives orexinergic inputs. The role of
      orexinergic inputs in the medial preoptic area in sexual behavior has not been
      studied, though they have been shown to play a role in some other physiological
      functions. In this study, the changes in male sexual behavior in rats were
      studied after local injection of orexin A (Hypocretin-1) at the medial preoptic
      area. The results of the study showed that orexin A application at the medial
      preoptic area increased sexual arousal as well as the copulatory performance.
      Sexual arousal is one of the physiological stimuli, which influences wakefulness.
      It is possible that the earlier reports showing increased wakefulness, on
      application of orexin A at the medial preoptic area/basal forebrain, has a
      contribution from sexual arousal.

PMID- 12617934
TI  - Temporal and sequential analysis of microglia in the substantia nigra following
      medial forebrain bundle axotomy in rat.
AB  - Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis
      after transection of the medial forebrain bundle. We have assessed the temporal
      and sequential activities of microglia in these events by examining the
      complement-3 (OX-42), major histocompatibility complex class II antigen
      presentation (OX-6) and phagocytic activity (ED1), and correlating these
      indicators with dopaminergic neuronal loss. Microglia in the ipsilateral
      substantia nigra pars reticulata evinced activation morphology at 12 h
      postaxotomy. Phagocytic microglia apposed dying dopaminergic neurons in the pars
      compacta starting at 3 days postlesion; their number increased through 14 days
      and slowly decreased. Nuclear chromatin condensation and significant loss of
      tyrosine hydroxylase-positive dopaminergic neurons occurred around 7 days
      postlesion. In contrast to microglial expression of interleukin-1beta and
      inducible nitric oxide synthase at the axotomy site, nigral microglia were
      interleukin-1beta and inducible nitric oxide synthase-negative. Consistently,
      RNase protection assays showed that interleukin-1beta and inducible nitric oxide
      synthase transcripts in nigra were equivocal. The present data support the idea
      that phagocytosis of axotomized neurons by activated microglia is not limited to
      dead neurons but includes dying neurons probably without cytotoxic effects of
      inflammatory substances, such as interleukin-1beta or nitric oxide.

PMID- 12617935
TI  - A lipoxygenase product, hepoxilin A(3), enhances nerve growth factor-dependent
      neurite regeneration post-axotomy in rat superior cervical ganglion neurons in
      vitro.
AB  - Hepoxilins are 12-lipoxygenase metabolites of arachidonic acid found in the CNS.
      They can modulate neuronal signaling but their functions are not known. We
      examined the effects of hepoxilin A(3) on neurite outgrowth post-axotomy in an in
      vitro model of spinal cord transection using superior cervical ganglion neurons.
      In the absence of nerve growth factor, hepoxilin A(3) did not support neuronal
      survival, or regeneration post-axotomy but did significantly enhance neurite
      regeneration in the presence of nerve growth factor. As early as 1 h post-injury
      hepoxilin A(3)-treated cultures (+nerve growth factor) had significantly more
      neurites than controls (nerve growth factor alone). Average hourly rates of
      outgrowth in hepoxilin A(3)-treated cultures were significantly higher than in
      controls for at least 12 h post-injury, suggesting that the effect of hepoxilin
      A(3) is maintained in vitro for several hours post-injury. In uninjured neurons
      hepoxilin A(3) caused a rapid but transient increase in intracellular calcium in
      the somata; by 2 min post-addition, calcium levels decreased to a new stable
      plateau significantly higher than pre treatment levels. In injured neurons,
      hepoxilin A(3) addition immediately post-transection caused a rapid transient
      increase in intracellular calcium in cell bodies; however, peak calcium levels
      were significantly lower than in uninjured neurons and the new baseline lower
      than in uninjured cells. In uninjured cells hepoxilin A(3) addition in zero
      calcium produced the same pattern, a transient elevation and subsequent decline
      to a new stable baseline significantly above rest but in injured cells levels
      fell rapidly to pretreatment values. Taken overall, these findings demonstrate a
      novel role for hepoxilins as a potentiator of neurite regeneration. They also
      provide the first evidence that this lipoxygenase metabolite can alter
      intracellular calcium in neurons by causing release of calcium from intracellular
      stores and modulating calcium influx mechanisms.

PMID- 12617936
TI  - Distribution of immunoreactivity for the adrenomedullin binding protein,
      complement factor H, in the rat brain.
AB  - Adrenomedullin is a multifunctional amidated peptide that has been found in most
      nuclei of the CNS, where it plays a neuromodulatory role. An adrenomedullin
      binding protein has recently been found in plasma and characterized as complement
      factor H. This regulator of the complement system inhibits the progression of the
      complement cascade and modulates the function of adrenomedullin. Our study shows
      the ample distribution of factor H immunoreactivity in neurons of telencephalon,
      diencephalon, mesencephalon, pons, medulla, and cerebellum in the rat CNS, using
      immunohistochemical techniques for both light and electron microscopy. Factor H
      immunoreactivity was found in the cytoplasm, but nuclear staining was also a
      common finding. Some blood vessels and glial cells were also immunoreactive for
      factor H. Colocalization studies by double immunofluorescence followed by
      confocal microscopy revealed frequent coexistence of factor H and adrenomedullin
      immunoreactivities, thus providing morphological evidence for the potential
      interaction of these molecules in the CNS. The presence of factor H
      immunoreactivity in glial cells was confirmed by colocalization with glial
      fibrillary acidic protein. In summary, factor H is highly expressed in the CNS
      where it could play important roles in regulating adrenomedullin actions and
      contributing to an intracerebral complement system.

PMID- 12617937
TI  - Potassium currents in vestibular type II hair cells activated by hydrostatic
      pressure.
AB  - An elevated hydrostatic pressure in the endolymphatic space of the inner ear is
      discussed as pathophysiological factor in hydrops-related diseases of the inner
      ear. An increase in pressure by fractions of 1 cm H(2)O is sufficient to induce
      vertigo-like symptoms in animal models. To establish a link between hydrostatic
      pressure and the function of vestibular hair cells, we studied potassium currents
      in isolated vestibular type II hair cells from guinea-pig utricles when the
      hydrostatic pressure was increased by raising the height of the bath from 0.2
      0.5, 0.7 or 1.0 cm. Elevated pressure enhanced K(+) currents significantly; a
      rise in pressure from 0.2-0.5 cm H(2)O increased the total K(+) current at +40 mV
      by 22+/-14% (+/-S.D.). The pressure-sensitive current I(K,p) was non-inactivating
      during depolarizing pulses. It was maintained when the pressure was kept elevated
      for several minutes and receded promptly after return to a pressure of 0.2 cm
      H(2)O. Voltage-gated Ca(2+) currents, in contrast, were not altered by
      hydrostatic pressure. A pharmacological characterization of I(K,p) revealed that
      tetraetylammonium (100 mM) abolished all outward currents including I(K,p).
      I(K,p) was partly and reversibly inhibited by 4-aminopyridine.
      Dihydrostreptomycin, a blocker of the transduction channel, left I(K,p)
      unaffected. Charybdotoxin (100 nM), a blocker of Ca(2+)-dependent K(+) channels,
      completely yet reversibly abolished I(K,p). We conclude that small elevations in
      hydrostatic pressure evoke a charybdotoxin-sensitive, probably Ca(2+)-dependent
      K(+) current in vestibular hair cells. This is likely to alter their frequency
      response and may be a relevant mechanism how hydrostatic pressure disturbs
      transduction.

PMID- 12617938
TI  - Morphological development and neurochemical differentiation of cerebellar
      inhibitory interneurons in microexplant cultures.
AB  - The cerebellar cortex comprises a rather limited variety of interneurons,
      prominently among them inhibitory basket and stellate cells and Golgi neurons. To
      identify mechanisms subserving the positioning, morphogenesis, and neurochemical
      maturation of these inhibitory interneurons, we analyzed their development in
      primary microexplant cultures of the early postnatal cerebellar cortex. These
      provide a well-defined, patterned lattice within which the development of
      individual cells is readily accessible to experimental manipulation and
      observation. Pax-2-positive precursors of inhibitory interneurons were found to
      effectively segregate from granule cell perikarya. They emigrate from the core
      explant and avoid the vicinity of granule cells, which also emigrate and
      aggregate into small clusters around the explant proper. This contrasts with the
      behavior of Purkinje neurons, which remain within the explant proper. During
      migration, a subset of Pax-2-positive cells gradually acquires a GABAergic
      phenotype, and subsequently also expresses the type 2 metabotropic receptor for
      glutamate, or parvalbumin, markers for Golgi neurons and basket or stellate
      cells, respectively. The latter eventually orient their dendrites such that they
      take a preferentially perpendicular orientation relative to granule cell axons.
      Both the neurochemical maturation of basket/stellate cells and the specific
      orientation of their dendrites are independent of their continuous contact with
      radially oriented glia or Purkinje cell dendrites projecting from the core
      explant. Numbers of parvalbumin-positive basket/stellate cells and the prevalence
      of glutamate-positive neurites, which form a dense network preferentially within
      cell clusters containing granule cell perikarya and their dendrites, are subject
      to regulation by chronic depolarization. In contrast, brain-derived neurotrophic
      factor results in a drastic decrease of numbers of basket/stellate cells. These
      findings document that granule cell axons (parallel fibers) are the major
      determinant of basket/stellate cell dendritic orientation. They also show that
      the neurochemical maturation of cerebellar interneurons is sensitive to
      regulation by activity and neurotrophic factors.

PMID- 12617939
TI  - Increase in the number of tyrosine hydroxylase-containing neurons in a primary
      culture system of the rat accessory olfactory bulb by co-culture with vomeronasal
      pockets.
AB  - Previously, we established a culture system of the accessory olfactory bulb in
      order to investigate the functional role of each accessory olfactory bulb neurons
      in pheromonal signal processing. In the present study, we developed a co-culture
      system of cultured accessory olfactory bulb neurons with partially dissociated
      cells of the vomeronasal organ. The dissociated cells of the vomeronasal organ
      form spherical structures surrounding a central cavity in culture, referred to as
      the vomeronasal pockets. The projection and activity of olfactory receptor
      neurons affect the differentiation and maturation of main olfactory bulb neurons.
      It was also reported induction of tyrosine hydroxylase expression in main
      olfactory bulb neurons when they were co-cultured with explants of the olfactory
      epithelium. Thus, we investigated the effects of co-culture with vomeronasal
      pockets on the differentiation and/or maturation of cultured accessory olfactory
      bulb neurons in relation to tyrosine hydroxylase expression. The number of
      tyrosine hydroxylase-containing neurons developmentally increased over time in
      the accessory olfactory bulb culture. This increase was significantly enhanced by
      coculture with vomeronasal pockets. Interestingly, a significant change in
      tyrosine hydroxylase expression was not observed when main olfactory bulb neurons
      were co-cultured with vomeronasal pockets. Moreover, significant changes in
      tyrosine hydroxylase expression were not observed when accessory olfactory bulb
      neurons were co-cultured with olfactory epithelium explants, as was previously
      observed in co-culture of main olfactory bulb neurons and olfactory epithelium
      explants. These results suggest that the differentiation and/or maturation of
      accessory olfactory bulb neurons is modified by vomeronasal organ neurons via
      specific interactions between the sensory organ and its target.

PMID- 12617940
TI  - Excitatory actions of GABA in developing brain are mediated by l-type Ca2+
      channels and dependent on age, sex, and brain region.
AB  - Although GABA is the major inhibitory neurotransmitter in adult brain, it exerts
      depolarizing actions in developing neurons that include activation of voltage
      gated calcium channels. The depolarizing actions of GABA serve an obvious trophic
      function, but the specific physiological significance of excitatory versus
      inhibitory GABA action has been largely ignored. We previously demonstrated that
      estradiol enhances the magnitude and duration of calcium influx through L-type
      voltage-gated calcium channels following GABA(A) receptor activation in neonatal
      hypothalamic neurons. This has led us to propose that GABA action represents a
      major divergence point in steroid-mediated sexual differentiation of rat brain.
      Presently, we examined sex differences in phosphorylation of the calcium
      regulated transcription factor, cyclic AMP response element binding protein,
      following activation of the GABA(A) receptor with muscimol, in vivo. Muscimol
      given 30 min before killing significantly increased the number of neurons
      exhibiting phosphorylated cyclic AMP response element binding protein in newborn
      male hypothalamus and CA1 hippocampus but decreased phosphorylated cyclic AMP
      response element binding protein in most brain regions in females. Muscimol
      induced increases in phosphorylated cyclic AMP response element binding protein
      in hypothalamus and hippocampus of newborn males were attenuated by pretreatment
      with the L-type voltage-gated calcium channel blocker, nimodipine, suggesting
      that calcium influx is involved in phosphorylation of cyclic AMP response element
      binding protein in neonate brain. Muscimol treatment had no effect on
      hypothalamic or hippocampal phosphorylated cyclic AMP response element binding
      protein levels in juvenile males and females. These results are consistent with a
      divergence in male and female rat brain in the calcium-mediated cellular response
      to muscimol that is restricted to the early neonatal period, a time critical for
      estradiol-mediated sexual differentiation.

PMID- 12617941
TI  - In vivo and in vitro effects of peripheral galanin on nociceptive transmission in
      naive and neuropathic states.
AB  - Galanin is widely distributed in the nervous system and is consistently
      upregulated in both dorsal root ganglion and spinal neurones by peripheral nerve
      injury. This study investigates the peripheral effects of galanin on nociceptive
      neurones using in vitro and in vivo electrophysiological techniques in naive and
      neuropathic rats. Using an in vitro skin-nerve preparation recording from single
      nociceptive fibres, galanin (1 microM) significantly inhibited firing induced by
      noxious heat in 65% of fibres examined. In the remaining 35% of fibres, galanin
      (1 microM) induced a facilitation of the responses to noxious heat. To examine
      the effect of peripheral galanin in vivo, extracellular recordings from
      convergent dorsal horn neurones were made in anaesthetised naive sham-operated
      and spinal nerve-ligated (SNL) rats. Injection of galanin (0.1-10 microg) into
      hindpaw receptive fields inhibited responses to innocuous mechanical, noxious
      mechanical and noxious heat stimuli in a proportion of neurones in each animal
      group and facilitated the remaining neurones. However, a higher proportion of
      neurones (80-90%) was inhibited by peripheral galanin administration in SNL rats
      compared with naive (45-55%) and sham (70-80%) rats. These results show that
      galanin can have both excitatory and inhibitory effects on peripheral sensory
      neurones, perhaps reflecting differential receptor activation, and that the
      proportion of these receptors may change following peripheral neuropathy.

PMID- 12617942
TI  - Metabotropic glutamate and muscarinic cholinergic receptor-mediated preferential
      inhibition of N-methyl-D-aspartate component of transmissions in rat ventral
      tegmental area.
AB  - Presynaptic inhibition is one of the major control mechanisms in the CNS. Our
      laboratory recently reported that presynaptic GABA(B) and adenosine A(1)
      receptors mediate a preferential inhibition on N-methyl-D-aspartate receptor
      mediated excitatory postsynaptic currents recorded in rat midbrain dopamine
      neurons. Here we extended these findings to metabotropic glutamate and muscarinic
      cholinergic receptors. Intracellular voltage clamp recordings were made from
      dopamine neurons in rat ventral tegmental area in slice preparations. (+/-)-1
      Aminocyclopentane-trans-1,3-dicarboxylic acid (agonist for groups I and II
      metabotropic glutamate receptors) and L(+)-2-amino-4-phosphonobutyric acid (L
      AP4; agonist for group III metabotropic glutamate receptors) were significantly
      more potent for inhibiting N-methyl-D-aspartate receptor-mediated excitatory
      postsynaptic currents, as compared with inhibition of excitatory postsynaptic
      currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
      receptors. Such preferential inhibition of the N-methyl-D-aspartate component was
      also observed for muscarine (agonist for muscarinic cholinergic receptors).
      Inhibitory effects of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, L
      AP4, and muscarine were blocked reversibly by their respective antagonists [(RS)
      alpha-methyl-4-carboxyphenylglycine, (RS)-alpha-methyl-4-phosphonophenylglycine,
      and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide]. In addition, all three
      agonists increased the ratio of excitatory postsynaptic currents in paired-pulse
      studies and did not reduce currents induced by exogenous N-methyl-D-aspartate and
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Interestingly, the
      glutamate release stimulator 4-aminopyridine (30 microM) and the glutamate uptake
      inhibitor L-anti-endo-3,4-methanopyrrolidine dicarboxylate (300 microM)
      preferentially increased the amplitude of N-methyl-D-aspartate excitatory
      postsynaptic currents.Thus, agonists for metabotropic glutamate and muscarinic
      cholinergic receptors act presynaptically to cause a preferential reduction in
      the N-methyl-D-aspartate component of excitatory synaptic transmissions. Together
      with the evidence for GABA(B) and adenosine A(1) receptor-mediated preferential
      inhibition of the N-methyl-D-aspartate component, the present results suggest
      that limiting glutamate spillover onto postsynaptic N-methyl-D-aspartate
      receptors may be a general rule for presynaptic modulation in midbrain dopamine
      neurons.

PMID- 12617943
TI  - Gamma-hydroxybutyrate receptor function determined by stimulation of rubidium and
      calcium movements from NCB-20 neurons.
AB  - Gamma-Hydroxybutyrate is derived from GABA in brain and plays specific functional
      roles in the CNS. It is thought to exert a tonic inhibitory control on dopamine
      and GABA release in certain brain areas, through specific gamma-hydroxybutyrate
      receptors. Apart from modifying certain calcium currents, the specific
      transduction mechanism induced by stimulation of gamma-hydroxybutyrate receptors
      remains largely unknown. We investigated the possible contribution of K(+)
      channels to the hyperpolarization phenomena generally induced by gamma
      hydroxybutyrate in brain, by monitoring (86)Rb(+) movements in a neuronal cell
      line (NCB-20 cells), which expresses gamma-hydroxybutyrate receptors.
      Physiological concentrations of gamma-hydroxybutyrate (5-25 microM) induce a slow
      efflux of (86)Rb(+), which peaks at 5-15 min and returns to baseline levels 20
      min later after constant stimulation. This effect can be reproduced by the gamma
      hydroxybutyrate receptor agonist NCS-356 and blocked by the gamma-hydroxybutyrate
      receptor antagonist 6,7,8,9-tetrahydro-5-[H]-benzocycloheptene-5-ol-4-ylidene.
      The GABA(B) receptor antagonist CGP 55845 has no effect on gamma-hydroxybutyrate
      induced (86)Rb(+) efflux. The pharmacology of this gamma-hydroxybutyrate
      dependent efflux of (86)Rb(+) is in favor of the involvement of
      tetraethylammonium and charybdotoxin insensitive, apamin sensitive Ca(2+)
      activated K(+) channels, identifying them as small conductance calcium activated
      channels. We demonstrated a gamma-hydroxybutyrate dose-dependent entry of calcium
      ions into NCB-20 neuroblastoma cells at resting potential. Electrophysiological
      data showed that this Ca(2+) entry corresponded mainly to a left-hand shift of
      the current/voltage relation of the T-type calcium channel. This process must at
      least partially trigger small conductance calcium activated channel activation
      leading to gamma-hydroxybutyrate-induced hyperpolarization.

PMID- 12617944
TI  - Neuronal location of 5-hydroxytryptamine3 receptor-like immunoreactivity in the
      rat colon.
AB  - The presence of 5-hydroxytryptamine(3) receptors on enteric neurons is known from
      pharmacological data that date back more than 40 years. However, an adequate
      account of which neurons bear these receptors has not been made because suitable
      antisera have not been available. We have found that the majority of antisera
      that have been raised against sequences from the 5-hydroxytryptamine(3) receptor
      also recognize pre-prosomatostatin. We report that this source of false labeling
      can be eliminated by pre-incubating the antisera with a peptide designed for this
      purpose. We have used the pre-absorbed antiserum to localize 5
      hydroxytryptamine(3) receptors in the rat colon. Immunoreactive nerve cell bodies
      occurred in the myenteric and submucosal ganglia. The majority had smooth cell
      bodies and long, smooth processes, that is, Dogiel type II morphology. The
      initial segments of the long processes of the Dogiel type II neurons were
      strongly immunoreactive. About 12% of immunoreactive myenteric nerve cells were
      of the same or smaller size, and had multiple short filamentous processes. Some
      of the immunoreactive Dogiel type II neurons were also immunoreactive for
      calretinin in both plexuses, and the majority were immunoreactive for calbindin
      in submucosal ganglia. Specific immunoreactivity occurred in non-varicose, but
      not in varicose, fibers in the myenteric and submucosal ganglia, and in fiber
      bundles that traversed the longitudinal and circular muscle layers.
      Immunoreactive varicose fibers were observed only in the mucosa. It is concluded
      that 5-hydroxytryptamine(3) receptors occur on intrinsic sensory neurons in the
      rat colon, and on extrinsic sensory nerve fibers that innervate the colon.

PMID- 12617945
TI  - Effect of endotoxin treatment on the expression of cyclooxygenase-2 and
      prostaglandin synthases in spinal cord, dorsal root ganglia, and skin of rats.
AB  - Peripheral inflammation causes upregulation of cyclooxygenase in the spinal cord
      and subsequent increase in prostaglandin biosynthesis. However, prostaglandin
      synthases, which are downstream of cyclooxygenase control the type of
      prostaglandin that is formed predominantly. Since there is little known about the
      regulation of prostaglandin synthases, the present study was conducted in order
      to determine the effect of endotoxin treatment on the expression of messenger RNA
      encoding interleukin 1beta, cyclooxygenase-2, and prostaglandin synthases
      mediating the formation of prostaglandin E(2) (membrane bound prostaglandin E
      synthase) and prostaglandin D(2) (lipocalin prostaglandin D synthase) in spinal
      cord, dorsal root ganglia and skin of rats. Endotoxin (2 mg/kg i.p.) induced the
      expression of interleukin-1beta, cyclooxygenase-2, and membrane bound
      prostaglandin E synthase messenger RNA in spinal cord, dorsal root ganglia, and
      skin as determined by reverse transcription polymerase chain reaction. In
      contrast, basal expression of lipocalin prostaglandin D synthase messenger RNA in
      spinal cord and dorsal root ganglia was not significantly altered by endotoxin.
      Dexamethasone (1 mg/kg s.c. at -18 h and -1 h) attenuated the effect endotoxin on
      the expression of interleukin-1beta, cyclooxygenase-2, and membrane bound
      prostaglandin E synthase messenger RNA in all tissues investigated, but did not
      significantly influence expression of lipocalin prostaglandin D synthase mRNA in
      spinal cord and dorsal root ganglia. In situ hybridisation histochemistry showed
      endotoxin-induced expression of cyclooxygenase-2 and membrane bound prostaglandin
      E synthase messenger RNA throughout gray and white matter of spinal cord
      sections. In dorsal root ganglia, expression of membrane bound prostaglandin E
      synthase seemed primarily located to non-neuronal cells, while cyclooxygenase-2
      messenger RNA was not detectable. The results show that the immune response
      elicited by endotoxin induced cyclooxygenase-2 and membrane bound prostaglandin E
      synthase, but not lipocalin prostaglandin D synthase messenger RNA in spinal cord
      and dorsal root ganglia of rats. The distribution of cyclooxygenase-2 and
      membrane bound prostaglandin E synthase messenger RNA expressing cells suggests
      major involvement of non-neuronal cells in spinal prostaglandin biosynthesis.
      Determination of the regulation of enzymes downstream of cyclooxygenase at the
      messenger RNA level may represent a valuable tool to investigate effects of
      analgesic/anti-inflammatory drugs on the regulation of spinal prostaglandin
      biosynthesis.

PMID- 12617946
TI  - Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of
      the rat CNS.
AB  - The messenger RNA for endothelial differentiation gene 8 receptors is known to be
      expressed almost exclusively in the rat CNS, but the nature of the expressing
      cells has not been defined. Using an antibody specific for endothelial
      differentiation gene 8, we investigated the immunohistochemical localization of
      endothelial differentiation gene 8 receptors in the rat CNS. Immunopositive
      staining was detected in a subset of glial cells distributed throughout the brain
      and spinal cord, including both gray and white matter, but not in the dorsal root
      ganglion. The distribution and morphological similarity in comparative
      immunostaining for endothelial differentiation gene 8 and various glial markers
      suggested that endothelial differentiation gene 8 is preferentially expressed in
      NG2-positive oligodendrocyte progenitor cells in adult rat brains. Counts of
      endothelial differentiation gene 8-positive cells and NG2-positive cells in the
      forebrain revealed that a subset of NG2-positive cells was endothelial
      differentiation gene 8-positive, and that the ratio of endothelial
      differentiation gene 8-positive cells to NG2-positive cells varied from region to
      region. In 17-day-old embryonic brains, the endothelial differentiation gene 8
      distribution was similar to that of an oligodendrocytic marker, 2',3'-cyclic
      nucleotide 3'-phosphodiesterase. These data suggest that endothelial
      differentiation gene 8 receptors are preferentially expressed in oligodendrocyte
      lineage cells including oligodendrocyte progenitor cells and immature/maturating
      oligodendrocytes in rat CNS, and that they might have important functions in
      oligodendrocytic maturation and myelination.

PMID- 12617947
TI  - Methamphetamine enhances the cleavage of the cytoskeletal protein tau in the rat
      brain.
AB  - The view that methamphetamine is neurotoxic to dopaminergic and serotonergic axon
      terminals has been based largely on biochemical and histological studies. In the
      present study, methamphetamine-induced structural damage to axons was quantified
      using a sensitive sandwich enzyme-linked immunosorbent assay developed for the
      detection of the cleaved form of the cytoskeletal protein tau. The administration
      of a monoamine-depleting regimen of methamphetamine (4 x 10 mg/kg, i.p. every 2
      hours for a total of four injections) produced a time-dependent increase in the
      concentration of cleaved tau in the striatum. Maximal concentrations of cleaved
      tau were detected 3 days following methamphetamine administration. Cleaved tau
      concentrations also were significantly elevated in the dorsal hippocampus and, to
      a lesser extent, in the prefrontal cortex of methamphetamine-treated rats.
      Maintenance of rats in a cold (4 degrees C) environment not only prevented the
      methamphetamine-induced depletion of striatal dopamine and serotonin but also
      prevented the methamphetamine-induced increase in striatal cleaved tau
      concentrations. The novel findings from this study are supportive of the view
      that methamphetamine produces acute structural damage to neurons that may lead to
      the long-term neurotoxic effects of repeated, high-dose administration of the
      drug and that cleaved tau reliably quantifies the time-dependent neurotoxic
      effects of methamphetamine.

PMID- 12617948
TI  - Stretch receptor-associated expression of alpha 3 isoform of the Na+, K+-ATPase
      in rat peripheral nervous system.
AB  - Expression of the neuronal alpha(3) isoform of the Na(+),K(+)-ATPase (alpha(3)
      Na(+),K(+)-ATPase) was studied in the rat peripheral nervous system using
      histological and immunohistochemical techniques. Non-uniform expression of the
      alpha(3) Na(+),K(+)-ATPase was observed in L5 ventral and dorsal roots, dorsal
      root ganglion, sciatic nerve and its branches into skeletal muscle. The alpha(3)
      Na(+),K(+)-ATPase was not detected in nerve fibers in skin, saphenous and sural
      nerves. In dorsal root ganglion 12+/-2% of neurons were immunopositive for
      alpha(3) Na(+),K(+)-ATPase and all these neurons were large primary afferents
      that were not labeled by Griffonia simplicifolia isolectin B4 (marker of small
      primary sensory neurons). In dorsal and ventral roots 27+/-3% and 40+/-3%,
      respectively, of myelinated axons displayed immunoreactivity for alpha(3)
      Na(+),K(+)-ATPase. In contrast to the dorsal roots, strong immunoreactivity in
      ventral roots was observed only in myelinated axons of small caliber, presumably
      gamma-efferents. In the mixed sciatic nerve alpha(3) Na(+),K(+)-ATPase was
      detected in 26+/-5% of myelinated axons (both small and large caliber). In
      extensor hallicus proprius and lumbricales hind limb muscles alpha(3) Na(+),K(+)
      ATPase was detected in some intramuscular axons and axonal terminals on
      intrafusal muscle fibers in the spindle equatorial and polar regions (regions of
      afferent and efferent innervation of the muscle stretch receptor, respectively).
      No alpha(3) Na(+),K(+)-ATPase was found in association with innervation of
      extrafusal muscle fibers or in tendon-muscle fusion regions. These data
      demonstrate non-uniform expression of the alpha(3) isoform of the Na(+),K(+)
      ATPase in rat peripheral nervous system and suggest that alpha(3) Na(+),K(+)
      ATPase is specifically expressed in afferent and efferent axons innervating
      skeletal muscle stretch receptors.

PMID- 12617949
TI  - Corticotropin-releasing hormone receptor blockade fails to alter stress-evoked
      catecholamine release in prefrontal cortex of control or chronically stressed
      rats.
AB  - Although it is well documented that stress can increase the activity of central
      dopamine and norepinephrine neurons, little is known about the role of other
      neurotransmitters in modulating this response. Previous studies have implicated
      corticotropin-releasing hormone in modulating stress-evoked changes in the
      activity of locus coeruleus neurons. The present study examines whether
      corticotropin-releasing hormone contributes to stress-evoked increases in
      extracellular norepinephrine and dopamine in rat medial prefrontal cortex, as
      monitored by in vivo microdialysis. As noted previously, 30 min of tail-shock
      increased extracellular levels of norepinephrine and dopamine in the medial
      prefrontal cortex of naive rats, and this was enhanced in rats previously exposed
      to chronic cold ( approximately 5 degrees C for 2-3 weeks). Previous
      intraventricular administration of a corticotropin-releasing hormone antagonist
      (D-Phe-corticotropin-releasing hormone; 3 and 9 microg) did not alter the tail
      shock evoked in increase in extracellular levels of norepinephrine and dopamine
      in either naive or chronically cold-exposed rats. Intraventricular administration
      of 3 microg of D-Phe-corticotropin-releasing hormone attenuated the increase in
      extracellular norepinephrine induced by co-administration of 3 microg of
      corticotropin-releasing hormone, confirming the efficacy of this compound.
      Results of the present study suggest that endogenous corticotropin-releasing
      hormone does not play a role in modulating the release of norepinephrine and
      dopamine occurring in response to acute tail-shock or the expression of a
      potentiated response to tail-shock in rats exposed chronically to cold.

PMID- 12617950
TI  - Non-oscillatory discharges of an F-prostaglandin responsive neuron population in
      the olfactory bulb-telencephalon transition area in lake whitefish.
AB  - Our previous studies on olfactory bulbar responses in salmonid fishes suggest
      that pheromone signals might be processed by a mechanism distinct from that of
      other odorants. Using in vivo single-unit and electroencephalographic recordings,
      we investigated response characteristics of olfactory neurons in lake whitefish,
      Coregonus clupeaformis, a species characterized by high electrophysiological and
      behavioral sensitivities to the reproductive pheromone candidates F
      prostaglandins. We found a neuron population responsive to F-prostaglandins in
      the ventromedial brain tissue strip connecting the olfactory bulb to the
      telencephalon. Of the 64 neurons examined in this area, 33% showed excitatory and
      11% inhibitory responses to F-prostaglandins, while 52% were non-responsive to
      all the stimuli tested. Both phasic and tonic F-prostaglandin neuron response
      patterns were observed during the 10-s stimulus period; some responses were
      delayed from the onset of stimulation, and some persisted for a long time
      following stimulus cessation. This neuron population did not induce synchronized
      oscillatory waves upon stimulation with F-prostaglandins, despite massive
      discharges. We demonstrate for the first time that the olfactory bulb
      telencephalon area of the brain is a distinct neural structure through which
      putative reproductive pheromone signals are integrated. Amino acid and F
      prostaglandin neuron population discharges have different temporal
      characteristics, suggesting different processing mechanisms exist for odorant and
      pheromone signals. The observed sustained neuron discharges may play a role in
      amplifying pheromone signals required for triggering stereotyped neuroendocrine
      and/or behavior changes.

PMID- 12617951
TI  - Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability
      of dorsal horn neurons after spinal hemisection in rat.
AB  - Hemisection of the rat spinal cord at thoracic level 13 provides a model of
      spinal cord injury that is characterized by chronic pain attributable to
      hyperexcitability of dorsal horn neurons. Presuming that this hyperexcitability
      can be explained in part by interruption of descending inhibitory modulation by
      serotonin, we hypothesized that intrathecal transplantation of RN46A-B14
      serotonergic precursor cells, which secrete serotonin and brain-derived
      neurotrophic factor, would reduce this hyperexcitability by normalizing the
      responses of low-threshold mechanoreceptive, nociceptive-specific, and
      multireceptive dorsal horn neurons. Three groups (n=45 total) of 30-day-old male
      Sprague-Dawley rats underwent thoracic level 13 spinal hemisection, after which
      four weeks were allowed for development of allodynia and hyperalgesia. The three
      groups of animals received transplants of no cells, 10(6) RN46A-V1 (vector-only)
      or 10(6) RN46A-B14 cells at lumbar segments 2-3. Electrophysiological experiments
      were done two weeks later. Low-threshold mechanoreceptive, nociceptive-specific,
      and multireceptive cells (n=394 total) were isolated at depths of 1-300 and 301
      1000 micro in the lumbar enlargement. Responses to innocuous and noxious
      peripheral stimuli were characterized, and analyses of population responses were
      performed. Compared with normal animals, dorsal horn neurons of all types in
      hemisected animals showed increased responsiveness to peripheral stimuli. This
      was true for neurons on both sides of the spinal cord. After hemisection, the
      proportion of neurons classified as multireceptive cells increased, and
      interspike intervals of spontaneous discharges became less uniform after
      hemisection. Transplantation of RN46A-B14 cells restored evoked responses to near
      control levels, normalized background activity, and returned the proportion of
      multireceptive cells to the control level. Restoration of normal activity was
      reversed with methysergide.These electrophysiological results corroborate
      anatomical and behavioral studies showing the effectiveness of serotonergic
      neural precursors in correcting phenomena associated with chronic central pain
      following spinal cord injury, and provide mechanistic insights regarding mode of
      action.

PMID- 12617952
TI  - Patterns of calcium-binding proteins in human inferior colliculus: identification
      of subdivisions and evidence for putative parallel systems.
AB  - The subdivisions of human inferior colliculus are currently based on Golgi and
      Nissl-stained preparations. We have investigated the distribution of calcium
      binding protein immunoreactivity in the human inferior colliculus and found
      complementary or mutually exclusive localisations of parvalbumin versus calbindin
      D-28k and calretinin staining. The central nucleus of the inferior colliculus but
      not the surrounding regions contained parvalbumin-positive neuronal somata and
      fibres. Calbindin-positive neurons and fibres were concentrated in the dorsal
      aspect of the central nucleus and in structures surrounding it: the dorsal
      cortex, the lateral lemniscus, the ventrolateral nucleus, and the intercollicular
      region. In the dorsal cortex, labelling of calbindin and calretinin revealed four
      distinct layers.Thus, calcium-binding protein reactivity reveals in the human
      inferior colliculus distinct neuronal populations that are anatomically
      segregated. The different calcium-binding protein-defined subdivisions may belong
      to parallel auditory pathways that were previously demonstrated in non-human
      primates, and they may constitute a first indication of parallel processing in
      human subcortical auditory structures.

PMID- 12617954
TI  - Comparative effects of lesions to the ponto-cerebellar and olivo-cerebellar
      pathways on motor and spatial learning in the rat.
AB  - Emerging evidence supports the role of the cerebellum in motor learning and
      previous studies have also shown that olivary projections to the cerebellum are
      involved in motor learning. Since the pontine nuclei make up the other main relay
      centre in the cerebro-cerebellar pathway, the purpose of the present study was to
      verify the involvement of the ponto-cerebellar pathway in motor and spatial
      learning, by comparing these functions in intact animals and in rats with
      selective injury of the olivary or pontine neurons. Two groups of rats were used:
      the first was treated with 3-acetylpyridine to destroy the inferior olivary
      complex, the second received electrolytic lesions of the middle cerebellar
      peduncle to interrupt the ponto-cerebellar pathway. Control and lesioned rats
      were then submitted to three tasks: unrotated rod, rota-rod at 20 r.p.m., and
      Morris water maze. In the first task both 3-acetylpyridine-treated rats and rats
      with lesions of the middle cerebellar peduncle showed static equilibrium
      deficiencies. Through training, however, they reached the maximal score attained
      by the controls. The rats submitted to the rota-rod at 20 r.p.m. obtained scores
      significantly inferior to the controls. The Morris water maze results indicated
      that the lesion of inferior olivary complex and middle cerebellar peduncle both
      alter learning of the spatial task. These findings show that both the ponto- and
      olivo-cerebellar pathways are involved in learning complex motor sequences and
      spatial tasks. Since both projections converge onto Purkinje cells, our results
      suggest an integration of these two pathways in the cerebellar control of
      learning mechanism.

PMID- 12617953
TI  - Motor behaviour deficits and their histopathological and functional correlates in
      the nigrostriatal system of dopamine transporter knockout mice.
AB  - Chronic dysregulation of dopamine homeostasis has been shown to induce
      behavioural impairment in dopamine transporter knockout mutant mice arising from
      the dysfunction of the mesolimbic and hypothalamo-infundibular system. Here, we
      assessed whether there are also any motor consequences of a chronic and
      constitutive hyperdopaminergia in the nigrostriatal system in dopamine
      transporter knockout mutant mice. For this, we analysed motor performances using
      tests assessing balance, coordinated motor skills (rotarod, pole test), stride
      lengths and locomotor activity. Dopamine transporter knockout mutant mice were
      markedly hyperactive in the open field with central compartment avoidance, as
      previously shown. However, sensorimotor integration was also found to be altered
      in dopamine transporter knockout mutant mice which displayed a reduced fore- and
      hind-limb mean stride length, impaired motor coordination on the pole test and
      reduced rearings in the open field. Moreover, dopamine transporter knockout
      mutant mice showed a slower task acquisition on the rotarod. Six-week-old
      dopamine transporter knockout wild type mice having the same femur size as adult
      dopamine transporter knockout mutant mice ruled out a possible size-effect bias.
      Whilst there was no significant difference in the striatal volume, we found a
      slight but significant reduction in neuronal density in the striatum but not in
      the nucleus accumbens of dopamine transporter knockout mutant mice. There was a
      reduced binding in the striatum and nucleus accumbens of dopamine(1) receptors
      ([(3)H]SCH 23390) and dopamine(2) receptors ([(3)H]YM-09151-2). There was no
      significant difference in the number of dopaminergic neurons in the substantia
      nigra between dopamine transporter knockout mutant mice and dopamine transporter
      knockout wild type mice. These results suggest an impaired functioning of the
      nigrostriatal system in dopamine transporter knockout mutant hyperdopaminergic
      mice, as illustrated by motor and sensorimotor integration deficits, despite
      their apparent hyperactivity. These dysfunctions may arise from combined striatal
      cell loss and/or functional changes of dopaminergic neurotransmission.

PMID- 12617956
TI  - Physiological changes in primate somatosensory thalamus induced by
      deafferentation are dependent on the spinal funiculi that are sectioned and time
      following injury.
AB  - The importance of spike bursts in thalamo-cortical processing of sensory
      information has received an increasing amount of interest over the past several
      years. Previously it has been reported that short high-frequency spike trains (3
      8 action potentials occurring at 67-167 Hz), or spike bursts, are increased in
      both human and non-human primate thalamus following deafferentation. Here we
      examine the effects of lesion of the ventral spinal quadrant alone versus
      combined lesion of the ventral and dorsal spinal quadrants on the evoked and
      spontaneous spike trains in thalamic neurons. A total of 1175 neurons were
      sampled from 13 animals, three intact, six with ventral quadrant lesions (three
      with prolonged survival and three with short-term survival after spinal lesion)
      and four with combined ventral and dorsal quadrant lesions. Detailed analysis was
      conducted on 256 of these neurons, which revealed that thalamic neurons of
      animals with ventral quadrant lesions had elevated burst and non-burst spike
      rates while neurons from animals with combined ventral-dorsal lesions showed two
      types of change. Neurons in the forelimb areas showed increased bursts without a
      change in non-burst activity, while neurons in lateral VPL without receptive
      fields showed very low non-burst activity, but high burst spike rates. The
      magnitude of the effects produced by ventral-lateral spinal lesions was more
      pronounced in the short-term survival animals than in the long-term survival
      animals. These results show that the effects of deafferentation on the
      physiological properties of thalamic neurons are dependent on the afferent tract
      or tracts that are lesioned and the time after lesion.

PMID- 12617955
TI  - The activity-regulated cytoskeleton-associated (Arc) gene is a new light
      inducible early gene in the mouse suprachiasmatic nucleus.
AB  - The mammalian circadian system is entrained to the environmental light/dark cycle
      by shifting the phase of the master clock in the suprachiasmatic nucleus.
      Accompanying the light-induced phase-shift, a variety of immediate-early genes
      appears in suprachiasmatic nucleus clock cells, and here, we report the
      expression of a new immediate-early gene Arc (activity-regulated cytoskeleton
      associated gene) in mice. Arc messenger RNAs were strongly induced at 30-120 min
      after the light exposure at subjective night (CT12-CT20) in neurons of the
      retinorecipient area of the suprachiasmatic nucleus, although their spontaneous
      expression was absent in usual light-dark cycles and in constant dark conditions.
      At protein level, ARC appeared not only in the nucleus but also in the perikarya
      and their processes of the suprachiasmatic nucleus neurons. These findings
      indicate that Arc is an activity-regulated cytoskeletal gene possibly involved in
      the light-induced phase-shift of the circadian rhythm.

PMID- 12617957
TI  - Glial cell line-derived neurotrophic factor contributes to delayed inflammatory
      hyperalgesia in adjuvant rat pain model.
AB  - Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic
      factor, are members of the structurally related neurotrophin family that play
      important roles in pain modulation. Although there are also indications for the
      involvement of glial cell line-derived neurotrophic factor (GDNF), it is unclear
      whether and how GDNF is involved in inflammatory pain. In the present study, we
      studied the expression pattern of GDNF in dorsal root ganglia (DRG) and spinal
      cord, using confocal microscopy. We demonstrate that GDNF is well associated with
      nonpeptidergic pain pathway and that GDNF could possibly be anterogradely
      transported from DRG neurons to superficial spinal cord dorsal horn. We also
      studied the dynamic changes of GDNF expression in rats during chronic
      inflammation using injection of complete Freund's adjuvant as a model of chronic
      pain. We found that GDNF was down-regulated in both dorsal root ganglia and
      spinal cords 2 weeks after arthritis induction. To assess the impact of this down
      regulation on pain transmission, we used a function-blocking antibody against
      GDNF delivered intrathecally in the same chronic-pain animal models. Injection of
      this antibody to GDNF produced no immediate effect, but decreased the delayed,
      bilateral hyperalgesia induced from a unilateral injection of complete Freund's
      adjuvant. The effect of this antibody coincided with the down-regulation of GDNF
      immunoreactivity in response to inflammation, suggesting that GDNF supports
      biochemical changes that contribute to hyperalgesia.

PMID- 12617958
TI  - Low-threshold heat receptor in chick sensory neurons is upregulated independently
      of nerve growth factor after nerve injury.
AB  - In mammals, the cloned low-threshold heat receptor, vanilloid receptor subtype 1
      (VR1), is involved in the genesis of thermal hyperalgesia after inflammation.
      However, there is evidence that VR1 is not involved in the thermal hyperalgesia
      that occurs after nerve injury. In search for other heat receptors which might be
      involved in this phenomenon, we previously demonstrated that chick dorsal root
      ganglion neurons, which are insensitive to capsaicin, respond to low-threshold
      heat. Here, we investigated whether expression of the low-threshold noxious heat
      receptor in chicks is regulated by nerve growth factor (NGF), as VR1 is in
      mammals. Heat (44 degrees C) responsiveness of isolated dorsal root ganglion
      neurons of chicks was investigated (i) under culture conditions for up to 4 days
      with and without NGF and (ii) after a tight ligation of the sciatic nerve for up
      to 6 days, using cobalt-uptake method. In every case, a significant upregulation
      in the proportion of heat-responsive neurons was observed. On the molecular
      level, there was an increase of chick VR1 mRNA level in dorsal root ganglion
      cells cultured for 3 days in medium lacking NGF. In rat dorsal root ganglion
      neurons cultured for 1-4 days without NGF, patch-clamp experiments revealed that
      after 1 day almost all neurons responding to heat also responded to capsaicin,
      whereas after 3-4 days, more than one-half of the heat-responsive neurons did not
      respond to capsaicin. These data suggest the existence of low-threshold heat
      receptors in chick dorsal root ganglion neurons, the expression of which is
      regulated independently of NGF.

PMID- 12617959
TI  - Predominantly neuronal expression of cytochrome P450 isoforms CYP3A11 and CYP3A13
      in mouse brain.
AB  - Despite the very small amounts of cytochrome P450 enzymes expressed in different
      areas and cell populations of the brain as compared with the liver, there is
      significant evidence for their specific involvement in brain development,
      function, and plasticity. Nevertheless, the current discussion about occurrence
      and importance of cerebral cytochrome P450 isoforms is determined by
      controversial interpretations of their function in general and with respect to
      single isoforms. Continuing a series of publications about brain P450 isoforms,
      we now present evidence for the expression of cytochrome P450 3A11 and 3A13 in
      mouse brain. Immunocytochemical and non-radioactive in situ hybridization studies
      revealed identical distribution of their proteins and mRNAs throughout the brain
      especially in neuronal populations, and to some extent in astrocytes. The
      cerebral expression of these P450 isoforms was confirmed by Western blot and
      RNAse protection assay analysis. The well-known testosterone-metabolizing
      capacity and the inducibility of cytochrome P450 3a isoforms by xenobiotics as
      well as their presence in steroid hormone-sensitive areas and neurons (e.g.
      hippocampus) clarify the significance of these isoforms for impairment of steroid
      hormone actions by P450-inducing environmental substances. Therefore,
      investigation of inducible cerebral P450 isoforms which are able to metabolize
      xenobiotics as well as steroid hormones might help us to understand
      neuroendocrine regulation of brain's plasticity.

PMID- 12617960
TI  - Migration of enhanced green fluorescent protein expressing bone marrow-derived
      microglia/macrophage into the mouse brain following permanent focal ischemia.
AB  - Brain ischemia induces a marked response of resident microglia and hematopoietic
      cells including monocytes/macrophages. The present study was designed to assess
      the distribution of microglia/macrophages in cerebral ischemia using bone marrow
      chimera mice known to express enhanced green fluorescent protein (EGFP). At 24 h
      after middle cerebral artery occlusion (MCAO), many round-shaped EGFP-positive
      cells migrated to the ischemic core and peri-infarct area. At 48-72 h after MCAO,
      irregular round- or oval-shaped EGFP/ionized calcium-binding adapter molecule 1
      (Iba 1)-positive cells increased in the transition zone, while many amoeboid
      shaped or large-cell-body EGFP/Iba 1-positive cells were increased in number in
      the innermost area of ischemia. At 7 days after MCAO, many process-bearing
      ramified shaped EGFP/Iba 1-positive cells were detected in the transition to the
      peri-infarct area, while phagocytic cells were distributed in the transition to
      the core area of the infarction. The distribution of these morphologically
      variable EGFP/Iba 1-positive cells was similar up to 14 days from MCAO. The
      present study directly showed the migration and distribution of bone marrow
      derived monocytes/macrophages and the relationship between resident microglia and
      infiltrated hematogenous element in ischemic mouse brain. It is important to
      study the distribution of intrinsic and extrinsic microglia/macrophage in
      ischemic brain, since such findings may allow the design of appropriate gene
      delivery system using exogenous microglia/macrophages to the ischemic brain area.

PMID- 12617962
TI  - In vitro hypoxia and excitotoxicity in human brain induce calcineurin-Bcl-2
      interactions.
AB  - Although pathogenesis of neuronal ischemia is incompletely understood, evidence
      indicates apoptotic neuronal death after ischemia. Bcl-2, an anti-apoptotic and
      neuroprotective protein, interacts with calcineurin in non-neuronal tissues.
      Activation of calcineurin, which is abundant in the brain, may play a role in
      apoptosis. Using co-immunoprecipitation experiments in biopsy-derived, fresh
      human cortical and hippocampal slices, we examined possible interactions between
      calcineurin and Bcl-2. Calcineuin-Bcl-2 interactions increased after exposure in
      vitro to excitotoxic agents and conditions of hypoxia/aglycia. This interaction
      may shuttle calcineurin to substrates such as the inositol-1,4,5-tris-phosphate
      receptor because under these experimental conditions interactions between
      calcineurin and inositol-1,4,5-tris-phosphate receptor also increased. A specific
      calcineurin inhibitor, FK-520, attenuated insult-induced increases in calcineurin
      Bcl-2 interactions and augmented caspase-3 like activity. These data suggest that
      Bcl-2 modulates neuroprotective effects of calcineurin and that calcineurin
      inhibitors increase ischemic neuronal damage.

PMID- 12617961
TI  - Calcium-dependent interaction of calcineurin with Bcl-2 in neuronal tissue.
AB  - Calcineurin, a calmodulin-dependent protein phosphatase, regulates transcription
      and possibly apoptosis. Previous studies demonstrated that in baby hamster kidney
      21 cells after co-transfection calcineurin interacts with Bcl-2, thereby altering
      transcription and apoptosis. Using co-immunoprecipitation and subcellular
      fractionation techniques, we observed that calcineurin occurred as a complex with
      Bcl-2 in various regions of rat and mouse brain. The calcineurin-Bcl-2 complex
      was identified in mitochondrial, nuclear, microsomal and cytosol fractions. In
      vitro induction of hypoxia and aglycia or N-methyl-D-aspartate treatment markedly
      altered both extent of complex formation and its subcellular localization. These
      observations suggest that Bcl-2 either sequesters calcineurin, that calcineurin
      dephosphorylates Bcl-2, or that Bcl-2 shuttles calcineurin to specific
      substrates. Calcineurin also co-immunoprecipitated with the inositol-tris
      phosphate receptor. This interaction increased after in vitro hypoxia/aglycia. In
      Bcl-2 (-/-) mice, interactions between calcineurin- and inositol-tris-phosphate
      receptor occurred less frequently than in wild-type mice under both control and
      hypoxic conditions. Experiments involving cell-free systems, as well as brain
      slices treated with thapsigargin or with N-methyl-D-aspartate suggested that
      calcium and calmodulin activation of calcineurin leads to interactions between
      calcineurin and Bcl-2. These data indicate that during times of cellular stress
      and damage, Bcl-2 targets activated calcineurin to specific compartments and
      substrates.

PMID- 12617963
TI  - Endogenous expression of inhibitor of apoptosis proteins in facial motoneurons of
      neonatal and adult rats following axotomy.
AB  - The inhibitor of apoptosis protein family members inhibit cell death resulting
      from a variety of apoptotic stimuli. However, the endogenous expression of
      neuronal inhibitor of apoptosis proteins following axonal injury has not been
      thoroughly examined. Neonatal facial motoneurons are highly susceptible to
      axotomy-induced apoptosis, whereas adult facial motoneurons survive axotomy. We
      hypothesized that the endogenous expression of inhibitor of apoptosis proteins
      may be involved in the differential susceptibility of adult and neonatal facial
      motoneurons to axonal injury. In this study, we examined the expression of two
      endogenous inhibitor of apoptosis proteins, neuronal apoptosis inhibitory protein
      and x-linked inhibitory apoptosis protein, in adult and neonatal rat facial
      motoneurons following axotomy. Analyses using reverse-transcription polymerase
      chain reaction and in situ hybridization indicated that neuronal apoptosis
      inhibitory protein mRNA was increased in neonatal facial nuclei 24 h post
      axotomy. In the adult, neuronal apoptosis inhibitory protein mRNA expression
      increased at 1, 3, 7 and 14 days post axotomy, while little change in the
      expression of X-linked inhibitory apoptosis protein mRNA was detected at any age
      or time point time point analyzed. Interestingly, immunohistochemistry using
      antibodies for neuronal apoptosis inhibitory protein and X-linked inhibitory
      apoptosis protein, revealed the level of these proteins was higher in the
      neonatal motoneurons when compared with the adult. Furthermore,
      immunohistochemistry and western blot for neuronal apoptosis inhibitory protein
      revealed, in contrast to the observed increase in neuronal apoptosis inhibitory
      protein mRNA, a decline in the expression of neuronal apoptosis inhibitory
      protein following axotomy in the adult, whereas no change in neuronal apoptosis
      inhibitory protein was detected in neonatal facial motoneurons. X-linked
      inhibitory apoptosis protein, as analyzed by immunohistochemistry and western
      blot, remained unchanged by axotomy in neonatal motoneurons and adult
      motoneurons. These results indicate differential expression and/or turnover of
      inhibitor of apoptosis proteins in neonatal versus adult facial motoneurons, and
      suggest the level of inhibitor of apoptosis protein expression alone is not an
      indicator of cell fate following axotomy.

PMID- 12617964
TI  - Stereologic analysis of neurofibrillary tangle formation in prefrontal cortex
      area 9 in aging and Alzheimer's disease.
AB  - Alzheimer's disease (AD) is characterized neuropathologically by several features
      including extensive neuronal death in the cerebral cortex. In fact, while
      neuropathological changes restricted to the hippocampal formation are a
      consistent reflection of age-related memory impairment, overt dementia is present
      only in cases with neocortical involvement. Several quantitative studies have
      reported a substantial loss of neurons from these regions and a parallel increase
      in the number of neurofibrillary tangles (NFT). However, accurate quantitative
      data on the dynamics of NFT formation are lacking. In the present study, we
      performed a stereologic analysis of the proportions of intracellular and
      extracellular (ghost) NFT, and unaffected neurons in the deep part of layer III
      (layer IIIc) and the superficial part of layer V (layer Va) of Brodmann's
      prefrontal cortex area 9. Elderly cognitively unimpaired cases were compared with
      cases with different degrees of cognitive dysfunction. The data revealed
      differential rates of formation of intracellular and extracellular NFT between
      the two layers, and confirmed the presence of a severe disease-associated, but
      not age-related, neuronal loss. It was also shown that a susbtantial number of
      pyramidal cells may persist either unaffected or in a transitional stage of NFT
      formation in both neocortical layers. These results suggest that a considerable
      number of neurons containing an intracellular NFT exists in the neocortex until
      late in the course of AD. Whereas it is not possible to assess whether such
      transitional neurons are fully functional, these affected neurons might respond
      positively to therapeutic strategies aimed at protecting the cells that are prone
      to neurofibrillary degeneration in AD.

PMID- 12617965
TI  - Distribution of OL-protocadherin protein in correlation with specific neural
      compartments and local circuits in the postnatal mouse brain.
AB  - OL-protocadherin (OL-pc) is a cell adhesion molecule that belongs to the cadherin
      superfamily. A previous study showed that expression of OL-pc mRNA was specific
      to certain brain nuclei including those of the olfactory and limbic systems, thus
      suggesting its involvement in neural circuit formation. Here, we examined the
      distribution of OL-pc protein in the postnatal mouse brain by
      immunohistochemistry to confirm the possibility of such a role. The results
      showed that the protein could be mapped to many brain compartments including
      brain nuclei and higher subdivisions as previously observed for the expression
      pattern of the mRNA. Sharp boundaries of the distribution were often seen in
      areas such as the interpedunclar nucleus, cerebellar cortex, and inferior olive.
      In addition, the protein was detected in some fibers that could not be examined
      by the previous study using in situ hybridization. For example, prominent
      staining was noted in the stria medularis, stria terminalis, fasciculus
      retroflexus, optic tract, and inferior thalamic radiation, structures that seem
      to connect OL-pc-positive brain regions. These OL-pc-positive brain nuclei and
      fiber tracts coincide with some local circuits of functional systems such as the
      olfactory system, nigrostriatal projection, olivo-cerebellar projection, and
      visual system. These results support the possibility that OL-pc is involved in
      the formation of specific neural compartments and circuits in the developing
      brain.

PMID- 12617966
TI  - Postsynaptic activation of calcium/calmodulin-dependent protein kinase II
      promotes coordinated pre- and postsynaptic maturation of Drosophila neuromuscular
      junctions.
AB  - The interaction between a neuron and its target cell(s) is essential for the
      development of synapses. To elucidate the role of target cells in synaptogenesis,
      the activity of postsynaptic calcium/calmodulin-dependent protein kinase II
      (CaMKII) was manipulated in a mosaic manner and its specific effect was examined
      at the developing Drosophila neuromuscular junction. We found that postsynaptic
      expression of constitutively active CaMKII augmented the amplitude of excitatory
      synaptic currents (ESCs) and the frequency of miniature ESCs. It also promoted
      morphological maturation of presynaptic as well as postsynaptic specializations,
      which presumably underlie the enhancement of synaptic activities. Expression of
      an inhibitory peptide of CaMKII in the postsynaptic cell partially affected the
      synaptic maturation. These results suggest two significant functions of
      postsynaptic CaMKII in synaptogenesis-retrograde modulation of presynaptic
      properties and coordinated regulation of pre- and postsynaptic maturation.

PMID- 12617967
TI  - Expression of the specific type IV phosphodiesterase gene PDE4B3 during different
      phases of long-term potentiation in single hippocampal slices of rats in vitro.
AB  - Hippocampal long-term potentiation (LTP), the most prominent cellular model for
      learning and memory formation, consists of phases: early-LTP (<4 h) and late-LTP
      (>4 h), with the latter dependent upon protein translation and transcription. To
      explore the molecular processes that might be specifically regulated during late
      LTP, we have modified standard electrophysiological and molecular biological
      methods, which allowed the cloning of activated genes and their products from
      single hippocampal slices in vitro 8 h after LTP induction. From one such screen
      we identified a specific type IV phosphodiesterase gene, PDE4B3, the first cAMP
      specific phosphodiesterase to be associated with LTP. Previous studies documented
      an integral role for the cAMP-PKA system in late-LTP and recently, inhibition of
      cAMP degradation facilitates LTP and ameliorates mnemonic deficits. We now report
      that PDE4B3 is modulated during LTP phases. Its activation is NMDA-receptor
      dependent and its transcription is transiently up-regulated 2 h after
      tetanization. Protein expression peaks 6 h after LTP induction and is rapidly
      down-regulated at 8 h, whereas cAMP levels decrease during LTP phases.
      Immunohistochemical studies identified that the majority of type IV
      phosphodiesterase protein staining is localized to the cell bodies and dendrites
      of neurones in hippocampal CA1.

PMID- 12617968
TI  - Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1
      receptor-mediated action in mice: enhancement of the methamphetamine-induced
      abuse state.
AB  - Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has
      been extensively evaluated for toxicity in a variety of tests in rodents,
      including developmental and reproductive toxicity, and carcinogenicity. However,
      little is known about its action on the CNS. In this report, we show that
      prenatal and neonatal exposure to BPA in mice leads to the enhancement of the
      dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant
      methamphetamine. Furthermore, this treatment with BPA markedly enhanced
      hyperlocomotion and its sensitization induced by methamphetamine, which reflects
      extensive abuse associated with sociological and psychiatric problems. We also
      demonstrated that chronic exposure to BPA produced an up-regulation of dopamine
      D1 receptor function to activate G-protein in the mouse limbic forebrain, which
      is thought to be a critical site for the expression of rewarding effects by abuse
      drugs. Additionally, chronic BPA exposure produced a significant increase in
      levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no
      change in protein levels of methamphetamine-targeted proteins, dopamine
      transporter or the type 2 vesicle monoamine transporter in the brain was observed
      by prenatal and neonatal exposure to BPA. The present data provide the first
      evidence that prenatal and neonatal exposure to BPA can potentiate the central
      dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity
      of methamphetamine-induced pharmacological actions related to psychological
      dependence on psychostimulants.

PMID- 12617969
TI  - Biochemical and ultrastructural analyses of IgLON cell adhesion molecules, Kilon
      and OBCAM in the rat brain.
AB  - Kilon (kindred of IgLON) and opioid-binding cell adhesion molecule belong to the
      IgLON subgroup of immunoglobulin superfamily together with the limbic system
      associated membrane protein and neurotrimin. In the present study, we have
      analyzed biochemical and ultrastructural characterization of Kilon and opioid
      binding cell adhesion molecule such as regional and developmental expression
      patterns, light and electron microscopic localization, and intermolecular
      interactions. Western blotting revealed a widespread distribution pattern of
      Kilon with high expression levels in the olfactory bulb, cerebral cortex,
      diencephalon, hippocampus, and cerebellum and low expression levels in the
      medulla oblongata and spinal cord. In contrast, opioid-binding cell adhesion
      molecule showed a regionally restricted expression pattern with high levels only
      in the cerebral cortex and hippocampus. Expression of Kilon and opioid-binding
      cell adhesion molecule was increased gradually during postnatal development and
      maintained until adulthood. Light microscopic immunohistochemistry demonstrated
      that the localization of opioid-binding cell adhesion molecule and Kilon
      coincided well with that of vesicle-associated membrane protein 2, a synaptic
      marker protein, in the cerebral cortex and hippocampus of adult brain. In the
      cerebellum, Kilon-immunoreactive puncta were observed to colocalize well with
      that of vesicle-associated membrane protein 2, while opioid-binding cell adhesion
      molecule immunoreactivity was observed only at part of synaptic glomeruli in the
      granular layer and rare in the molecular layer. Electron microscopic analysis
      revealed that Kilon and opioid-binding cell adhesion molecule immunoreactivity
      was observed mainly at postsynaptic sites of dendritic and somatic synapses in
      adult cerebral cortex and hippocampus. Only trace levels of Kilon and opioid
      binding cell adhesion molecule were detected in the soluble fraction of a
      cortical homogenate, although a substantial amount of F3 was present in the
      soluble fraction. A binding analysis using a cross-linker and the
      immunoprecipitation technique demonstrated that Kilon and opioid-binding cell
      adhesion molecule interacted heterophilically and homophilically. These findings
      show that Kilon and opioid-binding cell adhesion molecule are clearly
      distinguishable from each other in regional expression and localization, and
      binding patterns. These differences possibly represent diverse functions of each
      IgLON molecule.

PMID- 12617970
TI  - A peripheral cannabinoid mechanism suppresses spinal fos protein expression and
      pain behavior in a rat model of inflammation.
AB  - The present studies were conducted to test the hypothesis that systemically
      inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in
      vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of
      spinal Fos protein expression, a marker of neuronal activity, in a rat model of
      inflammation. Rats received unilateral intraplantar injections of carrageenan
      (3%). In behavioral studies, carrageenan induced allodynia and mechanical
      hyperalgesia in response to stimulation with von Frey monofilaments. The
      cannabinoid agonist WIN55,212-2 (30 microg intraplantarly), administered
      concurrently with carrageenan, attenuated carrageenan-evoked allodynia and
      hyperalgesia relative to control conditions. In immunocytochemical studies,
      WIN55,212-2 suppressed the development of carrageenan-evoked Fos protein
      expression in the lumbar dorsal horn of the spinal cord relative to vehicle
      treatment. The same dose administered systemically or to the noninflamed
      contralateral paw failed to alter either carrageenan-evoked allodynia and
      hyperalgesia or carrageenan-evoked Fos protein expression, consistent with a
      peripheral site of action. The suppressive effects of WIN55,212-2 (30 microg
      intraplantarly) on carrageenan-evoked Fos protein expression and pain behavior
      were blocked by local administration of either the CB(2) antagonist SR144528 (30
      microg intraplantarly) or the CB(1) antagonist SR141716A (100 microg
      intraplantarly). WIN55,212-3, the enantiomer of the active compound, also failed
      to suppress carrageenan-evoked Fos protein expression. These data provide direct
      evidence that a peripheral cannabinoid mechanism suppresses the development of
      inflammation-evoked neuronal activity at the level of the spinal dorsal horn and
      implicate a role for CB(2) and CB(1) in peripheral cannabinoid modulation of
      inflammatory nociception.

PMID- 12617971
TI  - Actions of Group I and Group II metabotropic glutamate receptor ligands on 5
      hydroxytryptamine release in the rat cerebral cortex in vivo: differential roles
      in the regulation of central serotonergic neurotransmission.
AB  - We have previously shown that the release of central neurotransmitters can be
      modulated by the activation of Group I and Group II subtypes of G-protein-linked
      metabotropic glutamate (mGlu) receptors. To date, however, very little is known
      about the regulation of serotonergic neurotransmission by these receptor
      subtypes. In the present study, we have utilized in vivo intracerebral
      microdialysis to elucidate the roles of Group I and Group II mGlu receptors in
      the regulation of neuronal 5-hydroxytryptamine (5-HT) release in the frontal
      cortex of conscious, freely moving rats. Dialysate 5-HT was of neuronal origin
      with basal release showing strong calcium dependency and tetrodotoxin sensitivity
      and marked elevation following K(+)-induced depolarization. The broad-spectrum
      mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)
      ACPD; 1-3 mM] did not significantly modify basal cerebrocortical 5-HT release.
      Similarly, the Group I mGlu receptor-specific agonist (RS)-3,5
      dihydroxyphenylglycine [(RS)-3,5-DHPG; 1-3 mM] showed no marked effect on
      cortical dialysate 5-HT levels. To eliminate the possibility that these findings
      were the result of receptor desensitization, the effects of lower concentrations
      of (RS)-DHPG (100-300 microM) and shorter ligand exposure time (15 min) were also
      evaluated. Dialysate 5-HT levels remained unmodified by these manipulations. In
      comparison, the Group II mGlu receptor agonist, (2S,1'S,2'S)-2
      (carboxycyclopropyl)glycine (L-CCG-1; 500 microM), evoked a marked facilitation
      of release (approximately 150% of basal) which was fully reversed by the Group
      I/II antagonist, (S)-alpha-methyl-4-carboxyphenylglycine [(S)-MCPG; 3 mM]. The
      modulatory action of L-CCG-1 showed a bell-shaped concentration-response
      relationship. (S)-MCPG (3 mM) and the potent and selective mGlu(5) receptor
      antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 100 microM), when given
      alone, did not significantly modify 5-HT levels.The current data provide strong
      evidence to suggest that while the release of neuronal 5-HT in the rat frontal
      cortex is not subject to regulation by facilitatory Group I mGlu receptors, it
      may be positively modulated by activation of Group II mGlu receptors. Taken
      together with data from other studies, the present investigation lends emphasis
      to the notion that neuromodulation by mGlu receptors is a region-specific
      phenomenon and also proposes that the heterogeneous distribution of these
      receptors is neurone-specific in its complexity. The failure of (S)-MCPG alone to
      modify cortical 5-HT release suggests that Group II mGlu receptors do not
      tonically modulate serotonergic neurotransmission in the cerebral cortex but this
      does not preclude an important functional role for these receptors during
      pathological conditions when endogenous neurotransmitter levels become
      excessively elevated. The strategic development of new subtype-specific mGlu
      receptor ligands may provide novel therapeutic agents for the treatment of a
      range of neurological and psychiatric disorders.

PMID- 12617972
TI  - Effects of clozapine, haloperidol and iloperidone on neurotransmission and
      synaptic plasticity in prefrontal cortex and their accumulation in brain tissue:
      an in vitro study.
AB  - The mode of action of the antipsychotic drugs clozapine, haloperidol and
      iloperidone was investigated in layer V of prefrontal cortex slices using
      extracellular field potential, intracellular sharp-electrode as well as whole
      cell voltage clamp recording techniques. Intracellular investigations on a broad
      range of concentrations revealed that the typical neuroleptic haloperidol at
      higher concentrations significantly depressed the excitatory postsynaptic
      component induced by electrical stimulation of layer II. This was not seen with
      the atypical neuroleptics clozapine and iloperidone. None of the three compounds
      had any effect on the resting membrane potential, spike amplitude or input
      resistance at relevant concentrations. Synaptic plasticity was assessed by means
      of extracellular field potential recordings. Clozapine significantly facilitated
      the potentiation of synaptic transmission, whereas haloperidol and iloperidone
      showed no effects. In line with its facilitating effect on synaptic plasticity,
      it could be demonstrated by whole-cell voltage clamp recordings that clozapine
      increased N-methyl-D-aspartic acid receptor-mediated excitatory postsynaptic
      currents in the majority of prefrontal cortical neurones. These investigations
      were made with neuroleptic drugs applied to the bath in the micromolar
      concentration range in order to approach clinical brain concentrations that are
      reached after administration of therapeutic doses. The drug concentrations
      reached in the slices after the experiments were assessed by means of high
      pressure liquid chromatography coupled with mass-spectrometric detection.
      Surprisingly, drug accumulation in the in vitro preparation was of similar degree
      as reported in vivo. In conclusion, the typical neuroleptic haloperidol
      significantly depressed excitatory synaptic transmission in layer V neurones of
      the prefrontal cortex. In contrast, the two atypical neuroleptics iloperidone and
      clozapine revealed no depressing effects. This feature of the atypical
      neuroleptics might be beneficial since a hypofunctionality of this brain area is
      thought to be linked with the pathophysiology of schizophrenia. Additionally,
      clozapine facilitated long-term potentiation, which might be linked with the
      clinically observed beneficial effects on certain cognitive parameters. The
      clozapine-induced increase of N-methyl-D-aspartic acid receptor-mediated currents
      suggests that clozapine facilitates the induction of long-term potentiation.
      Furthermore, the present study points to the importance of considering the
      significant accumulation of neuroleptic drugs in in vitro studies.

PMID- 12617973
TI  - Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in
      the rat prefrontal cortex: modulation by a group II selective metabotropic
      glutamate receptor agonist LY379268.
AB  - Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3
      agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC)
      induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist
      phencyclidine. In the present study we examined the effects of the more potent
      mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine
      (DA) release in mPFC of male rats. Subjects were implanted with a unilateral
      microdialysis probe in the mPFC and were tested 12-24 h after implantation.
      Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA,
      although the glutamate response was slower in onset compared with DA.
      Pretreatment with either systemic (3 mg/kg s.c.) or local (1 microM, in the
      probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When
      applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe)
      had no effect on glutamate release but did significantly enhance the release of
      DA. Application of NMDA (500 microM in the probe), on the other hand, decreased
      DA while increasing glutamate release. The effect of NMDA on evoking glutamate
      release was blocked by systemic but not local administration of LY379268. These
      findings indicate that systemic ketamine increases both glutamate and DA release
      in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group
      II mGluR receptors. Local ketamine, on the other hand, does not increase
      glutamate but does increase DA release. This suggests that ketamine acts outside
      of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The
      origin of the ketamine effect on mPFC glutamate is currently not known.

PMID- 12617974
TI  - Activation of the cyclic AMP response element-binding protein signaling pathway
      in the olfactory bulb is required for the acquisition of olfactory aversive
      learning in young rats.
AB  - Long-term memory formation requires both gene expression and protein synthesis.
      Phosphorylation of the transcription factor cyclic AMP response element-binding
      protein (CREB) is thought to be important in processes underlying long-term
      memory. To clarify the role of CREB in olfactory aversive learning in young rats,
      we carried out behavioral pharmacology and Western blot analyses. On postnatal
      day 11, oligodeoxynucleotides were infused directly into the bilateral olfactory
      bulbs through cannulae implanted prior to training in a classical conditioning
      paradigm with citral odor and foot shock. On the following day the odor
      preference test was performed. After training, saline-infused animals spent
      significantly shorter time over the citral odor zone. Infusion of CREB antisense
      oligodeoxynucleotides 6 h before or during training, however, prevented olfactory
      aversive learning without affecting memory retention 1 h after training. CREB
      scrambled oligodeoxynucleotides infusions had no effect on olfactory learning.
      When infused 6 h after training, none of oligodeoxynucleotides had an effect on
      time spent over the odor zone. Using Western blotting, we analyzed CREB in
      nuclear extracts obtained from the young rats after training. Marked increases in
      phosphorylated CREB were sustained from 10 to 360 min after the odor-shock
      pairing in animals which were subjected to both, in comparison with levels 30 min
      in animals which were subjected to odor only or no stimulation. Total CREB levels
      showed no differences among groups. Infusion of CREB antisense
      oligodeoxynucleotides significantly reduced the expression of phosphorylated and
      total CREBs in the olfactory bulb. These results show that the synthesis and
      phosphorylation of CREB are required for the acquisition of olfactory aversive
      learning in young rats, and that this requirement for the CREB signaling pathway
      has a critical time window.

PMID- 12617975
TI  - Thalamic neuronal activity in rats with mechanical allodynia following contusive
      spinal cord injury.
AB  - Pain and allodynia following spinal cord injury are poorly understood and
      difficult to treat. Since there is evidence that supraspinal mechanisms are
      important in such pain, we have studied the role of the thalamus in an
      experimental model of spinal injury. Extracellular recordings were obtained from
      neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats
      and those which had sustained a contusive spinal cord injury to the thoraco
      lumbar junction 7 days previously. Behavioural testing with von Frey hairs
      established that 11 spinally injured rats showed exaggerated vocal responses to
      normally innocuous mechanical stimulation (allodynia) whereas eight were non
      allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non
      allodynic) exhibited a dysrhythmia in that a significantly higher proportion
      fired spontaneously in an oscillatory mode when compared with neurones in
      uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to
      allodynia. The evoked responses of VPL thalamic neurones to brushing the skin,
      however, were significantly elevated in allodynic rats when compared with those
      in uninjured rats and neuronal afterdischarges to these stimuli (which were
      absent in uninjured rats) were more common in allodynic than in non-allodynic
      rats. We have previously reported that a proportion of spinal neurones in
      allodynic spinally injured rats show increased evoked responses and
      afterdischarges following brushing the skin and hence the enhanced thalamic
      responses may reflect a greater spinal input. In view of the increasing evidence
      that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive
      brain functions, we propose that pain following brushing the skin results from an
      exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both
      spinal and thalamic mechanisms may be important in the genesis of pain and
      allodynia following spinal cord injury.

PMID- 12617977
TI  - Role of postsynaptic density protein-95 in the maintenance of peripheral nerve
      injury-induced neuropathic pain in rats.
AB  - Our previous work has demonstrated that postsynaptic density protein-95, a
      molecular scaffolding protein that binds and clusters N-methyl-D-aspartate
      receptors at neuronal synapses, plays an important role in the development of
      peripheral nerve injury-induced neuropathic pain. The current study further
      investigated the possible involvement of postsynaptic density protein-95 in the
      maintenance of neuropathic pain. Mechanical and thermal hyperalgesia were induced
      within 3 days and maintained for 15 days or longer after unilateral injury to the
      fifth lumbar spinal nerve. The rats injected intrathecally with postsynaptic
      density protein-95 antisense oligodeoxynucleotide every 24 h for 4 days from day
      7 to day 10 post-surgery exhibited not only a marked decrease in spinal cord
      postsynaptic density protein-95 protein expression but also a significant
      reduction in mechanical and thermal hyperalgesia on day 11 post-surgery. The rats
      injected with sense oligodeoxynucleotide did not display these changes. However,
      in the rats without nerve injury, postsynaptic density protein-95 antisense
      oligodeoxynucleotide given intrathecally every 24 h for 4 days did not affect
      responses to mechanical and thermal stimulation. In addition, postsynaptic
      density protein-95 antisense oligodeoxynucleotide did not change locomotor
      activity of experimental animals. Our results indicate that the deficiency of
      postsynaptic density protein-95 protein in the spinal cord significantly
      attenuates nerve injury-induced mechanical and thermal hyperalgesia during both
      the development and maintenance of chronic neuropathic pain. These results
      suggest that postsynaptic density protein-95 might be involved in the central
      mechanisms of chronic neuropathic pain and provide a novel target for development
      of new pain therapies.

PMID- 12617976
TI  - In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the
      Alzheimer's brain using the positron emission tomography molecular imaging probe
      2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2
      naphthyl]ethylidene)malononitrile.
AB  - Epidemiological studies have suggested that the chronic use of non-steroidal anti
      inflammatory drugs (NSAIDs) reduces the relative risk of Alzheimer's disease
      (AD). The possible neuroprotection by NSAIDs in AD is generally attributed to
      anti-inflammatory activity. An additional mode of drug action may involve anti
      aggregation of beta-amyloid (Abeta) peptides by commonly used NSAIDs. We utilized
      in vitro competition assays, autoradiography, and fluorescence microscopy with AD
      brain specimens to demonstrate concentration-dependent decreases in the binding
      of the in vivo molecular imaging probe, 2-(1-[6-[(2
      [(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile
      ([(18)F]FDDNP), against (S)-naproxen and (R)- and (S)-ibuprofen (but not
      diclofenac) to Abeta fibrils and ex vivo Abeta senile plaques. Conversely, in
      vitro amyloid dyes Congo Red and Thioflavine T were demonstrated in the same
      experiments not to bind to the FDDNP binding site. FDDNP and the NSAIDs that
      share the same binding site also exhibit anti-aggregation effects on Abeta
      peptides, suggesting that the shared binding site on Abeta fibrils and plaques
      may be a site of anti-aggregation drug action. Our results indicate for the first
      time the binding of select NSAIDs to plaques, specifically to the binding site of
      the molecular imaging probe [(18)F]FDDNP. Our understanding of the molecular
      requirements of FDDNP binding may help in the optimization of the Abeta anti
      aggregation potency of experimental drugs. [(18)F]FDDNP has been used to image
      plaques in vivo with positron emission tomography (PET), and investigations into
      the influence of Abeta anti-aggregation on the risk-reduction effects of NSAIDs
      on AD could utilize [(18)F]FDDNP and PET in determining the occupancy rate of
      NSAIDs and experimental drugs in plaques in the living brain of AD patients.

PMID- 12617978
TI  - An immunohistochemical examination of the effects of sensitisation on the
      mesotelencephalic dopaminergic response to d-amphetamine.
AB  - The dopaminergic response to d-amphetamine with or without prior repeated
      experience with the drug was investigated immunohistochemically in key target
      regions of the mesotelencephalic dopamine system using antibodies raised against
      glutaraldehyde-conjugated dopamine. This methodology permitted the unambiguous
      determination of dopaminergic activity within specific subregions of structures
      implicated in the behavioural effects of psychomotor stimulants drugs, and in the
      expression of behavioural sensitisation. Experiment 1 examined dopamine
      immunoreactivity in central or basolateral amygdala, shell or core of the nucleus
      accumbens, medial and lateral caudate-putamen and medial prefrontal cortex
      following the administration of various doses of d-amphetamine to drug-naive
      rats. Whilst dose-related increases in dopaminergic activity were detected in all
      regions examined, a regional heterogeneity was clearly evident. For example, d
      amphetamine enhanced dopaminergic activity preferentially within the shell
      subregion of the nucleus accumbens both with respect to the core subregion and to
      other striatal and non-striatal areas. Experiment 2 examined changes in
      dopaminergic activity following the administration of a low dose of d-amphetamine
      to d-amphetamine-sensitised rats and saline-pretreated control animals. Regional
      heterogeneity both between and within terminal areas was again detected. Thus,
      there was evidence of a preferential increase in dopaminergic activity within the
      shell of the nucleus accumbens of sensitised rats. Moreover, sensitisation to d
      amphetamine increased the dopaminergic response to acute administration of d
      amphetamine within all striatal and non-striatal areas examined. Comparison of
      this effect across subterritories of the areas under investigation revealed that
      in sensitised rats, acute administration of d-amphetamine elevated dopaminergic
      activity within the shell of the nucleus accumbens to a greater extent than
      within the core. These data therefore indicate that systemic administration of d
      amphetamine is associated with regionally heterogeneous changes in dopaminergic
      activity within terminal regions of the mesotelencephalic dopamine system in both
      sensitised and unsensitised rats. Moreover, the present methodology permitted
      resolution of these changes at an anatomical level beyond that of conventional
      approaches.

PMID- 12617979
TI  - Immunohistochemical assessment of mesotelencephalic dopamine activity during the
      acquisition and expression of Pavlovian versus instrumental behaviours.
AB  - Dopaminergic activity during Pavlovian or instrumental learning in key target
      regions of the mesotelencephalic dopamine system was investigated
      immunohistochemically using antibodies raised against glutaraldehyde-conjugated
      dopamine. Experiment 1 examined dopamine immunoreactivity during acquisition of a
      Pavlovian conditioned-approach response. Observations were taken at three stages
      of learning: initial, intermediate and asymptotic; each with a conditioned
      stimulus+ (CS+) group for whom visual or auditory stimuli immediately preceded an
      unconditioned stimulus (sucrose), and a conditioned stimulus- (CS-) group for
      whom stimuli and the unconditioned stimulus were unpaired. Animals learned to
      approach the alcove during CS+ presentations, whilst approach behaviour of the CS
      group remained low. In general, target regions exhibiting a dopaminergic
      reaction responded maximally during the intermediate stage of acquisition, and
      were less responsive initially, and not responsive at all at asymptote.
      Specifically, the pattern of dopaminergic response was: shell more than core of
      the nucleus accumbens; prefrontal cortex, central and basolateral nuclei of the
      amygdala also significantly responsive. Mediodorsal and laterodorsal striatal
      regions were reactive only very early in training. Experiment 2 examined
      dopaminergic reaction following acquisition of a novel conditioned instrumental
      response. The conditioned response+ (CR+) group responded at a much higher rate
      on the lever for which unconditioned stimulus-associated stimuli were presented,
      than on the control lever. The conditioned response- (CR-) group responded at a
      low rate on both levers. In contrast with experiment 1, the most responsive
      regions were the core of the nucleus accumbens, medial prefrontal cortex and
      basolateral area of the amygdala. Thus, the acquisition, but not expression of
      Pavlovian associations activated dopamine within several key target regions of
      the mesotelencephalic dopamine system, and preferentially within the shell rather
      than core of the nucleus accumbens. By contrast, acquisition of a novel
      instrumental response preferentially activated the core of the nucleus accumbens,
      and basolateral area of the amygdala. These data carry significant implications
      for the potential role of these regions in learning and memory.

PMID- 12617980
TI  - Input-specific effects of acetylcholine on sensory and intracortical evoked
      responses in the "barrel cortex" in vivo.
AB  - The somatosensory neocortex processes extrinsic information from the thalamus and
      intrinsic information from local circuits. We compared the effects of
      acetylcholine (Ach) on neocortical field potential responses evoked by
      stimulation of the whiskers and by local electrical stimulation in the upper
      layers of the neocortex vibrissae representation ("barrel cortex") of adult rats
      anesthetized with urethane. In the barrel cortex, the cholinergic system was
      manipulated using microdialysis by exogenous application of Ach, by increasing
      the endogenous levels of Ach with physostigmine and by applying specific
      cholinergic agonists. The results revealed that Ach selectively enhances the
      sensory response relative to the intracortical response. Thus, pathways in the
      barrel cortex are differentially regulated by cholinergic inputs.

PMID- 12617981
TI  - Thrombophilia and pregnancy loss.
AB  - A large body of evidence obtained during the past 6 years suggests a significant
      role for inherited thrombophilia in the development of gestational vascular
      complications. While the majority of women with thrombophilia will have an
      uneventful gestation, case-control studies have demonstrated that thrombophilia
      is more prevalent in cohorts of women with pregnancy loss early onset
      preeclampsia, placental abruption, and severe intrauterine growth retardation
      (IUGR). Placental pathological findings in women with thrombophilia are
      hallmarked by thrombosis and fibrin deposition potentially to a greater degree
      than in normal pregnancy. Preliminary case-control studies suggest a benefit for
      prophylaxis with low molecular weight heparins (LMWH), and prospective randomized
      trials are in progress to define whether LMWH are effective in preventing
      pregnancy loss in women with thrombophilia and previous fetal wastage.

PMID- 12617982
TI  - Predictors of residual venous obstruction after deep vein thrombosis of the lower
      limbs: a prospective cohort study.
AB  - INTRODUCTION: Delayed thrombus regression after deep vein thrombosis (DVT) of the
      lower limbs is associated with increased risk of DVT recurrence. Predictors of
      residual venous occlusion are unknown. We hypothesized that obesity, which causes
      reduced fibrinolytic activity, can predict delayed thrombus regression. MATERIALS
      AND METHODS: In a prospective cohort study, 98 patients with objective diagnosis
      of DVT underwent compression ultrasonography (CUS) after 6 and 12 months.
      Persistent occlusion was arbitrarily defined as a thrombus occupying, at maximal
      point of compressibility, more than 20% of the vein area in the absence of
      compression. The body mass index (BMI) and waist circumference were measured at
      baseline and at follow up to assess individual patterns of body fat distribution.
      Information on antithrombotic treatment, family history of varicose veins,
      cigarette smoking, concomitant disorders, the presence of known risk factors for
      DVT, the duration of anticoagulant treatment and the use of elastic stockings was
      collected. RESULTS: Post-thrombotic recanalization was documented in 34 patients
      (34.7%) at 6 months and in 44 patients (44.9%) at 12 months. There was no
      difference in the mean BMI (p=0.469 at 12 months), in the prevalence of obesity
      (p=0.479) and visceral pattern of body fat distribution (p=0.239) between
      patients who did and did not show thrombus regression. The presence of a
      permanent risk factor for DVT was the only predictor of delayed thrombus
      regression (OR 11.0, 95% CI 1.359-61.978). CONCLUSIONS: Despite consistent
      evidence of impaired fibrinolysis, obesity is not associated with persistent
      venous obstruction.

PMID- 12617983
TI  - Association of prothrombin and protein S with plasma triglyceride-rich
      lipoproteins in humans after test meals rich in milk fat or soybean oil.
AB  - INTRODUCTION: Prothrombin can associate with rat chylomicrons in vitro. This
      enhances a platelet factor Xa mediated prothrombin activation when the
      chylomicron-prothrombin complex is exposed to platelets. Vitamin K-dependent pro-
      and anti-coagulation proteins are associated with TG-rich lipoproteins obtained
      from human plasma. In the present study, we examined the effects of saturated and
      unsaturated fat meals on the association of prothrombin and protein S with TG
      rich lipoproteins in vivo. MATERIALS AND METHODS: Human EDTA plasma was separated
      from normal subjects after overnight fasting and 2.5 h after ingestion of either
      a saturated fat meal (butter and cream) or an unsaturated fat meal (soybean oil)
      containing 54-80 g fat (60.2 E%). The prothrombin and protein S in delipidated
      lipoproteins were determined by SDS-PAGE combined with Western blotting. RESULTS:
      Both prothrombin and protein S associated with TG-rich lipoproteins in fasting
      and in postprandial samples. The levels of prothrombin and protein S in
      postprandial TG-rich lipoproteins, especially after ingestion of a saturated fat
      meal, were higher than those in fasting TG-rich lipoproteins. CONCLUSIONS: The
      levels of both prothrombin and protein S in TG-rich lipoproteins in plasma
      increased after a single fat meal. This association is more pronounced after
      saturated fat meals and one may hypothesize that it can be linked to atherogenic
      properties of TG-rich lipoproteins.

PMID- 12617984
TI  - Effects of mechanical ventilation on platelet microparticles in bronchoalveolar
      lavage fluid.
AB  - INTRODUCTION: Mechanical ventilation (MV) is considered to contribute to lung
      injury. Platelet membrane-derived microparticles (PMPs) are procoagulant and
      participate in the inflammatory process. The bronchoalveolar space could, besides
      plasma, be a site of origin of these microparticles. We evaluated the presence of
      these PMPs and two prostaglandin-derived metabolites in bronchoalveolar lavage
      fluid (BALF) regarding their possible relation to MV. MATERIALS AND METHODS:
      Before and after 1 h of MV, PMPs and prostaglandin metabolites were analyzed, in
      BALF from 14 anesthetized pigs, by flow cytometry and RIA, respectively. Tracheal
      mucus from five humans was analyzed for PMPs at extubation after surgery.
      RESULTS: Activated PMPs and prostaglandin metabolites were present in all BALF
      samples. The time needed to count 5000 cellular events was prolonged six-fold
      after 1 h of mechanical ventilation (p<0.001). The relative content of PMPs was
      constant in all samples. The PMPs were thrombogenic, i.e. they were fibrinogen, p
      selectin and von Willebrand factor positive. Lavage did not per se affect the
      period necessary to count 5000 cellular events. PMPs in human tracheal mucus were
      in the same range as in the pig after 1 h of MV aiming at a PaCO(2) between 5.0
      and 5.5 kPa. CONCLUSIONS: Activated PMPs are present in the pulmonary air-liquid
      interface. The prolongation of the time needed to count 5000 cellular events in
      BALF after MV indicates activation and adherence. Adherent microparticles bind
      neutrophils, which may aggravate pathological processes leading to pulmonary
      dysfunction. Evaluation of PMPs in BALF may be useful in evaluating strategies
      for lung-protective ventilator treatment.

PMID- 12617985
TI  - Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation
      system.
AB  - Vitamin K is an essential cofactor for post translational gamma-carboxylation of
      vitamin K-dependent coagulation factors. The modification is carried out by a
      system of integral proteins of the endoplasmic reticulum (ER) membrane where the
      warfarin sensitive vitamin K 2,3-epoxide reductase (VKOR) produces the reduced
      hydroquinone form of vitamin K (vit.KH(2)) needed by the gamma-carboxylase as the
      active cofactor. Currently, we have only limited knowledge about how the system
      functions at the molecular level. VKOR harbors a thiol red/ox center that is
      essential for electron transfer leading to vitamin K reduction. Reduction of this
      center with hydrophilic and hydrophobic trialkylphosphines shows that it is
      located in a hydrophobic environment which must be accessible by an as yet
      unidentified in vivo reductant of the center. Furthermore, we have addressed the
      question of whether VKOR or the gamma-carboxylase is the rate-limiting step in
      the vitamin K-dependent gamma-caboxylation system. A detailed kinetic analysis of
      an in vitro preparation of the system was undertaken in which gamma-carboxylation
      of the carboxylase peptide substrate FLEEL was measured as the gamma
      carboxylation capacity of the system. Adding VKOR to the test system increased
      the gamma-carboxylation capacity of the system suggesting that VKOR is the rate
      limiting step in the system. This finding puts VKOR in a central position to
      regulate biosynthesis of biologically active vitamin K-dependent proteins.

PMID- 12617986
TI  - Thrombomodulin expression by THP-1 but not by vascular endothelial cells is
      upregulated by pioglitazone.
AB  - Thrombomodulin-protein C pathway is a major anti-thrombotic mechanism present in
      endothelial cells (EC), and an important modulator of inflammation. Peroxisomal
      proliferator activated receptor-gamma (PPARgamma) expressed in
      monocytes/macrophages may have a role in cell differentiation. Since the
      expression of thrombomodulin (TM) by monocytes is upregulated during
      differentiation into macrophages, we investigated the effect of pioglitazone, a
      thiazolidinedione (TZD) that is a synthetic ligand of PPARgamma, on the
      expression of TM by a human monocyte/macrophage cell line; human acute monocytic
      leukemia (THP-1) cells. Pioglitazone dose-dependently upregulated TM antigen
      expression by THP-1 cells accompanied by an upregulation of TM cofactor activity
      for thrombin-dependent protein C activation. Thrombomodulin mRNA expression in
      THP-1 cells was also upregulated by pioglitazone, whereas tissue factor (TF) mRNA
      expression was not induced at all. Treatment cells with a natural PPARgamma
      ligand, 15-deoxy-delta12,14-prostaglandin J(2) (PGJ2), also enhanced TM protein
      expression. PGF(2alpha) an agent known to inactivate PPARgamma, diminished the
      stimulatory effect of pioglitazone and PGJ2 on TM protein expression. In
      contrast, pioglitazone had no effect on TM antigen expression by human umbilical
      vein ECs. These results suggest that PPARgamma activation in macrophages may
      counteract potentially prothrombotic and putative inflammatory properties in
      activated macrophages.

PMID- 12617988
TI  - Increase of arterial thrombosis parameters in chronic Helicobacter pylori
      infection in mice.
AB  - An animal model was developed to study arterial thrombosis and determine if
      animals infected with Helicobacter pylori behave differently after induction of
      direct damage to blood vessels. Twenty-one C56/BL6 mice inoculated with the
      "Sydney strain" of H. pylori and 19 uninfected animals were kept for 1 year
      before testing. Vascular lesions were induced to mesenteric arterioles (15-25
      microm diameter) by Argon laser. The dynamic course of thrombus formation was
      continuously monitored by a video camera for 10 min. Three parameters were
      assessed: (1) the number of laser pulses required to induce thrombus formation,
      (2) the number of platelet emboli removed by the blood flow and, (3) the duration
      of embolization. Additionally, blood was tested for platelet aggregation,
      fibrinogen, and cell count. Of the parameters measured, statistical differences
      between infected and uninfected mice concerned the number of emboli formed
      (6.00+/-2.18 infected vs. 3.89+/-1.37 non-infected, p=.0006) and the duration of
      embolization (2.41+/-0.73 min infected vs. 1.47+/-0.61 min non-infected p>.0001).
      A significant difference was also found in the fibrinogen levels between infected
      and uninfected mice. Chronic infection of mice with H. pylori leads to increased
      platelet embolization after damage to arterioles. These results are in favor of
      the possible involvement of H. pylori infection in the acute phase of coronary
      heart disease (CHD).

PMID- 12617987
TI  - Quantitative evaluation of the influence of ovarian steroids on plasminogen
      activators and inhibitors in human endometrial cells and trophoblasts.
AB  - INTRODUCTION: Plasminogen activators and inhibitors were quantitated in cultured
      human endometrial and trophoblast cells under the influence of ovarian steroids
      in order to investigate the role of the fibrinolytic system for trophoblast
      invasion and anchorage. MATERIALS AND METHODS: Plasminogen activators (t-PA and u
      PA) and their inhibitors (PAI-1 and PAI-2) secretions were assayed in cultures of
      epithelial, stromal, and trophoblast cells. These cells were also cultured on a
      fibrin substrate for microscopic examination of the fibrinolytic degradation.
      RESULTS: The u-PA from epithelial cells was predominant among PAs and PAI-1 in
      endometrial cells. Estradiol (E2) enhanced t-PA production in stromal cells and
      PAI-1 production in epithelial cells. Progesterone (P4) suppressed u-PA
      production in epithelial cells and enhanced PAI-1 production in both epithelial
      and stromal cells. Trophoblasts produced PAI-1, PAI-2, and small quantities of t
      PA and u-PA, none of which were notably influenced by E2 or P4. The PAI-1
      production in trophoblasts was more than four-fold greater than the u-PA
      production in epithelial cells. Epithelial and stromal cells initially grew on
      fibrin substrate but were gradually detached from the substrate with fibrinolytic
      degradation, with the exception of the stromal cells grown in the presence of P4
      (or E2+P4). Trophoblasts grew well on fibrin substrate without fibrinolytic
      degradation both in the presence and absence of the steroids tested. CONCLUSIONS:
      Fibrinolytic balance seemed to be basically maintained between the endometrial
      PAs and the relative excess of trophoblasts-derived PAI-1. This balance might be
      regulated principally by P4 and focally by E2 in the endometrial tissue for
      placental implantation.

PMID- 12617989
TI  - Influence of antithrombin on ischemia/reperfusion injury in the isolated blood
      free perfused rat heart.
AB  - INTRODUCTION: Antithrombin (AT) is well known as an important inhibitor of the
      coagulation system. An interesting new hypothesis is that antithrombin exerts
      specific anti-inflammatory effects by stimulating the production of prostacyclin
      in endothelial cells. Recent studies report beneficial influence on
      ischemia/reperfusion injury in several organs. These effects are independent of
      the coagulation system. We investigated the influence of antithrombin on
      ischemia/reperfusion injury and prostacyclin release in the isolated rat heart.
      Since the perfusion of the hearts was without blood, the used model essentially
      describes effects of antithrombin on endothelial cells. MATERIAL AND METHODS:
      Experiments were performed using the temperature-controlled and pressure-constant
      Langendorff apparatus. The hearts of 32 male Sprague-Dawley rats were subjected
      to 20 min of global ischemia followed by 30 min of reperfusion. Antithrombin was
      administered in three different concentrations (1, 4 and 8 U/ml) 15 min prior to
      global ischemia. Cardiac contractility parameters and biochemical parameters were
      measured. RESULTS: Treatment with antithrombin did not increase the release of
      prostacyclin significantly after ischemia. Antithrombin at a concentration of 8
      U/ml led to a significant increase in creatine kinase (CK; p<0.05) and troponin I
      (p<0.05), whereas measurements of lactate dehydrogenase (LDH) revealed no
      significant differences between treated and untreated hearts. CONCLUSION: Our
      study shows that antithrombin did not reduce ischemia/reperfusion injury in the
      isolated heart, and prostacyclin is not significantly released following
      antithrombin treatment. High concentrations of antithrombin, however, might have
      a negative influence on the reperfused heart. The underlying mechanism remains
      unclear.

PMID- 12617990
TI  - Participation of a galectin-dependent mechanism in the hepatic clearance of
      tissue-type plasminogen activator and plasma kallikrein.

PMID- 12617991
TI  - Induction of innate immunity by IL-2-expressing Salmonella confers protection
      against lethal infection.
AB  - Previously, we demonstrated that an attenuated Salmonella strain expressing IL-2
      (designated GIDIL2) is cleared from the circulation at a much faster rate than
      the non-cytokine-expressing parental strain (designated BRD509). These findings
      suggested that IL-2 expression led to the rapid induction of innate immune
      responses that, in turn, accounted for the accelerated rate of bacterial
      clearance. In the present study, the mechanism by which this early antibacterial
      response is mediated was investigated. We demonstrate that as early as 2 h after
      infection with GIDIL2, but not BRD509, peritoneal excudate cells exhibited
      enhanced NK cytotoxic activity and upregulated NOS2 mRNA and NO production. This
      early response coincided with an enhancement of GIDIL2 clearance from the
      peritoneal cavity, first evidenced 22 h post-infection. Moreover, it conferred a
      high level of protection against virulent Salmonella challenge given within 16-20
      h of GIDIL2 administration. These findings highlight the importance of innate
      immunity in the control of early bacterial proliferation and demonstrate the
      rapidity by which these responses are induced following bacterial entry.

PMID- 12617992
TI  - Binding of Ikaros to germline Ig heavy chain gamma1 and epsilon promoters.
AB  - Immunoglobulin (Ig) class switching occurs in activated B cells and results in
      production of antigen-specific IgA, IgE or IgG. It involves a DNA recombination
      event and is partly regulated by germline (GL) immunoglobulin heavy chain
      promoters. Ikaros is an abundant nuclear protein expressed in hematopoietic
      cells. Many different functions have been ascribed to Ikaros, such as
      transcriptional activation or repression, cell cycle control and tumor
      suppression. A typical feature of Ikaros is its expression in large clusters in
      the nucleus of activated lymphocytes. We give evidence that Ikaros can bind to
      several sites in the germline gamma1 and epsilon immunoglobulin heavy chain
      promoters, in a cooperative manner. Using a promoter reporter assay, we found
      evidence that Ikaros can suppress germline gamma1 and epsilon promoter activity
      in a B cell line. When a mutated non-DNA-binding form of Ikaros was introduced
      into primary activated B cells by retrovirus transduction, the endogenous Ikaros
      clusters were disrupted. In spite of this, there was no effect on transcription
      or Ig class switching. The data are discussed in relation to the different
      hypotheses for the function of Ikaros.

PMID- 12617993
TI  - Cell type specific targeted intracellular delivery into muscle of a monoclonal
      antibody that binds myosin IIb.
AB  - Methods for cell type specific targeted intracellular delivery of proteins in
      vivo remain limited. A murine monoclonal anti-dsDNA antibody, mAb 3E10, was
      selectively transported into skeletal muscle cells in vivo. The antibody bound a
      200 kDa protein only found in lysates of skeletal muscle by Western blotting. The
      200 kDa protein was purified from muscle lysate by antibody affinity
      chromatography and identified as the skeletal muscle specific heavy chain of
      myosin IIb by electrospray mass spectrometry. Antibody binding specificity for
      myosin IIb was demonstrated in Western blots by binding myosin in skeletal muscle
      lysates from mice null for myosin IId but not in mice null for myosin IIb. Myosin
      IIb is implicated in the specific targeting of mAb 3E10 to skeletal muscle.

PMID- 12617994
TI  - Specific over-expression of deltex and a new Kelch-like protein in human germinal
      center B cells.
AB  - Ig gene hypermutation was originally described as the molecular process
      underlying B cell affinity maturation following a T-dependent immune response.
      Somatic hypermutation is also used in some species such as sheep, to generate
      diversity during formation of the primary antibody repertoire. In sheep, B cells
      mutate their Ig receptor during antigen-independent development in the lymphoid
      follicles of ileal Peyer's patches, but this process is arrested when these same
      B cells are cultured in vitro. We have used these differences between in vivo and
      in vitro B cell development to perform a cDNA subtraction between these two cell
      populations, in order to search for genes that might be involved in the
      hypermutation process. We describe in this paper the characterization of two
      genes, highly expressed in sheep ileal Peyer's patch B cells and also in
      centroblasts of human tonsils: deltex (Drosophila) homolog 1 (DTX1), which is
      related to the Notch pathway and a new Kelch-like protein, KLHL6. The putative
      role of these proteins, which are more likely involved in the germinal center B
      cell differentiation pathway than in the hypermutation mechanism per se, is
      discussed.

PMID- 12617996
TI  - The snRNP-associated U1A levels change following IL-6 stimulation of human B
      cells.
AB  - The U1A protein can be found both in a small-ribonucleoprotein particle (snRNP)
      that contains U1 RNA, or in a distinctive fraction, free of the snRNP, the SF-A
      complex. Both components have been shown to influence post- or co-transcriptional
      RNA processing reactions in HeLa cells. Since U1A may influence the processing of
      the immunoglobulin heavy chain pre-mRNA in B-cells, we wanted to see if the
      levels of U1A in either of its two forms changed following IL-6 stimulation to
      IgM secretion. Using antibodies that specifically recognize the two forms of U1A,
      snRNP-associated and snRNP-free, we found that approximately 16% of U1A is in the
      SF-A form in B-cells. We measured the levels of U1A protein in its two states in
      human B-cell lines both by flow cytometry and exhaustive immunoprecipitations. We
      found a significant decrease in the amount of snRNP-associated U1A following
      cytokine stimulation that correlates with the change-over to the secretory
      specific poly(A) site use in the SKW 6.4 cell line. Meanwhile, the number of U1A
      molecules in the SF-A fraction of the pool remains nearly constant following
      induction to secretion. Our results suggest that the changing level of U1A in the
      snRNP fraction may be important for influencing Ig heavy chain mRNA processing.

PMID- 12617995
TI  - Thermodynamic and kinetic aspects of antibody evolution during the immune
      response to hapten.
AB  - We determined thermodynamic and kinetic parameters for the antigen-antibody
      interaction using a group of anti-(4-hydroxy-3-nitrophenyl)acetyl monoclonal
      antibodies whose differences in amino acid sequences had arisen only from somatic
      hypermutation. These monoclonal antibodies were considered to have originated
      from a common ancestor clone and to represent progression along the affinity
      maturation pathway. The kinetic measurements showed that both association and
      dissociation rate constants of the antigen-antibody interaction decreased during
      maturation. Thermodynamic measurements revealed that an increase in affinity was
      obtained by an increase in entropy without any significant change in enthalpy.
      These results suggested that the mechanism for the antigen-antibody interaction
      shifted from a "zipper" type to a "lock-and-key" type during antibody evolution.

PMID- 12617998
TI  - Isolation and characterization of a novel CXC chemokine in common carp (Cyprinus
      carpio L.).
AB  - A novel CXC chemokine was identified for the first time in fish from common carp
      (Cyprinus carpio L.). The gene was obtained from the head kidney (HK) stimulated
      with LPS and Con A. The cDNA consists of 619 bp with a 37 bp 5' UTR and a 287 bp
      3' UTR. An open reading frame of 368 bp encodes a 97 amino acid peptide, with a
      putative signal peptide of 20 aa. The gene has four cysteines residues, which are
      conserved, with first two cysteines separated with phenylalanine. By homology and
      phylogenetic analysis, the chemokine was found to be closer to human IP-10.
      Identities were significantly low to the CXC chemokines cloned from lamprey
      (Lampetra fluviatilis), flounder (Paralichthys olivaceus), rainbow trout
      (Onchorhynchus mykiss) and zebrafish (Danio rerio). The carp CXC chemokine
      contains three exons interrupted by two introns. The gene was transcribed from an
      early time point by stimulation with LPS and Con A. Organs in resting phase as
      well as stimulated expressed the gene.

PMID- 12617997
TI  - Ribotoxic stress activates p38 and JNK kinases and modulates the antigen
      presenting activity of dendritic cells.
AB  - Initiation of adaptive immunity requires activation of dendritic cells (DC) by
      "danger" signals. This study examines the functional consequences of activating a
      cellular stress response in human DC. Anisomycin, a potent inducer of this
      "stress" response, selectively activates p38 kinase in DC at low concentrations,
      and both p38 kinases and JNKs at higher concentrations. Activation of p38, was
      accompanied by an increase in the potency of dendritic cells to activate T cells.
      In contrast to LPS, anisomycin had no effect on the expression of several DC
      activation markers. Anisomycin synergised with LPS in driving release of IL-12
      and TNF-alpha. Anisomycin also enhanced the formation of clusters between DC and
      T cells. Enhanced cytokine release and clustering were both inhibited by the
      selective p38 alpha and p38 beta inhibitor SB203580. This study demonstrates that
      the cellular stress response, mediated via p38 kinases, plays an important role
      in the regulation of several aspects of DC function.

PMID- 12617999
TI  - Functional genomics of ageing I. Proceedings of an international conference.
      April 24-27, 2002. Seville, Spain.

PMID- 12618000
TI  - Functional genomics of ageing.
AB  - Ageing is the most complex phenotype currently known, since it becomes manifest
      in all organs and tissues, affects an organism's entire physiology, impacts
      function at all levels and increases susceptibility to all major chronic
      diseases. Insight into the molecular and cellular targets of the ageing process
      would offer the unprecedented opportunity to postpone and prevent some, if not
      all, of its deteriorative aspects by preventive and therapeutic means. Thus far,
      our understanding of the causes of ageing is limited. To an important extent this
      is due to our inability, in the past, to study ageing systems. Instead, ample
      information has been gathered about individual cellular components at various
      ages, but this has not allowed a clear understanding of the integrated genomic
      circuits that control mechanisms of ageing, survival and stress responses. With
      the emergence of functional genomics, we finally have the opportunity to study
      ageing in a comprehensive manner, as a function of the dynamic network of genes
      that determines the physiology of an individual organism over time.

PMID- 12618001
TI  - Systems biology: integrating technology, biology, and computation.
AB  - The Human Genome Project has changed the worlds of biology and medicine-helping
      to catalyze two major paradigm changes: systems biology and predictive,
      preventive and personalized medicine. These two themes will dominate 21st century
      biology and medicine. I will discuss these changes and indicate how they may
      interface with with the process of aging.

PMID- 12618002
TI  - DNA variability of human genes.
AB  - We have investigated the level of DNA-based variation (both SNPs and haplotypes)
      for several thousand human genes. In addition, we have characterized how this
      variation is distributed in a number of biologically and clinically important
      ways. First, we have determined how SNPs are distributed within human genes:
      where they occur relative to various functional regions; levels of variability of
      human SNPs; pattern of the molecular sequence of SNPs; and how these compare with
      the corresponding sequence of a chimpanzee. Second, we have determined how these
      aspects of SNP distribution vary among four human population samples. All genes
      were sequenced on DNA obtained from 82 unrelated individuals: 20 African
      Americans, 20 East Asians, 21 European-Americans, 18 Hispanic-Latinos and three
      Native Americans. In particular, we looked at patterns of SNP and haplotype
      sharing among the four larger population samples. Third, we have determined the
      patterns of linkage disequilibrium among SNPs, which also determines the
      haplotype variability of each gene. These characteristics also vary substantially
      among populations. A deeper understanding of these aspects of human genetic
      variation will be of vital importance when trying to identify the genetic
      contribution to complex phenotypes such as aging.

PMID- 12618003
TI  - Polymorphisms in the DNA repair gene XRCC1 and age-related disease.
AB  - The recent hypothesis that common variants (single nucleotide polymorphisms or
      SNPs) in the population may contribute significantly to genetic risk for common
      diseases permits a conceptually straightforward approach to identifying age
      related disease-causing mutations. Functional variants of DNA replication and
      repair genes might be expected to be highly significant to cancer and aging since
      replication must proceed with high fidelity in a cellular environment where an
      estimated 10000 nucleotides are damaged daily. Single-strand breaks (SSB) are one
      of the results of DNA damage either by methylation, oxidation, reduction or
      fragmentation of bases by ionizing radiation, and arise in cells directly by
      disintegration of damaged sugars or indirectly as intermediates of base excision
      repair. Studies have demonstrated a role for XRCC1 both in vitro and in vivo
      during the repair of SSB. A number of SNPs have been identified for the XRCC1
      gene, and several have been associated with age-related diseases, especially
      cancer. This report provides resequencing data confirming the existence of
      commonly occurring SNPs, including Arg194Trp and Arg399Gln, and briefly
      summarizes epidemiological and functional relevance to cancer and other age
      related diseases. XRCC1 SNPs will be useful probes for investigating age
      associated pathobiology in epidemiological and mechanistic studies.

PMID- 12618004
TI  - Comparative proteomics: characterization of a two-dimensional gel electrophoresis
      system to study the effect of aging on mitochondrial proteins.
AB  - To study the effect of aging and anti-aging strategies on mitochondria, we have
      characterized a two-dimensional polyacrylamide gel electrophoresis (2-D PAGE)
      system to analyze the profile of mitochondrial proteins. We have optimized the
      separation of proteins by 2-D PAGE and established the linearity and
      reproducibility of the system with mitochondria isolated from skeletal muscle of
      mice. Using total mitochondria protein ranging from 10 to 200 microg, we found
      that 74% of the proteins resolved by 2-D PAGE had coefficient of determination
      (R2) values greater than 0.8, showing a linear increase in fluorescence with
      increasing protein concentration. The coefficient of variation (CV) was less than
      50% for at least 93% of the 424 spots analyzed for both gel-to-gel variance and
      animal-to-animal variance. Using mitochondrial protein fractions prepared from
      skeletal muscle of 18-month-old mice, we show that 10 animals will be sufficient
      to detect a 100% difference in the 97% (i.e. 505) of the proteins resolved by 2-D
      PAGE. Thus, 2-D PAGE provides a sensitive and reliable technique for analysis of
      protein expression in mitochondria.

PMID- 12618005
TI  - Longevity and heat stress regulation in Caenorhabditis elegans.
AB  - Aging is the most complex phenotype for a multicellular organism. This process is
      now being under severe investigation. Here I will review the different processes
      known to affect longevity in the nematode Caenorhabditis elegans and their
      relationship with thermotolerance. All the longevity mutants that have been
      tested so far show an increase in stress resistance. In particular, long-lived
      mutants affected in the IGF/insulin pathway and those affected in the germ-line
      formation are both thermotolerant and long-lived. The mechanisms that activate
      the stress resistance are now been understood including the DAF-16 fork head
      transcription factor transport to the nucleus and the activation of genes
      involved in the defense to stress. The high correlation between stress resistance
      and longevity suggests that the same molecular activities that defend the cell
      from stress can defend the cell from the damage caused by aging.

PMID- 12618006
TI  - Mutation and intracellular clonal expansion of mitochondrial genomes: two
      synergistic components of the aging process?
AB  - The foundations of the Mitochondrial mutational theory of aging include two
      assumptions: the high abundance of mitochondrial mutations and their ability to
      clonally expand within individual cells. The up-to-date data pertinent to these
      assumptions is reviewed and semi-quantitative estimates of the frequencies of
      mutants and intracellular expansions are offered. The incidence of mutations in
      various aged tissues may be on the order of one mutant per mitochondrial genome
      copy, and most of the cells are likely to be affected by intracellular clonal
      expansions of mitochondrial genomes. Thus aged tissue may be considered a mosaic
      of cells with different mutant mitochondrial genotypes. Interestingly,
      independent studies show that a wide range of aged tissues presents with a mosaic
      of cells with different mitochondrial phenotypes. The necessary methodologies are
      available to explore whether the two mosaics are causally related. The answer
      apparently is positive in muscle; other tissues, brain in particular, await
      exploration.

PMID- 12618007
TI  - Influence of ageing, heat shock treatment and in vivo total antioxidant status on
      gene-expression profile and protein synthesis in human peripheral lymphocytes.
AB  - Ageing results in a progressive, intrinsic and generalised imbalance of the
      control of regulatory systems. A key manifestation of this complex biological
      process includes the attenuation of the universal stress response. Here we
      provide the first global assessment of the ageing process as it affects the heat
      shock response, utilising human peripheral lymphocytes and cDNA microarray
      analysis. The genomic approach employed in our preliminary study was supplemented
      with a proteomic approach. In addition, the current study correlates the in vivo
      total antioxidant status with the age-related differential gene expression as
      well as the translational kinetics of heat shock proteins (hsps). Most of the
      genes encoding stress response proteins on the 4224 element microarray used in
      this study were significantly elevated after heat shock treatment of lymphocytes
      obtained from both young and old individuals albeit to a greater extent in the
      young. Cell signaling and signal transduction genes as well as some
      oxidoreductases showed varied response. Results from translational kinetics of
      induction of major hsps, from 0 to 24 h recovery period were broadly consistent
      with the differential expression of HSC 70 and HSP 40 genes. Total antioxidant
      levels in plasma from old individuals were found to be significantly lower by
      comparison with young, in agreement with the widely acknowledged role of oxidant
      homeostasis in the ageing process.

PMID- 12618008
TI  - Genetic alterations in the ageing immune system: impact on infection and cancer.
AB  - The immune system, which is able to distinguish between self and non-self, is
      programmed to protect the organism from a huge spectrum of potential foreign
      invaders. Each T and B lymphocyte bears an antigen receptor of a single
      specificity, which is determined during development by a unique genetic mechanism
      that generates millions of different variants of the genes encoding the receptor
      molecules. When a particular antigen, such as a virus, is encountered, only those
      lymphocytes bearing the relevant receptors become activated and undergo massive
      clonal expansion. The expanded antigen-specific B cells produce antibodies, which
      neutralize free virus in the bloodstream, whereas the T cells, particularly the
      so-called CD8 T cells, actually kill cells that are infected with the virus. Once
      the infection is cleared, most of the expanded T cells undergo apoptosis, leaving
      a small number of memory cells to await future possible encounters with the same
      virus. During ageing, both latent and acute viral infections lead to increased
      morbidity and mortality, based, in large part, on the diminished ability of T
      cells to control the infection. To investigate the underlying mechanism of the T
      cell defects, we have analyzed the process of replicative senescence in human T
      cells. Our research has shown that following repeated stimulation with antigen in
      cell culture, the responding T cells eventually reach an irreversible state of
      cell cycle arrest, at which time they show loss of gene expression of a key T
      cell-specific signaling molecule required for proliferation, as well as reduced
      stress protein production, apoptosis resistance, shortened telomeres and
      inability to upregulate telomerase. Increased proportions of T cells with
      identical phenotypes are present in elderly individuals, suggesting that
      chronic/repeated stimulation of some T cells may lead to replicative senescence
      in vivo. Genetic modulation of this process may yield novel strategies to augment
      immune function in the elderly.

PMID- 12618009
TI  - Using cell transplantation to investigate genes involved in aging.
AB  - Cell transplantation provides a way to study genes that may be important in human
      tissue aging. Studies on gene action in human cells are usually restricted to
      cell culture investigations and clinical observations. Differences in human and
      rodent cellular biology, particularly with respect to telomere dynamics, show the
      need for new systems for investigating aging that use human cells or cells of
      other large, long-lived mammals, such as bovine cells. The system we describe
      uses human and bovine adrenocortical cells transplanted into scid (severe
      combined immunodeficiency) mice. They form a vascularized tissue structure that
      can replace the essential functions of the animals' own adrenal glands. The cells
      may be genetically modified before introduction into the animal. Using hTERT
      (telomerase reverse transcriptase) and oncoproteins, we show the potential for
      investigating gene action in genetically modified tissues created by cell
      transplantation.

PMID- 12618010
TI  - Somatic mutations and ageing in silico.
AB  - Considerable evidence points to an accumulation of somatic mutations in older
      cells and organisms but the causal role of mutations in the ageing process is
      still unclear. In addition to demonstrating that mutations accumulate, it is
      important to address the question of whether they do so at a sufficient rate and
      with a dynamic profile that is consistent with them playing a causative role. We
      describe the development of in silico models that can be used to explore the role
      of somatic mutations in ageing and which form a part of a growing effort to build
      predictive mathematical and computer models that can help unravel the complexity
      of the functional genomics of ageing. Our models address, in particular, how
      mutations affect populations of dividing cells like human fibroblasts, in which
      the challenge to the somatic mutation theory is greatest, since selection at the
      cellular level will tend to suppress the accumulation of mutations.

PMID- 12618011
TI  - RIKEN mouse genome encyclopedia.
AB  - We have been working to establish the comprehensive mouse full-length cDNA
      collection and sequence database to cover as many genes as we can, named Riken
      mouse genome encyclopedia. Recently we are constructing higher-level annotation
      (Functional ANnoTation Of Mouse cDNA; FANTOM) not only with homology search based
      annotation but also with expression data profile, mapping information and protein
      protein database. More than 1,000,000 clones prepared from 163 tissues were end
      sequenced to classify into 159,789 clusters and 60,770 representative clones were
      fully sequenced. As a conclusion, the 60,770 sequences contained 33,409 unique.
      The next generation of life science is clearly based on all of the genome
      information and resources. Based on our cDNA clones we developed the additional
      system to explore gene function. We developed cDNA microarray system to print all
      of these cDNA clones, protein-protein interaction screening system, protein-DNA
      interaction screening system and so on. The integrated database of all the
      information is very useful not only for analysis of gene transcriptional network
      and for the connection of gene to phenotype to facilitate positional candidate
      approach. In this talk, the prospect of the application of these genome resourced
      should be discussed. More information is available at the web page:
      http://genome.gsc.riken.go.jp/.

PMID- 12618012
TI  - Transcriptional tools for aging research.
AB  - The process of aging is controlled and influenced by genes and gene expression.
      Dissecting the roles individual genes play in aging requires molecular tools for
      manipulation of gene expression in a wide variety of experimental model systems.
      These tools include homologous recombination-based methods for the activation and
      repression of gene expression, gene activation by random insertion of strong
      promoters, the use of engineered dominant negative mutants, inhibition with
      antisense oligonucleotides, minor groove binding small molecules and via RNAi and
      the use of engineered transcription factors to either activate or repress
      endogenous gene expression.

PMID- 12618013
TI  - Integrated analysis of transcript profiling and protein sequence data.
AB  - Transcript profiling can be used to elucidate the molecular and cellular
      mechanisms involved in ageing and cancer. A recent study of human
      gastrointestinal stromal tumours (GISTs) with mutations in the KIT gene, Cancer
      Res. 61 (2001) 8624 exemplifies a common type of investigation. cDNA microarrays
      were used to generate measurements for 1987 clones in two types of tissues: 13
      KIT mutation-positive GISTs and 6 spindle cell tumours from locations outside the
      gastrointestinal tract. Statistical problems associated with such two-class, high
      dimensional profiling data include simultaneous classification and relevant
      feature identification, probabilistic clustering and protein sequence family
      modelling. Here, the GIST data were reexamined using specific solutions to these
      problems, namely sparse hyperplanes, nai;ve Bayes models and profile hidden
      Markov models respectively. The integrated analysis of molecular profiling and
      sequence data highlighted 6 clones that may be of clinical and experimental
      interest. The protein encoded by one of these putative biomarkers defined a novel
      protein family present in diverse eucarya. The family may be involved in
      chromosome segregation and/or stability. One family member is a potential
      biomarker identified recently from a retrospective analysis of transcript
      profiles for sporadic breast cancer samples from patients with poor and good
      prognosis, Signal Process. (in press).

PMID- 12618014
TI  - Preliminary studies on Alzheimer's disease using cDNA microarrays.
AB  - Alzheimer's disease (AD) is characterized by a progressive impairment of memory
      and intellectual functioning. The disease is a complex multi-factorial disease
      with the involvement of several possible genes. To study AD, a high-density cDNA
      array was developed to characterize the mRNA expression profile of 14160 genes.
      The preliminary results support the amyloid cascade hypothesis as the mechanism
      of the disease.

PMID- 12618015
TI  - Inverse Genomics as a powerful tool to identify novel targets for the treatment
      of neurodegenerative diseases.
AB  - Toward the prevention of neurodegeneration we have used Immusol's Inverse
      Genomics platform to identify gene targets involved in neuronal cell death.
      Inverse genomics uses a combinatorial library of unique hairpin ribozymes with
      randomized substrate binding sequences to cleave unique RNA transcripts, thereby
      decreasing translation of the encoded proteins. Using the SK-N-MC neuroblastoma
      cell line a cell based survival selection assay was designed with C2-ceramide or
      TNFalpha as an induction signal for apoptosis. SK-N-MC cells were stably
      transduced with a ribozyme vector library, and then exposed to 20 microM C2
      ceramide or 50 ng/ml TNFalpha to induce cell death. Surviving cells were
      harvested, their DNA isolated, and the ribozymes rescued by PCR for re
      introduction into fresh cells. After several rounds of selection and ribozyme
      rescue we have identified individual ribozymes that protect neuronal cells from
      C2-ceramide induced apoptosis. Three of the cellular targets of these ribozyme
      sequence tags have been validated. Microarray analysis and yeast two-hybrid
      screens have also been used to gain insight into the pathways involved by
      identifying additional players involved in these pathways. These target genes may
      also serve as therapeutic targets for development of drugs for Alzheimer and
      Parkinson's diseases.

PMID- 12618016
TI  - Microarray workshop on aging.
AB  - The advent of microarrays in studying gene expression in aging has created
      tremendous excitement due to its potential for uncovering molecular mechanisms of
      aging and age-related disease. However, the appropriate implementation of this
      technology in the science of aging requires serious attention to methodological
      detail and statistical rigor. This report highlights discussions from the
      microarray workshop on aging held at the First Conference on Functional Genomics
      of Aging in Seville, Spain. The topics discussed by the participants included
      technical issues relating to the printing of arrays, RNA isolation, cDNA labeling
      and hybridization, optimal design of microarray experiments, and statistical
      analysis of these data. Microarray analysis of complex tissues through the use of
      laser capture microdissection was also discussed.

PMID- 12618017
TI  - Proceedings and abstracts of the 7th European Symposium on Controlled Drug
      Delivery. Noordwijk aan Zee, The Netherlands, April 3-5, 2002.

PMID- 12618018
TI  - Adriamycin loaded pullulan acetate/sulfonamide conjugate nanoparticles responding
      to tumor pH: pH-dependent cell interaction, internalization and cytotoxicity in
      vitro.
AB  - The cytotoxicity of adriamycin (ADR)-loaded and pH-sensitive nanoparticles made
      of pullulan acetate (PA) and sulfonamide (sulfadimethoxine; SDM) (PA/SDM)
      conjugate to a breast tumor cell line (MCF-7) was investigated to test the
      feasibility of the nanoparticles in targeting acidic tumor extracellular pH
      (pH(e)). At pH 6.8, ADR loaded PA/SDM nanoparticles showed cytotoxicity in the
      cell culture experiment, comparable to that of free ADR at the same ADR
      concentrations, while the relative cytotoxicity at pH 7.4 was low at the tested
      concentration range. This pronounced cytotoxicity of the nanoparticles at low pH
      was attributed to the accelerated release of ADR triggered by pH, enhanced
      interaction with cells, and internalization. At pH 6.8 and 6.4, the PA/SDM
      nanoparticles aggressively bounded to MCF-7 cells, probably due to interactions
      of the cells with hydrophobized nanoparticle surfaces caused by SDM deionization.
      A confocal laser microscopic study revealed intracellular localization of the
      drug-loaded nanoparticles. Based on these findings, the pH-sensitive
      nanoparticles deserve further investigation with an in vivo animal model as a
      targeted carrier of pH(e).

PMID- 12618019
TI  - Artificial polymeric cells for targeted drug delivery.
AB  - Selectins are optimal biological molecules for targeted delivery of therapeutic
      agents because of their localized and carefully regulated expression in several
      human diseases, and their highly specific interactions with their counter
      receptors. In this study, we describe a targeted delivery system that can
      potentially deliver anti-inflammatory drug to sites of chronic inflammation using
      Poly(lactic-co-glycolic acid) (PLGA) and selectin-ligand chemistry. Biotinylated
      sialyl Lewis(x) (sLe(x)), a carbohydrate that serves as a ligand to selectins,
      was attached to the surface of avidin-linked PLGA microspheres. These
      carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on
      selectins in flow chambers, displaying slow rolling under flow. The rolling
      velocity of these artificial leukocytes is similar to that displayed by
      leukocytes rolling on P- or E-selectin coated surfaces. We can tune rolling
      velocity, and hence residence time of capsules on surfaces, by changing the
      density of sialyl Lewis(x) on the microsphere surfaces. Therefore, we have made a
      targeted drug delivery vehicle that mimics the adhesive properties of leukocytes
      and is biodegradable.

PMID- 12618020
TI  - Relative aggregation state and hemolytic activity of amphotericin B encapsulated
      by poly(ethylene oxide)-block-poly(N-hexyl-L-aspartamide)-acyl conjugate
      micelles: effects of acyl chain length.
AB  - We systematically altered the chemical structure of the core-forming poly(L-amino
      acid) block of an amphiphilic diblock copolymer series based on poly(ethylene
      oxide)-block-poly(N-hexyl-L-aspartamide), PEO-b-p(N-HA), acyl esters by varying
      the length of the attached acyl side chain. Drug-loaded micelles were prepared in
      good yield by a modified solvent evaporation procedure. In addition, the relative
      aggregation state and hemolytic activity of encapsulated amphotericin B (AmB)
      were analyzed by absorption spectroscopy. The length of the attached acyl side
      chain in PEO-b-p(N-HA) acyl ester micelles modulates the relative aggregation
      state of encapsulated AmB. Furthermore, acyl chain length appears to have a
      profound influence on the time-dependent hemolytic profile of encapsulated AmB
      toward bovine erythrocytes. For all acyl conjugate micelle-AmB formulations, the
      onset of hemolysis is delayed relative to free AmB. Particularly in the case of
      stearate ester micelles, the incomplete and gradual build-up of hemolysis might
      reflect the sustained release of drug over a period of 24 h. Based on the
      corresponding absorption spectrum, we speculate that encapsulated AmB may
      interact strongly with stearate side chains, resulting in sustained release. Via
      chemical manipulation of the core-forming region, it may be possible to fine-tune
      the release of encapsulated AmB from PEO-b-p(N-HA)-acyl ester micelles.

PMID- 12618021
TI  - HPMA copolymers with pH-controlled release of doxorubicin: in vitro cytotoxicity
      and in vivo antitumor activity.
AB  - Data on the synthesis, physicochemical characterisation and in vitro and in vivo
      biological properties of the new, nontargeted or antibody-targeted polymer
      doxorubicin conjugates designed as anticancer drugs are presented. In the
      conjugates, the anticancer drug doxorubicin (DOX) is attached to the polymer
      carrier via a simple hydrolytically labile spacer containing either a hydrazone
      bond or cis-aconitic acid residue. In vitro incubation of the conjugates in
      buffers led to a fast DOX release from the polymer at pH 5 (modelling
      intracellular environment) while at pH 7.4 (modelling blood) the conjugates are
      relatively stable. Cytotoxicity of the conjugates to T cell lymphoma EL4 depended
      on the detailed structure of the spacer and the method used for antibody
      attachment and was much higher compared with the effect of similar classic
      conjugates (DOX attached to the polymer via enzymatically degradable spacer). In
      both protective and therapeutic regimes of drug administration, the in vivo anti
      tumor activity of the hydrazone conjugates containing only DOX was significantly
      enhanced (T cell lymphoma EL4, C57BL/10 mice) in comparison with free DOX or
      classic PK1, the PHPMA-DOX conjugate clinically tested at present. Increasing the
      molecular weight of the polymer carrier resulted in a more pronounced in vivo
      antitumor effect. Antibody-targeted conjugates with DOX bound via hydrazone bond
      exhibited even more extensive inhibition of the tumor growth with some long-term
      survivors. No survivors were observed after treatment of mice with free DOX or
      the nontargeted PHPMA-DOX conjugate.

PMID- 12618022
TI  - Comparison of vascular endothelial growth factor and basic fibroblast growth
      factor on angiogenesis in SCID mice.
AB  - Therapeutic angiogenesis is a promising approach to treat patients with
      cardiovascular disease, and will likely be critical to engineering large tissues.
      Many growth factors have been found to play significant roles in angiogenesis,
      and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor
      (bFGF) are the most extensively investigated angiogenic factors to date. However,
      the appropriate dose to obtain a desired response and the effectiveness of each
      factor, relative to the other, in promoting angiogenesis at a specific site in
      the body remains unclear. We have used alginate hydrogels as localized delivery
      vehicles for VEGF and bFGF, and compared the ability of these factors to promote
      new blood vessel formation in the subcutaneous tissue of severe combined
      immunodeficient (SCID) mice. We have found that the thickness of a granulation
      tissue layer formed around the gel and the number of blood vessels in the layer
      increased with the dose of VEGF in the gel, but the density of new blood vessels
      remained relatively constant. Sustained and localized delivery of bFGF from the
      gels, while similarly leading to an increase in the density of blood vessels in
      the granulation tissue, did not lead to as high of a blood vessel density as
      VEGF. The results of this study support previous studies demonstrating the
      utility of both VEGF and bFGF in promoting angiogenesis, and suggest VEGF is more
      appropriate for creating a dense bed of new blood vessels in this model.

PMID- 12618023
TI  - A novel method to obtain protein release from porous polymer scaffolds: emulsion
      coating.
AB  - To obtain the controlled release of proteins from macro-porous polymeric
      scaffolds, a novel emulsion-coating method has been developed. In this process, a
      water-in-oil emulsion, from an aqueous protein solution and a polymer solution,
      is forced through a prefabricated scaffold by applying a vacuum. After solvent
      evaporation, a polymer film, containing the protein, is then deposited on the
      porous scaffold surface. This paper reports the effect of processing parameters
      on the emulsion coating characteristics, scaffold structure, and protein release
      and stability. Poly(ether-ester) multiblock copolymers were chosen as the polymer
      matrix for both scaffolds and coating. Macro-porous scaffolds, with a porosity of
      77 vol% and pores of approximately 500 microm were prepared by compression
      moulding/salt leaching. A micro-porous, homogeneous protein-loaded coating could
      be obtained on the scaffold surface. Due to the coating, the scaffold porosity
      was decreased, whereas the pore interconnection was increased. A model protein
      (lysozyme) could effectively be released in a controlled fashion from the
      scaffolds. Complete lysozyme release could be achieved within 3 days up to more
      than 2 months by adjusting the coated emulsion parameters. In addition, the
      coating process did not reduce the enzymatic activity. This new method appears to
      be promising for tissue engineering applications.

PMID- 12618025
TI  - Nanotechnological approaches for the delivery of macromolecules.
AB  - In this overview, novel approaches are described for the controlled release
      and/or for the targeted delivery of macromolecules such as proteins and DNA. The
      building stones of these highly complex systems are (phospho)lipids and/or
      (biodegradable) polymers. They should be carefully chosen and preparation
      protocols should be rationally designed to maximize chances for success.

PMID- 12618024
TI  - Biodegradable elastomeric scaffolds for soft tissue engineering.
AB  - Elastomeric copolymers of 1,3-trimethylene carbonate (TMC) and epsilon
      caprolactone (CL) and copolymers of TMC and D,L-lactide (DLLA) have been
      evaluated as candidate materials for the preparation of biodegradable scaffolds
      for soft tissue engineering. TMC-DLLA copolymers are amorphous and degrade more
      rapidly in phosphate-buffered saline (PBS) of pH 7.4 at 37 degrees C than (semi
      crystalline) TMC-CL copolymers. TMC-DLLA with 20 or 50 mol% TMC loose their
      tensile strength in less than 5 months and are totally resorbed in 11 months. In
      PBS, TMC-CL copolymers retain suitable mechanical properties for more than a
      year. Cell seeding studies show that rat cardiomyocytes and human Schwann cells
      attach and proliferate well on the TMC-based copolymers. TMC-DLLA copolymers with
      either 20 or 50 mol% of TMC are totally amorphous and very flexible, making them
      excellent polymers for the preparation of porous scaffolds for heart tissue
      engineering. Porous structures of TMC-DLLA copolymers were prepared by
      compression molding and particulate leaching techniques. TMC-CL (co)polymers were
      processed into porous two-ply tubes by means of salt leaching (inner layer) and
      fiber winding (outer layer) techniques. These grafts, seeded with Schwann cells,
      will be used as nerve guides for the bridging of large peripheral nerve defects.

PMID- 12618026
TI  - Cytoplasmic delivery and nuclear targeting of synthetic macromolecules.
AB  - Delivery of macromolecular drugs (e.g. antisense oligonucleotides, polymer-drug
      conjugates, etc.) designed to work in specific sites inside cells is complicated
      as macromolecules typically have access to fewer biological compartments than
      small molecules. To better understand the fate of macromolecules in cells and
      begin to alter that fate, we investigated the internalization and subcellular
      fate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers and HPMA copolymer
      drug conjugates in Hep G2 and A2780 cells. The subcellular fate of fluorescently
      labeled polymers was monitored by confocal microscopy and subcellular
      fractionation. Initially, the HPMA copolymers and HPMA copolymer-drug conjugates
      were internalized by endocytosis and remained in endosomes/lysosomes. At longer
      incubation times (>8 h), small amounts of the HPMA copolymers were observed to
      enter the cytoplasm and accumulate in the nucleus of the cells. Nuclear
      accumulation was confirmed after cytoplasmic microinjection. Oligonucleotides
      conjugated via lysosomally degradable spacers entered into the cytoplasm and
      nucleus of the cells faster than the polymers. The effect of the subcellular
      location was correlated to the toxicity of the photosensitizer, mesochlorin e(6)
      (Mce(6))-HPMA copolymer conjugates. The plasma membrane and late endosomes were
      more sensitive to damage by Mce(6). Targeting the polymer conjugates to the
      nucleus with the nuclear localization sequence (NLS) as well as conjugating the
      Mce(6) via a degradable spacer increased cell adhesion and uptake, promoted their
      entry into the cytoplasm and nucleus of the cells, and increased their toxicity.
      To further promote entry of the polymers into the cytoplasm and nucleus of the
      cells, the protein transduction domain, Tat peptide, was conjugated to the HPMA
      copolymers. This resulted in high binding to the cell membrane, but also
      facilitated rapid (<5 min) entry of the macromolecules into the cytoplasm and
      nucleus of cells. These results will prove valuable in the future design of
      macromolecular therapeutics.

PMID- 12618027
TI  - Comparative study of GDNF delivery systems for the CNS: polymer rods,
      encapsulated cells, and lentiviral vectors.
AB  - Glial cell line-derived neurotrophic factor (GDNF) holds great promise for the
      treatment of Parkinson's disease. In humans, its intracerebroventricular
      administration leads to limiting side effects. Direct parenchymal delivery using
      mechanical means, or cell and gene therapy represent potential alternatives. In
      the present study, a representative of each of these three approaches, i.e.
      polymer rods, genetically modified encapsulated cells and lentiviral vectors was
      analyzed for its ability to release GDNF in the striatum of rats. One week post
      surgery, GDNF was detected over a distance of 4 mm with all three methods. At 4
      weeks GDNF staining diminished with rods and to a lesser extent with encapsulated
      cells, whereas it increased with lentiviral vectors. Nanogram range of GDNF was
      measured with all methods at 1 week. At 4 weeks, GDNF levels decreased
      significantly with rods, whereas they remained stable with encapsulated cells and
      lentiviral vectors. We conclude that all three methods investigated allow
      striatal delivery of GDNF, but the time during which it needs to be released will
      determine the approach chosen for clinical application.

PMID- 12618028
TI  - Mobility and stability of gene complexes in biogels.
AB  - The tenacious secretions lining the conductive airways of cystic fibrosis (CF)
      patients may pose a significant barrier to successful gene therapy to the lung.
      In this work, we evaluated the diffusion of nanospheres and cationic DOTAP
      lipoplexes through CF sputum and the influence of CF mucus components on the
      physicochemical properties and gene expression of cationic DOTAP lipoplexes and
      neutral, pegylated GL67 lipoplexes. The number of particles transported through
      the sputum was extremely low (<0.5%) and strongly depending on the size of the
      particles, with almost no transport for the largest nanospheres (560 nm). For
      small particles (<150 nm), the low transport was primarily due to the long
      distance they have to travel through the sputum, while for larger particles also
      sterical obstruction was responsible for the low transport. Upon exposure of the
      cationic DOTAP lipoplexes to albumin, linear DNA or mucin (at concentration
      ratios expected to occur in vivo) a significant decrease in gene transfection
      activity was observed. This was primarily due to aggregation of the lipoplexes.
      However, exposure of pegylated GL67 lipoplexes to the same components did not
      affect their gene transfection activity. Indeed, it was determined that CF mucus
      components did not interact significantly with these neutral, pegylated GL67
      lipoplexes.

PMID- 12618029
TI  - Drug transport and metabolism characteristics of the human airway epithelial cell
      line Calu-3.
AB  - Pulmonary drug delivery serves two purposes, namely the application of locally
      active compounds for treatment of diseases afflicting the lung, and the
      utilization of the pulmonary epithelia as absorption sites for macromolecular
      drugs. To elucidate the mechanisms involved in the pulmonary absorption and
      metabolism of compounds on a cellular level, cell culture models have shown to
      be, though limited, rather useful in predicting in vivo conditions. The Calu-3
      cell line has been employed recently as a model for the airway epithelium in a
      number of drug transport and metabolism studies. The results of these studies, as
      well as an evaluation of the predictive potency of the model, are presented here.

PMID- 12618030
TI  - Targeting caveolae for vesicular drug transport.
AB  - Caveolae are morphologically evident as omega-shaped invaginations of the plasma
      membrane with a diameter of 50-100 nm. They may also exist in a variety of other
      forms including flattened domains indistinguishable from the plasma membrane
      itself. At least in some cell types caveolae undertake transport functions
      including that of the endocytic and transcytotic movement of macromolecules, and
      indeed microbes and microbial toxins. Opportunities exist for basic and applied
      investigators working within the pharmaceutical sciences to exploit caveolae
      membrane interactions with the aim to develop of novel cellular or transcellular
      drug delivery strategies. This overview article will provide: pertinent
      information on the biology of the caveolae membrane system; review the various
      caveolae isolation methods; highlight some of the literature evidence showing
      that caveolae are functional with regard to macromolecule transport; discuss the
      role that caveolae could fulfill in the pulmonary absorption of therapeutic
      proteins from alveolar airspace to capillary blood following inhalational drug
      delivery, and finally review some very recent work showing proof-of-principle
      that caveolae domains can be targeted in a tissue-specific manner with highly
      selective ligands.

PMID- 12618031
TI  - Optimising the therapeutic trinity of active ingredient, delivery system and
      functional packaging.
AB  - This paper introduces the "therapeutic trinity" concept for formulating and
      developing optimal drug products. It starts with the recognition that all drug
      products are constituted of three distinct elements: the active ingredient, the
      delivery system and the packaging. Union of these three elements into one trinity
      will bring therapeutic value to the patient under the condition that active
      ingredient, delivery system and packaging are developed and optimised
      interdependently. Optimisation should be performed with the patient in mind,
      taking into account the relevant efficacy and safety parameters, and the relevant
      quality and cost parameters. Since the patient plays the central role in the
      performance of the drug product, biopharmaceutical robustness of and patient
      compliance towards the active ingredient/delivery system/packaging trinity should
      be considered important determinants of therapeutic success.

PMID- 12618032
TI  - Targeted cancer gene therapy: the flexibility of adenoviral gene therapy vectors.
AB  - Recombinant adenoviral vectors are promising reagents for therapeutic
      interventions in humans, including gene therapy for biologically complex diseases
      like cancer and cardiovascular diseases. In this regard, the major advantage of
      adenoviral vectors is their superior in vivo gene transfer efficiency on a wide
      spectrum of both dividing and non-dividing cell types. However, this broad
      tropism at the same time represents an important limitation for their use in
      therapeutic applications where specific gene transfer is required. This
      limitation may be overcome by using targeting approaches. In this regard,
      targeting may be achieved at three levels: transductional targeting,
      translational targeting and targeting of the expressed transgene. Here we
      describe our research efforts towards cancer specific gene therapy using these
      different targeting approaches. The results show that targeting of adenoviral
      vectors may be achieved using cancer specific cell surface molecules for
      transductional and transgene targeting or cancer specific promoters for
      transcriptional targeting. Combinations of these targeting approaches should
      result in optimized cancer specific gene therapy.

PMID- 12618033
TI  - Preparation and characterization of folate-targeted pEG-coated pDMAEMA-based
      polyplexes.
AB  - A folate-poly(ethylene glycol) conjugate capable of covalent coupling to primary
      amines present at the surface of polyplexes was developed. Coating of
      poly(dimethylaminomethyl methacrylate (pDMAEMA)-based polyplexes with this folate
      pEG conjugate led to a sharp decrease of the zeta-potential, and a small increase
      in particle size. The size of the particles in isotonic medium did not change
      markedly in time demonstrating that rather stable particles were formed. The in
      vitro cellular toxicity of the pEGylated polyplexes with and without folate
      ligands was lowered considerably compared to uncoated polyplexes. The toxicity
      observed for the targeted pEGylated polyplexes was slightly higher than that of
      corresponding untargeted polyplexes, which might indicate an increased cellular
      association of targeted polyplexes. Transfection of OVCAR-3 cells in vitro was
      markedly increased compared to untargeted pEGylated polyplexes, suggesting
      targeted gene delivery.

PMID- 12618034
TI  - Tumor regression by repeated intratumoral delivery of water soluble
      lipopolymers/p2CMVmIL-12 complexes.
AB  - The recruitment of the body's own immune system is amongst the most potent
      defenses known against cancer. Recent attempts to harness this response have
      enlisted the use of the immune modulating cytokine, interleukin-12 (IL-12). The
      objective of this work is to investigate the organ distribution and anti-tumor
      response in vivo after intratumoral administration of IL-12 expression plasmid
      complexed with water soluble lipopolymer (WSLP). Formulations of WSLP/p2CMVmIL-12
      at N/P mol ratio of 20:1 were prepared in the presence of 5% (w/v) glucose. Organ
      distribution data following intratumoral injection of CT-26 subcutaneous tumor
      bearing BALB/c mice demonstrated enhanced retention of WSLP/p2CMVmIL-12 complexes
      within the tumor and limited accumulation in other organs for up to 96 h. Tumor
      bearing BALB/c mice received either single or repeated intratumoral injections at
      4- or 8-day intervals to examine the efficacy of single versus repeated
      injections on tumor regression and survival. Significant tumor growth inhibition
      during 4- and 8-day injection trials was observed with maximal survival in mice
      receiving 4-day injections of WSLP/p2CMVmIL-12 complexes. In conclusion, the
      water-soluble non-toxic lipopolymer complexed with p2CMVIL-12 showed enhanced
      transgene expression in vivo, inhibits the rate of tumor growth, and
      significantly increases survival.

PMID- 12618035
TI  - Nasal drug delivery--possibilities, problems and solutions.
AB  - This paper discusses the problems associated with nasal drug delivery and how it
      is possible, sometimes by means of quite simple concepts, to improve transport
      across the nasal membrane. In this way it is feasible to deliver efficiently
      challenging drugs such as small polar molecules, peptides and proteins and even
      the large proteins and polysaccharides used in vaccines or DNA plasmids exploited
      for DNA vaccines. The transport of drugs from the nasal cavity directly to the
      brain is also described and examples of studies in man, where this has been shown
      to be feasible, are discussed. Recent results from Phase I/II studies in man with
      a novel nasal chitosan vaccine delivery system are also described. Finally, the
      author's thoughts about the future for nasal drug delivery are also depicted.

PMID- 12618037
TI  - Production of mycelium biomass and ethanol from paper pulp sulfite liquor by
      Rhizopus oryzae.
AB  - The cultivation conditions for Rhizopus oryzae grown in synthetic medium and
      paper pulp spent sulfite liquor (SSL) were investigated to achieve high biomass
      and ethanol yields using shake flasks and bioreactors. The fungus assimilated the
      hexoses glucose, mannose and galactose, and the pentoses xylose and arabinose as
      well as acetic acid which are present in SSL. The assimilation of hexoses was
      faster than pentoses during cultivation in a synthetic medium. However, all
      sugars were assimilated concomitantly during growth in SSL supplemented with
      ammonium, magnesium, calcium, phosphate, sulfate and trace amounts of some other
      metal ions (SSL-S). The medium composition had an important influence on biomass
      yield. The highest biomass yields, viz. 0.18 and 0.43 g biomass/g sugar were
      obtained, when the cells were cultivated in shake flasks with a synthetic medium
      containing glucose as carbon and energy source and SSL-S, respectively. The
      corresponding yields in a bioreactor with more efficient aeration were 0.22 and
      0.55 g/g. In addition to the biomass, ethanol, lactic acid, and glycerol were
      important extracellular metabolites of the cultivation with maximum yields of
      0.37, 0.30 and 0.09 g/g, respectively. When the source of sugars in the medium
      was exhausted, the fungus consumed the metabolites produced, such that the liquid
      medium was depleted of potential oxidizable nutrients. In general, there was a
      direct competition between lactic acid and ethanol among the metabolites. Poor
      medium compositions and cultivation conditions resulted in higher yields of
      lactic acid, whereas the ethanol and biomass yields were higher in rich media.
      SSL-S supported good growth of mycelium and a high ethanol yield.

PMID- 12618038
TI  - Effect of abiotic factors on the antibacterial activity of chitosan against
      waterborne pathogens.
AB  - To assess the adaptability of chitosan (from agricultural waste) as a natural
      disinfectant, its antibacterial activity against bacteria associated with
      waterborne diseases was investigated by varying such abiotic conditions, as pH
      and ionic strength and by adding different amounts of acid solvent, metal ions,
      and EDTA. Two major waterborne pathogens, Escherichia coli and Staphylococcus
      aureus, were examined. Results showed that organic acids with low carbon number
      were better solvents for chitosan than were inorganic acids. The effect of pH
      below 6 on the antibacterial activity of chitosan was significant. The
      antibacterial activity of chitosan increased with ionic strength but decreased
      with the addition of metal ions. The addition of Zn(2+) ions inhibited the
      antibacterial activity of chitosan the most, while the addition of Mg(2+) ions
      inhibited the antibacterial activity of chitosan the least. This was due to the
      chelating capacity of chitosan toward metal ions. The antibacterial activity of
      chitosan against E. coli was enhanced by EDTA. However, the antibacterial
      activity of chitosan against S. aureus was partially suppressed by EDTA. The
      antibacterial activity of chitosan was also dependent on its charges and
      solubility. The antibacterial mechanism of chitosan has currently been
      hypothesized as being related to surface interference. The results show that the
      chitosan is a potential bactericide under various environmental conditions.

PMID- 12618039
TI  - Chemical modification of rubber wood with styrene in combination with a
      crosslinker: effect on dimensional stability and strength property.
AB  - Chemical modification of rubber wood (Hevea Brasiliensis) was carried out by
      impregnating the wood with styrene and in combination with a crosslinker Glycidyl
      Methacrylate (GMA). Polymerization was carried out by catalyst heat treatment.
      The dimensional stability in terms of % volumetric swelling and anti-shrink
      efficiency was determined and found to be improved on treatment. Water absorption
      was also found to be decreased considerably for treated wood samples. Mechanical
      strength of the treated samples in terms of modulus of rupture and modulus of
      elasticity were also found to be improved. The wood polymer interaction was
      confirmed by FT-IR spectroscopy. Biodegradability of the wood/polymer composites
      was determined and found to be improved on treatment with styrene/styrene-GMA.

PMID- 12618040
TI  - Quantitative estimation of peat, brown coal and lignite humic acids using
      chemical parameters, 1H-NMR and DTA analyses.
AB  - Humic acids extracted from peats (P), brown coals (BC) and lignites (L), were
      characterized using different (chemical, 1H-nuclear magnetic resonance
      spectroscopy and differential thermal analysis) techniques. Fourteen variables
      were obtained from these analyses and only five were selected because
      uncorrelated in multiple partial correlation. The chosen variables were C
      concentration, aliphatic and aromatic components and the heat of reaction of the
      second exothermic peak. The multivariate discriminant analysis was performed on
      these variables and a discriminant function was obtained which was able to
      efficiently separate the P, BC and L. This function enables simple predictions on
      samples of unknown origin. The straightforward method proposed and the results
      obtained are discussed.

PMID- 12618041
TI  - Comparative efficacy of three epigeic earthworms under different deciduous forest
      litters decomposition.
AB  - An experiment was conducted during 1998-1999, in a deciduous forest located in
      the semi-arid tropics of central India, to evaluate the suitability of different
      forest litters as food material for the tropical epigeic earthworms i.e. Eisenia
      fetida (Savigny), Perionyx excavatus (Perrier) and Dicogaster bolaui
      (michaelsen). The aim was to examine the influence of these earthworms on the
      decomposition processes of three types of forest litters i.e. Tectona grandis
      (teak), Madhuca indica (mahua) and Butea monosperma (palas), on the maintenance
      of quality in a vermicomposting system, and to assess the effect of applications
      of in situ prepared vermicomposts on the growth of forest trees. The results
      indicated that T. grandis litter was the most suitable food material for the
      earthworms possibly because it contained high reserves of mineral nutrients.
      Comparisons of the survival and reproduction rates of the three epigeic earthworm
      species indicated that a higher reproduction rate was maintained for E. fetida
      compared to P. excavatus and D. bolaui in the decomposition of these forest
      litters. The rates of growth and population increases of E. fetida approximately
      doubled after 12 weeks of litter decomposition. The litter decomposition process
      was associated strongly with the quality of the materials and their chemical
      composition. Irrespective of earthworm inoculations, the levels of available
      nutrient such as NH(4)-N, NO(3)-N, available P and K increased significantly
      (p</=0.05) in the order T. grandis litter compost>M. indica litter compost>B.
      monosperma litter compost. The mature decomposed litter had lower C/N ratios
      (11.3-24.8:1), water-soluble carbon (0.30-0.58%), water-soluble carbohydrates
      (0.35-0.71%) and larger cation exchange capacity/total organic carbon ratios than
      the values in the parent forest litter. The lignin content increased with
      maturation with a concomitant decrease in cellulose resulting in higher
      lignin/cellulose ratios. Application of all three vermicomposts to forest trees
      significantly improved their heights and diameters over those of control trees,
      although the increases were lower than those resulting from the chemical
      fertilizer applications. However, soil biological activities i.e. soil
      respiration, soil microbial biomass carbon and dehydrogenase activity were
      greater by application of vermicomposts over that after application of inorganic
      fertilizer in a new plantation of T. grandis.

PMID- 12618042
TI  - Comparison of laboratory-scale thermophilic biofilm and activated sludge
      processes integrated with a mesophilic activated sludge process.
AB  - A combined thermophilic-mesophilic wastewater treatment was studied using a
      laboratory-scale thermophilic activated sludge process (ASP) followed by
      mesophilic ASP or a thermophilic suspended carrier biofilm process (SCBP)
      followed by mesophilic ASP, both systems treating diluted molasses (dilution
      factor 1:500 corresponding GF/A-filtered COD (COD(filt)) of 1900+/-190 mgl(-1)).
      With hydraulic retention times (HRTs) of 12-18 h the thermophilic ASP and
      thermophilic SCBP removed 60+/-13% and 62+/-7% of COD(filt), respectively, with
      HRT of 8 h the removals were 48+/-1% and 69+/-4%. The sludge volume index (SVI)
      was notably lower in the thermophilic SCBP (measured from suspended sludge) than
      in the thermophilic ASP. Under the lowest HRT the mesophilic ASP gave better
      performance (as SVI, COD(filt), and COD(tot) removals) after the thermophilic
      SCBP than after the thermophilic ASP. Measured sludge yields were low (less than
      0.1 kg suspended solids (SS) kg COD(filt removed)(-1)) in all processes. Both
      thermophilic treatments removed 80-85% of soluble COD (COD(sol)) whereas
      suspended COD (COD(susp)) and colloidal COD (COD(col)) were increased. Both
      mesophilic post-treatments removed all COD(col) and most of the COD(susp) from
      the thermophilic effluents. In conclusion, combined thermophilic-mesophilic
      treatment appeared to be easily operable and produced high effluent quality.

PMID- 12618043
TI  - Effect of organic carbon shock loading on endogenous denitrification in
      sequential batch reactors.
AB  - This work was focused on the performance evaluation of sequential batch reactors
      (SBR) treating sewage, through a process of endogenous biological
      denitrification. Different operational conditions were carried out, and the
      behaviour under the effects of organic shock loading was examined. Three
      laboratory scale reactors were operated simultaneously and fed with similar
      wastewater. The substratum was molasses and nitrate, as carbon and nitrogen
      sources, respectively. The three reactors were operated during different aeration
      periods (0, 15 and 30 min). Sudden changes (shock loading) in organic matter
      concentration were performed during the experiment. Thus, influent load was
      quickly increased threefold in relation to the original concentration. Results
      indicated that SBR reactors withstand adequately moderate shock loading. With
      regard to substratum degradation, nitrate elimination achieved was approximately
      80%, while denitrification rate was approximately 0.87 mgg(-1)h(-1).

PMID- 12618044
TI  - Growth and mineral accumulation in Eucalyptus camaldulensis seedlings irrigated
      with mixed industrial effluents.
AB  - Effects of mixed industrial effluents on growth, dry matter accumulation and
      mineral nutrient in Eucalyptus camaldulensis seedlings were studied. The
      objective was to evaluate the adaptability of E. camaldulensis to effluent,
      tolerance to excess/deficiency of mineral elements and ultimately to determine
      suitable combinations of industrial/municipal effluent for their use in biomass
      production in dry areas. Different irrigation treatments were: T(1): good water;
      T(2): municipal effluent; T(3): textile effluent; T(4): steel effluent; T(5):
      textile effluent+municipal effluent in 1:1 ratio; T(6): steel effluent+municipal
      effluent in 1:2 ratio; T(7): steel+textile+municipal effluent in 1:2:2 ratio; and
      T(8): steel+textile effluent in 1:2 ratio. High concentrations of metal ions and
      low concentrations of Ca, Mg, K, Na, N and P in soil and seedlings of T(4)
      resulted in mortality of the seedlings within a few days. Addition of the
      textile/municipal effluent increased the survival time of the seedlings for two
      to three months in T(6), T(7) and T(8) treatments. Among the remaining
      treatments, the seedlings of T(2) attained 131 cm height, 1.97 cm collar
      diameter, 19 total branches and produced 158 g seedling(-1) of dry biomass at the
      age of 10 months. The seedling of T(3) produced the least growth and biomass.
      Growth equivalent to that of the seedlings of T(1) treatment was achieved when
      municipal effluent was mixed with textile effluent (T(5)). There was a decrease
      in soil pH, EC, SOC, NH(4)-N, NO(3)-N, PO(4)-P and basic cations and increase in
      the concentration of Cu, Fe, Mn and Zn with T(4) treatment. The reverse trend was
      observed in T(3) where a high concentration of Na might have reduced Mg and
      micronutrient concentration in seedlings potentially affecting root and leaf
      growth. Mixing of effluents may be useful in tree irrigation to increase biomass
      productivity, which is evidenced by improved growth in T(5) and survival in T(6),
      T(7) and T(8) treatments. Further, reduction of toxic concentration of metal ions
      in effluents may be helpful for a long-term field application.

PMID- 12618045
TI  - Impact of iron salts on activated sludge and interaction with nitrite or nitrate.
AB  - Iron salts are often used in activated sludge treatment plants as coagulants or
      to improve reactor performance. Previous studies have indicated that iron itself
      has an impact on the activated sludge process. However, the interaction of iron
      with nitrite or nitrate present in the sludge has received little attention. In
      this research, the influence of addition of Fe(II) or Fe(III), alone or together
      with NO(2)(-) or NO(3)(-) on bench-scale activated sludge reactors was examined.
      Large differences were established between the distinct treatments, regarding
      reactor performance, sludge characteristics as well as microbial community.
      Ferric iron was more detrimental than ferrous iron. In some cases, nitrite was
      found to enhance inhibitory effects of the added iron, whereas nitrate had more a
      neutralizing effect. It was found that precipitation of phosphate by the iron was
      not responsible for the observed inhibition. Decrease in pH upon formation of
      iron hydroxides and the impairment of the floc structure could partially explain
      the toxicity of the iron dosages. The formation of toxic nitrogen oxides, such as
      nitric oxide, can also be of importance. The observed positive effect of nitrate
      on the floc activity is of interest and warrants further elucidation.

PMID- 12618046
TI  - Influences of composted hazelnut husk on some physical properties of soils.
AB  - Some physical properties of clay loam and sandy loam soils amended with hazelnut
      husk (HH) were investigated. HH collected from hazelnut trees were dried, ground
      and composted for four months. Before use the composted material obtained was
      separated to three different aggregate sizes, smaller than 0.84 mm, 0.84-2.38 mm
      and bigger than 2.38 mm. Then these fractions were mixed with soil samples, at
      0%, 1%, 2%, 4% and 8% by weight. Huzelnut husk compost-soil mixtures were placed
      to plastic pots and kept in an incubator at 25+/-5 degrees C for 45 and 90 days.
      At the end of incubation periods, water stable aggregate (WSA), hydraulic
      conductivity, total porosity, aeration porosity and macro- and micro-pore
      percentages of the mixtures were determined. Results obtained showed that
      composted HH increased the WSA, hydraulic conductivity, total porosity and macro
      pore percentage in both clay loam and sandy loam soils depending on the
      incubation time and aggregate sizes.

PMID- 12618047
TI  - 5'-Phosphodiesterase (5'-PDE) from germinated barley for hydrolysis of RNA to
      produce flavour nucleotides.
AB  - 5'-Phosphodiesterase (5'-PDE) is an enzyme that hydrolyses RNA to a mixture of
      ribonucleotides, from which the flavour enhancers, 5'-guanosine monophosphate (5'
      GMP) and 5'-inosine monophosphate (5'-IMP) can be isolated. In the present work,
      5'-PDE was extracted and partially purified from germinated barley seeds. 5'-PDE
      activity was monitored using bis-p-nitrophenyl phosphate as the substrate. The
      enzyme acts on the substrate and releases the p-nitrophenol, which is measured at
      420 nm. Ultrafiltration using a polysulfone membrane having molecular weight cut
      off (MWCO) of 20 kDa gave 12-fold concentration. Further purification using
      ammonium sulphate gave 18-fold concentration. Heat shock for 15 min at 60 degrees
      C after the ultrafiltration enhanced the concentration of 5'-PDE 9.10 fold, while
      a similar treatment after ammonium sulphate treatment enhanced it by 17.83-fold.
      The enzyme had a pH optimum of 5, and was stable at 0 degrees C. This partially
      purified enzyme could be used for hydrolysis of RNA to produce 5'-GMP and 5'
      adenosine monophosphate, a precursor of 5'-IMP.

PMID- 12618048
TI  - Enhanced production of pectinase by Bacillus sp. DT7 using solid state
      fermentation.
AB  - Bacillus sp. DT7 produced very high levels of alkaline and thermotolerant
      pectinase by solid state fermentation. Production of this enzyme was affected by
      nature of solid substrate, level of moisture content, presence or absence of
      carbon, nitrogen, mineral and vitamin supplements. Maximum enzyme production of
      8050 U/g dry substrate was obtained in wheat bran supplemented with
      polygalacturonic acid (PGA; 1%, w/v) and neurobion (a multivitamin additive; 27
      micro l/g dry substrate) with distilled water at 75% moisture level, after 36 h
      of incubation at 37 degrees C.

PMID- 12618049
TI  - Electrochemical potential of free and immobilized Cratylia mollis seed lectin.
AB  - The electrochemical potentials for free or immobilized Cratylia mollis seed
      lectin (Cra) were obtained through potentiostatic techniques. A saline solution
      was used as support to control the charge distribution between saturated calomel
      electrode and platinum electrode (working electrode). The electrochemical
      potential to free Cra was determined at the following concentrations: 0.6, 0.9
      and 1.0 mg/ml in an aerated environment under different temperatures (5, 10 and
      20 degrees C). The best electrochemical potential was obtained with 1.0 mg/ml, at
      5 and 10 degrees C, 87 and 102 mV, respectively. Electrochemical potential to Cra
      immobilized on glass beads activated with 3-aminopropyltriethoxysilane described
      a linear behavior in relation to the increase in glucose concentration. The
      development of techniques to define interface electrical parameters will be able
      to give information about charged groups adsorbed to electrode surface revealing
      interactions particularly in biological systems.

PMID- 12618050
TI  - Characterization of five agricultural by-products as potential biofilter
      carriers.
AB  - Biofiltration is the most commonly used biological gas treatment technology and
      is extensively used for the treatment of polluted air with gas flow rates of up
      to 2 x 10(5) m(3)/h. It involves a filter bed of organic matter serving both as
      carrier for microorganisms and as nutrient supplier. Polluted gas passes through
      the filter bed and is cleaned by biological activity. Biofiltration is not being
      developed in Latin America as in the USA, Canada or Europe; the main reason
      probably being the absence of specific technology and of potential organic
      carriers locally available. Five different agriculture by-products available in
      Latin America: peanut shells, rice husk, coconut shells, cane bagasse and maize
      stubble, were chemically, physically and structurally characterized for their
      potential use as biofilter carrier. It was found that peanut shells could be used
      as biofilter carrier and therefore would have potential biological application.

PMID- 12618051
TI  - Improved arachidonic acids production from the fungus Mortierella alpina by
      glutamate supplementation.
AB  - The effect of various concentrations of glutamate on arachidonic acid (AA)
      production from Mortierella alpina in shaker flask culture was studied. Glutamate
      supplementation promoted Mortierella growth, accelerated substrate metabolism,
      and increased AA production, and a concentration of 0.8 g/l glutamate resulted in
      the greatest AA yield (1.41 g/l). In 10 l airlift stirred fermenter culture, AA
      yield in the cultures exposed to 0.8 g/l glutamate was also greater than that in
      the control (0.56 g/l).

PMID- 12618052
TI  - Myoclonus and neurodegenerative disease--what's in a name?
AB  - Myoclonus is a clinical symptom (or sign) defined as sudden, brief, shock-like,
      involuntary movements caused by muscular contractions or inhibitions. It may be
      classified by examination findings, etiology, or physiological characteristics.
      The main physiological categories for myocolonus are cortical, cortical
      subcortical, subcortical, segmental, and peripheral. Neurodegenerative syndromes
      are potential causes of symptomatic myoclonus. Such syndromes include multiple
      system atrophy, corticobasal degeneration, progressive supranuclear palsy,
      frontotemporal dementia and parkinsonism linked to chromosome 17, Huntington's
      disease, dentato-rubro-pallido-luysian atrophy, Alzheimer's disease, and
      Parkinson's disease, and other Lewy body disorders. Each neurodegenerative
      syndrome can have overlapping as well as distinctive clinical neurophysiological
      properties. However, claims of differentiating between neurodegenerative
      disorders by using the presence or absence of small amplitude distal action
      myclonus appear unwarranted. When the myoclonus is small and repetitive, it may
      not be possible to distinguish it from tremor by phenotypic appearance alone. In
      this case, clinical neurophysiological offers an opportunity to provide greater
      differentiation of the phenomenon. More study of the myoclonus in
      neurodegenerative disease will lead to a better understanding of the processes
      that cause phenotypic variability among these disorders.

PMID- 12618053
TI  - Two large Polish kindreds with levodopa-responsive Parkinsonism not linked to
      known Parkinsonian genes and loci.
AB  - PURPOSE: We describe two newly discovered large Polish families with
      Parkinsonism, PL-Krakow 1 and PL-Krakow 2. SCOPE: As illustrated by case reports
      from two patients, the disease phenotype is similar to that seen in patients with
      idiopathic Parkinson's disease, and affected individuals show a positive response
      to levodopa therapy. Molecular genetic studies failed to demonstrate a single
      chromosomal haplotype that segregated with disease for any of the known loci for
      Parkinsonism. CONCLUSIONS: The study of large kindreds such as this provides
      opportunities to find new Parkinsonian loci and mutations. This knowledge will
      help to better our understanding of the basic mechanisms leading to the
      degeneration of vulnerable substantia nigra neurons and other susceptible brain
      structures.

PMID- 12618054
TI  - Familial and sporadic Parkinson's disease usually display the same clinical
      features.
AB  - We examined the clinical features of familial (n = 26) and sporadic (n = 52)
      Parkinson's disease (PD) in patients presenting over the age of 40 years.
      Familial PD cases were tested for alpha-synuclein or parkin mutations as
      appropriate. No mutations were found in any of the families investigated. We
      found no between-group differences in the age at onset of PD, the pattern or
      severity of parkinsonian features, the dose of antiparkinsonian medications or
      treatment related complications. Cases of familial and sporadic PD in our cohort
      of patients display similar clinical features. This may suggest similar
      etiologies for both familial and sporadic PD.

PMID- 12618055
TI  - Executive function differences in multiple system atrophy and Parkinson's
      disease.
AB  - The aim of the present study was to assess executive function in patients with
      multiple system atrophy (MSA) and Parkinson's disease (PD) looking for specific
      differences and considering motor disability and disease duration. Performance of
      11 MSA patients was compared to that of 12 healthy controls and two groups of 12
      PD patients, one matched with respect to the severity of motor symptoms and the
      other with respect to disease duration. Compared to healthy controls, MSA and PD
      patients both presented executive dysfunction but, in MSA, the impairment was
      more severe and diffuse. This study suggests that despite the evidence of some
      differences in executive function in MSA and PD, the contribution of standard
      neuropsychological examination to the differential diagnosis of both syndromes
      remains still limited.

PMID- 12618056
TI  - Effect of the neurotoxic dose of methamphetamine on gene expression of parkin and
      Pael-receptors in rat striatum.
AB  - We previously reported that haloperidol, a dopamine-D(2) receptor antagonist,
      induced striatal expression of parkin gene, which mutations cause autosomal
      recessive juvenile parkinsonism. Because of an involvement of the parkin gene
      defect in selective degeneration of dopaminergic neurons, we herein examined the
      effect of the neurotoxic dose of methamphetamine (METH; 40 mg/kg, i.p.) on gene
      expression of parkin and its substrate Pael-receptor (R) in the dopamine-rich
      areas of the rat brain, using reverse transcription-polymerase chain reaction.
      parkin mRNA levels in the striatum, but not in other regions, decreased at 1 and
      2 h and returned to the pre-drug basal levels at 4 h after METH administration.
      METH also decreased Pael-R mRNA levels in the striatum and substantia nigra
      within 2 h after METH, while haloperidol (2 mg/kg, s.c.) increased Pael-R mRNA
      levels in the substantia nigra at 2 h after administration. These results suggest
      that temporary suppression of gene expression of parkin and Pael-R may be
      associated with the METH-induced dopaminergic neurotoxicity. Taken together with
      our previous report, dopaminergic modulation of the expression of parkin and Pael
      R genes in the nigro-striatal pathway may have significant implication for
      pathophysiology and treatment of parkinson disease.

PMID- 12618057
TI  - Selegiline in the treatment of Parkinson's disease: its impact on orthostatic
      hypotension.
AB  - Less than a consensus exists as to whether chronic treatment with selegiline in
      combination with levodopa/carbidopa in patients with Parkinson's disease, is
      associated with more pronounced orthostatic hypotension than treatment with
      levodopa/carbidopa alone. To resolve this issue, we compared orthostatic
      tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated
      chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n =
      49) or both agents combined (n = 36). Supine heart rate and blood pressure,
      autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic
      hypotension were similar in all three treatment groups.

PMID- 12618058
TI  - Co-occurrence of essential tremor and Parkinson's disease: clinical study of a
      large kindred with autopsy findings.
AB  - A multigenerational family complex with an admixture of essential tremor (ET) and
      PD is presented. Medical information obtained either by historic documentation
      and/or examination was available for five generations and included 36 members. Of
      these, 11 family members had tremor of the limbs and/or head. In all these
      instances ET made its first appearance at an early age, usually prior to the
      second decade of life. In one case focal dystonia of the hand, a possible prelude
      to PD occurred, while in three brothers of the third generation, two of them
      identical twins, classical Parkinson's disease (PD) developed. They had ET
      develop at an early age, which persisted and in their 50s began showing evidence
      of PD. Two decades later the twin brothers succumbed to cancer of the colon and
      at autopsy typical findings of PD with cell loss in the substantia nigra and Lewy
      body formation positive for alpha-synuclein by immunohistochemistry was found.
      Additionally, more than the usual number of senile plaques and neurofibrillatory
      tangles were present without clinical evidence of dementia or significant decline
      in cognitive function. This unusual set of clinical and pathological
      circumstances can hardly be attributed to chance occurrence and raise the
      question of a specific genetic mutation and/or clustering, which may link ET with
      PD.

PMID- 12618060
TI  - Skin color and the risk and severity of essential tremor: a reflectance
      spectroscopy study.

PMID- 12618059
TI  - The prevalence of Parkinson's disease in British Columbia, Canada, estimated by
      using drug tracer methodology.
AB  - OBJECTIVE: To estimate the prevalence of Parkinson's disease (PD) in British
      Columbia utilizing the prescription database of the College of Pharmacists.
      METHODS: Patients receiving anti-parkinsonian drug (anti-PD) prescriptions
      between 1996 and 1998 were stratified by year, age, gender, drug use category,
      and geographic location. The numbers of patients on levodopa alone, or levodopa
      and/or other anti-PD drugs were adjusted using published data which gave
      estimates of the proportion of undiagnosed patients with PD, the proportion of
      those treated for parkinsonism with definite PD, the proportion of patients with
      PD not being treated with anti-PD medications, and the proportion of patients
      treated with anti-PD medications who have PD. Use of the anti-PD drug
      bromocriptine for other purposes in women under 50 years of age was also
      considered. RESULTS: The estimated prevalences of PD based on all anti-PD
      medications used were 109, 121, and 125 per 100,000 population in 1996, 1997, and
      1998, respectively. Estimated prevalences of PD based on levodopa use were 126,
      134, and 144, respectively. The prevalence in both prescription groups increased
      with age. The male to female ratio of prevalence ranged from 1.16 to 1.21.
      CONCLUSIONS: Using a large, accurate database, it is possible to estimate the
      prevalence of PD in a large population, though the assumptions built into the
      estimate remain to be validated in the subject population.

PMID- 12618061
TI  - Animal disease eradication demands targetted resources and determination.

PMID- 12618062
TI  - Stereoselectivity in drug development. A clinical perspective?

PMID- 12618063
TI  - The trouble with life fluids: some parallels between mothers milk and lung juice.

PMID- 12618064
TI  - International conference on equine grass sickness, Dubai, United Arab Emirates
      September 22-23, 2001.

PMID- 12618065
TI  - Clinical signs and epidemiology of classical swine fever: a review of new
      knowledge.
AB  - Although classical swine fever (CSF) has been well known for decades and
      epidemics still occur, clinical diagnosis continues to cause problems for
      veterinary practitioners. This is due to the extensive differential diagnosis,
      further complicated by the emergence of new diseases such as porcine reproductive
      and respiratory syndrome (PRRS) and porcine dermatitis and nephropathy syndrome
      (PDNS). In addition, acute, chronic and prenatal courses of CSF have to be
      distinguished. As a cause of considerable economical losses within the EU,
      control of CSF requires knowledge of the primary outbreaks and spread of the
      disease. Genetic typing of CSF virus isolates has proved to be a potent method of
      supporting epidemiological investigations. Phylogenetic analysis of CSF virus
      strains and isolates originating from different continents has allowed three
      genetic groups and several subgroups within these groups to be distinguished.
      Whereas isolates belonging to group 3 seem to occur solely in Asia, all CSF virus
      isolates of the 1990s isolated in the EU belonged to one of the subgroups within
      group 2 (2.1, 2.2, or 2.3) and were clearly distinct from former CSF reference
      viruses, which belong to group 1. Within the EU, different strategies are
      followed for the eradication of CSF in domestic pigs and in wild boar. While a
      strict non-vaccination policy is followed for domestic pigs, eradication of the
      disease in wild boar is more complex, and oral immunisation together with special
      hunting strategies have been applied. Recently, marker vaccines with a companion
      discriminatory test designed to allow differentiation between vaccinated animals
      and animals having recovered from field virus infection have been developed.
      Preliminary studies indicated that the discriminatory tests had a reduced
      sensitivity and specificity. Further improvements are therefore necessary before
      marker vaccines can be considered for emergency use in EU Member States.
      Prevention of CSF remains the main objective within the EU.

PMID- 12618068
TI  - Differentiation between lumbosacral transitional vertebrae, pseudolumbarisation,
      and lumbosacral osteophyte formation in ventrodorsal radiographs of the canine
      pelvis.
AB  - Ventrodorsal radiographs of the pelvis (n=150) of Rottweilers, Golden Retrievers,
      and German Shepherd dogs and macerated spines (n=800) from a variety of breeds
      were assessed for morphological evidence of lumbosacral transitional vertebrae as
      well as for factors that might lead to radiographic misinterpretation of this
      condition. Those alterations closely resembling the radiographic appearance of
      transitional vertebrae were identified to be: (1) calcification of the dorsal and
      ventral sacroiliac ligaments (=pseudolumbarisation), which might be interpreted
      as a costal process at S1 (or the corresponding vertebra in cases of numerical
      vertebral variations); and (2) osteophyte formation at the lumbosacral junction
      simulating separation of the cranial articular processes from the assembly of the
      sacral wing as seen in transitional vertebrae.

PMID- 12618066
TI  - Ketoprofen in the cat: pharmacodynamics and chiral pharmacokinetics.
AB  - The non-steroidal anti-inflammatory drug ketoprofen (KTP) was administered as the
      racemate to cats intravenously (IV) and orally at clinically recommended dose
      rates of 2 and 1 mg/kg, respectively, to establish its chiral pharmacokinetic and
      pharmacodynamic properties. After IV dosing, clearance was more than five times
      greater and elimination half-life and mean residence time were approximately
      three times shorter for R(-) KTP than for S(+) KTP. Absorption of both S(+) and
      R(-) enantiomers was rapid after oral dosing and enantioselective
      pharmacokinetics was demonstrated by the predominance of S(+) KTP, as indicated
      by plasma AUC of 20.25 (S(+)KTP) and 4.09 (R(-)KTP) microg h/mL after IV and 6.36
      (S(+)KTP) and 1.83 (R(-)KTP) microg h/mL after oral dosing. Bioavailability after
      oral dosing was virtually complete. Reduction in ex vivo serum thromboxane
      (TX)B(2) concentrations indicated marked inhibition of platelet cyclo-oxygenase
      (COX)-1 for 24 h after both oral and IV dosing and inhibition was statistically
      significant for 72 h after IV dosing. Both oral and IV rac-KTP failed to affect
      wheal volume produced by intradermal injection of the mild irritant carrageenan
      but wheal skin temperature was significantly inhibited by IV rac-KTP at some
      recording times. Possible reasons for the disparity between marked COX-1
      inhibition and the limited effect on the cardinal signs of inflammation are
      considered. In a second experiment, the separate enantiomers of KTP were
      administered IV, each at the dose rate of 1mg/kg. S(+)KTP again predominated in
      plasma and there was unidirectional chiral inversion of R(-) to S(+)KTP.
      Administration of both enantiomers again produced marked and prolonged inhibition
      of platelet COX-1 and, in the case of R(-)KTP, this was probably attributable to
      S(+)KTP formed by chiral inversion.

PMID- 12618069
TI  - Influence of platelet count, acetylsalicylic acid, von Willebrand's disease,
      coagulopathies, and haematocrit on results obtained using a platelet function
      analyser in dogs.
AB  - The platelet function analyser PFA-100 aspirates blood in vitro from a sample
      reservoir in disposable test cartridges through a microscopic aperture cut into a
      biologically active membrane at the end of a capillary. In different cartridges
      the membrane is coated with collagen and adenosine diphosphate (ADP) or collagen
      and epinephrine (adrenaline) inducing a platelet plug and closure of the
      aperture. The closure time and total volume of blood flow through the capillary
      until closure of its aperture were measured. The correlation between platelet
      count in samples of thrombocytopenic dogs and results of the collagen/ADP
      cartridge (closure time: r(S)=-0.579; total volume: r(S)=-0.549) was closer than
      between platelet count and capillary bleeding time. No significant correlation
      was observed between platelet count and the results obtained with the
      collagen/epinephrine cartridge. In addition, a higher sensitivity was obtained
      for the collagen/ADP cartridge. Injection of acetylsalicylic acid into healthy
      dogs significantly increased closure time and total volume of both types of
      cartridges (P<0.01). Two dogs with von Willebrand's disease had abnormal values.
      In contrast, coagulopathies did not significantly influence the results of the
      platelet function analyser (P>0.05). Despite adequate sensitivity of measurements
      using the collagen/ADP cartridge to assess quantitative and qualitative platelet
      disorders in dogs, the influence of haematocrit (P<0.0001) will limit the
      clinical application of the analyser.

PMID- 12618071
TI  - Comparative expression of liver cytochrome P450-dependent monooxygenases in the
      horse and in other agricultural and laboratory species.
AB  - The apoprotein expression and the catalytic activities of cytochrome P450s
      involved in the biotransformation of xenobiotics were investigated in horse liver
      microsomes and compared with those of food producing (cattle, pigs, broiler
      chicks, and rabbits) and laboratory species (rats). Western blot analysis
      revealed the presence of proteins immunorelated to rat CYP 1A, CYP 2B, CYP 2E,
      and CYP 3A subfamilies in hepatic microsomes from horses and from any other
      examined species. With the exception of the N-demethylation of N
      nitrosodimethylamine in broiler chicks, all the recorded interspecies differences
      were quantitative in nature. Equine preparations proved the most active in the
      biotransformation of the CYP 1A substrates ethoxy- and methoxyresorufin and the
      least active in the metabolism of aminopyrine and ethoxycoumarin. On a
      comparative basis, large differences were observed in the rate of the in vitro
      metabolism of model substrates between "minor" (rabbits, horses) and "major" food
      producing species. Taken in due consideration the limitations of the in vitro
      approach, results from this study reinforce the conclusion that studies on drug
      efficacy and residue depletion should be performed in each target species.

PMID- 12618072
TI  - Pulmonary surfactant from healthy Belgian White and Blue and Holstein Friesian
      calves: biochemical and biophysical comparison.
AB  - The biochemical composition and biophysical behaviour of pulmonary surfactant
      samples isolated from healthy Belgian White and Blue (BWB) and Holstein Friesian
      (HF) calves have been investigated and compared. Interesting differences in
      composition have been demonstrated. In particular, a higher level of total
      hydrophobic surfactant-associated proteins (SP) (due to higher levels of SP-B and
      SP-C) is reported in HF calves compared to BWB calves. Higher levels of
      phosphatidylcholine (PC) and especially the disaturated form of PC were also
      found in HF as compared to BWB calves. No immediate effect on the surface tension
      properties evaluated by the pulsating bubble surfactometer was found between the
      surfactant samples of the two breeds under physiological conditions. However,
      since a high content of disaturated PC and the presence of the SP-B and SP-C are
      thought to be essential for the surface activity, we propose that the reported
      modifications could contribute to the apparently lower resistance of the BWB
      calves to respiratory troubles in comparison with HF calves.

PMID- 12618073
TI  - Morphological changes to early stage Taenia solium cysticerci following
      oxfendazole treatment.
AB  - The progressive morphological changes to early stage Taenia solium cysticerci
      following the treatment of pigs with a single therapeutic dose of oxfendazole (30
      mg/kg), are described. On Day 1 after treatment, no obvious changes occurred in
      the general appearance of the larvae but alternations were seen by electron
      microscope, with an apparent reduction in the number of microtriches, and a
      complete disappearance of the tegument. Numerous granules were seen to have
      accumulated in the tegument cells. As treatment progressed, damage to the
      cysticerci was more serious and, by five days, all cysticerci were seen to be in
      an advanced stage of degeneration. By 45 days post-treatment, all cysts were
      calcified. These results suggest that oxfendazole is a highly effective drug
      against T. solium cysticerci in the early stages of development.

PMID- 12618075
TI  - Escherichia coli in the rumen and colon of slaughter cattle, with particular
      reference to E. coli O157.
AB  - The distribution of Escherichia coli O157 and of total E. coli was surveyed in
      the digestive tract of cattle under 30 months of age, slaughtered between August
      1999 and May 2000 in three abattoirs in southern England. Samples were taken from
      the dorsal and ventral rumen wall, the rumen contents, the colon wall and colon
      contents, and from faeces or caudal rectal contents. Gut wall samples were
      processed by vortex-mixer to release loosely adherent bacteria, and by Stomacher
      to release firmly attached bacteria. E. coli O157 was detected by immunomagnetic
      separation followed by growth on selective culture media. The numbers of E. coli
      were higher in the colon than the rumen, and most were located in the digesta
      phase, rather than associated with the gut wall. The number of E. coli found in
      the gut and in faeces decreased during the winter months. E. coli O157 was
      detected more frequently in the colon than in the rumen, but the majority of
      detections(7/8) were in samples of rumen wall.

PMID- 12618076
TI  - Residue persistence in sheep milk following antibiotic therapy.
AB  - Drug residues in milk supplies may have public health implications and can
      interfere in the manufacture of dairy products, such as cheese. In Spain, most
      ewe milk production is destined for cheese making, often using raw milk. This
      study analyses the main factors influencing antibiotic depletion time in
      lactating dairy sheep. 42, Manchega ewes were distributed into three groups, each
      receiving a different treatment (cephalexin intramammary infusion, penicillin G
      intramuscular, and oxytetracycline intravenous injections). During and after the
      recommended withdrawal period, milk samples were taken at each milking. A
      microbiological inhibition test (Brilliant Black Reduction, BRT) was used to
      screen all samples and antibiotic withholding times were established using a
      logistic regression model. The response to the BRT method in milk from individual
      ewes treated showed that the effect of the milking order was significant
      (P<0.001) with the three antibiotics. However the only influence on milk yield
      was with the intramammary treatment (P<0.005). The BRT method was found to be
      very sensitive, particularly to the two beta-lactamic antibiotics.

PMID- 12618080
TI  - Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the
      art.
AB  - Since 1999 an increasing number of patients with phenylalanine hydroxylase (PAH)
      deficiency are reported to be able to decrease their plasma phenylalanine (Phe)
      concentrations after a 6R-tetrahydrobiopterin (BH(4)) challenge. The majority of
      these patients have mild PKU or MHP (mild hyperphenylalaninemia) and harbour at
      least one missense mutation in the PAH gene associated with this phenotype. The
      rate of decrease and the lowest achieved Phe level vary between patients with
      different genotypes but appears to be similar in patients with the same genotype.
      A number of the mutations associated with BH(4)-responsiveness have been studied
      in an 'in vitro' eukaryotic cell expression system leading to biosynthesis of a
      mutant PAH enzyme with some residual activity. Patients bearing mutations that
      cause severe structural distortion in the expressed protein (loss of function
      mutations), leading to undetectable PAH activity, are not responsive to BH(4).
      These observations suggest that residual PAH activity (in vitro) is a
      prerequisite for BH(4)-responsiveness. However, an in vitro residual PAH activity
      is not a guarantee for in vivo BH(4)-responsiveness. Mechanisms behind this
      responsiveness could be relieve of decreased binding affinity for BH(4), BH(4)
      mediated increase of PAH gene expression or stabilization of the mutant enzyme
      protein by BH(4). BH(4)-responsive PAH-deficient patients have only been reported
      since 1999. For the western countries this is explained by the fact that the
      manufacturer changed the diastereoisomeric purity of the BH4 preparation from 69%
      of the natural 6R-BH4 (31% of 6S-BH4) to 99.5% 6R-BH4. The new findings on BH(4)
      responsiveness may be of clinical relevance because these patients can be treated
      with BH(4) with concomitant relief or withdrawal of the burdensome PKU diet.
      These observations warrant further clinical studies to assess efficacy, optimal
      dosage, and safety of BH(4) treatment in this group. The data strongly emphasize
      the necessity of the BH(4) loading test in patients detected in the newborn PKU
      screening.

PMID- 12618082
TI  - Glutaric aciduria I: creatine supplementation restores creatinephosphate levels
      in mixed cortex cells from rat incubated with 3-hydroxyglutarate.
AB  - The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still
      unclear. Some evidence exists for compromised energy generation in the brain of
      patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have
      shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed
      cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH
      glut) for 24h. In the present study we measured cellular contents of high energy
      phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a
      24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut
      specifically led to a reduction of CP content in a dose-dependent manner, whereas
      concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP
      concentration could be prevented by preincubation with the non-competitive NMDA
      receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor
      associated ion channels may be opened due to a lack of energy inside the neurons
      caused by a reduction of CP. This is followed by membrane depolarization which
      could impair electrogenic creatine transport into the cell.

PMID- 12618081
TI  - Real time PCR assays to detect common mutations in the biotinidase gene and
      application of mutational analysis to newborn screening for biotinidase
      deficiency.
AB  - Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism
      caused by defects in the biotinidase gene. Symptoms of biotinidase deficiency are
      resolved or prevented with oral biotin supplementation and as such newborn
      screening is performed to prospectively identify affected individuals prior to
      the onset of symptoms. Biotinidase deficiency is detected by determining the
      activity of the biotinidase enzyme utilizing the newborn dried blood spot and
      colorimetric end point analysis. While newborn screening by enzyme analysis is
      effective, external factors may compromise results of the enzyme analysis and
      difficulty is encountered in distinguishing between complete and partial enzyme
      deficiencies. In the United States, the four mutations most commonly associated
      with complete biotinidase deficiency are c98:d7i3, Q456H, R538C, and the double
      mutation D444H:A171T. Partial biotinidase deficiency is almost universally
      attributed to the D444H mutation. To more effectively distinguish between
      profound and partial biotinidase deficiency, a panel of assays utilizing real
      time PCR and melting curve analysis using Light Cycler technology was developed.
      Employing DNA extracted from the original dried blood specimens from newborns
      identified through prospective newborn screening as presumptive positive for
      biotinidase deficiency, the specimens were analyzed for the presence of the five
      common mutations. Using this approach it was possible to separate newborns with
      partial and complete deficiency from each other as well as from many of those
      with false positive results. In most cases it was also possible to correlate the
      genotype with the degree of residual enzyme activity present. In newborn
      screening for biotinidase deficiency, we have shown that the analysis of common
      mutations is useful in distinguishing between partial and complete enzyme
      deficiency as well as improving specificity. Combining biotinidase enzyme
      analysis with genotypic data also increases the sensitivity of screening for
      biotinidase deficiency and provides information useful to clinicians earlier than
      would otherwise be possible.

PMID- 12618083
TI  - Characterization of fatty acid oxidation in human muscle mitochondria and
      myoblasts.
AB  - The mitochondrial oxidation of fatty acids (FAO) is the main energy-producing
      pathway in skeletal and cardiac muscle. Starting from standard muscle biopsies
      (100-200mg), we determined the optimal conditions of mitochondrial oxygen
      consumption by the FAO pathway, and in parallel we performed the isolation and
      primary culture of muscle cells to test their cellular FAO capacities. The
      determinations of maximal beta-oxidation rates in the presence of palmitoyl-CoA
      or palmitoyl-L-carnitine (mean+/-SEM: 32.5+/-2.0 and 34.1+/-1.3nmol O(2) min(-1)
      mg(-1) protein, n=16, respectively) provide a screening method of mitochondrial
      fatty acid transport system and intra-mitochondrial beta-oxidation. We also
      determined the conditions of tritiated palmitate oxidation by human myoblasts
      (mean+/-SEM: 6.6+/-0.1nmol 3H fatty acid h(-1) mg(-1) protein, n=8), and show
      that beta-oxidation defects can be detected in our experiments. Overall, we
      propose an original laboratory test to investigate FAO in human skeletal muscle
      and to screen for FAO disorders in myopathies and cardiomyopathies in human.

PMID- 12618084
TI  - Expression pattern and biochemical characteristics of a major epidermal retinol
      dehydrogenase.
AB  - The biological functions of vitamin A in the epidermis are mediated by all-trans
      retinoic acid, which is biosynthesized from retinol in two oxidative reactions.
      The first step involves enzymatic conversion of retinol to retinaldehyde. The
      physiological significance and relative contributions of the various retinol
      dehydrogenases to the oxidation of retinol in epidermal cells remain unclear. We
      report the characterization of a retinol dehydrogenase/reductase of the SDR
      superfamily, hRoDH-E2, which is abundantly expressed in the epidermis, epidermal
      appendages and in cultured epidermal keratinocytes. Both in live keratinocytes
      and in isolated keratinocyte microsomes, where the enzyme normally localizes,
      hRoDH-E2 functions as a bona fide retinol dehydrogenase. In the prevailing
      oxidative reaction it recognizes both free- and CRBP-bound retinol, and shows
      preference toward NADP as a co-substrate. In comparison, hRoDH-E2 retinol
      dehydrogenase activity in the simple epithelial HEK 293 cells is much lower and
      in CHO cells is non-existent. hRoDH-E2 transcripts are distributed throughout the
      epidermal layers but are more abundant in the basal cells. In contrast, the
      protein is detected predominantly in the basal and the most differentiated living
      layers. Its synthesis is negatively regulated by retinoic acid. The biochemical
      properties and the differential expression of hRoDH-E2 in the strata where
      retinoic acid signaling is critical for epidermal homeostasis support a
      conclusion that hRoDH-E2 bears the characteristics of the major microsomal
      retinol dehydrogenase activity in the epidermal keratinocytes in physiological
      circumstances.

PMID- 12618085
TI  - A C-reactive protein promoter polymorphism is associated with type 2 diabetes
      mellitus in Pima Indians.
AB  - Linkage analysis has identified a susceptibility locus for type 2 diabetes
      mellitus (T2DM) on chromosome 1q21-q23 in several populations. Results from
      recent prospective studies indicate that increased levels of C-reactive protein
      (CRP), a marker of immune system activation, are predictive of diabetes,
      independent of adiposity. Because CRP is located on 1q21, we considered it a
      potential positional candidate gene for T2DM. We therefore evaluated CRP and the
      nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as
      candidate diabetes susceptibility genes. Approximately 10.9kb of the CRP-APCS
      locus was screened for polymorphisms using denaturing high performance liquid
      chromatography and direct sequencing. We identified 27 informative polymorphisms,
      including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion,
      which were divided into 7 linkage disequilibrium clusters. We genotyped
      representative SNPs in approximately 1300 Pima samples and found a single variant
      in the CRP promoter (SNP 133552) that was associated with T2DM (P=0.014), as well
      as a common haplotype (CGCG) that was associated with both T2DM (P=0.029) and
      corrected insulin response, a surrogate measure of insulin secretion in non
      diabetic subjects (P=0.050). Linkage analyses that adjusted for the effect of
      these polymorphisms indicated that they do not in themselves account for the
      observed linkage with T2DM on chromosome 1q. However, these findings suggest that
      variation within the CRP locus may play a role in diabetes susceptibility in Pima
      Indians.

PMID- 12618086
TI  - In silico searching of human and mouse genome data identifies known and unknown
      HNF1 binding sites upstream of beta-cell genes.
AB  - HNF1-alpha is a transcription factor present in beta-cells. Mutations in the HNF1
      alpha gene cause maturity-onset diabetes of the young (MODY), but the exact
      mechanism is not known. Several studies have highlighted genes down-regulated in
      beta-cells lacking this gene, but it is not clear if these are directly regulated
      by HNF1-alpha. To better understand this, we used human and mouse genome data to
      examine 29 genes expressed in the beta-cell. Using an in silico approach (with
      software available at www.BindGene.org) we examined 2kb upstream of each gene for
      possible HNF1 binding sequences. In five genes we also examined 100kb upstream of
      each gene, but only the portions strongly conserved between humans and mice. We
      identified nine putative HNF1 binding sites upstream of seven genes (p<0.1 and
      good alignment between species or p<0.05). Six of these nine sites had some
      experimental corroboratory evidence and included the recently identified sites 6
      and 45kb upstream of HNF4-alpha. Three novel sites were identified. These were
      92bp upstream of SLC3A1, 52bp upstream of PCBD (DCOH), and 42202bp upstream of
      TCF2(HNF1-beta). In conclusion, our computer search identified some known HNF1
      sites, and suggested three novel sites indicating these genes are very likely to
      be directly activated by HNF1. This should help in designing experiments to
      discover the mechanisms of beta-cell dysfunction due to HNF1 disruption.

PMID- 12618087
TI  - New polymorphic sites within ornithine transcarbamylase gene: population genetics
      studies and implications for diagnosis.
AB  - Ornithine transcarbamylase (OTC) deficiency, transmitted as an X-linked trait, is
      the most common disorder of the urea cycle. At least 3.5% out of more than 230
      mutations consist of large gene deletions, involving one or more exons. Only in
      78% of OTC patients the diagnosis was confirmed on DNA level. We analysed OTC
      intragenic polymorphisms and haplotypes, in an attempt to contribute to the
      clarification of unresolved cases, in three populations (Czech, Portuguese, and
      Mozambican) and identified six novel nucleotide changes, all of them occurring
      with frequency higher than 12.5% in Europeans. Five of these polymorphisms occur
      with a significant frequency also in Africans. The number and frequency of
      haplotypes defined with the newly reported markers differ in individual
      populations.

PMID- 12618088
TI  - A novel point mutation (I137T) in the conserved 5-phosphoribosyl-1-pyrophosphate
      binding motif of hypoxanthine-guanine phosphoribosyltransferase (HPRTJerusalem)
      in a variant of Lesch-Nyhan syndrome.
AB  - We identified a novel point mutation (I137T) in the hypoxanthine-guanine
      phosphoribosyltransferase (HPRT; EC 2.4.2.8) encoding gene, in a patient with
      partial deficiency of the enzyme (variant of Lesch-Nyhan syndrome). The mutation,
      ATT to ACT, resulting in substitution of isoleucine to threonine, occurred at
      codon 137 (exon 6), which is within the region encoding the binding site for 5
      phosphoribosyl-1-pyrophosphate (PRPP). We suggest the mechanism by which the
      mutation-induced structural alteration of HPRT reduced the affinity of the enzyme
      for PRPP.

PMID- 12618089
TI  - Effects of surface nonuniformity and molecular association on mechanism of
      butanol adsorption from solution.
AB  - The paper presents the results of calorimetric measurements and surface excess
      adsorption isotherms for n-butanol adsorption from n-hexane on a series of
      controlled porosity glasses characterized by different mean pore diameters. It is
      demonstrated that, in the region of very low alcohol concentration in solution,
      the heat of adsorption exhibits sharp maximum, independently of the pore diameter
      of adsorbent. This rather puzzling result is explained by the heterogeneity of
      the surface and the effects of molecular association of alcohol molecules in the
      solution. A simple theoretical model that supports our predictions is presented.

PMID- 12618090
TI  - Kinetics of adsorption of polyvinylamine on cellulose fibers. I. Adsorption from
      salt-free solutions.
AB  - Adsorption of fully hydrolyzed polyvinylamine on cellulose fibers in the short
      term was investigated by supplying the polymer to the fibers, first
      instantaneously by pouring the polymer solution into a jar containing the fiber
      dispersion (jar experiments) and second, at controlled rates (the reactor
      experiments). In the latter case, the rate of supply of polymer to the fiber
      dispersion confined in the reactor was monitored by setting the concentration of
      the solution being injected at a controlled rate. The concentration of the
      polymer solution exerts a paramount influence on the kinetics of adsorption and
      on the amount of polymer adsorbed at (or near) fiber surface saturation, while
      the rate of polymer supply only plays a minor role. The main observation is the
      emergence of two types of polymer layers corresponding to diffuse and dense
      layers. The former were characterized by adsorption layers of density smaller
      than 0.65 mg/g cellulose that are composed of adsorbed polymers having sustained
      extended flattening in the adsorbed state. The latter reach densities as high as
      10 mg/g cellulose when the fiber surface is fully coated, thus indicating that
      reconformation is limited or even impeded at short terms. The threshold
      adsorption corresponds more or less to equilibrated layers, since the final
      coverage determined at adsorption equilibrium did not exceed 0.6 to 0.7 mg/g
      cellulose.

PMID- 12618091
TI  - Kinetics of adsorption of polyvinylamine on cellulose fibers. II. Adsorption from
      electrolyte solutions.
AB  - Adsorption from electrolyte solutions of fully hydrolyzed polyvinylamine on
      cellulose fibers was investigated by supplying the polymer to the fibers at
      controlled rate. This was implemented by employing a reactor only open to the
      fluid in which the fiber dispersion were confined and homogenized. The adsorbed
      layers may be defined as diffuse or dense layers. Diffuse layers are
      characterized by a surface coverage limited to 0.65 mg/g cellulose in salt-free
      solutions. Addition of NaCl or CaCl(2) to the fiber dispersion and the polymer
      solution promotes the adsorption rate and increases the amount of adsorption to
      1.5 mg/g cellulose. For dense polymer layers, for which the coverage amounts to
      values close to 10 mg/g cellulose in salt-free systems, addition of electrolyte
      does not change the kinetic and adsorption characteristics. Insofar as the
      variation of the molecular areas of the polymer within the diffuse layers as a
      function of the ionic strength parallels the variation of the molecular
      characteristics of solute molecules, the formation of diffuse layers is expected
      to proceed by random deposition of solute molecules which later individually
      sustain strong reconformation. Adsorption isotherms show a limited influence of
      the ionic strength. Obviously, the passage from dense layers of high surface
      coverage to low adsorption values at equilibrium requires extended reconformation
      of adsorbed macromolecules and desorption of a great part of the molecules
      already adsorbed.

PMID- 12618092
TI  - Consolidation behavior in sedimentation of TiO(2) suspensions in the presence of
      electrolytes.
AB  - The consolidation of TiO(2) suspensions (anatase and rutile) due to gravity
      sedimentation in the presence of electrolytes has been investigated as a function
      of pH. Sodium and barium nitrate were used as flocculating electrolytes. The
      particle interaction was related to the zeta potential and the thickness of the
      electrical double layer, kappa(-1), by utilizing the repulsive barrier in the
      classical DLVO theory. The stability of the suspensions was represented as the
      average final solids content of the sediment cake, phi(fin). The batch
      sedimentation process was followed by scanning the sample cell with X-rays, from
      which the solids content and the particle size were calculated. Generally, dense
      sediments, with phi(fin) up to volume fractions of 0.5, were found for stable
      suspensions. Flocculated suspensions produced sediments with low phi(fin). The
      phi(fin) was observed to increase linearly with increasing repulsive barrier.
      However, at pH values only slightly higher than the isoelectric point (pH(iep))
      the phi(fin) remained low until it returned to linearity at a pH much higher than
      pH(iep). This was attributed to the stronger affinity of sodium than of nitrate
      for the particle surface, which may be explained by the higher negative hydration
      energy of sodium. The stronger affinity of sodium was also shown as unsymmetrical
      distribution of phi(fin) around pH(iep), with stronger flocculation at
      pH>pH(iep). The interpretation of phi(fin) as a function of the repulsive barrier
      (or kappa(-1)) also made it possible to distinguish between the adsorption
      mechanisms of ions from solution. Addition of electrolyte at a fixed low and high
      pH (surface positively and negatively charged, respectively) clearly showed the
      specificity in adsorption and consequent flocculation of the barium ion from the
      indifferent nitrate. Sodium was, however, again observed to flocculate the TiO(2)
      suspensions slightly more strongly than nitrate.

PMID- 12618093
TI  - Preparation of silver nanocrystals in the presence of aniline.
AB  - The preparation and characterization of silver nanocrystals by chemical reduction
      of silver ions in the presence of aniline using hydrazine monohydrate
      (N(2)H(4).H(2)O) or sodium citrate as the reducing agent are described. A high
      yield of aniline-derivatized hexagonal silver nanoparticles is obtained by the
      reduction of Ag(2)SO(4) with N(2)H(4).H(2)O. An alternative strategy is the
      reduction of Ag(+) by citrate in the presence of aniline, by which the size and
      morphology of the Ag nanocrystals can be controlled to a certain degree by
      changing the concentration ratio of aniline to Ag(+). It is believed that the
      amount of aniline added in the starting solutions for the preparation influences
      the morphology of the Ag nanoparticles. In addition, the long Ag nanorods with a
      high mean aspect ratio are prepared in the presence of aniline at a low
      concentration or o-anisidine.

PMID- 12618094
TI  - Electrophoretic mobility of a charged cylindrical colloidal particle covered with
      an ion-penetrable uncharged polymer layer.
AB  - Expressions are derived for the electrophoretic mobility of a cylindrical charged
      colloidal particle carrying a low zeta potential covered with an ion-penetrable
      uncharged polymer layer in an electrolyte solution. These expressions involve
      numerical integration of modified Bessel functions but are easily calculable with
      Mathematica. The obtained mobility expressions are a modification of Henry's
      mobility formula for a cylindrical particle taking into account the presence of
      the uncharged polymer layer.

PMID- 12618095
TI  - Crystallographic rearrangement of platinum induced by square wave potentials.
AB  - This paper provides experimental evidences of crystalline rearrangements on
      platinum surfaces by applying square wave potential perturbations. The phenomenon
      was followed by differential ex situ X-ray diffraction patterns and in situ
      cyclic voltammetry in sulfuric acid solutions. Various upper and lower potential
      limits were employed covering anion, hydrogen, and/or oxygen adsorption ranges.
      When the -0.05 to 1.50 V (vs. reversible hydrogen) potential region is covered an
      increase in the distribution of (200) planes is observed. However, when the 0.65
      to 1.50 V region is used, (220), (311), and (420) planes developed. The
      development of a longitudinal propagation mode is responsible for this
      rearrangement. The new equilibrium position of the platinum surface atoms in the
      lattice was calculated from the minimization of the potential energy expression.

PMID- 12618096
TI  - Analysis of electroosmotic flow with step change in zeta potential.
AB  - The term electroosmotic flow refers to the bulk flow of an aqueous solution
      induced by the application of the electric field to the zeta potential. The
      characteristics of EOF in a microchannel depend upon the nature of the zeta
      potential, i.e., whether it is uniform or nonuniform. In this study, the full
      Navier-Stokes equation and the Nernst-Planck equation are used to model the
      change in EOF characteristics that occur when a step change in zeta potential is
      applied. It is found that the thickness of the electrical double layer gradually
      increases downstream from the location at which the zeta potential is increased.
      The results indicate that a step change in zeta potential causes a significant
      variation in the velocity profile and in the pressure distribution.

PMID- 12618097
TI  - Atomic-scale scanning tunneling microscopy study of plasma-oxidized ultrahigh
      modulus carbon fiber surfaces.
AB  - In the present work, scanning tunneling microscopy (STM) was employed to study
      the surface modification of ultrahigh modulus carbon fibers at the atomic level
      by oxygen plasma. As detected by STM, the distinctive feature of the fresh,
      untreated surface was the general presence of atomic-scale arrangements in
      different degrees of order (from atomic-sized spots without a clearly ordered
      disposition to triangular patterns identical to those typical of perfect
      graphite). Following fiber exposure to the plasma, the STM images showed evidence
      of the abstraction of carbon atoms from random locations on the fiber surface,
      giving rise to the development of defects (i.e., structural disorder), which in
      turn were the places where oxygen could be introduced during and after the plasma
      etching. It was observed that the most effective treatments in terms of extent of
      surface structural modification (disordering) and uniform introduction of oxygen
      were those carried out for just a few ( approximately 3) minutes. Considerably
      shorter exposures failed to provide a homogeneous modification and many locations
      on the fiber surface remained unaltered, retaining their original atomic-scale
      order, whereas longer treatments did not bring about further structural changes
      to the surface and only led to fiber consumption. These results are consistent
      with previous X-ray photoelectron spectroscopy measurements on these fibers and
      provide an atomic-level understanding of the saturation effect observed in the
      surface oxygen concentration of this and other types of carbon fibers with plasma
      oxidation. Such understanding may also prove helpful for the accurate control and
      optimization of fiber-matrix interaction in composite materials.

PMID- 12618098
TI  - Electrophoresis in a non-Newtonian fluid: sphere in a spherical cavity.
AB  - The electrophoretic behavior of a sphere in a non-Newtonian fluid is investigated
      theoretically by analyzing the phenomenon that occurs in a spherical cavity under
      the condition of a weak applied electrical field. Non-Newtonian behavior in the
      liquid phase may be due to, for example, the addition of polymer to a colloidal
      dispersion to improve its stability. It may also arise from the increase in the
      volume fraction of the dispersed phase such as the slurry used in chemical
      mechanical polishing. A Carreau model is adopted to characterize the shear
      thinning behavior of the liquid phase. We show that the difference between the
      mobility of the particle based on the present model and that based on the
      corresponding Newtonian fluid increases with the decrease in the thickness of a
      double layer. The shear-thinning nature of the liquid phase has the effect of
      increasing the mobility.

PMID- 12618099
TI  - The primary electroviscous effect, free solution electrophoretic mobility, and
      diffusion of dilute prolate ellipsoid particles (minor axis = 3 nm) in monovalent
      salt solution.
AB  - The principal objective of the present work is the modeling of the primary
      electroviscous effect of charged prolate ellipsoid models of low axial ratio.
      Other transport properties examined include (free solution) electrophoretic
      mobilities and translational diffusion constants. A numerical boundary element
      method is employed to solve the coupled Poisson, low Reynolds number Navier
      Stokes, and ion transport equations. The methodology is first applied to the
      primary electroviscous effect of spheres with a centrosymmetric charge
      distribution and excellent agreement with independent theory is obtained.
      Specific model studies are also carried out for prolate ellipsoid models with
      axial ratios less than 4 and a minor axis equal to 3 nm. Most studies are carried
      out in aqueous NaCl solution (2 to 50 mM) at 20 degrees C for a range of
      different particle charges, although limited results are also presented in LiCl
      and KCl solution. The primary electroviscous effect for weakly charged prolate
      ellipsoids is smaller than that of a sphere under similar conditions. These
      studies are also carried out at high absolute particle charge. A comparison is
      made between the primary electroviscous effect and electrophoretic mobilities of
      prolate ellipsoids and corresponding spherical models.

PMID- 12618100
TI  - Fusion of small unilamellar vesicles onto laterally mixed self-assembled
      monolayers of thiolipopeptides.
AB  - Monolayers of the thiolipopeptide NH(2)-Cys-Ala-Ser-Ala-Ala-Ser-Ser-Ala-Pro-Ser
      Ser-(Myr)Lys(Myr)-OH (III) were formed on gold surfaces by self-assembly, mixed
      with a lateral spacer of the same peptide composition, NH(2)-Cys-Ala-Ser-Ala-Ala
      Ser-Ser-Ala-Pro-Ser-Ser-Lys-OH (I). Different mixing ratios were employed ranging
      from 0.1 to 1, corresponding to 10-100% thiolipopeptide. These self-assembled
      monolayers (SAMs) were then exposed to a suspension of liposomes with the aim of
      forming lipid bilayers as a function of the mixing ratio. A clear optimum with
      respect to homogeneity and electrical properties of the membranes was obtained in
      the middle region (0.5) of mixing ratio, as revealed by surface plasmon resonance
      spectroscopy, impedance spectroscopy, and fluorescence microscopy. The
      combination of these methods was shown to be a powerful tool, although a true
      lipid bilayer was not obtained. Instead, vesicle adsorption was shown to be the
      predominant process, and FRAP (fluorescence recovery after photobleaching)
      measurements showed that the films were not fluid on the micrometer length scale.

PMID- 12618101
TI  - Computation of dynamic adsorption with adaptive integral, finite difference, and
      finite element methods.
AB  - Analysis of diffusion-controlled adsorption and surface tension in one
      dimensional planar coordinates with a finite diffusion length and a nonlinear
      isotherm, such as the Langmuir or Frumkin isotherm, requires numerical solution
      of the governing equations. This paper presents three numerical methods for
      solving this problem. First, the often-used integral (I) method with the
      trapezoidal rule approximation is improved by implementing a technique for error
      estimation and choosing time-step sizes adaptively. Next, an improved finite
      difference (FD) method and a new finite element (FE) method are developed. Both
      methods incorporate (a). an algorithm for generating spatially stretched grids
      and (b). a predictor-corrector method with adaptive time integration. The
      analytical solution of the problem for a linear dynamic isotherm (Henry isotherm)
      is used to validate the numerical solutions. Solutions for the Langmuir and
      Frumkin isotherms obtained using the I, FD, and FE methods are compared with
      regard to accuracy and efficiency. The results show that to attain the same
      accuracy, the FE method is the most efficient of the three methods used.

PMID- 12618102
TI  - Quadrature method of moments for aggregation-breakage processes.
AB  - Investigation of particulate systems often requires the solution of a population
      balance, which is a continuity statement written in terms of the number density
      function. In turn, the number density function is defined in terms of an internal
      coordinate (e.g., particle length, particle volume) and it generates integral and
      derivative terms. Different methods exist for numerically solving the population
      balance equation. For many processes of industrial significance, due to the
      strong coupling between particle interactions and fluid dynamics, the population
      balance must be solved as part of a computational fluid dynamics (CFD)
      simulation. Such an approach requires the addition of a large number of scalars
      and the associated transport equations. This increases the CPU time required for
      the simulation, and thus it is clear that it is very important to use as few
      scalars as possible. In this work the quadrature method of moments (QMOM) is
      used. The QMOM has already been validated for crystal growth and aggregation;
      here the method is extended to include breakage. QMOM performance is tested for
      10 different cases in which the competition between aggregation and breakage
      leads to asymptotic solutions.

PMID- 12618103
TI  - Tubular microstructures made from nonchiral single-chain fluorinated amphiphiles:
      impact of the structure of the hydrophobic chain on the rolling-up of bilayer
      membrane.
AB  - The nonchiral, single-chain fluorinated amphiphiles derived from
      dimorpholinophosphate, C(n)F(2n+1)(CH(2))(m)OP(O)[N(CH(2)CH(2))(2)O](2)
      (FnCmDMPs), form hollow tubular bilayer-based self-assemblies when dispersed in
      water, ethanol/water mixtures, and dimethylformamide. The fluorinated tubules are
      highly stable and sturdy. Upon heating, they transform reversibly into giant
      multilamellar vesicles. Uncommon U-shaped and V-shaped coiled membranes were
      obtained from mixtures of FnCmDMPs. Depending on conditions, fluorinated tubules
      can evolve with time into collapsed flattened crystallized needles. The
      successive steps involved in the formation and evolution of these tubules were
      identified, and the specific features of fluorinated chains that are relevant to
      membrane coiling and tubule formation are discussed.

PMID- 12618104
TI  - Formation of fluorinated nonionic surfactant microemulsions in hydrofluorocarbon
      134a (HFC 134a).
AB  - A structurally related series of fluorinated nonionic oxyethylene glycol
      surfactants of the type C(m)F(2m+1)(CH(2))(n)O[(CH(2)CH(2)O)(p)H], denoted
      C(m.n)E(p) (where m=4, 6, or 7, m=1 or 2, and p=4 or 6) were synthesized and
      their surface behavior in aqueous solution was characterized. The ability of
      these surfactants to form water-in-hydrofluorocarbon (HFC) propellant 134a
      microemulsions suitable for use in the aerosolized delivery of water-soluble
      drugs has been investigated. Phase studies showed that, regardless of the
      composition used, clear one-phase systems could not be prepared if a fluorinated
      nonionic surfactant was used alone, or in combination with a short or medium
      fluorocarbon alcohol cosurfactant. Clear one-phase systems could, however, be
      prepared if a short-chain hydrocarbon alcohol, such as ethanol, n-propanol, or n
      pentanol, was used as cosurfactant, with the extent of the one-phase region
      increasing with decreased chain length of the alcohol cosurfactant. Light
      scattering studies on a number of the hydrocarbon-alcoholcontaining systems in
      the propellant-rich part of the phase diagram showed that only systems prepared
      with C(4.2)E(6) and propanol contained microemulsion droplets (all other systems
      investigated were considered to be cosolvent systems).

PMID- 12618105
TI  - Fluorinated ionic surfactant microemulsions in hydrofluorocarbon 134a (HFC 134a).
AB  - The factors influencing the formation of water-in-134a-propellant microemulsions
      using the fluorinated ionic surfactants ammonium perfluorooctanoate, ammonium
      perfluoroheptanoate, and sodium perfluorooctanoate has been determined. None of
      the fluorinated ionic surfactants could be used to prepare clear, one-phase
      systems when used as sole surfactant, but they could be when combined with a
      short-chain fluoro- or hydrocarbon alcohol in surfactant:cosurfactant weight
      mixing ratios (K(m)) in the range 1:2 to 2:1. When hydrocarbon alcohols were used
      this clear region extended over a wide range of compositions and was confirmed by
      means of photon correlation spectroscopy (PCS) to contain microemulsion droplets
      in the propellant-rich part of the phase diagram. PCS studies performed in the
      presence of the water-soluble drug terbutaline sulfate showed that it was
      possible to solubilize the drug within water-in-propellant microemulsion
      droplets. These studies confirm for the first time that it is possible to prepare
      water-in-propellant 134a microemulsions using fluorinated ionic surfactants and
      to solubilize water-soluble drugs within these systems.

PMID- 12618106
TI  - Spectroscopic probing of the effect of alkanols on the properties of the head
      group region in reverse micelles of AOT-heptane-water.
AB  - The effects of addition of alkanols (ethanol, n-hexanol, and 3-ethyl-3-pentanol)
      on the micropolarity and microviscosity of the head group region in reverse
      micelles of AOT-heptane-water have been investigated by fluorescence probing
      methods (ANS fluorescence yield and TMADPH fluorescence anisotropy), complemented
      by the use of the solvatochromic probe E(T)(30) in absorption spectroscopy. For
      all the alkanols considered, ANS fluorescence in AOT reverse micelles (at W=3) is
      quenched by additive incorporation, being the effect elicited almost independent
      of the alkanol chain length and topology. As sensed by the E(T)(30) parameter,
      the micropolarity of the micelle surface increases, remains unmodified, and
      decreases upon addition of ethanol, 3-ethyl-3-pentanol, and hexanol,
      respectively. While ethanol barely modifies the fluorescence anisotropy of
      TMADPH, 3-ethyl-3-pentanol and n-hexanol addition strongly decrease it. The
      similarity of the tendencies of ANS data to TMADPH anisotropies and the
      differences between ANS data and E(T)(30) values would indicate that, at least
      for 3-ethyl-3-pentanol and n-hexanol, microviscosity, rather than micropolarity,
      must be considered to interpret the effect of the alkanols upon the fluorescent
      behavior of ANS.

PMID- 12618107
TI  - Micellization of economically viable surfactants in CO(2).
AB  - Stability and aggregation structures of various economically viable surfactants
      for CO(2) are reported. The compounds are either commercially available
      octylphenol nonionics (Triton X-100, X-100 reduced, and X-45) or custom-made
      analogues of aerosol-OT (J. Am. Chem. Soc. 123 (2001) 988). These were selected
      to reveal the influence of chain terminal group structure, namely highly
      methylated t-butyl units, on solubility and aggregation in CO(2). In addition the
      mean ethylene oxide block length is varied for the Triton surfactants (X-100
      approximately EO(10), X-45 approximately EO(8)). High-pressure small-angle
      neutron scattering (SANS) experiments revealed the presence of aggregates,
      consistent with spheroidal reverse micelles. The nonionics show a temperature and
      pressure dependence on solubility. These results confirm the special affinity of
      highly methyl-branched tails for CO(2). However, none of these systems were able
      to disperse significant amounts of water or brine; therefore hydrated reversed
      micelles or microemulsion droplets were not stabilized. Hence the utility of
      these cheap methyl-branched surfactants in CO(2) is limited, and so groups of
      greater CO(2)-philicity are needed to achieve the goal of water-hydrocarbon
      surfactant-CO(2) dispersions.

PMID- 12618108
TI  - Cloud point temperature of polyoxyethylene-type nonionic surfactants and their
      mixtures.
AB  - The cloud point temperature, T(c), was investigated for aqueous solutions of
      poly(oxyethylene) alkyl ethers, C(n)E(m), and their mixtures. The experimental
      T(c)'s for single surfactant systems were analyzed according to the Flory-Huggins
      model for cloud point phenomenon, and the enthalpy and the entropy changes
      associated with the process of the separation of micellar solution into pure
      water and pure surfactant were estimated. It was found that the enthalpy-entropy
      compensation relationship holds for this process. The Flory-Huggins model was
      extended to the binary surfactant mixtures, and the expression of T(c) as a
      function of the composition was derived assuming the regular solution for mixed
      micelles. The experimental results of T(c) obtained for mixtures of C(n)E(m) were
      well reproduced by the model calculation. Discussion is given concerning the
      interaction parameters of different surfactant species in mixed micelles
      determined by this model calculation.

PMID- 12618109
TI  - Measurement of emulsion droplet sizes using PFG NMR and regularization methods.
AB  - The droplet size distributions of emulsions have been measured using pulsed field
      gradient (PFG) nuclear magnetic resonance (NMR) for many years. This technique
      finds particular application with emulsions that are concentrated and/or opaque,
      since such emulsion systems are difficult to characterize by other methods. Most
      studies employing PFG techniques assume a lognormal form when extracting the
      droplet size distribution from the experimental data. It is clearly desirable to
      retrieve a droplet size distribution from the experimental data without assuming
      such a functional form. This is achieved for the first time using regularization
      techniques. Regularization based on the distribution area and on its second
      derivative are compared and assessed along with the following techniques for
      selecting the optimal regularization parameter: the L-curve method, generalized
      cross validation (GCV), and the discrepancy principle. Regularization is applied
      to both simulated data sets and experimental data. It is found that when the
      experimental error can be estimated accurately, the discrepancy principle with
      area regularization is the best approach. When the error is not known the GCV
      method, with second derivative regularization and allowing only nonnegative
      values, is most effective.

PMID- 12618110
TI  - An analytical expression for the approximate dependence of the degree of
      counterion binding on the composition of ionic-nonionic mixed micelles.
AB  - A simple analytical expression is presented to describe the dependence of the
      degree of counterion binding beta of ionic-nonionic mixed micelles on the
      composition x(I) (the micelle mole fraction of the ionic species): 1/(1-beta)=1
      x(I)+x(I)/[1-beta(x(I)=1)]. In the application of the relation, the value of beta
      for the pure ionic micelle, beta(x(I)=1), should be known in advance. An
      equivalent expression was first proposed by Hall et al. on purely empirical
      grounds but in the present study the relation is derived on the basis of the
      Poisson-Boltzmann equation of the plate model of micelles in a salt-free medium.
      The insensitive nature of beta toward a change in micelle concentration as well
      as to the addition of a salt is also derived under reasonable approximations.
      When the relation was applied to 12 mixed micelles both with and without added
      salt, it described quite well the observed composition dependencies of all
      examples examined. Two other simple analytical expressions are also derived, but
      they are much less satisfactory in describing the experimental data.

PMID- 12618111
TI  - The effect of triethylenetetraamine (Trien) on the ion flotation of Cu(2+) and
      Ni(2+).
AB  - Ion flotation is a separation process involving the adsorption of a surfactant
      and counterions at an air/aqueous solution interface. It shows promise for
      removing toxic heavy metal ions from dilute aqueous solutions. Here we report the
      effect of a neutral chelating ligand, triethylenetetraamine (Trien), on the ion
      flotation of cations with dodecylsulfate, DS(-), introduced as sodium
      dodecylsulfate, SDS. Ion flotation in the aqueous SD-Cu(II)-Ca(II)-Trien system
      gave strongly preferential removal of Cu(II) over Ca(II), which is a reversal of
      the order of selectivity seen in the SDS-Cu(II)-Ca(II) system containing no
      Trien. The removal rates of Cu(2+) and Ni(2+) with DS(-) were much faster in the
      presence of Trien than for simple aquo ions, and the final metal concentration
      was significantly lower. Surface tension measurements showed that Trien enhanced
      the surface activity and adsorption density for SDS-Cu(II) and SDS-Ni(II)
      solutions. The overall change in the Gibbs free energy for adsorption resulting
      from complexation was -3.60 kJ/mol for Cu(II) and -3.50 kJ/mol for Ni(II). This
      included the effects of hydrophobic interactions between the metal-Trien
      complexes at the air/solution interface, along with changes in the amount of
      dehydration associated with cosorption of the metal-Trien complex with DS(-) at
      the air/solution interface.

PMID- 12618112
TI  - Viscosity of emulsions: influence of flocculation.
AB  - A model has been suggested by Raijinder Pal (J. Colloid Interface Sci. 231 (2000)
      168) that describes experimental data on the viscosity of concentrated emulsions
      reasonably well. To deduce the final equation the author assumed that droplets
      are covered with a layer of surfactant molecules. This means that the effective
      volume of a single emulsion droplet is increased by a factor K>1. It has been
      found that K should vary between 1.166 and 2.070 to fit the experimental data. If
      the drop radii are around 1 microm (for an estimate) then the drops would be
      covered with a layer which thickness should range from 550 A (which is 10 times
      of the size of SDS micelles) to 3570 A. No doubt adsorption of surfactant
      molecules results in an increase of the effective drop radius but not by that
      much. We present an alternative theoretical model for description of the
      viscosity-volume fraction of droplets behavior of emulsions. The model is based
      on the assumption that clusters of drops (doublets, triplets, and so on) are
      formed under the influence of colloidal, hydrodynamic interactions and/or applied
      shear. According to the proposed model clustering determines the volume fraction
      dependency of the effective viscosity of emulsions. Two limiting cases are
      considered: a developed flocculation and a low-flocculated emulsion. In the first
      case the final equation is close to that deduced by Pal; however, the physical
      meaning of the equation is substantially different. Comparison with available
      experimental data shows good agreement with the equations deduced in both the
      cases of a developed flocculation and a low-flocculated emulsion.

PMID- 12618113
TI  - Cross-linked polyvinylpyrrolidone nanoparticles: a potential carrier for
      hydrophilic drugs.
AB  - Injectable hydrogel polymeric nanoparticles of polyvinylpyrrolidone cross-linked
      with N,N'-methylene bis-acrylamide and encapsulating water-soluble macromolecules
      such as FITC-dextran (FITC-Dx) have been prepared in the aqueous cores of reverse
      micellar droplets. These particles are 100 nm and below in diameter with a narrow
      size distribution. When dispersed in aqueous buffer these particles appear to be
      transparent and give an optically clear solution. Lyophilized powder of these
      nanoparticles is redispersable in aqueous buffer without any change in the size
      and morphology of the particles. The efficiency of FITC-Dx entrapment by these
      nanoparticles is high (>70%) and depends on the amount of cross-linking agent
      present in the polymeric material. The release of the entrapped molecules from
      these nanoparticles depends on the degree of cross-linking of the polymer,
      particle size, pH of the medium, and extent of loading, as well as temperature.

PMID- 12618114
TI  - Effect of fluorine plasma treatment on PMMA and their application to passive
      optical waveguides.
AB  - Poly(methylmethacrylate) (PMMA) has been a good prospect for the development of
      fully amorphous and highly transparent microphotonic devices. The possibilities
      of a hot embossing technique for the polymeric fabrication of optical waveguides
      were investigated in this work. A new technique based on radiofrequency plasma
      treatment was studied for thermal and optical properties, including glass
      transition temperature, thermal stability, refractive index, and optical
      transmission loss of PMMA. It is shown that the plasma treatment is effective in
      altering the functional groups of polymer surfaces without affecting the bulk
      properties, resulting in effective control of refractive indices and optical
      transmission losses for photonic applications.

PMID- 12618115
TI  - Synthesis of alkyl sulfonate/alcohol-protected gamma-Fe(2)O(3) nanocrystals with
      narrow size distributions.
AB  - Highly crystalline gamma-Fe(2)O(3) nanoparticles with narrow size distributions
      that are coated with 1-undecanesulfonic acid were synthesized via two distinct
      approaches using oxidation and site-exchange reactions. However, similar
      nanocrystals protected with 1-octanol could only be achieved via the site
      exchange method, while the oxidation approach led to Fe(2)O(3) nanoparticles of
      poor crystallinity and size uniformity. Our magnetization measurements confirmed
      the superparamagnetic nature of our Fe(2)O(3) nanoparticle products and the
      effects of the coating materials on magnetization properties.

PMID- 12618116
TI  - Strong blue-fluorescence-emitted stable monolayers formed in organic solvents by
      a coordination polymer with long-chained bis-Schiff base.
AB  - The coordination polymer, P(ZnL) (L=N,N'-bis[2-hydroxy-4
      (dodecyloxy)benzaldehyde)]-ethylenedimine), forms a novel uniform lamellar
      superstructure in organic liquids, which exhibits intense fluorescence in organic
      dispersions as well as in the corresponding cast films.

PMID- 12618117
TI  - Surface-modified silica colloid for diagnostic imaging.
AB  - A method of preparing nanometer-sized oxide colloids suitable as substance
      carriers for size-sensitive diagnostic imaging and other biomedical applications
      is described. The nanometer-sized silica particles prepared by the Stober process
      were reacted with silane to obtain amine-terminated colloidal surfaces under
      aqueous conditions. The surface-modified colloids can be further treated to
      combine or conjugate with imaging agents and other diagnostic or therapeutic
      substances. The water-stable colloidal carriers are spherical and have a narrow
      size distribution that can be controlled to range from 10 to 200 nm.

PMID- 12618120
TI  - Occurrence of nonconvulsive seizures, periodic epileptiform discharges, and
      intermittent rhythmic delta activity in rat focal ischemia.
AB  - A significant proportion of neurologic patients suffer electroencephalographic
      (EEG) seizures in the acute phase following traumatic or ischemic brain injury,
      including many without overt behavioral manifestations. Although such
      nonconvulsive seizures may exacerbate neuropathological processes, they have
      received limited attention clinically and experimentally. Here we characterize
      seizure episodes following focal cerebral ischemia in the rat as a model for
      brain injury-induced seizures. Cortical EEG activity was recorded continuously
      from both hemispheres up to 72 h following middle cerebral artery occlusion
      (MCAo). Seizure discharges appeared in EEG recordings within 1 h of MCAo in 13/16
      (81%) animals and consisted predominantly of generalized 1-3 Hz rhythmic spiking.
      During seizures animals engaged in quiet awake or normal motor behaviors, but
      exhibited no motor convulsant activity. Animals had a mean of 10.6 seizure
      episodes within 2 h, with a mean duration of 60 s per episode. On average,
      seizures ceased at 1 h 59 min post-MCAo in permanently occluded animals and did
      not occur following reperfusion at 2 h in transiently occluded animals. In
      addition to seizures, periodic lateralized epileptiform discharges (PLEDs)
      appeared over penumbral regions in the injured hemisphere while intermittent
      rhythmic delta activity (IRDA) recurred in the contralateral hemisphere with
      frontoparietal dominance. PLEDs and IRDA persisted up to 72 h in permanent MCAo
      animals, and early onset of the former was predictive of prolonged seizure
      activity. The presentation of these EEG waveforms, each with characteristic
      features replicating those in clinical neurologic populations, validates rat MCAo
      for study of acutely induced brain seizures and other neurophysiological aspects
      of brain injury.

PMID- 12618119
TI  - Excitotoxic lesioning of the rat basal forebrain with S-AMPA: consequent
      mineralization and associated glial response.
AB  - Regional depositions of calcium within the basal ganglia, cortex, cerebellum, and
      white matter and at perivascular sites have been observed in several pathological
      conditions. These generally indicate signs of ongoing apoptosis or necrotic
      processes, whereby the activation of glutamate receptors causes a rise in
      intracellular calcium levels leading to mineralization of neurons, and ultimately
      to cell death. The selective degeneration of cholinergic neurons in the basal
      forebrain is a major neuropathological component of Alzheimer's disease, and may
      result in abnormal deposition of calcium. In experimental models, selective
      lesions of the basal forebrain can be induced by intraparenchymal infusions of
      excito- or immunotoxins targeting cholinergic neurons. Excitotoxic lesions are
      often accompanied by calcium deposition within affected areas. In a previous
      study we also noted the presence of unusual deposition in areas close to the site
      of injections following unilateral S-AMPA-induced lesions of the basal forebrain
      (T. Perry, H. Hodges, and J. A. Gray, 2001, Brain Res. Bull. 54, 29-48). In this
      paper, we have characterized these deposits histologically and evaluated the
      microglial (CD11b) and astrocytic (GFAP) responses at 8 and 16 weeks following
      lesioning of the nucleus basalis magnocellularis with S-AMPA. The resulting
      deposits were heterogeneous in morphology and composed primarily of calcium.
      Small granular deposits were detected around blood vessels, whereas larger
      calcospherites were situated within the parenchyma. These deposits were more
      widely dispersed at 16 weeks postlesioning, affected neighboring nuclei, and
      displayed a progressive increase in size and frequency of occurrence. However,
      calcification within these regions was differentially associated with microglial
      and astrocytic reactivity at the two time points. Both microglial and astrocytic
      responses were pronounced at 8 weeks, whereas at 16 weeks, astrocytic reactivity
      prevailed and the microglial response was markedly attenuated. Importantly, the
      pattern of reactivity for microglia detected at 8 weeks was specifically
      localized to vulnerable nucleated areas prior to their substantial accumulation
      of calcium deposits, which was clearly evident by 16 weeks. We suggest that the
      initial microglial response could be used as a selective predictor of tissue
      necrosis and subsequent calcification, and that astrocytes, which form a glial
      scar in the affected tissues, may contribute toward the buildup of calcium
      deposits. The functional relevance of these findings is discussed.

PMID- 12618121
TI  - BACE1 and BACE2 in pathologic and normal human muscle.
AB  - BACE1 and BACE2 are recently discovered enzymes participating in processing of
      amyloid beta precursor protein (AbetaPP). Their discovery is contributing
      importantly to understanding the mechanism of amyloid-beta generation, and hence
      the pathogenesis of Alzheimer's disease (AD). Sporadic inclusion-body myositis (s
      IBM) and hereditary inclusion-body myopathy (h-IBM) are progressive muscle
      diseases in which overproduction of AbetaPP and accumulation of its presumably
      toxic proteolytic product amyloid-beta (Abeta) in abnormal muscle fibers appear
      to play an important upstream role in the pathogenic cascade. In normal human
      muscle AbetaPP was also shown to be present and presumably playing a role (a) at
      neuromuscular junctions and (b) during muscle development. To investigate whether
      BACE1 and BACE2 play a role in normal and diseased human muscle, we have now
      studied them by immunocytochemistry and immunoblotting in 35 human muscle
      biopsies, including: 5 s-IBM; 5 chromosome-9p1-linked quadriceps-sparing h-IBM;
      and 25 control muscle biopsies. In addition, expression of BACE1 and BACE2 was
      studied in normal cultured human muscle. Our studies demonstrate that BACE1 and
      BACE2 (a) are expressed in normal adult muscle at the postsynaptic domain of
      neuromuscular junctions, and in cultured human muscle; (b) are accumulated in the
      form of plaque-like inclusions in both s-IBM and h-IBM vacuolated muscle fibers;
      and (c) are immunoreactive in necrotizing muscle fibers. Accordingly, BACE1 and
      BACE2 participate in normal and abnormal processes of human muscle, suggesting
      that their functions are broader than previously thought.

PMID- 12618122
TI  - Proton magnetic resonance imaging and spectroscopy identify metabolic changes in
      the striatum in the MPTP feline model of parkinsonism.
AB  - We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult,
      male cats to model Parkinson's disease (PD), and utilized proton magnetic
      resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to
      identify metabolic degenerative changes in the striatum in vivo. Neurologic
      status and somatosensory-evoked potentials in vivo, as well as postmortem
      striatal histopathological and immunohistochemical parameters, were examined.
      Nine cats were equally divided into three groups and treated daily for 10 days as
      follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP.
      The MPTP-treated cats displayed bradykinesia, head tremor, and reduced
      oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted
      signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra
      indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine
      glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had
      low choline-containing compounds/CR ratio, whereas a lactate peak was present in
      all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a
      significant decline of tyrosine hydroxylase immunoreactivity and histological
      evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated
      the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological
      and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive,
      noninvasive measure of neural toxicity and biochemical alteration of the striatum
      in a feline model of PD.

PMID- 12618123
TI  - Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2
      expression in neocortex.
AB  - Recurrent and spontaneous seizures in epilepsy result from poorly defined cell
      signaling aberrations thought to include synaptic and extracellular matrix
      remodeling. Here we have used a rat hippocampal kindling model to study
      cyclooxygenase-2 (COX-2) gene expression in epileptogenesis. COX-2, encoded in an
      early-response gene, increases in a synaptic activity-dependent fashion and also
      during kainic acid-induced hippocampal damage. We found that during kindling, COX
      2 induction occurred initially only in hippocampal neurons, and then spread to
      neocortical neurons. When rats were rekindled 34 days later, this spreading of
      COX-2 expression persisted. Induction of hippocampal and neocortical cytosolic
      phospholipase A(2) (cPLA(2)), an enzyme that catalyzes the synthesis of COX-2
      substrate arachidonic acid (AA), occurred after 4 days of stimulation during
      kindling and rekindling. Moreover the COX-2 selective inhibitor nimesulide
      attenuated kindling development. We conclude that neuronal COX-2 gene induction
      and cPLA(2) activation are key signaling events in epileptogenesis.

PMID- 12618124
TI  - The efficacy of trientine or ascorbate alone compared to that of the combined
      treatment with these two agents in familial amyotrophic lateral sclerosis model
      mice.
AB  - One of the hypotheses regarding the pathogenesis of familial ALS (FALS) is a
      copper-mediated oxidative toxicity derived from the mutant Cu, Zn-superoxide
      dismutase (SOD1). We have previously demonstrated the efficacy of the combined
      treatment with a copper chelator (trientine) and an antioxidant (ascorbate) on
      the disease expression of the FALS-linked mutated SOD1 transgenic mice. Here, we
      investigated the efficacy of trientine or ascorbate alone on FALS mice when
      administered before or after the onset of the disease. The mice with a high dose
      of trientine or ascorbate administered before the onset survived significantly
      longer than the control. In the combined treatment with a high dose of trientine
      and ascorbate initiated before the onset, survival lengthened and the motor
      function of the mice remained more significantly than the control. None of the
      treatments affected the mean age of the onset, and none of the agents
      administered after the onset prolonged survival. These findings suggest that
      better outcomes may be expected by the administration of these agents at the
      preonset stage of the disease, and the combination of the agents acting on
      different sites might be useful in preserving the motor performance in FALS.

PMID- 12618125
TI  - Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons.
AB  - Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely
      employed in the treatment of the autoimmune disease myasthenia gravis. Due to its
      positively charged ammonium group, under normal conditions pyridostigmine cannot
      cross the blood-brain barrier (BBB) and penetrate the brain. However, several
      studies have suggested that under conditions in which the BBB is disrupted,
      pyridostigmine enters the brain, changes cortical excitability, and leads to long
      lasting alterations in gene expression. The aim of this study was to characterize
      the mechanisms underlying pyridostigmine-induced changes in the excitability of
      central neurons. Using whole cell intracellular recordings in hippocampal neurons
      we show that pyridostigmine decreases repetitive firing adaptation and increases
      the appearance of excitatory postsynaptic potentials. In voltage clamp
      recordings, both pyridostigmine and acetylcholine (ACh) increased the frequency
      but not the amplitude of excitatory postsynaptic currents. These effects were
      reversible upon the administration of the muscarinic receptor antagonist,
      atropine, and were not blocked by tetrodotoxin. We conclude that pyridostigmine,
      by increasing free ACh levels, causes muscarinic-dependent enhancement of
      excitatory transmission. This mechanism may explain central side effects
      previously attributed to this drug as well as the potency of AChE inhibitors,
      including nerve-gas agents and organophosphate pesticides, in the initiation of
      cortical synchronization, epileptic discharge, and excitotoxic damage.

PMID- 12618126
TI  - Restorative effects of neurotrophin treatment on diabetes-induced cutaneous axon
      loss in mice.
AB  - Chronic hyperglycemia in diabetes causes a variety of somatosensory deficits,
      including reduced cutaneous innervation of distal extremities. Deficient
      neurotrophin support has been proposed to contribute to the development of
      diabetic neuropathy. Here, studies were carried out in streptozotocin (STZ)
      treated mice to determine whether (1) cutaneous innervation deficits develop in
      response to hyperglycemia, (2) neurotrophin production is altered in the skin,
      and (3) neurotrophin treatment improves cutaneous innervation deficits. Cutaneous
      innervation was quantified in the hindlimb skin using antibodies that label nerve
      growth factor- (NGF) responsive (CGRP), glial cell line-derived neurotrophic
      factor (GDNF)/neurturin (NTN) -responsive (P2X(3)), or all cutaneous axons (PGP
      9.5). Diabetic mice displayed severely reduced cutaneous innervation for all
      three antibodies in both flank and footpad skin regions, similar to reports of
      cutaneous innervation loss in human diabetic patients. Qualitative assessment of
      mRNAs for NGF, GDNF, and NTN demonstrated that these mRNAs were expressed in
      hindlimb flank and footpad skin from diabetic mice. Next, diabetic mice were then
      treated intrathecally for 2 weeks with NGF, GDNF, or NTN. NGF treatment failed to
      improve cutaneous innervation, but stimulated axon branching. In comparison, GDNF
      and NTN treatment increased cutaneous innervation and axon branching. Our results
      reveal that similar to human diabetic patients, STZ-induced diabetes
      significantly reduces hindlimb cutaneous innervation in mice. Importantly,
      intrathecal treatment using GDNF or NTN strongly stimulated axon growth and
      branching, suggesting that administration of these trophic factors can improve
      cutaneous innervation deficits caused by diabetes.

PMID- 12618127
TI  - Increased mu-opioid receptor labeling is found on inner molecular layer terminals
      of the dentate gyrus following seizures.
AB  - The hippocampal formation is a brain region sensitive to seizure development, a
      phenomenon thought to be mediated in part by mu-opioid receptor (MOR) activation.
      Previous studies have found a delayed increase in MOR immunoreactivity (IR) in
      the inner molecular layer (IML) of the dentate gyrus after experimentally induced
      seizures. However, whether these increases in MOR-IR are restricted to certain
      cell types or cellular compartments (i.e., presynaptic, postsynaptic, or glial
      profiles) has not been determined. Thus, the present study examined which
      subcellular profiles demonstrate changes in MOR-IR after kainic acid (KA)-induced
      seizures. Light microscopic (LM) analysis demonstrated seizure-induced increases
      in MOR-IR at three points of the IML (dorsal blade, ventral blade, and crest) at
      three levels of section (septal, mid-septotemporal, and temporal). Electron
      microscopic analysis of the IML revealed that MOR-IR was present in the same
      types of cellular profiles in both control and KA-treated rats. However, a
      significant increase in the number of MOR-labeled terminal profiles was revealed
      in KA-treated rats compared to controls. Additionally, some MOR-labeled terminals
      in KA-treated rats possessed excitatory-type morphology and contained enkephalin
      or dynorphin, peptides found in mossy fiber terminals. These data suggest that
      most of the seizure-induced increases in MOR expression in the IML are associated
      with terminals originating from several different neuronal populations, including
      granule cells, and possibly, surviving GABAergic interneurons, septal
      cholinergic, and/or supramamillary projection neurons.

PMID- 12618128
TI  - The degenerative and regenerative processes after the elimination of the
      proliferative peripheral retina of fish.
AB  - We have analyzed the modifications in the tench (Tinca tinca) retina after the
      complete cryo-elimination of the proliferative growing zone (PGZ), which
      participates in the continuous growth of the retina throughout the life of the
      fish. By using immunohistochemistry and electron microscopy we demonstrated that,
      after the lesion, degenerative and regenerative processes take place in the PGZ,
      in the ciliary zone, and in the transition zone located between the PGZ and the
      central retina. After 120 days postlesion, the PGZ was completely regenerated and
      its composition was similar to that of the control animals. Numerous
      proliferative PCNA-positive cells reappeared and new ganglion cells were formed.
      In the transition zone and the central retina numerous proliferative PCNA
      positive cells also appeared. These are arranged, on occasion, as columnar units
      from the inner to the outer nuclear layer where the rod precursors and the
      progenitor cells, respectively, were located. The Muller cells, closely
      associated with these columnar units, appeared to use them as guides to migration
      during the regenerative process. Notably, modifications occurred in the ciliary
      zone, whose cells acquired similar characteristics to the PGZ cells. The ciliary
      zone cells, the Muller cells, the rod precursors, and the proliferative cells
      located in the inner nuclear layer appear to participate actively in the
      regeneration of the PGZ.

PMID- 12618129
TI  - Mitochondrial DNA from platelets of sporadic ALS patients restores normal
      respiratory functions in rho(0) cells.
AB  - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease,
      which affects the anterior horn cells of the spinal cord and cortical motor
      neurons. A pathophysiological role for mtDNA mutations was postulated based on
      the finding that cybrids obtained from mitochondria of sporadic ALS patients
      exhibited impaired respiratory chain activities, increased free radical
      scavenging enzymes, and altered calcium homeostasis. To date, however, no
      distinct mtDNA alterations associated with ALS have been reported. Therefore, we
      reexamined the hypotheses that mtDNA mutations accumulate in ALS and that cybrids
      generated from ALS patients' blood have impaired mitochondrial respiration.
      Cybrid cell lines were generated from 143B osteosarcoma rho(0) cells and platelet
      mitochondria of sporadic ALS patients or age-matched controls. We found no
      statistically significant differences in mitochondrial respiration between ALS
      and control cybrids, even when the electron transport chain was stressed with low
      concentrations of respiratory chain inhibitors. Mitochondrial respiratory chain
      enzyme activities were also normal in ALS cybrids, and there was no increase in
      free radical production. Therefore, we showed that mtDNA from platelets of ALS
      patients was able to restore normal respiratory function in rho(0) cells,
      suggesting that the presence of mtDNA mutations capable of affecting
      mitochondrial respiration was unlikely.

PMID- 12618130
TI  - Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel
      mechanisms.
AB  - During early vertebrate development, members of the transforming growth factor
      beta (TGFbeta) family play important roles in a variety of processes, including
      germ layer specification, patterning, cell differentiation, migration, and
      organogenesis. The activities of TGFbetas need to be tightly controlled to ensure
      their function at the right time and place. Despite identification of multiple
      regulators of Bone Morphogenetic Protein (BMP) subfamily ligands, modulators of
      the activin/nodal class of TGFbeta ligands are limited, and include follistatin,
      Cerberus, and Lefty. Recently, a membrane protein, tomoregulin-1 (TMEFF1,
      originally named X7365), was isolated and found to contain two follistatin
      modules in addition to an Epidermal Growth Factor (EGF) domain, suggesting that
      TMEFF1 may participate in regulation of TGFbeta function. Here, we show that,
      unlike follistatin and follistatin-related gene (FLRG), TMEFF1 inhibits nodal but
      not activin in Xenopus. Interestingly, both the follistatin modules and the EGF
      motif contribute to nodal inhibition. A soluble protein containing the
      follistatin and the EGF domains, however, is not sufficient for nodal inhibition;
      the location of TMEFF1 at the membrane is essential for its function. These
      results suggest that TMEFF1 inhibits nodal through a novel mechanism. TMEFF1 also
      blocks mesodermal, but not epidermal induction by BMP2. Unlike nodal inhibition,
      regulation of BMP activities by TMEFF1 requires the latter's cytoplasmic tail,
      while deletion of either the follistatin modules or the EGF motif does not
      interfere with the BMP inhibitory function of TMEFF1. These results imply that
      TMEFF1 may employ different mechanisms in the regulation of nodal and BMP
      signals. In Xenopus, TMEFF1 is expressed from midgastrula stages onward and is
      enriched in neural tissue derivatives. This expression pattern suggests that
      TMEFF1 may modulate nodal and BMP activities during neural patterning. In
      summary, our data demonstrate that tomoregulin-1 is a novel regulator of nodal
      and BMP signaling during early vertebrate embryogenesis.

PMID- 12618132
TI  - Ventral axial organs regulate expression of myotomal Fgf-8 that influences rib
      development.
AB  - Fgf-8 encodes a secreted signaling molecule mediating key roles in embryonic
      patterning. This study analyzes the expression pattern, regulation, and function
      of this growth factor in the paraxial mesoderm of the avian embryo. In the mature
      somite, expression of Fgf-8 is restricted to a subpopulation of myotome cells,
      comprising most, but not all, epaxial and hypaxial muscle precursors. Following
      ablation of the notochord and floor plate, Fgf-8 expression is not activated in
      the somites, in either the epaxial or the hypaxial domain, while ablation of the
      dorsal neural tube does not affect Fgf-8 expression in paraxial mesoderm.
      Contrary to the view that hypaxial muscle precursors are independent of
      regulatory influences from axial structures, these findings provide the first
      evidence for a regulatory influence of ventral, but not dorsal axial structures
      on the hypaxial muscle domain. Sonic hedgehog can substitute for the ventral
      neural tube and notochord in the initiation of Fgf-8 expression in the myotome.
      It is also shown that Fgf-8 protein leads to an increase in sclerotomal cell
      proliferation and enhances rib cartilage development in mature somites, whereas
      inhibition of Fgf signaling by SU 5402 causes deletions in developing ribs. These
      observations demonstrate: (1) a regulatory influence of the ventral axial organs
      on the hypaxial muscle compartment; (2) regulation of epaxial and hypaxial
      expression of Fgf-8 by Sonic hedgehog; and (3) independent regulation of Fgf-8
      and MyoD in the hypaxial myotome by ventral axial organs. It is postulated that
      the notochord and ventral neural tube influence hypaxial expression of Fgf-8 in
      the myotome and that, in turn, Fgf-8 has a functional role in rib formation.

PMID- 12618131
TI  - Unique and conserved aspects of gut development in zebrafish.
AB  - Although the development of the digestive system of humans and vertebrate model
      organisms has been well characterized, relatively little is known about how the
      zebrafish digestive system forms. We define developmental milestones during
      organogenesis of the zebrafish digestive tract, liver, and pancreas and identify
      important differences in the way the digestive endoderm of zebrafish and amniotes
      is organized. Such differences account for the finding that the zebrafish
      digestive system is assembled from individual organ anlagen, whereas the
      digestive anlagen of amniotes arise from a primitive gut tube. Despite
      differences of organ morphogenesis, conserved molecular programs regulate
      pharynx, esophagus, liver, and pancreas development in teleosts and mammals.
      Specifically, we show that zebrafish faust/gata-5 is a functional ortholog of
      gata-4, a gene that is essential for the formation of the mammalian and avian
      foregut. Further, extraembryonic gata activity is required for this function in
      zebrafish as has been shown in other vertebrates. We also show that a loss-of
      function mutation that perturbs sonic hedgehog causes defects in the development
      of the esophagus that parallel those associated with targeted disruption of this
      gene in mammals. Perturbation of sonic hedgehog also affects zebrafish liver and
      pancreas development, and these effects occur in a reciprocal fashion, as has
      been described during mammalian liver and ventral pancreas development. Together,
      these data define aspects of digestive system development necessary for the
      characterization of zebrafish mutants. Given the similarities of teleost and
      mammalian digestive physiology and anatomy, these findings have implications for
      developmental and evolutionary studies as well as research of human diseases,
      such as diabetes, liver cirrhosis, and cancer.

PMID- 12618133
TI  - Characterization of embryonic globin genes of the zebrafish.
AB  - Hemoglobin switching is a complex process by which distinct globin chains are
      produced during stages of development. In an effort to characterize the process
      of hemoglobin switching in the zebrafish model system, we have isolated and
      characterized several embryonic globin genes. The embryonic and adult globin
      genes are found in clusters in a head-to-head configuration. One cluster of
      embryonic and adult genes is localized to linkage group 3, whereas another
      embryonic cluster is localized on linkage group 12. Several embryonic globin
      genes demonstrate an erythroid-specific pattern of expression early during
      embryogenesis and later are downregulated as definitive hematopoiesis occurs. We
      utilized electrospray mass spectroscopy to correlate globin genes and protein
      expression in developing embryonic red cells. The mutation, zinfandel, has a
      hypochromic microcytic anemia as an embryo, but later recovers in adulthood. The
      zinfandel gene maps to linkage group 3 near the major globin gene locus, strongly
      suggesting that zinfandel represents an embryonic globin defect. Our studies are
      the first to systematically evaluate the embryonic globins in the zebrafish and
      will ultimately be useful in evaluating zebrafish mutants with defects in
      hemoglobin production and switching.

PMID- 12618134
TI  - Temporal restriction of migratory and lineage potential in rhombomere 1 and 2
      neural crest.
AB  - Migratory cranial neural crest cells differentiate into a wide range of cell
      types, such as ectomesenchymal tissue (bone and connective tissues) ventrally in
      the branchial arches and neural tissue (neurons and glia) dorsally. We
      investigated spatial and temporal changes of migration and differentiation
      potential in neural crest populations derived from caudal midbrain and
      rhombomeres 1 and 2 by back-transplanting cells destined for the first branchial
      arch and trigeminal ganglion from HH8-HH19 quail into HH7-HH11 chicks. Branchial
      arch cells differentiated down ectomesenchymal lineages but largely lost both the
      ability to localize to the trigeminal position and neurogenic differentiation
      capacity by HH12-HH13, even before the arch is visible, and lost long distance
      migratory ability around HH17. In contrast, neural crest-derived cells from
      trigeminal ganglia lost ectomesechymal differentiation potential by HH17. Despite
      this, they retain the ability to migrate into the branchial arches until at least
      HH19. However, many of the neural crest-derived trigeminal ganglia cells in the
      branchial arch localized to the non-neural crest core of the arch from HH13 and
      older donors. These results suggest that long distance migration ability, finer
      scale localization, and lineage restriction may not be coordinately regulated in
      the cranial neural crest population.

PMID- 12618135
TI  - Neurovascular congruence results from a shared patterning mechanism that utilizes
      Semaphorin3A and Neuropilin-1.
AB  - Peripheral nerves and blood vessels have similar patterns in quail forelimb
      development. Usually, nerves extend adjacent to existing blood vessels, but in a
      few cases, vessels follow nerves. Nerves have been proposed to follow vascular
      smooth muscle, endothelium, or their basal laminae. Focusing on the major axial
      blood vessels and nerves, we found that when nerves grow into forelimbs at E3.5
      E5, vascular smooth muscle was not detectable by smooth muscle actin
      immunoreactivity. Additionally, transmission electron microscopy at E5.5
      confirmed that early blood vessels lacked smooth muscle and showed that the
      endothelial cell layer lacks a basal lamina, and we did not observe physical
      contact between peripheral nerves and these endothelial cells. To test more
      generally whether lack of nerves affected blood vessel patterns, forelimb-level
      neural tube ablations were performed at E2 to produce aneural limbs; these had
      completely normal vascular patterns up to at least E10. To test more generally
      whether vascular perturbation affected nerve patterns, VEGF(165), VEGF(121), Ang
      1, and soluble Flt-1/Fc proteins singly and in combination were focally
      introduced via beads implanted into E4.5 forelimbs. These produced significant
      alterations to the vascular patterns, which included the formation of neo-vessels
      and the creation of ectopic avascular spaces at E6, but in both under- and
      overvascularized forelimbs, the peripheral nerve pattern was normal. The spatial
      distribution of semaphorin3A protein immunoreactivity was consistent with a
      negative regulation of neural and/or vascular patterning. Semaphorin3A bead
      implantations into E4.5 forelimbs caused failure of nerves and blood vessels to
      form and to deviate away from the bead. Conversely, semaphorin3A antibody bead
      implantation was associated with a local increase in capillary formation.
      Furthermore, neural tube electroporation at E2 with a construct for the soluble
      form of neuropilin-1 caused vascular malformations and hemorrhage as well as
      altered nerve trajectories and peripheral nerve defasciculation at E5-E6. These
      results suggest that neurovascular congruency does not arise from interdependence
      between peripheral nerves and blood vessels, but supports the hypothesis that it
      arises by a shared patterning mechanism that utilizes semaphorin3A.

PMID- 12618136
TI  - Diffusible signals and fasciculated growth in reticulospinal axon pathfinding in
      the hindbrain.
AB  - We have addressed the control of longitudinal axon pathfinding in the developing
      hindbrain, including the caudal projections of reticular and raphe neurons. To
      test potential sources of guidance signals, we assessed axon outgrowth from
      embryonic rat hindbrain explants cultured in collagen gels at a distance from
      explants of midbrain-hindbrain boundary (isthmus), caudal hindbrain, or cervical
      spinal cord. Our results showed that the isthmus inhibited caudally directed axon
      outgrowth by 80% relative to controls, whereas rostrally directed axon outgrowth
      was unaffected. Moreover, caudal hindbrain or cervical spinal cord explants did
      not inhibit caudal axons. Immunohistochemistry for reticular and raphe neuronal
      markers indicated that the caudal, but not the rostral projections of these
      neuronal subpopulations were inhibited by isthmic explants. Companion studies in
      chick embryos showed that, when the hindbrain was surgically separated from the
      isthmus, caudal reticulospinal axon projections failed to form and that
      descending pioneer axons of the medial longitudinal fasciculus (MLF) play an
      important role in the caudal reticulospinal projection. Taken together, these
      results suggest that diffusible chemorepellent or nonpermissive signals from the
      isthmus and substrate-anchored signals on the pioneer MLF axons are involved in
      the caudal direction of reticulospinal projections and might influence other
      longitudinal axon projections in the brainstem.

PMID- 12618137
TI  - Suppression of lens growth by alphaA-crystallin promoter-driven expression of
      diphtheria toxin results in disruption of retinal cell organization in zebrafish.
AB  - In order to study lens-retina relationships during development, we cloned the
      zebrafish alphaA-crystallin cDNA and its promoter region. Using a 2.8-kb fragment
      of the zebrafish alphaA-crystallin promoter (z(alpha)Acry), we expressed the
      diphtheria toxin A fragment (DTA) in zebrafish embryos in a lens-specific manner.
      Injection of the z(alpha)Acry-DTA plasmid into eggs at the one-or two-cell stage
      resulted in the formation of small eyes, in which both lens and retina were
      reduced in size. In the DTA-expressing lenses, their fiber structure was
      disorganized, indicating that normal lens development had been abrogated. The
      neural retina also showed abnormal development, although this tissue did not
      express DTA. Lamination in the retina did not develop well, and molecular markers
      for the outer and inner plexiform layers were either abnormally expressed or
      absent. However, cell type-specific markers of ganglion and bipolar cells, as
      well as photoreceptors, were expressed in appropriate positions, indicating that
      initial differentiation of these retinal subpopulations occurred in the DTA
      expressing embryos. Cell proliferation also proceeded normally in these embryos,
      although apoptosis was enhanced. These results suggest that the differentiated
      lens plays a critical role in the morphogenetic organization of retinal cells
      during eye development in zebrafish embryos.

PMID- 12618138
TI  - AmphiNk2-tin, an amphioxus homeobox gene expressed in myocardial progenitors:
      insights into evolution of the vertebrate heart.
AB  - We isolated a full-length cDNA clone of amphioxus AmphiNk2-tin, an NK2 gene
      similar in sequence to vertebrate NK2 cardiac genes, suggesting a potentially
      similar function to Drosophila tinman and to vertebrate NK2 cardiac genes during
      heart development. During the neurula stage of amphioxus, AmphiNk2-tin is
      expressed first within the foregut endoderm, then transiently in muscle precursor
      cells in the somites, and finally in some mesoderm cells of the visceral
      peritoneum arranged in an approximately midventral row running beneath the midgut
      and hindgut. The peritoneal cells that express AmphiNk2-tin are evidently
      precursors of the myocardium of the heart, which subsequently becomes
      morphologically detectable ventral to the gut. The amphioxus heart is a
      rostrocaudally extended tube consisting entirely of myocardial cells (at both the
      larval and adult stages); there are no chambers, valves, endocardium, epicardium,
      or other differentiated features of vertebrate hearts. Phylogenetic analysis of
      the AmphiNk2-tin sequence documents its close relationship to vertebrate NK2
      class cardiac genes, and ancillary evidence suggests a relationship with the
      Drosophila NK2 gene tinman. Apparently, an amphioxus-like heart, and the
      developmental program directing its development, was the foundation upon which
      the vertebrate heart evolved by progressive modular innovations at the genetic
      and morphological levels of organization.

PMID- 12618139
TI  - Transcriptional regulation of glial cell specification.
AB  - Neuronal differentiation relies on proneural factors that also integrate
      positional information and contribute to the specification of the neuronal type.
      The molecular pathway triggering glial specification is not understood yet. In
      Drosophila, all lateral glial precursors and glial-promoting activity have been
      identified, which provides us with a unique opportunity to dissect the regulatory
      pathways controlling glial differentiation and specification. Although glial
      lineages are very heterogeneous with respect to position, time of
      differentiation, and lineage tree, they all express and require two homologous
      genes, glial cell deficient/glial cell missing (glide/gcm) and glide2, that act
      in concert, with glide/gcm constituting the major glial-promoting factor. Here,
      we show that glial specification resides in glide/gcm transcriptional regulation.
      The glide/gcm promoter contains lineage-specific elements as well as quantitative
      and turmoil elements scattered throughout several kilobases. Interestingly, there
      is no correlation between a specific regulatory element and the type of glial
      lineage. Thus, the glial-promoting factor acts as a naive switch-on button that
      triggers gliogenesis in response to multiple pathways converging onto its
      promoter. Both negative and positive regulation are required to control glide/gcm
      expression, indicating that gliogenesis is actively repressed in some neural
      lineages.

PMID- 12618140
TI  - Pax6 regulates regional development and neuronal migration in the cerebral
      cortex.
AB  - Mutations in the Pax6 gene disrupt telencephalic development, resulting in a thin
      cortical plate, expansion of proliferative layers, and the absence of the
      olfactory bulb. The primary defect in the neuronal cell population of the
      developing cerebral cortex was analysed by using mouse chimeras containing a
      mixture of wild-type and Pax6-deficient cells. The chimeric analysis shows that
      Pax6 influences cellular activity throughout corticogenesis. At early stages,
      Pax6-deficient and wildtype cells segregate into exclusive patches, indicating an
      inability of different cell genotypes to interact. At later stages, cells are
      sorted further based on telencephalic domains. Pax6-deficient cells are
      specifically reduced in the mediocaudal domain of the dorsal telencephalon,
      indicating a role in regionalization. In addition, Pax6 regulates the process of
      radial migration of neuronal precursors. Loss of Pax6 particularly affects
      movement of neuronal precursors at the subventricular zone/intermediate zone
      boundary at a transitional migratory phase essential for entry into the
      intermediate zone. We suggest that the primary role of Pax6 is the continual
      regulation of cell surface properties responsible for both cellular identity and
      radial migration, defects of which cause regional cell sorting and abnormalities
      of migration in chimeras.

PMID- 12618141
TI  - Transgenic overexpression of BMP4 increases astroglial and decreases
      oligodendroglial lineage commitment.
AB  - Bone morphogenetic proteins (BMPs) promote astrocytic differentiation of cultured
      subventricular zone stem cells. To determine whether BMPs regulate the astrocytic
      lineage in vivo, transgenic mice were constructed that overexpress BMP4 under
      control of the neuron-specific enolase (NSE) promoter. Overexpression of BMP4 was
      first detectable by Western analysis on embryonic day 16 and persisted into the
      adult. The overexpression of BMP4 resulted in a remarkable 40% increase in the
      density of astrocytes in multiple brain regions accompanied by a decrease in the
      density of oligodendrocytes ranging between 11 and 26%, depending on the brain
      region and the developmental stage. No changes in neuron numbers or the pattern
      of myelination were detected, and there were no gross structural abnormalities.
      Similar phenotypes were observed in three independently derived transgenic lines.
      Coculture of transgenic neurons with neural progenitor cells significantly
      enhanced astrocytic lineage commitment by the progenitors; this effect was
      blocked by the BMP inhibitor Noggin, indicating that the stimulation of
      astrogliogenesis was due to BMP4 release by the transgenic neurons. These
      observations suggest that BMP4 directs progenitor cells in vivo to commit to the
      astrocytic rather than the oligodendroglial lineage. Further, differentiation of
      radial glial cells into astrocytes was accelerated, suggesting that radial glia
      were a source of at least some of the supernumerary astrocytes. Therefore, BMPs
      are likely important mediators of astrocyte development in vivo.

PMID- 12618142
TI  - Role of PI 3-kinase and PIP3 in submandibular gland branching morphogenesis.
AB  - The mouse submandibular gland (SMG) epithelium undergoes extensive morphogenetic
      branching during embryonic development as the first step in the establishment of
      its glandular structure. However, the specific signaling pathways required for
      SMG branching morphogenesis are not well understood. Using E13 mouse SMG organ
      cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3
      kinase), wortmannin and LY294002, substantially inhibited branching morphogenesis
      in SMG. Branching morphogenesis of epithelial rudiments denuded of mesenchyme was
      inhibited similarly, indicating that PI 3-kinase inhibitors act directly on the
      epithelium. Immunostaining and Western analysis demonstrated that the p85 isoform
      of PI 3-kinase is expressed in epithelium at levels higher than in the
      mesenchyme. A target of PI 3-kinase, Akt/protein kinase B (PKB), showed decreased
      phosphorylation at Ser(473) by Western analysis in the presence of PI 3-kinase
      inhibitors. The major lipid product of PI 3-kinase, phosphatidylinositol 3,4,5
      trisphosphate (PIP(3)), was added exogenously to SMG via a membrane-transporting
      carrier in the presence of PI 3-kinase inhibitors and was found to stimulate
      cleft formation, the first step of branching morphogenesis. Together, these data
      indicate that PI 3-kinase plays a role in the regulation of epithelial branching
      morphogenesis in mouse SMG acting through a PIP(3) pathway.

PMID- 12618143
TI  - Identification of interstitial cells of Cajal in the rabbit portal vein.
AB  - Two layers of interstitial cells (ICs) of Cajal were detected by c-kit and
      methylene blue staining in the media of the rabbit portal vein in subendothelial
      intramuscular and deeper intramuscular positions, displaced radially from each
      other by about 40-70 microm. Two morphologically distinct types of ICs were found
      among enzymatically dispersed cells from this vessel: small multipolar cells with
      stellate-shaped bodies not exceeding 20 microm, and spindle-shaped cells from 40
      to 300 microm in length with numerous branching processes. Relaxed smooth muscle
      cells (SMCs) had a more constant length (90-150 microm). The cell membrane
      capacitance was 46.5+/-2.2 pF in SMCs, 39.7+/-2.4 pF in spindle-shaped ICs and
      27.8+/-0.7 pF in multipolar ICs. Although darker under phase contrast, after
      loading with fluo-4 AM, single isolated ICs of both types usually had brighter
      fluorescence than SMCs and displayed various spontaneous calcium events,
      including Ca(2+) sparks and Ca(2+) waves. Ca(2+) waves were usually followed by
      contraction of SMCs but no change in shape of ICs. In some ICs spontaneous
      [Ca(2+)](i) transients (lasting about 2s) which propagated towards the end of the
      processes were observed. Physical contacts between the processes of ICs and the
      body of one or more SMCs survived the isolation procedure. Application of
      noradrenaline (1-10 microM), caffeine (1-10 mM) or high-K(+) solution (60mM) led
      to a rise of [Ca(2+)](i) in both SMCs and ICs evoking contraction of SMCs but not
      ICs. No differences in electrophysiological characteristics between single
      enzymatically isolated IC and SMC were detected; thus, the resting membrane
      potential estimated under current-clamp conditions was -46.5+/-2.0 mV in spindle
      shaped ICs and -45.6+/-2.7 mV in SMCs. Under voltage-clamp, both ICs and SMCs
      revealed a well-developed voltage-gated nifedipine-sensitive L-type Ca(2+)
      current, a set of K(+) currents, including spontaneous transient outward currents
      (STOCs) but no Na(+) current. This study for the first time directly demonstrated
      the presence in vascular tissue of ICs. Possible roles for ICs including their
      involvement in spontaneous activity of the vessel were discussed.

PMID- 12618144
TI  - Mechanism of action of the novel plasma membrane Ca(2+)-pump inhibitor caloxin.
AB  - Caloxin 2A1 is a novel inhibitor of the plasma membrane (PM) Ca(2+)-pump [Am. J.
      Physiol. Cell Physiol. 280 (2001) C1027]. The PM Ca(2+)-pump is a Ca(2+)-Mg(2+)
      ATPase that expels Ca(2+) from cells to help them maintain low concentrations of
      cytosolic Ca(2+). Caloxin 2A1 inhibits Ca(2+)-Mg(2+)-ATPase in human erythrocyte
      leaky ghosts. Here we report that this inhibition is non-competitive with respect
      to the substrates Ca(2+) and ATP and the activator calmodulin. This was
      anticipated since the high affinity binding site for Ca(2+) and sites for ATP and
      calmodulin are intracellular whereas caloxin 2A1 is a peptide selected for
      binding to the second extracellular domain of the pump. Caloxin 2A1 also
      inhibited the Ca(2+)-dependent formation of the acid stable 140 kDa acylphosphate
      intermediate from 32P-gamma-ATP. However, it did not inhibit the formation of the
      acylphosphate intermediate in the reverse direction-from 32P-orthophosphate.
      Consistent with results on mutagenesis of transmembrane residues in the pump
      protein, we suggest that caloxin 2A1 inhibits conformational changes required
      during the reaction cycle of the pump.

PMID- 12618145
TI  - Calcium content of peripheral and central mitochondria in the guinea pig
      myocardium: electron probe analysis.
AB  - We quantitated subcellular elemental concentrations in stimulated and resting
      guinea pig myocardium to determine whether species-specific properties of guinea
      pigs or the subcellular localization of mitochondria accounted for reports of
      higher mitochondrial Ca in guinea pigs than in other species. Small papillary
      muscles or trabeculae isolated from guinea pig ventricles were stimulated to
      raise cytosolic [Ca(2+)](i) by two methods: (1). tetanizing by rapid pacing
      preparations in which Ca(2+) uptake by the sarcoplasmic reticulum was inhibited
      with cyclopiazonic acid or (2). freeze trapping paced muscles near-peak systole.
      Electron probe X-ray microanalysis showed no significant difference between the
      (low, approximately 0.4 mmol/kg dry weight) mitochondrial Ca content of
      stimulated guinea pig hearts, compared to mitochondria of other species, such as
      rat and hamsters, and the Ca contents of peripheral and central mitochondria were
      also not significantly different.

PMID- 12618146
TI  - Intracellular Ca(2+) regulates the cellular iron uptake in K562 cells.
AB  - Fluorescence quenching was used to study the kinetics of the transferrin receptor
      (TfR)-mediated iron uptake in the calcein-loaded K562 cells. It was found that
      elevation of intracellular free Ca(2+) ([Ca(2+)](i)) by thapsigargin (TG) speeds
      up the initial rate of iron uptake and increases the overall capacity of the
      cells in taking up iron. Depletion of intracellular Ca(2+) or complete chelation
      of extracellular Ca(2+) results in complete inhibition of the iron uptake in
      cells. To gain insight into molecular mechanism, IANBD-labeled transferrin (Tf)
      and microscopic fluorescence imaging were used to observe the endocytosis and
      recycling of the Tf-TfR complex in single live cells. The study showed that the
      preincubation of cells with TG or phorbol myristate acetate (PMA), the direct
      activator of protein kinase C (PKC), accelerated the endocytosis and recycling of
      the complex in a dose-dependent manner. W-7, the calmodulin antagonist, and
      GF109203X, a selected cell-permeant inhibitor of PKC, can reverse the
      acceleration. Analysis of actin polymerization in controlled, [Ca(2+)](i)
      elevated and W-7-treated cells revealed that the actin polymerization is enhanced
      as [Ca(2+)](i) is raised, but reduced by W-7. The results suggest that the
      regulation of actin polymerization by intracellular Ca(2+) may play a central
      role in Ca(2+)-dependent iron uptake.

PMID- 12618147
TI  - Calcium requirements for exocytosis do not delimit the releasable neuropeptide
      pool.
AB  - Recently, it was proposed that secretory vesicles have widely varying Ca(2+)
      thresholds for exocytosis. This model can explain adaptation of secretory
      responses and predicts that incomplete release is a consequence of insufficient
      Ca(2+). However, membrane capacitance-based measurements have not supported
      varying Ca(2+) thresholds. Here, Green Fluorescent Protein (GFP) imaging is used
      to test whether a Ca(2+) limitation determines the size of the releasable
      neuropeptide pool in differentiated PC12 cells. We show that depolarization
      evoked release correlates with failure to sustain fully elevated [Ca(2+)](i).
      However, this is coincidental because release remains incomplete when [Ca(2+)](i)
      is maintained at a relatively high level by application of an ionophore or by
      dialysis with a buffered Ca(2+) solution. Furthermore, in contradiction with the
      existence of high threshold vesicles, stimulating maximal release with moderate
      [Ca(2+)](i) prevents secretory responses to large increases in [Ca(2+)](i)
      induced by photolysis of the caged dimethoxynitrophenyl-EGTA-4 (DMNPE-4). Thus,
      optical measurements show that limited capacity for neuropeptide release in
      response to depolarization is not caused by an insufficient duration of
      [Ca(2+)](i) elevation or by variation among vesicles in Ca(2+) sensitivity for
      exocytosis.

PMID- 12618148
TI  - The adenosine inhibition of glutamate exocytosis in synaptosomes is removed by
      the collapse of the vesicle-cytosol deltapH plus the opening of farnesol
      sensitive Ca(2+) channels.
AB  - Adenosine inhibits synaptosomal exocytosis of glutamate, triggered by KCl or by
      the K(+) channel inhibitor, 4-aminopyridine (4-AP), without affecting Ca(2+)
      influx. Its effect is removed by the activation of protein kinase C (PKC). We
      show that in the presence of the protein kinase inhibitor, staurosporine, the
      adenosine inhibition is removed also by collapsing deltapH between secretory
      vesicle and the cytosol with methylamine (MA), provided that exocytosis is
      triggered by KCl (which activates an initial transient spike of Ca(2+) influx)
      but not by 4-AP. If KCl is supplied prior to Ca(2+), the spike of Ca(2+) influx
      is absent and the adenosine inhibition is maintained. MA can remove the adenosine
      inhibition also with 4-AP, provided that tetraethylammonium (TEA), an inhibitor
      of a different class of K(+) channels, is supplied together with 4-AP. TEA
      promotes a further increase of cytosolic free Ca(2+) concentration ([Ca(2+)](i)),
      which adds to the 4-AP-induced Ca(2+) influx. Farnesol (5-10 microM), a
      physiological derivative of farnesyl pyrophosphate of the sterol biosynthetic
      pathway, specifically inhibits the Ca(2+) spike after KCl as well as the TEA
      promoted Ca(2+) increase. At the same time, it prevents the removal of the
      adenosine inhibition by MA. We conclude that the adenosine inhibition is removed
      by the coincidence of two signals, the alkalinization of secretory vesicles and
      the opening of a particular class of Ca(2+) channels associated to the TEA
      sensitive K(+) channels, equivalent to the Ca(2+) spike after KCl, and sensitive
      to farnesol.

PMID- 12618149
TI  - Arachidonic acid in astrocytes blocks Ca(2+) oscillations by inhibiting store
      operated Ca(2+) entry, and causes delayed Ca(2+) influx.
AB  - ATP-elicited oscillations of the concentration of free intracellular Ca(2+)
      ([Ca(2+)](i)) in rat brain astrocytes were abolished by simultaneous arachidonic
      acid (AA) addition, whereas the tetraenoic analogue 5,8,11,14-eicosatetraynoic
      acid (ETYA) was ineffective. Inhibition of oscillations is due to suppression by
      AA of intracellular Ca(2+) store refilling. Short-term application of AA, but not
      ETYA, blocked Ca(2+) influx, which was evoked by depletion of stores with
      cyclopiazonic acid (CPA) or thapsigargin (Tg). Addition of AA after ATP blocked
      ongoing [Ca(2+)](i) oscillations. Prolonged AA application without or with
      agonist could evoke a delayed [Ca(2+)](i) increase. This AA-induced [Ca(2+)](i)
      rise developed slowly, reached a plateau after 5 min, could be reversed by
      addition of bovine serum albumin (BSA), that scavenges AA, and was blocked by 1
      microM Gd(3+), indicative for the influx of extracellular Ca(2+). Specificity for
      AA as active agent was demonstrated by ineffectiveness of C16:0, C18:0, C20:0,
      C18:2, and ETYA. Moreover, the action of AA was not affected by inhibitors of
      oxidative metabolism of AA (ibuprofen, MK886, SKF525A). Thus, AA exerted a dual
      effect on astrocytic [Ca(2+)](i), firstly, a rapid reduction of capacitative
      Ca(2+) entry thereby suppressing [Ca(2+)](i) oscillations, and secondly inducing
      a delayed activation of Ca(2+) entry, also sensitive to low Gd(3+) concentration.

PMID- 12618151
TI  - Differences in perinatal mortality and suboptimal care between 10 European
      regions: results of an international audit.
AB  - OBJECTIVE: A European concerted action (the EuroNatal study) investigated the
      background of differences in perinatal mortality between countries of Europe. The
      study aimed to determine the contribution of differences in quality of care, by
      looking at differences in the presence of suboptimal factors in individual cases
      of perinatal death. DESIGN: Retrospective audit study. SETTING: Regions of 10
      European countries. POPULATION: 1619 cases of perinatal death. METHODS: Perinatal
      deaths between 1993 and 1998 in regions of 10 European countries were identified.
      Reviewed were singleton fetal deaths (28 or more weeks of gestational age),
      intrapartum deaths (28 or more weeks) and neonatal deaths (34 or more weeks).
      Deaths with (major) congenital anomalies were excluded. Cases were blinded for
      region and an international audit panel reviewed them using explicit audit
      criteria. MAIN OUTCOME MEASURES: Presence of suboptimal factors. RESULTS: The
      audit covered 1619 cases of perinatal death, representing 90% of eligible cases
      in the regions. Consensus was reached on 1543 (95%) cases. In 715 (46%) of these
      cases, suboptimal factors, which possibly or probably had contributed to the
      fatal outcome, were identified. The percentage of cases with such suboptimal care
      factors was significantly lower in the Finnish and Swedish regions compared with
      the remaining regions of Spain, the Netherlands, Scotland, Belgium, Denmark,
      Norway, Greece and England. Failure to detect severe IUGR (10% of all cases) and
      smoking in combination with severe IUGR and/or placental abruption (12%) was the
      most frequent suboptimal factor. There was a positive association between the
      proportion of cases with suboptimal factors and the overall perinatal mortality
      rate in the regions. CONCLUSIONS: The findings of this international audit
      suggest that differences exist between the regions of the 10 European countries
      in the quality of antenatal, intrapartum and neonatal care, and that these
      differences contribute to the explanation of differences in perinatal mortality
      between these countries. The background to these differences in quality of care
      needs further investigation.

PMID- 12618152
TI  - High caesarean rates in Madras (India): a population-based cross sectional study.
AB  - OBJECTIVE: To estimate the population caesarean section rate in urban India.
      DESIGN: Population-based cross sectional study. SETTING: Madras City (Chennai),
      India. Seven hundred and eighty resident women who delivered in Madras between
      June 1997 and May 1999. METHODS: Cluster sampling was done using streets as
      cluster units. Thirty clusters were selected from 1255 clusters by the
      probability proportion to size method and 26 women were selected randomly from
      each cluster. MAIN OUTCOME MEASURES: Total and primary caesarean rates. RESULTS:
      Total population caesarean section rate was 32.6% (95% CI 27-38) and primary
      caesarean section rate was 25% (95% CI 20-30). Total caesarean section rates in
      the public, charitable and private sectors were 20%, 38% and 47%, respectively.
      Private sector deliveries had an odds ratio of 2.4 (95% CI 1.5, 3.8) of a primary
      caesarean section delivery in comparison with the public sector after adjustment
      for parity, age at delivery of mother and educational status. CONCLUSIONS: Forty
      seven percent of births by caesarean section in the private sector is alarming
      and could implicate private sector care as the main contributing factor behind
      the high population caesarean section rates. Policymakers should urgently
      institute systems for accountability and ethical practice and regularly monitor
      all medical interventions, before large scale exploitation of the rural markets
      begins.

PMID- 12618153
TI  - Effect of timing and type of treatment on the risk of mother to child
      transmission of Toxoplasma gondii.
AB  - OBJECTIVE: To determine the effects on mother to child transmission of the timing
      and type of prenatal treatment, taking into account gestational age at maternal
      seroconversion. DESIGN: Prospective cohort study. SETTING: European centres
      offering prenatal screening for toxoplasmosis. POPULATION: Children born to a
      cohort of pregnant women with toxoplasma infection. METHODS: We determined the
      effects on mother to child transmission of the interval between seroconversion
      and start of treatment (treatment delay), and the type of treatment, taking into
      account gestational age at maternal seroconversion. MAIN OUTCOME MEASURE:
      Congenital infection status confirmed by toxoplasma IgG results at one year
      postnatal age. RESULTS: Of 1208 women analysed, 72% were first prescribed
      spiramycin, 19% pyrimethamine-sulphonamide and 9% (mostly infected during the
      last trimester) were untreated. The odds ratios for mother to child transmission
      for all women treated after a delay of four to seven weeks was 0.77 (95% CI 0.34
      1.69), and after eight weeks or more was 1.33 (0.56-2.89) compared with less than
      four weeks. The odds ratio per week of treatment delay was 1.01 (0.93-1.08).
      There was no evidence that transmission risk differed in women first treated with
      pyrimethamine-sulphonamide versus spiramycin: odds ratio 1.10 (0.63-1.91) or in
      untreated versus treated women: odds ratio 0.57 (0.27-1.17). CONCLUSION: We were
      unable to demonstrate a beneficial effect of the timing or type of prenatal
      treatment on the risk of mother to child transmission but we could not exclude a
      clinically important effect. Randomised controlled trials are required to
      determine the effect of prenatal treatment on mother to child transmission.

PMID- 12618154
TI  - Birth outcomes: utility values that postnatal women, midwives and medical staff
      express.
AB  - OBJECTIVE: To determine if and to what extent postnatal women's preferences for
      birth outcomes differ from those of midwives and medical staff, and whether any
      variations in utility scores are associated with demographic variables. DESIGN:
      Cross sectional cohort study. SETTING: The Women's and Children's Hospital,
      Adelaide. POPULATION: A total of 180 participants which included 90 postnatal
      women, 59 midwives and 31 medical staff. METHODS: Preferences (utility scores)
      were measured by direct interviews using utility techniques: the visual analogue
      scale and the standard gamble. MAIN OUTCOMES MEASURES: Preferences (utility
      scores) for eight birth outcomes. RESULTS: Women assigned higher utility scores
      for the five birth outcomes of jaundice requiring phototherapy, admission to
      neonatal nursery, shoulder dystocia, nerve palsy and transient neurological
      symptoms than midwives, which suggested that women regarded these outcomes as
      less severe (P < 0.01). Utility scores for the women and medical staff were
      similar. The majority of postnatal women, midwives and medical staff preferred
      permanent neurological sequelae to perinatal death. Eighty-nine percent of
      postnatal women preferred permanent neurological sequelae to perinatal death
      compared with 71% of midwives (P < 0.01), and 68% of medical staff (P < 0.01).
      CONCLUSION: Utility values for important birth outcomes varied between women who
      had recently given birth and health professionals. Clinical practice should
      recognise and respect the preferences of women, with appropriate balance between
      their preferences, those of health professionals and the known benefits of care.

PMID- 12618155
TI  - Postnatal morbidity after childbirth and severe obstetric morbidity.
AB  - OBJECTIVE: To identify the impact of pregnancy and childbirth, and severe
      obstetric morbidity on outcome 6 to 12 months postpartum. DESIGN: Questionnaire
      assessment of postnatal outcome in a cohort study. SETTING: South East Thames,
      UK. POPULATION: All women resident in South East Thames and delivering between
      1st March 1997 and 28th February 1998. METHODS: Questionnaire study of a cohort
      of women who experienced a severe obstetric morbidity during pregnancy or labour
      (cases), compared with a cohort of women who did not (controls). MAIN OUTCOME
      MEASURES: Assessment of postnatal depression risk [Edinburgh Postnatal Depression
      Scale (EPDS)], general health [Short Form 36 (SF-36)], sexual activity and use of
      health services between 6 and 12 months postpartum. RESULTS: There were 331 cases
      and 1339 controls out of 48,262 deliveries. Six to 12 months after delivery, 77
      (23.3%) of cases and 272 (20.5%) of the controls were at risk of postnatal
      depression (P = 0.25; 95% CI for difference -2.2% to 7.9%), 43.1% of cases were
      having problems with sexual relations compared with 18.7% of controls (P < 0.001;
      95% CI for difference 8.9% to 21.9%). There was evidence of poorer general health
      in cases. Some 31.5% of cases attended outpatients in the first six months and
      9.4% required emergency admission to hospital compared with 17.0% (P < 0.001; 95%
      CI for difference 9.1% to 19.9%) and 3.7% (P < 0.001; 95% CI for difference 2.4%
      to 9.0%), respectively, in controls. CONCLUSION: Both control pregnancy and
      childbirth and severe obstetric morbidity are associated with significant
      postnatal morbidity. A severe obstetric morbid event significantly influences
      women's sexual health and wellbeing and increases health services utilisation.
      Prevention and appropriate management of severe obstetric morbid events may
      reduce these outcomes.

PMID- 12618156
TI  - Validation of the Welch Allyn 'Vital Signs' blood pressure measurement device in
      pregnancy and pre-eclampsia.
AB  - OBJECTIVE: To establish the accuracy the Welch Allyn 'Vital Signs' blood pressure
      monitor in pregnancy and pre-eclampsia according to a modified British
      Hypertension Society protocol. DESIGN: Prospective observational study. SETTING:
      Maternity Unit/Obstetric Ward, Guy's and St Thomas' Hospital, London, UK.
      POPULATION: Forty-three pregnant women of whom 12 had pre-eclampsia. METHODS:
      Nine sequential same-arm measurements were taken from each woman by two trained
      observers, alternating between a mercury sphygmomanometer and the device. The
      last seven readings were analysed according to the British Hypertension Society
      protocol. The accuracy of the device was determined using the grading scale
      indicated by the British Hypertension Society protocol (grade A/B = pass, grade
      C/D = fail). MAIN OUTCOME MEASURES: Grading criteria of the British Hypertension
      Society Protocol. RESULTS: The Welch Allyn 'Vital Signs' monitor achieved a grade
      A for both systolic and diastolic pressures in pregnant women who did not have
      pre-eclampsia. In those women with pre-eclampsia, it achieved a grade D and B for
      systolic and diastolic pressures, respectively. The mean differences between the
      observers and the device in women without pre-eclampsia were -2.6 (6.4) and -1.5
      (7.2) mmHg for systolic and diastolic pressures [and in pre-eclamptic women -7.8
      (6.3) and -5.5 (6.5)mmHg]. It therefore fulfils criteria set by the Association
      for the Advancement of Medical Instrumentation (mean <5 mmHg and standard
      deviation <8 mmHg) in pregnancy, but not in pre-eclampsia. CONCLUSION: This is
      the first automated device suitable for robust clinical use that can be
      recommended for use in pregnancy. However, it should be borne in mind that
      similar to other devices--it significantly under--recorded readings obtained in
      pre-eclamptic women.

PMID- 12618158
TI  - Women's attitudes to HIV screening in pregnancy in an area of low prevalence.
AB  - OBJECTIVES: To identify factors that influence acceptance of the human
      immunodeficiency virus (HIV) screening test by pregnant women. DESIGN:
      Prospective survey using questionnaires. SETTING: An antenatal clinic at a
      tertiary referral hospital. POPULATION: 200 pregnant women of multiethnic origin
      residing in a low prevalence area. METHODS: Two hundred consecutive women
      attending the antenatal booking clinic were interviewed. We collected data on
      reasons for opting in or out and factors that could influence the rate of
      acceptance, such as ethnicity, age, parity, level of education, first language
      and marital or relationship status. MAIN OUTCOME MEASURES: Attitudes of pregnant
      women to HIV screening. The rate of acceptance of HIV screening was 160/200(80%).
      The most frequent reasons for opting in were the perceived benefits of screening
      (92/160, 58%) and the fact that the test is now routinely offered (87/160, 54%).
      The most frequent reason for refusal of screening was perceived low risk of HIV
      (27/40, 68%). Logistic regression analysis showed that ethnicity, age, parity and
      level of formal education did not play a role in influencing uptake of the test.
      However, women whose first language was English were more likely to opt in
      compared with those whose first language was not English (P = 0.016) and those
      who were married or in a stable relationship were more likely to opt in than
      those who were not (P < 0.001). CONCLUSION: We have not reached the national
      target of 90% in our region. This appears to be due to a combination of factors,
      the main one being a perception of low risk. Greater knowledge of the ease of
      transmission of HIV may alter this perception, which may improve acceptance of
      the test.

PMID- 12618157
TI  - Low molecular weight heparin (dalteparin) for the treatment of venous
      thromboembolism in pregnancy.
AB  - OBJECTIVE: To evaluate the effect and dose of dalteparin given to pregnant women
      with acute venous thromboembolism. DESIGN: An observational study of pregnant
      women in Norway. SETTING: Delivery and haematological departments in Norway.
      POPULATION: Twenty women, aged 22-41 years, with acute venous thromboembolism
      verified by objective means. METHODS: Patients were treated with dalteparin from
      diagnosis until delivery. Treatment was monitored with anti-activated factor Xa
      (anti-Xa) activity, and the dose was adjusted to achieve target 0.5-1.0 U/mL 2-3
      hours post-injection. MAIN OUTCOME MEASURES: Anti-Xa activity and side effects.
      RESULT: None of the patients suffered recurrent venous thromboembolism or major
      bleeding complications. In 9 of 13 women starting with conventional dose of
      dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa
      activity. None of the six women who started with 105-118 iu/kg bd required dose
      escalation. One woman who started with 133 iu/kg bd required dose reduction.
      Bioaccumulation of dalteparin was not observed. CONCLUSION: Our study suggests
      that dalteparin may be used for the treatment of acute venous thromboembolism in
      pregnancy. Approximately 10-20% higher doses of dalteparin may be needed as
      compared with non-pregnant individuals.

PMID- 12618159
TI  - Myometrial microvascular endothelial cells express oxytocin receptor.
AB  - OBJECTIVE: 1. To establish whether microvascular endothelial cells from the human
      myometrium (MMECs) express oxytocin receptor, and to compare its expression
      levels relative to HUVECs. 2. To verify an up-regulation of oxytocin receptor
      expression in MMECs as a result of vascular endothelial growth factor (VEGF),
      which had been found in a previous study. DESIGN: Laboratory scientific study.
      SETTING: University department. POPULATION OR SAMPLE: Myometrial biopsies from 12
      hysterectomy specimens. METHODS: MMECs and HUVECs were established in vitro.
      Immunohistochemistry of in vitro cultures was performed to investigate protein
      expression of the oxytocin receptor. Semi-quantitative RT-PCR and Northern blots
      were performed to examine the presence and relative abundance of oxytocin
      receptor mRNA in MMECs and HUVECs, and in both cell types with and without VEGF.
      Total RNA from oxytocin acetate (100 nmol/L) and vehicle stimulated endothelial
      cell cultures was used to examine gene expression differences on a 10.5K cDNA
      microarray. MAIN OUTCOME MEASURES: Oxytocin receptor mRNA and protein; gene
      expression anlysis. RESULTS: Oxytocin receptor mRNA and protein was present in
      MMECs. The level of expression was the same as for the HUVECs, but much less than
      the pregnant myometrium. No effect on gene expression could be demonstrated by
      gene expression microarray following 10 hours of oxytocin stimulation. Twenty
      four hours of VEGF stimulation did not significantly alter oxytocin receptor mRNA
      expression in MMECs or HUVECs. CONCLUSION: The myometrial microvasculature
      expresses oxytocin receptor. This finding means that oxytocin may exert some of
      its effects on the myometrial microvasculature. No evidence could be found for a
      transcriptional effect of oxytocin stimulation in this study, but further work on
      the role of the myometrial vessel oxytocin receptor is needed.

PMID- 12618160
TI  - A multicentre randomised trial to compare uterine safety of raloxifene with a
      continuous combined hormone replacement therapy containing oestradiol and
      norethisterone acetate.
AB  - OBJECTIVE: To compare the uterine effects of 60 mg of raloxifene with a
      continuous combined hormone replacement therapy, a preparation of 2 mg 17beta
      oestradiol (E(2)) and 1 mg norethisterone acetate for a duration of 12 months.
      DESIGN: A randomised, double-blind trial. SETTING: Multicentre: Europe, Israel,
      South Africa. POPULATION: Asymptomatic postmenopausal women with risk factors for
      osteoporosis or cardiovascular disease who had an endometrial thickness of less
      than 5 mm. One thousand and eight women were randomised for the six month core;
      of these 420 were invited to continue into a six month extension period. METHODS:
      Randomisation to either raloxifene or continuous combined hormone replacement
      therapy. Patients, recruiters and assessors were blinded to the treatment used.
      MAIN OUTCOME MEASURES: The frequency of vaginal spotting/bleeding as recorded in
      a diary, endometrial thickness and uterine volume as measured by transvaginal
      ultrasonography at baseline and after 6 and 12 months. RESULTS: After six months
      of therapy with raloxifene, the rate of women on raloxifene reporting vaginal
      bleeding and spotting (6.8%) was similar to the rate in the lead-in phase (8.3%)
      but increased from 7.0% to 55.1% in the continuous combined hormone replacement
      therapy group. Raloxifene treatment was not associated with a significant change
      from baseline to endpoint in mean endometrial thickness (P = 0.11), whereas
      continuous combined hormone replacement therapy treatment was associated with an
      increase in this value of mean (SD) of 1.2 (2.2) mm (P < 0.001). Compared with
      raloxifene, mean endometrial thickness for women on continuous combined hormone
      replacement therapy was significantly increased at endpoint [4.6 (2.1) mm vs 3.5
      (1.7) mm; change from baseline P < 0.001]. In the raloxifene group, there was a
      trend towards a decrease from baseline in uterine volume [from 31.4 (20.3) to
      30.3 (16.2) mm; P = 0.37]; in the continuous combined hormone replacement therapy
      group, there was a significant increase in uterine volume [from 31.3 (16.3) to
      54.0 (36.1) mm; P < 0.001], and the difference in the effect of both compounds on
      change in uterine volume at endpoint reached statistical significance (P <
      0.001). Statistically significant differences between the treatment groups were
      sustained for all parameters during the extension period. Early discontinuation
      rates, both overall and due to adverse events, were significantly lower (P <
      0.001) in the raloxifene group after 6 and 12 months. CONCLUSION: Compared with
      continuous combined hormone replacement therapy, 6 and 12 months of raloxifene
      treatment do not lead to vaginal bleeding/spotting, are not associated with
      increased endometrial thickness or uterine volume and result in a significantly
      lower rate of early treatment discontinuations in asymptomatic women receiving
      treatment to prevent long term postmenopausal health risks.

PMID- 12618161
TI  - Women awaiting hysterectomy: a qualitative study of issues involved in decisions
      about oophorectomy.
AB  - OBJECTIVE: Women awaiting abdominal hysterectomy have a further decision to take-
      whether or not to undergo a prophylactic oophorectomy. Prophylactic oophorectomy
      (removal of healthy ovaries) is commonly undertaken as an adjunct to hysterectomy
      to prevent ovarian cancer in women who are already having a hysterectomy for
      menorrhagia, fibroids or severe menstrual pain. It causes an immediate 'surgical
      menopause'--women no longer produce endogenous oestrogens and they are advised to
      take hormone replacement therapy (HRT). This descriptive study was undertaken as
      part of a larger pilot study. DESIGN: Qualitative interviewing study. SETTING:
      Hospital outpatient departments in southern England. SAMPLE: Women on waiting
      lists for hysterectomy for benign conditions. METHODS: In-depth semi-structured
      interviews were undertaken with 16 women awaiting hysterectomy to examine their
      views of prophylactic oophorectomy, menopause and HRT use. Interviews were
      transcribed. Nud*ist was used to organise the data. Analysis was undertaken by
      two researchers working independently who then met to agree themes. RESULTS:
      Women held treatment preferences both about the removal or retention of their
      ovaries and about subsequent HRT use. Many of the women did not want oophorectomy
      because of a dislike of a sudden menopause. Those who were planning to have an
      oophorectomy tended to have more severe symptoms. Some women were fearful of
      ovarian cancer--one woman described it as a 'silent killer'. A further theme was
      apparent in the discussion of ovaries as 'redundant' with further discussion of
      healthy versus problematic ovaries. Many women felt inadequately informed about
      their treatment options and were unaware of important longer term outcomes of
      oophorectomy such as an increased risk of osteoporosis or of coronary heart
      disease. CONCLUSION: It appears that many women emphasise the 'natural' when
      considering oophorectomy and the use of HRT. Women were uneasy both about a
      sudden menopause and about the risks of ovarian cancer. And although these women
      were all about to undergo surgery, they had experienced an apparent serious lack
      of information especially about long term risks and benefits on which they might
      base their decision.

PMID- 12618162
TI  - A viable alternative to surgical vacuum aspiration: repeated doses of
      intravaginal misoprostol over 9 hours for medical termination of pregnancies up
      to eight weeks.
AB  - OBJECTIVE: To study the efficacy of repeated doses of vaginal misoprostol over 9
      hours in a day care setting for terminating pregnancies up to eight weeks of
      gestation. DESIGN: An open, single arm prospective study conducted between
      January 2000 and December 2001. SETTING: Fertility Control Clinic, National
      University Hospital, Singapore. POPULATION: One hundred and fifty pregnant women
      with an unwanted pregnancy up to eight weeks of gestation requesting medical
      abortion. METHODS: The women were given an initial dose of 800 microg of vaginal
      misoprostol. A further dose of 400 microg was repeated every 3 hours for a
      maximum of three doses. MAIN OUTCOME MEASURES: The complete abortion rate defined
      as successful cases that did not require vacuum aspiration. RESULTS: The complete
      abortion rate was 84.7% and 96.0% at 15 days and 43 days after initial
      administration of vaginal misoprostol. The mean interval between first dose of
      misoprostol and the onset of expulsion of products of conception (SD) was 8.1
      hours (6.3). The mean and the median percentage changes in the serum beta-hCG
      levels at day 15 as compared with pre-abortion levels were statistically
      significant (P < 0.001) and were a good predictor of the likely outcome of the
      medical abortion. The mean duration of bleeding (SD) was 11.7 days (4.7) and the
      mean duration between the onset of procedure and the return of normal
      menstruation (SD) was 35.5 days (5.7). There was no significant change in
      haemoglobin concentration. Lower abdominal pain, fever (>38.0 degrees C) and
      diarrhoea were the most common side effects. CONCLUSIONS: This regimen of
      repeated doses of vaginal misoprostol every 3 hours over a period of 9 hours, in
      keeping with the plasma level and pharmacokinetic of misoprostol administered
      vaginally, is an effective method of medical abortion that approaches the
      efficacy of surgical vacuum aspiration. The regimen would offer a suitable option
      for women requesting termination of pregnancy up to eight weeks of gestation in
      countries where mifespristone is and will never be made available.

PMID- 12618163
TI  - Virtual reality laparoscopic simulator for assessment in gynaecology.
AB  - A validated virtual reality laparoscopic simulator minimally invasive surgical
      trainer (MIST) 2 was used to assess the psychomotor skills of 21 gynaecologists
      (2 consultants, 8 registrars and 11 senior house officers). Nine gynaecologists
      failed to complete the VR tasks at the first attempt and were excluded for
      sequential evaluation. Each of the remaining 12 gynaecologists were tested on
      MIST 2 on four occasions within four weeks. The MIST 2 simulator provided
      quantitative data on time to complete tasks, errors, economy of movement and
      economy of diathermy use--for both right and left hand performance. The results
      show a significant early learning curve for the majority of tasks which plateaued
      by the third session. This suggests a high quality surgeon-computer interface.
      MIST 2 provides objective assessment of laparoscopic skills in gynaecologists.

PMID- 12618165
TI  - Do bladder neck position and amount of elevation influence the outcome of
      colposuspension?
AB  - OBJECTIVE: To determine whether the amount of bladder neck elevation and the
      position of the bladder neck after surgery influence the cure rate after
      colposuspension. DESIGN: Prospective, observational study. SETTING:
      Urogynaecology unit, district general hospital. POPULATION: Seventy-seven women
      undergoing colposuspension for urodynamic stress incontinence. METHODS: The
      bladder neck was imaged pre-operatively and one week after surgery using magnetic
      resonance imaging. The position of the bladder neck after surgery and the amount
      of elevation were correlated to continence outcome one year after surgery
      (subjective and objective evidence of stress incontinence). MAIN OUTCOME
      MEASURES: Subjective and urodynamic stress incontinence one year after surgery.
      RESULTS: At one year the subjective and objective failure rates were 11.6% and
      10.5%, respectively. Measures using magnetic resonance imaging were obtained in
      73 women. No association was found between continence outcome and post-operative
      bladder neck position and elevation. CONCLUSION: The post-operative position of
      the bladder neck and the amount of elevation do not influence continence outcome.
      Post-operative morbidity (voiding dysfunction and detrusor instability) might be
      preventable by avoiding excessive bladder neck elevation and compression, without
      compromising the success of the procedure.

PMID- 12618164
TI  - Acceptability of a urinary continence promotion programme to women in postpartum.
AB  - OBJECTIVE: To assess the acceptability to postpartum women of a physiotherapist
      delivered urinary continence promotion programme. DESIGN: A survey of women
      participating in a randomised controlled trial where women received the
      intervention (which involved training in pelvic floor exercises and incorporated
      adherence-enhancing strategies) or usual postpartum care. SETTING: Postpartum
      wards of three tertiary teaching hospitals in the Hunter Region, NSW, Australia.
      SAMPLE: Women were eligible to participate in the trial if they had a
      forceps/ventouse assisted delivery and/or delivered a higher birthweight baby (>
      or =4000 g). This study is based primarily on data obtained for 348 women in the
      intervention group. METHODS: Baseline hospital-based interview; eight-week follow
      up appointment with physiotherapist; three-month follow up telephone interview.
      MAIN OUTCOME MEASURES: Comparative dropout rates for intervention and control
      groups; reasons for non-participation; attendance at hospital follow up; self
      reported acceptability of and embarrassment about per vaginum examination;
      utilisation and perceived usefulness of intervention components; self-reported
      adherence with recommended pelvic floor exercise regime. RESULTS: There was no
      significant difference in dropouts between intervention (5.9%) and control groups
      (6.3%). Only 14% of women gave not wanting the per vaginum assessments as their
      main reason for not participating in the study. Eighty-eight percent of women
      participated in the eight-week postpartum follow up visit with the
      physiotherapist, with two-thirds of these women attending the hospital for this;
      72.2% of women reported no embarrassment, and 22.5% just a little embarrassment
      about per vaginum assessment. The information components of the intervention were
      well received. At the eight-week follow up visit, 83.9% reported performing
      pelvic floor exercises at adequate frequency. CONCLUSIONS: The postpartum period
      provides an ideal opportunity for pelvic floor muscle testing and the delivery of
      continence promotion advice.

PMID- 12618166
TI  - Laparoscopic restaging of borderline ovarian tumours: results of 30 cases
      initially presumed as stage IA borderline ovarian tumours.
AB  - OBJECTIVES: To review our experience with the laparoscopic restaging procedure of
      presumed early stage borderline ovarian tumours. DESIGN: Retrospective study.
      SETTING: Cancer centre. POPULATION: Thirty patients with presumed stage I
      borderline ovarian tumours after limited initial surgery. METHODS: From April
      1991 to May 2001, the patients were laparoscopically reassessed. The procedure
      involved peritoneal cytology, exploration of the peritoneal cavity, infracolic
      omentectomy, directed or random peritoneal biopsies, and when appropriate,
      contralateral oophorectomy and hysterectomy and appendectomy. Medical records
      were reviewed for patients' age, interval time between procedures, tumour stage,
      histological type, operative time, hospital stay, peri-operative complications
      and follow up. MAIN OUTCOME MEASURES: Seroperative and postoperative data,
      pathology and clinical follow up. RESULTS: Laparoscopic restaging was completed
      in all 30 (100%) identified patients. The mean age was 34.8 (10.5) years; the
      delay between initial operation and restaging laparoscopy averaged 9.8 (6.6)
      weeks. The mean operative time was 165.4 (53.8) minutes, and the mean hospital
      stay was 2.7 (1.3) days. There were two (7.0%) major complications related
      directly to the procedure. Eight (26.6%) patients were upstaged. Mean follow up
      was 29.1 (6.6) months, all patients are alive and one (3.2%) recurrence was
      observed. CONCLUSIONS: Laparoscopic approach of restaging for borderline ovarian
      tumours is an accurate safe procedure. It is associated with an acceptable rate
      of minor complications, it has similar morbidity associated with laparotomy and
      it minimises the incidence of infertility in the young patients. Whenever staging
      of borderline ovarian tumours is to be considered in an individual patient,
      laparoscopy provides a suitable alternative approach.

PMID- 12618168
TI  - Laparoscopic gonadectomy in paediatric and adolescent girls with intersex
      disorders.
AB  - Gonadectomy is indicated in some children and teenagers with intersex disorders.
      Traditionally, this has been performed by laparotomy. This paper is a
      retrospective evaluation of laparoscopic gonadectomy in 10 girls (age range 8 to
      17 years). Clinical records were reviewed for diagnosis, indication for surgery,
      complications and recovery period. Operative notes were reviewed for details of
      technique and complications. In all cases, the procedure was uncomplicated and
      the maximum hospital stay was two days. Laparoscopic gonadectomy is an effective
      and safe procedure for children and teenagers with these rare conditions.

PMID- 12618167
TI  - The prognostic significance of HPV-16 genome status of the lymph nodes, the
      integration status and p53 genotype in HPV-16 positive cervical cancer: a long
      term follow up.
AB  - OBJECTIVE: Prognostic evaluation of HPV-16 genome status of the pelvic lymph
      nodes, the integration status of HPV-16 and p53 codon 72 polymorphism in cervical
      cancer. DESIGN: Prospective cohort study. SETTING: Department of Gynaecological
      Oncology, University of Debrecen, Hungary. SAMPLE: Thirty-nine patients with HPV
      16 positive cervical cancer. METHODS: Primary tumour specimens of 39 cervical
      cancer patients with HPV-16 positive primary tumour were subjected to multiplex
      polymerase chain reaction using HPV-16 E1/E2, E7 and p53 codon 72 allele-specific
      primers. Pelvic lymph nodes of the same patients were also tested for the
      presence of HPV-16 DNA and for its integration status using HPV-16 E7 and E1/E2
      ORF specific primers, respectively. MAIN OUTCOME MEASURES: Progression-free
      survival. RESULTS: Metastatic lymph nodes carried HPV-16 DNA more frequently than
      nodes with no evidence of disease (100.0% vs 35.7%, P = 0.001). Cases with HPV-16
      positive nodes had higher recurrence rate than those with HPV-16 negative nodes
      (42.9% vs 11.1%, P = 0.009). There was no difference between cases with and
      without histologically proven nodal disease with regard to integration status of
      HPV-16 DNA in the primary tumour (integrated 90.9% vs 71.4%, episomal 9.1% vs
      21.4%, mixed 0% vs 7.1%) and p53 codon 72 polymorphism (Arg/Arg 54.5% vs 67.9%,
      Pro/Pro 0 vs 7.1%, Arg/Pro 45.5% vs 21.4%). CONCLUSIONS: Regardless of the
      presence of nodal metastasis, HPV-16 status of the nodes is a significant
      predictor of recurrent disease. HPV-16 integration status and p53 codon 72
      genotype do not seem to have a bearing on disease outcome in cervical cancer with
      HPV-16 positive primary.

PMID- 12618169
TI  - Fatal puerperal sepsis with necrotising fasciitis due to Streptococcus
      pneumoniae.

PMID- 12618170
TI  - Massive vault necrosis with bladder fistula after uterine artery embolisation.

PMID- 12618171
TI  - Uterine rupture in a primigravida with misoprostol used for induction of labour.

PMID- 12618173
TI  - An exceptionally rare ectopic pregnancy.

PMID- 12618172
TI  - Symphysiotomy: a lifesaving procedure.

PMID- 12618174
TI  - Retroperitoneal fibrosis localised to the pelvis, imitating a gynaecologic
      tumour.

PMID- 12618175
TI  - Sebaceous carcinoma of the vulva.

PMID- 12618177
TI  - Astex, Structural Genomix, and Syrrx. I can see clearly now: structural biology
      and drug discovery.

PMID- 12618178
TI  - Microbia: engineering microbial network biology.

PMID- 12618179
TI  - Mammalian fatty acid synthase: closure on a textbook mechanism?
AB  - Mammalian fatty acid synthase is a classic example of a chain-building
      multienzyme. A cornerstone of its mechanism has been the obligatory collaboration
      of two identical subunits, with fatty acyl intermediates transferring between
      them. Now, fresh evidence has upset this view.

PMID- 12618180
TI  - Aptamer structures: a preview into regulatory pathways?
AB  - The crystal structure of a streptomycin binding RNA aptamer displays a novel
      bipartite fold able to clamp the antibiotic. In view of the recent findings that
      metabolites directly control mRNA translation, we might expect that similar
      structures exist in natural RNAs.

PMID- 12618181
TI  - Resisting bacterial drug resistance.
AB  - In this issue of Chemistry & Biology, Wright and colleagues report an elegant
      method for inhibiting enzymes critical for rendering bacteria drug resistant. By
      using cationic peptides as inhibitors, the authors have exploited two
      antibacterial mechanisms, making it doubly difficult for microbial retaliation.

PMID- 12618182
TI  - Emerging roles for plant topoisomerase VI.
AB  - Topoisomerase VI is a unique type II topoisomerase originally identified in
      archaea. Although lacking in most eukaryotic phyla, topoisomerase VI homologs
      have been recently identified and characterized in the plant Arabidopsis
      thaliana. Three new studies of Arabidopsis topoisomerase VI show that this enzyme
      is important to several processes involving DNA replication and gene expression.

PMID- 12618183
TI  - Combining combinatorial chemistry and affinity chromatography: highly selective
      inhibitors of human betaine: homocysteine S-methyltransferase.
AB  - A new method to find novel protein targets for ligands of interest is proposed.
      The principle of this approach is based on affinity chromatography and
      combinatorial chemistry. The proteins within a crude rat liver homogenate were
      allowed to interact with a combinatorial library of phosphinic pseudopeptides
      immobilized on affinity columns. Betaine: homocysteine S-methyltransferase (BHMT)
      was one of the proteins that was retained and subsequently eluted from these
      supports. The phosphinic pseudopeptides, which served as immobilized ligands for
      the isolation of rat BHMT, were then tested for their ability to inhibit human
      recombinant BHMT in solution. The most potent inhibitor also behaved as a
      selective ligand for the affinity purification of BHMT from a complex media.
      Further optimization uncovered Val-Phe-psi[PO(2-)-CH(2)]-Leu-His-NH(2) as a
      potent BHMT inhibitor that has an IC(50) of about 1 microM.

PMID- 12618184
TI  - Selective chemical treatment of cellular microdomains using multiple laminar
      streams.
AB  - There are many experiments in which it would be useful to treat a part of the
      surface or interior of a cell with a biochemical reagent. It is difficult,
      however, to achieve subcellular specificity, because small molecules diffuse
      distances equal to the extent of the cell in seconds. This paper demonstrates
      experimentally, and analyzes theoretically, the use of multiple laminar fluid
      streams in microfluidic channels to deliver reagents to, and remove them from,
      cells with subcellular spatial selectivity. The technique made it possible to
      label different subpopulations of mitochondria fluorescently, to disrupt selected
      regions of the cytoskeleton chemically, to dislodge limited areas of cell
      substrate adhesions enzymatically, and to observe microcompartmental endocytosis
      within individual cells. This technique does not require microinjection or
      immobilization of reagents onto nondiffusive objects; it opens a new window into
      cell biology.

PMID- 12618185
TI  - A novel action of terpendole E on the motor activity of mitotic Kinesin Eg5.
AB  - To reveal the mechanism of mitosis, the development of M phase-specific
      inhibitors is an important strategy. We have been screening microbial products to
      find specific M phase inhibitors that do not directly target tubulins, and
      rediscovered terpendole E (TerE) as a novel Eg5 inhibitor. TerE did not affect
      microtubule integrity in interphase, but induced formation of a monoastral
      spindle in M phase. TerE inhibited both motor and microtubule-stimulated ATPase
      activities of human Eg5, but did not affect conventional kinesin from either
      Drosophila or bovine brain. Although terpendoles have been reported as inhibitors
      of acyl-CoA:cholesterol O-acyltransferase (ACAT), the Eg5 inhibitory activity of
      TerE was independent of ACAT inhibition. Taken together, we demonstrate that TerE
      is a novel Eg5 inhibitor isolated from a fungal strain.

PMID- 12618186
TI  - Crystal structure of a transition state mimic for Tdp1 assembled from vanadate,
      DNA, and a topoisomerase I-derived peptide.
AB  - Tyrosyl-DNA phosphodiesterase (Tdp1) is a member of the phospholipase D
      superfamily and acts as a DNA repair enzyme that removes stalled topoisomerase I-
      DNA complexes by hydrolyzing the bond between a tyrosine side chain and a DNA 3'
      phosphate. Despite the complexity of the substrate of this phosphodiesterase,
      vanadate succeeded in linking human Tdp1, a tyrosine-containing peptide, and a
      single-stranded DNA oligonucleotide into a quaternary complex that mimics the
      transition state for the first step of the catalytic reaction. The conformation
      of the bound substrate mimic gives compelling evidence that the topoisomerase I
      DNA complex must undergo extensive modification prior to cleavage by Tdp1. The
      structure also illustrates that the use of vanadate as the central moiety in high
      order complexes has the potential to be a general method for capturing protein
      substrate interactions for phosphoryl transfer enzymes, even when the substrates
      are large, complicated, and unusual.

PMID- 12618187
TI  - Conformational restriction via cyclization in beta-amyloid peptide Abeta(1-28)
      leads to an inhibitor of Abeta(1-28) amyloidogenesis and cytotoxicity.
AB  - The aggregation process of beta-amyloid peptide Abeta into amyloid is strongly
      associated with the pathology of Alzheimer's disease (AD). Aggregation may
      involve a transition of an alpha helix in Abeta(1-28) into beta sheets and
      interactions between residues 18-20 of the "Abeta amyloid core." We applied an i,
      i+4 cyclic conformational constraint to the Abeta amyloid core and devised side
      chain-to-side chain lactam-bridged cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28).
      In contrast to Abeta(1-28) and [Lys(17), Asp(21)]Abeta(1-28), cyclo(17, 21)
      [Lys(17), Asp(21)]Abeta(1-28) was not able to form beta sheets and cytotoxic
      amyloid aggregates. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) was able to
      interact with Abeta(1-28) and to inhibit amyloid formation and cytotoxicity.
      Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28) also interacted with Abeta(1-40) and
      interfered with its amyloidogenesis. Cyclo(17, 21)-[Lys(17), Asp(21)]Abeta(1-28)
      or similarly constrained Abeta sequences may find therapeutic and diagnostic
      applications in AD.

PMID- 12618188
TI  - EF-Tu binding peptides identified, dissected, and affinity optimized by phage
      display.
AB  - The highly abundant GTP binding protein elongation factor Tu (EF-Tu) fulfills
      multiple roles in bacterial protein biosynthesis. Phage-displayed peptides with
      high affinity for EF-Tu were selected from a library of approximately 4.7 x
      10(11) different peptides. The lack of sequence homology among the identified EF
      Tu ligands demonstrates promiscuous peptide binding by EF-Tu. Homolog shotgun
      scanning of an EF-Tu ligand was used to dissect peptide molecular recognition by
      EF-Tu. All homolog shotgun scanning selectants bound to EF-Tu with higher
      affinity than the starting ligand. Thus, homolog shotgun scanning can
      simultaneously optimize binding affinity and rapidly provide detailed structure
      activity relationships for multiple side chains of a polypeptide ligand. The
      reported peptide ligands do not compete for binding to EF-Tu with various
      antibiotic EF-Tu inhibitors, and could identify an EF-Tu peptide binding site
      distinct from the antibiotic inhibitory sites.

PMID- 12618189
TI  - Engineering of an active animal fatty acid synthase dimer with only one competent
      subunit.
AB  - Animal fatty acid synthases are large polypeptides containing seven functional
      domains that are active only in the dimeric form. Inactivity of the monomeric
      form has long been attributed to the obligatory participation of domains from
      both subunits in catalysis of substrate loading and condensation reactions.
      However, we have engineered a fatty acid synthase containing one wild-type
      subunit and one subunit compromised by mutations in all seven functional domains
      that is active in fatty acid synthesis. This finding indicates that a single
      subunit, in the context of a dimer, is able to catalyze the entire biosynthetic
      pathway and suggests that, in the natural complex, each of the two subunits forms
      a scaffold that optimizes the conformation of the companion subunit.

PMID- 12618190
TI  - Encapsulating streptomycin within a small 40-mer RNA.
AB  - We describe a 2.9 A X-ray structure of a complex between the aminocyclitol
      antibiotic streptomycin and an in vitro selected RNA aptamer, solved using the
      anomalous diffraction properties of Ba cations. The RNA aptamer, which contains
      two asymmetric internal loops, adopts a distinct cation-stabilized fold involving
      a series of S-shaped backbone turns anchored by canonical and noncanonical pairs
      and triples. The streptomycin streptose ring is encapsulated by stacked arrays of
      bases from both loops at the elbow of the L-shaped RNA architecture. Specificity
      is defined by direct hydrogen bonds between all streptose functional groups and
      base edges that line the inner walls of the cylindrical binding pocket. By
      contrast, the majority of intermolecular interactions involve contacts to
      backbone phosphates in the published structure of streptomycin bound to the 16S
      rRNA.

PMID- 12618191
TI  - Broad-spectrum peptide inhibitors of aminoglycoside antibiotic resistance
      enzymes.
AB  - The action of aminoglycoside antibiotics is inhibited by chemical modification
      catalyzed by aminoglycoside inactivating enzymes, which bind these cationic
      saccharides with active site pockets that contain a preponderance of negatively
      charged residues. In this study, it was observed that several cationic
      antimicrobial peptides, representing different structural classes, could serve as
      inhibitors of such aminoglycoside resistance enzymes. The bovine antimicrobial
      peptide indolicidin and synthetic analogs appeared to be especially effective
      against a range of resistance enzymes, inhibiting enzymes belonging to both
      aminoglycoside phosphotransferase and aminoglycoside acetyltransferase classes,
      where the mode of action was dependent on the class of antibiotic resistance
      enzyme. These peptides represent the first example of broad-spectrum inhibitors
      of aminoglycoside resistance enzymes.

PMID- 12618192
TI  - Neck disease and distant metastases.
AB  - While the implementation of multi-modality neoadjuvant therapy for the treatment
      of head and neck cancer has resulted in an improvement in local regional control,
      there has been a resultant increase in the reported incidence of distant
      metastasis. This shift in the pattern of patient treatment failure highlights the
      importance of identifying patients at high risk of developing metastasis,
      accurately detecting metastasis, and improving treatment strategies for advanced
      disease. Currently, metastatic lesions from head and neck primaries portend a
      poor prognosis; however, molecular biologic techniques offer a promising approach
      to the diagnosis and treatment of micrometastasis and distant metastatic lesions.
      The identification of tumor-specific gene mutations and the cell surface antigens
      may play a key role in the future management of head and neck cancer. The
      following review outlines just several of the current issues related to the
      contemporary diagnosis and management of metastatic lesions of the head and neck.

PMID- 12618193
TI  - Oral cancer: reviewing the present understanding of its molecular mechanism and
      exploring the future directions for its effective management.
AB  - The present review aims to analyze the information available regarding the
      molecular mechanisms of Oral Carcinogenesis and explore the future directions
      where the field of Cancer Biology is venturing. Oncologists have excellently
      followed the proverb "Necessity is the mother of Invention". The desire to be
      more precise and comprehensive in their studies has led to the invention of some
      of the most innovative techniques like laser capture microdissection, comparative
      genomic hybridization, microarrays, and protein chips etc. Various Biotech
      companies and Cancer Institutes are on a hunt for anti-cancer drugs and molecular
      markers for cancers. These revolutionary approaches and the new breed of
      Oncologists have made the field very exciting and have generated the hope that
      finally the war against cancer would be won. In the end it is urged that the lead
      taken in other cancers like colon, breast, leukemia will be emulated in oral
      cancer. This is expected to provide a molecular blueprint for HNSCC, thus helping
      to identify suitable markers for the early detection of pre-neoplastic lesions,
      as well as novel targets for its pharmacological intervention.

PMID- 12618194
TI  - The p53 network in head and neck cancer.
AB  - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer
      worldwide and, despite advances in treatment, still represents a clinical
      challenge. Inactivation of one or more components of the p53 network is an
      extremely common event in human neoplasia. In HNSCC, disabling of p53 occurs in a
      high proportion of cases by mutation in the p53 gene, but other mechanisms of
      inactivation, such as the presence of human papillomavirus (HPV) and molecular
      abnormalities in other components of the pathway, are also recognised. The
      frequent changes occurring in the p53 pathway in HNSCC imply that molecular
      genetic and immunocytochemical analysis of this critical tumour suppressor
      network may be of diagnostic and prognostic utility in the clinical management of
      HNSCC. Further, these changes also provide targets for the development of novel
      therapeutic approaches to this increasingly common cancer, in which clinical cure
      for advanced disease remains an elusive goal.

PMID- 12618195
TI  - Familial upper aerodigestive tract cancers: incidence trends, familial clustering
      and subsequent cancers.
AB  - Familial risks in upper aerodigestive tract cancer have been assessed mainly
      through case-control studies based on reported but not medically verified cancers
      in family members. The nationwide Swedish Family-Cancer Database was used to
      describe the incidence trends for all subsites of upper aerodigestive tract
      cancer and to calculate standardized incidence ratios (SIRs) and 95% confidence
      intervals (CIs) for the cancer in 0-66-year-old offspring by cancers in family
      members. Additionally, SIRs for second primary cancer after upper aerodigestive
      tract cancers were analysed. SIRs in offspring for all upper aerodigestive tract
      cancer were not significant when a parent presented with concordant cancer. The
      population attributable fraction of familial upper aerodigestive tract cancer was
      0.43%. Risk for subsequent cancers in men and women after upper aerodigestive
      tract cancer were increased in smoking, alcohol and other life-style related
      sites and in skin cancer and non-Hodgkin's lymphoma.

PMID- 12618196
TI  - Effects of fibroblast growth inhibitor on proliferation and metastasis of oral
      squamous cell carcinoma.
AB  - Development of a new therapeutic approach to improve the prognosis of high grade
      invasion of oral squamous cell carcinoma is needed. To elucidate the effect of a
      fibroblast inhibitor (tranilast), we investigated the proliferation and
      metastasis of oral squamous cell carcinoma in a mouse model. The effect of
      tranilast on tumour growth, lymph node metastases, microvessel density, and the
      proliferating cell nuclear antigen (PCNA) labelling index of oral squamous cell
      carcinoma implanted into the tongue of nude mice was evaluated. Tumour growth and
      the incidence of cervical lymph node metastases were significantly suppressed by
      the administration of tranilast. The amount of fibrous tissue, the microvessel
      density, and the PCNA labelling index of tumour were also significantly reduced.
      Administration of a fibroblast inhibitor may well be clinically effective for the
      treatment of oral squamous cell carcinoma.

PMID- 12618197
TI  - Gene discovery in oral squamous cell carcinoma through the Head and Neck Cancer
      Genome Anatomy Project: confirmation by microarray analysis.
AB  - The near completion of the human genome project and the recent development of
      novel, highly sensitive high-throughput techniques have now afforded the unique
      opportunity to perform a comprehensive molecular characterization of normal,
      precancerous, and malignant cells, including those derived from squamous
      carcinomas of the head and neck (HNSCC). As part of these efforts, representative
      cDNA libraries from patient sets, comprising of normal and malignant squamous
      epithelium, were generated and contributed to the Head and Neck Cancer Genome
      Anatomy Project (HN-CGAP). Initial analysis of the sequence information indicated
      the existence of many novel genes in these libraries [Oral Oncol 36 (2000) 474].
      In this study, we surveyed the available sequence information using bioinformatic
      tools and identified a number of known genes that were differentially expressed
      in normal and malignant epithelium. Furthermore, this effort resulted in the
      identification of 168 novel genes. Comparison of these clones to the human genome
      identified clusters in loci that were not previously recognized as being altered
      in HNSCC. To begin addressing which of these novel genes are frequently expressed
      in HNSCC, their DNA was used to construct an oral-cancer-specific microarray,
      which was used to hybridize alpha-(33)P dCTP labeled cDNA derived from five HNSCC
      patient sets. Initial assessment demonstrated 10 clones to be highly expressed
      (>2-fold) in the normal squamous epithelium, while 14 were highly represented in
      the malignant counterpart, in three of the five patient sets, thus suggesting
      that a subset of these newly discovered transcripts might be highly expressed in
      this tumor type. These efforts, together with other multi-institutional genomic
      and proteomic initiatives are expected to contribute to the complete
      understanding of the molecular pathogenesis of HNSCCs, thus helping to identify
      new markers for the early detection of preneoplastic lesions and novel targets
      for pharmacological intervention in this disease.

PMID- 12618198
TI  - Genomic dissection for characterization of cancerous oral epithelium tissues
      using transcription profiling.
AB  - Genome-wide and high-throughput functional genomic tools offer the potential of
      identifying disease-associated genes and dissecting disease regulatory patterns.
      There is a need for a set of systematic bioinformatic tools that handles
      efficiently a large number of variables for extracting biological meaning from
      experimental outputs. We present well-characterized statistical tools to discover
      genes that are differentially expressed between malignant oral epithelial and
      normal tissues in microarray experiments and to construct a robust classifier
      using the identified discriminatory genes. Those tools include Wilks' lambda
      score, error rate estimated from leave-one out cross-validation (LOOCV) and
      Fisher Discriminant Analysis (FDA). High Density DNA microarrays and Real Time
      Quantitative PCR were employed for the generation and validation of the
      transcription profile of the oral cancer and normal samples. We identified 45
      genes that are strongly correlated with malignancy. Of the 45 genes identified,
      six have been previously implicated in the disease, and two are uncharacterized
      clones.

PMID- 12618199
TI  - Etoposide-mediated sensitization of squamous cell carcinoma cells to tumor
      necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced loss in
      mitochondrial membrane potential.
AB  - Squamous cell carcinoma (SCC) cell lines (MIT7-x(L), MIT8, and MIT16) that
      overexpress Bcl-x(L) have been demonstrated to show resistance to multiple
      chemotherapeutic drugs. Tumor necrosis factor (TNF)-related apoptosis-inducing
      ligand (TRAIL), which belongs to the TNF family of proteins, induces apoptosis in
      tumor, but not in normal, cells. In the present study, we examined whether
      etoposide sensitizes tumor cells with multiple-drug-resistance to TRAIL-induced
      apoptosis. Sequential treatment with etoposide and TRAIL resulted in a
      synergistically induced cell death in the two resistant lines (MIT7-x(L) and
      MIT16) but not MIT8, as assessed by WST-8 assay. As expected, MIT7 cells (a drug
      sensitive line) were sensitive to the combined treatment. The cell death caused
      by both etoposide and TRAIL appears to involve apoptosis, since the combined
      treatment caused a loss in mitochondrial membrane potential (DeltaPsim), which is
      closely associated with apoptosis induction. The density of the TRAIL-receptors
      (TRAIL-Rs) was not appreciably modulated by the etoposide treatment, suggesting
      that etoposide targets molecule(s) downstream of the TRAIL-Rs. Regardless of the
      molecular mechanisms underlying the cell death, sequential treatment with
      etoposide and TRAIL could be useful in the design of treatment modalities for
      patients with SCC, especially those with elevated levels of Bcl-x(L).

PMID- 12618200
TI  - Mel-CAM (CD146) expression in parotid mucoepidermoid carcinoma.
AB  - Mel-CAM (CD146) is a cell-cell adhesion protein found in normal and tumoral
      tissues. The aim of this study was to analyse Mel-CAM expression in
      mucoepidermoid carcinoma (MEC), and assess its importance in prognosis and its
      utility in differentiating high-grade MEC from squamous cell carcinoma (SCC).
      Immunohistochemical expression of Mel-CAM in 41 parotid MEC was correlated with
      clinical parameters. Ten cases of oral cavity SCC were included for comparison.
      Mel-CAM expression was found in 92.7% of the MEC but was not expressed by the
      SCC. Mel-CAM expression was greater in intermediate/high grade tumors, was weaker
      in patients that presented local recurrence, regional and distant metastasis, but
      no correlation between Mel-CAM and clinical stage and survival of the patients
      was found. Decreased Mel-CAM expression can impair cellular contact properties,
      facilitating growth, cell spreading and metastasis in MEC. Mel-CAM can also be
      useful in differentiating high grade MEC from SCC.

PMID- 12618201
TI  - Cisplatin induces apoptosis in oral squamous carcinoma cells by the mitochondria
      mediated but not the NF-kappaB-suppressed pathway.
AB  - Cisplatin (CDDP) is a potent DNA-damaging anticancer agent, and its cytotoxic
      action is exerted by the induction of apoptosis. However, activation of the
      transcription factor NF-kappaB results in protection against apoptosis. We
      examined the molecular mechanisms involved in the induction of apoptosis by CDDP
      as regards both suppression of NF-kappaB and activation of caspases. Human oral
      squamous carcinoma cells (B88) were employed in this study. We found that CDDP
      treatment affected neither NF-kappaB activity nor the expression levels of
      antiapoptotic proteins, including TRAF-1, TRAF-2, and cFLIP, in B88 cells.
      However, two apoptosome molecules, cytochrome c and Apaf-1, were significantly
      augmented in the cytoplasm by CDDP treatment. Further, the activation of caspase
      9 and caspase-3, downstream molecules leading to mitochondria-mediated apoptosis,
      were detected after treatment with CDDP. Finally, apoptosis was also clearly
      observed, as evidenced by cleavage of PARP through the activation of caspase-3.
      These findings suggest that CDDP exerts its apoptotic action by the mitochondria
      mediated activation of caspases but not by the activation of caspases due to the
      inhibition of NF-kappaB activity that follows the suppression of antiapoptotic
      proteins.

PMID- 12618202
TI  - Evaluation of tumor proliferation using dynamic contrast enhanced-MRI of oral
      cavity and oropharyngeal squamous cell carcinoma.
AB  - We investigated the relationship between the enhanced patterns acquired by
      dynamic MRI and the tumor cell proliferation estimated by immunostaining
      proliferating cell nuclear antigen (PCNA) in oral squamous cell carcinoma (SCC).
      Thirty patients with primary oral SCC underwent dynamic contrast enhanced (DCE)
      MRI using a three-dimensional fast imaging with steady-state precession sequence.
      Tumor cell proliferation of all surgical specimens was evaluated using
      immunohistochemical staining with the anti-PCNA antibody. The relationship
      between the dynamic MRI parameters (maximum CI and maximum CI gain) and the PCNA
      labeling index was statistically analyzed using regression analysis. The time
      contrast index curves of all cases showed a rapid and high uptake pattern. The
      PCNA labeling index showed a significant correlation with maximum CI and maximum
      CI gain (P<0.0001, r=0.866 and P=0.0019, r=0.544, respectively). The assessment
      of DCE-MRI parameters may provide valuable information for tumor cell
      proliferation of the patients with oral cancer.

PMID- 12618203
TI  - Detection of LMP-1 gene in middle ear effusion of NPC.
AB  - Nasopharyngeal carcinoma (NPC) is closely related with Epstein-Barr virus (EBV).
      Almost every NPC tumor cells carries clonal EBV genomes. Detection of EBV derived
      latent membrane protein-1 gene (LMP-1) indicate the presence of NPC. Middle ear
      effusion (MEE) is a frequent sign of NPC. There have been no reports on LMP-1 in
      MEE. Tympanocentesis of 88 ears with MEE of 66 patients were done in three groups
      of patients, group (I) NPC, 31 patients, 50 ears, (II) other head and neck
      cancers, five patients, six ears and (III) no cancer history, 30 patients, 32
      ears. The middle ear aspirate and nasopharyngeal swab specimen were collected to
      detect LMP-1 with a PCR-based method. Sixty aspirates (68%) out of 88 ears with
      MEE had enough DNA for PCR amplification. LMP-1 was detected in six middle ear
      aspirate specimen from three patients in group I who had petrous apex invasion.
      LMP-1 was detected in 30 swab specimen (93.8%) out of 32 nasopharyngeal swabs in
      group I. LMP-1 was not detected in middle ear aspirates or nasopharyngeal swab in
      group II and III patients. LMP-1 was not detected in MEE in patients without NPC.
      In NPC patients, the detection of LMP-1 may indicate petrous apex invasion.

PMID- 12618204
TI  - Fibrous dysplasia in the maxilla: possible mechanism of bone remodeling by
      calcitonin treatment.
AB  - The long-term follow-up case of monostotic fibrous dysplasia of the maxilla in a
      10-year-old girl is described with her endocrinologic data and therapeutic
      consequence of calcitonin administration in association with surgical
      interventions. The fibrous dysplasia tends to become more quiescent or static
      after skeletal growth ceases, but the causative has been still unknown to date.
      In this case reported changes of calciotropic hormones in the serum were well
      corresponding to the ceasing of the tumor growth at the puberty and reflected to
      the calcitonin administration. Although calcitonin has been applied to the
      fibrous dysplasia associated with McCune Albright syndrome, no histologic changes
      have been described after the calcitonin treatment. This report might be the
      first description of bone remodeling after the calcitonin treatment for the
      fibrous dysplasia of the maxilla in immature people. Data of this case may
      provide a clue to the pathogenesis of fibrous dysplasia. Surgical intervention
      can be performed after the local bone calcification by a calcitonin treatment,
      because of alleviation of vigorous hemorrhage by the bone remodeling.

PMID- 12618205
TI  - Oncocytic tumor in myoepithelioma arising from the grossopalatine gland.
AB  - Oncocytoma or oncocytic change in salivary glands normally occurs in old patients
      and mostly in the parotid gland, but those arising from the grossopalatine gland
      in young patients are extremely rare. The present case shows that oncocytic
      ductal structures were observed in myoepithelioma, consisting of spindle,
      plasmacytoid or epithelioid cells. The oncocytic tumor contained large amounts of
      eosinophilic granular cytoplasm and small nuclei.

PMID- 12618206
TI  - Clinical characteristics of oral adenosquamous carcinoma: report of a case and an
      analysis of the reported Japanese cases.
AB  - We present a case of adenosquamous carcinoma (ASC) which developed in the floor
      of the mouth of a 72-year-old Japanese man, and review 19 reported ASC cases in
      Japan from between 1986 and 2001, including the subject case herein. These ASCs
      occurred at an average age of 63 years, with 74% of the ASCs occurring in the
      floor of the mouth (8) and the tongue (6); the other sites of occurrence were the
      palate (3) and mandibular alveolus (2). Chief complaints were painless mass
      formation (28%), pain and/or sensational abnormality (28%), painful ulcer or
      swelling (22%), simple ulcer (11%), and miscellaneous others (11%). The clinical
      presentations of ASC were tumor with ulceration (58%), tumorous mass (26%), and
      ulcer (16%). Tumor size at first examination varied from bean-size to
      approximately 65 x 40 mm. In the pretreatment period, 31.3% were known to have
      cervical lymph node involvement, and descriptions on distant metastasis were not
      noted in any of the 19 cases. Some of the ASCs were initially diagnosed as other
      types of lesions, such as squamous cell carcinoma (SCC; 41%), adenocarcinoma
      (Ad.C; 12%) mucoepidermoid carcinoma (MEC; 6%), and MEC or SCC (6%). After
      initial treatments, neck and distant metastases were ascertained in 47.1 and
      17.6% of the cases, respectively. Generally, a surgical procedure was performed
      as one of the most critical methods of treatment. The overall 5-year survival
      rate was 57.0%, with that of patients who underwent active treatment at 60.6%.
      Our study demonstrates the extent of the varied nature of ASC.

PMID- 12618207
TI  - Infiltrating intramuscular lipoma of the temporal muscle. A case report with
      molecular cytogenetic analysis.
AB  - Intramuscular lipomas are uncommon benign mesenchymal tumors which infiltrate
      skeletal muscle and are exceedingly rare in the head and neck region. Because of
      the infiltrating nature of the lesion and a high propensity for recurrence, they
      are sometimes difficult to distinguish from well-differentiated liposarcomas
      (WDLS). We report, the first case of an infiltrating lipoma of the temporal
      muscle in a 62-year-old white man who presented with a slow growing mass in the
      left temporal region. The histopathological examination showed diffuse
      infiltration of the striated muscle fibers by mature adipocytes. There were no
      lipoblasts or cells with atypical nuclei as described in WDLS. We performed
      interphase fluorescence in situ hybridization (FISH) analyses using painting
      probes for chromosome 12 and a specific probe for the MDM2 gene and comparative
      genomic hybridization. The results did not identify MDM2 or 12q amplification and
      therefore confirmed the benign nature of the lesion.

PMID- 12618208
TI  - Spontaneous regression of extranodal malignant lymphoma occurred in the gingiva.
AB  - The spontaneous regression of malignant neoplasm is an extremely rare event. Here
      we report a case of extranodal malignant lymphoma occurring in the upper gingiva,
      which regressed spontaneously. A 78-year-old female had noticed a diffuse bucco
      lingual swelling of the left maxillary gingiva in the incisor regions for a
      month, and she visited our department on 20 January 1999. Intraoral examination
      revealed diffuse swelling and redness in the maxillary gingiva of the incisor
      regions. Cervical and underarm lymphadenopathy was not detected. Surgical biopsy
      of the swollen gingiva revealed a malignant lymphoma, with diffuse large cells, B
      cell type. She was clinically staged as IE. After biopsy, the tumor spontaneously
      decreased in size; finally, the mass completely disappeared after 3 weeks. After
      regression, the lesions were externally irradiated with 30 Gy total dose. The
      patient has been free from disease for 36 months after regression.

PMID- 12618209
TI  - CaMBOT: profiling and characterizing calmodulin-binding proteins.
AB  - Calmodulin (CaM) is an essential calcium-binding protein that binds to and
      activates a diverse population of downstream targets (calmodulin-binding
      proteins; CaMBPs) that carry out its critical signalling functions. In spite of
      the central importance of CaM in Ca(2+)-mediated signal transduction pathways in
      all eukaryotes, many CaMBPs remain to be identified and characterized. SDS-PAGE
      followed by gel overlay with recombinant, metabolically radiolabelled CaM
      (Calmodulin-binding Overlay Technique, CaMBOT) is a valuable method for following
      behavioural, developmental, forensic and physiological changes in total CaMBP
      populations and to identify candidate CaMBPs for further study. CaMBOT has also
      been adapted to isolate cDNAs encoding novel CaMBPs in various organisms.
      Recently, the method was used to examine the CaMBP complement encoded by the
      Arabidopsis genome and to identify a new family of transcription activators. To
      add to its diversity, CaMBOT may be useful for finding target proteins for work
      on phytoremediation and for the screening of pharmaceuticals and toxic agents
      that, directly or indirectly, affect CaM and its target proteins. This review
      discusses all of these topics and the role of CaMBOT in characterizing a
      functional unit of the proteome-proteins regulated by calmodulin.

PMID- 12618210
TI  - Nuclear receptors: integration of multiple signalling pathways through
      phosphorylation.
AB  - Nuclear receptors (NRs) orchestrate the transcription of specific gene networks
      in response to binding of their cognate ligand. They also act as mediators in a
      variety of signalling pathways through integrating diverse phosphorylation
      events. NR phosphorylation concerns all three major domains, the N-terminal
      activation function (AF-1), the ligand-binding and the DNA binding domains.
      Often, phosphorylation of NRs by kinases that are associated with general
      transcription factors (e.g. cdk7 within TFIIH), or activated in response to a
      variety of signals (MAPKs, Akt, PKA, PKC), facilitates the recruitment of
      coactivators or of components of the transcription machinery and, therefore,
      cooperates with the ligand to enhance transcription activation. But
      phosphorylation can also contribute to the termination of the ligand response
      through inducing DNA dissociation or NR degradation or through decreasing ligand
      affinity. These different modes of regulation reveal an unexpected complexity of
      the dynamics of NR-mediated transcription. In addition, deregulation of NR
      phosphorylation may impact their action in certain diseases or cancers.

PMID- 12618211
TI  - Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1
      phosphate.
AB  - Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are serum-borne
      lipid mediators with potential proinflammatory and atherogenic properties. We
      studied the effects of LPA and S1P on [Ca(2+)](i), a second messenger of cellular
      activation, in human monocytic Mono Mac 6 (MM6) cells. LPA and S1P induced
      [Ca(2+)](i) transients with EC(50) values of 47 and 340 nM, respectively. Ca(2+)
      signals evoked by LPA and S1P originated mainly from the stimulation of Ca(2+)
      entry, were blocked by the phospholipase C inhibitor U73122, and were inhibited
      by pertussis toxin. The LPA(1) and LPA(3) receptor antagonist dioctylglycerol
      pyrophosphate inhibited the LPA-induced Ca(2+) signal. Notably, serum and
      minimally modified LDL (mm-LDL) evoked [Ca(2+)](i) increases that were mediated
      entirely through activation of LPA receptors. Reverse transcriptase polymerase
      chain reaction (RT-PCR) analysis showed the presence of the LPA and S1P receptor
      subtypes LPA(1), LPA(2,) S1P(1), S1P(2), S1P(4) in MM6 cells, human monocytes and
      macrophages. Together these results indicate that LPA, mm-LDL and serum induce
      via activation of the LPA(1) receptor a G(i)/phospholipase C/Ca(2+) signalling
      pathway in monocytes. Our study is the first report showing the receptor-mediated
      activation of human monocytic cells by low nanomolar concentrations of LPA and
      S1P, and suggests a role of these lipid mediators in inflammation and
      atherogenesis.

PMID- 12618212
TI  - Formylpeptides trigger selective molecular pathways that are required in the
      physiological functions of human neutrophils.
AB  - For-Met-Delta(z)Leu-Phe-OMe ([Delta(z)Leu(2)]) is a conformationally restricted
      for-Met-Leu-Phe-OMe (fMLP-OMe) analogue able to discriminate between different
      responses of human neutrophils. In contrast, [Delta(z)Leu(2)] significantly
      activates the transduction pathways-involving Ca(2+), inositol phosphate, and
      cyclic AMP (cAMP) enhancement, as is the case with the full agonist fMLP-OMe.
      Here, we have studied the specific involvement of protein kinase C (PKC) isoforms
      and mitogen activated protein kinases (MAPKs) in the presence or absence of
      extracellular Ca(2+), being the cation clearly involved in the activation of
      neutrophils by fMLP. A strong correlation has been found between PKC isoforms,
      MAPKs and the selective physiological functions by [Delta(z)Leu(2)]-activated
      neutrophils. In a calcium-free condition, our data suggest that the failure of
      PKC beta1 translocation and of p38 MAPK phosphorylation by the analogue refers to
      its inability to induce chemotaxis, and that the failure by both fMLP-OMe and
      [Delta(z)Leu(2)] to evoke extracellular response kinase 1 and 2 (ERK1/2)
      phosphorylation would suggest a reduction in superoxide anion production.

PMID- 12618213
TI  - IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a
      murine T-cell lymphoma devoid of IGF-I receptors.
AB  - Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells,
      GH either directly or indirectly via IGF-I production. We have studied a
      spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which
      proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show
      that GH is more potent than insulin, with both GH and insulin dose-response
      curves for thymidine incorporation being bell-shaped. Binding showed somatogenic
      rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the
      insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This
      phosphorylated IRS-4 associated with PI3-kinase, which was activated along with
      the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using
      selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to
      be involved in insulin-stimulated DNA synthesis. GH induced tyrosine
      phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells
      constitute a new model for studying GH and insulin signalling without
      interference of IGF-1 receptors.

PMID- 12618214
TI  - Making human nasal cilia beat in the cold: a real time assay for cell signalling.
AB  - Human nasal epithelium must adapt to cold climates, and yet, in vitro, human
      ciliary beat frequency (CBF) is zero at 4 degrees C. Similarly, hibernating
      mammals do not die of pneumonia despite a core body temperature as low as 6
      degrees C, implying that cilia continue to beat. Here, we show that protein
      kinase C (PKC) and Ca(2+)/calmodulin-dependent kinase II (CaMKII) regulate the
      profile of human nasal CBF in response to rising temperature from 4 degrees C.
      Onset of ciliary beat was at 10 degrees C in Medium 199, 7 degrees C in the
      presence of the PKC activator phorbol 12-myristate 13-acetate (PMA), the calcium
      ionophore ionomycin, or the CAMKII blocker myristoylated autocamtide-2 related
      inhibitory peptide (MACI), and 6 degrees C for the myristoylated peptide PKC
      inhibitor EGF-R Fragment 651-658 (MyrPKCI). During cell warming to 32 degrees C,
      the thermal profile was sigmoid in all solutions except those containing
      MACI+PMA. Surprisingly, cilia continued to beat despite 4 degrees C and were
      significantly more responsive to rising temperature with either MACI+PMA, or
      MACI+MyrPKCI. Our data suggest that CaMKII and PKC regulate the thermal slope and
      profile of CBF in vitro, and that when these protein kinases are manipulated,
      cilia can continue to beat despite hypothermia. These findings may relate to
      adaptive responses to cold climates.

PMID- 12618215
TI  - Regulation of alpha(1)-adrenoceptor-linked phosphoinositide metabolism in
      cultured glia: involvement of protein phosphatases and kinases.
AB  - Noradrenaline-stimulated phosphoinositide breakdown in cultured glia was found to
      be mediated by alpha(1A)-adrenoceptors. The alpha(1A)-selective agonist A61603
      was as effective as noradrenaline in eliciting 3H-inositol phosphate (IP)
      accumulation but was approximately 50-fold more potent. In addition, the use of
      selective antagonists revealed a clear rank order of potency in the ability of
      these drugs to reverse the effect of noradrenaline on phosphoinositide breakdown:
      RS17053 (alpha(1A)-selective) >>AH11110A (alpha(1B)-selective)>BMY7378 (alpha(1D)
      selective). Pre-treatment of cultured glia with the protein phosphatase inhibitor
      okadaic acid resulted in a concentration- and time-dependent reduction in
      noradrenaline-evoked 3H-IP accumulation. This effect was mimicked by, but was not
      additive with, a phorbol ester, was reversed by protein kinase C (PKC) inhibitors
      and was not evident in cells which had been PKC depleted. The ability of cell
      extracts to dephosphorylate radiolabelled glycogen phosphorylase revealed the
      presence of the phosphatases PP1 and PP2A in almost equal abundance. Okadaic acid
      pre-treatment of intact cultures elicited a marked reduction in total phosphatase
      activity, particularly that mediated by PP2A. We also determined the effect of
      okadaic acid pre-treatment on PKC and cyclic AMP-dependent protein kinase (PKA)
      activities in these cells. PKC and PKA activities in cell extracts were assessed
      by determining the incorporation of 32P into histone and kemptide, respectively.
      Okadaic acid elicited increases in both Ca(2+)-dependent and Ca(2+)-independent
      PKC activity; in addition, increases in both initial and total PKA activities
      were also recorded. The effect of okadaic acid on noradrenaline-stimulated 3H-IP
      accumulation were not, however, mimicked by either forskolin or 8-bromo-cyclic
      AMP, suggesting that this event is not regulated by PKA. Our data point to roles
      for both PKC and PP2A in the regulation of alpha(1A)-adrenoceptor-linked
      phosphoinositide metabolism in cultured cortical glia.

PMID- 12618217
TI  - NF-kappaB is required for cell death induction by latent membrane protein 1 of
      Epstein-Barr virus.
AB  - NF-kappaB is a transcription factor known to promote or antagonize cell death
      depending on cell types and stimuli. Here, we demonstrate that expression of
      latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV)-encoded membrane
      protein, triggers programmed cell death in an NF-kappaB-dependent manner. Co
      expression of NF-kappaB inhibitors completely prevented activation of NF-kappaB
      and LMP1-induced cell death. Addition therein of RelA, an active subunit of NF
      kappaB, restored the NF-kappaB activation and cell death induction by LMP1, but
      RelA alone did not induce cell death. These results indicate that the activation
      of NF-kappaB is required for cell death induced by LMP1. Moreover, LMP1 induced
      activation of caspase-3 via the activation of NF-kappaB. Studies with z-VAD-fmk,
      a caspase inhibitor, indicated that NF-kappaB mediated both caspase-dependent and
      -independent death pathways. In conclusion, the cell death induced by LMP1
      uncovered caspase-dependent and -independent death pathways both of which require
      NF-kappaB.

PMID- 12618216
TI  - The N-terminal non-RGS domain of human regulator of G-protein signalling 1
      contributes to its ability to inhibit pheromone receptor signalling in yeast.
AB  - Regulators of G-protein signalling (RGS) are a family of proteins that interact
      with G-proteins to regulate negatively G-protein coupled receptor (GPCR)
      signalling. In addition to a conserved core domain that is necessary and
      sufficient for their GTPase activating protein (GAP) like activity, RGSs possess
      N- and C-terminal motifs that confer distinct functional differences. In order to
      identify the role of the non-RGS region of human RGS1, we have characterized a
      series of fusions between RGS1 and GFP in a yeast mutant lacking the RGS
      containing SST2 gene. Using both halo assays as well as a GPCR responsive FUS1
      LacZ reporter gene, we demonstrate that a RGS1-GFP fusion inhibits GPCR
      signalling in yeast while GFP fusions containing either the N-terminus non RGS
      sequence of RGS1(1-68) or the sequence containing the RGS box of RGS1(68-197)
      produce proteins that retain RGS1 activity. These results suggest that both the N
      terminal and the RGS box of RGS1 function to inhibit signalling. Analysis of a
      series of mutants spanning the entire N-terminal non-RGS region of RGS1 produced
      by conservative segment exchange (CSE) mutagenesis showed little loss of function
      in yeast. This suggests that the overall structure of the N-terminal region of
      RGS1 rather than specific motifs or residues is required for its function.

PMID- 12618218
TI  - Sphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists
      for the orphan receptor GPR63.
AB  - Five high affinity G-protein-coupled receptors for sphingosine 1-phosphate (S1P)
      have been characterised so far (S1P(1,2,3,4,5) formerly referred to as
      edg1,5,3,6,8). In this study, we show that S1P, dihydro-sphingosine 1-phosphate
      (dihydro-S1P) and dioleoylphosphatidic acid (doPA) are agonists for the orphan
      receptor GPR63. All three phospholipids mobilise intracellular calcium in CHO
      cells transiently transfected with GPR63. Calcium signals required cotransfection
      of a chimeric Galpha(q/i) protein in a fluorometric imaging plate reader (FLIPR)
      assay but did not require overexpressed G proteins in an aequorin assay, using a
      green fluorescent protein (GFP)-aequorin fusion protein as a bioluminescent
      Ca(2+) reporter. GPR63 expression in CHO cells confers proliferative responses to
      S1P in a pertussis toxin (PTX)-insensitive manner. Quantitative reverse
      transcriptase-polymerase chain reaction (RT-PCR) indicated highest expression in
      brain, especially in the thalamus and the nucleus caudatus. In peripheral
      tissues, highest expression was observed in thymus, stomach and small intestine;
      lower abundance of transcripts was detected in kidney, spleen, pancreas and
      heart. The discovery that S1P, dihydro-S1P and dioleoylphosphatidic acid activate
      GPR63 will facilitate the identification of agonists and antagonists, and help to
      unravel the biological function of this receptor.

PMID- 12618219
TI  - Stochastic description of the ligand-receptor interaction of biologically active
      substances at extremely low doses.
AB  - Signalling molecules can be effective at extraordinarily low concentrations (down
      to attomolar levels). To handle such cases, probabilistic methods have been used
      to describe the formal kinetics of action of biologically active substances in
      these low doses, although it has been necessary to review what is meant by such a
      term. The mean numbers of transformed/degraded molecules and their dispersions
      were calculated for the possible range of ligand-receptor binding schemes. We
      used both analytical equations and numerical simulations to calculate the
      coefficients of variation (ratio of standard deviation to mean) and demonstrated
      that the distribution of the coefficient is highly dependent on the reaction
      scheme. It may, therefore, be used as an additional factor for discriminating
      between cooperative and noncooperative models of ligand-receptor interaction over
      extreme ranges of ligand dilution. The relevance to signalling behaviour is
      discussed.

PMID- 12618220
TI  - Gender differences in cardiac development: are hormones at the heart of the
      matter?

PMID- 12618221
TI  - Collagen cross-linking: new dimension to cardiac remodeling.

PMID- 12618222
TI  - Repolarization alternans: implications for the mechanism and prevention of sudden
      cardiac death.
AB  - For nearly 100 years, beat to beat alternation of T wave amplitude, termed T wave
      alternans (TWA), has been closely linked to electrical instability in the heart.
      TWA is now established among the strongest markers of susceptibility to sudden
      cardiac death. Since computer technology allows for detection of very subtle yet
      clinically significant TWA during standard exercise testing, TWA has been used
      increasingly as a noninvasive clinical tool for identifying and treating patients
      at risk for sudden cardiac death. The observation of TWA hastening ventricular
      tachyarrhythmias in an extraordinary variety of clinical and experimental
      conditions suggest potential universality of TWA in the pathophysiological
      mechanism of sudden death. High resolution optical mapping studies have shown
      that TWA arises from alternans of repolarization at the level of the ventricular
      myocyte. Cellular alternans is likely due to the actions of one or more ionic
      currents and is closely related to, if not directly dependent on, the kinetics of
      intracellular calcium cycling. Impairment in calcium cycling at the cellular and
      sub-cellular levels has been implicated in the mechanism of cellulcar alternans.
      Importantly, spatially discordant alternans between cells is most likely a
      consequence of heterogeneities of electrophysiological properties between cells
      which span the ventricular wall, serving to amplify spatial heterogeneities of
      repolarization, and forming a substrate for reentrant excitation. Through this
      mechanism, TWA is linked directly and mechanistically to the pathogenesis of
      arrhythmias. Although available data would suggest that TWA is certainly closely
      related to a mechanism of arrhythmogenesis, and is a strong marker of clinical
      risk, the precise sequence of events which triggers sudden cardiac death, and the
      potential role of TWA in this process remains elusive.

PMID- 12618223
TI  - Current pathophysiological views on vibration-induced Raynaud's phenomenon.
AB  - This review attempts to summarize and discuss contemporary pathogenetic views on
      vibration-induced Raynaud's phenomenon assuming its multifactorial etiology. An
      increase in central and peripheral sympathetic nervous activity is discussed
      based on different physiological indicators of autonomic dysfunction and
      sympathetic hyperactivity. Local acral vasodysregulation is considered. Receptor
      and nerve endings dysfunction presented with predominance of alpha(2)-receptor
      function in the digital arteries and neuronal loss in those digital cutaneous
      perivascular nerves containing calcitonin gene-related peptide result in
      deficiency of endogenous release of this powerful vasodilator. Endothelial damage
      and dysregulation induced by vibration and increased shear stresses are
      demonstrated by the elevated plasma level of thrombomodulin and of von Willebrand
      factor and reduced endothelium-dependent vasodilator responses. The
      concentrations of endothelin-1 are high, the highest being in most advanced
      stages. Decreased plasma thiol level, indicating increased production and
      activity of free radicals, contribute to vasospastic paroxysms in vibration white
      finger patients. Dysbalance of local vasoactive factors with opposing effects on
      vascular smooth muscle like endothelin and nitric oxide, endothelin and
      calcitonin gene-related peptide, nitric oxide and superoxide anion are discussed.
      Disturbed smooth muscle response is supposed. Changes in hemostasis, fibrinolysis
      and hemorrheology, activation of blood cells with erythrocyte hyperaggregation
      and red cell hypodeformability, platelet aggregation with increased release of
      vasoconstricting thromboxane A(2) and serotonin as well as leukocyte activation,
      entrapment within capillaries and post-capillary venules and increased reactive
      oxygen species and lysosomal lytic enzymes release might also contribute to
      digital vasospasms and tissue damage. Elevated soluble intercellular adhesion
      molecule-1 levels involved in the adherence of leukocytes to endothelium and to
      other leukocytes have been found in patients with hand-arm vibration syndrome.

PMID- 12618224
TI  - Developmental changes of cardiac repolarization in rabbits: implications for the
      role of sex hormones.
AB  - OBJECTIVES: Firstly, to compare gender-dependent differences of cardiac
      repolarization in both adult and young rabbits. Secondly, to analyze the effect
      of gonadectomy on these gender differences in cardiac repolarization. METHODS: We
      evaluated potential gender differences in cardiac repolarization with both
      microelectrode and ECG recordings. QT(end), JT(end), and T(peak-end) intervals
      and action potential durations at 30%, 50% and 90% of full repolarization were
      used to assess ventricular repolarization in adult (normal and gonadectomized)
      and young rabbits of both sexes. RESULTS: Adult rabbits exhibited clear gender
      related differences in repolarization evidenced by significantly longer JT(end)
      and T(peak-end) intervals and significantly longer APD30, APD50 and APD90 in
      females. These gender-related differences in repolarization were absent in young
      rabbits and were abolished by gonadectomy. CONCLUSIONS: Developmental changes of
      repolarization are present in rabbits. These changes are in agreement with those
      reported in humans and may further support the role played by sex hormones in the
      modulation of cardiac repolarization.

PMID- 12618225
TI  - Cross-linking influences the impact of quantitative changes in myocardial
      collagen on cardiac stiffness and remodelling in hypertension in rats.
AB  - OBJECTIVE: To assess whether the variable impact of quantitative changes in
      myocardial collagen on left ventricular (LV) diastolic myocardial stiffness
      (myocardial k) and remodelling (increased volume intercept of diastolic pressure
      volume relations) in LV hypertrophy (LVH) is associated with alterations in
      myocardial collagen cross-linking. METHODS: We evaluated myocardial collagen
      content (hydroxyproline concentrations [HPRO]) and the degree of myocardial
      collagen cross-linking (solubility to cyanogen bromide digestion) in 14-15- and
      21-22-month-old spontaneously hypertensive rats (SHRs), and in aortic-banded rats
      with pressure overload hypertrophy (POH). RESULTS: In rats with POH and in SHRs
      irrespective of age, increases in myocardial [HPRO] were noted. However,
      hypertensive rats differed in the material and geometric properties of the
      myocardium, and in qualitative aspects of fibrosis. In 14-15-month-old SHRs
      myocardial k (determined from diastolic stress-strain relations) and insoluble
      (cross-linked) [HPRO] were increased, but no LV remodelling or increases in
      myocardial soluble (non-cross-linked) [HPRO] were noted. In rats with POH, LV
      remodelling and increases in soluble myocardial [HPRO] occurred, but no increase
      in k or insoluble myocardial [HPRO] were observed. In 21-22-month-old SHRs,
      increases in k, soluble and insoluble myocardial [HPRO], as well as LV
      remodelling occurred. CONCLUSIONS: Collagen cross-linking may determine the
      diverse relation that exists between increases in myocardial collagen
      concentrations and either myocardial stiffness or chamber remodelling in
      hypertension. These findings support the notion that fibrosis contributes to
      myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is
      modulated by collagen quality.

PMID- 12618226
TI  - [K(+)](o)-dependent change in conformation of the HERG1 long QT mutation N629D
      channel results in partial reversal of the in vitro disease phenotype.
AB  - OBJECTIVES: We hypothesized that exposure of N629D/wildtype channels to transient
      increases in [K(+)](o) could alter the conformation of the outer vestibule and
      thus reverse the disease phenotype. N629D is a recently described mutation of the
      HERG1 gene that causes familial long QT syndrome. This mutation alters the pore
      signature sequence resulting in loss of K(+) selectivity. Previous studies have
      reported that enforced occupancy of [K(+)](o) at sites near the selectivity
      filter alters the conformation/folding of the outer vestibule of the Kv2.1
      channel. METHODS: Since the long QT syndrome is manifest in individuals who are
      heterozygous for this HERG trait, we co-expressed N629D and the wildtype at
      equimolar concentrations. RESULTS: Co-expression of N629D/wildtype in Xenopus
      oocytes and mammalian cells resulted in a channel with a positive shift in
      reversal potential and a loss in the outward tail current, relative to the
      wildtype. Exposure of the N629D/wildtype to transient increases in [K(+)](o) from
      5 to 40 mM/l changed the tail current from inward to outward during
      repolarization and restored the reversal potential to values similar to the
      wildtype. These findings in Xenopus oocytes were also seen when N620D/wildtype
      channels were expressed in mammalian cells. These [K(+)](o)-dependent changes
      persisted for hours after the [K(+)](o) was returned to 2.5 mM. This potential
      therapeutic effect began with increases in [K(+)](o) from 2.5 to 5 mM.
      CONCLUSIONS: This study reports a novel therapeutic strategy and mechanism to
      partially restore physiologic function in this HERG LQTS mutation.

PMID- 12618227
TI  - Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid
      results in greater block at high stimulation frequency.
AB  - OBJECTIVE: We have reported identification of the amino acid whose mutation
      reduces effects of quinidine on the HERG channel. Although the residue
      (isoleucine at 647) is not in the recently reported methanesulfonanilide binding
      site, a single concentration of E-4031 (10 microM) was less effective to I647
      mutant channels than wild type HERG channel. We designed the present experiment
      to further investigate influence of mutations at 647 on the effects of
      methanesulfonanilides. METHODS AND RESULTS: HERG channels were expressed in
      Xenopus oocytes and their currents were measured by a two-microelectrode voltage
      clamp method. Of the two mutations initially studied (I647A and I647F), the I647F
      had a greater influence and differentially affected the effects of dofetilide and
      E-4031. The IC(50) for dofetilide of the two mutant channels (I647A and I647F)
      was increased only 2-fold, but the IC(50) for E-4031 was increased 6-fold (I647A)
      and 14-fold (I647F). Aromatic residues other than phenylalanine were then
      substituted for I647, and found to reduce the effects of E-4031. Whereas E-4031
      dissociated from the mutant channels during rested state, dofetilide little
      dissociated. The mutant channels that showed recovery from E-4031 block were
      inhibited greater at 1 Hz than at 0.1 Hz. CONCLUSIONS: The present results
      indicate that dissociation of a drug from the HERG channel results in greater
      block at high frequency. Although the mechanism by which the mutations cause the
      dissociation of E-4031 is uncertain, it is noteworthy that one
      methanesulfonanilide dissociates from the channel more easily than another.

PMID- 12618228
TI  - Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG
      channels.
AB  - OBJECTIVES: Propafenone is a class Ic antiarrhythmic drug used to maintain sinus
      rhythm in patients with atrial fibrillation. During chronic therapy, it undergoes
      extensive first-pass hepatic metabolism to 5-hydroxypropafenone. In the present
      study we have analysed the effects of propafenone and 5-hydroxypropafenone on
      HERG current. METHODS: The whole-cell configuration of the patch-clamp technique
      was used in CHO cells stably transfected with the gene encoding HERG channels.
      RESULTS: Propafenone and 5-hydroxypropafenone (2 microM) inhibited HERG current
      by 78.7+/-2.3% (n=7) and 71.1+/-4.1% (n=7, P>0.05) when measured at the end of 5
      s depolarizing pulses to -10 mV. Block measured at the maximum peak of tail
      currents recorded at -60 mV was similar for propafenone (78.3+/-2.0%, n=7,
      P>0.05) and higher for 5-hydroxypropafenone (79.3+/-1.5%, n=7, P<0.05).
      Propafenone and 5-hydroxypropafenone shifted the midpoint of the activation curve
      by -10.2+/-0.9 mV (n=7, P<0.01) and -7.4+/-1.1 mV (n=10, P<0.01), respectively.
      Both drugs accelerated the deactivation and the inactivation process of HERG
      current. Propafenone, but not 5-hydroxypropafenone, inhibited to a higher extent
      HERG current at the end of 5-s depolarizing pulses to 0 mV than after promoting
      the transition of HERG channels from the inactivated to the opened state.
      CONCLUSIONS: These results indicate that propafenone and its main active
      metabolite, 5-hydroxypropafenone, block HERG channels to a similar extent by
      binding predominantly to the open state of the channel.

PMID- 12618229
TI  - Ca2+ current-mediated regulation of action potential by pacing rate in rat
      ventricular myocytes.
AB  - OBJECTIVE: Pacing rate regulates the duration of the cardiac action potential
      (AP). It also regulates the decay kinetics of the L-type Ca(2+) current (I(Ca-L))
      which occurs via modulation of Ca(2+)-dependent inactivation. We investigated
      whether and how this latter process contributes to frequency-dependent (FD)
      changes in the AP waveform in rat ventricular cells. METHODS: We recorded APs
      using a microelectrode technique in rat papillary muscles, and using the whole
      cell current patch-clamp technique in single rat ventricular cells. RESULTS: The
      AP duration (APD) was increased by high rates encompassing the physiological
      range (0.1-5.7 Hz) in both papillary muscles and single cells. This prolongation
      was accompanied by concomitant depolarisation (approximately 7 mV at 5.7 Hz) of
      the membrane potential (MP) in papillary muscles. Equivalent artificial
      depolarisation of the MP enhanced the FD prolongation in single cells. The FD
      prolongation was enhanced in presence of the K(+) current blocker 4-aminopyridine
      (5 mmol/l), and decreased in absence of extracellular Ca(2+). It was antagonised
      by Ca(2+) channel blockers (Co(2+), nifedipine, nitrendipine) and decreased by
      use of high EGTA (10 vs. 0.5 mmol/l EGTA) or BAPTA (20 mmol/l) in the patch
      pipette. It was prevented by ryanodine or thapsigargin, two drugs that reduce or
      abolish SR-Ca(2+) function. CONCLUSION: I(Ca-L) contributes to the FD modulation
      of the AP, which occurs following a sudden change in cardiac frequency in rat
      ventricular cells. This highly dynamic physiological process is related to SR
      Ca(2+) release and occurs through beat-to-beat adaptation of Ca(2+)-dependent
      inactivation of I(Ca-L).

PMID- 12618231
TI  - New insights into beta2-adrenoceptor signaling in the adult rat heart.
AB  - OBJECTIVE: The role of cAMP in beta(2)-adrenoceptor signaling and its functional
      relevance in adult rat heart has been the subject of considerable controversy.
      Therefore, we investigated the beta(2)-adrenoceptor pathways in both adult
      cardiomyocytes and in the intact hearts of Wistar rats with respect to protein
      kinase A (at Ser16)-, the key event in shortening of relaxation time, and CaM
      kinase II (at Thr17)-dependent phospholamban phosphorylation. METHODS:
      Contractile and cellular beta(1)/beta(2)-adrenergic responses were studied in
      parallel on the same perfused rat heart. (-)Isoproterenol and the beta(2)
      adrenergic agonists zinterol and procaterol were used to discriminate the beta
      adrenoceptor subtype-related actions. RESULTS: Beta(2)-adrenoceptor stimulation
      induces protein kinase A-dependent phospholamban phosphorylation in both adult
      cardiomyocytes and in adult hearts of rats. The beta(2)-adrenoceptor-mediated
      shortening of relaxation time in the heart correlates with Ser16 phosphorylation.
      Adenosine elicited antiadrenergic action on both beta(1)- and beta(2)-adrenergic
      signaling cascades by reducing the phosphorylation status of phospholamban. Only
      beta(1)-adrenoceptor stimulation produced significant CaM kinase II-related Thr17
      phosphorylation, troponin I phosphorylation and activation of phosphorylase a.
      CONCLUSIONS: Our findings clearly show that beta(2)-adrenoceptor signaling is
      coupled to phospholamban phosphorylation and shortening of relaxation time in the
      adult rat heart.

PMID- 12618230
TI  - Nonuniform Ca2+ transients in arrhythmogenic Purkinje cells that survive in the
      infarcted canine heart.
AB  - OBJECTIVE AND METHODS: In this study, we investigated whether Ca(2+) transients
      are altered in Purkinje cell aggregates dispersed from the subendocardium
      overlying the infarcted zone of the left ventricle (IZPCs) 48 h after coronary
      artery occlusion. To do so, we combined epifluorescent imaging with
      microelectrode recordings of IZPCs and normal canine Purkinje cell aggregates
      (NZPCs). RESULTS: NZPCs respond to an action potential (AP) by a small Ca(2+)
      transient at the cell surface immediately after the AP upstroke followed by a
      large [Ca(2+)] transient, which propagates to the cell core. In addition, focal
      Ca(2+) waves can originate spontaneously later during the AP or during the
      diastolic interval (Circ Res 2000;86:448-55) and then propagate throughout the
      aggregate as 'cell-wide Ca(2+) waves'. Electrically-evoked Ca(2+) transients in
      IZPCs arose significantly faster than those in NZPCs, and showed substantial
      spatiotemporal nonuniformity within an IZPC aggregate as well as between IZPC
      aggregates. IZPCs showed, hitherto undetected, low amplitude, micro Ca(2+)
      transients (extent <or=5 microm) at a fivefold higher incidence than in NZPCs.
      Micro Ca(2+) transients appeared to meander over distances <or=100 microm and
      reduced the local Ca(2+) transient of the next paced beat. Micro Ca(2+)
      transients nearly always preceded the cell-wide Ca(2+)waves, which occurred more
      frequently in IZPCs than in NZPCs and caused non-driven electrical activity of
      the Purkinje aggregate. CONCLUSIONS: Micro Ca(2+) transients preceded cell-wide
      Ca(2+) waves so often that it is probable that micro Ca(2+) transients induced
      cell-wide Ca(2+) waves. Cell-wide Ca(2+) waves, in turn, clearly elicited
      spontaneous APs. We propose that the high incidence of micro Ca(2+) transients in
      IZPCs is a fundamental element of the abnormal Ca(2+) handling of diseased
      Purkinje cells, underlying arrhythmias originating in the subendocardial Purkinje
      network post myocardial infarction.

PMID- 12618232
TI  - Differential regulation of p38 mitogen-activated protein kinase mediates gender
      dependent catecholamine-induced hypertrophy.
AB  - OBJECTIVE: Exogenous catecholamine exposure has been associated with p38 mitogen
      activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we
      investigated the regulation of p38 MAPK in cardiac remodeling elicited by
      endogenous adrenergic mechanisms. METHODS: Transgenic male and female mice with
      fourfold phospholamban (PLB) overexpression exhibited enhanced circulating
      norepinephrine (NE), as a physiological compensatory mechanism to attenuate PLB's
      inhibitory effects. This enhanced noradrenergic state resulted in left
      ventricular hypertrophy/dilatation and depressed function. RESULTS: Male
      transgenics exhibited ventricular hypertrophy and mortality at 15 months,
      concurrent with cardiac p38 MAPK activation. Female transgenics, despite similar
      contractile dysfunction, displayed a temporal delay in p38 activation,
      hypertrophy, and mortality (22 months), which was associated with sustained
      cardiac levels of MAP Kinase Phosphatase-1 (MKP-1), a potent inhibitor of p38. At
      22 months, decreases in cardiac MKP-1 were accompanied by increased levels of p38
      activation. In vitro studies indicated that preincubation with 17-beta-estradiol
      induced high MKP-1 levels, which precluded NE-induced p38 activation. CONCLUSION:
      These findings suggest that norepinephrine-induced hypertrophy is linked closely
      with p38 MAP kinase activation, which can be endogenously modulated through
      estrogen-responsive regulation of MKP-1 expression.

PMID- 12618233
TI  - Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic
      gene expression.
AB  - OBJECTIVES: To identify potential molecular genetic determinants of
      cardiovascular ischemic tolerance in wild-type and transgenic hearts
      overexpressing A(1) adenosine receptors (A(1)ARs). METHODS: cDNA microarrays were
      used to explore expression of 1824 genes in wild-type hearts and ischemia
      tolerant mouse hearts overexpressing A(1)ARs. RESULTS: Overexpression of A(1)ARs
      reduced post-ischemic contractile dysfunction, limited arrhythmogenesis, and
      reduced necrosis by approximately 80% in hearts subjected to 30 min global
      ischemia 60 min reperfusion. Cardioprotection was abrogated by acute A(1)AR
      antagonism, and only a small number (19) of genes were modified by A(1)AR
      overexpression in normoxic hearts. Ischemia-reperfusion significantly altered
      expression of 75 genes in wild-type hearts (14 induced, 61 down-regulated),
      including genes for metabolic enzymes, structural/motility proteins, cell
      signaling proteins, defense/growth proteins, and regulators of transcription and
      translation. A(1)AR overexpression reversed the majority of gene down-regulation
      whereas gene induction was generally unaltered. Additionally, genes involved in
      cell defence, signaling and gene expression were selectively modified by ischemia
      in transgenic hearts (33 induced, 10 down-regulated), possibly contributing to
      the protected phenotype. Real-time PCR verified changes in nine selected genes,
      revealing concordance with array data. Transcription of the A(1)AR gene was also
      modestly reduced post-ischemia, consistent with impaired functional sensitivity
      to A(1)AR stimulation CONCLUSIONS: Data are presented regarding the early post
      ischemic gene profile of intact heart. Reduced A(1)AR transcription is observed
      which may contribute to poor outcome from ischemia. A(1)AR overexpression
      selectively modifies post-ischemic gene expression, potentially contributing to
      ischemic-tolerance.

PMID- 12618234
TI  - Effect of vasopeptidase inhibitor omapatrilat on cardiomyocyte apoptosis and
      ventricular remodeling in rat myocardial infarction.
AB  - We have shown earlier that cardiomyocyte apoptosis continues at a high level late
      after myocardial infarction and contributes to adverse cardiac remodeling. Here
      we studied whether this process can be inhibited by the vasopeptidase inhibitor
      omapatrilat, a drug which causes simultaneous inhibition of both angiotensin
      converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat
      treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac
      remodeling compared to rats treated with selective inhibitors of angiotensin
      converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was
      produced by ligation of the left anterior descending coronary artery. Rats were
      randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ
      28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac
      BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle
      treated rats. However, omapatrilat was more effective than captopril in
      attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs.
      3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular
      mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated
      both in the infarction border zone (0.129+/-0.017%) and in the remote area
      (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin
      converting enzyme inhibition proved to be important in the prevention of
      apoptosis since both omapatrilat and captopril reduced the number of apoptotic
      myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no
      effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after
      myocardial infarction, was reduced by angiotensin converting enzyme inhibition.
      Vasopeptidase inhibition was more effective than selective angiotensin converting
      enzyme inhibition in preventing adverse cardiac remodeling after myocardial
      infarction.

PMID- 12618235
TI  - High glucose induces cardiac insulin-like growth factor I resistance in
      ventricular myocytes: role of Akt and ERK activation.
AB  - OBJECTIVE: Cardiac resistance to IGF-1 occurs in diabetes and is attributed to
      cardiac dysfunction in diabetes. However, the mechanism of action responsible for
      cardiac IGF-1 resistance is still unknown. This study was designed to examine the
      impact of high glucose on IGF-1-induced contractile response and activation of
      serine-threonine kinase Akt as well as extracellular signal-regulated kinase
      (ERK1/2) in cardiac myocytes. METHODS: Isolated adult rat ventricular myocytes
      were cultured for 12-18 h in a serum-free medium containing either normal (NG,
      5.5 mM) or high (HG, 25.5 mM) glucose. Mechanical properties were evaluated using
      an IonOptix MyoCam system. Myocytes were electrically stimulated at 0.5 Hz and
      contractile properties analyzed included peak shortening (PS), time-to-PS (TPS)
      and time-to-90% relengthening (TR(90)). Intracellular Ca(2+)-induced Ca(2+)
      release was measured as fura-2 fluorescence intensity change (DeltaFFI). Protein
      levels of total and phosphorylated Akt and ERK1/2, indicators of Akt and ERK1/2
      activation, IGF-1 receptors (pro-IGF-1R and IGF-1Ralpha) as well as the glucose
      transporter GLUT4 were assessed by Western blot. RESULTS: IGF-1 (10(-10)-10(-6)
      M) elicited a dose-dependent increase in PS and DeltaFFI in myocytes maintained
      in NG medium. However, IGF-1 induced a negative response on PS and DeltaFFI in HG
      myocytes. The IGF-1-induced responses in NG or HG myocytes were blunted by the
      IGF-1 receptor antagonist H-1356. Western blot analysis revealed that IGF-1Ralpha
      but not pro-IGF-1R was reduced in HG myocytes. While IGF-1 (10(-6) M) upregulated
      total Akt protein levels in both NG and HG myocytes, it only induced a
      significant activation of Akt in NG but not HG myocytes. IGF-1 elicited
      comparable ERK1/2 activation in both NG and HG myocytes. CONCLUSION: These
      results suggest that the cardiac IGF-1 resistance in diabetes is likely
      attributed, at least in part, to reduced IGF-1R and attenuated IGF-1-induced Akt
      phosphorylation under elevated extracellular glucose.

PMID- 12618236
TI  - Sustained activation of nuclear factor kappa B and activator protein 1 in chronic
      heart failure.
AB  - OBJECTIVE: Innate immune response proteins such as inflammatory cytokines,
      inducible nitric oxide synthase, and toll like receptors are implicated in
      myocardial depression and left ventricular (LV) remodeling after myocardial
      infarction (MI). Although all these innate immunity proteins share the downstream
      activation of the transcription factor NF-kappaB (nuclear factor kappa B) and
      activator protein 1 (AP-1), the involvement of NF-kappaB and AP-1 in LV
      remodeling has not been demonstrated so far. METHODS AND RESULTS: Nuclear
      translocation of NF-kappaB and AP-1 was studied by electrophoretic mobility shift
      assays and ELISA 10 weeks after large experimental MI in rats, the chronic phase
      of LV remodeling. In the non-infarcted myocardium of MI rats, NF-kappaB and AP-1
      were significantly activated (2.5-fold) as compared to sham-operated animals.
      Immunohistochemistry demonstrated NF-kappaB activation mainly in cardiac
      myocytes. Treatment with the ACE (angiotensin converting enzyme) inhibitor
      trandolapril led to a further 2-fold increase in the activation of NF-kappaB and
      AP-1 when compared to placebo-treated animals with the same MI size (P<0.001).
      Human failing hearts explanted at the time of heart transplantation exhibited
      marked nuclear translocation of NF-kappaB in cardiac myocytes when compared to
      control hearts. NF-kappaB as well as AP-1 were both significantly activated in
      congestive heart failure due to ischemic or dilated cardiomyopathy. CONCLUSION:
      In experimental and human heart failure, both NF-kappaB and AP-1 are chronically
      activated in cardiac myocytes. These findings suggest an important involvement of
      NF-kappaB and AP-1 in the cardiac remodeling process.

PMID- 12618237
TI  - Temocapril prevents transition to diastolic heart failure in rats even if
      initiated after appearance of LV hypertrophy and diastolic dysfunction.
AB  - OBJECTIVE: Congestive heart failure with left ventricular (LV) diastolic
      dysfunction and preserved systolic function, i.e. diastolic heart failure (DHF),
      is often observed in hypertensive patients. Although angiotensin converting
      enzyme (ACE) inhibitors are widely used as antihypertensive therapy, there is a
      continued controversy about long-term effect of ACE inhibition on diastolic
      function. The current study was designed to elucidate a therapeutic effect of ACE
      inhibitor, temocapril, administration initiated after LV hypertrophy (LVH) and
      diastolic dysfunction are evident. METHODS: Dahl salt sensitive rats fed on 8%
      NaCl diet from 7 weeks (hypertensive DHF model) were studied at 13 weeks (n=6) or
      at 19 weeks following chronic administration of a subdepressor dose of temocapril
      (0.2 mg/kg/day, TEM(+), n=6) or placebo (TEM(-), n=7) from 13 weeks. RESULTS:
      Compensatory LVH was associated with prolonged time constant of LV relaxation
      (Tau) at 13 weeks. In TEM(-), progression of LVH and fibrosis and elevation of LV
      end diastolic pressure were observed at 19 weeks. Administration of temocapril
      from 13 weeks prevented the further progression of LVH and fibrosis, attenuated
      increases in myocardial stiffness constant and Tau, and prevented the development
      of DHF. These effects were accompanied with the attenuation of decreases in
      sarcoplasmic reticulum calcium(2+)-ATPase 2a and phosphorylated phospholamban and
      of hypertrophic signalings' upregulation. CONCLUSIONS: This study demonstrated
      that chronic administration of temocapril exerts a therapeutic effect on
      diastolic dysfunction and prevents the transition to DHF even if initiated after
      appearance of LVH and diastolic dysfunction.

PMID- 12618239
TI  - Reversal of interstitial fibroblast hyperplasia via apoptosis in hypertensive rat
      heart with valsartan or enalapril.
AB  - OBJECTIVE: Renin-angiotensin system inhibitors transiently induce apoptosis at
      the onset of cardiac hypertrophy regression in spontaneously hypertensive rats
      (SHRs). The focus of this study is to evaluate the cell selectivity of this
      response. METHODS: SHRs were treated with valsartan or enalapril (30 mg kg(-1)
      day(-1)) or placebo for 1 to 4 weeks. Stereological and morphological data were
      obtained from immunohistological analyses. Apoptosis was quantified by DEVDase
      (caspase-3-like) activity assay and immunoblot analysis of apoptosis-regulatory
      proteins (Bax and Bcl-2). Identification of the apoptotic cell type was conducted
      using in situ TUNEL labeling, in conjunction with alpha-sarcomeric actin or
      lectin immunoreactivity as markers for cardiomyocytes and endothelial cells,
      respectively. RESULTS: Stereological analysis of the left ventricle revealed
      significant non-cardiomyocyte hyperplasia in placebo-treated SHRs (239+/-29x10(6)
      nuclei) as compared to untreated age-matched normotensive Wistar-Kyoto (WKY) rats
      (107+/-12x10(6)). In contrast, the number of cardiomyocyte nuclei was comparable
      between untreated SHRs (48+/-4x10(6)) and WKY rats. After 4 weeks of valsartan or
      enalapril treatment, SHRs showed significant reductions in systolic blood
      pressure (>28%), left ventricular hypertrophy (>9%) and cardiomyocyte cross
      sectional area (>17%). Moreover, these treatments abolished non-cardiomyocyte
      hyperplasia in SHR left ventricle without affecting cardiomyocyte number,
      capillary density or number of capillary per cardiomyocyte nucleus. As a
      mechanism of cell deletion consistent with apoptosis induction, ventricles showed
      increased caspase-3 activation (>4.5-fold) as well as Bax to Bcl-2 protein ratio
      (>3.2-fold) within 2 weeks of valsartan or enalapril treatment.
      Immunohistological analysis revealed a significant increase in TUNEL-positive,
      lectin-negative non-cardiomyocytes, suggesting a rise in apoptotic interstitial
      fibroblasts in the left ventricle within 2 weeks of treatment with valsartan or
      enalapril (>63%), with a return to baseline (0.033+/-0.003%) at 4 weeks.
      Treatments did not affect right ventricular mass, apoptosis or cellularity.
      CONCLUSION: Cardiac apoptosis induction during regression of left ventricular
      hypertrophy reverses interstitial fibroblast hyperplasia in SHRs treated with
      inhibitors of the renin-angiotensin system.

PMID- 12618238
TI  - Differential activation of matrix metalloproteinases in heart failure with and
      without ventricular dilatation.
AB  - OBJECTIVE: Remodeling of extracellular matrix (ECM) is considered to contribute
      to progression of left ventricular (LV) remodeling and matrix metalloproteinases
      (MMPs) play crucial roles in regulation of ECM. Activation of MMPs is observed in
      systolic heart failure (SHF) and is suggested to be responsible for LV dilatation
      in SHF. Diastolic heart failure (DHF) that is not associated with LV dilatation
      is also accompanied with collagen accumulation; however, differences in ECM
      regulatory system, especially activation of MMPs, between SHF and DHF remain to
      be clarified. This study was conducted to clarify whether MMPs are activated even
      in DHF, and if so, to characterize the difference in activation of MMPs between
      SHF and DHF for identification of a target for the prevention of LV remodeling in
      SHF. METHODS: To exclude effects of differences in underling cardiovascular
      diseases and genetic background on the comparison between DHF and SHF, we used
      Dahl salt-sensitive rats fed on high salt diet starting at 7 weeks of age as DHF
      model and at 8 weeks as SHF model, both of which our laboratory recently
      developed. RESULTS: LV fibrosis progressed in the DHF and SHF model rats. MMP-2
      was activated to the same degree in both rats. Activation of MMP-9 was enhanced
      in the DHF model rats, but the activity was more enhanced in the SHF rats. Film
      in situ zymography showed that enhanced gelatinolytic activity appeared only in
      the mid layer of the LV wall in the DHF rats and throughout the wall in the SHF
      rats. The distribution of gelatinolytic activity was consistent with that of
      expression of MMP-9 as assessed in immunohistochemical study. CONCLUSIONS: MMP-9
      rather than MMP-2 may be involved in LV dilatation in SHF and be a specific
      target for the prevention of LV remodeling.

PMID- 12618240
TI  - Chronic beta2-adrenergic receptor stimulation increases proliferation of human
      cardiac fibroblasts via an autocrine mechanism.
AB  - OBJECTIVE: The aim of this study was to determine whether chronic beta-adrenergic
      receptor (beta-AR) stimulation induces proliferation of human cardiac fibroblasts
      and to investigate the mechanism(s) involved. METHODS AND RESULTS: In vitro
      cultures of human cardiac fibroblasts were established from biopsies of right
      atrial appendage. RT-PCR analysis and pharmacological studies demonstrated that
      these cells express predominantly the beta(2)-AR subtype coupled to activation of
      adenylyl cyclase and p44/42 mitogen-activated protein kinase (MAPK).
      Proliferation was determined by cell counting over a 6-day period in medium
      containing 2.5% fetal calf serum (control) or supplemented with the non-selective
      beta-AR agonist isoproterenol (ISO). ISO induced a concentration-dependent
      increase in cardiac fibroblast proliferation, which was maximal at 1 micromol/l.
      This increased proliferation was inhibited by the beta(2)-AR-selective antagonist
      ICI-118,551, but not the beta(1)-AR-selective antagonist atenolol. Direct
      activation of adenylyl cyclase alone (0.1-10 micromol/l forskolin) stimulated
      cyclic AMP production and MAPK activation, but did not induce cell proliferation.
      Since catecholamines are not considered to be 'classical' growth factors, we
      subsequently investigated whether beta(2)-AR stimulation results in secretion of
      growth factors that are able to stimulate proliferation in an autocrine manner.
      Conditioned medium obtained from cardiac fibroblasts treated with ISO for 48 h
      increased proliferation of parallel cultures of fibroblasts in the presence of
      the beta-AR antagonist alprenolol. Heat-treatment of this conditioned medium
      fully prevented the increase in cell proliferation, indicating that the autocrine
      factor(s) are heat-sensitive proteins. CONCLUSIONS: Chronic beta(2)-AR
      stimulation increases proliferation of human cardiac fibroblasts via a mechanism
      involving increased secretion of heat-sensitive growth factors.

PMID- 12618241
TI  - Activation and inactivation of a non-selective cation conductance by local
      mechanical deformation of acutely isolated cardiac fibroblasts.
AB  - OBJECTIVE: We describe mechanically induced non-selective cation currents in
      isolated rat atrial fibroblasts, which might play a role as a substrate for
      mechano-electrical feedback in the heart. METHODS: Isolated fibroblasts were used
      for voltage-clamp analysis of ionic currents generating mechanically-induced
      potentials. Fibroblasts were mechanically deformed (compressed or stretched) by
      two patch-pipettes. RESULTS: These cells had a resting potential (E(0)) of -37+/
      3 mV and an input resistance of 514+/-11 M(Omega). At intracellular pCa 7 (patch
      pipette solution), compression of 2 or 3 microm shifted E(0) from -36+/-7 to 
      17+/-3 mV, and to -10+/-2 mV. Compression by 2 or 3 microm induced a negative
      difference current (at -45 mV -0.06+/-0.02 and -0.20+/-0.04 nA, respectively)
      with a reversal potential (E(rev)) of approx. 0 mV. The currents were carried by
      Na(+), K(+) and Cs(+) ions, and were blocked by application of 8 microM Gd(3+).
      Stretch of 2 or 3 microm hyperpolarized E(0) from -34+/-4 to -45+/-5, and to 
      61+/-7 mV and induced a positive difference current (at -45 mV: 0.04+/-0.02 and
      0.18+/-0.03 nA) with an E(rev) close to 0 mV. Application of Gd(3+) shifted E(0)
      to potentials as negative as E(K) (-90+/-4 mV). Cell dialysis with 5 mM BAPTA
      (pCa 8) or 5 mM Ca(2+)/EGTA (pCa 6) had no influence on non-selective cation
      currents suggesting that Ca(2+) dependent conductances are unlikely to
      contribute. CONCLUSION: Compression of the isolated cardiac fibroblast caused
      depolarization of the membrane by activating inward currents through a non
      selective cation conductance (G(ns)). Stretch hyperpolarizes the fibroblast,
      however, not by Ca(2+) activation of K(+)-conductance. Ion selectivity, E(rev,)
      and Gd(3+)-sensitivity of stretch suppressed currents suggest that stretch
      reduces G(ns) that is activated by compression.

PMID- 12618242
TI  - Crucial role of local peroxynitrite formation in neutrophil-induced endothelial
      cell activation.
AB  - INTRODUCTION AND METHODS: The reaction of superoxide anions and NO not only
      results in a decreased availability of NO, but also leads to the formation of
      peroxynitrite, the role of which in the cardiovascular system is still discussed
      controversially. In cultured human endothelial cells, we studied whether there is
      a significant interaction between endothelial NO and neutrophil-derived
      superoxide anions in terms of endothelial peroxynitrite formation. We
      particularly studied whether a significantly higher redox-stress can be found in
      those endothelial cells directly adjacent to an activated neutrophil. RESULTS: A
      considerable part of the 2,7-dihydrodichlorofluoresceine signal in endothelial
      cells was due to oxidation by peroxynitrite. Providing superoxide radicals by
      enzymatic source or by the neutrophil respiratory burst increased the
      fluorescence, which was attenuated by blockade of endothelial NO-synthase,
      suggesting that peroxynitrite was formed from neutrophil- or extracellular enzyme
      derived superoxide and endothelial NO. Considerably higher fluorescence intensity
      was observed in endothelial cells in direct neighborhood to a neutrophil. This
      was particularly pronounced in the presence of a NO-donor and was accompanied by
      a strong activation of NF-kappaB and increased expression of E-selectin in these
      cells. CONCLUSION: Endothelial cells adjacent to neutrophils may have elevated
      levels of peroxynitrite that result in an increased expression of adhesion
      molecules. Such cells might represent a preferential site for adhesion and
      migration of additional neutrophils when simultaneously high concentrations of NO
      and neutrophil-derived superoxide are present.

PMID- 12618243
TI  - Coexpression of endothelial markers and CD14 by cytokine mobilized CD34+ cells
      under angiogenic stimulation.
AB  - OBJECTIVE: A subset of adult peripheral blood leukocytes functions as endothelial
      progenitor cells that incorporate into the vasculature in animal models of
      neovascularization. The basic mechanisms by which differentiation proceeds are
      still unclear. This study analyses the in vitro differentiation of cytokine
      mobilized, human CD34(+) cells. METHODS: Granulocyte-monocyte colony stimulating
      factor mobilized human CD34(+) cells were isolated and grown in culture in the
      presence of vascular endothelial growth factor (50 ng/ml) and basic fibroblast
      growth factor (10 ng/ml). Their differentiation was followed using cytological
      and immunohistochemical techniques. Fibronectin-coated culture dishes or three
      dimensional cultures were used. RESULTS: CD34(+) cells grown on fibronectin
      coated dishes differentiated along the granulocytic and monocytic/macrophage
      lineages with no evidence for an endothelial cell differentiation. CD14(+)
      macrophages appeared in long-term culture and then acquired endothelial cell
      markers such as VE-cadherin, the endothelial form of NO synthase and the von
      Willebrand factor. Yet they were unable to form tubular structures in Matrigel.
      Only typical macrophages were observed in Matrigel. CONCLUSION: Angiogenic
      stimulation of CD34(+) precursor cells leads to cells that expressed mixed
      macrophage and endothelial cell properties. They could represent an intermediate
      phenotype in the pathway that leads to mature endothelial cells.

PMID- 12618244
TI  - Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent
      relaxation by urocortin in the rat coronary artery.
AB  - OBJECTIVE: Urocortin possesses cardioprotective properties against the damaging
      effects of ischemia/reperfusion injury. Our previous study demonstrated that
      urocortin can induce both endothelium-dependent and -independent coronary
      relaxation. However, the mechanisms thereby urocortin triggers endothelium
      independent relaxation have not been investigated. The present study aimed to
      examine the role of cyclic AMP and Ca(2+)-activated K(+) channels in the relaxant
      response to urocortin in the isolated endothelium-denuded rat left anterior
      descending coronary arteries. METHODS: Changes in vessel tension were measured by
      using a force transducer built in a Multi Myograph System. RESULTS: In 9,11
      dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F(2alpha) (U46619)-contracted
      rings, urocortin-induced relaxation (pD(2): 8.40+/-0.04) was significantly
      reduced by cyclic AMP-dependent protein kinase (PKA) inhibitors, Rp-cAMPS
      triethylamine (Rp-cAMPS) and KT 5720. Treatment with the large-conductance Ca(2+)
      activated K(+) channel blockers, iberiotoxin or tetraethylammonium ions (TEA(+))
      attenuated urocortin-induced relaxation; this effect was abolished in the
      presence of 200 nmol/l KT 5720. In contrast, apamin (small-conductance Ca(2+)
      activated K(+) channel blocker), glibenclamide (ATP-sensitive K(+) channel
      blocker), or BaCl(2) (inwardly rectifier K(+) channel blocker) had no effect.
      Urocortin-induced relaxation was reduced in rings contracted with increasing
      concentrations of extracellular K(+) (35 and 50 mmol/l). Treatment with TEA(+) or
      Rp-cAMPS inhibited the relaxant effect of urocortin in 35 mmol/l K(+)-contracted
      rings. Combined treatment with TEA(+) and Rp-cAMPS had no additional effect.
      Similarly, forskolin produced significantly less relaxant response in 50 mmol/l
      K(+)-contracted than U46619-contracted rings. Forskolin-induced relaxation was
      attenuated by pretreatment with 3 mmol/l TEA(+). CONCLUSION: Urocortin relaxed
      the rat coronary artery in substantial part via activation of the vascular Ca(2+)
      activated K(+) channels and this effect appears to be primarily mediated through
      PKA-dependent intracellular mechanisms.

PMID- 12618245
TI  - Chlamydia pneumoniae induces neointima formation in coronary arteries of normal
      pigs.
AB  - OBJECTIVES: We evaluated the role of intracoronary, intrapulmonary and macrophage
      mediated delivery of C. pneumoniae (Cp) on coronary lesion formation. METHODS:
      Pigs were allocated to one of three coronary protocols (intracoronary, macrophage
      or control groups) or to a fourth-a pulmonary group. In the intracoronary group
      Cp was injected into the wall of the left anterior descending (LAD) and right
      coronary arteries (RCA) and vehicle into the circumflex (CX). In the macrophage
      group autologous macrophages preincubated with Cp or not were injected into the
      LAD and CX wall, respectively. Animals in the control group received vehicle in
      LAD and CX. In the pulmonary group aerosolised Cp was given intrabronchially,
      after a single injection of vehicle into the LAD wall. Delivery into the coronary
      artery wall was performed with a balloon catheter with low-profile injector
      ports. RESULTS: Seroconversion occurred in the following proportions: 5/6
      (intracoronary group), 4/5 (macrophage group), 0/6 (control group), and 1/6
      (intrapulmonary group). Significantly higher maximal intimal thickness (MIT) was
      observed in LADs of intracoronary and pulmonary groups when compared to
      corresponding CXs. The presence of Cp antigen was associated with higher MIT
      (r=0.73; P<0.0001). Injection of macrophages into the coronary artery wall did
      not induce proliferation. Arteries without coronary interventions were
      morphologically normal. CONCLUSIONS: Intracoronary and intrapulmonary but not
      macrophage-mediated Cp inoculation were associated with moderate intimal
      proliferation in the absence of a lipid-rich diet. Pre-existing coronary lesions
      seem a prerequisite for Cp-induced proliferation.

PMID- 12618246
TI  - Intramyocardial blood volume, perfusion and transit time in response to
      embolization of different sized microvessels.
AB  - OBJECTIVE: To study the role of the coronary microcirculation in response to
      different-sized microemboli, we measured changes in intramyocardial microvascular
      blood volume (Bv), perfusion (F) and transit time (TT) and also microvascular
      patterns of injury. METHODS: Bv, F and TT were quantitated in 24 pigs at baseline
      and again 2 min after repeat injections of 10- or 100-microm microspheres at rest
      or during intracoronary adenosine infusion. The association of Bv and TT was
      assessed in the microsphere pigs and in nine control pigs. Microvascular injury
      was studied on gross-pathologic and histologic samples. RESULTS: At rest, initial
      injection of 10-microm microspheres led to increases in Bv and F, but
      progressively decreased with additional injections. In contrast, even small
      numbers of 100-microm microspheres always led to decreases in Bv and F. Injection
      of microspheres during adenosine-induced vasodilation always resulted in
      decreases in peak Bv and F irrespective of their diameters, but microvascular TTs
      remained unaltered. In control pigs, however, TTs were inversely related to
      adenosine-induced changes in Bv. Histologically, 100-microm microspheres resulted
      in patchy distribution of microcirculatory plugging, while 10-microm microspheres
      induced contiguous hemorrhagic myocardial injury. CONCLUSION: Microsphere-induced
      changes in intramyocardial Bv and F and the associated pattern of myocardial
      injury are related to the size of embolized microvessels and the initial
      perfusion state. Microvascular functional volume reserve mechanisms appear to
      play a key role accompanying flow- and TT-preservation.

PMID- 12618248
TI  - Regular exercise, hormone replacement therapy and the age-related decline in
      carotid arterial compliance in healthy women.
AB  - OBJECTIVE: Carotid arterial compliance is reduced with age in sedentary estrogen
      deficient women, contributing to the development of cardiovascular disorders. We
      determined the effects of regular aerobic exercise, hormone replacement therapy
      (HRT), and their interaction on carotid arterial compliance using a combination
      of cross-sectional and intervention study designs. METHODS: Cross-sectionally, we
      studied three groups of healthy postmenopausal women (50-80 years): 20 sedentary
      not taking HRT; 24 sedentary taking HRT; and 14 endurance-trained not taking HRT;
      and 11 sedentary premenopausal controls (20-37 years). In the intervention study,
      12 sedentary postmenopausal women (58+/-3 years) who were taking HRT were studied
      before and after participation in a 3-month aerobic exercise (walking) program.
      Carotid arterial compliance was measured via simultaneous common carotid artery
      ultrasound imaging and applanation tonometry. RESULTS: Cross-sectional study.
      Carotid arterial compliance was lower (P<0.001) in all three postmenopausal
      groups compared with premenopausal women. Among the postmenopausal groups,
      arterial compliance was 33-43% higher in the sedentary HRT and endurance-trained
      women than in their sedentary estrogen-deficient peers. Intervention study.
      Arterial compliance increased (P<0.05) by approximately 40% to levels that were
      no longer different than premenopausal women. CONCLUSIONS: HRT use and regular
      aerobic exercise are associated with augmented carotid arterial compliance in
      healthy postmenopausal women. Moderate, short-term aerobic exercise can restore
      carotid arterial compliance in previously sedentary postmenopausal women taking
      HRT.

PMID- 12618247
TI  - A novel S-nitrosothiol causes prolonged and selective inhibition of platelet
      adhesion at sites of vascular injury.
AB  - OBJECTIVE: Platelet adhesion to areas of endothelial denudation following
      angioplasty is an important factor contributing to the limitations of this
      technique. Lipophilic S-nitrosothiols like S-nitroso-N-valerylpenicillamine
      (SNVP) are novel nitric oxide (NO) donor drugs with anti-platelet and vasodilator
      properties that are selective for areas of endothelial denudation. Here we assess
      the inhibitory effect of SNVP on platelet adhesion to angioplastied rabbit
      carotid arteries. METHODS: A rabbit model was used to measure adhesion of
      radiolabelled platelets to carotid arteries following balloon angioplasty. The
      effects of SNVP were compared to the conventional NO donor, nitroglycerin (NTG).
      Electron microscopy was used to visualize adhering platelets. RESULTS:
      Angioplasty resulted in endothelial denudation with only a modest reduction in
      vessel contractility. In vivo administration of NTG and SNVP (both 200 nmol)
      prevented the hyper-aggregability (approximately 20%) of circulating platelets
      caused by angioplasty. However, bolus NTG failed to inhibit adhesion of
      radiolabelled platelets 30 min after angioplasty, despite inducing a transient
      30% reduction in systemic blood pressure. In contrast, equimolar SNVP had little
      effect on blood pressure but markedly inhibited platelet adhesion (62% compared
      to control; P=0.003). Platelet adhesion was confirmed with electron microscopy.
      CONCLUSION: The prolonged effects of SNVP at sites of endothelial damage suggest
      that novel S-nitrosothiols might offer a means of targeted delivery of an
      antiplatelet agent to areas of vascular injury.

PMID- 12618250
TI  - Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of
      intercourse: implications for mechanism of action.
AB  - OBJECTIVE: The purpose of this study was to provide evidence about the mechanism
      of action of the Yuzpe method of emergency contraception by examining
      effectiveness by cycle day of intercourse relative to ovulation. METHODS: Through
      a literature search, we identified eight studies that present the number of women
      treated and outcome of treatment by cycle day of unprotected intercourse relative
      to expected day of ovulation. Using five sets of external estimates of conception
      probabilities by cycle day of intercourse among women not using contraception, we
      assessed and compared the effectiveness of the Yuzpe regimen by whether
      intercourse occurred on or before the second day before ovulation or afterward,
      and whether intercourse occurred on or before the first day before ovulation or
      afterward. RESULTS: In 36 of the 45 pairs of estimates of effectiveness, based on
      eight separate studies and the eight studies combined and five different sets of
      conception probabilities by cycle day, effectiveness was higher-and in most cases
      substantially higher-when intercourse occurred on or before the second day before
      ovulation (day -2) than when it occurred later. When data were stratified by
      whether intercourse occurred on or before the day before ovulation (day -1),
      effectiveness was greater when intercourse occurred early in 43 of 45 pairs.
      CONCLUSIONS: These results suggest that one hypothesized mechanism of action of
      the Yuzpe method, inhibiting implantation of a fertilized egg, is unlikely to be
      the primary mechanism of action.

PMID- 12618251
TI  - The effects of seven monophasic oral contraceptive regimens on hemostatic
      variables: conclusions from a large randomized multicenter study.
AB  - We investigated the effects of ethinylestradiol dose (50, 30 and 20 microg) and
      progestogen type [desogestrel (DSG), gestodene (GSD), levonorgestrel (LNG) and
      norgestimate (NGM)] in oral contraceptives on 24 hemostatic variables. In a
      multicenter, randomized, comparative study, 707 healthy, nonsmoking, nulliparous
      women were treated for six cycles with one of the seven monophasic oral
      contraceptives tested. Significantly greater increases in prothrombin fragment
      1+2 and factor VII (activity and antigen), were found in the DSG, NGM and GSD
      groups compared to the LNG group. Similarly, significantly lower levels of
      protein S (free and total) and increased APC-sr (endogenous thrombin potential
      based) were found in the same groups compared with the LNG group. In addition,
      the estradiol dose (50 vs. 30 microg) significantly influenced these parameters.
      All changes were within the normal range and have not been associated with an
      increased risk of venous thromboembolic event (VTE). However, raised levels of
      these variables are associated with prothrombotic states such as pregnancy. The
      significance of the haemostatic changes found in this study in relation to VTE
      risk remains to be determined, but results of this study probably cannot explain
      the differences in risk of VTE between OCs containing different progestogens.

PMID- 12618252
TI  - The combined contraceptive vaginal ring, NuvaRing: an international study of user
      acceptability.
AB  - The acceptability of the combined contraceptive vaginal ring, NuvaRing, was
      assessed during two trials conducted in North America and Europe. Women completed
      a questionnaire about the ring's clarity of instructions, ease of use, sexual
      comfort, cycle-related characteristics and satisfaction after 3, 6 and 13 cycles
      of use. A total of 1,950 women (82% of those recruited) completed a questionnaire
      at cycle 3. At baseline, 66% of participants preferred oral contraceptives, but
      after three cycles of ring use 81% preferred the ring. On study completion, 97%
      agreed that the instructions for use were clear; 85% of women and 71% of their
      partners never/rarely felt the ring during intercourse and 94% of partners
      never/rarely minded that the woman was using the ring. Overall acceptance was
      high, 96% were satisfied with the ring and 97% would recommend the ring. Similar
      responses were seen for women who prematurely discontinued from the studies,
      except that slightly fewer women were satisfied (60%) and would recommend the
      ring (75%). Reasons for liking the ring included 'not having to remember
      anything' (45%) and 'ease of use' (27%). In conclusion, there is a high level of
      user and partner acceptability for the contraceptive ring.

PMID- 12618253
TI  - Surfing on the morning after: analysis of an emergency contraception website.
AB  - The introduction of widespread nonprescription delivery of hormonal emergency
      contraception (EC) calls for development of innovative tools to provide
      information to and gather feedback from EC users. Individuals seeking
      confidential information on sexual health and contraception are increasingly
      turning to the Internet as the resource of choice. This study employed analytical
      software and manual content analysis to examine the use of a website dedicated to
      an EC product (www.norlevo.com) over the course of 2 years. Frequency of visits
      to and pageviews of the site increased consistently over the 2-year time period,
      and the bulk of the visitors to the site were EC users seeking responses to
      frequently asked questions. The most common concern raised by users was the
      occurrence of spotting and menstrual bleeding following EC use. This analysis
      reveals that within the context of nonprescription access to hormonal EC, a
      website can constitute a potent educational tool for health professionals and EC
      users and provide a valuable source of post-marketing feedback on product use.

PMID- 12618254
TI  - Acceptability of manual versus electric aspiration for first trimester abortion:
      a randomized trial.
AB  - This study was conducted to compare the acceptability of manual and electric
      vacuum aspiration for first trimester elective abortion. Eighty-four women
      seeking abortions at less than 10 weeks gestation were randomized to abortion by
      manual or electric vacuum aspiration. Post-procedure questionnaires were
      administered to patients to assess pain, noise disturbance and overall
      satisfaction with the abortion procedure. Physicians reported procedural
      difficulty, their perceptions of patient discomfort and their overall acceptance
      of the procedure. Other outcomes included amounts of anesthesia required and
      complication rates. There were no significant differences in pain levels or
      satisfaction reported by patients; however, significantly more women in the
      electric group were bothered by noise (19% vs. 2%, p = 0.03). There were no
      differences in physician assessments of procedural difficulty; however, there
      were significantly more times in the electric group that physicians would have
      preferred manual aspiration (43% vs. 17%, p = 0.02). There were four crossovers
      from manual to electric, and none from electric to manual. It is concluded that
      physicians and patients find manual vacuum aspiration as acceptable as electric
      vacuum aspiration for elective abortions performed at less than 10 weeks
      gestation.

PMID- 12618255
TI  - Similarities in women's perceptions and acceptability of manual vacuum aspiration
      and electric vacuum aspiration for first trimester abortion.
AB  - This paper examines women's acceptability of and experiences with manual vacuum
      aspiration (MVA) as compared with electric vacuum aspiration (EVA) for first
      trimester abortion. Women requesting pregnancy terminations were randomly
      assigned to either MVA (n = 64) or EVA (n = 63). Participants completed
      questionnaires before and after their abortions and approximately 2-4 weeks
      later. We observed some differences by group in participants' ratings of the
      importance of method characteristics and in their perceptions of their abortion
      methods after their abortions. The two groups did not, however, differ in their
      reports of pain, anxiety or bleeding or in the acceptability of their method.

PMID- 12618256
TI  - Role of sublingual misoprostol for cervical ripening prior to vacuum aspiration
      in first trimester interruption of pregnancy.
AB  - This is a prospective randomized clinical trial evaluating, for the first time,
      the effectiveness of sublingual route of misoprostol for cervical priming prior
      to vacuum aspiration (VA). The trial included 100 women seeking first trimester
      abortion who were sequentially randomized into two groups of 50 each. Patients of
      study group received 400 microg sublingual misoprostol 3 h prior to VA while
      those of the control group did not receive any premedication for cervical
      ripening. For all periods of gestation between 6 and 12 weeks, misoprostol
      significantly reduced pain score, blood loss, time duration and rate of
      complications without increasing the side effects. Sublingual misoprostol is an
      effective alternative to mechanical cervical dilatation. It can be self
      administered and has a good patient-acceptability rate. As no study has evaluated
      the role of sublingual route of misoprostol for cervical priming before VA, wider
      studies should be done to advocate its routine use.

PMID- 12618257
TI  - The effect of lorazepam on pain and anxiety in abortion.
AB  - In this double-blind study, 104 women were randomized to receive 1 mg lorazepam
      or placebo prior to a first-trimester abortion. In addition, 262 women were
      allowed to choose whether or not to take the lorazepam. The outcome measures were
      11-point verbal pain scales of pain during the abortion and anxiety measured
      before premedication and during the abortion. The mean anxiety and pain scores
      did not differ significantly in the lorazepam and placebo groups of the
      randomized trial. In the observational group, the women who took lorazepam had
      their mean anxiety score drop from 5.5 to 4.7 while in those who did not take it,
      the score rose from 3.8 to 4.9. This study indicates that giving oral
      benzodiazepines preoperatively is neither helping nor hurting our patients but
      the placebo effect can be helpful to make our patients more comfortable.

PMID- 12618259
TI  - Safety and acceptability of post-abortal IUD insertion and the importance of
      counseling.
AB  - This nonrandomized observational clinical study evaluated the safety and
      acceptability of intrauterine device insertion either immediately or 2 weeks
      after abortion, according to the patient's preference. Participants were 300
      women with first-trimester abortions who agreed to immediate or delayed
      insertion. End points were bleeding patterns, pregnancy, expulsion, perforation,
      infection and device removal at 2, 6 and 10 weeks after insertion, and acceptance
      rates before and after counseling procedures were improved. The overall initial
      acceptance rate was 35.8%, and the actual acceptance rate was 31.7%. After
      counseling procedures were improved, the initial and actual acceptance rates
      increased substantially (17.7% vs. 44.3% and 10.2% vs. 42.0%, respectively).
      Bleeding, expulsion rates and pain did not differ significantly between the
      immediate and delayed insertion groups after IUD insertion. No pregnancies,
      perforations or cases of pelvic inflammatory disease were recorded in either
      group. Immediate post-abortal insertion offers the advantage of being a painless
      procedure. The quality of counseling is critical to improving acceptance of post
      abortion contraception.

PMID- 12618258
TI  - The learning curve is rapid in medical termination of pregnancy--first-year
      results from the Helsinki area.
AB  - Medical termination of pregnancy by means of mifepristone and prostaglandin
      became available in Finland in May 2000. We summarize the first year results of
      medical abortion in a large tertiary care unit in Helsinki. A regimen of 200 mg
      of mifepristone followed by 0.4 mg vaginally administered misoprostol 2 days
      later was used. The maximum duration of pregnancy was 56 days. Four hundred and
      seventeen women, 47% of those with a pregnancy duration of up to 56 days, chose
      medical instead of surgical abortion. The monthly percentage of medical abortions
      varied from 27% to 63%. The percentage of complete terminations increased from
      92% among the first quarter of the subjects to 97% among the fourth quarter, the
      overall success rate being 95%. Subject satisfaction, duration and self-estimated
      amount of bleeding, as well as analgesia needs were similar to those reported
      elsewhere. Most subjects (61%) chose combined oral contraceptive (COC) pills for
      future contraception; 75% of the COCs were started around the day of misoprostol
      administration. The reported amounts and duration of bleeding were not influenced
      by the immediate start of oral contraceptives. Intrauterine contraception was
      planned for 28% of the subjects, and 16% of them chose a levonorgestrel-releasing
      intrauterine device. We conclude that the learning curve in medical termination
      of pregnancy is rapid, and results comparable to those in centers with extensive
      experience with the method can be reached within the first year.

PMID- 12618260
TI  - Uterine factors and risk of pregnancy in IUD users: a nested case-control study.
AB  - Scarce data are available on the relation between the effectiveness of
      intrauterine device (IUD) and the gynecologic features of a woman. A nested case
      control study was conducted to determine whether the uterine position and
      hysterometry affect the pregnancy rate of copper IUD. Seventy-one cases (pregnant
      women with IUD) and 284 matched controls (1:4) were included. Matching criteria
      were date of IUD insertion and duration of use. Data were analyzed by conditional
      logistic regression modeling that considered age, parity and copper surface of
      IUD as potential confounders. When cases were compared to nonpregnant controls
      with IUD, the results showed that uterine position and hysterometry were not
      associated with an increased risk of pregnancy. The findings suggest that the
      gynecological characteristics of the woman analyzed should not be a criterion for
      the selection of potential IUD users.

PMID- 12618261
TI  - Effect of diltiazem and methylene blue on human sperm motility, viability and
      cervical mucus penetration: potential use as vas irrigants at the time of
      vasectomy.
AB  - The purpose of this study was to identify compounds that could potentially be
      useful for vas irrigation at the time of vasectomy. We studied the in vitro
      effects of a group of membrane-active and ion-channel blocking agents on human
      sperm motility, viability and cervical mucus penetration. Diltiazem, an anti
      arrhythmic drug, and methylene blue, an agent commonly used in vasography, showed
      the most promising effects with marked reduction of sperm motility and cervical
      mucus penetration after incubation with sperm for a short period of 15 min.
      Diltiazem was more effective than methylene blue in inhibiting the motility and
      viability of sperm. Furthermore, unlike methylene blue, diltiazem significantly
      compromised sperm viability. Other compounds studied, such as lidocaine,
      nicardipine and Neosporin((R)), showed only partial inhibitory activity. Based on
      the data reported herein, both diltiazem and methylene blue appear to be suitable
      candidates to be developed for vas irrigation at the time of vasectomy.

PMID- 12618262
TI  - Copper ions dynamically regulate beta3 integrin subunit expression in Ishikawa
      cells.
AB  - Copper intrauterine device (IUD) users have a reduced expression of beta3
      integrin subunit during the implantation window. This integrin has been found to
      be a uterine marker for implantation. In order to verify if copper ions are
      involved in this reduction, beta3 integrin subunit expression was assessed in an
      in vitro model. The beta3 integrin subunit expression was determined by flow
      cytometry in the presence of copper D-gluconate and/or epidermal growth factor
      (EGF). The mean percentages of positive beta3 integrin subunit cells under
      different culture conditions were: 4.7 +/- 0.29 (mean +/- SEM) in controls; 8.6
      +/- 0.59 in the presence of copper; 13.4 +/- 0.05 in the presence of EGF and 20.8
      +/- 0.36 in the presence of EGF+copper (analysis of variance, p < 0.0001). Copper
      D-gluconate up-regulates beta3 integrin subunit expression in vitro both in the
      presence and absence of EGF. The differences between in vivo and in vitro results
      should be investigated and may represent interference by other factors such as
      the inflammatory process associated with the presence of IUDs.

PMID- 12618263
TI  - LDL apheresis.
AB  - Low density lipoprotein (LDL) apheresis provides a safe and effective means of
      treating patients with homozygous familial hypercholesterolaemia (FH). It also
      has a role in preventing the progression of coronary artery disease in
      heterozygotes and others with severe dyslipidaemia who are refractory to or
      intolerant of high doses of lipid-lowering drugs. Established methods involve
      either adsorption of apolipoprotein B-containing lipoproteins by affinity columns
      containing anti-apolipoprotein B antibodies or dextran sulphate, or their
      precipitation at low pH by heparin, in each instance after first separating
      plasma from blood cells with a cell separator. The most recently developed method
      enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate
      columns. All 4 methods have proved to be similarly efficient when used weekly or
      biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL
      cholesterol. Economic constraints restrict the use of LDL apheresis to the
      treatment of potentially fatal disorders such as FH, where there is clear
      evidence of benefit compared with conventional therapy. Widening the indications
      to include the treatment of other dyslipidaemic disorders such as steroid
      resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and
      prevention of re-stenosis after coronary angioplasty requires evidence from
      controlled trials that is currently lacking.

PMID- 12618265
TI  - CCR5 deficiency is not protective in the early stages of atherogenesis in apoE
      knockout mice.
AB  - The accumulation of macrophages and T lymphocytes in vessel walls is a hallmark
      of atherogenesis. It has recently been demonstrated in mouse models of
      atherosclerosis that full disease potential is dependent on several regulators of
      leukocyte trafficking, including the chemokine monocyte chemotactic protein 1
      (MCP-1) and the chemokine receptors CCR2 and CXCR2. A possible role for the
      chemokine receptor CCR5 in atherogenesis has been suggested by CCR5 expression on
      macrophages, T cells, coronary endothelial cells and aortic smooth muscle cells
      and by the presence of CCR5 ligands in atherosclerotic plaques. Moreover,
      individuals who are naturally deficient in CCR5 were reported to be at reduced
      risk for severe coronary artery disease (CAD) and early myocardial infarction
      (MI). To investigate whether CCR5 is pro-atherogenic in mice, we generated CCR5
      deficient mice and crossed them with atherosclerosis-prone apoE-deficient mice.
      Although CCR5-deficient mice exhibit defects in induced macrophage trafficking,
      mean atherosclerotic lesion area did not differ significantly between apoE
      deficient mice and apoE/CCR5-deficient mice after 16 weeks on a diet of normal
      chow. Ribonuclease protection assays (RPA) on RNA isolated from plaques from both
      apoE-deficient and apoE/CCR5-deficient animals showed strong signals for the
      macrophage marker F4/80 but no evidence for expression of prominent markers of T
      and B lymphocytes. These results indicate that the early stages of plaque
      formation in this model of lipid-mediated atherogenesis do not depend on CCR5.

PMID- 12618264
TI  - Increased calcium buffering in coronary smooth muscle cells from diabetic
      dyslipidemic pigs.
AB  - No studies exist concerning the ability of the plasma membrane Ca(2+) pump
      (PMCA), sarcoplasmic reticulum Ca(2+) pump (SERCA) and Na(+)-Ca(2+) exchanger
      (NCX) to regulate myoplasmic Ca(2+) (Ca(m)) in vascular smooth muscle cells from
      diabetic individuals with dyslipidemia. We tested the hypothesis that diabetic
      dyslipidemia would increase vascular smooth muscle cells to buffer Ca(m). Cells
      were isolated from the coronary artery of male Yucatan pigs treated for 20 weeks
      with: (1) a low fat diet (control group); (2) a high fat/cholesterol diet (F
      group); or (3) alloxan-induced diabetic pigs fed the high fat diet (DF group).
      The maximum Ca(m) response to a depolarizing 80 mM KCl (80 K) solution was
      evaluated in the absence and presence of thapsigargin (TSG; inhibits SERCA) and
      low Na (inhibits NCX). In response to 80 K alone, there was no difference in the
      Ca(m) response between groups. In the presence of TSG, the 80 K response
      decreased by 43% in the DF group; TSG did not affect the 80 K response in the
      control and F groups. When exposed to both TSG and low Na, the 80 K response also
      decreased by 55% in the DF group. This suggests increased Ca(m) buffering by the
      PMCA and/or mitochondria in the DF group when SERCA and NCX are inhibited.
      Compared to the control and F groups, low Na alone elicited a 50% lower Ca(m)
      amplitude in the DF group, which was reversed with TSG treatment; this suggests
      that SERCA activity is increased in DF pigs. Western blots also indicated a 7
      fold increase in the approximately 115 kDa band density of an anti-SERCA2
      antibody in DF compared to control pigs. This is the first report to demonstrate
      increased Ca(2+) buffering, specifically by SERCA, in vascular smooth muscle
      cells from diabetic individuals with dyslipidemia.

PMID- 12618266
TI  - Invasive and non-invasive evaluation of spontaneous arteriogenesis in a novel
      porcine model for peripheral arterial obstructive disease.
AB  - Our current knowledge regarding the efficacy of factors stimulating collateral
      artery growth in the peripheral circulation primarily stems from models in small
      animals. However, experimental models in large sized animals are a prerequisite
      for extrapolation of growth factor therapy to patients with peripheral
      atherosclerotic obstructive disease. Therefore, we have developed a novel porcine
      femoral artery ligation model using non-invasive and invasive evaluation
      techniques. In 12 young farm pigs and nine older minipigs, a ligation of the
      superficial femoral artery was performed. Using an intra-arterial catheter,
      phosphate buffered saline (PBS) was administered with a first-pass over the
      collateral vascular bed. Directly after ligation as well as after 2 weeks of
      continuous infusion of PBS, perfusion of the leg was measured using various flow
      and pressure parameters. Using a pump driven extracorporal system, collateral
      conductance was determined under maximal vasodilatation. Conductance decreased
      after acute ligation to similar levels in both young farm pigs as well as the
      older minipigs (both 9.3% of normal perfusion) and recovered after 2 weeks to a
      higher value in farm pigs compared with minipigs (22.4 vs. 12.7% of normal;
      P<0.05). Angiography using both X-ray and magnetic resonance imaging was
      performed to visualize the formed collateral arteries. To the best of our
      knowledge this is the first in vivo pig model for hemodynamic assessment of
      growth of collateral arteries in the peripheral circulation, that is suitable for
      evaluation of arteriogenic effects of growth factors or genes.

PMID- 12618267
TI  - Antioxidant vitamins increase the collagen content and reduce MMP-1 in a porcine
      model of atherosclerosis: implications for plaque stabilization.
AB  - Degradation of extracellular matrix, particularly interstitial collagen, promotes
      plaque instability and contributes to restenosis after vascular injury. We have
      explored the effects of vitamins C and E on the collagen content and
      metalloproteinase-1 (MMP-1) expression after angioplasty in hypercholesterolemic
      pigs. Iliac angioplasty was performed on 18 minipigs divided into three diet
      groups: a normal-cholesterol (NC), a high-cholesterol (HC) and a high-cholesterol
      plus vitamins C+E (HCV). Four weeks later, after sacrifice, the vascular collagen
      content and MMP-1 protein expression, along with the plasma caseinolytic activity
      and lipid peroxidation, were measured. MMP-1 was also determined in arterial
      rings stimulated with native low-density lipoproteins (LDL) isolated from
      experimental groups. Cholesterol-rich diet augmented plasma lipid peroxidation
      (P<0.05), reduced the collagen content and increased vascular MMP-1 expression
      after injury (P<0.05). Enhanced caseinolytic activity (identified as MMP-1) was
      also observed in HC plasma samples and in supernatants from arterial rings
      incubated with HC-LDL. Vitamins C and E markedly increased neointimal collagen
      content (P<0.01), reduced the hypercholesterolemia-induced changes in vascular
      MMP-1 (P<0.05) and diminished plasma and ex vivo caseinolytic activity. Vitamins
      C and E may help stabilize atherosclerotic plaque after angioplasty and favor
      vascular remodeling by increasing collagen content and reducing vascular MMP-1
      expression in porcine hypercholesterolemia.

PMID- 12618268
TI  - Differential intracellular trafficking of von Willebrand factor (vWF) and vWF
      propeptide in porcine endothelial cells lacking Weibel-Palade bodies and in human
      endothelial cells.
AB  - Von Willebrand factor (vWF) is an adhesive protein involved in primary
      haemostasis virtually absent in the thoracic aorta of swine, an animal model
      widely used in thrombosis and atherosclerosis. By RT-PCR analysis we show that
      porcine aortic endothelial cells (PAEC) express the vWF gene, although vWF mRNA
      levels were 8+/-0.8-fold (p<0.05) or 290+/-8.9-fold (p<0.0001) lower than those
      in porcine pulmonary artery EC (PPEC) or human aortic EC (HAEC), respectively.
      Although vWF was rare in the thoracic aorta of swine, vWF propeptide (vWFpp) was
      present in the endothelium of this artery and in both primary and passaged PAEC.
      In addition, vWFpp but not vWF was detected in PAEC by Western blot. In PAEC
      neither vWFpp nor P-selectin immunostaining depicted Weibel-Palade bodies (WPB)
      like structures, and acute stimuli (alpha-thrombin or the calcium ionophore
      A23187) did not increase vWF secretion. vWFpp co-localized with a Golgi marker,
      that cycles between the stacked Golgi (SG fraction) and earlier compartments of
      the secretory pathway. Our results confirm that PAEC express very low levels of
      vWF mRNA and indicate that in these cells, that do not have WPB, vWF and vWFpp
      have divergent intracellular trafficking pathways.

PMID- 12618269
TI  - Chlamydial LPS antibodies, intima-media thickness and ischemic events in patients
      with established atherosclerosis.
AB  - BACKGROUND: Chlamydia pneumoniae has been associated with cardiovascular disease.
      However, studies on the presence of chlamydial antibodies and intima-media
      thickness (IMT) or future ischemic events are inconclusive. We examined the
      relation between circulating antibodies to chlamydial lipopolysaccharide (cLPS
      Ab), IMT and the occurrence of ischemic events during follow-up in patients with
      manifest atherosclerotic disease. METHODS: IgG and IgA antibodies against cLPS
      were determined in 273 out of 307 consecutive patients with a recent ischemic
      stroke (IS, n=90), a recent myocardial infarction (MI, n=87) or peripheral
      arterial disease (PAD, n=96). B-mode ultrasound IMT measurement of carotid and
      femoral arteries was performed and ischemic events, IS or MI, during follow-up
      were registered. RESULTS: IgG and IgA were found in 66 and 46% of the patients,
      respectively. We did not detect any difference in IMT between patients with or
      without antibodies: IgA-0.97(0.28) mm versus IgA+0.95(0.26) mm, P=0.63, IgG
      0.96(0.28) mm versus IgG+0.96(0.26) mm, P=0.98. During follow-up with a mean
      duration of 3.5 years the combined endpoint, MI or IS, was similar in patients
      with or without antibodies (IgA-24% vs. IgA+19%, IgG-23% vs. IgG+22%). However, a
      lower frequency of MI was observed in IgA positive patients (IgA-13% vs. IgA+8%).
      The number of ischemic events in the 12 patients who used anti-chlamydial
      antibiotics was similar compared with those who did not use antibiotics.
      CONCLUSION: In patients with manifest atherosclerotic disease no association
      between the presence of cLPS Ab and IMT could be detected. In addition, no
      influence of cLPS Ab on the number of ischemic events was observed, the frequency
      of MI during follow-up in IgA positive patients was even lower.

PMID- 12618270
TI  - Relations of plasma high-sensitivity C-reactive protein to traditional
      cardiovascular risk factors.
AB  - Variations of circulating C-reactive protein (CRP) levels are supposed to reflect
      chronic inflammatory process of the cardiovascular system. In particular, it has
      been reported that high-sensitivity CRP (hsCRP) is a promising marker of coronary
      heart disease. In the present study, we assessed the relationship between hsCRP
      and classic cardiovascular risk factors, such as age, blood pressure, smoking
      habit and serum lipids. Plasma hsCRP was measured by ELISA in 908 subjects, aged
      30-79 years, who entered our health-check program. Plasma hsCRP level was 0.54+/
      0.02 mg/l in 566 subjects without any disease currently treated. The level was
      significantly higher in patients treated for hypertension (0.74+/-0.06 mg/l,
      P=0.002), diabetes mellitus (0.77+/-0.09 mg/l, P=0.016) or coronary artery
      disease (0.99+/-0.16 mg/l, P=0.008) than in subjects without diseases. In a
      simple regression analyses of the 566 subjects without diseases, plasma hsCRP
      positively correlated with male gender, smoking, body mass index, systolic blood
      pressure, white blood cell count, blood hemoglobin, fasting blood glucose, serum
      gamma-GTP, uric acid and triglycerides, and inversely correlated with serum
      albumin and HDL-cholesterol. In multiple regression analysis, white blood cell
      count (r=0.276, P<0.001), body mass index (r=0.246, P<0.001), age (r=0.122,
      P=0.001) and smoking (r=0.112, P=0.009) showed independent correlations with
      plasma hsCRP. It is suggested that variation of circulating hsCRP, even within
      normal range, is involved in the interrelation of cardiovascular risk factors,
      such as age, smoking, obesity, high blood pressure and dyslipidemia, which are
      supposed to promote atherosclerosis and ultimately provoke cardiovascular
      diseases, such as coronary artery disease.

PMID- 12618271
TI  - Limited association of Chlamydia pneumoniae detection with coronary
      atherosclerosis.
AB  - The association of Chlamydia pneumoniae (C. pneumoniae) detection with
      atherosclerosis has been controversial because of recent conflicting results. In
      order to assess how and to what extent C. pneumoniae detection contributes to
      atherosclerosis, the association between immunohistochemical detection of C.
      pneumoniae antigen, intimal lesions, and the intimal thickening ratio was
      examined in 1674 left anterior descending coronary arterial segments from 100
      autopsied Japanese patients being free from coronary heart disease. These
      specimens contained full spectrum of atherosclerotic lesions as defined by the
      American Heart Association classification. The intimal thickening ratio increased
      in C. pneumoniae-positive sections comparing to that in C. pneumoniae-negative
      sections only in the group with normal intima and diffuse intimal thickening, but
      there was no such association in the other advanced intimal lesion groups.
      Furthermore, in 50 C. pneumoniae-positive cases out of 100 investigated, the
      frequency and extent of immunoreactivity did not associate with progression of
      intimal lesions or the intimal thickening ratio, and the mean score of C.
      pneumoniae detection did not correlate with the mean intimal thickening ratio in
      individual cases. These results suggest only a limited association between C.
      pneumoniae detection and coronary atherosclerosis development and that C.
      pneumoniae does not influence promotion of atherosclerotic lesions. The role of
      C. pneumoniae on atherogenesis may be limited only at the beginning stage of
      atherosclerosis development.

PMID- 12618272
TI  - Src family kinases and nitric oxide production are required for hepatocyte growth
      factor-stimulated endothelial cell growth.
AB  - Hepatocyte growth factor (HGF) is a potent mitogen for vascular endothelial cells
      (EC); however, signal transduction pathways for HGF-stimulated EC growth remain
      unclear. In the present study we investigated the role of Src family kinases and
      nitric oxide (NO) in HGF-stimulated EC growth. Human umbilical vein endothelial
      cells (HUVEC) were stimulated with HGF and NO was measured by an NOx analyzing
      HPLC system. Activation of ERK1/2 and p38 MAPK was assessed by Western blot. NO
      production in HUVEC increased 1.8-fold by HGF. A Src family kinases inhibitor PP1
      inhibited HGF-stimulated NO production by 71%. HUVEC growth increased 1.9-fold in
      cell number by HGF. PP1 and Nitro-L-arginine methylester (L-NAME) inhibited HGF
      stimulated HUVEC growth by 51 and by 71%. ERK1/2 and p38 MAPK were phosphorylated
      by HGF and a MEK inhibitor PD98059 and a p38 MAPK inhibitor SB203580 inhibited
      HGF-stimulated HUVEC growth by 66% and by 58%; however, HGF-induced
      phosphorylation of ERK1/2 and p38 MAPK was not inhibited by L-NAME, indicating
      that NO is not an upstream activator of ERK1/2 and p38 MAPK. These findings
      demonstrated that Src family kinases regulate HGF-stimulated NO production in
      HUVEC and that HGF stimulates HUVEC growth through NO-dependent and NO
      independent pathways.

PMID- 12618273
TI  - Effects of atorvastatin on electrophoretic characteristics of LDL particles among
      subjects with heterozygous familial hypercholesterolemia.
AB  - The effects of the HMG CoA reductase inhibitor atorvastatin on electrophoretic
      characteristics of LDL particles were evaluated in 46 patients (28 males and 18
      females) with heterozygous familial hypercholesterolemia (FH) aged 20-61 carrying
      either a negative or a defective LDL receptor gene mutation. Following a 6 week
      drug-free baseline period, FH heterozygotes were treated with atorvastatin
      (median dose: 20 mg/day, range 10-80 mg/day)) for 6 months to maintain their
      plasma LDL-cholesterol concentrations between 4.0 and 5.0 mmol/l. Atorvastatin
      treatment significantly reduced plasma total cholesterol, LDL-cholesterol and
      triglyceride levels and increased plasma HDL-cholesterol. Furthermore,
      atorvastatin treatment significantly increased LDL peak particle diameter (LDL
      PPD) by 0.5% (from 255.0+/-6.2 to 256.4+/-5.5 A, P=0.004) and reduced the
      absolute concentration of cholesterol among small (<255 A) and large (>260 A) LDL
      particles by 35% (P<0.001). Changes in LDL-PPD and plasma triglyceride levels
      were inversely correlated (R=-0.34; P=0.02). Stepwise multiple linear regression
      analyses showed that 41.6% of the variation in the LDL-PPD response to
      atorvastatin was attributable to the initial LDL-PPD (14.4%, P=0.003), the apo E
      polymorphism (12.4%, P=0.02), the nature of the LDL receptor gene mutation (9.6%,
      P=0.01) and change in triglyceride levels (5.2%, P=0.04). Moreover, the reduction
      in the cholesterol content of LDL <255 A was directly correlated with the daily
      dosage of atorvastatin (P=0.05). Results of the present study showed that
      atorvastatin alters significantly LDL heterogeneity in patients at high risk of
      coronary heart disease (CHD) such as FH heterozygotes. These results also suggest
      that genetic and metabolic factors may be important determinants of atorvastatin
      induced changes of LDL particle size and distribution among FH heterozygotes.

PMID- 12618274
TI  - Insulin sensitivity and plasma homocysteine concentrations in non-diabetic obese
      and normal weight subjects.
AB  - OBJECTIVE: To determine whether plasma homocysteine (tHcy) levels were related to
      insulin resistance and obesity in subjects without diabetes or vascular disease.
      RESEARCH DESIGN AND METHODS: We studied correlates of plasma tHcy in 26 subjects
      covering a wide spectrum of obesity and insulin sensitivity (S(I)). The
      measurement of in vivo insulin sensitivity was performed using the minimal model
      analysis of the frequently sampled intravenous glucose tolerance test (FSIVGTT).
      RESULTS: There was no relationship between tHcy and body mass index. There was a
      significant relationship between plasma tHcy and S(I) (r=0.53, P=0.006),
      demonstrating that the more insulin sensitive subjects had higher levels of tHcy.
      On log transformation of the plasma insulin values, log insulin correlated
      negatively with plasma tHcy (r=-0.47; P=0.02). None of the subjects were
      deficient in vitamin B(12) and folate. Plasma vitamin B(12) was significantly
      related to plasma tHcy (r=-0.44, P=0.017), although we found no significant
      relationship between plasma folate and tHcy (r=-0.21, P=0.27). S(I) correlated
      significantly with vitamin B(12) (r=0.4, P=0.045) whereas, we found no
      significant relationship between S(I) and plasma folate (r=0.27, P=0.2). On
      multiple linear regression using tHcy as the dependent variable, S(I) and vitamin
      B(12) remained significant predictors of plasma tHcy, whereas, age and plasma
      folate were not predictors of tHcy. CONCLUSIONS: We conclude that in vitamin
      replete lean and obese individuals, insulin sensitivity correlates significantly
      with plasma tHcy. This relationship may need to be considered when evaluating the
      role of plasma homocysteine as a risk factor in patients with obesity and type 2
      diabetes.

PMID- 12618275
TI  - Fatty acid oxidation products in human atherosclerotic plaque: an analysis of
      clinical and histopathological correlates.
AB  - Markers of lipid peroxidative damage have been shown to be elevated in
      individuals with risk factors for cardiovascular disease, and human
      atherosclerotic plaque contains products resulting from lipid peroxidation. In
      particular, the presence of fatty acid oxidation products such as
      hydroxyeicosatetraenoic acids (HETEs) has previously been suggested as a marker
      of plaque instability and symptomatic cerebrovascular disease. The aim of the
      present study was to quantitate the levels of various oxidation products of
      linoleic acid (HODEs) and arachidonic acid (HETEs), respectively, in human
      atherosclerotic plaque tissue and assess their level in relation to plaque
      histopathology, symptoms of cerebrovascular disease and preexisting
      atherosclerotic risk factors. We also assessed the correlation between the levels
      of the hydroxy fatty acid compounds and F(2)-isoprostanes, an established marker
      of in vivo free radical mediated oxidation. Hydroxy fatty acid oxidation products
      were identified in all histological subtypes of advanced plaque. However, there
      were no significant differences in levels between the histopathologically
      classified sub-groups or between patients symptomatic or asymptomatic for
      cerebrovascular disease. Arachidonic acid oxidation products were significantly
      higher in those subjects who also had symptomatic peripheral vascular disease.
      The level of linoleic acid oxidation products was significantly higher in
      individuals who consumed alcohol on a regular basis. While F(2)-isoprostanes and
      fatty acid oxidation products were highly correlated (P<0.01), levels of the
      hydroxy fatty acid compounds were 20-40-fold higher than F(2)-isoprostanes.
      Chiral analysis of the plaque extracts indicated that all HODEs and HETEs
      originated primarily from non-enzymatic lipid peroxidation. While our results do
      not support previous reports that fatty acid oxidation products such as the HETEs
      are associated with plaque instability and symptomatic cerebrovascular disease,
      further work is warranted to determine the potential of these compounds as
      circulating markers for underlying atherosclerotic disease and lipid peroxidative
      stress.

PMID- 12618276
TI  - Effects of raloxifene on carotid blood flow resistance and endothelium-dependent
      vasodilation in postmenopausal women.
AB  - Raloxifene is one of the most important selective estrogen receptor modulators
      currently employed for the treatment of postmenopausal osteoporosis. However, it
      has also been suggested that this compound affects the vascular system. We
      evaluated both carotid blood flow resistance and endothelium-dependent
      vasodilation in 50 healthy postmenopausal women randomly assigned to receive, in
      a double blind design, either raloxifene (60 mg per day; N=25 subjects) or
      placebo (N=25 subjects) for 4 months. Indices of carotid blood flow resistance,
      such as the pulsatility index (PI) and resistance index (RI), as well as the flow
      mediated brachial artery dilation were measured both at baseline and at the end
      of treatment. Changes in PI were -1.86+/-2.24 and -2.15+/-2.22% after placebo and
      raloxifene treatment, respectively, with no significant differences between
      groups. Changes in RI were -0.77+/-1.72 and -1.81+/-1.54% after placebo and
      raloxifene treatment, respectively, with no significant differences between
      groups. At the end of the treatment period, the increments in artery diameter
      measured after the flow stimulus were 10.79+/-2.39 and 6.70+/-1.23% for placebo
      and raloxifene, respectively, with no significant differences between groups.
      These results demonstrate no significant effects of raloxifene on either carotid
      blood flow resistance or brachial artery flow-mediated dilation in postmenopausal
      women.

PMID- 12618277
TI  - Increased expression of a scavenger receptor (CD36) in monocytes from subjects
      with Type 2 diabetes.
AB  - Uptake of modified low density lipoprotein (LDL) by monocyte-macrophages is
      mediated by the scavenger receptor CD36, which is upregulated in vitro by high
      glucose concentrations and oxidatively modified LDL. We hypothesised that
      monocyte CD36 expression would be higher in Type 2 diabetes, and would increase
      during acute hyperglycaemia. Sixteen subjects with Type 2 diabetes and 11
      controls underwent a 75 g oral glucose load. Monocyte CD36 expression (by laser
      flow cytometry), plasma LDL diene conjugates, plasma LDL hydroxyoctadecadienoic
      acid-13 (a peroxisome proliferator activator receptor gamma agonist) were
      measured at 0, 2 and 4 h. Mean monocyte CD36 expression at baseline was 34%
      higher in the diabetes group (P=0.01), did not change during acute hyperglycaemia
      and plasma LDL conjugated diene concentration was the only variable directly
      related to CD36 expression (F=4.53; P=0.05; r=0.51). Higher baseline CD36
      expression in Type 2 diabetes could reflect increased post-transcriptional
      efficiency of CD36 mRNA in response to chronic hyperglycaemia and could be a
      proatherogenic mechanism in Type 2 diabetes.

PMID- 12618278
TI  - G protein beta 3 subunit 825T allele carriage and risk of coronary artery
      disease.
AB  - C825T polymorphism in the G protein beta3 subunit gene (GNB3) is associated with
      increased transmembrane signal transduction via adenylyl cyclase inhibiting G
      (G(i)) proteins. We tested whether GNB3 C825T is associated with an increased
      risk of coronary artery disease (CAD). Genotypes were determined with polymerase
      chain reaction and allele-specific fluorogenic probes. Angiographically examined,
      consecutive patients (n=998) with CAD and angiographically examined, sex- and age
      matched controls (n=340) with no evidence of CAD were studied. The proportion of
      T allele carriers was significantly higher in the group with CAD compared with
      the control group (55.6 vs. 48.5; P=0.02). T allele carriage was associated with
      a 33% increase in the unadjusted risk (OR 1.33 [95% confidence interval, 1.04
      1.70]) and a 37% increase in the adjusted risk (OR from the multivariate model
      1.37 [95% CI, 1.06-1.76]) for CAD. Moreover, an increase in T allele carriage was
      associated with an increase in disease severity (P=0.006; test for trend). The
      strongest association was observed between T allele carriage and three-vessel
      disease (unadjusted OR 1.47 [95% CI, 1.10-1.96]). Thus, carrying this allele is
      associated with the presence as well as the severity of CAD.

PMID- 12618279
TI  - A paraoxonase gene polymorphism, PON 1 (55), as an independent risk factor for
      increased carotid intima-media thickness in middle-aged women.
AB  - Paraoxonase (PON) gene polymorphisms have been proposed as genetic markers of
      risk for cardiovascular disease (CVD). Sporadic results suggest they are
      correlated with intima-media thickness (IMT), an indicator of preclinical
      atherosclerotic disease. We have investigated whether polymorphisms PON 1 (M/L)
      55, (Q/R) 192, PON 2 (S/C) 311 are related to site-specific carotid plaques in
      310 middle-aged women. Subjects were also investigated for physical and
      biochemical parameters including oxidative markers to evaluate their effect on
      development of atherosclerotic plaques (IMT>1.2 mm) identified by high resolution
      B-mode ultrasound. We demonstrate that PON 1 (LL+ML) 55 is associated with
      plaques both at the bifurcation (OR=2.40; 95% CI 1.00-5.90) and at the common
      carotid artery (OR=2.75; 95% CI 1.01-7.50), and to the total number of plaques at
      any site (P<0.05). This polymorphism is an independent parameter with respect to
      other variables that are significantly associated with plaques, i.e. systolic
      blood pressure (OR=2.06; 95% CI 1.11-3.81) and oxidized low-density lipoprotein
      (LDL) antibodies (OR=1.96; 95% CI 1.05-3.69) in cases of common carotid plaques,
      and lipid peroxides (OR=1.86; 95% CI 1.00-3.50) in cases of bifurcation plaques.
      In conclusion, PON 1 (LL+ML) 55 but not PON 1 (Q/R) 192 or PON 2 (S/C) 311,
      appears to be an independent risk factor for increased carotid IMT in middle-aged
      women.

PMID- 12618280
TI  - Effects of dietary saturated, monounsaturated and n-3 fatty acids on fasting
      lipoproteins, LDL size and post-prandial lipid metabolism in healthy subjects.
AB  - BACKGROUND: The influence of the quality of dietary fat on some aspects of lipid
      metabolism-i.e. lipoprotein concentrations, post-prandial lipids and LDL size-is
      not completely understood, especially in healthy individuals. OBJECTIVES: Aim of
      this study was to evaluate the effects of different types of dietary fat
      (monounsaturated vs. saturated fatty acids, and n-3 or placebo supplementation)
      on fasting lipoproteins, LDL size and post-prandial lipids in healthy people.
      DESIGN: One hundred and sixty-two individuals were randomly assigned to follow
      two isoenergetic diets, one rich in saturated fatty acids (SFA diet) and the
      other in monounsaturated fatty acids (MUFA diet). Each group was further
      randomised to receive supplementation with fish oil (3.6 g/day) or placebo.
      RESULTS: The type of diet significantly affected LDL cholesterol and
      triacylglycerol content, which was higher with the SFA diet and lower with the
      MUFA diet. The changes between the two diets were statistically significant for
      cholesterol (P<0.01) and triacylglycerol (P<0.03). VLDL cholesterol and
      triacylglycerol were significantly reduced and LDL cholesterol significantly
      increased by fish oil supplementation. Plasma triacylglycerol was significantly
      lower in those taking n-3 fatty acids, also 1 and 3 h after a test-meal. Neither
      type of diet nor n-3 supplementation affected LDL size. CONCLUSIONS: A moderate
      substitution of saturated fatty acids with monounsaturated fatty acids has
      beneficial effects on lipid metabolism also in healthy individuals. A moderate
      supplementation of long-chain n-3 fatty acids in healthy individuals reduces both
      fasting and post-prandial triacylglycerol concentrations but increases LDL
      cholesterol, irrespective of the type of diet.

PMID- 12618281
TI  - European lipoprotein club: report of the 25th ELC annual conference. Tutzing, 9
      12 September 2002.

PMID- 12618282
TI  - Interactions of stored iron with traditional and inflammatory cardiovascular risk
      factors.

PMID- 12618283
TI  - Ferritin and cardiovascular risk.

PMID- 12618286
TI  - Sexual dimorphism in very low dose nalbuphine postoperative analgesia.
AB  - In recent studies we demonstrated that the analgesic effect of the kappa-like
      opioids is significantly greater in women, that low dose nalbuphine (5 mg)
      produces profound anti-analgesia (i.e. enhances pain) in men, and that addition
      of a low dose of the non-selective opioid receptor antagonist naloxone (0.4 mg)
      to nalbuphine (5 mg) abolishes the sex difference and results in significantly
      enhanced analgesia in both sexes. To further delineate the dose-dependent
      analgesic and anti-analgesic effects of nalbuphine, the present study evaluated
      the effect of a lower dose of nalbuphine (2.5 mg), with and without naloxone, on
      dental postoperative pain. In women, nalbuphine alone induced modest, short
      duration analgesia, which was antagonized rather than enhanced by the addition of
      naloxone (0.4 mg). In men, this dose of nalbuphine alone did not produce
      analgesia or anti-analgesia, and naloxone (0.4 mg) did not alter the response to
      nalbuphine. Thus, the anti-analgesic effect of nalbuphine, present in both sexes
      at the 5 mg dose disappears at the lower dose of nalbuphine. In addition, the
      mild analgesia in women produced by this lower dose of nalbuphine is antagonized
      by naloxone.

PMID- 12618287
TI  - Analysis of a cluster of polymorphisms in AKT1 gene in bipolar pedigrees: a
      family-based association study.
AB  - We have previously performed a genome scan in 22 multiplex pedigrees with bipolar
      disorder and detected a moderate linkage signal on distal portion of chromosome
      14q22-32. One of the large pedigrees displayed a parametric lod score >3 at a
      marker on 14q23-32. Upon inspection of genes located in this region revealed
      AKT1, a kinase that activates a lithium-responsive cell-survival pathway. Because
      lithium is an effective mood stabilizer for bipolar disorder patients, AKT1 is an
      interesting candidate for further investigation. We screened the gene for
      possible mutations and detected 14 polymorphisms. Seven polymorphic sites were
      clustered in a small segment spanning exon 14 and downstream intron. Transmission
      of haplotypes constructed from this cluster showed a weak evidence of association
      between the AKT1 and bipolar disorder.

PMID- 12618288
TI  - The chronic inhibition of nitric oxide synthase enhances cell proliferation in
      the adult rat hippocampus.
AB  - We investigated the effect of chronic blocking nitric oxide synthase (NOS), an
      enzyme producing NO from L-arginine, on granule cell proliferation in the dentate
      gyrus of adult rats under normal conditions. We treated 7-nitroindazole (7-NI)
      for 5, 15, and 25 days or N-nitro-L-arginine-methyl ester (L-NAME) for 25 days to
      block NOS activity and subsequently injected 5-bromo-2-deoxyuridine (BrdU) to
      detect proliferating cells. The BrdU-immunoreactive (IR) cell number was
      significantly increased in the 7-NI 15 and 25 day treated group, but not in the
      control or in the 7-NI 5 day treated group. L-NAME treatment for 25 days
      significantly increased BrdU-IR cells versus the control and 7-NI 25 day treated
      group. In addition, nissl staining showed no cell death occurred in the dentate
      gyrus after 7-NI or L-NAME 25 day treatments. Our results demonstrate that
      chronic inhibition of NOS increases cell proliferation and has no effect on cell
      death in the dentate gyrus of the rat hippocampus, which suggests that NO may
      regulate cell proliferation in the dentate gyrus.

PMID- 12618290
TI  - Different pattern of association of paraoxonase Gln192-->Arg polymorphism with
      sporadic late-onset Alzheimer's disease and coronary artery disease.
AB  - The paraoxonase (PON1) Gln192-->Arg polymorphism was examined in a group of
      sporadic late-onset Alzheimer's disease (AD) patients, in a group of coronary
      artery disease (CAD) patients, and in normal subjects. The AD sample showed a
      PON1*R allele frequency significantly lower than the control group (0.225 vs.
      0.281, P=0.049). In the CAD patients the *R allele was more frequent than in the
      controls (0.230 vs. 0.213), though not significantly (P=0.28). The odds ratios
      (OR) adjusted for age, gender, and APOE polymorphism by logistic regression
      analysis highlighted that in AD the PON1 RR genotype was significantly protective
      (OR=0.41, 95% CI=0.19-0.90; P=0.025), whereas in CAD it appeared to be a
      significant risk factor (OR=5.11, 95% CI=1.09-23.9; P=0.038) limited to younger
      patients.

PMID- 12618289
TI  - Retinoic acid downregulates the expression of ciliary neurotrophic factor in rat
      Schwann cells.
AB  - Neuropoietic cytokines, which serve as mediators in neuroglial interactions, are
      differentially regulated after peripheral nerve injury. In Schwann cells, the
      expression of ciliary neurotrophic factor (CNTF) decreases. Pursuing the
      hypothesis that retinoic acid (RA) serves as a regulator of lesion-induced
      cytokine signaling we found that all RA receptors and retinoid X receptors are
      expressed in Schwann cell primary cultures. Using quantitative reverse
      transcription-polymerase chain reaction, we have investigated the effect of RA on
      the expression of CNTF in these cells. After treatment with 10 nM all-trans RA
      for 22 h the concentration of CNTF mRNA was reduced to 63% of the control level,
      reminiscent of the regulation after nerve injury in vivo. In addition to CNTF,
      the mRNAs of leukemia inhibitory factor, interleukin-6, ciliary neurotrophic
      factor receptor component alpha and gp130 were detected in the Schwann cells.

PMID- 12618291
TI  - Downregulation of voltage-gated sodium channels by dexamethasone in clonal rat
      pituitary cells.
AB  - The effect of chronic dexamethasone (DEX) treatment (4-5 days) on Na(+) channel
      expression was examined in a clonal strain of rat pituitary cells secreting
      growth hormone (GH) and prolactin (GH3 cells). Using whole-cell patch clamp
      recording, we found that DEX (1 microM) induces an 80% decrease in Na(+) current
      density. No concomitant changes in current kinetics or voltage dependence of
      Na(+) channel function were detected. Instead, the decrease in current density
      was accompanied by a similar reduction in maximal Na(+) conductance, suggesting
      the loss of Na(+) channels from the plasma membrane. Accordingly, saxitoxin
      binding assays carried out on intact cells showed that the average number of
      Na(+) channels per cell is markedly decreased by DEX. Thus, this glucocorticoid
      inhibits the cell surface expression of Na(+) channels when chronically applied
      to GH3 cells.

PMID- 12618292
TI  - Intravenous amantadine sulphate application improves the performance of complex
      but not simple motor tasks in patients with Parkinson's disease.
AB  - Intravenous application of amantadine sulphate induces a rapid improvement of
      motor symptoms in Parkinson's disease (PD), but there are no trials on the
      efficacy of this compound on bradykinesia, rigidity and tremor in detail in
      combination with standardized instrumental measurement of tapping and peg
      insertion abilities. We treated 31 stable non fluctuating PD patients with
      amantadine, scored motor symptoms of both arms and performed peg insertion and
      tapping under cued conditions before and after 3 days. Motor symptoms and peg
      insertion significantly improved in contrast to tapping. Tapping asks for
      repetitive performance of simple standardized movements, therefore it needs low
      cognitive efforts. Since peg insertion depends on more complex movements and thus
      more dopamine dependent cognitive processes, it improved after application of the
      indirect dopaminomimetic substance amantadine.

PMID- 12618293
TI  - Tyrosine kinase and tyrosine phosphatase participate in regulation of
      interactions of NMDA receptor subunit 2A with Src and Fyn mediated by PSD-95
      after transient brain ischemia.
AB  - In this study, we investigated the effects of protein tyrosine kinase (PTK) and
      protein tyrosine phosphatase (PTP) on the tyrosine phosphorylation of N-methyl-D
      aspartate receptor subunit 2A (NR2A) and the interactions among NR2A,
      postsynaptic density protein 95 (PSD-95), Fyn/Src after brain
      ischemia/reperfusion (I/R). The following results were observed: (1) the increase
      in tyrosine phosphorylation of NR2A induced by I/R was suppressed by genistein,
      an inhibitor of PTK, but was further enhanced by sodium orthovanadate, an
      inhibitor of PTP, which were administered to the SD rats 20 min before ischemia.
      (2) Importantly, genistein and sodium orthovanadate increased and decreased the
      interactions involving NR2A, PSD-95, Fyn and Src, respectively. These results
      demonstrated that PTK and PTP were involved in regulating tyrosine
      phosphorylation of NR2A through changing the interaction among NR2A, PSD-95,
      Fyn/Src.

PMID- 12618294
TI  - Differential expression of multidrug resistance genes in naive rat brain.
AB  - The multidrug resistance (mdr1) gene family encodes the efflux transporter P
      glycoprotein (P-gp) which contributes to the functionality of the blood-brain
      barrier. We have characterised the regional expression of mdr1 genes in nai;ve
      rat brain. Adult male Sprague-Dawley rats (n=6) were sacrificed and their brains
      rapidly removed. Seven distinct anatomical regions were isolated by
      microdissection and the expression of mdr1a and mdr1b determined by quantitative
      reverse-transcriptase polymerase chain reaction. The mdr1a isoform was expressed
      in all brain regions investigated, while mdr1b was expressed to a quantifiable
      degree in hippocampus alone. These findings reveal a differential expression of
      mdr1 genes in normal rodent brain tissue and suggest that P-gp may afford a
      broader protection of the hippocampus than other brain structures.

PMID- 12618295
TI  - Detection and identification of Vav1 protein in primary cultured murine
      cerebellar neurons and in neuroblastoma cells (SH-SY5Y and Neuro-2a).
AB  - Vav1 was detected in neuronal cells during a screening for 1
      methylthiodihydroceramide (1-MSDH-Cer) binding proteins. 1-MSDH-Cer is a
      metabolically stable analogue of dihydroceramide that was reported to strongly
      interfere with the formation of ceramide and hence the biosynthesis of all
      sphingolipids in neuronal cells. To identify target proteins that function as
      putative mediators of this molecule, a 1-MSDH-Cer affinity chromatography was
      utilised. When the cytosolic fraction of human neuroblastoma SH-SY5Y cells was
      subjected to 1-MSDH-Cer affinity chromatography, the sodium dodecyl sulphate
      polyacrylamide gel electrophoresis of the eluted protein fraction revealed an
      about 2-fold enrichment of the 98 kD protein band. Tryptic digestion of the
      excised band in combination with MALDI mass spectrometry strongly suggested that
      this band contained Vav1 protein. This was surprising since Vav1 in contrast to
      the other two isoforms Vav2 and Vav3 is believed to be exclusively expressed in
      hematopoietic cells and has not been detected in neuronal cells until now. The
      expression of Vav1 was confirmed in human SH-SY5Y neuroblastoma cells and
      additionally in murine Neuro-2A neuroblastoma cells as well as in primary
      cultured murine cerebellar neurons by Western blot analysis and reverse
      transcription polymerase chain reaction.

PMID- 12618296
TI  - Comparison of actual and imagined execution of whole-body movements after a long
      exposure to microgravity.
AB  - Five cosmonauts were tested 30 days before a six-month space flight and also on
      the 2nd and the 6th day after their return to Earth. Cosmonauts performed and
      imagined a task that involved climbing two stairs to step onto a platform,
      jumping down with both feet and walking normally for a distance of 4 m. Durations
      of actual and imagined movements were measured by an electronic stopwatch.
      Results indicated that cosmonauts performed actual and imagined movements with
      similar durations before and after the space flight. However, the 2nd day after
      their return to Earth, cosmonauts significantly increased the durations of both
      actual and imagined movements. The durations of the imagined and actual movements
      returned to approximate pre-flight values 6 days after landing. Our results
      provide evidence that motor imagery process accurately replicates the neural and
      mechanical modifications which occur during the re-adaptation of the motor system
      on Earth's gravito-inertial environment after a long space flight.

PMID- 12618297
TI  - Effects of a phorbol ester and cyclosporin A on hippocampal synaptic plasticity
      in streptozotocin-induced-diabetic rats: reduced sensitivity to phorbol esters.
AB  - In streptozotocin-induced diabetic (STZ-diabetic) rats, an animal model of
      diabetes mellitus, a reduced expression of long-term potentiation (LTP) and
      enhanced long-term depression (LTD) are observed. This study examined the role of
      protein kinase C (PKC) and protein phosphatase 2B in hippocampal synaptic
      transmission in STZ-diabetic rats. The phorbol ester 4beta-phorbol-12,13
      dibutyrate (PDB) induced a concentration-dependent potentiation of synaptic
      responses in area CA1 that could partially be inhibited by the PKC inhibitor
      chelerythrine. In slices from STZ-diabetic rats the effectivity of PDB to
      increase synaptic transmission was reduced compared to slices from control
      animals. In STZ-diabetic rats the protein phosphatase 2B (PP2B) inhibitor
      cyclosporin A inhibited LTD induction, but did not affect the induction of LTP.
      In conclusion, these data show a reduced response to PDB in STZ-diabetic rats,
      and indicate that the lack of LTP induction in these animals is not due to
      increased PP2B activity.

PMID- 12618298
TI  - Functional MRI of amblyopia before and after levodopa.
AB  - Functional magnetic resonance imaging (fMRI) was applied to five older amblyopes
      with monocular amblyopia before and after levodopa treatment. During the
      experiment, images were acquired in two runs with visual stimulation delivered
      through the sound and the amblyopic eyes, respectively. The experiment was
      performed on each of the subjects, before and after their oral administration of
      levodopa/carbidopa (0.5/0.12 mg/kg) three times per day for 7 weeks. Our study
      demonstrated that there was no effect on the spatial extent of the visual
      cortical activation during the sound eye stimulation (P=0.17), but some
      improvement during the amblyopic eye stimulation (P=0.06). The volume ratio
      between the amblyopic and sound eye stimulation significantly increased after the
      treatment (P<0.05). This finding supports the previous studies of levodopa effect
      on amblyopia at the visual cortical level, and suggests that fMRI can be a useful
      tool in assessing changes of visual cortical activity after the treatment

PMID- 12618299
TI  - Huntingtin distribution among striatal output neurons of normal rat brain.
AB  - Huntingtin is the protein whose mutation leads to Huntington's disease (HD). The
      protein is heterogeneously distributed in the telencephalon, and not consistently
      correlated with cell vulnerability in HD [Fusco, F.R., Chen, Q., Lamoreaux, W.J.,
      Figueredo-Cardenas, G., Jiao, Y., Coffman, J.A., Surmeier, D.J., Honig, M.G.,
      Carlock, L.R., and Reiner, A., J. Neurosci., 19 (1999) 1189-1202]. The aim of our
      study was to investigate a possible preferential distribution of huntingtin among
      the two main striatal output pathways, namely, the striatonigral and the
      striatopallidal circuit. Dual label immunofluorescence by means of confocal
      microscopy was used to detect the presence of huntingtin among striatal
      projection neurons identified by their cellular content of Substance P,
      Enkephalin, CB1 receptor, and D1a dopamine receptor. Our data showed that
      striatopallidal neurons co-containing SP and D1a [Surmeier, D.J., Song, W.J., and
      Yan, Z., J. Neurosci., 16 (1996) 6579-6591] co-localized with huntingtin in a
      higher proportion than striatonigral neurons.

PMID- 12618300
TI  - Asymmetric Fos labeling in lobule X of the cerebellum following transtympanic
      tetrodotoxin (TTX) in the rat.
AB  - Unilateral transtympanic administration of the sodium channel blocker
      tetrodotoxin (75 microl of 3 mM TTX in 0.1 M citrate buffer, pH 5.0) produced
      behavioral symptoms indicative of unilateral vestibular disruption. Following
      survival times of 2 and 24 h immunocytochemistry for Fos revealed asymmetric
      labeling in the granular and molecular layers of lobule X of the cerebellum and
      in the medial cerebellar nucleus. The granular and molecular layers as well as
      the medial cerebellar nucleus ipsilateral to TTX treatment contained elevated
      levels of Fos relative to the same regions contralaterally and when compared to
      controls receiving equal volume injections of vehicle. The asymmetric changes in
      neuronal activity as measured by Fos (genetic activity) in lobule X implicate
      this region of the vestibulocerebellum in recovery from transient vestibular
      disruption in the intact system.

PMID- 12618301
TI  - Assumption-free analysis of quantitative real-time polymerase chain reaction
      (PCR) data.
AB  - Quantification of mRNAs using real-time polymerase chain reaction (PCR) by
      monitoring the product formation with the fluorescent dye SYBR Green I is being
      extensively used in neurosciences, developmental biology, and medical
      diagnostics. Most PCR data analysis procedures assume that the PCR efficiency for
      the amplicon of interest is constant or even, in the case of the comparative C(t)
      method, equal to 2. The latter method already leads to a 4-fold error when the
      PCR efficiencies vary over just a 0.04 range. PCR efficiencies of amplicons are
      usually calculated from standard curves based on either known RNA inputs or on
      dilution series of a reference cDNA sample. In this paper we show that the first
      approach can lead to PCR efficiencies that vary over a 0.2 range, whereas the
      second approach may be off by 0.26. Therefore, we propose linear regression on
      the Log(fluorescence) per cycle number data as an assumption-free method to
      calculate starting concentrations of mRNAs and PCR efficiencies for each sample.
      A computer program to perform this calculation is available on request (e-mail:
      bioinfo@amc.uva.nl; subject: LinRegPCR).

PMID- 12618302
TI  - Spatial pre-training attenuates hippocampal impairments in rats exposed to
      intermittent hypoxia.
AB  - Intermittent hypoxia (IH), such as occurs in sleep apnea, is associated with
      increased apoptosis and neurobehavioral impairments in rats. To determine whether
      pre-training (P) modifies the effect of IH on spatial learning, adult male rats
      were trained in a spatial version of the water maze, exposed to IH or room air
      (RA) for 14 days, and then trained in a novel spatial task. P-RA had lower
      initial pathlengths than naive RA (N-RA), which were similar in P-IH and N-IH,
      indicating an adverse effect of IH on retention of behavioral strategies to solve
      the maze. However, P-IH acquired the later spatial task faster than N-IH. Pre
      training was associated with increased phosphorylation of the cAMP-response
      element binding protein (CREB) in the hippocampus. Further, IH-induced decreases
      in CREB phosphorylation were attenuated by pre-training. We conclude that prior
      exposure to the water maze behavioral requirements attenuates the behavioral
      deficits occurring after IH exposure.

PMID- 12618303
TI  - Deletion of the preprotachykinin A gene in mice does not reduce scratching
      behavior elicited by intradermal serotonin.
AB  - Itch is thought to be signaled by a sub-population of pruritogen-selective C
      fiber primary afferents. To assess a possible role of the neuropeptide, substance
      P (SP), in the central neurotransmission of itch, we investigated itch-related
      scratching behavior elicited by intradermal injection of serotonin (5-HT; 0.03
      0.3%) in normal mice (wildtype, WT) and knockout mice (KO) with deletion of the
      preprotachykinin A gene. Both KO and WT groups showed dose-related increases in
      the number of 5-HT-evoked scratching bouts over the 44 min observation period.
      There were no significant differences in the numbers or durations of scratching
      bouts between WT and KO groups, although KO mice exhibited numerically more
      spontaneous and 5-HT-evoked scratching. It is concluded that either SP is not
      involved in the central neurotransmission of itch-related scratching behavior in
      this strain of mouse, or that compensatory developmental changes in the KO mice
      allow itch-related signaling.

PMID- 12618304
TI  - Neuronal differentiation and myenteric plexus organization are delayed in
      gastroschisis: an immunohistochemical study in a rat model.
AB  - Gastroschisis is a malformation due to prenatal rupture of the abdominal wall and
      evisceration of the midgut. Intestinal loops are shortened, matted, and covered
      by a peel caused by the harmful effect of the amniotic fluid. Babies born with
      gastroschisis suffer from gastrointestinal dysmotility. The present aim was to
      verify whether the myenteric plexus is damaged in a rat model of gastroschisis.
      In the gastroschisis rat model fetus, the myenteric plexus was not yet organized
      in the well-defined ganglia and, in the most damaged loops, the neuronal cells
      were scattered or absent. Immunohistochemistry for alpha-internexin and
      peripherin (markers of neuronal maturity) gave results similar to those of
      earlier embryonic ages. These findings indicate a delay in neuronal
      differentiation and myenteric plexus organization that might play a role in the
      postnatal dysmotility observed in gastroschisis.

PMID- 12618305
TI  - Time-dependent depotentiation in the dentate gyrus of freely moving rats by
      repeated brief 7 Hz stimulation.
AB  - Long-term potentiation (LTP) in the hippocampus of awake animals is known to be
      reversed by long trains of low-frequency stimulation (LFS). Here we show that a
      persistent LTP reversal, i.e. depotentiation (DP), can be induced in the dentate
      gyrus of freely moving rats by brief 7 Hz stimulations (three trains of 100
      pulses, 1 min intertrain-interval) if LFS was applied 2 min after tetanization.
      In contrast, the same LFS protocol given 15 min after tetanization failed to
      induce long-lasting DP. Likewise, reduction of LFS (given 2 min post-tetanus) to
      two trains resulted only in short-term DP. Because naturally occurring
      hippocampal 7 Hz oscillatory events are correlated to new sensory input, our
      results might be relevant for the understanding of the mechanisms of LTP reversal
      induced by processing new information.

PMID- 12618306
TI  - 5-Hydroxytryptamine 6 receptor (5-HT(6)) receptor and apolipoprotein E (ApoE)
      polymorphisms in patients with Alzheimer's disease in the Basque Country.
AB  - Although there is considerable evidence implicating apolipoprotein E (ApoE)
      epsilon4 in the development of the Alzheimer's disease (AD), additional factors
      are also known to be involved. Thus, an association has been described between
      C267T polymorphism of the 5-hydroxytryptamine 6 receptor (5-HT(6)) receptor gene
      and AD. This case-control study analyzes the ApoE and 5-HT(6) receptor
      polymorphisms in 173 cases and 102 age and sex matched controls from Araba and
      Bizkaia (The Basque Country, Spain). The analysis of ApoE showed the frequencies
      of epsilon4 allele to be significantly higher in AD patients (0.292) than in the
      controls (0.083). When 5-HT(6) receptor polymorphism was analyzed, a greater
      frequency of 267C allele was observed in AD patients than in controls, though the
      difference was not statistically significant. Likewise regarding ApoE epsilon4
      status, no statistically significant difference was observed. In conclusion, the
      association of ApoE epsilon4 to AD in a sample of patients from the Basque
      Country is confirmed, though the association to C267T polymorphism of the 5-HT(6)
      receptor has not been observed.

PMID- 12618307
TI  - Systemic agmatine attenuates tactile allodynia in two experimental neuropathic
      pain models in rats.
AB  - Recent evidence suggests that agmatine, an endogenous polyamine metabolite, might
      be an important neurotransmitter in central nervous system and has potential as a
      treatment of pain. The aim of our study was to evaluate the effect of agmatine on
      allodynia in two experimental neuropathic pain models, the spinal nerve ligation
      (SNL) model and the streptozocin (STZ)-induced diabetic neuropathy in rats, and
      to determine if the N-methyl-D-aspartate (NMDA) receptor antagonists and the
      nitric oxide synthase (NOS) inhibitors influence this effect of agmatine. Nerve
      injury was produced by tight ligation of the left L5 and L6 spinal nerves, and
      diabetic neuropathy is induced with the injection of a single dose of STZ; these
      procedures resulted in tactile allodynia in the hindpaw. Tactile allodynia was
      detected by application of von Frey filaments to the plantar surface of the foot.
      Agmatine reduced mechanical allodynia with its higher doses. Dizocilpine maleate
      (MK-801), a NMDA receptor antagonist, and the NOS inhibitors, N(G)-nitro-L
      arginine methyl ester and 7-nitroindazole, did not influence the antiallodynic
      effect of agmatine. These results suggest that agmatine has an antiallodynic
      effect in both spinal nerve ligation and diabetic models and may be a promising
      drug in the treatment of neuropathic pain.

PMID- 12618308
TI  - GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in
      man and Drosophila.
AB  - Typical members of the Ras superfamily of small monomeric GTP-binding proteins
      function as regulators of diverse processes by cycling between biologically
      active GTP- and inactive GDP-bound conformations. Proteins that control this
      cycling include guanine nucleotide exchange factors or GEFs, which activate Ras
      superfamily members by catalyzing GTP for GDP exchange, and GTPase activating
      proteins or GAPs, which accelerate the low intrinsic GTP hydrolysis rate of
      typical Ras superfamily members, thus causing their inactivation. Two among the
      latter class of proteins have been implicated in common genetic disorders
      associated with an increased cancer risk, neurofibromatosis-1, and tuberous
      sclerosis. To facilitate genetic analysis, I surveyed Drosophila and human
      sequence databases for genes predicting proteins related to GAPs for Ras
      superfamily members. Remarkably, close to 0.5% of genes in both species (173
      human and 64 Drosophila genes) predict proteins related to GAPs for Arf, Rab,
      Ran, Rap, Ras, Rho, and Sar family GTPases. Information on these genes has been
      entered into a pair of relational databases, which can be used to identify
      evolutionary conserved proteins that are likely to serve basic biological
      functions, and which can be updated when definitive information on the coding
      potential of both genomes becomes available.

PMID- 12618309
TI  - BAG-1: a multifunctional regulator of cell growth and survival.
AB  - BAG-1 is multifunctional protein which interacts with a wide range of cellular
      targets to regulate growth control pathways important for normal and malignant
      cells, including apoptosis, signaling, proliferation, transcription and cell
      motility. Of particular relevance to tumour cells, BAG-1 interacts with the anti
      apoptotic BCL-2 protein, various nuclear hormone receptors and the 70 kDa heat
      shock proteins, Hsc70 and Hsp70. Interaction with chaperones may account for many
      of the pleiotropic effects associated with BAG-1 overexpression. Recent studies
      have shown that BAG-1 expression is frequently altered in malignant cells, and
      BAG-1 expression may have clinical value as a prognostic/predictive marker. This
      review summarises current understanding of molecular mechanisms of BAG-1
      expression and function.

PMID- 12618311
TI  - Autophagy: a barrier or an adaptive response to cancer.
AB  - Macroautophagy or autophagy is a degradative pathway terminating in the lysosomal
      compartment after the formation of a cytoplasmic vacuole that engulfs
      macromolecules and organelles. The recent discovery of the molecular controls of
      autophagy that are common to eukaryotic cells from yeast to human suggests that
      the role of autophagy in cell functioning is far beyond its nonselective
      degradative capacity. The involvement of proteins with properties of tumor
      suppressor and oncogenic properties at different steps of the pathway implies
      that autophagy must be considered in tumor progression. Autophagy as a stress
      response mechanism protects cancer cells from low nutrient supply or therapeutic
      insults. Autophagy is also involved in the elimination of cancer cells by
      triggering a non-apoptotic cell death program, suggesting a negative role in
      tumor development. These two aspects of autophagy will be discussed in this
      review.

PMID- 12618310
TI  - Cancer pharmacogenomics: current and future applications.
AB  - Heterogeneity in patient response to chemotherapy is consistently observed across
      patient populations. Pharmacogenomics is the study of inherited differences in
      interindividual drug disposition and effects, with the goal of selecting the
      optimal drug therapy and dosage for each patient. Pharmacogenomics is especially
      important for oncology, as severe systemic toxicity and unpredictable efficacy
      are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug
      metabolizing enzymes and other molecules are responsible for much of the
      interindividual differences in the efficacy and toxicity of many chemotherapy
      agents. This review will discuss clinically relevant examples of gene
      polymorphisms that influence the outcome of cancer therapy, and whole-genome
      expression studies using microarray technology that have shown tremendous
      potential for benefiting cancer pharmacogenomics. The power and utility of the
      mouse as an experimental system for pharmacogenomic discovery will also be
      discussed in the context of cancer therapy.

PMID- 12618312
TI  - Migration of cochlear lateral wall cells.
AB  - The role of apoptosis and proliferation in maintenance of cochlear lateral wall
      cells was examined. The methods employed for detection of apoptosis were the
      Hoechst fluorescence stain and TUNEL (TdT-mediated dUTP-biotin nick-end-labeling)
      assay, and proliferations were 5-bromo-2'-deoxyuridine (BrdU) incorporation and
      presence of the proliferating cell nuclear antigen. The incidence of apoptosis in
      the strial marginal cell was 50% greater (32.9+/-3.7%) than strial intermediate
      and basal cells but similar to spiral ligament cells. Although division of
      marginal strial cells was rarely detected, a significant number of proliferating
      cells in the remaining stria vascularis and spiral ligament were observed. These
      data implied that replacement of marginal cells arose elsewhere and could be
      followed by a BrdU-deoxythymidine pulse-chase study. At 2 h post injection,
      nuclear BrdU in marginal cells was not detected; however, by 24 h post injection,
      20-25% of marginal cell nuclei were BrdU-positive. These observations are
      consistent with the hypothesis that marginal cells were replaced by underlying
      cells. Cell migration appears to be an important mechanism for preserving the
      function and structure of the stria vascularis.

PMID- 12618313
TI  - Dystroglycan expression in the mouse cochlea.
AB  - Viable dominant spotting (W(v)/W(v)) mice have a c-kit gene mutation, which
      impedes the migration of neural crest cells to the developing cochlea where they
      normally differentiate into intermediate cells (ICs). A prominent pathological
      feature shared by these mutants and the aging human and gerbil cochlea is
      thickening of the basement membrane (BM) of strial capillaries. Atrophy of strial
      capillaries in the aging gerbil has been associated with changes in the
      expression of dystroglycan (DG), a cell-surface receptor that regulates BM
      assembly. Here we evaluated the expression of DG in W(v)/W(v) mutant and C57BL/6J
      wild-type mice to investigate the possible role of ICs in regulating strial
      capillary BM homeostasis. The DG gene product was identified in lateral wall
      dissections from both W(v)/W(v) mutant and wild-type mice by reverse
      transcription-polymerase chain reaction. Subunit-specific antibodies were
      employed to localize the alpha and beta subunits of the DG heterodimer. Some
      sites in both wild-type and mutant mice, such as the subepithelial BM lining the
      scala media and regions of contact between selected epithelial cells, expressed
      alpha-DG alone. Other sites such as the perineural BM and the perivascular BM
      subtending strial capillaries and capillaries in the central portion of the
      auditory nerve coexpressed alpha- and beta-DG. The strong diffuse staining for
      alpha-DG along the basolateral membrane of strial marginal cells disappeared with
      advancing strial degeneration in abnormal turns of W(v)/W(v) mutants. Variations
      in staining intensity for both alpha- and beta-DG also occurred in the
      subendothelial BM of strial capillaries in turns lacking ICs and appeared to
      correspond with the degree of capillary atrophy. The results support the
      possibility that ICs play a role in the homeostasis of the strial capillary BM.

PMID- 12618314
TI  - Influence of pH on the ototoxicity of cisplatin: a round window application
      study.
AB  - Cisplatin is an antineoplastic agent that produces a number of dose-limiting side
      effects, including ototoxicity. We investigated the effect of pH on cisplatin
      ototoxicity. Auditory brainstem responses (ABR) were recorded in chinchillas.
      Then the auditory bullae were opened and acidic (pH=6.5), neutral (pH=7.4) or
      alkaline (pH=10.2) phosphate-buffered saline (PBS) was applied to the round
      window membrane. After 30 min, any remaining solution was removed and cisplatin
      solution was applied to the round window membrane. After 3 days, follow-up ABRs
      were performed and the cochleae were processed for morphological analysis.
      Neutral PBS+cisplatin administration resulted in profound threshold changes at
      all frequencies. Acidic PBS+cisplatin administration showed had a trend of
      increased threshold changes, but the change did not reach statistical
      significance. However, the degree of hair cell loss was significantly higher than
      that of the neutral PBS-cisplatin group. Alkaline PBS significantly reduced
      cisplatin-induced threshold changes (P<0.05) compared to the neutral PBS group.
      Because the pH of cisplatin solution was 6.0, pH 6.0 PBS was applied to round
      window membrane. This acidic PBS solution did not cause any hearing impairment.
      These results demonstrate that pH can modulate the ototoxic effects of cisplatin.

PMID- 12618315
TI  - Quantitative measurement of afferent layers in the ferret inferior colliculus:
      DNLL projections to sublayers.
AB  - In the central nucleus of the inferior colliculus (IC), afferent projections are
      aligned with dendritic arbors of disk-shaped cells, forming fibrodendritic
      layers. One feature that may serve as a guide for study of the intrinsic
      organization of the IC layers is the segregation of certain inputs to bands and
      patches within the layers of the central nucleus. In this study, we used
      Phaseolus leucoagglutinin as an anterograde tracer to examine the projections
      from the dorsal nucleus of the lateral lemniscus to the contralateral IC in adult
      ferrets. The labeled afferent projections distributed along the IC layers in a
      series of bands where there were dense endings and interband spaces where there
      were few if any endings. Branches of individual labeled axons that were
      reconstructed distributed within a single afferent band. Measurements of both the
      terminal density distribution and the optical density across the band were
      similar indicating that afferent bands were approximately 85 microm thick.
      Quantitative measurements of the labeled afferent bands will enhance comparison
      with other afferent projections and analysis of afferent development and
      plasticity.

PMID- 12618316
TI  - Altered expression of inducible nitric oxide synthase (iNOS) in the cochlea.
AB  - Using immunohistochemistry and Western blot, the expression of inducible nitric
      oxide synthase (iNOS) in the lateral wall and organ of Corti was examined in
      normal (unstimulated) and stimulated mice and guinea pigs. The stimuli were: (1).
      injection of bacterial lipopolysaccharide (LPS, 5 mg/ml) into the middle ear
      through the tympanic membrane and (2). exposure to a 110 dB SPL (A-weighted)
      broadband noise, 3 h/day, for three consecutive days. For the unstimulated
      condition, weak iNOS expression was found in the vascular endothelium, marginal
      cells, nerve fibers, stereocilia of hair cells and Hensen's cells of the organ of
      Corti. More intense iNOS fluorescence signals were observed in cochlear tissues
      (particularly in hair cells and stria vascularis marginal cells) in animals
      exposed to loud sound or treated with LPS. Although the precise roles of iNOS
      expression in normal cochlear function have yet to be determined, enhanced iNOS
      expression following noise exposure and LPS suggests its participation in
      cochlear pathophysiology, including noise- and inflammatory factor-induced
      hearing loss.

PMID- 12618317
TI  - Effects of conductive hearing loss on temporal aspects of sound transmission
      through the ear.
AB  - Effects of conductive hearing loss on level and spectrum are well known. However,
      little is known about possible additional effects on temporal aspects of sound
      transmission. This study investigated effects of earplugs and middle ear
      effusions on amplitude and timing of cochlear microphonic (CM) responses in
      gerbils. Bilateral CM responses to pure tones (1-16 kHz) were monitored before
      and after (i). unilateral earplug insertion or (ii). injection of silicone oil,
      of various viscosities, into one middle ear. Earplugs produced flat hearing
      losses (mean 13 dB) and delayed CMs more at lower (mean 80 micros, 1-6 kHz) than
      at higher (20 micros, 8-16 kHz) frequencies. Effusions also produced flat hearing
      loss. On average, high viscosity effusions produced larger hearing losses (36 dB)
      than medium (25 dB) or low (20 dB) viscosity effusions. Low and medium viscosity
      effusions delayed responses to lower (mean 82 and 65 micros respectively, 1-6
      kHz) more than to higher (mean 20 and 10 micros respectively, 8-16 kHz)
      frequencies. High viscosity effusions produced smaller delays across all
      frequencies (mean 31 micros, 1-16 kHz). In normal animals, CM responses were not
      delayed over a wide range of stimulus levels. Therefore, in addition to
      attenuation, conductive loss distorts acoustic temporal cues important for
      hearing.

PMID- 12618318
TI  - Relationship between the local stiffness of the outer hair cell along the cell
      axis and its ultrastructure observed by atomic force microscopy.
AB  - As electromotility may arise from a conformational change of the molecules'
      'protein motors', which might be distributed along the outer hair cell (OHC)
      lateral wall, the force generated by the OHC electromotility would be related not
      only to the conformational change of the protein motors but also to the
      mechanical properties of the lateral wall. Therefore, a detailed understanding of
      the mechanical properties of the OHC lateral wall is important. In our previous
      reports, to understand the difference in the stiffness along the cell axis, the
      local deformation of the OHC in response to hypotonic stimulation was analyzed by
      measuring the displacement of microspheres attached randomly to the cell lateral
      wall, and the distribution of Young's modulus along the cell axis was obtained
      using the contact mode of an atomic force microscope (AFM). These investigations
      revealed that the stiffness of the cell in the apical region was greater than
      that in other regions where the stiffness is constant. In this study, the
      ultrastructure of the OHC lateral wall was investigated with the oscillation
      imaging mode of the AFM (Tapping Mode), and the relationship between the
      stiffness along the cell axis and the ultrastructure that was observed by the AFM
      imaging was analyzed. From the analysis, it was concluded that the
      circumferential filaments observed in the tapping mode AFM are actins which are
      part of the cortical lattice, and that the difference between the intervals of
      the circumferential filaments in the apical region and those in other regions is
      one factor that causes the high stiffness in the apical region.

PMID- 12618319
TI  - Time course of inner ear degeneration and deafness in mice lacking the Kir4.1
      potassium channel subunit.
AB  - The Kir4.1 gene (KCNJ10) encodes an inwardly rectifying K(+) channel subunit
      abundantly expressed in the CNS. Its expression in the mammalian inner ear has
      been suggested but its function in vivo in the inner ear is unknown. Because
      diverse human hereditary deafness syndromes are associated with mutations in K(+)
      channels, we examined auditory function and inner ear structure in mice with a
      genetically inactivated Kir4.1 K(+) channel subunit. Startle response experiments
      suggest that Kir4.1-/- mice are profoundly deaf, whereas Kir4.1+/- mice react
      like wild-type mice to acoustic stimuli. In Kir4.1-/- mice, the Reissner membrane
      is collapsed, the tectorial membrane is swollen, and type I hair cells and spiral
      ganglion neurons as well as their central processes degenerate over the first
      postnatal weeks. In the vestibular ganglia, neuronal cell death with apoptotic
      features is also observed. Immunostaining reveals that Kir4.1 is strongly
      expressed in stria vascularis of wild-type but not Kir4.1-/- mice. Within the
      spiral ganglion, Kir4.1 labeling was detected on satellite cells surrounding
      spiral ganglion neurons and axons. We conclude that Kir4.1 is crucial for normal
      development of the cochlea and hearing, via two distinct aspects of extracellular
      K(+) homeostasis: (1). in stria vascularis, Kir4.1 helps to generate the cochlear
      endolymph; and (2). in spiral and vestibular ganglia, Kir4.1 in surrounding glial
      cells helps to support the spiral and vestibular ganglion neurons and their
      projecting axons.

PMID- 12618320
TI  - The relationship between noise-induced hearing loss and hair cell loss in rats.
AB  - Noise-induced hearing loss (NIHL) and hair cell loss are known to show only a
      moderate correlation. One reason for this is that NIHL may reflect not only the
      sum of dead hair cells, but also the sum of impaired but still living hair cells.
      This report compares hair cell loss in different cochlear regions in rats with
      noise-induced compound action potential (CAP) threshold elevation at
      corresponding frequencies. CAP threshold elevation and hair cell loss were
      determined 4 weeks after noise exposure. In the apical turn (<35% from the apex)
      there was no hair cell loss even when a 60 dB CAP threshold elevation was
      induced. In the region of 40-60% from the apex in the middle turn, significant
      hair cell loss was not observed until CAP threshold elevation exceeded about 40
      50 dB. This critical level decreased towards the basal turn. In the basal turn,
      outer hair cell (OHC) loss was observed in almost all of the noise-exposed rats,
      even in some cases without detectable NIHL, but inner hair cell (IHC) loss was
      still not observed until 50 dB threshold elevation. In the region of 75-90% from
      the apex related to the highest frequencies tested in this study (30-40 kHz), a
      linear NIHL/OHC loss relationship was observed. The results of this paper suggest
      that the high frequency hair cells in rat cochlea may die relatively rapidly
      after injury, leading to a linear relation between NIHL and hair cell loss, but
      that the low frequency hair cells may survive without auditory function.

PMID- 12618321
TI  - Neuronal responses in the inferior colliculus of mutant mice (Bronx waltzer) with
      hereditary inner hair cell loss.
AB  - Bronx waltzer mice lose a great proportion of their cochlear inner hair cells
      during early development. Hair cell counts revealed that these mice lacked on
      average 86% of their inner hair cells. Outer hair cells were present in a normal
      number, but appeared disarranged. The effect of this inner hair cell loss on the
      properties of central auditory neurons was investigated by recording neuronal
      responses in the inferior colliculus. Neuronal thresholds were on average
      elevated by 40 dB compared to CBA controls. The frequency tuning curves of the
      mutants were broad, and in part (18.5%) multi-peaked. The tonotopy found in the
      inferior colliculus of the Bronx waltzer mice appeared diffuse. Both the driven
      and spontaneous discharge rates were not statistically significantly different
      from the controls. However, the average first spike latency was significantly
      longer in the Bronx waltzer mice.

PMID- 12618322
TI  - Binaural interaction in the inferior colliculus of the big brown bat, Eptesicus
      fuscus.
AB  - Binaural interaction plays an important role in shaping response properties of
      central auditory neurons. Using single unit recording and iontophoresis, we
      examined frequency tuning curves (FTCs), interaural intensity difference (IID)
      curves, and rate-intensity functions of inferior collicular (IC) neurons of the
      big brown bat, Eptesicus fuscus, under closed system or free field stimulation
      conditions. We isolated 46 EI (excitation-inhibition), 24 EO (monaural
      excitation) and 6 EE (excitation-excitation) neurons. Inhibitory FTCs of EI
      neurons plotted under ipsilateral sound stimulation fell within (n=10, 22%),
      partly overlapped (n=26, 56%), or almost entirely encompassed (n=10, 22%)
      excitatory FTCs plotted by contralateral sound stimulation. The discharge rate of
      EI neurons was a sigmoid function of IID. The peak discharge rate occurred at
      IIDs at which contralateral sound stimulation was stronger than ipsilateral sound
      stimulation. Application of bicuculline, an antagonist for gamma-aminobutyric
      acid A receptors, raised the IID curves and broadened the excitatory FTCs but
      partly or completely abolished the ipsilateral inhibitory FTCs. For EE neurons,
      excitatory FTCs and rate-intensity functions plotted by contralateral sound
      stimulation were always broader and higher than those plotted by ipsilateral
      sound stimulation. The sharpness of FTCs of EI neurons was significantly greater
      at ipsilateral 30 degrees than at 30 degrees contralateral. This direction
      dependent frequency tuning was effectively abolished by occlusion of the
      ipsilateral ear. Possible mechanisms underlying these observations are discussed.

PMID- 12618323
TI  - Suppression and enhancement of distortion-product otoacoustic emissions by
      interference tones above f(2). II. Findings in humans.
AB  - Distortion-product otoacoustic emission (DPOAE) suppression tuning curves (STCs)
      can be obtained in a variety of laboratory animals and humans by sweeping the
      frequencies and levels of a third tone (f(3)) around a set of f(1) and f(2)
      primaries. In small laboratory animals, it was previously observed that, when the
      suppressor tone (f(3)) is above f(2), substantial suppression and or enhancement
      (suppression/enhancement) could be obtained. In the present study, it was of
      interest to determine if similar suppression/enhancement phenomena could be
      observed in humans and to what extent this might influence the interpretation of
      STC results reported in the literature. To this end, STCs were measured for
      DPOAEs at 2f(1)-f(2) and 2f(2)-f(1) in human subjects at geometric-mean
      frequencies (GM) of 1, 2, 3, and 4 kHz, and primary-tone equilevels of 80/80 and
      75/75 dB SPL and unequal levels of 65/55 dB SPL. Overall, STC parameters were
      found to be comparable to those reported in the literature. For the 2f(1)-f(2)
      DPOAE, STC tip frequencies tuned to the region of the primaries, and tip
      frequencies were slightly influenced by primary-tone level. STC tip thresholds
      were typically within 10 dB of the level of L(2), and Q(10dB) values ranged from
      1.0 to 2.5, which was consistent with the higher-level primaries employed. The
      2f(1)-f(2) DPOAE showed consistent regions of suppression that were approximately
      an octave above the GM for the 1-kHz, 65/55-dB SPL condition. The 2f(2)-f(1)
      DPOAE tuned to its characteristic place above f(2) and showed reliable
      enhancement above the STC tip region for the 1-kHz, 75/75-dB SPL primaries.
      Overall, the results clearly revealed that human ears also display
      suppression/enhancement phenomena when f(3) reaches frequencies considerably
      above f(2). If suppression/enhancement phenomena reflect secondary DPOAE sources,
      then these sources are present in the ear-canal signal from humans as well as
      small laboratory animals.

PMID- 12618325
TI  - Cyclooxygenase-2 and prostate carcinogenesis.
AB  - In recent years a dramatic surge has occurred on studies defining to the role of
      cyclooxygenase (COX)-2 in causation and prevention of cancer. Prostaglandin (PG)
      endoperoxidase synthase also commonly referred to as COX is a key enzyme involved
      in the conversion of arachidonic acid to PGs and other eicosanoids. COX exists as
      two isoforms, namely COX-1 and COX-2 with distinct tissue distribution and
      physiological functions. COX-1 is constitutively expressed in many tissues and
      cell types and is involved in normal cellular physiological functions whereas COX
      2 is pro-inflammatory in nature and is inducible by mitogens, cytokines, tumor
      promoters and growth factors. A large volume of data exists showing that COX-2 is
      overexpressed in a large number of human cancers and cancer cell lines. The
      possibility of COX-2 as a candidate player in cancer development and progression
      evolved from the epidemiological studies which suggest that regular use of
      aspirin or other non-steroidal anti-inflammatory drugs could significantly
      decrease the risk of developing cancers in experimental animals and in humans. In
      our recently published study (Prostate, 42 2000 73-78), we provided the first
      evidence that COX-2 is overexpressed in human prostate adenocarcinoma. Many other
      studies verified our initial observation and reported that compared to normal
      tissue, COX-2 is overexpressed in human prostate cancer. It should be noted that
      some recent work has suggested that COX-2 is only up-regulated in proliferative
      inflammatory atrophy of the prostate, but not in prostate carcinoma. In this
      scenario, COX-2 inhibitors could afford their effects against prostate
      carcinogenesis by modulating COX-2 activity in other cells in prostate. An
      exciting corollary to this ongoing work is that selective COX-2 inhibitors may
      exhibit chemopreventive and even chemotherapeutic effects against prostate
      carcinogenesis in humans.

PMID- 12618326
TI  - Modulation of carcinogenic response and antioxidant enzymes of rats administered
      with 1,2-dimethylhydrazine by Picroliv.
AB  - The effect of Picroliv treatment on the carcinogenic response and, hepatic and
      renal antioxidant enzymes of rats administered with 1,2-dimethylhydrazine
      hydrochloride (DMH) was studied in male Sprague-Dawley rats. DMH-induced hepatic
      carcinogenic response and necrosis were inhibited by oral administration of
      Picroliv (40 and 200 mg/kg). Liver gamma-glutamyl transpeptidase, which was
      elevated to 0.41 +/- 0.06 nmol/mg protein by DMH administration was found to be
      reduced to 0.22 +/- 0.04 and 0.18 +/- 0.03 nmol/mg protein by Picroliv treatment
      40 and 200 mg/kg, respectively. Elevated number of Argyrophilic Nucleolar
      Organizer Region dots and clusters, an index of proliferation, of DMH treated rat
      liver was reduced by Picroliv treatment. DMH-induced depletion of hepatic and
      renal antioxidant enzymes such as catalase and superoxide dismutase levels were
      restored to normal by Picroliv treatment. Picroliv treatment reduced the DMH
      induced elevation of lipidperoxidation in liver, kidney and serum. Elevated
      levels of serum total bilirubin by DMH administration was reduced by Picroliv
      treatment. Depleted renal glutathione S-transferase and hepatic glutathione
      levels after DMH administered rats were found to be significantly increased by
      Picroliv treatment. Histological analysis of the DMH administered rat liver
      showed hepatic cell necrosis, coalescent nodular areas and cystic hyperplasia of
      the bile ducts with inflammation. Picroliv treated liver resembled normal liver
      except the presence of a few degenerating cells. Renal anatomy was not altered by
      DMH administration.

PMID- 12618327
TI  - Exposure to soil contaminated with an environmental PCB/PCDD/PCDF mixture
      modulates ultraviolet radiation-induced non-melanoma skin carcinogenesis in the
      Crl:SKH1-hrBR hairless mouse.
AB  - Chlorinated aromatic contaminants are active in carcinogenic processes within the
      skin and may have the potential to modulate ultraviolet radiation (UV)-induced
      skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture
      (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated
      dibenzofurans) during the irradiation phase of photocarcinogenesis was associated
      with significant (P < or = 0.001) reductions in papilloma incidence and squamous
      cell carcinoma multiplicity at irradiated skin sites. This protective effect was
      associated with significantly (P < 0.0001) reduced chronic epidermal thickening
      in UV and contaminant-exposed mice compared with mice exposed to UV only.
      Contaminant exposure was also associated with increased UV absorbance of skin
      methanol extracts implying a sunscreen-like effect.

PMID- 12618328
TI  - Consistent downregulation of human lactoferrin gene, in the common eliminated
      region 1 on 3p21.3, following tumor growth in severe combined immunodeficient
      (SCID) mice.
AB  - Lactoferrin (LF) is one of 19 active genes in the common eliminated region 1 at
      3p21.3 identified by us. LF was transfected into mouse fibrosarcoma A9. Fourteen
      severe combined immunodeficient (SCID) derived tumors from two PI based
      artificial chromosome (PAC)-transfectants containing the entire LF gene and two
      LF-cDNA transfectants were analyzed by real time polymerase chain reaction at the
      DNA and RNA level. Following SCID tumor passage, LF expression was decreased or
      eclipsed, in all tumors although DNA levels did not change considerably. Promoter
      methylation and/or rearrangement of the insertion site may be responsible for
      human LF downregulation in mouse fibrosarcoma derived tumors.

PMID- 12618329
TI  - Resistance to the anti-proliferative activity of recombinant arginine deiminase
      in cell culture correlates with the endogenous enzyme, argininosuccinate
      synthetase.
AB  - Recombinant mycoplasma enzyme, arginine deiminase (rADI), has been proposed as a
      possible cancer treatment via arginine depletion. However, many cell lines are
      resistant to rADI-treatment, even though most require arginine for proliferation.
      We compared eight different cell lines for sensitivity in cell proliferation to
      the effect of either rADI or arginine deprivation. The activity of
      argininosuccinate synthetase (AS), the rate-limiting enzyme for converting
      citrulline to arginine, was also measured. Our results indicate that resistance
      to rADI-treatment may correlate with cellular AS activity, either constitutive or
      inducible, allowing cell survival by conversion of the product of the rADI
      reaction, i.e. citrulline to arginine.

PMID- 12618330
TI  - Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the
      risk of lung cancer among male smokers in Finland.
AB  - Associations between lung cancer risk and common polymorphisms in the DNA repair
      genes xeroderma pigmentosum complementation group D (XPD), X-ray repair cross
      complementing group 1 (XRCC1), XRCC3 and apurinic/apyrimidinic endonuclease/redox
      factor 1 were examined within a randomized clinical trial designed to determine
      whether alpha-tocopherol, beta-carotene, or both would reduce cancer incidence
      among male smokers in Finland. We found no direct association between lung cancer
      risk and any of the DNA repair genotypes studied, however, the association
      between XPD codon 751 genotype and lung cancer was modified by alpha-tocopherol
      supplementation, and the association between XRCC1 codon 399 genotype and lung
      cancer was modified by the amount of smoking. Our results suggest that common
      alterations in single DNA repair genes are not major determinants of lung cancer
      susceptibility among smokers.

PMID- 12618331
TI  - Methylenetetrahydrofolate reductase polymorphisms and risk of sporadic and
      hereditary colorectal cancer with or without microsatellite instability.
AB  - Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in the folate
      metabolism, which affects DNA synthesis and methylation. Low enzyme activity may
      reduce the capacity of DNA methylation, and possibly reduce uracil
      misincorporation into DNA, which can result in double strand breaks. Both
      processes may be critical for the oncogenic transformation of human cells. Two
      common amino acid-changing and enzyme activity-reducing nucleotide polymorphisms
      (677C --> T/Ala222Val and 1298A --> C/Glu428Ala) have been described in MTHFR. We
      performed estimations of the relative risk associated with these two
      polymorphisms in samples from 287 colorectal cancer patients, compared to 346
      healthy controls. Relative risk were further determined for subpopulations of
      cancer patients having sporadic (n = 227) or suspected/verified hereditary
      disease (n = 60) and tumours exhibiting high-level microsatellite instability (n
      = 41) or not (n = 246). No significant differences for the relative risk of
      colorectal cancer were observed for the MTHFR genotypes either alone or in
      combination in the analysed cohorts, although the frequency of the 1298AA + AC
      genotypes was increased among the 60 cases with hereditary disease. Whereas our
      results do not support an association of high enzyme activity and increased risk
      of colorectal cancer in general, we can not exclude an association of patients
      with hereditary disease and the MTHFR 1298A --> C variant.

PMID- 12618332
TI  - Methylenetetrahydrofolate reductase polymorphism C677T is not associated to the
      risk of cervical dysplasia.
AB  - The aim of the study was to explore a possible association between
      methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cervical
      neoplasia. A total of 229 women were subjected to cytologic and colposcopic
      evaluation. Ninety-one of them were found to be normal, and served as the control
      group, while the other 138 of them had present or past histologically proven
      cervical pathology (patients group). All patients and controls were investigated
      for the MTHFR C677T polymorphism. Statistical analysis between the groups of
      cases with cervical intraepithelial neoplasia or invasive cervical cancer and the
      control group did not reveal any statistically significant difference in the
      frequency of the MTHFR C677T polymorphism.

PMID- 12618334
TI  - The effects of prostaglandin A2 on cell growth, cell cycle status and apoptosis
      induction in HeLa and MCF-7 cells.
AB  - The effects of 20 microg/ml exogenous prostaglandin A(2) (PGA(2)) were evaluated
      on cell numbers in HeLa (human epithelial cervix carcinoma) and MCF-7 (human
      breast carcinoma) cells. In HeLa cells, PGA(2) reduced cell numbers significantly
      to 75% after 24 h (P < 0.05) and exposure of 48 h decreased cell numbers to 61%
      (P < 0.05) of the control. In MCF-7 cells, PGA(2) significantly reduced cell
      numbers to 48% after 24 h and to 20% after 48 h, compared to vehicle-treated
      control cells (P < 0.05). The anti-mitogenic effects were confirmed by
      morphological studies conducted after 48 h of exposure to PGA(2), when optimal
      effects were observed. HeLa and MCF-7 cells exposed to PGA(2), showed chromatin
      aggregation, cell membrane blebbing and uneven distribution of chromosomes. Cell
      cycle progression analysis of HeLa and MCF-7 cells, showed an increase in DNA
      content preceding the G(0)/G(1) peak after 48 h of exposure, which is indicative
      of apoptotic body formation.

PMID- 12618333
TI  - Differential expression of IGFBP-5 and two human ESTs in thyroid glands with
      goiter, adenoma and papillary or follicular carcinomas.
AB  - Here, we describe the identification of three human genes with altered expression
      in thyroid diseases. One of them corresponds to insulin-like growth factor
      binding protein 5 (IGFBP5), which has already been described as over expressed in
      other cancers and, for the first time, is identified as overexpressed in thyroid
      tumors. The other genes, named 44 and 199, are ESTs with yet unknown function and
      were mapped on human chromosomes seven and four, respectively. We determined by
      RT-PCR the expression level of these genes in ten samples of disease-free
      thyroid, ten of goiter, nine of papillary carcinoma, ten of adenoma and seven of
      follicular carcinoma and the significance of observed differences was
      statistically determined. IGFBP-5 and gene 44 were significantly overexpressed in
      papillary carcinoma when compared to normal and goiter. Genes 44 and 199 were
      differentially expressed in follicular carcinoma and adenoma when compared to
      normal thyroid tissue.

PMID- 12618335
TI  - A novel Q3034R BRCA2 germline mutation identified in a fallopian tube cancer
      patient.
AB  - Fallopian tube cancer (FTC) accounts for 0.1-0.5% of all gynaecological
      malignancies, so that very few studies have demonstrated a significant linkage
      between this cancer type and BRCA1/BRCA2 mutations. We report the identification
      of a novel germline mutation (Q3034R) in BRCA2 gene in a 41-year-old patient. The
      nucleotide change (CAG > CGG) abolishes a DdeI restriction site, making genotype
      identification rapid and inexpensive. Our findings support the hypothesis that
      the primary FTC should be considered, at least in a subset of patients, as a
      BRCA2-associated tumor. Genetic counselling could result, in these cases, in
      early diagnosis of genetically predisposed individuals.

PMID- 12618336
TI  - Loss of ligand-binding specificity of fibroblast growth factor receptor 2 by RNA
      splicing in human chondrosarcoma cells.
AB  - We have previously reported the alternatively spliced transcripts of fibroblast
      growth factor receptor (FGFR) 3 derived by aberrant splicing in human cancers.
      Here, we describe a novel splice variant of FGFR2 (FGFR2DeltaIII) arising from
      skipping exons 7-10, resulting in the deletion of Ig-like-III domain in human
      chondrosarcoma cell. Sf9 cells expressing FGFR2DeltaIII were able to bind FGF1,
      FGF2, and FGF7, leading to loss of ligand-binding specificity. Together with our
      previous findings, the present studies suggest that mRNA splicing plays an
      important role in the regulation of FGFRs' function.

PMID- 12618337
TI  - Human telomerase reverse transcriptase (hTERT) gene expression in FNA samples
      from thyroid neoplasms.
AB  - Identifying a tumor marker that can help distinguish benign from malignant
      thyroid tumors is crucial, because up to 30% of thyroid fine-needle aspirations
      (FNA) are diagnosed as 'suspicious' or follicular neoplasm for malignancy.
      Recently, the detection of human telomerase reverse transcriptase (hTERT) gene
      expression in thyroid FNA samples has been identified as a promising diagnostic
      marker in distinguishing benign and malignant thyroid tumors. Twenty-seven FNA
      samples from thyroid tumors that were suspected to be malignant were collected
      preoperatively, hTERT gene expression was examined by reverse transcriptase
      polymerase chain reaction (RT-PCR), and the cytological and histological results
      were compared. The results demonstrated that 13 (92.8%) of 14 thyroid carcinomas,
      including eight of eight papillary, three of four follicular, and two of two
      Hurthle cell thyroid carcinomas have corresponding FNA samples that were positive
      for hTERT. Meanwhile, eight (61.5%) of 13 benign thyroid nodules, including three
      of six nodular goiter, two of two Graves' disease, two of two Hurthle cell
      adenomas, and one of three follicular adenomas were positive for hTERT. In
      conclusion, hTERT was more prevalent in malignant thyroid FNA samples than in the
      benign thyroid FNA samples. Notably, the extent of the differences in hTERT
      expression between benign and malignant follicular thyroid tumors require further
      investigation. Moreover, further information including semi-quantitative real
      time RT-PCR, is required to verify whether hTERT mRNA expression could serve as
      an adjunctive molecular marker for the preoperative diagnosis of thyroid
      malignancies.

PMID- 12618338
TI  - Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in
      human breast cancer.
AB  - Expression and activity of c-Jun N-terminal and p38 protein kinases were explored
      in malignant and non-malignant tissue samples from patients with primary breast
      cancer. Differential expression was observed for p38 and c-Jun N-terminal protein
      kinases (JNK) in samples from 14 patients in whom there were sufficient malignant
      and non-malignant tissue to perform the entire assays. As previously noted,
      Erk1,2 expression and activity were increased sharply in the malignant tissue.
      The p38 kinase expression and activity were increased 3-fold in breast cancer.
      The expression of c-Jun N-terminal protein kinase JNK1, but not JNK2, was
      increased 2.5-fold in malignant as compared to normal breast tissue.
      Immunohistochemical analysis in situ with antibodies to JNK1 revealed intense
      staining in samples of cancerous epithelium. In spite of a 3-fold increase in
      expression, malignant samples displayed a 35% decrease in the activity of this
      pro-apoptotic protein kinase. The expression of mitogen and extracellularly
      activated protein kinase kinase (MEK)2 and MEK3, upstream protein kinases of
      Erkl,2 and p38, respectively, was elevated 4- to 5-fold. The upstream regulator
      of JNK (e.g., MEK4), however, displayed normal levels of expression, providing no
      basis for the reduction in JNK activity observed for breast cancer. Mitogen
      activated protein kinase phosphatases (MKP)1 and MKP2 were assayed and the
      expression was found to be increased 5-fold and 3-fold, respectively, in
      malignant as compared to non-malignant samples. The reduced activity of JNK1, in
      spite of its overexpression, appears to reflect increased MKP activity associated
      with primary breast cancer. Suppression of MKP activity therapeutically may
      enable the expression of the pro-apoptotic signals from JNK in malignant cells.

PMID- 12618339
TI  - NF-kappaB dependent activation of human endothelial cells treated with soluble
      products derived from human lymphomas.
AB  - Nuclear factor of the Immunoglobulin Kappa chain of B cells (NF-kappaB)
      activation is an early event during cytokine-mediated endothelial activation
      related to increased adhesion of leucocytes. We report that soluble products
      secreted by two human lymphomas activate NF-kappaB, and increase the ability of
      endothelial cells to adhere U937 cells in vitro. Analysis of the tumor-derived
      products revealed the absence of tumor necrosis factor-alpha and interleukin
      1beta. Interference of NF-kappaB activation prevented the increase in U937 cell
      adhesion, suggesting a potential role for endothelial NF-kappaB activation in the
      establishment of physical interactions between the vascular endothelium and tumor
      cells.

PMID- 12618340
TI  - RAGE is expressed in pyramidal cells of the hippocampus following moderate
      hypoxic-ischemic brain injury in rats.
AB  - The receptor for advanced glycation end products (RAGE) is a multi-ligand member
      of the immunoglobulin superfamily of cell surface molecules. The RAGE-ligand
      interaction has a putative role in a range of chronic disorders and is also known
      to contribute to both inflammatory/degenerative processes as well as regeneration
      in peripheral nerve injury. We have investigated the expression of RAGE in the
      moderate hypoxic-ischemic (HI) rat brain injury model in order to determine if
      this receptor is involved in the cellular perturbation mediated by ischemic
      stress. RAGE mRNA levels were detected by in situ hybridization using a DIG
      labelled 48 mer oligonucleotide probe. Results showed a high level of expression
      of RAGE mRNA in the CA1/2 pyramidal cell layer of the hippocampus on the lesioned
      side of the brain 72 h after a moderate hypoxic-ischemic insult. RAGE was not
      expressed on the control side of the hippocampus. The RAGE-positive cells had a
      unique morphology, being angular in shape and atrophied with a condensed cell
      nucleus. They were NeuN-positive and were identified as dying cells by staining
      with thionin/acid fuchsin. A subset of cells was positive for cleaved Caspase-3,
      a marker for apoptosis. Together these data show that RAGE is expressed in dying
      neurons and suggest that RAGE may have a role in neuronal cell death mediated by
      ischemic stress. Identification of the ligand for RAGE in the ischemic brain may
      lead to a better understanding of RAGE-mediated cellular dysfunction in the CNS.

PMID- 12618341
TI  - Differential effects of bupivacaine enantiomers, ropivacaine and lidocaine on up
      regulation of cell surface voltage-dependent sodium channels in adrenal
      chromaffin cells.
AB  - In cultured bovine adrenal chromaffin cells, (+/-)-bupivacaine inhibited
      veratridine-induced 22Na(+) influx (IC(50) 6.8 microM). The IC(50) of (+)
      bupivacaine (2.8 microM) was 6.2-, 7.4-, and 17.1-fold lower than those of (-)
      bupivacaine (17.3 microM), (-)-ropivacaine (20.6 microM), and lidocaine (47.8
      microM). Chronic (i.e. 3-h) treatment of cells with (+/-)-bupivacaine increased
      cell surface [3H]saxitoxin ([3H]STX) binding capacity by 48% (EC(50) of 233
      microM; t(1/2)=7.4 h), without changing the K(d) value. Treatment for 24 h with
      either (+)- or (-)-bupivacaine, or (-)-ropivacaine elevated [3H]STX binding,
      whereas 24-h treatment with lidocaine had no effect. The rise of [3H]STX binding
      by (+/-)-bupivacaine was prevented by cycloheximide, an inhibitor of protein
      synthesis, or brefeldin A, an inhibitor of cell surface vesicular exit from the
      trans-Golgi network; however, (+/-)-bupivacaine did not increase Na(+) channel
      alpha- and beta(1)-subunit mRNA levels. In cells subjected to (+/-)-bupivacaine
      treatment (1 mM for 24 h) followed by 3-h washout, veratridine-induced 22Na(+)
      influx was enhanced, even when measured in the presence of ouabain, an inhibitor
      of Na(+),K(+)-ATPase. Ptychodiscus brevis toxin-3 potentiated veratridine-induced
      22Na(+) influx by 2.3-fold in the (+/-)-bupivacaine-treated cells, as in non
      treated cells. These results suggest that lipophilic bupivacaine enantiomers or (
      )-ropivacaine acutely inhibit Na(+) channel gating, whereas its chronic treatment
      up-regulates cell surface expression of Na(+) channels via translational and
      externalization events.

PMID- 12618342
TI  - Intracellular analysis of directional sensitivity of tectal neurons of the frog.
AB  - The directional sensitivity of tectal neurons of the frog was examined by means
      of in vivo whole cell recording technique. Three kinds of stimulus were applied;
      (1) diffuse light 'on-off', (2) moving dark spot and (3) light spot given at one
      dimensional grid points. The first stimulus revealed whether or not retinal 'on
      off' (R3) or 'off' (R4) fibers contribute to the response. As reported earlier,
      the following patterns were found for both light 'on' and light 'off': EPSPs
      only, IPSPs only or a combination of EPSPs and IPSPs. Four directionally
      sensitive neurons and three non-directionally sensitive neurons were found using
      the second stimulus. Using the third stimulus, responses at up to 11 positions
      separated by 2 degrees or 4 degrees were recorded. By measuring the amplitudes of
      'on' and 'off' responses at different times, spatio-temporal receptive fields
      were composed. Two types of directional sensitivity were found. The response of
      the first type was composed of exclusively excitatory potentials, but the second
      type was composed of a combination of excitatory and inhibitory potentials. The
      spatio-temporal receptive field of the second type showed spatially separated
      excitatory and inhibitory regions with constant latencies. Such simple spatio
      temporal receptive field organization was not found for directional sensitive
      neurons of the cat visual cortex. The spatio-temporal receptive field
      organization of the second type of directionally sensitive neuron in the present
      study is in agreement with striated receptive field found in some of the T5
      neurons classified by extracellular unit recording [Frog Neurobiology (1976)
      297].

PMID- 12618343
TI  - Localization of the O-GlcNAc transferase and O-GlcNAc-modified proteins in rat
      cerebellar cortex.
AB  - O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous nucleocytoplasmic protein
      modification that has a complex interplay with phosphorylation on cytoskeletal
      proteins, signaling proteins and transcription factors. O-GlcNAc is essential for
      life at the single cell level, and much indirect evidence suggests it plays an
      important role in nerve cell biology and neurodegenerative disease. Here we show
      the localization of O-GlcNAc Transferase (OGTase) mRNA, OGTase protein, and O
      GlcNAc-modified proteins in the rat cerebellar cortex. The sites of OGTase mRNA
      expression were determined by in situ hybridization histochemistry. Intense
      hybridization signals were present in neurons, especially in the Purkinje cells.
      Fluorescent-tagged antibody against OGTase stained almost all of the neurons with
      especially intense reactivity in Purkinje cells, within which the nucleus,
      perikaryon, and dendrites were most intensely stained. Using immuno-electron
      microscopic labeling, OGTase was seen to be enriched in euchromatin, in the
      cytoplasmic matrix, at the nerve terminal, and around microtubules in dendrites.
      In nerve terminals, immuno-gold labeling was observed around synaptic vesicles,
      with the enzyme more densely localized in the presynaptic terminals than in the
      postsynaptic ones. Using an antibody to O-GlcNAc, we found the sugar
      localizations reflected results seen for OGTase. Collectively, these data support
      hypothesized roles for O-GlcNAc in key processes of brain cells, including the
      regulation of transcription, synaptic vesicle secretion, transport, and signal
      transduction. Thus, by modulating the phosphorylation or protein associations of
      key regulatory and cytoskeletal proteins, O-GlcNAc is likely important to many
      functions of the cerebellum.

PMID- 12618344
TI  - Calretinin/PSA-NCAM immunoreactive granule cells after hippocampal damage
      produced by kainic acid and DEDTC treatment in mouse.
AB  - There is a dramatic increase in the number of lightly immunoreactive calretinin
      cells in the granular layer of the dentate gyrus of the mouse hippocampus 1 day
      after excitotoxic injury using kainic acid combined with the zinc chelator
      diethyldithiocarbamate. At 7 days after treatment, these cells are strongly
      immunoreactive for calretinin and for the polysialated form of the glycoprotein
      neural cell adhesion molecule (PSA-NCAM). The reexpression of calretinin and PSA
      NCAM after treatment corresponds well with the loss of input from the damaged
      hilar mossy cells. These cells could be considered immature granule cells since
      they are immunoreactive to markers for immature cells such as PSA-NCAM, and are
      not immunoreactive to calbindin D28k and neuronal nuclear specific protein NeuN
      (present in mature granule cells), or GABA (present in interneurons).
      Ultrastructural analysis of these cells indicates that they are immature.
      Labelling of cell proliferation with 5-bromo-2'-deoxyuridine (BrdU) shows that by
      day 1 no calretinin immunoreactive cell of the dentate gyrus corresponds to newly
      generated cells. By day 7 only 6% of the calretinin immunoreactive cells in the
      dentate gyrus are marked for BrdU. Our data indicate that the CR/PSA-NCAM
      immunoreactive cells of the dentate gyrus, in spite of their immature
      characteristics, are not the products of reactive neurogenesis. These cells could
      represent a reservoir of pre-existing not completely differentiated granule cells
      that react to damage.

PMID- 12618345
TI  - Mechanism of electrical stimulation-induced neuroprotection: effects of verapamil
      on protection of primary auditory afferents.
AB  - In order to assess the role of L-type voltage-gated calcium channels in
      electrical stimulation-mediated neuroprotection in vivo, we assessed survival of
      primary auditory afferents (spiral ganglion cells) in systemically deafened
      guinea pigs following chronic electrical stimulation with or without
      intracochlear infusion of verapamil, an L-type voltage-gated calcium channel
      antagonist. Continuous intracochlear drug delivery (0.5 microl/h) was provided
      using a delivery system developed previously in our laboratory using Alzet mini
      osmotic pumps. In the absence of chronic stimulation, spiral ganglion cell
      survival was relatively symmetric in animals treated unilaterally with either
      artificial perilymph or verapamil (50 microg/ml). In the presence of unilateral
      chronic electrical stimulation, spiral ganglion cell survival was significantly
      greater in stimulated, perilymph-infused ears, relative to the contralateral ear.
      In contrast, spiral ganglion cell survival was bilaterally symmetric in
      chronically stimulated, verapamil-infused animals. The difference in symmetry of
      spiral ganglion cell survival between the two groups was statistically
      significant. In vitro, passive depolarization has been demonstrated to enhance
      survival of cultured neurons via activation of L-type calcium channels. The
      results of this study indicate that, as suggested by in vitro depolarization
      models, in vivo electrical stimulation-mediated neuroprotection requires the
      activation of L-type voltage-gated calcium channels. Chronic electrical
      stimulation of the deaf ear is an ideal preparation for further studies in which
      to extrapolate findings from in vitro depolarization models.

PMID- 12618347
TI  - Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or
      celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic
      neurotoxicity in rats.
AB  - We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti
      inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in
      Fenton's reaction and their neuroprotective effects in 1-methyl-4
      phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats.
      Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to
      assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and
      time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM)
      showed no effect on *OH formation and diclofenac caused a reduction in *OH
      generation only at high doses (100 microM-10 mM). Administration of the non
      selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly
      attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100
      nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor,
      diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The
      selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)
      induced decrease in DA. Failure of celecoxib or diclofenac to render protection
      in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin
      involvement in MPP(+) action. These results also suggest that the neuroprotective
      ability of SA is independent of prostaglandin mediation. A relationship between
      inactivation of *OH by SA and its ability to protect DA depletion in the striatum
      caused by MPP(+) indicates a direct involvement of *OH in the action of this
      neurotoxin. The present study establishes potent neuroprotective activity of SA
      and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.

PMID- 12618346
TI  - Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor
      protein and amyloid precursor-like protein 2 resulting in cellular accumulation.
AB  - The Alzheimer's disease Abeta peptide can increase the levels of cell-associated
      amyloid precursor protein (APP) in vitro. To determine the specificity of this
      response for Abeta and whether it is related to cytotoxicity, we tested a diverse
      range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion
      peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these
      peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2)
      in primary cultures of astrocytes and neurons. Specificity was shown by a lack of
      change to amyloid precursor-like protein 1, tau-1 and cellular prion protein
      (PrP(c)) levels. APP and APLP2 levels were elevated only in cultures exposed to
      fibrillar peptides as assessed by electron microscopy and not in cultures treated
      with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that
      PrP106-126 and the non-toxic but fibril-forming PrP178-193 increased APP levels
      in cultures derived from both wild-type and PrP(c)-deficient mice indicating that
      fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and
      irrespective of parental protein expression. Fibrillar PrP106-126 and Abeta
      peptides bound recombinant APP and APLP2 suggesting the accumulation of these
      proteins was mediated by direct binding to the fibrillated peptide. This was
      supported by decreased APP accumulation following extensive washing of the
      cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with
      recombinant APP18-146, the putative fibril binding site, also abrogated the
      accumulation of APP. These findings show that diverse fibrillogenic peptides can
      induce accumulation of APP and APLP2 and this mechanism could contribute to
      pathogenesis in neurodegenerative disorders.

PMID- 12618348
TI  - Differential induction of c-fos expression in brain nuclei by noxious and non
      noxious colonic distension: role of afferent C-fibers and 5-HT3 receptors.
AB  - Experimental animal models have been established to gain insight into the
      pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel
      syndrome (IBS). However, data about the mechanisms and pathways involved in the
      induction of neuronal activity in forebrain and midbrain structures by a
      physiological GI stimulus, like colonic distension (CD), in the range from non
      noxious to noxious intensities are scarce. Thus, the effect of proximal CD with
      non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on
      neuronal activity in brain nuclei, as assessed by c-fos expression, was
      established. In additional studies, the role of vagal and non-vagal afferent
      sensory C-fibers and 5-HT(3) receptors in the mediation of visceral nociception
      was investigated in this experimental model at noxious colonic distension (70
      mmHg). At CD, the number of c-Fos like immunoreactivity (c-FLI)-positive neurons
      increased pressure-dependently in the nucleus of the solitary tract (NTS),
      rostral ventrolateral medulla (RVLM), nucleus cuneiformis (NC), periaqueductal
      gray (PAG), and the amygdala (AM). In the dorsomedial (DMH) and ventromedial
      nucleus (VMH) of the hypothalamus, as well as in the thalamus (TH), neuronal
      activity was also increased after CD, but independently of stimulus intensities.
      A decrease of the CD-induced c-fos expression after sensory vagal denervation by
      perivagal capsaicin treatment was only observed in brainstem nuclei (NTS and
      RVLM). In all other activated brain nuclei examined, the CD-related induction of
      c-fos expression was diminished only after systemic neonatal capsaicin treatment.
      In the NTS and RVLM, a trend of decrease of c-fos expression was also observed
      after systemic neonatal capsaicin treatment. In order to assess the role of the 5
      HT(3) receptor in CD-induced neuronal activation of brain nuclei, animals were
      pretreated with the 5-HT(3) receptor antagonist granisetron (1250 microg/kg, i.p.
      within 18 h before CD). Pretreatment with granisetron significantly reduced the
      number of c-FLI-positive cells/section in the NTS by 40%, but had no significant
      effect on the CD-induced c-fos expression in other brain areas. The data suggest
      that distinct afferent pathways and transmitters are involved in the transmission
      of nociceptive information from the colon to the brain nuclei activated by
      proximal colonic distension. Activation of NTS neurons at such a condition seems
      to be partially mediated via capsaicin-sensitive vagal afferents and 5-HT(3)
      receptors. In contrast, activation of brain nuclei in the di- and telencephalon
      by nociceptive mechanical stimulation of the proximal colon, as assessed by c-fos
      expression, is partially mediated by capsaicin-sensitive, non-vagal afferents,
      and independent of neurotransmission via 5-HT(3) receptors. The modulation of CD
      induced c-fos expression exclusively in the NTS by granisetron points to a role
      of 5-HT(3) receptor antagonists in the modulation of vago-vagal sensomotoric
      reflexes rather than an influence on forebrain nuclei involved in nociception.

PMID- 12618349
TI  - Protection from noise-induced lipid peroxidation and hair cell loss in the
      cochlea.
AB  - In order to delineate mechanisms of noise-induced hearing loss, we assessed noise
      trauma and its pharmacological modulation in the guinea pig. Auditory threshold
      shifts (measured by auditory brainstem responses), hair cell loss and lipid
      peroxidation (8-isoprostane formation) were determined in the absence or presence
      of agents known to influence the formation or action of reactive oxygen species
      (ROS): the non-specific N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK
      801, its inactive isomer (-)-MK-801, the selective NR1/2B NMDA receptor
      antagonist PD 174494, the nitric oxide synthase (NOS) inhibitor L-N(omega)
      Nitroarginine methyl ester (L-NAME) and the anti-oxidant N-acetylcysteine (NAC).
      (+)-MK-801 and NAC attenuated threshold shifts and hair cell loss effectively
      while PD 174494 did so partially. L-NAME attenuated threshold shifts at 2 kHz but
      increased them at 20 kHz, and (-)-MK-801 was ineffective. Noise-induced elevation
      in 8-isoprostane in the cochlea was significantly attenuated by (+)-MK-801 and PD
      174494 in the organ of Corti and modiolar core, by L-NAME in the lateral wall and
      modiolar core, and by NAC in all three regions. (-)-MK-801 did not influence
      noise-induced 8-isoprostane formation. There was a significant correlation
      between threshold shifts at 4 kHz, hair cell loss and the level of 8-isoprostane
      formed in the organ of Corti, but not in the lateral wall tissues. This finding
      suggests a causal relationship between ROS formation and functional and
      morphological damage. NMDA receptors and, to some extent, NOS may be involved in
      noise-induced ROS formation. The data also indicate that lipid peroxidation in
      the lateral wall tissues does not influence permanent threshold shifts.

PMID- 12618350
TI  - Angiotensin converting enzyme inhibition partially prevents deficits in water
      maze performance, hippocampal synaptic plasticity and cerebral blood flow in
      streptozotocin-diabetic rats.
AB  - Vascular dysfunction is important in the pathogenesis of peripheral complications
      of diabetes. However, the effects of diabetes on cerebral blood flow and the role
      of vascular deficits in the pathogenesis of diabetic encephalopathy are still
      unknown. The present study examined whether experimental diabetes is associated
      with reduced cerebral blood flow and whether treatment with enalapril can improve
      cerebral perfusion and function (blood flow and functional cerebral deficits).
      Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24
      mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated
      and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were
      tested in a spatial version of the Morris water maze. After 16 weeks of diabetes,
      in the same groups, blood flow in the hippocampus and thalamus was measured by
      hydrogen clearance microelectrode polarography. In a separate study, hippocampal
      long-term potentiation was measured after 26 weeks of diabetes. Water maze
      performance and hippocampal long-term potentiation were impaired in diabetic
      rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in
      the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic
      controls. Enalapril treatment significantly improved water maze performance
      (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow
      (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls.
      Treatment aimed at the vasculature can improve cerebral blood flow, deficits in
      Morris maze performance and long term potentiation. These findings suggest that
      vasculopathy plays a role in the development of cerebral dysfunction in diabetic
      rats.

PMID- 12618351
TI  - Dopamine inhibits ATP-induced responses in the cat petrosal ganglion in vitro.
AB  - The petrosal ganglion (PG) provides sensory innervation to the carotid sinus and
      carotid body through the carotid (sinus) nerve (CN). Application of either
      acetylcholine (ACh) or adenosine 5'-triphosphate (ATP) to the PG superfused in
      vitro activates CN fibers. Dopamine (DA) modulates the effects of ACh. We have
      previously shown that DA when applied to the PG modulates the effects of ACh on
      carotid sinus nerve fibers. We currently report the effects of DA on the ATP
      induced responses in the isolated PG in vitro. While DA had no effect on the
      basal activity recorded from the CN, it reduced ATP-induced responses in a dose
      dependent manner, when preceding ATP applications by 30 s. Our results suggest
      that DA-a transmitter present in a group of PG neurons and in carotid body cells
      may act as an inhibitory modulator of ATP-evoked responses in PG neurons.

PMID- 12618352
TI  - Identification of active thoracic spinal segments responsible for tonic and
      bursting sympathetic discharge in neonatal rats.
AB  - The isolated thoracic cord of a neonatal rat in vitro generates tonic sympathetic
      activities in the splanchnic nerves. This tonic sympathetic nerve discharge (SND)
      has a prominent quasi-periodic oscillation at approximately 1-2 Hz. Bath
      application of bicuculline and strychnine, which removes endogenous GABA(A) and
      glycine receptor activities, transforms the quasi-periodic tonic SND into
      synchronized bursts (bSND). Picrotoxin, another GABA(A) receptor antagonist, also
      induces bSND. Serial transections of the thoracic cord (T1-12) were performed to
      identify the cord segments responsible for these tonic and bursting SNDs. Removal
      of T1-5 did not affect tonic SND. Nerve-cord preparation with either T6-8 or T10
      12 segments could generate a substantial amount of tonic SND that retained
      comparable oscillating patterns. On the other hand, removal of T1-5 significantly
      reduced bSND amplitude without affecting its rhythmicity. Either T6-8 or T10-12
      segments alone could generate bSND. Mid-point transection of T6-12 at T9 might
      split bSND rhythmogenesis, leading to the occurrence of bSND that could be
      attributed to two independent oscillators. Our results demonstrated that three
      segments within the T6-12 cord were sufficient to generate a rudimentary tonic
      and bursting SNDs. The thoracic cord segments, however, are dynamically
      interacting so that a full size bSND could only be produced with the intact
      thoracic cord.

PMID- 12618353
TI  - Kynurenic acid enhances electroacupuncture analgesia in normal and carrageenan
      injected rats.
AB  - The interaction between electroacupuncture (EA) and an intrathecally administered
      wide-spectrum excitatory amino acid (EAA) receptor(s) antagonist, kynurenic acid
      (KYNA) on carrageenan-induced thermal hyperalgesia and spinal Fos expression was
      investigated. Intrathecal (i.t.) injection of 0.1, 1, 10, and 100 nmol KYNA
      markedly and dose-dependently increased the latency of paw withdrawal (PWL) of
      the carrageenan-injected paw. While the PWLs of the non-injected and normal
      saline (NS)-injected paws were not obviously affected by application of KYNA at
      the doses tested. Intrathecal injection of 0.1 nmol KYNA significantly
      potentiated the anti-nociception induced by EA stimulation of contralateral 'Zu
      San-Li' and 'Kun-Lun' acupoints either in the carrageenan- or NS-injected rats.
      Three hours after intraplantar (i.pl.) injection of carrageenan, the number of
      Fos-like immunoreactive (Fos-LI) neurons was significantly increased in all
      layers of ipsilateral spinal cord at L(4)-L(5) with the higher density in laminae
      I-II and V-VI. Intrathecally pre-administered KYNA (10 nmol) significantly
      reduced the total number of carrageenan-induced Fos-LI neurons with more apparent
      reduction in laminae I-II and IV-V. Pre-coapplication of 10 nmol KYNA and EA of
      bilateral 'Zu-San-Li' and 'Kun-Lun' acupoints, the numbers of carrageenan-induced
      Fos-LI neurons in laminae I-II and V-VI further reduced. The level of Fos
      expression in the spinal cord induced by carrageenan was significantly lower
      compared with that of i.t. injection of KYNA or EA alone. These results
      demonstrated that EAA receptor(s) antagonist could enhance EA-induced anti
      nociception and anti-hyperalgesia.

PMID- 12618355
TI  - Pre- or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol
      attenuates striatal quinolinate lesions.
AB  - We have examined the neuroprotective efficacy of the mitochondrial uncoupler 2,4
      dinitrophenol (DNP) in animals receiving striatal injections of the neurotoxin
      quinolinic acid. Animals administered DNP either 1 h before or 3 h following QA
      infusion developed lesions that were 25% smaller than control animals. Animals
      treated with the DNP analogue 2,4,6-trinitrophenol, which does not possess
      uncoupling activity in intact mitochondria, showed no neuroprotection. These
      results indicate that DNP, and other compounds that diminish the mitochondrial
      membrane potential, might provide a novel approach to the treatment of acute
      neurological injury.

PMID- 12618354
TI  - L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient
      mice.
AB  - Delayed administration of the nitric oxide precursor L-arginine increases brain
      injury in models of focal cerebral ischemia. We tested the hypothesis that L
      arginine worsens the damage by acting as a substrate for inducible nitric oxide
      synthase (iNOS) and increasing the output of this enzyme. iNOS-null mice or wild
      type littermates were treated with L-arginine (300 mg/kg; i.p, three times/day)
      starting 12 h after occlusion of the middle cerebral artery. Infarct volume was
      determined 96 h after ischemia. We found that L-arginine enlarges infarct volume
      in wild-type mice (+28+/-5% in neocortex) but not in iNOS-null mice. Thus, the
      worsening of ischemic damage produced by L-arginine depends on iNOS. The findings
      support the hypothesis that L-arginine worsens ischemic injury by increasing the
      catalytic output of iNOS and suggest that administration of L-arginine should be
      avoided in patients with acute stroke.

PMID- 12618356
TI  - Intrahippocampal histamine delays arousal from hibernation.
AB  - Hibernation is a state of extremely reduced physiological functions and a deep
      depression of CNS activity, which is thought to be under hippocampal control. Our
      previous findings indicate increased histamine turnover during hibernation in
      several brain regions, including the hippocampus. In this study we showed that
      histamine infused into the hippocampus significantly delayed arousal from
      hibernation. These findings indicate that histamine may contribute to maintaining
      the hibernating state, suggesting a novel role for histamine in controlling
      arousal state.

PMID- 12618357
TI  - Isomer-specific actions of conjugated linoleic acid on muscle glucose transport
      in the obese Zucker rat.
AB  - The fatty acid-conjugated linoleic acid (CLA) enhances glucose tolerance and
      insulin action on skeletal muscle glucose transport in rodent models of insulin
      resistance. However, no study has directly compared the metabolic effects of the
      two primary CLA isomers, cis-9,trans-11-CLA (c9,t11-CLA) and trans-10,cis-12-CLA
      (t10,c12-CLA). Therefore, we assessed the effects of a 50:50 mixture of these two
      CLA isomers (M-CLA) and of preparations enriched in either c9,t11-CLA (76%
      enriched) or t10,c12-CLA (90% enriched) on glucose tolerance and insulin
      stimulated glucose transport in skeletal muscle of the insulin-resistant obese
      Zucker (fa/fa) rat. Animals were treated daily by gavage with either vehicle
      (corn oil), M-CLA, c9,t11-CLA, or t10,c12-CLA (all CLA treatments at 1.5 g total
      CLA/kg body wt) for 21 consecutive days. During an oral glucose tolerance test,
      glucose responses were reduced (P < 0.05) by 10 and 16%, respectively, in the M
      CLA and t10,c12-CLA animals, respectively, whereas insulin responses were
      diminished by 21 and 19% in these same groups. There were no significant
      alterations in these responses in the c9,t11-CLA group. Insulin-mediated glucose
      transport activity was enhanced by M-CLA treatment in both type I soleus (32%)
      and type IIb epitrochlearis (58%) muscles and by 36 and 48%, respectively, with
      t10,c12-CLA. In the soleus, these increases were associated with decreases in
      protein carbonyls (index of oxidative stress, r = -0.616, P = 0.0038) and
      intramuscular triglycerides (r = -0.631, P = 0.0028). Treatment with c9,t11-CLA
      was without effect on these variables. These results suggest that the ability of
      CLA treatment to improve glucose tolerance and insulin-stimulated glucose
      transport activity in insulin-resistant skeletal muscle of the obese Zucker rat
      are associated with a reduction in oxidative stress and muscle lipid levels and
      can be specifically ascribed to the actions of the t10,c12 isomer. In the obese
      Zucker rat, the c9,t11 isomer of CLA is metabolically neutral.

PMID- 12618358
TI  - Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls
      during hindlimb suspension.
AB  - Myostatin inhibits myogenesis. Therefore, we sought to determine if mice lacking
      the myostatin gene [Mstn(-/-)] would lose less muscle mass than wild-type mice
      during 7 days of hindlimb suspension (HS). Male Mstn(-/-) and wild-type (C57)
      mice were subjected to HS or served as ground-based controls (n = 6/group). Wild
      type mice lost 8% of body mass and approximately 13% of wet mass from biceps
      femoris, quadriceps femoris, and soleus, whereas the mass of extensor digitorum
      longus (EDL) was unchanged after HS. Unexpectedly, Mstn(-/-) mice lost more body
      (13%, P < 0.05) and quadriceps femoris (17%, P < 0.05) mass than wild-type mice
      and lost 33% of EDL mass (P < 0.01) after HS. Protein expression of myostatin in
      biceps femoris and quadriceps femoris was not altered, whereas expression of
      MyoD, Myf-5, and myogenin increased in wild-type mice and tended to decrease in
      muscles of Mstn(-/-) mice. These data suggest that HS induced myogenesis in wild
      type mice to counter atrophy, whereas myogenesis was not induced in Mstn(-/-)
      mice, thereby resulting in a greater loss of muscle mass.

PMID- 12618359
TI  - alpha -melanocyte-stimulating hormone is a novel regulator of bone.
AB  - alpha-Melanocyte-stimulating hormone (alpha-MSH), a 13-amino acid peptide
      produced in the brain and pituitary gland, is a regulator of appetite and body
      weight, and its production is regulated by leptin, a factor that affects bone
      mass when administered centrally. alpha-MSH acts via melanocortin receptors.
      Humans deficient in melanocortin receptor 4 (MC4-R) have increased bone mass, and
      MC4-R has been identified in an osteoblast-like cell line. Thus alpha-MSH may act
      directly on the skeleton, a question addressed by the present studies. In primary
      cultures of osteoblasts and chondrocytes, alpha-MSH dose dependently (>or=10(-9)
      M) stimulated cell proliferation. In bone marrow cultures, alpha-MSH (>10(-9) M)
      stimulated osteoclastogenesis. Systemic administration of alpha-MSH to mice (20
      injections of 4.5 microg/day) decreased the trabecular bone volume in the
      proximal tibiae from 19.5 +/- 1.8 to 15.2 +/- 1.4% (P = 0.03) and reduced
      trabecular number (P = 0.001). Radiographic indexes of trabecular bone, assessed
      by phase-contrast X-ray imaging, confirmed the bone loss. It is concluded that
      alpha-MSH acts directly on bone, increasing bone turnover, and, when administered
      systemically, it decreases bone volume. The latter result may also be contributed
      to by alpha-MSH effects elsewhere, such as the adipocyte, pancreatic beta-cell,
      or central nervous system.

PMID- 12618360
TI  - Resistin inhibits glucose uptake in L6 cells independently of changes in insulin
      signaling and GLUT4 translocation.
AB  - Elevated levels of resistin have been proposed to cause insulin resistance and
      therefore may serve as a link between obesity and type 2 diabetes. However, its
      role in skeletal muscle metabolism is unknown. In this study, we examined the
      effect of resistin on insulin-stimulated glucose uptake and the upstream insulin
      signaling components in L6 rat skeletal muscle cells that were either incubated
      with recombinant resistin or stably transfected with a vector containing the myc
      tagged mouse resistin gene. Transfected clones expressed intracellular resistin,
      which was released in the medium. Incubation with recombinant resistin resulted
      in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG)
      uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was
      not the result of impaired GLUT4 translocation to the plasma membrane.
      Furthermore, resistin did not alter the insulin receptor (IR) content and its
      phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate
      (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of
      phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic
      activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one
      of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also
      not affected by resistin. Expression of resistin also inhibited insulin
      stimulated 2-DG uptake when compared with cells expressing the empty vector
      (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3
      kinase signaling. We conclude that resistin does not alter IR signaling but does
      affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic
      activity of cell surface glucose transporters.

PMID- 12618361
TI  - Impaired transport of leptin across the blood-brain barrier in obesity is
      acquired and reversible.
AB  - Leptin resistance is a major cause of obesity in humans. A major component of
      this resistance is likely an impaired transport of leptin across the blood-brain
      barrier (BBB). The fattest subgroup of otherwise normal 12-mo-old CD-1 mice have
      severely impaired transport of leptin across the BBB. However, it is unknown
      whether these mice are born with a BBB impairment or acquire it with aging and
      obesity. Here, we found within an otherwise normal population of CD-1 mice that
      the 10% fattest mice gained weight throughout a 12-mo-life span, whereas the 10%
      thinnest mice gained little weight after 3 mo of age. The fattest mice acquired a
      progressive impairment in their ability to transport leptin across the BBB,
      whereas the thinnest mice had a rate of transport that did not change with age.
      Fasting fat mice for 24 h or treating them with leptin resulted in modest weight
      reduction and development of transport rates for leptin across the BBB similar to
      those of thin mice. These results show that, in obese CD-1 mice, the impaired
      transport of leptin across the BBB develops in tandem with obesity and is
      reversible with even modest weight reduction.

PMID- 12618362
TI  - Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left
      ventricular hypertrophy in rat offspring.
AB  - In humans, low birth weight and increased placental weight can be associated with
      cardiovascular disease in adulthood. Low birth weight and increased placental
      size are known to occur after fetal alcohol exposure or prenatal glucocorticoid
      administration. Thus the effects of removing the alcohol-induced increase in
      maternal corticosterone by maternal adrenalectomy on predictors of cardiovascular
      disease in adulthood were examined in rats. Alcohol exposure of dams during the
      last 2 wk of gestation resulted in significantly decreased fetal weight and
      increased placental weight on gestational day 21. Adult female, but not male,
      offspring of alcohol-consuming mothers exhibited left ventricular hypertrophy.
      Placental 11beta-hydroxysteroid dehydrogenase-2 (11beta-HSD-2) mRNA levels,
      measured by Northern blot, were decreased in females but not males. Adrenalectomy
      of alcohol-consuming dams reversed the increase in placental weight and the
      decrease in female placental 11beta-HSD-2 expression and eliminated the left
      ventricular hypertrophy of adult female offspring. These data suggest that
      alcohol-induced changes in placental 11beta-HSD-2 mRNA levels and left
      ventricular weight are coupled in female offspring only and depend on maternal
      adrenal status.

PMID- 12618363
TI  - Gene expression analyses of Arabidopsis chromosome 2 using a genomic DNA amplicon
      microarray.
AB  - The gene predictions and accompanying functional assignments resulting from the
      sequencing and annotation of a genome represent hypotheses that can be tested and
      used to develop a more complete understanding of the organism and its biology. In
      the model plant Arabidopsis thaliana, we developed a novel approach to
      constructing whole-genome microarrays based on PCR amplification of the 3' ends
      of each predicted gene from genomic DNA, and constructed an array representing
      more than 94% of the predicted genes and pseudogenes on chromosome 2. With this
      array, we examined various tissues and physiological conditions, providing
      expression-based validation for 84% of the gene predictions and providing clues
      as to the functions of many predicted genes. Further, by examining the
      distribution of expression along the physical chromosome, we were able to
      identify a region of repressed transcription that may represent a previously
      undescribed heterochromatic region.

PMID- 12618364
TI  - Genomic DNA insertions and deletions occur frequently between humans and nonhuman
      primates.
AB  - Comparative DNA sequence studies between humans and nonhuman primates will be
      important for understanding the genetic basis of the phenotypic differences
      between these species. Here we compare approximately 27 Mb of human chromosome 21
      with chimpanzee DNA sequences identifying 57 genomic rearrangements (deletions
      and insertions ranging in size from 0.2 to 8.0 kb) between the two species. These
      rearrangements are distributed along the entire length of chromosome 21, with
      approximately 35% found in genomic intervals encoding genes (genic intervals),
      and have occurred in the genomes of both humans and chimpanzees. Comparison of
      approximately 9 Mb of human chromosome 21 with orangutan, rhesus macaque, and
      woolly monkey DNA sequences identified a combined total of 114 genomic
      rearrangements between humans and nonhuman primates. Analysis of these
      rearrangements revealed that they are randomly distributed with respect to genic
      and nongenic intervals and identified one deletion that has likely resulted in
      the inactivation of a gene (beta1,3-galactosyltransferase) in the woolly monkey.
      Our data show that genomic rearrangements have occurred frequently during primate
      genome evolution and significantly contribute to the DNA differences between
      these species. These DNA rearrangements are commonly found in genic intervals,
      and thus provide natural starting points for focused investigations of
      qualitative and quantitative gene expression differences between humans and other
      primates.

PMID- 12618365
TI  - Large-scale variation among human and great ape genomes determined by array
      comparative genomic hybridization.
AB  - Large-scale genomic rearrangements are a major force of evolutionary change and
      the ascertainment of such events between the human and great ape genomes is
      fundamental to a complete understanding of the genetic history and evolution of
      our species. Here, we present the results of an evolutionary analysis utilizing
      array comparative genomic hybridization (array CGH), measuring copy-number gains
      and losses among these species. Using an array of 2460 human bacterial artificial
      chromosomes (BACs) (12% of the genome), we identified a total of 63 sites of
      putative DNA copy-number variation between humans and the great apes (chimpanzee,
      bonobo, gorilla, and orangutan). Detailed molecular characterization of a subset
      of these sites confirmed rearrangements ranging from 40 to at least 175 kb in
      size. Surprisingly, the majority of variant sites differentiating great ape and
      human genomes were found within interstitial euchromatin. These data suggest that
      such large-scale events are not restricted solely to subtelomeric or
      pericentromeric regions, but also occur within genic regions. In addition, 5/9 of
      the verified variant sites localized to areas of intrachromosomal segmental
      duplication within the human genome. On the basis of the frequency of duplication
      in humans, this represents a 14-fold positional bias. In contrast to previous
      cytogenetic and comparative mapping studies, these results indicate extensive
      local repatterning of hominoid chromosomes in euchromatic regions through a
      duplication-driven mechanism of genome evolution.

PMID- 12618366
TI  - Analysis of primate genomic variation reveals a repeat-driven expansion of the
      human genome.
AB  - We performed a detailed analysis of both single-nucleotide and large
      insertion/deletion events based on large-scale comparison of 10.6 Mb of genomic
      sequence from lemur, baboon, and chimpanzee to human. Using a human genomic
      reference, optimal global alignments were constructed from large (>50-kb) genomic
      sequence clones. These alignments were examined for the pattern, frequency, and
      nature of mutational events. Whereas rates of single-nucleotide substitution
      remain relatively constant (1-2 x 10(-9) substitutions/site/year), rates of
      retrotransposition vary radically among different primate lineages. These
      differences have lead to a 15%-20% expansion of human genome size over the last
      50 million years of primate evolution, 90% of it due to new retroposon
      insertions. Orthologous comparisons with the chimpanzee suggest that the human
      genome continues to significantly expand due to shifts in retrotransposition
      activity. Assuming that the primate genome sequence we have sampled is
      representative, we estimate that human euchromatin has expanded 30 Mb and 550 Mb
      compared to the primate genomes of chimpanzee and lemur, respectively.

PMID- 12618367
TI  - Segmental duplications in euchromatic regions of human chromosome 5: a source of
      evolutionary instability and transcriptional innovation.
AB  - Recent analyses of the structure of pericentromeric and subtelomeric regions have
      revealed that these particular regions of human chromosomes are often composed of
      blocks of duplicated genomic segments that have been associated with rapid
      evolutionary turnover among the genomes of closely related primates. In the
      present study, we show that euchromatic regions of human chromosome 5-5p14, 5p13,
      5q13, 5q15-5q21-also display such an accumulation of segmental duplications. The
      structure, organization and evolution of those primate-specific sequences were
      studied in detail by combining in silico and comparative FISH analyses on human,
      chimpanzee, gorilla, orangutang, macaca, and capuchin chromosomes. Our results
      lend support to a two-step model of transposition duplication in the euchromatic
      regions, with a founder insertional event at the time of divergence between
      Platyrrhini and Catarrhini (25-35 million years ago) and an apparent burst of
      inter- and intrachromosomal duplications in the Hominidae lineage. Furthermore,
      phylogenetic analysis suggests that the chronology and, likely, molecular
      mechanisms, differ regarding the region of primary insertion-euchromatic versus
      pericentromeric regions. Lastly, we show that as their counterparts located near
      the heterochromatic region, the euchromatic segmental duplications have
      consistently reshaped their region of insertion during primate evolution,
      creating putative mosaic genes, and they are obvious candidates for causing
      ectopic rearrangements that have contributed to evolutionary/genomic instability.

PMID- 12618368
TI  - Genome duplication, a trait shared by 22000 species of ray-finned fish.
AB  - Through phylogeny reconstruction we identified 49 genes with a single copy in
      man, mouse, and chicken, one or two copies in the tetraploid frog Xenopus laevis,
      and two copies in zebrafish (Danio rerio). For 22 of these genes, both zebrafish
      duplicates had orthologs in the pufferfish (Takifugu rubripes). For another 20 of
      these genes, we found only one pufferfish ortholog but in each case it was more
      closely related to one of the zebrafish duplicates than to the other. Forty-three
      pairs of duplicated genes map to 24 of the 25 zebrafish linkage groups but they
      are not randomly distributed; we identified 10 duplicated regions of the
      zebrafish genome that each contain between two and five sets of paralogous genes.
      These phylogeny and synteny data suggest that the common ancestor of zebrafish
      and pufferfish, a fish that gave rise to approximately 22000 species, experienced
      a large-scale gene or complete genome duplication event and that the pufferfish
      has lost many duplicates that the zebrafish has retained.

PMID- 12618369
TI  - Large-scale analysis of the meningococcus genome by gene disruption: resistance
      to complement-mediated lysis.
AB  - The biologic role of a majority of the Neisseria meningitidis 2100 predicted
      coding regions is still to be assigned or experimentally confirmed. Determining
      the phenotypic effect of gene disruption being a fundamental approach to
      understanding gene function, we used high-density signature-tagged transposon
      mutagenesis, followed by a large-scale sequencing of the transposon insertion
      sites, to construct a genome-wide collection of mutants. The sequencing results
      for the first half of the 4548 mutants composing the library suggested that we
      have mutations in 80%-90% of N. meningitidis nonessential genes. This was
      confirmed by a whole-genome identification of the genes required for resistance
      to complement-mediated lysis, a key to meningococcal virulence. We show that all
      the genes we identified, including four previously uncharacterized, were
      important for the synthesis of the polysialic acid capsule or the
      lipooligosaccharide (LOS), suggesting that these are likely to be the only
      meningococcal attributes necessary for serum resistance. Our work provides a
      valuable and lasting resource that may lead to a global map of gene function in
      N. meningitidis.

PMID- 12618370
TI  - Schizosaccharomyces pombe essential genes: a pilot study.
AB  - After completion of the Schizosaccharomyces pombe genome sequence, we have
      carried out a pilot gene deletion project to assess the feasibility of a genome
      wide deletion project and to estimate the percentage of essential genes. Using a
      PCR-based gene deletion procedure, we investigated 100 genes within a 253-kb
      region of chromosome II. Eight of nine genes located within a region of 18 kb
      could not be deleted, suggesting that systematic deletion of all fission yeast
      genes may be difficult to achieve using this PCR approach. The percentage of
      essential genes was found to be 17.5%. Further deletion of selected S. pombe
      genes revealed that whether a gene is essential or not is correlated with the
      timing of its appearance on the tree of life and its conservation within all
      branches of the tree. None of the investigated ancient genes in fission yeast
      that have been lost in the Saccharomyces cerevisiae lineage are essential. In
      agreement with S. cerevisiae and Caenorhabditis elegans genome analyses, our data
      suggest that natural selection has preferentially kept the genes required for
      vital functions. We propose that many of the essential eukaryotic genes appeared
      with the first eukaryotic cell and have remained conserved in all species.

PMID- 12618371
TI  - The genetic core of the universal ancestor.
AB  - Molecular analysis of conserved sequences in the ribosomal RNAs of modern
      organisms reveals a three-domain phylogeny that converges in a universal ancestor
      for all life. We used the Clusters of Orthologous Groups database and information
      from published genomes to search for other universally conserved genes that have
      the same phylogenetic pattern as ribosomal RNA, and therefore constitute the
      ancestral genetic core of cells. Our analyses identified a small set of genes
      that can be traced back to the universal ancestor and have coevolved since that
      time. As indicated by earlier studies, almost all of these genes are involved
      with the transfer of genetic information, and most of them directly interact with
      the ribosome. Other universal genes have either undergone lateral transfer in the
      past, or have diverged so much in sequence that their distant past could not be
      resolved. The nature of the conserved genes suggests innovations that may have
      been essential to the divergence of the three domains of life. The analysis also
      identified several genes of unknown function with phylogenies that track with the
      ribosomal RNA genes. The products of these genes are likely to play fundamental
      roles in cellular processes.

PMID- 12618372
TI  - A global search reveals epistatic interaction between QTL for early growth in the
      chicken.
AB  - We have identified quantitative trait loci (QTL) explaining a large proportion of
      the variation in body weights at different ages and growth between chronological
      ages in an F(2) intercross between red junglefowl and White Leghorn chickens. QTL
      were mapped using forward selection for loci with significant marginal genetic
      effects and with a simultaneous search for epistatic QTL pairs. We found 22
      significant loci contributing to these traits, nine of these were only found by
      the simultaneous two-dimensional search, which demonstrates the power of this
      approach for detecting loci affecting complex traits. We have also estimated the
      relative contribution of additive, dominance, and epistasis effects to growth and
      the contribution of epistasis was more pronounced prior to 46 days of age,
      whereas additive genetic effects explained the major portion of the genetic
      variance later in life. Several of the detected loci affected either early or
      late growth but not both. Very few loci affected the entire growth process, which
      points out that early and late growth, at least to some extent, have different
      genetic regulation.

PMID- 12618373
TI  - The phylogenetic extent of metabolic enzymes and pathways.
AB  - The evolution of metabolic enzymes and pathways has been a subject of intense
      study for more than half a century. Yet, so far, previous studies have focused on
      a small number of enzyme families or biochemical pathways. Here, we examine the
      phylogenetic distribution of the full-known metabolic complement of Escherichia
      coli, using sequence comparison against taxa-specific databases. Half of the
      metabolic enzymes have homologs in all domains of life, representing families
      involved in some of the most fundamental cellular processes. We thus show for the
      first time and in a comprehensive way that metabolism is conserved at the enzyme
      level. In addition, our analysis suggests that despite the sequence conservation
      and the extensive phylogenetic distribution of metabolic enzymes, their groupings
      into biochemical pathways are much more variable than previously thought.

PMID- 12618374
TI  - Comparative analysis of superintegrons: engineering extensive genetic diversity
      in the Vibrionaceae.
AB  - Integrons are natural tools for bacterial evolution and innovation. Their
      involvement in the capture and dissemination of antibiotic-resistance genes among
      Gram-negative bacteria is well documented. Recently, massive ancestral versions,
      the superintegrons (SIs), were discovered in the genomes of diverse
      proteobacterial species. SI gene cassettes with an identifiable activity encode
      proteins related to simple adaptive functions, including resistance, virulence,
      and metabolic activities, and their recruitment was interpreted as providing the
      host with an adaptive advantage. Here, we present extensive comparative analysis
      of SIs identified among the Vibrionaceae. Each was at least 100 kb in size,
      reaffirming the participation of SIs in the genome plasticity and heterogeneity
      of these species. Phylogenetic and localization data supported the sedentary
      nature of the functional integron platform and its coevolution with the host
      genome. Conversely, comparative analysis of the SI cassettes was indicative of
      both a wide range of origin for the entrapped genes and of an active cassette
      assembly process in these bacterial species. The signature attC sites of each
      species displayed conserved structural characteristics indicating that symmetry
      rather than sequence was important in the recognition of such a varied collection
      of target recombination sequences by a single site-specific recombinase. Our
      discovery of various addiction module cassettes within each of the different SIs
      indicates a possible role for them in the overall stability of large integron
      cassette arrays.

PMID- 12618376
TI  - 15000 unique zebrafish EST clusters and their future use in microarray for
      profiling gene expression patterns during embryogenesis.
AB  - A total of 15590 unique zebrafish EST clusters from two cDNA libraries have been
      identified. Most significantly, only 22% (3437) of the 15590 unique clusters
      matched 2805 (of 15200) clusters in the Danio rerio UniGene database, indicating
      that our EST set is complementary to the existing ESTs in the public database and
      will be invaluable in assisting the annotation of genes based on the upcoming
      zebrafish genome sequence. Blast search showed that 7824 of our unique clusters
      matched 6710 known or predicted proteins in the nonredundant database. A cDNA
      microarray representing approximately 3100 unique zebrafish cDNA clusters has
      been generated and used to profile the gene expression patterns across six
      different embryonic stages (cleavage, blastula, gastrula, segmentation,
      pharyngula, and hatching). Analysis of expression data using K-means clustering
      revealed that genes coding for muscle-specific proteins displayed similar
      expression patterns, confirming that the coordinate gene expression is important
      for myogenesis. Our results demonstrate that the combination of microarray
      technology with the zebrafish model system can provide useful information on how
      genes are coordinated in a genetic network to control zebrafish embryogenesis and
      can help to identify novel genes that are important for organogenesis.

PMID- 12618377
TI  - Genotyping on a thermal gradient DNA chip.
AB  - Silicon-based chips with discrete, independently temperature-controlled islands
      have been developed for use in DNA microarray hybridization studies. Each island,
      containing a heater made of a diffusion layer and a temperature sensor based on a
      p-n junction, is created on a silicon dioxide/nitride surface by anisotropic
      etching. Different reactive groups are subsequently added to the surface of the
      islands, and allele-specific oligonucleotide probes are attached to discrete
      spots on the chip. Hybridization is performed with Cy5-tagged single-stranded
      targets derived by PCR from genomic DNA. Results are assessed by measuring
      fluorescence of bound dye-tagged targets after hybridization and washing.
      Temperatures at each island can be set at different values to obtain optimal
      distinction between perfect matches and mismatches. This approach facilitates
      definition of optimal temperatures for probe/target annealing and for distinction
      between perfectly matched versus mismatched solution-phase targets. The thermal
      gradient DNA chips were then tested for genotyping, and the results for four
      different loci in two genes are presented. Unambiguous typing was achieved for
      clinically relevant loci within the factor VII and hemochromatosis genes.

PMID- 12618378
TI  - A highly efficient recombineering-based method for generating conditional
      knockout mutations.
AB  - Phage-based Escherichia coli homologous recombination systems have recently been
      developed that now make it possible to subclone or modify DNA cloned into
      plasmids, BACs, or PACs without the need for restriction enzymes or DNA ligases.
      This new form of chromosome engineering, termed recombineering, has many
      different uses for functional genomic studies. Here we describe a new
      recombineering-based method for generating conditional mouse knockout (cko)
      mutations. This method uses homologous recombination mediated by the lambda phage
      Red proteins, to subclone DNA from BACs into high-copy plasmids by gap repair,
      and together with Cre or Flpe recombinases, to introduce loxP or FRT sites into
      the subcloned DNA. Unlike other methods that use short 45-55-bp regions of
      homology for recombineering, our method uses much longer regions of homology. We
      also make use of several new E. coli strains, in which the proteins required for
      recombination are expressed from a defective temperature-sensitive lambda
      prophage, and the Cre or Flpe recombinases from an arabinose-inducible promoter.
      We also describe two new Neo selection cassettes that work well in both E. coli
      and mouse ES cells. Our method is fast, efficient, and reliable and makes it
      possible to generate cko-targeting vectors in less than 2 wk. This method should
      also facilitate the generation of knock-in mutations and transgene constructs, as
      well as expedite the analysis of regulatory elements and functional domains in or
      near genes.

PMID- 12618379
TI  - The development of a highly informative mouse Simple Sequence Length Polymorphism
      (SSLP) marker set and construction of a mouse family tree using parsimony
      analysis.
AB  - To identify highly informative markers for a large number of commonly employed
      murine crosses, we selected a subset of the extant mouse simple sequence length
      polymorphism (SSLP) marker set for further development. Primer pairs for 314 SSLP
      markers were designed and typed against 54 inbred mouse strains. We designed new
      PCR primer sequences for the markers selected for multiplexing using the
      fluorescent dyes FAM, VIC, NED, and ROX. The number of informative markers for
      C57BL/6J x DBA/2J is 217, with an average spacing of 6.8 centiMorgans (cM). For
      all other pairs of strains, the mean number of informative markers per cross is
      197.0 (SD 37.8) with a mean distance between markers of 6.8 cM (SD 1.1). To
      confirm map positions of the 224 markers in our set that are polymorphic between
      Mus musculus and Mus spretus, we used The Jackson Laboratory (TJL) interspecific
      backcross mapping panel (TJL BSS); 168 (75%) of these markers had not been
      previously mapped in this cross by other investigators, adding new information to
      this community map resource. With this large data set, we sought to reconstruct a
      phylogenetic history of the laboratory mouse using Wagner parsimony analysis. Our
      results are largely congruent with the known history of inbred mouse strains.

PMID- 12618380
TI  - Screening of gene-associated polymorphisms by use of in-gel competitive
      reassociation and EST (cDNA) array hybridization.
AB  - In-gel competitive reassociation (IGCR) is a method of differential subtraction
      to enrich polymorphic DNA restriction fragments between two DNA samples without
      probes or specific sequence information. Here, we show that by combining IGCR and
      expressed sequence tags (EST) array hybridization, polymorphic DNA fragments
      associated with genes in complex higher organisms (Arabidopsis thaliana) can be
      effectively screened, demonstrating that this procedure offers a simple and
      efficient way to obtain gene-associated polymorphic DNA markers.

PMID- 12618375
TI  - Gene discovery in the apicomplexa as revealed by EST sequencing and assembly of a
      comparative gene database.
AB  - Large-scale EST sequencing projects for several important parasites within the
      phylum Apicomplexa were undertaken for the purpose of gene discovery. Included
      were several parasites of medical importance (Plasmodium falciparum, Toxoplasma
      gondii) and others of veterinary importance (Eimeria tenella, Sarcocystis
      neurona, and Neospora caninum). A total of 55192 ESTs, deposited into
      dbEST/GenBank, were included in the analyses. The resulting sequences have been
      clustered into nonredundant gene assemblies and deposited into a relational
      database that supports a variety of sequence and text searches. This database has
      been used to compare the gene assemblies using BLAST similarity comparisons to
      the public protein databases to identify putative genes. Of these new entries,
      approximately 15%-20% represent putative homologs with a conservative cutoff of p
      < 10(-9), thus identifying many conserved genes that are likely to share common
      functions with other well-studied organisms. Gene assemblies were also used to
      identify strain polymorphisms, examine stage-specific expression, and identify
      gene families. An interesting class of genes that are confined to members of this
      phylum and not shared by plants, animals, or fungi, was identified. These genes
      likely mediate the novel biological features of members of the Apicomplexa and
      hence offer great potential for biological investigation and as possible
      therapeutic targets.

PMID- 12618381
TI  - SLAM: cross-species gene finding and alignment with a generalized pair hidden
      Markov model.
AB  - Comparative-based gene recognition is driven by the principle that conserved
      regions between related organisms are more likely than divergent regions to be
      coding. We describe a probabilistic framework for gene structure and alignment
      that can be used to simultaneously find both the gene structure and alignment of
      two syntenic genomic regions. A key feature of the method is the ability to
      enhance gene predictions by finding the best alignment between two syntenic
      sequences, while at the same time finding biologically meaningful alignments that
      preserve the correspondence between coding exons. Our probabilistic framework is
      the generalized pair hidden Markov model, a hybrid of (1). generalized hidden
      Markov models, which have been used previously for gene finding, and (2). pair
      hidden Markov models, which have applications to sequence alignment. We have
      built a gene finding and alignment program called SLAM, which aligns and
      identifies complete exon/intron structures of genes in two related but
      unannotated sequences of DNA. SLAM is able to reliably predict gene structures
      for any suitably related pair of organisms, most notably with fewer false
      positive predictions compared to previous methods (examples are provided for Homo
      sapiens/Mus musculus and Plasmodium falciparum/Plasmodium vivax comparisons).
      Accuracy is obtained by distinguishing conserved noncoding sequence (CNS) from
      conserved coding sequence. CNS annotation is a novel feature of SLAM and may be
      useful for the annotation of UTRs, regulatory elements, and other noncoding
      features.

PMID- 12618382
TI  - A classification-based machine learning approach for the analysis of genome-wide
      expression data.
AB  - Three important areas of data analysis for global gene expression analysis are
      class discovery, class prediction, and finding dysregulated genes (biomarkers).
      The clinical application of microarray data will require marker genes whose
      expression patterns are sufficiently well understood to allow accurate
      predictions on disease subclass membership. Commonly used methods of analysis
      include hierarchical clustering algorithms, t-, F-, and Z-tests, and machine
      learning approaches. We describe an approach called the maximum difference subset
      (MDSS) algorithm that combines classification algorithms, classical statistics,
      and elements of machine learning and provides a coherent framework. By
      integrating prediction accuracy, the MDSS algorithm learns the critical threshold
      of statistical significance (the alpha or P-value), eliminating the arbitrariness
      of setting a threshold of statistical significance and minimizing the effect of
      the normality assumptions. To reduce the false positive rate and to increase
      external validity of the predictive gene set, a jackknife step is used. This step
      identifies and removes genes in the initial MDSS with low combined predictive
      utility. The overall MDSS provides a prediction that is less dependent on an
      arbitrary study design (sample inclusion or exclusion) and should thus have high
      external validity. We demonstrate that this approach, unlike other published
      methods, identifies biomarkers capable of predicting the outcome of anthracycline
      cytarabine chemotherapy in cases of acute myeloid leukemia. By incorporating two
      criteria-statistical significance and predictive utility-the approach learns the
      significance level relevant for a given data set. The MDSS approach can be used
      with any test and classifier operator pair.

PMID- 12618383
TI  - Large-scale identification of single-feature polymorphisms in complex genomes.
AB  - We have developed a high-throughput genotyping platform by hybridizing genomic
      DNA from Arabidopsis thaliana accessions to an RNA expression GeneChip
      (AtGenome1). Using newly developed analytical tools, a large number of single
      feature polymorphisms (SFPs) were identified. A comparison of two accessions, the
      reference strain Columbia (Col) and the strain Landsberg erecta (Ler), identified
      nearly 4000 SFPs, which could be reliably scored at a 5% error rate. Ler sequence
      was used to confirm 117 of 121 SFPs and to determine the sensitivity of array
      hybridization. Features containing sequence repeats, as well as those from high
      copy genes, showed greater polymorphism rates. A linear clustering algorithm was
      developed to identify clusters of SFPs representing potential deletions in 111
      genes at a 5% false discovery rate (FDR). Among the potential deletions were
      transposons, disease resistance genes, and genes involved in secondary
      metabolism. The applicability of this technique was demonstrated by genotyping a
      recombinant inbred line. Recombination break points could be clearly defined, and
      in one case delimited to an interval of 29 kb. We further demonstrate that array
      hybridization can be combined with bulk segregant analysis to quickly map
      mutations. The extension of these tools to organisms with complex genomes, such
      as Arabidopsis, will greatly increase our ability to map and clone quantitative
      trait loci (QTL).

PMID- 12618384
TI  - Large-scale discovery of induced point mutations with high-throughput TILLING.
AB  - TILLING (Targeting Induced Local Lesions in Genomes) is a general reverse-genetic
      strategy that provides an allelic series of induced point mutations in genes of
      interest. High-throughput TILLING allows the rapid and low-cost discovery of
      induced point mutations in populations of chemically mutagenized individuals. As
      chemical mutagenesis is widely applicable and mutation detection for TILLING is
      dependent only on sufficient yield of PCR products, TILLING can be applied to
      most organisms. We have developed TILLING as a service to the Arabidopsis
      community known as the Arabidopsis TILLING Project (ATP). Our goal is to rapidly
      deliver allelic series of ethylmethanesulfonate-induced mutations in target 1-kb
      loci requested by the international research community. In the first year of
      public operation, ATP has discovered, sequenced, and delivered >1000 mutations in
      >100 genes ordered by Arabidopsis researchers. The tools and methodologies
      described here can be adapted to create similar facilities for other organisms.

PMID- 12618385
TI  - An analysis of why highly similar enzymes evolve differently.
AB  - The TEM-1 and SHV-1 beta-lactamases are important contributors to resistance to
      beta-lactam antibiotics in gram-negative bacteria. These enzymes share 68% amino
      acid sequence identity and their atomic structures are nearly superimposable.
      Extended-spectrum cephalosporins were introduced to avoid the action of these
      beta-lactamases. The widespread use of antibiotics has led to the evolution of
      variant TEM and SHV enzymes that can hydrolyze extended-spectrum antibiotics.
      Despite being highly similar in structure, the TEM and SHV enzymes have evolved
      differently in response to the selective pressure of antibiotic therapy. Examples
      of this are at residues Arg164 and Asp179. Among TEM variants, substitutions are
      found only at position 164, while among SHV variants, substitutions are found
      only at position 179. To explain this observation, the effects of substitutions
      at position 164 in both TEM-1 and SHV-1 on antibiotic resistance and on enzyme
      catalytic efficiency were examined. Competition experiments were performed
      between mutants to understand why certain substitutions preferentially evolve in
      response to the selective pressure of antibiotic therapy. The data presented here
      indicate that substitutions at position Asp179 in SHV-1 and Arg164 in TEM-1 are
      more beneficial to bacteria because they provide increased fitness relative to
      either wild type or other mutants.

PMID- 12618386
TI  - Probability of fixation of an advantageous mutant in a viral quasispecies.
AB  - The probability that an advantageous mutant rises to fixation in a viral
      quasispecies is investigated in the framework of multitype branching processes.
      Whether fixation is possible depends on the overall growth rate of the
      quasispecies that will form if invasion is successful rather than on the
      individual fitness of the invading mutant. The exact fixation probability can be
      calculated only if the fitnesses of all potential members of the invading
      quasispecies are known. Quasispecies fixation has two important characteristics:
      First, a sequence with negative selection coefficient has a positive fixation
      probability as long as it has the potential to grow into a quasispecies with an
      overall growth rate that exceeds that of the established quasispecies. Second,
      the fixation probabilities of sequences with identical fitnesses can nevertheless
      vary over many orders of magnitudes. Two approximations for the probability of
      fixation are introduced. Both approximations require only partial knowledge about
      the potential members of the invading quasispecies. The performance of these two
      approximations is compared to the exact fixation probability on a network of RNA
      sequences with identical secondary structure.

PMID- 12618387
TI  - Molecular evolution of the Escherichia coli chromosome. VI. Two regions of high
      effective recombination.
AB  - Two 6- to 8-min regions, centered respectively near 45 min (O-antigen region) and
      99 min (restriction-modification region) on the Escherichia coli chromosome,
      display unusually high variability among 11 otherwise very similar strains. This
      variation, revealed by restriction fragment length polymorphism (RFLP) and
      nucleotide sequence comparisons, appears to be due to a great local increase in
      the retention frequency of recombinant replacements. We infer a two-step
      mechanism. The first step is the acquisition of a small stretch of DNA from a
      phylogenetically distant source. The second is the successful retransmission of
      the imported DNA, together with flanking native DNA, to other strains of E. coli.
      Each cell containing the newly transferred DNA has a very high selective
      advantage until it reaches a high frequency and (in the O-antigen case) is
      recognized by the new host's immune system. A high selective advantage increases
      the probability of retention greatly; the effective recombination rate is the
      product of the basic recombination rate and the probability of retention. Nearby
      nucleotide sequences clockwise from the O-antigen (rfb) region are correlated
      with specific O antigens, confirming local hitchhiking. Comparable selection
      involving imported restriction endonuclease genes is proposed for the region near
      99 min.

PMID- 12618388
TI  - RecFOR function is required for DNA repair and recombination in a RecA loading
      deficient recB mutant of Escherichia coli.
AB  - The RecA loading activity of the RecBCD enzyme, together with its helicase and 5'
      --> 3' exonuclease activities, is essential for recombination in Escherichia
      coli. One particular mutant in the nuclease catalytic center of RecB, i.e.,
      recB1080, produces an enzyme that does not have nuclease activity and is unable
      to load RecA protein onto single-stranded DNA. There are, however, previously
      published contradictory data on the recombination proficiency of this mutant. In
      a recF(-) background the recB1080 mutant is recombination deficient, whereas in a
      recF(+) genetic background it is recombination proficient. A possible explanation
      for these contrasting phenotypes may be that the RecFOR system promotes RecA
      single-strand DNA filament formation and replaces the RecA loading defect of the
      RecB1080CD enzyme. We tested this hypothesis by using three in vivo assays. We
      compared the recombination proficiencies of recB1080, recO, recR, and recF single
      mutants and recB1080 recO, recB1080 recR, and recB1080 recF double mutants. We
      show that RecFOR functions rescue the repair and recombination deficiency of the
      recB1080 mutant and that RecA loading is independent of RecFOR in the recB1080
      recD double mutant where this activity is provided by the RecB1080C(D(-)) enzyme.
      According to our results as well as previous data, three essential activities for
      the initiation of recombination in the recB1080 mutant are provided by different
      proteins, i.e., helicase activity by RecB1080CD, 5' --> 3' exonuclease by RecJ-
      and RecA-single-stranded DNA filament formation by RecFOR.

PMID- 12618389
TI  - Saccharomyces cerevisiae Hsp70 mutations affect [PSI+] prion propagation and cell
      growth differently and implicate Hsp40 and tetratricopeptide repeat cochaperones
      in impairment of [PSI+].
AB  - We previously described an Hsp70 mutant (Ssa1-21p), altered in a conserved
      residue (L483W), that dominantly impairs yeast [PSI(+)] prion propagation without
      affecting growth. We generated new SSA1 mutations that impaired [PSI(+)]
      propagation and second-site mutations in SSA1-21 that restored normal
      propagation. Effects of mutations on growth did not correlate with [PSI(+)]
      phenotype, revealing differences in Hsp70 function required for growth and
      [PSI(+)] propagation and suggesting that Hsp70 interacts differently with
      [PSI(+)] prion aggregates than with other cellular substrates. Complementary
      suppression of altered activity between forward and suppressing mutations
      suggests that mutations that impair [PSI(+)] affect a similar Hsp70 function and
      that suppressing mutations similarly overcome this effect. All new mutations that
      impaired [PSI(+)] propagation were located in the ATPase domain. Locations and
      homology of several suppressing substitutions suggest that they weaken Hsp70's
      substrate-trapping conformation, implying that impairment of [PSI(+)] by forward
      mutations is due to altered ability of the ATPase domain to regulate substrate
      binding. Other suppressing mutations are in residues important for interactions
      with Hsp40 or TPR-containing cochaperones, suggesting that such interactions are
      necessary for the impairment of [PSI(+)] propagation caused by mutant Ssa1p.

PMID- 12618390
TI  - Std1p (Msn3p) positively regulates the Snf1 kinase in Saccharomyces cerevisiae.
AB  - The Snf1 protein kinase of the glucose signaling pathway in Saccharomyces
      cerevisiae is regulated by an autoinhibitory interaction between the regulatory
      and catalytic domains of Snf1p. Transitions between the autoinhibited and active
      states are controlled by an upstream kinase and the Reg1p-Glc7p protein
      phosphatase 1. Previous studies suggested that Snf1 kinase activity is also
      modulated by Std1p (Msn3p), which interacts physically with Snf1p and also
      interacts with glucose sensors. Here we address the relationship between Std1p
      and the Snf1 kinase. Two-hybrid assays showed that Std1p interacts with the
      catalytic domain of Snf1p, and analysis of mutant kinases suggested that this
      interaction is incompatible with the autoinhibitory interaction of the regulatory
      and catalytic domains. Overexpression of Std1p increased the two-hybrid
      interaction of Snf1p with its activating subunit Snf4p, which is diagnostic of an
      open, uninhibited conformation of the kinase complex. Overexpression of Std1p
      elevated Snf1 kinase activity in both in vitro and in vivo assays. These findings
      suggest that Std1p stimulates the Snf1 kinase by an interaction with the
      catalytic domain that antagonizes autoinhibition and promotes an active
      conformation of the kinase.

PMID- 12618391
TI  - MLH1 mutations differentially affect meiotic functions in Saccharomyces
      cerevisiae.
AB  - To test whether missense mutations in the cancer susceptibility gene MLH1
      adversely affect meiosis, we examined 14 yeast MLH1 mutations for effects on
      meiotic DNA transactions and gamete viability in the yeast Saccharomyces
      cerevisiae. Mutations analogous to those associated with hereditary nonpolyposis
      colorectal cancer (HNPCC) or those that reduce Mlh1p interactions with ATP or DNA
      all impair replicative mismatch repair as measured by increased mutation rates.
      However, their effects on meiotic heteroduplex repair, crossing over, chromosome
      segregation, and gametogenesis vary from complete loss of meiotic functions to no
      meiotic defect, and mutants defective in one meiotic process are not necessarily
      defective in others. DNA binding and ATP binding but not ATP hydrolysis are
      required for meiotic crossing over. The results reveal clear separation of
      different Mlh1p functions in mitosis and meiosis, and they suggest that some, but
      not all, MLH1 mutations may be a source of human infertility.

PMID- 12618392
TI  - Targeted nucleotide repair of cyc1 mutations in Saccharomyces cerevisiae directed
      by modified single-stranded DNA oligonucleotides.
AB  - Modified single-stranded DNA oligonucleotides have been used to direct base
      changes in the CYC1 gene of Saccharomyces cerevisiae. In this process, the
      oligonucleotide is believed to hybridize to the target site through the action of
      a DNA recombinase and, once bound, DNA repair enzymes act to excise the
      nucleotide, replace it, and revert the gene to wild-type status. Nucleotide
      exchange exhibits a strand bias as, in most cases, a higher level of base
      reversal appears in cells in which the oligonucleotide is designed to hybridize
      to the nontemplate strand. But, in one case, a higher level was observed when an
      oligonucleotide complementary to the transcribed strand was used. Mutant haploid
      and diploid strains are reverted to wild type at this locus with approximately
      the same frequency and all strains take up the oligonucleotide with approximately
      equal efficiency. Some repair preference for certain base mismatches was
      observed; for example, T/T and C/C mispairs exhibited the highest degree of
      reactivity. Finally, we demonstrate that proteins involved in DNA pairing can
      enhance the repair activity up to 22-fold, while others affect the reaction
      minimally. Taken together, these results confirm the importance and versatility
      of yeast as a model system to elucidate the factors regulating the frequency of
      nucleotide exchange directed by oligonucleotides.

PMID- 12618393
TI  - Lateral elements inside synaptonemal complex-like polycomplexes in ndt80 mutants
      of yeast bind DNA.
AB  - The synaptonemal complex (SC) keeps the synapsed homologous chromosomes together
      during pachytene in meiotic prophase I. Structures that resemble stacks of SCs,
      polycomplexes, are sometimes found before or after pachytene. We have
      investigated ndt80 mutants of yeast, which arrest in pachytene. SCs appear normal
      in spread chromosome preparations, but are only occasionally found in intact
      nuclei examined in the electron microscope. Instead, large polycomplexes occur in
      almost every ndt80 mutant nucleus. Immunoelectron microscopy using DNA antibodies
      show strong preferential labeling to the lateral element parts of the
      polycomplexes. In situ hybridization using chromosome-specific probes confirms
      that the chromosomes in ndt80 mutants are paired and attached to the SCs. Our
      results suggest that polycomplexes can be involved in binding of chromosomes and
      possibly also in synapsis.

PMID- 12618394
TI  - Short-chain fatty acid activation by acyl-coenzyme A synthetases requires SIR2
      protein function in Salmonella enterica and Saccharomyces cerevisiae.
AB  - SIR2 proteins have NAD(+)-dependent histone deacetylase activity, but no
      metabolic role has been assigned to any of these proteins. In Salmonella
      enterica, SIR2 function was required for activity of the acetyl-CoA synthetase
      (Acs) enzyme. A greater than two orders of magnitude increase in the specific
      activity of Acs enzyme synthesized by a sirtuin-deficient strain was measured
      after treatment with homogeneous S. enterica SIR2 protein. Human SIR2A and yeast
      SIR2 proteins restored growth of SIR2-deficient S. enterica on acetate and
      propionate, suggesting that eukaryotic cells may also use SIR2 proteins to
      control the synthesis of acetyl-CoA by the level of acetylation of acetyl-CoA
      synthetases. Consistent with this idea, growth of a quintuple sir2 hst1 hst2 hst3
      hst4 mutant strain of the yeast Saccharomyces cerevisiae on acetate or propionate
      was severely impaired. The data suggest that the Hst3 and Hst4 proteins are the
      most important for allowing growth on these short-chain fatty acids.

PMID- 12618395
TI  - Genetic loci modulating fitness and life span in Caenorhabditis elegans:
      categorical trait interval mapping in CL2a x Bergerac-BO recombinant-inbred
      worms.
AB  - Quantitative trait loci (QTL) can implicate an unbiased sampling of genes
      underlying a complex, polygenic phenotype. QTL affecting longevity in
      Caenorhabditis elegans were mapped using a CL2a x Bergerac-BO recombinant-inbred
      population. Genotypes were compared at 30 transposon-specific markers for two
      paired sample sets totaling 171 young controls and 172 longevity-selected worms
      (the last-surviving 1%) from a synchronously aged population. A third sample set,
      totaling 161 worms from an independent culture, was analyzed for confirmation of
      loci. At least six highly significant QTL affecting life span were detected both
      by single-marker (chi(2)) analysis and by two interval-mapping procedures--one
      intended for nonparametric traits and another developed specifically for mapping
      of categorical traits. These life-span QTL were located on chromosomes I (near
      the hP4 locus), III (near stP127), IV (near stP44), V (a cluster of three peaks,
      near stP192, stP23, and stP6), and X (two distinct peaks, near stP129 and stP2).
      Epistatic effects on longevity were also analyzed by Fisher's exact test, which
      indicated a significant life-span interaction between markers on chromosomes V
      (stP128) and III (stP127). Several further interactions were significant in the
      initial unselected population; two of these, between distal loci on chromosome V,
      were completely eliminated in the long-lived subset. Allelic longevity effects
      for two QTL, on chromosomes IV and V, were confirmed in backcrossed congenic
      lines and were highly significant in two very different environments-growth on
      solid agar medium and in liquid suspension culture.

PMID- 12618396
TI  - Characterization of Caenorhabditis elegans homologs of the Down syndrome
      candidate gene DYRK1A.
AB  - The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits.
      Increased expression of the dual-specificity protein kinase DYRK1A kinase
      (DYRK1A) appears to play a significant role in the neuropathology of Down
      syndrome. To shed light on the cellular role of DYRK1A and related genes we
      identified three DYRK/minibrain-like genes in the genome sequence of
      Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to
      be widely expressed and to localize to distinct subcellular compartments. We
      isolated deletion alleles in all three genes and show that loss of mbk-1, the
      gene most closely related to DYRK1A, causes no obvious defects, while another
      gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down
      syndrome led us to examine the effects of overexpression of its C. elegans
      ortholog mbk-1. We found that animals containing additional copies of the mbk-1
      gene display behavioral defects in chemotaxis toward volatile chemoattractants
      and that the extent of these defects correlates with mbk-1 gene dosage. Using
      tissue-specific and inducible promoters, we show that additional copies of mbk-1
      can impair olfaction cell-autonomously in mature, fully differentiated neurons
      and that this impairment is reversible. Our results suggest that increased gene
      dosage of human DYRK1A in trisomy 21 may disrupt the function of fully
      differentiated neurons and that this disruption is reversible.

PMID- 12618397
TI  - Deficiencies in C20 polyunsaturated fatty acids cause behavioral and
      developmental defects in Caenorhabditis elegans fat-3 mutants.
AB  - Arachidonic acid and other long-chain polyunsaturated fatty acids (PUFAs) are
      important structural components of membranes and are implicated in diverse
      signaling pathways. The Delta6 desaturation of linoleic and linolenic acids is
      the rate-limiting step in the synthesis of these molecules. C. elegans fat-3
      mutants lack Delta6 desaturase activity and fail to produce C20 PUFAs. We
      examined these mutants and found that development and behavior were affected as a
      consequence of C20 PUFA deficiency. While fat-3 mutants are viable, they grow
      slowly, display considerably less spontaneous movement, have an altered body
      shape, and produce fewer progeny than do wild type. In addition, the timing of an
      ultradian rhythm, the defecation cycle, is lengthened compared to wild type.
      Since all these defects can be ameliorated by supplementing the nematode diet
      with gamma-linolenic acid or C20 PUFAs of either the n6 or the n3 series, we can
      establish a causal link between fatty acid deficiency and phenotype. Similar
      epidermal tissue defects and slow growth are hallmarks of human fatty acid
      deficiency.

PMID- 12618398
TI  - Female site-specific transposase-induced recombination: a high-efficiency method
      for fine mapping mutations on the X chromosome in Drosophila.
AB  - P-element transposons in the Drosophila germline mobilize only in the presence of
      the appropriate transposase enzyme. Sometimes, instead of mobilizing completely,
      P elements will undergo site-specific recombination with the homologous
      chromosome. Site-specific recombination is the basis for male recombination
      mapping, since the male germline does not normally undergo recombination. Site
      specific recombination also takes place in females, but this has been difficult
      to study because of the obscuring effects of meiotic recombination. Using map
      functions, I demonstrate that it is possible to employ female site-specific
      transposase-induced recombination (FaSSTIR) to map loci on the X chromosome and
      predict that FaSSTIR mapping should be more efficient than meiotic mapping over
      short genetic intervals. Both FaSSTIR mapping and meiotic mapping were used to
      fine map the crossveinless locus on the X chromosome. Both techniques identified
      the same 10-kb interval as the probable location of the crossveinless mutation.
      Over short intervals (< approximately 7.6 cM), FaSSTIR produces more informative
      recombination events than does meiotic recombination. Over longer intervals,
      FaSSTIR is not always more efficient than meiotic mapping, but it produces the
      correct gene order. FaSSTIR matches the expectations suggested by the map
      functions and promises to be a useful technique, particularly for mapping X
      linked loci.

PMID- 12618399
TI  - Evidence of a high rate of selective sweeps in African Drosophila melanogaster.
AB  - Assessing the rate of evolution depends on our ability to detect selection at
      several genes simultaneously. We summarize DNA sequence variation data in three
      new and six previously published data sets from the left arm of the second
      chromosome of Drosophila melanogaster in a population from West Africa, the
      presumed area of origin of this species. Four loci [Acp26Aa, Fbp2, Vha68-1, and
      Su(H)] were previously found to deviate from a neutral mutation-drift equilibrium
      as a consequence of one or several selective sweeps. Polymorphism data from five
      loci from intervening regions (dpp, Acp26Ab, Acp29AB, GH10711, and Sos) did not
      show the characteristic deviation from neutrality caused by local selective
      sweeps. This genomic region is polymorphic for the In(2L)t inversion. Four loci
      located near inversion breakpoints [dpp, sos, GH10711, and Su(H)] showed
      significant structuring between the two arrangements or significant deviation
      from neutrality in the inverted class, probably as a result of a recent shift in
      inversion frequency. Overall, these patterns of variation suggest that the four
      selective events were independent. Six loci were observed with no a priori
      knowledge of selection, and independent selective sweeps were detected in three
      of them. This suggests that a large part of the D. melanogaster genome has
      experienced the effect of positive selection in its ancestral African range.

PMID- 12618400
TI  - Knockout targeting of the Drosophila nap1 gene and examination of DNA repair
      tracts in the recombination products.
AB  - We used ends-in gene targeting to generate knockout mutations of the nucleosome
      assembly protein 1 (Nap1) gene in Drosophila melanogaster. Three independent
      targeted null-knockout mutations were produced. No wild-type NAP1 protein could
      be detected in protein extracts. Homozygous Nap1(KO) knockout flies were either
      embryonic lethal or poorly viable adult escapers. Three additional targeted
      recombination products were viable. To gain insight into the underlying molecular
      processes we examined conversion tracts in the recombination products. In nearly
      all cases the I-SceI endonuclease site of the donor vector was replaced by the
      wild-type Nap1 sequence. This indicated exonuclease processing at the site of the
      double-strand break (DSB), followed by replicative repair at donor-target
      junctions. The targeting products are best interpreted either by the classical
      DSB repair model or by the break-induced recombination (BIR) model. Synthesis
      dependent strand annealing (SDSA), which is another important recombinational
      repair pathway in the germline, does not explain ends-in targeting products. We
      conclude that this example of gene targeting at the Nap1 locus provides added
      support for the efficiency of this method and its usefulness in targeting any
      arbitrary locus in the Drosophila genome.

PMID- 12618401
TI  - The promoter of the heterochromatic Drosophila telomeric retrotransposon, HeT-A,
      is active when moved into euchromatic locations.
AB  - The Drosophila telomeric retrotransposon, HeT-A, is found only in
      heterochromatin; therefore, its promoter must function in this chromatin
      environment. Studies of position effect variegation suggest that promoters of
      heterochromatic genes are very different from euchromatic promoters, but this
      idea has not been tested with isolated promoter sequences. The HeT-A promoter is
      the first heterochromatin promoter to be isolated and it is of interest to
      investigate its activity when removed from telomeric heterochromatin. This
      promoter was initially characterized by testing reporter constructs in transient
      transfection of cultured cells, an environment that may approximate its
      endogenous heterochromatin. We now report P-element-mediated transpositions of
      these constructs, testing the function of different parts of the putative
      promoter in euchromatin. Expression of endogenous HeT-A RNA shows marked
      developmental regulation and accumulates preferentially in replicating diploid
      tissues. HeT-A promoter constructs are active in all euchromatic locations tested
      and some display aspects of endogenous HeT-A stage- and cell-type expression
      programs. The activity of each promoter construct in euchromatic locations is
      also generally consistent with its activity in the transient transfection tests;
      a possibly significant exception is one sequence segment that appreciably
      enhanced activity in transient transfection but repressed promoter activity in
      euchromatin.

PMID- 12618402
TI  - Transcription profiling in Drosophila eyes that overexpress the human glaucoma
      associated trabecular meshwork-inducible glucocorticoid response protein/myocilin
      (TIGR/MYOC).
AB  - The availability of the human genome sequence together with sequenced genomes of
      several model organisms provides an unprecedented opportunity to utilize
      comparative genomic approaches for the discovery of genes that contribute to
      human disease. We have used transgenic flies to establish an experimental
      paradigm for the discovery of genes that might be involved in the development of
      glaucoma, a prevalent disease affecting a large segment of the population.
      Inherited mutations in the trabecular meshwork-inducible glucocorticoid response
      protein/myocilin (TIGR/MYOC) are associated with juvenile glaucoma and some cases
      of adult primary open angle glaucoma. The interrelationships between TIGR/MYOC
      and the development of glaucoma, however, are not understood. We show that
      overexpression of human TIGR/MYOC in the eyes of Drosophila melanogaster results
      in distortion of ommatidia accompanied by fluid discharge. High-density
      oligonucleotide microarrays identified altered expression of 50 transcripts in
      response to TIGR/MYOC overexpression, including homologs of aquaporin-4 and
      cytochrome-P450, previously associated with glaucoma, and several proteins of
      unknown function. We found that expression of Swiss Cheese, a neurodegenerative
      protein, increased 34-fold and that its human ortholog, neuropathy target
      esterase, is also upregulated in response to adenovirus-mediated overexpression
      of TIGR/MYOC in perfused postmortem human eyes. Our observations establish the
      Drosophila eye as an advantageous system for the discovery of genes that are
      associated with glaucoma.

PMID- 12618403
TI  - piggyBac-based insertional mutagenesis and enhancer detection as a tool for
      functional insect genomics.
AB  - Transposon mutagenesis provides a fundamental tool for functional genomics. Here
      we present a non-species-specific, combined enhancer detection and binary
      expression system based on the transposable element piggyBac: For the different
      components of this insertional mutagenesis system, we used widely applicable
      transposons and distinguishable broad-range transformation markers, which should
      enable this system to be operational in nonmodel arthropods. In a pilot screen in
      Drosophila melanogaster, piggyBac mutator elements on the X chromosome were
      mobilized in males by a Hermes-based jumpstarter element providing piggyBac
      transposase activity under control of the alpha1-tubulin promoter. As primary
      reporters in the piggyBac mutator elements, we employed the heterologous
      transactivators GAL4delta or tTA. To identify larval and adult enhancer
      detectors, strains carrying UASp-EYFP or TRE-EYFP as secondary reporter elements
      were used. Tissue-specific enhancer activities were readily observed in the
      GAL4delta/UASp-based systems, but only rarely in the tTA/TRE system. Novel
      autosomal insertions were recovered with an average jumping rate of 80%. Of these
      novel insertions, 3.8% showed homozygous lethality, which was reversible by
      piggyBac excision. Insertions were found in both coding and noncoding regions of
      characterized genes and also in noncharacterized and non-P-targeted CG-number
      genes. This indicates that piggyBac will greatly facilitate the intended
      saturation mutagenesis in Drosophila.

PMID- 12618404
TI  - Gene duplication and spectral diversification of cone visual pigments of
      zebrafish.
AB  - Zebrafish is becoming a powerful animal model for the study of vision but the
      genomic organization and variation of its visual opsins have not been fully
      characterized. We show here that zebrafish has two red (LWS-1 and LWS-2), four
      green (RH2-1, RH2-2, RH2-3, and RH2-4), and single blue (SWS2) and ultraviolet
      (SWS1) opsin genes in the genome, among which LWS-2, RH2-2, and RH2-3 are novel.
      SWS2, LWS-1, and LWS-2 are located in tandem and RH2-1, RH2-2, RH2-3, and RH2-4
      form another tandem gene cluster. The peak absorption spectra (lambdamax) of the
      reconstituted photopigments from the opsin cDNAs differed markedly among them:
      558 nm (LWS-1), 548 nm (LWS-2), 467 nm (RH2-1), 476 nm (RH2-2), 488 nm (RH2-3),
      505 nm (RH2-4), 355 nm (SWS1), 416 nm (SWS2), and 501 nm (RH1, rod opsin). The
      quantitative RT-PCR revealed a considerable difference among the opsin genes in
      the expression level in the retina. The expression of the two red opsin genes and
      of three green opsin genes, RH2-1, RH2-3, and RH2-4, is significantly lower than
      that of RH2-2, SWS1, and SWS2. These findings must contribute to our
      comprehensive understanding of visual capabilities of zebrafish and the evolution
      of the fish visual system and should become a basis of further studies on
      expression and developmental regulation of the opsin genes.

PMID- 12618405
TI  - Trichothecene nonproducer Gibberella species have both functional and
      nonfunctional 3-O-acetyltransferase genes.
AB  - The trichothecene 3-O-acetyltransferase gene (FgTri101) required for
      trichothecene production by Fusarium graminearum is located between the phosphate
      permease gene (pho5) and the UTP-ammonia ligase gene (ura7). We have cloned and
      sequenced the pho5-to-ura7 regions from three trichothecene nonproducing Fusarium
      (i.e., F. oxysporum, F. moniliforme, and Fusarium species IFO 7772) that belong
      to the teleomorph genus Gibberella. BLASTX analysis of these sequences revealed
      portions of predicted polypeptides with high similarities to the TRI101
      polypeptide. While FspTri101 (Fusarium species Tri101) coded for a functional 3-O
      acetyltransferase, FoTri101 (F. oxysporum Tri101) and FmTri101 (F. moniliforme
      Tri101) were pseudogenes. Nevertheless, F. oxysporum and F. moniliforme were able
      to acetylate C-3 of trichothecenes, indicating that these nonproducers possess
      another as yet unidentified 3-O-acetyltransferase gene. By means of cDNA
      expression cloning using fission yeast, we isolated the responsible FoTri201 gene
      from F. oxysporum; on the basis of this sequence, FmTri201 has been cloned from
      F. moniliforme by PCR techniques. Both Tri201 showed only a limited level of
      nucleotide sequence similarity to FgTri101 and FspTri101. The existence of Tri101
      in a trichothecene nonproducer suggests that this gene existed in the fungal
      genome before the divergence of producers from nonproducers in the evolution of
      Fusarium species.

PMID- 12618406
TI  - Alternative transcription initiation sites and polyadenylation sites are
      recruited during Mu suppression at the rf2a locus of maize.
AB  - Even in the absence of excisional loss of the associated Mu transposons, some Mu
      induced mutant alleles of maize can lose their capacity to condition a mutant
      phenotype. Three of five Mu-derived rf2a alleles are susceptible to such Mu
      suppression. The suppressible rf2a-m9437 allele has a novel Mu transposon
      insertion (Mu10) in its 5' untranslated region (UTR). The suppressible rf2a-m9390
      allele has a Mu1 insertion in its 5' UTR. During suppression, alternative
      transcription initiation sites flanking the Mu1 transposon yield functional
      transcripts. The suppressible rf2a-m8110 allele has an rcy/Mu7 insertion in its
      3' UTR. Suppression of this allele occurs via a previously unreported mechanism;
      sequences in the terminal inverted repeats of rcy/Mu7 function as alternative
      polyadenylation sites such that the suppressed rf2a-m8110 allele yields
      functional rf2a transcripts. No significant differences were observed in the
      nucleotide compositions of these alternative polyadenylation sites as compared
      with 94 other polyadenylation sites from maize genes.

PMID- 12618407
TI  - A linkage map of an F2 hybrid population of Antirrhinum majus and A. molle.
AB  - To increase the utility of Antirrhinum for genetic and evolutionary studies, we
      constructed a molecular linkage map for an interspecific hybrid A. majus x A.
      molle. An F(2) population (n = 92) was genotyped at a minimum of 243 individual
      loci. Although distorted transmission ratios were observed at marker loci
      throughout the genome, a mapping strategy based on a fixed framework of
      codominant markers allowed the loci to be placed into eight robust linkage groups
      consistent with the haploid chromosome number of Antirrhinum. The mapped loci
      included 164 protein-coding genes and a similar number of unknown sequences
      mapped as AFLP, RFLP, ISTR, and ISSR markers. Inclusion of sequences from mutant
      loci allowed provisional alignment of classical and molecular linkage groups. The
      total map length was 613 cM with an average interval of 2.5 cM, but most of the
      loci were aggregated into clusters reducing the effective distance between
      markers. Potential causes of transmission ratio distortion and its effects on map
      construction were investigated. This first molecular linkage map for Antirrhinum
      should facilitate further mapping of mutations, major QTL, and other coding
      sequences in this model genus.

PMID- 12618408
TI  - Quantitative trait loci analysis of water and anion contents in interaction with
      nitrogen availability in Arabidopsis thaliana.
AB  - In plants, water and anion parameters are linked, for example through the
      integration of nutritional signaling and the response to diverse stress. In this
      work, Arabidopsis thaliana is used as a model system to dissect the genetic
      variation of these parameters by quantitative trait loci (QTL) mapping in the 415
      recombinant inbred lines of the Bay-0 x Shahdara population. Water, nitrate,
      chloride, and phosphate contents were measured at the vegetative stage in the
      shoots of plants grown in controlled conditions. Two contrasting nitrogen (N)
      conditions were studied, one leading to the complete depletion of the nitrate
      pool in the plants. Most of the observed genetic variation was identified as QTL,
      with medium but also large phenotypic contributions. QTL colocalization provides
      a genetic basis for the correlation between water and nitrate contents in
      nonlimiting N conditions and water and chloride contents in limiting N
      conditions. The 34 new QTL described here represent at least 19 loci polymorphic
      between Bay-0 and Shahdara; some may correspond to known genes from water/anion
      transport systems, while others clearly identify new genes controlling or
      interacting with water/anion absorption and accumulation. Interestingly,
      flowering-time genes probably play a role in the regulation of water content in
      our conditions.

PMID- 12618410
TI  - Natural selection for polymorphism in the disease resistance gene Rps2 of
      Arabidopsis thaliana.
AB  - Pathogen resistance is an ecologically important phenotype increasingly well
      understood at the molecular genetic level. In this article, we examine levels of
      avrRpt2-dependent resistance and Rps2 locus DNA sequence variability in a
      worldwide sample of 27 accessions of Arabidopsis thaliana. The rooted parsimony
      tree of Rps2 sequences drawn from a diverse set of ecotypes includes a deep
      bifurcation separating major resistance and susceptibility clades of alleles. We
      find evidence for selection maintaining these alleles and identify the N-terminal
      part of the leucine-rich repeat region as a probable target of selection.
      Additional protein variants are found within the two major clades and correlate
      well with measurable differences among ecotypes in resistance to the avirulence
      gene avrRpt2 of the pathogen Pseudomonas syringae. Long-lived polymorphisms have
      been observed for other resistance genes of A. thaliana; the Rps2 data suggest
      that the long-term maintenance of phenotypic variation in resistance genes may be
      a general phenomenon and are consistent with diversifying selection acting in
      concert with selection to maintain variation.

PMID- 12618411
TI  - Genome-wide analysis of mariner-like transposable elements in rice reveals
      complex relationships with stowaway miniature inverted repeat transposable
      elements (MITEs).
AB  - Stowaway is a superfamily of miniature inverted repeat transposable elements
      (MITEs) that is widespread and abundant in plant genomes. Like other MITEs,
      however, its origin and mode of amplification are poorly understood. Several
      lines of evidence point to plant mariner-like elements (MLEs) as the autonomous
      partners of the nonautonomous Stowaway MITEs. To better understand this
      relationship, we have taken advantage of the nearly complete genome sequences of
      two rice subspecies to generate the first inventory of virtually all MLEs and
      Stowaway families coexisting in a single plant species. Thirty-four different
      MLEs were found to group into three major clades and 25 families. More than
      22,000 Stowaway MITEs were identified and classified into 36 families. On the
      basis of detailed sequence comparisons, MLEs were confirmed to be the best
      candidate autonomous elements for Stowaway MITEs. Surprisingly, however, sequence
      similarity between MLE and Stowaway families was restricted to the terminal
      inverted repeats (TIRs) and, in a few cases, to adjacent subterminal sequences.
      These data suggest a model whereby most of the Stowaway MITEs in rice were cross
      mobilized by MLE transposases encoded by distantly related elements.

PMID- 12618412
TI  - Molecular and cytological analyses of large tracks of centromeric DNA reveal the
      structure and evolutionary dynamics of maize centromeres.
AB  - We sequenced two maize bacterial artificial chromosome (BAC) clones anchored by
      the centromere-specific satellite repeat CentC. The two BACs, consisting of
      approximately 200 kb of cytologically defined centromeric DNA, are composed
      exclusively of satellite sequences and retrotransposons that can be classified as
      centromere specific or noncentromere specific on the basis of their distribution
      in the maize genome. Sequence analysis suggests that the original maize sequences
      were composed of CentC arrays that were expanded by retrotransposon invasions.
      Seven centromere-specific retrotransposons of maize (CRM) were found in BAC
      16H10. The CRM elements inserted randomly into either CentC monomers or other
      retrotransposons. Sequence comparisons of the long terminal repeats (LTRs) of
      individual CRM elements indicated that these elements transposed within the last
      1.22 million years. We observed that all of the previously reported centromere
      specific retrotransposons in rice and barley, which belong to the same family as
      the CRM elements, also recently transposed with the oldest element having
      transposed approximately 3.8 million years ago. Highly conserved sequence motifs
      were found in the LTRs of the centromere-specific retrotransposons in the grass
      species, suggesting that the LTRs may be important for the centromere specificity
      of this retrotransposon family.

PMID- 12618409
TI  - Selection on rapidly evolving proteins in the Arabidopsis genome.
AB  - Genes that have undergone positive or diversifying selection are likely to be
      associated with adaptive divergence between species. One indicator of adaptive
      selection at the molecular level is an excess of amino acid replacement fixed
      differences per replacement site relative to the number of synonymous fixed
      differences per synonymous site (omega = K(a)/K(s)). We used an evolutionary
      expressed sequence tag (EST) approach to estimate the distribution of omega among
      304 orthologous loci between Arabidopsis thaliana and A. lyrata to identify genes
      potentially involved in the adaptive divergence between these two Brassicaceae
      species. We find that 14 of 304 genes (approximately 5%) have an estimated omega
      > 1 and are candidates for genes with increased selection intensities. Molecular
      population genetic analyses of 6 of these rapidly evolving protein loci indicate
      that, despite their high levels of between-species nonsynonymous divergence,
      these genes do not have elevated levels of intraspecific replacement
      polymorphisms compared to previously studied genes. A hierarchical Bayesian
      analysis of protein-coding region evolution within and between species also
      indicates that the selection intensities of these genes are elevated compared to
      previously studied A. thaliana nuclear loci.

PMID- 12618414
TI  - Estimating polygenic effects using markers of the entire genome.
AB  - Molecular markers have been used to map quantitative trait loci. However, they
      are rarely used to evaluate effects of chromosome segments of the entire genome.
      The original interval-mapping approach and various modified versions of it may
      have limited use in evaluating the genetic effects of the entire genome because
      they require evaluation of multiple models and model selection. Here we present a
      Bayesian regression method to simultaneously estimate genetic effects associated
      with markers of the entire genome. With the Bayesian method, we were able to
      handle situations in which the number of effects is even larger than the number
      of observations. The key to the success is that we allow each marker effect to
      have its own variance parameter, which in turn has its own prior distribution so
      that the variance can be estimated from the data. Under this hierarchical model,
      we were able to handle a large number of markers and most of the markers may have
      negligible effects. As a result, it is possible to evaluate the distribution of
      the marker effects. Using data from the North American Barley Genome Mapping
      Project in double-haploid barley, we found that the distribution of gene effects
      follows closely an L-shaped Gamma distribution, which is in contrast to the bell
      shaped Gamma distribution when the gene effects were estimated from interval
      mapping. In addition, we show that the Bayesian method serves as an alternative
      or even better QTL mapping method because it produces clearer signals for QTL.
      Similar results were found from simulated data sets of F(2) and backcross (BC)
      families.

PMID- 12618415
TI  - The coalescent and infinite-site model of a small multigene family.
AB  - The infinite-site model of a small multigene family with two duplicated genes is
      studied. The expectations of the amounts of nucleotide variation within and
      between two genes and linkage disequilibrium are obtained, and a coalescent-based
      method for simulating patterns of polymorphism in a small multigene family is
      developed. The pattern of DNA variation is much more complicated than that in a
      single-copy gene, which can be simulated by the standard coalescent. Using the
      coalescent simulation of duplicated genes, the applicability of statistical tests
      of neutrality to multigene families is considered.

PMID- 12618413
TI  - Quantitative trait loci responsible for variation in sexually dimorphic traits in
      Drosophila melanogaster.
AB  - To understand the mechanisms of morphological evolution and species divergence,
      it is essential to elucidate the genetic basis of variation in natural
      populations. Sexually dimorphic characters, which evolve rapidly both within and
      among species, present attractive models for addressing these questions. In this
      report, we map quantitative trait loci (QTL) responsible for variation in
      sexually dimorphic traits (abdominal pigmentation and the number of ventral
      abdominal bristles and sex comb teeth) in a natural population of Drosophila
      melanogaster. To capture the pattern of genetic variation present in the wild, a
      panel of recombinant inbred lines was created from two heterozygous flies taken
      directly from nature. High-resolution mapping was made possible by cytological
      markers at the average density of one per 2 cM. We have used a new Bayesian
      algorithm that allows QTL mapping based on all markers simultaneously. With this
      approach, we were able to detect small-effect QTL that were not evident in single
      marker analyses. Our results show that at least for some sexually dimorphic
      traits, a small number of QTL account for the majority of genetic variation. The
      three strongest QTL account for >60% of variation in the number of ventral
      abdominal bristles. Strikingly, a single QTL accounts for almost 60% of variation
      in female abdominal pigmentation. This QTL maps to the chromosomal region that
      Robertson et al. have found to affect female abdominal pigmentation in other
      populations of D. melanogaster. Using quantitative complementation tests, we
      demonstrate that this QTL is allelic to the bric a brac gene, whose expression
      has previously been shown to correlate with interspecific differences in
      pigmentation. Multiple bab alleles that confer distinct phenotypes appear to
      segregate in natural populations at appreciable frequencies, suggesting that
      intraspecific and interspecific variation in abdominal pigmentation may share a
      similar genetic basis.

PMID- 12618416
TI  - The evolution of sex dimorphism in recombination.
AB  - Sex dimorphism in recombination is widespread on both sex chromosomes and
      autosomes. Various hypotheses have been proposed to explain these dimorphisms.
      Yet no theoretical model has been explored to determine how heterochiasmy--the
      autosomal dimorphism--could evolve. The model presented here shows three
      circumstances in which heterochiasmy is likely to evolve: (i) a male-female
      difference in haploid epistasis, (ii) a male-female difference in cis-epistasis
      minus trans-epistasis in diploids, or (iii) a difference in epistasis between
      combinations of genes inherited maternally or paternally. These results hold even
      if sources of linkage disequilibria besides epistasis, such as migration or Hill
      Robertson interference, are considered and shed light on previous verbal models
      of sex dimorphism in recombination rates. Intriguingly, these results may also
      explain why imprinted regions on the autosomes of humans or sheep are
      particularly heterochiasmate.

PMID- 12618417
TI  - Inferring modes of colonization for pest species using heterozygosity comparisons
      and a shared-allele test.
AB  - Long-range dispersal of a species may involve either a single long-distance
      movement from a core population or spreading via unobserved intermediate
      populations. Where the new populations originate as small propagules, genetic
      drift may be extreme and gene frequency or assignment methods may not prove
      useful in determining the relation between the core population and outbreak
      samples. We describe computationally simple resampling methods for use in this
      situation to distinguish between the different modes of dispersal. First,
      estimates of heterozygosity can be used to test for direct sampling from the core
      population and to estimate the effective size of intermediate populations.
      Second, a test of sharing of alleles, particularly rare alleles, can show whether
      outbreaks are related to each other rather than arriving as independent samples
      from the core population. The shared-allele statistic also serves as a genetic
      distance measure that is appropriate for small samples. These methods were
      applied to data on a fruit fly pest species, Bactrocera tryoni, which is
      quarantined from some horticultural areas in Australia. We concluded that the
      outbreaks in the quarantine zone came from a heterogeneous set of genetically
      differentiated populations, possibly ones that overwinter in the vicinity of the
      quarantine zone.

PMID- 12618418
TI  - Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases.
AB  - Fifteen years have passed since the first description of interleukin (IL)-8/CXCL8
      as a potent neutrophil chemotactic factor. Accumulating evidence has demonstrated
      that various types of cells can produce a large amount of IL-8/CXCL8 in response
      to a wide variety of stimuli, including proinflammatory cytokines, microbes and
      their products, and environmental changes such as hypoxia, reperfusion, and
      hyperoxia. Numerous observations have established IL-8/CXCL8 as a key mediator in
      neutrophil-mediated acute inflammation due to its potent actions on neutrophils.
      However, several lines of evidence indicate that IL-8/CXCL8 has a wide range of
      actions on various types of cells, including lymphocytes, monocytes, endothelial
      cells, and fibroblasts, besides neutrophils. The discovery of these biological
      functions suggests that IL-8/CXCL8 has crucial roles in various pathological
      conditions such as chronic inflammation and cancer. Here, an overview of its
      protein structure, mechanisms of production, and receptor system will be
      discussed as well as the pathophysiological roles of IL-8/CXCL8 in various types
      of lung pathologies.

PMID- 12618419
TI  - Controlling from within: neurophysiological plasticity of parasympathetic airway
      neurons.

PMID- 12618420
TI  - Role of cyclooxygenase activation and prostaglandins in antigen-induced
      excitability changes of bronchial parasympathetic ganglia neurons.
AB  - In vitro antigen challenge has multiple effects on the excitability of guinea pig
      bronchial parasympathetic ganglion neurons, including depolarization, causing
      phasic neurons to fire with a repetitive action potential pattern and
      potentiating synaptic transmission. In the present study, guinea pigs were
      passively sensitized to the antigen ovalbumin. After sensitization, the bronchi
      were prepared for in vitro electrophysiological intracellular recording of
      parasympathetic ganglia neurons to investigate the contribution of cyclooxygenase
      activation and prostanoids on parasympathetic nerve activity. Cyclooxygenase
      inhibition with either indomethacin or piroxicam before in vitro antigen
      challenge blocked the change in accommodation. These cyclooxygenase inhibitors
      also blocked the release of prostaglandin D(2) (PGD(2)) from bronchial tissue
      during antigen challenge. We also determined that PGE(2) and PGD(2) decreased the
      duration of the action potential after hyperpolarization, whereas PGF(2alpha)
      potentiated synaptic transmission. Thus prostaglandins released during antigen
      challenge have multiple effects on the excitability of guinea pig bronchial
      parasympathetic ganglia neurons, which may consequently affect the output from
      these neurons and thereby alter parasympathetic tone in the lower airways.

PMID- 12618421
TI  - Phenotypic comparison of allergic airway responses to house dust mite in three
      rat strains.
AB  - Brown Norway (BN) rats develop a robust response to antigens in the lung,
      characterized by a large increase in allergen-specific immune function and
      pulmonary eosinophilia. The objective of this study was to investigate
      alternative models by determining whether other rat strains could be sensitized
      to house dust mite (HDM) antigen and whether the allergic disease process could
      be worsened with repeated allergen exposure. In general, BN rats sensitized by
      either subcutaneous or intratracheal routes exhibited increased pulmonary allergy
      compared with Sprague-Dawley (SD) and Lewis (L) rats. Multiple intratracheal
      allergen exposures incrementally increased HDM-specific immune function in BN
      rats but progressively decreased eosinophil recruitment and markers of lung
      injury. SD rats had more moderate responses, whereas L rats were relatively
      unresponsive. Because BN rats developed stronger clinical hallmarks of allergic
      asthma under various immunization regimes compared with SD and L rats, we
      conclude that the BN is the most appropriate strain for studying allergic asthma
      like responses in rats. Phenotypic differences in response to HDM were associated
      with differences in the Th1/Th2 cytokine balance and antioxidant capacity.

PMID- 12618422
TI  - Receptors and pathways mediating the effects of prostaglandin E2 on airway tone.
AB  - Prostaglandin E(2) (PGE(2)) has complex effects on airway tone, and the existence
      of four PGE(2) [E-prostanoid (EP)] receptors, each with distinct signaling
      characteristics, has provided a possible explanation for the seemingly
      contradictory actions of this lipid mediator. To identify the receptors mediating
      the actions of PGE(2) on bronchomotor tone, we examined its effects on the
      airways of wild-type and EP receptor-deficient mice. In conscious mice the
      administration of PGE(2) increased airway responsiveness primarily through the
      EP1 receptor, although on certain genetic backgrounds a contribution of the EP3
      receptor was detected. These effects of PGE(2) were eliminated by pretreatment
      with either atropine or bupivacaine and were undetectable in anesthetized mice or
      in denervated tracheal rings, where only EP2-mediated relaxation of airway smooth
      muscle was observed. Together, our findings are consistent with a model in which
      PGE(2) modulates airway tone by activating multiple receptors expressed on
      various cell populations and in which the relative contribution of these
      receptors might depend on the expression of modifier alleles. PGE(2)/EP1/EP3
      induced airway constriction occurs indirectly through activation of neural
      pathways, whereas PGE(2)-induced bronchodilation results from direct activation
      of EP2 receptors on airway smooth muscle. This segregation of EP receptor
      function within the airway suggests that PGE(2) analogs that selectively activate
      the EP2 receptor without activating the EP1/EP3 receptors might prove useful in
      the treatment of asthma.

PMID- 12618423
TI  - Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular
      smooth muscle cells.
AB  - We examined the hypothesis that the potent vasoconstrictor endothelin (ET)-1
      regulates both its own production and production of the vasodilator
      prostaglandins PGE(2) and prostacyclin in sheep peripheral lung vascular smooth
      muscle cells (PLVSMC). Confluent layers of PLVSMC were exposed to 10 nM ET-1;
      expression of the prepro (pp)-ET-1, cyclooxygenase (COX)-1, and COX-2 genes was
      examined by RT-PCR and Western analysis. Intracellular levels of ET-1 were
      measured by ELISA with and without addition of the protein synthesis inhibitor
      brefeldin A (50 microg/ml). Prostaglandin levels were measured by gas
      chromatography-mass spectrometry. Through use of ET(A) and ET(B) antagonists (BQ
      610 and BQ-788, respectively), the contribution of the ET receptors to COX-1 and 
      2 expression and ppET-1 gene expression was examined. The contribution of
      phosphorylated p38 and p44/42 MAPK on COX-1 and COX-2 expression was also
      examined with MAPK inhibitors (p38, SB-203580 and p44/42, PD-98056). ET-1
      resulted in transient increases in ppET-1, COX-1, and COX-2 gene and protein
      expression and release of 6-keto-PGF(1alpha) and PGE(2) (P < 0.05). Both
      internalization of ET-1 and synthesis of new peptide contributed to an increase
      in intracellular ET-1 (P < 0.05). Although increased ppET-1 was regulated by both
      ET(A) and ET(B), COX-2 expression was upregulated only by ET(A); COX-1 expression
      was unaffected by either antagonist. ET-1 treatment resulted in transient
      phosphorylation of p38 and p44/42 MAPK; inhibitors of these MAPKs suppressed
      expression of COX-2 but not COX-1. Our data indicate that local production of ET
      1 regulates COX-2 by activation of the ET(A) receptor and phosphorylation of p38
      and p44/42 MAPK in PLVSMC.

PMID- 12618424
TI  - In vivo tracheal occlusion in fetal mice induces rapid lung development without
      affecting surfactant protein C expression.
AB  - Fetal tracheal occlusion (TO) reverses lung hypoplasia by inducing rapid lung
      growth. Although increases in lung size accompanied by increased numbers of
      alveoli and capillaries have been reported, effects of TO on lung development
      have not been formally assessed. In the present study, the objective was to
      verify our prediction that the main effect of TO would be to accelerate fetal
      lung development. We have developed and characterized a new fetal mouse model of
      TO to best realize this goal. At embryonic day 16.5, pregnant CD1 mice were
      operated under general anesthesia. One fetus per dam was selected to undergo
      surgical TO with a surgical clip or a sham operation. The fetuses were delivered
      24 or 36 h postsurgery. The maturation of lung parenchyma, evaluated by counting
      the generations of alveolar saccules from the terminal bronchiole to the pleura,
      was significantly accelerated in the TO group with a complexity of the gas
      exchange region comparable with postnatal days 1 and 3 after 24 or 36 h of TO.
      Cellular proliferation and apoptosis peaks, assessed by immunohistochemistry
      directed against PCNA and the active form of caspase-3, were significantly
      increased 24 h after surgery in the TO group compared with the sham group.
      However, in situ hybridization showed no significant difference in the density of
      type II pneumocytes expressing surfactant protein C mRNA. Our results show that
      brief TO during late gestation in fetal mice induces accelerated lung development
      with minimal effects on surfactant protein C mRNA expression.

PMID- 12618425
TI  - Sustained changes in lung expansion alter tropoelastin mRNA levels and elastin
      content in fetal sheep lungs.
AB  - Our objective was to determine the effects of sustained alterations in fetal lung
      expansion on pulmonary elastin synthesis. In fetal sheep, lung expansion was
      either decreased between 111 and 131 days' gestation (term approximately 147
      days) by tracheal drainage or increased for 2, 4, 7, or 10 days by tracheal
      obstruction, ending at 128 days' gestation. Lung tropoelastin mRNA levels were
      assessed by Northern blot analysis, total elastin content was measured
      biochemically, and staining of lung sections was used to assess the localization
      and form of elastic fibers. Tracheal obstruction significantly elevated pulmonary
      tropoelastin mRNA levels 2.5-fold at 2 days, but values were not different from
      controls at 4, 7, and 10 days; elastin content tended to be increased at all time
      points. A sustained decrease in lung expansion by tracheal drainage reduced
      pulmonary tropoelastin mRNA levels 2.5-fold; elastin content was also decreased
      compared with controls, and tissue localization was altered. Our results indicate
      that the degree of lung expansion in the fetus influences elastin synthesis,
      content, and tissue deposition.

PMID- 12618426
TI  - Evidence for extracellular superoxide dismutase as a mediator of hemorrhage
      induced lung injury.
AB  - Hemorrhage results in excessive production of superoxide that is associated with
      severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic
      manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) could
      attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice
      would have increased hemorrhage-induced lung injury. Compared with wild-type
      mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9
      fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor
      (NF)-kappaB activation, and a 1.5-fold increase in lipid peroxidation 1 h after
      hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil
      accumulation but significantly reduced NF-kappaB activation and lipid
      peroxidation in both wild-type and EC-SOD-deficient mice. The increase in
      hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice
      suggests that EC-SOD might play a role in mediating neutrophil recruitment to the
      lung.

PMID- 12618427
TI  - Identification of acyl coenzyme A:monoacylglycerol acyltransferase 3, an
      intestinal specific enzyme implicated in dietary fat absorption.
AB  - Acyl coenzyme A:monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis
      of diacylglycerol using 2-monoacylglycerol and fatty acyl coenzyme A. This
      enzymatic reaction is believed to be an essential and rate-limiting step for the
      absorption of fat in the small intestine. Although the first MGAT-encoding cDNA,
      designated MGAT1, has been recently isolated, it is not expressed in the small
      intestine and hence cannot account for the high intestinal MGAT enzyme activity
      that is important for the physiology of fat absorption. In the current study, we
      report the identification of a novel MGAT, designated MGAT3, and present evidence
      that it fulfills the criteria to be the elusive intestinal MGAT. MGAT3 encodes a
      approximately 36-kDa transmembrane protein that is highly homologous to MGAT1 and
      -2. In humans, expression of MGAT3 is restricted to gastrointestinal tract with
      the highest level found in the ileum. At the cellular level, recombinant MGAT3 is
      localized to the endoplasmic reticulum. Recombinant MGAT3 enzyme activity
      produced in insect Sf9 cells selectively acylates 2-monoacylglycerol with higher
      efficiency than other stereoisomers. The molecular identification of MGAT3 will
      facilitate the evaluation of using intestinal MGAT as a potential point of
      intervention for antiobesity therapies.

PMID- 12618428
TI  - 14-3-3beta is a p90 ribosomal S6 kinase (RSK) isoform 1-binding protein that
      negatively regulates RSK kinase activity.
AB  - p90 ribosomal S6 kinase 1 (RSK1) is a serine/threonine kinase that is activated
      by extracellular signal-related kinases 1/2 and phosphoinositide-dependent
      protein kinase 1 upon mitogen stimulation. Under basal conditions, RSK1 is
      located in the cytosol and upon stimulation, RSK1 translocates to the plasma
      membrane where it is fully activated. The ability of RSK1 to bind the adapter
      protein 14-3-3beta was investigated because RSK1 contains several putative 14-3-3
      binding motifs. We demonstrate that RSK1 specifically and directly binds 14-3
      3beta. This interaction was dependent on phosphorylation of serine 154 within the
      motif RLSKEV of RSK1. Binding of RSK1 to 14-3-3beta was maximal under basal
      conditions and decreased significantly upon mitogen stimulation. After 5 min of
      serum stimulation, a portion of 14-3-3beta and RSK1 translocated to the membrane
      fraction, and immunofluorescence studies demonstrated colocalization of RSK1 and
      14-3-3beta at the plasma membrane in vivo. Incubation of recombinant RSK1 with 14
      3-3beta decreased RSK1 kinase activity by approximately 50%. Mutation of RSK1
      serine 154 increased both basal and serum-stimulated RSK activity. In addition,
      the epidermal growth factor response of RSK1S154A was enhanced compared with wild
      type RSK. The amount of RSK1S154A was significantly increased in the membrane
      fraction under basal conditions. Increased phosphorylation of two sites essential
      for RSK1 kinase activity (Ser(380) and Ser(363)) in RSK1S154A compared with RSK1
      wild type, demonstrated that 14-3-3 interferes with RSK1 phosphorylation. These
      data suggest that 14-3-3beta binding negatively regulates RSK1 activity to
      maintain signal specificity and that association/dissociation of the 14-3-3beta
      RSK1 complex is likely to be important for mitogen-mediated RSK1 activation.

PMID- 12618429
TI  - p47phox participates in activation of RelA in endothelial cells.
AB  - Activation of endothelial cell NF-kappaB by interleukin (IL)-1 constitutes an
      event critical to the progression of the innate immune response. In this context,
      oxidants have been associated with NF-kappaB activation, although the molecular
      source and mechanism of targeting have remained obscure. We found that RelA,
      essential for NF-kappaB activation by IL-1, was associated with the NADPH oxidase
      adapter protein p47(phox) in yeast two-hybrid, coprecipitation, and in vitro
      binding studies. RelA and p47-GFP also colocalized in endothelial cells in focal
      submembranous dorsoventral protrusions. Overexpression of p47(phox) synergized
      with IL-1beta in the activation of an artificial kappaB-luciferase reporter and
      specifically augmented IL-1beta-induced RelA transactivation activity. p47(phox)
      overexpression also greatly increased IL-1beta-stimulated RelA phosphorylation,
      whereas it had no effect on I-kappaB degradation or on RelA nuclear translocation
      or kappaB binding. The tandem SH3 domains of p47(phox) were found to associate
      with a proline-rich mid-region of RelA (RelA-PR) located between the Rel homology
      and transactivation domains. The RelA-PR peptide blocked interaction of p47(phox)
      and RelA, and ectopic expression of RelA-PR abrogated IL-1beta-induced
      transactivation of the NF-kappaB-dependent E-selectin promoter. Further,
      suppression of NADPH oxidase function through the inhibitor diphenylene iodonium,
      the superoxide dismutase mimetic Mn(III) tetrakis(4-benzoic acid)porphyrin
      (MnTBAP), or expression of a dominant interfering mutant of a separate NADPH
      oxidase subunit (p67(V204A)) decreased IL-1beta-induced E-selectin promoter
      activation, suggesting that p47(phox) facilitates NF-kappaB activation through
      linkage with the NADPH oxidase. IL-1beta rapidly increased tyrosine
      phosphorylation of IL-1 type I receptor-associated proteins, suggesting that
      oxidants may operate through inactivation of local protein-tyrosine phosphatases
      in the proximal IL-1beta signaling pathway leading to RelA activation.

PMID- 12618430
TI  - Farnesyl pyrophosphate synthase is an essential enzyme in Trypanosoma brucei. In
      vitro RNA interference and in vivo inhibition studies.
AB  - We report the cloning and sequencing of a gene encoding the farnesyl
      pyrophosphate synthase (FPPS) of Trypanosoma brucei. The protein (TbFPPS) is an
      attractive target for drug development because the growth of T. brucei has been
      shown to be inhibited by analogs of its substrates, the nitrogen containing
      bisphosphonates currently in use in bone resorption therapy. The protein
      predicted from the nucleotide sequence of the gene has 367 amino acids and a
      molecular mass of 42 kDa. Several sequence motifs found in other FPPSs are
      present in TbFPPS, including an 11-mer peptide insertion present also in the
      Trypanosoma cruzi FPPS. Heterologous expression of TbFPPS in Escherichia coli
      produced a functional enzyme that was inhibited by several nitrogen-containing
      bisphosphonates, such as pamidronate and risedronate. Risedronate was active in
      vivo against T. brucei infection in mice (giving a 60% survival rate), but
      pamidronate was not effective. The essential nature of TbFPPS was studied using
      RNA interference (RNAi) to inhibit the expression of the gene. Expression of
      TbFPPS double-stranded RNA in procyclic trypomastigotes caused specific
      degradation of mRNA. After 4 days of RNAi, the parasite growth rate declined and
      the cells subsequently died. Similar results were obtained with bloodstream form
      trypomastigotes, except that the RNAi system in this case was leaky and mRNA
      levels and parasites recovered with time. Molecular modeling and structure
      activity investigations of enzyme and in vitro growth inhibition data resulted in
      similar pharmacophores, further validating TbFPPS as the target for
      bisphosphonates. These results establish that FPPS is essential for parasite
      viability and validate this enzyme as a target for drug development.

PMID- 12618431
TI  - ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through
      induction of Egr-1.
AB  - 4E-BP1 plays a major role in translation by inhibiting cap-dependent translation
      initiation. Several reports have investigated the regulation of 4E-BP1
      phosphorylation, which varies along with cell differentiation and upon various
      stimulations, but very little is known about the regulation of its expression. In
      a first part, we show that the expression of 4E-BP1 protein and transcript
      decreases in hematopoietic cell lines cultivated in the presence of phorbol 12
      myristate 13-acetate (PMA). This decrease depends on the activation of the
      ERK/mitogen-activated protein kinases. 4E-BP1 expression also decreases when the
      p38/mitogen-activated protein kinase pathway is activated by
      granulocyte/macrophage colony-stimulating factor but to a lesser extent than with
      PMA. In a second part, we examine how 4e-bp1 promoter activity is regulated. PMA
      and granulocyte/macrophage colony-stimulating factor induce Egr-1 expression
      through ERK and p38 activation, respectively. Using a dominant negative mutant of
      Egr, ZnEgr, we show that this transcription factor is responsible for the
      inhibition of 4e-bp1 promoter activity. In a third part we show that histidine
      decarboxylase, whose activity and expression are inversely correlated with 4E-BP1
      expression, is a potential target for the translational machinery. These data (i)
      are the first evidence of a new role of ERK and p38 on the translational
      machinery and (ii) demonstrate that 4E-BP1 is a new target for Egr-1.

PMID- 12618432
TI  - Cytochrome c nitrite reductase from Desulfovibrio desulfuricans ATCC 27774. The
      relevance of the two calcium sites in the structure of the catalytic subunit
      (NrfA).
AB  - The gene encoding cytochrome c nitrite reductase (NrfA) from Desulfovibrio
      desulfuricans ATCC 27774 was sequenced and the crystal structure of the enzyme
      was determined to 2.3-A resolution. In comparison with homologous structures, it
      presents structural differences mainly located at the regions surrounding the
      putative substrate inlet and product outlet, and includes a well defined second
      calcium site with octahedral geometry, coordinated to propionates of hemes 3 and
      4, and caged by a loop non-existent in the previous structures. The highly
      negative electrostatic potential in the environment around hemes 3 and 4 suggests
      that the main role of this calcium ion may not be electrostatic but structural,
      namely in the stabilization of the conformation of the additional loop that cages
      it and influences the solvent accessibility of heme 4. The NrfA active site is
      similar to that of peroxidases with a nearby calcium site at the heme distal side
      nearly in the same location as occurs in the class II and class III peroxidases.
      This fact suggests that the calcium ion at the distal side of the active site in
      the NrfA enzymes may have a similar physiological role to that reported for the
      peroxidases.

PMID- 12618434
TI  - The dynamin-like GTPase DLP1 is essential for peroxisome division and is
      recruited to peroxisomes in part by PEX11.
AB  - Peroxisome division involves the conserved PEX11 peroxisomal membrane proteins
      and in yeast has been shown to require Vps1p, a dynamin-like protein. We show
      here that DLP1, the human homolog of the yeast DNM1 and VPS1 genes, plays an
      important role in peroxisome division in human cells. Disruption of DLP1 function
      by either RNA interference or overexpressing dominant negative DLP1 mutants
      causes a dramatic reduction in peroxisome abundance, although overexpression of
      functional DLP1 has no effect on peroxisome abundance. Overexpression of PEX11
      induces peroxisome division in a multistep process involving elongation of
      preexisting peroxisomes followed by their division. We find that DLP1 is
      dispensable for the first phase of this process but essential for the second.
      Furthermore, we show that DLP1 associates with peroxisomes and that PEX11
      overexpression recruits DLP1 to peroxisome membranes. However, we were unable to
      detect physical interaction between PEX11 and DLP1, and the stoichiometry of
      PEX11 and peroxisome-associated DLP1 was far less than 1:1. Based on these and
      other aspects, we propose that DLP1 performs an essential but transient role in
      peroxisome division and that PEX11 promotes peroxisome division by recruiting
      DLP1 to peroxisome membranes through an indirect mechanism.

PMID- 12618433
TI  - Homomeric ring assemblies of eukaryotic Sm proteins have affinity for both RNA
      and DNA. Crystal structure of an oligomeric complex of yeast SmF.
AB  - Sm and Sm-like proteins are key components of small ribonucleoproteins involved
      in many RNA and DNA processing pathways. In eukaryotes, these complexes contain
      seven unique Sm or Sm-like (Lsm) proteins assembled as hetero-heptameric rings,
      whereas in Archaea and bacteria six or seven-membered rings are made from only a
      single polypeptide chain. Here we show that single Sm and Lsm proteins from yeast
      also have the capacity to assemble into homo-oligomeric rings. Formation of homo
      oligomers by the spliceosomal small nuclear ribonucleoprotein components SmE and
      SmF preclude hetero-interactions vital to formation of functional small nuclear
      RNP complexes in vivo. To better understand these unusual complexes, we have
      determined the crystal structure of the homomeric assembly of the spliceosomal
      protein SmF. Like its archaeal/bacterial homologs, the SmF complex forms a
      homomeric ring but in an entirely novel arrangement whereby two heptameric rings
      form a co-axially stacked dimer via interactions mediated by the variable loops
      of the individual SmF protein chains. Furthermore, we demonstrate that the
      homomeric assemblies of yeast Sm and Lsm proteins are capable of binding not only
      to oligo(U) RNA but, in the case of SmF, also to oligo(dT) single-stranded DNA.

PMID- 12618435
TI  - Purification and mass spectrometric identification of GA-binding protein (GABP)
      as the functional pituitary Ets factor binding to the basal transcription element
      of the prolactin promoter.
AB  - The Ets-binding site within the basal transcription element (BTE) of the rat
      prolactin (rPRL) promoter is critical for both basal and growth factor-regulated
      rPRL gene expression. Here we report the purification and identification of the
      factor that binds to the BTE. This factor was purified from GH3 pituitary nuclear
      extracts using ammonium sulfate fractionation, heparin-Sepharose and Mono Q
      chromatography, and BTE-affinity magnetic beads. We purified two proteins of 57
      and 47 kDa and identified the 57-kDa protein by mass spectrometry as the Ets
      factor GABPalpha. Western blot analysis identified the 47-kDa protein as
      GABPbeta1. Co-transfection of dominant-negative GABPbeta1 blocks prolactin
      promoter basal activity by 85-88% in GH3 cells in the presence or absence of FGF
      4. Additionally, expression of wild-type GABPalpha/beta1 selectively activates a
      minimal BTE promoter 24-28-fold in GH3 cells, and this activation is dependent on
      the Ets-binding site. Finally, small interfering RNA depletion of GABP in GH3
      cells results in the loss of prolactin protein. Thus, we have identified
      GABPalpha/GABPbeta1 as a critical and functionally relevant Ets factor that
      regulates rPRL promoter activity via the BTE site.

PMID- 12618436
TI  - Requirement of dimerization for RNA editing activity of adenosine deaminases
      acting on RNA.
AB  - Adenosine deaminases acting on RNA (ADAR) convert adenosine residues into
      inosines in double-stranded RNA. Three vertebrate ADAR gene family members,
      ADAR1, ADAR2, and ADAR3, have been identified. The catalytic domain of all three
      ADAR gene family members is very similar to that of Escherichia coli cytidine
      deaminase and APOBEC-1. Homodimerization is essential for the enzyme activity of
      those cytidine deaminases. In this study, we investigated the formation of
      complexes between differentially epitope-tagged ADAR monomers by sequential
      affinity chromatography and size exclusion column chromatography. Both ADAR1 and
      ADAR2 form a stable enzymatically active homodimer complex, whereas ADAR3 remains
      as a monomeric, enzymatically inactive form. No heterodimer complex formation
      among different ADAR gene family members was detected. Analysis of HeLa and mouse
      brain nuclear extracts suggested that endogenous ADAR1 and ADAR2 both form a
      homodimer complex. Interestingly, endogenous ADAR3 also appears to form a
      homodimer complex, indicating the presence of a brain-specific mechanism for
      ADAR3 dimerization. Homodimer formation may be necessary for ADAR to act as
      active deaminases. Analysis of dimer complexes consisting of one wild-type and
      one mutant monomer suggests functional interactions between the two subunits
      during site-selective RNA editing.

PMID- 12618437
TI  - Crystal structures of 4-alpha-glucanotransferase from Thermococcus litoralis and
      its complex with an inhibitor.
AB  - Thermococcus litoralis 4-alpha-glucanotransferase (TLGT) belongs to glucoside
      hydrolase family 57 and catalyzes the disproportionation of amylose and the
      formation of large cyclic alpha-1,4-glucan (cycloamylose) from linear amylose. We
      determined the crystal structure of TLGT with and without an inhibitor, acarbose.
      TLGT is composed of two domains: an N-terminal domain (domain I), which contains
      a (beta/alpha)7 barrel fold, and a C-terminal domain (domain II), which has a
      twisted beta-sandwich fold. In the structure of TLGT complexed with acarbose, the
      inhibitor was bound at the cleft within domain I, indicating that domain I is a
      catalytic domain of TLGT. The acarbose-bound structure also clarified that Glu123
      and Asp214 were the catalytic nucleophile and acid/base catalyst, respectively,
      and revealed the residues involved in substrate binding. It seemed that TLGT
      produces large cyclic glucans by preventing the production of small cyclic
      glucans by steric hindrance, which is achieved by three lids protruding into the
      active site cleft, as well as an extended active site cleft. Interestingly,
      domain I of TLGT shares some structural features with the catalytic domain of
      Golgi alpha-mannosidase from Drosophila melanogaster, which belongs to glucoside
      hydrolase family 38. Furthermore, the catalytic residue of the two enzymes is
      located in the same position. These observations suggest that families 57 and 38
      evolved from a common ancestor.

PMID- 12618438
TI  - Domain architectures of sigma54-dependent transcriptional activators.

PMID- 12618439
TI  - Roles of the enantioselective glutathione S-transferases in cleavage of beta-aryl
      ether.
AB  - Cleavage of the beta-aryl ether linkage is the most important process in lignin
      degradation. Here we characterize the three tandemly located glutathione S
      transferase (GST) genes, ligF, ligE, and ligG, from low-molecular-weight lignin
      degrading Sphingomonas paucimobilis SYK-6, and we describe the actual roles of
      these genes in the beta-aryl ether cleavage. Based on the identification of the
      reaction product by electrospray ionization-mass spectrometry, a model compound
      of beta-aryl ether, alpha-(2-methoxyphenoxy)-beta-hydroxypropiovanillone (MPHPV),
      was transformed by LigF or LigE to guaiacol and alpha-glutathionyl-beta
      hydroxypropiovanillone (GS-HPV). This result suggested that LigF and LigE
      catalyze the nucleophilic attack of glutathione on the carbon atom at the beta
      position of MPHPV. High-pressure liquid chromatography-circular dichroism
      analysis indicated that LigF and LigE each attacked a different enantiomer of the
      racemic MPHPV preparation. The ligG gene product specifically catalyzed the
      elimination of glutathione from GS-HPV generated by the action of LigF. This
      reaction then produces an achiral compound, beta-hydroxypropiovanillone, which is
      further degraded by this strain. Disruption of the ligF, ligE, and ligG genes in
      SYK-6 showed that ligF is essential to the degradation of one of the MPHPV
      enantiomers, and the alternative activities which metabolize the substrates of
      LigE and LigG are present in this strain.

PMID- 12618440
TI  - Uptake of N,N'-diacetylchitobiose [(GlcNAc)2] via the phosphotransferase system
      is essential for chitinase production by Serratia marcescens 2170.
AB  - The chiR gene of Serratia marcescens 2170, encoding a LysR-type transcriptional
      activator, was identified previously as an essential factor for expression of
      chitinases and a chitin-binding protein, CBP21. To identify other genes that are
      essential for chitinase production, transposon mutagenesis with mini-Tn5Km1 was
      carried out, and 25 mutants that were unable to produce chitinases and CBP21 were
      obtained. Analysis of the mutated gene of one of the mutants, N22, revealed the
      presence of a pts operon in this bacterium, and a mutation was found in ptsI in
      the operon. In addition to its inability to produce chitinase, N22 did not grow
      well on N-acetyl-D-glucosamine (GlcNAc), (GlcNAc)(2), and some other carbon
      sources, most of which were phosphotransferase system (PTS) sugars. Thus, the
      inability to produce chitinase was assumed to be caused by the defect in uptake
      of (GlcNAc)(2) via the PTS, considering that (GlcNAc)(2) is the minimal substrate
      for chitinase induction and the major product of chitin hydrolysis by chitinases
      of this bacterium. To confirm this assumption, the chb operon, encoding the
      (GlcNAc)(2)-specific enzyme II permease, was cloned by reference to its
      Escherichia coli counterpart, and the Serratia chb operon was shown to comprise
      chbB, chbC, bglA, chbR, and chbG. Disruption of chbC drastically reduced
      production of chitinases and CBP21 and impaired growth on colloidal chitin. These
      results indicate that uptake of (GlcNAc)(2) is mediated by the PTS and that the
      (GlcNAc)(2)-specific enzyme II permease constitutes its major pathway. Since
      (GlcNAc)(2) uptake is essential for induction of chitinases and CBP21 production,
      (GlcNAc)(2) appears to be the key molecule in recognition and utilization of
      chitin by S. marcescens.

PMID- 12618441
TI  - The activator of GntII genes for gluconate metabolism, GntH, exerts negative
      control of GntR-regulated GntI genes in Escherichia coli.
AB  - Gluconate is one of the preferred carbon sources of Escherichia coli, and two
      sets of gnt genes (encoding the GntI and GntII systems) are involved in its
      transport and metabolism. GntR represses the GntI genes gntKU and gntT, whereas
      GntH was previously suggested to be an activator for the GntII genes gntV and
      idnDO-gntWH. The helix-turn-helix residues of the two regulators GntR and GntH
      exhibit extensive homologies. The similarity between the two regulators prompted
      analysis of the cross-regulation of the GntI genes by GntH. Repression of gntKU
      and gntT by GntH, as well as GntR, was indeed observed using transcriptional
      fusions and RNA analysis. High GntH expression, from cloned gntH or induced
      through 5-ketogluconate, was required to observe repression of GntI genes. Two
      GntR-binding elements were identified in the promoter-operator region of gntKU
      and were also shown to be the target sites of GntH by mutational analysis.
      However, the GntI genes were not induced by gluconate in the presence of enhanced
      amounts of GntH, whereas repression by GntR was relieved by gluconate. The
      repression of GntI genes by GntH is thus unusual in that it is not relieved by
      the availability of substrate. These results led us to propose that GntH
      activates GntII and represses the GntI genes in the presence of metabolites
      derived from gluconate, allowing the organism to switch from the GntI to the
      GntII system. This cross-regulation may explain the progressive changes in gnt
      gene expression along with phases of cell growth in the presence of gluconate.

PMID- 12618443
TI  - The Escherichia coli mazEF suicide module mediates thymineless death.
AB  - In 1954, Cohen and Barner discovered that a thymine auxotrophic (thyA) mutant of
      Escherichia coli undergoes cell death in response to thymine starvation. This
      phenomenon, called thymineless death (TLD), has also been found in many other
      organisms, including prokaryotes and eukaryotes. Though TLD has been studied
      intensively, its molecular mechanism has not yet been explained. Previously we
      reported on the E. coli mazEF system, a regulatable chromosomal suicide module
      that can be triggered by various stress conditions. MazF is a stable toxin, and
      MazE is an unstable antitoxin. Here, we show that cell death that is mediated by
      the mazEF module can also be activated by thymine starvation. We found that TLD
      depends on E. coli mazEF and that under thymine starvation, the activity of the
      mazEF promoter P(2) is significantly reduced. Our results, which describe thymine
      starvation as a trigger for a built-in death program, have implications for
      programmed cell death in both prokaryotes and eukaryotes.

PMID- 12618442
TI  - The FecI extracytoplasmic-function sigma factor of Escherichia coli interacts
      with the beta' subunit of RNA polymerase.
AB  - Transcription of the ferric citrate transport system of Escherichia coli K-12 is
      mediated by the extracytoplasmic-function (ECF) sigma factor FecI, which is
      activated by ferric citrate in the growth medium. By using a bacterial two-hybrid
      system, it was shown in vivo that FecI binds to the beta' subunit of RNA
      polymerase. The inactive mutant protein FecI(K155E) displayed reduced binding to
      beta', and small deletions along the entire FecI protein led to total impairment
      of beta' binding. In vitro, FecI was retained on Ni(2+)-nitrilotriacetic acid
      agarose loaded with a His-tagged beta'(1-313) fragment and coeluted with beta'(1
      313). Binding of FecI to beta' and beta'(1-313) was enhanced by FecR(1-85), which
      represents the cytoplasmic portion of the FecR protein that transmits the
      inducing signal across the cytoplasmic membrane. Interaction of FecR with FecI
      was demonstrated by showing that isolated FecR inhibited degradation of FecI by
      trypsin. This is the first demonstration of binding of an ECF sigma factor of the
      FecI type to the beta' subunit of RNA polymerase and of binding being enhanced by
      the protein that activates the ECF sigma factor.

PMID- 12618444
TI  - Purification and in vitro characterization of the Serratia marcescens NucC
      protein, a zinc-binding transcription factor homologous to P2 Ogr.
AB  - NucC is structurally and functionally homologous to a family of prokaryotic zinc
      finger transcription factors required for late gene expression in P2- and P4
      related bacteriophages. Characterization of these proteins in vitro has been
      hampered by their relative insolubility and tendency to aggregate. We report here
      the successful purification of soluble, active, wild-type NucC protein. Purified
      NucC exhibits site-specific binding to a conserved DNA sequence that is located
      upstream of NucC-dependent Serratia marcescens promoters and the late promoters
      of P2-related phages. This sequence is sufficient for binding of NucC in vitro.
      NucC binding to the S. marcescens nuclease promoter P(nucA) and to the sequence
      upstream of the P2 late promoter P(F) is accompanied by DNA bending. NucC
      protects about 25 nucleotides of the P(F) upstream region from DNase I digestion,
      and RNA polymerase protects the promoter region only in the presence of NucC.
      Template DNA, RNA polymerase holoenzyme, and purified NucC are the only
      macromolecular components required for transcription from P(F) in vitro.

PMID- 12618445
TI  - Identification of a novel membrane-associated gene product that suppresses
      toxicity of a TrfA peptide from plasmid RK2 and its relationship to the DnaA host
      initiation protein.
AB  - The toxicity of a peptide derived from the amino-terminal portion of 33-kDa TrfA,
      one of the initiation proteins encoded by the broad-host-range plasmid RK2, was
      suppressed by a host protein related to DnaA, the initiation protein of
      Escherichia coli. The newly identified 28.4-kDa protein, termed a DnaA paralog
      (Dp) because it is similar to a region of DnaA but likely has a different
      function in initiation of plasmid RK2 replication, interacts physically with the
      33-kDa TrfA initiation protein, including the initiation-active monomeric form.
      The Dp has a cellular distribution similar to that of the 33-kDa TrfA initiation
      protein, being found primarily in the inner membrane fraction, with lesser
      amounts detected in the outer membrane fraction and almost none in the soluble
      fraction of E. coli. Maintenance and inner membrane-associated replication of
      plasmid RK2 were enhanced in a Dp knockout strain and inhibited in strains
      containing extra copies of the Dp gene or in membrane extracts to which a tagged
      form of Dp was added. Recently, the Dp was independently shown to help prevent
      overinitiation in E. coli and was termed Hda (S. Kato and T. Katayama, EMBO J.
      20:4253-4262, 2001).

PMID- 12618446
TI  - tmRNA in Caulobacter crescentus is cell cycle regulated by temporally controlled
      transcription and RNA degradation.
AB  - SsrA, or tmRNA, is a small RNA found in all bacteria that intervenes in selected
      translation reactions to target the nascent polypeptide for rapid proteolysis. We
      have found that the abundance of SsrA RNA in Caulobacter crescentus is regulated
      with respect to the cell cycle. SsrA RNA abundance increases in late G(1) phase,
      peaks during the G(1)-S transition, and declines in early S phase, in keeping
      with the reported role for SsrA in the timing of DNA replication initiation. Cell
      cycle regulation of SsrA RNA is accomplished by a combination of temporally
      controlled transcription and regulated RNA degradation. Transcription from the
      ssrA promoter peaks late in G(1), just before the peak in SsrA RNA abundance.
      SsrA RNA is stable in G(1)-phase cells and late S-phase cells but is degraded
      with a half-life of 4 to 5 min at the onset of S phase. This degradation is
      surprising, since SsrA RNA is both highly structured and highly abundant. This is
      the first observation of a structural RNA that is cell cycle regulated.

PMID- 12618448
TI  - A Rhizobium leguminosarum AcpXL mutant produces lipopolysaccharide lacking 27
      hydroxyoctacosanoic acid.
AB  - The structure of the lipid A from Rhizobium etli and Rhizobium leguminosarum
      lipopolysaccharides (LPSs) lacks phosphate and contains a galacturonosyl residue
      at its 4' position, an acylated 2-aminogluconate in place of the proximal
      glucosamine, and a very long chain omega-1 hydroxy fatty acid, 27
      hydroxyoctacosanoic acid (27OHC28:0). The 27OHC28:0 moiety is common in lipid A's
      among members of the Rhizobiaceae and also among a number of the facultative
      intracellular pathogens that form chronic infections, e.g., Brucella abortus,
      Bartonella henselae, and Legionella pneumophila. In this paper, a mutant of R.
      leguminosarum was created by placing a kanamycin resistance cassette within
      acpXL, the gene which encodes the acyl carrier protein for 27OHC28:0. The result
      was an LPS containing a tetraacylated lipid A lacking 27OHC28:0. A small amount
      of the mutant lipid A may contain an added palmitic acid residue. The mutant is
      sensitive to changes in osmolarity and an increase in acidity, growth conditions
      that likely occur in the nodule microenvironment. In spite of the probably
      hostile microenvironment of the nodule, the acpXL mutant is still able to form
      nitrogen-fixing root nodules even though the appearance and development of
      nodules are delayed. Therefore, it is possible that the acpXL mutant has a host
      inducible mechanism which enables it to adapt to these physiological changes.

PMID- 12618447
TI  - Analysis of genome plasticity in pathogenic and commensal Escherichia coli
      isolates by use of DNA arrays.
AB  - Genomes of prokaryotes differ significantly in size and DNA composition.
      Escherichia coli is considered a model organism to analyze the processes involved
      in bacterial genome evolution, as the species comprises numerous pathogenic and
      commensal variants. Pathogenic and nonpathogenic E. coli strains differ in the
      presence and absence of additional DNA elements contributing to specific
      virulence traits and also in the presence and absence of additional genetic
      information. To analyze the genetic diversity of pathogenic and commensal E. coli
      isolates, a whole-genome approach was applied. Using DNA arrays, the presence of
      all translatable open reading frames (ORFs) of nonpathogenic E. coli K-12 strain
      MG1655 was investigated in 26 E. coli isolates, including various extraintestinal
      and intestinal pathogenic E. coli isolates, 3 pathogenicity island deletion
      mutants, and commensal and laboratory strains. Additionally, the presence of
      virulence-associated genes of E. coli was determined using a DNA "pathoarray"
      developed in our laboratory. The frequency and distributional pattern of genomic
      variations vary widely in different E. coli strains. Up to 10% of the E. coli K
      12-specific ORFs were not detectable in the genomes of the different strains. DNA
      sequences described for extraintestinal or intestinal pathogenic E. coli are more
      frequently detectable in isolates of the same origin than in other pathotypes.
      Several genes coding for virulence or fitness factors are also present in
      commensal E. coli isolates. Based on these results, the conserved E. coli core
      genome is estimated to consist of at least 3,100 translatable ORFs. The absence
      of K-12-specific ORFs was detectable in all chromosomal regions. These data
      demonstrate the great genome heterogeneity and genetic diversity among E. coli
      strains and underline the fact that both the acquisition and deletion of DNA
      elements are important processes involved in the evolution of prokaryotes.

PMID- 12618449
TI  - Comprehensive studies of drug resistance mediated by overexpression of response
      regulators of two-component signal transduction systems in Escherichia coli.
AB  - In Escherichia coli, there are 32 open reading frames (ORFs) that are assumed to
      be response regulator genes of two-component signal transduction systems on the
      basis of sequence similarities. We cloned all of these 32 ORFs into a multicopy
      expression vector and investigated whether or not they confer drug resistance via
      control of drug resistance determinants. Fifteen of these ORFs, i.e., baeR, citB,
      cpxR, evgA, fimZ, kdpE, narL, narP, ompR, rcsB, rstA, torR, yedW, yehT, and dcuR,
      conferred increased single- or multidrug resistance. Two-thirds of them conferred
      deoxycholate resistance. Five of them, i.e., evgA, baeR, ompR, cpxR, and rcsB,
      modulated the expression of several drug exporter genes. The drug resistance
      mediated by evgA, baeR, and cpxR could be assigned to drug exporters by using
      drug exporter gene knockout strains.

PMID- 12618450
TI  - Novel genomic rearrangement that affects expression of the Streptococcus pyogenes
      streptolysin O (slo) gene.
AB  - A RecA-independent chromosomal rearrangement in the upstream region of the
      streptolysin O (slo) gene of Streptococcus pyogenes which affects slo expression
      was identified. PCR analysis was used to demonstrate that this kind of
      rearrangement was found in several strains of different lineages. Chromosomal
      loci involved in the recombination were found to be 746 kb apart on the 1.85-Mb
      long chromosome. The primary structure of the splicing region, the
      reproducibility of the rearrangement, and the fact that reconstructed recombinant
      molecules fused to erm and lacZ reporter genes affected their expression indicate
      that this event is not accidental but may play a role in the expression of the
      slo gene. In addition, the product of the recombining DNAs, including the
      splicing site, does not follow any example of a known recombination mechanism.
      The implications of this rearrangement for slo expression are discussed.

PMID- 12618451
TI  - Interactions between the outer membrane ferric citrate transporter FecA and TonB:
      studies of the FecA TonB box.
AB  - Both induction of transcription of the ferric citrate transport genes and
      transport of ferric citrate by the Escherichia coli outer membrane receptor FecA
      require energy derived from the proton motive force (PMF) of the inner membrane.
      The energy is transduced to FecA by the inner membrane complex, TonB, ExbB, and
      ExbD. Region 160 of TonB and the conserved TonB box of other TonB-dependent
      receptors are implicated as sites of interaction. In the present study, the
      postulated TonB box (D(80)A(81)L(82)T(83)V(84)) of FecA was deleted in frame,
      with a subsequent loss of both FecA functions. DALTV of FecA could be
      functionally replaced with the core TonB boxes of FhuA (DTITV) and FepA (DTIVV).
      Each residue of the TonB box of FecA was sequentially replaced with cysteine
      residues, and only the D80C replacement showed a loss (reduction) of both FecA
      functions. A physical interaction between TonB and FecA was demonstrated using
      both in vivo site-specific disulfide bond cross-linking and nonspecific
      formaldehyde (FA) cross-linking. Pairwise combinations of FecA (DALTV)/Cys
      substitutions were cross-linked via disulfide bond formation with TonBQ160C,
      TonBQ162C, and TonBY163C. Unexpectedly, this cross-linking was not enhanced by
      substrate (ferric citrate). In contrast, the TonB-FecA interaction was enhanced
      by ferric citrate in the FA-cross-linking assay. Energy derived from the PMF was
      not required for the TonB-FecA interaction in either the disulfide- or FA-cross
      linking assay. TonB/CysExbB/ExbD(D25N) was still able to cross-link with the FecA
      (DALTV)/Cys derivatives in a tonB tolQ background, even though ExbD25N renders
      the TonB/ExbBD complex nonfunctional (V. Braun, S. Gaisser, C. Herrmann, K.
      Kampfenkel, H. Killmann, and I. Traub, J. Bacteriol. 178:2836-2845, 1996). TonB
      cross-linked to FecA via FA was not inhibited by either carbonylcyanide-m
      chlorophenylhydrazone or 1 mM 2,4-dinitrophenol, which dissipate the
      electrochemical potential of the cytoplasmic membrane and disrupt both FecA
      functions. The studies shown here demonstrate the significance of the TonB box
      for FecA functions and are consistent with the view that it is the structure and
      not the sequence of the TonB box that is important for activity. Demonstrated
      here for the first time is the physical interaction of TonB and FecA, which is
      enhanced by ferric citrate.

PMID- 12618452
TI  - Leucine-responsive regulatory protein-mediated repression of clp (encoding CS31A)
      expression by L-leucine and L-alanine in Escherichia coli.
AB  - CS31A produced by septicemic and diarrheic Escherichia coli belongs to the Pap
      regulatory family of adhesive factors, which are under methylation-dependent
      transcriptional regulation. Common features of operons encoding members of this
      family include two conserved GATC sites in the upstream regulatory region, and
      transcriptional regulators homologue to the PapB and PapI proteins. Methylation
      protection of GATC sites was previously shown to be dependent on the leucine
      responsive regulatory protein (Lrp). Lrp and ClpB, the PapB equivalent, repressed
      clp basal transcription. A PapI homologue (AfaF) was required together with Lrp
      to establish the phase variation control, which gave rise to phase-ON cells that
      expressed CS31A and phase-OFF cells that did not express CS31A. In phase-OFF
      cells, the GATC(dist) site was methylated and the GATC(prox) site was protected
      from methylation, whereas in phase-ON cells, the inverse situation was found.
      Unlike Pap fimbriae, CS31A synthesis was dramatically reduced in media containing
      L-alanine or L-leucine. L-Alanine prevented the OFF-to-ON switch, locking clp
      expression in the OFF phase, whereas L-leucine repressed transcription without
      obvious effect on the switch frequency of phase variation. In phase-variable
      cells, leucine and alanine promoted methylation of GATC(dist) and methylation
      protection of GATC(prox), increasing the methylation pattern characteristic of
      repressed cells. Furthermore, alanine prevented the AfaF-dependent methylation
      protection of GATC(dist) and thus the appearance of phase-ON cells. In addition,
      analysis of clp expression in a Lrp-negative background indicated that alanine
      and leucine also repressed clp transcription by a methylation-independent
      mechanism.

PMID- 12618453
TI  - Operon structure and regulation of the nos gene region of Pseudomonas stutzeri,
      encoding an ABC-Type ATPase for maturation of nitrous oxide reductase.
AB  - The synthesis of a functional nitrous oxide reductase requires an assembly
      apparatus for the insertion of the prosthetic copper. Part of the system is
      encoded by maturation genes located in Pseudomonas stutzeri immediately
      downstream of the structural gene for the enzyme. We have studied the
      transcriptional organization and regulation of this region and found a nosDFYL
      tatE operon structure. In addition to a putative ABC transporter, consisting of
      NosD, NosF, and NosY, the operon encodes a Cu chaperone, NosL, and a component of
      the Tat translocon, TatE. The nosD operon was activated in response to
      anaerobiosis and nitrate denitrification. The membrane-bound regulator NosR was
      required for operon expression; in addition, DnrD, a regulator of the Crp-Fnr
      family, enhanced expression under anaerobic conditions. This establishes a likely
      signal transduction sequence of NO --> DnrD --> nosR/NosR --> nosD operon. DnrD
      dependent expression was also observed for the nnrS operon (located immediately
      downstream of the nosD operon), which encodes a putative heme-Cu protein (NnrS)
      and a member of the short-chain dehydrogenase family (ORF247). The NosF protein,
      encoded within the nosD operon, exhibits sequence similarity to ABC-type ATPases.
      It was fused to the Escherichia coli maltose-binding protein and overexpressed in
      soluble form. The fusion protein was purified and shown to have ATPase activity.
      NosF is the first maturation factor for which a catalytic function has been
      demonstrated in vitro.

PMID- 12618454
TI  - Identification of the immunodominant protein and other proteins of the Bacillus
      anthracis exosporium.
AB  - Spores of Bacillus anthracis, the causative agent of anthrax, are enclosed by a
      prominent loose-fitting, balloon-like layer called the exosporium. Although the
      exosporium serves as the source of surface antigens and a primary permeability
      barrier of the spore, its molecular structure and function are not well
      characterized. In this study, we identified five major proteins in purified B.
      anthracis (Sterne strain) exosporia. One protein was the recently identified
      collagen-like glycoprotein BclA, which appears to be a structural component of
      the exosporium hair-like nap. Using a large panel of unique antispore monoclonal
      antibodies, we demonstrated that BclA is the immunodominant antigen on the B.
      anthracis spore surface. We also showed that the BclA protein and not a
      carbohydrate constituent directs the dominant immune response. In addition, the
      length of the central (GXX)(n) repeat region of BclA appears to be strain
      specific. Two other unique proteins, BxpA and BxpB, were identified. BxpA is
      unusually rich in Gln and Pro residues and contains several different tandem
      repeats, which also exhibit strain-specific variation. In addition, BxpA was
      found to be cleaved approximately in half. BxpB appears to be glycosylated or
      associated with glycosylated material and is encoded by a gene that (along with
      bclA) may be part of an exosporium genomic island. The other two proteins
      identified were alanine racemase and superoxide dismutase, both of which were
      reported to be associated with the surface of other Bacillus spores. Possible
      functions of the newly identified proteins are discussed.

PMID- 12618456
TI  - Design of antisense RNA constructs for downregulation of the acetone formation
      pathway of Clostridium acetobutylicum.
AB  - We investigated the effect of antisense RNA (asRNA) structural properties on the
      downregulation efficacy of enzymes in the acetone-formation pathway (acetoacetate
      decarboxylase [AADC] and coenzyme A-transferase [CoAT]) of Clostridium
      acetobutylicum strain ATCC 824. First, we generated three strains, C.
      acetobutylicum ATCC 824 (pADC38AS), 824(pADC68AS), and 824(pADC100AS), which
      contain plasmids that produce asRNAs of various lengths against the AADC (adc)
      transcript. Western analysis showed that all three strains exhibit low levels of
      AADC compared to the plasmid control [ATCC 824(pSOS95del)]. By using
      computational algorithms, the three different asRNAs directed toward AADC, along
      with previously reported clostridial asRNAs, were examined for structural
      features (free nucleotides and components). When the normalized metrics of these
      structural features were plotted against percent downregulation, only the
      component/nucleotide ratio correlated well with in vivo asRNA effectiveness.
      Despite the significant downregulation of AADC in these strains, there were no
      concomitant effects on acetone formation. These findings suggest that AADC does
      not limit acetone formation and, thus, we targeted next the CoAT. Using the
      component/nucleotide ratio as a selection parameter, we developed three strains
      [ATCC 824 (pCTFA2AS), 824(pCTFB1AS), and 824(pCOAT11AS)] which express asRNAs to
      downregulate either or both of the CoAT subunits. Compared to the plasmid control
      strain, these strains produced substantially low levels of acetone and butanol
      and Western blot analyses showed significantly low levels of both CoAT subunits.
      These results show that CoAT is the rate-limiting enzyme in acetone formation and
      strengthen the hypothesis that the component/nucleotide ratio is a predictive
      indicator of asRNA effectiveness.

PMID- 12618455
TI  - Additional targets of the Bacillus subtilis global regulator CodY identified by
      chromatin immunoprecipitation and genome-wide transcript analysis.
AB  - Additional targets of CodY, a GTP-activated repressor of early stationary-phase
      genes in Bacillus subtilis, were identified by combining chromatin
      immunoprecipitation, DNA microarray hybridization, and gel mobility shift assays.
      The direct targets of CodY newly identified by this approach included regulatory
      genes for sporulation, genes that are likely to encode transporters for amino
      acids and sugars, and the genes for biosynthesis of branched-chain amino acids.

PMID- 12618457
TI  - Mutational analysis of the residue at position 48 in the Salmonella enterica
      Serovar Typhimurium PhoQ sensor kinase.
AB  - The PhoP/PhoQ two-component regulatory system of Salmonella enterica serovar
      Typhimurium plays an essential role in controlling virulence by mediating the
      adaptation to Mg(2+) depletion. The pho-24 allele of phoQ harbors a single amino
      acid substitution (T48I) in the periplasmic domain of the PhoQ histidine kinase
      sensor. This mutation has been shown to increase net phosphorylation of the PhoP
      response regulator. We analyzed the effect on signaling by PhoP/PhoQ of various
      amino acid substitutions at this position (PhoQ-T48X [X = A, S, V, I, or L]).
      Mutations T48V, T48I, and T48L were found to affect signaling by PhoP/PhoQ both
      in vivo and in vitro. Mutations PhoQ-T48V and PhoQ-T48I increased both the
      expression of the mgtA::lacZ transcriptional fusion and the net phosphorylation
      of PhoP, conferring to cells a PhoP constitutively active phenotype. In contrast,
      mutation PhoQ-T48L barely responded to changes in the concentration of external
      Mg(2+), in vivo and in vitro, conferring to cells a PhoP constitutively inactive
      phenotype. By analyzing in vitro the individual catalytic activities of the PhoQ
      T48X sensors, we found that the PhoP constitutively active phenotype observed for
      the PhoQ-T48V and PhoQ-T48I proteins is solely due to decreased phosphatase
      activity. In contrast, the PhoP constitutively inactive phenotype observed for
      the PhoQ-T48L mutant resulted from both decreased autokinase activity and
      increased phosphatase activity. Our data are consistent with a model in which the
      residue at position 48 of PhoQ contributes to a conformational switch between
      kinase- and phosphatase-dominant states.

PMID- 12618458
TI  - High levels of intracellular cysteine promote oxidative DNA damage by driving the
      fenton reaction.
AB  - Escherichia coli is generally resistant to H(2)O(2), with >75% of cells surviving
      a 3-min challenge with 2.5 mM H(2)O(2). However, when cells were cultured with
      poor sulfur sources and then exposed to cystine, they transiently exhibited a
      greatly increased susceptibility to H(2)O(2), with <1% surviving the challenge.
      Cell death was due to an unusually rapid rate of DNA damage, as indicated by
      their filamentation, a high rate of mutation among the survivors, and DNA lesions
      by a direct assay. Cell-permeable iron chelators eliminated sensitivity,
      indicating that intracellular free iron mediated the conversion of H(2)O(2) into
      a hydroxyl radical, the direct effector of DNA damage. The cystine treatment
      caused a temporary loss of cysteine homeostasis, with intracellular pools
      increasing about eightfold. In vitro analysis demonstrated that cysteine reduces
      ferric iron with exceptional speed. This action permits free iron to redox cycle
      rapidly in the presence of H(2)O(2), thereby augmenting the rate at which
      hydroxyl radicals are formed. During routine growth, cells maintain small
      cysteine pools, and cysteine is not a major contributor to DNA damage. Thus, the
      homeostatic control of cysteine levels is important in conferring resistance to
      oxidants. More generally, this study provides a new example of a situation in
      which the vulnerability of cells to oxidative DNA damage is strongly affected by
      their physiological state.

PMID- 12618459
TI  - Identification of catabolite repression as a physiological regulator of biofilm
      formation by Bacillus subtilis by use of DNA microarrays.
AB  - Biofilms are structured communities of cells that are encased in a self-produced
      polymeric matrix and are adherent to a surface. Many biofilms have a significant
      impact in medical and industrial settings. The model gram-positive bacterium
      Bacillus subtilis has recently been shown to form biofilms. To gain insight into
      the genes involved in biofilm formation by this bacterium, we used DNA
      microarrays representing >99% of the annotated B. subtilis open reading frames to
      follow the temporal changes in gene expression that occurred as cells
      transitioned from a planktonic to a biofilm state. We identified 519 genes that
      were differentially expressed at one or more time points as cells transitioned to
      a biofilm. Approximately 6% of the genes of B. subtilis were differentially
      expressed at a time when 98% of the cells in the population were in a biofilm.
      These genes were involved in motility, phage-related functions, and metabolism.
      By comparing the genes differentially expressed during biofilm formation with
      those identified in other genomewide transcriptional-profiling studies, we were
      able to identify several transcription factors whose activities appeared to be
      altered during the transition from a planktonic state to a biofilm. Two of these
      transcription factors were Spo0A and sigma-H, which had previously been shown to
      affect biofilm formation by B. subtilis. A third signal that appeared to be
      affecting gene expression during biofilm formation was glucose depletion. Through
      quantitative biofilm assays and confocal scanning laser microscopy, we observed
      that glucose inhibited biofilm formation through the catabolite control protein
      CcpA.

PMID- 12618460
TI  - Molecular analysis of the multiple GroEL proteins of Chlamydiae.
AB  - Genome sequencing revealed that all six chlamydiae genomes contain three groEL
      like genes (groEL1, groEL2, and groEL3). Phylogenetic analysis of groEL1, groEL2,
      and groEL3 indicates that these genes are likely to have been present in
      chlamydiae since the beginning of the lineage. Comparison of deduced amino acid
      sequences of the three groEL genes with those of other organisms showed high
      homology only for groEL1, although comparison of critical amino acid residues
      that are required for polypeptide binding of the Escherichia coli chaperonin
      GroEL revealed substantial conservation in all three chlamydial GroELs. This was
      further supported by three-dimensional structural predictions. All three genes
      are expressed constitutively throughout the developmental cycle of Chlamydia
      trachomatis, although groEL1 is expressed at much higher levels than are groEL2
      and groEL3. Transcription of groEL1, but not groEL2 and groEL3, was elevated when
      HeLa cells infected with C. trachomatis were subjected to heat shock. Western
      blot analysis with polyclonal antibodies raised against recombinant GroEL1,
      GroEL2, and GroEL3 demonstrated the presence of the three proteins in C.
      trachomatis elementary bodies, with GroEL1 being present in the largest amount.
      Only C. trachomatis groEL1 and groES together complemented a temperature
      sensitive E. coli groEL mutant. Complementation did not occur with groEL2 or
      groEL3 alone or together with groES. The role for each of the three GroELs in the
      chlamydial developmental cycle and in disease pathogenesis requires further
      study.

PMID- 12618461
TI  - Global characterization of disulfide stress in Bacillus subtilis.
AB  - We used DNA macroarray and proteome analysis to analyze the regulatory networks
      in Bacillus subtilis that are affected by disulfide stress. To induce disulfide
      stress, we used the specific thiol oxidant diamide. After addition of 1 mM
      diamide to an exponentially growing culture, cell growth stopped until the medium
      was cleared of diamide. Global analysis of the mRNA expression pattern during
      growth arrest revealed 350 genes that were induced by disulfide stress by greater
      than threefold. Strongly induced genes included known oxidative stress genes that
      are under the control of the global repressor PerR and heat shock genes
      controlled by the global repressor CtsR. Other genes that were strongly induced
      encode putative regulators of gene expression and proteins protecting against
      toxic elements and heavy metals. Many genes were substantially repressed by
      disulfide stress, among them most of the genes belonging to the negative
      stringent response. Two-dimensional gels of radioactively labeled protein
      extracts allowed us to visualize and quantitate the massive changes in the
      protein expression pattern that occurred in response to disulfide stress. The
      observed dramatic alteration in the protein pattern reflected the changes found
      in the transcriptome experiments. The response to disulfide stress seems to be a
      complex combination of different regulatory networks, indicating that redox
      sensing cysteines play a key role in different signaling pathways sensing
      oxidative stress, heat stress, toxic element stress, and growth inhibition.

PMID- 12618462
TI  - Sequence of the 165-kilobase catabolic plasmid pAO1 from Arthrobacter
      nicotinovorans and identification of a pAO1-dependent nicotine uptake system.
AB  - The 165-kb catabolic plasmid pAO1 enables the gram-positive soil bacterium
      Arthrobacter nicotinovorans to grow on the tobacco alkaloid L-nicotine. The
      165,137-nucleotide sequence, with an overall G+C content of 59.7%, revealed,
      besides genes and open reading frames (ORFs) for nicotine degradation, a complete
      set of ORFs for enzymes essential for the biosynthesis of the molybdenum
      dinucleotide cofactor, as well as ORFs related to uptake and utilization of
      carbohydrates, sarcosine, and amino acids. Of the 165 ORFs, approximately 50%
      were related to metabolic functions. pAO1 conferred to A. nicotinovorans the
      ability to take up L-[(14)C]nicotine from the medium, with an K(m) of 5.6 +/- 2.2
      micro M. ORFs of putative nicotine transporters formed a cluster with the gene of
      the D-nicotine-specific 6-hydroxy-D-nicotine oxidase. ORFs related to
      replication, chromosome partitioning, and natural transformation functions (dprA)
      were identified on pAO1. Few ORFs showed similarity to known conjugation
      promoting proteins, but pAO1 could be transferred by conjugation to a pAO1
      negative strain at a rate of 10(-2) to 10(-3) per donor. ORFs with no known
      function represented approximately 35% of the pAO1 sequence. The positions of
      insertion sequence elements and composite transposons, corroborated by the G+C
      content of the pAO1 sequence, suggest a modular composition of the plasmid.

PMID- 12618463
TI  - Mass distribution and spatial organization of the linear bacterial motor of
      Spiroplasma citri R8A2.
AB  - In the simple, helical, wall-less bacterial genus Spiroplasma, chemotaxis and
      motility are effected by a linear, contractile motor arranged as a flat
      cytoskeletal ribbon attached to the inner side of the membrane along the shortest
      helical line. With scanning transmission electron microscopy and diffraction
      analysis, we determined the hierarchical and spatial organization of the
      cytoskeleton of Spiroplasma citri R8A2. The structural unit appears to be a
      fibril, approximately 5 nm wide, composed of dimers of a 59-kDa protein; each
      ribbon is assembled from seven fibril pairs. The functional unit of the intact
      ribbon is a pair of aligned fibrils, along which pairs of dimers form tetrameric
      ring-like repeats. On average, isolated and purified ribbons contain 14 fibrils
      or seven well-aligned fibril pairs, which are the same structures observed in the
      intact cell. Scanning transmission electron microscopy mass analysis and sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis of purified cytoskeletons
      indicate that the 59-kDa protein is the only constituent of the ribbons.

PMID- 12618464
TI  - Identification and biosynthesis of cyclic enterobacterial common antigen in
      Escherichia coli.
AB  - Phosphoglyceride-linked enterobacterial common antigen (ECA(PG)) is a cell
      surface glycolipid that is synthesized by all gram-negative enteric bacteria. The
      carbohydrate portion of ECA(PG) consists of linear heteropolysaccharide chains
      comprised of the trisaccharide repeat unit Fuc4NAc-ManNAcA-GlcNAc, where Fuc4NAc
      is 4-acetamido-4,6-dideoxy-D-galactose, ManNAcA is N-acetyl-D-mannosaminuronic
      acid, and GlcNAc is N-acetyl-D-glucosamine. The potential reducing terminal
      GlcNAc residue of each polysaccharide chain is linked via phosphodiester linkage
      to a phosphoglyceride aglycone. We demonstrate here the occurrence of a water
      soluble cyclic form of enterobacterial common antigen, ECA(CYC), purified from
      Escherichia coli strains B and K-12 with solution nuclear magnetic resonance
      (NMR) spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and
      additional biochemical methods. The ECA(CYC) molecules lacked an aglycone and
      contained four trisaccharide repeat units that were nonstoichiometrically
      substituted with up to four O-acetyl groups. ECA(CYC) was not detected in mutant
      strains that possessed null mutations in the wecA, wecF, and wecG genes of the
      wec gene cluster. These observations corroborate the structural data obtained by
      NMR and ESI-MS analyses and show for the first time that the trisaccharide repeat
      units of ECA(CYC) and ECA(PG) are assembled by a common biosynthetic pathway.

PMID- 12618465
TI  - The membrane domain of SpoIIIE is required for membrane fusion during Bacillus
      subtilis sporulation.
AB  - During Bacillus subtilis sporulation, SpoIIIE is required for both
      postseptational chromosome segregation and membrane fusion after engulfment. Here
      we demonstrate that SpoIIIE must be present in the mother cell to promote
      membrane fusion and that the N-terminal membrane-spanning segments constitute a
      minimal membrane fusion domain, as well as direct septal localization.

PMID- 12618466
TI  - Gene expression profile of Campylobacter jejuni in response to growth temperature
      variation.
AB  - The foodborne pathogen Campylobacter jejuni is the primary causative agent of
      gastroenteritis in humans. In the present study a whole genome microarray of C.
      jejuni was constructed and validated. These DNA microarrays were used to measure
      changes in transcription levels over time, as C. jejuni cells responded to a
      temperature increase from 37 to 42 degrees C. Approximately 20% of the C. jejuni
      genes were significantly up- or downregulated over a 50-min period after the
      temperature increase. The global change in C. jejuni transcriptome was found to
      be essentially transient, with only a small subset of genes still differentially
      expressed after 50 min. A substantial number of genes with a downregulated
      coexpression pattern were found to encode for ribosomal proteins. This suggests a
      short growth arrest upon temperature stress, allowing the bacteria to reshuffle
      their energy toward survival and adaptation to the new growth temperature. Genes
      encoding chaperones, chaperonins, and heat shock proteins displayed the most
      dramatic and rapid upregulation immediately after the temperature change.
      Interestingly, genes encoding proteins involved in membrane structure
      modification were differentially expressed, either up- or downregulated,
      suggesting a different protein membrane makeup at the two different growth
      temperatures. Overall, these data provide new insights into the primary response
      of C. jejuni to surmount a sudden temperature upshift, allowing the bacterium to
      survive and adapt its transcriptome to a new steady state.

PMID- 12618468
TI  - Plasmid R16 ArdA protein preferentially targets restriction activity of the type
      I restriction-modification system EcoKI.
AB  - The ArdA antirestriction protein of the IncB plasmid R16 selectively inhibited
      the restriction activity of EcoKI, leaving significant levels of modification
      activity under conditions in which restriction was almost completely prevented.
      The results are consistent with the hypothesis that ArdA functions in bacterial
      conjugation to allow an unmodified plasmid to evade restriction in the recipient
      bacterium and yet acquire cognate modification.

PMID- 12618467
TI  - Definition of the Escherichia coli MC4100 genome by use of a DNA array.
AB  - We have used an Escherichia coli K-12 whole-genome array based on the DNA
      sequence of strain MG1655 as a tool to identify deletions in another E. coli K-12
      strain, MC4100, by probing the array with labeled chromosomal DNA. Despite the
      continued widespread use of MC4100 as an experimental system, the specific
      genetic relationship of this strain to the sequenced K-12 derivative MG1655 has
      not been resolved. MC4100 was found to contain four deletions, ranging from 1 to
      97 kb in size. The exact nature of three of the deletions was previously
      unresolved, and the fourth deletion was altogether unknown.

PMID- 12618469
TI  - Identification and functional characterization of Sphingomonas macrogolitabida
      strain TFA genes involved in the first two steps of the tetralin catabolic
      pathway.
AB  - Five genes involved in the two initial steps of the tetralin biodegradation
      pathway of Sphingomonas macrogolitabida strain TFA have been characterized.
      ThnA1A2 and ThnA3A4, components of the ring-hydroxylating dioxygenase, were
      encoded in divergently transcribed operons. ThnA1, ThnA2, and ThnA3 were
      essential for tetralin ring-hydroxylating dioxygenase activity. ThnB was
      identified as a dehydrogenase required for tetralin biodegradation.

PMID- 12618470
TI  - Measurement of adhesive forces between individual Staphylococcus aureus MSCRAMMs
      and protein-coated surfaces by use of optical tweezers.
AB  - The force required to rupture bonds between individual Staphylococcus aureus
      MSCRAMMs and surfaces coated with extracellular matrix molecules has been
      quantified by using optical tweezers. The observed binding forces between
      fibrinogen or fibronectin and S. aureus MSCRAMMs occurred as an approximate
      integer multiple of 20 or 25 pN, respectively.

PMID- 12618472
TI  - Effects of ISSo2 insertions in structural and regulatory genes of the
      trimethylamine oxide reductase of Shewanella oneidensis.
AB  - We have isolated three Shewanella oneidensis mutants specifically impaired in
      trimethylamine oxide (TMAO) respiration. The mutations arose from insertions of
      an ISSo2 element into torA, torR, and torS, encoding, respectively, the TMAO
      reductase TorA, the response regulator TorR, and the sensor TorS. Although TorA
      is not the sole enzyme reducing TMAO in S. oneidensis, growth analysis showed
      that it is the main respiratory TMAO reductase. Use of a plasmid-borne torE'-lacZ
      fusion confirmed that the TorS-TorR phosphorelay mediates TMAO induction of the
      torECAD operon.

PMID- 12618471
TI  - Excision and integration of cassettes by an integron integrase of Nitrosomonas
      europaea.
AB  - We found in the environmental strain Nitrosomonas europaea a chromosomal integron
      like structure with an integrase gene, intI(Neu). We have tested the capacity of
      the IntINeu integrase to excise and integrate several resistance gene cassettes.
      The results allow us to consider IntINeu a new functional integron integrase.

PMID- 12618473
TI  - Identification of an unknown promoter, OUTIIp, within the IS10R element.
AB  - A novel promoter in IS10R (OUTIIp) has been found in one of its ends in an
      inverted position relative to promoter pOUT. OUTIIp shows characteristics similar
      to those of rpoS-dependent promoters such as a gearbox expression pattern. It is
      under catabolite repression and positively regulated by ppGpp or conditioned
      media. This opens new challenges in IS10R transposition.

PMID- 12618475
TI  - Asynchronous differentiation models explain bone marrow labeling kinetics and
      predict reflux between the pre- and immature B cell pools.
AB  - B lymphopoiesis has historically been depicted as a unidirectional process, in
      which cohorts of developing cells transit through successive differentiative
      stages in an irreversible, synchronous manner. Here, we examine this view by
      combining kinetic analysis of developing B cell subsets in the bone marrow with
      mathematical modeling. Our bromo-deoxyuridine (BrdU) labeling data are
      incompatible with B cell development being a synchronous process, because
      labeling curves are non-linear. Moreover, we show that B cell development may not
      be completely unidirectional, because our results support the possibility of a
      phenotypic "reflux" among the immature to the pre-B cell subsets.

PMID- 12618474
TI  - Characterization of a novel fucose-regulated promoter (PfcsK) suitable for gene
      essentiality and antibacterial mode-of-action studies in Streptococcus
      pneumoniae.
AB  - The promoter of the Streptococcus pneumoniae putative fuculose kinase gene
      (fcsK), the first gene of a novel fucose utilization operon, is induced by fucose
      and repressed by glucose or sucrose. When the streptococcal polypeptide
      deformylase (PDF) gene (def1, encoding PDF) was placed under the control of
      P(fcsK), fucose-dependent growth of the S. pneumoniae (P(fcsK)::def1) strain was
      observed, confirming the essential nature of PDF in this organism. The mode of
      antibacterial action of actinonin, a known PDF inhibitor, was also confirmed with
      this strain. The endogenous fuculose kinase promoter is a tightly regulated,
      titratable promoter which will be useful for target validation and for
      confirmation of the mode of action of novel antibacterial drugs in S. pneumoniae.

PMID- 12618476
TI  - CD2BP3, CIN85 and the structurally related adaptor protein CMS bind to the same
      CD2 cytoplasmic segment, but elicit divergent functional activities.
AB  - Interaction trap cloning was used to identify a CD2 cytoplasmic tail-binding
      protein termed CD2BP3. CD2BP3 is the major RNA splice variant of the CIN85 locus
      in human T lymphocytes, lacking SH3A, the first of three SH3 domains found in
      CIN85, but retaining SH3B, SH3C, a proline-rich domain and C-terminal coiled
      coil. CD2BP3 has 35% amino acid identity to CMS, a structurally related protein
      binding to the same highly conserved segment of the CD2 tail and known to be
      involved in T cell polarization/cytoskeletal interactions. Unlike CMS, however,
      CD2BP3 does not co-localize with F-actin and binds p130(Cas) weakly, if at all.
      Moreover, CIN85/CD2BP3 proteins are readily degraded by TCR cross-linking,
      consistent with the presence of a PEST sequence C-terminal to SH3C. CIN85 SH3A
      and CIN85/CD2BP3 SH3B bind to proline-rich segments within CIN85/CD2BP3
      themselves as evidenced by mAb accessibility analysis and protein interaction
      studies including c-Cbl binding. This form of intramolecular regulation is not
      manifest by CMS. CMS and CIN85 activities are antagonistic, while the functions
      of CIN85 and CD2BP3 are also distinct. Thus, CD2-mediated adhesion, signaling and
      cell motility are regulated in a highly complex manner.

PMID- 12618477
TI  - Class I HLA oligomerization at the surface of B cells is controlled by exogenous
      beta(2)-microglobulin: implications in activation of cytotoxic T lymphocytes.
AB  - Submicroscopic molecular clusters (oligomers) of class I HLA have been detected
      by physical techniques [e.g. fluorescence resonance energy transfer (FRET) and
      single particle tracking of molecular diffusion] at the surface of various
      activated and transformed human cells, including B lymphocytes. Here, the
      sensitivity of this homotypic association to exogenous beta(2)-microglobulin
      (beta(2)m) and the role of free heavy chains (FHC) in class I HLA oligomerization
      were investigated on a B lymphoblastoid cell line, JY. Scanning near-field
      optical microscopy and FRET data both demonstrated that FHC and class I HLA
      heterodimers are co-clustered at the cell surface. Culturing the cells with
      excess beta(2)m resulted in a reduced co-clustering and decreased molecular
      homotypic association, as assessed by FRET. The decreased HLA clustering on JY
      target cells (antigen-presenting cells) was accompanied with their reduced
      susceptibility to specific lysis by allospecific CD8(+) cytotoxic T lymphocytes
      (CTL). JY B cells with reduced HLA clustering also provoked significantly weaker
      T cell activation signals, such as lower expression of CD69 activation marker and
      lower magnitude of TCR down-regulation, than did the untreated B cells. These
      results together suggest that the actual level of beta(2)m available at the cell
      surface can control CTL activation and the subsequent cytotoxic effector function
      through regulation of the homotypic HLA-I association. This might be especially
      important in some inflammatory and autoimmune diseases where elevated serum
      beta(2)m levels are reported.

PMID- 12618478
TI  - Targeting of platelet integrin alphaIIbbeta3 determines systemic reaction and
      bleeding in murine thrombocytopenia regulated by activating and inhibitory
      FcgammaR.
AB  - Previous work on cellular destruction induced by several clinically relevant anti
      platelet IgG antibodies suggested antigen-specific mechanisms in the development
      of immune thrombocytopenia in mice. mAb directed against mouse platelet GPIbalpha
      and integrin alpha(IIb)beta(3) were highly pathogenic, and mediated their effects
      via different Fc-dependent (alpha(IIb)beta(3)) and Fc-independent (GPIbalpha)
      pathways, indicating that clearance of IgG-bound platelets is only one event in
      the pathogenesis of murine thrombocytopenia. Here, we demonstrate that in
      addition to thrombocytopenia, targeting of platelet integrin alpha(IIb)beta(3)
      results in acute systemic reaction and bleeding that is regulated by activating
      IgG Fc receptors (FcgammaR) and the inhibitory FcgammaRII. As shown by electron
      microscopy, anti-alpha(IIb)beta(3) IgG mediated initial loss of alpha(IIb)beta(3)
      integrin from platelet surfaces followed by rapid accumulation of
      alpha(IIb)beta(3) antibody-containing immune complex (IC)-like structures in
      spleen and liver in vivo. In FcRgamma chain deficiency, mice resisted bleeding,
      but not platelet destruction, while genetic ablation of FcgammaRII resulted in
      uncontrolled systemic reaction and severe hemorrhage leading to enhanced
      mortality. Together, these results provide evidence that IC formation and
      engagement of FcgammaR on effector cells determines the alpha(IIb)beta(3)
      specific part of the platelet pathology of the systemic reaction and bleeding in
      murine thrombocytopenia.

PMID- 12618479
TI  - A crucial role of CD4 T cells as a functional source of CD154 in the initiation
      of insulin-dependent diabetes mellitus in the non-obese diabetic mouse.
AB  - Although the critical requirement of CD4 T cells in type I (insulin-dependent)
      diabetes mellitus (T1DM) has been well documented, information on the exact
      role(s) of CD4 T cells in T1DM development is still limited. Here, utilizing non
      obese diabetic (NOD) mice deficient for CD154 (CD154-KO/NOD), we have identified
      a mandatory role of CD4 T cells as the functional source of CD154 in the
      initiation of T1DM. Without CD154, CD4 T cells were not capable of mediating help
      in disease development in NOD mice. In fact, full expression of CD154 on the CD4
      T cells seems to be essential in the normal spontaneous development of T1DM,
      since no diabetes was observed in CD154(+/-) mice in which around half of CD4 T
      cells do not express CD154 at all, at least by the time they were 40 weeks old.
      It was also shown that transgenic expression of CD80 on beta cells of pancreatic
      islets, which is believed to provide beta cells with the ability to prime
      cytotoxic T lymphocytes specific for islet antigens, did not restore insulitis in
      CD154-KO/NOD mice. Taken collectively, these results indicated that CD4 T cells
      play a crucial role in T1DM as a source of CD154, and that the role of CD154 on
      CD4 T cells in insulitis may not be just to facilitate priming and expanding of
      auto-reactive CD8 T cells by activating antigen-presenting cells bearing islet
      antigens.

PMID- 12618481
TI  - Expansion of human gammadelta T cells after in vitro stimulation with
      Campylobacter jejuni.
AB  - Campylobacter jejuni is currently the prime cause of food-borne bacterial gastro
      enteritis. An important complication of C. jejuni enteritis is Guillain-Barre
      syndrome (GBS), an immune-mediated disorder of peripheral nerve tissue. Because
      little is known about T cell reactivity to C. jejuni, we have analyzed the in
      vitro immune response of normal individuals against five isolates of C. jejuni
      representing five different serotypes. We found a preferential expansion of
      peripheral blood gammadelta T cells after exposure to crude sonicates of all five
      C. jejuni serotypes. Expansion of gammadelta T cells was dependent on the
      presence of CD4+/alphabeta+ T cells in the cultures or addition of exogenous IL-2
      or IL-15. C. jejuni stimulation was mediated via the TCR and appeared to be
      induced by a non-proteinaceous bacterial antigen, most likely of phosphoantigenic
      origin.

PMID- 12618480
TI  - Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory
      signal required to provide an antitumor immune response.
AB  - CD70 and CD80 are co-stimulatory molecules which belong to the tumor necrosis
      factor family and the B7 family respectively. When they are co-expressed by gene
      modified TS/A tumor cells, they provide an efficient protective and long-lasting
      T-dependent antitumor response. We first showed that when CD70 and CD80 were
      delivered in the tumor environment by gene-modified fibroblasts, but were not
      expressed by the tumor cells themselves, no antitumor response was observed. We
      next assessed whether the intracytoplasmic domains of CD70 and CD80 contribute to
      enhance the co-stimulatory activity necessary to induce effective T cell-tumor
      cell interactions and T cell-dependent antitumor response. TS/A cells were gene
      modified to express different combinations of deleted (CD70Delta and CD80Delta)
      or full-length CD70 and CD80 co-stimulatory molecules. In vitro, the CD80
      intracytoplasmic domain was required to regulate CD80 membrane redistribution by
      interacting with the actin cytoskeleton. The loss of the CD70 intracytoplasmic
      domain did not alter its ability to relocate on the surface membrane, but failed
      to co-stimulate T cell proliferation. In vivo experiments in syngeneic BALB/c
      mice showed that the CD70/CD80-TS/A and the CD70Delta/CD80-TS/A tumors were
      rejected via CD8 T cells, whereas CD70/CD80Delta-TS/A and CD70Delta/CD80Delta
      TS/A tumors were not. The mice that rejected CD70Delta/CD80-TS/A tumors showed
      decreased protection against injection of parental TS/A cells when compared to
      mice which rejected CD70/CD80-TS/A tumors. These results showed that the
      intracytoplasmic domain of CD80 was critical for the effector phase of CD8 T cell
      dependent tumor rejection and that the CD70 intracytoplasmic domain could mediate
      proliferative or surviving signals required for optimal effector/memory CD8 T
      cell generation.

PMID- 12618483
TI  - Expression of recombination-activating gene in mature peripheral T cells in
      Peyer's patch.
AB  - Recombination-activating gene (RAG) 1 and 2 are essential for the gene
      rearrangement of antigen receptors of both T and B cells. To investigate RAG gene
      expression in peripheral lymphoid organs other than the thymus and bone marrow,
      we established mice in which a green fluorescent protein (GFP) gene is knocked-in
      the RAG2 gene locus (RAG2-GFP mice). In the thymus and bone marrow of
      heterozygous RAG2-GFP mice, as expected, GFP expression was detected in the
      appropriate stages of developing T and B cells. Interestingly, only a fraction of
      Thy-1.2(+) cells in the Peyer's patch were found to be GFP(+) amongst the
      peripheral lymphoid organs. The GFP(+) cells expressed high levels of surface
      TCRbeta and CD3, suggesting mature T cells with rearranged TCRalphabeta. However,
      they showed activated/memory phenotypes, i.e. CD45RB(low), CD69(high), CD44(high)
      and CD62L(low), and belonged to a CD4(+)CD8(+) population expressing c-kit, IL-7R
      and pTalpha characteristic of immature developing lymphocytes. Moreover, RAG(+)
      Peyer's patch T cells seem to be of thymic origin as judged by their expression
      of CD8alphabeta. These results show that there exists a fraction of mature T
      cells expressing RAG genes in the Peyer's patch, implying a potential for a
      secondary rearrangement of TCR in extrathymic tissues.

PMID- 12618482
TI  - Haploinsufficiency of B cell linker protein enhances B cell signaling defects in
      mice expressing a limiting dosage of Bruton's tyrosine kinase.
AB  - Current models of lymphocyte activation suggest that formation of a signaling
      complex, or "signalosome", composed of Syk, Bruton's tyrosine kinase (Btk),
      phospholipase gamma2 and the adaptor protein B cell linker protein (BLNK) is
      critical for transmission of signals from the BCR. However, impaired B cell
      development in mice lacking each individual signalosome component has made it
      difficult to study the functional consequences of the formation of this complex
      in mature B cells. Sensitized genetic systems, commonly used in Drosophila,
      define signaling pathways by combining partial loss of function mutations in the
      components of interest. This allows genetic interactions to be observed in the
      absence of pleiotropic or lethal effects of complete deficiency of either gene.
      We used this approach to demonstrate that Btk and BLNK are limiting components of
      a common signaling pathway that mediates the mitogenic response of mature B cells
      to antigen. B cells from transgenic mice expressing a limiting dosage of Btk
      (Btk(lo)) have normal numbers of mature B cells that have reduced, but
      measurable, responses to BCR cross-linking. Haploinsufficiency of BLNK did not
      affect the development of Btk(lo) B cells. However, it exacerbated their defects
      in BCR-induced Ca(2+) flux, IkappaB degradation, and up-regulation of cyclin D2,
      bcl-x(L) and A1 leading to dramatic impairment of B cell mitogenic responses. In
      contrast, no effect of reduced Btk and BLNK dosage was observed on extracellular
      signal-regulated kinase activation. These results suggest that the signals
      regulating the maintenance and activation of mature B cells are differentially
      sensitive to the strength of the signal emanating from the signalosome.

PMID- 12618484
TI  - Functional association of cytokine-induced SH2 protein and protein kinase C in
      activated T cells.
AB  - TCR signaling is mediated by intracellular signaling molecules and nuclear
      transcription factors, which are tightly regulated by interaction with regulatory
      proteins such as Grb2 and SLAP. We reported recently that TCR stimulation induces
      the expression of cytokine-induced SH2 protein (CIS). The expression of CIS
      promotes TCR-mediated activation. We have now found specific interactions between
      CIS and activated protein kinase C (PKC) alpha, beta and theta in TCR-stimulated
      T cells. CIS was shown by in vitro kinase assay to associate with activated PKC.
      In CIS-expressing T cells isolated from CIS-transgenic mice, the amount of
      activated PKC associated with CIS was found to increase following TCR
      stimulation. By immunohistochemical analysis, CIS was also found to co-localize
      with PKCtheta at the plasma membrane of activated T cells. In addition to the
      interaction and intracellular co-localization of the CIS and PKC, an increase in
      the activation of AP-1 and NF-kappaB was noted in CIS-expressing T cells, after
      stimulation by either anti-CD3/CD28 or phorbol myristate acetate + ionomycin.
      These results suggest that CIS regulates PKC activation, and that this may be
      important for the activation of both the AP-1 and NF-kappaB pathways in TCR
      signaling.

PMID- 12618485
TI  - Expression cloning and function of the rat NK activating and inhibitory receptors
      NKR-P1A and -P1B.
AB  - We have characterized the rat NK receptors NKR-P1A and -P1B. A cDNA library was
      constructed from the rat NK cell line, RNK-16. Using the pMX retroviral cloning
      system, the library was expressed in the human NK cell line, YTSeco, and cells
      staining with the anti-rat mAb 10/78 identified, FACS sorted and cloned. Two
      genes, corresponding to rat NK receptors NKR-P1A and -P1B, were identified.
      YTSeco clones expressing either NKR-P1A or -P1B were functionally tested using
      (51)Cr-release redirected lysis assays and calcium flux experiments. This
      demonstrated that NKR-P1A functions as an activation receptor, as previously
      shown, and that NKR-P1B functions as an inhibitory receptor, as predicted by the
      presence of an immunoreceptor tyrosine-based inhibition motif. Although annotated
      as NKR-P1A specific, we found that mAb 10/78 stained YTSeco clones expressing NKR
      P1A or -P1B equally well, as did the mAb 3.2.3 used for the original cloning of
      rat NKR-P1A.

PMID- 12618486
TI  - Evidence of allosteric conformational changes in the antibody constant region
      upon antigen binding.
AB  - We have addressed the question of whether antigen binding induces a
      conformational change in the heavy chain constant (C(H)) domain of antibodies
      using staphylococcal protein A or streptococcal protein G as probes, since these
      proteins are known to bind to IgG domains such as C(H)1 and C(H)2-C(H)3 domains.
      Biosensor assays on interactions between these proteins and mouse IgG specific to
      (4-hydroxy-3-nitrophenyl)acetyl (NP) or their enzymatic fragments conducted in
      the presence or absence of the hapten, NP-epsilon-aminocaproic acid (NP-Cap),
      showed that the binding of IgG to these proteins was inhibited by the binding of
      NP-Cap. The results of isothermal titration calorimetry also revealed that the
      association constant for the interaction of protein A with IgG2b decreased by the
      addition of NP-Cap. These results suggested that antigen binding induced
      conformational changes in binding sites for protein G or protein A located at
      C(H)1 and C(H)2-C(H)3 domains, respectively.

PMID- 12618487
TI  - Inducing long-term survival with lasting anti-tumor immunity in treating B cell
      lymphoma by a combined dendritic cell-based and hydrodynamic plasmid-encoding IL
      12 gene therapy.
AB  - In a previous study we showed that immunization with dendritic cells (DC) pulsed
      with idiotype (Id) fused with CD40 ligand (CD40L) could break the tolerance to Id
      which is expressed on B lymphoma cells and restored the responsiveness of T(h)
      cells, and, subsequently, induced IgG antibody response. However, this treatment
      had no therapeutic effect. In the present study, we found that using a
      hydrodynamic transfection-based technique, a high level of IL-12 production was
      noticed as early as 7 h after administering plasmid encoding IL-12 (pIL-12) and
      persisted at a detectable level for at least 9 days. In evaluating the efficacy
      of DC-based and/or IL-12 gene-based therapy in the treatment of 38C13 B cell
      lymphoma, it was found that either treatment alone was ineffective. However, a
      combined treatment induced 100% long-term survival. Furthermore, a long-lasting
      anti-tumor immunity was induced in these mice which resisted further tumor
      challenge at 58 days after initial inoculation. The surviving mice showed a
      strong IFN-gamma-producing T(h) cell response and humoral antibody response, but
      there were no detectable cytotoxic T lymphocytes. The antibody from the immune
      sera mediated a complement-dependent lysis of tumor cells that was tumor
      specific. Furthermore, immunization of mice with DC-based vaccine and pIL-12
      treatment elicited higher levels of anti-Id IgG titer and an enhanced IgG2a
      response which increased the efficacy in mediating 38C13 tumor lysis. On
      examining the mechanism for this isotype change, we found that IFN-gamma
      production by CD4(+) T cells is not the only determining factor for achieving a
      successful therapy. DC-based treatment alone could induce the increase of IFN
      gamma production, but lacked any therapeutic effect. The deciding factor appears
      to be the abrogation of IL-4 production that was achieved by combing with IL-12
      gene therapy. Our study provides a basis for exploring the combined use of
      cytokines or cytokine genes in DC-based treatment for achieving effective cancer
      immunotherapy.

PMID- 12618488
TI  - Acquired thymic tolerance to autoimmune encephalomyelitis is associated with
      activation of peripheral IL-10-producing macrophages/dendritic cells.
AB  - Antigen injection into the thymus of adult animals induces systemic tolerance and
      protects animals from subsequent challenge for the autoimmune disease. However,
      its mechanisms are not well understood. In this study, we analyzed tolerance to
      experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats by
      intrathymic (i.t.) injection of myelin basic protein (MBP). Intrathymic injection
      of MBP 7 days before immunization with MBP/complete Freund's adjuvant resulted in
      complete suppression of clinical signs of EAE in most animals and markedly
      reduced the histological severity in the central nervous system lesion. However,
      immunohistochemical examination and the TCR repertoire analysis revealed that
      there was no significant difference in the T cell composition in the lesion and
      the TCR spectratype pattern between MBP and saline i.t. rats, suggesting that
      encephalitogenic T cell activation occurs equally in both protected and
      symptomatic rats. In contrast, quantitative analysis of cytokine mRNA and flow
      cytometry revealed a marked increase of IL-10 production in the splenic
      macrophages/dendritic cell (Mo/DC) population of MBP i.t. rats. Adoptive transfer
      of this population significantly suppressed the clinical course of EAE in
      recipients. Taken together, IL-10-secreting Mo/DC in peripheral lymphoid organs
      activated by MBP i.t. injection may play a critical role in the induction and
      maintenance of tolerance.

PMID- 12618489
TI  - Stimulation by food proteins plays a critical role in the maturation of the
      immune system.
AB  - The majority of contacts with foreign antigenic materials occur on the gut
      mucosa, and are represented by food proteins and the autochthonous microbiota. In
      the present study, we replaced intact dietary proteins by equivalent amounts of
      amino acids from weaning on and investigated its effects on the development of
      the immune system of mice. Adult animals reared on a balanced protein-free diet
      (Aa-mice) have a poorly developed gut-associated lymphoid tissue resembling
      suckling mice. They also display low numbers of lamina propria cells and
      TCRalphabeta intraepithelial lymphocytes, and low levels of secretory IgA. Levels
      of circulating IgG and IgA are also reduced in Aa-mice, whereas IgM levels are
      normal. In vitro cytokine production by cells from several lymphoid organs shows
      a predominant T(h)2 profile with a high concentration of IL-10 and IL-4, and a
      low concentration of IFN-gamma. These parameters also resemble the immunological
      patterns observed in pre-weaned mice. Thus, our data clearly show that exposure
      to food proteins after weaning has a physiological role in the maturation of the
      immune system both locally and systemically.

PMID- 12618490
TI  - Evaluation of hypothalamic gene expression in mice divergently selected for heat
      loss.
AB  - Mouse lines divergently selected for heat loss were evaluated for correlated
      responses in the hypothalamic transcriptome. High (MH) heat loss mice have
      approximately 50% greater heat loss, approximately 35% less body fat,
      approximately 20% greater feed intake, approximately 100% greater locomotor
      activity levels, and higher core body temperature compared with low (ML) heat
      loss mice. We evaluated hypothalamic expression between inbred lines derived from
      MH and ML lines (IH and IL, respectively) using cDNA microarrays and selected
      genes previously isolated in a large differential-display PCR experiment.
      Northern analysis was used to confirm differences, revealing higher hypothalamic
      mRNA expression of oxytocin (Oxt) and tissue inhibitor of metalloproteinase 2
      (Timp-2) in the IH line. Real-time PCR assays were developed for Oxt, Timp-2, and
      ribosomal protein L3 (Rpl3, previously found to be upregulated in IL) and
      confirmed differential expression of these genes with potential physiological
      relevance in energy balance. These results provide information on correlated
      responses in the transcriptome of mice selected for high and low energy
      expenditure and reveal new information regarding genetic regulation of energy
      balance.

PMID- 12618491
TI  - Is tamoxifen the Rosetta stone for breast cancer?

PMID- 12618492
TI  - Chemotherapy for elderly patients with advanced non-small-cell lung cancer.

PMID- 12618493
TI  - Mammography and beyond: building better breast cancer screening tests.

PMID- 12618495
TI  - The pomegranate: nature's power fruit?

PMID- 12618496
TI  - Biotech industry tries to recover from 2-year lull.

PMID- 12618497
TI  - Stat bite: Incidence of colon and rectum cancer by age and ethnicity, 1992-1999.

PMID- 12618498
TI  - Microarray studies challenge theories of metastasis.

PMID- 12618500
TI  - Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen
      resistance in breast cancer.
AB  - BACKGROUND: AIB1 (SRC-3) is an estrogen receptor (ER) coactivator that, when
      overexpressed in cultured cells, can reduce the antagonist activity of tamoxifen
      bound ERs. Signaling through the HER-2 receptor pathway activates AIB1 by
      phosphorylation. To determine whether high AIB1 expression alone or together with
      HER-2 reduces the effectiveness of tamoxifen in breast cancer patients, we
      quantified expression of AIB1 and HER-2 in tumors from breast cancer patients
      with long-term clinical follow-up who received either no adjuvant therapy or
      adjuvant tamoxifen therapy after breast cancer surgery. METHODS: AIB1 and HER-2
      protein levels in tumors from 316 breast cancer patients were determined using
      western blot analysis. Molecular variables (e.g., expression of AIB1, ER,
      progesterone receptor, p53, Bcl-2), tumor characteristics, and patient outcome
      were assessed using Spearman rank correlation. Disease-free survival (DFS) curves
      were derived from Kaplan-Meier estimates, and the curves were compared by log
      rank tests. The effect of AIB1 on DFS adjusted for other prognostic factors was
      assessed by multivariable analysis using the Cox proportional hazards model. All
      statistical tests were two-sided. RESULTS: High AIB1 expression in patients not
      receiving adjuvant tamoxifen therapy was associated with better prognosis and
      longer DFS (P =.018, log-rank test). In contrast, for patients who did receive
      tamoxifen therapy, high AIB1 expression was associated with worse DFS (P =.049,
      log-rank test), which is indicative of tamoxifen resistance. The test for
      interaction between AIB1 expression and tamoxifen therapy was statistically
      significant (P =.004). When expression of AIB1 and HER-2 were considered
      together, patients whose tumors expressed high levels of both AIB1 and HER-2 had
      worse outcomes with tamoxifen therapy than all other patients combined (P =.002,
      log-rank test). CONCLUSIONS: The antitumor activity of tamoxifen in patients with
      breast cancer may be determined, in part, by tumor levels of AIB1 and HER-2.
      Thus, AIB1 may be an important diagnostic and therapeutic target.

PMID- 12618501
TI  - Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the
      Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized
      trial.
AB  - BACKGROUND: Vinorelbine prolongs survival and improves quality of life in elderly
      patients with advanced non-small-cell lung cancer (NSCLC). Some studies have also
      suggested that gemcitabine is well tolerated and effective in such patients. We
      compared the effectiveness and toxicity of the combination of vinorelbine plus
      gemcitabine with those of each drug given alone in an open-label, randomized
      phase III trial in elderly patients with advanced NSCLC. METHODS: Patients aged
      70 years and older, enrolled between December 1997 and November 2000, were
      randomly assigned to receive intravenous vinorelbine (30 mg/m(2) of body surface
      area), gemcitabine (1200 mg/m(2)), or vinorelbine (25 mg/m(2)) plus gemcitabine
      (1000 mg/m(2)). All treatments were delivered on days 1 and 8 every 3 weeks for a
      maximum of six cycles. The primary endpoint was survival. Survival curves were
      drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test.
      Secondary endpoints were quality of life and toxicity. RESULTS: Of 698 patients
      available for intention-to-treat analysis, 233 were assigned to receive
      vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine.
      Compared with each single drug, the combination treatment did not improve
      survival. The hazard ratio of death for patients receiving the combination
      treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients
      receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving
      gemcitabine. Although quality of life was similar across the three treatment
      arms, the combination treatment was more toxic than the two drugs given singly.
      CONCLUSION: The combination of vinorelbine plus gemcitabine is not more effective
      than single-agent vinorelbine or gemcitabine in the treatment of elderly patients
      with advanced NSCLC.

PMID- 12618502
TI  - Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer.
AB  - BACKGROUND: In several epidemiologic investigations, folate intake has appeared
      to reduce the elevated risk of breast cancer associated with moderate alcohol
      consumption. However, data relating plasma folate levels to breast cancer risk
      are sparse. We investigated the association between plasma folate and other
      vitamins with breast cancer in a prospective, nested case-control study. METHODS:
      Blood samples were obtained during 1989 and 1990 from 32 826 women in the Nurses'
      Health Study who were followed through 1996 for the development of breast cancer.
      We identified 712 breast cancer case patients and selected 712 individually
      matched control subjects. Dietary information was obtained using food frequency
      questionnaires given in 1980, 1984, 1986, and 1990. Logistic regression was used
      to estimate the relative risks (RRs) of breast cancer (after adjustment for
      potential risk factors), and a generalized linear model was used to calculate the
      Pearson correlation coefficients between plasma estimates of folate, vitamin
      B(6), vitamin B(12), and homocysteine, and intakes of folate, vitamin B(6), and
      vitamin B(12). All statistical tests were two-sided. RESULTS: The multivariable
      RR comparing women in the highest quintile of plasma folate with those in the
      lowest was 0.73 (95% confidence interval [CI] = 0.50 to 1.07; P(trend) =.06). The
      inverse association between plasma folate and breast cancer risk was highly
      statistically significant among women consuming at least 15 g/day (i.e.,
      approximately 1 drink/day) of alcohol (multivariable RR = 0.11, 95% CI = 0.02 to
      0.59 for highest versus lowest quintile) in contrast with that of women consuming
      less than 15 g/day (multivariable RR = 0.72, 95% CI = 0.49 to 1.05). The
      multivariable RR comparing women in the highest quintile of plasma vitamin B(6)
      levels with those in the lowest quintile was 0.70 (95% CI = 0.48 to 1.02;
      P(trend) =.09). Plasma vitamin B(12) levels were inversely associated with breast
      cancer risk among premenopausal women (multivariable RR = 0.36, 95% CI = 0.15 to
      0.86 for highest versus lowest quintile) but not among postmenopausal women.
      Plasma homocysteine was not associated with breast cancer risk. CONCLUSIONS:
      Higher plasma levels of folate and possibly vitamin B(6) may reduce the risk of
      developing breast cancer. Achieving adequate circulating levels of folate may be
      particularly important for women at higher risk of developing breast cancer
      because of higher alcohol consumption.

PMID- 12618503
TI  - Cancer risk in nontransplanted and transplanted cystic fibrosis patients: a 10
      year study.
AB  - BACKGROUND: Cancer in patients with cystic fibrosis (CF), the most common genetic
      disorder in Caucasians, has been a rare event. However, more patients now reach
      adulthood, and more patients undergo organ transplantation-factors associated
      with an increased cancer risk. Our aim was to assess the risk of cancer in
      nontransplanted and transplanted CF patients. METHODS: We followed 28 858
      patients whose data were reported to the Cystic Fibrosis Foundation patient
      registry from 1990 through 1999 and compared the number of cancers observed in
      transplanted and nontransplanted patients to the number expected from population
      based cancer incidence data. All statistical tests were two-sided. RESULTS: In
      202 999 person-years of observation of nontransplanted CF patients, 75 cancers
      were observed, but 69.7 were expected (standardized incidence ratio [SIR] = 1.1,
      95% confidence interval [CI] = 0.8 to 1.4). Twenty-three digestive tract tumors
      were observed, but 4.5 were expected (SIR = 5.1, 95% CI = 3.2 to 7.6). More
      cancers than expected were observed of the small bowel, colon, and biliary tract
      but not of the stomach or rectum. We found that the deficit of non-digestive
      tract tumors was not statistically significant (52 observed versus 65.2 expected;
      SIR = 0.80, 95% CI = 0.6 to 1.0; P =.055). In 2725 person-years of observation of
      1063 transplanted patients, 13 cancers were observed, but 2.05 were expected (SIR
      = 6.3, 95% CI = 3.4 to 10.8), and more digestive tract tumors (four observed
      versus 0.19 expected; SIR = 21.2, 95% CI = 5.8 to 54.2) and lymphomas (seven
      observed versus 0.16 expected; SIR = 44.0, 95% CI = 17.7 to 90.7) were observed
      than expected. CONCLUSIONS: We observed an increased risk of digestive tract
      cancers among adult CF patients, particularly of the small bowel, colon, and
      biliary tract. This increased risk appeared to be more pronounced in patients who
      had had an organ transplantation.

PMID- 12618504
TI  - In vitro and in vivo induction of antiangiogenic activity by plasminogen
      activators and captopril.
AB  - BACKGROUND: Many antiangiogenic molecules are proteolytically cleaved from larger
      plasma proteins. For example, plasminogen activators cleave plasminogen into
      plasmin, and plasmin is converted into angiostatin in the presence of sulfhydryl
      donors. We thus investigated whether the antiangiogenic activity in plasma could
      be increased by treatment with recombinant tissue plasminogen activator (rt-PA)
      and the sulfhydryl donor captopril. METHODS: Human plasma was treated with rt-PA
      (10 micro g/mL) and/or captopril (1 micro M). Angiogenesis was measured in vitro
      by human endothelial cell tube formation and endothelial cell proliferation and
      in vivo in mice with the Matrigel plug assay. Angiostatin was removed from
      treated plasma by affinity chromatography, immunoprecipitation, or ion-exchange
      chromatography, and the antiangiogenic activity of the depleted plasma was
      assessed by tube formation. Three cancer patients were treated with rt-PA and
      captopril, and their pretreatment and post-treatment plasmas were tested for
      antiangiogenic activity in vitro. RESULTS: Angiogenesis in vitro was stimulated
      by untreated plasma and inhibited by plasma that had been treated with rt-PA and
      captopril but was not affected by treatment with rt-PA and/or captopril alone. In
      vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with
      rt-PA and captopril than in untreated control mice. Antiangiogenic activity in
      treated plasma was largely retained after angiostatin was removed: treated plasma
      inhibited angiogenesis by 64.3% (95% confidence interval [CI] = 46.4% to 82.2%),
      relative to untreated plasma, and treated plasma depleted of angiostatin by
      affinity chromatography or immunoprecipitation inhibited angiogenesis by 65.1%
      (95% CI = 53.8% to 76.4%) or 63.7% (95% CI = 50.9% to 76.5%), respectively.
      Antiangiogenic activity of plasma from three cancer patients was higher after
      treatment with rt-PA and captopril than before such treatment. CONCLUSION:
      Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and
      in vivo that appears to be independent of angiostatin.

PMID- 12618505
TI  - Inhibition of DNA methylation and reactivation of silenced genes by zebularine.
AB  - BACKGROUND: Gene silencing by abnormal methylation of promoter regions of
      regulatory genes is commonly associated with cancer. Silenced tumor suppressor
      genes are obvious targets for reactivation by methylation inhibitors such as 5
      azacytidine (5-Aza-CR) and 5-aza-2'-deoxycytidine (5-Aza-CdR). However, both
      compounds are chemically unstable and toxic and neither can be given orally. We
      characterized a new demethylating agent, zebularine [1-(beta-D-ribofuranosyl)-1,2
      dihydropyrimidin-2-one], which is a chemically stable cytidine analog. METHODS:
      We tested the ability of zebularine to reactivate a silenced Neurospora crassa
      gene using a hygromycin gene reactivation assay. We then analyzed the ability of
      zebularine to inhibit DNA methylation in C3H 10T1/2 Cl8 (10T1/2) mouse embryo
      cells as assayed by induction of a myogenic phenotype and in T24 human bladder
      carcinoma cells, using the methylation-sensitive single nucleotide primer
      extension (Ms-SNuPE) assay. We also evaluated the effects of zebularine
      (administered orally or intraperitoneally) on growth of EJ6 human bladder
      carcinoma cells grown in BALB/c nu/nu mice (five mice per group) and the in vivo
      reactivation of a methylated p16 gene in these cells. All statistical tests were
      two-sided. RESULTS: In N. crassa, zebularine inhibited DNA methylation and
      reactivated a gene previously silenced by methylation. Zebularine induced the
      myogenic phenotype in 10T1/2 cells, which is a phenomenon unique to DNA
      methylation inhibitors. Zebularine reactivated a silenced p16 gene and
      demethylated its promoter region in T24 bladder carcinoma cells in vitro and in
      tumors grown in mice. Zebularine was only slightly cytotoxic to T24 cells in
      vitro (1 mM zebularine for 48 hours decreased plating efficiency by 17% [95%
      confidence interval (CI) = 12.8% to 21.2%]) and to tumor-bearing mice (average
      maximal weight change in mice treated with 1000 mg/kg zebularine = 11% [95% CI =
      4% to 19%]). Compared with those in control mice, tumor volumes were
      statistically significantly reduced in mice treated with high-dose zebularine
      administered by intraperitoneal injection (P<.001) or by oral gavage (P<.001).
      CONCLUSIONS: Zebularine is a stable DNA demethylating agent and the first drug in
      its class able to reactivate an epigenetically silenced gene by oral
      administration.

PMID- 12618506
TI  - Re: Folliculitis associated with weekly paclitaxel treatment.

PMID- 12618507
TI  - The emerging science of body weight regulation and its impact on obesity
      treatment.

PMID- 12618508
TI  - The expanding network of redox signaling: new observations, complexities, and
      perspectives.

PMID- 12618509
TI  - T cell apoptosis and reactive oxygen species.

PMID- 12618511
TI  - Integrating the quality of the cytotoxic response and tumor susceptibility into
      the design of protective vaccines in tumor immunotherapy.

PMID- 12618512
TI  - Calcium and the heart: a question of life and death.

PMID- 12618513
TI  - Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?

PMID- 12618510
TI  - Endogenous generation of reactive oxidants and electrophiles and their reactions
      with DNA and protein.

PMID- 12618514
TI  - Nephrolithiasis: site of the initial solid phase.

PMID- 12618515
TI  - Randall's plaque of patients with nephrolithiasis begins in basement membranes of
      thin loops of Henle.
AB  - Our purpose here is to test the hypothesis that Randall's plaques, calcium
      phosphate deposits in kidneys of patients with calcium renal stones, arise in
      unique anatomical regions of the kidney, their formation conditioned by specific
      stone-forming pathophysiologies. To test this hypothesis, we performed
      intraoperative biopsies of plaques in kidneys of idiopathic-calcium-stone formers
      and patients with stones due to obesity-related bypass procedures and obtained
      papillary specimens from non-stone formers after nephrectomy. Plaque originates
      in the basement membranes of the thin loops of Henle and spreads from there
      through the interstitium to beneath the urothelium. Patients who have undergone
      bypass surgery do not produce such plaque but instead form intratubular
      hydroxyapatite crystals in collecting ducts. Non-stone formers also do not form
      plaque. Plaque is specific to certain kinds of stone-forming patients and is
      initiated specifically in thin-limb basement membranes by mechanisms that remain
      to be elucidated.

PMID- 12618516
TI  - Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through
      protein kinase A-independent activation of Ca2+/calmodulin kinase II.
AB  - beta(1)-adrenergic receptor (beta(1)AR) stimulation activates the classic
      cAMP/protein kinase A (PKA) pathway to regulate vital cellular processes from the
      change of gene expression to the control of metabolism, muscle contraction, and
      cell apoptosis. Here we show that sustained beta(1)AR stimulation promotes
      cardiac myocyte apoptosis by activation of Ca(2+)/calmodulin kinase II (CaMKII),
      independently of PKA signaling. beta(1)AR-induced apoptosis is resistant to
      inhibition of PKA by a specific peptide inhibitor, PKI14-22, or an inactive cAMP
      analogue, Rp-8-CPT-cAMPS. In contrast, the beta(1)AR proapoptotic effect is
      associated with non-PKA-dependent increases in intracellular Ca(2+) and CaMKII
      activity. Blocking the L-type Ca(2+) channel, buffering intracellular Ca(2+), or
      inhibiting CaMKII activity fully protects cardiac myocytes against beta(1)AR
      induced apoptosis, and overexpressing a cardiac CaMKII isoform, CaMKII-deltaC,
      markedly exaggerates the beta(1)AR apoptotic effect. These findings indicate that
      CaMKII constitutes a novel PKA-independent linkage of beta(1)AR stimulation to
      cardiomyocyte apoptosis that has been implicated in the overall process of
      chronic heart failure.

PMID- 12618517
TI  - FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T
      cell chemotaxis to lymph nodes.
AB  - FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes
      T cell homing from spleen and peripheral blood to LNs by acting as an agonist for
      sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances
      the activity of the sphingosine transporter Abcb1 (Mdr1) and the leukotriene C(4)
      transporter Abcc1 (Mrp1). Both transporters must be active for FTY720-mediated T
      cell migration and LN homing. Migration and homing driven by FTY720,
      phosphorylated FTY720, or S1P also require 5-lipoxygenase-mediated synthesis of
      cysteinyl leukotrienes and their efflux from the cell. FTY720-mediated LN homing
      events further downstream are dependent on CCL19, CCL21, VLA-4alpha, and CD44.
      Use of T cells deficient in 5-lipoxygenase, Abcb1, and Abcc1, and comparison of
      the effects of FTY720 with those of S1P, suggest a model of sequential engagement
      of Abcb1, SP1 receptors, 5-lipoxygenase, and Abcc1 to enhance T cell migration
      and homing.

PMID- 12618518
TI  - Chronic myelogenous leukemia shapes host immunity by selective deletion of high
      avidity leukemia-specific T cells.
AB  - We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2-restricted
      nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to
      the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or
      allogeneic bone marrow transplant. Some patients with persistent disease also
      have circulating PR1-specific T cells, however, suggesting the likelihood of
      immune tolerance. Here we show that both high- and low-avidity PR1-specific T
      cells from the peripheral blood of healthy donors can be identified and
      selectively expanded in vitro. Although high-avidity PR1-specific T cells killed
      CML more effectively than low-avidity T cells, only high-avidity T cells
      underwent apoptosis when stimulated with high PR1 peptide concentration or when
      exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific
      T cells could be identified or expanded from newly diagnosed leukemia patients,
      whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1
      specific T cells were identified in IFN-sensitive patients in cytogenetic
      remission, however. These results provide evidence that CML shapes the host
      immune response and that leukemia outgrowth may result in part from leukemia
      induced selective deletion of high-avidity PR1-specific T cells.

PMID- 12618519
TI  - Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to
      endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
AB  - Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal
      and fetal morbidity and mortality. The pathophysiology of preeclampsia remains
      largely unknown. It has been hypothesized that placental ischemia is an early
      event, leading to placental production of a soluble factor or factors that cause
      maternal endothelial dysfunction, resulting in the clinical findings of
      hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms
      like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor
      (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of
      sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1
      in patients with preeclampsia is associated with decreased circulating levels of
      free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be
      rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause
      microvascular relaxation of rat renal arterioles in vitro that is blocked by
      sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension,
      proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia.
      These observations suggest that excess circulating sFlt1 contributes to the
      pathogenesis of preeclampsia.

PMID- 12618520
TI  - Graft-versus-host disease can be separated from graft-versus-lymphoma effects by
      control of lymphocyte trafficking with FTY720.
AB  - Graft-versus-host disease (GvHD) mediated by donor T cells recognizing host
      alloantigens is associated with beneficial graft-versus-tumor effects in
      recipients of allogeneic hematopoietic cell transplants. Since leukemias and
      lymphomas reside largely within the lymphohematopoietic system, we have proposed
      that the desired graft-versus-leukemia or graft-versus-lymphoma effect can be
      separated from the complication of GvHD by confinement of the graft-versus-host
      alloresponse to the lymphohematopoietic tissues. Since the new sphingosine-1
      phosphate receptor agonist immunosuppressive drug FTY720 leads to trapping of T
      cells in secondary lymphoid tissues, we evaluated the possibility that this drug
      could diminish GvHD, a disease involving epithelial target tissues, while
      permitting a beneficial alloresponse to take place within the lymphohematopoietic
      system, leading to graft-versus-lymphoma effects. We demonstrate here that FTY720
      markedly reduces GvHD in a clinically relevant, haploidentical strain
      combination, while permitting antitumor effects against a T cell lymphoma of
      unshared host MHC haplotype to proceed unhindered. These results establish a
      potential new immunotherapeutic approach to separating graft-versus-leukemia
      effects from GvHD.

PMID- 12618521
TI  - IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that
      cause myocarditis.
AB  - Cardiac antigen-specific CD8(+) T cells are involved in the autoimmune component
      of human myocarditis. Here, we studied the differentiation and migration of
      pathogenic CD8(+) T cell effector cells in a new mouse model of autoimmune
      myocarditis. A transgenic mouse line was derived that expresses cardiac myocyte
      restricted membrane-bound ovalbumin (CMy-mOva). The endogenous adaptive immune
      system of CMy-mOva mice displays tolerance to ovalbumin. Adoptive transfer of
      naive CD8(+) T cells from the ovalbumin-specific T cell receptor-transgenic (TCR
      transgenic) OT-I strain induces myocarditis in CMy-mOva mice only after
      subsequent inoculation with ovalbumin-expressing vesicular stomatitis virus (VSV
      Ova). OT-I effector T cells derived in vitro in the presence or absence of IL-12
      were adoptively transferred into CMy-mOva mice, and the consequences were
      compared. Although IL-12 was not required for the generation of cytolytic and IFN
      gamma-producing effector T cells, only effectors primed in the presence of IL-12
      infiltrated CMy-mOva hearts in significant numbers, causing lethal myocarditis.
      Furthermore, analysis of OT-I effectors collected from a mediastinal draining
      lymph node indicated that only effectors primed in vitro in the presence of IL-12
      proliferated in vivo. These data demonstrate the importance of IL-12 in the
      differentiation of pathogenic CD8(+) T cells that can cause myocarditis.

PMID- 12618522
TI  - CD44 is a macrophage binding site for Mycobacterium tuberculosis that mediates
      macrophage recruitment and protective immunity against tuberculosis.
AB  - Cell migration and phagocytosis are both important for controlling Mycobacterium
      tuberculosis infection and are critically dependent on the reorganization of the
      cytoskeleton. Since CD44 is an adhesion molecule involved in inflammatory
      responses and is connected to the actin cytoskeleton, we investigated the role of
      CD44 in both these processes. Macrophage (Mphi) recruitment into M. tuberculosis
      infected lungs and delayed-type hypersensitivity sites was impaired in CD44
      deficient (CD44(-/-)) mice. In addition, the number of T lymphocytes and the
      concentration of the protective key cytokine IFN-gamma were reduced in the lungs
      of infected CD44(-/-) mice. The production of IFN-gamma by splenocytes of CD44(-/
      ) mice was profoundly increased upon antigen-specific stimulation. Flow cytometry
      analysis revealed that soluble CD44 can directly bind to virulent M.
      tuberculosis. Mycobacteria also interacted with Mphi-associated CD44, as
      reflected by reduced binding and internalization of bacilli by CD44(-/-) Mphis.
      This suggests that CD44 is a receptor on Mphis for binding of M. tuberculosis.
      CD44(-/-) mice displayed a decreased survival and an enhanced mycobacterial
      outgrowth in lungs and liver during pulmonary tuberculosis. In summary, we have
      identified CD44 as a new Mphi binding site for M. tuberculosis that mediates
      mycobacterial phagocytosis, Mphi recruitment, and protective immunity against
      pulmonary tuberculosis.

PMID- 12618523
TI  - Mechano-oxidative coupling by mitochondria induces proinflammatory responses in
      lung venular capillaries.
AB  - Elevation of lung capillary pressure causes exocytosis of the leukocyte adhesion
      receptor P-selectin in endothelial cells (ECs), indicating that lung ECs generate
      a proinflammatory response to pressure-induced stress. To define underlying
      mechanisms, we followed the EC signaling sequence leading to P-selectin
      exocytosis through application of real-time, in situ fluorescence microscopy in
      lung capillaries. Pressure elevation increased the amplitude of cytosolic Ca(2+)
      oscillations that triggered increases in the amplitude of mitochondrial Ca(2+)
      oscillations and in reactive oxygen species (ROS) production. Responses to
      blockers of the Ca(2+) oscillations and of mitochondrial electron transport
      indicated that the ROS production was Ca(2+) dependent and of mitochondrial
      origin. A new proinflammatory mechanism was revealed in that pressure-induced
      exocytosis of P-selectin was inhibited by both antioxidants and mitochondrial
      inhibitors, indicating that the exocytosis was driven by mitochondrial ROS. In
      this signaling pathway mitochondria coupled pressure-induced Ca(2+) oscillations
      to the production of ROS that in turn acted as diffusible messengers to activate
      P-selectin exocytosis. These findings implicate mitochondrial mechanisms in the
      lung's proinflammatory response to pressure elevation and identify mitochondrial
      ROS as critical to P-selectin exocytosis in lung capillary ECs.

PMID- 12618524
TI  - Inducible costimulator is essential for collagen-induced arthritis.
AB  - CD4(+) helper Th cells play a major role in the pathogenesis of rheumatoid
      arthritis. Th cell activation, differentiation, and immune function are regulated
      by costimulatory molecules. Inducible costimulator (ICOS) is a novel
      costimulatory receptor expressed on activated T cells. We, as well as others,
      recently demonstrated its importance in Th2 cytokine expression and Ab class
      switching by B cells. In this study, we examined the role of ICOS in rheumatoid
      arthritis using a collagen-induced arthritis model. We found that ICOS knockout
      mice on the DBA/1 background were completely resistant to collagen-induced
      arthritis and exhibited absence of joint tissue inflammation. These mice, when
      immunized with collagen, exhibited reduced anti-collagen IgM Ab's in the initial
      stage and IgG2a Ab's at the effector phase of collagen-induced arthritis.
      Furthermore, ICOS regulates the in vitro and in vivo expression of IL-17, a
      proinflammatory cytokine implicated in rheumatoid arthritis. These data indicate
      that ICOS is essential for collagen-induced arthritis and may suggest novel means
      for treating patients with rheumatoid arthritis.

PMID- 12618525
TI  - Glomerular-specific alterations of VEGF-A expression lead to distinct congenital
      and acquired renal diseases.
AB  - Kidney disease affects over 20 million people in the United States alone.
      Although the causes of renal failure are diverse, the glomerular filtration
      barrier is often the target of injury. Dysregulation of VEGF expression within
      the glomerulus has been demonstrated in a wide range of primary and acquired
      renal diseases, although the significance of these changes is unknown. In the
      glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion
      of the barrier between the blood and urinary spaces. In this paper, we show that
      glomerular-selective deletion or overexpression of VEGF-A leads to glomerular
      disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal
      disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the
      renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli
      resulted in perinatal lethality. Mutant kidneys failed to develop a filtration
      barrier due to defects in endothelial cell migration, differentiation, and
      survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform
      led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated
      nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is
      critical for establishment and maintenance of the glomerular filtration barrier
      and strongly supports a pivotal role for VEGF-A in renal disease.

PMID- 12618526
TI  - VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates
      secondary lymphedema.
AB  - Although lymphedema is a common clinical condition, treatment for this disabling
      condition remains limited and largely ineffective. Recently, it has been reported
      that overexpression of VEGF-C correlates with increased lymphatic vessel growth
      (lymphangiogenesis). However, the effect of VEGF-C-induced lymphangiogenesis on
      lymphedema has yet to be demonstrated. Here we investigated the impact of local
      transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal
      models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a
      rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was
      significantly increased. This gene transfer led to a decrease in thickness and
      volume of lymphedema, improvement of lymphatic function demonstrated by serial
      lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the
      skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on
      lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis
      using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan
      receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF
      C transfection potently induced new lymphatic vessel growth. This study, we
      believe for the first time, documents that gene transfer of phVEGF-C resolves
      lymphedema through direct augmentation of lymphangiogenesis. This novel
      therapeutic strategy may merit clinical investigation in patients with
      lymphedema.

PMID- 12618527
TI  - Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by
      the prostaglandin EP2 receptor.
AB  - Prostaglandin E(2) (PGE(2)), a major COX metabolite, plays important roles in
      several facets of tumor biology. We characterized the contribution of the PGE(2)
      EP2 receptor to cancer-associated immune deficiency using EP2(-/-) mice. EP2(-/-)
      mice exhibited significantly attenuated tumor growth and longer survival times
      when challenged with MC26 or Lewis lung carcinoma cell lines as compared with
      their wild-type littermates. While no differences in T cell function were
      observed, PGE(2) suppressed differentiation of DCs from wild-type bone marrow
      progenitors, whereas EP2-null cells were refractory to this effect. Stimulation
      of cells in mixed lymphocyte reactions by wild-type DCs was suppressed by
      treatment with PGE(2), while EP2(-/-)-derived DCs were resistant to this effect.
      In vivo, DCs, CD4(+), and CD8(+) T cells were significantly more abundant in
      draining lymph nodes of tumor-bearing EP2(-/-) mice than in tumor-bearing wild
      type mice, and a significant antitumor cytotoxic T lymphocyte response could be
      observed only in the EP2(-/-) animals. Our data demonstrate an important role for
      the EP2 receptor in PGE(2)-induced inhibition of DC differentiation and function
      and the diminished antitumor cellular immune responses in vivo.

PMID- 12618530
TI  - Subjective body complaints as an indicator of somatization in elderly patients.
AB  - The authors examined the correlation of subjective body complaints (measured by
      the Giessen Subjective Complaints List) with sociodemographic data, objective
      health measures, measures of subjective well-being, and clinicians' ratings of
      somatization and psychological impairment in 251 cognitively unimpaired general
      hospital inpatients aged >/=60 years. The level of subjective body complaints
      correlated most highly with self-assessed life satisfaction and age-related
      changes and with the clinicians' rating of somatization. The results suggest that
      the level of subjective body complaints is determined by subjective well-being
      rather than by objective health measures, and thus subjective body complaints may
      be an indicator of somatization in elderly inpatients.

PMID- 12618529
TI  - c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation.
AB  - beta(3) integrin-null osteoclasts are dysfunctional, but their numbers are
      increased in vivo. In vitro, however, the number of beta(3)(-/-) osteoclasts is
      reduced because of arrested differentiation. This paradox suggests cytokine
      regulation of beta(3)(-/-) osteoclastogenesis differs in vitro and in vivo. In
      vitro, additional MCSF, but not receptor activator of NF-kappaB ligand (RANKL),
      completely rescues beta(3)(-/-) osteoclastogenesis. Similarly, activation of
      extracellular signal-regulated kinases (ERKs) and expression of c-Fos, both
      essential for osteoclastogenesis, are attenuated in beta(3)(-/-) preosteoclasts,
      but completely restored by additional MCSF. In fact, circulating and bone marrow
      cell membrane-bound MCSFs are enhanced in beta(3)(-/-) mice, correlating with the
      increase in the osteoclast number. To identify components of the MCSF receptor
      that is critical for osteoclastogenesis in beta(3)(-/-) cells, we retrovirally
      transduced authentic osteoclast precursors with chimeric c-Fms constructs
      containing various cytoplasmic domain mutations. Normalization of
      osteoclastogenesis and ERK activation, in beta(3)(-/-) cells, uniquely requires c
      Fms tyrosine 697. Finally, like high-dose MCSF, overexpression of c-Fos
      normalizes the number of beta(3)(-/-) osteoclasts in vitro, but not their ability
      to resorb dentin. Thus, while c-Fms and alpha(v)beta(3) collaborate in the
      osteoclastogenic process via shared activation of the ERK/c-Fos signaling
      pathway, the integrin is essential for matrix degradation.

PMID- 12618528
TI  - Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty
      liver but aggravates diabetic phenotypes.
AB  - To elucidate the function of PPARgamma in leptin-deficient mouse (ob/ob) liver, a
      PPARgamma liver-null mouse on an ob/ob background, ob/ob
      PPARgamma(fl/fl)AlbCre(+), was produced using a floxed PPARgamma allele,
      PPARgamma(fl/fl), and Cre recombinase under control of the albumin promoter
      (AlbCre). The liver of ob/ob-PPARgamma(fl/fl)AlbCre(+) mice had a deletion of
      exon 2 and a corresponding loss of full-length PPARgamma mRNA and protein. The
      PPARgamma-deficient liver in ob/ob mice was smaller and had a dramatically
      decreased triglyceride (TG) content compared with equivalent mice lacking the
      AlbCre transgene (ob/ob-PPARgamma(fl/fl)AlbCre(-)). Messenger RNA levels of the
      hepatic lipogenic genes, fatty acid synthase, acetyl-CoA carboxylase, and
      stearoyl-CoA desaturase-1, were reduced in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice,
      and the levels of serum TG and FFA in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice were
      significantly higher than in the control ob/ob-PPARgamma(fl/fl)AlbCre(-) mice.
      Rosiglitazone treatment exacerbated the fatty liver in ob/ob
      PPARgamma(fl/fl)AlbCre(-) mice compared with livers from nonobese Cre(-) mice;
      there was no effect of rosiglitazone in ob/ob-PPARgamma(fl/fl)AlbCre(+) mice. The
      deficiency of hepatic PPARgamma further aggravated the severity of diabetes in
      ob/ob mice due to decreased insulin sensitivity in muscle and fat. These data
      indicate that hepatic PPARgamma plays a critical role in the regulation of TG
      content and in the homeostasis of blood glucose and insulin resistance in
      steatotic diabetic mice.

PMID- 12618531
TI  - The internet for medical information about cancer: help or hindrance?
AB  - OBJECTIVE: The authors tested a strategy for screening Internet sites to identify
      those that provide scientifically accurate information regarding
      complementary/alternative medicine treatments commonly used by cancer patients.
      METHOD: Separate Internet searches were conducted for three
      complementary/alternative medicine treatments: floressence, amalaki, and
      selenium. Sites (N=194) were assessed according to four criteria: availability of
      online purchasing, inclusion of patient testimonials, description of the
      treatment as a "cancer cure," and description of the treatment as "having no side
      effects." The presence of any of these criteria was considered a "red flag"
      denoting questionable scientific accuracy of the site. Sites were categorized
      based on the number of red flags. MEDLINE searches were performed and peer
      reviewed literature used to determine the scientific accuracy of sites. RESULTS:
      Over 90% of the sites for floressence and amalaki had at least one red flag. In
      these searches, sites with no red flags provided some scientifically accurate
      information, while sites with red flags provided a large amount of vague and
      inaccurate information. Less than one-quarter of sites for selenium had at least
      one red flag, and sites in this search generally provided scientifically accurate
      information, regardless of the number of red flags. CONCLUSIONS: There is a
      staggering amount of medical misinformation on the Internet. For cancer
      treatments that have not been rigorously studied, the red flag criteria offer a
      rapid way of screening Internet sites for likely scientific accuracy. It may be
      advisable for patients to avoid sites with one or more red flags.

PMID- 12618532
TI  - A prospective study of neuropsychiatric symptoms associated with interferon-alpha
      2b and ribavirin therapy for patients with chronic hepatitis C.
AB  - The purpose of this study was to systematically describe the neuropsychiatric
      side effects of treatment with interferon-alpha-2b (INF-alpha) and ribavirin in
      patients with chronic hepatitis C as well as to compare different instruments
      used to measure these side effects. Fifty-five patients with chronic hepatitis C
      were prospectively followed for 24 weeks and assessed with seven neuropsychiatric
      symptom measures and one quality of life scale. Of 42 patients treated with INF
      alpha and ribavirin, 11 (26%) were receiving psychiatric treatment at baseline.
      They scored higher on all rating scales at baseline and became more symptomatic
      during treatment. Of the 31 patients (74%) not in psychiatric care at baseline,
      15 (48%) required treatment for neuropsychiatric symptoms, and seven (23%) met
      criteria for major depression during INF-alpha therapy. The control group of 13
      untreated subjects showed little change over the 24-week period. All symptom
      scales were highly intercorrelated, suggesting that use of one is sufficient for
      monitoring symptoms.

PMID- 12618533
TI  - Assessment of cortisol response with low-dose and high-dose ACTH in patients with
      chronic fatigue syndrome and healthy comparison subjects.
AB  - A reduced secretion of cortisol has been proposed as a possible explanation of
      the symptoms in chronic fatigue syndrome. However, the evidence of
      hypocortisolism in chronic fatigue syndrome is conflicting. In order to
      simultaneously assess possible alterations in adrenocortical sensitivity and
      secretory adrenal reserve, the authors administered both low-dose and high-dose
      ACTH to a group of 18 chronic fatigue syndrome patients and 18 age- and gender
      matched healthy comparison subjects. No response differences for salivary and
      plasma cortisol were detectable after administration of either low-dose or high
      dose ACTH, indicating that primary adrenal insufficiency is unlikely to play a
      significant role in the etiology of chronic fatigue syndrome.

PMID- 12618534
TI  - A prospective trial of sustained-release bupropion for depression in HIV
      seropositive and AIDS patients.
AB  - To date, the authors know of no prospective studies of sustained-release
      bupropion in depressed HIV-seropositive patients. The purpose of this study was
      to evaluate the efficacy and tolerability of sustained-release bupropion in 20
      depressed HIV-positive adult outpatients. Twenty outpatients with HIV spectrum
      illness, a DSM-IV-diagnosed major depressive disorder confirmed with the
      Structured Clinical Interview for DSM-IV, and Mini-Mental State Examination
      scores >20 were recruited into a 6-week, open-label, flexible-dose study of
      sustained-release bupropion (100-300 mg/day). Twelve patients (60%) responded to
      sustained-release bupropion at a mean dose of 265 mg/day. Five patients (25%)
      discontinued study participation secondary to adverse events. Preliminary
      findings suggest that sustained-release bupropion is effective for the treatment
      of depression in HIV-positive patients, regardless of HIV clinical staging.
      Furthermore, it appears to be well tolerated in patients with AIDS-related
      medical conditions.

PMID- 12618535
TI  - The delirium rating scale in children and adolescents.
AB  - The study of delirium has been neglected in pediatric patients, and there are no
      diagnostic criteria or rating scales adapted for use in this age group. The
      Delirium Rating Scale is widely used to diagnose and rate the severity of
      delirium in adults. It was retrospectively administered to 84 children and
      adolescents diagnosed with delirium to evaluate its applicability in pediatric
      patients. Delirium Rating Scale scores were comparable to those reported for
      delirium in adults, although single cross-sectional Delirium Rating Scale scores
      did not predict length of hospital stay or mortality outcome. Therefore, the
      Delirium Rating Scale can be used to evaluate delirium in the pediatric
      population.

PMID- 12618536
TI  - Pharmacokinetic drug interactions of morphine, codeine, and their derivatives:
      theory and clinical reality, part I.
AB  - Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and
      oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate
      that is metabolized chiefly through glucuronidation by uridine diphosphate
      glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an
      active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug
      interaction studies with morphine are few, but they do suggest that inhibition or
      induction of UGT enzymes could alter morphine and its metabolite levels. These
      interactions could change analgesic efficacy. Hydromorphone and oxymorphone,
      close synthetic derivatives of morphine, are also metabolized primarily by UGT
      enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo
      drug-drug interaction studies with hydromorphone and oxymorphone have not been
      done, so it is difficult to make conclusions with these drugs.

PMID- 12618537
TI  - Pain in liver donors.

PMID- 12618538
TI  - Chronic fatigue syndrome, fibromyalgia, and complex regional pain syndrome type
      I.

PMID- 12618539
TI  - QTc prolongation and high-dose olanzapine.

PMID- 12618540
TI  - Olanzapine and quick-response hyperglycemia.

PMID- 12618543
TI  - A fluorescence resonance energy transfer sensor for the beta-domain of
      metallothionein.
AB  - We have designed a nanosensor to study the potential function of metallothionein
      (MT) in metal transfer and its interactions with redox partners and ligands by
      attaching two fluorescent probes to recombinant human MT. The specific labeling
      takes advantage of two different modification reactions. One is based on the fact
      that recombinant MT has a free N-terminal amino group when produced by the IMPACT
      T7 expression and purification system, the other on the observation that one
      human MT isoform (1b) contains an additional cysteine at position 32. It is
      located in the linker region of the molecule, allowing the introduction of a
      probe between the two domains. An S32C mutation was introduced into hMT-2. Its
      thiol reactivity, metal binding capacity, and CD and UV spectra all demonstrate
      that the additional cysteine contains a free thiol(ate); it perturbs neither the
      overall structure of the protein nor the formation of the metalthiolate clusters.
      MT containing only cadmium was labeled stoichiometrically with Alexa 488
      succinimidyl ester at the N terminus and with Alexa 546 maleimide at the free
      thiol group, followed by conversion to MT containing only zinc. Energy transfer
      between Alexa 488 (donor) and Alexa 546 (acceptor) in double-labeled MT allows
      the monitoring of metal binding and conformational changes in the N-terminal beta
      domain of the protein.

PMID- 12618545
TI  - Pseudolesions related to uterine contraction: characterization with multiphase
      multisection T2-weighted MR imaging.
AB  - PURPOSE: To evaluate whether multiphase-multisection T2-weighted magnetic
      resonance (MR) images help exclude pseudolesions mimicking leiomyoma and
      adenomyosis on static T2-weighted fast spin-echo (FSE) MR images and to
      characterize temporal changes in uterine signal intensity related to uterine
      contraction. MATERIALS AND METHODS: T2-weighted FSE and multiphase-multisection
      single-shot FSE (SSFSE) MR imaging were performed in 43 patients who underwent
      hysterectomy. Each imaging set was evaluated separately by two independent
      readers, and receiver operating characteristic analysis was performed. In the 43
      patients and in 49 other patients suspected of having pelvic abnormality, a
      combination of signal intensity changes on FSE and SSFSE MR images was classified
      into five patterns, and temporal low-signal-intensity changes on SSFSE MR images
      were characterized. RESULTS: For detection of leiomyoma on FSE and SSFSE MR
      images, the respective values of the area under the receiver operating
      characteristic curve were 0.98 and 0.97 for reader 1 and 0.96 and 0.96 for reader
      2; for detection of adenomyosis on FSE and SSFSE MR images, the respective values
      were 0.82 and 0.84 for reader 1 and 0.80 and 0.89 for reader 2 (P >.05). SSFSE MR
      images helped exclude pseudolesions in 1%-3% cases of leiomyoma and in 3%-4%
      cases of adenomyosis. Temporal signal intensity changes were observed in 53% of
      368 segments. The most frequent shape of temporal low signal intensity was
      diffuse followed by ill-defined focal type. Characteristic shape of temporal low
      signal intensities was band- or sticklike, which was observed in as many as 19%
      of 368 segments. CONCLUSION: Multiphase-multisection T2-weighted SSFSE MR images
      do not improve accuracy in detection of leiomyoma and adenomyosis compared with
      FSE MR images; however, they helped characterize features of temporal low signal
      intensities in the uterus, which are related to uterine contractions.

PMID- 12618544
TI  - CloQ, a prenyltransferase involved in clorobiocin biosynthesis.
AB  - Ring A (3-dimethylallyl-4-hydroxybenzoic acid) is a structural moiety of the
      aminocoumarin antibiotics novobiocin and clorobiocin. In the present study, the
      prenyltransferase involved in the biosynthesis of this moiety was identified from
      the clorobiocin producer (Streptomyces roseochromogenes), overexpressed, and
      purified. It is a soluble, monomeric 35-kDa protein, encoded by the structural
      gene cloQ. 4-Hydroxyphenylpyruvate and dimethylallyl diphosphate were identified
      as the substrates of this enzyme, with K(m) values determined as 25 and 35
      microM, respectively. A gene inactivation experiment confirmed that cloQ is
      essential for ring A biosynthesis. Database searches did not reveal any
      similarity of CloQ to known prenyltransferases, and the enzyme did not contain
      the typical prenyl diphosphate binding site (N/D)DXXD. In contrast to most of the
      known prenyltransferases, the enzymatic activity was not dependent on the
      presence of magnesium, and in contrast to the membrane-bound
      polyprenyltransferases involved in ubiquinone biosynthesis, CloQ did not accept 4
      hydroxybenzoic acid as substrate. CloQ and the similar NovQ from the novobiocin
      producer seem to belong to a new class of prenyltransferases.

PMID- 12618546
TI  - [Iberogast: a modern phytotherapeutic combined herbal drug for the treatment of
      functional disorders of the gastrointestinal tract (dyspepsia, irritable bowel
      syndrome)--from phytomedicine to "evidence based phytotherapy." A systematic
      review].
AB  - Iberogast is a complex herbal preparation. As a fixed drug combination (9
      constituents) it is composed of a fresh plant extract of Iberis amara and of
      extracts of 8 other dried herbal drugs ( Chelidonii herba, Cardui mariae fructus,
      Melissae folium, Carvi fructus, Liquiritiae radix, Angelicae radix, Matricariae
      flos, Menthae piperitae folium). The pharmacological effects as well as the
      therapeutic effectiveness, tolerability, and toxicity of Iberogast were
      experimentally and clinically recorded and documented using modern investigation
      tools. Both the experimental as well as the clinical studies indicated a
      regulatory influence of Iberogast on the whole gastrointestinal tract by a
      special dual action. While the included extracts of the dried herbal drugs have
      mainly spasmolytic properties, the fresh plant extract of Iberis amara has a
      tonic effect on the gastrointestinal tract. Depending on the predistension of the
      gastric or intestinal wall, the tonic or the spasmolytic effects of Iberogast
      prevail. Both the fresh plant extract of Iberis amara and the combined
      preparation of Iberogast were found to be toxicologically safe in therapeutically
      effective doses. For the estimation of the clinical effectiveness a systematic
      review was performed (data research: January 1970 to September 2002). As shown in
      controlled (according GCP standard) as well as supportive and uncontrolled
      clinical studies, the symptoms of functional dyspepsia and of irritable bowel
      syndrome (one controlled study and one observational study) could be
      significantly reduced by these herbal preparation in comparison to placebo. Two
      trials comparing Iberogast with the prokinetics metoclopramide and cisapride
      demonstrated a comparable therapeutic effectiveness of the herbal preparation and
      the prokinetics in the treatment of dyspepsia. Adverse events were rare and, with
      respect to frequency and spectrum, partly the same as found with placebo. Another
      advantage of Iberogast is that it targets only the gastrointestinal tract and the
      enteral nervous system, but not the central nervous system. Because of its
      special dual action, its clinically proven effectiveness, and its good
      tolerability, Iberogast may be a drug of first choice in the treatment of
      functional gastrointestinal diseases and their corresponding symptoms.

PMID- 12618547
TI  - [Iberis amara L. (bitter candytuft)--profile of a medicinal plant].
AB  - Iberis amara L (Brassicaceae) is wide-spread in Europe and grows preferably in
      grain fields, in warm, sunny and dry, mainly loamy and loessial soil which is
      high in calcium. The plants contain amines, cucurbitacines, flavonoglycosides,
      and mustard oil glycosides. A fixed combination of the whole, blooming, fresh
      plant with clear seed formation ( Iberis amara totalis) is used in a
      phytotherapeutical product (Iberogast). In pharmacological studies both in vitro
      (e.g., in guinea pig ileum) and in vivo (e.g., in Wistar rats) the fresh plant
      extract of Iberis amara (IF) exhibited a tonicising effect on the smooth muscles
      of the stomach and small intestine. In the rat IF produced a dose-dependent
      antiulcerogenic effect (indomethacin-induced ulcer) comparable to that of
      cimetidine (reference substance). The stomach acid release and the leucotriene
      concentration, increased by indomethacin, were reduced by IF, whereas the
      prostaglandin E2 content, reduced by indomethacin, was increased. In patients
      with irritable bowel syndrome as a subtypological symptom associated with
      diarrhea and in patients with alternating diarrhea and obstipation, clear
      differences were found between drug and placebo in a multicenter, prospective,
      double-blind, randomized parallel group comparison. Toxological studies conducted
      with various cell lines in vitro and in rats and mice have shown that the fresh
      plant extract of Iberis amara in therapeutical relevant doses has no cytotoxic
      and no acute toxic action. In mutagenicity investigations there were no
      indications of genotoxic or mutagenic potential.

PMID- 12618548
TI  - [Nightmare impact factor].

PMID- 12618549
TI  - [Childhood diseases, infectious diseases, and fever as potential risk factors for
      cancer?].
AB  - OBJECTIVE: We investigated the assertion that past childhood diseases, acute and
      febrile infections as well as allergies have a preventive effect on cancer.
      Former studies on this topic show controversial results and methodical deficits.
      PATIENTS AND METHODS The investigation was conducted as a retrospective case
      control study with 111 cancer patients and a group of 109 control persons from 3
      hospitals in Berlin. RESULTS: A significant change in the risk of developing
      cancer could only be observed for mumps (OR = 2.6; increased risk), whooping
      cough (OR = 2.7; increased risk), and colds in the recent past (OR = 0.7;
      decreased risk). Fever within the last 5 years showed no association with the
      development of malign tumors. CONCLUSION: We could not confirm the results of
      former studies which assumed a preventive effect of childhood diseases and fever
      on the cancer risk. On the contrary, on the basis of this investigation one might
      postulate a 2- to 3-fold rise of the cancer risk by mumps or whooping cough.
      Because of divergent study results, deficits in the study designs, and a low
      evidence of the present findings no final statement on the association between
      childhood diseases or fever and cancer should be made.

PMID- 12618550
TI  - [Effects of active and passive movement stimuli on cerebral hemodynamics and the
      cerebral metabolism].
AB  - INTRODUCTION: In contrast to the well-examined cardiovascular changes during
      movement stimuli, up to now changes of cerebral hemodynamics and cerebral
      metabolism have rarely been studied. We investigated the question if active and
      passive movement stimuli cause changes in the cerebral hemodynamics and the
      cerebral metabolism. METHOD: Active and passive repetitive movement stimuli on 14
      volunteers (8 females, 6 males, age 35 +/- 8 years) were examined. As a parameter
      of cerebral hemodynamics the mean and the peak blood flow velocity (mCBFV(MCA),
      pCBFV(MCA)) in the middle cerebral artery (MCA) were recorded by transcranial
      Doppler sonography. At the same time the noninvasive blood pressure (Penaz
      method) and the CO(2) expiration concentration were investigated on 8 volunteers
      of the collective. As cerebral metabolic parameters we examined in 4 volunteers
      additionally the cerebral respiratory chain enzyme cytochrome aa3 (ccytaa3) and
      the cerebral oxygen saturation (cHbO(2)) by the transcranial near infrared
      spectroscopy. With each volunteer 4 measurement series were carried out with a
      special active and passive exercise program for the right upper as well as the
      right lower extremity. Each measurement series was formed according to the evoked
      flow test (R. Aaslid): Exercises were carried out for 20 s, followed by a break
      of 20 s; this was repeated 10 times for each series. RESULTS: During active
      exercises of the right lower extremity we found an increase of 13.6% (p < 0.001)
      of pCBFV(MCA) and an increase of 3.8% (p = 0.003) of mCBFV(MCA). During passive
      exercises of the lower extremity the increases ran up to 12.3% (p < 0.001) for
      pCBFV(MCA) and 3.4% (p = 0.004) for mCBFV(MCA). The increases of pCBFV(MCA) came
      up to 12.5% (p < 0.001) at active exercises of the right upper extremity, those
      of mCBFV(MCA) to 3.5% (p = 0.15). During passive exercises of the upper extremity
      the pCBFV(MCA) increased by 12.2% (p < 0.001) and the mCBFV(MCA) by 4.6% (p =
      0.007). Significant increases of ccytaa3 were measured during active exercises of
      the upper extremity (1.6%; p = 0.04) and of the lower extremity (2.7%, p =
      0.007). We also found an increase of ccytaa3 during passive exercises of the
      upper extremity (1.5%, p = 0.04). Significant changes of cHbO(2) were measured
      with 2.5% (p < 0.05) at active exercises of the lower extremity. CONCLUSION:
      These studies show that active as well as passive clinical exercises cause an
      increase of cerebral blood flow velocity. We attribute the increase of cerebral
      hemodynamics and cerebral metabolism to cerebral activation and autoregulative
      mechanisms.

PMID- 12618551
TI  - [Diagnosis of appendicitis with particular consideration of the acupuncture point
      Lanwei--a prospective study].
AB  - BACKGROUND: In almost all Western industrial nations, appendicitis is the most
      frequent cause for acute abdomen. Nevertheless, the diagnosis of appendicitis is
      often difficult, which manifests in highly negative laparotomy rates. In a
      prospective study we aimed to investigate if palpation of the acupuncture point
      Lanwei (extra point 22, extra point 33) which is located on the right leg may
      increase the accuracy in the diagnosis of appendicitis. PATIENTS AND METHODS:
      Presurgically, the Lanwei point was examined for reproducible tenderness on 116
      cooperative nonanesthetized patients admitted to hospital for suspected
      appendicitis. The results were compared with those of histological diagnosis. The
      examination of tenderness of the Lanwei sign was performed without knowing the
      results of other examinations. Additionally, other signs and laboratory
      parameters for appendicitis were examined using a standardized documentation
      form. Altogether, 17 presurgical variables, 18 clinical signs, and 3 tests were
      evaluated. RESULTS: A positive Lanwei sign was documented in 65 cases (56%),
      whereas 51 patients (44%) had a negative Lanwei sign. 65 of the 116 patients were
      operated. 59 of those had a histologically proven appendicitis. The sensitivity
      of the Lanwei sign was 64.4%, specificity ranged at 50%. Rates for positive and
      negative predictive values were 92.7% and 12.5%, respectively. Odds ratio was
      estimated as 1.8. When comparing these parameters, the Lanwei sign ranged between
      the 7th and 10th place of the 22 most important clinical signs for appendicitis.
      The negative laparotomy rate was 9%, of which 4 of 6 patients had other
      indications for an operation. The rate of perforation was 15%. CONCLUSION:
      Compared with many conventional signs for appendicitis as for example Mc Burney,
      tender Sherren triangle, reduced peristalsis, the diagnostic value of the Lanwei
      sign is not sufficient. Although a reproducible positive Lanwei sign is a good
      hint for a true appendicitis, in case of a negative Lanwei sign the probability
      for an appendicitis may be relatively high. Because of the low negative
      predictive value, the Lanwei sign is not suitable for reducing negative
      laparatomy rates. As in many other studies, the one and only indicator for
      appendicitis which yields high results in all statistical parameters was not
      detected in this study. In comparison to the statistical parameters of
      traditional signs for appendicitis, the Lanwei sign cannot be regarded as a good
      diagnostic parameter for appendicitis.

PMID- 12618552
TI  - Comparative investigation of the antimicrobial activity of PADMA 28 and selected
      European herbal drugs.
AB  - OBJECTIVE: PADMA 28 is a multicompound preparation of 20 herbs, calcium sulphate,
      and camphor, derived from Tibetan medicine. It is usually used in the treatment
      of peripheral circulatory disorders, accompanied by the symptoms tingling,
      formication, heaviness and tenseness in arms and legs, numbness in hands and
      feet, and cramps in the calf. Recently, the question of whether appropriate
      preparations of PADMA 28 also exhibit antibacterial and antimycotic activity has
      often been raised. As there are as yet no experimental findings that answer this
      question, an in vitro study was carried out. In a parallel survey we investigated
      the antimicrobial properties of 5 herbal drugs which are commonly used in the
      traditional European folk medicine for the topical treatment of mild skin
      infections, wounds and eczematous skin lesions. METHODS: The minimum inhibitory
      concentrations (MIC) and the minimum bactericidal concentrations (MBC) of alcohol
      based (tinctures) and aqueous (teas) herbal drug preparations were determined in
      vitro by a broth microdilution method for 5 Gram-positive and 5 Gram-negative
      bacteria, as well as the yeast Candida albicans. RESULTS: The aqueous and alcohol
      based PADMA 28 preparations as well as the corresponding preparations of the
      European herbal drugs showed an antibacterial effect against Gram-positive
      bacteria in vitro. These bacteria revealed a somewhat higher sensitivity to the
      teas prepared from the European herbal drugs (MIC: 1.3-20.0 mg/ml) than to the
      aqueous preparations of PADMA 28 (MIC: 5.0-40.0 mg/ml). The better antibacterial
      activity of the European herbal drugs is probably based on their relatively high
      amount of tanning agents. On the other hand, all tested plant preparations
      inhibited not at all or only insufficiently the growth of the Gram-negative
      bacteria tested and that of Candida albicans. The ethanolic PADMA 28 tinctures
      showed an improved inhibitory effect on the Gram-positive bacteria (MIC: 0.38
      1.51% tincture or 0.38-1.51 mg PADMA 28/ml) compared with the aqueous
      preparations; this effect is comparable to the ethanolic tinctures of the tested
      European herbal drugs (MIC: 0.4-1.6/3.2% tincture or 0.4-1.6/3.2 mg herbal
      drug/ml). CONCLUSION: All tested tea preparations and alcoholic tinctures of
      PADMA 28 as well as those of the selected European herbal drugs exhibited evident
      antibacterial effects against Gram-positive bacteria in vitro. On the other hand,
      except for Klebsiella pneumoniae, all Gram-negative bacteria tested and the yeast
      Candida albicans were insensitive against the different aqueous and alcohol-based
      plant extracts.

PMID- 12618553
TI  - Availability of research results on traditional chinese pharmacotherapy.
AB  - INTRODUCTION: The use of Traditional Chinese Medicine (TCM) has been increasing
      in the Western world over the last few years. Although Traditional Chinese
      Pharmacotherapy (TCP) plays a central role in TCM treatment in China, acupuncture
      is a more common form of treatment in the Western world than TCP. OBJECTIVE: The
      aim of our study was to evaluate the quantity and availability of clinical trials
      on TCP using Medline. METHODS: Medline searches were performed in PubMed (1966
      June 2001) using the MeSH (Medical Subjects Heading) term 'drugs, Chinese
      herbal.' In a second step we restricted the search to meta-analyses, reviews,
      randomized controlled trials and clinical trials. Additionally we used the PubMed
      Research- Methodology-Filter. Abstracts and information concerning the
      publication type were used to assess the available information. RESULTS: Using
      the MeSH term 'drugs, Chinese herbal', 6,504 publications (50% in Chinese)
      published in 662 journals were identified. The specific search using the PubMed
      Research-Methodology-Filter adjusted to 'therapy' and 'specificity' identified
      118 studies (11 reviews, 55 randomized controlled trials, 26 controlled trials, 7
      longitudinal studies, 12 experiments, and 7 others), 65 of which were written in
      English. Most studies used western diagnoses for treatment. The most common
      investigated diagnosis was atopic dermatitis (7 trials) followed by angina
      pectoris (6 trials). CONCLUSION: Only limited information about TCP research is
      accessible for physicians using PubMed. Moreover, half of the studies are
      published in Chinese. The PubMed-Research- Methodology-Filter proved to be an
      effective tool in restricting the search to relevant publications.

PMID- 12618554
TI  - [Re: Ludtke R, et al.: An example on the value of non-randomisation in clinical
      trials in complementary medicine. Forsch Komplementarmed Klass Naturheilkd
      2002;9:105-109].

PMID- 12618556
TI  - New insights into the genetics of neonatal diabetes.

PMID- 12618555
TI  - Developmental aspects of the endocrine pancreas.

PMID- 12618558
TI  - Type 2 diabetes in children and youth.

PMID- 12618557
TI  - Autonomic dysfunction of the beta-cell and the pathogenesis of obesity.

PMID- 12618560
TI  - Wolfram syndrome.

PMID- 12618559
TI  - Newly defined genetic diabetes syndromes: maturity onset diabetes of the young.

PMID- 12618561
TI  - Lipoatrophic diabetes and other related syndromes.

PMID- 12618563
TI  - Glycogen storage diseases.

PMID- 12618565
TI  - EMG power spectra of intercollegiate athletes and anterior cruciate ligament
      injury risk in females.
AB  - PURPOSE: Females have a disproportionately high incidence of anterior cruciate
      ligament (ACL) injuries compared with males in analogous sports. Although the
      pathogenesis of this higher frequency has not been elucidated, gender differences
      in neuromuscular control of the knee may play an important role. This study
      evaluates EMG power spectra of the quadriceps and hamstring muscles during
      dynamic, fatiguing exercise to examine differences between male and female
      intercollegiate athletes. METHODS: Fifty-one collegiate basketball and soccer
      players (25 female, 26 male) were studied. Maximum voluntary contraction (MVC)
      was determined for knee flexion and extension. Three consecutive 2-min bouts of
      isokinetic knee flexion and extension exercise were performed at 40% MVC. EMG
      activity in the biceps femoris and vastus medialis obliquus was recorded using
      bipolar surface electrodes. RESULTS: MVC normalized to body weight was
      significantly greater in males than in females for the quadriceps (P< 0.01).
      Quadriceps coactivation ratios were significantly higher in females than in males
      during knee flexion exercises (P< 0.01). CONCLUSIONS: This study demonstrates
      differences in the EMG power spectra for females when compared with a matched
      group of males. Increased quadriceps coactivation in females may increase
      anterior tibial loads under dynamic conditions, thus placing the ACL at higher
      risk for injury in the female athlete.

PMID- 12618566
TI  - Is there an association between athletic amenorrhea and endothelial cell
      dysfunction?
AB  - PURPOSE: To test the hypothesis that young females with athletic amenorrhea and
      oligomenorrhea show signs of early cardiovascular disease manifested by decreased
      endothelium-dependent dilation of the brachial artery. METHODS: Ten women with
      athletic amenorrhea (mean +/- SE, age 21.9 +/- 1.2 yr), 11 with oligomenorrhea
      (age 20.8 +/- 1.1 yr), and 11 age-matched controls (age 20.2 +/- 1.1 yr) were
      studied. Study subjects were amenorrheic an average of 2.3 (range 0.6-5) yr and
      oligomenorrheic an average of 6.2 yr. All ran a minimum of 25 miles.wk. They were
      nonpregnant and free of metabolic disease. Brachial artery flow-mediated dilation
      (endothelium-dependent) was measured with a noninvasive ultrasound technique in
      each group. RESULTS: Endothelium-dependent brachial artery dilation was reduced
      in the amenorrheic group (1.08 +/- 0.91%) compared with oligomenorrheic (6.44 +/-
      1.3%; P< 0.05) and eumenorrheic (6.38 +/- 1.4%; P< 0.05) groups. CONCLUSION:
      Athletic amenorrhea is associated with reduced endothelium-dependent dilation of
      the brachial artery. This may predispose to accelerated development of
      cardiovascular disease.

PMID- 12618564
TI  - New disorders in carbohydrate metabolism: congenital disorders of glycosylation
      and their impact on the endocrine system.

PMID- 12618567
TI  - PoleStriding exercise and vitamin E for management of peripheral vascular
      disease.
AB  - PURPOSE: The purpose of this investigation was to evaluate the efficacy of
      PoleStriding exercise (a form of walking that uses muscles of the upper and lower
      body in a continuous movement similar to cross-country skiing) and vitamin E
      (alpha-tocopherol) to improve walking ability and perceived quality of life (QOL)
      of patients with claudication pain secondary to peripheral arterial disease
      (PAD). METHODS: Fifty-two subjects were randomized into four groups: PoleStriding
      with vitamin E (N = 13), PoleStriding with placebo (N= 14), vitamin E without
      exercise (N= 13), and placebo without exercise (N = 12). The dose of vitamin E
      was 400 IU daily. Only the PoleStriding with vitamin E and PoleStriding with
      placebo groups received PoleStriding instruction and training. Assignment to
      vitamin E or placebo was double blind. Subjects trained three times weekly for 30
      45 min (rest time excluded). Individuals in vitamin E and placebo groups came to
      the laboratory biweekly for ankle blood-pressure measurements. RESULTS: Results
      of this randomized clinical trial provide strong evidence that PoleStriding
      significantly (P< 0.001) improved exercise tolerance on the constant work-rate
      and incremental treadmill tests. Ratings of perceived claudication pain were
      significantly less after the PoleStriding training program (P= 0.02). In
      contrast, vitamin E did not have a statistically significant effect on the
      subjects' ratings of perceived leg pain (P= 0.35) or treadmill walking duration (
      P= 0.36). Perceived distance and walking speed (Walking Impairment Questionnaire)
      and perceived physical function (Rand Short Form-36) improved in the PoleStriding
      trained group only (P< 0.001, 0.022 and 0.003, respectively). CONCLUSION:
      PoleStriding effectively improved the exercise tolerance and perceived QOL of
      patients with PAD. Little additional benefit to exercise capacity was realized
      from vitamin E supplementation.

PMID- 12618568
TI  - Can relaxation lower metaboreflex-mediated blood pressure elevations?
AB  - PURPOSE: Relaxation can lower resting blood pressure, and this investigation
      sought to determine whether relaxation could reduce mean blood pressure (MBP)
      elevations produced by postexercise circulatory occlusion (PECO). METHODS:
      Sixteen volunteers trained with relaxation and were able to decrease MBP at rest
      by at least 5 mm Hg within 2 min. Subjects performed four tests assigned
      randomly: i). rest with cuff occlusion, ii). rest and cuff occlusion with
      relaxation, iii). hand-grip exercise followed by PECO rest with cuff occlusion,
      and iv) hand-grip exercise followed by PECO with relaxation. Data for HR and MBP
      were collected using a Finapres; ratings of relaxation and discomfort from cuff
      occlusion were obtained using a 1- to 10-unit scale. Stroke volume (SV) and HR
      were collected from six subjects to calculate cardiac output and total peripheral
      conductance (TPC). Dependent variables were compared using an ANOVA. RESULTS: HR
      (mean +/-SD) was lower during both relaxation conditions as compared with control
      (-7 +/- 4 bpm vs -2 +/- 3 bpm; P< 0.05). The MBP was reduced during relaxation
      alone (-6 +/- 3.7 mm Hg; < 0.05) but not during PECO with relaxation. The rating
      of relaxation was higher during relaxation (6.8 +/- 1.3 units) versus control
      (3.5 +/- 1.2 units), but ratings were not different between relaxation
      conditions. Ratings of discomfort were higher during PECO ( P< 0.05). Relaxation
      did not significantly alter CO or SV (N= 6). During relaxation alone, TPC was
      increased (0.046 +/- 0.001 vs 0.049 +/- 0.002 L.min.mm Hg; P< 0.05). However, TPC
      was significantly increased during PECO with relaxation. CONCLUSIONS: These
      findings suggest that although relaxation can affect cardiovascular regulation
      and lower HR and MBP at rest, this central signal cannot lower reflex increases
      in blood pressure originating from a peripheral metabolic stimulus.

PMID- 12618562
TI  - Congenital malformations in offspring of diabetic mothers--animal and human
      studies.

PMID- 12618569
TI  - Exercise and diet in obesity treatment: an integrative system dynamics
      perspective.
AB  - PURPOSE: Demonstrate the utility of System Dynamics computer modeling to study
      and gain insight into the impacts of physical activity and diet on weight gain
      and loss. METHODS: A holistic System Dynamics computer model is presented that
      integrates the processes of human metabolism, hormonal regulation, body
      composition, nutrition, and physical activity. These processes are not
      independent of one another, and the model captures the complex interdependencies
      between them in the regulation of body weight and energy metabolism. The article
      demonstrates how such an integrative simulation model can serve as a viable
      laboratory tool for controlled experimentation to investigate the impacts of
      physical activity and diet on body weight and composition. RESULTS: In one
      experiment, weight loss from a moderate level of daily exercise was slightly less
      than the loss from dieting. Although exercise did have a favorable impact on body
      composition by protecting against the loss in fat-free mass (FFM), it, however,
      failed to blunt the drop in resting energy expenditure (REE) that accompanies
      diet-based weight loss. The smaller loss in FFM did indeed induce a smaller drop
      in REE, however, the preservation of FFM also affected a relatively larger loss
      in FM, which, in turn, induced a larger adaptive reduction in the metabolic rate.
      The two adaptations almost totally offset one another, causing minimal
      differences in REE. In a second experiment, exercise regimens of moderate- to
      high-level intensity proved counterproductive as weight-reducing strategies.
      However, when the diet was changed from a balanced composition to one that was
      highly loaded with carbohydrates, it became possible to sustain the intense
      exercise regimen over the experimental period and achieve a significant drop in
      body weight. CONCLUSION: The results underscore the significant interaction
      effects between physical activity, diet, and body composition and demonstrate the
      utility of computer-based experimentation to study, gain insight into, and make
      predictions about their dynamics.

PMID- 12618570
TI  - Design of FRESH START: a randomized trial of exercise and diet among cancer
      survivors.
AB  - PURPOSE: FRESH START is a randomized controlled trial that will test whether a
      personally tailored, distance-medicine-based program will increase exercise and
      fruit and vegetable consumption, and decrease fat intake of individuals recently
      diagnosed with breast or prostate cancer. METHODS: Early-stage breast and
      prostate cancer cases (N= 530) will be identified within 9 months of diagnosis
      from hospital cancer registries and large oncologic practices throughout the
      United States. These individuals will be sent a letter of invitation and screened
      for eligibility. After a baseline telephone interview, participants will be
      randomized into one of two arms that receive materials aimed at increasing
      exercise and fruit and vegetable intake, and decreasing dietary fat: 1). an
      experimental arm that receives a workbook and a series of six 4-page newsletters
      delivered every 7 wk and personally tailored on type of cancer, cancer coping
      style, race, age, self-efficacy, stage of readiness, and barriers and/or progress
      toward goal behavior (i.e., >or= 30 min of exercise at least 5 d.wk, >or= 5
      servings of vegetables and fruit per day, and <or= 30% of calories from fat); or
      2). a control arm that receives a series of nontailored health brochures. Follow
      up interviews scheduled 1 and 2 yr postbaseline will determine short- and long
      term efficacy and the effects of the interventions on other endpoints (quality of
      life, perceived health, etc.). Factors, such as gender, race, and social support,
      also will be explored to determine potential interactions with program efficacy.
      CONCLUSION: Given the growing number of cancer survivors, distance-medicine-based
      interventions addressing multiple behaviors and targeting this high-risk group
      have the potential to make a positive and broad public health impact.

PMID- 12618571
TI  - A more efficient magnetic resonance imaging-based strategy for measuring
      quadriceps muscle volume.
AB  - PURPOSE: To determine the accuracy of several magnetic resonance imaging (MRI)
      based strategies for assessment of quadriceps muscle volume (MV) and changes in
      MV with training. METHODS: Images were acquired along the length of both thighs
      from young (26 +/- 3 yr, N= 23) and older (69 +/- 3 yr, N= 24) men and women
      before and after strength training. The quadriceps cross-sectional area (QCSA) of
      each section was measured before and after training. MV was directly assessed
      using all of the sections (each 9-mm thick with a 1-mm gap). Alternative
      estimates of MV were calculated using increasingly greater intervals between
      sections: every 1.1 cm (MV2), 3.1 cm (MV4), 5.1 cm (MV6), 7.1 cm (MV8), 9.1 cm
      (MV10), and a single QCSA (L1). The 95% limits of agreement (LOA, +/- 2 SD)
      between each alternative measure and the criterion measure MV were determined
      with Bland and Altman plots. Regression was used to predict MV from L1 and to
      obtain the standard error of the estimate (SEE). RESULTS: Before training, the
      95% LOA with MV for the alternative measures ranged from 0.7% to 6.36% of MV, and
      the prediction of MV from L1 yielded a SEE x 2 of 14.1% of MV. For change in the
      alternative measures, the 95% LOA ranged from 10.3% to 26.3% of the total change
      in MV, and the prediction of deltaMV from deltaL1 yielded a SEE x 2 of 60% of the
      change in MV. CONCLUSION: Increasingly greater intervals between axial MRI
      sections result in substantially reduced agreement with a criterion measure of
      MV. The use of one axial section results in relatively higher error and thus
      should be used only when large effect sizes are expected.

PMID- 12618572
TI  - Single muscle fiber myosin heavy chain distribution in elite female track
      athletes.
AB  - PURPOSE: Myosin heavy chain (MHC) characterization of tissue samples from the
      gastrocnemius muscle of six elite female athletes and 10 untrained females was
      performed using myosin ATPase histochemistry and gel electrophoresis. Athletes
      were of national and international caliber, whereas their untrained counterparts
      were healthy individuals not involved in a regular exercise program. METHODS:
      Muscle biopsies for the athletes were performed 14 wk into their training season
      and analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS
      PAGE) and myosin ATPase techniques. RESULTS: Electrophoretic analysis of single
      muscle fibers from elite athletes revealed a MHC phenotype composition of 46 +/-
      6% type I, 21 +/- 6% type IIa, and 0% type IIx, whereas 34% of the single fibers
      expressed multiple MHC isoforms. When compared with the elite women, untrained
      subjects demonstrated higher percentages of type I MHC and lower percentages of
      IIa MHC muscle fibers, 57 +/- 5 and 16 +/- 3%, respectively (P < 0.05). Similar
      to the female athletes, 27% of the fibers from untrained women possessed multiple
      myosin isoforms. Myosin ATPase staining demonstrated a greater percentage of type
      I fibers in untrained subjects versus the elite women (67 +/- 3 vs 41 +/- 2%, P<
      0.05) (mean +/- SE), whereas the athletes had a higher percentage of type IIa
      fibers compared with the untrained women (49 +/- 5 vs 19 +/- 2%, P< 0.05). There
      were no differences in the percentage of IIb fibers between elite and untrained
      women (11 +/- 4 vs 14 +/- 2%, respectively). CONCLUSIONS: Whereas a preponderance
      of hybrid fibers is generally observed in untrained populations, the diverse MHC
      phenotype seen in these elite female athletes is uncommon. These unique findings
      are attributed to the chronic and varied nature of training in which these
      athletes were involved.

PMID- 12618573
TI  - Estrogen receptor alpha mRNA in human skeletal muscles.
AB  - INTRODUCTION/PURPOSE: To explain the effect of estrogen on skeletal muscle, the
      presence of estrogen receptor alpha mRNA (ERalpha mRNA) was investigated in human
      skeletal muscle. METHODS: The highly sensitive technique of nested reverse
      transcriptase-polymerase chain reaction (nested RT-PCR) was applied on a variety
      of tissue samples of both sexes: women (deltoid, pectoral, and uterus muscles)
      (N= 3) and men (deltoid muscle) (N= 3). The total ribonucleic acid was isolated
      from each tissue sample, reverse transcribed in a thermocycler, and nested PCR
      was then performed with specific primers. The by-products were analyzed by
      agarose gel electrophoresis. Internal standard 28S was simultaneously amplified.
      The ERalpha mRNA level was quantitated by using the ERalpha mRNA/28S mRNA ratio.
      RESULTS: The expected 204-bp product corresponding to ERalpha was amplified in
      all tested tissue samples, i.e., deltoid, pectoral, and uterine muscles from
      women and deltoid muscle from men. The ERalpha mRNA/28S mRNA ratios indicating
      the receptor expression levels in deltoid muscle from men and women were 0.945 +/
      0.393 (mean +/- SD) (N= 3) and 0.973 +/- 0.136 (mean +/- SD) (N= 2),
      respectively. CONCLUSIONS: In conclusion, the nested RT-PCR technique identified
      the presence of transcript encoding ERalpha mRNA in human skeletal muscles. Semi
      quantification did not reveal gender difference.

PMID- 12618574
TI  - Exercise-induced increases in cardiac troponins and prothrombotic markers.
AB  - Cardiac troponin I and T are potent tools for risk stratification and clinical
      decision-making for patients in the appropriate clinical setting of an acute
      coronary syndrome. Although these findings are relevant to patients with a
      typical clinical presentation, caution should be exercised in generalizing the
      results to troponin-positive athletes with a low clinical suspicion of coronary
      artery disease. This review addresses the clinical relevance of increased
      troponin levels induced by strenuous exercise. The imprecision and lack of
      standardization of currently available troponin assays merit caution with the
      application of these findings. In addition, it may well be that if reparative
      processes are present and/or the release is not due to irreversible injury that
      increases in troponins after vigorous exercise are normal and should not be
      expected to be of pathophysiological significance. Due to this potential for
      misclassification, the crux of appropriate interpretation of troponin testing is
      careful consideration of the corresponding clinical scenario. Troponin-positive
      patients often have complex coronary lesion morphology with intracoronary
      thrombus and understandably derive particular benefit from platelet glycoprotein
      GpIIb/IIa inhibitors as well as low molecular weight heparins. Studies on
      exercise-induced activation of blood coagulation have produced conflicting
      results. At present, there is no clear evidence that a hemostatic imbalance may
      trigger acute cardiac events after strenuous exercise. In contrast to troponin
      positive patients, it may thus be premature and even dangerous to recommend
      pharmacologic intervention (low molecular weight heparins) to (troponin-positive)
      endurance athletes even when exercising during high-altitude exposure.

PMID- 12618575
TI  - Independent and combined effects of amino acids and glucose after resistance
      exercise.
AB  - PURPOSE: This study was designed to assess the independent and combined effects
      of a dose of amino acids (approximately 6 g) and/or carbohydrate (approximately
      35 g) consumed at 1 and 2 h after resistance exercise on muscle protein
      metabolism. METHODS: Following initiation of a primed constant infusion of H 
      phenylalanine and N-urea, volunteers performed leg resistance exercise and then
      ingested one of three drinks (amino acids (AA), carbohydrate (CHO), or AA and CHO
      (MIX)) at 1- and 2-h postexercise.(5) RESULTS: Total net uptake of phenylalanine
      across the leg over 3 h was greatest in response to MIX and least in CHO. The
      individual values for CHO, MIX, and AA were 53 +/- 6, 114 +/- 38, and 71 +/- 13
      mg x leg x 3h. Stimulation of net uptake in MIX was due to increased muscle
      protein synthesis. CONCLUSIONS: These findings indicate that the combined effect
      on net muscle protein synthesis of carbohydrate and amino acids given together
      after resistance exercise is roughly equivalent to the sum of the independent
      effects of either given alone. The individual effects of carbohydrate and amino
      acids are likely dependent on the amount of each that is ingested. Further, prior
      intake of amino acids and carbohydrate does not diminish the metabolic response
      to a second comparable dose ingested 1h later.

PMID- 12618576
TI  - A meta-analysis to determine the dose response for strength development.
AB  - PURPOSE: The identification of a quantifiable dose-response relationship for
      strength training is important to the prescription of proper training programs.
      Although much research has been performed examining strength increases with
      training, taken individually, they provide little insight into the magnitude of
      strength gains along the continuum of training intensities, frequencies, and
      volumes. A meta-analysis of 140 studies with a total of 1433 effect sizes (ES)
      was carried out to identify the dose-response relationship. METHODS: Studies
      employing a strength-training intervention and containing data necessary to
      calculate ES were included in the analysis. RESULTS: ES demonstrated different
      responses based on the training status of the participants. Training with a mean
      intensity of 60% of one repetition maximum elicits maximal gains in untrained
      individuals, whereas 80% is most effective in those who are trained. Untrained
      participants experience maximal gains by training each muscle group 3 d.wk and
      trained individuals 2 d.wk. Four sets per muscle group elicited maximal gains in
      both trained and untrained individuals. CONCLUSION: The dose-response trends
      identified in this analysis support the theory of progression in resistance
      program design and can be useful in the development of training programs designed
      to optimize the effort to benefit ratio.

PMID- 12618577
TI  - Objective physical activity of filipino youth stratified for commuting mode to
      school.
AB  - PURPOSE: The Cebu Longitudinal Health and Nutrition Survey included self-report
      measures and objective measures (Caltrac accelerometer) of Filipino adolescent
      (ages 14-16) physical activity (PA) in 1998-99. The purpose of this subanalysis
      was to compare objectively monitored PA of adolescents who differed by their self
      reported habitual commuting mode to school, specifically commuting by walking,
      motorized transport, or a combination of the two. METHODS: Descriptive analysis
      included the proportion of adolescents who reported commuting to school by the
      different modes, participating in sport/exercise during or after school, or
      currently working. ANCOVA was used to estimate and compare adjusted mean Caltrac
      derived energy expenditure (kcal.d ) by commuting mode for each gender.
      Covariates were age, weight, and height. RESULTS: The analysis sample of 1518
      Filipino adolescents included 691 male (BMI = 18.5 +/- 2.5) and 827 female
      subjects (BMI = 18.7 +/- 2.3). A total of 323 male subjects (46.8% of all male
      subjects) walked to school, 160 (23.2%) took motorized transport, and 208 (30.0%)
      used a combination of the two modes. The corresponding values for female subjects
      were 303 (36.6%), 177 (21.4%), and 347 (42.0%). The absolute difference in
      Caltrac-derived energy expenditure that appeared to be due to active commuting
      was 44.2 kcal.d for Filipino male adolescents and 33.2 kcal.d for female
      adolescents. These differences between commuting modes could not be explained by
      participation in sport/exercise or by current employment. CONCLUSIONS: Assuming
      200 school days in a year, the difference in energy expended due to active
      commuting translates to a 8840 kcal and 6640 kcal in male and female subjects,
      respectively. For those youth who commute to school by motorized transport a
      yearly positive energy balance (i.e., weight gain) of 2-3 lb would be
      anticipated, all other things being held constant.

PMID- 12618578
TI  - Biomechanical analysis of running in military boots with new and degraded
      insoles.
AB  - PURPOSE: The purpose of the present study was to investigate the influence of
      degradation using repeated impacts on the ability of different shock-absorbing
      insoles to reduce peak impact loading during running in military boots. METHODS:
      Four insole types were degraded mechanically to simulate typical running loads
      that occur during approximately 100 km of running. The influence of insole
      mechanical degradation on stiffness and impact-absorbing ability was assessed
      using standard test procedures. The ability of new and degraded insole samples to
      reduce peak impact loading during running was assessed by monitoring peak impact
      force and rate of loading. In addition, the influence of insoles on sagittal
      plane kinematics was quantified by measurement of hip, knee, and ankle joint
      flexion. RESULTS: Insole mechanical degradation resulted in an increase in
      mechanical stiffness and a decrease in ability to reduce mechanical impacts for
      all test insoles. Measurements taken during running indicated that only one
      insole type reduced peak impact loading when new, as indicated by a significant
      (P< 0.05) reduction in peak rate of loading. The ability of this insole type to
      reduce peak rate of loading during running was maintained after mechanical
      degradation. This insole was also found to significantly (P< 0.05) reduce peak
      ankle dorsiflexion. CONCLUSION: The present study identifies an insole type that
      reduces peak rate of loading during running both when new and when mechanically
      degraded. It is suggested that this indicates an insole that could potentially
      reduce the frequency of overuse injuries. Based on these results, this insole is
      recommended for use in the investigation of the practical use of insoles by
      military recruits, particularly for study of the influence on injury occurrence.

PMID- 12618579
TI  - Physiological correlates with endurance running performance in trained
      adolescents.
AB  - PURPOSE: To examine the relationship between competitive 800-m and 1500-m
      performance times and a number of physiological variables in a group of endurance
      trained, adolescent runners. METHODS: Twenty-three boys and 17 girls volunteered
      to participate in the study. Track-based, running performance times were
      available for 18 boys and 14 girls for the 800 m, and 16 boys and 13 girls for
      the 1500 m. The relationships between these times and the following physiological
      variables were determined: peak VO(2) running economy (RE), estimated running
      speed at peak vV0(2peak), peak and mean anaerobic power, and fixed [BLa ] at 2.0,
      2.5, and 4.0 mmol.L. RESULTS: RE and vV0(2peak) were significant independent
      variables for the boys' 800 m (r = 0.62 and -0.62, < 0.01). For the girls, once
      chronological age was partialled out, none of the measured variables were
      significantly related to 800-m performance. For the 1500-m event, peak V0(2),
      vV0(2peak), and the running speed at 2.5 mmol.L (v2.5) were significant
      independent variables in the boys (r = -0.43, -0.39, and -0.53, < 0.05) and girls
      (r = -0.50, -0.61, and -0.54, < 0.05). In addition, the V0(2) at 2.5 mmol.L V0(2)
      (2.5) was related to the 1500-m time in the girls (r = -0.54, < 0.05).
      CONCLUSION: The physiological variables that were most strongly correlated with
      middle-distance running performance were v2.5 and the vV0(2peak). To a lesser
      extent peak V02 may also play a role although it is understood that its
      contribution may be accounted by vV0(2 peak).

PMID- 12618580
TI  - Modeling maximum oxygen uptake of elite endurance athletes.
AB  - PURPOSE: To compare the maximum oxygen uptake V0(2max) of elite endurance
      athletes and to explain why the body mass exponent, necessary to render V0(2max)
      independent of body mass, appears to be greater than 0.67. METHODS: Study 1:
      V0(2max) of 174 international sportsmen and women was assessed. Athletes were
      recruited from seven sports (middle- and long-distance runners, heavyweight and
      lightweight rowers, triathletes, and squash and badminton players). Study 2: calf
      and thigh leg muscle masses were estimated in 106 male and 30 female athletes
      from 11 sports. Differences in V0(2max) and leg muscle masses between "sports"
      and "sex" were analyzed independent of body mass by using allometric log-linear
      ANCOVA. RESULTS: Heavyweight rowers had the greatest V0(2max) when expressed in
      L.min but long-distance runners had the highest V0(2max)in mL.kg.min. However,
      the ANCOVA identified no difference in "mass independent" V0(2max) between the
      five "pure" endurance sports (runners, rowers, and triathletes) (P > 0.05) with
      the two racket sports being significantly lower. The body mass covariate exponent
      was inflated, estimated as 0.94. The results from study 2 estimated calf and
      thigh leg muscle masses to increase in proportion to body mass, and,
      respectively. CONCLUSIONS: After having controlled for differences in body mass,
      V0(2max) did not differ between pure endurance sports (P > 0.05). Assuming that
      athletes' thigh muscle mass increases in proportion to body mass as observed in
      study 2, a similar disproportional increase in V0(2max) would be anticipated,
      providing a plausible explanation for the inflated mass exponent associated with
      V0(2max) identified in this and other studies.

PMID- 12618581
TI  - Gender differences in workload effect on coordination between breathing and
      cycling.
AB  - PURPOSE: To investigate the gender differences in the effect of increasing
      workload level and thus of an increasing metabolic drive to ventilation on the
      degree of coordination between breathing and cycling rhythms. METHODS: Twenty-one
      men and 21 women cycled on an electromagnetically braked ergometer while
      breathing through a pneumotachograph at workloads corresponding to 55, 75, and
      95% of V0(2peak) (WL1, WL2, and WL3). Leg movements, respiratory parameters, and
      heart rate were continuously recorded. The degree of coordination (%coord) was
      quantified as the percentage of breaths starting during the same phase of leg
      movement. RESULTS: In men, %coord increased with increasing exercise intensity
      (WL1: mean +/- SE = 18.8 +/- 2.6%, WL2: 30.9 +/- 4.9%, WL3: 40.9 +/- 5.6%),
      whereas in women exercise intensity had no influence on %coord (WL1: 25.0 +/-
      5.0%, WL2: 29.7 +/- 5.1, WL3: 31.7 +/- 4.7%). There were no gender differences in
      breathing pattern during high metabolic demands. A major effect on %coord came
      from the regularity of the breathing rhythm, whereas cycling frequency, fitness
      level, or cycling experience exerted no influence. CONCLUSIONS: The present study
      demonstrates that the effect of exercise intensity on the occurrence of
      coordination between breathing and cycling rhythms differs between men and women.

PMID- 12618582
TI  - Evaluation of air displacement for assessing body composition of collegiate
      wrestlers.
AB  - PURPOSE: To evaluate the accuracy of air displacement plethysmography (ADP) by
      using the BOD POD in comparison with hydrostatic weighing (HW) in a collegiate
      wrestling population in hydrated and acutely dehydrated states. METHODS: Body
      composition was determined by ADP, HW, and three-site skinfolds (SK) in 66 NCAA
      Division I collegiate wrestlers before and after acute dehydration (2.6%
      reduction in body mass). For all methods, body density (D(b)) was converted to
      percent body fat (%BF) by using the Brozek equation for Euro-Americans and the
      Schutte equation for African-Americans. RESULTS: There were no significant
      differences between ADP and HW for D(b), %BF, and fat-free mass (FFM) in either
      the hydrated or dehydrated states. The standard errors of the estimate for %BF
      estimated from ADP with HW as the reference method were 2.12% (hydrated) and
      2.16% (dehydrated); prediction errors were 2.35% (hydrated) and 2.49%
      (dehydrated). Bland-Altman plots of D(b) and %BF showed no systematic bias, and
      64 out 66 subjects fell within the 95% limits of agreement (mean difference +/- 2
      SD) for both variables. For SK, %BF was significantly higher than HW in both the
      hydrated and dehydrated state. All methods (ADP, HW, and SK) showed a significant
      decrease in FFM from the hydrated to the dehydrated state. CONCLUSIONS: This
      study demonstrates that the BOD POD air displacement method provides similar
      estimates of D (b), %BF, and FFM when compared with HW in a heterogeneous
      collegiate wrestling population during hydrated and acutely dehydrated states.
      Pretest guidelines to ensure normal hydration status before body composition
      assessment using any method must be followed to minimize measurement error in
      %BF.

PMID- 12618583
TI  - Sport and home physical activity are independently associated with bone density.
AB  - PURPOSE: To study the relations between four domains of physical activity-sport,
      home, work, and active living-and bone mineral density (BMD). METHODS: Baseline
      data from African-American (N = 544), Caucasian (N= 1044), Chinese (N= 230), and
      Japanese (N= 239) participants, aged 42-52 yr, from the study of Women's Health
      Across the Nation were analyzed. BMD was measured with Hologic 2000 or 4500A
      densitometers. Physical activity was assessed with the Kaiser Physical Activity
      Scale, which rates each domain of activity between 1 (low) and 5 (high). Multiply
      adjusted linear regression models were used to estimate the relations between
      each activity domain and BMD. RESULTS: The mean and median values of sport, home,
      work, and active living each approximated the midpoint of the scale and did not
      differ substantially among ethnic groups. Scores for each domain of activity were
      not highly correlated, with r values ranging between -0.03 and 0.33. Independent
      of age, body mass index, ethnic group, alcohol use, dietary calcium, smoking,
      menopause status, SWAN site, and other domains of physical activity, higher sport
      activity was statistically significantly associated with greater BMD at the
      lumbar spine (P= 0.008), femoral neck (P= 0.0002), and total hip (P< 0.0001).
      More home physical activity was associated with higher BMD at the spine (P=
      0.049) and femoral neck (P= 0.008). Neither work physical activity nor active
      living was related to BMD at any bone site. CONCLUSIONS: These results highlight
      the need to consider domain-specific physical activity in relation to health
      outcomes in women.

PMID- 12618584
TI  - Strength indices of the proximal femur and shaft in prepubertal female gymnasts.
AB  - INTRODUCTION/PURPOSE: The role of impact loading activity on bone mass is well
      established; however, there are little data on the effects of exercise on bone
      geometry and indices of bone strength. The primary purpose of this study was to
      compare indices of bone strength at the proximal femur (PF) between elite
      premenarcheal gymnasts (N= 30) and age-matched controls (N= 30). METHODS:
      Structural properties of the proximal femur were derived from the hip analyses
      program and included measurement of subperiosteal width, endosteal diameter,
      cross-sectional area, bone mineral density, cross-section moment of inertia
      (CSMI), and section modulus (Z). These parameters were measured for two regions
      of the PF: the narrow neck (NN), and the shaft (S). In addition, a strength index
      (S-SI) was calculated at the shaft by dividing the Z at the shaft by the femur
      length. A secondary purpose was to compare bone mineral content (BMC) values at
      the total body, lumbar spine, and three sites at the PF (neck, trochanter, and
      total) between the groups. All dependent values were compared adjusting for
      height and weight using an ANCOVA procedure and for relative lean body mass.
      RESULTS The gymnasts had significantly greater size-adjusted strength indices
      (CSMI, Z, and SI) at the NN and S. Gymnasts also had significantly greater size
      adjusted BMC at all sites investigated. However, these differences disappeared
      when adjusted for relative lean body mass. CONCLUSION: When adjusted for body
      size, gymnasts had significantly greater indices of both axial strength and
      bending strength at the NN region of the PF and S, as well as a greater bone SI
      at the femoral shaft. These differences may be related to greater relative lean
      body mass attained in gymnastics training.

PMID- 12618585
TI  - Effect of a FastSkin suit on submaximal freestyle swimming.
AB  - PURPOSE: Nine male collegiate swimmers swam three 183-m freestyle trials at
      "moderate, moderately hard, and hard" paces while wearing a traditional brief
      style suit and on another occasion while wearing a newly designed suit covering
      the torso and legs with a material designed to reduce drag (FS). METHODS:
      Postswim blood lactate concentration, V0(2), and rating of perceived exertion
      were measured. Average stroke length and rate, and breakout distance were
      determined for each swimming trial. Passive drag and buoyant force were also
      determined on swimmers while wearing both suits. RESULTS: Swimmers swam at a
      higher mean velocity while wearing the FS (pooled mean % difference = 2%), but
      this was accompanied by a significant increase in V0(2) (4% difference, P< 0.05)
      and blood lactate concentration (10% difference, P< 0.05). Comparison of
      physiological responses at standardized freestyle swimming speeds of 1.4 and 1.6
      m.s revealed no significant difference between the two suit conditions. Passive
      drag of the swimmers while being towed was not significantly different between
      the suits. Swimmers were significantly more buoyant while wearing the brief-style
      suit than the FS suit (P< 0.05). CONCLUSION: These findings provide no evidence
      of either physical or physiological benefits of wearing these suits during
      submaximal freestyle swimming.

PMID- 12618586
TI  - Habitual physical activity in children and adolescents during school and free
      days.
AB  - PURPOSE: The purpose of this study was to analyze habitual physical activity
      (HPA) of boys and girls from primary school to high school. METHODS: One hundred
      eighty-two schoolchildren and teenagers (6-20 yr) were studied at primary school
      (PS, N= 64), junior high school (JHS, N= 67), and senior high school (SHS, N=
      51). HR was continuously monitored during the whole week to assess HPA during
      school days and free days. Total physical activity (TPA), low physical activity
      (LPA), moderate physical activity (MPA), and vigorous physical activity (VPA)
      were evaluated from the time spent each day above 50%HR reserve (HRR), below
      50%HRR, between 50% and 70%HRR, and above 70%HRR, respectively. RESULTS: During
      school days, TPA decreased by 69% in male subjects (P< 0.05) and by 36% in female
      subjects (N= 0.058) from PS to SHS. In contrast, TPA did not vary significantly
      during free days (male subjects, PS: 62 +/- 37 min x d, SHS: 63 +/- 67 min x d;
      female subjects, PS: 75 +/- 59 min x d, SHS: 62 +/- 44 min x d ). Gender
      differences were only observed during school days at PS for TPA (male subjects:
      121 +/- 37 min x d vs female subjects: 92 +/- 44 min x d, P< 0.05) and VPA (male
      subjects: 38 +/- 21 min x d vs female subjects: 18 +/- 12 min x d, P< 0.05). Male
      and female subjects were more inactive during free days than during school days
      at PS (P< 0.05). No effect of the type of day and gender was observed for all
      indices of HPA at high schools. CONCLUSIONS: Our results highlight the importance
      of taking into account the type of day (school day vs free day) in the analysis
      of children and adolescents' HPA.

PMID- 12618588
TI  - Specificity of respiratory training may account for the improvement of endurance
      capacity.

PMID- 12618587
TI  - Validity and reliability of activity measures in African-American girls for GEMS.
AB  - PURPOSE: To determine the reliability and validity of physical activity monitors
      and self-report instruments suitable for young African-American girls. METHODS: A
      validation study was conducted by the Girls health Enrichment Multi-site Studies
      (GEMS) research team to compare an accelerometer with a pedometer and two self
      report instruments for assessing physical activity in African-American girls, age
      8-9 yr. Girls (N= 68) attended two clinic visits spaced 4 d apart. Each girl wore
      a MTI/CSA accelerometer (used as the criterion standard for validity) and a
      pedometer simultaneously for four consecutive days. Girls completed on two
      occasions a 24-h physical activity checklist of yesterday and usual activities,
      including sedentary activities (GEMS Activity Questionnaire, GAQ), and a 3-d
      computerized self-report instrument (Activitygram). RESULTS: Girls were (mean +/-
      SD) 9.0 +/- 0.6 yr old and had a body mass index of 19.4 kg x m. Reliability
      measured by intraclass correlations (ICC) and Pearson correlation coefficients
      (r) were calculated for the MTI/CSA (ICC = 0.37, P< 0.0001), pedometer (ICC =
      0.08, = 0.094), Activitygram (ICC = 0.24) (P = 0.005), and GAQ for physical (r =
      0.80, P< 0.0001) and sedentary (r = 0.3-0.5, P< 0.005) activities. Significant
      Pearson correlations between the MTI/CSA and the other instruments, as a measure
      of validity, were observed for the 4-d average pedometer score (r = 0.47, P<
      0.0001), 3-d average Activitygram score (r = 0.37, P= 0.002), and the average of
      the two yesterday and two usual GAQ activity scores for a subset of 18 physical
      activities questions (r = 0.27, = 0.03; and r = 0.29,P = 0.02, respectively). The
      MTI/CSA was uncorrelated with single day scores from the three other instruments.
      CONCLUSION: The reliability of the instruments tested was acceptable, except the
      pedometer. Validity correlations were significant when more than one day was
      used. Self-report instruments need further development for improved reliability
      and validity.

PMID- 12618589
TI  - Novel polymorphisms in the glutathione transferase superfamily.

PMID- 12618590
TI  - Genetic polymorphism of the human manganese superoxide dismutase: what difference
      does it make?

PMID- 12618591
TI  - Characterization of the human Omega class glutathione transferase genes and
      associated polymorphisms.
AB  - The Omega class glutathione transferases (GSTs) have been identified in many
      organisms, including human, mouse, rat, pig, Caenorhabditis eglands and
      Drosophila melanogaster. These GSTs have poor activity with common GST
      substrates, but exhibit novel glutathione-dependent thioltransferase,
      dehydroascorbate reductase and monomethylarsonate reductase activities, and
      modulate Ca release by ryanodine receptors. An investigation of the genomic
      organization of human GSTO1 identified a second actively transcribed member of
      the Omega class (GSTO1). Both GSTO1 and GSTO2 are composed of six exons and are
      separated by 7.5 kb on chromosome 10q24.3. A third sequence that appears to be a
      reverse-transcribed pseudogene (GSTO3p) has been identified on chromosome 3.
      GSTO2 has 64% amino acid identity with GSTO1 and conserves the cysteine residue
      at position 32, which is thought to be important in the active site of GSTO1.
      Expression of GSTO2 mRNA was seen in a range of tissues, including the liver,
      kidney, skeletal muscle and prostate. The strongest GSTO2 expression was in the
      testis, which also expresses a larger transcript than other tissues.
      Characterization of recombinant GSTO2 has been limited by its poor solubility.
      Two functional polymorphisms of GSTO1 have been identified. One alters a splice
      junction and causes the deletion of E155 and another results in an A140D
      substitution. Characterization of these variants revealed that the A140D
      substitution affects neither heat stability, nor activity towards 1-chloro-2,4
      dinitrobenzene or hydroxyethyl disulphide. In contrast, deletion of residue E155
      appears to contribute towards both a loss of heat stability and increased
      enzymatic activity.

PMID- 12618592
TI  - The Ala16Val genetic dimorphism modulates the import of human manganese
      superoxide dismutase into rat liver mitochondria.
AB  - A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the
      mitochondrial targeting sequence (MTS) of human manganese superoxide dismutase
      (MnSOD) and has been reported to modulate the risk of some cancers,
      neurodegenerative diseases and severe alcoholic liver disease. Although
      functional consequences of this dimorphism on MnSOD activity have not been
      assessed, computer models predict a partial alpha-helix structure for the Ala
      MnSOD/MTS, but a beta-sheet structure for the Val-variant, which could hamper
      mitochondrial import. To investigate this hypothesis, we studied the in-vitro
      import of chimaeric proteins composed of either one of the MnSOD/MTS fused to the
      mouse dihydrofolate reductase (DHFR) protein, and the import of the two human
      MnSOD precursor variants into rat liver mitochondria. Compared to Ala-proteins,
      the Val-MnSOD/MTS-DHFR precursor and Val-MnSOD precursor were both partly
      arrested within the inner mitochondrial membrane. The Ala-MnSOD precursor
      generated 30-40% more of the active, matricial, processed MnSOD homotetramer than
      the Val-MnSOD precursor. These results show that the Ala-MnSOD/MTS allows
      efficient MnSOD import into the mitochondrial matrix, while the Val-variant
      causes partial arrest of the precursor within the inner membrane and decreased
      formation of the active MnSOD tetramer in the mitochondrial matrix.

PMID- 12618593
TI  - Prostate expression of N-acetyltransferase 1 (NAT1) and 2 (NAT2) in rapid and
      slow acetylator congenic Syrian hamster.
AB  - Arylamine carcinogens induce prostate tumours in rodent models and may contribute
      to the aetiology of human prostate cancers. N-acetylation and O-acetylation,
      catalysed by N-acetyltransferase 1 (NAT1) and 2 (NAT2), activate and/or
      deactivate arylamines to electrophilic intermediates that bind DNA and initiate
      tumours in target organs. NAT1 and NAT2 are both subject to genetic polymorphism
      in humans, and molecular epidemiological investigations suggest that NAT1 and/or
      NAT2 acetylator genotype modifies risk for prostate cancers. A Syrian hamster
      model congenic at the NAT2 locus was used to investigate the role of acetylator
      genotype in N- and O-acetylation of aromatic and heterocyclic amine carcinogens
      in the liver and prostate. A gene dose-response
      (NAT2*15/*15>NAT2*15/*16A>NAT2*16A/*16A) relationship was observed in liver and
      prostate cytosol towards the N-acetylation of p-aminobenzoic acid, 2
      aminofluorene, beta-napthylamine, 4-aminobiphenyl, and 3,2'-dimethyl-4
      aminobiphenyl. NAT1 and NAT2 were separated and partially purified from liver and
      prostate cytosol. NAT1 and NAT2 in liver and prostate catalysed -acetylation of
      the arylamines above and O-acetylation of N-hydroxy derivatives of 2
      aminofluorene, 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo[4,5
      b]pyridine. Rates were higher in rapid versus slow acetylators when catalysed by
      NAT2 but not when catalysed by NAT1. Partially purified prostate NAT2 exhibited
      higher apparent K(m) and V(max) than NAT1. Prostate NAT1 mRNA levels were higher
      than NAT2 and neither NAT1 nor NAT2 mRNA level differed with NAT2 acetylator
      genotype. The results provide mechanistic support for a role of NAT1 and/or NAT2
      acetylator polymorphism(s) in human prostate cancer risk related to aromatic
      and/or heterocyclic amine carcinogens.

PMID- 12618594
TI  - The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on
      clozapine clearance and dose requirement.
AB  - Clozapine is an atypical antipsychotic drug that is metabolized to a major extent
      by the cytochrome P450 enzyme CYP1A2. Smoking is a potent inducer of CYP1A2
      enzyme activity, resulting in significant lower clozapine serum concentrations in
      smokers compared with non-smokers, upon a given dose. Recently, a single
      nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was
      reported to affect the inducibility of the enzyme. Because this polymorphism in
      relation to smoking behaviour may be relevant in treatment with clozapine, we
      studied the effect of CYP1A2 genotype on clozapine clearance and dose requirement
      in a group of 80 smoking and non-smoking schizophrenic patients on long-term
      clozapine therapy. Clozapine serum concentration and CYP1A2 genotype had been
      determined routinely by high-performance liquid chromatography and polymerase
      chain reaction analyses, respectively. In smokers, the clozapine serum
      concentration corrected for dose (C/D ratio) was on average 2.5 times lower
      compared with non-smokers, indicating an enhanced clearance. The mean required
      maintenance doses of clozapine for smokers and non-smokers were 382 mg/day and
      197 mg/day, respectively (P < 0.01). Neither among smokers, nor among non-smokers
      mean C/D ratios and daily doses did vary significantly between patients with the
      different CYP1A2 genotypes. The results show that clozapine clearance and daily
      dose requirement are strongly associated with smoking behaviour, while the CYP1A2
      genetic polymorphism seems to have no significant clinical effect. Dosage
      adjustment based on smoking behaviour would be of value in order to lower the
      incidence of non-therapeutic serum drug levels and, consequently, intoxication or
      inadequate antipsychotic response.

PMID- 12618595
TI  - Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6.
AB  - Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central
      neurons but its function in human brain is currently unknown. Using recombinant
      enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5
      MT), a metabolite and precursor of melatonin, is a specific and high-turnover
      endogenous substrate of CYP2D6. This potent serotonergic neuromodulator in
      numerous physiological systems binds tightly to recombinant CYP2D6 enzyme with an
      equilibrium dissociation constant (K(s)) of 23.4 micromol/l, and is O
      demethylated to serotonin (5-hydroxytryptamine, 5-HT) with a high turnover of
      51.7 min(-1) and low Michaelis-Menten constant of 19.5 micromol/l. The production
      of 5-HT from 5-MT catalyzed by CYP2D6 was inhibited by selective serotonin
      reuptake inhibitors, and their inhibition potency (K(i), micromol/l) decreased in
      the order of fluoxetine (0.411) > norfluoxetine (1.38) > fluvoxamine (10.1) >
      citalopram (10.9). Liver microsomes prepared from CYP2D6-transgenic mice showed
      about 16-fold higher 5-MT O-demethylase activity than that from wild-type mice.
      After the intravenous co-administration of 5-MT (10 mg/kg) and pargyline (20
      mg/kg), serum 5-HT level was about 3-fold higher in CYP2D6-transgenic mice than
      wild-type mice. When dosed with alpha,alpha,beta,beta-d -5-MT,
      alpha,alpha,beta,beta-d4-5-HT was detected in transgenic mouse serum, and its
      content was much higher than wild-type mouse. alpha,alpha,beta,beta-d4-5-HT was
      not produced in CYP2D6-transgenic mice pretreated with quinidine. The
      regeneration of 5-HT from 5-MT provides the missing link in the serotonin
      melatonin cycle. Up to 10% of the population lacks this enzyme. It is proposed
      that this common inborn error in 5-MT O-demethylation to serotonin influences a
      range of neurophysiologic and pathophysiologic events.

PMID- 12618596
TI  - Complications of microsurgical reconstruction of obstetrical brachial plexus
      palsy.
AB  - The charts of the 173 consecutive patients who underwent microsurgical
      reconstruction for obstetrical brachial plexus palsy from 1988 to 1999
      (inclusive) in the Division of Plastic Surgery at the Hospital for Sick Children
      were analyzed. The overall complication rate was 33.5 percent, and there was no
      mortality in this series. The most significant intraoperative complication was
      accidental extubation, which occurred five times in the first 84 patients (6
      percent of this early group; 2.9 percent of the whole series). This complication
      was addressed by suturing the endotracheal tube to the membranous septum and by
      using a transparent drape to allow direct visualization of the tube in all 89
      subsequent patients. There have been no further accidental extubations.
      Postoperative fluid overload occurred in 14 patients (8.1 percent), three (1.7
      percent) of whom developed pulmonary edema. Intensive care unit admission was
      required in two of those patients. Diuretic treatment was required in seven
      patients. No patient receiving less than or equal to 4 ml/kg/hour developed fluid
      overload, whereas 50 percent of the patients receiving greater than or equal to
      10 ml/kg/hour did. Currently, the authors' policy is to strictly limit
      intravenous maintenance fluids to 4 ml/kg/hour or less. Despite the long and
      complex procedure required to reconstruct obstetrical brachial plexus palsy, the
      incidence of significant complications can be minimized with simple precautions,
      such as suturing the endotracheal tube to the septum or reducing the amount of
      fluids administered during the operation.

PMID- 12618597
TI  - Total ear reconstruction in the devascularized temporoparietal region: II. Use of
      the omental free flap.
AB  - Total ear reconstruction using the omental free flap technique was performed on
      five patients who presented with a devascularized temporoparietal region. The
      main indication for this technique was unavailability of the contralateral
      temporoparietal fascia in those requesting autogenous auricular reconstruction.
      There were no microvascular failures in the procedures conducted. In one case
      there was a partial loss of the transferred omentum, which resulted from an
      inadequate omental tailoring. A normal convoluted auricle was obtained after
      multistage debulking operations and meticulous postoperative molding. The average
      follow-up period was 3.4 years. Final aesthetic results were graded as
      satisfactory in four patients and poor in one patient.

PMID- 12618598
TI  - Lengthening of the reconstructed mandible using extraoral distraction devices:
      report of five cases.
AB  - Fibular and scapular osteocutaneous free-tissue transfer represents the workhorse
      procedure in the reconstruction of large oromandibular defects. However,
      transplanted bone segments for mandibular reconstruction may be too short for a
      correct interarch alignment, which is a prerequisite for further functional
      rehabilitation. Extraoral distraction osteogenesis was performed in the
      neomandible of five patients after tumor resection following neoadjuvant
      radiotherapy-chemotherapy. The neomandible was distracted bilaterally in two
      patients and unilaterally in three patients. Gradual distraction was applied at a
      rate of 0.5 mm twice a day after osteotomy in the region of vascularized fibular
      and scapular reconstruction. An average sagittal bone gain of 11 mm was achieved
      following active distraction. In three patients, the distraction procedure
      rendered good results with full compensation of the deficit; in one patient, the
      sagittal bone gain did not compensate for a lateral deviation of the mandible;
      and in another patient, the fixation pins loosened and had to be reaffixed.
      Osteodistraction is a treatment option in patients in whom vascularized bone
      grafts have been used for mandibular reconstruction, but due to contractures or
      lack of hard and soft tissues, no satisfactory interarch alignment could be
      achieved. Distraction procedures in irradiated and reconstructed neomandibles
      bear a higher risk of failure and complications than those in nonirradiated
      tissues. A correct and stable intermaxillary relation always has to be attempted
      in the first surgical approach, as osteodistraction cannot be suggested as a
      routine procedure in this special group of patients.

PMID- 12618599
TI  - Muscle-sparing latissimus dorsi myocutaneous flap with maintenance of muscle
      innervation, function, and aesthetic appearance of the donor site.
AB  - In this report, the authors describe the application of a muscle-sparing
      technique to harvest a myocutaneous latissimus dorsi muscle flap, including only
      a tiny lateral muscle segment but carrying a large skin paddle, with the
      advantage of leaving intact innervation and function of the remaining latissimus
      dorsi muscle. According to the experiences and complications associated with the
      pure thoracodorsal artery perforator harvest at the authors' institution, the
      necessity of increasing the reliability of the vascular pedicle demands that a
      small muscle strip be left embedding the perforator vessels attached to the skin
      paddle. This procedure was applied in eight cases with only one minor
      complication, which was a distal flap tip necrosis in the largest flap used. The
      muscle function and aesthetic contour of the posterior axillary fold were
      preserved in every case. Harvesting a large skin paddle flap that is carried by a
      diminutive longitudinal segment of latissimus dorsi muscle circumvents
      thoracodorsal nerve damage and maintains muscle function. In contrast to a
      thoracodorsal artery perforator flap without muscle, the harvesting of which is a
      delicate procedure, this procedure is regarded as easier and safer.

PMID- 12618600
TI  - Free flap from the flexor aspect of the wrist for resurfacing defects of the hand
      and fingers.
AB  - The distal portion of the flexor aspect of the forearm has been used as the donor
      site of full-thickness skin grafts, venous skin grafts, and Chinese forearm
      flaps. This article describes the use of a free flap harvested from the flexor
      aspect of the wrist and based on the superficial palmar branch of the radial
      artery to repair skin defects of the hand and fingers. The advantages of this
      flap are as follows: (1) the operative field is the same; (2) the radial artery
      is preserved; (3) it is thin, pliable, and hairless and thus can supply a gliding
      surface for tendons beneath it; (4) when it involves a palmaris longus tendon
      and/or the palmar cutaneous branch of the median nerve, it can be used as a
      vascularized tendon or nerve graft; and (5) in view of the flow-through type of
      the pedicle of the flap, the digital artery can be reconstructed simultaneously.
      However, it should be noted that a hypesthesia in the proximal central carpal
      area remains when the palmar cutaneous branch of the median nerve is harvested as
      a vascularized nerve graft. The scar of the donor site should be left in the
      distal wrist crease. If it is not lying in the distal wrist crease, it may
      suggest that the patient has tried to commit suicide.

PMID- 12618601
TI  - TIMP-1, MMP-2, MMP-9, and PIIINP as serum markers for skin fibrosis in patients
      following severe burn trauma.
AB  - The wound-healing process of patients with severe burns often leads to the
      formation of extensive fibrotic scars. In this study, serum concentrations of
      tissue inhibitors of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-2
      (MMP-2), matrix metalloproteinase-9 (MMP-9), and amino-terminal propeptide of
      procollagen type III (PIIINP) were measured by enzyme-linked immunosorbent assay
      as markers for excessive cicatrization in 22 patients with acute burn injuries.
      All patients were followed up for 6 months to determine a fibrotic reaction
      during the wound-healing process after operative treatment using the Burn Scar
      Index. Blood samples were drawn immediately before the operation; at
      postoperative days 1, 3, 7, and 14; and 1, 3, and 6 months after the operation.
      Twenty patients who underwent elective plastic surgical operations served as the
      control group. There was a significant increase (p < 0.05) of TIMP-1 in the
      burned patients by the third postoperative day. Later in the follow-up period,
      the serum concentrations remained at a significantly elevated level (p < 0.05)
      compared with preoperative values. In comparison with the control group, the
      postoperative serum concentrations of TIMP-1 of the burned patients were
      significantly higher (p < 0.05) at any time and correlated with the total body
      surface area burned at the third and seventh postoperative days (p < 0.05; r2 =
      0.46 versus r2 = 0.53) and the Burn Scar Index after 6 months (p < 0.05; r2 =
      0.65). Serum levels of MMP-2 and MMP-9 showed a significant elevation (p < 0.05)
      only between postoperative days 3 and 14 in patients with burn wounds. PIIINP
      increased significantly (p < 0.05) in the sera of the burned patients at
      postoperative day 3 and remained significantly elevated up to 6 months after
      injury. At any time after trauma, PIIINP serum levels were significantly higher
      (p < 0.05) in the burned patients than in the control group and correlated with
      the total body surface area burned at postoperative days 3 and 7 (p < 0.05; r2 =
      0.41 versus r2 = 0.44) and the Burn Scar Index after 6 months (p < 0.05; r2 =
      0.5). Obviously, the physiological balance between matrix metalloproteinases and
      their endogenous inhibitors is disturbed after burn trauma. The elevated systemic
      TIMP-1 concentration might contribute to tissue fibrosis, leading to pathological
      scar formation. The increase of PIIINP after thermal trauma indicates a
      fibrogenic component of wound healing.

PMID- 12618602
TI  - Effect of unilateral partial facial paralysis on periosteal growth at the muscle
      bone interface of facial muscles and facial bones.
AB  - In a previous study, the influence of the midfacial musculature upon growth and
      development of the maxilla and mandible was established macroscopically. Dry
      skull measurements revealed a reduced premaxillary, maxillary, mandibular, and
      anterior corpus length with a simultaneous increase in mandibular ramal height on
      the paralyzed side. It was demonstrated that these reduced premaxillary and
      maxillary lengths were among others the result of reduced nasofrontal growth,
      whereas the increased ramal height was accompanied by condylar growth
      alterations. This study investigated whether the growth alterations at the
      mandibular corpus region could be explained by altered periosteal growth at the
      muscle-bone interface of the zygomatico-auricular muscle and the mandibular
      corpus, caused by altered muscle activity acting upon the periosteal sleeve.
      Fifty-six 12-day-old New Zealand White rabbits were randomly assigned to either a
      control or an experimental group. In the experimental group, left-sided partial
      facial paralysis was induced surgically when the animals were 12 days old. To
      study the muscle-bone interface, seven follow-up time intervals were defined
      between 3.5 and 60 days following the surgery. At these time intervals, four
      randomly selected control animals and four randomly selected experimental animals
      were killed. The anterior mandibular corpus region with the muscle-bone interface
      of the left control hemimandible and the left and right experimental
      hemimandibles was processed for undecalcified tissue preparation. Quantitative
      analysis of the total bone area at the muscle-bone interface revealed no
      significant differences between the left control hemimandible and the left and
      right experimental hemimandibles. Also, qualitative study of the histologic
      sections showed no major changes in the appearance or development of the
      trabecular pattern between the groups. However, slight differences in the
      distribution pattern of osteoblasts and osteoclasts along the bony surface were
      found between the left control hemimandible and the left and right experimental
      hemimandibles, which seemed to explain the alterations in mandibular corpus shape
      between these groups. It was suggested that these changes in the distribution
      pattern of osteoblasts and osteoclasts were the result of changes in the loading
      distribution pattern acting upon the mandible, caused by an altered neuromuscular
      recruitment pattern of the remaining functionally intact, mandibularly attached
      muscles. The latter was probably the result of adaptive mandibular positioning in
      response to an altered occlusal relationship, which was induced by the abnormal
      maxillary growth as a result of the unilateral partial facial paralysis.

PMID- 12618603
TI  - Mast cells: an unexpected finding in the modulation of cutaneous wound repair by
      charged beads.
AB  - Increased numbers of mast cells are affiliated with a broad spectrum of
      pathologic skin conditions, including ulcers, atopic dermatitis,
      neurofibromatosis, hemangiomas, keloids, and hypertrophic scars. It has been
      proposed that mast cells play a primary pathophysiologic role in these disorders
      and that their presence represents not merely a secondary event. While
      investigating their recent hypothesis that positively charged cross-linked
      diethylaminoethyl dextran (CLDD) beads potentiate cutaneous wound healing, the
      authors serendipitously observed increased numbers of mast cells in the deep
      dermis of wounds treated with CLDD beads. The authors propose that mast cells may
      play an important role in the modulation of healing seen with CLDD beads.
      Incisional wounds were studied in 30 Sprague-Dawley rats partitioned into two
      groups that were killed 7 or 14 days after wounding. The wounds were treated with
      positively, negatively, or neutrally charged CLDD beads. Physiologic saline
      served as a control. At the designated times after incisional wounding, biopsy
      specimens were tested for wound breaking strength or processed for histologic
      testing, fixed in 4% paraformaldehyde, and stained with Giemsa and Goldner-Masson
      trichrome. Mast cells were counted under light microscopy in a blinded fashion
      and were expressed as the number of cells per millimeter squared. Significant
      increases in the number of mast cells were observed in the deep dermis of
      incisional wounds after implantation with positively or negatively charged CLDD
      beads. In contrast, neutrally charged beads had no effect on mast cell numbers.
      At 7 days, the incisions treated with positively charged beads averaged 2.1 times
      more mast cells compared with those treated with physiologic saline or neutrally
      charged beads, whereas the incisions treated with negatively charged beads
      displayed 3.2 times more mast cells. By day 14, the incisions treated with
      positively charged beads averaged 2.5 times more mast cells than those wounds
      treated with saline or neutrally charged beads; the incisions treated with
      negatively charged CLDD beads had 3.4 times more mast cells. The 7-day
      tensiometric data indicated that wounds treated with negatively charged CLDD
      beads had increased breaking strength compared with wounds treated with neutrally
      charged beads or saline (1.8 and 1.7 times, respectively; p = 0.01 and p = 0.02).
      Wounds treated with positively charged beads also showed increased breaking
      strength compared with wounds treated with neutrally charged beads or saline (1.5
      and 1.4 times greater); however, this did not reach statistical significance.
      There was no apparent difference in breaking strength when neutrally charged
      beads were compared with those treated with saline. At 14 days, there was no
      statistically significant difference in wound breaking strength between different
      treatments. These findings are clinically germane to the assessment of proposed
      therapeutic applications of CLDD beads for a variety of impaired wound-healing
      states. Furthermore, if increased mast cell populations are intimately linked to
      hypertrophic scar and keloid formation, the results of the authors' study suggest
      that CLDD bead therapy of cutaneous wounds may lead to pathologic wound healing
      in humans.

PMID- 12618604
TI  - Antley-Bixler syndrome: correction of facial deformities and long-term survival.

PMID- 12618605
TI  - Periorbital correction in Kabuki syndrome.

PMID- 12618606
TI  - Contralateral normal C7 nerve transfer after upper arm shortening for the
      treatment of total root avulsion of the brachial plexus: a preliminary report.

PMID- 12618607
TI  - Distally based sural fasciocutaneous cross-leg flap: a new application of an old
      procedure.

PMID- 12618608
TI  - Pelvic reconstruction with a free fillet lower leg flap.

PMID- 12618609
TI  - Evaluation of changes in skeletal muscle blood flow in the dog with contrast
      ultrasonography revisited: has the technique been useful, and where are we headed
      now?

PMID- 12618610
TI  - Apoptosis and plastic surgery.
AB  - Apoptosis, or programmed cell death, is a phenomenon that is integral to
      development and cellular homeostasis. In the last decade, many of the essential
      molecules and pathways that control this phenomenon have been elucidated. Because
      apoptosis is involved in almost all physiologic and pathologic processes, the
      understanding of its regulation has significant clinical ramifications. This
      article reviews the basic understanding of programmed cell death in terms of the
      effector molecules and pathways. Areas of interest to plastic surgeons are
      reviewed as they pertain to apoptosis. These areas include allotransplantation,
      craniofacial and limb development, flap survival, wound healing, stem cell
      science, and physiologic aging. These topics have not yet been studied
      extensively in the context of cell death. In this review article, other related
      and more comprehensively studied scientific areas are used to extrapolate their
      relevance to apoptosis. Apoptosis is an increasingly better understood process.
      With the knowledge of how programmed cell death is controlled, combined with the
      improved ability to effectively perform genetic manipulation and to design
      specific chemical approaches, apoptosis is gaining clinical relevance. In the
      next few years, practical clinical breakthroughs will help the medical community
      to understand the phenomenon of apoptosis and how it relates to the needs of
      patients.

PMID- 12618611
TI  - Common craniofacial anomalies: conditions of craniofacial atrophy/hypoplasia and
      neoplasia.
AB  - The spectrum of craniofacial malformations includes conditions of congenital and
      acquired etiology. The conditions of craniofacial atrophy and hypoplasia may
      arise primarily or secondary to previous therapeutic interventions. The
      conditions of progressive hemifacial atrophy (Romberg disease) and radiation
      induced hypoplasia will be reviewed on the basis of their etiology, pathogenesis,
      anatomy, and treatment. Approaches to the surgical management of these conditions
      will be discussed. The craniofacial neoplastic conditions of fibrous dysplasia,
      neurofibromatosis, and craniofacial tumors will also be reviewed and discussed.

PMID- 12618612
TI  - Surgery by surgeons: is this what patients really want?

PMID- 12618613
TI  - Incidence of breast and chest wall asymmetry in breast augmentation: a
      retrospective analysis of 100 patients.
AB  - Although much is written concerning breast augmentation, few authors have
      addressed preoperative chest wall analysis as it pertains to postoperative
      outcome. In the present study, 100 patients were randomly selected, underwent
      bilateral augmentation, and were examined retrospectively by four independent
      physicians using standardized preoperative photographs. Each patient was examined
      for ptosis and asymmetry of the nipples, breast mound, and chest wall. Results
      revealed significant asymmetries in all parameters. Nipple-areola complex
      asymmetry was present in 24 percent (nipple/areola size) and 53 percent (nipple
      position) of the women. Mound asymmetry was noted in 44 percent (volume), 29
      percent (base constriction), and 30 percent (inframammary fold position) of the
      women, and finally, 29 percent of the women had grade I to III ptosis. Chest wall
      asymmetry was observed in 9 percent of the women. Overall, 88 percent of the
      women had some degree of asymmetry, and 65 percent of the women had more than one
      parameter of asymmetry. These findings underscore the importance of developing a
      systematic preoperative breast and chest wall analysis that can be individualized
      for each patient. The resulting asymmetries should then be discussed with the
      patient, along with the potential for continued or even more pronounced asymmetry
      postoperatively.

PMID- 12618614
TI  - Side effects and complications of variable-pulsed erbium:yttrium-aluminum-garnet
      laser skin resurfacing: extended experience with 50 patients.
AB  - Recent advances in technology have provided laser surgeons with new options for
      cutaneous laser resurfacing. Despite its popularity, there is limited information
      on the short-term and long-term side effects and complications of variable-pulsed
      erbium:yttrium-aluminum-garnet (erbium:YAG) laser skin resurfacing. The purpose
      of this study was to prospectively evaluate postoperative wound healing, side
      effects, and complications of multiple-pass, variable-pulsed erbium:YAG laser
      skin resurfacing for facial photodamage, rhytides, and atrophic scarring. Fifty
      consecutive patients with facial photodamage, rhytides, or atrophic scarring were
      treated with a variable-pulsed erbium:YAG laser. Side effects and complications
      relating to postoperative healing, erythema, and pigmentary changes were
      tabulated. Patients were evaluated at postoperative days 3 through 7 and at 1, 3,
      6, and 12 months after laser skin resurfacing. The average time for
      reepithelialization was 5.1 days. Prolonged erythema (>1 month) was observed in
      three patients (6 percent). Transient hyperpigmentation occurred in 20 patients
      (40 percent), with an average duration of 10.4 weeks. No cases of
      hypopigmentation or scarring were seen. In summary, a variable-pulsed erbium:YAG
      laser can safely be used for the treatment of facial photodamage, rhytides, and
      atrophic scarring. Although more postoperative erythema is seen after variable
      pulsed erbium:YAG laser treatment than is usually produced with a short-pulsed
      erbium:YAG system, the side-effect profile and recovery period after variable
      pulsed erbium:YAG laser skin resurfacing still are more favorable than after
      multiple-pass carbon dioxide laser skin resurfacing.

PMID- 12618615
TI  - Lengthening the nose with a tongue-and-groove technique.
AB  - Lengthening the short nose is often a major task. The ability to maintain proper
      alignment between the nasal base and dorsum may prove difficult without
      sacrificing the suppleness of the former. In this article, the authors introduce
      a technique of nose lengthening that ensures alignment of the tip with the rest
      of the nose yet avoids tip rigidity, unless a significant increase in tip
      projection is also planned. Two spreader grafts are placed, one on either side of
      the septum, and are extended beyond the caudal septal angle proportional to the
      planned nasal lengthening. A columella strut, with the cephalocaudal dimension
      equaling the combination of the width of the existing medial crura plus the
      amount of planned nasal lengthening, is placed between the medial crura in
      continuity with the caudal septum and is fixed to the medial crura using 5-0
      clear nylon or polydioxanone suture. If additional projection beyond what is
      achievable by mere placement of a columella strut is required, the strut is fixed
      to the spreader grafts in a more projected position. Otherwise, the columella
      strut is simply positioned between the extensions of the spreader grafts. It is
      necessary to mobilize the lower lateral cartilages to prevent excessive columella
      show. This procedure has been performed on 23 patients over the past 12.5 years,
      with 20 patients enjoying good-to-excellent results. The advantages of this
      technique include its predictability and reproducibility, and the ability to
      elongate the nose with a mobile nasal base that is in line with the rest of the
      nose. If suture fixation is used to gain more projection, the technique proves
      dependable but the nose will become more rigid than is optimal. The requirement
      of three pieces of properly shaped septal cartilage, which might not be available
      when a secondary rhinoplasty is performed, is the major disadvantage of this
      operation. Furthermore, the procedure is, to some degree, labor-intensive.

PMID- 12618616
TI  - Chin surgery III: revelations.
AB  - This article is a logical extension of previous articles written on the topic of
      aesthetic chin surgery. In it, the authors expand on previously published
      surgical techniques and provide specific updates to increase success in some
      unusual situations. They review the indications for and uses of reduced-height
      implants, discuss the validity of centralized chin incisions in both
      reconstruction and revisions, show the diversity of mentalis muscle anatomy and
      chin pad variations, reveal the importance of the lip-to-labiomental crease
      inclination in cases of macrogenia, note a key update on reefing the mentalis
      muscle to a higher position for permanent sulcus position, discuss the issues of
      lower lip position and lower incisor show, and expound on the horizontal
      smile/chin ptosis phenomenon.

PMID- 12618617
TI  - Pro bono publico.

PMID- 12618618
TI  - Doctoring via the media!

PMID- 12618619
TI  - Stamp and paper method: a superior technique for the walking track analysis.

PMID- 12618620
TI  - Brow suspension.

PMID- 12618621
TI  - Self-involution of giant keratoacanthoma on the tip of the nose.

PMID- 12618622
TI  - An atypical lesion on the forehead: warty dyskeratoma.

PMID- 12618624
TI  - A system for breast implant selection.

PMID- 12618623
TI  - About skin grafting.

PMID- 12618625
TI  - Clear visualization of capsular calcifications around breast implants.

PMID- 12618626
TI  - Late complication of abdominoplasty in an obese patient: systemic inflammatory
      response syndrome and seroma.

PMID- 12618627
TI  - Lengthening of the extensor tendon for anatomic restoration of the digitus
      quintus superductus pedis.

PMID- 12618628
TI  - Ray amputation as a treatment for recurrent myxohyaline tumor of the distal
      extremity.

PMID- 12618629
TI  - Avoiding tourniquet complications: a simple idea.

PMID- 12618630
TI  - A novel device for upper extremity elevation.

PMID- 12618631
TI  - The reverse latissimus dorsi flap for lumbar defects.

PMID- 12618632
TI  - A rare variant of the deep inferior epigastric perforator: importance of
      preoperative color-flow duplex scanning assessment.

PMID- 12618633
TI  - The interaction of leeches: a clinical observation.

PMID- 12618634
TI  - The effect of low-molecular-weight heparin on the survival of rabbit congested
      skin flap.

PMID- 12618636
TI  - Public insurance expansions and crowd out of private coverage.

PMID- 12618637
TI  - Quality of care for breast cancer.

PMID- 12618638
TI  - Public insurance expansions and crowd out of private coverage.
AB  - BACKGROUND: The extent to which persons enrolling in new public insurance
      programs substitute the public coverage for private insurance is of concern to
      policy makers. OBJECTIVE: To look at the extent of the substitution resulting
      from new state programs that cover a broad base of the low-income population and
      to look at the responses of both families and employers. METHODS: The March CPS
      for 1991-1993 and 1997-1998 were used to study the responses of families. Two
      large national surveys of employers with information about the employment-based
      system in 1993 and 1997 were used to study employer responses. The analysis looks
      at changes in coverage and employer offer rates before and after the public
      insurance expansions in selected states and compares these changes to those in a
      control group in states without expansions. RESULTS: Coverage by private
      insurance for low-income persons in states with expansions fell by more than
      expected based on the control states, indicating some substitution of public
      coverage for private insurance. Changes in employee coverage in own-employer
      sponsored insurance accord with this result. The expansion of public insurance
      has a bigger effect on employer offer decisions when a large share of its workers
      is eligible for public programs. CONCLUSIONS: The results show a significant
      substitution of public insurance for private coverage in the expansions studied.
      However, endogeneity of state expansion policies and possible confounding with
      other policy changes temper the conclusions. More recent public insurance
      expansions as part of the State Childrens' Health Insurance Program have adopted
      a range of methods to limit crowd out. Future research is needed to evaluate
      whether these procedures and rules have succeeded.

PMID- 12618639
TI  - Utilization and cost impact of integrating substance abuse treatment and primary
      care.
AB  - OBJECTIVE: To examine the impact of integrating medical and substance abuse
      treatment on health care utilization and cost. RESEARCH DESIGN: Randomized
      clinical trial assigning patients to one of two treatment modalities: an
      Integrated Care model where primary health care is provided along with substance
      abuse treatment within the unit and an Independent Care model where medical care
      is provided in the HMO's primary care clinics independently from substance abuse
      treatment. SUBJECTS: Adult patients entering treatment at the outpatient Chemical
      Dependency Recovery Program in Kaiser Sacramento. MEASURES: Medical utilization
      and cost for 12 months pretreatment and 12 months after treatment entry. RESULTS:
      For the full, randomized cohort, there were no statistically significant
      differences between the two treatment groups over time. However, among the subset
      of patients with substance abuse related medical conditions (SAMC), Integrated
      Care patients had significant decreases in hospitalization rates (P = 0.04),
      inpatient days (P = 0.05) and ER use (P = 0.02). Total medical costs per member
      month declined from 431.12 US dollars to 200.03 US dollars (P = 0.02). Among SAMC
      Independent Care patients, there was a downward trend in inpatient days (P =
      0.08) and ER costs (P = 0.05) but no statistically significant decrease in total
      medical cost. CONCLUSIONS: (Non)findings for the full sample suggest that
      integrating substance abuse treatment with primary care, may not be necessary or
      appropriate for all patients. However, it may be beneficial to refer patients
      with substance abuse related medical conditions to a provider also trained in
      addiction medicine. There appear to be large cost impacts of providing integrated
      care for such patients.

PMID- 12618640
TI  - Antidepressant use: concordance between self-report and claims records.
AB  - BACKGROUND: Researchers need valid methods to assess whether patients are taking
      their antidepressant medications. Two important sources of data on drug exposure
      are patients' self-reports and pharmacy claims. OBJECTIVE: To compare self-report
      and claims data for antidepressant exposure. RESEARCH DESIGN: Cross-sectional
      analysis. SUBJECTS: This study comprised 422 contemporaneous self-report and
      claims data points obtained from 164 unique patients in a longitudinal depression
      study in which patients completed up to five surveys during an 18-month period.
      MEASURES: For the self-report measure, the following question was asked: Do you
      now take any prescription medicines for depression? Using claims data, patients
      were considered to be using an antidepressant if they had filled at least one
      antidepressant prescription in the 90 days before survey dates. RESULTS: Self
      report and claims agreed in 85% (358/422) of cases, with a kappa of 0.69. Eighty
      eight percent (56/64) of discrepant cases using other study data sources was
      resolved. Reasons for discrepancies included the use of medications for
      conditions other than depression (32/64), recent AD discontinuations (6/64),
      samples usage (3/64), and low-frequency/PRN use (7/64). CONCLUSIONS: Self-report
      and claims showed good concordance, but they reflect different truths. Self
      report identifies medications intended primarily for the treatment of depressive
      disorders, whereas claims data identify use of medicines with antidepressant
      effects. Our assessment of discordant cases showed self-report to be more valid
      than claims to assess current antidepressant use for depression therapy.

PMID- 12618641
TI  - Personalized targeted mailing increases mammography among long-term noncompliant
      medicare beneficiaries: a randomized trial.
AB  - OBJECTIVES: The study purpose was to increase mammography screening among older
      women by identifying female Medicare beneficiaries without a recent mammogram and
      assesses the cost-effectiveness of a personalized targeted mailing encouraging
      them to have a mammogram. METHODS: A randomized paired controlled trial included
      1229 pairs of women matched on zip code, race, and urban or rural county.
      Postintervention mammography claims were measured from November 1997 through
      December 1998. The subjects were female Medicare beneficiaries age > or = 70,
      living in Michigan for > or = 5 years, having no significant comorbidity likely
      to affect screening, and no mammogram for > or = 5 years. Intervention subjects
      received a personally addressed letter from the Medical Director of Michigan
      Medicare with materials emphasizing the individual's lack of use of the Medicare
      mammography screening benefit, reasons for screening, and how to be screened.
      RESULTS: Women who received the mailing were 60% more likely to have a subsequent
      mammogram (OR 1.6, P <0.005), with diagnostic mammograms increasing more than
      screening mammograms (2.8% vs. 0.8%). The absolute increase was greatest for
      women age 70 to 79, 10.6% in the intervention group versus 6.5% for controls,
      odds ratio 1.7 (P <0.02). A statewide Medicare intervention in Michigan would
      cost of 108,000 US dollars to 238,000 US dollars, producing 3500 to 4300
      additional mammograms at 31 US dollars to 55 US dollars per additional mammogram.
      CONCLUSION: The intervention increased mammography among long-term noncompliant
      older women, particularly increasing diagnostic mammograms. This approach can be
      directly implemented in other states and nationally. It may also be useful for
      other preventive services.

PMID- 12618642
TI  - Length of stay data as a guide to hospital economic performance for ICU patients.
AB  - CONTEXT: Length of stay data are increasingly used to monitor ICU economic
      performance. How such material is presented greatly affects its utility.
      OBJECTIVE: To develop a weighted length of stay index and to estimate expected
      length of stay. To assess alternative ways to summarize weighted length of stay
      to evaluate ICU economic performance. DESIGN: Retrospective database study.
      SUBJECTS: Data for 751 ICU patients in 1998 at two hospitals used to develop
      weighted length of stay index. Data on 42,237 patients from 72 ICUs used as the
      basis of economic performance evaluation. MAIN OUTCOME MEASURES: Difference
      between actual and expected weighted length of stay, where expected weighted
      length of stay is based on patient clinical characteristics. RESULTS: Length of
      stay statistically explains approximately 85 to 90% of interpatient variation in
      hospital costs. The first ICU day is approximately four times as expensive, and
      other ICU days approximately 2.5 times as expensive, as non-ICU hospital days. In
      a regression model for weighted length of stay, patient clinical characteristics
      explain 26% of variation. ICU economic performance can be measured by excess
      weighted length of stay of a "typical" patient or by occurrence of long excess
      weighted lengths of stay. Although different summary measures of performance are
      highly correlated, choice of measure affects relative ranking of some ICUs'
      performance. CONCLUSION: Providers of statistical data on ICU economic
      performance should adjust length of stay for patient characteristics and provide
      multiple summary measures of the statistical distribution, including measures
      that address both the typical patient and outliers.

PMID- 12618643
TI  - Effect of tiered prescription copayments on the use of preferred brand
      medications.
AB  - BACKGROUND AND OBJECTIVE: Health plans are increasingly using more open drug
      formularies that offer differential prescription copayments as an incentive to
      enrollees to use brands that plans prefer. How much this financial incentive
      affects use of preferred brands has not been widely reported. The aim of this
      study was to estimate the effect of tiered copayments on the choice between
      preferred and nonpreferred brand medications. MATERIALS AND METHODS: Longitudinal
      logistic regression analyses of pharmacy claims from 1998 and 1999 comparing
      concurrent groups that were or were not exposed to tiered copayments. SUBJECTS:
      Enrollees in four independent physician practice association model health plans
      who had pharmacy claims for angiotensin converting enzyme inhibitors (ACEI),
      proton pump inhibitors (PPI), or hydroxymethylglutaryl coenzyme A reductase
      inhibitors (STATINS). OUTCOME MEASURE: Change in the percentage of prescription
      claims that were for preferred brands. MAIN RESULTS: Regression adjusted
      estimates of the average net increase in the percentage use of preferred brands
      of ACEI, PPI and STATIN from first quarter 1998 to third quarter 1999 attributed
      to tiered prescription copayments were 13.3 (P = 0.001), 8.9 (P = 0.03), and 6.0
      (P <0.001) percentage points, respectively. CONCLUSIONS: Tiered prescription
      copayments were associated with a significant shift from nonpreferred to
      preferred brand medications. This type of financial incentive can help purchasers
      providing open access drug benefits by steering use of medications toward lower
      cost brands. The clinical effects of changes in medication use brought about
      differential copayments warrant further investigation.

PMID- 12618644
TI  - Can pharmacy data improve prediction of hospital outcomes? Comparisons with a
      diagnosis-based comorbidity measure.
AB  - OBJECTIVES: The performance of comorbidity measures derived from the hospital
      discharge abstract, the outpatient pharmacy record, and from both sources
      combined, were compared in predicting all-cause and unplanned hospital
      readmission and length of stay. MATERIALS AND METHODS: Automated hospital and
      pharmacy data came from Kaiser-Permanente and included 6721 acute
      hospitalizations in Southern California from April 1993 to February 1995. The
      Deyo adaptation of Charlson's 17 comorbidities was derived from hospital
      discharge data and the 29 Chronic Disease Score (CDS) comorbidity markers were
      derived from outpatient pharmacy claims data. Logistic and OLS regression models
      were used to compare the performance of each measure in baseline models and to
      evaluate whether the CDS contributed additional explanatory power in a combined
      model. RESULTS: The CDS was a significant predictor of unplanned readmission (C =
      0.68) and LOS (Adjusted R(2) = 0.26) in multivariable models adjusted for
      baseline patient demographic and hospitalization characteristics. The Deyo
      measure was a significant predictor of all-cause readmission (C = 0.63),
      unplanned readmission (C = 0.68), and LOS (Adjusted R(2) = 0.26). When pharmacy
      based disease markers were added to the Deyo baseline model, modest,
      statistically significant improvements in predictive power were noted in the
      unplanned readmission and LOS models. CONCLUSIONS: The finding that both measures
      of comorbid disease demonstrated similar predictive power is noteworthy, because
      secondary diagnosis data document relevant illness in hospital patients and
      pharmacy claims data were never intended for that purpose. The results suggest
      that small improvements in model performance may come from combining both sources
      of data in models to predict hospital readmission and LOS.

PMID- 12618645
TI  - Do local opinion leaders augment hospital quality improvement efforts? A
      randomized trial to promote adherence to unstable angina guidelines.
AB  - BACKGROUND: The influence of an opinion leader intervention on adherence to
      Unstable Angina (UA) guidelines compared with a traditional quality improvement
      model was investigated. RESEARCH DESIGN: A group-randomized controlled trial with
      2210 patients from 21 hospitals was designed. There were three intervention arms:
      (1) no intervention (NI); (2) a traditional Health Care Quality Improvement
      Program (HCQIP); and (3) a physician opinion leader in addition to the HCQIP
      model (OL). Quality indicators included: electrocardiogram within 20 minutes,
      antiplatelet therapy within 24 hours and at discharge, and heparin and beta
      blockers during hospitalization. Hospitals could determine the specific
      indicators they wished to target. Potential cases of UA were identified from
      Medicare claims data. UA confirmation was determined by a clinical algorithm
      based on data abstracted from medical records. Data analyses included both
      hospital level analysis (analysis of variance) and patient level analysis
      (generalized linear models). RESULTS: The only statistically significant
      postintervention difference in percentage compliant was greater improvement for
      the OL group in the use of antiplatelet therapy at 24 hours in both hospital
      level (P = 0.01) and patient level analyses (P <0.05) compared with the HCQIP and
      NI groups. When analyses were confined to hospitals that targeted specific
      indicators, compared with the HCQIP hospitals, the OL hospitals showed
      significantly greater change in percentage compliant postintervention in both
      antiplatelet therapy during the first 24 hours (20.2% vs. -3.9%, P = 0.02) and
      heparin (31.0% vs.9.1%, P = 0.05). CONCLUSIONS: The influence of physician
      opinion leaders was unequivocally positive for only one of five quality
      indicators. To maximize adherence to best practices through physician opinion
      leaders, more research on how these physicians influence health care delivery in
      their organizations will be required.

PMID- 12618646
TI  - A multicenter cluster randomized controlled trial of strategies to improve
      thyroid function testing.
AB  - OBJECTIVES: This project aimed to compare the independent and combined
      effectiveness of two implementation interventions of guidelines for ordering
      thyroid function tests: a Memorandum Pocket Card (MPC) and a Test Request Form
      (TRF). RESEARCH DESIGN: Intervention groups were wards. The study used an
      experimental 2*2 factorial design with matching hospitals according to size and
      activity and wards according to preintervention appropriateness for test
      ordering. Four ward groups were established: the dual intervention group, the
      order form group, the pocket card group and the control group. Physicians in all
      groups received guidelines and were invited to a local information meeting.
      MEASURES: The main outcome measure of effectiveness was the Guideline Conformity
      Rate (GCR). RESULTS: Six hospitals participated in the study (two middle-sized
      hospitals, two small-sized hospitals and two psychiatric hospitals). A total of
      1412 orders for thyroid function tests were collected. GCR was 78% in the dual
      intervention group, 83% in the order form group, 73% in the pocket card group and
      62% in the control group. The interaction between TRF and MPC was not significant
      (beta = -0.70; P = 0.21). Compared with simple information, TRF was effective in
      increasing GCR (OR, 2.65; 95% CI, 1.52-4.62), unlike MPC (OR, 1.28; CI, 0.75
      2.19). CONCLUSIONS: Using a robust design, our study shows the greater
      effectiveness of TRF than MPC and their association in implementing thyroid
      function test guidelines.

PMID- 12618647
TI  - Physicians' reasons for failing to deliver effective breast cancer care: a
      framework for underuse.
AB  - OBJECTIVE: Despite numerous randomized trials showing the health benefits of
      systemic and local therapies for early-stage breast cancer, underuse of these
      therapies remains a significant quality problem. Little is known about causes of
      underuse of effective cancer treatments. We sought to understand these causes to
      design effective interventions to improve care. RESEARCH DESIGN: To identify
      categories of causes of underuse, semistructured interviews were performed with
      physicians of breast cancer patients who did not receive effective adjuvant care
      in the 4 years following surgery. Underuse was defined by expert consensus based
      on evidence-based guidelines. SUBJECTS: Surgeons (n = 13) of all early-stage
      breast cancer cases who underwent surgical treatment at a tertiary care hospital
      and had underuse of local or systemic adjuvant therapies. RESULTS: Of all the 275
      women with early-stage breast cancer, there were 44 episodes of underuse of
      effective therapies (16%). In 48% of cases, physicians thought treatment should
      occur but the treatment failed to take place (32%) or the patient refused (16%).
      For the other 52% of cases, physicians thought treatment should not occur because
      evidence did not support treatment in clinical circumstances such as older age
      (32%), a good prognosis based on tumor size or histology (11%), a second primary
      breast cancer (5%), or because of comorbidities (5%). All surgeons were aware of
      the benefits of adjuvant treatments. CONCLUSIONS: Causes of underuse can be
      identified and categorized. Using these categories, a framework of causes of
      underuse was constructed and interventions targeting the specific causes to
      improve the quality of care are suggested.

PMID- 12618649
TI  - [Clinical presentation of immune mediated cerebellar ataxia].
AB  - Over the last decades, clinical evidence has accumulated indicating that the
      immune system may play an important role in some central nervous system diseases
      usually regarded as degenerative. The best known example is paraneoplastic
      cerebellar ataxia (PCA), which is thought to involve autoimmune cross-reaction
      between tumor and nervous system antigens. In the past twenty years, several
      antibodies directed against neuronal and tumor antigens have been described in
      association with PCA, leading to the description of different subtypes of PCA
      depending on the associated antibodies, the clinical course and the type of
      tumor. In some types, cerebellar ataxia occurs alone, whereas, in others, it is
      only one clinical feature in the setting of extensive nervous system disease.
      Circulating antibodies have also been described in patients with non
      paraneoplastic cerebellar ataxia (N-PCA), suggesting that the immune system may
      be involved in certain cases of sporadic cerebellar ataxia. In this review, the
      clinical presentation of the different subtypes of potentially immune-mediated
      PCA and N-PCA will be described, and the experimental approaches developed in
      order to understand the pathogenic importance of the immune system in these
      ataxias will be discussed.

PMID- 12618650
TI  - [Lyme borreliosis].
AB  - Lyme disease is a multisystemic disease caused by a spirochete, Borrelia
      Burgdorferi that is transmitted by ticks. A clinical diagnosis is easy when a
      tick bite is followed 3 weeks later by erythema migrans, than by involvement of
      nervous system, joints or heart. In case of neuroborreliosis, serological tests,
      performed in blood and cerebro-spinal fluid, support the diagnosis and patients
      recover rapidly with antibacterial treatments. However an accurate diagnosis
      remains sometimes problematic, especially distinction between a coincidental
      positive serologic test and a nervous system Lyme borreliosis which require
      antibiotics. Furthermore, the role of autoimmunity in the pathophysiology of late
      Lyme disease, antibiotic choice in early disease, duration of treatment, and
      utility of vaccination are discussed.

PMID- 12618651
TI  - [Progressive supranuclear palsy: a clinical, natural history and disability
      study].
AB  - We studied the clinical features, the natural history and disability in 47
      progressive supranuclear palsy patients and brain imaging aspects by routinely
      performed MRI in a subgroup of 25. Unexplained falls together with atypical
      parkinsonism (symmetric, levodopa unresponsive without resting tremor) are good
      clinical pointers of the early diagnosis, since they occurred within the first
      year. Cognitive slowness and unspecific visual complains are also early symptoms,
      while usual cardinal signs such as supranuclear palsy are more delayed.
      Blepharospasm and eyelid opening apraxia as well as deep sighs are also quite
      characteristic clinical features (1/3 of cases). Cardinal signs (falls,
      pseudobulbar signs, supranuclear gaze palsy) worsened rapidly (20 to 30 months)
      towards a major disability. In the 20 patients deceased during follow-up, the
      mean survival time was about 5 years. The MRI study showed typical cortical
      fronto-temporo-parietal atrophy, mesencephalic and quadrigeminal plate atrophy
      with third ventricle dilatation. In conclusion, unexplained falls associated with
      atypical parkinsonism are contributive for the early clinical diagnosis. Non
      specific visual complains could be useful pointers in the absence of supranuclear
      ophthalmoplegia. MRI contributes to the clinical diagnosis even in the first 3
      years of the disease course.

PMID- 12618653
TI  - [Microcystic meningiomas: comparison of histology and computed tomography].
AB  - INTRODUCTION: Microcystic meningiomas are defined by large vacuolated and
      stellate shaped cells. We recently examined a microcystic meningioma mimicking a
      malignant tumor on computed tomography (CT). The aim of the current study was to
      compare the radiological features of microcystic meningiomas with their
      histological patterns. METHODS: We have diagnosed 7 intracranial microcystic
      meningiomas among 204 meningiomas registered in the files of our Department of
      Pathology from 1994 to 2001. All CT scans performed before surgery were reviewed.
      RESULTS: Three of the microcystic meningiomas appeared as entirely microcystic
      tumors. Two of them were homogeneously hypodense or isodense on CT scan. The
      third mening was heterogeneous, containing some blood. The histologic pattern of
      the 4 other meningiomas showed microcystic tumor cells associated with
      meningothelial or fibrous tumor cells. These meningiomas were heterogeneous on CT
      scan. All meningiomas seemed to be connected to the dura mater. Three tumors were
      strongly and homogeneously enhanced after contrast media injection while 3 others
      were heterogeneously enhanced. No enhanced CT scan was available for 1 case.
      Astrocytomas were incorrectly diagnosed by CT scan in the 3 heterogeneously
      enhanced tumors. Meningiomas were correctly diagnosed in the 3 strongly enhanced
      tumors. CONCLUSION: The presence of microcystic tumour cells in meningiomas often
      results in erroneous diagnosis on CT scan, particularly for those which are
      heterogeneously enhanced. In these cases, a diagnosis of astrocytoma is often
      made.

PMID- 12618652
TI  - [Familial idiopathic striato-pallido-dentate calcifications: clinical and brain
      imaging study in a family].
AB  - Familial idiopathic basal ganglia calcification (FIBGC) is a rare condition and
      its pathophysiology has not so far been elucidated. We report the results of a
      clinical study in two patients of a family affected with FIBGC. Brain imaging
      with 18-FDG-PET was performed in one. Psychiatric and cognitive troubles were the
      main clinical symptoms. Basal ganglia calcifications were associated with white
      matter lesions. The PET study performed in one patient revealed a striatal and a
      posterior cingulate hypometabolism. Posterior cingulate gyrus is involved in
      episodic memory processing, and could be involved in episodic memory deficit
      observed in this patient. These results suggest that a cortical dysfunction could
      be associated to the disease. The underlying mechanism, that could be a neuronal
      loss, a cortical deafferentation or an alteration of synaptic transmission,
      remains to be elucidated.

PMID- 12618655
TI  - [Cerebral angiitis and Goodpasture's syndrome].
AB  - Goodpasture's syndrome is a form of rapidly progressive glomerulonephritis with
      pulmonary hemorrhage in the presence of antiglomerular basement membrane
      antibodies. Concomittant central nervous system manifestations are exceptionally
      reported. We report such a case of an 55-year-old woman who developed fluctuant
      neurobehavioral manifestations over a 9 months period. Angiography showed
      cerebral arterial distal lesions compatible with the diagnosis of angiitis. The
      antiglomerular basement membrane antibody titer was elevated. Search for anti
      neutrophil cytoplasmic antibody was negative. After the reintroduction of
      cyclophosphamide agent, clinical evolution was favourable. Clinical cerebral
      manifestations in our case are probably du to a angiitis. Few cases are reported
      in the literature. The role of antiglomerular basement membrane antibody in the
      development of the cerebral angiitis is possible.

PMID- 12618654
TI  - [Exploration of exercise intolerance by 31P NMR spectroscopy of calf muscles
      coupled with MRI and ergometry].
AB  - One hundred patients presenting with exercise intolerance or rhabdomyolysis
      episodes have been examined successively by 31P Nuclear Magnetic Resonance
      Spectroscopy (MRS) of leg plantar flexor muscles with exercise test. In all cases
      a muscle biopsy was performed. At the end of investigations, diagnosis of a
      metabolic myopathy was made in 33 patients: glycogenolysis or glycolysis
      deficiency in 8 cases, mitochondrial myopathy in 24 cases and CPT II deficiency
      in one case. Muscular dystrophy or congenital myopathy were diagnosed in 6 cases.
      No precise etiology could be found in 30 patients with either high CK levels or
      muscle biopsy abnormalities. Seven patients had rhabdomyolysis related to
      excessive physical activities. Twenty-four patients had functional symptoms. The
      principal MRS parameters used for diagnosis were the values of intracellular pH
      at the end of exercise and the time constant of phosphocreatine resynthesis
      during recovery. Lack of acidosis after exercise was observed in all patients
      with blockade of glycogenolysis or glycolysis. A slowing in phosphocreatine
      resynthesis was found in 66 p.cent of patients with definite mitochondrial
      myopathy. The specificity of these parameters were respectively 92.4 p.cent and
      85.5 p.cent for the two groups. In conclusion (31)P MRS allows the detection of
      muscular glycogenoses with a sensitivity close to 100 p.cent. However, its
      sensitivity was lower for the detection of mitochondrial myopathies, as is also
      known for the other in vivo metabolic investigations, reflecting the
      heterogeneity of expression of mitochondrial abnormalities in a given muscle. The
      integration of imaging in the examination protocol may help to orientate towards
      the diagnostic of a dystrophy in some patients.

PMID- 12618656
TI  - [Hypertensive encephalopathy as revealing symptom of Takayasu's arteritis].
AB  - A 29-year-old patient presented with Takayasu's arteritis which was revealed by
      heart failure, epilepsy, right hemiparesis and fever. Transient abnormalities of
      MRI and CSF (raised protein and cell content) were initially observed. The
      hypothesis of a hypertensive encephalopathy is suggested.

PMID- 12618657
TI  - [Favorable course of Lance-Adams postanoxic action myoclonus].
AB  - Clinical and electrophysiologic data concerning the postanoxic action myoclonus
      syndrome were described by Lance and Adams in 1963. A patient presented myoclonus
      involving all parts of the body after laryngospasm. The myoclonus was worsened by
      emotion and voluntary activity and was clearly attenuated by sleep. Spectacular
      improvement was observed within one week after valproate and piracetam
      administration. Clinicians should be aware of this syndrome in order to propose
      appropriate treatment and avoid delay in the therapeutic decision.

PMID- 12618658
TI  - [An atypical infectious paraplegia].
AB  - Spinal cord abscess is an unusual cause of progressive paraplegia. We report the
      case of a 75-year-old man who presented Chlamydia pneumoniae bronchopulmonary
      infection with secondary spinal cord localization. Little clinical improvement
      was observed with antibiotic therapy, but the neuroradiological course was
      favorable.

PMID- 12618659
TI  - [Acute motor axonal neuropathy, enterovirus and Amyotrophic lateral sclerosis:
      can there be a link?].
AB  - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of both upper
      and lower motor neurons. Acute motor axonal neuropathy (AMAN) affects only the
      lower motor neuron and occurs, in the majority of cases, after an infection. To
      date, the etiology of ALS remains unknown but seems multifactorial. A 60 year-old
      man with a past medical history of AMAN developed ALS 9 years later. At that
      time, genomic sequences of enterovirus (echovirus 6 and 7) were detected in
      cerebrospinal fluid by RT-PCR. This particular succession led to discuss a
      possible link between theses two disorders and consequently the involvement of
      enterovirus in the development of ALS.

PMID- 12618660
TI  - [Hypertrophy of the biceps surae after post-radiation lumbar radiculopathy].
AB  - A 44 year-old man who underwent radiotherapy for Hodgkin disease in 1987
      developed in 1996 pain and calf hypertrophy. Nerve conduction studies were normal
      and needle electromyography revealed a neurogenic pattern in the L-5 and S-1
      roots, predominantly on the left side. An abdominal tomodensitometry revealed a
      splenic and left renal atrophy. Cerebrospinal fluid analysis showed an elevated
      protein level (1.35 g/l) and no malignant cell. Spinal cord magnetic resonance
      imaging revealed no abnormality of the roots and the cauda equina. Muscular
      hypertrophy, as the consequence of post-irradiation lumbar radiculopathy is
      rarely reported. We discuss the possible mechanism of neurogenic muscular
      hypertrophy.

PMID- 12618661
TI  - [An enlightened psychotic?].

PMID- 12618662
TI  - [Malignant externa otitis].

PMID- 12618663
TI  - [A patient with suspected muscle disease?].

PMID- 12618664
TI  - [Modafinil: pharmacology and therapeutic perspectives].

PMID- 12618665
TI  - [Diagnosis and treatment of migraine in adults and children].

PMID- 12618666
TI  - Salivary gland tumours in Mexico.

PMID- 12618668
TI  - Burning mouth syndrome in the Basque Country: a preliminary study of 30 cases.
AB  - OBJECTIVES: To know the most important clinical features of Burning Mouth
      Syndrome (BMS) in our environment. MATERIAL AND METHODS: A prospective study of
      30 BMS patients, 29 female and 1 male, with a mean age of 60.2 years (range 37
      89), was made. A previously designed clinical protocol, including blood counts,
      levadure culture, oral pH measurement and non-stimulated salivary flow rate, was
      completed by all patients. Comparative and descriptive statistical analysis was
      performed. The Chi-square test was applied (p< 0.05). RESULTS: Moreover of a
      burning sensation, 60 % of patients presented oral dryness and 60 % dysgeusia.
      The tongue was the most frequent site affected of burning sensation (66.7 %).
      Type II of BMS was the most common (53.3%). In women, 82.9 % were postmenopausal.
      A 13.3 % of patients suffered type II Diabetes, 6.7 % vitamin deficiency and 56.6
      % used xerostomy-inducer medication. The 56.6 % of patients showed chronic
      anxiety and/or depression. The 46.7 % had a deficient oral hygiene level and 44.4
      % wore inadequate dentures. Salivary flow rate was decreased in 50 % of patients.
      Significant levadure growth was not detected in any case. CONCLUSIONS: BMS
      patients in our environment are principally postmenopausal women, with tongue
      burning, xerostomy, dysgeusia and chronic anxiety and/or depression.

PMID- 12618669
TI  - A comparative study of age-related changes between palatal and labial salivary
      glands.
AB  - OBJECTIVES: The purpose of this article was to compare age-related
      histomorphometric changes between palatal and labial salivary glands (PSG and
      LSG, respectively). STUDY DESIGN: Analysis of the mean proportional volume (MPV)
      of the acinar component (AC), ductal component (DC) and of the inflammatory
      component (IC) was performed on 120 samples of PSG and LSG obtained from subjects
      with no known history of salivary gland tumors/diseases. Samples were divided
      into young (n=30, < or =30y), adult (n=45, 31-60y) and old (n=45, >60y) age
      groups. RESULTS: In PSG, a significant decrease in MPV of AC (p<0.0001) with a
      concomitant significant increase in MPV of DC (p<0.0001) was found among all age
      groups. In LSG, a significant decrease in MPV of AC (p=0.002) with a concomitant
      increase in MPV of DC (p=0.002) was found between the adult and old age groups. A
      significant increase in MPV of IC in PSG was found between the young and adult
      groups (p<0.0001), while in LSG it became evident only between the adult and old
      groups (p<0.0001). Inflammatory and ductal components demonstrated the same
      pattern of age-related changes in both PSG and LSG. CONCLUSIONS: In light of
      these results, it is suggested that earlier and continuous changes in PSG, as
      compared to LSG, may partially explain the more frequent involvement of PSG in
      pathologic conditions.

PMID- 12618670
TI  - Bucco-dental problems in patients with Diabetes Mellitus (I) : Index of plaque
      and dental caries.
AB  - Diabetes mellitus is presently considered as one of the most frequent chronic
      disease, thus, it is important to know what its most relevant buccal disorders
      are. OBJECTIVES: Study the different signs and symptoms that diabetic patients
      present in the oral cavity. Assess the status of oral hygiene and prevalence of
      dental caries in a diabetic population in regards to a control population. STUDY
      DESIGN: We have performed the study on 70 diabetic patients (30 men and 40 women)
      whose ages ranged from 11 to 81 years, and a control population of 74 non
      diabetic (29 men and 45 women) whose ages ranged from 11 to 75 years. Within the
      diabetic population, the type of diabetes, degree of control of their disease by
      glycosylated hemoglobin, diabetes evolution time and existence of late
      complications were assessed. Oral hygiene was measured with the O'Leary plaque
      index. The prevalence of caries was studied with the CAOD index. RESULTS: The
      oral hygiene status was significantly worse in the diabetic patients in regards
      to the controls after 56 years of age. We did not find any significant
      differences in the prevalence of caries or in the CAOD index, although this was
      slightly higher in the diabetic patients. The study of the diabetic patients
      showed that only the type and evolution of their disease were significant
      parameters in relationship to the number of caries, while no significance was
      found on the plaque index for any of the parameters analyzed. CONCLUSIONS: In
      this study, we have observed a larger number of dental absences in the diabetic
      population in regards to a healthy population. We have found no differences in
      the number of caries, absences and obturations based on metabolic control,
      evolution time and existence of late complications of diabetes.

PMID- 12618672
TI  - Tuberous sclerosis: presentation of a clinical case with oral manifestations.
AB  - Tuberous sclerosis (TS) is a genetic disorder affecting multiple body systems,
      and resulting from alterations in cell differentiation and proliferation. The
      disease is characterized by the development of benign hamartomatous tumors:
      neurofibromas and angiofibromas, located in the skin, central nervous system,
      mucosas and other organs. Abnormal neural cell migration plays an important role
      in the neurological dysfunctions found in TS, the predominant features being
      mental retardation, seizures and behavioral disorders. The condition is produced
      by mutations in genes TSC1 of chromosome 9q34 and TSC2 of chromosome 16p13.3, and
      exhibits a dominant autosomal hereditary trait--though 60-70% of cases are
      sporadic and represent new mutations. The phenotype is highly variable. The
      prevalence of TS varies between 1/6000 and 1/10,000 live births. The present
      study reports the case of a 21-year-old male with TS and oral manifestations of
      the disease. The clinical characteristics are described, along with the
      diagnostic criteria and the management strategies, with a review of the
      literature on the disease.

PMID- 12618671
TI  - Malignant odontogenic tumors. A retrospective and collaborative study of seven
      cases.
AB  - The frequency, clinico-pathologic features and outcome of malignant odontogenic
      tumors diagnosed according to the current WHO classification in three pathology
      services in Mexico City are presented. There were seven cases (5 male and 2
      female patients), which represent less than 4% of all odontogenic tumors
      diagnosed in these services. There were six odontogenic carcinomas (two malignant
      ameloblastomas, two clear cell odontogenic carcinomas, one primary intraosseous
      carcinoma and one carcinoma arising in an odontogenic cyst) and one ameloblastic
      fibrosarcoma. Age ranged from 25 to 72 years (mean: 43.8). Clear cell odontogenic
      carcinomas occurred in the canine-premolar region, one in the maxilla and one in
      the mandible (one ia a man and one in a woman), while the remaining lesions
      affected the posterior region of the mandible, with a male predominance (4:1),
      which agrees with previously reported cases. Surgical resection was the treatment
      employed in all carcinomas, while the ameloblastic fibrosarcoma was treated with
      chemotherapy due to its large extension, but without favorable response. The
      patient with primary intraosseous carcinoma had submaxillary and cervical
      metastases and the neoplasm was the cause of death. In spite of their extremely
      low frequency, malignant odontogenic tumors are an important cause of extensive
      surgical procedures in the oral and maxillofacial region.

PMID- 12618673
TI  - Dental treatment under general anesthesia: a useful procedure in the third
      millennium? (l).
AB  - Advances in medical science have increasingly extended human life expectancy,
      thereby increasing the number of risk patients who require dental treatment under
      conditions of maximum safety. On the other hand, a part of the population
      presents physical or mental impairments which preclude minimum cooperation with
      the dental professional to ensure treatment with the necessary guarantees.
      Dentists and stomatologists must therefore consider the possibility of performing
      general anesthesia in these special patients, as the only way to ensure adequate
      dental treatment.

PMID- 12618674
TI  - Etiopathogenic analysis of the caries on three patients with Noonan Syndrome.
AB  - INTRODUCTION: Noonan syndrome is a genetic disease frequently characterized by
      short height, winged neck and a thoracic defect, among other alterations.
      However, there are no reports that mention oral health complications. In this
      article three children are presented with this syndrome in which multiple caries
      are observed, determining in each case which factors increase their
      susceptibility to caries. CLINICAL CASES: 1. A 4 year old girl who suffered
      neonatal sepsis, pyelocalyceal ecstasia, congenital hypertrophic pyloric
      stenosis, cardiopathy, hypoacusia and psychomotor delay. Presented multiple
      cavitated caries, requiring the extraction of the 4 incisors. 2. A 4-year-old boy
      afflicted with myocardiopathy pyelocalyceal ecstasia and psychomotor delay.
      Exhibited multiple cavitated caries of atypical locations. 4 incisors were
      extracted and replaced with preformed crowns. 3. A 9-year-old boy affected with
      plagiocephaly, laryngomalasia, hiatal hernia, urinary infections and psycho-motor
      delay. Presented multiple profound and extensive caries, which needed pulp
      treatment and preformed crown placement. DISCUSSION: The caries in all three
      patients were similar and of rapid progression. The most relevant factors were:
      reflux and vomiting of 2 of the patients and continuous and prolonged ingestion
      of fruit juices of the other. In all three of them there was abnormal exposure to
      both intrinsic and extrinsic acids in the oral cavity, so as muscular hypotony
      and psychomotor deficiency that hindered the autoclisis and oral hygiene. It is
      inferred that in all 3 cases the initial pathology was a description of
      demineralization of chemical origin concordant to dental erosion, upon which an
      immediate colonization of microorganisms arose, accelerating tissue destruction.
      It is concluded that the systemic and familial conditions of children with Noonan
      Syndrome favor erosion and the establishment of caries that are potentially
      harmful foci, of which adequate and preventive measures should be implemented.

PMID- 12618675
TI  - A comparative study of direct mandibular nerve block and the Akinosi technique.
AB  - A study is made of 56 patients subjected to lower molar extraction, comparing the
      efficacy of the Akinosi technique as an alternative to direct or conventional
      mandibular nerve block in two groups of 28 subjects each. The parameters
      evaluated were pain in response to puncture, percentage positive aspiration,
      latency, pain during the intervention and complications. Patient pain in response
      to puncture was comparatively less intense and frequent with the Akinosi
      technique. The latency to anesthesia was briefer with conventional mandibular
      block than with the Akinosi technique (2.9 versus 3.8 minutes). Pain during the
      intervention and the duration of the anesthetic effect were similar for both
      techniques. The patients anesthetized with the Akinosi technique required more
      buccal nerve reinforcement infiltrations to complete the procedure. The
      anesthetic failure rates were 10.7% and 17.8% for the conventional and Akinosi
      technique, respectively. It is concluded that while the Akinosi technique can be
      used to extract lower molars, direct mandibular block offers superior anesthetic
      performance.

PMID- 12618676
TI  - Ameloblastic fibroma of the mandible. Report of two cases.
AB  - The ameloblastic fibroma (AF)-ameloblastic fibro-odontoma (AFO), is an uncommon
      benign mixed odontogenic tumor (epithelial and mesenchymal), that represents the
      2% of all odontogenic tumors. It usually appears in the mandible and in the
      posterior segments of young patients without gender predilection, and sometimes
      is associated with an impacted tooth. The classification of the WHO includes it
      in the subtype of odontogenic tumors with a defined histologic features. The AF
      and the AFO are considered as an unique entity as they are variations of the same
      tumor, only distinct for the presence of an odontoma in the case of the AFO.
      Surgical conservative treatment with excision followed by curettage seems to be
      the most appropriate therapeutic option. The objective of this paper is to report
      two cases of this tumor, to make a brief review of the literature and its
      differential diagnosis, to analyse its clinical and histologic features and the
      therapeutic option.

PMID- 12618677
TI  - Treatment of bacterial orofacial infections.

PMID- 12618678
TI  - Extraction of impacted third molars.

PMID- 12618679
TI  - Differential diagnosis of white lesions.

PMID- 12618680
TI  - Systematic versus selective stent placement after superficial femoral artery
      balloon angioplasty: a multicenter prospective randomized study.
AB  - PURPOSE: Outcome with selective or systematic stenting with the Palmaz vascular
      stent was compared in patients with limb-threatening ischemia or persistent
      disabling claudication despite medical therapy, with less than 7 cm stenosis or
      occlusion of the superficial femoral artery. METHODS: This was a multicenter
      prospective randomized trial with centralized allocation of treatment and
      independent review of vascular events. The primary end point was presence of more
      than 50% stenosis at 1-year angiographic follow-up. Secondary end points were
      survival; occurrence of vascular events in the treated leg; and number of failed
      procedures, defined as more than 50% stenosis or death at 1 year. RESULTS: Two
      hundred twenty-seven patients were enrolled in the study, 112 in the selective
      stent group, and 115 in the systematic stent group. Seventeen patients (15%) in
      the selective stent group received a stent after suboptimal results of
      percutaneous transluminal angioplasty. Angiograms for 140 patients were available
      at 1-year follow-up and demonstrated no statistical difference between the two
      groups; more than 50% stenosis of the dilated site was noted in 21 of 65 patients
      (32,3%) in the selective stent group and 26 of 75 patients (34.7%) in the
      systematic stent group (P =.85, Fisher exact test). Survival in the percutaneous
      transluminal angioplasty and stent groups was, respectively, 92% and 96% at 1
      year, 89% and 93% at 2 years, and 82% and 80% at 4 years (P =.40, log-rank test).
      Survival free of new vascular events in the treated limb was 77% and 65% at 1
      year, 70% and 53% at 2 years, and 57% and 44% at 4 years (P =.017, log-rank
      test). Number of failed procedures at 1 year was 29 of 86 (33%) and 30 of 89
      (34%) (P = 0.9). CONCLUSION: Systematic stenting of short stenosis or occlusion
      of the superficial femoral artery is not justified. Palmaz vascular stent
      placement should be reserved for use in patients with suboptimal results of
      balloon angioplasty.

PMID- 12618681
TI  - Is early postoperative duplex scan surveillance of leg bypass grafts clinically
      important?
AB  - PURPOSE: The typical leg bypass surveillance program begins with a duplex scan
      evaluation of the vein graft 3 months after surgery; studies are repeated every 3
      months during the first year of follow-up and are fully reimbursed by our
      Medicare carrier. Some authors have recommended early (before discharge or first
      postoperative visit) duplex scanning to identify high-risk grafts. However, the
      natural history of velocity disturbances detected with early scans is unclear,
      and furthermore, such studies are not reimbursed by Medicare. METHODS: We
      reviewed all infrainguinal vein bypass grafts prospectively entered into a
      surveillance protocol that included an early (<6 weeks) duplex scan study.
      Routine completion angiography was performed at the initial operation in all
      patients. Early duplex scan results, the need for graft revision, and detailed
      follow-up of these bypass grafts were analyzed. RESULTS: Early duplex scans were
      performed in 224 bypass grafts placed in 204 patients. Early scans were abnormal
      (peak systolic velocity [PSV], >200 cm/s) in 58 grafts (26%). Six grafts of the
      58 (10.3%; 2.7%) with an early abnormal duplex scan and unrepaired defects
      occluded during the follow-up period. Thirty grafts were revised on the basis of
      the initial early scan; 23 of these revisions were performed for critical or
      rapidly progressive lesions in the first 3 postoperative months. Seven lesions
      progressed more slowly and were repaired at a mean of 8 months after surgery.
      Interestingly, 22 flow abnormalities (37%) resolved or stabilized despite a PSV
      of more than 300 cm/s in six cases (27%). Clear duplex scan evidence of
      regression or progression of these early flow abnormalities occurred within 3
      months in 51/58 cases (88%). A total of 68 grafts (30%) were revised during the
      entire study period; 30 of these (44%) were on the basis of the early abnormal
      scan. CONCLUSION: Despite normal completion arteriography, early graft velocity
      abnormalities are strikingly common and were detected in 26% of the 224
      infrainguinal vein grafts in this series. These lesions were clinically important
      because 52% necessitated revision. Surprisingly, however, 38% of these early flow
      disturbances resolved, despite a PSV of more than 300 cm/s in 27% of cases. Early
      duplex scan surveillance singularly detects a clinically significant subgroup of
      grafts that need revision. The possible origin of these early lesions deserves
      further inquiry, but on the basis of its clinical yield, we recommend that early
      duplex scan surveillance of infrainguinal bypass grafts should be routine and
      should be considered for Medicare reimbursement.

PMID- 12618682
TI  - Calciphylaxis and nonhealing wounds: the role of the vascular surgeon in a
      multidisciplinary treatment.
AB  - OBJECTIVE: Calciphylaxis, a disorder of calcium-phosphate metabolism that can
      result in arterial calcification, skin and solid organ calcium deposits, and
      nonhealing ulcerations, is associated with significant morbidity and mortality.
      Although its most common cause is secondary hyperparathyroidism in patients with
      renal failure, vascular surgeons are frequently called on to evaluate these
      nonhealing extremity wounds. We reviewed our experience of a multidisciplinary
      approach in treating patients with calciphylaxis and nonhealing ulcers. PATIENTS
      AND METHODS: Over a 14-month period at a tertiary center, five patients were seen
      with calciphylaxis and nonhealing leg wounds. Demographics, disease
      characteristics, surgical treatment, and outcomes were analyzed. RESULTS: All
      five patients were black women aged 40 +/- 8.9 years with hypertensive renal
      failure undergoing long-term hemodialysis (80 +/- 43 months). They had large,
      painful lower extremity wounds or necrotic ulcers (mean size, 135 cm(2)) that had
      developed over 2 to 4 months. Three patients had palpable pedal pulses, one
      patient had Doppler pedal signals, and one patient had absent pedal flow.
      Arteriogram was performed in the latter two patients, and one patient underwent
      lower extremity revascularization because of superficial femoral artery stenosis
      with symptomatic improvement. Four patients underwent aggressive debridement by
      the vascular surgical service, and two needed plastic surgeon-performed skin
      grafting. All patients had elevated parathyroid hormone levels (mean, 1735 pg/mL;
      > 25 x normal level); mean preoperative calcium levels were normal (10 mg/dL).
      After either subtotal (n = 4) or total (n = 1) parathyroidectomy by an
      experienced endocrine surgeon, a significant reduction in parathyroid hormone and
      calcium levels was seen (122 pg/mL and 7.9 mg/dL, respectively; P <.05). There
      were no postoperative complications or amputations; one patient died 12 months
      after parathyroidectomy of severe preexisting cardiopulmonary disease. Complete
      wound healing was observed by 4.8 +/- 2 months. During a mean follow-up period of
      9 months (range, 1 to 18 months), all wounds remained healed without ulcer
      recurrence. CONCLUSION: The diagnosis of calciphylaxis should be considered in
      patients with end-stage renal disease with atypical tissue necrosis or
      subcutaneous nodules. Early recognition of calciphylaxis and multidisciplinary
      treatment, including diligent wound care, frequent debridement,
      parathyroidectomy, and appropriate skin grafting or revascularization, can result
      in improved wound healing and limb salvage.

PMID- 12618683
TI  - Sympathectomy for complex regional pain syndrome.
AB  - BACKGROUND: With the easier and earlier recognition of complex regional pain
      syndrome (CRPS), a reappraisal of its therapy, particularly the role and timing
      of sympathectomy, is warranted. PATIENTS AND METHODS: Over a 9-year period, 42
      patients with CRPS type II of the upper extremity were referred for
      sympathectomy. Patients were categorized according to the duration of the
      symptoms (group I, <3 months; group II, >3 months). All patients underwent
      initial medical treatment; stellate ganglion blocks were performed when symptoms
      persisted beyond 6 weeks. Patients were referred for thoracoscopic sympathectomy
      on persistence of the pain syndrome. A visual linear analogue scale was used to
      evaluate outcome of sympathectomy. RESULTS: Thoracoscopic dorsal sympathectomy
      was successfully undertaken in 32 patients. In the remaining 10 patients,
      thoracoscopy was not technically feasible and open sympathectomy was performed.
      There was an overall improvement in all 42 patients undergoing sympathectomy (P
      <.001, Wilcoxon signed rank test). The outcome in group I was significantly
      better than in group II (P <.003, Mann-Whitney U test). The diagnosis of
      sympathetically mediated pain with stellate blockade did not correlate with
      clinical outcome. Patients undergoing thoracoscopic sympathectomy had a better
      outcome than those undergoing open sympathectomy. There were no complications,
      and the hospital stay was shorter in the thoracoscopic group. CONCLUSION: Early
      recognition of CRPS and prompt recourse to surgical sympathectomy is a useful
      option in the management of CRPS.

PMID- 12618684
TI  - The safety, efficacy, and pharmacoeconomics of low-dose alteplase compared with
      urokinase for catheter-directed thrombolysis of arterial and venous occlusions.
AB  - PURPOSE: The purpose of this study was to compare the efficacy, complications,
      and costs associated with low-dose (<2 mg/h) alteplase (tissue plasminogen
      activator [t-PA]) versus urokinase for the catheter-directed treatment of acute
      peripheral arterial occlusive disease (PAO) and deep vein thrombosis (DVT).
      MATERIALS AND METHODS: A retrospective review was performed during sequential
      time periods on two groups with involved extremities treated with either t-PA
      with subtherapeutic heparin (TPA group) or urokinase with full heparin (UK group)
      at a single center. Treatment group characteristics, success rates,
      complications, dosages, infusion time, and costs were compared. RESULTS: Eighty
      nine patients with 93 involved limbs underwent treatment (54 with DVT, 39 with
      PAO). The treatment groups were statistically identical (TPA: 45 limbs; 24 with
      DVT, 53.3%; 21 with PAO, 46.7%; UK: 48 limbs; 30 with DVT, 62.5%; 18 with PAO,
      37.5%). The overall average hourly infused dose, total dose, infusion time,
      success rates, and cost of thrombolytic agent were as follows (+/- standard
      deviation): TPA, 0.86 +/- 0.50 mg/h, 21.2 +/- 15.1 mg, 24.6 +/- 11.2 hours,
      89.4%, $466 +/- $331; and UK, 13.5 +/- 5.6 (10(4)) U/h, 4.485 +/- 2.394 million
      U, 33.3 +/- 13.3 hours, 85.7%, $6871 +/- $3667, respectively. Major and minor
      complication rates were: TPA, 2.2% and 8.9%; and UK, 2.1% and 10.4%,
      respectively. No statistical differences in success rates or complications were
      observed; however, t-PA was significantly (P <.05) less expensive and faster than
      urokinase. CONCLUSION: Low-dose t-PA combined with subtherapeutic heparin is
      equally efficacious and safe compared with urokinase. Infusions with t-PA were
      significantly shorter and less expensive than those with urokinase.

PMID- 12618685
TI  - Proximal extent of pelvic vein thrombosis and its association with pulmonary
      embolism.
AB  - OBJECTIVE: Conventional methods such as duplex ultrasound scanning do not provide
      accurate information about proximal extension of pelvic vein thrombosis. We
      evaluated proximal extent of thrombus toward pelvic veins with magnetic resonance
      imaging in patients with suspected deep vein thrombosis (DVT) proximal to the
      inguinal ligament on the basis of duplex ultrasound scans. In addition, frequency
      of pulmonary embolism (PE) and early (4 weeks) clinical outcome were evaluated.
      METHODS: Two hundred twelve patients with acute symptomatic DVT proximal to the
      inguinal ligament, diagnosed at duplex ultrasound scanning, were enrolled in this
      prospective study. All patients underwent magnetic resonance imaging of the
      abdominal and pelvic veins, as well as lung scintigraphy to detect the presence
      of pulmonary embolism. RESULTS: In 24 of 212 patients (11%), thrombus was
      restricted to the femoral vein. The thrombus extended into iliac veins in 142
      patients (67%) and into the inferior vena cava in 46 patients (22%). The
      frequency of PE was not associated with the most proximal extension of thrombus
      (P =.61). No patients died as a consequence of thromboembolic events.
      CONCLUSIONS: Extension of DVT into the inferior vena cava occurs relatively
      frequently. In our patients this finding was not associated with higher risk for
      PE compared with DVT of the femoral or iliac veins.

PMID- 12618686
TI  - Short-term natural history of isolated gastrocnemius and soleal vein thrombosis.
AB  - OBJECTIVE: Lower extremity deep vein thrombosis is often isolated to the
      sinusoidal veins draining the gastrocnemius and soleus muscles. The purpose of
      this study was to establish the incidence rate of propagation of isolated
      gastrocnemius and soleal vein thrombosis (IGSVT) into the deep veins of the calf
      and thigh. METHODS: All patients who were referred for color flow duplex
      ultrasonography (CFDU) for suspected deep vein thrombosis were prospectively
      evaluated for IGSVT. Patients with IGSVT received no systemic anticoagulation
      therapy and underwent serial CFDU at 5, 9, 14, 30, and 90 days after recruitment.
      The incidence and extent of IGSVT propagation were noted. Factors predictive of
      IGSVT extension were sought, including age, gender, side, symptoms, ambulatory
      status, and the presence of comorbid illness, including cardiac disease, cancer,
      hypercoagulable states, recent surgery or trauma, and previous venous disease.
      RESULTS: One hundred thirty-five limbs with IGSVT were studied for 3 months, and
      16.3% of cases with IGSVT extended the thrombus to the level of the adjacent
      tibial, or peroneal, veins or higher. Only 3% of the cases with IGSVT propagated
      as cephalad as the popliteal vein, and 90.9% of IGSVT propagation occurred within
      2 weeks of CFDU diagnosis. No IGSVT propagated to the level of the popliteal vein
      beyond 2 weeks from the time of CFDU diagnosis. No IGSVT extended into the deep
      veins of the thigh. By the end of the 3-month study period, 45.9% of thrombi had
      completely resolved. Only the presence of cancer was prognostic for IGSVT
      progression. CONCLUSION: During the 3-month study period, the short-term
      incidence rate of untreated IGSVT propagation to the level of the popliteal vein,
      even in the presence of cancer, was only 3%. Follow-up imaging to detect IGSVT
      propagation beyond 2 weeks from the time of diagnosis may not be necessary.

PMID- 12618687
TI  - Deep venous thrombosis during pregnancy and after delivery: indications for and
      results of thrombectomy.
AB  - PURPOSE: Pregnancy and the puerperium are time periods of an increased risk for
      venous thromboembolism. An ideal treatment should lead to complete restoration of
      the venous lumen, elimination of the embolic source, and prevention of severe
      postphlebitic syndrome. Anticoagulation therapy with heparin or thrombectomy are
      treatment options. In the current literature, these options are discussed
      controversially. METHODS: From January 1982 to December 2001, 97 women underwent
      (93% transfemoral) thrombectomy and construction of an arteriovenous fistula
      (AVF) for deep venous thrombosis related to pregnancy. The clinical and
      coagulation parameters were evaluated. The AVF was ligated 3 to 6 months later.
      Follow-up with duplex ultrasound scan, photoplethysmography, and strain-gauge
      plethysmography was completed in 87 women. RESULTS: Surgery was performed without
      any maternal death or pulmonary embolization. A cesarean section was carried out
      during the same anesthesia in 11 cases. Thrombectomy was completed with
      construction of a temporary AVF in 90 patients (92.8%). One fetal death occurred
      in the recovery room for unknown reasons. In the early postoperative course, 16
      patients (16.5%) underwent redo surgery for rethrombosis with or without the
      occlusion of the fistula. In 14 of these patients, the venous system remained
      patent thereafter. Fetal or neonatal death occurred in five cases 2 to 10 weeks
      after surgery, mainly because of abruption of the placenta probably from
      anticoagulation. Among 247 preoperatively occluded anatomic regions, 221 could be
      restored, and the secondary patency rate amounted to 89.5%. After a mean follow
      up period of 6 years, 49 patients (56.3%) were seen without a postphlebitic
      syndrome, and only three patients (3.5%) had had a leg ulcer develop. CONCLUSION:
      In experienced hands, venous thrombectomy is a safe method to prevent pulmonary
      embolism and postphlebitic syndrome in women during pregnancy and the puerperium.
      The frequency of a severe postphlebitic syndrome after our surgical approach is
      lower than the rates published for anticoagulation treatment alone.

PMID- 12618688
TI  - Advanced management of venous malformation with ethanol sclerotherapy: mid-term
      results.
AB  - PURPOSE: This paper is an update of previously published data on the basis of a
      retrospective review of midterm results of ethanol sclerotherapy on 87 patients
      (January 1995 to December 2000) for assessment of its efficacy as an improved
      treatment method for venous malformation (VM). According to this assessment, VMs
      were defined with a new classification and studied with advanced diagnostic
      technology and an advanced care system. METHODS: The average follow-up period was
      24 months after completion of a multisession treatment (mean, 8.2 months).
      Classification of VM was based on a modification of the Hamburg classification.
      Advanced diagnostic technology, mostly noninvasive, was used on 226 of 520
      patients with congenital vascular malformation registered at the Congenital
      Vascular Malformation Clinic at the Samsung Medical Center. Of the 226 patients
      with VM, 87 with infiltrating extratruncular lesions had a total of 399 sessions
      of sclerotherapy. Follow-up assessment with periodic clinical examinations by the
      multidisciplinary team was supplemented with body blood pool scans, duplex scans,
      and magnetic resonance imaging, according to protocol, once the multisession
      therapy was completed. Angiographic assessment was seldom included. The endpoint
      of this phase II study was 24 months. RESULTS: Of 399 sessions, initial success
      was seen in 379 sessions (95.0%) and failure was seen in 20 sessions (5%). This
      was mostly caused by forced abandonment from technical difficulty in delivering
      ethanol safely to the lesion (eg, direct drainage of VM into normal deep vein
      system). Later results after completion of the multisession therapy with a
      minimum follow-up of 24 months on 71 VMs have shown no evidence of recurrence.
      Eighty-seven patients have shown the same results without recurrence on an
      average of 18.2 months of follow-up. Fifty-one minor to major complications,
      mostly skin damage, developed after 47 sessions among the 379 sessions (12.4% in
      24/87 patients; 27.9%). However, complications resolved spontaneously or were
      managed successfully, except for one permanent facial nerve palsy and one
      peroneal nerve palsy. CONCLUSION: Absolute ethanol sclerotherapy can deliver
      excellent results as an independent therapy to the infiltrating type of
      extratruncular form of VM, which was once taboo because of prohibitively high
      morbidity. Absolute ethanol may be accepted as an effective treatment method
      because no recurrence has been observed in the relatively long-term observation
      period and the morbidity has been acceptable. However, it should be reserved only
      for individuals and centers with expertise. The morbidity involved should be
      clearly understood and accepted by the patient or family, and the risk of acute
      and chronic complications, both major or minor, should be explained to the
      patient. Long-term assessment of the complication's sequelae is warranted.

PMID- 12618689
TI  - A systematic review of pneumatic compression for treatment of chronic venous
      insufficiency and venous ulcers.
AB  - INTRODUCTION: As part of a reconsideration of coverage policy, the Centers for
      Medicare and Medicaid Services requested a systematic review of the evidence on
      the use of pneumatic compression devices in the home environment for treatment of
      chronic venous insufficiency (CVI) and venous ulcers. METHODS: Articles were
      found with a systematic literature search of MEDLINE, EMBASE, and AMED (Allied
      and Complementary Medicine) databases, hand searches of reference lists, and
      suggestions of experts. RESULTS: Eight trials that met the inclusion criteria,
      including several randomized control trials, were found. Most studies were small
      and may have been underpowered. However, several were well-designed randomized
      controlled trials. Three studies showed that the devices could alleviate symptoms
      of CVI. No studies directly measured whether the devices could prevent the
      occurrence of venous ulcers. Some studies on the treatment of venous ulcers did
      not show a benefit for pneumatic compression, but other studies showed a benefit
      for the devices in healing long-standing chronic ulcers that had not healed with
      other methods. No studies directly compared single-chamber and multiple-chamber
      devices or studied whether the effectiveness of the pump was dependent on types
      of treatment used concurrently with the pump. Few adverse events were reported in
      the trials. Patients generally expressed satisfaction with the pneumatic
      compression devices, and several studies reported higher compliance than with
      other compression methods. CONCLUSION: The available data cannot be relied on to
      inform the optimal choice of compression therapy or optimal protocol for patients
      with CVI or venous ulcers. Methodologically rigorous research designed to answer
      these questions would be useful for treatment decisions. The Centers for Medicare
      and Medicaid Services considered the results of this study and issued a decision
      that pneumatic compression will only be covered for patients with refractory
      edema with significant ulceration of the lower extremities after a 6-month trial
      of standard therapies, such as compression stockings, has failed.

PMID- 12618691
TI  - Venous reflux repair with cryopreserved vein valves.
AB  - PURPOSE: The purpose of this study was to evaluate the immediate and short-term
      outcome of inserted cryopreserved vein valve allografts and the clinical outcome
      of treated limbs. METHOD: Twenty-seven cryovalves were inserted in 25
      postthrombotic limbs because of active leg ulcer (20 limbs) or severe disabling
      leg pain (five limbs) as a procedure of last resort. Previous venous surgery had
      been performed in 80% of the limbs. Main stem superficial reflux and iliac venous
      outflow obstruction were controlled before cryovalve insertion. The most common
      insertion site was the superficial femoral or popliteal vein. Patients were
      followed up with clinical examination and with intermittent duplex Doppler
      scanning or ascending venography to assess patency and competency of the valve
      station. RESULTS: After thawing, but before insertion, 74% of the cryovalves were
      incompetent and needed repair with transcommissural valvuloplasty. After
      insertion, mortality was zero. Morbidity was 48%, mainly because of seroma
      formation and deep wound infection. One cryovalve was explanted because of acute
      rejection. Six cryovalves occluded early (<6 weeks), and five occluded late.
      Cumulative rates of patent cryovalves and both patent and competent cryovalves at
      24-month follow-up were 41% and 27%, respectively. Cumulative ulcer recurrence
      free rate at 36 months was 50%. Pain relief was poor, and degree of swelling
      remained the same. CONCLUSION: Compared with autologous vein transfer, cryovalve
      insertion is associated with high morbidity, high occlusion rate, poor cumulative
      midterm rate of patent graft with competent valve, and poor clinical results. The
      procedure should not be used as a primary technique for valve reconstruction, and
      it is questionable whether it is useful even in patients in whom autologous
      reconstruction techniques have been exhausted. The basis of the high failure rate
      is unclear; it may be immunologic or due to loss of endothelial cover after
      implantation. If cryovalves are to be a viable valve repair alternative, improved
      cryopreservation technique, immunologic modifications, or better matching must be
      achieved.

PMID- 12618690
TI  - Optimal therapy for advanced chronic venous insufficiency.
AB  - INTRODUCTION: While definitive therapy awaits level I evidence, controversy
      persists regarding the optimal operation for treatment of advanced chronic venous
      insufficiency (CVI). We propose a pragmatic approach to the correction or
      amelioration of venous hypertension resulting from hydrodynamic and hydrostatic
      venous reflux. We evaluated a strategy of balloon dissection, subfascial
      endoscopic perforating vein surgery (SEPS) with routine posterior deep
      compartment fasciotomy, including ligation and stripping of the superficial
      system, for use when reflux is documented at duplex ultrasound (US) scanning.
      METHODS: This is a cooperative, multicenter, retrospective review of 832 patients
      stratified by CEAP classification. The series consisted of 300 patients with C4
      CVI, 119 patients with C5 CVI, and 413 patients with C6 CVI. A subset of 92
      patients with C4 disease were prospectively randomized, and ambulatory venous
      pressure (AVP) was determined preoperatively and postoperatively. All patients
      underwent duplex US scanning to document reflux in the deep, superficial, and
      perforating venous systems. Efficacy, safety, and durability were evaluated over
      follow-up of 1 to 9 years (mean, 31/2 years). Uniformity was attempted by
      adoption of the senior author's protocol and technique through on-site
      preceptorship in each surgeon's operative theater. RESULTS: This technique
      interrupted 3 to 14 (mean, 7) incompetent perforating veins per patient. Of the
      832 patients undergoing SEPS, 460 (55%) underwent saphenous vein ligation and
      stripping at the same operation. In 92% ulcers healed or were significantly
      improved within 4 to 14 weeks. In 64 (8%) patients, ulcers failed to heal or
      there was no benefit from the operation. Thirty-two patients (4%) experienced
      recurrent ulceration or skin deterioration at 6 months-2 years (mean, 15 mo).
      Repeat SEPS was successful in 25 of these 96 patients, and deep valve repair was
      successful in 4 patients. In the 92 randomized patients with C4 disease, 41
      refused postoperative AVP, leaving 51 compliant patients. The SEPS group (n = 25)
      had significantly reduced AVP (P <.01) compared with the control group (n = 26).
      Complications in 825 patients were less than 3% and consisted mostly of transient
      neurologic disorders (eg, paradysthesia), but deep venous thrombosis occurred in
      2 patients, with pulmonary embolus in 1. No operative deaths occurred. Follow-up
      for 1 to 9 years (mean, 31/2 years) demonstrated durability. CONCLUSION: The
      efficacy, safety, and durability of this operative protocol proved beneficial in
      our clinical experience with 832 patients during 9 years of follow-up. The SEPS
      subset of randomized patients with C4 disease experienced significant decrease in
      AVP, objectively supporting the effectiveness of reflux surgery in advanced CVI.
      Until definitive level I evidence is available, this operative technique is
      advocated as optimal therapy for CVI.

PMID- 12618692
TI  - The thigh extension of the lesser saphenous vein: from Giacomini's observations
      to ultrasound scan imaging.
AB  - BACKGROUND: Giacomini described a vein that now bears his name almost 130 years
      ago. Subsequent anatomic studies detail his findings but receive inadequate
      attention in clinical and surgical textbooks. The purpose of this study was to
      present a summary of the original observations by Giacomini, present our
      ultrasound scan findings, and review later anatomic, venographic, and ultrasound
      scan studies. METHODS: The study was a literature review and experience with
      duplex ultrasound scanning from units in Italy and Australia. RESULTS: Giacomini
      described a thigh extension from the lesser saphenous vein that passed to join
      with the greater saphenous vein, which since then bears his name, and described
      also the other destinations of the thigh extention to deep veins through
      perforators or an end as multiple tributaries in the superficial tissues or
      muscles. Duplex ultrasound scanning shows that the vein can be affected by
      varicose disease with reflux either upwards or downwards in the thigh to the
      greater or lesser saphenous veins respectively. CONCLUSION: Ultrasound scan
      imaging has brought the vein of Giacomini from the realm of anatomic dissection
      to an important structure to be considered in the clinical management of chronic
      venous disease.

PMID- 12618693
TI  - Brachial artery dilatation after arteriovenous fistulae in patients after renal
      transplantation: a 10-year follow-up with ultrasound scan.
AB  - BACKGROUND: Dilatation of the artery proximal to arteriovenous fistula (AF) is
      not well known but is a potential serious complication in patients for renal
      transplant. METHODS: From 1991 until 2001, the diameters of the brachial arteries
      of 29 patients after successful renal transplantation and with existing AF were
      prospectively evaluated with ultrasound scan. Nine patients with longstanding AF
      without transplantation were included as a control group. RESULTS: In 1991, the
      mean brachial artery diameter was 6.4 mm (+/-1.8 mm) with patent AF and 5.2 mm
      (+/-1.5 mm) with occluded AF (P= not significant). The 1994 mean diameter was 6.6
      mm (+/-1.7 mm) versus 5.3 mm (+/-2.0 mm; P =.029). In 2001, the mean diameter
      rose to 7.4 mm (+/-1.3 mm) versus 5.7 mm (+/-2.8 mm; P =.022). Compared with the
      side without fistula, the diameter of brachial artery on the AF side was
      significantly greater during the whole study period. The increase in the diameter
      correlates significantly with the time the AF had been patent (P =.001, according
      to Spearman test). The dilatation of the brachial arteries of patients without
      transplantation was smaller compared with patients after transplantation but did
      not reach statistical significance. Two patients had to undergo operation on a
      symptomatic aneurysm of the axillobrachial artery. CONCLUSION: According to our
      results, dilatation of the brachial artery after AV is time dependent. Higher
      flow in the AF seems to be the main trigger of dilatation.

PMID- 12618694
TI  - Does female gender or hormone replacement therapy affect early or late outcome
      after carotid endarterectomy?
AB  - OBJECTIVE: Subgroup analyses of the Asymptomatic Carotid Atherosclerosis Study
      and the North American Symptomatic Carotid Endarterectomy Trial trials have
      questioned the ability of carotid endarterectomy (CEA) to reduce the risk of
      stroke in women. The purpose of this study was to test the effect of female
      gender and estrogen-based hormone replacement therapy on perioperative (30-day)
      and long-term (5-year) outcomes after CEA. METHODS: From 1988 to 1998, 361 CEAs
      were performed in 326 patients (246 male, 115 female) by a single surgeon.
      Retrospective data were collected with chart review, and follow-up data were
      obtained with clinical examination or telephone interview. Follow-up was possible
      in 95% of patients. Reoperative CEAs and combined aortic or cardiac procedures
      were excluded. Statistical analysis used life-table methods, Student t test, and
      Pearson chi(2) tests when appropriate. RESULTS: Age and preoperative risk factors
      were similar between women and men. CEA was performed for symptomatic (50%
      female, 42% male) and asymptomatic carotid stenosis (50% female, 58% male; P
      =.19). Perioperative (30-day) stroke rate was similar for women and men (3.6%
      female, 1.2% male; P =.13). No perioperative strokes occurred in asymptomatic
      patients. With previous stroke or transient ischemic attack, a trend was seen
      towards an increased perioperative stroke rate in women (7.0% female, 2.8% male;
      P =.25). Long-term follow-up showed a similar trend in the 5-year stroke rate in
      symptomatic patients (7.0% female, 2.8 male; P =.23). The stroke-free survival
      rate was not significantly different between genders (87% female, 75% male; P
      =.58). Reoperation was performed for asymptomatic recurrent carotid stenosis in
      five men (2.3%) and two women (1.9%; P =.84). Interestingly, the use of estrogen
      based hormone replacement therapy in women showed a trend toward increasing
      stroke rate at 30 days (1.2% versus 8.7%; P =.08) and at 5 years (2.3% versus
      8.7%; P =.16). CONCLUSION: This retrospective study confirms that CEA provides
      long-term reduction in stroke risk and improved stroke-free survival rates in
      both men and women. However, women with previous neurologic symptoms and those
      using hormone replacement therapy appear to be at higher stroke risk at the time
      of surgery.

PMID- 12618695
TI  - Is the rationale for carotid angioplasty and stenting in patients excluded from
      NASCET/ACAS or eligible for ARCHeR justified?
AB  - PURPOSE: To compare outcome after carotid endarterectomy (CEA) in patients who
      would have been excluded from the North American Symptomatic Carotid
      Endarterectomy Trial (NASCET) or the Asymptomatic Carotid Atherosclerosis Study
      (ACAS) or would have been eligible for Acculink for Revascularization of Carotids
      in High Risk Patients (ARCHeR), a current high-risk stent registry, with outcome
      in a similar cohort at low risk. METHODS: Records of all CEAs performed at our
      institution from July 1993 to December 2000 were reviewed. Patients were assigned
      to groups either eligible or ineligible for NASCET and ACAS or ARCHeR, and
      criteria were stratified according to whether risk was defined by anatomic or
      medical problems or whether patients were ineligible according to nonmedical
      protocol exclusion criteria only. RESULTS: Preoperative and postoperative data
      were sufficient to determine risk status according to various study criteria in
      857 patients. Stroke or death within 30 days, the primary end point, occurred in
      2.1% of patients. Rates were similar in patients excluded from (2.7%) or included
      in (1.6%) NASCET and ACAS and in patients eligible (3.1%) or ineligible (2.1%)
      for ARCHeR. Rates did not differ according to whether exclusion or inclusion was
      based on anatomic risk, medical risk, or protocol exclusion, although trends
      favored worse outcome in the ARCHeR medical risk subgroup. A higher rate of minor
      complications was found in the elderly; however, stroke and death rates were
      similar according to age, gender, repeat procedure, or the presence of
      contralateral occlusion. CONCLUSIONS: No statistically or clinically significant
      differences were found in combined 30-day stroke or death rates after CEA in any
      group defined by previous surgical trials or current ongoing high-risk stent
      registry. While high-risk groups may exist, the premise that operative risk is
      higher in patients excluded from NASCET and ACAS or eligible for ARCHeR is not
      supported.

PMID- 12618696
TI  - Carotid-carotid crossover bypass: is it a durable procedure?
AB  - PURPOSE: Reconstruction of a diseased common carotid artery may necessitate
      direct repair via aortic artery-based revascularization. However, carotid-carotid
      artery crossover grafting is an alternative extra-anatomic option that obviates
      the need for median sternotomy. We analyzed our results with carotid-carotid
      artery crossover bypass surgery. METHODS: Data were analyzed for all patients
      undergoing carotid-carotid crossover bypass surgery from 1995 to 2000. Data on
      patient demographics, indications for surgery, perioperative morbidity and
      mortality, and graft patency were retrieved from a vascular surgery data base and
      hospital records. Stroke-free survival and graft patency were determined with
      life table methods. RESULTS: Over 5 years, 24 carotid-carotid artery crossover
      bypass procedures were performed to treat both symptomatic (n = 19, 79%) and
      asymptomatic (n = 5, 17%) disease. Nine procedures (38%) were performed in men, 3
      (13%) in patients with diabetes, 12 (50%) in active smokers, and 2 in patients
      with a history of Takayasu arteritis. Patient mean age was 63 years (range, 38-79
      years). Twenty-three patients (96%) received polytetrafluoroethylene conduit
      grafts, and the remaining patients received vein grafts. Ten (42%) patients
      underwent concomitant endarterectomy. There were no perioperative deaths. One
      patient (4%) had asymptomatic early occlusion, one had transient neurologic
      deficit (4%), one (4%) required additional surgery because of bleeding, and one
      (4%) had a perioperative cerebrovascular accident (stroke). Three (17%)
      asymptomatic late occlusions were identified at 11, 57, and 64 months,
      respectively. Mean follow-up was 30 months (range, 1-70 months). Primary patency
      was 88%, and secondary patency was 92% at 3 years. Stroke-free survival was 94%
      at 4 years. CONCLUSION: Carotid-carotid artery crossover bypass surgery is a safe
      and durable procedure. Its use precludes the need for median sternotomy and
      provides acceptable stroke-free survival.

PMID- 12618697
TI  - Surgery of popliteal artery aneurysms: a 12-year experience.
AB  - BACKGROUND: Management of asymptomatic popliteal aneurysm is controversial, and
      the prognosis for acutely thrombosed aneurysm is notoriously poor. We evaluated
      the management and outcome for popliteal aneurysm. PATIENTS AND METHODS: A
      retrospective review of all patients with popliteal aneurysm between 1988 and
      2000 was carried out. Fifty-two limbs were operated on in 41 patients. Data
      collected included findings at presentation, operative details, graft patency,
      limb salvage, complications, and 30-day mortality. RESULTS: Initial findings
      included acute ischemia (n = 14), no symptoms (n = 29), acute rupture (n = 2),
      chronic ischemia (n = 5), and symptoms of nerve or vein compressive (n = 2). All
      patients with symptomatic aneurysms and 22 patients with asymptomatic aneurysms
      (21 larger than 2 cm in diameter, 1 with thrombus at duplex ultrasound scanning)
      underwent surgery as first-line treatment. Of the 7 patients with asymptomatic
      aneurysm managed with surveillance with duplex ultrasound scanning, acute
      ischemia developed in three, 1 aneurysm ruptured, compressive symptoms developed
      in 1, and 2 remained asymptomatic but required surgery because of aneurysm
      enlargement (>2 cm). Of the 17 patients with acute ischemia, 13 had neurologic
      signs and underwent immediate thromboembolectomy (trifurcation alone in 8, ankle
      level arteriotomy in 4) and bypass grafting (n = 12) or inlay grafting (n = 1),
      and the other 4 underwent intra-arterial thrombolysis initially. Of these 4
      procedures, 2 were successful and had elective surgery; the other 2 required
      urgent surgery because of secondary distal embolism and failure of
      recanalization. Thirteen of the 17 grafts were to the crural vessels. Bypass
      grafting (medial approach) was used in 16 of the 17 patients with acute ischemia,
      all 5 patients with chronic ischemia, and the 8 patients with no symptoms. An
      inlay technique (posterior approach) was used in 16 patients with no symptoms,
      the 3 patients with symptoms of nerve or vein compression, and 1 patient with
      acute ischemia. The distal anastomoses were to the below-knee popliteal artery in
      35 patients and the crural arteries in 15 patients, using autologous vein. Two of
      the patients with rupture underwent ligation alone, the other undergoing bypass
      grafting in addition. The overall 5-year primary patency rate was 69%, secondary
      patency rate was 87%, and limb salvage rate was 87%. Limb salvage was achieved in
      14 of the 17 patients with acute ischemia. Patients with asymptomatic aneurysms
      had better secondary graft patency (100%) compared with symptomatic aneurysms
      (74%; P <.01). Acute ischemia, technique used, and crural artery grafts were not
      predictors of graft failure with either univariate or multivariate analysis.
      Symptomatic aneurysms were associated with more postoperative complications and
      greater 30-day mortality (4 of 28 vs 0 of 24). CONCLUSION: Thromboembolectomy
      followed by crural bypass grafting is an effective treatment for popliteal
      aneurysm with severe acute limb ischemia. Outcome is better with surgical
      management of asymptomatic popliteal aneurysm compared with symptomatic aneurysm.

PMID- 12618698
TI  - Predictors of severe morbidity and death after elective abdominal aortic
      aneurysmectomy in patients with chronic obstructive pulmonary disease.
AB  - OBJECTIVE: This study sought to identify risk factors associated with an
      unfavorable outcome after elective abdominal aortic aneurysm (AAA) repair in
      patients with chronic obstructive pulmonary disease (COPD). METHODS: The clinical
      records of 158 patients who underwent elective open AAA repair with COPD
      determined from preadmission International Classification of Diseases-ninth
      revision codes during a 12-year period at the University of Michigan were
      reviewed. Patients with uncomplicated outcomes (group I) were compared with those
      with unfavorable postoperative outcomes (group II). The unfavorable outcomes were
      defined as myocardial infarction, acute renal failure, worsening respiratory
      insufficiency necessitating tracheostomy, or death within 30 days of surgery.
      Logistic regression analyses of variables that were identified as being
      statistically significant in the univariate analysis were used to develop a
      predictive model of these events. RESULTS: Group I included 133 patients (77 men,
      56 women) with a mean age of 70.1 years, and group II included 25 patients (13
      men, 12 women) with a mean age of 71.4 years. Preoperative factors statistically
      related (P =.002) to an unfavorable outcome in group II patients included:
      suboptimal COPD management (fewer prescribed inhalers), lower hematocrit,
      preoperative renal insufficiency, and coronary artery disease. Importantly,
      abnormal preoperative spirometry and arterial blood gases were not predictive of
      a poor outcome. Univariate analysis also revealed increased hospital (25 versus
      13 days; P =.0001) and intensive care unit (14 versus 4 days; P =.001) length of
      stays and a greater need for prolonged ventilation (8 versus 1 day; P =.039) for
      group II patients compared with group I patients. The 30-day mortality rate in
      the entire experience was 3.2% (5/158). No specific variables associated with
      mortality were identified. CONCLUSION: Fewer prescribed inhalers, lower
      hematocrit, renal insufficiency, and coronary artery disease are preoperative
      factors associated with unfavorable outcomes after open elective surgical repair
      of AAA in patients with COPD. Intensive management of these factors may reduce
      the hazards of AAA operations in these patients. COPD alone should not be
      considered a deterrent to the surgical treatment of AAAs.

PMID- 12618699
TI  - The systemic inflammatory response syndrome, organ failure, and mortality after
      abdominal aortic aneurysm repair.
AB  - BACKGROUND: Organ failure is a major cause of morbidity and mortality after
      abdominal aortic aneurysm (AAA) repair. The aim of this study was to determine
      the relationships between the systemic inflammatory response syndrome (SIRS),
      organ failure, and mortality after AAA repair and to determine whether the
      clinical monitoring of SIRS was a useful adjunct to clinical method. METHODS: One
      hundred consecutive patients undergoing open AAA repair were prospectively
      studied. Patients were divided into three groups: those undergoing elective AAA
      repair, those with symptomatic but nonruptured AAA, and those with ruptured AAA.
      The presence of SIRS and organ failure was recorded on a daily basis for each
      patient until discharge or death. RESULTS: Most patients had SIRS develop during
      the postoperative period: 89% of the elective group, 92% of the emergency
      nonruptured (urgent) group, and 100% of the ruptured group. Multiorgan failure
      occurred in 3.8% of the elective group, 38% of the urgent group, and 64% of the
      ruptured AAA group. After ruptured AAA repair, the concurrent absence of both
      SIRS and any organ failure for 48 hours had a sensitivity of 93% and a
      specificity of 91% as a predictive indicator of subsequent survival to hospital
      discharge. Patients in whom multiorgan failure developed after ruptured AAA
      repair had a significantly higher mortality rate (69%) than those who did not
      (0%; P =.001; 95% CI for the difference, 30.2% to 85.8%). CONCLUSION: The
      differences in the incidence rate of multiorgan failure between the patient
      groups compared with the high incidence rate of SIRS in all patient groups
      supports the two-hit hypothesis of multiorgan failure. The presence of multiorgan
      failure after ruptured AAA repair is associated with poor outcome. The absence of
      SIRS and organ failure in these patients is a good predictive indicator of
      survival.

PMID- 12618700
TI  - Simultaneous surgical treatment of abdominal aortic aneurysm and carcinoma of the
      bladder.
AB  - OBJECTIVE: The purpose of this study was to evaluate the short-term and long-term
      results of simultaneous surgical treatment of coexisting abdominal aortic
      aneurysm and bladder carcinoma. METHODS: A prospective study was carried out to
      compare patients undergoing simultaneous surgical treatment of abdominal aneurysm
      and bladder carcinoma with control patients undergoing surgery for either one of
      the two diseases alone. From January 1995 to December 2000, 16 consecutive
      patients were seen with concomitant abdominal aortic aneurysm and bladder
      carcinoma at our institutional referral center. All patients underwent a standard
      operative protocol that included aneurysm graft replacement, radical
      cystoprostatectomy, and urinary reconstruction. Endovascular treatment of the
      aneurysm was considered in the last 2 years of the study. After each simultaneous
      treatment case, two control patients were selected according to the same type of
      vascular or urinary procedure, respectively, and pathologic staging. The analyzed
      endpoint was mortality, and confounder variables included common and disease
      specific risk factors. Frequencies of vascular, urologic, and systemic
      complications were carefully considered with special attention to graft infection
      and tumor recurrence. RESULTS: Endovascular treatment was not performed for
      morphologic reasons. No perioperative mortality was observed. A trend toward
      inferior survival rates in simultaneously treated patients was observed in the
      early follow-up period, but survival analysis with log-rank test showed no
      statistical difference among the groups (P =.19). Cox proportional hazard model
      results proved no influence of the different group treatments on survival (P
      =.49) and no influence of age and risk factors, except for preoperative renal
      status (P =.015). The increased mortality rate of the simultaneous treatment
      group could be ascribed to the presence of preoperative moderate renal
      insufficiency in two study group patients. Long-term survival of treated patients
      is mainly dependent on cancer progression. Graft infection and other vascular
      complications were not observed. Systemic and urologic complications were similar
      in study and control groups. CONCLUSION: This study shows that the simultaneous
      surgical approach to coexisting abdominal aortic aneurysm and transitional cell
      carcinoma of the bladder represents a suitable choice of treatment in highly
      specialized centers, but patients with preoperative renal insufficiency should be
      carefully evaluated. Endovascular treatment represents an appealing alternative
      whenever indicated.

PMID- 12618701
TI  - Intravascular ultrasound aids in the performance of endovascular repair of
      abdominal aortic aneurysm.
AB  - PURPOSE: The purpose of this retrospective review was to assess the accuracy of
      aortic measurements with intravascular ultrasound scan (IVUS) compared with
      computed tomographic (CT) scan and to assess the role of IVUS in the performance
      of endovascular repair of abdominal aortic aneurysms (AAAs). METHODS: Seventy
      eight patients undergoing repair of AAA with the AneuRx stent graft (Medtronic
      AVE, Inc, Santa Rosa, Calif) underwent measurement with CT scan and IVUS. The
      initial selection of stent graft size was made on the basis of the CT scan
      measurements, but the final decision for size was made on the basis of the IVUS
      measurements. Standard measurements of a phantom tube obtained with IVUS, CT
      scan, and digital caliper were also compared. RESULTS: IVUS measurements of the
      phantom standard agreed closely with CT scan measurements. However, stent graft
      size initially selected with CT measurement was altered in 28% of cases on the
      basis of intraoperative IVUS measurements. No type I endoleaks were encountered
      in our series, and no aortic cuffs were necessary for endoleak repair.
      CONCLUSION: IVUS accurately measures the aorta for selection of stent grafts for
      endovascular repair of AAA and may prevent type I endoleaks and remedial
      procedures for their repair.

PMID- 12618702
TI  - Evaluation of aortoiliac aneurysm before endovascular repair: comparison of
      contrast-enhanced magnetic resonance angiography with multidetector row computed
      tomographic angiography with an automated analysis software tool.
AB  - PURPOSE: The purpose of this study was to assess accuracy and reliability of a
      volumetric analysis of abdominal aneurysms on the basis of multidetector row
      computed tomographic angiography (CTA) and magnetic resonance angiography (MRA)
      with a commercially available automated vessel analysis software program.
      MATERIALS AND METHODS: Twenty patients with abdominal aortic aneurysms underwent
      preoperative CTA and MRA before endovascular repair. Postdeployment CTA was
      performed in 15 of these 20 patients (75%). All preoperative CTA and MRA and
      postdeployment CTA data sets were analyzed with an automated software tool. The
      length of the stent grafts on postdeployment CTA was measured and compared with
      the true length of the primary component. Two readers independently evaluated 13
      vessel parameters on preoperative CTA and MRA, which are considered to be
      important in planning stent graft deployment. RESULTS: With the automated
      analysis software tool, all measurements could be performed on either CTA or MRA
      data sets. There was no statistically significant difference between
      postdeployment measurements of stent graft length on CTA and the true dimensions
      of the implanted stent grafts. Interobserver agreement for all of the
      measurements with either CTA or MRA was good to excellent (interclass
      coefficient, 0.71 to 0.99) with only minimal mean differences of measured
      dimensions between both readers (range, -2.0 to +2.3 mm, Bland-Altman).
      Intermodality agreement between CTA and MRA was good to excellent (interclass
      coefficient, 0.62 to 0.98) with small mean differences of measured dimensions
      between both methods (range, -4.1 to +2.1 mm, Bland-Altman). CONCLUSION:
      Volumetric measurement with an automated analysis software tool allows a fast,
      precise, and reliable noninvasive preoperative determination of all aortic
      dimensions on the basis of either CTA or MRA data sets.

PMID- 12618703
TI  - Macrophage migration inhibitory factor is associated with aneurysmal expansion.
AB  - BACKGROUND: Macrophage migration inhibitory factor (MIF) is an inflammatory
      cytokine released mainly from macrophages and activated lymphocytes. Both
      atherosclerosis and abdominal aortic aneurysm (AAA) are inflammatory diseases
      tightly linked to the function of these cells. The correlation and contribution
      of MIF to these human diseases remain unknown, although a recent rabbit study
      showed expression of this cytokine in atherosclerotic lesions. MATERIAL AND
      METHODS: MIF immunohistochemistry was performed on tissue sections from five
      normal aortas, seven atherosclerotic carotids, and six AAAs. A group of 112 men
      with small AAAs (defined as 3 to 5 cm) was recruited at the time of diagnosis,
      had serum samples taken, and was followed annually for 1 to 5 years (mean, 2.9
      years) and referred for surgery if the AAA exceeded 5 cm in diameter. Of this
      study group, 98 had serum MIF measured with an enzyme-linked immunosorbent assay
      and 61 had detectable levels. RESULTS: In human atherosclerotic and aneurysmal
      lesions, MIF protein colocalized in macrophages, endothelial cells, and smooth
      muscle cells, but normal arteries had negligible MIF expression. Furthermore,
      serum-MIF levels correlated significantly with annual expansion rate (r = 0.28; P
      =.005), persisting after adjustment for initial AAA size, smoking habits,
      diastolic blood pressure, ankle blood pressure index, and age. After exclusion of
      38 cases with MIF levels below the detection limit, initial AAA size was also
      significantly correlated with the MIF levels (r = 0.42; P =.001), persisting
      after adjustment for similar confounders, and the correlation coefficient with
      expansion rate increased to 0.42 (P =.001). CONCLUSION: Highly expressed MIF in
      macrophages, endothelial cells, and smooth muscle cells in lesions from
      atherosclerosis and AAA and significant association between serum MIF level and
      AAA initial size and AAA expansion rate in a group of patients with AAA suggest a
      potential involvement of this proinflammatory cytokine in the pathogenesis of
      these cardiovascular diseases.

PMID- 12618704
TI  - Opioid growth factor inhibits intimal hyperplasia in balloon-injured rat carotid
      artery.
AB  - OBJECTIVE: The endogenous opioid [Met(5)]-enkephalin (opioid growth factor [OGF])
      is a tonically active, receptor-mediated inhibitory growth peptide in developing
      and adult vasculature. This study was designed to determine the role of OGF in
      neointimal hyperplasia. METHODS: The carotid artery in adult male Sprague-Dawley
      rats was denuded with balloon catheterization. OGF (10 mg/kg), the opioid
      antagonist naltrexone (NTX; 30 mg/kg), or saline solution (0.2 mL) was injected
      intraperitoneally daily for 28 days into the rats, and restenosis of the carotid
      artery was examined with morphometric analysis using Optimas software.
      Proliferation of the neointima and media was measured by radioactive thymidine
      incorporation over 3 hours. The presence of OGF and its receptor, OGFr, were
      examined with immunofluorescence microscopy. RESULTS: OGF depressed DNA synthesis
      in the intima and media from 16% to 78% of control levels in the first 2 weeks
      after deendothelialization, whereas NTX exposure elevated DNA synthesis by 21% to
      89%. OGF action was receptor-mediated. In the month after injury the thickness of
      the intima in OGF-treated rats was decreased by 18% to 31% from control values,
      whereas intimal thickness was increased in the NTX group by 10% to 31%. Luminal
      area was almost 25% greater than control values in the OGF group, but was reduced
      17% by NTX. OGF and the OGF receptor were detected in the carotid artery with
      immunohistochemistry. CONCLUSIONS: These results demonstrate for the first time
      that a native opioid system modulates repair of vascular injury. OGF is a
      constitutively active peptide that has a receptor-mediated action in the negative
      regulation of neointimal growth, a major cause of restenosis.

PMID- 12618705
TI  - Blockade of the epidermal growth factor receptor decreases intimal hyperplasia in
      balloon-injured rat carotid artery.
AB  - HYPOTHESIS: Arterial intimal hyperplasia is induced by injury and is frequently
      the cause of luminal narrowing after vascular reconstruction. Smooth muscle cells
      (SMC) respond to injury by proliferating and migrating into the intima. This
      process is regulated by thrombin, endothelin, and angiotensin II, all ligands of
      G protein-coupled receptors. Signal transduction from these receptors in cultured
      cells depends in part on transactivation of epidermal growth factor receptor
      (EGFR). We hypothesize that EGFR has a substantial role in activation of SMC in
      vivo and development of intimal hyperplasia. METHODS: Intimal hyperplasia was
      induced in rat carotid arteries by passage of a balloon catheter. Animals were
      given a monoclonal blocking antibody to rat EGFR, matched mouse immunoglobulin G
      (IgG) control antibody, or saline solution. RESULTS: Blocking EGFR antibody
      inhibited medial SMC proliferation, as determined by 5-bromo-2'-deoxyuridine
      labeling at 2 days (IgG control, 8.0% +/- 2.0%; anti-EGFR, 3.2% +/- 0.8%) and
      intimal hyperplasia at 14 days (intimal area: IgG control, 0.07 +/- 0.01 mm(2);
      anti-EGFR, 0.04 +/- 0.01 mm(2)). CONCLUSION: Activation of EGFR is important for
      early induction of SMC proliferation and subsequent intimal thickening.

PMID- 12618706
TI  - Regulation of tissue factor expression in smooth muscle cells with nitric oxide.
AB  - OBJECTIVE: This study was undertaken to determine the effect of nitric oxide (NO)
      on tissue factor (TF) expression in vascular smooth muscle cells. STUDY DESIGN:
      Rat aortic smooth muscle cells (RASMCs) were exposed to NO delivered exogenously
      with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) or produced endogenously
      after infection with an adenoviral vector carrying human inducible NO synthase
      (AdiNOS). Functional TF activity was assessed with chromogenic TF assay. TF
      antigen was determined with immunohistochemistry. Northern blot analysis was used
      to determine steady- state TF messenger RNA (mRNA). Electrophoretic mobility gel
      shift assay was performed to determine the nuclear binding activity of nuclear
      factor kappa-B (NFkappaB). NFkappaB activity was inhibited by either prior
      transduction of RASMCs with mutant IkappaB or treatment with pyrrolidine
      dithiocarbamate. RESULTS: RASMCs exposed to SNAP or infected with AdiNOS
      exhibited increased functional TF activity and antigen. Regardless of the source
      of NO, a time-dependent and concentration-dependent increase in TF activity was
      observed. Steady-state TF mRNA levels were also increased by NO delivered via
      either method. NFkappaB nuclear binding activity was also increased by NO.
      Inhibition of NFkappaB activity by either pyrrolidine dithiocarbamate treatment
      or mutant IkappaB transduction abrogated NO-induced enhancement of TF mRNA and
      functional activity. CONCLUSION: In RASMC, NO exposure results in upregulation of
      TF functional activity, antigen, and mRNA. This effect appears to be mediated by
      an NFkappaB-dependent pathway.

PMID- 12618707
TI  - Modulation of vascular smooth muscle cell alignment by cyclic strain is dependent
      on reactive oxygen species and P38 mitogen-activated protein kinase.
AB  - PURPOSE: The aim of this study was to investigate the molecular targets of
      reactive oxygen species (ROS) and to determine whether cyclic strain induces
      smooth muscle cell (SMC) alignment via the ROS system. We assessed stretch
      induced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activation
      and the redox sensitivity of cyclic strain-stimulated activation of the mitogen
      activated protein kinase (MAPK) family. METHODS: SMCs were seeded on flexible
      collagen I-coated plates and exposed to cyclic strain. NAD(P)H oxidase activation
      was measured with lucigenin-enhanced chemiluminescent detection of superoxide.
      Activation of MAPK was detected by determining phosphorylation of extracellular
      signal-regulated protein kinase (ERK1/2), c-jun N-terminal kinase (JNK1/2), and
      p38 MAPK with immunoblotting. In other experiments, SMCs were exposed to
      diphenylene iodonium (DPI), an NAD(P)H inhibitor, 30 minutes before stretch. MAPK
      activation and cell orientation were then assessed. RESULTS: Cyclic strain
      elicits a rapid increase in intracellular NADH/NADPH oxidase in SMCs. There was
      also a rapid and robust phosphorylation of ERK1/2, JNK1/2, and p38 MAPK. Cyclic
      strain-induced intracellular NAD(P)H generation was almost completely blocked
      with DPI. DPI also inhibited the strain-induced phosphorylation of ERK1/2,
      JNK1/2, and p38 MAPK. Both the p38 MAPK specific inhibitor, SB 202190, and DPI
      blocked cyclic strain-induced cell alignment, but PD98059, an ERK1/2-specific
      inhibitor, and SP600125, an anthrazolone inhibitor of JNK, did not. CONCLUSION:
      Our results provide evidence that p38 MAPK is a critical component of the oxidant
      stress ROS-sensitive signaling pathway and plays a crucial role in vascular
      alignment induced by cyclic stain.

PMID- 12618708
TI  - Postraumatic popliteal pseudoaneurysm from femoral osteochondroma: case report
      and review of the literature.
AB  - Osteochondroma is the most frequent bone tumor and can be responsible for
      vascular complications. The case of an 14-year-old boy with a popliteal
      pseudoaneurysm after a blunt trauma is presented. The diagnosis and treatment of
      this condition is discussed, and the English-language literature is reviewed.

PMID- 12618709
TI  - Pseudoaneurysm of the lateral plantar artery after foot laceration.
AB  - Two children with lateral plantar artery pseudoaneurysms are presented. Both
      cases were associated with a plantar laceration and were successfully treated
      with ligation. Only one other report of a lateral plantar artery pseudoaneurysm
      was found in the literature; no reports involving the medial plantar artery have
      been reported. A cadaver dissection supports the hypothesis that the lateral
      plantar artery is more superficially located and therefore more vulnerable to
      injury compared with the medial plantar artery. Clinicians treating patients with
      lacerations of the foot should be aware that an arterial injury may be present,
      even in the absence of active bleeding.

PMID- 12618710
TI  - Ergotism associated with HIV antiviral protease inhibitor therapy.
AB  - Ergotism is a rare condition of acute vasospasm found classically in young and
      middle-aged women taking ergot alkaloid agents to treat migraine headache. We
      report the case of a young man with human immunodeficiency virus (HIV) positivity
      and describe the drug interaction between protease inhibitors and ergot alkaloid
      agents, which most likely predisposed to development of ergot toxicity. The HIV
      positive population receiving antiviral therapy may be an under-recognized group
      at risk for ergotism through decreased hepatic metabolism of ergot preparations.

PMID- 12618711
TI  - Aneurysm and stenosis of the celiomesenteric trunk: a rare anomaly.
AB  - A celiomesenteric trunk (CMT) anomaly is extremely rare, occurring in less than
      0.5% of people. We describe two cases of CMT anomaly treated surgically for
      median arcuate ligament compression with stenosis causing intestinal angina and
      an asymptomatic aneurysm. Disease involving a CMT is extremely uncommon. This
      comprises the first report of symptomatic median arcuate ligament compression of
      a CMT. Only four cases of aneurysmal disease are reported so far. Indications and
      technique of surgical repair of CMT aneurysms are similar to those used for
      splanchnic artery aneurysms.

PMID- 12618712
TI  - Congenital anomaly of the external iliac artery: a case report.
AB  - A 51-year-old man was admitted with acute ischemic pain in the left leg. An
      angiogram demonstrated a well-developed left internal iliac artery that appeared
      to be continuous with the left common femoral artery, but no left external iliac
      artery. The left superficial and proximal deep femoral arteries were obstructed
      with thrombi. At surgery it was revealed that the distal end of the left common
      iliac artery was continuous with the dilated left internal iliac artery, forming
      the continuation with the left common femoral artery in the pelvic cavity. The
      left external iliac artery was absent between the common iliac and femoral
      arteries.

PMID- 12618713
TI  - Primary aortoduodenal fistula: a case report and review of the literature.
AB  - Abdominal aortic aneurysms (AAAs) can cause aortoenteric fistulae (AEF). AEF can
      either be primary, arising from the aneurysm or other diseases, causing the aorta
      to erode into the bowel, or secondary, from previous aortic grafting. Primary
      aortoduodenal fistula (ADF) is a rare clinical entity that usually presents with
      gastrointestinal bleeding that can be occult, intermittent, or massive. We report
      a 71-year-old woman with acute onset of abdominal pain and massive hematemesis.
      Esophagogastroduodenal endoscopy (EGD) and arteriography were nondiagnostic. The
      patient's condition became unstable, and she was brought emergently to the
      operating room where the diagnosis of an ADF was made. The ADF and AAA were
      surgically repaired, and the patient recovered without complications. This case
      represents an example of a rare complication of AAA with the unusual presentation
      of multiple aortic aneurysms. We will address the pathophysiology, diagnostic
      evaluation, and management of AEF.

PMID- 12618714
TI  - Delayed neurologic deficit after endovascular abdominal aortic aneurysm repair.
AB  - Paraplegia or paraparesis secondary to spinal cord ischemia is an extremely rare
      complication after elective repair of abdominal aortic aneurysm. We report
      delayed paraparesis after endovascular abdominal aortic aneurysm repair in which
      one hypogastric artery was unintentionally occluded due to atheroembolism. A
      spinal catheter was immediately inserted after onset of paraplegia to promote
      cerebrospinal fluid drainage, which partially reversed the neurologic deficit.
      Our case underscores both the importance of the critical spinal collateral supply
      from the hypogastric artery and the role of spinal fluid drainage to maximize
      spinal cord perfusion in the setting of spinal cord ischemia.

PMID- 12618715
TI  - Endovascular treatment of aortic aneurysms in patients with renal transplants.
AB  - Endovascular treatment of an abdominal aortic aneurysm was undertaken in two
      orthotopic renal transplant recipients with US Food and Drug Administration
      approved aortic stents without specific measures taken to protect the
      transplanted kidney. Renal function remained unchanged in both patients. Follow
      up imaging studies showed successful aneurysm exclusion. Endovascular abdominal
      aortic aneurysm treatment in renal transplant recipients does not appear to place
      the transplanted kidney at undue ischemic risk and may be the preferred approach
      in select patients.

PMID- 12618716
TI  - Hypothenar hammer syndrome.

PMID- 12618717
TI  - Patient responsibilities, family responsibilities.

PMID- 12618718
TI  - Regarding "Expansion rates and outcomes for the 3.0-cm to 3.9-cm infrarenal
      abdominal aortic aneurysm".

PMID- 12618719
TI  - Regarding "Anticoagulation with enoxaparin versus intravenous unfractionated
      heparin in postoperative vascular surgery patients".

PMID- 12618721
TI  - Regarding "Bovine thrombin injection for the treatment of iatrogenic arterial
      pseudoaneurysms: is it too good to be true?".

PMID- 12618722
TI  - Regarding "Percutaneous coil embolization of postcatheterization arterial femoral
      pseudoaneurysms".

PMID- 12618724
TI  - Is revascularization and limb salvage always the best treatment for critical limb
      ischemia?

PMID- 12618725
TI  - Feasibility of real-time echocardiographic evaluation during patient transport.
AB  - Echocardiography is a key diagnostic tool in evaluating patients with cardiac
      emergencies and chest trauma. The lack of qualified real-time interpretation
      limits its use by emergency first responders. Early diagnosis of cardiac
      emergencies has the potential to facilitate triage and medical intervention to
      improve outcomes. We investigated the feasibility of remote, real-time
      interpretation of echocardiograms during patient transport. Echocardiograms using
      a hand-carried ultrasound device were transmitted from an ambulance in transit to
      a tertiary care facility using a distributed mobile local area network.
      Transmitted studies were reviewed by a cardiologist for ability to interpret
      predefined features. Transmission quality and reliability were assessed.
      Echocardiographic images were successfully transmitted greater than 88% of
      transport time. The evaluation of left-ventricular size and function, and
      presence of pericardial effusion were greater than 90% concordant, but only 66%
      of all echocardiographic features were concordant. Most transmission losses were
      brief (<or=10 seconds) with little impact on interpretability. Wireless
      infrastructures in metropolitan areas provide the ability for real-time
      transmission of echocardiograms during patient transport of adequate quality for
      accurate interpretation.

PMID- 12618726
TI  - Screening fetal echocardiography by telemedicine: efficacy and community
      acceptance.
AB  - OBJECTIVE: Our aim was to assess whether tertiary level screening fetal
      echocardiography can be extended to primary care facilities with telemedicine
      assistance. METHODS: Assessment of image quality and the adequacy of fetal
      echocardiograms recorded after random transmission at 128, 384, or 768 kbits/s
      was performed. Live fetal echocardiograms were transmitted at 384 kbits/s (3
      integrated services digital network lines) from the remote primary care center.
      Patient satisfaction was assessed by surveys obtained after office-based and
      telemedicine consultations. RESULTS: A total of 58 recorded normal studies had
      similar image quality and adequacy on transmission at 384 and 768 kbits/s (P =.08
      and.49, respectively) and were significantly better than 128 kbits/s (P <.01).
      During live screening transmitted at 384 kbits/s from the primary care center, 3
      of 34 fetuses were diagnosed with heart disease. Surveys from patients with
      direct physician contact and by telemedicine showed a high satisfaction with
      telemedicine-assisted screening and counseling. CONCLUSION: Adequate screening
      for fetal heart disease is technically feasible at or above data transmission
      rates of 384 kbits/s. Community acceptance for telemedicine-assisted screening
      and counseling is not adversely affected by a lack of direct personal contact
      with the specialist.

PMID- 12618727
TI  - Echocardiographic characteristics of perimembranous ventricular septal defects
      associated with aortic regurgitation.
AB  - Development of aortic regurgitation (AR) can complicate an isolated
      perimembranous ventricular septal defect (VSD). The objective of this study was
      to identify echocardiographic features of perimembranous VSDs associated with AR.
      Echocardiograms were evaluated for the presence of aortic cusp override, aortic
      cusp movement abnormality, and presence of color flow mapping across the
      ventricular septum in a standard, parasternal long-axis view. Echocardiograms of
      26 patients with isolated VSDs were included in the study, 13 had AR and 13 had
      no evidence of AR. Aortic cusp override in the apical 5-chamber and subcostal
      coronal views were correlated with the presence of AR, with high sensitivity and
      low specificity. Flow across the septum in the parasternal long-axis view was
      associated with AR, with moderate sensitivity and specificity. Aortic cusp
      movement abnormalities had high sensitivity and low specificity. Our data
      indicate that these findings may identify patients with perimembranous VSD
      susceptible to AR.

PMID- 12618728
TI  - Left ventricular remodeling, mechanics, and tissue characterization in congenital
      aortic stenosis.
AB  - BACKGROUND: As the response of the myocardium to pressure overload is age
      dependent, this study was designed to examine left ventricular (LV) remodeling,
      mechanics, and tissue characterization in children with moderate congenital
      aortic stenosis. METHODS: We studied by echocardiography Doppler 22 patients
      (mean age 12.4 +/- 5.6 years) with peak and mean transvalvular gradient of 63 +/-
      6 and 32 +/- 4 mm Hg, respectively. In addition, 30 age- and body surface area
      matched participants with structurally normal hearts were used as a control
      group. Sex- and age-specific cut-off levels for LV mass/height(2.7) and relative
      wall thickness were defined to assess LV geometry. As a load-independent index of
      myocardial contractility, the relation between the rate-corrected velocity of
      circumferential fiber shortening both at endocardium and midwall, and meridional
      end-systolic stress was assessed. In addition, LV diastolic function was also
      evaluated by the mitral flow indexes. Finally, ultrasonic tissue characterization
      of the LV myocardium was performed by calculating the magnitude of cyclic
      variation, which reflects the intramural contractile function, and the averaged
      myocardial intensity of integrated backscatter, which is directly related to the
      myocardium collagen content. RESULTS: The endocardial velocity of circumferential
      fiber shortening endocardium and meridional end-systolic stress relationship was
      within the normal range (mean +/- 2SD) in 18 of 22 patients (81.8%), and midwall
      velocity of circumferential fiber shortening at endocardium and meridional end
      systolic stress was normal in all 22 patients. No mitral flow index of LV
      diastolic function was significantly different between aortic stenosis group and
      normal participants. In our study population, 16 of 22 patients (72.7%) showed
      normal LV geometry, 3 (13.6%) had a pattern of concentric remodeling, and 3
      (13.6%) concentric hypertrophy. LV hypertrophy was not marked (left ventricular
      mass index [LVMI] < 51 g/m(2.7)) in any patient. Finally, compared with control
      participants our study population showed, both at interventricular septum and
      posterior wall, comparable values of cyclic variation integrated backscatter, but
      significantly higher values of averaged myocardial integrated backscatter
      intensity (P <.01). CONCLUSIONS: In children with moderate congenital aortic
      stenosis, the total amount of myocardial collagen was increased despite normal LV
      myocardial contractility and diastolic function. Furthermore, LV remodeling was
      abnormal in only about a quarter of our patients and none had more than mild
      hypertrophy. Although the majority of these patients do not have markers now
      recognized to predict higher risk of cardiovascular events, the long-term
      significance of myocardial fibrosis and its response to treatment remain to be
      investigated.

PMID- 12618729
TI  - Isovolumic relaxation time corrected for heart rate has a constant value from
      infancy to adolescence.

PMID- 12618730
TI  - Doppler tissue imaging: regional myocardial function in hypertrophic
      cardiomyopathy and in athlete's heart.
AB  - BACKGROUND: The distinction between hypertrophic cardiomyopathy (HCM) and the
      athlete's (AT) heart is an important clinical problem, and the analysis of
      regional myocardial function with Doppler tissue imaging may be useful in the
      differential diagnosis. OBJECTIVE: Our aim was to compare regional function
      assessed by Doppler tissue imaging in rowers and in a group of patients with HCM.
      METHODS: In 24 patients with nonobstructive HCM and in 20 competitive rowers with
      similar age, blood pressure, and heart rate, we analyzed with pulsed Doppler
      tissue imaging left ventricular (LV) regional function (velocities, time
      intervals, heterogeneity and asynchrony indices, and meridional gradient) in the
      longitudinal (8 segments, apical views) and in the radial (2 segments, short-axis
      view) axis. RESULTS: Compared with AT, patients with HCM showed: (1). systolic
      function; (a). longitudinal: lower velocities and meridional gradient; longer
      precontraction period (PCP); and higher PCP/LV contraction time; (b). radial:
      lower velocities and gradient; longer PCP; and higher PCP/LV contraction time;
      (2.diastolic function; (a). logitudinal: lower e (early diastolic), a (late
      diastolic), and e/a velocities; and longer prerelaxation time and time to peak e.
      The percentage of segments with e/a < 1 was 25% in the HCM group and 0% in the AT
      heart group; (b). radial: lower e velocity and gradient; lower e/a gradient; and
      longer medial prerelaxation and basal time to peak e. Most of these differences
      also occurred in the nonhypertrophied inferior wall of patients with HCM.
      CONCLUSIONS: There are significant differences between regional LV function of
      competitive rowers and patients with HCM. These differences (1). occur in systole
      and diastole; (2). affect velocities and time intervals; (3). are more striking
      in the long axis, but are also seen in the short axis, and (4). also occur in
      nonhypertrophied segments, suggesting the usefulness of the technique in the
      differential diagnosis between the 2 situations, namely in individuals that fall
      in Maron's "grey zone."

PMID- 12618731
TI  - Use of strain imaging in detecting segmental dysfunction in patients with
      hypertrophic cardiomyopathy.
AB  - BACKGROUND: The distribution and magnitude of left ventricular hypertrophy are
      not uniform in patients with hypertrophic cardiomyopathy (HCM). Previous
      echocardiographic studies have focused on global left ventricular function.
      Recently, myocardial Doppler strain (epsilon) imaging, a newly developed
      technique, has allowed the quantification of regional myocardial motion. The aim
      of this study was to characterize regional left ventricular systolic function by
      myocardial Doppler epsilon imaging in patients with HCM. METHODS: Included in
      this study were 31 patients with asymmetric septal hypertrophy and HCM, and 41
      age-matched healthy patients. Regional longitudinal axial systolic epsilon was
      assessed at the basal, mid, and apical segments of the septal and lateral walls
      and compared between both groups. RESULTS: Patients with HCM had reduced epsilon
      at the ventricular septum (-10.3 +/- 5.7%) compared with control patients (-19.4
      +/- 3.3%, P <.001). In the HCM group, epsilon in the midseptum (-1.3 +/- 8.2%)
      was significantly less than at the basal (-12.2 +/- 8.7%, P <.01) and apical
      septum (-17.3 +/- 10.4%, P <.01), and was also less than at the midlateral wall (
      9.4 +/- 5.3%, P <.05). There was a significant correlation between midseptal
      epsilon and intraventricular septum to posterior wall thickness ratio (r = 0.81,
      P <.001). CONCLUSION: Midseptal longitudinal epsilon was markedly decreased, even
      reversed in patients with HCM (paradoxic longitudinal systolic expansion), which
      was directly related to the degree of septal hypertrophy. Myocardial Doppler
      epsilon imaging could offer a unique approach to quantify regional systolic
      dysfunction in these patients.

PMID- 12618732
TI  - Assessment of left ventricular function using mitral annular velocities in
      patients with congestive heart failure with or without the presence of
      significant mitral regurgitation.
AB  - Myocardial velocities in patients with congestive heart failure (CHF) were
      studied using pulsed wave Doppler tissue imaging. Velocities were recorded at the
      mitral and tricuspid annulus. Four sites at the mitral annuli were selected
      corresponding to the septal, lateral, inferior, and anterior walls of the left
      ventricle from apical 4- and 2-chamber views. A mean value from the above 4 sites
      was selected to describe the mitral annular velocities. Only one site of the
      tricuspid annulus was selected, corresponding to the right ventricular free wall.
      Three different annular velocities were recorded: the peak systolic, and the peak
      early and late diastolic velocities. A total of 96 patients were compared with 12
      age-matched healthy participants. Patients with CHF had significantly decreased
      mitral and tricuspid systolic velocities compared with healthy participants (4.9
      vs 9.3 cm/s, P <.001, for the mitral annulus and 10.4 vs 14.6 cm/s, P <.001, for
      the tricuspid annulus). The early diastolic velocity was also reduced in patients
      compared with healthy participants (5.9 vs 10.9 cm/s, P <.001, for the mitral
      annulus and 8.6 vs 12.9 cm/s, P <.001, for the tricuspid annulus). Patients with
      CHF had a severely depressed left ventricular ejection fraction (EF) (27%). The
      correlation the between systolic mitral annular velocity and EF was relatively
      good (r = 0.59 and P <.001). The patients with CHF were divided into 2 subgroups
      depending on the presence or absence of significant mitral regurgitation. There
      was a correlation between EF and the systolic mitral annular velocity both in
      patients with (r = 0.61, P <.001) and without (r = 0.59, P <.001) significant
      mitral regurgitation. In conclusion, compared with healthy participants, the
      mitral and tricuspid annular velocities are significantly decreased in patients
      with CHF. The correlation between EF and the systolic mitral annular velocity is
      relatively good irrespective of the presence or absence of significant mitral
      regurgitation. Measurements of annular velocities constitute a simple and useful
      method for evaluating patients with CHF.

PMID- 12618733
TI  - Myocardial velocity gradient reflects the severity of myocardial damage
      regardless of the presence or absence of mitral regurgitation.
AB  - Complicating mitral regurgitation (MR) apparently enhances left ventricular
      ejection fraction, thereby leading to the underestimation of myocardial damage by
      routine echocardiography. We sought to assess the significance of myocardial
      velocity gradient (MVG) derived from Doppler tissue imaging as an indicator of
      the severity of myocardial damage in the presence or absence of MR. Peak systolic
      and diastolic MVG was obtained from 39 participants: 12 healthy participants, 10
      patients with dilated cardiomyopathy complicating moderate to severe MR [MR (+)
      group], and 17 patients with dilated cardiomyopathy without significant MR [MR (
      ) group]. MVG was compared with standard echocardiographic and Doppler
      transmitral flow velocity indices. Plasma brain natriuretic peptide levels were
      measured in all patients. Left ventricular dimension and fractional shortening
      was similar between MR (+) and MR (-) groups. Plasma brain natriuretic peptide
      levels were significantly increased in MR (+) group (440 +/- 417 pg/mL) as
      compared with MR (-) group (122 +/- 107 pg/mL, P <.05). Peak systolic MVG was
      significantly attenuated in dilated cardiomyopathy group with or without MR [MR
      (+) group = 1.3 +/- 0.5 seconds(-1), MR (-) group = 2.1 +/- 0.5 seconds(-1),
      where normal = 4.0 +/- 0.9 seconds(-1), P <.01, respectively]. Peak systolic MVG
      was further attenuated in MR (+) group than in MR (-) group (P <.01). Plasma
      brain natriuretic peptide levels were negatively correlated with peak systolic
      MVG (r = -0.66, P <.0005). Peak diastolic MVG was attenuated in MR (+) and also
      in MR (-) groups [MR (+) group = -4.5 +/- 2.0 seconds(-1), MR (-) group = -4.4 +/
      1.1 seconds(-1), where normal = -8.7 +/- 2.4 seconds(-1), P <.01, respectively],
      whereas transmitral flow indices failed to distinguish MR (+) group from normal
      as a result of pseudonormalization. MVG may reflect the severity of myocardial
      damage regardless of the presence or absence of complicating MR.

PMID- 12618734
TI  - Apical tissue tracking echocardiography for characterization of regional left
      ventricular function: comparison with magnetic resonance imaging in patients
      after myocardial infarction.
AB  - OBJECTIVE: The purpose of this study was to characterize the normal pattern of
      apical tracking and to investigate whether tissue tracking imaging is more useful
      for evaluation of regional left-ventricular function than noncontrast harmonic
      echocardiography in patients after myocardial infarction. BACKGROUND: Left
      ventricular longitudinal shortening plays an important role in cardiac
      contraction, and can be evaluated online by a new Doppler tissue imaging method.
      METHODS: We included 40 healthy participants and 40 patients after myocardial
      infarction. They underwent tissue tracking imaging and noncontrast harmonic
      imaging by an experienced and an inexperienced observer. Diagnostic accuracy of
      semiquantitative evaluation of left ventricular function was compared using
      magnetic resonance imaging as reference method. RESULTS: Velocity-time integrals
      decreased from basal to apical segments in healthy participants. Tissue tracking
      imaging has a higher diagnostic sensitivity than noncontrast imaging for the
      diagnosis of regional wall-motion abnormalities (expert, 78% vs 97%, P <.01;
      beginner, 63% vs 91%, P <.001), whereas specificity remained unchanged (expert,
      99% vs 97%, not significant; beginner, 91% vs 92%, not significant). CONCLUSIONS:
      Tissue tracking imaging is feasible and evaluates regional systolic myocardial
      function quantitatively with high diagnostic accuracy compared with magnetic
      resonance imaging in patients after myocardial infarction, and is more accurate
      than noncontrast harmonic echocardiography.

PMID- 12618735
TI  - Quantification of myocardial blood flow and assessment of its transmural
      distribution with real-time power modulation myocardial contrast
      echocardiography.
AB  - BACKGROUND: The purpose of this study was to examine the ability of real-time
      myocardial contrast echocardiography (MCE) with power modulation to quantitate
      myocardial blood flow (MBF) and to assess its transmural distribution in open
      chest dogs undergoing partial or total coronary stenoses. METHODS AND RESULTS:
      MBF was measured in 12 dogs instrumented with a cuff occluder around the left
      anterior descending coronary artery at rest, during partial coronary stenosis
      (during infusion of adenosine), and during coronary occlusion. The MCE-derived
      rate of microbubble velocity, beta, and myocardial blood volume, A, were obtained
      by curve fitting of videointensity versus time plots, after the transient
      destruction of microbubbles by high-energy ultrasound. The data were compared
      with MBF measured with radiolabeled microspheres. Significant correlations were
      found between radiolabeled microsphere-derived MBF and both beta (r = 0.93) and
      the product of A x beta (r = 0.91). MCE beta reserve also correlated well with
      microsphere-derived flow reserve. Comparing endocardial/epicardial MCE ratios and
      microsphere-derived MBF ratios, significant correlation was also found between
      endomicropsheres/epimicrospheres MBF ratio and both endo/epi beta (r = 0.90) and
      endo/epi A x beta (r = 0.88). CONCLUSIONS: Real-time power modulation MCE allows
      for an accurate quantification of MBF and of its transmural distribution in open
      chest dogs undergoing partial or total coronary stenoses.

PMID- 12618736
TI  - Left atrial size after cardioversion for atrial fibrillation: effect of external
      direct current shock.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of external direct
      current (DC) shock on left atrial (LA) dimension and volumes after cardioversion
      for atrial fibrillation, and the relation between LA size and atrial function.
      METHODS: We evaluated 180 patients who were randomly cardioverted with DC shock
      (90 patients) or drugs (90 patients). Echocardiographic evaluations included LA
      size and volumes. LA passive and active emptying volumes were calculated, and LA
      function was measured as atrial ejection force. Changes in LA diameters and
      volumes were correlate with atrial systolic function. RESULTS: The LA was dilated
      in all patients during arrhythmia and decreased after the restoration of sinus
      rhythm. The entity of reduction was different in the 2 groups of patients. LA
      maximal and minimal volumes were increased after DC shock as compared with
      patients treated with drugs (LA maximal volume 34 +/- 4 vs 31 +/- 5; P <.01; LA
      minimal volume 18 +/- 2.6 vs 15 +/- 3.6; P <.01). The atrial function was also
      depressed after DC shock and the delay in the recovery of atrial contractility
      was related to LA dilation. Patients treated with drugs had a higher atrial
      ejection force that was associated with a more marked reduction in LA maximal
      volume after the restoration of in sinus rhythm. A relationship between LA
      volumes and atrial ejection force was observed in the group of patients with
      depressed atrial mechanic function (r = -0.78; P <.001). The active emptying
      fraction was lower, although not significantly, in this group, whereas the
      conduit volume was increased. CONCLUSION: External DC shock induced a depressed
      atrial mechanic function in many patients and this was associated with a
      persistence of LA dilation.

PMID- 12618737
TI  - Variability of area measurements obtained with different intravascular ultrasound
      catheter systems: Impact on clinical trials and a method for accurate
      calibration.
AB  - BACKGROUND: Atherosclerotic plaque burden is the major end point in ongoing
      progression trials. Intravascular ultrasound allows precise measurements of
      coronary artery dimensions. However, the variability of measurements among
      different catheter systems is incompletely characterized. METHODS: Intravascular
      ultrasound imaging was performed in a cylindric phantom with 5 sections of
      different, known, cross-sectional area ranging from 3.24 to 27.99 mm(2). A total
      of 3637 measurements with different catheter systems (Atlantis SR and Ultracross,
      Scimed/Boston Scientific; and Invision and Avanar, Jomed) were performed.
      Measurements were divided into model building and validation datasets. For each
      catheter, calibration models were developed. RESULTS: Overestimation and
      underestimation of the true cross-sectional area of up to 18% was observed with
      different catheter systems. Calibration equations for the different systems could
      be developed that predicted the true diameter and area with high statistical
      precision (adjusted R(2) > 0.99). CONCLUSIONS: Area measurements vary among
      different intravascular ultrasound catheter systems. Calibration equations can
      correct for these differences and allow the comparison of measurements among
      catheters.

PMID- 12618739
TI  - Diagnosis of coronary pseudoaneurysm by Optison.
AB  - Intravenous contrast agents that traverse the pulmonary circulation have been
      used for endocardial border definition, myocardial perfusion, diagnosis of
      intracardiac thrombi, and in cardiovascular emergencies such as myocardial
      rupture. We report a patient who presented with a new inferior myocardial
      infarction and an extracardiac mass compressing the right atrium, in whom
      diagnosis of right coronary pseudoaneurysm was made on the basis of delayed
      appearance of Optison contrast into the pseudoaneurysm and was subsequently
      confirmed by angiography and surgery. Thus, we extend the diagnostic indication
      of myocardial contrast agents to patients with extracardiac masses.

PMID- 12618738
TI  - Acute aortic intimal tear without a mobile flap mimicking an intramural hematoma.
AB  - Several variants of aortic pathology must be considered in the differential
      diagnosis of the patient presenting with an acute aortic syndrome. In addition to
      aortic dissection, such entities include intramural hematoma, penetrating aortic
      ulcer, and localized intimal tear without dissection. These lesions, which lack a
      mobile intimal flap, may be difficult to correctly identify by transesophageal
      echocardiography or other imaging modalities. We present a case of an acute
      aortic syndrome with unusual features on transesophageal echocardiography.

PMID- 12618740
TI  - Abnormal myocardial strain rate in noncompaction of the left ventricle.
AB  - A 28-year-old woman presented in the second trimester of pregnancy with
      palpitations and left heart failure. Transthoracic echocardiography showed
      features consistent with isolated noncompaction of the left ventricle. Doppler
      tissue echocardiography with strain-rate imaging revealed unique appearances of
      paradoxical alternating bands of compression and expansion throughout systole and
      diastole. These features may be pathognomonic for this disease.

PMID- 12618741
TI  - A novel approach to calculation of mean atrial valve gradient by Doppler
      echocardiography.

PMID- 12618743
TI  - Clinical advances in adult asthma.
AB  - From October 2001 through September 2002, reports of clinical research on asthma
      in adults focused on the epidemiology of asthma, the investigation of
      pharmacologic and immunologic therapy in the context of new national guidelines,
      and discussions of medical economics. Epidemiologic findings include the
      observation that overall mortality has declined and hospitalizations have
      remained constant in the United States since 1995, although these rates are at
      least twice as high in Blacks. Socially and economically disadvantaged groups
      receive poorer health care for asthma. Young children who have fewer than 5
      episodes of wheezing in conjunction with respiratory infections generally have a
      good prognosis and do not have compromised lung function as adults. Pharmacologic
      reports and the National Asthma Education and Prevention Program Update recommend
      low- to medium-dose inhaled steroids combined with a long-acting beta-agonist as
      the preferred therapy for moderate persistent asthma. The use of
      chlorofluorocarbon-free medications for asthma is increasing. Medications
      comprise the largest cost category for asthma.

PMID- 12618744
TI  - Advances in childhood asthma: hygiene hypothesis, natural history, and
      management.
AB  - There is significant interest in early identification and intervention in
      childhood asthma. Current asthma guidelines identify inhaled corticosteroids
      (ICS) as the preferred initial long-term control therapy even in young children.
      ICS clearly improve asthma control in children with mild to moderate persistent
      asthma, but it is not clear that they can alter the natu-ral history and
      progression of asthma. New insights regarding the origins of asthma and allergy
      and their natural history will continue to stimulate questions regarding the
      appropriate time for intervention and will stimulate the design of new treatment
      strategies and the discovery of new medications.

PMID- 12618745
TI  - Advances in upper airway diseases and allergen immunotherapy.
AB  - Epidemiologic studies continue to find an increased prevalence of rhinitis,
      asthma, and atopy in more westernized countries. Both allergic and nonallergic
      rhinitis are risk factors for development of asthma, particularly in adulthood.
      In patients who have both asthma and rhinitis, treatment of the latter decreases
      the likelihood of emergency department visits or hospitalization for asthma. The
      protective effect of intranasal cortico-steroids is much greater than that of
      antihistamines. This mirrors the effect on rhinitis symptoms, in which nasal
      corticosteroids are much more effective than antihistamines, leukotriene receptor
      antagonists, or the combination of both. In patients with severe asthma, sinus
      mucosal thickening on computed tomography (CT) correlates with the severity of
      lower airway disease indicated by sputum eosinophilia, exhaled nitrous oxide
      (NO), functional residual capacity, and diffusing capacity. Preseasonal specific
      immunotherapy (SIT) is less effective, but additive to treatment with omalizumab.
      It is also somewhat less effective in reducing nasal symptoms than nasal
      corticosteroids; however, it is superior to them for reducing lower airway
      inflammation. SIT in children with only allergic rhinitis reduces both the
      incidence of asthma and bronchial hyperresponsiveness to methacholine. High-dose
      sublingual immunotherapy appears to be safe and effective, but less effective
      than injection immunotherapy. It is not clear that there are cost savings with
      sublingual immunotherapy, as home administration savings may be offset by the
      much larger amount of allergen extracts required. New approaches to allergen
      immunotherapy, designed to increase efficacy and safety, include conjugation of
      allergens to immunostimulatory sequences and encapsulation in liposomes. Cross
      reactivity between inhalants and foods demonstrated by skin prick tests is more
      predictive of clinically important sensitivity than is that demonstrated by RAST
      testing. The latter, because of cross-reacting profilins, is often clinically
      irrelevant.

PMID- 12618746
TI  - Mechanisms of asthma.
AB  - Airway inflammation is a key factor in the mechanisms of asthma. Articles
      published in the Journal of Allergy and Clinical Immunology this past year have
      highlighted the utility of investigative bronchoscopy with segmental antigen
      challenge and induced sputum analyses to evaluate features of airway inflammation
      in relationship to asthma severity. Peripheral blood cell generation of cytokines
      IFN-gamma (T(H)1) and IL-5 (T(H)2) was used to evaluate the relationship of the
      balance of T(H)1/T(H)2 cytokines to asthma persistence and severity in a 42-year,
      longitudinal study. Chemokines, including thymus and activation-regulated
      chemokine, are important to the regulation of inflammation and IgE synthesis.
      Their potential role in asthma has also been evaluated. Finally, albuterol (R)-
      and (S)-enantiomers may have distinct effects on airway relaxation and regulation
      of inflammation, suggesting the possibility that monoisomeric therapy has
      therapeutic advantages. The potential contribution of genetic factors and
      mechanisms to airway inflammation and remodeling also continues to be an area of
      intense investigation. During the past year a number of articles published in the
      Journal of Allergy and Clinical Immunology have identified and clarified
      potential genetic mechanisms in asthma. The contribution of genetics to asthma
      has been examined in a wide variety of studies, ranging from epidemiologic
      association and twin studies all the way to molecular analysis through microarray
      gene expression experiments.

PMID- 12618747
TI  - Advances in allergic skin diseases.
AB  - During the past year there have been significant advances in our understanding of
      the mechanisms underlying allergic skin diseases. This article reviews some of
      these advances in atopic dermatitis and urticaria. The introduction of a new
      class of topical anti-inflammatory medications, topical calcineurin inhibitors,
      has significantly increased our treatment options and led to a rethinking of
      potential management approaches in atopic dermatitis.

PMID- 12618748
TI  - Basic and clinical immunology.
AB  - Progress in immunology continues to grow exponentially every year. New
      applications of this knowledge are being developed for a broad range of clinical
      conditions. Conversely, the study of primary and secondary immunodeficiencies is
      helping to elucidate the intricate mechanisms of the immune system. We have
      selected a few of the most significant contributions to the fields of basic and
      clinical immunology published between October 2001 and October 2002. Our choice
      of topics in basic immunology included the description of T-bet as a determinant
      factor for T(H)1 differentiation, the role of the activation-induced cytosine
      deaminase gene in B-cell development, the characterization of CD4(+)CD25(+)
      regulatory T cells, and the use of dynamic imaging to study MHC class II
      transport and T-cell and dendritic cell membrane interactions. Articles related
      to clinical immunology that were selected for review include the description of
      immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked
      agammaglobulinemia; the mechanism of action, efficacy, and complications of
      intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in
      HIV pathogenesis and vaccine development. We also reviewed two articles that
      explore the possible alterations of the immune system caused by spaceflights, a
      new field with increasing importance as human space expeditions become a reality
      in the 21st century.

PMID- 12618749
TI  - Advances in mechanisms of allergy.
AB  - This review summarizes selected "mechanisms of allergy" articles appearing
      between 2001 and 2002 in the Journal of Allergy and Clinical Immunology (JACI).
      Papers chosen include those dealing with human eosinophil and basophil biology
      from life to death, as well as studies with animal models of allergic disease,
      including knock-out mice, Brown Norway rats, and ovalbumin (OVA)-sensitized and
      challenged BALB/c mice, that further our understanding of mechanisms of allergic
      diseases. When appropriate, articles from other journals have been included to
      supplement the topics being presented.

PMID- 12618750
TI  - Advances in environmental and occupational disorders.
AB  - The environment plays a crucial role in determining the development and
      expression of allergic disorders. Epidemiologic studies allow us to understand
      risk factors for allergic disease, which may lead to interventional studies to
      provide the evidence base for our clinical advice. Articles published in The
      Journal of Allergy and Clinical Immunology last year highlighted the relevance of
      mold exposure and environmental tobacco smoke as risk factors for the development
      of asthma and the expression of symptoms. The role of fitted carpets as a
      reservoir for house dust allergens was also challenged by data arising from this
      work. Occupational allergy is an important clinical and socioeconomic problem. A
      large body of work on latex allergy has been reported in the past year,
      demonstrating the impact of containment strategies on exposure to latex and the
      incidence of sensitization to latex. Other articles have explored the range of
      latex allergens to which patients are sensitized and the HLA associations of
      latex allergy. Two models of isocyanate sensitization were reported, providing
      some insight into possible mechanisms of isocyanate asthma and some clues for
      understanding nonallergic asthma. Environmental and occupational disorders are
      highly relevant to our readership, and the new Editorial Board hopes to encourage
      submission and publication of relevant articles in this area.

PMID- 12618751
TI  - Advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and
      insect venom.
AB  - This review highlights some of the research advances in anaphylaxis and
      hypersensitivity reactions to foods, drugs, and insect venom that were reported
      primarily in this Journal from 2001 to 2002. Among the topics highlighted:
      Epinephrine injected intramuscularly into the thigh provides the most efficient
      absorption profile for adults and children; determination of serum IgE antibody
      specific food allergen concentrations and atopy patch tests with foods show
      promise for enhanced diagnostic accuracy; numerous food allergens are now
      characterized on the molecular level, allowing for improved diagnostic and
      treatment modalities; the complex immunologic mechanisms underlying drug
      hypersensitivity reactions are being elucidated; venom immunotherapy improves
      quality of life for sufferers, and increased venom immunotherapy doses are useful
      in recalcitrant cases.

PMID- 12618752
TI  - C/EBP family transcription factors are degraded by the proteasome but stabilized
      by forming dimer.
AB  - CCAAT/enhancer-binding protein (C/EBP) family transcription factors are critical
      for transcription of several genes involved in tissue development and cellular
      function, proliferation, and differentiation. Here we show that
      inhibitory/regulatory C/EBP family proteins, Ig/EBP (C/EBPgamma) and CHOP
      (C/EBPzeta), but not positively functioning NF-IL6 (C/EBPbeta), are
      constitutively multiubiquitinated and subsequently degraded by the proteasome. In
      addition, ubiquitination and degradation of these proteins are suppressed by
      forming dimer through their leucine zipper domains. Deletion of leucine zipper
      domain in NF-IL6 caused the loss of its homodimerization activity and the
      degradation of protein by the ubiquitin-proteasome system. In addition, Ig/EBP
      with its leucine zipper domain substituted for that of NF-IL6 formed homodimer
      and was stabilized. These observations suggest that mammalian cells equip a novel
      regulatory system abrogating the excess C/EBP family transcription factors bereft
      of dimerizing partner.

PMID- 12618753
TI  - Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of
      the JNK or PI3K pathways.
AB  - CC139 fibroblasts are one of several model systems in which the Raf --> MEK -->
      ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however,
      the precise mechanism for this protective effect is not known. Serum withdrawal
      from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was
      prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid,
      de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2
      protein family. Bim(EL) expression was an early event, occurring several hours
      prior to caspase activation. In contrast to studies in neurons, activation of the
      JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL)
      expression. Selective inhibition of either the ERK pathway (with U0126) or the
      PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL).
      Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER*
      substantially reduced Bim(EL) expression, abolished conformational changes in Bax
      and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to
      repress Bim(EL) expression required the ERK pathway but was independent of the
      PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of
      Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by
      the ERK pathway independently of the PI3K pathway. This may contribute to Raf-
      and Ras-induced cell survival at low serum concentrations.

PMID- 12618754
TI  - Activation of ErbB3-PI3-kinase pathway is correlated with malignant phenotypes of
      adenocarcinomas.
AB  - Signet-ring cell carcinomas are malignant dedifferentiated carcinomas, which are
      frequently found in the stomach. We previously demonstrated that a 200 kDa
      protein is often constitutively phosphorylated on tyrosine and bound to
      phosphatidylinositol 3-kinase (PI3-kinase) in signet-ring cell carcinoma cells.
      In this study, we purified the 200 kDa protein from an extract of NUGC-4 cells, a
      cell line of signet-ring cell carcinoma, and identified it as ErbB3. ErbB3 was
      found to be phosphorylated selectively in dedifferentiated adenocarcinoma cell
      lines among various gastric cancer cell lines. Expression of a constitutively
      active chimeric receptor consisting of ErbB2 and ErbB3 in HCC2998 cells, a highly
      differentiated adenocarcinoma cell line, revealed that the signaling triggered by
      phosphorylation of ErbB3 was important for dedifferentiated phenotypes such as
      loss of cell-cell interaction and high expression of MUC1/DF3 antigen, a marker
      of the malignant tumors. Taken together, activation of ErbB3 pathway may
      contribute to the development of dedifferentiated carcinomas.

PMID- 12618756
TI  - TGF-beta-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer
      cell lines.
AB  - Smad4 is a tumor suppressor gene that is commonly lost or mutated in colorectal
      and pancreatic cancers. The activated transforming growth factor-beta (TGF-beta)
      receptor phosphorylates Smad2 and Smad3, which then complex with Smad4 and
      translocate to the nucleus. Smad4 mutations when detected as present in some
      human cancers have been considered sufficient to inactivate TGF-beta signaling.
      In this work, we describe a colon cancer cell line, VACO-9M, that is Smad4 null
      when analysed by multiple assays. To study the role of Smad4 in TGF-beta-induced
      translocation of the receptor-activated Smads to the nucleus, we analysed by
      immunofluorescence the cellular localization of endogenous Smad2 and Smad3 after
      TGF-beta treatment of VACO-9M, plus four additional Smad4 null cell lines of
      breast (MDA-MB-468), or pancreatic (BxPC3, Hs766T, CFPAC-1) origin. In each cell
      line, TGF-beta treatment resulted in both Smad2 and Smad3 moving to the nucleus
      in a Smad4-independent fashion. Nuclear translocation of Smad2 and Smad3 was,
      however, not sufficient to activate reporters for TGF-beta-induced
      transcriptional responses, which were however restored by transient transfection
      of wild-type Smad4. We conclude that Smad4 is not required for nuclear
      translocation of Smad2 and Smad3, but is needed for activation of at least
      certain transcriptional responses.

PMID- 12618755
TI  - Grape seed extract inhibits EGF-induced and constitutively active mitogenic
      signaling but activates JNK in human prostate carcinoma DU145 cells: possible
      role in antiproliferation and apoptosis.
AB  - A loss of functional androgen receptor and an enhanced expression of growth
      factor receptors and associated ligands are causal genetic events in prostate
      cancer (PCA) progression. These genetic alterations lead to an epigenetic
      mechanism where a feedback autocrine loop between membrane receptor and ligand
      (e.g. EGFR-TGFalpha) results in a constitutive activation of MAPK-Elk1-AP1
      mediated mitogenic signaling in human PCA at an advanced and androgen-independent
      stage. We rationalized that inhibiting these epigenetic events could be useful in
      controlling advanced PCA growth. Recently, we found that grape seed extract
      (GSE), a dietary supplement rich in flavonoid procyanidins, inhibits advanced and
      androgen-independent human PCA DU145 cell growth in culture and nude mice. Here,
      we performed detailed mechanistic studies to define the effect of GSE on EGFR-Shc
      MAPK-Elk1-AP1-mediated mitogenic signaling in DU145 cells. Pretreatment of serum
      starved cells with GSE resulted in 70% to almost complete inhibition of EGF
      induced EGFR activation and 50% to complete inhibition of Shc activation, which
      corroborated with a comparable decrease in EGF-induced Shc binding to EGFR.
      Conversely, EGF-induced ERK1/2 phosphorylation was inhibited only by lower doses
      of GSE; in fact, higher doses showed an increase. Additional studies showed that
      GSE alone causes a dose- and time-dependent increase in ERK1/2 phosphorylation in
      starved DU145 cells that is inhibited by an MEK1 inhibitor PD98059. Independent
      of this increase in ERK1/2 phosphorylation, GSE showed a strong inhibition of
      ERK1/2 kinase activity to Elk1 in both cellular and cell-free systems. GSE
      treatment of cells also inhibited both EGF-induced and constitutively active Elk1
      phosphorylation and AP1 activation. GSE treatment also showed DNA synthesis
      inhibition in starved and EGF-stimulated cells as well as loss of cell viability
      and apoptotic death that was further increased by adding MEK1 inhibitor. Since
      GSE strongly induced apoptosis independent of its affect on an increase in
      phospho-ERK1/2, we hypothesized that apoptotic effect of GSE could be by other
      mechanism(s) including its effect on stress-associated MAPK, the JNK. Indeed, GSE
      treated cells showed a strong and sustained increase in phospho-JNK1/JNK2 levels,
      JNK activity and phospho-cJun levels. An inhibition of GSE-induced JNK activation
      by a novel JNK inhibitor SP600125 resulted in a significant reversal of GSE
      induced apoptotic death suggesting the involvement of JNK activation by GSE in
      its apoptosis response. Together, these results suggest that anticancer effects
      of GSE in PCA be mediated via impairment of EGFR-ERK1/2-Elk1-AP1-mediated
      mitogenic signaling and activation of JNK causing growth inhibition and
      apoptosis, respectively.

PMID- 12618757
TI  - MUC1 alters beta-catenin-dependent tumor formation and promotes cellular
      invasion.
AB  - MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet
      its function as a tumor antigen is not fully understood. Recently, studies have
      shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and
      protein kinase Cdelta, possibly in a complex that promotes the disassembly of
      adherens junctions and the invasion of cells. Here we show that the deletion of
      Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase
      in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild
      type Muc1 background shows a tumor-specific complex formation between Muc1 and
      beta-catenin that can be observed in both the membrane and the cytoplasm of
      transformed epithelium. Analysis of primary human adenocarcinomas revealed that
      this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors,
      but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic
      domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases
      their invasive capability, and these peptides colocalize with both beta-catenin
      and the focal adhesion protein vinculin, primarily at sites of membrane invasion
      into a collagen matrix. These data indicate a potential mechanism for MUC1
      promotion of invasive tumorigenesis in the breast through the modulation of beta
      catenin localization and subsequent cytoskeletal dynamics.

PMID- 12618758
TI  - An unexpected role for FosB in activation-induced cell death of T cells.
AB  - The CD95 (APO-1/Fas) system plays a major role in induction of apoptosis in
      lymphoid and nonlymphoid tissues. The CD95 (APO-1/Fas) ligand (CD95L) is induced
      in response to a variety of signals including TCR/CD3 stimulation or application
      of chemotherapeutic drugs. Here we report that an AP-1 site located in the 5'
      untranslated region of the CD95L gene is required for TCR/CD3-mediated induction
      of the human CD95L promoter. Electrophoretic mobility shift assays using nuclear
      extracts of Jurkat T cells as well as TCR/CD3-restimulated primary human T cells
      demonstrated specific binding of AP-1, predominantly composed of c-Jun and FosB,
      to this sequence. Ectopic expression of transdominant negative Jun mutants
      strongly reduced CD95L promoter activity and activation-induced cell death
      (AICD), confirming the functional significance of FosB/c-Jun binding. Thus, our
      results demonstrate an important novel function for FosB dimerized with c-Jun in
      TCR/CD3-mediated AICD in human T cells.

PMID- 12618759
TI  - Elimination of the vertebrate Escherichia coli Ras-like protein homologue leads
      to cell cycle arrest at G1 phase and apoptosis.
AB  - Homologues of the Escherichia coli (E. coli) Ras-like protein (ERA), a GTP
      binding protein with RNA binding activity, have recently been found in various
      species, including human, mouse, and Antirrhinum majus. Depletion of prokaryotic
      ERA blocks cell division without affecting chromosome segregation. However, the
      physiological function of eukaryotic ERA is largely unknown. We have performed a
      genetic analysis of chicken ERA (GdERA) in DT40 cells. Depletion of GdERA
      diminished the growth rate of the cells, accompanied by an accumulation of
      apoptotic cells. The analysis of cell cycle indicates that the elimination of
      GdERA caused arrest at G1 phase, but not at M phase, which highlights the
      distinct role of vertebrate ERA in the cell cycle progression compared to
      prokaryotic ERA. Furthermore, human ERA (HsERA) rescued the phenotype of GdERA
      deficient cells, whereas a mutant of HsERA deprived of RNA-binding activity did
      not. These data suggest that vertebrate ERA regulates the G1 phase progression
      via an as yet unknown molecular mechanism, which involves RNA recognition by ERA.

PMID- 12618760
TI  - Glutathione depletion-induced apoptosis of Ha-ras-transformed NIH3T3 cells can be
      prevented by melatonin.
AB  - It is well known that intracellular antioxidant glutathione (GSH) plays major
      roles in the maintenance of redox status and defense of oxidative stress. Ras, a
      small GTP-binding protein, may send growth-stimulating message to the nucleus
      through downstream Rac oncoprotein and superoxide (O(2*-)). These findings led us
      to investigate the effects of GSH and melatonin, a free-radical scavenger, on Ras
      Rac-O(2*-)-related growth signal transduction. Our results demonstrate that
      overexpression of the inducible Ha-ras oncogene by isopropyl-beta-D
      thiogalactoside (IPTG) increases the levels of reactive oxygen species (ROS,
      including O(2*-) and hydrogen peroxide (H(2)O(2))) and GSH in an Ha-ras
      transformed NIH/3T3 fibroblast cell line. On the contrary, melatonin
      significantly suppresses ras-triggered cell growth by inhibiting the increase of
      ROS and GSH. Moreover, severe apoptosis of this transformed cell line occurred
      when the cell redox balance between ROS and GSH was dramatically changed in the
      presence of IPTG and L-buthionine-[S,R]-sulfoximine (BSO, a specific inhibitor of
      GSH synthetase). That BSO-induced cell apoptosis needs Ras to increase the ROS
      level was demonstrated by the free-radical scavenger melatonin. It effectively
      blocked cell apoptosis, but cell growth was also slowed without affecting Ras
      expression. Based on our studies, two approaches can be applied to treating ras
      related cancers. One is utilizing melatonin to suppress cancer cell
      proliferation, and the other is utilizing BSO to induce cancer-cell apoptosis.
      Cotreatment of ras-related cancer cells with melatonin and BSO stops cell growth
      as well as apoptosis. Whether these cancer cells will undergo further regression
      or become recurrent merits investigation.

PMID- 12618761
TI  - Novel succinate dehydrogenase subunit B (SDHB) mutations in familial
      phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations
      in sporadic phaeochromocytomas.
AB  - Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas
      of the head and neck, in particular of the carotid bodies, occur sporadically and
      also in a familial setting. In addition to mutations in RET and VHL in familial
      disease, germline mutations in SDHD and SDHB genes that encode subunits of
      mitochondrial complex II have also been associated with the development of
      familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in
      the development of these tumours we determined the occurrence of germline SDHD
      and SDHB mutations in four patients with a family history of phaeochromocytoma
      with associated head and neck paraganglioma, one patient with a family history of
      phaeochromocytoma only and two patients with apparently sporadic extra-adrenal
      phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated
      whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in
      a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive
      phaeochromocytomas. Novel SDHB mutations were identified in the probands from
      four families and two apparently sporadic cases (six of seven probands studied),
      including two missense mutations, a single nonsense and frameshift mutation, as
      well as two splice site mutations, one of which was shown to have partial
      penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in
      SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB
      mutations were found in the remaining allele of the 11 sporadic adrenal
      phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET
      mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a
      major role in the pathogenesis of familial phaeochromocytomas, but the possible
      role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be
      ascertained.

PMID- 12618762
TI  - Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses
      tumorigenesis.
AB  - We have demonstrated that nuclear factor-kappa B (NF-kappa B) is constitutively
      activated in human pancreatic adenocarcinoma and human pancreatic cancer cell
      lines but not in normal pancreatic tissues or in immortalized, nontumorigenic
      pancreatic epithelial cells, suggesting that NF-kappa B plays a critical role in
      the development of pancreatic adenocarcinoma. To elucidate the role of
      constitutive NF-kappa B activity in human pancreatic cancer cells, we generated
      pancreatic tumor cell lines that express a phosphorylation defective I kappa B
      alpha (S32, 36A) (I kappa B alpha M) that blocks NF-kappa B activity. In this
      study, we showed that inhibiting constitutive NF-kappa B activity by expressing I
      kappa B alpha M suppressed the tumorigenicity of a nonmetastatic human pancreatic
      cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical
      analysis showed that PANC-1-derived tumors expressed vascular endothelial growth
      factor (VEGF) and induced angiogenesis. Inhibiting NF-kappa B signaling by
      expressing I kappa B alpha M significantly reduced expression of Bcl-x(L) and Bcl
      2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is
      also decreased. Taken together, these results suggest that the inhibition of NF
      kappa B signaling can suppress tumorigenesis of pancreatic cancer cells and that
      the NF-kappa B signaling pathway is a potential target for anticancer agents.

PMID- 12618763
TI  - The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15)
      breakpoint associated with Wilms' tumour.
AB  - Wilms' tumour (WT) has a diverse and complex molecular aetiology, with several
      different loci identified by cytogenetic and molecular analyses. One such locus
      is on chromosome 7p, where cytogenetic abnormalities and loss of heterozygosity
      (LOH) indicate the presence of a Wilms' tumour suppressor gene. In order to
      isolate a candidate gene for this locus, we have characterized the breakpoint
      regions at a novel constitutional chromosome translocation (t(1;7)(q42;p15)),
      found in a child with WT and skeletal abnormalities. We identified two genes that
      were interrupted by the translocation: the parathyroid hormone-responsive B1 gene
      (PTH-B1) at 7p and obscurin at 1q. With no evidence for LOH at 1q42, we focused
      on the characterization of PTH-B1. We detected novel alternately spliced isoforms
      of PTH-B1, which were expressed in a wide range of adult and foetal tissues.
      Importantly, expression of two isoforms were disrupted in the WT of the t(1;7)
      patient. We also identified an additional splice isoform expressed only in 7p LOH
      tumours. The disruption of PTH-B1 by the t(1;7), together with aberrant splicing
      in sporadic WTs, suggests that PTH-B1 is a candidate for the 7p Wilms' tumour
      suppressor gene.

PMID- 12618764
TI  - MEK5 overexpression is associated with metastatic prostate cancer, and stimulates
      proliferation, MMP-9 expression and invasion.
AB  - The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular
      signal-regulated kinase-5 (MEK5/ERK5) pathway has been implicated in the
      regulation of cellular proliferation. MEK5 expression has been detected in
      prostate cancer cells, although the significance of the MEK5/ERK5 pathway in
      human prostate cancer has not been tested. We examined MEK5 expression in 127
      cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by
      immunohistochemistry and compared the results to clinical parameters. We
      demonstrated that MEK5 expression is increased in prostate cancer as compared to
      benign prostatic tissue. Strong MEK5 expression correlates with the presence of
      bony metastases and less favourable disease-specific survival. Furthermore, among
      the patients with high Gleason score of 8-10, MEK5 overexpression has an
      additional prognostic value in survival. MEK5 transfection experiments confirm
      its ability to induce proliferation (P < 0.0001), motility (P = 0.0001) and
      invasion in prostate cancer cells (P = 0.0001). MEK5 expression drastically
      increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest
      that the -670/MMP-9 promoter is upregulated by MEK5 and electromobility shift
      assay further suggests the involvement of activator protein-I (AP-1), but not the
      NF-kappa B, binding site in the MMP-9 promoter. Using an AP-1 luciferase
      construct, activation of MEK5 was confirmed to enhance AP-1 activities up to
      twofold. Taken together, our results establish MEK5 as a key signalling molecule
      associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly
      specific, it represents a potential target of therapy.

PMID- 12618765
TI  - Do cancer cells die because of Nogo-B?
AB  - Nogo-A is a potent neurite outgrowth inhibitory protein in vitro and is suggested
      to play a role in the lack of regeneration in the central nervous system of adult
      higher vertebrates. A shorter splice isoform, ASY/Nogo-B, has recently been
      reported to act as a proapoptotic protein, the loss of which would be typical for
      cancer cells. Here, we show that the osteosarcoma cell line SaOS-2 and the cell
      line CHO do express high levels of endogenous Nogo-B and that stable
      transfectants overexpressing high levels of Nogo-B do not differ significantly
      from the respective parental wild-type or control cell lines both in respect to
      cell proliferation and to spontaneous apoptosis or cell death induced by
      staurosporine and tunicamycin. The deletion of the second transmembrane domain of
      Nogo-B, which has been claimed to abolish its proapoptotic activity, leads to a
      shift of the protein from the ER to a cytoplasmic localization, suggesting that
      ER stress of highly overexpressed Nogo-B may lead to aversive cellular reactions
      under particular conditions. Our data do not support a function of Nogo-B as a
      physiological pro-apoptotic protein in certain types of cancer.

PMID- 12618766
TI  - A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on
      chromosome 15.
AB  - The mixed lineage leukemia gene (MLL, also known as HRX, ALL-1 and Htrx) located
      at 11q23 is involved in translocations with over 40 different chromosomal bands
      in a variety of leukemia subtypes. Here we report our analysis of a rare but
      recurring translocation, t(11;15)(q23;q14). This translocation has been described
      in a small subset of cases with both acute myeloblastic leukemia and ALL. Recent
      studies have shown that MLL is fused to AF15q14 in the t(11;15). Here we analyse
      a sample from another patient with this translocation and confirm the presence of
      an MLL-AF15q14 fusion. However, we have also identified and cloned another fusion
      transcript from the same patient sample. In this fusion transcript, MLL is fused
      to a novel gene, MLL partner containing FYVE domain (MPFYVE). Both MLL-AF15q14
      and MLL-MPFYVE are in-frame fusion transcripts with the potential to code for
      novel fusion proteins. MPFYVE is also located on chromosome 15, approximately 170
      kb telomeric to AF15q14. MPFYVE contains a highly conserved motif, the FYVE
      domain which, in other proteins, has been shown to bind to phosphotidyl-inositol
      3 phosphate (PtdIns(3)P). The MLL-MPFYVE fusion may be functionally important in
      the leukemia process in at least some patients containing this translocation.

PMID- 12618767
TI  - Cysteine residues in the C-terminal lobe of Src: their role in the suppression of
      the Src kinase.
AB  - To evaluate the function of cysteine residues of the Src kinase, we constructed a
      series of Src mutants in which some of cysteines were replaced to alanines. With
      these mutants, we studied the effect of SH-alkylating agents, N-[p-(2
      benzimidazolyl)phenyl] maleimide (BIPM) and N-(9-acridinyl) maleimide (NAM), on
      their kinase activity. Of 10 cysteine residues scattered over v-Src, either a
      single mutation at Cys520 or multiple mutations at the four clustered cyteines,
      Cys483, Cys487, Cys496 and Cys498, yielded clear resistance to the treatment with
      10 microM BIPM or 1 microM NAM. In contrast, other cysteines including those in
      the SH2 domain and those in the catalytic cleft of the kinase domain were
      dispensable for the inactivation by BIPM and NAM. Similarly, deletion of SH2 and
      SH3 did not confer the resistance to v-Src, suggesting the inactivation by the SH
      alkylating agents is SH2/SH3-independent. Although Cys520-mutated v-Src was
      resistant to 1 microM NAM, it was inactivated by 5 microM NAM. However, combined
      mutation including all of Cys483, Cys487, Cys496, Cys498 and Cys520 yielded clear
      resistance to 5 microM NAM. Among these mutants, those with double mutations in
      the four clustered cysteines yielded a temperature sensitive phenotype in the
      transfected cells, whereas Cys520 did not, suggesting that Cys520 has, at least
      in part, a discrete function. In contrast to v-Src, c-Src, which lacks cysteine
      at position 520, was resistant to 1 microM NAM but sensitive to 5 microM NAM.
      While replacement of Phe520 of c-Src to cysteine made it sensitive to 1 microM
      NAM, double mutation in clustered cysteines again yielded resistance to 5 microM
      NAM. Taken together, our results strongly suggest that the multiple cysteine
      residues clustered at the end of the C-terminal lobe are critical for the
      inhibition by the SH-alkylating agents and, thereby, have an allosteric repressor
      effect on the catalytic activity of Src in a SH2-phosphoTyr527 independent
      manner.

PMID- 12618769
TI  - Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by
      microarray-based comparative genomic hybridization.
AB  - DNA amplifications are important mechanisms for proto-oncogene activation.
      Comparative genomic hybridization (CGH) to metaphase chromosome preparations has
      revealed amplifications in 10-20% of B-cell lymphomas (B-NHL). We analysed a
      series of 16 aggressive non-Hodgkin lymphomas by the new approach termed Matrix
      CGH (M-CGH) using genomic DNA microarrays as hybridization target. For M-CGH, a
      dedicated B-cell lymphoma chip was constructed containing 496 genomic targets
      covering oncogenes, tumor suppressor genes as well as chromosome regions
      frequently altered in B-NHL. In 10 of 16 samples a total of 15 DNA amplifications
      were identified. The amplicons included BCL2, REL, CCND1, CCND2, JAK2, FGF4 and
      MDM2. Four of the 15 amplifications remained undetected by chromosomal CGH. The
      respective amplicons mapped to bands 2p13, 9p13-p21 and 12q24 and, were confirmed
      by fluorescence in situ hybridization. Furthermore, for four genomically
      amplified genes real-time quantitative reverse transcription polymerase chain
      reaction revealed elevated mRNA expression levels. These data show the superior
      diagnostic sensitivity of the newly developed diagnostic tool. As only a small
      portion of the genome (approximately 1.5%) has been analysed by the present DNA
      array, it is likely that gene amplifications are much more common in aggressive
      lymphomas than previously assumed.

PMID- 12618768
TI  - Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14).
AB  - Translocations interrupting the mixed lineage leukemia gene (MLL) occur in 7-10%
      of acute lymphoblastic leukemia (ALL) and 5-6% of acute myeloid leukemia (AML)
      cases. One of these translocations, t(11;15)(q23;q14), occurs rarely in both ALL
      and AML. The gene on chromosome 15, AF15q14, was cloned recently in a patient
      with AML-M4. We have identified the same gene in a de novo T-ALL patient.
      However, both the MLL and AF15q14 breakpoints in these patients differed: in the
      previously reported AML-M4, both gene breaks were within exons, while in our ALL
      case the MLL break is intronic and the AF15q14 break is exonic. The MLL-AF15q14
      fusion described previously shares no AF15q14 residues in common with the chimera
      reported here. The fusion proteins also differ with respect to MLL--the
      previously described fusion contains 55 extra amino acids as its MLL break is in
      exon 11, while the chimera we report breaks in intron 9. Contrary to the
      originally described normal AF15q14 (5925-bp cDNA encoding a 1833-aa protein), we
      identify a 7542-bp cDNA and a 2342-aa AF15q14 protein. AF15q14 appears identical
      to an mRNA previously found to be expressed in melanoma rendered nontumorigenic
      by microcell-mediated introduction of normal chromosome 6, suggesting the gene
      may function normally to suppress cell growth and/or enhance maturation.

PMID- 12618770
TI  - Patent or perish?

PMID- 12618771
TI  - Read patents, not just papers.

PMID- 12618774
TI  - Surface science: The going rate for catalysts.

PMID- 12618773
TI  - Nanotube electronics: High-performance transistors.

PMID- 12618775
TI  - Biotechnology: Unnatural biopolymers.

PMID- 12618776
TI  - Optical materials: A new twist for nonlinear optics.

PMID- 12618777
TI  - Fuel cell technology: A sweeter fuel.

PMID- 12618778
TI  - Quantum computing: Fine lines from dots.

PMID- 12618779
TI  - Artificial photosynthesis: Light-activated calcium gradients.

PMID- 12618781
TI  - Inducing and probing non-thermal transitions in semiconductors using femtosecond
      laser pulses.
AB  - Soon after it was discovered that intense laser pulses of nanosecond duration
      from a ruby laser could anneal the lattice of silicon, it was established that
      this so-called pulsed laser annealing is a thermal process. Although the
      radiation energy is transferred to the electrons, the electrons transfer their
      energy to the lattice on the timescale of the excitation. The electrons and the
      lattice remain in equilibrium and the laser simply 'heats' the solid to the
      melting temperature within the duration of the laser pulse. For ultrashort laser
      pulses in the femtosecond regime, however, thermal processes (which take several
      picoseconds) and equilibrium thermodynamics cannot account for the experimental
      data. On excitation with femtosecond laser pulses, the electrons and the lattice
      are driven far out of equilibrium and disordering of the lattice can occur
      because the interatomic forces are modified due to the excitation of a large (10%
      or more) fraction of the valence electrons to the conduction band. This review
      focuses on the nature of the non-thermal transitions in semiconductors under
      femtosecond laser excitation.

PMID- 12618782
TI  - Efficient and robust multiphoton data storage in molecular glasses and highly
      crosslinked polymers.
AB  - As electronics become ever faster and more powerful, there is growing interest in
      three-dimensional laser-based optical data storage techniques, which can
      potentially provide efficient storage at densities significantly higher than
      those that are likely to be available from magnetic media. The development of
      inexpensive, efficient and robust media has been a major obstacle in optical data
      storage. However, we have discovered a class of materials that become highly
      fluorescent on multiphoton absorption of pulses of 800-nm light from a
      Ti:sapphire oscillator, making them excellent candidate storage media. The
      materials are inexpensive, of high optical quality, can be processed readily, and
      can take a number of useful forms, including molecular glasses and highly
      crosslinked polymers. Three-dimensional data can be stored at high densities in
      these materials, and are highly robust to readout.

PMID- 12618783
TI  - Long-range structuring of nanoparticles by mimicry of a cholesteric liquid
      crystal.
AB  - Patterning nano-objects is an exciting interdisciplinary research area in current
      materials science, arising from new optical and optoelectronic properties and the
      need to miniaturize electronic components. Many techniques have been developed
      for assembling nanoparticles into two- and three-dimensional arrays. Most studies
      involving liquid crystals as templates have dealt with colloidal particles and
      nematic and smectic phases. Here, we demonstrate the long-range ordering of
      nanoparticle assemblies that adopt the helical configuration of the cholesteric
      liquid crystalline phase. Because we used glass-forming cholesterics, the
      nanostructures could be examined by transmission electron microscopy. The
      platinum nanoparticles form periodic ribbons that mimic the well-known
      'fingerprint' cholesteric texture. Surprisingly, the nanoparticles do not
      decorate the original cholesteric texture but create a novel helical structure
      with a larger helical pitch. By varying the molar fraction of cholesterol
      containing mesogen in the liquid crystal host, we show that the distance between
      the ribbons is directly correlated to the pitch. Therefore this inherent
      lengthscale becomes a simple control parameter to tune the structuring of
      nanoparticles. These results demonstrate how such an assembly process could be
      modulated, providing a versatile route to new materials systems.

PMID- 12618784
TI  - The myosin coiled-coil is a truly elastic protein structure.
AB  - Coiled-coils occur in a variety of proteins involved in mechanical and structural
      tasks in the cell. Their mechanical properties are important in various contexts
      ranging from hair elasticity to synaptic fusion. Beyond their importance in
      biology, coiled-coils have also attracted interest as programmable protein
      sequences for the design of novel hydrogels and materials. We have studied the
      elastic properties of the myosin coiled-coil at the single molecule level. The
      coiled-coil undergoes a massive structural transition at forces between 20 and 25
      pN where the coil extends to about 2.5 times its original length. Unlike all
      other proteins investigated mechanically so far, this transition is reversible on
      a timescale of less than a second, making the coiled-coil a truly elastic
      protein.

PMID- 12618785
TI  - Biosynthesis of novel thermoplastic polythioesters by engineered Escherichia
      coli.
AB  - The development of non-petrochemical sources for the plastics industry continues
      to progress as large multinationals focus on renewable resources to replace
      fossil carbon. Many bacteria are known to accumulate polyoxoesters as water
      insoluble granules in the cytoplasm. The thermoplastic and/or elastomeric
      behaviour of these biodegradable polymers holds promise for the development of
      various technological applications. Here, we report the synthesis and
      characterization of microbial polythioesters (PTEs), a novel class of biopolymers
      of general technological relevance. Biosynthesis of PTE homopolymers was achieved
      using a recombinant strain of Escherichia coli that expressed a non-natural
      pathway consisting of a butyrate kinase, a phosphotransbutyrylase, and a PHA
      synthase. Different homopolymers were produced, consisting of either 3
      mercaptopropionate, 3-mercaptobutyrate, or 3-mercaptovalerate repeating units, if
      the respective mercaptoalkanoic acids were provided as precursor substrates to
      the fermentative process. The PTEs contributed up to 30% (w/w) of the cellular
      dry weight and were identified as hydrophobic inclusions in the cytoplasm. The
      chemical and stereochemical homogeneity of the purified PTEs were identified by
      different methods, and the estimated physical properties were compared to the
      oxypolyester equivalents, revealing low crystalline order and, for the poly(3
      mercaptopropionate) improved thermal stability. The ability to produce PTEs
      through a biosynthetic route opens up new avenues in the field of biomaterials.

PMID- 12618786
TI  - High-kappa dielectrics for advanced carbon-nanotube transistors and logic gates.
AB  - The integration of materials having a high dielectric constant (high-kappa) into
      carbon-nanotube transistors promises to push the performance limit for molecular
      electronics. Here, high-kappa (approximately 25) zirconium oxide thin-films
      (approximately 8 nm) are formed on top of individual single-walled carbon
      nanotubes by atomic-layer deposition and used as gate dielectrics for nanotube
      field-effect transistors. The p-type transistors exhibit subthreshold swings of S
      approximately 70 mV per decade, approaching the room-temperature theoretical
      limit for field-effect transistors. Key transistor performance parameters,
      transconductance and carrier mobility reach 6,000 S x m(-1) (12 microS per tube)
      and 3,000 cm2 x V(-1) x s(-1) respectively. N-type field-effect transistors
      obtained by annealing the devices in hydrogen exhibit S approximately 90 mV per
      decade. High voltage gains of up to 60 are obtained for complementary nanotube
      based inverters. The atomic-layer deposition process affords gate insulators with
      high capacitance while being chemically benign to nanotubes, a key to the
      integration of advanced dielectrics into molecular electronics.

PMID- 12618787
TI  - Ordered nanoparticle arrays formed on engineered chaperonin protein templates.
AB  - Traditional methods for fabricating nanoscale arrays are usually based on
      lithographic techniques. Alternative new approaches rely on the use of nanoscale
      templates made of synthetic or biological materials. Some proteins, for example,
      have been used to form ordered two-dimensional arrays. Here, we fabricated
      nanoscale ordered arrays of metal and semiconductor quantum dots by binding
      preformed nanoparticles onto crystalline protein templates made from genetically
      engineered hollow double-ring structures called chaperonins. Using structural
      information as a guide, a thermostable recombinant chaperonin subunit was
      modified to assemble into chaperonins with either 3 nm or 9 nm apical pores
      surrounded by chemically reactive thiols. These engineered chaperonins were
      crystallized into two-dimensional templates up to 20 microm in diameter. The
      periodic solvent-exposed thiols within these crystalline templates were used to
      size-selectively bind and organize either gold (1.4, 5 or 10nm) or CdSe-ZnS
      semiconductor (4.5 nm) quantum dots into arrays. The order within the arrays was
      defined by the lattice of the underlying protein crystal. By combining the self
      assembling properties of chaperonins with mutations guided by structural
      modelling, we demonstrate that quantum dots can be manipulated using modified
      chaperonins and organized into arrays for use in next-generation electronic and
      photonic devices.

PMID- 12618791
TI  - Facing up to fraud.

PMID- 12618788
TI  - DNA-modified nanocrystalline diamond thin-films as stable, biologically active
      substrates.
AB  - Diamond, because of its electrical and chemical properties, may be a suitable
      material for integrated sensing and signal processing. But methods to control
      chemical or biological modifications on diamond surfaces have not been
      established. Here, we show that nanocrystalline diamond thin-films covalently
      modified with DNA oligonucleotides provide an extremely stable, highly selective
      platform in subsequent surface hybridization processes. We used a photochemical
      modification scheme to chemically modify clean, H-terminated nanocrystalline
      diamond surfaces grown on silicon substrates, producing a homogeneous layer of
      amine groups that serve as sites for DNA attachment. After linking DNA to the
      amine groups, hybridization reactions with fluorescently tagged complementary and
      non-complementary oligonucleotides showed no detectable non-specific adsorption,
      with extremely good selectivity between matched and mismatched sequences.
      Comparison of DNA-modified ultra-nanocrystalline diamond films with other
      commonly used surfaces for biological modification, such as gold, silicon, glass
      and glassy carbon, showed that diamond is unique in its ability to achieve very
      high stability and sensitivity while also being compatible with microelectronics
      processing technologies. These results suggest that diamond thin-films may be a
      nearly ideal substrate for integration of microelectronics with biological
      modification and sensing.

PMID- 12618792
TI  - Scientific credit and credibility.

PMID- 12618794
TI  - Superconductivity: Controlling the motion of quanta.

PMID- 12618795
TI  - Disordered materials: One liquid, two glasses.

PMID- 12618796
TI  - Computational materials science: Think locally, act globally.

PMID- 12618797
TI  - Soft matter dynamics: Searching for equilibrium.

PMID- 12618800
TI  - Carbon nanotubes: Structure and transport in nanotubes.

PMID- 12618798
TI  - Polymer light-emitting devices: Light from insulated organic wires.

PMID- 12618802
TI  - Interface pattern formation in nonlinear dissipative systems.
AB  - The problem of interface pattern selection in nonlinear dissipative systems is
      critical in many fields of science, occurring in physical, chemical and
      biological systems. One of the simplest pattern formations is the Saffman-Taylor
      finger pattern that forms when a viscous fluid is displaced by a less viscous
      fluid. Such finger-shaped patterns have been observed in distinctly different
      fields of science (hydrodynamics, combustion and crystal growth) and this has led
      to a search for a unified concept of pattern formation, as first proposed by the
      classic work of D'arcy Thomson. Two-dimensional finger-shaped patterns, observed
      in flame fronts and the ensembled average shape of the diffusion-limited
      aggregation pattern, have been shown to be similar to Saffman-Taylor finger
      shapes. Here we present experimental studies that establish that the cell shapes
      formed during directional solidification of alloys can be described by the form
      of the Saffman-Taylor finger shape equation when a second phase is present in the
      intercellular region.

PMID- 12618803
TI  - Cyclodextrin-threaded conjugated polyrotaxanes as insulated molecular wires with
      reduced interstrand interactions.
AB  - Control of intermolecular interactions is crucial to the exploitation of
      molecular semiconductors for both organic electronics and the viable manipulation
      and incorporation of single molecules into nano-engineered devices. Here we
      explore the properties of a class of materials that are engineered at a
      supramolecular level by threading a conjugated macromolecule, such as poly(para
      phenylene), poly(4,4'-diphenylene vinylene) or polyfluorene through alpha- or
      beta-cyclodextrin rings, so as to reduce intermolecular interactions and solid
      state packing effects that red-shift and partially quench the luminescence. Our
      approach preserves the fundamental semiconducting properties of the conjugated
      wires, and is effective at both increasing the photoluminescence efficiency and
      blue-shifting the emission of the conjugated cores, in the solid state, while
      still allowing charge-transport. We used the polymers to prepare single-layer
      light-emitting diodes with Ca and Al cathodes, and observed blue and green
      emission. The reduced tendency for polymer chains to aggregate allows solution
      processing of individual polyrotaxane wires onto substrates, as revealed by
      scanning force microscopy.

PMID- 12618804
TI  - Large-area synthesis of carbon nanofibres at room temperature.
AB  - Carbon nanotubes, first identified by Iijima, require for their production a
      source of elemental carbon and a transfer of energy that is specific to the type
      of source and the growth environment. Methods developed so far involve arc
      discharge, and vaporization using laser, pyrolysis and chemical vapour deposition
      of hydrocarbons. Here, we show growth of carbon nanofibres from radio-frequency
      plasma-enhanced chemical vapour deposition at room temperature, which was made
      possible by substituting the thermal energy requirements for the growth with
      plasma decomposition of methane on the Ni catalyst. Electron microscopy analysis
      provides evidence for a 'tip' growth model, with the Ni catalyst particle
      attached to the tip of the nanofibre. Energy-filtered imaging shows the Ni
      catalyst has a surface layer rich in carbon, consistent with the formation of a
      eutectic Ni-C droplet as a nucleation site for the carbon nanofibres, so that the
      carbon diffuses across the surface. The reduced distortion of the catalyst
      particles at low temperatures leads to a more uniform growth of the carbon
      nanofibres over large areas. The lower growth temperature allows for the removal
      of the silicon dioxide barrier layer associated with catalytic growth, and should
      allow in situ growth of nanofibres on relatively large areas of temperature
      sensitive substrates, such as plastics, organics and even paper.

PMID- 12618805
TI  - Biomimetic synthesis and patterning of silver nanoparticles.
AB  - The creation of nanoscale materials for advanced structures has led to a growing
      interest in the area of biomineralization. Numerous microorganisms are capable of
      synthesizing inorganic-based structures. For example, diatoms use amorphous
      silica as a structural material, bacteria synthesize magnetite (Fe3O4) particles
      and form silver nanoparticles, and yeast cells synthesize cadmium sulphide
      nanoparticles. The process of biomineralization and assembly of nanostructured
      inorganic components into hierarchical structures has led to the development of a
      variety of approaches that mimic the recognition and nucleation capabilities
      found in biomolecules for inorganic material synthesis. In this report, we
      describe the in vitro biosynthesis of silver nanoparticles using silver-binding
      peptides identified from a combinatorial phage display peptide library.

PMID- 12618806
TI  - Control of a biomolecular motor-powered nanodevice with an engineered chemical
      switch.
AB  - The biophysical and biochemical properties of motor proteins have been well
      studied, but these motors also show promise as mechanical components in hybrid
      nano-engineered systems. The cytoplasmic F(1) fragment of the adenosine
      triphosphate synthase (F1-ATPase) can function as an ATP-fuelled rotary motor and
      has been integrated into self-assembled nanomechanical systems as a mechanical
      actuator. Here we present the rational design, construction and analysis of a
      mutant F1-ATPase motor containing a metal-binding site that functions as a zinc
      dependent, reversible on/off switch. Repeated cycles of zinc addition and removal
      by chelation result in inhibition and restoration, respectively, of both ATP
      hydrolysis and motor rotation of the mutant, but not of the wild-type F1
      fragment. These results demonstrate the ability to engineer chemical regulation
      into a biomolecular motor and represent a critical step towards controlling
      integrated nanomechanical devices at the single-molecule level.

PMID- 12618807
TI  - Experimentally realizable devices for controlling the motion of magnetic flux
      quanta in anisotropic superconductors.
AB  - A new generation of microscopic ratchet systems is currently being developed for
      controlling the motion of electrons and fluxons, as well as for particle
      separation and electrophoresis. Virtually all of these use static spatially
      asymmetric potential energies to control transport properties. Here we propose
      completely new types of ratchet-like systems that do not require fixed spatially
      asymmetric potentials in the samples. As specific examples of this novel general
      class of ratchets, we propose devices that control the motion of flux quanta in
      superconductors and could address a central problem in many superconducting
      devices; namely, the removal of trapped magnetic flux that produces noise. In
      layered superconductors there are two interpenetrating perpendicular vortex
      lattices consisting of Josephson vortices (JVs) and pancake vortices (PVs). We
      show that, owing to the JV-PV mutual interaction and asymmetric driving, the a.c.
      motion of JVs and/or PVs can provide a net d.c. vortex current. This controllable
      vortex motion can be used for making pumps, diodes and lenses of quantized
      magnetic flux. These proposed devices sculpt the microscopic magnetic flux
      profile by simply modifying the time dependence of the a.c. drive, without the
      need for samples with static pinning--for example, without lithography or
      irradiation.

PMID- 12618808
TI  - Mutual passivation of electrically active and isovalent impurities.
AB  - The alloy GaN(x) As(1-x) (with x typically less than 0.05) is a novel
      semiconductor that has many interesting electronic properties because of the
      nitrogen-induced dramatic modifications of the conduction band structure of the
      host material (GaAs). Here we demonstrate the existence of an entirely new effect
      in the GaN(x) As(1-x) alloy system in which the Si donor in the substitututional
      Ga site (Si(Ga)) and the isovalent atom N in the As sublattice (N(As)) passivate
      each other's electronic activity. This mutual passivation occurs in Si-doped
      GaN(x) As(1-x) through the formation of nearest-neighbour Si(Ga) -N(As) pairs and
      is thermally stable up to 950 degrees C. Consequently, Si doping in GaN(x) As(1
      x) under equilibrium conditions results in a highly resistive GaN(x) As(1-x)
      layer with the fundamental bandgap governed by a net 'active' N, roughly equal to
      the total N content minus the Si concentration. Such mutual passivation is
      expected to be a general phenomenon for electrically active dopants and localized
      state impurities that can form nearest-neighbour pairs.

PMID- 12618811
TI  - The European Materials Research Society looks east.

PMID- 12618809
TI  - Molecular design of strong single-wall carbon nanotube/polyelectrolyte multilayer
      composites.
AB  - The mechanical failure of hybrid materials made from polymers and single-wall
      carbon nanotubes (SWNT) is primarily attributed to poor matrix-SWNT connectivity
      and severe phase segregation. Both problems can be successfully mitigated when
      the SWNT composite is made following the protocol of layer-by-layer assembly.
      This deposition technique prevents phase segregation of the polymer/SWNT binary
      system, and after subsequent crosslinking, the nanometre-scale uniform composite
      with SWNT loading as high as 50 wt% can be obtained. The free-standing
      SWNT/polyelectrolyte membranes delaminated from the substrate were found to be
      exceptionally strong with a tensile strength approaching that of hard ceramics.
      Because of the lightweight nature of SWNT composites, the prepared free-standing
      membranes can serve as components for a variety of long-lifetime devices.

PMID- 12618812
TI  - Cryptic crystallography.

PMID- 12618814
TI  - Lithium-ion batteries: An unexpected conductor.

PMID- 12618815
TI  - Materials characterization: Optics up close and personal.

PMID- 12618816
TI  - Block copolymers: Copolymers close the loop.

PMID- 12618817
TI  - Amorphous materials: Order within disorder.

PMID- 12618819
TI  - Kagome lattice: A molecular toolkit for magnetism.

PMID- 12618818
TI  - Cluster nucleation: Watching nanoclusters nucleate.

PMID- 12618821
TI  - Terahertz polariton propagation in patterned materials.
AB  - Generation and control of pulsed terahertz-frequency radiation have received
      extensive attention, with applications in terahertz spectroscopy, imaging and
      ultrahigh-bandwidth electro-optic signal processing. Terahertz 'polaritonics', in
      which terahertz lattice waves called phonon-polaritons are generated, manipulated
      and visualized with femtosecond optical pulses, offers prospects for an
      integrated solid-state platform for terahertz signal generation and guidance.
      Here, we extend terahertz polaritonics methods to patterned structures. We
      demonstrate femtosecond laser fabrication of polaritonic waveguide structures in
      lithium tantalate and lithium niobate crystals, and illustrate polariton focusing
      into, and propagation within, the fabricated waveguide structures. We also
      demonstrate a 90 degrees turn within a structure consisting of two waveguides and
      a reflecting face, as well as a structure consisting of splitting and recombining
      elements that can be used as a terahertz Mach-Zehnder interferometer. The
      structures permit integrated terahertz signal generation, propagation through
      waveguide-based devices, and readout within a single solid-state platform.

PMID- 12618822
TI  - Direct determination of epitaxial interface structure in Gd2O3 passivation of
      GaAs.
AB  - Obtaining accurate structural information on epitaxial films and interfaces is
      nowhere more critical than in semiconductor passivation layers, where details of
      the atomic structure and bonding determine the nature of the interface electronic
      states. Various non-destructive methods have been used to investigate the
      structure of films and interfaces, but their interpretation is model-dependent,
      leading occasionally to wrong conclusions. We have developed a new X-ray method
      for the direct determination of epitaxial structures, coherent Bragg rod analysis
      (COBRA). The usefulness of our technique is demonstrated by mapping, with atomic
      precision, the structure of the interfacial region of a Gd2O3 film grown
      epitaxially on a (100) GaAs substrate. Our findings reveal interesting behaviour
      not previously suggested by existing structural methods, in particular a lock-in
      of the in-plane Gd atomic positions to those of the Ga/As atoms of the substrate.
      Moreover, we find that the bulk stacking of the Gd2O3 atomic layers is abandoned
      in favour of a new structure that is directly correlated with the stacking
      sequence of the substrate. These results have important implications for Gd2O3 as
      an effective passivation layer for GaAs (ref. 7). Our work shows that the COBRA
      technique, taking advantage of the brilliance of insertion device synchrotron X
      ray sources, is widely applicable to epitaxial films and interfaces.

PMID- 12618823
TI  - Direct observation of defect-mediated cluster nucleation.
AB  - Ion implantation is widely used to introduce electrically or optically active
      dopant atoms into semiconductor devices. At high concentrations, the dopants can
      cluster and ultimately form deactivating precipitates, but deliberate nanocrystal
      formation offers an approach to self-assembled device fabrication. However, there
      is very little understanding of the early stages of how these precipitates
      nucleate and grow, in no small part because it requires imaging an inhomogenous
      distribution of defects and dopant atoms buried inside the host material. Here we
      demonstrate this, and address the long-standing question of whether the cluster
      nucleation is defect-mediated or spontaneous. Atomic-resolution illustrations are
      given for the chemically dissimilar cases of erbium and germanium implanted into
      silicon carbide. Whereas interstitial loops act as nucleation sites in both
      cases, the evolution of nanocrystals is strikingly different: Erbium is found to
      gather in lines, planes and finally three-dimensional precipitates, whereas
      germanium favours compact, three-dimensional structures.

PMID- 12618825
TI  - Lasing in a three-dimensional photonic crystal of the liquid crystal blue phase
      II.
AB  - Photonic-bandgap materials, with periodicity in one, two or three dimensions,
      offer control of spontaneous emission and photon localization. Low-threshold
      lasing has been demonstrated in two-dimensional photonic-bandgap materials, both
      with distributed feedback and defect modes. Liquid crystals with chiral
      constituents exhibit mesophases with modulated ground states. Helical
      cholesterics are one-dimensional, whereas blue phases are three-dimensional self
      assembled photonic-bandgap structures. Although mirrorless lasing was predicted
      and observed in one-dimensional helical cholesteric materials and chiral
      ferroelectric smectic materials, it is of great interest to probe light
      confinement in three dimensions. Here, we report the first observations of lasing
      in three-dimensional photonic crystals, in the cholesteric blue phase II. Our
      results show that distributed feedback is realized in three dimensions, resulting
      in almost diffraction-limited lasing with significantly lower thresholds than in
      one dimension. In addition to mirrorless lasing, these self-assembled soft
      photonic-bandgap materials may also be useful for waveguiding, switching and
      sensing applications.

PMID- 12618824
TI  - Single gallium nitride nanowire lasers.
AB  - There is much current interest in the optical properties of semiconductor
      nanowires, because the cylindrical geometry and strong two-dimensional
      confinement of electrons, holes and photons make them particularly attractive as
      potential building blocks for nanoscale electronics and optoelectronic devices,
      including lasersand nonlinear optical frequency converters. Gallium nitride (GaN)
      is a wide-bandgap semiconductor of much practical interest, because it is widely
      used in electrically pumped ultraviolet-blue light-emitting diodes, lasers and
      photodetectors. Recent progress in microfabrication techniques has allowed
      stimulated emission to be observed from a variety of GaN microstructures and
      films. Here we report the observation of ultraviolet-blue laser action in single
      monocrystalline GaN nanowires, using both near-field and far-field optical
      microscopy to characterize the waveguide mode structure and spectral properties
      of the radiation at room temperature. The optical microscope images reveal
      radiation patterns that correlate with axial Fabry-Perot modes (Q approximately
      10(3)) observed in the laser spectrum, which result from the cylindrical cavity
      geometry of the monocrystalline nanowires. A redshift that is strongly dependent
      on pump power (45 meV microJ x cm(-2)) supports the idea that the electron-hole
      plasma mechanism is primarily responsible for the gain at room temperature. This
      study is a considerable advance towards the realization of electron-injected,
      nanowire-based ultraviolet-blue coherent light sources.

PMID- 12618826
TI  - Closed-loop phase behaviour in block copolymers.
AB  - Closed-loop phase diagrams are known in systems with specific intermolecular
      interactions. In weakly interacting systems, however, such behaviour has never
      been observed. Here, diblock copolymers formed from polystyrene covalently linked
      to poly (n-pentylmethacrylate), P(S-b-nPMA), which have only weak segmental
      interactions, are shown to exhibit a closed-loop phase behaviour over a narrow
      range of molecular weight. The endothermic transitions from the disordered to
      ordered and back to the disordered state, as a function of increasing
      temperature, are dominantly entropic in origin. The morphology and rheological
      properties of P(S-b-nPMA) undergo characteristic changes at the transitions.
      Whereas the disorder-to-order transition temperature increases with decreasing
      molecular weight, the order-to-disorder transition temperature decreases. At a
      limiting molecular weight, the closed-loop vanishes and no ordering occurs. These
      findings provide quantitative insight into an elusive transition in weakly
      interacting multicomponent systems.

PMID- 12618827
TI  - A functional zeolite analogue assembled from metalloporphyrins.
AB  - The assembly of molecular building blocks with metal ions generating microporous
      network solids has been the focus of intense activity. Because of their potential
      applications associated with channels and cavities, such materials have been
      examined for size- and shape-selective catalysis, separations, sensors, molecular
      recognition and nanoscale reactors. Within this context, assemblies of robust and
      chemically versatile porphyrin and metalloporphyrin building blocks remain rare.
      Supramolecular architectures of porphyrin solids based on weak van der Waals
      interactions, hydrogen bonding and metal-ligand coordination networks have been
      reported. Although there are frequent allusions to zeolite-like microporosity
      from crystallography and loss of initial guest solvent molecules, evidence of
      functional microporous behaviour is scarce. We have demonstrated repeatable
      sorption-desorption with high selectivity on the basis of size, shape and
      functional group of the sorbate by a microporous metalloporphyrin solid in
      analogy to zeolites.

PMID- 12618828
TI  - Electronically conductive phospho-olivines as lithium storage electrodes.
AB  - Lithium transition metal phosphates have become of great interest as storage
      cathodes for rechargeable lithium batteries because of their high energy density,
      low raw materials cost, environmental friendliness and safety. Their key
      limitation has been extremely low electronic conductivity, until now believed to
      be intrinsic to this family of compounds. Here we show that controlled cation non
      stoichiometry combined with solid-solution doping by metals supervalent to Li+
      increases the electronic conductivity of LiFePO4 by a factor of approximately
      10(8). The resulting materials show near-theoretical energy density at low
      charge/discharge rates, and retain significant capacity with little polarization
      at rates as high as 6,000 mA x g(-1). In a conventional cell design, they may
      allow development of lithium batteries with the highest power density yet.

PMID- 12618829
TI  - Phospholipid membranes as substrates for polymer adsorption.
AB  - A largely unsolved problem in soft materials is how surface reconstruction
      competes with the rate of adsorption. Here, supported phospholipid bilayers of
      DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) were employed as substrates
      for the adsorption of a weak polyelectrolyte, polymethacrylic acid, whose time
      dependent ratio of charged to uncharged functional groups served to probe the
      local dielectric environment. Chains that encountered sparsely covered surfaces
      spread to maximize the number of segment-surface contacts at rates independent of
      the molar mass (which was varied by a factor of 30), but dependent on the phase
      of the lipid bilayer, gel or liquid crystal. Surface reconstruction rather than
      molar mass of the adsorbing molecules seemed to determine the rate of spreading.
      The significance of these findings is the stark contrast with well-known views of
      polymer adsorption onto surfaces having structures that are 'frozen' and
      unresponsive, and is relevant not just from biological and biophysical
      standpoints, but also in the formulation of many cosmetics and pharmaceutical
      products.

PMID- 12618833
TI  - The science of dirt.

PMID- 12618834
TI  - Magnesium diboride: Superior thin films.

PMID- 12618835
TI  - Electron microscopy: Better vision with electron lenses.

PMID- 12618836
TI  - Polymer science: Designer polymer blends.

PMID- 12618837
TI  - Photonic materials: Teaching silicon new tricks.

PMID- 12618838
TI  - Biosensors: Barcoded molecules.

PMID- 12618839
TI  - Surface chemistry: Fakir droplets.

PMID- 12618841
TI  - Nanomaterials: Top-to-bottom functional design.

PMID- 12618840
TI  - Computational materials science: Nanoscale plasticity.

PMID- 12618843
TI  - New materials from high-pressure experiments.
AB  - High-pressure synthesis on an industrial scale is applied to obtain synthetic
      diamonds and cubic boron nitride (c-BN), which are the superhard abrasives of
      choice for cutting and shaping hard metals and ceramics. Recently, high-pressure
      science has undergone a renaissance, with novel techniques and instrumentation
      permitting entirely new classes of high-pressure experiments. For example,
      superconducting behaviour was previously known for only a few elements and
      compounds. Under high-pressure conditions, the 'superconducting periodic table'
      now extends to all classes of the elements, including condensed rare gases, and
      ionic compounds such as CsI. Another surprising result is the newly discovered
      solid-state chemistry of light-element 'gas' molecules such as CO2, N2 and N2O.
      These react to give polymerized covalently bonded or ionic mineral structures
      under conditions of high pressure and temperature: the new solids are potentially
      recoverable to ambient conditions. Here we examine innovations in high-pressure
      research that might be harnessed to develop new materials for technological
      applications.

PMID- 12618844
TI  - Materials for terahertz science and technology.
AB  - Terahertz spectroscopy systems use far-infrared radiation to extract molecular
      spectral information in an otherwise inaccessible portion of the electromagnetic
      spectrum. Materials research is an essential component of modern terahertz
      systems: novel, higher-power terahertz sources rely heavily on new materials such
      as quantum cascade structures. At the same time, terahertz spectroscopy and
      imaging provide a powerful tool for the characterization of a broad range of
      materials, including semiconductors and biomolecules.

PMID- 12618845
TI  - In situ epitaxial MgB2 thin films for superconducting electronics.
AB  - The newly discovered 39-K superconductor MgB2 holds great promise for
      superconducting electronics. Like the conventional superconductor Nb, MgB2 is a
      phonon-mediated superconductor, with a relatively long coherence length. These
      properties make the prospect of fabricating reproducible uniform Josephson
      junctions, the fundamental element of superconducting circuits, much more
      favourable for MgB2 than for high-temperature superconductors. The higher
      transition temperature and larger energy gap of MgB2 promise higher operating
      temperatures and potentially higher speeds than Nb-based integrated circuits.
      However, success in MgB2 Josephson junctions has been limited because of the lack
      of an adequate thin-film technology. Because a superconducting integrated circuit
      uses a multilayer of superconducting, insulating and resistive films, an in situ
      process in which MgB2 is formed directly on the substrate is desirable. Here we
      show that this can be achieved by hybrid physical-chemical vapour deposition. The
      epitaxially grown MgB2 films show a high transition temperature and low
      resistivity, comparable to the best bulk samples, and their surfaces are smooth.
      This advance removes a major barrier for superconducting electronics using MgB2.

PMID- 12618846
TI  - Biomolecular screening with encoded porous-silicon photonic crystals.
AB  - Strategies to encode or label small particles or beads for use in high-throughput
      screening and bioassay applications focus on either spatially differentiated, on
      chip arrays or random distributions of encoded beads. Attempts to encode large
      numbers of polymeric, metallic or glass beads in random arrays or in fluid
      suspension have used a variety of entities to provide coded elements (bits)-
      fluorescent molecules, molecules with specific vibrational signatures, quantum
      dots, or discrete metallic layers. Here we report a method for optically encoding
      micrometre-sized nanostructured particles of porous silicon. We generate
      multilayered porous films in crystalline silicon using a periodic electrochemical
      etch. This results in photonic crystals with well-resolved and narrow optical
      reflectivity features, whose wavelengths are determined by the etching
      parameters. Millions of possible codes can be prepared this way. Micrometre-sized
      particles are then produced by ultrasonic fracture, mechanical grinding or by
      lithographic means. A simple antibody-based bioassay using fluorescently tagged
      proteins demonstrates the encoding strategy in biologically relevant media.

PMID- 12618847
TI  - Living bacteria in silica gels.
AB  - The encapsulation of enzymes within silica gels has been extensively studied
      during the past decade for the design of biosensors and bioreactors. Yeast spores
      and bacteria have also been recently immobilized within silica gels where they
      retain their enzymatic activity, but the problem of the long-term viability of
      whole cells in an inorganic matrix has never been fully addressed. It is a real
      challenge for the development of sol-gel processes. Generic tests have been
      performed to check the viability of Escherichia coli bacteria in silica gels.
      Surprisingly, more bacteria remain culturable in the gel than in an aqueous
      suspension. The metabolic activity of the bacteria towards glycolysis decreases
      slowly, but half of the bacteria are still viable after one month. When confined
      within a mineral environment, bacteria do not form colonies. The exchange of
      chemical signals between isolated bacteria rather than aggregates can then be
      studied, a point that could be very important for 'quorum sensing'.

PMID- 12618848
TI  - Dislocation processes in the deformation of nanocrystalline aluminium by
      molecular-dynamics simulation.
AB  - The mechanical behaviour of nanocrystalline materials (that is, polycrystals with
      a grain size of less than 100 nm) remains controversial. Although it is commonly
      accepted that the intrinsic deformation behaviour of these materials arises from
      the interplay between dislocation and grain-boundary processes, little is known
      about the specific deformation mechanisms. Here we use large-scale molecular
      dynamics simulations to elucidate this intricate interplay during room
      temperature plastic deformation of model nanocrystalline Al microstructures. We
      demonstrate that, in contrast to coarse-grained Al, mechanical twinning may play
      an important role in the deformation behaviour of nanocrystalline Al. Our results
      illustrate that this type of simulation has now advanced to a level where it
      provides a powerful new tool for elucidating and quantifying--in a degree of
      detail not possible experimentally--the atomic-level mechanisms controlling the
      complex dislocation and grain-boundary processes in heavily deformed materials
      with a submicrometre grain size.

PMID- 12618849
TI  - Highest electron affinity as a predictor of cluster anion structures.
AB  - Small clusters have a range of unique physical and chemical phenomena that are
      strongly size dependent. However, analysis of these phenomena often assumes that
      thermodynamic equilibrium conditions prevail. We compare experimentally measured
      and ab initio computed photoelectron spectra of bare and deuterated silicon
      cluster anions produced in a plasma environment. We find that the isomers
      detected experimentally are usually not the ground-state isomers, but metastable
      ones, which indicates that cluster relaxation is strongly limited kinetically by
      a dwell time that is much shorter than the relaxation time. We show that, under
      these conditions, the highest electron affinity replaces the traditional lowest
      total energy as the appropriate criterion for predicting isomer structures. These
      findings demonstrate that a stringent examination of non-equilibrium effects can
      be crucial for a correct analysis of cluster properties.

PMID- 12618850
TI  - Design and properties of co-continuous nanostructured polymers by reactive
      blending.
AB  - With an annual production of hundreds of millions of tons, the few commodity
      polymers that dominate the plastics market cannot satisfy all the applications
      and expectations. In this context, the fabrication of thermodynamically stable
      polymer blends structured on submicrometre scales raises much hope, but poses
      significant scientific and industrial challenges. Here, we propose and
      demonstrate for an industrially relevant system, polyethylene and polyamide, that
      hitherto inaccessible co-continuous morphologies can be produced over a wide
      range of compositions by reactive blending. Paradoxically, the self-assembled
      structures are thermodynamically stable because of the molecular polydispersity
      inherent in the production method. These nanostructured materials present a
      unique combination of properties impossible to achieve with classical blends.
      This versatile, low-cost and simple strategy should be widely applicable.

PMID- 12618851
TI  - Reversibly erasable nanoporous anti-reflection coatings from polyelectrolyte
      multilayers.
AB  - For nearly two centuries, researchers have sought novel methods to increase light
      transmission in optical systems, as well as to eliminate unwanted reflections and
      glare. Anti-reflection coatings and surfaces have enabled the increasing
      performance demands of optical components fabricated from glass-based optical
      materials. With the current trend of technology moving towards optically
      transparent polymeric media and coatings, the need for anti-reflection technology
      and environmentally benign processing methods for polymeric materials independent
      of shape or size has become quite apparent. We describe an economical, aqueous
      based process controlled at the molecular level that simultaneously coats all
      surfaces of almost any material. Systematically designed nanoporous polymer films
      are used, which are suitable for optical applications operating at both visible
      and near-infrared wavelengths. These high-efficiency anti-reflection coatings are
      created from phase-separated polyelectrolyte multilayer films that undergo a
      reversible pH-induced swelling transition. Furthermore, such films, easily
      patterned by an inkjet printing technique, possess potential for pH-responsive
      biomaterial and membrane applications.

PMID- 12618852
TI  - Polymer-stabilized liquid crystal blue phases.
AB  - Blue phases are types of liquid crystal phases that appear in a temperature range
      between a chiral nematic phase and an isotropic liquid phase. Because blue phases
      have a three-dimensional cubic structure with lattice periods of several hundred
      nanometres, they exhibit selective Bragg reflections in the range of visible
      light corresponding to the cubic lattice. From the viewpoint of applications,
      although blue phases are of interest for fast light modulators or tunable
      photonic crystals, the very narrow temperature range, usually less than a few
      kelvin, within which blue phases exist has always been a problem. Here we show
      the stabilization of blue phases over a temperature range of more than 60 K
      including room temperature (260-326 K). Furthermore, we demonstrate an electro
      optical switching with a response time of the order of 10(-4) s for the
      stabilized blue phases at room temperature.

PMID- 12618853
TI  - Bridge-mediated hopping or superexchange electron-transfer processes in
      bis(triarylamine) systems.
AB  - Hopping and superexchange are generally considered to be alternative electron
      transfer mechanisms in molecular systems. In this work we used mixed-valence
      radical cations as model systems for the investigation of electron-transfer
      pathways. We show that substituents attached to a conjugated bridge connecting
      two triarylamine redox centres have a marked influence on the near-infrared
      absorption spectra of the corresponding cations. Spectral analysis, followed by
      evaluation of the electron-transfer parameters using the Generalized Mulliken
      Hush theory and simulation of the potential energy surfaces, indicate that
      hopping and superexchange are not alternatives, but are both present in the
      radical cation with a dimethoxybenzene bridge. We found that the type of electron
      transfer mechanism depends on the bridge-reorganization energy as well as on the
      bridge-state energy. Because superexchange and hopping follow different distance
      laws, our findings have implications for the design of new molecular and
      polymeric electron-transfer materials.

PMID- 12618855
TI  - Toll-like receptors and their role in experimental models of microbial infection.
AB  - Effective host defense against microbial infection depends upon prompt
      recognition of pathogens, activation of immediate containment measures, and
      ultimately the generation of a specific and definitive adaptive immune response.
      The innate immune system of the host is responsible for providing constant
      surveillance against infection; when confronted by pathogens it deploys a series
      of rapidly acting antimicrobial effectors while simultaneously instructing the
      adaptive immune system as to the nature and context of the infectious threat.
      Pathogen recognition and activation of innate immunity is mediated by members of
      the Toll-like receptor (TLR) family through detection of conserved microbial
      structures that are absent from the host. Experimental models of infection using
      TLR-deficient mice, as well as limited human studies, have clearly demonstrated
      the critical role of TLRs in host defense against most major groups of mammalian
      pathogens.

PMID- 12618856
TI  - Subversion of B lymphocyte signaling by infectious agents.
AB  - Infectious agents and their hosts interact in a complex manner, involving not
      only superficially apparent mechanisms, but also the signaling machinery that
      governs host cells responses. Thus, signaling events, surface molecule
      expression, and transcriptional control may be affected in various cell types,
      with profound consequences for the function of individual cells and organ
      systems. Studies of the biochemistry of cell signaling and cell invasion by
      infectious agents have begun to detail the interplay between elements of
      infectious organisms and the host at the molecular level. Consequently, the
      resulting interferences with lymphocyte signaling may disturb the function of the
      immune system. In B cells, alterations of immune receptor signaling has
      implications for human diseases. By affecting the mechanisms of the host's immune
      defense, this may not only lead to inadequate elimination of an infectious agent,
      but also to autoimmunity or neoplasia.

PMID- 12618858
TI  - Dissecting the associations of endemic pemphigus foliaceus (Fogo Selvagem) with
      HLA-DRB1 alleles and genotypes.
AB  - Endemic pemphigus foliaceus (EPF) is a blistering skin disease characterized by
      autoantibodies against the desmosomal protein desmoglein 1. Genetic and
      environmental factors influence its pathogenesis. A total of 128 patients and 402
      controls from an ethnically admixed Brazilian population were analyzed for
      associations by allele and genotype with HLA-DRB1. The alleles DRB1(*)0101,
      (*)0102, (*)0103, (*)0404, (*)0406, (*)0410, (*)1406 and (*)1601 are
      significantly more frequent among patients, while DRB1(*)0301, (*)0701, (*)0801,
      (*)1101, (*)1104 and (*)1402 are negatively associated to EPF. Results of
      association analysis with protein motifs composed of polymorphic amino-acid
      residues do not add much to comprehension of the molecular basis of the HLA
      DRB1/EPF associations. Interactions between susceptible (SU), protective (PR) and
      neutral (NE) alleles clearly deviate from the codominant model. Protection is
      dominant, since the PR/NE and PR/PR genotypes are both equally (P=0.95) and
      strongly protective (odds ratio OR=0.07 and 0.05, respectively; P<10(-6) for
      both). The SU/SU genotype confers a higher (P=0.012) risk than genotype SU/NE
      (OR=8.7 and 4.0; P<10(-6) for both), an evidence of a semi-dominant effect of SU
      alleles relative to NE alleles. The OR for the SU/PR genotype (statistically
      close to 1) is consistent with semi-dominance between PR and SU alleles.
      Knowledge of these allelic interactions is relevant for understanding the
      mechanisms underlying autoimmune disease pathogenesis.

PMID- 12618857
TI  - Genetic control of visceral leishmaniasis in a Sudanese population: candidate
      gene testing indicates a linkage to the NRAMP1 region.
AB  - There is some evidence showing that genetic factors are involved in human
      susceptibility to parasitic diseases such as schistosomiasis and malaria. Studies
      have shown that the Nramp1 and H-2 genes are implicated in the control of
      Leishmania donovani infection in mice. We sought genetic loci involved in the
      control of susceptibility to visceral disease caused by L. donovani in humans. We
      studied 37 families with at least two affected sibs living in a village in
      eastern Sudan, where an outbreak of visceral leishmaniasis occurred between 1995
      and 2000. The genetic markers located in five chromosomal regions containing
      candidate genes were typed: 2q35 (NRAMP1), 5q31-q33 (Th2 cytokine cluster), 6p21
      (HLA/TNF-alpha), 6q23 (INFGRI) and 12q15 (INF-gamma). Linkage (multipoint lod
      score=1.08; P=0.01) was observed for the 5'(CA) repeat polymorphism in the NRAMP1
      promoter. This suggests that genetic variations of this gene affect
      susceptibility to visceral leishmaniasis in this population.

PMID- 12618859
TI  - Genetic polymorphisms in Spanish rheumatoid arthritis patients: an association
      and linkage study.
AB  - HLA polymorphism accounts only for approximately one-third of the genetic
      predisposition to rheumatoid arthritis (RA). To investigate the role of other
      loci in the susceptibility to RA, we have performed an analysis of several
      polymorphisms in genes of immune-related function: IL-10 -1082, -819, -592
      promoter single nucleotide polymorphisms (SNPs), IL-10G and IL-10R
      microsatellites, IL-6 -622 promoter SNP, FcgammaRIIIA Val/Phe-158 polymorphism,
      IL-1 receptor antagonist VNTR, and the IKBL+738 T/C mutation. The analysis has
      been performed on a case-control study and also on RA trios. IL-10G12 was found
      to be associated with RA in the case-control study (18% in RA patients vs 9% in
      controls: P=0.001; pc<0.05). This allele was also more often transmitted than not
      transmitted (10 vs 5). No other allele in the present study is found to be
      associated to RA. Our data suggest that most of the loci studied play no major
      role in the susceptibility to RA, the IL-10 gene being the sole exception.

PMID- 12618860
TI  - Aberrant HS1 molecule in a patient with systemic lupus erythematosus.
AB  - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the
      activation of autoreactive B lymphocytes, which are supposed to carry aberrant
      signal transduction after the stimulation of B-cell receptor (BCR). To
      investigate abnormalities in BCR-mediated signaling pathway in lupus B
      lymphocytes, we analyzed HS1, a molecule downstream of BCR, in 80 Japanese SLE
      patients. We identified 37 amino acid deletion of HS1 in a 25-year-old female
      patient, and the aberrant HS1 lacked a part of a functional motif. Analysis of
      genomic DNA revealed that the aberrant HS1 was caused by exon skipping. Family
      study showed that the patient as well as her father and sister are heterozygous
      for the abnormality. WEHI-231 cell, a mouse B cell line, transfected with the
      aberrant HS1 displayed a significantly increased cell death upon cross-linking of
      BCR. Additionally, peripheral B lymphocytes from the patient exerted increased
      apoptosis after BCR stimulation compared to those from control SLE patients.
      These data suggest that the aberrant HS1 molecule may transmit an accelerated
      signal after BCR stimulation and may play a role in the activation of
      autoreactive B lymphocytes.

PMID- 12618861
TI  - Association of the CTLA4 promoter region (-1661G allele) with type 1 diabetes in
      the South Moroccan population.
AB  - The contribution of the candidate gene CTLA4 to type 1 diabetes is not well
      established. Although several polymorphisms have been repeatedly associated to
      the disease, several studies have not confirmed the association. The joint
      analysis of three SNPs in the CTLA4 promoter region (-1722, -1661, and -319), one
      SNP in the first exon (+49), and one dinucleotide repeat in the 3' untranslated
      region, in a case-control study in a North African population, shows a strong
      association of the CTLA4 region with the disease. The -1661G allele showed a
      significant association with an odds ratio of 2.13. Moreover, the internal
      structure of the dinucleotide repeat has been deeply analyzed. The present
      results reveal the importance of polymorphisms in the CTLA4 promoter region,
      their probable role in gene expression and, ultimately, their relation to the
      etiology of type 1 diabetes. Previous contradictory association studies might be
      due to the effect of linkage disequilibrium between the polymorphism analyzed and
      the alteration within the CTLA4 region. This alteration may be different
      depending on the genetic background of the population. The present work stresses
      the need to perform exhaustive analysis of the promoter region polymorphisms in
      order to detect association with the disease.

PMID- 12618862
TI  - Linkage disequilibrium between the MBP tetranucleotide repeat and multiple
      sclerosis is restricted to a geographically defined subpopulation in Finland.
AB  - We have previously found evidence for linkage as well as allelic and haplotype
      association between the myelin basic protein (MBP) gene and multiple sclerosis
      (MS). These findings have, however, not been reproduced in other populations.
      Here, we have analyzed association between MBP and MS in a new set of 349 Finnish
      triad families. Families with a parent born in the Southern Ostrobothnian region
      in western Finland (Bothnia families, n=98) were analyzed as a separate group
      since our previous studies included a high proportion of patients and families
      from this high-incidence region. Other families (n=251) were collected at five
      hospitals in southern, eastern, and northern Finland. The MBP short tandem repeat
      was genotyped, and haplotype patterns were verified by sequencing. In the Bothnia
      families, the previously detected associations with the 1.27 kb allele and
      haplotype 1.27-B10 were confirmed (P=0.01 and 0.02, respectively), whereas in the
      other families there was not even a trend toward association. These results
      demonstrate a geographic/genealogical restriction in the association between MS
      and the MBP short tandem repeat, highlight the importance of genealogical
      information in genetic studies of complex traits, and may provide an explanation
      why the association has not been found in many other populations.

PMID- 12618864
TI  - Genomic structure and inducible expression of the IL-22 receptor alpha chain in
      mice.
AB  - IL-22 is a newly identified member of the interferon/IL-10 family. In humans, IL
      22 signals through a heteroduplex receptor consisting of IL-22R and CRF2-4/IL
      10Rbeta. To investigate the physiological function of IL-22 and IL-22R, we
      isolated a cDNA encoding the mouse IL-22R, which has been a missing component of
      the functional receptor complex for mouse IL-22. Subsequently, we identified the
      genomic sequence of the mouse IL-22R gene by a database search. The gene consists
      of about 24 kb and is split into seven exons. Interestingly, intron 2 begins with
      a GC dinucleotide instead of the consensus GT, although otherwise the overall
      structure of the mouse IL-22R gene is strikingly similar to its human
      counterpart. The gene was mapped to mouse chromosome 4 in the region syntenic to
      the human IL-22R gene locus. In normal mice, IL-22R mRNA is detected at very low
      levels in restricted organs such as the kidney, liver, and lung. However, upon
      lipopolysaccharide stimulation, IL-22R mRNA expression is highly upregulated in
      the liver, in contrast to CRF2-4, which is expressed constitutively in a variety
      of tissues. Thus, the expression of the functional IL-22 receptor in the liver is
      regulated at the gene transcription level.

PMID- 12618863
TI  - Pharmacogenomic analysis of interferon receptor polymorphisms in multiple
      sclerosis.
AB  - Multiple sclerosis (MS) is a common inflammatory disease of the central nervous
      system characterized by progressive neurological dysfunction. No curative therapy
      is currently available, and approximately 80-90% of afflicted individuals are
      ultimately disabled. Interferon beta (IFNbeta) has been shown to decrease
      clinical relapses, reduce brain disease activity, and possibly slow progression
      of disability. However, the overall effect of treatment is partial and a
      substantial number of patients are considered poor or nonresponders. For this
      report, we tested the pharmacogenomic effects of eight polymorphisms in the
      interferon receptor genes (IFNAR1 and IFNAR2) in a group of 147 patients
      undergoing open-label IFNbeta therapy. Overall, no significant differences in the
      distribution of responders and nonresponders, classified based on prospectively
      acquired primary and secondary clinical end points, were observed when stratified
      by any of the studied IFNAR gene polymorphisms. A trend detected with a single
      nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1
      gene, suggesting modest association with relapse-free status, will require
      confirmation in an independent data set. In addition, no significant association
      was observed of any of the IFNAR gene polymorphisms with susceptibility to MS, as
      studied by a family-based association analysis.

PMID- 12618865
TI  - Variations of human killer cell lectin-like receptors: common occurrence of NKG2
      C deletion in the general population.
AB  - CD94 and NKG2 are members of the NK cell receptor families, and are encoded in
      the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the
      candidate chromosomal regions for rheumatic diseases. To examine a possible
      association between variations in CD94 and NKG2 genes and genetic susceptibility
      to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), we carried
      out a systematic polymorphism screening of NKG2-A (KLRC1), NKG2-C (KLRC2) and
      CD94 (KLRD1) genes on a population basis. In NKG2-A, previously considered to be
      highly conserved, 10 polymorphisms in the noncoding region and introns, as well
      as one rare variation leading to an amino acid substitution within the
      transmembrane region, c.238T>A (Cys80Ser), were detected. In NKG2-C, in addition
      to the previously described two nonsynonymous substitutions, c.5G>A (Ser2Asn) and
      c.305C>T (Ser102Phe), two polymorphisms were newly detected in the noncoding
      region. In CD94, only one single nucleotide substitution was identified in the 5'
      untranslated region. When the patients and healthy individuals were genotyped for
      these variations, no significant association was observed. However, although
      statistically not significant, NKG2-A c.238T>A (Cys80Ser) was observed in three
      patients with RA, but in none of the healthy individuals and the patients with
      SLE. Unexpectedly, in the process of polymorphism screening, we identified
      homozygous deletion of NKG2-C in approximately 4.3% of healthy donors; under the
      assumption of Hardy-Weinberg equilibrium, the allele frequency of NKG2-C deletion
      was estimated to be 20.7%. These results demonstrated that, although human NKG2
      A, -C and CD94 are generally conserved with respect to amino acid sequences, NKG2
      A is polymorphic in the noncoding region, and that the number of genes encoded in
      the human NKC is variable among individuals, as previously shown for the
      leukocyte receptor complex (LRC), HLA and Fcgamma receptor (FCGR) regions.

PMID- 12618866
TI  - Enhanced frequency of a PTPRC (CD45) exon A mutation (77C-->G) in systemic
      sclerosis.
AB  - A point mutation in exon A (C to G transversion at position 77) of human PTPRC
      (CD45) has recently been associated with the development of multiple sclerosis
      (MS) for at least a subgroup of patients. In the present report, we studied the
      frequency of the 77C-->G transversion in two other autoimmune diseases namely
      systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The mutation was
      found with significantly enhanced frequency in patients suffering from SSc
      suggesting that PTPRC could play a role as susceptibility gene not only in MS but
      also in other autoimmune diseases. Further understanding of the mode of
      interaction of mutant PTPRC with other susceptibility genes may uncover
      mechanisms common in various autoimmune disorders.

PMID- 12618867
TI  - Insertion/deletion coding polymorphisms in hHAVcr-1 are not associated with
      atopic asthma in the Japanese population.
AB  - Hepatitis A virus receptor (HAVcr-1) and T-cell immunoglobulin- and mucin-domain
      containing molecule (TIM)-3 were recently implicated as asthma susceptibility
      genes in the study of congenic mice. In a genome-wide screen, we found strong
      evidence for linkage of atopic asthma with marker D5S820, located approximately
      0.5 Mb from hHAVcr-1 and human TIM3. We screened for mutations in human HAVcr-1
      (hHAVcr-1) and in TIM3 and found seven, including two insertion/deletion
      polymorphisms, in hHAVcr-1 and two in TIM3. We conducted transmission
      disequilibrium tests (TDTs) in families identified through children with atopic
      asthma. None of the hHAVcr-1 allele were transmitted preferentially to asthma
      affected children (P>0.1). In quantitative TDT analysis, no association was
      observed between the log[total IgE] and either allele of the hHAVcr-1
      polymorphism (P>0.1). The two TIM3 mutations were rare in the Japanese
      population, occurring in only one of 48 unrelated asthmatic subjects. Our results
      indicate that hHAVcr-1 polymorphisms are not likely to be associated with the
      development of atopy-related phenotypes in the Japanese population.

PMID- 12618868
TI  - Peptide receptor radiotherapy: a new option for the management of aggressive
      fibromatosis on behalf of the Italian Sarcoma Group.
AB  - The management of aggressive fibromatosis (AF) is problematic, and few options
      are available to patients unsuitable for surgery and resistant to external-beam
      radiation therapy (EBRT). We report on two patients with fast-growing recurrences
      of AF resistant to EBRT who obtained protracted clinical benefits with (90)Y
      DOTATOC. (90)Y-DOTATOC should be further investigated in this setting.

PMID- 12618869
TI  - Carcinosarcoma of the ovary.
AB  - We report our experience in the management of patients with carcinosarcoma of the
      ovary, a rare but aggressive variant of ovarian cancer. Forty patients were
      treated at a single centre, which is the largest reported series. The median age
      at diagnosis was 65 years (range 45-86) and the median Karnofsky performance (KP)
      status was 70. Thirty-two patients (80%) presented with FIGO stage III or IV
      disease. Twenty-four had heterologous and 14 homologous carcinosarcoma on review
      of histopathology, but there was no significant difference in survival between
      these groups (P=0.28). Twenty-seven of the 40 patients had bulk residual disease
      present after surgery and this was associated with a worse prognosis (P=0.045).
      Chemotherapy was given to 32 patients (80%) of whom 26 (81%) received platinum
      based regimens. Of these 32 patients, three (9.4%) achieved a complete response
      (CR), 10 (31%) a partial response (PR), five (16%) had stable disease, 10 (31%)
      had progressive disease and four were not assessable. Of the 19 patients who had
      a CR, PR or stable disease after chemotherapy or were unevaluable (stage Ic), the
      median survival was 29.6 months. Currently, seven patients are still alive
      although one has cancer. The overall censored median survival was 8.7 months
      after a median follow-up of 34 months, and the 1- and 5-year survival were 40 and
      7.5%, respectively.

PMID- 12618870
TI  - Association of perceived physician communication style with patient satisfaction,
      distress, cancer-related self-efficacy, and perceived control over the disease.
AB  - The aim of the study was to investigate the association of physician
      communication behaviours as perceived by the patient with patient reported
      satisfaction, distress, cancer-related self-efficacy, and perceived control over
      the disease in cancer patients. Questionnaires measuring distress, self-efficacy,
      and perceived control were completed prior to and after the consultation by 454
      patients attending an oncology outpatient clinic. After the consultation, the
      patients also rated the physicians' communicative behaviours by completing a
      patient-physician relationship inventory (PPRI), and the physicians were asked to
      estimate patient satisfaction. The overall results showed that higher PPRI scores
      of physician attentiveness and empathy were associated with greater patient
      satisfaction, increased self-efficacy, and reduced emotional distress following
      the consultation. In contrast, lower PPRI scores were associated with reduced
      ability of the physician to estimate patient satisfaction. The results confirm
      and expand previous findings, suggesting that communication is a core clinical
      skill in oncology.

PMID- 12618871
TI  - Lack of communication between healthcare professionals and women with ovarian
      cancer about sexual issues.
AB  - Gynaecological cancer has been shown to affect women's sexual functioning, yet
      evidence suggests that healthcare professionals rarely discuss sexual issues with
      women diagnosed with a gynaecological cancer. Few studies have investigated why
      there is a lack of communication between healthcare professionals and women about
      sexual issues. Our study investigated the attitudes and behaviours of the 27
      doctors and 16 nurses treating women with ovarian cancer in our centre towards
      the discussion of sexual issues, and also investigated women's experiences of
      such communication. Our findings showed that although most healthcare
      professionals thought that the majority of women with ovarian cancer would
      experience a sexual problem, only a quarter of doctors and a fifth of nurses
      actually discussed sexual issues with the women. Reasons for not discussing
      sexual issues included 'it is not my responsibility', 'embarrassment', 'lack of
      knowledge and experience' and 'lack of resources to provide support if needed'.
      While some of these reasons were also viewed as barriers by the women, the
      results demonstrate that there is a need from the women's perspective to improve
      communication about sexual issues, although the most appropriate approach to this
      remains to be investigated.

PMID- 12618872
TI  - Aspirin use and cancers of the upper aerodigestive tract.
AB  - The role of aspirin on the risk of cancers of the upper aerodigestive tract was
      investigated in the combined data of three Italian case-control studies,
      including 965 cases and 1779 hospital controls. The odds ratio was 0.33 for users
      of > or = 5 years, and 0.51 for > or = 5 years since first use.

PMID- 12618873
TI  - Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast
      cancer risk in Korean women.
AB  - A case-control study was performed to assess the potential influence of CYP19
      Arg(264)Cys and CYP1B1 Leu(432)Val polymorphisms on breast cancer risk in a
      series of Korean breast cancer patients and controls. The results suggest that
      the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95%
      CI=1.1-2.2), especially in association with alcohol consumption (P for
      interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no
      role here.

PMID- 12618874
TI  - A population-based cohort study of the risk of colorectal and other cancers among
      users of low-dose aspirin.
AB  - Using data from the population-based Prescription Database of North Jutland
      County and the Danish Cancer Registry, we compared cancer incidence among 29 470
      individuals prescribed low-dose aspirin at maximum doses of 150 mg with expected
      incidence based on county-specific cancer rates, during a 9-year study period. We
      observed 2381 cancer cases compared with 2187 expected, yielding a standardised
      incidence ratio (SIR) of 1.09 (95% confidence interval (CI), 1.05-1.13). No
      apparent risk reductions were found for cancers of the colon (SIR, 0.9; 95% CI,
      0.7-1.1) or rectum (SIR, 1.0; 95% CI, 0.8-1.2), or for other site-specific
      cancers. Increased SIRs were observed for kidney cancer (SIR, 1.4; 95% CI, 1.1
      1.7) and brain cancer (SIR, 1.7; 95% CI, 1.3-2.2), although the excess in the
      latter was confined to the first year of follow-up. Stratification by number of
      prescriptions and duration of follow-up revealed no apparent trends. The SIR for
      colorectal cancer was close to unity (SIR, 0.9; 95% CI, 0.6-1.2) among persons
      with 10 or more prescriptions who were followed for at least 5 years. Our results
      do not support a major protective effect of low-dose aspirin on the development
      of colorectal or other cancers. The observed excesses of kidney and brain cancers
      are not likely to be causally related to the use of low-dose aspirin.

PMID- 12618875
TI  - Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life
      Span Study.
AB  - The association between green-yellow vegetables and fruit consumption and risk of
      cancer death was investigated in a prospective study of 38 540 men and women who
      were atomic-bomb survivors in Hiroshima and Nagasaki, Japan. Study participants
      completed a dietary questionnaire in 1980-1981 and were followed-up for cancer
      deaths until March 1998, during which time 3136 cancer deaths were identified.
      Daily or almost daily fruit consumption was associated with a significant 12%
      reduction in total cancer mortality (RR=0.88; 95% CI, 0.80-0.96 for daily intake
      compared with intake once per week or less). Daily or almost daily green-yellow
      vegetables consumption was associated with a marginally significant 8% reduction
      in total cancer mortality (0.92; 0.94-1.01). Green-yellow vegetables consumption
      was associated with a significant reduction in liver cancer mortality (0.75; 0.60
      0.95). Fruit consumption was associated with a significantly reduced risk of
      stomach cancer and lung cancer mortality (0.80; 0.65-0.98). Green-yellow
      vegetables and fruit consumption was associated with a reduction in oesophageal
      cancer, but these associations were not statistically significant. Neither green
      yellow vegetables nor fruit consumption was associated with colorectal cancer or
      breast cancer mortality. These results support the evidence that daily
      consumption of fruit and vegetables reduces the risk of total cancer, and
      specifically cancers of the stomach, liver, and lung.

PMID- 12618876
TI  - Childhood leukaemia and non-Hodgkin's lymphoma in relation to proximity to
      railways.
AB  - We investigated whether living close to railway lines is a risk factor for
      childhood leukaemia and non-Hodgkin's lymphoma in electoral wards in England and
      Wales, 1966-1987. The national rail network, 1966-1987, was digitised and the
      numbers of cases in each ward were related to two measures of environmental
      exposure to railways: a proximity and a density function, contributions to these
      functions being weighted by the frequency of use and time in use of each stretch
      of railway. Poisson regression was used to derive rate ratios in relation to
      these measures of exposure to railways, both unadjusted and adjusted for
      population mixing. We found no association between risk of leukaemia and railway
      proximity (unadjusted rate ratio for trend from the lowest to the median
      value=1.006, 95% CI: 0.998 - 1.013, P=0.14) and a very small association with
      railway density, of marginal statistical significance (rate ratio for
      trend=1.001, 95% CI: 1.000 - 1.003, P=0.05). This effect depended on two
      deprived, urban wards with high railway density and high population mixing and
      became nonsignificant (P=0.09) after allowing for population mixing. The very
      weak association between railway density and risk of childhood leukaemia is
      likely to be a consequence of the association between population mixing and
      proximity to railways in very deprived, urban wards.

PMID- 12618877
TI  - KOC is a novel molecular indicator of malignancy.
AB  - The detection of malignant cells in fine-needle aspirates (FNA's) using marker
      genes is hampered by the fact that these markers are only expressed by certain
      malignancies or lack sensitivity and/or specificity. Here we report the results
      of a prospective pilot study examining the expression of KOC (KH-domain
      containing protein over expressed in cancer), a novel onco-foetal gene, in 76
      patients who underwent fine-needle aspiration for further diagnosis of abdominal
      lesions, aszites, cysts or cerebrospinal fluid. Aspirates were examined by
      cytology and by a KOC RT-PCR assay. KOC expression was a highly sensitive and
      specific indicator of malignancy. The KOC assay could be useful to facilitate
      screening for malignant disease and to improve the diagnostic accuracy of FNAs.

PMID- 12618878
TI  - Ultrasonographically-guided fine-needle aspiration of axillary lymph nodes: role
      in breast cancer management.
AB  - The knowledge of the status of axillary lymph nodes (LN) of patients with breast
      cancer is a fundamental prerequisite in the therapeutic decision. In the present
      work, we evaluated the impact of fine-needle aspiration cytology (FNAC) of
      ultrasonographically (US) selected axillary LN in the diagnosis of LN metastases
      and subsequently in the treatment of patients with breast cancer. Axillary US was
      performed in 298 patients with diagnosed breast cancer (267 invasive carcinomas
      and 31 ductal carcinoma in situ DCIS), and in 95 patients it was followed by FNAC
      of US suspicious LN. Smears were examined by routine cytological staining. Cases
      of uncertain diagnosis were stained in immunocytochemistry (ICC) with a
      combination of anticytokeratin and anti-HMFG2 antibodies. Eighty-five FNAC were
      informative (49 LN were positive for metastases, 36 were negative). In 49 of 267
      patients with invasive breast carcinoma (18%), a preoperative diagnosis of
      metastatic LN in the axilla could be confirmed. These patients could proceed
      directly to axillary dissection. In addition, US-guided FNAC presurgically scored
      49 out of 88 (55%) metastatic LN. Of all others, with nonsuspicious LN on US (203
      cases including 31 DCIS), in which no FNAC examination was performed, 28 invasive
      carcinomas (16%) turned out to be LN positive on histological examination. Based
      on these data, US examination should be performed in all patients with breast
      cancer adding ICC-supported FNAC only on US-suspect LN. This presurgical protocol
      is reliable for screening patients with LN metastases that should proceed
      directly to axillary dissection or adjuvant chemotherapy, thus avoiding sentinel
      lymph node biopsy.

PMID- 12618879
TI  - The influence of tamoxifen treatment on the oestrogen receptor in metachronous
      contralateral breast cancer.
AB  - Adjuvant tamoxifen treatment reduces the occurrence of contralateral breast
      cancer (CBC). The aim of the study was to investigate the hypothesis that
      adjuvant tamoxifen reduces the occurrence of oestrogen-receptor (ER)-positive
      CBC, but not the growth of ER-negative CBCs, and to examine survival after
      diagnosis of CBC. For the study, ER status was immunohistochemically assessed in
      CBCs of 35 tamoxifen-treated patients and 115 patients without previous hormonal
      treatment. Cases were retrieved from a series of patients treated from 1984 to
      1995 at nine hospitals. The interval between ipsi- and contralateral breast
      cancer was at least 1 year. It was seen that the proportion of patients with an
      ER-negative CBC was significantly higher among those with prior tamoxifen
      treatment: 37% vs 18% (P=0.047). No difference between the two groups in overall
      and disease-specific survival following CBC was found. However, the stage
      differed for both groups: tamoxifen users more often had node-positive
      contralateral disease (P= 0.045). In conclusion, metachronous CBCs developing
      after 1-3 years of tamoxifen treatment are more often ER-negative breast cancers.
      So far this does not seem to have a major impact on survival.

PMID- 12618880
TI  - Molecular analysis of local relapse in high-risk breast cancer patients: can
      radiotherapy fractionation and time factors make a difference?
AB  - Large primary breast tumours and extensive lymph node involvement are linked to a
      high rate of local recurrence after surgery. In 10-20% of such high-risk breast
      cancer patients, local relapse will occur despite postoperative radiotherapy. In
      the present study, we investigated whether molecular features, such as
      angiogenesis, cancer cell proliferation, steroid receptor expression, c-erbB-2
      oncoprotein overexpression, p53 protein nuclear accumulation or bcl-2
      antiapoptotic protein expression, can predict failure of local therapy. We
      further examined as to which subgroups of patients could benefit from altered
      fractionation schemes of radiotherapy. In univariate analysis, high intratumoural
      angiogenesis, c-erbB overexpression and mutant-p53 nuclear accumulation were
      significantly associated with increased relapse rate (P=0.0002, 0.009 and 0.05,
      respectively). In multivariate analysis, the microvessel density and the c-erbB-2
      status were independent and significant factors related to local relapse
      (P=0.001, t-ratio 3.36 and P=0.02, t-ratio 2.26, respectively). Hypofractionated
      and accelerated radiotherapy supported with amifostine (HypoARC regimen) was
      significantly more effective than standard radiotherapy in cases with high cancer
      cell proliferation index, c-erbB-2 and p53 overexpression. High angiogenesis,
      however, was linked with local relapse regardless of the radiotherapy regimen.

PMID- 12618881
TI  - Inflammatory breast cancer shows angiogenesis with high endothelial proliferation
      rate and strong E-cadherin expression.
AB  - Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer.
      Improved understanding of the mechanisms responsible for the differences between
      IBC and non-IBC might provide novel therapeutic targets. We studied 35
      consecutive patients with IBC, biopsied prior to the initiation of chemotherapy.
      Angiogenesis was evaluated by Chalkley counting and by assessment of endothelial
      cell proliferation (ECP) and vessel maturity. The presence of fibrin, expression
      of the hypoxia marker carbonic anhydrase IX (CA IX) and epithelialcadherin (E
      cadherin) expression were immunohistochemically detected. The same parameters
      were obtained in a group of 104 non-IBC patients. Vascular density, assessed by
      Chalkley counting (P<0.0001), and ECP (P=0.01) were significantly higher in IBC
      than in non-IBC. Abundant stromal fibrin deposition was observed in 26% of IBC
      and in only 8% of non-IBC (P=0.02). Expression of CA IX was significantly less
      frequent in IBC than in non-IBC with early metastasis (P=0.047). There was a
      significant positive correlation between the expression of CA IX and ECP in IBC
      (r=0.4, P=0.03), implying that the angiogenesis is partly hypoxia driven.
      However, the higher ECP in IBC and the less frequent expression of CA IX in IBC
      vs non-IBC points at a role for other factors than hypoxia in stimulating
      angiogenesis. Strong, homogeneous E-cadherin expression was found at cell-cell
      contacts in all but two IBC cases, both in lymphovascular tumour emboli and in
      infiltrating tumour cells, challenging our current understanding of the
      metastatic process. Both the intense angiogenesis and the strong E-cadherin
      expression may contribute to the highly metastatic phenotype of IBC.

PMID- 12618882
TI  - Prognostic significance of dysadherin expression in advanced colorectal
      carcinoma.
AB  - A novel glycoprotein, dysadherin, has an anti-cell - cell adhesion function
      through downregulating E-cadherin. In this study, we investigated the expressions
      of dysadherin and E-cadherin in 82 patients with stage II and III colorectal
      carcinomas to determine the correlation between the two molecules and the
      clinicopathologic features of each tumour. Dysadherin was not expressed in normal
      colorectal epithelium. Fifty-one per cent of tumours showed dysadherin
      immunopositivity in over 50% of cancer cells. Thirty-eight per cent of tumours
      showed reduced E-cadherin immunopositivity. The increased expression of
      dysadherin was significantly associated with lung metastasis (P=0.003). The
      increased expression of dysadherin had a significant impact on patient survival
      (P=0.0099 and 0.0036, log-rank test for overall and recurrence-free survival
      rate, respectively). Furthermore, tumour with increased expression of dysadherin
      and reduced expression of E-cadherin showed the worst prognosis (P=0.0043 and
      0.0028, log-rank test for overall and recurrence-free survival rate,
      respectively). These results suggest that increased dysadherin expression is a
      significant indicator of poor prognosis for patients with advanced colorectal
      carcinoma.

PMID- 12618883
TI  - Focal overexpression of insulin-like growth factor 2 by hepatocytes and
      cholangiocytes in viral liver cirrhosis.
AB  - Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma
      and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1
      receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2
      receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by
      in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of
      different aetiology without neoplastic or dysplastic lesions. Immunohistology was
      also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High
      focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV-
      or HCV-induced cirrhosis (n=10), but in only one of the cirrhoses with nonviral
      aetiology (n=8). IGF-2 was overexpressed in biliary duct epithelial cells in one
      case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced
      hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced
      expression in perisinusoidal cells. Immunostaining for the other antigens did not
      reveal significant differences. Upregulation of IGF-2 in some hepatocytes may
      lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding
      capacities, and may result in an increased susceptibility to cellular
      dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular
      M6P/IGF-2R and upregulation of IGF-2 seem to be early events in
      hepatocarcinogenesis prior to the appearance of morphologically distinct
      dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate
      an increased risk for hepatocellular and cholangiocellular carcinomas.

PMID- 12618885
TI  - Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma
      cells: differential activation of PKC and MAP kinases.
AB  - Butyrate, produced in the colon by fermentation of dietary fibre, induces
      apoptosis in colon adenoma and cancer cell lines, which may contribute to
      protection against colorectal cancer. However, butyrate is present in the colon
      along with other dietary factors, including unconjugated bile acids, which are
      tumour promoters. We have shown previously that the proapoptotic effects of
      butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids.
      To determine the cellular basis of this interaction, we examined the effects of
      butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling
      pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC
      delta and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC
      alpha and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3
      mediated proteolysis of PKC-delta. Butyrate-induced apoptosis was reduced by
      inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3
      (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by
      inhibitors of PKC-alpha (Go6976) and MEK 1 (PD98059). The effects of butyrate and
      bile acids are therefore mediated by the differential activation of signalling
      pathways that are known to regulate apoptosis.

PMID- 12618886
TI  - p53 protein regulates the effects of amifostine on apoptosis, cell cycle
      progression, and cytoprotection.
AB  - To determine the role of p53 protein on the cellular effects of amifostine, we
      used molecularly engineered HCT116 colon cancer cells in which the p53 gene was
      inactivated by targeted homologous recombination or p53 protein was degraded by
      high-level expression of papillomavirus E6 protein. Amifostine induced a G1
      arrest and protected against paclitaxel toxicity in p53-proficient but not in p53
      deficient cells. In the absence of p53 protein, amifostine enhanced the
      cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with
      amifostine alone resulted in apoptotic cell death. Compared with p53-deficient
      cells, p53-proficient cells exhibited low-level resistance to amifostine-induced
      apoptosis. Amifostine induced the expression of p53 protein in p53-proficient
      cells and the expression of p21 protein in both p53-proficient and -deficient
      cells. These findings indicate that amifostine-induced G1 arrest and
      cytoprotection are mediated via a pathway that is dependent on p53 protein and
      that amifostine-induced expression of p21 protein is not sufficient to sustain a
      G1 arrest or to mediate cytoprotection. In addition, these findings identify p53
      protein as a mechanism of resistance to amifostine-induced apoptosis.British

PMID- 12618884
TI  - Impaired Delta Np63 expression associates with reduced beta-catenin and
      aggressive phenotypes of urothelial neoplasms.
AB  - p63, a homologue of the p53 gene, is considered to be essential for the normal
      development of stratified epithelia including urothelium. To examine possible
      roles of p63 in urothelial tumorigenesis, p63 expression was systematically
      examined in normal urothelium, low-grade papillary noninvasive (LPN) urothelial
      tumours, and high-grade or invasive carcinomas, using either an isoform
      nonspecific or a Delta N-isoform-specific antibody. Expression profiles of p63
      were also analysed in cultured cells. Immunoreactivity with the two antibodies
      was virtually identical in tissue samples examined. Basal and intermediate cell
      layers of normal urothelium showed intense nuclear p63 immunostaining. This
      normal staining pattern was preserved in a majority of LPN tumours, whereas it
      was frequently impaired in high-grade or muscle-invasive carcinomas. At the mRNA
      level, Delta Np63 expression predominated over TAp63, and amounts of Delta Np63
      mRNA correlated with p63 immunoreactivity, confirming that Delta Np63 accounts
      for p63 expressed in urothelial tissues. In cultured cells, Delta Np63 was also
      expressed in low-grade tumour cells as well as normal urothelial cells, but
      undetectable in high-grade aggressive carcinoma cells. Interestingly, impaired
      Delta Np63 expression significantly associated with reduced beta-catenin
      expression that was possibly related to progression of urothelial neoplasms.
      Thus, impaired Delta Np63 expression characterises aggressive phenotypes of
      urothelial neoplasms.

PMID- 12618887
TI  - Ischaemia-reperfusion injury in photodynamic therapy-treated mouse tumours.
AB  - Prompted by the observation of ischaemia development during the treatment of
      tumours by photodynamic therapy (PDT) that is typically followed by a restoration
      of tumour blood flow and by the indications of secondary superoxide generation
      after PDT, we aimed in this study to obtain evidence of the induction of
      ischaemia-reperfusion (I/R) injury in PDT-treated tumours. Using subcutaneous
      mouse FsaR fibrosarcoma model and Photofrin-based PDT treatment, we have examined
      the activity of xanthine oxidase (XO, a key enzyme in the I/R injury development)
      in tumours before and after the therapy. Compared to the levels in nontreated
      tumours, there was a five-fold increase in the activity of this enzyme in tumours
      excised immediately after PDT. This burst of elevated XO activity declined
      rapidly, returning to the pretreatment levels within the next 30 min. Visible
      reflectance spectroscopy confirmed the occurrence of a PDT-induced strong but
      temporary reduction in tumour oxygenation. The administration of XO inhibitor
      oxypurinol prevented this PDT-induced rise in XO activity. The oxypurinol
      treatment also decreased the extent of neutrophil accumulation in PDT-treated
      tumours and reduced the level of PDT-mediated cures. These results demonstrate
      the induction of I/R injury in PDT-treated tumours, and show that it can
      contribute to the therapy outcome. Since I/R injury is a well-recognised
      proinflammatory insult, we suggest that its induction in PDT-treated tumours
      promotes the development of inflammatory response that has become established as
      a key element of the antitumour effect of PDT.

PMID- 12618889
TI  - Cell proliferation is related to in vitro drug resistance in childhood acute
      leukaemia.
AB  - Bone marrow and peripheral blood samples from 362 patients with acute
      lymphoblastic leukaemia (ALL) proliferating cell and 90 patients with acute
      myeloid leukaemia (AML) were analysed for S-phase fractions, Ki67 antigen, and
      proliferating cell nuclear antigen expression. The S-phase fractions were
      correlated with in vitro drug resistance to 15 different anticancer agents.
      Leukaemia cells isolated from bone marrow had higher S-phase fractions than
      leukaemia cells isolated from peripheral blood (in initial ALL, median values
      resp. 6.9 and 2.7%, in initial AML resp. 5.3 and 1.3%; both P<0.01). Relapse ALL
      samples derived from bone marrow showed increased S-phase fractions (median 9.9%)
      compared with initial ALL samples (median 6.9%; P<0.01). ALL samples obtained at
      initial diagnosis showed higher S-phase fractions (median 6.9%) and higher Ki67
      expression (median 30%) than initial AML samples (median resp. 5.3 and 14%; both
      P<0.05). The S-phase fractions were not related to white blood cell count, age,
      or gender. Within initial ALL, the S-phase fraction correlated significantly but
      modestly strong (rho=0.3-0.5; P<0.05) with sensitivity to antimetabolites
      (cytarabine, mercaptopurine, thioguanine), L-asparaginase, teniposide, and
      vincristine. Similar results were found within subgroups of initial ALL
      (nonhyperdiploid and common/precursor-B-lineage ALL). In relapsed ALL and AML
      such correlations were not found. In conclusion, cell proliferation differs
      between leukaemia subgroups and increased proliferation is associated with
      increased in vitro sensitivity to several anticancer agents in initial ALL.

PMID- 12618888
TI  - A proliferation-dependent bystander effect in primary porcine and human
      urothelial explants in response to targeted irradiation.
AB  - The aim of this study was to test whether radiation-induced bystander effects are
      involved in the response of multicellular systems to targeted irradiation. A
      primary explant technique was used that reconstructed the in vivo
      microarchitecture of normal urothelium with proliferating and differentiated
      cells present. Sections of human and porcine ureter were cultured as explants and
      irradiated on day 7 when the urothelial outgrowth formed a halo around the tissue
      fragment. The Gray Cancer Institute charge particle microbeam facility allowed
      the irradiation of individual cells within the explant outgrowth with a
      predetermined exact number of (3)He(2+) ions (which have very similar biological
      effectiveness to alpha-particles). A total of 10 individual cell nuclei were
      irradiated with 10 (3)He(2+) ions either on the periphery, where proliferating
      cells are located, or at the centre of the explant outgrowth, which consisted of
      terminally differentiated cells. Samples were fixed 3 days after irradiation,
      stained and scored. The fraction of apoptotic and micronucleated cells was
      measured and a significant bystander-induced damage was observed. Approximately
      2000-6000 cells could be damaged by the irradiation of a few cells initially,
      suggesting a cascade mechanism of cell damage induction. However, the fraction of
      micronucleated and apoptotic cells did not exceed 1-2% of the total number of the
      cells within the explant outgrowth. It is concluded that the bystander-induced
      damage depends on the proliferation status of the cells and can be observed in an
      in vitro explant model.

PMID- 12618890
TI  - Penetration of capecitabine and its metabolites into malignant and healthy
      tissues of patients with advanced breast cancer.
AB  - Capecitabine is an oral prodrug of 5-fluorouracil (FU). Since FU concentrations
      achieved in malignant lesions are an important determinant of efficacy, we
      investigated the intratumoral transcapillary transfer of capecitabine and its
      metabolites in vivo. A total of 10 patients with skin metastases from breast
      cancer received a daily dose of 2500 mg m(-2) capecitabine administered orally in
      two divided doses for 2 weeks. Microdialysis probes were inserted into a
      cutaneous metastasis and subcutaneous connective tissue to evaluate the
      interstitial tissue pharmacokinetics of capecitabine and its metabolites 5'-deoxy
      5-fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and FU by capillary
      electrophoresis. As intended with the prodrug design of capecitabine, FU was
      present in low concentrations in tumour interstitium (median c(max): 0.26 microg
      ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66,
      4.22, and 2.13 microg ml(-1), respectively). Capecitabine and its metabolites
      easily penetrated malignant and healthy tissue and equilibrated within 45 min
      between plasma and tissue interstitium. Considering tissue exposure at the
      extracellular level, no significant differences between healthy and malignant
      tissues were observed. Our data show that absorption and metabolism determined
      the tissue pharmacokinetics of capecitabine. There was no evidence of drug
      tolerance, which may be attributed to impaired transcapillary transfer into
      tissue, even after repeated administration as shown for three patients.

PMID- 12618891
TI  - Endothelin-receptor antagonists are proapoptotic and antiproliferative in human
      colon cancer cells.
AB  - Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an
      antiapoptotic factor in human cancers. To study the role of ET-1 in human colon
      cancer, proliferation and apoptosis of colon carcinoma cells was investigated
      using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these
      cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist,
      decreased cell number. Inhibition of DNA synthesis by bosentan was observed only
      in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis
      in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were
      resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to
      FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis.
      Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or
      FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(
      13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These
      results suggest that the binding of ET-1 to high-affinity sites inhibits FasL
      induced apoptosis, while the binding of either ET-1 or receptor antagonists to
      low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin
      signalling pathways do not induce human colon cancer cell proliferation, but are
      survival signals controling resistance to apoptosis.

PMID- 12618893
TI  - Cardiovascular emergencies: pericardial effusion and cardiac tamponade.

PMID- 12618892
TI  - Induction of neuropilin-1 and vascular endothelial growth factor by epidermal
      growth factor in human gastric cancer cells.
AB  - The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the
      progression of human gastric cancer. The angiogenic factor vascular endothelial
      growth factor (VEGF) has been shown to be induced by EGF in various cancer cell
      lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its
      affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1
      has been found to be expressed by tumour cells and has been shown to enhance
      tumour angiogenesis and growth in preclinical models. We examined the expression
      of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1
      expression was expressed in five of seven cell lines, and EGF-R expression
      closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2
      cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal
      antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells
      in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in
      increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk,
      phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented
      EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1
      expression in human gastric cancer is intimately associated with the EGF/EGF-R
      system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a
      mechanism that involves upregulation of VEGF and NRP-1 expression via multiple
      signalling pathways.

PMID- 12618894
TI  - Vitamin K(2) selectively induced apoptosis in ovarian TYK-nu and pancreatic MIA
      PaCa-2 cells out of eight solid tumor cell lines through a mechanism different
      from geranylgeraniol.
AB  - PURPOSE: In this study, we examined the effects of vitamin K(2) (menaquinone 4),
      which has a geranylgeranyl side chain, on various lines of cells derived from
      human solid tumors and compared them with the effects of geranylgeraniol (GGO).
      METHODS: Cell proliferation was determined with 3'-[1-[(phenylamino)carbonyl]-3,4
      tetrazolium- bis (4-methoxy-6-nitro) benzene-sulfonic acid hydrate (XTT), and the
      induction of apoptosis was analyzed by TUNEL staining and flow cytometry as well
      as by measurement of DNA fragmentation, released nucleosomes and caspase-3
      activity. Levels of Bcl-2, Bax and cytochrome c were determined by
      immunoblotting. RESULTS: GGO inhibited the growth of all eight cell lines derived
      from solid tumors, while vitamin K(2) selectively inhibited the proliferation of
      ovarian TYK-nu and pancreatic MIA PaCa-2 cancer cells, inducing apoptosis in both
      cell lines. Far more time was required for the induction of apoptosis in these
      two cell lines by vitamin K(2) than by GGO. Apoptotic signals induced in TYK-nu
      cells during the first 2 days that followed the addition of vitamin K(2) to the
      culture medium were reversible, but these signals became irreversible after 3
      days of treatment with vitamin K(2). The induction of apoptosis in TYK-nu cells
      by vitamin K(2) was inhibited by cycloheximide and also by starvation at a low
      concentration of serum. Neither cycloheximide nor starvation had any effect on
      the induction of apoptosis by GGO. Cytochrome c was released simultaneously with
      the initiation of apoptosis on treatment of TYK-nu cells with vitamin K(2) or
      GGO. However, GGO induced the release of cytochrome c from isolated mitochondria,
      while vitamin K(2) did not. The amount of Bcl-2 in TYK-nu cells was reduced by
      vitamin K(2), but not by GGO. CONCLUSIONS: In contrast to GGO, vitamin K(2)
      induced apoptosis selectively in pancreatic MIA-PaCa 2 and ovarian TYK-nu cancer
      cells. It is suggested that de novo protein synthesis might be necessary for
      induction of apoptosis by vitamin K(2) but not by GGO, and thus, that vitamin
      K(2) and GGO might induce apoptosis by different mechanisms.

PMID- 12618895
TI  - Evidence for a graft-versus-tumor effect in refractory ovarian cancer.
AB  - PURPOSE: A 31-year-old woman suffered a 4th relapse of epithelial ovarian cancer
      refractory to several cytotoxic drugs including platinum, paclitaxel, and
      topotecan. METHODS: Sequential high-dose chemotherapy with autografting (three
      courses) led to a minor response of short duration. In order to induce a graft
      versus-tumor effect, allogeneic hematopoietic stem cell transplantation (HSCT)
      from an HLA-identical sibling donor, after dose-reduced conditioning, was
      performed in January 2001. RESULTS: On day +51 the patient developed acute grade
      II graft-versus-host disease of the skin and gastrointestinal tract, which was
      successfully treated by prednisolone. Six months after allogeneic HSCT a complete
      disappearance of the tumor could be seen. Unfortunately, 14 months later a 5th
      relapse was diagnosed. CONCLUSIONS: This case demonstrates, on the one hand, that
      allogeneic HSCT is able to induce complete remissions (CR) in chemoresistant
      ovarian cancer. On the other hand, despite achievement of CR after allografting,
      the chance of cure remains limited for these patients.

PMID- 12618896
TI  - Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with
      hepatocellular carcinoma-A phase II trial.
AB  - PURPOSE: To study the combination of 5FUDR, recombinant leukocyte interferon
      (IFN), and doxorubicin in patients with unresectable hepatocellular carcinoma.
      METHODS: IFN was administered at a dose of 6 miu/m(2) subcutaneously followed in
      2 h by doxorubicin 20 mg/m(2) intravenously. After doxorubicin, 5FUDR was given
      as a 24-h infusion at a starting dose of 80 mg/kg. The dose of IFN was escalated
      to three times a week if tolerated. Both doxorubicin and 5FUDR were administered
      once weekly. RESULTS: There were 30 patients entered into the study. Among the 30
      patients, there were two partial responses (7%) and one patient had stable
      disease. Toxicity was generally tolerable with fever, and chills, fatigue, and
      myelosuppression as the most common side effects. CONCLUSIONS: This chemotherapy
      combination was generally well tolerated, but has limited activity in
      unresectable, advanced hepatocellular carcinoma.

PMID- 12618897
TI  - Potential of alpha-amino alcohol p-boronophenylalaninol as a boron carrier in
      boron neutron capture therapy, regarding its enantiomers.
AB  - PURPOSE: We evaluated the potential of a newly developed (10)B-containing alpha
      amino alcohol of p-boronophenylalanine-(10)B (BPA), p-boronophenylalaninol
      (BPAol), as a boron carrier in boron neutron capture therapy. METHODS: C57BL mice
      bearing EL4 tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously via
      implanted mini-osmotic pumps to label all proliferating (P) cells. After oral
      administration of L-BPA or D-BPA, or intraperitoneal injection of L-BPAol or D
      BPAol, the tumors were irradiated with reactor thermal neutron beams. Some of the
      tumors were heated at 40 degrees C for 30 min (mild temperature hyperthermia
      (MTH)) right before neutron exposure, and/or tirapazamine (TPZ) was
      intraperitoneally injected 30 min before irradiation. The tumors were then
      excised, minced, and trypsinized. The tumor cell suspensions thus obtained were
      incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN)
      frequency in cells without BrdU labeling [ =quiescent (Q) cells] was determined
      using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation,
      tumor cell suspensions obtained in the same manner were used for determining the
      apoptosis frequency in Q cells. The apoptosis and MN frequency in total (P+Q)
      tumor cells were determined from the tumors that were not pretreated with BrdU.
      RESULTS: Without TPZ or MTH, L- and D-BPAol increased both frequencies markedly,
      especially for total cells. Although not significantly larger, L-BPA and D-BPAol
      increased both frequencies slightly more than D-BPA and L-BPAol, respectively.
      Combination with both MTH and TPZ markedly reduced the sensitivity difference
      between total and Q cells. CONCLUSION: Both L- and D-BPAol have potential as a
      (10)B-carrier in neutron capture therapy, especially when combined with both MTH
      and TPZ.

PMID- 12618898
TI  - Human kallikrein 2 (hK2) mRNA in peripheral blood of patients with thyroid
      cancer: a novel molecular marker?
AB  - PURPOSE: To elucidate whether hK2 mRNA can be detected in peripheral blood of
      patients with thyroid disease using reverse transcription polymerase chain
      reaction (RT-PCR). METHODS: A nested RT-PCR protocol for the detection of hK2
      mRNA was established, and blood samples of 72 patients with a history of thyroid
      cancer, 10 patients with current metastases of thyroid cancer, and 32 volunteers
      were tested. RESULTS: hK2-transcripts were significantly more often detected in
      patients with thyroid cancer (20/72=28%) than in the control group (2/32=6%, P =
      0.03, chi-square analysis). CONCLUSIONS: This is the first study reporting on hK2
      as a potential molecular marker for patients with thyroid cancer. We could
      demonstrate a correlation between diagnosis of thyroid cancer and the positive
      signal for hK2 in the RT-PCR assay. Future studies are necessary to prove the
      clinical value of hK2 as a molecular marker regarding recurrence and outcome.

PMID- 12618899
TI  - 19-nor-1alpha,25-dihydroxyvitamin D(2) (paricalcitol): effects on clonal
      proliferation, differentiation, and apoptosis in human leukemic cell lines.
AB  - PURPOSE: 19-Nor-1alpha,25-dihydroxyvitamin D(2) (paricalcitol) is an analogue of
      1,25(OH)(2)D(3) with reduced calcemic effects that is approved for the
      suppression of parathyroid hormone in chronic renal failure. Paricalcitol has
      recently been reported to have anticancer activity in prostate cancer. In order
      to explore paricalcitol as a potential agent against leukemia, we tested its
      effects on HL-60 and U937 leukemia cell lines. METHODS: We studied cellular
      differentiation via expression of CD11b and CD14 surface antigens using flow
      cytometry, and via the nitroblue tetrazolium (NBT) assay. Cell cycle was analyzed
      using propidium iodide staining. Apoptosis was assessed with the annexin V assay.
      Cellular proliferation was determined via colony inhibition on semisolid medium.
      RESULTS: Paricalcitol induced the maturation of HL-60 and U937 cells, as shown by
      increased expression of CD11b differentiation surface antigen. CD14 showed
      increased expression in HL-60 but not in U937 cells. After exposure to
      paricalcitol at 10(-8) M for 72 h, the ability of HL-60 cells to reduce NBT was
      markedly increased. Conversely, U937 cells were unchanged. Paricalcitol inhibited
      colony formation of both HL-60 and U937 cell lines in semisolid medium after a 10
      day incubation (estimated IC(50) of 3x10(-8) M in HL-60 cells and 4x10(-8) M in
      U937 cells). Paricalcitol at 10(-8) M and 10(-7) M caused a significant dose- and
      time-dependent increase of apoptosis in HL-60 cells ( P<0.05). In both HL-60 and
      U937 cells, exposure to 10(-7) M paricalcitol for 72 h increased the number of
      cells in G(0)/G(1) phase, and decreased the number of cells in S phase.
      CONCLUSIONS: Paricalcitol inhibits colony formation, induces maturation and
      causes cell cycle arrest in HL-60 and U937 cells. Additionally, paricalcitol
      induces apoptosis in HL-60 cells. These findings support the further evaluation
      of paricalcitol as an antileukemia agent.

PMID- 12618900
TI  - Establishment of a hepatocellular carcinoma cell line with unique metastatic
      characteristics through in vivo selection and screening for metastasis-related
      genes through cDNA microarray.
AB  - PURPOSE: To establish a hepatocellular carcinoma (HCC) cell line from lung
      metastatic lesions of human HCC in nude mice so as to provide a suitable model
      for the study of lung-metastasis-related molecular mechanisms. METHODS: HCC clone
      cells MHCC97-H were inoculated into BALB/c nude mice, and the pulmonary
      metastatic lesions were harvested and re-implanted into nude mice for the second
      round of in vivo selection. The same procedure was repeated twice. A new cell
      line from the third round of lung metastases was established. RESULTS: A human
      HCC cell line with unique metastatic characteristics was established by in vivo
      selection. This cell line, designated as HCCLM3, was polygonal epithelial cell
      with hypotriploid karyotype and population doubling time of 34.9 h. The cells
      were positive for alpha fetoprotein (AFP), albumin, cytokeratin 8 (CK8), and
      negative for hepatitis B surface antigen (HBsAg) by immunocytochemistry.
      Fluorescence polymerase chain reaction (PCR) showed HBV DNA integration in the
      cellular genome. When 5 x 10(6) cells were injected subcutaneously into nude
      mice, tumorigenicity was 100%, with a latency period of 11+/-1 days. Five weeks
      after s.c. injection, the pulmonary metastatic rate was 100%, the median number
      of lung metastases being 121 per mouse. After orthotopic implantation of tumor
      tissue into nude mouse liver for 35 days, widespread loco-regional and distant
      metastases occurred, with 100% abdominal wall metastases, 80% intra-abdominal
      cavity metastases, 100% intrahepatic metastases, 70% diaphragm metastases, and
      100% pulmonary metastases. The median number of lung metastatic lesions was 268
      per mouse. Gene expression profile of HCCLM3 was compared by cDNA microarray with
      MHCC97-L, a clonal cell strain from the same parental cell line but with low
      metastatic potential; 25 differentially expressed genes were identified, 18 of
      which showed decreased expression and seven increased expression in HCCLM3,
      including the decreased expression of cell cycle control gene Rb2, mismatch
      repair gene hMSH2, and signal transduction gene protein kinase C beta2, and
      increased expression of signal transduction gene MAP kinase, kinase 6.
      CONCLUSIONS: A new HCC cell line characterized by high pulmonary metastases via
      s.c. and orthotopic inoculation was established, which provides a new model for
      the study of liver cancer metastasis. Its gene expression profile could help in
      the understanding of the mechanism of metastasis and provide potential targets
      for anti-metastasis intervention.

PMID- 12618901
TI  - Preliminary results of radiotherapy with or without weekly paclitaxel in locally
      advanced non-small cell lung cancer.
AB  - PURPOSE: In this study our objective was to evaluate the therapeutic significance
      of concurrent paclitaxel and radiotherapy compared with radiotherapy alone.
      PATIENTS AND METHODS: Patients with stage III A/B NSCLC were randomly assigned to
      receive either radiotherapy alone (group 2) or concurrent weekly paclitaxel with
      radiotherapy (group 1) in GMMA. Radiotherapy was given as a split-course schedule
      with the total dose of 56 Gy. Paclitaxel, 60 mg/m(2), was administered only to
      group 1 on the first day of each radiotherapy week. To assess differences between
      values, P values were calculated with the chi(2) test. A Mann Whitney U-test was
      used to assess significant differences between the two values. Actuarial survival
      curves were calculated by the Kaplan-Meier method. RESULTS: There were 25
      patients who underwent chemoradiotherapy and 26 who underwent radiotherapy only.
      Median follow-up was 14 months. The overall response rate was 92% and 70% for
      groups 1 and 2, respectively ( P= 0.003). Median survival was 15.2 months for
      group 1, and 12.0 months for group 2 ( P= 0.027). CONCLUSION: Based on this
      response and the toxicity profile, outpatient split-course radiotherapy and
      weekly paclitaxel seems to be feasible and safe.

PMID- 12618902
TI  - DC-CLM, a cadherin-like molecule cloned from human dendritic cells, inhibits
      growth of breast cancer cells.
AB  - PURPOSE: To identify the characteristics and function of a cadherin-like
      molecule, cloned from a human dendritic cell (DC) cDNA library and designated DC
      derived cadherin-like molecule (DC-CLM). METHODS: The mRNA expression of DC-CLM
      in tissues and cells was analyzed by Northern blot and RT-PCR, respectively. In
      order to express DC-CLM in target cells, we constructed a pcDNA3.1/DC-CLM
      expression vector and transfected it into MCF-7 human breast cancer cells. Tumor
      growth was demonstrated by cell proliferation and colony formation. RESULTS: DC
      CLM cDNA encoded a protein of 260 amino acids and the gene was localized to
      chromosome 5q31. The predicted protein possessed a definitive cadherin-specific
      sequence motif and shared homology with classical cadherin. However, no
      transmembrane segment was observed in DC-CLM. Northern blot revealed the
      ubiquitous nature of DC-CLM transcripts in human tissues, with high expression in
      heart, brain, prostate, testis and ovary. RT-PCR demonstrated that DC-CLM was
      widely expressed in hematopoietic and epithelial tumor cell lines, but was not
      expressed in MCF-7. Interestingly, DC-CLM expression was upregulated in DC
      activated by lipopolysaccharides. DC-CLM expression in the stable transfectant
      (MCF-7/DC-CLM) was confirmed by RT-PCR and Western blot. DC-CLM protein was found
      to be secreted by MCF-7/DC-CLM but not expressed on the membrane of MCF-7/DC-CLM.
      DC-CLM transfection resulted in significant inhibition of in vitro growth and
      colony formation of MCF-7 cells. CONCLUSIONS: A cadherin-like molecule DC-CLM was
      cloned from human DC and it may be a soluble cadherin-like molecule for tumor
      suppression. DC-CLM was upregulated in activated DC and may be involved in the
      effector function of activated DC.

PMID- 12618903
TI  - Liposomal daunorubicin in tumor stage cutaneous T-cell lymphoma: report of three
      cases.
AB  - PURPOSE: Advanced cutaneous T-cell lymphoma (CTCL) is a hard-to-treat condition.
      Complete response is rare even with polychemotherapy. The use of liposomal
      formulation anti-cancer drugs can improve the efficacy and the risk-benefit
      ratio. Liposomal doxorubicin was shown to be effective as a second-line treatment
      in CTCL. There is no data available on another classical anthracycline,
      daunorubicin, when given in liposomal formulation as a monotherapy. METHODS:
      Monotherapy with liposomal-encapsulated daunorubicin (DNX) was given as a
      monotherapy once a month at 20 mg/m(2) three times to achieve a clinical
      response. In the case of limited response the drug was given once every 3 weeks
      and a dose increase was performed. Three patients were treated. RESULTS: A
      complete response was achieved in one patient (dosage 20 mg/m(2 )once per month).
      Two other patients achieved a partial response. The final outcome was disease
      free survival of more than 10 months in the patient with a complete response and
      survival of >8 months and 6 months in those with a partial response. Adverse
      effects were grade 4 anemia in one patient, lymphopenia grade 2 with grade 1
      anemia, and grade 1 lymphopenia in the other patients. CONCLUSION: This is the
      first report on DNX monotherapy in CTCL. In a small group of three patients a
      response rate of 100% was achieved with one complete response. DNX seems to be
      another option in advanced cases of CTCL.

PMID- 12618904
TI  - 18F-DOPA positron emission tomography for the detection of glomus tumours.
AB  - The purpose of this study was to evaluate (18)F-DOPA whole-body positron emission
      tomography ((18)F-DOPA PET) as a biochemical imaging approach for the detection
      of glomus tumours. (18)F-DOPA PET and magnetic resonance imaging (MRI) were
      performed in ten consecutive patients with proven mutations of the succinate
      dehydrogenase subunit D ( SDHD) gene predisposing to the development of glomus
      tumours and other paragangliomas. (18)F-DOPA PET and MRI were performed according
      to standard protocols. Both methods were assessed under blinded conditions by two
      experienced specialists in nuclear medicine (PET) and diagnostic radiology (MRI).
      Afterwards the results were compared. A total of 15 lesions (four solitary and
      four multifocal tumours, the latter including 11 lesions) were detected by (18)F
      DOPA PET. Under blinded conditions, (18)F-DOPA PET and MRI revealed full
      agreement in seven patients, partial agreement in two and complete disagreement
      in one. Eleven of the 15 presumed tumours diagnosed by (18)F-DOPA PET were
      confirmed by MRI. The correlation of (18)F-DOPA PET and MRI confirmed three
      further lesions previously only detected by PET. All of them were smaller than 1
      cm and had the signal characteristics of lymph nodes. For one small lesion
      diagnosed by PET, no morphological MRI correlate could be found even
      retrospectively. No tumour was detected by MRI that was negative on (18)F-DOPA
      PET. All tumours diagnosed by MRI showed a hyperintense signal on T2-weighted
      images and a distinct enhancement of contrast medium on T1-weighted images. The
      mean tumour size was 1.5+/-0.5 cm. (18)F-DOPA PET seems to be a highly sensitive
      metabolic imaging procedure for the detection of glomus tumours and may have
      potential as a screening method for glomus tumours in patients with SDHD gene
      mutations.

PMID- 12618905
TI  - 99mTc-M-TRODAT is not superior to (99m)Tc-TRODAT-1 for the diagnosis of
      Parkinson's disease.

PMID- 12618906
TI  - Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated
      RFXANK mutant binds the promoter without transactivating MHC II.
AB  - MHC class II deficiency is a combined immunodeficiency caused by defects in the
      four regulatory factors, CIITA, RFXANK, RFX5 and RFXAP, that control MHC II
      expression at the transcriptional level. The RFXANK gene encodes one subunit of
      the heterotrimeric RFX complex that is involved in the assembly of several
      transcription factors on MHC II promoters. Seven different RFXANK mutations have
      previously been reported in 26 unrelated patients. The most frequent mutation, a
      26-bp deletion (752delG-25), has been identified in 21 patients. The other
      mutations are all nonsense or splice-site mutations, leading to proteins lacking
      all or part of the RFXANK ankyrin repeat region. We report two novel missense
      mutations, D121V and R212X, resulting in loss of function of the gene. We
      investigated the in vivo effects of these mutations and of three other point
      mutations on the expression of the RFXANK RNA and protein. The number of RFXANK
      transcripts was severely reduced in all patients except one. The RFXANK protein
      was barely detected in two cases. In addition, guided by a structural model of
      RFXANK, we investigated experimental mutants of the C-terminal tyrosine 224.
      Substitution Y224A, but not Y224F, led to the loss of function of RFXANK. Two
      null mutants, D121V and Y224A, were tested in protein interaction and DNA binding
      assays. The D121V mutant was unable to form the RFX complex, indicating that D121
      is required for RFXAP binding. The Y224A mutant formed an RFX complex that bound
      normally to the MHC II promoter, but did not lead to MHC class II expression,
      whereas Y224F RFXANK retained the wild-type function. This indicates that an
      aromatic ring, but not the phenyl chain of tyrosine, is necessary at position 224
      for normal RFXANK function. Studies on the Y224A mutant suggest that, in addition
      to the RFX subunits and CIITA, another protein is essential for MHC class II
      expression. This protein appears to interact with the fourth ankyrin repeat of
      RFXANK.

PMID- 12618907
TI  - Distribution of HLA-B alleles in Mexican Amerindian populations.
AB  - In the present study we analyzed by PCR-SSO technique the HLA-B gene frequencies
      in 281 healthy individuals from four Mexican Amerindian populations (66 Mayos, 90
      Mazatecans, 72 Nahuas and 53 Teenek). The most frequent alleles in all studied
      populations were HLA-B35, HLA-B39, and HLA-B40; however, some differences were
      observed between populations. The HLA-B35 allele was the most frequent in three
      of the four populations studied (Mayos, Nahuas and Teenek), whereas in Mazatecans
      the most frequent allele was HLA-B39. HLA-B40 presented frequencies higher than
      10% in all groups. On the other hand, only Mayos presented an HLA-B51 gene
      frequency higher than 10%. When comparisons were made, important differences
      between groups were observed. The Teenek group presented an increased frequency
      of HLA-B35 when compared to Mazatecans and the HLA-B52 allele was increased in
      Nahuas and Teenek when compared to Mayos. An increased frequency of HLA-B39 was
      observed in Mazatecans when compared to Nahuas, Mayos and Teenek. Also, an
      increased frequency of HLA-B51 was observed in Mayos when compared to Mazatecans
      and Nahuas. These data corroborate the restricted polymorphism of HLA-B alleles
      and the high frequency of HLA-B35, HLA-B39 and HLA-B40 alleles in autochthonous
      American populations. In spite of the restriction in this polymorphism,
      differences in frequencies of HLA-B alleles could be helpful in distinguishing
      each of these populations.

PMID- 12618908
TI  - Extensive polymorphism and different evolutionary patterns of intron 2 were
      identified in the HLA-DQB1 gene.
AB  - Exon 2 and intron 2 of the HLA DQB1 gene from 20 individuals were cloned and
      sequenced and eight alleles were obtained. Based on our analysis, the nucleotide
      diversity of the 5' end of intron 2 was higher than the synonymous nucleotide
      diversity of exon 2, which may be due to the lower GC content and the 'hitch
      hiking effect'. In contrast, the opposite phenomenon was observed for the 3' end
      of intron 2, which may be the result of the recombination between the 3' end and
      5' end of intron 2 and the subsequent genetic drift. The results indicated that
      different regions of intron 2 in the DQB1 gene had different evolutionary
      patterns.

PMID- 12618909
TI  - Analysis of HLA-E expression in human tumors.
AB  - Downregulation of MHC class Ia molecule expression is a widespread mechanism used
      by tumor cells to escape antitumor T-cell-mediated immune responses. However, it
      is not known why NK cells cannot lyse these MHC class-Ia-deficient tumor targets.
      Tumors must select additional routes of escape from NK cells. An attractive
      hypothesis is that the aberrant expression of nonclassical HLA class Ia molecules
      in tumors provides the required inhibitory signal to NK cells, rendering tumor
      cells resistant to NK lysis. To analyze the possible role of HLA-E molecules in
      providing tumor cells with an NK escape mechanism, we studied the cell surface
      expression of this HLA class Ib molecule in a variety of tumor cell lines with
      well-defined HLA class Ia alterations. Tests were done with the monoclonal
      antibody 3D12 recognizing cell surface HLA-E molecules. Our results indicate that
      HLA-E was mainly detected in leukemia-derived cell lines. In addition, HLA-E was
      detected in tumor cell lines of different origin. This expression was related
      with the availability of free beta(2)-microglobulin (beta(2)m) in the cytoplasm
      of tumor cells. Expression was detected in tumor cell lines showing an imbalance
      in heavy chain/beta(2)m expression, particularly in tumor cell lines with
      alterations in the expression of heavy-chain genes. Several lines of evidence
      favor these conclusions: (1) In the FM55 and NW145 melanoma tumor systems, the
      reduction in HLA class Ia expression paralleled the increased cell surface
      detection of HLA-E. (2) A cervical tumor (808) and a melanoma cell line (R22.2)
      expressing a single HLA-A1 allele also expressed HLA-E. (3) The addition of human
      beta(2)m to tumor cell lines that expressed the HLA-E(G) allele increased HLA-E
      cell surface expression. (4) There was no HLA-E cell surface expression in tumor
      cell lines with total loss of HLA class Ia expression, including cell lines with
      low transcription of HLA class I heavy chains or with beta(2)m mutations. Our
      findings suggest that the biological consequences of these cumulative genetic and
      molecular changes in tumor cells lead to the appearance of HLA-E in a limited
      number of tumor cell lines with peculiar phenotypic and genotypic
      characteristics, namely: HLA-class Ia downregulation, free beta(2)m and HLA-E(G)
      genotype. The aberrant HLA-E expression might be of particular biological
      relevance in those HLA tumor phenotypes that express a single HLA-A allele when
      NK inhibition is markedly reduced due to the downregulation of HLA-B and -C
      alleles.

PMID- 12618910
TI  - The CD1d natural killer T-cell antigen presentation pathway is highly conserved
      between humans and rhesus macaques.
AB  - Natural killer T (NKT) cells play an important role in controlling cancers,
      infectious diseases and autoimmune diseases. Although the rhesus macaque is a
      useful primate model for many human diseases such as infectious and autoimmune
      diseases, little is known about their NKT cells. We analyzed V alpha 24TCR+ T
      cells from rhesus macaque peripheral blood mononuclear cells stimulated with
      alpha-galactosylceramide (alpha-GalCer) and interleukin-2. We found that rhesus
      macaques possess V alpha 24TCR+ T cells, suggesting that recognition of alpha
      GalCer is highly conserved between rhesus macaques and humans. The amino acid
      sequences of the V-J junction for the V alpha 24TCR of rhesus macaque and human
      NKT cells are highly conserved (93% similarity), and the CD1d alpha1-alpha2
      domains of both species are highly homologous (95.6%). These findings indicate
      that the rhesus macaque is a useful primate model for understanding the
      contribution of NKT cells to the control of human diseases.

PMID- 12618911
TI  - Identification of the mouse killer immunoglobulin-like receptor-like (Kirl) gene
      family mapping to chromosome X.
AB  - Natural killer (NK) inhibitory receptors, which recognize major
      histocompatability complex (MHC) proteins in humans, are known as killer Ig-like
      receptors (KIRs) and are encoded by a multi-gene immunoglobulin (Ig) superfamily.
      In a screen for genes differentially expressed in the mouse thymus, we discovered
      the first close rodent homologue of the NK receptor KIR family, which we named
      KIR- Like (Kirl). KIRL1 shares 40% amino acid identity with primate KIR family
      members, with the majority of the homology contained within the Ig-like
      ectodomains. KIRL1 is more similar to the KIRs than to any other known member of
      the Ig domain-containing leukocyte receptor superfamily. This highly significant
      homology suggests that the KIR family did not arise independently in primates, as
      has been previously suggested, but rather evolved from a primordial gene already
      present in the common rodent/primate ancestor. KIRL1 lacks the cytoplasmic
      protein motifs that mediate inhibition in KIRs (immunoregulatory tyrosine
      inhibiting motif, ITIM); KIRL1 also lacks the transmembrane activation signature
      (a conserved K residue involved in association with the immunoregulatory tyrosine
      activating motif-containing DAP12 molecule) found in some KIRs. Nevertheless, we
      hypothesize that Kirl1 is functional, for the following reasons: (1) Kirl1 mRNA
      is expressed at high levels in immature thymocytes; (2) Kirl1 is regulated during
      thymocyte development; (3) KIRL1 protein is detected in thymus. We also show that
      the mouse genome contains a closely related, transcribed gene, which we name
      Kirl2. Kirl2 encodes a KIR-like molecule with three Ig-like domains and also
      lacks tyrosine-based immunoregulatory motifs in its cytoplasmic region.

PMID- 12618912
TI  - Prediction of the prototype of the human Toll-like receptor gene family from the
      pufferfish, Fugu rubripes, genome.
AB  - The insect Toll family of proteins and their mammalian counterparts seemingly
      shared one common ancestor and evolved independently. Here we demonstrated that
      the prototype of the mammalian-type (M-type) Toll family is shared by the fish
      and humans. According to the draft of the pufferfish Fugu genome project, the
      signature Toll-IL-1 receptor homology domain (TIR domain) has been conserved
      during evolution. FuguTLR2, 3, 5, 7, 8 and 9 members correspond structurally to
      respective mammalian TLRs. One Fugu TLR showed equally high amino acid identity
      to human TLR1, 6 and 10, and we named it FuguTLR1. Fugu rubripes has genes for
      TLR21 and 22, which are unique to fish. One possible interpretation of these
      findings is that TLR1, 2, 3, 4, 5, 7, 8, 9, 21 and 22 existed in the ancestral
      genome common to fish and mammals, and that TLR4 was lost in the fish lineage,
      while TLR21 and 22 were lost in the mammalian lineage. Strikingly, a solitary
      ascidian, Halocynthia roretzi, has only a few Toll-like proteins, which, like
      Caenorhabditis elegans Toll, represent primitive ones before the expansion of the
      Toll family. Therefore, the expansion of TLR genes should have occurred earlier
      than fish, but not C. intestinalis, separated evolutionarily from mammals. These
      results infer that the appearance of the M-type innate system was completed
      before or concomitant with the appearance of acquired immunity. We interpret the
      present data to mean that the differences of TLRs identified in this study
      between fishes and humans may be rather peripheral, partially due to selection
      pressure exerted by pathogens in distinct environments.

PMID- 12618913
TI  - Molecular cloning of the complement regulatory factor I isotypes from the common
      carp (Cyprinus carpio).
AB  - Factor I is a novel serine protease that regulates complement activation. Here we
      report the complete primary structure of two isotypic factor Is isolated from the
      common carp ( Cyprinus carpio), a pseudotetraploid teleost. A carp hepatopancreas
      cDNA library was screened using two RT-PCR-amplified cDNA fragments encoding part
      of the carp factor I-like serine protease domain. Two distinct cDNA clones,
      designated FI-A and FI-B, were isolated. Their deduced amino acid sequences share
      75.2% identity with each other. FI-A has a typical factor I-like domain
      organization composed of two disulfide-linked polypeptides (H-chain and L-chain).
      On the other hand, FI-B contains a novel sequence of 115 amino acids inserted at
      the N-terminus of the H-chain. Genomic Southern hybridization suggests that FI-A
      and FI-B are encoded by distinct genes in the carp genome. Expression analysis by
      RT-PCR revealed that the major site of FI-A expression is the ovary, whereas FI-B
      expression is detected mainly in the hepatopancreas at a level higher than that
      of FI-A. The present data, taken together, suggest that carp have duplicated
      genes coding for factor I, and FI-B with the novel insertion plays a dominant
      role in the complement system. In addition, homology search of the fugu genome
      database using the carp FI-A and FI-B sequences identified a putative fugu factor
      I gene, which has an exon/intron organization different from that of the human
      orthologue.

PMID- 12618914
TI  - The complement component C5 of the common carp (Cyprinus carpio): cDNA cloning of
      two distinct isotypes that differ in a functional site.
AB  - The complement component C5 plays important roles in inflammatory responses and
      complement-mediated cytolysis. In bony fish, although C5 has been identified at
      the DNA or the protein level in trout, carp and gilthead seabream, only partial
      C5 sequences are available. The present study was designed to obtain the complete
      primary structure of C5 from the common carp ( Cyprinus carpio) and to examine
      its possible structural diversity. Reverse-transcribed polymerase chain reaction
      amplification from carp hepatopancreatic RNA resulted in isolation of six
      distinct C5-like cDNA segments, which were grouped into two divergent types (type
      I and type II). Using two sequences representative of the two types as probes,
      two distinct full-length cDNA clones (C5-1 and C5-2) were isolated, in addition
      to a truncated isoform of C5-1 (C5-1'). The deduced amino acid sequences of C5-1
      and C5-2 share 83% identity and predict a typical two-chain structure of the
      mature protein that lacks the thioester bond, as in C5 from other animals.
      Southern hybridization of genomic DNA suggested the presence of multiple genes
      encoding C5-type I and a single gene encoding C5-type II. Interestingly, carp C5
      type I contains novel subtypes like C5-1 that have a histidine instead of the
      well-conserved arginine at the cleavage site for the C5 convertase, both in the
      complete and truncated forms. Northern blotting analysis suggested that C5-type I
      and C5-type II are mainly expressed in hepatopancreas, and the expression levels
      are significantly increased by stimulating carp with lipopolysaccharide or beta
      1,3-glucan. Possible functional divergence among the C5 isotypes in carp is
      discussed.

PMID- 12618915
TI  - The soya isoflavone content of rat diet can increase anxiety and stress hormone
      release in the male rat.
AB  - RATIONALE: Most commercial rodent diets are formulated with soya protein and
      therefore contain soya isoflavones. Isoflavones form one of the main classes of
      phytoestrogens and have been found to exert both oestrogenic and anti-oestrogenic
      effects on the central nervous system. The effects have not been limited to
      reproductive behaviour, but include effects on learning and anxiety and actions
      on the hypothalamo-pituitary axis. It is therefore possible that the soya content
      of diet could have significant effects on brain and behaviour and be an important
      source of between-laboratory variability. OBJECTIVES: To determine whether
      behaviour in two animal tests of anxiety, and stress hormone production, would
      differ between rats that were fed a diet which was free of soya isoflavones and
      other phytoestrogens (iso-free) and those that were fed a diet which contained
      150 microg/g of the isoflavones genistein and daidzein (iso-150). This controlled
      diet has an isoflavone concentration similar to that in the maintenance diet
      routinely used in our institution. METHODS: Male rats were randomly allocated to
      the iso-free and iso-150 diets and their body weights and food and water
      consumption were recorded for 14 days. They were then maintained on the same
      diets, but housed singly for 4 days, before testing in the social interaction and
      elevated plus-maze tests of anxiety. Corticosterone concentrations in both
      dietary groups were determined under basal conditions and after the stress of the
      two tests of anxiety. Vasopressin and oxytocin concentrations were determined
      after brief handling stress. RESULTS: The groups did not differ in food or water
      intake, body weight or oxytocin concentrations. Compared with the rats fed the
      iso-free diet, the rats fed the iso-150 diet spent significantly less time in
      active social interaction and made a significantly lower percentage of entries
      onto the open arms of the plus-maze, indicating anxiogenic effects in both animal
      tests. The groups did not differ in their basal corticosterone concentrations,
      but the iso-150 group had significantly elevated stress-induced corticosterone
      concentrations. Stress-induced plasma vasopressin concentrations were also
      significantly elevated in the iso-150 diet group compared with the iso-free rats.
      CONCLUSIONS: Major changes in behavioural measures of anxiety and in stress
      hormones can result from the soya isoflavone content of rat diet. These changes
      are as striking as those seen following drug administration and could form an
      important source of variation between laboratories.

PMID- 12618916
TI  - Reversal of visual attention dysfunction after AMPA lesions of the nucleus
      basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a
      5-HT1A receptor antagonist WAY 100635.
AB  - RATIONALE: Degeneration of the cholinergic magnocellular neurons in the basal
      forebrain and their cortical projections is a major feature of the neuropathology
      of Alzheimer's disease (AD). In addition to memory dysfunction, attentional
      functions are also impaired in AD. OBJECTIVE: We investigated the extent to which
      the cholinesterase inhibitor donepezil reversed the attentional performance
      deficit in nucleus basalis magnocellularis (NBM) lesioned rats. We also examined
      the effects of a selective and potent 5-HT(1A) receptor antagonist, WAY 100635,
      on the attentional deficit of NBM lesioned rats. METHODS: We injected alpha-amino
      3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the NBM to selectively
      destroy cholinergic neurons projecting to the neocortex. Attentional functions
      were examined using the 5-CSRT task, in which hungry rats were required to locate
      brief visual targets presented randomly in one of five locations in a specially
      designed chamber. RESULTS. AMPA lesions of the NBM caused marked reductions in
      choline acetyltransferase activity (ChAT) ranging from 30 to 46% in medial areas
      of the cortex (medial-frontal and cingulate) and from 58 to 72% in more lateral
      areas (anterior-dorso-lateral and parietal). AMPA lesioned rats made fewer
      correct responses (choice accuracy), longer latency to correct response and an
      increase in the number of premature and perseverative responses. These
      impairments showed some recovery over the next 12 weeks. Reducing the duration of
      the visual stimulus reinstated the impairments in choice accuracy. The
      anticholinesterase inhibitor donepezil at 1.0 mg/kg but not 0.5 mg/kg reversed
      the impairments in choice accuracy and correct response latency. The premature
      and perseverative over-responding of AMPA lesioned rats remained unchanged. A
      dose of 0.1 mg/kg WAY 100635 to AMPA-lesioned rats improved their choice accuracy
      but did not shorten correct response latencies. The number of premature responses
      was reduced by WAY 100635 but perseverative over-responding was not affected.
      CONCLUSIONS: The attentional impairments induced due to cortical cholinergic
      dysfunction may be ameliorated by cholinergic treatments such as cholinesterase
      inhibitors. In addition, 5-HT(1A) receptors and the cortical cholinergic system
      exert balanced opposition in regulating attentional performance in the rat.
      Blockade of 5-HT(1A) receptors may be useful to treat some aspects of attentional
      dysfunction in AD.

PMID- 12618917
TI  - Evaluation of health-related quality of life using the MOS 36-Item Short-Form
      Health Status Survey in patients receiving noninvasive positive pressure
      ventilation.
AB  - OBJECTIVE: To collect benchmark data on the MOS 36-Item Short-Form Health Status
      Survey (SF-36) in patients receiving noninvasive positive pressure ventilation
      and to examine whether health-related quality of life is influenced by the
      underlying disease or by physical parameters. DESIGN AND SETTING: Multicentric
      clinical cross-sectional trial in four general wards specialized in noninvasive
      positive pressure ventilation. PATIENTS AND PARTICIPANTS: 226 patients (78
      chronic obstructive pulmonary disease, 57 kyphoscoliosis, 20 posttuberculosis
      sequelae, 17 Duchenne muscular dystrophy, 13 polyneuropathy, 13 myopathy, 6
      amyotrophic lateral sclerosis, 12 obesity-hypoventilation syndrome, 4
      poliomyelitis sequelae, 3 phrenic nerve lesion, 3 central hypoventilation
      syndrome) who used noninvasive positive pressure ventilation for home mechanical
      ventilation. MEASUREMENTS AND RESULTS: Health-related quality of life as assessed
      by the SF-36 was lower than in the general population. Overall the Physical
      Component Summary (PCS) was significantly lower than the general population norm;
      the Mental Component Summary (MCS) was also reduced but less markedly. Patients
      with chronic obstructive pulmonary disease were more impaired in MCS than those
      with kyphoscoliosis. PCS was significantly associated with age. Gender, lung
      function, and arterial blood gas values were not significant predictors of health
      related quality of life. CONCLUSIONS: Benchmark SF-36 data in patients receiving
      noninvasive positive pressure ventilation are given. Although physical health is
      significantly impaired in these patients, this does not necessarily lead to
      mental limitation, and mental health is influenced by the underlying disease, but
      not by physical parameters.

PMID- 12618920
TI  - Cannabinoids in supportive care: are they necessary?

PMID- 12618918
TI  - Nasal carriage of Staphylococcus aureus on admission to intensive care: incidence
      and prognostic significance.
AB  - We retrospectively studied the prevalence of the nasal carriage of methicillin
      sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus
      aureus (MRSA) on admission to a medical surgical intensive care unit (ICU). We
      also compared the intensive care survival of MSSA carriers with non-carriers.
      Records of 678 patients admitted over a 24-month period were retrospectively
      reviewed. Nasal swabs were taken from 565 patients on admission to the ICU. MSSA
      was isolated from the anterior nares of 126 (22%) patients, MRSA was isolated in
      16 (3%) patients and 423 (75%) patients had no nasal carriage identified. MSSA
      carriers were more likely to have been admitted to the ICU after less than 24 h
      hospital stay (28% non-carriers, 44% MSSA carriers) and were significantly
      younger (mean age of 50 years) than non-carriers (mean age 55 years). The median
      survival (with confidence intervals (CI)) was 29 days (CI 14-44) in non-carriers,
      16 days (CI 10-22) in MSSA carriers and 6 days (CI 4-8) for the MRSA carriers.
      This difference was significant when MSSA carriers were compared with non
      carriers ( p=0.003). The ICU mortality was also significantly higher ( p=0.004)
      in MSSA carriers (88 of the 423 (21%) non-carriers and 40 of 126 (32%) MSSA
      carriers died prior to ICU discharge).

PMID- 12618921
TI  - Progress in central venous access?

PMID- 12618922
TI  - Established and potential therapeutic applications of cannabinoids in oncology.
AB  - Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis
      sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids
      are the active compounds extracted from cannabis. Recently, there has been
      renewed interest in cannabinoids for medicinal purposes. The two proven
      indications for the use of the synthetic cannabinoid (dronabinol) are
      chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other
      possible effects that may prove beneficial in the oncology population include
      analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of
      insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected.
      CB1 receptors are expressed mainly in the central and peripheral nervous system.
      CB2 receptors are found in certain nonneuronal tissues, particularly in the
      immune cells. Recent discovery of both the cannabinoid receptors and
      endocannabinoids has opened a new era in research on the pharmaceutical
      applications of cannabinoids. The use of cannabinoids should be continued in the
      areas indicated, and further studies are needed to evaluate other potential uses
      in clinical oncology.

PMID- 12618923
TI  - Managing taxane toxicities.
AB  - The two commercially available taxanes (paclitaxel and docetaxel) are widely
      employed in standard oncologic practice. Toxicity of the agents includes bone
      marrow suppression (principally neutropenia), complete alopecia, and
      hypersensitivity reactions. While both drugs can cause neurotoxicity and
      myalgias/arthralgias, this is a greater clinical concern with paclitaxel.
      Docetaxel can be associated with the development of significant fluid retention
      (e.g., edema, ascites, pleural effusions), the incidence and severity of which
      appear to be limited by prophylactic treatment with corticosteroids both before
      and after each treatment. If patients are monitored closely (e.g., for
      hypersensitivity reactions, bone marrow suppression) the taxanes have a favorable
      side effect profile, and it is currently uncommon for treatment to be
      discontinued because of the development of excessive toxicity.

PMID- 12618924
TI  - Evaluation of an ultrasound-guided technique for central venous access via the
      internal jugular vein in 493 patients.
AB  - Ultrasound guidance for percutaneous puncture of the internal jugular vein
      provides many advantages over the classic landmark-guided technique, particularly
      in complicated cases (e.g. thrombocytopenia, obesity, dyspnea). The present
      prospective investigation involved analysis of 493 punctures and provides patient
      and operator-dependent variables with respect to the impact on puncture success
      and the complication rate. These 493 punctures of the internal jugular vein were
      performed using identical puncturing equipment and a standardized two-operator
      catheterization technique and were prospectively recorded on the hematology
      oncology ward of a university hospital. Alongside success rates, the frequency
      and nature of complications, patient-inherent risk variables (obesity,
      thrombocytopenia, patient cooperation, vein diameter, etc.) and the individual
      experience of the physician performing the puncture and ultrasound were analyzed
      with respect to possible impact on success and complication rate. Internal
      jugular vein cannulation was successful in 94.5% of all patients. Catheter
      placement was successful at the first attempt in 87.6% of cases. Arterial fail
      punctures occurred in 1.4% of the patients and local hematoma in a further 4.3%.
      Among the patient-dependent variables, only poor patient compliance and a maximum
      vein diameter smaller than 7 mm showed a negative influence on the success rate.
      The experience of the physician carrying out the puncture influenced neither the
      success rate nor the complication rate. In contrast, both failure and
      complication rates were significantly lower when the physician guiding the
      sonographic probe was familiar with the method. Ultrasound-guided cannulation of
      the internal jugular vein provides safe central venous access with high success
      rates and low complication rates. Difficulties due to patient-inherent risk
      factors (e.g. thrombocytopenia, obesity, dyspnea) can be managed well using
      ultrasonographic guidance. The success rate achieved and the frequency of
      complications are decisively influenced not by the experience of the physician
      performing the puncture, but by the experience of the physician acting as
      sonographer.

PMID- 12618925
TI  - Is delayed chemotherapy-induced emesis well managed in oncological clinical
      practice? An observational study.
AB  - Nausea and vomiting have a negative influence on the quality of life of patients
      receiving chemotherapy. The Consensus Conference held in 1997 outlined the
      therapeutic procedure to prevent delayed emesis that might otherwise be induced
      by chemotherapy. So far, no study has evaluated the correct management of delayed
      emesis in clinical practice. This study was performed in an attempt to verify the
      conformity of the delayed emesis therapy administered in some oncological centres
      with the Consensus Conference guidelines. A total of 149 patients were observed
      for a minimum of one up to a maximum of four chemotherapy cycles; analysis of the
      data took account of whether the chemotherapy had a high (HEC), moderate (MEC) or
      low (LEC) emetogenic potential. Among 42 patients who received HEC, 18 (43%)
      received antiemetic prophylaxis conforming to standards; 23 (54.7%) of these 42
      had delayed emesis, only 8 (34.7%) of whom were treated with adequate antiemetic
      protection. MEC was administered to 72 patients, 46 (64%) of whom received
      adequate prophylaxis; delayed emesis was observed in 31 (43%) of the 72 patients,
      20 (64.5%) of whom received antiemetic prophylaxis according to established
      guidelines. Of 35 patients treated with LEC, 22.8% manifested delayed emesis; a
      high percentage of these patients, 68.5%, received prophylaxis, even though it
      was unnecessary. Of all patients observed, only 50.3% received correct antiemetic
      protection. We deduce from the study that antiemetic treatment for delayed emesis
      in clinical practice needs more attention. Correct prophylaxis is necessary when
      HEC is given, and antiemetic protection for patients receiving MEC must be
      improved; among patients treated with LEC those at high risk must be identified
      so that overtreatment can be avoided.

PMID- 12618926
TI  - The patient's perspective: a qualitative study of acute myeloid leukaemia
      patients' need for information and their information-seeking behaviour.
AB  - In recent years there has been an increased focus on cancer patients' information
      needs. The majority of the studies have led to the conclusion that most patients
      want as much information as possible about their disease and treatment. These
      studies have been large survey studies, and most of the patients enrolled in them
      have been out-patients. Very little is known about the information needs of
      severely ill cancer patients being treated as in-patients-such as those with
      acute myeloid leukaemia (AML). As part of a larger study dealing with AML
      patients' illness narratives, this work describes the information needs from the
      patients' perspective and their information-seeking behaviour. In-depth
      ethnographic interviews were conducted with each of 21 patients on two occasions:
      at the time of diagnosis and again 2-5 months later. Most patients did not recall
      much information from the time of diagnosis, except the diagnosis itself and the
      feelings it had aroused in them. All patients had basic medical knowledge about
      their disease. However, many patients-especially the elderly-expressed no need to
      receive further medical details about their disease. Avoiding information, in
      particular about the prognosis, was explained as a strategy to maintain hope.
      Most patients attached more importance to information about problems affecting
      their everyday life and how other persons had coped with their illness. They did
      not seek medical information on their own, although especially younger patients
      expressed the feeling that they "ought" to do this. There was a discrepancy
      between their expressed attitudes regarding the need for medical information in
      general and their actual information-seeking behaviour. Being informed and
      seeking information are discussed as society's expectations of today's cancer
      patient.

PMID- 12618927
TI  - Changes in family relationships affect the development of chemotherapy-related
      nausea symptoms.
AB  - This study examined the effect of changes in family relationships (cohesion,
      expression, and conflict) on patients' physical adjustment to chemotherapy and
      whether the effect would differ depending on the patient's age and gender. Two
      hundred thirty-three married cancer patients completed questionnaires consisting
      of measures of family relationships and chemotherapy-related nausea symptoms, at
      two assessments. Results revealed that the prevalence of nausea symptoms was
      related to the degree of conflict in the family, depending on the patient's age
      and gender. An increase in family conflict was associated with an increased
      duration of post-treatment nausea and greater severity of anticipatory nausea for
      younger adult patients but not for older adult patients. An increase in family
      conflict was also associated with a greater severity of anticipatory nausea for
      female patients but not for male patients. These findings suggest that
      intervention programs to help reduce family conflict may be especially beneficial
      for younger adult and female patients.

PMID- 12618928
TI  - Factors related to patient's mental adjustment to breast cancer: patient
      characteristics and family functioning.
AB  - Previous studies have suggested that patients who adopted a coping response
      characterized as helplessness or hopelessness reported higher levels of
      psychological distress than patients who adopted a response characterized as
      fighting spirit. There are also studies suggesting a relationship between family
      functioning and psychological well-being of cancer patients and their family
      members. The aim of this cross-sectional study was to investigate the
      relationship between breast cancer patients' coping response to the diagnosis of
      cancer and family functioning. A total of 46 postoperative ambulatory female
      breast cancer patients and their husbands participated in this study. Patients
      and husbands completed the Family Assessment Device (FAD), and patients also
      completed the Mental Adjustment to Cancer (MAC) scale. They filled in these self
      report questionnaires at home. The results of multiple regression analysis showed
      that patients' perception of poor family functioning in the area of Communication
      measured by the FAD correlated with high Helplessness/Hopelessness score of the
      MAC, whereas high education in the patients was correlated with low Fighting
      Spirit score on the MAC. The results suggested a link between a patient's
      attitude of helplessness or hopelessness in the face of cancer and inappropriate
      communication among family members. Consequently, health care professionals
      should devote attention not only to the patient but also to other family members
      and intervene to promote appropriate communication patterns among the family
      members.

PMID- 12618929
TI  - Psychosocial correlates of paediatric cancer in the United Arab Emirates.
AB  - To study the psychosocial factors and illness variables associated with
      children's and parents' perceptions of and ways of coping with cancer, in 38
      childhood cancer patients aged 5-15 years, coping was studied in relation to
      sociodemographic variables and self-perception in terms of competence, behaviour
      and self-worth. Less optimal coping was found to be associated with poor family
      communications and lack of sharing/expression of emotions ( P=0.005), presence of
      behavioural and emotional problems in the child ( P=0.008) and parental lack of
      hope ( P=0.001). No association was found with gender, parental education or
      occupation, socioeconomic status, or child's self-perception including global
      estimation of self-worth. Furthermore, none of the illness variables was found to
      be associated with coping. Awareness about health-related issues was found to be
      strongly associated with parental education ( P=0.000). Our findings suggest that
      parental hope and both social and family communication are integral to helping
      patients and families cope with the illness experience.

PMID- 12618930
TI  - Long-term central venous catheterization via persistent left superior vena cava:
      a case report.
AB  - We report a case of a cancer patient who displayed a persistent left superior
      vena cava (PLSVC) after implantation of a central venous catheter (Port-a-Cath),
      as revealed by angiography. This anomaly is rather rare (0.3% of healthy
      individuals), and the few studies on the long-term maintenance of an implant in
      situ are not very informative. Nevertheless, based on the acceptable venous
      caliber and the patient's serious clinical situation, we decided to leave the
      catheter in place and perform infusional chemotherapy and supportive therapy with
      careful and continuous control. The patient died after 8 months of this therapy.
      No complications attributable to the catheter were observed. We think that the
      risk is acceptable in similar conditions.

PMID- 12618932
TI  - The clinical spectrum of band erosion following laparoscopic adjustable silicone
      gastric banding for morbid obesity.
AB  - BACKGROUND: Morbid obesity is effectively treated by restrictive surgery. A
      severe complication associated with gastric banding is gastric erosion. We review
      here our experience over a 5-year period. METHODS: A total of 1496 patients
      underwent gastric banding. Eighty-five percent of patients were available for
      follow-up. When band erosion was diagnosed, laparoscopic removal was performed.
      RESULTS: Band erosion was identified in 17 patients (1.13%). The time from
      primary operation to diagnosis of band erosion ranged from 3 weeks to 45 months
      (mean, 19 months). Clinical manifestations included weight gain in 2 (11.6%),
      band system leak in 1 (5.8%), chronic port-cutaneous fistula in 2 (11.6%),
      neglected peritonitis in 1 (5.8%), left subphrenic abscess in 2 (11.6%), but most
      commonly, protracted port-site infection that occurred in 7 patients (40.6%).
      CONCLUSIONS: Patients were effectively treated by band removal and suturing of
      the stomach wall. We suggest that different pathologies contribute to the same
      complication depending upon the time of presentation. We recommend a high index
      of suspicion in order to diagnose this life-threatening complication.

PMID- 12618933
TI  - Gasless laparoscopic surgery for ulcerative colitis and familial adenomatous
      polyposis:initial experience of 7 cases.
AB  - PURPOSE: We evaluated the data on initial experience of gasless laparoscopic
      surgery for patients with ulcerative colitis (UC) and familial adenomatous
      polyposis (FAP). PATIENTS AND METHODS: Seven patients (male/female = 3:4, median
      age 23, UC/FAP=5:2) underwent gasless laparoscopic total (procto) colectomy. Our
      basic surgical procedure involved (1) a 6- to 8-cm incision made at the beginning
      of the operation, (2) the wound pulled upward and/or laterally by retractors, and
      (3) conventional surgical instruments used through the wound; occasionally
      laparoscopic assistance and abdominal lifting were employed. The results were
      compared to those of 7 patients who had undergone conventional open surgery.
      RESULTS: Oral intake started earlier (p = 0.03) and C-reactive protein level on
      POD 4 was lower (p = 0.03) in the gasless group than in the control group.
      Duration of surgery, blood loss, requirement of analgesia, and morbidity rate
      were not significantly different between the groups. CONCLUSION: Our preliminary
      results suggest that gasless laparoscopic surgery for UC and FAP is feasible and
      can be an alternative method for minimally invasive surgery.

PMID- 12618931
TI  - 140 consecutive cases of minimally invasive, radio-guided parathyroidectomy:
      lessons learned and long-term results.
AB  - BACKGROUND: The advent of highly accurate parathyroid imaging and the ever
      increasing trend towards minimally invasive procedures have changed considerably
      the surgical approach to the patient with primary hyperparathyroidism (PHPT)
      caused by a single parathyroid adenoma. This study analyzes the short- and longer
      term results of 140 patients who underwent minimally invasive, radio-guided
      parathyroidectomy. METHODS: Demographic, clinical, and pre-operative imaging
      data, operative findings, and short- and long-term results of 140 consecutive
      patients operated within a 20 months period (8/1999-4/2002), were prospectively
      entered into a database. Immediate pre-operative sestamibi scintigraphy with skin
      marking of focal adenoma uptake were followed by intraoperative hand-held gamma
      probe for the removal of the parathyroid adenoma by unilateral minimal access
      surgery. Preoperative and surgical data were analyzed and correlated to outcomes,
      measured by success or failure to cure PHPT, associated morbidity and mortality,
      predictive value of localizing studies, and postoperative laboratory results in
      the immediate as well as long-term period. RESULTS: 140 patients, mean age: 55.1
      +/- 14.1 years (range 19-88 years), female to male ratio 94:46 with PHPT proven
      by concomitantly elevated serum calcium and parathormone (PTH) levels, with a
      single adenoma identified by sestamibi single photon emission tomography (SPECT)
      scintigraphy and high-resolution sonography, underwent minimally invasive, radio
      guided parathyroidectomy. Mean serum levels of preoperative calcium, phosphorus,
      and PTH were 11.6 +/- 0.8 mg/dL (range 9.1-14), 3.0 +/- 0.3 mg/dL, and 147.1 +/-
      94.3 pg/mL (range 68-784), respectively. Overall, in 3 out of 140 patients
      (2.1%), focused, minimally invasive surgery failed to identify and remove the
      adenoma. Positive predictive value when both localizing modalities concurred was
      99.2%. Positive predictive value of SPECT scan alone was 97.2%. Overall success
      rate was 97.8% (137/140). 24 hours postoperative mean serum calcium was 9.2 +/-
      0.8 mg/dL and at 6 months mean serum calcium, phosphorus, and PTH were 9.4 +/-
      1.06 mg/dL, 3.2 +/- 0.8 mg/dL, and 32.1 +/- 11.9 pg/mL, respectively (p =
      0.0001). There was no mortality. In 2 patients (1.4%) there was transient vocal
      cord paresis and there were 8 instances of clinically significant hypocalcemia.
      In 3 cases (2.1%), a second adenoma manifested itself 9-14 months following
      surgery and was removed by minimal access procedure. CONCLUSIONS: Minimally
      invasive, radio-guided focused parathyroidectomy for a single adenoma is safe and
      effective in curing hyperparathyroidism with a 97% success rate. A second adenoma
      occurring in less than 3% may be successfully treated with a second minimal
      access operation. The combined positive predictive value of concurring sestamibi
      SPECT scintigraphy and sonography of 99.2% may increase success rate, and thus
      implementing this technique in patients with concurring sonography and
      scintigraphy may be advocated.

PMID- 12618934
TI  - Laparoscopic antireflux surgery: disease-related quality of life assessment
      before and after surgery in GERD patients with and without Barrett's esophagus.
AB  - BACKGROUND: Several findings suggest that gastroesophageal reflux disease (GERD)
      has a significant impact on patients' quality of life. The aim of this
      prospective study was (a) to evaluate and compare quality-of-life data before and
      after laparoscopic antireflux surgery (LARS) in GERD patients with and without
      Barrett's esophagus (BE); and (b) to compare quality-of-life data of these
      patients to normative data for a comparable general population. METHODS: The
      Gastrointestinal Quality of Life Index (GIQLI) was administrated to 75 BE
      patients and to 174 patients with GERD without BE (Savary-Miller classification:
      grade 1: n = 49; grade 2: n = 69; grade 3: n = 56). The questionnaire was given
      to all patients preoperatively, 3months, 1 year, and 3 years after laparoscopic
      "floppy" Nissen fundoplication. RESULTS: Before surgery, BE patients (mean: 96.8
      +/- 9.3 points) had a better but not significant (p<0.06) general score of the
      GIQLI when compared with patients without BE (mean: 86.4 +/- 10.1 points). This
      difference is solely based on the subdimension "gastrointestinal symptoms" which
      means that GERD symptoms are less intensively and frequently recognized in BE
      patients than in patients without BE. There are no other differences in the other
      four subdimensions of the GIQLI between both groups. Three months, 1 year, and 3
      years after LARS, GIQLI was significantly (p<0.01) improved in both groups (BE
      patients mean after 3 years: 121.9 +/- 8.2 points; non-BE patients mean after 3
      years: 122.8 +/- 9.3 points). This improvement was significantly better (p<0.05)
      in patients without BE than in BE patients. Before surgery, both groups scored
      significantly below average on all subscores of GIQLI compared to general
      population (mean: 122.6 +/- 8.5 points). After surgery, there are no differences
      detectable. CONCLUSION: As our data show, non-BE patients undergoing LARS achieve
      a better quality-of-life improvement than those patients with BE. However, after
      surgery GIQLI of both groups is comparable to the mean value of general
      population. This means that LARS is able to improve quality of life significantly
      in all GERD patients, with and without BE.

PMID- 12618936
TI  - Port-site tuberculosis after laparoscopy: report of eight cases.
AB  - In light of the explosive increase in laparoscopic surgery, there is concern
      about the effectiveness of sterilizing reusable laparoscopic instruments by
      immersion in 2% glutaraldehyde. This article describes the clinical features of
      eight patients who presented with biopsy-proven tuberculosis at the port-site
      unassociated with other clinical features of tuberculosis. Three of the eight
      patients had positive cultures for Mycobacterium tuberculosis. The port-site
      sinuses healed with antituberculous chemotherapy. There is conflicting
      information in the literature regarding the effectiveness of a 20-min instrument
      soak in 2% glutaraldehyde to clear M. tuberculosis. In light of the preceding
      information, the current practice of glutaraldehyde disinfection for reusable
      laparoscopes needs to be reexamined.

PMID- 12618935
TI  - Prospective evaluation of a new self-expanding plastic stent for inoperable
      esophageal strictures.
AB  - BACKGROUND: High stent cost is considered the major drawback of self-expanding
      metal stents for dysphagia palliation in patients with inoperable esophageal
      strictures. We report our experience with a self-expanding plastic (Polyflex)
      stent, the cost of which is half that of the metal stents. METHODS: Between
      September 1999 and April 2001, 16 dysphagic patients (15 men; mean age, 69.4 +/-
      14.5 years; range, 49-100 years; mean dysphagia score, 3.31 +/- 0.6) with
      esophageal strictures who underwent Polyflex stent placement (insertion device
      diameter, 12-14 mm; postexpansion inner stent diameter, 16-21 mm; stent length,
      9, 12, and 15 cm) were studied prospectively. The strictures were caused by
      postsurgical recurrence of gastric/esophageal cancer at the anastomotic site in
      five patients, primary esophageal cancer in four patients, esophagocardia
      junction cancer in four patients, metastatic mediastinal lymph nodes from a
      primary lung cancer invading the esophagus in 1 patient, and benign peptic
      stricture in two elderly patients. All the patients were prospectively followed
      until death. RESULTS: Stent insertion was technically successful in 12 patients
      (75%). Stent placement failed in four patients (25%) because of failure to pass
      the delivery catheter across the stricture in three patients and failure of the
      stent to open in one patient. Early and late stent migration occurred in two
      patients and 1 patient, respectively. Tumor overgrowth occurred in 1 patient. The
      mean dysphagia score 7 days after stent placement was 1.1 +/- 0.9. Mean survival
      was 100.6 +/- 71.2 days (range, 8-225 days). CONCLUSION: Self-expanding Polyflex
      stents are safe and effective for inoperable esophageal strictures and have an
      acceptable technical success rate. Further experience, better selection criteria,
      and design improvements should improve results.

PMID- 12618937
TI  - Age and type of procedure influence the choice of patients for laparoscopic
      colectomy.
AB  - BACKGROUND: The aim of this retrospective, case-matched controlled study was to
      determine the benefit of laparoscopic-assisted colectomy (LC) for the elderly
      (>75 years of age) and the young (<75 years of age) compared to an open colectomy
      (OC) control group. METHODS: A retrospective review of 39 patients older than 75
      years of age and 38 patients younger than 75 years of age who underwent LC for
      colorectal cancer between 1991 and 1999 was performed. LC patients were matched
      with an open control group for procedure, age, gender, year of procedure, and
      surgeon. Procedures included right and left colectomy, anterior resection of the
      rectosigmoid, and abdominoperineal resection. Measured intraoperative variables
      included anesthesia time, operative time, and estimated blood loss. Postoperative
      parameters consisted of duration of intravenous or epidural narcotic usage,
      return of bowel function (RBF), length of stay, and independence at discharge.
      These variables were compared in the entire group of 154 patients. RESULTS: Mean
      ages were 81.4 and 81.8 years for LC and OC age >75 and 62.9 and 62.7 for LC and
      OC age <75. Mean anesthesia time and operative time were significantly longer (p
      < 0.05) for LC compared to OC (46.8 vs 39.3 and 159.3 vs 111.7 min, respectively)
      for age >75 and for age <75 (47.1 vs 40.3 and 182.8 vs 135.5 min, respectively).
      LC achieved faster recovery in both age groups: RBF (3.9 vs 4.9 days for age >75;
      6.7 vs 7.7 days for age <75) (p < 0.05). Narcotic usage was shorter for the LC
      group age <75 (3.3 vs 4.4 days; p < 0.05). There was no significant difference in
      independence at discharge between LC and OC in either age group. Faster recovery
      was seen with left LC in age >75 and right LC in age <75 compared to OC.
      CONCLUSION: The advantages of LC over OC are the same for the elderly and the
      young. There may be a selective benefit of laparoscopic left colectomy in the
      elderly and laparoscopic right colectomy in the young.

PMID- 12618938
TI  - The percentage of CD31+ T cells decreases after open but not laparoscopic
      surgery.
AB  - BACKGROUND: Efficient killing of tumor cells depends on T cells that migrate from
      the circulation to the peripheral tissues; these cells express CD31. This study
      was undertaken to determine the impact of open (OS) and laparoscopic (LS)
      colorectal surgery on the percentage of circulating CD3+CD31+ cells. METHODS:
      Peripheral blood was collected from 27 OS and 24 LS colon cancer patients
      preoperatively (preOP) and on postoperative days 1 (POD1) and 3 (POD3). CD31+ T
      cells were assessed by flow cytometry using monoclonal antibodies. RESULTS: In
      the OS group, the percentage of CD3+CD31+ cells was significantly lower in POD1
      and POD3 samples compared to the preOP results. LS surgery did not result in a
      significant change in the percentage of these T cells. A significant correlation
      was found between the decrease in the percentage of CD3+CD31+ cells and the
      length of incision in OS patients. CONCLUSIONS: The percentage of CD3+CD31+ cells
      decreases following OS but not LS and may be related to incision length. This may
      compromise T cell function in the peripheral tissues in the postoperative period.

PMID- 12618939
TI  - Intraabdominal abscess following open and laparoscopic appendectomy in the
      pediatric population.
AB  - BACKGROUND: Studies comparing intraabdominal abscess (IAA) rates following
      laparoscopic appendectomy (LA) and open appendectomy (OA) have shown conflicting
      results. METHODS: The charts of 324 children undergoing appendectomy were
      reviewed retrospectively to examine the incidence of IAA. RESULTS: Of the 324
      appendectomies, 204 (63.0%) were completed laparoscopically and 119 (36.7%) were
      performed open. The conversion rate was 0.2% (1/324). Of the 15 (4.6%) IAAs, 7
      occurred in the LA group (3.4%) and 8 occurred in the OA group (6.7%) [p = not
      significant (NS)]. The incidence of IAA for perforated appendicitis for LA was
      15% (7/46) and that for OA was 10% (7/70) (p = NS). CONCLUSION: This study
      demonstrates no statistically significant difference in the rate of IAA among
      children following LA and OA. LA can be performed for perforated appendicitis
      without increasing the risk of IAA.

PMID- 12618941
TI  - Role of endoscopic retrograde cholangiopancreatography in the management of
      suspected choledocholithiasis.
AB  - BACKGROUND: Indications for endoscopic retrograde cholangiopancreatography (ERCP)
      are not precisely defined. With the increasing availability of magnetic resonance
      cholangiopancreatography (MRCP) and several prospective studies proving the
      accuracy of this modality, it is important to select appropriate criteria for
      invasive testing when common bile duct (CBD) pathology is suspected. METHODS: We
      reviewed 200 consecutive ERCPs performed for jaundice, pancreatitis, noninvasive
      visualization of CBD stones, radiologic evidence of CBD dilatation, elevated
      liver function tests, or biliary colic. Diagnostic and therapeutic yields are
      determined for each indication and various combinations thereof. RESULTS: Of the
      180 ERCPs performed for suspected choledocholithiasis, 97 (53.8%) were performed
      for multiple indications, whereas 83 (46.2%) were performed for only one
      indication. One hundred two patients (56.6%) had CBD pathology, whereas 78
      explorations (43.4%) were negative. If multiple indications for ERCP were
      present, the diagnostic yield was 85.6%. When there was only one indication, the
      diagnostic yield decreased to 25.3%. CONCLUSIONS: ERCP is an invasive procedure
      with significant morbidity that should be used selectively. MRCP may be a more
      appropriate initial evaluation of suspected CBD pathology in many patients.

PMID- 12618940
TI  - Clinical predictors of leak after laparoscopic Roux-en-Y gastric bypass for
      morbid obesity.
AB  - BACKGROUND: Gastrointestinal leak is a complication of laparoscopic Roux-en-Y
      gastric bypass (LRYGB). Contrast studies may underdiagnose leaks, forcing
      surgeons to rely solely on clinical data. This study was designed to evaluate
      various clinical signs for detecting leakage after LRYGB. METHODS: We
      retrospectively reviewed 210 consecutive patients who underwent LRYGB between
      April 1999 and September 2001. There were nine documented leaks (4.3%). Clinical
      signs between patients with leaks (group 1) and those without leaks (group 2)
      were compared using univariate and multivariate logistic regression analysis.
      RESULTS: Evidence of respiratory distress and a heart rate exceeding 120 beats
      per min were the two most sensitive indicators of gastrointestinal leak. Routine
      upper gastrointestinal contrast imaging detected only two of nine leaks (22%).
      CONCLUSION: Leak after LRYGB may be difficult to detect. Evidence of respiratory
      distress and tachycardia exceeding 120 beats per min may be the most useful
      clinical indicators of leak after laparoscopic Roux-en-Y gastric bypass.

PMID- 12618942
TI  - Laparoscopic distal gastrectomy with regional lymph node dissection for gastric
      cancer.
AB  - Recently, a minimally invasive operation for gastric malignancies has been
      advocated, and the laparoscopic operation is noted as a technique that increases
      the quality of life. We performed distal gastrectomy with regional lymph node
      dissection on 160 cases of gastric cancer located in the middle or lower third of
      the stomach. In 123 cases, Billroth I reconstruction was performed
      intracorporeally using the quadrilateral (square) stapling technique with a
      laparoscopic linear stapling device to prevent postoperative anastomotic bleeding
      and stenosis. In the remaining 37 cases, the Billroth II method was performed
      with a linear stapling device [1]. This technique is not only less invasive but
      also as safe as open gastrectomy, which was performed on 100 gastric cancer cases
      of similar staging.

PMID- 12618943
TI  - The quality of information about laparoscopic bariatric surgery on the Internet.
AB  - BACKGROUND: Although easy access to the Internet can provide much information for
      patients, the quality and accuracy of information are uncertain. This
      investigation evaluated information concerning laparoscopic bariatric surgery
      available via the Internet. METHODS: Searches on the six most popular search
      engines and two metasearch engines were performed. The first 20 "hits" for each
      separate search were included in the study. RESULTS: A total of 602 "hits" were
      found. Only 119 unique Web sites were found. Although 63 of the 119 sites
      discussed some procedure related to laparoscopic obesity surgery, 18 of the 63
      had biased or misleading information, 30 did not discuss the details of the
      procedure, 37 did not discuss other procedures, 30 did not discuss complications,
      37 did not discuss death as a risk, and 7 did not discuss laparoscopic procedure
      as an option. Only 89 of the original 602 "hits" led to Web sites that discussed
      laparoscopic obesity surgery, details of the procedure, and complications in an
      unbiased manner. CONCLUSIONS: A large amount of information is available via the
      Internet. However, it is difficult for the patient to identify the unbiased
      information. The Internet is not a dependable source of information for patients.

PMID- 12618945
TI  - Intraoperative localization of colorectal tumors in the early stages using a
      magnetic marking clip detector system (MMCDS).
AB  - BACKGROUND: In the laparoscopic surgical treatment of early stage colorectal
      carcinomas, intraoperative tumor site identification is often difficult. We
      developed a novel marking method using a magnetic marking clip and a modified
      magnetometer system. METHODS: We applied magnetic marking clips at the tumor site
      during preoperative colonoscopy and identified the clip site with a magnetic
      marking clip detector system (MMCDS) of our design. Eleven patients who underwent
      laparoscopic colectomy were studied. RESULTS: In a basic ex vivo study, magnetic
      bodies of more than 300 mT magnetic force were easily detected with a 100%
      detection ratio. In a clinical study, the marking site was detected in all 11
      patients. The mean length between the detected site and clip along the
      longitudinal bowel axis was 14.1 mm (SD 5.6). The mean detection time was 2.4 min
      (SD 0.2). CONCLUSION: MMCDS accurately identifies tumor sites. This method may be
      useful for tumor site identification during laparoscopic colectomy.

PMID- 12618944
TI  - Late-presenting appendicitis: a laparoscopic approach to a complicated problem.
AB  - BACKGROUND: Acute appendicitis is the most common abdominal condition
      necessitating urgent surgical intervention in the United States. The objective of
      this study was to determine if interval laparoscopic appendectomy after initial
      nonoperative treatment for late appendicitis presenting as an appendiceal mass is
      a safe alternative to immediate appendectomy. METHODS: Thirty two consecutive
      patients (aged 16-74 years) during a 5-year period presented with appendiceal
      mass. Seventeen received initial nonsurgical treatment followed by interval
      laparoscopic appendectomy (aged 16-60 years; group 1). Fifteen underwent
      immediate appendectomy (aged 16-74 years; group 2). RESULTS: All patients in the
      interval laparoscopic appendectomy group improved with initial therapy and
      underwent surgery an average of 4.9 months later. Although the operative time and
      the complication rate were similar between groups 1 and 2, the time to return to
      baseline activities was significantly less in group 1 after adjusting for age (p
      = 0.02 or less). CONCLUSIONS: Interval laparoscopic appendectomy is safe in
      patients with chronic appendicitis and allows for judicious diagnostic evaluation
      of the appendiceal mass and planned surgery under controlled conditions.

PMID- 12618946
TI  - Micropuncture cholecystectomy vs conventional laparoscopic cholecystectomy: a
      randomized controlled trial.
AB  - BACKGROUND: The aim of this study was to compare micropuncture laparoscopic
      cholecystectomy (MPLC), with three 3.3-mm cannulas and one 10-mm cannula with
      conventional laparoscopic cholecystectomy (CLC). METHODS: Patients were
      randomized to undergo either CLC or MPLC. The duration of each operative stage
      and the procedure were recorded. Interleukin-6 (IL-6), adrenocorticotropic
      hormone (ACTH), and vasopressin were sampled for 24 h. Visual analogue pain
      scores (VAPS) and analgesic consumption were recorded for 1 week. Pulmonary
      function and quality of life (EQ-5D) were monitored for 4 weeks. Statistical
      analysis was performed using the Mann-Whitney test or Fisher's exact test.
      Results are expressed as median (interquartile range). RESULTS: Forty-four
      patients entered the study, but four were excluded due to unsuspected
      choledocholithiasis (n = 3) or the need to reschedule surgery (n = 1). The groups
      were comparable in terms of age, duration of symptoms, and indications for
      surgery. Total operative time was similar (CLC, 63 [52-81] min vs MPLC 74 [58-95]
      min; p = 0.126). However, time to place the cannulas after skin incision (CLC,
      5:42 [3:45-6:37] min vs MPLC, 7:38 [5:57-10:15] min; p = 0.015) and to clip the
      cystic duct after cholangiography (CLC, 1:05 [0:40-1:35] min vs MPLC, 3:45 [2:26
      7:49] min; p <0.001) were significantly longer for MPLC. Six CLC patients and one
      MPLC patient required postoperative parenteral opiates (p = 0.04). Oral analgesic
      consumption was similar in both groups (p = 0.217). Median VAPS were lower at all
      time points for MPLC, but this finding was not significant (p = 0.431). There
      were no significant differences in postoperative stay, IL-6, ACTH or vasopressin
      responses, pulmonary function, or EQ-5D scores. CONCLUSIONS: The thinner
      instruments did not significantly increase the total duration of the procedure.
      MPLC reduced the use of parenteral analgesia postoperatively, which may prove
      beneficial for day case patients, but it did not have a significant impact on
      laboratory variables, lung function or quality of life.

PMID- 12618947
TI  - Endoscopic management of submandibular sialolithiasis.
AB  - BACKGROUND: Transoral removal and sialoadenectomy are the two main modalities of
      treatment for submandibular stones. However, missed ductal stones are not
      uncommon, and there is a risk of lingual or hypoglossal nerve injury. We
      attempted to avoid these complications by using an endoscopic technique. METHODS:
      The case notes of the patients who had undergone endoscopic removal of
      submandibular stones were studied retrospectively. The procedure was performed
      under general anesthesia. The submandibular orifice was incised by carbon dioxide
      laser, and a 3.1-mm rigid scope was inserted under direct vision with normal
      saline irrigation after dilatation. The stones were either broken down by laser
      or removed with a Dormia basket or forceps. RESULTS: A total of 13 patients
      underwent the procedure. The duration of median follow-up was 15 months. In 11
      patients, the stones were identified and removed. No stone was found in two
      patients (15.4%). There were no false negatives, since no stones were discovered
      subsequently in these two patients. One, two, three, and four stones were present
      inside the ducts in seven patients (54.6%), one patient (7.7%), two patients
      (15.4%), and one patient (7.7%), respectively. The symptoms subsided completely
      in 11 patients within 4 weeks after the procedure. Persistent swelling occurred
      in two patients. In one of them, no residual stone was revealed by CT scan. The
      other patient had a large calculus that was only partially fragmented by laser
      lithotripsy at the initial operation. No lingual nerve or hypoglossal nerve
      injury was detected in any patient. CONCLUSION: Sialoendoscopy is a safe and
      efficacious treatment for submandibular ductal stones. It reduces the incidence
      of missed stones, and nerve injury, as well as the need for sialoadenectomy.

PMID- 12618948
TI  - Totally extraperitoneal laparoendoscopic repair of lumbar hernia.
AB  - BACKGROUND: The repair of congenital and acquired lumbar hernias has remained a
      significant surgical challenge for over three centuries. Transperitoneal
      laparoendoscopic techniques have been reported that have achieved success in
      repairing these difficult hernias using a variety of synthetic mesh. Careful
      review of the surgical literature addressing the repair of lumbar hernia reveals
      that only fourteen successful cases have been reported using minimally invasive
      techniques. All of these cases elected a transperitonal approach to repair.
      Encouraged by established success in the repair of inguinal hernia using an
      extraperitoneal approach, the repair of a large inferior triangle lumbar hernia
      was attempted using overlapping synthetic mesh technique while remaining entirely
      in an extraperitoneal plane. METHODS: A seventy-eight-year-old patient presented
      for repair of a large symptomatic right lumbar hernia, one year following iliac
      bone harvest for lumbar laminectomy/fusion. Under general anesthesia, the patient
      was placed in a lateral decubitus position with lumbar roll in place. Using a
      muscle splitting dissection through the lateral abdominal musculature, a plane
      was developed bluntly between the transversalus muscle and the peritoneum. Using
      a three trocar technique, the plane was matured posteriorly, achieving an ample
      working space to identify the hernia and complete a synthetic mesh (PTFE) repair.
      RESULTS: A large inferior triangle lumbar hernia was successfully repaired using
      overlapping synthetic mesh technique while remaining entirely in an
      extraperitoneal plane. Eighteen month reevaluation including physical examination
      and computer tomographic (CT) study confirms successful repair without recurrence
      of symptoms. CONCLUSIONS: A totally extraperitoneal approach to the
      identification, mobilization, and repair of lumbar hernia can be successfully
      accomplished using established laparoendoscopic surgical techniques.

PMID- 12618957
TI  - Meetings, millions, mentors, motives.

PMID- 12618950
TI  - Recurrence after laparoscopic and open Nissen fundoplication: a comparison of the
      mechanisms of failure.
AB  - BACKGROUND: Laparoscopic Nissen fundoplication as treatment for gastroesophageal
      reflux disease (GERD) in adults has a reported recurrence rate of 2-17%. We
      investigated the rates and mechanisms of failure after laparoscopic Nissen
      fundoplication in children. METHODS: All patients who underwent a laparoscopic
      Nissen fundoplication for GERD and who subsequently required a redo Nissen were
      reviewed (n = 15). The control group consisted of the most recent 15 patients who
      developed recurrent GER after an open Nissen, fundoplication. RESULTS: Between
      1994 and 2000, laparoscopic Nissen fundoplication was performed in 179 patients.
      Fifteen patients (8.7%) underwent revision. The mechanisms of failure were
      herniation in four patients, wrap dehiscence in four, a too-short wrap in three,
      a loosened wrap in two, and other reasons in two. The reoperation was performed
      laparoscopically in five patients (33%). The failure mechanisms were different in
      the open patients: eight were due to slipped wraps; three to dehiscences; and two
      to herniations. CONCLUSION: The failure rate after laparoscopic Nissen is
      acceptably low. A redo laparoscopic Nissen can be performed safely after an
      initial laparoscopic approach.

PMID- 12618949
TI  - Influence of spastic motor disorders of the esophageal body on outcomes from
      laparoscopic antireflux surgery.
AB  - BACKGROUND: The clinical outcomes of laparoscopic antireflux surgery (LARS) in
      patients with the spectrum of nonspecific spastic esophageal motor disorders
      (NSSDs) are not known. METHODS: From a prospective database of patients
      undergoing LARS between 1997 and 2000, those with preoperative manometry at our
      institution and follow-up at ?6 months were identified. RESULTS: Of the 121
      patients, 35 had NSSDs. There were no differences in symptoms between groups
      preoperatively, but in the immediate postoperative period NSSD patients had more
      symptoms than nonspastic patients. At 18-month mean follow-up, NSSD patients
      reported significantly more heartburn (22% vs 7%), waterbrash (14% vs 4%), and
      medication usage (17% vs 5%) than nonspastic patients (p <0.05 for each). Despite
      this difference, nearly all patients reported subjective improvement
      postoperatively, and the degree of improvement was similar between groups.
      CONCLUSIONS: Patients with NSSDs are more likely to have esophageal symptoms
      following LARS than subjects without these abnormalities. However, these patients
      still experience significant improvement in preoperative symptoms.

PMID- 12618958
TI  - Ethical issues in endoscopic surgery.

PMID- 12618959
TI  - Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta
      hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B
      receptor gene.
AB  - Hydrops-ectopic calcification-"moth-eaten" (HEM) or Greenberg skeletal dysplasia
      is an autosomal recessive chondrodystrophy with a lethal course, characterized by
      fetal hydrops, short limbs, and abnormal chondro-osseous calcification. We found
      elevated levels of cholesta-8,14-dien-3beta-ol in cultured skin fibroblasts of an
      18-wk-old fetus with HEM, compatible with a deficiency of the cholesterol
      biosynthetic enzyme 3beta-hydroxysterol delta(14)-reductase. Sequence analysis of
      two candidate genes encoding putative human sterol delta(14)-reductases (TM7SF2
      and LBR) identified a homozygous 1599-1605TCTTCTA-->CTAGAAG substitution in exon
      13 of the LBR gene encoding the lamin B receptor, which results in a truncated
      protein. Functional complementation of the HEM cells by transfection with control
      LBR cDNA confirmed that LBR encoded the defective sterol delta(14)-reductase.
      Mutations in LBR recently have been reported also to cause Pelger-Huet anomaly,
      an autosomal dominant trait characterized by hypolobulated nuclei and abnormal
      chromatin structure in granulocytes. The fact that the healthy mother of the
      fetus showed hypolobulated nuclei in 60% of her granulocytes confirms that
      classic Pelger-Huet anomaly represents the heterozygous state of 3beta
      hydroxysterol delta(14)-reductase deficiency.

PMID- 12618960
TI  - Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a
      genomewide scan in the Framingham study.
AB  - There is an inverse relationship between serum bilirubin concentrations and risk
      of coronary artery disease. The strength of the association is similar to that of
      smoking, systolic blood pressure, and HDL cholesterol. We carried out a
      genomewide scan in a Framingham Heart Study. Our study sample consisted of 330
      families with 1,394 sibling pairs, 681 cousin pairs, and 89 avuncular pairs.
      Using variance-component methods, the heritability was estimated to be 49%+/-6%,
      and the genome scan demonstrated significant evidence of linkage of serum
      bilirubin to chromosome 2q, with a LOD score of 3.8 at location 243 cM. The peak
      multipoint LOD score is located 1 cM away from the uridine diphosphate
      glycosyltransferase 1 (UGT1A1) gene. UGT1A1 catalyzes the conjugation of
      bilirubin with glucuronic acid and thus enhances bilirubin elimination;
      therefore, it is an important candidate gene for serum bilirubin. Gilbert
      syndrome, a hyperbilirubinemic syndrome, has a population frequency of 2%-19% and
      is mainly due to a TA insertion at the promoter region of UGT1A1. Only one other
      region in the genome produced a multipoint LOD score >1 (LOD = 1.3). Our findings
      suggest that UGT1A1 may be a major gene controlling serum bilirubin levels in the
      population.

PMID- 12618961
TI  - Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the
      fibulin-5 (FBLN5) gene.
AB  - Inherited cutis laxa is a connective tissue disorder characterized by loose skin
      and variable internal organ involvement, resulting from paucity of elastic
      fibers. Elsewhere, frameshift mutations in the elastin gene have been reported in
      three families with autosomal dominant inheritance, and a family with autosomal
      recessive cutis laxa was recently reported to have a homozygous missense mutation
      in the fibulin-5 gene. In the present study, we analyzed the gene expression of
      elastin and fibulins 1-5 in fibroblasts from five patients with cutis laxa. One
      patient was found to express both normal (2.2 kb) and mutant (2.7 kb) fibulin-5
      mRNA transcripts. The larger transcript contains an internal duplication of 483
      nucleotides, which resulted in the synthesis and secretion of a mutant fibulin-5
      protein with four additional tandem calcium-binding epidermal growth factor-like
      motifs. The mutation arose from a 22-kb tandem gene duplication, encompassing the
      sequence from intron 4 to exon 9. No fibulin-5 or elastin mutations were detected
      in the other patients. The results demonstrate that a heterozygous mutation in
      fibulin-5 can cause cutis laxa and also suggest that fibulin-5 and elastin gene
      mutations are not the exclusive cause of the disease.

PMID- 12618964
TI  - Anatomically based health care.

PMID- 12618962
TI  - Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.
AB  - Mitochondrial (mt) impairment, particularly within complex I of the electron
      transport system, has been implicated in the pathogenesis of Parkinson disease
      (PD). More than half of mitochondrially encoded polypeptides form part of the
      reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme.
      To test the hypothesis that mtDNA variation contributes to PD expression, we
      genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European
      mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control
      subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55;
      95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90;
      P=.02) demonstrated a significant decrease in risk of PD versus individuals
      carrying the most common haplogroup, H. Furthermore, a specific SNP that defines
      these two haplogroups, 10398G, is strongly associated with this protective effect
      (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino
      acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of
      complex I. After stratification by sex, this decrease in risk appeared stronger
      in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A
      of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93;
      P=.03). Our results suggest that ND3 is an important factor in PD susceptibility
      among white individuals and could help explain the role of complex I in PD
      expression.

PMID- 12618963
TI  - Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene
      in Crohn disease.
AB  - A common haplotype spanning 250 kb in the cytokine gene cluster on chromosome
      5q31 has recently been reported to be strongly associated with Crohn disease (CD)
      in Canadian families. We have replicated this finding by both the transmission
      disequilibrium test (TDT) (P=.016) and in a case-control association study
      (P=.008) in a large European cohort of patients with CD, although the increase in
      disease risk was small (odds ratio 1.49 for homozygotes, 95% CI 1.11-2.0). No
      association was detected in families or individuals with ulcerative colitis (UC).
      Stratification of offspring with CD in the TDT sample by mutation status in the
      CD susceptibility gene CARD15 showed that the association with the 5q31 risk
      haplotype was present only in offspring with at least one of the known CARD15
      disease susceptibility alleles (P=.044). The 5q31 risk haplotype frequency was
      53.1% in unrelated individuals with CD who had one or two CARD15 mutations versus
      43.7% in control subjects (P=.0001) but was not significantly elevated in
      individuals with CD who had no CARD15 mutations (45.4%, P=.41). Kaplan-Meier
      survival analysis of age at disease onset showed a significantly earlier onset in
      homozygotes for the 5q31 risk haplotype (P=.0019). These findings suggest that
      genetic variants at the 5q31 (IBD5) locus may hasten the onset of Crohn disease
      and cooperate with CARD15 in disease causation.

PMID- 12618965
TI  - Is detection of oral and oropharyngeal squamous cancer by a dental health care
      provider associated with a lower stage at diagnosis?
AB  - PURPOSE: Stage at diagnosis is the most important prognostic indictor for oral
      and oropharyngeal squamous cell cancers (SCCs). Unfortunately, approximately 50%
      of these cancers are identified late (stage III or IV). We set out to
      examinationine the detection patterns of oral and oropharyngeal SCCs and to
      determine whether detection of these cancers by various health care providers was
      associated with a lower stage. PATIENTS AND METHODS: Data were gathered on 51
      patients with newly diagnosed oral or oropharyngeal SCC through patient interview
      and chart audit. In addition to demographic data, specific inquiry was made
      regarding the circumstances surrounding the identification of the lesion. The
      main outcome measure was tumor stage grouping based on detection source. RESULTS:
      Health care providers detecting oral and oropharyngeal SCCs during non-symptom
      driven (screening) examinations were dentists, hygienists, oral and maxillofacial
      surgeons, and, in 1 case, a denturist. All lesions detected by physicians
      occurred during a symptom-driven examination. Lesions detected during a non
      symptom-driven examination were of a statistically significant lower average
      clinical and pathologic stage (1.7 and 1.6, respectively) than lesions detected
      during a symptom-directed examination (2.6 and 2.5, respectively). Additionally,
      a dental office is the most likely source of detection of a lesion during a
      screening examination (Fisher exact test, P =.0006). Overall, patients referred
      from a dental office were of significantly lower stage than those referred from a
      medical office. Finally, patients who initially saw a regional specialist
      (dentist, oral and maxillofacial surgeon, or otolaryngologist) with symptoms
      related to their lesion were more likely to have appropriate treatment initiated
      than those who initially sought care from their primary care provider.
      CONCLUSION: Overall, detection of oral and oropharyngeal SCCs during a non
      symptom-driven examination is associated with a lower stage at diagnosis, and
      this is most likely to occur in a dental office. A regional specialist was more
      likely than a primary care provider to detect an oral or oropharyngeal SCC and
      initiate the appropriate treatment during the first visit for symptoms related to
      the lesion.

PMID- 12618966
TI  - Micro-lightguide spectrophotometry as an intraoral monitoring method in free
      vascular soft tissue flaps.
AB  - PURPOSE: The aim of this prospective study was to measure the hemoglobin oxygen
      saturation (HbO(2)%) and relative Hb concentration of free vascular soft tissue
      flaps using micro-lightguide spectrophotometry. The objective was to measure the
      normal range and topographic differences in HbO(2)% and rel. Hb conc. in tissue
      transfers before establishing this as a clinical method for monitoring perfusion
      and vitality. PATIENTS AND METHODS: In 39 patients who had received free vascular
      soft tissue flaps (34 radial forearm flaps; 8 latissimus flaps) to cover defects
      after tumor surgery, the capillary HbO(2)% in transferred tissue was measured
      spectrophotometrically preoperatively at the donor site and postoperatively up to
      the third postoperative day. On average about 500 hemoglobin spectra (200 to 800
      spectra) were measured over each 24-hour period. Additionally, the relative Hb
      concentration was determined for the individual measuring times. The measurements
      were carried out topographically on the flap base, flap center, and flap
      periphery. RESULTS: The preoperative HbO(2) values at the donor site of free soft
      tissue flaps were between 20% and 40% in all topographic regions. In the case of
      clinically successful flaps, a normal distribution of the HbO(2) values of 20% to
      80% was obtained in the immediate postoperative period, and from the second day
      on, a normal distribution of 45% to 60%. In the case of 2 flaps with partial
      necrosis, HbO(2) values of less than 10% to 15% were measured from the second
      postoperative day on. The relative Hb concentration had no influence on the
      amount of HbO(2)% measured in the transferred capillaries. In the postoperative
      phase, here was no topographic difference between the individual flap regions.
      CONCLUSIONS: As a noninvasive method, micro-lightguide spectrophotometry permits
      quantitative determination of HbO(2)% and relative Hb concentration over the
      entire surface of soft tissue flaps. In the case of partially unsuccessful flaps,
      HbO(2) values of less than 10% to 15% were measured beforehand, thus indicating
      that these HbO(2) values are not sufficient to support the vitality of the free
      tissue transfer. When combined with clinical observation, application can be
      recommended for the vitality measurement of free soft tissue flaps and permits
      more information to be obtained on topographic capillary perfusion conditions.

PMID- 12618968
TI  - Relationship between facial asymmetry and masseter reflex activity.
AB  - PURPOSE: In this study, we evaluated the tonic vibration reflex (TVR) of the
      masseter muscles in patients with facial asymmetry. SUBJECTS AND METHODS: The
      study was conducted with 10 volunteers without facial asymmetry and 12
      orthognathic patients with facial asymmetry. Subjects were seated in a chair and
      held a stimulator composed of an electric motor and an acrylic bite block between
      the upper and lower dentitions at facial midline, to elicit TVR.
      Electromyographic activity was recorded using a pair of silver electrodes affixed
      bilaterally with adhesive tape to the skin over the superficial masseter. The
      amount of mandibular deviation was measured on the frontal cephalogram. The
      reflex response was evaluated with the following: TVR index (%) = integral TVR x
      100/ integral maximum voluntary contraction (MVC), and with the TVR ratio:
      integral TVR on the high MVC side/ integral TVR on the low MVC side. RESULTS: In
      the patient group, the average TVR index on the deviated side was significantly
      higher than that on the nondeviated side. In all subjects, including the control
      and patient groups, a negative correlation between the amount of mandibular
      deviation and the side-to-side difference in TVR index was seen (r = -0.536, P
      <.05, n = 22). In addition, patients with a lower MVC on the deviated side than
      on the nondeviated side showed a significantly higher TVR ratio than did the
      control group. CONCLUSIONS: These results suggest that the difference between the
      right and left reflex responses elicited by TVR might be related to frontal
      craniofacial morphology.

PMID- 12618969
TI  - Indications to the use of condylar repositioning devices in the surgical
      treatment of dental-skeletal class III.
AB  - PURPOSE: The aim of this report was to compare the clinical and radiographic
      findings observed at the 12-month follow-up in 2 groups of 15 patients who
      underwent Le Fort I and bilateral sagittal split osteotomy for the correction of
      dental-skeletal Class III. In the first group, the condylar positioning devices
      were used, whereas in the second group, an alternative method was used for the
      intraoperative assessment of mandibular repositioning. MATERIALS AND METHODS: All
      of the patients of our study in the immediate presurgical period were without
      temporomandibular joint disorders and with a normal anatomic relationship between
      condyle and fossae. The condyle position and morphology were examined at the 12
      month follow-up through cephalometric measurements and the postsurgical findings
      in both groups were compared with those observed in the presurgical period.
      RESULTS: In all of the 30 patients in our study, no relapse or postsurgical
      temporomandibular joint disturbance was observed at the 12-month follow-up.
      Variations in condyle position of more than 2 mm or 2 degrees were not observed
      in the 15 patients treated with condylar positioning devices. Changes in condyle
      position between 2 and 4 mm and 2 degrees and 4 degrees were observed in 6 of the
      15 patients treated without the devices. CONCLUSIONS: The use of condylar
      positioning devices can be avoided in patients with dental-skeletal Class III
      without presurgical temporomandibular dysfunction. The manual positioning of the
      mandibular condyle is easier, but it requires the utmost care and an experienced
      operator.

PMID- 12618971
TI  - Botulinum toxin A: a review of 1,085 oral and maxillofacial patient treatments.
AB  - PURPOSE: Botulinum toxin A (Botox; Allergan, Inc, Irvine, CA) has been used
      safely and effectively for the management of rhytids and dynamic lines of the
      face. Much of the initial anecdotal experience with Botox has changed with
      experience and is reported by the author. PATIENTS AND METHODS: In a 56-month
      period, 439 vials of Botox were used for primarily cosmetic improvement of facial
      lines and rhytids. Four hundred seventeen patients underwent 1,085 treatment
      episodes with an estimated 17,000 injections that were tracked on a database and
      reviewed. RESULTS: Botox is a safe and effective treatment for the temporary
      improvement of facial lines and dynamic rhytids in selected anatomic regions. The
      techniques of reconstitution, storage, use, dose, and technique may not be as
      sensitive as originally described. CONCLUSION: When following minimal guidelines,
      the use of Botox for cosmetic facial applications is safe, predictable, and
      without serious complications and provides generalized patient satisfaction.

PMID- 12618970
TI  - The efficacy of azithromycin in the treatment of acute infraorbital space
      infection.
AB  - PURPOSE: In this study, we aimed to evaluate the role of azithromycin in the
      treatment of acute infraorbital space infection. MATERIALS AND METHODS: Sixty
      patients (39 men and 21 women; age range, 18 to 47 years) who had acute
      infraorbital space infection with pain, swelling, and general malaise were
      included in the study. After initial surgical therapy, patients were randomly
      allocated to receive either 500 mg azithromycin once daily for 3 days, 250 mg
      erythromycin stearate every 6 hours for 3 days, or no antibiotic. Patients were
      assessed at the time of admission and after 1, 2, 3, and 7 days. Pain, swelling,
      cervical lymphadenopathy, and sublingual temperature were assessed at each visit.
      Data were collected, and all groups were compared for differences in pain and
      swelling using the Mann-Whitney U test and for differences in lymphadenopathy and
      sublingual temperature using Fisher's exact test. RESULTS: At the time of
      admission, no 2 groups were statistically different at the.05 level in relation
      to age, gender, and presenting clinical signs or symptoms. At days 2 and 3,
      patients who received azithromycin had a significant reduction in pain (P =.002
      and P =.02, respectively) and swelling (P =.001 and P =.013, respectively)
      compared with those who received no antibiotic. At day 3, patients who received
      erythromycin had a significant reduction in pain (P =.03) and swelling (P =.046)
      compared with those who received no antibiotic. In a comparison of the patients
      who received azithromycin with those who received erythromycin, there was no
      significant difference (P >.05) in the reduction of pain at any time of the
      study. However, at day 2, patients who received azithromycin had a significantly
      greater reduction in swelling (P =.002) than those who received erythromycin. In
      relation to the percentage of the patients with cervical lymphadenopathy and
      raised sublingual temperature (>37.2 degrees C), no 2 groups were statistically
      different at any time of the study. After 3 days of treatment, patients who
      received the antibiotics were clinically improved, and all patients (n = 60
      patients) reviewed after 7 days had resolution of their clinical signs and
      symptoms. CONCLUSION: This study emphasizes the importance of surgical drainage
      and proves that both azithromycin and erythromycin are effective adjunctive
      treatments in the therapy of relatively mild odontogenic orofacial infections.

PMID- 12618972
TI  - A study of the clinical characteristics of benign trigeminal sensory neuropathy.
AB  - PURPOSE: The purpose of this study was to describe the clinical characteristics
      of a series of patients presenting with benign trigeminal sensory neuropathy.
      PATIENTS AND METHODS: We conducted a retrospective analysis of the clinical and
      pathologic characteristics of 23 patients presenting with facial numbness of
      unknown etiology. RESULTS: Patients presented with diverse medical histories but
      could be grouped into those with a connective tissue disorder, neurologic
      disease, psychologic problems, or a medical history of unknown significance. The
      age of the patient, the severity and distribution of the trigeminal neuropathy,
      and symptoms other than neuropathy closely reflected the patient's medical
      history. The majority of patients underwent magnetic resonance imaging, but the
      results did not facilitate the diagnosis of the condition or reflect the extent
      and severity of the symptoms. In 60% of patients, the symptoms remained unchanged
      during the course of the study and outcome was not influenced by medical
      treatment. CONCLUSIONS: The diagnosis and management of benign trigeminal sensory
      neuropathy remain a significant clinical challenge.

PMID- 12618973
TI  - The accuracy of video imaging prediction in soft tissue outcome after bimaxillary
      orthognathic surgery.
AB  - PURPOSE: The purpose of the present study was to evaluate the accuracy of the
      outcome in soft tissue prediction through use of a computer imaging system after
      bimaxillary orthognathic surgery. MATERIALS AND METHODS: The study sample
      consisted of 30 adults who had undergone orthognathic surgery that included the
      Wassmund and Kole procedures and optional genioplasty to correct bimaxillary
      protrusion. All the patients had lateral cephalometric radiographs and profile
      photographs taken within 6 months before surgery and at least 6 months after
      surgery. The computer-generated soft tissue image and the actual postsurgical
      profile were compared. The accuracy of this computer-generated profile image was
      evaluated. RESULTS: The results indicated that the nasal tip, soft tissue A
      point, and upper lip presented the least predicted errors in sagittal plane.
      While the nasal tip presented higher reliability. Lower lip prediction was found
      to be the least accurate region and it tended to be located anterior to the
      actual position. In the vertical plane, most of the predictions revealed higher
      accuracy than those in the sagittal plane. There were no statistically
      significant differences between the predictions of the groups with and those
      without genioplasty. CONCLUSIONS: Computer-generated image prediction was
      suitable for patient education and communication. However, efforts are still
      needed to improve the accuracy and reliability of the prediction program and to
      include the consideration of changes in soft tissue tension and muscle strain.
      The accuracy of this system in soft tissue prediction should be carefully
      interpreted.

PMID- 12618974
TI  - The transcervical incision for use in oral and maxillofacial surgical procedures.
AB  - PURPOSE: The aim of this study was to evaluate the long-term outcome of the
      transcervical approach to treat various mandibular problems. MATERIALS AND
      METHODS: Sixty-two patients (37 males and 25 females; age range, 15 to 80 years;
      mean age, 45.1 years) were treated via the transcervical approach. Twenty-eight
      patients (45.1%) had multiple mandibular fractures, 23 (31.7%) had tumor
      resections and selective neck dissections with microsurgical reconstruction, 7
      (11.3%) had severe micrognathia and temporomandibular joint ankylosis, and 4
      (6.4%) had mandibular atrophy requiring grafting. The patients were followed up
      to 15 years. The rates of complications due to surgery were evaluated. RESULTS:
      The most common complication was dysesthesia at the C2-4 distribution in 54
      patients (87.1%), which was usually transient. Nine patients (12.9%) had
      permanent damage to the inferior alveolar nerve (V3) unilaterally due to
      segmental mandibulectomy. Other less common complications were transient
      dysesthesia at the V3 distribution and transient weakness of the lip commissure
      unilaterally. Hypertrophic scars, seroma formation, soft tissue infection, and
      orocervical fistula formation were rare. Most of the patients (96.8%) were
      satisfied with the amount of scarring. CONCLUSION: The transcervical approach
      provides broad exposure of the mandible and neck structures with excellent access
      to the operative field and a minimal rate of complications.

PMID- 12618975
TI  - Alveolar ridge augmentation using titanium micromesh: an experimental study in
      dogs.
AB  - PURPOSE: Augmentation of the alveolar ridge before implant placement is
      frequently performed. The purpose of this study was to compare the amount and
      quality of bone formation under Micro Titanium Augmentation Mesh (M-TAM) when
      used alone for guided tissue regeneration or in combination with a porous
      hydroxyapatite (HA) bone graft substitute. MATERIALS AND METHODS: Nine adult
      female dogs underwent extraction of premolars and molars and had a knife-edge
      ridge created. Three months later, the ridges were augmented with either M-TAM
      alone or M-TAM with a nonresorbable porous HA (Interpore 200; Interpore Cross
      International, Irvine, CA). Six months after augmentation, the dogs were killed,
      and the mandibles were harvested and imaged using 3-dimensional computed axial
      tomography. Statistical analysis was performed from the data obtained from the
      scans. The mandibles were then fixed, sectioned, and examined by light
      microscopy. RESULTS: Dehiscence occurred in 22 of 32 experimental sites. Seven of
      these 22 dehisced sites showed increased ridge width. Ridge width increased in
      both the HA and non-HA groups. The HA group showed a greater increase in ridge
      width. CONCLUSION: A high rate of dehiscence was observed in this animal study
      using M-TAM for guided tissue regeneration. In animals that did not dehisce,
      increased width was greater when nonresorbable porous HA was used as a bone graft
      substitute.

PMID- 12618976
TI  - An anthropometric analysis of the key foramina for maxillofacial surgery.
AB  - PURPOSE: The study goal was to determine the location of important maxillofacial
      foramina relative to frequently encountered surgical landmarks. MATERIALS AND
      METHODS: Measurements (1,120) were made on 80 cadaveric heads of known race and
      gender to evaluate the position of the supraorbital, infraorbital, and mental
      foramina relative to surgical landmarks. RESULTS: Analysis of the data determined
      the supraorbital foramen to be an average of 2.5 cm lateral to the nasal midline
      and 2.6 cm medial to the temporal crest of the frontal bone. Of the supraorbital
      foramina, 92.5% were notches and not true foramen. The infraorbital foramen was
      an average of 2.7 cm lateral to the nasal midline, 0.64 cm caudad to the inferior
      orbital rim, and 0.03 cm medial to the zygomaticomaxillary suture. The mental
      foramen was an average of 2.2 cm lateral to the mandibular skeletal midline. The
      average position of the mental foramen, relative to adjacent teeth, was between
      the first and second premolars for whites and just posterior to the second
      premolar in blacks. CONCLUSION: The measurements show small but significant
      differences in foramen location between whites and blacks and males and females.
      The knowledge of the distances from surgically encountered anatomic landmarks may
      be of assistance in locating these important maxillofacial neurologic structures
      during many procedures. This information may play an even more important role as
      new techniques for minimally invasive surgery are developed. Understanding the
      location of these foramina will also assist the clinician in performing local
      anesthetic blocks.

PMID- 12618977
TI  - Medial approach for tibial bone graft: anatomic study and clinical technique.
AB  - PURPOSE: The purpose of this study is to quantify the amount of bone graft
      material present in the proximal tibia via a lateral versus a medial approach, as
      well as describe an alternative technique for obtaining this bone graft material.
      A quantitative anatomic and statistical analysis and comparison are presented.
      The goal of this study is to demonstrate the advantages and simplicity associated
      with utilizing the proximal tibia as a bone graft harvest site in oral and
      maxillofacial surgery via a medial approach. MATERIAL AND METHODS: Forty lower
      extremities from 20 cadavers were studied. All specimens were dissected, and
      anatomic landmarks were recorded. Anatomic structures, including vessels, nerves,
      muscle attachments, articular surfaces, and their relationships to various
      anatomic landmarks were identified, measured with a linear millimeter ruler, and
      recorded. Bone harvest was accomplished using either a medial (20 extremities) or
      lateral (20 extremities) approach. The amount of bone available for harvest using
      both techniques was compared. Variables evaluated included volume of graft, age,
      gender, and relationships among anatomic structures. RESULTS: The mean volume of
      bone harvested was 25.0 mL for the lateral approach and 24.9 mL for the medial
      approach (range, 14 to 34 mL). The Mann-Whitney U test revealed no significant
      difference in mean volume of graft obtained when comparing the medial and lateral
      approaches (P =.9250). Pearson's correlation test revealed no correlation between
      age (P =.089 medial and P =.174 lateral) or gender (P =.3120 medial and P =.4440
      lateral). The lateral anatomic structures evaluated included the anterior tibial
      vessels that emerged from the interosseous hiatus 14.3 mm inferior to tibial
      perpendicular and 42.6 mm lateral to the tibial parallel line. The distance from
      the tibial perpendicular to the articular surface did not significantly differ
      when comparing the medial (33.65 mm) and lateral (33.25 mm) anterior tibial
      surfaces. The mean length of the oblique line was 17.9 mm, and the superior
      portion of this line was 14.65 mm above the tibial perpendicular line.
      CONCLUSIONS: Equal amounts of bone graft material are available for harvest from
      the medial and lateral aspects of the proximal tibia. Knowledge of important
      anatomic landmarks can be used preoperatively to allow for safe dissection and
      harvest of autogenous bone from the proximal tibia. The dissection of medial
      proximal tibia and harvest of bone graft material may be accomplished efficiently
      with minimal chances of damage or morbidity to vital adjacent structures.

PMID- 12618978
TI  - Theoretical considerations for the surgical correction of mandibular deformity in
      hemifacial microsomia patients using multifocal distraction osteogenesis.
AB  - PURPOSE: This theoretical pilot study investigated the geometric changes
      necessary to normalize the mandibular shape in hemifacial microsomia. Using the
      mandibular deformity of a 13-year-old patient affected by hemifacial microsomia
      as an example, we addressed 2 main issues. First, the number of segments needed
      for adequate reshaping of the deformed mandible is evaluated. Second, the
      geometry of the intersegmental gaps resulting from reposition of the segments is
      correlated with established parameters of distraction osteogenesis to
      theoretically predict the practicability of correction using multifocal
      distraction osteogenesis. MATERIALS AND METHODS: Virtual surgery was performed on
      a solid mandible model created from computed tomography (CT) data from a patient
      with hemifacial microsomia type IIB. In the first step, ideal mandibular
      reshaping was achieved according to anthropometric standard measurements using 7
      osteotomies. By scanning and superimposition of the virtual models and variation
      of distraction sites and numbers, we assessed the minimal number of osteotomies
      necessary for optimal correction of the deformity. Geometrical evaluation of the
      regeneration and assessment of the possibilities of continuous curved distraction
      were also performed. RESULTS: Three osteotomies were shown to be sufficient for
      complete mandibular reshaping. Using accepted parameters for distraction
      osteogenesis, the geometry of the regenerate allows for continuous curved
      distraction. However, simultaneous movements at several distraction sites result
      in interfering vector forces, making coordination of multifocal distraction
      difficult. CONCLUSION: Theoretical assessment of a severe mandibular hypoplasia
      in hemifacial microsomia revealed the 3-dimensional (3D) complexity of the
      deformity for corrective procedures, especially distraction osteogenesis. Despite
      precise planning and transfer of the plan to the patient, multifocal 3D
      distraction may result in deviations from the planned result. Manipulation of the
      fresh regeneration may be necessary to correct inaccuracies.

PMID- 12618979
TI  - Mucoceles and ranulas.

PMID- 12618980
TI  - Intraosseous myoepithelial neoplasms of the maxilla: diagnostic and therapeutic
      considerations in 5 South African patients.

PMID- 12618981
TI  - Osteomyelitis of the maxilla caused by methicillin-resistant Staphylococcus
      aureus.

PMID- 12618982
TI  - Submucosal lymphangioma of the maxillary sinus.

PMID- 12618983
TI  - Cartilaginous choristoma of the tongue.

PMID- 12618984
TI  - Neuromuscular hamartoma in the mental region.

PMID- 12618985
TI  - Removal of osteosynthesis material by minimally invasive surgery based on 3
      dimensional computed tomography-guided navigation.

PMID- 12618986
TI  - Mandibular subluxation and stabilization for access in distal carotid
      endarterectomy.

PMID- 12618987
TI  - Combining professional goals and personal lives.

PMID- 12618988
TI  - The usefulness of intraoral ultrasonography for the treatment of large
      leukoplakia of the tongue.

PMID- 12618989
TI  - The promise of tissue engineering.

PMID- 12618990
TI  - Maxillary sinus augmentation with deproteinated bovine bone and platelet rich
      plasma with simultaneous insertion of endosseous implants.
AB  - PURPOSE: To investigate the clinical applicability of using deproteinated bovine
      bone mixed with autologous platelet rich plasma (PRP) in human maxillary sinus
      augmentations in severely resorbed posterior maxillary alveolar processes with
      simultaneous insertion of endosseous dental implants. MATERIALS AND METHODS:
      Fifteen patients with less than 5 mm of residual alveolar bone height in the
      posterior maxillary alveolus underwent a total of 24 maxillary sinus
      augmentations. Seventy endosseous implants were inserted simultaneously in the
      grafted sinuses. The implants were uncovered and loaded 4 months after insertion
      and the sinus augmentation. An osseous biopsy specimen was obtained from the
      augmented maxillary sinus in 1 patient. In 3 patients, computed tomography scans
      of the grafted maxillae were obtained and the bone density quantified and
      compared with native bone density using SIMPlant 7 (Columbia Scientific,
      Columbia, MD) software 4 months postoperatively. RESULTS: Although a total of 5
      implants in 4 patients were lost, this did not result in the loss of any of the
      restorations, for an overall success rate of 92.9 %. Follow-up for patients in
      this study after insertion of the permanent restoration was between 6 and 36
      months. The bone biopsy from the patients showed evidence of viable new bone
      formation in close approximation to the xenograft. The bone density of the
      grafted bone was similar or exceeded the bone density of the surrounding native
      maxillary bone. CONCLUSION: Based on our clinical experience, we believe that the
      use of platelet rich plasma in combination with deproteinated bovine bone is
      effective for maxillary sinus augmentation with simultaneous insertion of
      endosseous dental implants in severely resorbed posterior maxillae.

PMID- 12618991
TI  - Clinical success in harvesting autogenous bone using a minimally invasive
      trephine.
AB  - PURPOSE: Autogenous bone grafting is well established for use in the
      maxillofacial skeleton. We present our experience with minimally invasive bone
      harvesting using a power-driven trephine, with favorable patient and clinical
      results. MATERIALS AND METHODS: This retrospective study evaluation patients
      requiring autogenous bone harvested using a trephine, treated consecutively over
      a 3-year period. Mean patient age was 27.2 years (range, 8 to 77 years). Only
      those patients requiring elective surgery and admission on the same day were
      included in the study. Intraoperative assessment included the description of
      complications and the quantity and volume of the bone cores harvested. The
      complications monitored included bleeding, nerve injury, and perforation of the
      medial or lateral walls of the ilium. Postoperatively, patients were assessed for
      ambulation, pain, bleeding, and suitability for discharge. The patients were
      evaluated 1 week after surgery and were examined for wound complications
      (incision breakdown, infection, paresthesia, pain) and ambulatory deficits. All
      patients were then surveyed using a questionnaire outlining short-term (1 to 14
      days), and long-term (>6 months postoperative) deficits, pain, and general
      remarks about the procedure. RESULTS: A total of 84 patients underwent bone
      harvesting using a power-driven trephine. Bone was harvested from a total of 86
      anterior iliac crest sites, for a total of 333 cores (3.96 cores per patient).
      Forty-one patients were discharged on the day of surgery. Intraoperatively, the
      volume of bone obtained ranged from 3 to 21 mL per harvest site (1 to 7 cores, 4
      mm x 30 to 38 mm). The bone volume obtained was dependent on the size of the
      defect to be filled. Intraoperatively, 1 complication occurred (1 of 333 cores;
      0.3%)-a broken instrument-and there were no perforations of the medial or lateral
      walls of the ilium or excessive bleeding. The complications totaled 3 (3.6%);
      none of these produced long term effects. Patients surveyed up to 6 months
      postoperatively noted positive results. CONCLUSIONS: The harvesting of bone from
      the anterior iliac crest using a power driven trephine appears to be safe and
      results in minimal morbidity and ample bone volume for many maxillofacial
      procedures, without delaying discharge from hospital.

PMID- 12618992
TI  - Autologous cultured mucosal graft to cover large intraoral mucosal defects: a
      clinical study.
AB  - PURPOSE: The study evaluated the performance of cultured mucosal grafts (CMG) for
      large intraoral mucosal defects caused by surgical excision of mucosal pathology.
      PATIENTS AND METHODS: Eleven patients (10 men and 1 woman; mean age, 52.4 +/-
      14.1 years) were treated using CMG following mucosal defects. A biopsy specimen
      (0.2 to 0.5 cm(2)) was taken from a clinically healthy oral mucosa a few weeks
      before the surgery. Mucosal epithelial cells were cultured in vitro over a feeder
      layer of fibroblasts. Usually, within 3 to 4 weeks, multilayered sheets (50 to
      250 cm(2)) were generated. The cultured sheets were placed on the mucosal defects
      (48.4 +/- 21.7 cm(2); 8 to 70 cm(2)) and anchored to the adjacent tissue with
      sutures. RESULTS: One week after surgery, the CMG survived and adhered to the
      wound bed. Three weeks postoperatively, the grafted site was smooth and
      keratinized, without infection or scar contraction. Three months postoperatively,
      the grafted area was covered with a healthy mucosa, indistinguishable from the
      adjacent mucosa. CONCLUSION: CMG is a useful grafting material for large
      intraoral mucosal defects.

PMID- 12618993
TI  - Health-related quality of life after maxillectomy: a comparison between
      prosthetic obturation and free flap.
AB  - PURPOSE: The purpose of this cross sectional study was to evaluate the health
      related quality of life of patients following maxillectomy and to compare
      obturation and free flap reconstruction. PATIENTS AND METHODS: At the Regional
      Maxillofacial Unit in Liverpool, United Kingdom, between 1992 to 1996, 39
      patients underwent maxillectomy for malignant pathology. Of these patients, 28
      (10 underwent obturation and 18 underwent free tissue reconstruction) completed a
      postoperative semi-structured interview. Eight questionnaires were used to test
      aspects of health-related quality of life and function. RESULTS: The main
      findings were the associations between the size of maxillectomy defect and the
      University of Washington activity (-0.53; P =.005) and recreation (-0.70; P
      <.001) domains, and with the physical functioning (-0.58; P =.001) and quality of
      life (-0.51; P =.007) domains of the European Organization for Research and
      Treatment of Cancer questionnaire. No statistically significant differences were
      seen between the obturator and free flap groups. Borderline trends were for
      obturator patients to be more concerned about their appearance, to have more pain
      and soreness in their mouths, to be more aware of their upper teeth, more self
      conscious and less satisfied with their upper dentures, and less satisfied with
      function. CONCLUSION: Similar subjective outcomes were found for both groups, and
      a larger longitudinal study is needed to test these relationships more
      rigorously.

PMID- 12618994
TI  - Unilateral subcutaneous pedicled nasolabial island flap for anterior mouth floor
      reconstruction.
AB  - PURPOSE: This article describes the successful use of unilateral subcutaneous
      pedicled flaps in the reconstruction of defects of the anterior floor of the
      mouth by raising the flaps as skin islands, relying on a pedicle of subcutaneous
      tissue. PATIENTS AND METHODS: Nine flap procedures were performed on 9 patients
      for reconstruction of small defects of the anterior floor of the mouth. One
      patient underwent secondary reconstruction to release tongue that was
      functionally tethered anteriorly. RESULTS: All flaps healed without evidence of
      infection, dehiscence, or necrosis. This particular choice of unilateral flap
      seems to provide improved functional integrity of the anterior floor of the
      mouth. CONCLUSIONS: The unilateral inferiorly and subcutaneously based nasolabial
      island flap provides reliable coverage of small and intermediate-sized defects of
      the anterior floor of the mouth when used alone, improving the tongue mobility,
      articulation, and deglutition.

PMID- 12618995
TI  - Histopathologic damage to vessels in head and neck microsurgery.
AB  - PURPOSE: This study assessed the incidence of pre-existing damage in recipient
      arteries excised before the vessels were used for microvascular anastomoses
      between 1988 and 1999. PATIENTS AND METHODS: Recipient arteries of the head and
      neck region from 100 patients who had undergone ablative surgery requiring
      microvascular tissue reconstruction were examined histologically. Past illnesses
      believed to be risk factors included hypertension, myocardial disease, and
      diabetes. Blood vessels chosen for microsurgical anastomoses were examined using
      histological staining, scanning electron microscopy, and immunofluorescence.
      RESULTS: Of the patients undergoing microvascular surgery, 51% showed histologic
      vessel abnormalities. Marked thickening of the blood vessel wall and severe
      exfoliation of the endothelial cells were observed in most arteries. Thickening
      of the intima was evaluated using scanning electron microscopy (Friedman's
      method; Microvasc Res 3:416, 1971). Values higher than twice the ratio of wall
      thickness-to-lumen diameter were observed in 9 recipient arteries. Six graft
      failures were correlated with both technical errors and pre-existing vessel
      lesions. CONCLUSIONS: This study revealed that most patients undergoing
      microsurgery in the head and neck region had pre-existing damage to vessels that
      hindered anastomoses. Pre-existing changes in the recipient arteries may cause
      technical difficulties and must be regarded as additional factors contributing to
      graft failure.

PMID- 12618996
TI  - Litigation and the lingual nerve.
AB  - PURPOSE: A "malpractice crisis" exists in the United States. Litigation analysis
      helps to understand the causes and may be useful in prevention of suits. This
      study reviews litigation regarding the lingual nerve. MATERIALS AND METHODS: Jury
      verdict reports were obtained from a computerized legal database for the years
      1987 through 2000. The study reviews all state and federal civil trials in the
      United States. Reviews compile information on plaintiffs and defendants,
      allegations of wrong-doing, reasons for litigation, anatomic sites of injuries,
      specialties of expert witnesses, verdict results, and awards received. RESULTS:
      Thirty-three suits from 12 states were obtained. Dentists or oral surgeons were
      involved in 87%, and otolaryngologists were involved in 13% of suits. Tooth
      extractions were involved in 79%, and 50% of these resulted in financial awards.
      Lack of informed consent was alleged in 52% of suits overall and in 46% of tooth
      extraction suits. Expert witnesses were of the same specialty for both sides in
      81%. Inadequate training and selection of the wrong surgical approach were
      alleged in 18% and 15%, respectively. Anatomic variations were thought to be
      present in 15%. CONCLUSIONS: Surgeons must be aware of anatomic variations and
      regions in which injury to the lingual nerve frequently occurs. Written informed
      consent may help decrease litigation in known risk regions.

PMID- 12618998
TI  - Flow-cytometric analysis of T-lymphocyte subsets after different treatment
      methods in patients with pericoronitis.
AB  - PURPOSE: The aim of this study was to determine whether there was any change in T
      lymphocyte subsets in patients with periocoronitis after the application of
      different treatment methods. PATIENTS AND METHODS: Twenty-six patients with acute
      pericoronitis were included in the study. In every phase of the treatment
      (pretreatment, postcurettage, and postextraction), the biopsy samples were taken
      from the gingival tissues at sites of pericoronitis. Then, CD4(+) and CD8(+)
      lymphocyte and CD4(+)/CD8(+) ratio values were determined using flow cytometry in
      the biopsy samples. At the same time, gingival index (Loe-Silness) and plaque
      index (Silness-Loe) scores were recorded to assess the periodontal status in
      patients. To determine the correlation between the clinical measurements and the
      laboratory results obtained before the treatment, after curettage, and after
      extraction, we conducted an analysis using a paired t-test. RESULTS: The normal
      values in peripheral blood of CD4(+) and CD8(+) lymphocytes are 25% to 29% and
      19% to 48%, respectively. However, the CD4(+) and CD8(+) lymphocyte values in the
      patients with acute pericoronitis were found to be 22.12% +/- 6.15% and 7.69% +/-
      4.12%, respectively. These values are lower than the normal values. The CD4(+)
      lymphocyte value increased to 31.06% +/- 7.09% postcurettage and to 32.24% +/-
      3.11% postextraction. The CD8(+) lymphocyte value increased to 16.21% +/- 5.27%
      postcurettage and to 18.25% +/- 3.13% postextraction. The CD4/CD8 ratio increased
      postcurettage and postextraction. This increase was statistically significant (P
      <.001). Postcurettage, there was decrease in clinical indexes, which was
      statistically significant (P <.001). A significant correlation between CD4(+)
      lymphocyte and ginigival index values and also between CD8(+) lymphocyte and
      plaque index values was determined postcurettage (P <.05). CONCLUSION: CD4(+) and
      CD8(+) T-lymphocytes could play a significant role in pericoronitis pathobiology.

PMID- 12618999
TI  - Bond strength for orthodontic brackets contaminated by blood: composite versus
      resin-modified glass ionomer cements.
AB  - PURPOSE: The purpose of this study was to evaluate and compare the shear bond
      strengths of a self-cured glass ionomer versus composite cement for bonding of
      stainless steel buttons with various enamel surface and setting conditions.
      MATERIALS AND METHODS: Stainless steel orthodontic buttons were bonded using
      composite material under 3 different enamel and setting conditions: 1)
      conditioned and dry enamel surface, 2) conditioned and precontamination of the
      enamel surface with blood before bonding, 3) conditioned and immediate blood
      contamination postbonding and were compared with 3 different enamel conditions
      and setting for bonding with the glass ionomer cement: 1) nonconditioned and wet
      enamel surfaces, 2) nonconditioned and blood contamination of enamel before
      bonding, and 3) nonconditioned and immediate blood contamination postbonding. The
      brackets were bonded to 109 recently extracted teeth and allowed to set in a
      moist plastic container for 24 hours. They were subsequently tested in shear mode
      with a universal testing machine. The maximum bond strength and the site of bond
      failure were recorded. In addition, the location of the bond failure was studied.
      RESULTS: Composite was capable of sustaining greater forces than the resin
      modified glass ionomer materials. Hence, it took more force to debond a bracket
      cemented with composite than with resin-modified glass ionomer. The effect of
      contamination was similar in both of the materials, and the magnitude of the
      decrease in bond strength was nearly of the same proportion. The
      postcontamination values were not significantly different from the uncontaminated
      bond strength for either material. The type of bond failure was significantly
      different for the different materials, and there were significant differences
      among the treatment conditions. CONCLUSION: Composite resin had significantly
      greater shear strength than resin-reinforced glass ionomer cement. Both materials
      showed a significant decrease in bond strength when precontaminated with blood.
      The postcontamination values were not significantly different from the
      uncontaminated bond strength for either material.

PMID- 12619000
TI  - Frontal sinus obliteration with heterogeneous corticocancellous bone versus
      spontaneous osteoneogenesis in monkeys (Cebus apella): histologic analysis.
AB  - PURPOSE: In this study, we evaluated the results of spontaneous osteoneogenesis
      of the frontal sinus with autogenous bone plug versus obliteration with
      heterogeneous (human) bone in monkeys (Cebus apella). MATERIALS AND METHODS:
      Eight young adult male C apella monkeys underwent an ostectomy of the anterior
      wall of the frontal sinus, removal of the sinus mucosa, and inner decortication
      of the bony walls and then were divided into 2 groups of 4 each, as follows.
      Group I monkeys underwent obliteration of the nasofrontal ducts with a free
      segment of frontallis muscle and corticocancellous heterogeneous bone, followed
      by full obliteration of the sinus with corticocancellous heterogeneous bone
      (Dayton Regional Tissue Bank, Dayton, OH). Group II monkeys underwent
      obliteration of the nasofrontal ducts with a frontal muscle segment and tibial
      autogenous bone plug, without full obliteration of the frontal sinus. In all
      animals, the sinus anterior wall was repositioned and fixed with 1.0 plate and
      screws. The monkeys were killed after 180 days, and routine laboratory procedures
      were followed for hematoxylin-eosin staining and histologic evaluation of the
      specimens. RESULTS: The 2 studied techniques were both effective in obliterating
      the frontal sinus with newly formed bone. The nasofrontal ducts were obliterated
      by new bone formation or fibrous tissue (1 animal only). CONCLUSIONS: Both
      methods used for frontal sinus obliteration were effective; the heterogeneous
      bone (human bone) was well tolerated and presented low antigenicity. The
      nasofrontal duct obliteration with autogenous muscle associated with autogenous
      tibial bone (group II) or with heterogeneous bone (group I) was effective,
      isolating the frontal sinus from the nasal cavity. The spontaneous obliteration
      resulted, in the period analyzed, in earlier bone maturation compared with the
      obliteration by heterogeneous bone.

PMID- 12619001
TI  - A new technique for the creation of a computerized composite skull model.
AB  - PURPOSE: The goals of this study were to develop a technique for creating a
      computerized composite skull model and to test its accuracy. The computerized
      composite skull model is the combination of a 3-dimensional (3D) computed
      tomography (CT) bone model with digital dental models. MATERIALS AND METHODS: A
      dry skull with intact dentition was used in development of the technique. The
      creation of the computerized composite skull model was divided into 3 steps. The
      first step was to create digital dental models. The second step was to create a
      3D CT bone model of the craniomaxillofacial skeleton. The last step was to
      incorporate the digital dental models into the 3D CT skull model, creating a
      computerized composite skull model. The accuracy of the computerized composite
      skull model was assessed. Bone-to-bone, tooth-to-tooth, and bone-to-tooth
      measurements were made on the computerized composite skull model and the dry
      skull. Pearson correlation coefficient and linear regression tests were
      performed. RESULTS: A technique to create a computerized composite skull model
      was developed. This computerized model not only represented bony structures from
      CT data but also reproduced dentition from digital dental models. For the bone-to
      bone measurements, the mean difference between the computerized composite skull
      model and the dry skull was 0.5 +/- 0.6 mm. For the tooth-to-tooth measurements,
      the mean difference was 0.1 +/- 0.2 mm. For the bone-to-tooth measurements, the
      mean difference was 0.2 +/- 0.3 mm. CONCLUSIONS: This study showed the
      feasibility of creating a computerized composite skull model as well as its
      accuracy.

PMID- 12619002
TI  - The residents' viewpoint of the matching process, factors influencing their
      program selection, and satisfaction with the results.
AB  - PURPOSE: The purpose of this study was to determine the factors considered by
      oral and maxillofacial surgery residents in selecting residency programs, to
      estimate the level of their satisfaction with the selection and matching
      processes, and to analyze the relationship between these factors and overall
      satisfaction with their match. MATERIALS AND METHODS: A questionnaire was sent to
      675 residents listed as members of the American Association of Oral and
      Maxillofacial Surgeons, and 208 responded to the survey. Of these residents,
      56.7% were in an MD integrated program, 30.3% were in a 4-year certificate
      program, 10.6% were in an MD optional program, and 2.4% were in a combined PhD
      program. RESULTS: There were no differences between the program types and the
      number of resident applications or the number of interviews. Residents in the MD
      integrated programs had significantly higher board scores than both the MD
      optional residents and the 4-year certificate residents. The most important
      factors that residents considered when making their match list were as follows:
      good relationships between residents, good relationships between residents and
      attendings, training in orthognathic surgery, training in implant surgery, and
      training in dentoalveolar surgery. When residents were asked whether they were
      satisfied with the program in which they were currently enrolled, MD integrated
      residents were significantly more satisfied than were those residents in the MD
      optional and 4-year certificate program. Additional predictors of residence
      satisfaction were satisfied with the results of the match process, accuracy of
      the program in representing itself during the interview process, and less
      importance placed on orthognathic surgery training. Although generally satisfied,
      25% would want to go to a different program if they could go through the match
      again. CONCLUSIONS: The majority of residents seem to be satisfied with the
      program in which they matched. Among the important factors determining
      satisfaction are the degree of honesty during the interview process, good
      relations among residents and between residents and attending doctors, the scope
      of clinical training, and the didactic/academic content of the program.

PMID- 12619003
TI  - A new vascularized mandible heterotopic transplant model for studies on the
      growth of condylar cartilage.
AB  - PURPOSE: We developed a vascularized mandibular heterotopic transplant (VMHT)
      model to allow the observation of condylar cartilage growth in the absence of
      external and dynamic factors, such as mastication. MATERIALS AND METHODS: In
      VMHT, we performed a transplantation between 2 age-matched inbred rats (male
      Lewis rats aged 6 weeks). The hemimandibular tissue, with the common carotid
      artery and external jugular vein as vascular pedicle, was harvested from the
      donor rat and transplanted to the neck of the recipient rat with the use of
      vascular anastomosis under an operating microscope. To evaluate the stability of
      VMHT, we investigated both the weight change of the recipient rats and the blood
      circulatory conditions of the grafts via the radioactive microsphere method,
      laser Doppler blood flowmeter, and angiography. RESULTS: Although the body weight
      of the recipient rats decreased immediately after transplantation, these values
      subsequently increased, indicating a good nutritional environment in the
      recipient rat. Also, the VMHT graft tissue and the mandibular condyle had
      favorable blood circulation, equivalent to normal conditions. CONCLUSIONS: In
      VMHT, transplantation between the 2 age-matched inbred rats using anastomosis of
      the similar blood vessels enables us to minimize the influences of genetic
      factors, hemodynamics, hormones, and other external factors. Our investigation
      indicated that the transplant possessed favorable growth conditions, equivalent
      to the environment of the endogenous mandibular condyle. Thus, we are able to
      maintain conditions similar to the normal environment of the mandibular condyle.
      This model will be very useful in future investigations of the influences of
      external and functional factors on chondrogenesis and enchondral ossification of
      the mandibular condyle.

PMID- 12619004
TI  - An experimental study on the growth of condylar cartilage, using a new
      vascularized mandible heterotopic transplant model.
AB  - PURPOSE: To clarify the influence of external and dynamic factors on the growth
      of mandibular condyle, we developed vascularized mandible heterotopic transplant
      (VMHT) model. In this report, we discuss histologic changes in the mandibular
      condylar cartilage in the absence of external factors, using VMHT models.
      MATERIALS AND METHODS: Thirty VMHT model using male Lewis rats aged 6 weeks were
      produced. Six VMHT rats were randomly selected for death at 1, 2, 4, 7, and 14
      days after transplantation. We histologically investigated the mandibular
      condyles of the grafts and controls, the left mandibles of recipient rats.
      RESULTS: In the transplanted mandibular condyle of VMHT models, the cell
      arrangement became increasingly irregular with the passage of time, with a
      concomitant, irregular thickening or thinning of the cartilage layer. There was
      heterotopic fibrous ossification, extending horizontally under the proliferative
      cell layer in these regions of thin cartilage. After these events, cartilage
      cells had disappeared almost completely by 14 days after transplantation.
      CONCLUSIONS: This study indicated that external and dynamic factors are not
      necessary for the differentiation and proliferation of the condylar cartilage
      cells. Instead, these factors affect the maintenance of the orderly growth of the
      cartilage cells and may serve a critical role in the differentiation of
      undifferentiated mesenchymal cells into chrondroblasts.

PMID- 12619005
TI  - Intraosseous mandibular lesion.

PMID- 12619006
TI  - Cardiac sarcoidosis: an overview of management for the patient requiring oral and
      maxillofacial surgery.
AB  - PURPOSE: The study goal was to present a current definition of sarcoidosis and an
      overview of cardiac involvement and implications in perioperative management of
      cardiac sarcoidosis. MATERIALS AND METHODS: Materials included a retrospective
      review of 4 patients with cardiac sarcoidosis who underwent minor oral surgery.
      Laboratory data, medical data, and data obtained through monitoring the patient's
      general condition related to the surgery were critically analyzed. RESULTS:
      Preoperative understanding of cardiac pathophysiology, evaluation of the
      patient's general condition, laboratory data, medical records, and physician
      correspondence were important, as was precise treatment planning against cardiac
      emergencies that could occur in surgical treatments. It was essential to monitor
      vital signs, any electrocardiographic changes, blood pressure, and heart rate,
      starting from the pretreatment period and continuing through the oral and
      maxillofacial surgery into the post-treatment period. Glucocorticosteroid
      coverage and prevention of endocarditis were also considered during oral and
      maxillofacial surgery planning. CONCLUSIONS: Critical issues were identified in
      the performance of oral and maxillofacial surgery for patients with cardiac
      sarcoidosis.

PMID- 12619007
TI  - Immunolocalization of the p53 protein in a case of ameloblastic fibrosarcoma.

PMID- 12619008
TI  - Radiation-induced leiomyosarcomas as second primary tumors in the head and neck
      region: report of 2 cases.

PMID- 12619009
TI  - A look at the biology of spindle cell squamous carcinoma of the oral cavity:
      report of a case.

PMID- 12619010
TI  - Benign fibrous histiocytoma of the buccal mucosa: case report with
      immunohistochemical features.

PMID- 12619011
TI  - Modified sagittal osteotomy of the mandible for marginal oncologic resection.

PMID- 12619012
TI  - Aesthetic placement of single-stage ITI implants using a tissue punch and a
      lateral bone condensing technique.

PMID- 12619016
TI  - Transjugular intrahepatic portosystemic shunts: an update.
AB  - Transjugular intrahepatic portosystemic shunts (TIPS) have been used in the
      treatment of complications of portal hypertension. TIPS is used for the control
      of acute variceal bleeding and for the prevention of vericeal rebleeding when
      pharmacologic therapy and endoscopic therapy have failed. Patients with
      refractory ascites with adequate hepatic reserve and renal function who fail to
      respond to large volume paracentesis may be reasonable candidates for TIPS.
      Promising indications for TIPS are Budd-Chiari syndrome uncontrolled by medical
      therapy, severe portal hypertensive gastropathy, refractory hepatic hydrothorax,
      and hepatorenal syndrome. TIPS cannot be recommended for preoperative portal
      decompression solely to facilitate liver transplantation. Special care should be
      taken to insure proper placement of the stent to avoid increasing the technical
      difficulty of the transplantation procedure. The major limiting factors for TIPS
      success are shunt dysfunction and hepatic encephalopathy. Because shunt stenosis
      is the most important cause of recurrent complications of portal hypertension, a
      surveillance program to monitor shunt patency is mandatory. The MELD score may be
      useful in predicting post-TIPS survival, and also in counseling patients and
      their families.

PMID- 12619013
TI  - Nitric oxide and squamous carcinoma.

PMID- 12619018
TI  - Severe recurrent hepatitis C after liver retransplantation for hepatitis C virus
      related graft cirrhosis.
AB  - An increase in the number of hepatitis C virus (HCV)-infected transplant
      recipients at need for repeated liver transplantation is anticipated. To date,
      there is a certain reluctance to accept these patients because of an increased
      organ shortage, early reports suggesting a poor outcome, and uncertainty
      regarding the natural history of recurrent hepatitis C in the second graft. The
      aim of this study is to determine the outcome of patients undergoing
      retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients
      with HCV-related allograft cirrhosis, 31 patients developed decompensation with
      criteria for retransplantation. Thirteen patients were denied this option. Of the
      18 patients accepted, 6 patients died while on the waiting list (5 patients died
      of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have
      undergone retransplantation (median, 10 months since HCV cirrhosis). After
      retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients
      (33%) remain alive after 1.9 years of follow-up. Causes and times of death from
      retransplantation were: surgical complications, n = 3 (perioperative period); HCV
      cirrhosis of the second graft, n = 2 (at 9 and 54 months); fibrosing cholestatic
      hepatitis, n = 1 (at 2 years); lymphoproliferative disorder, n = 1 (at 7 months);
      and endocarditis, n = 1 (at 3.5 years, with underlying cirrhosis). Of the 4
      patients alive, fibrosis stages in the last biopsy specimens are stage 1 (n = 1),
      stage 3 (n = 1), and stage 4 or cirrhosis (n = 1; one patient has not undergone
      biopsy), despite antiviral therapy. The outcome of retransplantation for HCV
      cirrhosis of the first graft is very poor because of multiple complications. The
      severity of recurrent HCV disease in the second graft seems to be related to that
      observed in the first graft.

PMID- 12619017
TI  - Human leukocyte antigen-C in short- and long-term liver graft acceptance.
AB  - In liver transplantation, rejection is still an important problem, and the role
      of human leukocyte antigens (HLA) has not been clearly established. At present,
      the possible involvement of HLA-C antigen in liver transplantation is still
      unexplored. The aim of this work was to analyze the influence of HLA-C
      polymorphism on the outcome of liver transplantation. For this purpose,
      genotyping of 100 orthotopic liver transplant recipient-donor pairs for HLA-C was
      performed with polymerase chain reaction-sequence-specific primers (PCR-SSPs).
      Liver recipients were stratified according to the occurrence of acute rejection.
      Patients without acute rejection were found to have a lower frequency of the HLA
      Cw*06 allele compared with those with acute rejection or the control group.
      Moreover, when the role of HLA-C dimorphism was analyzed, natural killer (NK)1
      alloantigens were found to be predominant in recipients without acute rejection.
      When the match of HLA-C single alleles and NK-alloantigens between donor and
      recipient was analyzed, it appeared that the frequency of acute rejection
      gradually decreased with decrease of the number of allele mismatches. Graft
      survival was increased when the number of mismatches in both HLA-C or NK
      alloantigens was lower. In conclusion, the HLA-C locus may play a role in liver
      graft alloreactivity or allotolerance and, therefore, may be useful to avoid
      acute rejection and to achieve graft acceptance, resulting in a better final
      outcome in liver transplantation.

PMID- 12619019
TI  - Should HCV-related cirrhosis be a contraindication for retransplantation?

PMID- 12619020
TI  - Orthotopic liver transplantation in patients with human immunodeficiency virus
      and end-stage liver disease.
AB  - Patients with human immunodeficiency virus (HIV) most often have hepatitis C
      virus (HCV) or hepatitis B (HBV) virus coinfection, or both, as a cause of their
      liver disease. Recent survival statistics show that patients infected with HIV
      treated with highly active antiretroviral therapy (HAART) can expect a
      significant prolongation of life by interfering with the natural progression of
      HIV to acquired immune deficiency syndrome (AIDS). Therefore, HIV-positive
      patients experiencing complications of liver failure are at greater immediate
      risk of dying from their end-stage liver disease (ESLD) rather than their HIV.
      Many transplant centers still consider HIV infection as a contraindication for
      orthotopic liver transplantation (OLT). At our two institutions, we believe that
      patients with HIV suffering from ESLD should be considered for OLT. This study
      evaluates the survival of patients undergoing OLT with HIV under HAART therapy.
      OLT was performed in 16 patients with HIV suffering from ESLD as a result of
      chronic HCV, chronic HBV, or fulminant hepatic failure (FHF). Collected data
      include patient demographics, patient and graft survival, pre-OLT assessments,
      and postoperative complications (including opportunistic infections). Ten
      patients at Pittsburgh and 6 patients at Miami received OLT. Of the 16 patients
      who received OLT, 14 remain alive to date. Thirteen of 16 patients are more than
      12 months post-OLT, whereas the last patient is currently 6 months post-OLT. Five
      patients at Miami and 9 of 10 patients at Pittsburgh received HAART therapy
      before OLT, although 2 of the Pittsburgh patients had their HAART therapy
      discontinued before OLT because of significant liver dysfunction. The pre-OLT
      viral loads were undetectable in 13 of 16 patients. The cluster determinant (CD)4
      count was less than 200 in 6 patients and greater than 100 in 2 patients before
      OLT. In all patients, CD4 counts increased above 200 in the post-OLT period.
      Tacrolimus toxicity associated with the pharmacologic inhibition of cytochrome
      p450 metabolism caused by protease inhibitors occurred in 6 patients after OLT.
      Six patients (38%) experienced acute cellular rejection immediately after OLT.
      Our experience suggests that OLT is effective in selected HIV-positive patients
      suffering from ESLD. Patient and graft survival was similar to non-HIV-positive
      patients suffering from the same indications for OLT. Acute cellular rejection
      was no less frequent that seen in non-HIV-positive patients. Given the complex
      pharmacologic interactions between the protease inhibitors and tacrolimus,
      careful monitoring, and attention is required to prevent toxicity or underdosing.

PMID- 12619021
TI  - Serum phosphorus levels predict clinical outcome in fulminant hepatic failure.
AB  - The aim of this pilot study was to evaluate the incidence of hypophosphatemia and
      its association with clinical outcome in fulminant hepatic failure (FHF).
      Patients with FHF referred for orthotopic liver transplantation (OLT) between
      January, 1991 and May, 2002 were identified. FHF was defined as the development
      of coagulopathy and encephalopathy within 8 weeks of onset of jaundice.
      Demographic and laboratory data, including serum phosphate, calcium, magnesium,
      creatinine, and PT/INR were obtained from medical records. Clinical outcomes
      (death, OLT, or hepatic recovery) and associated morbidities (renal failure,
      bleeding, and sepsis) also were noted. Thirty-eight patients, 8 men and 30 women,
      aged 34 +/- 4 years, were included in the study. Hypophosphatemia (< 2.5 mg/dL)
      developed in 33 of 38 (87%) patients within 10 days of referral. Twelve patients
      (32%) died, 14 patients (37%) underwent OLT, and 12 patients (32%) recovered. The
      mean nadir serum phosphorus level was significantly lower in those who recovered
      compared with those who either died or required OLT (1.18 +/- 0.54 versus 1.79 +/
      1.00 mg/dL; P =.02). A trend toward lower mean serum phosphorus level also was
      noted in those who recovered compared with those who died (1.18 +/- 0.54 versus
      1.96 +/- 1.35 mg/dL; P =.09). Serum phosphorus levels > 2.5 mg/dL was a predictor
      of mortality, and when used alone, was equivalent to the King's College Criteria.
      In conclusion, hypophosphatemia occurred frequently in patients with FHF. Lower
      serum phosphorus levels were observed in patients who recovered as compared with
      those who died or required OLT, and may be associated with recovery of hepatic
      function. The greater decline in serum phosphorus level in those who recover
      hepatic function may represent cellular use of phosphorus during hepatocyte
      regeneration.

PMID- 12619022
TI  - Clinical and ethnic differences in candidates listed for liver transplantation
      with and without potential living donors.
AB  - The shortage of cadaver livers and improved outcomes in partial liver transplants
      has led to an increase in adult living donor liver transplantation (LDLT). Only a
      fraction of potential liver recipients have donors. The characteristics of
      candidates who have volunteers for living donation may be different than those
      without donors. We compared adult patients on the waiting list who had potential
      living donors with those who did not have living donors. Two-hundred and four
      consecutive patients were listed for transplantation. During evaluation, all were
      informed and educated about LDLT. To avoid coercion, we did not solicit a living
      donor. Sixty (29%) potential recipients had at least one living donor volunteer
      for evaluation. Twenty-eight (14%) patients from the entire cohort and 46% of the
      60 patients who had potential living donors underwent LDLT. Compared with
      Caucasians, Hispanics were more likely to have living donors (P =.006). No
      patient with alcoholic liver disease (ALD) had a donor come forward (P =.006).
      Patients with living donors were twice as likely to have cancer (P =.08).
      Systematic differences exist between patients who have potential living donors
      versus those without donors. Candidates with potential donors are more likely to
      be Hispanic and have cancer and less likely to have ALD compared with cadaveric
      recipients. Only a minority of patients listed for orthotopic liver
      transplantation (OLT) will lead to LDLT. Further understanding of the cultural
      differences and motivating factors for why people volunteer for evaluation and
      subsequently choose to donate may help improve cadaveric and living donor
      transplant rates.

PMID- 12619023
TI  - Predictive models of short- and long-term survival in patients with nonbiliary
      cirrhosis.
AB  - The limited number of donor organs has placed a burden on the medical community
      to improve patient selection and timing of liver transplantation (LT). We aim to
      evaluate short- and long-term survival of 124 consecutive patients with a
      diagnosis of nonbiliary cirrhosis. Seventeen clinical, biochemical, functional,
      and hemodynamic parameters were computed. Patient survival was evaluated in the
      short term (3 months) by logistic regression, and the predictive power of the
      model was evaluated using receiver operating characteristic curves and the log
      likelihood ratio. For the long-term (up to 5 years) prognosis, the Cox
      proportional model was used. During follow-up, 54 patients died and 20 patients
      underwent LT. In the short-term study, the Model for End-Stage Liver Disease
      score (including bilirubin level, international normalized ratio [INR], and
      creatinine level) was as predictive as our score, which contained only two
      independent indicators (bilirubin and creatinine levels). In the long-term study,
      three independent variables (albumin level, INR, and creatinine level) emerged
      from the Cox model, and patients were classified into three survival-risk groups
      according to a prognostic index (PI): -1.039 x albumin (grams per deciliter) +
      1.909 x log(e) INR + 1.207 x log(e) serum creatinine (milligrams per deciliter).
      Survival probabilities at 1 and 5 years were 89% and 80%, 63% and 52%, and 23%
      and 10% with a low, medium, and high PI, respectively. The validation study using
      the split-sample technique and data from independent patients confirmed that a
      high PI (>-2.5) identifies patients with a poor prognosis within 5 years. We thus
      have shown and validated that risk for death at the short and long term of
      patients with nonbiliary cirrhosis can be predicted with great accuracy using
      models containing a few simple and easily obtained objective variables, and these
      survival models are useful tools in clinical decision making, especially in
      deciding to list patients for LT and prioritization on the liver waiting list.

PMID- 12619024
TI  - Preservation of mouse liver tissue during cold storage in experimental solutions
      assessed by x-ray microanalysis.
AB  - The increasing use of organs for transplantation necessitates the development of
      optimal preservation techniques. The goal of this study was to investigate
      changes in elemental content in mouse liver cells during cold storage by x-ray
      microanalysis in parallel with morphologic studies. Tissue was stored at 4
      degrees C for 4 to 12 hours in normal Krebs-Ringer solution (high
      sodium/potassium ratio), modified Krebs-Ringer solution (low Na(+)/K(+) ratio),
      Euro-Collins solution, University of Wisconsin (UW) solution, or seven modified
      versions of the UW solution. Incubation of liver in normal Krebs-Ringer solution
      caused a significant increase in sodium and decrease in potassium concentrations
      in contrast to incubation in other solutions. The concentration of sodium,
      potassium, and chlorine in the cells closely followed the concentration in the
      storage solution, indicating that the intracellular concentration of these ions
      during storage is entirely dependent on diffusion processes. The calcium
      concentration was independent of the storage solution used. Studies by light and
      transmission electron microscopy showed good preservation of hepatocytes after
      storage for 8 and 12 hours in UW solution and its variants, modified Krebs-Ringer
      solution and Euro-Collins solution, but showed moderate damage to mitochondria
      and swelling of the endoplasmic reticulum in normal Krebs-Ringer solution. In
      addition, damage to the sinusoidal endothelial cells was observed after 4 hours
      in normal Krebs-Ringer solution and after 8 to 12 hours in the other solutions.
      In conclusion, the only factor determining the intracellular concentration of
      diffusible ions after cold tissue storage is the ionic composition of the
      extracellular medium. X-ray microanalysis provides an objective method for
      assessing whether the intracellular ionic composition of tissue is maintained
      during storage.

PMID- 12619025
TI  - The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in
      sinusoidal endothelial cells during liver preservation injury.
AB  - Cold ischemia (CI)-warm reperfusion (WR) liver injury remains a problem in liver
      transplantation. CI-WR initially causes sinusoidal endothelial cell (SEC)
      apoptosis through a caspase-dependent mechanism. We previously showed that the
      caspase inhibitor IDN-1965 prevents CI-WR-induced SEC apoptosis. However, this
      agent required to be administered to the donor, preservation solution, and
      recipient for efficacy. Here, we show that a second-generation caspase inhibitor,
      IDN-6556, effectively prevents CI-WR-induced SEC injury when added only to
      University of Wisconsin (UW) cold storage media. Rat livers were stored in UW
      solution for 24 hours at 4 degrees C and reperfused for 1 hour at 37 degrees C.
      Apoptosis was quantitated using terminal deoxynucleotide transferasemediated
      deoxyuridine triphosphate nick end labeling (TUNEL) assay and caspase 3
      activation determined by biochemical measurement and immunohistochemical
      analysis. Pan-caspase inhibitors (IDN-8066, IDN-7503, IDN-7436, IDN-1965, and IDN
      6556) were applied at preischemic, cold preservation, or reperfusion periods.
      TUNEL-positive SEC and caspase 3-like activity in the liver was increased by CI
      WR. Three caspase inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively
      attenuated SEC apoptosis and caspase 3 activation. The most potent inhibitor, IDN
      6556, reduced SEC apoptosis and caspase 3 activity by 55% and 94%, respectively.
      Prevention of SEC apoptosis by IDN-6556 was not reduced when this agent was
      administered only during the cold preservation period. When added to the
      preservation solution, the caspase inhibitor IDN-6556 appears to be a feasible
      therapeutic agent against ischemia-reperfusion injury in liver transplantation.

PMID- 12619027
TI  - Systemic hemodynamic effects of treatment with the molecular adsorbents
      recirculating system in patients with hyperacute liver failure: a prospective
      controlled trial.
AB  - The aim of the study is to evaluate the effect of a single treatment with the
      molecular adsorbents recirculating system (MARS) on systemic hemodynamics and
      oxygen consumption (VO(2)) in patients with hyperacute liver failure (HALF). In a
      controlled design, eight patients with HALF were assigned to a 6-hour MARS
      treatment, and five patients, to a control group that was mechanically cooled to
      match the MARS group. Systemic hemodynamic variables were determined hourly
      during the study period. In the MARS group, systemic vascular resistance index
      increased by 46% from 1,215 +/- 437 to 1,778 +/- 710 dynes x s x cm(-5) x m(-2)
      (P <.0001), which significantly exceeded a 6% increase in the control group. Mean
      arterial pressure increased from 69 +/- 5 to 83 +/- 11 mm Hg in the MARS group (P
      <.0001) and was unchanged in the control group. Cardiac index decreased by 20%
      from 4.6 +/- 1.8 to 3.7 +/- 1.1 L/min x m(-2) (P =.0007) in the MARS group and by
      7% in the control group. Heart rate decreased from 105 +/- 21 to 85 +/- 15
      beats/min in the MARS group (P <.0001) and was unchanged in the control group. In
      the MARS group, oxygen delivery decreased from 621 +/- 198 to 486 +/- 141 mL/min
      x m(-2) (P <.05), and VO2, from 142 +/- 31 to 112 +/-21 mL/min x m(-2) (P <.05).
      Arterial lactate and pH levels were unchanged. In conclusion, systemic
      hemodynamic values tend to normalize, whereas systemic VO(2) decreases during
      MARS treatment in patients with HALF. These effects cannot be explained by the
      degree of cooling associated with MARS.

PMID- 12619026
TI  - Prevention of ischemic-type biliary lesions by arterial back-table pressure
      perfusion.
AB  - Ischemic-type biliary lesions (ITBLs) lead to considerable morbidity after
      orthotopic liver transplantation (OLT). The exact pathogenesis is unknown. We
      tested the hypothesis that insufficient perfusion of biliary arterial vessels
      might be responsible for ITBLs. This could be prevented by improved perfusion
      techniques. Since February 2000, we performed a controlled study using arterial
      back-table pressure perfusion (AP) to achieve reliable perfusion of the biliary
      tract capillary system, which may be impaired by the high viscosity of University
      of Wisconsin solution. We retrospectively analyzed 190 OLTs performed between
      September 1997 and July 2002 with regard to ITBLs. One hundred thirty-one grafts
      were preserved by in situ standard perfusion (SP), including portal perfusion,
      whereas in 59 cases, additional AP was performed. Donor-related factors,
      recipient age, indication for OLT, OLT technique, immunosuppression, and ischemia
      time were similar in both groups. In the SP group, 21 of 131 patients (16%)
      developed ITBLs. Only 1 of 59 patients with grafts receiving AP developed ITBLs.
      This difference was highly significant (P =.004). Peak aspartate aminotransferase
      (AST) and alanine aminotransferase (ALT) levels within the first 3 days were
      significantly lower in the AP group (AST, P =.016; ALT, P =.007). Multivariate
      analysis showed a significant influence of AP (P =.010) and donor age (P =.003)
      on the development of ITBLs. AP is an easy and reliable method to prevent ITBLs
      in OLT. It therefore should be used as the standard technique in liver
      procurement.

PMID- 12619028
TI  - Membrane barrier of a porcine hepatocyte bioartificial liver.
AB  - Pores in the membrane of a bioartificial liver (BAL) allow it to function as a
      semipermeable barrier between its contents (i.e., liver cells) and components of
      the recipient's immune system. This study is designed to assess the influence of
      pore size on immune response to a BAL containing porcine hepatocytes. Sixteen
      healthy dogs were divided into four groups (four dogs per group) based on pore
      size of the BAL membrane and level of exposure to porcine hepatocytes. Group 1
      dogs were administered porcine hepatocytes by intraperitoneal injection and
      served as positive controls. Group 2 dogs were exposed to porcine hepatocytes in
      a large-pore (200-nm) BAL, and group 3 dogs were exposed to porcine hepatocytes
      in a small-pore (10-nm) BAL. Group 4 dogs were exposed to a no-cell (unloaded)
      BAL and served as negative controls. Intraperitoneal injection of hepatocytes or
      3 hours of BAL hemoperfusion was performed day 0 and 3 weeks later on day 21.
      Biochemical, humoral, and cellular measures of immune response were collected
      until day 44. The initiation of BAL hemoperfusion was associated with a rapid
      decline in CH(50) levels of complement and transient neutropenia and
      thrombocytopenia during all BAL exposures. Xenoreactive antibody response to BAL
      was increased by use of membranes with large pores and secondary exposures. Skin
      testing on day 42 showed a delayed-type hypersensitivity response to porcine
      hepatocytes that also correlated with level of previous antigen exposure. BAL
      treatment was associated with both immediate and elicited immunologic responses.
      The immediate response was transient and not influenced by membrane pore size,
      whereas elicited responses were influenced by pore size of the BAL during
      previous exposures.

PMID- 12619030
TI  - Epithelioid hemangioendothelioma and the elusive vacuole.

PMID- 12619029
TI  - Outflow reconstruction in extended right liver grafts from living donors.
AB  - The risk of outflow obstruction in extended right liver grafts remains a concern.
      We developed two procedures to minimize torsion in venous anastomosis and to
      achieve a short warm ischemic time of the graft. When there were no major short
      hepatic veins in the graft, a square-shaped vein graft was used to make a single
      orifice using the middle and right hepatic veins in the graft. When
      reconstruction of multiple short hepatic veins was necessary, a cryopreserved
      inferior vena cava graft was used, which was anastomosed with the hepatic veins
      of the graft ex situ. These techniques were applied in 10 patients with good
      results without torsion of the hepatic venous reconstruction or other
      complications. Our new techniques might be useful for recipients of extended
      right liver grafts to secure nontortuous venous reconstructions with a short warm
      ischemic time of the graft.

PMID- 12619032
TI  - Seventeenth Aspen Cancer Conference: mechanisms of toxicity, carcinogenesis,
      cancer prevention, and cancer therapy.

PMID- 12619033
TI  - Requirement of c-jun for testosterone-induced sensitization to N-(4
      hydroxyphenyl)retinamide-induced apoptosis.
AB  - Androgen stimulation strongly affects the sensitivity to anticancer drug-induced
      apoptosis in prostate cancer cells. We investigated the influence of androgen
      stimulation with testosterone on N-(4-hydroxyphenyl)retinamide (4-HPR)-induced
      apoptosis in the androgen-sensitive prostate cancer cell line LNCaP.
      Overexpression of a dominant negative form of mitogen-activated protein kinase
      kinase 7, a specific kinase of c-jun NH(2)-terminal kinase (JNK), significantly
      inhibited 4-HPR-induced JNK activation and apoptosis and canceled the hormone
      dependent sensitization. Testosterone activated extracellular signal-regulated
      kinase (ERK), activating protein-1, subsequently increased the expression of c
      jun. In addition, testosterone significantly enhanced in vivo phosphorylation of
      c-jun by 4-HPR as well as JNK activation. Transfection with an antisense
      oligonucleotide of c-jun blocked 4-HPR-induced apoptosis and the testosterone
      induced sensitization, suggesting a major contribution of the JNK/c-jun mediated
      pathway in androgen-dependent sensitization. Interestingly, inhibition of
      testosterone-induced activation by PD98059 also canceled an upregulation of c-jun
      and increased apoptosis. These results suggested that modulation of JNK
      activation and expression of c-jun through ERK might have been essentially
      involved in androgen-mediated sensitization to 4-HPR-induced apoptosis in
      prostate cancer cells.

PMID- 12619034
TI  - Overexpression of hMTH in peripheral lymphocytes and risk of prostate cancer: a
      case-control analysis.
AB  - Oxidative damage is an important factor in prostate carcinogenesis, and
      overexpression of human MutT homolog (hMTH), a repair gene that removes oxidative
      damage, is a molecular marker of cellular oxidative stress. Therefore, we tested
      the hypothesis that overexpression of hMTH in unaffected (normal) surrogate
      tissue is associated with risk of prostate cancer in a pilot study of 51 patients
      with diagnosed prostate cancer and 50 age- and ethnicity-matched controls. Total
      RNA was extracted from phytohemagglutinin-stimulated peripheral blood lymphocytes
      of these subjects. We performed the real-time reverse transcription-polymerase
      chain reaction assay to evaluate the relative mRNA expression of three oxidative
      damage-repair genes, human MutM homolog (hMMH), hMTH, and human MutY homolog
      (hMYH), with beta-actin and human O(6)-methylguanine DNA methyltransferase
      (hMGMT) as the internal controls. The relative gene expression levels of hMMH and
      hMTH were borderline higher in the cases than in controls (15.3% and 28.8%
      higher, respectively; P = 0.046 and P = 0.035, respectively), whereas no increase
      was observed for hMYH and hMGMT. With the median of the controls' values as the
      cutoff point, we observed that a high expression level of hMTH, but not of other
      genes, was associated with a significantly increased risk of prostate cancer
      (odds ratio = 2.62; 95% confidence interval = 1.13-6.75) after adjustment for age
      and ethnicity. These results suggested that increased expression of hMTH in
      peripheral lymphocytes may be a risk factor for prostate cancer and support our
      priori hypothesis. Although our findings were biologically plausible and
      consistent with the literature, they were preliminary and need to be confirmed in
      larger studies. In addition, a correlation between the expression level of hMTH
      and the level of oxidative DNA damage in the target tissues needs to be
      established as well.

PMID- 12619035
TI  - Hepatocyte growth factor, transforming growth factor alpha, and their receptors
      as combined markers of prognosis in hepatocellular carcinoma.
AB  - A change in the balance between proliferation and apoptosis in the course of
      hepatocellular carcinoma (HCC) development and progression has been suspected. We
      wanted to identify related genes whose mRNA levels could provide markers of
      severity and prognosis after resection. The extent of cell apoptosis,
      proliferation, and differentiation was measured with a terminal deoxynucleotidyl
      transferase-mediated deoxyuridine 5-triphosphate-biotin nick-end labeling assay,
      and the Ki-67 index was determined in paired tumor and cirrhotic tissue samples
      from patients who had undergone HCC resection after diagnosis of hepatitis C
      related or alcoholism-related cirrhosis. These patients included two groups with
      highly versus poorly differentiated tumor cells, and the latter was split into
      two subgroups of those with versus without early recurrence. The mRNA levels for
      various apoptosis-related or proliferation-related genes and those for the growth
      factor/receptor systems were measured by quantitative reverse transcriptase
      polymerase chain reaction in paired tumor and cirrhotic liver samples from every
      patient, and some of the corresponding proteins were detected by
      immunohistochemistry. In all instances, protein expression was highly
      heterogeneous within groups and similar between groups. In contrast, some
      differences in mRNA level between tumor and cirrhotic tissues were quite
      informative. Low levels of hepatocyte growth factor and transforming growth
      factor alpha mRNAs were found concomitantly in highly differentiated tumors,
      whereas overexpression of mRNAs for the cognate receptors c-met and epidermal
      growth factor receptor were found in poorly differentiated tumors and primarily
      in patients with early tumor recurrence. These results argue for growth factor
      dependent HCC development and provide novel and combined prognosis markers after
      HCC surgery.

PMID- 12619036
TI  - Insulin-like growth factor binding protein-1 over-expression in transgenic mice
      inhibits hepatic preneoplasia.
AB  - Insulin-like growth factor binding protein-1 (IGFBP-1) is synthesized in the
      liver and regulates the mitogenic effects of the insulin-like growth factors
      (IGFs). The evidence that IGFBP-1 plays a role in hepatocarcinogenesis, however,
      is equivocal. We have, therefore, investigated the development of preneoplastic
      hepatic lesions in transgenic mice in which the human IGFBP-1 gene is under the
      control of the mouse metallothionein promoter. The lesions were induced by
      treating 15-d-old male mice with a single intraperitoneal injection of 5 mg/kg
      diethylnitrosamine (DENA). Lesions were scored when the mice were 28 wk of age.
      Quantitative microscopy of liver sections revealed that significantly fewer
      transgenic mice treated with zinc to activate the transgene had focal lesions
      compared to either transgenic mice not treated with zinc or wild-type mice
      treated with zinc (36.4% versus 85.7% and 83.3%, respectively, P < 0.05 in each
      case). Zinc-treated transgenic mice also had significantly fewer lesions per
      liver (11.5 +/- 5.0 versus 74.7 +/- 18.4 and 59.4 +/- 15.6, respectively, P <
      0.01 in each case) and a smaller percentage of liver volume occupied by lesions
      (0.2 +/- 0.1 versus 1.4 +/- 0.3 and 1.1 +/- 0.4 respectively, P < 0.05 in each
      case). Immunohistochemical staining showed that both IGF-I and IGF-II were
      overexpressed in most of the lesions. These results show that expression of the
      IGFBP-1 transgene leads to a marked inhibition of hepatic preneoplasia, possibly
      by decreasing the mitogenic activity of IGF-I and/or IGF-II. This study adds new
      evidence to the notion that the IGF axis plays an important role in liver cancer
      development.

PMID- 12619037
TI  - Fhit gene alterations in hepatocarcinogenesis induced by a choline-deficient L
      amino acid-defined diet in rats.
AB  - Alterations of the fragile histidine triad (Fhit) gene were investigated in rat
      hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined (CDAA)
      diet. Males of the F344 strain, 6 wk of age, were fed a CDAA diet, and subgroups
      were killed at 2, 4, 12, 20, and 75 wk after the beginning of the experiment.
      Fifteen hepatocellular carcinomas (HCCs) were noted in rats by the last time
      point; they were dissected free from the surrounding tissue. Normal control liver
      specimens were obtained from 6-wk-old rats. Total RNAs were extracted from whole
      livers of animals fed the CDAA diet for 2, 4, 12, and 20 wk and from HCCs, for
      assessment of aberrant transcription of the Fhit gene by reverse transcription
      polymerase chain reaction. Aberrant transcripts were detected in livers of rats
      fed the CDAA diet for 4, 12, and 20 wk, but not 2 wk, as well as in 11 of 15 HCCs
      (73.3%). Southern blot analysis showed a genomic DNA abnormality in one of seven
      informative HCCs (14.3%), while Western blot analysis showed reduction of Fhit
      protein expression in seven of nine HCCs (77.8%). No abnormal expression was
      evident in the livers after exposure to the CDAA diet for 2-20 wk. These results
      suggest that Fhit alterations may play important roles in hepatocarcinogenesis
      due to choline deficiency in rats.

PMID- 12619038
TI  - Inhibition of cell-cycle effectors of proliferation in bladder tumor epithelial
      cells by the p75NTR tumor suppressor.
AB  - The neurotrophin (NTR) receptor (p75(NTR)) is a cell-surface glycoprotein that
      binds to the neurotrophin family of growth factors, of which the prototypic
      member is nerve growth factor (NGF). This receptor was previously shown to retard
      cell-cycle progression by inducing accumulation of cells in G(1) with a
      concomitant reduction of cells in the S phase of the cell cycle. Furthermore,
      p75(NTR) was shown to be an effective tumor suppressor of bladder cancer cell
      growth in vivo. In order to investigate the mechanism of p75(NTR)-dependent
      suppression of cell-cycle progression, we utilized transgenic clones of bladder
      tumor cells that express p75(NTR) in increasing concentrations to demonstrate an
      effect of p75(NTR) on the levels of cell-cycle regulatory proteins that modulate
      proliferation of tumor cells. A rank-order (dose-dependent) increase in p75(NTR)
      protein expression was associated with a decrease in cell proliferation. This
      p75(NTR)-dependent suppression of proliferation was rescued with NGF. In the
      absence of ligand, a dose-dependent increase in p75(NTR) protein expression was
      associated with reduced expression of cyclin D1, cyclin E, and cyclin-dependent
      kinase 2 (cdk2) as well as decreased cdk2 activity. There was also a decrease in
      the expression of hyper-phosphorylated retinoblastoma protein, the transcription
      factor E2F1, and proliferating cell nuclear antigen, and there was an increase in
      expression of hypophosphorylated Rb and the cdk inhibitor p16(Ink4a) with
      increasing p75(NTR) expression. Treatment of tumor cells with NGF ameliorated
      these p75(NTR)-dependent changes in the levels of cell-cycle regulatory proteins
      and rescued the tumor cells from p75(NTR)-dependent inhibition of proliferation.
      Hence, it can be concluded that p75(NTR) inhibits proliferation by altering the
      expression of cell-cycle regulatory proteins and that NGF ameliorates this
      effect.

PMID- 12619039
TI  - Rundown of a transient potassium current is attributable to changes in channel
      voltage dependence.
AB  - Many ionic currents undergo significant rundown during whole-cell recording.
      Although rundown is an artifact associated with the recording method, studying
      the mechanism of rundown may lead to understanding mechanisms regulating channel
      functions in physiological conditions. The mechanisms for rundown, however,
      remain obscure for many channels. Here we have studied the mechanism for rundown
      of an A-type K(+) current in mouse striatal cholinergic interneurons. The
      interneuron expressed a prominent component of A-type current which exhibited
      significant rundown during whole-cell recording. When the current was assessed
      with a highly hyperpolarized prepotential (-140 mV), however, the rundown was
      virtually fully suppressed, suggesting its being dependent on voltage. Estimation
      of channel voltage dependence revealed that both activation and inactivation
      curves shifted towards hyperpolarized potentials during rundown. The shift was
      suppressed by intracellular ATP, but was affected neither by phosphatase
      inhibitors nor by antioxidative reagents. The gradual shift of inactivation curve
      towards negative potentials would make the holding potential progressively
      inactivate the channel, resulting in apparent loss of activity of the channels.
      Our results thus provide a biophysical explanation for rundown of A-type current.
      .

PMID- 12619040
TI  - Differential effects of atypical and typical antipsychotic drugs on N-methyl-D
      aspartate- and electrically evoked responses in the pyramidal cells of the rat
      medial prefrontal cortex.
AB  - In the present study, we have demonstrated that atypical antipsychotic drugs
      (APDs, e.g., clozapine, olanzapine, risperidone, and quetiapine) and atypical APD
      candidates (e.g., M100907 and Y-931) share a common property in facilitating
      responses evoked by electrical stimulation of the forceps minor and by N-methyl-D
      aspartate (NMDA), but not (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4
      propionic acid (AMPA), in pyramidal cells of the medial prefrontal cortex (mPFC).
      The concentrations of these drugs to exert their action are in a clinically
      relevant range. Although haloperidol has shown a considerably smaller
      potentiation of NMDA-evoked current at 50 and 100 nM, it consistently depressed
      the AMPA-induced current. Chlorpromazine and loxapine failed to modulate
      significantly NMDA- or AMPA-induced current in the pyramidal cells. Moreover,
      haloperidol and loxapine demonstrated depression of excitatory postsynaptic
      currents, whereas chlorpromazine did not show any effect. These findings combined
      indicate that atypical, but not typical, APDs augment glutamatergic
      neurotransmission in pyramidal cells of the mPFC. We propose that the beneficial
      effect of atypical APDs in cognitive dysfunction and negative symptoms in
      schizophrenia is due to their ability to enhance glutamatergic neurotransmission
      in the PFC and functionally related limbic structures. Our results further
      suggest the possible use of glutamatergic neurotransmission in the mPFC as a
      model for screening and studying the action of potential atypical APDs.

PMID- 12619041
TI  - Different brain kinetics of two sigma 1 receptor ligands, [3H](+)-pentazocine and
      [11C]SA4503, by P-glycoprotein modulation.
AB  - We compared the brain kinetics of radiolabeled (+)-pentazocine and SA4503, which
      have a high and selective affinity for sigma(1) receptors. Brain uptake of
      [(11)C]SA4503 was high after intravenous injection followed by a gradual decrease
      in mice, whereas that of [(3)H](+)-pentazocine rapidly decreased. The brain
      uptake of the two radioligands was dose-dependently reduced, but the reduction of
      [(3)H](+)-pentazocine was found at higher doses. Percentages of the saturable
      binding of [(3)H](+)-pentazocine was much lower than that of [(11)C]SA4503. The
      brain uptake of [(3)H](+)-pentazocine was greatly blocked by SA4503 at a dose of
      2 micromol/kg, while that of [(11)C]SA4503 was blocked by (+)-pentazocine at a
      dose of 20 micromol/kg and over. When mice were treated with cyclosporin A, a P
      glycoprotein modulator, the uptake of [(3)H](+)-pentazocine was enhanced, but
      that of [(11)C]SA4503 was not. Under control and P-glycoprotein-modulated
      conditions, the brain uptake of both radioligands was reduced by haloperidol,
      another representative sigma receptor ligand, to a different extent. We concluded
      that the P-glycoprotein modulation resulted in the different brain kinetics of
      the two radioligands. The radiolabeled SA4503 is suitable as an in vivo probe,
      but radiolabeled (+)-pentazocine is not.

PMID- 12619042
TI  - Dopamine transporter gene, response to methylphenidate and cerebral blood flow in
      attention-deficit/hyperactivity disorder: a pilot study.
AB  - The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1)
      seems to be associated with a poor response to methylphenidate (MPH) in children
      with attention-deficit/hyperactivity disorder (ADHD). This pilot study aimed to
      simultaneously assess polymorphisms at DAT1, response to MPH, and neuroimaging.
      Only ADHD children with at least a moderate response to MPH were included.
      Significantly higher regional cerebral blood flows assessed by single photon
      emission computerized tomography (SPECT) were detected in medial frontal and left
      basal ganglia areas in children with homozygosity for the 10-repeat allele at
      DAT1 gene (n = 4) than in children without this genotype (n = 4) (P < 0.05).
      These findings provide a preliminary connection between pharmacogenetics and
      neurobiological investigations on stimulant treatment of ADHD.

PMID- 12619043
TI  - Behavioral and subthalamic effects of combining a fetal ventral mesencephalic
      transplant in striatum with an electrolytic lesion of the entopeduncular nucleus
      in the rat with a unilateral 6-OHDA lesion of substantia nigra.
AB  - Behavioral and electrophysiological methods were used to determine whether a
      transplant of dopamine-rich fetal tissue in striatum combined with an
      electrolytic lesion of the entopeduncular nucleus have additive effects in the
      unilaterally lesioned rat model for Parkinson's disease. The subjects were rats
      with the left substantia nigra lesioned with 6-hydroxydopamine (6-OHDA) and
      responding to systemic amphetamine with rotation toward the side of the lesion
      (ipsilateral rotation). The motor response to amphetamine was fractionated into
      six aspects, half reflecting the unilateral deafferentation in striatum and half
      representing those aspects of the response evoked in normal rats. After
      collection of baseline values, 25 rotators received a transplant of fetal ventral
      mesencephalic tissue in the left striatum and 20 received a transplant and, at
      the same time, an electrolytic lesion of the left entopeduncular nucleus. Testing
      for the motor response to amphetamine resumed after 4 weeks of recovery and
      continued at weekly intervals for 5 weeks. Upon completion of these tests, each
      rotator was implanted with multiple electrodes in the subthalamic nucleus. After
      recovery, multiunit responses to amphetamine and apomorphine were recorded from
      several electrodes in parallel during the motor response to the drugs. In
      rotators with transplant only, treatment with amphetamine evoked oral stereotypy
      and an attenuated ipsilateral rotation response. In rotators with combined
      transplant and entopeduncular lesion, ipsilateral rotation did not change or
      increased. Subthalamic responses to amphetamine and apomorphine were larger in
      rotators with combined transplant and entopeduncular lesion than in rotators with
      transplant alone. These findings indicate that the combination of transplant and
      pallidotomy in the 6-OHDA rat model for parkinsonism does not lead to additive
      benefits, an effect that may have been due to the nonselectivity of the
      electrolytic damage and/or of the lesion extending beyond the entopeduncular
      nucleus into the lateral hypothalamus.

PMID- 12619044
TI  - Nitric oxide modulates striatal neuronal activity via soluble guanylyl cyclase:
      an in vivo microiontophoretic study in rats.
AB  - It is now well established that nitric oxide (NO) acts as a neuromodulator in the
      central nervous system. To assess the role of NO in modulating striatal activity,
      single-unit recording was combined with iontophoresis to study presumed spiny
      projection neurons in urethane-anesthetized male rats. Striatal neurons recorded
      were essentially quiescent and were therefore activated to fire by the
      iontophoretic administration of glutamate, pulsed in cycles of 30 sec on and 40
      sec off. In this study, iontophoresis of 3-morpholinosydnonimine hydrochloride
      (SIN 1), a nitric oxide donor, produced reproducible, current-dependent
      inhibition of glutamate-induced excitation in 12 of 15 striatal neurons, reaching
      its maximal inhibitory effect (76.2 +/- 5.6% below baseline) during the
      application of a 100 nA current. Conversely, microiontophoretic application of N
      omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide
      synthase, produced clear and reproducible excitation of glutamate evoked firing
      in 7 of 10 cells (51.4 +/- 2.3%, at 100 nA). To evaluate the involvement of
      cyclic guanosine monophosphate (cGMP) in the electrophysiological effects
      produced by the NO donor, the effects of methylene blue, an inhibitor of guanylyl
      cyclase, on the responses of nine neurons to SIN 1 were tested. In six of nine
      neurons the effect of SIN 1 was significantly reduced during continuous
      iontophoretic administration (50 nA) of methylene blue. Taken together, these
      data show that NO modulates the striatal network and that inhibitory control of
      the output neurons is involved in this effect. These results also suggest that
      the effects of nitric oxide on striatal neurons are partially mediated via cGMP.

PMID- 12619045
TI  - Demography, female life history, and reproductive profiles among the chimpanzees
      of Mahale.
AB  - Demography provides critical data to increase our understanding of the evolution,
      ecology, and conservation of primate populations. The chimpanzees of the Mahale
      Mountains National Park, Tanzania, have been studied for more than 34 yr on the
      basis of individual identification and standardized attendance records. From this
      long-term study, we derived the following demographic data: The major cause of
      death was disease (48%), followed by senescence (24%) and within-species
      aggression (16%). Fifty percent of Mahale chimpanzees died before weaning. The
      median ages of female life history variables were: first maximal swelling, 10.0
      yr (n = 5); emigration, 11.0 yr (n = 11); and first birth, 13.1 yr (n = 5). The
      median period of adolescent infertility was 2.8 yr (n = 4) when calculated from
      the age at immigration to that at first birth. Female fecundity was highest
      between 20 and 35 yr of age, with an annual birth rate of 0.2. Twenty-six females
      that were observed from a young age (10-13 yr) to death at various ages (15-40
      yr) gave birth to an average of 3.9 and weaned an average of 1.4 offspring.
      Twenty-five females that were observed from middle age (18-33 yr) to death in
      older age (31-48) gave birth to an average of 2.7 and weaned an average of 2.0
      offspring. The post-reproductive lifespan for female chimpanzees was defined as
      the number of years that passed from the year when the last offspring was born to
      the year when the female died, minus 5. Twenty-five percent of old females had a
      post-reproductive lifespan. The interbirth interval after the birth of a son (x =
      72 mo) tended to be longer than that after the birth of a daughter (x = 66 mo).
      The extent of female transfer, which is a rule in chimpanzees, is influenced by
      the size and composition of the unit group and size of the overall local
      community.

PMID- 12619046
TI  - Prevalence of antibodies to selected viruses in a long-term closed breeding
      colony of rhesus macaques (Macaca mulatta) in Brazil.
AB  - The rhesus macaque breeding colony of the Oswaldo Cruz Foundation (FIOCRUZ) was
      established in 1932 from a founding stock of 100 animals. This population has
      remained closed to new animal introductions for almost 70 years. A serologic
      survey was performed to determine the prevalence of antibodies to selected
      viruses as a first approach to identifying viral pathogens endemic in this
      population. Banked serum samples were tested for antibodies to simian
      immunodeficiency virus (SIV), simian T-lymphotropic virus (STLV), simian type D
      retrovirus (SRV), cercopithecine herpesvirus type-1 (B virus), rhesus
      cytomegalovirus (RhCMV), measles virus (MV), and hepatitis A virus (HAV). All
      samples were negative for antibodies against the simian retroviruses. The overall
      prevalence of antibodies was 95% for RhCMV, 45% for B virus, 35% for HAV, and 1%
      for MV. Prevalence was found to vary by age group.

PMID- 12619047
TI  - Ranging behavior and foraging ecology of lowland woolly monkeys (Lagothrix
      lagotricha poeppigii) in Yasuni National Park, Ecuador.
AB  - In a year-long study, I investigated the ranging behavior of lowland woolly
      monkeys (Lagothrix lagotricha poeppigii) in a terra firma rainforest in Yasuni
      National Park, Ecuador, and examined the relationship between ranging, diet, food
      availability, and food patch use for this population. In Yasuni the total home
      range sizes for two social groups were 124 and 108 ha, which are much smaller
      than has been reported previously for Lagothrix elsewhere in its geographic
      distribution. The mean yearly day range estimates for these same groups were
      1,792 m and 1,878 m, which are well within the range of variation previously
      reported. Ranging behavior was not correlated with the current habitat-wide
      abundance of ripe fruit, which comprises 76.3% of the yearly diet for this
      population, but was associated with one measure of likely insect prey abundance
      and with the availability of immature fruits, a minimal part of the diet.
      Specifically, one study group moved significantly greater distances during months
      of high likely insect prey abundance and when immature fruits were abundant. The
      second study group also traveled farther when likely insect prey abundance was
      high and when immature fruits were abundant, although the latter relationship
      only approached significance. This group also devoted significantly more of its
      daily activity budget to travel during these times. These results indicate that
      variation in ripe fruit abundance makes no meaningful contribution to explaining
      variation in ranging behavior for this population of woolly monkeys. Instead, the
      results raise the possibility that some aspects of the ranging behavior of
      frugivorous primates may be related to the availability of alternative food
      sources, such as animal prey, or to monitoring the phenological status of
      important fruit trees, rather than simply reflecting the degree of intragroup
      feeding competition.

PMID- 12619048
TI  - Colors of primate pelage and skin: objective assessment of conspicuousness.
AB  - We present a quantitative means of assessing the conspicuousness of animal coats
      or other objects in terms of the color vision of each possible observer. We
      measured reflectance spectra from the fur and skin of many primate species in
      order to provide an objective survey of the possibilities of pelage coloration
      found in extant primates. We show that the orange coloration displayed by many
      platyrrhine and some strepsirhine primates, while being conspicuous to humans,
      would be cryptic amongst foliage to all males and many females of their own
      species. In relation to this finding, we briefly review what is known of the
      color vision of birds that prey on primates, and assess how conspicuous the
      orange pelage would be to these predators.

PMID- 12619050
TI  - Pharmacokinetics of intravenous chlorzoxazone in rats with dehydration and
      rehydration: effects of food intakes.
AB  - The following results were obtained recently from our laboratories; in rats with
      72-h water deprivation (rats with dehydration), the hepatic cytochrome P450 2E1
      (CYP2E1) was three-fold induced with an increase in the mRNA. Rehydration of 48-h
      water-deprived rats for the next 24 h with free access of food (rats with
      rehydration) restored CYP2E1 level to that of control. However, rehydration of 48
      h water-deprived rats for the next 24 h with limited food supply (20% of control)
      failed to restore the CYP2E1 level to that of control. Hence, the CYP2E1 changes
      in rats with dehydration and rehydration resulted from differences in food
      intakes but not from dehydration or rehydration per'se. Chlorzoxazone (CZX) is
      metabolized to 6-hydroxychlorzoxazone (OH-CZX) mainly by CYP2E1 in rats.
      Therefore, the pharmacokinetics of CZX and OH-CZX were compared after intravenous
      administration of CZX, 25 mg/kg, to control rats and rats with dehydration and
      rehydration with free access of food. In rats with dehydration, the amount of 24
      h urinary excretion of free OH-CZX plus its glucuronide conjugates (Ae (OH-CZX, 0
      24 h,) expressed in terms of intravenous dose of CZX) was significantly greater
      (45.6 compared with 35.6%) and area under the plasma concentration-time curve
      from time zero to time infinity (AUC) of CZX was significantly smaller (2190
      compared with 3200 micro g min/ml) than those in control rats. The above data
      indicated that the formation of OH-CZX increased significantly in rats with
      dehydration due to 3-fold induction of CYP2E1. In rats with rehydration with free
      access of food, the Ae (OH-CZX, 0-24 h) (39.0 compared with 35.6%) and AUC of CZX
      (2870 compared with 3200 micro g min/ml) were restored (comparable) to control
      levels since the expression of CYP2E1 in rats with dehydration returned to
      control level by rehydration. The above data indicate that CZX could be used as a
      chemical probe to assess the activity of CYP2E1 in rats with dehydration and
      rehydration.

PMID- 12619051
TI  - Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein
      calorie malnutrition.
AB  - The effects of cysteine on the pharmacokinetics of itraconazole were investigated
      after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to
      control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein
      calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral
      cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After
      intravenous administration of itraconazole to rats with PCM, the area under the
      plasma concentration-time curve from time zero to time infinity (AUC) of
      itraconazole was significantly greater (3580 compared with 2670 and 2980 microg
      min/ml) than those in control rats and rats with PCMC (the values between control
      rats and rats with PCMC were not significantly different). The above data
      suggested that metabolism of itraconazole decreased significantly in rats with
      PCM due to suppression of hepatic microsomal cytochrome p450 (CYP) 3A23 in the
      rats. The results could be expected since in rats with PCM, the level of CYP3A23
      decreased significantly as compared to control. Itraconazole was reported to be
      metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in
      human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology.
      By cysteine supplementation (rats with PCMC), the AUC of itraconazole was
      restored fully to control levels.

PMID- 12619052
TI  - Characterisation of the human liver in vitro metabolic pattern of artemisinin and
      auto-induction in the rat by use of nonlinear mixed effects modelling.
AB  - AIMS: The aims of the study were to characterise the metabolic pattern of
      artemisinin in human and rat liver microsomes and to assess the magnitude of auto
      induction in the rat. METHODS: (14)C-artemisinin was incubated with human liver
      microsomes and with liver microsomes from rats pretreated with oral artemisinin
      or placebo. The metabolic fate of (14)C-artemisinin in microsomes from human B
      lymphoblastoid cell lines transformed with CYP2A6, CYP2B6 and CYP3A4 was also
      investigated. The human liver microsome data and the rat liver microsomes data
      were analysed by nonlinear mixed effects modelling and naive pooling using
      NONMEM, respectively. RESULTS: Four metabolites were radiometrically detected in
      experiments with rat liver microsomes. The model that best described the data
      involved three primary metabolites of which one metabolite was further
      metabolised to a secondary metabolite. The formation of the four metabolites was
      induced 2.8, 7.2, 4.8 and 2.5-fold, respectively, in liver microsomes from rats
      pre-treated with artemisinin. Three metabolites were formed in human liver
      microsomes; having the same retention times as three of the metabolites formed in
      the rat. The final model consisted of two primary metabolites and a secondary
      metabolite with CYP2B6 and CYP2A6 influencing the formation rates of the major
      and minor primary metabolites, respectively. CONCLUSIONS: CYP2B6 and CYP2A6
      activities described variability in the formation of the major and minor primary
      metabolites, respectively, in human liver microsomes. All artemisinin metabolic
      pathways in rat liver microsomes were induced in artemisinin pretreated animals.
      We suggest modelling as a method for the discrimination and detection of more
      complex metabolic patterns from in vitro metabolism rate data.

PMID- 12619054
TI  - What is a false-negative result for sentinel node procedures in breast cancer?

PMID- 12619053
TI  - Human cytochromes mediating gepirone biotransformation at low substrate
      concentrations.
AB  - Biotransformation of gepirone to 1-(2-pyrimidinyl)-piperazine (1-PP) and 3'-OH
      gepirone, as well as two other hydroxylated metabolites, was studied in vitro
      using a human liver microsomal preparation and heterologously expressed human
      CYP3A4 and CYP2D6. The focus was on a low range of gepirone concentrations (1000
      nM and below). Liver microsomes formed 1-PP and 3'-OH-gepirone with similar
      reaction velocities. Two other hydroxylated metabolites (2-OH- and 5-OH-gepirone)
      were also formed, but pure reference standards were not available for purposes of
      quantitative analysis. The CYP3A inhibitor ketoconazole completely eliminated 1
      PP formation, reduced 3'-OH-gepirone formation to less than 20% of control, and
      reduced 2-OH-gepirone formation to 7% of control. All metabolites were formed by
      expressed CYP3A4; however, CYP2D6 formed 3'-OH- and 5-OH-gepirone, but not 1-PP
      or 2-OH-gepirone. Based on estimated relative abundances of the two isoforms in
      human liver, CYP3A4 was predicted to account for more than 95% of net clearance
      of gepirone in vivo at low concentrations approaching the therapeutic range.
      CYP2D6 would account for less than 5% of net clearance. The findings are
      consistent with previous in vitro studies of gepirone using higher substrate
      concentrations.

PMID- 12619055
TI  - Previous wide local excision of primary melanoma is not a contraindication for
      sentinel lymph node biopsy of the trunk and extremity.
AB  - BACKGROUND AND OBJECTIVES: The role of sentinel lymph node biopsy (SLNB) in
      patients with a previous wide local excision (WLE) was examined with case-control
      methodology. METHODS: A total of 168 consecutive cases of SLNB were performed in
      patients with truncal and extremity melanoma with tumor thickness of > or = 1 mm
      between October 1997 and June 2000 and were followed prospectively. For
      comparison, 65 of the 103 SLNB patients referred to us after their WLE (cases)
      were matched by tumor thickness to 65 patients who had SLNB with concurrent WLE
      (controls). Radiocolloid (technetium-99m sulfur colloid) was used in all cases;
      in addition, vital blue dye (patent blue) was used in the control group. The two
      groups were followed for a median of 15.4 months. RESULTS: SLNs were identified
      in all patients with an average of 2.1 (cases) and 2.0 (controls) SLNs excised
      per patient (P = 0.77). Twenty one (32.3%) of those having SLNB after previous
      WLE (cases) and 23 (35.4%) of those with concurrent WLE and SLNB (controls) were
      found to have metastatic disease in the SLN. The only false-negative in this
      group was detected in clinical follow-up in a patient whose truncal WLE was
      previously closed with a rotation flap (case). There was no significant
      difference in relapse-free survival (P = 0.209) and overall survival (P = 0.692)
      between groups. CONCLUSIONS: SLNB is feasible in patients with previous WLE for
      extremity and truncal melanoma. Similar rates of sentinel positivity are found
      when compared with those in whom their WLE was done concurrently.

PMID- 12619056
TI  - Postoperative taste and smell deficit after upper gastrointestinal cancer surgery
      -an unreported complication.
AB  - BACKGROUND AND OBJECTIVES: Patients undergoing upper gastrointestinal cancer
      surgery were noted to suffer loss of taste and/or smell, a previously unreported
      problem. Our aim was to investigate the extent of this phenomenon, quantify
      recovery time, and identify potentially associated factors. METHODS: In this
      retrospective study, a postal questionnaire was sent to all patients still alive
      after oesophagectomy or gastrectomy, with a minimum 1-year follow-up and no
      clinical or radiological evidence of recurrence. Data were analysed for
      prevalence of deficit in relation to operation, age, sex, respiratory
      complications, and disease stage. RESULTS: A total of 109/119 (92%) patients
      completed the questionnaire: 50 gastrectomies and 69 oesophagectomies. Ten
      patients were excluded with prior sensory deficit. Overall, 45/99 patients (45%)
      suffered deficit (M:F = 1.6:1). No association was found with type of surgery:
      deficits for subtotal gastrectomy, total gastrectomy, and oesophagectomy were 44,
      46 and 46% respectively (chi(2) = 0.355, 2 df P > 0.5). No other parameter was
      associated, and full recovery occurred in 30 patients (67%) within a mean of 6
      months. CONCLUSIONS: Loss of taste and smell occurs in nearly one-half of all
      cases after upper gastrointestinal surgery. The pathophysiology is unknown, but
      it resolves in most patients within 6-12 months. This complication should be
      discussed as part of informed consent for patients undergoing oesophagogastric
      cancer surgery.

PMID- 12619058
TI  - Immunohistochemically detected micrometastasis in lymph nodes from superficial
      esophageal squamous cell carcinoma.
AB  - BACKGROUND AND OBJECTIVES: This study was conducted to determine the incidence
      and clarify the patterns of nodal micrometastasis, to elucidate the
      histopathologic parameters of tumor extension correlating with micrometastasis,
      and to evaluate whether nodal micrometastasis has clinical significance in
      patients with superficial esophageal cancer. METHODS: Lymph nodes resected from
      78 patients with superficial esophageal squamous cell carcinoma were examined
      immunohistochemically using the monoclonal antibody cocktail AE1/AE3 to define
      histologically undetectable micrometastasis. Clinical records and pathologic
      features of all cases were reviewed. RESULTS: Of the 78 patients, 34 had neither
      micro- nor overt disease in the lymph nodes, 12 had nodal micrometastasis only,
      and 32 had histologically overt metastasis. Nodal micrometastasis was found in
      carcinomas reaching the muscularis mucosae or deeper tissues of the esophagus.
      Multivariate analysis showed that intraesophageal multicentric cancer and venous
      invasion had significant correlation with nodal micrometastasis (P = 0.005 and
      0.017, respectively). However, no clinical impact of nodal micrometastasis could
      be detected regarding patient outcome. CONCLUSIONS: Nodal micrometastasis is not
      rare in patients with superficial esophageal cancer, but it does not appear to
      have clinical significance in these patients. Nodal micrometastasis correlates
      with intraesophageal multicentric cancer and venous invasion.

PMID- 12619059
TI  - Sensitization of thermotolerant SCK cells to hyperthermia and freezing with
      reduction of intracellular pH: implications for cryosurgery.
AB  - BACKGROUND AND OBJECTIVES: During cryosurgery, cells frozen slowly at the outer
      part of the ice ball undergo severe dehydration and are subject to solute effects
      injury, which may be caused in part by protein denaturation. This study was
      undertaken to determine whether heat shock proteins (HSPs), the molecular
      chaperones that stabilize proteins against denaturation, have a protective effect
      on cells during slow freezing. In addition, we aimed to determine whether acidic
      conditions, similar to those found in many solid tumors, would effect this
      protection. METHODS: SCK cells were frozen at 5 degrees C/min to -10 degrees C or
      -20 degrees C before or after induction of thermotolerance, and at neutral or low
      pH conditions. Lethal damage was determined by clonogenics. RESULTS: Clonogenic
      survival was decreased by 50% in thermotolerant cells frozen to -10 degrees C
      after culture in acidic conditions (pH 6.6) compared with non-thermotolerant
      cells cultured at neutral pH. Induction of thermotolerance alone or low pH alone
      did not significantly sensitize SCK cells to freezing. All treatment groups were
      equally susceptible to killing when frozen to -20 degrees C. CONCLUSIONS: Our
      results show that induction of thermal tolerance does not protect SCK cells
      against subsequent freezing injury and that a low pH environment actually
      sensitizes these cells to freeze injury.

PMID- 12619060
TI  - Mitochondrial DNA alterations in thyroid cancer.
AB  - BACKGROUND: Alterations in mitochondrial DNA have been identified in a number of
      solid tumor types, including gastric, head and neck, breast, colorectal, lung,
      and bladder carcinomas. Recently, a homopolymeric C stretch (D310) located within
      the noncoding D-loop of the mitochondrial genome was identified and described as
      a mutational hotspot. The objective of the present study was to examine a series
      of thyroid cancers for genetic alterations in this region. METHODS: Seventy-two
      (72) thyroid cancers were examined for alterations in D310 using PCR-based
      methods. The primary tumors tested included 35 papillary carcinomas, 18 medullary
      carcinomas, 9 anaplastic carcinomas, 9 follicular carcinomas, and 1 insular
      carcinoma. RESULTS: Alterations in D310 were observed in 2/35 papillary
      carcinomas (5.7%), 1/18 medullary carcinomas (5.6%), 1/9 anaplastic carcinomas
      (11.1%), and 1/9 follicular carcinomas (11.1%). Overall, the rate of alterations
      was 5/72 (6.9%). CONCLUSIONS: Mutations in the D310 region of the D-loop of
      mitochondrial DNA are found in thyroid tumors of varying histologic types and
      grades. This mutation rate is lower than the reported rate of alteration in
      tumors of epithelial origin, and shows no relationship to histologic grade.

PMID- 12619062
TI  - Cytochrome P-450 expression and lipid peroxidation in gallbladder cancer.
AB  - BACKGROUND AND OBJECTIVES: Carcinoma of the gallbladder is the commonest neoplasm
      of the biliary tract; however, the etiology of this tumor remains unclear.
      METHODS: A case-control study was carried out comprising 50 patients with
      gallbladder cancer and 50 patients with cholelithiasis. Cytochrome P-450
      estimation was carried out in the gallbladder tissue, and lipid peroxide product
      melonaldehyde (MDA) was measured in gallbladder bile. Statistical analysis was
      carried out by Student's t-test, and one-way analysis of variance (ANOVA). The
      Pearson correlation coefficient was calculated, and linear regression analysis
      was performed. RESULTS: The mean cytochrome P-450 concentration was significantly
      higher in patients with carcinoma of the gallbladder than in controls (t = 3.9, P
      < 0.001; F = 15.2, P = 0.002). Similarly, the mean concentration of melonaldehyde
      was significantly higher among cancer patients than in patients with gallstones
      (t = 2.7, P < 0.003; F = 7.37, P = 0.0078). No significant correlation was
      observed between tissue MDA and cytochrome P-450 levels (Pearson r = 0.1, P =
      0.28). CONCLUSIONS: The results of the present study show that the rise in
      concentration of MDA is independent of the rise in concentration of cytochrome P
      450; however, this is statistically insignificant. This could be due to biliary
      stasis leading to a rise in biliary concentration of melonaldeyde that is
      disproportionate to its production.

PMID- 12619063
TI  - Quantitative expression of protein markers of plasminogen activation system in
      prognosis of colorectal cancer.
AB  - BACKGROUND AND OBJECTIVES: Certain pathophysiological markers may be helpful in
      selecting further therapies for patients with resected colorectal cancer (CRC).
      The aim of this study was to determine whether expression of proteins of the
      plasminogen activation system (PAS), which are important in tumor spread and
      growth, can predict outcome of human CRC. METHODS: Protein expression of the PAS,
      including urokinase-type plasminogen activator (uPA) and its receptor (uPAR),
      plasminogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI
      2), was determined in the colonic tissue samples of 56 patients with resected
      primary CRC by quantitative immunohistochemistry and correlated with
      clinicopathological parameters and patient outcome. RESULTS: Overexpression of
      uPA (t-test, P < 0.001), uPAR (P < 0.001) and PAI-1 (P = 0.031) was significantly
      associated with liver metastatic CRC tumors. Higher uPA or uPAR expression level
      was significantly correlated with overall survival (OS; log-rank, P = 0.001 and P
      < 0.0001) and cancer-specific survival (CSS; P = 0.001 and P < 0.0001) after the
      first CRC resection. The predictive value of both uPA and uPAR in liver
      metastasis, OS and CSS was independent from other parameters (multivariate Cox
      regression: all P < 0.001). CONCLUSIONS: uPA and uPAR may be independent
      predictors of liver metastasis, patient overall survival and cancer-specific
      survival after resection of colorectal tumors.

PMID- 12619061
TI  - Increased dihydropyrimidine dehydrogenase activity in breast cancer.
AB  - BACKGROUND AND OBJECTIVES: Although studies have focused on modulating the
      bioavailability of 5-FU through inhibition of dihydropyrimidine dehydrogenase
      (DPD) to improve efficacy of the drug, activity of this enzyme in breast cancer
      has not been thoroughly examined. We measured DPD activity in primary and
      metastatic lesions and benign breast tumors to evaluate the clinical significance
      of this enzyme in the treatment of breast cancer. METHODS: DPD activity was
      measured by catalytic assay and compared in 100 primary tumors (95 invasive
      carcinomas, 5 intraductal carcinomas), 26 uninvolved adjacent breast tissue
      specimens, 6 metastatic sites, and 7 intraductal papillomas. RESULTS: The enzyme
      level in the carcinomas was 4-fold that of adjacent uninvolved breast tissues
      (101 vs 23 pmol/min/mg protein, P < 0.001). Enzyme activity in intraductal
      papilloma (120 pmol/min/mg protein) was comparable to that in invasive carcinoma.
      There were no significant differences in DPD activity related to
      clinicopathologic features, but a tendency toward increased DPD activity was
      observed in progesterone receptor-negative breast cancer (P = 0.09). There was
      marginal correlation in enzyme activity between primary and metastatic lesions (P
      = 0.07). CONCLUSIONS: DPD activity is substantially upregulated in breast cancer
      tissue and is higher than that reported previously. The clinical implications of
      DPD inhibitors in patients being treated for breast cancer with oral
      fluoropyrimidine chemotherapy should be further investigated.

PMID- 12619064
TI  - Combined loss of expression of O6-methylguanine-DNA methyltransferase and hMLH1
      accelerates progression of hepatocellular carcinoma.
AB  - BACKGROUND AND OBJECTIVES: O(6)-methylguanine-DNA methyltransferase (MGMT) and
      human Mut L homologue 1 (hMLH1) are proteins that play an important role in DNA
      repair. No reports have yet described whether deficient MGMT and hMLH1 expression
      correlates with tumor progression and the prognosis of patients with
      hepatocellular carcinoma (HCC). METHODS: Using immunohistochemical analysis, we
      evaluated the expression status of MGMT and hMLH1 protein in 60 paraffin-embedded
      samples from consecutive patients with curatively resected HCC. RESULTS: The lack
      of expression of both MGMT and hMLH1 in HCCs (n = 7) correlated with advanced
      pTNM stage (P = 0.039), as compared with HCCs expressing both proteins (n = 25).
      The absence of both MGMT and hMLH1 was a significant indicator of malignant
      potential. The expression status of both MGMT and hMLH1 was a predictive factor
      for overall survival in patients with HCC (P < 0.001). CONCLUSIONS: HCC lacking
      both MGMT and hMLH1 is correlated with an advanced stage and a poor prognosis.
      The expression status of both repair proteins is a predictive prognostic marker
      in patients with HCC after surgical resection.

PMID- 12619065
TI  - Metastatic potential of dermatofibrosarcoma protuberans with fibrosarcomatous
      change.
AB  - Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon fibrohistiocytic
      tumor that is locally aggressive. DFSP is associated with frequent local
      recurrences but rarely metastasizes. It has been suggested that fibrosarcomatous
      change within a dermatofibrosarcoma protuberans (DFSP-FS) is associated with
      increased risk of local recurrence and distant metastases. Metastases remain
      rare, however, and are typically preceded by multiple local recurrences. We
      report a rare case of a DFSP-FS metastasis to the head of the pancreas without
      any preceding local recurrence.

PMID- 12619066
TI  - Current management of melanoma: benefits of surgical staging and adjuvant
      therapy.
AB  - Issues regarding appropriate management of stage I to III melanoma are addressed.
      Accurate surgical staging is critical to identifying patients who can benefit
      from therapeutic lymph node dissection and adjuvant therapy. Patients with
      primary tumors > or = 1 mm thick are appropriate candidates for sentinel lymph
      node biopsy, and node-positive patients benefit from therapeutic lymphadenectomy.
      Although the overall survival benefit of high-dose interferon has been
      questioned, the weight of evidence supports the use of adjuvant therapy in
      patients with stage IIB and III disease.

PMID- 12619067
TI  - Impact of very old age on hypothalamic dopaminergic neurons in the female rat: a
      morphometric study.
AB  - Dopaminergic neurons of the A(12) (tuberoinfundibular dopaminergic system) and
      A(14) (periventricular dopaminergic system) hypothalamic areas exert a tonic
      inhibitory control of prolactin secretion. Tuberoinfundibular dopaminergic system
      neuron function is known to decline during aging in rats, but little is known
      about the impact of extreme age on neuron number and morphology in the two
      systems. We morphometrically assessed the neurons of the tuberoinfundibular
      dopaminergic system and the periventricular dopaminergic system in female rats 6
      (young, Y), 24 (old, O), and 30-32 (senescent, S) months old. Serial coronal
      sections of fixed hypothalami were immunohistochemically labeled for tyrosine
      hydroxylase, and immunoreactive perikarya from the A(12) and A(14) areas were
      quantitatively characterized and compared among the three age groups.
      Radioimmunoassay was used to measure serum prolactin. The number of A(12)
      tyrosine hydroxylase-immunoreactive perikarya showed a steady decline with age,
      whereas the number of A(14) tyrosine hydroxylase-immunoreactive perikarya
      remained stable from young to old age but showed a sharp drop in the senescent
      rats. In the old rats, tyrosine hydroxylase-immunoreactive neuronal area (A(12) =
      135.37 and A(14) = 158.79 microm(2)) was significantly higher than that of young
      (A(12) = 72.56 and A(14) = 99.7 microm(2)) and senescent animals (A(12) = 95.5
      and A(14) = 106.5 microm(2)). Densitometric assessment of median eminence
      tyrosine hydroxylase immunoreactivity revealed a steady age-related reduction of
      tyrosine hydroxylase content in the median eminence. Serum prolactin levels
      increased steadily with age. We conclude that, in the female rat, aging brings
      about a progressive loss of both tuberoinfundibular dopaminergic system and
      periventricular dopaminergic system neurons, which becomes more conspicuous at
      extreme ages.

PMID- 12619068
TI  - Ribosomal RNA transcriptional activation and processing in hamster rubrospinal
      motoneurons: effects of axotomy and testosterone treatment.
AB  - Rubrospinal motoneurons (RSMN) represent a population of androgen receptor
      expressing central motoneurons with limited regenerative potential relative to
      their peripheral counterparts. A key determinant of regenerative capability lies
      in the nucleolar reaction of injured neurons. To date, characterization of the
      nucleolar reaction in injured central motoneurons has not been accomplished.
      Furthermore, it has been documented that testosterone propionate (TP) augments
      peripheral motoneuron regeneration through regulation of the nucleolar reaction
      to injury. In this study, the effects of injury alone, or in conjunction with TP,
      on the nucleolar response of injured RSMN were examined using in situ
      hybridization (ISH) techniques. Castrated adult male hamsters were subjected to
      right spinal cord hemisection at the C7/T1 vertebral level. Half the animals were
      subcutaneously implanted with one Silastic TP capsule, with the other half sham
      implanted. ISH for precursor 45S and mature 28S rRNA was accomplished with a (3)H
      labeled ribosomal DNA probe specific to the external transcribed spacer region or
      to the 28S region of the ribosomal gene, respectively. Postoperative times of 2,
      6, and 24 hours were selected for examination of precursor 45S rRNA (i.e., rRNA
      transcriptional activation) levels and 0.25, 2, 4, and 14 days for examination of
      mature rRNA (i.e., ribosome) levels. Transcriptional activation of the rRNA gene
      was rapidly and transiently increased in injured RSMN, analogously to previously
      documented effects of injury on rRNA transcription in peripheral motoneurons,
      but, in contrast, this did not translate into an increase in mature ribosomes. TP
      administration failed to affect positively the nucleolar response of injured RSMN
      at all. From this study, a key component underlying inherent differences in the
      regenerative capacity of peripheral vs. central motoneurons has been identified,
      which can be targeted in future experiments designed to enhance the regenerative
      potential of selective neuronal populations.

PMID- 12619069
TI  - Not all butterfly eyes are created equal: rhodopsin absorption spectra, molecular
      identification, and localization of ultraviolet-, blue-, and green-sensitive
      rhodopsin-encoding mRNAs in the retina of Vanessa cardui.
AB  - Surveys of spectral sensitivities, visual pigment spectra, and opsin gene
      sequences have indicated that all butterfly eyes contain ultraviolet-, blue-, and
      green-sensitive rhodopsins. Some species also contain a fourth or fifth type,
      related in amino acid sequence to green-sensitive insect rhodopsins, but red
      shifted in absorbance. By combining electron microscopy, epi
      microspectrophotometry, and polymerase chain reaction cloning, we found that the
      compound eye of Vanessa cardui has the typical ultrastructural features of the
      butterfly retina but contains only the three common insect rhodopsins. We
      estimated lambda-max values and relative densities of the rhodopsins in the
      Vanessa retina (0.72, P530; 0.12, P470; and 0.15, P360) from
      microspectrophotometric measurements and calculations based on a computational
      model of reflectance spectra. We isolated three opsin-encoding cDNA fragments
      that were identified with P530, P470, and P360 by homology to the well
      characterized insect rhodopsin families. The retinal mosaic was mapped by opsin
      mRNA in situ hybridization and found to contain three kinds of ommatidia with
      respect to their patterns of short wavelength rhodopsin expression. In some
      ommatidia, P360 or P470 was expressed in R1 and R2 opposed receptor cells; in
      others, one cell expressed P360, whereas its complement expressed P470. P530 was
      expressed in the other seven cells of all ommatidia. P470-expressing cells were
      abundant in the ventral retina but nearly absent dorsally. Our results indicated
      that there are major differences between the color vision systems of nymphalid
      and papilionid butterflies: the nymphalid Vanessa has a simpler, trichromatic,
      system than do the tetrachromatic papilionids that have been studied.

PMID- 12619070
TI  - Ultrastructural analysis of a putative magnetoreceptor in the beak of homing
      pigeons.
AB  - With the use of different light and electron microscopic methods, we investigated
      the subcellular organization of afferent trigeminal terminals in the upper beak
      of the homing pigeon, Columba livia, which are about 5 microm in diameter and
      contain superparamagnetic magnetite (SPM) crystals. The SPM nanocrystals are
      assembled in clusters (diameter, approximately 1-2 microm). About 10 to 15 of
      these clusters occur inside one nerve terminal, arranged along the cell membrane.
      Each SPM cluster is embedded in a solid fibrous cup, open towards the cell
      surface, to which the cluster adheres by delicate fiber strands. In addition to
      the SPM clusters, a second inorganic iron compound has been identified:
      noncrystalline platelets of iron phosphate (about 500 nm wide and long and
      maximally 100 nm thick) that occur along a fibrous core of the terminal. The
      anatomic features suggested that these nerve endings could detect small intensity
      changes of the geomagnetic field. Such stimuli can induce deformations of the SPM
      clusters, which could be transduced into primary receptor potentials by
      mechanosensitive membrane receptor channels. The subepidermal fat cells
      surrounding the nerve endings prevent the inside from external mechanical
      stimuli. These structural findings corresponded to conclusions inferred from rock
      magnetic measurements, theoretical calculations, model experiments, and
      behavioral data, which also matched previous electrophysiologic recordings from
      migratory birds.

PMID- 12619071
TI  - Spatial organization of the pigeon tectorotundal pathway: an interdigitating
      topographic arrangement.
AB  - The retinotectofugal system is the main visual pathway projecting upon the
      telencephalon in birds and many other nonmammalian vertebrates. The ascending
      tectal projection arises exclusively from cells located in layer 13 of the optic
      tectum and is directed bilaterally toward the thalamic nucleus rotundus. Although
      previous studies provided evidence that different types of tectal layer 13 cells
      project to different subdivisions in Rt, apparently without maintaining a
      retinotopic organization, the detailed spatial organization of this projection
      remains obscure. We reexamined the pigeon tectorotundal projection using
      conventional tracing techniques plus a new method devised to perform small deep
      brain microinjections of crystalline tracers. We found that discrete injections
      involving restricted zones within one subdivision retrogradely label a small
      fraction of layer 13 cells that are distributed throughout the layer, covering
      most of the tectal representation of the contralateral visual field. Double
      tracer injections in one subdivision label distinct but intermingled sets of
      layer 13 neurons. These results, together with the tracing of tectal axonal
      terminal fields in the rotundus, lead us to propose a novel "interdigitating"
      topographic arrangement for the tectorotundal projection, in which intermingled
      sets of layer 13 cells, presumably of the same particular class and distributed
      in an organized fashion throughout the surface of the tectum, terminate in
      separate regions within one subdivision. This spatial organization has
      significant consequences for the understanding of the physiological and
      functional properties of the tectofugal pathway in birds.

PMID- 12619072
TI  - Some glial progenitors in the neonatal subventricular zone migrate through the
      corpus callosum to the contralateral cerebral hemisphere.
AB  - The great majority of glial cells of the mammalian forebrain are generated in the
      perinatal period from progenitors in the subventricular zone (SVZ). We
      investigated the migration of progenitors from the neonatal (postnatal day 0, P0)
      rat forebrain SVZ by labeling them in vivo with a green fluorescence protein
      (GFP) retrovirus and monitoring their movements by time-lapse video microscopy in
      P3 slices. We identified a small number of progenitors that migrated tangentially
      within the corpus callosum (CC) and crossed the midline. These cells retained a
      relatively uniform morphology: the leading process was extended toward the
      contralateral side but showed no process branching or turning away from the
      migratory direction. Net migration requires the elongation of the leading process
      and nuclear translocation, and the migrating cells in the CC showed both modes.
      We confirmed the presence of unmyelinated axon bundles within the P3 CC, but
      failed to detect any radially directed glial processes (vimentin- or GLAST
      immunolabeled fibers) spanning through the CC. Confocal images showed a close
      proximity between neurofilament-immunolabeled axons and the leading process of
      the GFP-expressing progenitors in the CC. The destination of the callosal fibers
      was examined by applying DiI to the right cingulum; the labeled fibers ran
      throughout the CC and reached the left cingulate and motor areas. The
      distribution and final fates of the retrovirus-labeled cells were examined in P28
      brains. A small proportion of the labeled cells were found in the contralateral
      hemisphere, where, as oligodendrocytes and astrocytes, they colonized
      predominantly the cortex and the underlying white matter of the cingulate and
      secondary motor areas. The distribution pattern appears to coincide well with the
      projection direction of the callosal fibers. Thus, glial progenitors migrate
      across the CC, presumably in conjunction with unmyelinated axons, to colonize the
      contralateral hemisphere.

PMID- 12619073
TI  - Inverse expression of olfactory cell adhesion molecule in a subset of olfactory
      axons and a subset of mitral/tufted cells in the developing rat main olfactory
      bulb.
AB  - The projection of olfactory sensory neuron (OSN) axons from the olfactory
      epithelium (OE) to the olfactory bulb (OB) is highly organized but
      topographically complex. Evidence suggests that odorant receptor expression zones
      in the OE map to the OB about orthogonal axes. One candidate molecule for the
      formation of zone-specific targeting of OSN axon synapses onto the OB is the
      olfactory cell adhesion molecule (OCAM). OCAM(+) OSNs are restricted to three of
      the four zones in the OE and project their axons to the ventral OB where they
      form synapses with mitral/tufted (M/T) cells. To determine when this zonal
      connection is established, we have examined OCAM expression in rat olfactory
      system, during seminal periods of glomerular formation. OCAM(+) axons sort out in
      the ventral olfactory nerve layer of the OB before glomerular formation.
      Surprisingly, OCAM was also expressed transiently by subsets of M/T cell
      dendrites located in the dorsal OB. The expression of OCAM by OSN axons and M/T
      dendrites was asymmetrical; in the dorsal OB, OCAM(-) OSN axons synapsed on
      OCAM(+) M/T dendrites, whereas in the ventral OB, OCAM(+) OSN axons synapsed on
      OCAM(-) M/T dendrites. The restricted spatial map of OCAM(+) M/T cells appeared
      earlier in development than the zonal segregation of OCAM(+) OSN axons. Thus,
      OCAM on M/T cell dendrites may act in a spatiotemporal window to specify regions
      of the developing rat OB, thereby establishing a foundation for mapping of the OE
      zonal organization onto the OB.

PMID- 12619074
TI  - Neurochemically distinct classes of myenteric neurons express the mu-opioid
      receptor in the guinea pig ileum.
AB  - The mu-opioid receptor (muOR), which mediates many of the opioid effects in the
      nervous system, is expressed by enteric neurons. The aims of this study were to
      determine whether 1) different classes of myenteric neurons in the guinea pig
      ileum contain muOR immunoreactivity by using double- and triple-labeling
      immunofluorescence and confocal microscopy, 2) muOR immunoreactivity is localized
      to enteric neurons immunoreactive for the endogenous opioid enkephalin, and 3)
      muOR immunoreactivity is localized to interstitial cells of Cajal visualized by c
      kit. In the myenteric plexus, 50% of muOR-immunoreactive neurons contained
      choline acetyltransferase (ChAT) immunoreactivity, whereas about 43% of ChAT
      immunoreactive neurons were muOR immunoreactive. Approximately 46% of muOR
      myenteric neurons were immunoreactive for vasoactive intestinal polypeptide
      (VIP), and about 31% were immunoreactive for nitric oxide synthase (NOS). MuOR
      immunoreactivity was found in about 68% of VIP-containing neurons and 60% of NOS
      immunoreactive neurons. Triple labeling showed that about 32% of muOR neurons
      contained VIP and ChAT immunoreactivities. The endogenous opioid enkephalin (ENK)
      was observed in about 30% of muOR neurons; conversely, 48% of ENK neurons
      contained muOR immunoreactivity. MuOR was not detected in neurons containing
      calbindin, nor in interstitial cells of Cajal. MuOR-immunoreactive fibers formed
      a dense network around interstitial cells of Cajal in the deep muscular plexus.
      This study demonstrates that muOR is expressed by neurochemically distinct
      classes of myenteric neurons that are likely to differ functionally, is
      colocalized with the endogenous opioid ENK, and is not expressed by interstitial
      cells of Cajal.

PMID- 12619075
TI  - Compartmentation of the mouse cerebellar cortex by neuronal calcium sensor-1.
AB  - Neuronal calcium sensor-1 (NCS-1) is a member of the EF-hand calcium-binding
      protein superfamily, which is considered to modulate synaptic transmission and
      plasticity. The detailed distribution of NCS-1 was analyzed in the mouse
      cerebellar cortex. In coronal sections, the NCS-1 immunostaining displayed
      characteristic parasagittal banding pattern in the Purkinje cell layer and
      molecular layer, while there were no apparent bands in the granule cell layer.
      The alternating positively and negatively NCS-1-labeled Purkinje cell clusters
      contributed to this cerebellar compartmentation. In contrast, stellate-basket
      cells were uniformly NCS-1-positive throughout the cerebellum. Immunofluorescent
      double staining showed that NCS-1 and zebrin II exhibited a similar parasagittal
      banding pattern. Then, we performed mapping of NCS-1- and/or zebrin II-labeled
      Purkinje cell somata using seven sequential coronal sections. NCS-1
      positive/zebrin II-positive Purkinje cell clusters were seen throughout the
      cerebellum, but NCS-1-positive/zebrin II-negative Purkinje cells were exceedingly
      rare. On the other hand, NCS-1-negative/zebrin II-positive Purkinje cell clusters
      were found in anterior lobule vermis and paraflocculus, whereas they were rarely
      seen in posterior lobules. The digitized quantitative analysis showed close
      relationship between NCS-1 and zebrin II immunoreactivity in the molecular layer.
      The correspondence between NCS-1 and zebrin II demonstrated here indicates a
      novel anteroposterior difference of cerebellar compartmentation and provides
      fundamental information of cerebellar organization.

PMID- 12619076
TI  - Normal chiasmatic routing of uncrossed projections from the ventrotemporal retina
      in albino Xenopus frogs.
AB  - Albino mammals lacking melanin in the embryonic retinal pigment epithelium (RPE)
      have abnormal retinal decussation patterns at the optic chiasm: their uncrossed
      projections are smaller and arise from fewer, more peripheral temporal retinal
      ganglion cells than in con-specific wild-types. To determine whether these
      abnormalities generalize to nonmammalian mutants, we used anterograde and
      retrograde labeling methods to compare the distribution of retinal projections to
      the thalamus in adult normal and albino Xenopus frogs. In both pigmentation
      phenotypes, crossed retinal terminations covered approximately 80% of the
      neuropil of Bellonci (nB) and corpus geniculatum thalamicum (cgt) and uncrossed
      inputs occupied, respectively, approximately 75% and 25% of these two main visual
      centers. In the wild-type frogs and in the albinos, ganglion cells giving rise to
      the crossed projections were distributed throughout the retina, whereas
      ipsilaterally projecting cells were confined to a specific ventrotemporal retinal
      division. This region comprised approximately 40% of the total retinal area, was
      bordered by a well-defined line of decussation, and contained an average of
      approximately 3,000 ipsilaterally projecting ganglion cells of equivalent soma
      sizes in the two pigmentation phenotypes. In summary, we found no evidence of
      chiasmatic misrouting in the uncrossed retinothalamic projections of albino
      Xenopus, even though these pathways are substantial in normal frogs and share
      features in common with mammalian retinogeniculate projections. Our findings
      suggest that congenital RPE melanin deficiency results in major defects in the
      development of the retina and its central projections only in mammals.

PMID- 12619077
TI  - Subzonal organization of olfactory sensory neurons projecting to distinct
      glomeruli within the mouse olfactory bulb.
AB  - Olfactory sensory neurons located in the nasal neuroepithelium send their axons
      directly into the olfactory bulb, where they contact the dendrites of second
      order neurons in specialized spherical structures called glomeruli; each sensory
      neuron projects to a single glomerulus. All neurons expressing the same odorant
      receptor gene are confined to distinct zones within the epithelium and converge
      their axons onto a small number of common glomeruli. In the present study, we
      analyzed transgenic mouse lines in which the projection of a neuron population
      expressing a particular receptor gene can be visualized as a result of axonal
      markers that are coexpressed. The target glomeruli could thus reproducibly be
      identified and allowed to deposit retrograde tracers precisely. After an
      appropriate incubation time, olfactory sensory neurons within distinct areas of
      the olfactory epithelium were labeled. The two subpopulations of neurons
      retrogradely stained by differently colored fluorescent dyes deposited at the
      dorsal and the dorsomedial glomerulus, respectively, were found to be segregated
      within distinct areas of the expression zone, where the cells expressing the same
      receptor type displayed a stochastic distribution.

PMID- 12619078
TI  - Reductions in N-acetylaspartylglutamate and the 67 kDa form of glutamic acid
      decarboxylase immunoreactivities in the visual system of albino and pigmented
      rats after optic nerve transections.
AB  - This study compares the immunohistochemical distributions of N
      acetylaspartylglutamate (NAAG) and the large isoform of the gamma-aminobutyric
      acid (GABA)-synthesizing enzyme glutamic acid decarboxylase (GAD(67)) in the
      visual system of albino and pigmented rats. Most retinal ganglion cells and their
      axons were strongly immunoreactive for NAAG, whereas GAD(67) immunoreactivity was
      very sparse in these cells and projections. In retinorecipient zones, NAAG and
      GAD(67) immunoreactivities occurred in distinct populations of neurons and in
      dense networks of strongly immunoreactive fibers and synapses. Dual-labeling
      immunohistochemistry indicated that principal neurons were stained for NAAG,
      whereas local interneurons were stained for GAD(67). In contrast to the
      distribution observed in retinorecipient zones, most or all neurons were doubly
      stained for NAAG and GAD(67) in the thalamic reticular nucleus. Ten days after
      unilateral optic nerve transection, NAAG-immunoreactive fibers and synapses were
      substantially reduced in all contralateral retinal terminal zones. The
      posttransection pattern of NAAG-immunoreactive synaptic loss demarcated the
      contralateral and ipsilateral divisions of the retinal projections. In addition,
      an apparent transynaptic reduction in GAD(67) immunoreactivity was observed in
      some deafferented areas, such as the lateral geniculate. These findings suggest a
      complicated picture in which NAAG and GABA are segregated in distinct neuronal
      populations in primary visual targets, yet they are colocalized in neurons of the
      thalamic reticular nucleus. This is consistent with NAAG acting as a
      neurotransmitter release modulator that is coreleased with a variety of classical
      transmitters in specific neural pathways.

PMID- 12619079
TI  - Morphology and axonal arborization of rat spinal inner lamina II neurons
      hyperpolarized by mu-opioid-selective agonists.
AB  - The ventral or inner region of spinal substantia gelatinosa (SG; lamina II(i)) is
      a heterogeneous sublamina important for the generation and maintenance of
      hyperalgesia and neuropathic pain. To test whether II(i) neurons can be
      hyperpolarized by the mu-opioid agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]
      enkephalin (DAMGO; 500 nM) and to address possible downstream consequences of mu
      opioid-evoked inhibition of II(i) neurons, we combined in vitro whole-cell, tight
      seal recording methods with fluorescent labeling of the intracellular tracer
      biocytin and confocal microscopy. Twenty-one of 23 neurons studied had
      identifiable axons. Nine possessed axons that projected ventrally into laminae
      III-V; six of these were hyperpolarized by DAMGO. Three of four neurons with
      identifiable axons that projected to lamina I were hyperpolarized by DAMGO. Most
      neurons could be classified as either islet cells or stalked cells. Five of nine
      labeled islet cells and only two of seven stalked cells were hyperpolarized by
      DAMGO. Three were stellate cells: one resembled a spiny cell and three could not
      be classified. DAMGO hyperpolarized each of the stellate cells, the spiny cell,
      and 1 of the unclassified cells. Our data support the hypothesis that part of the
      action of mu-opioid agonists involves the inhibition of interneurons that are
      part of a polysynaptic excitatory pathway from primary afferents to neurons in
      the deep and/or superficial dorsal horn.

PMID- 12619080
TI  - Differentiation of lamina I spinomedullary and spinothalamic neurons in the cat.
AB  - We characterized spinomedullary neurons that project to the ventrolateral portion
      of the medulla that receives lamina I terminations in two sets of experiments in
      the cat. First, their distribution was examined using single unilateral
      iontophoretic injections of cholera toxin subunit B. The injection sites were
      characterized by microelectrode recordings from nociceptive- and thermoreceptive
      specific units, indicative of lamina I input. The spinomedullary neurons were
      symmetrically distributed bilaterally, predominantly (63-69%) in lamina I but
      also in laminae V-VIII and the thoracic lateral horn (intermediolateral cell
      column). In horizontal sections, spinomedullary lamina I neurons included all
      three main morphological types described earlier. Second, spinomedullary and
      spinothalamic neurons were compared in retrograde double-labeling experiments.
      Different combinations of tracers were injected in the right thalamus and the
      left or right ventrolateral medulla (guided by recordings). The numbers of
      spinomedullary and spinothalamic neurons on the left side were comparable, and
      the segmental and laminar distributions were similar, except that a greater
      proportion of spinomedullary neurons originated from thoracic segments. However,
      the proportion of double-labeled neurons was consistently approximately 1%,
      indicating that spinomedullary and spinothalamic pathways arise from separate
      subpopulations. Spinomedullary neurons were more ventrally located within lamina
      I than spinothalamic neurons. A significantly greater proportion of
      spinomedullary neurons had fusiform somata (49% vs. 36%). These observations
      indicate that lamina I is the major source of spinal input to this portion of the
      ventrolateral medulla, that the projection includes several morphological types
      of inputs, and that this projection is distinct from the spinothalamic
      projection. These findings are consistent with the concept that lamina I
      projections constitute an ascending homeostatic afferent pathway relating the
      physiological condition of the body.

PMID- 12619081
TI  - Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic
      acid-treated rats.
AB  - The mossy fiber pathway in the dentate gyrus undergoes sprouting and synaptic
      reorganization in response to seizures. The types of new synapses, their location
      and number, and the identity of their postsynaptic targets determine the
      functional properties of the reorganized circuitry. The goal of this study was to
      characterize the types and proportions of sprouted mossy fiber synapses in
      kindled and kainic acid-treated rats. In normal rats, synapses labeled by Timm
      histochemistry or dynorphin immunohistochemistry were rarely observed in the
      supragranular region of the inner molecular layer when examined by electron
      microscopy. In epileptic rats, sprouted mossy fiber synaptic terminals were
      frequently observed. The ultrastructural analysis of the types of sprouted
      synapses revealed that 1) in the supragranular region, labeled synaptic profiles
      were more frequently axospinous than axodendritic, and many axospinous synapses
      were perforated; 2) sprouted mossy fiber synaptic terminals formed exclusively
      asymmetric, putatively excitatory synapses with dendritic spines and shafts in
      the supragranular region and with the soma of granule cells in the granule cell
      layer; 3) in contrast to the large sprouted mossy fiber synapses in resected
      human epileptic hippocampus, the synapses formed by sprouted mossy fibers in rats
      were smaller; and 4) in several cases, the postsynaptic targets of sprouted
      synapses were identified as granule cells, but, in one case, a sprouted synaptic
      terminal formed a synapse with an inhibitory interneuron. The results demonstrate
      that axospinous asymmetric synapses are the most common type of synapse formed by
      sprouted mossy fiber terminals, supporting the viewpoint that most sprouted mossy
      fibers contribute to recurrent excitation in epilepsy.

PMID- 12619082
TI  - Reaction of spinal cord central canal cells to cord transection and their
      contribution to cord regeneration.
AB  - After transection, the spinal cord of the eel Anguilla quickly regrows and
      reconnects, and function recovers. We describe here the changes in the central
      canal region that accompany this regeneration by using serial semithin plastic
      sections and immunohistochemistry. The progress of axonal regrowth was followed
      in material labeled with DiI. The canal of the uninjured cord is surrounded by
      four cell types: S-100-immunopositive ependymocytes, S-100- and glial fibrillary
      acidic protein (GFAP)-immunopositive tanycytes, vimentin-immunopositive dorsally
      located cells, and lateral and ventral liquor-contacting neurons, which label for
      either gamma-aminobutyric acid (GABA) or tyrosine hydroxylase (TH). After cord
      transection, a new central canal forms rapidly as small groups of cells at the
      leading edges of the transection create flat "plates" that serve as templates for
      subsequent formation of the lateral and dorsal walls. Profile counts and 5-bromo
      2'-deoxyuridine immunohistochemistry indicate that these cells are dividing
      rapidly during the first 20 days of the repair process. The newly formed canal,
      which bridges the transection by day 10 but is not complete until about day 20,
      is greatly enlarged (</=100 times) and is dominated by ependymocytes that are
      vimentin immunopositive, but cells expressing GABA, TH, and GFAP do not appear
      until days 11, 13, and 16, respectively. The proliferating ependyma do not
      provide a supportive scaffold for the regrowing axons, inasmuch as some have
      crossed the bridge before the canal has formed. However, their modified phenotype
      suggests a role, possibly trophic, for the central canal region following injury.

PMID- 12619083
TI  - Dendritic orientation and laminar architecture in the rabbit auditory thalamus.
AB  - A laminar organization composed of the dendritic fields of principal neurons and
      afferent axonal arbors has been proposed as the anatomical substrate for the
      frequency map at several levels of the mammalian central auditory system,
      including the inferior colliculus and medial geniculate body (MGB). In contrast
      to the auditory thalamus in most mammals, the ventral division of the rabbit
      medial geniculate body (MGV) has cellular laminae visible in routine Nissl
      stains, allowing a direct comparison of the laminar organization with the
      dendritic architecture and frequency organization. In total 30 presumptive relay
      neurons in the MGV were labeled with the juxtacellular recording method, and
      their dendritic arbors were fully reconstructed from serial sections with the aid
      of a computer microscope. The spatial organization of MGV dendritic fields was
      analyzed using the dendritic prism, dendritic stick, and fan-in projection
      methods. Quantitative spatial analyses revealed that, for MGV neurons in the
      central pars lateralis subdivision, the major axis of the dendritic fields
      (approximately 29 degrees relative to the horizontal plane) was closely aligned
      with that of the Nissl laminae (approximately 25 degrees). Both were oriented
      orthogonally to the tonotopic axis. In contrast, cells in the pars ovoidea had
      their major axis of orientation parallel to the anteroposterior axis of the
      brain. Although a bitufted dendritic field was the norm, it was not uncommon for
      MGV neurons to have pronounced spatial asymmetries in their dendritic fields. A
      model is presented that incorporates cellular laminae and oriented dendritic
      growth to form frequency-related slabs within the MGV.

PMID- 12619085
TI  - A clinician's view of spinal cord injury.
AB  - The primary cause of spinal cord injury (SCI) is automobile collisions, followed
      by violence, falls, and injuries in sporting events. The patient is most
      frequently a young male. Regardless of cause and age, SCI is a potentially
      catastrophic injury. The unique anatomical relationship of the spinal cord, being
      enclosed in the dural sac within the bony vertebral column, make it venerable to
      a wide range of traumatic insults. SCI is classified as complete or incomplete
      with several subclasses arranged under each of these respective headings. The
      probability of recovery to a functional state is usually better for patients with
      incomplete injuries. Treatment for SCI involves initially immobilizing the
      injured vertebral column, medications to prevent secondary injury, and potential
      surgery to release pressure on the spinal cord and restore stability to the
      vertebral column. Postsurgical care is directed toward prevention and treatment
      of secondary complications of SCI such as respiratory failure, deep venous
      thrombosis, and decubitus ulcers. Advances in these areas are providing patients
      with a greater probability of recovery, a longer life, and a better quality of
      life. Research in the clinical and basic sciences is opening new avenues of hope
      for the spinal cord injury patient.

PMID- 12619086
TI  - Olfactory ensheathing cells: historical perspective and therapeutic potential.
AB  - Olfactory ensheathing cells (OECs) are the glial cells that ensheath the axons of
      the first cranial nerve. They are attracting increasing attention from
      neuroscientists as potential therapeutic agents for use in the repair of spinal
      cord injury and as a source of myelinating glia for use in remyelinating axons in
      demyelinating diseases such as multiple sclerosis. This review mainly addresses
      the cell biological aspects of OECs pertinent to addressing two questions.
      Namely, where do OECs fit into the groupings of central nervous system
      (CNS)/peripheral nervous system (PNS) glial cells and should OECs be viewed as a
      clinically relevant alternative to Schwann cells in the treatment of spinal cord
      injury? The evidence indicates that OECs are indeed a clinically relevant
      alternative to Schwann cells. However, much more work needs to be done before we
      can even come close to answering the first question as to the lineage and
      functional relationship of OECs to the other types of CNS and PNS glial cells.

PMID- 12619087
TI  - Use of a cell line to investigate olfactory ensheathing cell-enhanced axonal
      regeneration.
AB  - Olfactory ensheathing cells (OECs), a unique type of macroglia required for
      normal olfactory axonal regeneration throughout the lifetime of an individual,
      have been shown to have regeneration-enhancing properties when used to treat
      various neuronal injuries. Availability of OECs is a hurdle facing future
      clinical use of the cells for spinal cord injury (SCI) therapy. The number of
      OECs that can realistically be harvested from each animal is limited, and
      ensuring a pure cell population is difficult. We have begun to characterize a
      nonsyngeneic strain of OECs, i.e., from a homogenous OEC clonal cell line
      (nOECs). The purpose of this study was to determine whether nOECs have the same
      properties and provide the same functional recovery after SCI, as primary
      cultures of OECs. The results indicate that nOECs survive in vivo, produce growth
      promoting proteins, and possess regeneration-promoting capabilities. Spinal cord
      injured rats that were treated with nOECs performed significantly better on
      functional tests than injured control animals beginning at 5 weeks after
      operation. In summary, evidence of nOEC regeneration-promoting capabilities
      suggests that this cell line can be used as potential therapy in SCI research.

PMID- 12619088
TI  - Remyelination by transplanted olfactory ensheathing cells.
AB  - The olfactory ensheathing cells (OECs) of the peripheral olfactory system
      associate with the axons of the first cranial nerve. These axons are not
      myelinated by OECs because of their very small diameter. However, when OECs are
      transplanted into areas where they encounter larger-diameter axons, such as in a
      model of primary demyelination, these cells assume a myelinating phenotype.
      Myelinating OECs very closely resemble myelinating Schwann cells by all criteria
      currently examined, including morphology, ultrastructure, biochemistry, and
      transcriptional regulation. Indeed, it is currently impossible to reliably
      distinguish myelinating OECs and myelinating Schwann cells that have been
      transplanted into experimental models of CNS demyelination. This article
      describes recent studies on the myelinating properties of transplanted OECs,
      focusing on their intrinsic myelinating potential and how this can be augmented
      by the presence of meningeal cells. The relative merits of OECs compared with
      Schwann cells when transplanted into astrocyte-containing lesions in the CNS are
      discussed together with their potential role in transplanted-mediated repair of
      demyelinating disease such as multiple sclerosis.

PMID- 12619089
TI  - Olfactory ensheathing glia transplantation: a therapy to promote repair in the
      mammalian central nervous system.
AB  - A therapy to treat injuries to the central nervous system (CNS) is, to date, a
      major clinical challenge. The devastating functional consequences they cause in
      human patients have encouraged many scientists to search, in animal models, for a
      repair strategy that could, in the future, be applied to humans. However,
      although several experimental approaches have obtained some degree of success,
      very few have been translated into clinical trials. Traumatic and demyelinating
      lesions of the spinal cord have attracted several groups with the same aim: to
      find a way to promote axonal regeneration, remyelination, and functional
      recovery, by using a simple, safe, effective, and viable procedure. During the
      past decade, olfactory ensheathing glia (OEG) transplantation has emerged as a
      very promising experimental therapy to promote repair of spinal cords, after
      different types of injuries. Transplants of these cells promoted axonal
      regeneration and functional recovery after partial and complete spinal cord
      lesions. Moreover, olfactory ensheathing glia were able to form myelin sheaths
      around demyelinated axons. In this article, we review these recent advances and
      discuss to what extent olfactory ensheathing glia transplantation might have a
      future as a therapy for different spinal cord affections in humans.

PMID- 12619090
TI  - Use of ThinPrep monolayer technique and cytospin preparation in urine cytology: a
      comparative analysis.
AB  - We compared the ThinPrep (TP) technique to the cytospin (CS) preparation in the
      cytological diagnosis of urine by processing 79 specimens by these two
      techniques. Ten cases were positive for malignancy (six high grade (HG)/carcinoma
      in situ; four low grade (LG) transitional cell carcinomas (TCC)). Forty-eight
      cases were within normal limits (59%) and 21 cases had atypical cytological
      features (19%). The TP technique was better in terms of a cleaner background with
      fewer obscuring inflammatory cells and blood and with a more even distribution of
      cells. In general, the cytomorphology was comparable in both techniques. However,
      in cases with malignancy, CS was relatively superior in the cytomorphologic
      details; in TP, the diagnostic cells were mostly dispersed as single cells with
      loss of architectural features and were difficult to find. Artifactual empty
      spaces and air-drying were more frequently present in TP. In cases contaminated
      with squamous cells, the urothelial cells were difficult to find in TP. Screening
      time was comparable for both techniques. In conclusion, to avoid false-negative
      diagnosis, CS would be complementary to the TP technique in malignant cases and,
      in particular, those with low cellularity.

PMID- 12619091
TI  - Fine-needle aspiration of leiomyosarcoma: a correlative cytohistopathological
      study of 96 tumors in 68 patients.
AB  - To better define the cytological features of various leiomyosarcoma (LMS)
      variants, we reviewed the fine-needle aspiration material and the corresponding
      histologic sections of 96 tumors in 68 patients. Histological variants of LMS
      were as follows: 80 (83.3%) were of the classical/usual, seven (7.3%) were
      epithelioid, and nine (9.4%) were myxoid. Review of original cytology reports
      showed that 23 (24%) tumors were diagnosed as LMS and 69 (71.8%) as other types
      of malignancies. Two (2.1%) cases were reported as suspicious and two (2.1%) were
      unsatisfactory. The classical variants of LMS were characterized cytologically by
      various proportions of spindle-shaped, cohesive, small- or large-sized cells
      arranged in parallel alignment. Large spindle, round, binucleated, giant cells
      with intracytoplasmic granulations were frequently seen. Blunt-ended nuclei,
      intranuclear inclusions and mitotic figures were occasionally seen, as well as
      stromal fragments. The epithelioid tumors were composed of an admixture of small
      and large, spindle-shaped and round cells, also arranged in parallel alignment.
      Tumor cells with granular cytoplasm, blunt-ended nuclei, intranuclear inclusions,
      mitotic figures, fibrous or myxoid stroma were not observed. The myxoid tumors
      disclosed large amounts of background myxoid matrix containing large spindle
      shaped and giant cells. Entities such as leiomyoma, malignant peripheral nerve
      sheath tumor, monophasic synovial sarcoma, and malignant fibrous histiocytoma
      should be considered in the differential diagnosis of LMS of the classical type.
      Epithelioid leiomyoma may share similar cytological features with epithelioid
      LMS. The cytological features of the myxoid variant of LMS can be easily confused
      with other types of benign and malignant mesenchymal tumors depicting
      degenerative myxoid changes and/or a myxoid matrix component.

PMID- 12619092
TI  - Marginal zone and mantle cell lymphomas: assessment of cytomorphology in
      subtyping small B-cell lymphomas.
AB  - The diagnosis of malignant lymphomas by fine-needle aspiration biopsy (FNAB) is
      increasing in utilization. The cytomorphologic distinction among the small B-cell
      lymphomas may be quite difficult. We are unaware of anyone who has compared
      directly mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) in FNAB. Our
      major goal was to examine the cytomorphologic attributes of MCL and MZL and to
      look for features distinctive of or suggestive of either neoplasm. Seven
      immunophenotypic MCL and seven immunophenotypic MZL aspirates were evaluated for
      a number of cytomorphologic features in direct smears. Features favoring MCL
      include a relatively monomorphic cellular population, prominent nuclear membrane
      contour irregularities, and mitotic figures. Conversely, a polymorphic cellular
      population suggested MZL. However, due to extensive overlap of specific cytologic
      features, the two lymphomas cannot be definitively distinguished based solely on
      cytomorphology. Although there are cytomorphologic attributes suggestive of
      either MCL or MZL, considerable overlap exists. Based on an individual case
      basis, the distinction cannot be made reliably by morphology alone; ancillary
      studies, e.g., immunophenotyping, are essential.

PMID- 12619093
TI  - Fine-needle aspiration cytology and immunocytochemistry in the diagnosis of 24
      gastrointestinal stromal tumors: a quick, reliable diagnostic method.
AB  - The diagnosis of gastrointestinal stromal tumors (GISTs) is generally established
      on histopathologic examination of surgical specimens. Fine-needle aspiration
      (FNA), performed under the guidance of ultrasound or computed tomography, is
      being used with increasing frequency in an attempt to diagnose primary and/or
      metastatic GISTs before surgery. The present study was undertaken to characterize
      the cytological appearance of these tumors and to assess the role of cytology,
      together with immunocytochemistry (ICC), in the diagnosis of GISTs. Twenty-four
      GISTs diagnosed by FNA cytology at our institution have been reviewed.
      Immunocytochemical studies with c-kit and CD34 were performed in all cases on
      current or archival Papanicolaou-stained smears. All cases stained with c-kit,
      and 19 reacted with CD34. Cytomorphology and immunocytochemical characteristics
      are discussed. Our results confirm the utility of FNA together with ICC in the
      diagnosis of primary and/or metastatic GISTs.

PMID- 12619094
TI  - Lymphnode localization of extramedullary myeloid cell tumor in myelodysplastic
      syndrome: report of one case diagnosed by fine-needle cytology.
AB  - Trilineage extramedullary myeloid tumor (EMT) is an uncommon medical condition
      mostly diagnosed in patients affected by acute or chronic myeloid leukemia or,
      more rarely, by a myelodysplastic syndrome, among which the most frequent is
      refractory anemia with excess of blasts in transformation (RAEB-t). The
      prognostic significance of EMT is still unclear, although the appearance of
      trilineage EMT is often considered to affect the outcome adversely. A 70-year-old
      lady with previous history of intestinal resection for colonic adenocarcinoma in
      1995 and subsequently treated with 5-fuorouracyl developed a refractory anemia
      with excess of blasts (RAEB) in 1998. During the follow-up, a progression to RAEB
      t was recorded. During chemotherapy for this condition, slight enlargement of
      left supraclavicular and right submandibular nodes was noticed. Fine-needle
      biopsy was performed with ancillary studies. A diagnosis of trilineage
      extramedullary myeloid tumor was reached. The patient was treated with low doses
      of chemotherapy with a good response lasting 12 months. The peculiar cytologic
      picture of this condition when corroborated by ancillary studies
      (immunocytochemistry and flow cytometry) is diagnostic of this rare condition.
      Furthermore, the extramedullary myeloid tumor in this case did not significantly
      affect the response to the chemotherapy of RAEB-t.

PMID- 12619095
TI  - Detection of human papillomavirus in sanitary napkins: a new paradigm in cervical
      cancer screening.
AB  - Human papillomavirus was successfully detected by polymerase chain reaction (PCR)
      in menstrual blood or vaginal discharge collected in sanitary napkins in 100% of
      17 women having koilocytosis, cervical intraepithelial neoplasia, or squamous
      carcinoma. We advocate this form of cervical cancer screening because of its high
      sensitivity and acceptance by patients.

PMID- 12619096
TI  - Immunocytochemical evaluation of HER-2/neu on fine-needle aspirates from primary
      breast carcinomas.
AB  - Detection of HER-2/neu alterations is increasingly used in breast cancer patients
      for therapeutic purposes. This study examines the reliability of HER-2/neu
      immunocytochemical assessment on 66 cytospin smears obtained by fine-needle
      aspiration biopsy from breast cancer patients. Results were compared with those
      obtained by both fluorescence in situ hybridization (FISH) on fine-needle
      aspirate (FNA) and immunohistochemistry (IHC) on matched histologic section.
      Concordance between immunocytochemistry (ICC) and FISH was 78% and between ICC
      and IHC was 84%. Discordance mainly concerned seven unamplified cases that
      resulted positive by ICC and four cases scored negative by IHC but positive by
      ICC. Simultaneous assessment of HER-2/neu by ICC, IHC, and FISH was available in
      24 cases; the concordance was 75%. In this study, the false positivity of
      immunocytochemical technique represents the major criticism. In our experience,
      FISH remains the most objective and powerful technique for HER-2/neu assessment
      on breast cancer FNAs.

PMID- 12619097
TI  - Telecytology of fine-needle aspiration biopsies of the pancreas: a study of well
      differentiated adenocarcinoma and chronic pancreatitis with atypical epithelial
      repair changes.
AB  - Four experienced cytopathologists provided consultations using telecytology and
      routine microscopy. Twenty-seven fine-needle aspiration biopsies (FNABs) from
      patients with chronic pancreatitis with atypical epithelial repair changes (n =
      9) and pancreatic low-grade adenocarcinomas (LG-AC) (n = 18) were studied. False
      positive and false-negative diagnostic rates were 19.4% and 12.5% by microscopy
      and 11.1% and 2.8% by telecytology. Comparisons of agreements between the correct
      diagnoses and consultations rendered by the two methods and among the diagnoses
      rendered on the same cases by the two modalities yielded kappa coefficients
      ranging from 0.444-1.000. Telecytology yielded slightly better kappa coefficients
      than microscopy. This method, which to our knowledge has not been previously
      applied to pancreatic FNAB, provides a potentially useful consultative tool for
      the interpretation of these difficult specimens. The diagnosis of FNAB from
      patients with chronic pancreatitis and LG-AC is difficult even for experienced
      consultants, as underscored by the considerable intraobserver and interobserver
      variability encountered in this study.

PMID- 12619099
TI  - Fine-needle aspiration biopsy of solid aneurysmal bone cyst in the humerus.
AB  - We report the fine-needle aspiration biopsy (FNAB) cytology findings of a solid
      aneurysmal bone cyst in the left humerus of a 69-yr-old woman. Radiographically,
      the lesion showed an extensive, relatively well-defined osteolysis in the
      diaphysis, with a pathologic fracture. FNAB smears of the lesion consisted of
      benign, mononuclear cells and numerous osteoclast-like multinucleated giant
      cells. Some clusters of the mononuclear cells were closely associated with dense,
      homogeneous, extracellular, matrix material. To our knowledge, the FNAB features
      of solid ABC of the long bones have not been described previously in the English
      language literature. The cytologic features are indistinguishable from those of
      giant cell tumors of bone and brown tumors of hyperparathyroidism.

PMID- 12619098
TI  - Metaplastic carcinoma of the breast with rhabdomyosarcomatous element: aspiration
      cytology with histological, immunohistochemical, and ultrastructural
      correlations.
AB  - We studied a metaplastic breast carcinoma with a rhabdomyosarcomatous element
      from a 62-yr-old woman. In the fine-needle aspirates processed by Ultrafast
      Papanicolaou stain, there were small undifferentiated cells with scanty cytoplasm
      and differentiated cells with red macronucleoli and abundant cytoplasm. Some
      differentiated cells contained a brown inclusion with a blue rim.
      Ultrastructurally, the brown inclusion correlated to a central aggregate of
      sarcomeres and the blue rim correlated to actin filaments surrounding the
      sarcomeres. The differentiated cells without cytoplasmic inclusions expressed
      cytokeratin and contained tonofilaments. A transitional cell type containing both
      sacromeres and tonofilaments was absent. Immunohistochemically, the small
      undifferentiated cells expressed vimentin diffusely and showed >90% MIB-1
      proliferating index, whereas the differentiated cells expressed cytokeratin,
      actin, or myoglobin and had virtually absent MIB-1 nuclear labeling.
      Histologically, the small cells were more concentrated along the capsule and the
      large cells were more concentrated in the center of the tumor. These findings
      suggest the bidirectional differentiation of the small undifferentiated cells
      into carcinoma cells and rhabdomyosarcoma cells in this tumor.

PMID- 12619100
TI  - Fine-needle aspiration cytological findings in five cases of epithelial
      myoepithelial carcinoma of salivary glands.
AB  - The cytologic features of five cases of epithelial-myoepithelial carcinoma
      arising in major salivary glands (four parotid and one submandibular gland) are
      presented. All cases were initially diagnosed as low-grade malignancies. The
      smears were generally cellular, with no specific architectural pattern. Single
      cells and naked nuclei were prominent in all cases. A biphasic epithelial (small
      cell) and myoepithelial (large/clear-cell) pattern was identified readily in two
      cases and with difficulty in one case. The biphasic pattern may be subtle or
      absent since the clear cells have a fragile cytoplasm and often appear as naked
      nuclei. The differential diagnosis includes adenoid cystic carcinoma,
      polymorphous low-grade adenocarcinoma, and cellular pleomorphic adenoma.

PMID- 12619101
TI  - Sarcomatous cholangiocarcinoma.

PMID- 12619102
TI  - Focus on the p53 gene and cancer: advances in TP53 mutation research.

PMID- 12619103
TI  - The UMD-p53 database: new mutations and analysis tools.
AB  - The tumor suppressor gene TP53 (p53) is the most extensively studied gene
      involved in human cancers. More than 1,400 publications have reported mutations
      of this gene in 150 cancer types for a total of 14,971 mutations. To exploit this
      huge bulk of data, specific analytic tools were highly warranted. We therefore
      developed a locus-specific database software called UMD-p53. This database
      compiles all somatic and germline mutations as well as polymorphisms of the TP53
      gene which have been reported in the published literature since 1989, or
      unpublished data submitted to the database curators. The database is available at
      www.umd.necker.fr or at http://p53.curie.fr/. In this paper, we describe recent
      developments of the UMD-p53 database. These developments include new fields and
      routines. For example, the analysis of putative acceptor or donor splice sites is
      now automated and gives new insight for the causal role of "silent mutations."
      Other routines have also been created such as the prescreening module, the UV
      module, and the cancer distribution module. These new improvements will help
      users not only for molecular epidemiology and pharmacogenetic studies but also
      for patient-based studies. To achieve theses purposes we have designed a
      procedure to check and validate data in order to reach the highest quality data.

PMID- 12619104
TI  - TP53 family members and human cancers.
AB  - Based on gene sequence homologies, a p53 (TP53) gene family become apparent with
      the addition of the most recently identified p63 (TP73L; formerly TP63) and p73
      (TP73) genes to the already known p53. The p53 gene encodes for a unique protein
      eliciting well-known tumor suppressor gene (TSG) properties that mediate cellular
      response to DNA damage, e.g., cell cycle arrest or apoptosis. In contrast, both
      homologues specify an array of isoforms different in their N- and C-terminal
      domains. Transactivating isoforms, such as TAp63/p73, show TSG properties similar
      to p53, while isoforms lacking N-terminal transactivating domain such as
      DeltaNp63/p73, induce a functional block against p53 as well as TAp63/p73
      activities. Both p63/p73 types of isoforms are involved in development: p63 is
      critical for epithelial stem cell renewal and epithelial homeostasis, and p73 is
      involved in neurogenesis and natural immune response. These facts support
      interdependent functions for the p53 family members, which appear linked together
      in a complex and tight regulation network to fulfill cellular functions related
      to DNA damage and tissue homeostasis maintenance. The lack of p63/p73 mutations
      in human cancers rule out a typical TSG role for either of the p53 homologues.
      Nonetheless, p63 and p73 genes seem strongly involved in malignancy acquisition
      and maintenance process because of: 1) their tissue identities, and 2) their
      close interplay activities within the p53 family members, and primarily through
      the negative regulatory role played by DeltaNp63/p73 isoforms for cell death
      control and differentiation.

PMID- 12619105
TI  - Significance of TP53 mutations in human cancer: a critical analysis of mutations
      at CpG dinucleotides.
AB  - A detailed analysis of p53 (TP53) mutations involving the 42 CpG dinucleotides
      was performed to gain greater insight into the mutational mechanism leading to
      specific selection of these mutations. Although the majority of these CpG
      dinucleotides have been found to be mutated in cancer cells, the heterogeneous
      frequency of mutational events suggests that some mutations are not true
      mutations, but neutral changes that have been co-selected during oncogenic
      transformation. Among the 1,400 variants found in the 15,000 mutations of the p53
      database, 5% have only been described once, indicating that either the mutational
      event is rare, or the mutation phenotype is very mild, or both. Overall, these
      data indicate that great caution is required when analyzing the significance of
      p53 mutations.

PMID- 12619106
TI  - TP53 and liver carcinogenesis.
AB  - Primary hepatocellular carcinoma (HCC) is one of the most common malignancies and
      has the fourth highest mortality rate worldwide. The major risk factors,
      including chronic infections with the hepatitis B or C virus, are exposure to
      dietary aflatoxin B1(AFB1), vinyl chloride, or alcohol consumption. Southern
      China and sub-Saharan Africa have the highest dietary AFB1 exposure, making it
      and hepatitis B virus (HBV) the major causes of cancer mortality in these
      geographic areas. Recent studies have discovered genetic and epigenetic changes
      involved in the molecular pathogenesis of HCC, including somatic mutations in the
      p53 tumor suppressor gene (TP53). AFB1 induces typical G:C to T:A transversions
      at the third base in codon 249 of p53. Chronic active hepatitis B and C (HCV)
      infection, and further inflammatory and oxyradical disorders including Wilson
      disease (WD) or hemochromatosis, generate reactive oxygen/nitrogen species that
      can damage DNA and mutate the p53 gene. The X gene of HBV (HBx) is the most
      common open reading frame integrated into the host genome in HCC. The integrated
      HBx is frequently mutated and has a diminished ability to function as a
      transcriptional cotransactivator and to activate the NF-kappa B pathway. However,
      the mutant HBx proteins still retain their ability to bind to and abrogate p53
      mediated apoptosis. In summary, both viruses and chemicals are implicated in the
      etiology and molecular pathogenesis of HCC. The resultant molecular changes in
      the ras and Wnt signal-transduction pathways, and the p53 and Rb tumor suppressor
      pathways significantly contribute to liver carcinogenesis

PMID- 12619107
TI  - TP53 mutations in human skin cancers.
AB  - The p53 gene (TP53) is mutated in numerous human cancers. We have used it as a
      molecular target to characterize the induction of mutations in human skin
      cancers. About 50% of all skin cancers in normal individuals exhibit p53
      mutations. This frequency rises to 90% in skin cancers of patients with the DNA
      repair deficiency known as xeroderma pigmentosum (XP). These mutations are
      characterized by a specific signature, attributed to the ultraviolet uvB part of
      the solar spectrum. In this review, we will describe different p53 mutation
      spectra, in relation to the various histopathological types of skin cancers such
      as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant
      melanoma as well as to the DNA repair efficiency of the patients. In particular,
      different mutational hot spots are found among the various spectra. We have tried
      to elucidate them in terms of induced DNA lesion hot spots, as well as speed of
      local nucleotide excision repair (NER) or sequence effects. The molecular
      analysis of these mutagenic characteristics should help in the understanding of
      the origin of human skin cancers in the general population.

PMID- 12619108
TI  - The TP53 gene, tobacco exposure, and lung cancer.
AB  - Of the various genetic alterations in lung cancer, the abnormalities of the TP53
      gene (p53) are among the most frequent and important events. Because of its
      importance, many aspects of TP53 have been studied, including preneoplastic
      lesions and TP53as a marker for early detection and prognosis and as a
      therapeutic option. We summarize recent knowledge of TP53 in lung cancer with a
      special emphasis on the relationship between smoking exposure (e.g, cigarette,
      etc.) and specific mutational pattern of TP53by analyzing the latest version of
      the International Agency for Research on Cancer (IARC) database on TP53 mutations
      in human cancer. Our analysis confirmed several other studies showing significant
      differences in the frequencies of G:C to T:A transversions between ever-smokers
      and never-smokers. Furthermore, when comparing the mutational spectrum by gender,
      important differences were noted between male and female never-smokers. We
      concluded that the previously noted G:C to T:A transversions were mainly due to
      female smokers having a high frequency of these changes compared to female never
      smokers. There was no relationship between adenocarcinomas and squamous cell
      carcinomas independent of gender. We also examined the seven codons which have
      been previously identified as hot spots, that is, the sites of frequent G:C to
      T:A transversions in smoking-related lung cancers. However, there was no specific
      codon which was strongly related to smoke exposure despite a moderate
      relationship. We considered the term "warmspot" may be more appropriate. While
      mutations of TP53 are frequent in lung cancers, further investigation is
      necessary to understand their role for lung carcinogenesis, especially as they
      relate to gender differences, and to translate our laboratory knowledge to
      clinical applications.

PMID- 12619109
TI  - TP53 mutations in workers exposed to occupational carcinogens.
AB  - In some cases, evidence exists that exogenous carcinogenic exposures contribute
      to the mutation spectrum of the TP53 gene (p53) in human cancers. Although the
      clearest examples come from dietary and environmental sources, only a restricted
      number of papers have concentrated specifically on TP53 mutations in tumors from
      workers exposed to occupational carcinogens. In populations exposed to dietary
      aflatoxin B1 with liver cancer (AFB1) and ultraviolet (UV)-radiation with skin
      cancer, a single specific-looking TP53 mutation has been described in some of the
      tumors. Whether these fingerprints in the TP53 gene can be used to reveal an
      occupational etiology remains to be shown. In other cases, although differences
      in the TP53 mutation spectrum exist, they are more diffuse and difficult to
      interpret at this point. For instance, cigarette smoking seems to induce long
      lasting molecular footprints in TP53. However, their use to rule out other
      occupational exposures as etiological factors in occupational cancers is still
      very questionable, especially due to the putative synergistic effects of
      cigarette smoke with other carcinogens. Although interesting implications of
      possible typical mutation spectra among cancers with other occupational
      etiologies exist, the data are scanty and await further development of TP53
      mutation databases.

PMID- 12619110
TI  - TP53 and head and neck neoplasms.
AB  - Head and neck cancer is an important health problem around the world, accounting
      for approximately 500,000 new cases each year of head and neck squamous cell
      carcinoma (HNSCC). Carcinogenesis of head and neck results from a dysregulation
      of cellular proliferation, differentiation, and cell death. The major etiologic
      agents are tobacco and alcohol consumption and for some cases, human papilloma
      virus (HPV) infection. All three factors are associated with the disruption of a
      cellular pathway essential for the maintenance of cellular integrity, the p53
      pathway. The objective of this review is to point out the specificity of p53 gene
      (TP53) alterations in head and neck cancer in relation with chemocarcinogenesis
      and to discuss whether or not the determination of p53 alterations will be of
      clinical relevance in the management of head and neck cancer in terms of
      prognosis and response to treatments.

PMID- 12619111
TI  - TP53 and gastric carcinoma: a review.
AB  - In this article, we survey the major p53 (TP53) alterations identified in gastric
      carcinomas and their precursors. These include p53 expression, mutations, and
      loss of heterozygosity (LOH). Not only are the various abnormalities summarized,
      but in addition there is a survey of the literature with respect to the impact of
      these changes on patient prognosis and treatment response. The majority of
      published studies involve the immunohistochemical detection of the protein. These
      use different antibodies, different detection techniques, and different methods
      of interpretation. Therefore not surprisingly, the results of many of the studies
      are contradictory with one another. Overall, however, it appears that p53
      alterations occur early in the development of gastric carcinoma, being present
      even in the nonneoplastic mucosa and they increase in frequency as one progresses
      along the pathway of gastric carcinoma development. p53 immunoreactivity is seen
      in 17%-90.7% of invasive gastric carcinomas. p53 alterations occur much more
      commonly in proximal lesions than in distal ones, suggesting that the molecular
      events leading to the development of gastric carcinoma may be very different in
      proximal vs. distal tumors. p53 mutations occur in 0%-77% of gastric carcinomas.
      The mutations are distributed widely across the gene from exons 4-11 with hot
      spots of mutation at codons 175, 248, 273, 282, 245, and 213. G:C>A:T transitions
      at CpG sites are the commonest type of mutation. At least 60% of carcinomas with
      mutations also exhibit p53 LOH.

PMID- 12619112
TI  - TP53 mutation in colorectal cancer.
AB  - Approximately half of all colorectal cancers show p53 (TP53) gene mutations, with
      higher frequencies observed in distal colon and rectal tumors and lower
      frequencies in proximal tumors and those with the microsatellite instability or
      methylator phenotypes. Alterations to this gene appear to have little or no
      prognostic value for colorectal cancer patients treated by surgery alone, but are
      associated with worse survival for patients treated with chemotherapy. There is
      some evidence that different p53 mutations are associated with different clinical
      features including prognosis and response to therapy, although further large
      studies are required to confirm this. Several in vitro, animal and clinical
      studies have shown that normal p53 is required for the response of colorectal
      cancers to 5-fluorouracil-based chemotherapy. This should be confirmed by
      additional retrospective cohort studies and by the incorporation of P53 status in
      ongoing and future clinical trials. The evaluation of p53 overexpression, using a
      standardized immunohistochemical (IHC) procedure, could be a clinically useful
      marker for the identification of colorectal cancer patients likely to benefit
      from the standard chemotherapy regime currently used for this disease.

PMID- 12619113
TI  - TP53 in hematological cancer: low incidence of mutations with significant
      clinical relevance.
AB  - Inactivation of the wild-type p53 gene (TP53) by various genetic alterations is a
      major event in human tumorigenesis. More than 60% of human primary tumors exhibit
      a mutation in the p53 gene. Hematological malignancies present a rather low
      incidence of genetic alterations in this gene (10-20%). Nevertheless,
      epidemiological studies of the hematological malignancies indicate that the
      prognosis of patients with a mutation in the p53 gene is worse than those
      expressing the wild-type p53 protein. Correlations between drug resistance,
      altered apoptosis, and mutations in the p53 gene are found in hematological
      malignancies and leukemias. These issues, as well as the possibility of
      exploiting p53 and its various functions for new therapeutic strategies, are
      discussed in the present review.

PMID- 12619114
TI  - TP53 and ovarian cancer.
AB  - Ovarian cancer represents the fourth most frequent type of cancer among females
      and is the leading cause of death from gynecological cancer in the western world.
      This review describes gene alterations in ovarian cancer. Specific emphasis is
      placed on genetic alterations and the prevalence of TP53 (p53) gene alterations
      in the distinct biological ovarian tumors (benign, borderline, and malignant) and
      histological subtypes (serous, mucinous, endometrioid, clear cell), as well as in
      BRCA1-associated hereditary ovarian cancer. Although multi-modality treatment
      regimens, including cytoreductive surgery and cisplatin-containing combination
      chemotherapy, have usefully prolonged survival, the overall cure rate of the
      disease has not changed dramatically. Ovarian cancer is difficult to eradicate
      completely by surgery and many patients have only a partial response to
      postoperative chemotherapy and/or many will develop chemotherapy resistance. All
      these important factors contribute to the poor prognosis of ovarian cancer
      patients. In this review, the putative prognostic or predictive value of TP53 in
      ovarian cancer is addressed.

PMID- 12619115
TI  - TP53 and breast cancer.
AB  - The TP53 gene (p53) is found altered in breast carcinomas in approximately 20-40%
      of all cases depending on tumor size and stage of the disease. It seems to be an
      early event in breast tumorigenesis. Several polymorphisms in the TP53 gene have
      been detected and their possible roles in breast cancer risk and association to
      type of cancer developed are discussed. The different mutation spectra seen in
      geographical and ethnic populations may be used to identify environmental
      exposure contributing to breast cancer development. The role of TP53 mutation as
      a prognostic marker is reviewed as well as its role as a predictor for therapy
      response. All data available on TP53 mutation analyses of human breast
      carcinomas, as well data from transgenic animal studies and experimental cell
      studies, support an important role for TP53 in mammary carcinogenesis.

PMID- 12619116
TI  - TP53 mutations in familial breast cancer: functional aspects.
AB  - Mutation in p53 (TP53) remains one of the most commonly described genetic events
      in human neoplasia. The occurrence of mutations is somewhat less common in
      sporadic breast carcinomas than in other cancers, with an overall frequency of
      about 20%. There is, however, evidence that p53 is mutated at a significantly
      higher frequency in breast carcinomas arising in carriers of germ-line BRCA1 and
      BRCA2 mutations. Some of the p53 mutants identified in BRCA1 and BRCA2 mutation
      carriers are either previously undescribed or infrequently reported in sporadic
      human cancers. Functional characterization of such mutants in various systems has
      revealed that they frequently possess properties not commonly associated with
      those occurring in sporadic cases: they retain apoptosis-inducing,
      transactivating, and growth-inhibitory activities similar to the wild-type
      protein, yet are compromised for transformation suppression and also possess an
      independent transforming phenotype. The occurrence of such mutants in familial
      breast cancer implies the operation of distinct selective pressures during
      tumorigenesis in BRCA-associated breast cancers.

PMID- 12619117
TI  - The role of TP53 in Cervical carcinogenesis.
AB  - Functional loss of the tumor suppressor p53 by alterations in its TP53 gene is a
      frequent event in cancers of different anatomical regions. Cervical cancer is
      strongly linked to infection by high-risk human papillomavirus (HPV) types. The
      viral oncoprotein E6 has the ability to associate with and neutralize the
      function of p53. E6 interacts with a 100-kDa cellular protein, termed E6
      associated protein (E6AP; also called ubiquitin-protein ligase E3A or UBE3A),
      which functions as an ubiquitin protein ligase. The dimeric complex then binds
      p53 and E6AP catalyzes multi-ubiquitination and degradation of p53. The ability
      to promote p53 degradation is an exclusive property of E6 from the high-risk HPV
      types. Indeed, the low-risk E6 proteins lack this activity, although they can
      bind p53. Consistent with the E6 function of the high-risk HPV types, the
      majority of cervical cancer cells have a wild-type p53 gene, but the protein
      levels are strongly decreased. Several independent studies have shown that in a
      small percentage of cervical tumors the p53 gene is mutated. However, this event
      appears to be unrelated to the presence or absence of HPV infection and the
      nature of the tumor.

PMID- 12619118
TI  - Germline TP53 mutations and Li-Fraumeni syndrome.
AB  - There are now reports of nearly 250 independent germline TP53 (p53) mutations in
      over 100 publications. Such mutations are typically associated with Li-Fraumeni
      or Li-Fraumeni-like syndrome, although many have been identified in cohorts of
      patients with tumors considered to be typical of LFS. In general, the spectrum of
      mutations that has been detected in the germline reflects that found in tumors,
      although there are some notable exceptions in certain tumor types. Detailed
      knowledge of the pedigrees allows a comprehensive analysis of genotype-phenotype
      correlations and an understanding of the tumors that are associated with germline
      TP53 mutations. This review will discuss the spectrum of mutations and the
      methods for mutation detection, the tumors associated with inheritance of a
      germline mutation, and some of the ethical and clinical problems in patients with
      a germline TP53 mutation.

PMID- 12619119
TI  - Disrupting TP53 in mouse models of human cancers.
AB  - Manipulation of the mouse genome allows emulation of the genetic defects that
      give rise to human cancers and evaluation of the cooperating nature of different
      mutations in the transformation of distinct cell types. Here we review the
      generation of mice with specific missense mutations in p53 (TP53) and disruption
      of the p53 pathway by deletion of p53 inhibitors. Missense mutations in the DNA
      binding domain result in viable mice with gain-of-function and dominant negative
      phenotypes. Loss of either of the p53 inhibitors mdm2 or mdm4 gives rise to a p53
      dependent embryonic lethal phenotype. A cell can thus tolerate the absence of p53
      function but not excess p53 function, a characteristic that is being exploited in
      the treatment of human cancers.

PMID- 12619120
TI  - Absence of exon 15 BRAF germline mutations in familial melanoma.
AB  - We have analyzed DNA from peripheral blood of 42 cases of familial melanoma for
      germline mutations in exon 15 of the BRAF gene. No evidence of mutation was
      found. We have also analyzed DNA extracted from secondary melanoma from two
      members of these families. These results were also negative. In addition we have
      searched for exon 15 BRAF mutations in 24 samples of secondary melanoma from 22
      cases of sporadic melanoma and detected the 1796T>A BRAF mutation which leads to
      a substitution of valine by glutamic acid at position 599 (V599E) in six samples.
      Peripheral blood DNA from two of these tumor-positive cases of sporadic melanoma
      were negative for the V599E BRAF mutation. This mutation therefore appears to be
      a somatic mutation associated with melanoma development and/or progression in a
      proportion of affected individuals.

PMID- 12619122
TI  - Prospects for tooth regeneration in the 21st century: a perspective.
AB  - The prospects for tooth regeneration in the 21st century are compelling. Using
      the foundations of experimental embryology, developmental and molecular biology,
      the principles of biomimetics (the mimicking of biological processes), tooth
      regeneration is becoming a realistic possibility within the next few decades. The
      cellular, molecular, and developmental "rules" for tooth morphogenesis are
      rapidly being discovered. The knowledge gained from adult stem cell biology,
      especially associated with dentin, cartilage, and bone tissue regeneration,
      provides additional opportunities for eventual tooth organogenesis. The centuries
      of tooth development using xenotransplantation, allotransplantation, and
      autotransplantation have resulted in many important insights that can enhance
      tooth regeneration. In considering the future, several lines of evidence need to
      be considered: (1) enamel organ epithelia and dental papilla mesenchyme tissues
      contain stem cells during postnatal stages of life; (2) late cap stage and bell
      stage tooth organs contain stem cells; (3) odontogenic adult stem cells respond
      to mechanical as well as chemical "signals"; (4) presumably adult bone marrow as
      well as dental pulp tissues contain "odontogenic" stem cells; and (5) epithelial
      mesenchymal interactions are pre-requisite for tooth regeneration. The authors
      express "guarded enthusiasm," yet there should be little doubt that adult stem
      cell-mediated tooth regeneration will be realized in the not too distant future.
      The prospects for tooth regeneration could be realized in the next few decades
      and could be rapidly utilized to improve the quality of human life in many
      nations around the world.

PMID- 12619123
TI  - Study on tooth development, past, present, and future.
AB  - For decades, the understanding of craniofacial development has been a central
      issue in odontology and developmental biology. As a consequence, a significant
      number of deformities are being studied for their variety of genotype and
      phenotype. Although there is little doubt about the essential roles of homeobox
      genes, transcription factors, and growth factors, we now know at least the
      fundamental strategy of craniofacial biology. The tooth as an organ performs a
      whole range of functions, each of which is truly indispensable for the
      maintenance of life. The possession of teeth is, therefore, obviously coupled
      with the complication of the natural structure of an individual organism. In the
      following, we shall focus on a brief history of tooth studies and some
      suggestions for obtaining a full understanding of teeth in the future.

PMID- 12619125
TI  - Regulatory mechanisms of periodontal regeneration.
AB  - The periodontal ligament, located between the cementum and the alveolar bone, has
      a width ranging from 0.15 to 0.38 mm. Regeneration and homeostasis of the
      periodontal ligament are highly significant functions in relation to periodontal
      therapy, tooth transplantation or replantation, and orthodontic tooth movement.
      The purpose of this review is to discuss the regulatory mechanisms of
      regenerative and homeostatic functions in the periodontal ligament based on
      currently published studies and also on our own experimental data. We consider
      the capability of the ligament tissue to promote or to suppress calcification in
      connection with bone and cementum formation and the maintenance of the
      periodontal ligament space. Also discussed are the involvement of the periodontal
      ligament tissue in the regenerative ability, cell proliferation, growth and
      differentiation factors, extracellular matrix proteins, homeostatic phenomena,
      function of Malassez epithelial rests, tooth movement, or occlusal loading.
      Regulatory mechanisms for regeneration and homeostasis of the periodontal
      ligament are hypothetically proposed.

PMID- 12619124
TI  - Pulpal regeneration after cavity preparation, with special reference to close
      spatio-relationships between odontoblasts and immunocompetent cells.
AB  - The regeneration process of the odontoblast cell layer incident to tooth injury,
      especially its relationship with immunocompetent cells in pulp healing, has not
      been fully understood. The purpose of the present study was to clarify this
      relationship between odontoblasts and immunocompetent cells in the process of
      pulp regeneration following cavity preparation in rat molars by
      immunocytochemistry for heat shock protein (Hsp) 25 as well as class II major
      histocompatibility complex (MHC) molecules. In untreated control teeth, intense
      Hsp 25-immunoreactivity was found in the cell bodies of odontoblasts and their
      processes within the predentin, whereas class II MHC-positive cells were
      predominantly located beneath the odontoblast cell layer. Cavity preparation
      caused the destruction of the odontoblast layer to form an edematous lesion and
      the shift of class II MHC-positive cells with the injured odontoblasts toward the
      pulp core at the affected site. Some damaged odontoblasts without apparent
      cytoplasmic processes, round in profile, retained the immunoreactivity for Hsp25,
      suggesting the survival of a part of the odontoblasts against artificial external
      stimuli. Twelve hours after cavity preparation, numerous class II MHC-positive
      cells appeared along the pulp-dentin border and extended their processes deep
      into the exposed dentinal tubules. By postoperative 72 hours, newly
      differentiated odontoblasts with Hsp 25-immunoreactivity were arranged at the
      pulp-dentin border, but the class II MHC-positive cells moved from the pulp
      dentin border to the subodontoblastic layer. These findings indicate that the
      time course of changes in the expression of Hsp 25-immunoreactivity reflects the
      regeneration process of odontoblasts. The functional roles of Hsp 25-positive
      odontoblasts and immunocompetent cells such as class II MHC-positive cells in the
      process of pulp regeneration after cavity preparation are discussed in
      conjunction with our previous experimental data.

PMID- 12619126
TI  - Dental neuroplasticity, neuro-pulpal interactions, and nerve regeneration.
AB  - This review covers current information about the ability of dental nerves to
      regenerate and the role of tooth pulp in recruitment of regenerating nerve
      fibers. In addition, the participation of dental nerves in pulpal injury
      responses and healing is discussed, especially concerning pulp regeneration and
      reinnervation after tooth replantation. The complex innervation of teeth is
      highly asymmetric and guided towards specific microenvironments along blood
      vessels or in the crown pulp and dentin. Pulpal products such as nerve growth
      factor are distributed in the same asymmetric gradients as the dentinal sensory
      innervation, suggesting regulation and recruitment of those nerve fibers by those
      specific factors. The nerve fibers have important effects on pulpal blood flow
      and inflammation, while their sprouting and cytochemical changes after tooth
      injury are in response to altered pulpal cytochemistry. Thus, their pattern and
      neuropeptide intensity are indicators of pulp status, while their local actions
      continually affect that status. When denervated teeth are injured, either by pulp
      exposure on the occlusal surface or by replantation, they have more pulpal
      necrosis than occurs for innervated teeth. However, small pulp exposures on the
      side of denervated crowns or larger lesions in germ-free animals can heal well,
      showing the value of postoperative protection from occlusal trauma or from
      infection. Current ideas about dental neuroplasticity, neuro-pulpal interactions,
      and nerve regeneration are related to the overall topics of tooth biomimetics and
      pulp/dentin regeneration.

PMID- 12619127
TI  - Regeneration of periodontal Ruffini endings in adults and neonates.
AB  - We reviewed the regeneration of periodontal Ruffini endings, primary
      mechanoreceptors in the periodontal ligament, following injury to the inferior
      alveolar nerve (IAN) in adult and neonatal rats. Morphologically, mature Ruffini
      endings are characterized by an extensive arborization of axonal terminals and
      association with specialized Schwann cells, called lamellar or terminal Schwann
      cells. Following injury to IAN in the adult, the periodontal Ruffini endings of
      the rat lower incisor ligament regenerate more rapidly than Ruffini endings in
      other tissues. During regeneration, terminal Schwann cells migrate into regions
      where they are never found under normal conditions. The development of
      periodontal Ruffini endings of the rat incisor is closely associated with the
      eruption of the teeth; the morphology and distribution of the terminal Schwann
      cells became almost identical to those in adults during postnatal days 15-18 (PN
      15-18d) when the first molars appear in the oral cavity, while the axonal
      elements showed extensive ramification around PN 28d when the functional
      occlusion commences. When the IAN was injured in neonates, the regeneration of
      periodontal Ruffini endings was delayed compared with the adults. The migration
      of terminal Schwann cells is also observed following IAN injury, after which the
      distribution of terminal Schwann cells became almost identical to that of the
      adults, i.e., PN 14d. Since the interaction between axon and Schwann cell is
      important during regeneration and development, further studies are required to
      elucidate its molecular mechanism during the regeneration as well as the
      development of the periodontal Ruffini endings.

PMID- 12619128
TI  - Preservation of the negative image of tooth enamel with dental impression
      material enhances morphometric measurements of gingival overgrowth.
AB  - Gingival overgrowth is a common health problem caused by genetic and
      environmental risk factors. Animal models for quantitative histological studies
      are needed to uncover genetic predisposition and dose-response data that might
      put individuals at increased risk for gingival disease. Gingival height,
      thickness, inflammation, and the degree of encroachment of gingiva over the
      tooth, are clinical measures of overgrowth; most of these parameters can be
      measured histologically, but in order to quantify gingival coverage of the tooth,
      the image of the crown must be present. Tooth and bone typically require
      decalcification for histology; thus, the tooth crown, a critical landmark, is
      lost. We describe a method for imaging the crown histologically, using impression
      materials applied to dissected mouse mandibles. Four dental alginates, three
      polyvinyl siloxanes, and one polyether and gelatin were used. The impression
      material/mandibular tissue blocks were processed routinely. Polyvinyl siloxanes
      were incompatible with embedding resin; alginates, polyether and gelatin could be
      fixed, decalcified, embedded, and sectioned. Alginates and gelatin could be
      stained. Success in imaging the tooth crown varied with the preparation, but the
      alginates, polyether, and gelatin permitted a useful degree of measurement of
      exposed crown and enamel thickness, along with other morphometric parameters such
      as thickness of the dentin, lateral mandibular ramus, rete pegs, height of the
      gingiva, and volume density of vessels and inflammatory cells in the lamina
      propria. In conclusion, this new application for impression materials allows
      gingival coverage of tooth crown, as well as numerous other parameters to be
      measured for comparison with clinical data.

PMID- 12619129
TI  - Bone morphogenetic protein 4 (BMP4): a regulator of capsule chondrogenesis in the
      developing mouse inner ear.
AB  - Formation of the cartilaginous otic capsule is directed by otic epithelial
      periotic mesenchymal interactions. In response to induction by otic epithelium,
      condensations of mesenchyme appear in the periotic region and form a chondrified
      otic capsule that serves as the template for the subsequent formation of the
      endochondral bony labyrinth. Previous studies indicate that members of the
      transforming growth factor beta superfamily, including transforming growth factor
      beta(1), participate in guiding these tissue interactions. In this study, we
      report the localization of bone morphogenetic protein 4 (BMP4) to the mesenchymal
      and epithelial-derived tissues of the mouse inner ear between 10.5 and 14 days of
      embryonic development. We demonstrate modulation of chondrogenesis in cultured
      mouse periotic mesenchyme by exogenous BMP4 protein and investigate the function
      of endogenous BMP4 in otic capsule chondrogenesis. We show that in the presence
      of the BMP antagonist, Noggin, otic capsule chondrogenesis is suppressed in
      culture in a dose-dependent manner. Consistent with this finding, addition of
      BMP4-specific antisense oligonucleotide to cultures of mouse periotic mesenchyme
      containing otic epithelium decreases levels of endogenous BMP4 protein and
      suppresses the chondrogenic response of the cultured periotic mesenchyme,
      providing evidence of the necessity for BMP4 in mediating otic capsule
      chondrogenesis. Supplementation of either Noggin- or BMP4 antisense
      oligonucleotide-treated cultures with BMP4 protein can restore the extent of
      chondrogenesis to normal levels. Our findings support BMP4 as an essential
      mediator of chondrogenesis in the developing otic capsule in situ.

PMID- 12619130
TI  - Development of transgenic chickens expressing bacterial beta-galactosidase.
AB  - Replication-defective retroviral vectors are efficient vehicles for the delivery
      of exogenous genes, and they may be used in the generation of transgenic animals.
      The replication-defective retroviral SNTZ vector carrying the lacZ gene with a
      nuclear localized signal was injected into the subgerminal cavity of freshly laid
      eggs. Subsequently, the eggs were allowed to hatch, and the chickens were
      screened for the lacZ gene by using the polymerase chain reaction. Eight of 15
      male chickens that survived to sexual maturity contained the lacZ gene in their
      semen. Subsequently, these males were mated with wild-type female chickens. From
      one of the eight lacZ-positive G(0) males, two lacZ-positive male chickens were
      produced from a total of 224 G(1) progeny for a germline transmission rate of
      0.89%. Both G(1) male chickens carrying the lacZ gene were mated with wild-type
      female chickens and 46.5% of the G(2) progeny contained the lacZ gene, which is
      consistent with the expected Mendelian 50% ratio for a heterozygous dominant
      allele. The product of the lacZ gene, nuclear localized beta-galactosidase, was
      expressed in primary myoblast cultures derived from G(2) chickens, and it was
      also expressed in whole G(2) chicken embryos.

PMID- 12619131
TI  - Mouse Mix gene is activated early during differentiation of ES and F9 stem cells
      and induces endoderm in frog embryos.
AB  - In frog and zebrafish, the Mix/Bix family of paired type homeodomain proteins
      play key roles in specification and differentiation of mesendoderm. However, in
      mouse, only a single Mix gene (mMix) has been identified to date and its function
      is unknown. We have analyzed the expression of mouse Mix RNA and protein in
      embryos, embryoid bodies formed from embryonic stem cells and F9 teratocarcinoma
      cells, as well as several differentiated cell types. Expression in embryoid
      bodies in culture mirrors that in embryos, where Mix is transcribed transiently
      in primitive (visceral) endoderm (VE) and in nascent mesoderm. In F9 cells
      induced by retinoic acid to differentiate to VE, mMix is coordinately expressed
      with three other endodermal transcription factors, well before AFP, and its
      protein product is localized to the nucleus. In a subpopulation of nascent
      mesodermal cells from embryonic stem cell embryoid bodies, mMix is coexpressed
      with Brachyury. Intriguingly, mMix mRNA is detected in a population (T+Flk1+) of
      cells which may contain hemangioblasts, before the onset of hematopoiesis and
      activation of hematopoietic markers. In vitro and in vivo, mMix expression in
      nascent mesoderm is rapidly down-regulated and becomes undetectable in
      differentiated cell types. In the region of the developing gut, mMix expression
      is confined to the mesoderm of mid- and hindgut but is absent from definitive
      endoderm. Injection of mouse mMix RNA into early frog embryos results in axial
      truncation of developing tadpoles and, in animal cap assays, mMix alone is
      sufficient to activate expression of several endodermal (but not mesodermal)
      markers. Although these observations do not exclude a possible cell-autonomous
      function for mMix in mesendodermal progenitor cells, they do suggest an
      additional, non-cell autonomous role in nascent mesoderm in the formation and/or
      patterning of adjacent definitive endoderm.

PMID- 12619132
TI  - Dynamic spatiotemporal expression of LIM genes and cofactors in the embryonic and
      postnatal cerebral cortex.
AB  - LIM-homeodomain (LIM-HD) genes encode a family of transcription factors known to
      be involved in development and patterning in several systems. Previously, we have
      shown that LIM-HD gene Lhx2 is required for the formation of a crucial boundary
      in the dorsal telencephalon (Bulchand et al. [2001] Mech Dev 100:165-175). To
      further explore the role of LIM-HD genes as well as the broader LIM gene family
      in dorsal telencephalic development, we examined the expression pattern of the
      members of this gene family and their cofactors in the developing mouse cerebral
      cortex. Transcription factor activity of the LIM-HD proteins requires the
      formation of a tetrameric complex consisting of two LIM-HD molecules linked by a
      dimer of cofactor (Clim) molecules. LIM-only (Lmo) proteins can interfere with
      this process by competing for the cofactors. LIM-HD protein function, thus, can
      be modulated by the presence of the appropriate Clim or Lmo molecules. At least
      13 LIM-HD, 4 Lmo, and 2 Clim genes have been identified in the mouse. Several of
      these genes exhibit complex spatiotemporal patterns spanning different stages of
      cortical development, from embryonic to postnatal ages. Noteworthy features of
      the expression patterns include delineation of boundaries within the developing
      cortex, up- or down-regulation during formation of selected cortical layers, and
      a striking complementarity of expression of several members consistent with
      specific functions in cortical development. Significantly, in some cases, Lmo or
      Clim gene expression is robust where no LIM-HD gene expression is detectable.
      These results suggest multiple and distinct roles for LIM-HD, Lmo, and Clim genes
      in cortical development, and also support a LIM-HD-independent role for some Lmo
      and Clim members.

PMID- 12619133
TI  - Methods for introducing morpholinos into the chicken embryo.
AB  - The use of antisense morpholino oligos to inhibit the translation of a target
      transcript has been applied recently to studies of the chicken embryo. In
      contrast to other developmental systems such as in frog, sea urchin, and
      zebrafish that permit the direct microinjection of morpholinos into a blastomere,
      square pulse electroporation is used to introduce fluorescently tagged
      morpholinos into specific populations of chick embryo cells in ovo. This article
      reviews the methods that have proven successful, the types of controls that are
      necessary when performing knockdowns of gene expression in the chick embryo, and
      discusses the limitations of the current technique, as well as directions for
      further research.

PMID- 12619134
TI  - Determination of retinal cell fates is affected in the absence of extraocular
      striated muscles.
AB  - Neural retinas of genetically modified mouse embryos and fetuses entirely lacking
      extraocular striated muscles (designated as Myf5-/-:MyoD-/- or amyogenic) are
      used to study in vivo the role of extraocular muscle (i.e., fetal ocular
      movements) in the genesis of retinal cell diversity. Although retinal lamination
      and the total number of cells per retinal layer appeared unaffected in amyogenic
      fetuses, electron microscopy and histochemistry revealed the absence of
      cholinergic amacrine cell type. By contrast, the amounts of other amacrine cell
      subpopulations (calretinin-, tyrosine hydroxylase-, and parvalbumin-expressing)
      were increased, whereas the amounts of Islet1/2-expressing retinal ganglion cells
      were decreased. Surprisingly, it was not possible to detect any change in
      proliferation or cell death. Consistently, the number of progenitors for retinal
      ganglion cells (nestin-expressing precursors) were increased, whereas the amounts
      of precursors for amacrine cells (syntaxin- and VC1.1-expressing precursors) were
      decreased in the mutant retinas. The difference in requirements for extraocular
      muscle support in regulation of precise ratios of retinal neuronal cell types
      suggests an essential role of extrinsic cues in the determination of retinal cell
      fates. Taken together, it appears that patterning mechanisms intrinsic to the
      neural retina specify the basic organization of retinal spatial organization
      (e.g., retinal layers and total number of cells). However, extrinsic cues seem to
      change intrinsic properties (e.g., competence) of retinal progenitor cells and
      influence the ratios of the differentiated cell types (i.e., cell fate choice)
      they produce.

PMID- 12619135
TI  - Differentially expressed nucleolar TGF-beta1 target (DENTT) in mouse development.
AB  - Differentially expressed nucleolar TGF-beta1 target (DENTT) is a recently
      identified gene whose mRNA is differentially affected by TGF-beta1 in TGF-beta1
      responsive human lung cancer cells and who is a new member of the TSPY/TSPY
      like/SET/NAP-1 (TTSN) protein superfamily. Here, we report that mouse DENTT mRNA
      contains a 2031-bp open reading frame that encodes a predicted polypeptide of 677
      amino acids with a relative molecular mass of 77,671 Da. The mouse and human
      DENTT sequences show 77% and 78% homology at the nucleotide and amino acid level,
      respectively. Mouse DENTT is predicted to be a nuclear protein with two nuclear
      localization signals (NLS), two coiled-coil regions, and a domain that shows
      significant identity to a region that defines the TTSN superfamily. Green
      fluorescent protein (GFP)-tagged full-length mouse DENTT transfected into COS-7
      cells showed localization predominantly in the nucleolus. Reverse transcription
      polymerase chain reaction amplification, Northern hybridization, and Western blot
      analyses showed expression of mouse DENTT mRNA and protein throughout mouse
      embryogenesis. Immunohistochemical staining analysis showed that DENTT is
      expressed in multiple tissues in a defined spatiotemporal pattern during mouse
      embryogenesis. The heart and primitive brain were the first organs of the embryo
      that showed immunoreactivity for the DENTT antibody by day 8 of development (E8).
      In the developing mouse brain, the choroid plexus was intensely stained for DENTT
      in all stages of development. The spinal cord and dorsal root ganglia were also
      positive for DENTT staining beginning in the 11-day-old embryo (E11), where
      homogeneous immunostaining was observed throughout the developing neurons. By day
      16 of development (E16), only a small subset of the neuronal population in the
      spinal cord and dorsal root ganglia was positively stained for DENTT. DENTT
      immunoreactivity increased steadily with maturation as the differentiation of
      cartilage and osteoblasts proceeded and reached a maximum in the growth plate
      during endochondral ossification. DENTT expression was also detected in multiple
      rodent cell types in vitro, including mouse F9 embryonal carcinoma (EC) cells.
      Addition of retinoic acid or sodium butyrate to F9 EC cells showed a rapid
      decrease in expression of DENTT protein occurring by 1 hr that continued to
      decrease to almost undetectable levels after 24 hr. Cotransfection of full-length
      mouse DENTT expression plasmid with 3TPLux or COL7A1Luc Luciferase reporter
      plasmids into F9 EC cells significantly increased the level of 3TPLux reporter
      transcription while decreasing the level of COL7A1Luc reporter transcription,
      suggesting that DENTT may play multiple roles in modulating transcriptional
      responses. These findings suggest new roles for the TTSN superfamily during
      embryogenesis and differentiation.

PMID- 12619136
TI  - Pod1 is required in stromal cells for glomerulogenesis.
AB  - Pod1 (capsulin/epicardin/Tcf21) is a basic-helix-loop-helix transcription factor
      that is highly expressed in the mesenchyme of developing organs that include the
      kidney, lung, gut, and heart. Null Pod1 mice are born but die shortly after birth
      due to a lack of alveoli in the lungs and cardiac defects. In addition, the
      kidneys are hypoplastic and demonstrate disrupted branching morphogenesis of the
      ureteric bud epithelium, a marked reduction in the number of nephrons, a delay in
      glomerulogenesis, and blood vessel abnormalities. To further dissect the cellular
      function of Pod1 during kidney development, chimeric mice were generated through
      aggregations of null Pod1 embryonic stem cells and murine embryos ubiquitously
      expressing enhanced green fluorescent protein (GFP). Histologic,
      immunohistochemical, and in situ hybridization analysis of the resulting chimeric
      offspring demonstrated both cell autonomous and non-cell autonomous roles for
      Pod1 in the differentiation of specific renal cell lineages that include
      peritubular interstitial cells and pericytes. Most strikingly, the
      glomerulogenesis defect was rescued by the presence of wild-type stromal cells,
      suggesting a non-cell autonomous role for Pod1 in this cell population.

PMID- 12619137
TI  - Caenorhabditis elegans exoskeleton collagen COL-19: an adult-specific marker for
      collagen modification and assembly, and the analysis of organismal morphology.
AB  - The integral role that collagens play in the morphogenesis of the nematode
      exoskeleton or cuticle makes them a useful marker in the examination of the
      collagen synthesizing machinery. In this study, a green fluorescent protein
      collagen fusion has been constructed by using the Caenorhabditis elegans adult
      specific, hypodermally synthesized collagen COL-19. In wild-type nematodes, this
      collagen marker localized to the circumferential annular rings and the lateral
      trilaminar alae of the cuticle. Crosses carried out between a COL-19::GFP
      integrated strain and several morphologically mutant strains, including blister,
      dumpy, long, small, squat, and roller revealed significant COL-19 disruption that
      was predominantly strain-specific and provided a structural basis for the
      associated phenotypes. Disruption was most notable in the cuticle overlying the
      lateral seam cell syncytium, and confirmed the presence of two distinct forms of
      hypodermis, namely the circumferentially contracting lateral seam cells and the
      laterally contracting ventral-dorsal hypodermis. The effect of a single aberrant
      collagen being sufficient to mediate widespread collagen disruption was
      exemplified by the collagen mutant strain dpy-5 and its disrupted COL-19::GFP and
      DPY-7 collagen expression patterns. Through the disrupted pattern of COL-19 and
      DPY-7 in a thioredoxin mutant, dpy-11, and through RNA interference of a dual
      oxidase enzyme and a vesicular transport protein, we also show the efficacy of
      the COL-19::GFP strain as a marker for aberrant cuticle collagen synthesis and,
      thus, for the identification of factors involved in the construction of
      collagenous extracellular matrices.

PMID- 12619138
TI  - Cardiac neural crest in zebrafish embryos contributes to myocardial cell lineage
      and early heart function.
AB  - Myocardial dysfunction is evident within hours after ablation of the cardiac
      neural crest in chick embryos, suggesting a role for neural crest in myocardial
      maturation that is separate from its role in outflow septation. This role could
      be conserved in an animal that does not have a divided systemic and pulmonary
      circulation, such as zebrafish. To test this hypothesis, we used cell marking to
      identify the axial level of neural crest that migrates to the heart in zebrafish
      embryos. Unlike the chick and mouse, the zebrafish cardiac neural crest does not
      originate from the axial level of the somites. The region of neural crest cranial
      to somite 1 was found to contribute cells to the heart. Cells from the cardiac
      neural crest migrated to the myocardial wall of the heart tube, where some of
      them expressed a myocardial phenotype. Laser ablation of the cardiac premigratory
      neural crest at the three- to four-somite stage resulted in loss of the neural
      crest cells migrating to the heart as shown by the absence of AP2- and HNK1
      expressing cells and failure of the heart tube to undergo looping. Myocardial
      function was assessed 24 hr after the cardiac neural crest ablation in a
      subpopulation of embryos with normal heart rate. Decreased stroke volume,
      ejection fraction, and cardiac output were observed, indicating a more severe
      functional deficit in cardiac neural crest-ablated zebrafish embryos compared
      with neural crest-ablated chick embryos. These results suggest a new role for
      cardiac neural crest cells in vertebrate cardiac development and are the first
      report of a myocardial cell lineage for neural crest derivatives.

PMID- 12619139
TI  - MRF4 gene expression in Xenopus embryos and aneural myofibers.
AB  - Vertebrate embryos express the transcription factor MRF4 during skeletal muscle
      differentiation. Previous studies of MRF4 expression in embryonic Xenopus laevis
      and its response to muscle denervation in adults have led to the suggestion that
      its transcription may be activated in myotomes and in multinucleate myofibers
      through an interaction with the motor nerves. We tested this hypothesis by
      assaying for MRF4 gene transcripts in early neurula stage embryos, beginning
      before the appearance of neurons. MRF4 transcripts were detectable by reverse
      transcriptase-polymerase chain reaction (RT-PCR) from at least stage 13-14, well
      before the differentiation of either nerves or myocytes. We also tested the nerve
      dependence of MRF4 gene expression in multinucleate myofibers by comparing
      transcript levels between interhyoideus muscles in normal larvae and muscles
      whose motor innervation had been prevented through surgical removal of the brain
      before cranial motor axon outgrowth. RT-PCR demonstrated similar MRF4 transcript
      levels in the aneural muscles and controls. These results fail to support the
      hypothesis that MRF4 gene expression is triggered or is significantly up
      regulated in myogenic cells by signals from motor axons.

PMID- 12619140
TI  - Extending the table of stages of normal development of the axolotl: limb
      development.
AB  - The existing table of stages of the normal development of the axolotl (Ambystoma
      mexicanum) ends just after hatching. At this time, the forelimbs are small buds.
      In this study, we extend the staging series through completion of development of
      the forelimbs and hindlimbs.

PMID- 12619141
TI  - Expression of neuropeptide FF, prolactin-releasing peptide, and the receptor
      UHR1/GPR10 genes during embryogenesis in the rat.
AB  - Recently, several RF-amide peptides have been identified in mammals. These
      peptides have a similar C-terminal RF-motif and share some G-protein coupled
      receptors. Neuropeptide FF (NPFF) and prolactin-releasing peptide (PrRP) are
      expressed in the same brain areas in the adult rat and act both in prolactin
      release and cardiovascular regulation. Here, we characterized the embryonal
      expression from embryonal day 14 to postnatal day 0 of both peptide mRNAs and the
      mRNA distribution of UHR1/GPR10-like receptor by using in situ hybridization
      (ISH) and quantitative reverse transcriptase-polymerase chain reaction. NPFF mRNA
      was found in the spinal cord, caudal solitary tract nucleus, and surprisingly, in
      the medullary reticular formation. The only peripheral organs displaying NPFF
      mRNA expression were the lungs and the spleen. PrRP gene expression was seen in
      the caudal solitary tract nucleus, medullary reticular formation, pontine isthmus
      and liver, kidney, and testis. The receptor UHR1/GPR10 gene was expressed
      consistently in the medullary reticular formation and the adrenal gland but also
      transiently in several locations. All three genes showed weak but even ISH signal
      in the pituitary. These findings suggest different roles for the peptides during
      development and indicate that UHR1/GPR10-like receptor could also bind other
      ligands in addition to PrRP.

PMID- 12619142
TI  - N-cadherin is essential for retinal lamination in the zebrafish.
AB  - N-cadherin is one of the major Ca(2+)-dependent cell adhesion proteins in the
      developing nervous system. Here, we analyze eye development in the zebrafish N
      cadherin loss-of-function mutant parachute(paR2.10) (pac(paR2.10)). The zebrafish
      visual system is fully developed by the time pac(paR2.10) mutants show lethality
      at day 5. Already at 24 hr postfertilization (hpf), mutant retinal cells are more
      disorganized and more rounded than in wild-type. At later stages, mutant retinae
      display a severe lamination defect with rosette formation (mostly islands of
      plexiform layer tissue surrounded by inner nuclear layer or photoreceptor cells),
      even though all major classes of cell types appear to be present as determined by
      histology. Of interest, electron microscopy reveals that the islands of plexiform
      layer tissue contain a normal amount of synapses with normal morphology. Although
      mutant photoreceptor cells are sometimes deformed, all typical structural
      components are present, including the membranous discs for rhodopsin storage. The
      lens fibers of the pac(paR2.10) mutants develop completely normally, but in some
      cases, lens epithelial cells round up and become multilayered. We conclude that
      cell adhesion mediated by N-cadherin is of major importance for retinal
      lamination and involved in maintenance of the lens epithelial sheet, but is not
      essential for the formation of photoreceptor ultrastructure or for
      synaptogenesis.

PMID- 12619143
TI  - Racial/ethnic differences and potential psychological benefits in use of the
      internet by women with breast cancer.
AB  - Many websites on the Internet offer information to breast cancer patients and are
      increasingly being used. The authors investigated the potential psychological
      benefits of Internet use and how it varied as a function of race/ethnicity among
      180 white, African American, and Hispanic American breast cancer patients who
      used the Internet for medical information. Using standardized psychological
      measures, as measured by the Interpersonal Support Evaluation List (ISEL),
      Internet use among minorities was associated with greater overall, appraisal, and
      tangible social support (p's<0.05) but not belonging and self-esteem social
      support than among whites. No differences were observed for stress, depressive
      symptoms, loneliness, and coping. Since numerous studies suggest that social
      support may be related to survival, Internet use for breast health issues may
      have special clinical relevance to racial/ethnic minority groups.

PMID- 12619144
TI  - Psychological and fitness changes associated with exercise participation among
      women with breast cancer.
AB  - Exercise participation has been shown to improve cardiovascular fitness and
      reduce psychological distress among women receiving chemotherapy and/or
      radiation. The purpose of this pilot study was to examine the changes in distress
      and body image, and fitness following exercise participation among 24 women who
      had been diagnosed with breast cancer within the previous 3 years. The women were
      randomly assigned to participate in a 12-week supervised aerobic exercise program
      in a hospital setting or a wait-list control group. Assessments of distress and
      body image were conducted at pre- and post-treatment. Data showed that the women
      in the exercise group improved significantly in body image (Physical Condition
      and Weight Concerns subscales) vs control group participants at post-treatment.
      Reductions in distress were also noted in the exercise group, but these were
      nonsignificant. At post-treatment, there were modest improvements in fitness in
      the exercise group.

PMID- 12619145
TI  - The evolving experience of illness for Chinese women with breast cancer: a
      qualitative study.
AB  - The study of illness meaning in cancer in western communities has usually focused
      on causal attributions. We report a phenomenological study of 17 Hong Kong
      Chinese women with breast cancer, interviewed on completion of initial treatment,
      and describe how the illness experience and hence, meaning evolves for women in
      the Hong Kong Chinese culture. Themes arising from the identification and
      treatment of the disease include the difficulty of living in uncertainty and of
      maintaining and regaining normalcy in a superstitious society. The initial
      uncertainty of disease detection and the diagnostic process are characterized by
      shock and disbelief mingled with fear of death. Treatment choice presents women
      with difficulties arising from more uncertainty over the pressure to make quick
      decisions and the dilemma of death or mutilation. Following treatment, re
      evaluation, re-prioritizing and positive life-re-evaluation occur. Changes in
      appearance proved problematic for those women who tried to hide their disease to
      protect themselves against stigmatization and social exclusion. In many ways,
      these findings parallel studies on western populations, suggesting that a common
      disease-medical care process is a predominant influence in shaping breast cancer
      experience. Implications for care are drawn from these data.

PMID- 12619146
TI  - The psycho-social impact of infertility on young male cancer survivors: a
      qualitative investigation.
AB  - Intensive treatment regimes that are known to have a potential risk of
      infertility sometimes have to be given to boys who have aggressive malignant
      disease. Long-term care must therefore include further discussion of these
      patients' impaired fertility. This study describes the results of a series of
      semi-structured interviews with 15 young male cancer survivors regarding their
      experience of receiving feedback on their probable fertility status. All the
      interviews were conducted by a psychologist formerly uninvolved with their
      treatment. The interviews were analysed qualitatively using a grounded theory
      approach. The findings of the study are organised under four headings: (a)
      Emotional reaction to news of probable infertility. (b) Coping style adopted. (c)
      Response to the offer of semen analysis. (d) Implications for clinical
      practice.The results of this thematic analysis are compared to the wider research
      literature in oncology and health psychology.

PMID- 12619147
TI  - Patient barriers to optimal cancer pain control.
AB  - Poorly controlled pain is a significant problem for cancer patients. Contributing
      factors may include concerns about analgesics and fears about the implications of
      pain, which may hinder open communication. We surveyed the prevalence of these
      concerns in Australian oncology patients and investigated associations with
      inadequate pain control. Ninety-three adult patients with cancer, undergoing
      treatment at a teaching hospital, completed the patient barriers questionnaire
      (BQ) and a self-report questionnaire to determine pain severity, interference
      with daily activities, use of analgesics and alternative therapies, and
      hesitation to report pain. Overall, there was a high prevalence of agreement with
      the BQ scales assessing concerns about communication and analgesic use. One-third
      of patients had clinically significant pain, which interfered with daily
      activities, despite use of analgesics. They were more likely to use alternative
      therapies for pain control, to hesitate to discuss their pain, and had
      significantly greater concerns about side effects of analgesics and injections.
      Our study confirms that patient barriers exist in this Australian population and
      are associated with inadequate pain control. Oncology staff need to actively
      screen for pain, particularly targeting patients using alternative therapies and
      experiencing side effects, develop communication and prescribing skills, and
      diversify pain management approaches beyond analgesics.

PMID- 12619148
TI  - Living with the worry of cancer: health perceptions and behaviors of elderly
      people with self, vicarious, or no history of cancer.
AB  - Cancer is a major health threat that has a long-term impact on quality of life
      and health worries. The present study is focused on two major issues: (1) the
      impact that a history of cancer has on reactions to other diseases, in addition
      to cancer and general health worries; and, (2) the impact that having lived with
      someone who had cancer has on health perceptions and behaviors. All 108
      participants had osteoarthritis, a symptomatic but benign disease (49 people have
      had cancer, 22 had lived with a cancer patient, and 37 had not had any close
      experience with cancer). Cancer and health worries were lowest among the people
      with vicarious experience, while monitoring for bodily signs was similar and
      highest in both cancer experience groups. Reactions to arthritis suggest more
      vigilance among people who have had self or vicarious experience with cancer,
      while reactions to ambiguous symptoms suggest vigilance especially among those
      with a personal history of cancer. Overall, the findings suggest that the effects
      of self-experience with cancer and of close experience with a cancer patient may
      be long-term and impact upon both health perceptions and behaviors.

PMID- 12619149
TI  - Comparisons of distress in adolescents of cancer patients and controls.
AB  - Having a family member with cancer has been associated with symptoms of distress.
      While studies have reported distress in adolescents with a parent with cancer,
      few have included control groups of adolescents with healthy parents. Adolescents
      who had at least one parent diagnosed with cancer (n=27) and controls (n=23)
      completed questionnaires on PTSD, anxiety, depression, cancer risk perceptions,
      and family environment. Groups did not differ on anxiety and depression, but
      adolescents with an ill parent perceived their own risk for developing cancer as
      significantly higher than controls. Controls reported significantly higher levels
      of intrusive thoughts and avoidance regarding other stressful life events. A
      positive family environment was correlated with higher anxiety and depression,
      and expressiveness mediated the relations between family cohesion and anxiety.
      These preliminary findings suggest that distress reported in previous studies of
      adolescents with parents with cancer may be due to this transitional period of
      life.

PMID- 12619150
TI  - Psychosocial and demographic predictors of quality of life in a large sample of
      cancer patients.
AB  - In recent years, there has been increasing emphasis on understanding how the
      cancer experience affects individuals' quality of life (QOL). The goal of this
      study was to assess the QOL and to identify psychosocial predictors of QOL among
      a large sample of patients with a variety of cancers. Specifically, we assessed
      the unique contribution of demographic variables, medical variables, and social
      support on patients' QOL and psychological adjustment. Three hundred and fifty
      one participants completed measures of social support, depression, anxiety, and
      QOL at their follow-up medical visits. Analyses indicated that patients who were
      older and had better social support reported less anxiety (p<0.001), and patients
      who were older, married or who had more social support reported less depressive
      symptoms (p<0.01). Men, individuals whose cancer had not recurred, and those not
      undergoing active treatment reported better QOL in the physical health domain
      (p<0.05). Patients who were older, married, with more formal education, less
      advanced disease, and better social support reported better QOL in the mental
      health domain (p<0.05). Demographic variables (age, gender, marital status,
      education) were generally associated with measures of adjustment and QOL whereas
      medical variables (time since diagnosis, recurrence status, treatment variables,
      stage of disease) were not. Patients with more support reported less anxiety and
      depression and better QOL in the mental health domain, independent of demographic
      and medical variables. Assessing patients' level of social support may help to
      identify patients at risk for distress.

PMID- 12619151
TI  - Cancer knowledge among Spanish women participating in literacy schemes.
AB  - Access to information on cancer prevention and treatment is often difficult for
      ethnic or low socio-economic groups. This study aimed to ascertain level of
      knowledge about cancer, and breast cancer in particular, in Spanish women from
      low socio-economic groups participating in literacy schemes. A study specific
      questionnaire was administered to 541 women All participants were married with a
      median of 2 children, and a total family income of less than 10,000 euros per
      year. The main themes covered: understanding of and access to screening,
      knowledge about cancer risk, diagnosis and prognosis. The majority of these women
      (66%) feel they have no control over getting cancer and 26% report that it can be
      caught from others. Most believe that a mammogram is the best method of diagnosis
      (87%) but a minority (14%) agree with the statement that breast cancer can be
      caused by breast feeding. In general, younger women are better informed and more
      optimistic about prognosis. In Spain there are problems in disseminating
      information about cancer to lower social-economic groups. These results confirm
      that more cancer education needs to be directed to low income and socially
      deprived groups.

PMID- 12619152
TI  - How to improve communication between physicians and cancer patients about use of
      complementary and alternative medicine?

PMID- 12619154
TI  - Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal
      instability, and reduced life span in mice.
AB  - The Brca2 tumor-suppressor gene contributes to genomic stability, at least in
      part by a role in homologous recombinational repair. BRCA2 protein is presumed to
      function in homologous recombination through interactions with RAD51. Both exons
      11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes
      eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain.
      Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A
      less severe phenotype is seen with BRAC2 truncations that preserve some, but not
      all, of the BRC motifs. These mice can survive beyond weaning, but are runted and
      infertile, and die very young from cancer. Cells from such mice show
      hypersensitivity to some genotoxic agents and chromosomal instability. Here, we
      have analyzed mice and cells with a deletion of only the RAD51-interacting region
      encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a
      shorter life span than that of control littermates, possibly because of early
      onsets of cancer and sepsis. No other phenotype was observed in these animals;
      therefore, the brca2(lex1) mutation is less severe than truncations that delete
      some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes
      reduced viability, hypersensitivity to the DNA interstrand crosslinking agent
      mitomycin C, and gross chromosomal instability, much like more severe
      truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is
      important for BRCA2 function, probably because it is required for a fully
      functional interaction between BRCA2 and RAD51.

PMID- 12619155
TI  - Alterations of the SDHD gene locus in midgut carcinoids.

PMID- 12619156
TI  - RxFISH karyotype and MYC amplification in the HT-29 colon adenocarcinoma cell
      line.

PMID- 12619157
TI  - Prostate cancer aggressiveness locus on chromosome segment 19q12-q13.1 identified
      by linkage and allelic imbalance studies.
AB  - Whole-genome scan studies recently identified a locus on chromosome segments
      19q12-q13.11 linked to prostate tumor aggressiveness by use of the Gleason score
      as a quantitative trait. We have now completed finer-scale linkage mapping across
      this region that confirmed and narrowed the candidate region to 2 cM, with a peak
      between markers D19S875 and D19S433. We also performed allelic imbalance (AI)
      studies across this region in primary prostate tumors from 52 patients unselected
      for family history or disease status. A high level of AI was observed, with the
      highest rates at markers D19S875 (56%) and D19S433 (60%). Furthermore, these two
      markers defined a smallest common region of AI of 0.8 Mb, with 15 (29%) prostate
      tumors displaying interstitial AI involving one or both markers. In addition, we
      noted a positive association between AI at marker D19S875 and extension of tumor
      beyond the margin (P = 0.02) as well as a higher Gleason score (P = 0.06). These
      data provide strong evidence that we have mapped a prostate tumor aggressiveness
      locus to chromosome segments 19q12-q13.11 that may play a role in both familial
      and non-familial forms of prostate cancer.

PMID- 12619158
TI  - Pancreatic carcinoma cell lines with SMAD4 inactivation show distinct expression
      responses to TGFB1.
AB  - Transforming growth factor beta-1 (TGFB1)-induced gene expression was studied in
      five pancreatic carcinoma cell lines and one known TGFB1-sensitive cell line
      (HaCaT) by use of high-density filter-based cDNA microarrays representing over
      4,000 human genes. The results indicate a complex cellular response to TGFB1 with
      10% of the investigated genes showing altered expression after 3 or 48 hr of
      TGFB1 exposure. The tumor cell lines displayed a gradually inversed gene
      expression pattern, which correlated with reduced sensitivity to TGFB1, as
      compared to the HaCaT cell line. In the HaCaT cells, several proapoptotic genes
      showed increased expression in response to TGFB1, whereas the expression of
      antiapoptotic genes was decreased. In contrast, two pancreatic carcinoma cell
      lines, previously found to be growth stimulated by TGFB1, displayed an expression
      pattern opposite to that of these genes. Similarly, the expression of other
      functional groups of genes, such as cell cycle and transcription factor related
      genes, was almost completely reversed in these two tumor cell lines. Importantly,
      three of the five investigated pancreatic carcinoma cell lines responded to
      TGFB1, although they had SMAD4 inactivations, suggesting that the observed gene
      expression changes in these cell lines must be accomplished by SMAD-independent
      pathways.

PMID- 12619159
TI  - Genomic deletions on other chromosomes involved in variant t(9;22) chronic
      myeloid leukemia cases.
AB  - The Philadelphia (Ph) chromosome is the cytogenetic hallmark of chronic myeloid
      leukemia (CML) and is observed in more than 90% of CML cases. At diagnosis, in 5
      10% of CML patients the Ph chromosome is derived from variant translocations
      other than the standard t(9;22). Deletions adjacent to the translocation junction
      on the derivative chromosome 9 were recently described by different groups. The
      deletions may identify a subgroup with a worse prognosis. The presence of similar
      deletions on the third derivative other than the 9 and 22 chromosomes in CML with
      variant translocation has never been investigated. We studied three cases of CML
      variants showing relatively large deletions on the third chromosome involved in
      the translocation. Known tumor-suppressor genes (TSGs) or genes involved in
      signal transduction and in the modulation of cell proliferation were found to be
      located inside these deleted regions. As an alternative to Knudson's two-hit
      model, the "haplo-insufficiency" hypothesis suggests that the deletion of a
      single allele of a TSG can play an important role in tumor progression. Our
      findings suggest that great attention should be paid to the molecular cytogenetic
      characterization of variant t(9;22) CML patients to unveil fully the biological
      heterogeneity of CML.

PMID- 12619161
TI  - Characterization of the recurrent translocation t(1;1)(p36.3;q21.1-2) in non
      Hodgkin lymphoma by multicolor banding and fluorescence in situ hybridization
      analysis.
AB  - Aberrations of chromosomal bands 1p36 and 1q11-q23 are among the most common
      chromosomal alterations in non-Hodgkin lymphoma (NHL). In this study, 16 cases of
      NHL showing recurrent unbalanced translocation t(1;1)(p36;q11-23) by G-band
      analysis were selected for further analysis. To delineate the exact breakpoints,
      multicolor band analysis for chromosome 1 (M-BAND1), and locus-specific
      fluorescence in situ hybridization (LS-FISH) using human genome designated BAC
      clones were performed. In all but one dicentric case, the breakpoint was
      determined to involve chromosomal bands 1p36.3 and 1q21.1-2. LS-FISH analysis for
      the TP73, MEL1, SKI, and CASP9 loci at 1p36, and the loci IRTA1, IRTA2, BCL9,
      AF1Q, JTB, and MUC1 at 1q21, verified the MBAND1 results and further delineated
      the breakpoints. In band 1p36, two hybridization patterns were observed, one
      involving deletions of MEL1, TP73, and SKI, but not CASP9, and the second
      involving a breakpoint telomeric to TP73. In region 1q21, four hybridization
      patterns were observed, the first involving duplication/translocation of all five
      genes; the second involving duplication/translocation of BCL9, AF1Q, JTB, and
      MUC1; the third involving duplication/translocation of AF1Q, JTB, and MUC1; and
      the fourth with a breakpoint telomeric to MUC1. Using an alpha-satellite probe
      for chromosome 1 (D1Z5), centromeric involvement in the unbalanced translocation
      t(1;1)(p36.3;q21.1-2) was excluded in all but the one dicentric case, that is,
      dic(1;1)(p36.3;q10). In conclusion, deletion of 1p36 and duplication of 1q21
      through formation of an unbalanced translocation t(1;1)(p36.3;q21.1-2) is a non
      random event in NHL, suggesting a deletion-duplication mechanism involved in
      lymphoma progression and justifying further systematic research.

PMID- 12619160
TI  - DNA microarrays for comparative genomic hybridization based on DOP-PCR
      amplification of BAC and PAC clones.
AB  - We have designed DOP-PCR primers specifically for the amplification of large
      insert clones for use in the construction of DNA microarrays. A bioinformatic
      approach was used to construct primers that were efficient in the general
      amplification of human DNA but were poor at amplifying E. coli DNA, a common
      contaminant of DNA preparations from large insert clones. We chose the three most
      selective primers for use in printing DNA microarrays. DNA combined from the
      amplification of large insert clones by use of these three primers and spotted
      onto glass slides showed more than a sixfold increase in the human to E. coli
      hybridization ratio when compared to the standard DOP-PCR primer, 6MW. The
      microarrays reproducibly delineated previously characterized gains and deletions
      in a cancer cell line and identified a small gain not detected by use of
      conventional CGH. We also describe a method for the bulk testing of the
      hybridization characteristics of chromosome-specific clones spotted on
      microarrays by use of DNA amplified from flow-sorted chromosomes. Finally, we
      describe a set of clones selected from the publicly available Golden Path of the
      human genome at 1-Mb intervals and a view in the Ensembl genome browser from
      which data required for the use of these clones in array CGH and other
      experiments can be downloaded across the Internet.

PMID- 12619162
TI  - Detailed gene copy number and RNA expression analysis of the 17q12-23 region in
      primary breast cancers.
AB  - Chromosome region 17q12-23 commonly shows an increase in DNA copy number in
      breast cancers, suggesting that several oncogenes are located at this site. We
      performed a high-resolution expression array and comparative genomic
      hybridization analysis of genes mapped to the entire 17q12-23 region, to identify
      novel candidate oncogenes. We identified 24 genes that showed significant
      overexpression in breast cancers with gain of 17q12-23, compared to cancers
      without gain. These genes included previously identified oncogenes, together with
      several novel candidate oncogenes. FISH analysis using specific gene probes
      hybridized to tissue arrays confirmed the underlying amplification of
      overexpressed genes. This high-resolution analysis of the 17q12-23 region
      indicates that several established and novel candidate oncogenes, including a Wnt
      signaling pathway member, are amplified and overexpressed within individual
      primary breast cancer samples. We were also able to confirm the presence of two
      apparently separate and reciprocally amplified groups of genes within this
      region. Investigation of these genes and their functional interactions will
      facilitate our understanding of breast oncogenesis and optimal management of this
      disease.

PMID- 12619163
TI  - Analysis of t(9;11) chromosomal breakpoint sequences in childhood acute leukemia:
      almost identical MLL breakpoints in therapy-related AML after treatment without
      etoposides.
AB  - The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in
      acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within
      MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5'
      portions of MLL to a variety of heterologous genes in various 11q23
      translocations. AF9 is one of the most common fusion partners of MLL. It spans
      more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified
      in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We
      investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t
      AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with
      cytogenetically diagnosed translocations t(9;11). By use of an optimized
      multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from
      each sample was amplified and directly sequenced. In four patients and two cell
      lines, the AF9 breakpoints were located within BCR1 and in two patients within
      BCR2, respectively. However, in five patients the AF9 breakpoints were found
      outside the previously described BCRs within the centromeric region of intron 4
      and even within intron 3 in one case. All five patients with a secondary AML, who
      had not received etoposides during treatment of the primary malignant disease,
      revealed almost identical MLL breakpoints very close to a breakage hot spot
      inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence
      patterns around the breakpoints indicated involvement of a "damage-repair
      mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute
      leukemia.

PMID- 12619164
TI  - t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid
      leukemia.
AB  - Recently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in
      a case of childhood acute myeloid leukemia (AML) M5a, with a complex karyotype
      containing other rearrangements. Here, we report a new case with the MORF-CREBBP
      fusion in an 84-year-old patient diagnosed with AML M5b, in which the
      t(10;16)(q22;p13) was the only cytogenetic aberration. This supports that this is
      a recurrent pathogenic translocation in AML.

PMID- 12619165
TI  - De novo erythroleukemia chromosome features include multiple rearrangements, with
      special involvement of chromosomes 11 and 19.
AB  - Erythroid leukemia (ERL or AML-M6) is an uncommon subtype of acute myeloid
      leukemia, the clinical, morphological, and genetic behavior of which needs
      further characterization. We analyzed a homogeneous group of 23 de novo AML-M6
      patients whose bone marrow cells showed complex karyotypes. We also analyzed
      eight leukemia cell lines with erythroid phenotype, performing detailed molecular
      cytogenetic analyses, including spectral karyotyping (SKY) in all samples. The
      main features are: (1) A majority of patients (56%) had hypodiploidy. Loss of
      genetic material was the most common genetic change, especially monosomies of
      chromosome 7 or 18, and deletions of chromosome arm 5q. Taken together, 87% of
      the cases displayed aberrations involving chromosome 5 or 8. (2) We describe a
      novel, cryptic, and recurrent translocation, t(11;19)(p11.2;q13.1). Another
      translocation, t(12;21)(p11.2;q11.2), was found to be recurrent in a patient with
      ERL and in the K562 cell line. (3) MLL gene rearrangements were detected in 20%
      of cases (three translocations and three amplifications) and, overall, we defined
      52 rearrangements (excluding deletions) with a mean of 2.3 translocations per
      patient. (4) Of the structural aberrations, 21% involved chromosomes 11 and 19.
      Most of the rearrangements were unbalanced; only 13 reciprocal translocations
      were observed. The general picture of chromosomal aberrations in cell lines did
      not reflect what occurred in patient samples. However, both primary samples and
      cell lines shared three common breakpoints at 19q13.1, 20q11.2, and 21q11.2. This
      is the first molecular cytogenetic description of the karyotype abnormalities
      present in patients with ERL. It should assist in the identification of genes
      involved in erythroleukemogenesis.

PMID- 12619166
TI  - Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic
      syndrome with a novel chromosomal translocation t(2;8)(p23;p11).
AB  - In this study, we examined a pediatric case of therapy-related myelodysplastic
      syndrome (tMDS). The symptoms developed 17 months after treatment for acute
      myeloblastic leukemia (AML, M2 subtype according to the French-American-British
      [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22).
      Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal
      translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ
      hybridization analysis suggested a rearrangement in the monocytic leukemia zinc
      finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no
      partner gene on 2p23 could be identified. To our knowledge, this is the first
      report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion
      proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional
      intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are
      associated with AML chromosomal abnormalities at t(8;16)(p11;p13),
      inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account
      for leukemogenesis occurring through the aberrant regulation of histone
      acetylation. Through a similar mechanism, we believe that MOZ, fused to an
      unidentified partner gene at 2p23, may have caused an alteration in histone
      acetylation, resulting in the development of tMDS in this patient.

PMID- 12619167
TI  - Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid
      leukemia with t(11;12)(p15;q13).
AB  - The chimeric gene NUP98/HOXC13 was detected in a patient with a de novo acute
      myeloid leukemia and a t(11;12)(p15;q13). Fluorescence in situ hybridization with
      PAC1173K1 identified the breakpoint on 11p15, indicating that the NUP98 gene was
      involved in the translocation. At 12q13, the breakpoint fell within BAC 578A18,
      selected for the homeobox C (HOXC) cluster genes. RACE-PCR showed that HOXC13 was
      the partner gene of NUP98. To date, HOXC13 is the eighth homeobox gene that, as
      the result of a reciprocal translocation, fuses with NUP98 in myeloid
      malignancies.

PMID- 12619168
TI  - A telephone-delivered intervention to improve glycemic control in type 2 diabetic
      patients.
AB  - This study was performed to investigate the effect of a telephone-delivered
      intervention on glycemic control and body mass index in Korean type 2 diabetic
      patients. 38 patients were randomly selected, with 20 assigned to a telephone
      group and 18 to a control group. The goal of the intervention was to keep blood
      glucose concentrations close to the normal range. The intervention was applied to
      the telephone group for 12 weeks. It consisted of continuous education and
      reinforcement of diet, exercise and medication adjustment, as well as frequent
      self-monitoring of blood glucose levels. Telephone intervention was performed
      twice per week for the first month, and then weekly for the second and third
      months. Subjects were requested to write self- management logs, including blood
      glucose, diet and an exercise diary. The diet diaries were analyzed by a
      dietitian, and subjects instructed about the results by telephone counseling or
      mail. All medication adjustments were communicated to the subjects' diabetes
      specialist. Glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG) and 2
      hour postprandial glucose were measured before, and after, the intervention.
      Patients in the telephone group had a mean decrease of 1.2%, with those in the
      control group having a mean increase of 0.6%, in HbA1c. There were no significant
      differences in the body mass index (BMI) between the two groups. These findings
      indicated that a telephone-delivered intervention would improve HbA1c, but would
      not affect BMI.

PMID- 12619169
TI  - Influence of sex and age on the activity of antioxidant enzymes of
      polymorphonuclear leukocytes in healthy subjects.
AB  - In this study, the main antioxidant enzymes (AOE) of glutathione peroxidase
      (GPX), superoxide dismutase (SOD), catalase (CAT) and myeloperoxidase (MPO) were
      identified, and the influence of sex and age in healthy human polymorphonuclear
      leukocytes (PMNL) was determined. The SOD, GPX, CAT and MPO activities were
      investigated in intestinal parasite negative human PMNL from 109 healthy subjects
      aged from 6 to 70 years (55 males and 54 females) using simple and sensitive
      enzyme assays. Blood cells, such as eosinophils, platelets, neutrophils,
      monocytes, and macrophages also synthesize antioxidant enzymes (AOE). They
      constitute an important proportion and are also the major participants in a
      number of pathological conditions that suggest the involvement of AOE. A linear
      effect of age on SOD activity (p < 0.05) both in males and females was found. A
      similar effect with GPX activity (p < 0.05) was observed in males only. This
      showed that the activities of all these enzymes increase with age. In addition,
      SOD activity was significantly higher in females than males between the age of 19
      and 70 years (p < 0.001). This analysis also showed that there is a negative
      correlation between the CAT-GPX (p < 0.05) activities and positive correlations
      between MPO-GPX (p < 0.05) activities only in females. No correlation among the
      other enzyme activities was found in either sex group. This study showed the
      activities of antioxidant enzyme activities and the correlations of these enyzmes
      activities with each other in healthy human PMNLs were age- and sex-dependent.
      This information may assisit in understanding the importance of antioxidant
      enzymes in the physiological and pathological conditions associated with PMNL.

PMID- 12619170
TI  - Relationship between utrophin and regenerating muscle fibers in duchenne muscular
      dystrophy.
AB  - Duchenne muscular dystrophy (DMD) is a dystrophinopathy, and its associated gene
      is located on Xp21. Moreover, utrophin, a recently identified structural
      homologue of dystrophin is reported to be up-regulated in DMD. In order to
      investigate the association between utrophin and muscle regeneration in DMD, an
      immunohistochemical study using antibodies to utrophin, dystrophin, vimentin and
      desmin was carried out in 17 cases of DMD, 3 cases of polymyositis and 1 case of
      dermatomyositis. Dystrophin was negative in almost all cases of DMD, but positive
      in all cases of inflammatory myopathy (IM). Utrophin was positive in 94.0% of DMD
      and in 75.0% of IM. 36.4% of the myofibers were positive in DMD, as compared to
      10.5% in IM (p=0.001). In both groups, utrophin positivity was present most
      commonly in small regenerating fibers (p=0.001, 0.013). Vimentin and desmin were
      intensely positive in regenerating fibers in all cases of DMD and IM. 34.4% and
      35.4% of myofibers were positive for vimentin and desmin in DMD, as compared to
      21.8% and 20.9% in IM (p=0.001, 0.001). In both groups, vimentin and desmin
      positivity were present most commonly in small regenerating fibers (p=0.001,
      0.001). The staining intensities of utrophin, vimentin and desmin were also
      higher in small regenerating fibers. These results show that utrophin up
      regulation is regeneration-associated, and that it is proportional to the
      quantity of regenerating myofibers, but is not specific for DMD.

PMID- 12619171
TI  - Serum lipid levels in psoriasis.
AB  - A predisposition to occlusive vascular diseases has been reported in patients
      with psoriasis and it has been suggested that some of these patients have some
      disorders of lipid metabolism. In this study, serum lipid levels were
      investigated in psoriatic patients to explore to the knowledge of this
      relationship. One hundred psoriatic patients and 100 non- psoriatic controls were
      included in the study. Total cholesterol, triglyceride, high-density lipoprotein
      cholesterol (HDL-cholesterol), low-density lipoprotein-cholesterol (LDL
      cholesterol), and very low-density lipoprotein-cholesterol (VLDL-cholesterol)
      levels were measured. In patients with psoriasis, total cholesterol and LDL
      cholesterol levels were found to be significantly higher than those of controls.
      No significant differences were found in the other parameters. We concluded that
      psoriatic patients should be evaluated and followed up for the risk of
      hyperlipidemia and obstructive vascular diseases.

PMID- 12619172
TI  - MR imaging and electrophysiological evaluation in carpal tunnel syndrome.
AB  - The objective of this study was to compare the MRI findings of wrists in patients
      diagnosed with CTS with those of the healthy controls, and to evaluate the
      correlation between the MRI differences and the electrophysiological findings in
      the patient group. This study involved 55 wrists, 30 of which were clinically and
      electrophysiologically diagnosed with CTS and 25 healthy controls. These 55
      wrists were evaluated electrophysiologically, and in terms of median nerve
      diameter, ratio of median nerve diameter at psiform bone level to distal radio
      ulnar joint level, the flexor retinaculum bulging ratio and the median nerve
      intensity by MRI. When the patient group, which were clinically and
      electrophysiologically diagnosed with CTS, and the healthy control group were
      compared, a significant difference (p < 0.001) was observed between the two in
      terms of median nerve diameters (at psiform bone level: 8.47 +/- 1.41mm and 2.91
      +/- 1.01 mm, distal radio-ulnar joint level: 4.04 +/- 1.06 mm and 2.42 +/- 0.95
      mm), ratio of median nerve diameter at psiform bone level to distal radio-ulnar
      joint level (2.17 +/- 0.54 and 1.25 +/- 0.12), their flexor retinaculum bulging
      ratios (26.21 +/- 5.98% and 7.27 +/- 4.53%) and their median nerve intensities.
      In the patient group, no significant correlation between MRI and the
      electrophysiological findings was found (p > 0.05). According to the data
      obtained from the study, we believe that the MRI examination of structural
      changes that occur in the carpal tunnel, neighboring structures and the median
      nerve would be useful in the diagnosis of CTS, especially in cases with suspected
      clinical and electrophysiological diagnosis.

PMID- 12619173
TI  - Complications of brucellosis in different age groups: a study of 283 cases in
      southeastern Anatolia of Turkey.
AB  - We carried out a retrospective analysis of 283 patients diagnosed with
      brucellosis in our hospital, which serves almost 5.5 million inhabitants in
      Southeastern Anatolia in Turkey. Our study focuses on the frequency of
      complications in cases with brucellosis across different age groups. Patients
      were classified into three groups according to age: less than 15 years old (group
      A), 15-45 years old (group B) and over 45 years old (group C). Of 283 patients,
      138 (49%) were female and 145 (51%) male. Fifty-three (19%) were younger than 15
      years old (group A), 178 (63%) were 15-45 (group B), and 52 (18%) were over 45
      (group C). When the distribution of all cases was examined according to months of
      the year, an increase was seen in June. Osteoarticular complications were the
      most frequent, found in 195 (69%) cases, followed by cutaneous (17%),
      genitourinary (8%), nervous (7%), respiratory (5%) and hematological (4%)
      complications. Treatment failed in 15 patients (5%), owing to true relapse in ten
      and to non-compliance and drug side effects in the other five. Two hundred
      seventy-two patients received medical treatment alone and 11 required medical and
      surgical treatment as well (9 spondylitis and 2 carditis). Complications in
      brucellosis were frequent because 25% of all patients with brucellosis had more
      than one complication, more so in group C (38%) than in group A (28%) or B (20%).
      Cutaneous, hematological and respiratory complications in childhood;
      osteoarticular and cardiac complications in adults; and genitourinary,
      neurological and gastrointestinal complications in middle aged were more
      prominent. In conclusion, the frequency of brucella complications was variable in
      different age groups in Southeastern Anatolia of Turkey. Since brucellosis is a
      preventable disease, knowledge and early diagnosis of the complications are
      especially important. Therefore, population education and medical precautions are
      necessary to prevent the harmful effects of brucella and its complications. In
      addition, primary health care physicians should be alerted regarding the clinical
      and laboratory findings of brucella complications.

PMID- 12619174
TI  - Measurement of peritoneal fluid pH in patients with non-serosal invasive gastric
      cancer.
AB  - The accurate pH range of peritoneal fluid is clinically valuable for the
      evaluation of some pathological conditions of the body, however, it is not easy
      to measure in healthy individuals. The aim of this study was to measure; pH,
      pCO2, pO2, Na+, K++, Ca++, HCO3-, and O2 saturation of the peritoneal fluid in
      patients with non-serosal invasive gastric cancer. One hundred and thirty four
      patients (86 men and 48 women), ranging in age from 24 to 91 years were enrolled
      in this study. After opening the abdominal wall, the probe of a portable pH meter
      was placed in the peritoneal fluid in the subhepatic space. In addition, I
      collected the peritoneal fluid from the subhepatic space to measure, pH, pCO2,
      pO2, Na+, K++, Ca++, HCO3-, and O2 saturation using an autoanalyzer. The pHs of
      the peritoneal fluids tested has a mean of 7.73 (range 7.46 - 8.10), and the
      other parameters were pCO2, 22.81 mmHg; pO2, 136.49 mmHg; Na+, 146.57 mmol/L;
      K++, 4.80 mmol/L; Ca++, 0.89 mmol/L; HCO3-, 30.54 mmol/L, and O2 saturation,
      99.74%. This study describes a practical method of measuring the pH of peritoneal
      fluid. The result obtained reflects the normal adult peritoneal pH value, which I
      propose as a reference value.

PMID- 12619175
TI  - Imaging findings of mantle cell lymphoma involving gastrointestinal tract.
AB  - Clinical manifestations and imaging findings of mantle cell lymphoma involving
      gastrointestinal tract were evaluated. The subjects were 7 cases of mantle cell
      lymphoma involving the gastrointestinal tract. All cases were pathologically
      confirmed in our hospital during the period from April 1994 to July 2000. Five
      patients were male and 2 were female, and their age ranged from 49 to 63 years
      (average 57.4). The objectives were: 1) characteristics and distribution of
      multiple polyposis, 2) presence, location and enhancement pattern of bowel wall
      thickening or mass formation, 3) presence of splenomegaly, 4) presence and
      location of abdominal lymph node enlargement, 5) involved extra-abdominal organs,
      6) combined cancer and location, and 7) other findings. All mantle cell lymphomas
      occurred in elderly persons, over 40 years, and most showed multiple polyposis
      (6/7), bowel wall thickening or mass formation (6/7), lymph node enlargements
      (6/7) and extra- abdominal involvement (5/7). All cases of polyposis involved the
      small bowel and colon, and the size of the polyps ranged from 0.1-4.0cm. Four of
      6 patients showed combined sessile and polypoid polyps, while the other 2 showed
      only sessile polyps. Most of or some of the polyps in 3 patients showed small
      central ulcerations. Most of the patients (5/6) showed an uncountable number of
      polyps. Polyposis was predominant in the rectum, ascending colon, rather than
      other sections in the colon, and the ileum were almost always involved by
      polyposis. Bowel wall thickening or mass formation developed exclusively in the
      ascending colon, rectum or ileum. Extra- abdominal involvement developed either
      simultaneously or nonconcurrently with gastrointestinal involvement. Some of
      patients showed splenomegaly (3/7), appendiceal enlargement (2/7), and
      intussusception (1/7), and some had associated adenocarcinomas (3/7).

PMID- 12619176
TI  - Anti-HER2/neu peptide producing vector system for biologic therapy - is it
      possible to mass-produce the peptide?
AB  - A humanized monoclonal antibody against HER2 has been using in a clinical setting
      and has been shown to possess therapeutic properties. A mimetic peptide against
      HER2 was also reported to bind to the HER2 receptor with some therapeutic
      potential. Based on a previous report and the sequence of Herceptin, we designed
      oligonucleotides of anti-HER2 mimetic peptides, named V2 and V3 peptides, in
      order to develop a peptide- producing vector system for biologic therapy against
      HER2- overexpressing cancers. We also adopted the sequence of a previously
      reported mimetic peptide, V1 (Park BW et al. Nat. Biotechnol, 2000, 18:194-198),
      as a reference peptide. We examined the effects of the V2 and V3 peptides against
      the HER2-overexpressing cell lines, SK-BR-3 and T6-17. Transient transfection of
      the construct expressing V1 and V2 inhibited cell proliferation in HER2
      overexpressing cell lines by 20 - 30%, but had no effect on the HER2-negative
      NIH3T3 cells. The proliferation inhibition shown by V2 was slightly better than
      that shown by V1. Recombinant peptides V2 and V3 were produced on a large scale
      in an E. coli system, and the V2 peptide showed anti-HER2-specific tumor cell
      proliferation inhibition of 10% to 30%. Current results suggest that anti-HER2
      mimetic peptides, overexpressed by a constitutive promoter or produced in an E.
      coli system, could specifically inhibit the proliferation of HER2-expressing
      cancer cells. Further efforts to augment the biologic specificity and efficacy
      and to develop new technologies for the purification of the peptide from the E
      coli system are needed.

PMID- 12619177
TI  - Identification of tumor suppressor loci on the long arm of chromosome 15 in
      primary small cell lung cancer.
AB  - Small cell lung cancer (SCLC) frequently shows a loss of heterozygosity (LOH) on
      chromosome 15q. In order to define the commonly affected region on chromosome
      15q, we tested 23 primary SCLCs by microsatellite analysis. By analyzing 43
      polymorphic microsatellite markers located on chromosome 15q, we found that 14
      (60.8%) of 23 tumors exhibited a LOH in at least one of the tested microsatellite
      markers. Two (14.3%) of the 14 tumors were found to have more than a 50% LOH on
      chromosome 15q. LOH was observed in five commonly deleted regions on 15q. Of
      those regions, LOH from D15S1012 to D15S1016 was the most frequent (47.8%). LOH
      was also observed in more than 20-30% of tumors at four other regions, from
      D15S1031 to D15S1007, from D15S643 to D15S980, from D15S979 to D15S202, and from
      D15S652 to D15S642. Four of the 23 tumors exhibited shifted bands in at least one
      of the tested microsatellite markers. Shifted bands occurred in 3.2% (29 of 914)
      of the loci tested. Our data suggests the presence of at least five tumor
      suppressor loci on chromosome 15q in SCLC, and further that these may play an
      important role in SCLC tumorigenesis.

PMID- 12619178
TI  - Glomerular C4d deposition indicates in situ classic complement pathway
      activation, but is not a marker for lupus nephritis activity.
AB  - This study was designed to evaluate whether glomerular C4d deposition may be a
      useful marker of lupus nephritis activity. Twenty-one patients diagnosed as
      having lupus nephritis (WHO class III: 4 cases; IV: 12 cases; V: 5 cases) were
      included. Mean patient age was 29.3 +/- 13.5 years (range: 7-55 years). The
      presence and intensity of glomerular C4d deposition were compared with the
      corresponding histologic activity index for each case. Immunofluorescence for C4d
      showed diffusely granular staining along glomerular capillary loops, in all cases
      examined (1+, in 8 cases; 2+, in 7 cases; 3+, in 6 cases). In eight cases, C4d
      deposition was found in the absence of capillary or mesangial C4 deposits.
      Moreover, the intensity of C4d deposits correlated with those of capillary IgG,
      IgA, C4, C1q, and fibrinogen deposits. However, C4d staining intensity did not
      correlate with the lupus nephritis activity index. Although glomerular capillary
      C4d deposition is a sensitive marker of classic complement pathway activation, it
      is not a sensitive marker for active lupus nephritis.

PMID- 12619179
TI  - The effects of the critical pathway for inguinal hernia repair.
AB  - This study was conducted to develop a case management program using the critical
      pathway (CP) as an intervention method for patients with an inguinal hernia for a
      herniorrhaphy, and to determine the effects of the CP on the period of
      hospitalization, medical costs, the rates of postoperative complaints, patient
      satisfaction and the nurses' job satisfaction. One hundred patients (60 in the
      experimental group, 40 in the control group) who were admitted to a general
      hospital in Seoul for inguinal herniorrhaphy were enrolled in this study. The
      results showed that the period of hospitalization and the postoperative hospital
      stay were significantly reduced in the CP group. In addition, the total medical
      cost, was lowered significantly by use of the CP for patients undergoing an
      inguinal herniorrhaphy. The rates of postoperative complaints, patients'
      satisfaction and the information on the treatment were enhanced after
      implementing the CP. These results suggests that the CP may be a useful tool for
      enhancing the health care outcome by decreasing the period of hospitalization,
      overall medical costs and by improving the quality of care, all of which can
      benefit the patients, the patients' family, caregivers and the hospital.

PMID- 12619180
TI  - Auditory p300 event-related potentials in fibromyalgia patients.
AB  - This study assessed the cognitive brain function measured by the cognitive P300
      auditory event-related potentials (ERPs) in female fibromyalgia (FM) patients and
      compared the results with those from healthy age and education-matched controls.
      The relationship of the P300 potentials to the pain threshold of patients was
      also investigated. The P300 component of the auditory ERPs were studied in 11
      female FM patients and 10 age and education-matched healthy controls. None of the
      patients were taking antidepressants such as amitriptyline or serotonin-reuptake
      inhibitors. The P300 latencies of the patients were not significantly different
      whereas the N2P3 amplitudes were significantly lower than the controls. The P300
      latencies in the patients negatively correlated with the total myalgic scores
      (TMS) (r= -0.73) and the control point scores (CPS) (r=-0.85). On the other hand,
      the P300 amplitudes showed a significant correlation with the TMS (r=0.61) and
      the CPS (r=0.60). There was no significant correlation between the anxiety and
      depression scores with the P300 latency or amplitudes. These results showed
      cognitive impairment, which was mainly expressed by the lower N2P3 amplitudes in
      patients with FM, and its clinical relevance requires further research.

PMID- 12619181
TI  - The effect of pelvic organ prolapse on lower urinary tract function.
AB  - Pelvic organ prolapse (POP) is a process in which the pelvic contents, including
      the reproductive organ, bladder, rectum, and/or small intestines become herniated
      through defects in the vaginal wall. The pelvic organs are closely related to the
      urinary tract and thus various urinary functions can be affected. The purpose of
      this study was to evaluate the relationship between pelvic organ prolapse and
      lower urinary tract function by urodynamic studies. From March 1999 to May 2000,
      40 patients with pelvic organ prolapse who underwent urodynamic studies
      (uroflowmetry, filling cystometry, urethral pressure profile) without barrier
      reduction of prolapse were analyzed. The majority of the cases of low grade POP
      involvedpatients with anterior wall prolapse, whereas the higher POP stages were
      more frequent in women with cervical cuff prolapse. Symptoms of stress urinary
      incontinence and hesitancy were more frequent in the patients with anterior wall
      prolapse. The urodynamic study showed a statistically significant increase in
      MUCP in patients with POP stage IV and the leading point of POP was cervical
      cuff. The subjective urinary symptoms of patients with POP appear to be less
      reliable as a diagnostic tool. POP had no adverse effect on the bladder storage
      function. However, POP affected the voiding function through an increase in MUCP,
      especially in patients with stage IV prolapse and when the leading point of POP
      was cervical cuff. Following the surgical correction of POP, an evaluation of the
      preoperative changes in the urodynamic study parameters should be performed.

PMID- 12619182
TI  - The effects of alendronate and calcitonin on cytokines in postmenopausal
      osteoporosis: a 6-month randomized and controlled study.
AB  - The present study was designed to determine if levels of serum cytokines, such as
      interleukin (IL)-1beta, IL-2, IL-2r, IL-6, IL-6r, IL-8, IL-10, and TNF-alpha are
      different in osteoporotic and non-osteoporotic postmenopausal women, and to
      evaluate the effects of calcitonin and alendronate therapies over a six month
      period on serum cytokine levels in postmenopausal osteoporotic women. Serum
      levels of IL-2, TNF-alpha and IL-8 were found to be significantly higher (p <
      0.05), and serum IL-10, and IL-6r significantly lower in the calcitonin (N=60)
      and the alendronate (N=60) treatment groups than in the control group (N=50) (p <
      0.05). But, no significant difference was apparent between the calcitonin and
      alendronate treated groups before treatment. Statistically significant changes
      occurred in patients, with respect to the levels of serum IL-6r, and IL-8 after
      one month (p < 0.05), in IL-2r, IL-6r, IL-8, IL-10 after three months, and in IL
      1beta, IL-6r, IL-8, IL-10 and TNF-alpha after six months of calcitonin therapy (p
      < 0.05). No significant difference was observed in IL-6r after one month, in IL-8
      and IL-10 after three months, and in TNF-alpha after six months in the calcitonin
      treated group and in the control group, whereas these parameters were
      significantly different at baseline. In the alendronate treated group,
      statistically significant changes occurred in the levels of serum IL-1alpha and
      IL-6 after three months, and in IL-1beta, IL-6, IL-6r and TNF-alpha after six
      months (p < 0.05). No significant difference was observed in IL-6r after one
      month, in IL-10 after three months or in TNF-alpha after six months between the
      alendronate treatment group and the control group, whereas these parameters were
      significantly different at baseline. In conclusion, we suggest that; 1) not only
      IL-1, IL-6, TNF-alpha and IL-11 but also IL-2, IL-8 and IL-10 may have roles in
      the etiopathogenesis of osteoporosis, 2) calcitonin therapy have a more distinct
      influence on serum levels of some cytokines and have an earlier effect than
      alendronate therapy (especially upon IL-2r, IL-8, and IL-10). Nevertheless,
      further longitudinal studies are needed to identify the cytokines involved in the
      pathogenesis of postmenopausal osteoporosis and to evaluate the influence of
      different treatments on these cytokines.

PMID- 12619183
TI  - Search for genes potentially related to germ tube formation in Candida albicans
      by differential-display reverse transcription polymerase chain reaction.
AB  - Candida albicans exhibits the ability to grow in either a yeast or a mycelia form
      in response to different environmental factors. The mycelia form, found in
      infected tissues, is important as a virulence factor in the adherence of the
      organism to the host epithelium. In vitro, the morphological transition can be
      induced by environmental shifts in the growing conditions, or by a variety of
      exogenous factors, including ambient pH, nutritional status and temperature. The
      differential-display reverse transcription polymerase chain reaction (DDRT-PCR)
      is a powerful technique for comparing gene expression between cell types, stages
      of development or differentiation. Hyphae related genes were identified and
      characterized using a PCR-based differential display. Candida albicans formed a
      germ tube when cultured in rabbit serum, RPMI 1640 medium or 39 degrees C-YPD
      medium. We gained 21 cDNA bands showing a different expression pattern from that
      of the uninduced culture. DNA was extracted from the same location of the
      isolated bands, and PCR was performed under the same conditions, which
      reamplified the PCR product, showing the specific expression patterns according
      to the culture conditions. We cloned 18 germ tube-related cDNA clones (inserts
      average size is 80 - 700 bp) and sequenced them. The nucleotide sequences of the
      18 clones were identified through in the present study from GenBank, and were
      found to have the accession number (AF405213-AF405230). We could not find any
      nucleotide sequence having a high homology with these clones. This study could
      form a part of the projects in the search for genes related to the germ tube
      formation of C. albicans.

PMID- 12619184
TI  - Infrared thermographic imaging in the assessment of successful block on lumbar
      sympathetic ganglion.
AB  - This study examined the net changes in temperature at various regions of the
      lower extremities in an attempt to identify the regions demonstrating the most
      significant temperature changes following a lumbar sympathetic ganglion block
      (LSGB). Thermography was performed before and after the LSGB in 26 sympathetic
      nerve system disorder cases. The inspection points were the anterior and
      posterior surfaces of the thigh, the knee and leg, and the dorsal and plantar
      surfaces of the feet. The net increases in skin temperature following the LSGB
      (deltaT(net)) at the plantar and dorsal surfaces of the feet, were 6.2 +/- 2.68
      degrees C (mean +/- SD) and 3.9 +/- 1.89 degrees C, respectively, which were
      higher than those observed in the other regions of the lower extremities (p <
      0.05). The areas, in order of decreasing deltaT(net), are as follows: the plantar
      surface of the foot, the dorsal surface of the foot, the shin, the anterior
      surface of the knee, the calf, the posterior surface of the knee, the anterior
      surface of the thigh, and the posterior surface of the thigh. There was one case
      of orthostatic hypotension during the thermography procedure. In conclusion,
      thermographic imaging is a useful method for demonstrating the success of a LSGB
      in various diseases. An evaluation of the deltaT(net) on the plantar surface of
      the feet using thermographic imaging is the most effective, simple, and safe
      method for assessing a successful LSGB.

PMID- 12619185
TI  - Glutamine synthetase induced spinal seizures in rats.
AB  - Glutamine synthetase (GS) is a key enzyme in the regulation of glutamate
      neurotransmission in the central nervous system. It is responsible for converting
      glutamate to glutamine, consuming one ATP and NH3 in the process. Glutamate is
      neurotoxic when it accumulates in extracellular fluids. We investigated the
      effects of GS in both a spinal cord injury (SCI) model and normal rats. 0.1-ml of
      low (2- micro M) and high (55- micro M) concentrations of GS were applied,
      intrathecally, to the spinal cord of rats under pentobarbital anesthesia.
      Immediately after an intrathecal injection into the L1-L3 space, the rats
      developed convulsive movements. These movements initially consisted of myoclonic
      twitches of the paravertebral muscles close to the injection site, repeated tonic
      and clonic contractions and extensions of the hind limbs (hind limb seizures)
      that spread to the fore limbs, and finally rotational axial movements of the
      body. An EMG of the paravertebral muscles, fore and hind limbs, showed the extent
      of the muscle activities. GS (2- micro M) caused spinal seizures in the rats
      after the SCI, and GS (6- micro M) produced seizures in the uninjured
      anesthetized rats. Denatured GS (70 degrees C, 1 hour) also produced spinal
      seizures, although higher concentrations were required. We suggest that GS may be
      directly blocking the release of GABA, or the receptors, in the spinal cord.

PMID- 12619187
TI  - Gadolinium dimeglumine as a contrast agent for digital subtraction angiography:
      in vitro hounsfield unit measurement and clinical efficacy.
AB  - The purpose of this study was to evaluate the feasibility and safety of using
      gadolinium-chelates for digital subtraction angiography (DSA) in patients with
      contraindications to iodinated contrast material, and to assess the clinically
      effective concentration of gadolinium (Gd). Gadopentetate dimeglumine and
      iopromide were used in density measurements. Using 20 mL disposable syringes,
      serial dilutions of Gd and iopromide with saline were performed. Computed
      tomography scanning was done and the attenuation of each was recorded as mean
      Hounsfield units using region of interest analysis. Clinical trials were done in
      twelve patients with the following types of angiogram or intervention:
      hemodialysis access, percutaneous biliary drainage, percutaneous nephrostomy,
      cerebral angiography and transarterial chemoembolization (TACE) in hepatocellular
      carcinoma. The density of 1 : 1 diluted Gd was nearly equal to that of 1 : 4
      dilution of iopromide, and that of pure Gd was similar to or less than that of 1
      : 1 dilution of iopromide. Serum creatinine level was not elevated in any of the
      patients. Gd is a safe alternative agent in patients with contraindications to
      iodinated contrast materials. Pure Gd without dilution is the most clinically
      useful concentration.

PMID- 12619186
TI  - How much are anesthesiologists exposed to electromagnetic fields in operating
      rooms?
AB  - Numerous electronic devices have been introduced into the operating room.
      Although little is known about the relationship between exposure to
      electromagnetic fields (EMF) and health hazards, some authors reported its
      association with cancer or other diseases. We measured the amount of EMF exposure
      that an anesthesiologist gets in the operating room. The density of the magnetic
      field was checked by an extremely low frequency (ELF) field strength measurement
      system in the 19 operating rooms of our hospital. We measured the magnetic field
      intensity at a distance of 30 cm, 50 cm, and at the place where the
      anesthesiologist usually stands from the center of the main monitor. The average
      exposure quantities of magnetic fields in 19 operating rooms were 2.22 +/- 1.13
      mG at 30 cm, 1.29 +/- 0.84 mG at 50 cm and 1.00 +/- 0.78 mG at the
      anesthesiologist's standing points respectively. Because quantities over 2 or 3
      mG were accepted to be high radiation levels of EMF by many reports describing
      the hazards of EMF, we set 2 mG to be the cutoff value. In some of the 19
      operating rooms, the measured EMF density exceeded our cutoff value. Although the
      health hazards related to EMF exposure are still equivocal, anesthesiologists
      should consider making an effort to improve their environment and reduce their
      exposure to EMF.

PMID- 12619188
TI  - Perioperative stroke in the brain and spinal cord following an induced
      hypotension.
AB  - A 49-year-old woman presented with stupor and paraplegia following an induced
      hypotension. The temporal relationship to the induced hypotension and the absence
      of a clear embolic source on diagnostic tests support a causal association
      between the hypotensive episode and the ischemic infarct. However, despite the
      association, a cause-and-effect relationship could not be automatically inferred.

PMID- 12619189
TI  - A case of pulmonary Microsporidiasis in an acute myeloblastic leukemia (AML) - M3
      patient.
AB  - Reported here is a case of microsporidiasis that occurred in an acute
      myeloblastic leukemia (AML)-M3 patient who underwent chemotherapy. Fever, cough,
      expectorate and dyspnea were observed during the therapy. Since this case was
      considered as adult respiratory distress syndrome due to the chest X-ray and
      arterial blood gas findings, the male patient was bounded to a mechanical
      ventilator. As coagulation tests showed compatible findings with disseminate
      intravascular coagulation (DIC), it was thought to be a case of sepsis
      originating from the lungs and DIC. Pseudomonas aeruginosa and Staphylococcus
      aureus were found in the sputum of the patient. Although he was given combined
      antibiotic therapy, there was no reduction in the fever. A bronchoalveolar lavage
      (BAL) sample was taken and Microsporidia sp. was found upon staining with Giemsa.
      The patient died due to sepsis and DIC just before receiving therapy for
      microsporidiasis. Pulmonary infection with Microsporidia, although classically
      occurring in patients with HIV infection, may occur rarely in leukemia patients,
      especially if previously treated with systemic immune suppression. This case
      reinforces the need to consider Microsporidia as a possible pathogen in
      immunocompromised patients with pulmonary infections.

PMID- 12619190
TI  - Sclerosing hemangioma with lymph node metastasis.
AB  - Sclerosing hemangioma (SH) of the lung is an uncommon type of tumor, which is
      composed of polygonal and cuboidal cells. This disease is generally regarded as
      benign but extremely rare cases with lymph node metastasis have been reported. We
      report a case of SH with a metastasis to the regional lymph nodes. A 19-year-old
      girl presented with a 2-year history of coughing. A chest X-ray and a CT scan
      indicated a large mass in the lower lobe. As a result, a left lower lobectomy
      with a dissection of the hilar and interlobar lymph nodes was performed. The
      tumor was a well-defined huge mass with partial adhesion to the mediastinal and
      parietal pleura. The dissected hilar, interlobar, and intrapulmonary lymph nodes
      demonstrated metastasis. Histologically, the primary and metastatic tumor
      consisted of polygonal and cuboidal cells. Both types of tumor cells were
      uniformly immunoreactive to the epithelial membrane antigen (EMA) and the thyroid
      transcription factor-1 (TTF-1). However, the cuboidal cells tested positive for
      pancytokeratin, whereas the polygonal cells tested consistently negative.
      Postoperatively, the patient received chemotherapy and no recurrence or
      metastasis 2 years after surgery was noted. Although a pulmonary SH is considered
      to be benign, this case highlights the need for the evaluation of lymph node
      metastasis.

PMID- 12619191
TI  - Is visual loss due to giant cell arteritis reversible?
AB  - Giant cell arteritis (GCA) is a common systemic vasculitis with an unknown
      etiology. It mainly affects people older than 50 years of age and often presents
      with symptoms such as headache, jaw claudication, visual loss, polymyalgia
      rheumatica and increased erythrocyte sedimentation rate (ESR). Established
      blindness is irreversible if the steroid treatment is not administered within a
      few days. Here, we report a case of GCA in a patient with a normal ESR whose left
      eye perceived just light at the initiation of treatment. Immediately prior to the
      combined treatment with high dose oral steroids and cyclophosphamide, the ESR
      level had increased to 80 mm/h and the vision improved after the combined
      treatment four months later.

PMID- 12619192
TI  - Bilateral popliteal artery aneurysms with rupture and pseudoaneurysm formation on
      the left.
AB  - The rupture of a popliteal artery aneurysm is very rare, and can lead to serious
      complications if untreated. Any reports of a huge pseudoaneurysm, following
      rupture of the popliteal artery aneurysm could not be found in a review of the
      literature. A pulsatile huge mass leading to a deep venous thrombosis, was
      observed in a 74 years old male patient who for 2 months had had a progressively
      swollen and painful left leg. On angiographic evaluation, the mass was found to
      be a pseudoaneurysm originating from a ruptured true aneurysm of the popliteal
      artery. There was also a small true aneurysm in the contralateral extremity at
      the same localization. Both the false, and true aneurysms were resected
      surgically and arterial continuity was established with a synthetic
      polytetrafluoroethylene graft.

PMID- 12619194
TI  - A case of focal acantholytic dyskeratosis occurring on both the lip and the anal
      canal.
AB  - Focal acantholytic dyskeratosis has a distinctive histological pattern that is
      associated with various clinical expressions. It rarely occurs on the lip or the
      perianal area. We report a patient with focal acantholytic dyskeratosis occurring
      on both the upper lip and the anal canal. Histopathologically, the lesions showed
      hyperkeratosis, suprabasilar clefting, epidermal acantholysis and dyskeratosis.
      This case represents the first report of a focal acantholytic dyskeratosis
      occurring on both the lip and the anal canal.

PMID- 12619193
TI  - Hemorrhagic cystitis due to intravesical instillation of gentian violet
      completely recovered with conservative therapy.
AB  - Chemical cystitis due to intravesical instillation of gentian violet or crystal
      violet is rare and all of the reported cases have been in adults using undiluted
      solution, which resulted in long-term sequelae. This is a case report on a 16
      month-old boy with hemorrhagic cystitis after the instillation of diluted gentian
      violet into the bladder to rule out bladder injury during inguinal herniorrhaphy.
      Although he was completely recovered with conservative therapy, gentian violet,
      even when diluted, should not be used on the urinary tract.

PMID- 12619196
TI  - Panic disorder in children and adolescents.
AB  - Panic disorder (PD) in children and adolescents is a disabling and chronic
      condition, which is accompanied by psychosocial and academic difficulties both
      during adolescence and into adulthood. In this article, the prevalence, clinical
      characteristics, risk factors, comorbid states, differential diagnosis, and
      treatment of PD are reviewed. Although PD was thought to be rare in children and
      adolescents, the prevalence of PD in community samples ranges between 0.5% and
      5.0, and in pediatric psychiatric clinics from 0.2% to 10%. Panic attacks are
      reported to be equally prevalent in males and females. Clinical studies have
      shown that the majority of the PD pediatric patients receiving consultation in
      clinics are older adolescents, Caucasian, female, and middle class. Up to 90% of
      children and adolescents with PD have other anxiety disorders (generalized
      anxiety disorder/overanxious disorder, separation anxiety disorder, social phobia
      or agoraphobia), or mood disorders (major depressive disorder or bipolar
      disorder). PD patients can be misdiagnosed or having neurologic, cardiovascular,
      pulmonary, or gastrointestinal illness. Psychoeducation and psychosocial
      treatments are recommended, and it appears that selective serotonin reuptake
      inhibitors (SSRIs) are a safe and promising treatment for children and
      adolescents with PD. The clinical characteristics, long-term course, and
      treatment of PD in children and adolescents needs to be further assessed by well
      designed studies.

PMID- 12619195
TI  - Dental technician's pneumoconiosis: mineralogical analysis of two cases.
AB  - Pneumoconiosis was diagnosed by open lung biopsy in two dental technicians who
      had interstitial lung disease. Mineralogical analysis was performed to
      investigate the origin of the dust that had been inhaled. A marked accumulation
      of silicon and phosphorus was found in both cases. The hard metals chromium and
      cobalt were also found. Dental technician's pneumoconiosis is a complex
      pneumoconiosis in which such dust and hard metals may play a role.

PMID- 12619197
TI  - [Early diagnosis and new therapeutic options. More power against rheumatoid
      arthritis].

PMID- 12619198
TI  - [When the cardiac patient with arthritis needs aspirin and NSAID: how to protect
      the stomach?].

PMID- 12619199
TI  - [In high risk patients cyclooxygenase inhibitor plus proton pump inhibitor].

PMID- 12619200
TI  - [Burn-out, depression, suicide. When physicians marry their profession].

PMID- 12619201
TI  - [Why precise diagnosis is worthwhile. Only he who knows about dementia can treat
      it].

PMID- 12619202
TI  - [Early detection of colon carcinoma. Flexible sigmoidoscopy--who does it?].

PMID- 12619203
TI  - [Cox-2 inhibitor i.m. in lumbago. This is not without risk!].

PMID- 12619204
TI  - [German physicians discover a possible correlation. Heart failure caused by
      vitamin D deficiency? (interview by Dr. Kirsten Westphal)].

PMID- 12619205
TI  - [Your patient with carcinoma of the urinary bladder. Options for organ
      preservation].
AB  - Every year, some 18,000 persons develop cancer of the bladder, making it one of
      the most common of the malignant diseases. Major underlying causal factors are
      exposure to aromatic amines, nicotine abuse, chronic infections and various
      medications. On the basis of the TMN system, a differentiation is made between
      superficial, invasive and metastasizing (lymphogeneous, hematogenous) carcinomas.
      A classical symptom is painless hematuria. The diagnosis is established primarily
      by white-light cystoscopy. Superficial urothelial lesions, which are often
      overlooked with this method, may be detected with the aid of the more sensitive
      method of fluorescence endoscopy. Depending upon local tumor spread and degree of
      differentiation, treatment includes transurethral electrocoagulation, laser
      coagulation, instillation of cytostatics and immunotherapeutic agents, as well as
      -in the case of muscle invasion--radical cystectomy.

PMID- 12619206
TI  - [Carcinomas of the upper urinary tract. With early diagnosis 80-100% of patients
      survive 5 years].
AB  - About 5% of all urothelial cancers develop in the upper urinary tract, i.e. in
      the ureter or renal pelvis. 40-70% of the tumors appear to be associated with
      cigarette smoking. The most common symptom seen in ureteral cancer is painless
      hematuria. The diagnosis is established by radiography and endoscopy. The most
      important diagnostic aids are urinary status, ultrasonography, excretory
      urography, ureteropyelography and endoscopy. Owing to the fact that this tumor
      entity is often multifocal, cystoscopy to exclude involvement of the bladder is
      mandatory. Superficial "low-grade" tumor stages can be treated endoscopically, in
      particular in the case of patients with only a single kidney or bilateral
      involvement. For more advanced stages, nephroureterectomy, together with the
      removal of a "cuff" of the bladder and ipsilateral lymphadenectomy, is indicated.

PMID- 12619207
TI  - [Hormone disorders and HPV infection. Risk factors for tumors of the urethra?].
AB  - Overall, epithelial growths in the urethra are rare, and present as benign or
      malignant lesions at different periods of life; their incidence varies between
      the sexes. Among the benign urethral growths, condylomata in younger men, and
      urethral caruncles in elderly women are relatively common. In contrast, cancer of
      the urethra is relatively rare and shows a clear predilection for female sex
      (4:1). In patients with persistent urethral and urination problems, with or
      without macrohematuria, the rare urethral carcinoma should be included in the
      differential diagnostic considerations, in particular in elderly patients. Only
      when cancer is suspected early on and confirmed endoscopically and
      histologically, thus allowing rapid initiation of urological-oncological therapy,
      is there a good chance of a cure.

PMID- 12619208
TI  - [Increases in hay fever in children. Pollen season already begins in January].

PMID- 12619209
TI  - [The police asks for help. Indications in roentgen image].

PMID- 12619210
TI  - [Diabetic patients with increased blood pressure in family practice. 38% already
      have microalbuminuria!].

PMID- 12619211
TI  - [How many colleagues handle cadavers? Physician protest effective despite
      national health insurance objections].

PMID- 12619212
TI  - [Individual patient care versus bill. Patients have no qualms with IGeLn].

PMID- 12619213
TI  - [Very concrete and studied IGeL examples. Stress course supports general practice
      finances].

PMID- 12619214
TI  - [Pre-diabetes calls for aggressive RR value decrease. Defusing the time bomb
      early].

PMID- 12619215
TI  - [New potency pill. Treating (vascular) bed failure].

PMID- 12619216
TI  - [Sudden cardiac death. Targets every 2nd person without warning].

PMID- 12619217
TI  - [Allergic rhinitis. Treating symptoms or desensitization?].

PMID- 12619218
TI  - [When the left ventricle can no longer relax properly. Beta blocker improves
      diastolic function].

PMID- 12619219
TI  - [New AT1 receptor antagonist. Rapid and effective blood pressure decrease].

PMID- 12619220
TI  - [New therapeutic recommendations for severe migraine. High beginning dosage
      rather than slow dosage increase].

PMID- 12619221
TI  - [New ointment with vitamin D derivative and corticoid. Psoriasis therapy
      combined].

PMID- 12619222
TI  - [Depot calcium antagonist. General practice study confirms good tolerance].

PMID- 12619223
TI  - [Public health visit in the Republic of China/Taiwan. Medical power apart from
      WHO].

PMID- 12619224
TI  - [Summit meeting of breast cancer experts--many new ideas and practical progress.
      When the breast becomes malignant].

PMID- 12619225
TI  - [Interview with private lecturer Dr. med. Nadia Harbeck, Munich. Prognostic
      markers guide therapy (interview by Jochen Aumiller)].

PMID- 12619226
TI  - [Emergencies in the elderly. Alarm signs are often absent--or atypical].

PMID- 12619227
TI  - [Difficult therapy of chronic inflammatory bowel diseases. No symptoms, but
      sequelae instead?].

PMID- 12619228
TI  - [After the heart catheter. 2 thrombocyte inhibitors for a whole year?].

PMID- 12619229
TI  - [Worms and allergy excluded. What is the etiology of eosinophilia?].

PMID- 12619230
TI  - [Influenza--the last big epidemic. What makes it so dangerous?].
AB  - In Germany, influenza lays low millions--and causes up to 15,000 deaths--every
      year. Three factors in particular are responsible for the severity of the
      disease: the cytocidal action of the virus--which, via hematogeneous spread, can
      involve not only the respiratory tract but also other organs such as the heart--,
      the immune response with fever and the production of pro-inflammatory cytokines,
      and bacterial superinfection of the virally predamaged respiratory mucosa. A
      particular threat is posed by influenza pandemics, which are usually associated
      with extremely high mortality and morbidity rates. The development of pandemics
      is furthered by the potential of the viral genome to undergo a so-called shift,
      as a result of which a reservoir of, for example, avian influenza A viruses can
      give rise to subtypes that are a danger to humans, and against which there is
      initially no protection. While the deaths caused by an epidemic are to be seen
      largely among old and multimorbid people, a pandemic also endangers the health
      and life of young and healthy persons.

PMID- 12619231
TI  - [Rapid diagnosis at the bedside. True influenza or influenza-like infection?].

PMID- 12619232
TI  - [Oral neuraminidase inhibitor and an early warning system. New weapons against
      influenza].

PMID- 12619233
TI  - [Acute metabolic emergencies in diabetic patients. Hypoglycemic shock or diabetic
      coma?].

PMID- 12619234
TI  - [Apoplexy, diverticulum or Alzheimer disease? Deglutition disorders in seniors
      must always be evaluated!].
AB  - Problems with swallowing (dysphagia) occur in association with numerous
      illnesses. In many cases, however, they are either not recognized or considered
      not to require clarification, since other symptoms are of greater importance. In
      elderly, often multimorbid patients, neurodegenerative diseases, such as
      apoplexy, are the most common causes of dysphagia, but medications with central
      nervous side effects may also impair swallowing. The difficulty may be localized
      either in the oropharyngeal region or in the esophagus. There is considerable
      danger that such complications as aspiration pneumonia and malnutrition may occur
      and thus increase morbidity and mortality. In addition, the quality of life of
      the patient may also be diminished. The family doctor has the important task of
      initiating a differentiated diagnosis based on careful history-taking and a
      clinical examination that should include an inspection of the oral cavity and the
      nerves supplying the brain. Early treatment, for example, involving a logopedist,
      can be effective.

PMID- 12619235
TI  - [Dangerous duo: hypertension and pre-diabetes--the underestimated risk].

PMID- 12619236
TI  - [Despite therapy morning dangerous RR spikes. Headache and vertigo are alarm
      signals].

PMID- 12619237
TI  - [Hepatitis C therapy is not pleasant. Patients must be prepared!].

PMID- 12619238
TI  - [Already in altered glucose tolerance an antidiabetic drug. Significantly fewer
      heart attacks].

PMID- 12619239
TI  - [Reducing hospital stay and costs in heart failure. The proper diuretic makes the
      difference].

PMID- 12619240
TI  - [Uncomplicated community-acquired pneumonia. Under control in 3 treatment days].

PMID- 12619242
TI  - [Ayurvedic medicine in Sri Lanka. Enjoying a thousand year old healing art at the
      source].

PMID- 12619241
TI  - [Lowering cholesterol becomes easier. Combining instead of increasing dosage].

PMID- 12619243
TI  - [40. For alcoholic patients the family physician is the most important addiction
      therapist].

PMID- 12619244
TI  - Physician on scene. CPR at Caesar's.

PMID- 12619245
TI  - Recalling Dr. Caroline.

PMID- 12619246
TI  - Approaching the patient.

PMID- 12619247
TI  - Geriatrics and their meds: problems and perils.
AB  - The EMS provider often encounters the elderly patient at home, where a
      comprehensive medication history can be obtained. Because of the aging process,
      the older patient may not be able to tolerate drug therapy as well as a younger
      adult. When obtaining a medication history, look and ask for detailed
      information, including the use of dietary and herbal supplements, especially if
      the signs and symptoms do not match existing or known conditions. The astute EMT
      or paramedic may be able to recognize drug-induced illness and alert the
      emergency department physician. Early intervention may save the elderly patient's
      life.

PMID- 12619248
TI  - Universal truths of patient care documentation.

PMID- 12619249
TI  - Is aspirin part of your chest pain protocol?

PMID- 12619251
TI  - 6th Annual Website Review.

PMID- 12619250
TI  - Sleep deprivation and shift work in EMS.

PMID- 12619252
TI  - The EMS mentor. Assisting in new staff development.

PMID- 12619253
TI  - Secrets of the sagittal.

PMID- 12619254
TI  - The jaws and early orthodontics.

PMID- 12619255
TI  - AAFO interview with Dr. Derek Mahony. 1999 clinician of the year--Part II.

PMID- 12619256
TI  - Helping your patients overcome dental phobia.
AB  - Dental phobias stem from various sources and can lead to strongly conditioned
      fear responses. The following are the most common origins of dental fear:
      Previously painful or negative experiences during visits to a dentist's office. A
      severe discomfort with feeling vulnerable and/or out of control in a dental
      situation. A sense of embarrassment from dental neglect and fear of ridicule
      and/or belittlement. Scary anecdotes of negative dental experiences from family
      and friends. Negative, menacing portrayals of dentists in movies, television,
      newspapers, and magazines. A sense of depersonalization in the dental process,
      intensified by today's necessity for the use of barrier precautions, such as
      masks, latex gloves, and shields. A general fear of the unknown. Once you
      recognize the possible sources of your patients' fears, you will be in a much
      better position to help them identify and overcome their particular brand of
      dental phobia.

PMID- 12619257
TI  - Evolving technology in endodontic posts.
AB  - This article provides a brief overview of important, recent changes in the
      philosophy, materials, and technology that have impacted significantly on the art
      and science of endodontic post placement.

PMID- 12619258
TI  - The effect of root modification and biomodification on periodontal therapy.
AB  - Root surface biomodification has been used to treat periodontitis and gingival
      recession. The rationale for this procedure is that removing the smear layer from
      the root surfaces exposes collagen fibers, which leads to improved healing.
      Although animal studies have shown promising results, human studies have been
      disappointing. Some experts claim that the use of low-pH biomodification agents
      may cause necrotizing effects, and the use of neutral-pH agents does not.
      However, clinical investigations generally have failed to find any improvement in
      clinical parameters when using such agents.

PMID- 12619259
TI  - A two-and-a-half year perspective on simplified endodontic techniques.
AB  - Simplified Endodontic Techniques (SET), along with EZ-Fill, a bidirectional
      spiral and epoxy root canal cement, have been used for more than 2 1/2 years.
      This particular sequence of instrumentation and obturation provides the dentist
      with predictable and easily attained success. Periapical areas demonstrate
      healing, and excess EZ-Fill cement is resorbing. Postoperatively, patients
      experience approximately 80% less pain in both occurrence and intensity. The
      adoption of SET, along with EZ-Fill, allows dentists to significantly increase
      their productivity while dramatically improving the quality of their work.

PMID- 12619260
TI  - How a spectrophotometer can help you achieve esthetic shade matching.

PMID- 12619261
TI  - Intentional replantation of endodontically treated teeth: an update.
AB  - The IR technique is a clinically successful procedure, so long as the following
      conditions, as outlined by Niemczyk, are met: 1) Avoid any crushing or scraping
      contact with the root surface or socket; 2) Root surface must be continually
      hydrated with tissue culture media (e.g., HBSS); 3) Tooth should be splinted, if
      indicated; and 4) Soft diet and hygiene instructions must be implemented and
      reinforced. The IR technique should not be considered a procedure of last resort.
      Rather, it should be used in situations where conventional apical surgery is
      difficult or places the patient at risk. The IR technique expands potential
      treatment alternatives and allows the patient to successfully retain his or her
      own tooth following treatment.

PMID- 12619263
TI  - Identification of occlusal sealants using optical coherence tomography.
AB  - OBJECTIVE: Optical coherence tomography (OCT) is a new imaging technique that
      uses light to image dental structures interferometrically. OCT creates cross
      sectional images that have potential diagnostic value for dental applications.
      When used in epidemiological studies, OCT offers a safe, non-invasive technique
      to discriminate occlusal sealants and composite restorations. This paper
      summarizes a study in which dentists were asked to interpret and discriminate
      between OCT images. METHODOLOGY: Twenty-one dentists were asked to interpret OCT
      images of nine extracted premolars that were either not restored, contained an
      occlusal sealant or were restored with a composite restoration. RESULTS: Although
      the dentists were previously unfamiliar with OCT images, they adapted well and
      felt confident in their diagnoses using this new technology. The sensitivity of
      OCT to discriminate composite and sealants was > 0.92, while the specificity of
      discrimination was > 0.94. The capacity of OCT to discriminate sealants from non
      restored occlusal surfaces was slightly less (sensitivity 0.88; specificity
      0.86), but still within a clinically acceptable level. Inter- and intra-rater
      reliability, as measured by the kappa statistic, also revealed excellent
      performance by dentists using this new imaging technology. Intra-rater
      reliability was very good, ranging from 0.82 to 1.0. Inter-rater reliability was
      also high, predominately in the "Good" to "Very Good" agreement range.
      CONCLUSION: This preliminary study indicates OCT imaging may be an important new
      technology for discriminating occlusal sealants and composite restorations.

PMID- 12619264
TI  - A six-week study to evaluate the anti-calculus efficacy of a chewing gum
      containing pyrophosphate and tripolyphosphate.
AB  - OBJECTIVE: A six-week, double-blind, cross-over clinical study was conducted to
      compare the effect of a new chewing gum containing pyrophosphate (1%) and
      tripolyphosphate (1%), versus a control chewing gum on supragingival calculus
      deposits. METHODOLOGY: Twenty-eight adult subjects (mean age 34 +/- 8 years) who
      entered the study were given a full oral prophylaxis and were assigned to chew
      two pieces of gum, four times a day for five minutes. The gum, either a test
      chewing gum or placebo chewing gum, was randomly assigned and the subjects were
      directed to chew their assigned gum for six weeks. All participants also received
      a 12-week supply of a sodium fluoride (0.32%) dentifrice (Colgate). They were
      then scored for calculus deposits using the modified Volpe-Manhold Calculus Index
      (VMI) by the same two examiners. At the end of the first six weeks, the subjects
      received a second oral prophylaxis and used the alternate chewing gum for a
      second six-week period of time. The subjects were again scored for calculus
      deposits and the study was completed. RESULTS: The results demonstrated a mean
      VMI of 3.65 +/- 2.82 for the test group, and a mean of 4.24 +/- 3.25 for the
      placebo group. This difference was significant with paired sample t-test (p <
      0.001). CONCLUSION: These results indicated that chewing gum containing
      pyrophosphate and tripolyphosphate reduced supragingival calculus formation by
      13.9%, compared to the placebo chewing gum.

PMID- 12619262
TI  - Efficacy and tolerability of an intraoral benzocaine patch in the relief of
      spontaneous toothache pain.
AB  - OBJECTIVE: In this randomized, double-blind, placebo-controlled clinical trial,
      the effectiveness and tolerability of a novel intraoral benzocaine patch was
      evaluated in 60 patients who presented to the Dental School's emergency clinic
      with spontaneous toothache pain of at least a moderate intensity. METHODOLOGY:
      Mucoadhesive patches, containing either 12 mg of benzocaine or a matching
      placebo, were applied approximately two millimeters apical to the mucogingival
      junction of the symptomatic tooth and remained in place for 60 minutes. Pain
      intensity (0-4 scale) and pain relief (0-4 scale) were recorded every five
      minutes through 30 minutes, and then every ten minutes through the 90-minute time
      point. The onset times of first perceptible and meaningful relief were recorded
      using two stopwatches. The occurrence of adverse events was also monitored.
      RESULTS: While the benzocaine patches were numerically superior to the placebo
      patches at all time points with respect to pain relief, PID (pain intensity
      difference) and their summed measures (TOTPAR and SPID scores), an analysis of
      covariance revealed no significant differences between treatments. Survival
      analysis indicated that the percentage of patients reporting meaningful pain
      relief by 30 minutes was significantly (p < 0.05) greater in the benzocaine group
      than in the placebo group (77% for benzocaine and 47% for placebo). The median
      onset times to first perceptible and meaningful relief were 5.4 and 18.1 minutes
      in the benzocaine group, and 7.8 and 30.4 minutes in the placebo group. Only two
      side effects (headache) were reported in the entire study. CONCLUSION: Although
      the results of the present study were promising, further research on this novel
      delivery system of benzocaine is warranted to firmly establish efficacy in
      patients with spontaneous toothache pain.

PMID- 12619265
TI  - The influence of a hexametaphosphate-containing chewing gum on the wetting
      ability of salivary conditioning films in vitro and in vivo.
AB  - OBJECTIVE: Adsorbed conditioning films of salivary components on dental enamel
      surfaces or pellicles form the interface between teeth and the oral environment.
      The wetting ability of salivary conditioning films dictates biological adhesion
      phenomena such as plaque formation, calcification and staining, and also
      influences mouth perception through effects on lubricity. This study assessed the
      effects of hexametaphosphate release from a chewing gum matrix on the wetting
      ability of salivary conditioning films in vitro and in vivo. METHODOLOGY: Results
      obtained for hexametaphosphate chewing gum were compared with those produced by
      hexametaphosphate-containing dentifrice, which has been clinically proven to have
      efficacy for stain removal and prevention and dental calculus prevention.
      RESULTS: Contact angle assessments revealed that hexametaphosphate dentifrice
      produced markedly hydrophilic conditioning films in vitro. Hexametaphosphate
      chewing gums had only minor effects on surface contact angles in vitro. However,
      in vivo intra-oral contact angle measurements on tooth surfaces in volunteers
      showed that both hexametaphosphate dentifrice and chewing gum produced more
      hydrophilic tooth surfaces. CONCLUSION: These results support the activity of
      hexametaphosphate on tooth surfaces delivered both from dentifrice and chewing
      gum forms.

PMID- 12619266
TI  - Laboratory evaluations of two toothbrushes for removal of artificial plaque
      above, around and below the gingival margin.
AB  - OBJECTIVE: Two toothbrushes were evaluated with a laboratory method for the
      ability to remove artificial plaque deposits around interproximal sites
      (interproximal access efficacy, IAE) at the gingival margin (gingival margin
      cleaning, GMC), and below simulated gingivae (subgingival access, SA) using
      clinical toothbrushing motions under wet brushing conditions. METHODOLOGY: The
      toothbrushes tested were Meridol or an ADA reference standard. The Meridol
      toothbrush has a flat profile and contains double-tapered filaments. The ADA
      reference standard also has a flat profile, with traditional end-rounded
      bristles. Both toothbrushes have a soft texture. Six toothbrushes of each design
      were evaluated four times for a total of 24 assessments. RESULTS: The Meridol
      toothbrush had significantly (p < 0.001) higher mean IAE, GMC and SA values
      compared to the ADA reference standard toothbrush tested. CONCLUSION: From these
      results, the Meridol toothbrush with tapered bristles is more likely to be
      effective in clinical studies on plaque removal compared to other manual
      toothbrushes with rounded bristles in a flat head design, that are similar to the
      ADA reference standard toothbrush.

PMID- 12619267
TI  - The improved remineralization and fluoride uptake in vivo of
      triclosan/copolymer/sodium fluoride toothpaste vs. sodium fluoride toothpaste.
AB  - OBJECTIVE: It has been shown that the twice-daily use of the
      triclosan/copolymer/sodium fluoride toothpaste can significantly reduce caries
      formation. The objective of this report was to review human studies comparing a
      triclosan/copolymer/sodium fluoride toothpaste to a placebo toothpaste (no
      fluoride), and a sodium fluoride toothpaste (positive control) for their ability
      to enhance remineralization of tooth enamel and increase the retention of
      fluoride by dental plaque for extended periods (up to 12 hours) after treatment.
      METHODOLOGY: Two human plaque fluoride studies were conducted, measuring fluoride
      levels before brushing (baseline) and at two, six and twelve hours after
      brushing. An in situ enamel remineralization study, using microhardness
      measurements, was conducted as well. RESULTS: In the first study, the
      triclosan/copolymer/sodium fluoride toothpaste group was associated with a two
      times increase of mean plaque fluoride as compared to the placebo control
      dentifrice. This increase was statistically significant at p < 0.05. In the
      second study, the triclosan/copolymer/sodium fluoride toothpaste group was
      associated with a 38% increase of mean plaque fluoride as compared to the sodium
      fluoride toothpaste group. This increase was statistically significant at p <
      0.05. In the enamel remineralization study, the triclosan/copolymer/sodium
      fluoride toothpaste was significantly better (p < 0.05) than the sodium fluoride
      toothpaste (positive control) at promoting percent mineral recovery. CONCLUSION:
      The results obtained from the plaque fluoride studies and in situ
      remineralization study corroborated the findings of a recently completed two-year
      caries clinical study, which demonstrated that the triclosan/copolymer/sodium
      fluoride toothpaste provided superior cavity protection over the sodium fluoride
      toothpaste.

PMID- 12619268
TI  - [Valuation of forest damage cost from SO2 emission: a case study in Hunan
      Province].
AB  - Large amount SO2 emission caused serious damage of forest ecosystem in China and
      calculation of the damage cost is an important issue for policy-making. However,
      no applicable method was developed to estimate forest damage under different SO2
      emission scenarios. Basing on previous field researches on sulfur-related forest
      impact in China and recent critical load mapping research, this paper presented a
      model for forest damage calculation by developing a dose-response function that
      related the damage to cumulative sulfur critical loads. This model was applied to
      the forests in Hunan, a province in acid rain control zone in China. Results
      showed that in the business-as-usual case, SO2 emission in Hunan will increase by
      120% from 1995 (8.82 mil. ton) to 2020 (19.56 mil. ton), but damage cost will
      increase by 4.3 times, reaching 6.19 billion RMB in 2020. Results also showed the
      measures for SO2 control were cost-effective because the marginal damage cost
      will be about 6000 RMB per ton SO2 in 2020 in BAU case. At current SO2 emission
      level, marginal benefit will be about 1500 RMB per ton. Uncertainty analysis
      demonstrated that this model provides reasonable damage estimates and would
      therefore be applicable in a broad range of policy settings.

PMID- 12619269
TI  - [Parameters identification and uncertainty analysis for environmental model].
AB  - This paper examined a case study of hydrological model for identifying parameter
      uncertainty by using three sensitivity analysis methods: HSY algorithm, linear
      regressional method and coupling analysis method. The results showed that optimal
      algorithms cannot give a sound explanation for complexity of model structure and
      identifying model parameters via uncertainty analysis methods presented an
      effective alternative to understand model system.

PMID- 12619270
TI  - [Source apportionment on fine particles in Beijing].
AB  - The positive matrix factorization(PMF) method was used to apportion the sources
      for fine particles in Beijing. The data were obtained from four samplings from
      1999 to 2000. The number of this data set was 40. The chemical compositions used
      in analysis include element carbon(EC), organics, SO4(2-), F-, Cl-, Fe, Ca, K,
      Mg, Al, Na, Zn, Mn, Ti, Pb, Ba and P. Six main sources, soil dust, construction
      dust, secondary source (by photochemical action), biomass burning, motor vehicle
      and coal burning were found.

PMID- 12619271
TI  - [Degradation of toluene in the gas phase by combined ozone and photocatalysis].
AB  - The degradation of toluene (10-80 mg/m3) in the gas phase by combined ozone and
      photocatalysis was studied. The effect of the inlet concentration, air flow rate
      and humidity on the degradation efficiency and removal load was investigated.
      Then the efficiency of combined ozone and photocatalysis was compared with that
      of photocatalysis. The experiment results indicated that combination of ozone and
      photocatalysis was far more efficient than photocatalysis in degrading toluene,
      especially under high-level inlet concentration. When the inlet concentration was
      in the range of 10-40 mg/m3, the degradation efficiency of combined ozone and
      photocatalysis was over 90% and dropped linearly and very slowly with the
      increase of inlet concentration of toluene. The degradation efficiency of
      combined ozone and photocatalysis was slightly affected by humidity with the
      efficiency difference less than 2.5%.

PMID- 12619272
TI  - [Study on the SCR of NO over automobile exhaust catalyst Ag/SAPO-34].
AB  - The activity of Ag/SAPO-34 molecular sieve catalyst was investigated, and the
      selective catalytic reduction (SCR) of NO was studied by in-situ diffuse
      reflectance FTIR spectroscopy(DRIFTS). The results show that the prepared
      catalyst had high activity at low temperature and the conversion of NO reduction
      to N2 was about 70% at 3.6% O2 and 573K-673K of temperature. The catalysis
      activity rised with the concentration of C3H6 but light decrease with GHSV. Based
      on in-situ DRIFTS, a reaction mechanism was proposed that NO, propene and oxygen
      react to form organo-nitro and organo-nitro adsorbed species as key
      intermediates, then these intermediates were decompose to nitrogen. NO and
      propene were easily activated in oxygen. Furthermore, the presence of oxygen is
      necessary to form a series of intermediates.

PMID- 12619273
TI  - [Dissolved N2O concentrations and N2O emissions from aquatic systems of lake and
      river in Taihu Lake Region].
AB  - Aquatic systems are an important source of N2O emissions. N2O concentrations
      dissolved in lake and river water in Taihu Lake region and N2O fluxes from these
      waterbodies were monitored twice a month in three replicate from Sept. 26, 2000
      to Sept. 26, 2001. At the same time, both top and bottom water were analyzed for
      N2O concentrations four times in a consecutive year. Results demonstrated that
      rather high N2O-N concentrations of 11.31 micrograms/L were dissolved in river
      water and resulted in high N2O-N fluxes of 122.5 micrograms/(m2.h) from river
      water surfaces while low N2O-N concentration of 0.36 microgram/L and N2O-N flux
      of 3.53 micrograms/(m2.h) was found in lake water. No obvious difference was
      found in dissolved N2O concentration between top water and bottom water. Results
      also indicated that there existed significantly positive relationship between
      dissolved N2O concentration and N2O flux and water temperature. The results
      indicate that the aquatic systems are an important source of N2O.

PMID- 12619274
TI  - [Observational characteristics of the concentrations of NOx, O3, SO2 and CO over
      Bohai Sea in summer].
AB  - By using the observational data obtained over the Bohai sea in Aug.-Sep., 2000,
      the variation characteristics of NOx, O3, SO2 and CO concentrations were firstly
      shown. The effects of solar radiation and weather conditions on the trace
      concentrations were analyzed. SO2 concentration was very stable, its' average
      value was about 0.006 mg.m-3. O3 concentration was mainly controlled by solar
      radiation. The concentration of CO and NOx was around 2.5-3.5 mg.m-3 and 0.1 mg.m
      3, respectively, in weak weathers. Typhoon weather may made their concentrations
      increasing abruptly in a short time. The distinct differences of the pollutant
      concentrations between land and sea were also revealed, and the air quality over
      the Bohai sea in summer season was assessed based on the measurements.

PMID- 12619275
TI  - [Simulation of N2O emissions in agroecosystems].
AB  - A numerical model for simulating N2O emissions in agroecosystem was established.
      Validation of the model with the observed data showed that the model simulated
      the process of N2O emissions in fields fairly well. The numerical analysis showed
      that the N2O emissions were interrelated well with average temperature during
      rice growth periods. Analysis of N2O emissions and meteorological factors by
      using power spectrum found that the change of N2O emissions had 7-9 year cycles.
      Sensitivity test showed that the N2O emission increased with temperature
      enhancement.

PMID- 12619276
TI  - [Influence of doping the nanosized SiO2 powder on structure and activity of
      photocatalytic films].
AB  - Regard to the poor adsorbability of the fixing film photocatalyst, a new TiO2
      thin film by doping the nanosized SiO2 power with large specific surface area
      into sol for coating film was prepared. According to the results of
      characterization by XRD, SEM, FTIR techniques, it was found that the films were
      mainly anatase structure, containing a little rutile and its mean crystallite
      size was about 27 nm. And doped SiO2 was dispersed into films forming the
      amorphous cluster with the size form more than ten nanometers to scores of
      nanometers. The doping of SiO2 had no effect on the crystal structure and the
      surficial group of TiO2, except for increasing specific surface area. The result
      of photocatalytic degradation showed that activity of the film doped by SiO2
      largely increased and was greatly influenced by the size and amount of doped
      SiO2. Besides, this photocatalyst also had very good stability. During the course
      of continuous experiment for more than 30 days, removal efficiency of reactive
      brilliant red X-3B was kept at about 80% all the time.

PMID- 12619277
TI  - [Effect on trihalomethane forming for different molecular weight dissolved
      organic matter in water resource].
AB  - A raw water sample was collected from Guangzhou section of Pearl River to support
      experiment studies. The sample were passed through Amicon YC-05, YM-1, YM-3, YM
      10, YM-30, YM-100 and ZM-500 series membranes after being pretreated. The
      molecular weight distribution of the isolate for each membranes were analyzed,
      and the isolates were disinfected by chlorine and chlorine dioxide. The results
      showed that the RO isolate was the main dissolved organic matter (DOM) in the
      water sample, which proved that the water was highly contaminated by human
      activities, and it was the main THMs precursor in the disinfection process with
      chlorine and chlorine dioxide for all the isolates. Meanwhile, the disinfection
      process for water sample contain DOM that its molecular smaller than 500 were
      very different from raw water.

PMID- 12619278
TI  - [A submerged dynamic membrane bioreactor for domestic wastewater treatment].
AB  - The dynamic membrane forming on the surface of 0.1 mm Dacron mesh was utilized
      instead of static membrane, e.g. hollow fiber membrane, to develop a submerged
      dynamic membrane bioreactor (DMBR). The DMBR had high quality effluents when
      treating domestic wastewater at HRT = 3.5 h. The dynamic membrane could work
      steadily at a pressure no more than several centimeters water head drop. The
      highest SS concentration in the effluents was 4.05 mg/L, whereas the measured SS
      concentrations were zero in most circumstances. At condition of MLSS = 7000-8000
      mg/L, the effluent head drop was only 5.8 mm when flux = 14.9 L/(m2.h), and it
      had little change during a continuous run for 27 days. The dynamic membrane
      averagely removed 28.74% of COD and 36.9% of TOC in the supernatant of the mixed
      liquor. The DMBR could remove NH3-N more than 96% when DO in the mixed liquor was
      no less than 2-3 mg/L.

PMID- 12619279
TI  - [Pilot study on subsurface wastewater infiltration system applied in rural sewage
      treatment].
AB  - A pilot plant of subsurface wastewater infiltration system (SWIS) filled with red
      clay was tested to treat rural sewage with hydraulic loading of 2 cm/d. The
      experiment results showed that average removal rates of COD, NH4(+)-N, total
      phosphorus, and total nitrogen were 84.7%, 70.0%, 98.0% and 77.7%, with average
      effluent concentrations of COD, NH4(+)-N, total phosphorus, and total nitrogen
      being 11.7 mg/L, 4.0 mg/L, 0.04 mg/L and 4.7 mg/L respectively, which met the
      standard for water reuse issued by the Ministry of Construction of China.
      Nitrogen removal mechanism analysis revealed that nitrogen in the influent was
      mainly eliminated through biological removal via nitrification/denitrification
      processes. In the pilot system, denitrification was well proceeded but
      nitrification was not satisfactory. How to improve nitrification performance
      through change of soil environment was the key to enhance nitrogen removal rate.
      The measurement results of redox potential in the filled soil showed that
      reductive property of soil was main hindrance to nitrification process.

PMID- 12619280
TI  - [14C-extractable residue, C-bound residue and mineralization of 14C-labeled
      metsulfuron-methyl in soils].
AB  - The purpose of the present study was to investigate 14C-extractable residue(14C
      ER), 14C-bound residue(14C-BR) and mineralization of 14C-labeled metsulfuron
      methyl in soils. The main factors affecting 14C-BR formation and the distribution
      pattern of 14C-BR in humus were also discussed in details. The results were as
      follows: (1) The total 14C-ER content of 14C-metsulfuron-methyl in seven kinds of
      soil was positively related to soil pH and negatively related to clay content
      significantly during the initial 20 days of incubation, however, only positively
      relation to soil pH was found after 30 days of incubation. Moreover, the half
      life values of 14C-metsulfuron-methyl parent compound derived from 14C-ER in
      soils tested ranged from 13.3 to 66.6 days. The degradation rate coefficient
      lambda (day-1) was negatively related to soil pH. (2) The 14C-BR content of 14C
      metsulfuron-methyl in soils was significantly negatively related to soil pH and
      positively related to the clay content during the initial 20 days of incubation,
      but only was significantly negatively related to soil pH after 30 days
      incubation. Again, the soil pH was found to be the dominant factor affecting BR
      formation of 14C-metsulfuron-methyl among the basic properties of soil. The
      maximum content of 14C-BR of 14C-metsulfuron-methyl in the soils accounted for
      19.3%-52.6% of applied amount. (3) During the whole periods of the incubation,
      the 14C-BR of 14C-metsulfuron-methyl in the soils was found to be mainly
      associated with fulvic acid and humin. The relative percentage of 14C-BR in
      fulvic acid was higher than in humin, while the content of the 14C-BR distributed
      in humic acid only account for less than 1% of applied amount. Therefore, fulvic
      acid played an important role in the process of BR formation of 14C-metsulfuron
      methyl. (4) About 12.9%-27.0% of applied amount of 14C-metsulfuron-methyl was
      mineralized to 14CO2 through opening 14C-triazine ring in soils tested after 180
      days of the incubation. It was difficult for 14C-metsulfuron-methyl to mineralize
      to 14CO2 in an alkaline soil.

PMID- 12619281
TI  - [Effects of aromatics on the degradation of benzo(a) pyrene in slurry reactors].
AB  - Benzo(a) pyrene (BaP) can't be biodegraded in the soil easily, the degradation of
      BaP is know as a cometabolic process. This paper dealed with the effects of some
      polycyclic aromatic hydrocarbons (PAHs) and two kinds of monoaromatics on the
      degradation of BaP. The test soil was pre-incubated with the aromatics for 3d and
      spiked with BaP stock solution, which eventually formed into slurry system in
      Erlenmeyer flasks and was incubated on rotary shaker. 42 d experiment
      demonstrated that lag period in degradation process of BaP disappeared due to the
      preexposure to phenanthrene, and degradation rate of BaP was enhanced. On the
      contrary, degradation pattern of BaP was not obviously improved by the
      preexposure to anthracene or pyrene, and was even inhibited by benz(a)
      anthracene. The lag period also disappeared after the preexposure to salicyclic
      acid or phthalic acid, and the degradation of BaP was accelerated by both
      monoaromatics, even though the impact of mass difference on the degradation of
      BaP was not detected.

PMID- 12619282
TI  - [Fractionation and relevant influencing factors of rare-earth elements (REEs) in
      a soil-plant system].
AB  - A potted method was carried out in this paper to research fractionation and some
      influencing factors (including the concentrations of REEs, humic acids and pH of
      soil) of the REEs (La, Ce, Nd, Sm, Eu, Gd, Tb and Yb) in a soilplant- system. The
      results showed that the fractionation model of REEs in red soil used in this
      experiment was similar to the average fractionation model of soil in China. The
      fractionation model of REEs in wheat root was similar to the model of the soil,
      but the fractionation model of REEs in wheat tops was not similar to that one.
      When REEs were added, the fractionation model of REEs in wheat root was changed
      similarly to that of the soil, but the model of wheat tops was kept constant. The
      results suggest the adsorbing way of REEs by wheat root and wheat tops were
      different. Humic acid showed little influence on the fractionation of REEs in
      wheat. High pH value (pH = 6.7) promoted the adsorption of light REEs by wheat;
      whereas, low pH value (pH = 4.2) promoted the adsorption of heavy REEs by wheat.

PMID- 12619283
TI  - [Effect of marine culture on the quality of coastal water in Guangdong Province
      in the summer].
AB  - The contents of nitrogen, phosphorus and plankton in aquatic areas and non-sea
      farming areas, which were found in Shantou, Huiyang, Zhuhai, Yangjiang and
      Zhanjiang in Guangdong Province respectively, were measured in 2000 in the summer
      with the aim of estimating the environmental problem of marine culture. The
      concentration of total nitrogen(TN), particle total nitrogen(PTN), total
      phosphorus(TP), particle total phosphorus(PTP) in aquatic areas, which were 0.506
      1.244 mumol/L, 0.367-1.066 mumol/L, 0.112-0.232 mumol/L and 0.054-0.157 mumol/L
      respectively, were higher than non-sea-farming areas, but marine culture had no
      effect on the concentration of dissolvable total nitrogen(DTN) and dissolvable
      total phosphorus(DTP), TN:TP ratios and DTN:DTP ratios. The most phytoplankton in
      both aquatic areas and non-sea-farming areas was Chaetoceros, and that of
      zooplankton was Copepoda (including adult and larva). Marine culture affected the
      diversity of plankton and the population densities of some species, but not to
      the number of plankton kinds and the total individuals of all phytoplankton or
      all zooplankton.

PMID- 12619284
TI  - [Influence of atrazine on the tyrosine environment of catalase].
AB  - By the UV difference spectrum and fluorescence spectrum technique, the influence
      of atrazine on tyrosine environment of catalase was studied. According to the
      results of the UV difference spectrum curve, the UV difference adsorption delta
      A260nm showed changing rapidly when pH ranging from 9.1 to 9.9. UV difference
      spectrum and fluorescence spectrum of atrazine-catalase were red shift that maybe
      caused by effect of hydrogen bonding. The fluorescence spectrum was sensitive to
      SDS and quenchable by KI. The results indicated that the tyrosine residues of
      catalase reside in hydrophilic core, and there is hydrogen bonding between
      atrazine and catalase probably. Atrazine has little effect on tyrosine
      environment of catalase.

PMID- 12619285
TI  - [A primary study on thermal effect of soil-plant-atmosphere continuum in tropical
      seasonal rain forest gap].
AB  - Made use of measurement data of microclimatic elements of canopy gap in tropical
      seasonal rain forest in fog-cool and dry-hot season in Xishuangbanna, the daytime
      characteristics of temporal-spatial distribution and variation of soil surface
      temperature, air temperature, and leaf temperature of understory plants in canopy
      gap were discussed. The finding showed that influenced by fog and solar altitude,
      the maximum value of microclimatic elements displayed at different site of gap in
      different time and season and there existed phenomenon about higher value area of
      leaf temperature dynamic displacement. In addition, the direction of heat
      transferring of soil-plant-atmosphere continuum varied with time and season,
      indeed at the same time, the different part of gap had the different heat
      transferring directions. The results would supply a research basis for further
      studying heat and water vapor transport, microclimatic formation, biodiversity
      and succession of canopy gap.

PMID- 12619286
TI  - [Fluoride in the environment and brick-tea-type fluorosis in Tibet].
AB  - To explore whether endemic fluorosis in Tibet is related to local factors, an
      epidemiological survey of fluorosis was conducted in 3 districts in Tibet. The
      survey used the WHO and FAO established "Guideline for the study of dietary
      intake of chemical contaminants" and the Horowitz suggested criteria for children
      dental fluorosis examination. The fluorine in the local environment of the 3
      selected districts was studied in detail. The possible fluorine sources examined
      indicated that only the brick-tea carried a high content of fluoride; water,
      other food materials, and fuel contents were insignificant. The children daily
      fluorine intake was high, where Naqu was 8.03 mg, Lahsa was 6.93 mg, Dingri was
      7.68 mg. All the dietary fluoride was come from the brick-tea processed foods:
      the buttered-tea and zamba, these two contributed 99.74%, 98.70% and 99.60% of
      their daily fluorine intake respectively. The dental fluorisis index indicated
      that Naqu and Dingri were severe epidemic and Lahsa was moderate epidemic. The
      endemic fluorosis that occurs in Tibet was essentially due to heavy consumption
      of foodstuffs prepared with brick-tea, however, the high altitude, harsh living
      conditions, and poor nutritional status aggravated the fluorosis. Brick-tea type
      fluorosis is a new type of fluorosis recently discovered in China. Compared with
      the drinking water type and coal combustion type of fluorosis, it covered
      extensive area, more covert, and difficult to control. Decrease the fluorine
      content of brick-tea might be the most promising measure.

PMID- 12619287
TI  - [Distribution pattern of hair fluoride and its affected factors in coal-exposed
      environment].
AB  - To find out the distribution pattern of hair fluoride and its affected factors in
      coal-exposed environment, human hairs were collected according epidemiological
      investigation, and contents of fluoride and other life-relative elements in the
      samples were determined. Results shown that the fluoride content in human hairs
      had a notable individual differentia, its distribution pattern was anomalous
      distribution with average fluoride content 67.08 +/- 64.68 micrograms/g and
      coefficient of variation 96.42%. There were significant positive correlation
      between F and Ca, Mn, Se as well as significant negative correlation between F
      and Ti. Factor analysis shown the fluoride content in human hairs was affected by
      factors such as inner biochemical reaction, outer geochemical environment,
      structure of food-web and quality of drinking water.

PMID- 12619288
TI  - [Denitrification of drinking water with an active carbon-electrochemical
      biological reactor].
AB  - A packed bed electrochemical biological reactor was studied and utilized for
      denitrification of drinking water. Using active carbon as the filter, graphite
      plate as anode, and active carbon fibre as cathodes, an optimum reductive
      condition in the reactor was established for denitrification of nitrate. The test
      results proved that both nitrate and nitrite in the water could be removed
      effectively. At the case of 40 mL/h inflow, 40 mg/L of NO3-N, and 14 mA of
      current density, a 100% denitrification rate was achieved and no nitrite was
      detected. Because there is no any additional pollution in the treating process,
      this method is suggested to be a safety process for drinking water
      denitrification.

PMID- 12619289
TI  - [The degradation of dye X-3B in photocatalysis enhanced by the electric field].
AB  - Using 365 nm and 254 nm UV lamp as light source, the degradation of dye X-3B in
      photolysis, photocatalysis and electrical enhanced photocatalysis was studied in
      this research. The result shows that the degradation rate of photocatalysis of X
      3B was faster than one of photolysis of X-3B. The degradation rate of electrical
      enhanced photocatalysis was faster than the photocatalysis while the direction of
      the electric field was opposite with the direction of UV radiation and its
      degradation rate was slower while the direction of the electric field was of the
      same direction as UV radiation.

PMID- 12619290
TI  - [Transfer of Pb(II) through the liquid membrane with alkylphosphonic acid as
      carrier].
AB  - The transfer behavior of Pb(II) through the bulk liquid membrane system of PC-88A
      CHCl3 was studied. The study include to analysis the effect of Pb(II) transport
      rate of the pH values in external aqueous phase, carrier concentration,
      temperature and external aqueous phase concentration. The results showed that the
      transport rate of Pb(II) markedly raised with the carrier concentration and
      temperature. The transfer rate can reach 100% under the condition of pH values
      2.8-4.0, carrier concentration 5.00%-7.00% and temperature 289 K-303 K.

PMID- 12619291
TI  - [Concept and application of ecological industry chain system].
AB  - This paper is the first to present the concept of the ecological industry chain
      system and universality method. By this concept the developing and implementing
      of the ecological industry chain system of hemp products in Chaoyang, Taian and
      other areas of China's northern region and testify its effectiveness were
      analyzed.

PMID- 12619292
TI  - New screen could 'change the prognosis' for ovarian cancer.

PMID- 12619293
TI  - Program to promote bone health cited as a model of prevention.
AB  - Health care organizations are well-aware of the huge costs associated with
      osteoporotic fractures. However, many have been slow to initiate preventive
      programs--even though there is evidence that such programs can boost outcomes on
      a number of indicators. See how one PA health plan is leading the way on bone
      health.

PMID- 12619294
TI  - New study suggests Medicare could save millions [correction of billions] with
      increased BMD testing.
AB  - That's at least according to one new study that suggests Medicare could save
      millions [correction of billions] if just 10% more elderly women received the
      bone mineral density (BMD) test used to diagnose low bone mass.

PMID- 12619295
TI  - Innovative CareEngine system roots out sub-optimal care.
AB  - America's health care system is rife with medical errors, and an astounding
      percentage of care provided would, upon review, be classified as "sub-optimal,"
      prompting researchers and entrepreneurs to develop information technology systems
      to help plug these common gaps in care. ActiveHealth Management's innovative
      CareEngine service is doing just that--and already producing savings in the range
      of 1% to 4% in commercial, Medicare, and Medicaid populations.

PMID- 12619296
TI  - Lupus 'summit' highlights need for greater awareness, earlier diagnosis.
AB  - Why? Because early diagnosis and treatment can help to prevent or delay
      irreversible organ damage and premature death. Find out what role DM can play in
      alleviating the difficult symptoms and high utilization associated with this
      disease, and get an early look at new approaches to treatment that could be
      available in the not-too-distant future.

PMID- 12619298
TI  - PBGH disease management effectiveness project: diabetes.

PMID- 12619297
TI  - Tread lightly when risk contracting for disease management.

PMID- 12619299
TI  - As Medicare fees decrease, risk plans may gain favor.

PMID- 12619300
TI  - Behavioral health admissions climbing, but LOS is down.

PMID- 12619301
TI  - Tracking report: physicians earning more from managed care.

PMID- 12619302
TI  - Plasma leptin responses to lipopolysaccharide and tumor necrosis factor alpha in
      cows.
AB  - Peripheral administration of bacterial lipopolysaccharide (LPS) and various
      inflammatory cytokines to rodents is known to raise plasma levels of leptin, a
      potent satiety factor secreted from adipocytes, implying a role of leptin in
      endotoxin-induced anorexia. We previously reported no effect of LPS on serum
      leptin levels in sheep, despite marked anorexia and fever. Our results suggest
      that leptin might not be involved in the endotoxin-induced anorexia in ruminants.
      To test this idea, in the present study, plasma leptin levels were measured
      during acute experimental endotoxemia in Holstein cows. Intravenous injection of
      LPS induced anorexia accompanied with increases in plasma levels of cortisol and
      insulin, all of which are known to stimulate leptin secretion in rodent and
      human, while it did not affect plasma leptin levels at all in cows. Similar
      results were also obtained after injection of recombinant bovine tumor necrosis
      factor alpha. These results indicate that plasma leptin levels in cows during
      acute endotoxemia are differentially regulated from those in rodents, and that
      leptin might not be involved in the endotoxin-induced anorexia in ruminants.

PMID- 12619303
TI  - Expression and distribution of inducible nitric oxide synthase in mouse testis.
AB  - Nitric oxide (NO) is a simple and relatively unstable radical under physiological
      conditions. It is synthesized by three isoforms of NO synthase, that is neuronal,
      endothelial and inducible (iNOS) isoforms. In the present study, we investigated
      the distribution of iNOS with immunohistochemical methods in the mouse testis.
      The iNOS-immunoreactivity was detected on the basal region of the seminiferous
      tubules, where the cytoplasm of Sertoli cells was selectively immunolabeled. This
      immunoreactivity was observed by both immunofluorescent and immunoenzyme methods.
      Weak immunoreactivity was detected on the perinuclear cytoplasm of Sertoli cells
      throughout the seminiferous stages, whereas in stages I-VIII, it was remarkable
      on the processes of Sertoli cells surrounding the spermatogonia and early
      spermatocytes, and elongating into the lumina of seminiferous tubules. By reverse
      transcriptase-polymerase chain reaction, mRNA for iNOS was found to be expressed
      in the mouse testis. These results reveal that iNOS is consistently distributed
      at the front of the testicular environment.

PMID- 12619304
TI  - Cellular architecture of the synovium in the tendon sheath of horses: an
      immunohistochemical and scanning electron microscopic study.
AB  - The intimal lining cells of the synovium in joints have been studied
      morphologically and histochemically and shown to consist of macrophagic cells
      (type A) and fibroblast-like cells (type B). It is believed that the structure of
      the synovium in the tendon sheath is similar to that in the joint, but there have
      been only a few morphological studies of the tendon sheath. The present study
      revealed the cellular architecture of synovium in the tendon sheath of horses by
      histochemistry and scanning electron microscopy (SEM). Like the joint, the inner
      surface of the tendon sheath was covered with a cell-rich intimal layer. Acid
      phosphatase-positive A cells accumulated in the mesotendon but few in other
      regions. B cells were selectively immunolabeled with protein gene product (PGP)
      9.5 antiserum and distributed in the entire length of the synovial intima in the
      tendon sheath. The synovial intima consisted of a surface layer rich in the
      processes of B cells and a deep layer containing cell bodies of B cells. Using
      SEM, B cells could be classified into two types according to the morphology of
      their processes. B cells of dendritic type were located mainly in the joint-side
      of the tendon sheath and extended branched processes to form a meshwork on the
      intimal surface. B cells of flat type were located in the skin-side of the tendon
      sheath and in the mesotendon. Their membranous processes extended in a horizontal
      direction and covered the intimal surface, resembling epithelium. It appears
      likely that the morphology and distribution of synovial intimal cells are
      influenced by various factors, such as the nature of the underlying tissues and
      the magnitude of mechanical stress.

PMID- 12619305
TI  - A positive slant on ethics and professionalism.

PMID- 12619307
TI  - Nanotechnology in dentistry: reduction to practice.
AB  - The speed at which advances are being made in science has catapulted
      nanotechnology from its theoretical foundations straight into the real world.
      There are now many examples of commercially available products demonstrating
      that, in given situations, the technology really does work and that its scope for
      further application is wide. Healthcare, along with society as a whole, is facing
      a major revolution in the wake of ongoing technological developments in the field
      of nanotechnology. Dentistry as an individual healthcare discipline is not
      exempt, having already been targeted directly with novel 'nano-materials' at the
      same time as indirectly enjoying the benefits of nano-related advances in the
      electronics industry through the ongoing computerization of the modern practice.
      This article examines current practical applications of nanotechnology alongside
      proposed applications in the future and aims to demonstrate that, as well as a
      good deal of science fiction, there is some tangible science fact emerging from
      this novel multi-disciplinary science.

PMID- 12619306
TI  - A clinical overview of removable prostheses: 4. Technological considerations when
      designing removable partial dentures.
AB  - This fourth article in a series concerning the prescription of removable partial
      dentures is a precis of the technical aspects of RPD construction, commencing
      with the definitive or 'working' impressions, although all impressions ought to
      be considered as 'working' impressions.

PMID- 12619309
TI  - Choosing a career in dentistry.
AB  - There is a wide range of careers available for the recently qualified dentist,
      and graduates need to know what the choices are and how a particular career
      pathway may be best accessed. Additional qualifications are often necessary; new
      graduates also need to be aware of the most useful postgraduate qualifications
      for their chosen path. Many young dentists would benefit from careers advice and
      should talk to colleagues working in the field in which they are interested.

PMID- 12619308
TI  - Dental appliances for snoring and obstructive sleep apnoea: construction aspects
      for general dental practitioners.
AB  - The medical and dental aspects of management for patients diagnosed with snoring
      and obstructive sleep apnoea are well documented. However, guidance for treatment
      by the general dental practitioner is lacking. This article reviews aspects of
      appliance provision and presents the use of a silicone material in an attempt to
      improve the longevity of a recognized prosthesis.

PMID- 12619310
TI  - Classification of periodontal diseases: where were we? Where are we now? Where
      are we going?
AB  - This paper discusses the past, present and possible future classification of
      periodontal diseases. It outlines the reasons for using a classification system
      from a clinical perspective and provides a critical appraisal of the latest
      classification. The major changes introduced in the 1999 system are discussed
      alongside the rationale behind the recommended nomenclature.

PMID- 12619311
TI  - Steroid cover in dentistry: recommendations following a review of current policy
      in UK dental teaching hospitals.
AB  - This article reports a project that was undertaken to determine current UK dental
      hospital policy with regard to the management of patients taking therapeutic
      doses of corticosteroids receiving dental treatment under local anaesthesia.
      There is variation in the medical management of this patient group, and whether
      practice should be standardized by means of a national policy document warrants
      consideration.

PMID- 12619312
TI  - Physical signs for the general dental practitioner.

PMID- 12619313
TI  - [The prevalence of gestational diabetes mellitus in Polish population].
AB  - OBJECTIVE: The aim of the study was to determine the frequency of GDM in
      different parts of Poland and to assess whether 1 h--glucose plasma levels after
      50 g glucose tolerance test (50 g OGTT) reflect the risk of GDM. MATERIAL AND
      METHODS: A total of 5778 pregnant women were screened with 50 g OGTT between 24
      and 28 weeks of gestation. All subjects whose post-challenge glucose levels
      exceeded 140 mg/dl had 75 g OGTT performed according to WHO criteria. RESULTS:
      The rate of abnormal screening test results ranged from 8.0% to 20.7% for
      different regions of Poland, respectively. The pathological 50 g OGTT results
      were from 140 mg/dl to 320 mg/dl. Screening test results within 140 mg/dl to 149
      mg/dl were confirmed by positive 75 g OGTT only in 2.9% subjects. All patients
      whose 1 h--glucose levels at 50 g OGTT were greater than 190 mg/dl had
      pathological 75 g OGTT results as well. CONCLUSION: The prevalence of GDM in
      different parts of Poland ranged from 2.0% to 3.8% (the average 3.4%).

PMID- 12619314
TI  - [Urinary tract infections in diabetic pregnancy].
AB  - The analysis of urine culture was performed twice in 120 pregnant women with
      diabetes mellitus: on their first visit and during the 3rd trimester of
      pregnancy. During the first evaluation 10% of patients had germ-free culture,
      46.7% non-significant bacteriuria and 43.3% significant ones. The percentage of
      results in the studied group indicating significant bacteriuria decreased as far
      as to 35.8%, but germ-free culture were still 10% during the second analyses, in
      3rd trimester. The incorrect urine culture decreasing count during pregnancy
      stood in relation with better diabetes control based on 24-hours glucose profile.
      Staphylococcus and Escherichia coli culture occurred more frequently. The control
      group comprised of 60 pregnant women without diabetes mellitus-significant
      bacteriuria occurred in 15% and germ-free culture were observed in 43.4% of
      patients.

PMID- 12619315
TI  - [The evaluation how FIGO stage in cervical cancer depends on frequency of
      gynaecological control].
AB  - OBJECTIVES: The authors sought to evaluate how FIGO stage in cervical cancer
      depends on frequency of gynaecological control. MATERIAL AND METHODS: From March
      2000 to January 2001, 74 patients with cervical cancer were treated in 2-nd Dept.
      of Obstetrics and Gynaecology Medical University of Gdansk. The authors analysed
      frequency of gynaecological control, although patients age, number of delivery,
      socio-economic status, living place. RESULTS: The median interval, from last
      gynaecological examination to cervical cancer diagnosis was 8.6 year (1-26),
      number of delivery: 0-0.5%, 1-10%, 2-21%, 3-21%, 10-1%, 67% patients lived in
      town and 32.4% in villages. CONCLUSION: Women from Gdansk area who developed
      cervical cancer were not gynaecological controlled from 1 to 26 year (median-
      8.6). Authors noticed that FIGO stage of ovarian cancer depends seriously on
      interval between last gynaecological control and cervical cancer diagnosis. The
      old, not working, and those who live in villages in Gdansk area have an
      especially low level of health education.

PMID- 12619316
TI  - [Leptin levels during estrogenization phases in pubertal girls].
AB  - OBJECTIVE: We searched for associations between leptin levels, basic body
      composition, primary, secondary and tertiary sex features during pre-menarche
      without signs of estrogenization, estrogenic crisis and full estrogenization.
      MATERIAL AND METHODS: The study group consisted of 45 healthy girls over the age
      of 8 years. Height, body mass, BMI, basic body composition and plasma
      concentration of leptin were determined every three months. In addition,
      ultrasound of the ovaries, uterus and breasts was done. RESULTS: The highest
      levels of leptin were observed in girls without signs of estrogenization. The
      ratio of leptin/fat (ng/ml/kg) was higher in pubertal girls, particularly those
      without signs of estrogenization, than in adult women. CONCLUSIONS: The
      estrogenic crisis was accompanied by a reduction in body mass, followed by the
      pubertal acceleration of growth and increase in fatty, lean and total body mass.
      The correspondence of tertiary sex features with pre-menarche, estrogenic crisis
      and full estrogenization phases did not exceed 55%. Enlargement of the uterine
      body was followed by a dynamic growth of ovaries. Individual variation in ovarian
      size was significant. Changes in leptin levels occurring during estrogenization
      point to the importance of this protein in metabolic signaling.

PMID- 12619317
TI  - [Two treatment methods of infertility associated with polycystic ovarian
      syndrome].
AB  - OBJECTIVES: 30 patients treated for infertility associated with PCO were
      analyzed. Anovulatory cycles and US scans of ovaries were taken as criteria for
      PCO. MATERIALS AND METHODS: Patients were treated either by the laparoscopic
      electrocauterization (n = 16) of ovaries or by the ultrasonographic punction of
      follicles (n = 14). Number of ovulatory cycles, cumulative pregnancy rate and
      hormonal changes were analyzed. RESULTS: We observed the same efficacy of both
      methods in terms of ovulatory cycles and pregnancy rates. The cumulative
      pregnancy rate was 37.5% in laparoscopic and 35.7% in ultrasonographic groups
      during the 3 months' observation. CONCLUSIONS: Ultrasonographic punction has
      appeared to be easier to do and safer for the patient and have the same pregnancy
      rate. It also gives opportunity for in vitro culture and maturation of obtained
      oocytes.

PMID- 12619318
TI  - [The influence of asymptomatic leukocytospermia on interleukin IL-2 and IL-6
      levels in male semen plasma].
AB  - AIM: The study presents the results of the search for a correlation between
      leukocytospermia and the interleukin IL-2 and IL-6 levels in male semen plasma.
      MATERIAL AND METHODS: Interleukin levels were assessed by immunoenzymatic method
      (ELISA). Study covered 3 groups of males: I--fertile (No. = 16); II--with
      leukocytospermia (No = 16); III--with oligoasthenozoospermia (No = 20). RESULTS:
      The study revealed higher levels of IL-6 in a group of males with
      leukocytospermia (10.01 +/- 2.57 pg/ml) and with oligoasthenozoospermia (13.53 +/
      2.78 pg/ml) compared to a group of fertile males (7.68 +/- 1.4 pg/ml) (p <
      0.01), however no statistically significant differences in IL-6 levels between
      group II and III have been observed. Higher level of IL-2 has been noted in III
      group (16.68 +/- 5.86 pg/ml) compared to I and II group (9.77 +/- 3.18 pg/ml and
      6.05 +/- 2.16 pg/ml, respectively) (p < 0.01). No statistically significant
      difference in IL-2 semen plasma level between the fertile male group and the
      group with leukocytospermia has been revealed. CONCLUSION: Leukocytospermia is
      accompanied by an increase in IL-6 semen plasma level whereas IL-2 level remains
      statistically unchanged.

PMID- 12619319
TI  - [Sperm evaluation in testicular cancer patients before and after chemotherapy].
AB  - OBJECTIVES: Over the last 20 years treatment results of testicular cancer have
      improved. At present, up to 90% of patients are cured. DESIGN: Semen analysis has
      been performed in 50 patients before and 3, 6, 12, 12, 18, 24, 30 months after
      i.t. MATERIALS: 50 Patients with testicular cancer underwent chemotherapy based
      on cisplatin. Before and after treatment the semen analysis has been performed on
      each patients. The results of the patient groups have been compared to healthy
      group of men. RESULTS: The quality of the semen is much worse in the group with
      cancer compared to healthy controls. The deepest impairment of the
      spermatogenesis has been found 3 mounts after chemotherapy. CONCLUSIONS:
      Orchidectomy has no influence on sperm parameters. Semen analysis revealed
      normospermia in 30% of the patients. 30 months after chemotherapy.

PMID- 12619320
TI  - [Urethral obstruction caused by endometriosis].
AB  - Two cases of unilateral urethral obstruction caused by endometriosis were
      reported. Two patients aged 48 and 35 years old were fully diagnosed with above
      mentioned abnormalities prior to a surgical operation. During the surgical
      operations the initial diagnosis was confirmed macroscopically, followed by the
      surgical amputation of the urethral parts pathologically changed. The anastomosis
      of urethra was finally performed after confirmation that the remaining parts were
      macroscopically unchanged. Histopathological examinations confirmed the initial
      diagnosis. After the surgical operation both patients were subjected to hormonal
      treatment attaining full recovery. The above presented cases--urethral
      endometriosis is one of rare complications caused by endometriosis. Proper and
      early diagnosis, followed by an effective treatment is important in obviating
      grievous consequences e.g. total renal failure.

PMID- 12619321
TI  - [The coexistence of vulvovaginal warts and cervical dysplasia with HPV infection
      and cervicitis].
AB  - We present a case of 30-year old female patient with persistent cervicitis and
      vulvovaginal warts. In the course of diagnosis were found cervical dysplasia and
      a HPV infection type 6 and 11. In therapy we applied antibiotics, chemical
      therapy of the warts, laser vaporization of the warts, laser conisation,
      immunotherapy. Three years' intensive therapy didn't lead to satisfactory
      results. Finally hysterectomy led to the acceptable therapeutical effect.

PMID- 12619322
TI  - [The late recurrence of ovarian cancer seventeen years after radical surgery].
AB  - The study presents a very interesting case of ovarian cancer with long-term
      survival. The patient was primary treated by conservative surgery without
      chemotherapy. Cystadenocarcinoma mucinous G-1 was recognized. Ovarian cancer
      relapsed after eight years and the second operation was performed. During next,
      radical operation other histological typ of ovarian cancer (mixed, sero-mucinous
      cystadenocarcinoma) was recognized. Eight years after second surgery and
      seventeen years after primary surgery ovarian cancer again recurred. There were a
      very diffuse neoplastic process at the abdominal cavity. Although patient was
      treated by surgery and chemotherapy, she died. The study presents new opinions of
      pathogenesis of ovarian cancer and origin of recurrences, including theory of
      multifocal neoplasia of mesothelium.

PMID- 12619323
TI  - [Laparoscopic correction of uterus retroflexion by sewing the round ligament of
      the uterus to the abdomen fascia in treatment and prophylaxis of pain syndromes].
AB  - The use of laparoscopy in diagnosis, investigation, and therapy is very
      important. The paper describes the laparoscopic technique of correction of a
      retroflexed uterus. This technique is based on sewing the round ligaments of the
      uterus to the abdomen fascia. Both simplicity and usefulness of the method are
      demonstrated.

PMID- 12619324
TI  - [The role of leptin in human reproduction].
AB  - The article reviews the current literature about leptin, a hormone produced
      mainly in the adipose tissue, in terms of its role in reproduction. The structure
      of leptin, its biological activity as well as its influence on secretion of their
      hormones has been discussed. The leptin concentrations during the ovulatory
      cycle, pregnancy puerperium and assisted reproduction have been presented. It has
      been suggested that leptin may have an advantageous effect not only on oocyte and
      zygote development in the early stages, but also on the process of implantation
      and therefore its evaluation may be useful for the clinical determination of
      embryo quality in IVF-ET program.

PMID- 12619325
TI  - [Improvement of computer program for cytology screening of the female population
      in Bialystok].
AB  - In the article authors present a new edition of computer programme managing
      active and population cytology screening in the selected group of women in
      Bialystok. All improvements came out of the slow date base transforming. From the
      other hand so called "2000 year mistake" was eliminated. In the previous
      programme single date transfer between only two PC terminals was possible.
      Additionally way of assignment of particular groups of women to proper out
      patient rooms districts also by the zip codes were presented. Process of creation
      of cytology invitations to all women participating in screening examination was
      accelerate. Increase effectiveness of screening examinations was available as a
      result of using a new edition of computer programme. Percentage of mistakes and
      exam expenses were also minimized. Two main cytology screening foundation, its
      active and population were achieved.

PMID- 12619326
TI  - [Healing is a form of art--thesis based on daily work observation at a Gynecology
      Obstetrics Hospital].
AB  - In the therapeutic process the means of communication between a physician and a
      patient and the interactions between them constitute an important element of
      medical procedures. The gynecologist and obstetrician accompany women from their
      births till late old age. The aim of the study was to describe from the
      psychological point of view certain situations arising in everyday work in
      Gynecological-Obstetrical Hospital: motherhood, the place of a newborn and
      his/her parents in the Neonatal Ward, gynecological surgery, climacteric and
      senium.

PMID- 12619327
TI  - The professional liability emergency.

PMID- 12619328
TI  - Single suture synostosis and intracranial hypertension.
AB  - It is difficult to determine the incidence and importance of intracranial
      hypertension in children with single suture synostosis. A review of the
      literature suggested that some number of affected children have high intracranial
      pressure. The incidence of cognitive disability also appears to be high in this
      population. Currently, it cannot be proven that the intracranial hypertension
      seen in these children causes the cognitive dysfunction or that, for the group as
      a whole, surgical intervention alters cognitive outcome.

PMID- 12619329
TI  - The impact of changing age-adjustment population standards on Kentucky's cancer
      incidence rates.

PMID- 12619330
TI  - Physician, heal thyself.

PMID- 12619331
TI  - Orthopaedic care in haemophilia.

PMID- 12619332
TI  - Developments in clinical electrophysiology.

PMID- 12619334
TI  - Emergency management of pelvic fractures.
AB  - Pelvic fractures are relatively uncommon, accounting for 1-3% of all fracture.
      Around 60% occur in men. This article discusses the multidisciplinary management
      of pelvic ring disruptions resulting from high energy transfer.

PMID- 12619333
TI  - Management of maxillofacial injuries.
AB  - Maxillofacial injuries account for 5% of all acute attendances at accident and
      emergency units, and are often seen in the multiply injured patient. A systematic
      method of examining and investigating these patients is required for all staff
      involved with trauma patients and an understanding of the principles of their
      management will help to prioritize treatment needs.

PMID- 12619336
TI  - Carotid sinus syndrome.
AB  - This article reviews the recent literature about carotid sinus syndrome. It looks
      principally at the various ways in which it may present, the limited knowledge of
      its pathophysiology, and the role of carotid sinus massage in the investigation
      of carotid sinus syndrome.

PMID- 12619335
TI  - Osteoporosis and fractures: the size of the problem.
AB  - The public health impact of osteoporosis-related fractures is enormous, with
      important economic implications. Government agencies and health-care providers
      must recognize the importance of early diagnosis of osteoporosis, implement
      policies for the prevention of disease, and develop effective payment policies
      for densitometry examinations.

PMID- 12619337
TI  - Best practice for hypertensive patients with kidney disease.
AB  - Many patients with non-diabetic and diabetic renal disease undergo chronic renal
      function loss leading to dialysis or renal transplantation. The US National
      Kidney Foundation guidelines recommend that angiotensin-converting enzyme
      inhibitors and angiotensin type receptor antagonists are first choice therapy for
      these patients.

PMID- 12619338
TI  - Broadening medical horizons.
AB  - In the rush to acquire ever more and detailed knowledge, the medical profession
      appears to have forgotten that there are other academic disciplines, the study of
      which would benefit both doctors and patients.

PMID- 12619339
TI  - Cervical lymphadenopathy in children.
AB  - The management of cervical lymphadenopathy in children varies widely between
      clinicians. It is recognized that clinical management can be improved by
      standardizing the diagnostic and treatment methods. This article presents an
      algorithm based on the available evidence for the management of cervical
      lymphadenopathy in children.

PMID- 12619340
TI  - A study on surgical knowledge of house officers and their role in consent.
AB  - This study shows a targeted training for house officers relating to surgical
      procedures and consenting issues was helpful. The authors recommend that advice
      on obtaining consent should be a part of the induction programme for surgical
      house officers.

PMID- 12619341
TI  - The eye in lung disease.

PMID- 12619342
TI  - Benign prostatic hyperplasia.

PMID- 12619343
TI  - Thyrotoxicosis-induced hyperferritinaemia.

PMID- 12619344
TI  - Herpes zoster misdiagnosed as testicular torsion.

PMID- 12619345
TI  - A giant pilar tumour of the scalp.

PMID- 12619346
TI  - Parapharyngeal abscess: a diagnosis not to miss.

PMID- 12619348
TI  - [Factors affecting geographic choice in setting up medical office in France].
AB  - So far French medical doctors are free in selecting the city where they set up
      their private office. However, opinion surveys during the period 1974-1999
      evidence certain determinants in the matter. Proximity of the family and
      occupation of spouse are two increasing determinants during the period. The same
      upward trend is observed as concerns the proximity of a hospital or the contacts
      which the doctor has had previously with the local population during his post
      graduate probation. On the other side, the pleasant character of the city and the
      opportunity to obtain (or to rent) an office are two decreasing factors.
      Surprisingly analysis of the potential market of patients remains stable as
      factor determining the geographic choice of the young doctors. During the last 25
      years, more and more young doctors made payment to retiring colleagues to be
      introduced to the patients of the latter. The practice is legal. Due to manpower
      surplus, it became increasingly a factor of geographic distribution of young
      doctors. It will however decrease its weight in the coming years, with the
      downing turn in the number of new graduates.

PMID- 12619347
TI  - Oxygen delivery and venous oxygen saturation monitoring.

PMID- 12619349
TI  - The evolution of national health care systems: from the Soviet Union to Russia.

PMID- 12619350
TI  - [Why do young doctors decide to set up their practice in Ile de France].
AB  - The survey was conducted among the 700 young practitioners setting up their
      private practice in the region of Ile de France (the Greater Paris region)
      between October 2000 and October 2001. They were requested to mention the various
      reasons which led them to select the region. The 3 most mentioned reasons were:
      the acceptance of a proposal for setting up his/her practice, the doctor has been
      trained in the region, the region is medically well-equipped: I have accepted a
      proposal: 59% of the surveyed doctors I have been trained in the region: 47% The
      region is medically well equipped: 45% Because of my spouse: 39% This his my
      region of birth: 34% Other family reasons: 28% I have been locum tenens there:
      23% I have an other activity there: 22% I am not willing to go to an other
      region: 13% Financial opportunities: 7% When asked to mention the most important
      reason, the surveyed doctors provide a slightly different picture: acceptance of
      a proposal (26%); spouse in the region (17%); region of birth (12%); regional
      facilities (12%).

PMID- 12619352
TI  - [Common cold wave in progress... developed a cold?!].

PMID- 12619351
TI  - [The first 15 years of FICOSSER (Federation for International Cooperation of
      Health Services and Systems Research Centers): 1987-2002].
AB  - The Federation for International Cooperation of Health Services and Systems
      Research Centers (FICOSSER) has been established for promoting interchange and
      cooperation across the borders of nations, scientific disciplines or
      institutional settings. During the period 1987-2002, the Federation has convened
      4 general conferences--large forums for assessing the state-of-the-art--and 11
      research meetings, each dealing with a specific research topic. The proceedings
      of each conference or research meeting were published by a volunteering member
      center, with its own resources, on behalf of FICOSSER. One of the salient
      features of FICOSSER activities was the continuity of the efforts deployed by its
      member-centers for working together and furthering certain research areas: heath
      care financing, human resources of the health system, rural health issues, health
      care reform in the former socialist countries, research for appropriate health
      response to disasters and major emergencies, etc. Certain activities of FICOSSER
      were carried out in close collaboration with the World Health Organization. Since
      its inception, FICOSSER has highlighted two principles--self-help and mutual
      enrichment--for the involvement of its members-centers.

PMID- 12619353
TI  - [Preparing for bioterrorism. Smallpox panic? (interview by Marion Kaden)].

PMID- 12619354
TI  - [Totally wild for Aloe vera. Is all only marketing or what?].

PMID- 12619355
TI  - [New surgical method in bladder paralysis. Contracting the latissimus muscle to
      urinate (interview by Dr. Judith Neumaier)].

PMID- 12619357
TI  - [Consulting the physician before suicide. When silence is fatal].

PMID- 12619356
TI  - [Alerting your pacemaker patients to risks. Microwave is innocuous, but during
      lawn mowing the pump races].

PMID- 12619358
TI  - [Alarming skin manifestations: eczema, urticaria or cancer? How to discriminate
      between benign and dangerous skin changes].
AB  - Numerous dermatological lesions can be provisionally diagnosed by the family
      doctor on the basis of such parameters as location, duration, degree of pruritus,
      involvement of the epidermis, and the age of the patient. Whenever a lesion is
      difficult to interpret or suspicious for malignancy, the patient should be
      referred to a specialist without delay. This is also mandatory in all such cases
      in which accepted therapeutic measures initiated on the basis of an apparently
      certain diagnosis on the part of the family doctor fail to cure the problem
      within a reasonable period of time.

PMID- 12619360
TI  - [Blunt abdominal trauma. Remain alert even when there are few initial symptoms!].

PMID- 12619359
TI  - [Placebo wonder drug. Why it is so effective in pain therapy].
AB  - Placebos play an important role as controls in the evaluation of specific
      treatment techniques and as unspecific therapy. In the last years, a series of
      studies with controversial statements were published. The placebo response cannot
      be reduced to a single point. Evidence based factors are instruction of the
      probands in experimental investigations resp. information of the patients, their
      expectancy, suggestion, setting, kind of treatment and indication. Acute,
      recurrent and chronic pain states were in relation to placebo most thoroughly
      investigated. In this field, placebo is better than no treatment.

PMID- 12619361
TI  - [Migraine and tension headache. Are over the counter analgesics effective?].

PMID- 12619362
TI  - [From bypasser to life saver. Reducing hesitancy with defibrillators in lay
      persons].

PMID- 12619364
TI  - [Generous treatment with gastric acid blockers. For patients with gastric reflux
      the proton pump inhibitor power is cost-effective].

PMID- 12619363
TI  - [Pallid patient. The second colonoscopy diagnosed the problem].

PMID- 12619365
TI  - [Exaggerated interaction claims. With esomeprazole the data corroborate safety].

PMID- 12619366
TI  - [Every 2nd heart failure patient without beta blocker. "Intolerance" is often a
      dosage error].

PMID- 12619367
TI  - [Robert Koch Award for acarbose. Antidiabetic drug prevents myocardial infarct].

PMID- 12619369
TI  - [High dose sartan plus thiazide. Power duo in hypertension].

PMID- 12619368
TI  - [New treatment approach. Patients with neurodermatitis need less cortisone].

PMID- 12619370
TI  - [Treatment of chronic wounds. Maggots replace the surgeon].

PMID- 12619371
TI  - [Also keeps long migraine attacks in check. A new triptan].

PMID- 12619372
TI  - Respiratory effects of environmental pollution: epidemiological data.
AB  - A recent document of the American Thoracic Society and two previous reports of
      the International Union Against Tuberculosis and Lung Disease have summarized the
      negative health effects due to air pollution in a list ranging from the increase
      of mortality to the perception of bad odors. A significant attempt to estimate,
      on an annual basis, the negative effects of air pollution from particulate matter
      less than 10 microns in aerodynamic diameter (PM10) has been carried out on data
      from Austria, France, and Switzerland: e.g. in France, air pollution from PM10 is
      responsible annually for 31,700 deaths, 36,700 new cases of chronic bronchitis
      and 577,000 attacks of asthma in adults, 450,000 cases of acute bronchitis and
      243,000 attacks of asthma in children. Recently, a study on the long-term effects
      of air pollution on about 500,000 residents in metropolitan US areas evidenced
      that each 10 micrograms/m3 elevation in fine particulate air pollution is
      associated with approximately a 4%, 6% and 8% increased risk of all-cause,
      cardiopulmonary and lung cancer mortality, respectively. Some Italian experiences
      have also confirmed respiratory health damages from air pollution, namely the
      prospective epidemiologic studies on general population samples of the Po Delta
      and Pisa areas; the cross-sectional study on schoolchildren of the 'Italian study
      on respiratory disorders in childhood and environment' (SIDRIA); and a meta
      analysis of the Italian studies on short-term effects of air pollution. In
      conclusion, epidemiologic studies suggest that air pollution plays an important
      role in the exacerbation and in the pathogenesis of chronic respiratory diseases.
      Thus, respiratory physicians, as well as public health professionals, should
      advocate for a cleaner environment.

PMID- 12619373
TI  - Respiratory allergic diseases induced by outdoor air pollution in urban areas.
AB  - A wealth of evidence suggests that allergic respiratory diseases such as
      rhinosinusitis and bronchial asthma have become more common worldwide in recent
      years and a great deal of etiologic and pathogenic research has been carried out
      to evaluate the possible causes of this increasing trend. There is also some
      evidence that increased atmospheric concentrations of pollutants such as ozone
      (O3), oxides of nitrogen (NOX), respirable particulate (PM10) and volatile
      organic chemicals (VOC5), which result from increased use of liquid petroleum gas
      or kerosene, may be linked to the increased prevalence of allergic diseases which
      develop more frequently in urban areas of developed countries. Since bronchial
      asthma is a disease which can be aggravated by inhaled compounds, health effects
      of air pollutants have received attention. In fact various studies have
      demonstrated that inhalation of air pollutants such as O3, nitrogen dioxide (NO2)
      and sulphur dioxide (SO2), either individually or in combination, can enhance the
      airway response to inhaled allergens in atopic subjects inducing asthma
      exacerbations. Moreover, experimental studies have shown that diesel exhaust
      particulate (DEP) causes respiratory symptoms and is able also to modulate the
      immune response by increasing immunoglobulin (Ig)E synthesis in predisposed
      animals and humans. There is also some evidence that air pollutants can interact
      with aeroallergens in the atmosphere and/or on human airways, potentiating their
      effects. In fact, by inducing airway inflammation which increases epithelial
      permeability, some pollutants overcome the mucosal barrier and so prime allergen
      induced responses. However, air pollution and climatic changes may also have an
      indirect effect on the allergic response by influencing quantitatively and
      qualitatively the pollen production of allergenic plants.

PMID- 12619374
TI  - Air pollution and reversible chronic respiratory diseases.
AB  - Air pollution is one of the world's most serious environmental problems. It has
      been common knowledge for many years now that the lung is one of the main target
      organs of environmental agents. Over the last ten years, in particular, lung
      diseases have increased dramatically and the literature on the subject reports
      high death rates from lung cancer and an increased incidence of bronchial asthma
      and chronic obstructive pulmonary disease (COPD). These respiratory diseases are
      also caused by exposure to environmental agents, especially air pollution.
      Outdoor pollution is related to many compounds and, in assessing the air-borne
      pollutants and their association with respiratory damage, the role of particulate
      matter (PM) is of major importance. In addition to outdoor pollution, indoor
      pollution also exists and consists of environmental substances usually found
      outside which enter the internal environment, and/or of locally produced
      substances. Air pollution exposure involves the contact of pollutants with the
      respiratory tract, such exposure being measured according to two parameters:
      intensity and duration. Generally speaking, the pathogenic effects of
      environmental pollution on the organism fall into two categories: acute, or short
      term effects, and long-term effects, depending on the time required from exposure
      to the manifestation of its effect. Short-term effects consist of irritant
      symptoms affecting the airways with different degrees of severity, while long
      term effects, related to chronic exposure, are associated with chronic
      respiratory diseases, and unremitting symptoms such as coughing, wheezing, etc.
      Moreover, air irritants can give rise to inflammatory damage of the mucous
      membrane of the airways, thereby making it more susceptible to various types of
      allergens. In conclusion, air pollution is an important etiological factor for
      many chronic respiratory disorders, such as bronchial asthma and COPD. Prevention
      programs and early treatments are essential in an attempt to block the clinical
      functional deterioration caused by these respiratory diseases.

PMID- 12619376
TI  - Risk factors for tuberculosis infection and disease.
AB  - We conducted a prospective study among patients with newly diagnosed pulmonary
      tuberculosis and their close contacts to identify clinical and socio-economic
      risk factors for tuberculosis infection and disease. Ninety patients and 277
      contacts were enrolled. The prevalence of infection was 45% [95% confidence
      interval (CI): 39-51%] among contacts. Factors like age, gender, race, delay of
      diagnosis and treatment, presence of cavitation in chest radiograph, cough,
      unwillingness to cover the mouth, volume of air shared by close contacts and
      patients were investigated. Inclusion of all these factors in a multivariate
      logistic regression model showed that only delay in diagnosis is significantly
      associated to the increase of prevalence (p < 0.0002), documenting that delay in
      diagnosis of the case is a crucial factor for tuberculosis infection and/or
      disease.

PMID- 12619375
TI  - Environmental exposure and occupational asthma.
AB  - Environmental exposure in relation to occupational asthma (OA) concerns the
      exposure of subjects in the work-place. There are qualitative and quantitative
      differences in occupational exposures which may influence the development and/or
      the course of OA. Although more than 300 different agents have been described
      causing OA, 5-6 groups of substances are sufficient to explain more than 80% of
      all cases of OA. In addition, a variant of occupational asthma without latency
      period may occur after an acute inhalation of massive concentrations of
      irritants, and exacerbations of a pre-existent asthma may be due to products or
      conditions in the work-place. Despite our increased knowledge of the etiology and
      pathophysiology of OA, its prevalence in the industrialised world has been
      relatively steady over the last decade. Therefore, the transfer of knowledge has
      not been sufficiently effective in the prevention of the disease. The results of
      studies on the exposure-response relationship for several high molecular weight
      chemicals (and fewer low molecular weight) indicate that sensitisation may be
      prevented in large part by reducing work-place concentrations of these agents.
      These data give support to the attempt to develop Threshold Limit Values (TLV)
      for sensitisers.

PMID- 12619377
TI  - Role of oxidative stress in pulmonary fibrosis.
AB  - Pulmonary fibrosis can be observed as an end state in a number of chronic
      inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis
      develops are not fully ascertained, recent findings suggest that oxidative stress
      may play an important role in the pathogenesis of tissue fibrosis affecting
      apoptosis of both structural and inflammatory cells and altering the cytokine
      microenvironment balance. Damage and alteration of alveolar epithelial cells is
      one of the hallmarks of interstitial lung fibrosis. Recently, it has been
      demonstrated that the presence of oxidative stress may lead to the damage,
      activation and/or apoptosis of alveolar epithelial cells either directly, through
      an imbalanced intracellular redox equilibrium, or indirectly, by activating redox
      sensitive effector pathways, such as transcription factors and angiotensin
      converting enzyme, increasing the conversion of angiotensinogen into angiotensin
      II that can be considered a mediator of oxidative stress, capable of inducing
      apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a
      proinflammatory cytokine and is effective in activating fibroblasts through the
      release of transforming growth factor (TGF-beta). As well as activation,
      differentiation, proliferation and apoptosis of fibroblasts seem related to the
      oxidant/antioxidant balance, and the maintenance of a high intracellular level of
      reduced glutathione (GSH) is considered crucial in providing a reducing
      environment within the cell, able to protect against oxidative stress. In those
      conditions where oxidants, either inhaled or produced by inflammatory cell,
      increase, the ratio between GSH and oxidized glutathione (GSSH) may lower,
      influencing a variety of cellular redox-sensitive signaling processes such as the
      activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead
      to a transcriptional up-regulation of a number of genes involved in inflammation
      and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis
      factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1)
      and growth factors (GM-CSF). In addition, several studies have shown that
      oxidative stress may also affect the immune response by inducing an up-regulation
      of HLA-DR as well as the expression of two costimulatory molecules such as CD40
      and CD86, determining a persistent state of immune activation, and affecting the
      Th1/Th2 balance, modulating the T-cell effector response towards the Th2
      phenotype. It is clear that a better understanding of the precise sequence of
      events that make the difference between normal tissue repair and fibrosis,
      including the role played by oxidative stress, will certainly improve our
      therapeutic approach to pulmonary fibrosis.

PMID- 12619378
TI  - Air pollution and respiratory pathology: lung cancer.
AB  - Lung cancer is the most frequent cause of death from neoplastic pathology in the
      western world (28% of total mortality from neoplasia); in 90% of cases it is
      caused by tobacco smoke. In Italy, a stabilisation trend in males is observed,
      while female mortality is still increasing. During the first two decades of 2000,
      a more or less evident pathology decline is expected in males and a
      decline/stabilisation in females, according to the results of anti-smoking and
      anti-pollution campaigns. Lung cancer can be considered a pathology of
      multifactorial etiopathogenesis, where out- and indoor environmental risk
      factors, together with genetic factors and living habits, combine to explain the
      differences in increase of neoplasy incidence in exposed populations and
      categories. Several chemical, physical and biological agents have been identified
      as promoting or initiating factors of a series of genic modifications inducing
      "genetic instability" and subsequent alteration of the programmed cell death
      regulation ("apoptosis") and of the cell cycle responsible for somatic cell
      alterations ("transformed phenotype") in previously normal tissues. This paper
      outlines the different risk factors responsible for lung neoplasies, and
      discusses the molecular-biological mechanisms involved in the pathogenesis of
      lung cancer.

PMID- 12619379
TI  - Oxidative stress and lung diseases.
AB  - Several different lung diseases are characterized by an oxidant/antioxidant
      imbalance, which is a major cause of cell damage. Oxidative stress activates a
      complex network of intracellular signal transduction pathways involved in the
      regulation of transcription factors such as nuclear factor kappa B (NF-kappa B)
      and activator protein-1 (AP-1). Within this context, a key role is played by
      mitogen-activated protein kinases (MAPK), which are highly expressed by pulmonary
      endothelial and airway epithelial cells. By exposing these cell lines to oxidant
      agents, our group has shown that oxidative stress leads to a significant MAPK
      activation, which can be effectively inhibited by corticosteroids. We believe
      that studies such as ours may contribute to further elucidate the molecular
      events underlying the therapeutic action of these drugs in many respiratory
      disorders caused by oxidative/proinflammatory pathogenic mechanisms. In addition,
      our findings may help to unveil new anti-oxidant treatments based on MAPK
      modulation.

PMID- 12619380
TI  - Exhaled nitric oxide as a marker of adverse respiratory health effect in
      environmental disease.
AB  - The presence of, and the possibility to assay, nitric oxide (NO) in exhaled
      breath of humans caused a great deal of interest in relation to understanding the
      physiological and pathophysiological role of this molecule. Most studies have
      measured exhaled NO by chemiluminescence and detection depends on the
      photochemical reaction between NO and ozone generated in the analyzer. Here we
      discuss the role of exhaled NO as a physiological method to evaluate the effect
      of environmental changes on lower and upper airways in healthy subjects;
      particularly, its potential application as non invasive marker of the effect of
      outdoor and indoor air pollution on the respiratory tract.

PMID- 12619381
TI  - Virus-induced asthma.
AB  - Clinical and experimental investigations indicate that respiratory viral
      infections are important triggers for asthma attacks. Viral upper respiratory
      infections have been associated with 80% of asthma exacerbations in children and
      50% of all asthma episodes in adults. Human Rhinovirus (HRV) has been implicated
      as the most common virus associated with asthma episodes. The observation that
      the great majority of wheezing lower respiratory tract illnesses in early life
      are associated with acute viral infections suggests that viruses may also alter
      the development of the lungs or of the immune system, acting as co-factors for
      the inception of asthma. Whilst there is no doubt that viruses are important
      asthma exacerbation factors, the role of viral infections in the development of
      asthma still remains controversial.

PMID- 12619382
TI  - Genetically modified animals as models of pulmonary disease.
AB  - Improvements in biological research and the development of new techniques for
      human health protection require animal experimentation of various species. In
      particular, animal models are always necessary to test new therapies for the
      treatment of various human diseases. The latest advances in molecular biology
      involving genetic modification are aimed at developing new animal models of human
      diseases that are not present in spontaneous murine broods or obtainable with
      other experimental manipulations. Transgenic techniques and, in particular, the
      possibility to directly modify specific genetic information in the experimental
      animal have led to the acquisition of important knowledge on the physiologic
      functions of many proteins and their function in the course of various diseases.
      The advent of new transgenic animals is opening up new and interesting frontiers,
      full of hope and opportunity, for the research into pulmonary diseases. New
      advances in cystic fibrosis, emphysema, and pulmonary fibrosis have been made
      through the study of a large number of proteins implicated in the complex of
      acute and chronic inflammatory processes of lung parenchyma, which are
      responsible for permanent changes in organ structure and function. Recent studies
      carried out on murine inbred strains have yielded significant new data on the
      multifactor origin of pulmonary disease, because of their correlation with the
      major histocompatibility complex (H2 in mice) or through the different genetic
      map of the strains. Today it is possible to outweigh or potentiate the function
      and expression of some genes, obtaining a deficit or abundance, respectively, of
      specific proteins. These techniques have permitted and will continue to permit
      the development of new models of human disease, leading to further therapeutic
      advances as a consequence.

PMID- 12619383
TI  - Detection and qualitative identification of mineral fibers and particles in
      alveolar macrophages of BAL fluid by SEM and EDXA.
AB  - Inorganic dust inhalation diseases represent one of the most important chapters
      in respiratory medicine because of their diagnostic, therapeutic, legal,
      ecological and social implications. While, in fact, toxic substances inhalation
      may be easily related to particular occupations, it is more difficult to
      recognize the potential damage represented by occasional and fortuitous
      exposition due to pollution of one's living environment. The aim of this study
      was to suggest a useful investigative method for detecting the presence of
      mineral substances (dusts and fibers) in the lung in pulmonary fibrosis of
      uncertain origin. We used scanning electron microscopy (SEM) and semi
      quantitative energy-dispersive x-ray microanalysis (EDXA) on broncholaveolar
      lavage (BAL) and sputum samples of 10 patients, all males, aged 41-66 years,
      smokers, affected by interstitial lung disease. Two subjects had a negative
      professional anamnesis while the other 8 declared a potential exposition to
      inorganic toxic dusts: 2 subjects were involved in the production of asbestos
      containing building materials, 2 were miners, 1 a ceramic worker, and 3
      insulating materials handlers. Data are reported on the detection of asbestos
      bodies, vitreous fibers and silica content of alveolar macrophages in BAL fluid.

PMID- 12619384
TI  - Respiratory function and atmospheric pollution.
AB  - The effects of environmental pollutants on human health and, in particular, on
      the respiratory apparatus, can be studied fundamentally by means of
      epidemiological and controlled exposure studies. One epidemiological study has
      reported the results of research which compared pulmonary function in adults with
      the average annual concentration of major pollutants in 8 geographical areas of
      Switzerland; the results demonstrated a direct relationship between atmospheric
      pollution and a worsening of pulmonary function. Controlled exposure studies, on
      the other hand, document the effects of specific air pollutants. Ozone (O3) is a
      secondary pollutant produced in the atmosphere by photochemical reactions which
      exerts a potent antioxidant and peroxidant action on biomolecules, whether intra
      or extracellular, with the production of free radicals. Nitrogen dioxide (NO2) is
      found mainly indoors due to its being a product of combustion of kitchen gas--it
      possesses low reactivity and low solubility that allows its penetration to the
      periphery of the lungs; the harmful mechanisms induced by NO2 are not well
      understood and could differ from those of O3. Sulphur dioxide (SO2) is found
      above all outdoors and is documented to affect the respiratory function of
      asthmatic subjects at concentrations above 1 part per million (ppm) while it has
      a doubtful effect on healthy subjects. Suspended particulate matter (SPM) is one
      of the major pollutants present in the air that comes mainly from vehicle
      exhausts, especially diesel models. Although the epidemiological data indicates a
      close relationship with both cardiac and respiratory pathology, the biological
      mechanisms by which it exerts its toxicity are still not well established. The
      great variability in individual response to pollutants suggests the need for
      further sensitivity tests to be carried out: it is of importance to identify
      specific genes with a stabilising role in cellular protection against oxidative
      stress, that influence the production of chemical mediators of inflammation.

PMID- 12619385
TI  - Future treatment of chronic obstructive pulmonary disease.
AB  - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and
      mortality. Theoretically, an appropriate management of the disease should be
      aimed to prevent and reduce symptoms, to reduce the number and the severity of
      exacerbations, to improve exercise tolerance and lung function and to decrease
      the rate of mortality. However, the rapid progress in understanding the
      pathophysiologic aspects of COPD has been followed by very few advances in its
      management and currently there is no pharmacological treatment which is able to
      reduce the decline in lung function that occurs in these patients or to affect
      mortality. Effective symptomatic relief and improvement in exercise capacity can
      be obtained with inhaled bronchodilators and a new long-acting (> 24 h) inhaled
      anticholinergic, tiotropium bromide, is now available. New pharmacological
      approaches for COPD include the development of drugs which should be able to
      control the neutrophilic, steroid-insensitive inflammation, to reassess the
      protease/antiprotease balance and to reduce oxidative stress in the airways.
      While most of these drugs are still in preclinical evaluation, some recent phase
      II-III clinical trials have shown the beneficial effects of a new class of anti
      inflammatory compounds, the phosphodiesterase-4 (PDE-4) inhibitors, in patients
      with COPD. Given the relevance of mucus hypersecretion in the pathophysiology of
      this disease, efforts have been made also to draw definitive conclusions on the
      effectiveness of the available mucoactive drugs and in the development of new
      mucoactive molecules. Further studies are required to understand the impact of
      each potential therapeutic strategy in the effective control of COPD.

PMID- 12619387
TI  - Prevention of occupational asthma.
AB  - Occupational asthma (OA) is a type of bronchial asthma due to causes and
      conditions attributable to a particular occupational environment. It is the most
      prevalent occupational lung disease in industrialized countries, accounting for
      approximately 5% of asthma in adults. Since OA has important medical, social and
      economic consequences, its prevention is mandatory, and the most important
      measure is primary prevention at the workplace. Control of environmental exposure
      can be realized by completely eliminating the causative substances, or, failing
      that, by reducing exposure to the lowest practicable levels. This goal may be
      achieved in a variety of ways, e.g. by automation of a process, improvement of
      ventilation, modification of the  process or agents, and use of personal
      protection devices. However, the control of  environmental exposure presents
      several difficulties. First of all, exposure levels that favour respiratory
      sensitization to high molecular weight (HMW) or low molecular weight (LMW) agents
      are not completely defined. There is a critical need for the development of
      methods able to quantify the airbone levels of  sensitizing agents at the
      workplace and to establish limits of exposure for respiratory sensitization.
      Development of assays (e.g. immunochemical assays) able to quantify airbone
      allergen levels should facilitate determination both of  exposure-response
      relationships and of exposure limits for preventing respiratory sensitization and
      development of  OA. Quantification of risk at the workplace is also often rough
      and based on indirect markers of exposure. At present, the target for an optimal
      approach to the primary prevention of OA is the development of methods able to
      evaluate both the sensitizing and the asthmogenic properties of the substances
      before their introduction in the work environment.

PMID- 12619386
TI  - The biotechnology for the removal of specific pollutants.
AB  - In the last century, thanks to the development of molecular trials such as those
      involving genetic modification, biotechnologies have asserted themselves in
      diversified sectors and their evolution has been rapid, resulting in an enormous
      impact on the productive sector, on the quality of life, and on the consequences
      that their employment can have for man and, above all, for the environment. In
      particular, the application of biotechnologies in the sector concerned with the
      management and disposal of dangerous and non dangerous wastes, as well as in the
      sector concerned with the remediation of grounds contaminated by organic and
      inorganic pollutants, has led to the development of systems and processes that
      represent a valid and consolidated methodology for environmental improvement.
      This paper reviews the various different ways in which biotechnologies have been
      employed in the above sectors, citing the conditions necessary for their
      successful application, and stressing the great potential that these
      methodologies have, if optimised by means of further research, for solving
      environmental problems.

PMID- 12619389
TI  - Unrestrained nursing home pt. falls from second floor.

PMID- 12619390
TI  - 'Don't you dare question my authority or me, ever'. Case on point: Smilow v. John
      Muir Medical Center, 2003 WL 122611 P.2d-CA.

PMID- 12619388
TI  - Asthma treatment must be always tailored to the individual patient.
AB  - Several studies have shown that there are notable benefits in adding a long
      acting beta 2-agonist to an inhaled corticosteroid. Particularly, long acting
      beta 2-agonists allow to reduce the amount of steroid that is required to induce
      a specific response and, consequently, its possible side effects. Currently the
      pharmaceutical market promotes, and physicians tend in any case to privilege, the
      use of fixed combinations for the treatment of the asthmatic patient and this
      also in the first phases of the illness. Nevertheless, for the majority of
      patients with mild to moderate asthma, it seems more reasonable to optimize the
      dose of the inhaled steroid before considering the addition of a long-acting beta
      2-agonist, and use this latter on an 'as needed' basis if its pharmacodynamic
      characteristics allow it. Use of combinations is the more reasonable therapeutic
      choice for patients with a more severe pathological picture, who, despite the
      optimized dosage of the inhaled glucocorticoid, also require a long acting beta 2
      agonist. After having verified the stability of the clinical control, it is
      possible to continue with the combined therapy provided, however, that this
      allows the treatment of the patient with the lowest dose of corticosteroid able
      to prevent, as far as is possible, exacerbations. Asthma exacerbations are less
      frequent with this therapy, but when they appear it is necessary to be
      immediately able to increase and, sometimes, also maximize the dosage of
      corticosteroid without being forced to double, or even triple, the dose of the
      long acting beta 2-agonist unless there is a real need--and which probably,
      rather, would induce unwanted side effects.

PMID- 12619391
TI  - IL: Discovery of disciplining of RN post pt.'s death: RN's voluntary termination
      too remote in time.

PMID- 12619392
TI  - AL: Confused pt. at risk for fall restrained: patient escapes from restraints and
      falls.

PMID- 12619393
TI  - Nurse's relationship with pt. results in disciplinary action. Case on point: Tapp
      v. Board of Registered Nursing, 2002 WL 31820206 P.2d-CA.

PMID- 12619394
TI  - Look out the window and open the door.

PMID- 12619395
TI  - Learning from today's clinicians in vocational practice to educate tomorrow's
      therapists.
AB  - BACKGROUND: In response to the demand for therapists and changes in vocational
      practice, a needs assessment was conducted to update an occupational therapy
      educational program. METHOD: Employing focus groups, interviews and
      questionnaires, 66 therapists from a wide range of graduating institutions
      working in vocational practice were asked to: a) identify the essential
      knowledge, skills and professional behaviours required for vocational practice;
      b) determine to what extent training is preparing students for vocational
      practice; and c) make recommendations for curriculum revision and/or for
      additional curriculum development. Participants and their jobs were profiled
      together with the challenges and issues of vocational practice. RESULTS: There
      was strong agreement among participants regarding what is required to practice
      effectively but disparate views concerning the extent they were prepared for
      practice. CLINICAL IMPLICATIONS: Recommendations were given for entry and
      postgraduate level curricula. Findings were compared to a past community practice
      survey. Implications for practicums, professional integrity and ethical issues
      were discussed.

PMID- 12619396
TI  - [Evaluation of a wheelchair recycling program].
AB  - BACKGROUND: In 1998, 11.8% of the Quebec population over 15 years showed mobility
      problems and 2.3% of that group revealed that their needs were not met. The same
      year, the Regie de l'assurance-maladie du Quebec distributed more than 4,500
      wheelchairs and repaired some 30,000 others, at a cost of over $20 million. The
      recycling of wheelchairs is seen as a solution for improving this situation. This
      paper presents an evaluation of a wheelchair recycling program. METHODS: Three
      groups of participants involved in the recycling of wheelchairs contributed to
      the gathering of information. These were: personnel (n = 9), occupational
      therapists in the community (n = 5) and users of refurbished wheelchairs (n =
      20). RESULTS: A participative and qualitative research approach was conducted
      with the 1st group. The results outline the inefficacy of the process on the
      structural level (e.g. not enough resources to collect unused wheelchairs),
      operational level (e.g. absence of norms to recycle), strategic level (e.g.
      absence of policy to encourage people to give back their unused wheelchair) and
      systemic level (e.g. the state is not imputable). A quantitative approach with
      the 2nd and 3rd groups revealed high satisfaction with regard to the efficacy,
      appearance, safety, durability and comfort as well as the delivery and follow-up
      services rendered. PRACTICE IMPLICATIONS: The evaluation procedure herein
      proposed can be customized to fit other contexts and provides policy-makers with
      quick access to field data to help them choose the appropriate course of action.

PMID- 12619397
TI  - Compliance with administration procedures of tests for children with pervasive
      developmental disorders: does it exist?
AB  - BACKGROUND: There are no specific tools to evaluate functional performance that
      accommodate the special needs of children with pervasive developmental disorders
      (PDD). METHOD: Pediatric occupational therapists in Quebec were surveyed to
      identify assessments that are currently being used, the modifications made, and
      the use of results for treatment planning and service recommendations. RESULTS:
      Results from 59 therapists treating children with PDD indicated that 52 different
      assessments, both standardized and non-standardized, were used. Standardized
      tests were used infrequently and were rarely administered without modifications.
      Equal weight is attributed to the results from standardized and non-standardized
      tests and clinical observations for the purpose of treatment planning and
      services. PRACTICE IMPLICATIONS: This study highlights the need for practice
      parameters that would guide the assessment process and create a consensus among
      therapists and practice centres.

PMID- 12619398
TI  - Private practice: benefits, barriers and strategies of providing fieldwork
      placements.
AB  - BACKGROUND: Occupational therapists are entering private practice in ever
      increasing numbers. In order to gain the skills to practice in this area,
      students should have the opportunity to experience private practice fieldwork
      placements. However, the number offered in private practice settings continues to
      be limited. The purpose of this exploratory qualitative study was to identify the
      benefits, the barriers, and the strategies associated with providing fieldwork
      opportunities in private practice. METHODS: Data were obtained through semi
      structured interviews with six occupational therapists in private practice.
      RESULTS: Results indicated that participating in fieldwork education affords
      benefits to the profession of occupational therapy, to the clinician, and to the
      facility. Potential barriers included student characteristics, cost, time, travel
      and legalities. Involvement from the university and the private setting were
      considered necessary for providing and implementing strategies. CLINICAL
      IMPLICATIONS: The findings have implications for increasing private practice
      placements for future students in occupational therapy and other health care
      professions offering clinical placements as a component of their formal
      education.

PMID- 12619399
TI  - Well-being and older people: a review of the literature.
AB  - BACKGROUND: Most countries in the world are experiencing an expansion in their
      population of older people. As people now expect to live longer, they also seek
      continuing health and well-being throughout their extended old age. Occupational
      therapists are involved in working towards the attainment of well-being with
      their older clients. However, their understandings of what well-being for older
      people entails seems varied, as this examination of the occupational therapy and
      related gerontological literature reveals. RESULTS: Three key points emerge from
      the literature review: first, the definition of well-being is usually assumed, or
      is lacking in clarity, and a range of similar terms, such as happiness and life
      satisfaction, are used interchangeably; second, well-being has been measured in
      research using various scales, which may not capture the complexity of the
      concept; and third, the perspective of the older person is often missing in
      discussions of well-being. CLINICAL IMPLICATIONS: It is suggested that one way of
      moving occupational therapists' understanding of well-being forward is to conduct
      research into what older people themselves understand or perceive well-being to
      be.

PMID- 12619400
TI  - The more you do, the more you get. Interview by Adele Waters.

PMID- 12619401
TI  - Handing over.

PMID- 12619402
TI  - Bright sparks.

PMID- 12619403
TI  - Here for good. Animosity towards asylum seekers is bred in ignorance.

PMID- 12619404
TI  - Taken to heart.

PMID- 12619405
TI  - The first year of a problem-based learning curriculum.
AB  - This article examines the first 12 months (the common foundation programme) of a
      problem-based learning curriculum in an adult-branch nursing diploma programme
      based at the school of nursing at the University of Salford. An overview of the
      curriculum and operational issues of all three branches of the nursing diploma is
      given before examining an evaluation of adult branch programme.

PMID- 12619406
TI  - Benchmarking best practice in relapse management of multiple sclerosis.
AB  - The Midlands multiple sclerosis (MS) nurse group developed a benchmark for
      relapse management in MS, using the framework outlined in the DoH document
      Essence of Care (DoH 2001). The authors discuss the benchmarking process and
      demonstrate how specialist nurses can collaboratively establish best practice and
      influence the quality of care. The potential benefits of applying the
      benchmarking process to relapse management are discussed. Good practice for
      management of patients with relapsing MS has been developed.

PMID- 12619407
TI  - Nursing management of chest drains.
AB  - This article provides an overview of the essential physiology of the respiratory
      system to enhance understanding of the principles of intrapleural drainage.
      Indications for chest drain insertion, related signs and symptoms, potential
      complications and nursing reponsibilities are discussed.

PMID- 12619408
TI  - Clinical pinnacle.

PMID- 12619409
TI  - Frontiers of electrochemistry.

PMID- 12619410
TI  - The characterisation of supported platinum nanoparticles on carbon used for
      enantioselective hydrogenation: a combined electrochemical-STM approach.
AB  - The action of chiral modifiers like cinchonine and cinchonidine in facilitating
      enationselectivity in heterogeneous catalysis is investigated using a combination
      of electrochemical and scanning probe methods. The surface chirality of corner
      kink sites is suggested as being crucial for chirality recognition at supported
      catalyst nanoparticles. Other aspects of chirality in relation to one, two, three
      and four dimensions are also discussed.

PMID- 12619412
TI  - In situ observation of the surface processes involved in dissolution from the
      cleavage surface of calcite in aqueous solution using combined scanning
      electrochemical-atomic force microscopy (SECM-AFM).
AB  - The surface processes involved in the initial stages of the proton-assisted
      dissolution of the calcite single crystal cleavage plane (1014) have been
      identified using a combined scanning electro-chemical-atomic force microscope
      (SECM-AFM). This instrument employs a platinum-coated AFM probe, which functions
      as an electrode as well as a high-resolution topographical sensor. Dissolution in
      this arrangement is effected by the local electrogeneration of protons, produced
      by oxidation of water at the probe electrode. By careful control of the applied
      potential, it is possible to vary the magnitude of the electrogenerated flux of
      protons from the probe towards the calcite surface. Crucially, by generating a
      small proton flux for short time periods (0.5 s) it is possible to observe and
      monitor the initial sites in the dissolution process. Topographical images were
      recorded in the same area of the surface both prior to and after inducing
      dissolution, as a function of the proton flux. At low proton fluxes, of the order
      of 1 nmol cm-2s-1 or less, the surface was observed to dissolve by the nucleation
      of monolayer deep pits, with densities of about 10(8) cm-2. These pits are likely
      to be formed at point vacancies or atomic (impurity, for example) defects in the
      crystal lattice. As the proton flux was increased (over two orders of magnitude),
      these same etch pits were found to open into wider macro-pits, with an outline
      morphology that reflected the crystallographic orientation of the surface. At the
      highest proton fluxes, dissolution from macroscopic step edges became
      significant.

PMID- 12619411
TI  - Metal nanowire arrays by electrodeposition.
AB  - We describe two related methods for preparing arrays of nanowires composed of
      molybdenum, copper, nickel, gold, and palladium. Nanowires were obtained by
      selectively electrodepositing either a metal oxide or a metal at the step edges
      present on the basal plane of highly oriented pyrolytic graphite (HOPG)
      electrodes. If a metal oxide was electrodeposited, then nanowires of the parent
      metal were obtained by reduction at elevated temperature in hydrogen. The
      resulting nanowires were organized in parallel arrays of 100-1000 wires. These
      nanowires were long (some > 500 microns), polycrystalline, and approximately
      hemicylindrical in cross-section. The nanowire arrays prepared by
      electrodeposition were also "portable": After embedding the nanowires in a
      polymer or cyanoacrylate film, arrays of nanowires could be lifted off the
      graphite surface thereby facilitating the incorporation of metal nanowire arrays
      into devices such as sensors.

PMID- 12619413
TI  - Dynamics of full fusion during vesicular exocytotic events: release of adrenaline
      by chromaffin cells.
AB  - Vesicular exocytosis is important in the communication between cells in complex
      organisms. It controls the release of specific chemical or biochemical messengers
      stored in the emitting cell, which elicit a response upon detection by the target
      cells. Secretion of a messenger molecule (a neurotransmitter) was measured
      electrochemically, which allowed the quantification of cellular events and the
      validation of current physicochemical models. This model led us to formulate
      predictions about the occurrence and kinetics of vesicular exocytotic events
      based on the physicochemical meaning of its key parameters. These predictions
      were tested successfully through a series of experiments on chromaffin cells,
      involving changes of osmotic conditions, presence of trivalent ions and
      cholesterol-induced structuring of the cell plasmic membrane.

PMID- 12619414
TI  - A microscopic, continuous, optical monitor for interstitial electrolytes and
      glucose.
AB  - Ions, such as hydrogen (pH), sodium, or potassium, as well as metabolites, such
      as glucose or lactate, diffuse easily between blood in the capillaries and the
      interstitial fluid (ISF) residing between cells, and tissues. This work
      represents a synthesis of several unique concepts to achieve accurate,
      continuous, in vivo monitoring of critical ions and glucose in the ISF under the
      human skin. Ionic levels are monitored using optode technology that translates
      the respective concentrations into variable colors of ionophore/dye/polymeric
      liquid membranes. Glucose is monitored indirectly, by coupling through
      immobilized glucose oxidase with pH, that is then detected using a similar color
      scheme. The monitor consists of a tiny plastic bar ("sliver sensor"), 100-300
      microns wide and 1-15 mm long, placed just under the skin, with optical spots or
      stripes for each analyte as well as blanks for calibration. The colors are read
      and translated into concentration values by a watchlike device placed above the
      skin. Direct optical coupling between the in vivo sensing bar and the ex vivo
      detector device requires negligible power, and eliminates the need for wires or
      optical fibers crossing the skin. The microminiature sliver penetrates the skin
      easily and painlessly, so that the user could insert it him- or herself. No risk
      of track infection exists. We are reporting here on the first successful in vitro
      tests of this approach.

PMID- 12619416
TI  - Voltammetric exploration and applications of ultrasonic cavitation.
AB  - Voltammetric measurements carried out in the presence of power ultrasound are
      reviewed, and the physical processes responsible for the observed substantial
      augmentation of mass transport identified as resulting from a mixture of acoustic
      streaming and cavitation. The benefits conferred in electroanalysis or
      electrosynthesis of insonation simultaneous with electrolysis are summarised. The
      use of ultrafast ("nanosecond") voltammetric measurements to probe the nature of
      the interfacial cavitational bubble dynamics is described and shown to provide
      information not readily accessed by other experiments. Lastly, voltammetry in
      acoustically emulsified (organic/aqueous) media is discussed. This has
      considerable "green" potential for electrosynthesis, whilst the use of nanosecond
      voltammetry to probe the charge transferred as emulsion droplets impinge on the
      electrode allows a generic approach to the determination of the potential of zero
      charge of the latter.

PMID- 12619417
TI  - Regular irregularity in the transfer of anionic surfactant across the
      liquid/liquid interface.
AB  - Irregular current spikes and other anomalies seen in voltammetry of the transfer
      of anionic surfactants, alkyl sulfonates, and alkyl sulfates across the 1,2
      dichloroethane/water (DCE/W) interface are reproducible. The anomalies have a
      certain regularity that is predicted by a recently proposed concept, the
      electrochemical instability. Irregular current spikes follow after the
      augmentation of the current induced when the phase-boundary potential is brought
      close to the mid-point potential of the transferring surfactant ions. Potential
      step chronoamperometry clearly demonstrates the presence of the instability
      window, that is, the potential region where the interface becomes unstable only
      in the limited range of the phase-boundary potential.

PMID- 12619415
TI  - Electrochemical approaches for chemical and biological analysis on Mars.
AB  - Obtaining in situ chemical data from planetary bodies such as Mars or Europa can
      present significant challenges. The one analytical technique that has many of the
      requisite characteristics to meet such a challenge is electroanalysis. Described
      here are three electroanalytical devices designed for in situ geochemical and
      biological analysis on Mars. The Mars Environmental Compatibility Assessment
      (MECA) was built and flight qualified for the now cancelled NASA Mars 2001
      Lander. Part of MECA consisted of four "cells" containing arrays of
      electrochemical based sensors for measuring the ionic species in soil samples. A
      next-generation MECA, the Robotic Chemical Analysis Laboratory (RCAL), uses a
      carousel-type system to allow for greater customization of analytical procedures.
      A second instrument, proposed as part of the 2007 CryoScout mission, consists of
      a flow-through inorganic chemical analyzer (MICA). CryoScout is a torpedo-like
      device designed for subsurface investigation of the stratigraphic climate record
      embedded in Mars' north polar cap. As the CryoScout melts its way through the ice
      cap, MICA will collect and analyze the meltwater for a variety of inorganics and
      chemical parameters. By analyzing the chemistry locked in the layers of dust,
      salt, and ice, geologists will be able to determine the recent history of
      climate, water, and atmosphere on Mars and link it to the past. Finally,
      electroanalysis shows its abilities in the detection of possible microorganism on
      Mars or elsewhere in the solar system. To identify an unknown microorganism, one
      that may not even use Earth-type biochemistry, requires a detection scheme which
      makes minimal assumptions and looks for the most general features. Recent work
      has demonstrated that the use of an array of electrochemical sensors which
      monitors the changes in a solution via electrical conductivity, pH, and ion
      selective electrodes, can be used to detect minute chemical perturbations caused
      by the growth of bacteria and with the correct methodology provide unamibiguous
      detection of such life forms.

PMID- 12619418
TI  - The use of optical fiber bundles combined with electrochemistry for chemical
      imaging.
AB  - The present Review describes the progress made in using imaging optical fiber
      bundles for fluorescence and electrochemical-initiated chemiluminescence imaging.
      A novel optoelectrochemical micro-ring array has been fabricated and demonstrated
      for concurrent electrochemical and optical measurements. The device comprises
      optical fibers coated with gold via electroless gold deposition and assembled in
      a random array format. The design yielded an array of approximately 200 micro
      ring electrodes, where interdiffusional problems were minimized. The inner
      diameter of the ring electrode is fixed by the diameter of the individual optical
      fibers (25 microns), while the outer radius is determined by the thickness of the
      deposited gold. While all the fibers are optically addressable, they are not all
      electrochemically addressable. The resolution of this device is in the tens of
      micrometers range, determined by the diameter of the optical fiber (25 microns)
      and by the spacing between each electrically connected fiber. For the purpose of
      having well-behaved microelectrode characteristics, this spacing was designed to
      be larger than 60 microns. The array was characterized using ferrocyanide in
      aqueous solution as a model electroactive species to demonstrate that this
      microelectrode array format exhibits steady-state currents at short response
      times. This device has potential application to be used as an optoelectronic
      sensor, especially for the electrolytic generation and transmission of
      electrochemiluminescence, and was used to demonstrate that electrochemically
      generated luminescent products can be detected with the fiber assembly.

PMID- 12619419
TI  - Electrocatalytic oxidation of formic acid at an ordered intermetallic PtBi
      surface.
AB  - The electrocatalytic oxidation of formic acid at a PtBi ordered intermetallic
      electrode surface has been investigated using cyclic voltammetry, rotating disk
      electrode (RDE) voltammetry and differential electrochemical mass spectrometry
      (DEMS). The results are compared to those at a polycrystalline platinum electrode
      surface. The PtBi electrode exhibits superior properties when compared to
      polycrystalline platinum in terms of oxidation onset potential, current density,
      and a much diminished poisoning effect by CO. Using the RDE technique, a value of
      1.4 x 10(-4) cm s-1 was obtained for the heterogeneous charge transfer rate
      constant. The PtBi surface did not appear to be poisoned when exposed to a CO
      saturated solution for periods exceeding 0.5 h. The results for PtBi are
      discussed within the framework of the dual-path mechanism for the
      electrocatalytic oxidation of formic acid, which involves formation of a reactive
      intermediate and a poisoning pathway.

PMID- 12619420
TI  - Mechanistic aspects of on-line electrochemical tagging of free L-cysteine
      residues during electrospray ionisation for mass spectrometry in protein
      analysis.
AB  - The mechanistic details behind an electrochemically induced tagging of L-cysteine
      residues in peptides and proteins have been unravelled using cyclic voltammetry.
      It was found that when hydroquinone is oxidised in the medium used in
      electrospray ionisation mass spectrometry (ESI-MS) a protonated form of
      benzoquinone is produced that acts as an efficient electrophile for free L
      cysteine residues. Upon substitution of L-cysteine the reduced form of the adduct
      is formed, which may be further oxidised leading to further substitution of L
      cysteine. Digital simulations of the cyclic voltammograms corroborated the
      mechanism and allowed a determination of the homogeneous second order rate
      constant corresponding to the addition of L-cysteine onto the protonated form of
      benzoquinone. The selectivity of the tagging process was confirmed using ESI-MS,
      which showed that a protein without L-cysteine residues does not react with
      benzoquinone dissolved in the medium. Finally, the kinetic information obtained
      in this investigation is used to discuss the optimal parameters for a nanospray
      capable of quantitative tagging of L-cysteine residues.

PMID- 12619421
TI  - Etched electrochemical detection for electrophoresis in nanometer inner diameter
      capillaries.
AB  - Capillary electrophoresis in nanometer inner diameter capillaries allows for the
      analysis of extremely small volume samples, such as the contents of single cells.
      However, the utilization of these ultrasmall capillaries requires a very
      sensitive and low volume detector. An improved method for end-column amperometric
      detection for capillary electrophoresis in nanometer inner diameter (i.d.)
      capillaries is presented. This new method involves etching both the electrode and
      the detection end of the capillary. These design improvements allow for better
      alignment between the capillary bore and the electrode. As a result, dead volume
      in the detector is minimized. The etched method for electrochemical detection in
      ultrasmall capillaries provides average coulometric efficiencies of 70 +/- 10%
      for dopamine and 40 +/- 20% for catechol in 770 nm i.d. capillaries. Furthermore,
      this technique provides peak efficiencies as high as 100,000 theoretical plates
      and detection limits as low as 340 zmol for both dopamine and catechol.

PMID- 12619422
TI  - Finite-element analysis of magnetic field driven transport at inlaid platinum
      microdisk electrodes.
AB  - We describe a computer-assisted analysis of three-dimensional magnetohydrodynamic
      (MHD) fluid flow resulting from the passage of electrochemically generated charge
      through a uniform magnetic field. Magnetic field driven molecular transport in
      electrochemical systems offers a number of emerging opportunities in research and
      technology. For instance, electrochemical microfluidic transport and molecule
      trapping using magnetic fields and field gradients have been demonstrated in
      recent reports from this laboratory. A key limitation of these investigations is
      the difficulty in analyzing magnetic field driven flow and transport, due to the
      complexity of the governing equations of fluid mechanics, electrochemical
      molecular transport, and magnetic forces. In general, quantitative expressions
      describing the distribution and fluxes of electroactive species under the
      influence of a magnetic field cannot be obtained by a direct analytical solution.

PMID- 12619423
TI  - A randomized trial of botulinum toxin vs lidocain pomade for chronic anal
      fissure.
AB  - PURPOSE: As lateral sphincterotomy and anal dilatation causes complications, a
      reversible chemical sphincterotomy method has been recently proposed as an
      alternative treatment in patients with anal fissure. In this study, the effect of
      botulinum toxin causing temporary paralysis in internal anal sphincter was
      compared with that of lidocaine in patients with chronic anal fissure. METHOD: A
      total of 62 outpatients were randomly assigned to receive botulinum toxin or
      lidocaine pomade. The patients were evaluated before and after two months of
      treatment with physical examination and anal manometry. Pain and nocturnal pain
      were scored. RESULTS: In an evaluation period of two months, in 24 of 34 patients
      of botulinum group (70.58%), and in six of 28 patients of lidocaine group
      (21.42%) showed complete epithelization (p = 0.006). All patients who had
      previously reported nocturnal pain became symptom free in botulinum group and in
      four patients of lidocaine group. Pain following defecation disappeared in 24
      patients of botulinum group and in 20 patients of control group (p = 0.959).
      There was no adverse effect in both groups. While resting anal pressure and
      maximum voluntary pressure were significantly low in botulinum toxin group, both
      parameters did not change in lidocaine group. CONCLUSIONS: Botulinum toxin is a
      reliable and effective method for patients with chronic anal fissure. It can be
      applied easily without any anesthesia and instrumentation. It is cheaper in
      comparison with surgical methods and it can be a good alternative treatment in
      patients with risk of incontinence.

PMID- 12619424
TI  - Misoprostol induces gallbladder contraction during fasting, but does not
      influence postprandial emptying: an ultrasound study in healthy subjects.
AB  - OBJECTIVE: The aim of this study was to evaluate the effect of the PGE1 analogue,
      Misoprostol, on gallbladder fasting volume and meal-stimulated emptying.
      Prostaglandins' effects on the gallbladder were studied principally regarding
      mucus production during lithogenesis. In the few in vitro and in vivo studies,
      contradictory results concerning their influence upon gallbladder motility were
      obtained. SUBJECTS: 13 healthy subjects, 8 females, 5 males, aged 23.4 years
      (ranges 22-25). METHODS: Gallbladder volumes were assessed by ultrasound, after
      measuring the three diameters of the gallbladder in two perpendicular planes,
      using a conventional 2D equipment and a 3D equipment, after the 3D-reconstruction
      of the gallbladder. The volumes were calculated by means of the ellipsoid
      formula. Gallbladder emptying variables (residual volume, ejection fraction, area
      under emptying curve) were assessed during 90 minutes after a test meal (14 g
      fat, 425 kcal). Gallbladder emptying was evaluated in each subject on three
      different days: without prior Misoprostol administration, after 200 mg
      Misoprostol, and after 400 mg Misoprostol. Misoprostol was given orally as a
      single dose, 60 minutes before the meal. The two-tailed Student's t test for
      paired observations was used to compare the results. RESULTS: Misoprostol induced
      a significant decrease of the gallbladder fasting volume: from 12.8 +/- 4.4 (SD)
      ml (controls) to 9.1 +/- 3.6 ml (200 mg Misoprostol) and 5.4 +/- 2.6 ml (400 mg
      Misoprostol). Gallbladder meal-stimulated emptying was not influenced by
      Misoprostol. CONCLUSIONS: Our results indicated that, in healthy subjects,
      misoprostol induced a dose-dependent gallbladder emptying in the fasting state,
      but did not influence gallbladder postprandial emptying. Pre-prandial Misoprostol
      administration might be useful to treat gallbladder stasis in patients with
      chronic constipation, thus preventing gallstone formation.

PMID- 12619426
TI  - NASH/NAFLD management.

PMID- 12619425
TI  - The role of aminosalicylates in the treatment of ulcerative colitis.
AB  - Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the
      treatment of ulcerative colitis (UC). For acute treatment of mild to moderate
      flares and in maintenance treatment, their efficacy has been established. Since
      ulcerative colitis is limited to the distal colon in two thirds of the patients,
      topical therapy also plays an important role. In mild/moderate active disease 5
      ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is
      treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to
      4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally
      well tolerated. The risk of colorectal tumours is increased in patients with
      longstanding ulcerative colitis and epidemiological evidence indicates that
      chronic 5-ASA treatment reduces this risk. However, at present there is
      insufficient evidence to maintain patients on life-long 5-ASA maintenance
      treatment for this indication.

PMID- 12619427
TI  - Vasculitis and the gastrointestinal tract.
AB  - Vasculitis, defined as a non-infectious inflammatory disorder of blood vessels,
      can affect vessels of any type in any organ. The gastrointestinal (GI) tract may
      thus also be involved. In systemic disorders as mixed connective tissue disease
      (MCTD) and systemic lupus erythematodes (SLE), patients may present with symptoms
      of gastrointestinal disfunction such as motility disorders, caused by alterations
      in the connective tissue. True vasculitis however also occurs in the GI tract.
      Severe, occlusive damage often leads to ischemia that may result in ulceration
      and perforation. Non-occlusive vascular disease may lead to vascular leakage
      resulting in oedema and haemorrhage. Those patients often present with diarrhoea
      or symptoms of bleeding. GI involvement is frequent in Henoch-Schonlein purpura
      and also often noted in polyarteritis nodosa (PAN), microscopic polyangiitis,
      Wegener's syndrome and Churg-Strauss syndrome. Furthermore, GI vasculitis has
      also been described in giant cell arteritis, Takayasu's disease, Buerger's
      disease and leucocytoclastic vasculitides as essential mixed cryoglubulinemia,
      lupus vasculitis, rheumatoid disease, MCTD, drug-induced vasculitis and Behcet's
      disease. The diagnosis and classification of vasculitis relies upon a combination
      of clinical, serological, haematological, radiological and histological findings.
      Establishing a precise diagnosis can be difficult but is important because
      treatment and prognosis can be highly variable.

PMID- 12619428
TI  - Vascular lesions of the gastrointestinal tract.
AB  - Vascular lesions of the gastrointestinal (GI) tract include arterio-venous
      malformations as angiodysplasia and Dieulafoy's lesion, venous ectasias (multiple
      phlebectasias and haemorroids), teleangiectasias which can be associated with
      hereditary hemorrhagic teleangiectasia (HHT), Turner's syndrome and systemic
      sclerosis, haemangioma's, angiosarcoma's and disorders of connective tissue
      affecting blood vessels as pseudoxanthoma elasticum and Ehlers-Danlos's disease.
      As a group, they are relatively rare lesions that however may be a major source
      of upper and lower gastrointestinal bleeding. Clinical presentation is variable,
      ranging from asymptomatic cases over iron deficiency anaemia to acute or
      recurrent bleeding that may be life-threatening. Furthermore, patients may
      present with other symptoms, e.g. pain, dysphagia, odynophagia, the presence of a
      palpable mass, intussusception, obstruction, haemodynamic problems resulting from
      high cardiac output, lymphatic abnormalities with protein loosing enteropathy and
      ascites, or dermatological and somatic features in syndromal cases. Diagnosis can
      usually be made using endoscopy, sometimes with additional biopsy. Barium
      radiography, angiography, intraoperative enteroscopy, tagged red blood cell scan,
      CT-scan and MRI-scan may offer additional information. Treatment can be
      symptomatic, including iron supplements and transfusion therapy or causal,
      including therapeutic endoscopy (laser, electrocautery, heater probe or injection
      sclerotherapy), therapeutic angiography and surgery. The mode of treatment is of
      course depending on the mode of presentation and other factors such as associated
      disorders. If endoscopic or angiographic therapy is impossible and surgical
      intervention not indicated, pharmacological therapy may be warranted. Good
      results have been reported with different drugs, albeit most of them have not
      been tested in large trials.

PMID- 12619429
TI  - Acute mesenteric ischemia: classification, evaluation and therapy.
AB  - Mortality rates of acute mesenteric ischemia still range between 60 and 100%.
      Unfortunately, retrospective series have not shown any significant improvement in
      mortality in the past decades. With approximately 50%, superior mesenteric artery
      (SMA) embolism is the most common form of acute mesenteric ischemia, followed by
      SMA thrombosis (approximately 25%), nonocclusive mesenteric ischemia
      (approximately 20%) and mesenteric venous thrombosis (approximately 5%). Clinical
      presentation may be unspecific, but is often characterised by an initial
      discrepancy between severe subjective pain and relatively unspectacular findings
      on physical examination. The key to a better outcome (and the main problem in
      clinical practice) is early diagnosis. Up to now, helas, there are no simple and
      noninvasive diagnostic tests of sufficient sensitivity and specificity. Thus,
      angiography remains the cornerstone of diagnosis and should be performed early in
      all patients with a risk profile and a clinical presentation suspicious of AMI.
      The initial therapeutic step in all patients with AMI is resuscitation and a
      stabilization of circulation. If an advanced stage of ischemia is suspected,
      broad spectrum antibiotics have to be given. Nonocclusive mesenteric ischemia
      without signs of peritoneal infarction may be managed by pharmacological
      vasodilation, and vasodilators are also considered as a valuable supportive
      treatment option in patients with obstructive mesenteric ischemia. Patients with
      mesenteric venous thrombosis have to be treated by immediate anticoagulation,
      followed by laparotomy if peritoneal signs are present. Standard treatment for
      patients with obstructive mesenteric arterial syndromes is a laparotomy with
      embolectomy or revascularization and, if indicated, resection of infarcted bowel.
      -. This review will give an overview on the different forms of mesenteric
      ischemia and then focus on the diagnosis and on generally recommended forms of
      treatment.

PMID- 12619430
TI  - Vascular lesions of the liver and gastrointestinal tract.
AB  - In the liver, imaging can show lesions of large and medium-sized vessels,
      perfusion disorders related to vascular lesions, and parenchymal lesions
      including infarcts, regenerative nodules, and focal nodular hyperplasia. In the
      gastrointestinal tract, vascular lesions often result in bowel ischemia. Imaging
      can be used to show the vascular lesions and bowel wall abnormalities, including
      mural thickening, lack of perfusion, and pneumatosis. Doppler sonography,
      multislice helical computed tomography (CT), magnetic resonance (MR) imaging, and
      angiography are useful to demonstrate vascular lesions. Doppler sonography offers
      high spatial and temporal resolution. Information about blood flow and velocity
      can be obtained. However, the visualization of retroperitoneal vessels is often
      limited because of intestinal gas. A global view of the abdominal vasculature can
      be observed by using helical CT. High spatial and temporal resolution are
      obtained, especially when new multislice CT scanners are used. MR imaging has a
      better contrast resolution than CT, but its spatial resolution is lower. MR
      imaging can also be used to measure flow with phase contrast methods. The role of
      arteriography in the diagnosis of vascular lesions is decreasing. However, its
      role remains important to definitively demonstrate obstruction of the hepatic
      artery and to show arterial lesions in acute mesenteric ischemia. In addition, it
      is used as a problem-solving method to detect lesions in medium-sized vessels and
      to guide intravascular treatment.

PMID- 12619431
TI  - Pregnancy and inflammatory bowel disease.
AB  - Overall, around 25% of women with inflammatory bowel disease will conceive during
      their disease. Most of the women with inflammatory bowel disease will have a
      normal pregnancy and healthy children. However, specific problems may arise
      related to these pregnancies. This paper reviews what is known on fertility, risk
      of disease transmission, effect of the disease on the pregnancy and the reverse,
      delivery, medical follow up and treatment as well as breastfeeding in the setting
      of inflammatory bowel disease.

PMID- 12619432
TI  - Economic evaluation of chronic hepatitis C treatment by interferon-ribavirin
      combination therapy in Belgium.
AB  - With present treatments for chronic hepatitis C by the combination of interferon
      alpha and ribavirin, it is possible to obtain a sustained viral response in a
      large number of patients. This viral response is associated with long-term
      disappearance of the C virus, improvement of histology, improvement in quality of
      life and, most than likely, a reduction in the risk of premature death or
      infection-linked complications. This therapy is, however, expensive and the
      number of potentially treatable patients is high in view of the relatively high
      prevalence of the disease in the population. An economic evaluation is thus
      indispensable in order, on the one hand, to assess the cost-effectiveness ratio
      of the treatment (i.e. the extra cost to be paid for obtaining the greater
      effectiveness provided by the therapeutic combination in comparison with absence
      of treatment or treatment by interferon alone), and, on the other hand, to
      estimate practically the global cost of treatment for Belgium (i.e. the annual
      expense for society according to the number of patients treated per year).

PMID- 12619433
TI  - Primary neutrophil-rich, CD30-positive anaplastic large cell lymphoma of the
      stomach: case report and review of the literature.
AB  - Primary T-cell lymphoma of the stomach is a rare disease, most gastric lymphomas
      being of B-cell type. Here we describe a unique case of primary neutrophil-rich
      CD30-positive anaplastic large cell lymphoma (ALCL) of the stomach that was
      treated and cured by combined chemotherapy. According to our literature review,
      only 7 cases of primary gastric ALCL have been previously reported, none of them
      being of the neutrophil-rich subtype. Although very peculiar in its histological
      presentation, which may simulate an inflammatory or carcinomatous process, the
      natural history as well as the clinical features of this unusual gastric lymphoma
      does not differ from the other reported cases of gastric ALCL.

PMID- 12619435
TI  - Hypoplasia of the right hepatic lobe and portal hypertension. A forty years
      follow-up.

PMID- 12619434
TI  - Cyclospora cayetanensis associated with diarrhea in a patient with idiopathic
      compensated hepatic cirrhosis.
AB  - A 52 year-old male patient with idiopathic hepatic cirrhosis complaining of
      diarrhea and weakness was accepted to the gastroenterology clinic. In order to
      find out the causative etiologic agent of diarrhea, stool samples were examined
      by different methods and stained using modified Kinyoun's acid-fast stain.
      Following examination, approximately 9 microns diameter, acid-fast variable
      wrinkled spheres were seen and diagnosed as Cyclospora cayetanensis. Confirmation
      of the diagnosis was established by fluorescent microscope (380 to 420 nm
      excitation filter), which showed bright green to intense blue autofluorescent
      oocysts. It has been shown that, Cyclospora cayetanensis is a coccidian parasite
      mainly found in immunocompromised patients and that it may be the agent of
      prolonged diarrhea. Only three cyclosporiosis cases have been previously reported
      in our country; all three cases were AIDS patients. We report here a further case
      of Cyclospora cayetanensis infection in a patient with hepatic cirrhosis and we
      consider that this is the first case, which was reported in hepatic cirrhosis.

PMID- 12619436
TI  - [The Brill-Zinsser disease still occurs in Croatia: retrospective analysis of 25
      hospitalized patients].
AB  - The article presents epidemiological, clinical, laboratory and therapeutic
      characteristics of Brill-Zinsser disease (BZD). A total of 25 cases of BZD were
      retrospectively analyzed during the period from January 1, 1980 through December
      31, 2000, and etiology was confirmed by rickettsial complement-fixation test
      (CFT). The majority of cases 15 (60%) quoted history of primary attack of
      epidemic typhus during or after the World War II. During the course of the
      disease in our patients different organic systems were involved. Aseptic
      meningitis was verified in 21 (84%) patients, rash in 17 (68%), liver lesion in
      14 (56%), pneumonitis in 7 (28%), myopericarditis in 7 (28%) and 5 (20%) had
      renal lesion. Not a single clinical symptom or finding of disease has a
      diagnostic particularity. However, long term fever, headache, rash and aseptic
      meningitis, or information of infestation with lice in childhood, or a history of
      epidemic typhus should arouse a suspicion of this disease, which still occurs in
      Croatia.

PMID- 12619437
TI  - [Anesthesiology and economics].
AB  - The reform of government financing of health services has caused a lot of
      significant changes in hospitals. The main points of the reform are limited
      hospital expenses, and reduced financial calculation. The following three factors
      are influencing upon hospital expenses is the only factor that hospital
      management can effectively influence upon. Therefore, management and running of
      financial services are the most responsible and significant for hospital
      prosperity. The most convenient and prospective way of payment restriction is
      expenses accounting according to the case of treatment. Furthermore, general
      expenses should be reduced too. However, economic evaluation should include the
      analysis of alternative therapeutic possibilities in the framework of expenses,
      and the outcome of treatment. Following all these, it has been shown how it is
      possible to reduce the expenses at the Department of Anesthesiology. There are
      potential factors of savings such as low-flow anesthesia, ABC-analysis of
      expenses etc. Other ones are staff expenses, that include improvement of working
      process and adaptable time-table. Pharmaco-economical evaluation of the new drugs
      has shown how analysis of expenses structure could be acceptable in the scope of
      anesthesiology. Because of the permanent deficit of financial resources,
      permanent decentralized control is indispensable.

PMID- 12619438
TI  - [Risks for measles and mumps in recruits of the Croatian army].
AB  - In order to estimate the transmission risk of measles and mumps viruses and a
      possible change in the strategy of vaccination against these infectious diseases,
      seroprevalence of antibodies to measles and mumps was determined in the
      population of young adults, i.e. in the recruits of the Croatian Army. Factors
      that may influence the state of immunity were analyzed as well. The study was
      performed during 1995 and 1996, comprising a total of 300 recruits. The
      serological part of the study included 260 conscripts. The status of antibodies
      was evaluated using commercially available ELISA tests for the detection of IgG
      antibodies in blood. Seronegativity rates measured 40.80% for measles and 8.80%
      for mumps. With regard to specific age groups (18-19; 20-24; over 25)
      seronegativity rates were similar for both diseases in all subjects. It has been
      confirmed by this study that the place of birth and residence does not have any
      significant influence upon the rate of infections in the recruits. The results of
      the study show that there is a very high risk of measles and mumps infection in
      the military. This finding indicates that the introduction of additional
      vaccination for the high-risk population groups should be considered, against
      measles in particular. The detected differences in the degree of immunity to
      measles and mumps (vaccination of which is performed simultaneously) indicate a
      need for additional epidemiological and serological studies that should be
      performed using other laboratory techniques. The fact that soldiers do not have
      medical records on vaccination, and that anamnestic data on disease contraction
      and vaccination are unreliable, suggests that the regulations on the keeping of
      vaccination records in Croatia should be implemented in a more consistent way.

PMID- 12619439
TI  - [Bronchial reactivity in patients with seasonal allergic rhinitis].
AB  - The allergic rhinitis (AR) is an important risk factor for the development of
      asthma. In significant number of patients with AR, the non-specific bronchial
      hyperresponsiveness (BHR) could be demonstrated. It has been anticipated that
      these patients were at the greater risk for asthma. This study was aimed to
      determine the frequency and intensity of BHR in patients with seasonal AR (SAR)
      due to Wall pellitory allergy. The patients who were sensitized solely to
      Parietaria officinalis (Wall pellitory) pollen allergen were recruited in the
      study, namely patients with SAR (n = 26), SAR with seasonal asthma (n = 23) as
      well as healthy volunteers (n = 10). In all subjects the clinical check-up,
      spirometry and bronchial challenge test with metacholine were performed before,
      during the peak, and after the peak of pollination of pellitory. Comparing to
      initial findings (23%), in patients with SAR the prevalence of BHR significantly
      increased during the peak of pollination (50%, p = 0.0039), and remained
      increased thereafter (43%, p = 0.0319). In patients with SAR and asthma
      prevalence and intensity of BHR was even higher with the similar seasonal
      variations. Comparing to initial findings (83%), the prevalence of BHR
      significantly increased during the peak of season (100%, p = 0.0001), and
      remained increased thereafter (87%, p = 0.061). In both groups of patients the
      intensity of BHR (median PC20) increased as well: 4.8, 2.05, and 2.45 mg/mL in
      patients with SAR, and 0.35, 0.16, and 0.20 mg/mL in patients with SAR and
      asthma. In healthy volunteers no significant BHR was observed. The results of the
      present study confirm significant prevalence of BHR in patients with SAR due to
      pellitory allergy. It is important to determine BHR in patients with SAR and
      without asthma because the appropriate pharmacotherapeutic and preventive
      measures (anti-inflammatory medication and specific immunotherapy) could prevent
      the development of asthma in these patients.

PMID- 12619440
TI  - [Endocarditis associated with atrial and ventricular cardiac pacing leads. Case
      report].
AB  - The infection of a transvenous lead implanted for cardiac stimulation is a rare,
      but serious complication. We report observation of a 25-year old man whose
      Staphylococcus epidermidis sepsis linked to endocarditis was related to atrial
      and ventricular pacing leads, and was diagnosed after two months of medical
      treatment. The most important role during the diagnostic process was played by
      the echocardiographic examination, especially transoesophageal, which revealed
      the large vegetations on atrial as well as ventricular pacing lead. The diagnosed
      condition was treated by complete removal of pacing system using open chest
      surgery and cardiopulmonary pump. After four weeks of vigorous antibiotic
      treatment, a new DDDR pacing system was implanted, but with epicardial leads.

PMID- 12619441
TI  - [Hepatitis E in tourists to India].
AB  - Hepatitis E (HE) is a serious problem in developing countries worldwide,
      affecting in epidemics or as sporadic cases millions of people. Hepatitis E virus
      (HEV) is the main cause of enterically transmitted acute viral hepatitis,
      especially in tropic and subtropic areas. We presented two patients, our citizens
      who traveled to India, and contracted HE. The source of infection was
      contaminated drinking water in both of them. The diagnosis of HE was confirmed by
      the finding of anti-HEV antibodies of class IgG and IgM (ELISA) in acute phase,
      and by dissappearing of IgM anti-HEV in convalescent period. Thus, these patients
      are the first documented cases of imported sporadic HE in Croatia.

PMID- 12619442
TI  - [Overview and methods for determination of antiplatelet antibodies and
      thrombocyte antigens].
AB  - The last twenty years have been characterized by great interest in the study of
      the role of antiplatelet antibodies and platelet antigens in the mechanism of
      thrombocytopenia. The use of numerous serologic methods for the determination of
      antiplatelet antibodies has contributed to the better understanding and
      differential diagnosis of immunologically induced thrombocytopenias. Development
      of the methods of molecular biology has allowed for a more accurate determination
      of platelet antigens and assessment of the prevalence of particular antigens in
      the population. These concepts have improved the possibilities of evaluation of
      particular antigenic systems in the genesis of auto- and alloimmune
      thrombocytopenic syndromes. Although majority of tests for determination of
      antiplatelet antibodies were initially introduced for antibody demonstration in
      patients with idiopathic thrombocytopenic purpura, these methods are now employed
      for all diseases associated with platelet impairments, when an immunologic
      pathomechanism of the disease onset is suspected. The methods are mostly used in
      serodiagnosis of neonatal thrombocytopenic purpura, posttransfusion purpura and
      refractoriness to platelet transfusion, and primary and secondary autoimmune
      thrombocytopenia.

PMID- 12619444
TI  - [New findings in acupuncture therapy].
AB  - Acupuncture is an ancient method of healing coming from the Chinese traditional
      medicine. In Western medical science it is accepted and proven method of healing
      based on neurophysiological, neurobiochemical and neuroendocrinological research.
      Acupuncture as a method of healing has been accepted also by the World Health
      Organisation with strongly defined indications and contraindications. Indications
      for acupuncture included: acute and chronic pain syndrome, allergic disorders,
      addiction, psychosomatic and psychosexual illness and acupuncture
      analgesia/anaesthesia. It is very important that there are no harms of
      acupuncture treatment, although mild side effects are possible. Acupuncture is
      based on characteristics of meridian points, afferent nerve information evoked by
      acupuncture stimulation, inhibitory mechanisms in the central nervous system,
      endogenous antinociceptive substances concerned with acupuncture analgesia and
      descending mechanisms of antinociceptive control.

PMID- 12619443
TI  - [Mouth dryness (xerostomia)--causes, diagnosis and therapy].
AB  - Xerostomia or dry mouth is a state of decreased salivary flow rate in the oral
      cavity, i.e. symptom which could be caused by various systemic diseases and
      states, as well as iatrogenically. The importance of recognizing xerostomia
      results in better conditions in the oral cavity, because loss of saliva manifests
      itself in frequent infections in the oral cavity, rampant caries, especially of
      the cervical parts of the teeth, inflammation of the major salivary glands,
      various unspecific symptoms as well as decreased ability to speak and eat.

PMID- 12619445
TI  - Role of coccidian parasites in causation of diarrhoea in HIV infected patients in
      Chennai.
AB  - BACKGROUND & OBJECTIVES: Diarrhoea is one of the major problems of HIV positive
      patients. A coproparasitological study was carried out to assess the role of
      coccidian parasites in the causation of diarrhoea in HIV infected patients in
      Chennai. METHODS: During May 2000 to January 2001, 152 stool samples from HIV
      seropositive individuals (43 with acute diarrhoea, 59 with chronic diarrhoea, 50
      without diarrhoea) and 50 normal individuals without diarrhoea were examined for
      enteric coccidian and other intestinal parasites by microscopy and special
      staining methods. RESULTS: A total of 52 enteric parasites, 15 from patients with
      acute diarrhoea and 24 from patients with chronic diarrhoea, 7 from patients
      infected with HIV without diarrhoea and 6 from normal individuals without
      diarrhoea were detected from 49 patients. Isospora belli was detected in 14 of
      102 (13.7%) patients with acute and chronic diarrhoea. The association with
      diarrhoea among HIV positive individuals was significant (P < 0.001).
      Cryptosporidium was detected in 7 patients each with acute and chronic diarrhoea
      and 4 patients with HIV infection without diarrhoea, its association with
      diarrhoea among HIV patients was found to be not significant in the present
      study. Cyclospora and Microsporidia each were detected in only one HIV positive
      patient with chronic diarrhoea. INTERPRETATION & CONCLUSION: The study revealed
      that the coccidian parasites are one of the important etiologic agents of
      diarrhoea (P < 0.001) especially of chronic diarrhoea among HIV positive
      patients. Isospora belli was found to be a frequent enteric parasite associated
      with diarrhoea among HIV positive patients in Chennai.

PMID- 12619447
TI  - Quinolone susceptibility of Vibrio cholerae O1 & O139 isolates from Vellore.
AB  - BACKGROUND & OBJECTIVES: Vellore is an endemic area for cholera. The relative
      prevalence of clinical cases of Vibrio cholerae O1 and O139 has been fluctuating.
      Few studies have examined the susceptibility of local isolates to quinolones. The
      objective of the present study was to look at quinolone susceptibility and
      determine MIC of ciprofloxacin to representative clinical isolates of V. cholerae
      O1 and O139 in Vellore, obtained between 1997 and 1999. METHODS: Antimicrobial
      susceptibility testing of V. cholerae strains was performed by disc diffusion
      technique and MIC determination by E test. RESULTS: Five of 30 O1 and all the
      O139 serogroup isolates were susceptible to nalidixic acid. All isolates of both
      serogroups were sensitive to norfloxacin. All isolates of both serogroups gave
      MIC results in the susceptible range to ciprofloxacin; the MICs being lower for
      V. cholerae O139 (MIC50 = 0.004 microgram/ml and MIC90 = 0.047 microgram/ml) than
      for O1 serogroup (MIC50 = 0.38 microgram/ml and MIC90 = 0.5 microgram/ml).
      INTERPRETATION & CONCLUSION: V. cholerae O1 and O139 show differences in
      quinolone susceptibility, the reason for this is not clear. This could be because
      of longer exposure of the O1 serogroup to quinolone antimicrobials as compared to
      the O139 serogroup.

PMID- 12619446
TI  - Increased number of CCR5+ CD4 T cells among south Indian adults probably
      associated with the low frequency of X4 phenotype of HIV-1 in India.
AB  - BACKGROUND & OBJECTIVE: The shift of the human immunodeficiency virus (HIV) from
      nonsyncytium inducing strains (NSI/R5) to syncytium inducing strains (SI/X4) seen
      in subtype B infections during progression to acquired immunodeficiency syndrome
      (AIDS) is less frequently reported in subtype C. NSI and SI strains differ in the
      co-receptor they utilize to infect a T-cell. We postulated that a larger pool of
      CD4 T cells expressing CCR5 would be present among individuals in the Indian
      population. To validate this hypothesis, we estimated the percentage of CD4 cells
      expressing CCR5 or CXCR4 molecules among healthy south Indian adults and HIV
      infected individuals. METHODS: HIV-1 infected and uninfected adult volunteers,
      belonging to the four southern states of India with Tamil/Malayalam/Kannada or
      Telugu as their spoken language were prospectively recruited. A two colour
      flowcytometry examination of the blood sample was done using the following
      monoclonals; anti-CD45 (FITC)/CD14 (PE), anti IgG1 (FITC)/IgG2a (PE), anti-CD3
      (FITC)/CD4 (PE), anti-CD3 (FITC)/CD8 (PE), anti-CD4 (FITC) and anti CCR5 (PE) or
      anti CXCR4 (PE). RESULTS: In the healthy population (n = 30) studied, 24.6 per
      cent of CD4 T cells expressed CCR5 and the percentage of CD4 T cells expressing
      CXCR4 was 80.4. Among the HIV infected individuals (n = 51) the percentage of CD4
      T cells expressing CCR5 and CXCR4 was 26.8 and 78.7 per cent respectively.
      INTERPRETATION & CONCLUSION: The percentage of CD4 cells expressing CCR5 and
      CXCR4 in both the HIV uninfected and infected adults was significantly higher in
      the south Indian population than in the West. The larger pool of CCR5 positive
      CD4 cells probably allows for the R5 HIV strain to have a replication advantage
      over X4 HIV strains. This may explain the lack of shift in the viral phenotype
      during disease progression and also the perceived rapid progression of the
      disease in India compared to the West.

PMID- 12619448
TI  - Photodynamic inactivation of antibiotic resistant strain of Pseudomonas
      aeruginosa by porphyrins induced by delta-aminolaevulinic acid.
AB  - BACKGROUND & OBJECTIVES: The widespread occurrence of antibiotic resistant
      strains of Pseudomonas aeruginosa in hospitals is a matter of growing concern. We
      report the results of a study on photodynamic inactivation of antibiotic
      resistant strain of P. aeruginosa by delta-aminolaevulinic acid (ALA). METHODS:
      Exponentially growing P. aeruginosa cells were incubated in growth medium with
      ALA for various durations. Subsequently, the cells were washed and resuspended in
      phosphate buffered saline (PBS). These cells were incubated with different
      concentrations of glutathione (GSH) in PBS for 15 min. Porphyrins synthesized
      with and without GSH were detected by fluorescence spectroscopy. The ALA treated
      cells were irradiated with light at 405 nm with and without subsequent incubation
      in GSH. Cell survival was measured by colony forming ability. RESULTS: Incubation
      of cells in growth medium with ALA led to increased synthesis of protoporphyrins
      in cells which saturated beyond 4 h. The level of protoporphyrin synthesis
      increased significantly when ALA treated cells were subsequently incubated with
      GSH in PBS for 15 min. Irradiation of cells incubated with ALA alone led to weak
      inactivation. However, substantial cell death was observed in ALA treated cells
      irradiated in the presence of 15 mM GSH. INTERPRETATION & CONCLUSION:
      Photodynamic inactivation of P. aeruginosa by ALA induced porphyrins can be
      enhanced if ALA treated cells are further incubated with GSH and irradiated using
      405 nm light. These findings may be useful for inactivation of antibiotic
      resistant strains of P. aeruginosa causing burn and wound infections in
      hospitalized patients.

PMID- 12619449
TI  - See & treat protocol for evaluation & management of cervical intraepithelial
      neoplasia.
AB  - BACKGROUND & OBJECTIVES: The incidence of cervical cancer in India remains high,
      largely due to ineffective screening and poor patient compliance for follow up. A
      one step procedure where evaluation and treatment are performed at the same
      sitting may be a good strategy. Therefore the present study was undertaken to
      evaluate the feasibility of a see and treat protocol for cervical intraepithelial
      neoplasia in a hospital population. METHODS: A prospective study was carried out
      on 285 women with using cytology and colposcopy followed by large loop excision
      of the transformation zone when indicated as a one step procedure. RESULTS: There
      was a concordance between colposcopic and cytologic diagnosis. Eighteen women
      underwent large loop excision. Over treatment rate was 61 per cent but 80 per
      cent of them occurred in the low grade squamous intraepithelial lesions. The over
      treatment rate in high grade lesions was 20 per cent. INTERPRETATION &
      CONCLUSION: A single step see and treat protocol is a feasible management
      strategy for high grade squamous intraepithelial lesions. However, patient
      education is essential before undertaking the procedure.

PMID- 12619450
TI  - Voluntary alcohol drinking & caloric intake in rats exposed to crowding stress.
AB  - BACKGROUND & OBJECTIVES: Alcohol intake in animals is regulated in much the same
      way as intake of food. The effect of alcohol on feeding behaviour is not well
      documented. The objective of this study was to test whether alcohol was ingested
      as a source of calories after crowding stress in rats. METHODS: Male albino rats
      were exposed to crowding stress continuously for two weeks and the effect of
      stress on the body weight, food intake, voluntary alcohol consumption and caloric
      intake in terms of food and alcohol was studied. RESULTS: A significant decrease
      in the body weight was seen after one (P < 0.05), 7 and 14 days (P < 0.01) of
      stress compared to controls. Food intake decreased significantly (P < 0.01) after
      one day of stress and there was recovery after 7 days stress. Absolute alcohol
      intake (g/kg body weight) increased significantly (P < 0.001) after one day of
      stress. Prolonged stress for two weeks significantly (P < 0.01) increased the
      alcohol consumption. Total caloric intake in stressed rats decreased
      significantly (P < 0.001) after acute stress. After 14 days, stressed rats showed
      significant (P < 0.001) increase in total caloric intake compared to day one.
      INTERPRETATION & CONCLUSION: Crowding stress decreased the body weight gain
      throughout the period of stress. Chronic stress for two weeks increased the
      voluntary alcohol consumption and total caloric intake. Food intake alone seemed
      insufficient to provide the extra demand of energy due to prolonged stress and
      hence, the rats may be drinking increasing amounts of alcohol (when provided) to
      supply the extra energy required to combat stress.

PMID- 12619451
TI  - Smallpox vaccine is here: avoid 3 'worst-case scenarios' in your ED.
AB  - Your staffing and patient care will be affected dramatically by the smallpox
      vaccination program, so you'll need to educate the entire ED staff and plan for
      scheduling changes. Vaccinate staff in small groups to avoid major staffing
      problems. You'll always need to schedule a vaccinated nurse at triage. Most of
      your staff could become ill with side effects from the vaccine.

PMID- 12619453
TI  - Keep your nurses from choosing another ED.
AB  - Emergency department (ED) nurses are increasingly choosing to work at hospitals
      certified by the Magnet Nursing Recognition Program of the American Nurses
      Credentialing Center, and more than 60 hospitals have this certification. To
      avoid losing nurses, adopt some of their ideas. Use committees with ED nursing
      representation to develop policies. Offer nursing grand rounds to give nurses the
      opportunity to present on a variety of topics. If nurses don't want to complete a
      degree, offer incentives, such as reimbursement for health club memberships, for
      completed projects.

PMID- 12619452
TI  - Dramatic changes needed to address vaccine plan.

PMID- 12619454
TI  - Warning: conflicts may result in more vacancies.
AB  - A new study underscores the risk of losing nurses to other facilities because of
      conflict with physicians. Instruct staff to be clear about their needs. If you
      have to confront a disruptive staff member, do so without delay. Ask both parties
      to brainstorm for solutions.

PMID- 12619456
TI  - Joint Commission urges protocols for meningitis.

PMID- 12619455
TI  - Novel strategies to handle nonemergent ED visits.
AB  - Although a study reports that most emergency department (ED) visits are not
      emergencies, experts in ED management counter that caring for nonemergent
      patients is part of the ED's role. Patients will continue to rely on the ED for
      unscheduled care. Implement urgent care centers or fast tracks to handle less
      acute patients. Physician triage allows patients to be rapidly discharged.

PMID- 12619457
TI  - Surprise! Are you ready for a random survey?

PMID- 12619458
TI  - The turbinates in nasal and sinus surgery: a consensus statement.

PMID- 12619459
TI  - Obscure temporal bone fracture with conductive hearing loss.

PMID- 12619460
TI  - Symptomatic bilateral nasolacrimal duct cysts in a newborn.

PMID- 12619461
TI  - Vocal fold pseudocysts.

PMID- 12619462
TI  - Electronystagmography in a 74-year-old woman with vertigo.

PMID- 12619463
TI  - Wegener's granulomatosis of the nasal cavity.

PMID- 12619464
TI  - 'Steakhouse syndrome' in a man with a lower esophageal ring and a hiatal hernia.

PMID- 12619465
TI  - Cystic chondromalacia of the ear.

PMID- 12619466
TI  - Relative value units.

PMID- 12619467
TI  - The prevention of fire during oropharyngeal electrosurgery.
AB  - We report the results of our study of 25 children who underwent tonsillectomy
      and/or adenoidectomy under endotracheal general anesthesia with respect to their
      risk of fire in the oropharynx. We also attempt to explain the reasons for the
      difference between the relatively high incidence of airway explosions and fires
      that have occurred during tracheostomy with electrosurgery and electrocautery and
      the low incidence of these events during electrosurgical dissection of the
      tonsils. Finally, we review the precautions that physicians can take to lower the
      risk of operating-room fires and explosions.

PMID- 12619468
TI  - The Stout prosthesis: an alternate means of restoring speech in selected
      laryngectomy patients.
AB  - We discuss the effectiveness of the Stout prosthesis, a device that was developed
      more than 30 years ago to restore speech in postlaryngectomy patients. This
      prosthesis has not been previously described in the literature. The placement of
      this device entails the creation of a pharyngeal cutaneous fistula that extends
      to the musculature at the base of the tongue. The prosthesis is then used to
      connect the fistula and the stoma. Central to this discussion was our evaluation
      of a patient who had used the Stout prosthesis for 30 years. In this patient, the
      prosthesis produced excellent long-term voice production with minimal leakage of
      saliva or other liquids. We conclude that in light of the device's simplicity,
      low cost, and minimal maintenance requirements with regard to the fistula site,
      the Stout prosthesis should be considered as an alternative to the standard
      tracheosophageal puncture method for patients who are unable to comply with the
      latter's maintenance requirements and for those in poorly developed countries
      where costs and hygiene are paramount considerations. Moreover, because the Stout
      technique does not involve the esophagus and does not require invasive procedures
      around the stoma, it is also practical for patients who have esophageal rigidity
      or stomal problems.

PMID- 12619469
TI  - Modified tubeless anesthesia during endoscopy for assessment of head and neck
      cancers.
AB  - We evaluated a modified technique of administering anesthesia without a tube and
      with spontaneous respiration during video-assisted tele-laryngo-tracheo-broncho
      endoscopy (TLTBE). The endoscopy was performed as an alternative to rigid
      ventilatory bronchoscopy during screening for synchronous tumors in the
      tracheobronchial tree in patients who had head and neck malignancies. Thirty
      consecutive patients who required diagnostic panendoscopy were selected for this
      study. During direct-suspension laryngoscopy, anesthesia was delivered by
      administering intravenous bolus injections of propofol at 0.5 to 2 mg/kg every 5
      to 10 minutes. A good view of the larynx, trachea, and main bronchi was obtained
      with a 50-cm 0 degree telescope, which caused no obstruction of the airway.
      During laryngoscopy, arterial oxygen saturation levels, pulse rates, and blood
      pressures were stable in all patients. No apnea was associated with the use of
      propofol during any procedure, and we observed no intraoperative or postoperative
      complication in any patient. Video-assisted TLTBE is appropriate for patients
      with a grade 1 or 2 larynx, good cardiopulmonary function, and no significant
      airway obstruction. It is a safe and time-saving alternative to rigid ventilatory
      bronchoscopy for staging primary tumors and for screening for synchronous tumors
      in the respiratory tract.

PMID- 12619470
TI  - Comparison of direct vision and video imaging during bronchoscopy for pediatric
      airway foreign bodies.
AB  - Rigid ventilation bronchoscopy is a most useful means of detecting and removing
      foreign bodies in the airway. We performed a retrospective study of 114 children
      who had undergone such a procedure during a 12-year period. During bronchoscopy,
      48 of these patients had been examined under direct vision and 66 by videotape
      recording. We found that the positive rate on first-look direct vision was 93.8%
      and the positive rate on first-look video imaging was 89.4%. The lower positive
      rate during the first-look examination by video imaging might be attributable to
      the facts that it is safer and that it provides a better visual field, which can
      encourage operators to choose video ventilation bronchoscopy, either as a
      diagnostic or therapeutic tool. In addition, three foreign-body-negative patients
      in the direct-vision group under-went a second procedure, and a foreign body was
      found in all three. Only one of the video-imaging patients under-went a second
      procedure, and no foreign body was found. The difference in the positive rates
      after the second procedure was statistically significant (p < 0.05). This might
      be attributable to the higher success rate with video imaging following the first
      procedure, which significantly reduced the need for a second look and the
      possibility of overlooked or residual foreign bodies. The condition of the mucosa
      postprocedurally was described in every case after video imaging but after only
      41.7% of the direct-vision cases--a statistically significant difference (p <
      0.001). Video imaging provides the physician with a clear, magnified view of the
      area under examination. It allows for later review of the videotape when
      necessary, and it reduces the risk that residual foreign-body material will
      remain in the airway.

PMID- 12619471
TI  - Lack of night-to-night variability of sleep-disordered breathing measured during
      home monitoring.
AB  - The apnea-hypopnea index (AHI) is an important objective measure used in the
      diagnosis of sleep-disordered breathing. In affected patients, the AHI has been
      reported to vary across successive nights. We conducted a multi-channel home
      sleep study on 44 patients with sleep-disordered breathing to determine whether
      the AHI does indeed vary and, if so, to quantify the degree of night-to-night
      variability. Of this group, 23 patients were tested for 3 consecutive nights and
      21 were tested for 2 consecutive nights. Among the group as a whole, we found no
      statistically significant change in AHI across nights, although we did identify
      variations among individual patients.

PMID- 12619472
TI  - The quality of student papers augurs well for the future of nursing research.

PMID- 12619473
TI  - Daily struggles: living with long-term childhood technology dependence.
AB  - With advances in technology, children with chronic illnesses are surviving
      longer. This improved survival rate has resulted in a growing population of
      families caring for their children with complex needs at home. This grounded
      theory study explored how caring for a child who requires home ventilation
      affects family members. Families moved through a process of struggling daily as
      they cared for their child with complex needs. This ongoing struggle was
      characterized by three distinct dimensions: getting over the hump, starting to
      breathe, and having to deal with a subsequent event. Implications for practice
      and future directions for nursing research are discussed.

PMID- 12619474
TI  - First-time fathers: perceptions of preparedness for fatherhood.
AB  - Little is known about how men prepare to become fathers. The purpose of this
      phenomenological study was to describe first-time fathers' perceptions of
      preparedness for and the transition to parenthood. Nineteen prospective and new
      fathers participating in 4 focus groups described the unique experiences of men
      as they prepared to become fathers. A total of 15 themes emerged from the data.
      The authors discuss themes in the transition to fatherhood--the reality of the
      pregnancy; physical, emotional, and financial preparation; and relationships with
      friends, parents-in-law, and health professionals--and conclude that the
      participants actively prepared for fatherhood, attempted to adjust to the
      perceived expectations of their new role, and sought information on how to be a
      good father. These results contribute to our understanding of behaviour among new
      fathers and to the body of research on fathering. Appropriate preparation for
      fatherhood has the potential to enhance maternal, child, and family health.

PMID- 12619475
TI  - Effects of demographic characteristics on preoperative teaching outcomes: a meta
      analysis.
AB  - Patient education is an integral part of nursing practice. Since the 1960s many
      primary studies and several meta-analyses have been conducted to assess the
      effectiveness of education for patients undergoing surgery. Although these
      studies demonstrate that preoperative teaching is beneficial to the "average"
      patient, they have paid little attention to the representativeness of the sample
      and the generalizability of the results. Therefore, a meta-analysis of 20 studies
      was conducted to identify the demographic characteristics of patients who
      participated in preoperative teaching effectiveness studies, and to assess
      variation in length of hospital stay and pain outcomes in relation to age,
      ethnicity, gender, and education. The findings confirm the positive and moderate
      effects of preoperative teaching on these outcomes. However, the participants
      were primarily 41-60-year-old white females educated beyond the secondary level.
      Therefore, the findings are not generalizable to all patients undergoing surgery.
      This points to the need for preoperative teaching that is individually tailored
      and evaluated in everyday practice and for studies that examine the influence of
      demographic characteristics, particularly education and ethnicity, on the
      outcomes of preoperative teaching.

PMID- 12619476
TI  - Revisiting the issue of co-dependency in nursing: caring or caretaking?
AB  - It is purported in the literature that individuals who demonstrate co-dependent
      traits (consistently taking responsibility for others to the point of neglecting
      onself) enter the nursing profession to fulfill  pathological needs and that
      nursing encourages co-dependent behaviour through its focus on "caring." This
      study was undertaken to determine whether nursing students have higher co
      dependency scores than students in other programs. Data were collected through a
      questionnaire. A continuum-based Co-dependency Index was constructed with a
      Caring and Caretaking Sub-index to allow for more accurate measurement of co
      dependency traits. In contrast to results reported in the literature, one-tailed
      testing indicated no significant relationship between co-dependency and
      university program. The results of this study suggest the need for a continuum
      approach to measuring co-dependency, to ensure that the presence of caring
      behaviours in measurement tools do not create a bias against nursing, a
      profession based on caring.

PMID- 12619477
TI  - Strength in adversity: motherhood for women who have been battered.
AB  - Research into violence against women in intimate relationships has begun to
      uncover women's experiences of abuse. However, there is a paucity of research
      addressing women's mothering experiences in the context of partner abuse. The
      purpose of this study was to explore the experience of motherhood from the
      perspective of women who have been battered. The methodology used was
      interpretive description, a qualitative research approach in which the women's
      accounts could be conceptualized as constructed narratives. Five mothers who had
      been battered were interviewed twice. Analysis revealed that the abuse shaped
      their experiences of motherhood and that they faced complex mothering challenges,
      but that motherhood nevertheless acted as a buffer against the abuse and as a
      source of strength. The findings extend our understanding of the complexities of
      mothering in the context of abuse and provide direction for improving health-care
      support for mothers who have been abused.

PMID- 12619478
TI  - Opening doors: factors influencing the establishment of a working relationship
      between paraprofessional home visitors and at-risk families.
AB  - The purpose of this phenomenological study was to identify and describe factors
      that influence the establishment of a working relationship between
      paraprofessionals and at-risk families. In-depth, semi-structured interviews were
      conducted with a purposive sample of 6 family visitors and 6 public health nurses
      hired to visit at-risk families in their homes. Analysis revealed that nurses
      have an important role to play in marketing home visiting programs and
      facilitating family visitor access to the home. Factors related to the family
      visitor, the client, and the client's household influenced relationship
      development. Family visitor-client engagement occurred through "finding common
      ground" and "building trust." Increased understanding of these factors will help
      both nurses and family visitors to access those families who are hard to reach
      and resist support and the provision of services. The findings have implications
      for nurses who are responsible for hiring, training, and supervising family
      visitors.

PMID- 12619479
TI  - Evidence of adequacy of postpartum care for immigrant women.
AB  - The purpose of this pilot study was to ascertain the need for a large-scale
      investigation of the adequacy of postpartum care for immigrant women in whom
      health and/or social concerns have been identified. A descriptive, cross
      sectional design was used to gather data from hospital and community health
      records of 22 immigrant women who had been found to have health or social
      concerns requiring a longer than usual postpartum hospital stay (more than 36
      hours). The results show that 40% to 100% of concerns were not recorded as having
      been resolved and 30% to 100% of families were not recorded as having received
      optimal care as defined in the literature. Even allowing for measurement error
      due to recording failures, the paucity of recorded data to support adequacy of
      care for specific concerns and adequacy of postpartum care suggests that
      immigrant women may be receiving sub-optimal care in the postpartum period.
      Therefore a larger, more definitive investigation of these issues is imperative.

PMID- 12619480
TI  - Information needs of cancer patients receiving chemotherapy in an ambulatory-care
      setting.
AB  - The purpose of this study was to assess the information needs of cancer patients
      receiving chemotherapy and to explore their preferred styles of receiving
      education in an ambulatory-care setting. Patient information needs and
      preferences were measured using a 17-item questionnaire. This descriptive study
      included a sample of 101 cancer patients undergoing outpatient chemotherapy. The
      most commonly expressed information needs concerned: side effects of treatment,
      drug information, and coping strategies. Some patients expressed a preference for
      information in their primary language. The results support the use of online
      learning in this setting. Patients identified one-on-one discussion with nurses
      and doctors as the preferred way to receive information. In order to meet the
      individual needs of cancer patients, education should be provided in a variety of
      learning modalities. The results of this study should help to guide patient
      education initiatives in oncology ambulatory care.

PMID- 12619481
TI  - Symptoms and distress in patients awaiting coronary artery bypass surgery.
AB  - In this examination of symptom distress in patients awaiting coronary artery
      bypass graft (CABG) surgery, a convenience sample of 42 patients on a waiting
      list for first-time CABG-only surgery were contacted via mail as part of a larger
      study into the experience of waiting for CABG surgery. They were asked to respond
      to questions about the frequency and distress of their coronary artery disease
      symptoms. A modified version of the Symptom Frequency and Symptom Distress Scale
      (SFSDS) was used. The mean symptom distress score was 77.7 out of a possible 386.
      Strong correlations were established between each individual item on the scale
      and the total score. The most frequent and distressing symptoms were fatigue,
      shortness of breath with activity, and chest pain. The most frequent' symptoms
      were also the most distressing. The findings underscore the significance of
      symptom experience in patients on a waiting list for CABG surgery and also point
      to the need for further testing of this version of the SFSDS.

PMID- 12619482
TI  - Spirit of the drum: the development of cultural nursing praxis.
AB  - The integration of culture is essential for nursing education and practice with
      diverse populations. Educators and students in the multicultural classroom must
      adopt culturally responsive behaviours that validate cultural identity and
      enhance cultural caring both in the classroom and in clinical areas. Fourth
      generation evaluation as described by Guba and Lincoln was used to evaluate the
      cultural curriculum of a nursing program in northern Canada. The findings suggest
      that we should adopt a process of integrating difference through the nurse-client
      relationship and ways of being. Implications for including the traditional
      knowledge policy of the government of the Northwest Territories in nursing
      education and practice, as depicted in the Northern Knowledge Model, are
      discussed.

PMID- 12619483
TI  - A comparison of adolescent and adult mothers' satisfaction with their postpartum
      nursing care.
AB  - The purpose of this matched-cohort survey was to determine whether there is a
      difference between unmarried adolescent mothers and married adult mothers in
      terms of satisfaction with inpatient postpartum nursing care. Eighty
      adolescent/adult postpartum mother pairs from a mid-sized teaching hospital were
      matched according to parity, mode of delivery, infant health status, and infant
      feeding method. Adolescents scored lower than adults on both the Experiences of
      Nursing Care Scale and the Satisfaction with Nursing Care Scale of the Newcastle
      Satisfaction with Nursing Scales. Among the adolescents, post-caesarean mothers
      were less satisfied than mothers who had delivered vaginally. Adolescent mothers'
      dissatisfaction with nurse availability and nurse-client communication are
      possible explanatory factors. Future qualitative studies will inform the design
      of interventions to improve satisfaction among adolescent mothers.

PMID- 12619484
TI  - Multidisciplinarity in nursing research: a challenge for today's doctoral
      student.
AB  - Doctorally prepared nurses entering today's research environment must be adept at
      transcending the research chasm that exists across disciplines and within nursing
      and be prepared to play leadership roles in multidisciplinary and nursing
      research. In order to fulfill these roles and meet the need for well-educated
      nurse scientists, doctoral students must be exposed to research from a
      multidisciplinary perspective and be able to think across disciplines so as to
      become familiar with the differences in design language. This paper compares
      research terminology across the disciplines of epidemiology, psychology, and
      nursing based on a sample of four research textbooks. It is apparent that
      although similarities exist, there is also diversity in the language used in
      research. Doctoral students preparing for comprehensive examinations must avoid
      becoming caught up in semantics and instead focus on the broad issues with each
      of the designs. With that knowledge, students will be not only more successful in
      their examinations but also more effective as leaders in nursing and
      multidisciplinary research.

PMID- 12619485
TI  - Burgeoning opportunities in nursing research.

PMID- 12619486
TI  - [Arguments against the distinction between primary and secondary prevention and
      prevention and treatment].

PMID- 12619488
TI  - [Hormones and ischemic cardiopathy in women: here it starts again!].

PMID- 12619487
TI  - [Prevention of the menopause: the end and the beginning].

PMID- 12619489
TI  - [Lecture on the evaluation of technologies, but with what kind of teaching?].

PMID- 12619490
TI  - [Hormonal replacement therapy in postmenopause: an endless story].

PMID- 12619491
TI  - [Risks and benefits of hormone replacement therapy: clinical considerations and
      research implications].

PMID- 12619492
TI  - [Mortality among patients with pleural and peritoneal tumors in Alta Valle di
      Susa].
AB  - Tremolite asbestos in rocks surfacing by natural ground erosion as well as
      originating from construction activities in the Upper Susa Valley (Piedmont,
      Italy) was recently reported. We investigated the spatial distribution of cases
      of pleural (ICD Rev 9 163) and peritoneal cancers (ICD Rev 9 158.8 and 158.9) in
      that area. Mortality and hospital discharge statistics were analyzed by
      municipality of residence respectively for the periods 1980-98 and 1995-99.
      Kernel and empirical bayesian estimators of standardized proportional mortality
      ratios (SPMR) were computed in circular areas of 25, 50, 75, and 100 km distance
      from Sauze d'Oulx. Pleural and peritoneal malignancies were found to occur in
      excess in this town and in the surrounding municipalities. A survey is being
      undertaken to identify cases, verify diagnoses, and assess occupational and
      environmental exposures.

PMID- 12619493
TI  - [Summary of systematic revisions of the efficacy of smoking cessation therapy].
AB  - Smoking cessation can be considered the most effective strategy to reduce smoking
      related mortality at medium term. The aim of this study is to conduct an overview
      of systematic reviews of effectiveness of smoking cessation interventions in the
      general population. Medline, Embase and the Cochrane Library for the years 1990
      march 2001 have been searched for those systematic reviews of primary studies
      evaluating the effectiveness of smoking cessation interventions in the general
      population, adult smokers. The outcome measure was abstinence from smoking at 6
      months after the start of the intervention. Thirty papers were found, 15 Cochrane
      reviews and 15 other systematic reviews. The present overview focuses on Cochrane
      reviews, because they were more recent and followed a standardised methodology.
      The interventions which proved to be successful were: the simple medical advice,
      a structured intervention from nurses, individual counselling, group therapy,
      nicotine replacement therapy, and bupropion. There is not enough evidence yet
      that one strategy is better than another. Even though there is evidence that it
      is possible to quit smoking without any intervention, we can recommend that every
      physician register the smoking habits of his patients, encourage smokers to quit
      and offer all the available effective strategies.

PMID- 12619494
TI  - [Risk factors of malignant skin melanoma in Italian population: review of results
      of a case-control study].
AB  - Cutaneous melanoma incidence rates are rapidly increasing worldwide, including in
      the Mediterranean countries. Sunlight exposure has been associated with melanoma,
      but the mechanisms of UV radiation-induced carcinogenesis is still largely
      unknown. In mammalian cells, UV radiation induces DNA damage that can be repaired
      mostly by the nucleotide excision repair system. We summarize here the results of
      a case-control study conducted at the Bufalini Hospital in Cesena, Italy to
      assess host and environmental risk factors for melanoma. We recruited 183
      incident cutaneous melanoma cases and 179 controls selected predominantly among
      partners or close friends of the cases. Presence of dysplasticlatypical nevi (OR:
      4.2; 95% CI: 2.4-7.4), low propensity to tan (OR: 2.4; 95% CI 1.1-5.0), light
      skin (OR: 4.1; 95% CI: 1.4-12.1), and light eye color (OR: 2.4; 95% CI: 1.1-5.2)
      were the strongest risk factors for melanoma in this population. A chart
      identifying melanoma risk associated with multiple combinations of these factors
      is presented. We used the host-cell reactivation assay on subjects' lymphocytes
      to measure individual DNA repair capacity (DRC) after UV-induced DNA damage.
      Subjects with low tanning ability and low DRC had a higher melanoma risk (OR:
      8.6; 95% CI: 2.7-27.5) than those with higher tanning ability and high DRC.
      Subjects with dysplastic nevi and low DRC had a higher risk (OR: 6.7; 95% CI: 2.4
      18.6) than those lacking dysplastic nevi and with high DRC. These results may
      help identify high-risk subjects in the Mediterranean populations who would the
      benefit from preventive measures.

PMID- 12619495
TI  - [Prevention in the workplace suffers two setbacks].

PMID- 12619496
TI  - [What is hiding behind the classification of fibers?].

PMID- 12619498
TI  - [Conflict of interest of the expert].

PMID- 12619497
TI  - [Some reflexions on ethics in oncological screening].

PMID- 12619499
TI  - [Glass fibers: we are guinea pigs].

PMID- 12619500
TI  - [Esterification of fatty acids by alcohols and functional role of polar and non
      polar lipids in blood flow. Double bonds of lipid fatty acids in lipoproteins].
AB  - An original method of automatic titration of dual bindings by ozone was made use
      of to show the functional role of alcohols, i.e. glycerin and cholesterol, in the
      transfer, within the lipoproteins' composition, and in the receptor absorption of
      saturated and essential polyene acids by cells. The values of correlations dual
      bindings/glycerin and dual bindings/cholesterol are indicative of that the
      saturated fat acids are etherified by glycerin in blood serum, and the essential
      polyene fat acids are etherified by cholesterol. The presence of dual bindings in
      lipids of some lipoproteins shows that lipoproteins of a very low density are
      carriers of saturated fat acids (in the form of non-polar triacilglycerides), and
      lipoproteins of low density are the key carrier of essential polyene fat acids
      (in the form of non-polar ethers of cholesterol). The cells absorb passively the
      fat acids (in the form of polar lipids); and they absorb actively the fat acids
      (in the form of non-polar lipids and by means of receptor endocytosis). A stable
      correlation dual binding/cholesterol at alterations of the alcohol content in the
      blood serum by 20 times, and similar correlation values in man, rats and mice
      demonstrate that the cells absorb, be means of receptor endocytosis, the
      essential polyene fat acids (in the form of ethers of cholesterol). The level of
      cholesterol depends on a content of fat acids, mainly of the omega-3 and omega-6
      essential polyene fat acids, in the blood serum.

PMID- 12619502
TI  - [Fructosamine, high density lipoproteins and degree of dyslipidemia in patients
      with vascular complications of diabetes mellitus type I].
AB  - The contents of products from lipid peroxidation (LP) and from fructosamine
      oxidation, associated with high-density lipoproteins (HDLP), were examined in the
      blood of patients with diabetes mellitus (DM) of type 1. It was established that,
      as the vascular complications of DM, type 1, (i.e. micro- and macroangiopathies)
      aggravated, the HDLP level, modified by LP heptanophil products, was growing up
      in the blood serum. The content of the above category of HDLP-associated
      lipoperoxides depended directly on a quantity of HDLP-bound fructosamine, and it
      reached a maximum value at the most pronounced dislipidemic disorders accompanied
      by clinical signs of arteriosclerosis (macroangiopathies).

PMID- 12619503
TI  - [Dehydrogenase activity in mononuclear cells of peripheral blood in infectious
      mononucleosis in children].
AB  - The study of the activity of dehydrogenases in blood cells could be an additional
      method at diagnostics of etiological variants of infectious mononucleosis (IM) of
      the viral and bacterial types. The activity of succinatedehydrogenasa (SDG) and
      of alpha-glycerophosphatedehydrogenase (alpha-GPDG) was increasing in lymphocytes
      and monocyte of the peripheral blood as compared to the same activity in healthy
      children. Such changes were preserved in the reconvalescense phase. The activity
      of enzymes in the lymphoid and monocytic cells was found at viral IM to meet the
      normal value. The atypical mononuclear cells, found in blood of patients with IM
      of both viral and bacterial nature, are a population of different-activity
      cellular dehydrogenases, in which cellular elements with the activity of SDG and
      alpha-GPDG, corresponding to the enzyme status of monocytes, are predominant.

PMID- 12619501
TI  - [Biochemical parameters of connective tissue in diagnosis of the initial stage of
      liver cirrhosis].
AB  - Hepatocirrhosis is an independent progressing disease of the hepatic connective
      tissue. It is characterized biochemically at all stages (i.e. compensation,
      subcompensation and decompensation) by low indices of free oxyproline, of total
      cholesterol and glycoproteins; simultaneously, it is described by a high level of
      glycosaminoglycanes. A low content of serum non-hemin iron was also pointed out.
      An early diagnosis of hepatocirrhosis at the initial stage is important for a
      correct and timely choice of treatment aimed at recovering the patients or
      prolonging their lives.

PMID- 12619505
TI  - [Methods of neutrophil motility studies (a literature review)].

PMID- 12619504
TI  - [Changes in blood hormone levels in gout and methods of their correction (an
      experimental and clinical study)].
AB  - Gout belongs to often-occurring rheumatic pathologies and its incidence among the
      male population of Europe has been rapidly increasing during the recent years.
      The pathogenesis of the disease is insufficiently studied and the existing
      methods of pathogenetic therapy are low effective. The disease pathogenesis with
      regard for dishormonal disorders has been recently under discussion. 107 patients
      with primary gout and 70 white outbred male rats were examined. Disorders in the
      hypophysis-gonad system (i.e. hyperproduction of progesterone, and suppression of
      the synthesis of testosterone and estradiol, which are to a great extent typical
      for patients with chronic arthritis and with nephropathy of the proteinuric type)
      developed in men with gout. Similar changes were provoked experimentally by
      purine-exchange violations, which is indicative of their secondary nature. An
      exogenous administration of androgens at experimental hyperuricemy led to the
      normalization of purine exchange and of blood hormones, it also ensured an
      alleviation of pronounced morphological signs of arthritis. The application of
      testosterone and its analogues for people exceeds, by their effectiveness, the
      known treatment methods.

PMID- 12619506
TI  - [Theory and practice in estimation of microorganism sensitivity to antimicrobial
      preparations by the disc diffusion method].

PMID- 12619508
TI  - [Bone marrow hematopoiesis in leptospirosis and its role in anemia pathogenesis].
AB  - Sternal biopsy was made for and the dynamics of medullary hemopoiesis was
      examined in 20 patients with leptospirosis caused by L. icterohaemorragiae, L.
      canicola and L. gebdomadis. A severe icteric disease form complicated on day
      10.75 +/- 1.26 by anemia was observed in all patients. A moderate activation of
      erythropoiesis, irritation of the lymphomonocytic sprout as well as oppression of
      the basophile and neutrophile series were the characteristic features of
      myelograms at the acute illness stage. Leptospirosis did not affect the
      functional ability of the bone marrow and no oppressive myelotoxic action as
      produced by Leptospira was observed. Anemia in patients with leptospirosis is
      predominantly of the hyperregenerative nature with the normoblastic hemopoiesis
      type.

PMID- 12619507
TI  - [Detection of autoantibodies to neutrophils in patients with immune (hapten)
      agranulocytosis].

PMID- 12619509
TI  - [Reference values for automated reticulocyte analysis].
AB  - Reference values for all 7 parameters of the analysis of reticulocytes by using
      hematological analyzer GEN-S and obtained during blood examination of 115 men and
      120 women, aged 20 to 60, are presented in the paper. Reference limits can be
      used in practical medicine to evaluate the results obtained through an automated
      analysis of reticulocytes.

PMID- 12619510
TI  - [Integral mathematical parameters of a gemogram as criteria for evaluation of
      severity of chronic adnexitis and of treatment efficacy in conservative therapy].
AB  - A number of hematological indices of the peripheral blood in patients with
      chronic adnexitis were mathematically calculated to evaluate a disease severity
      and an effect of recovery by using the traditional therapy method. It was
      established that the integral-and-mathematical indices of hemogram reflect
      clinical disease acuteness while receiving patients to hospital. A comprehensive
      evaluation of hematological indices makes it possible to determine the severity
      of inflammatory process in women, to detect the efficacy of a conducted therapy
      and to choose a strategy for further metabolic correction to ensure a maximum
      treatment effect.

PMID- 12619511
TI  - [Normal parameters of leukocyte index of intoxication].
AB  - A formula was suggested to determine the leukocytic index of intoxication (LII),
      which is a correlation between the level of neutrophils and the content of other
      cells in the blood leukocytic composition. The above formula was used to estimate
      the minimal, maximal and mean LII indices in patients, who had no inflammatory or
      purulent pathologies, i.e. normal indices, which respectively amounted to 1, 3
      and 1.9. Such approach to composing a formula is in line with the specific
      features of vital activity, unlike Ya.Ya. Kalf-Kalif formula, which (when it was
      composed) it was added a number of coefficients. The application of the offered
      formula to determine the LII at acute appendicitis showed that the more severe an
      acute appendicitis was so much the LII increase was more intensive. It is
      noteworthy, that the high LII indices did not always correlate with an increased
      quantity of blood leukocytes. The above stated proves that the offered LII
      formula can be used in practice.

PMID- 12619512
TI  - [Thinking about ways of laboratory service development].

PMID- 12619513
TI  - [Radioprotective and antineoplastic activity of polyene antibiotics combined with
      dimethyl sulfoxide].
AB  - Radioprotective and antineoplastic activity of polyene, its derivatives and
      combinations with dimethyl sulfoxide (DMSO) was studied. The most potent
      radioprotective effect was demonstrated by methylated levorin, original levorin
      and by its isomer--isolevorin. Survival rate of the animals on 12th day after X
      ray exposure was 100, 60, 60 per cent, at the control group 33.6, 20 and 0 per
      cent consequently. Levorin and alkyl derivatives of amphotericin B--methamphocin
      and buthamphocin inhibited growth of ascites and solid tumors to 46.3-79.0 per
      cent when compared to control group. Polyen antibiotics combined with DMSO also
      demonstrated antineoplastic activity at the animals treated with carcinogenic
      agent--diethyl nitrosoamine (DENA). 5-month survival of the animals was 76 per
      cent at nystatin and levorin group and 35.7 per cent at the control group
      (animals treated with DENA only).

PMID- 12619514
TI  - [Topical pectins for the treatment of burn wounds].
AB  - The results of the burned wounds treatment with 1-2% solution of apple or beet
      pectins were analysed. The control results were examined at the same patients
      with symmetrical wounds treated by chlorhexidine, levomecol, furacillin liniment.
      Clinical evaluation demonstrated good tolerability of the treatment regime,
      absence of side effects and complications, inhibition of inflammation,
      acceleration of epithelisation of the burns II-IIIA class, allowed to diminish
      the preliminary period before autodermoplastic operation (burns of IIIB class),
      diminished microbial dissemination and dissemination with Pseudomonas aeruginosa.
      The best results were demonstrated when the pectins application was performed
      since the first day after the burned injury.

PMID- 12619515
TI  - [On fluoroquinolones treatment safety in children (clinical, morphological and
      catamnesis data)].
AB  - Results of prospective comparative investigation of monofluoroquinolones
      (ciprofloxacin, ofloxacin, pefloxacin) arthropathy are presented. The trial was
      performed at 144 children with mucoviscidosis (aged 0.5-16) and at 37 children
      with aplastic anemia (aged 1.75-15). Two groups differ by necessary
      antibacterials regimes and hence by different abilities for arthropathy
      development: patients with mucoviscidosis were treated with fluoroquinolones
      followed by repeated short courses in combination with other antibacterials;
      patients with aplastic anemia--were treated permanently for a long time with low
      doses as monotherapy for autoinfection prophylaxis. Analysis was performed on the
      base of catamnesis, year growth rate, postmortal morphological investigation of
      the right knee joint. It was shown that quinolone arthropathy development didn't
      depend on treatment duration, as it developed during the first three weeks of the
      fluoroquinolone use, but depended on the drug, patient age and nosology.
      Arthropathy has favourable prognosis and was fully resolved at the period from 7
      days to 3 month according to the arthropathy form (arthrologic, arthritic).
      Quinolones arthropathy at the children has specific features, the main one is
      absence of cartilage damage confirmed by morphological analysis.

PMID- 12619517
TI  - [Sparflo in the treatment of urogenital mycoplasmosis and ureaplasmosis].

PMID- 12619516
TI  - [Evaluation of clarithromycin efficacy in the treatment of community-acquired
      pneumonia on the basis of the Binax NOW test results (a prospective open trial)].
AB  - The results of the treatment of community-acquired pneumonia with clarithromycin
      (500 mg bid for 6-8 days) at 172 patients (military recruits aged 18-25) are
      presented. Diagnosis, infection performance, treatment efficacy were evaluated by
      complex of data (X-ray, sputum analysis by bacteriological and cultural tests and
      immunochromatography test Binax NOW for pneumococcal antigen identification).
      High efficacy of clarithromycin for the treatment of moderate and mild pneumonia
      (including pneumococcal pneumonia) was demonstrated. Side effects were registered
      at 6.2 per cent of patients (gastro-intestinal disorders at 5 patients) and 1
      general urticaria at 1 patient whose treatment had to be changed).

PMID- 12619518
TI  - [Antibacterial therapy: pharmacoeconomic aspects].

PMID- 12619519
TI  - [Modern potential of antimicrobial therapy in the treatment of wounded soft
      tissue infections and osteomyelitis].

PMID- 12619521
TI  - [Caution for false advertising].

PMID- 12619522
TI  - [Bacterial resistance in Germany. How great is the danger?].

PMID- 12619520
TI  - [Fungal endocarditis].

PMID- 12619523
TI  - [A picture of the mind. Nuclear magnetic resonance tomography gives the first
      view of the somatic basis of psychic processes].

PMID- 12619525
TI  - [Schizophrenia: adverse effects of atypical neuroleptics].

PMID- 12619524
TI  - [Palliative therapy in cancer patients].

PMID- 12619526
TI  - [Interactions of asthma spray-beta blockers].

PMID- 12619527
TI  - Uncommon cures.

PMID- 12619529
TI  - The importance of reporting sample characteristics in measurement studies.

PMID- 12619528
TI  - Dental health tips every new parent should know.

PMID- 12619530
TI  - Psychometric characteristics of the Depressive Cognition Scale in African
      American women.
AB  - Depression in African-American women frequently goes unnoticed and untreated
      since commonly used depression scales fail to focus on early symptom recognition,
      do not address contextual factors, and lack adequate psychometric testing in
      African-American women. This analysis of the Depressive Cognition Scale was
      conducted with 213 African-American female caregivers and noncaregivers. Alpha
      coefficients for both groups (alpha 's = .75 and .87) showed internal
      consistency. Correlations with resourcefulness, depression, and daily hassles
      scales in the expected directions demonstrated construct validity (R's = -.36,
      .26, and .31, respectively). Factor structures for caregivers and noncaregivers
      differed, suggesting certain depressive cognitions were strongly integrated into
      the caregiver role. As a reliable and valid measure of depressive cognitions, the
      DCS would be useful for early detection of depression in African-American women.

PMID- 12619531
TI  - The infant care questionnaire: assessment of reliability and validity in a sample
      of healthy mothers.
AB  - Few instruments are available to assess perceptions of competence in the specific
      maternal role function of infant care provider. This article reports on a
      methodological study of the development and evaluation of the Infant Care
      Questionnaire (ICQ), a self-report scale designed to measure the mother's
      perceptions of her abilities and competence as an infant care provider. The
      sample consisted of healthy low-risk primiparous and multiparous mothers (N =
      164) of term infants. Principal components factor analysis with a Varimax
      rotation produced a three factor solution that explained 42% of the total
      variance. The three factors were Mom&Baby, Emotionality, and Responsiveness with
      Cronbach alpha coefficients of .86, .79, and .58, respectively. Validity evidence
      included higher Mom&Baby scores for multiparous mothers, F (1, 139) = 10.78, p =
      .001; those with greater time in the mothering role, F (2, 138) = 21.78, p =
      .000; and a significant correlation with the similar Maternal Confidence Scale, r
      (155) = .48, p = .000. Acquisition of competence was shown in a greater
      proportion of mothers rated "competent" at five weeks compared with one week
      postnatal, chi 2 (1, N = 156) = 22.77, p = .000. While the ICQ demonstrated
      adequate reliability and validity, establishment of clinical relevance and
      appropriateness with other groups is required.

PMID- 12619532
TI  - Reliability of transportable instruments for assessment of infant length.
AB  - Transportable instruments for use in home and field settings have been used for
      decades on the basis of assumed reliability. This article describes a study that
      compares two portable devices for measuring length, the tape measure and the
      Measure Mat, against a clinical standard stadiometer with two convenience samples
      of Hispanic and African-American infants in an urban general pediatrics practice
      setting. Mean net difference between the stadiometer and the tape measure was
      1.68 inches in the first sample and 0.92 inches in the second; the difference
      between the stadiometer and the Measure Mat was 0.92 inches. The least
      variability and random error (SD = 0.57 inch) was shown in the paired
      measurements using the stadiometer and the Measure Mat. Bland-Altman plots showed
      positive bias for both portable devices across the range of measurements.

PMID- 12619533
TI  - Development of a self-efficacy instrument for coronary artery bypass graft
      patients.
AB  - Research related to self-efficacy has demonstrated that measures of this concept
      need to be specific to the behavior of interest. Self-efficacy is the degree of
      confidence one has to perform an activity. This article describes the development
      and testing of the Barnason Efficacy Expectation Scale (BEES). The instrument is
      a 15-item tool that uses a Likert scale to determine the coronary-artery-bypass
      graft (CABG) patient's self-efficacy related to the risk-reduction-related
      aspects of recovery and lifestyle adjustment following CABG surgery (physical
      functioning, psychosocial functioning, coronary artery disease risk factor
      modification and self-care management). Internal consistency reliability of the
      instrument was 0.93, and principal components analysis revealed a single factor
      (Eigenvalue = 10.59, percent variance = 70.61%). Three phases of tool development
      are described in the article that document satisfactory reliability and validity
      (face, content, criterion, and construct).

PMID- 12619534
TI  - Minimizing sample size when using exploratory factor analysis for measurement.
AB  - Traditional protocol for the determination of an adequate sample size is power
      analysis. Such a protocol is not useful when the primary hypothesis focuses on
      psychometric measurement properties. Traditional psychometrics advises that there
      should be 10 respondents per item. Both hypothetical and real research examples
      illustrate the usefulness of subsample analysis in determining that a sample size
      of at least 50 and not more than 100 subjects is adequate to represent and
      evaluate the psychometric properties of measures of social constructs. The "10
      respondents per item" advice builds a sample size disincentive into the research
      design; it also represents "sample size overkill." Sample-size overkill occurs
      when the research design specifies a number of cases needed, which is in excess
      of the number actually needed for a desired inference.

PMID- 12619536
TI  - Overview of head and neck cancer.

PMID- 12619535
TI  - Assessing data adequacy for clinical research: reliability and validity of a
      surgical database.
AB  - As clinical databases are utilized more frequently for clinical research, it is
      essential that researchers assess the quality of databased information. While
      researchers have begun to report strategies to measure accuracy of databased
      information, knowledge remains limited. The purpose of this study was to assess
      the reliability and validity of databased information among selected study
      variables contained within a computerized coronary artery surgery clinical
      database using the written patient medical record as an external standard. Both
      reliability (N = 400) and validity (N = 100) samples were randomly selected from
      a databased sampling frame of 548 Medicare subjects who underwent coronary artery
      bypass grafting surgery in 1998. Reliability assessed by consistency rates were
      age (95%), race (94%), gender (99%), congestive heart failure (CHF) (60.5%),
      angina (91.5%), renal insufficiency (82%), hypertension (91.7%), diabetes
      mellitus (93.7%), chronic obstructive pulmonary disease (COPD) (75.5%), clinical
      status (97%), American Society of Anesthesiologists classification (99%), prior
      peripheral vascular surgery (15.5%), prior CABGS (99%), and duration of
      mechanical ventilation (87.5%). These percentages reflected a large portion of
      missing data for CHF, COPD, and prior peripheral vascular surgery. Validity
      assessed by sensitivity and specificity analyses were all greater than 80%. The
      majority of computerized databased information among selected study variables was
      the same information recorded in the written patient medical record. Using the
      same external standard to assess both reliability and validity was a significant
      limitation of this study, which resulted in the same measure of data adequacy by
      utilizing differing statistical methods.

PMID- 12619537
TI  - Epidemiology, staging, and screening of head and neck cancer.

PMID- 12619538
TI  - Oral preneoplasia and chemoprevention of squamous cell carcinoma of the head and
      neck.

PMID- 12619539
TI  - Early stage head and neck cancer-surgery.

PMID- 12619540
TI  - Radiation therapy in the management of early-stage head and neck cancer.

PMID- 12619541
TI  - Advanced head and neck cancer-surgery and reconstruction.

PMID- 12619542
TI  - Modified fractionated radiotherapy in head and neck squamous cell carcinoma
      (HNSCC) & re-irradiation in recurrent head and neck carcinomas.

PMID- 12619544
TI  - Organ preservation for advanced head and neck cancer concomitant chemoradiation.

PMID- 12619543
TI  - Organ preservation-induction chemotherapy.

PMID- 12619545
TI  - Unresectable, locoregionally advanced head and neck cancer.

PMID- 12619546
TI  - Nasopharyngeal cancer.

PMID- 12619547
TI  - Treatment of metastatic head and neck cancer: chemotherapy and novel agents.
AB  - For more than a decade, the de facto "standard of care" for palliative mangement
      of recurrent head/neck squamous carcinoma (HNSCC) has been the combination of
      cisplatin/5-flourouracil. With the advent of new cytotoxins, such as the taxanes,
      and of the molecularly targeted agents, eg., the EGFR inhibitors, the number of
      options for treatment  in this setting has increased. However, none of these new
      approaches has yet been proven to be more effective than cisplatin/5
      fluorouracil. Further, despite the pallitive intent of therapy in this setting,
      the palliative effects have been only infrequently assessed, with many studies
      relying on response as a surrogate for palliation. This chapter will focus on
      clinical and translational research efforts in the past decade focusing on the
      patient with incurable locoregionally recurrent or metastatic HNSCC. Ongoing and
      planned future trails will also be discussed.

PMID- 12619548
TI  - New therapies for locoregionally advanced and locoregionally recurrent head and
      neck cancer.

PMID- 12619549
TI  - Quality of life and late toxicities in head and neck cancer.

PMID- 12619550
TI  - Oral, dental, and supportive care in the cancer patient.

PMID- 12619551
TI  - Age should not be a factor in determining whether or not to administer
      chemotherapy.

PMID- 12619552
TI  - An ethicist's commentary on sharing new prevention and treatment regimens.

PMID- 12619553
TI  - Infection of growing swine with porcine reproductive and respiratory syndrome
      virus and Mycoplasma hyopneumoniae--effects on growth, serum metabolites, and
      insulin-like growth factor-I.
AB  - This study evaluated the influence of concomitant infections with porcine
      reproductive and respiratory syndrome virus (PRRSV) and Mycoplasma hyopneumoniae
      on growth performance, serum metabolite concentrations, and serum insulin-like
      growth factor-I (IGF-I) in growing pigs. Twenty-two barrows (10 weeks of age)
      were treated with either an intranasal administration of PRRSV and an
      intratracheal infusion of M. hyopneumoniae (treatment; n = 8) or a sham
      inoculation with medium (sham; n = 8), or were not treated (control; n = 6). The
      sham pigs were matched by body weight and pair-wise fed with treatment pigs. Pigs
      were weighed on the day of inoculation (day 0) and at 4 weeks postinoculation
      (day 28). Blood samples were collected prior to inoculation and at weekly
      intervals for 4 weeks. Pigs in the treatment group exhibited clinical signs
      consistent with PRRSV infection and M. hyopneumoniae pneumonia. Diagnostic
      procedures confirmed that treatment pigs were inoculated with PRRSV and M.
      hyopneumoniae and that sham and control pigs remained free of both pathogens.
      Average daily gain and feed conversion did not differ among the 3 groups. The IGF
      I levels differed (P < 0.05) between control and treatment pigs, even after feed
      intake returned to similar levels among groups. At day 7, IGF-I concentrations
      were greater in sham pigs compared with treatment pigs, despite similar feed
      intake. Sham inoculation and decreased feed intake in sham pigs did not alter
      serum IGF-I concentrations. Evidently, IGF-I status of pigs affected with disease
      is influenced by nutritional and nonnutritional factors during the disease
      process.

PMID- 12619554
TI  - A retrospective study of 44 canine apocrine sweat gland adenocarcinomas.
AB  - Apocrine sweat gland adenocarcinomas (AACs) are relatively uncommon skin tumors
      in dogs. Little prognostic or behavioral information has been published for these
      tumors. In this retrospective study, 44 AACs from diagnostic archives were
      reexamined and clinical postexcisional follow-ups for 25 of the 44 cases were
      obtained by a survey. There were 28 out of 44 (65.9%) AACs that invaded the
      capsule, stroma, or both, 5 of 44 (11.4%) invaded blood vessels and stroma, and 1
      out of 25 (4%) had distant metastases. The presence or absence of stromal and
      vascular invasion was predicted by clinical examination with more than 80%
      accuracy. Postexcisional median survival of dogs with AACs was 30 mo at the time
      of survey. Determination of a correlation between histological features and
      malignant behavior of AACs was compromised by the low number of cases with
      clinical AAC-related problems; however, it appears that intravascular invasion is
      an important indicator of potential systemic metastases.

PMID- 12619556
TI  - Implementation of a validated HACCP system for the control of microbiological
      contamination of pig carcasses at a small abattoir.
AB  - To guide the implementation of a Hazard Analysis Critical Control Point (HACCP)
      system at a small abattoir, the microbiological conditions of pig carcasses at
      various stages of processing were assessed by enumerating total aerobes,
      coliforms, and Escherichia coli in samples collected from randomly selected sites
      on the carcasses. Those data indicated that carcasses were contaminated with
      bacteria mainly during dehairing and operations on the head. When carcasses were
      pasteurized after head removal, the numbers of total aerobes on dressed carcasses
      were reduced by about 1 order and the numbers of coliforms and E. coli were
      reduced by more than 2 orders of magnitude. Implementation of an HACCP system on
      the basis of the microbiological data gave cooled carcasses with mean numbers of
      total aerobes < 100/cm2, and mean numbers of coliforms and E. coli about 1/1000
      cm2.

PMID- 12619555
TI  - Comparison of a multivalent viral vaccine program versus a univalent viral
      vaccine program on animal health, feedlot performance, and carcass
      characteristics of feedlot calves.
AB  - A field study was conducted under commercial feedlot conditions at 2 sites in
      western Canada to determine the relative effects of a univalent viral vaccine
      (MLV 1) program versus a multivalent viral vaccine (MLV 4) program on animal
      health; feedlot performance; and carcass characteristic variables of fall-placed,
      auction market derived, feedlot calves. Five thousand one hundred and sixty-three
      calves were processed and randomly allocated to 1 of 2 experimental groups as
      follows: MLV 1, which received a modified live infectious bovine rhinotracheitis
      (IBR) virus vaccine upon arrival at the feedlot and again at approximately 70
      days on feed (DOF); or MLV 4, which received a modified live IBR virus,
      parainfluenza-3 virus, bovine viral diarrhea virus, and bovine respiratory
      syncytial virus vaccine upon arrival at the feedlot and again at approximately 70
      DOF. A total of 20 pens (10 pens at the site located near High River, Alberta and
      10 pens at the site located near Vegreville, Alberta) were allocated to the
      study. On both a live and carcass weight basis, final weight, weight gain, and
      average daily gain (ADG) were significantly (P < 0.05) improved in the MLV 4
      group as compared with the MLV 1 group. However, there were no significant (P >
      or = 0.05) differences in DOF, daily dry matter intake, dry matter intake to gain
      ratio (DM:G) live, or DM:G carcass between the experimental groups. In addition,
      there were no significant (P > or = 0.05) differences between the experimental
      groups in any of the carcass characteristic variables measured. The initial
      undifferentiated fever (UF) treatment rate was significantly (P < 0.05) lower in
      the MLV 4 group as compared with the MLV 1 group. There were no significant (P >
      or = 0.05) differences in the other measures of health between the experimental
      groups. In the economic analysis, there was a net advantage of $0.74 CDN per
      animal in the MLV 4 group as compared with the MLV 1 group due to lower initial
      UF treatment and improved ADG, even though the cost of the vaccine program was
      higher in the MLV 4 group.

PMID- 12619557
TI  - A case of cephalothoracopagus in sheep in Trinidad and Tobago.
AB  - A case of cephalothoracopagus in sheep complicated with several defects of
      skeletal, cardiovascular, respiratory, gastrointestinal, and urogenital systems
      is reported.

PMID- 12619558
TI  - Diagnosis of natural exposure to bovine viral diarrhea in a vaccinated herd by
      measuring extended antibody titers against bovine viral diarrhea virus.
AB  - Two abortions occurred in a 150-head commercial cow-calf herd. Bovine viral
      diarrhea was suspected and confirmed by measuring extended titers against bovine
      viral diarrhea virus (BVDV) in a sample of 15 breeding females. Fifteen were sero
      positive and 11 had significantly high titers (1:972-1:8748), likely due to
      natural exposure to cattle persistently infected with BVDV.

PMID- 12619559
TI  - Multicentric lymphoma and disseminated coccidioidomycosis in a dog.
AB  - An 11-year-old, spayed female Alaskan malamute with a history of coccidioidal
      osteomyelitis was evaluated for inappetance and lethargy. Findings included
      generalized lymphadenopathy, pale mucous membranes, tachycardia, and labored
      breathing. Laboratory findings and radiographic imaging were consistent with
      generalized lymphoma and disseminated coccidioidomycosis. Treatment consisted of
      antibiotics, chemotherapeutic agents, and antifungals.

PMID- 12619561
TI  - Veterinarians, the Royal Society of Canada, and the future of veterinary
      medicine: Part 2.

PMID- 12619560
TI  - Protein-losing enteropathy caused by Lawsonia intracellularis in a weanling foal.
AB  - A 5-month-old Morgan filly was presented to the Atlantic Veterinary College with
      a history of lethargy, fever, depression, anorexia, and dependent ventral edema.
      Diagnostic tests revealed severe inflammation, hypoproteinemia, and thickened
      small intestinal loops. Protein-losing enteropathy caused by Lawsonia
      intracellularis was diagnosed and treated successfully with erythromycin
      rifampin.

PMID- 12619562
TI  - What's new in orthopedics? Part 1.

PMID- 12619563
TI  - Water relations and leaf growth rate of three Agropyron genotypes under water
      stress.
AB  - The effects of water stress on leaf water relations and growth are reported for
      three perennial tussock grass genotypes under glasshouse conditions. Studies were
      performed in genotypes El Palmar INTA and Seleccion Anguil of Agropyron
      scabrifolium (Doell) Parodi, and El Vizcachero of A. elongatum (Host) Beauv.
      Agropyron scabrifolium El Palmar INTA is native to a region with warm-temperate
      and humid climate without a dry season, and an average annual precipitation of
      900 mm. Agropyron scabrifolium Seleccion Anguil comes from a region with a sub
      humid, dry to semiarid climate and a mean annual precipitation of 600 mm.
      Agropyron elongatum is a widespread forage in semiarid Argentina with well-known
      water stress resistance. A mild water stress treatment was imposed slowly; plants
      reached a minimum pre-dawn leaf water potential of about -1.83 MPa by day 21
      after watering was withheld. In all genotypes, water stress led to a reduction of
      leaf growth. There was a tendency for a greater epicuticular wax accumulation on
      water-stressed plants of A. scabrifolium Seleccion Anguil and A. elongatum than
      on those of A. scabrifolium El Palmar INTA. This may have contributed to obtain
      greater turgor pressures and relative water contents in the first two than in the
      later genotype. In turn, this may have contributed to determine smaller leaf
      growth rate reductions in A. scabrifolium Seleccion Anguil and A. elongatum than
      in A. scabrifolium El Palmar INTA under water stress. This study demonstrated
      variation in water stress resistance between genotypes in A. scabrifolium, and
      between A. scabrifolium Seleccion Anguil and A. elongatum versus A. scabrifolium
      El Palmar INTA, which was related to their differential responses in water
      relations.

PMID- 12619564
TI  - In vitro propagation of Opuntia ellisiana Griff. and acclimatization to field
      conditions.
AB  - The genus Opuntia is a valuable forage resource in arid and semiarid lands during
      periods of drought and shortage of herbaceous plants. However, absolute minimum
      temperatures in the plains of Mendoza represent a limiting factor to cultivate
      several species. Opuntia ellisiana is a cold hardy species, so the goals of this
      study were to massively propagate is using in vitro culture techniques, and then
      to acclimatize plantlets obtained to field conditions. Different sterilization
      protocols were tested. Areoles were isolated in laminar airflow cabinet, and
      cultured on Murashige-Skoog medium, supplemented with sucrose and different BAP
      and IBA combinations. Explants were grown at 27 +/- 2 degrees C, under a 16-h
      photoperiod. The shoots produced were used in the rooting assay using different
      auxin combinations. In the most efficient growth treatment, plantlets reached
      100% shooting after 35 days of culture, and a mean length of 10.2 mm after 49
      days of culture. A 100% rooted plantlets was obtained on a medium containing 5 mg
      L-1 IBA, after 12 days of culture. Acclimatization was achieved under greenhouse
      conditions, showing 100% plantlet survival. This study suggests that O. ellisiana
      can be successfully micropropagated by areoles, and easily acclimatizated to
      field conditions.

PMID- 12619566
TI  - Effects of high molybdenum intake on 1,2-dimethylhydrazine-induced intestinal
      tumors in rats.
AB  - Wistar male rats, 3 months of age were given ad-libitum a nutritionally adequate
      diet and demineralized drinking water. The Molybdenum (Mo) and Tungsten (W) were
      provided in the drinking water at 200 ppm concentration. Intestinal tumors were
      induced by 1,2-dimethylhydrazine (DMH) given subcutaneously as 16 weekly doses at
      20 mg/kg body weight. Mo in the form of (NH4)6 Mo7O24 4H2O or W in the form of
      (Na2WO4) were provided in the drinking water two months before the first DMH
      treatment and were continued during 4 months more until the last DMH treatment.
      Three months after the last carcinogen injection, all animals were sacrificed and
      examined for intestinal tumors. The number, size and location of the tumors were
      recorded and the pathology was examined. The addition of Mo to the drinking water
      induced an increase of hepatic Mo content. At the end of the second month, the
      hepatic content of Mo was 5.61 ppm, compared with control and W groups (2.18 and
      0.96 ppm, respectively). A significantly lower incidence of tumors was observed
      in the Mo group (47), compared with the control group given DMH alone (105) and W
      group (113). On the other hand, the Mo group showed a significant decrease in the
      numbers of multiple tumors per rat.

PMID- 12619565
TI  - Oogenesis in the swamp eel Synbranchus marmoratus (Bloch, 1795) (Teleostei;
      Synbranchidae). Ovarian anatomy, stages of oocyte development and micropyle
      structure.
AB  - Synbranchus marmoratus (Synbranchidae), commonly known as the swamp eel, is a
      protogynous diandric teleost fish widely distributed throughout South America.
      The purpose of this work was to study the ovarian anatomy and to describe oocyte
      developmental stages in the swamp eel, Synbranchus marmoratus. S. marmoratus has
      a unique sacular ovary. It is covered by a conspicuous muscular wall, probably
      involved in an egg-releasing system acting as a peristaltic-like mechanism. The
      internal ovarian anatomy shows a U-shaped ovarian lamella delimiting a dorsal
      ovarian lumen. The microscopic study shows evidence of the existence of a
      germinal epithelium in the inner surface of the lamella, which contains germinal
      cells, pre-follicular cells and epithelial cells. The complete oogenesis process
      is divided into four stages: oogonia, primary growth, cortical alveoli and
      vitellogenesis. Besides, the ovulated oocytes, and atretic structures were
      described. The structure of the micropyle was studied by scanning electron
      microscopy (MEB). Near the animal pole the vitelline envelope forms crests that
      fuse together becoming furrow-like structures with a slightly spiraled direction
      that converge into the micropyle pit where is located the micropylar canal.
      Although the sex reversal process of Synbranchids has been subject of many
      studies, this is the first complete description of the ovarian anatomy and
      oogenesis.

PMID- 12619567
TI  - Microanatomical characteristics of marginal ommatidia in three different size
      classes of the semi-terrestrial isopod Ligia exotica (Crustacea; Isopoda).
AB  - The aims of this paper have been (a) to characterize marginal ommatidia from
      different eye regions through a detailed description of their distinct
      ultrastructural features in three different size-classes of L. exotica, and (b)
      to compare microanatomical characteristics of the marginal ommatidia with those
      of ommatidia of the same eye, but located further centrally. On the basis of
      transverse as well as longitudinal sections we conclude that new ommatidia are
      added from a crescentic dorso-anterio-ventral edge of the eye and that maturing
      ommatidia go through a sequence in which originally the nuclei of cone-, pigment
      , and retinula cells are arranged in three separate layers. At the beginning of
      the microvillar development, the organization of the corresponding rhabdomeres is
      still quite different (much less regular) from that of those rhabdomeres that
      make up the mature rhabdom. Marginal ommatidia always possess smaller diameters
      than more centrally located ones and retinal screening pigment granules are most
      apparent in the retinula cells only after the first microvilli have appeared. The
      diameters of rhabdom microvilli (approx. 55 nm) do not differ in ommatidia from
      the five investigated eye regions in small specimens (< 1.5 cm body length), but
      show a tendency to be slightly wider in the anterior (= frontal or rostral)
      regions of the eye (approx. 65 nm) in larger specimens (> 2.0 cm body length).

PMID- 12619568
TI  - Stimulation of jasmonic acid production in Zea mays L. infected by the maize
      rough dwarf virus-Rio Cuarto. Reversion of symptoms by salicylic acid.
AB  - In the present paper we study the possible biological relevance of endogenous
      jasmonic acid (JA) and exogenous salicylic acid (SA) in a plant-microbial system
      maize-virus. The virus disease "Mal de Rio Cuarto" is caused by the maize rough
      dwarf virus-Rio Cuarto. The characteristic symptoms are the appearance of galls
      or "enations" in leaves, shortening of the stem internodes, poor radical system
      and general stunting. Changes in JA and protein pattern in maize control and
      infected plants of a virus-tolerant cultivar were investigated. Healthy and
      infected-leaf discs were collected for JA measurement at different post-infection
      times (20, 40, 60 and 68 days). JA was also measured in roots on day 60 after
      infection. For SDS-PAGE protein analysis, leaf discs were also harvested on day
      60 after infection. Infected leaves showed higher levels of JA than healthy
      leaves, and the rise in endogenous JA coincided with the enation formation. The
      soluble protein amount did not show differences between infected and healthy
      leaves; moreover, no difference in the expression of soluble protein was revealed
      by SDS-PAGE. Our results show that the octadecanoid pathway was stimulated in
      leaves and roots of the tolerant maize cultivar when infected by this virus. This
      finding, together with fewer plants with the disease symptoms, suggest that
      higher foliar and roots JA content may be related to disease tolerance. SA
      exogenous treatment caused the reversion of the dwarfism symptom.

PMID- 12619569
TI  - [Problems of functional study of the stomach in contemporary gastrology].
AB  - In the assessment of the functional state of the stomach the interest to its
      secretory functioning has remained constant and in the center of attention of
      physiologists and clinicians during the past century. That is understandable.
      After all, the level of secretion of gastric juice enriched with the acid and
      pepsins defines numerous aspects in the functioning of this organ and its peptic,
      bactericidal and even evacuation functions. Moreover, under certain conditions
      active gastric juice can turn from a mediator in the normal peptic process into a
      solely pathogenetic factor and promote the development of a number of so-called
      acid-dependent diseases that have conventionally included stomach ulcer, reflux
      esophagitis, postgastrectomy ulcers of the anastomosis and other more infrequent
      pathological states. A distinct positive reaction to the application of anti-acid
      preparations is common for all these diseases. At the same time, the role of HCI
      in their development remains comprehensible only in some aspects.

PMID- 12619570
TI  - [Complicated form of chronic stomach ulcer].
AB  - Stomach ulcer is one of the most important problems of gastroenterology.
      Complicated, often recurring, giant and refractory stomach ulcers are most
      complex in the pathogenetic and treatment regard. The chronic and often recurring
      course of the disease, high percent of complications including such severe ones
      as perforation and bleeding, malignization, penetration and stenosis quite often
      result in a partial or complete disability in patients. As is well known, it is
      generally the most active and capable part of population that suffers from this
      disease.

PMID- 12619571
TI  - [Problem of antibiotic-resistant Helicobacter pylori and ways of overcoming it].
AB  - Application of non-drug treatment methods along with the basic drug therapy can
      promote the overcoming of antibiotic resistance and contribute to the eradication
      of H. pylori.

PMID- 12619572
TI  - [Features of mucosal flora associated with relapse of ulcers and acute erosive
      ulcer damage to the gastroduodenal zone during an unstable course of ischemic
      heart disease].
AB  - There was a study of 34 patients both with an unstable course of ischemic heart
      disease and a recurrence of ulcer or acute gastroduodenal ulcers and erosions.
      Irrespective of the nature of the pathologic process 14-15 different genera and
      species of microorganisms with features of potential pathogenecity were revealed
      in the tissue samplings from the periulcerous and perierosive zones of the
      mucosa. The greatest frequency, quantity and fermentative activity were marked in
      staphylococci, streptococci, enterococci and candidas. H. pylori yielded to a
      number of specimens of the gastroduodenal zone microbiocenosis in this regard. A
      less marked activation of the microflora pathogenic potential was observed in the
      intact mucosa remote from the lesions as in its tissue samplings 10-12 genera and
      species of microorganisms were revealed. The pathomicrobiocenosis being formed
      there might inhibit the healing of gastroduodenal erosions and ulcers in patients
      with an unstable course of ischemic heart disease, which must be taken into
      consideration in the development of methods for their treatment and prophylaxis.

PMID- 12619573
TI  - [Role of stress in the etiopathogenesis of duodenal ulcer in young patients].
AB  - The analysis of the acid-forming function of the stomach, both basal and
      stimulated with insulin, atropine test, tests for the content of the
      adrenocorticotropic hormone, somatotropic hormone, thyrotropic hormone,
      triiodothyronine, thyroxin, cortisol in the blood and the content of gastrin in
      the blood and gastric juice, activity of the processes of lipid peroxidation,
      content of ceruloplasmin in the blood, content of Helicobacter pylori (Hp) in the
      gastric mucosa were conducted in 68 men and 64 women at the age from 18 to 40
      years suffering from gastroduodenal ulcer in order to examine the role of stress
      in ulcer formation. 38 patients with duodenal ulcer took proton pump blockers and
      antioxidants for 3 years whenever they were in a stress situation. The research
      revealed that young patients with duodenal ulcer show enhanced sensitivity of
      parietal cells and sympathoadrenal system to stressful situations, and
      stimulation of the acid-forming stomach function takes place under the effect of
      both catecholamines and gastrin. Men can have both Hp-dependent and Hp
      independent duodenal ulcers, while women have mostly Hp-dependent duodenal
      ulcers. Prescription of proton pump blockers of and antioxidants for patients
      with duodenal ulcer, who are in a stressful situation, reduces the frequency of
      duodenal ulcer recurrences.

PMID- 12619574
TI  - [Features of deontology in patient with duodenal ulcer].
AB  - The presented data demonstrate the frequency and variety of different disorders
      of mental response to the fact of the disease among patients with duodenal ulcer.
      It may be seen from experience the doctor's deontology assists essentially to
      patients in restoring their mental functions disturbed in the period of
      exacerbation. A psychodiagnostic examination allows detecting patients that
      require a psychotherapeutic consultation (and a psychiatrist's consultation in a
      number of cases).

PMID- 12619575
TI  - [Lactulose in treatment of hepatic encephalopathy in patient with liver
      cirrhosis].
AB  - Our research demonstrated the high efficiency of using lactulose in patients with
      the latent and first grades of portal-systemic encephalopathy. Lactulose is an
      efficient and safe remedy, and its consistent application prevents the
      development of portal-systemic encephalopathy and makes it possible to control
      the level of hyperammonemia and improve a patient's quality of life.

PMID- 12619576
TI  - [Clinico-immunologic effect of immunomodulin and bactim in duodenal ulcer under
      environmental pollution conditions].
AB  - There was a study of the effect of immunomodulin and bactrim (biseptol-480)
      preparations in 53 patients with duodenal ulcer living in the ecologically
      polluted Southern Aral region. It was revealed that the application of
      immunomodulator immunomodulin and bactrim, a combined sulfanilamide preparation,
      in combination with the conventional anti-ulcer treatment promotes stronger
      bactericidal activity with respect to Helicobacter pylori, development of the
      immune status of the organism, acceleration of ulcer cicatrisation, reduction of
      the average period of staying in an in-patient hospital, which is an indication
      of its economic efficiency.

PMID- 12619577
TI  - [Pathophysiology and principles of treating acute blood loss].
AB  - The success of medical measures in case of acute hemorrhage depends substantially
      on the adequacy of determination of the volume deficiency of the circulating
      blood and its components as well as on the timely conduction of a
      pathigenetically grounded complex of infusion-transfusion therapy. Modern
      transfusiology has a great number of blood substitutes at its disposal, which
      allow fighting against acute hypovolemia with the minimal replacement of the
      blood loss with blood components. As there is no single remedy for treatment of
      acute hemorrhage, in each specific case it is necessary to select an adequate
      combination of transfusion media to conduct specific infusion-transfusion
      therapy.

PMID- 12619579
TI  - [Crystallo-optic structures of bile in chronic acalculous cholecystitis].
AB  - A crystal optical study of the cystic bile under the conditions of compulsory
      dehydration in patients with acalculous cholecystitis made it possible to
      determine selective markers of lithogenic dyscholia according to the bile
      oversaturation with cholesterol, bilirubin and calcium. Chronic acalculous
      cholecystitis (CAC) is a chronic polyetiologic inflammatory disease of the gall
      bladder (GB) combined with motor-tonic impairments of the bile-excreting tract
      function and with changes of physical and chemical properties and biochemical
      bile structure (dyscholia). CAC contributes to cholestasia, metabolic disorders
      and formation of calculi. The identification of lithogenic bile properties and
      early, pre-clinical diagnostics of cholelithiasis remain as urgent as before.
      Complicated physical and chemical methods are used for diagnostics of
      cholelithiasis: nuclear magnetic resonance spectroscopy, laser quasielastic
      scattering, electron microscope studies, gel-distribution chromatography. At
      present these methods are inaccessible for wide practical application due to
      their high cost. At the same time it is known that the diagnostics of
      cholelithiasis at early stages can be based on the detection of liquid
      crystalline structures in the bile. The object of this study was an early crystal
      optical diagnostics of dyscholia in patients with CAC and detection of bile
      lithogenicity markers.

PMID- 12619578
TI  - [Treatment and outcome of chronic hepatitis B in children].
AB  - 225 children at the age from 6 months to 15 years with chronic hepatitis type B
      (CHB) were under observation. In addition to clinical biochemical evaluation and
      morphological recording, there also was the serologic monitoring of the
      pathologic process condition by means of determination of hepatitis type B and
      other hepatitis viruses markers. The patients were observed during 1-10 years. It
      was found that almost all of the patients, with the exception of 3 children
      (1.3%), had no acute onset of the disease. According to the morphological study
      data, changes in the liver varied from minimal to apparent activity, up to the
      formation of hepatocirrhosis in single cases. The clinical presentation of CHB in
      children included mainly the enlargement and induration of the liver, enlargement
      of the spleen and anhepatic signs (capillaritis and telangiectasia). After 4
      years from the onset of CHB stable and prolonged remission was formed in most of
      the patients (64.6%); in 35.4% of cases clinical biochemical activity of the
      disease remained for a longer period of time (5-10 years or longer). The gradual
      cessation of the disease activity correlates with seroconversion of HBeAg on anti
      Hbe. Children with the continuous pathologic process in the liver have HBV DNA in
      their blood. The main outcome of CHB in children is a prolonged remission with
      permanent HBs-antigenemia in 89% of cases. The recovery was recorded in 9.68% of
      cases (disappearance of HbsAg and acquisition of anti-HBs). Hepatocirrhosis was
      formed in 3 children (1.32%).

PMID- 12619580
TI  - [Essential microelements and gallstones in children].
AB  - The article presents a study of particular features of the essential
      microelements content in the hair, blood, bile and gallstones in infants with
      cholelithiasis. It was shown that this disease is accompanied by a lack of
      microelements, which appears as a lack of selenium, imbalance of zinc and
      accumulation of iron and copper in biological objects. In conjunction with other
      factors (vegetative dysfunction, comorbidities of the gastrointestinal tract and
      maldevelopment of the bile-excreting tract), the lack of microelements can
      promote the formation of gallstones in infants. It is possible to obtain complete
      information on particular features of microelements changes with the help of
      simultaneous studies of tissues of the hair, blood, bile and gallstones.

PMID- 12619582
TI  - [Treatment of patients with chronic pancreatitis in ambulatory care facilities].
AB  - Application of up-to-date differentiated therapy in outpatient conditions and
      conduction of anti-recurrence courses combined with dietary food make it possible
      to prevent the development of severe forms of the disease and to retain long-run
      capacity for work and sufficient standard of living in chronic pancreatitis
      patients.

PMID- 12619581
TI  - [Features of composition of bile acids in duodenal bile in patients with chronic
      pancreatitis].
AB  - A number of conditions contributing to changes in metabolism of bile acids (BA)
      appears in case of chronic pancreatitis (CP). There was a study of particular
      features of the BA composition in the bile of 20 patients with CP and 10 donors
      with the help of the thin-layer chromatography method. The first group consisted
      of patients with alcoholic pancreatitis (AP) at the acute stage of the disease,
      and the second one consisted of patients with chronic biliary pancreatitis. A
      substantial increase in the content of conjugated BA was recorded in the bile of
      AP patients. The dependence of changes of bile secretion and its content on the
      duration of the disease was established. A reduction of bile secretion and
      decrease in the content of conjugated BA and cholesterol therein were recorded in
      the second group of patients. A particular feature of the BA composition was a
      decrease in the percentage of conjugates of cholic acid and glycodioxicholan
      acids. Cholic acid prevailed among free BAs. The lithocholic acid content
      increased depending on the duration and severity of the disease. Possible reasons
      of cholesterol deficit and high free cholic acid content in the bile of CP
      patients were noted. The findings indicate a colloidal stability of the bile in
      case of CP. An abnormal conjugation of BAs with glycine and especially with
      taurine can be not only the reason for changes in the qualitative BA composition
      but can also lead to changes in absorption of exogenous cholesterol. These
      changes are most apparent in patients with biliary-dependent forms of
      pancreatitis.

PMID- 12619583
TI  - [Clinical aspects of using pariet in treating chronic pancreatitis].
AB  - Three groups of patients were studied with the purpose of assessing the
      efficiency of the application of Pariet in the complex treatment of chronic
      pancreatitis. The first group (16 people) underwent conventional treatment
      (spasmolytics, enzymes, disintoxication therapy). In addition to conventional
      treatment, the second (22 people) and third (21 people) groups were administered
      Pariet (rabeprazole), 20 mg per day, or Quamatel (famotidine), 40 mg per day,
      respectively. The intragastric and intraduodenal pH was higher against the
      background of the treatment with Pariet than against the background of the
      application of Quamatel even within the first hours and days of treatment. A
      faster pain relief was observed in the second group of patients (p 0.05) than in
      the third one. According to the MRI data, the seven-day Pariet treatment of
      patients with chronic pancreatitis was accompanied by a reduction of the pancreas
      size, the diameter of the main pancreatic duct and the pancreatic edema. Thus,
      the application of Pariet in the complex treatment of chronic pancreatitis
      promotes a faster and more efficient pain relief and reduction of pancreatic
      edemas, as compared to the Quamatel therapy.

PMID- 12619584
TI  - [Pathogenetic therapy of alcoholic liver disease].
AB  - Ademetionine (Geptral) can be recommended both for reducing acute attacks of
      alcoholic hepatitis and for a supporting therapy in patients with chronic liver
      lesions of the toxic genesis, taking into account its vast positive effect on the
      liver.

PMID- 12619585
TI  - [Pharmacoeconomics of ulcers: a view from Saint-Petersburg].
AB  - Only in Saint Petersburg the application of omeprazole, hiconcil and fromilid in
      the treatment of adult patients with duodenal ulcer could save up to 26 million
      rubles per year due to the decrease in the number of recurrences. Yet these funds
      are still wasted with the persistence worthy of better application, since most
      general practitioners do not realize either economic or even clinical value of
      eradication. The above-mentioned calculations provide a ground for reflections on
      the improvement of methods of advanced training for specialists with the use of
      pharmacoepidemiological and pharmacoeconomic grounds for the selection of optimum
      remedies for the treatment of duodenal ulcer. A thorough clinical and economic
      evaluation of our actions, methods and preparations for treatment will make it
      possible to enhance the efficiency and quality of treatment, to avoid not only
      considerable undesirable drug reactions but also unjustified social costs in the
      way it is done in many countries.

PMID- 12619586
TI  - [Pathogenetic and surgical aspects of treating gastroesophageal reflux and hiatal
      hernia].
AB  - Gastroesophageal reflux is a diesease caused by a disorder of the esophagus motor
      function, weakening of the barrier lower esophageal sphincter function, slowing
      down of gastric evacuation, and as result, prolonged contact of the gullett
      mucosa with the acidic gastric content.

PMID- 12619588
TI  - [Antibiotic-associated diarrhea].
AB  - There are more than 500 species of microbes in the human bowels, and their total
      amount reaches 10(14), which is much higher than the total quantity of the
      cellular content in human organism. The history of teaching about microbiocenosis
      demonstrates various connections of microorganisms with the bowels and other
      organs and systems of human body. The available data about the significance of
      the bowels microbe flora for human organism give grounds for comparing it with
      the nervous, cardiovascular or any other organism system.

PMID- 12619587
TI  - [Diagnosis of peritoneal adhesions of abdominal cavity organs].
AB  - The best results produced by objective methods in cases of scheduled examinations
      of patients with peritoneal commissures of the abdominal cavity organs are
      observed in a complex study being a combination of X-ray and radionuclide methods
      of study, ultrasonic method, MRI and laparoscopy.

PMID- 12619589
TI  - [Crohn's disease in children].
AB  - Crohn's disease is a chronic transmural inflammation that can involve any part of
      the digestive system, from the oral cavity to the anal canal, being combined with
      many abenteric manifestations. It can appear at any age. The first description of
      this disease in a teenager was made in 1834 by B.B. Crohn, and 11 years later a
      series of observations describing 48 children with this disease was published.
      The concept of the Crohn's disease as a non-children illness underwent a change
      with the widening of diagnostic possibilities, wide use of the endoscopic method
      of diagnostics in pediatric practice, and histological studies of biopsy
      materials. A steady growth of the frequency of Crohn's disease detections has
      been recorded since the middle of the 1980s. Morbidity in Great Britain and
      Sweden doubled reaching 3.1 for 100,000 infants, and in 1993 its spread made up
      16.6 for 100,000.

PMID- 12619590
TI  - [Treatment and rehabilitation of patients with chronic opisthorchiasis with skin
      manifestations].
AB  - Our studies demonstrated that chronic opisthorchosis with a skin syndrome is
      accompanied by a severer clinical course. The course of rehabilitation measures
      with the use of resort recreation (mud-bad cure) combined with traditional
      treatment stages makes it possible to considerably enhance the efficiency of
      treatment of both opisthorchosis and its skin manifestations, and should be
      applied more often in practice.

PMID- 12619591
TI  - [Prospects for ultrasonic diagnosis in peritoneal commissures of the abdominal
      organs].
AB  - In the nearest future the ultrasonic method of study will enable clinicians to
      diagnose quicker and more directly patients with peritoneal commissures of the
      abdominal cavity and will help to localize more directly the places of the
      greatest accumulation of commissures, confirm or discover various complications
      of peritoneal commissures. It will be especially important for the patients who
      have contraindications to X-ray examinations. It is certain that clinicians
      should be attracted by the precision of the ultrasonic method and by its non
      traumatic nature and safety for a patient.

PMID- 12619592
TI  - [Change in hormonal regulation in experimental adrenaline stomach ulcer].
AB  - The activation or inhibition of the activity of various hormone subsystems
      depending on the phase of the ulcerative process was shown in experiments on rats
      with adrenal ulcers. The early (catabolic) phase of the ulcerative process
      develops against the background of the pituitary-adrenal system pituitary-adrenal
      with an increase of the outlet of adrenocorticotropic hormone (ACTH) and
      glucocorticoids. In the early period of ulcer formation a suppression of the
      gonadotropic system activity was observed with an abrupt decrease of the level of
      sex hormones, especially estradiol, during the whole period of adrenal ulcers
      existence. A suppression of the growth hormone system activity was also observed
      with a further increase of its level in the stomach mucosa in the anabolic phase.
      The level of gastrin in the stomach mucosa was increased in the anabolic phase of
      the ulcerative process, which can testify to the participation of the growth
      hormone and gastrin in the healing of an ulcerative defect.

PMID- 12619593
TI  - [Effect of warm and cold honey solutions on acid-forming function of the
      stomach].
AB  - Apitherapy is treatment of diseases with biologically active products of bee
      keeping (BAPB), which is developing in an intensive way all over the world. The
      interest in apitherapy is explained, on the one hand, by a great number of
      natural compounds produced by bees as a result of their vital functions and
      having high physiological activity, and on the other hand, by the universal
      nature of bees occurrence and comparative simplicity of getting the bee-keeping
      products. In apitherapy literature many authors point to the fact that honey has
      an impact on gastric secretion: a cold honey solution stimulates, and a warm one
      inhibits acid excretion. Yet there are no results of studies confirming this
      action in all publications.

PMID- 12619594
TI  - The specialty of medical-surgical nursing: the solid rock, not the stepping
      stone.

PMID- 12619596
TI  - Latex protein allergy and your choice of gloves: a balanced consideration.
AB  - Natural rubber gloves have been acknowledged as the best protective devices
      available for protecting health care personnel and their patients against viral
      transmission and infectious fluids. Yet, with the adoption of standard safety
      precautions and the increase in the use of gloves, an increasing number of people
      are being affected with latex allergy. Negative publicity related to latex
      allergy has resulted in health care personnel deciding against using the highly
      protective natural rubber gloves. The relationship between natural rubber gloves
      and latex protein allergy needs to be better understood in order for health care
      professionals to make an informed choice in their selection of gloves.

PMID- 12619595
TI  - Assessing and managing acute pain in older adults: a research base to guide
      practice.
AB  - Older adults experiencing acute pain are often underassessed and undertreated.
      This review summarizes recommendations from an evidence-based practice guideline
      on acute pain management in older adults. Key areas highlighted are pain
      assessment and monitoring, patient education, pharmacologic management, and
      nonpharmacologic management.

PMID- 12619597
TI  - Managing the oral sequelae of cancer therapy.
AB  - Patients undergoing systemic chemotherapy and/or head and neck radiotherapy
      frequently experience treatment side effects. Oral complications are among the
      most common problems associated with these therapies. These sequelae include
      mucositis, oral hemorrhage, infection, and xerostomia (dry mouth). Occasionally,
      oral complications are so severe that the cancer treatment must be reduced or
      even terminated. By providing comprehensive care, nurses work to help prevent,
      identify, and manage these oral sequelae, and thus maximize quality of life.
      Limiting the effects of oral sequelae increases patient adherence to treatment
      protocols, improves the quality of life, and increases the odds of long-term
      survival.

PMID- 12619598
TI  - Testicular cancer: an overview.
AB  - Testicular cancer (TC) strikes men between the ages of 15 and 35. If detected
      early, this disease can be irradicated in virtually every patient. Unfortunately,
      several hundred men will die from this disease each year. Research has shown that
      men do not know the importance of testicular self-examination, and they are not
      knowledgeable about TC. Nurses should be able to discuss treatment modalities,
      side-effect management related to those treatments, and special issues dealing
      with sexuality, body image perception, and infertility.

PMID- 12619599
TI  - Genetic susceptibility to lung cancer: implications for smoking cessation.
AB  - Lung cancer is the leading cause of cancer death in the United States. As
      information from the Human Genome Project becomes integrated into clinical
      practice, knowledge of genetic susceptibility for lung cancer will be used to
      identify persons at risk and to individualize treatments, such as prescribing
      chemoprevention. Nurses who assimilate genetic information into their practice
      can help patients to understand the implications of genetic susceptibility to
      lung cancer for their health and to reduce their disease risk with adaptive
      behaviors.

PMID- 12619600
TI  - Stricter cholesterol guidelines broaden indications for the 'statin' drugs.

PMID- 12619601
TI  - Antipsychotics and children: wide disparities in prescribing.

PMID- 12619602
TI  - Community provider services: growing demand, fewer resources.

PMID- 12619604
TI  - Integrating evidence-based practice with quality management.

PMID- 12619605
TI  - Evidence-based practice in managed care: more propaganda than reality?

PMID- 12619606
TI  - 'We are the evidence'--consumers seek shift in research focus.

PMID- 12619607
TI  - I'm a psychologist, not a prescriber.

PMID- 12619608
TI  - A clinical perspective: identifying and analyzing loss exposures.

PMID- 12619609
TI  - A lifesaving jolt from within.

PMID- 12619610
TI  - Dietary rumble: protein, fats, and carbohydrates.

PMID- 12619611
TI  - Breast cancer: good results with less trauma.

PMID- 12619612
TI  - Working in an effective workout.

PMID- 12619613
TI  - House calls. Compression fractures in my back have been causing pain for about a
      month. Is there anything that can help?

PMID- 12619615
TI  - Health tips. Strengthening ankles.

PMID- 12619614
TI  - Reducing diabetes risk. Diet, exercise are key.

PMID- 12619616
TI  - Researchers link new hormone to appetite suppression.

PMID- 12619617
TI  - Blood pressure drugs may help prevent stroke.

PMID- 12619618
TI  - Abscesses. The result of an infection.

PMID- 12619620
TI  - Otosclerosis. Untimely hearing loss.

PMID- 12619619
TI  - Multiple sclerosis. Treatment is shifting.

PMID- 12619621
TI  - A friend recommended I take a dietary supplement for my arthritis that contains
      glucosamine and chondroitin. What are these made from? Do they help?

PMID- 12619623
TI  - Cholesterol drugs: very safe and highly beneficial.

PMID- 12619624
TI  - Giving your healthcare plan a checkup.

PMID- 12619622
TI  - Best defense against bioterrorism.

PMID- 12619625
TI  - Reducing your risk of pancreatic cancer.

PMID- 12619626
TI  - What are the best options for brightening stained teeth?

PMID- 12619627
TI  - Your liver. A vital organ that's durable but not indestructible.

PMID- 12619628
TI  - The destruction of the quarantine station on Staten Island in 1858, 1926.

PMID- 12619629
TI  - New Academy member demonstrates sustaining success with innovative efforts to
      meet community needs.

PMID- 12619630
TI  - NurseWeek/AONE national Survey of Registered Nurses.

PMID- 12619633
TI  - [Bacteriophage therapy: Stalin's forgotten medicine].

PMID- 12619634
TI  - [Typhus].

PMID- 12619635
TI  - Follow the yellow brick road.

PMID- 12619632
TI  - [The emergence of Korean modern hospitals: hospitals in the late period of Chosun
      Dynasty].
AB  - Hospitals are confronting in the transforming or reforming period to cope with
      the rapid social and environmental changes worldwide. By the researches in the
      history of Korean health, we could understand the context of the introduction of
      Western medicine and institutions to Korea. However there have been few studies
      on the historical review of hospitals in relations to their roles in the modern
      medicine. This article is to review the issues around the rise of modern
      hospitals in Korean history of health affairs. The introduction of Western
      medicine in Korea was on the road with the establishment of Kwanghyewon, the
      Royal Hospital, which was possible due to favorable conditions under the Korean
      socio-political background for the emerging and accepting the entirely new
      medical system. And also the emergence of modern and transformed the Korean
      traditional health system from the fundamentals through the corruption of the old
      dynasty to nowadays. Most national health affairs including medical services,
      prevention of diseases, health promotion, and the training of health personnels
      have performed along with the development of modern hospitals, which have the
      roots in the period after the end of 19th century. Thus the Korean history of
      health care around the end of 19th century and beginning of 20th century could be
      defined as a period of emergence of modern hospitals. The hospitals also have
      played core roles in establishing the Korean modern health system and culture.
      Compared to the cases of Western countries, Korean modern hospitals were emerged
      with the exogenous factors in the turbulence of political and cultural changes in
      the world system. In sum, Korean modern hospitals in the period of late Chosun
      have the great meaning in that they are the beginning point to shape the current
      Korean health care system and the driving forces or carriers of this new system.

PMID- 12619636
TI  - [What do you see? Crohn disease (ileitis terminalis)].

PMID- 12619637
TI  - The painful reality.

PMID- 12619638
TI  - Eplerenone.

PMID- 12619639
TI  - Analytical jobs for analytical minds.

PMID- 12619640
TI  - Multislice/spiral computed tomography for screening for coronary artery disease.
AB  - Multislice computed tomography (MSCT) and spiral (or helical) computed tomography
      (CT) are designed to provide faster images with better resolution than
      conventional CT scanning. MSCT and spiral CT have been used to quantify
      calcification in the coronary arteries, in an effort to link this to coronary
      artery disease. Long-term studies on clinical outcomes of people screened with
      MSCT or spiral CT are lacking, as are comparisons with established screening
      modalities like risk factor algorithms. Low specificity gives rise to concern
      over false positive results. False positives may cause harm (and expense) due to
      inappropriate and invasive follow-up. One study was identified in which spiral CT
      was compared with electron beam CT (EBCT) to evaluate coronary calcifications in
      33 asymptomatic individuals, giving a sensitivity of 74% and a specificity of
      70%. There is insufficient evidence at this time to suggest that asymptomatic
      people derive clinical benefit from undergoing coronary calcification screening
      using MSCT or spiral CT scanning.

PMID- 12619641
TI  - Current awareness in NMR in biomedicine.

PMID- 12619642
TI  - Fulfilling the dream of nursing.

PMID- 12619643
TI  - Putting research into practice: behavioral and pharmacologic management of
      dementia.

PMID- 12619644
TI  - Hematology-neurology connection: Association between Factor XIII and hemorrhagic
      stroke in young women through genetic polymorphism.

PMID- 12619645
TI  - Some thoughts on the pressure dependence of uveoscleral flow.

PMID- 12619646
TI  - Some thoughts on the pressure dependence of uveoscleral flow.

PMID- 12619647
TI  - Some thoughts on the pressure dependence of uveoscleral flow.

PMID- 12619648
TI  - [Medicine and orientalism in the late nineteenth century Korea].
AB  - The paper investigates medical missionaries that exerted a significant role in
      establishing Western medicine in the late nineteenth century Chosun, in relation
      to orientalism, an academically popularized concept introduced by Edward Said.
      Historical analysis is focused on several important medical missionaries such as
      Horace N. Allen, William B. Scranton, John W. Heron, C. C. Vinton, and Oliver R.
      Avison to explain how their activism as medical missionary contributed to the
      formation of medical orientalism in which Western medicine was 'taught, studied,
      administered, and judged' in that period. In addition, I explore into how medical
      orientalism was in service of Japanese imperialism by showing that medical
      missionaries had to be under imperial surveillance by Japanese colonizers. The
      article explores the medical system of the Koryo Dynasty period and its social
      characteristics. First, the structure of medical system and roles of medical
      institutions during the Koryo Dynasty period will be summarized. Then the
      characteristics of the medical system will be identified through exploring the
      principles of its formation in a view of social recognition of medical care and a
      view of social recognition of medical care and a view of public policy.

PMID- 12619649
TI  - The Triple Forced Duction Test(s) for diagnosis and treatment of superior oblique
      palsy -- with an updated flow chart for unilateral superior oblique palsy.
AB  - PURPOSE: To review and update the management of superior oblique extraocular
      muscle clinical paresis and palsy, (SOP) employing and applying recent advances
      in the diagnosis and surgical methods. METHODS: These include three recently
      introduced forced duction tests, respectively for laxity of the SO tendon,
      absence of the SO tendon, and contracture of the ipsilateral superior rectus
      muscle. Also discussed are the pathophysiologic mechanisms behind various modes
      of clinical presentation of SOP, older concepts requiring scrutiny, and prior
      surgical methods which should no longer be employed due to advances in our
      knowledge. RESULTS AND CONCLUSIONS: These newer aspects of SOP management are
      organized and displayed in a revised Plager flow sheet to facilitate their
      application.

PMID- 12619650
TI  - Commentary on terminology and therapeutic principles: challenges in classifying
      complementary and alternative medicine practices.

PMID- 12619651
TI  - [Establishment of transsphenoidal approach in skull base surgery: a historical
      analysis].
AB  - Many approaches are being used for exposure of the anterior cranial base regions,
      ranging from extracranial to intracranial, such as transsphenoidal approach. This
      intracranial approach, developed in the beginning of the twentieth century, has
      recently become one of the most commonly used approaches after many incremental
      improvements. This thesis aims at examining the development of the approach and
      those who contributed to this procedure. The author also contemplate problems
      which may occur in the historical analysis. From the nineteenth century, advances
      have been made in anesthesiology, sterilization, cerebral localization and
      knowledge of anatomical and physiologic aspects of the skull base. The
      development of new knowledge and technique has helped to overcome obstacles,
      making surgery of the skull base through extracranial approach both technically
      feasible and therapeutically effective. To avoid serious postoperative
      complications after the extracranial approach, transsphenoidal approach had been
      developed in the beginning of the twentieth century. Transsphenoidal approach had
      been widely used right after its introduction. But it had not been used popularly
      since late 1920s in the United States. In early 1960s, this technique, spread
      from Europe, has regained popularity and become one of the most widely-used
      approaches. In the history of the transsphenoidal approach, it has been though
      that the effort of Harvey Cushing and Oskar Hirsch, the endeavor of Cushing's
      scholars, several new attempts of otolaryngologists played an important role.
      However, comparing to great appreciation of neurosurgeons, especially Harvey
      Cushing on their significant contribution to the further development of this
      technique, the role of other pioneering doctors have been underestimated in
      previous historical studies on the transsphenoidal approach. It was because
      dynamical relationships among several specialties had influence on the historical
      analysis. This cases shows that historical analysis is influenced not only by
      past figures bu also by current situations.

PMID- 12619652
TI  - Progress over a decade, a century, a millennium.

PMID- 12619653
TI  - Bibliography. Current world literature. Strabismus.

PMID- 12619654
TI  - Bibliography. Current world literature. Oculoplastic and orbital surgery.

PMID- 12619655
TI  - The efficacy of salt?

PMID- 12619656
TI  - [The development of private hospital in modern Korea, 1885-1960].
AB  - Modern hospital in Korea was the space of competition and comprise among
      different forces such as the state power and social forces, imperialism and
      nationalism, and the traditional and modern medicine. Hospital in the Japanese
      colonialism was the object of control for establishing the colonial medical
      system. Japanese colonialism controlled not only the public hospital but also the
      private hospital which had to possess more than 10 infectious beds in the
      isolation building by the Controlling Regulation of Private Hospital. In fact,
      the private hospital had to possess more than 20 beds for hospital management. As
      a result, its regulation prevented the independent development of the private
      hospital. But because the public hospital could not accommodate many graduates of
      medical school, most of them had to serve as practitioner. Although some
      practitioners had more than 20 beds in their clinics, they were not officially
      included in the imperial medicine. By concentrating on the trend of the number of
      beds in the hospital, this paper differs from most previous studies of the system
      of hospital, which have argued that the system of hospital was converted the
      public-centered hospital system under the colonial medical system into the
      private-centered hospital system under the U. S. medical system after the
      Liberation in 1945. After Liberation, medical reformers discussed arranging the
      public and the private hospital. Lee Yong-seol, who was a Health-Welfare
      minister, disagreed the introduction of the system of state medicine. Worrying
      about the flooding of practitioners, he did not want to intervene the
      construction of hospital by state power. Because the private hospital run short
      of the medical leadership and the fundamental basis, the state still controlled
      the main disease in the public health and the prevention of epidemics. This means
      the state also played important part in the general medical examination and
      treatment. The outbreak of Korean War in 1950 reinforced the role of state. The
      leadership of the public hospital verified the trend of the quantity of beds. The
      number of beds in the private hospital exceeded that of the public hospital in
      1966 for the first time. Futhermore, the number of beds in the public hospital
      doubled that of private hospital in the new general hospital of 1950s. This means
      the system of hospital after the Liberation was not converted the public-centered
      hospital system into the private-centered hospital system, but maintained the
      public-centered hospital system until 1960s.

PMID- 12619657
TI  - Cross contamination by amalgam carriers.

PMID- 12619658
TI  - History of the body politic: French royal doctors, history, and the birth of a
      nation 1560-1634.
AB  - This article examines the role played by royal doctors in forming an empirical
      political science in France at the end of the sixteenth century. Bringing with
      them tools from the Galenic tradition, doctors such as Rodolphe Le Maistre,
      Abraham-Nicolas de La Framboisiere, and Jean Heroard doubled as political
      counselors. They not only looked for ways to heal the king's body, they also
      looked for ways to heal and regulate the body of the nation. Their new vision of
      the monarch as a practicing physician of the state is an essential yet unknown
      facet of the origins of political modernity.

PMID- 12619659
TI  - Retail pharmacy operations in World War II: a profit and loss statement.

PMID- 12619660
TI  - The traffic in eighteen-century medicines and medical ideas and the Medicina
      Pennsylvania of George de Benneville.

PMID- 12619661
TI  - Critical care medicine: anesthesiology steps forward.

PMID- 12619662
TI  - William D. Hamilton, 1 August 1936 - 7 March 2000.

PMID- 12619663
TI  - Floyd Ratliff, 1 May 1919 - 13 June 1999.

PMID- 12619664
TI  - George Wald, 18 November 1906 - 12 April 1997.

PMID- 12619665
TI  - Women's little secrets: defining the boundaries of reproductive knowledge in
      sixteenth-century France. Society for the social history of medicine student
      essay competition winner, 1999.
AB  - Although there has been much recent work on the contribution of midwives to early
      modern medical practice, there has been less investigation of the participation
      of other women outside of the corporative or professional medical arena. This
      article seeks to examine how elite women were involved in medical discussion of
      reproduction, using the sixteenth-century correspondence surrounding the
      reproductive health of Elisabeth de Valois, Queen of Spain. Letters passed
      between the courts of France and Spain demonstrate that control of Elisabeth's
      reproductive health became a source of conflict between the Spanish and French.
      National rivalries created possibilities for women to be authoritative
      contributors in medical discussion with the support of university-trained
      physicians.

PMID- 12619666
TI  - Production and characterization of recombinant Phanerochaete chrysosporium beta
      glucosidase in the methylotrophic yeast Pichia pastoris.
AB  - The extracellular beta-glucosidase from the white-rot fungus Phanerochaete
      chrysosporium was expressed heterologously in the methylotrophic yeast Pichia
      pastoris. After 7 days' cultivation in an induction medium containing 1% (v/v)
      methanol, the expression level of the recombinant enzyme was 28,500 U/l, 38 times
      that of the wild-type enzyme. The specific activity of the crude recombinant
      enzyme for p-nitrophenyl-beta-D-glucoside was 52 U/mg, 37 times that of the wild
      type enzyme; this difference made the purification of the enzyme simple. On a SDS
      PAGE, the molecular mass of the recombinant enzyme was 133 kDa, and that of the
      wild-type enzyme was 116 kDa, but the difference had no effect on the hydrolysis
      of cellobiose or p-nitrophenyl-beta-D-glucoside. We concluded that the
      recombinant enzyme produced by Pichia pastoris retains the catalytic properties
      of the wild-type enzyme from Phanerochaete chrysosporium.

PMID- 12619667
TI  - Extracellular acidic polysaccharide production by a two-membered bacterial
      coculture.
AB  - A two-membered coculture of strains KYM-7 and KYM-8, identified as Cellulomonas
      cellulans and Agrobacterium tumefaciens, respectively, produced a large amount of
      an extracellular polysaccharide, designated APK-78, from starch. Each strain in
      pure culture produced only very little amount of polysaccharide from starch; the
      coexistence of the two strains from the early stage of cultivation was
      indispensable for a large amount of polysaccharide to be produced. The
      polysaccharide APK-78 was acidic and composed of glucose, galactose, succinic
      acid, and pyruvic acid with a molar ratio of 8.1:1.0:1.7:1.0, indicating that it
      is a succinoglycan type of polysaccharide.

PMID- 12619668
TI  - Effect of phytate in soy protein on the serum and liver cholesterol levels and
      liver fatty acid profile in rats.
AB  - Dietary soy protein, in comparison with casein, generally lowers the serum
      cholesterol concentration in rats fed on a cholesterol-enriched diet, while mixed
      results were observed in rats fed on a diet free of cholesterol. Soy protein also
      suppresses the conversion of linoleic acid to arachidonic acid in the rat liver.
      The present study examines whether phytate, a minor component of a soy protein
      isolate, is responsible for these beneficial effects of soy protein. Weanling
      male rats were fed for 4 weeks on a purified diet containing a 20% level of
      protein (either casein (CAS), soy protein (SOY), phytate-depleted SOY (PDSOY) or
      phytate-replenished PDSOY (PRSOY)) and cholesterol (0 or 0.5%). The dietary
      protein source and phytate level only affected the serum and liver cholesterol
      concentrations when the animals were fed on the cholesterol-enriched diet, being
      significantly lower in those rats fed on the SOY and PRSOY diets than in those
      fed on the CAS diet, while the concentrations in the rats fed on the PDSOY diet
      were intermediate. When the animals were fed on the cholesterol-free diet, the
      ratio of (20:3n-6 + 20:4n-6)/18:2n-6 in liver phosphatidylcholine, a delta6
      desaturation index, was significantly lower in the SOY diet group than in the
      CAS, PDSOY and PRSOY diet groups. Dietary cholesterol significantly depressed the
      ratio, but neither depletion nor replenishment of phytate affected the ratio.
      These results suggest that phytate in soy protein played a limited role in the
      cholesterol-lowering effect of soy protein and was not involved in the metabolism
      of linoleic acid.

PMID- 12619669
TI  - Regulation of the peripheral body temperature by foods: a temperature decrease
      induced by the Japanese persimmon (kaki, Diospyros kaki).
AB  - We investigated whether the ingestion of the Japanese persimmon (kaki, Diospyros
      kaki) could lower the human peripheral body temperature. It was found that the
      temperatures recorded at the foot and wrist were depressed after kaki consumption
      compared to after the same amount of water consumption. The effects of ingesting
      freeze-dried kaki and eating a cookie (as its nutritional counterpart) containing
      the same amount of carbohydrate, protein, fat, and water were compared. A similar
      temperature-reducing effect of kaki was observed. The recovery of finger
      temperature after soaking the finger in ice-cooled water was also studied. The
      temperature recovery was delayed after kaki consumption. It was thus
      quantitatively demonstrated that ingesting kaki indeed had the effect of lowering
      (or repressing the rise) of the peripheral human body temperature, as has been
      traditionally believed in China for many hundreds of years.

PMID- 12619670
TI  - Purification and characterization of a new type of alpha-glucosidase from
      Paecilomyces lilacinus that has transglucosylation activity to produce alpha-1,3-
      and alpha-1,2-linked oligosaccharides.
AB  - A fungus producing an alpha-glucosidase that synthesizes alpha-1,3- and alpha-1,2
      linked glucooligosaccharides by transglucosylation was isolated and identified as
      Paecilomyces lilacinus. The cell-bound enzyme responsible for the synthesis was
      extracted by suspension of mycelia with 0.1 M phosphate buffer (pH 8.0), and the
      extract was purified. The molecular weight and the isoelectric point were
      estimated to be 54,000 and 9.1, respectively. The enzyme was most active at pH
      5.0 and 65 degres C. The enzyme hydrolyzed maltose, nigerose, and kojibiose. The
      enzyme also hydrolyzed soluble starch and amylose with the rate toward maltose. p
      Nitro-phenyl alpha-glucoside and isomaltose were not good substrates. The enzyme
      had high transglucosylation activity to synthesize oligosaccharides containing
      alpha-1,3- and alpha-1,2-linkages. At an early stage of the reaction,
      considerable maltotriose, 4-O-alpha-nigerosyl-D-glucose, and 4-O-alpha-kojibiosyl
      D-glucose were synthesized. Afterwards, nigerose and kojibiose were accumulated
      gradually with glucose as an acceptor.

PMID- 12619672
TI  - Effect of medium-chain triglycerides on the postprandial triglyceride
      concentration in healthy men.
AB  - This study compared the serum lipid concentrations after a single dose of medium
      chain triglycerides (MCT) or long-chain triglycerides (LCT) between individuals
      grouped according to the body mass index (BMI). Twenty-five males participated as
      volunteers, the test diet containing 10 g of MCT or LCT. Blood samples were
      collected up to 6 h after the intake of a test diets. The LCT diet resulted in
      significantly greater increases in areas under the curves (AUCs) for serum and
      chylomicron triglyceride in the BMI > or = 23 kg/m2 group than those in the BMI <
      23 kg/m2 group. The magnitude of response after intake of the MCT diet by the BMI
      > or = 23 kg/m2 group was significantly lower than that after the LCT diet. These
      results suggest that, in subjects with BMI > or = 23 kg/m2, the intake of MCT is
      preferable to that of LCT for maintaining postprandial triglyceride at a low
      concentration.

PMID- 12619671
TI  - Purification and characterization of meta-cleavage compound hydrolase from a
      carbazole degrader Pseudomonas resinovorans strain CA10.
AB  - 2-Hydroxy-6-oxo-6-(2'-aminophenyl)-hexa-2,4dienoic acid [6-(2'-aminophenyl)-HODA]
      hydrolase, involved in carbazole degradation by Pseudomonas resinovorans strain
      CA10, was purified to near homogeneity from an overexpressing Escherichia coli
      strain. The enzyme was dimeric, and its optimum pH was 7.0-7.5. Phylogenetic
      analysis showed the close relationship of this enzyme to other hydrolases
      involved in the degradation of monocyclic aromatic compounds, and this enzyme was
      specific for 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (6-phenyl-HODA),
      having little activity toward 2-hydroxy-6-oxohepta-2,4-dienoic acid and 2
      hydroxymuconic semialdehyde. The enzyme had a Km of 2.51 microM and k(cat) of
      2.14 (s(-1)) for 6-phenyl-HODA (50 mM sodium phosphate, pH 7.5, 25 degrees C).
      The effect of the presence of an amino group or hydroxyl group at the 2'-position
      of phenyl moiety of 6-phenyl-HODA on the enzyme activity was found to be small;
      the activity decreased only in the order of 6-(2'-aminophenyl)-HODA (2.44 U/mg) >
      6-phenyl-HODA (1.99 U / mg) > 2-hydroxy-6-oxo-6-(2'-hydroxyphenyl)-hexa-2,4
      dienoic acid (1.05 U/mg). The effects of 2'-substitution on the activity were in
      accordance with the predicted reactivity based on the calculated lowest
      unoccupied molecular orbital energy for these substrates.

PMID- 12619674
TI  - Structural characterization of triacylglycerol in several oils containing gamma
      linolenic acid.
AB  - The differences are reported in the triacylglycerol (TG) structures of oils
      containing gamma-linolenic acid (GLA) from Oenothera biennis Linn seed oil (OBLO)
      from the wild plant, evening primrose seed oil (EPO) from a cultured plant, and
      bio-GLA oil (BIO) from a mold, the physiological functions of which were
      ascertained by animal testing. Reverse-phase high-performance liquid
      chromatographic separation detected 12 TG peaks each for OBLO and EPO, and 28 TG
      peaks for BIO. TG-containing GLA were composed of five molecular species each in
      OBLO and EPO, and ten molecular species in BIO. The totals of the molecular
      species containing GLA were 29.8% in OBLO, 23.8% in EPO, and 56.6% in BIO. In
      OBLO, the GLA level at the sn-2 position of the major TG species was higher than
      that in EPO. In BIO, the GLA level at the sn-2 position of the major TG species
      was lower than those in OBLO and EPO.

PMID- 12619673
TI  - Antioxidative activity of the blue pigment formed in a D-xylose-glycine reaction
      system.
AB  - A blue compound was prepared from 1 M D-xylose and 0.1 M glycine, and designated
      Blue-M1, an intermediate color product of melanoidins. As melanoidins are well
      known to have antioxidative activity as well as high scavenging activity against
      active oxygen species, the antioxidative activity of Blue-M1 against the
      peroxidation of linoleic acid was investigated, in addition to the scavenging
      activity of Blue-M1 toward hydroxyl and DPPH radicals. Blue-M1 suppressed the
      peroxidation of linoleic acid as effectively as melanoidins did. The scavenging
      activity of Blue-M1 toward hydroxyl and DPPH radicals was also as strong as that
      of melanoidins. Blue-M1 showed higher activity with increasing concentration. The
      pyrrolopyrrole ring and a methine bridge between two pyrrolopyrrole rings in Blue
      M1 could be related to the ability for radical scavenging activity, but not four
      carboxyl groups.

PMID- 12619675
TI  - beta-Galactosidase and its significance in ripening of "Saijyo" Japanese
      Persimmon fruit.
AB  - The fruit extracts of ripening cv. Japanese Persimmon, "Saijyo", contained a
      number of glycosidases and glycanases. Among them, beta-galactosidase appeared to
      be the most significant, and the activity increased in parallel with tissue
      ripening. Persimmon beta-galactosidase was presented in at least three isoforms,
      beta-galactosidase-I (pI = 4.88), beta-galactosidase-II (pI = 6.76), and beta
      galactosidase-III (pI = 7.05). beta-Galactosidase-III had exo-type galactanase
      activity, while the others did not. The activity of endo-type glycanases was a
      maximum in immature green or yellow fruits. The firmness of the pulp tissue
      decreased dramatically, and the amount of water-soluble polysaccharide (WSS)
      increased. The enzyme activities of exo-type glycosidases, especially beta
      galactosidase, appeared maximal in mature red fruits. The amount of extractable
      pectin remained unchanged, although the galactose content of the high-molecular
      weight fraction in WSS decreased dramatically. These results suggest that the
      ripening of persimmon was caused by the solubilization of pectic polysaccharide
      by endo-type glycanases and digestion by exo-type glycosidases. beta
      Galactosidase, in particular, seemed to play a major role in ripening the fruit.

PMID- 12619676
TI  - Identification and characterization of Scp15, a protein from Streptomyces
      coelicolor A3(2) inducing neurites in PC12 cells.
AB  - We previously showed that a fungal protein, p15, induces neurite outgrowth and
      differentiation of rat pheochromocytoma PC12 cells. We report here the
      identification and characterization of a protein similar to p15, found in
      Streptomyces coelicolor A3(2). This hypothetical protein, tentatively named
      Scp15, has significant similarity with p15, including conserved positions of four
      cysteine residues involved in the formation of essential disulfide bonds in p15.
      Hexahistidine-tagged recombinant Scp15 proteins were produced in Escherichia
      coli, purified, and analyzed for their neurite-inducing activity. Although they
      were less active than p15, they dose-dependently induced neurites and the
      expression of neurofilament M. Neurite outgrowth by Scp15 was inhibited by
      nicardipine, suggesting that Scp15 induces neurites via activation of a calcium
      signaling pathway.

PMID- 12619677
TI  - Novel aminopeptidase specific for glycine from Actinomucor elegans.
AB  - Glycyl aminopeptidase was purified 600-fold from a cell extract of Actinomucor
      elegans by ammonium sulfate fractionation and sequential chromatography on DEAE
      Toyopearl, Toyopearl HW65C, and FPLC-Superdex 200 HR, with recovery of 3.3% of
      the activity. The enzyme highly specifically hydrolyzed Gly-X (amino acid,
      peptide, or arylamide) bonds. The enzyme hydrolyzed other amino acid residues but
      at a rate of less than one fifth that with Gly. The order was Gly >> Ala >> Met >
      Arg > Ser > Leu. The Km value for glycyl-2-naphthylamide was 0.24 mM. The enzyme
      was most active at pH 8.0 with glycyl-2-naphthylamide as the substrate and its
      optimal temperature was 40 degrees C. The enzyme was inhibited by iodoacetic
      acid, and p-chloromercuribenzoate but not done by diisopropylfluorophosphate, o
      phenanthroline, or EDTA. Magnesium and calcium had no effect on enzymic activity,
      but the activity was suppressed by cadmium, zinc, and copper ions. The molecular
      mass was estimated to be 320 kDa by gel filtration on FPLC-Superdex 200 HR and
      56.5 kDa by SDS-PAGE, so the enzyme probably was a hexamer.

PMID- 12619678
TI  - Effect of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on the
      susceptibility to Listeria infection.
AB  - We studied the effect of lactational exposure to 2,3,7,8-tetrachlorodibenzo-p
      dioxin (TCDD) on the susceptibility to Listeria infection of offspring in C57BL
      /6NCji mice. The offspring were nursed by TCDD-treated dams and exposed to TCDD
      from birth to weaning via milk. The exposure had little effect on the weights of
      immune organs and the spleen or the thymus cell population in the dams and
      offspring, but it enhanced the production of tumor necrosis factor alpha (TNF
      alpha) and interferon gamma (IFN-gamma) in the serum after Listeria infection.
      The clearance of Listeria monocytogenes from the spleen was impaired in the off
      spring. These results suggest that the exposure to TCDD of the offspring via milk
      disrupted the host resistance of the offspring, even though the main immune
      parameters were unchanged.

PMID- 12619679
TI  - Binding properties of Bacillus thuringiensis Cry1C delta-endotoxin to the midgut
      epithelial membranes of Culex pipiens.
AB  - The Cry1C delta-endotoxin from Bacillus thuringiensis is toxic to both
      lepidopteran and dipteran insect larvae. To analyze the dipteran-specific
      insecticidal mechanisms, we investigated the properties of Cry1C binding to the
      epithelial cell membrane of the larval midgut from the mosquito Culex pipiens in
      comparison with dipteran-specific Cry4A. Immunohistochemical staining of the
      larval midgut sections from Culex pipiens showed that Cry1C and Cry4A bound to
      the microvilli of the epithelial cells. The Cry1C binding to brush border
      membrane vesicles from the mosquito larvae was specific and irreversible, and did
      not compete with Cry4A. By ligand blotting analyses, we detected several Cry1C
      binding proteins, the Cry1C binding to which did compete with excess unlabeled
      Cry4A. These results suggested that Cry1C and Cry4A recognized the same binding
      site(s) on the epithelial cell surface but that their interaction with the target
      membrane differed.

PMID- 12619680
TI  - Interactions of heterologous mycelia colonized in the substrate govern fruit body
      production in the cultivated homobasidiomycete Pholiota nameko.
AB  - The spawn of cultivated mushrooms are generally produced, propagated, and
      distributed to growers as a mycelial culture without genetic purification, in
      which phenotypic variants frequently occur. We investigated how heterologous
      mycelia present in a spawn influence fruit body production in the cultivated
      basidiomycete Pholiota nameko. The 'di-mon' dual cultivation of protoplast clones
      produced mosaic fruit bodies, which could result from the 'di-mon' mating. In the
      'di-di' dual cultivation of heterologous strains with different fruiting times,
      authentic fruit bodies of each dikaryon and chimera showing a feature combining
      characteristics of the two dikaryons emerged simultaneously. Mycelia isolated
      from the chimera produced all three types of fruit bodies, indicating
      unlikeliness of the occurrence of anastomosis. These results suggest that mycelia
      colonized in the substrate interact with each other and coordinately promote
      fruit body production in P. nameko. This phenomenon masks a clonal variability
      that may be surfaced through multiplication and distribution of the spawn,
      occasionally bringing about abnormal fruiting.

PMID- 12619681
TI  - Specific RNA interference in psbP genes encoded by a multigene family in
      Nicotiana tabacum with a short 3'-untranslated sequence.
AB  - RNA interference with double-stranded RNA is a new method for the study of gene
      function in various organisms. In this report, we show that an inverted repeat of
      a short (103-bp) 3'-untranslated sequence of an isogene, 1A, of psbP genes,
      encoded by a small multigene family of four genes (1A, 2AF, 3F, and 5B) in
      Nicotiana tabacum, can specifically suppress the expression of psbP isogenes 1A
      and 5B with a 3'-untranslated sequence similar to a transcribed double-stranded
      RNA. The expression of other psbP isogenes, 2AF and 3F, was not affected,
      although the coding sequences of the psbP family genes are highly conserved.
      Consistent with this observation, small interfering RNAs were detected for the 3'
      untranslated sequence used for the inverted-repeat transgene, and not for the
      coding sequence. These results suggest that double-stranded RNA having a 3'
      untranslated sequence could be useful for an isogene-specific RNA interference of
      the family genes in Nicotiana tabacum.

PMID- 12619682
TI  - Purification and characterization of NADP-linked isocitrate dehydrogenase from
      the copper-tolerant wood-rotting basidiomycete Fomitopsis palustris.
AB  - NADP-linked isocitrate dehydrogenase (EC 1.1.1.42), a key enzyme of the
      tricarboxylic acid cycle, was purified 672-fold as a nearly homogeneous protein
      from the copper-tolerant wood-rotting basidiomycete Fomitopsis palustris. The
      purified enzyme, with a molecular mass of 115 kDa, consisted of two 55-kDa
      subunits, and had the Km of 12.7, 2.9, and 23.9 microM for isocitrate, NADP, and
      Mg2+, respectively, at the optimal pH of 9.0. The enzyme had maximum activity in
      the presence of Mg2+, which also helped to prevent enzyme inactivation during the
      purification procedures and storage. The enzyme activity was competitively
      inhibited by 2-oxoglutarate (K(i), 127.0 microM). Although adenine nucleotides
      and other compounds, including some of the metabolic intermediates of glyoxylate
      and tricarboxylic acid cycles, had no or only slight inhibition, a mixture of
      oxaloacetate and glyoxylate potently inhibited the enzyme activity and the
      inhibition pattern was a mixed type.

PMID- 12619683
TI  - Need for cytochrome bc1 complex for dissimilatory nitrite reduction of
      Pseudomonas aeruginosa.
AB  - Pseudomonas aeruginosa strains deficient in the genes for cytochrome c1, a
      subunit of the cytochrome bc1 complex, or the tetraheme membrane protein NapC,
      which is similar to NirT of Pseudomonas stutzeri, were constructed and their
      growth was investigated. The cytochrome c1 mutant could not grow under anaerobic
      conditions with nitrite as an electron acceptor and did not reduce nitrite in
      spite of its producing active nitrite reductase. NirM (cytochrome c551) and
      azurin, which are the direct electron donors for nitrite reductase, were reduced
      by succinate in the presence of the membrane fraction from the wild-type strain
      as a mediator but not in the presence of that from the cytochrome c1 mutant.
      These results indicated that cytochrome bc1 complex was necessary for electron
      transfer from the membrane quinone pool to nitrite reductase. The NapC mutant
      grew anaerobically at the expense of nitrite, indicating that NapC was not
      necessary for nitrite reduction.

PMID- 12619684
TI  - Characterization of the biosynthetic gene cluster of rebeccamycin from
      Lechevalieria aerocolonigenes ATCC 39243.
AB  - The biosynthetic gene cluster for rebeccamycin, an indolocarbazole antibiotic,
      from Lechevalieria aerocolonigenes ATCC 39243 has 11 ORFs. To clarify their
      functions, mutants with rebG, rebD, rebC, rebP, rebM, rebR, rebH, rebT, or orfD2
      disrupted were constructed, and the gene products were examined. rebP disruptants
      produced 11,11'-dichlorochromopyrrolic acid, found to be a biosynthetic
      intermediate by a bioconversion experiment. Other genes encoded N
      glycosyltransferase (rebG), monooxygenase (rebC), methyltransferase (rebM), a
      transcriptional activator (rebR), and halogenase (rebH). rebT disruptants
      produced rebeccamycin as much as the wild strain, so rebT was probably not
      involved in rebeccamycin production. Biosynthetic genes of staurosporine, an
      another indolocarbazole antibiotic, were cloned from Streptomyces sp. TP-A0274.
      staO, staD, and staP were similar to rebO, rebD, and rebP, respectively, all of
      which are responsible for indolocarbazole biosynthesis, But a rebC homolog,
      encoding a putative enzyme oxidizing the C-7 site of pyrrole rings, was not found
      in the staurosporine biosynthetic gene cluster. These results suggest that
      indolocarbazole is constructed by oxidative decarboxylation of chromopyrrolic
      acid (11,11'-dichlorochromopyrrolic acid in rebeccamycin) generated from two
      molecules of tryptophan by coupling and that the oxidation state at the C-7
      position depends on the additional enzyme(s) encoded by the biosynthetic genes.

PMID- 12619685
TI  - Mepanipyrim, a novel inhibitor of pharmacologically induced Golgi dispersion.
AB  - Mepanipyrim inhibited retrograde Golgi-to-ER trafficking induced by brefeldin A
      (BFA), nordihydroguaiaretic acid, clofibrate, and arachidonyltrifluoromethyl
      ketone in NRK and other types of cells, but did not inhibit anterograde
      trafficking of Golgi-resident proteins translocated to ER by BFA and newly
      synthesized VSV-G. However, mepanipyrim did not block the TGN38 dispersion
      induced by any of these compounds. Mepanipyrim acted on the Golgi, and swollen
      vesicular Golgi structures were formed and similar structures accumulated during
      rebuilding of the Golgi after BFA removal. These actions of mepanipyrim were
      readily reversed after its removal. Mepanipyrim did not stabilize microtubules,
      but prevented nocodazole-induced fragmentation and dispersion of the Golgi. These
      results suggest that the mepanipyrim-sensitive molecules participated in
      stabilizing the Golgi and its anchoring in the perinuclear region, and equally
      importantly, that the novel action of mepanipyrim may be used as a
      pharmacological tool for investigating membrane transport, Golgi membrane
      dynamics, and differentiation of the Golgi from TGN.

PMID- 12619686
TI  - Nordihydroguaiaretic acid, of a new family of microtubule-stabilizing agents,
      shows effects differentiated from paclitaxel.
AB  - Nordihydroguaiaretic acid (NDGA) protected microtubules in NRK cells from
      depolymerization caused by structurally and functionally diverse drugs such as
      nocodazole, colchicine, vinblastine, and ilimaquinone. Hitherto reported drugs,
      although structurally unrelated to paclitaxel, stabilize microtubules in a way
      similar to that of paclitaxel and compete for paclitaxel binding to tubulin.
      However, NDGA had activity toward microtubules different from the effects of
      paclitaxel. In NRK cells, paclitaxel caused microtubule bundle formation in the
      presence and absence of microtubule-depolymerizing drugs. However, microtubule
      bundle did not form, and microtubules radiated from the microtubule-organizing
      center, in cells treated with NDGA. Acceleration of tubulin polymerization in
      vitro by paclitaxel was strong but that by NDGA was weak. Microtubules
      polymerized in vitro in the presence of paclitaxel, but not those polymerized in
      the presence of NDGA, resisted the effects of cold. NDGA seemed to bind to
      tubulin, but did not compete for [3H]paclitaxel binding to tubulin. These
      observations indicate that NDGA belongs to a novel family of microtubule
      stabilizing drugs.

PMID- 12619687
TI  - Nuclear localization of senescence marker protein-30, SMP30, in cultured mouse
      hepatocytes and its similarity to RNA polymerase.
AB  - Senescence marker protein-30 (SMP30), expressed mostly in the liver, protects
      cells against various injuries by stimulating membrane calcium-pump activity. By
      immunohistochemistry and western blotting, we found that SMP30 was in both the
      nuclei and cytoplasm of cultured mouse hepatocytes. By a homology search, we
      found that a domain of the SMP30 sequence 51 amino acid residues long was 60-66%
      similar to bacterial and yeast RNA polymerases.

PMID- 12619688
TI  - Selective accumulation of delphinidin derivatives in tobacco using a putative
      flavonoid 3',5'-hydroxylase cDNA from Campanula medium.
AB  - Blue flowers generally contain 3',5'-hydroxylated anthocyanins (delphinidin
      derivatives) as pigments, which are formed only in the presence of flavonoid
      3',5'-hydroxylases (F3'5'H). Heterologous expression of a F3'5'H gene therefore
      provides an opportunity to produce novel blue flowers for a number of ornamental
      plants missing blue flowering varieties. However, our previous study indicated
      difficulties in obtaining good accumulation of delphinidin derivatives in plants
      expressing F3'5'H. Here we report the isolation of a putative F3'5'H cDNA (Ka1)
      from canterbury bells (Campanula medium) and its expression in tobacco.
      Surprisingly, compared with other F3'5'H cDNAs, Ka1 encoded a protein with a
      unique primary structure that conferred high competence in the accumulation of
      delphinidin derivatives (up to 99% of total anthocyanins) and produced novel
      purple flowers. These results suggest that, among F3'5' H cDNAs, Ka1 is the best
      genetic resource for the creation of fine blue flowers by genetic engineering.

PMID- 12619689
TI  - Adjuvant activity of alum in inducing antigen specific IgE antibodies in BALB/c
      mice: a reevaluation.
AB  - The IgE production was compared in the presence and absence of aluminum hydroxide
      gel (alum). Without alum, the IgE production was induced within a suitable range
      of the antigen dosage; however, alum enhanced it. Alum did not affect the minimum
      requirement for the antigen dosage, indicating that alum may not take part in the
      efficiency of antigen presentation.

PMID- 12619690
TI  - Stimulation by caffeic acid, coumalic acid, and corilagin of the germination of
      resting spores of the clubroot pathogen Plasmodiophora brassicae.
AB  - Some chemicals were examined for their effects on the germination of resting
      spores of the clubroot pathogen Plasmodiophora brassicae, and on the control of
      clubroots in Chinese cabbage. Caffeic acid, coumalic acid, and corilagin
      stimulated the germination of Plasmodiophora spores and prevented the formation
      of clubroots in Chinese cabbage. Clubroot might be controlled by agents with
      germination-stimulating effects.

PMID- 12619691
TI  - Primary structure of cytochrome c gene from the white root rot fungus Rosellinia
      necatrix.
AB  - The nucleotide sequence of the cytochrome c (CytC) gene of the white root rot
      fungus Rosellinia necatrix was analyzed. The structure of this gene, which had
      three introns in the coding region, was similar to that of Aspergillus nidulans.
      The second intron of the R. necatrix CytC gene was not present in Neurospora
      crassa or Fusarium oxysporum. However, the amino acid sequence of R. necatrix was
      most similar to that of Neurospora crassa. Thus, it seemed that the second intron
      of the R. necatrix CytC gene was inserted into its present position after R.
      necatrix and its closest relatives diverged evolutionarily.

PMID- 12619692
TI  - Structural analysis of conjugated linoleic acid produced by Lactobacillus
      plantarum, and factors affecting isomer production.
AB  - An isomer of the conjugated linoleic acid (CLA) produced from linoleic acid by
      Lactobacillus plantarum was identified as cis-9,trans-11-octadecadienoic acid by
      proton nuclear magnetic resonance spectroscopy. Together with earlier results, we
      concluded that the bacterium produces two CLA isomers, cis-9,trans-11- and trans
      9,trans-11-octadecadienoic acid from linoleic acid. The addition of L-serine,
      glucose, AgNO3, or NaCl to the reaction mixture reduced production of the latter.

PMID- 12619693
TI  - A novel cellulolytic, anaerobic, and thermophilic bacterium, Moorella sp. strain
      F21.
AB  - A cellulolytic and thermophilic anaerobe was isolated from soil. This bacterium
      made a halo on a roll-tube culture containing Avicel. Analysis of the PCR-based
      16S rRNA gene sequence showed that the bacterium was closely related to Moorella
      thermoacetica. Scanning electron microscopy showed the bacterium is a rod and has
      no protuberant structure on the surface of cells growing on cellulose, suggesting
      that this strain is a non-cellulosomal cellulolytic bacterium. Carboxymethyl
      cellulase and xylanase activities were detected in the culture broth. A major
      fermentation product from ball-milled cellulose was acetate. This strain has a
      potential to convert cellulosic biomass to acetate, directly.

PMID- 12619694
TI  - Putative homologs of SSK22 MAPKK kinase and PBS2 MAPK kinase of Saccharomyces
      cerevisiae encoded by os-4 and os-5 genes for osmotic sensitivity and fungicide
      resistance in Neurospora crassa.
AB  - We cloned and characterized Neurospora NcSSK22 and NcPBS2 genes, similar to yeast
      SSK22 mitogen-activated protein (MAP) kinase kinase kinase and the PBS2 MAP
      kinase kinase genes, respectively. Disruptants of the NcSSK22 gene were sensitive
      to osmotic stress and resistant to iprodione and fludioxonil. Their phenotypes
      were similar to those of osmotic-sensitive (os) mutants os-1, os-2, os-4, and os
      5. The os-4 mutant strain transformed with the wild-type NcSSK22 gene grew on a
      medium containing 4% NaCl and was sensitive to iprodione and fludioxonil. In
      contrast, the NcPBS2 gene complemented the osmotic sensitivity and fungicide
      resistance of the os-5 mutant strain. We sequenced the NcPBS2 gene of the os-5
      mutant strain (NM216o) and found five nucleotides deleted within the kinase
      domain. This result suggests that the gene products of os-4 and os-5 are
      components of the MAP kinase cascade, which is probably regulated upstream by two
      component histidine kinase encoded by the os-1/nik1 gene.

PMID- 12619695
TI  - Biocatalytic deprotection of a cetraxate ester by Microbacterium sp. strain 7-1W
      cells.
AB  - Enzymatic deprotection of the terminal ester bond of a cetraxate methyl ester was
      done with resting cells of Microbacterium sp. strain 7-1W, which produces an
      esterase catalyzing a regioselective hydrolysis reaction, as the catalyst. When
      20 g of cetraxate methyl ester in 50 ml of a reaction mixture was incubated with
      5 g of wet cells for 17 h, 96% of the substrate was converted to the desired
      product, cetraxate, quantitatively.

PMID- 12619696
TI  - Antioxidative effect of citrus essential oil components on human low-density
      lipoprotein in vitro.
AB  - We studied the antioxidative action to evaluate the effect of citrus essential
      oil components on human LDL in vitro. Among the authentic volatile compounds
      tested, gamma-terpinene showed the strongest antioxidative effect, and inhibited
      both the Cu(2+)-induced and AAPH-induced oxidation of LDL. gamma-Terpinene added
      after 30 min (mid-lag phase) and 60 min (propagation phase) of incubation of LDL
      with Cu(2+) inhibited LDL oxidation.

PMID- 12619698
TI  - Catalytic properties of lipases immobilized on various mesoporous silicates.
AB  - Lipases SP525, AK, LIP, and PS were immobilized on three kinds of mesoporous
      silicates (FMS, PESO, and SBA) with diameters of 27 to 92 A. The amount of lipase
      activity adsorbed on these supports was related to the pore size of the silicate.
      Enantioselectivities of immobilized lipases were similar to those of free
      lipases, and recycling could be done in both aqueous and organic solvents.

PMID- 12619697
TI  - Efficient release of overproduced gene products from Escherichia coli BL21(DE3)
      by lytic infection with newly isolated bacteriophages.
AB  - Overproduced proteins from Escherichia coli BL21(DE3) were efficiently released
      with virulent bacteriophages. Leviviridae-like bacteriophages were isolated from
      soil and used to lyse BL21(DE3) cells transformed with beta-glucosidase,
      chitinase, or chitosanase genes. This method caused lysis of bacterial cells
      similar to that by conventional sonication and enabled us to effectively recover
      and purify the enzymes.

PMID- 12619699
TI  - Differential scanning calorimetry of the effects of Ca2+ on the thermal unfolding
      of Pseudomonas cepacia lipase.
AB  - Thermal unfolding of P. cepacia lipase was observed by adiabatic differential
      scanning microcalorimetry in the absence and presence of calcium ions at pH 8,
      and thermodynamic parameters of unfolding were evaluated to analyze the unfolding
      mechanism of the enzyme. The temperature of unfolding was higher at higher
      concentrations of Ca2+. From the Ca2+ concentration-dependence of the unfolding
      temperature, the number of calcium ions that dissociated from the enzyme molecule
      upon unfolding was estimated to be one. These results confirmed the validity of
      the unfolding mechanism proposed previously: NCa2+ < = => D + Ca2+, where N and D
      represent the native and denatured states, respectively, of the enzyme.

PMID- 12619700
TI  - Construction of a vector plasmid for use in Gluconobacter oxydans.
AB  - A host vector system in Gluconobacter oxydans was constructed. An Acetobacter
      Escherichia coli shuttle vector was introduced with the efficiency of 10(4)
      transformants/microg of DNA. Next, aiming for a self-cloning vector, we found a
      cryptic plasmid (which we named pAG5) of 5648 bp in G. oxydans strain IFO 3171,
      and sequenced the nucleotides. The plasmid seemed to have only one open reading
      flame (ORF) for a possible replication protein. Shuttle vectors of Gluconobacter
      E. coli were constructed with the plasmid pAG5 and an E. coli vector, pUC18.

PMID- 12619701
TI  - Functions of malonate decarboxylase subunits from Pseudomonas putida.
AB  - Malonate decarboxylase from Pseudomonasputida is composed of five subunits,
      alpha, beta, gamma, delta, and epsilon. Two subunits, delta and epsilon, have
      been identified as an acyl-carrier protein (ACP) and malonyl-CoA:ACP
      transacylase, respectively. Functions of the other three subunits have not been
      identified, because recombinant subunits expressed in Escherichia coi formed
      inclusion bodies. To resolve this problem, we used a coexpression system with
      GroEL/ES from E. coli, and obtained active recombinant subunits. Enzymatic
      analysis of the purified recombinant subunits showed that the alpha subunit was
      an acetyl-S-ACP:malonate ACP transferase and that the betagamma-subunit complex
      was a malonyl-S-ACP decarboxylase.

PMID- 12619702
TI  - Biodegradation of bisphenol A by cultured cells of Caragana chamlagu.
AB  - The biological degradation of 2,2-bis(4-hydroxyphenol)propane (1; bisphenol A,
      BPA), a representative endocrine disruptor, was studied with plant-cultured cells
      of Caragana chamlagu. An initial BPA concentration of 425 microM in an aqueous
      solution was degraded by C. chamlagu at 25 degrees C for 2 days in the dark, and
      two intermediates were then completely dissipated after 10 days.

PMID- 12619703
TI  - Plant chitinase as a possible biocontrol agent for use instead of chemical
      fungicides.
AB  - We investigated whether a plant chitinase can be used as a biocontrol agent
      instead of chemical fungicides by spraying chitinase E (family 19; class IV) from
      a yam (Dioscorea opposita Thunb) alone or together with beta-1,3-glucanase
      directly onto the surface of a powdery mildew infecting strawberry berries and
      leaves. Results were observed by eye and with a scanning electron microscope. The
      powdery mildew infecting the strawberries was degraded, mainly by the chitinase,
      and the disease did not appear again for more than 2 weeks. These results
      indicated that this kind of plant chitinase might be safe and biodegradable
      biocontrol agent for use instead of conventional fungicides.

PMID- 12619704
TI  - Clinical applications of cytokine assays.

PMID- 12619705
TI  - Current concepts on diagnosis and treatment of acute pancreatitis.

PMID- 12619706
TI  - Mitochondrial DNA mutations and oxidative stress in mitochondrial diseases.

PMID- 12619707
TI  - Autoantibodies to dsDNA, Ro/SSA, and La/SSB in systemic lupus erythematosus.

PMID- 12619708
TI  - Pathobiochemistry of nephrotic syndrome.
AB  - Nephrotic syndrome is a clinical and laboratory syndrome caused by the increased
      permeability of the glomerular capillary wall for macromolecules. Nephrotic
      syndrome is a potentially life-threatening state and persistent nephrotic
      syndrome has a poor prognosis with a high risk of progression to end-stage renal
      failure and a high risk of cardiovascular complications due to severe
      hyperlipidemia. Pathogenesis of increased glomerular permeability in different
      glomerular diseases has not been fully elucidated. Recently, identification of
      the mutated genes for some podocyte proteins (nephrin, podocin, alpha-actinin-4)
      in rare familial forms of nephrotic syndrome shed has new light on the molecular
      mechanisms of glomerular permselectivity. Gradually it becomes apparent that
      sporadic mutations of podocyte proteins (e.g., podocin) may be present even in
      some patients with acquired nephrotic syndrome. Expression of other podocyte
      proteins may change during the course of experimental nephrotic syndrome,
      possibly as a response to podocyte damage resulting either in apoptosis or
      stimulation of proliferation and some form of repair, including glomerular
      sclerosis. Better understanding of these mechanisms could clearly also have
      therapeutic implications. Glomerular permeability factors are believed to play a
      role in some noninflammatory glomerular diseases, mainly minimal change disease
      and focal segmental glomerulosclerosis, but their molecular identification
      remains elusive, possibly due to the nonhomogeneous nature of the underlying
      diseases. As an example, focal segmental glomerulosclerosis possibly can be
      caused by the sporadic mutation of some genes for podocyte proteins, increased
      production of glomerular permeability factor (possibly by T lymphocytes), or the
      loss of inhibitors of glomerular permeability factors in nephrotic urine. Clearly
      the factors causing increased glomerular permeability and factors perpetuating
      glomerular sclerosis are not necessarily the same. Proteinuria does not seem to
      be only the consequence of glomerular damage, but it may possibly cause tubular
      damage and initiate interstitial fibrosis and thus contribute to the progression
      of chronic renal failure in proteinuric renal diseases. Recent insights into the
      mechanisms of tubular protein reabsorption may give new tools for preventing the
      progression of chronic renal disease. Cubilin inhibitors could potentially
      ameliorate tubular and interstitial damage in patients with heavy proteinuria
      refractory to treatment. Nephrotic hyperlipidemia is accompanied with increased
      risk of cardiovascular complications and should be treated in all patients with
      persistent nephrotic syndrome. The putative positive effect of hypolipidemic
      drugs (namely statins) on the cardiovascular risk and potentially also on the
      rate of progression of chronic renal failure remains to be demonstrated in
      prospective controlled studies. Recent progress in understanding podocyte biology
      in rare inherited glomerular diseases gives the chance to understand in the near
      future the molecular pathogenesis of increased glomerular permeability in the
      much more common acquired forms of nephrotic syndrome.

PMID- 12619709
TI  - Total antioxidant capacity.

PMID- 12619710
TI  - Lymphoid malignancies: immunophenotypic analysis.

PMID- 12619711
TI  - Isolation of islets of Langerhans from rodent pancreas.

PMID- 12619712
TI  - Purification of rat pancreatic B-cells by fluorescence-activated cell sorting.

PMID- 12619713
TI  - Assessment of insulin secretion in the mouse.

PMID- 12619714
TI  - Detection of insulin production by immunohistochemistry.

PMID- 12619715
TI  - Quantification of the level of insulin gene expression.

PMID- 12619716
TI  - Chromatin immunoprecipitation using isolated islets of Langerhans.

PMID- 12619717
TI  - Adenoviral gene transfer into beta-cell lines.

PMID- 12619718
TI  - Utilization of NOD mice in the study of type 1 diabetes.

PMID- 12619719
TI  - Introduction of DNA into 3T3-L1 adipocytes by electroporation.

PMID- 12619720
TI  - Analysis of insulin-stimulated glucose uptake in differentiated 3T3-L1
      adipocytes.

PMID- 12619721
TI  - Fractionation analysis of the subcellular distribution of GLUT-4 in 3T3-L1
      adipocytes.

PMID- 12619723
TI  - Assaying tyrosine phosphorylation of insulin receptor and insulin receptor
      substrates.

PMID- 12619722
TI  - Visualization and quantitation of integral membrane proteins using a plasma
      membrane sheet assay.

PMID- 12619724
TI  - Measuring insulin-stimulated phosphatidyl-inositol 3-kinase activity.

PMID- 12619725
TI  - Assaying AKT/protein kinase B activity.

PMID- 12619727
TI  - Measurement of glycogen synthesis and glycogen synthase activity in 3T3-L1
      adipocytes.

PMID- 12619726
TI  - Measurements of cellular phosphoinositide levels in 3T3-L1 adipocytes.

PMID- 12619728
TI  - Measurement of contraction-stimulated GLUT-4 translocation in isolated skeletal
      muscle.

PMID- 12619729
TI  - Single-embryo measurement of basal- and insulin-stimulated glucose uptake.

PMID- 12619730
TI  - Immunohistologic staining of muscle and embryos to detect insulin-stimulated
      translocation of glucose transporters.

PMID- 12619731
TI  - Decisions about hormone replacement therapy. Whose responsibility are they?

PMID- 12619732
TI  - Influenza vaccine given during pregnancy.

PMID- 12619733
TI  - How much fish is too much?

PMID- 12619734
TI  - Another drug database for hand-held computers.

PMID- 12619735
TI  - Lessons for us all. One doctor's experience with a fatal illness.

PMID- 12619736
TI  - Exposure to electromagnetic fields during pregnancy.
AB  - QUESTION: Several of my patients quote recent media coverage claiming that
      working with home appliances could increase the risk of misarriages. What is your
      advice? ANSWER: Two recent epidemiologic studies from California have suggested
      an increased risk of miscarriages associated with exposure to magnetic fields.
      Even if the threshold associated with such risk is a biologic and true risk (and
      not just an association), it does not appear to arise from typical use of hair
      dryers, microwave ovens, vacuum cleaners, and similar home appliances.

PMID- 12619737
TI  - Hormone replacement therapy: the final frontier.

PMID- 12619738
TI  - Echocardiography or auscultation? How to evaluate systolic murmurs.
AB  - OBJECTIVE: To compare cardiac physical examination with echocardiography for
      evaluating systolic murmurs. QUALITY OF EVIDENCE: Three databases were searched
      for studies comparing echocardiography and auscultation as to sensitivity and
      diagnostic accuracy: MEDLINE (Ovid Online), EMBASE, and Current Contexts. The
      quality of reported data is lowered by subjective interpretation of results of
      both cardiac physical examination and echocardiography, especially Doppler colour
      flow imaging. MAIN MESSAGE: In adults, functional systolic murmurs can usually be
      distinguished from organic murmurs. Pathologic murmurs frequently have one or
      more associated clinical abnormalities. If a clinician determines a murmur is
      benign, results of echocardiography are very likely to be normal, especially in
      young and middle-aged adults. According to current guidelines, echocardiography
      should not be ordered for "innocent" systolic murmurs in patients who are
      asymptomatic and have otherwise normal findings on examination. If patients with
      functional systolic murmurs could be identified and not routinely referred for
      echocardiography, great cost savings could be realized. CONCLUSION:
      Echocardiography is not required for all patients with systolic murmurs and
      should not replace cardiac physical examination.

PMID- 12619739
TI  - Saline nasal irrigation: Its role as an adjunct treatment.
AB  - OBJECTIVE: To review clinical evidence on the efficacy of saline nasal irrigation
      for treatment of sinonasal conditions and to explore its potential benefits.
      QUALITY OF EVIDENCE: Clinical trials, reviews, and treatment guidelines
      discussing nasal irrigation were obtained through a MEDLINE search from January
      1980 to December 2001. Most trials were small and some were not controlled;
      evidence, therefore, is level II, or fair. MAIN MESSAGE: Flushing the nasal
      cavity with saline solution promotes mucociliary clearance by moisturizing the
      nasal cavity and by removing encrusted material. The procedure has been used
      safely for both adults and children, and has no documented serious adverse
      effects. Patients treated with nasal irrigation rely less on other medications
      and make fewer visits to physicians. Treatment guidelines in both Canada and the
      United States now advocate use of nasal irrigation for all causes of
      rhinosinusitis and for postoperative cleaning of the nasal cavity. CONCLUSION:
      Nasal irrigation is a simple, inexpensive treatment that relieves the symptoms of
      a variety of sinus and nasal conditions, reduces use of medical resources, and
      could help minimize antibiotic resistance.

PMID- 12619740
TI  - Case report: prescribing caution. When a simple disease isn't so simple.

PMID- 12619741
TI  - Short report: managing anticoagulation. Comparison of results at three primary
      care centres.

PMID- 12619742
TI  - Canadian consensus on hormone replacement therapy. Estrogen and progestin use in
      postmenopausal women.

PMID- 12619743
TI  - Coming home to family (medicine).

PMID- 12619744
TI  - Learning with the community. Evolution to transformative action research.

PMID- 12619745
TI  - The effect of test position on lumbar spine position sense.
AB  - STUDY DESIGN: Repeated-measures experimental design. OBJECTIVES: The purpose of
      this study was to compare lumbar spine position sense in 3 test positions
      (standing, sitting, and 4-point kneeling [FPK]) to determine if position sense is
      affected by test position. BACKGROUND: Several recent studies have tested
      position sense in the spine. There has, however, been no consistency in the
      testing methods or test positions used in these studies. METHODS AND MEASURES:
      Seventy asymptomatic males (range, 20-51 years) volunteered for testing. Active
      lumbar spine repositioning accuracy and precision was tested 3-dimensionally in 3
      test positions (standing, sitting, and FPK) and under 2 conditions (eyes open and
      blindfolded), using the neutral spine posture as the initial reference position.
      RESULTS: Both the accuracy and precision of lumbar spine repositioning was found
      to be significantly affected by test position. Repositioning errors (reflective
      of accuracy) were significantly larger in FPK than in both sitting and standing,
      and significantly larger in sitting than in standing, under both eyes-open and
      blindfolded conditions. Precision of repositioning was significantly less in the
      FPK position as compared to the standing position. CONCLUSION: The results of
      this study suggest that test position has a significant effect on the acuity of
      lumbar spine position sense and should be considered when examining the current
      literature on spine proprioception.

PMID- 12619746
TI  - Isokinetic profile of elbow flexion and extension strength in elite junior tennis
      players.
AB  - STUDY DESIGN: Descriptive study. OBJECTIVES: To determine whether bilateral
      differences exist in concentric elbow flexion and extension strength in elite
      junior tennis players. BACKGROUND: The repetitive nature of tennis frequently
      produces upper extremity overuse injuries. Prior research has identified tennis
      specific strength adaptation in the dominant shoulder and distal upper extremity
      musculature of elite players. No previous study has addressed elbow flexion and
      extension strength. METHODS AND MATERIALS: Thirty-eight elite junior tennis
      players were bilaterally tested for concentric elbow flexion and extension muscle
      performance on a Cybex 6000 isokinetic dynamometer at 90 degrees/s, 210
      degrees/s, and 300 degrees/s. Repeated-measures ANOVAs were used to test for
      differences between extremities, muscle groups, and speed. RESULTS: Significantly
      greater (P<0.002) dominant-arm elbow extension peak torque values were measured
      at 90 degrees/s, 210 degrees/s, and 300 degrees/s for males. Significantly
      greater (P<0.002) dominant-arm single-repetition work values were also measured
      at 90 degrees/s and 210 degrees/s for males. No significant difference was
      measured between extremities in elbow flexion muscular performance in males and
      for elbow flexion or extension peak torque and single-repetition work values in
      females. No significant difference between extremities was measured in elbow
      flexion/extension strength ratios in females and significant differences between
      extremities in this ratio were only present at 210 degrees/s in males (P<0.002).
      CONCLUSION: These data indicate muscular adaptations around the dominant elbow in
      male elite junior tennis players but not females. These data have ramifications
      for clinicians rehabilitating upper extremity injuries in patients from this
      population.

PMID- 12619747
TI  - A new concept of estimating tibiofibular torsion: an in vivo reliability study.

PMID- 12619748
TI  - Innovation in environmental analysis.
AB  - As the EU launches its latest 17 billion research programme, which includes
      significant funding for environmental research, JEM takes a look at the trends in
      and dynamics of innovation in environmental analysis.

PMID- 12619749
TI  - The application of proton transfer reaction-mass spectrometry (PTR-MS) to the
      monitoring and analysis of volatile organic compounds in the atmosphere.
AB  - Proton transfer reaction-mass spectrometry (PTR-MS) is a new and emerging
      technique for the measurement and monitoring of volatile organic compounds (VOCs)
      at low concentrations in gaseous samples in more-or-less real time. Utilising
      chemical ionisation, it combines the desirable attributes of high sensitivity and
      short integration times with good precision and accuracy. Recently it has been
      exploited in applications related to atmospheric science. Here, the principles of
      operation of the PTR-MS are described, its advantages and disadvantages
      discussed, its inherent uncertainties highlighted, some of its uses in
      atmospheric sciences reviewed, and some suggestions made on its future
      application to atmospheric chemistry.

PMID- 12619751
TI  - Measurements of C6-C8 hydrocarbons at a UK rural site during January 1999. Site
      evaluation and correlations between species.
AB  - Ambient concentrations of C6-C8 aromatic hydrocarbons and n-heptane, determined
      by gas chromatography with flame ionisation detection, are presented from a
      winter campaign during January 1999 at a rural site near Leeds. Absolute
      concentrations are significantly lower than those obtained from the only
      designated UK rural site (Harwell) in the automated UK hydrocarbon network. Both
      absolute and relative concentrations of hydrocarbons measured at the site have
      been interpreted in terms of the arriving back-trajectories. The site is subject
      to two main airflows during the winter months; relatively polluted air from the
      southwest and much cleaner air from the northwest. Ratios of hydrocarbon
      concentrations show evidence of significant chemical processing consistent with
      chemical removal by OH. Uncertainties in the ages of the trajectories prevent a
      reliable estimation of the average OH concentration over the trajectory. The
      dependence of the variance of the hydrocarbon concentrations with their lifetime
      with respect to removal by OH does not show the expected behaviour.

PMID- 12619750
TI  - A two-column method for long-term monitoring of non-methane hydrocarbons (NMHCs)
      and oxygenated volatile organic compounds (o-VOCs).
AB  - A method has been developed for concurrent analysis of C2-C7 hydrocarbons and C2
      C5 oxygenated volatile organic compounds (o-VOCs) including alcohols, aldehydes,
      ketones and ethers. A multi-bed, Peltier-cooled adsorbent trap, consisting of
      Carboxen 1000 and Carbopack B, was used to acquire one sample per hour. Upon
      injection the sample was split in an approximately 50:50 ratio between a 50 m
      aluminium oxide (Al2O3) porous layer open tubular (PLOT) column and a 10 m LOWOX
      column. Eluents from each column were then analysed using flame ionisation
      detection (FID). Regular calibration of the system was performed using a standard
      cylinder mixture at the parts per billion by volume (ppbV) level for non-methane
      hydrocarbons (NMHCs) and a permeation tube method for the oxygenated species. The
      system is fully automated with NMHC detection limits between 1 and 10 parts per
      trillion by volume (pptV) and o-VOC detection limits between 10 and 40 pptV.

PMID- 12619752
TI  - Application of a compact all solid-state laser system to the in situ detection of
      atmospheric OH, HO2, NO and IO by laser-induced fluorescence.
AB  - A tuneable, high pulse-repetition-frequency, solid state Nd:YAG pumped titanium
      sapphire laser capable of generating radiation for the detection of OH, HO2, NO
      and IO radicals in the atmosphere by laser induced fluorescence (LIF) has been
      developed. The integration of the laser system operating at 308 nm into a field
      measurement apparatus for the simultaneous detection of hydroxyl and hydroperoxy
      radicals is described, with detection limits of 3.1 x 10(5) molecule cm(-3)
      (0.012 pptv in the boundary layer) and 2.6 x 10(6) molecule cm(-3) (0.09 pptv)
      achieved for OH and HO2 respectively (30 s signal integration, 30 s background
      integration, signal-to-noise ratio = 1). The system has been field tested and
      offers several advantages over copper vapour laser pumped dye laser systems for
      the detection of atmospheric OH and HO2 radicals by LIF, with benefits of greater
      tuning range and ease of use coupled with reduced power consumption, instrument
      footprint and warm-up time. NO has been detected in the atmosphere at
      approximately 1 ppbv by single photon LIF using the Alpha 2Sigma+ <-- Chi 2Pi1/2
      (0,0) transition at 226 nm, with absolute concentrations in good agreement with
      simultaneous measurements made using a chemiluminescence analyser. With some
      improvements in performance, particularly with regard to laser power, the
      theoretical detection limit for NO is projected to be approximately 2 x 10(6)
      molecule cm(-3) (0.08 pptv). Whilst operating at 445 nm, the laser system has
      been used to readily detect the IO radical in the laboratory, and although it is
      difficult to project the sensitivity in the field, an estimate of the detection
      limit is < 1 x 10(5) molecule cm(-3) (< 0.004 pptv), well below previously
      measured atmospheric concentrations of IO.

PMID- 12619753
TI  - Measuring reactive nitrogen emissions from point sources using visible
      spectroscopy from aircraft.
AB  - Accurate measurements of nitrogen dioxide (NO2), a key trace gas in the formation
      and destruction of tropospheric ozone, are important in studies of urban
      pollution. Nitrogen dioxide column abundances were measured during the Texas Air
      Quality Study 2000 using visible absorption spectroscopy from an aircraft. The
      method allows for quantification of the integrated total number of nitrogen
      dioxide molecules in the polluted atmosphere and is hence a useful tool for
      measuring plumes of this key trace gas. Further, we show how such remote-sensing
      observations can be used to obtain information on the fluxes of nitrogen dioxide
      into the atmosphere with unique flexibility in terms of aircraft altitude, and
      the height and extent of mixing of the boundary layer. Observations of nitrogen
      dioxide plumes downwind of power plants were used to estimate the flux of
      nitrogen oxide emitted from several power plants in the Houston and Dallas
      metropolitan areas and in North Carolina. Measurements taken over the city of
      Houston were also employed to infer the total flux from the city as a whole.

PMID- 12619754
TI  - Fossil-fueled power plants as a source of atmospheric carbon monoxide.
AB  - Elevated carbon monoxide (CO) mixing ratios in excess of those derived from
      emissions inventories have been observed in plumes from one gas- and coal-fired
      power plant and three of four lignite coal-fired electric utility power plants
      observed in east and central Texas. Observations of elevated CO on days
      characterized by differing wind directions show that CO emissions from the
      lignite plants were relatively constant over time and cannot be ascribed to
      separate sources adjacent to the power plants. These three plants were found to
      be emitting CO at rates 22 to 34 times those tabulated in State and Federal
      emissions inventories. Elevated CO emissions from the gas- and coal-fired plant
      were highly variable on time scales of hours to days, in one case changing by a
      factor of 8 within an hour. Three other fossil-fueled power plants, including one
      lignite-fired plant observed during this study, did not emit substantial amounts
      of CO, suggesting that a combination of plant operating conditions and the use of
      lignite coal may contribute to the enhanced emissions. Observed elevated CO
      emissions from the three lignite plants, if representative of average operating
      conditions, represent an additional 30% of the annual total CO emissions from
      point sources for the state of Texas.

PMID- 12619755
TI  - Evaluating a Canadian regional air quality model using ground-based observations
      in north-eastern Canada and United States.
AB  - The simulated concentrations from a numerical 3-dimensional regional air quality
      model (MC2AQ) are compared to those of ground-based observations in north-eastern
      Canada and the United States. The model has oxidant chemistry for both inorganic
      and organic species and deposition routines driven online by a mesoscale
      compressible community meteorological model (MC2). A standard emission inventory
      of anthropogenic, natural and biogenic sources for the year 1990 for 21
      atmospheric trace species was used in the simulation. The model was run for July
      1999, because of the occurrence of a high ozone episode and the availability of
      the monitoring data for surface O3, SO2, NO, NO2 and NOx. The comparisons during
      the episode show that the model performs quite well for predicting concentrations
      and diurnal variations of the surface ozone. The predictions for other gaseous
      species show some discrepancies with observations, but they are consistent with
      the results from other models evaluated in the literature. The uncertainties in
      the emission inventory for these species might be the main causes of the
      discrepancies. Further studies are needed to improve the predictability of SO and
      NOx, especially as the model is developed to include particulate matter formation
      as a result of these gaseous precursors.

PMID- 12619756
TI  - On the usefulness of an airborne lidar for O3 layer analysis in the free
      troposphere and the planetary boundary layer.
AB  - Ozone vertical profiling with a lidar is well adapted to the spatial and temporal
      O3 variability analysis either in the free troposphere, when studying the
      respective impact of chemical production and dynamical processes, or in the
      planetary boundary layer (PBL) when characterizing the diurnal evolution of ozone
      plumes during pollution episodes. Comparisons with other measuring techniques
      (ozonesonde and aircraft in-situ measurements) demonstrate the lidar ability to
      characterize narrow layers (< 500 m) with a good accuracy (deltaO3 < 5-10 ppb).
      Application of airborne or ground-based operation of the CNRS airborne ozone
      lidar show its ability (i) to observe O3 layering above the PBL during two field
      experiments held to study air pollution in the Po Valley, Northern Italy, and the
      city of Marseille, Southern France, (ii) to improve airborne campaign planning
      (real time information on position of O3 layers) and analysis (three-dimensional
      perspective for layers detected by in-situ measurements) when chemical
      characterization of narrow O3 layers in the free troposphere is sought, (iii) to
      map O3 inhomogeneity down to an horizontal scale of 10-20 km within or above the
      polluted PBL by airborne measurements. For O3 pollution studies, understanding
      the origin and the life cycle of O3 layering is the first priority, and in this
      case the optimum use of the lidar remains the continuous operation of a ground
      based instrument.

PMID- 12619757
TI  - Systematic DIAL lidar monitoring of the stratospheric ozone vertical distribution
      at Observatoire de Haute-Provence (43.92 degrees N, 5.71 degrees E).
AB  - Long term stratospheric DIAL (Differential Absorption Lidar) ozone lidar (Light
      Detection and Ranging) measurements have been performed at the Observatoire de
      Haute-Provence (OHP) since 1985 and as part of the Network for the Detection of
      Stratospheric Changes (NDSC) since 1991. This paper provides a detailed
      description of the DIAL lidar instrument implemented at OHP and a discussion of
      the ozone retrieval analysis. The instrument includes the detection of
      atmospheric nitrogen Raman scattering wavelengths, which is required for ozone
      measurements in the presence of strong volcanic aerosol loading. A comprehensive
      evaluation of the error budget in the 10-50 km altitude range is performed with
      particular emphasis on the bias associated with background and volcanic
      stratospheric aerosol. This bias is evaluated using ancillary measurements of the
      aerosol size distribution obtained from 1991 to 1999 after the Mount Pinatubo
      volcanic eruption. Results show that the bias associated with background aerosols
      is smaller than 1% above 13 km while the bias due to volcanic aerosols reaches a
      maximum of 5% above 15 km in the DIAL Raman ozone retrieval. In background
      aerosol conditions the total accuracy of the DIAL ozone vertical distribution at
      OHP ranges from 5% below 20 km to 15-30% above 45 km with a vertical resolution
      varying from 0.5 km to 5 km.

PMID- 12619759
TI  - Airborne measurements of peroxy radicals using the PERCA technique.
AB  - The Peroxy Radical Chemical Amplifier (PERCA) technique is a proven method for
      measurement of ambient levels of peroxy radicals at ground level, but there are
      no published instances of the technique being used on an aerial platform. Here we
      describe deployment of a PERCA on the former UK Meteorological Office C-130
      Hercules research aircraft. The instrument uses the established method of
      chemical amplification and conversion of peroxy radicals to nitrogen dioxide
      (NO2) by doping the sample air-flow matrix with CO and NO, subsequently measuring
      the NO2 yield with an improved 'Luminox' LMA-3 NO2 detector. NO2 from the
      amplification chemistry is distinguished from other sources of NO2 reaching the
      detector by periodically injecting CO approximately 1 s downstream of the NO
      injection point (termination mode). Chain lengths (CL's) for the amplification
      chemistry were typically approximately 260 (ground level) to approximately 200
      (7,000 m). This variation with altitude is less than the variation associated
      with the 'age' of the PFA inlet material where the amplification chemistry
      occurs; CL's of approximately 200 with old tubing to approximately 300 with new
      clean tubing were typical (ground level values). The CL determinations were made
      in-flight using an onboard calibration unit based on the 254 nm photolysis of 7.5
      to 10 parts per billion (by volume, ppbv) of CH3I in air, producing CH3O2 in a
      quantitative manner. The noise-equivalent detection limit for peroxy radicals
      (HO2 + RO2) is 2 parts per trillion (by volume, pptv) at 3,650 m when the
      background ambient ozone levels are stable, based on a 5 min average of five 30 s
      amplification cycles and five 30 s termination cycles. This detection limit is a
      function of several factors but is most seriously degraded when there is large
      variability in the ambient ozone concentration. This paper describes the
      instrument design, considers its performance and proposes design improvements. It
      concludes that the performance of an airborne PERCA in the free troposphere can
      be superior to that of ground-based instruments when similar sampling frequencies
      are compared.

PMID- 12619758
TI  - Direct measurements of urban OH reactivity during Nashville SOS in summer 1999.
AB  - Emissions of volatile chemicals control the hydroxyl radical (OH), the
      atmosphere's main cleansing agent, and thus the production of secondary
      pollutants. Accounting for all of these chemicals can be difficult, especially in
      environments with mixed urban and forest emissions. The first direct measurements
      of the atmospheric OH reactivity, the inverse of the OH lifetime, were made as
      part of the Southern Oxidant Study (SOS) at Cornelia Fort Airpark in Nashville,
      TN in summer 1999. Measured OH reactivity was typically 11 s(-1). Measured OH
      reactivity was 1.4 times larger than OH reactivity calculated from the sum of the
      products of measured chemical concentrations and their OH reaction rate
      coefficients. This difference is statistically significant at the 1sigma
      uncertainty level of both the measurements and the calculations but not the
      2sigma uncertainty level. Measured OH reactivity was 1.3 times larger than the OH
      reactivity from a model that uses measured ambient concentrations of volatile
      organic compounds (VOCs), NO, NO2, SO2, and CO. However, it was within
      approximately 10% of the OH reactivity from a model that includes hydrocarbon
      measurements made in a Nashville tunnel and scaled to the ambient CO at Cornelia
      Fort Airpark. These comparisons indicate that 30% of the OH reactivity in
      Nashville may come from short-lived highly reactive VOCs that are not usually
      measured in field intensive studies or by US EPA's Photochemical Assessment
      Monitoring Stations.

PMID- 12619760
TI  - Manganese air exposure assessment and biological monitoring in the manganese
      alloy production industry.
AB  - One hundred workers carried personal air sampling equipment during three days to
      assess exposure to inhalable and respirable Mn. A novel four-step chemical
      fractionation procedure developed for the speciation of Mn in workroom aerosols
      was applied for selected aerosol filters. Blood and urine samples were analysed
      for Mn. The geometric mean (GM) concentrations of inhalable (n = 265) and
      respirable (n = 167) Mn determined in all filters were 254 microg m(-3) and 28
      microg m(-3) respectively. Only 10.6% (95% CI 8.9-12.5) respirable Mn was found
      in the inhalable fraction when inhalable and respirable samples collected in
      parallel were considered (n = 153 pairs). There was a high correlation (Pearson's
      r = 0.70; p < 0.001) between respirable and inhalable Mn. The largest amounts of
      Mn in the inhalable aerosol fraction were found as Mn0 and Mn2+ (47.4%), whereas
      28% was practically "insoluble". The associations between B-Mn and aerosol
      concentrations of Mn were weak, but an association was found between U-Mn and
      respirable Mn; Pearson's r being 0.38 between "soluble" respirable Mn and U-Mn.
      No significant association was found between the "insoluble" components (probably
      SiMn) and Mn in biological samples.

PMID- 12619761
TI  - Impact of automobile emissions on the levels of platinum and lead in Accra,
      Ghana.
AB  - Examination of car fleet records in Accra demonstrates an increasing proportion
      of catalytic converter-equipped cars in the relatively old car fleet (average age
      13 years) due to their import from developed countries. However, only leaded
      petrol is sold in Ghana. Lead anti-knocking additives, which are known to affect
      catalyst activity and promote thermal sintering and mechanical abrasion, may
      increase Pt emissions. This possible synergism prompted the concomitant
      determination of Pb and Pt levels in road dust and roadside soils in Ghana. Both
      metals followed traffic density with higher concentrations in urban areas
      compared to remote sites. In urban areas, the range for Pb (365 +/- 93 microg g(
      1) for dust and 291 +/- 76 microg g(-1) for soil) reflects precatalyst levels in
      Europe and the US, while the range for Pt (39 +/- 24 ng g(-1) for dust and 15 +/-
      5.3 ng g(-1) for soil) is typical for the same countries. The elevated Pt
      concentrations were unexpected due to recent introduction of catalysts to Ghana
      compared to the prolonged use of catalysts in Europe and the US.

PMID- 12619762
TI  - A passive sampling method to determine ammonia in ambient air.
AB  - Ambient ammonia concentrations, mainly originating from agricultural activities,
      have increased in the last few decades in Europe. As a consequence, critical
      loads on oligotrophic ecosystems such as forests and mires are greatly exceeded.
      Monitoring of ambient ammonia concentrations is necessary in order to investigate
      source-receptor relationships. Measuring ambient ammonia concentrations
      continuously with high time resolution is very expensive and cost-efficient
      systems are required. Where time resolution is of minor importance, several cost
      effective systems, mainly dry denuder and passive samplers, can be applied. In
      this paper the Zurcher passive sampler, a diffusive sampling system, is
      presented. It is a Palmes type sampler with an acidic solution as absorbent and
      is easy to handle. It was tested at 46 sites in Switzerland over one year. The
      average concentration in ambient air was 2.5 microg m(-3) +/- 0.4 microg m(-3).
      The average of the blank values were 0.21 microg m(-3). The detection limit
      (double the standard deviation of the blank values) was 0.36 microg m(-3). Three
      passive samplers were exposed at each site and each period. The mean standard
      deviation of these triplicate measurements was 9.5%. Compared with a
      discontinuous tubular denuder system and a continuous annular denuder system, the
      deviation was less than 10%. The Zurcher passive sampler is a useful and cost
      efficient tool to determine long-term average ammonia concentrations (one- to
      four-week periods) in ambient air for mean concentrations above 1 microg m(-3).

PMID- 12619763
TI  - Diffusive sampling of methyl isocyanate using 4-nitro-7-piperazinobenzo-2-oxa-1,3
      diazole (NBDPZ) as derivatizing agent.
AB  - A diffusive sampling method for the determination of methyl isocyanate (MIC) in
      air is introduced. MIC is collected using a glass fiber filter impregnated with 4
      nitro-7-piperazinobenzo-2-oxa-1,3-diazole (NBDPZ). The urea derivative formed is
      desorbed from the filter with acetonitrile and analyzed by means of high
      performance liquid chromatography (HPLC) using fluorescence detection (FLD) with
      lambdaex = 471 nm and lambdaex = 540 nm. Additionally, a method was developed
      using tandem mass spectrometric (MS-MS) detection, which was performed as
      selected reaction monitoring (SRM) on the transition [MIC-NBDPZ + H]+ (m/z 307)
      to [NBDPZ + H]+ (m/z 250). The diffusive sampler was tested with MIC
      concentrations between 1 and 35 microg m(-3). The sampling periods varied from 15
      min to 8 h, and the relative humidity (RH) was set from 20% up to 80%. The
      sampling rate for all 15 min experiments was determined to be 15.0 mL min(-1)
      (using HPLC-FLD) with a relative standard deviation of 9.9% for 56 experiments.
      At 80% RH, only 15 min sampling gave acceptable results. Further experiments
      revealed that humidity did not affect the MIC derivative but the reagent on the
      filter prior to and during sampling. The sampling rate for all experiments
      (including long term sampling) performed at 20% RH was found to be 15.0 mL min(
      1) with a relative standard deviation of 6.3% (N = 42). The limit of
      quantification was 3 microg m(-3) (LC-MS-MS: 1.3 microg m(-3)) for 15 min
      sampling periods and 0.2 microg m(-3) (LC-MS-MS: 0.15 microg m(-3)) for 8 h
      sampling runs applying fluorescence detection.

PMID- 12619764
TI  - The influence of water vapour on the determination of glutaraldehyde vapour
      concentrations using an electrochemical fuel cell sensor.
AB  - The effects of relative humidity (40-90% RH) and varying glutaraldehyde vapour
      concentrations (< 0.1 ppm) on the response of an electrochemical fuel cell sensor
      have been investigated over time (0-400 s). These studies have identified changes
      in the response of the fuel cell with time after sampling. In particular, it has
      been found that the maximum cell output for water vapour occurs ca. 10 s after
      sampling whilst the response to glutaraldehyde occurs much later (> 100 s). For
      mixtures containing different ratios of water and glutaraldehyde vapours, the
      time taken to reach maximum fuel cell response varies between 10 and 100 s,
      depending on the ratio of the two vapours. For instance, glutaraldehyde vapour
      containing higher % RH has been found to result in shorter times to reach maximum
      fuel cell response. A comparison was made between measuring glutaraldehyde vapour
      concentrations in the presence of water vapour at the maximum fuel cell response
      and also at a fixed interval (240 s) after sampling. Such a comparison resulted
      in a reduction in the standard error from 36% to 5% for a glutaraldehyde vapour
      sample (0.023 ppm) measured at different values of relative humidity (40 to 80%).
      Examination of the effect of the sample volume (30-60 ml) on the response of the
      fuel cell shows, as expected, an approximate doubling of the fuel cell response.
      Optimisation of the fuel cell measurement parameters to measure a 60 ml sample
      leads to a lowering of the limit of detection from 0.083 ppm (for data taken at
      the maximum cell response) to 0.017 ppm for data measured 240 s after sampling.
      In the light of recent reductions in the legal limits for exposure to
      glutaraldehyde, this has important implications for the measurement of
      glutaraldehyde vapour in the workplace.

PMID- 12619765
TI  - Two thousand years of atmospheric rare earth element (REE) deposition as revealed
      by an ombrotrophic peat bog profile, Jura Mountains, Switzerland.
AB  - A peat core from a Swiss bog represents 2110 14C years of peat accumulation and
      provides a continuous record of atmospheric rare earth element (REE) deposition.
      This is the first study providing a time-series of all REE originating from the
      atmosphere. Concentrations of the 14 REE (La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho,
      Er, Tm, Yb and Lu) were determined using inductively coupled plasma-mass
      spectrometry (ICP-MS) after dissolution of 200 mg aliquots of age-dated peat
      samples with 3 ml HNO3 and 0.1 ml HBF4 at 240 degrees C in a microwave autoclave.
      Strict quality control schemes were applied to ensure the accuracy of the applied
      analytical methodology. Previous analyses of selected REE by instrumental neutron
      activation analysis (INAA) in the same set of peat samples revealed that INAA
      frequently under- or overestimated REE concentrations in a systematic manner.
      Concentration profiles obtained for all REE were almost identical, except for Ce
      and Eu. Calculation of enrichment factors (EF) revealed a distinct depletion of
      heavy REE relative to light REE in peat samples since the beginning of the 19th
      century which marks the onset of the Industrial Revolution in Europe, suggesting
      a pronounced influence by anthropogenic activities. Enrichments of REE calculated
      using Sc as a reference element exceeded unity, relative to the Upper Continental
      Crust. Overall, EF in all peat samples ranged from 1.96 for Sm to 2.34 for Gd,
      with considerably lower EF for Ce (1.82) and Eu (1.44), respectively. A
      significant enrichment of all REE which may have been caused by military
      activities, was observed in the peat sample dating from World War II (1944); this
      exceptional sample, however, is not enriched in Ce. The concentration profiles of
      REE were similar but not identical to those of other lithogenic, conservative
      reference elements such as Sc, Y, Al, Zr and Ti. While it has been suggested that
      individual REE concentrations or the sum of REE can be used as a reference
      parameter to calculate crustal EF in environmental samples the data presented
      here indicates that anthropogenic emissions of REE cannot simply be ignored.

PMID- 12619766
TI  - Radon monitoring in groundwater of some areas of Himachal Pradesh and Punjab
      states, India.
AB  - Radon measurements have been carried out in groundwater of Himachal Pradesh and
      Punjab states, India. Radon concentration values in potable water show a wide
      range of variation from source to source and from place to place. Generally,
      radon concentration values in thermal springs groundwater have been found to be
      higher than the values from other sources.

PMID- 12619767
TI  - Groundwater monitoring plans at small-scale sites--an innovative spatial and
      temporal methodology.
AB  - An innovative methodology for improving existing groundwater monitoring plans at
      small-scale sites is presented. The methodology consists of three stand-alone
      methods: a spatial redundancy reduction method, a well-siting method for adding
      new sampling locations, and a sampling frequency determination method. The
      spatial redundancy reduction method eliminates redundant wells through an
      optimization process that minimizes the errors in plume delineation and the
      average plume concentration estimation. The well-siting method locates possible
      new sampling points for an inadequately delineated plume via regression analysis
      of plume centerline concentrations and estimation of plume dispersivity values.
      The sampling frequency determination method recommends the future frequency of
      sampling for each sampling location based on the direction, magnitude, and
      uncertainty of the concentration trend derived from representative historical
      concentration data. Although the methodology is designed for small-scale sites,
      it can be easily adopted for large-scale site applications. The proposed
      methodology is applied to a small petroleum hydrocarbon-contaminated site with a
      network of 12 monitoring wells to demonstrate its effectiveness and validity.

PMID- 12619768
TI  - Solid-phase microextraction to monitor the sonochemical degradation of polycyclic
      aromatic hydrocarbons in water.
AB  - Solid-phase microextraction (SPME) coupled with GC-MS has been used to monitor
      the degradation of polycyclic aromatic hydrocarbons (PAHs) by ultrasound
      treatment. Immersion SPME sampling enabled the fast and solventless extraction of
      target contaminants at the low microg l(-1) concentration level. The developed
      protocol was found to be linear in the concentration range from 0.1 to 50 microg
      l(-1) for most target analytes, with the limits of detection ranging between 0.01
      and 0.70 microg l(-1) and the relative standard deviations between 4.31 and 27%.
      The developed SPME protocol was used to follow concentration profiles of aqueous
      solutions containing 16 PAHs, which were subject to low frequency ultrasonic
      irradiation. At the conditions employed in this study (80 kHz of ultrasound
      frequency, 130 W l(-1) of applied electric power density, 30 microg l(-1) of
      initial concentration for each of the 16 PAHs), sonochemical treatment was found
      capable of destroying the lower molecular weight PAHs (naphthalene,
      acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene
      and pyrene) within 120-180 min of irradiation. The higher molecular weight PAHs
      were more recalcitrant to ultrasound treatment.

PMID- 12619769
TI  - Identification and quantification of bisphenol A by gas chromatography and mass
      spectrometry in a lab-scale dual membrane system.
AB  - Endocrine disruptor contamination is an emerging issue of concern in the field of
      water quality engineering. In this study, a lab-scale microfiltration (MF) and
      reverse osmosis (RO) based water reclamation system was set up to monitor and
      evaluate the removal of bisphenol A (BPA), which is a known oestrogenic compound.
      The identification and quantification of BPA were performed by using gas
      chromatography coupled with mass spectrometry. It was noted that the detection
      method used in this study was able to achieve an average recovery ranging from
      88.2 to 94.1% of BPA with standard deviations of less than 10% in different
      spiked samples. The detection limit of the analytical protocol was determined at
      20 ng L(-1). Based on the analytical protocol, it was noted that a low level of
      BPA (1.18-3.04 microg L(-1)) could be detected in feed water (effluent of an
      activated sludge treatment system) to the dual membrane water reclamation system.
      The results obtained suggested that BPA could be easily chlorinated by sodium
      hypochlorite with a dosage of 4 to 5 mg L(-1) and a contact time of 1 to 2 min.
      In this lab-scale study, a satisfactory removal of BPA was readily obtained by RO
      and BPA was abated to an undetectable level in the product water. It was noted
      that the RO rejection characteristic of BPA was not sensitive to the variations
      in raw feed water characteristics experienced in this study. In addition, it was
      noted that BPA concentration present in raw feed water did not exert any
      significant impact on RO performance in terms of BPA rejection. The results of
      this study demonstrated that membrane technology could be effectively used for
      BPA removal.

PMID- 12619770
TI  - Monitoring of labile metals in turbid coastal seawater using diffusive gradients
      in thin-films.
AB  - Diffusive gradients in thin-films (DGT) have been investigated for in situ
      monitoring of labile metals in north Australian coastal seawater. Field and
      experimental data showed that DGT devices provided adequate detection limits,
      accuracy and precision for monitoring of near-pristine levels of labile Mn, Co,
      Cu, Cd and Pb when deployed for periods of 3 days. However, Zn could not be
      adequately determined due to high blank levels. The ratio of DGT-labile to 0.45
      microm-filtered metal levels in natural seawater ranged from 0.44-0.63 for Cu but
      was close to unity for Co and Cd. Elevated levels of suspended particulate matter
      up to 57.3 mg l(-1) did not have an adverse effect on the performance of DGT.

PMID- 12619771
TI  - The polycyclic aromatic hydrocarbon composition of mussels (Mytilus edulis) from
      Scottish coastal waters.
AB  - Blue mussels (Mytilus edulis) were collected from coastal areas and voes in
      Shetland and Orkney during March and April 1998 and from various coastal
      locations around mainland Scotland and from the Islands during October and
      December 1999. The polycyclic aromatic hydrocarbon concentration and composition
      (2- to 6-ring parent and branched) were determined for all samples. Additional
      analysis, including sensory assessment and the determination of n-alkanes and
      geochemical biomarkers, was also undertaken on the Shetland and Orkney mussels
      collected in 1998. Mussels from Shetland and Orkney exhibited a wide range of
      total PAH concentration (14.7 to 7,177 ng g(-1) wet weight). Those mussels
      collected in 1999 exhibited a narrower concentration range. The lowest value
      (mussels from Loch Kentra) was 8.4 ng g(-1) wet weight while the maximum
      concentration was 344.1 ng g(-1) wet weight and was determined in mussels from
      Granton East in the Firth of Forth. The PAH concentration ratios in mussels from
      Dury Voe (Grunna), Long Hope and Kirkwall Bay were consistent with a
      predominately petrogenic source for these contaminants. This was supported by
      both the sensory assessment and the n-alkane and triterpane profiles. Comparisons
      of the PAH concentrations in mussels with sediments collected from the same
      locations around Shetland and Orkney showed that in areas of high sediment PAH
      concentration the bioavailability of these contaminants was limited.

PMID- 12619772
TI  - Change in levels of persistent organic pollutants in human plasma after
      consumption of a traditional northern Norwegian fish dish-molje (cod, cod liver,
      cod liver oil and hard roe).
AB  - The traditional northern Norwegian fish dish "molje", consisting of boiled cod,
      cod liver, cod liver oil and hard roe, is still consumed frequently during the
      winter months January to March. The liver of the cod is rich in lipids and the
      levels of persistent organic pollutants (POPs) are relatively high. To better
      understand the short-term consequences of this traditional meal on the plasma
      levels of PCBs and p,p'-DDE, individual intake of liver and cod liver oil during
      one meal was measured. Blood samples were collected from 33 participants before
      the meal, and then 4 h, 12 h and 5 days after it. Lipid-weight and wet-weight
      levels of 10 PCB congeners and p,p'-DDE were determined in the plasma samples and
      the food. The plasma levels of p,p'-DDE was found to increase significantly from
      0 to 4 h, both when expressed as wet-weight (35% change) and lipid-weight (20%
      change). The corresponding changes (0-4 h) in wet-weight levels of the most
      prevalent PCB congeners were non significant. By contrast, PCB congeners with low
      levels in the food showed a significant drop in lipid-weight levels during the
      first 4 h. The observed changes were independent of amount consumed. Significant
      differences in fasting and non-fasting samples were found for most PCBs and p,p'
      DDE. For the lipid weight levels of sum PCBs there was a significant decrease of
      16% from non-fasting to fasting samples. To obtain reliable data on human levels
      of POPs it is, on the basis of these findings, recommended that blood samples
      should be collected from fasting individuals and both wet-weight and lipid-weight
      levels should be reported.

PMID- 12619773
TI  - Intercommunity and temporal variation of eleven essential and five toxic elements
      in human placentas from deliveries in thirteen arctic and sub-arctic areas of
      Russia and Norway.
AB  - Research is described that constitutes an extension of an earlier paper (J.
      Environ. Monit., 2001, 3, 177-184), in which concentrations were measured in 263
      human placentas of 11 essential elements (P, Ca, Mg, Cu, S, Na, Fe, Zn, K, Se,
      Mn) and 5 toxic elements (Ba, Sr, Pb, Ni, Cd). The additional data considered
      derive from earlier visits to 4 of the original 6 communities and 3 others, all
      but one of which are located in northern Norway and neighbouring areas of Russia.
      This more than doubled the number of placental samples available (263 to 571).
      Unfortunately, the personal, life-style and morphometric information obtained for
      the first study group was not available for the additional mothers. Country
      differences were evident for all elements except Ba, Fe and Zn; Cd, Cu, Mn, Na,
      Se, Ni, Pb, Sr and S were higher and K, P, Ca and Mg were lower in Russia (p <
      0.03). Not unexpectedly, the highest median lead concentration was observed for
      the largest city in the western arctic region of Russia, namely Murmansk.
      Similarly, the higher median nickel level observed for Russia reflects the
      established observation that urinary nickel concentrations are higher in the
      Russian than in the Norwegian communities. Even though sampling was performed at
      different times of the year and before and after a 3-year interval in four
      centres, inter-collection differences were of relatively small magnitude and
      appear not to be linked to seasonal or temporal changes. Principal component
      analysis (PCA) confirmed the prominence of Factor 1, which grouped those metals
      that are known to form insoluble phosphate complexes and whose concentrations
      showed a dependence on gestational age and maternal smoking in the earlier study.
      It is concluded that PCA is a powerful statistical tool for exploring and
      identifying fundamental pathways and processes involved in governing the
      inorganic elemental composition of placental tissue. It also has the potential of
      identifying study limitations and quality assurance shortfalls. Further our
      findings show promise that placental concentrations of toxic elements may serve
      as an index of exposure and of nutritional intake for selected essential micro
      elements.

PMID- 12619775
TI  - What can our nose tell us about possible treatments for Alzheimer's disease?

PMID- 12619774
TI  - A rapid and accurate method for the determination of plutonium in food using
      magnetic sector ICP-MS with an ultra-sonic nebuliser and ion chromatography.
AB  - In the event of a nuclear incident it is essential that analytical information on
      the distribution and level of contamination is available. An ICP-MS method is
      described which can provide data on plutonium contamination in food within 3 h of
      sample receipt without compromising detection limits or accuracy relative to
      traditional counting methods. The method can also provide simultaneous
      determinations of americium and neptunium. Samples were prepared by HNO3 closed
      vessel microwave digestion, evaporated to dryness and diluted into a mobile phase
      comprising 1.5 M HNO3 and 0.1 mM 2,6-pyridinedicarboxylic acid. A commercially
      available polystyrene-divinylbenzene ion chromatography column provides on-line
      separation of 239Pu and 238U reducing the impact of the 238U1H interference.
      Oxidation of the sample using H2O2 ensures all Pu is in the Pu(+4) state. The
      oxidation also displaces Np away from the solvent front by changing the oxidation
      state from Np(+3) to Np(+4) and produces the insoluble Am(+4) ion. Simultaneous
      Pu, Am and Np analyses therefore require omission of the oxidation stage and some
      loss of Pu data quality. Analyses were performed using a magnetic sector ICP-MS
      (Finnigan MAT Element). The sample is introduced to the plasma via an ultrasonic
      nebuliser-desolvation unit (Cetac USN 6000AT+). This combination achieves an
      instrumental sensitivity of 238U > 2 x 10(7) cps/ppb and removes hydrogen from
      the sample gas, which also inhibits the formation of 238U1H. The net effect of
      the improved sample introduction conditions is to achieve detection levels for Pu
      of 0.020 pg g(-1) (4.6 x 10(-2) Bq kg(-1)) which is significantly below 1/10th of
      the most stringent EU (European Union) legislation, currently 0.436 pg g(-1) (1
      Bq kg(-1)) set for baby food. The new method was evaluated with a range of
      biological samples ranging from cabbage to milk and meat. Recovery of Pu agrees
      with published values (100% +/- 20%).

PMID- 12619776
TI  - Epileptogenesis, ictogenesis and the design of future antiepileptic drugs.
AB  - There is still no medical cure for epilepsy. Clinical epileptology is in need of
      a "paradigm shift" when it comes to the continuing development of therapeutics.
      An important first step in this conceptual evolution is differentiating between
      the notions of ictogenesis and epileptogenesis. All traditional therapeutics are
      anti-ictogenic, not antiepileptogenic. The future of antiepileptic drug
      development lies in the discovery of antiepileptogenics. Just as aspirin is not
      the drug of choice for meningitis, an anticonvulsant is not the drug of choice
      for epilepsy. Drug design for epilepsy needs to discover a penicillin, not more
      aspirins.

PMID- 12619777
TI  - Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy.
AB  - Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder
      characterized by progressive eyelid drooping (ptosis), swallowing difficulties
      (dysphagia), and proximal limb weakness. The autosomal dominant form of this
      disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1
      gene. These mutations lead to the expansion of a polyalanine stretch from 10 to
      12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1)
      induces the formation of muscle intranuclear inclusions that are thought to be
      the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and
      PABPN I function studies; 2) diseases caused by polyalanine expansions and
      cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion
      toxicity; 4) role of oligomerization of mPABPNI in the formation and toxicity of
      OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the
      OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis
      that accounts for these observations.

PMID- 12619778
TI  - Perioperative ulnar neuropathies: a medicolegal review.
AB  - BACKGROUND: Perioperative ulnar neuropathies have long been attributed to
      inappropriate arm positioning and padding during operations and have resulted in
      many lawsuits. METHODS: A recent Canadian lawsuit is described and the literature
      regarding perioperative ulnar and other focal neuropathies reviewed. RESULTS: The
      evidence strongly suggests that ulnar nerve damage is usually sustained in the
      postoperative rather than the intraoperative period. There is no evidence that
      positioning or padding of the arm during the operation prevents perioperative
      ulnar neuropathies. CONCLUSIONS: There should generally be no basis for a claim
      against medical or nursing staff or hospitals when an ulnar neuropathy develops
      following anesthesia and surgery.

PMID- 12619780
TI  - Selection of neurosurgical trainees.
AB  - BACKGROUND: Medical students in Canada must make career choices by their final
      year of medical school. Selection of students for a career in neurosurgery has
      traditionally been based on marks, reference letters and personal interviews.
      Studies have shown that marks alone are not accurate predictors of success in
      medical practice; personal skills and attributes which can best be assessed by
      letters of reference and interviews may be more important. This study was an
      attempt to assess the importance of, and ability to teach, personal skills and
      attitudes necessary for successful completion of a neurosurgical training
      program. METHODS: A questionnaire was sent to 185 active members of the Canadian
      Neurosurgical Society, asking them to give a numerical rating of the importance
      of 22 personal skills and attributes, and their ability to teach those skills and
      attributes. They were asked to list any additional skills or attributes
      considered important, and rate their ability to teach them. RESULTS: Sixty-six
      (36%) questionnaires were returned. Honesty, motivation, willingness to learn,
      ability to problem solve, and ability to handle stress were the five most
      important characteristics identified. Neurosurgeons thought they could teach
      problem solving, willingness to consult informed sources, critical thinking,
      manual dexterity, and communication skills, but honesty, motivation, willingness
      to learn and ability to handle stress were difficult or impossible to teach.
      CONCLUSIONS: Honesty, motivation, willingness to learn, ability to problem solve
      and handle stress are important for success in a neurosurgical career. This
      information should be transmitted to medical students at "Career Day" venues.
      Structuring letters of reference and interviews to assess personal skills and
      attributes will be important, as those that can't be taught should be present
      before the start of training.

PMID- 12619781
TI  - Neuromagnetic somatosensory responses to natural moving tactile stimulation.
AB  - OBJECTIVE: To explore the somatosensory cortical responses to natural moving
      tactile stimulation in adult subjects using magnetoencephalography. METHODS: We
      measured cortical somatosensory magnetic evoked fields (SEFs) to moving tactile
      stimuli by a brush over the right thumb once every 1.5 s in seven subjects.
      Electric SEFs with various intensity or simulated jitter were used for
      comparison. RESULTS: Tactile SEFs in primary somatosensory cortex (SI) consisted
      of two deflections: N24mT and P55mT. Electric SEFs consisted of N24mE, P30mE,
      P40mE, and P55mE. The amplitude of N24mT was only 34% +/- 12% of N24mE, whereas
      P55mT and P55mE were of about the same size. With increased jitter or decreased
      intensity, attenuation of electric SEFs was more clearly found in early
      deflection than late deflection. CONCLUSIONS: Natural moving tactile stimulation
      produced simpler cortical somatosensory waveforms in comparison with electric
      SEFs, partly related to less sharp intensity and stimulation jitter with moving
      tactile stimulation. We propose that of all the afferent fibers conveying the
      early deflection, the low threshold components participate the generation of the
      late deflection.

PMID- 12619779
TI  - Early olfactory involvement in Alzheimer's disease.
AB  - BACKGROUND: In Alzheimer's disease (AD) the olfactory system, including the
      olfactory bulb, a limbic paleocortex is severely damaged. The occurrence of early
      olfactory deficits and the presence of senile plaques and neurofibrillary tangles
      in olfactory bulb were reported previously by a few authors. The goal of the
      present study was to analyze the occurrence of AD-type degenerative changes in
      the peripheral part of the olfactory system and to answer the question whether
      the frequency and severity of changes in the olfactory bulb and tract are
      associated with those of the cerebral cortex in AD. MATERIAL AND METHODS: In 110
      autopsy cases several cortical areas and the olfactory bulb and tract were
      analyzed using histo- and immunohistochemical techniques. Based on a
      semiquantitative analysis of cortical senile plaques, neurofibrillary tangles and
      curly fibers, the 110 cases were divided into four groups: 19 cases with severe
      (definite AD), 14 cases with moderate, 58 cases with discrete and 19 control
      cases without AD-type cortical changes. RESULTS: The number of cases with
      olfactory involvement was very high, more than 84% in the three groups with
      cortical AD-type lesions. Degenerative olfactory changes were present in all 19
      definite AD cases, and in two of the 19 controls. The statistical analysis showed
      a significant association between the peripheral olfactory and cortical
      degenerative changes with respect to their frequency and severity (P < 0.001).
      Neurofibrillary tangles and neuropil threads appear in the olfactory system as
      early as in entorhinal cortex. CONCLUSION: The results indicate a close
      relationship between the olfactory and cortical degenerative changes and indicate
      that the involvement of the olfactory bulb and tract is one of the earliest
      events in the degenerative process of the central nervous system in AD.

PMID- 12619782
TI  - Neonatal herpes encephalitis: a case series and review of clinical presentation.
AB  - OBJECTIVE: To describe the clinical and laboratory findings in cases of neonatal
      herpes simplex virus (HSV) encephalitis. BACKGROUND: Neonatal HSV encephalitis is
      a devastating infection which requires a high degree of clinical suspicion and
      rapid initiation of antiviral therapy. METHODS: We performed a retrospective
      search for all cases of HSV encephalitis within the two Saskatchewan pediatric
      tertiary care centers for the period of 1985-2001. Only those patients with
      consistent clinical presentations along with direct evidence of presence of HSV,
      such as positive cerebrospinal fluid (CSF) viral cultures, positive polymerase
      chain reaction (PCR) for HSV from CSF, or positive immunoglobulin G against HSV
      from neonatal blood, were selected. RESULTS: Five male and four female infant
      patients were identified. At a mean age of presentation of 24 +/- 20 days,
      seizures occurred in six neonates, lethargy in six neonates, temperature changes
      in five neonates, and apnea in three neonates. Examination of CSF demonstrated an
      initial monocytosis or lymphocytosis, elevated CSF protein and depressed CSF
      glucose in 100% of patients. Electroencephalography (EEG) was abnormal in 100% of
      patients. Initial computerized tomography was abnormal in 55% of patients.
      Clinical follow-up over an average of two years demonstrated developmental delay
      in four patients and upper motor neuron findings in four patients. No patients
      suffered from postencephalitic epilepsy or mortality. CONCLUSIONS: Neonatal HSV
      encephalitis most commonly presents with seizures, lethargy, and dysthermia.
      Cerebrospinal fluid testing and EEG have 100% sensitivity in cases with
      laboratory confirmation of HSV presence. Improvements in morbidity and mortality
      as compared to previous reports may relate to better recognition of this illness
      and acyclovir therapy. The lack of postinfection epilepsy in our series may also
      relate to better recognition and acyclovir therapy within this series of
      patients.

PMID- 12619783
TI  - MRI contributes to the differentiation between MS and HTLV-I associated
      myelopathy in British Columbian coastal natives.
AB  - BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I)-associated
      myelopathy/tropical spastic paraparesis (HAM/TSP) in British Columbian Coastal
      Natives has, to date, been a clinical and laboratory diagnosis. However, magnetic
      resonance imaging (MRI) abnormalities have been well-described in other
      populations in which HAM/TSP is endemic. METHODS: In order to assess the
      usefulness of MRI as a diagnostic tool in this population, we compared scans of
      HAM/TSP patients with those of HTLV-I positive non-HAM/TSP British Columbian
      Coastal Natives (carriers) and multiple sclerosis patients presenting with
      progressive paraparesis. RESULTS: The typical nonspecific findings of thoracic
      cord atrophy and increased signal in the periventricular and subcortical white
      matter on T2-weighted images were confirmed in the HAM/TSP patients. Despite a
      lack of specificity of the MRI findings between HAM/TSP patients and HTLV-I
      carriers, criteria that could effectively differentiate HAM/TSP patients from
      multiple sclerosis patients with similar clinical presentations were determined.
      CONCLUSIONS: Clinical and radiological correlations suggest that longitudinal MRI
      investigations charting the course of HAM/TSP may reveal the clinical
      significance of these lesions and further define the role of MRI in the diagnosis
      of this entity. Magnetic resonance imaging is an important supplement to
      immunological and clinical data in differentiating multiple sclerosis from
      HAM/TSP.

PMID- 12619784
TI  - Combined endovascular/neurosurgical therapy of blister-like distal internal
      carotid aneurysms.
AB  - OBJECTIVE: To describe a novel therapeutic strategy for the treatment of "blister
      like" aneurysms of the distal internal carotid artery (ICA). Direct surgical
      treatments of these fragile lesions have been associated with generally poor
      outcomes. METHODS: Two consecutive patients presenting with acute subarachnoid
      hemorrhage from "blister-like" aneurysms were treated with preliminary balloon
      occlusion of the ICA, followed by surgical trapping of the ICA beyond the
      aneurysm. RESULTS: The treatment resulted in complete thrombosis of both
      aneurysms with no clinical complications. CONCLUSION: This combined endovascular
      neurosurgical approach offers a controlled, safer alternative to primary surgical
      therapy of "blister-like" aneurysms.

PMID- 12619785
TI  - EEG power spectra changes and forebrain ischemia in rats.
AB  - BACKGROUND: Several animal models of cerebral ischemia have been developed to
      investigate both pathophysiology and pharmacological treatment. The aim of this
      study was to verify the prognostic value of EEG power spectra analysis in a two
      vessel plus hypotension rat model of transient global ischemia. METHODS:
      Spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs) were
      subjected to 20 min bilateral common carotid artery occlusion plus hypotension by
      sodium nitroprusside followed by reperfusion for seven days. Sham-operated
      animals served as controls. The changes after ischemia in EEG power spectra, and
      their relations with neuronal damage and astrocytic response were investigated.
      RESULTS: The EEG analysis revealed that in SHRs and WKYs, ischemia produced a
      dramatic increase in delta activity and a decrease in theta, beta and alpha
      activities derived from both cortical and hippocampal areas. EEG activity
      reverted to normal values more quickly in WKYs than in SHRs which did not recover
      cortical and hippocampal alpha and beta activities even at six days of
      reperfusion. SHRs presented more severe damage and intense astrocytosis than WKYs
      in almost all the brain regions analyzed. In SHRs, hippocampal delta activity was
      positively correlated with the degree of neuronal necrosis and astrocytic
      activation, whereas theta, alpha and beta activities correlated negatively. No
      correlations were found in WKYs. CONCLUSIONS: These data indicate that the
      hippocampal bioelectrical activity recorded in SHRs from the beginning of
      reperfusion could be useful for predicting the ischemic outcome and evaluating
      the effects of pharmacological interventions.

PMID- 12619786
TI  - Ossification of the posterior longitudinal ligament.

PMID- 12619787
TI  - Intracranial malignant glioma presenting as subarachnoid hemorrhage.
AB  - OBJECTIVE: Cerebral aneurysms are the predominant cause of spontaneous
      subarachnoid hemorrhage (SAH). However, if an aneurysmal cause has been excluded,
      there remains but a short list of other potential etiologies. Cerebral neoplasms
      are clearly on this list but are most commonly meningiomas or metastatic lesions.
      This article details a case of a neoplasm that presented exclusively with SAH.
      CLINICAL PRESENTATION: A 40-year-old male presented with a SAH with normal
      cerebral angiography. The initial magnetic resonance image revealed a lesion in
      the right insula thought to be resolving hemorrhage. Subsequent images, however,
      revealed the mass to be enlarging. INTERVENTION: Craniotomy and resection of the
      lesion established a diagnosis of a malignant oligodendroglioma. CONCLUSION: An
      affirmation is made that patients experiencing 'angiographically-negative' SAH
      should undergo MRI, occasionally on a serial basis, to exclude other etiologies
      for hemorrhage, including neoplasia.

PMID- 12619788
TI  - Pineal apoplexy: is it a facilitator for the development of pineal cysts?
AB  - BACKGROUND: The radiographic identification of pineal cysts has increased
      dramatically within the last two decades due to the advent of magnetic resonance
      imaging. Pineal cysts are often found incidentally with only a minority of these
      lesions ever becoming symptomatic and requiring treatment. Many theories
      attempting to explain the pathogenesis of these cysts exist. METHODS: We describe
      a case of a 12-year-old girl who presents with a pineal hemorrhage of unknown
      etiology with associated hydrocephalus. RESULTS: Her hydrocephalus was initially
      treated with an external ventricular drain followed by a third ventriculostomy.
      She had no evidence of elevated beta human chorionic gonadotropin or alpha
      fetoprotein within the serum or cerebrospinal fluid. Follow-up imaging at seven
      weeks revealed resolution of her hemorrhage, however, there was development of a
      progressive cystic lesion within the pineal region. In order to make a definitive
      tissue diagnosis, a supracerebellar infratentorial surgical approach with
      complete resection was performed. During the resection, brownish fluid was
      aspirated from the cyst and the cyst wall was removed. The pathological diagnosis
      was a pineal cyst. CONCLUSIONS: Although cases have been described of pineal
      apoplexy with an underlying cyst, this case describes the development of a
      progressive pineal cyst secondary to a hemorrhage. This case demonstrates that
      pineal hemorrhage may be a promotor for the development or progression of pineal
      cysts.

PMID- 12619789
TI  - Postoperative reversal of complete (monocular) blindness in skull base
      meningioma: case report.
AB  - BACKGROUND: Meningiomas of the anterior cranial fossa frequently present with
      impaired visual function. Recognition of this entity in the differential
      diagnosis of painless, progressive, and asymmetric optic neuropathy is important
      since reversal of visual loss is possible given timely surgical excision of the
      tumour. METHODS: A 76-year-old man presented with no perception of light in his
      right eye and a reduced visual acuity of 20/60 in his left eye with a markedly
      constricted visual field. His visual deterioration had progressed over the
      previous three months and was not associated with headache. Ophthalmoscopy showed
      normal optic discs. MRI scanning showed a large frontal basal meningioma, which
      was subsequently resected. RESULTS: The patient noticed an immediate improvement
      in his vision in his right eye. Visual acuity in his right eye improved to 20/50
      at six weeks postoperatively and to 20/25 at five months, with corresponding
      improvement of the visual field. CONCLUSION: Complete monocular blindness due to
      tumour compressing or distorting the anterior visual pathways does not preclude
      recovery following timely decompressive surgery, especially when the appearance
      of the optic disc is normal.

PMID- 12619790
TI  - Late onset polyneuropathy due to organophosphate (DDVP) intoxication.
AB  - BACKGROUND: Organophosphate intoxication can cause some well-known life
      threatening acute neurological complications such as seizures, paralysis,
      neuromuscular and cardiac conduction disorders. Less often, a predominantly motor
      and delayed axonal neuropathy can occur. This syndrome is due to inhibition of
      neuropathy target esterase. CASE REPORT: A 30-year-old woman attempted suicide by
      drinking approximately 1,000mg/kg dimethyl-2,2-dichloro vinyl phosphate (DDVP).
      After a muscarinic and cholinergic syndrome lasting four days, she developed a
      purely motor distal axonal polyneuropathy on the fifth week after ingestion
      confirmed by electroneuromyography and sural nerve biopsy. Neurological
      examination and electroneuromyography revealed a slight recovery at the end of
      the 21st month. CONCLUSION: This case of late onset polyneuropathy caused by
      organophosphate intoxication had unusual features such as intact sensory nerves
      and worse prognosis when compared to previously reported cases.

PMID- 12619791
TI  - Re: Auditing carotid endarterectomy: a regional experience. J. Max Findlay, Linda
      Nykolyn, Tracey B. Can J Neurol Sci 2002; 29:326-332.

PMID- 12619792
TI  - Re: Tests of motor function in patients suspected of having mild unilateral
      cerebral lesions. Teitelbaum JS, Eliasziw M, Garner M. Can J Neurol Sci 2002; 29:
      337-344.

PMID- 12619793
TI  - Effect of selection for growth on onset of sexual maturity in randombred and
      growth-selected lines of Japanese quail.
AB  - An experiment was conducted to determine the effect of selection for growth (BW)
      on the onset of reproduction (first egg) in Japanese quail hens from growth
      selected (HW) and randombred (R1) lines. The HW line had undergone over 40
      generations of selection for increased 4-wk BW and was originally developed from
      the R1 line. Data were collected over two consecutive hatches and summarized by
      hatch and within lines. Body weight at 35 d of age was positively correlated with
      BW at sexual maturity (first egg) in both the R1 and HW lines, but these
      correlations were not significant in both hatches for either line (Hatch 1-R1;
      Hatch 2-HW; P < or = 0.05). There was a negative correlation between age at
      sexual maturity (days to first egg) and 35 d BW in both lines with the exception
      of the HW hens in Hatch 2. Age at sexual maturity and BW at sexual maturity was
      positively correlated (P < or = 0.001) in the R1 line but did not show the same
      relationship in the HW line. Age at sexual maturity and weight of the abdominal
      fat pad were positively correlated in the R1 line (Hatch 1, P < or = 0.01; Hatch
      2, P < or = 0.001), but this relationship was not significant in the HW line. Age
      at sexual maturity and follicle number was negatively correlated in both lines
      but was not significant in Hatch 2 of the HW line. Follicle size, however, was
      positively correlated with days to first egg in only Hatch 2 (P < or = 0.001) of
      the HW line. The data suggest that the relationships between the onset of sexual
      maturity and both reproductive parameters and carcass traits in hens from
      consecutive hatches of HW quail are less clear than in the R1 line.

PMID- 12619794
TI  - Social stress in laying hens: differential effect of stress on plasma dopamine
      concentrations and adrenal function in genetically selected chickens.
AB  - Genetic selection for high or low group productivity and survivability (HGPS,
      LGPS) has created two phenotypically distinct chicken lines. Each line has unique
      characteristics in behavioral and physiological adaptability to multiple-bird
      cage system. The present study was designed to examine whether these differences
      reflect genetic variation in the control of plasma dopamine (DA) concentrations
      and adrenal function in response to social stress. Chickens from the HGPS and
      LGPS lines were randomly assigned to single- or 10-bird cages at 17 wk of age.
      The 10-bird cages were the same as those used in the development of the two
      lines. Differences in regulation of DA concentrations and adrenal function in
      response to different social environments were measured between the two lines
      when the study was conducted at 24 wk of age. In the 10-bird cages, the HGPS line
      had lower levels of DA (P < 0.05) and heavier adrenal glands (AG, P < 0.05) than
      those of the LGPS line, but concentrations of corticosterone (CORT) from the two
      lines were not significantly different. In the single-bird cages, DA levels in
      both lines were greater than in that of their siblings in the 10-bird cages, but
      a greater increase was found in the LGPS line (P < 0.01 and P < 0.05, 405% vs.
      293%). Likewise, both lines had lower concentrations of CORT (P < 0.05) in the
      single- vs. 10-bird cages, but the AG were less heavy in the LGPS line but not in
      HGPS line in the single-bird cages (P < 0.05). The results indicated that the two
      strains reacted differently in terms of their stress hormone levels in the two
      different environments. These differences could contribute to the behavioral and
      physiological differences existing between the two lines.

PMID- 12619795
TI  - Detection of septicemia in chicken livers by spectroscopy,.
AB  - To establish a procedure for differentiating normal chickens from chickens with
      septicemia/toxemia (septox) by machine inspection under the Hazard Analysis and
      Critical Control Point-Based Inspection Models Project, spectral measurements of
      300 chicken livers, of which half were normal and half were condemned due to
      septox conditions, were collected and analyzed. Neural network classification of
      the spectral data after principal component analysis (PCA) indicated that normal
      and septox livers were correctly differentiated by spectroscopy at a rate of 96%.
      Analysis of the data established 100% correlation between the spectroscopic
      identification and the subset of samples, both normal and septox, that were
      histopathologically diagnosed. In an attempt to establish the microbiological
      etiology of the diseased livers, isolates from 30 livers indicated that the
      poultry carcasses were contaminated mostly with coliforms present in the
      environment, hindering the isolation of pathogenic microorganisms. Therefore, to
      establish the cause of diseased livers, a strictly aseptic environment and
      procedure for sample collection is required.

PMID- 12619796
TI  - Synthesis of betaine-homocysteine S-methyltransferase is continuously enhanced in
      fatty livers of thyroidectomized chickens.
AB  - We examined thyroidectomized chickens in terms of plasma lipid concentration and
      protein expression within the liver. Although the body weight of thyroidectomized
      chickens was remarkably low due to growth retardation, the livers were enlarged
      and fatty compared to those of sham-operated chickens. An increase in
      phospholipid, triglyceride, and total cholesterol levels within the blood plasma
      of thyroidectomized chickens was observed, clearly reflecting increased lipid
      synthesis within the liver. Overexpression of some proteins, for example, 29- and
      45-kDa proteins, was observed in thyroidectomized chicken livers by means of
      electrophoresis. A peptide map was made for the protein that exhibited the
      greatest degree of overexpression. One of them demonstrated a molecular mass of
      45 kDa and an isoelectric point (pI) between 7.5 and 8.0, depending on its form.
      Partial N-terminal amino acid sequences were determined from three random
      peptides of this protein. The amino acid sequence of this protein showed a high
      degree of homology with the betaine-homocysteine S-methyltransferase (BHMT, EC
      2.1.1.5) of some mammalian species. We identified this protein as chicken BHMT
      because, in addition to its sequence homology with mammalian BHMT, there were
      similarities were also observed between this 45-kDa protein and mammalian BHMT
      with respect to molecular mass and isoelectric behavior. In the liver, 10 d after
      thyroidectomy, the synthesis of hepatic BHMT had already been enhanced, and the
      high expression was maintained at 50 d of age. Generally, BHMT catalyzes the
      transfer of a methyl group from betaine to L-homocysteine. In addition, it seems
      that this enzyme is also closely related to lipid metabolism in the liver; in
      this study expression of BHMT in the liver corresponded to plasma lipid levels.
      Moreover, hypothyroidism may be directly or indirectly related to overexpression
      of BHMT. Due to similarities between the BHMT of chickens and mammalian species,
      the chicken model might provide a useful means by which to study BHMT, its role
      in lipid metabolism, and methods of targeting the expression of BHMT. Another 29
      kDa protein was unidentified in the homology search.

PMID- 12619797
TI  - A model for failure of a chicken embryo to survive incubation.
AB  - Proper assessment of factors contributing to failure of an egg to hatch, i.e.,
      infertility and embryonic mortality, is important in poultry production. A model
      consisting of the sum of two cumulative logistic distributions was proposed
      previously to describe the distribution for time of mortality during incubation;
      model parameters, including probabilities of infertility and mortality, were
      estimated by the method of least squares. The objective of this paper was to
      improve the previous model and method of estimation by evaluating alternative
      distributions and methods; we propose four recommendations. First, probabilities
      of infertility and mortality should be estimated as observed proportions rather
      than as model parameters. Second, parameters of the distribution for time of
      mortality should be estimated using a diphasic Weibull distribution rather than a
      diphasic logistic distribution. Third, parameters of the distribution for time of
      mortality should be estimated using noncumulative proportions rather than
      cumulative proportions. Fourth, parameters of the distribution for time of
      mortality should be estimated by maximum likelihood rather than by least squares.
      The minimum Hellinger distance, however, is a good alternative to maximum
      likelihood to estimate distribution parameters if the distribution of mortality
      is not known exactly or if the data contain outliers.

PMID- 12619798
TI  - Effect of minerals on activity of microbial uricase to reduce ammonia
      volatilization in poultry manure.
AB  - Inhibition of microbial uricase in poultry manure is critical to reduce NH3
      volatilization, because hydrolysis of uric acid by microbial uricase is the first
      step in the production of NH3 gas in poultry manure. Three experiments were
      conducted to evaluate the effects of minerals on uricase activity and NH3
      volatilization from poultry manure. In Experiment 1, an in vitro enzyme assay was
      used to evaluate the effects of Zn, Cu, Mg, and Mn on the activity of microbial
      uricase. There were three treatments: uricase, uricase + minerals, and uricase
      preincubated with minerals. Uric acid concentration was measured at 293 nm with a
      spectrophotometer. The results indicated that Zn and Cu greatly blocked the
      activity of microbial uricase (>90% inhibition), whereas Mg and Mn were less
      inhibitory. Experiment 2 was designed to evaluate the effect of ZnSO4 on the
      growth of uric acid-utilizing microorganisms by an in vitro assay. There were
      three treatments: control, ZnSO4 (10 mM), and ZnSO4 (50 mM). The results
      indicated that ZnSO4 significantly reduced the number of uric acid-utilizing
      microorganisms compared to the control. In Experiment 3, an NH3-trapping system
      was used to evaluate the effect of different levels of ZnSO4 on NH3
      volatilization and nitrogen retention in poultry manure. Poultry manure (300 g)
      was mixed with 0, 0.15, 0.3, 1.5, 3, or 6 g ZnSO4 to create manure concentrations
      of Zn at 0, 0.05, 0.1, 0.5, 1, or 2% (wt/wt), respectively. The 1 and 2% ZnSO4
      treatments significantly increased manure uric acid and total nitrogen retention
      by reducing NH3 volatilization compared to the control during the 3-wk
      incubation.

PMID- 12619799
TI  - The effects of high-air velocity on broiler performance.
AB  - Two trials using a total of 1,484 Ross male broilers were conducted to study the
      effect of air velocities of 180 and 120 m/min versus still air (<15 m/min) on BW
      gain (BWG) and feed:gain from 3 to 7 wk of age. Broilers were raised in a common
      environment to 3 wk of age. The experimental facility was a closed sided house
      containing eight wind tunnel floor pens and six floor pens. There were two wind
      tunnels (four pens/tunnel) used to test air velocities of 180 or 120 m/min. At 3
      wk of age, 53 birds were placed in pens on litter in each of two wind tunnels
      (four pens/tunnel) or on litter in floor pens (six pens) in an environmentally
      controlled facility. All floor pens contained 3.75 square meters of floor space,
      one tube feeder, and one trough waterer. The temperature regimen was a diurnal
      cycle of 25-30-25 C with 23 C dewpoint. Air velocities of 180 and 120 m/min had
      no significant effect on BWG or feed:gain during the first week (3 to 4 wk) in
      the tunnels as compared with the still air. However, significant improvements
      were noted in BWG and feed:gains for increased air velocities from 4 to 5 and 5
      to 6 wk of age. During the last week (6 to 7), an air velocity of 180 m/min
      significantly improved BWG and feed:gain, as compared with the 120 m/min or the
      still air.

PMID- 12619800
TI  - Serum levels of mannan-binding lectin in chickens prior to and during
      experimental infection with avian infectious bronchitis virus.
AB  - Mannan-binding lectin (MBL) is a glycoprotein and a member of the C-type lectin
      super family, the collectin family, and the acute phase protein family. The MBL
      exerts its function by directly binding to microbial surfaces through its
      carbohydrate recognition domains, followed by direct opsonization or complement
      activation via MBL-associated serine proteases (MASP)-1 and -2. Thus, MBL plays a
      major role in the first-line innate defense against pathogens. We investigated
      the MBL concentrations in serum during experimental infectious bronchitis virus
      (IBV) infections in chickens. The results showed that the acute phase MBL
      response to infection with IBV was, to a degree (P < 0.0068), dependent on
      whether the chickens were inoculated after 12 h of rest (dark) or after 12 h of
      activity (light). The acute phase response in chickens challenged after 12 h of
      activity peaked after 4.6 d with an increase of 24%, whereas the acute phase
      response in chickens challenged after 12 h of rest peaked after 3.1 d with an
      increase of 51%. The specific antibody titer against IBV was also tested, and a
      difference (P < 0.0091) between the two experimental groups was found with peak
      titer values of 6,816 and 4,349. However, the highest value was found in chickens
      inoculated after 12 h of activity. Thus, an inverse relation exists between the
      MBL response and the IBV specific antibody response. The ability of MBL to
      activate the complement cascade was tested in a heterologous system by deposition
      of human C4 on the chicken MBL/MASP complex. The complement activation was
      directly associated with the concentration of MBL in serum, indicating
      neutralization of the virus before the humoral antibody response took over.

PMID- 12619801
TI  - Cloning and characterization of HEP21, a new member of the uPAR/Ly6 protein
      superfamily predominantly expressed in hen egg white.
AB  - Using two-dimensional (2D)-PAGE, partial protein internal sequencing, and PCR
      with degenerate primers, we cloned a novel cDNA named HEP21 from hen egg white.
      The 0.5-kb cDNA encodes a 106 amino acid protein with a cysteine spacing pattern
      suggesting that HEP21 is a new member of the uPAR/CD59/Ly-6/ snake neurotoxin
      superfamily. The closest homology of HEP21 is to mouse Ly-6C. Unlike most members
      of this protein family, HEP21 is not glycosylphosphatidylinositol (GPI)-anchored
      but is a secreted protein, as indicated by its localization and the presence of a
      signal peptide in its sequence. Moreover, HEP21 appears as an original member of
      this protein superfamily because it is predominantly expressed in a tissue, i.e.,
      the oviduct, and especially the magnum where the egg white components are
      secreted.

PMID- 12619802
TI  - Molecular characterization of fluoroquinolone-resistant Campylobacter spp.
      isolated from poultry.
AB  - Campylobacteriosis, an infectious disease caused by Campylobacter jejuni and
      Campylobacter coli, is treated by fluoroquinolone antibiotics in clinical
      practices. However, use of these drugs in animal husbandry may select for
      fluoroquinolone-resistant campylobacters and, thereby, compromise the clinical
      treatment of infection. In this study, 21 fluoroquinolone-resistant
      campylobacters were isolated from poultry samples. Morphological and biochemical
      characteristics indicated that 19 isolates were C. jejuni and two were C. coli.
      All isolates were resistant to multiple antibiotics but sensitive to
      chloramphenicol and gentamicin. These isolates were characterized at the
      molecular level by amplifying the flagellin gene (flaA) by PCR. The PCR protocol
      amplified a 1.7-kb flaA gene from all isolates. RFLP analysis of the 1.7-kb
      amplicons after digestion with DdeI yielded four distinct patterns. The 21
      fluoroquinolone-resistant campylobacter isolates were further characterized by
      pulsed-field gel electrophoresis (PFGE) and compared with the PFGE patterns of
      nine fluoroquinolone-sensitive campylobacter strains. Four of the 21
      fluoroquinolone-resistant isolates were untypable by the PFGE protocol. The PFGE
      analysis with SalI or SmaI indicated that seven or five, respectively, of the 17
      resistant isolates had identical macrorestriction profiles (mrps). However, PFGE
      analysis with a combination of SalI and SmaI indicated that four of the 17
      isolates had similar macrorestriction profiles. The PFGE patterns of the 17
      fluoroquinolone-resistant isolates were different from the nine sensitive
      campylobacter strains.

PMID- 12619803
TI  - Natural resistance-associated macrophage protein 1 gene polymorphisms and
      response to vaccine against or challenge with Salmonella enteritidis in young
      chicks.
AB  - Salmonella enteritidis (SE) contamination of poultry products is of global food
      safety concern. The natural resistance-associated macrophage protein 1 (NRAMP1)
      affects host innate immunity to intracellular bacteria because of its ability to
      transport divalent cations in late endosome/lysosomes. Studying the association
      of the NRAMP1 gene and chicken innate immune response to SE can, therefore, aid
      understanding and enhancement of chicken genetic resistance to SE. The chicken
      NRAMP1 gene was investigated as a candidate gene for SE response in a unique
      resource population. Outbred broiler sires and three diverse, highly inbred dam
      lines (two major histocompatibility complex-congenic Leghorn and one Fayoumi
      line) produced F1 progeny that were evaluated as young chicks for either
      bacterial load in spleen and cecum after pathogenic SE inoculation or antibody
      level after SE vaccination. Thirty-seven single nucleotide polymorphisms (SNP)
      were identified in 3.1 kb of genomic DNA of the NRAMP1 gene. A PCR-RFLP assay was
      developed to identify a SNP in a conserved transport motif. The sire NRAMP1 gene
      SNP was associated (P < 0.02) with antibody level to SE vaccine for Sire 8170
      offspring in the two Leghorn crosses. In Sire 8296 offspring, NRAMP1 was
      associated (P < 0.02) with spleen bacterial load in the combined dam-line
      crosses. This study demonstrated the association of a SNP polymorphism in a
      highly conserved region of NRAMP1 with SE vaccine and pathogen challenge response
      in young chicks, indicating that either NRAMP1 or a linked gene controls these SE
      response traits.

PMID- 12619804
TI  - Nutritive value of high-oil corn grown under semi-arid conditions and its impact
      on broiler performance and carcass composition.
AB  - A series of experiments was conducted to evaluate nutritive value of a high-oil
      corn (HOC) cultivar, grown under semiarid conditions, and its impact on
      performance and carcass characteristics of male broilers raised to market age.
      Conventional corn (CC) and HOC used in this research were produced under similar
      semi-arid conditions. By using a glucose containing reference diet in Experiment
      1, the AMEn of CC, as determined on 11-d-old male broilers, was lower (P < 0.05)
      than that of HOC (3,541 vs. 3,669 kcal/kg DM). The TME, TMEn, and true amino acid
      availability of CC and HOC were determined in Experiment 2 through individual
      precision feeding of eight intact mature roosters per ingredient. The TMEn of HOC
      was significantly higher than that of CC (4,126 vs. 3,870 kcal/kg DM), but true
      availability of amino acids was comparable for both cultivars. By using the CP
      and TMEn values determined in Experiment 2, two corn soybean meal starter and
      grower diets, containing no added fat, were prepared in Experiment 3, in which
      HOC replaced CC. Diets were provided ad libitum in five replicates to 5-d-old
      male broilers with eight birds per replicate until market age. Broiler
      performance, carcass yield, and carcass composition were comparable between both
      corn cultivars. Birds on HOC diet, however, deposited more (P < 0.05) abdominal
      fat (0.695%) than those on CC diet (0.575%). The results indicated that the extra
      calories derived from HOC could have been funneled primarily toward abdominal fat
      pad deposition rather than increased growth.

PMID- 12619805
TI  - Growth performance of different breed crosses of chicks fed diets with different
      protein and energy sources.
AB  - Six experiments (EXP) were conducted to evaluate growth performance of different
      breed crosses of broiler chicks fed diets containing soybean meal, soy protein
      isolate (SPI), soy protein concentrate (SPC), or rice and casein. Cornish x
      Plymouth Rock (C x PR; EXP 1, 3, 4, 5, and 6) or New Hampshire x Columbian (NH x
      C; EXP 2 and 4) cross chicks were used. The chicks were fed a corn-soybean meal
      (C-SBM) diet before allotment to treatment. The age of the chicks ranged from 5
      to 9 d posthatching at the start of the EXP, and the assay periods ranged from 8
      to 14 d. Initial weights were 194.9, 96.1, 102.1, 84.7 [84.1 (C x PR) or 85.3 (NH
      x C)], 101.8, and 145.1 g in EXP 1 to 6, respectively. A completely randomized
      design was used in all EXP, and treatments were replicated four to six times with
      four or five chicks each. All diets were formulated to meet the NRC nutrient
      requirements of chicks. In EXP 1 (C x PR male chicks) and EXP 2 (NH x C female
      chicks), gain and gain:feed (G:F) were greater (P < 0.01) in chicks fed the C-SBM
      diet compared with chicks fed diets containing SPI. In EXP 3, C x PR chicks were
      fed a C-SBM diet, a SPI-dextrose-cornstarch diet (dextrose:cornstarch, 1:1)
      formulated by Louisiana State University Agricultural Center (LSU) or a similar
      SPI diet (dextrose:cornstarch, 0.53:1) formulated by the University of Illinois
      (UI). Daily gain, average daily feed intake (ADFI), and G:F were increased (P <
      0.01) in chicks fed the C-SBM diet relative to chicks fed the two SPI diets, and
      there were only minor differences between the two SPI diets. In EXP 4, the C x PR
      and NH x C male chicks were fed the same diets used in EXP 3. Daily gain and ADFI
      were greater in the C x PR and NH x C chicks fed the C-SBM diet relative to
      chicks fed the SPI diets (P < 0.01), but the increased average daily gain (ADG)
      and ADFI in chicks fed the C-SBM diet were much greater in the C x PR chicks
      (chick x C-SBM vs. SPI, P < 0.01). Daily gain, ADFI, and G:F were greater (P <
      0.01) in C x PR chicks than in NH x C chicks. In EXP 5, ADG, ADFI, and G:F were
      greater (P < 0.04) in chicks fed the C-SBM diet compared with those fed a C-SPC
      diet. In EXP 6, C x PR chicks fed the C-SBM diet grew faster (P < 0.09) than
      those fed a rice and casein diet. Variable effects of diet on growth of chicks
      were affected by breed crosses of chicks.

PMID- 12619806
TI  - The relation between starch digestion rate and amino acid level for broiler
      chickens.
AB  - Digestion coefficients of nutrients give information about the amount of
      nutrients available to the animal but not about the rate or site of absorption.
      Gradual digestion of starch may have an amino acid sparing effect and therefore
      enhance growth efficiency of broiler chickens. A growth trial was performed with
      6,800 broiler chickens from 9 to 30 d of age to investigate interactions between
      starch digestion rate and amino acid level. Birds were fed either a pea-corn
      based diet (slowly digestible starch) or a tapioca-corn-based diet (rapidly
      digestible starch). Both diets were formulated with five levels of digestible
      lysine, varying from 8.5 to 11.0 g/kg. The minimal levels of other amino acids
      varied accordingly. Starch source did not affect feed intake (2,213 g), but
      weight gain was consistently higher for birds on pea-corn diets than for those on
      tapioca-corn diets (1,426 vs. 1,400 g; P < 0.01). Feed conversion was better (P <
      0.01) for birds on pea-corn diets (1.55) than for birds on tapioca-corn diets
      (1.58). The difference in feed conversion between birds on pea-corn and tapioca
      corn diets was greater with lower amino acid levels (0.043) than with higher
      amino acid levels (0.019) in the diet (P = 0.11). This interaction was more
      pronounced during the first 9 d of the experiment (P < 0.05). It was concluded
      that feeding slowly digestible starch improved protein and energy utilization in
      broiler chickens.

PMID- 12619807
TI  - Administration of triiodothyronine and dopamine to broiler chicks increases
      growth, feed conversion and visceral organ mass.
AB  - The influences of triiodothyronine (T3) or dopamine (DA) administration on
      growth, feed conversion, and visceral weights in broiler chicks between the ages
      of 6 and 12 d posthatch were investigated. In Trial 1, six chicks at age 6 d were
      randomly administered one of the following treatments: 0.37, 0.74, 1.48, and 2.96
      micromol T3/kg BW or 0.07, 0.14, 0.28, and 0.56 micromol DA/kg BW. Both T3 and DA
      were administered via intraperitoneal injections between the end of sternum and
      the ends of os pubis, with 0.9% saline as the excepient. In addition, two groups
      of six birds each were either not injected or injected with excepient only, as
      controls. Four replications were carried out with a total of 264 chicks. Heart
      weight as a percentage of feed-deprived body weight (FDBW) of the chicks injected
      with 2.96 micromol T3/kg BW was heavier than that of controls. Other variables
      measured were not significantly different between treatments. In trial 2, six
      chicks at age 6 d were randomly administered, one of the following treatments:
      0.56, 1.12, 2.24, and 4.48 micromol T3/kg diet or 0.40, 0.80, 1.60, and 3.20
      micromol DA/kg diet as well as a nonsupplemented control. Four replications were
      carried out with 216 chicks. The results in Trial 2 showed that the effects of T3
      (X, micromol/kg diet) on body weight gain (Y1, g) and feed consumption (Y2, g)
      were linear (Y1 = 310 - 21.5X, R2 = 0.868, P < 0.001 and Y2 = 398 - 22.3X, R2 =
      0.765, P < 0.001, respectively). The feed conversion ratio, the weight of liver,
      the weights of various intestinal segments, the lengths of the duodenum, jejunum
      and the ileum, as well as weight per centimeter jejunal length, gizzard weight as
      percentage of FDBW, and the duodenal length per kilogram FDBW all had linear
      responses (P < 0.05) to the level of dietary supplementation of T3. The effect of
      dietary supplementation of T3 on the heart weight was quadratic (Y16 = 2.58 +
      0.89X - 0.17 X2, R2 = 0.526, P < 0.01). Similarly, the weights of pancreas and
      gizzard, the heart weight as a percentage of FDBW and the pancreas weight as a
      percentage of FDBW all had second-order curve responses. Dietary DA
      supplementation exerted no effect on the variables measured except that the
      regression of the heart weight as a percentage of FDBW on dietary DA
      supplementation (X1, micromol/kg diet) existed, namely, Z1 = 0.64 + 0.24 X1 -
      0.23 X1(2) + 0.05 X1(3) (R2 = 0.868, P < 0.05).

PMID- 12619808
TI  - Phosphorus requirements of broiler chicks six to nine weeks of age as influenced
      by phytase supplementation.
AB  - Two trials of similar design were conducted to determine the nonphytate
      phosphorus (NPP) requirements for broilers from 42 to 63 d of age in diets with
      or without phytase supplementation. Male broilers of a commercial strain were
      grown to 42 d on nutritionally complete diets with NRC (1994) recommended levels
      of Ca and NPP. At 42 d, the birds were placed on experimental diets and fed to 63
      d. The experimental treatments consisted of a 2 x 6 factorial arrangement with
      two levels of phytase (0 or 800 U/kg) and six levels of NPP (0.10 to 0.35% in
      0.05% increments). Body weight gain, feed conversion, and mortality were
      determined during the period. At 49, 56, and 63 d, excreta samples were taken,
      and samples of birds were killed for tibia ash determination. The lowest level of
      NPP, with or without phytase supplementation, was sufficient for maximum BW gain,
      feed conversion, and livability. Using nonlinear regression, levels of NPP needed
      to optimize tibia ash in the absence of phytase were 0.31 +/- 0.004%, 0.23 +/-
      0.02%, and 0.22 +/- 0.029% at 49, 56, and 63 d, respectively. When diets were
      supplemented with 800 U/kg of phytase, the NPP requirement for optimum tibia ash
      was 0.15 +/- 0.049% at 49 d. At 56 and 63 d, no more than 0.10% NPP (lowest level
      tested) was sufficient to maximize tibia ash. Compared to current NRC (1994)
      recommendations, the application of these reduced dietary phosphorus levels could
      markedly reduce excreta excretion of phosphorus by broilers.

PMID- 12619809
TI  - Dietary electrolyte balance for broiler chickens under moderately high ambient
      temperatures and relative humidities.
AB  - Cobb male broiler chicks (1,000) on new litter were used to evaluate effects of
      dietary electrolyte balance [DEB; Na+K-Cl, milliequivalents (mEq) per kilogram]
      under tropical summer conditions. Corn-soybean meal-based mash diets had salt
      (NaCl) alone or in combination with one or more supplements: sodium bicarbonate
      (NaHCO3), ammonium chloride (NH4Cl), or potassium bicarbonate (KHCO3). A
      completely randomized design, with five starter and grower feed treatments
      (control: 145, then 130 mEq/kg; or 0, 120, 240, or 360 mEq/kg throughout) and
      four replicate pens (1.5 x 3.2 m) per treatment (50 chicks per pen), was used.
      Diets were analyzed for Na, K, and Cl for confirmation. There were no significant
      (P < 0.05) effects of treatments on mortality or processing parameters. Water
      intake increased linearly with increasing DEB, giving higher litter moistures and
      lower rectal temperatures. Blood HCO3 and pH increased with the highest DEB (360
      mEq/kg) causing respiratory alkalosis. The DEB of 240 mEg/kg gave best weight
      gain and feed conversion ratio, and ideal DEB predicted by regression analyses
      were 186 and 197 mEq/kg from 0 to 21 d of age and 236 and 207 mEq/kg of feed from
      0 to 42 d, respectively. These DEB corresponded to estimated (interpolated)
      values in predicted optimal 186 to 197 mEq/kg starter of Na 0.38 to 0.40% and Cl
      0.405 to 0.39% (K = 0.52%), in 207 to 236 mEq/kg starter, Na 0.409 to 0.445% and
      Cl 0.326 to 0.372% Cl (K = 0.52%), and in grower Na 0.41 to 0.445%, Cl 0.315 to
      0.267% (K = 0.47%).

PMID- 12619810
TI  - Response of growing Pekin ducks to supplementation of monobasic calcium phosphate
      to low-phosphorus diets.
AB  - The effects of a supplementation of P from monobasic calcium phosphate (MCP;
      Ca(H2PO4)2) to low-P basal diets were studied in growing Pekin ducks. Body weight
      gain and feed conversion were studied in two separate periods between Days 1 to
      21 (Experiment 1) and between Days 21 to 49 (Experiments 2 and 3). Retention of P
      was measured by comparative slaughter technique in Experiment 1. Additionally,
      two balance trials with quantitative determination of intake and excretion of P
      were conducted between Days 12 to 17 and between Days 30 to 35. MCP was
      supplemented in 7 or 6 graded levels at the expense of sand. In cases when ANOVA
      showed a significant effect of MCP supplementation, the response of ducks was
      described by nonlinear functions. No significant effect of supplemental MCP on
      growth, feed intake or feed/gain ratio was detected in the period between Days 21
      and 49 with a basal P level of 3.0 g/kg. Between Days 1 and 21, ducks needed 5.1
      g P/kg diet to achieve 95% of ymax in BW gain. The ymax for P concentration in
      gained BW, determined from balance trials, was 5.6 and 5.1 g/kg between Days 12
      to 17 and Days 30 to 35, respectively. Ninety-five percent of ymax in P retention
      was achieved with a dietary P concentration of 6.2 and 4.3 g/kg between Days 12
      to 17 and Days 30 to 35. The cumulative efficiency of utilization
      (retention/intake x 100) of dietary P from the basal diet was 49% (Days 12 to 17)
      and 43% (Days 30 to 35), and approached maximum with increasing supplementation
      of MCP of 55 and 53%, respectively, before it decreased again with further
      increase in MCP supplementation. The marginal efficiency of supplemental P
      (deltay/deltax) showed a maximum of 86% (Days 12 to 17) and 92% (Days 30 to 35),
      and this maximum was achieved where only 75 and 72% of ymax in P retentions were
      achieved. It is concluded that ducks require a lower P concentration in the diet
      with increase in age, but that the efficiency of utilization of P from inorganic
      salts is not clearly affected by age. Conclusions regarding the P requirement
      largely depend on the response criterion chosen. Based on P retention data, a
      dietary level of available P is recommended to be 3.4 (Days 1 to 21) and 2.3 g/kg
      (Days 21 to 49), although growth was unaffected by P even at lower concentrations
      of available P. Future comparative studies on the availability of P from
      ingredients should be conducted at a dietary P concentration that allows for
      identifying the maximum in utilization.

PMID- 12619811
TI  - Pre- and posthatch development of goblet cells in the broiler small intestine:
      effect of delayed access to feed.
AB  - Mucin glycoproteins play a key role in the regular function of the epithelium of
      the gastrointestinal tract, and in this study, the ontogenesis and development of
      mucin producing cells was examined in the broiler. Mucin-producing cells were
      observed in the small intestine from 3 d before hatch, and at this time contained
      only acidic mucin. After hatch and until Day 7 posthatch, the proximal, middle,
      and distal segments of the small intestine contained similar proportions of
      goblet cells producing acidic and neutral mucins. A gradient of goblet cell
      density was observed increasing along the duodenal to ileal axis. Delayed access
      to feed for 48 h posthatch resulted in an increase in intestinal intracellular
      mucins, which might have been due to impaired mucin secretion or enhanced mucin
      production. Changes in mucin dynamics could affect absorptive and protective
      functions of the small intestine.

PMID- 12619812
TI  - Potential relationships between physical traits and male broiler breeder
      fertility.
AB  - Genetic selection in primary broiler breeders may modify skeletal structure,
      possibly impeding semen transfer, and could alter the size and degree of
      fluctuating asymmetry (FA) of bilateral traits associated with fertility. Hence,
      we hypothesized specific morphometric traits could predict differential
      fertility. Sixty primary broiler breeder males from Strains A and B (n =
      30/strain) were individually housed with an average of 10 females per male. Male
      fertility and sperm penetration (SP) through the perivitelline layer were
      estimated on fresh eggs. At 50 wk, BW, keel length (KL), posterior pelvic width
      and length (PPW, PPL), dorsal pelvic width and length (DPW, DPL), tarsometatarsal
      length and width (TL, TW), comb length and width (CL, CW), and wattle length,
      width, and area (WL, WW, WA) were measured. Results indicated that Strain A had
      smaller BW, KL, WL, WW, WA, CL, CW, PPL, DPL, and DPW. A higher degree of FA was
      found in Strain A TL and WL (P < 0.05), yet DPW FA was greater for Strain B (P <
      0.001). In addition, DPW FA negatively correlated with Strain B fertility (r = 
      0.369; P < 0.01); however, other FA measurements did not correlate with estimated
      fertility or SP. Strain A WL correlated with SP (r = 0.383; P < 0.01) and
      fertility (r = 0.346; P < 0.01). Results indicate DPW alteration may impact semen
      transfer upon copulation, as Strain A fertility negatively correlated with DPW (r
      = -0.298; P < 0.05). This research provides evidence that morphometric traits
      might be useful to predict fertility in broiler breeders.

PMID- 12619813
TI  - Expression pattern of messenger ribonucleic acid for the activin type II
      receptors and the inhibin/activin subunits during follicular development in
      broiler breeder hens.
AB  - The expression of mRNA for the activin type II receptors (ActRII and ActRIIB),
      follistatin, and the inhibin/activin subunits was investigated in the follicles
      of broiler breeder hens. Total RNA was isolated from individual granulosa and
      theca layers of the F1 through F5 follicles, a pool of the F6 and F7 follicles,
      the small yellow follicles, and from the combined granulosa and theca layers of
      the large white follicles from six birds. Northern blot analysis was performed,
      and two ActRII mRNA transcripts of 6.5 and 3.7 kb were detected in granulosa and
      theca samples. Both ActRII transcripts were equally expressed in the granulosa
      samples, but in the theca samples expression of the 3.7-kb transcript was greater
      than the 6.5-kb transcript. ActRIIB was not detected by Northern analysis in any
      of the samples. Expression of the mRNA for the activin/inhibin binding protein,
      follistatin, was detected in theca and granulosa samples with the greatest
      expression found in small yellow follicle samples for both cell layers.
      Expression of the inhibin alpha-subunit was detected in the granulosa layer of
      all the follicles, but expression was greatest in the F6 and F7 follicles.
      Granulosa from the large hierarchical follicles expressed the most
      inhibin/activin betaA-subunit, whereas expression of the inhibin/activin betaB
      subunit was greatest in the granulosa of small yellow and F6 and F7 follicles.
      This report is the first, to our knowledge, on detection of activin type II
      receptor mRNA in the hen ovary and characterization of the expression pattern of
      the inhibin family in both the theca and granulosa layers throughout follicular
      development. The presence of activin receptor and follistatin mRNA in the theca
      and granulosa layers of the small developing follicles suggests that locally
      produced activin may be highly regulated and have a vital role in early
      follicular development.

PMID- 12619814
TI  - Arginine vasotocin induces bearing down for oviposition in the hen.
AB  - An intravenous injection of arginine vasotocin (AVT) at 16 h before the expected
      oviposition of the initial egg of an egg-laying sequence caused bearing down for
      oviposition. Oviposition was increased up to 100% by increasing the dose of AVT
      up to 1 microg, but it decreased when the dose was 10 and 20 microg. Bearing down
      was observed even when the oviposition was not induced by the injection of a
      higher dose of AVT. The results of the present experiment suggest that bearing
      down is not necessarily caused by the entering of egg into the vagina, but
      instead may be caused by hormonal stimulus of AVT receptors present in vaginal
      tissue.

PMID- 12619815
TI  - Tannic acid induces transcription of laccase gene cglcc1 in the white-rot fungus
      Coriolopsis gallica.
AB  - Laccase, a phenoloxidase enzyme secreted by white-rot fungi, has a significant
      role in the degradation of lignin and environmental pollutants. Coriolopsis
      gallica is a ligninolytic basidiomycete that produces high levels of this
      extracellular enzyme. A laccase gene cglcc1 from this fungus has been cloned and
      sequenced. The capacity of C. gallica to efficiently degrade polyphenols has been
      successfully applied in our laboratory to the biotreatment and decolorization of
      several industrial wastewaters. This study focused on the effect of tannic acid,
      a natural compound widely distributed in plants, on the production of laccase
      activity by C. gallica. Our results showed an evident increase of extracellular
      laccase levels when C. gallica was grown in the presence of tannic acid.
      Concentrations of 50 and 100 microM of this compound increased laccase activity
      when compared with control samples grown without tannic acid. In addition, we
      found an increase in laccase transcript levels in C. gallica grown in culture
      media supplemented with tannic acid. The role of tannic acid was shown to be an
      inductor of laccase activity in this fungus, due to the enhancement of expression
      of the laccase gene at the transcriptional level.

PMID- 12619816
TI  - Hemoglobin in five genetically diverse Frankia strains.
AB  - Five strains of Frankia were selected to represent a wide range of genetic
      diversity and examined for presence of hemoglobin. All five strains produced
      hemoglobin when grown on media without (-N) or with (+N) combined nitrogen. This
      indicates that hemoglobin is common in Frankia and is not directly associated
      with nitrogen fixation. Frankia strain EAN1(pec) was examined in more detail. It
      showed greater hemoglobin concentration when grown at 2% O2 than at 20% O2 in the
      -N treatment but no effect of oxygen on hemoglobin concentration in the +N
      treatment. At both oxygen levels, it produced substantially more biomass in +N
      than in -N culture. It also produced significantly more biomass when the medium
      contained 0.2% CO2 than in the absence of CO2. The molecular mass of the
      hemoglobin as determined by size exclusion chromatography was 13.4 +/- 0.2 kDa
      (mean +/- SE, n = 3) and is consistent with that of a truncated hemoglobin. The
      hemoglobin had absorption spectra that were typical of a hemoglobin. The oxygen
      dissociation rate constants for the hemoglobin were 131.2 +/- 5.8 s(-1) for -N
      culture and 166 +/- 8.2 s(-1) for +N culture. These rapid rates are consistent
      with a function in facilitated diffusion of oxygen.

PMID- 12619817
TI  - The improvement of lipase secretion and stability by addition of inert compounds
      into Acinetobacter calcoaceticus cultures.
AB  - Acinetobacter calcoaceticus BD413 produces variable amounts of an exocellular
      lipase that becomes rapidly inactivated upon secretion. To achieve high yield and
      protect the enzyme, we assayed the addition of several inert compounds to cell
      free supernatants, cell fractions, and whole cultures. Glass beads, poly(ethylene
      glycol) 600, Triton X-100, saccharose, gum arabic, and beta-cyclodextrin were
      among the compounds tested. beta-Cyclodextrin and gum arabic (and saccharose to a
      lesser extent) were effective enzyme stabilizers in cell-free supernatants, while
      gum arabic, glass beads, and Triton X-100 improved lipase secretion from cells,
      and, therefore, total lipase yield (30-50%, according to the additive). In whole
      cultures, beta-cyclodextrin was the most effective additive, particularly in
      combination with glass beads or gum arabic. Indeed, cultures containing beta
      cyclodextrin plus gum arabic were able to maintain 95% (+/- 1.5%) of the initial
      lipase activity for more than 16 h, while control cultures with no additives
      maintained only 10% (+/- 4%) of the enzyme activity after the same period. In
      conclusion, the addition of inert compounds in cultures may be considered a
      useful approach for achieving increased yield and lipase stabilization, amenable
      for downstream processing.

PMID- 12619818
TI  - Multiple phytoplasmas associated with potato diseases in Mexico.
AB  - In recent years, the potato crop in Mexico has been notably affected by diseases
      recognized as potato purple top (PPT) in foliage and potato hair sprouts (PHS) in
      germinating tubers. In both cases, these syndromes reduce production by affecting
      viability of the tubers used as seeds. There is evidence indicating that
      phytoplasmas are associated with these syndromes. This study presents data on the
      molecular detection, characterization, and ecology of the pathogens related to
      PPT and PHS. Restriction fragment length polymorphism (RFLP) and sequence
      analysis indicated that PPT phytoplasma belongs to the 16SrI group and PHS
      phytoplasma fits in the 16SrII group. In this paper, we report that the two
      different phytoplasmas have been found coexisting in the same potato plant, which
      demonstrates the presence of mixed infection in the field. These phytoplasmas
      were also detected in weeds surrounding potato fields; therefore they should be
      considered as alternative hosts or natural reservoirs of PPT and PHS
      phytoplasmas.

PMID- 12619819
TI  - Enhancement of population densities of fluorescent pseudomonads in the
      rhizosphere of tomato plants by addition of acibenzolar-S-methyl.
AB  - Fluorescent pseudomonad isolates G309 and CW2, in combination with the resistance
      inducer acibenzolar-S-methyl (ASM), improved control of fungal and bacterial
      diseases on tomato plants. The interactions of the bacteria in the presence of
      ASM showed that in vitro growth of Pseudomonas fluorescens G309 and Pseudomonas
      sp. strain CW2 was not affected in King's B broth supplemented with 10 and 20
      microM ASM. Also, the bacterial cells were not able to utilize ASM as a nutrient
      source. In vitro production of the two antimicrobial secondary metabolites
      phenazine-1-carboxylic acid and 2-OH-phenazine by the isolate CW2 was not
      affected within 3 days from incubation. In contrary, addition of ASM at a
      concentration of 20 microM to King's B liquid medium significantly increased
      production of salicylic acid by isolate G309. When roots of tomato plants were
      treated with G309 or CW2 cell suspensions containing 20 microM ASM, the number of
      bacterial cells recovered from the rhizosphere was significantly higher in the
      combined treatments than in the single applications 5, 10, and 15 days after
      inoculation. However, ASM at a higher concentration (50 microM) did not
      appreciably enhance the population sizes of either bacterial isolate in the
      rhizosphere. Enhanced bacterial cell densities in the rhizosphere of tomato
      plants were also determined following simultaneous treatments of tomato roots
      with 10 and 20 microM ASM in combination with the transformed isolate G309-384
      (mini-Tn5gfp), which encodes the green fluorescent protein.

PMID- 12619820
TI  - Control of pyrimidine formation in Pseudomonas putida ATCC 17536.
AB  - The regulation of de novo pyrimidine biosynthesis in Pseudomonas putida ATCC
      17536 by pyrimidines was explored. The pathway enzyme activities were higher in
      glucose-grown cells than in succinate-grown cells, indicating catabolite
      repression by succinate. In P. putida cells grown on succinate as a carbon
      source, only aspartate transcarbamoylase activity was greatly diminished by
      uracil supplementation. When glucose was the carbon source, orotic acid
      supplementation significantly decreased orotate phosphoribosyltransferase and
      orotidine 5'-monophosphate (OMP) decarboxylase activities. Uracil auxotrophs,
      deficient for dihydroorotase activity or with reduced phosphoribosyltransferase
      activity, were isolated. After pyrimidine limitation of both auxotrophs, the
      greatest derepression of enzyme activity was observed for OMP decarboxylase
      independent of carbon source. Orotic acid induced both phosphoribosyltransferase
      and decarboxylase activities in glucose-grown cells of the dihydroorotase
      deficient strain. Regulation at the transcriptional level of de novo pyrimidine
      biosynthetic enzyme synthesis in P. putida ATCC 17536 was observed, which
      contrasts with previous observations.

PMID- 12619821
TI  - Water activity, temperature, and pH effects on growth of the biocontrol agent
      Pantoea agglomerans CPA-2.
AB  - The growth response of the biocontrol agent Pantoea agglomerans to changes in
      water activity (a(w)), temperature, and pH was determined in vitro in nutrient
      yeast extract-sucrose medium. The minimum temperature at which P. agglomerans was
      able to grow was 267-272 kelvins (-6 to -1 degrees C), and growth of P.
      agglomerans did not change at varying pH levels (4.5-8.6). The minimum a(w) for
      growth was 0.96 in media modified with glycerol and 0.95 in media modified with
      NaCl or glucose. Solute used to reduce water activity had a great influence on
      bacterial growth, especially at unfavourable conditions (e.g., low pH or
      temperature). NaCl stimulated bacterial growth under optimum temperatures but
      inhibited it under unfavourable pH conditions (4.5 or 8.6). In contrast, the
      presence of glucose in the medium allowed P. agglomerans to grow over a broad
      range of temperature (3-42 degrees C) or pH (5-8.6) regimes. This study has
      defined the range of environmental conditions (a(w), pH, and temperature) over
      which the bacteria may be developed for biological control of postharvest
      diseases.

PMID- 12619822
TI  - Ralstonia basilensis M91-3, a denitrifying soil bacterium capable of using s
      triazines as nitrogen sources.
AB  - The purpose of this study was to characterize the phylogenetic and phenotypic
      traits of M91-3, a soil bacterium capable of mineralizing atrazine (2-chloro-4-N
      isopropyl-6-N-ethyl-s-triazine). The isolate was identified as Ralstonia
      basilensis based on 99.5% homology of the 16S rRNA sequence and various
      chemotaxonomic data. The isolate used atrazine as the sole source of energy,
      carbon, and nitrogen. It could also use several other s-triazines as nitrogen
      sources. Ralstonia basilensis M91-3 was capable of denitrification, which was
      confirmed by gas chromatographic analysis of nitrous oxide under acetylene
      blockage conditions.

PMID- 12619823
TI  - Activity of sulfate-reducing bacteria in human periodontal pocket.
AB  - Samples of subgingival dental tissues were examined for the presence of sulfate
      reducing bacteria (SRB). Using enrichment cultures, SRBs were detected in 9 of 17
      individuals. A pure culture of SRB was obtained from one sample collected from a
      patient with type IV periodontal disease. The characterization of this isolate
      showed that it belongs to the genus Desulfovibrio. The isolate used pyruvate,
      lactate, glucose, fructose, and ethanol as the sole source of carbon. However,
      the isolate was unable to use acetate and methanol as a carbon source, indicating
      it as an incomplete oxidizer unable to carry out the terminal oxidation of
      substrates. Apart from using sulfate as electron acceptor, the isolate also used
      thiosulfate and nitrate as an electron acceptor. It has the ability to use a
      variety of nitrogen sources, including ammonium chloride, nitrate, and glutamate.
      The optimum growth temperature of the isolate was 37 degrees C and the optimum pH
      for growth was 6.8. The SRB isolate contained the electron carrier
      desulfoviridin. The numbers of SRB in the mouth are assumed to be limited by
      sulfate. Potential sources of sulfate in the subgingival area include free
      sulfate in pocket fluid and glycosaminoglycans and sulfur-containing amino acids
      from periodontal tissues.

PMID- 12619824
TI  - Regulation of expression of the Rhizopus oryzae uricase and urease enzymes.
AB  - The regulation of intracellular urease and uricase activities was examined in
      Rhizopus oryzae. Urease activity (2.4 U/mg protein) was present in R. oryzae
      mycelium grown in minimal medium containing NH4CI as sole nitrogen source. This
      activity increased threefold under nitrogen derepression conditions, but no
      induction by urea was detected. Control of urease activity in R. oryzae differs
      from that found in Neurospora crassa but resembles the situation in Aspergillus
      nidulans. No uricase activity was detected in R. oryzae mycelium grown in minimal
      medium containing NH4Cl as sole nitrogen source. Uricase activity was increased
      10- to 40-fold under derepression conditions and was induced by exogenous uric
      acid (60- to 78-fold). Control of the R. oryzae uricase differs from that found
      in N. crassa and A. nidulans. This is the first analysis of the regulation of
      enzymes from the purine catabolic pathway in any member of the Zygomycetes.

PMID- 12619825
TI  - Enzymatic activity of endophytic fungi of six native seedling species from Doi
      Suthep-Pui National Park, Thailand.
AB  - Endophytic fungi were isolated from the stems, petioles, midribs, and leaves of
      seedlings of six native tree species collected from Doi Suthep-Pui National Park,
      Thailand. Endophytes were isolated from all tissue samples investigated, and taxa
      included five ascomycetes, eight anamorphic taxa, and numerous sterile mycelia.
      Twenty-six strains were tested for their ability to produce cellulase, mannanase,
      proteinase, and xylanase. The ability to produce these enzymes was distributed
      amongst the strains tested. Rainforest seedlings supported a diverse array of
      endophytes that have a wide range of enzymatic activities. The implication of
      enzyme production in relation to lifestyle abilities of the endophytes is
      discussed.

PMID- 12619826
TI  - The EU bans cosmetics testing on animals.

PMID- 12619827
TI  - California city weighs ban on animal declawing.

PMID- 12619829
TI  - From seahorses to sawfish.

PMID- 12619828
TI  - Pet owners in San Francisco become 'pet guardians'.

PMID- 12619830
TI  - Retiring to a chimp paradise.

PMID- 12619831
TI  - Gut warfare.

PMID- 12619832
TI  - FIV vaccine recommendation.

PMID- 12619833
TI  - Elevating the role and status of food animal veterinarians.

PMID- 12619834
TI  - Service in major public health regulatory agencies.

PMID- 12619835
TI  - What is your diagnosis? Pneumoperitoneum.

PMID- 12619836
TI  - What is your neurologic diagnosis? Stylohyoid bone fracture and possible petrous
      temporal bone fracture.

PMID- 12619837
TI  - Potential for dietary protection against the effects of aflatoxins in animals.

PMID- 12619838
TI  - Employment of male and female graduates of US veterinary medical colleges, 2002.

PMID- 12619839
TI  - Seroprevalence of antibodies against Leishmania spp among dogs in the United
      States.
AB  - OBJECTIVE: To determine seroprevalence of antibodies against Leishmania spp among
      dogs other than Foxhounds in the United States. DESIGN: Cross-sectional study.
      SAMPLE POPULATION: 957 serum samples from dogs throughout the United States
      submitted between January 2000 and August 2001 to the Diagnostic Center for
      Population and Animal Health at Michigan State University for serologic testing
      for tick-borne diseases. PROCEDURE: Samples were tested for antibodies against
      Leishmania spp with an immunofluorescent antibody (IFA) assay. Samples with
      positive results were submitted to the Centers for Disease Control and Prevention
      for confirmatory testing. RESULTS: Results of the IFA assay were negative for 939
      of 957 samples. For 16 samples, titers were from 1:16 to 1:64, and titers in
      these dogs were considered likely to be a result of cross-reactivity with
      antibodies directed against other organisms. For the remaining 2 samples, the
      titers were > or = 1:128. One of these samples was from a blood donor dog that
      had never had any clinical signs of leishmaniasis. Follow-up samples from both
      dogs also had Leishmania IFA titers > or = 1:128. Both dogs had antibodies
      against Trypanosoma cruzi, as determined with a radioimmunoprecipitation assay.
      CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the seroprevalence of
      antibodies against Leishmania spp in dogs in the United States was low. However,
      results further suggested that leishmaniasis may not be limited to Foxhounds in
      the United States.

PMID- 12619840
TI  - Use of thermokeratoplasty for treatment of ulcerative keratitis and bullous
      keratopathy secondary to corneal endothelial disease in dogs: 13 cases (1994
      2001).
AB  - OBJECTIVE: To evaluate the outcome of thermokeratoplasty for treatment of
      ulcerative keratitis and bullous keratopathy secondary to corneal endothelial
      disease in dogs. DESIGN: Retrospective study. ANIMALS: 13 dogs. PROCEDURES:
      Medical records from 1994 to 2001 for dogs evaluated because of ulcerative
      keratitis and bullous keratopathy and treated with thermokeratoplasty were
      reviewed. RESULTS: There were 7 spayed females, 5 castrated males, and 1 sexually
      intact male, ranging from 6 to 16 years of age. Ten dogs had endothelial
      degeneration, and 3 dogs had breed-related endothelial dystrophy. All dogs had
      bullous keratopathy, characterized by microbullae formation that was detected via
      biomicroscopy. Recurrent or nonhealing corneal ulcers were detected unilaterally
      in 5 dogs and bilaterally in 8 dogs. Mean +/- SD duration from thermokeratoplasty
      until ulcerations were healed for all dogs was 2.2 +/- 1.1 weeks. All dogs that
      underwent thermokeratoplasty for nonhealing corneal ulceration secondary to
      endothelial disease and corneal edema had epithelial wound healing and resolution
      of corneal ulceration. Mean duration of treatment (ie, topical treatment required
      until resolution of ulceration) was significantly less after thermokeratoplasty
      than duration of treatment (with multiple treatments) prior to referral.
      CONCLUSIONS AND CLINICAL RELEVANCE: It may be necessary to perform
      thermokeratoplasty of the entire cornea to prevent recurrence of ulcerations in
      areas that have not been treated with thermokeratoplasty.

PMID- 12619841
TI  - Case-control study of factors associated with excessive proportions of early
      fetal losses associated with mare reproductive loss syndrome in central Kentucky
      during 2001.
AB  - OBJECTIVE: To identify factors associated with excessive proportions of early
      fetal losses associated with mare reproductive loss syndrome in central Kentucky
      during 2001. DESIGN: Case-control study. PROCEDURE: Questionnaires were used to
      collect information on farm-, pasture-, and individual animal-level factors
      purportedly associated with mare reproductive loss syndrome. Data were collected
      for 133 farms (97 with excessive proportions of early feta losses and 36 control
      farms) representing 6,576 mares. RESULTS: Factors significantly associated with
      an increased risk of excessive early fetal losses were exposure to moderate to
      high concentrations of Eastern tent caterpillars, exposure to cherry trees, farm
      size > or = 50 broodmares, being bred during February 2001, and frequent exposure
      to waterfowl. Feeding hay to mares outside was associated with a decreased risk
      of excessive proportions of early fetal losses. Pasture composition and
      management factors were not significantly different between affected and control
      pastures. Individual animal-level factors were investigated on 6 farms
      representing 340 mares, and age, parity, and pre- and postbreeding treatments
      were not significantly associated with risk of early fetal loss. CONCLUSIONS AND
      CLINICAL RELEVANCE: Results suggest that limiting exposure to Eastern tent
      caterpillars and cherry trees and feeding hay to mares outside may help decrease
      the risk of excessive proportions of early fetal losses associated with mare
      reproductive loss syndrome.

PMID- 12619842
TI  - Toxic shock syndrome in a horse with Staphylococcus aureus pneumonia.
AB  - A 3-year-old Thoroughbred gelding was examined because of clinical signs of
      pneumonia and shock. Mucous membrane petechiation and ventral edema were observed
      and considered to be a result of vasculitis. Epidermal necrosis developed on the
      distal portions of the limbs. The horse had a persistent high fever that was
      unresponsive to nonsteroidal anti-inflammatory treatment, and Staphylococcus
      aureus was isolated from a nasal swab specimen and 2 transtracheal wash fluid
      samples. Antimicrobial, anti-inflammatory, and supportive treatment resulted in
      clinical improvement. However, resolution of the pulmonary infection required
      long-term (42 days) antimicrobial administration. Staphylococcus aureus strains
      isolated from this horse were positive for the toxic shock syndrome toxin-1 gene
      and were shown to produce toxic shock syndrome toxin-1, the causative factor in
      toxic shock syndrome in humans. The horse's clinical signs were attributed to
      toxic shock syndrome secondary to pulmonary S. aureus infection.

PMID- 12619843
TI  - Evaluation of an inactivated Neospora caninum vaccine in beef feedlot steers.
AB  - OBJECTIVE: To evaluate effects of vaccination of feedlot steers against bovine
      neosporosis on weight gain, feed intake and efficiency (feed intake per gain),
      and carcass characteristics. DESIGN: Longitudinal observational study. ANIMALS:
      60 weaned Brangus steers seronegative for Neospora caninum. PROCEDURE: Steers
      were assigned to age-matched control and treatment groups. Steers in the
      treatment group received N. caninum vaccine on days 79 and 106, while control
      steers received 2 placebo injections. For each steer, serologic status for N.
      caninum was determined on days 0 (weaning), 51, 79, 106, 135, 163, 191, 219, and
      247 by use of an ELISA; body weight was determined on the same days and at
      slaughter (day 259). Daily feed intake per steer was measured from days 79 to
      259. RESULTS: Seroconversion occurred in 23 of 30 (76.7%) steers in the
      vaccinated group. Immediately after vaccination, average daily gain, average
      daily feed intake, and feed efficiency were significantly greater in the
      treatment group than in the control group, but these differences did not persist.
      No differences between groups were found in regard to live weight at slaughter,
      hot carcass weight, dressing percentage, or quality grade; however, steers in the
      vaccinated group had significantly lower yield grades than did control steers.
      CONCLUSIONS AND CLINICAL RELEVANCE: In feedlot steers, use of this vaccine
      against N. caninum was safe and did not affect overall feedlot performance or
      meat quality; effects on yield grade require further evaluation.

PMID- 12619844
TI  - Prepubic urethrostomy and placement of a caudal superficial epigastric flap for
      treatment of a self-mutilation injury in a serval.
AB  - A 10-year-old male serval was examined for treatment of a self-inflicted perineal
      wound that obliterated the ventral anocutaneous junction, penis, scrotum,
      testicles, and proximal portions of the caudomedial thigh muscles. Repair
      required placement of a caudal superficial epigastric flap and prepubic
      urethrostomy. Although it is generally preferable to delay repair of contaminated
      wounds until a healthy wound bed is established, circumstances related to wound
      location, affected tissues, and patient compliance led to a decision for
      immediate wound closure. In this serval, a history of food intolerance, recent
      diet change, eosinophilia, and eosinophilic granuloma-like skin lesions suggested
      that the self-mutilation injury was a result of food hypersensitivity, although
      foreign body or a spider bite could not be ruled out.

PMID- 12619846
TI  - Creating the culture of safety.

PMID- 12619845
TI  - Trends in national surveillance for rabies among bats in the United States (1993
      2000).
AB  - OBJECTIVE: To describe surveillance trends and epidemiologic features of rabies
      in bats in the United States, focusing on 3 bat species primarily associated with
      variants of the rabies virus that affect humans. DESIGN: Retrospective study.
      ANIMALS: 31,380 bats. PROCEDURE: Data on rabies for bats identified to species
      and reported by state laboratories from 1993 to 2000 were analyzed, focusing on
      silver-haired, eastern pipistrelle, and Brazilian free-tailed bats. Categoric
      variables were derived from other provided information. RESULTS: Data were
      reported from 37 states during the study interval; complete species-specific data
      were not reported by any state for the entire interval. Bats primarily associated
      with rabies virus variants affecting humans were more likely to yield positive
      test results for rabies (22.7%), compared with all other bats (5.5%) in most
      seasons and from most regions of the United States. However, certain other bat
      species had higher percentages of positive results. Risk of positive results was
      highest in the fall and highest among bats originating in the southwestern United
      States. CONCLUSIONS AND CLINICAL RELEVANCE: Increased risk of rabies among
      certain groups of bat species was consistently found across seasons and most
      geographic regions of the United States. Results were in general agreement with
      those of previous studies conducted within smaller geographic regions. There are
      ongoing efforts to improve surveillance of rabies in bats, although surveillance
      is incomplete in some regions.

PMID- 12619847
TI  - Are you educationally biased?

PMID- 12619848
TI  - Endometriosis--a missed malady.
AB  - Endometriosis is a disease that affects approximately 5.5 million girls and women
      in their reproductive years in the United States and Canada. During the menstrual
      cycle, the endometrial lining of the uterus thickens in preparation to receive a
      fertilized egg. If fertilization does not occur, this lining sloughs off during
      menstruation. Endometrial tissue can migrate out of the fallopian tubes and grow
      outside of the uterus as endometrial implants. This can result in severe pain.
      Endometriosis is very difficult to detect because most women become accustomed to
      painful menstrual cycles at an early age. The disease often will go undiagnosed
      because even with extensive endometriosis it is possible to have minimal symptoms
      or none at all. Physicians have few diagnostic tools to detect the scars and
      growths of endometriosis. The only way to confirm the diagnosis and stage of
      endometriosis is by laparoscopy. Treatment options include hormone therapy and
      surgery. In the past, the most successful treatment was open laparotomy with
      excision of the endometrial implants. This article discusses the use of the
      ultrasonic scalpel to resect endometrial implants through the laparoscope. The
      patient's perioperative course also is discussed.

PMID- 12619849
TI  - Endometrial ablation as an alternative to hysterectomy.
AB  - In the United States, as many as two million women (ie, 22%) each year will
      consult a physician about menorrhagia (ie, excessive menstrual bleeding). Seven
      hundred thousand hysterectomies are performed in the United States each year for
      symptomatic menorrhagia. The procedure cost, risk, and complications, combined
      with the fact that a large number of posthysterectomy specimens show no
      abnormality, suggest that the majority of hysterectomies performed for
      menorrhagia are unnecessary. These data suggest that a less invasive procedure
      that destroys the endometrial lining but preserves the uterus would be a
      beneficial procedure for patients with excessive uterine bleeding. Treatment for
      menorrhagia may include hormone therapy, endometrial curettage, endometrial
      ablation, and hysterectomy. Women who are opposed to hysterectomy and those for
      whom other treatment options were unsuccessful can consider ablation rather than
      hysterectomy.

PMID- 12619850
TI  - Deep vein thrombosis and airline travel--the deadly duo.
AB  - A number of deaths from pulmonary embolism caused by deep vein thrombosis (DVT)
      have been attributed to long-distance airplane travel. Although airplanes provide
      the most convenient means of long-distance travel, the aircraft environment can
      take a physical toll on passengers. This article describes the causes and risk
      factors for discusses preventive strategies, and offers recommendations for
      making air travel safer.

PMID- 12619851
TI  - Clinical nurse specialist practice--spheres of influence.
AB  - Many nurses are uncertain of the differences in the educational backgrounds and
      practice domains of clinical nurse specialists (CNSs) and nurse practitioners
      (NPs). This uncertainty may make it difficult for perioperative nurses to select
      the advanced practice role that is most congruent with their career goals and
      interests. The National Association of Clinical Nurse Specialists developed the
      Statement on Clinical Nurse Specialist Practice and Education, which provides an
      organizing framework for the CNS practice role. This article offers distinctions
      between the educational experiences of CNSs and NPs and suggestions for
      perioperative CNS practice.

PMID- 12619852
TI  - Changing acute pain management outcomes in surgical patients.
AB  - Patient outcome studies indicate that patients accept pain as part of
      hospitalization. The majority of hospitalized patients who report experiencing
      pain are recovering from surgical intervention. To achieve successful outcomes, a
      comprehensive multidisciplinary effort must begin preoperatively and continue
      through discharge. The perioperative period is an essential link in effective
      pain management, and perioperative nurses are key in helping direct the care of
      surgical patients before, during, and after surgical procedures. Pain relief and
      the patients satisfaction with care frequently are used to measure pain
      management outcomes. This article examines the results of a secondary analysis of
      a subset of surgical patients drawn from a larger data set that was collected
      during two studies in urban and rural hospitals. It focuses on two outcomes,
      namely characteristics of pain and patient satisfaction with pain management
      after surgery. These outcomes were measured using the American Pain Society
      patient outcome questionnaire and the pain management index. Correlational,
      descriptive, and regression analyses indicate that postoperative management of
      patients' pain in these studies was less than optimal. From this new
      understanding, strategies for effective pain management of surgical patients are
      recommended.

PMID- 12619853
TI  - Effects of music on patient anxiety.
AB  - Undergoing surgery with local anesthesia is stressful because patients often are
      aware of their surroundings. This study investigated music as a method of
      reducing patients' anxiety during minor surgery with local anesthesia. For this
      study, researchers assessed the effectiveness of music as a relaxation modality
      by measuring patients' vital signs and self-reported anxiety before and after
      surgery. Study results indicate that patients who listened to their choice of
      music during surgery experienced significantly lower anxiety levels, heart rates,
      and blood pressure than patients who did not listen to music.

PMID- 12619855
TI  - Involving family members in a thyroplasty procedure.

PMID- 12619854
TI  - Using intraoperative radiation therapy--a case study.
AB  - The introduction of a mobile linear accelerator in the OR has made intraoperative
      radiation therapy (IORT) more plausible. An IORT treatment can deliver a single
      high dose of radiation to a tumor or tumor bed after surgical resection or
      surgical exposure of high risk areas. This article details a case study in which
      IORT was used on a patient with sigmoid carcinoma and the procedure outcomes.

PMID- 12619856
TI  - Learning from near misses in an effort to promote patient safety.

PMID- 12619857
TI  - Recommended practices for cleaning and processing endoscopes and endoscope
      accessories.

PMID- 12619858
TI  - Beyond legislation--understanding another public policy arena.

PMID- 12619859
TI  - Decoy calcium channel beta subunits modulate contractile function in myocytes.
AB  - To test the hypothesis that mutated beta2-subunits of the L-type calcium channel
      could serve as a decoy and interdict calcium channel trafficking and function, we
      engineered a beta2 subunit that contained the beta interaction domain for alpha1c
      subunit interaction, but lacked N- and C-terminal domains that might be essential
      for sarcolemmal localization. An adenoviral vector was constructed containing the
      gene for the beta-interaction domain (BID) fused to green fluorescence protein
      (GFP), using a vector containing only GFP as control. Freshly plated, dissociated
      adult rat myocytes were infected and expression and function were assessed at 60
      h. Fluorescence microscopy confirmed GFP expression; immunoblot analysis
      confirmed dose-dependent GFP-BID expression. Mechanical properties of adult rat
      ventricular myocytes were evaluated using a video edge-detection system.
      Contractility analysis (optical/video, field stimulation) demonstrated that
      contracting cells decreased from 60 to 2%. Contractile amplitude (percent
      shortening) decreases significantly from 5.6 vs. 2.4% with no change in time to
      peak twitch. Recombinant adenovirus overexpressing mutated beta2 subunits in
      adult mammalian myocytes can markedly alter excitation-contraction coupling. This
      paradigm may offer new approaches to understanding and modulating EC coupling.

PMID- 12619860
TI  - Importance of Ca2+ influx by Na+/Ca2+ exchange under normal and sodium-loaded
      conditions in mammalian ventricles.
AB  - Na+/Ca2+ exchange (NCX) is a major Ca2+ extrusion system in cardiac myocytes, but
      can also mediate Ca2+ influx and trigger sarcoplasmic reticulum Ca2+ release.
      Under conditions such as digitalis toxicity or ischemia/reperfusion, increased
      [Na+]i may lead to a rise in [Ca2+]i through NCX, causing Ca2+ overload and
      triggered arrhythmias. Here we used an agent which selectively blocks Ca2+ influx
      by NCX, KB-R7943 (KBR), and assessed twitch contractions and Ca2+ transients in
      rat and guinea pig ventricular myocytes loaded with indo-1. KBR (5 microM) did
      not alter control steady-state twitch contractions or Ca2+ transients at 0.5 Hz
      in rat, but significantly decreased them in guinea pig myocytes. When cells were
      Na+-loaded by perfusion of strophanthidin (50 microM), the addition of KBR
      reduced diastolic [Ca2+]i and abolished spontaneous Ca2+ oscillations. In guinea
      pig papillary muscles exposed to substrate-free hypoxic medium for 60 min, KBR
      (10 microM applied 10 min before and during reoxygenation) reduced both the
      incidence and duration of reoxygenation-induced arrhythmias. KBR also enhanced
      the recovery of developed tension after reoxygenation. It is concluded that (1)
      the importance of Ca2+ influx via NCX for normal excitation-contraction coupling
      is species-dependent, and (2) Ca2+ influx via NCX may be critical in causing
      myocardial Ca2+ overload and triggered activities induced by cardiac glycoside or
      reoxygenation.

PMID- 12619861
TI  - Compensated hypertrophy of cardiac ventricles in aged transgenic FVB/N mice
      overexpressing calsequestrin.
AB  - Cardiac-specific overexpression of murine cardiac calsequestrin results in
      depressed contractile parameters and hypertrophy in transgenic mice. To determine
      the long-term consequences of calsequestrin overexpression, the cardiac phenotype
      of young (2-3-months old) and aged (17 months old) transgenic FVB/N mice was
      characterized. Ventricular/body weight ratios, which were increased in young
      transgenics compared with wild-types, were unaltered with age. Left atria of aged
      transgenics exhibited enlargement and mineralization, but their ventricles did
      not display fibrosis, mineralization and other injuries. Although
      echocardiography suggested a time-dependent change in ventricular geometry and
      loading conditions in vivo, as well as an age-dependent reduction of left
      ventricular fractional shortening in transgenic mice, Langendorff-perfused hearts
      of young and aged transgenics indicated that there were no age-related reductions
      of contractile parameters (+/-dP/dt). Furthermore, neither genotype nor age
      altered lung/body weight ratios. Thus, our findings suggest that left ventricular
      performance in calsequestrin overexpressing mice becomes apparently depressed
      with age, but this depression is not associated with progressive reduction of
      left ventricular contractility and heart failure.

PMID- 12619862
TI  - The myocardial protein S100A1 plays a role in the maintenance of normal gene
      expression in the adult heart.
AB  - S100A1 and S100B are members of a family of 20 kDa Ca2+-binding homodimers that
      play a role in signal transduction in mammalian cells. S100A1 is the major
      isoform in normal heart and S100B, normally a brain protein, is induced in
      hypertrophic myocardium and functions as an intrinsic negative modulator of the
      hypertrophic response. In order to examine the function of S100A1, we first
      showed that, in contrast to S100B, S100A1 was downregulated in rat experimental
      models of myocardial hypertrophy following myocardial infarction or pressure
      overload. Second, in co-transfection experiments in cultured neonatal rat cardiac
      myocytes, S100A1 inhibited the alpha1-adrenergic activation of promoters of genes
      induced during the hypertrophic response including the fetal genes skeletal alpha
      actin (skACT), and beta-myosin heavy chain (MHC) and S100B, but not the
      triiodothyronine (T3) activation of the promoter of the alpha-MHC gene, that is
      normally expressed in adult myocardium. These results suggest that S100A1 is
      involved in the maintenance of the genetic program that defines normal myocardial
      function and that its downregulation is permissive for the induction of genes
      that underlie myocardial hypertrophy.

PMID- 12619863
TI  - The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell
      growth.
AB  - Gap junctions are plasma membrane intercellular communication channels that in
      addition to ensuring electrical coupling and coordinated mechanical activity, can
      act as growth suppressors. To define the role of a non-channel forming domain of
      connexin-43 (Cx43), the main constituent of cardiomyocyte gap junctions, on
      growth regulation, we expressed its C-terminal portion (CT-Cx43) in
      cardiomyocytes and HeLa cells. In addition to broad cytoplasmic localization, CT
      Cx43 was also localized to the nucleus of both cell types, detected by
      immunofluorescence as well as immunoblotting of subcellular fractions.
      Furthermore, stable expression of CT-Cx43 in HeLa cells induced a significant
      decrease in proliferation. It is therefore suggested that plasma membrane
      localization and formation of channels are not required for growth inhibition by
      Cx43, and that nuclear localization of CT-Cx43 may exert effects on gene
      expression and growth.

PMID- 12619864
TI  - Porcine aortic endothelial cells show little effects on smooth muscle cells but
      are potent stimulators of cardiomyocyte growth.
AB  - Smooth muscle cells (SMC) and endothelial cells (EC) play a pivotal role in
      arteriogenesis and atherosclerosis. We evaluated the role of EC on the growth of
      SMC and neonatal cardiomyocytes (NEO) by using serum-free EC-supernatant (AoCM).
      Five percent fetal calf serum was used in order to mimic growth effects of blood.
      EC and SMC purities were 99% as determined by absence or presence of markers such
      as CD31, desmin, alpha-smooth muscle actin and tropomyosin using immunostaining
      and FACS analysis. AoCM markedly influenced the morphology of NEO as determined
      by alpha-actinin staining but showed only little effect on the phenotype of SMC.
      Protein synthesis after 2 days increased 2.5-fold in SMC and 3.7-fold in NEO as
      determined by tritium incorporation. The values for serum (2.8 and 2.3-fold,
      respectively) were comparable. The induction of DNA-synthesis by serum in NEO was
      twice that of AoCM (3.9-fold). However, proliferative effects of serum and AoCM
      on SMC differed markedly: Serum induced a 66-fold increase in DNA-synthesis
      resulting in a 54% higher cell number. DNA-synthesis after AoCM treatment lead to
      a nonsignificant small increase and no proliferation was detected. Platelet
      derived growth factor (PDGF-AB), present in blood, induced a 47-fold increase in
      DNA-synthesis and a 38% increase in cell number. Our data suggest that EC in the
      absence of physical forces exert strong morphogenic effects on cardiomyocytes but
      they lack specific effects on smooth muscle cells. In vessels EC might function
      as a border to isolate SMC from key regulators in blood such as PDGFs.

PMID- 12619865
TI  - Differential cytokine expression in myocytes and non-myocytes after myocardial
      infarction in rats.
AB  - The proinflammatory cytokines interleukin (IL)-1beta and IL-6 are increased after
      acute myocardial infarction (MI). Moreover, serum IL-6 level is elevated after
      MI, but has also been associated with heart failure. In the present study, heart
      function was monitored in a rat model of chronic MI. Cytokine expression in the
      infarcted and non-infarcted myocardium as well as in hearts of sham-operated
      controls was measured by the ribonuclease-protection assay. To identify the cells
      contributing to the increased cytokine expression, we further analyzed myocytes
      and non-myocytes isolated in the acute phase as well as during congestive heart
      failure (CHF) after MI. There was a strong induction in cytokine expression in
      the myocytes of the infarct area 6 h after MI. In the non-infarcted myocardium,
      cytokine expression increased only slightly in the non-myocytes after 6 h. This
      was not different from sham-operated controls and may, therefore, be induced by
      stress and catecholamines. In CHF, however, cytokine expression level in myocytes
      was normal. It increased slightly but significantly in the non-myocytes 4 and 8
      weeks after MI. In conclusion, we suggest that pro-inflammatory cytokines,
      produced by the ischemic myocytes may be involved in the initiation of wound
      healing of the necrotic area, whereas the effect of pro-inflammatory cytokines in
      CHF, if any, seems not to be crucial.

PMID- 12619866
TI  - Increased salt sensitivity secondary to leptin resistance in SHHF rats is
      mediated by endothelin.
AB  - A link between leptin resistance, obesity, and salt sensitivity has been
      suggested. SHHF/Mcc-fa(cp) rats (SHHF) were used to study the effect of gene
      dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and
      response to a combined endothelin A and B receptor antagonist (bosentan). Obese
      (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low
      salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7
      days. There were no significant differences in systolic blood pressure between
      genotypes on low salt. In response to high salt, cp/cp had significantly greater
      systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a
      significant increase in 24 h urinary endothelin excretion and increased renal
      expression of preproendothelin mRNA. There was no effect of high salt diet on
      renal excretion of nitric oxide (NOx) or on gene expression of endothelial,
      neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS,
      respectively). Treatment with bosentan prevented the high salt-induced increment
      in systolic blood pressure in cp/cp. This was associated with a doubling of renal
      NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin
      receptor antagonism did not normalize systolic pressure in any of the genotypes.
      Our studies indicate that obesity secondary to leptin resistance (cp/cp) results
      in increased salt sensitivity that is mediated by endothelin in the SHHF rat.

PMID- 12619867
TI  - Cloning and bacterial expression of postnatal mouse heart FGF-16.
AB  - Fibroblast growth factor-16 (FGF-16) has been reported as the sixteenth member of
      the heparin sulphate proteoglycan binding growth factor family, which includes
      acidic and basic FGFs (FGF-1 and FGF-2), based on sequence similarity. The
      sequences of human (h) and rat (r) FGF-16 complimentary DNA (cDNA) sequences are
      known. Rat FGF-16 is expressed in brown adipose tissue during embryonic
      development but also shows some specificity for the postnatal heart. In spite of
      the importance of other FGF family members in cardiac physiology, there is scant
      information about FGF-16 function. As a first step towards exploiting mouse
      genetics in this regard, we have used reverse transcriptase-polymerase chain
      reaction and primers based on the rFGF-16 sequence to clone the adult mouse (m)
      FGF-16 cDNA. An mFGF-16 cDNA of 624 base pairs was generated. Based on sequence
      analysis, mFGF-16 and hFGF-16 share at least 95.2 and 99% nucleotide and amino
      acid similarity, respectively. In terms of other family members, FGF-16 is most
      closely related to FGF-9. When used as a radiolabeled probe, the mFGF-16 cDNA
      detected a single 1.8 kilobase transcript in adult mouse heart RNA. The mFGF-16
      cDNA was also used to generate an amino-terminal poly-histidine tagged FGF-16
      protein in bacteria. Using sodium dodecyl sulphate-polyacrylamide gel
      electrophoresis and taking into account the poly-histidine tag, an FGF-16 protein
      of 26.3 kDa was detected. The generation of cardiac mFGF-16 cDNA and a purified
      FGF-16 protein preparation are seen as important tools in the further
      characterization of FGF-16 expression and function in the mammalian heart.

PMID- 12619868
TI  - An ischemic beta-dystroglycan (betaDG) degradation product: correlation with
      irreversible injury in adult rabbit cardiomyocytes.
AB  - A loss of sarcolemmal dystrophin was observed by immuno-fluorescence studies in
      rabbit hearts subjected to in situ myocardial ischemia and by immuno-blotting of
      the Triton soluble membrane fraction of isolated rabbit cardiomyocytes subjected
      to in vitro ischemia. This ischemic loss of dystrophin was a specific event in
      that no ischemic loss of sarcolemmal alpha-sarcoglycan, gamma-sarcoglycan,
      alphaDG, or betaDG was observed. The maintenance of sarcolemmal betaDG (43 Kd)
      during ischemia was interesting in that dystrophin binds to the C-terminus of
      betaDG. However, during late in vitro ischemia, a 30 Kd band was observed that
      was immuno-reactive for betaDG. Additionally, this 30 Kd-betaDG band was observed
      in rabbit myocardium subjected to autolysis. Finally, the 30 Kd-betaDG was
      observed in the purified sarcolemmal fraction of rabbit cardiomyocytes subjected
      to a prolonged period of in vitro ischemia, confirming the sarcolemmal
      localization of this band. The potential patho-physiologic significance of this
      band was indicated by the appearance of this band at 120-180 min of in vitro
      ischemia, directly correlating with the onset of irreversible injury, as
      manifested by osmotic fragility. Additionally the appearance of this band was
      significantly reduced by the endogenous cardioprotective mechanism, in vitro
      ischemic preconditioning, which delays the onset of osmotic fragility. In
      addition to dystrophin, betaDG binds caveolin-3 and Grb-2 at its C-terminus. The
      presence of Grb-2 and caveolin-3 in the membrane fractions of oxygenated and
      ischemic cardiomyocytes was determined by Western blotting. An increase in the
      level of membrane Grb-2 and caveolin-3 was observed following ischemic
      preconditioning as compared to control cells. The formation of this 30 Kd-betaDG
      degradation product is potentially related to the transition from the reversible
      to the irreversible phase of myocardial ischemic cell injury and a decrease in 30
      Kd-betaDG might mediate the cardioprotection provided by ischemic
      preconditioning.

PMID- 12619869
TI  - Effects of glyburide (glibenclamide) on myocardial function in Langendorff
      perfused rabbit heart and on myocardial contractility and slow calcium current in
      guinea-pig single myocytes.
AB  - Glyburide, also known as glibenclamide, was shown to have positive inotropic
      effect in human and animal hearts. The objectives of the present study was to
      investigate the effects of glyburide on developed left ventricular pressure
      (DLVP), coronary flow (CF), and heart rate (HR), in isolated rabbit heart as well
      as its effects on myocardial contractility and L-type calcium current, iCa, in
      guinea pig myocytes. Rabbit hearts were mounted on Langendorff apparatus and
      perfused with an oxygenated Krebs for 30 min until reaching steady state to be
      followed by 20 min of experimental perfusion divided into 5 min of control
      perfusion and 15 min of perfusion with Glyburide (10 microM). Ventricular
      myocytes were isolated by enzymatic dispersion technique and superfused in an
      oxygenated Tyrode solution. Cells were voltage-clamped at holding potential -40
      mV to inactivate Na+ current and a step depolarizations, 200 msec duration, to 0
      mV was applied to elicit iCa. The contractions of the myocytes were measured by
      optical methods. Glyburide significantly increased DLVP by 30% and CF by 36% but
      had no effect on HR. Glyburide increased cell contractility by 7 +/- 6, 18 +/- 7,
      28 +/- 9 and 54 +/- 15% for 0.1, 1, 10 and 100 microM respectively, p < 0.001.
      Meanwhile it depressed iCa by 9 +/- 6 and 19 +/- 8% for 1 and 10 microM
      respectively. In conclusion, glyburide increased contractility of guinea pig
      single myocytes and of isolated rabbit heart, as indicated by increased developed
      left ventricular pressure while it depressed iCa. It is hypothesized that an
      elevation in intracellular calcium, which caused increased myocardial
      contractility, could be attributed to an increase in intracellular Na+ that could
      increase intracellular calcium via Na+/Ca2+ exchange.

PMID- 12619870
TI  - Metabolic phenotyping of the diseased rat heart using 13C-substrates and ex vivo
      perfusion in the working mode.
AB  - The objective of the present study was to compare energy substrate fluxes through
      metabolic pathways leading to mitochondrial citrate synthesis and release in
      normal and diseased rat hearts using 13C-substrates and mass isotopomer analysis
      by gas chromatography-mass spectrometry (GCMS). This study was prompted by our
      previous finding of a modulated citrate release by perfused rat hearts and by the
      possibility that a dysregulated myocardial citrate release represents a specific
      chronic alteration of energy metabolism in cardiac patients. The 15-week-old
      spontaneously hypertensive rat (SHR) was chosen as our animal model of disease
      and the Wistar-Kyoto (WKY) rat as its matched control. Ex vivo work-performing
      hearts were perfused with a semi-recirculating buffer containing physiological
      concentrations of unlabeled (glucose) and 13C-labeled ([U-13C3](lactate +
      pyruvate) and/or [1-(13)C]oleate) substrates. In parallel to the continuous
      monitoring of indices of the heart's functional and physiological status, the
      following metabolic parameters were documented: (i) citrate release rates and
      citric acid cycle intermediate tissue levels, (ii) the contribution of fatty
      acids as well as pyruvate decarboxylation and carboxylation to citrate synthesis,
      and (iii) lactate and pyruvate uptake and efflux rates. Working hearts from both
      rat species showed a similar percent contribution of carbohydrates for citrate
      synthesis through decarboxylation (70%) and carboxylation (10%). SHR hearts
      showed the following metabolic alterations: a higher citrate release rate, which
      was associated with a parallel increase in its tissue level, a lower contribution
      of oleate beta-oxidation to citrate synthesis, and an accelerated efflux rate of
      unlabeled lactate from glycolysis. These metabolic changes were not explained by
      differences in myocardial oxygen consumption, cardiac performance or efficiency,
      nor correlated with indices of tissue necrosis or ischemia. This study
      demonstrates how the alliance between ex vivo semi-recirculating working perfused
      rat hearts with 13C-substrates and mass isotopomer analysis by GCMS, can provide
      an unprecedented insight into the metabolic phenotype of normal and diseased rat
      hearts. The clinical relevance of metabolic alterations herein documented in the
      SHR heart is suggested by its resemblance to those reported in cardiac patients.
      Taken altogether, our results raise the possibility that the increased citrate
      release of diseased hearts results from an imbalance between citrate synthesis
      and utilization rates, which becomes more apparent underconditions of substrate
      abundance.

PMID- 12619871
TI  - Increased glycolysis as protective adaptation of energy depleted, degenerating
      human hibernating myocardium.
AB  - In the current study on human hibernating myocardium (HHM), we tested the
      hypothesis that increased glycolysis might exert a positive effect during a
      supply-demand balance situation by augmentation of myocardial energy formation.
      In 14 patients HHM was preoperatively detected by clinical methods and validated
      by the recovery of contractile function three months following revascularization.
      During open-heart surgery, transmural biopsies were removed from the hibernating
      areas and analyzed using biochemical and morphologic methods. Metabolite contents
      were normalized for the degree of fibrosis (control: 9.8 +/- 0.5%, HHM 28.1 +/-
      3.0%; p < 0.05), providing values for cardiomyocytes only. In energy depleted
      HHM, severe intracellular degeneration, glycogen accumulation and myocyte loss
      were found. Elevated lactate levels (2.22 +/- 0.26 vs. 25.38 +/- 3.53
      micromol/wet wt, p < 0.001) were indicative of an increased anaerobic glycolytic
      flux. In conclusion the presence of abundant intracellular glycogen and an
      increased anaerobic glycolysis in HHM is indicative of a protective adaptation of
      this myocardium, which might balance energy deficit and may limit structural
      damage.

PMID- 12619872
TI  - Optimal conditions for heart cell cryopreservation for transplantation.
AB  - Cultured myocyte transplantation into an infarcted myocardium has been shown to
      improve contractile function. Cryopreservation of cultured muscle cells or heart
      tissue will be important for the technology to be practical. This study, using
      fetal cardiomyocytes, evaluated the optimal conditions for muscle cell
      cryopreservation. Study 1: Fetal rat cardiomyocytes were isolated and cultured.
      The freshly isolated and passage 1, 2, 3 and 4 cells were cryopreserved in a
      solution containing 70% IMDM, 20% FBS and 10% DMSO and stored in -196 degrees C
      for 1, 2, 4, 8, 12 and 24 weeks. The cells were thawed and cultured. Cell number
      and contractility were evaluated at 0, 2, 4, 6, 8 and 10 days of culture. Study
      2: Rat myocardium was cryopreserved in sizes of 0.2, 2 and 6 mm3 for 1 week. The
      tissue was thawed and cells were isolated. Cell growth and contractility were
      evaluated. (1) Cardiomyocytes grew and contracted after cryopreservation. Storage
      time did not affect cell survival rate, beating cell numbers and beating rates.
      Increasing cell passage prior to cryopreservation decreased the percentage of
      beating cells. (2) Cells isolated from cryopreserved tissue grew in vitro and
      contracted normally. Cell yield decreased with increased cryopreserved tissue
      size. Fetal rat cardiomyocytes survived and functioned after in vitro
      cryopreservation. Viable cells can be isolated from cryopreserved myocardium and
      cultured. Cryopreservation of small pieces of myocardium is preferred for maximal
      cell yields.

PMID- 12619873
TI  - Different pathways for sodium entry in cardiac cells during ischemia and early
      reperfusion.
AB  - A number of data are consistent with the hypothesis that increases in
      intracellular Na+ concentration (Na+i) during ischemia and early reperfusion lead
      to calcium overload and exacerbation of myocardial injury. However, the
      mechanisms underlying the increased Na+i remain unclear. 23Na nuclear magnetic
      resonance spectroscopy was used to monitor Na+i in isolated rat hearts perfused
      with a high concentration of fatty acid as can occur under some pathological
      conditions. Whole-cell patch-clamp experiments were also performed on isolated
      cardiomyocytes in order to investigate the role of voltage-gated sodium channels.
      Na+i increased to substantially above control levels during no-flow ischemia. The
      results show that a pharmacological reduction of Na+i increase by cariporide (1
      micromol/L, a Na+/H+ exchange blocker) is not the only protection against
      ischemia-reperfusion damage, but that such protection may also be brought about
      by metabolic action aimed at reducing fatty acid utilization by myocardial cells.
      This action was obtained in the presence of etomoxir (0.1 micromol/L), an
      inhibitor of carnitine palmitoyltransferase-1 (the key enzyme involved in fatty
      acid uptake by the mitochondria) which also decreases long-chain acyl carnitine
      accumulation. The possibility of Na+ channels participating in Na+i increase as a
      consequence of alterations in cardiac metabolism was studied in isolated cells.
      Sustained I(Na) was stimulated by the presence of lysophosphatidylcholine (LPC,
      10 micromol/L) whose accumulation during ischemia is, at least partly, dependent
      on increased long-chain acyl carnitine. Current activation was particularly
      significant in the range of potentials between -60 and -20 mV. This may have
      particular relevance in ischemia. The quantity of charge carried by sustained
      I(Na) was reduced by 24% in the presence of 1 micromol/L cariporide. Therefore,
      limitation of long-chain fatty acid metabolism, and consequent limitation of
      ischemia-induced long-chain acyl carnitine accumulation, may contribute to
      reducing intracellular Na+ increase during ischemia-reperfusion.

PMID- 12619874
TI  - Comparison of connexin expression patterns in the developing mouse heart and
      human foetal heart.
AB  - Heart muscle cells are electrically coupled by gap junctions, clusters of low
      resistance transmembrane channels composed of connexins (Cx). The expression of
      the three major connexins (Cx43, Cx40 and Cx45) present in cardiac myocytes is
      known to be developmentally regulated but it is not clear how the patterns in the
      human heart compare with those found in the mouse. This issue is of importance
      given the wide use of transgenic mice to investigate gene function with the aim
      of extrapolating the results to human. In the present study we applied
      immunoconfocal microscopy to investigate the spatial distribution of the three
      connexins in the developing mouse heart and foetal human heart. Although Cx45
      labelling was present at low levels throughout the developing mouse heart and
      human foetal (9-week) heart, it was most prominent in the conduction tissues. In
      the developing mouse heart, Cx40 was widely expressed at embryonic day 12.5
      (E12.5) but at E17.5 expression was restricted to the conduction tissues and
      atria. In the 9-week human foetal heart, the Cx40 labelling pattern was similar
      to the E15 mouse heart, being far more abundant in conduction tissues (bundle
      branches to Purkinje fibres) and atria than in the ventricular muscle. Cx43
      labelling became more apparent in the ventricular myocardium as development of
      the mouse heart progressed but was virtually undetectable in the central
      conduction system. In the human foetal heart Cx43 was virtually undetectable in
      the atria but was the predominant connexin in the ventricles. We conclude that,
      at least in some key aspects, the pattern of connexin expression in the
      developing mouse heart parallels that found in the human embryonic heart.

PMID- 12619875
TI  - Ischemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by
      okadaic acid and calyculin A but not fostriecin.
AB  - The gap junction protein connexin-43 (Cx43) exists mainly in the phosphorylated
      state in the normal heart, while ischemia induces dephosphorylation.
      Phosphatase(s) involved in cardiac Cx43 dephosphorylation have not as yet been
      identified. We examined the acute effects of ischemia on the dephosphorylation of
      the gap junction protein connexin-43 in isolated adult cardiomyocytes and
      isolated perfused hearts. In addition we tested the effectiveness of protein
      phosphatase 1 and 2A (PP1/2A) inhibitors in preventing Cx43 dephosphorylation. In
      both models, significant accumulation of the 41 kDa non-phosphorylated Cx43,
      accompanied by decreased relative levels of the 43-46 kDa phosphorylated Cx43,
      was observed at 30 min of ischemia. Okadaic acid decreased ischemia-induced Cx43
      dephosphorylation; it also decreased the accumulation of non-phosphorylated Cx43
      at the intercalated discs of myocytes in the whole heart. Calyculin A, but not
      fostriecin, also decreased ischemia-induced Cx43 dephosphorylation in isolated
      cardiomyocytes. It is concluded that isolated adult myocytes respond to ischemia
      in a manner similar to whole hearts and that ischemia-induced dephosphorylation
      of Cx43 is mediated, at least in part, by PP1-like phosphatase(s).

PMID- 12619876
TI  - Gap junction remodeling and altered connexin43 expression in the failing human
      heart.
AB  - Gap junctions (GJ) are important determinants of cardiac conduction and the
      evidence has recently emerged that altered distribution of these junctions and
      changes in the expression of their constituent connexins (Cx) may lead to
      abnormal coupling between cardiomyocytes and likely contribute to
      arrhythmogenesis. However, it is largely unknown whether changes in the
      expression and distribution of the major cardiac GJ protein, Cx43, is a general
      feature of diverse chronic myocardial diseases or is confined to some particular
      pathophysiological settings. In the present study, we therefore set out to
      investigate qualitatively and quantitatively the distribution and expression of
      Cx43 in normal human myocardium and in patients with dilated (DCM), ischemic
      (ICM), and inflammatory cardiomyopathies (MYO). Left ventricular tissue samples
      were obtained at the time of cardiac transplantation and investigated with
      immunoconfocal and electron microscopy. As compared with the control group, Cx43
      labeling in myocytes bordering regions of healed myocardial infarction (ICM),
      small areas of replacement fibrosis (DCM) and myocardial inflammation (MYO) was
      found to be highly disrupted instead of being confined to the intercalated discs.
      In all groups, myocardium distant from these regions showed an apparently normal
      Cx43 distribution at the intercalated discs. Quantitative immunoconfocal analysis
      of Cx43 in the latter myocytes revealed that the Cx43 area per myocyte area or
      per myocyte volume is significantly decreased by respectively 30 and 55% in DCM,
      23 and 48% in ICM, and by 21 and 40% in MYO as compared with normal human
      myocardium. In conclusion, focal disorganization of GJ distribution and down
      regulation of Cx43 are typical features of myocardial remodeling that may play an
      important role in the development of an arrhythmogenic substrate in human
      cardiomyopathies.

PMID- 12619877
TI  - Alterations in protein kinase C isoenzyme expression and autophosphorylation
      during the progression of pressure overload-induced left ventricular hypertrophy.
AB  - Cardiomyocytes express several isoenzymes of protein kinase C (PKC), which as a
      group have been implicated in the induction of left ventricular hypertrophy (LVH)
      and its transition to heart failure. Individual PKC isoenzymes also require
      transphosphorylation and autophosphorylation for enzymatic activity. To determine
      whether PKC isoenzyme expression and autophosphorylation are altered during LVH
      progression in vivo, suprarenal abdominal aortic coarctation was performed in
      Sprague-Dawley rats. Quantitative Western blotting was performed on LV tissue 1,
      8 and 24 weeks after aortic banding, using antibodies specific for total
      PKCalpha, PKCdelta and PKCepsilon, and their C-terminal autophosphorylation
      sites. Aortic banding produced sustained hypertension and gradually developing
      LVH that progressed to diastolic heart failure over time. PKCepsilon levels and
      autophosphorylation were not significantly different from sham-operated controls
      during any stage of LVH progression. PKCalpha expression levels were also
      unaffected during the induction of LVH, but increased 3.2 +/- 0.8 fold during the
      transition to heart failure. In addition, there was a high degree of correlation
      between PKCalpha levels and the degree of LVH in 24 week banded animals. However,
      autophosphorylated PKCalpha was not increased at any time point. In contrast,
      PKCdelta autophosphorylation was increased prior to the development of LVH, and
      also during the transition to heart failure. The increased PKCdelta
      autophosphorylation in 1 week banded rats was not accompanied by an increase in
      total PKCdelta, whereas total PKCdelta levels were markedly increased (6.0 +/-
      1.7 fold) in 24 week banded animals. Furthermore, both phosphorylated and total
      PKCdelta levels were highly correlated with the degree of LVH in 24 week banded
      rats. In summary, we provide indirect evidence to indicate that PKCdelta may be
      involved in the induction of pressure overload LVH, whereas both PKCdelta and
      PKCalpha may be involved in the transition to heart failure.

PMID- 12619878
TI  - CaM kinase IIdeltaC phosphorylation of 14-3-3beta in vascular smooth muscle
      cells: activation of class II HDAC repression.
AB  - The myocyte enhancer factor-2 (MEF2) family of transcription factors regulates
      transcription of muscle-dependent genes in cardiac, skeletal and smooth muscle.
      They are activated by calcium/calmodulin (CaM)-dependent protein kinases I and IV
      and silenced by CaM KIIdeltaC. MEF2 is held in an inactive form by the class II
      histone deacetylases (HDAC) until phosphorylated by either CaM kinase I or IV.
      Upon phosphorylation, HDAC is transported out of the nucleus via a 14-3-3
      dependent mechanism freeing MEF2 to drive transcription. The 14-3-3 chaperone
      protein exists as a homodimer. In the region of homodimerization, there are two
      canonical CaM kinase II phosphorylation sites (ser60 and ser65). In vitro
      phosphorylation assay results indicate that 14-3-3beta is indeed a substrate for
      CaM kinase II. We hypothesize that CaM kinase IIdeltaC phosphorylation of 14-3
      3beta will disrupt homodimer formation resulting in the return of HDAC to the
      nucleus and their reassociation with MEF2. To test this, we mutated serines 60
      and 65 of 14-3-3beta to aspartates to mimic the phosphorylated state. In MEF2
      enhancer-reporter assays in smooth muscle cells, expression of the 14-3-3beta
      double mutant attenuated MEF2-enhancer activity driven by CaM kinase I or IV. The
      intracellular fate of HDAC4 was followed by transfection of smooth muscle cells
      with an HDAC4-Green Fluorescent Protein fusion hybrid. The 14-3-3beta double
      mutant prevented HDAC4 cytoplasmic localization in the presence of active CaM
      kinase I or IV. These data suggest that the mechanism of CaM kinase IIdeltaC
      silencing of MEF-2-dependent genes is by phosphorylation of 14-3-3beta, which
      allows HDAC to return to the nucleus to reform a complex with MEF2, thereby
      silencing MADS box-dependent gene induction in smooth muscle.

PMID- 12619879
TI  - Regulation of MAPK pathways in response to purinergic stimulation of adult rat
      cardiac myocytes.
AB  - We investigated the activation of mitogen-activated protein kinases (MAPKs)
      pathways by purinergic stimulation in cardiac myocytes from adult rat hearts.
      ATPgammaS increased the phosphorylation (activation) of the extracellular signal
      regulated kinase 1 and 2 (ERK1/2) and p38 MAPK. ERK1/2 and p38 MAPK activation
      was differential, ERK1/2 being rapid and transient while that of p38 MAPK slow
      and sustained. Using selective inhibitors, activation of ERK1/2 was shown to
      involve protein kinase C and MEK1/2 while that of p38 MAPK was regulated by both
      protein kinase C and protein kinase A. Furthermore, we show that purinergic
      stimulation induces the phosphorylation of the MAPK downstream target, mitogen-
      and stress-activated protein kinase 1 (MSK1), in cardiac myocytes. The time
      course of MSK1 phosphorylation closely follows that of ERK activation. Inhibitors
      of the ERK and p38 MAPK pathways were tested on the phosphorylation of MSK1 at
      two different time points. The results suggest that ERKs initiate the response
      but both ERKs and p38 MAPK are required for the maintenance of the complete
      phosphorylation of MSK1. The temporal relationship of MSK1 phosphorylation and
      cPLA2 translocation induced by purinergic stimulation, taken together with
      previous findings, is an indication that cPLA2 may be a downstream target of
      MSK1.

PMID- 12619881
TI  - Involvement of mitogen-activated protein kinases and reactive oxygen species in
      the inotropic action of ouabain on cardiac myocytes. A potential role for
      mitochondrial K(ATP) channels.
AB  - Binding of ouabain to Na+/K+-ATPase activated multiple signal transduction
      pathways including stimulation of Src, Ras, p42/44 MAPKs and production of
      reactive oxygen species (ROS) in rat cardiac myocytes. Inhibition of either Src
      or Ras ablated ouabain-induced increase in both [Ca2+]i and contractility. While
      PD98059 abolished the effects of ouabain on [Ca2+]i it only caused a partial
      inhibition of ouabain-induced increases in contractility. On the other hand, pre
      incubation of myocytes with N-acetyl cysteine (NAC) reduced the effects of
      ouabain on contractility, but not [Ca2+]i. Furthermore, 5-hydroxydecanoate (5-HD)
      blocked ouabain-induced ROS production and partially inhibited ouabain-induced
      increases in contractility in cardiac myocytes. Pre-incubation of myocytes with
      both 5-HD and PD98059 completely blocked ouabain's effect on contractility.
      Finally, we found that opening of mitochondrial K(ATP) channel by diazoxide
      increased intracellular ROS and significantly raised contractility in cardiac
      myocytes. These new findings indicate that ouabain regulates cardiac
      contractility via both [Ca2+]i and ROS. While activation of MAPKs leads to
      increases in [Ca2+]i, opening of mitochondrial K(ATP) channel relays the ouabain
      signal to increased ROS production in cardiac myocytes.

PMID- 12619880
TI  - Thyroid hormone and cardioprotection: study of p38 MAPK and JNKs during ischaemia
      and at reperfusion in isolated rat heart.
AB  - It has been recently shown that long-term thyroxine administration increases the
      tolerance of the heart to ischaemia. The present study investigated whether
      thyroxine induced cardioprotection involves alterations in the pattern of p38
      mitogen activated protein kinase (p38MAPK) and c-Jun NH2-terminal kinases (JNKs)
      activation during ischaemia-reperfusion. L-thyroxine (T4) was administered in
      Wistar rats (25 microg/100 g/day, subcutaneously) for 2 weeks (THYR), while
      normal animals served as controls (NORM). NORM and THYR isolated rat hearts were
      perfused in Langendorff mode and subjected to 10 or 20 min of zero-flow global
      ischaemia only and also to 20 min of ischaemia followed by 10, 20 or 45 min of
      reperfusion. Postischaemic recovery of left ventricular developed pressure at 45
      min of reperfusion was expressed as % of the initial value. Activation of p38
      MAPK and JNKs was assessed at the different times of the experimental setting by
      standard Western blotting techniques using a dual phospho p38MAPK and phospho
      JNKs (p46/p54) antibodies. Activation of p38 MAPK was significantly attenuated
      during ischaemia and reperfusion in thyroxine treated hearts compared to normal
      hearts. JNKs were found to be activated only during the reperfusion period. The
      levels of phospho JNKs were found to be lower in thyroxine treated hearts as
      compared to untreated hearts, though not at a statistically significant level.
      Postischaemic functional recovery was higher in THYR as compared to NORM, p <
      0.05. In summary, in hearts pretreated with thyroxine, p38 MAPK was attenuated
      during ischaemia and at reperfusion and this was associated with improved
      postischaemic recovery of function.

PMID- 12619882
TI  - Characterisation of nuclear pore complex oxalate binding protein from human
      kidney.
AB  - Both rat and human kidney nuclei exhibited time and pH dependent oxalate or
      histone-oxalate uptake which was inhibited by anion transport inhibitor, 4,4'
      dithiocyanostilbene-2,2'-disulphonic acid. Sodium chloride had no effect. Nuclear
      membrane had oxalate binding at pH 7.4. Extraction of nuclear membrane by Triton
      high salt mixture showed maximal oxalate binding activity with nuclear pore
      complex while nuclear lamin had no oxalate binding. The rat and human kidney
      nuclear pore complex showed oxalate binding of 144 and 220 pmoles/mg protein
      respectively. Subsequent purification of the protein on diethyl amino ethyl
      Sephadex A 50 column and Sephadex G-200 column yielded 4-fold purification. The
      protein revealed a molecular weight of 205 kDa on SDS-PAGE. The protein was found
      to be saturable at 2 microM oxalate and had a Kd of 2.98 pM and a Bmax of 197
      pmoles. Antibody for 205 kD was separated from primary biliary cirrhosis serum
      containing auto antibody against 205 kDa using affinity column chromatography.
      The oxalate binding activity as well as the nuclear uptake of oxalate or histone
      oxalate were inhibited by its antibody.

PMID- 12619883
TI  - Metabolism of ovorubin, the major egg lipoprotein from the apple snail.
AB  - The site of synthesis of molluscs lipoproteins is little known and was
      investigated for the egg lipoprotein perivitellin 1 (PV 1) or ovorubin in the
      freshwater snail Pomacea canaliculata. Tissues (albumen gland, gonad-digestive
      gland complex and muscle) of vitellogenic females were incubated in vitro at 25
      degrees C for 12 h with 14C Leucine. After that, soluble proteins from tissue
      homogenates and medium samples were analysed for de novo protein synthesis by
      electrophoresis and HPLC, and radiolabelled proteins quantified by liquid
      scintillation. Gonad-digestive gland complex did not synthesise ovorubin, in
      spite its high protein synthesis levels. Three albumen gland radiolabelled
      proteins (35, 32 and 28 kDa) comigrated with the subunits of ovorubin and
      represented 1.3% of the total labelled protein of that tissue. Western blot
      analysis with polyclonal antibodies confirmed that these were ovorubin subunits.
      In vivo experiments where vitellogenic females were injected with 3H Leucine,
      revealed that ovorubin was not present in hemolymph. ELISA analysis confirmed
      ovorubin presence only in albumen gland and developing eggs with levels of 800
      and 582 mg/g protein, which represent 30.3 and 28.4 mg ovorubin/g of tissue,
      respectively. Therefore, albumen gland is the single site of ovorubin synthesis
      as no extragland synthesis, circulation or accumulation could be detected in the
      apple snail.

PMID- 12619884
TI  - Single amino acid substitution enhances bacterial expression of PARP-4D214A.
AB  - Poly(ADP-ribose) polymerase-1 (PARP-1) is the canonical member of the PARP family
      of enzymes and modulates many crucial nuclear functions. PARP-1 is involved in
      apoptosis and is the substrate of caspase-3, a protease that cleaves PARP-1 at
      the conserved sequence 211DEVD214. To generate a caspase-3-uncleavable PARP-1, we
      introduced an amino acid substitution D214-->A214 at the site of cleavage. We
      observed that following over-expression in bacteria, the mutant protein HIS-PARP
      1D214A was expressed several-fold more than a unmutated copy, HIS-PARP-1. The
      specific activity of HIS-PARP-1 enzyme in total bacterial extracts was 6.94 U/mg
      and 4.61 U/mg for HIS-PARP-1D214A. This approach should provide new avenues for
      crystallographic study of PARP-1 as well as new information for drug design
      targeting PARP-1.

PMID- 12619885
TI  - Preventive effects of Cassia auriculata L. flowers on brain lipid peroxidation in
      rats treated with streptozotocin.
AB  - The effect of aqueous extract of the flowers of Cassia auriculata were examined
      on antioxidants and lipid peroxidation in the brain of streptozotocin diabetic
      rats. Significant increase in the activities of superoxide dismutase, catalase,
      glutathione peroxidase, glutathione-S-transferase and reduced glutathione were
      observed in brain on treatment with Cassia auriculata flower extract (CFEt) and
      glibenclamide. Both the treated groups showed significant decrease in
      thiobarbituric reactive substances (TBARS) and hydroperoxide formation in brain,
      suggesting its role in protection against lipid peroxidation induced membrane
      damage. Since the study of induction of the antioxidant enzymes is considered to
      be a reliable marker for evaluating the antiperoxidative efficacy of medicinal
      plant, these findings are suggestions of possible antiperoxidative role played by
      Cassia auriculata flower extract.

PMID- 12619886
TI  - The bactericidal effects of Lactobacillus acidophilus, garcinol and Protykin
      compared to clarithromycin, on Helicobacter pylori.
AB  - Chronic infection with Helicobacter pylori causes peptic ulcers, gastric cancer
      and lymphoma. We evaluated the inhibitory effects of the probiotic Lactobacillus
      acidophilus DDS-1J, the antibiotic clarithromycin and the natural antioxidants
      garcinol and Protykin (containing 50% trans-resveratrol) on Helicobacter pylori
      strain ATCC 49503. The findings of this study indicate that Lactobacillus
      acidophilus DDS-1J exerts a growth inhibitory effect on H. pylori at a ratio of
      1:1 or higher in vitro. In the case of clarithromycin, garcinol and resveratrol,
      the bactericidal effect is time and concentration dependent. Clarithromycin
      completely inhibited growth at > or = 62.5 microg/ml at 6 h and at > or = 31.5
      microg/ml at 12 h. For garcinol the highest concentration needed for complete
      inhibition was 31.5 microg/ml at 6 h and 3.9 microg/ml after 12 h incubation. For
      resveratrol, significant inhibition was noted at 1000 microg/ml at 12 h only. The
      bactericidal effect of garcinol was reduced by the addition of resveratrol at all
      concentrations < or = 125 microg/ml at 6 and 12 h. We conclude from this study
      that Lactobacillus acidophilus DDS-1J inhibits H. pylori at 1:1 and higher
      ratios. Also, between the two antioxidants, garcinol is much more potent than
      resveratrol as a bactericidal agent against H. pylori, and that resveratrol may
      antagonize this effect. Finally, our study showed equivalent or better
      bactericidal activity of garcinol compared to clarithromycin against H. pylori at
      6 and 12 h incubation, indicating a potential role for this antioxidant in
      treatment for H. pylori infection.

PMID- 12619887
TI  - Homocysteine stimulates inducible nitric oxide synthase expression in
      macrophages: antagonizing effect of ginkgolides and bilobalide.
AB  - Hyperhomocysteinemia is an independent risk factor for atherosclerotic diseases.
      Inducible nitric oxide synthase (iNOS) is mainly expressed in macrophages upon
      stimulation. Overproduction of nitric oxide (NO) by iNOS can exacerbate the
      development of atherosclerosis. Our previous studies demonstrated that the
      extract of ginkgo biloba leaves (EGb) inhibited the iNOS-mediated NO production
      in monocyte-derived macrophage. We also reported that homocysteine could
      stimulate monocyte chemoattractant protein-1 (MCP-1) expression in vascular cells
      causing enhanced monocyte chemotaxis. The objective of the present study was to
      investigate the effect of homocysteine on iNOS-mediated NO production in
      macrophages and the antagonizing effect of EGb. Human monocytic cell (THP-1)
      derived macrophages were incubated with homocysteine for various time periods.
      Homocysteine at concentrations of 0.05-0.1 mM significantly stimulated NO
      production and iNOS activity in macrophages via increased expression of iNOS mRNA
      and protein. The increased iNOS expression was associated with activation of
      nuclear factor-kappa B (NF-kappaB) arising from reduced expression of inhibitor
      protein (IkappaB alpha) mRNA as well as increased phosphorylation of IkappaB
      alpha protein in homocysteine-treated cells. EGb and its terpenoids (ginkgolide
      A, ginkgolide B and bilobalide) could antagonize the homocysteine effect on iNOS
      expression in macrophages via their antioxidant effect resulting in attenuation
      of NF-kappaB activation. Taken together, our results have demonstrated that
      homocysteine, at pathophysiological concentrations, stimulates iNOS-mediated NO
      production in macrophages. EGb and its terpenoids can antagonize such stimulatory
      effect via antioxidation and attenuation of NF-kappaB activation.

PMID- 12619888
TI  - Identification of HepG2 variant cell lines by short tandem repeat (STR) analysis.
AB  - In the past years, in our laboratory, several cell lines have been generated
      starting from a human liver (H7). Some of them have been used successfully in
      studies of the infection with and propagation of Hepatitis B and Hepatitis C
      viruses. Recently, several lines of evidence indicated that the origin of these
      cell lines was uncertain. Therefore, we now have determined the genetic
      characteristics of these cell lines in comparison to HepG2 cells received from
      ATCC and to HepG2 isolates grown at other laboratories. Quadruplex fluorescent
      short tandem repeat (STR) typing and karyotyping were performed. In addition,
      some biochemical characteristics of selected clones were studied. Genetically,
      all H7-derived cell lines were identical to HepG2 cells. However, some liver
      specific functions varied between the different sub-cloned lines. The H7-derived
      cell lines that were generated proved to be sub-cloned lines of HepG2. The
      problem of cross-contamination during cloning of cell lines appears to be not
      uncommon. We found that two out of six HepG2 isolates obtained from other
      laboratories were not derived from the same individual as the original HepG2
      cells. Therefore, STR typing should be applied as a rapid and sensitive technique
      to determine and monitor the origin of cell lines and to safeguard against
      contamination.

PMID- 12619889
TI  - Involvement of oxygen free radicals in the respiratory uncoupling induced by free
      calcium and ADP-magnesium in isolated cardiac mitochondria: comparing
      reoxygenation in cultured cardiomyocytes.
AB  - Recently, we have observed that the simultaneous application of free calcium
      (fCa) and ADP-magnesium (Mg) reduced the ADP:O ratio in isolated cardiac
      mitochondria. The uncoupling was prevented by cyclosporin A, an inhibitor of the
      permeability transition pore. The purpose of this study was to know if the
      generation of oxygen free radicals (OFR) is involved in this phenomenon and if it
      occurs during reoxygenation (Reox) of cultured cardiomyocytes. Cardiac
      mitochondria were harvested from male Wistar rats. Respiration was assessed in
      two media with different fCa concentrations (0 or 0.6 microM) with
      palmitoylcarnitine and ADP-Mg as respiration substrates. The production of Krebs
      cycle intermediates (KCI) was determined. Without fCa in the medium, the
      mitochondria displayed a large production of citrate + isocitrate + alpha
      ketoglutarate. fCa drastically reduced these KCI and promoted the accumulation of
      succinate. To know if OFR are involved in the respiratory uncoupling, the effect
      of 4OH-TEMPO (250 microM), a hydrosoluble scavenger of OFR, was tested. 4OH-TEMPO
      completely abolished the fCa- and ADP-Mg-induced uncoupling. Conversely, vitamin
      E contributed to further decreasing the ADP:O ratio. Since no hydrosoluble
      electron acceptor was added in our experiment, the oxygen free radical-induced
      oxidized vitamin E was confined near the mitochondrial membranes, which should
      reduce the ADP:O ratio by opening the permeability transition pore. The
      generation of OFR could result from the matrix accumulation of succinate. Taken
      together, these results indicate that mitochondrial Ca uptake induces a slight
      increase in membrane permeability. Thereafter, Mg enters the matrix and, in
      combination with Ca, stimulates the isocitrate and/or alpha-ketoglutarate
      dehydrogenases. Matrix succinate favors oxygen free radical generation that
      further increases membrane permeability and allows respiratory uncoupling through
      proton leakage. To determine whether the phenomenon takes place during Reox,
      cultured cardiomyocytes were subjected to hypoxia and Reox. 14C-palmitate was
      added during Reox to determine the KCI profile. Succinate had not increased
      during Reox. In conclusion, calcium- and ADP-Mg-induced respiratory uncoupling is
      due to oxygen free radical generation through excess matrix accumulation of
      succinate. The phenomenon does not occur during reoxygenation because of a total
      restoration of mitochondrial magnesium and/or ADP concentration.

PMID- 12619891
TI  - Cleavage of in vitro and in vivo formed lens protein cross-links by a novel cross
      link breaker.
AB  - The purpose of this study was to investigate the effect of N-phenacyl-4,5
      dimethylthiazolium bromide (DMPTB), an advanced glycation end product (AGE) cross
      link breaker, on lens protein cross-links formed in vitro and in vivo. DMPTB was
      synthesized and its structure confirmed by its NMR spectrum. To show whether
      DMPTB can inhibit AGE cross-linking, recombinant human alphaA-crystallin was
      glycated with glucose-6-phosphate (G6P) in the presence and absence of DMPTB.
      Reversal of the already formed cross-links was studied by treating pre-glycated
      alphaA-crystallin with DMPTB. The ability of DMPTB to cleave in vivo formed cross
      links was ascertained by treating water-insoluble protein fractions from diabetic
      human lenses with this compound. Glycation of alphaA-crystallin with G6P showed
      several high molecular weight (HMW) protein bands on the SDS-PAGE gel; DMPTB
      inhibited the formation of these HMW proteins. Molecular sieve HPLC confirmed the
      inhibition of formation of larger aggregates not separated by SDS-PAGE. Treatment
      of pre-glycated alphaA-crystallin with DMPTB gave evidence for the degradation of
      the already formed cross-linked HMW aggregates. Both molecular sieve HPLC and
      reverse-phase HPLC of the water-insoluble protein fractions from two diabetic
      human lenses showed that DMPTB could degrade a major portion of the cross-linked
      HMW aggregates to lower molecular weight proteins. This suggests that the cross
      linked proteins in human lenses are formed predominantly by the advanced
      glycation process and cross-link breakers like DMPTB may have application for the
      intervention of protein cross-linking in the eye lens.

PMID- 12619890
TI  - Regulation of norepinephrine-induced proliferation in cardiac fibroblasts by
      interleukin-6 and p42/p44 mitogen activated protein kinase.
AB  - Norepinephrine (NE) is involved in many cardiovascular diseases such as
      congestive heart failure. We have recently reported that NE had a comitogenic
      effect in isolated cardiac fibroblasts, and that it activated p42/p44 mitogen
      activated protein kinase (MAPK). This study was designed to characterize a
      possible mechanism involved in the proliferative effect of NE. Isolated rat
      cardiac fibroblasts were exposed to NE (10 microM) for up to 8 h, and interleukin
      6 (IL-6) expression was measured by Ribonuclease Protection Assay and Western
      blotting. The activity of p42/p44MAPK was analyzed by Western blotting. Cell
      number was assessed by use of a Coulter Counter. IL-6/GAPDH mRNA was increased by
      NE in a time-dependent manner reaching 23 fold stimulation after 1 h compared to
      untreated samples. Immunoreactivity to IL-6 was not found in controls. After 16 h
      of exposure to NE, IL-6 protein was detected. It further increased up to 48 h.
      The effect of NE on IL-6 mRNA was abolished by the beta-adrenoceptor blockers
      propranolol, metoprolol (beta1) and ICI 118.551 (beta2), but not by the alpha
      adrenoceptor blockers prazosin (alpha1) and yohimbine (alpha2). The MAPK
      inhibitor PD98059 suppressed the NE-induced MAPK activation in a concentration
      dependent fashion after 5 min, attenuated the NE-induced IL-6 expression after 2
      h, and suppressed the proliferative effect of NE from 53 to 18% after 48 h.
      Recombinant IL-6 caused an increase in proliferation by 31% after 48 h.
      Simultaneous application of the IL-6 antibody reduced the NE-induced
      proliferation to 34%, and completely prevented the IL-6 induced effect. These
      results suggest that NE induces proliferation of rat cardiac fibroblasts in part
      by increasing the expression of IL-6 through regulation of MAPK.

PMID- 12619892
TI  - Involvement of beta 1,4 galactosyltransferase 1 and Gal beta1-->4GlcNAc groups in
      human hepatocarcinoma cell apoptosis.
AB  - Beta 1,4 galactosyltransferase 1 (beta 1,4GT1) synthesizes Gal beta 1-->4GlcNAc
      groups in N-linked sugar chains of animal glycoproteins, which have been
      demonstrated to play an important role in many biological events, including sperm
      egg interaction, cell migration and mammalian embryonic development. In this
      study, the mRNA level of beta 1,4GT1 was found to increase greatly during the
      7721 hepatocarcinoma cells apoptosis induced by cycloheximide. Ricinus Communis
      Agglutinin-I staining indicated generous increase of Gal beta 1-->4GlcNAc groups
      during apoptosis. Further study showed that the 7721 hepatocarcinoma cells
      transiently transfected with beta 1,4GT1 were more susceptible to the apoptosis
      induced by cycloheximide. The increased susceptibility was in accordance to the
      transfection concentration of beta 1,4GT1, which also led to the increased Gal
      beta 1-->4GlcNAc groups on the transfected cell surface. All the observations
      suggested that beta 1,4GT1 and Gal beta 1-->4GlcNAc groups might be associated
      with the apoptosis of human hepatocarcinoma cells.

PMID- 12619893
TI  - Transcriptional regulation of Na+/H+ exchanger expression in the intact mouse.
AB  - We examined regulation of the Na+/H+ exchanger (NHE1 isoform) in the developing
      mouse. We generated transgenic mice with the Na+/H+ exchanger promoter directing
      expression of the beta-Galactosidase reporter. We found that expression of the
      Na+/H+ exchanger was maximum in the heart and liver of 12-day-old embryonic mice.
      Similar results were found in mice using the green fluorescent protein reporter
      driven by the Na+/H+ exchanger promoter. Detailed examination of the myocardium
      revealed that the GFP reporter protein was expressed in the cytoplasm of
      cardiomyocyte cells. We examined NHE1 protein expression in transgenic mice
      lacking the transcription factors AP-2alpha or the transcription factor COUP-TF1.
      Eighteen-day-old AP-2alpha heterozygote mice show no large changes in NHE1
      expression in heart, lung, liver, kidney and brain. In contrast, 18-day-old
      embryos from AP-2alpha null mice showed a large increase in Na+/H+ exchanger
      protein expression in the brain. NHE1 protein levels in COUP-TF1 knockout embryos
      did not differ from wild type embryos. The results suggest that AP-2alpha and
      COUP-TF1 are not critical to NHE1 expression in the late stage embryo and that
      other related transcription factors may function in regulation of the Na+/H+
      exchanger.

PMID- 12619894
TI  - The urea cycle in the liver of arthritic rats.
AB  - The urea cycle in the liver of adjuvant-induced arthritic rats was investigated
      using the isolated perfused liver. Urea production in livers from arthritic rats
      was decreased during substrate-free perfusion and also in the presence of the
      following substrates: alanine, alanine + ornithine, ammonia, ammonia + lactate,
      ammonia + pyruvate and glutamine but increased when arginine and citrulline +
      aspartate were the substrates. No differences were found with ammonia +
      aspartate, ammonia + aspartate + glutamate, aspartate, aspartate + glutamate and
      citrulline. Ammonia consumption was smaller in the arthritic condition when the
      substance was infused together with lactate or pyruvate but higher when the
      substance was simultaneously infused with aspartate or aspartate + glutamate.
      Glucose production tended to correlate with the smaller or higher rates of urea
      synthesis. Blood urea was higher in arthritic rats (+25.6%), but blood ammonia
      was lower (-32.2%). Critical for the synthesis of urea from various substrates in
      arthritic rats seems to be the availability of aspartate, whose production in the
      liver is probably limited by both the reduced gluconeogenesis and
      aminotransferase activities. This is indicated by urea synthesis which was never
      inferior in the arthritic condition when aspartate was exogenously supplied,
      being even higher when both aspartate and citrulline were simultaneously present.
      Possibly, the liver of arthritic rats has a different substrate supply of
      nitrogenous compounds. This could be in the form of different concentrations of
      aspartate or other aminoacids such as citrulline or arginine (from the kidneys)
      which allow higher rates of hepatic ureogenesis.

PMID- 12619895
TI  - Antiangiogenic effects of butyric acid involve inhibition of VEGF/KDR gene
      expression and endothelial cell proliferation.
AB  - The formation of new blood vessels from pre-existing ones is required for the
      growth of solid tumors and for metastasis. Interaction of tumor-secreted vascular
      endothelial growth factor (VEGF) with its receptor(s) on endothelial cells
      triggers endothelial cell proliferation and migration, which facilitate tumor
      angiogenesis. Butyric acid (BuA), a fermentation product of dietary fibers in the
      colon, is shown to alter gene expression and is postulated to be
      anticarcinogenic. The results presented in this paper indicate that BuA can be
      antiangiogenic in vivo by inhibiting angiogenesis in chorioallantoic membrane
      assay. BuA was not cytotoxic to endothelial cells but was a potent
      antiproliferative agent besides being proapoptotic to endothelial cells as
      verified by FACS analysis. Conditioned media from BuA-treated Ehrlich ascites
      tumor cells showed a 30% decrease in VEGF concentration when compared with
      untreated cells. The decrease in VEGF mRNA and its receptor, KDR mRNA levels in
      EAT and endothelial cells respectively, suggests that the VEGF-KDR system of
      angiogenesis is the molecular target for the antiangiogenic action of BuA.

PMID- 12619896
TI  - Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are
      associated with p53-independent cell cycle (G2) arrest and apoptosis.
AB  - Poly(ADP-ribose) polymerase (PARP), which is activated by DNA strand breaks, is
      involved in DNA repair and replication but, during apoptosis, undergoes early
      caspase-mediated cleavage. Activation of programmed cell death in response to DNA
      damage may rely on functional p53 protein. Tumor cells are commonly deficient in
      this oncogene product resulting in resistance to many cytostatic drugs. Here we
      report that nicotinamide-induced inhibition of poly(ADP-ribosyl)ation and
      cytokine-induced nitric oxide production both result in a transient increase in
      p53 levels in pancreatic tumor RINm5F cells. These treatments also induce
      disruption of the mitochondrial membrane potential (delta psi(m)), as revealed
      using the mitochondrial probe JC-1, followed by PARP cleavage and apoptosis all
      of which are inhibited by the anti-apoptotic protein Bcl-2. Moreover, PARP
      inhibition by nicotinamide or 3-aminobenzamide induces apoptosis and/or cell
      cycle arrest at the G2 checkpoint in all of four tested tumor cell lines of both
      mesenchymal and epithelial origin including mouse NIH-3T3 cells and p53 deficient
      human HeLa and Jurkat cells. Bcl-2 counteracts cytokine-, but not nicotinamide
      induced G2 arrest. These findings indicate that both chemical and caspase
      mediated inhibition of PARP activity, possibly by interfering with DNA
      replication and repair, may promote a p53-independent G2 arrest and apoptosis.

PMID- 12619897
TI  - Preparation and characterization of a human aurora-A kinase monoclonal antibody.
AB  - We have developed monoclonal antibodies against the human aurora-A
      serine/threonine kinase. After immunization of a mouse, a fusion was performed to
      obtain hybridomas that were selected because they produced immunoglobulin
      positively reacting against the protein used for immunization. We isolated one
      particular monoclonal that we named 35C1 using a series of selective assays. The
      first criteria of the screen for monoclonals was an ELISA (Enzyme Linked
      Immunosorbant Assay) assay performed in 96-well plates against the purified
      recombinant histidine-tagged aurora-A. The second was a positive Western blot
      against the same recombinant protein. The third criteria was a positive western
      blot against an HeLa cell extract, the selected monoclonal should detect only one
      protein migrating at 46 kDa (kiloDalton) on SDS (Sodium Dodecyl Sulfate)
      polyacrylamide gel electrophoresis. Finally, the monoclonal had to bind to
      duplicated centrosomes and spindle poles in human MCF7 cultured cells by indirect
      immunofluorescence. At this stage several monoclonals were still positive. We
      then increased the selectivity by searching for antibodies that were able to
      cross-react with the mouse aurora-A kinase both by western blot and indirect
      immunofluorescence. We selected and cloned the 35C1 hybridoma to produce the
      antibody. Further characterization of the 35C1 antibody revealed that it was able
      to immunoprecipitate the kinase, that it did not inhibit the aurora-A kinase
      activity and consequently could be used to measure the aurora-A kinase activity
      in vivo after immunoprecipitation.

PMID- 12619898
TI  - Synergistic effect of Nicorandil and Amlodipine on tissue defense system during
      experimental myocardial infarction in rats.
AB  - The synergistic protective effect of Nicorandil (K(ATP) channel opener) and
      Amlodipine (calcium channel blocker) on heart tissue antioxidant defense system
      and lipid profile were examined on isoproterenol induced myocardial infarction in
      rats. The rats given isoproterenol (150 mg kg(-1) daily, i.p.) for 2 days showed
      significant changes in antioxidant defense system and lipid profile levels.
      Pretreatment with Nicorandil (2.5 mg kg(-1) daily, p.o.) and Amlodipine (5.0 mg
      kg(-1) daily, p.o.) for 3 days significantly prevented these alterations and
      restored the enzyme activities to near normal. These findings indicate the
      synergistic protective effect of Nicorandil and Amlodipine on tissue defense
      system and lipid metabolism during isoproterenol induced cardiac damage.

PMID- 12619899
TI  - Prolonged glutamate excitotoxicity: effects on mitochondrial antioxidants and
      antioxidant enzymes.
AB  - Glutamate, a major excitatory amino acid neurotransmitter is also an endogenous
      excitotoxin. The present study examined the prolonged and delayed effects of
      glutamate excitotoxicity on mitochondrial lipid peroxidation and antioxidant
      parameters in different brain regions, namely, cerebral hemisphere, cerebellum,
      brain stem and diencephalon. Wistar rats (male) were exposed to monosodium
      glutamate (MSG) (4 mg x g body wt(-1), i.p.) for 6 consecutive days and
      sacrificed on 30th and 45th day after last MSG dose. MSG treatment markedly
      decreased the mitochondrial manganese superoxide-dismutase (Mn-SOD), catalase and
      reduced glutathione (GSH) content, and increased the lipid peroxidation (LPx),
      uric acid and glutathione peroxidase (GPx) activity. These results indicate that
      oxidative stress produced by glutamate in vulnerable brain regions may persist
      for longer periods and mitochondrial function impairment is an important
      mechanism of excitatory amino acid mediated neurotoxicity in chronic
      neurodegeneration.

PMID- 12619900
TI  - Oxidative stress and gene expression of antioxidant enzymes in the renal cortex
      of streptozotocin-induced diabetic rats.
AB  - The present study was aimed at addressing the effect of hyperglycemia on
      antioxidant enzymes. The expression of catalase, superoxide dismutase and
      glutathione peroxidase, the three primary scavenger enzymes involved in
      detoxifying reactive oxygen species has been evaluated in the renal cortex of
      rats after 6 weeks of streptozotocin-induced diabetes. Lipid peroxidation and
      protein oxidation in the renal cortical homogenate were first performed to
      confirm a state of oxidative stress. The enzyme assays showed significant and
      varied alterations in catalase, superoxide dismutase and glutathione peroxidase
      activities. An opposing response of catalase and glutathione peroxidase
      activities to diabetes was observed. RT-PCR analysis was used to ascertain
      whether steady-state transcription levels were altered. While an increase in
      glutathione peroxidase and Cu-Zn superoxide dismutase mRNA parallels the increase
      in the activities of the enzymes, an increase in catalase gene expression in
      contrast to a decrease in enzyme activity suggests a role for post-translational
      modification in altering the activity of this enzyme.

PMID- 12619902
TI  - Functional MRI of human amygdala activity during Pavlovian fear conditioning:
      stimulus processing versus response expression.
AB  - Although laboratory animal studies have shown that the amygdala plays multiple
      roles in conditional fear, less is known about the human amygdala. Human subjects
      were trained in a Pavlovian fear conditioning paradigm during functional magnetic
      resonance imaging (fMRI). Brain activity maps correlated with reference waveforms
      representing the temporal pattern of visual conditional stimuli (CSs) and subject
      derived autonomic responses were compared. Subjects receiving paired CS-shock
      presentations showed greater amygdala activity than subjects receiving unpaired
      CS-shock presentations when their brain activity was correlated with a waveform
      generated from their behavioral responses. Stimulus-based waveforms revealed
      learning differences in the visual cortex, but not in the amygdala. These data
      support the view that the amygdala is important for the expression of learned
      behavioral responses during Pavlovian fear conditioning.

PMID- 12619901
TI  - Quercetin suppresses proinflammatory cytokines production through MAP kinases
      andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage.
AB  - Quercetin is a flavonoid molecule ubiquitous in nature and functions as an anti
      oxidant and anti-inflammatory agent with little toxicity in vivo and in vitro.
      Dose- and time-dependent effect of quercetin has been investigated on
      proinflammatory cytokine expression and NO production, focusing on its effects on
      the MAP kinases and the NF-kappaB signal transduction pathways in LPS-stimulated
      RAW 264.7 cells by using RT-PCR and immunoblotting. Quercetin strongly reduced
      activation of phosphorylated ERK kinase and p38 MAP kinase but not JNK MAP kinase
      by LPS treatment. In addition, quercetin treatment inhibited NF-kappaB activation
      through stabilization of the NF-kappaB/IkappaB complex and IkappaB degradation
      and proinflammatory cytokines and NO/iNOS expression. Quercetin may exert its
      anti-inflammatory and immunomodulatory properties in the effect molecules such as
      proinflammatory cytokines and NO/iNOS by suppressing the activation of ERK and
      p38 MAP kinase, and NF-kappaB/IkappaB signal transduction pathways.

PMID- 12619904
TI  - Social transmission of food preference in mice: methodology and application to
      galanin-overexpressing transgenic mice.
AB  - Social transmission of food preference (STFP) is a test of olfactory memory that
      can be used in mice. Confounds in STFP that can lead to misinterpretation of an
      STFP deficit as a memory impairment include changes in social interaction and
      olfaction. The issue of changes in social interaction was addressed by evaluating
      an observer-centric and a demonstrator-centric method for scoring the interaction
      phase of STFP in mice. The demonstrator-centric method was applied to a line of
      STFP-impaired, galanin-overexpressing transgenic (GAL-tg). GAL-tg mice were
      impaired in STFP without deficits in social interaction. In tests of olfactory
      ability, GAL-tg mice were unimpaired on buried-food and habituation
      dishabituation tasks. The current studies describe an expanded method for using
      STFP in mice and confirm a deficit in olfactory memory in GAL-tg mice.

PMID- 12619903
TI  - Right frontal brain activity, cortisol, and withdrawal behavior in 6-month-old
      infants.
AB  - Although several studies have examined anterior asymmetric brain electrical
      activity and cortisol in infants, children, and adults, the direct association
      between asymmetry and cortisol has not systematically been reported. In nonhuman
      primates, greater relative right anterior activation has been associated with
      higher cortisol levels. The current study examines the relation between frontal
      electroencephalographic (EEG) asymmetry and cortisol (basal and reactive) and
      withdrawal-related behaviors (fear and sadness) in 6-month-old infants. As
      predicted, the authors found that higher basal and reactive cortisol levels were
      associated with extreme right EEG asymmetry. EEG during the withdrawal-negative
      affect task was associated with fear and sadness behaviors. Results are
      interpreted in the context of the previous primate work, and some putative
      mechanisms are discussed.

PMID- 12619905
TI  - Consumption of solutions containing sodium chloride is enhanced in female
      oxytocin-deficient mice.
AB  - Intact and ovariectomized oxytocin (OT)-deficient (OT-/-) and wild-type (OT+/+)
      mice were tested for consumption of 0.5 M NaCl solution or tap water in a 2
      bottle choice test. During 3 days of acclimation, voluntary ingestion of NaCl was
      equal between genotypes. After overnight fluid deprivation, intact OT-/- mice
      ingested 2 times more NaCl solution than OT+/+ mice in the 6th hr, but not the
      1st hr, after reintroduction of fluid. Ovariectomized mice consumed less than
      intact mice after overnight fluid deprivation. When a 0.2 M NaCl solution was
      administered for 6 days in ovariectomized mice, OT-/- mice voluntarily consumed
      greater amounts than OT+/+ mice. After overnight fluid deprivation, consumption
      by OT-/- mice was 3 times that of OT+/+ mice at 1 hr and 2-fold greater after 6
      hr. Enhanced intake of NaCl-containing solutions in female OT-/- mice suggests
      that central OT may be an important inhibitor of sodium consumption.

PMID- 12619906
TI  - Aggression in male mice lacking functional estrogen receptor alpha.
AB  - Estrogen receptor alpha knockout (ERaKO) male mice fail to display sexual
      behavior. The authors hypothesized that ERalphaKOs require higher testosterone
      (T) concentrations than wild-type (WT) males to exhibit copulatory behavior.
      Increasing T stimulated sexual behavior and preference for females in WT males
      but failed to do so in ERalphaKOs. However, T did induce female-directed
      aggression in ERaKOs. In aggression tests, WT residents selectively attacked T
      treated male intruders. ERaKO residents attacked female, T-treated male, and
      estrogen-treated male intruders equally. Increased access to olfactory cues prior
      to direct contact reduced overall aggression in ERalphaKO versus WT males but did
      not cause ERalphaKOs to differentially attack male and female opponents. Results
      suggest that ERalpha is essential for normal social behavior, perhaps via
      processing of chemoinvestigatory cues, which are required to discriminate males
      from females.

PMID- 12619907
TI  - Altered feeding responses in mice with targeted disruption of the dopamine-3
      receptor gene.
AB  - Dopamine signaling has been implicated in the control of food intake and body
      weight. In particular, dopamine is important in the control of meal size and
      number and is thought to mediate the response to metabolic deprivation states. In
      the present experiments, the authors assessed the role of the dopamine-3 receptor
      (D3R) in the feeding responses to 2-deoxy-D-glucose, mercaptoacetate, and
      peripheral insulin. All 3 compounds increased food intake in wild-type mice, but
      the hyperphagic responses were blunted in D3R-/- mice. In other experiments, D3R
      /- mice were hyperresponsive to the administration of amylin and leptin relative
      to wild-type mice. These results support the hypothesis that D3Rs chronically
      inhibit the effects of adiposity hormones, thereby contributing to a net anabolic
      state.

PMID- 12619908
TI  - Lack of opioid or dopaminergic effects on unconditioned sexual incentive
      motivation in male rats.
AB  - The effects of dopaminergic and opioidergic drugs on sexual incentive motivation
      were evaluated in sexually inexperienced male rats subjected to a choice
      procedure. Various parameters of ambulatory activity were recorded as well. Two
      drugs stimulating dopaminergic neurotransmission, amphetamine and apomorphine,
      failed to affect sexual incentive motivation, although ambulatory activity was
      enhanced by amphetamine. The dopamine antagonist cis(Z)-flupenthixol reduced
      sexual incentive motivation, but only at a dose that severely disrupted motor
      function. Morphine had marginal effects on sexual motivation but reduced
      ambulatory activity. These effects were not reduced by a peripheral opioid
      antagonist, methylnaloxone. Loperamide, a peripheral opioid agonist, reduced
      sexual motivation through an opioid-independent action. Naloxone was ineffective.
      Neither dopamine nor opioids seem to be important for sexual incentive
      motivation.

PMID- 12619909
TI  - An NMDA antagonist impairs copulation and the experience-induced enhancement of
      male sexual behavior in the rat.
AB  - Sexual experience facilitates subsequent male sexual behavior; activation of the
      N-methyl-D-aspartate (NMDA) glutamate receptor may play a role in this experience
      induced enhancement. In this article, the authors report that systemic injections
      of MK-801, an NMDA receptor antagonist, impaired male sexual behavior in sexually
      naive and sexually experienced male rats. Furthermore, saline-treated rats that
      received 7 daily exposures to an inaccessible estrous female instead of sexual
      experience displayed enhancement of copulation on the following day. Injections
      of MK-801 before each of these exposures inhibited the experience-induced
      enhancement on the drug-free test on Day 8. These data suggest that stimulation
      of NMDA receptors enhances sexual performance immediately and mediates the
      experience-induced enhancement of subsequent copulatory behavior.

PMID- 12619910
TI  - Sex-related differences in spatial divided attention and motor impulsivity in
      rats.
AB  - The acquisition and performance of a self-paced test of spatial divided attention
      linked with frontal cortex function were assessed in postpubertal (> 60 days)
      normal or gonadectomized male and female rats. Males were more accurate at
      detecting relatively brief visual stimuli than females, but this difference was
      eliminated by increasing the target stimulus duration, indicating an attentional
      basis for this effect. Premature errors were, however, greater in males than in
      females, suggesting greater impulsivity in males. Subsequent experiments in
      gonadectomized rats suggest that circulating hormones influence attention and
      impulsivity, but not necessarily sex differences. These results demonstrate a
      double dissociation between components of impulse control and divided attention
      in male and female rats and may have implications for sex differences in
      disorders of attention and cognition.

PMID- 12619911
TI  - Estrogen effects on the hyperactivity induced by (+)-MDMA and cocaine in female
      rats.
AB  - This study compared the effects of estrogen (E) on the hyperactivity induced by
      (+)-3,4-methylenedioxymethamphetamine (MDMA) with E effects on cocaine-evoked
      hyperactivity in female rats. Sprague-Dawley rats were ovariectomized (OVX); half
      of them received a 17beta-estradiol (E2) implant (OVX + E). Three weeks later,
      rats received saline, (+)-MDMA (1, 2, or 4 mg/kg) or cocaine (5, 10, or 20
      mg/kg), and locomotor activity was monitored. OVX + E rats exhibited greater
      locomotor hyperactivity in response to both psychostimulants than did OVX rats.
      The enhanced response to cocaine appeared within 5 min following drug injection
      whereas the enhanced response to (+)-MDMA was delayed for approximately 30 min.
      The differential effects of E on hyperactivity may be due to the unique profiles
      of DA and 5-HT in response to (+)-MDMA and cocaine.

PMID- 12619912
TI  - Tolerance to amphetamine hypophagia: a microstructural analysis of licking
      behavior in the rat.
AB  - The development of tolerance to amphetamine-induced hypophagia was assessed by
      recording changes in lick parameters in rats given chronic administration of the
      drug (2 mg/kg) and access to sweetened milk. Although licking and milk intake
      gradually recovered, the volume of milk ingested per lick remained suppressed.
      Amphetamine had no effect on the interlick interval or the force per lick. In
      contrast, the drug caused a sustained increase in the number of lick bursts
      (defined by pause criteria of 0.5-2.0 s) and a decrease in the number of licks
      per burst (but only at pause criteria of 0.5 and 1.0 s). These results suggest
      that tolerant rats frequently interrupt licking, resulting in less efficient
      capture of milk.

PMID- 12619913
TI  - Vestibular lesions selectively abolish body rotation-induced, but not lithium
      induced, conditioned taste aversions (oral rejection responses) in rats.
AB  - Pairing a novel taste with provocative vestibular stimulation results in
      conditioned taste aversions in both rats and humans. Vestibular system
      involvement in gustatory conditioning was examined in sham-lesioned or
      labyrinthectomized rats. Three conditioning trials consisted of 30 min access to
      asaccharin (0.1%) solution followed by 30 min of rotation (70 rpm) or sham
      rotation. In a taste reactivity test with saccharin, rotated sham-lesioned rats,
      but not labyrinthectomized rats, exhibited increased oral rejection reactions
      compared with control rats. When conditioned with lithium chloride, both
      labyrinthectomized and sham-lesioned rats displayed robust conditioned rejection
      reactions. The finding that normal vestibular function is necessary in obtaining
      rotation-induced conditioned taste aversions supports the face and construct
      validity of a rat model of motion sickness.

PMID- 12619914
TI  - Stimulus preexposure reduces generalization of conditioned taste aversions
      between alcohol and non-alcohol flavors in infant rats.
AB  - Results of 3 experiments showed that infant rats (age 13-17 days) generalize
      conditioned taste aversions between alcohol and non-alcohol tastes such as a
      mixture of sucrose and quinine, apple cider vinegar, or coffee. Nonreinforced
      preexposure to those tastes reduced generalized aversions between them.
      Generalization between alcohol and sucrose-quinine was reduced not only after
      preexposure to both tastes, but also when only the nonconditioned taste was
      preexposed, whereas with alcohol and vinegar, both tastes had to be preexposed to
      obtain that effect. In no case was generalization reduced when only the to-be
      conditioned taste was preexposed. Previous experience with alcohol alone, as well
      as with similar gustatory stimuli, may enhance subjects' ability to differentiate
      them during infantile stages in rats.

PMID- 12619915
TI  - Helplessness and escape performance: glutamate-adenosine interactions in the
      frontal cortex.
AB  - Adenosine has been implicated as a proximate mediator of escape deficits in the
      learned helplessness paradigm, suggesting that neuronal overactivation-a typical
      precursor to adenosine release-precedes the inescapable shock-induced impairment
      (T. R. Minor, W. C. Chang, & J. L. Winslow, 1994). In the present experiments,
      glutamate (100 microg) injection into the rat frontal cortex produced a deficit
      in escape performance. Pretest treatment with the adenosine receptor antagonist
      caffeine (7 mg/kg ip) reversed the effect of glutamate when infused 1 hr. but not
      72 hr, after glutamate injection. Finally, microinjection of 2-amino-5
      phosphonovaleric acid (5 ng) into the frontal cortex prior to inescapable shock
      prevented the escape deficit. These findings are consistent with the involvement
      of N-methyl-D-aspartate receptor activation in the frontal cortex in the
      helplessness effect.

PMID- 12619916
TI  - Quetiapine produces a prolonged reversal of the sensorimotor gating-disruptive
      effects of basolateral amygdala lesions in rats.
AB  - Prepulse inhibition (PPI) of startle is impaired in schizophrenia and in rats
      after manipulations of limbic cortical and subcortical regions. The atypical
      antipsychotic quetiapine was used to reverse PPI deficits after basolateral
      amygdala (BLA) lesions in rats. BLA quinolinic acid lesions significantly
      disrupted PPI 1 week postsurgery. Tests with quetiapine (0 vs. 7.5 mg/kg) in a
      within-subject design 2-3 weeks postsurgery revealed a normalization of PPI.
      Carry-over effects lasted up to 3 weeks, with a return of lesion-induced deficits
      by Week 5 postsurgery. This dose of quetiapine also blocked the PPI-disruptive
      effects of phencyclidine. PPI deficits after BLA lesions are reversed by
      quetiapine, in a manner that is sustained beyond its acute pharmacological
      effects and which may be mediated downstream from the BLA.

PMID- 12619917
TI  - Differential effects of courtship and mating on receptivity and brain metabolism
      in female red-sided garter snakes (Thamnophis sirtalis parietalis).
AB  - In the female red-sided garter snake (Thamnophis sirtalis parietalis), the loss
      of receptivity following intromission during mating can be prevented by injection
      of a local anesthetic (tetracaine) in the cloacal region prior to courtship and
      mating. Females that were courted and then mated had significantly higher uptake
      of radio-labeled [14C]2-fluoro-2-deoxyglucose (2-DG) in the preoptic area (25%)
      and significantly lower uptake in the ventromedial hypothalamus (-20%) compared
      with females that were courted but not mated. Tetracaine-treated females had
      accumulation patterns similar to courted but unmated females and to females
      exposed only to other females. These results suggest that in the female red-sided
      garter snake, sensory input from the cloaca during mating alters patterns of
      metabolism in those brain areas most often associated with female sexual
      behavior.

PMID- 12619918
TI  - A differential involvement of the shell and core subterritories of the nucleus
      accumbens of rats in memory processes.
AB  - The role of the core and the shell subterritories of the nucleus accumbens in
      conditioned freezing and spatial learning was investigated by means of selective
      N-methyl-D-aspartate lesions. Shell-lesioned rats showed reduced conditioned
      freezing to context and a tendency toward reduced freezing to the discrete
      stimulus compared with controls. However, lesions of the core did not modify the
      freezing response either to the context or to the discrete stimuli. Although
      spatial memory, as assessed by a water-maze paradigm, was not disrupted by the
      lesions, in a 4-arm baited, 4-arm unbaited radial-arm maze paradigm, the shell
      lesioned rats showed selective deficits in working memory, but not in reference
      memory. In contrast, core-lesioned rats showed no memory deficits.

PMID- 12619919
TI  - Differential effects of lesions of the vomeronasal and olfactory nerves on garter
      snake (Thamnophis sirtalis) responses to airborne chemical stimuli.
AB  - The roles of the main (MOS) and accessory (AOS) olfactory systems of garter
      snakes in response to airborne chemicals were investigated. Preoperatively, all
      snakes responded to airborne odors with increased tongue-flick rate and duration.
      Postoperatively, sham-operated snakes responded to airborne odors with increased
      tongue-flick rates, but snakes with main olfactory nerve cuts failed to respond
      to the odors, and snakes with vomeronasal nerve cuts responded to nonprey odors
      only. Preoperatively, exposure to earthworm odor produced more frequent and
      shorter duration tongue-flicks during locomotion compared with exposure to water.
      Postoperatively, only sham-lesioned snakes exhibited differential responding to
      earthworm odors. This study demonstrates that the MOS is critical for the
      initiation of tongue-flick behavior in response to airborne odors and that
      discrimination of odors with biological significance requires a functional AOS.

PMID- 12619920
TI  - Modulation of memory consolidation for olfactory learning by reversible
      inactivation of the basolateral amygdala.
AB  - The role of the basolateral amygdala (BLA) in the consolidation of an association
      between an olfactory stimulus and footshock was investigated with a reversible
      lesion technique of post-training intra-BLA infusions of tetrodotoxin. Rats
      receiving tetrodotoxin infusions following paired odor-shock presentations spent
      more time near the odor, and reacted differently on contact with the odor when
      tested 24 hr after training, than did rats receiving paired presentations and
      saline infusions, but they did not differ from rats receiving unpaired
      presentations and saline infusions. The results indicate that the BLA plays a
      similar role in influencing consolidation of olfactory-based memory as it does
      for memory based on other modalities. Thus, these findings strengthen the view
      that the BLA plays a general role in modulation of memory storage for emotionally
      arousing events.

PMID- 12619921
TI  - Growth hormone increases bone mineral content in postmenopausal osteoporosis: a
      randomized placebo-controlled trial.
AB  - Eighty osteoporotic, postmenopausal women, 50-70 years of age, with ongoing
      estrogen therapy (HRT), were randomized to recombinant human growth hormone (GH),
      1.0 U or 2.5 U/day, subcutaneous, versus placebo. This study was double-blinded
      and lasted for 18 months. The placebo group then stopped the injections, but both
      GH groups continued for a total of 3 years with GH and followed for 5 years.
      Calcium (750 mg) and vitamin D (400 U) were given to all patients. Bone mineral
      density and bone mineral content were measured with DXA. At 18 months, when the
      double-blind phase was terminated, total body bone mineral content was highest in
      the GH 2.5 U group (p = 0.04 vs. placebo). At 3 years, when GH was discontinued,
      total body and femoral neck bone mineral content had increased in both GH-treated
      groups (NS between groups). At 4-year follow-up, total body and lumbar spine bone
      mineral content increased 5% and 14%, respectively, for GH 2.5 U (p = 0.01 and p
      = 0.0006 vs. placebo). Femoral neck bone mineral density increased 5% and bone
      mineral content 13% for GH 2.5 U (p = 0.01 vs. GH 1.0 U). At 5-year follow-up, no
      differences in bone mineral density or bone mineral content were seen between
      groups. Bone markers showed increased turnover. Three fractures occurred in the
      GH 1.0 U group. No subjects dropped out. Side effects were rare. In conclusion,
      bone mineral content increased to 14% with GH treatment on top of HRT and
      calcium/vitamin D in postmenopausal women with osteoporosis. There seems to be a
      delayed, extended, and dose-dependent effect of GH on bone. Thus, GH could be
      used as an anabolic agent in osteoporosis.

PMID- 12619922
TI  - Growth hormone rising: did we quit too quickly?

PMID- 12619923
TI  - Primary hyperparathyroidism with multiple osteosclerotic lesions of the
      calvarium.

PMID- 12619924
TI  - Autosomal dominant gnathodiaphyseal dysplasia maps to chromosome 11p14.3-15.1.
AB  - Gnathodiaphyseal dysplasia (GDD) is a syndrome characterized by bone fragility,
      sclerosis of tubular bones, and cemento-osseous lesions of jawbones. Although
      some cases of this syndrome exist in families with autosomal dominant
      inheritance, the underlying gene has never been identified. We analyzed a large
      four-generation family with GDD by linkage analysis using genomic DNA from nine
      affected and six nonaffected family members. A genome-wide search using a set of
      highly polymorphic microsatellite markers showed evidence for linkage to
      chromosome 11p14.3-15.1. Two-point linkage analysis of microsatellite markers
      spanning this locus resulted in a maximum logarithm of odds (LOD) score of 2.70
      with a recombination fraction (theta) of 0 at D11S1755, D11S1759, and D11S915,
      and a maximum LOD score of 3.01 at D11S4114 was obtained in multipoint linkage
      analysis. Haplotype analysis detected no recombination between GDD and six
      closely linked markers (D11S928, D11S1755, D11S4114, D11S1759, D11S915, and
      D11S929) and established the candidate interval of 8.7 cM on chromosome 11p for
      GDD. Although GDD has been considered to be a variation of osteogenesis
      imperfecta (MIM 166260), our results indicate that this syndrome is a new and
      distinct disease entity from other systemic bone diseases. Furthermore, these
      genetic markers are useful for presymptomatic diagnosis of GDD in some families
      and for identification of the GDD gene.

PMID- 12619925
TI  - Association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor
      associated kinase (IRAK1) gene with low radial bone mineral density in two
      independent populations.
AB  - Osteoporosis, a multifactorial common disease, is believed to result from the
      interplay of multiple environmental and genetic determinants, including factors
      that regulate bone mineral density. Interleukin-1 (IL-1) is one of the most
      potent bone-resorbing factors, and interleukin-1-associated kinase 1 (IRAK1) is
      an essential effector of the IL-1 receptor signaling cascade. In genetic studies
      of two independent populations of postmenopausal women (cohort A: 220 individuals
      and cohort T: 126 individuals) from separated geographical regions of Japan, we
      found that radial bone mineral density levels had similar associations with IRAK1
      genotypes in both populations. Two amino acid-substituting variations in the
      gene, encoding Phe196Ser and Ser532Leu, were in complete linkage disequilibrium
      (D' = 1.0000, r2 = 1.0000, chi2 = 192.000, p = 1.2 x 10(-43)), and we found two
      exclusive haplotypes (196F/532S, frequency 0.74; 196S/532L, frequency 0.26) of
      the IRAK1 gene among our test subjects. In both populations, a significant
      association with decreased radial bone mineral density was identified with
      haplotype 196F/532S (in cohort A: r = 0.21, p = 0.0017; in cohort T: r = 0.23, p
      = 0.011). Radial bone mineral density was lowest among 196F/532S homozygotes,
      highest among 196S/532L homozygotes, and intermediate among heterozygotes.
      Accelerated bone loss also correlated with the 196F/532S haplotype in a 5-year
      follow-up. These results suggest that variation of IRAK1 may be an important
      determinant of postmenopausal osteoporosis, in part through the mechanism of
      accelerated postmenopausal bone loss.

PMID- 12619926
TI  - The pseudohypoparathyroidism type lb locus is linked to a region including GNAS1
      at 20q13.3.
AB  - Pseudohypoparathyroidism (PHP) is characterized by biochemical hypoparathyroidism
      with elevated parathyroid hormone levels owing to reduced target tissue
      responsiveness to parathyroid hormone. Patients with PHP la have somatic defects
      termed Albright's hereditary osteodystrophy (AHO) and exhibit resistance to
      additional hormones because of heterozygous mutations in the GNAS1 gene that lead
      to a generalized deficiency of the a subunit of Gs, the heterotrimeric G protein
      that couples receptors to adenylyl cyclase. By contrast, patients with PHP 1b
      lack AHO and have selective parathyroid hormone (PTH) resistance, presumably
      because of an imprinting defect that impairs expression of G(s)alpha in the
      proximal renal tubule. Although an epigenetic defect in GNAS1 has been identified
      in subjects with PHP1b, the genetic defect is unknown. To define the genetic
      defect in PHP 1b, we performed a genome-wide linkage analysis in five multi
      generational PHP lb families. Of the 408 polymorphic microsatellite markers
      examined, markers located on chromosome 20q13.3, the region containing GNAS1,
      demonstrated linkage to PHP lb. Fine-mapping and multipoint linkage analysis of
      this region demonstrated linkage to a 5.7-cM region between 907rep2 and the
      telomere. Haplotype analysis established that affected individuals shared a 5-cM
      region including part of the GNAS1 gene to the telomere. Our data confirm that
      PHP1b is linked to a region that includes GNAS1, and further refine the locus,
      although the primary genetic mutation(s) that causes defective imprinting of
      GNAS1 remains undefined.

PMID- 12619927
TI  - Abnormal regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase activity in X
      linked hypophosphatemia: a translational or post-translational defect.
AB  - The hyp mouse exhibits abnormal metabolic/hormonal regulation of renal 25(OH)D
      1alpha-hydroxylase activity. Whether this results from aberrant transcriptional
      regulation of the 1alpha-hydroxylase gene, CYP27B1, remains unknown. To
      investigate this possibility, we compared phosphate and parathyroid hormone
      effects on renal proximal convoluted tubule and thyrocalcitonin effects on
      proximal straight tubule enzyme activity and mRNA expression in normal and hyp
      mice. We assayed 25(OH)D-1alpha-hydroxylase activity by measuring 1,25(OH)2D
      production and mRNA by ribonuclease protection. Phosphate-depleted mice exhibited
      a 3-fold increment of 25(OH)D-1alpha-hydroxylase activity compared with normals,
      whereas hyp mice displayed no enhanced enzyme function. Phosphate-depleted mice
      concurrently displayed a 2-fold increase in mRNA transcripts; in contrast,
      despite failure to alter enzyme activity, hyp mice exhibited a similar increment
      in mRNA transcripts. Parathyroid hormone stimulation of normal mice increased
      25(OH)D-1alpha-hydroxylase activity 10-fold, while eliciting only a 2-fold
      increment in hyp mouse enzyme function. This disparity occurred despite
      increments of mRNA transcripts to comparable levels (22.2 +/- 3.5- vs. 19.9 +/-
      1.8-fold). The dissociation between phosphate- and parathyroid hormone-mediated
      transcriptional activity and protein function was not universal. Thus,
      thyrocalcitonin stimulation of normal and hyp mice resulted in comparable
      enhancement of mRNA transcripts and enzyme activity. These observations indicate
      that abnormal regulation of vitamin D metabolism in hyp mice occurs in the
      proximal convoluted tubule and results, not from aberrant transcriptional
      regulation, but from a defect in translational or post-translational activity.

PMID- 12619928
TI  - TRAF5 functions in both RANKL- and TNFalpha-induced osteoclastogenesis.
AB  - Although TRAF6 is essential for both RANKL- and TNFalpha-induced
      osteoclastogenesis, it has remained unclear whether other members of the TRAF
      family are involved in osteoclastogenesis. We examined TRAF5 function in both
      RANKL- and TNFalpha-induced osteoclastogenesis by using osteoclast progenitor
      cells from TRAF5-deficient mice. The results demonstrated that RANKL or TNFalpha
      did not effectively induce osteoclast differentiation from osteoclast progenitor
      cells derived from these mice into mature multinucleated osteoclasts, although c
      jun N-terminal kinase (JNK) and NF-kappaB activation was apparently observed in
      osteoclast progenitor cells. In the parathyroid hormone (PTH)-induced
      hypercalcemia model, calcium concentration peaked at day 3 after administration.
      However, in TRAF5-deficient mice, this peak was delayed and found at day 5,
      showing less effective osteoclast differentiation. Thus, we have provided the
      first evidence showing that TRAF5 is involved in osteoclastogenesis.

PMID- 12619929
TI  - Effects of cyclosporine on osteoclast activity: inhibition of calcineurin
      activity with minimal effects on bone resorption and acid transport activity.
AB  - Cyclosporine results in rapid and profound bone loss in transplant patients, an
      effect ascribed to osteoclasts. Cyclosporine, complexed with the appropriate
      immunophilin, inhibits calcineurin (the calcium/calmodulin dependent
      serine/threonine phosphatase) activity. We tested the hypothesis that
      cyclosporine inhibits calcineurin activity in osteoclasts, resulting in
      stimulation of osteoclast activity. We compared the effects of cyclosporine A and
      the calmodulin antagonist, tamoxifen, on bone resorption by avian osteoclasts.
      Tamoxifen inhibits bone resorption approximately 60%, whereas cyclosporine A only
      inhibited bone resorption 12%. One-hour treatment with 100 nM cyclosporine
      inhibited osteoclast calcineurin activity 70% in whole cell lysates, whereas 10
      microM tamoxifen only inhibited calcineurin activity 25%. We compared the effects
      of cyclosporine A and tamoxifen on acid transport activity in isolated membrane
      vesicles and in isolated membrane vesicles obtained from osteoclasts treated with
      cyclosporine A or tamoxifen under conditions that inhibit calcineurin activity.
      Direct addition of cyclosporine A in the acid transport assay, or pretreatment of
      cells with cyclosporine A followed by membrane isolation, had no effect on acid
      transport activity in membrane vesicles. In contrast, direct addition of
      tamoxifen to membranes inhibits acid transport activity, an effect that can be
      prevented by addition of exogenous calmodulin. Furthermore, acid transport
      activity was also inhibited in membrane vesicles isolated from cells treated with
      tamoxifen. In conclusion, cyclosporine A inhibits osteoclast calcineurin
      activity; however, calcineurin inhibition does not correspond to a significant
      effect on acid transport activity in isolated membrane vesicles or bone
      resorption by osteoclasts.

PMID- 12619930
TI  - CytokineRegulation and the signaling mechanism of osteoclast inhibitory peptide-1
      (OIP-1/hSca) to inhibit osteoclast formation.
AB  - The osteoclast (OCL) is the primary bone resorbing cell. OCL formation and
      activity is regulated by local factors produced in the bone microenvironment. We
      recently identified OCL inhibitory peptide-1 (OIP-1/ hSca) as a novel inhibitor
      of OCL formation and bone resorption that is produced by OCLs. OIP-1 is a
      glycosylphosphatidyl-inositol (GPI)-linked membrane protein (16 kDa) related to
      the mouse Ly-6 family of hematopoietic proteins. OIP-1 mRNA is expressed in human
      OCL precursors, granulocyte-macrophage colony-forming unit (GM-CFU), bone marrow
      cells, and osteoblast cells. We used cycle-dependent reverse transcriptase
      polymerase chain reaction (RT-PCR) analysis, which further demonstrated that
      interferon-gamma (IFN-gamma) strongly enhanced OIP-1/hSca mRNA expression in bone
      marrow cells and GM-CFU. Similarly, interleukin (IL)-1beta also enhanced OIP-1
      mRNA expression in GM-CFU. To determine the participation of OIP-1 in IFN-gamma
      inhibition of OCL formation, we tested the capacity of a neutralizing antibody
      specific to OIP-1 c-peptide to inhibit IFN-gamma's effects on OCL-like cell
      differentiation of mouse macrophages, RAW 264.7 cells. Anti-OIP-1 c-peptide
      specific antibody partially neutralized IFN-gamma inhibition of OCL
      differentiation. Furthermore, OIP-1 inhibited phospho-c-Jun (p-c-Jun) kinase
      activity in RAW 264.7 cells. However, OIP-1/hSca did not affect NF-kappaB
      activation in these cells. Western blot analysis further demonstrated that OIP-1
      significantly decreased TNF receptor associated factor 2 (TRAF-2) expression in
      RAW 264.7 cells. However, OIP-1 had no effect on TRAF-6 expression in these
      cells. These data show that IFN-gamma enhances OIP-1/hSca expression in OCL
      precursors, GM-CFU, and that OIP-1 inhibits OCL formation through suppression of
      TRAF-2 and p-c-Jun kinase activity.

PMID- 12619931
TI  - Functional domains for amelogenin revealed by compound genetic defects.
AB  - We have previously used the yeast two-hybrid assay and multiple in vitro
      methodologies to show that amelogenin undergoes self-assembly involving two
      domains (A and B). Using transgenic animals, we show that unique enamel
      phenotypes result from disruptions to either the A- or B-domain, supporting the
      role of amelogenin in influencing enamel structural organization. By
      crossbreeding, animals bearing two defective amelogenin gene products have a more
      extreme enamel phenotype than the sum of the defects evident in the individual
      parental lines. At the nanoscale level, the forming matrix shows alteration in
      the size of the amelogenin nanospheres. At the mesoscale level of enamel
      structural hierarchy, 6-week-old enamel exhibits defects in enamel rod
      organization caused by perturbed organization of the precursor organic matrix.
      These studies reflect the critical dependency of amelogenin self-assembly to form
      a highly organized enamel organic matrix, and that amelogenins engineered to be
      defective in self-assembly produce compound defects in the structural
      organization of enamel.

PMID- 12619932
TI  - The effects of tamoxifen and toremifene on bone cells involve changes in plasma
      membrane ion conductance.
AB  - Selective estrogen receptor modulators (SERMs), tamoxifen (Tam) and toremifene
      (Tor), are widely used in the treatment of breast cancer. In addition, they have
      been demonstrated to prevent estrogen deficiency-induced bone loss in
      postmenopausal women. These effects are thought to be caused by the interaction
      of the SERMs with the estrogen receptor, although SERMs have also been shown to
      conduct non-receptor-mediated effects such as rapid changes in membrane
      functions. We compared the effects of Tam, Tor, and 17beta-estradiol (E2) on the
      viability of rat osteoclasts and osteoblasts. Both Tam and Tor were found to
      cause osteoclast apoptosis in in vitro cultures, which was reversed by E2. In
      addition, at higher concentration (10 microM), both SERMs had an estrogen
      receptor-independent effect, which involved interaction with the plasma membrane
      as demonstrated with UMR-108 osteosarcoma cells by Tam and Tor, but not E2. A
      leak of protons leading to changes in intracellular pH was shown both in
      medullary bone derived membrane vesicles and in intact cells. These effects were
      followed by a rapid loss of cell viability and subsequent cell lysis. Our results
      show that both Tam and Tor have an ionophoric effect on the plasma membranes of
      bone cells and that these SERMs differed in this ability: Tor induced rapid
      membrane depolarization only in the presence of high concentration of potassium.
      These non-receptor-mediated effects may be involved in therapeutic responses and
      explain some clinical side effects associated with the treatment of patients with
      these SERMs.

PMID- 12619933
TI  - Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of
      myeloma bone disease: evidence for decreased osteolysis, tumor burden and
      angiogenesis, and increased survival.
AB  - Multiple myeloma is characterized by the growth of plasma cells in the bone
      marrow and the development of osteolytic bone disease. Myeloma cells are found
      closely associated with bone, and targeting this environment may therefore affect
      both the bone disease and the growth of myeloma cells. We have investigated the
      effect of the potent bisphosphonate, zoledronic acid, on the development of bone
      disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma.
      5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice.
      After 8 weeks, all animals had a paraprotein. Animals were treated with
      zoledronic acid (120 microg/kg, subcutaneously, twice weekly) or vehicle, from
      the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks,
      respectively. All animals injected with tumor cells developed osteolytic lesions,
      a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a
      decrease in bone mineral density. Zoledronic acid prevented the formation of
      lesions, prevented cancellous bone loss and loss of bone mineral density, and
      reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein
      concentration, decreased tumor burden, and reduced angiogenesis. In separate
      experiments, Kaplan-Meier analysis demonstrated a significant increase in
      survival after treatment with zoledronic acid when compared with control (47 vs.
      35 days). A single dose of zoledronic acid was also shown to be effective in
      preventing the development of osteolytic bone disease. These data show that
      zoledronic acid is able to prevent the development of osteolytic bone disease,
      decrease tumor burden in bone, and increase survival in a model of established
      myeloma.

PMID- 12619935
TI  - Enhancement of fibronectin synthesis and fibrillogenesis by BMP-4 in cultured rat
      osteoblast.
AB  - The skeletal extracellular matrix produced by osteoblasts contains the
      glycoprotein fibronectin (Fn), which regulates the adhesion, differentiation, and
      function of osteoblasts. Fn fibrillogenesis is involved in the process of bone
      mineralization. Bone morphogenetic proteins (BMPs) can be isolated from organic
      bone matrix and are able to initiate de novo cartilage and bone formation. In
      this study, the effect of BMP-4 on Fn fibrillogenesis in cultured rat osteoblasts
      was examined. BMP-4 enhanced Fn synthesis and extracellular Fn assembly in
      primary cultured osteoblasts. In addition, the extracellular assembly of Fn from
      exogenously applied soluble human Fn was also increased by BMP-4. It has been
      reported that alpha5beta1 integrin is related to Fn fibrillogenesis. The
      synthesis of both alpha5 and beta1 integrins was upregulated by BMP-4.
      Immunocytochemistry showed that the clustering of alpha5 and beta1 integrins was
      also increased by BMP-4. BMP-4 increased fibril formation of Fn and the adhesion
      of osteoblasts onto Fn matrix, which was inhibited by disintegrin triflavin and
      Gly-Arg-Gly-Asp-Ser (GRGDS) peptide. Phosphorylation of extracellular signal
      regulated kinase (ERK) and focal adhesion kinase (FAK) was increased by BMP-4.
      Enhancement of extracellular Fn fibrillogenesis and the mRNA expression of beta1
      integrin by BMP-4 were inhibited by ERK kinase (MEK) inhibitor PD98059. These
      results suggest that the enhancement of extracellular Fn fibrillogenesis by BMP-4
      in cultured osteoblasts is related to the increase of the synthesis of Fn and
      clustering of alpha5 and beta1 integrins. ERK is involved in the signaling
      pathway of BMP-4 in regulating Fn fibrillogenesis in osteoblasts.

PMID- 12619934
TI  - S100A4: a novel negative regulator of mineralization and osteoblast
      differentiation.
AB  - S100A4 is an intracellular calcium-binding protein expressed by osteoblastic
      cells. However, its roles in bone physiology are unknown. Because before matrix
      mineralization, its expression is markedly diminished, we hypothesized that
      S100A4 negatively regulates the mineralization process. In this study, we
      investigated the effects of the inhibition of S100A4 synthesis on osteoblast
      differentiation and in vitro mineralized nodule formation. Inhibition of S100A4
      synthesis was achieved by an antisense approach in the mouse osteoblastic cell
      line MC3T3-E1. Cell clones that synthesized low levels of S100A4 (AS clones)
      produced markedly increased number of mineralized nodules at much earlier stages
      in comparison with controls as demonstrated by Alizarin red S and von Kossa
      staining. The expression of type I collagen (COLI) and osteopontin (OPN)
      increased in AS clones compared with controls. Bone sialoprotein (BSP) and
      osteocalcin (OCN), molecules associated with mineralization and markers for
      mature osteoblastic phenotype, were expressed in AS clones before their detection
      in controls. Because S100A4 was not localized in the nucleus of MC3T3-E1 cells
      and AS clones, it is unlikely that S100A4 directly regulates the expression of
      these genes. Moreover, the expression of Cbfal/Osf-2 and Osx, transcription
      factors necessary for the expression of osteoblast-associated genes, remained
      unchanged in AS clones, indicating that S100A4 may be downstream to these
      transcription factors. These findings indicate that S100A4 is a novel negative
      regulator of matrix mineralization likely by modulating the process of osteoblast
      differentiation.

PMID- 12619936
TI  - Long-term treatment of incadronate disodium accumulates microdamage but improves
      the trabecular bone microarchitecture in dog vertebra.
AB  - This study aimed to investigate the effect of long-term suppression of bone
      resorption by bisphosphonate on the microstructure, accumulation of microdamage,
      and mechanical properties of trabecular bone. Twenty-nine 1-year-old beagles (15
      males, 14 females) were divided into three groups. The control group (CNT) was
      treated daily with vehicle, and the other two groups were treated with
      incadronate at a dose of 0.3 mg/kg/day (LOW) or 0.6 mg/kg/day (HIGH) orally for 3
      years. After death, the second thoracic vertebra was scanned with microcomputed
      tomography (micro-CT) and assigned to histomorphometric and microdamage
      measurements. The fourth lumbar vertebra was mechanically tested by compression.
      Incadronate concentration in bone was measured in the 11th thoracic vertebra.
      Micro-CT analysis demonstrated a platelike trabecular structure and increased
      concave surface of trabeculae in the thoracic vertebra of incadronate-treated
      groups. Three-year incadronate treatment significantly suppressed trabecular
      activation rates by 56% in LOW and 67% in HIGH without impairment of
      mineralization, and increased microdamage accumulation in both incadronate
      treated groups. Trabecular bone volume was significantly increased in both LOW
      and HIGH groups, and vertebral strength was significantly increased in the HIGH
      group compared with the CNT group. However, intrinsic material properties such as
      normalized ultimate stress and normalized toughness were reduced in incadronate
      treated groups. Incadronate concentration in bone was dose-dependent. This study
      suggests that long-term suppression of bone remodeling increases microdamage
      accumulation, but this is not necessarily associated with vertebral fragility
      because of compensated increase of bone mass and improved microarchitecture.

PMID- 12619937
TI  - Suture growth modulated by the oscillatory component of micromechanical strain.
AB  - Sutures are fibrous connective tissue articulations between intramembranous
      craniofacial bones. Sutures are composed of fibroblastic cells with their
      matrices in the center and osteogenic cells in the periphery producing a matrix
      that is mineralized during skeletal growth. Whether oscillatory forces stimulate
      sutural growth is unknown. In the present work, we applied static and cyclic
      forces with the same peak magnitude of 5N to the maxilla in growing rabbits and
      quantified (1) acute in vivo sutural bone strain responses and (2) chronic growth
      responses in the premaxillomaxillary suture (PMS) and nasofrontal suture (NFS).
      Bone strain recordings showed that the waveforms of static force and 1-Hz cyclic
      force were expressed as corresponding static and cyclic sutural strain patterns
      in both the PMS and NFS, with the mean peak PMS strain (-1451 +/- 137
      microepsilon for the cyclic and -1572 +/- 138 microepsilon for the static)
      approximately 10-fold higher than the mean peak NFS strain (124 +/- 9
      microepsilon for the cyclic and 134 +/- 9 microepsilon for the static). Strain
      polarity was the opposite: compressive for the PMS but tensile for the NFS.
      However, on application of repetitive 5N cyclic and static forces in vivo for 10
      minutes/day over 12 days, cyclic loading induced significantly greater sutural
      widths for the compressed PMS (95.1 +/- 8.3 microm) than sham control (69.8 +/-
      8.2 microm) and static loading (58.9 +/- 2.8 microm; p < 0.01). Interestingly,
      the same trend was true for the NFS under tensile strain: significantly greater
      sutural width for cyclic loading (267.4 +/- 64.2 microm) than sham control (196.0
      +/- 10.1 microm) and static loading (169.9 +/- 11.4 microm). Cell counting in 110
      x 110 microm grids laid over sutures disclosed significantly more sutural cells
      on repetitive cyclic loading than sham control and static loading (p < 0.05) for
      both the PMS and NFS. Fluorescent labeling of newly formed sutural bone
      demonstrated more osteogenesis on cyclic loading in comparison with sham control
      and static loading. Thus, the oscillatory component of cyclic force or more
      precisely the resulting cyclic strain experienced in sutures is a potent stimulus
      for sutural growth. The increased sutural growth by cyclic mechanical strain in
      the tensed NFS and compressed PMS suggests that both microscale tension and
      compression induce anabolic sutural growth response.

PMID- 12619938
TI  - Cytokines, osteoprotegerin, and RANKL in vitro and histomorphometric indices of
      bone turnover in patients with different bone diseases.
AB  - Cytokines are supposed to play an essential role in the regulation of the bone
      metabolic unit. However, information on cytokine production of primary human
      osteoblasts from patients with metabolic bone disease is scarce, and few attempts
      have been made to correlate such data to histomorphometric parameters of
      individual patients. We investigated 11 patients with metabolic bone disease
      referred to our outpatient department for bone biopsy and analyzed interleukin
      (IL)-1, IL-6, and TNF-alpha protein release and gene expression in primary
      osteoblast cultures. Compared with four controls, five patients showed normal
      cytokine protein release, whereas six patients showed much higher levels of
      interleukin-6 (26-fold) and TNF-alpha (84-fold). All three cytokines were
      strongly correlated concerning gene expression and/or protein levels (r = 0.72
      0.96). Histomorphometric analysis of the bone samples showed that eroded surface
      (ES/BS) as a parameter of bone resorption was significantly associated with TNF
      a. In addition, RANKL gene expression was positively associated with ES/BS and
      osteoclast surface (Oc.S/BS). Finally, the formation parameters osteoid volume
      and osteoid surface were negatively associated with TNF-alpha. In conclusion, in
      an in vitro-ex vivo model of bone cells obtained from a group of 11 patients with
      different forms of metabolic bone disease, cytokine release in conditioned medium
      was significantly associated with bone resorption and bone formation, as
      quantified by histomorphometry. TNF-alpha seemed to be the more important
      cytokine; its effect on bone resorption could be mediated by RANKL.

PMID- 12619939
TI  - Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on
      cortical bone in postmenopausal women with osteoporosis.
AB  - Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant
      human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and
      nonvertebral fragility fractures and increases cancellous bone mineral density in
      postmenopausal women with osteoporosis, but its effects on cortical bone are less
      well established. This cross-sectional study assessed parameters of cortical bone
      quality by peripheral quantitative computed tomography (pQCT) in the nondominant
      distal radius of 101 postmenopausal women with osteoporosis who were randomly
      allocated to once-daily, self-administered subcutaneous injections of placebo (n
      = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained
      measurements of moments of inertia, bone circumferences, bone mineral content,
      and bone area after a median of 18 months of treatment. The results were adjusted
      for age, height, and weight. Compared with placebo, patients treated with
      teriparatide 40 microg had significantly higher total bone mineral content, total
      and cortical bone areas, periosteal and endocortical circumferences, and axial
      and polar cross-sectional moments of inertia. Total bone mineral content, total
      and cortical bone areas, periosteal circumference, and polar cross-sectional
      moment of inertia were also significantly higher in the patients treated with
      teriparatide 20 microg compared with placebo. There were no differences in total
      bone mineral density, cortical thickness, cortical bone mineral density, or
      cortical bone mineral content among groups. In summary, once-daily administration
      of teriparatide induced beneficial changes in the structural architecture of the
      distal radial diaphysis consistent with increased mechanical strength without
      adverse effects on total bone mineral density or cortical bone mineral content.

PMID- 12619940
TI  - The bone gain induced by exercise in puberty is not preserved through a virtually
      life-long deconditioning: a randomized controlled experimental study in male
      rats.
AB  - To investigate the controversial issue whether exercise-induced positive effects
      on bone can be maintained after cessation of exercise, 100 5-week-old male
      Sprague-Dawley rats were used to assess the effects of long-term exercise (EX,
      treadmill running) and subsequent deconditioning (DC, free cage activity) on the
      femoral neck and femoral midshaft. At entry, the rats were randomly assigned into
      eight groups: four control groups (C14, C28, C42, and C56), and four exercise
      groups (EX, EX + DC14, EX + DC28, and EX + DC42). Rats in the exercise groups
      were first subjected to a 14-week period of progressively intensifying running,
      after which the rats of group EX were killed and the remaining exercise groups
      (EX + DC14, EX + DC28, and EX + DC42) were allowed to move freely in their cages
      for a subsequent deconditioning period of 14, 28, or 42 weeks, whereas control
      rats were kept free in their cages for the entire study period (0-56 weeks) and
      killed with their respective exercise group. At each time point, a comprehensive
      analysis of the femoral neck and midshaft characteristics (peripheral
      quantitative computed tomography analysis and fracture load [Fmax]) was
      performed. In comparison with their age-matched controls, 14 weeks of treadmill
      training resulted in significant (p < 0.05) increases in all measured femoral
      neck parameters of the growing male rats (i.e., +25% in total cross-sectional
      area [tCSA], +28% in total bone mineral content [tBMC], +11% in total bone
      mineral density [tBMD], and +30% in Fmax). On the contrary, no exercise-induced
      positive effects were seen in femoral midshaft. The exercise-induced benefits in
      the femoral neck were partially maintained during the deconditioning period of 14
      weeks, the tCSA being + 17%, tBMC + 18% (both p < 0.05), and the Fmax + 11% (p =
      0.066) higher in the exercised group than control group. However, after 42 weeks
      of deconditioning, these benefits were eventually lost. In conclusion, exercise
      through the period of the fastest skeletal growth results in significant
      improvements in size, mineral mass, and strength of the femoral neck of male
      rats. However, these exercise-induced bone benefits are eventually lost if
      exercise is completely ceased, and thus, continued training is probably needed to
      maintain the positive effects of youth exercise into adulthood. Further studies
      should focus on assessing the minimal level of activity needed to maintain the
      exercise-induced bone gains.

PMID- 12619941
TI  - Influence of environmental cadmium exposure on forearm bone density.
AB  - Cadmium may have both direct and indirect effects on bone turnover. It is
      nephrotoxic and can interfere with vitamin D metabolism. Such perturbation may
      result in osteoporosis and osteomalacia. In this study, a total of 790 persons
      (302 males and 488 females) participated; they were all over 35 years old and
      resided in an area near a cadmium smelter in southeast China. All participants
      completed a questionnaire, and bone mineral density was measured by SPA-4 single
      photon absorptiometry at the radius and ulna. Cadmium content of urine was
      determined by graphite-furnace atomic absorption spectrophotometry as a measure
      of dose. The decline in bone mineral density with age in a heavily polluted area
      was greater than that in a control area for subjects over 60 years of age of both
      sexes (p < 0.05). In single regression, forearm bone densities were negatively
      correlated with urinary cadmium excretion in both males and females (p < 0.001),
      whereas stepwise regression showed that forearm bone density decreased linearly
      with age (p < 0.001) and urinary cadmium (p < 0.01) in both sexes, suggesting a
      dose-effect relationship between cadmium dose and bone mineral density. Based on
      the World Health Organization criteria, (bone mineral density < -2.5 SDs below
      the normal young adult), the prevalence of osteoporosis in women increased from
      34.0% in the control area to 51.9% in the heavily polluted area (p < 0.01) among
      subjects over 50 years old, and the odds ratio value was 2.09 (95% CI: 1.08-4.03)
      for the highly polluted area compared with the control area. A striking
      observation in the study was the marked increase of the prevalence of fracture in
      the cadmium-polluted area in both sexes. It was concluded that environmental
      exposure to cadmium is associated with an increased loss of bone mineral density
      in both males and females, leading to osteoporosis and increased risk of
      fractures, especially in the elderly and in females.

PMID- 12619942
TI  - Tail suspension induces bone loss in skeletally mature mice in the C57BL/6J
      strain but not in the C3H/HeJ strain.
AB  - We assessed the effects of tail-suspension in two skeletal genetic backgrounds,
      the high C3H/HeJ (C3H) and low C57BL/6J (B6) bone masses inbred mice (male, 4
      months old). Cancellous bone mass and structural parameters were evaluated in
      distal femoral metaphysis by three dimensional microcomputed tomography. Bone
      cellular activities were evaluated by histomorphometry and measurements of
      alkaline phosphatase activity (ALP) and osteocalcin in blood and
      deoxypyridinoline (D-pyr) in urine. In C3H mice, 2- and 3-week unloading
      experiments were performed. After an early and transient decrease in body weight,
      a 2-week suspension period resulted in stimulation of both bone formation rate by
      45% and active osteoclastic surfaces by 19%. D-pyr did not change, but ALP and
      osteocalcin levels increased by 18% and 72%, respectively, in 2-week suspended
      mice, and osteocalcin remained elevated by 30% in the 3-week suspended mice. Such
      cellular modifications allowed the C3H mice to maintain their initial bone mass
      and trabecular structural parameters even after a 3-week suspension period. In B6
      mice, 1- and 2-week unloading experiments were performed. Tail suspension
      resulted in decreased body weight during the first days followed by an incomplete
      recovery during the second week of unloading. The resorption activity was
      unaffected by any suspension time period, whereas a decrease of 42.5% in bone
      formation rate and of 21.5% in ALP were seen by the end of the first week of
      suspension, both values being restored after a 2-week suspension period. At this
      latter time, trabeculae were thinner, leading to a 24.5% cancellous bone loss.
      Trabecular number and connectivity, rod-plate index, and degree of anisotropy
      were not modified. We concluded that C3H mice constituted a unique model in which
      genetic background overwhelmed the usual effects of reduced biomechanical usage
      in bone, whereas B6 mice, compared with the standardized rat model, offered an
      alternative model of bone loss in a mature skeleton.

PMID- 12619943
TI  - Molecular imaging of the skeleton: quantitative real-time bioluminescence
      monitoring gene expression in bone repair and development.
AB  - Monitoring gene expression in vivo, noninvasively, is a critical issue in
      effective gene therapy systems. To date, there are no adequate molecular imaging
      techniques, which quantitatively monitor gene expression in vivo in skeletal
      development and repair. The aim of this study was to monitor gene expression in
      skeletal development and repair, using a real-time molecular imaging system,
      which quantitatively and noninvasively detects bioluminescence in vivo. Our
      experimental model consisted of transgenic mice harboring the luciferase marker
      gene under the regulation of the human osteocalcin (hOC) promoter. A new light
      detection cooled charge coupled device (CCCD) camera was applied to monitor
      luciferase expression. In vitro, mesenchymal stem cells (MSCs) isolated from bone
      marrow of transgenic mice exhibited hOC promoter regulation, detected by
      luciferase expression that correlated with their osteogenic differentiation.
      During development from 1 week to 1.5 years, transgenic mice exhibited transgene
      expression in a wide spectrum of skeletal organs, including calvaria, vertebra,
      tail, and limbs, reaching a peak at 1 week in most of the skeletal organs. In two
      skeletal repair models, bone fracture and marrow ablation, the noninvasive CCCD
      system revealed a peak of luciferase expression at 6 days postsurgery. All
      quantitative, noninvasive, real-time CCCD measurements correlated with a
      luciferase biochemical assay and luciferase immunohistochemistry, which
      demonstrated luciferase expression in hypertrophic chondrocytes and trabecular
      osteoblasts. Our studies show for the first time (1) the CCCD detection system is
      a reliable quantitative gene detection tool for the skeleton in vivo, (2)
      expression of luciferase regulated by the hOC promoter is significantly decreased
      with age in most skeletal sites, and (3) the dynamics of hOC regulation during
      mice skeletal development and repair in real time, quantitatively and
      noninvasively.

PMID- 12619944
TI  - Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by
      tumor-adjacent macrophages.
AB  - Nearly one-half of all hypercalcemic patients with lymphoma present with
      inappropriately elevated circulating concentrations of the active vitamin D
      metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3). However, the cellular source of
      the vitamin D hormone in lymphomas remains unclear. To address this, we report
      the case of a 75-year-old man with hypercalcemia associated with raised
      circulating concentrations of 1,25(OH)2D3 and suppressed parathyroid hormone
      (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT)
      imaging revealed the presence of a large lymphoma that was confined to the
      spleen; subsequent pathological analysis showed that this was an intermediate
      grade B-cell lymphoma. After surgical removal of the spleen, serum calcium and
      1,25(OH)2D3 levels became normalized within 24 h. Immunolocalization of the
      vitamin D-activating enzyme 25-hydroxyvitamin D3-1alpha-hydroxylase (la
      hydroxylase) in sections of resected spleen showed that staining was negative in
      the lymphoma cells but positive in neighboring macrophages. This case study
      indicates that the hypercalcemia associated with lymphomas may be due, in some
      instances, to excessive extrarenal production of 1,25(OH)2D3. Furthermore, by
      using immunohistochemistry to assess the distribution of la-hydroxylase, we have
      been able to show for the first time that tissue macrophages, rather than actual
      tumor cells, are the most likely ectopic source of this enzyme. Based on this
      case study, we propose that the abnormal synthesis of 1,25(OH)2D3 associated with
      some lymphomas is because of paracrine regulation of tumor-associated
      macrophages.

PMID- 12619945
TI  - Cox-2 inhibitors and fracture healing: an argument against such an effect.

PMID- 12619946
TI  - Imaging in acute abdomen.
AB  - OBJECTIVE: The present study aims at establishing the exact role and limitation
      of ultrasound in pediatric acute abdomen. METHODS: Fifty children less than 14
      years of age presenting with acute abdomen were evaluated by US and other imaging
      modalities. The mean age of presentation was 3 1/2 years. Maximum number of cases
      were seen in less than two years of age. There were 17 cases of intussusception
      with US sensitivity and specificity of 88.2% and 100% respectively and positive
      and negative predictive values of 100% and 94.5% respectively. There were 13
      cases of appendicitis. US was diagnostic in 11 with sensitivity and specificity
      of 91.6% and 97%; the positive and negative predictive values were 91.6% and 97%
      respectively. RESULTS: There were two cases each of congenital bands, adhesive
      intestinal obstruction, malrotation of bowel with volvulus, incarcerated inguinal
      hernia, hypertrophic pyloric stenosis, duplication cyst and pseudopancreatic
      cyst, one case each of trichobezoar, Meckel's diverticulum, ureteric calculus and
      worms as a cause of intestinal obstruction. The sensitivity of US for diagnosing
      specific cause of acute abdomen was found to be 77.5%. The main limitation of US
      was in the diagnosis of acute intestinal obstruction such as congenital bands and
      adhesions. CONCLUSION: US should now be considered as imaging modality of choice
      in pediatric acute abdomen. However, at times, plain radiography, conventional
      contrast studies and CT may be vital to reach the true diagnosis.

PMID- 12619947
TI  - Uncommon manifestations of shunt infection.
AB  - Shunt infection is one of the commonest and most troublesome cause of shunt
      failure. According to the etiology and clinical presentations it has been divided
      into external and internal types. METHOD: We hereby present four pediatric cases,
      who presented with atypical manifestations not coinciding with the above
      mentioned types of shunt infection. Three patients developed round, globular or
      diffuse fluctuant CSF filled swellings at the burr hole site, one of whom had
      involvement of the entire pericatheteral extent upto the abdomen. RESULT: The
      fourth child developed spontaneous expulsion of ventricular end of shunt tube
      through the dehiscent and infected chest wall incision site. CONCLUSION: First
      three of the above children were diagnosed as having internal type of shunt
      infections, while the fourth had mixed manifestations of external and internal
      type.

PMID- 12619948
TI  - Validation of hemoglobin estimation using Hemocue.
AB  - OBJECTIVE: This piece of work is an attempt to compare Hemocue and
      Cyanmethemoglobin methods for hemoglobin estimation. METHODS: In 100 apparently
      healthy children of 1-6 years of age, Hb was estimated using Hemocue and
      cyanmethemoglobin methods from finger prick blood sample. The results obtained by
      the two methods were compared using appropriate statistical methods. RESULTS:
      Mean +/- SD values for hemoglobin (g/dl) were 9.33 +/- 2.719 by Hemocue and 8.14
      +/- 2.448 by cyanmethemoglobin method. When assessed by Hemocue method the
      proportion of children with anemia was 66% while it was 88% with
      cyanmethemoglobin method. The sensitivity of Hemocue method was 0.75 and
      specificity 1.0 considering cyanmethemoglobin method as gold standard. The
      corresponding values by cyanmethemoglobin method for a given Hemocue value fell
      within the Mean difference +/- 2 SD with correlation coefficient being r = 0.922.
      Despite the good association, the two methods agreed, the magnitude of difference
      being -1.19 g/dl (CI: -1.40 to -0.98) thus suggesting an overestimate of hemocue
      values ranging from 10 to 15%. A correction factor was arrived for converting Hb
      values obtained by Hemocue method to arrive at the expected value by the
      reference method, this factor being 0.389 + 0.831 Hb (Hemocue). CONCLUSION: As
      there are limitations expressed for both the methods in accurately estimating Hb,
      it is difficult to decide whether one is an overestimate or the other an
      underestimate. By virtue of the principle involved in estimating Hb,
      cyanmethemoglobin method may be taken as an indirect indicator of iron status.
      However, it is not clear whether such a principle is involved in estimating Hb by
      Hemocue. Therefore, these two methods need to be further validated against a
      sensitive and specific indicator for iron status like circulating transferrin
      receptor to decide which of the methods can be used to accurately determine the
      prevalence of iron deficiency anemia in the community.

PMID- 12619949
TI  - Diagnosing iron deficiency in cyanotic heart disease.
AB  - OBJECTIVE: To determine the incidence of iron deficiency in children with CCHD by
      noninvasive, inexpensive and easy laboratory methods. METHODS: Forty four
      children with cyanotic congenital heart disease (CCHD), aged 6 to 48 months were
      included in this study. The patients were categorized as iron deficient (n:28)
      and iron sufficient group (n:16). Children with CCHD who had iron deficiency were
      treated with iron for 3 months. RESULT: Iron sufficient patients were followed
      during 3 months without giving iron preparation. Mean corpuscular volume (MCV),
      mean corpuscular hemoglobin (MCH), red cell distribution width (RDW), serum iron
      (SI), total iron binding capacity (TIBC) and serum ferritin levels were measured
      in all patients at the beginning and at the end of the study. CONCLUSION: In
      children with CCHD, hemoglobin (Hb), hematocrit (Hct) and red blood cell (RBC)
      counts were not considered significant parameters in the diagnosis of iron
      deficiency. Determination of MCV, MCH, RDW values is relatively easy and
      inexpensive method requiring small amount of blood for the diagnosis of iron
      deficiency during the follow-up of patients with CCHD.

PMID- 12619950
TI  - Etiology of acute lower respiratory tract infection.
AB  - OBJECTIVE: To identify pathogens responsible for acute severe lower respiratory
      tract infection (ALRTI) in under five children by non-invasive methods. METHOD:
      95 children hospitalized with acute severe lower respiratory tract infection were
      investigated for identification of viruses, bacteria, chlamydia or mycoplasma by
      nasopharyngeal aspirates, blood culture and serology. RESULT: Etiological agents
      could be identified in 94% of the patients. Viruses from NP aspirate could be
      isolated in 36 (38%), bacterial isolates from blood cultures in 15 (16%);
      mycoplasma was identified in 23 (24%) and chlamydia in 10 (11%) by serological
      tests; mixed infections were present in 8 (8%) patients. CONCLUSION: Noninvasive
      methods can be useful in identifying etiological agents in severe ALRTI.

PMID- 12619951
TI  - Mother-to-child transmission of hepatitis E virus infection.
AB  - OBJECTIVES: Water borne or enterically transmitted non-A-non-B hepatitis is a
      major public health problem in India. Many of these cases carry fatal outcome.
      The hepatitis E virus (HEV) has been considered to be the most important
      causative agent of this entity. The severity and fatality rates of HEV infection
      are reported to be rather more in pregnant women. However, there is meager
      information from India, on mother to child transmission of this agent. METHODS:
      During 1997-98, we studied 60 pregnant women suspected to have acute viral
      hepatitis to understand the frequency of various viral etiologies, disease course
      and outcome of the pregnancy. Six cord blood samples were tested for IgG, and IgM
      antibodies against hepatropic viral agents and also for hepatitis E virus RNA by
      RT-nested PCR using ORF-1 as target. RESULTS: Of the 60 pregnant patients
      hospitalised at All India Institute of Medical Sciences, New Delhi for acute
      hepatitis, 22 (37%) were positive for IgM anti-HEV antibodies and 10% were
      infected with hepatitis B virus. Co-infection of HEV with Hepatitis B and C was
      seen in 1 and 2 patents, respectively. Most (72%) of the HEV infected patients
      were in third trimester of pregnancy (P<0.05). Of the 6 cord blood samples tested
      3 (50%) were positive for HEV RNA. Though, all mothers were RNA positive, half of
      the babies did not get infected in utero with HEV. Fourteen of the 22 (63.6%) HEV
      infected mothers developed fulminant hepatic failure and all died. CONCLUSION:
      The mortality rate in HEV [corrected] infected mothers was 100%. Mother to child
      transmission of hepatitis E virus infection was established in 50%.

PMID- 12619953
TI  - Latest guidelines on neonatal resuscitation.

PMID- 12619952
TI  - What is new in pediatric cardiology.
AB  - Enormous advances in the diagnosis and management of heart disease in pediatric
      patient have taken place during the last-four decades. In this review the authors
      will concentrate on the developments within the last five to ten years. It will
      deal with what may be called medical advances. Recent advances in molecular
      genetics and defining the familial patterns have led to finding that certain
      genetic and molecular factors are linked to congenital heart disease and
      arrythmia, thus providing opportunity for improved genetic counseling and future
      gene therapy. Medical treatment of congenital heart disease targets not only the
      augmentation of ventricular contractility (positive inotropy) but also addresses
      the neuro-humoral derangement associated with it. The ultrasound technology for
      the evaluation of the heart has come a long way from the early A-mode and M-mode
      capabilities to color Doppler, 2-dimentional and 3-dimentional capabilities.

PMID- 12619954
TI  - Tuberculosis clinical grand round.

PMID- 12619955
TI  - Long-term management of asthma.
AB  - Long-term management of asthma includes identification and avoidance of
      precipitating factors of asthma, pharmacotherapy and home management plan. Common
      precipitating factors include viral upper respiratory infections, exposure to
      smoke, dust, cold food and cold air. Avoidance of common precipitating factors
      has been shown to help in better control of asthma. Pharmacotherapy is the main
      stay of treatment of asthma. Commonly used drugs for better control of asthma are
      long and short acting bronchodilators, mast cell stabilizers, inhaled steroids,
      theophylline and steroid sparing agents. After assessment of severity most
      appropriate medications are selected. For mild episodic asthma the medications
      are short acting beta agonists as and when required. For mild persistent asthma:
      as and when required bronchodilators along with a daily maintenance treatment in
      form of low dose inhaled steroids or cromolyn or oral theophylline or leukotriene
      antagonists are required. Moderate persistent asthma should be treated with
      inhaled steroids along with long acting beta agonists for symptom control. For
      severe persistent asthma the recommended treatment includes inhaled steroids,
      long acting beta agonists with or without theophylline. If symptoms are not well
      controlled, a minimal dose of oral prednisolone preferably on alternate days may
      be needed in few patients. Patients should be followed up every 8-12 weeks. On
      each follow up visit patients should be examined by a doctor, compliance to
      medications should be checked and actual inhalation technique is observed.
      Depending on the assessment, medications may be decreased or stepped up. For
      exercise induced bronchoconstriction: cromolyn, short or long acting beta
      agonists or leukotriene antagonists may be used. In children with seasonal
      asthma, maintenance treatment according to assessed severity should be started 2
      weeks in advance and continued throughout the season. These patients should be
      reassessed after discontinuing the treatment. Parents should be given a written
      plan for management of acute exacerbation at home.

PMID- 12619956
TI  - Acute liver failure.
AB  - Acute liver failure in children is associated with a high mortality. Most cases
      in our setup are due to water borne hepatotropic viruses HAV and HEV. The
      clinician must be aware of the earliest and the subtle signs of acute liver
      failure to identify cases early enough and institute supportive therapy. Focus of
      therapy has to be on prevention, early recognition and appropriate management of
      complications. Despite good intensive care, about 40-60% children with liver
      failure die. As and when liver transplantation becomes available in India, it
      would be an attractive option.

PMID- 12619957
TI  - Prenatal diagnosis.
AB  - With the leaping advances in knowledge of genetics, its applications in patient
      management are also increasing. Prenatal diagnosis is the most useful application
      as it offers prospective parents the assurance of having an unaffected child in
      situations of high recurrence risks. Pretest and post test counseling is an
      integral part of prenatal diagnosis. All Pediatricians and Obstetricians should
      be familiar with the basic prerequisites of prenatal screening/testing. Timely
      referral, preferably pre-pregnancy is important. There is more or less a
      consensus regarding offering prenatal diagnosis for lethal/chronic disabling or
      difficult/expensive to treat conditions. Ethical issues are already around
      regarding prenatal testing for disabilities like deafness and late onset
      disorders. The present communication is an effort to present the clinician's
      perspective of prenatal diagnosis.

PMID- 12619958
TI  - Cardiac rhabdomyoma and tuberous sclerosis: prenatal diagnosis and follow-up.
AB  - This article reports 4 cases with cardiac rhabdomyomas diagnosed during
      intrauterine life. Echocardiographic follow-up at 9-30 months showed regression
      of the tumors in 3 cases (75%). Two cases (50%) developed tuberous sclerosis
      during that period. Fetal echocardiography promotes early diagnosis of tuberous
      sclerosis through prenatal detection of cardiac rhabdomyoma, and facilitates
      genetic counselling of families at risk.

PMID- 12619959
TI  - Embryonal rhabdomyosarcoma of the common bile duct.
AB  - A two-and half-year-old boy presented with a short history of fever, jaundice and
      abdominal distension. At laparotomy, a rhabdomyosarcoma (RMS) arising from the
      common bile duct (CBD) was found. The tumor including the CBD was successfully
      excised and a Roux-en-Y hepaticodochojejunostomy was performed. Postoperatively,
      the child received chemotherapy and is doing well on one-year follow-up the
      recent literature on the subject is reviewed.

PMID- 12619960
TI  - Hematuria with mumps infection.
AB  - Two cases with macroscopic hematuria as complication of acute mumps infection is
      reported. The patients have neither been vaccinated against mumps nor had mumps
      infection earlier. Macroscopic hematuria resolved spontaneously and renal
      functions did not deteriorate in both the patients. Although mumps has a benign
      course, mild and rarely severe renal involvement may occur. Therefore, renal
      functions in patients with hematuria and mumps should be followed closely.

PMID- 12619961
TI  - Osteogenesis imperfecta with bleeding diathesis.
AB  - Osteogenesis imperfecta (OI) is a disorder of type 1 collagen synthesis with
      varied complications in form of brittle bones, hearing loss, dental, skin, and
      ocular changes. Osteogenesis imperfecta may have bleeding diathesis rarely due to
      defective vascular integrity for the same reason. Here we come across a rare case
      of Sillence type IB Osteogenesis imperfecta with bleeding in the form of repeated
      epistaxis and petechial rash, which seem to have a collagenous link.

PMID- 12619962
TI  - Long QT syndrome manifesting as pulseless epilepsy.
AB  - A-10-year-old child admitted with repeated seizures due to the long QT syndrome
      is described. The cardiac origin of the epilepsy was suggested by the fact that
      during the episode of convulsions his peripheral pulses were not palpable.

PMID- 12619963
TI  - Congenital varicella syndrome.
AB  - The fetal consequences of chickenpox complicating pregnancy depends on the period
      of gestation at which the infection is contracted. The extremely rare classical
      form of congenital varicella syndrome, resulting from maternal varicella
      infection in the first trimester of pregnancy, is being reported here. The
      unusual features in this baby are bilateral hypoplastic lower extremities,
      fracture of bones, a normal electroencephalogram and phantom hernias of the
      anterior abdominal wall.

PMID- 12619964
TI  - Mermaid syndrome with amniotic band disruption.
AB  - An association of Amniotic Band Disruption Sequence and Mermaid Syndrome in a
      newborn having multiple congenital anomalies is being reported. The newborn had
      aberrant string like tissues attached to the amputed fingers and toes. Adhesions
      of amniotic bands had disrupted the fetal parts especially anteriorly in the
      midline, causing multiple anomalies. Apart from these features of Amniotic Band
      Disruption Sequence, the newborn had complete fusion of the lower limbs by
      cutaneous tissue, a characteristic of Mermaid Syndrome (Sirenomelia). Associated
      malformations were anal stenosis, rectal atresia, small horseshoe kidney,
      hypoplastic urinary bladder and a bicomuate uterus. The single umbilical artery
      had a high origin, arising directly from the aorta just distal to the celiac
      axis, which is unique to sirenomelia. Theories put forward regarding the
      etiopathogenesis of both the conditions are discussed.

PMID- 12619965
TI  - Congenital insensitivity of pain with anhidrosis.
AB  - Congenital insensitivity to pain with anhidrosis is an autosomal recessive
      disorder included in a group of rare diseases termed as hereditary sensory-motor
      neuropathies. The diagnosis is made usually in early childhood period as most of
      the children present with recurrent unexplained hyperpyrexia. This case report is
      of a neonate who presented with tachypnea and fever on second day of life being
      treated for clinical sepsis and had no response to antibiotics. On pricking for
      i.v. canulation there was no cry, and temperature of the baby returned to normal
      on removing the covering blankets. Diagnosis was established by family history,
      skin and sural nerve biopsy. Early diagnosis is important for prevention of
      injury, self mutilation and growth retardation. This case report points to the
      question that should assessment of pain sensation be a part of routine
      examination of newborn.

PMID- 12619966
TI  - The making of a polio-free India.

PMID- 12619967
TI  - Radioiodination of proteins using prosthetic group: a convenient way to produce
      labelled proteins with in vivo stability.
AB  - Radiolabelled peptides can provide new approaches for radiopharmaceutical
      development. Several prosthetic groups have been developed for radioiodination of
      proteins in order to minimize in vivo dehalogenation. In this work, the
      prosthetic group N-succinimidyl 4-[131I]iodobenzoate ([131I]SIB) was obtained by
      an alternative procedure that employs Cu(I) assisted radioiododebromination to
      produce p-[131I]iodobenzoic acid with a radiochemical yield of 92.73 +/- 1.51% (N
      = 6), followed by the reaction with TSTU (O-(N-succinimidyl)-N,N,N'N'
      tetramethyluronium) in alkaline medium. The HPLC profile of the final product,
      revealed that [131I]SIB was obtained with a radiochemical purity of 98.19 +/-
      1.14% (N = 6 Swiss mices (normal group) and animals with inflammation focus
      developed on the right thigh by tupertine injection) were injected with human
      immunoglobulin (IgG) radioiodinated with [131I]SIB and by direct method
      (Iodogen). The comparison of results showed a fast blood clearance, better target
      organ/background relation and low uptake in thyroid and stomach (p < 0.01) for
      the protein labelled with [131I]SIB, what suggests a greater in vivo stability.

PMID- 12619969
TI  - The effect of murine B16F10 melanoma on the biodistribution of 99mTc-MDP in male
      C57BL/6J mice.
AB  - The biodistribution of radiopharmaceuticals used in diagnostic imaging can be
      altered by a wide variety of factors. We studied the effect of murine B16F10
      melanoma on the biodistribution in mice of 99mTechnetium-methylenediphosphonic
      acid (99mTc-MDP). Viable B16-F10 cell lines (1 x 10(5)) were inoculated
      subcutaneously in the dorsal region of 8-12 week-old male isogenic C57BV/6j mice.
      14-16 days after inoculation, 99mTc-MDP was injected in the ocular plexus and
      after 0.5 hr the animals were rapidly sacrificed. The organs and tumor were
      isolated, the mass determined and the percentage per gram of injected activity
      (%ATI/g) calculated. The results shown that the %ATI/g:i/ has not been altered in
      inguinal lymph nodes, prostate, pancreas, testis, seminal vesicle, bladder,
      kidney, stomach, small intestine, spleen, thymus, heart, lung, brain and muscle;
      but ii/ significantly decreased in thyroid, bone, blood and liver. In conclusion,
      the B16F10 melanoma can alter the 99mTc-MDP uptakes in some organs.

PMID- 12619968
TI  - Labeling and quality control of 188Re-lanreotide.
AB  - Lanreotide was labelled with 188Re obtained from 188W/188Re generator, using
      stannous ion as reducing agent, ascorbic acid as stabilizers and hydroxy
      ethylidene bisphosphonate (HEDP) as intermediary ligand at different molar
      ratios, pH and incubation times. Best yields (>95%) were obtained using molar
      ratios SnF2/lanreotide, ascorbic/lanreotide and HEDP/lanreotide of 40, 12 and
      260, respectively, pH 1-2 with an incubation at 100 degrees C for 30 min. Quality
      control evaluation and stability of the radiolabel compound was done by the
      following selected methods: chromatography in Whatman 3 MM with MEK and NaCl 0.15
      M as solvents, ITLC-SG with ethanol-HCl 0.01N (90:10); reverse phase extraction
      cartridge (Sep-pak C18, Waters Associated) and RP-HPLC with radiometric and UV
      detection (220 nm) using MCH-5 n-capp column with linear gradient from 90% H2O
      (TFA 0.1%): 10% ACN (TFA 0.1%) up to 10% H2O (TFA 0.1%):90% ACN (TFA 0.1%) in 30
      min, at flow 1 ml/min. Biodistribution in normal mice showed that 188Re
      lanreotide is excreted mainly through the hepatobiliary system: more than 70%
      I.D. is present in gallbladder and intestines at 2 hr post injection. The
      stability of the 188Re-peptide bond by cysteine challenge test at 37 degrees C,
      during 2 and 24 hr of incubation time, reveals that approximately 300 and 100
      molar ratio cys/peptide is required to displace 50% of the 188Re from the
      complex. In vitro stability of 188Re-lanreotide at room temperature (Rt) was
      demonstrated during 24 hr Future works must be done in order to investigate its
      binding capacity to somatostatin receptors.

PMID- 12619970
TI  - Effect of a chayotte (Sechium edule) extract on the labeling of red blood cells
      and plasma proteins with technetium-99m: in vitro and in vivo studies.
AB  - Sechium edule (chayotte) is used as food or as medication in popular medicine.
      The labeling of blood elements with technetium-99m (99mTc) has been altered by
      drugs (synthetic and natural). Some authors have reported biological effects
      concerning the chayotte. We have evaluated the influence of chayotte extracts
      (macerated and infusion) on the labeling of blood elements with 99mTc. In vitro
      study, blood was incubated with the extracts, (6.25, 12.5, 25, 50 and 100% v/v).
      In in vivo study, the animals were treated with the extracts (100% v/v), as
      drinking water (15 and 60 days) and samples of blood were withdrawn. The blood
      samples were incubated with stannous chloride and with 99mTc. Plasma (P) and
      blood cells (BC) were isolated, also precipitated with trichloroacetic acid and
      soluble (SF) and insoluble fractions (IF) separated. There was a (p < 0.05)
      decrease in the radioactivity in BC, IF-BC and IF-P with the infusion (100%) and
      a slight decrease in the uptake of 99mTc by BC and a strong decrease in the
      fixation in IF-P with the macerated when the extracts were administrated in vivo
      (15 days). In 60 days, there was a decrease in BC (98.77 to 53.53%), in IF-BC
      (90.36 to 21.20%) and in IF-P (77.20 to 11.01%). In vitro study no alterations on
      the labeling of blood elements were found, however, we have found alterations on
      the fixation of 99mTc in the in vivo study, probably, due to the metabolization
      of chayotte capable to induce the generation of active metabolites.

PMID- 12619971
TI  - Evaluation of the effect of mitomycin-C on the bioavailability of technetium-99m
      labelled sodium pyrophosphate in mice.
AB  - We have reported that drugs alter the biodistribution of radiopharmaceuticals
      used in diagnostic imaging in nuclear medicine. Knowledge of such altered
      biodistribution is important in making diagnostic from scintigraphy. Mitomycin-C
      is used as component of many chemotherapeutic regimens to treat different tumors.
      The biological activities of mitomycin-C can be explained by its ability to
      inhibit deoxyribonucleic acid synthesis. Since patients on chemotherapeutic
      treatment can be submitted to nuclear medicine procedures, we studied the
      mitomycin-C effect on the bioavailability of the technetium-99m-labelled sodium
      pyrophosphate (9mTc-PYP) using an animal model. Mitomycin (0.45 mg) was
      administered by ocular plexus way Balb/c mice. One hour after the last dose,
      99mTc-PYP (7.4 MBq) was administered and after 0.5 hr the animals (n = 15) were
      rapidly sacrificed. The organs were isolated, the radioactivity counted in a well
      counter and the percentage of radioactivity (%ATI) calculated. The results have
      shown that in the treated animals the %ATI has been decreased in spleen, thymus,
      heart and brain and increased in lung, liver and bone. The effect of this
      chemotherapeutic drug on the 99mTc-PYP biodistribution was statistically
      significant (Wilcoxon test, p < 0.05) and it could be explained by the
      metabolization or therapeutic action of mitomycin-C.

PMID- 12619972
TI  - Effects of the glucantime on the kinetic of biodistribution of
      radiopharmaceuticals in Wistar rats.
AB  - There are evidences that some drugs used for the human diseases can modify the
      biodistribution of radiopharmaceuticals. The N-methyl meglumine antimoniate,
      commercially known as glucantime (Rhodia, Brazil), is the elected drug for the
      treatment of all the clinical forms of leishmaniasis. As therapeutic drugs can
      present important toxic effects, we studied the effects of the glucantime on the
      kinetic of biodistribution of radiopharmaceuticals. To study the glucantime
      effect on the biodistribution of technetium-99m-methylenediphosphonic acid (99mTc
      MDP), glucantime IM (80 mg/kg/day) was administered into male Wistar rats (3
      months old age) in single dose during 7 days. 99mTc-MDP was injected 1 hr after
      the last dose. The animals (n = 24) were divided into two groups: treated (n =
      12) and control (n = 12) and they were rapidly sacrificed, respectively, in 3
      periods (5, 30 and 120 min) after administration of the 99mTc-MDP. The organs
      were isolated (brain, heart, thyroid, lungs, kidneys, testis, stomach,
      intestines, pancreas, spleen, liver, muscle, bone and bladder) and the
      percentages of radioactivity (%ATI) in each organ were calculated. The results
      were analyzed by the Wilcoxon test (p < 0.05). The analysis of the results has
      shown a significant increase of the %ATI after 5 min administration of the 99mTc
      MDP in spleen, kidneys, testis, heart, liver and a reduction of %ATI in bladder.
      Thirty minutes after administration of the 99mTc-MDP, the analysis ofthe results
      reveals a significant reduction of the %ATI in femur, kidneys, thin bowel, lungs,
      heart, liver and an increase in abdominal muscle and stout bowel. One hundred
      twenty min after administration of the 99mTc-MDP, the analysis of the results
      shows a significant reduction of the %ATI in spleen, thyroid, blood, femur,
      kidneys, liver and an increase in bladder, pancreas and lungs. Biochemical
      dosages were also performed before (control group, n = 12) and after (treated
      group, n = 12) treatment with glucantime. There was a significant (p < 0.05)
      decrease to the biochemical levels after the treatment with glucantime in
      following dosages: blood urea nitrogen, creatinine, alkaline phosphatase, lactic
      dehydrogenase, aspartate amino transferase, total creatine kinase, total protein,
      globulin and albumin. These results were compared with the control group, without
      glucantime, and statistical analyses were performed (t-student test, p < 0.05).
      These results could be associated with the biological effects and/or
      metabolization of the studied drug.

PMID- 12619973
TI  - Study of the biodistribution of the amantadine labelled with technetium-99m in
      Wistar female rats.
AB  - Amantadine (AMA) has been described as dopamine stimulant and norepineprhine
      release, capable to block the N-methyl-D aspartate (NMDA) glutamatergic and
      nicotinic receptors, enhancing the sexual behavior of the male rats and inducing
      hypersexuality in humans. The use of technetium-99m (99mTc) can be justified for
      its physical and chemical properties. The aim of this study was to label and
      evaluate the bioavailability of the AMA labelled with 99mTc (99mTc-AMA) in Wistar
      female rats. The solution of 99mTc-AMA was administered by intraperitoneal way
      and the animals were sacrificed in CO2 chamber 10 min after the administration of
      the radiotracer. Various organs were removed, weighted, their radioactivity was
      determined using an auto-gamma counter and the results were expressed as the
      percentage of the injected activity per gram of tissue (%ATI/g). In the control
      group only Na99mTcO4 was administered. The analysis of results shows that the
      highest uptakes 99mTc-AMA treated group were: ovary (7.11 +/- 1.43), spleen (3.54
      +/- 1.05), thyroid (2.67 +/- 0.15), stomach (1.56 +/- 1.10), duodenum (0.87 +/-
      0.52), muscular tissue (0.57 +/- 0.06), liver (0.52 +/- 0.25), and at control
      group: thyroid (16.45 +/- 2.57), ovary (1.28 +/- 0.12), liver (1.10 +/- 0.04),
      spleen (0.57 +/- 0.07) and muscular tissue (0.26 +/- 0.03). The results obtained
      suggest that 99mTc-AMA may be used to study the bioavailability of amantadine and
      evaluate its effect in sexual behavior in female rats.

PMID- 12619974
TI  - Effect of eggplant (Solanum melongena) extract on the in vitro labeling of blood
      elements with technetium-99m and on the biodistribution of sodium pertechnetate
      in rats.
AB  - The use of eggplant has been suggested to treat different diseases. We studied
      the effect of eggplant extract on the labeling of red blood cells (RBC) and
      plasma proteins with technetium-99m (Tc-99m) and on biodistribution of sodium
      pertechnetate (Tc-99m) in rats. Blood was incubated with an eggplant extract
      (final concentrations 3.12 to 250.00 mg/ml) for 60 min. Then, stannous chloride
      (SnCl2) (0.06 or 1.2 microg/ml) and Tc-99m, as sodium pertechnetate, were added.
      Samples of RBC and plasma (P) were separated and also precipitated and soluble
      (SF) and insoluble (IF) fractions were isolated. The percent of radioactivity
      (%ATI) in the fractions was calculated. In the biodistribution study, Wistar rats
      were treated with eggplant extract (300 mg/ml) for 4 weeks, in drinking water. Tc
      99m was administered in the rats, after 90 min they were sacrificed and organs
      and blood were isolated. When 0.06 microg/ml SnCl2 was used, eggplant extract: i/
      inhibited the label of RBC (97.14 +/- 2.01 to 52.21 +/- 3.97%ATI), ii/ decreased
      the labeling in IF-P from 38.79 +/- 11.73 to 5.49 +/- 2.65%ATI, and iii/
      diminished the labeling in IF-RBC from 90.04 +/- 2.65 to 46.17 +/- 9.49%ATI. This
      inhibitory effect was not observed with SnCl2 1.2 microg/ml. In the
      biodistribution study, the %ATI: i/ increased in the liver from 2.15 +/- 0.54 to
      3.11 +/- 1.29 and ii/ in the other organs the Tc-99m uptake was not modified. The
      uptake of Tc-99m in red blood cells protein (IF-RBC) decreased from 66.62 +/-
      19.67 to 31.66 +/- 8.84%. It is possible to suggest that some components of the
      eggplant extract present an oxidation power able to alter the fixation of the Tc
      99m on the blood elements. Moreover, as eggplant is metabolized in the liver,
      this fact could justify the alteration of the uptake in this organ.

PMID- 12619975
TI  - Assessment of the stannous fluoride and phytic acid effect in the yeast
      Saccharomyces cerevislae.
AB  - Stannous fluoride (SnF2) is a powerful reducing agent in 99mTc-labelled
      radiopharmaceuticals for nuclear medicine procedures. SnF2 may enhance reactive
      oxidative species (ROS) in prokaryotic cells. Phytic acid (PA) is a wide-ranging
      regulator of many important cellular functions such as intracellular regulations
      of surface receptions channels and it is known to have antioxidant and chelating
      properties. In order to analyze whether membrane transporters of the facilitator
      or the ABC type (SNQ1 and SNQ2) have an influence on Sn2+ toxicity in yeast we
      used the respective mutants and compared their responses to the wild type (WT).
      Since ABC transporters are YAP1p transcription activator inducible, we included a
      yap1 mutant in our Sn2+ toxicity assay. Finally, we tested the PA influence on
      Sn2+ toxicity in these strains. Yeast cells in stationary growth phase were
      exposed to different concentrations of SnF2 (ranging from 2 to 6 mg/ml) and PA
      (0.1 M) for one hour. The snq1 mutant exhibited the highest sensitivity to SnF2
      while the snq2 and snq3/yap1 mutants had an equally intermediate sensitivity. The
      presence of PA was not able to produce a significant protection against the
      cytotoxicity of SnF2. This is probably due to its reduced chelating power in
      complex liquid media Our results with yeast support the genotoxic effects
      described for SnF2 in bacteria andindicate that the biological effect of this
      reducing agent could be related to the generation of reactive oxygen species.

PMID- 12619976
TI  - Evaluation of the cytotoxic and mutagenic potentiality of technetium-99m in
      Escherichi coli.
AB  - Since technetium-99m (99mTc) was introduced in medical research it has become one
      of the most employed radionuclides in nuclear medicine. 99mTc is ideal for
      routine use on the labeling of different radiopharmaceuticals due to its
      favorable characteristics. However, some biological effects have been described.
      These effects may be related to internal conversion electron and/or Auger
      electron emissions from 99mTc decay that present high linear energy transfer and
      can generate reactive oxygen species (ROS) in the medium. We evaluated in
      Escherichia coli K12S and Salmonella typhimurium TA102, both proficient in DNA
      repair, contribution of those decay emissions on the cytotoxicity induced by
      99mTc, both either by generating lesions on DNA or by inducing alterations at
      membrane. We also studied the genotoxic and/or mutagenic potentiality of 99mTc,
      in Salmonella typhimurium, using the Ames test. The results showed that: i/ 99mTc
      is cytotoxic to the Escherichia coli K12S strains; ii/ this effect is related to
      the electrons (Auger and internal conversion) emissions, and iii/ the 99mTc is
      not mutagenic and/or genotoxic, when measured by Ames test.

PMID- 12619977
TI  - Dna damage in peripheral blood nuclear cells assessed by comet assay from
      individuals submitted to scintigraphic examinations.
AB  - Stannous chloride (SnCl2) is employed as a reducing agent to obtain Technetium
      99m-labelled radiophamaceuticals in nuclear medicine kits, being injected
      endovenously in humans. Toxic effects of these kits were not studied, thus making
      it important to evaluate their impact in humans. In this study, the toxic effects
      were evaluated from peripheral blood nuclear cells (PBNC) from patients who
      received radiopharmaceuticals obtained using such kits. The analyses included
      results performed by comet assay. DNA damage was visualized in PBNC samples
      collected within a time up to 2 hr, and 24 hr after radiopharmaceutical injection
      in the patients. Initially we observed an increase of comet signals, which
      subsequently were reduced to zero after 24 hr. The diminishing of comet amounts
      probably is associated with DNA repair of damaged cells or with the elimination
      by apoptosis of cells whose DNA are not repaired.

PMID- 12619978
TI  - Assessment of the effect of antiseizure drugs on the labeling process of red
      blood cells and plasma proteins with technetium-99m.
AB  - It is estimated that about 2.5 million people only in the United States are
      affected by epilepsy. Labelled red blood cells (RBC) and plasma proteins (PP) are
      used for several evaluations in nuclear medicine and drugs affecting those
      labelings have previously been described. The aim of this study was to evaluate
      whether the most popular antiseizure drugs interfere with the 99mTc labeling
      process of RBC and PP. Heparinized blood withdrawn from Wistar rats was incubated
      with phenobarbital (0.2, 2, 20, 200, 2,000 microg/ml), phenytoin (0.15, 1.5, 15,
      150, 1,500 microg/ml), carbamazepine (0.7, 7, 70 microg/ml), clonazepam (0.5, 5,
      50, 500 microg/ml) or valproic acid (0.5, 5, 50, 500 microg/ml) for I hr.
      Stannous chloride (SnCl2), in two different concentrations (0.012 or 1.2
      microg/ml) and 99mTc were added. Plasma and cellular fractions were isolated by
      centrifugation, soluble and insoluble fractions were separated by trichloroacetic
      acid precipitation. The percentage of radioactivity was calculated for each
      fraction. Statistical analysis was performed with ANOVA and Dunnet tests. The
      analysis of the results has shown that phenobarbital (2,000 microg/ml) and
      clonazepam (50 microg/ml) significantly have reduced the RBC labeling efficiency
      when it was used the optimal SnCl2 concentration (1.2 microg/ml) and clonazepam
      (5, 50 microg/ml) has significantly decreased the PP labeling efficiency with
      99mTc. Phenytoin (1,500 microg/ml) has decreased the RBC labeling efficiency when
      the experiments were carried out with a small SnCl2 concentration (0.012
      microg/ml). We can suggest that with this in vitro assay, at the therapeutic
      level of phenytoin, phenobarbital, carbamazepine and valproic acid will not
      interfere on the 99mTc labeling process of RBC. Interference is displayed at
      higher phenobarbital concentrations (2,000 microg/ml). However, humans do not
      tolerate this concentration. On the other hand, a decreased RBC and PP labeling
      efficiency with 99mTc may be expected for clonazepam at therapeutic levels.

PMID- 12619979
TI  - Sterilization of skin allografts by ionizing radiation.
AB  - The skin has a fundamental role in the viability of human body. In the case of
      extensive wounds, skin allografts provide an alternative to cover temporarily the
      damaged areas. After donor screening and preservation in glycerol 85%, the skin
      can be stored in a Skin Bank. Glycerol at this concentration has a bacteriostatic
      effect after certain time of preservation. On the other hand, skin sterilization
      by ionizing radiation may reduce the quarentine period for transplantation in
      patients. The objective of this work was to evaluate allograft sterilization
      using two sources of ionizing radiation. Through the analysis of stress-strain,
      it was intended to verify possible effects of the radiation on the structure of
      preserved grafts. Three groups of skin samples were selected. The first group was
      maintained in the initial conditions, not irradiated. The second was exposed to
      cobalt-60, while the third one was irradiated using an Dynamitron Accelerator
      JOB188 electron beam. The irradiation dose was 25 kGy for both tests. Both
      irradiation sources, and the Instron Universal Machine used for biomechanical
      experiments, are installed at the Centro de Tecnologia das Radiacoes/Instituto de
      Pesquisas Energeticas e Nucleares (Sao Paulo, Brazil). According to the
      preliminary results, biomechanical characteristics of the samples irradiated seem
      to be maintained with regard to the non irradiated group.

PMID- 12619980
TI  - Unstable chromosome aberrations in peripheral blood lymphocytes from patients
      with cervical uterine cancer following radiotherapy.
AB  - Scoring of unstable chromosomes aberrations (dicentrics, rings and fragments) in
      circulating lymphocytes is the most extensively studied biologic system for
      estimating individual exposure to ionizing radiation. In this work, blood samples
      from 5 patients, with cervical uterine cancer, were analyzed by conventional
      cytogenetic in order to correlate the frequency of chromosome aberrations in
      lymphocytes with the dose absorbed by the patient, as a result of radiotherapy
      with 60Co gamma. The samples were collected in three phases of the treatment:
      before irradiation, 24 hr after receiving 0.08 Gy and 1.8 Gy, respectively. On
      the basis of the frequencies of unstable aberrations observed, a good agreement
      was obtained between doses estimated by calibration curve and the doses
      previously planned to radiotherapy. This report discusses the methodology
      employed as an important tool for dose assessment as a result of partial-body
      exposure to ionizing radiation.

PMID- 12619981
TI  - The use of neutron radiography in agriculture to improve the food quality.
AB  - The report presented in the 7th ONU's Conference (USA, 2001) about climatic
      changes that took place at the end of 2001 informs that, in less than 50 years,
      more than 45% of the world population will be suffering from lack of water. This
      fact occurs by the absence of management on water resources, mainly, in
      agriculture. As the excess as the lack of humidity in soil can change the harvest
      quality, causing physiologic anomalies in food and promoting soil diseases
      incidence caused by bacteria and fungus. In order to establish a larger control
      in the food quality, a study has been performed, through the neutron radiographic
      technique, that proposes the optimization of agricultural harvests in relation to
      the minimum quantity of water necessary for the plant to develop and, also, of
      the soil compactness. Thus, neutron radiographic images of the system root-soil
      can be produced so that each root will be evaluated for its ability to penetrate
      in the soil layers, having the advantage of not interfering in this system what
      it is not possible through the usual techniques yet. The initial tests using bean
      roots showed that the soil thickness, which involved the roots, resulted in low
      contrast images, what impeded their visualization with enough clearness so that
      their grow could not be observed. For this reason, it was opted to the gadolinium
      as a contrast agent so that we have been studying its transport through the
      roots.

PMID- 12619982
TI  - Structural and functional diversity of glycoconjugates: a formidable challenge to
      the glycoanalyst.

PMID- 12619983
TI  - Chemical and enzymatic release of glycans from glycoproteins.

PMID- 12619984
TI  - Derivatization of carbohydrates.

PMID- 12619986
TI  - Monosaccharide analysis by capillary electrophoresis.

PMID- 12619985
TI  - Preparation of oligosaccharides from sulfated glycosaminoglycans using bacterial
      enzymes.

PMID- 12619987
TI  - Separation of oligosaccharides by capillary electrophoresis using buffer
      modifiers.

PMID- 12619988
TI  - Characterization of oligosaccharides from starch, dextran, cellulose, and
      glycoproteins by capillary electrophoresis.

PMID- 12619989
TI  - Affinity capillary electrophoresis of oligosaccharides.

PMID- 12619990
TI  - Characterization of glycosaminoglycans by capillary electrophoresis.

PMID- 12619991
TI  - Analysis of 2-aminoacridone-derivatized complex oligosaccharides using micellar
      electrokinetic capillary chromatography and laser-induced fluorescence detection.

PMID- 12619992
TI  - Separation of protein glycoforms by capillary electrophoresis.

PMID- 12619993
TI  - Separation of glycoproteins by capillary isoelectric focusing.

PMID- 12619994
TI  - Glycoprotein analysis by capillary zone electrophoresis-electrospray mass
      spectrometry.

PMID- 12619995
TI  - Analysis of bacterial glycolipids by capillary electrophoresis-electrospray mass
      spectrometry: Haemophilus influenzae and Neisseria meningitidis
      lipopolysaccharides.

PMID- 12619996
TI  - Capillary electrophoresis as an assay method for monitoring glycosyltransferase
      activity.

PMID- 12619997
TI  - Determination of association constant of carbohydrate-protein interaction.

PMID- 12619998
TI  - Structures of carbohydrates found n animals and bacteria.

PMID- 12619999
TI  - Southern California's marine monitoring system ten years after the National
      Research Council evaluation.
AB  - In 1990, the National Research Council (NRC) published two in-depth assessments
      of marine environmental monitoring effectiveness. The first of these, Managing
      Troubled Waters: The Role of Marine Environmental Monitoring, provided a national
      perspective and the second, Monitoring Southern California's Coastal Waters,
      examined the specifics of monitoring design and implementation in a densely
      populated, highly urbanized coastal region. The reports include explicit
      recommendations about the need for greater regionalization of monitoring efforts,
      supported by greater standardization of field, laboratory, and data analysis
      methods. They also identified the need for centralized data management and for
      greater flexibility in the language of standard discharge permits, flexibility
      that would permit discharge agencies to more readily participate in regional
      monitoring and research programs. Other recommendations identified a need for EPA
      and NOAA to focus on creating a national monitoring program structured as a
      network of coordinated local and regional efforts. Finally, the NRC emphasized
      the need for better reporting and for periodic review of monitoring's relevance
      to management concerns. In this paper, we use southern California as a test case
      to assess progress made in implementing the NRC's recommendations. We review
      progress made on each recommendation and discuss the features of the regulatory
      and management climate that contributed to or impeded this progress. We also
      consider whether, and to what extent, the NRC's recommendations remain relevant
      in the present context.

PMID- 12620000
TI  - Effective application of monitoring information: the case of San Francisco Bay.
AB  - The San Francisco Estuary Regional Monitoring Program (RMP) for Trace Substances
      is an innovative partnership among a regulatory agency, more than 70 regulated
      entities, and an independent scientific organization. The institutional
      arrangement behind the RMP has made the regulatory system increasingly responsive
      to emerging management needs, particularly with regard to the development of
      total maximum daily loads and ecosystem impairment assessment. Through
      multiagency partnerships within and outside the RMP institutional structure,
      major information gaps for several pollutants of concern have been narrowed,
      resulting in a successful consensus-based regulatory approach to managing copper
      and nickel mass inputs into the Estuary. Short-term research efforts, based upon
      monitoring results, helped identify the most cost-effective control and
      remediation options for various bioaccumulative substances. Additionally,
      adaptive changes to the monitoring program documented the existence of widespread
      aquatic toxicity in the Estuary that is apparently due to pesticide runoff from
      agricultural and urban areas. One of the most important contributions of this
      collaborative monitoring program is the deliberate and systematic adjustment of
      management and research questions that serve to influence and add relevance to
      the overall research agenda related to San Francisco Estuary ecosystem
      assessment.

PMID- 12620001
TI  - Bi-national assessment of the Great Lakes: SOLEC partnerships.
AB  - Many administrative jurisdictions have authority over parts of the Great Lakes,
      sometimes with competing purposes as well as governance at differing scales of
      time and space. As demand increases for high quality information that is relevant
      to environmental managers, environmental and natural resource agencies with
      limited budgets must look to interdisciplinary, collaborative approaches for the
      collection, analysis and reporting of data. The State of the Lakes Ecosystem
      Conferences (SOLEC) were begun in 1994 in response to reporting requirements of
      the Great Lakes Water Quality Agreement between Canada and the U.S. The biennial
      conferences provide independent, science-based reporting on the state of health
      of the Great Lakes ecosystem components. A suite of indicators necessary and
      sufficient to assess Great Lakes ecosystem status was introduced in 1998. and
      assessments based on a subset of the indicators were presented in 2000. Because
      SOLEC is a multi-agency, multi-jurisdictional reporting venue, the SOLEC
      indicators require acceptance by a broad spectrum of stakeholders in the Great
      Lakes basin. The SOLEC indicators list is expected to provide the basis for
      government agencies and other organizations to collaborate more effectively and
      to allocate resources to data collection, evaluation and reporting on the state
      of the Great Lakes basin ecosystem.

PMID- 12620002
TI  - The MYSound Project: building an estuary-wide monitoring network for Long Island
      Sound, USA.
AB  - A network of five water quality monitoring stations has been established in Long
      Island Sound, measuring temperature, salinity, and dissolved oxygen since 1999.
      The stations are located in areas of extreme water quality degradation (western
      Long Island Sound) as well as in pristine areas (eastern Long Island Sound). The
      data from these stations are collected every 15 minutes and posted to the project
      web site in real time as provisional data. After subsequent quality assurance
      procedures, the data are archived to the project File Transfer Protocol (FSP)
      site for downloading by the user community. The network of stations is in part
      supported logistically by a number of partners, including state and local
      agencies, schools, and non-governmental organizations. Data from the monitoring
      programs of some of these partners are also published to the project website
      providing a more comprehensive and complete picture of the status of the Sound
      than can be provided independently. This repository of information is used by
      marine educators, resource managers, scientists, and the general public, each
      with a different end purpose. We use the data from two of the stations to show
      that these high frequency time series measurements can be used to complement and
      enhance other monitoring programs within the Sound, documenting in greater detail
      the occurrence and duration of hypoxic events.

PMID- 12620003
TI  - Conservation and management applications of the REEF volunteer fish monitoring
      program.
AB  - The REEF Fish Survey Project is a volunteer fish monitoring program developed by
      the Reef Environmental Education Foundation (REEF). REEF volunteers collect fish
      distribution and abundance data using a standardized visual method during regular
      diving and snorkeling activities. Survey data are recorded on preprinted data
      sheets that are returned to REEF and optically digitized. Data are housed in a
      publicly accessible database on REEF's Web site (http://www.reef.org). Since the
      project's inception in 1993, over 40,000 surveys have been conducted in the
      coastal waters of North America, tropical western Atlantic, Gulf of California
      and Hawaii. The Fish Survey Project has been incorporated into existing
      monitoring programs through partnerships with government agencies, scientists,
      conservation organizations, and private institutions. REEF's partners benefit
      from the educational value and increased stewardship resulting from volunteer
      data collection. Applications of the data include an evaluation of fish/habitat
      interactions in the Florida Keys National Marine Sanctuary, the development of a
      multi-species trend analysis method to identify sites of management concern,
      assessment of the current distribution of species, status reports on fish
      assemblages of marine parks, and the evaluation of no-take zones in the Florida
      Keys. REEF's collaboration with a variety of partners, combined with the Fish
      Survey Project's standardized census method and database management system, has
      resulted in a successful citizen science monitoring program.

PMID- 12620004
TI  - The coastal component of the U.S. integrated ocean observing system.
AB  - The combined effects of human activities and natural variability present
      significant challenges to the goals of protecting, restoring, and sustaining
      coastal ecosystems. Meeting these challenges and resolving conflicts in an
      informed fashion will require: (1) more timely detection and prediction of
      environmental changes and their consequences; and (2) more timely access to
      relevant environmental information. The achievement of these goals depends on the
      development of a sustained and integrated coastal ocean observing system (ICOOS)
      that insures timely access to the data and information required to improve: (1)
      climate predictions and the effects of changes in the weather on coastal
      populations; (2) efforts to sustain and restore healthy coastal marine ecosystems
      and living marine resources; and (3) compliance monitoring and evaluations of the
      efficacy of environmental policies. Although the responsible federal and state
      agencies all require similar environmental information, many separate programs
      have evolved for collecting, managing, and analyzing data for various purposes.
      Consequently, there is too much redundancy; access to diverse data from disparate
      sources is limited and time consuming; and individual programs are inevitably
      underfunded and too limited in scope. A system is needed that coordinates and
      integrates many of the elements of these programs to minimize redundancy, be more
      comprehensive, provide more timely access to data and information, and satisfy
      the information needs of a greater number of user groups in a more cost-effective
      fashion. This is the purpose of the ICOOS.

PMID- 12620005
TI  - Great Lakes monitoring results--comparison of probability based and deterministic
      sampling grids.
AB  - The Great Lakes may be viewed as a coastal environment, affected by the same
      meteorological and physical forces as the coastal ocean. The U.S. EPA, Great
      Lakes National Program Office (GLNPO) has monitored the open waters of the lakes,
      annually, since 1983. As part of the U.S. EPA Environmental Monitoring and
      Assessment Program (EMAP), a pilot study was performed in Lake Michigan to
      compare the existing GLNPO deterministic sampling grid with the EMAP
      probabilistic grid. Results of chemical analyses of trophic status indicators
      (total phosphorus and chlorophyll a) as well as nutrients and conventional
      limnological measurements, from spring and summer surveys in 1992 indicate little
      difference between the grids in the offshore region of the lake. The few
      statistically significant differences may be due to station distribution
      throughout the lake, or simple chance. This might be expected due to the well
      mixed nature of the open waters of Lake Michigan. The detection of a long-term
      trend for total phosphorus in Lake Michigan benefits from an annual program:
      viewing cumulative frequency distributions based on a four year EMAP interval
      does not convey information on the decrease in phosphorus in the lake. If the
      EMAP sampling grid were to be used in the Great Lakes, pilots in each of the
      lakes would be necessary for utilization of the existing long-term record as a
      basis for trend detection.

PMID- 12620006
TI  - A hydrologic network supporting spatially referenced regression modeling in the
      Chesapeake Bay Watershed.
AB  - The U.S. Geological Survey has developed a methodology for statistically relating
      nutrient sources and land-surface characteristics to nutrient loads of streams.
      The methodology is referred to as SPAtially Referenced Regressions On Watershed
      attributes (SPARROW), and relates measured stream nutrient loads to nutrient
      sources using nonlinear statistical regression models. A spatially detailed
      digital hydrologic network of stream reaches, stream-reach characteristics such
      as mean streamflow, water velocity, reach length, and travel time, and their
      associated watersheds supports the regression models. This network serves as the
      primary framework for spatially referencing potential nutrient source information
      such as atmospheric deposition, septic systems, point-sources, land use, land
      cover, and agricultural sources and land-surface characteristics such as land
      use, land cover, average-annual precipitation and temperature, slope, and soil
      permeability. In the Chesapeake Bay watershed that covers parts of Delaware,
      Maryland, Pennsylvania, New York, Virginia, West Virginia, and Washington D.C.,
      SPARROW was used to generate models estimating loads of total nitrogen and total
      phosphorus representing 1987 and 1992 land-surface conditions. The 1987 models
      used a hydrologic network derived from an enhanced version of the U.S.
      Environmental Protection Agency's digital River Reach File, and course resolution
      Digital Elevation Models (DEMs). A new hydrologic network was created to support
      the 1992 models by generating stream reaches representing surface-water pathways
      defined by flow direction and flow accumulation algorithms from higher resolution
      DEMs. On a reach-by-reach basis, stream reach characteristics essential to the
      modeling were transferred to the newly generated pathways or reaches from the
      enhanced River Reach File used to support the 1987 models. To complete the new
      network, watersheds for each reach were generated using the direction of surface
      water flow derived from the DEMs. This network improves upon existing digital
      stream data by increasing the level of spatial detail and providing consistency
      between the reach locations and topography. The hydrologic network also aids in
      illustrating the spatial patterns of predicted nutrient loads and sources
      contributed locally to each stream, and the percentages of nutrient load that
      reach Chesapeake Bay.

PMID- 12620007
TI  - The importance of considering spatial attributes in evaluating estuarine habitat
      condition: the South Carolina experience.
AB  - The South Carolina Estuarine and Coastal Assessment Program (SCECAP) was
      initiated in 1999 to assess the condition of the state's coastal habitats using
      multiple measures of water quality, sediment quality, and biological condition.
      Sampling was subsequently expanded to include components required for the
      National Coastal Assessment (Coastal 2000) Program. Habitats are classified as
      either "tidal creeks" (< 100 meters in width) or larger "open water" bodies.
      Approximately 30 sites are sampled within each habitat during the summer months
      using a probability-based random sampling design. Results obtained from the first
      two years of sampling documented significant differences in several water quality
      parameters (DO, salinity, pH, turbidity, fecal coliform bacteria, total nitrogen,
      TKN, total phosphorus) and biological measures (chlorophyll-a, finfish and
      crustacean abundance and biomass and a number of benthic species) between the
      tidal creek and open water habitats. These differences highlight the value of
      partitioning shallow water habitats separately from the larger open water bodies
      traditionally sampled in estuarine monitoring programs, especially since tidal
      creeks serve as critical nursery areas for many species. Based on the differences
      observed, there is a clear need to identify different physical and biological
      thresholds for evaluating the condition of each habitat type.

PMID- 12620008
TI  - Living with a large reduction in permited loading by using a hydrograph
      controlled release scheme.
AB  - The Total Maximum Daily Load (TMDL) for ammonia and biochemical oxygen demand for
      the Pee Dee, Waccamaw, and Atlantic Intracoastal Waterway system near Myrtle
      Beach, South Carolina, mandated a 60-percent reduction in point-source loading.
      For waters with a naturally low background dissolved-oxygen concentrations, South
      Carolina anti-degradation rules in the water-quality regulations allows a
      permitted discharger a reduction of dissolved oxygen of 0.1 milligrams per liter
      (mg/L). This is known as the "0.1 rule." Permitted dischargers within this region
      of the State operate under the "0.1 rule" and cannot cause a cumulative impact
      greater than 0.1 mg/L on dissolved-oxygen concentrations. For municipal water
      reclamation facilities to serve the rapidly growing resort and retirement
      community near Myrtle Beach, a variable loading scheme was developed to allow
      dischargers to utilize increased assimilative capacity during higher streamflow
      conditions while still meeting the requirements of a recently established TMDL.
      As part of the TMDL development, an extensive real-time data-collection network
      was established in the lower Waccamaw and Pee Dee River watershed where
      continuous measurements of streamflow, water level, dissolved oxygen,
      temperature, and specific conductance are collected. In addition, the dynamic
      BRANCH/BLTM models were calibrated and validated to simulate the water quality
      and tidal dynamics of the system. The assimilative capacities for various
      streamflows were also analyzed. The variable-loading scheme established total
      loadings for three streamflow levels. Model simulations show the results from the
      additional loading to be less than a 0. 1 mg/L reduction in dissolved oxygen. As
      part of the loading scheme, the real-time network was redesigned to monitor
      streamflow entering the study area and water-quality conditions in the location
      of dissolved-oxygen "sags." The study reveals how one group of permit holders
      used a variable-loading scheme to implement restrictive permit limits without
      experiencing prohibitive capital expenditures or initiating a lengthy appeals
      process.

PMID- 12620009
TI  - A proposed coast-wide reference monitoring system for evaluating wetland
      restoration trajectories in Louisiana.
AB  - Wetland restoration efforts conducted in Louisiana under the Coastal Wetlands
      Planning, Protection and Restoration Act require monitoring the effectiveness of
      individual projects as well as monitoring the cumulative effects of all projects
      in restoring, creating, enhancing, and protecting the coastal landscape. The
      effectiveness of the traditional paired-reference monitoring approach in
      Louisiana has been limited because of difficulty in finding comparable reference
      sites. A multiple reference approach is proposed that uses aspects of
      hydrogeomorphic functional assessments and probabilistic sampling. This approach
      includes a suite of sites that encompass the range of ecological condition for
      each stratum, with projects placed on a continuum of conditions found for that
      stratum. Trajectories in reference sites through time are then compared with
      project trajectories through time. Plant community zonation complicated selection
      of indicators, strata, and sample size. The approach proposed could serve as a
      model for evaluating wetland ecosystems.

PMID- 12620010
TI  - Stormwater toxicity in Chollas Creek and San Diego Bay, California.
AB  - Stormwater discharges from Chollas Creek, a tributary of San Diego Bay, have been
      shown to be toxic to aquatic life. The primary objective of this study was to
      provide the linkage between in-channel measurements and potential impairments in
      the receiving waters of San Diego Bay. This study addressed this objective within
      the context of four questions: (1) How much area in San Diego Bay is affected by
      the discharge plume from Chollas Creek during wet-weather conditions?; (2) How
      much of the wet-weather discharge plume is toxic to marine aquatic life?; (3) How
      toxic is this area within the wet-weather discharge plume?; and (4) What are the
      constituent(s) responsible for the observed toxicity in the wet-weather plume?
      The stormwater plume emanating from Chollas Creek was dynamic, covering areas up
      to 2.25 km2. Approximately half of the plume was estimated to be toxic to marine
      life, based upon the results of purple sea urchin (Strongylocentroutus
      purpuratus) fertilization tests. The area nearest the creek mouth was the most
      toxic (NOEC = 3 to 12% plume sample), and the toxicity decreased with distance
      from the creek mouth. The toxicity of plume samples was directly proportional to
      the magnitude of plume mixing and dilution until, once outside the plume margin,
      no toxicity was observed. Trace metals, most likely zinc, were responsible for
      the observed plume toxicity based upon toxicity identification evaluations
      (TIEs). Zinc was also the constituent identified from in-channel samples of
      Chollas Creek stormwater using TIEs on the storms sampled in this study, and in
      storms sampled during the previous storm season.

PMID- 12620011
TI  - Managing troubled data: coastal data partnerships smooth data integration.
AB  - Understanding the ecology, condition, and changes of coastal areas requires data
      from many sources. Broad-scale and long-term ecological questions, such as global
      climate change, biodiversity, and cumulative impacts of human activities, must be
      addressed with databases that integrate data from several different research and
      monitoring programs. Various barriers, including widely differing data formats,
      codes, directories, systems, and metadata used by individual programs, make such
      integration troublesome. Coastal data partnerships, by helping overcome
      technical, social, and organizational barriers, can lead to a better
      understanding of environmental issues, and may enable better management
      decisions. Characteristics of successful data partnerships include a common need
      for shared data, strong collaborative leadership, committed partners willing to
      invest in the partnership, and clear agreements on data standards and data
      policy. Emerging data and metadata standards that become widely accepted are
      crucial. New information technology is making it easier to exchange and integrate
      data. Data partnerships allow us to create broader databases than would be
      possible for any one organization to create by itself.

PMID- 12620012
TI  - Incidence of stress in benthic communities along the U.S. Atlantic and Gulf of
      Mexico coasts within different ranges of sediment contamination from chemical
      mixtures.
AB  - Synoptic data on concentrations of sediment-associated chemical contaminants and
      benthic macroinfaunal community structure were collected from 1,389 stations in
      estuaries along the U.S. Atlantic and Gulf of Mexico coasts as part of the
      nationwide Environmental Monitoring and Assessment Program (EMAP). These data
      were used to develop an empirical framework for evaluating risks of benthic
      community-level effects within different ranges of sediment contamination from
      mixtures of multiple chemicals present at varying concentrations. Sediment
      contamination was expressed as the mean ratio of individual chemical
      concentrations relative to corresponding sediment quality guidelines (SQGs),
      including Effects Range-Median (ERM) and Probable Effects Level (PEL) values.
      Benthic condition was assessed using diagnostic, multi-metric indices developed
      for each of three EMAP provinces (Virginian, Carolinian, and Louisianian).
      Cumulative percentages of stations with a degraded benthic community were plotted
      against ascending values of the mean ERM and PEL quotients. Based on the observed
      relationships, mean SQG quotients were divided into four ranges corresponding to
      either a low, moderate, high, or very high incidence of degraded benthic
      condition. Results showed that condition of the ambient benthic community
      provides a reliable and sensitive indicator for evaluating the biological
      significance of sediment-associated stressors. Mean SQG quotients marking the
      beginning of the contaminant range associated with the highest incidence of
      benthic impacts (73-100% of samples, depending on the province and type of SQG)
      were well below those linked to high risks of sediment toxicity as determined by
      short-term toxicity tests with single species. Measures of the ambient benthic
      community reflect the sensitivities of multiple species and life stages to
      persistent exposures under actual field conditions. Similar results were obtained
      with preliminary data from the west coast (Puget Sound).

PMID- 12620013
TI  - Application of the benthic index of biotic integrity to environmental monitoring
      in Chesapeake Bay.
AB  - The Chesapeake Bay benthic index of biotic integrity (B-IBI) was developed to
      assess benthic community health and environmental quality in Chesapeake Bay. The
      B-IBI provides Chesapeake Bay monitoring programs with a uniform tool with which
      to characterize bay-wide benthic community condition and assess the health of the
      Bay. A probability-based design permits unbiased annual estimates of areal
      degradation within the Chesapeake Bay and its tributaries with quantifiable
      precision. However, of greatest interest to managers is the identification of
      problem areas most in need of restoration. Here we apply the B-IBI to benthic
      data collected in the Bay since 1994 to assess benthic community degradation by
      Chesapeake Bay Program segment and water depth. We used a new B-IBI
      classification system that improves the reliability of the estimates of
      degradation. Estimates were produced for 67 Chesapeake Bay Program segments.
      Greatest degradation was found in areas that are known to experience hypoxia or
      show toxic contamination, such as the mesohaline portion of the Potomac River,
      the Patapsco River, and the Maryland mainstem. Logistic regression models
      revealed increased probability of degraded benthos with depth for the lower
      Potomac River, Patapsco River. Nanticoke River, lower York River, and the
      Maryland mainstem. Our assessment of degradation by segment and water depth
      provided greater resolution of relative condition than previously available, and
      helped define the extent of degradation in Chesapeake Bay.

PMID- 12620014
TI  - Spatial scales and probability based sampling in determining levels of benthic
      community degradation in the Chesapeake Bay.
AB  - The extent of degradation of benthic communities of the Chesapeake Bay was
      determined by applying a previously developed benthic index of biotic integrity
      at three spatial scales. Allocation of sampling was probability-based allowing
      areal estimates of degradation with known confidence intervals. The three spatial
      scales were: (1) the tidal Chesapeake Bay; (2) the Elizabeth River watershed: and
      (3) two small tidal creeks within the Southern Branch of the Elizabeth River that
      are part of a sediment contaminant remediation effort. The areas covered varied
      from 10(-1) to 10(4) km2 and all were sampled in 1999. The Chesapeake Bay was
      divided into ten strata, the Elizabeth River into five strata and each of the two
      tidal creeks was a single stratum. The determination of the number and size of
      strata was based upon consideration of both managerially useful units for
      restoration and limitations of funding. Within each stratum 25 random locations
      were sampled for benthic community condition. In 1999 the percent of the benthos
      with poor benthic community condition for the entire Chesapeake Bay was 47% and
      varied from 20% at the mouth of the Bay to 72% in the Potomac River. The
      estimated area of benthos with poor benthic community condition for the Elizabeth
      River was 64% and varied from 52-92%. Both small tidal creeks had estimates of
      76% of poor benthic community condition. These kinds of estimates allow
      environmental managers to better direct restoration efforts and evaluate progress
      towards restoration. Patterns of benthic community condition at smaller spatial
      scales may not be correctly inferred from larger spatial scales. Comparisons of
      patterns in benthic community condition across spatial scales, and between
      combinations of strata, must be cautiously interpreted.

PMID- 12620015
TI  - An approach for identifying the causes of benthic degradation in Chesapeake Bay.
AB  - We developed an index to differentiate between low dissolved oxygen effects and
      sediment contamination effects for sites classified as degraded by the Chesapeake
      Bay Benthic Index of Biotic Integrity (B-IBI), using discriminant analysis. We
      tested 126 metrics for differences between sites with low dissolved oxygen and
      sites with contaminated sediments. A total of 16 benthic community metrics met
      the variable selection criteria and were used to develop a discriminant function
      that classified degraded sites into one of two stress groups. The resulting
      discriminant function correctly classified 77% of the low dissolved oxygen sites
      and 80% of the contaminated sites in the validation data.

PMID- 12620016
TI  - Variability in the identification and enumeration of marine benthic invertebrate
      samples and its effect on benthic assessment measures.
AB  - Studies designed to measure anthropogenic impacts on marine benthic communities
      depend on the ability of taxonomists to consistently discriminate, identify, and
      count benthic organisms. To quantify errors and discrepancies in identification
      and enumeration, 20 samples were completely reprocessed by another one of four
      participating laboratories. Errors were detected in 13.0% of the data records,
      affecting total abundance by 2.1%, numbers of taxa by 3.4%, and identification
      accuracy by 4.7%. Paired t-tests were used to test for differences in the Benthic
      Response Index (BRI), total abundance, numbers of taxa, and the Shannon-Wiener
      index between the original and the reanalysis data. Differences in the BRI were
      statistically insignificant. Although statistically significant differences were
      observed for numbers of taxa, total abundance, and the Shannon-Wiener index, the
      differences were small in comparison to the magnitude of differences typically
      observed between anthropogenically affected and reference sites.

PMID- 12620017
TI  - Production, respiration and net ecosystem metabolism in U.S. estuaries.
AB  - Primary production, respiration, and net ecosystem metabolism (NEM) are useful
      indicators of ecosystem level trophic conditions within estuaries. In this study,
      dissolved oxygen data collected every half hour between January 1996 to December
      1998 by the National Estuarine Research Reserve System Wide Monitoring Program
      were used to calculate primary production, respiration, and net ecosystem
      metabolism. Data from two sites at each of 14 Reserves were analyzed. On average,
      three quarters of the data available could be used to calculate metabolic rates.
      Data from two of the Reserves were used to evaluate the assumption of homogeneity
      of water masses moving past the oxygen sensor. Temperature was the single most
      important factor controlling metabolic rates at individual sites, although
      salinity was also important at about half the sites. On an annual basis,
      respiration exceeded gross primary production demonstrating that all but 4 of the
      28 sites were heterotrophic.

PMID- 12620019
TI  - Monitoring nekton as a bioindicator in shallow estuarine habitats.
AB  - Long-term monitoring of estuarine nekton has many practical and ecological
      benefits but efforts are hampered by a lack of standardized sampling procedures.
      This study provides a rationale for monitoring nekton in shallow (< 1 m),
      temperate, estuarine habitats and addresses some important issues that arise when
      developing monitoring protocols. Sampling in seagrass and salt marsh habitats is
      emphasized due to the susceptibility of each habitat to anthropogenic stress and
      to the abundant and rich nekton assemblages that each habitat supports. Extensive
      sampling with quantitative enclosure traps that estimate nekton density is
      suggested. These gears have a high capture efficiency in most habitats and are
      small enough (e.g., 1 m2) to permit sampling in specific microhabitats. Other
      aspects of nekton monitoring are discussed, including spatial and temporal
      sampling considerations, station selection, sample size estimation, and data
      collection and analysis. Developing and initiating long-term nekton monitoring
      programs will help evaluate natural and human-induced changes in estuarine nekton
      over time and advance our understanding of the interactions between nekton and
      the dynamic estuarine environment.

PMID- 12620018
TI  - Foraminifera as bioindicators in coral reef assessment and monitoring: the FORAM
      Index. Foraminifera in Reef Assessment and Monitoring.
AB  - Coral reef communities are threatened worldwide. Resource managers urgently need
      indicators of the biological condition of reef environments that can relate data
      acquired through remote-sensing, water-quality and benthic-community monitoring
      to stress responses in reef organisms. The "FORAM" (Foraminifera in Reef
      Assessment and Monitoring) Index (FI) is based on 30 years of research on reef
      sediments and reef-dwelling larger foraminifers. These shelled protists are ideal
      indicator organisms because: Foraminifers are widely used as environmental and
      paleoenvironmental indicators in many contexts. Reef-building, zooxanthellate
      corals and foraminifers with algal symbionts have similar water-quality
      requirements. The relatively short life spans of foraminifers as compared with
      long-lived colonial corals facilitate differentiation between long-term water
      quality decline and episodic stress events. Foraminifers are relatively small and
      abundant, permitting statistically significant sample sizes to be collected
      quickly and relatively inexpensively, ideally as a component of comprehensive
      monitoring programs; and, collection of foraminifers has minimal impact on reef
      resources. USEPA guidelines for ecological indicators are used to evaluate the
      Fl. Data required are foraminiferal assemblages from surface sediments of reef
      associated environments. The Fl provides resource managers with a simple
      procedure for determining the suitability of benthic environments for communities
      dominated by algal symbiotic organisms. The FI can be applied independently, or
      incorporated into existing or planned monitoring efforts. The simple calculations
      require limited computer capabilities and therefore can be applied readily to
      reef-associated environments worldwide. In addition, the foraminiferal shells
      collected can be subjected to morphometric and geochemical analyses in areas of
      suspected heavy-metal pollution, and the data sets for the index can be used with
      other monitoring data in detailed multidimensional assessments.

PMID- 12620020
TI  - Interlaboratory variability of amphipod sediment toxicity tests in a cooperative
      regional monitoring program.
AB  - Marine sediment toxicity tests are widely applied in monitoring programs, yet
      relatively little is known about the comparability of data from different
      laboratories. The need for comparability information is increased in cooperative
      monitoring programs, where multiple laboratories (often with variable skill
      levels) perform toxicity tests. An interlaboratory comparison exercise was
      conducted among seven laboratories in order to document the comparability of
      sediment toxicity measurements during the Bight '98 regional sediment survey in
      southern California. Sediments from four stations in Los Angeles and Long Beach
      Harbors were tested using a 10-day survival test of the amphipod Eohaustorius
      estuarius. All laboratories successfully performed the sediment test and
      associated reference toxicant test. Statistically significant differences were
      found in mean amphipod survival rates among some laboratories for the field
      collected sediments, but there was little evidence of a consistent bias among
      laboratories. Although the reference toxicant test indicated a five-fold
      variation in test sensitivity among laboratories, these results were not accurate
      predictors of interlaboratory performance for the sediment tests. The
      laboratories demonstrated excellent concordance (Kendall's W = 0.91) in ranking
      the field-collected sediments by toxicity. Agreement on classifying the sediments
      into categories (nontoxic, moderately toxic, and highly toxic) based upon the
      percent of survival was best for highly toxic sediments. An analysis of test
      precision based upon the variance among replicates within a test indicated that
      the measured survival rate for a sample may vary by up to 12 percentage points
      from the actual response.

PMID- 12620021
TI  - Making performance-based chemistry work: how we created comparable data among
      laboratories as part of a Southern California marine regional assessment.
AB  - Quality assurance procedures to ensure consistency among chemistry laboratories
      typically involves the use of standard methods and state certification programs
      that require laboratories to demonstrate their ability to attain generic
      performance criteria. To assess whether these procedures are effective for
      ensuring comparability when processing local samples with potentially complex
      matrices, seven experienced, state-certified laboratories participated in an
      intercalibration exercise. Each laboratory was permitted to use their typical
      methodology for quantifying PAH, PCB and DDT on shared samples collected from
      Santa Monica Bay and the Palos Verdes Shelf, two sites with a complex mix of
      constituents. In the initial intercalibration exercise, results from these
      laboratories differed by as much as an order of magnitude for all three chemical
      groups. Much, but not all, of the difference was attributable to differences in
      detection capability. A series of studies was conducted to identify the reasons
      for the observed differences, which varied among laboratories and included
      methodological differences, instrument sensitivity differences, and differing
      interpretations of chromatograms. Following these investigations and resulting
      modifications to laboratory procedures, the exercise was repeated. The average
      coefficient of variation among laboratories across all chemical parameters was
      reduced to less than 30%. Our results suggest that performance-based chemistry
      can produce comparable results, but the certification processes presently in
      place that focus on general laboratory procedures and simple matrices are
      insufficient to achieve comparability.

PMID- 12620022
TI  - Characterization and statistical modeling of bacterial (Escherichia coli)
      outflows from watersheds that discharge into southern Lake Michigan.
AB  - Two watersheds in northwestern Indiana were selected for detailed monitoring of
      bacterially contaminated discharges (Escherichia coli) into Lake Michigan. A
      large watershed that drains an urbanized area with treatment plants that release
      raw sewage during storms discharges into Lake Michigan at the outlet of Burns
      Ditch. A small watershed drains part of the Great Marsh, a wetland complex that
      has been disrupted by ditching and limited residential development, at the outlet
      of Derby Ditch. Monitoring at the outlet of Burns Ditch in 1999 and 2000
      indicated that E. coli concentrations vary over two orders of magnitude during
      storms. During one storm, sewage overflows caused concentrations to increase to
      more than 10,000 cfu/100 mL for several hours. Monitoring at Derby Ditch from
      1997 to 2000 also indicated that E. coli concentrations increase during storms
      with the highest concentrations generally occurring during rising streamflow.
      Multiple regression analysis indicated that 60% of the variability in measured
      outflows of E. coli from Derby Ditch (n = 88) could be accounted for by a model
      that utilizes continuously measured rainfall, stream discharge, soil temperature
      and depth to water table in the Great Marsh. A similar analysis indicated that
      90% of the variability in measured E. coli concentrations at the outlet of Burns
      Ditch (n = 43) during storms could be accounted for by a combination of
      continuously measured water-quality variables including nitrate and ammonium.
      These models, which utilize data that can be collected on a real-time basis,
      could form part of an Early Warning System for predicting beach closures.

PMID- 12620023
TI  - Comparison of beach bacterial water quality indicator measurement methods.
AB  - Three methods (membrane filtration, multiple tube fermentation, and chromogenic
      substrate technology kits manufactured by IDEXX Laboratories, Inc.) are routinely
      used to measure indicator bacteria for beach water quality. To assess
      comparability of these methods, quantify within-laboratory variability for each
      method, and place that variability into context of variability among laboratories
      using the same method, 22 southern California laboratories participated in a
      series of intercalibration exercises. Each laboratory processed three to five
      replicates from thirteen samples, with total coliforms, fecal coliforms or
      enterococci measured depending on the sample. Results were generally comparable
      among methods, though membrane filtration appeared to underestimate the other two
      methods for fecal coliforms, possibly due to clumping. Variability was greatest
      for the multiple tube fermentation method. For all three methods, within
      laboratory variability was greater than among laboratories variability.

PMID- 12620025
TI  - Characterization of microbial communities from coastal waters using microarrays.
AB  - Molecular methods, including DNA probes, were used to identify and enumerate
      pathogenic Vibrio species in the Chesapeake Bay; our data indicated that Vibrio
      vulnificus exhibits seasonal fluctuations in number. Our work included a
      characterization of total microbial communities from the Bay; development of
      microarrays that identify and quantify the diversity of those communities; and
      observation of temporal changes in those communities. To identify members of the
      microbial community, we amplified the 16S rDNA gene from community DNA isolated
      from a biofilm sample collected from the Chesapeake Bay in February, 2000. The
      resultant 75 sequences were 95% or more similar to 7 species including two
      recently described Shewanella species, baltica and frigidimarina, that have not
      been previously isolated from the Chesapeake. When the genera of bacteria from
      biofilm after culturing are compared to those detected by subcloning amplified
      16S fragments from community DNA, the cultured sample exhibited a strong bias. In
      oysters collected in February, the most common bacteria were previously unknown.
      Based on our 16S findings, we are developing microarrays to detect these and
      other microbial species in these estuarine communities. The microarrays will
      detect each species using four distinct loci, with the multiple loci serving as
      an internal control. The accuracy of the microarray will be measured using
      sentinel species such as Aeromonas species, Escherichia coli, and Vibrio
      vulnificus. Using microarrays, it should be possible to determine the annual
      fluctuations of bacterial species (culturable and non-culturable, pathogenic and
      non-pathogenic). The data may be applied to understanding patterns of
      environmental change; assessing the "health" of the Bay; and evaluating the risk
      of human illness associated with exposure to and ingestion of water and
      shellfish.

PMID- 12620024
TI  - Molecular approaches to microbiological monitoring: fecal source detection.
AB  - Molecular methods are useful both to monitor natural communities of bacteria, and
      to track specific bacterial markers in complex environments. Length-heterogeneity
      polymerase chain reaction (LH-PCR) and terminal restriction fragment length
      polymorphism (T-RFLP) of 16S rDNAs discriminate among 16S rRNA genes based on
      length polymorphisms of their PCR products. With these methods, we developed an
      alternative indicator that distinguishes the source of fecal pollution in water.
      We amplify 16S rRNA gene fragments from the fecal anaerobic genus Bacteroides
      with specific primers. Because Bacteroides normally resides in gut habitats, its
      presence in water indicates fecal pollution. Molecular detection circumvents the
      complexities of growing anaerobic bacteria. We identified Bacteroides LH-PCR and
      T-RFLP ribosomal DNA markers unique to either ruminant or human feces. The same
      unique fecal markers were recovered from polluted natural waters. We cloned and
      sequenced the unique markers; marker sequences were used to design specific PCR
      primers that reliably distinguish human from ruminant sources of fecal
      contamination. Primers for more species are under development. This approach is
      more sensitive than fecal coliform assays, is comparable in complexity to
      standard food safety and public health diagnostic tests, and lends itself to
      automation and high-throughput. Thus molecular genetic markers for fecal
      anaerobic bacteria hold promise for monitoring bacterial pollution and water
      quality.

PMID- 12620026
TI  - Using Multiple Antibiotic Resistance and land use characteristics to determine
      sources of fecal coliform bacterial pollution.
AB  - Multiple Antibiotic Resistance (MAR) analysis and regression modeling techniques
      were used to identify surface water areas impacted by fecal pollution from human
      sources, and to determine the effects of land use on fecal pollution in Murrells
      Inlet, a small, urbanized, high-salinity estuary located between Myrtle Beach and
      Georgetown, South Carolina, MAR analysis was performed to identify areas in the
      estuary that are impacted by human-source fecal pollution. Additionally,
      regression analysis was performed to determine if an association exists between
      land use and fecal coliform densities over the ten-year period from 1989 to 1998.
      Land-use variables were derived using Geographic Information System (GIS)
      techniques and were used in the regression analysis. MAR analyses were conducted
      by comparing the frequency and patterns of antibiotic resistance found in
      Escherichia coli isolates derived from surface water samples and from sewage
      sources in the Murrells Inlet sewage collection system. The MAR results suggest
      that the majority of the fecal pollution detected in the Murrells Inlet estuary
      may be from non-human sources, including fecal coliforms isolated from areas in
      close proximity to high densities of active septic tanks. A MAR Index, which
      measures the frequency of antibiotic resistance, was calculated for each of
      twenty-three water samples and nine sewage samples. The antibiotic resistance
      pattern comparisons were performed using cluster analysis. Although the MAR
      indices indicated that several surface water sites had potential human-source
      contamination, the cluster analysis suggests that only one sampling site had MAR
      patterns that were similar to those found in the sewage samples. This site was in
      close proximity to several large pleasure boats as well as a sewage collection
      system lift station, but was not near areas with active septic tanks. The results
      of the regression analysis also suggest that sewage sources and rainfall runoff
      from urbanized areas may contribute to fecal pollution in the estuary.

PMID- 12620027
TI  - Long-term phytoplankton trends and related water quality trends in the lower
      Chesapeake Bay, Virginia, USA.
AB  - Long-term trends (i.e., 1985 through 1999; 14 1/2 yrs) of the phytoplankton
      community in Chesapeake Bay indicated patterns of increasing phytoplankton
      abundance and biomass associated with mainly diatoms and chlorophytes, and to a
      lesser degree dinoflagellates. Decreasing trends in productivity rates above the
      pycnocline were present over a shorter time period (10 1/2 yrs.), with evidence
      for increasing nitrogen limitation is indicated. Reduced light availability is
      inferred due to decreasing trends of Secchi depths and increased suspended solids
      trends, which were associated with decreasing trends in productivity rates.

PMID- 12620028
TI  - Initial results from a multi-institutional collaboration to monitor harmful algal
      blooms in South Carolina.
AB  - The rapid rate of development in the South Carolina (SC) coastal zone has
      heightened public concern for the condition of the state's estuaries, and alerted
      scientists to the potential that novel and adverse effects on estuarine
      ecosystems may result. Although well-developed databases from long-term
      monitoring programs exist for many variables valuable in predicting and following
      system responses, information on phytoplankton distributions in SC estuaries has
      lagged. Knowledge of the dynamical relationship between environmental (e.g.,
      nutrient quantity and quality) and biological (e.g., grazing) regulation, and
      phytoplankton biomass and composition is critical to understanding estuarine
      susceptibility to eutrophication or harmful algal blooms (HABs). Recently, SC
      scientists from federal, state, and academic institutions established a
      collaborative monitoring program to assess HAB distribution and ecology
      statewide. The South Carolina Harmful Algal Bloom Program includes: a) intensive
      temporal monitoring at areas of known HAB occurrence or those exhibiting symptoms
      potentially related to HABs (e.g., prevalent fish lesions), b) extensive spatial
      monitoring in coordination with existing statewide efforts, c) a citizen
      volunteer monitoring network, d) nutrient response bioassays, and e) laboratory
      based physiological experiments on HAB isolates. By combining "trip-wire"
      surveillance and rapid response systems, routine monitoring of environmental
      parameters and HAB distribution, and process-oriented studies examining the
      physiological functioning of HAB species, an enhanced understanding of the impact
      and environmental control of HABs in SC estuaries will be achieved. The
      application of this approach to studies on the distribution and physiological
      ecology of a new widespread SC red tide, and to the discovery of several
      potentially toxic blooms (including Pfiesteria) in SC holding ponds, are
      described.

PMID- 12620029
TI  - A pilot project to detect and forecast harmful algal blooms in the northern Gulf
      of Mexico.
AB  - More timely access to data and information on the initiation, evolution and
      effects of harmful algal blooms can reduce adverse impacts on valued natural
      resources and human health. To achieve this in the northern Gulf of Mexico, a
      pilot project was initiated to develop a user-driven, end-to-end (measurements to
      applications) observing system. A key strategy of the project is to coordinate
      existing state, federal and academic programs at an unprecedented level of
      collaboration and partnership. Resource managers charged with protection of
      public health and aquatic resources require immediate notice of algal events and
      a forecast of when, where and what adverse effects will likely occur. Further,
      managers require integrated analyses and interpretations, rather than raw data,
      to make effective decisions. Consequently, a functional observing system must
      collect and transform diverse measurements into usable forecasts. Data needed to
      support development of forecasts will include such properties as sea surface
      temperature, winds, currents and waves; precipitation and freshwater flows with
      related discharges of sediment and nutrients; salinity, dissolved oxygen, and
      chlorophyll concentrations (in vivo fluorescence); and remotely-sensed spatial
      images of sea surface chlorophyll concentrations. These data will be provided via
      a mixture of discrete and autonomous in situ sensing with near real-time data
      telemetry, and remote sensing from space (SeaWiFS), aircraft (hyperspectral
      imagery) or land (high-frequency radar). With calibration across these platforms,
      the project will ultimately provide a 4-dimensional visualization of harmful
      algae events in a time frame suitable to resource managers.

PMID- 12620030
TI  - Preliminary investigation of submerged aquatic vegetation mapping using
      hyperspectral remote sensing.
AB  - The use of airborne hyperspectral remote sensing imagery for automated mapping of
      submerged aquatic vegetation (SAV) in the tidal Potomac River was investigated
      for near to real-time resource assessment and monitoring. Airborne hyperspectral
      imagery and field spectrometer measurements were obtained in October of 2000. A
      spectral library database containing selected ground-based and airborne sensor
      spectra was developed for use in image processing. The spectral library is used
      to automate the processing of hyperspectral imagery for potential real-time
      material identification and mapping. Field based spectra were compared to the
      airborne imagery using the database to identify and map two species of SAV
      (Myriophyllum spicatum and Vallisneria americana). Overall accuracy of the
      vegetation maps derived from hyperspectral imagery was determined by comparison
      to a product that combined aerial photography and field based sampling at the end
      of the SAV growing season. The algorithms and databases developed in this study
      will be useful with the current and forthcoming space-based hyperspectral remote
      sensing systems.

PMID- 12620031
TI  - Effect of El Nino on demographic, morphological, and chemical parameters in
      turtle-grass (Thalassia testudinum): an unexpected test of indicators.
AB  - We examined the response of demographic, morphological, and chemical parameters
      of turtle grass (Thalassia testudinum), to much-higher-than-normal rainfall
      associated with an El Nino event in the winter of 1997-1998. Up to 20 inches of
      added rain fell between December 1997 and March 1998. triggering widespread and
      persistent phytoplankton blooms along the west coast of Florida. Water-column
      chlorophyll concentrations estimated from serial Sea WiFS imagery were much
      higher during the El Nino event than in the previous or following years, although
      the timing and magnitude of phytoplankton blooms varied among sites. Seagrass
      samples collected in 1997, 1998, and 1999 provided an excellent opportunity to
      test the responsiveness of Thalassia to decline and subsequent improvement of
      water quality and clarity in four estuaries. Using a scoring technique based on
      temporal responsiveness, spatial consistency, and statistical strength of
      indicators, we found that several morphological parameters (Thalassia shoot
      density, blade width, blade number, and shoot-specific leaf area) were responsive
      and consistent measures of light stress. Some morphological parameters, such as
      rhizome apex density, responded to declines and subsequent improvement in water
      clarity, but lacked the statistical discriminating power necessary to be useful
      indicators. However, rhizome sugar, starch, and total carbohydrate concentrations
      also exhibited spatially and temporally consistent variation as well as
      statistical strength. Because changes in shoot density, as well as water clarity,
      affect rhizome carbohydrate levels, a composite metric based on Thalassia shoot
      density and rhizome carbohydrate levels together is probably more useful than
      either parameter alone as an indicator of seagrass health.

PMID- 12620032
TI  - Fasciolosis causes losses in cattle, sheep and camelids.

PMID- 12620033
TI  - Use of a PCR assay to assess the prevalence and risk factors for Mycoplasma
      haemofelis and 'Candidatus Mycoplasma haemominutum' in cats in the United
      Kingdom.
AB  - Blood samples from 426 healthy and sick cats in the UK were tested in a PCR assay
      for 'Candidatus Mycoplasma haemominutum' and Mycoplasma haemofelis (basonym
      Haemobartonella felis). Seventy-two of the cats (16.9 per cent) were positive for
      'Candidatus M. haemominutum' alone, six (1.4 per cent) were positive for M.
      haemofelis alone and one (0.2 per cent) was positive for both. Logistic
      regression analysis indicated that older male cats were significantly more likely
      to be infected with 'Candidatus M. haemominutum', but there was no significant
      association between it and any of the haematological variables measured. M.
      haemofelis infection was uncommon in the anaemic cats sampled, and there were too
      few positive cases for multivariable analysis to be performed for M. haemofelis
      positive status.

PMID- 12620034
TI  - Morphological, histological and histochemical studies of the pituitary glands of
      ovine freemartins.
AB  - Freemartins are XX/XY chimaeras that develop as a result of the fusion of the
      placental circulation of at least one male and one female fetus. The pituitary
      glands of eight normal ewes at various stages of the oestrous cycle and three
      rams were compared with those of two male-type and three undifferentiated-type
      freemartins. The pituitaries were heaviest in the male-type freemartins, and
      their pattern of gonadotrophs, assessed by differential staining, was more
      intense than in the normal males. The pituitaries of the undifferentiated-type
      freemartins weighed less than those of the normal ewes but had more stained
      gonadotrophs than the normal ewes or rams. In both types of freemartins the
      pattern of cells resembled that of a castrated male.

PMID- 12620035
TI  - Abortion epidemic in a dairy herd associated with horizontally transmitted
      Neospora caninum infection.
AB  - A dairy herd experienced an abortion epidemic during which 43 per cent of the
      cows at risk aborted. Neospora caninum infection was demonstrated in four of six
      fetuses suitable for examination and the group of at-risk cows that aborted had
      significantly higher N. caninum antibody concentrations than the at-risk cows
      that delivered a live calf at term (P<0.001). The antibody concentrations in the
      cow herd were significantly higher than in the youngstock (P<0.001), and the
      concentrations in the youngstock increased significantly (P<0.001) with age. When
      seven months to a year old, the calves born at term to the at-risk cows had
      significantly higher (P=0.007) antibody concentrations than age-matched calves
      born before the epidemic. At the time of the epidemic, there was a significant
      increase in the antibody levels of the herd that was not consistent with vertical
      infection alone, indicating that there appeared to have been a sudden large
      increase in the incidence of horizontal postnatal transmission of N. caninum to
      the cow herd, or to the surviving offspring of the at-risk cows, or to both of
      these groups.

PMID- 12620036
TI  - Bacterial associations with the sheep scab mite (Psoroptes ovis).

PMID- 12620037
TI  - Extracorporeal shock wave therapy for supraspinatus calcifying tendinopathy in
      two dogs.

PMID- 12620038
TI  - Sinonasal myxoma in a four-year-old thoroughbred gelding.

PMID- 12620039
TI  - Prion protein gene polymorphisms in a population of Spanish cows.

PMID- 12620040
TI  - Sarcoptic mange in foxes.

PMID- 12620041
TI  - Fees for retired RCVS members.

PMID- 12620042
TI  - Fertile mules.

PMID- 12620043
TI  - Equine referrals for two ongoing studies.

PMID- 12620044
TI  - Magnetic resonance imaging of the presumed normal canine adrenal glands.
AB  - Forty-three dogs without evidence of endocrine disease that underwent spinal or
      abdominal magnetic resonance imaging (MRI) for clinical reasons were studied.
      Because the procedures were not optimized for inclusion of the adrenal glands,
      they were not always visible in all planes. Eighty-five of the 86 adrenal glands
      were seen and only the left gland in a 6-month-old Irish wolfhound could not be
      found. The right adrenal gland lay cranial to the left in all of the animals in
      which both glands were seen. The best landmarks for localization of the glands
      were vascular; both adrenal glands were always cranial to the ipsilateral renal
      vessels and in the region of the celiac and cranial mesenteric arteries. Various
      measurements were made on all the available scan planes. In some dogs the whole
      adrenal gland was difficult to visualize clearly, and this hindered the measuring
      process, especially when the right adrenal gland was in close contact with the
      caudal vena cava. The adrenal glands were mainly linear in shape but also had a
      variable degree of modification of their poles, especially the cranial pole of
      the right adrenal gland, which tended to be consistently wider and to present
      different shapes (rounded, arrowhead, inverted P, hook-shaped, triangular, or
      dome-shaped). Two main patterns of signal intensity were seen on fast spin echo
      (FSE) sequences (T2-weighted, T1-weighted, and T1-weighted after administration
      of a paramagnetic contrast medium): homogeneous and hypointense to surroundings
      or a corticomedullary type pattern with a hyperintense central area surrounded by
      a hypointense rim of tissue. The outline of the left adrenal gland was always
      very clear. The clarity of outline of the right adrenal gland was more variable,
      especially if it was in contact with the liver or the caudal vena cava. It was
      felt that the amount of retroperitoneal fat was not as important as stated in the
      human literature for visualization of the adrenal glands and that with an
      appropriate selection of scan planes and pulse sequences good assessment of the
      adrenal glands can be performed with MRI in canine patients.

PMID- 12620045
TI  - Radiographic features of aortic bulb/valve mineralization in 20 dogs.
AB  - The radiographic features of aortic bulb/valve mineralization in 20 dogs were
      reviewed. Extent, shape, number, and location of mineralization were recorded.
      Five of the dogs had additional alternate imaging examinations, including bone
      scintigraphy, echocardiography, and thoracic computed tomography. A necropsy was
      done on one dog, and the area of mineralization was evaluated using routine
      histology. The median age was 10 (mean 9.7; SD +/- 2.7) years. There were five
      males, seven neutered males, one female, and seven neutered females. The breeds
      were: Irish setter (6); rottweiler (7); chow-chow (1); miniature dachshund (1);
      borzoi (1); English setter (1); English springer spaniel (1); great Dane (1); and
      greyhound (1). Dogs with both right and left lateral radiographs (n = 17) had
      mineralization visible on both views, more conspicuously on the right lateral
      radiograph (n = 12). Aortic bulb mineralization was identified on the
      ventrodorsal radiograph of only one dog. On lateral radiographs, the aortic bulb
      mineralization was localized within the 4th intercostal space and in the
      craniodorsal quadrant of the cardiac silhouette. In nine of the dogs, there were
      complex or multiple mineralizations and in 11 dogs, there was a single
      curvilinear mineral opacity oriented in a caudoventral to craniodorsal direction.
      In all radiographs, the mineralization was in the expected position of the aortic
      bulb, and echocardiography (n = 4), spiral computed tomography (n = 2), and
      necropsy (n = 1) confirmed that the mineralization was within the aortic bulb.
      Clinical pathologic data of the dogs suggested no reason for metastatic
      mineralization. Exact etiopathogenesis of the lesions were not determined in this
      study. Based on the histologic findings in one dog, the mineralization seen in
      the aortic root is similar to a form of dystrophic mineralization called
      Monckeberg's calcific arteriosclerosis in humans. No clinical signs attributable
      to the mineralization were observed.

PMID- 12620046
TI  - Otolithiasis in three dogs.
AB  - Mineral opacities within the tympanic bullae, termed otoliths, were detected in
      three dogs by means of radiography and computed tomography. Radiographic signs of
      otitis externa were present in two dogs. One dog had clinical signs of vestibular
      disease, whereas the other two dogs had no clinical evidence of ear disease.
      Otolithiasis may represent mineralized necrotic material of a current or previous
      case of otitis media.

PMID- 12620047
TI  - Transvenous coil embolization of portosystemic shunt in dogs.
AB  - This paper describes transvenous coil embolization of portosystemic shunt in 10
      dogs. Clinical signs resolved in 4 dogs with extrahepatic shunt, and in 3 dogs
      with intrahepatic shunt. Two dogs of less than 3 kg died because of migration of
      coils to the level of the main pulmonary artery. One dog was euthanized when
      acute portal hypertension developed following transvenous coil embolization.
      Transvenous coil embolization seems to be a less invasive alternative to surgical
      ligation in dogs with a single intrahepatic portosystemic shunt.

PMID- 12620048
TI  - Simultaneous congenital and acquired extrahepatic portosystemic shunts in two
      dogs.
AB  - Two dogs with simultaneous congenital and acquired portosystemic shunts are
      reported. The first dog was an eight-month-old, male Golden Retriever with a
      history of peritoneal effusion, polyuria/polydipsia, and stunted growth. The dog
      had a microcytic, hypochromic anemia, a mildly elevated AST, and a moderate to
      severely elevated preprandial and postprandial serum bile acids. Transcolonic
      portal scintigraphy confirmed the presence of a portosystemic shunt. An
      intraoperative mesenteric portogram was performed. Two conjoined congenital
      extrahepatic portosystemic shunts and multiple acquired extrahepatic
      portosystemic shunts were identified. The second dog was a five-month-old, mixed
      breed with two week history of peritoneal effusion. Abdominal ultrasound and
      transcolonic scintigraphy were used to diagnose a portosystemic shunt. A single
      extrahepatic portosystemic shunt, portal hypertension, and multiple acquired
      collateral shunts were identified at surgery. The histologic alterations observed
      in these dogs were consistent with a portosystemic shunt. In these dogs, the
      presence of congenital and acquired portosystemic shunts and histopathologic
      findings are considered to represent a combination of congenital portosystemic
      shunts and noncirrhotic portal hypertension or portal vein hypoplasia.

PMID- 12620049
TI  - Radiography and image-intensified fluoroscopy of barium passage through the
      gastrointestinal tract in six healthy Amazon parrots (Amazona aestiva).
AB  - Gastrointestinal contrast studies were performed in six clinically healthy blue
      fronted Amazon parrots (Amazona aestiva) using radiography and image-intensified
      fluoroscopy. During examination, the birds were confined in a perspex cage. The
      quality of the lateral radiographs was adequate for assessment of the contrast
      medium-filled gastrointestinal tract. Thirty minutes after administration of 20
      mL/kg of a 25% barium sulphate suspension directly in the crop, in all birds the
      ventriculus was totally outlined by barium. After 60 min, the small intestine was
      filled in five of six birds. After 180 min, the crop was empty in all birds. The
      barium-outlined ventriculus had differences in shape on radiographs of individual
      birds and also between birds. The colon and cloaca had further filling after 120
      to 300 min. With image-intensified fluoroscopy, gastrointestinal motility was
      evaluated. Contractions of the crop were seen, and boluses of contrast medium
      passing through the esophagus toward the proventriculus were easily identified.
      Proventricular contractions were rarely noted, but ventriculus motility was
      present and clearly defined. The ventriculus had a mean of 3.7 contraction
      cycles/min. In the duodenum and small intestine, rapid antegrade and retrograde
      peristaltic movements in combination with segmental contractions were seen. In
      the colon, occasionally very slow peristaltic activity, mainly of segmental
      nature, was present. During the examinations, no defeacation was recorded.
      Confinement in a small perspex cage provides an adequate and handy radiological
      set-up for evaluation of gastrointestinal passage and motility in birds,
      minimizing the influences of stress and anesthesia.

PMID- 12620050
TI  - Accuracy and precision of dual-energy x-ray absorptiometry for ex vivo
      determination of mineral content in turkey poult bones.
AB  - The right humerus was removed from 30 20-week-old male turkey poults for humerus
      strength analysis using dual-energy x-ray absorptiometry and humerus-breaking
      strength. Specimens were cleaned and dried before scanning. To determine the most
      precise and accurate protocol of bone densitometry analysis for avian long bones,
      we scanned each specimen using five different techniques, all aimed to simulate
      soft-tissue thickness. Correlation coefficients and linear regression equations
      between 1) bone mineral content and humerus ash, and 2) bone mineral density and
      humerus-breaking strength were estimated with each technique and compared. The
      coefficient of variation values for precision ranged from 0.40% to 1.69% for bone
      mineral content and from 0% to 4.19% for bone mineral density. The accuracy was
      determined by comparing the bone mineral content of each humerus with the
      corresponding ash weight; the correlation coefficients between the two parameters
      were highly significant (range 0.949-0.963; P < or = 0.01). Significant
      correlations were also observed between humerus-breaking strength and bone
      density measurements (range 0.762-0.785; P < or = 0.01). Linear regression
      coefficients relating both parameters considered were also highly significant. We
      concluded that dual-energy x-ray absorptiometry is an accurate and precise method
      with which to determine ex vivo bone mineral content and strength in turkey
      bones. Further investigations are requested for field applications of this method
      to study factors affecting bone physiology and strength.

PMID- 12620051
TI  - Balloon dilatation of nasopharyngeal stenosis in a cat.
AB  - A cat was diagnosed with nasopharyngeal stenosis on the basis of clinical signs,
      survey and contrast radiography, endoscopy and magnetic resonance imaging. The
      condition was successfully managed with repeated balloon dilatation.

PMID- 12620053
TI  - Effect of perineural anesthesia on the ultrasonographic appearance of equine
      palmar metacarpal structures.
AB  - The purpose of this study was to describe ultrasonographic changes of the equine
      palmar metacarpal area attributed to the infiltration of local anesthetic
      solution and to determine whether these changes were noted immediately or at 24
      h. The palmar metacarpal region of one forelimb in each of six horses was
      examined ultrasonographically with a 10-MHz linear array transducer and a 7.5-MHz
      curvilinear transducer. Transverse and longitudinal images were recorded at 5-cm
      intervals distal to the accessory carpal bone. High and low palmar and palmar
      metacarpal nerve blocks were performed with a 2% mepivacaine hydrochloride
      solution. Ultrasonographic examinations similar to the initial examination then
      were performed immediately, 1 h and 24 h postinjection. Cross-sectional area and
      mean pixel value were determined for the superficial and deep digital flexor
      tendons, the accessory ligament of the deep digital flexor tendon, the suspensory
      ligament, and the suspensory branches at each level and time period. Subjective
      ultrasonographic changes also were noted. No significant difference was noted in
      the cross-sectional area or mean pixel value of any structure at any level or
      time period compared to baseline. Subjective changes in the tendons and ligaments
      were not noted. There was mild hypoechoic swelling of the surrounding soft
      tissues and gas in the region of the injections. Gas could interfere with the
      evaluation of the origin of the suspensory ligament and the proximal portion of
      the accessory ligament of the deep digital flexor tendon within the first hour
      but was not detectable ultrasonographically at 24 h. Based on these findings, if
      gas interferes with an ultrasonographic examination performed temporally close to
      perineural anesthesia, a repeat examination at 24 h is recommended.

PMID- 12620052
TI  - Radiographic diagnosis--lateralized vertebral osseous compression causing
      cervical spondylomyelopathy in a Great Dane.

PMID- 12620054
TI  - Ultrasonographic diagnosis of foreign bodies associated with chronic draining
      tracts and abscesses in dogs.
AB  - This is a retrospective study that describes the historical, physical exam,
      radiographic, fistulographic, ultrasonographic, and surgical findings associated
      with non-gastrointestinal and extrathoracic foreign bodies in six dogs. All dogs
      had a chronic draining tract or abscess. Although radiographs were obtained in
      five of the six dogs, no foreign bodies were identified with this modality.
      Fistulography was performed in four of the six dogs, and a filling defect
      consistent with a foreign body was found in two of four dogs. A foreign body was
      identified in five of the six dogs with ultrasound. Foreign bodies were removed
      surgically in five of six dogs. This report clarifies the importance of
      ultrasound in the evaluation of chronic draining tracts and abscesses in dogs.

PMID- 12620055
TI  - Combined use of ultrasonography and contrast enhanced computed tomography to
      evaluate acute necrotizing pancreatitis in two dogs.
AB  - The imaging findings in two miniature schnauzers with acute necrotizing
      pancreatitis are described. Both dogs were treated previously for diabetes
      mellitus and hyperlipidemia. Vomiting, anorexia, and lethargy were observed in
      both dogs at presentation. Laboratory evaluations supportive of pancreatitis
      included left shift, abnormally high serum amylase and lipase activities,
      hypocalcemia, and abnormally high serum activities of liver enzymes.
      Sonographically, both dogs had diffusely enlarged hypoechoic pancreatic tissue
      with anechoic foci compatible with necrosis, abscessation, phlegmon, and
      pseudocysts formation. Contrast-enhanced computed tomography (CT) findings in
      both dogs were compatible with pancreatic necrosis. Dog 1 was managed medically
      for 11 days. Follow-up CT scan in this dog disclosed decreased pancreatic size
      and increased contrast enhancement compatible with partial resolution of
      pancreatitis.

PMID- 12620056
TI  - Ultrasonographic diagnosis-small bowel infarction in a cat.
AB  - An 8-year-old, domestic short hair cat with a known history of hypertrophic
      cardiomyopathy and previous aortic thromboembolism was presented for 24 h of
      vomiting and pyrexia. Initial abdominal radiographs were unremarkable. On an
      upper gastrointestinal series, delayed gastric emptying and prolonged small
      intestinal transit time were found. An initial abdominal ultrasound revealed a
      focal region of aperistaltic small intestine with mild wall thickening, however,
      intestinal wall layering in this area appeared normal. By 72 h, there was a
      diffusely hypoechoic portion of thickened small bowel (0.51 cm) with loss of the
      normal layering and hyperechoic mesentery surrounding this segment of bowel. A
      small bowel infarction and focal peritonitis were suspected and confirmed at
      surgery.

PMID- 12620058
TI  - Images from the 2002 ACVR certifying examination: abdomen section.

PMID- 12620057
TI  - Determination of time of onset and location of early skeletal lesions in young
      dogs experimentally infected with Hepatozoon americanum using bone scintigraphy.
AB  - Canine hepatozoonosis caused by Hepatozoon americanum has periosteal
      proliferation on long bones, pelvis, vertebrae, and skull. The pathogenesis of
      the periosteal proliferation is unknown but may be similar to hypertrophic
      osteopathy. Objectives were to determine the time frame for onset of bone
      lesions, to characterize spatial distribution of early bone lesions, and to
      describe the scintigraphic appearance of bone lesions in six immature dogs
      infected with 400 H. americanum oocysts on day 0. 99mTc-MDP bone scintigraphy was
      performed before and after infection. The onset bone lesions noted using
      scintigraphy was before day 35/36 in three dogs, day 46 in one dog, day 53 in one
      dog, and between days 46 and 67 in one dog. Early bone lesions primarily occur
      proximal to the carpus/tarsus and on the axial skeleton. Bone lesions were
      diffuse, bilaterally symmetric, homogenous, high intensity regions of
      radiopharmaceutical uptake.

PMID- 12620060
TI  - Images in medicine. A ten-year-old, neutered male, mixed-breed dog with a history
      of polyuria and polydipsia.

PMID- 12620059
TI  - Images from the 2002 ACVR certification examination: small animal diagnosis
      elective.

PMID- 12620061
TI  - Eat and run? The hunger/satiation hypothesis in vertical migration: history,
      evidence and consequences.
AB  - The study of vertical migrations in aquatic organisms has a long and colourful
      history, much of it to do with the effects of changing sampling technology on our
      understanding of the phenomenon. However, the overwhelming majority of such
      studies carried out today still depend on detecting differences in vertical
      distribution profiles during some course of time, or acoustic echoes of migrating
      bands of organisms. These can not distinguish migratory activity of individual
      organisms, but can only assess net results of mass transfers of populations,
      which may integrate many individual migrations. This is an important distinction,
      for without knowing the actual movements of individuals it seems unlikely that we
      will be able to understand their causes, nor the effects of vertical migrations
      on the environment or on the migrators themselves. This review examines evidence
      for individual vertical movements gathered from 'tracers', mainly gut contents,
      and reviews the evidence for the hypothesis that such movements are in fact
      driven by hunger and satiation. The more recently appreciated vertical migrations
      of phytoplankters and their similarities in form and driving forces to those of
      zooplankton and nekton are also discussed. Finally, the role of vertical
      migrators in vertical fluxes of materials is discussed, along with the
      consequences of satiation-driven descent for such estimates.

PMID- 12620062
TI  - Animal colour vision--behavioural tests and physiological concepts.
AB  - Over a century ago workers such as J. Lubbock and K. von Frisch developed
      behavioural criteria for establishing that non-human animals see colour. Many
      animals in most phyla have since then been shown to have colour vision. Colour is
      used for specific behaviours, such as phototaxis and object recognition, while
      other behaviours such as motion detection are colour blind. Having established
      the existence of colour vision, research focussed on the question of how many
      spectral types of photoreceptors are involved. Recently, data on photoreceptor
      spectral sensitivities have been combined with behavioural experiments and
      physiological models to study systematically the next logical question: 'what
      neural interactions underlie colour vision?' This review gives an overview of the
      methods used to study animal colour vision, and discusses how quantitative
      modelling can suggest how photoreceptor signals are combined and compared to
      allow for the discrimination of biologically relevant stimuli.

PMID- 12620063
TI  - Identification, measurement and interpretation of tree rings in woody species
      from mediterranean climates.
AB  - We review the literature dealing with mediterranean climate, vegetation,
      phenology and ecophysiology relevant to the understanding of tree-ring formation
      in mediterranean regions. Tree rings have been used extensively in temperate
      regions to reconstruct responses of forests to past environmental changes. In
      mediterranean regions, studies of tree rings are scarce, despite their potential
      for understanding and predicting the effects of global change on important
      ecological processes such as desertification. In mediterranean regions, due to
      the great spatio-temporal variability of mediterranean environmental conditions,
      tree rings are sometimes not formed. Often, clear seasonality is lacking, and
      vegetation activity is not always associated with regular dormancy periods. We
      present examples of tree-ring morphology of five species (Arbutus unedo, Fraxinus
      ornus, Quercus cerris, Q. ilex, Q. pubescens) sampled in Tuscany, Italy, focusing
      on the difficulties we encountered during the dating. We present an
      interpretation of anomalies found in the wood structure and, more generally, of
      cambial activity in such environments. Furthermore, we propose a classification
      of tree-ring formation in mediterranean environments. Mediterranean tree rings
      can be dated and used for dendrochronological purposes, but great care should be
      taken in selecting sampling sites, species and sample trees.

PMID- 12620064
TI  - A sigmoidal transcriptional response: cooperativity, synergy and dosage effects.
AB  - A sigmoidal transcriptional response (STR) is thought to act as a molecular
      switch to control gene expression. This nonlinear behaviour arises as a result of
      the cooperative recognition of a promoter/enhancer by transcription factors (TFs)
      and/or their synergy to attract the basal transcriptional machinery (BTM).
      Although this cooperation between TFs is additive in terms of energy, it leads to
      an exponential increase in affinity between the BTM and the pre-initiation
      complexes. This exponential increase in the strength of interactions is the
      principle that governs synergistic systems. Here, I propose a minimalist quasi
      equilibrium model to explore qualitatively the STR taking into account
      cooperative recognition of the promoter/enhancer and synergy. Although the focus
      is on the effect of activators, a similar treatment can be applied to inhibitors.
      One of the main insights obtained from the model is that generation of a
      sigmoidal threshold is possible even in the absence of cooperative DNA binding
      provided the TFs synergistically interact with the BTM. On the contrary, when
      there is cooperative binding, the impact of synergy diminishes. It will also be
      shown that a sigmoidal response to a morphogenetic gradient can be used to
      generate a nested gradient of another morphogen. Previously, I had proposed that
      halving the amounts of TFs involved in sigmoidal transcriptional switches could
      account for the abnormal dominant phenotypes associated with some of these genes.
      This phenomenon, called haploinsufficiency (HI), has been recognised as the basis
      of many human diseases. Although a formal proof linking HI and a sigmoidal
      response is lacking, it is tempting to explore the model from the perspective of
      dosage effects.

PMID- 12620065
TI  - Antiestrogens and selective estrogen receptor modulators as multifunctional
      medicines. 1. Receptor interactions.

PMID- 12620066
TI  - A novel atypical retinoid endowed with proapoptotic and antitumor activity.
AB  - The novel atypical retinoid E-3-(4'-hydroxy-3'-adamantylbiphenyl-4-yl)acrylic
      acid (ST1926, 4) exhibited a potent antiproliferative activity on a large panel
      of human tumor cells. Despite almost complete loss of ability to activate RARs,
      the compound was an effective apoptosis inducer and surprisingly produced DNA
      damage, that likely contributes to the proapoptotic activity. Following oral
      administration, 4 was well tolerated and caused tumor growth inhibition in the
      ovarian carcinoma, A2780/DX, and in the human melanoma, MeWo, growing in nude
      mice, thus supporting the therapeutic interest of the novel agent.

PMID- 12620067
TI  - 1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible
      nitric oxide synthase which show antiinflammatory activity in vivo.
AB  - The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2
      substituted 1,2-dihydro-4-quinazolinamines, and the related 4'
      aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of
      both series exhibit nanomolar potency and high selectivity for the inducible
      isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro.
      Efficacy in acute and chronic animal models of inflammatory disease following
      oral administration has also been demonstrated using these compounds.

PMID- 12620068
TI  - Simple, potent, and selective pyrrole inhibitors of monoamine oxidase types A and
      B.
AB  - N-Benzyl- and N-propargyl-1H-pyrrole-2-carboxyamides and some related
      methylenamines were synthesized and tested for their monoamine oxidase types A
      and B inhibitory activity. 2-(N-Methyl-N-propargylaminomethyl)-1H-pyrrole (24)
      was the most potent MAO-A inhibitor of the series [K(i)(MAO-A) = 0.0054 microM],
      but it was not selective. Inhibitors N-4-fluorobenzyl-1H-pyrrole-2-carboxamide
      (12) and N-cyclohexylmethyl-1H-pyrrole-2-carboxamide (25) showed the highest MAO
      A selectivity indexes (SI) corresponding to 2025 and >2500, respectively, while 2
      (N-methyl-N-benzylaminomethyl)-1H-pyrrole (21) was the most selective MAO-B
      inhibitor, having an SI of 0.0057.

PMID- 12620069
TI  - Synthesis, nicotinic acetylcholine receptor binding affinities, and molecular
      modeling of constrained epibatidine analogues.
AB  - Conformationally constrained epibatidine analogues 20a,b and 23a,b were
      synthesized using a radical cyclization as the key step. Radioligand displacement
      assays to six defined rat nicotinic acetylcholine receptor (nAChR) subtypes
      showed that 20a,b bind with moderate affinities, while 23a,b have low affinities.
      20a exhibits higher affinity for the beta2 containing subtype than for the beta4
      containing counterpart, while 20b possesses reversed selectivity. Modeling
      studies suggest that the spatial distribution of the ligand's atoms around the
      pharmacophore elements may control their nAChR subtype selectivity.

PMID- 12620070
TI  - Synthesis and characterization of iodine-123 labeled 2beta-carbomethoxy-3beta-(4'
      ((Z)-2-iodoethenyl)phenyl)nortropane. A ligand for in vivo imaging of serotonin
      transporters by single-photon-emission tomography.
AB  - 2beta-Carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl)nortropane (ZIENT) (6) and
      2beta-carbomethoxy-3beta-(4'-((E)-2-iodoethenyl)phenyl)nortropane (EIENT) (10)
      were prepared and evaluated in vitro and in vivo for serotonin transporter (SERT)
      selectivity and specificity. High specific activity [(123)I]ZIENT and
      [(123)I]EIENT were synthesized in 45% (n = 5) and 42% (n = 4) radiochemical yield
      (decay-corrected to end of bombardment (EOB)), respectively, by preparation of
      the precursor carbomethoxy-3beta-(4'-((Z)-2
      trimethylstannylethenyl)phenyl)nortropane (7) and 2beta-carbomethoxy-3beta-(4'
      ((E)-2-tributylstannylethenyl)phenyl)nortropane (9), respectively, followed by
      treatment with no carrier-added sodium [(123)I]iodide and hydrogen peroxide in
      ethanolic HCl. Competition binding in cells stably expressing the transfected
      human SERT, dopamine transporter (DAT), and norepinephrine transporter (NET)
      using [(3)H]citalopram, [(3)H]WIN 35,428, and [(3)H]nisoxetine, respectively,
      demonstrated the following order of SERT affinity (K(i) in nM): ZIENT (0.05) >
      nor-CIT (0.12) >> EIENT (1.15) > fluvoxamine (1.46). The affinity of ZIENT and
      EIENT for DAT was 69 and 1.6-fold lower, respectively, than for SERT. In vivo
      biodistribution and blocking studies were performed in male rats and demonstrated
      that the brain uptake of [(123)I]ZIENT was selective and specific for SERT-rich
      regions (hypothalamus, striatum, pons, and prefrontal cortex). SPECT brain
      imaging studies in monkeys demonstrated high [(123)I]ZIENT uptake in the
      diencephalon, which resulted in diencephalon-to-cerebellum ratios of 2.12 at 190
      min. [(123)I]ZIENT uptake in the diencephalon achieved transient equilibrium at
      157 min. In a displacement experiment of [(123)I]ZIENT in a cynomolgus monkey,
      radioactivity was reduced by 39% in the diencephalon at 101 min following
      injection of citalopram. The high specific activity one-step radiolabeling
      preparation and high selectivity of [(123)I]ZIENT for SERT support its candidacy
      as a radioligand for mapping brain SERT sites.

PMID- 12620071
TI  - Regioselective covalent modification of hemoglobin in search of antisickling
      agents.
AB  - Although the molecular defect in sickle hemoglobin that produces sickle cell
      disease has been known for decades, there is still no effective drug treatment
      that acts on hemoglobin itself. In this work, a series of diversely substituted
      isothiocyanates (R-NCS) were examined for their regioselective reaction with
      hemoglobin in an attempt to alter the solubility properties of sickle hemoglobin.
      Electrospray mass spectrometry, molecular modeling, X-ray crystallography, and
      conventional protein chemistry were used to study this regioselectivity and the
      resulting increase in solubility of the modified hemoglobin. Depending on the
      attached R-group, the isothiocyanates were found to react either with the
      Cysbeta93 or the N-terminal amine of the alpha-chain. One of the most effective
      compounds in the series, 2-(N,N-dimethylamino)ethyl isothiocyanate, selectively
      reacts with the thiol of Cysbeta93 which, in conjunction with the cationic group,
      was seen to perturb the local hemoglobin structure. This modified HbS shows an
      approximately 30% increase in solubility for the fully deoxygenated state, along
      with a significant increase in oxygen affinity. This compound and a related
      analogue appear to readily traverse the erythrocyte membrane. A discussion of the
      relation of these structural changes to inhibition of gelation is presented. The
      dual activities of increasing HbS oxygen affinity and directly inhibiting deoxy
      HbS polymerization, in conjunction with facile membrane traversal, suggest that
      these cationic isothiocyanates show substantial promise as lead compounds for
      development of therapeutic agents for sickle cell disease.

PMID- 12620072
TI  - Structure-activity relationships of acetylcholinesterase noncovalent inhibitors
      based on a polyamine backbone. 2. Role of the substituents on the phenyl ring and
      nitrogen atoms of caproctamine.
AB  - Continuing our studies on polyamine-based compounds of potential interest in the
      field of Alzheimer's disease therapeutics, we investigated the structure-activity
      relationships (SAR) of a lead compound (caproctamine, 3) identified in a previous
      work. In particular, we varied the substituents on the phenyl ring and on the
      nitrogen functions (both the amine and the amide), and studied the effects of
      such modifications on the inhibitory potency against isolated acetyl- and butyryl
      cholinesterase (AChE and BChE). Moreover, the ability of selected compounds to
      reverse the d-tubocurarine-induced neuromuscular blockade and their antagonism
      toward muscarinic M(2) receptors in guinea pig left atrium were assayed. The most
      interesting SAR result was the identification of a relationship between the
      electronic characteristics of 2-substituents (measured by pK(a)) and the AChE
      inhibitory potency (pIC(50)) of tertiary amine compounds 6-12, which was
      confirmed by the invariance of the pIC(50) values of the corresponding methiodide
      derivatives 14-20. With regard to the biological profile, the most interesting
      compound was the N-ethyl-analogue of caproctamine (9), that showed pIC(50) values
      of 7.73 (+/-0.02) and 5.65 (+/-0.03) against AChE and BChE, respectively. The
      ability to increase the acetylcholine level was maintained in the functional
      assay (pAI(50) for reversing the neuromuscular blockade was 6.45 (+/-0.07)), as
      well as the ability to antagonize the M(2) receptors (pK(b) = 5.65 (+/-0.06)).
      Moreover, 9 showed a long duration of action as AChE inhibitor, an useful
      property in view of a possible development of this compound as a therapeutic
      agent.

PMID- 12620074
TI  - Synthesis and cytotoxic activity of conjugates of muramyl and normuramyl
      dipeptides with batracylin derivatives.
AB  - The synthesis of MDP (muramyl dipeptide) or nor-MDP (normuramyl dipeptide)
      conjugates modified at the peptide part with batracylin (BAT) or batracylin
      derivatives is described. Batracylin was synthesized by our modified method
      (Scheme 3). The synthesis of BAT via this modified route now appears to be
      feasible on a multigram scale. Preliminary screening data obtained at the
      National Cancer Institute (NCI, Bethesda, MD) have revealed that the conjugates
      did not expose any cytotoxic activity even at 10(-4)-10(-8) M or microg/mL.
      During tests performed at Medical University of Gdansk, Poland, two analogues 11c
      and 11e reduced the proliferation of Ab melanoma cells in vitro compared with
      batracylin alone (Table 2, Figure 1).

PMID- 12620073
TI  - 4-Hydroxymethyl-3-aminoacridine derivatives as a new family of anticancer agents.
AB  - 3-Amino- and 3-alkylamino-4-hydroxymethylacridines bearing various substituents
      on the C ring have been prepared by regioselective electrophilic aromatic
      substitution of the corresponding 3-aminoacridines and ring opening of the
      dihydrooxazinoacridine key intermediates. Most of the new compounds show potent
      cytotoxic activities against murine L1210 (leukemia), human A549 (lung), and HT29
      (colon) cancer cell lines. The most cytotoxic molecules, 1 and 13, are active at
      nanomolar concentrations. As predicted for acridine derivatives, the new
      compounds intercalate in DNA, but interestingly they do not interfere with
      topoisomerase I and II activities. The mode of action remains uncertain because
      intracellular distribution indicated very different behaviors for 1 and 13.
      Compound 13 is uniformly distributed in the cell both in the cytoplasm and in the
      nucleus, whereas compound 1 is essentially localized in cytoplasmic granules.

PMID- 12620075
TI  - Antitumor activity of novel deoxoartemisinin monomers, dimers, and trimer.
AB  - The first primary amines 9 and bromoalkyl analogues 7 of deoxoartemisinin with
      nonacetal functionality at C-12 are prepared as versatile intermediates for the
      synthesis of various derivatives. Eight C-12 nonacetal type dimers and one trimer
      of deoxoartemisinin were prepared using novel chemistry. Dimers, particularly
      12a, 18a,b, and trimer 17, were especially potent and selective at inhibiting the
      growth of certain human cancer cell lines and were comparable to that of
      clinically used anticancer drugs. The linker with one amide- or one sulfur
      centered two ethylene groups of the dimers is essential for high anticancer
      activity. Trimer 17 shows very potent activity against most of the human cancer
      cell lines tested.

PMID- 12620076
TI  - Synthesis of 3'- and 5'-nitrooxy pyrimidine nucleoside nitrate esters: "nitric
      oxide donor" agents for evaluation as anticancer and antiviral agents.
AB  - A group of 3'-O-nitro-2'-deoxyuridines, 3'-O-nitro-2'-deoxycytidines, and 5'-O
      nitro-2'-deoxyuridines possessing a variety of substituents (H, Me, F, I) at the
      C-5 position were synthesized for evaluation as anticancer/antiviral agents that
      have the ability to concomitantly release cytotoxic nitric oxide (*NO). Although
      these compounds generally released a greater percent of *NO than the reference
      drug isosorbide dinitrate upon incubation in the presence of l-cysteine, or
      serum, their cytotoxicity (CC(50) = 10(-3) to 10(-6) M range) was comparable to 5
      iodo-2'-deoxyuridine, but weaker than 5-fluoro-2'-deoxyuridine, against a variety
      of cancer cell lines. No differences in cytotoxicity against nontransfected
      (KBALB, 143B), and the corresponding transfected (KBALB-STK, 143B-LTK) cancer
      cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase
      gene (TK(+)) were observed, indicating that expression of the viral TK enzyme did
      not provide a gene therapeutic effect. These nitrate esters were inactive
      antiviral agents except for 5-iodo-3'-O-nitro-2'-deoxyuridine that showed modest
      activity against HSV-1, HSV-2, and vaccinia virus.

PMID- 12620077
TI  - Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2
      fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having
      fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents.
AB  - A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8
      methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1
      yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs
      for infections caused by Gram-positive pathogens, which include resistant strains
      such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant
      Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE).
      These fluorinated compounds 2-4 exhibited potent antibacterial activity
      comparable with that of a compound bearing a non-fluorinated (3R)-3-(1
      aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least
      4 times more potent activity against representative Gram-positive bacteria than
      ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them,
      the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3
      (=DQ-113), which showed favorable profiles in preliminary toxicological and
      nonclinical pharmcokinetic studies, exhibited potent antibacterial activity
      against clinically isolated resistant Gram-positive pathogens.

PMID- 12620079
TI  - Systematic development of high affinity bis(ammonio)alkane-type allosteric
      enhancers of muscarinic ligand binding.
AB  - Bis(ammonio)alkane compounds carrying lateral phthalimidopropyl substituents on
      the nitrogen atoms belong to the archetypal muscarinic allosteric agents. Herein,
      a series of symmetrical and nonsymmetrical compounds was synthesized in which the
      phthalimide residues were replaced by differently substituted imide moieties. The
      allosteric action was measured in porcine heart muscarinic M(2) receptors using
      [(3)H]N-methylscopolamine (NMS) as a ligand for the orthosteric receptor site in
      equilibrium binding and dissociation experiments. 1,8-Naphthalimido residues
      conferred an up to 100-fold gain in affinity leading into the low nanomolar
      range, while the inhibition of NMS binding was maintained. Additional propyl
      chain methylation was accompanied by an allosteric elevation of orthosteric
      ligand binding. In general, the gain in allosteric activity achieved by ring
      variation plus propyl chain methylation on one side of the molecule could not be
      augmented by symmetrical variations. The elevation of the ligand binding can be
      explained by different quantitative structure-activity relationships for the
      affinities to the free and the orthoster-liganded receptor.

PMID- 12620078
TI  - Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution
      on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4
      trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.
AB  - The preparation and characterization of a series of C-10 substituted 5-allyl-2,5
      dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of
      selective ligands for the glucocorticoid receptor is described. Substitution at
      the C-10 position of the tetracyclic core with linear, two-atom appendages
      (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of
      high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with
      limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal
      analogues showed slightly less potent but highly efficacious E-selectin
      repression with reduced levels of GRE activation efficacy in reporter gene assays
      relative to prednisolone. Preliminary SAR of analogues containing substitution at
      the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH,
      10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition
      in a conconavalin A stimulated T-cell proliferation assay in both rodent and
      human whole blood monocytes. When evaluated for their in vivo effects in
      carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed
      dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15
      mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for
      prednisolone).

PMID- 12620080
TI  - Trypanocidal activity of conformationally restricted pentamidine congeners.
AB  - A series of conformationally restricted congeners of pentamidine in which the
      flexible pentyl bridge of pentamidine was replaced by trans-1,2
      bismethylenecyclopropyl, phenyl, pyridinyl, piperazinyl, homopiperazinyl, and
      piperidinyl groups were synthesized. The compounds were evaluated for
      trypanocidal activity in vitro and in vivo against one drug-sensitive and three
      drug-resistant trypanosome isolates. The DNA binding affinity of the compounds
      was also studied using calf thymus DNA and poly(dA-dT). The nature of the linker
      influenced the DNA binding affinity as well as the trypanocidal activity of the
      compounds. trans-1,2-Bis(4-amidinophenoxymethylene)cyclopropane (1) was over 25
      fold more potent than pentamidine against the drug-resistant isolate KETRI 243As
      10-3, albeit with comparable DNA binding affinity. N,N'-Bis(4
      amidinophenyl)homopiperazine (8) was the most potent trypanocide in vitro against
      all four trypanosome isolates studied, but N,N'-bis(4-amidinophenyl)piperazine
      (6) was the most effective agent in vivo against both drug-sensitive and drug
      resistant trypanosomes.

PMID- 12620081
TI  - Synthesis and cytotoxic activity of carboxamide derivatives of
      benzo[b][1,6]naphthyridines.
AB  - The reaction of 4-dimethylaminomethylene-6-methyl-4H-pyrano[4,3-b]quinoline-1,3
      dione with a range of primary amines gave rise to a series of 2-substituted 6
      methyl-1-oxo-1,2-dihydrobenzo[b][1,6]naphthyridine-4-carboxylic acids. The
      derived 4-N-[2-(dimethylamino)ethyl]carboxamides were tested for growth
      inhibitory properties against murine P388 leukemia, Lewis lung carcinoma (LLTC),
      and human Jurkat leukemia cell lines. Most compounds were potent cytotoxins, with
      some having IC(50) values less than 10 nM. Five were tested in vivo against
      subcutaneous colon 38 tumors in mice, and a single dose (3.9 mg/kg) proved to be
      curative for the 2-methyl and 2-(3,4-dimethoxyphenyl) derivatives in this
      refractory model.

PMID- 12620082
TI  - [(3-Chlorophenyl)piperazinylpropyl]pyridazinones and analogues as potent
      antinociceptive agents.
AB  - A number of [(3-chlorophenyl)piperazinylpropyl]pyridazinones and the
      corresponding isoxazolopyridazinones, showing the arylpiperazinyl substructure
      present in very potent antinociceptive agents reported in the literature, were
      synthesized and tested for their analgesic activity. The investigated compounds
      showed antinociceptive properties in the mouse hot-plate test (thermal
      nociceptive stimulus) after systemic administration with an efficacy similar to
      that exerted by morphine. The increase of the pain threshold induced by the
      compounds labeled 5a, 7, 8, and 11 was prevented by reserpine, suggesting the
      involvement of the noradrenergic and/or serotoninergic system in their mechanism
      of action. Among them, 7 and 11 showed the highest analgesic potency and efficacy
      together with a good ratio (133 and 200, respectively) of the minimal nontoxic
      dose (MNTD) to the minimal analgesic dose (MAD). Furthermore, they were also
      active after icv administration and in the presence of a chemical, painful
      stimulus (abdominal constriction test).

PMID- 12620083
TI  - Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with
      high stability and efficacy.
AB  - In only two steps and in 70% overall yield, naturally occurring trioxane
      artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3.
      This new, very stable dimer was then transformed easily in one additional step
      into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer
      7 are 10 times more antimalarially potent in vitro than artemisinin (1), and
      alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic
      toward several human cancer cell lines. Water-soluble carboxylic acid derivatives
      8aand 9 were easily prepared in one additional step from dimers 4 and 5.
      Carboxylic acid dimers 8a and 9 are thermally stable even at 60 degrees C for 24
      h, are more orally efficacious as antimalarials in rodents than either artelinic
      acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward
      several human cancer cell lines.

PMID- 12620084
TI  - QSAR and classification of murine and human soluble epoxide hydrolase inhibition
      by urea-like compounds.
AB  - A data set of 348 urea-like compounds that inhibit the soluble epoxide hydrolase
      enzyme in mice and humans is examined. Compounds having IC(50) values ranging
      from 0.06 to >500 microM (murine) and 0.10 to >500 microM (human) are categorized
      as active or inactive for classification, while quantitation is performed on
      smaller compound subsets ranging from 0.07 to 431 microM (murine) and 0.11 to 490
      microM (human). Each compound is represented by calculated structural descriptors
      that encode topological, geometrical, electronic, and polar surface features.
      Multiple linear regression (MLR) and computational neural networks (CNNs) are
      employed for quantitative models. Three classification algorithms, k-nearest
      neighbor (kNN), linear discriminant analysis (LDA), and radial basis function
      neural networks (RBFNN), are used to categorize compounds as active or inactive
      based on selected data split points. Quantitative modeling of human enzyme
      inhibition results in a nonlinear, five-descriptor model with root-mean-square
      errors (log units of IC(50) [microM]) of 0.616 (r(2) = 0.66), 0.674 (r(2) =
      0.61), and 0.914 (r(2) = 0.33) for training, cross-validation, and prediction
      sets, respectively. The best classification results for human and murine enzyme
      inhibition are found using kNN. Human classification rates using a seven
      descriptor model for training and prediction sets are 89.1% and 91.4%,
      respectively. Murine classification rates using a five-descriptor model for
      training and prediction sets are 91.5% and 88.6%, respectively.

PMID- 12620085
TI  - Autonomy or professionalism?

PMID- 12620086
TI  - An investigation into the analgesic effects of interferential currents and
      transcutaneous electrical nerve stimulation on experimentally induced ischemic
      pain in otherwise pain-free volunteers.
AB  - BACKGROUND AND PURPOSE: Interferential currents (IFC) and transcutaneous
      electrical nerve stimulation (TENS) are used for pain management. This study
      compared the analgesic effects of IFC and TENS on experimentally induced ischemic
      pain in otherwise pain-free subjects using a modified version of the submaximal
      effort tourniquet technique. SUBJECTS: The subjects were 30 volunteers (18 male,
      12 female) without known pathology that could cause pain. Their mean age was 33.5
      years (SD=9.9, range=21-54). METHOD: A single-blind, sham-controlled, parallel
      group method was used. The primary outcome measure was the change in the self
      report of pain intensity during 1 of 3 possible interventions: (1) IFC, (2) TENS,
      or (3) sham electrotherapy. The IFC and TENS were administered on the forearm,
      and the sham electrotherapy group received no current output via a dummy
      stimulator. RESULTS: A 2-way repeated-measures analysis of variance revealed that
      there was no change in pain intensity during treatment when all 3 groups were
      considered together. Further analysis revealed that IFC reduced pain intensity
      when compared with sham electrotherapy but not when compared only with TENS.
      DISCUSSION AND CONCLUSION: There were no differences in the magnitude of
      analgesia between IFC and TENS. Interferential currents reduced pain intensity to
      a greater extent than sham electrotherapy.

PMID- 12620087
TI  - A qualitative study of clinical decision making in recommending discharge
      placement from the acute care setting.
AB  - BACKGROUND AND PURPOSE: One of the roles of rehabilitation professionals in the
      acute care setting is making recommendations for patients' discharge placement.
      The purpose of this investigation was to explore the decision-making process of
      physical therapists and occupational therapists when recommending discharge
      destination for patients following acute care hospitalization. SUBJECTS:
      Participants were 7 physical therapists and 2 occupational therapists in an acute
      care rotation at a large academic medical center. METHODS: A grounded-theory
      strategy was used. Three interviews were conducted and guided by questions about
      participants' approaches to discharge decision making. Information from the
      interview transcripts was used to define constructs. A model was generated to
      explain the relationships among the constructs. RESULTS: Decision making
      regarding discharge recommendations was guided by 4 constructs: patients'
      functioning and disability, patients' wants and needs, patients' ability to
      participate in care, and patients' life context. Information was filtered through
      therapists' experiences and modified by the health care team's opinions and by
      health care regulations. DISCUSSION AND CONCLUSION: The decision making of the
      rehabilitation professionals studied in recommending discharge placements for
      their patients reflects consideration of patients as individuals and the
      environments in which they live. Information about patients is filtered through
      the experience of therapists and influenced by health care regulations and
      opinions of other health care professionals, the patients, and their associates.
      The findings might be used in teaching clinical decision making to clinicians and
      students as they learn to make discharge recommendations.

PMID- 12620088
TI  - A physiological profile approach to falls risk assessment and prevention.
AB  - The purpose of this perspective article is to describe the use of a physiological
      profile approach to falls risk assessment and prevention that has been developed
      by the Falls and Balance Research Group of the Prince of Wales Medical Research
      Institute, Sydney, Australia. The profile's use for people with a variety of
      factors that put them at risk for falls is discussed. The Physiological Profile
      Assessment (PPA) involves a series of simple tests of vision, peripheral
      sensation, muscle force, reaction time, and postural sway. The tests can be
      administered quickly, and all equipment needed is portable. The results can be
      used to differentiate people who are at risk for falls ("fallers") from people
      who are not at risk for falls ("nonfallers"). A computer program using data from
      the PPA can be used to assess an individual's performance in relation to a
      normative database so that deficits can be targeted for intervention. The PPA
      provides valid and reliable measurements that can be used for assessing falls
      risk and evaluating the effectiveness of interventions and is suitable for use in
      a range of physical therapy and health care settings.

PMID- 12620089
TI  - Use of power mobility for a young child with spinal muscular atrophy.
AB  - BACKGROUND AND PURPOSE: Young children with severe motor impairments, such as
      spinal muscular atrophy, are often unable to move around their environment
      independently; therefore, they may be at risk for delays in areas of development
      not directly related to their motor limitations. Power mobility is an
      intervention that provides young children a means of independent movement and
      enables them to independently explore their environment. CASE DESCRIPTION: The
      participant was a 20-month-old girl with type II spinal muscular atrophy.
      INTERVENTION: The authors provided the child with a power wheelchair and gave her
      mother and physical therapist general guidelines to encourage her use of the
      power wheelchair. OUTCOMES: Within 6 weeks after receiving the power wheelchair,
      the child operated the wheelchair independently. She showed developmental gains
      in all domains of the Battelle Developmental Inventory and the Pediatric
      Evaluation of Disability Inventory over 6 months. The authors conducted an
      interview with the child's mother before and after intervention. She reported
      that the child was more independent after receiving the power wheelchair.
      DISCUSSION: The power wheelchair may have been associated with the changes in the
      child's mobility and her developmental changes over 6 months.

PMID- 12620090
TI  - Musculoskeletal deterioration and hemicorporectomy after spinal cord injury.
AB  - BACKGROUND AND PURPOSE: The long-term management following an hemicorporectomy
      (HCP) is not well documented in the scientific literature. The purpose of this
      case report is to describe the 25-year history of a man with a spinal cord injury
      who experienced severe musculoskeletal deterioration and hemicorporectomy. CASE
      DESCRIPTION: The client sustained T10 complete paraplegia at age 18 years,
      developed severe decubitus ulcers, and required an HCP as a life-saving measure
      13 years later. The authors describe the chronology of several rehabilitation and
      prosthetic strategies and speculate on factors that may have contributed to their
      successes and failures. OUTCOMES: The client survived 12 years after the HCP and
      returned to independent mobility, self-care, and schooling despite complications
      with continued skin breakdown. Over the 12 years following discharge from the
      hospital after the spinal cord injury, he spent 749 days in the hospital. During
      the 12 years he lived after discharge from the hospital following the HCP, he was
      hospitalized 190 days. DISCUSSION: The authors discuss factors contributing to
      the client's musculoskeletal deterioration including chronic wounds, postural
      deviations, and incomplete adherence to pressure-relief recommendations and raise
      considerations for physical therapists who treat patients after HCP.

PMID- 12620091
TI  - Obesity: overview of prevalence, etiology, and treatment.

PMID- 12620092
TI  - Identification of a novel mannose-capped lipoarabinomannan from Amycolatopsis
      sulphurea.
AB  - The genus Amycolatopsis is a member of the phylogenetic group nocardioform
      actinomycetes, which also includes the genus Mycobacterium. Members of this group
      have a characteristic cell envelope structure, dominated by various complex
      lipids and polysaccharides. Amongst these, lipoglycans are of particular interest
      since mycobacterial lipoarabinomannans are important immunomodulatory molecules.
      In this study we report the isolation and structural characterization of
      Amycolatopsis sulphurea lipoarabinomannan, designated AsuLAM. SDS/PAGE analysis
      revealed that AsuLAM was of an intermediate size between Mycobacterium
      tuberculosis lipoarabinomannan and lipomannan, confirmed by matrix-assisted laser
      desorption ionization-time-of-flight mass spectrometry that predicted an average
      molecular mass of 10 kDa. Using a range of chemical degradations, NMR experiments
      and capillary electrophoresis analysis, AsuLAM was revealed as an original
      structure. The mannosyl-phosphatidyl- myo -inositol anchor exhibits a single acyl
      form, characterized by a diacylated glycerol moiety, and contains, as one of the
      main fatty acids, 14-methyl-pentadecanoate, a characteristic fatty acid of the
      Amycolatopsis genus. AsuLAM also contains a short mannan domain; and is dominated
      by a multi-branched arabinan domain, composed of an (alpha1-->5)-Ara f
      (arabinofuranose) chain substituted, predominately at the O -2 position, by a
      single beta-Ara f. The arabinan domain is further elaborated by manno
      oligosaccharide caps, with around one per molecule. This is the first description
      of manno-oligosaccharide caps found in a non-mycobacterial LAM. AsuLAM was unable
      to induce the production of the pro-inflammatory cytokine tumour necrosis factor
      alpha when tested with human or murine macrophage cell lines, reinforcing the
      paradigm that mannose-capped LAM are poor inducers of pro-inflammatory cytokines.

PMID- 12620093
TI  - Cytosolic iron superoxide dismutase is a part of the triacylglycerol biosynthetic
      complex in oleaginous yeast.
AB  - A novel multienzyme complex for the biosynthesis of triacylglycerol in oleaginous
      yeast has been identified recently in the cytosol and characterized [Gangar,
      Karande and Rajasekharan (2001) J. Biol. Chem. 276, 10290-10298]. Screening the
      library of Rhodotorula glutinis with an oligonucleotide probe derived from the N
      terminal sequence of one of the protein components in the complex (21 kDa
      protein) resulted in the isolation of a 0.7 kb cDNA. Nucleotide sequence analysis
      revealed that the isolated gene codes for superoxide dismutase (SOD). Atomic
      absorption spectroscopy and inhibition assays showed that this cytosolic SOD
      utilizes Fe as its cofactor. Enzymic assays, immunoprecipitation and cross
      linking experiments revealed that SOD is a part of the triacylglycerol
      biosynthetic complex, which could protect the substrate and the complex from
      oxidative damages. These results indicate for the first time the presence of iron
      containing SOD in a soluble form in yeast.

PMID- 12620095
TI  - Still no flying cars.
AB  - Why, after less than two centuries of almost incomprehensible technological
      progress has progress in so many areas seemed to slow almost to a halt.

PMID- 12620094
TI  - The random-coil 'C' fragment of the dihydropyridine receptor II-III loop can
      activate or inhibit native skeletal ryanodine receptors.
AB  - The actions of peptide C, corresponding to (724)Glu-Pro(760) of the II-III loop
      of the skeletal dihydropyridine receptor, on ryanodine receptor (RyR) channels
      incorporated into lipid bilayers with the native sarcoplasmic reticulum membrane
      show that the peptide is a high-affinity activator of native skeletal RyRs at
      cytoplasmic concentrations of 100 nM-10 microM. In addition, we found that
      peptide C inhibits RyRs in a voltage-independent manner when added for longer
      times or at higher concentrations (up to 150 microM). Peptide C had a random-coil
      structure indicating that it briefly assumes a variety of structures, some of
      which might activate and others which might inhibit RyRs. The results suggest
      that RyR activation and inhibition by peptide C arise from independent stochastic
      processes. A rate constant of 7.5 x 10(5) s(-1).M(-1) was obtained for activation
      and a lower estimate for the rate constant for inhibition of 5.9 x 10(3) s(-1).M(
      1). The combined actions of peptide C and peptide A (II-III loop sequence
      (671)Thr-Leu(690)) showed that peptide C prevented activation but not blockage of
      RyRs by peptide A. We suggest that the effects of peptide C indicate functional
      interactions between a part of the dihydropyridine receptor and the RyR. These
      interactions could reflect either dynamic changes that occur during excitation
      contraction coupling or interactions between the proteins at rest.

PMID- 12620096
TI  - Beenomes to Bombyx: future directions in applied insect genomics.
AB  - The recent sequencing of the Anopheles gambiae genome showcases the genetic
      breadth of insects and a trend towards sequencing organisms directly involved
      with human welfare. We describe traits in other insect species that make them
      important candidates for genomics projects, and review several recent workshops
      aimed at uniting researchers working with insect species to efficiently address
      problems in medicine, biotechnology, and agriculture.

PMID- 12620098
TI  - Seeing chordate evolution through the Ciona genome sequence.
AB  - A draft sequence of the compact genome of the sea squirt Ciona intestinalis, a
      non-vertebrate chordate that diverged very early from other chordates, including
      vertebrates, illuminates how chordates originated and how vertebrate
      developmental innovations evolved.

PMID- 12620097
TI  - Overview of the voltage-gated sodium channel family.
AB  - Selective permeation of sodium ions through voltage-dependent sodium channels is
      fundamental to the generation of action potentials in excitable cells such as
      neurons. These channels are large integral membrane proteins and are encoded by
      at least ten genes in mammals. The different sodium channels have remarkably
      similar functional properties, but small changes in sodium-channel function are
      biologically relevant, as underscored by mutations that cause several human
      diseases of hyperexcitability.

PMID- 12620099
TI  - Genomics and chloroplast evolution: what did cyanobacteria do for plants?
AB  - The complete genome sequences of cyanobacteria and of the higher plant
      Arabidopsis thaliana leave no doubt that the plant chloroplast originated,
      through endosymbiosis, from a cyanobacterium. But the genomic legacy of
      cyanobacterial ancestry extends far beyond the chloroplast itself, and persists
      in organisms that have lost chloroplasts completely.

PMID- 12620100
TI  - The epigenetics of the cell.

PMID- 12620101
TI  - From linear genome sequence to three-dimensional organization of the cell
      nucleus.

PMID- 12620102
TI  - MicroSAGE is highly representative and reproducible but reveals major differences
      in gene expression among samples obtained from similar tissues.
AB  - BACKGROUND: Serial analysis of gene expression using small amounts of starting
      material (microSAGE) has not yet been conclusively shown to be representative,
      reproducible or accurate. RESULTS: We show that microSAGE is highly
      representative, reproducible and accurate, but that pronounced differences in
      gene expression are seen between tissue samples taken from different individuals.
      CONCLUSIONS: MicroSAGE is a reliable method of comprehensively profiling
      differences in gene expression among samples, but care should be taken in
      generalizing results obtained from libraries constructed from tissue obtained
      from different individuals and/or processed or stored differently.

PMID- 12620103
TI  - Feminizing chicks: a model for avian sex determination based on titration of Hint
      enzyme activity and the predicted structure of an Asw-Hint heterodimer.
AB  - BACKGROUND: In birds and some lizards, females are heterogametic with a ZW
      karyotype, while males are ZZ homogametes. The molecular basis for sexual
      differentiation in birds is unknown: arguments exist for doses of Z masculinizing
      chicks and for W information feminizing. ASW was identified as a tandemly
      repeated gene conserved on avian W chromosomes that is expressed in early female
      development and appears to be an inactive form of avian Z-encoded HINT. Hint is a
      dimeric enzyme that hydrolyzes AMP linked to lysine, whose enzyme activity is
      required for regulation of the Cdk7 homologous Kin28 kinase in yeast. Of 16
      residues most conserved across all life forms for AMP interactions, 15 are
      sexually dimorphic in birds, that is, altered in the female-specific Asw protein.
      Genomic and expression data suggest that Asw may feminize chicks, dominantly
      interfering with Hint function by heterodimerization. RESULTS: We consider
      whether positive cooperativity could explain how Hint heterodimerization with an
      inert enzyme might reduce specific activity by more than 50% and provide data
      sufficient to reject this model. Instead, we hypothesize that Asw carries a
      signal for mislocalization and/or proteolysis, and/or dominantly suppresses the
      remaining Hint active site to function as a dominant negative. CONCLUSIONS:
      Molecular modeling suggests that Asw and Hint can heterodimerize and that Gln
      127, an Asw-specific alteration for Trp123, dominantly interferes with the Hint
      active site. An extra dose of HINT in ZZW chicks, and thus more Hint homodimer,
      may partially overcome the feminizing influence of ASW and lead to the observed
      intersexual characteristics of ZZW triploids.

PMID- 12620104
TI  - The rhomboids: a nearly ubiquitous family of intramembrane serine proteases that
      probably evolved by multiple ancient horizontal gene transfers.
AB  - BACKGROUND: The rhomboid family of polytopic membrane proteins shows a level of
      evolutionary conservation unique among membrane proteins. They are present in
      nearly all the sequenced genomes of archaea, bacteria and eukaryotes, with the
      exception of several species with small genomes. On the basis of experimental
      studies with the developmental regulator rhomboid from Drosophila and the AarA
      protein from the bacterium Providencia stuartii, the rhomboids are thought to be
      intramembrane serine proteases whose signaling function is conserved in
      eukaryotes and prokaryotes. RESULTS: Phylogenetic tree analysis carried out using
      several independent methods for tree constructions and the corresponding
      statistical tests suggests that, despite its broad distribution in all three
      superkingdoms, the rhomboid family was not present in the last universal common
      ancestor of extant life forms. Instead, we propose that rhomboids evolved in
      bacteria and have been acquired by archaea and eukaryotes through several
      independent horizontal gene transfers. In eukaryotes, two distinct, ancient
      acquisitions apparently gave rise to the two major subfamilies, typified by
      rhomboid and PARL (presenilins-associated rhomboid-like protein), respectively.
      Subsequent evolution of the rhomboid family in eukaryotes proceeded by multiple
      duplications and functional diversification through the addition of extra
      transmembrane helices and other domains in different orientations relative to the
      conserved core that harbors the protease activity. CONCLUSIONS: Although the near
      universal presence of the rhomboid family in bacteria, archaea and eukaryotes
      appears to suggest that this protein is part of the heritage of the last
      universal common ancestor, phylogenetic tree analysis indicates a likely
      bacterial origin with subsequent dissemination by horizontal gene transfer. This
      emphasizes the importance of explicit phylogenetic analysis for the
      reconstruction of ancestral life forms. A hypothetical scenario for the origin of
      intracellular membrane proteases from membrane transporters is proposed.

PMID- 12620107
TI  - Osprey: a network visualization system.
AB  - We have developed a software platform called Osprey for visualization and
      manipulation of complex interaction networks. Osprey builds data-rich graphical
      representations that are color-coded for gene function and experimental
      interaction data. Mouse-over functions allow rapid elaboration and organization
      of network diagrams in a spoke model format. User-defined large-scale datasets
      can be readily combined with Osprey for comparison of different methods.

PMID- 12620106
TI  - Identification of expressed genes linked to malignancy of human colorectal
      carcinoma by parametric clustering of quantitative expression data.
AB  - BACKGROUND: Individual human carcinomas have distinct biological and clinical
      properties: gene-expression profiling is expected to unveil the underlying
      molecular features. Particular interest has been focused on potential diagnostic
      and therapeutic applications. Solid tumors, such as colorectal carcinoma, present
      additional obstacles for experimental and data analysis. RESULTS: We analyzed the
      expression levels of 1,536 genes in 100 colorectal cancer and 11 normal tissues
      using adaptor-tagged competitive PCR, a high-throughput reverse transcription-PCR
      technique. A parametric clustering method using the Gaussian mixture model and
      the Bayes inference revealed three groups of expressed genes. Two contained large
      numbers of genes. One of these groups correlated well with both the differences
      between tumor and normal tissues and the presence or absence of distant
      metastasis, whereas the other correlated only with the tumor/normal difference.
      The third group comprised a small number of genes. Approximately half showed an
      identical expression pattern, and cancer tissues were classified into two groups
      by their expression levels. The high-expression group had strong correlation with
      distant metastasis, and a poorer survival rate than the low-expression group,
      indicating possible clinical applications of these genes. In addition to c-yes, a
      homolog of a viral oncogene, prognostic indicators included genes specific to
      glial cells, which gives a new link between malignancy and ectopic gene
      expression. CONCLUSIONS: The malignancy of human colorectal carcinoma is
      correlated with a unique expression pattern of a specific group of genes,
      allowing the classification of tumor tissues into two clinically distinct groups.

PMID- 12620105
TI  - Characterizing the stress/defense transcriptome of Arabidopsis.
AB  - BACKGROUND: To understand the gene networks that underlie plant stress and
      defense responses, it is necessary to identify and characterize the genes that
      respond both initially and as the physiological response to the stress or
      pathogen develops. We used PCR-based suppression subtractive hybridization to
      identify Arabidopsis genes that are differentially expressed in response to
      ozone, bacterial and oomycete pathogens and the signaling molecules salicylic
      acid (SA) and jasmonic acid. RESULTS: We identified a total of 1,058
      differentially expressed genes from eight stress cDNA libraries. Digital northern
      analysis revealed that 55% of the stress-inducible genes are rarely transcribed
      in unstressed plants and 17% of them were not previously represented in
      Arabidopsis expressed sequence tag databases. More than two-thirds of the genes
      in the stress cDNA collection have not been identified in previous studies as
      stress/defense response genes. Several stress-responsive cis-elements showed a
      statistically significant over-representation in the promoters of the genes in
      the stress cDNA collection. These include W- and G-boxes, the SA-inducible
      element, the abscisic acid response element and the TGA motif. CONCLUSIONS: The
      stress cDNA collection comprises a broad repertoire of stress-responsive genes
      encoding proteins that are involved in both the initial and subsequent stages of
      the physiological response to abiotic stress and pathogens. This set of stress-,
      pathogen- and hormone-modulated genes is an important resource for understanding
      the genetic interactions underlying stress signaling and responses and may
      contribute to the characterization of the stress transcriptome through the
      construction of standardized specialized arrays.

PMID- 12620108
TI  - The GRID: the General Repository for Interaction Datasets.
AB  - We have developed a relational database, called the General Repository for
      Interaction Datasets (The GRID) to archive and display physical, genetic and
      functional interactions. The GRID displays data-rich interaction tables for any
      protein of interest, combines literature-derived and high-throughput interaction
      datasets, and is readily accessible via the web. Interactions parsed in The GRID
      can be viewed in graphical form with a versatile visualization tool called
      Osprey.

PMID- 12620109
TI  - Funky, not junky.
AB  - In many respects, the most intriguing part of the mouse genome sequence is what
      it has told us about so-called 'junk' DNA sequences.

PMID- 12620110
TI  - Exploiting microarrays to reveal differential gene expression in the nervous
      system.
AB  - Microarrays have been used in a wide variety of experimental systems, but
      realizing their full potential is contingent on sophisticated and rigorous
      experimental design and data analysis. This article highlights what is needed to
      get the most out of microarrays in terms of accurately and effectively revealing
      differential gene expression and regulation in the nervous system.

PMID- 12620111
TI  - DNA replication: telling time with microarrays.
AB  - A long-standing hypothesis about eukaryotic DNA replication is that the late
      replicating regions are transcriptionally inert and that repressing transcription
      delays replication initiation. But do contrasting results from yeast and a recent
      study in Drosophila imply that replication timing and transcriptional activity
      are differentially regulated in yeast and higher eukaryotes?

PMID- 12620112
TI  - Impressive expressions: developing a systematic database of gene-expression
      patterns in Drosophila embryogenesis.
AB  - The establishment of a database of gene-expression patterns derived from
      systematic high-throughput in situ hybridization studies on whole-mount
      Drosophila embryos, together with new information on the reannotated Drosophila
      genome and several recent microarray-based genomic analyses of Drosophila
      development, vastly increase the breadth and depth that can be reached by
      developmental genetics.

PMID- 12620114
TI  - The application of basic science to translational cancer research.
AB  - A report on the inaugural symposium of the Hutchison/MRC Research Centre,
      Cambridge, UK, 24-25 October 2002.

PMID- 12620115
TI  - Identifying transcribed sequences, and beyond.
AB  - A report on the 12th International Workshop 'Beyond the Identification of
      Transcribed Sequences (BITS): Functional, Expression and Evolutionary Analysis',
      Washington DC, USA, 25-28 October 2002.

PMID- 12620113
TI  - Sp1- and Kruppel-like transcription factors.
AB  - Sp1-like proteins and Kruppel-like factors (KLFs) are highly related zinc-finger
      proteins that are important components of the eukaryotic cellular transcriptional
      machinery. By regulating the expression of a large number of genes that have GC
      rich promoters, Sp1-like/KLF transcription regulators may take part in virtually
      all facets of cellular function, including cell proliferation, apoptosis,
      differentiation, and neoplastic transformation. Individual members of the Sp1
      like/KLF family can function as activators or repressors depending on which
      promoter they bind and the coregulators with which they interact. A long-standing
      research aim has been to define the mechanisms by which Sp1-like factors and KLFs
      regulate gene expression and cellular function in a cell- and promoter-specific
      manner. Most members of this family have been identified in mammals, with at
      least 21 Sp1-like/KLF proteins encoded in the human genome, and members are also
      found in frogs, worms and flies. Sp1-like/KLF proteins have highly conserved
      carboxy-terminal zinc-finger domains that function in DNA binding. The amino
      terminus, containing the transcription activation domain, can vary significantly
      between family members.

PMID- 12620116
TI  - Myriads of protein families, and still counting.
AB  - From the historical record of genome sequencing, we show that the rate of
      discovery of new families has remained constant over time, indicating that our
      knowledge of sequence space is far from complete.

PMID- 12620117
TI  - Positional clustering of differentially expressed genes on human chromosomes 20,
      21 and 22.
AB  - BACKGROUND: Clusters of genes co-expressed are known in prokaryotes (operons) and
      were recently described in several eukaryote organisms, including Human.
      According to some studies, these clusters consist of housekeeping genes, whereas
      other studies suggest that these clustered genes exhibit similar tissue
      specificity. Here we further explore the relationship between co-expression and
      chromosomal co-localization in the human genome by analyzing the expression
      status of the genes along the best-annotated chromosomes 20, 21 and 22. METHODS:
      Gene expression levels were estimated according to their publicly available ESTs
      and gene differential expressions were assessed using a previously described and
      validated statistical test. Gene sequences for chromosomes 20, 21 and 22 were
      taken from the Ensembl annotation. RESULTS: We identified clusters of genes
      specifically expressed in similar tissues along chromosomes 20, 21 and 22. These
      co-expression clusters occurred more frequently than expected by chance and may
      thus be biologically significant. CONCLUSION: The co-expression of co-localized
      genes might be due to higher chromatin structures influencing the gene
      availability for transcription in a given tissue or cell type.

PMID- 12620118
TI  - A search for doxycycline-dependent mutations that increase Drosophila
      melanogaster life span identifies the VhaSFD, Sugar baby, filamin, fwd and Cctl
      genes.
AB  - BACKGROUND: A P-type transposable element called PdL has been engineered with a
      doxycycline-inducible promoter directed out through the 3' end of the element.
      Insertion of PdL near the 5' end of a gene often yields doxycycline-dependent
      overexpression of that gene and a mutant phenotype. This functional genomics
      strategy allows for efficient screening of large numbers of genes for
      overexpression phenotypes. RESULTS: PdL was mobilized to around 10,000 new
      locations in the Drosophila melanogaster genome and used to search for genes that
      would extend life span when overexpressed. Six lines were identified in which
      there was a 5-17% increase in life span in the presence of doxyxcycline. The
      mutations were molecularly characterized and in each case a gene was found to be
      overexpressed using northern blots. Two genes did not have previously known
      phenotypes and are implicated in membrane transport: VhaSFD encodes a regulatory
      subunit of the vacuolar ATPase proton pump (H+-ATPase), whereas Sugar baby (Sug)
      is related to a maltose permease from Bacillus. Three PdL mutations identified
      previously characterized genes: filamin encodes the homolog of an actin
      polymerizing protein that interacts with presenilins. four wheel drive (fwd)
      encodes a phosphatidylinositol-4-kinase (PI 4-kinase) and CTP:phosphocholine
      cytidylyltransferase-l (Cctl) encodes the rate-limiting enzyme in
      phosphatidylcholine synthesis. Finally, an apparently novel gene (Red herring,
      Rdh) was found in the first intron of the encore gene. CONCLUSIONS: Screening for
      conditional mutations that increase Drosophila life span has identified genes
      implicated in membrane transport, phospholipid metabolism and signaling, and
      actin cytoskeleton organization.

PMID- 12620119
TI  - Expression profiling of the schizont and trophozoite stages of Plasmodium
      falciparum with a long-oligonucleotide microarray.
AB  - BACKGROUND: The worldwide persistence of drug-resistant Plasmodium falciparum,
      the most lethal variety of human malaria, is a global health concern. The P.
      falciparum sequencing project has brought new opportunities for identifying
      molecular targets for antimalarial drug and vaccine development. RESULTS: We
      developed a software package, ArrayOligoSelector, to design an open reading frame
      (ORF)-specific DNA microarray using the publicly available P. falciparum genome
      sequence. Each gene was represented by one or more long 70 mer oligonucleotides
      selected on the basis of uniqueness within the genome, exclusion of low
      complexity sequence, balanced base composition and proximity to the 3' end. A
      first-generation microarray representing approximately 6,000 ORFs of the P.
      falciparum genome was constructed. Array performance was evaluated through the
      use of control oligonucleotide sets with increasing levels of introduced
      mutations, as well as traditional northern blotting. Using this array, we
      extensively characterized the gene-expression profile of the intraerythrocytic
      trophozoite and schizont stages of P. falciparum. The results revealed extensive
      transcriptional regulation of genes specialized for processes specific to these
      two stages. CONCLUSIONS: DNA microarrays based on long oligonucleotides are
      powerful tools for the functional annotation and exploration of the P. falciparum
      genome. Expression profiling of trophozoites and schizonts revealed genes
      associated with stage-specific processes and may serve as the basis for future
      drug targets and vaccine development.

PMID- 12620120
TI  - Evidence from comparative genomics for a complete sexual cycle in the 'asexual'
      pathogenic yeast Candida glabrata.
AB  - BACKGROUND: Candida glabrata is a pathogenic yeast of increasing medical concern.
      It has been regarded as asexual since it was first described in 1917, yet
      phylogenetic analyses have revealed that it is more closely related to sexual
      yeasts than other Candida species. We show here that the C. glabrata genome
      contains many genes apparently involved in sexual reproduction. RESULTS: By
      genome survey sequencing, we find that genes involved in mating and meiosis are
      as numerous in C. glabrata as in the sexual species Kluyveromyces delphensis,
      which is its closest known relative. C. glabrata has a putative mating-type (MAT)
      locus and a pheromone gene (MFALPHA2), as well as orthologs of at least 31 other
      Saccharomyces cerevisiae genes that have no known roles apart from mating or
      meiosis, including FUS3, IME1 and SMK1. CONCLUSIONS: We infer that C. glabrata is
      likely to have an undiscovered sexual stage in its life cycle, similar to that
      recently proposed for C. albicans. The two Candida species represent two
      distantly related yeast lineages that have independently become both pathogenic
      and 'asexual'. Parallel evolution in the two lineages as they adopted mammalian
      hosts resulted in separate but analogous switches from overtly sexual to
      cryptically sexual life cycles, possibly in response to defense by the host
      immune system.

PMID- 12620122
TI  - Genesis and evolution of the Evx and Mox genes and the extended Hox and ParaHox
      gene clusters.
AB  - BACKGROUND: Hox and ParaHox gene clusters are thought to have resulted from the
      duplication of a ProtoHox gene cluster early in metazoan evolution. However, the
      origin and evolution of the other genes belonging to the extended Hox group of
      homeobox-containing genes, that is, Mox and Evx, remains obscure. We constructed
      phylogenetic trees with mouse, amphioxus and Drosophila extended Hox and other
      related Antennapedia-type homeobox gene sequences and analyzed the linkage data
      available for such genes. RESULTS: We claim that neither Mox nor Evx is a Hox or
      ParaHox gene. We propose a scenario that reconciles phylogeny with linkage data,
      in which an Evx/Mox ancestor gene linked to a ProtoHox cluster was involved in a
      segmental tandem duplication event that generated an array of all Hox-like genes,
      referred to as the 'coupled' cluster. A chromosomal breakage within this cluster
      explains the current composition of the extended Hox cluster (with Evx, Hox and
      Mox genes) and the ParaHox cluster. CONCLUSIONS: Most studies dealing with the
      origin and evolution of Hox and ParaHox clusters have not included the Hox
      related genes Mox and Evx. Our phylogenetic analyses and the available linkage
      data in mammalian genomes support an evolutionary scenario in which an ancestor
      of Evx and Mox was linked to the ProtoHox cluster, and that a tandem duplication
      of a large genomic region early in metazoan evolution generated the Hox and
      ParaHox clusters, plus the cluster-neighbors Evx and Mox. The large 'coupled' Hox
      like cluster EvxHox/MoxParaHox was subsequently broken, thus grouping the Mox and
      Evx genes to the Hox clusters, and isolating the ParaHox cluster.

PMID- 12620121
TI  - Evolutionary history, structural features and biochemical diversity of the
      NlpC/P60 superfamily of enzymes.
AB  - BACKGROUND: Peptidoglycan is hydrolyzed by a diverse set of enzymes during
      bacterial growth, development and cell division. The N1pC/P60 proteins define a
      family of cell-wall peptidases that are widely represented in various bacterial
      lineages. Currently characterized members are known to hydrolyze D-gamma-glutamyl
      meso-diaminopimelate or N-acetylmuramate-L-alanine linkages. RESULTS: Detailed
      analysis of the N1pC/P60 peptidases showed that these proteins define a large
      superfamily encompassing several diverse groups of proteins. In addition to the
      well characterized P60-like proteins, this superfamily includes the AcmB/LytN and
      YaeF/YiiX families of bacterial proteins, the amidase domain of bacterial and
      kinetoplastid glutathionylspermidine synthases (GSPSs), and several proteins from
      eukaryotes, phages, poxviruses, positive-strand RNA viruses, and certain archaea.
      The eukaryotic members include lecithin retinol acyltransferase (LRAT), nematode
      developmental regulator Egl-26, and candidate tumor suppressor H-rev107. These
      eukaryotic proteins, along with the bacterial YaeF/poxviral G6R family, show a
      circular permutation of the catalytic domain. We identified three conserved
      residues, namely a cysteine, a histidine and a polar residue, that are involved
      in the catalytic activities of this superfamily. Evolutionary analysis of this
      superfamily shows that it comprises four major families, with diverse domain
      architectures in each of them. CONCLUSIONS: Several related, but distinct,
      catalytic activities, such as murein degradation, acyl transfer and amide
      hydrolysis, have emerged in the N1pC/P60 superfamily. The three conserved
      catalytic residues of this superfamily are shown to be equivalent to the
      catalytic triad of the papain-like thiol peptidases. The predicted structural
      features indicate that the N1pC/P60 enzymes contain a fold similar to the papain
      like peptidases, transglutaminases and arylamine acetyltransferases.

PMID- 12620123
TI  - Genome-wide analysis of microsatellite repeats in humans: their abundance and
      density in specific genomic regions.
AB  - BACKGROUND: Simple sequence repeats (SSRs) are found in most organisms, and
      occupy about 3% of the human genome. Although it is becoming clear that such
      repeats are important in genomic organization and function and may be associated
      with disease conditions, their systematic analysis has not been reported. This is
      the first report examining the distribution and density of simple sequence
      repeats (1-6 base-pairs (bp)) in the entire human genome. RESULTS: The densities
      of SSRs across the human chromosomes were found to be relatively uniform.
      However, the overall density of SSR was found to be high in chromosome 19.
      Triplets and hexamers were more predominant in exonic regions compared to
      intronic and intergenic regions, except for chromosome Y. Comparison of densities
      of various SSRs revealed that whereas trimers and pentamers showed a similar
      pattern (500-1,000 bp/Mb) across the chromosomes, di- tetra- and hexa-nucleotide
      repeats showed patterns of higher (2,000-3,000 bp/Mb) density. Repeats of the
      same nucleotide were found to be higher than other repeat types. Repeats of A,
      AT, AC, AAT, AAC, AAG, AGC, AAAC, AAAT, AAAG, AAGG, AGAT predominate, whereas
      repeats of C, CG, ACT, ACG, AACC, AACG, AACT, AAGC, AAGT, ACCC, ACCG, ACCT, CCCG
      and CCGG are rare. CONCLUSIONS: The overall SSR density was comparable in all
      chromosomes. The density of different repeats, however, showed significant
      variation. Tri- and hexa-nucleotide repeats are more abundant in exons, whereas
      other repeats are more abundant in non-coding regions.

PMID- 12620125
TI  - Transcriptome analysis of Sinorhizobium meliloti during symbiosis.
AB  - BACKGROUND: Rhizobia induce the formation on specific legumes of new organs, the
      root nodules, as a result of an elaborated developmental program involving the
      two partners. In order to contribute to a more global view of the genetics
      underlying this plant-microbe symbiosis, we have mined the recently determined
      Sinorhizobium meliloti genome sequence for genes potentially relevant to
      symbiosis. We describe here the construction and use of dedicated nylon
      macroarrays to study simultaneously the expression of 200 of these genes in a
      variety of environmental conditions, pertinent to symbiosis. RESULTS: The
      expression of 214 S. meliloti genes was monitored under ten environmental
      conditions, including free-living aerobic and microaerobic conditions, addition
      of the plant symbiotic elicitor luteolin, and a variety of symbiotic conditions.
      Five new genes induced by luteolin have been identified as well as nine new genes
      induced in mature nitrogen-fixing bacteroids. A bacterial and a plant symbiotic
      mutant affected in nodule development have been found of particular interest to
      decipher gene expression at the intermediate stage of the symbiotic interaction.
      S. meliloti gene expression in the cultivated legume Medicago sativa (alfalfa)
      and the model plant M. truncatula were compared and a small number of differences
      was found. CONCLUSIONS: In addition to exploring conditions for a genome-wide
      transcriptome analysis of the model rhizobium S. meliloti, the present work has
      highlighted the differential expression of several classes of genes during
      symbiosis. These genes are related to invasion, oxidative stress protection, iron
      mobilization, and signaling, thus emphasizing possible common mechanisms between
      symbiosis and pathogenesis.

PMID- 12620124
TI  - Lateral gene transfer and ancient paralogy of operons containing redundant copies
      of tryptophan-pathway genes in Xylella species and in heterocystous
      cyanobacteria.
AB  - BACKGROUND: Tryptophan-pathway genes that exist within an apparent operon-like
      organization were evaluated as examples of multi-genic genomic regions that
      contain phylogenetically incongruous genes and coexist with genes outside the
      operon that are congruous. A seven-gene cluster in Xylella fastidiosa includes
      genes encoding the two subunits of anthranilate synthase, an aryl-CoA synthetase,
      and trpR. A second gene block, present in the Anabaena/Nostoc lineage, but not in
      other cyanobacteria, contains a near-complete tryptophan operon nested within an
      apparent supraoperon containing other aromatic-pathway genes. RESULTS: The gene
      block in X. fastidiosa exhibits a sharply delineated low-GC content. This, as
      well as bias of codon usage and 3:1 dinucleotide analysis, strongly implicates
      lateral gene transfer (LGT). In contrast, parametric studies and protein tree
      phylogenies did not support the origination of the Anabaena/Nostoc gene block by
      LGT. CONCLUSIONS: Judging from the apparent minimal amelioration, the low-GC gene
      block in X. fastidiosa probably originated by LGT at a relatively recent time.
      The surprising inability to pinpoint a donor lineage still leaves room for
      alternative, albeit less likely, explanations other than LGT. On the other hand,
      the large Anabaena/Nostoc gene block does not seem to have arisen by LGT. We
      suggest that the contemporary Anabaena/Nostoc array of divergent paralogs
      represents an ancient ancestral state of paralog divergence, with extensive
      streamlining by gene loss occurring in the lineage of descent representing other
      (unicellular) cyanobacteria.

PMID- 12620126
TI  - Integrating computationally assembled mouse transcript sequences with the Mouse
      Genome Informatics (MGI) database.
AB  - Databases of experimentally generated and computationally derived transcript
      sequences are valuable resources for genome analysis and annotation. The utility
      of such databases is enhanced when the sequences they contain are integrated with
      such biological information as genomic location, gene function, gene expression
      and phenotypic variation. We present the analysis and results of a semi-automated
      process of connecting transcript assemblies with highly curated biological
      information for mouse genes that is available through the Mouse Genome
      Informatics (MGI) database.

PMID- 12620127
TI  - Low self-esteem and psychiatric patients: Part I - The relationship between low
      self-esteem and psychiatric diagnosis.
AB  - BACKGROUND: The objective of the current study was to determine the prevalence
      and the degree of lowered self-esteem across the spectrum of psychiatric
      disorders. METHOD: The present study was carried out on a consecutive sample of
      1,190 individuals attending an open-access psychiatric outpatient clinic. There
      were 957 psychiatric patients, 182 cases with conditions not attributable to a
      mental disorder, and 51 control subjects. Patients were diagnosed according to
      DSM III-R diagnostic criteria following detailed assessments. At screening,
      individuals completed two questionnaires to measure self-esteem, the Rosenberg
      self-esteem scale and the Janis and Field Social Adequacy scale. Statistical
      analyses were performed on the scores of the two self-esteem scales. RESULTS: The
      results of the present study demonstrate that all psychiatric patients suffer
      some degree of lowered self-esteem. Furthermore, the degree to which self-esteem
      was lowered differed among various diagnostic groups. Self-esteem was lowest in
      patients with major depressive disorder, eating disorders, and substance abuse.
      Also, there is evidence of cumulative effects of psychiatric disorders on self
      esteem. Patients who had comorbid diagnoses, particularly when one of the
      diagnoses was depressive disorders, tended to show lower self-esteem.
      CONCLUSIONS: Based on both the previous literature, and the results from the
      current study, we propose that there is a vicious cycle between low self-esteem
      and onset of psychiatric disorders. Thus, low self-esteem increases the
      susceptibility for development of psychiatric disorders, and the presence of a
      psychiatric disorder, in turn, lowers self-esteem. Our findings suggest that this
      effect is more pronounced with certain psychiatric disorders, such as major
      depression and eating disorders.

PMID- 12620128
TI  - Complementary and alternative medicine: the need for data.

PMID- 12620129
TI  - Alternating bundle branch block.

PMID- 12620130
TI  - The ten most commonly asked questions about measuring left ventricular function.

PMID- 12620131
TI  - Risk assessment by myocardial perfusion imaging for coronary revascularization,
      medical therapy, and noncardiac surgery.
AB  - Stress myocardial perfusion imaging (MPI) has become an important tool in risk
      stratification of patients with known coronary artery disease. A normal
      myocardial perfusion scan has a high negative predictive value and is associated
      with low annual mortality rate (< 1%). Patients with extensive ischemia (> 20% of
      the left ventricle), defects in more than 1 coronary vascular territory,
      transient or persistent left ventricular cavity dilation, and ejection fraction
      less than 45% have a high annual mortality rate (> 3%). Those patients should
      undergo coronary revascularization whenever feasible, as the cardiac event rate
      increases in proportion to the magnitude of the jeopardized myocardium. Stress
      MPI can be used to demonstrate ischemia in patients with symptoms early after
      coronary artery bypass surgery (< 5 years) or in those without symptoms late (>/=
      5 years) after coronary artery bypass surgery. With respect to patients who
      underwent percutaneous interventions, stress MPI can help detect in-stent
      restenosis early after the intervention (3-6 months) or assess the progression of
      native coronary disease afterward. Since preliminary data suggest that a
      reduction in the perfusion defect size may translate to a reduction of coronary
      events, stress MPI can help assess the efficacy of medical management of coronary
      disease. Finally, stress MPI is indicated for perioperative cardiac risk
      stratification for noncardiac surgery in patients with intermediate risk
      predictors (mild angina, prior myocardial infarction or heart failure symptoms,
      diabetes mellitus, renal insufficiency) and poor functional capacity or in those
      who undergo high-risk surgery with significant implications in further
      preoperative management.

PMID- 12620133
TI  - National Center for Complementary and Alternative Medicine perspectives for
      complementary and alternative medicine research in cardiovascular diseases.
AB  - The National Center for Complementary and Alternative Medicine (NCCAM) was
      established in 1998 by the US Congress to conduct and support basic and applied
      research and research training and disseminate information with respect to
      identifying, investigating, and validating complementary and alternative
      therapies. Because of limited appropriations, NCCAM prioritizes its research
      programs according to the relative use of a modality, the evidence supporting its
      value and safety, and opportunities to advance the relevant fields of science.
      While NCCAM's top priority is supporting clinical trials of alternative
      therapeutics, increasingly it is supporting basic and preclinical research. To
      accomplish its mission, NCCAM encourages the research community to undertake high
      quality and rigorous research in complementary and alternative medicine (CAM). In
      the area of cardiovascular diseases, NCCAM is supporting clinical trials,
      specialized centers, research training, and investigator-initiated projects.
      Virtually all aspects of CAM modalities are open for investigation. Current NCCAM
      projects are investigating Tai Chi (Taiji) exercise, hawthorn, phytoestrogens,
      biofeedback, Ayurvedic herbals, acupuncture, qigong, Reiki, meditation,
      spirituality, Ginkgo biloba, ethylenediaminetetraacetic acid chelation therapy,
      and special diets.

PMID- 12620132
TI  - Neuropsychiatric effects of cardiovascular drug therapy.
AB  - Various cardiovascular drugs have been shown to have neuropsychiatric effects
      that can be harmful or therapeutically beneficial to patients. As an example,
      both sedation and mental depression have been described in patients receiving
      centrally acting antihypertensive drugs and beta-adrenergic blockers, related to
      their antiadrenergic actions. In contrast, because of these antiadrenergic
      actions, agents like clonidine have been used to treat opiate, alcohol, and
      nicotine withdrawal, while beta blockers have been used to treat symptoms of
      performance anxiety, migraine, and psychocardiac disorders. Some antiarrhythmic
      drugs have been associated with delirium, and digitalis toxicity has been shown
      to cause hallucinations, mania, euphoria, and depression. The calcium-channel
      blocker verapamil has been used as an adjunctive treatment in patients with
      bipolar disorders. Since neuropsychiatric symptoms are seen in patients with
      cardiovascular disease, clinicians should be aware of the possible relationship
      between these symptoms and concurrent cardiovascular drug therapy.

PMID- 12620134
TI  - Thrombus formation after aortic valvular replacement using Bjork-Shiley valve
      occluding the right coronary orifice.
AB  - We describe a patient with unstable angina due to occlusion of the orifice of the
      right coronary artery by thrombus formation after aortic valvular replacement
      using a Bjork-Shiley valve. After strict anticoagulant treatment, transesophageal
      echocardiography demonstrated disappearance of the thrombus formation around the
      orifice of the right coronary artery.

PMID- 12620135
TI  - Stent implantation to the stenosed right coronary artery in a patient whose right
      and left coronary arteries originate from a single ostium in the right sinus of
      Valsalva.
AB  - The authors report a rare case of a patient who had anomalous origin of left and
      right coronary arteries from a single coronary ostium in the right sinus of
      Valsalva. The stenosed right coronary artery was successfully dilated with stent
      implantation.

PMID- 12620136
TI  - False aneurysm of the ascending aorta with perforation into the right ventricle
      presenting as acute inferior myocardial infarction.
AB  - The authors describe the case of a 76-year-old woman who presented with acute
      inferior myocardial infarction 8 years after prosthetic aortic valve replacement.
      Echocardiography and cardiac catheterization revealed a false aneurysm of the
      ascending aorta with fistulous communication to the right ventricle. The right
      coronary artery originated from the false aneurysm with no antegrade perfusion.

PMID- 12620137
TI  - Clinical colorectal cancer: the epidermal growth factor receptor signaling
      pathway as a chemotherapeutic target.

PMID- 12620138
TI  - The combination of capecitabine and oxaliplatin in metastatic colorectal cancer.

PMID- 12620139
TI  - Advances in the use of fecal DNA screening for the detection of colorectal
      cancer.

PMID- 12620140
TI  - Adjuvant radiation therapy of patients with rectal cancer.
AB  - The standard in rectal cancer has been to add adjuvant radiation therapy to
      surgery in patients with stage II and III disease. Total mesorectal excision has
      led to lower local recurrence rates, and, if properly performed, may make
      adjuvant radiation unnecessary for certain stage II and III patients, such as T3
      N0 patients with proximal lesions. There is also debate about the best method of
      delivering adjuvant radiotherapy. Preoperative radiotherapy at low dose per
      fraction with concurrent chemotherapy offers the advantages of maximizing
      sphincter preservation and greater tolerability. However, this will occasionally
      result in treating patients who are overstaged by ultrasound and may lead to
      greater postoperative morbidity and mortality than postoperative radiation.
      Preoperative radiotherapy has stronger data to support a survival advantage when
      added to surgery than postoperative radiation. Two randomized, phase III European
      studies may answer the question of which radiation technique is best for the near
      future. Protracted venous infusion of 5-fluorouracil (5-FU) is the standard
      method of radiosensitization. However, studies are ongoing using concurrent
      oxaliplatin, irinotecan, and oral 5-FU prodrugs. For now, we recommend that stage
      II and III rectal cancer patients receive protracted venous infusion 5-FU
      concurrent with preoperative radiation.

PMID- 12620141
TI  - Predictive markers for colorectal cancer: current status and future prospects.
AB  - Colorectal cancer (CRC) is the second leading cause of cancer death in the United
      States. Although there is clear evidence of the benefit of chemotherapy in
      adjuvant and metastatic settings, its use continues to be suboptimal because of
      intrinsic or acquired drug resistance. 5-Fluorouracil continues to be the
      mainstay of CRC therapy, and combinations with newer chemotherapeutic agents such
      as irinotecan and oxaliplatin have resulted in improved response rates and
      survival. The role of other agents including cyclooxygenase-2 inhibitors,
      epidermal growth factor receptor, and farnsyl transferase inhibitors remains to
      be elucidated. Despite these improvements, many patients undergo chemotherapy
      without benefit. Increased understanding of the biology of CRC has led to the
      identification of prognostic markers that may help identify patients who will
      benefit from chemotherapy. Furthermore, studies have also begun to identify
      markers that predict whether a tumor will respond to a particular chemotherapy.
      The ultimate goal of this research is to prospectively identify patients who
      should receive chemotherapy and, thus, to tailor treatment to the molecular
      profile of the tumor and patient. Such an approach has the potential to
      dramatically improve response rates. This review highlights potentially important
      prognostic and predictive factors in CRC and discusses the potential for their
      use in the treatment of this disease.

PMID- 12620143
TI  - Clinical and molecular prognostic factors in patients with metastatic colorectal
      cancer treated with 5-fluorouracil-based chemotherapy.

PMID- 12620142
TI  - Analysis of clinical prognostic factors for survival and time to progression in
      patients with metastatic colorectal cancer treated with 5-fluorouracil-based
      chemotherapy.
AB  - Colorectal cancer (CRC) is one of the most common malignant tumors in adults.
      Twenty-five percent of patients are not amenable to surgical resection because
      they have locally advanced or metastatic disease. For these patients, median
      survival time is between 4 and 13 months, and chemotherapy is used mainly with
      palliative intent. We conducted this study to evaluate potential prognostic
      factors for time to progression and survival. A retrospective review of 91
      patients with metastatic CRC treated with bolus 5-fluorouracil-based chemotherapy
      (Mayo Clinic schedule) was performed. Univariate and multivariate analyses of
      clinical prognostic factors were carried out. Median follow-up time was 53 months
      (range, 17-107 months). Median time to disease progression was 9.6 months, and
      median survival time was 15.4 months. Actuarial 5-year survival was 17%. In the
      univariate analyses, factors predictive of time to progression were visceral
      metastases, elevated alkaline phosphatase (AP) levels, performance status (PS),
      and elevated carcinoembryonic antigen (CEA) and CA 19-9 levels. Multivariate
      analyses confirmed the independent prognostic value of PS and AP levels. In the
      univariate analyses for survival, significant prognostic factors were visceral
      metastases, hypoalbuminemia, elevated lactate dehydrogenase levels, elevated AP
      levels, PS, and elevated CEA and CA 19-9 levels. In the multivariate analyses,
      only PS, elevated CEA and CA 19-9 levels, and liver involvement retained
      prognostic significance. This study confirms the prognostic value of PS for both
      time to progression and survival. AP levels are significantly related to time to
      progression. Additional factors influencing survival time are elevated tumor
      marker levels and the existence of liver metastases.

PMID- 12620144
TI  - Neural networks in the prediction of survival in patients with colorectal cancer.
AB  - It is important to predict outcome for colorectal cancer patients following
      surgery, as almost 50% of patients undergoing a potentially curative resection
      will experience relapse. It is clear that present prognostic categories such as
      Dukes or TNM staging are too broad, and further refining is required to
      prognosticate for high-risk subgroups. One approach is to determine a phenotype
      associated with recurrence. We compared 2 methods of analyzing such data.
      Pathologic data from a large clinical trial was analyzed for 403 patients. The
      outcome modeled was disease recurrence. The results from logistic regression
      analysis and a neural network approach are compared with respect to receiver
      operator characteristic plots, which estimate the fit of the model. The best
      logistic regression model gives a result of 66%, and the neural network approach
      78%. The conclusion from this study is that the neural network approach is
      superior to regression analysis. Further analyses are in progress using a larger
      patient sample size (n > 1000), improved statistical models, and a more refined
      neural network.

PMID- 12620145
TI  - Predicting survival with artificial neural networks.

PMID- 12620146
TI  - Epidermal growth factor receptor as a therapeutic target in colorectal cancer.
AB  - The epidermal growth factor receptor (EGFR) is widely expressed in advanced
      colorectal cancers (CRCs), and higher levels of EGFR are inversely related to
      survival in these patients. Two general strategies have been used to block EGFR
      signaling: preventing ligand binding with anti-EGFR monoclonal antibodies (eg,
      cetuximab and ABX-EGF) and inhibiting its intrinsic tyrosine kinase with small
      molecules (eg, gefitinib [Iressa] and erlotinib [OSI-774,Tarceva]). Phase II
      trials of cetuximab suggest that it might be an effective treatment option alone
      or in combination with standard therapies as first- or second-line therapy. Phase
      I studies evaluating other EGFR inhibitors in patients with CRC have been
      reported. The inclusion of anti-EGFR therapies into standard treatment is the
      subject of current clinical trials.

PMID- 12620147
TI  - Epidermal growth factor receptor and other molecular targets in the treatment of
      cancer.

PMID- 12620148
TI  - Phase I/IIA randomized study of PHY906, a novel herbal agent, as a modulator of
      chemotherapy in patients with advanced colorectal cancer.

PMID- 12620151
TI  - Clinical development of the STn-KLH vaccine (Theratope).
AB  - The development of active specific immunotherapy depends on the identification of
      altered cancer cell-specific molecules or epitopes that are immunogenic. Many
      cancer-specific peptide or glycoprotein target antigens have been identified.
      Tumors carrying aberrant epitopes as a result of underglycosylation of mucins are
      associated with poor prognosis in many epithelial cancers. The aberrant mucin
      sialyl-Tn (STn) epitope, in addition to being a predictor of poor prognosis when
      expressed in tumors, is associated with increased aggressiveness and metastatic
      potential, making it a promising target for immunotherapy. The STn-keyhole limpet
      hemocyanin (KLH) vaccine (Theratope) is an investigational active specific
      immunotherapy consisting of a synthetic STn epitope conjugated to a high
      molecular weight protein carrier, KLH. The immune response generated by the STn
      KLH vaccine is both humoral and cellular. More than 1000 breast cancer patients
      with metastatic disease are currently enrolled in a phase III clinical trial to
      assess the safety and efficacy of the STn-KLH vaccine. Interim analysis from a
      current phase III trial has confirmed the safety of the STn-KLH vaccine, and the
      clinical outcome awaits the final analysis expected in 2003.

PMID- 12620150
TI  - Rationale for the clinical development of STn-KLH (Theratope) and anti-MUC-1
      vaccines in breast cancer.
AB  - Mucin-1 (MUC-1) is a high-molecular-weight glycoprotein rich in serine and
      threonine residues that are O-glycosylated. Expression of MUC-1 is increased in
      breast, ovarian, and other adenocarcinomas, and altered glycosylation results in
      exposure of novel peptide epitopes and the expression of tumor-associated
      carbohydrate residues, such as Thomsen-Freidenreich and sialyl-Tn (STn) antigens.
      Preclinical studies suggested that induction of immune response to tumor
      associated carbohydrate moieties results in inhibition of tumor growth. A
      synthetic STn-keyhole limpet hemocyanin (KLH) vaccine (Theratope) is currently
      being evaluated in clinical trials as active specific immunotherapy in the
      treatment of advanced breast cancer. Two phase II trials in 50 breast cancer
      patients compared the STn-KLH vaccine with and without a single low-dose infusion
      of cyclophosphamide used as an immunomodulator prior to initiation of treatment.
      Humoral immune responses were higher in patients who had received low-dose
      cyclophosphamide intravenously (I.V.) compared with patients who had received no
      cyclophosphamide or oral cyclophosphamide. There was a statistically significant
      survival difference between all patients treated with the STn-KLH vaccine
      (overall median survival, 19.1 months; n = 50) and the retrospective control
      patients (overall median survival, 9.2 months; n = 104). Furthermore, patients
      who received cyclophosphamide I.V. prior to the STn-KLH vaccine had median
      survival rates close to 3 times that of patients in a retrospective, frequency
      matched, control group who received conventional therapies (cyclophosphamide-I.V.
      group, 26.5 months vs. 9.2 months, control group). The trials reported minimal
      toxicity profile with local reactions in the injection site and some flu-like
      symptoms. On the basis of the phase II trial results, a phase III clinical trial
      of the STn-KLH vaccine is underway. The trial was closed to enrollment in March
      2001 with the accrual of 1030 women. The final analysis is event driven and is
      expected to commence mid 2003.

PMID- 12620152
TI  - The role of cancer vaccines following autologous stem cell rescue in breast and
      ovarian cancer patients: experience with the STn-KLH vaccine (Theratope).
AB  - The success of high-dose chemotherapy followed by autologous stem-cell rescue as
      treatment for breast and ovarian cancer is limited by a high incidence of
      relapse. After autologous transplantation, patients are likely to have a low
      tumor burden and thus would be more likely to respond immunologically to a cancer
      vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on
      breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy.
      Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a
      synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate
      and is designed to stimulate tumor antigen-specific immune responses in patients
      with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage
      II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV
      breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity,
      outcome, and immune response data are reported. STn-KLH was well-tolerated with
      minimal toxicity. The most common side effects were indurations and erythema at
      the sites of injections. Humoral and cellular responses were elicited in the
      majority of patients. Overall, these data indicate that post-autologous
      transplant patients are able to mount an effective immune response to vaccine
      immunotherapy with minimal side effects, and that vaccine immunotherapy may be a
      useful addition to high-dose chemotherapy regimens.

PMID- 12620154
TI  - Fusions of breast cancer and dendritic cells as a novel cancer vaccine.
AB  - The use of dendritic cell (DC)-based cancer vaccines has emerged as a promising
      area of investigation in the field of tumor immunotherapy. DCs are potent antigen
      presenting cells that are essential for the initiation of primary immune
      responses. DCs that have been manipulated to express tumor antigens are capable
      of stimulating tumor-specific immunity. The fusion of tumor cells with DCs
      results in the presentation of a broad spectrum of tumor antigens in the context
      of the immune-stimulating machinery of the DC. Animal models have demonstrated
      that vaccination with DC/tumor fusions is protective from a lethal challenge with
      tumor cells and results in regression of established disease. Preclinical human
      studies in breast cancer have shown that fusion cells stimulate cellular immune
      responses capable of lysing autologous tumor cells. Based on these findings, a
      phase I clinical trial has been conducted in patients with metastatic breast
      cancer to examine the toxicity profile and immunologic impact associated with
      vaccination with DC/tumor fusions.

PMID- 12620155
TI  - HER2 dendritic cell vaccines.
AB  - HER2/neu, a tumor antigen overexpressed by a third of breast cancers, is a
      potential target for vaccine therapies. A particularly potent immunization
      strategy to induce T-cell responses against tumor antigens is to use dendritic
      cells (DCs) loaded with the tumor antigen. We performed two small studies to test
      the safety, feasibility, and immunologic and clinical responses to immunizations
      with in vitro-generated DCs loaded with either a human leukocyte antigen A2
      restricted peptide fragment of the extracellular domain of the tumor antigen HER2
      (E75) or a HER2 intracellular domain (ICD) protein in patients with high-risk
      resected breast cancer or metastatic cancers expressing HER2. There were no
      toxicities due to the immunizations in any of the patients. In the study of DCs
      loaded with the E75 peptide, 1 of 6 patients with metastatic HER2-expressing
      malignancies who completed all immunizations had stable disease for 6 months; the
      remainder of the patients had progressive disease. Delayed-type hypersensitivity
      (DTH) reactivity (2-3 mm of induration) at E75-loaded DC injection sites was
      observed in 2 of 5 patients evaluated but was similar at the unloaded DC
      injection sites. In 2 patients, the DTH sites underwent biopsy and a perivascular
      infiltrate of CD4 and CD8 cells was demonstrated, which was greater in the E75
      loaded DC injection sites than in the unloaded DC sites. In the pilot study of
      ICD-loaded DC in patients with high-risk resected breast cancer, all 3 patients
      enrolled had no evidence of recurrence at a follow-up of up to 2.5 years.
      Intracellular domain-specific T-cell responses were detected directly from the
      peripheral blood by enzyme-linked immunospot and proliferation assay in 2
      patients. We conclude that it is feasible and safe to generate and administer
      HER2-loaded DCs to patients with advanced HER2/neu-expressing malignancies and
      high-risk breast cancer. The magnitude of the immune responses generated is
      fairly modest, and more potent DC loading and maturation strategies will be
      necessary to optimize these vaccines.

PMID- 12620153
TI  - Use of the anti-idiotype breast cancer vaccine 11D10 in conjunction with
      autologous stem cell transplantation in patients with metastatic breast cancer.
AB  - The results of cytotoxic therapy, including dose-intensive therapy requiring
      autologous stem cell transplantation (ASCT), have been disappointing in patients
      with metastatic breast cancer, as almost all patients eventually experience
      disease progression. There has been a renewed interest in immunotherapeutic
      strategies in this disease, including evaluation of several breast cancer
      vaccines. In the current study, we describe the results of a program in which the
      anti-idiotype breast cancer vaccine 11D10 (TriAb) was administered before and
      after ASCT in patients with metastatic breast cancer chemosensitive to previous
      conventional therapy. The toxicity of this approach was acceptable, and idiotype
      specific humoral and T-cell proliferative responses were observed in the majority
      of patients within a few weeks post-ASCT. The actuarial 3-year overall survival
      rate was 48% (95% CI, 32%-64%), while the progression-free survival rate was 32%
      (95% CI, 19%-45%). Multivariate analysis identified achievement of a strong
      antibody and cellular immune response to the vaccine as the only significant
      prognostic factors for outcome. The ability to reliably produce robust immune
      responses after ASCT is encouraging. Further studies are required to determine if
      the immune response mediates an antitumor benefit in these patients.

PMID- 12620157
TI  - Synchronization in networks of excitatory and inhibitory neurons with sparse,
      random connectivity.
AB  - In model networks of E-cells and I-cells (excitatory and inhibitory neurons,
      respectively), synchronous rhythmic spiking often comes about from the interplay
      between the two cell groups: the E-cells synchronize the I-cells and vice versa.
      Under ideal conditions-homogeneity in relevant network parameters and all-to-all
      connectivity, for instance-this mechanism can yield perfect synchronization. We
      find that approximate, imperfect synchronization is possible even with very
      sparse, random connectivity. The crucial quantity is the expected number of
      inputs per cell. As long as it is large enough (more precisely, as long as the
      variance of the total number of synaptic inputs per cell is small enough), tight
      synchronization is possible. The desynchronizing effect of random connectivity
      can be reduced by strengthening the E --> I synapses. More surprising, it cannot
      be reduced by strengthening the I --> E synapses. However, the decay time
      constant of inhibition plays an important role. Faster decay yields tighter
      synchrony. In particular, in models in which the inhibitory synapses are assumed
      to be instantaneous, the effects of sparse, random connectivity cannot be seen.

PMID- 12620156
TI  - Allogeneic breast cancer cell vaccines.
AB  - Cancer vaccines are currently a major focus of immunotherapy research. The
      combination of specific targeting and low levels of toxicity makes vaccination an
      attractive approach. There are a variety of immunogens that can be employed to
      vaccinate patients in order to induce or enhance an antitumor response. The
      observation that most T-cell priming occurs via presentation of tumor antigens
      from tumor cells engulfed by host antigen-presenting cells, rather than by direct
      presentation by vaccine tumor cells themselves, provides the immunological
      rationale for an allogeneic tumor cell vaccine approach. Furthermore, there are
      practical advantages over an autologous tumor cell vaccine approach. We summarize
      herein the limited experience using allogeneic whole cell vaccines in patients
      with breast cancer. We also describe in vitro immunological results using
      peripheral blood mononuclear cells from women with stage IV breast cancer who
      were enrolled in a phase I trial employing a human leukocyte antigen-A2-matched,
      CD80-modified, allogeneic, whole cell vaccine. Clinical trials employing
      allogeneic tumor cell vaccines have achieved encouraging immunological and
      clinical effects in stage IV patients. Allogeneic tumor cell vaccines are safe,
      feasible, and associated with low toxicity, and the early clinical results
      suggest that they are worthy of further study

PMID- 12620158
TI  - Spike-driven synaptic dynamics generating working memory states.
AB  - The collective behavior of a network, modeling a cortical module of spiking
      neurons connected by plastic synapses is studied. A detailed spike-driven
      synaptic dynamics is simulated in a large network of spiking neurons,
      implementing the full double dynamics of neurons and synapses. The repeated
      presentation of a set of external stimuli is shown to structure the network to
      the point of sustaining working memory (selective delay activity). When the
      synaptic dynamics is analyzed as a function of pre- and postsynaptic spike rates
      in functionally defined populations, it reveals a novel variation of the Hebbian
      plasticity paradigm: in any functional set of synapses between pairs of neurons
      (e.g., stimulated-stimulated, stimulated-delay, stimulated-spontaneous), there is
      a finite probability of potentiation as well as of depression. This leads to a
      saturation of potentiation or depression at the level of the ratio of the two
      probabilities. When one of the two probabilities is very high relative to the
      other, the familiar Hebbian mechanism is recovered. But where correlated working
      memory is formed, it prevents overlearning. Constraints relevant to the stability
      of the acquired synaptic structure and the regimes of global activity allowing
      for structuring are expressed in terms of the parameters describing the single
      synapse dynamics. The synaptic dynamics is discussed in the light of experiments
      observing precise spike timing effects and related issues of biological
      plausibility.

PMID- 12620159
TI  - A stochastic method to predict the consequence of arbitrary forms of spike-timing
      dependent plasticity.
AB  - Synapses in various neural preparations exhibit spike-timing-dependent plasticity
      (STDP) with a variety of learning window functions. The window functions
      determine the magnitude and the polarity of synaptic change according to the time
      difference of pre- and postsynaptic spikes. Numerical experiments revealed that
      STDP learning with a single-exponential window function resulted in a bimodal
      distribution of synaptic conductances as a consequence of competition between
      synapses. A slightly modified window function, however, resulted in a unimodal
      distribution rather than a bimodal distribution. Since various window functions
      have been observed in neural preparations, we develop a rigorous mathematical
      method to calculate the conductance distribution for any given window function.
      Our method is based on the Fokker-Planck equation to determine the conductance
      distribution and on the Ornstein-Uhlenbeck process to characterize the membrane
      potential fluctuations. Demonstrating that our method reproduces the known
      quantitative results of STDP learning, we apply the method to the type of STDP
      learning found recently in the CA1 region of the rat hippocampus. We find that
      this learning can result in nearly optimized competition between synapses.
      Meanwhile, we find that the type of STDP learning found in the cerebellum-like
      structure of electric fish can result in all-or-none synapses: either all the
      synaptic conductances are maximized, or none of them becomes significantly large.
      Our method also determines the window function that optimizes synaptic
      competition.

PMID- 12620160
TI  - Permitted and forbidden sets in symmetric threshold-linear networks.
AB  - The richness and complexity of recurrent cortical circuits is an inexhaustible
      source of inspiration for thinking about high-level biological computation. In
      past theoretical studies, constraints on the synaptic connection patterns of
      threshold-linear networks were found that guaranteed bounded network dynamics,
      convergence to attractive fixed points, and multistability, all fundamental
      aspects of cortical information processing. However, these conditions were only
      sufficient, and it remained unclear which were the minimal (necessary) conditions
      for convergence and multistability. We show that symmetric threshold-linear
      networks converge to a set of attractive fixed points if and only if the network
      matrix is copositive. Furthermore, the set of attractive fixed points is
      nonconnected (the network is multiattractive) if and only if the network matrix
      is not positive semidefinite. There are permitted sets of neurons that can be
      coactive at a stable steady state and forbidden sets that cannot. Permitted sets
      are clustered in the sense that subsets of permitted sets are permitted and
      supersets of forbidden sets are forbidden. By viewing permitted sets as memories
      stored in the synaptic connections, we provide a formulation of long-term memory
      that is more general than the traditional perspective of fixed-point attractor
      networks. There is a close correspondence between threshold-linear networks and
      networks defined by the generalized Lotka-Volterra equations.

PMID- 12620161
TI  - Multistability analysis for recurrent neural networks with unsaturating piecewise
      linear transfer functions.
AB  - Multistability is a property necessary in neural networks in order to enable
      certain applications (e.g., decision making), where monostable networks can be
      computationally restrictive. This article focuses on the analysis of
      multistability for a class of recurrent neural networks with unsaturating
      piecewise linear transfer functions. It deals fully with the three basic
      properties of a multistable network: boundedness, global attractivity, and
      complete convergence. This article makes the following contributions: conditions
      based on local inhibition are derived that guarantee boundedness of some
      multistable networks, conditions are established for global attractivity, bounds
      on global attractive sets are obtained, complete convergence conditions for the
      network are developed using novel energy-like functions, and simulation examples
      are employed to illustrate the theory thus developed.

PMID- 12620162
TI  - Simple-cell-like receptive fields maximize temporal coherence in natural video.
AB  - Recently, statistical models of natural images have shown the emergence of
      several properties of the visual cortex. Most models have considered the
      nongaussian properties of static image patches, leading to sparse coding or
      independent component analysis. Here we consider the basic time dependencies of
      image sequences instead of their nongaussianity. We show that simple-cell-type
      receptive fields emerge when temporal response strength correlation is maximized
      for natural image sequences. Thus, temporal response strength correlation, which
      is a nonlinear measure of temporal coherence, provides an alternative to
      sparseness in modeling simple-cell receptive field properties. Our results also
      suggest an interpretation of simple cells in terms of invariant coding
      principles, which have previously been used to explain complex-cell receptive
      fields.

PMID- 12620163
TI  - Continuous-time symmetric Hopfield nets are computationally universal.
AB  - We establish a fundamental result in the theory of computation by continuous-time
      dynamical systems by showing that systems corresponding to so-called continuous
      time symmetric Hopfield nets are capable of general computation. As is well
      known, such networks have very constrained Lyapunov-function controlled dynamics.
      Nevertheless, we show that they are universal and efficient computational
      devices, in the sense that any convergent synchronous fully parallel computation
      by a recurrent network of n discrete-time binary neurons, with in general
      asymmetric coupling weights, can be simulated by a symmetric continuous-time
      Hopfield net containing only 18n + 7 units employing the saturated-linear
      activation function. Moreover, if the asymmetric network has maximum integer
      weight size w(max) and converges in discrete time t*, then the corresponding
      Hopfield net can be designed to operate in continuous time Theta(t*/epsilon) for
      any epsilon > 0 such that w(max)2(12n) </= epsilon2(1/epsilon). In terms of
      standard discrete computation models, our result implies that any polynomially
      space-bounded Turing machine can be simulated by a family of polynomial-size
      continuous-time symmetric Hopfield nets.

PMID- 12620164
TI  - Is permethrin 5% cream effective for rosacea?
AB  - Permethrin 5% cream is a safe alternative for the topical treatment of
      papulopustular rosacea. Permethrin 5% cream is superior to metronidazole 0.75%
      gel and placebo in decreasing Demodex folliculorum, and is as effective as
      metronidazole 0.75% gel in treating erythema and papules.

PMID- 12620165
TI  - Is imiquimod effective and safe for actinic keratosis?
AB  - Imiquimod 5% cream, applied 3 times per week for 12 weeks, is effective for
      treatment of actinic keratosis. Severe erythema and other local reactions
      occurred in almost everyone receiving treatment, due to imiquimod's immune system
      modulating effects. The 25 patients in the treatment group tolerated these
      adverse effects well. Despite these effects, imiquimod can be used as an
      alternative to traditional cryotherapy for the treatment of actinic keratosis
      among selected, motivated

PMID- 12620166
TI  - Does C-reactive protein predict cardiovascular events in women better than LDL?
AB  - C-reactive protein (CRP) is an independent predictor of a first cardiovascular
      event in women and appears to be a stronger predictor than low-density
      lipoprotein (LDL) cholesterol levels. Unfortunately, this information does not
      lead directly to a therapeutic intervention. As an accompanying editorial stated,
      low carotenoid levels also predict cardiovascular events, but supplementation
      with beta carotene does not reduce an individual's risk. This study does not
      clarify whether CRP is a causative agent, a marker, or a result of cardiovascular
      disease. Our focus should remain on identifying and treating conventional risk
      factors until we better understand the exact role CRP has in therapeutic
      decisions regarding cardiovascular disease.

PMID- 12620167
TI  - Does acetaminophen affect liver function in alcoholic patients?
AB  - Acetaminophen in doses of 4 g/d did not affect liver function of alcoholic
      patients in this randomized study. These results do not rule out the possibility
      of acetaminophen-induced liver failure in alcoholic patients, especially patients
      with pre-existing liver disease or those who continue to drink. Patient-oriented
      outcomes (ie, studying chronic acetaminophen use in alcoholics to determine the
      incidence of developing hepatic failure) ultimately would resolve this
      controversy. However, these data do cast doubt on the medical myth (based on case
      reports) that acetaminophen use in alcoholics causes hepatotoxicity.

PMID- 12620168
TI  - Are diuretics helpful in acute renal failure?
AB  - Although widely used to treat acute renal failure, diuretics may actually be
      harmful. The results of this observational study demonstrated a higher risk of
      death and non-recovery of renal function when diuretics were initiated during the
      first week of hospitalization. It didn't matter whether a single or combination
      diuretic was used. A randomized controlled trial would better answer this
      question by minimizing the inherent flaws in an observational study. Although
      this study doesn't conclusively prove that diuretics cause poorer outcomes, it
      certainly raises the possibility and should prompt us to think twice before
      initiating diuretic therapy for acute renal failure.

PMID- 12620169
TI  - Is topical nifedipine effective for chronic anal fissures?
AB  - Patients in this study showed remarkable improvement when 1.5% lidocaine and 0.3%
      nifedipine were applied twice daily for 6 weeks. This extremely safe, well
      tolerated, and effective treatment should provide family physicians with a
      reliable nonsurgical method for treating chronic anal fissures.

PMID- 12620170
TI  - Is rate control better than rhythm control for atrial fibrillation in older high
      risk patients?
AB  - Mortality with atrial fibrillation is similar with rhythm control and rate
      control treatment. However, adverse drug events and hospitalizations are more
      frequent with rhythm control therapy. Rate control therapy for atrial
      fibrillation should be the primary treatment strategy for an older high-risk
      population, but should not be extrapolated to younger and healthier patients (eg,
      patients with lone atrial fibrillation). These findings are consistent with
      another smaller study of patients with recurrent persistent atrial fibrillation.

PMID- 12620171
TI  - Are ionized wrist bracelets better than placebo for musculoskeletal pain?
AB  - As a result of a profound placebo effect, this study showed that Q-Ray ionized
      wrist bracelets were not superior to placebo bracelets in self-reported pain
      improvement among patients with musculoskeletal pain. Like many other studies
      involving the treatment of pain, the perception that the treatment would work
      profoundly improved its effectiveness. While the bracelet did not work better
      than placebo, many patients may experience less pain if they purchase and use it.

PMID- 12620172
TI  - Does magnesium therapy early in acute MI reduce mortality?
AB  - Short-term mortality is not reduced with early administration of intravenous
      magnesium in high-risk patients having an acute myocardial infarction (MI). There
      is no reason to give intravenous magnesium unless patients have other indications
      for repletion, such as a low magnesium level or arrhythmia responsive to
      magnesium therapy.

PMID- 12620173
TI  - What are the risks of long-term NSAIDs and COX-2 inhibitors?
AB  - This review presents an interesting new analysis of cyclo-oxygenase-2 (COX-2)
      inhibitor safety, concluding that long-term use results in more serious adverse
      events than traditional nonsteroidal anti-inflammatory drugs (NSAIDs). The
      nonsystematic and retrospective properties of this analysis limit its validity.
      However, the fact that an evaluation of long-term data found some small harm to
      COX-2 inhibitors relative to traditional NSAIDs (number needed to harm=78 over 9
      months) should give clinicians pause. Until better meta-analyses or new safety
      data are published, clinicians should prescribe COX-2 inhibitors long-term only
      for those patients deemed to be at high risk of ulcer complications.

PMID- 12620174
TI  - Achieving the best outcome in treatment of depression.
AB  - Combined treatment with psychotherapy or psychiatric consult and drug therapy has
      shown better response in several studies than either therapy alone. Although not
      proven by clinical trials, selecting a medication by matching its side-effect
      profile to patient characteristics is supported by case reports and likely
      enhances compliance. Patients who do not improve with initial therapy often
      benefit from being switched to another class of antidepressants, or having a drug
      from another class added to their therapy.

PMID- 12620175
TI  - Diagnosing skin malignancy: assessment of predictive clinical criteria and risk
      factors.
AB  - Expect to encounter 6 to 7 cases of basal cell cancer, 1 to 2 cases of squamous
      cell cancer, and approximately 1 case of melanoma every year. There is good
      evidence for using the American Cancer Society's ABCDE criteria as a clinical
      diagnostic test to rule out malignant melanoma). The revised 7-point checklist
      has high sensitivity and is therefore useful for ruling out a diagnosis of
      malignant melanoma. However, its low specificity yields many false-positive
      results. The gold standard for diagnosis of skin malignancies is a tissue biopsy.
      If any doubt exists about the diagnosis, a biopsy should be performed.

PMID- 12620176
TI  - Recognition for the diagnosis of skin cancer.

PMID- 12620177
TI  - After-hours telephone triage affects patient safety.
AB  - OBJECTIVE: To describe the management of after-hours calls to primary care
      physicians and identify potential errors that might delay evaluation and
      treatment. STUDY DESIGN: Survey of primary care practices and audit of after
      hours phone calls. Ninety-one primary care offices (family medicine, internal
      medicine, obstetrics, and pediatrics) were surveyed in October and November 2001.
      Data collected included number of persons answering the calls, information
      requested, instructions to patients, who decided whether to contact the on-call
      physician, and subsequent handling of all calls. We evaluated all after-hours
      calls to an index office that were not forwarded to the on-call physician. Four
      family physicians independently reviewed the calls while unaware that these calls
      had not been forwarded to the physician on call to determine the appropriate
      triage. POPULATION: Primary care physicians and their telephone answering
      services. OUTCOME MEASURES (1) Who decided to initiate immediate contact with the
      physician? (2) Percentage of calls identified as emergent or nonemergent by
      patients. (3) Independent physician ratings of nonemergent calls. RESULTS: More
      than two thirds of the offices used answering services to take their calls.
      Ninety-three percent of the practices required the patient to decide whether the
      problem was emergent enough to require immediate notification of the on-call
      physician. Physician reviewers reported that 50% (range, 22%-77%) of the calls
      not forwarded to the on-call physician represented an emergency needing immediate
      contact with the physician. CONCLUSIONS: After-hours call systems in most primary
      care offices impose barriers that may delay care. All clinical patient calls
      should be sent to appropriately trained medical personnel for triage decisions.
      We urge all clinicians that use an answering service to examine their policies
      and procedures for possible sources of medical error.

PMID- 12620178
TI  - Patient safety after hours: time for action.

PMID- 12620179
TI  - Clinical inquiries. Does screening for microalbuminuria in diabetes prevent
      complications?

PMID- 12620180
TI  - Clinical inquiries. Is MRI useful for evaluation of acute low back pain?

PMID- 12620181
TI  - Clinical inquiries. Do calcium supplements prevent postmenopausal osteoporotic
      fractures?

PMID- 12620182
TI  - Clinical inquiries. Do glucosamine or chondroitin cause regeneration of cartilage
      in osteoarthritis?

PMID- 12620183
TI  - Gastroesophageal reflux disease.
AB  - Heartburn on 2 or more days a week warrants medical attention, as patients are
      likely to suffer from gastroesophageal reflux disease (GERD). Chronic GERD can
      lead to the development of complications including erosive esophagitis, stricture
      formation, and Barrett's esophagus, which increases the risk of esophageal
      adenocarcinoma. A trial with a proton pump inhibitor (PPI) is the quickest and
      most cost-effective way to diagnose GERD, and is at least as sensitive as 24-hour
      intra-esophageal pH monitoring. As PPIs only bind to actively secreting proton
      pumps, they should be dosed 30 to 60 minutes before a meal. Despite these
      recommendations, a recent survey of over 1000 US primary care physicians found
      that 36% instructed their patients to take a PPI with or after a meal or did not
      specify the timing of dosing. The patients who will have the best response to
      surgical therapy for GERD are those who had clearly documented acid reflux with
      typical symptoms, and who have responded to PPI treatment. Unfortunately, the
      same survey found that most physicians recommend antireflux surgery for patients
      in whom medical therapy has failed.

PMID- 12620184
TI  - Determinants of S. cerevisiae dynein localization and activation: implications
      for the mechanism of spindle positioning.
AB  - BACKGROUND: During anaphase in budding yeast, dynein inserts the mitotic spindle
      across the neck between mother and daughter cells. The mechanism of dynein
      dependent spindle positioning is thought to involve recruitment of dynein to the
      cell cortex followed by capture of astral microtubules (aMTs). RESULTS: We report
      the native-level localization of the dynein heavy chain and characterize the
      effects of mutations in dynein regulators on its intracellular distribution.
      Budding yeast dynein displays discontinuous localization along aMTs, with
      enrichment at the spindle pole body and aMT plus ends. Loss of Bik1p (CLIP-170),
      the cargo binding domain of Bik1p, or Pac1p (LIS1) resulted in diminished
      targeting of dynein to aMTs. By contrast, loss of dynactin or a mutation in the
      second P loop domain of dynein resulted in an accumulation of dynein on the plus
      ends of aMTs. Unexpectedly, loss of Num1p, a proposed dynein cortical anchor,
      also resulted in selective accumulation of dynein on the plus ends of anaphase
      aMTs. CONCLUSIONS: We propose that, rather than first being recruited to the cell
      cortex, dynein is delivered to the cortex on the plus ends of polymerizing aMTs.
      Dynein may then undergo Num1p-dependent activation and transfer to the region of
      cortical contact. Based on the similar effects of loss of Num1p and loss of
      dynactin on dynein localization, we suggest that Num1p might also enhance dynein
      motor activity or processivity, perhaps by clustering dynein motors.

PMID- 12620185
TI  - The degradation of two mitotic cyclins contributes to the timing of cytokinesis.
AB  - BACKGROUND: Cytokinesis occurs just as chromosomes complete segregation and
      reform nuclei. It has been proposed that cyclin/Cdk kinase inhibits cytokinesis
      until exit from mitosis; however, the timer of cytokinesis has not been
      experimentally defined. Whereas expression of a stable version of Drosophila
      cyclin B blocks cytokinesis along with numerous events of mitotic exit, stable
      cyclin B3 allows cytokinesis even though it blocks late events of mitotic exit.
      We examined the interface between mitotic cyclin destruction and the timing of
      cytokinesis. RESULTS: In embryonic mitosis 14, the cytokinesis furrow appeared 60
      s after the metaphase/anaphase transition and closed 90 s later during telophase.
      In cyclin B or cyclin B3 mutant cells, the cytokinesis furrow appeared at an
      earlier stage of mitosis. Expression of stable cyclin B3 delayed and prolonged
      furrow invagination; nonetheless, cytokinesis completed during the extended
      mitosis. Reduced function of Pebble, a Rho GEF required for cytokinesis, also
      delayed and slowed furrow invagination, but incomplete furrows were aborted at
      the time of mitotic exit. In functional and genetic tests, cyclin B and cyclin B3
      inhibited Pebble contributions to cytokinesis. CONCLUSIONS: Temporal coordination
      of mitotic events involves inhibition of cytokinesis by cyclin B and cyclin B3
      and punctual relief of the inhibition by destruction of these cyclins. Both
      cyclins inhibit Pebble-dependent activation of cytokinesis, whereas cyclin B can
      inhibit cytokinesis by additional modes. Stable cyclin B3 also blocks the later
      return to interphase that otherwise appears to impose a deadline for the
      completion of cytokinesis.

PMID- 12620186
TI  - Cortactin interacts with WIP in regulating Arp2/3 activation and membrane
      protrusion.
AB  - BACKGROUND: Modulation of actin cytoskeleton assembly is an integral step in many
      cellular events. A key regulator of actin polymerization is Arp2/3 complex.
      Cortactin, an F-actin binding protein that localizes to membrane ruffles, is an
      activator of Arp2/3 complex. RESULTS: A yeast two-hybrid screen revealed the
      interaction of the cortactin Src homology 3 (SH3) domain with a peptide fragment
      derived from a cDNA encoding a region of WASp-Interacting Protein (WIP). GST
      cortactin interacted with WIP in an SH3-dependent manner. The subcellular
      localization of cortactin and WIP coincided at the cell periphery. WIP increased
      the efficiency of cortactin-mediated Arp2/3 complex activation of actin
      polymerization in a concentration-dependent manner. Lastly, coexpression of
      cortactin and WIP stimulated membrane protrusions. CONCLUSIONS: WIP, a protein
      involved in filopodia formation, binds to both actin monomers and cortactin.
      Thus, recruitment of actin monomers to a cortactin-activated Arp2/3 complex
      likely leads to the observed increase in cortactin activation of Arp2/3 complex
      by WIP. These data suggest that a cortactin-WIP complex functions in regulating
      actin-based structures at the cell periphery.

PMID- 12620187
TI  - Combinatorial coexpression of neural and immune multigene families in mouse
      vomeronasal sensory neurons.
AB  - The vomeronasal organ (VNO) is a chemosensory organ specialized in the detection
      of pheromones in higher vertebrates. In mouse and rat, two gene superfamilies,
      V1r and V2r vomeronasal receptor genes, are expressed in sensory neurons whose
      cell bodies are located in, respectively, the apical and basal layers of the VNO
      epithelium. Here, we report that neurons of the basal layer express another
      multigene family, termed H2-Mv, representing nonclassical class I genes of the
      major histocompatibility complex. The nine H2-Mv genes are expressed
      differentially in subsets of neurons. More than one H2-Mv gene can be expressed
      in an individual neuron. In situ hybridization with probes for H2-Mv and V2r
      genes reveals complex and nonrandom combinations of coexpression. While neural
      expression of Mhc class I molecules is increasingly being appreciated, the H2-Mv
      family is distinguished by variegated expression across seemingly similar neurons
      and coexpression with a distinct multigene family encoding neural receptors. Our
      findings suggest that basal vomeronasal sensory neurons may consist of multiple
      lineages or compartments, defined by particular combinations of V2r and H2-Mv
      gene expression.

PMID- 12620188
TI  - Golgi recruitment of GRIP domain proteins by Arf-like GTPase 1 is regulated by
      Arf-like GTPase 3.
AB  - Golgins are Golgi-localized proteins present in all molecularly characterized
      eukaryotes that function in Golgi transport and maintenance of Golgi structure.
      Some peripheral membrane Golgins, including the yeast Imh1 protein, contain the
      recently described GRIP domain that can independently mediate Golgi localization
      by an unknown mechanism. To identify candidate Golgi receptors for GRIP domain
      proteins, a collection of Saccharomyces cerevisiae deletion mutants was visually
      screened by using yeast, mouse, and human GFP-GRIP domain fusion proteins for
      defects in Golgi localization. GFP-GRIP reporters were localized to the cytosol
      in cells lacking either of two ARF-like (ARL) GTPases, Arl1p and Arl3p. In vitro
      binding experiments demonstrated that activated Arl1p-GTP binds specifically and
      directly to the Imh1p GRIP domain. Arl1p colocalized with Imh1p-GRIP at the
      Golgi, and Golgi localization of Arl1p was regulated by the GTPase cycle of
      Arl3p. These results suggest a cascade in which the GTPase cycle of Arl3p
      regulates Golgi localization of Arl1p, which in turn binds to the GRIP domain of
      Imh1p and recruits it to the Golgi. The similar requirements for localization of
      GRIP domains from yeast, mouse, and human when expressed in yeast, and the
      presence of Arl1p and Arl3p homologs in these species, suggest that this is an
      evolutionarily conserved mechanism.

PMID- 12620189
TI  - The ARF-like GTPases Arl1p and Arl3p act in a pathway that interacts with vesicle
      tethering factors at the Golgi apparatus.
AB  - The ARLs are a diverse family of GTPases that are related to ADP-ribosylation
      factors (ARFs), but whose function is poorly understood. There are at least ten
      ARLs in humans, two of which have homologs in the yeast Saccharomyces cerevisiae
      (ARL1/Arl1p and ARFRP1/Arl3p). The function of ARFRP1 is unknown, but mammalian
      ARL1 has recently been found to interact with a number of effectors including the
      GRIP domain that is present in a family of Golgi-localized long coiled-coil
      proteins. We find that in yeast, the intracellular targeting of Imh1p, the only
      yeast GRIP domain protein, is dependent on both Arl1p and Arl3p, but not on the
      ARF proteins. A recombinant form of the Imh1p GRIP domain binds to Arl1p in a GTP
      dependent manner, but not to Arl3p. Yeast also contain a relative of SCOCO, a
      protein proposed to bind human ARL1, but this yeast protein, Slo1p, appears to
      bind Arl3p rather than Arl1p in vitro. However, Imh1p is not the sole effector of
      Arl1p since affinity chromatography of cytosol with immobilized Arl1p:GTP
      revealed an interaction with the GARP/VFT complex that is thought to act in the
      tethering of vesicles to the Golgi apparatus. Finally, we find that Arl3p is
      required in vivo for the targeting of Arl1p, explaining its requirement for the
      normal distribution of Imh1p.

PMID- 12620190
TI  - Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon.
AB  - Holoprosencephaly (HPE), the most common developmental defect of the forebrain
      and midface, is caused by a failure to delineate the midline in these structures.
      Despite the identification of several HPE genes, its genetic basis is largely
      unknown. Furthermore, the phenotype of affected individuals is highly variable,
      even within pedigrees. Facial defects in HPE range from cyclopia and proboscis in
      severe cases to solitary median maxillary central incisor in individuals with
      microforms of HPE. Cdon (also known as Cdo), an Ig superfamily member, is a
      component of a cell surface receptor that positively regulates skeletal
      myogenesis. Cdon is also highly expressed in the frontonasal and maxillary
      processes (FNP and MXP, respectively) of the developing mouse embryo, structures
      that contain signaling centers that pattern the face. We report here that mice
      homozygous for targeted mutations of Cdon display the hallmark facial defects
      associated with microforms of HPE. This is the first example of a mouse mutant
      with this phenotype, and this finding implicates a new family of receptors in
      development of the facial midline and suggests a potential role for Cdon in the
      pathogenesis and expressivity of HPE in humans.

PMID- 12620191
TI  - Absence of the candidate male sex-determining gene dmrt1b(Y) of medaka from other
      fish species.
AB  - Although the sex-determining genes are known in mammals, Drosophila, and C.
      elegans, little is known in other animals. Fishes are an attractive group of
      organisms for studying the evolution of sex determination because they show an
      amazing variety of mechanisms, ranging from environmental sex determination and
      different forms of hermaphroditism to classical sex chromosomal XX/XY or WZ/ZZ
      systems and modifications thereof. In the fish medaka, dmrt1b(Y) has recently
      been found to be the candidate male sex-determining gene. It is a duplicate of
      the autosomal dmrt1a gene, a gene acting in the sex determination/differentiation
      cascade of flies, worms, and mammals. Because in birds dmrt1 is located on the Z
      chromosome, both findings led to the suggestion that dmrt1b(Y) is a "non
      mammalian Sry" with an even more widespread distribution. However, although Sry
      was found to be the male sex-determining gene in the mouse and some other
      mammalian species, in some it is absent and has obviously been replaced by other
      genes that now fulfil the same function. We have asked if the same might be true
      of the dmrt1b(Y) gene. We find that the gene duplication generating dmrt1b(Y)
      occurred recently during the evolution of the genus Oryzias. The gene is absent
      from all other fish species studied. Therefore, it may not be the male-sex
      determining gene in all fishes.

PMID- 12620192
TI  - Role of CG and non-CG methylation in immobilization of transposons in
      Arabidopsis.
AB  - Methylation of cytosine residues in eukaryotic genomes is often associated with
      repeated sequences including transposons and their derivatives. Methylation has
      been implicated in control of two potential deleterious effects of these repeats:
      (1) uncontrolled transcription, which often disturbs proper expression of nearby
      host genes, and (2) changes in genome structure by transposition and ectopic
      recombination. Arabidopsis thaliana provides a genetically tractable system to
      examine these possibilities, since viable mutants in DNA methyltransferases are
      available. Arabidopsis MET1 (METHYLTRANSFERASE1, ortholog of mammalian DNA
      methyltransferase Dnmt1) is necessary for maintaining genomic cytosine
      methylation at 5'-CG-3' sites. Arabidopsis additionally methylates non-CG sites
      using CHROMOMETHYLASE3 (CMT3). We examined the mobility of endogenous CACTA
      transposons in met1, cmt3, and cmt3-met1 mutants. High-frequency transposition of
      CACTA elements was detected in cmt3-met1 double mutants. Single mutants in either
      met1 or cmt3 were much less effective in mobilization, despite significant
      induction of CACTA transcript accumulation. These results lead us to conclude
      that CG and non-CG methylation systems redundantly function for immobilization of
      transposons. Non-CG methylation in plants may have evolved as an additional
      epigenetic tag dedicated to transposon control. This view is consistent with the
      recent finding that CMT3 preferentially methylates transposon-related sequences.

PMID- 12620193
TI  - Identification of a DAF-16 transcriptional target gene, scl-1, that regulates
      longevity and stress resistance in Caenorhabditis elegans.
AB  - In Caenorhabditis elegans, an insulin-like signaling pathway, which includes the
      daf-2 and age-1 genes, controls longevity and stress resistance. Downregulation
      of this pathway activates the forkhead transcription factor DAF-16, whose
      transcriptional targets are suggested to play an essential role in controlling
      the phenotypes governed by this pathway. We have surveyed the genes that have the
      DAF-16 consensus binding element (DBE) within putative regulatory regions. Here,
      we show that one such gene, termed scl-1, is a positive regulator of longevity
      and stress resistance. Expression of scl-1 is upregulated in long-lived daf-2 and
      age-1 mutants and is undetectable in a short-lived daf-16 mutant. SCL-1 is a
      putative secretory protein with an SCP domain and is homologous to the mammalian
      cysteine-rich secretory protein (CRISP) family. scl-1 is required for the
      extension of the life span of daf-2 and age-1 mutants, and downregulation of scl
      1 reduces both life span and stress resistance of this animal. SCL-1, whose
      expression is dependent on DAF-16, is the first example of a putative secretory
      protein that positively regulates longevity and stress resistance.

PMID- 12620194
TI  - Female control of male gamete delivery during fertilization in Arabidopsis
      thaliana.
AB  - Fertilization in both animals and plants relies on the correct targeting of the
      male gametes to the female gametes. In flowering plants, the pollen tube carries
      two male gametes through the maternal reproductive tissues to the embryo sac,
      which contains two female gametes. The pollen tube then releases its two male
      gametes into a specialized receptor cell of the embryo sac, the synergid cell.
      The mechanisms controlling this critical step of gamete delivery are unknown.
      Here, data based on the new sirene (srn) mutant of Arabidopsis thaliana provide
      the first evidence for female control over male gamete delivery. Live imaging of
      fertilization shows that wild-type pollen tubes do not stop their growth and do
      not deliver their contents in srn embryo sacs.

PMID- 12620195
TI  - The c-Myc Oncoprotein Interacts with Bcr.
AB  - Bcr is a multifunctional protein that is the fusion partner for Abl (p210 Bcr
      Abl) in Philadelphia chromosome positive leukemias. We have identified c-Myc as a
      binding partner for Bcr in both yeast and mammalian cells. We are also able to
      observe interactions between natively expressed c-Myc and Bcr in leukemic cell
      lines. Although Bcr and Max have overlapping binding sites on c-Myc, Bcr cannot
      interact with Max, or with the c-Myc.Max heterodimer. Bcr expression blocks
      activation of c-Myc-responsive genes, as well as the transformed phenotype
      induced by coexpression of c-Myc and H-Ras, and this finding suggests that one
      function of Bcr is to limit the activity of c-Myc. However, Bcr does not block c
      Myc function by preventing its nuclear localization. Interestingly, increased Bcr
      dosage in COS-7 and K-562 cells correlates with a reduction in c-Myc protein
      levels, suggesting that Bcr may in fact be limiting c-Myc activity by regulating
      its stability. These data indicate that Bcr is a novel regulator of c-Myc
      function whose disrupted expression may contribute to the high level of c-Myc
      protein that is observed in Bcr-Abl transformed cells.

PMID- 12620196
TI  - A new noncanonical nuclear genetic code: translation of UAA into glutamate.
AB  - Deviant genetic codes reported in ciliates share the same feature: one (UGA) or
      two (UAR) of the three canonical stop codons are translated into one particular
      amino acid. In many genera, such as Oxytricha, Paramecium, and Tetrahymena, UAR
      codons are translated into glutamine. UGA is translated into cysteine in Euplotes
      or into tryptophan in Colpoda inflata and Blepharisma americanum. Here, we show
      that three peritrich species (Vorticella microstoma, Opisthonecta henneguyi, and
      Opisthonecta matiensis) translate UAA into glutamate and that at least UAA in O.
      matiensis is decoded through a mutant suppressor-like tRNA. This kind of genetic
      code has never been reported for any living organism. Phylogenetic analysis with
      alpha-tubulin sequences corroborates that peritrichs, peniculines (Paramecium),
      and hymenostomates (Tetrahymena) form a monophyletic group (class
      Oligohymenophorea). The differential translation (glu/gln) of UAR codons, the
      monophyly of the Oligohymenophorea, and the common evolutionary origin of
      glutamate and glutamine suggest that deviant genetic codes of present-day
      oligohymenophoreans could have the same origin.

PMID- 12620197
TI  - Molecular genetics and evolution of melanism in the cat family.
AB  - Melanistic coat coloration occurs as a common polymorphism in 11 of 37 felid
      species and reaches high population frequency in some cases but never achieves
      complete fixation. To investigate the genetic basis, adaptive significance, and
      evolutionary history of melanistic variants in the Felidae, we mapped, cloned,
      and sequenced the cat homologs of two putative candidate genes for melanism (ASIP
      [agouti] and MC1R) and identified three independent deletions associated with
      dark coloration in three different felid species. Association and transmission
      analyses revealed that a 2 bp deletion in the ASIP gene specifies black
      coloration in domestic cats, and two different "in-frame" deletions in the MC1R
      gene are implicated in melanism in jaguars and jaguarundis. Melanistic
      individuals from five other felid species did not carry any of these mutations,
      implying that there are at least four independent genetic origins for melanism in
      the cat family. The inferred multiple origins and independent historical
      elevation in population frequency of felid melanistic mutations suggest the
      occurrence of adaptive evolution of this visible phenotype in a group of related
      free-ranging species.

PMID- 12620199
TI  - Stemming species loss.

PMID- 12620198
TI  - Seeking balance in the GM crop debate.

PMID- 12620200
TI  - The emperor's new clothes.

PMID- 12620202
TI  - Nervous systems.

PMID- 12620201
TI  - Robert Insall.

PMID- 12620203
TI  - Nuclear pore complexes.

PMID- 12620204
TI  - Tactile perception, cortical representation and the bodily self.

PMID- 12620205
TI  - Membrane traffic: Arl GTPases get a GRIP on the Golgi.
AB  - A subset of the golgin family of large coiled-coil proteins have a GRIP domain
      that mediates their localization to the trans-Golgi. Two recent papers show that
      the Arl3p and Arl1p small GTPases act sequentially to recruit GRIP domain
      proteins to the Golgi.

PMID- 12620206
TI  - Sex determination: the fishy tale of Dmrt1.
AB  - The idea that the Dmrt1 gene provides a unifying sex-determining mechanism in non
      mammalian vertebrates is left high and dry by recent observations in fish.

PMID- 12620207
TI  - Brain imaging: how stable are synaptic connections?
AB  - Cortical circuits can undergo experience-dependent remodeling, while retaining
      the capacity for long-term information storage. The stability of individual
      synaptic connections is fundamental to both processes, but poorly understood; two
      studies using new in vivo imaging techniques have finally shed some light on this
      important issue.

PMID- 12620208
TI  - Mechanosensitive channels: stress relief.
AB  - Bacterial responses to decreasing osmolality involve mechanosensitive channels.
      The crystal structure has been determined of the small conductance
      mechanosensitive channel (MscS) from Escherichia coli, providing new insights
      into mechanical and voltage sensing by this and other channel proteins.

PMID- 12620209
TI  - Calcium signaling: NAADP ascends as a new messenger.
AB  - NAADP is now established as a Ca(2+) messenger by recent studies which have shown
      that it is active in various cells, identified the targeted Ca(2+) stores and
      demonstrated a stimulus-activated increase in its endogenous levels.

PMID- 12620210
TI  - T-cell differentiation: chromatin remodelling in CD4/CD8 regulation.
AB  - CD4 and CD8 genes are integral indicators of T-cell lineage commitment. New
      insights into the control of expression of these genes have come from recent
      reports implicating chromatin-remodelling factors in their regulation.

PMID- 12620211
TI  - Chemokine signaling: rules of attraction.
AB  - The chemokine SDF-1 and its receptor CXCR4 control cell migration in the immune
      and nervous systems. Recent studies in zebrafish have shown that SDF-1 and CXCR4
      also guide the migration of germ cells and sensory organs of the lateral line.

PMID- 12620212
TI  - Transcriptional activation: getting a grip on condensed chromatin.
AB  - Chromosomal transcription involves the concerted action of enormous, multisubunit
      chromatin remodeling complexes. A recent study, however, suggests a different and
      surprising viewpoint in which these protein assemblies are quite dynamic and
      individual subunits play key roles in chromatin remodeling.

PMID- 12620213
TI  - The network of time: understanding the molecular circadian system.
AB  - The circadian clock provides a temporal structure that modulates biological
      functions from the level of gene expression to performance and behaviour.
      Pioneering work on the fruitfly Drosophila has provided a basis for understanding
      how the temporal sequence of daily events is controlled in mammals. New insights
      have come from work on mammals, specifically from studying the daily activity
      profiles of clock mutant mice; from more detailed recordings of clock gene
      expression under different experimental conditions and in different tissues; and
      from the discovery and analysis of a growing number of additional clock genes.
      These new results are moving the model paradigm away from a simple negative
      feedback loop to a molecular network. Understanding the coupling and interactions
      of this network will help us to understand the evolution of the circadian system,
      advance medical diagnosis and treatment, improve the health of shift workers and
      frequent travellers, and will generally enable the treatment of clock-related
      pathologies.

PMID- 12620214
TI  - Histone deposition at the replication fork: a matter of urgency.
AB  - In this issue of Molecular Cell, Ye et al. provide a biological rationale for
      rapid histone deposition behind the replication fork. They show that defects in
      nucleosome assembly lead to DNA double-strand breaks and S phase arrest. Their
      results have important implications for the maintenance of genome integrity in
      proliferating cells.

PMID- 12620216
TI  - The Kin I kinesins are microtubule end-stimulated ATPases.
AB  - The Kin I kinesins are microtubule-destabilizing enzymes important for neuronal
      transport, spindle assembly, and chromosome segregation. now show that the Kin I
      MCAK is a microtubule end-stimulated ATPase that can catalytically depolymerize
      MT's.

PMID- 12620217
TI  - Asymmetric cell division: Miranda chauffeured by Jaguar?
AB  - Drosophila neuroblasts divide to produce daughters of distinct fate by
      asymmetrically localizing cell fate determinants and segregating them
      preferentially to one daughter. An intact F-actin cytoskeleton was known to be
      required, and now a myosin VI (Jaguar) has been shown to be necessary for basal
      targeting of cell fate determinants in neuroblasts.

PMID- 12620215
TI  - Plant defense: one post, multiple guards?!
AB  - Arabidopsis RIN4 is a key bacterial virulence target that is guarded by the
      resistance (R) protein RPM1. Two recent studies suggest that another R protein,
      RPS2, also guards RIN4. Bacterial avirulence (Avr) effectors AvrB, AvrRpm1, and
      AvrRpt2 alter this key protein. R proteins RPM1 and RPS2 recognize the altered
      status and initiate a defense-signaling response. The guard hypothesis is in!

PMID- 12620218
TI  - Enforced proximity in the function of a famous scaffold.
AB  - Recent studies by Park, Zarrinipar, and Lim with reengineered Ste5 scaffold
      proteins underscore the fundamental importance of proximity in enzyme regulation
      and of keeping a proper distance for maintaining signaling specificity.

PMID- 12620219
TI  - Functional diversity and regulation of different interleukin-1 receptor
      associated kinase (IRAK) family members.
AB  - Interleukin-1 receptor-associated kinase (IRAK) was first described as a signal
      transducer for the proinflammatory cytokine interleukin-1 (IL-1) and was later
      implicated in signal transduction of other members of the Toll-like receptor
      (TLR)/IL-1 receptor (IL-1R) family. In the meantime, four different IRAK-like
      molecules have been identified: two active kinases, IRAK-1 and IRAK-4, and two
      inactive kinases, IRAK-2 and IRAK-M. All IRAKs mediate activation of nuclear
      factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways.
      Although earlier observations suggested that IRAKs have redundant functions, this
      hypothesis is now challenged by knockout studies. Furthermore, recent data imply
      a role for IRAK-1 in tumor necrosis factor receptor (TNFR) superfamily-induced
      signaling pathways as well. The scope of this review is to highlight the specific
      role of different IRAKs and to discuss several mechanisms that contribute to
      their activation and regulation.

PMID- 12620220
TI  - The telomere protein Taz1 is required to prevent and repair genomic DNA breaks.
AB  - One fundamental function of telomeres is to prevent the ends of chromosomes from
      being sensed and treated as DNA damage. Here we present evidence for additional
      roles of telomeres in promoting proper chromosome segregation and DNA repair. We
      find that the fission yeast telomere protein Taz1p is required for cell cycle
      progression at 20 degrees C, a temperature at which taz1Delta cells exhibit a
      G(2)/M DNA damage checkpoint delay, chromosome missegregation, and DNA double
      strand breaks (DSBs). Spindle assembly checkpoint components and a checkpoint
      independent function of Rad3p are required for taz1Delta cells to survive at 20
      degrees C. Disruption of topoisomerase II activity suppresses the cold
      sensitivity of taz1Delta cells, suggesting a scenario in which telomeric
      entanglement is the primary defect. Furthermore, hypersensitivity to treatments
      that induce DSBs suggests that Taz1p is involved in DSB repair. Our observations
      imply roles for Taz1p-containing telomeres in preventing and repairing DNA breaks
      throughout the genome.

PMID- 12620221
TI  - Mechanism of the E. coli tau processivity switch during lagging-strand synthesis.
AB  - The E. coli replication machinery employs a beta clamp that tethers the
      polymerase to DNA, thus ensuring high processivity. The replicase also contains a
      processivity switch that dissociates the polymerase from its beta clamp. The
      switch requires the tau subunit of the clamp loader and is regulated by different
      DNA structures. At a primed site, the switch is "off." When the replicase reaches
      the downstream primer to form a nick, the switch is flipped, and tau ejects the
      polymerase from beta. This switch has high fidelity for completed synthesis,
      remaining "off" until just prior to incorporation of the last nucleotide and
      turning "on" only after addition of the last dNTP. These actions of tau are
      confined to its C-terminal region, which is located outside the clamp loading
      apparatus. Thus, this highly processive replication machine has evolved a
      mechanism to specifically counteract processivity at a defined time in the
      lagging-strand cycle.

PMID- 12620222
TI  - Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin
      independently of RPA, ATR, and Rad17.
AB  - Claspin is required for the ATR-dependent activation of Chk1 in Xenopus egg
      extracts containing incompletely replicated DNA. We show here that Claspin
      associates with chromatin in a regulated manner during S phase. Binding of
      Claspin to chromatin depends on the pre-replication complex (pre-RC) and Cdc45
      but not on replication protein A (RPA). These dependencies suggest that binding
      of Claspin occurs around the time of initial DNA unwinding at replication
      origins. By contrast, both ATR and Rad17 require RPA for association with DNA.
      Claspin, ATR, and Rad17 all bind to chromatin independently. These findings
      suggest that Claspin plays a role in monitoring DNA replication during S phase.
      Claspin, ATR, and Rad17 may collaborate in checkpoint regulation by detecting
      different aspects of a DNA replication fork.

PMID- 12620223
TI  - Defective S phase chromatin assembly causes DNA damage, activation of the S phase
      checkpoint, and S phase arrest.
AB  - The S phase checkpoint protects the genome from spontaneous damage during DNA
      replication, although the cause of damage has been unknown. We used a dominant
      negative mutant of a subunit of CAF-I, a complex that assembles newly synthesized
      DNA into nucleosomes, to inhibit S phase chromatin assembly and found that this
      induced S phase arrest. Arrest was accompanied by DNA damage and S phase
      checkpoint activation and required ATR or ATM kinase activity. These results show
      that in human cells CAF-I activity is required for completion of S phase and that
      a defect in chromatin assembly can itself induce DNA damage. We propose that
      errors in chromatin assembly, occurring spontaneously or caused by genetic
      mutations or environmental agents, contribute to genome instability.

PMID- 12620224
TI  - Different sensitivities of bromodomain factors 1 and 2 to histone H4 acetylation.
AB  - The histone code hypothesis proposes that covalently modified histone tails are
      binding sites for specific proteins. In vitro evidence suggests that factors
      containing bromodomains read the code by binding acetylated histone tails.
      Bromodomain Factor 1 (Bdf1), a protein that associates with TFIID, binds histone
      H4 with preference for multiply acetylated forms. In contrast, the closely
      related protein Bdf2 shows no preference for acetylated forms. A deletion of BDF1
      but not BDF2 is lethal when combined with a mutant allele of ESA1 (a histone H4
      acetyltransferase) or with nonacetylatable histone H4 variants. Bromodomain point
      mutations that block Bdf1 binding to histones disrupt transcription and reduce
      Bdf1 association with chromatin in vivo. Therefore, bromodomains with different
      specificity generate further complexity of the histone code.

PMID- 12620225
TI  - Bromodomains mediate an acetyl-histone encoded antisilencing function at
      heterochromatin boundaries.
AB  - Bromodomains bind acetylated histone H4 peptides in vitro. Since many chromatin
      remodeling complexes and the general transcription factor TFIID contain
      bromodomains, they may link histone acetylation to increased transcription. Here
      we show that yeast Bdf1 bromodomains recognize endogenous acetyl-histone H3/H4 as
      a mechanism for chromatin association in vivo. Surprisingly, deletion of BDF1 or
      a Bdf1 mutation that abolishes histone binding leads to transcriptional
      downregulation of genes located at heterochromatin-euchromatin boundaries. Wild
      type Bdf1 protein imposes a physical barrier to the spreading of telomere- and
      mating-locus-proximal SIR proteins. Biochemical experiments indicate that Bdf1
      competes with the Sir2 deacetylase for binding to acetylated histone H4. These
      data suggest an active role for Bdf1 in euchromatin maintenance and antisilencing
      through a histone tail-encoded boundary function.

PMID- 12620226
TI  - Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling
      complexes.
AB  - Mammalian SWI/SNF chromatin remodeling complexes are involved in critical aspects
      of cellular growth and genomic stability. Each complex contains one of two highly
      homologous ATPases, BRG1 and BRM, yet little is known about their specialized
      functions. We show that BRG1and BRM associate with different promoters during
      cellular proliferation and differentiation, and in response to specific signaling
      pathways by preferential interaction with certain classes of transcription
      factors. BRG1 binds to zinc finger proteins through a unique N-terminal domain
      that is not present in BRM. BRM interacts with two ankyrin repeat proteins that
      are critical components of Notch signal transduction. Thus, BRG1 and BRM
      complexes may direct distinct cellular processes by recruitment to specific
      promoters through protein-protein interactions that are unique to each ATPase.

PMID- 12620227
TI  - SWI/SNF unwraps, slides, and rewraps the nucleosome.
AB  - The structure of the SWI/SNF-remodeled nucleosome was characterized with single
      base-pair resolution by mapping the contacts of specific histone fold residues
      with nucleosomal DNA. We demonstrate that SWI/SNF peels up to 50 bp of DNA from
      the edge of the nucleosome, translocates the histone octamer beyond the DNA ends
      via a DNA bulge propagation mechanism, and promotes the formation of an
      intramolecular DNA loop between the nucleosomal entry and exit sites. This stable
      altered nucleosome conformation also exhibits alterations in the distance between
      contacts of specific histone residues with DNA and higher electrophoretic and
      sedimentation mobility, consistent with a more compact molecular shape. SWI/SNF
      converts a nucleosome to the altered state in less than 1 s, hydrolyzing fewer
      than 10 ATPs per event.

PMID- 12620228
TI  - ERK-dependent phosphorylation of the transcription initiation factor TIF-IA is
      required for RNA polymerase I transcription and cell growth.
AB  - Phosphorylation of transcription factors by mitogen-activated protein kinase
      (MAPK) cascades links cell signaling with the control of gene expression. Here we
      show that growth factors induce rRNA synthesis by activating MAPK-dependent
      signaling cascades that target the RNA polymerase I-specific transcription
      initiation factor TIF-IA. Activation of TIF-IA and ribosomal gene transcription
      is sensitive to PD98059, indicating that TIF-IA is targeted by MAPK in vivo.
      Phosphopeptide mapping and mutational analysis reveals two serine residues (S633
      and S649) that are phosphorylated by ERK and RSK kinases. Replacement of S649 by
      alanine inactivates TIF-IA, inhibits pre-rRNA synthesis, and retards cell growth.
      The results provide a link between growth factor signaling, ribosome production,
      and cell growth, and may have a major impact on the mechanism of cell
      transformation.

PMID- 12620229
TI  - Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing.
AB  - The p19(Arf) tumor suppressor, a nucleolar protein, binds to Mdm2 to induce p53
      dependent cell cycle arrest. Arf also prevents the proliferation of cells lacking
      Mdm2 and p53, albeit less efficiently. We show that p19(Arf) inhibits production
      of ribosomal RNA, retarding processing of 47/45S and 32S precursors. These
      effects correlate with but do not strictly depend upon inhibition of rRNA
      biosynthesis or cell cycle arrest, are not mimicked by p53, and require neither
      p53 nor Mdm2. Arf mutants lacking conserved amino acid residues 2-14 do not block
      rRNA synthesis and processing or inhibit cell proliferation. Evolution may have
      linked a primordial nucleolar Arf function to Mdm2 and p53, creating a more
      efficient checkpoint-signaling pathway for coordinating ribosomal biogenesis and
      cell cycle progression.

PMID- 12620230
TI  - Ribosome structure and activity are altered in cells lacking snoRNPs that form
      pseudouridines in the peptidyl transferase center.
AB  - One of the oldest questions in RNA science is the role of nucleotide
      modification. Here, the importance of pseudouridine formation (Psi) in the
      peptidyl transferase center of rRNA was examined by depleting yeast cells of 1-5
      snoRNAs that guide a total of six Psi modifications. Translation was impaired
      substantially with loss of a conserved Psi in the A site of tRNA binding.
      Depletion of other Psis had subtle or no apparent effect on activity; however,
      synergistic effects were observed in some combinations. Pseudouridines are
      proposed to enhance ribosome activity by altering rRNA folding and interactions,
      with some Psis having greater effects than others. The possibility that modifying
      snoRNPs might affect ribosome structure in other ways is also discussed.

PMID- 12620231
TI  - The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase.
AB  - The silent information regulator 2 protein (Sir2p) of Saccharomyces cerevisiae is
      an NAD-dependent histone deacetylase that plays a critical role in
      transcriptional silencing. Here, we report that a human ortholog of Sir2p,
      sirtuin type 2 (SIRT2), is a predominantly cytoplasmic protein that colocalizes
      with microtubules. SIRT2 deacetylates lysine-40 of alpha-tubulin both in vitro
      and in vivo. Knockdown of SIRT2 via siRNA results in tubulin hyperacetylation.
      SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase.
      Enzymatic analysis of recombinant SIRT2 in comparison to a yeast homolog of Sir2
      protein (Hst2p) shows a striking preference of SIRT2 for acetylated tubulin
      peptide as a substrate relative to acetylated histone H3 peptide. These
      observations establish SIRT2 as a bona fide tubulin deacetylase.

PMID- 12620232
TI  - The kinesin-related protein MCAK is a microtubule depolymerase that forms an ATP
      hydrolyzing complex at microtubule ends.
AB  - MCAK belongs to the Kin I subfamily of kinesin-related proteins, a unique group
      of motor proteins that are not motile but instead destabilize microtubules. We
      show that MCAK is an ATPase that catalytically depolymerizes microtubules by
      accelerating, 100-fold, the rate of dissociation of tubulin from microtubule
      ends. MCAK has one high-affinity binding site per protofilament end, which, when
      occupied, has both the depolymerase and ATPase activities. MCAK targets
      protofilament ends very rapidly (on-rate 54 micro M(-1).s(-1)), perhaps by
      diffusion along the microtubule lattice, and, once there, removes approximately
      20 tubulin dimers at a rate of 1 s(-1). We propose that up to 14 MCAK dimers
      assemble at the end of a microtubule to form an ATP-hydrolyzing complex that
      processively depolymerizes the microtubule.

PMID- 12620233
TI  - Selective dimerization of a C2H2 zinc finger subfamily.
AB  - The C2H2 zinc finger is the most prevalent protein motif in the mammalian
      proteome. Two C2H2 fingers in Ikaros are dedicated to homotypic interactions
      between family members. We show here that these fingers comprise a bona fide
      dimerization domain. Dimerization is highly selective, however, as homologous
      domains from the TRPS-1 and Drosophila Hunchback proteins support
      homodimerization, but not heterodimerization with Ikaros. Ikaros-Hunchback
      selectivity is determined by 11 residues concentrated within the alpha-helical
      regions typically involved in base recognition. Preferential homodimerization of
      one chimeric protein predicts a parallel dimer interface and establishes the
      feasibility of creating novel dimer specificities. These results demonstrate that
      the C2H2 motif provides a versatile platform for both sequence-specific protein
      nucleic acid interactions and highly specific dimerization.

PMID- 12620234
TI  - Structural basis for specific binding of the Gads SH3 domain to an RxxK motif
      containing SLP-76 peptide: a novel mode of peptide recognition.
AB  - The SH3 domain, which normally recognizes proline-rich sequences, has the
      potential to bind motifs with an RxxK consensus. To explore this novel
      specificity, we have determined the solution structure of the Gads T cell adaptor
      C-terminal SH3 domain in complex with an RSTK-containing peptide, representing
      its physiological binding site on the SLP-76 docking protein. The SLP-76 peptide
      engages four distinct binding pockets on the surface of the Gads SH3 domain and
      upon binding adopts a unique structure characterized by a right-handed 3(10)
      helix at the RSTK locus, in contrast to the left-handed polyproline type II helix
      formed by canonical proline-rich SH3 ligands. The structure, and supporting
      mutagenesis and peptide binding data, reveal a novel mode of ligand recognition
      by SH3 domains.

PMID- 12620235
TI  - Structure of Rab escort protein-1 in complex with Rab geranylgeranyltransferase.
AB  - Posttranslational geranylgeranylation of Rab GTPases is catalyzed by Rab
      geranylgeranyltransferase (RabGGTase), which consists of a catalytic alpha/beta
      heterodimer and an accessory Rab escort protein (REP). The crystal structure of
      isoprenoid-bound RabGGTase complexed to REP-1 has been solved to 2.7 A
      resolution. The complex interface buries a surprisingly small surface area of ca.
      680 A and is unexpectedly formed by helices 8, 10, and 12 of the RabGGTase alpha
      subunit and helices D and E of REP-1. We demonstrate that the affinity of
      RabGGTase for REP-1 is allosterically regulated by phosphoisoprenoid via a long
      range trans-domain signal transduction event. Comparing the structure of REP-1
      with the closely related RabGDI, we conclude that the specificity of the
      REP:RabGGTase interaction is defined by differently positioned phenylalanine
      residues conserved in the REP and GDI subfamilies.

PMID- 12620236
TI  - The crystal structure of a truncated ErbB2 ectodomain reveals an active
      conformation, poised to interact with other ErbB receptors.
AB  - ErbB2 does not bind ligand, yet appears to be the major signaling partner for
      other ErbB receptors by forming heteromeric complexes with ErbB1, ErbB3, or
      ErbB4. The crystal structure of residues 1-509 of ErbB2 at 2.5 A resolution
      reveals an activated conformation similar to that of the EGFR when complexed with
      ligand and very different from that seen in the unactivated forms of ErbB3 or
      EGFR. The structure explains the inability of ErbB2 to bind known ligands and
      suggests why ErbB2 fails to form homodimers. Together, the data suggest a model
      in which ErbB2 is already in the activated conformation and ready to interact
      with other ligand-activated ErbB receptors.

PMID- 12620237
TI  - EGF activates its receptor by removing interactions that autoinhibit ectodomain
      dimerization.
AB  - Epidermal growth factor (EGF) receptor is the prototype of the ErbB (HER) family
      receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation
      and are implicated in many human cancers. EGF activates its receptor by inducing
      dimerization of the 621 amino acid EGF receptor extracellular region. We describe
      the 2.8 A resolution crystal structure of this entire extracellular region
      (sEGFR) in an unactivated state. The structure reveals an autoinhibited
      configuration, where the dimerization interface recently identified in activated
      sEGFR structures is completely occluded by intramolecular interactions. To
      activate the receptor, EGF binding must promote a large domain rearrangement that
      exposes this dimerization interface. This contrasts starkly with other RTK
      activation mechanisms and suggests new approaches for designing ErbB receptor
      antagonists.

PMID- 12620238
TI  - Mechanism of XIAP-mediated inhibition of caspase-9.
AB  - The inhibitor of apoptosis (IAP) proteins potently inhibit the catalytic activity
      of caspases. While profound insight into the inhibition of the effector caspases
      has been gained in recent years, the mechanism of how the initiator caspase-9 is
      regulated by IAPs remains enigmatic. This paper reports the crystal structure of
      caspase-9 in an inhibitory complex with the third baculoviral IAP repeat (BIR3)
      of XIAP at 2.4 A resolution. The structure reveals that the BIR3 domain forms a
      heterodimer with a caspase-9 monomer. Strikingly, the surface of caspase-9 that
      interacts with BIR3 also mediates its homodimerization. We demonstrate that
      monomeric caspase-9 is catalytically inactive due to the absence of a supporting
      sequence element that could be provided by homodimerization. Thus, XIAP
      sequesters caspase-9 in a monomeric state, which serves to prevent catalytic
      activity. These studies, in conjunction with other observations, define a unified
      mechanism for the activation of all caspases.

PMID- 12620240
TI  - Insights into the regulatory mechanism for caspase-8 activation.
AB  - In the death receptor induced apoptotic pathway, caspase-8 autocatalytically
      cleaves itself at specific cleavage sites. To better understand the regulatory
      mechanisms behind caspase-8 activation, we compared active wild-type caspase-8
      (wtC8) and an uncleavable form of procaspase-8 (uncleavable C8). We demonstrate
      that wtC8 predominantly exists as a monomer and dimerizes in a concentration and
      inhibitor binding-dependent fashion. The K(D) for dimeric wtC8 is approximately
      50 micro M and decreases when inhibitor bound. Uncleavable C8 is mainly
      monomeric, but a small amount that dimerizes is as active as wtC8. Inhibitor
      binding does not favor dimerization but induces active site rearrangements in
      uncleavable C8. Our findings suggest that dimerization is the crucial factor for
      caspase-8 activation.

PMID- 12620239
TI  - A unified model for apical caspase activation.
AB  - Apoptosis is orchestrated by the concerted action of caspases, activated in a
      minimal two-step proteolytic cascade. Existing data suggests that apical caspases
      are activated by adaptor-mediated clustering of inactive zymogens. However, the
      mechanism by which apical caspases achieve catalytic competence in their
      recruitment/activation complexes remains unresolved. We explain that proximity
      induced activation of apical caspases is attributable to dimerization. Internal
      proteolysis does not activate these apical caspases but is a secondary event
      resulting in partial stabilization of activated dimers. Activation of caspases-8
      and -9 occurs by dimerization that is fully recapitulated in vitro by
      kosmotropes, salts with the ability to stabilize the structure of proteins.
      Further, single amino acid substitutions at the dimer interface abrogate the
      activity of caspases-8 and -9 introduced into recipient mammalian cells. We
      propose a unified caspase activation hypothesis whereby apical caspases are
      activated by dimerization of monomeric zymogens.

PMID- 12620241
TI  - An immunohistochemical study on the neuropeptide-producing endocrine cells in the
      alimentary tract of wrinkled frog, Rana rugosa (Ranidae).
AB  - The regional distribution and relative frequency of neurohormonal peptides
      producing endocrine cells were demonstrated in the alimentary tract of wrinkled
      frog, Rana rugosa, using eight types of specific antisera raised against
      mammalian regulatory peptides. The alimentary tract of frog was divided into six
      portions from esophagus to rectum. Most of the cells in the epithelial lining
      portion, between epithelial cells, were generally spherical or spindle shaped
      having long cytoplasmic process that was reached to the lumen (open-typed cell)
      while cells showing round shape (close-typed cell) were also found in the
      gastric, esophageal or intestinal glands occasionally. All of eight
      immunoreactive (IR) cells against serotonin, somatostatin, bovine Sp
      1/chromogranin (BCG), gastrin, cholecystokinin (CCK)-8, bombesin, glucagon, and
      human pancreatic polypeptide (HPP) were observed in this study. Serotonin-IR
      cells were demonstrated throughout whole alimentary tract including esophagus and
      showed most predominant frequency in antrum. Somatostatin-IR cells were also
      detected throughout whole alimentary tract including esophagus and showed most
      predominant in pylorus and antrum. BCG-IR cells were restricted to stomach
      regions with relatively low frequencies. CCK-8-IR cells were observed from antrum
      to ileum and showed highest frequency in antrum. Gastrin-IR cells were restricted
      to antrum with low frequency and bombesin-IR cells were demonstrated from
      esophagus to antrum with various frequencies. Glucagon-IR cells were located
      throughout whole alimentary tract except for rectum and showed most predominant
      frequency at antrum. HPP-IR cells were detected from antrum to ileum with highest
      frequency in antrum. In conclusion, the regional distribution and relative
      frequency of these IR cells correspond well to the previous report in anuran
      species but somewhat peculiar patterns are also detected.

PMID- 12620242
TI  - The effects of long-term estradiol-17beta treatment on the growth and physiology
      of female triploid brook trout (Salvelinus fontinalis).
AB  - Triploid female fish show impaired gonadal development, which results in the
      production of only a few oocytes relative to diploids. The rate of maturation of
      these few oocytes in much slower relative to those of diploids and is attributed
      to an insufficient estradiol-17beta (E(2)) stimulus. Female triploid brook trout,
      aged 2+, were fed E(2) for seven months (i.e., July 1998 to February 1999) in an
      attempt to increase plasma E(2) comparable to diploid levels and thereby
      accelerate rates of oocyte growth. Compared to triploids fed a normal diet (i.e.,
      control-triploids), the administration of 30 mg E(2)/kg feed to triploids (i.e.,
      E(2)-treated-triploids) led to the development of secondary sex characteristics,
      a significant reduction in hematocrit and total blood hemoglobin level, a
      decrease in plasma testosterone and no weight gain. Plasma vitellogenin was
      significantly higher in E(2)-treated-triploids than in control-triploids and
      diploids at every month except October 1999. Although greater than in the control
      triploids, plasma E(2) for the E(2)-treated-triploids did not attain the high
      levels shown by the diploids during the months of peak vitellogenesis (i.e.,
      September and October). Following maturation and spawning of diploids, sacrificed
      E(2)-treated and control-triploids showed no differences in ovarian development
      or liver size. The E(2) dose for the treated-triploids was increased to 80 mg
      E(2)/kg feed for approximately seven more weeks in a further attempt to increase
      plasma E(2), with no success. It is suggested that the low plasma E(2) of the
      treated-triploids was the result of a high metabolic clearance rate.

PMID- 12620243
TI  - Effects of testosterone on pedicle formation and its transformation to antler in
      castrated male, freemartin and normal female red deer (Cervus elaphus).
AB  - Pedicles and antlers are male deer secondary sexual characters. As such,
      development of these structures is under the control of androgen hormones.
      Pedicle growth is caused by increasing and elevated plasma testosterone (T)
      levels, whereas first antler transformation from a fully formed pedicle occurs
      when the T levels are decreasing. Castration prior to pedicle initiation
      abrogates future pedicle and antler formation. Female deer also have the
      potential to develop pedicles and antlers, but they do not normally express this
      phenotype due to lack of sufficient androgen stimulation. Previous studies have
      shown that female white-tailed deer could be readily induced to grow pedicles as
      well as antlers by singular administration of exogenous androgens (EA), but in
      red deer (Cervus elaphus) singular or irregular EA treatment could only stimulate
      castrated male, normal or ovariectomised females to grow pedicles, but not
      antlers. The present study was set out to test whether these EA-induced pedicles
      in red deer failed to give rise to antlers was because they were constitutively
      incapable of doing so, or because the plasma T profile naturally exhibited in
      intact stags was not achieved by the androgen treatment used in these previous
      studies. Eight castrated red deer stag calves, 3 freemartins (females which were
      born co-twin to males), and 3 normal female red deer were used in the present
      study and treated with EA, either as biweekly injections for the castrates or as
      implants for freemartin and females until the late stage of pedicle growth. Blood
      sampling was carried out biweekly for the analyses of plasma T and IGF1
      concentration. The results showed that the natural plasma T profile in the
      experimental deer was successfully mimicked through regular EA treatment and
      subsequent withdrawal at late pedicle growth stage. All castrated males, 2 out of
      3 freemartin, and 1 out of 3 normal female red deer formed not only pedicles, but
      also antlers. Based on these results, we conclude that EA-induced pedicles at
      least in red deer of the genus Cervus, like those in the genus Odocoileus, are
      constitutively capable of giving rise to antlers, if they are of sufficient
      height.

PMID- 12620244
TI  - Occurrence of prohormone convertase-like substances in the neural complex cells
      of the ascidian Halocynthia roretzi.
AB  - Our previous study on the distribution of adrenocorticotropin (ACTH)-like
      substances in the neural complex (cerebral ganglion, dorsal strand, and neural
      gland) of an ascidian Halocynthia roretzi revealed that some of the cells in the
      cerebral ganglion and the cells scattered along the dorsal strand were
      immunopositive with antiserum against ACTH. In order to ascertain whether these
      cells are equipped with prohormone convertases, we performed immunohistochemical
      studies on the neural complex by using antisera against PC1 and PC2. A
      considerable number of cells around the dorsal strand and a few cells in the
      neural ganglion were immunopositive with PC1 and/or PC2 antibodies.
      Immunoelectron microscopic study demonstrated that some granulated cells situated
      in the cerebral ganglion and along the dorsal strand contained PC1- or PC2-like
      substances within their secretory granules. Western blot analysis revealed the
      presence of 66-kDa PC1-like and 70-kDa PC2-like substances in the neural complex.
      Moreover, immunostaining of consecutive sections showed that the majority of the
      cells containing PC1- and/or PC2-like substances corresponded to the cells
      immunoreactive with antisera against ACTH and CLIP but not to those
      immunoreactive with an antiserum against PRL. Cells belonging to the neural gland
      neither contained electron-dense granules nor showed immunoreactivity with any
      antisera employed in this experiment. The possibility that some of the cells
      situated in the cerebral ganglion and along the dorsal strand are progenitors of
      vertebrate adenohypophyseal cells is discussed.

PMID- 12620245
TI  - Ethane 1,2-dimethane sulphonate is a useful tool for studying cell-to-cell
      interactions in the testis of the frog, Rana esculenta.
AB  - Ethane 1,2-dimethane sulphonate (EDS), a toxin which specifically destroys Leydig
      cells (LC), has been used to study cellular interactions in the testis of the
      frog Rana esculenta. Animals received three consecutive EDS injections and were
      sacrificed on day 4, 8, and 28 from the first injection. No significant
      morphological differences were observed between present observation and that
      obtained, in a previous experiment, after four consecutive EDS injections. In
      fact, on day 4, in the germinal tubules adjacent to apparently normal LC, Sertoli
      cells surrounding primary spermatogonia (I SPG) show heterochromatic nuclei and
      loss of cellular adhesion. Interestingly, I SPG surrounded by the heterochromatic
      Sertoli cells present grossly swollen mitochondria with ballooned cristae. On day
      8, sometimes in the interstitium many LC appear strongly damaged and the germinal
      tubules appear disorganized; the only cell type still distinguishable is the I
      SPG. On day 28 from the first EDS injection a new population of LC reappear in
      the interstitium and spermatogenesis normalizes. These data confirm the close
      relationship between the interstitial and the geminal compartments.
      Immunocytochemical data obtained using a polyclonal antibody anticonnexin-43 (Cx
      43, the most abundant Cx found in mammalian testis) demonstrate the presence of
      Cx-43 in the frog testis. In particular, Cx-43 is present between LC in the
      interstitium, between Sertoli and germ cells in the cysts and between Sertoli
      cells and I SPG. Cx-43 immunopositivity sharply decreases on day 4 from the first
      EDS injection simultaneously with the loss of cellular adhesion between Sertoli
      and germ cells. On day 8 and 28 from the first EDS injection Cx-43,
      immunopositivity is restored and, this data is also supported by Western blot
      analysis. Our data provide, for the first time, evidence that Cx-43 protein is
      present in the frog testis and confirm that EDS is a useful tool for studying
      cellular communication at the paracrine pathway or through direct contact
      depending on the gap junctional pathway in R. esculenta testis

PMID- 12620246
TI  - Identification of cGnRH-II in the median eminence of Japanese quail (Coturnix
      coturnix japonica).
AB  - In a previous paper, we described the presence of cGnRH-II in the quail (Coturnix
      coturnix japonica) and chicken (Gallus gallus) median eminence using highly
      specific antibodies directed against a polypeptide corresponding to the C
      terminal portion of cGnRH-II (van Gils et al., 1993). This finding remained very
      controversial, since no other study, with any other antibody, had ever reported
      the presence of cGnRH-II immunoreactive fibers in the median eminence of birds.
      In this study, the cGnRH-II immunoreactive substances in quail median eminence
      were isolated by RP-HPLC and identified by RIA. To eliminate the possibility that
      the cGnRH-II-like immunoreactivity in the median eminence was due to a cross
      reaction of our anti-cGnRH-II antiserum with an unknown peptide, the cGnRH-II
      immunoreactive substances, present in a quail median eminence extract, were
      isolated by immunoaffinity chromatography using immunoaffinity-purified
      antibodies. In the eluate of the immunoaffinity column only one peptide could be
      detected by mass spectrometry. This peptide had a mass of 1235.56 Da, which is
      the same as synthetic cGnRH-II. In addition, MS/MS fragmentation generated an
      amino acid sequence corresponding to the sequence of cGnRH-II. The present study
      therefore identified indisputably cGnRH-II in the median eminence of the quail.

PMID- 12620247
TI  - Leptin depresses food intake in great tits (Parus major).
AB  - Food availability for wild organisms typically varies both in time and space,
      requiring a mechanism that regulates the storage of excess energy and makes it
      possible to use stores during energy shortfall. Leptin, a protein hormone encoded
      by an obesity gene, has been suggested to be the signal mediator for this flux of
      energy. In a controlled laboratory experiment on caged great tits (Parus major)
      we evaluated the effect of leptin on food intake and behaviour. Experimental
      birds were given an intramuscular injection of 10 microg leptin dissolved in
      phosphate buffered saline (PBS), while the control birds were injected with PBS
      only at 09:00 h after a night's fasting. Within the first 20 min after injections
      we observed a significant difference in food intake between groups: control birds
      initially fed at higher rates compared to leptin treated birds. The cumulative
      food intake suggested that the effect of leptin disappeared after approximately
      40-50 min post-injections. Similar results have previously been found in
      domesticated chickens. To our knowledge, this is the first study to show that
      leptin depresses food intake in wild birds.

PMID- 12620248
TI  - Pheromonal stimulation of spawning release of gametes by gonadotropin releasing
      hormone in the chiton, Mopalia sp.
AB  - The chiton Mopalia sp., a mollusc, was exposed to various dilutions of
      gonadotropin releasing hormone (GnRH) in sea water to determine whether this
      peptide is capable of acting as a pheromone that could stimulate release of ripe
      gametes (spawning). Two of the peptides, lamprey GnRH-1 and tunicate GnRH-2, had
      this action at a higher concentration (1.0 mg/L) but dilutions to 50 microg/L no
      longer were effective. Three other GnRHs: lamprey GnRH-3, tunicate GnRH-1, and a
      modified chicken GnRH-2, had no such action under the same test conditions. Since
      the spawning response could be produced by some GnRHs and not by others, it would
      appear that some kind of molecular recognition is involved, possibly by specific
      binding to a receptor. In earlier preliminary experiments tunicate GnRH-2 rapidly
      stimulated gamete release in a hemichordate, Saccoglossus. Thus it is suggested
      that GnRHs, in at least some invertebrates, may function as pheromones, serving
      to stimulate simultaneous spawning of individuals in a population of animals, and
      in this way assure more successful fertilization in species that must release
      their gametes into the water in which they live.

PMID- 12620249
TI  - Immunocytochemical studies on the pituitary gland of Anguilla anguilla L., in
      relation to early growth stages and diet-induced sex differentiation.
AB  - Mammalian and teleost antisera against pituitary hormones were used to identify
      and localize pituitary cell types in the European eel (Anguilla anguilla L.). The
      investigation was conducted on unpigmented glass eels of 5.6-6.2 of total body
      length (L(T)) caught in river mouths, then on yellow eels reared from the
      pigmented glass eel (or elver) stage up to 12-14 cm of L(T), in an eel farm in
      warm freshwater. Treated elvers were fed with commercial paste food supplemented
      with mature carp ovaries, containing oestradiol, that induced an early ovarian
      differentiation and a higher growth rate. The antisera detected seven types of
      immunoreactive (ir) cells, six of which were already found in glass eel
      adenohypophysis, suggesting differentiation of these cell types during the
      leptocephalus stage. In 12-14 cm treated yellow eels with small ovaries, a
      seventh type (ir-GtH) was detected in the proximal pars distalis; in the same
      animals the ir-TSH cells increased in number and size. From unpigmented glass
      eels to 12-14 cm yellow eels, the whole pituitary volume of controls increased
      nearly four times, while that of treated ones increased nearly six times. The
      larger volume of pituitary in treated eels was mainly due to volume increase of
      proximal pars distalis and rostral pars distalis. The %GH, that is the potential
      index of GH production, was significantly higher in treated yellow eels with
      gonads differentiating into ovaries than in controls; no difference was detected
      in %PRL between treated and control eels. The above results strongly suggest that
      in eels the feminizing effects of oestrogen is first exerted on the pituitary,
      probably through the hypothalamus, and later on the gonads.

PMID- 12620250
TI  - Growth hormone and insulin-like growth factor I of a Euryhaline fish Cottus
      kazika: cDNA cloning and expression after seawater acclimation.
AB  - The four-spine sculpin Cottus kazika is a euryhaline teleost, in which faster
      growth in seawater (SW) and freshwater (FW) has been reported. In this study,
      cDNA clones encoding growth hormone (GH) and insulin-like growth factor I (IGF-I)
      were isolated from this species to examine the involvement of the GH/IGF-I axis
      in osmotic adaptation. The amino acid sequence of GH predicted from cDNA was
      highly similar to those of other fish species, 92% to Sparus aurata, 67% to
      Paralichthys olivaceus, and 63% to Oncorhynchus keta. The predicted sequence of
      IGF-I was also exhibited high similarity to those of other fishes, 97% to
      Myxocephalus scorpius, 95% to P. olivaceus, and 81% to O. keta. Tissue
      distribution of GH and IGF-I mRNA in fish reared in FW and SW was examined by
      reverse transcription-polymerase chain reaction (RT-PCR). The GH mRNA was
      detected only in the pituitary gland. The major site of IGF-I mRNA expression was
      the liver while minor signals were detected in various tissues including the
      pituitary, gill, fin, heart, spleen, intestine, and kidney. The expression level
      of GH mRNA in the pituitary was not different between FW- and SW-reared fish.
      However, the level of IGF-I mRNA in the liver of SW-reared fish was significantly
      higher than that of FW-reared fish. These results suggest the possible
      involvement of hepatic IGF-I in SW adaptation of this species.

PMID- 12620252
TI  - Biosynthesis of fungal melanins and their importance for human pathogenic fungi.
AB  - For more than 40 years fungi have been known to produce pigments known as
      melanins. Predominantly these have been dihydroxyphenylalanine (DOPA)-melanin and
      dihydroxynaphthalene (DHN)-melanin. The biochemical and genetical analysis of the
      biosynthesis pathways have led to the identification of the genes and
      corresponding enzymes of the pathways. Only recently have both these types of
      melanin been linked to virulence in some human pathogenic and phytopathogenic
      fungi. The absence of melanin in human pathogenic and phytopathogenic fungi often
      leads to a decrease in virulence. In phytopathogenic fungi such as Magnaporthe
      grisea and Colletotrichum lagenarium, besides other possible functions in
      pathogenicity, DHN-melanin plays an essential role in generating turgor for plant
      appressoria to penetrate plant leaves. While the function of melanin in human
      pathogenic fungi such as Cryptococcus neoformans, Wangiella dermatitidis,
      Sporothrix schenckii, and Aspergillus fumigatus is less well defined, its role in
      protecting fungal cells has clearly been shown. Specifically, the ability of both
      DOPA- and DHN-melanins to quench free radicals is thought to be an important
      factor in virulence. In addition, in several fungi the production of fungal
      virulence factors, such as melanin, has been linked to a cAMP-dependent signaling
      pathway. Many of the components involved in the signaling pathway have been
      identified.

PMID- 12620253
TI  - IGS sequence variation, group-I introns and the complete nuclear ribosomal DNA of
      the entomopathogenic fungus Metarhizium: excellent tools for isolate detection
      and phylogenetic analysis.
AB  - The complete nuclear rDNA gene complex of Metarhizium anisopliae var. anisopliae
      isolate ME1 is 8118bp long and contains the 18S, 5.8S, and 28S rRNA genes as well
      as the ITS and IGS regions. Variation in the ITS of isolates of M. anisopliae
      var. anisopliae and one each of Metarhizium anisopliae var. acridum, Metarhizium
      flavoviride var. flavoviride, and Metarhizium flavoviride var. minus, clustered
      39 out of 40 of M. anisopliae var. anisopliae isolates in one clade. Nucleotide
      sequence variation in the IGS among 21 of M. anisopliae var. anisopliae isolates
      showing IGS length variation sorted them into three strongly supported clades,
      which were weakly correlated with insect hosts and were not correlated with
      geographic location. Two group-I introns, Ma-int4 and Ma-int5, were discovered in
      the 18S and the 3(') end of the 28S, in M. anisopliae var. anisopliae isolates
      ITALY-12 and IMBST 9601. The insertion sites and sub-group of these introns
      correlated with their closest relatives, as judged by phylogenetic analysis of
      intron nucleotide sequence.

PMID- 12620254
TI  - Specific induction and carbon/nitrogen repression of arginine catabolism gene of
      Aspergillus nidulans--functional in vivo analysis of the otaA promoter.
AB  - The arginine catabolism gene otaA encoding ornithine transaminase (OTAse) is
      specifically induced by arginine and is under the control of the broad-domain
      carbon and nitrogen repression systems. Arginine induction is mediated by a
      product of arcA gene coding for Zn(2)C(6) activator. We have identified a region
      responsible for arginine induction in the otaA promoter (AnUAS(arg)). Deletions
      within this region result in non-inducibility of OTAse by arginine, whether in an
      arcA(+) strain or in the presence of the arcA(d)47 gain of function allele.
      AnUAS(arg) is very similar to the Saccharomyces cerevisiae UAS(arg), a sequence
      bound by the Zn(2)C(6) activator (ArgRIIp), acting in a complex with two MADS-box
      proteins (McmIp and ArgRIp). We demonstrate here that two CREA in vitro binding
      sites in the otaA promoter are functional in vivo. CREA is directly involved in
      carbon repression of the otaA gene and it also reduces its basal level of
      expression. Although AREA binds to the otaA promoter in vitro, it probably does
      not participate in nitrogen metabolite repression of the gene in vivo. We show
      here that another putative negatively acting GATA factor AREB participates
      directly or indirectly in otaA nitrogen repression. We also demonstrate that the
      high levels of OTAse activity are an important factor in the suppression of
      proline auxotrophic mutations. This suppression can be achieved neither by
      growing of the proline auxotroph under carbon/nitrogen derepressing conditions
      nor by introducing of a creA(d) mutation.

PMID- 12620255
TI  - Analysis of expressed sequence tags from Gibberella zeae (anamorph Fusarium
      graminearum).
AB  - Gibberella zeae is a broad host range pathogen that infects many crop plants,
      including wheat and barley, and causes head blight and rot diseases throughout
      the world. To better understand fungal development and pathogenicity, we have
      generated 7996 ESTs from three cDNA libraries. Two libraries were generated from
      carbon-(C-) and nitrogen- (N-) starved mycelia and one library was generated from
      cultures of maturing perithecia (P). In other fungal pathogens, starvation
      conditions have been shown to act as cues to induce infection-related gene
      expression. To assign putative function to cDNAs, sequences were initially
      assembled using StackPack. The estimated total number of genes identified from
      the three EST databases was 2110: 1088 contigs and 1022 singleton sequences.
      These 2110 sequences were compared to a yeast protein sequence reference set and
      to the GenBank nonredundant database using BLASTX. Based on presumptive gene
      function identified by this process, we found that the two starved cultures had
      similar, but not identical, patterns of gene expression, whereas the
      developmental cultures were distinct in their pattern of expression. Of the three
      libraries, the perithecium library had the greatest percentage (46%) of ESTS
      falling into the "unclassified" category. Homologues of some known fungal
      virulence or pathogenicity factors were found primarily in the N- and C
      libraries. Comparisons also were made with ESTs from the related fungi,
      Neurospora crassa and Magnaporthe grisea and the genomic sequence of N. crassa.

PMID- 12620256
TI  - Constitutively activated Galpha negatively regulates virulence, reproduction and
      hydrophobin gene expression in the chestnut blight fungus Cryphonectria
      parasitica.
AB  - Disruption of the gene encoding Galpha subunit cpg-1 in the chestnut blight
      fungus Cryphonectria parasitica reduces growth and pigmentation and abolishes
      reproduction and virulence. We now report the consequences of mutations designed
      to constitutively activate (Q204-L and R178-C) CPG-1-mediated signaling.
      Introduction of cpg-1-QL or cpg-1-RC into wild type, Deltacpg-1 and Deltacpgb-1
      (Gbeta) mutant strains resulted in a dominant phenotype characterized by a
      complete absence of aerial hyphae, pigmentation, conidia production and
      virulence. Opposing responses of Deltacpg-1 and activated mutant strains to
      chronic heat, hyperosmolarity and oxidative stress suggested that CPG-1 plays a
      role in mediating stress response. Growth of the cpg-1 mutant strains proceeded
      at wild-type level in rich liquid medium, but was severely curtailed on solid
      medium and absent in chestnut tissue, indicating the importance of CPG-1 mediated
      signaling under these harsher conditions. Both cpg-1 deletion and activating CPG
      1 mutations resulted in post-transcriptional alterations in the accumulation of
      CPG-1 and/or CPGB-1, providing evidence for extensive post-transcriptional
      regulation of G-protein subunit accumulation in C. parasitica. Finally, the
      absence of aerial hyphae and the easily wettable phenotype exhibited by the QL
      and RC mutants correlated with reduced expression of the gene encoding cryparin,
      suggesting G-protein-mediated regulation of a fungal hydrophobin.

PMID- 12620257
TI  - On the independence of barrage formation and heterokaryon incompatibility in
      Neurospora crassa.
AB  - A barrage is a line or zone of demarcation that may develop at the interface
      where genetically different fungi meet. Barrage formation represents a type of
      nonself recognition that has often been attributed to the heterokaryon
      incompatibility system, which limits the co-occurrence of genetically different
      nuclei in the same cytoplasm during the asexual phase of the life cycle. While
      the genetic basis of the heterokaryon incompatibility system is well
      characterized in Neurospora crassa, barrage formation has not been thoroughly
      investigated. In addition to the previously described Standard Mating Reaction
      barrage, we identified at least three types of barrage in N. crassa; dark line,
      clear zone, and raised aggregate of hyphae. Barrage formation in N. crassa was
      evident only when paired mycelia were genetically different and only when
      confrontations were carried out on low nutrient growth media. Barrages were
      observed to occur in some cases between strains that were identical at all major
      heterokaryon incompatibility (het) loci and the mating-type locus, mat, which
      acts as a heterokaryon incompatibility locus during the vegetative phase of N.
      crassa. We also found examples where barrages did not form between strains that
      had genetic differences at het-6, het-c, and/or mat. Taken together, these
      results suggest that the genetic control of barrage formation in N. crassa can
      operate independently from that of heterokaryon incompatibility and mating type.
      Surprisingly, barrages were not observed to form when wild-collected strains of
      N. crassa were paired. However, an increase in the frequency of pairings that
      produced barrages was observed among strains obtained by back-crossing wild
      strains to laboratory strains, or through successive rounds of inbreeding of wild
      derived strains, suggesting the presence in wild strains of genes that suppress
      barrage.

PMID- 12620258
TI  - Mutation in a calpain-like protease affects the posttranslational mannosylation
      of phosphatases in Aspergillus nidulans.
AB  - In this communication, we show that the palB7 mutation drastically reduced the
      mannose and N-acetylgalactosamine content of the pacA-encoded acid phosphatase
      secreted by the fungus Aspergillus nidulans at pH 5.0, compared to a control
      strain. By using mRNA differential display reverse transcription and polymerase
      chain reaction, we isolated two cDNAs from the control pabaA1 strain that were
      not detected in the palB7 mutant strain that encode a mannosyl transferase and a
      NADH-ubiquinone oxidoreductase. Thus, a defect in the posttranslational
      mannosylation of proteins could be the consequence of mutations in the palB gene,
      which encodes for a nuclear calpain-like protease that may have specific
      functions in the processing of transcription factor(s) similar to its homolog,
      RIM13, in Saccharomyces cereviseae.

PMID- 12620259
TI  - Expression of the mnpA gene that encodes the mannoprotein of Aspergillus nidulans
      is dependent on fadA and flbA as well as veA.
AB  - The single copy mnpA gene that encodes a mannoprotein of Aspergillus nidulans and
      its cDNA were isolated from the genomic and cDNA libraries, respectively. The
      determined nucleotide sequences of the genomic DNA and its cDNA revealed that the
      gene has an open-reading frame of 261 amino acids without introns. The deduced
      amino acid sequence showed a 60% identity to that of Aspegillus fumigatus
      galactomannoprotein MP1. The mnpA gene was expressed more abundantly in the wild
      type than in the veA-null mutant. It was expressed at a lower level in fadA-null
      mutants, veA(+) or veA1 (regardless of their genetic background), than in the
      fadA(+) strain. However, the expression level was slightly higher in the veA(+)
      DeltafadA strain than in the veA1 DeltafadA strain. Furthermore, the amount of
      the mnpA transcript was higher in the flbA(+) strain than in the flbA-null
      mutant. These results indicate that the fadA and flbA genes in addition to the
      veA gene are necessary for the mnpA expression. The mnpA gene was expressed
      highly in vegetative mycelia and at a reduced level in sexual structures, but not
      in conidia. Its expression was almost constitutive during asexual development up
      to 18h after the transfer of mycelial balls onto a solid medium, and decreased
      thereafter. During sexual development, its expression reached its maximum 0-20h
      after the induction of sexual development, and then decreased thereafter. The
      mnpA-null mutant, that was still viable, showed no phenotypic difference in
      development, growth rate, protein secretion, and germination of both the
      ascospores and conidia from the wild-type. This suggests that the mannoprotein
      that is encoded by the mnpA gene is dispensable.

PMID- 12620260
TI  - Co-expression of 15 contiguous genes delineates a fumonisin biosynthetic gene
      cluster in Gibberella moniliformis.
AB  - Fumonisins are mycotoxins produced by the maize pathogen Gibberella moniliformis
      and are associated with cancer in rodents. In this study, we determined the
      nucleotide sequence of a 75-kb region of G. moniliformis DNA and identified 18
      heretofore undescribed genes flanking a cluster of five previously identified
      fumonisin biosynthetic (FUM) genes. Ten of the newly identified genes downstream
      of the cluster were coregulated with FUM genes and exhibited patterns of
      expression that were correlated with fumonisin production. BLASTX analyses
      indicated that the predicted functions of proteins encoded by the 10 genes were
      consistent with activities expected for fumonisin biosynthesis or self
      protection. These data indicate that the 10 newly identified genes and the
      previously identified FUM genes constitute a fumonisin biosynthetic gene cluster.
      Disruption of two of the new genes, encoding longevity assurance factors, had no
      apparent effect on fumonisin production, but disruption of a third, encoding an
      ABC transporter, had a subtle effect on ratios of fumonisins produced.

PMID- 12620261
TI  - Characterization of 1,3-beta-glucanase and 1,3;1,4-beta-glucanase genes from
      Phytophthora infestans.
AB  - Three putative exo-1,3-beta-glucanase genes (Piexo1, Piexo2, Piexo3), one endo
      1,3-beta-glucanase (Piendo1) and one endo-1,3;1,4-beta-glucanase (Piendo2) gene
      were cloned and characterized from the oomycete Phytophthora infestans. Southern
      hybridization revealed that Piexo1, Piexo2, Piexo3, and Piendo2 are single copy,
      and that Piendo1 is encoded by two copies. Furthermore, the analyses showed that
      for each gene, one or two closely related gene family members were present. The
      genes contain no introns. Nucleotide sequence analysis of the promoter regions
      (200nt upstream of ATG start codon) showed that the regions have 56-81%
      similarity to a 16-nt core sequence hypothesized to be the initiation of
      transcription point in oomycetes. The predicted molecular weights (32-83kDa), iso
      electric points (4.2-6.7) and amino acid sequences of the five proteins are
      diverse. All the genes are expressed in in vitro grown mycelia and sporangia, as
      well as during infection of potatoes. Further, Piendo1 and Piendo2 are also
      expressed in germinating cysts, and Piendo2 in zoospores.

PMID- 12620263
TI  - Malpositioning of Hickman catheters, left versus right sided attempts.
AB  - BACKGROUND: Central venous catheters (CVC) are frequently used for stem cell
      collection and recurrent therapeutic hemapheresis procedures for patients with
      poor peripheral venous access. There is a tendency to prefer a right sided
      approach for insertion of a CVC via the subclavian route. We designed a
      sequential randomized study to examine the issue of catheter insertion side and
      analyzed all the technical data on surgical skill and observed complications.
      METHOD: Seventy-five patients who are candidates for stem cell collection and
      high dose chemotherapy underwent placement of Hickman catheters via the
      percutaneous subclavian vein (SCV) route. One experienced surgeon inserted 12F,
      double lumen, tunnelled, silicon based catheters in the operation room via
      fluoroscopic control. All of the procedure related complications, morbidity and
      mortality were analyzed on the basis of the side of catheter insertion. RESULTS:
      The total rate of malpositioning in this series was 14.66%. The Jugular vein was
      the most common malpositioning site (66.6%). We observed a statistically
      significant difference in malpositioning between left versus right sided
      attempts, at 5.55% versus 20.51%, respectively (p = 0.032). The routes of
      malpositioning encountered for left sided attempts were the right SCV and the
      left internal jugular vein, the right internal jugular vein (n = 5), the left SCV
      vein (n = 2), and one left internal jugular vein. There was no significant
      difference between the right and left sided attempts for mechanical complications
      other than malpositioning (p < 0.05). CONCLUSION: In this study the rate of
      malpositioning was greater in the right sided approach (p = 0.032) and the other
      mechanical complication rates did not differ for the two methods. Our results
      indicate that there is no need for hesitancy in using left sided attempts at CVC
      insertion.

PMID- 12620262
TI  - Effects of replacement fluids on coagulation system used for therapeutic plasma
      exchange.
AB  - Therapeutic apheresis is a widely used treatment alternative for several
      diseases. In 29 patients with different diseases, we have monitored the PT, aPTT,
      thrombin time (TT), fibrinogen, D-dimer, factor VIII, IX, X, XI, XII, VWF,
      Protein C, S, Active Protein C Resistance (APCR) and Antithrombin-III during TPE.
      Patients were divided into four groups based on the replacement fluids used: 3%
      VARIHES or ISOHES + 4% albumin (1:1) (group 1), fresh frozen plasma (FFP) (group
      2), 3% VARIHES or ISOHES (group 3) and 4% albumin (group 4). In our study, the
      fibrinogen level decreased to 83% of the base line level after the end of 48 h
      therapy. The APTT, PT, and TT increased during TPE. However no statistical
      difference was observed between the groups. We found a significant change in
      factor levels with time, only the difference in factors IX and XI between the
      groups was significant. In addition, factor levels measured at 48 h were close to
      the levels measured before aphereses. In our study, time the related change in AT
      3 values was significant. Time-related changes of the Protein S and APCR were not
      statistical significant significant but on the other hand, we found a significant
      difference in AT-III and Protein C values between groups. The side effects of HES
      on coagulation factors and tests were comparable to those of other replacement
      fluids. Its low cost makes it favourable.

PMID- 12620264
TI  - Plasmapheresis therapy in pemphigus vulgaris and bullous pemphigoid.
AB  - Blistering dermatitises are characterized by the presence of blisters that begin
      owing to acantholysis (intraepidermic blister) such as pemphigus vulgaris (PV) or
      owing to dermoepidermic detachment (subepidermic blister) such as bullous
      pemphigoid (BP). Both diseases are autoimmune pathologies characterized by the
      presence of autoantibodies against specific adhesion molecules of the skin and
      mucous membranes. PV, in which oral lesions are always present, has a progressive
      course that, if the disease is not treated, nearly always brings to death from
      sepsis within a few years. In BP, oral lesions are rare and the disease, that is
      most frequent in older individuals, has a chronic course with spontaneous
      remissions. Systemic corticosteroids and immunosuppressants are the mainstay of
      treatment of these two diseases. Although this therapy had reduced the mortality
      of the two pathologies it is associated with serious side effects. To reduce the
      corticosteroids dose and to improve the symptomatology in resistant therapy
      cases, we treated five patients with several procedures of plasma exchange. Four
      patients were affected by BP and one by PV. Their disease severity at onset of
      plasmapheresis ranged from mild to severe. One of 5 patients suffered a
      plasmapheresis side effect. All patients responded with complete remission of
      symptomatology and had a prednisone dosage reduction until 70%. Plasmapheresis is
      an effective treatment for PV and BP patients who have been unresponsive to
      conventional therapy, for those for whom conventional drugs are contraindicated,
      for those who show severe clinical manifestations and for those who need high
      doses of corticosteroids and immunosuppressants to keep the disease under
      control.

PMID- 12620265
TI  - Yersinia septic shock following an autologous transfusion in a pediatric patient.
AB  - Although the literature on infections transmitted via transfused blood focuses on
      viruses, Yersinia enterocolitica can also cause severe infections in patients
      receiving transfusions. A 13-year-old patient developed severe sepsis after an
      autologous blood transfusion contaminated with Y. enterocolitica. The patient was
      an otherwise healthy female undergoing posterior spinal fusion for congenital
      scoliosis. Prior to surgery, the patient donated blood for perioperative and
      postoperative use. A few days before the donation, she had complained of
      abdominal pain and was experiencing mild diarrhea. The patient received four
      units of packed red blood cells (PRBCs) during the surgery. Intraoperatively, the
      patient developed fever up to 103.6 degrees F, became hypotensive requiring
      epinephrine and dopamine, and developed metabolic acidosis with serum bicarbonate
      concentration dropping to 16 mmol/l. The surgery team believed the patient was
      experiencing malignant hyperthermia and attempted to cool patient during the
      procedure. Postoperatively, the patient was transferred to the pediatric
      intensive care unit and treated for severe shock of unknown etiology. The patient
      further developed disseminated intravascular coagulation. The patient received
      supportive care and was started on ampicillin/sulbactam on postoperative day
      (POD) one which was changed to clindamycin, ciprofloxacin and tobramycin on POD
      two when blood cultures grew gram-negative bacilli. On POD three, cultures were
      identified as Y. enterocolitica and antibiotics were changed to tobramycin and
      cefotaxime based on susceptibility data. Sequelae of the shock included adult
      respiratory distress syndrome requiring intubation and a tracheostomy and
      multiple intracranial hemorrhagic infarcts with subsequent seizure disorder. Due
      to severe lower extremity ischemia, she required a bilateral below the knee
      amputation. The cultures of the snippets from the bags of blood transfused to the
      patient also grew Y. enterocolitica. This case illustrates the importance of
      considering transfusion related bacterial infections in patients receiving PRBCs.
      All patients in shock following any type of transfusion may require aggressive
      antibiotic therapy, until the diagnosis and etiology are known.

PMID- 12620266
TI  - Extracorporeal photochemotherapy: a historical perspective.

PMID- 12620268
TI  - PUVA apoptotic response in activated and resting human lymphocytes.
AB  - In extracorporeal photopheresis (ECP) collected cells are treated by 8
      methoxypsoralen and UVA (PUVA) which induced apoptosis. The mechanism of action
      of reinfused cell is unclear. A vaccination model postulates an efficient
      presentation of apoptotic alloreactive cells to the patient immune system. The
      efficiency may depend upon a predominance of apoptotic alloreactive cells after
      PUVA. Such selectivity could result from their activation. We studied apoptosis
      in resting and PHA-activated lymphocytes. Both were equally susceptible. Changes
      in early apoptosis were possibly missed. We evaluated the effect of preincubation
      before PUVA. During preincubation monocyte could affect lymphocytes
      susceptibility to apoptosis as an increase of number of apoptotic cells was
      observed after 72 hours in stimulated and resting cells. Our findings do not
      preclude a selectivity of other PUVA effects since expression of membrane marker
      also targets to PUVA is modified by activation.

PMID- 12620267
TI  - Follow-up of the T-cell clonality in Sezary patients treated by extracorporeal
      photopheresis using a new assay: the immunoscope technique.
AB  - Sezary syndrome is a leukemic form of epidermotropic cutaneous T-cell lymphoma
      related to the malignant proliferation of clonal CD4+ T-cells. Extracorporeal
      photochemotherapy (ECP) may induce a transient improvement of the clinical signs
      but it's efficiency is discussed. In order to investigate the T-cell clonality in
      the peripheral blood of patients with Sezary syndrome and to monitor its
      evolution in 8 patients treated by ECP, we used the Immunoscope technique. In one
      patient, we observed a decrease of the T-cell clonality from 15.6% to 0%,
      paralleling a complete remission of the clinical disease with a disappearance of
      the circulating Sezary cells. In the other cases, the evolution of the relative
      frequency paralleled the clinical status of the patient. In 3 cases, we observed
      a quick-acting direct cytotoxicity of the association 8MOP + UVA on the T-cell
      clone present in the cellular product. Immunoscope technique appears to be an
      efficient assay to appreciate the amount of tumoral cells and monitor the
      evolution of the clonal component in Sezary syndrome.

PMID- 12620269
TI  - Extracorporeal photopheresis technical aspects.
AB  - Extracorporeal photochemotherapy is a monotherapy first developed by Edelson et
      al. in 1987. It is a therapy in which 8-methoxypsoralen (8-MOP) containing
      lymphocytes are exposed to a long wavelength ultraviolet radiation (UVA) in an
      extracorporeal system. The initial design of the treatment was based on the use
      of the UVAR system (Therakos) for both the collection and photoirradiation of the
      mononuclear cells. This machine is replaced now by XTS apparatus, which is fully
      automatic and has integrated the fluid logic module (the "heart" of the system).
      Another principle is used: the two independent steps technique. It consists in
      first collection of mononuclear cells by a continuous blood cell separator and
      secondly irradiation in an independent machine: UV-MATIC irradiator (VILBER
      LOURMAT). These three techniques are analyzed through numerous parameters:
      technical, biological, hematological data. In the future, we consider we need to
      precise our requirements for adequate UVA energy and 8-MOP concentration. We also
      have to define therapeutic dose of irradiated cells and so standardize the
      process.

PMID- 12620270
TI  - Quality control for the validation of extracorporeal photopheresis process using
      the Vilbert-Lourmat UV-A irradiation's system.
AB  - In agreement with good practices for therapeutic use of human cells, quality
      control has to be performed to valid the process of extracorporeal photopheresis
      (ECP) with the Vilbert-Lourmat system. Since no protocol exists, we evaluated a
      technique based on the measurement of the inhibition of mitogen (PHA, Con-A,
      OKT3)-induced proliferation, in 164 procedures from 16 patients. Whatever the
      pathology, we observed a high proliferation rate in most samples, and we obtained
      over 90% ECP-induced inhibition in as many as 94% of the cases. Since this
      approach proved to be relevant regarding our objective, a protocol for the ECP
      process validation is proposed.

PMID- 12620271
TI  - Extracorporeal photochemotherapy for graft versus host disease in pediatric
      patients.
AB  - Although worldwide experience with extracorporeal photochemotherapy (ECP) for
      GvHD treatment has grown enormously over the past decade, only a few pediatric
      centers have experience with ECP. Studies reporting clinical outcome in children
      with GvHD treated by ECP comprises a very limited number of patients with only
      few information described. This review article remain focused on the efficacy and
      the safety aspect of ECP in pediatric patients to provide information about the
      steps that should be taken to overcome the difficulties with ECP use in children
      with GvHD. Data concerning 19 children with acute GvHD and 54 children with
      chronic GvHD treated with ECP and reported so far have been considered. The
      principal reasons for the restriction in the use of ECP in children such as: (1)
      technical difficulties of leukapheresis procedures (venous access, hemodynamic,
      metabolic and hematological tolerance); and (2) the necessity of a specially
      adapted pediatric patient approach to improve the psychological tolerance of this
      treatment are discussed. The data of this retrospective review demonstrate that
      ECP is beneficial and well tolerated in children with GvHD. It can be safely used
      even in young children with low body weight and a poor performance status when it
      was performed by a qualified pediatric team. The observations concerning the
      response rate and onset suggest that in children with acute GvHD, ECP should be
      started early in the course of disease and employed over a relatively short
      period of time. As far as chronic GvHD is concerned, despite the fact that it is
      preferable to begin ECP early as second line therapy, it may also be beneficial
      in patients with late-stage disease.

PMID- 12620272
TI  - Extracorporeal photochemoimmunotherapy in cutaneous T-cell lymphoma.
AB  - Extracorporeal photochemotherapy was originally conceived for the treatment of
      cutaneous T-cell lymphoma (CTCL) and as well as other T-cell mediated diseases.
      Evidence collected in the past 17 years has demonstrated that this treatment
      modality can have a very significant effect on the course of a subset of CTCL
      patients. The evidence available is positive but for a variety of reasons has
      been controversial within the medical community. A number of very well-designed
      multi-center trials which have been lacking since the first publication by
      Edelson et al. are being carried out so that hopefully a number of open questions
      will be resolved with greater clarity in the coming years. The fact remains that
      this innovative approach for the treatment of CTCL and T-cell mediated diseases
      has certainly opened new avenues of therapy and thought in photoimmunology and
      photomedicine. Clearly the very low side effect profile of this therapy has made
      it more attractive than the chemotherapeutic and immunosuppressive substances
      that are presently available or in experimental protocols. If and when the
      mechanisms of action are fully understood and appropriate studies investigating
      different treatment schedules and different combination therapies and
      modifications of its present form are performed the place of photopheresis in the
      therapeutics of CTCL as well as other T-cell mediated diseases and oncology will
      be better placed.

PMID- 12620273
TI  - Extracorporeal photochemotherapy. Regulation, norms and vigilance.

PMID- 12620274
TI  - The Norwegian Plasma Fractionation Project--a 12 year clinical and economic
      success story.
AB  - The establishment of the Norwegian Fractionation Project (Project) was of major
      importance in preserving national self-sufficiency when plasma, cryoprecipitate
      and small batch factor IX-concentrates were replaced by virus inactivated
      products in the last part of the 1980s. Fractionation was performed abroad by
      contract with Octapharma after tenders on the European market. All Norwegian
      blood banks (>50) participated in the Project. Total yearly production was 50-60
      tons of mainly recovered plasma. From 1993 solvent detergent (SD) treated plasma
      has replaced other plasma for transfusion. The blood banks paid for the
      fractionation and/or viral inactivation process, while the plasma remained the
      property of the blood banks and the final products were returned to the blood
      banks. The Project sold surplus products to other Norwegian blood banks and the
      majority of the coagulation factor concentrates to The Institute of Haemophilia
      and Rikshospitalet University Hospital. Both plasma and blood bank quality was
      improved by the Project. Clinical experience with the products has been
      satisfactory and self-sufficiency has been achieved for all major plasma proteins
      and SD plasma, but a surplus exceeding 3 years consumption of albumin has
      accumulated due to decreasing clinical use.The Project has secured high yields of
      the fractionated products and the net income from the produced products is NOK
      1115 (140 Euros or US dollars) per litre plasma. An increasing surplus of albumin
      and the possibility of significant sales abroad of currently not fractionated
      IVIgG, could lead to a reorganisation of the Project from that of a co-ordinator
      to a national plasma handling unit. This unit could buy the plasma from the blood
      banks and have the plasma fractionated by contract after tender, before selling
      the products back for cost recovery. The small blood banks could produce plasma
      for products for the Norwegian market, while surplus products from the larger
      blood banks which are certified for delivery of plasma for fractionation of
      products to be consumed in the European Community, could be sold on the
      international market.

PMID- 12620275
TI  - Hydroxyethylstarch as a replacement fluid in therapeutic plasma exchange for
      lupus nephritis in a Jehovah's Witness.

PMID- 12620278
TI  - Characterisation of an uridine-specific binding site in rat cerebrocortical
      homogenates.
AB  - Parameters of [3H]uridine binding to synaptic membranes isolated from rat brain
      cortex (K(D)=71+/-4 nM, B(max)=1.37+/-0.13 pmol/mg protein) were obtained.
      Pyrimidine and purine analogues displayed different rank order of potency in
      displacement of specifically bound [3H]uridine (uridine>5-F-uridine>5-Br-uridine
      approximately adenosine>>5-ethyl-uridine approximately suramin>theophylline) and
      in the inhibition of [14C]uridine uptake (adenosine>uridine>5-Br-uridine
      approximately 5-F-uridine approximately 5-ethyl-uridine) into purified
      cerebrocortical synaptosomes. Furthermore, the effective ligand concentration for
      the inhibition of [14C]uridine uptake was about two order of magnitude higher
      than that for the displacement of specifically bound [3H]uridine. Adenosine
      evoked the transmembrane Na(+) ion influx, whereas uridine the transmembrane
      Ca(2+) ion influx much more effectively. Also, uridine was shown to increase free
      intracellular Ca(2+) ion levels in hippocampal slices by measuring Calcium-Green
      fluorescence. Uridine analogues were found to be ineffective in displacing
      radioligands that were bound to various glutamate and adenosine-recognition and
      modulatory-binding sites, however, increased [35S]GTPgammaS binding to membranes
      isolated from the rat cerebral cortex. These findings provide evidence for a
      rather specific, G-protein-coupled site of excitatory action for uridine in the
      brain.

PMID- 12620277
TI  - Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane
      potential, and calpain activity on the mechanism of neuron death induced by 3
      nitropropionic acid.
AB  - 3-Nitropropionic acid (3NP), an irreversible inhibitor of succinate
      dehydrogenase, induces both rapid necrotic and slow apoptotic death in rat
      hippocampal neurons. Low levels of extracellular glutamate (10 microM) shift the
      3NP-induced cell death mechanism to necrosis, while NMDA receptor blockade
      results in predominantly apoptotic death. In this study, we examined the 3NP
      induced alterations in free cytosolic and mitochondrial calcium levels, ATP
      levels, mitochondrial membrane potential, and calpain and caspase activity, under
      conditions resulting in the activation of apoptotic and necrotic pathways. In the
      presence of 10 microM glutamate, 3NP administration resulted in a massive
      elevation in [Ca(2+)](c) and [Ca(2+)](m), decreased ATP, rapid mitochondrial
      membrane depolarization, and a rapid activation of calpain but not caspase
      activity. In the presence of the NMDA receptor antagonist MK-801, 3NP did not
      induce a significant elevation of [Ca(2+)](c) within the 24h time period
      examined, nor increase [Ca(2+)](m) within 1h. ATP was maintained at control
      levels during the first hour of treatment, but declined 64% by 16h. Calpain and
      caspase activity were first evident at 24h following 3NP administration. 3NP
      treatment alone resulted in a more rapid decline in ATP, more rapid calpain
      activation (within 8h), and elevated [Ca(2+)](m) as compared to the results
      obtained with added MK-801. Together, the results demonstrate that 3NP-induced
      necrotic neuron death is associated with a massive calcium influx through NMDA
      receptors, resulting in mitochondrial depolarization and calpain activation;
      while 3NP-induced apoptotic neuron death is not associated with significant
      elevations in [Ca(2+)](c), nor with early changes in [Ca(2+)](m), mitochondrial
      membrane potential, ATP levels, or calpain activity.

PMID- 12620279
TI  - Halothane attenuated haloperidol and enhanced clozapine-induced dopamine release
      in the rat striatum.
AB  - The effect of halothane anesthesia on changes in the extracellular concentrations
      of dopamine (DA) and its metabolites (3-methoxytyramine (3-MT), 3,4
      dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA)) induced by
      neuroleptics was studied using in vivo microdialysis techniques. Halothane
      attenuated haloperidol-induced dopamine release and enhanced clozapine-induced
      dopamine release in the rat striatum.A microdialysis probe was implanted into the
      right striatum of male SD rats. Rats were given saline or the same volume of 200
      microg kg(-1) haloperidol (D(2) receptor antagonist), 10 mg kg(-1) sulpiride
      (D(2) and D(3) antagonist), or 10 mg kg(-1) clozapine (D(4) and 5-HT(2)
      antagonist) intraperitoneally with or without 1-h halothane anesthesia (0.5 or
      1.5%). Halothane anesthesia did not change the extracellular concentration of DA,
      but increased the metabolite concentrations in a dose-dependent manner. The
      increased DA concentration induced by haloperidol was significantly attenuated by
      halothane anesthesia, whereas the metabolite concentrations were unaffected.
      Halothane had no effect on the changes in the concentrations of DA or its
      metabolites induced by sulpiride. The clozapine-induced increases in DA and its
      metabolites were enhanced by halothane anesthesia. Our results suggest that
      halothane anesthesia modifies the DA release modulated by antipsychotic drugs in
      different ways, depending on the effects of dopaminergic or serotonergic
      pathways.

PMID- 12620280
TI  - Neurosteroid modulation of the presynaptic NMDA receptors regulating hippocampal
      noradrenaline release in normal rats and those exposed prenatally to diazepam.
AB  - Prenatal exposure to diazepam (DZ), a positive allosteric modulator of the gamma
      aminobutyric acid(A) (GABA(A)) receptor complex, exerts profound effects that
      become more evident during puberty and in many cases are sex-specific, suggesting
      that such exposure interferes with the activity of steroid hormones. Apart from
      their well known effects on the genome, the reduced metabolites of many steroid
      hormones also interact directly with membrane receptors, including those for N
      methyl-D-aspartate (NMDA). In this study, we compared the effects of several
      neurosteroids on NMDA receptors from normal rats and those exposed in utero to DZ
      (1.25mg/kg per day) from the 14th through the 20th day of gestation. In
      superfused rat hippocampal synaptosomes, activation of the NMDA receptor
      stimulates the basal release of [3H]noradrenaline ([3H]NA), which was used in our
      study as an index of receptor function. [3H]NA release was evoked in a
      concentration-dependent manner by NMDA (100 microM) plus glycine (GLY). The
      maximal increase (68.23+/-3.86%) with respect to basal release was achieved with
      a GLY concentration of 10 microM, and the EC(50) for GLY was 0.1 microM. Release
      stimulated by 100 microM NMDA + 0.1 microM GLY was not modified by any of the
      neurosteroids tested, with the exception of pregnenolone sulfate (PREG-S), which
      produced a 78.57+/-3.94% reduction in release at the maximal concentration used
      (0.3 microM). In synaptosomes from animals exposed in utero to DZ, the inhibitory
      effect of PREG-S was reduced by 46.55+/-2.33%. Given the important roles played
      by NMDA receptors in physiological and pathological processes within the central
      nervous system (CNS), characterization of NMDA receptor modulation is an
      important objective. The fact that this modulation can be altered by exposure in
      utero to DZ indicates that the behavioral abnormalities observed in exposed
      animals might be partially attributed to an altered sensitivity of NMDA receptors
      to the modulatory effects of neurosteroids.

PMID- 12620281
TI  - Deficits in a tricarboxylic acid cycle enzyme in brains from patients with
      Parkinson's disease.
AB  - Parkinson's disease (PD) is associated with mitochondrial dysfunction,
      specifically a deficiency of complex I of the electron transport chain. Most,
      although not all, studies indicate that this deficiency is limited to brain
      regions with neurodegeneration. The current studies tested for deficiencies in
      other mitochondrial components in PD brain in a neuropathologically unaffected
      region where the abnormality cannot be attributed to secondary effects of
      neurodegeneration. The activity of a key (and arguably rate-limiting)
      tricarboxylic acid cycle enzyme, the alpha-ketoglutarate dehydrogenase complex
      (KGDHC), was measured in the cerebellum of patients with PD. Activity in 19 PD
      brains was 50.5% of that in 18 controls matched for age, sex, post-mortem
      interval, and method of preservation (P<0.0019). The protein subunits of KGDHC
      were present in normal amounts in PD brains, indicating a relatively discrete
      abnormality in the enzyme. The activities of another mitochondrial enzyme,
      glutamate dehydrogenase (GDH), were normal in PD brains. These results
      demonstrate that specific reductions in KGDHC occur even in pathologically
      unaffected areas in PD, where the decline is unlikely to be a non-specific result
      of neurodegeneration. Reductions in the activity of this enzyme, if widespread in
      the brain, may predispose vulnerable regions to further damage.

PMID- 12620282
TI  - Effects of ammonia on high affinity glutamate uptake and glutamate transporter
      EAAT3 expression in cultured rat cerebellar granule cells.
AB  - Increased levels of extracellular glutamate are a consistent feature of hepatic
      encephalopathy (HE) associated with liver failure and other hyperammonemic
      pathologies. Reduction of glutamate uptake has been described in ammonia-exposed
      cultured astrocytes, synaptosomes, and in animal models of hyperammonemia. In the
      present study, we examine the effects of pathophysiological concentrations of
      ammonia on D-aspartate (a non-metabolizable analog of glutamate) uptake by
      cultured rat cerebellar granule neurons. Exposure of these cells to ammonia
      resulted in time-dependent (24% reduction at 24h and 60% reduction at 5 days,
      P<0.001) and dose-dependent (21, 37, and 57% reduction at 1, 2.5, and 5mM for 5
      days, P<0.01) suppression of D-aspartate uptake. Kinetic analyses revealed
      significant decreases in the velocity of uptake (V(max)) (37% decrease at 2.5mM
      NH(4)Cl, P<0.05 and 52% decrease at 5mM NH(4)Cl, P<0.001) as well as significant
      reductions in K(m) values (25% reduction at 2.5mM NH(4)Cl, P<0.05 and 45%
      reduction at 5mM NH(4)Cl, P<0.001). Western blotting, on the other hand, showed
      no significant changes in the neuronal glutamate transporter EAAC1/EAAT3 protein,
      the only glutamate transporter currently known to be expressed by these cells. In
      addition, 1H combined with 13C-NMR spectroscopy studies using the stable isotope
      [1-13C]-glucose demonstrated a significant increase in intracellular glutamate
      levels derived from the oxidative metabolism of glucose, rather than from the
      deamidation of exogenous glutamine in cultured granule neurons exposed to
      ammonia. The present study provides evidence that the effects of ammonia on
      glutamate uptake are not solely an astrocytic phenomenon and that unlike the
      astrocytic glutamate transporter counterpart, EAAT3 protein expression in
      cultured cerebellar granule cells is not down-regulated when exposed to ammonia.
      Decrease of glutamate uptake in these cellular preparations may afford an
      additional regulatory mechanism aimed at controlling intracellular levels of
      glutamate and ultimately the releasable pool of glutamate in neurons.

PMID- 12620283
TI  - Combined effect of dopamine and MPP+ on membrane permeability in mitochondria and
      cell viability in PC12 cells.
AB  - The present study examined the combined effect of dopamine and 1-methyl-4
      phenylpyridinium (MPP(+)) on the membrane permeability in isolated brain
      mitochondria and on cell viability in PC12 cells. MPP(+) increased effect of
      dopamine against the swelling, membrane potential, and Ca(2+) transport in
      isolated mitochondria, which was not inhibited by the addition of antioxidant
      enzymes (SOD and catalase). Dopamine or MPP(+) caused the decrease in
      transmembrane potential, increase in reactive oxygen species, depletion of GSH,
      and cell death in PC12 cells. Antioxidant enzymes reduced each effect of dopamine
      and MPP(+) against PC12 cells. Co-addition of dopamine and MPP(+) caused the
      decrease in the transmembrane potential and increase in the formation of reactive
      oxygen species in PC12 cells, in which they showed an additive effect. Dopamine
      plus MPP(+)-induced the depletion of GSH and cell death in PC12 cells were not
      decreased by the addition of antioxidant enzymes, rutin, diethylstilbestrol, and
      ascorbate. Melanin caused a cell viability loss in PC12 cells. The N
      acetylcysteine, N-phenylthiourea, and 5-hydroxyindole decreased the cell death
      and the formation of dopamine quinone and melanin induced by co-addition of
      dopamine and MPP(+), whereas deprenyl and chlorgyline did not show an inhibitory
      effect. The results suggest that co-addition of dopamine and MPP(+) shows an
      enhancing effect on the change in mitochondrial membrane permeability and cell
      death, which may be accomplished by toxic quinone and melanin derived from the
      MPP(+)-stimulated dopamine oxidation.

PMID- 12620284
TI  - Diazepam and chlormethiazole attenuate the development of hyperthermia in an
      animal model of the serotonin syndrome.
AB  - The serotonin (5-HT) syndrome is the most serious toxic interaction of
      antidepressants, but no pharmacotherapy has yet been established. In the present
      study, we created an animal model of the 5-HT syndrome by intraperitoneally
      injecting rats with clorgyline (2 mg/kg) and 5-hydroxy-L-tryptophan (5-HTP) (100
      mg/kg) and evaluated the effectiveness of potent 5-HT(2A) receptor antagonists
      and GABA-enhancing drugs, including diazepam and chlormethiazole. The rectal
      temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels
      in the anterior hypothalamus were measured by microdialysis. In the group pre
      treated with saline, the rectal temperature increased to more than 40 degrees C,
      and all of the animals died within 90 min after administration. Pre-treatment
      with potent 5-HT(2A) receptor antagonists prevented the development of
      hyperthermia and death in the rats. Pre-treatment with diazepam, 10 and 20mg/kg,
      and chlormethiazole, 50 and 100mg/kg, attenuated the development of hyperthermia.
      Although neither of these drugs completely prevented the rats from dying, they
      prolonged their survival time. Regardless of the type of therapeutic agents, the
      concentration of 5-HT increased to about 1100-fold the pre-administration level.
      The NA levels in the saline group increased to about 16-fold the pre
      administration levels, but the increase was significantly lower in the rats that
      survived as a result of drug therapy. These results suggest that GABA-mimetic
      drugs may be effective against the 5-HT syndrome, although they have a somewhat
      weaker effect than the potent 5-HT(2A) receptor blockers, and that not only is 5
      HT activity increased in the brain in the 5-HT syndrome, but the NA system is
      also enhanced.

PMID- 12620285
TI  - Characterization of monoaminergic systems in brain regions of prematurely ageing
      mice.
AB  - We have previously shown that differences in life span among members of Swiss
      mouse populations appear to be related to their exploration of a T-maze, with a
      slow exploration ("slow mice") being linked to increased levels of
      emotionality/anxiety, an impaired immune function and a shorter life span. Thus,
      we proposed the slow mice as prematurely ageing mice (PAM). We have now compared
      the monoaminergic systems of the PAM and of the non-prematurely ageing mice
      (NPAM), in discrete brain regions. PAM had decreased noradrenaline (NA) levels in
      all the brain regions analysed, whereas the 3-methoxy-4-hydroxyphenyl glycol
      (MHPG)/NA ratios were not significantly modified. PAM also showed decreased
      serotonine (5-HT) levels in hypothalamus, striatum and midbrain, as well as
      increased 5-hydroxyindol-3-acetic acid (5-HIAA)/5-HT ratios in hypothalamus and
      hippocampus. The dopamine (DA) content was lower in PAM in most regions, whereas
      the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA and homovanillic acid (HVA)/DA
      ratios were either increased or unchanged depending on the region analysed. In
      most cases, the differences between PAM and NPAM involved both sexes. One
      exception was the hypothalamus where the differences only affected the male mice.
      The neurochemical alterations found in PAM resemble some changes reported for
      aged animals and are related with their behavioural features.

PMID- 12620286
TI  - Flupentixol and trifluperidol reduce secretion of tumor necrosis factor-alpha and
      nitric oxide by rat microglial cells.
AB  - Tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which are
      produced by activated microglial cells, are involved in the neuropathogenesis of
      many diseases affecting the central nervous system (CNS). There is a need to
      develop drugs that inhibit neurotoxic processes in neurodegenerative diseases.
      The aim of this study was to evaluate the effect of two neuroleptics, flupentixol
      and trifluperidol, on the release of pro-apoptotic TNF-alpha and NO by LPS
      activated rat microglial cells. Flupentixol and trifluperidol reduced the TNF
      alpha and NO release by cultured microglia exposed to LPS for 6 and 24h. The
      results suggest that flupentixol and trifluperidol, which are well-known
      antipsychotic drugs, may be used in the treatment of CNS diseases associated with
      excessive TNF-alpha and NO release.

PMID- 12620287
TI  - Pilot study of recombinant human soluble tumor necrosis factor (TNF) receptor
      (p75) fusion protein (TNFR:Fc; Enbrel) in patients with refractory multiple
      myeloma: increase in plasma TNF alpha levels during treatment.
AB  - Elevated tumor necrosis factor (TNF)-alpha levels are associated with poor
      prognosis in patients with multiple myeloma (MM). Enbrel is a TNF antagonist
      fusion protein consisting of the extracellular, ligand-binding domain of the
      human p75 TNF receptor linked to the Fc portion of human IgG1. Ten patients with
      refractory MM were treated with Enbrel 25mg s.c twice weekly for a minimum of
      eight median age was 63 years (range, 43-76). The total number of Enbrel doses
      was 191 (median 16; range, 3-55). TNF alpha plasma levels increased significantly
      during treatment with Enbrel. No objective response occurred. Acceleration of
      disease occurred in four patients. While well-tolerated, Enbrel did not have anti
      myeloma activity as administered on this study.

PMID- 12620288
TI  - Maternal and fetal outcomes in pregnancy complicated with acute leukemia: a
      single institutional experience with 10 pregnancies at 16 years.
AB  - The incidence of acute leukemia in pregnancy is low and the management of acute
      leukemia during pregnancy is difficult. We have observed a total of 10
      pregnancies in 8 patients. Six of the patients had acute myeloblastic leukemia
      (AML) and two of them had acute lymphoblastic leukemia (ALL). Three of the
      pregnancies were diagnosed when the leukemia was in remission, six at the time of
      leukemia diagnosis and one at the time of leukemic relapse. Six of the
      pregnancies were found in first trimester, three in the second and one early in
      the third. Three pregnancies ended with spontaneous abortion, three with
      intrauterine death and three with medical termination. One of spontaneous
      abortions and one intrauterine death developed during combination chemotherapy
      (daunorubicin, cytarabine). Only 1 healthy baby survived from the 10 pregnancies
      and this child was the not exposed to chemotherapeutic agents. None of the cases
      had gynecologic and obstetric complications. Five of eight pregnant women with
      leukemia died because of the primary disease.

PMID- 12620289
TI  - The level of MEF but not ELF-1 correlates with FAB subtype of acute myeloid
      leukemia and is low in good prognosis cases.
AB  - ETS proteins (such as PU.1, Fli-1 and ETS-1) have been shown to play important
      roles in normal and abnormal hematopoiesis. We examined the expression of the ELF
      subfamily of ETS genes (ELF-1, MEF and NERF) in acute myeloid leukemia (AML)
      cells using Northern blot analysis. ELF-1 and MEF were expressed in all samples,
      whereas NERF was not. The relative expression (RE) of MEF, but not ELF-1, was
      significantly lower (P<0.0001) in AML with t(8;21) and t(15;17) compared with AML
      with normal karyotype. The pattern of MEF expression was not uniform among cells
      with CD34(+)/CD33(+). It is suggested that the low RE of MEF might be part of a
      gene expression profile characterizing AML with a good prognosis.

PMID- 12620290
TI  - The expression of PRAME in chronic lymphoproliferative disorders.
AB  - The PRAME gene encodes an antigen recognized by autologous T lymphocytes and is
      expressed in trophoblasts, testis and frequently in human solid cancers and acute
      leukemias, making it a candidate for immunotherapy and for detecting MRD. We
      demonstrate expression of PRAME by RT-PCR in the peripheral blood or bone marrow
      of 26% of 58 patients with CLD (38 cases of CLL, 4 cases of PLL and 16 cases of
      NHL). Seven out 16 cases of MCL, 2 out 4 of PLL and 6 cases of CLL demonstrated
      some degree of gene expression. Thus, CLD are among the hematopoietic
      malignancies for which PRAME may be the target of immunological therapy or used
      to evaluate MRD. The stronger and more frequent expression of PRAME in MCL is
      apparently an additional distinguishing feature on this group of
      lymphoproliferative disorders.

PMID- 12620291
TI  - Refractory anemia with excess of blasts in transformation: analysis of
      reclassification according to the WHO proposals.
AB  - The category of "refractory anemia with excess blasts in transformation" (RAEB-T)
      has been abandoned in the new WHO-classification of myelodysplastic syndromes
      (MDS). The majority of patients previously belonging to this category are now
      classified as acute myeloid leukaemia (AML). In the FAB-classification, patients
      had been assigned to the RAEB-T category if they had either (1) a medullary blast
      count between 20 and 30% or (2) a peripheral blast count of at least 5%, or (3)
      Auer rods detectable, irrespective of the blast count. We analyzed these subtypes
      of RAEB-T in terms of hematological characteristics, karyotype anomalies, and
      prognosis. Patients with more than 20% medullary blasts and patients with at
      least 5% peripheral blasts as the sole defining parameter for RAEB-T had a median
      survival of 6 months, as compared to 11 months in patients with Auer rods as the
      sole defining parameter. The presence of Auer rods therefore does not convey a
      particularly bad prognosis and does not justify placing patients in a high-risk
      category of MDS or even classifying them as AML. This finding supports the
      elimination of Auer rods as a parameter for classification in the new WHO system.
      On the other hand, the reclassification into RAEB II (according to WHO proposals)
      of previous RAEB-T patients with a peripheral blast count of at least 5% is
      problematic, because this feature predicts a median survival not different from
      that of AML patients.

PMID- 12620292
TI  - A randomized study comparing interferon (IFN alpha) plus low-dose cytarabine and
      interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia
      (CML).
AB  - This multicenter randomized phase III study was designed to compare the efficacy
      and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10
      mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML
      patients. A total of 114 patients were randomized. Following a median observation
      period of 36 (range 1-73) months the major cytogenetic response rates were 25 and
      27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group,
      respectively. While the overall toxicity profile was comparable between both
      groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3
      and 4 non-hematological toxicities.

PMID- 12620294
TI  - NOD/SCID mice transplanted with marrow from patients with myelodysplastic
      syndrome (MDS) show long-term propagation of normal but not clonal human
      precursors.
AB  - Sublethally irradiated NOD/SCID mice were transplanted with hematopoietic
      progenitor cells obtained from the marrow of patients with myelodysplastic
      syndromes (MDS). Engraftment of MDS cells, as determined by flow cytometry, was
      delayed compared to marrow from normal donors. Human CD38(+)CD34(-) cells were
      prominent in marrows and spleens of MDS chimeras. CD34(+)CD38(-), CD34(+)CD38(+)
      and T cells were also easily detected. Human myeloid cells (CD33(+); CD15(+))
      were present in low proportions. No clonal precursors were identified by
      fluorescent in situ hybridization (FISH) or by molecular analysis of polymorphic
      X-linked markers in mice with documented engraftment of human cells more than 2
      months after transplantation. These data indicate that human cells present in
      murine MDS chimeras, at the levels of sensitivity of our assays, were derived
      from residual normal cells in human MDS marrow, and suggest that the NOD/SCID
      environment was not conducive to the expansion of clonal MDS precursors. This
      model may allow identification of factors relevant for sustaining or expanding
      clonal precursors.

PMID- 12620293
TI  - Multidrug resistance modulators PSC 833 and CsA show differential capacity to
      induce apoptosis in lymphoid leukemia cell lines independently of their MDR
      phenotype.
AB  - Among the mechanisms that induce multidrug resistance (MDR), one of those most
      frequent is over-expression of a phosphoglycoprotein (Pgp) encoded in the mouse
      by the mdr-1 and mdr-3 genes. We have demonstrated that cyclosporin-A (CsA) as
      well as its analogue PSC 833 were able to revert the MDR phenotype in murine cell
      lines resistant to vincristine (LBR-V160) or doxorubicin (LBR-D160). The aim of
      this work was to evaluate the ability of PSC 833 and CsA to modulate mdr-1, mdr-3
      and mrp-1 genes as well as to induce apoptosis analyzing the mechanism involved
      in the above tumor cell lines. By semi-quantitative RT-PCR, we demonstrated that
      mdr-3 was over-expressed in both resistant lines while mdr-1 was over-expressed
      only in LBR-V160; in contrast, mrp-1 expression was not evidenced in any of the
      cell lines. After treatment with 0.1 microg ml(-1) of either PSC 833 or CsA, LBR
      V160 showed no changes in mdr-1 but decreased mdr-3 expression, while LBR-D160
      failed to display any modification in the expression of these genes. Apoptosis
      was evidenced by fluorescence microscopy, S minuscule accumulation and agarose
      gel electrophoresis. Our results demonstrated that CsA (1 microg ml(-1)) was able
      to induce apoptosis in all cell lines: 18.31% (+/-4.46) for LBR-, 25.96% (+/
      5.24) for LBR-V160 and 27.36% (+/-4.12) for LBR-D160, while PSC 833 (1 microg ml(
      1)) only induced apoptosis 21.51% (+/-5.73) in LBR-V160 cell line. The expression
      of Bcl-2 family proteins (Bcl-2, Bax and Bcl-x(L)) was analyzed by flow cytometry
      showing high expression of the three proteins which was not significantly
      modified after treatment with either PSC 833 or CsA on the sensitive as well as
      on the resistant cell lines. Single stranded conformation polymorphisms analysis
      of p53 (Trp53) gene in the cell lines showed no mutation in exons 5-8 of the
      tumor suppressor gene. We conclude that depending on the concentration used, PSC
      833 and CsA may act either by modulating the mdr-3 gene (0.1 microg ml(-1)) or by
      direct impact on the cells through induction of apoptosis (1 microg ml(-1)), in
      the latter case through a mechanism that might act independent of the Bcl-2
      family proteins.

PMID- 12620295
TI  - Preclinical evaluation of antineoplastic activity of inhibitors of DNA
      methylation (5-aza-2'-deoxycytidine) and histone deacetylation (trichostatin A,
      depsipeptide) in combination against myeloid leukemic cells.
AB  - During the development of leukemia, genes that suppress growth and induce
      differentiation can be silenced by aberrant DNA methylation and by changes in
      chromatin structure that involve histone deacetylation. It has been reported that
      a positive interaction between DNA methylation and histone deacetylation takes
      place to inhibit transcription. Based on this observation, our working hypothesis
      was that a combination of inhibitors of these processes should produce an
      enhancement of their antineoplastic activity on leukemic cells. The cytosine
      nucleoside analog, 5-aza-2'-deoxycytidine (5AZA), is a potent inhibitor of DNA
      methylation, which can activate tumor suppressor genes in leukemic cells that
      have been silenced by aberrant methylation. In clinical trials, 5AZA was
      demonstrated to be an active antileukemic agent. Histone deacetylase inhibitors
      (HDI) can also activate gene expression in leukemic cell lines by producing
      changes in chromatin configuration, and show antineoplastic activity in
      preclinical studies. In this report, we investigated the in vitro antineoplastic
      activity of 5AZA, alone and in combination with the HDI, trichostatin A (TSA) and
      depsipeptide (FR901228, depsi), on the human myeloid leukemic cell lines, HL-60
      and KG1a. The results showed that the combination of 5AZA with TSA or depsi
      produced a greater inhibition of growth and DNA synthesis and a greater loss of
      clonogenicity than either agent alone. These results suggest that 5AZA used in
      combination with HDI may be an interesting chemotherapeutic regimen to
      investigate in patients with acute myeloid leukemia that is resistant to
      conventional chemotherapy.

PMID- 12620296
TI  - Inactivation of deoxycytidine kinase and overexpression of P-glycoprotein in AraC
      and daunorubicin double resistant leukemic cell lines.
AB  - AraC resistance in vitro is explained by inactivation of dCK, while resistance to
      DNR is described by overexpression of multidrug efflux pumps like Pgp or MRP.
      Thus far, no correlation between resistance mechanisms in vitro and in patients
      with AML has been documented. We generated AraC and DNR double resistant cell
      lines to investigate resistance mechanisms of both agents. In these cell lines
      involvement of dCK was extensively investigated and Pgp expression and activity
      was determined. Our data implicate that similar resistance mechanisms like
      inactivation of dCK coincided by alternatively spliced dCK forms and
      overexpression of Pgp are induced in single-as well as in double resistant
      leukemic cell lines.

PMID- 12620298
TI  - Waldenstrom's macroglobulinemia: is there a place and time for a cease-fire?

PMID- 12620297
TI  - In vitro culture of human acute lymphoblastic leukemia (ALL) cells in serum-free
      media; a comparison of native ALL blasts, ALL cell lines and virus-transformed B
      cell lines.
AB  - The aim of this study was to standardize in vitro culture conditions for human
      acute lymphoblastic leukemia (ALL) cells. The cells were cultured in medium
      containing 10% fetal calf serum (FCS) and in the four serum-free media X-vivo 10,
      X-vivo 15, X-vivo 20 and Stem Span. Native ALL blasts could proliferate in all
      four serum-free media, but the strongest responses were usually observed with
      Stem Span. Native leukemia blasts were also cultured in the presence of various
      single cytokines or cytokine combinations. The highest proliferation was usually
      observed in the presence of Flt3-Ligand (Flt3-L) when single cytokines were
      examined, and these responses could be further increased especially by combining
      Flt3-L with interleukin 3 (IL3), IL7 or stem cell factor (SCF). Proliferation
      could also be increased when ALL blasts were cultured in the presence of two
      commercially available fibroblast cell lines (Hs27 and HFL1). Based on these
      results we suggest that in vitro culture conditions for native human ALL blasts
      can be standardized by using serum-free culture media supplemented with exogenous
      Flt3-L+IL3+SCF, and the use of accessory cells can also be standardized by using
      well-characterized fibroblast cell lines. Detectable ALL blast proliferation can
      then be observed for most patients. Our experimental model can thereby be used
      for in vitro evaluation of possible antileukemic treatment strategies, and it
      will then allow comparison of experimental results between different studies.

PMID- 12620299
TI  - Some historical remarks on picture archiving and communication systems.
AB  - This Special Issue contains one Editorial and 15 papers. The Editorial reviews
      some key events, conferences, and publications which propel PACS to its current
      status. The fifteen papers describe current and future PACS research and
      development trends grouped in four categories: system-wide trends and clinical
      experience, tools, key technologies, and PACS-based applications. We see that
      PACS has gradually become a necessary tool for daily clinical operation, its
      future trends will be in the development of research methods to fully utilize its
      large image database for better healthcare delivery.

PMID- 12620300
TI  - Filmless radiology at the Baltimore VA Medical Center: a 9 year retrospective.
AB  - The transition from conventional film based to filmless operation at the
      Baltimore VA Medical Center in 1993 was successful and has resulted in a number
      of clinical and economic benefits. The subsequent integration of the Department
      of VA hospitals in Maryland into a single network, the VA Maryland Health Care
      System, resulted in the opportunity to establish a 'virtual' radiology and
      nuclear medicine department. This integrated department is based upon a wide area
      network in which outlying medical centers utilize a central HIS/RIS and a central
      commercial Picture archival and communication system (PACS) as well as a VA 'home
      grown' image management and communication system, the VISTA imaging system. The
      creation of this virtual radiology/nuclear medicine department has resulted in
      additional savings and improvements in clinical care. The benefits of the PACS
      were made possible, to a large extent, by the high level of integration of the
      PACS and medical modalities with the hospital information and transcription
      systems. Our experience suggests that it is absolutely essential to integrate the
      PACS into the patient's electronic medical record in order to maximize efficiency
      and clinical effectiveness of the system.

PMID- 12620301
TI  - PACS developments in Europe.
AB  - Although the concept of picture archiving and communications systems (PACS) was
      developed in Europe during the latter part of the 1970s, no working system was
      completed at that time. The first PACS implementations took place in the United
      States in the early 1980s, e.g. at Pennsylvania University, UCLA, and Kansas City
      University. Some more or less successful PACS developments also took place in
      Europe in the 1980s, particularly in the Netherlands, Belgium, Austria, the
      United Kingdom, France, Italy, Scandinavia, and Germany. Most systems could be
      characterized by their focus on a single department, such as radiology or nuclear
      medicine. European hospital-wide PACS with high visibility evolved in the early
      1990s in London (Hammersmith Hospital) and Vienna (SMZO). These were followed
      during the latter part of the 1990s by approximately 10-20 PACS installations in
      each of the major industrialized countries of Europe. Wide-area PACS covering
      several health care institutions in a region are now in the process of being
      implemented in a number of European countries. Because of limitations of space,
      some countries, for i.e. Switzerland, Denmark, Finland, Spain, Greece, as well as
      Eastern European countries, etc. could not be appropriately represented in this
      paper.

PMID- 12620302
TI  - PACS development in Asia.
AB  - First, history of PACS in Japan from 1982 to 2002 has been investigated. By 2002
      total of 1468 PACS units have been installed. Of these, 1174 are small-size PACS
      with less than four image display terminals, 203 are medium-size with 5-14
      terminals, and 91 are large-size with 15 up to 1300 terminals. The main nine
      large-size PACS of 91 have been retrospectively investigated from 1984 for PACS
      experiments and from 1989 for PACS operation. Most of these nine hospitals have
      increased the number of PACS terminals by installing additional PACS units,
      instead of reinforcing the existing single PACS. The use of DICOM interfaces has
      increased the number of modalities connected to PACS and influenced the spreading
      of PACS installations in Japan. The status of HIS and RIS coupling to PACS, and
      the use of PACS in primary diagnosis or in image referral are discussed.
      Assessment of PACS is now in an early stage. Baseline studies of HIS/RIS/PACS
      effectiveness have been carried out to assess quantitatively the PACS merit.
      Second, history of PACS development in Korea is described. Very acute climbing up
      of filmless PACS diffusion was observed from 2000 to 2002. The reasons seem to be
      lack of domestic X-ray film industry, economic crisis in 1997 and PACS
      Reimbursement Act in health insurance in Korea. Third, the Hong Kong Wide Area
      Image Distribution/PACS Project is reported. It is now under phase 1 of design
      and partial implementation employing the latest and the highest ends of advanced
      technology such as failure resilience.

PMID- 12620303
TI  - The role of the Department of Defense in PACS and telemedicine research and
      development.
AB  - The United States Department of Defense (DOD) has played a leading role in the
      movement of digital imaging, picture archiving and communications systems, and
      more recently telemedicine with its associated technologies into the mainstream
      of healthcare. Beginning in the 1980s with domestic implementations, and followed
      in the 1990s by both small and large-scale military deployments, these
      technologies have been put into action with varying degrees of success. These
      efforts however, have always served as a guidepost for similar civilian efforts
      and the establishment of a marketplace for the technologies. This paper examines
      the history of the DOD's role in these areas, the projects and programs
      established, assessing their current state of development and identifying the
      future direction of the DOD's research and implementation efforts in telemedicine
      and advanced medical technologies.

PMID- 12620304
TI  - IHE: a model for driving adoption of standards.
AB  - The development of communication standards in healthcare is a major ongoing
      engineering effort. While there is little doubt that this effort has made
      possible significant advances in the performance of healthcare information and
      imaging systems, overall levels of systems interoperability have not improved as
      dramatically as one might reasonably expect and the cost of implementing
      effectively integrated systems remains high. The lag between the development of
      information standards and their implementation in real systems and institutions
      is a genuine problem in healthcare. This paper describes an ongoing initiative
      that attempts to bring together healthcare professionals and industry experts to
      coordinate the implementation of standards in ways that enhance operational
      efficiency and the quality of patient care.

PMID- 12620305
TI  - New direction in PACS education and training.
AB  - The picture archiving and communication system (PACS) is an image information
      system that has become widely installed. For its successful implementation,
      training has been found indispensable. A review of PACS training thus far shows
      major emphasis was placed on the use of display workstations. As an integrated
      system, the PACS is much broader than the display workstations, having many
      components that need connectivity and customization. With the many potentials of
      further development, a more comprehensive education program on PACS is called for
      and a PACS simulator as a standalone training and research tool is deemed
      necessary.

PMID- 12620306
TI  - Changing learning with new interactive and media-rich instruction environments:
      virtual labs case study report.
AB  - Technology has created a new dimension for visual teaching and learning with web
      delivered interactive media. The Virtual Labs Project has embraced this
      technology with instructional design and evaluation methodologies behind the
      simPHYSIO suite of simulation-based, online interactive teaching modules in
      physiology for the Stanford students. In addition, simPHYSIO provides the
      convenience of anytime web-access and a modular structure that allows for
      personalization and customization of the learning material. This innovative tool
      provides a solid delivery and pedagogical backbone that can be applied to
      developing an interactive simulation-based training tool for the use and
      management of the Picture Archiving and Communication System (PACS) image
      information system. The disparity in the knowledge between health and IT
      professionals can be bridged by providing convenient modular teaching tools to
      fill the gaps in knowledge. An innovative teaching method in the whole PACS is
      deemed necessary for its successful implementation and operation since it has
      become widely distributed with many interfaces, components, and customizations.
      This paper will discuss the techniques for developing an interactive-based
      teaching tool, a case study of its implementation, and a perspective for applying
      this approach to an online PACS training tool.

PMID- 12620307
TI  - Trends in PACS image storage and archive.
AB  - PACS is widely used in hospitals and is considered a mission critical system for
      around-the-clock daily clinical operation. Scheduled or unscheduled downtime of
      the main PACS archive storage or server could potentially cripple the entire PACS
      operation. This is especially the case in a filmless hospital environment.
      Therefore, in a downtime event, it is most desirable for users to have only a
      minimal performance impact without interruption of clinical data flow or loss of
      data and to have available historical PACS studies. This paper summarizes some of
      the developments in the design and implementation of a reliable PACS that insures
      maximum uptime for end users while preserving the integrity of the PACS data and
      making it available during downtime events. It also details strategy for
      developing proper clinical workflow contingency procedures when a scheduled
      downtime event to the main archive storage and server occurs. Specifically, the
      design and implementation of a fault-tolerant (FT) main archive server, the
      development of a FT back-up archive using an application service provider (ASP)
      model, and the clinical experiences while upgrading a main archive server and
      migrating the stored PACS data to new storage media will be discussed.

PMID- 12620308
TI  - The evolution of display technologies in PACS applications.
AB  - Picture archiving and communications systems (PACS) systems have been around for
      over a decade now. The most visible components in a PACS system are the PACS
      workstations. Most of the clinical users of PACS only interact with the display
      hardware/software pieces and never truly think about the archival and
      communications that occur behind the scenes. This paper discusses the evolution
      of PACS display technology in the past 16 yr, which can roughly be divided into
      three phases and will also discuss future emerging trends.

PMID- 12620309
TI  - Medical image security in a HIPAA mandated PACS environment.
AB  - Medical image security is an important issue when digital images and their
      pertinent patient information are transmitted across public networks. Mandates
      for ensuring health data security have been issued by the federal government such
      as Health Insurance Portability and Accountability Act (HIPAA), where healthcare
      institutions are obliged to take appropriate measures to ensure that patient
      information is only provided to people who have a professional need. Guidelines,
      such as digital imaging and communication in medicine (DICOM) standards that deal
      with security issues, continue to be published by organizing bodies in
      healthcare. However, there are many differences in implementation especially for
      an integrated system like picture archiving and communication system (PACS), and
      the infrastructure to deploy these security standards is often lacking. Over the
      past 6 years, members in the Image Processing and Informatics Laboratory,
      Childrens Hospital, Los Angeles/University of Southern California, have actively
      researched image security issues related to PACS and teleradiology. The paper
      summarizes our previous work and presents an approach to further research on the
      digital envelope (DE) concept that provides image integrity and security
      assurance in addition to conventional network security protection. The DE,
      including the digital signature (DS) of the image as well as encrypted patient
      information from the DICOM image header, can be embedded in the background area
      of the image as an invisible permanent watermark. The paper outlines the
      systematic development, evaluation and deployment of the DE method in a PACS
      environment. We have also proposed a dedicated PACS security server that will act
      as an image authority to check and certify the image origin and integrity upon
      request by a user, and meanwhile act also as a secure DICOM gateway to the
      outside connections and a PACS operation monitor for HIPAA supporting
      information.

PMID- 12620310
TI  - PACS and Web-based image distribution and display.
AB  - Picture archiving and communication system (PACS) delivers images to the display
      workstations mostly through digital image communication in medicine (DICOM)
      protocols in radiology departments, and there are lots of medical applications in
      healthcare community needing to access PACS images for different application
      purposes. In this paper, we first reviewed a hospital-integrated PACS image data
      flow and typical diagnostic display software architecture, and discussed some Web
      technologies and Web-based image application server architectures, as well as
      image accessing and viewing methods in these architectures. Then, we present one
      approach to develop component-based image display architecture and use image
      processing and display component to build a diagnostic display workstation, and
      also, give a method to integrate this component into Web-based image distribution
      server to enable users using Web browsers to access, view and manipulate PACS
      DICOM images as easy as with PACS display workstations. Finally, we test and
      evaluate the performance of image loading and displaying by using the diagnostic
      display workstation and the component-based Web display system, the experimental
      results show that the image distribution and display performance from the Web
      server to browser clients is similar with that of the image loading and
      displaying procedure of the diagnostic workstation as more browser clients
      accessing the Web server at same time. We also discuss the advantages and
      disadvantages of the Web-based image distribution and display in different
      medical applications.

PMID- 12620311
TI  - From PACS to integrated EMR.
AB  - The integration of medical images as part of the patient record has always been a
      critical component of documentation and information supporting clinical
      decisions. In the past two decades the increased number of imaging procedures
      that allows a more accurate and more specific diagnosis has significantly
      increased and their role in patient management has grown rapidly. With the
      evolution toward digital modalities and management of medical images in a fully
      digital environment with the deployment of enterprise wide Picture Archiving
      Communication Systems (PACS) a wider and more rapid access to the images by
      referring physicians and clinicians has become possible. The parallel evolution
      of electronic medical records (EMR) supporting all other documents and clinical
      data in electronic format led to the necessity of integrating medial image data
      with the rest of the patient record. Although the marriage of medical images and
      patient record data in electronic format seems a very natural and necessary
      combination it has often been very slow in development due to the lack of
      standardization and clear understanding of clinical workflows and clinical
      requirements. Several early implementations demonstrated the added value of
      combining medical images with the patient record and have shown that the
      availability of data and images facilitates and improves the accuracy and
      efficiency of patient management. Recent efforts in industry and the academic
      community to harmonize and improve the integration of medical images with patient
      record, with the promotion of new standards and better definitions of clinical
      workflows and standard mechanism of integration of different types of data into
      unified data models, has facilitated the deployment of modern EMR. Also, a shift
      in paradigm due to recent technological revolutions such as the development of
      the World Wide Web and the concepts of portal servers for accessing data for
      multiple sources has significantly boosted the trends into open systems which
      allows easier and more functional integration of medical data from different
      sources. Furthermore, the emergence of a new strategy for software development,
      based on open source components, allows software programs to be shared and
      exchanged between different institutions leading to more rapid deployment of
      standardized electronic patient record.

PMID- 12620312
TI  - Integration of computer assisted bone age assessment with clinical PACS.
AB  - Computer assisted bone age assessment (BAA) integrated with a clinical PACS is
      described. The image analysis is performed on a DICOM compliant workstation able
      to accept images from a PACS server or directly from an image modality (digital
      radiography or film scanner). Images can be processed in two modes. If the image
      is acquired from a normally developed subject, it can be added to the digital
      hand atlas. An image may also be subjected only to a diagnostic analysis for the
      BAA without archiving the features in the database. The image analysis is
      performed in three steps. A location of six region of interest is followed by
      their segmentation and feature extraction. The features analysis results in
      retrieving the closest image match from the standard database. Based on currently
      analyzed image data in the hand atlas, the standard deviation of the assessment
      bone age does not exceed 1 yr of age.

PMID- 12620313
TI  - PACS-based functional magnetic resonance imaging.
AB  - The picture archiving and communication system (PACS) technology reaches its 10th
      anniversary. Retrospectively no one could foresee the impact the PACS would have
      to the health care enterprise, but it is common consent today, that PACS is the
      key technology crucial to daily clinical image operations and especially to image
      related basic and clinical research. During the past 10 years the PACS has been
      matured from a research and developmental stage into commercial products which
      are provided by all major modality and health care equipment vendors. The PACS,
      originally implemented in the Radiology Department, needs to grow and has already
      carried well beyond departmental limits conquering all image relevant areas
      inside the hospital. During the past 10 years a dramatic development in imaging
      techniques especially within MRI emerged. Advanced 3D- and 4D-MR imaging
      techniques result in much more images and more complex data objects than ever
      before which need to be implemented into the existing PACS. These new imaging
      techniques require intensive post-processing apart from the imaging modality
      which need to be integrated into the image workflow and the PACS implementation.
      Along with these new imaging techniques new clinical applications, e.g. stroke
      detection, and research applications, e.g. study of heart and brain function, in
      Neurology and Cardiology require changes to the traditional PACS concept.
      Therefore inter-disciplinary image distribution will become the high-water mark
      for the next 10 years in the PACS endeavor. This paper focuses on one new
      advanced imaging technique, functional magnetic resonance imaging (fMRI), and
      discusses how fMRI data is defined, what fMRI requires in terms of clinical and
      research applications and how to implement fMRI in the existing PACS.

PMID- 12620314
TI  - Enterprise PACS and image distribution.
AB  - Around the world now, because of the need to improve operation efficiency and
      better cost effective healthcare, many large-scale healthcare enterprises have
      been formed. Each of these enterprises groups hospitals, medical centers, and
      clinics together as one enterprise healthcare network. The management of these
      enterprises recognizes the importance of using PACS and image distribution as a
      key technology in cost-effective healthcare delivery in the enterprise level. As
      a result, many large-scale enterprise level PACS/image distribution pilot
      studies, full design and implementation, are underway. The purpose of this paper
      is to provide readers an overall view of the current status of enterprise PACS
      and image distribution. reviews three large-scale enterprise PACS/image
      distribution systems in USA, Germany, and South Korean. The concept of enterprise
      level PACS/image distribution, its characteristics and ingredients are then
      discussed. Business models for enterprise level implementation available by the
      private medical imaging and system integration industry are highlighted. One
      current system under development in designing a healthcare enterprise level chest
      tuberculosis (TB) screening in Hong Kong is described in detail.

PMID- 12620315
TI  - Aphid sex pheromones: from discovery to commercial production.
AB  - This review charts the progress made with aphid sex pheromone chemistry, from
      initial identification of cyclopentanoid nepetalactones, for example (4aS,7S,7aR)
      nepetalactone (1). and (1R,4aS,7S,7aR)-nepetalactol (2). to commercial production
      from a renewable non-food crop, the catmint, Nepeta cataria (Lamiaceae). The
      availability of aphid sex pheromone components is now facilitating the
      development of new aphid pest control strategies, incorporating the use of other
      semiochemicals, particularly in the manipulation of populations of aphid
      parasitoids and aphid predators such as lacewings, which can utilise the
      nepetalactones and closely related molecules to locate their hosts and prey. This
      is the first example of a plant resource being developed as a feedstock for the
      production of a commercially valuable insect pheromone. The development of a
      plant-based production route highlights the tremendous potential that higher
      plants offer as cheap and renewable resources for the production of insect
      semiochemicals, through the wide array of secondary metabolites that they can
      generate.

PMID- 12620316
TI  - Large differences in amino acid sequences among ferredoxins from several species
      of genus Solanum.
AB  - The complete amino acid sequences of [2Fe-2S] ferredoxins from four species of
      genus Solanum (S. nigrum, S. lyratum, S. indicum, and S. abutiloides) were
      determined by automated Edman degradation of the entire S-carboxymethylcysteinyl
      proteins and of the peptides obtained by enzymatic digestion. The amino acid
      sequences of these four ferredoxins differed from each other by 12-19, whereas 0
      4 differences have been observed among ferredoxins from plants in the same genus
      and 14-40 differences were seen between different families. This suggests that
      these Solanum plants are distantly related to each other taxonomically.

PMID- 12620317
TI  - Pigmentation in the developing seed coat and seedling leaves of Brassica carinata
      is controlled at the dihydroflavonol reductase locus.
AB  - Flavonoid differences between near-isogenic lines of yellow- and brown-seeded
      Brassica carinata were used to identify a genetic block in seed coat and seedling
      leaf pigment biosynthesis. Seed coat pigment in the brown-seeded line consisted
      of proanthocyanidins (condensed tannins), while anthocyanin was absent.
      Dihydroquercetin, dihydrokaempferol, quercetin and kaempferol accumulated only in
      the mature seed coat of the yellow-seeded line, indicating dihydroflavonol
      reductase (DFR) as an element of genetic control in pigment biosynthesis. DFR
      transcripts from the developing seed coat in the yellow-seeded line were absent
      or less abundant at 5-30 days after pollination compared to transcript levels in
      the brown-seeded line. Seedling leaves of the yellow-seeded line exhibited
      reduced expression of DFR and contained less anthocyanin compared to the
      respective tissues from plants of the brown-seeded line when grown at 25/20
      degrees C (day/night). Cooler (18/15 degrees C) growing temperatures affected
      seedling leaf pigmentation, mature seed coat colouration and DFR expression in
      the yellow-seeded line. Comparable brown-seeded line tissues were unaffected by
      these temperature changes. These results are suggestive of a temperature
      sensitive regulator of DFR in the yellow-seeded line of Brassica carinata which
      ultimately affects the formation of pigments in the seedling leaves and in the
      mature seed coats.

PMID- 12620318
TI  - Microbial transformation of xanthohumol.
AB  - Microbial transformation of xanthohumol using the culture broth of Pichia
      membranifaciens afforded three metabolites, (E)-2"-(2"'-hydroxyisopropyl)
      dihydrofurano[2",3":4',3']-2', 4-dihydroxy-6'-methoxychalcone, (2S)-2"-(2"'
      hydroxyisopropyl)-dihydrofurano[2",3":7,8]-4'-hydroxy-5-methoxyflavanone and (E)
      2"-(2"'-hydroxyisopropyl)-dihydrofurano[2",3":2',3']-4'-hydroxy-5
      methoxychalcone.

PMID- 12620319
TI  - First detection of a chloroperoxidase in bryophytes.
AB  - Chlorinated cyclic bisbibenzyls of the isoplagiochin type are the first verified
      halometabolites from bryophytes. They could be obtained by in vitro chlorination
      of isoplagiochin C with chloroperoxidase from Caldariomyces fumago. Furthermore,
      an enzyme of this type was detected for the first time in bryophytes namely in
      the liverwort Bazzania trilobata using the monochlorodimedon assay.

PMID- 12620320
TI  - Monoterpenoid accumulation in 1,8-cineole, terpinolene and terpinen-4-ol
      chemotypes of Melaleuca alternifolia seedlings.
AB  - Individual leaves of the three most common chemotypes of Melaleuca alternifolia
      were examined both quantitatively and qualitatively for volatile constituents
      from the emergence of the first true leaves, through to 6-week-old tenth leaf set
      material. The 1,8-cineole and terpinolene chemotypes were investigated and
      compared with the recently reported commercial terpinen-4-ol chemotype. The 1,8
      cineole chemotype was found to accumulate 1,8-cineole and associated p-menthanes
      limonene, terpinen-4-ol and alpha-terpineol gradually with increasing leaf set
      number. As with the terpinen-4-ol variety, higher than expected concentrations of
      the pinenes and terpinolene were found only in the early leaf sets. The
      terpinolene variety showed two stages of terpinolene accumulation, the first at
      leaf sets 2-3 similar to the unexpected biosynthesis of terpinolene in the
      terpinen-4-ol chemotype and the second at leaf sets 8-9 which is characteristic
      of the terpinolene variety.

PMID- 12620321
TI  - Seed phosphorus and inositol phosphate phenotype of barley low phytic acid
      genotypes.
AB  - myo-Inositol-1,2,3,4,5,6-hexakisphosphate (Ins P(6) or "phytic acid") typically
      represents approximately 75% of the total phosphorus and >80% of soluble myo
      inositol (Ins) phosphates in seeds. The seed phosphorus and Ins phosphate
      phenotypes of four non-lethal barley (Hordeum vulgare L.) low phytic acid
      mutations are described. In seeds homozygous for M 635 and M 955 reductions in
      Ins P(6), approximately 75 and >90% respectively, are accompanied by reductions
      in other Ins phosphates and molar-equivalent increases in Pi. This phenotype
      suggests a block in supply of substrate Ins. In seeds homozygous for barley low
      phytic acid 1-1 (lpa1-1), a 45% decrease in Ins P(6) is mostly matched by an
      increase in Pi but also accompanied by small increases in Ins(1,2,3,4,6)P(5). In
      seeds homozygous for barley lpa2-1, reductions in seed Ins P(6) are accompanied
      by increases in both Pi and in several Ins phosphates, a phenotype that suggests
      a lesion in Ins phosphate metabolism, rather than Ins supply. The increased Ins
      phosphates in barley lpa2-1 seed are: Ins(1,2,3,4,6)P(5); Ins(1,2,4,6)P(4) and/or
      its enantiomer Ins(2,3,4,6)P(4); Ins(1,2,3,4)P(4) and/or its enantiomer
      Ins(1,2,3,6)P(4); Ins(1,2,6)P(3) and/or its enantiomer Ins(2,3,4)P(3);
      Ins(1,5,6)P(3) and/or its enantiomer Ins(3,4,5)P(3) (the methods used here cannot
      distinguish between enantiomers). This primarily "5-OH" series of Ins phosphates
      differs from the "1-/3-OH" series observed at elevated levels in seed of the
      maize lpa2 genotype, but previous chromosomal mapping data indicated that the
      maize and barley lpa2 loci might be orthologs of a single ancestral gene.
      Therefore one hypothesis that might explain the differing lpa2 phenotypes is that
      their common ancestral gene encodes a multi-functional, Ins phosphate kinase with
      both "1-/-3-" and "5-kinase" activities. A putative pyrophosphate-containing Ins
      phosphate, possibly an Ins P(7), was also observed in the mature seed of all
      barley genotypes except lpa2-1. Barley M 955 indicates that at least for this
      species, the ability to accumulate Ins P(6) can be nearly abolished while
      retaining at least short-term ( approximately 1.0 years) viability.

PMID- 12620322
TI  - Identification of a hydroxy substituted calamenene--a sesquiterpene associated
      with wound reactions in non-infected xylem of Tilia spp.
AB  - Xylem of lime trees (Tilia spp.) with wound reactions was structurally
      investigated by scanning (SEM) and transmission electron microscopy (TEM) as well
      as chemically analyzed by direct thermal desorption-gas chromatography-mass
      spectrometry (DTD-GC-MS). Wound reactions in the outer xylem lead to distinct
      discolorations around the wound. Within a 4-week response no fungal infection
      occurred in discoloured xylem. At the fine structural level, wound reactions
      become primarily visible as the secretion of dark-staining substances from
      parenchyma cells into lumens of vessels and fibres. With increasing reaction time
      vessels aggregate large amounts of secretion products, whereas in fibres wall
      associated linings are formed and the inner secondary wall appears incrusted.
      After 2-3 months a narrow, greenish-brown boundary developed at the transition
      between the discoloured outer and the unchanged inner xylem. This green-brown
      boundary layer remained non-infected also in older wounds. DTD-GC-MS analyses
      revealed that the sesquiterpene Hydroxycalamenene represents a key substance of
      wound reactions in non-infected lime trees. Other substances such as fatty acids
      or their esters and coniferyl aldehydes or their derivatives were also found. TEM
      investigations of the samples after DTD-GC-MS showed less pronounced cell wall
      attached linings in fibres as well as reduced incrustation of inner secondary
      walls. The massive deposits in the vessel lumens remained unchanged. The role of
      these wound reaction products and their ways of synthesis are discussed.

PMID- 12620323
TI  - Phytotoxicity of the tetramic acid metabolite trichosetin.
AB  - Trichosetin, a tetramic acid-containing metabolite produced in the dual culture
      of Trichoderma harzianum and Catharanthus roseus (L.) G. Don callus, was
      subjected to phytotoxicity assays. In seedling growth assays, trichosetin
      inhibited root and shoot growth of all five plant species tested by damaging the
      cell membrane, as evidenced by the dose-dependent increase in electrolyte leakage
      and lipid peroxidation. Vital staining of trichosetin-treated Nicotiana tabacum
      BY-2 cells, with rhodamine 123, showed a weaker green fluorescence compared to
      controls indicating damaging effects on mitochondria. FDA-PI staining, to
      determine cell viability, indicated that cells of the trichosetin-treated roots
      were mostly dead.

PMID- 12620324
TI  - Xanosporic acid, an intermediate in bacterial degradation of the fungal
      phototoxin cercosporin.
AB  - The red fungal perylenequinone phototoxin cercosporin is oxidized by Xanthomonas
      campestris pv zinniae to a non-toxic, unstable green metabolite xanosporic acid,
      identified via its lactone as 1,12-bis(2'R-hydroxypropyl)-4,9-dihydroxy-6,7
      methylenedioxy-11-methoxy-3-oxaperylen-10H-10-one-2-carboxylic acid.
      Xanosporolactone was isolated in approximately 2:1 ratio of M:P atropisomers.

PMID- 12620325
TI  - Identification of 6-methylsulfinylhexyl isothiocyanate as an apoptosis-inducing
      component in wasabi.
AB  - The ethanol extract from Japanese horseradish wasabi was found to inhibit cell
      proliferation in human monoblastic leukemia U937 cells by inducing apoptotic cell
      death. Separation by methods including silica gel chromatography and preparative
      HPLC gave an active compound, which was identified as 6-methylsulfinylhexyl
      isothiocyanate (6-HITC). Several lines of evidence indicated that 6-HITC induced
      apoptosis in U937 cells and human stomach cancer MKN45 cells. Thus, 6-HITC is
      potentially useful as a natural anti-cancer agent.

PMID- 12620327
TI  - Antiplasmodial and antifungal activities of iridal, a plant triterpenoid.
AB  - Iridal, a triterpenoidic compound extracted from Iris germanica L., was
      previously shown to have an interesting activity on two cultured human tumor cell
      lines (A2780 and K562). In the present work, this same product was tested in
      vitro on Plasmodium falciparum chloroquine-resistant and -sensitive strains, in
      vivo on P. vinckei, and on some Candida albicans and C. parapsilosis strains too.
      The IC(50) obtained in vitro on human malaria strain ranged from 1.8 to 26.0
      microg/ml and the ED(50) in vivo is about 85 mg/kg/day by intraperitoneal route.
      The minimal inhibitory concentrations were higher than to 50 microg/ml, whatever
      the strain of yeast tested. This product presents an antiplasmodial activity
      similar to that obtained with extracts from the plant Azadirachta indica
      classically taken as reference in malaria phytomedicine. Conversely iridal shows
      no important antifungal activity. The specific activity of iridal on human
      malaria parasite and on tumor cell lines is discussed.

PMID- 12620326
TI  - Bioactive sucrose esters from Bidens parviflora.
AB  - An investigation on Bidens parviflora led to the isolation of three sucrose
      esters and a substituted truxillate. Their structures were elucidated as (6-O-(E)
      p-coumaroyl)-beta-D-fructofuranosyl-(2-->1)-alpha-D-glucopyranoside, (6-O-(E)-p
      coumaroyl)-beta-D-fructofuranosyl-(2-->1)-(6-O-(E)-p-coumaroyl)-alpha-D
      glucopyranoside II, 6,6'-sucrose ester of (1alpha,2alpha,3beta,4beta)-3,4-bis(4
      hydroxyphenyl)-1,2-cyclobutanedicarboxylic acid, dimethyl ester of
      (1alpha,2alpha,3alpha,4alpha)-2,4-bis(3,4-dihydroxyphenyl)-1,3
      cyclobutanedicarboxylic acid on the basis of spectral and chemical evidence.
      These compounds were subjected to the following bioassays: the histamine release
      inhibition of rat mast cells induced by antigen-antibody reaction and the
      inhibitory activity of PGE(2) production by macrophages.

PMID- 12620328
TI  - Scavenging of reactive oxygen species by a novel glucurinated flavonoid
      antioxidant isolated and purified from spinach.
AB  - NAO is a natural water soluble antioxidant that was isolated and purified from
      spinach leaves. Using HPLC, NMR, and CMR spectroscopy, the main components were
      identified as flavonoids and p-coumaric acid derivatives. The NAO was found to be
      a very effective antioxidant in several in vivo and in vitro biological systems.
      In the present study, the antioxidant activity of the novel antioxidant
      glucurinated flavonoid (GF) isolated and characterized from NAO, is compared to
      well-known antioxidants. In addition, the direct free radical scavenging
      properties of the purified component GF were studied using the electron spin
      resonance (ESR) technique. GF and NAO were found to be superior to EGCG and NAC
      and to the Vitamin E homologue Trolox in inhibiting reactive oxygen species (ROS)
      formation in the autooxidation system of linoleic acid and in fibroblasts exposed
      to metal oxidation. GF and NAO were found to inhibit the ESR signal intensity of
      DMPO-O(2) radical formation during the riboflavin photodynamic reaction. 10 mM GF
      caused approximately 90% inhibition in the intensity of the ESR signal, while NAO
      at a concentration of 60 microg/ml caused an inhibition of about 50%. Using the
      Fenton reaction, GF and NAO were found to inhibit DMPO-OH radical formation. A
      concentration of 2 mM GF caused a 70% inhibition in the intensity of the DMPO-OH
      radical ESR signal, while propyl gallate at the same concentration caused only
      50% inhibition. Furthermore, both GF and NAO also inhibited the (1)O(2) dependent
      TEMPO radical generated in the photoradiation TPPS4 system. About 80% inhibition
      was obtained by 4 mM GF. The results obtained indicate that the natural
      antioxidants derived from spinach may directly affect the scavenging of ROS and,
      as a consequence, may be considered as effective sources for combating oxidative
      damage.

PMID- 12620329
TI  - Stereochemistry of megastigmane glucosides from Glochidion zeylanicum and
      Alangium premnifolium.
AB  - From Glochidion zeylanicum, two megastigmane glucosides, 3- and 9-O-beta-D
      glucopyranosides of (3S,5R,6R,7E,9S)-megastigman-7-ene-3,5,6,9-tetrol (1 and 2,
      respectively), were isolated. Their structures were different from those of
      kiwiionoside (3) and actinidioionoside (4), isolated from Actinidia chinensis and
      Actinidia polygama, respectively, in the stereochemistry at the 9-positions.
      Alangionosides E (5) and O (6), isolated from the leaves of Alangium
      premnifolium, are also megastigmane glucosides, and the latter is closely related
      to 1 and actinidioionoside (4). However, the absolute configurations of the 9
      position remained to be determined. They were analyzed to be R by means of a
      modified Mosher's method. Alangionoside E (5) is identical with corchoionoside A
      in all aspects. The name of corchoionoside A must be retained thereafter.

PMID- 12620330
TI  - Lignan derivatives from the liverwort Bazzania trilobata.
AB  - Eight lignan derivatives trilobatin D-K, as well as jamesopyrone were isolated
      from the liverwort Bazzania trilobata. Their structures have been elucidated
      based on extensive NMR spectral evidence.

PMID- 12620331
TI  - Dihydroisocoumarins and a tetralone from Cytospora eucalypticola.
AB  - Two dihydroisocoumarins, 3,5-dimethyl-8-hydroxy-7-methoxy-3,4-dihydroisocoumarin
      and 3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin were isolated from a culture
      filtrate of Cytospora eucalypticola, together with three known
      dihydroisocoumarins and a tetralone derivative. Their structures were determined
      by spectroscopic methods. These isocoumarins are mildly antifungal, and
      antibacterial towards gram positive bacteria. A known compound, 5
      hydroxymethylmellein, showed mild antifeedant activity towards Spodoptera
      littoralis.

PMID- 12620332
TI  - New insights on the structure of algaenan from Botryoccocus braunii race A and
      its hexane insoluble botryals based on multidimensional NMR spectroscopy and
      electrospray-mass spectrometry techniques.
AB  - Through solution state NMR spectroscopy and quadrupole-time-of-flight mass
      spectrometry (Q-TOF MS) studies of the hexane insoluble botryal extract of the
      algae Botryococcus braunii race A, coupled with high-resolution magic-angle
      spinning (HR-MAS) NMR spectroscopy of the algaenan from this alga, it has been
      possible to advance the structural understanding of this geochemically important
      biopolymer. It was found that the hexane insoluble botryals in this study
      constitute a mixture of low molecular weight unsaturated aliphatic aldehydes and
      unsaturated hydrocarbons with an average chain length of about 40 carbons. Exact
      assignments were provided for many of the structural units present and describe
      the average constitution of the mixture as a whole. Reticulation of the low
      molecular weight chains via acetal and ester links explains the primary make up
      of algaenan. In this study, it is concluded that the algaenan results from the
      reticulation of low molecular weight hexane insoluble botryal species rather than
      the polyaldehyde as previously observed in studies of algae at alternate stages
      of their growth cycle.

PMID- 12620333
TI  - Homoisoflavonoids and xanthones from the tubers of wild and in vitro regenerated
      Ledebouria graminifolia and cytotoxic activities of some of the
      homoisoflavonoids.
AB  - Eleven homoisoflavonoids and two xanthones were isolated and characterized from
      the bulbs of Ledebouria graminifolia. Five of the homoisoflavonoids are new
      compounds and were identified as: 5-hydroxy-7-methoxy-3-(4'-hydroxybenzyl)-4
      chromanone, 5-hydroxy-6,7-dimethoxy-3-(4'-hydroxybenzyl)-4-chromanone, 5,7,8
      trimethoxy-3-(4'-hydroxybenzyl)-4-chromanone, 5-hydroxy-3',4',7
      trimethoxyspiro[2H-1-benzopyran-7'-bicyclo[4.2.0]octa-trien]-4-one, 5,7-dihydroxy
      3',4'-dimethoxyspiro[2H-1-benzopyran-7'-bicyclo[4.2.0]octa-trien]-4-one.
      Structures were elucidated by extensive 1D, and 2D NMR spectroscopy and HRMS. A
      method for tissue culture was developed and the bulbs of mature plants were found
      to contain all the compounds isolated from the wild specimens of L. graminifolia.

PMID- 12620334
TI  - Sesquineolignans and other constituents from the seeds of Joannesia princeps.
AB  - From the methanolic extract of the seeds of the Brazilian Joannesia princeps 3,3'
      bisdemethylpinoresinol and six new sesquineolignans were isolated besides the
      known neolignans americanol A, isoamericanol A and isoamericanin A which were
      found to be the major constituents. A method was developed to distinguish
      americanol- from isoamericanol-type compounds spectroscopically.

PMID- 12620337
TI  - Recent advances in betalain research.
AB  - Betalains replace the anthocyanins in flowers and fruits of plants of most
      families of the Caryophyllales. Unexpectedly, they were also found in some higher
      fungi. Whereas the anthocyanin-analogous functions of betalains in flower and
      fruit colouration are obvious, their role in fungi remains obscure. The nature of
      newly identified betalains as well as final structure elucidation of earlier
      putatively described compounds published within the last decade is compiled in
      this report. Recent advances in research on betalain biosynthesis is also
      covered, including description of some 'early' reactions, i.e. betalain-specific
      dopa formation in plants and fungi and extradiolic dopa cleavage in fungi. Work
      on betalain-specific glucosyltransferases (GTs) has given new insights into the
      evolution of secondary plant enzymes. It is proposed that these GTs are
      phylogenetically related to flavonoid GTs. It was found that the decisive steps
      in betalain biosynthesis, i.e. condensation of the betalain chromophore betalamic
      acid with cyclo-dopa and amino acids or amines in the respective aldimine
      formation of the red-violet betacyanins and the yellow betaxanthins, are most
      likely to be non-enzymatic. Betalains have attracted workers in applied fields
      because of their use for food colouring and their antioxidant and radical
      scavenging properties for protection against certain oxidative stress-related
      disorders.

PMID- 12620338
TI  - Stilbenecarboxylate biosynthesis: a new function in the family of chalcone
      synthase-related proteins.
AB  - Chalcone (CHS), stilbene (STS) synthases, and related proteins are key enzymes in
      the biosynthesis of many secondary plant products. Precursor feeding studies and
      mechanistic rationalization suggest that stilbenecarboxylates might also be
      synthesized by plant type III polyketide synthases; however, the enzyme activity
      leading to retention of the carboxyl moiety in a stilbene backbone has not yet
      been demonstrated. Hydrangea macrophylla L. (Garden Hortensia) contains
      stilbenecarboxylates (hydrangeic acid and lunularic acid) that are derived from 4
      coumaroyl and dihydro-4-coumaroyl starter residues, respectively. We used
      homology-based techniques to clone CHS-related sequences, and the enzyme
      functions were investigated with recombinant proteins. Sequences for two proteins
      were obtained. One was identified as CHS. The other shared 65-70% identity with
      CHSs and other family members. The purified recombinant protein had
      stilbenecarboxylate synthase (STCS) activity with dihydro-4-coumaroyl-CoA, but
      not with 4-coumaroyl-CoA or other substrates. We propose that the enzyme is
      involved in the biosynthesis of lunularic acid. It is the first example of a STS
      type reaction that does not lose the terminal carboxyl group during the ring
      folding to the end product. Comparisons with CHS, STS, and a pyrone synthase
      showed that it is the only enzyme exerting a tight control over decarboxylation
      reactions. The protein contains unusual residues in positions highly conserved in
      other CHS-related proteins, and mutagenesis studies suggest that they are
      important for the structure or/and the catalytic activity. The formation of the
      natural products in vivo requires a reducing step, and we discuss the possibility
      that the absence of a reductase in the in vitro reactions may be responsible for
      the failure to obtain stilbenecarboxylates from substrates like 4-coumaroyl-CoA.

PMID- 12620339
TI  - Flavonol synthase from Citrus unshiu is a bifunctional dioxygenase.
AB  - Flavonol synthase was classified as a 2-oxoglutarate-dependent dioxygenase
      converting natural (2R,3R)-dihydroflavonols, i.e. dihydrokaempferol, to the
      corresponding flavonols (kaempferol). Flavonol synthase from Citrus unshiu
      (Satsuma mandarin), expressed in Escherichia coli and purified to homogeneity,
      was shown to accept also (2S)-naringenin as a substrate, producing kaempferol in
      high yield and assigning sequential flavanone 3beta-hydroxylase and flavonol
      synthase activities to the enzyme. In contrast, dihydrokaempferol was identified
      as the predominant product from assays performed with the unnatural (2R)
      naringenin as substrate. The product which was not converted any further on
      repeated incubations was identified by 1H NMR and CD spectroscopies as (-)-trans
      dihydrokaempferol. The data demonstrate that Citrus flavonol synthase encompasses
      an additional non-specific activity trans-hydroxylating the flavanones (2S)
      naringenin as well as the unnatural (2R)-naringenin at C-3.

PMID- 12620340
TI  - Molecular cloning and characterization of an amidase from Arabidopsis thaliana
      capable of converting indole-3-acetamide into the plant growth hormone, indole-3
      acetic acid.
AB  - Acylamidohydrolases from higher plants have not been characterized or cloned so
      far. AtAMI1 is the first member of this enzyme family from a higher plant and was
      identified in the genome of Arabidopsis thaliana based on sequence homology with
      the catalytic-domain sequence of bacterial acylamidohydrolases, particularly
      those that exhibit indole-3-acetamide amidohydrolase activity. AtAMI1 polypeptide
      and mRNA are present in leaf tissues, as shown by immunoblotting and RT-PCR,
      respectively. AtAMI1 was expressed from its cDNA in enzymatically active form and
      exhibits substrate specificity for indole-3-acetamide, but also some activity
      against L-asparagine. The recombinant enzyme was characterized further. The
      results show that higher plants have acylamidohydrolases with properties similar
      to the enzymes of certain plant-associated bacteria such as Agrobacterium-,
      Pseudomonas- and Rhodococcus-species, in which these enzymes serve to synthesize
      the plant growth hormone, indole-3-acetic acid, utilized by the bacteria to
      colonize their host plants. As indole-3-acetamide is a native metabolite in
      Arabidopsis thaliana, it can no longer be ruled out that one pathway for the
      biosynthesis of indole-3-acetic acid involves indole-3-acetamide-hydrolysis by
      AtAMI1.

PMID- 12620341
TI  - Oxidation of pentagalloylglucose to the ellagitannin, tellimagrandin II, by a
      phenol oxidase from Tellima grandiflora leaves.
AB  - A new enzyme has been isolated from leaves of the weed Tellima grandiflora
      (fringe cups, Saxifragaceae) that catalyzed the O(2)-dependent oxidation of
      1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose to tellimagrandin II, the first
      intermediate in the (4)C(1)-glucose derived series of ellagitannins. CD-spectra
      revealed that the 4,6-O-HHDP-residue of the in vitro product had the (S)
      stereoconfiguration characteristic of tellimagrandin II from natural sources. The
      enzyme, for which a M(r) of ca. 60,000 was determined, was purified to apparent
      homogeneity. It had a pH-optimum at pH 5.0, an isoelectric point at pH 6.3 and
      was most stable at pH 4.2. Inhibition studies suggested that this new enzyme, for
      which the systematic name 'pentagalloylglucose: O(2) oxidoreductase' is proposed,
      belongs to the vast group of laccase-type phenol oxidases (EC 1.10.3.2).

PMID- 12620342
TI  - Oxidative biosynthesis of phenylbenzoisochromenones from phenylphenalenones.
AB  - 13C NMR analysis demonstrated incorporation of two 13C labelled phenylalanine
      units into phenylphenalenones and phenylbenzoisochromenones co-occurring in
      Wachendorfia thyrsiflora. These results suggest oxidative formation of
      phenylbenzoisochromenones following a late branching from a common
      phenylphenalenone biosynthetic pathway. A dioxygenase-type mechanism, followed by
      decarboxylation, is suggested for the key steps of this conversion.

PMID- 12620343
TI  - Aromatic and pyrone polyketides synthesized by a stilbene synthase from Rheum
      tataricum.
AB  - A cDNA encoding a stilbene synthase, RtSTS, was isolated from the rhizomes of
      Tatar rhubarb, Rheum tataricum L. (Polygonaceae), a medicinal plant containing
      stilbenes and other polyketides. Recombinant RtSTS was expressed in E. coli and
      assayed with acetyl-coenzyme A (CoA), n-butyryl-CoA, isovaleryl-CoA, n-hexanoyl
      CoA, cinnamoyl-CoA and p-coumaroyl-CoA as primers of polyketide synthesis. RtSTS
      synthesized resveratrol and a trace amount of naringenin chalcone from p
      coumaroyl-CoA, supporting the enzyme's identification as a resveratrol-type
      stilbene synthase (EC 2.3.1.95). Bis-noryangonin and p-coumaroyl triacetic acid
      lactone (CTAL)-type pyrones were observed in minor amounts in the reaction with p
      coumaroyl-CoA and as major products with cinnamoyl CoA. As well, such pyrones,
      and not aromatic polyketides, were identified as the only products in assays with
      aliphatic and benzoyl CoA esters. Acetonyl-4-hydroxy-2-pyrone, a pyrone
      synthesized from acetyl-CoA, was identified as a new product of a stilbene
      synthase. Using Northern blot analysis, RtSTS transcript was found to be highly
      expressed in R. tataricum rhizomes, with low transcript levels also present in
      young leaves. This expression pattern correlated with the occurrence of
      resveratrol, which was detected in higher amounts in R. tataricum rhizomes
      compared with leaves and petioles using HPLC. Few stilbene synthases have been
      found in plants, and the identification of RtSTS provides additional sequence and
      catalytic information with which to study the evolution of plant polyketide
      synthases.

PMID- 12620344
TI  - Biosynthesis of calystegines: 15N NMR and kinetics of formation in root cultures
      of Calystegia sepium.
AB  - Calystegines are nortropane alkaloids bearing between three and five hydroxyl
      groups in various positions. [15N]Tropinone was administered to root cultures of
      Calystegia sepium and the incorporation into calystegines was followed. Increase
      of label in calystegines was measured by one-dimensional 15N NMR and inverse
      detected 2D NMR techniques. The results show that tropinone and pseudotropine are
      metabolites in the biosynthetic pathway of calystegines. The velocity of
      calystegine accumulation was followed kinetically by transfer of root cultures
      from 15N-enriched medium to 14N-medium and analysis by GC-MS. A constant
      calystegine formation with no interference by excretion or degradation was
      observed. A biosynthetic rate for individual calystegines at each time point was
      calculated, the maximum was 0.4 mg/day/g of biomass. This allowed the velocity of
      individual biosynthetic steps to be estimated.

PMID- 12620345
TI  - Antifungal diterpenes from Hypoestes serpens (Acanthaceae).
AB  - Two new diterpenes, fusicoserpenol A and dolabeserpenoic acid A, with antifungal
      activity, were isolated from leaves of Hypoestes serpens (Acanthaceae). Their
      structures were elucidated by means of spectrometric methods including 1D and 2D
      NMR experiments and MS analysis. X-ray crystallographic analysis confirmed the
      structure of fusicoserpenol A and established the relative configuration.

PMID- 12620346
TI  - Evidence for general occurrence of homospermidine in plants and its supposed
      origin as by-product of deoxyhypusine synthase.
AB  - Deoxyhypusine synthase (DHS) is involved in the post-translational activation of
      the eukaryotic initiation factor 5A (eIF5A) and, as a side-reaction, catalyzes
      the formation of homospermidine if its substrate, the eIF5A precursor protein, is
      replaced by putrescine. Plant homospermidine synthase is assumed to be
      phylogenetically derived from DHS; it represents a DHS having lost its intrinsic
      activity. The enzyme is expressed in plants producing pyrrolizidine alkaloids
      where it catalyzes the formation of homospermidine the unique precursor of
      pyrrolizidine alkaloids. Here we show that 29 species randomly selected from 18
      angiosperm families as well as a few other terrestrial plant species, all were
      able to produce small amounts of homospermidine. Basing on these results and in
      the context of literature on the occurrence of homospermidine in the organismic
      kingdoms, a universal occurrence of homospermidine is assumed and ubiquitous DHS
      is suggested to be responsible for its formation. The synthesis of homospermidine
      as an enzymatic by-product of an essential enzyme is discussed in respect to the
      evolutionary origin of homospermidine synthase and the biosynthetic pathway of
      pyrrolizidine alkaloids.

PMID- 12620347
TI  - Habropetaline A, an antimalarial naphthylisoquinoline alkaloid from
      Triphyophyllum peltatum.
AB  - The isolation, structural elucidation, and antiprotozoal activities of
      habropetaline A, a novel naphthylisoquinoline alkaloid from Triphyophyllum
      peltatum, are described. This alkaloid had previously only been identified on
      line, by the LC-MS/MS-NMR-CD triad, in the crude extract of the rare and
      difficult-to-provide related plant species Habropetalum dawei, whose small
      quantities available had not permitted to isolate the compound. As predicted by
      quantitative structure-activity relationship (QSAR) investigations, habropetaline
      A exhibits strong antimalarial activity against Plasmodium falciparum, while it
      is inactive against other protozoal pathogens (Trypanosoma brucei rhodesience, T.
      cruzi, and Leishmania donovani).

PMID- 12620348
TI  - Biosynthesis of 14,15-dehydro-12-oxo-phytodienoic acid and related
      cyclopentenones via the phytoprostane D(1) pathway.
AB  - A novel group of cyclopentenone prostaglandin-like compounds, deoxy
      phytoprostanes J(1), together with their precursors, phytoprostanes D(1), were
      identified in tobacco, tomato and Arabidopsis. Previously, it was thought that
      14,15-dehydro-12-oxo-phytodienoic acid, a member of the deoxy phytoprostanes J(1)
      family, is derived from either 12-oxo-phytodienoic acid or diketols via the
      allene oxide synthase pathway. Results suggest that 14,15-dehydro-12-oxo
      phytodienoic acid as well as structurally related cyclopentenones of the
      chromomoric acid family are synthesized via the phytoprostane D(1) pathway in
      planta. Notably, 14,15-dehydro-12-oxo-phytodienoic acid is more abundant than 12
      oxo-phytodienoic acid in all three species so far analyzed.

PMID- 12620349
TI  - Two chromone-secoiridoid glycosides and three indole alkaloid glycosides from
      Neonauclea sessilifolia.
AB  - From the dried roots of Neonauclea sessilifolia, two new chromone-secoiridoid
      glycosides, sessilifoside and 7"-O-beta-D-glucopyranosylsessilifoside, and three
      novel indole alkaloid glycosides, neonaucleosides A, B, and C, were isolated
      along with the main known glycosides, 5-hydroxy-2-methylchromone-7-O-beta-D
      apiofuranosyl-(1-->6)-beta-D-glucopyranoside, sweroside, loganin,
      grandifloroside, and quinovic acid 3 beta-O-beta-D-quinovopyranoside-28-O-beta-D
      glucopyranoside. The structures of these new glycosides were determined by
      spectroscopic and chemical means. Neonaucleoside A and its C-3 epimer were
      prepared from secologanin and tryptamine.

PMID- 12620350
TI  - A 2-oxoglutarate-dependent dioxygenase is integrated in DIMBOA-biosynthesis.
AB  - Benzoxazinoids are secondary metabolites of grasses that function as natural
      pesticides. While many steps of DIMBOA biosynthesis have been elucidated, the
      mechanism of the introduction of OCH(3)-group at the C-7 position was unknown.
      Inhibitor experiments in Triticum aestivum and Zea mays suggest that a 2
      oxoglutarate-dependent dioxygenase catalyses the hydroxylation reaction at C-7.
      Cloning and reverse genetics analysis have identified the Bx6 gene that encodes
      this enzyme. Bx6 is located in the Bx-gene cluster of maize.

PMID- 12620351
TI  - Occurrence and non-detectability of maytansinoids in individual plants of the
      genera Maytenus and Putterlickia.
AB  - Individual plants belonging to different species of the family Celastraceae
      collected from their natural habitats in South Africa (Putterlickia verrucosa (E.
      Meyer ex Sonder) Szyszyl., Putterlickia pyracantha (L.) Szyszyl., Putterlickia
      retrospinosa van Wyk and Mostert) and Brazil (Maytenus ilicifolia Mart. ex
      Reiss., Maytenus evonymoides Reiss., Maytenus aquifolia Mart.) were investigated
      for the presence of maytansinoids and of maytansine, an ansamycin of high
      cytotoxic activity. Maytansinoids were not detectable in plants grown in Brazil.
      Analysis of plants growing in South Africa, however, showed clearly that
      maytansinoids were present in some individual plants but were not detectable in
      others. Molecular biological analysis of a Putterlickia verrucosa cell culture
      gave no evidence for the presence of the aminohydroxybenzoate synthase gene which
      is unique to the biosynthesis of aminohydroxybenzoate, a precursor of the
      ansamycins including maytansinoids. Moreover, this gene was not detectable in DNA
      extracted from the aerial parts of Putterlickia plants. In contrast, observations
      indicate that this gene may be present in microbes of the rhizosphere of
      Putterlickia plants. Our observations are discussed with respect to the
      possibility that the roots of Putterlickia plants may be associated with
      microorganisms which are responsible for the biosynthesis of maytansine or
      maytansinoids.

PMID- 12620353
TI  - On the origin of family 1 plant glycosyltransferases.
AB  - The phylogeny of highly divergent multigene families is often difficult to
      validate but can be substantiated by inclusion of data outside of the phylogeny,
      such as signature motifs, intron splice site conservation, unique substitutions
      of conserved residues, similar gene functions, and out groups. The Family 1
      Glycosyltransferases (UGTs) comprises such a highly divergent, polyphyletic
      multigene family. Phylogenetic comparisons of UGTs from plants, animals, fungi,
      bacteria, and viruses reveal that plant UGTs represent three distinct clades. The
      majority of the plant sequences appears to be monophyletic and have diverged
      after the bifurcation of the animal/fungi/plant kingdoms. The two minor clades
      contain the sterol and lipid glycosyltransferases and each show more homology to
      non-plant sequences. The lipid glycosyltransferase clade is homologous to
      bacterial lipid glycosyltransferases and reflects the bacterial origin of
      chloroplasts. The fully sequenced Arabidopsis thaliana genome contains 120 UGTs
      including 8 apparent pseudogenes. The phylogeny of plant glycosyltransferases is
      substantiated with complete phylogenetic analysis of the A. thaliana UGT
      multigene family, including intron-exon organization and chromosomal
      localization.

PMID- 12620352
TI  - Biosynthesis of beta-sitosterol and stigmasterol in Croton sublyratus proceeds
      via a mixed origin of isoprene units.
AB  - A green callus culture of Croton sublyratus Kurz established from the leaf
      explants appeared to actively synthesize two well-known phytosterols, beta
      sitosterol and stigmasterol. The phytosterol biosynthesis was highly active
      during the linear phase of the culture. Feeding of [1-13C]glucose into the callus
      culture at this growth phase showed that the label from glucose was highly
      incorporated into both phytosterols. Isolation of the labeled products followed
      by 13C NMR analysis revealed that the phytosterols had their 13C-labeling
      patterns consistent with the acquisition of isoprene units via both the
      mevalonate pathway and the deoxyxylulose pathway with relatively equal
      contribution. Since the biosynthesis of phytosterol has so far been reported to
      be mainly from the classical mevalonate pathway, this study provides a new
      evidence on the biosynthesis of phytosterols via the novel deoxyxylulose pathway.

PMID- 12620354
TI  - Kinetic analysis of the inhibition of phenylalanine ammonia-lyase by 2-aminoindan
      2-phosphonic acid and other phenylalanine analogues.
AB  - The conformationally restricted phenylalanine analogue 2-aminoindan-2-phosphonic
      acid (AIP) inhibits phenylalanine ammonia-lyase (PAL) competitively in a time
      dependent manner. This phenomenon was investigated in more detail with the
      heterologously expressed, highly purified homotetrameric PAL-1 isozyme from
      parsley. The kinetic analysis revealed that the enzyme-inhibitor complex is
      formed in a single "slow" step with an association rate of k(2)=2.6+/-0.04 10(4)
      M(-1) s(-1). The inhibition is reversible with a dissociation rate of k(-2)=1.8+/
      0.04 10(-4) s(-1) and an equilibrium constant of K(i)=7+/-2 nM. The previously
      described PAL inhibitor (S)-2-aminooxy-3-phenylpropanoic acid [(S)-AOPP] was also
      found to be a slow-binding inhibitor of PAL-1. The carboxyl analogue of AIP, 2
      aminoindan-2-carboxylic acid, served as a substrate of PAL-1 and was converted to
      indene-2-carboxylic acid.

PMID- 12620355
TI  - Phytochelatin synthase catalyzes key step in turnover of glutathione conjugates.
AB  - Conjugation of xenobiotic compounds and endogenous metabolites to glutathione is
      an ubiquitous process in eukaryotes. In animals, the first and rate-limiting step
      of glutathione-S-conjugate metabolism is characterized by the removal of the
      aminoterminal glutamic acid residue of glutathione. In plants, however,
      glutathione-S-conjugates are generally metabolized by removal of the
      carboxylterminal glycine residue of the tripeptide glutathione to give rise to
      the S-glutamylcysteinyl-derivative. Purification of the glutathione-conjugate
      catabolizing activity from cell suspension cultures of the plant Silene cucubalus
      indicated that phytochelatin synthase catalyzes the first step of the pathway.
      Heterologously expressed phytochelatin synthase from Arabidopsis efficiently
      converted S-bima ne-glutathione to S-bimane-glutamylcysteine, the formation of
      which was unequivocally identified by mass spectrometry. No further products,
      such as S-derivatives of phytochelatins, were observed. Several different
      glutathione-S-conjugates served as substrates for the enzyme and were processed
      to the corresponding glutamylcysteinyl-adducts. Affinity-purified phytochelatin
      synthase preparations required divalent heavy metal ions such as Cd(2+), Zn(2+)
      or Cu(2+) for detectable turnover of glutathione-S-conjugates. Characterization
      of the enzymatic properties of phytochelatin synthase argues for both cellular
      functions of the gamma-glutamylcysteinyl-dipeptidyltransferase: (1) formation of
      heavy-metal binding peptides and (2) degradation of glutathione-S-conjugates.
      Mechanistically, the former role is the result of gamma-glutamylcysteinyl
      transpeptidation onto glutathione or derivatives thereof, while the catabolic
      function reflects transpeptidation of S-glutamylcysteinyl-adducts onto the
      acceptor molecule water. Thus, phytochelatin synthase seems to fulfil a second
      crucial role in glutathione metabolism.

PMID- 12620356
TI  - Homologous very-long-chain 1,3-alkanediols and 3-hydroxyaldehydes in leaf
      cuticular waxes of Ricinus communis L.
AB  - Surface extracts from primary leaves of Castor bean were found to contain 1.8
      microg cm(-2) of cuticular waxes. The mixture comprised alkanes (C(26)-C(29)),
      primary alcohols (C(22)-C(38)), aldehydes (C(26) and C(28)), fatty acids (C(20)
      C(34)) and triterpenoids (lupeol, beta- and alpha-amyrin). Besides, a series of n
      alkane-1,3-diols was detected, with chain lengths ranging from C(22) to C(28), a
      strong predominance of even-numbered homologs, and a maximum for hexacosane-1,3
      diol. Seven other compounds were assigned to a novel class of wax constituents
      and identified as homologous unbranched 3-hydroxyaldehydes ranging from C(22) to
      C(28). As the chain length distribution of this series closely paralleled the
      homolog pattern of 1,3-diols, it seems likely that both compound classes are
      biosynthetically related.

PMID- 12620357
TI  - Volatile components of selected species of the liverwort genera Frullania and
      Schusterella (Frullaniaceae) from New Zealand, Australia and South America: a
      chemosystematic approach.
AB  - The volatile components of 25 taxa of the liverwort family Frullaniaceae from New
      Zealand, Australia and South America have been analyzed by GC-MS. The present
      Frullania species are chemically divided into five major types: (1) sesquiterpene
      lactones, (2) sesquiterpene lactones-bibenzyls, (3) bibenzyls, (4) 2-alkanone and
      (5) triterpene types; the latter two chemo-types are newly proposed for the
      genus. Schusterella chevalierii, belonging to the Frullaniaceae, is closely
      related chemically to the sesquiterpene lactone type of the Frullania species
      since it elaborates two eudesmanolides, beta-cyclocostunolide and dihydro-beta
      cyclocostunolide as major components.

PMID- 12620358
TI  - Regulation of phytochelatin synthesis by zinc and cadmium in marine green alga,
      Dunaliella tertiolecta.
AB  - Although Cd(2+) is a more effective inducer of phytochelatin (PC) synthesis than
      Zn(2+) in higher plants, we have observed greater induction of PC synthesis by
      Zn(2+) than Cd(2+) in the marine green alga, Dunaliella tertiolecta. To elucidate
      this unique regulation of PC synthesis by Zn(2+), we investigated the effects of
      Zn(2+) and Cd(2+) on the activities of both phytochelatin synthase (PC synthase)
      and enzymes in the GSH biosynthetic pathway. PC synthase was more strongly
      activated by Cd(2+) than by Zn(2+), but the difference was not very big. On the
      other hand, gamma-glutamylcysteine synthetase (gamma-ECS) and glutathione
      synthetase (GS) were activated by both heavy metals, but their activities were
      higher in Zn-treated cells than in Cd-treated cells. Dose-dependent stimulation
      of intracellular reactive oxygen species (ROS) production was observed with
      Zn(2+), but not Cd(2+) treatment. These results suggest that Zn(2+) strongly
      promotes the synthesis of GSH through indirect activation of gamma-ECS and GS by
      stimulating ROS generation. This acceleration of the flux rate for GSH synthesis
      might mainly contribute to high level PC synthesis.

PMID- 12620359
TI  - Metabolite profiling of alkaloids and strictosidine synthase activity in
      camptothecin producing plants.
AB  - Camptothecin derivatives are clinically used anti-neoplastic alkaloids that
      biogenetically belong to monoterpenoid indole alkaloids. Camptothecin-related
      alkaloids from the methanol extracts of Ophiorrhiza pumila, Camptotheca acuminata
      and Nothapodytes foetida plants were profiled and identified using a reverse
      phase high performance liquid chromatography coupled with on-line photodiode
      array detection and electrospray-ionization ion-trap mass spectrometry. A natural
      10-glycosyloxy camptothecin, chaboside, was accumulated in tissues of O. pumila
      but not in C. acuminata and N. foetida. Anthraquinones regarded as phytoalexins
      were present in the extracts of hairy roots and calli but not in the
      differentiated plants of O. pumila. These findings demonstrated a remarkable
      difference in the constituents between the differentiated plants and the hairy
      roots or calli tissues. The activity of strictosidine synthase, a key enzyme of
      camptothecin biosynthesis, was detected in the protein extracts of stems and
      roots of O. pumila, being correlated with the pattern of strictosidine synthase
      mRNA expression.

PMID- 12620361
TI  - Thalictrum minus cell cultures and ABC-like transporter.
AB  - Cultured Thalictrum minus cells produce a benzylisoquinoline alkaloid, berberine,
      in the presence of benzyladenine, and excrete it into the culture medium. T.
      minus cells excluded berberine, even if berberine was exogenously added to the
      medium, without benzyladenine treatment. Similarly, T. minus cells excluded a
      heterocyclic dye (neutral red) and calcein AM, which is used as a fluorescent
      probe to detect the drug efflux pump activity by ABC transporters. The addition
      of several inhibitors of P-glycoprotein, a representative ABC transporter,
      induced the accumulation in of both berberine and calcein AM ATP-dependent
      manner. The expression of P-glycoprotein-like ABC transporter genes was also
      demonstrated. The involvement of ABC transporter in the secretion of berberine in
      T. minus cells is discussed.

PMID- 12620360
TI  - Variation of glucosinolate accumulation among different organs and developmental
      stages of Arabidopsis thaliana.
AB  - The glucosinolate content of various organs of the model plant Arabidopsis
      thaliana (L.) Heynh., Columbia (Col-0) ecotype, was analyzed at different stages
      during its life cycle. Significant differences were noted among organs in both
      glucosinolate concentration and composition. Dormant and germinating seeds had
      the highest concentration (2.5-3.3% by dry weight), followed by inflorescences,
      siliques (fruits), leaves and roots. While aliphatic glucosinolates predominated
      in most organs, indole glucosinolates made up nearly half of the total
      composition in roots and late-stage rosette leaves. Seeds had a very distinctive
      glucosinolate composition. They possessed much higher concentrations of several
      types of aliphatic glucosinolates than other organs, including methylthioalkyl
      and, hydroxyalkyl glucosinolates and compounds with benzoate esters than other
      organs. From a developmental perspective, older leaves had lower glucosinolate
      concentrations than younger leaves, but this was not due to decreasing
      concentrations in individual leaves with age (glucosinolate concentration was
      stable during leaf expansion). Rather, leaves initiated earlier in development
      simply had much lower rates of glucosinolate accumulation per dry weight gain
      throughout their lifetimes. During seed germination and leaf senescence, there
      were significant declines in glucosinolate concentration. The physiological and
      ecological significance of these findings is briefly discussed.

PMID- 12620362
TI  - Selective desensitization of jasmonate- and pH-dependent signaling in the
      induction of benzophenanthridine biosynthesis in cells of Eschscholzia
      californica.
AB  - The biosynthesis of benzophenanthridine alkaloids, phytoalexins of Eschscholzia
      californica, in cultured cells can be induced by a glycoprotein preparation from
      yeast, methyljasmonate, artificial acidification with permeant acids, or mild
      osmotic stress. Each of these stimuli strongly attenuated the subsequent response
      to the same stimulus (homologous desensitization). Elicitor contact and
      artificial acidification mutually desensitized the cells for either signal. In
      contrast, elicitor-treated cells maintained their responsiveness to
      methyljasmonate or hyperosmolarity (sorbitol). Elicitor concentrations that
      nearly saturated the alkaloid response did not cause a detectable increase of
      jasmonate content. Transient acidification of the cytoplasm is a necessary step
      of signaling by low elicitor concentrations but was not detectable after
      jasmonate treatment. Seen together, the data indicate the existence of a
      jasmonate-dependent and jasmonate-independent (Delta pH controlled) signal
      pathway towards the expression of benzophenanthridine biosynthesis. Selective
      desensitization allows either stimulus to activate a distinct share of the
      biosynthetic capacity of the cell and limits the accumulation of toxic defense
      metabolites.

PMID- 12620364
TI  - A family of polyketide synthase genes expressed in ripening Rubus fruits.
AB  - Quality traits of raspberry fruits such as aroma and color derive in part from
      the polyketide derivatives, benzalacetone and dihydrochalcone, respectively. The
      formation of these metabolites during fruit ripening is the result of the
      activity of polyketide synthases (PKS), benzalcetone synthase and chalcone
      synthase (CHS), during fruit development. To gain an understanding of the
      regulation of these multiple PKSs during fruit ripening, we have characterized
      the repertoire of Rubus PKS genes and studied their expression patterns during
      fruit ripening. Using a PCR-based homology search, a family of ten PKS genes
      (Ripks1-10) sharing 82-98% nucleotide sequence identity was identified in the
      Rubus idaeus genome. Low stringency screening of a ripening fruit-specific cDNA
      library, identified three groups of PKS cDNAs. Group 1 and 2 cDNAs were also
      represented in the PCR amplified products, while group 3 represented a new class
      of Rubus PKS gene. The Rubus PKS gene-family thus consists of at least eleven
      members. The three cDNAs exhibit distinct tissue-specific and developmentally
      regulated patterns of expression. RiPKS5 has high constitutive levels of
      expression in all organs, including developing flowers and fruits, while RiPKS6
      and RiPKS11 expression is consistent with developmental and tissue-specific
      regulation in various organs. The recombinant proteins encoded by the three RiPKS
      cDNAs showed a typical CHS-type PKS activity. While phylogenetic analysis placed
      the three Rubus PKSs in one cluster, suggesting a recent duplication event, their
      distinct expression patterns suggest that their regulation, and thus function(s),
      has evolved independently of the structural genes themselves.

PMID- 12620363
TI  - [13C]-Specific labeling of 8-2' linked (-)-cis-blechnic, (-)-trans-blechnic and (
      )-brainic acids in the fern Blechnum spicant.
AB  - In vivo administration experiments using stable (13C) and radio (14C) labeled
      precursors established that the optically active 8-2' linked lignans, (-)-cis
      blechnic, (-)-trans-blechnic and (-)-trans-brainic acids, were directly derived
      from L-phenylalanine, cinnamate, and p-coumarate but not either from tyrosine or
      acetate. The radiochemical time course data suggest that the initial coupling
      product is (-)-cis-blechnic acid, which is then apparently converted into both (
      )-trans-blechnic and (-)-trans-brainic acids in vivo. These findings provide
      additional evidence for vascular plant proteins engendering distinct but specific
      phenolic radical-radical coupling modes, i.e., for full control over
      phenylpropanoid coupling in vivo, whether stereoselective or regiospecific.

PMID- 12620365
TI  - Allometric analysis of the induced flavonols on the leaf surface of wild tobacco
      (Nicotiana attenuata).
AB  - Trichomes excrete secondary metabolites that may alter the chemical composition
      of the leaf surface, reducing damage caused by herbivores, pathogens and abiotic
      stresses. We examined the surface exudates produced by Nicotiana attenuata Torr.
      Ex Wats., a plant known to contain and secrete a number of secondary metabolites
      that are toxic or a deterrent to herbivorous insects. Extractions specific to the
      leaf surface, the trichomes, and the laminar components demonstrated the
      localization of particular compounds. Diterpene glycosides occurred exclusively
      in leaf mesophyll, whereas nicotine was found in both the trichomes and
      mesophyll. Neither rutin nor nicotine was found on the leaf surface. Quercetin
      and 7 methylated derivatives were found in the glandular trichomes and appeared
      to be excreted onto the leaf surface. We examined the elicitation of these
      flavonols on the leaf surface with a surface-area allometric analysis, which
      measures changes in metabolites independent of the effects of leaf expansion. The
      flavonols responded differently to wounding, methyl jasmonate (MeJA), herbivore
      attack and UV-C radiation, and the response patterns corresponded to their
      compound-specific allometries. Finding greater amounts of quercetin on younger
      leaves and reduced amounts after herbivore feeding and MeJA treatment, we
      hypothesized that quercetin may function as an attractant, helping the insects
      locate a preferred feeding site. Consistent with this hypothesis, mirids
      (Tupiocoris notatus) were found more often on mature leaves sprayed with
      quercetin at a concentration typical of young leaves than on unsupplemented
      mature leaves. The composition of metabolites on the leaf surface of N. attenuata
      changes throughout leaf development and in response to herbivore attack or
      environmental stress, and these changes are mediated in part by responses of the
      glandular trichomes.

PMID- 12620366
TI  - Repeated episodes of ozone inhalation attenuates airway injury/repair and release
      of substance P, but not adaptation.
AB  - To determine the impact of repeated episodes of ozone exposure on physiologic
      adaptation, epithelial injury/repair, and tracheal substance P levels, adult rats
      were subjected to episodes of ozone (5 days, 1 ppm, 8 h/day) followed by 9 days
      of filtered air for four cycles. Rats were sampled on days 1 and 5 of each
      episode and 9 days after day 5 of episodes 1, 2, and 4. One hour before being
      euthanized each rat was injected with 5-bromo-2'-deoxyuridine to label
      proliferating cells. Each 5-day episode showed a characteristic pattern of rapid
      shallow breathing (days 1 and 2), epithelial injury, and interstitial and
      intraluminal inflammation. In contrast, the neutrophil component of inflammation,
      tracheal substance P release, and cell proliferation became attenuated with each
      consecutive episode of exposure. Concurrent with this cyclic and attenuated
      response there was progressive hypercellularity and hyperplasia in all airways
      studied and a progressive remodeling present in the terminal bronchioles. Our
      findings are consistent with the notion that the cumulative distal airway lesion
      is at least in part the result of a depressed cell proliferative response to
      injury in these airways. This depressed cell proliferative response may be in
      part the result of diminished neutrophil inflammation and/or release of mitogenic
      neuropeptides in response to ozone-induced injury.

PMID- 12620367
TI  - CYP-specific bioactivation of four organophosphorothioate pesticides by human
      liver microsomes.
AB  - The bioactivation of azinphos-methyl (AZIN), chlorpyrifos (CPF), diazinon (DIA),
      and parathion (PAR), four widely used organophosphorothioate (OPT) pesticides has
      been investigated in human liver microsomes (HLM). In addition, the role of human
      cytochrome P450 (CYPs) in OPT desulfuration at pesticide levels representative of
      human exposure have been defined by means of correlation and immunoinhibition
      studies. CYP-mediated oxon formation from the four OPTs is efficiently catalyzed
      by HLM, although showing a high variability (>40-fold) among samples. Two
      distinct phases were involved in the desulfuration of AZIN, DIA, and PAR,
      characterized by different affinity constants (K(mapp1) = 0.13-9 microM and
      K(mapp2) = 5- 269 microM). Within the range of CPF concentrations tested, only
      the high-affinity component was evidenced (K(mapp1) = 0.27-0.94 microM). Oxon
      formation in phenotyped individual HLM showed a significant correlation with
      CYP1A2-, 3A4-, and 2B6-related activities, at different levels depending on the
      OPT concentration. Anti-human CYP1A2, 2B6, and 3A4 antibodies significantly
      inhibited oxon formation, showing the same OPT concentration dependence. Our data
      indicated that CYP1A2 is mainly involved in OPT desulfuration at low pesticide
      concentrations, while the role of CYP3A4 is more significant to the low-affinity
      component of OPT bioactivation. The contribution of CYP2B6 to total hepatic oxon
      formation was relevant in a wide range of pesticide concentrations, being a very
      efficient catalyst of both the high- and low-affinity phase. These results
      suggest CYP1A2 and 2B6 as possible metabolic biomarkers of susceptibility to OPT
      toxic effect at the actual human exposure levels.

PMID- 12620368
TI  - Toxic carriers in pepper sprays may cause corneal erosion.
AB  - We describe four patients who developed corneal erosion after an exposure to a
      pepper spray containing toxic carriers. Two of these patients were exposed to a
      pepper gas containing 5% oleoresin capsicum (OC) as an irritant and 92%
      trichlorethylene or unknown amount of dichloromethane as a carrier. One patient
      was exposed to a mock (containing 92% trichlorethylene as a carrier) training
      pepper gas without OC. The fourth patient was exposed to an unidentified Russian
      pepper gas spray. Two of the patients were examined by in vivo confocal
      microscopy to demonstrate the depth and quality of the stromal damage. To test
      the toxicity of the commercial tear spray, it was analyzed and test sprayed on a
      soft contact lens and into a plastic cup. Visual acuity was measured and the eyes
      were examined with a slit-lamp up to 5 months. Physical damage to a soft contact
      lens was visually acquired. All patients showed a long-lasting, deep corneal and
      conjuctival erosion, which resolved partly with medical therapy during the
      following weeks/months. Confocal microscopy revealed corneal nerve damage, and
      keratocyte activation reaching two-thirds of stroma for one patient. The spray
      caused serious damage to both the soft contact lens and the plastic cup. The
      safety of the commercially available pepper sprays should be assessed before
      marketing, and a list of acceptable ingredients created. The sprays should also
      have instructions on the use of the compound as well as on the first aid measures
      after the exposure. Solvents known to be toxic should not be used.

PMID- 12620369
TI  - Molecular handling of cadmium in transporting epithelia.
AB  - Cadmium (Cd) is an industrial and environmental pollutant that affects adversely
      a number of organs in humans and other mammals, including the kidneys, liver,
      lungs, pancreas, testis, and placenta. The liver and kidneys, which are the
      primary organs involved in the elimination of systemic Cd, are especially
      sensitive to the toxic effects of Cd. Because Cd ions possess a high affinity for
      sulfhydryl groups and thiolate anions, the cellular and molecular mechanisms
      involved in the handling and toxicity of Cd in target organs can be defined
      largely by the molecular interactions that occur between Cd ions and various
      sulfhydryl-containing molecules that are present in both the intracellular and
      extracellular compartments. A great deal of scientific data have been collected
      over the years to better define the toxic effects of Cd in the primary target
      organs. Notwithstanding all of the new developments made and information
      gathered, it is surprising that very little is known about the cellular and
      molecular mechanisms involved in the uptake, retention, and elimination of Cd in
      target epithelial cells. Therefore, the primary purpose of this review is to
      summarize and put into perspective some of the more salient current findings,
      assertions, and hypotheses pertaining to the transport and handling of Cd in the
      epithelial cells of target organs. Particular attention has been placed on the
      molecular mechanisms involved in the absorption, retention, and secretion of Cd
      in small intestinal enterocytes, hepatocytes, and tubular epithelial cells lining
      both proximal and distal portions of the nephron. The purpose of this review is
      not only to provide a summary of published findings but also to provide
      speculations and testable hypotheses based on contemporary findings made in other
      areas of research, with the hope that they may promote and serve as the impetus
      for future investigations designed to define more precisely the cellular
      mechanisms involved in the transport and handling of Cd within the body.

PMID- 12620370
TI  - Sper/NO-induced reversible proliferation inhibition and cycle arrests associated
      with a micronucleus induction in HSG cells.
AB  - Nitric oxide (NO) is an important messenger molecule with multiple biological
      activities. In the present study, sper/NO, a NO generator, showed a biphasic
      effect on the proliferation of human salivary gland neoplastic (HSG) cells.
      Sper/NO of less than 20 micro M stimulated cells to depart from the G2/M phase
      and so enhanced cell division and cell proliferation. But sper/NO at higher
      concentrations restrained cell proliferation and blocked cell-cycle progression.
      Cells were mainly arrested in the G2/M phase and S phase when they were treated
      with 100-200 and 300-500 micro M sper/NO, respectively. A special S-phase peak
      was detected in a histogram of the cell-phase distribution of sper/NO-treated
      HSG. When the concentration of sper/NO increased, the S-phase peak shifted from
      early the G2/M-phase to later the G1-S-phase boundary. Sper/NO-induced cell-cycle
      arrests were reversible when the cells were released from NO stress for 48h and
      hence cell proliferation was recovered. In addition, micronucleus, but no
      apoptosis, was produced in the sper/NO-treated cells, and its yield tended to a
      saturation value with increasing concentrations of sper/NO. The sper/NO-induced
      effects were effectively eliminated or reduced by treating cells with PTIO, a NO
      specific scavenger, indicating that NO is the main source of these effects.

PMID- 12620371
TI  - Inhibition of cyclic guanosine 5'-monophosphate-dependent protein kinase I (PKG
      I) in lumbar spinal cord reduces formalin-induced hyperalgesia and PKG
      upregulation.
AB  - Nitric oxide-mediated nociception has been suggested to involve formation of
      cyclic guanosine 5'-monophosphate (cGMP) and activation of cGMP-dependent protein
      kinase (PKG). To further evaluate this pathway we assessed the effects of the PKG
      inhibiting cGMP analog Rp-8-Br-cGMPS in the rat formalin assay and analyzed the
      regulation of PKG expression in rat lumbar spinal cord. Spinally delivered Rp-8
      Br-cGMPS (0.1-0.5 micro mol i.t.) reduced the nociceptive behavior in a dose
      dependent manner. Similar effects were achieved with Rp-8-Br-PET-cGMPS (0.5 micro
      mol i.t.), another PKG-inhibitory cGMP analog. In contrast, Rp-8-Br-cAMPS (0.5
      micro mol i.t.), an inhibitor of protein kinase A, had no effect in this model.
      Formalin treatment resulted in a rapid (within 1h), long-lasting (up to 96h)
      upregulation of PKG-I protein expression. This increase was prevented in animals
      pretreated with Rp-8-Br-cGMPS (0.5 micro mol i.t.) or morphine (2.5-5mg/kg i.p.)
      10min prior to formalin injection. Spinal delivery of 8-Br-cGMP, a PKG-activating
      cGMP analog, without subsequent formalin treatment also caused an increase of PKG
      I protein expression. Hence, the upregulation of PKG-I might possibly be mediated
      by cGMP itself. Our data suggest that PKG-I activation is involved in the
      synaptic transmission of nociceptive stimuli in the spinal cord and that PKG-I
      inhibitors might be interesting novel drugs for pain treatment.

PMID- 12620372
TI  - Comparison of the signal transduction pathways for the induction of gene
      expression of nitric oxide synthase-2 in response to two different stimuli.
AB  - Human optic nerve astrocytes induce nitric oxide synthase-2 (NOS-2) in vitro in
      response to cytokines (interferon-gamma/interleukin-1beta) and elevated
      hydrostatic pressure. Using relatively specific inhibitors, we have compared
      induction of NOS-2 in response to these two stimuli to determine whether the same
      or different signal transduction pathways participate in the responses. Using
      SN50 and CAGE, which inhibit the NFkappaB pathway, the induction of NOS-2 in
      response to both cytokines and elevated hydrostatic pressure was blocked. Using
      SB202190 and SB203580, which inhibit p38 mitogen-activated protein kinase, only
      the response to cytokines was blocked. In contrast, when inhibitors of epidermal
      growth factor receptor tyrosine kinase AG 82 and AG 18 were used, the induction
      of NOS-2 in response to pressure, but not in response to cytokines, was blocked.
      Signal transduction pathways presumably regulate the synthesis of NOS-2 through
      downstream events that induce transcription of the NOS-2 gene. Our data suggest
      that activation of different sites in the promoter region of the NOS-2 gene is
      needed for these different stimuli to induce NOS-2.

PMID- 12620373
TI  - Mechanism-based partial inactivation of glutathione S-transferases by
      nitroglycerin: tyrosine nitration vs sulfhydryl oxidation.
AB  - Liver glutathione-S-transferases (GSTs) are responsible for the detoxification of
      electrophiles, and specifically for the metabolism of orally administered organic
      nitrates such as nitroglycerin (NTG). Recent studies showed that reactive
      nitrogen species produced by tetranitromethane (TNM), peroxynitrite, or the
      myeloperoxidase/H2O2/nitrite system can inactivate GST. It is not known whether
      NTG can similarly inactivate liver GSTs, and if shown, by what mechanism(s). We
      incubated purified GSTs with NTG, S-nitroso-N-acetylpenicillamine (SNAP), TNM, or
      vehicle (5% dextrose, D5W), followed by determination of GST activity. Incubation
      of GST with NTG and TNM caused significant decreases in GST activity whereas no
      changes were observed with SNAP or D5W. The relative GST activity (vs
      preincubation) was 73+/-14% for NTG, 37+/-8% for TNM, 98+/-13% for SNAP, and 98+/
      9% for D5W, respectively. Exogenous glutathione (GSH) prevented both NTG- and TNM
      induced changes in GST activity, consistent with the observed oxidative
      modification of GST, such as -SH oxidation and dimerization of oxidized GST. In
      contrast, NTG and TNM exhibited substantial differences in their ability to
      nitrate tyrosine (TYR) sites in GST. These results demonstrated that NTG can
      reduce the activity of its own metabolizing enzyme such as GST and this
      inhibitory effect of NTG was unlikely to be mediated through NO, as such, since
      SNAP had no effect on GST activity. The partial inactivation of GST by NTG
      appeared to involve -SH oxidation, but not TYR nitration. These findings provided
      the first evidence of mechanism-based protein inactivation by NTG, and may lend
      insight into the hepatic metabolism of NTG and other organic nitrates after
      repeated oral exposure.

PMID- 12620375
TI  - Overexpression of the human inducible nitric oxide synthase gene enhances
      radiation-induced apoptosis in colorectal cancer cells via a caspase-dependent
      mechanism.
AB  - Nitric oxide (NO) has been reported to sensitize cancer cells to radiation. Since
      delivery of NO to tumors is limited in vivo by systemic toxicity of NO, we
      examined the potential of gene delivery of the human inducible nitric oxide
      synthase (iNOS) gene as a means of achieving high output NO production. We
      successfully transduced two colorectal cancer cell lines as evidenced by
      increased iNOS protein accumulation and nitrite production. We found that
      overexpression of iNOS enhanced the effects of radiation on apoptosis in both
      cell lines in a caspase-dependent fashion. Gene transfer of iNOS holds much
      promise as a potential radiosensitizer of cancer cells since it increases
      apoptosis in an additive manner with radiation.

PMID- 12620374
TI  - Inducible nitric oxide synthase-mediated proliferation of a T lymphoma cell line.
AB  - Nitric oxide (NO)-derived from T lymphocytes in an autocrine fashion can modulate
      events in the cell. However, the exact role of NO on the control of lymphocyte
      growth is controversial since both stimulation and inhibition have been
      demonstrated. Nitric oxide synthase (NOS) activity in normal and tumor T
      lymphocyte proliferation was studied here. Resting normal T lymphocytes displayed
      low levels of NOS activity that were slightly increased upon mitogenic
      stimulation. In contrast, BW5147 T lymphoma cells displayed higher basal levels
      than normal T lymphocytes that were significantly augmented when induced to
      proliferate. This activity was slightly modified in the presence of the calcium
      chelator EGTA and was blocked by competitive and irreversible NOS inhibitors, as
      well as by selective blockers of iNOS. Furthermore, tumor but not normal cell
      proliferation was impaired by NOS and iNOS blockers, while a calcium blocker only
      affected normal cell growth. iNOS expression, both at the protein and at the mRNA
      levels, was demonstrated on growing BW5147 cells but not on arrested tumor or
      normal lymphocytes. The contribution of iNOS to sustained proliferation of tumor
      cells is discussed.

PMID- 12620376
TI  - Regulation of nitric oxide production from macrophages by lipopolysaccharide and
      catecholamines.
AB  - Catecholamines are elaborated in stress responses to mediate vasoconstriction,
      and elevate systemic vascular resistance and blood pressure. They are elaborated
      in disorders such as sepsis, cocaine abuse, and cardiovascular disease. The aim
      of the study was to determine whether catecholamines affect nitric oxide (NO)
      production, as NO is a vasodilator and counteracts the harmful effects of
      catecholamines. RAW264.7 macrophage cells were cultured with lipopolysaccharide
      (LPS)+/-epinephrine, norepinephrine, and dopamine at 5x10(-6)M concentrations for
      24h. Supernatants were harvested for measuring NO by spectrophotometry using the
      Greiss reagent and cells were harvested for detecting inducible NO synthase
      (iNOS) by Western blot. NO production in RAW 264.7 macrophages was increased
      significantly by addition of LPS (0.5-10ng/ml) in a dose-dependent fashion. The
      NO production induced by LPS was further enhanced by epinephrine and
      norepinephrine, and to a lesser extent by dopamine. These increases in NO
      correlated with expression of iNOS protein in these cells. The enhancing effect
      of iNOS synthesis by epinephrine and norepinephrine on LPS-induced macrophages
      was down regulated by beta-adrenoceptor antagonist, propranolol, and
      dexamethasone. The results suggest that catecholamines have a synergic effect on
      LPS in induction of iNOS synthesis and NO production, and this may mediate some
      of the vascular effects of infection. These data support a novel role for
      catecholamines in disorders such as septic shock and cocaine use, and indicate
      that beta-adrenoceptor antagonists and glucocorticoids may be used
      therapeutically for modulation of the catecholamine-NO axis in disease states.

PMID- 12620377
TI  - Role of nitric oxide in D-galactosamine-induced cell death and its protection by
      PGE1 in cultured hepatocytes.
AB  - Prostaglandin E(1) (PGE(1)) reduces cell death in experimental and clinical
      manifestations of liver dysfunction. Nitric oxide (NO) has been shown to exert a
      protective or noxious effect in different experimental models of liver injury.
      The aim of the present study was to investigate the role of NO during PGE(1)
      protection against D-galactosamine (D-GalN) citotoxicity in cultured hepatocytes.
      PGE(1) was preadministered to D-GalN-treated hepatocytes. The role of NO in our
      system was assessed by iNOS inhibition and a NO donor. Different parameters
      related to apoptosis and necrosis, NO production such as nitrite+nitrate (NO(x))
      release, iNOS expression, and NF-kappaB activation in hepatocytes were evaluated.
      The inhibition of iNOS reduced apoptosis induced by D-GalN in hepatocytes. PGE(1)
      protection against D-GalN injury was associated with its capacity to reduce iNOS
      expression and NO production induced by D-GalN. Nevertheless, iNOS inhibition
      showed that protection by PGE(1) was also mediated by NO. Low concentrations of a
      NO donor reduced D-GalN injury with a decrease in the extracellular NO(x)
      concentration. High concentrations of the NO donor enhanced NO(x) concentration
      and increased cell death by D-GalN. The present study suggests that low NO
      production induced by PGE(1) preadministration reduces D-GalN-induced cell death
      through its capacity to reduce iNOS expression and NO production caused by the
      hepatotoxin.

PMID- 12620378
TI  - Role of nitric oxide in radiation-induced initiation of mammary tumorigenesis in
      rats.
AB  - Nitric oxide (NO) and its reaction products have been shown to cause DNA damage
      and to be mutagenic. To elucidate whether NO produced by irradiation participates
      in the initiation of mammary tumorigenesis, we performed experiments using the
      nitric oxide-specific scavenger Fe(2+)-diethyldithiocarbamate complex
      (Fe(DETC)(2)) or a selective inhibitor for inducible nitric oxide synthase
      (iNOS), S,S(')-(4-phenylene-bis(1,2-ethanedinyl))bis-isothiourea (1,4-PB-ITU).
      Mother rats at day 21 of lactation were injected simultaneously with
      diethyldithiocarbamate intraperitoneally and Fe(2+)-citrate subcutaneously to
      form Fe(DETC)(2), in vivo, and then irradiated with 1.5Gy gamma-rays immediately
      after the injection. An additional injection of chemicals followed twice at 8 and
      24h after the irradiation in the same manner. Both control and treated rats were
      then implanted with diethylstilbestrol pellets as a tumor promoter. The mammary
      tumor incidence in the experimental group was significantly reduced to one-fourth
      of that in the irradiated-alone group as the control. On the other hand, when
      mother rats took drinking water containing 0.005% 1,4-PB-ITU for 6 days from 3
      days prior to irradiation at day 21 of lactation, a low tumor incidence in the
      iNOS inhibitor-treated groups was observed in the 1-year period. This report is
      the first to show that the NO derived from iNOS is an important radical for
      radiation-induced initiation of tumorigenesis of mammary glands in rats.

PMID- 12620379
TI  - Milk complement and the opsonophagocytosis and killing of Staphylococcus aureus
      mastitis isolates by bovine neutrophils.
AB  - Phagocytosis of bacteria by bovine polymorphonuclear neutrophils (PMN) has long
      been regarded as essential for host defense against mastitis infection.
      Complement-mediated opsonisation by complement component 3 (C3) binding is an
      important component of the innate immune system. We investigated the role of milk
      complement as an opsonin and its involvement in the phagocytosis and killing of
      Staphylococcus aureus isolates from cases of bovine mastitis by bovine blood PMN.
      We show that deposition of milk C3 component occurred on six different isolates
      of S. aureus and that the alternative pathway was the sole complement pathway
      operating in milk of uninflamed mammary gland. This deposition was shown to occur
      at the same location as the capsule, but not on capsular antigen. Milk complement
      enhanced the chemiluminescence response of PMN induced by S. aureus.
      Nevertheless, the association of S. aureus to cells and the overall killing of
      bacteria by bovine PMN were not affected by the presence of milk complement.
      Therefore, as all milk samples contained antibodies to capsular polysaccharide
      type 5 and to other surface antigens, it is likely that milk antibodies were
      responsible for these two phagocytic events. Results of this study suggest that
      the deposition of milk complement components on the surface of S. aureus does not
      contribute to the defence of the mammary gland against S. aureus.

PMID- 12620380
TI  - Differential expression of genes encoding membrane proteins between acute and
      continuous Chlamydia pneumoniae infections.
AB  - Chlamydia pneumoniae is associated with several chronic human diseases, including
      chronic obstructive pulmonary disease and atherosclerotic cardiovascular disease.
      During chronic disease, organisms are believed to exist in a persistent phase
      that is not well understood at the genetic level. Long-term in vitro continuous
      infections are spontaneously persistent and are less susceptible than in vitro
      acute infections to treatment with antibiotics, and are therefore particularly
      relevant as an in vitro model of in vivo chronic disease. Real-time reverse
      transcriptase-PCR (r-t RT-PCR) was used to quantitate transcript copy numbers of
      13 genes in continuous and acute infections with C. pneumoniae. The set of genes
      studied encodes proteins with known or predicted functions in the cell membrane,
      the inclusion membrane, cell division, metabolism, and immunopathology.
      Significant upregulation was seen for five genes (CPn0483, nlpD, ompA, pmp1 and
      porB) in continuous cultures. The genes omcB, pmp1, and porB, all of which encode
      membrane proteins, shared similar patterns of expression over both acute and
      continuous profiles. These results show that Chlamydia in the long-term
      continuous model of persistence have a unique transcription profile, adding to
      our knowledge of regulation of this important stage of chlamydial growth.

PMID- 12620381
TI  - Interleukin-1beta responses to Mycoplasma pneumoniae infection are cell-type
      specific.
AB  - Interleukin-1beta (IL-1beta) is a major proinflammatory cytokine that is involved
      in many important cellular functions such as proliferation, differentiation, and
      activation of different cell types. Its mature form is released from the cells in
      response to various bacterial and viral infections, and it plays a significant
      role in host defense. Mycoplasma pneumoniae is a small bacterium without a cell
      wall that causes tracheobronchitis and atypical pneumonia in humans following
      attachment to respiratory epithelium, as well as extrapulmonary infections. Very
      little is known about the role of cytokines in pathogenesis or the response of
      target cells to M.pneumoniae attachment. The purpose of this study was to
      investigate the ability of M. pneumoniae to induce IL-1beta in human lung
      epithelial carcinoma A549 and in human monocytic U937 cell lines. Following M.
      pneumoniae infection, both IL-1beta mRNA and protein were induced in A549 cells
      vs. no induction in uninfected cells; however, the protein remained inside the
      A549 cells. Similarly, M. pneumoniae infection strongly increased mRNA and
      extracellular protein levels in U937 cells, which unlike A549 cells did exhibit
      baseline constitutive levels. De novo IL-1beta protein expression was verified by
      cycloheximide studies. M. pneumoniae infection did not affect constitutive
      caspase-1 mRNA or protein levels in either cell line. Reduced caspase-1 activity
      in A549 cell lysates suggests the presence of an endogenous caspase-1 inhibitory
      component in the A549 cells. These collective data confirm previous studies that
      show that M. pneumoniae is a potent inducer of cytokines following adherence to
      host target cells, and establish that IL-1beta release in response to M.
      pneumoniae infection is cell-type specific, thus emphasizing the importance of
      carefully considering multiple cell types in M. pneumoniae pathogenesis studies
      involving both immune cells and cytokine release patterns.

PMID- 12620382
TI  - Role of suilysin in pathogenesis of Streptococcus suis capsular serotype 2.
AB  - Three suilysin (SLY) knockout mutant strains of Streptococcus suis serotype 2
      were generated by allelic replacement from one North American and two European
      wild type strains. The mutants were characterized by Southern blot, Western blot
      and phenotyping. In vitro bactericidal testing showed that both wild type and SLY
      mutants were resistant to bactericidal factors in whole pig blood. To demonstrate
      the role of SLY during S. suis infection, four animal trials were carried out
      using young pigs. Either high dose (4 x 10(6)CFU/ml/pig) or low dose (0.5 x
      10(6)CFU/ml/pig) live cell aerosol was applied to the pharynx. In one trial, a
      low challenge dose of North American strain SX332 and its isogenic sly(-) mutant
      strain (SX932) resulted in acute disease in 3/5 of pigs exposed to the wild type
      strain, while 5/5 of pigs exposed to the mutant strain survived the trial. In the
      repeat trial, 1/8 of pigs in wild type group and 6/8 of pigs in mutant group
      developed disease. The high dose trial with 332/932 pair showed that 4/8 pigs
      challenged with wild type and 5/8 of pigs challenged with mutant strain developed
      disease respectively. The third low dose trial, using European strain 31533 and
      its isogenic sly(-) mutant strain SX911, showed that 1/8 of pigs challenged with
      the wild type strain and 4/8 of pigs challenged with the corresponding mutant
      strain developed disease. All the diseased pigs showed fever, clinical signs and
      developed septicemia. S. suis was isolated from tissue samples such as brain,
      submandibular lymph node, lung, spleen, liver, heart or joint. Serum antibody
      titer against cell surface proteins changed little while the antibody titer
      against SLY increased only in the wild type group after challenge. sly gene was
      cloned and expressed in E. coli. The recombinant SLY (rSLY) protein showed 800
      hemolysin units per microg protein. In vitro study showed that rSLY triggered
      TNFalpha production by human monocytes and IL-6 production by pig pulmonary
      alveolar macrophages and monocytes. Thus, the results of this study suggest that
      SLY does not seem to be a critical virulence factor for S. suis serotype 2
      respiratory infection, but by stimulating cytokine release it may play a role in
      innate immunity.

PMID- 12620383
TI  - Mice intradermally-inoculated with the intact lipopolysaccharide, but not the
      lipid A or O-chain, from Francisella tularensis LVS rapidly acquire varying
      degrees of enhanced resistance against systemic or aerogenic challenge with
      virulent strains of the pathogen.
AB  - The present study examines the relationship between the structure and important
      biological effects of the lipopolysaccharide (LPS) of the intracellular bacterial
      pathogen, Francisella tularensis LVS. It shows that treating mice with sub
      immunogenic amounts of intact F. tularensis LPS rapidly induces an enhanced
      resistance to intradermal or aerogenic challenge with strains of the pathogen of
      varying virulence. However, neither the free Lipid A nor core-O-chain produced by
      mild acid hydrolysis of LPS appeared able to elicit this host defense mechanism.

PMID- 12620384
TI  - Elastase-producing Pseudomonas aeruginosa degrade plasma proteins and
      extracellular products of human skin and fibroblasts, and inhibit fibroblast
      growth.
AB  - Leg ulcers of venous origin represent a disease affecting 0.1-0.2% of the
      population. It is known that almost all chronic ulcers are colonized by different
      bacteria, such as staphylococci, enterococci and Pseudomonas aeruginosa. We here
      report that P. aeruginosa, expressing the major metalloproteinase elastase,
      induces degradation of complement C3, various antiproteinases, kininogens,
      fibroblast proteins, and proteoglycans (PG) in vitro, thus mimicking proteolytic
      activity previously identified in chronic ulcer fluid in vivo. Elastase-producing
      P. aeruginosa isolates were shown to significantly degrade human wound fluid as
      well as human skin proteins ex vivo. Elastase-containing conditioned P.
      aeruginosa medium and purified elastase inhibited fibroblast cell growth. These
      effects, in conjunction with the finding that proteinase production was detected
      in wound fluid ex vivo, suggest that bacterial proteinases play a pathogenic role
      in chronic ulcers.

PMID- 12620385
TI  - Characterization of the human common fragile site FRA2G.
AB  - Common fragile sites are nonrandom loci that show gaps and breaks when cells are
      exposed to specific compounds. They are preferentially involved in recombination,
      chromosomal rearrangements, and foreign DNA integration. These sites have been
      suggested to play a role in chromosome instability observed in cancer. In this
      work we used a FISH-based approach to identify a BAC contig that spans the FRA2G
      fragile site located at the 2q31 region. Our observations indicate that a very
      fragile region spanning at least 450 kb is present within a large fragile region
      that extends over 1 Mb. At least seven genes are mapped in the fragile region.
      One of these seems to be a good candidate as a potential tumor suppressor gene
      impaired by the recurrent deletions observed at the 2q31 region in some
      neoplasms. In the fragile region, a considerable number of regions of high
      flexibility that may be related to the fragility are present.

PMID- 12620386
TI  - Global functional profiling of gene expression.
AB  - The typical result of a microarray experiment is a list of tens or hundreds of
      genes found to be differentially regulated in the condition under study.
      Independent of the methods used to select these genes, the common task faced by
      any researcher is to translate these lists of genes into a better understanding
      of the biological phenomena involved. Currently, this is done through a tedious
      combination of searches through the literature and a number of public databases.
      We developed Onto-Express (OE) as a novel tool able to automatically translate
      such lists of differentially regulated genes into functional profiles
      characterizing the impact of the condition studied. OE constructs functional
      profiles (using Gene Ontology terms) for the following categories: biochemical
      function, biological process, cellular role, cellular component, molecular
      function, and chromosome location. Statistical significance values are calculated
      for each category. We demonstrate the validity and the utility of this
      comprehensive global analysis of gene function by analyzing two breast cancer
      datasets from two separate laboratories. OE was able to identify correctly all
      biological processes postulated by the original authors, as well as discover
      novel relevant mechanisms.

PMID- 12620387
TI  - Candidate tumor suppressor genes at FRA7G are coamplified with MET and do not
      suppress malignancy in a gastric cancer.
AB  - Common fragile sites predispose to specific chromosomal breakage associated with
      deletion, amplification, and/or translocation in certain forms of cancer.
      Chromosomal fragile sites not only are susceptible to DNA instability in cancer
      cells, but may also be associated with genes that contribute to the neoplastic
      process. FRA7G is a common fragile site containing the candidate tumor suppressor
      genes CAV1, CAV2, and TESTIN (TES). The human gastric cancer cell line GTL-16 has
      an amplification of this genomic region and was used to seek evidence for the
      suppressor candidacy of one of these genes. Our results demonstrate that CAV1,
      CAV2, and TESTIN are coamplified with the MET oncogene and overexpressed in GTL
      16. Somatic mutation was not detected in the coding regions of these genes,
      although they were each overexpressed. The results show that CAV1, CAV2, and
      TESTIN are not tumor suppressor genes in this gastric cancer.

PMID- 12620388
TI  - Transposition of the Drosophila hydei Minos transposon in the mouse germ line.
AB  - We tested the suitability of the fly transposon Minos, a member of the
      Tc1/mariner superfamily, for insertional mutagenesis in the mouse germ line. We
      generated a transgenic mouse line expressing Minos transposase in growing oocytes
      and another carrying a tandem array of nonautonomous transposons. The frequency
      of transposition in the progeny derived from oocytes carrying both transgenes is
      8.2%. Analysis of the new integration sites shows a high frequency of
      transpositions to a different chromosome. Thus Minos transposition could be an
      effective system for insertional mutagenesis and functional genomic analysis in
      the mouse.

PMID- 12620389
TI  - Novel raf kinase protein-protein interactions found by an exhaustive yeast two
      hybrid analysis.
AB  - We have performed an exhaustive unbiased yeast two-hybrid analysis to identify
      interaction partners of two human Raf kinase isoforms, A-Raf and C-Raf, using
      their N-terminal regulatory domain as "bait." A total of 20 different human
      proteins were found to interact with Raf isoforms. Several of these interactions
      were novel and an extensive bioinformatics evaluation was performed for each. The
      novel putative interactions include a signalosome component, TOPK/PBK kinase, and
      two new putative protein phosphatases. The cysteine-rich zinc-binding domain
      (CRD) of Raf was found to interact with all 20 proteins and to achieve isoform
      specific interactions. Since similar putative CRDs are present in a variety of
      protein serine-threonine kinases, the data suggest that the CRD may function as a
      major protein-protein interaction domain of these kinases. We propose possible
      functional consequences of these novel Raf interactions.

PMID- 12620390
TI  - Genomic definition of RIM proteins: evolutionary amplification of a family of
      synaptic regulatory proteins.
AB  - RIMs are synaptic proteins that are essential for normal neurotransmitter
      release. We now show that while invertebrates contain only a single RIM gene,
      vertebrates contain four: two large genes encoding RIM1alpha (0.50 Mb) or
      RIM2alpha, 2beta, and 2gamma (0.50-0.75 Mb) and two smaller genes encoding
      RIM3gamma (14 kb) or RIM4gamma (55 kb). RIM1alpha and RIM2alpha consist of an N
      terminal Zn(2+)-finger domain, central PDZ and C(2)A domains, and a C-terminal
      C(2)B domain; RIM2beta consists of a short beta-specific sequence followed by
      central PDZ and C(2)A domains and a C-terminal C(2)B domain; and RIM2gamma,
      3gamma, and 4gamma consist of only a C(2)B domain. In the RIM2 gene, RIM2beta and
      2gamma are transcribed from internal promoters. alpha- and beta-RIMs are
      extensively alternatively spliced at three canonical positions, resulting in >200
      variants that differ by up to 400 residues. Thus gene duplication, alternative
      splicing, and multiple promoters diversify a single invertebrate RIM into a large
      vertebrate protein family. The multiplicity of vertebrate RIMs may serve to fine
      tune neurotransmitter release beyond a fundamental, evolutionarily conserved, and
      common function for RIMs.

PMID- 12620391
TI  - Radiation hybrid map, physical map, and low-pass genomic sequence of the canine
      prcd region on CFA9 and comparative mapping with the syntenic region on human
      chromosome 17.
AB  - Progressive rod-cone degeneration (prcd) is a canine retinal disease that maps to
      the centromeric end of CFA9 in a region of synteny with the distal part of
      HSA17q. As such, prcd has been postulated as the only animal model of RP17, a
      human retinitis pigmentosa locus that maps to 17q22. In an effort to establish
      more detailed regions of synteny between dog CFA9 and the HSA17q-ter region, we
      created a robust gene-enriched CFA9-RH08(3000) map with 34 gene-based markers and
      12 microsatellites, with the highest resolution and number of markers for the
      centromeric end of CFA9. Furthermore, we built an approximately 1.5-Mb physical
      map containing both GRB2 and GALK1, genes so far identified by meiotic linkage
      analysis as being closest to the prcd locus, and generated about 1.2 Mb low-pass
      (3.2x) canine sequence. Canine to human comparative sequence analysis identified
      49 transcripts that had been previously mapped to the HSA17q25 region. The
      generated low-pass canine sequence was annotated with a working draft of human
      sequence from HSA17q25, and we used this scaffold to order and orient the canine
      sequence against human. This order and orientation are preliminary, as high
      throughput genomic sequencing of HSA17q-ter has not been fully completed.

PMID- 12620392
TI  - Human-specific subfamilies of HERV-K (HML-2) long terminal repeats: three master
      genes were active simultaneously during branching of hominoid lineages.
AB  - Using 40 known human-specific LTR sequences, we have derived a consensus sequence
      for an evolutionary young HERV-K (HML-2) LTR family, which was named the HS
      family. In the human genome the HS family is represented by approximately 150-160
      LTR sequences, 90% of them being human-specific (hs). The family can be
      subdivided into two subfamilies differing in five linked nucleotide
      substitutions: HS-a and HS-b of 5.8 and 10.3 Myr evolutionary ages, respectively.
      The HS-b subfamily members were transpositionally active both before the
      divergence of the human and chimpanzee ancestor lineages and after it in both
      lineages. The HS-a subfamily comprises only hs LTRs. These and other data
      strongly suggest that at least three "master genes" of HERV-K (HML-2) LTRs were
      active in the human ancestor lineage after the human-chimpanzee divergence. We
      also found hs HERV-K (HML-2) LTRs integrations in introns of 12 human genes and
      identified 13 new hs HERV-K (HML-2) LTRs.

PMID- 12620393
TI  - Error-correcting microarray design.
AB  - We describe a microarray design based on the concept of error-correcting codes
      from digital communication theory. Currently, microarrays are unable to
      efficiently deal with "drop-outs," when one or more spots on the array are
      corrupted. The resulting information loss may lead to decoding errors in which no
      quantitation of expression can be extracted for the corresponding genes. This
      issue is expected to become increasingly problematic as the number of spots on
      microarrays expands to accommodate the entire genome. The error-correcting
      approach employs multiplexing (encoding) of more than one gene onto each spot to
      efficiently provide robustness to drop-outs in the array. Decoding then allows
      fault-tolerant recovery of the expression information from individual genes. The
      error-correcting method is general and may have important implications for future
      array designs in research and diagnostics.

PMID- 12620394
TI  - High-throughput analysis of informative CYP2D6 compound haplotypes.
AB  - We describe a high-throughput protocol for detecting key polymorphisms in the
      drug-metabolizing enzyme gene CYP2D6 and a number of linked microsatellites that
      is both fast and relatively inexpensive to perform. This approach employs
      GeneScan technology to enable a researcher to determine rapidly the status of
      seven simple nucleotide polymorphisms in CYP2D6 and also to assay repeat number
      variation at five closely linked dinucleotide microsatellite loci. The method
      requires only three PCRs and two GeneScan runs per sample. We anticipate that
      this will be of value to researchers in three different ways: (1) rapid
      discrimination of common CYP2D6 alleles, (2) high-resolution haplotyping for
      association studies involving chromosome 22q13.1 using microsatellite variation,
      and (3) generation of compound haplotypes for investigating the evolution of
      CYP2D6 variation. We also report compound haplotype frequencies for an Ashkenazi
      Jewish and a British sample.

PMID- 12620395
TI  - Distribution of new human beta-defensin genes clustered on chromosome 20 in
      functionally different segments of epididymis.
AB  - Human beta-defensins are a family of cationic peptides that share a pattern of
      six conserved cysteine residues. We describe the cloning and characterization of
      the cDNAs of five novel beta-defensin genes (DEFB25-DEFB29) clustered on
      chromosome 20p13, which were identified using a bioinformatics approach.
      Expression analysis revealed the occurrence of the transcripts in only a few
      organs, with the highest abundance in the male genital tract. Examination of beta
      defensin expression in human epididymis by real-time quantitative RT-PCR revealed
      a distribution along the functionally different segments of the epididymal duct.
      In situ hybridization for one of the cDNAs shows mRNA restriction to the
      epithelial cell layer of the epididymis, known to secrete factors responsible for
      sperm maturation. We suggest that the novel peptides carry out physiological
      functions in the male genital tract that may not be directly related to bacterial
      growth inhibition in host defense.

PMID- 12620396
TI  - The structure and evolution of the melanocortin and MCH receptors in fish and
      mammals.
AB  - Zebrafish are an excellent genetic model system for studying developmental and
      physiological processes. Pigment patterns in zebrafish are affected by mutations
      in three types of chromatophores. The behavior of these cells is influenced by
      alpha-melanocyte-stimulating hormone (alphaMSH) and melanin-concentrating hormone
      (MCH). Mammals have five alphaMSH receptors (melanocortin receptors) and one or
      two MCH receptors. We have identified the full complement of melanocortin and MCH
      receptors in both zebrafish and the pufferfish, Fugu. Zebrafish have six
      melanocortin receptors, including two MC5R orthologues, while Fugu, lacking MC3R,
      has only four. We also demonstrate that Fugu and zebrafish have two and three
      MCHR genes, respectively. MC2R and MC5R are physically linked in all species
      examined. Unlike other species, we find the Fugu genes contain introns, one of
      which is in a conserved location and is probably ancestral. We also detail the
      differential expression of the zebrafish genes throughout development.

PMID- 12620397
TI  - Molecular cloning, genomic structure and interactions of the putative breast
      tumor suppressor TACC2.
AB  - The human transforming acidic coiled-coil 2 (TACC2) gene has been suggested
      recently to be a putative breast tumor suppressor. Now we can report the cloning
      of full length TACC2 cDNAs corresponding to the major isoforms expressed during
      development. The TACC2 gene is encoded by 23 exons, and spans 255 kb of
      chromosome 10q26. In breast cancer cell lines, TACC2 is expressed as a 120 kDa
      protein corresponding to the major transcript expressed in the mammary gland.
      Although only slight differences in the expression of TACC2 in normal versus
      breast tumors were observed, overexpression of TACC2 can alter the in vitro
      cellular dynamics of some breast cancer cell lines. Significantly, we demonstrate
      that TACC2 interacts with GAS41 and the SWI/SNF chromatin remodeling complex.
      This suggests that defects in TACC2 expression may affect gene regulation, thus
      contributing to the pathogenesis of some tumors.

PMID- 12620398
TI  - Receiver operating characteristic analysis: a general tool for DNA array data
      filtration and performance estimation.
AB  - A critical step for DNA array analysis is data filtration, which can reduce
      thousands of detected signals to limited sets of genes. Commonly accepted rules
      for such filtration are still absent. We present a rational approach, based on
      thresholding of intensities with cutoff levels that are estimated by receiver
      operating characteristic (ROC) analysis. The technique compares test results with
      known distributions of positive and negative signals. We apply the method to
      Atlas cDNA arrays, GeneFilters, and Affymetrix GeneChip. ROC analysis
      demonstrates similarities in the distribution of false and true positive data for
      these different systems. We illustrate the estimation of an optimal cutoff level
      for intensity-based filtration, providing the highest ratio of true to false
      signals. For GeneChip arrays, we derived filtration thresholds consistent with
      the reported data based on replicate hybridizations. Intensity-based filtration
      optimized with ROC combined with other types of filtration (for example, based on
      significances of differences and/or ratios), should improve DNA array analysis.
      ROC methodology is also demonstrated for comparison of the performance of
      different types of arrays, imagers, and analysis software.

PMID- 12620399
TI  - Localization of a blood pressure QTL to a 2.4-cM interval on rat chromosome 9
      using congenic strains.
AB  - A blood pressure (BP) quantitative trait locus (QTL) was previously found on rat
      chromosome 9 using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. A
      congenic strain, S.R(chr9), constructed by introgressing an R chromosomal segment
      into the S background, previously proved the existence of a BP QTL in a large
      34.2-cM segment of chromosome 9. In the current work congenic substrains were
      constructed from the progenitor congenic strain, S.R(chr9). BP and heart weight
      comparisons between these congenic substrains and their S control localized the
      BP QTL to a 4.6-cM interval. Two solute carrier (Na(+)/H(+) exchanger) genes,
      Nhe2 and Nhe4, were excluded as candidates based on their map locations. A second
      iteration of congenic substrains was used to localize the QTL further to a 2.4-cM
      interval. Another solute carrier (Cl(-)/HCO3- exchanger) gene, Ae3, is in this
      reduced interval and was sequenced for both S and R strains, but no coding
      sequence variations were found. Ae3 mRNA was not differentially expressed in the
      kidney of congenic compared to S rats. Although the identity of the QTL remains
      unknown its map location has been reduced from an interval of 34.2 to 2.4 cM.

PMID- 12620400
TI  - Molecular cloning of the mouse AMY-1 gene and identification of the synergistic
      activation of the AMY-1 promoter by GATA-1 and Sp1.
AB  - We have reported that a novel c-Myc binding protein, AMY-1, stimulated the
      transcription activity of c-Myc and was translocated from the cytoplasm to the
      nucleus in a c-Myc-dependent manner. AMY-1 works as an inducer of human K562 cell
      differentiation upon induction of AraC. To characterize the expression or
      functional importance of AMY-1, the genomic DNA of mouse AMY-1 was cloned and
      characterized. Both mouse and human genomic DNAs, the latter of which was
      retrieved from a human DNA database, comprise five exons spanning about 11 kb. To
      characterize the promoter of the mouse AMY-1 gene, a series of deletion
      constructs of the region upstream of the first ATG was linked to the luciferase
      gene, and their luciferase activities were measured in human HeLa and K562 cells.
      The results showed that Sp1 was essential for AMY-1 expression in both cell lines
      and that GATA-1 is also necessary in K562 cells. Sp1 in both cell lines and GATA
      1 only in K562 cells were identified as proteins binding to these sites by a
      mobility shift assay. Furthermore, it was found that GATA-1 stimulated AMY-1
      expression synergistically with Sp1 in ectopically expressed insect cells and
      that both proteins were associated in K562 cells.

PMID- 12620401
TI  - In silico analysis of the EPS8 gene family: genomic organization, expression
      profile, and protein structure.
AB  - EPS8 codes for a protein essential in Ras to Rac signaling leading to actin
      remodeling. Three genes highly homologous to EPS8 were discovered, thereby
      defining a novel gene family. Here, we report the genomic structure of EPS8 and
      the EPS8-related genes in human and mouse. We performed BLASTN searches against
      the Celera Human Genome and Mouse Fragments Database. The mouse fragments were
      manually assembled, and the organization of both human and mouse genes was
      reconstructed. The gene structures in Celera annotations of the human and mouse
      genomes were compared to outline correspondences and divergences. We also
      compared the EPS8 family gene structures predicted by Celera with those predicted
      by NCBI. Moreover, we performed a virtual analysis of the expression of the EPS8
      gene family members by using the SAGEmap Database in NCBI. Finally, we analyzed
      the domain organization of the gene products and their evolutionary conservation
      to define novel putative domains, thereby helping to predict novel modality of
      action for the members of this gene family. The data obtained will be
      instrumental in directing further experimental functional characterization of
      these genes.

PMID- 12620402
TI  - PTEN and p53: who will get the upper hand?

PMID- 12620403
TI  - Expression arrays illuminate a way forward for mantle cell lymphoma.

PMID- 12620404
TI  - Oncogene at last--c-Jun promotes liver cancer in mice.

PMID- 12620405
TI  - Considering the cancer consequences of altered DNA polymerase function.
AB  - Our appreciation of the DNA transactions that replicate and maintain a stable
      human genome is changing rapidly due to recent discoveries indicating that
      eukaryotic cells contain many more DNA polymerases than previously thought. This
      review describes emerging information on the properties and functions of human
      DNA polymerases, with emphasis on connections between DNA polymerase functions
      and cancer.

PMID- 12620406
TI  - p27 as a target for cancer therapeutics.

PMID- 12620407
TI  - PTEN tumor suppressor regulates p53 protein levels and activity through
      phosphatase-dependent and -independent mechanisms.
AB  - We show in this study that PTEN regulates p53 protein levels and transcriptional
      activity through both phosphatase-dependent and -independent mechanisms. The
      onset of tumor development in p53(+/-);Pten(+/-) mice is similar to p53(-/-)
      animals, and p53 protein levels are dramatically reduced in Pten(-/-) cells and
      tissues. Reintroducing wild-type or phosphatase-dead PTEN mutants leads to a
      significant increase in p53 stability. PTEN also physically associates with
      endogenous p53. Finally, PTEN regulates the transcriptional activity of p53 by
      modulating its DNA binding activity. This study provides a novel mechanism by
      which the loss of PTEN can functionally control "two" hits in the course of tumor
      development by concurrently modulating p53 activity.

PMID- 12620408
TI  - Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes
      human endothelial cells by activation of the VEGF receptor-2/ KDR.
AB  - The G protein-coupled receptor oncogene (vGPCR) of the Kaposi's sarcoma (KS)
      associated herpesvirus (KSHV), an oncovirus implicated in angioproliferative
      neoplasms, induces angiogenesis by VEGF secretion. Accordingly, we found that
      expression of vGPCR in human umbilical vein endothelial cells (HUVEC) leads to
      immortalization with constitutive VEGF receptor-2/ KDR expression and activation.
      vGPCR immortalization was associated with anti-senescence mediated by alternative
      lengthening of telomeres and an anti-apoptotic response mediated by vGPCR
      constitutive signaling and KDR autocrine signaling leading to activation of the
      PI3K/AKT pathway. In the presence of the KS growth factor VEGF, this mechanism
      can sustain suppression of signaling by the immortalizing gene. We conclude that
      vGPCR can cause an oncogenic immortalizing event and recapitulate aspects of the
      KS angiogenic phenotype in human endothelial cells, pointing to this gene as a
      pathogenic determinant of KSHV.

PMID- 12620410
TI  - MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed
      lineage leukemias in mice.
AB  - A specific association with mixed lineage leukemias suggests that MLL
      oncoproteins may selectively target early multipotent hematopoietic progenitors
      or stem cells. We demonstrate here that a representative MLL fusion protein, MLL
      GAS7, impairs the differentiation and enhances the in vitro growth of murine
      hematopoietic cells with multipotent features. The multilineage differentiation
      potential of these cells was suggested by their immuno-phenotypes and
      transcriptional programs and confirmed by their ability to induce three
      pathologically distinct leukemias in mice, including an acute biphenotypic
      leukemia (ABL) that recapitulates the distinctive hallmark features of many MLL
      associated leukemias in humans. This experimental modeling of ABL in mice
      highlights its origin from multipotential progenitors that arrest at a
      bipotential stage specifically targeted or induced by MLL oncogenes.

PMID- 12620409
TI  - BCR/ABL activates mdm2 mRNA translation via the La antigen.
AB  - In a BCR/ABL-expressing myeloid precursor cell line, p53 levels were markedly
      downmodulated. Expression of MDM2, the negative regulator of p53, was upregulated
      in a tyrosine kinase-dependent manner in growth factor-independent BCR/ABL
      expressing cells, and in accelerated phase and blast crisis CML samples.
      Increased MDM2 expression was associated with enhanced mdm2 mRNA translation,
      which required the interaction of the La antigen with mdm2 5' UTR. Expression of
      MDM2 correlated with that of La and was suppressed by La siRNAs and by a dominant
      negative La mutant, which also enhanced the susceptibility to drug-induced
      apoptosis of BCR/ABL-transformed cells. By contrast, La overexpression led to
      increased MDM2 levels and enhanced resistance to apoptosis. Thus, La-dependent
      activation of mdm2 translation might represent an important molecular mechanism
      involved in BCR/ABL leukemogenesis.

PMID- 12620411
TI  - Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene
      expression based classification.
AB  - We recently found that MLL-rearranged acute lymphoblastic leukemias (MLL) have a
      unique gene expression profile including high level expression of the receptor
      tyrosine kinase FLT3. We hypothesized that FLT3 might be a therapeutic target in
      MLL and found that 5 of 30 MLLs contain mutations in the activation loop of FLT3
      that result in constitutive activation. Three are a newly described deletion of
      I836 and the others are D835 mutations. The recently described FLT3 inhibitor
      PKC412 proved cytotoxic to Ba/F3 cells dependent upon activated FLT3 containing
      either mutation. PKC412 is also differentially cytotoxic to leukemia cells with
      MLL translocations and FLT3 that is activated by either overexpression of the
      wild-type receptor or mutation. Finally, we developed a mouse model of MLL and
      used bioluminescent imaging to determine that PKC412 is active against MLL in
      vivo.

PMID- 12620413
TI  - Ligands for expression cloning and isolation of GABA(B) receptors.
AB  - The scope of the plenary lecture at the occasion of the Xth Meeting on
      Heterocyclic Structures in Medicinal Chemistry, Palermo 2002, is considerably
      larger than that of the main lecture at the XVIth International Symposium on
      Medicinal Chemistry, Bologna 2000, described by Froestl et al. in Farmaco 56
      (2001) 101. Additional information is presented, in particular, on the reaction
      conditions for the 31 step synthesis of the combined affinity chromatography and
      photoaffinity radioligand [125I]CGP84963 and on the recent developments of the
      molecular biology of GABA(B) receptors.

PMID- 12620412
TI  - The proliferation gene expression signature is a quantitative integrator of
      oncogenic events that predicts survival in mantle cell lymphoma.
AB  - We used gene expression profiling to establish a molecular diagnosis of mantle
      cell lymphoma (MCL), to elucidate its pathogenesis, and to predict the length of
      survival of these patients. An MCL gene expression signature defined a large
      subset of MCLs that expressed cyclin D1 and a novel subset that lacked cyclin D1
      expression. A precise measurement of tumor cell proliferation, provided by the
      expression of proliferation signature genes, identified patient subsets that
      differed by more than 5 years in median survival. Differences in cyclin D1 mRNA
      abundance synergized with INK4a/ARF locus deletions to dictate tumor
      proliferation rate and survival. We propose a quantitative model of the aberrant
      cell cycle regulation in MCL that provides a rationale for the design of cell
      cycle inhibitor therapy in this malignancy.

PMID- 12620414
TI  - In silico screening with benzofurane- and benzopyrane-type MDR-modulators.
AB  - Development of inhibitors of the drug efflux pump P-glycoprotein is a versatile
      approach to overcome multi drug resistance (MDR) in tumor therapy. In an approach
      to lower the conformational flexibility of the lead compound propafenone, we
      synthesized a set of dihydrobenzofuranes and benzopyranones. In the case of the 4
      diastereomeric dihydrobenzofuranes, no significant differences in activity
      regarding the configuration on the side-chains at the dihydrofurane moiety (cis
      or trans) was observed. This may be due to the high flexibility of the side
      chains, which still allow mutually overlap of pharmacophores. The benzopyranones
      showed a good correlation between lipophilicity and activity with gnerally lower
      logpotency/logP ratios. This decrease may be due to the rigidization of the
      molecules. In an in silico screening approach, a set of diverse propafenone-type
      compounds was used to establish a pharmacophore model, which was used to screen
      the world drug index. Among the hits retrieved there are several compounds, which
      were previously described as MDR-modulators. This demonstrates the validity of
      the model.

PMID- 12620415
TI  - Purine and deazapurine nucleosides: synthetic approaches, molecular modelling and
      biological activity.
AB  - A number of ligands for the adenosine binding sites has been obtained by using
      nucleoside convergent and divergent synthesis. Most of our nucleosides have been
      synthesized by coupling 2,6-dichloropurine (1), 2,6-dichloro-1-deazapurine (2),
      2,6-dichloro-3-deazapurine (3) with ribose, 2- and 3-deoxyribose and 2,3
      dideoxyribose derivatives. The use of these versatile synthons allowed the
      introduction of various substituents in 2- and/or 6-positions. The glycosylation
      site and the anomeric configuration of the obtained nucleosides were assigned on
      the basis of spectroscopic studies and confirmed by molecular models. A series of
      potent adenosine receptor ligands has been obtained by using divergent
      approaches, mostly starting from guanosine. Substitutions in 2, 6, 8, and 5'
      position of adenosine molecule led to ligands selective for the different
      adenosine receptor subtypes. Furthermore, we investigated the molecular bases of
      the different behavior of 2- and 8-alkynyl adenosines, by means of NMR
      experiments and molecular modeling studies. With docking experiments, we
      demonstrated that the two class of molecules should have different binding modes
      that explain their different degree of affinity and the shift of their activity
      from agonistic (2-substituted derivatives) to antagonistic (8-substituted
      derivatives).

PMID- 12620416
TI  - Ceramide analogues in apoptosis: a new strategy for anticancer drug development.
AB  - A survey on the role played by ceramide within the sphingolmyelin pathway is here
      reported, taking into account its importance as an intracellular effector
      molecule in apoptosis. Recently, several analogs of ceramide, able to pass the
      cell membrane and then to induce apoptosis, have been developed as a new
      potential approach in anticancer therapy.

PMID- 12620417
TI  - The discovery of a new potential anticancer drug: a case history.
AB  - DNA minor groove binders (MGB) represent a class of anticancer agents whose DNA
      sequence specificity was hypothesized to lead to high selectivity of action.
      Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST),
      showed excellent antitumor activity in preclinical tests, but also a severe
      myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard
      derivatives of DST showing excellent activity were recently identified and SAR
      reported. In particular nitrogen half-mustard and sulfur mustard derivatives, as
      one-arm alkylating agents, represent interesting structural novelties. A further
      new class of cytotoxic anticancer agents is that of alpha-halogenoacrylamido
      derivatives of DST-like oligopeptides, which show an activity profile
      substantially improved in comparison to TAM. In particular brostallicin (PNU
      166196), alpha-bromo-acrylamido tetra-pyrrole derivative ending with a guanidino
      moiety, showed high cytotoxic potency and myelotoxicity dramatically reduced in
      comparison to TAM and other MGB. Brostallicin binds to the minor groove but
      appears unreactive in classical in vitro DNA alkylation assays. About the
      apparent lack of DNA alkylation we speculated that an intracellular nucleophile,
      e.g. glutathione (GSH), could activate the reactivity of the compound leading to
      alkylation of DNA in vivo. Evidence of both covalent interaction of brostallicin
      with plasmidic DNA in the presence of GSH and of enhanced cytotoxicity in cancer
      cells characterized by high levels of GSH were obtained. Brostallicin was
      selected for clinical development and is now undergoing Phase II studies.

PMID- 12620418
TI  - Anticancer bisquaternary heterocyclic compounds: a ras-ional design.
AB  - A new family of symmetrical bisquaternary compounds with semirigid linkers have
      shown to be highly specific for Choline Kinase (ChoK) inhibition and to exert
      antitumoural activity in cell lines and in mice. A three-parameter regression
      equation has been derived which satisfactorily describes the ex vivo inhibitory
      potency of ChoK of the title compounds. The electronic effect of the group at
      position 4 of the cationic head plays a critical role although the hydrophobic
      contribution, especially that of the linker, favors the ChoK inhibitory activity.
      The antiproliferative activity (in vitro assay) is correlated with the ChoK
      inhibition (ex vivo assay) through the electronic effect and a squared term of
      the overall lipophilicity of the molecules. We also provide in vivo evidence that
      ChoK is a novel target for the design of antitumoural drugs. All these results
      suggest that ChoK plays a crucial role in the onset of carcinogenesis.

PMID- 12620419
TI  - Synthesis and biological evaluation of enantiomerically pure pyrrolyl
      oxazolidinones as a new class of potent and selective monoamine oxidase type A
      inhibitors.
AB  - Due to the key role played by monoamine oxidases (MAOs) in the metabolism of
      neurotransmitters, MAO inhibitors (MAOIs) represent an useful tool for the
      treatment of several neurological diseases. Among selective MAOIs, MAO-A
      inhibitors (e.g. clorgyline) are used as antidepressant and antianxiety drugs and
      are claimed to protect neuronal cells against apoptosis, and selective MAO-B
      inhibitors (e.g. L-deprenyl) can be used in the treatment of Parkinson's disease
      either alone or in combination with L-DOPA. However, they engender covalent bonds
      with the active site of the enzyme and induce irreversible inhibition; moreover,
      they tend to lose their initial selectivity at high dosages or with repeated
      administrations. Phenyloxazolidinones belong to third-generation-MAOIs,
      characterized by a selective and reversible inhibition of the enzyme. Among these
      molecules, the most representative are toloxatone and befloxatone, two selective
      and reversible MAO-A inhibitors used in therapy as antidepressant drugs. Going on
      our searches on CNS potentially active compounds containing a pyrrole moiety we
      prepared 3-(1H-pyrrol-1-yl)-2-oxazolidinones (1) and isomeric 3-(1H-pyrrol-2-and 
      3-yl)-2-oxazolidinones (2 and 3) as anti-MAO agents. Such derivatives resulted
      selective and reversible MAO-A inhibitors. The most potent compound is (R)-5
      methoxymethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinone (1b), endowed with very high
      potency (K(iMAO-A) = 4.9 nM) and A-selectivity (A-selectivity = 10,200, about 116
      fold greater than that of befloxatone).

PMID- 12620420
TI  - Structural modifications of antisense oligonucleotides.
AB  - Antisense oligonucleotides are efficient tools for the inhibition of gene
      expression in a sequence specific way. Natural oligonucleotides are decomposed
      rapidly in biological systems, which strongly restrict their application. In
      contrast, artificial oligonucleotides are designed to be more stable against
      degradation than the target mRNA, which results in a catalytic effect of the
      drug. Modification of the phosphate linkage has been the first successful
      strategy for antisense drug developments and Fomivirsene the first antisense drug
      in therapy. The launch of Fomivirsene has resulted in a revolutionary spin off to
      antisense research leading to a second generation of antisense oligonucleotides,
      which are stable against oligonucleotide cleaving enzymes. Among these,
      oligonucleotides bearing an alkoxy substituent in position 2' were the most
      successful ones. The third generation of antisense oligonucleotides contains
      structure elements, which enhance the antisense action. Zwitterionic
      oligonucleotides show remarkable results, first, because the stability against
      ribozymes is largely increased, and secondly, because the electrostatic repulsion
      between the anionic sense and the zwitterionic antisense cords is minimized.
      Promising new target molecules in antisense research are oligonucleotide
      chimares, which enhance the antisense action (chimares with intercalators,
      chelators or polyamines) or enable an application as sequence specific detectors
      (chimares with biotin, fluorescein or radioligands).

PMID- 12620421
TI  - Anti-HIV agents: design and discovery of new potent RT inhibitors.
AB  - This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs).
      On the basis of extensive studies on 1H,3H-thiazolo[3,4-a]benzimidazole
      derivatives (TBZs) followed by structure-activity relationship (SAR)
      considerations and molecular modeling, the design and synthesis of a series of
      2,3-diaryl-1,3-thiazolidin-4-ones have been performed. Some derivatives proved to
      be highly effective in inhibiting human immunodeficiency virus type-1 (HIV-1)
      replication at nanomolar concentrations with minimal toxicity, acting as reverse
      transcriptase (RT) inhibitors. Computational studies were used in order to probe
      the binding of our ligands to HIV-1-RT.

PMID- 12620422
TI  - Cytisine derivatives as ligands for neuronal nicotine receptors and with various
      pharmacological activities.
AB  - Neuronal nicotinic acetylcholine receptors (nAChRs) form a family of ACh-gated
      cation channels made up of different subtypes. They are widely distributed in
      peripheral and central nervous systems and are involved in complex cerebral
      processes as learning, memory, nociception, movement, etc. The possibility that
      subtype-selective ligands be used in the treatment of CNS disorders promoted the
      synthesis of a large number of structural analogues of nicotine and epibatidine,
      two very potent nAChR agonists. Pursuing our long standing research on the
      structural modification of quinolizidine alkaloids, we devoted our attention to
      cytisine, another very potent ligand for many nAChR subtypes. Thus a systematic
      structural modification of cytisine was undertaken in order to obtain compounds
      of potential therapeutic interest at peripheral as well as central level, with a
      particular concern for achieving nAChR subtype selective ligands. Up to the
      present more than 80 cytisine derivatives, mainly of N-substitution and a few by
      modifying the pyridone ring, have been prepared. The biological results, which
      concern so far about an half of the prepared compounds, indicate that the
      introduction of a nitro group in position 3 of the pyridone nucleus further
      enhances the high affinity of cytisine, while the introduction of substituents on
      the basic nitrogen, though reducing in different degrees the affinity, gives rise
      to compounds with a higher selectivity for central (alpha(4)beta(2)) versus
      gangliar (alpha(3)-containing) receptor subtype. On the other hand, the
      analgesic, antihypertensive and inotropic activities found in some N-substituted
      cytisines, represent an attractive starting point for the development of more
      active compounds.

PMID- 12620423
TI  - H3 receptor ligands: new imidazole H3-antagonists endowed with NO-donor
      properties.
AB  - Synthesis and pharmacological properties of a group of compounds obtained by
      coupling the H(3)-antagonist SKF 91486 with the NO-donor 3-phenylfuroxan-4-yloxy
      and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding
      furazan analogues, devoid of NO-donating properties, are reported. All the
      products were tested for their H(3)-antagonistic and H(2)-agonistic properties on
      electrically-simulated guinea-pig ileum segments and guinea-pig papillary muscle,
      respectively. All the synthesised compounds displayed good H(3)-antagonistic
      properties (pA(2) range 7.02-8.49) while behaving only as weak partial H(2)
      agonists. Derivative 28, the best NO-donor of the series, was able to trigger a
      dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig
      illeum.

PMID- 12620424
TI  - Effects of metformin on body mass index, menstrual cyclicity, and ovulation
      induction in women with polycystic ovary syndrome.
AB  - OBJECTIVE: Metformin has been used as a treatment in many studies of the
      infertility associated with polycystic ovary syndrome (PCOS). We will review the
      literature on this topic as it specifically relates to changes in body mass index
      (BMI), improvement in menstrual cyclicity, and effects on ovulation and pregnancy
      rates. DESIGN: Review of studies addressing biochemical and clinical changes in
      women with PCOS on metformin. MAIN OUTCOME MEASURE(S): Changes in BMI, menstrual
      cyclicity, ovulation rate, and pregnancy rate. RESULT(S): Metformin has been
      shown to produce small but significant reductions in BMI. Multiple observational
      studies have confirmed an improvement in menstrual cyclicity with metformin
      therapy. The studies addressing the concomitant use of metformin with clomiphene
      citrate initially predicted great success, but these have been followed by more
      modest results. There is little data in the literature concerning the use of
      metformin and hMGs. CONCLUSION(S): Some (but not all) women with PCOS have
      improvements in their menstrual cycles while on metformin. The data supporting
      the use of metformin in ovulation induction with clomiphene citrate and hMG
      remain to be confirmed by large, randomized, prospective studies.

PMID- 12620425
TI  - Women older than 40 years of age and those with elevated follicle-stimulating
      hormone levels differ in poor response rate and embryo quality in in vitro
      fertilization.
AB  - OBJECTIVE: To investigate whether IVF outcome of patients older than 40 years of
      age with basal FSH levels less than 15 IU/L differs from that in patients 40
      years of age or younger with basal FSH levels of 15 IU/L or greater. DESIGN:
      Prospective observational study. SETTING: Tertiary academic fertility center.
      PATIENT(S): Women 41 years of age or older with basal FSH levels less than 15
      IU/L (n = 50), and women 40 years of age or younger with elevated basal FSH
      levels (n = 36) undergoing their first IVF cycle. INTERVENTION(S): IVF treatment
      using a long suppression protocol with recombinant FSH at a fixed starting dose
      of 150 IU/L. MAIN OUTCOME MEASURE(S): Ovarian response, ongoing pregnancy rates,
      and implantation rates. RESULT(S): The high FSH group experienced more cycle
      cancellations due to absent follicular growth than did the high age group (31%
      vs. 8%). However, the high FSH group had better implantation rates per embryo
      (34% vs. 11%), higher ongoing rates per ET (40% vs.13%), and higher ongoing
      pregnancy rates per cycle (25% vs. 10%). In both groups, poor responders had
      lower pregnancy rates. CONCLUSION(S): The outcome of IVF differs between patients
      older than 40 years of age with normal FSH levels and relatively young patients
      with elevated FSH levels. This finding may have implications for the management
      of these patients.

PMID- 12620427
TI  - Age = egg quality, FSH level = egg quantity.

PMID- 12620428
TI  - Testosterone levels in pregnant women correlate with the insulin response during
      the glucose tolerance test.
AB  - OBJECTIVE: To evaluate the association between insulin/insulin-like growth factor
      I (IGF-I) systems and androgen levels in pregnancy. DESIGN: Prospective cohort
      study. SETTING: Yale University School of Medicine. PATIENT(S): Pregnant women
      undergoing a 100-gram 3-hour glucose tolerance test (GTT). INTERVENTION(S): Serum
      samples collected during GTT were analyzed for insulin, androgens, free IGF-I,
      insulin-like growth factor-binding protein (IGFBP) 1, and estriol. MAIN OUTCOME
      MEASURE(S): Observing the relationship between insulin/IGFs and androgen levels.
      RESULT(S): The insulin area under the curve (I(AUC)) during GTT correlated
      positively with total T and free T, but not with dehydroepiandrosterone (DHEA),
      dehydroepiandrosterone sulphate (DHEAS), or estriol. The peak insulin values
      (I(max)) during GTT also correlated positively with total T and free T, but not
      with DHEA, DHEAS, or estriol. There was no statistically significant correlation
      of T levels with free IGF-I, IGFBP-1, glucose, DHEAS, or estriol. Multiple linear
      regression analysis modeling showed that I(AUC) and I(max) did have a
      statistically significant correlation with free T levels. CONCLUSION(S): This
      study demonstrates for the first time that I(AUC) and I(max) measured in
      hyperinsulinemic states such as pregnancy correlate with T levels. In view of the
      lack of correlation between insulin and DHEAS or estriol, insulin-related T
      production during pregnancy is likely of ovarian origin.

PMID- 12620426
TI  - Value of elevated basal follicle-stimulating hormone levels and the differential
      diagnosis during the diagnostic subfertility work-up.

PMID- 12620429
TI  - Maternal serum cytokine levels in women with hyperemesis gravidarum in the first
      trimester of pregnancy.
AB  - OBJECTIVE: To compare serum cytokine levels in patients with hyperemesis
      gravidarum with levels in healthy pregnant and nonpregnant women. DESIGN: Case
      control study. SETTING: Clinical and academic research center. PATIENT(S): Thirty
      women with hyperemesis gravidarum, 30 healthy women in the first trimester of
      pregnancy, and 30 healthy nonpregnant women. MAIN OUTCOME MEASURE(S): Serum
      levels of interleukin-1beta, interleukin-2 receptor, interleukin-6, interleukin
      8, and tumor necrosis factor (TNF)-alpha. RESULT(S): Median serum levels of
      interleukin-2 receptor and interleukin-8 did not differ significantly among the
      three groups. Serum levels of interleukin-1beta and interleukin-6 were
      significantly higher in healthy pregnant women than in healthy nonpregnant women.
      Median TNF-alpha levels were significantly higher in women with hyperemesis (25.8
      pg/mL [range, 4.9-140 pg/mL]) than in healthy pregnant and nonpregnant women
      (10.85 pg/mL [range, 4.1-35.8 pg/mL] and 12 pg/mL [4.3-68.2 pg/mL],
      respectively). CONCLUSION(S): Levels of TNF-alpha were significantly higher in
      patients with hyperemesis gravidarum than in healthy pregnant and nonpregnant
      women. Thus, TNF-alpha may be involved in the etiology of hyperemesis gravidarum.

PMID- 12620430
TI  - Incidence of monozygotic twinning with blastocyst transfer compared to cleavage
      stage transfer.
AB  - OBJECTIVE: To evaluate the incidence of monozygotic twinning (MZT) in pregnancies
      conceived after blastocyst transfer compared to cleavage-stage transfer. DESIGN:
      Retrospective study. SETTING: University IVF program. PATIENT(S): All IVF
      patients with viable pregnancies conceived during a 4-year period.
      INTERVENTION(S): Blastocyst transfer or day 3 ET. MAIN OUTCOME MEASURE(S):
      Incidence of MZT assessed by transvaginal ultrasound. RESULT(S): There were 11
      incidences of MZT in 197 viable pregnancies (5.6%) with blastocyst transfer
      compared to 7 of 357 viable pregnancies (2%) with day 3 ET. In 10 of 18
      pregnancies, MZT was observed in the setting of a higher order multiple gestation
      (6 of 11 for blastocyst transfer and 4 of 7 for day 3 ET). In the day 3 ET group,
      assisted hatching or intracytoplasmic sperm injection (ICSI) did not increase MZT
      (4 of 213, 1.9%) compared to cycles without zona breaching (3 of 144, 2.1%).
      Similarly, in the blastocyst-transfer group, ICSI did not increase the incidence
      of MZT (4 of 74, 5.5% for ICSI and 7 of 123, 5.7% for non-ICSI IVF).
      CONCLUSION(S): Compared to day 3 ET, blastocyst transfer appears to significantly
      increase the incidence of gestations with MZT. This information should be taken
      into account when counseling patients about the pros and cons of extended
      culture.

PMID- 12620431
TI  - Detection of the subendometrial vascularization flow index by three-dimensional
      ultrasound may be useful for predicting the pregnancy rate for patients
      undergoing in vitro fertilization-embryo transfer.
AB  - OBJECTIVE: To obtain quantitative data on endometrial volume and subendometrial
      blood flow by three-dimensional ultrasound clue to endometrial receptivity.
      DESIGN: A prospective, nonrandomized clinical study. SETTING: One tertiary center
      for assisted reproduction. PATIENT(S): Fifty-four patients aged <38 years with
      normal basal serum FSH level experiencing their first IVF cycle, whose uteri were
      morphologically normal as confirmed by 3-dimensional (3-D) ultrasound, were
      studied. INTERVENTION(S): Ultrasound evaluation was performed for all patients
      with 3-D facility by a single operator on the day of hCG administration. MAIN
      OUTCOME MEASURE(S): Ultrasonographic parameters and conception rates. RESULT(S):
      Subendometrial vascularization flow index (VFI) in predicting the pregnancy rate
      of IVF was superior to that using vascularization index, flow index, or
      endometrial volume in the receiver operating characteristics curve analysis. The
      best prediction rate was achieved by a VFI cutoff value of >0.24. CONCLUSION(S):
      The detection of subendometrial blood flow by 3-D power Doppler ultrasound may be
      a useful ultrasound parameter in the prediction of pregnancy rate of IVF,
      especially subendometrial VFI.

PMID- 12620432
TI  - A retrospective case-control study of developmental and other outcomes in a
      cohort of Australian children conceived by intracytoplasmic sperm injection
      compared with a similar group in the United Kingdom.
AB  - OBJECTIVE: To investigate the possibility that children born after ICSI were at
      increased risk for neurodevelopmental delay. DESIGN: Retrospective case-control
      study. SETTING: IVF clinic. PATIENT(S): Fifty-eight singleton children born after
      ICSI and 38 normally conceived singleton children (controls), matched for
      relevant sociodemographic characteristics, from Australia and 208 case-patients
      and 221 controls from the United Kingdom. MAIN OUTCOME MEASURE(S): Antenatal and
      perinatal, and sociodemographic characteristics; physical health, including
      congenital abnormalities; and neurodevelopment by using the Griffiths scales of
      mental development. RESULT(S): Eighty-five percent of case-patients and 96%
      controls were assessed at a mean age of 13 months. Neurodevelopmental scores were
      similar in all children. Perinatal outcome was similar, apart from more caesarean
      sections in the case-patients. Rates of congenital anomalies were similar (5.6%
      among case-patients vs. 5.7% among controls). Children from fathers with
      oligozoospermia showed no extra problems. Children born after ICSI in the United
      Kingdom and Australia were similar. CONCLUSION(S): Children conceived after ICSI
      did not differ from their naturally conceived peers in physical health or
      development at ages up to 15 months.

PMID- 12620433
TI  - Genetic analysis of three polymorphic sites of the luteinizing hormone beta
      subunit gene in infertile Korean men with nonobstructive azoospermia.
AB  - OBJECTIVE: To investigate the genetic background of nonobstructive male factor
      infertility. DESIGN: Clinical and controlled study. PATIENT(S): Ninety-five
      nonobstructive male infertile patients (75 with azoospermia, 18 with
      oligoasthenoteratozoospermia, and two with oligozoospermia) and 200 healthy
      fertile control men. INTERVENTION(S): Patients were investigated for genetic
      background including karyotype, Yq chromosome deletion, and three polymorphisms
      of the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser). MAIN OUTCOME
      MEASURE(S): To determine three polymorphisms of the LH beta-subunit gene.
      RESULT(S): An abnormal karyotype was found in 11 of the 75 patients with
      azoospermia and one of the 18 patients with oligoasthenoteratozoospermia. Eleven
      (12%) had one or more deleted sites at 13 loci on Yq. The Gly102Ser variant of
      the LH beta-subunit gene was not detected at all. The frequency of double Trp8Arg
      and Ile15Thr heterozygotes was similar between the fertile (14.5%, n = 200) and
      infertile (12.6%, n = 95) groups, with the exception of one homozygous mutation
      (Arg8 and Thr15) from patient with azoospermia. CONCLUSION(S): Three variants of
      the LH beta-subunit gene (Trp8Arg, Ile15Thr, and Gly102Ser) may not be associated
      with male factor infertility. We found one homozygous Arg8 and Thr15 mutation in
      a patient with azoospermia with normal hormone levels (FSH, LH, PRL, T), a normal
      karyotype, and no Yq microdeletions.

PMID- 12620434
TI  - Validity of a rapid assay for antisperm antibodies in semen.
AB  - OBJECTIVE: To determine the validity of a rapid assay for antisperm antibodies in
      semen. DESIGN: Prospective comparison of the results of standard and rapid
      antisperm antibody assays performed simultaneously. SETTING: Tertiary care
      infertility center. PATIENT(S): Couples who presented for infertility evaluation.
      INTERVENTION(S): Semen analysis and measurement of antisperm antibodies in semen
      using a standard and a rapid immunobead binding test (IBT). MAIN OUTCOME
      MEASURE(S): [1] Comparison of sperm parameters between semen-containing antisperm
      antibodies and semen free of antisperm antibodies. [2] Validation of the rapid
      test by calculation of sensitivity, specificity, positive and negative predictive
      values of the rapid assay using the standard assay as a gold standard. [3] Cost
      comparison of the standard and rapid test. RESULT(S): [1] Nine semen specimens
      with antisperm antibodies had a significantly lower sperm concentration,
      motility, and total motile fraction compared to 44 specimens without antisperm
      antibodies. Also, specimens with antisperm antibodies had a significantly higher
      percentage of vibratory sperm and percent of bound antisperm antibodies. The
      strict morphology, liquefaction time, semen volume, and white blood cell
      concentration were no different between the two groups. [2] Using a threshold of
      > or =12% of bound antisperm antibodies in the rapid assay, the sensitivity,
      specificity, positive and negative predictive values of the test are 100% when
      correlated with a threshold of > or =20% in the standard assay. Increasing the
      threshold in the standard assay decreases the specificity and positive predictive
      value of the rapid assay but not the sensitivity and the negative predictive
      value. [3] The cost of the rapid assay was 16% that of the standard test and its
      performance took 20% of the time it took to set and perform the standard test.
      CONCLUSION(S): A rapid test for antisperm antibodies is valid, reliable, and more
      cost and labor effective than a standard IBT.

PMID- 12620435
TI  - Intracytoplasmic sperm injection with testicular spermatozoa is less successful
      in men with nonobstructive azoospermia than in men with obstructive azoospermia.
AB  - OBJECTIVE: To assess the efficiency of intracytoplasmic sperm injection (ICSI)
      using testicular spermatozoa in cases of nonobstructive azoospermia. DESIGN:
      Retrospective case series. SETTING: Tertiary university-based infertility center.
      PATIENT(S): Overall, 595 couples were included. In 360 couples, the man had
      normal spermatogenesis. In 118, 85, and 32 couples the man had germ-cell aplasia,
      maturation arrest, and tubular sclerosis/atrophy, all with focal spermatogenesis
      present. INTERVENTION(S): We performed 911 ICSI cycles using fresh sperm obtained
      after testicular biopsies: 306 ICSI cycles used testicular sperm from men with
      nonobstructive azoospermia, and 605 ICSI cycles used testicular sperm from men
      with obstructive azoospermia. MAIN OUTCOME MEASURE(S): Fertilization, cleavage,
      implantation, and pregnancy rates. RESULT(S): Overall, the 2PN fertilization rate
      was lower in the nonobstructive group: 48.5% vs. 59.7%. There were no differences
      in in vitro development or in the morphological quality of the embryos. In the
      nonobstructive group, a total of 718 embryos were transferred (262 transfers) vs.
      1,525 embryos in the obstructive group (544 transfers). Both the clinical
      implantation rate and clinical pregnancy rate per cycle were significantly lower
      in the nonobstructive group compared with the obstructive group: 8.6% vs. 12.5%
      and 15.4% vs. 24.0%, respectively. CONCLUSION(S): A statistically significant
      lower rate of fertilization and pregnancy results from ICSI with testicular sperm
      from men with nonobstructive azoospermia, compared with men with obstructive
      azoospermia.

PMID- 12620437
TI  - Cytologic aspects of the nasal respiratory epithelium in postmenopausal women
      treated with hormone therapy.
AB  - OBJECTIVE: To investigate the effects of hormone therapy (HT) on nasal
      respiratory epithelium in postmenopausal women. DESIGN: Prospective open clinical
      trial. SETTING: Outpatient menopausal clinic. PATIENT(S): One hundred three
      healthy postmenopausal women, of whom 55 treated with HT, and 48 untreated women
      (controls). INTERVENTION(S): Different regimens of HT by patch, gel, or oral
      administration. MAIN OUTCOME MEASURE(S): Cytologic changes of nasal, middle and
      inferior turbinate cells compared with vaginal cytologic findings by using the
      maturation index. RESULT(S): Hematoxylin-eosin staining for the maturation index
      confirmed similar trophic cytologic aspects between the nasal respiratory
      epithelium and vaginal smears in HT-treated women and controls. Women treated
      with sequential HT or estrogen therapy (ET) showed better trophic characteristics
      in the nasal cytological samples compared with women treated with continuous
      combined HT. CONCLUSION(S): Along with vaginal cells the nasal respiratory
      epithelium is an estrogen target. The activity of HT in the nasal respiratory
      epithelium may depend on the type of hormone regimen used.

PMID- 12620436
TI  - Variability of serum estrogens among postmenopausal women treated with the same
      transdermal estrogen therapy and the effect on androgens and sex hormone binding
      globulin.
AB  - OBJECTIVE: To examine the variability of serum estrogens in response to
      transdermal estrogen replacement therapy (ET), and to determine the effects on
      androgens and sex hormone binding globulin (SHBG). DESIGN: Randomized, double
      blind, placebo-controlled study. SETTING: Women's hospital. PATIENT(S): Two
      groups of postmenopausal women: [1] 21 women not on ET enrolled and 17 completed
      the study; [2] 19 women on continuous transdermal ET enrolled and 13 completed
      the study. INTERVENTION(S): Women not on ET were administered a placebo patch or
      a newly initiated estrogen patch, then crossed over to the alternate treatment.
      Serum samples were obtained at baseline and the subsequent 3 days from the
      placebo and new-patch groups and from a separate group of women receiving
      continuous estrogen patch treatment. MAIN OUTCOME MEASURE(S): Estradiol (E(2)),
      estrone, estrone sulfate, T, dehydroepiandrosterone (DHEA),
      dehydroepiandrosterone sulfate (DHEAS), androstenedione, free androgen index, and
      SHBG. RESULT(S): There was considerable intrapatient and interpatient variability
      in the estrogen response to identical treatment doses, with E(2) values differing
      between women as much as 138 pg/mL and E(2) increases above baseline differing as
      much as 90 pg/mL. Continuous treatment increased SHBG and decreased
      androstenedione levels; however, levels of T, DHEA, DHEAS, and free androgen
      index did not change. CONCLUSION(S): There is great variability of estrogen in
      response to transdermal ET, but minimal effect on circulating androgens.

PMID- 12620438
TI  - Low-dose hormone therapy and carbohydrate metabolism.
AB  - OBJECTIVE: To evaluate the influence by two low doses of oral continuous-combined
      formulations of 17 beta-estradiol (E(2)) and norethisterone acetate (NETA) on
      carbohydrate metabolism in healthy postmenopausal women. DESIGN: A double-blind,
      randomized, placebo-controlled trial. SETTING: Volunteers at a university
      hospital. SUBJECT: One hundred twenty healthy postmenopausal women.
      INTERVENTION(S): One hundred twenty women were randomized to three treatment
      arms: (1) E(2) 1 mg/NETA 0.25 mg group (n = 40); (2) E(2) 1 mg/NETA 0.5 mg group
      (n = 40); (3) placebo group (n = 40). A total of 102 women completed 12 months of
      treatment. An oral glucose tolerance test (OGTT) was performed at baseline and at
      3, 6, and 12 months. MAIN OUTCOME MEASURE(S): Fasting glucose, fasting insulin,
      total area under the curve (AUC) and insulin/glucose index during OGTT.
      RESULT(S): Fasting levels of glucose and insulin declined significantly in the
      E(2)/NETA 0.5 mg group. At OGTT, the total AUC for insulin declined in both
      active arms. The curve for glucose increased significantly in the E(2)/NETA 0.25
      mg group. A lower insulin/glucose index was observed during OGTT in both active
      regimens when compared with placebo. In the active treatment groups, a
      significant reduction of fasting glucose and/or fasting insulin was encountered
      in women with higher basal fasting levels (fasting glucose >4.2 mmol/L or log
      fasting insulin >0.87). CONCLUSION(S): Oral low-dose E(2) 1 mg/NETA 0.5 mg
      regimen did not impair carbohydrate metabolism, but seemed to improve insulin
      sensitivity in healthy postmenopausal women.

PMID- 12620439
TI  - Effects of patch or gel estrogen therapies on auditory brainstem response in
      surgically postmenopausal women: a prospective, randomized study.
AB  - OBJECTIVE: To study the effects of gonadal steroids on the nongenital
      audiological target in surgically postmenopausal women treated with patch or gel
      transdermal estrogen therapy (ET). DESIGN: Prospective randomized study. SETTING:
      Research Group for Sexology, University of Catania, Italy. PATIENT(S): One
      hundred twenty-two surgically postmenopausal women. INTERVENTION(S): Transdermal
      E(2) by patch or gel, and evaluation of auditory brainstem response by auditory
      evoked potentials for waves I, III, and V latencies, and for interpeak I-III, I
      V, and III-V intervals. MAIN OUTCOME MEASURE(S): Changes in auditory wave
      latencies and in interpeak intervals during treatment with ET with respect to
      baseline levels. RESULT(S): One hundred two women completed the study. Forty
      eight subjects used E(2) patches and 54 E(2) gel. No significant difference was
      observed in plasma E(2) improvement and in auditory brainstem response values
      with the two estrogen (E) formulations. The wave latencies and the interpeak
      intervals showed lower values during the E treatment than at baseline.
      CONCLUSION(S): Auditory brainstem response seems to depend on the type of E
      given. Our data suggest that fluctuating E levels act on waves, even if the exact
      mechanism of the gonadal steroids is not clear. However, we believe that E could
      influence neuronal plasticity, the metabolic levels of neurotransmitters, and
      thus, the neuronal conduction time into the audiological system.

PMID- 12620440
TI  - Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation
      in women with polycystic ovary syndrome.
AB  - OBJECTIVE: In women suffering from polycystic ovary syndrome (PCOS), correction
      of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the
      responsiveness to ovulation induction agents such as clomiphene citrate (CC). We
      investigated the effect of rosiglitazone maleate on ovulation induction in
      overweight and obese, CC-resistant women with PCOS. DESIGN: Double-blind,
      randomized, placebo-controlled trial. SETTING: Academic reproductive
      endocrinology clinic. PATIENT(S): Overweight and obese women with clinical and
      laboratory manifestations of PCOS who desired pregnancy and were resistant to CC.
      INTERVENTION(S): Twenty-five women were randomized into two treatment groups.
      Subjects in Group I (n = 12) were randomized to receive rosiglitazone 4 mg b.i.d.
      with a placebo on cycle days 5-9. Group II (n = 13) was randomized to receive
      rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study
      was 2 months. MAIN OUTCOME MEASURE(S): The primary outcome was ovulation as
      defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21,
      24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin
      sensitivity, serum lipoproteins, and androgens. RESULT(S): Overall, 14 of 25
      (56%) women, who were previously resistant to CC, successfully ovulated. In
      subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated
      compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II)
      (P=.04, Fisher's exact). One subject in Group I became pregnant, resulting in one
      uncomplicated live birth; two subjects in Group II conceived, with one successful
      live birth and one first trimester, spontaneous abortion. For all subjects,
      fasting insulin declined from 29.4 +/- 13.8 microU/mL to 17.3 +/- 7.8 microU/mL
      after rosiglitazone (P=.003, paired t-test). Although mean levels of total
      testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline
      significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 +/- 0.3
      microg/dL to 1.0 +/- 0.3 microg/dL after rosiglitazone therapy (P=.001, paired t
      test). There was also a decrease in luteinizing hormone (LH) from 9.4 +/- 6.3
      mU/mL to 7.2 +/- 3.7 mU/mL (P=.01). Lipoproteins including total cholesterol, low
      density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did
      not change. CONCLUSIONS: Short-term rosiglitazone therapy enhances both
      spontaneous and clomiphene-induced ovulation in overweight and obese women with
      PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases
      hyperandrogenemia primarily through increases in SHBG.

PMID- 12620441
TI  - Decreased expression of tissue inhibitor of matrix metalloproteinases in
      follicular fluid from women with polycystic ovaries compared with normally
      ovulating patients undergoing in vitro fertilization.
AB  - OBJECTIVE: To compare activity of matrix metalloproteinases (MMP) and expression
      of their tissue-specific inhibitor (TIMP) in the follicular fluid of normally
      ovulating women and women with the polycystic ovary syndrome (PCOS). DESIGN:
      Prospective study. SETTING: IVF unit and endocrine research unit. PATIENT(S):
      Fourteen patients undergoing IVF treatment (seven with normal ovulation and seven
      with PCOS). MAIN OUTCOME MEASURE(S): Activity of MMP-2 and MMP-9 and expression
      of MMP-1, TIMP-1, and TIMP-2 was measured in follicular fluid of the leading
      follicles by using gel zymography and immunoblot analysis. RESULT(S): The
      activity of MMP-2 and MMP-9 and expression of MMP-1 was similar in follicular
      fluid of normally ovulating patients and patients with PCOS. Significantly lower
      expression of TIMP-1 was found in follicular fluid of patients with PCOS women
      compared with normally ovulating patients. CONCLUSION(S): Because MMPs and TIMPs
      play a role in the physical and chemical structure of the follicular compartment,
      the decreased expression of TIMP in patients with PCOS may be part of a
      compensatory process to overcome the physical properties of the thick ovarian
      capsule.

PMID- 12620442
TI  - Seeking help for sexual function complaints: what gynecologists need to know
      about the female patient's experience.
AB  - OBJECTIVE: To further explore the patient experience of seeking help for a sexual
      function complaint. DESIGN: Survey administered on a Web-based instrument.
      SETTING: Healthy volunteers visiting an online Website. PATIENT(S): The majority
      of participants were married (73%), Caucasian (88%), and premenopausal (67%).
      Most commonly reported sexual complaints included low desire (77%), low arousal
      (62%), and difficulty achieving orgasm (56%). INTERVENTION(S): None. MAIN OUTCOME
      MEASURE(S): Patient experience survey on a women's sexual health website.
      RESULT(S): Although 40% of the women reported that they did not seek help from a
      physician for sexual function complaints, 54% reported that they would like to.
      Although only a minority of the women internalized their experience with
      extremely negative emotions like shame, devaluation, or disgust, the experience
      was not a particularly emotionally positive one along the lines of relief,
      optimism, or confidence, and a great deal of frustration and anxiety about
      treatment was reported. CONCLUSION(S): The extent to which health professionals
      currently receive exposure to training in human sexuality as well as the way in
      which female sexual complaints are handled in the medical setting remain
      ambiguous. The inflow of patients with sexual function complaints only will
      increase, and it is time for physicians to start to acknowledge women's sexuality
      with the same importance their patients do.

PMID- 12620443
TI  - Conception, early pregnancy loss, and time to clinical pregnancy: a population
      based prospective study.
AB  - OBJECTIVE: To examine rates of conception and pregnancy loss and their relations
      with time to clinical pregnancy and reproductive outcomes. DESIGN: A prospective
      observational study. SETTING: Population-based cohort in China. PATIENT(S): Five
      hundred eighteen healthy newly married women who intended to conceive. Upon
      stopping contraception, daily records of vaginal bleeding and daily first-morning
      urine specimens were obtained for < or =1 year or until a clinical pregnancy was
      achieved. Daily urinary hCG was assayed to detect early pregnancy loss (EPL).
      INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Conception, pregnancy loss, and
      time to clinical pregnancy. RESULT(S): The conception rate per cycle was 40% over
      the first 12 months. Of the 618 detectable conceptions, 49 (7.9%) ended in
      clinical spontaneous abortion, and 152 (24.6%) in EPL. Early pregnancy loss was
      detected in 14% of all the cycles without clinically recognized pregnancy, but
      the frequencies were lower among women with delayed time to clinical pregnancy.
      Early pregnancy loss in the preceding cycle was associated with increased odds of
      conception (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.8-3.9),
      clinical pregnancy (OR, 2.0; 95% CI, 1.3-3.0), and EPL (OR, 2.4; 95% CI, 1.4-4.2)
      but was not associated with spontaneous abortion, low birth weight, or preterm
      birth in the subsequent cycle. CONCLUSION(S): We demonstrated substantial EPL in
      the non-clinically pregnant cycles and a positive relation between EPL and
      subsequent fertility.

PMID- 12620444
TI  - Luteal estradiol administration strengthens the relationship between day 3
      follicle-stimulating hormone and inhibin B levels and ovarian follicular status.
AB  - OBJECTIVE: To investigate whether the prevention of early follicular growth by
      luteal E(2) administration improves the relationship between day 3 hormone
      measurements and the ovarian follicular status. DESIGN: Prospective, cohort
      study. SETTING: Assisted reproductive technology unit in Clamart, France.
      PATIENT(S): One hundred sixty-two infertile women. INTERVENTION(S): Participants
      received oral 17beta-E(2), 4 mg/day, from day 20 to the next cycle day 1 (n = 81)
      or served as controls (n = 81). Serum E(2), inhibin B, and FSH were measured
      during the 3 days after E(2) discontinuation (FD1, FD2, and FD3) in E(2)-treated
      women and on cycle day 3 (CD3) in controls. Early antral follicles were counted
      at ultrasound scans on FD3 and CD3. MAIN OUTCOME MEASURE(S): Hormonal-follicular
      correlations on FD3 and CD3. RESULT(S): As expected, after E(2) withdrawal,
      inhibin B and FSH increased from FD1 to FD3 whereas E(2) decreased. Correlations
      between FSH and inhibin B and follicular counts were stronger on FD3 than on CD3.
      CONCLUSION(S): Luteal E(2) administration notably strengthens the relationship
      between serum FSH and inhibin B levels and the number of antral follicles on day
      3. This approach may represent an alternative test of ovarian follicular status.

PMID- 12620445
TI  - Evaluation of a nonhomogeneous endometrial echo pattern in the midluteal phase as
      a potential factor associated with unexplained infertility.
AB  - OBJECTIVE: To determine whether the failure to develop a homogeneous
      hyperechogenic pattern in the midluteal phase is associated with decreased
      fecundity in infertile women who are not receiving follicle-maturing drugs.
      DESIGN: Observational study. SETTING: Outpatient infertility clinic of a
      University Medical Center. PATIENT(S): Two hundred ninety-six infertile women (>
      or =6 months) with regular menses, normal fallopian tubes and uterine cavity, and
      absence of severe male factor on their initial investigation cycle for follicular
      dynamic studies. INTERVENTION(S): Midluteal phase sonographic endometrial
      evaluation. MAIN OUTCOME MEASURE(S): Viable pregnancy rates (live fetus at end of
      first trimester) according to endometrial echo pattern in the midluteal phase.
      Other variables considered were age of patient, endometrial thickness and serum
      E(2) levels at midcycle and midluteal phase, midcycle echo pattern, and P levels
      in the midluteal phase. RESULT(S): The viable pregnancy rate was significantly
      higher in those women who exhibited a homogeneous hyperechogenic pattern (8.5%)
      compared to those women whose endometrium was found to be nonhomogenous (2.2%).
      No other confounding variables were found that could explain this outcome.
      CONCLUSION(S): A nonhomogeneous hyperechogenic sonographic endometrial echo
      pattern predicts lower fertility potential in women who are not receiving
      follicle-maturing drugs.

PMID- 12620447
TI  - Concurrent ganirelix and follitropin beta therapy is an effective and safe
      regimen for ovulation induction in women with polycystic ovary syndrome.
AB  - OBJECTIVE: To evaluate controlled ovarian stimulation cycles using the GnRH
      antagonist ganirelix in combination with the recombinant FSH, follitropin-beta,
      in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective,
      nonrandomized clinical study. SETTING: Hospital-based infertility practice.
      PATIENT(S): Twenty women with PCOS planning to undergo ovarian stimulation.
      INTERVENTION(S): Fasting glucose and insulin levels were used to calculate
      insulin resistance ratios (FG/I). After pretreatment with oral contraceptives,
      serum LH levels were determined, and 250 microg ganirelix was administered on
      cycle day 2. Upon suppression of LH, concurrent ganirelix and follitropin-beta
      therapy (morning ganirelix and evening follitropin-beta) was started and
      continued until the day of hCG. MAIN OUTCOME MEASURES: Days of stimulation, dose
      of follitropin-beta, pregnancy, and ongoing pregnancy were compared based on FG/I
      ratios. RESULTS: One dose of ganirelix effectively suppressed LH levels in all
      patients. All patients ovulated as documented by a rise in progesterone.
      Significant differences were observed between the insulin-resistant and non
      insulin-resistant groups for both days of stimulation and dose of follitropin
      beta. The overall clinical pregnancy rate was 44.4%, with an ongoing pregnancy
      rate of 27.8%. CONCLUSIONS: In this preliminary study, we demonstrate the
      effectiveness of a concurrent ganirelix and follitropin-beta therapy for ovarian
      stimulation in women with PCOS.

PMID- 12620446
TI  - Restoration of ovarian function after autotransplantation of intact frozen-thawed
      sheep ovaries with microvascular anastomosis.
AB  - OBJECTIVE: To test the feasibility of transplanting an intact frozen-thawed ovary
      with microvascular anastomosis of the ovarian vascular pedicle to the deep
      inferior epigastric vessels. DESIGN: Chronic survival study. SETTING: Biological
      Resources Unit, The Cleveland Clinic Foundation. ANIMAL(S): Adult merino ewes.
      INTERVENTION(S): Bilateral laparoscopic oophorectomy was performed on 17
      synchronized ewes. In one group of animals (Group I, n = 11), both ovaries were
      cryopreserved intact with their vascular pedicles. In another group of animals
      (Group II, n = 6), ovarian cortical strips were prepared from each ovary and
      cryopreserved. After thawing, follicular viability and apoptosis rates were
      assessed using one ovary. The other ovary was transplanted to the abdominal wall
      with microvascular anastomosis (Group I). In Group II, the ovarian cortical
      strips were placed in the anterior abdominal wall. Ovaries were harvested after 8
      10 days in situ and subjected to histological evaluation. MAIN OUTCOME
      MEASURE(S): Blood flow, apoptotic signals, follicular viability, serum estradiol
      (E(2)), follicle-stimulating hormone (FSH), and histology. RESULT(S): No
      significant differences were found in the mean values of apoptosis (mostly in the
      atretic and some secondary follicles) and follicular viability in both groups. In
      Group I, immediate and long-term patency were documented in 100% and 27% (3/11)
      of the grafts, respectively; and postoperative FSH levels were similar to
      preoperative values in animals with patent vessels. In Group II, postoperative
      FSH levels were significantly higher than the preoperative ones (P=.03).
      CONCLUSION(S): Transplantation of an intact frozen-thawed ovary is technically
      feasible. Using this approach, immediate restoration of vascular supply and
      ovarian hormonal functions is possible.

PMID- 12620448
TI  - "Z"-plasty of the transverse vaginal septum using Garcia's procedure and the
      Grunberger modification.
AB  - OBJECTIVE: Evaluation of the Grunberger modification of Garcia's "Z"-plasty of
      the obstructed and nonobstructed transverse vaginal septum. DESIGN: Description
      of the surgical procedure and record of postoperative results and follow-up
      evaluations yearly after the operation. SETTING: Department of gynecology and
      obstetrics at a university hospital. PATIENT(S): The operation was performed over
      a period of 25 years on 13 patients. INTERVENTION(S): Z-plasty of the obstructed
      and nonobstructed transverse vaginal septum using Grunberger's modification of
      Garcia's procedure. MAIN OUTCOME MEASUREMENT(S): Width of the vagina and quality
      of postoperative sexual life. RESULT(S): In all cases, a functioning vagina with
      at least a 4-cm width in the former area of the septum was created and no
      postoperative contractures occurred. Lubrication during copulation is perceived
      to be adequate. A satisfactory sexual life was reported by all of the patients.
      Cosmetically, the results were always satisfying. CONCLUSION(S): The Grunberger
      modification of the Garcia Z-plasty method is a convenient and effective
      technique for the surgical treatment of transverse vaginal septa.

PMID- 12620449
TI  - Diagnostic and therapeutic value of selective salpingography and tubal
      catheterization in an unselected infertile population.
AB  - OBJECTIVE: To present diagnostic findings and fertility outcome after selective
      salpingography and tubal catheterization in an unselected infertile population.
      DESIGN: Cohort study. SETTING: Tertiary reproductive medicine unit. PATIENT(S):
      One hundred ten consecutive infertile women. No exclusion criteria were applied.
      Follow-up ranged from 16 to 54 months. INTERVENTION(S): Selective salpingography
      and tubal catheterization under fluoroscopic guidance as the primary test for the
      assessment of the fallopian tubes. MAIN OUTCOME MEASURE(S): Incidence of tubal
      disease at selective salpingography, therapeutic effectiveness of tubal
      catheterization, and fertility outcome after the procedure. RESULT(S): Tubal
      disease was present in 31.4% of the tubes examined. Of tubes proximally blocked
      at selective salpingography, 52.1% were found to be normal after tubal
      catheterization. Proximal tubal blockage (bilateral or unilateral) was detected
      in 34.8% of women. This was reduced to 5.5% after tubal catheterization.
      Spontaneous conceptions occurred in 21.9% of the women. In total, 36.2% conceived
      without IVF or ICSI. CONCLUSION(S): Selective salpingography and tubal
      catheterization can be useful as a primary tubal assessment tool in the
      investigation of infertility. In cases of proximal tubal blockage, an effective
      see-and-treat approach can be adopted. More research into the possible
      therapeutic benefits of the procedure is justified.

PMID- 12620450
TI  - Percutaneous vasal sperm aspiration and intrauterine insemination for infertile
      males with anejaculation.
AB  - OBJECTIVE: To explore the effectiveness of percutaneous vasal sperm aspiration
      (PVSA) in combination with intrauterine insemination (IUI) to treat infertile men
      with anejaculation. DESIGN: Clinical study. SETTING: Department of reproductive
      endocrinology and andrology of a family planning research clinic. PATIENT(S):
      Twenty-six anejaculatory infertile men. INTERVENTION(S): Spermatozoa obtained
      from the vas deferens by percutaneous aspiration were incubated in sperm
      preparation medium. MAIN OUTCOME MEASURE(S): Sperm quality by PVSA and pregnancy
      outcome. RESULT(S): Thirty-four PVSA-IUI procedures were performed in 26 men with
      anejaculation. Nineteen pregnancies were achieved (pregnancy rate, 73.1%). Mean
      (+/-SD) values for sperm variables were as follows: motility, 78.6% +/- 14.2%;
      progressive motility, 60.4% +/- 11.2%; density, 37.6 +/- 13.2 x 10(6) cells/mL;
      total count, 35.2 +/- 13.2 x 10(6) cells; and abnormal sperm, 18.6% +/- 7.6%.
      CONCLUSION(S): Percutaneous vasal sperm aspiration may obtain high-motility
      sperm, and PVSA plus IUI is an effective treatment for male infertility with
      anejaculation.

PMID- 12620451
TI  - First live birth after ovarian stimulation using a chimeric long-acting human
      recombinant follicle-stimulating hormone (FSH) agonist (recFSH-CTP) for in vitro
      fertilization.
AB  - OBJECTIVE: To report the first pregnancy and live birth after ovarian stimulation
      using a chimeric long-acting human recombinant FSH agonist (recFSH-CTP) for IVF.
      DESIGN: Case report. SETTING: Tertiary fertility center. PATIENT(S): A 32-year
      old woman with a 7-year history of primary infertility. INTERVENTION(S): Ovarian
      stimulation with a single SC injection of 180 microg recFSH-CTP on cycle day 3,
      followed by daily injections of 150 IU recFSH from cycle day 10 onward, combined
      with daily GnRH antagonist 0.25 mg SC to prevent a premature LH rise. Final
      oocyte maturation was induced by 10,000 IU hCG. MAIN OUTCOME MEASURE(S): First
      ongoing pregnancy obtained with recFSH-CTP. RESULT(S): Twelve oocytes were
      retrieved. Ten oocytes were fertilized in vitro by intracytoplasmic sperm
      injection, and from these 10 oocytes, two embryos were subsequently transferred
      after 3 days of culture. A pregnancy test 2 weeks after ET was positive, and
      ultrasound investigation revealed an intact, intrauterine, singleton pregnancy
      after 12 weeks. CONCLUSION(S): The first pregnancy and live birth was achieved
      after ovarian stimulation using recFSH-CTP for IVF.

PMID- 12620452
TI  - An unusual complication of tubal anastomosis.
AB  - OBJECTIVE: To report an unusual complication associated with the use of a long
      term intrafallopian stent during microsurgical tubal anastomosis. DESIGN: Case
      report. SETTING: Tertiary academic center. PATIENT(S): A 36-year-old woman in
      whom an intrafallopian stent used during a sterilization reversal procedure could
      not be transcervically retrieved in the office. INTERVENTION(S): Hysteroscopic
      evaluation for removal of intrafallopian stent, followed by operative laparoscopy
      for postoperative abdominal pain. MAIN OUTCOME MEASURE(S): Patient symptoms,
      potential for morbidity, and review of the literature. RESULT(S): Hysteroscopic
      view of the uterine cavity failed to identify the intrafallopian stent.
      Laporoscopic evaluation of postoperative abdominal pain revealed significant
      formation of pelvic and abdominal adhesions. The 2-0 nylon suture used as an
      intrafallopian stent was seen sitting freely on top of the liver serosa.
      Adhesiolysis and successful retrieval of the stent resolved the patient's
      symptoms. CONCLUSION(S): To our knowledge, this is the first report describing
      complete dislodgment and cephalad migration of an intrafallopian stent. Patient
      morbidity and health care costs may increase when long-term stents are used for
      sterilization reversal.

PMID- 12620454
TI  - Determination of the best-fitting ultrasound formulaic method for ovarian volume
      measurement in women with polycystic ovary syndrome.

PMID- 12620453
TI  - Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman
      with a nonsteroidal aromatase inhibitor.
AB  - OBJECTIVE: To assess the management of symptomatic leiomyomas using a
      nonsteroidal aromatase inhibitor in perimenopausal women. DESIGN: Case report.
      SETTING: Academic clinical practice. PATIENT(S): A 53-year-old woman suffering
      from recurrent urinary retention secondary to a uterine leiomyoma.
      INTERVENTION(S): Fadrozole, orally, 2 mg daily for 8 weeks and then 1 mg daily
      for 4 weeks. MAIN OUTCOME MEASURE(S): Measurements of leiomyoma volume, and
      levels of serum E(2), LH, and FSH. RESULT(S): Urinary retention resolved after 2
      weeks of treatment and did not recur. Leiomyoma volume estimated by
      ultrasonography revealed a 71% reduction after 8 weeks of treatment.
      CONCLUSION(S): Fadrozole was useful for the management of a symptomatic leiomyoma
      without transient deterioration of symptoms. Clinical trials are warranted.

PMID- 12620455
TI  - Apoptosis and proliferation factors in serum and follicular fluid from women
      undergoing in vitro fertilization.

PMID- 12620456
TI  - Effect of hysteroscopy performed in the cycle preceding controlled ovarian
      hyperstimulation on the outcome of in vitro fertilization.

PMID- 12620457
TI  - Sex chromosome aberrations and transsexualism.

PMID- 12620458
TI  - Effect of sperm-immobilizing antibodies bound to the surface of ejaculated human
      spermatozoa on sperm motility in immunologically infertile men.

PMID- 12620459
TI  - Male infertility and adult polycystic kidney disease are associated with
      necrospermia.

PMID- 12620460
TI  - Extremes of body mass index reduce in vitro fertilization pregnancy rates.

PMID- 12620461
TI  - Sperm to zona pellucida binding depends on the use of a gonadotropin-releasing
      hormone agonist or a gonadotropin-releasing hormone antagonist.

PMID- 12620462
TI  - Assessment of tissue injury in cryopreserved ovarian tissue.

PMID- 12620463
TI  - Difficult embryo transfer has a negative impact on the outcome of in vitro
      fertilization.

PMID- 12620464
TI  - Ultrasonographic assessment of endometrial receptivity at embryo transfer in an
      in vitro maturation of oocyte program.

PMID- 12620465
TI  - Long-term response to naltrexone in polycystic ovary syndrome?

PMID- 12620467
TI  - Comparative efficacy of hydroxyethyl starch and haemaccel in the treatment of
      severe ovarian hyperstimulation syndrome.

PMID- 12620469
TI  - Aging, twinning, and perinatal outcomes.

PMID- 12620475
TI  - Use of diamide-acridine orange fluorescence staining to detect aberrant
      protamination of human-ejaculated sperm nuclei.
AB  - OBJECTIVE: To investigate the influence of human sperm nuclear chromatin on
      fertilization. DESIGN: Prospective study. SETTING: Assisted reproductive
      technology unit at a university teaching hospital. PATIENT(S): Fifty men starting
      an IVF-ET program. INTERVENTION(S): Epifluorescent microscopic observation of
      human-ejaculated sperm nuclei stained with diamide-acridine orange. Sodium
      dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of
      extracted sperm nucleoproteins. MAIN OUTCOME MEASURE(S): Usefulness of diamide
      acridine orange in analysis of human sperm nuclear chromatin and fertilization
      ability. RESULT(S): There was no correlation between the semen parameters and the
      diamide-acridine orange observation. A positive correlation was observed between
      the fertilization rate after conventional IVF and the green-type increase ratio
      (percentage of green-pattern sperm after diamide-acridine orange
      staining/percentage of green-pattern sperm after acridine orange staining).
      Furthermore, it was suggested by SDS-PAGE that structural differences were
      noticed between the fertile men and the men with sperm immaturity diagnosed after
      diamide-acridine orange staining. CONCLUSION(S): Diamide-acridine orange staining
      was a more precise method for detecting chromatin abnormalities in human
      ejaculated sperm and evaluating fertilization ability than acridine orange
      staining alone. This method can be used as a diagnostic tool to assess the
      fertilization ability of human-ejaculated spermatozoa before IVF procedures.

PMID- 12620476
TI  - Microfilament disruption is required for enucleation and nuclear transfer in
      germinal vesicle but not metaphase II human oocytes.
AB  - OBJECTIVE: To evaluate the usefulness of microfilament disruption before
      enucleation and nuclear transfer in human oocytes at different stages of
      maturation. DESIGN: Prospective experimental study. SETTING: Private clinics.
      PATIENT(S): Infertile couples undergoing assisted reproduction attempts.
      INTERVENTION(S): Oocyte enucleation and nuclear transfer, activation of
      reconstructed oocytes. MAIN OUTCOME MEASURE(S): Oocyte survival, nuclear transfer
      efficacy, activation outcomes. RESULT(S): Survival rate and nuclear transfer
      efficacy of germinal vesicle oocytes exposed to the microfilament disrupting
      agent cytochalasin B before enucleation were 88% and 80%, respectively. These
      figures dropped, respectively, to 8% and 2% when cytochalasin treatment was
      omitted. By contrast, cytochalasin-treated and -untreated metaphase II oocytes
      showed similar survival rate (87% vs. 90%) and nuclear transfer efficacy (78% vs.
      87%). This also applied to metaphase II oocytes matured in vitro from the
      germinal vesicle stage. Cytochalasin treatment did not affect activation rate of
      reconstructed oocytes, but it increased the occurrence of oocytes with multiple
      female pronuclei. CONCLUSION(S): Microfilament disruption before enucleation is
      required for germinal vesicle oocytes but not for metaphase II oocytes.

PMID- 12620477
TI  - Cryopreservation of ovine primordial follicles using dimethyl sulfoxide.
AB  - OBJECTIVE: To verify the viability of isolated primordial follicles after
      exposure to different concentrations of dimethyl sulfoxide (DMSO) and after
      cryopreservation. DESIGN: Randomized control trial. SETTING: Laboratorio Renzo
      Giuliani, University of Florence, Italy. ANIMAL(S): Thirty- to 40-day-old lambs.
      MAIN OUTCOME MEASURE(S): Isolated primordial follicles were stained with trypan
      blue to evaluate the effect of different DMSO concentrations before and after the
      cryopreservation. Histological structure and follicular mortality were evaluated.
      RESULT(S): After the isolation procedure (control), a mean (+/-SE) of 800 +/-
      203.86 live primordial follicles/mL were obtained. The number of live follicles
      in the toxicity test using the DMSO at 0, 0.5, 1.0, 1.5, 2.0, and 2.5 M was 782
      +/- 193.96, 754 +/- 172.03, 778 +/- 191.58, 736 +/- 191.92, 476 +/- 122.9, and
      316 +/- 83.52, respectively. The number of live follicles at 2.5 M was lower than
      that in the control procedure. After cryopreservation, the numbers decreased to 0
      +/- 0, 232 +/- 44.20, 636 +/- 161.82, 628 +/- 181.28, 208 +/- 11.57, and 184 +/-
      47.07, respectively at 0, 0.5, 1.0, 1.5, 2.0, and 2.5 M. The number of live
      follicles at 0, 0.5, 2.0, and 2.5 M were lower than that in the control
      procedure. CONCLUSION(S): After cryopreservation, only DMSO concentrations of 1.0
      and 1.5 M showed a number of live follicles similar to that of the control
      procedure.

PMID- 12620479
TI  - Regulation of matrix metalloproteinase-9 (MMP-9), tissue inhibitor of MMP, and
      progesterone secretion in luteinized granulosa cells from normally ovulating
      women with polycystic ovary disease.
AB  - OBJECTIVE: To investigate the regulation of MMP-9, TIMP-1, and progesterone via
      three signal transduction pathways in luteinized granulosa cells from normal
      ovulatory and PCOD women. DESIGN: In vitro study. SETTING: Laboratory for
      Research in Reproductive Sciences, Department of Obstetrics and Gynecology,
      Ha'Emek Hospital, Afula, Israel. PATIENT(S): Ten normal ovulatory and 10 women
      with polycystic ovary disease (PCOD) treated in an assisted reproduction program.
      INTERVENTION(S): Cultured cells were exposed to phorbol 12-myristate 13-acetate
      (TPA), acting via protein kinase C (PKC), to epidermal growth factor (EGF),
      acting via protein tyrosine kinase (PTK), and to forskolin, acting via protein
      kinase A (PKA). MAIN OUTCOME MEASURE(S): Secretion of MMP-9, TIMP-1, and
      progesterone. RESULT(S): Phorbol 12-myristate 13-acetate elicited an increase in
      MMP-9 and TIMP-1 secretion in both groups and apparently did not affect
      progesterone secretion. Epidermal growth factor did not change significantly
      neither MMP-9 nor TIMP-1 secretion but dose dependently decreased MMP-9-TIMP-1
      ratio and increased progesterone secretion in the PCOD group. Forskolin inhibited
      MMP-9 activity and increased TIMP-1 and progesterone secretion in both groups.
      Progesterone production was inversely related to the ratio of MMP-9-TIMP-1
      regardless of cell origin. CONCLUSION(S): In this preliminary study, similar and
      divergent patterns have emerged in the regulation of MMP-9 and TIMP-1 in human
      luteinized granulosa cells. Repressing MMP-9-TIMP-1 ratio may have an important
      modulatory effect on progesterone secretion.

PMID- 12620478
TI  - Effects of nitric oxide and cGMP on inhibin A and inhibin subunit mRNA levels
      from cultured rat granulosa cells.
AB  - OBJECTIVE: To determine the effects of nitric oxide (NO) and cGMP on inhibin A
      and inhibin subunit mRNA levels from cultured rat granulosa cells. DESIGN: Basic
      research study. SETTING: University research laboratory. ANIMAL(S): Primary cell
      culture of granulosa cells obtained from estrogen-treated, immature Sprague
      Dawley female rats. INTERVENTION(S): Functionally immature rat granulosa cells
      were incubated for 48 hours with media alone; FSH; forskolin; the NO generator
      DETA/NO; an inhibitor of soluble guanylyl cyclase (ODQ); and/or a cell-permeable
      cGMP analog. MAIN OUTCOME MEASURE(S): Media concentrations of inhibin A were
      measured by solid-phase immunosorbent assay. Inhibin alpha and betaA subunit mRNA
      levels were determined by Northern and slot blot analyses. RESULT(S): Whereas FSH
      caused a 20-fold increase in inhibin A levels compared with untreated granulosa
      cells, the NO generator DETA/NO significantly inhibited FSH-stimulated inhibin A
      concentrations. Similarly, cotreatment with FSH plus dibutyryl cGMP significantly
      attenuated inhibin A concentrations, compared with those in cells treated with
      FSH alone. Incubation with forskolin (FSK) stimulated inhibin A levels sevenfold,
      whereas cotreatment with FSK plus DETA/NO or FSK plus dibutyryl cGMP effectively
      decreased inhibin A concentrations. The effects of NO on inhibin A levels were
      not prevented by cotreatment with an inhibitor of soluble guanylyl cyclase. In
      addition, there was no influence of DETA/NO or dibutyryl cGMP on inhibin subunit
      mRNA levels. CONCLUSION(S): These findings indicate that NO and cGMP can
      attenuate inhibin A concentrations through actions at one or more post-FSH
      receptor sites. These influences may reflect inhibition of inhibin A secretion,
      rather than gene expression and protein synthesis. In addition, NO decreases
      inhibin A concentrations through both cGMP-dependent and -independent pathways.
      These results suggest local roles for NO and cGMP in the regulation of granulosa
      cell function.

PMID- 12620480
TI  - CYP1A1, CYP19, and GSTM1 polymorphisms increase the risk of endometriosis.
AB  - OBJECTIVE: To investigate the possibility of genetic contribution of CYP1A1,
      CYP19, GSTM1, and GSTT1 polymorphisms to endometriosis. DESIGN: Genetic
      polymorphism analysis. SETTING: Case-control study. PATIENT(S): A group of 275
      women with sporadic endometriosis was compared with a group of 346 fertile,
      endometriosis-free women. INTERVENTION(S): Surgical, laparoscopic, and
      histological examination. MAIN OUTCOME MEASURE(S): Blood specimens were obtained
      from endometriosis cases and controls. Polymerase chain reaction-based assays
      were performed for the determination of individual's genotype. RESULT(S): The
      CYP19 VNTR, located in intron 4 (TTTA)(10) allele increases the risk for
      endometriosis development (odds ratio [OR], 4.99; 95% confidence interval [95%
      CI], 1.351 to 18.436). The combined genotype CYP1A1 wt/m1 or m1/m1 and GSTM1 null
      deletion adds to this risk (OR, 1.95; 95% CI, 1.266 to 2.995 and OR, 2.23; 95%
      CI, 0.631 to 7.906, respectively). In contrast, the CYP1A1 wt/wt genotype
      exhibits a protective effect, with a 38% reduction in the odds for endometriosis
      development (OR, 0.62; 95% CI, 0.440 to 0.883). CONCLUSION(S): Our data suggest
      that CYP19 VNTR (TTTA)(10) allele as well as the combined genotype CYP1A1 m1
      polymorphism and GSTM1 null deletion associate with the endometriosis phenotype,
      whereas the GSTT1 null deletion does not.

PMID- 12620481
TI  - Resolution of clonal origins for endometriotic lesions using laser capture
      microdissection and the human androgen receptor (HUMARA) assay.
AB  - OBJECTIVE: To determine the clonal origins of endometriotic lesions using laser
      capture microdissection and PCR-based HUMARA assay. DESIGN: Molecular genetic
      study of human tissue. SETTING: Molecular genetics laboratory in an academic
      setting. PATIENT(S): Twenty patients with endometriosis. Forty specimens of
      endometriotic lesions from these patients and one specimen of normal endometrium
      were analyzed. INTERVENTION(S): Laser capture microdissection was used to harvest
      epithelial cells from single and multifocal endometrial lesions from paraffin
      embedded and frozen tissues, and their clonality was determined with the HUMARA
      assay. MAIN OUTCOME MEASURE(S): Polymerase chain reaction-based HUMARA assay of
      clonality. RESULT(S): Thirty-eight specimens were polymorphic and thus
      informative. Most specimens were monoclonal, as determined by the HUMARA assay.
      In four specimens of multifocal lesions, polyclonality was detected, but upon
      more refined microdissections and further analyses, we found that each focus was
      monoclonal individually. CONCLUSION(S): Previously reported polyclonality is very
      likely to be attributed to the pooling of multifocal lesions or contamination of
      normal tissues. These results suggest that endometriotic lesions were monoclonal
      in origin, and in the case of multifocal lesions, each focus originates
      monoclonally; hence, different foci have independent origins. The monoclonality
      of endometriotic lesions suggests that they may carry neoplastic potentials, and
      the apparent independent origins of multifocal lesions suggest that
      reconstruction of individual lesion histories may help us to understand the
      initiation and progression of endometriosis.

PMID- 12620482
TI  - Evidence for cycle-dependent expression of full-length human chorionic
      gonadotropin/luteinizing hormone receptor mRNA in human endometrium and decidua.
AB  - OBJECTIVE: To investigate the expression of full-length and truncated hCG/LH
      receptor mRNA in human endometrium and decidua. DESIGN: In vitro experiment.
      SETTING: Tertiary university center. PATIENT(S): Premenopausal women undergoing
      hysterectomy because of benign diseases or induced abortions. INTERVENTION(S):
      Isolation of RNA from endometrial samples, reverse transcription, selective
      preamplification of full-length hCG/LH receptor mRNA and several shorter
      fragments of the receptor gene (exons 1-11, 1-10, and 1-5), nested polymerase
      chain reaction with internal primers. MAIN OUTCOME MEASURE(S): Appropriately
      sized cDNA product confirmed by sequencing. RESULT(S): All samples derived from
      the proliferative as well as from the early and mid-luteal phases were positive
      for all four amplification products, suggesting the expression of a full-length
      hCG/LH receptor mRNA. Only 5 of 8 samples derived from the late secretory phase
      and 2 of 12 samples derived from early decidua amplified the entire receptor
      sequence. In contrast, the shortest fragment (exons 1-5), coding for part of the
      extracellular receptor domain, was amplified in all samples. CONCLUSION(S): The
      data suggest cycle-dependent regulation of hCG/LH-receptor mRNA by changes in the
      alternative splicing pattern and down-regulation of full-length hCG/LH receptor
      mRNA in early decidua. The major splicing site appears to be located between
      introns 5 and 9. Alternative splicing may be a mechanism regulating hCG/LH
      receptor down-regulation.

PMID- 12620483
TI  - Adhesion of endometrial cells labeled with 111Indium-tropolonate to peritoneum: a
      novel in vitro model to study endometriosis.
AB  - OBJECTIVE: To evaluate, in a new original in vitro assay, putative factors that
      could modulate the adhesion of endometrial cells to peritoneum. DESIGN:
      Prospective, controlled in vitro study. SETTING: Academic research laboratory.
      PATIENT(S): Fourteen nonmenopausal women undergoing hysterectomy or laparoscopy
      for benign gynecologic indication. INTERVENTION(S): Endometrial cells obtained
      from women with regular cycles without endometriosis were labeled with 111Indium
      and confronted in vitro with mouse peritoneum in the presence of various
      cytokines and/or antiadhesive compounds. MAIN OUTCOME MEASURE(S): Radioactivity
      in 111Indium-labeled endometrial cells. RESULT(S): The adhesion of human
      endometrial cells to mouse peritoneum was increased by treatment with pro
      inflammatory cytokines (interleukin IL-1beta, IL-6, TNF alpha, TGF-beta1).
      Whereas heparan sulfate had no effect on cell adhesion, a gel of ferric
      hyaluronate (Intergel) was able to counteract the pro-adhesive effect of
      cytokines. Interestingly, the pretreatment of peritoneum with cytokines, 24 hours
      before cell seeding in the presence of the ferric hyaluronate gel, restored the
      cytokine-promoting effect on cell adhesion. CONCLUSION(S): Proinflammatory
      cytokines promote the in vitro peritoneal adhesion of endometrial cells. An
      antiadhesive hyaluronate gel used in clinics decreases the adhesion in a dose
      dependent manner and reduces cytokine bioavailability.

PMID- 12620484
TI  - Effect of female sex steroids on human endometrial CD16neg CD56bright natural
      killer cells.
AB  - OBJECTIVE: To clarify whether female sex steroids directly affect the bioactivity
      of the human endometrial CD16neg CD56bright natural killer (NK) cells. DESIGN: In
      vitro study. SETTING: University obstetrics and gynecology department.
      PATIENT(S): Thirteen women with histologically normal endometrium who were
      undergoing hysterectomy and seven women during the first trimester of pregnancy
      who were undergoing selective termination. INTERVENTION(S): Endometrium or
      decidua was obtained. MAIN OUTCOME MEASURE(S): The effects of 17beta-estradiol or
      progesterone (10(-6), 10(-7), and 10(-8) M) on the proliferation, cytolytic
      activity, and cytokine secretion of the isolated endometrial CD16neg CD56bright
      NK cells were examined using a 3H-thymidine incorporation assay, 51Cr-releasing
      assay, and enzyme-linked immunosorbent assay, respectively. RESULT(S): Neither
      17beta-estradiol nor progesterone had significant effects on the proliferation,
      cytolytic activity, and cytokine secretion of endometrial CD16neg CD56bright NK
      cells. CONCLUSION(S): Female sex steroids do not directly affect the bioactivity
      of the human endometrial CD16neg CD56bright NK cells.

PMID- 12620485
TI  - Gonadotropin-releasing hormone agonist and danazol normalize aromatase cytochrome
      P450 expression in eutopic endometrium from women with endometriosis,
      adenomyosis, or leiomyomas.
AB  - OBJECTIVE: To investigate whether GnRH agonists or danazol therapy normalizes
      estrogen metabolism in the eutopic endometrium of women with endometriosis,
      adenomyosis, or leiomyomas. DESIGN: Prospective clinical study. SETTING:
      University hospital. PATIENT(S): Fifty-three women with endometriosis,
      adenomyosis, or leiomyomas. INTERVENTION(S): Patients received GnRH agonist or
      danazol. Biopsy samples of the endometrium were obtained before and after
      endocrine therapy. Nontreated endometrial explants were cultured in the presence
      of either drug. MAIN OUTCOME MEASURE(S): Reverse transcription polymerase chain
      reaction-Southern blot and immunohistochemical analyses of the endometrial
      expression of aromatase cytochrome P450, estrogen receptor, progesterone
      receptor, and Ki-67. Nontreated endometrial explants were cultured in the
      presence of either drug. RESULT(S): Messenger RNA and protein of aromatase
      cytochrome P450 were greatly reduced in the eutopic endometrium of patients
      treated with GnRH agonist for 2 months or more or with danazol for 1 month or
      more. Culture of endometrial explants with GnRH agonist (10(-9)-10(-7) M) did not
      change the amount of aromatase cytochrome P450, whereas danazol (10(-7)-10(-6) M)
      efficiently reduced aromatase cytochrome P450 expression. CONCLUSION(S): Therapy
      with GnRH agonist or danazol decreases expression of aromatase cytochrome P450 in
      diseased eutopic endometrium. Endocrine therapy normalized in part the impaired
      hormonal expression of the eutopic endometrium. GnRH agonist reduced aromatase
      cytochrome P450 expression mainly by promoting a hypoestrogenic state, whereas
      danazol reduced aromatase cytochrome P450 in part by direct action on the eutopic
      endometrium.

PMID- 12620486
TI  - Inhibin and follicular development in heterotopical ovary transplants without
      vascular pedicle in syngeneic Lewis rats.
AB  - OBJECTIVE: To evaluate the role of inhibin in elevated base levels of FSH and
      follicular hyperplasia in ovarian autotransplantation in rats. DESIGN:
      Experimental animal study. SETTING: Unit of Experimental Research at the
      Barcelona University School of Medicine. ANIMAL(S): Female syngeneic Lewis rats
      aged 16 weeks. INTERVENTION(S): The animals were randomized into two groups:
      group A, control group undergoing only laparotomy (n = 5) and group B,
      oophorectomized with SC autologous heterotopic transplant (n = 5). The animals
      were killed and their ovaries removed for histologic, morphometric, and
      immunohistochemical analysis at 28 days after surgery in both groups. MAIN
      OUTCOME MEASURE(S): Serum levels of E2 and FSH were determined on day 0 (the day
      of surgery or baseline) and days 4, 7, 14, 21, and 28. Morphometric analysis of
      ovarian structure for evaluation of antral follicles and their granulosa cell
      area and immunohistochemistry for inhibin staining were also done. RESULT(S): The
      endocrinological function recovered at 28 days, and the FSH levels for the
      transplant group were significantly higher than for the group with normoinsert
      ovary. Morphometric analysis showed that the mean granulosa cell area was greater
      in group B when compared with the control group. Immunohistochemistry revealed
      almost null inhibin staining of the stroma in transplanted ovarian tissue.
      CONCLUSION(S): Tissue damage brought on by ischemia in the transplant of
      nonvascularized ovaries may bring about an inhibin deficit in the ovarian stroma,
      which might explain the increased levels of FSH. These increased levels, in turn,
      would be responsible for the follicular hyperplasia seen in this tissue when it
      recovers its function.

PMID- 12620487
TI  - Nitric oxide synthesis in human nonpregnant myometrium and uterine myomas.
AB  - OBJECTIVE: To clarify whether nitric oxide (NO) synthesis in myomas differs from
      that in parental human myometrium. DESIGN: Prospective study. SETTING: Academic
      research institution. PATIENT(S): Twenty-one patients undergoing laparoscopy or
      laparotomy for uterine myoma. MAIN OUTCOME MEASURE(S): Measurement of NO synthase
      activity in homogenates from myoma and parental myometrium biopsies, and NO
      synthesis assessment in cultured smooth-muscle cells. RESULT(S): Nitric oxide
      synthase activity in homogenates did not significantly differ between myoma and
      healthy myometrium. The medium taken from myoma cultures showed a significant
      increase in nitrite concentration compared with that taken from control
      myometrium cultures, but 24-hour incubation of both cell types with physiologic
      concentrations of 17beta-estradiol or progesterone did not significantly modify
      nitrite production. CONCLUSION(S): The maximal activity of NO synthase does not
      differ in myoma cells and in normal myometrial cells, but basal NO synthesis
      seems to be enhanced by an unknown signaling pathway that is not controlled by
      17beta-estradiol or progesterone.

PMID- 12620488
TI  - Differences in mitochondrial and nuclear DNA status of high-density and low
      density sperm fractions after density centrifugation preparation.
AB  - OBJECTIVE: To determine the mitochondrial DNA and nuclear DNA fragmentation of
      sperm populations separated by using discontinuous density gradient. DESIGN:
      Analysis of mitochondrial and nuclear DNA status of sperm from high and low
      density layers. SETTING: Regional fertility center. PATIENT(S): Twenty-eight men
      who presented for an initial infertility investigation. MAIN OUTCOME MEASURE(S):
      Semen was prepared by using discontinuous density gradient (90.0%:45.0%) and
      subjected to a modified long polymerase chain reaction to assess mitochondrial
      DNA deletions and to a modified single-cell alkaline gel electrophoresis assay to
      determine nuclear DNA fragmentation. RESULT(S): The high-density fraction
      displayed significantly more wild-type mitochondrial DNA (75% of samples) than
      did the low-density fraction (25% of samples). In the high-density fraction, the
      incidence of single deletions was higher than that of double or multiple
      deletions, and the deletions were predominantly small. A strong correlation was
      observed between nuclear DNA fragmentation and the number and size of
      mitochondrial DNA deletions. CONCLUSION(S): Density centrifugation isolates a
      population of sperm with high-quality mitochondrial DNA and nuclear DNA.

PMID- 12620490
TI  - Time series analysis of transmesothelial invasion by endometrial stromal and
      epithelial cells using three-dimensional confocal microscopy.
AB  - OBJECTIVE: To evaluate endometrial adhesion and invasion of peritoneal
      mesothelium. DESIGN: Descriptive study using confocal laser-scanning microscopy.
      SETTING: University-based laboratory. PATIENT(S): Women undergoing surgery for
      benign conditions. INTERVENTION(S): Fluorescence-labeled peritoneal mesothelial
      cells (PMCs) were grown on coverslips. Fluorescence-labeled endometrial stromal
      cells (ESCs) and epithelial cells (EECs) and myometrial cells (Myos) were plated
      on the PMCs. Cultures were examined at 1, 6, 12, and 24-27 hours with
      differential interference contrast and confocal laser-scanning microscopy. MAIN
      OUTCOME MEASURE(S): Demonstration of adherence and invasion of endometrial cells
      through peritoneal mesothelium. RESULT(S): At 1 hour, there was adherence of the
      ESCs, EECs, and Myos on the perimeter of PMCs. There was no invasion by the Myos.
      By 6 hours, ESCs and EECs spread over the surface of the PMCs and extended cell
      processes through PMC junctions. Extension of pseudopodia under the PMCs
      followed. By 12 hours, there was vacuolization and lifting of PMCs that had been
      undermined by endometrial cells. CONCLUSION(S): This is the first time-phase
      study to demonstrate adherence and the process of invasion of endometrial cells
      through the mesothelium. The application of three-dimensional confocal laser
      scanning microscopy is a novel technique that can be used to further examine
      mechanisms involved in the pathogenesis of the early endometriotic lesion.

PMID- 12620489
TI  - Cytokine regulation by peroxisome proliferator-activated receptor gamma in human
      endometrial cells.
AB  - OBJECTIVE: To determine whether peroxisome proliferator-activated receptor (PPAR)
      gamma ligands can affect the expression of interleukin-6 (IL-6) and cytokines
      related to the pathogenesis of endometriosis. DESIGN: In vitro study to determine
      whether PPARs are expressed in human endometrial cells and determine the effects
      of various PPAR-gamma ligands on IL-6 and other cytokine expression in these
      cells. SETTING: Academic medical center. PATIENT(S): Women presenting for
      infertility workup. INTERVENTION(S): Endometrial cell cultures were treated with
      PPAR-gamma ligands. MAIN OUTCOME MEASURE(S): Interleukin-6, IL-8, colony
      stimulating factor-1 (CSF-1) and macrophage chemotactic factor (MCP-1) protein
      secretion, messenger RNA expression of IL-6, PPAR-alpha, -beta, and -gamma.
      RESULT(S): Using a human endometrial cell line (EM42), as well as primary stromal
      and epithelial endometrial cells, we show the presence of PPAR-alpha, -beta, and 
      gamma by reverse transcription-polymerase chain reaction (RT-PCR) in these cells.
      PPAR-gamma ligands stimulated IL-6 secretion and induced enhancement of IL-6 mRNA
      levels. These ligands also stimulated the secretion of IL-8 and CSF-1.
      CONCLUSION(S): PPAR-gamma may play a role in the pathogenesis of endometriosis
      related to the production of IL-6 and some other cytokines.

PMID- 12620491
TI  - Value of the micropig model of menopause in the assessment of benefits and risks
      of postmenopausal therapies for cardiovascular and reproductive tissues.
AB  - OBJECTIVE: To extend the comparative database demonstrating the cardioprotective
      benefits of estrogen therapy to an additional relevant species and to assess the
      usefulness of this model for studies designed to assess benefits and risks of
      postmenopausal therapies. DESIGN: Prospective, randomized, controlled
      periclinical trial. SETTING: Medical university animal facility. ANIMAL(S):
      Fifteen sexually mature Yucatan micropigs and 15 ovariectomized micropigs.
      INTERVENTION(S): Oral conjugated equine estrogens (CEE), 0.625 mg/d, or
      levormeloxifene, 37.5 mg/d, for 182 days. MAIN OUTCOME MEASURE(S): Coronary
      artery atherosclerosis was measured by digitization, uteri were weighed, and
      uterine and mammary tissues were evaluated histologically and morphometrically.
      Mean blood pressure was measured by oscillometry, C-reactive protein by enzyme
      linked immunosorbent assay, and serum lipids by enzymatic methods. RESULT(S):
      Coronary artery atherosclerosis was reduced 51% in animals that received CEE
      compared with controls. Levels of C-reactive protein increased by 12% with both
      treatments. Serum lipid levels and mean blood pressure did not differ among
      groups. Levormeloxifene produced a 5.9-fold increase in the uterine-to-body
      weight ratio. Histologic and morphometric data indicate that levormeloxifene has
      uterotrophic and mammotrophic effects. CONCLUSION(S): The micropig model extends
      the comparative evidence for cardioprotection provided by estrogen therapy to an
      additional highly relevant species, thus supporting the rationale for a
      clinically beneficial role of estrogen for the heart. The marked uterine effects
      of levormeloxifene detected by this model are probably highly predictive of the
      adverse events that would be encountered in clinical trials.

PMID- 12620492
TI  - Presence of endometrial epithelial cells in the peritoneal cavity and the
      mesothelial inflammatory response.
AB  - OBJECTIVE: To determine the contribution of endometrial cells in the development
      of endometriosis. Specifically the response of the mesothelium to endometrial
      cells in the production of monocyte chemotactic protein-1 (MCP-1), interleukin-6
      (IL-6), and IL-8 was studied. DESIGN: In vitro study. SETTING: University
      Research Laboratory. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME
      MEASURE(S): Cellular MCP-1, IL-6 secretion and MCP-1, and IL-6 and IL-8 messenger
      RNA expression were evaluated by ELISA and reverse transcription-polymerase chain
      reaction (RT-PCR) assay. RESULT(S): The mesothelial cells produced more MCP-1 and
      IL-6 than endometrial epithelial and stromal cells. Mesothelial cells cultured in
      the presence of endometrial epithelial cells produced even greater levels of MCP
      1 and IL-6 than those cultured in the presence of stromal cells or cultured
      alone. The MCP-1, IL-6, and IL-8 mRNA expression also increased when mesothelial
      cells were co-cultured with endometrial epithelial cells. CONCLUSION(S): The
      results suggest that endometrial epithelial cells may be important in evoking the
      inflammatory reaction in the peritoneal cavity during retrograde menstruation and
      that mesothelial cells may play an important role in the chemotaxis of monocytes
      and in the inflammatory process during the development of endometriosis.

PMID- 12620493
TI  - Completion of meiosis in human primary spermatocytes through in vitro coculture
      with Vero cells.
AB  - OBJECTIVE: To examine whether human primary spermatocytes will develop into round
      spermatids after completing meiosis in an in vitro coculture with Vero cells.
      DESIGN: Prospective, controlled in vitro study. SETTING: A private infertility
      clinic and a university laboratory. PATIENT(S): Five azoospermic men whose
      spermatogenesis was proved to be arrested at the level of the primary
      spermatocyte in open biopsies. INTERVENTION(S): In vitro coculture of isolated
      primary spermatocytes with Vero cells and chromosomal analysis for assessment of
      the completion of meiosis. MAIN OUTCOME MEASURE(S): Isolated primary
      spermatocytes were cocultured with Vero cells under various conditions. The
      number of chromosomes and chromatids in newly generated cells was determined by
      Giemsa staining after the cells were injected into mouse oocytes. RESULT(S): The
      generation rates of round spermatids in six types of in vitro culture with Vero
      cells were 0%-10% (highest rates of division were in minimum essential medium
      (MEM) + 50% boar rete testicular fluid or in human synthetic oviduct fluid + 10%
      human serum). The number of chromosomes and chromatids in the newly developed
      cells was 23. CONCLUSION(S): A single primary spermatocyte was observed to divide
      into four cells during in vitro coculture with Vero cells. These newly developed
      cells were proved to be round spermatids by chromosomal analysis. It was verified
      that a primary spermatocyte developed into round spermatids after completing two
      cycles of meiosis through in vitro culture.

PMID- 12620494
TI  - Cumulus cells reduce the spermatozoa-zona binding inhibitory activity of human
      follicular fluid.
AB  - OBJECTIVE: To investigate the effects of human follicular fluid cultured with
      cumulus cells to inhibit the binding of spermatozoa to the zona pellucida of
      oocytes. DESIGN: Controlled experimental laboratory study. SETTING: University
      gynecology unit. PATIENT(S): Women undergoing assisted reproduction program and
      men visiting the subfertility clinics. INTERVENTION(S): Culture medium and human
      follicular fluid were used to culture cumulus cells in vitro for specified time
      periods. MAIN OUTCOME MEASURE(S): Zona binding capacity and motility of
      spermatozoa after incubation with cumulus cells treated culture medium or human
      follicular fluid. RESULT(S): Compared with the control medium, spent culture
      media after culturing cumulus cells for 3, 5, and 7 hours did not affect the
      motility and zona binding capacity of the treated spermatozoa. Significantly more
      spermatozoa treated with human follicular fluid that had been preincubated with
      cumulus cells for 5 and 7 hours bound onto hemizona in hemizona binding assay
      when compared with those preincubated in human follicular fluid without cumulus
      treatment. The hemizona index increased with the increase in the duration of
      cumulus cell treatment. Human follicular fluid with or without cumulus cells
      maintained sperm motility to similar extent for 3 hours. CONCLUSION(S): Cumulus
      cells reduced the inhibitory effect of human follicular fluid on spermatozoa-zona
      binding in vitro in a time-dependent manner.

PMID- 12620495
TI  - Coexpression of pinopodes and leukemia inhibitory factor, as well as its
      receptor, in human endometrium.
AB  - OBJECTIVE: To determine cell-type-specific expression of leukemia inhibitory
      factor (LIF) and LIF receptor (LIFR) proteins relative to formation of pinopodes
      in human endometrial samples. DESIGN: Prospective clinical study. SETTING:
      Hospital-based unit for reproductive health and university-affiliated
      reproductive research laboratories. PATIENT(S): Twenty-six healthy fertile women
      with normal menstrual cycles. MAIN OUTCOME MEASURE(S): Routine blood and urine
      samples were obtained, and vaginal ultrasonography and endometrial biopsy were
      performed. Pinopode formation and expression of LIF and LIFR were examined in
      endometrial samples. RESULT(S): Samples obtained during LH days 6 through 9 had
      pinopodes at different developmental stages. Both surface and glandular
      epithelial cells expressed maximal levels of LIF and LIFR protein, in biopsy
      samples showed fully developed pinopodes. Immunostaining of LIF was more intense
      in the glandular epithelium, whereas immunostaining of LIFR was most intense in
      the surface epithelium. Before and after the appearance of pinopodes, LIF and
      LIFR immunostaining was less intense or faint. Stromal endometrial cells showed
      faint LIF accumulation. CONCLUSION(S): The simultaneous positive spatial and
      temporal expression of pinopodes and LIF and LIFR proteins in endometrial samples
      from healthy women suggests that both molecular and structural cell changes are
      important in the initiation of human blastocyst implantation.

PMID- 12620496
TI  - Epithelial neutrophil-activating peptide 78 concentrations are elevated in the
      peritoneal fluid of women with endometriosis.
AB  - OBJECTIVE: To investigate the presence of epithelial neutrophil-activating
      peptide 78 (ENA-78) in peritoneal fluid of women with and without endometriosis
      and to identify the cells that produce this inflammatory protein. DESIGN: Case
      control study. SETTING: University hospital. PATIENT(S): Eighteen women with and
      9 women without endometriosis. MAIN OUTCOME MEASURE(S): ENA-78 protein and mRNA
      levels were compared among women with and without endometriosis in samples of
      peritoneal fluid, samples of endometriotic lesions obtained by biopsy during
      laparoscopy, and peritoneal macrophages. Enzyme-linked immunosorbent assay,
      reverse transcription polymerase chain reaction, and in situ hybridization
      methods were used. Secretion of ENA-78 protein by interleukin-1beta-stimulated
      endometriotic stromal cells and in the media of lipopolysaccharide-stimulated
      peritoneal macrophages were compared to that in unstimulated cell cultures.
      RESULT(S): Peritoneal fluid concentrations of ENA-78 were significantly higher in
      affected women than in controls. Ectopic epithelial and stromal cells and
      peritoneal macrophages express ENA-78 messenger RNA. Interleukin-1beta
      stimulation of stromal cell cultures resulted in a 23-fold increase in ENA-78
      concentration, and lipopolysaccharide stimulation of peritoneal macrophages
      increased concentrations by 8-fold. CONCLUSION(S): Levels of ENA-78 are elevated
      in the peritoneal fluid of women with endometriosis. Ectopic glandular cells,
      ectopic stromal cells, and peritoneal macrophages express this inflammatory
      chemokine. Epithelial neutrophil-activating peptide 78 may play an important role
      in the pathogenesis of endometriosis.

PMID- 12620497
TI  - Interleukin-13 and tumor necrosis factor-beta differentially regulate the
      production of cytokines by cultured human endometrial stromal cells.
AB  - OBJECTIVE: To evaluate the effects of interleukin (IL)-13, a T-helper (Th)2
      cytokine, and tumor necrosis factor (TNF)-beta, a Th1 cytokine, on the production
      of IL-6 family cytokines and chemokines by endometrial stromal cells (ESC).
      DESIGN: The effects of IL-13 and TNF-beta, on the production of IL-6, IL-11,
      leukemia inhibitory factor (LIF), IL-8, growth-regulated oncogene alpha
      (GROalpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation,
      T-cell expressed and secreted (RANTES), and eotaxin were investigated. SETTING:
      Research laboratory at a medical university. PATIENT(S): Thirteen endometrial
      specimens in the late proliferative phase were used. INTERVENTION(S): The ESC
      were incubated for 24 hours with recombinant human IL-13 and recombinant human
      TNF-beta. MAIN OUTCOME MEASURE(S): The concentration of IL-6, IL-11, LIF, IL-8,
      GROalpha, MCP-1, RANTES, and eotaxin in the culture media was measured using
      ELISA. RESULT(S): The increase in levels of IL-6, IL-8, MCP-1, and eotaxin in the
      culture media of ESC paralleled the addition of increasing amounts of IL-13 and
      TNF-beta, whereas the levels of IL-11 and LIF were decreased with increasing
      amounts of IL-13, but were increased with increasing amounts of TNF-beta. Tumor
      necrosis factor-beta enhanced the production of GROalpha and RANTES in dose
      dependent manner; however, IL-13 did not affect the expression of GROalpha or
      RANTES. CONCLUSION(S): These results suggest that IL-13 and TNF-beta secreted in
      the cyclic endometrial tissue and in the decidua may differentially regulate the
      production of IL-6 family cytokines and chemokines by ESC. The controlled
      expression of these cytokines in the endometrium may contribute to the modulation
      of the immune reaction during the menstrual cycle and in early pregnancy by the
      regulation of leukocyte trafficking and functions.

PMID- 12620498
TI  - Inhibitory effects of ursodeoxycholic acid on the induction of nitric oxide
      synthase in vascular smooth muscle cells.
AB  - The expression of inducible nitric oxide synthase (iNOS) and the resultant
      increased nitric oxide production are associated with endotoxemia and
      atherosclerotic lesions observed in transplant hearts or balloon-injured artery.
      Ursodeoxycholic acid has been shown to have cardiovascular protective effects,
      such as inhibition of the development of transplant arteriosclerosis, but its
      mechanism remains unclear. Here, we investigated the effects of ursodeoxycholic
      acid on nitric oxide production and the expression of iNOS in vascular smooth
      muscle cells isolated from adult rat aorta and rabbit coronary artery. Nitrite
      released from cells in the culture medium was measured with the Griess reaction.
      iNOS mRNA and protein were measured by Northern and Western blot analyses.
      Treatment with ursodeoxycholic acid (30-1000 microM) significantly inhibited
      lipopolysaccharide plus interferon-gamma-induced nitric oxide production in a
      concentration-dependent manner, but ursodeoxycholic acid showed only small
      inhibitory effects on nitric oxide production that had already been induced by
      lipopolysaccharide plus interferon-gamma. Ursodeoxycholic acid by itself did not
      affect basal nitric oxide production. Ursodeoxycholic acid also suppressed
      lipopolysaccharide plus interferon-gamma-induced expression of iNOS mRNA and
      protein. Ursodeoxycholic acid had the most potent inhibitory effect among various
      kinds of bile acids examined, i.e. chenodeoxycholic acid, deoxycholic acid,
      cholic acid and conjugated bile acids such as tauroursodeoxycholic acid. These
      results suggest that ursodeoxycholic acid inhibits the induction of iNOS and then
      nitric oxide production in aortic and coronary artery smooth muscle cells,
      suggesting a possible mechanism for the cardiovascular protective effect of
      ursodeoxycholic acid under various pathophysiological conditions such as
      endotoxemia and atherosclerosis.

PMID- 12620499
TI  - Human proximal tubular cell responses to angiotensin II analyzed using DNA
      microarray.
AB  - Angiotensin II has been shown to exert complex effects on proximal tubular cell
      function and growth. To assess some of the direct effects on proximal tubular
      cells, changes in gene expression of selected cellular pathways were determined
      after exposure to angiotensin II. We used DNA microarrays to analyze multiple
      gene expression responses to increasing angiotensin II concentrations. Human
      proximal tubular cells were grown in flasks, and the presence of angiotensin type
      1 receptor was confirmed by Western blot analysis. At passages 4-6, these cells
      were exposed to angiotensin II and harvested 4 h later and mRNA of the cells was
      extracted; 2 microg of mRNA was fluorescently conjugated for cDNA microarray
      hybridization. A custom-made DNA microarray was designed by selecting 300 human
      genes from 10 different functional systems and amplifying clones using polymerase
      chain reaction. Cells were subjected to 10 and 100 nM angiotensin II with paired
      untreated cells as controls. RNA was isolated, reverse transcribed, labeled and
      hybridized to the arrays and the ratios calculated. Ratios of > or =2.0 and < or
      =0.5 were considered significant. Coordinated changes were observed in genes of
      the hepatocyte nuclear factor 3 family (NHF3; HNF3A, HNF3B and HNF3G), in the E2F
      genes (E2F1, E2F3) and the interferon regulatory factors IRF1 and IRF5. Induction
      of the expression of transcription factors points towards complex regulation of
      gene expression upon angiotensin II exposure. Three genes involved in the
      dampening of oxidative stress were enhanced. Taken together, brief exposure of
      human tubular epithelial cells to angiotensin II elicited a marked induction of
      nuclear factors, antioxidant genes and hormones and hormone receptor genes. The
      quick activation of transcription factors by angiotensin II indicates that
      angiotensin II can directly initiate a cascade of expressional events in proximal
      tubular cells.

PMID- 12620500
TI  - Synergy between retigabine and GABA in modulating the convulsant site of the
      GABAA receptor complex.
AB  - The molecular mechanism underlying the activity of the novel antiepileptic drug
      retigabine is not yet fully understood. The aim of this study was to investigate
      whether retigabine interacts directly with the GABA(A) receptor complex (gamma
      aminobutyric acid). Receptor-binding assays were conducted using rat brain
      membranes. [3H]-t-Butyl-bicyclo-orthobenzoate ([3H]TBOB) was used as a tracer
      ligand. We determined the effects of GABA and retigabine in the presence of
      several concentrations of GABA on the binding of [3H]TBOB. GABA inhibited
      [3H]TBOB binding with an EC(50) of 4.8 microM. In the absence of GABA, retigabine
      inhibited [3H]TBOB with an EC(50) of 124 microM and an EC(50) of 42 microM in the
      presence of 2.5 microM GABA. Isobolic analysis revealed that retigabine acts in
      synergy with GABA in displacing [3H]TBOB. This synergy could be quantified by a
      molecular model in which GABA and retigabine both allosterically displace
      [3H]TBOB, and retigabine allosterically enhances the binding of GABA and vice
      versa with a factor of 4. In summary, we found that retigabine does indeed
      interact with a site on the GABA(A) receptor complex, and this site is positively
      allosterically coupled with the GABA site. This GABA-positive effect may well
      contribute to the clinical anticonvulsive effects of retigabine.

PMID- 12620501
TI  - Effects of H2O2 on membrane potential of smooth muscle cells in rabbit mesenteric
      resistance artery.
AB  - The effects of H(2)O(2) on the membrane potential of smooth muscle cells of
      rabbit mesenteric resistance arteries were investigated. H(2)O(2) (3-30 microM)
      concentration-dependently hyperpolarized the membrane; this was inhibited by
      catalase but not by superoxide dismutase or the hydroxyl-radical scavenger
      dimethylthiourea. The cyclooxygenase inhibitor diclofenac partly inhibited the
      responses; the subsequent addition of the 5-lipoxygenase inhibitor 2-(12
      hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone (AA-861) (but not the
      cytochrome P(450) inhibitor 17-octadecynoic acid) further attenuated H(2)O(2)
      induced hyperpolarizations. The sarcolemmal ATP-sensitive K(+) (K(ATP)) channel
      inhibitor 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenylsulfonyl]-3
      methylthiourea, sodium salt (HMR-1098), blocked the H(2)O(2)-induced
      hyperpolarization in the absence and presence of diclofenac. H(2)O(2) increased
      the production of prostaglandin E(2) and prostacyclin (estimated from its stable
      metabolite 6-keto-prostaglandin F(1alpha)), both of which produce a HMR-1098
      sensitive hyperpolarization in the smooth muscle cells. It is concluded that, in
      smooth muscle cells of rabbit mesenteric artery, H(2)O(2) increases the synthesis
      of vasodilator prostaglandins and possibly 5-lipoxygenase products, which produce
      a hyperpolarization by activating sarcolemmal K(ATP) channels.

PMID- 12620502
TI  - The expression of mRNA for calcitonin receptor-like receptor/receptor-activity
      modifying proteins in rat peritoneal mast cells.
AB  - Adrenomedullin is a hypotensive peptide secreted from various cells. Recently, we
      found that adrenomedullin, but not calcitonin gene-related peptide (CGRP),
      stimulates histamine release from rat peritoneal mast cells. In the present
      studies, we investigated the expression of mRNA for calcitonin-receptor-like
      receptor (CRLR) and receptor-activity modifying proteins (RAMPs), the components
      of proposed adrenomedullin receptors, in rat peritoneal mast cells by reverse
      transcription-polymerase chain reaction (RT-PCR). Results revealed that mRNA for
      CRLR, RAMP2 and RAMP3 was expressed in rat peritoneal mast cells, whereas mRNA
      for RAMP1 was not. These data suggest that adrenomedullin might stimulate
      histamine release via its proposed receptor (CRLR/RAMP2 or 3), rather than via
      the CGRP receptor (CRLR/RAMP1).

PMID- 12620503
TI  - Endogenous adenosine prevents post-tetanic release facilitation mediated by
      alpha3beta2 nicotinic autoreceptors.
AB  - We investigated the modulatory role of endogenous adenosine on tetanic-induced
      (50 Hz for 5 s) nicotinic facilitation of [3H]acetylcholine release (5 Hz for 50
      s) from rat motoneurons. Adenosine deaminase (0.5 U/ml) and the adenosine A(2A)
      receptor antagonist, 3,7-dimethyl-1-propargyl xanthine (DMPX, 30 microM),
      facilitated post-tetanic [3H]acetylcholine release. Release inhibition caused by
      tubocurarine (1 microM), dihydro-beta-erythroidine (1 microM) and alpha-conotoxin
      MII (0.1 microM) was attenuated after tetanic preconditioning. Nicotinic
      inhibitory action was fully restored after adenosine A(2A) receptor block by DMPX
      or adenosine deaminase. DMPX (10 microM) caused a leftward shift of the
      inhibitory dose-response curves for d-tubocurarine (0.1-1 microM), dihydro-beta
      erythroidine (0.03-10 microM) and alpha-conotoxin MII (1-300 nM) on post-tetanic
      twitch amplitude. In contrast, the post-tetanic twitch depression caused by alpha
      bungarotoxin (3-100 nM, which had no effect on transmitter release) was
      attenuated by DMPX (10 microM). It is concluded that activation of adenosine
      A(2A) receptors by endogenously generated adenosine prevents the post-tetanic
      release facilitation mediated by nicotinic alpha3beta2 autoreceptors.

PMID- 12620504
TI  - The CRF1 receptor antagonist, DMP695, abolishes activation of locus coeruleus
      noradrenergic neurones by CRF in anesthetized rats.
AB  - Corticotropin-releasing factor (CRF)(1) receptors have been implicated in the
      excitatory influence of CRF upon noradrenergic perikarya of the locus coeruleus.
      This study thus characterized the influence of the novel CRF(1) receptor
      antagonist, DMP695 (N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2
      methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine mesylate), upon
      the electrical activity of noradrenergic perikarya in the locus coeruleus of
      anesthetized rats. Intracerebroventricular injection of CRF dose-dependently
      (0.05-4.0 microg) enhanced the firing rate of noradrenergic cell bodies and
      transformed their firing pattern into a burst mode. This action was dose
      dependently abolished by i.v. administration of DMP695 (0.125-2.0 mg/kg i.v.),
      which did not itself modify the electrical activity of noradrenergic neurones.
      These data demonstrate antagonist properties of DMP695 at central CRF(1)
      receptors excitatory to ascending noradrenergic neurones, an action which may
      contribute to its distinctive profile of anxiolytic properties.

PMID- 12620505
TI  - Activation of 5-HT2 receptors induces glycogenolysis in the rat brain.
AB  - The effect of 5-HT(2) receptor activation on brain glycogen and the extracellular
      concentration of glucose was investigated in the present study. An injection of 1
      (2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2 mg/kg, i.p.) or mescaline
      (10 mg/kg, i.p.) at an ambient temperature of 29 degrees C produced a 35-45%
      decrease in brain glycogen that persisted for at least 2 h. DOI also increased
      the extracellular concentration of glucose in the striatum by 60%. Maintenance of
      rats at 22 degrees C significantly attenuated DOI-induced glycogenolysis, as well
      as DOI-induced hyperthermia, and the increase in the extracellular concentration
      of glucose in the striatum. DOI-induced hyperthermia, glycogenolysis and increase
      in the extracellular concentration of glucose also were attenuated in rats
      treated with the 5-HT(2) receptor antagonist, 6-methyl-1-(methylethyl)-ergoline
      8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY-53,857) (3
      mg/kg, ip). These results support the conclusion that 5-HT(2) receptor activation
      promotes glycogenolysis and that hyperthermia exerts a prominent role in this
      process.

PMID- 12620506
TI  - Anxiolytic-like effects of baicalein and baicalin in the Vogel conflict test in
      mice.
AB  - A previous receptor binding assay indicated that baicalein, one of the active
      principles of the Chinese herbal drug, Huangqin (Scutellariae Radix), interacts
      with the benzodiazepine binding site of GABA(A) receptors in mouse cortex
      membrane preparations with a K(i) value of 13.1 microM. Therefore, the present
      study examined whether baicalein and its 7-glucuronide, baicalin, have anxiolytic
      like effects in a Vogel conflict test adapted for ICR mice. The results showed
      that both baicalein (10 mg/kg, i.p.) and baicalin (20 mg/kg, i.p.) significantly
      increased the number of shocks accepted in the Vogel lick-shock conflict paradigm
      over 9 min, as did a benzodiazepine receptor agonist, chlordiazepoxide (5.0
      mg/kg, i.p.) and a 5-HT(1A) receptor agonist, 8-hydroxy-2(di-n
      propylamino)tetralin (0.5 mg/kg, i.p.). Since the total volume of water intake
      and the shock sensitivity of mice were not significantly changed after drug
      treatment, the effect of baicalein or baicalin was not due to an enhancement of
      thirst or shock tolerance. Furthermore, this anxiolytic-like effect of baicalein
      or baicalin was antagonized by co-administration with a benzodiazepine receptor
      antagonist, flumazenil (2 mg/kg, i.p.), but not with a 5-HT(1A) receptor
      antagonist, pindolol (10 mg/kg, i.p.). It is concluded that the anxiolytic-like
      effect of baicalein or baicalin may be mediated through activation of the
      benzodiazepine binding site of GABA(A) receptors.

PMID- 12620507
TI  - The superior colliculus contains a discrete region involved in the control of jaw
      movements: role of GABAA receptors.
AB  - The role of GABA(A) receptors in the superior colliculus in the production of rat
      repetitive jaw movements was examined, as this nucleus receives tonic GABAergic
      inhibitory inputs from the dorsolateral part of the substantia nigra pars
      reticulata and the entopeduncular nucleus. Both regions are also connected with
      the ventrolateral striatum where stimulation of either dopamine or acetylcholine
      receptors has been found to elicit distinct types of jaw movements in rats. The
      GABA(A) receptor antagonist bicuculline (50 and 150 ng/0.2 microl per side) dose
      dependently produced repetitive jaw movements only when injected bilaterally into
      a circumscribed region (A 3.0) of the lateral deeper layers of the superior
      colliculus; this region is known to receive input predominantly from the
      dorsolateral part of the substantia nigra pars reticulata. The effects of
      bicuculline were GABA(A) receptor specific because the effects were abolished by
      muscimol, a GABA(A) receptor agonist, given into the same site. The bicuculline
      induced jaw movements differed qualitatively from those elicited by injection of
      a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H
      3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), agonist
      at dopamine D1 and D2 receptors, respectively, or carbachol (2.5 microg), an
      acetylcholine receptor agonist, into the ventrolateral striatum. Nevertheless,
      injection of muscimol into the lateral deeper layers of the superior colliculus
      (A 3.0) inhibited jaw movements evoked by the dopamine D1/D2 receptor
      stimulation. Conversely, the jaw movements evoked by acetylcholine receptor
      stimulation were enhanced by injection of muscimol into the superior colliculus.
      In conclusion, GABA(A) receptor blockade in a circumscribed region (A 3.0) of the
      lateral deeper layers of the superior colliculus elicits characteristic
      repetitive jaw movements, and the GABA(A) receptors in that region modulate the
      dopamine D1/D2 receptor-mediated and acetylcholine receptor-mediated jaw
      movements in an opposite manner.

PMID- 12620508
TI  - R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic
      vocalisation model.
AB  - Escitalopram mediates the serotonin reuptake inhibitory effect of citalopram. To
      investigate the potential interactive effects between escitalopram and R
      citalopram, they were studied at standard and elevated serotonin levels in a
      model predictive of anxiolytic activity (inhibition of footshock-induced
      ultrasonic vocalisation in adult rats). At standard levels, citalopram partially
      inhibited (64%) and escitalopram abolished (97%) vocalisation. Co-treatment with
      L-5-hydroxytryptophan resulted in complete inhibition with citalopram and a
      substantially enhanced response to escitalopram, while R-citalopram increased the
      vocalisation significantly. Furthermore, R-citalopram attenuated the effect of
      escitalopram. These findings may be relevant to the enhanced clinical efficacy
      seen with escitalopram compared to citalopram.

PMID- 12620509
TI  - Nitroglycerin induces hyperalgesia in rats--a time-course study.
AB  - Nitroglycerin is a nitric oxide (NO) donor which activates nuclei involved in
      nociceptive transmission following systemic administration. The effect of
      nitroglycerin on the nociceptive threshold was studied in rats by means of two
      experimental tests that explore different modalities of pain: the tail-flick test
      and the formalin test. Nitroglycerin induced a significant reduction in the
      latency of the tail flick 2 and 4 h after its administration. Similarly, formalin
      induced pain-related behaviour increased significantly 2 and 4 h after
      nitroglycerin administration.

PMID- 12620510
TI  - Involvement of tyrosine kinase in peroxynitrite-induced preconditioning in rat
      isolated heart.
AB  - We have investigated the role of tyrosine kinase in the antiarrhythmic effects of
      peroxynitrite preconditioning in rat isolated heart by using a tyrosine
      phosphatase inhibitor, sodium orthovanadate, and tyrosine kinase inhibitors,
      genistein and tyrphostin. Rat hearts were preconditioned by peroxynitrite
      administration at 1 microM for 3 min, which was followed by 10-min washout and 30
      min of ischemia. None of the hearts had ventricular fibrillation in the
      peroxynitrite preconditioning group (from 64%, n=11, to 0%, n=11). Neither sodium
      orthovanadate (10 microM) nor genistein (50 microM) or tyrphostin (100 microM)
      alone showed any effects on arrhythmias. Peroxynitrite preserved its beneficial
      effects on arrhythmias (to 0% ventricular fibrillation, n=7) during sodium
      orthovanadate infusion (for 23 min) prior to 30 min of an ischemic period. On the
      other hand, genistein or tyrphostin treatment significantly reversed the
      protective effects of the peroxynitrite preconditioning (to 71% ventricular
      fibrillation, n=14, genistein and, to 75% ventricular fibrillation, n=8,
      tyrphostin). These results suggest that the tyrosine kinase pathway plays a
      significant role in peroxynitrite-induced preconditioning in rat isolated heart.

PMID- 12620511
TI  - Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias
      during coronary artery occlusion in conscious rats.
AB  - Heart failure is frequently associated with cardiac arrhythmias. The aim of the
      present study was to investigate the effect of levosimendan, a new cardiotonic
      drug for the treatment of congestive heart failure, on experimental ischaemic
      arrhythmias. Acute coronary artery occlusion was produced in conscious rats 7-10
      days after placement of ligature around the left main coronary artery. Acute
      pretreatment with levosimendan (0.2 or 0.6 mg/kg orally 1 h before coronary
      artery occlusion) did not influence the incidence, onset and duration of
      arrhythmias. Long-term pretreatment with levosimendan (0.2 or 0.6 mg/kg orally
      twice a day for 2 weeks) increased the survival rate (50% and 81% vs. 44% in
      controls) and the number of animals without any arrhythmia (37% and 31% vs. 5% in
      controls). The present results demonstrate that chronic oral treatment with
      levosimendan could be beneficial in congestive heart failure and arrhythmias
      resulting from regional myocardial ischaemia.

PMID- 12620513
TI  - Hemodynamic response profile predicts susceptibility to cocaine-induced toxicity.
AB  - Cocaine evokes pressor responses due either to a large increase in systemic
      vascular resistance despite a decrease (>8%) in cardiac output (vascular
      responders) or to small increases in both cardiac output and vascular resistance
      (mixed responders) in conscious rats. These studies were designed to determine
      (1) if the hemodynamic response pattern to cocaine correlates with relative
      sensitivity to toxicity and (2) if altering the hemodynamic response pattern to
      cocaine using propranolol enhances toxicity. Rats were instrumented for
      determination of cardiac output and arterial pressure. After recovery, rats were
      classified as vascular or mixed responders to cocaine (5 mg/kg, i.v., four to six
      trials). Two weeks later, cocaine was infused (1.5 mg/kg/min) until death after
      pretreatment with saline or propranolol (1 mg/kg). Saline-pretreated mixed
      responders (n=6) had greater tolerance to cocaine toxicity compared to vascular
      responders (n=11). Furthermore, saline-pretreated vascular responders were less
      sensitive than propranolol-pretreated vascular responders (n=9) to cocaine
      toxicity. Therefore, we propose that the initial hemodynamic response pattern to
      cocaine predicts sensitivity to cocaine toxicity. In addition, propranolol, a
      drug that enhances the increase in vascular resistance to cocaine, also increases
      toxicity to cocaine in vascular responders.

PMID- 12620512
TI  - Role of Na+/H+ exchanger in acetylcholine-mediated pulmonary artery contraction
      of spontaneously hypertensive rats.
AB  - Compared to sympathetic nervous system, the role of parasympathetic innervation
      on tone development, especially under diseased conditions, of the pulmonary
      artery is relatively unknown. In this study, the contractile effect of
      acetylcholine and the type(s) of muscarinic (M) receptor involved in the
      pulmonary artery (1st intralobar branch; endothelium-denuded, under resting
      tension) of the normotensive Wistar-Kyoto (WKY) and age-matched (male, 22-26
      weeks old) Spontaneously hypertensive rats (SHR) were investigated. Cumulative
      administration of acetylcholine (> or =0.1 microM) caused a concentration
      dependent increase in tension (antagonised by p-fluoro-hexahydro-sila-difenidol
      and 4-diphenylacetoxy-N-methylpiperidine, both are selective muscarinic M(3)
      receptor antagonists) and the magnitude of maximum contraction (expressed as % of
      50 mM [K(+)](o)-induced contraction) was markedly enhanced in the presence of
      neostigmine (10 microM, an anti-cholinesterase) (acetylcholine 30 microM, SHR:
      72% vs. 35%; WKY: 32% vs. 20%). In SHR only, acetylcholine-elicited contraction
      was suppressed by 1-[beta-[3-(4-Methoxyphenyl)-propoxyl]-4-methoxyphenethyl]-1H
      imidazole (SK&F 96365, 1 microM), amiloride (500 microM), ethyl-isopropyl
      amiloride (EIPA, 10 microM), 2-[2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea
      (KB-R 7943, 5 microM), 2,4-dichlorobenzamil (10 microM), and an equal molar
      substitution of [Na(+)](o) (< or =30 mM) with choline or N-methyl-D-glucamine. In
      nominally [Ca(2+)](o)-free, EGTA (0.5 mM)-containing Krebs' solution,
      acetylcholine (> or =3 microM) only elicited a small contraction. In conclusion,
      muscarinic M(3) receptor activation is responsible for the pulmonary artery
      contraction induced by acetylcholine, with a greater magnitude observed in SHR.
      The exaggerated contraction in SHR is probably due to an influx of [Na(+)](o)
      through the Na(+)/H(+) exchanger and the store-operated channels (SOC) into
      smooth muscle cells. Elevation of cytosolic [Na(+)](i) subsequently leads to an
      influx of [Ca(2+)](o) through the reverse mode of the Na(+)/Ca(2+) exchanger
      seems to play a permissive role in mediating the exaggerated contractile response
      of acetylcholine recorded in the SHR.

PMID- 12620514
TI  - Effect of SNI-2011 on amylase secretion from parotid tissue in rats and in
      neuronal nitric oxide synthase knockout mice.
AB  - The effect of (+/-)cis-2-methylspilo(1,3-oxathiolane-5,3')quinuclidine (SNI-2011)
      on the secretory pathway of amylase in parotid tissues was investigated. SNI-2011
      induced exocytosis was inhibited by a cell-permeable Ca(2+) chelator or
      inhibitors of calmodulin kinase II, neuronal nitric oxide synthase (nNOS),
      soluble guanyl cyclase, cyclic GMP-dependent protein kinase (PKG), and myosin
      light chain kinase, suggesting that these enzymes were coupled with the
      exocytosis. Stimulation with SNI-2011 of isolated rat parotid acinar cells loaded
      with 4,5-diaminofluorescein/diacetate (DAF-2/DA) induced a fast increase in DAF
      fluorescence corresponding to an increase in the NO production. SNI-2011-induced
      amylase secretion from parotid tissues in nNOS knockout mice has not been
      observed yet in spite of the expression of muscarinic M(3) receptors and the
      maintenance of secretory response to isoproterenol in the tissues. These results
      indicate the implication of the activation of Ca(2+)- and calmodulin-dependent
      enzymes and NOS-PKG signaling pathway in SNI-2011-induced amylase secretion from
      parotid acinar cells.

PMID- 12620515
TI  - Pharmacological characterisation of cannabinoid receptors inhibiting interleukin
      2 release from human peripheral blood mononuclear cells.
AB  - The effects of a range of cannabinoid receptor agonists and antagonists on
      phytohaemagglutinin-induced secretion of interleukin-2 from human peripheral
      blood mononuclear cells were investigated. The nonselective cannabinoid receptor
      agonist WIN55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-[4
      morpholinylmethyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone
      mesylate) and the selective cannabinoid CB(2) receptor agonist JWH 015 ((2-methyl
      1-propyl-1H-indol-3-yl)-1-napthalenylmethanone) inhibited phytohaemagglutinin (10
      microg/ml)-induced release of interleukin-2 in a concentration-dependent manner
      (IC(1/2max), WIN55212-2=8.8 x 10(-7) M, 95% confidence limits (C.L.)=2.2 x 10(-7)
      3.5 x 10(-6) M; JWH 015=1.8 x 10(-6) M, 95% C.L.=1.2 x 10(-6)-2.9 x 10(-6) M,
      n=5). The nonselective cannabinoid receptor agonists CP55,940 ((-)-3-[2-hydroxy-4
      (1,1-dimethyl-hepthyl)-phenyl]4-[3-hydroxypropyl]cyclo-hexan-1-ol), Delta(9)
      tetrahydrocannabinol and the selective cannabinoid CB(1) receptor agonist ACEA
      (arachidonoyl-2-chloroethylamide) had no significant (P>0.05) inhibitory effect
      on phytohaemagglutinin-induced release of interleukin-2. Dexamethasone
      significantly (P<0.05) inhibited phytohaemagglutinin-induced release of
      interleukin-2 in a concentration-dependent manner (IC(1/2max)=1.3 x 10(-8) M, 95%
      C.L.=1.4 x 10(-9)-3.2 x 10(-8) M). The cannabinoid CB(1) receptor antagonist
      SR141716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl
      1H-pyrazole-3-carboxamide hydrochloride) (10(-6) M) did not antagonise the
      inhibitory effect of WIN55212-2 whereas the cannabinoid CB(2) receptor antagonist
      SR144528 (N-(1,S)-endo-1,3,3-trimethyl bicyclo(2,2,1)heptan-2-yl)-5-(4-chloro-3
      methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) antagonised the
      inhibitory effect of WIN55212-2 (pA(2)=6.3+/-0.1, n=5). In addition, CP55,940
      (10(-6) M) and Delta(9)-tetrahydrocannabinol (10(-6) M) also antagonised the
      inhibitory effects of WIN55212-2 (pA(2)=6.1+/-0.1, n=5 and pA(2)=6.9+/-0.2, n=5).
      In summary, WIN55,212-2 and JWH 015 inhibited interleukin-2 release from human
      peripheral blood mononuclear cells via the cannabinoid CB(2) receptor. In
      contrast, CP55,940 and Delta(9)-tetrahydrocannabinol behaved as partial
      agonists/antagonists in these cells.

PMID- 12620517
TI  - Effects of cannabinoid receptor agonists on immunologically induced histamine
      release from rat peritoneal mast cells.
AB  - Immunologic activation of mast cells through the cross-linking of high affinity
      IgE receptors results in the release of inflammatory mediators which are
      important in the pathogenesis of allergic reactions. Early studies investigating
      the effects of palmitoylethanolamide on animal models of inflammation and on rat
      mast cells led to the hypothesis that endogenous cannabinoids might act as local
      autacoids which suppressed inflammation by reducing the activation of mast cells.
      However, more recent studies produced contradicting results. In order to evaluate
      if cannabinoid receptors are present in mast cells, we studied the effects of
      endocannabinoids (anandamide and palmitoylethanolamide) and synthetic
      cannabimimetics (CP 55,940, WIN 55,212-2 and HU-210) on histamine release from
      rat peritoneal mast cells. When incubated with mast cells alone, only anandamide
      could induce significant level of histamine release at concentrations higher than
      10(-6) M. When mast cells were activated with anti-IgE, the histamine release
      induced was not affected by anandamide, palmitoylethanolamide and CP 55,940. In
      contrast, both WIN 55,212-2 and HU-210 enhanced anti-IgE-induced histamine
      release at 10(-5) M and preincubation did not increase the potency. The histamine
      releasing action of anandamide and the enhancing effects of WIN 55,212-2 and HU
      210 on anti-IgE-induced histamine release were not reduced by the cannabinoid
      receptor antagonists, AM 281 and AM 630. In conclusion, the present study does
      not support the hypothesis that cannabinoids suppress mast cell activation.
      Instead, some of the cannabinoid receptor-directed ligands tested enhanced mast
      cell activation. However, the high concentrations required and the failure of
      cannabinoid receptor antagonists to reverse such effects also question the
      existence of functional cannabinoid receptors in mast cells.

PMID- 12620516
TI  - The anti-inflammatory effect of methylprednisolone occurs down-stream of nuclear
      factor-kappaB DNA binding in acute pancreatitis.
AB  - Glucocorticoids are potent anti-inflammatory drugs. The molecular mechanisms
      underlying these effects have not yet been fully revealed. The aim of the present
      study was to establish whether methylprednisolone pretreatment is beneficial and
      if it can block the pancreatic DNA binding of the transcription factor nuclear
      factor-kappaB (NF-kappaB) and proinflammatory cytokine synthesis during
      cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats.
      Additionally, we set out to investigate the potential effects of
      methylprednisolone and CCK on pancreatic heat shock protein (HSP) synthesis. The
      dose-response (5-40 mg/kg) and time-course (6-72 h) curves of methylprednisolone
      on pancreatic HSP60 and HSP72 synthesis were evaluated following
      methylprednisolone treatment. We demonstrated that methylprednisolone
      specifically and dose-dependently induced HSP72 in the pancreas of rats, while it
      did not have a significant effect on HSP60 expression. The pancreatitis was
      induced near the peak level of HSP72 synthesis (2 x 30 mg/kg body weight [b.w.]
      methylprednisolone i.m. at an interval of 12 h, followed by a 12-h recovery
      period after the second injection of methylprednisolone) by administering 2 x 100
      microg/kg CCK subcutaneously at an interval of 1 h. The injections of CCK in the
      vehicle-pretreated group significantly elevated the levels of pancreatic HSP60
      and HSP72 2-4 h after the second CCK injection. Methylprednisolone pretreatment
      ameliorated many of the examined laboratory (the pancreatic weight/body weight
      [p.w./b.w.] ratio, the serum amylase activity, the plasma trypsinogen activation
      peptide concentration, the pancreatic levels of tumor necrosis factor-alpha and
      interleukin-6, the degree of lipid peroxidation, protein oxidation, nonprotein
      sulfhydryl group content and the pancreatic myeloperoxidase activity) and
      morphological parameters of the disease. Methylprednisolone pretreatment did not
      influence pancreatic NF-kappaB DNA binding, but decreased proinflammatory
      cytokine synthesis in this acute pancreatitis model. The findings suggest that
      the anti-inflammatory effect of large doses of methylprednisolone in secretagogue
      induced pancreatitis occurs downstream of NF-kappaB DNA binding, and that
      increased pancreatic HSP72 synthesis may play a role in the protective effect of
      the drug.

PMID- 12620518
TI  - Chronic [D-Ala2, D-Leu5]enkephalin treatment increases the nerve growth factor in
      adult mouse brain.
AB  - The delta opioid peptide [D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been shown to
      enhance the survival of dopaminergic neurons. Here, we found that chronic
      treatment with DADLE caused a significant increase in nerve growth factor (NGF)
      in the hippocampus and the midbrain of adult albino Swiss (CD-1) mice, but not in
      the striatum or frontal cortex. Glia-derived neurotrophic factor (GDNF) was not
      significantly affected. Thus, the neuroprotective action of DADLE may be mediated
      in part by NGF.

PMID- 12620520
TI  - Enteral versus parenteral nutrition: the story of a pragmatic trial study.

PMID- 12620521
TI  - Aids and nutrition: a personal journey.

PMID- 12620522
TI  - Soybean oil, stress response, and immune function: a clinical study.

PMID- 12620523
TI  - Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus.
      Effect of omega-3 fatty acids.
AB  - In a previous study, we showed that prior oral feeding of oils rich in omega-3
      eicosapentaenoic acid and docosahexaenoic acid and omega-6 gamma-linolenic acid
      and arachidonic acid prevent the development of alloxan-induced diabetes mellitus
      in experimental animals. We also observed that 99% pure omega-6 fatty acids gamma
      linolenic acid and arachidonic acid protect against chemically induced diabetes
      mellitus. Here we report the results of our studies with omega-3 fatty acids.
      Alloxan-induced in vitro cytotoxicity and apoptosis in an insulin-secreting rat
      insulinoma cell line, RIN, was prevented by prior exposure of these cells to
      alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. Prior oral
      supplementation with alpha-linolenic acid, eicosapentaenoic acid, and
      docosahexaenoic acid prevented alloxan-induced diabetes mellitus. alpha-Linolenic
      acid, eicosapentaenoic acid, and docosahexaenoic acid not only attenuated
      chemical-induced diabetes mellitus but also restored the anti-oxidant status to
      normal range in various tissues. These results suggested that omega-3 fatty acids
      can abrogate chemically induced diabetes in experimental animals and attenuate
      the oxidant stress that occurs in diabetes mellitus.

PMID- 12620524
TI  - Effect of supplementing a high-fat, low-carbohydrate enteral formula in COPD
      patients.
AB  - OBJECTIVE: One of the goals in treating patients with chronic obstructive
      pulmonary disease (COPD) who suffer from hypoxemia, hypercapnia, and malnutrition
      is to correct the malnutrition without increasing the respiratory quotient and
      minimize the production of carbon dioxide. This 3-wk study evaluated the efficacy
      of feeding a high-fat, low-carbohydrate (CHO) nutritional supplement as opposed
      to a high-carbohydrate diet in COPD patients on parameters of pulmonary
      function.S METHODS: Sixty COPD patients with low body weight (<90% ideal body
      weight) were randomized to the control group, which received dietary counseling
      for a high-CHO diet (15% protein, 20% to 30% fat, and 60% to 70% CHO), or the
      experimental group, which received two to three cans (237 mL/can) of a high-fat,
      low-CHO oral supplement (16.7% protein, 55.1% fat, and 28.2% CHO) in the evening
      as part of the diet. Measurements of lung function (forced expiratory volume in 1
      s or volume of air exhaled in 1 s of maximal expiration, minute ventilation,
      oxygen consumption per unit time, carbon dioxide production in unit time, and
      respiratory quotient) and blood gases (pH, arterial carbon dioxide tension, and
      arterial oxygen tension) were taken at baseline and after 3 wk. RESULTS: Lung
      function measurements decreased significantly and forced expiratory volume
      increased significantly in the experimental group. CONCLUSION: This study
      demonstrates that pulmonary function in COPD patients can be significantly
      improved with a high-fat, low-CHO oral supplement as compared with the
      traditional high-CHO diet.

PMID- 12620525
TI  - Comparison of formulaic equations to determine energy expenditure in the
      critically ill patient.
AB  - OBJECTIVE: Inappropriate energy intake can negatively affect patient outcome
      during critical illness. Measuring energy expenditure via indirect calorimetry
      (IC) is the most accurate method of determining needs. Often predictive equations
      are used because IC is not available at all institutions or for all populations.
      METHODS: This study compared 24-h IC measures with five previously published
      formulaic equations and nomograms using kilocalorie per kilogram of body weight
      to determine their accuracy in predicting energy needs in critically ill adults
      receiving nutrition support. Two different weight categories were analyzed: body
      mass indexes below 25 kg/m(2) and below 30 kg/m(2). RESULTS: The Harris-Benedict
      equation using adjusted body weight multiplied by a stress factor of 1.6 and the
      Swinamer equation predicted measured energy expenditure (MEE) within 20% of IC
      values 80% of the time for the entire population studied. For those individuals
      at the lower weight range, the Harris-Benedict equation using actual weight
      reference weight via the Hamwi equation and via adjusted weight times a stress
      factor of 1.6 and the Swinamer equation predicted MEE within 20% of IC values 89%
      of the time. The Frankenfield equation overestimated MEE; whereas the Penn State
      and Ireton-Jones equations underestimated energy needs in the population studied.
      CONCLUSIONS: Predictive equations such as the Harris-Benedict equation multiplied
      by a stress factor of 1.6 and the Swinamer equation may be accurate enough for
      short-term nutrition support of critically ill patients when IC is unavailable.

PMID- 12620526
TI  - Influence of smoking on markers of oxidative stress and serum mineral
      concentrations in teenage girls in Korea.
AB  - OBJECTIVE: The purpose of this study was to examine the effect of cigarette
      smoking on serum oxidative damage, antioxidant status, and mineral concentrations
      in teenage girls. METHODS: Subjects were randomly chosen from female senior high
      school students (15-17 y) in a rural community in Korea. Smoker (n = 19) was
      defined as a person who had smoked 10 or more cigarettes/d continually for at
      least 1 y while non-smoker (n = 19) was a person who had no previous smoking
      experience. All individuals in smoker group had serum cotinine concentrations
      greater than 110 ng/mL, and those in non-smoker group had concentrations of less
      than 30 ng/mL. Serum oxidative defense enzyme activities, serum antioxidant
      nutrient concentrations, anthropometric data, and dietary nutrient intakes were
      evaluated. RESULTS: Serum selenium glutathione peroxidase, glutathione reductase,
      and extracellular superoxide dismutase activities were lower in smokers than in
      non-smokers. Serum ascorbic acid and folate concentrations were lower in smokers
      than in non-smokers, whereas serum thiobarbituric acid-reactive substances
      (TBARS) were higher. Serum copper, iron, and magnesium concentrations were
      similar in the two groups. Serum zinc concentrations were higher in smokers.
      CONCLUSIONS: Teenagers with a short smoking history can have evidence of
      oxidative stress (high serum TBARS and low serum ascorbic acid and folate
      concentrations) and an impaired oxidant defense system. However, in contrast to
      common findings in adult smokers, blood pressure was lower in teenage smokers,
      and hypozincemia and hypercupremia were not observed. Alterations observed in
      mineral metabolism in adult smokers are probably secondary to chronic diseases
      associated with long-term smoking.

PMID- 12620527
TI  - Plasma carotenoids, tocopherols, and antioxidant capacity in a 12-week
      intervention study to reduce fat and/or energy intakes.
AB  - OBJECTIVE: We examined plasma levels of carotenoids, tocopherols, and total
      antioxidant activity in women before and after dietary intervention to reduce fat
      and/or energy intakes. Dietary fat and energy may affect intake and
      bioavailability of carotenoids and tocopherols, and these micronutrient levels in
      turn can contribute to the antioxidant capacity of plasma. METHODS: Women were
      randomized onto one of four diets for 12 wk: non-intervention, low fat (15% of
      energy from fat with maintenance of energy intake), low energy (25% energy
      reduction with maintenance of percentage of energy from fat), and combined low
      fat and low energy. Fasting plasma was available for analysis from a subset (n =
      41) of women enrolled in the study. RESULTS: Levels of carotenoids and
      tocopherols did not change significantly over 12 wk on any diet arm, despite a
      modest but statistically significant increase in fruit and vegetable intake in
      the women following the low-fat diet (from 3.3 to 5.2 servings/d excluding
      potatoes). Levels of Trolox-equivalent antioxidant capacity (TEAC), total
      cholesterol, and two major plasma antioxidants (urate and bilirubin) also did not
      change significantly. Of the individual micronutrients measured, lycopene and
      lutein/zeaxanthin correlated most strongly with TEAC values, and the correlation
      with lycopene was statistically significant before intervention. CONCLUSION: The
      decreases in dietary fat and energy intakes in this study were quite large, but
      this did not appear to have detrimental effects on plasma micronutrient levels,
      nor did it appreciably affect plasma antioxidants. Because lycopene levels were
      significantly associated with plasma TEAC before intervention, interventions that
      increase levels of lycopene might be more likely to increase the antioxidant
      capacity of plasma.

PMID- 12620528
TI  - Apolipoproteins A-I and B as predictors of complications in gallbladder lithiasis
      surgical patients.
AB  - Specific serum proteins have been traditionally used in the assessment of protein
      energy malnutrition. Some short half-life serum proteins have been related to the
      appearance of postoperative complications in surgical patients with low-risk
      pathologies that, far from undernutrition, showed a trend toward overweight and
      obesity. Apolipoproteins have been proposed as potential tools to assess protein
      status and nutritional recovery, so we investigated apolipoproteins A-I and B as
      new tools with prognostic value to detect postoperative complications. We
      analyzed the interrelation between apolipoproteins level and the appearance of
      complications after programed surgical procedures of gallbladder lithiasis.
      Assessment was performed, and postoperative complications were recorded in 52
      patients (39 women and 13 men, age range = 21-69 y). Assessment included
      measurements of weight and height and determinations of apolipoprotein A-I and B
      by quantitative radial immunodiffusion on gel layers. Apolipoproteins levels
      showed no statistical differences between complicated and uncomplicated patients.
      The apolipoproteins included in this study did not predict surgical complications
      because abnormal values were not associated with the presence of complications in
      this kind of patient.

PMID- 12620529
TI  - Weight loss associated with a daily intake of three apples or three pears among
      overweight women.
AB  - OBJECTIVE: We investigated the effect of fruit intake on body weight change.
      METHODS: Hypercholesterolemic, overweight (body mass index > 25 kg/m2), and non
      smoking women, 30 to 50 y of age, were randomized to receive, free of charge, one
      of three dietary supplements: apples, pears, or oat cookies. Women were
      instructed to eat one supplement three times a day in a total of six meals a day.
      Participants (411 women) were recruited at a primary care center of the State
      University of Rio de Janeiro, Brazil. Fifty-one women had fasting blood
      cholesterol levels greater than 6.2 mM/L (240 mg/dL) and 49 were randomized.
      Subjects were instructed by a dietitian to eat a diet (55% of energy from
      carbohydrate, 15% from protein, and 30% from fat) to encourage weight reduction
      at the rate of 1 kg/mo. RESULTS: After 12 wk of follow-up, the fruit group lost
      1.22 kg (95% confidence interval = 0.44-1.85), whereas the oat group had a non
      significant weight loss of 0.88 kg (0.37-2.13). The difference between the two
      groups was statistically significant (P = 0.004). To explore further the body
      weight loss associated with fruit intake, we measured the ratio of glucose to
      insulin. A significantly greater decrease of blood glucose was observed among
      those who had eaten fruits compared with those who had eaten oat cookies, but the
      glucose:insulin ratio was not statistically different from baseline to follow-up.
      Adherence to the diet was high, as indicated by changes in serum
      triacylglycerols, total cholesterol, and reported fruit intake. Fruit intake in
      the oat group throughout treatment was minimal. CONCLUSIONS: Intake of fruits may
      contribute to weight loss.

PMID- 12620530
TI  - Early versus late nutrition support in premature neonates with respiratory
      distress syndrome.
AB  - OBJECTIVE: This retrospective study evaluated two different modes of nutrition
      supplementation in premature neonates with respiratory distress syndrome.
      METHODS: Data were collected from the medical records of premature infants
      treated from January 1, 1997 to July 31, 2000. Seventeen infants were given
      peripheral amino acids and gradual advanced minimal hypocaloric enteral feeding
      within the first 48 h (early nutrition group), and 19 infants received nutrition
      supplementation more than 48 h after birth (late nutrition group). Groups were
      similar with regard to gestational age, birth weight, Apgar score, mode of
      delivery, and diagnosis. RESULTS: Compared with infants in the late nutrition
      group, those in the early nutrition group required fewer days of parenteral
      nutrition, fewer days to reach full enteral feeding, fewer days of mechanical
      ventilation, fewer days of aminophylline use, fewer days to regain birth weight,
      and had a lower percentage of maximal weight loss. Other physiologic parameters
      such as age at maximal weight loss, weight gain after day 10, and hospital days
      required favored the use of early nutrition. CONCLUSIONS: Early nutrition to
      maintain a positive energy balance in premature neonates with respiratory
      distress syndrome is beneficial.

PMID- 12620531
TI  - Dietary supplementation with fermented soybeans suppresses intimal thickening.
AB  - Although soy foods have been consumed for more than 1000 y, it is only in the
      past 20 y that they have made inroads into Western diets. We investigated the
      effect of dietary supplementation with natto extracts produced from fermented
      soybeans on intimal thickening of arteries after vessel endothelial denudation.
      Natto extracts include nattokinase, a potent fibrinolytic enzyme having four
      times greater fibrinolytic activity than plasmin. Intimal thickening was induced
      in the femoral arteries by intravenous infusion of rose bengal followed by focal
      irradiation with a transluminal green light. Dietary natto extract
      supplementation was started 3 wk before endothelial injury and continued for
      another 3 wk after. In ex vivo studies, euglobulin clot lysis times were measured
      3 wk after the initial supplementation. Neointima formation and thickening were
      also initiated successfully. The intima media ratio 3 wk after endothelial injury
      was 0.15 +/- 0.03 in the control group. Dietary natto extract supplementation
      suppressed intimal thickening (0.06 +/- 0.01; P < 0.05) compared with the control
      group. Natto extracts shortened euglobulin clot lysis time, suggesting that their
      thrombolytic activities were enhanced. These findings suggest that natto
      extracts, because of their thrombolytic activity, suppress intimal thickening
      after vascular injury as a result of the inhibition of mural thrombi formation.

PMID- 12620532
TI  - Defective antigen-presenting capacity of murine dendritic cells during
      starvation.
AB  - Significant impairments of several aspects of immunity have been described in
      acute and chronic nutritional deficiencies; however, there have been few studies
      on antigen-presenting cells during starvation. We examined the antigen-presenting
      capacities of mouse dendritic cells (DCs) from lymphoid organ (spleen DCs) and
      non-lymphoid tissue (liver DCs) during starvation. The total numbers of spleen
      DCs and liver DCs were significantly fewer in starved mice than in control mice.
      Functional analysis showed that the proliferative activities of spleen DCs and
      liver DCs were significantly impaired in starved mice compared with control mice.
      In particular, liver DCs from starved mice were unable to induce interferon
      gamma. Liver DCs from starved mice were unable to induce proliferation of antigen
      specific memory lymphocytes. These data indicated that one major cause of
      impairment of immunologic responses during starvation may be mediated through
      DCs.

PMID- 12620533
TI  - Oral administration of Bifidobacterium longum culture condensate in a diet
      restricted murine peritonitis model enhances polymorphonuclear neutrophil
      recruitment into the local inflammatory site.
AB  - Dietary restriction impairs polymorphonuclear neutrophil (PMN) recruitment into
      the local inflammatory site, resulting in susceptibility to infection. Probiotics
      enhance host immunity via conditioning host intestinal microflora. Oral
      administration of Bifidobacterium longum culture condensate (BCC) in a diet
      restricted murine peritonitis model may enhance PMN recruitment into the
      inflammatory site. Male ICR mice (n = 40) were assigned in equal numbers to
      control or BCC groups and subjected to 75% restricted food intake for 7 d. During
      dietary restriction, controls received only standard mouse chow, whereas the BCC
      group received standard mouse chow containing 1% BCC. Mice were killed before (0
      h) or after (2 or 4 h) intraperitoneal glycogen injection. Peritoneal lavage
      fluid and exudative cells were recovered by peritoneal lavage. Peritoneal
      exudative cell number was counted. Tumor necrosis factor-alpha, interleukin-6,
      macrophage inflammatory protein-2, and interleukin-10 concentrations in
      peritoneal lavage fluid were determined by enzyme-linked immunosorbent assay.
      CD11b, CD18, CD31, and CD62L expressions on circulating PMNs were measured by
      flow cytometry. Oral BCC administration upregulated PMN recruitment into the
      peritoneal cavity and increased peritoneal fluid cytokine concentrations as well
      as CD18 and CD62L expressions on circulating PMNs during glycogen-induced
      peritonitis. Oral BCC administration in a diet-restricted murine peritonitis
      model augmented PMN recruitment into the inflammatory site by upregulating
      cytokine concentrations in the local inflammatory site and adhesion molecule
      expression on circulating PMNs. Oral BCC administration may be a favorable
      modality for improving dietary restriction-induced host immunosuppression.

PMID- 12620534
TI  - Effects of fish oil in parenteral nutrition.
AB  - OBJECTIVE: Fish oil is a rich source of omega-3 fatty acids (FAs), especially
      eicosapentaenoic acid and docosahexaenoic acid. The existing data suggest that
      eicosapentaenoic acid and docosahexaenoic acid are the active agents in fish oil.
      A number of clinical trials have shown that dietary fish oil supplementation has
      antiatherogenic properties and immunomodulation effects. Fish oils are not used
      widely in parenteral nutrition because fish oil emulsions have not been
      commercially available until very recently. Studies concerning the use of fish
      oil in parenteral route are rare. METHODS: We reviewed the effect of parenteral
      fish oil infusion on lipid metabolism and immune response in normal and disease
      conditions. RESULTS: Studies showed that the main effects of parenteral infusion
      of fish oil are: 1) incorporation of omega-3 FAs into cellular membranes of many
      cell populations that consequently influence the disease process of some disease
      conditions, 2) an effect on eicosanoid metabolism leading to a decrease in
      platelet aggregation and thrombosis, 3) amelioration of the severity of diet
      induced hepatic steatosis, 4) less accumulation of lipid peroxidation products in
      liver tissue, and 5) immunomodulation effects and therapeutic benefits in animal
      disease models or various disease conditions of humans. Most of these studies
      suggested that parenteral infusion of omega-3 FAs have clinical beneficial
      effects comparable to those of dietary administration. However, different effects
      of omega-3 and omega-6 FAs in some situations has been reported. For example,
      plasma triacylglycerol levels were not lowered after fish oil infusion in normal
      or diabetic rats when compared with those of safflower oil or soybean oil
      infusion. The reason for the difference remain unclear. CONCLUSION: The metabolic
      and immunologic effects of parenteral use of omega-3 FAs requires further
      evaluation, especially in some disease conditions.

PMID- 12620535
TI  - Potential public health implications of the hypocholesterolemic effects of soy
      protein.

PMID- 12620536
TI  - Contributions of industry to parenteral nutrition.

PMID- 12620540
TI  - Assessment of the anomalous pulmonary circulation by dynamic contrast-enhanced MR
      angiography in under four seconds.
AB  - The purpose of this study was to demonstrate the initial results of the dynamic
      contrast-enhanced MRA in under four seconds in the assessment of anomalous
      pulmonary circulation. We performed dynamic contrast enhanced MRA on ten patients
      with a temporal resolution of 2-3 sec for each phase. Five patients had pulmonary
      vascular anomaly and five patients had reconstructed pulmonary circulation. On
      nine patients catheter angiography was performed for the correlation. Dynamic
      contrast-enhanced MRA successfully demonstrated congenital pulmonary vascular
      anomalies and the pathway of anomalous pulmonary circulation in our series. With
      the improved temporal and spatial resolution, the dynamic contrast-enhanced MRA
      can be used in children and infants for the assessment of congenital vascular
      disease.

PMID- 12620541
TI  - Age-related changes in the pediatric brain: proton T1 in healthy children and in
      children with sickle cell disease.
AB  - The goal of this study was to characterize the expected range of variation in T1
      (spin-lattice relaxation time) of brain tissue in vivo, as a function of age, and
      to use these maturational norms to study children with sickle cell disease (SCD).
      A well-validated method (TurboPAIR) was used to measure T1 in 10 tissues in a
      study group of 200 healthy subjects (ages 4.5 to 79.3; 101 male and 99 female),
      in a transverse slice at the level of the basal ganglia. Brain T1 was
      significantly related to age in every tissue characterized (p < 0.001), including
      the splenium (p < 0.01). Quantitative MRI suggests that brain T1 continues to
      change throughout the lifespan of healthy subjects free of neurologic complaints.
      Age-related changes follow a different schedule in each tissue, and age is a
      stronger determinant of T1 in gray matter than in white matter. Analysis of 141
      patients with SCD shows that patients have lower T1 than normal, in both the
      caudate and the cortex (p < 0.001).

PMID- 12620542
TI  - Water diffusion in biomedical systems as related to magnetic resonance imaging.
AB  - Water diffusion within the brain is studied numerically for various clinical
      conditions. The numerical procedure used in this work is based on the Galerkin
      weighted residual method of finite-element formulation. A wide range of pertinent
      parameters such as Lewis number, cell volume, and the buoyancy ratio are
      considered in the present study. Comparisons with previously published work show
      excellent agreement. The results show that the diffusion coefficient, cell
      volume, and the buoyancy ratio play significant roles on the characterization of
      the mass and heat transfer mechanisms within the cell. Concentration maps are
      developed for various clinical conditions. Pertinent results for the streamlines,
      isotherms and the mass and heat transfer rates in terms of the average Sherwood
      and Nusselt numbers are presented and discussed for different parametric values.
      Experimental tests are also conducted to produce an 8 Tesla image which is
      compared with our numerical simulation. The present study provides essential maps
      for brain disorders classified based on several pertinent clinical attributes.

PMID- 12620543
TI  - Reliability of mean transit time obtained using perfusion-weighted MR imaging;
      comparison with positron emission tomography.
AB  - The purpose of this project was to assess the reliability of the cerebral mean
      transit time (MTT) obtained using perfusion-weighted MR imaging by comparing it
      with the MTT obtained when performing positron emission tomography (PET). Ten
      patients with chronic occlusive cerebrovascular disease were investigated. They
      had either unilateral internal carotid artery occlusion or middle cerebral artery
      occlusion. The regions-of-interest were placed in non-infarcted areas within the
      territory of the middle cerebral artery on the affected side. Control regions-of
      interest were placed in mirrored regions of the contralateral side. Linear
      regression analyses were performed using the parameters of the MTT obtained with
      perfusion-weighted MR imaging and the MTT, cerebral blood flow, vascular
      reactivity, and oxygen extraction fraction obtained with PET. The respective MTTs
      of the affected and non-affected sides obtained with perfusion-weighted MR
      imaging versus those with PET were 7.3 +/- 2.2 s and 6.0 +/- 1.2 s versus 8.2 +/-
      3.0 s and 6.4 +/- 1.7 s. The MTT obtained using perfusion-weighted MR imaging and
      PET demonstrated statistically significant correlation (r = 0.87, p < 0.0001).
      The MTT obtained with perfusion-weighted MR imaging correlated statistically with
      cerebral blood flow (r = -0.74, p < 0.001), vascular reactivity (r = -0.73, p <
      0.001) and oxygen extraction fraction (r = 0.61, p < 0.01). Similarly, the MTT
      obtained using PET statistically correlated with cerebral blood flow (r = -0.78,
      p < 0.0001), vascular reactivity (r = -0.51, p < 0.05) and oxygen extraction
      fraction (r = 0.68, p < 0.01). The reliability of the MTT obtained using
      perfusion-weighted MR imaging appears to be approximately equal to that obtained
      with positron emission tomography.

PMID- 12620544
TI  - MRI-negative rotator cuff tears.
AB  - We report two cases of rotator cuff tear in which the T(2)-weighted MRI signal
      was negative at the first examination, but positive by the second examination
      without any changes in symptoms. Many authors have reported on correlations
      between the MRI and operative findings of rotator cuff tears. However, MRI
      findings, history of symptoms and operative findings in our patients suggest that
      there was a discrepancy between symptoms and MRI findings dependent on the period
      from the injury. Operative findings also indicate that intratendinous tears might
      have occurred first in these patients then progressed to partial or full
      thickness tears over time. We concluded that physicians should keep rotator cuff
      pathology in mind even in patients whose MRI findings are negative but symptoms
      of rotator cuff tear persist.

PMID- 12620545
TI  - MnDPDP-enhanced magnetization transfer MR imaging: implications for effective
      liver imaging.
AB  - The benefit of combining magnetization transfer (MT) MR imaging technique with
      liver-specific contrast agent manganese dipyridoxyldiphosphate (MnDPDP) was
      assessed in our experimental investigation. The study was accomplished by imaging
      a phantom containing serial concentrations of MnDPDP in cross-linked bovine serum
      albumin (BSA) with various protein concentrations. A 0.1T clinical MR imager with
      different parameters for MT and conventional MR sequences were used. The
      combination of an offset frequency of 8 kHz and an amplitude of 25 microT
      produced nearly maximal MT effect for all protein samples either without MnDPDP
      or with different MnDPDP concentrations. With long TRs (TR > 200 ms) MT
      dramatically improved CNR in conjunction with MnDPDP. With short TRs, the gain in
      CNR with MT was negligible. However, long TRs with increased number of images are
      beneficial in liver imaging. We conclude that MT like preparation pulse is useful
      when paramagnetic contrast agents such as MnDPDP are employed.

PMID- 12620546
TI  - Iterative temporal clustering analysis for the detection of multiple response
      peaks in fMRI.
AB  - The temporal clustering analysis (TCA) is a novel and effective technique for
      obtaining brain activation maps when the timing and location of the activation
      are completely unknown. Performing the TCA method once can only detect the
      largest peak of the activation time windows well, if multiple response peaks at
      the same location of the brain occur. However, this limitation can be removed by
      using a TCA method in an iterative way in order for the smaller peaks to be
      detected. Our in vivo fMRI experiments with event-related visual tasks have
      demonstrated this ability.

PMID- 12620547
TI  - Feasibility of proton chemical shift imaging with a stereotactic headframe.
AB  - To prove feasibility of proton chemical shift imaging ((1)H CSI) during
      stereotactic procedure, authors performed (1)H CSI in combination with a
      stereotactic headframe and selected targets according to local metabolic
      information, evaluated the pathologic results. The (1)H CSI directed stereotactic
      biopsy was performed in four patients. (1)H CSI and conventional Gd-enhancement
      stereotactic MRI were performed simultaneously after the fitting of a
      stereotactic headframe. Focal areas of increased
      phosphocholine(Cho)/phosphocreatine(Cr) and Lactate/Cr ratios were selected as
      target sites in the stereotactic MR images. (1)H CSI is possible with the
      stereotactic headframe in place. Pathologic samples taken from areas of increased
      Cho/Cr ratios and decreased NAA/Cr ratios provided information upon increased
      cellularity, mitoses and cellular atypism, and facilitated diagnosis. Pathologic
      samples taken from areas of increased Lac/Cr ratio showed predominant feature of
      necrosis. (1)H CSI was feasible with the stereotactic headframe in place. The
      final pathologic results obtained were concordant with the local metabolic
      information from (1)H CSI. We believe that (1)H CSI-directed stereotactic biopsy
      has the potential to significantly improve the accuracy of stereotactic biopsy
      targeting.

PMID- 12620548
TI  - A novel RF coil configuration for in-vivo and ex-vivo imaging of arthritic rabbit
      knee joints.
AB  - The purpose of this study was to design and build an optimized Radio Frequency
      (RF) coil configuration, that would facilitate the acquisition of high resolution
      3-dimensional (3D) images of arthritic and normal rabbit knees. A surface coil
      transmit surface coil receive configuration was built, in order to ensure
      adequate B(1) homogeneity over the imaging volume and maximum filling factor, and
      hence to maximize the Signal to Noise ratio (SNR) and resolution of the 3
      dimensional images. The two coils were passively decoupled using crossed diodes
      and lambda/4 lines, both during the transmit and receive phases of the imaging
      experiment. A specialized animal bed, to optimize the use of the coils and
      minimize the experiment setup time was designed and constructed. Three
      dimensional images of resolution 156 x 156 x 468 microm, were acquired in 20 min;
      the results, in terms both of the high resolution images and the ease with which
      the experimental setup could be reproduced, demonstrated that this configuration
      is ideal for imaging rabbit knee joints.

PMID- 12620549
TI  - Experimental determination of pore shape and size using q-space NMR microscopy in
      the long diffusion-time limit.
AB  - The signal obtained with q-space NMR imaging applied to a confined liquid is
      directly related to the pore shape in the limit where all molecules have sampled
      the whole pore. We investigate the diffusion of water across a approximately 50
      microm thick film formed between planes of glass. The diffusion time t is changed
      almost three orders of magnitude. For short t, the root-mean-square displacement
      increases with a rate which is slightly less than for freely diffusing water. At
      t longer than 0.3 s, the displacement is constant at 24 microm which implies that
      the water is confined in the measuring direction defined by the applied gradient
      pulses. Perfectly smooth and aligned planes give rise to sharp diffraction-like
      features on the echo attenuation curve, i.e., NMR signal vs. the reciprocal space
      vector q. The experimental data with rather smooth local minima and maxima can be
      explained in terms of either surface roughness or a misalignment of the planes.
      We discuss the averaging effect of diffusion along a laterally inhomogeneous film
      and propose two model-free methods to determine the pore shape from the echo
      attenuation curve obtained in the long-t limit.

PMID- 12620550
TI  - Delayed myelination in a rhizomelic chondrodysplasia punctata case: MR
      spectroscopy findings.
AB  - Rhizomelic chondrodysplasia punctata is a member of genetic peroxisomal
      disorders. Delayed myelination, which is probably related to the inadequacy of
      plasmalogens biosynthesis, is an important feature of this disorder. Direct
      assessment of neuropathologic aspects of RCDP syndrome such as neuronal
      degeneration and delayed myelination is possible with MR spectroscopy. In this
      report, MR spectroscopy findings (decreased Cho/Cr and increased Ins-Gly/Cr
      ratios and increased levels of mobile lipids) of a rhizomelic chondrodysplasia
      punctata case supporting delayed myelination are presented. This is the second
      report of MR spectroscopy examination of the specific brain metabolic changes
      associated with rhizomelic chondrodysplasia punctata.

PMID- 12620551
TI  - Asymptomatic adult cystic lymphangioma of the spleen: case report and review of
      the literature.
AB  - In the present report we describe a case of an asymptomatic splenic cystic
      lymphangioma in a 43 year-old female. Only a few cases of this benign tumor have
      been reported in adult patients so far. Clinical examination revealed a tender
      mass in the upper left quadrant of the abdomen. Abdominal ultrasound and CT-scan
      revealed a large well-defined splenic cystic mass surrounded by multiple
      peripheral cysts, all divided by thin septa. MRI confirmed these findings and
      excluded the possibility of malignant degeneration. Histologic examination
      permitted the accurate diagnosis to be made. Different imaging findings of this
      tumor have been described but only a few reports have focused on the value of MRI
      imaging.

PMID- 12620552
TI  - Intermediate follow-up of carotid artery stent placement.
AB  - BACKGROUND: Carotid artery stent placement (CAS) is becoming more popular among
      various specialties for the treatment of primary and recurrent carotid artery
      disease. The morbidity associated with this procedure is improving but the
      intermediate- and long-term follow-up remains unknown. We report our restenosis
      rates and follow-up associated with CAS. METHODS: Thirty-one interventions on 29
      patients from May 1998 to January 2002 were reviewed. All patients have undergone
      serial follow-up using Doppler ultrasound at 3 and 6 months and every 6 months
      thereafter. Ten interventions (32%) were performed on patients with recurrent
      carotid artery disease and 21 (68%) on patients with primary disease. RESULTS:
      Five periprocedural complications occurred (transient ischemic attack, n = 3;
      major stroke, n = 1; immediate intrastent restenosis requiring lysis, n = 1) for
      a total immediate complication rate of 16%. No deaths occurred. Follow-up was
      achieved in all 29 patients (mean 28 months; range 20 to 46). Twenty-seven
      patients (29 vessels; 94%) remain asymptomatic with less than 50% stenosis. Two
      vessels (6%) have been found to have a critical restenosis of greater than 90%.
      Both patients were symptomatic from their recurrence (transient ischemic attack,
      n = 1; acute stroke, n = 1). Cumulative major stroke and death rate including all
      follow-up was 6%. CONCLUSIONS: CAS can be performed with an acceptable
      stroke/death rate (3%) in a properly selected patient population. In our small
      series of patients, the restenosis rate at a mean of 28 months after CAS is 6%.

PMID- 12620553
TI  - Allogenic blood transfusion is an independent risk factor for infective
      complications after less invasive gastrointestinal surgery.
AB  - BACKGROUND: The present study aimed to clarify the predisposing factors for
      postoperative infectious complications after less invasive surgery. METHODS: A
      total 150 surgical patients were placed in either group H (operative blood loss >
      or = 500 mL) or group L (<500 mL). The patients' background factors and
      postoperative inflammatory responses were assessed. RESULTS: The operating time
      was an independent risk factor for infectious complication in group H. In
      contrast, allogenic blood transfusion was the only significant risk factor for
      infection in group L. In the patients who received blood transfusion, exaggerated
      postoperative interleukin-6 response was found in group H, whereas an increased
      consumption of interleukin-6 soluble receptor with resultant induction of
      immunosuppressive acidic protein (IAP) were found in group L. CONCLUSIONS:
      Perioperative blood transfusion may predominantly contribute to increased
      susceptibility to infection after less invasive surgery through increased
      affinity of interleukin-6 soluble receptor and enhanced IAP response.

PMID- 12620554
TI  - Liberal use of computed tomography scanning does not improve diagnostic accuracy
      in appendicitis.
AB  - BACKGROUND: Based on a study at our hospital in 1994, we established a practice
      guideline for appendicitis patients. The practice guideline was followed well
      except for an increased number of preoperative computed tomography (CT) scans.
      METHODS: Data collected from the previous study of 100 patients were compared
      with data from consecutive patients, 118 total, seen over a similar time period
      in the year 2000. RESULTS: The percentage of CT scans ordered for the diagnosis
      of patients who underwent appendectomy markedly increased from 11% in 1994 to
      48.3% in 2000. (P <0.001) The percentage of normal appendixes removed did not
      change significantly from 12% in 1994 to 17.8% in 2000 (P = 0.317). Patients who
      had a CT scan were no less likely to have a normal appendix at surgery (P =
      0.386) and a significant increase in preoperative Emergency Department length of
      stay (P <0.001). CT was accurate 80% of the time in 2000 and 81% of the time in
      1994. Only 14 of 57 CT scans were ordered by surgeons. CONCLUSIONS: The use of
      preoperative abdominal CT scanning has not improved the accuracy of the diagnosis
      of appendicitis at our institution. It has resulted in a significant increase in
      Emergency Department preoperative length of stay and the finding of a normal
      appendix at surgery. As nonsurgeons ordered the majority of preoperative CT
      scans, earlier input by surgeons might increase the rate of accurate clinical
      diagnosis and decrease the number of CT scans ordered.

PMID- 12620555
TI  - What have we learned over the past 20 years about appendicitis in the elderly?
AB  - BACKGROUND: This study evaluates appendicitis in the elderly, comparing our
      findings to those previously published a decade earlier. METHODS: Comparison of
      appendicitis in the elderly (aged 60 years and older) from 1978 to 1988 with the
      following 10 years, 1988 to 1998. RESULTS: Overall (1978-1998) 26% of patients
      presented typically, one third delayed seeking care, with only half diagnosed
      correctly on admission. Computed tomography (CT) use increased (44% versus rarely
      in the previous decade). Perforation rates declined (72% first group versus 51%
      second group) with a concomitant drop in complications from 32% to 21%
      respectively. Overall, three fourths of complications occurred in patients with
      perforated appendicitis. Mortality rates remained constant. CONCLUSIONS:
      Appendicitis in the elderly is a difficult problem with delays in medical care,
      non-typical presentation resulting in incorrect diagnosis, relatively high rates
      of perforation often with associated postoperative complications and mortality. A
      higher index of suspicion with liberal early utilization of CT in uncertain cases
      may result in more appropriate management.

PMID- 12620556
TI  - How many cases are enough for accreditation in sentinel lymph node biopsy in
      breast cancer?
AB  - BACKGROUND: There is considerable argument concerning the number of sentinel node
      biopsy cases with axillary dissection that surgeons should perform before they
      are eligible on abandoning axillary dissection in negative sentinel node
      patients. DATA SOURCES: Papers that (1) address directly or indirectly the
      subject of credentialing or of learning curve, (2) report on a surgeon's
      performance, (3) are reported as feasibility or learning curve studies, or both,
      (4) discuss the learning curve issue, and (5) express an expert's opinion on the
      learning curve. CONCLUSIONS: The number of procedures of the learning curve can
      not be fixed for all surgeons. Only surgeons in specialized breast cancer centers
      can succeed in meeting current recommendations with 20 to 30 cases. Surgeons from
      affiliated community hospitals will need more than 30 cases, whereas broad-based
      surgeons might need as many as 60 cases with their current caseload. Not all
      surgeons will be able to offer the procedure to their patients by the current
      recommendations.

PMID- 12620557
TI  - An Internet-based tool for evaluating third-year medical student performance.
AB  - BACKGROUND: Shortened non-primary care medical school clerkships have increased
      time pressures for accurate assessment of student knowledge, skills, and
      attitudes. Paper-based student evaluations suffer from low response rates,
      inefficient data acquisition and analysis, and difficulty obtaining input from
      multiple evaluators. This project describes the development of a Web-based model
      for evaluating third-year medical student performance, improving evaluation
      response rates, and including multiple evaluators' input. METHODS: A secure Web
      based system was designed to maintain evaluation data (11-item competency-based
      evaluations, oral examinations, National Board of Medical Examiners surgery test,
      and objective structured clinical examination) for the third-year surgery
      clerkship. Historical response rate, completion time, and administrative effort
      data were compared with data obtained using the Web-based model. RESULTS: Faculty
      response rates improved from 71.3% to 89.9%, with response times decreased from
      28.0 +/- 3.0 to 9.0 +/- 0.7 days using the Web-based model. Administrative time
      requirements decreased from 5 days to 2 hours per rotation, and manual data
      entry, analysis, and reporting were eliminated through e-mail evaluator
      notification, direct data entry, and real-time analysis. Evaluator satisfaction
      was subjectively higher using the Web-based model. CONCLUSIONS: The Web-based 360
      degree evaluation model improves third-year medical student assessment by
      including residents, reducing time and cost, and by providing a faster, more
      inclusive, and efficient evaluation.

PMID- 12620558
TI  - Who are the surgery clerkship directors and what are their educational needs?
AB  - BACKGROUND: The surgery clerkship director is a key individual in the surgery
      department's educational mission and yet there has been no prior effort to
      describe this group or identify their learning needs. The purpose of this study
      was to develop a demographic profile and an educational needs assessment for
      surgery clerkship directors. METHODS: A survey instrument was designed based on
      existing literature and distributed to surgery clerkship directors in the United
      States and Canada. RESULTS: Surveys were returned from 108 subjects (77%). The
      majority of clerkship directors strongly agree that directing is a positive
      experience but express concern that the job demands may impede their professional
      careers. The perceived educational needs identified related primarily to the
      development and management of the student education curriculum. CONCLUSIONS:
      Surgery clerkship directors are experienced academic surgeons who report high
      levels of satisfaction. They identify a number of important educational needs of
      the position and express concern about the requirements of the position on their
      academic careers.

PMID- 12620559
TI  - Three-dimensional images of pancreatic pseudocyst prior to percutaneous drainage.

PMID- 12620560
TI  - One or two-stage hepatectomy combined with portal vein embolization for initially
      nonresectable colorectal liver metastases.
AB  - BACKGROUND: Portal vein embolization (PVE), proposed to induce contralateral
      hepatic hypertrophy before major hepatectomy, carries some negative side effects
      since growth rate of metastases in the future remnant liver (RL) can be more
      rapid than that of nontumoral liver parenchyma. Therefore, metastases in the RL
      should be ideally resected before PVE, and a major hepatectomy can then be
      performed after PVE in patients with multiple bilobar colorectal liver metastases
      (MBLM). The aim of this study was to assess feasibility and outcome in patients
      with initially unresectable colorectal liver metastases treated by a one- or two
      stage hepatectomy procedure (TSHP) combined with PVE. PATIENTS AND METHODS: From
      December 1996 to December 1999, 180 patients with colorectal liver metastases
      underwent hepatectomy. During the same period, 18 were initially considered as
      unresectable. TSHP combined with PVE was attempted for 7 patients (group A) among
      those with MBLM, and a one-stage hepatectomy after PVE was attempted in another
      group of 11 patients (group B) among those with non-MBLM. RESULTS: Nonanatomical
      resections for left liver metastases were performed as a first stage without any
      complications in group A. A right hepatectomy (RH) was performed in 5 patients in
      group A (feasibility = 71%). In group B, 7 of the 11 patients underwent a RH or
      an extended RH after PVE (feasibility = 64%). Postoperative complications rate
      did not differ between group A and B. Mortality was nil. Three-year survival rate
      was 53% in group A and 100% in group B. CONCLUSIONS: These results suggest that
      one- or two-stage hepatectomy combined with PVE can be applied safely to selected
      patients initially considered as unresectable. Three-year survival was similar to
      that observed in patients with initially resectable liver metastases.

PMID- 12620561
TI  - Reconstruction of portal vein using a hepatic vein patch graft after combined
      hepatectomy and portal vein resection.
AB  - BACKGROUND: Surgical resection is the only treatment modality that ensures
      complete tumor removal in patients with liver tumors involving a major portal
      vein branch or its bifurcation. Restoration of good portal blood flow is
      essential for recovery in the early postoperative period and for long-term
      survival. However, such extended resections often result in large defects at the
      bifurcation of the portal vein that are not amenable to suturing or end-to-end
      anastomosis. METHODS: A patch graft technique is very useful for reconstruction
      of long and elongated defects when other methods are not technically appropriate.
      We describe a simple technique for reconstructing the portal vein using a patch
      graft obtained from the hepatic vein stump of the resected specimen. CONCLUSIONS:
      This technique permits surgeons to reconstruct the portal vein without any need
      for harvesting another vein and with no need for an additional incision.

PMID- 12620563
TI  - Does additional surgical training increase participation in randomized controlled
      trials?
AB  - BACKGROUND: The prospective randomized controlled trial (PRCT) is agreeably the
      gold standard in reporting data on patient management. This study evaluates the
      impact of specialty training on the leadership, development, and enrollment in
      PRCT. METHODS: Questionnaires were sent to surgical oncology as well as general
      surgery graduates from 1985 to 1999. RESULTS: A total of 67% (201 of 300) of the
      surgeons responded, with one half of the respondents completing a surgical
      oncology (SO) fellowship (50%, 100 of 201), 33% (66 of 201) another type of
      fellowship (OF), and 17% (35 of 201) general surgery (GS) training alone. The
      utilization of PRCT in the decision making of their clinical practice was
      reported by a majority of SO graduates (99%) as well as GS graduates (88%) with a
      smaller number (77%) of OF trained surgeons. The opinions on PRCT were evenly
      distributed with breast disease, colorectal cancer, and melanoma having the
      greatest impact on surgeons practicing in these fields. A greater percentage of
      SO (89%) reported participation in a PRCT than did the GS (42%) or OF (54%). The
      most frequent reason for the lack of participation in a PRCT by both GS and OF
      trained graduates was absence of active recruitment (80%) to participate with the
      second most common being no time available (18%). CONCLUSIONS: PRCT are utilized
      and continue to change surgeons' decision making for a majority of the surgeons
      surveyed. There are certain disease sites for which PRCT have failed to influence
      practice decisions. Unfortunately, few surgeons take a leadership role in PRCT.
      Emphasizing the existence of PRCT at both meetings, and in journals, with a more
      aggressive recruitment of participating surgeons with minimal time commitment,
      should enhance the patients included in prospective randomized controlled trials.

PMID- 12620562
TI  - Pathology of Barrett's esophagus by proton magnetic resonance spectroscopy and a
      statistical classification strategy.
AB  - BACKGROUND: Barrett's esophagus is thought to be a precursor of adenocarcinoma.
      The incidence of adenocarcinoma of the lower esophagus in the Western world is
      rising and accounts for more than 40% of esophageal carcinomas in males. It is
      not possible to identify which Barrett's patients are at high risk of developing
      malignancy. Here we applied a statistical classification strategy to the analysis
      of magnetic resonance spectroscopy and histopathological data from esophageal
      biopsies to ascertain whether this risk could be identified in Barrett's
      patients. METHODS: Tissue specimens from 72 patients (29 noncancer-bearing and 43
      cancer-bearing) were analyzed by one-dimensional proton magnetic resonance
      spectroscopy at 8.5 Tesla. Diagnostic correlation was performed between the
      magnetic resonance spectra and histopathology. The magnetic resonance magnitude
      spectra were preprocessed, followed by identification of optimal spectral
      regions, and were then classified by cross-validated linear discriminant analysis
      of rank orders of the first derivative of magnetic resonance spectra. RESULTS:
      Magnetic resonance spectroscopy combined with a statistical classification
      strategy analysis distinguished normal esophagus from adenocarcinoma and
      Barrett's epithelium with an accuracy of 100%. Barrett's epithelium and
      adenocarcinoma were distinguished with an accuracy of 98.6% but only when 4 of
      the Barrett's specimens and 7 of the carcinoma specimens, determined to be
      "fuzzy" (ie, unable to be accurately assigned to either class) were withdrawn.
      The 7 cancer and 4 Barrett's specimens, determined to be "fuzzy" using the
      Barrett's versus cancer (B versus C) classifier, were submitted to the other two
      classifiers (Barrett's versus normal [B versus N] and normal versus cancer [N
      versus C], respectively). The 4 Barrett's specimens were assigned to Barrett's by
      the N versus B classifier and to normal (n = 2) or cancer (n = 2) classes by the
      N versus C classifier. The 7 cancer specimens were crisply assigned to the cancer
      class (N versus C), or for the B versus N classifier, to the Barrett's class (ie,
      more similar to Barrett's than to normal tissue). Visual inspection of the
      spectra from histologically identified Barrett's epithelium showed a gradation
      from normal to carcinoma. CONCLUSIONS: Proton magnetic resonance spectroscopy of
      esophageal biopsies combined with a statistical classification strategy data
      analysis provides a robust diagnosis with a high degree of accuracy for
      discriminating normal epithelium from esophageal adenocarcinoma and Barrett's
      esophagus. Different spectral categories of Barrett's epithelium were identified
      both by visual inspection and by statistical classification strategy, possibly
      reflecting the risk of future malignant transformation.

PMID- 12620564
TI  - Efficiency of the operating room suite.
AB  - BACKGROUND: The need to control high costs of running operating rooms while
      providing for timely patient care led us to assess the time wasted in the
      operating room (OR). METHODS: OR use by two general surgery and two orthopedic
      departments in a metropolitan public hospital were analyzed, and the time elapsed
      when a scheduled OR remained unused or the patient was still awaiting surgery was
      measured. RESULTS: OR "time-waste" defined as the time in which the scheduled OR
      was not busy with the scheduled patient amounted to 79 hours over the 30-day
      study period (15% of total time). It was wasted owing to inappropriately prepared
      patients (12%), unavailability of surgeons (7%), insufficient nursing staff,
      anesthesiologists, or OR assignment to emergency surgery (59%), congestion of the
      postanesthesia care unit (10%), and delay in transport to the OR (2%) Another
      issue delineated was the frequent occurrence of surgical cases running longer
      than their scheduled time (termed "spill-over"), outrunning the staffing
      expectations after 3:00 PM and delaying admission of add-on and emergency
      procedures, adding 33% to the time wasted. A quality-assurance committee review
      resulted in implementation of new guidelines, and within 3 months several
      underlying causes were rectified, and time-waste and spill over time was reduced
      by 35%. Surgical time predictions were also improved. Shortage of nurses and
      anesthesiologists, and OR emergency reassignment remained the major causes of OR
      waste time. CONCLUSIONS: Continuous surveillance on OR suite-patients' prompt
      care, repeated evaluation, and wise staff deployment-could maximize OR
      efficiency.

PMID- 12620565
TI  - Magnetic resonance cholangiopancreatography for postoperative follow-up of
      intraductal papillary-mucinous tumors of the pancreas.
AB  - BACKGROUND: After resection of an intraductal papillary-mucinous tumor (IPMT),
      benign tumors or portions of the resected tumor are sometimes left in place to
      avoid total pancreatectomy. We evaluated the role of magnetic resonance
      cholangiopancreatography (MRCP) in postoperative follow-up. METHODS: Twenty-two
      patients underwent MRCP 0.5 to 6.5 years after pancreatic resection for IPMT.
      RESULTS: Two patients with surgical margin involvement of the main pancreatic
      duct showed mildly enhanced ductal dilatation due to anastomotic stenosis. In 4
      patients with residual IPMT of the branch ducts, postoperative MRCP demonstrated
      no changes. MRCP revealed new IPMT 1 year after surgery in 1 patient. No patients
      showed intraductal or intracystic mural nodules postoperatively. In 3 patients
      with postoperative pancreatitis or recurrent abdominal discomfort, MRCP
      demonstrated ductal dilatation and poor secretin-stimulated pancreatic secretion
      into the gastrointestinal tract, which suggested pancreatoenterostomic stenosis.
      CONCLUSIONS: MRCP is useful for postoperative follow-up of IPMT, in terms of
      investigating residual or recurrent IPMT and evaluating postpancreatectomy long
      term complications.

PMID- 12620566
TI  - Human botfly.

PMID- 12620568
TI  - A learning prescription permits feedback on feedback.
AB  - BACKGROUND: Students consistently identified inadequate feedback as a deficiency
      in our third-year clerkship. METHODS: We asked students to solicit one faculty
      and one resident every 2 weeks for written feedback on a "feedback prescription
      pad." Each prescription requested four comments: two things the student did well
      and two things the student needs to improve. Students rated feedback using a five
      point scale. A three-point categorization scheme was employed to assess the
      quality of feedback. RESULTS: Students' rating of feedback improved significantly
      compared with a previous time period (3.5 +/- 1.2 versus 2.6 +/- 1.2, P <0.01).
      Interrater reliability of our categorization scheme was high (kappa > or =0.75, P
      <0.01) and demonstrated that only 10% of comments were specific enough to qualify
      as effective feedback. CONCLUSIONS: Feedback prescription pads were a simple
      method to facilitate feedback. Although students appreciated feedback, most
      feedback was inadequate. Faculty development programs to enhance student feedback
      should be a priority of clinical medical education.

PMID- 12620567
TI  - Predictive factors and timing for liver recurrence after curative resection of
      gastric carcinoma.
AB  - BACKGROUND: Advanced and reliable diagnostic methods in order to identify the
      site of recurrence of gastric cancer in an early stage are needed. METHODS: One
      hundred twenty patients whose recurrence was confirmed after curative resection
      for gastric cancer were enrolled in this study. RESULTS: Liver recurrence was
      evident in 41 patients. Advanced age, tumor invasion into subserosa, intestinal
      and mixed type of histology, Borrmann type 0 to 2, tumor diameter (<6.5 cm), and
      tumor marker (carcinoembryonic antigen and alpha-fetoprotein) elevation were
      related to liver recurrence. By logistic regression analysis, independent risk
      factors for liver recurrence included Borrmann's classification, histology, and
      tumor marker elevation. The median time from the primary operation to liver
      recurrence was shortest in the tumor marker elevation group when compared with
      other independent predictors. CONCLUSIONS: This information may help to design a
      better follow-up program and appropriate treatment strategy for gastric cancer
      patients with liver metastasis.

PMID- 12620569
TI  - Elimination of mucosectomy during restorative proctocolectomy in patients with
      ulcerative colitis may provide better results in low-volume centers.
AB  - BACKGROUND: To compare the outcomes of hand-sewn and double-stapling techniques
      among ulcerative colitis patients undergoing restorative proctocolectomy at a
      center that has limited experience with restorative proctocolectomy. METHODS:
      Forty-four patients with ulcerative colitis were divided into two groups
      according to the anastomosis techniques: hand sewing and double stapling.
      Postoperative early and late complications, postoperative hospital stay, and long
      term functional results were compared. RESULTS: Pelvic sepsis (9% versus 36%, P =
      0.03), operation time (median 240 minutes versus 270 minutes, P = 0.01),
      postoperative hospital stay (median 9 days versus 12 days, P = 0.04), and night
      incontinence (42% versus 80%, P = 0.07) were less common in the double-stapling
      group. CONCLUSIONS: We recommend the double-stapling technique to centers that do
      not have extensive experience with restorative proctocolectomy for ulcerative
      colitis. This technique provides a good postoperative course in most patients and
      provides satisfactory long-term results. The results of the double-stapling group
      were similar to the results of the high-volume centers.

PMID- 12620570
TI  - Laparoscopic treatment using an argon beam coagulator for nonparasitic liver
      cysts.
AB  - BACKGROUND: Laparoscopic deroofing has been shown to produce good patient
      satisfaction and to have results similar to those of open surgical techniques. We
      evaluated the feasibility and efficacy of laparoscopic deroofing using an argon
      beam coagulator (ABC) in the patients with nonparasitic liver cysts. METHODS:
      Laparoscopic deroofing for the treatment of liver cysts was attempted on 14
      patients. After the deroofing, the secreting epithelium within the residual
      cystic cavity wall was destroyed using the ABC. RESULTS: Laparoscopic deroofing
      was successful in all patients. No deaths or surgical morbidity occurred, and no
      postoperative complications were recorded. The median postoperative hospital stay
      was 7 days. The median follow-up was 56 months for all patients, and all patients
      have remained completely asymptomatic for 6 months after the surgery, with no
      recurrence of the cysts. CONCLUSIONS: Our results indicate that laparoscopic
      deroofing using the ABC method in patients with nonparasitic liver cysts was
      effective in preventing cyst recurrence.

PMID- 12620571
TI  - Impact of lymph node metastasis on the pattern of failure and survival in oral
      carcinomas.
AB  - BACKGROUND: Carcinomas of the oral cavity present a high risk for neck metastases
      that decrease the disease control and survival. METHODS: A total of 106 patients
      with squamous cell carcinoma of the oral cavity who had metastatic neck nodes
      were studied. The impact of neck metastasis and treatment modalities on outcome
      was assessed. RESULTS: Thirty-eight patients developed neck recurrence or distant
      metastasis. The 5-year survival, neck recurrence-free, and distant metastases
      free rates were 56%, 84%, and 77%, respectively. Univariate analyses showed
      extranodal spread (ENS), number of positive nodes, and adjuvant chemotherapy were
      predictors for survival. In multivariate analysis, ENS and postoperative
      radiotherapy were of borderline significance. There was no prognostic factor for
      neck control. The presence of ENS and lower levels of positive nodes and no
      chemotherapy were associated with high distant failure rates. CONCLUSIONS: To
      prevent distant metastases, patients with ENS should be considered for adjuvant
      chemotherapy.

PMID- 12620572
TI  - Endoscopic mucosal resection for early cardia cancer by minimum laparotomy.
AB  - Endoscopic mucosal resection (EMR) has been widely accepted as a minimally
      invasive and standard treatment for early gastric cancers without ulceration or
      signs of submucosal invasion and meeting the criteria for diameter, macroscopic
      appearance, and well- or moderately differentiated histology. However, EMR cannot
      be applied to some cases owing to technical difficulties relating to the
      intragastric location of the cancers even when the above criteria are satisfied.
      We report here a new approach to EMR for early cancers of the cardia located
      close to the esophagocardia junction that are outside the indications for
      ordinary EMR.

PMID- 12620573
TI  - Extra-anatomic gallbladder torsion.

PMID- 12620574
TI  - Alkaline phosphatase in stallion semen: characterization and clinical
      applications.
AB  - Significant amounts of alkaline phosphatase (AP) activity have been found in
      semen plasma from numerous species. In species in which the majority of semen
      plasma AP (SPAP) activity originates from the epididymis and testicle, SPAP
      activity can be used clinically as a marker to differentiate testicular origin
      azoospermia or oligospermia from ejaculatory failure. Information on SPAP
      activity in stallions to date has been limited. In this study, a standard
      clinical chemistry analyzer was used to determine AP activity in pre-ejaculatory
      fluid and ejaculates from groups of normal stallions. Additionally, accessory
      glands, epididymides, testicles and other components of the urogenital tract of
      normal stallions were assayed to determine which tissues contain SPAP activity.
      The results indicated that levels of AP activity are low in pre-ejaculatory
      fluid, but significantly higher in ejaculatory fluid from normal stallions.
      Spermatozoa were not a significant source of SPAP activity. High levels of SPAP
      activity were found in the testes and epididymides. These findings suggest that
      SPAP activity is a candidate for a sperm-independent marker for ejaculation in
      the stallion. Finally, AP activity was determined in ejaculatory fluid from a
      stallion with bilaterally blocked ampullae, both before and after relief of the
      blockage. While the blockage was present, AP activity in ejaculatory fluid was
      low. However, following relief of the blockage, AP activity in ejaculatory fluid
      rose dramatically, thus suggesting that AP activity will be useful as an
      inexpensive, simple clinical assay for differentiating ejaculatory failure or
      excurrent duct blockages from testicular origin azoospermia and oligospermia.

PMID- 12620575
TI  - Factors affecting follicular populations on Day 3 postweaning and interval to
      ovulation in a commercial sow herd.
AB  - Sows (n=146) in a commercial herd were studied to determine factors affecting
      follicular populations and interval to ovulation after weaning. Ovaries were
      examined daily by ultrasonography beginning on Day 3 postweaning and twice daily
      from Day 4.5 until ovulation. Ovarian images were recorded on videotape on Day 3
      postweaning and follicles were counted. Subsequent ultrasounds were used to
      determine time of ovulation. Sows with short weaning to ovulation intervals
      (<or=6.5 days) had follicular populations on Day 3 postweaning that were more
      advanced (comprised of follicles with greater diameter) when compared to sows
      with long (>or=9 days) weaning to ovulation intervals (P<0.001). Follicular
      populations in sows with intermediate (7-8.5 days) intervals to ovulation were
      intermediate in diameter when compared to sows with short or long intervals to
      ovulation. Parity and body condition score (BCS) affected interval to ovulation;
      first parity and low body condition sows had longer intervals to ovulation
      (P<0.001 and 0.05, respectively). The longer intervals to ovulation in first
      parity and low body condition sows were associated with lesser follicular
      diameters on Day 3 after weaning. We conclude that follicular populations
      measured by ultrasonography on Day 3 after weaning were different for sows with
      different intervals to ovulation. Furthermore, production factors (i.e. parity
      and BCS) known to influence interval to ovulation were associated with
      differences in follicular growth within the first 3 days after weaning in sows.

PMID- 12620576
TI  - Insemination time and dilution rate of cooled and chilled ram semen affects
      fertility.
AB  - Adult Merino ewes (n=448) were apportioned into two groups and inseminated with:
      extended at 30 degrees C with skim milk and stored for 6h at 15 degrees C (cooled
      semen) or extended with skim milk-citrate trisodium with egg yolk and stored for
      24h at 5 degrees C (chilled semen). Each group was further subdivided according
      to the time of cervical insemination at 42, 46 and 50h after pessary (MAP-60 mg)
      removal and according to the dilution of the semen (120 x 10(6) spermatozoa in
      0.05, 0.1 and 0.2 ml). The pregnancy rate after insemination with cooled semen
      was 50% better than that after chilled semen (56.7 vs. 37.5%; P<0.001). Pregnancy
      rate was not affected by the volume of insemination; however, there was a
      tendency of increased lambing rate with an insemination dose of 0.1 cc (1:2,
      dilution), especially when the ewes were inseminated with cooled semen. The
      effect of time on insemination was significant only in ewes inseminated with
      chilled semen at 5 degrees C (P<0.01). Insemination carried out 46 h after
      pessary removal resulted in higher pregnancy and lambing rate (36.5, 31.1; 52.0,
      45.3; and 24.0, 20.0 at 42, 46 and 50h, respectively). Pregnancy of ewes
      inseminated with chilled semen at 46 h after pessary removal was similar to that
      obtained using cooled semen (52.0 vs. 56.7%). From this study, it is concluded
      that advancing the time of insemination with chilled semen at 5 degrees C
      improves pregnancy and that the lambing obtained under these conditions is
      similar to the one obtained with cooled semen.

PMID- 12620577
TI  - Testicular development and its relationship to semen production in Murrah buffalo
      bulls.
AB  - The objectives of this study were to determine the relationship of age and body
      weight to testicular development and to establish norms for breeding soundness
      evaluations of Murrah buffalo bulls. Testicular measurements of 133 Murrah
      buffalo bulls of various ages were recorded with a caliper and a tape. Semen was
      collected twice a week for 5 weeks from groups of bulls which were 25-36 (n=17),
      37-48 (n=16), 49-60 (n=14), of >60 (n=10) months of age. After examining volume,
      sperm concentration, and progressive motility semen was diluted in Tris-citric
      acid-egg yolk-fructose extender and frozen in 0.5 ml French straws. Testicular
      measurements of buffalo bulls were lower than those recorded for European breeds
      of cattle bulls. Nevertheless, like cattle bulls, scrotal circumference was
      highly correlated with other testicular measurements. Also, it had a significant
      positive relationship with semen volume and sperm concentration per ejaculate.
      Average sperm output per week in order of increasing age group was 15.3, 18.2,
      19.8 and 23.6 x 10(9). Corresponding values for sperm output per week per gram of
      testis were 59.1, 45.8, 41.1, 36.2 x 10(6) indicating a reduction in
      spermatogenesis per unit of testis with advancing age. Compared to European
      breeds, daily sperm output in Murrah bulls was nearly 45% lower, presumably due
      to their nearly 40% lower scrotal circumference than Holstein bulls of the same
      age. These results indicate that in buffalo, as in cattle, scrotal circumference
      is a useful indicator of potential sperm output and may serve as an important
      criterion for selecting young bulls as AI sires.

PMID- 12620578
TI  - Medroxyprogesterone priming and response to the ram effect in Corriedale ewes
      during the nonbreeding season.
AB  - The "ram effect" (RE) is an inexpensive technique that allows farmers to obtain
      out-of-season lambs. Five hundred and ninety-six Corriedale ewes were used in
      three experiments to determine the effectiveness of different medroxyprogesterone
      (MAP) treatments associated with the ram effect during the nonbreeding season.
      The aim of the first experiment was to evaluate the effectiveness of short-term
      (6-day) MAP priming. We obtained similar results in estrus incidence and
      fertility after using MAP sponges for 6, 9, and 13 days. In the second
      experiment, we compared the effect of sponges containing 20, 40, or 60 mg of MAP
      used in 6-day priming. Estrous behavior and fertility were not affected by
      dosage. In the third experiment, 2.5mg of MAP was administered in single
      treatments 0, 1, 3, or 5 days before the introduction of the rams.
      Medroxyprogesterone administration 1, 3, or 5 days before the introduction of the
      rams concentrated estrus in ewes 17 to 20 days later.

PMID- 12620579
TI  - Comparison of ceftiofur hydrochloride and estradiol cypionate for metritis
      prevention and reproductive performance in dairy cows affected with retained
      fetal membranes.
AB  - The objective of this study was to compare the effect of ceftiofur hydrochloride
      and estradiol cypionate (ECP) administration for metritis prevention and
      reproductive performance in dairy cows affected with retained fetal membranes
      (RFMs). After parturition, 97 dairy cows affected with RFM from a single dairy
      herd were randomly allocated to 1 of 3 treatment groups. Cows in-group 1 (n=31)
      were treated daily for 5 days with ceftiofur hydrochloride (2.2mg/kg, i.m.); cows
      in group 2 (n=33) were treated once with ECP (4 mg, i.m.); and cows in group 3
      (n=33) were not treated. The proportion of cows with metritis, uterine involution
      patterns and the calving-to-conception interval were compared between groups. The
      proportion of cows that developed metritis was significantly different (P<0.05)
      in cows treated with ceftiofur hydrochloride (13%), compared with cows treated
      with ECP (42%) or cows that received no treatment (42%). Uterine involution
      patterns (i.e. median time to complete retraction of the uterus and mean diameter
      measure of cervix and uterine horns) were not significantly different between
      groups. Cows treated with ECP were 0.40 times as likely to conceive as control
      cows (P=0.05); median time to conception in cows treated with ECP (192 days) was
      longer, compared to control cows (124 days). We conclude that systemic
      administration of ceftioufur hydrochloride is beneficial for prevention of
      metritis, but its effect on reproductive performance was not significantly
      different to that of ECP or no treatment. In addition, administration of ECP did
      not have beneficial effects on metritis prevention and reproductive performance.

PMID- 12620580
TI  - Influence of reproductive status on in vitro oocyte maturation in dogs.
AB  - In the bitch, oocytes need 48-72 h to complete post-ovulatory maturation to the
      metaphase II stage in the isthmus of the oviduct, an interval similar to that
      found in in vitro studies. The effect of estrous cycle stage on in vitro meiotic
      competence of dog oocytes has been described in several studies. However, there
      are no reports evaluating the possible effects of pyometra or pregnancy on
      subsequent potential of oocytes recovered from such females to undergo in vitro
      maturation. In this study, immature cumulus-oocyte complexes (COCs) were
      recovered from fresh excised domestic dog ovaries in various reproductive states.
      The donor females were classified into groups based on stage of the estrous
      cycle: follicular (proestrus or estrus), luteal (diestrus) or anestrus or at the
      clinical conditions of pregnancy and pyometra. Grades 1 and 2 oocytes were
      cultured in vitro at 37 degrees C in TCM-199, supplemented with 25 mM Hepes/l
      (v/v), and with 10% heat inactived estrous cow serum (ECS), 50 microg/ml
      gentamicin, 2.2 mg/ml sodium carbonate, 22 microg/ml pyruvic acid, 1.0 microg/ml
      estradiol, 0.5 microg/ml FSH and 0.03 IU/ml hCG. The nuclear maturation rate was
      evaluated at 72 h of incubation under Hoechst 33342 (10 microg/ml) staining for
      fluorescence microscopy. There was no statistical difference in nuclear
      progression to the MII stage among the various reproductive states (follicular
      phase, 5.4%; diestrus, 4.2%; anestrus, 4.4%; pyometra, 8.1% and pregnancy, 4.7%).
      Resumption of meiosis was 24.6% at the follicular phase, 19.6% for diestrus,
      16.4% for anestrus, 37.1% for pyometra and 29.2% for pregnancy. Positive and
      higher numbers of residue above the expected value were observed for the pyometra
      and pregnancy conditions at the metaphase/anaphase I (MI/AI) stages.Our results
      indicate that in vitro nuclear maturation of dogs oocytes is not influenced by
      the in vivo reproductive status of the female. The quality of the oocyte is a
      more reliable indicator of its potential for meiotic maturation in vitro than the
      hormonal environment of the donor female at the time of oocyte retrieval.

PMID- 12620581
TI  - Factors associated with first service conception in artificially inseminated
      nulliparous Holstein heifers.
AB  - Animal and management factors associated with first service conception in
      nulliparous dairy heifers were determined in 601 Holstein heifers from a dairy
      farm in north central Florida. Animal data collected included body weight, height
      at the withers and tail head, body condition score at 6 months of age and just
      prior to first artificial insemination (AI), and pelvimetry measurements taken
      just prior to first AI. Management data included season of first AI, inseminator,
      service sire, method of estrus detection, whether the estrus of first
      insemination was induced using prostaglandin F(2alpha) (PGF(2alpha)), and whether
      the heifer received a modified live virus (MLV) vaccine within 21 days of first
      insemination. Data were analyzed using multivariable logistic regression. Heifers
      inseminated in the summer were more than four times less likely to become
      pregnant to first insemination than heifers bred during the rest of the year
      (odds ratio (OR)=0.24; 95% CI=0.14, 0.41). Using secondary signs for estrus
      detection instead of standing estrus resulted in significantly reduced odds of
      conception to first service (OR=0.37; 95% CI 0.13, 1.02). Also, heifers
      inseminated at estrus induced by PGF(2alpha) were approximately one-third less
      likely to conceive than those heifers inseminated to a naturally occurring estrus
      (OR=0.66; 95% CI 0.46, 0.95). An interaction between pelvic size and breeding
      season was found indicating that large pelvic size had a significant positive
      effect on fertility in the summer, but was not associated with conception to
      first service in the winter.

PMID- 12620582
TI  - Fertility of weaned sows after deep intrauterine insemination with a reduced
      number of frozen-thawed spermatozoa.
AB  - The present study evaluates the effectiveness of the transcervical deep
      intrauterine insemination (DUI) with a reduced number of frozen-thawed boar
      spermatozoa in weaned sows. DUI was performed using a specially designed flexible
      device (length 180 cm, outer diameter 4mm, working channel 1.8mm, working
      channel's volume 1.5 ml) that was inserted through an artificial insemination
      spirette to cross the cervix lumen and moved into one uterine horn as far as
      possible. Spermatozoa diluted in 7.5 ml of BTS were flushed into the uterine horn
      by a syringe attached to the working channel. In Experiment 1, 111 hormonally
      treated (eCG/hCG) weaned sows were inseminated once using one of the following
      three regimens: (1) DUI with frozen-thawed spermatozoa (1000 x 10(6) cells per
      dose; n=49); (2) DUI with fresh semen (150 x 10(6) cells per dose; n=29, as
      control of DUI procedure); and (3) cervical insemination with frozen-thawed
      spermatozoa (6000 x 10(6) cells diluted in 100ml; n=33). No differences (P>0.05)
      were found for farrowing rates (77.55, 82.76, and 75.76, respectively) or litter
      sizes (9.31+/-0.41, 9.96+/-0.32, and 9.60+/-0.53 piglets born per litter,
      respectively) among the groups. In Experiment 2, DUI was performed on the
      spontaneous estrus in weaned sows (2-6 parity) with 1000 x 10(6) frozen-thawed
      (40 sows) or 150 x 10(6) fresh spermatozoa (38 sows). The farrowing rate of sows
      inseminated twice with frozen-thawed spermatozoa (70%) was significantly (P<0.05)
      lower than with fresh semen (84.21%). No significant difference (P>0.05) was
      found in litter size between frozen-thawed spermatozoa (9.25+/-0.23 piglets born
      per litter) and fresh semen (9.88+/-0.21 piglets born per litter). These
      preliminary results indicate that application of DUI provides acceptable
      fertility in weaned sows using a relatively low number of frozen-thawed
      spermatozoa.

PMID- 12620583
TI  - Is fertility declining in dairy cattle? A retrospective study in northeastern
      Spain.
AB  - The past few decades have seen a dramatic increase in infertility and
      reproductive disorders associated with a rising milk yield. Herein, we present a
      10-year (from 1991 to 2000) retrospective survey of these factors using data from
      a reproductive management program performed on high-yielding dairy herds in north
      east Spain. The data series included 12,711 lactations. The year was divided into
      warm and cool periods. Data were obtained from cows first inseminated or examined
      45-70 days postpartum. The reproductive tract of each animal was examined by
      palpation per rectum within 43-48 days postpartum. Cows were then weekly examined
      until insemination or until postpartum Day 70. Cows with a corpus luteum were
      synchronized for estrus and timed AI. Cows showing natural estrus in the same
      period were also inseminated. All inseminations were pooled as a single group and
      inseminated cows were considered cyclic. Inactive ovaries and ovarian cysts were
      recorded as ovarian disorders. Incomplete uterine involution, endometritis and
      pyometra were grouped as uterine disorders. Overall cyclicity and pregnancy rates
      of all AI cows, and cyclicity and pregnancy rates corresponding to the warm
      period significantly decreased over the 10-year period, yet remained practically
      constant during the cool period. The incidence of inactive ovaries in the entire
      population and that corresponding only to cows examined during the warm period
      significantly increased with time but was similar during the cool period. Ovarian
      cysts were more frequent during the warm (12.3%) than during the cool (2.4%)
      period, though these proportions were maintained throughout the study. The
      incidence of uterine disorders significantly decreased with time and did not
      differ between cool and warm periods. Milk yield per cow and year increased from
      7800 kg in 1991 to 10,200 kg in 2000. Regression analysis revealed that, for all
      cows and those inseminated or examined in the warm period respectively, each 1000
      kg increase in average milk yield was related to decreases of 3.2 and 6% in
      pregnancy rate, 4.4 and 7.6% in cyclicity, and to increase of 4.6 and 8% in the
      incidence of inactive ovaries. The rate of uterine disorders decreased 1.1%
      regardless of season. Our overall results clearly reflect the increased
      infertility and incidence of reproductive disorders over the study period. This
      occurred simultaneous to increasing average milk yield. Nevertheless, under our
      study conditions, a cool environment appears to preserve fertility and reduce the
      risk of reproductive disorders irrespective of the milk yield. These findings
      prompt the need to improve management practices by attempting to reduce the
      effects of factors provoking stress.

PMID- 12620584
TI  - Post-thaw functional status of boar spermatozoa cryopreserved using three
      controlled rate freezers: a comparison.
AB  - This study compared variation in the quality of cryopreserved boar spermatozoa
      and the control and accuracy of cooling rates between three semen freezers
      (CryoLogic Freeze Control CL3000, Planer Products Kryo Save Compact KS1.7/Kryo 10
      Control module and a controlled rate 'Watson' freezing machine developed within
      our laboratory). Five ejaculates were collected from each of 15 boars (five boars
      from each of three breeds). Semen was diluted into a commercial freezing buffer
      (700 mOsm/kg, 3% v/v glycerol) and placed into 0.5 ml straws. Three straws per
      treatment, from each ejaculate were cooled to -5 degrees C at 6 degrees C/min,
      held at -5 degrees C for 30s while ice crystal formation was induced, then
      further cooled from -5 to 80 degrees C at either 40 degrees C/min (Kryo Save
      Compact KS1.7 and Watson) or 6 degrees C/min (Freeze Control CL3000). Precise
      measurements of temperature fluctuations during the programmed cooling curves
      were made by inserting thermocouples into the semen filled straws. Semen was
      assessed for %motile cells, motility characteristics using computer-assisted
      semen analysis (CASA), plasma membrane integrity (%SYBR-14 positive stained
      spermatozoa) and acrosome integrity (%FITC-PNA positive stained spermatozoa).
      Spermatozoa cryopreserved using the Freeze Control CL3000 system (maximum rate of
      6 degrees C/min) exhibited reduced post-thaw viability (14.2+/-2.8% mean plasma
      membrane intact spermatozoa) when compared to both the KS1.7 and Watson freezers
      (optimal rate of 40 degrees C/min) (18.4+/-3.2 and 25.7+/-3.7% mean plasma
      membrane intact spermatozoa, respectively). Differences in motility
      characteristics were observed between spermatozoa cryopreserved at 40 degrees
      C/min with the Watson apparatus preserving a larger proportion of sperm with
      progressive motility. Cooling curves in the CL3000 and KS1.7 were interrupted by
      a pronounced increase in temperature at -5 degrees C that corresponded with the
      latent heat of fusion released with ice crystal formation. This temperature
      change was significantly reduced in the cooling curves produced by the Watson
      freezer. These findings suggest that preserving spermatozoa using the Watson
      freezer improved post-thaw semen quality, with regard to sperm motility
      characteristics. Furthermore, that post-thaw semen viability was enhanced by
      minimising temperature fluctuations resulting from the release of the latent heat
      of fusion at ice crystal formation.

PMID- 12620585
TI  - Effect of freezing-thawing protocols on the performance of semen from three
      rabbit lines after artificial insemination.
AB  - The effect of different freezing and thawing protocols on the results observed
      after artificial insemination with semen from three different rabbit lines (two
      maternal lines selected for litter size at weaning, lines A and V, and one line
      selected for growth rate from weaning to slaughter, line R) was studied. The
      sperm were frozen with a Tris-citric acid-glucose extender which included 1.75 M
      DMSO and 0.05 M sucrose as cryoprotectants. The straws were cooled to 5 degrees C
      for 45 min and then some of them were frozen in a freezer at -30 degrees C for 30
      min, whereas the other group of straws were frozen in liquid nitrogen vapor (LNV,
      5 cm above the liquid nitrogen level) for 10 min. Straws were thawed at two
      different temperatures: 50 or 70 degrees C for 10-12s. Significant differences
      were observed between freezing-thawing protocols, obtaining better results in
      fertility rate (percentage of pregnant females) when sperm had been frozen in LNV
      (fertility rate increased between 30 and 50 points in all the lines); the best
      prolificacy was observed when sperm had been frozen in LNV and thawed at 50
      degrees C (70% versus 32% fertility rate, P<0.01 and 7.4 versus 5.9 total number
      of young born, P<0.01 when sperm had been frozen in LNV or at -30 degrees C and
      thawed at 50 degrees C, respectively). As for the rabbit line, significant
      differences were observed between lines in fertility rate (62 and 68% versus 45%
      fertility rate for lines A, V and R, P<0.01), and total number of young born (5.8
      versus 6.9 versus 4.6 total number of young born for lines A, V and R, P=0.02).
      The best results for all lines in both fertility and total number of young born
      were observed when sperm had been frozen in LNV and thawed at 50 degrees C (85%
      versus 84% versus 50% fertility rate and 6.7 versus 8.3 versus 7.3 total number
      of young born for lines A, V and R, respectively), when compared to the results
      of the control group, frozen at -30 degrees C and thawed at 50 degrees C (30%
      versus 52% versus 19% fertility rate and 6.7 versus 6.4 versus 4.5 total number
      of young born for lines A, V and R, respectively). In conclusion, the best
      results (fertility rate and prolificacy) for all the rabbit lines were obtained
      after freezing in liquid nitrogen vapor and thawing at 50 degrees C, being more
      pronounced in the line selected for high growth rate (line R).

PMID- 12620586
TI  - Comparison of pregnancy rates with two estrus synchronization protocols in
      Italian Mediterranean Buffalo cows.
AB  - The aim in this study was to compare two estrus synchronization protocols in
      buffaloes. Animals were divided into two groups: Group A (n=111) received 100
      microg GnRH on Day 0, 375 microg PGF(2alpha) on Day 7 and 100 microg GnRH on Day
      9 (Ovsynch); Group B (n=117) received an intravaginal drug release device (PRID)
      containing 1.55 g progesterone and a capsule with 10mg estradiol benzoate for 10
      days and were treated with a luteolytic dose of PGF(2alpha) and 1000 IU PMSG at
      the time of PRID withdrawal. Animals were inseminated twice 18 and 42 h after the
      second injection of GnRH (Group A) and 60 and 84 h after PGF(2alpha) and PMSG
      injections (Group B). Progesterone (P(4)) concentrations in milk samples
      collected 12 and 2 days before treatments were used to determine cyclic and non
      cyclic buffaloes, and milk P(4) concentrations 10 days after Artificial
      insemination (AI) were used as an index of a functional corpus luteum. Cows were
      palpated per rectum at 40 and 90 days after AI to determine pregnancies. All
      previously non-cyclic animals in Group B had elevated P(4) (>120 pg/ml milk whey)
      on Day 10 after AI. Accordingly, a greater (P<0.01) relative percentage of
      animals with elevated P(4) 10 days after AI were observed in Group B (93.2%) than
      in Group A (81.1%). However, there was no difference in overall pregnancy rates
      between the two estrus synchronization protocols (Group A, 36.0%; Group B 28.2%).
      When only animals with elevated P(4) on Day 10 after AI were considered,
      pregnancy rate was higher (P<0.05) for animals in Group A (44.4%) than Group B
      (30.3%). The findings indicated that treatment with PRID can induce ovulation in
      non-cyclic buffalo cows. However, synchronization of estrus with Ovsynch resulted
      in a higher pregnancy rate compared with synchronization with PRID, particularly
      in cyclic buffalo.

PMID- 12620587
TI  - Cumulus contributions during bovine fertilization in vitro.
AB  - A mandatory step in performing micromanipulation techniques, studying sperm
      oocyte interactions and evaluating morphological aspects of oocyte quality is the
      removal of cumulus cells from oocytes or zygotes at various stages. In cattle,
      cumulus removal shortly before fertilization in vitro strongly decreases sperm
      penetration rates. This study was conducted to evaluate the function of the
      cumulus oophorus during bovine fertilization in vitro. The importance of cumulus
      secretions during IVF was investigated by inseminating cumulus-denuded oocytes
      (CDOs) in fertilization medium supplemented with individual cumulus secretions,
      such as progesterone or hyaluronic acid. None of these substances increased the
      fertilization rate of CDOs. However, fertilizing CDOs in cumulus-conditioned
      medium or on a cumulus monolayer partially restored the reduction in
      fertilization rate (P<0.05). The fertilization rate of CDOs inseminated on a
      cumulus monolayer further increased when physical contact between the gametes and
      the monolayer was prevented by fertilizing them inside a culture plate insert
      placed on the monolayer (P<0.05). Finally, the importance of reactive oxygen
      species (ROS) generation and O(2) concentration during IVF was studied. Luminol
      dependent chemiluminescence revealed a higher ROS load in conditioned medium of
      cumulus-enclosed oocytes (CEOs) than in that of CDOs after sperm-oocyte co
      incubation (P<0.05). Furthermore, lowering the external O(2) concentration from
      20 to 5% decreased the fertilization rate of both CEOs and CDOs, but had a higher
      impact on CEOs (P<0.05). In conclusion, this study provides evidence that the
      cumulus oophorus benefits the fertilizing ability of penetrating spermatozoa by
      creating a complex microenvironment of both cumulus secretions and metabolic
      products around the oocyte. Gap junctional communication between the oocyte and
      corona cells as well as sperm trapping by the cumulus oophorus seem to be
      essential factors in supporting fertilization.

PMID- 12620588
TI  - Acute fasting in heifers as a model for assessing the relationship between plasma
      and follicular fluid NEFA concentrations.
AB  - It is known from epidemiological studies that negative energy balance in early
      lactating dairy cows is related to a depression in reproductive performance.
      Elevated plasma concentrations of non-esterified fatty acids (NEFA) are a typical
      metabolic characteristic of these animals and are proposed as the possible link.
      The suggestion is that NEFA might have a direct effect on the ovary, by affecting
      development of the oocyte or the granulosa cells. However, no data is available
      concerning the relationship between the concentration of NEFA in follicular fluid
      and plasma. Therefore, a cross-over study with 10 heifers around 15 months of age
      was conducted to analyze this relationship and examine the suggested effects of
      the negative energy balance on follicular growth. Investigation of these effects
      was performed on fasted heifers. The experimental treatment consisted of feeding
      hay with a subsequent period of fasting, to induce elevated plasma NEFA
      concentrations. Sampling of follicular fluid was performed using transvaginal
      aspiration of follicles, which were standardized using a synchronization
      protocol. In addition, concentrations of glucose, insulin, NEFA, and estradiol
      were measured in plasma. Follicular estradiol and progesterone concentrations
      were also measured to assess the quality of the dominant follicle. Fasting
      resulted in significantly lower plasma glucose (P=0.0006) and plasma insulin
      (P<0.0001) concentrations, higher plasma estradiol (P=0.008) and higher NEFA
      (P<0.001) concentrations, and smaller follicles (P=0.04) with lower
      estradiol:progesterone (E/P) ratios (P=0.05). Concentrations of NEFA in
      follicular fluid and plasma were closely related. Given this close relationship,
      we concluded that the presence of high plasma NEFA concentrations might link
      energy metabolism in early lactation with fertility.

PMID- 12620589
TI  - Somatostatin treatment affects testicular function in stallions.
AB  - This study investigated the regulation of growth hormone (GH) release in
      stallions and tested the hypothesis that the somatotrophic axis influences
      testicular function. Basal plasma GH concentrations, effects of an experimental
      decrease of GH release on testicular function and an opioidergic regulation of GH
      release were investigated in Shetland stallions (n=6). No seasonal variations in
      plasma GH concentrations were found over a 12-month period. Treatment with the
      somatostatin analogue octreotid (100mg twice daily over 10 days) caused a
      decrease in semen motility from 38.7+/-8.4% progressively motile spermatozoa
      before treatment to 18.3+/-5.4% on day 3 after end of treatment (P<0.05). Values
      returned to 35.0+/-8.5% on day 5 after treatment. On the last day of octreotid
      treatment, a hCG stimulation test was performed (3000IU hCG i.v.). The hCG
      induced testosterone release was significantly higher in saline treated than in
      octreotid pretreated animals (P<0.05). Neither plasma GH concentrations nor
      volume and density of ejaculates, total sperm count, or semen morphology were
      different between saline and octreotid treatments. Injection of the opioid
      antagonist naloxone (0.5mg/kg) significantly increased GH release in June (from
      1.1+/-0.3ng/ml before to 3.7+/-2.2), while a minor and not significant increase
      occurred in January. In conclusion, our results indicate a non-seasonal basal GH
      release with a fine-modulation by season-dependent opioidergic mechanisms in the
      male horse. A transient decrease in semen motility and hCG-induced testosterone
      release following ocreotid treatment indicate a role of GH in the regulation of
      testicular function in stallions.

PMID- 12620590
TI  - Two different schemes of twice-weekly ovum pick-up in dairy heifers: effect on
      oocyte recovery and ovarian function.
AB  - The aim of the present study was to compare two different schemes of twice-weekly
      ovum pick-up (OPU), continuous (C) and discontinuous (DC), with special emphasis
      on differences in oocyte yield and quality, estrous cyclicity, ovarian dynamics,
      and progesterone production. Subsequent to characterization of their normal
      estrous cycles (pre-OPU period), eight dairy heifers were subjected to 4 months
      of twice-weekly OPU under two different schemes: the DC (OPU restricted to Days 0
      12 of the cycle) and the C schemes. Effects of the two different schemes on
      oocyte yield, quality, and in vitro competence, together with effects on ovarian
      dynamics and progesterone production, were monitored. The mean numbers of
      punctured follicles and recovered oocytes per session were slightly higher (not
      significant (n.s.)) using the DC scheme, but in total, similar numbers of oocytes
      were obtained. The quality of the oocytes as well as cleavage rate after in vitro
      fertilization of the oocytes did not differ between the two OPU schemes. There
      was no influence of a corpus luteum (CL) producing progesterone on the oocyte
      yield and quality, whereas the presence of dominant follicles appeared to
      decrease the number of recovered ooctyes. During the pre-OPU period, all heifers
      showed normal cyclicity. In the DC scheme, the heifers showed regular and normal
      cyclic activity throughout the puncture period, with one to two complete
      follicular waves during the interval from the last OPU to the next estrus. In the
      C scheme, the heifers occasionally revealed cyclicities with irregular
      interestrous intervals and weaker signs of estrus. No complete follicular waves
      were seen during the OPU period in this scheme. The CL developed from the
      ovulation of the preovulatory follicles in the DC scheme showed similar
      characteristics to the CLs of the pre-OPU period; however, the CL-like structures
      from the puncture of follicles, in both the DC and the C schemes, revealed a
      shorter life span and inferior competence in producing progesterone (P<0.05). The
      present results indicate that the DC OPU scheme, which allows animals to go into
      natural ovulation prior to the first OPU, does not affect their ovarian function,
      whereas the C OPU scheme does. Our study further demonstrates that an equal
      number of oocytes can be obtained with both schemes, but that fewer OPUs are
      needed when the DC scheme is applied.

PMID- 12620591
TI  - Translation of symptoms and signs into mechanisms in neuropathic pain.

PMID- 12620592
TI  - Involvement of local cholecystokinin in the tolerance induced by morphine
      microinjections into the periaqueductal gray of rats.
AB  - The ventrolateral periaqueductal gray (PAG) is a key structure for the
      development of opioid tolerance. An increased activity of 'anti-opioids' like
      cholecystokinin (CCK) has been proposed as a possible mechanism for opioid
      tolerance. The present study evaluates the role of PAG-located CCK in the opioid
      tolerance induced by repeated microinjections of morphine (MOR) into PAG. Male
      rats were implanted with chronic guide cannulae aimed at the PAG. Microinjection
      of MOR (0.5 microg in 0.5 microl) into PAG caused antinociception as quantified
      with the tail flick and the hot plate tests. When MOR microinjection was repeated
      twice daily, the antinociceptive effect disappeared within 2 days (tolerance).
      However, if each MOR microinjection was preceded (within 15 min) by a
      microinjection of the non-selective CCK receptor antagonist proglumide (PRO),
      (0.4 microg in 0.5 microl) into the same PAG site, the microinjections of MOR
      always produced antinociception and did not induce tolerance. If PRO
      microinjections were suspended, subsequent MOR microinjections induced tolerance.
      In MOR-tolerant rats, a single PRO microinjection into the same PAG site was
      enough to restore the antinociceptive effect of MOR. On the other hand, if CCK (1
      ng in 0.5 microl) was microinjected into PAG, then MOR microinjection
      administered 15 min later into the same PAG site did not elicit antinociception.
      These results show that CCK has anti-opioid activity in PAG and that tolerance to
      MOR in PAG can be prevented or reversed if CCK receptors are blocked with PRO.
      Finally, opioid tolerance induced by repeated systemic MOR injections (5mg/kg
      intraperitoneal ) was reversed by a single microinjection of PRO into PAG. This
      emphasizes the central importance of PAG in the MOR/CCK interactions that lead to
      opioid tolerance.

PMID- 12620594
TI  - Affective associative learning modifies the sensory perception of nociceptive
      stimuli without participant's awareness.
AB  - The present experiment examined the possibility to change the sensory and/or the
      affective perception of thermal stimuli by an emotional associative learning
      procedure known to operate without participants' awareness (evaluative
      conditioning). In a mixed design, an aversive conditioning procedure was compared
      between subjects to an appetitive conditioning procedure. Both groups were also
      compared within-subject to a control condition (neutral conditioning). The
      aversive conditioning was induced by associating non-painful and painful thermal
      stimuli - delivered on the right forearm - with unpleasant slides. The appetitive
      conditioning consisted in an association between thermal stimuli - also delivered
      on the right forearm - and pleasant slides. The control condition consisted in an
      association between thermal stimuli - delivered for all participants on the left
      forearm - and neutral slides. The effects of the conditioning procedures on the
      sensory and affective dimensions were evaluated with visual analogue scale (VAS)
      intensity and VAS-unpleasantness. Startle reflex was used as a physiological
      index of emotional valence disposition. Results confirmed that no participants
      were aware of the conditioning procedure. After unpleasant slides (aversive
      conditioning), non-painful and painful thermal stimuli were judged more intense
      and more unpleasant than when preceded by neutral slides (control condition) or
      pleasant slides (appetitive conditioning). Despite a strong correlation between
      the intensity and the unpleasantness scales, effects were weaker for the
      affective scale and, became statistically non-significant when VAS-intensity was
      used as covariate. This experiment shows that it is possible to modify the
      perception of intensity of thermal stimuli by a non-conscious learning procedure
      based on the transfer of the valence of the unconditioned stimuli (pleasant or
      unpleasant slides) towards the conditioned stimuli (non-painful and painful
      thermal stimuli). These results plead for a conception of pain as a conscious
      output of complex informational processes all of which are not accessible to
      participants' awareness. Mechanisms by which affective input may influence
      sensory experience and clinical implications of the present study are discussed.

PMID- 12620593
TI  - Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker, in experimental
      animal models of inflammatory and neuropathic pain.
AB  - NW-1029, a benzylamino propanamide derivative, was selected among several
      molecules of this chemical class on the basis of its affinity for the
      [(3)H]batracotoxin ligand displacement of the Na(+) channel complex and also on
      the basis of its voltage and use-dependent inhibitory action on the Na(+)
      currents of the rat DRG (dorsal root ganglia) sensory neuron. This study
      evaluated the analgesic activity of NW-1029 in animal models of inflammatory and
      neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic
      constriction injury in rats) as well as in acute pain test (hot-plate and tail
      flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative
      licking time in the early and late phase of the formalin test (ED(50)=10.1 mg/kg
      in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von
      Frey test) after both i.p. and p.o. administration (ED(50)=0.57 and 0.53 mg/kg),
      respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model
      after both i.p. and p.o. administration yielding an ED(50) of 0.89 and 0.67
      mg/kg, respectively. No effects were observed in the hot-plate and tail-flick
      tests up to 30 mg/kg p.o. The compound orally administered (0.1-10 mg/kg) was
      well tolerated, without signs of neurological impairment up to high doses
      (ED(50)=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These
      results indicate that NW-1029 has anti-nociceptive properties in models of
      inflammatory and neuropathic pain.

PMID- 12620595
TI  - Vagal afferents are necessary for the establishment but not the maintenance of
      kainic acid-induced hyperalgesia in mice.
AB  - Systemic administration of a single, sub-convulsive dose (20mg/kg) of kainic acid
      (KA) produces long-term hyperalgesia. The robustness and reproducibility of this
      effect makes this a valuable model of chronic pain. However, the mechanism by
      which KA produces hyperalgesia remains unknown. We evaluated the role of vagal
      afferents on KA-induced hyperalgesia in mice by assessing the influence of
      bilateral subdiaphragmatic vagotomy and of direct application of KA to vagal
      afferents on the development of hyperalgesia. The hot plate and tail flick tests
      were used to assess pain behavior. Central nervous system (CNS) activity evoked
      by acute administration of KA or exposure to a nociceptive stimulus was also
      determined by the immunocytochemical detection of Fos and of phosphorylated
      extracellular signal-regulated protein kinases 1 and 2 (pErk). Mice exhibited a
      persistent hyperalgesia after either systemic application of KA or topical
      treatment with KA on vagal afferents. Vagotomy performed 2 weeks before the
      application of KA was able to prevent the establishment of hyperalgesia, but
      vagotomy performed 2 weeks after the application of KA was unable to reverse the
      already established hyperalgesia. This result establishes that vagal afferents
      are pivotal to the onset of hyperalgesia. Consistent with this, KA evoked the
      expression of Fos in vagal related areas of the brainstem, including the nucleus
      tractus solitarius (NTS) and area postrema (AP), as well as widespread areas of
      the forebrain. Vagotomy selectively decreased KA-evoked Fos in the NTS while
      sparing that in other brain areas. In addition to hyperalgesia, weeks after KA
      treatment, stimulus induced pErk was increased in spinal nociceptive neurons and
      the medial hypothalamus, a phenomenon that was prevented by prior vagotomy. No
      signs of cell death were detected using in situ nick end-labeling (TUNEL) assay
      and Nissl staining at 1, 5, 24, 36 h and 12 days post-KA. These findings suggest
      that the mechanism underlying KA-induced hyperalgesia is a long-term dysfunction
      of CNS areas that are activated by vagal afferents and involved in descending
      control of spinal nociceptive neurons.

PMID- 12620596
TI  - Clinical and workplace factors associated with a return to modified duty in work
      related upper extremity disorders.
AB  - Return to work following treatment for a work-related upper extremity disorder
      (WRUED) is affected by a variety of medical, workplace, and personal factors, and
      returning to modified duty may ease the transition to normal work activities.
      This study surveyed 165 federal government employees (127 females, 38 males) who
      were unable to resume their normal work after filing a workers' compensation
      claim for a WRUED (<90 days from claim filing) and who volunteered for a
      randomized study of alternative case management strategies. Before randomization,
      participants completed a baseline survey of upper extremity (UE) symptoms,
      functional limitations, and workplace factors. At baseline, 58 participants (35%)
      were working modified duty and 107 participants (65%) were not working. Compared
      with participants working modified duty, those who were not working were more
      likely to report: (a). a diagnosis of mononeuropathy, odds ratio (OR)=3.16 (95%
      confidence interval (CI)=1.37-7.14) versus enthesopathy, (b). higher pain
      ratings, OR=1.43 (95% CI=1.01-2.01), (c). greater functional limitations, OR=1.63
      (95% CI=1.11-2.38), and (d). higher level of ergonomic stressors, OR=1.62 (95%
      CI=1.09-2.43) in a multivariable logistic regression. Measures of high risk work
      styles (fast pace and working despite pain) were associated with greater
      perceptions of ergonomic exposure, but not with work status. The model had 87.9%
      sensitivity and 43.1% specificity to correctly classify those not working
      (overall classification 72.1% correct). The results suggest that modified duty
      for workers with persistent WRUEDs may be enhanced by assessing perceived
      functional limitation and ergonomic exposure as well as the type and severity of
      symptoms.

PMID- 12620597
TI  - Chronic neck pain disability due to an acute whiplash injury.
AB  - Several theories about musculoskeletal pain syndromes such as whiplash-associated
      disorder (WAD) suggest that pain and muscle activity interact and may contribute
      to the chronicity of symptoms. Studies using surface electromyography (sEMG) have
      demonstrated abnormal muscle activation patterns of the upper trapezius muscles
      in the chronic stage of WAD (grade II). There are, however, no studies that
      confirm that these muscle reactions are initiated in the acute stage of WAD, nor
      that these muscle reactions persist in the transition from acute neck pain to
      chronic neck pain disability. We analyzed the muscle activation patterns of the
      upper trapezius muscles in a cohort of 92 subjects with acute neck pain due to a
      motor vehicle accident (MVA). This cohort was followed up in order to evaluate
      differences in muscular activation patterns between subjects who have recovered
      and those subjects who have not recovered following an acute WAD and developed
      chronic neck pain. sEMG parameters were obtained at 1, 4, 8, 12, and 24 weeks
      after an MVA. The level of muscle reactivity (the difference in pre- and post
      exercise EMG levels) and the level of muscle activity during an isometric and a
      dynamic task were used as EMG parameters. The results revealed no elevated muscle
      reactivity either in the acute stage, or during the follow-up period. The results
      of both the isometric and dynamic task, showed statistically significant
      different EMG levels between four neck pain disability subgroups (analysis of
      variance reaching P-levels of 0.000), with an inverse relationship between the
      level of neck pain disability and EMG level. Furthermore, follow-up assessments
      of the EMG level during these two tasks, did not show a time related change. In
      conclusion, in subjects with future disability, the acute stage is characterized
      by a reorganization of the muscular activation of neck and shoulder muscles,
      possibly aimed at minimizing the use of painful muscles. This change of motor
      control, is in accordance with both the (neurophysiological) 'pain adaptation
      model' and (cognitive behavioral) 'fear avoidance model'.

PMID- 12620598
TI  - The cerebral hemodynamics of headache associated with sexual activity.
AB  - Headache associated with sexual activity is an idiopathic headache disorder and
      regarded to be a vascular headache but no pathophysiological studies have been
      performed to date to elucidate the underlying mechanisms. We investigated 12
      patients with the explosive type of sexual headache according to the criteria of
      the International Headache Society during a headache-free state by means of
      acetazolamide test and of stress Doppler sonography. Twelve age-matched migraine
      patients and 14 healthy subjects served as control groups. Changes of blood
      pressure, cerebral blood flow velocity (CBFV), and pulsatility index (PI) were
      evaluated. Patients with sexual headache showed a significantly higher increase
      of blood pressure during standardized physical exercise as compared to healthy
      subjects and migraine patients. Changes of CBFV by physical exercise were not
      different between the three examination groups. After 1g acetazolamide, CBFV
      showed a significantly higher increase in patients with sexual headache (plus
      66%+/-16%) than in healthy subjects (plus 46%+/-18%), and PI showed a
      significantly lower decrease as compared to healthy subjects and migraine
      patients. These data suggest that in patients with sexual headache the metabolic
      rather than the myogenic component of the cerebral vasoneuronal coupling is
      impaired.

PMID- 12620599
TI  - Visceral and cutaneous hypersensitivity in Persian Gulf war veterans with chronic
      gastrointestinal symptoms.
AB  - Approximately 697000 United States military personnel participated in the Persian
      Gulf War (PGW) between August 1990 and March 1991. By April 1997, over 25% of
      veterans reported chronic health complaints of underdetermined etiology.
      Gastrointestinal symptoms were among the most frequently reported symptoms
      including abdominal pain and diarrhea. The objectives of this study were (1). to
      determine if PGW veterans chronic abdominal pain and diarrhea exhibit visceral
      and cutaneous hypersensitivity, (2). to determine if these differences in pain
      sensitivity are significantly associated with psychological stress. A total of 12
      veterans (ten males, two females) (39+/-9 years) who were deployed to the Persian
      Gulf were enrolled. Seven civilians without prior military experience (five
      males, two females) and five veterans (five males) who had previously been
      deployed for active combat were enrolled as controls (35+/-9 years). All 12 PGW
      veterans reported chronic abdominal pain and diarrhea (negative diagnostic
      workup) that developed during their tour of duty in the Persian Gulf region. All
      patients completed a battery of psychological assessments and then randomly
      received experimental visceral (rectal distension of 35 and 55 mmHg for 30s) and
      cutaneous (immersion of right foot in 45 and 47 degrees C water for 30s) pain
      stimuli after which they rated their pain intensity and pain unpleasantness on a
      continuous visual analogue scale (M-VAS) scale. The trials were repeated and the
      mean M-VAS scores for the two trials were recorded for each subject. In
      comparison to controls, PGW subjects reported statistically significant higher
      mean ratings of pain intensity and pain unpleasantness in response to 35 and 55
      mmHg rectal distention (P<0.001) and in response to 45 and 47 degrees C water
      immersion (P<0.001) of the hand and foot. Results of the hierarchical regressions
      indicated that the psychological measures (i.e. anxiety, somatic focus) accounted
      for a significant amount of variance in each of the pain measures. PGW veterans
      who developed chronic abdominal pain and diarrhea during their tour of duty
      exhibit visceral hypersensitivity similar to patients with the irritable bowel
      syndrome. These veterans also have cutaneous hypersensitivity and higher levels
      of anxiety and somatic focus accounting for these differences in pain reporting.

PMID- 12620600
TI  - Temporal summation of pain from mechanical stimulation of muscle tissue in normal
      controls and subjects with fibromyalgia syndrome.
AB  - Individuals diagnosed with fibromyalgia syndrome (FMS) report chronic pain that
      is frequently worsened by physical activity and improved by rest. Palpation of
      muscle and tendinous structures suggests that nociceptors in deep tissues are
      abnormally sensitive in FMS, but methods of controlled mechanical stimulation of
      muscles are needed to better characterize the sensitivity of deep tissues.
      Accordingly, force-controlled mechanical stimulation was applied to the flexor
      digitorum muscle of the forearm in a series of brief contacts (15 stimuli, each
      of 1s duration, at 3 or 5s interstimulus intervals). Repetitive stimulation was
      utilized to determine whether temporal summation of deep muscular pain would
      occur for normal subjects and would be enhanced for FMS subjects. Moderate
      temporal summation of deep pain was observed for normal controls (NC), and
      temporal summation was greatly exaggerated for FMS subjects. Temporal summation
      for FMS subjects occurred at substantially lower forces and at a lower frequency
      of stimulation. Furthermore, painful after-sensations were greater in amplitude
      and more prolonged for FMS subjects. These observations complement a previous
      demonstration that temporal summation of pain and after-sensations elicited by
      thermal stimulation of the skin are moderately enhanced for FMS subjects.
      Abnormal input from muscle nociceptors appears to underlie production of central
      sensitization in FMS that generalizes to input from cutaneous nociceptors.

PMID- 12620601
TI  - Pain and the defense response: structural equation modeling reveals a coordinated
      psychophysiological response to increasing painful stimulation.
AB  - The defense response theory implies that individuals should respond to increasing
      levels of painful stimulation with correlated increases in affectively mediated
      psychophysiological responses. This paper employs structural equation modeling to
      infer the latent processes responsible for correlated growth in the pain report,
      evoked potential amplitudes, pupil dilation, and skin conductance of 92 normal
      volunteers who experienced 144 trials of three levels of increasingly painful
      electrical stimulation. The analysis assumed a two-level model of latent growth
      as a function of stimulus level. The first level of analysis formulated a
      nonlinear growth model for each response measure, and allowed intercorrelations
      among the parameters of these models across individuals. The second level of
      analysis posited latent process factors to account for these intercorrelations.
      The best-fitting parsimonious model suggests that two latent processes account
      for the correlations. One of these latent factors, the activation threshold,
      determines the initial threshold response, while the other, the response
      gradient, indicates the magnitude of the coherent increase in response with
      stimulus level. Collectively, these two second-order factors define the defense
      response, a broad construct comprising both subjective pain evaluation and
      physiological mechanisms.

PMID- 12620602
TI  - Self-reports of pain intensity and direct observations of pain behavior: when are
      they correlated?
AB  - Meta-analytic techniques were utilized to investigate the relationship between
      self-reports of pain intensity and direct observations of pain behavior.
      Estimation of the overall effect size from 29 studies and 85 effect sizes yielded
      a moderately positive association, z=0.26. High variability across studies
      permitted a random-effects moderator analysis that determined chronicity of pain,
      the timing of the pain assessment, the use of global measures of pain behavior,
      and pain site significantly moderate the relationship between self-reports of
      pain intensity and direct observations of pain behavior. These findings indicate
      that self-reports of pain intensity and direct observations of pain behavior are
      more likely to be significantly related to each other when the individual being
      studied has acute pain (z=0.35), when the self-report of pain intensity data are
      collected soon after the observation of pain behavior (z=0.40), when global
      composite measures are used to quantify pain behavior (z=0.37), and when the
      person being observed suffers from chronic low back pain (z=0.30). Other factors
      not found to be significant moderators include: extent of observer training,
      relevance of the pain-inducing task, and pain behavior observation measure used.
      The implications of the findings for the assessment of pain are discussed.

PMID- 12620603
TI  - Placebo analgesia and the heart.
AB  - Placebo-activated endogenous opioids act on pain mechanisms inducing analgesia,
      as well as on the respiratory centers inducing respiratory depression. Here, we
      show that placebo analgesia is accompanied by a reduced beta-adrenergic activity
      of the heart. We measured heart rate during placebo-induced expectation of
      analgesia, both in the clinical and the laboratory setting. In the clinical
      setting, we found that the placebo analgesic response to an electrical noxious
      stimulus was accompanied by a reduced heart rate response. In order to
      investigate this effect from a pharmacological viewpoint, we reproduced the same
      effect in the laboratory setting by using experimental ischemic arm pain. We
      found that the opioid antagonist naloxone completely antagonized both placebo
      analgesia and the concomitant reduced heart rate response, whereas the beta
      blocker propranolol antagonized the placebo heart rate reduction, but not placebo
      analgesia. By contrast, both placebo responses were present during muscarinic
      blockade with atropine, indicating no involvement of the parasympathetic system.
      In order to better understand the effects of naloxone and propranolol, we
      performed a spectral analysis of the heart rate variability for the
      identification of the sympathetic and parasympathetic components, and found that
      the beta-adrenergic low frequency (0.15 Hz) spectral component was reduced during
      placebo analgesia, an effect that was reversed by naloxone. These findings
      indicate that placebo analgesia is accompanied by a complex cascade of events
      which affect the cardiovascular system.

PMID- 12620604
TI  - Transgene-mediated enkephalin release enhances the effect of morphine and evades
      tolerance to produce a sustained antiallodynic effect in neuropathic pain.
AB  - We examined the pharmacologic characteristics of herpes simplex virus (HSV)
      vector-mediated expression of proenkephalin in the dorsal root ganglion in a
      rodent model of neuropathic pain. We found that: (i). vector-mediated enkephalin
      produced an antiallodynic effect that was reversed by naloxone; (ii). vector
      mediated enkephalin production in animals with spinal nerve ligation prevented
      the induction of c-fos expression in second order sensory neurons in the dorsal
      horn of spinal cord; (iii). the effect of vector-mediated enkephalin enhanced the
      effect of morphine, reducing the ED(50) of morphine 10-fold; (iv). animals did
      not develop tolerance to the continued production of vector-mediated enkephalin
      over a period of several weeks; and, (v). vector transduction continued to
      provide an analgesic effect despite the induction of tolerance to morphine. This
      is the first demonstration of gene transfer to provide an analgesic effect in
      neuropathic pain. The pharmacologic analysis demonstrates that transgene-mediated
      expression and local release of opioid peptides produce some effects that are
      distinct from peptide analogues delivered pharmacologically.

PMID- 12620605
TI  - Prevalence and description of chronic daily headache in the general population in
      France.
AB  - The objective of this study was to describe the epidemiology, clinical
      presentation and consequences of chronic daily headache (CDH) in France. A
      representative nation-wide sample of the general population was identified using
      a stratified sampling method. Ten thousand five hundred and eight-five subjects
      were screened in face-to-face interviews, and data collected using a standard
      questionnaire. An overall point prevalence of CDH in the general population of
      2.98% was observed. Two-thirds of these subjects presented migraine-like
      features. Severity, functional impact and healthcare consumption were higher than
      in subjects reporting episodic migraine in the same sample. Of the subjects,
      28.2% reported the most severe migraine disability assessment scores (Grades 3
      and 4), compared to 12% of episodic migraineurs. A qualite de vie et migraine
      score of 68.4 was observed, indicating severely attenuated quality of life. Only
      6.6% of subjects were taking prophylactic treatment, whilst 88% were using non
      specific acute headache treatments. The frequency of physician consultations and
      laboratory examinations was significantly higher than in individuals with
      episodic headache. CDH is thus a relatively prevalent condition in the general
      French population, associated with an important burden of suffering and with
      considerable expenditure in the health service. Management of this condition is
      generally inappropriate.

PMID- 12620606
TI  - The mu-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and
      punctuated stimuli with different potency: a pharmacological evaluation of the
      freeze lesion in humans.
AB  - Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to
      noxious stimuli often present in clinical pain, are important tools for studying
      antinociceptive drug profiles. The correct interpretation of results obtained in
      these models necessitates their mechanistic understanding. This study evaluated
      the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve
      healthy subjects were tested with mechanical (brush, punctuated and blunt) and
      electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after
      freezing the skin, and during a computer-controlled infusion of the mu-opioid
      agonist remifentanil targeting five different plasma concentrations between 0 and
      6 ng/ml in a two-staged, single occasion, randomized, and double blind study
      design. Pharmacodynamic modeling techniques were used to describe the effect of
      freezing and drug administration on the mechanical and electrical pain
      thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated
      stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to
      brushing or electrical stimuli was not detected. Remifentanil attenuated
      hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to
      punctuated stimuli, as indicated by a significantly steeper linear relationship
      between the remifentanil plasma concentration and the increase of the pain
      threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater
      potency for low frequency stimulation. The potency difference of remifentanil
      suggests that different neuronal mechanisms mediate hyperalgesia to blunt and
      punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is
      compatible with the view that mechanical hyperalgesia to blunt and punctuated
      stimulation of the freeze lesion is predominantly caused by a peripheral
      mechanism.

PMID- 12620607
TI  - Management of chronic intractable angina - spinal opioids offer an alternative
      therapy.
AB  - The successful treatment of chronic intractable angina by spinally administered
      opioids via an Algomed drug delivery device (hereinafter called the pump) is
      reported in seven patients. All patients had at least two prior cardiac surgeries
      and the duration of minimally controlled chronic intractable angina varied from 5
      to 19 years prior to spinally administered opioids. The duration of effective
      spinally administered analgesia to either the epidural (two cases) or intrathecal
      (five cases) spaces varied from 2 to 7 years. The opioid used was either morphine
      or fentanyl and the dose increase (either mg/year or microg/year, respectively)
      varied from 1.2 to 16. We suggest that bolus spinal morphine or fentanyl
      administered via the pump is a viable alternative for the effective control of
      angina when more established therapies have been found to provide insufficient
      pain relief.

PMID- 12620608
TI  - Musculoskeletal pain in the Netherlands: prevalences, consequences and risk
      groups, the DMC(3)-study.
AB  - The objective of this paper was to present estimates on the prevalence of
      musculoskeletal pain of five different anatomical areas and ten anatomical sites,
      and their consequences and risk groups in the general Dutch population. Cross
      sectional data from a population-based study of a sex-age stratified sample of
      Dutch inhabitants of 25 years and older were used. With a postal questionnaire
      data was assessed on musculoskeletal pain, additional pain characteristics
      (location, duration, course), its consequences (utilization of health care, sick
      leave and limitation in daily life) and general socio-demographic
      characteristics. The top three of self-reported musculoskeletal pain (point
      prevalence (P(p)) with 95% confidence interval (CI)) was: (1). low back pain,
      P(p)=26.9% (95% CI 25.5-28.3); (2). shoulder pain, P(p)=20.9% (95% CI 19.6-22.2);
      and (3). neck pain, P(p)=20.6% (95% CI 19.3-21.9). In most cases the pain was
      described as continuous or recurrent and mild. In every three out of ten cases
      the complaints about pain were accompanied by limitations in daily living.
      Between 33 and 42% of those with complaints consulted their general practitioner
      about their pain. With the exception of persons who are work disabled, general
      sociodemographic characteristics cannot be used to identify high risk groups.
      Musculoskeletal pain is common in all subgroups of the population and has far
      reaching consequences for health, work and the use of health care.

PMID- 12620609
TI  - Peripheral interactions between dextromethorphan, ketamine and amitriptyline on
      formalin-evoked behaviors and paw edema in rats.
AB  - The local, peripheral administration of antidepressants and excitatory amino acid
      receptor antagonists can cause analgesia in a number of conditions. The present
      study examined the effects of combinations of dextromethorphan and ketamine, two
      clinically used N-methyl-D-aspartate (NMDA) receptor antagonists, with
      amitriptyline on formalin-evoked behaviors and paw edema. Pretreatment with
      amitriptyline or dextromethorphan (10-300 nmol) resulted in suppression of
      flinching behaviors induced by 2.5% formalin, but ketamine had no intrinsic
      effect. Combination of an inactive dose of dextromethorphan with amitriptyline,
      and vice versa, resulted in an increase of analgesia so that previously inactive
      doses now caused significant analgesia. Combinations of multiple doses of
      ketamine with amitriptyline did not modify the response to amitriptyline. Both
      dextromethorphan and ketamine increased the paw edema induced by formalin, and
      this was blocked by low doses of amitriptyline. In the absence of formalin,
      amitriptyline (1-100 nmol) caused a dose-related suppression of the paw edema
      produced by dextromethorphan and ketamine. Amitriptyline also blocked paw edema
      produced by 5-hydroxytryptamine and compound 48/80. Each of the drugs used in
      this study exerts multiple pharmacological effects. Increased analgesia by drug
      combinations (amitriptyline/dextromethorphan) could show the involvement of a
      number of these mechanisms (e.g. NMDA receptor blockade, blockage of sodium
      channels, blockage of biogenic amine receptors), while a lack of intensification
      (amitriptyline/ketamine) could reflect occluded actions due to expression of
      similar actions by the other drug. Paw edema induced by dextromethorphan and
      ketamine involves inhibition of biogenic amine reuptake, and the ability of
      amitriptyline to block biogenic amine receptors likely accounts for its inhibiton
      of these actions. Combinations of these particular agents could represent a
      method for augmented analgesia and minimization of local adverse reactions.

PMID- 12620610
TI  - Changes in intensity, location, and quality of vaso-occlusive pain in children
      with sickle cell disease.
AB  - A descriptive, longitudinal design was used to examine changes in current, worst,
      and least pain intensity during hospitalization for a vaso-occlusive episode in
      children with sickle cell disease. Other dimensions of the pain experience
      including location and quality were also evaluated. Children reported severe pain
      on the day of admission with 50% of the episodes showing a current pain intensity
      score of >70 and a worst pain intensity score of >80. Although both pain
      intensity scores demonstrated statistically significant decreases by
      approximately 5% over the course of the hospitalization, these decreases were not
      clinically significant based on the recommendations made in the American Pain
      Society's Guideline for the management of acute and chronic pain in sickle cell
      disease. In contrast to the pain intensity ratings, which did not decrease in 25%
      of the episodes, pain location surface area decreased in 100% of the episodes.
      Children described the quality of vaso-occlusive pain using all categories of
      word descriptors from the adolescent pediatric pain tool. These findings suggest
      that pain associated with a vaso-occlusive episode is inadequately assessed and
      managed during hospitalization.

PMID- 12620611
TI  - Development of opioid tolerance with repeated transcutaneous electrical nerve
      stimulation administration.
AB  - The analgesia produced by low and high frequency transcutaneous electrical nerve
      stimulation (TENS) is mediated by the release of mu- or delta-opioids,
      respectively in the central nervous system. Repeated administration of either mu-
      or delta-opioid agonists induce opioid analgesic tolerance. Thus, we tested if
      repeated administration of TENS (either low or high frequency) in rats leads to a
      development of tolerance to its antihyperalgesic effects with a corresponding
      cross-tolerance to mu- and delta-opioid agonists. Unilateral knee joint
      inflammation (3% carrageenan) was induced in adult Sprague-Dawley rats. Either
      low (4 Hz) or high frequency (100 Hz) TENS was administered for 6 days (20 min
      daily) to the inflamed knee joint under halothane anesthesia. The no TENS
      controls were administered anesthesia only for the same period. Withdrawal
      threshold to mechanical stimuli was measured before and after administration of
      TENS on each day and also on the sixth day. A separate group of animals was
      tested for tolerance to either the mu-opioid agonist, morphine (1.32, 3.95, 13.2
      nmol/10 ml, intrathecal (i.t.)) or the delta-opioid agonist, SNC-80 (6, 20, 60,
      120 nmol/10 ml, i.t.) 30 min after i.t. administration. The reduced mechanical
      withdrawal threshold following the induction of inflammation was reversed by the
      application of TENS. However, repeatedly administering either low or high
      frequency TENS for 6 days, lead to a diminution in its effectiveness in reversing
      the ipsilateral secondary mechanical hyperalgesia by the fourth day. The effects
      of morphine in the low and SNC-80 in the high frequency TENS groups were
      significantly less than the group that did not receive TENS. On the other hand,
      morphine and SNC-80 were similar to the no TENS control in the high and low
      frequency TENS groups, respectively. Thus, repeated administration of low and
      high frequency TENS leads to a development of opioid tolerance with a
      corresponding cross-tolerance to i.t. administered mu- and delta-opioid agonists,
      respectively. Clinically, it can be inferred that a treatment schedule of
      repeated daily TENS administration should be avoided to possibly obviate the
      induction of tolerance.

PMID- 12620612
TI  - 'CatWalk' automated quantitative gait analysis as a novel method to assess
      mechanical allodynia in the rat; a comparison with von Frey testing.
AB  - A characteristic symptom of neuropathic pain is mechanical allodynia. In animal
      models of neuropathic pain, mechanical allodynia is often assessed using von Frey
      filaments. Although the forces applied with these filaments are highly
      reproducible, there are various disadvantages of using this method. Testing
      paradigms and definitions of withdrawal threshold are not standardised. Moreover,
      measurements may be influenced by various conditions, such as ambient
      temperature, humidity, weight bearing of the limb and stress. We have therefore
      investigated another technique to assess mechanical allodynia, the 'CatWalk'
      automated quantitative gait analysis. With this computer-assisted method of
      locomotor analysis, it is possible to objectively and rapidly quantify several
      gait parameters, including duration of different phases of the step cycle and
      pressure applied during locomotion. We tested rats with a chronic constriction
      injury of the sciatic nerve, a model of neuropathic pain, both with von Frey
      filaments and the CatWalk method. We demonstrate that these rats minimise contact
      with the affected paw during locomotion, as demonstrated by a reduction in stance
      phase and pressure applied during stance. Moreover, these parameters show a high
      degree of correlation with mechanical withdrawal thresholds as determined by von
      Frey filaments. We therefore suggest that the CatWalk method might serve as an
      additional tool in the investigation of mechanical allodynia.

PMID- 12620613
TI  - Cannabis use for chronic non-cancer pain: results of a prospective survey.
AB  - There has been a surge in interest in medicinal cannabis in Canada. We conducted
      a questionnaire survey to determine the current prevalence of medicinal cannabis
      use among patients with chronic non-cancer pain, to estimate the dose size and
      frequency of cannabis use, and to describe the main symptoms for which relief was
      being sought. Over a 6-week period in mid-2001, 209 chronic non-cancer pain
      patients were recruited in an anonymous cross-sectional survey. Seventy-two (35%)
      subjects reported ever having used cannabis. Thirty-two (15%) subjects reported
      having used cannabis for pain relief (pain users), and 20 (10%) subjects were
      currently using cannabis for pain relief. Thirty-eight subjects denied using
      cannabis for pain relief (recreational users). Compared to never users, pain
      users were significantly younger (P=0.001) and were more likely to be tobacco
      users (P=0.0001). The largest group of patients using cannabis had pain caused by
      trauma and/or surgery (51%), and the site of pain was predominantly neck/upper
      body and myofascial (68% and 65%, respectively). The median duration of pain was
      similar in both pain users and recreational users (8 vs. 7 years; P=0.7). There
      was a wide range of amounts and frequency of cannabis use. Of the 32 subjects who
      used cannabis for pain, 17 (53%) used four puffs or less at each dosing interval,
      eight (25%) smoked a whole cannabis cigarette (joint) and four (12%) smoked more
      than one joint. Seven (22%) of these subjects used cannabis more than once daily,
      five (16%) used it daily, eight (25%) used it weekly and nine (28%) used it
      rarely. Pain, sleep and mood were most frequently reported as improving with
      cannabis use, and 'high' and dry mouth were the most commonly reported side
      effects. We conclude that cannabis use is prevalent among the chronic non-cancer
      pain population, for a wide range of symptoms, with considerable variability in
      the amounts used. Discussions between patients and health care providers
      concerning cannabis use may facilitate education and follow up, and would allow
      side effects and potential interactions with other medications to be monitored.
      Clinical trials of cannabis for chronic non-cancer pain are warranted.

PMID- 12620614
TI  - The multitalented type III chaperones: all you can do with 15 kDa.
AB  - Despite the fact that type III chaperones were discovered approximately 10 years
      ago, the precise role of most of them is still mysterious. A panoply of functions
      has been proposed for the members of this family of proteins. Type III chaperones
      have been suggested to act as anti-aggregation and stabilizing factors. They have
      also been proposed to keep their substrates in unfolded or partially folded
      structures, set a hierarchy on secretion, and participate in the regulation of
      the transcription of the type III substrates. Here, we review this enigmatic
      family of proteins, and discuss the experimental data supporting the roles
      proposed for type III chaperones.

PMID- 12620615
TI  - rRNA and nifD phylogeny of Bradyrhizobium from sites across the Pacific Basin.
AB  - Many undomesticated legumes harbor nodule bacteria related to the soybean
      symbiont Bradyrhizobium elkanii, but little is known about their phylogenetic
      relationships or geographic distribution. Sequences of ribosomal genes (16S rRNA
      and partial 23S rRNA) and the nitrogenase alpha-subunit gene (nifD) were analyzed
      in 22 isolates of this group sampled from diverse legumes in Korea, Japan, the
      USA, Mexico, Costa Rica and Panama. Some strains from Asia and North America
      shared identical sequences for both ribosomal genes. However, pairs of strains
      with closely related nifD sequences were almost never found in different regions.
      The major exceptions involved North American isolates B. elkanii USDA 76 and USDA
      94, which had nifD sequences highly similar to certain Korean strains. However,
      16S rRNA sequences of USDA 76 and USDA 94 were closely related to Central
      American rather than Asian bradyrhizobia, implying that these strains are genetic
      mosaics combining sequences from distinct ancestral areas. Several other
      conflicts between rRNA and nifD tree topologies indicated that the genealogical
      histories of these loci have been influenced by recurrent lateral gene transfer
      events.

PMID- 12620616
TI  - Genetic diversity of phlD gene from 2,4-diacetylphloroglucinol-producing
      Pseudomonas spp. strains from the maize rhizosphere.
AB  - In biocontrol Pseudomonads, phlD is an essential gene involved in the
      biosynthesis of 2,4-diacetylphloroglucinol (DAPG). HaeIII restriction of
      amplified phlD gene, previously proposed as the most discriminant analysis,
      showed no polymorphism among 144 Pseudomonas strains isolated from maize roots.
      However, these strains fell into three statistically significant DAPG production
      level groups. phlD sequences of 13 strains belonging to the three DAPG groups
      revealed a KspI restriction site only in good DAPG-producing strains. This result
      was confirmed on the 144 strains, 82 of which were identified as good-DAPG
      producers by both biochemical and amplified phlD KspI restriction analysis. They
      are candidates as potential biocontrol agents.

PMID- 12620618
TI  - Cloning and expression of a putative cyclodextrin glucosyltransferase from the
      symbiotically competent cyanobacterium Nostoc sp. PCC 9229.
AB  - A polymerase chain reaction-based method was used to isolate a Nostoc sp. PCC
      9229 cDNA from infected glands of Gunnera chilensis. The complete gene sequence
      was isolated from a genomic Nostoc sp. PCC 9229 library. Sequence analysis showed
      84% amino acid similarity to a putative cyclodextrin glycosyltransferase from
      Nostoc sp. PCC 7120 and the gene was therefore termed cgt. Southern blot revealed
      that the cgt gene was present in symbiotically competent cyanobacteria. The cgt
      gene was expressed in free-living nitrogen-fixing cultures in light or in
      darkness when supplemented with fructose. This is the first expression analysis
      of a cgt gene from a cyanobacterium.

PMID- 12620617
TI  - Investigation of mechanisms involved in phagocytosis of Legionella pneumophila by
      human cells.
AB  - Legionella pneumophila, the causative agent of Legionnaires' disease, is able to
      survive and multiply efficiently in a variety of mammalian cells. By using in
      vitro assays, the uptake of L. pneumophila into monocytes has shown to be
      mediated, at least in part, through attachment of complement-coated bacteria to
      complement receptors, but complement-independent phagocytosis could also be
      demonstrated. Since complement levels in the human lung are normally low, the
      role of complement-dependent phagocytosis in the pathogenesis of Legionnaires'
      disease is doubtful. However, the contribution of other potential phagocytosis
      related host cell surface molecules to the phagocytosis of L. pneumophila has
      never been investigated. We therefore analyzed the role of complement receptors 1
      (CD35) and 3 (CD11b/18), the lipopolysaccharide (LPS) receptor (CD14), the
      beta(1)-integrin chain of the fibronectin receptor (CD29), the intercellular
      adhesion molecule 1 (ICAM-1, CD54) and the transferrin receptor (CD71) in the
      complement-independent uptake of L. pneumophila. To exclude any influence of
      culture conditions onto phagocytosis rates, we compared a fresh clinical isolate
      with an agar-adapted isolate of L. pneumophila. In addition, we used three
      different host cell types (MM6, HeLa and Jurkat cells) expressing different rates
      of complement receptors. We could show that both strains of L. pneumophila were
      phagocytized by the three host cell lines to the same extent, but intracellular
      multiplication was only found in MM6 and, although to a much lesser degree, in
      Jurkat cells. Preincubation of MM6 cells with monoclonal antibodies directed
      against the above cited phagocytosis-related receptors did not result in
      inhibition of L. pneumophila uptake. We therefore conclude that typical
      phagocytosis-related cell surface receptors are not involved in the complement
      independent phagocytosis of L. pneumophila.

PMID- 12620619
TI  - Utilization of glutathione as an exogenous sulfur source is independent of gamma
      glutamyl transpeptidase in the yeast Saccharomyces cerevisiae: evidence for an
      alternative gluathione degradation pathway.
AB  - gamma-Glutamyl transpeptidase (gamma-GT) is the only enzyme known to be
      responsible for glutathione degradation in living cells. In the present study we
      provide evidence that the utilization of glutathione can occur in the absence of
      gamma-GT. When disruptions in the CIS2 gene encoding gamma-GT were created in
      met15Delta strains, which require organic sulfur sources for growth, the cells
      were able to grow well with glutathione as the sole sulfur source suggesting that
      a gamma-GT-independent pathway for glutathione degradation exists in yeast cells.
      The CIS2 gene was strongly repressed by ammonium and derepressed in glutamate
      medium, and was found to be regulated by the nitrogen regulatory circuit. The
      utilization of glutathione as a sulfur source was, however, independent of the
      nitrogen source in the medium, further underlining that the two degradatory
      pathways were distinct.

PMID- 12620620
TI  - Allelic variation in srtAs of Streptococcus suis strains.
AB  - Streptococcus suis NCTC10234 possesses five srtA homologs: srtA encodes sortase,
      which anchors surface proteins with an LPXTG motif to the cell wall, while the
      functions of the other four homologs (the srtBCD cluster and srtE) remain
      unknown. The genetic organization of the srtA region was found to be conserved in
      the 59 S. suis strains examined in this study. Although the srtAs in three of
      these strains showed strong sequence divergence, their functions were verified to
      be overlapping by genetic complementation, indicating the functional conservation
      of srtAs during the evolution of these strains. These results indicate the
      importance of an srtA-mediated cell wall sorting system for displaying proteins
      on the surface of S. suis.

PMID- 12620621
TI  - Bicarbonate uptake by marine Crenarchaeota.
AB  - Biphytanyl membrane lipids and 16S rRNA sequences derived from marine
      Crenarchaeota were detected in shallow North Sea surface water in February 2002.
      To investigate the carbon fixation mechanism of these uncultivated archaea in
      situ (13)C bicarbonate tracer experiments were performed with this water in the
      absence of light. About 70% of the detected (13)C incorporation into lipids
      (including fatty acids and sterols) is accounted for by the crenarchaeotal
      biphytanyl membrane lipids. This finding indicates that marine Crenarchaeota can
      utilize bicarbonate or CO(2) derived thereof in the absence of light and are
      chemoautotrophic organisms.

PMID- 12620622
TI  - Development of PCR assays for detection of Streptococcus canis.
AB  - Streptococcus canis isolates, also including S. canis of artificially
      contaminated milk, could be identified by polymerase chain reaction (PCR)
      amplification using oligonucleotide primers designed according to species
      specific parts of the 16S rRNA gene and, after sequencing, according to S. canis
      specific parts of the 16S-23S rDNA intergenic spacer region and with
      oligonucleotide primers detecting an internal fragment of the group G
      streptococcal CAMP factor gene cfg. The 16S rRNA gene- and CAMP factor gene cfg
      specific oligonucleotide primers could be used together in a multiplex PCR. No
      cross-reactivities could be observed with other group G streptococcal isolates or
      with any of the other control strains of various streptococcal species and
      serogroups. The PCR methods presented in this study allowed a rapid and reliable
      identification of S. canis and might help to improve the diagnosis of this
      bacterial species in animal and human infections.

PMID- 12620623
TI  - Histopathological study of rabbit intestinal mucosa infected with a hybrid strain
      of Shigella dysenteriae 1 carrying LPS biosynthesis genes of Salmonella enterica
      serovar typhimurium.
AB  - The rfb gene cluster and the rfc gene of Salmonella enterica were introduced
      earlier into an invasive Shigella dysenteriae 1 strain by triparental cross.
      Antiserum was raised in rabbit against lipopolysaccharide isolated from the
      hybrid strain. Both the hybrid and the invasive S. dysenteriae 1 strain were
      found to have a titer of 1:2560 while for S. enterica, it was 1:640. Ligated
      ileal loops were prepared in rabbit, which were inoculated with 10(8) CFU ml(-1)
      each of the hybrid strain, and invasive S. dysenteriae 1 strain used as positive
      control. Escherichia coli K12 was also used as a negative control. After 18 h,
      the fluid accumulation ratios were 0.2 and 1.6 for hybrid and invasive strains of
      S. dysenteriae 1, respectively. Rabbit intestinal mucosa infected with hybrid S.
      dysenteriae 1 strain showed the presence of intact villus tips and unruptured
      intestinal mucosa whereas total necrosis of intestinal mucosa and villi was
      observed in the S. dysenteriae 1-infected region.

PMID- 12620624
TI  - The FliS chaperone selectively binds the disordered flagellin C-terminal D0
      domain central to polymerisation.
AB  - Assembly of each Salmonella typhimurium flagellum filament requires export and
      polymerisation of ca. 30000 flagellin (FliC) subunits. This is facilitated by the
      cytosolic chaperone FliS, which binds to the 494 residue FliC and inhibits its
      polymerisation. Yeast two-hybrid assays, co-purification and affinity blotting
      showed that FliS binds specifically to the C-terminal 40 amino acid component of
      the disordered D0 domain central to polymerisation. Without FliS binding, the C
      terminus is degraded. Our data provide further support for the view that FliS is
      a domain-specific bodyguard preventing premature monomer interaction.

PMID- 12620625
TI  - Activation of the nodA promoter by the nodD genes of Rhizobium galegae induced by
      synthetic flavonoids or Galega orientalis root exudate.
AB  - Rhizobial nodD genes produce transcriptional regulators that, together with
      appropriate inducer compounds, activate the other symbiotic nodulation (nod)
      genes and initiate the nodule formation process. Two nodD homologues, nodD1 and
      nodD2, are present in the Rhizobium galegae strain HAMBI 1174. In this work we
      analysed their ability to induce the nodA promoter with synthetic inducers known
      to activate nod genes in other rhizobia. According to phylogenetic analysis, the
      inducer-specific carboxy-terminal part of the R. galegae nodD protein sequence
      groups together with those of Rhizobium leguminosarum and Sinorhizobium meliloti.
      However, the respective inducer compounds for their NodD proteins are not highly
      effective with R. galegae nodD products. The best inducer discovered with R.
      galegae nodD1 was the root exudate of the host plant of R. galegae, Galega
      orientalis. HPLC analyses revealed the presence of many divergent flavonoid
      compounds in the G. orientalis root exudate. The most effective HPLC fractions
      induced R. galegae nodD1 up to the level obtained by intact G. orientalis root
      exudate while apigenin and luteolin, which were also present in the root exudate,
      were only moderate inducers. A UV-Vis diode array spectrum of the most active
      peak indicated that the main inducer present in the G. orientalis root exudate is
      an unidentified chalcone-type compound. In the Galega-R. galegae interaction the
      first recognition between the NodD protein and the flavonoid inducer secreted
      from the roots of Galega is specific for these organisms, and thus partly
      responsible of the strict host specificity of this symbiosis.

PMID- 12620626
TI  - kdpE and a putative RsbQ homologue contribute to growth of Listeria monocytogenes
      at high osmolarity and low temperature.
AB  - The kdp locus of Listeria monocytogenes encodes products with homology to
      structural proteins of a high-affinity potassium uptake system and to a two
      component signal transduction system commonly involved in controlling gene
      expression. We have investigated the role of kdpE, encoding the transcriptional
      response regulator, as well as of the downstream gene, orfX, in adaptation of L.
      monocytogenes EGD to NaCl and low temperature. When grown in chemically defined
      medium the addition of NaCl to 2% decreased the growth rate of a mutant with an
      insertional inactivated kdpE, while mutants carrying in-frame deletions of either
      kdpE or orfX were unaffected by high osmolarity. Transcriptional analysis of kdpE
      and orfX revealed that their products are encoded by the same transcript. Thus,
      our data indicate that the absence of both KdpE and OrfX influences growth under
      osmotic pressure. Interestingly, OrfX contains a conserved domain of alpha/beta
      hydrolases and resembles RsbQ that in Bacillus subtilis participates in the
      activation cascade of the general stress sigma factor SigB. When shifted to low
      temperature the deletion mutant lacking orfX resumed growth slightly faster than
      the wild-type. This phenotype was shared by a mutant carrying an in-frame
      deletion of sigB supporting the notion that OrfX could be a RsbQ homologue.

PMID- 12620627
TI  - The response regulator LetA regulates the stationary-phase stress response in
      Legionella pneumophila and is required for efficient infection of Acanthamoeba
      castellanii.
AB  - In order to identify a potential regulator of virulence gene expression in
      Legionella pneumophila, the L. pneumophila homologue of the response regulator
      GacA, LetA, was identified and cloned, facilitating the generation of a L.
      pneumophila letA insertion mutant. The L. pneumophila letA insertion mutant was
      more sensitive to oxidative and acid stress than the wild-type. The letA mutant
      exhibited reduced infectivity and was defective for intracellular growth within
      Acanthamoeba castellanii. Transcription of the rpoS and dotA genes was reduced in
      the letA mutant. Our data indicate that the response regulator LetA functions as
      a regulator of the stationary-phase stress response in L. pneumophila and is
      required for efficient replication within A. castellanii.

PMID- 12620628
TI  - Characterization of a novel unique restriction-modification system from Yersinia
      enterocolitica O:8 1B.
AB  - Genetic manipulations with enteropathogenic Yersinia enterocolitica O:8 are
      complicated by the presence of an efficient PstI-like YenI restriction
      modification (R-M) system. We have characterized the YenI R-M system in Y.
      enterocolitica O:8, biotype 1B. A 5039 bp DNA fragment of the pSAK2 recombinant
      plasmid carrying the yenI locus was used to determine the nucleotide sequence.
      DNA sequence analysis identified a single 2481 bp open reading frame (ORF) that
      encodes an 826 amino acid large polypeptide having an apparent molecular mass of
      93 kDa. The N-terminal part of the YenI ORF has 45 and 40% identity to PstI and
      BsuI methyltransferases (MTases), respectively; while the C-terminal part depicts
      55 and 45% identity to endonucleases (ENases) of both isoschyzomeric enzymes. The
      yenI gene was cloned into pT7-5 plasmid and has been shown to encode a single
      polypeptide of expected molecular mass. A specific recognition sequence, typical
      to the type II R-M systems and single peptide organization, typical to type IV R
      M systems, make YenI unique among known restriction-modification systems. We have
      constructed a truncated recombinant variant of YenI enzyme, which conserved only
      MTase activity, and that can be applied to YenI methylation of the DNA to be
      transformed into Y. enterocolitica O:8 biotype 1B strains.

PMID- 12620629
TI  - Saprolegnia oliviae sp. nov. isolated from an Argentine river (Tierra del Fuego
      Province, Argentina).
AB  - Saprolegnia oliviae sp. nov. is described from litter (floating dead twigs,
      leaves and roots) in the Olivia River, Ushuaia Department, Tierra del Fuego
      Province (Argentina). The new species is illustrated and compared with other
      species of the genus. Distinguishing characteristics of S. oliviae are the
      production of smooth oogonia (with some lateral or terminal projections) and the
      absence of antheridial branches on the majority of the oogonia, but when present,
      they are mostly diclinous, at times oogonia are supplied with androgynous and
      monoclinous antheridial branches. The oogonial stalks are predominantly short and
      straight or long and bent, curved or many times coiled; oospores are distinctive
      subcentric, (1-) 15-50 (-70) per oogonium. Morphological details of the new
      species and its comparison with other described species are discussed here.

PMID- 12620630
TI  - Production of unmarked mutations in mycobacteria using site-specific
      recombination.
AB  - Gene disruption experiments play an important role in the functional
      characterization of genes in mycobacteria and rely mostly on the use of one or
      two antibiotic resistance markers. We have developed a system for mycobacteria
      which features both the advantages of the use of antibiotic resistance markers
      for gene disruption experiments and the ability to efficiently rescue the marker
      leaving an unmarked mutation on the chromosome. This new genetic tool relies on
      the transposon gammadelta site-specific recombination system. A res-OmegaKm-res
      cassette was used to generate an insertional mutation by allelic exchange both in
      Mycobacterium smegmatis and Mycobacterium bovis BCG. Upon expression in the
      mutated strains of tnpR, the transposon gammadelta resolvase gene, res-OmegaKm
      res, was excised efficiently leaving behind a single res sequence at the mutated
      locus. A plasmid was engineered allowing expression of tnpR from an easily
      curable mycobacterial vector. This system will be useful for simple construction
      of unmarked mutations or repeated use of the same antibiotic marker to generate
      multiple mutants.

PMID- 12620631
TI  - Pythium carbonicum, a new species isolated from a spoil heap in northern France,
      the ITS region, taxonomy and comparison with related species.
AB  - Pythium carbonicum (F-72) sp. nov. was found in soil samples taken on the top of
      a spoil heap in northern France. The morphology of this new species resembles
      that of a recently described species: Pythium megacarpum. However, the
      antheridial and oogonial characteristics of this new species are unique, and the
      comparison of its ITS region of the nuclear ribosomal DNA indicates that this
      species is also related to the genus Phytophthora. The fungus does not sporulate,
      the sporangia germinate directly into mycelium through germ tubes. The oogonia of
      P. carbonicum are smooth-walled and also papillated, and are provided with
      monoclinous and diclinous antheridia that wrap around, forming a complicated
      knot. Morphological features of this new species, together with the sequences of
      the ITS region of its nuclear ribosomal DNA and its comparison with related
      species are discussed here.

PMID- 12620632
TI  - Complete nucleotide sequence and molecular characterization of two lytic
      Staphylococcus aureus phages: 44AHJD and P68.
AB  - The first complete nucleotide sequences of two lytic Staphylococcus aureus double
      stranded DNA phages, 44AHJD (16784 bp) and P68 (18227 bp), are reported. Both are
      small isometric phages, with short, non-contractile tails and a pre-neck
      appendage. Based on their morphology, their genome size, the similarity of the
      encoded gene products, the type of infection and on the possession of a type B
      DNA polymerase, 44AHJD and P68 are allocated to the order Caudovirales, family
      Podoviridae, genus 'phi29-like phages'. The genome of 44AHJD differs from that of
      P68 by a deletion spanning nucleotides 10091 to 11531 of the P68 genome. The
      electrophoretic analysis of the terminal DNA fragments of P68 DNA and P68 DNA
      protein complex suggested the presence of a terminal protein at either DNA end.
      In contrast to the lysis cassette of the phi29-like phages, which is located at
      the end of the late operon, the lysis cassette of 44AHJD and P68 is located
      within the structural genes.

PMID- 12620633
TI  - Isolation and characterization of bluensomycin biosynthetic genes from
      Streptomyces bluensis.
AB  - The biosynthetic gene cluster for bluensomycin, a member of the aminoglycoside
      family of antibiotics, was isolated and characterized from the bluensomycin
      producing strain, Streptomyces bluensis ATCC27420. PCR primers were designed
      specifically to amplify a segment of the dTDP-glucose synthase gene based on its
      conserved sequences among several actinomycete strains. By screening a cosmid
      library using amplified PCR fragments, a 30-kb DNA fragment was isolated.
      Sequence analysis identified 15 open reading frames (ORFs), eight of which had
      previously been identified by Piepersberg et al. But seven are novel to this
      study. We demonstrated that one of these ORFs, blmA, confers resistance against
      the antibiotic dihydrostreptomycin, and another, blmD, encodes a dTDP-glucose
      synthase. These findings suggest that the isolated gene cluster is very likely to
      be responsible for the biosynthesis of bluensomycin.

PMID- 12620634
TI  - Presence of streptococcal pyrogenic exotoxin A and C genes in human isolates of
      group G streptococci.
AB  - The bacteriophage-associated genes speA and speC encode streptococcal pyrogenic
      exotoxins of group A streptococci (GAS). Human isolates of group C and G
      streptococci (GCS and GGS) are commensals and the closest known genetic relatives
      of GAS; on occasion, GCS-GGS can cause infection that is clinically similar to
      GAS disease. Thirty-four human isolates of GCS-GGS were tested for speA and speC.
      Two GGS isolates harbored speA only, whereas a third GGS had both genes. All spe
      alleles found in GGS were identical to known spe alleles of GAS, except for one
      speA allele, which was unique. The presence of shared speA and speC alleles in
      GAS and GGS is highly suggestive of recent interspecies transfer. Acquisition of
      GAS-like virulence genes by GGS may lead to enhanced pathogenicity in this
      usually commensal-like organism.

PMID- 12620635
TI  - Methanogenic population structure in a variety of anaerobic bioreactors.
AB  - The methanogenic community structures of six anaerobic sludges were examined
      using culture-independent techniques. The sludges were obtained from full-scale
      and laboratory-scale bioreactors, treating a variety of low- and high-strength,
      simple and complex wastewaters at psychrophilic (10-14 degrees C), mesophilic (37
      degrees C) and thermophilic (55 degrees C) temperatures. Amplified rDNA
      restriction analysis identified 18 methanogenic operational taxonomic units in
      the six samples. 16S rRNA gene sequencing and phylogenetic reconstruction
      demonstrated that five separate groups of methanogens were represented with
      Methanosaeta-like species dominant in all sludges, but particularly in samples
      from a psychrophilic bioreactor treating low-strength synthetic sewage (75% of
      all clones detected).

PMID- 12620636
TI  - Isolation and properties of a tripeptidyl peptidase from a periodontal pathogen
      Prevotella nigrescens.
AB  - Prolyltripeptidyl amino peptidase activity was found in a crude extract of
      Prevotella nigrescens and this enzyme was purified by procedures including
      concentration with ammonium sulfate, ion exchange chromatography, gel filtration,
      and isoelectric focusing. This peptidase hydrolyzed Ala-Ala-Pro-p-nitroanilide as
      well as Ala-Phe-Pro-p-nitroanilide. Furthermore, several p-nitroanilide
      derivatives of dipeptides with a proline residue in the second position from the
      amino-terminal end (Xaa-Pro) were also cleaved detectably. The molecular mass of
      this tripeptidase was calculated as 56 kDa and its isoelectric point was 5.8. The
      enzyme was inactivated completely by heating at 60 degrees C for 5 min and
      inhibited significantly by specific serine enzyme inhibitors.

PMID- 12620638
TI  - Mu and delta receptors mediate morphine effects on phagocytosis by murine
      peritoneal macrophages.
AB  - Studies with selective opioid agonists show that mu- and delta(2)-opioid
      receptors, but not kappa, are involved in opioid inhibition of phagocytosis in
      elicited murine macrophages. All mu and delta(2) agonists tested had similar
      maximal effects on phagocytosis, and all dose-response curves suggest positive
      cooperativity. In addition, mu and delta antagonists antagonized the effect of
      both mu and delta agonists. Furthermore, in mu-opioid receptor knockout mice
      (MORKO), we observed a decrease in potency and maximal effect for a delta
      agonist. These data suggest that mu and delta receptors are not only involved in
      the modulation of phagocytosis in macrophages, but they also affect each other's
      activity by an unknown cooperative mechanism.

PMID- 12620639
TI  - Salivary secretion of immunoglobulin A by submandibular glands in response to
      autonomimetic infusions in anaesthetised rats.
AB  - Salivary secretion of immunoglobulin A (lgA) by submandibular glands is increased
      by stimuli from autonomic nerves. Since it is unclear which specific autonomic
      receptors transduce such stimuli, we have infused autonomimetics intravenously
      and compared secretion of fluid, IgA and stored proteins (peroxidase and total
      protein) with secretory responses during electrical stimulation of the
      parasympathetic nerve supply in anaesthetized rats. The greatest secretion of IgA
      was evoked by the alpha-adrenoceptor agonist phenylephrine and this was reduced
      by the beta-adrenoceptor blocking drug propranolol. The secretion of fluid or
      proteins but not IgA was increased with frequency of nerve stimulation and dose
      of methacholine (cholinergic), isoprenaline (beta-adrenergic) or phenylephrine
      (alpha-adrenergic).

PMID- 12620637
TI  - Infectious agents and multiple sclerosis--are Chlamydia pneumoniae and human
      herpes virus 6 involved?
AB  - A good deal of evidence suggests an infectious component in the development of
      multiple sclerosis (MS) and, to date, some 20 bacteria and viruses have been
      associated with the disease. Recent independent sets of studies have implicated
      the respiratory bacterium Chlamydia pneumoniae and human herpes virus 6 (HHV-6)
      in the pathogenesis of MS. However, as is the case for essentially all earlier
      microbial associations, experimental evidence linking either this bacterium or
      this virus to MS is equivocal. We review the published reports concerning
      involvement of C. pneumoniae and HHV-6 in MS, and data relating to possession of
      the APOE epsilon 4 allele, which some studies indicate might influence how these
      or other pathogens affect disease genesis. Based on the large set of inconsistent
      observations available and given important new information regarding the
      neuropathology of MS, we contend that no conclusion is possible at this point
      regarding the potential role of either C. pneumoniae or HHV-6 in MS. We therefore
      propose future studies that should clarify whether, and if so how, these and
      other organisms function in the pathogenesis of this disease.

PMID- 12620640
TI  - IL-1beta-dependent neurological effects of the whole cell pertussis vaccine: a
      role for IL-1-associated signalling components in vaccine reactogenicity.
AB  - Immunization with the whole cell pertussis vaccine (Pw), but not the acellular
      pertussis vaccine (Pa), is associated with a number of neurological side effects.
      Previously, we have demonstrated a role for interleukin-1beta (IL-1beta) in Pw
      reactogenicity. Here we report that parenteral Pw administration resulted in a
      concomitant increase IL-1 type I receptor (IL-1RI) mRNA and a decrease in IL-1
      type II receptor (IL-1RII) mRNA expression in the murine hypothalamus. These Pw
      induced changes were accompanied by an increase in caspase-1 and interleukin
      1beta (IL-1beta), and were associated with increased activity of the stress
      activated kinase, p38. In contrast, immunization with Pa failed to activate pro
      inflammatory IL-1 responses but resulted in increased IL-1 receptor antagonist
      (IL-1ra) production. These results suggest that the neurological effects of Pw
      are associated with central activation of IL-1beta and IL-1-associated signalling
      components.

PMID- 12620641
TI  - Distinct immune regulation of the response to H-2b restricted epitope of MOG
      causes relapsing-remitting EAE in H-2b/s mice.
AB  - To find immune mechanisms underlying relapse regulation, we developed a model of
      relapsing-remitting experimental autoimmune encephalomyelitis (EAE) in (B6xSJL)
      F1 (H-2(b/s)) mice by immunization with myelin oligodendrocyte glycoprotein
      peptide 35-55 (MOG(35-55)) and compared with low/non-relapsing B6 (H-2(b)) mice.
      In relapsing H-2(b/s) mice, inflammatory lesions scattered throughout the white
      matter with extensive demyelination, consisted of CD4(+) T and B220(+) B cells
      with fewer Mac3(+) macrophages. Memory T cell proliferation to MOG(35-55) was
      significantly enhanced. Switch of macrophage chemoattractant protein-1 (MCP-1)
      production from GFAP(+) astrocytes to CD3(+) T cells was observed. Distinct
      patterns of inflammation and demyelination, MOG(35-55) memory T cell response and
      regulation of MCP-1 are associated with relapsing H-2(b/s) phenotype.

PMID- 12620642
TI  - Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes.
AB  - In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is
      the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9
      predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may
      participate in the remodeling of the extracellular matrix (ECM) such as in
      chronic disease and is inhibited by TIMP-2. These differences may be reflected in
      serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP
      9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of
      different types of the disease, as this information was not previously clearly
      stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in
      secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than
      short disease duration (SDD) relapsing-remitting (RR) MS, but not different from
      the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed
      higher (p=0.04) values in SDD RR MS than PP but also in active patients,
      evaluated either clinically (p=0.006) or from the magnetic resonance imaging
      (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not
      differ between MS subtypes, suggesting systemic rather CNS-restricted changes.
      These results show that an increase in MMP-2/TIMP-2 ratio marks chronic
      progression in MS, but it is as high as in HC, and also confirm that high MMP-9
      activity characterizes short duration relapsing and active forms of the disease.

PMID- 12620643
TI  - Activated/effector CD4+ T cells exacerbate acute damage in the central nervous
      system following traumatic injury.
AB  - CD4(+) helper T cells (Th) have been demonstrated to participate in the chronic
      phase of traumatic injury repair in the central nervous system (CNS). Here, we
      show that CD4(+) T cells can also contribute to the severity of the acute phase
      of CNS traumatic injury. We compared the area of tissue damage and the level of
      cellular apoptosis in aseptic cerebral injury (ACI) sites of C57BL/6 wild type
      and RAG1(-/-) immunodeficient mice. We demonstrate that ACI is attenuated in
      RAG1(-/-) mice compared to C57BL/6 animals. Adoptive transfer of
      CD4(+)CD62L(low)CD44(high) activated/effector T cells 24 h prior to ACI into
      RAG1(-/-) mice resulted in a significantly enhanced acute ACI that was comparable
      to ACI in the C57BL/6 animals. Adoptive transfer of CD4(+)CD62L(high)CD44(low)
      naive/non-activated T cells did not increase ACI in the brains of RAG1(-/-) mice.
      T cell inhibitory agents, cyclosporin A (CsA) and FK506, significantly decreased
      ACI-induced acute damage in C57BL/6 mice. These results suggest a previously
      undescribed role for activated/effector CD4(+) T cells in exacerbating ACI
      induced acute damage in the CNS and raise a novel possibility for acute treatment
      of sterile traumatic brain injury.

PMID- 12620644
TI  - The neuregulin GGF2 attenuates free radical release from activated microglial
      cells.
AB  - The neuregulin glial growth factor 2 (GGF2) is a neural growth factor that is
      best known for its ability to promote the survival and proliferation of
      oligodendrocytes and Schwann cells. While it has been shown in recent years that
      GGF2 is effective in the treatment of autoimmune models of brain injury, it is
      not known if the beneficial effects of GGF2 are based in part on modulation of
      brain inflammation. In this report, we document the anti-inflammatory effects of
      recombinant human GGF2 (rhGGF2) on microglial free radical production in vitro.
      The presence of the neuregulin receptors ErbB2, 3, and 4 was confirmed in N9
      microglial cells by Western blot analysis. Pretreatment of N9 cells with 10-100
      ng/ml rhGGF2 24 h before either phorbol 12-myristate 3-acetate (PMA) or
      interferon gamma (IFNgamma) caused dose-dependent decreases in oxidative burst
      activity and nitrite release, respectively, with 50 and 100 ng/ml causing
      significant effects. When cells were co-treated with increasing doses of rhGGF2
      and PMA or IFNgamma, only concentrations of 50 ng/ml, but not 10 or 100 ng/ml,
      were able to decrease oxidative burst activity and nitrite release. Finally, when
      microglial cell viability following treatment of cells with IFNgamma with or
      without rhGGF2 was evaluated, it was observed that 50 and 100 ng/ml rhGGF2
      conferred significant protection against IFNgamma-induced cell death in
      microglial cells. Overall, these results indicate that the neuregulin rhGGF2 may
      have anti-inflammatory and antioxidant properties in the brain, and may also
      provide trophic support for brain-resident microglial cells.

PMID- 12620645
TI  - Murine gammaherpesvirus-68 infects microglia and induces high levels of pro
      inflammatory cytokine production.
AB  - Murine gammaherpesvirus-68 (MHV-68) has been established as a tractable model for
      the study of human herpesvirus infections. Recent associations between
      herpesvirus infections and inflammatory central nervous system (CNS) disorders,
      including multiple sclerosis (MS), have prompted us to investigate the
      susceptibility of cultured microglia and astrocytes to MHV-68 infection. In the
      present study, we demonstrate that MHV-68 can infect both cell types.
      Importantly, we show that MHV-68-infected microglia and astrocytes can produce
      pro-inflammatory cytokines. Such cytokine production may either contribute to
      protective host responses to viral challenges or could exacerbate damaging CNS
      inflammation.

PMID- 12620646
TI  - Regulation of chemokine receptor expression in human microglia and astrocytes.
AB  - It has been proposed that the positioning of mobile cells within a tissue is
      determined by their overall profile of chemokine receptors. This study examines
      the profiles of chemokine receptors expressed on resting and activated adult
      human microglial cells, astrocytes and a microglial cell line, CHME3. Microglia
      express highest levels of CXCR1, CXCR3 and CCR3. Astrocytes also have moderate
      levels of CXCR1 and CXCR3, and some CCR3, while both cell types also expressed
      CCR4, CCR5, CCR6, CXCR2, CXCR4 and CXCR5 at lower levels. Activation of the cells
      with the inflammatory cytokine tumour necrosis factor-alpha (TNFalpha) and
      interferon-gamma (IFNgamma) increased the expression of some but not all
      receptors over a period of 24 h. Microglia showed moderate enhancement of
      receptor expression, while astrocytes responded particularly strongly to TNFalpha
      with enhanced CXCR3, CCR3 and CXCR1. However, the migratory and proliferative
      responses of the microglia and astrocytes to the same chemokine were different,
      with microglia migrating and astrocytes proliferating in response to CXCL10. The
      data indicates a mechanism by which activated microglia and astrocytes become
      selectively more sensitive to inflammatory chemokines during CNS disease, and the
      paper discusses which of the many chemokines present in CNS would have priority
      of action on microglia and astrocytes.

PMID- 12620647
TI  - Regional and temporal expression patterns of interleukin-10, interleukin-10
      receptor and adhesion molecules in the rat spinal cord during chronic relapsing
      EAE.
AB  - Adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell
      adhesion molecule-1 (VCAM-1) mediate leukocyte infiltration into the CNS, in
      experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS).
      Because exogenous interleukin-10 (IL-10) inhibits ICAM-1 and VCAM-1 expression
      and clinical EAE, we hypothesize that endogenous IL-10 signaling may suppress
      expression of adhesion molecules. In a rat model of chronic relapsing EAE,
      expression levels of IL-10 and its receptor (IL-10R1), ICAM-1 and VCAM-1 mRNA in
      the spinal cord are markedly increased, whereas levels of IL-10 mRNA remain
      relatively low. The temporal pattern of mRNA and protein expression showed marked
      differences between spinal cord levels. During relapse, IL-10, IL-10R1, ICAM-1,
      VCAM-1 mRNA levels and neurological scores show positive correlations. We
      conclude that endogenous IL-10 is not a crucial factor inhibiting adhesion
      molecule expression in this model.

PMID- 12620649
TI  - Nitric oxide metabolite determinations reveal continuous inflammation in multiple
      sclerosis.
AB  - Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme
      during inflammatory disorders. To investigate NO production in multiple sclerosis
      (MS), we determined the concentrations of its oxidation products (NOx) in the
      cerebrospinal fluid (CSF) and plasma of 61 MS patients. The patients were divided
      into three groups on the basis of their clinical disease activity. The total
      levels of NOx in CSF were significantly increased in all MS groups as compared to
      healthy controls and tension headache patients. CSF nitrite correlated with
      clinical disease activity. At exacerbation, the CSF nitrite levels exceed the
      plasma level. This suggests that clinical disease activity is due to a CNS
      inflammatory response, which is more intense and qualitatively different from
      that during clinical stable phases. This study supports NO involvement in the
      pathogenesis of MS and determination of nitrite levels may be useful a surrogate
      marker for disease activity.

PMID- 12620650
TI  - Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal
      fluid from multiple sclerosis patients.
AB  - Neuronal apoptosis has recently been implicated in multiple sclerosis (MS).
      Apoptotic cell death of neurons is induced in cultures exposed to cerebrospinal
      fluid (CSF) from MS patients. Since caspases are essential in the regulation of
      apoptosis, direct evidence was sought linking caspases to CSF-induced neuronal
      death. Caspase activity was measured in cell extracts from MS CSF-treated
      cultured neurons by the cleavage of caspase-1 and caspase-3 substrates. Caspase-3
      activity, but not caspase-1, was induced in neuronal cultures in response to MS
      CSF treatment. This caspase-3 activity was inhibited in vitro by Ac-YVAD-cmk and
      Ac-DEVD-cmk caspase inhibitors. Treatment of MS CSF-incubated neuronal cells with
      these caspase inhibitors completely preserved neuronal survival and largely
      attenuated DNA fragmentation detected in situ. These findings show that neuronal
      cells are rescued from MS CSF-induced death by caspase inhibitors and suggest
      ways to treat MS.

PMID- 12620648
TI  - Effects of glossopharyngeal nerve transection on central and peripheral cytokines
      and serum corticosterone induced by localized inflammation.
AB  - Bilateral transection of the glossopharyngeal nerves (GLOx) disrupts the immune
      to-brain communication from the posterior oral cavity. The current report tested
      whether this effect is due to the afferent (sensory) or efferent (parasympathetic
      motor) components of the nerve. Injection of lipopolysaccharide (LPS) into the
      soft palate (ISP) of GLOx or sham-operated (SHAM) rats increased the circulating
      levels of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL
      1ra) and corticosterone (CORT), as well the hypothalamic content of IL-1beta; no
      difference in circulating levels and hypothalamic content was found between GLOx
      and SHAM at 2 and 4.5 h after LPS injection. These results indicate that
      glossopharyngeal neural efferents do not mediate the effects of GLOx on the
      immune-to-brain communication.

PMID- 12620651
TI  - Genetic polymorphisms of osteopontin in association with multiple sclerosis in
      Japanese patients.
AB  - Osteopontin (OPN) exhibits pleiotropic functions and abundant transcripts for OPN
      are present in brains of patients with multiple sclerosis (MS). The aim of this
      study was to investigate the role of OPN genes in the pathogenesis of MS.
      Polymorphisms at the 8090th, 9250th and 9583rd positions in OPN were detected by
      PCR-RFLP from DNAs of 116 MS Japanese patients and 124 healthy controls. The C/C
      genotype at the 8090th position in exon 6 was more prevalent in MS than in
      control (p<0.0001), and C allele was more prevalent in MS than in control
      (p<0.0001, OR=2.57, 95% CI=1.65-4.00). For the 9583rd position polymorphism in
      exon 7, patients with G/G genotype (age; 32.1+/-12.5 years, mean+/-S.D.) showed a
      later disease onset than G/A (age; 25.9+/-7.8 years, p=0.01) and A/A (age; 25.2+/
      8.9 years, p=0.01) genotypes. There were no significant correlations between OPN
      gene polymorphisms and disease progression. Our results suggest that the 8090th
      polymorphism might be associated with susceptibility to MS, while the 9583rd
      polymorphism might be associated with age of onset of MS.

PMID- 12620652
TI  - CD34-positive cells in human umbilical cord blood express nerve growth factor and
      its specific receptor TrkA.
AB  - In this study, we investigated whether hematopoietic stem cells (HSC) and
      progenitors present in human cord blood can express nerve growth factor (NGF)
      specific receptors, TrkA and p75. Our results showed a marked expression of TrkA
      and NGF in cord blood CD34(+) cells. A gradient of TrkA and NGF expression exists
      and is highest in cord blood CD34(+) cells, reduced in cord blood mononuclear
      cells (MNC) and minimal in mononuclear cells isolated from adult peripheral
      blood. Our findings suggest that NGF may play a role in the differentiation of
      hematopoietic progenitors and indicate a different requirement for NGF by immune
      cells, depending on their state of maturity.

PMID- 12620653
TI  - Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid
      of multiple sclerosis patients are characterized by low-affinity interactions.
AB  - The presence of autoantibodies to the immunodominant antigen, myelin basic
      protein (MBP), in the serum and cerebrospinal fluid (CSF) of patients with
      multiple sclerosis (MS) has been poorly characterized. Many studies report
      detectable levels of autoantibodies to myelin basic protein though other studies,
      using similar techniques, report their absence. We compared a solution-phase
      assay that has detected clinically relevant autoantibodies in diabetes and other
      autoimmune diseases to solid phase assays similar to those used in previous
      reports. The solution-phase assay consistently measured autoantibodies to MBP in
      serum from human subjects with Semple rabies vaccine (SRV)-induced demyelinating
      disease and from MBP-immunized animals. A solid phase assay detected MBP
      autoantibodies in the serum of a fraction of patients with MS. Autoantibodies
      capable of binding to MBP in the solution-phase were not detected in the CSF or
      serum of patients with MS. Additional solution-phase measurements revealed that
      anti-MBP antibodies from individuals with SRV-induced demyelinating disease
      demonstrated a binding affinity profile consistent with that of polyclonal
      antibodies with a range of affinities from low to high. In contrast, antibodies
      to MBP in the serum of MS patients detected by ELISA did not bind soluble MBP in
      the same assay. These results indicate that the humoral response in patients with
      MS does not include moderate- or high-affinity autoantibodies to MBP.

PMID- 12620654
TI  - CSF and serum immune parameters in Sydenham's chorea: evidence of an autoimmune
      syndrome?
AB  - Previous investigations have suggested that Sydenham's chorea (SC) may be an
      autoantibody mediated disorder. We examined this autoimmune hypothesis by
      measuring Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-10) cytokines, oligoclonal
      bands (OCB) and anti-basal ganglia antibodies (ABGA). CSF IL-4 was elevated in
      31% of acute SC and 50% of persistent SC. CSF IL-10 was also elevated in 31% of
      acute SC but 0% of persistent SC. CSF IFN-gamma was undetectable in all patients.
      Serums IL-4, IL-10 and IL-12 were elevated in acute compared to persistent SC.
      OCB were found in 46% of acute SC, ABGA were in 93% of acute SC and 50% of
      persistent SC was of IgG(1) and IgG(3) subclass. These findings support an
      autoantibody pathogenesis.

PMID- 12620655
TI  - Anti-basal ganglia antibody abnormalities in Sydenham chorea.
AB  - Anti-basal ganglia antibodies (ABGA) were measured in nine children with Sydenham
      chorea (SC) and compared to nine controls. Enzyme-linked immunosorbent assay
      (ELISA) and Western blot (WB) methods were used to detect ABGA against
      supernatant (S1), pellet, and synaptosomal preparations from adult and pediatric
      postmortem caudate, putamen, and globus pallidus. ELISA optical density (OD)
      values were higher in SC patients than controls across all preparations, but did
      not reach a level of significance. Although WB identified multiple bands in all
      subjects, discriminant analysis showed that the mean binding patterns of SC
      patients were significantly different from control, most notably in the caudate
      S1 fraction (Wilks' lambda=0.011, p<0.0001). Numerous antigens contributed to
      differences between groups; the two most defining molecular masses were at 126
      and 113 kDa. In contrast to WB with discriminant analysis, ELISA measurements did
      not significantly differentiate between the SC group and controls.

PMID- 12620656
TI  - Time course of T-cell responses to MOG and MBP in patients with clinically
      isolated syndromes.
AB  - CD4(+) T-cell lines (TCLs) from patients with clinically isolated syndromes (CIS)
      were selected with purified human myelin basic protein (MBP) and recombinant
      human myelin oligodendrocyte glycoprotein (rhMOG), at onset of neurological
      symptoms and when patients developed clinically definite multiple sclerosis
      (CDMS). The epitope specificity of each TCL was mapped with overlapping synthetic
      peptides. TCLs were assessed for their ability to secrete IFN-gamma, IL-4, and IL
      6. Diverse patterns of epitope recognition were observed: (a) recognition of a
      broad spectrum of MBP peptide epitopes with evidence of shifts over time; (b) an
      initial T-cell response focused to a restricted segment of the MBP molecule (83
      102) that broadened over the course of disease; and (c) persistence of a focused
      anti-MOG T-cell response. CIS patients who failed to develop CDMS maintained a
      focused epitope response against two to six MBP epitopes. Most MBP peptide
      specific TCLs secreted considerable amounts of IFN-gamma and low amounts of IL-4
      and IL-6, whereas anti rhMOG(Igd) peptide-specific TCLs secreted preferentially
      IL-4 and IL-6. These data raise important issues for the pathogenesis and
      treatment of multiple sclerosis (MS).

PMID- 12620657
TI  - Molecular identification and antibody testing of Chlamydophila pneumoniae in a
      subgroup of patients with HIV-associated dementia complex. Preliminary results.
AB  - Chlamydophila pneumoniae DNA was investigated by polymerase chain reaction (PCR),
      in cerebrospinal fluid (CSF) specimens from patients suffering from HIV-1
      associated dementia complex (HADC). Four (17.3%) cases of C. pneumoniae infection
      were identified among 23 HADC individuals with DNA amplification of major outer
      membrane protein (MOMP) gene and 16S rRNA gene sequences. Sequence analysis
      revealed significant homologies with C. pneumoniae compared to Chlamydia
      trachomatis and Chlamydia psittaci. High mean levels of CSF specific anti-C.
      pneumoniae antibodies and C. pneumoniae antibody specific index values
      significantly elevated were also found by enzyme-linked immunosorbent assay
      (ELISA) in these patients. The results suggest a hypothetical role of C.
      pneumoniae in the pathogenesis or progression of HADC.

PMID- 12620658
TI  - Rebeccamycin analogues as anti-cancer agents.
AB  - Rebeccamycin, a microbial metabolite possessing a maleimide indolo[2,3
      a]carbazole framework with a carbohydrate moiety attached to one of the indole
      nitrogens, is a well-known topoisomerase I inhibitor. This review reports the
      various total syntheses of rebeccamycin and structure-activity relationship
      studies on rebeccamycin analogues. Rebeccamycin analogues were prepared either by
      semi-synthesis from the natural metabolite or by total synthesis. Different
      families of rebeccamycin analogues were obtained by modifications at the imide
      heterocycle, dechlorination and substitutions on the indole moieties,
      modifications of the sugar residue, construction of dimers, coupling the sugar
      unit to the second indole nitrogen, changing indolo[2,3-a]carbazole skeleton to
      indolo[2,3-c]carbazole, replacing one or both indole moieties by 7-azaindole
      units. The biological activities of the rebeccamycin analogues are described.
      According to their chemical structure, the analogues can inhibit topoisomerase I
      and/or kinases. From the structure-activity relationships, some important rules
      were established. Several compounds exhibit stronger antiproliferative activities
      than the natural metabolite with IC(50) values in the nanomolar range. Some
      analogues, especially those possessing azaindole moieties, are much more
      selective than rebeccamycin toward the tumour cell lines tested.

PMID- 12620659
TI  - QSAR and molecular modelling studies on B-DNA recognition of minor groove
      binders.
AB  - Aromatic bisamidines have been proved to be efficient compounds against
      Leishmania spp. and Pneumocystis carinii. Although the mode of action is still
      not known, these molecules are supposed to be DNA minor groove binders (MGBs).
      This paper describes a molecular modelling study for a set of MGBs in order to
      rank them through their complementarity to the Dickerson Drew Dodecamer (DDD)
      according to their interaction energies with B-DNA. A comparative molecular field
      analysis (CoMFA) has shown the importance of relatively bulky positively charged
      groups attached to the MGB aromatic rings, and small and negatively charged
      substituents into the middle chain. Models were obtained for DNA denaturation
      related to H-bonding processes of binding modes. Validation of the model
      demonstrated the robustness of CoMFA in terms of independent test set of similar
      MGBs. GRID results allotted bioisosteric substitution of z.sbnd;Oz.sbnd; by
      z.sbnd;NHz.sbnd; in furan ring of furamidine and related compounds as being
      capable to enhance the binding to DDD.

PMID- 12620660
TI  - Synthesis of heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)
      (arylmethyloxy)amine COX-2 inhibitors: effects on the inhibitory activity of the
      replacement of the cyclopentene central core with pyrazole, thiophene or
      isoxazole ring.
AB  - Several heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)
      (arylmethyloxy)amine COX-2 inhibitors, in which the cyclopentene moiety was
      replaced by pyrazole, thiophene or isoxazole ring, were synthesized, in order to
      verify the influence of the different nature of the central core on the COX
      inhibitory properties of these kinds of molecules. Among the compounds tested,
      only the 3-(p-methylsulfonylphenyl) substituted thiophene derivatives 17 and 22,
      showed a certain COX-2 inhibitory activity, accompanied by an appreciable COX-2
      versus COX-1 selectivity. Only one of the 1-(p-methylsulfonylphenyl)pyrazole
      compounds (16) displayed a modest inhibitory activity towards both type of
      isoenzymes, while the pyrazole 1-(p-aminosulfonylphenyl) substituted 12 proved to
      be significantly active only towards COX-1. All the isoxazole derivatives were
      inactive on both COX isoforms.

PMID- 12620661
TI  - Cytotoxic analogues of 2,6-bis(arylidene)cyclohexanones.
AB  - A series of 2,6-bis(arylidene)cycloalkanones (1) and related compounds containing
      one or two substituents at the four position of the cyclohexyl ring were prepared
      and shown to display cytotoxic activity towards murine P388 and L1210 cells as
      well as human Molt 4/C8 and CEM T-lymphocytes. In some of the series of
      compounds, positive correlations were noted between the potencies of the enones
      and the magnitude of the Hammett sigma values of the aryl substituents. Four
      representative compounds were cytotoxic to a number of human tumours in vitro,
      particularly towards colon cancer and leukemic cells. A noteworthy feature of the
      compounds prepared in this study is that, in general, they were well tolerated
      when administered to rodents. A number of lead molecules emerged from this
      investigation as well as guidelines for future expansion of these series of
      compounds.

PMID- 12620662
TI  - Cytotoxic 2',5'-dihydroxychalcones with unexpected antiangiogenic activity.
AB  - A series of 2',5'-dihydroxychalcones were synthesized and evaluated for
      cytotoxicity against tumor cell lines and human umbilical venous endothelial
      cells (HUVEC). It was found that chalcones with electron-withdrawing substituents
      on the B ring exhibited potent cytotoxicity against a variety of tumor cell lines
      while compounds with electron-releasing groups were less potent in general. Those
      compounds with B ring replaced by extended or heteroaromatic rings exhibited
      significant bioactivity. Several compounds were shown to have marked cytotoxic
      selectivity towards HUVECs. Especially, among the synthesized compounds, 2-chloro
      2',5'-dihydroxychalcone (2-3) showed the highest selectivity index up to 66 in
      comparison to HCT116 cells. This compound also exhibited strong inhibitory
      effects on the HUVEC tube formation in an in vitro model. When administered into
      BDF1 mice bearing Lewis lung carcinoma cells at 50 mg kg(-1) day(-1), 2-3 was
      found to inhibit the growth of tumor mass by 60.5%.

PMID- 12620663
TI  - New propylamine oligopyrrole carboxamides linked to a heterocyclic or
      anthraquinone system: synthesis, DNA binding, topoisomerase I inhibition and
      cytotoxicity.
AB  - Continuing our studies on combilexines, compounds consisting of a DNA
      intercalator linked to a minor groove ligand, new results are presented. The
      synthesis of a series of new propylamine oligopyrrole carboxamides closely
      related to netropsin and distamycin A, linked to a heterocyclic or anthraquinone
      system is reported. The cytotoxic activity in vitro, the DNA binding
      characteristics and the inhibition of the topoisomerase I of the compounds were
      studied in order to explain the biological mechanism of action of these new
      potential combilexines. Some of the synthesised compounds showed cytotoxic
      activity against human tumour cell lines, as well as DNA binding and
      topoisomerase I inhibiting properties.

PMID- 12620665
TI  - Synthesis and investigation of tuberculosis inhibition activities of some 1,2,3
      triazole derivatives.
AB  - In this study, alpha-diazo-beta-oxoaldehyde compounds were condensed with
      different amines to yield 4-acyl-1H-1,2,3-triazole derivatives. The 1,2,3
      triazole compounds were investigated for their inhibition activities against
      tuberculosis.

PMID- 12620666
TI  - Determination of the diastereoisomeric purity of D,L- and meso-HM-PAO by 13C-NMR
      spectroscopy.
AB  - D,L-hexamethylpropyleneamine oxime (HM-PAO) is well known to be the effective
      isomer when HM-PAO is used as a radiopharmaceutical. Its diastereoisomeric purity
      is of great importance because meso-impurity decreases the concentration of the
      99mTc-complex in the brain. The described investigation shows that 13C-NMR
      spectroscopy is a suitable analytical method for the determination of the
      diastereoisomeric purity of HM-PAO. It also can be used for assessment of the
      relative ratio of both isomers in diastereoisomeric mixtures. It is important to
      note that the patterns of behaviour of both isomers in 13C-NMR spectra are the
      same in all solvents tested. The method is simple, fast and explicit.

PMID- 12620664
TI  - Design, synthesis and structure-activity relationships of a series of 9
      substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors.
AB  - Adenine derivatives substituted in position 9 have been demonstrated to have
      potent cyclic nucleotide phosphodiesterase (PDE) inhibition properties with high
      selectivity toward PDE-4. Starting from our initial lead compound 9-(2
      fluorobenzyl)-N(6)-methyl-2-trifluoromethyladenine (4, NCS613), we designed and
      synthesized a new series of 9-substituted derivatives for developing structure
      activity relationship studies. This new series of derivatives showed increased
      potencies and better selectivity profiles. Structural modifications were achieved
      in parallel on three different positions of the adenine ring, and led to the
      following observations: (i) introduction of a lipophilic substituent such as
      trifluoromethyl, n-propyl group or iodine in the C-2 position is favourable for
      both the PDE-4 inhibitory activity and the selectivity towards other isoenzymes;
      (ii) functionalization of the N9 benzyl group with a 2-methoxy substituent led to
      remarkably more active compounds; (iii) replacement of the N(6)-methylamino
      moiety by other amino groups is detrimental to the activity. Among all
      derivatives prepared, the 9-(2-methoxybenzyl)-N(6)-methyl-2
      trifluoromethyladenine (9r), 9-(2-methoxybenzyl)-N(6)-methyl-2-n-propyladenine
      (9s), and the 2-iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) were found to
      be the most potent inhibitors within this series (PDE-4-IC(50)=1.4, 7.0, and
      0.096 nM, respectively). Compared to our reference compound 4, which showed an
      IC(50) of 42 nM, the derivative 13b was found 450-fold more potent. Moreover, 2
      iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) and 9-(2-methoxybenzyl)-N(6)
      methyl-2-trifluoromethyladenine (9r), were at least 50000-150000 times more
      selective for the PDE-4 than for the other PDE families. Additionally, these new
      derivatives showed improved efficiency in inhibiting the TNFalpha release from
      mononuclear cells from healthy subjects (e.g. adenines 7l, 9s and 13b). Thus,
      compounds 7l, 9r, 9s and 13b are among the most potent and selective PDE-4
      inhibitors reported so far and represent very promising pharmacological tools for
      a better understanding of the signal transduction involving cyclic AMP within the
      cell: this pathway is implicated in the physiology and the pathophysiology of
      inflammation, asthma and autoimmune disorders.

PMID- 12620667
TI  - Inhibition of human serum arylesterase by metal chlorides.
AB  - The inhibition of arylesterase (paraoxonase, EC 3.1.8.1) by metal chlorides was
      studied with both pooled human serum (A phenotype) and purified enzyme, using
      phenyl acetate as substrate. Inhibition data were analysed with the Hill
      equation. Results obtained with whole serum and purified enzyme were very
      similar. On the basis of the Hill coefficient, n(H), three groups of inhibitors
      were distinguished: (1) Cu(2+) and Hg(2+) for which n(H)=1, suggesting a single
      binding site (probably the free cysteine at position 283); these metals were
      mixed inhibitors, with more affinity for the free enzyme than for the enzyme
      substrate complex; (2) Mn(2+), Co(2+), Ni(2+), Zn(2+), and Cd(2+) for which
      n(H)>1, suggesting several cooperative binding sites; (3) La(3+), for which
      n(H)<1. Within groups (1) and (2) the inhibiting potency followed the order of
      the periodic table. For the 3d elements the inhibiting order followed the Irving
      Williams series, with the classical exception of Cu(2+). Only Zn(2+) was
      inhibitory at its physiological concentration.

PMID- 12620668
TI  - Potential binding modes of beryllium with the class II major histocompatibility
      complex HLA-DP: a combined theoretical and structural database study.
AB  - In an effort to understand the molecular basis of chronic beryllium disease
      (CBD), a study of the chemical relationship between beryllium, antigen, and the
      major histocompatibility complex II, HLA-DP, was undertaken. A homology model of
      the HLA-DP protein was developed. An analysis of the sequences of HLA-DPB1 and
      HLA-DPA1 alleles most common among CBD patients revealed several carboxylate rich
      regions in the peptide-binding cleft. These regions contain many hard Lewis base
      sites that may provide bonding opportunities for beryllium, a hard Lewis acid.
      Quantum chemistry calculations and structural database results support the
      presence of beryllium clusters, bridged by carboxylate, hydroxo, and/or oxo
      ligands, in the HLA-DP binding cleft. These results strongly suggest that
      beryllium clusters are an integral part of the antigen, and may even act solely
      as antigen. This work provides an initial model for thinking about beryllium
      interactions with proteins relevant to CBD and other metal-induced diseases.

PMID- 12620669
TI  - Modeling of matrix vesicle biomineralization using large unilamellar vesicles.
AB  - Stable, large unilamellar vesicles (LUV) have been constructed that model matrix
      vesicles (MV) in inducing de novo mineral formation when incubated in synthetic
      cartilage lymph (SCL). Using a dialysis method for incorporation of predetermined
      pure lipid, electrolyte and protein constituents, the detergent n-octyl beta-D
      glucopyranoside enabled formation of stable, impermeable LUV with a diameter (
      approximately 300 nm), lipid composition (phosphatidylcholine-phosphatidylserine
      cholesterol, 7:2:2, molar ratio) and enclosed inorganic phosphate level (25-100
      mM) similar to that of native MV. Mineral formation by these LUVs was measured by
      45Ca(2+) uptake and FTIR analysis following incubation in SCL. Addition of the
      ionophore A23187 to SCL enabled 45Ca(2+) uptake comparable to that of native MV.
      FTIR analysis revealed that crystalline mineral formed in the LUV during
      incubation in SCL, but not in the absence of ionophore. This mineral had an IR
      absorption spectrum like that of the acid-phosphate-rich, octacalcium phosphate
      like mineral formed by native MV. Perturbing the LUV membrane with either
      detergents or phospholipase A(2) following prior incubation in SCL enabled egress
      of mineral crystallites from the vesicle lumen, stimulating further mineral
      formation. Annexin V, a major protein in native MV with known Ca(2+) channel
      activity, incorporated into the LUV lumen or added to the external medium,
      induced only limited 45Ca(2+) uptake. This indicates that additional factors are
      required for annexin V to form Ca(2+) channels. Nevertheless for the first time,
      stable LUVs have been constructed with MV-like lipid, electrolyte, and protein
      composition and size that induce formation of mineral like that formed by native
      MV.

PMID- 12620670
TI  - Structural analysis and sheep pituitary receptor binding of GnRH and its
      complexes with metal ions.
AB  - Binding of GnRH and its metal complexes to a sheep pituitary receptor have been
      investigated showing that Cu(II)-GnRH complex is more effectively bound to the
      receptor than the metal-free ligand, while Ni(II) and Co(II) complexes are less
      effective than the metal-free GnRH. Earlier studies have explained reasonably
      well the complex formation with cupric ion, while in this work extensive 1H NMR
      measurements have been performed for free gonadotropin-releasing hormone (GnRH)
      and its complexes with Ni(II) in DMSO (dimethyl sulfoxide) solution. This study
      shows the high order of organization of the metal-free peptide in DMSO solution
      with two structured 'domains' whose relative orientation is modulated by the
      mobility of the central glycine. Furthermore, theoretical calculations were
      performed for the Ni(II)-GnRH complex. The data obtained in this work supports
      previous studies on the co-ordination of Ni(II) ions with GnRH in aqueous
      solutions at high pH [J. Inorg. Biochem. 33 (1988) 11] and suggest an
      experimental procedure to reproduce high pH in DMSO solution. In the Ni(II)
      complex, the metal ion was found to co-ordinate with four nitrogen atoms inducing
      a well definite arrangement of aromatic side-chains and a rigid backbone
      structure.

PMID- 12620671
TI  - Changes in function of iron-loaded alveolar macrophages after in vivo
      administration of desferrioxamine and/or chloroquine.
AB  - Both desferrioxamine (DFO) and chloroquine can significantly reduce hepatic iron
      in experimental animals with iron overload by chelating iron from the low
      molecular-weight pool or decreasing iron uptake by the transferrin-transferrin
      receptor cycle, respectively. However, no previous studies have investigated
      whether combination therapy of these two drugs would further decrease the tissue
      iron overload as well as iron-induced toxicity. Chloroquine administration, 15
      mg/kg, 5x/week, to rats during the iron loading regime, 10 mg/kg, 3x/week for 4
      weeks, significantly decreased both hepatic (54%) and macrophage iron content
      (24%). However when administered in combination with desferrioxamine, 10 mg/kg,
      3x/week for 2 weeks at the cessation of iron loading, no further reduction of
      hepatic iron content was noted while the iron content of the macrophages
      significantly increased, possibly indicating the flux of ferrioxamine through
      these cells. Further studies are warranted to investigate the speciation of iron
      within these macrophages. Macrophages isolated from chloroquine-treated iron
      loaded rats showed a reduction in latent NFkappaB activation and a significant
      increase in lipopolysaccharide-stimulated nitrite release by comparison to these
      parameters in iron loaded macrophages. Co-administration of chloroquine and
      desferrioxamine normalised the latent activity of NFkappaB to that of control
      macrophages as well as increasing LPS-stimulated NO release towards control
      values. However, DFO alone did not have any significant effect upon either of
      these parameters. Such results may have important relevance for the reduced
      immune function of iron loaded macrophages isolated from thalassaemia patients
      receiving chelation therapy and their propensity to increased infection.

PMID- 12620672
TI  - Sugar interaction with metal ion: crystal structure and spectroscopic study of
      SrCl2.galactitol.4H2O.
AB  - The crystal structure of SrCl(2).galactitol.4H(2)O has been determined. It
      belongs to monoclinic system, C2/c space group with unit cell dimensions:
      a=13.9849(3), b=14.1601(5), c=8.3026(3) A, beta=104.621(2) degrees, V=1590.9(9)
      A(3) and Z=4. Each Sr(2+) ion in the unit cell binds to two molecules of
      galactitol through O2 and O3 in one alditol and O2' and O3' in the other, as well
      as to four water molecules. Sr-O distances in SrCl(2).galactitol.4H(2)O complex
      range from 2.5420 to 2.6359 A. FT-IR, Raman and far-IR spectra of
      SrCl(2).galactitol.4H(2)O all show that SrCl(2) coordinates with galactitol
      through OH groups of the sugar molecule to form the new complex.

PMID- 12620673
TI  - Enhanced conformational changes in DNA in the presence of mercury(II),
      cadmium(II) and lead(II) porphyrins.
AB  - The interactions of the metalloporphyrins of tetrakis (1-methylpyridinium
      4yl)porphyrin ([M(TMPyP)](4+)) where M=Hg(II), Cd(II) and Pb(II)) with
      pBluescript II plasmid DNA have been studied by the measurement of circular
      dichroism (CD), UV-visible and fluorescence spectra at 0.1 M NaNO(3), pH 7.5 and
      25 degrees C. The CD spectra of the DNA changed quite significantly, with the
      conformational changes in the presence of the metalloporphyrins being much more
      enhanced compared to that of their free metal ion counterparts. The
      conformational changes in DNA upon binding to the Hg(II) porphyrin and Hg(II)
      were, however, different from those of the Cd(II) porphyrin, Pb(II) porphyrin,
      Pb(II), Cd(II) and H(2)(TMPyP)(4+). In the concentration range of 0-2.30 x 10(-5)
      M of DNA, the absorption spectra of H(2)(TMPyP)(4+) showed substantial
      hypochromicity at 423 nm and a red shift of Deltalambda=16 nm in the presence of
      DNA whereas the Hg(II)-, Pb(II)- and Cd(II) porphyrins showed blue shifts of
      absorption maximum wavelengths of Deltalambda=-17 nm, Deltalambda=-35 nm and
      Deltalambda=-4.5 nm, respectively. Furthermore, the shifted absorption maximum
      wavelengths/nm of the porphyrins in excess amount of DNA were comparable; 438,
      439, 440 and 440 for H(2)(TMPyP)(4+), Hg(II)-, Pb(II)- and Cd(II) porphyrins,
      respectively. The changes in absorption spectra for Hg(II)-, Pb(II)- and Cd(II)
      porphyrins revealed that these metalloporphyrins dissociated upon binding to DNA
      which was confirmed by CD as well as fluorescence spectra. The CD results, UV-Vis
      and fluorescence data indicate that the metalloporphyrins interact differently
      with DNA based on their binding modes. And the enhanced changes in conformation
      of DNA in the presence of the metalloporphyrins are due to the synergistic
      effects of the simultaneous binding of the metal ions and the free base porphyrin
      to DNA compared to their free metal ion counterparts: [M(TMPyP)](4+)+DNA+2H(+)
      right harpoon over left harpoon [M(II)(DNA)H(2)(TMPyP)(4+)]. The detailed
      equilibrium reactions have been described along with suggestions of possible
      applications in the medical and biological fields.

PMID- 12620674
TI  - The vanadium environment in blood cells of Ascidia ceratodes is divergent at all
      organismal levels: an XAS and EPR spectroscopic study.
AB  - K-edge X-ray absorption and EPR spectroscopies were used to test the variation in
      blood cell vanadium between and within specimens of the tunicate Ascidia
      ceratodes from Bodega Bay, California. Intracellular vanadium was speciated by
      fitting the XAS spectra of whole blood cells with linear combinations of the XAS
      spectra of models. Blood cell samples representing one specimen each,
      respectively, revealed 92.5 and 38.7% of endogenous vanadium as
      [V(H(2)O)(6)](3+), indicating dissimilar distributions. Conversely, vanadium
      distributions within blood cell samples respectively representing one and six
      specimens proved very similar. The derived array of V(III) complexes was
      consistent with multiple intracellular regions that differ both in pH and
      c(sulfate), both within and between specimens. No systematic effect on vanadium
      distribution was apparent on mixing blood cells. EPR and XAS results indicated at
      least three forms of endogenous vanadyl ion, two of which may be dimeric. An
      inverse linear correlation was found between soluble and complexed forms of
      vanadyl ion, implying co-regulation. The EPR A value of endogenous vanadyl ion
      [A(0)=(1.062+/-0.008)x10(-2) cm(-1)] was marginally different from that
      representing Monterey Bay A. ceratodes [A(0)=(1.092+/-0.006) x10(-2) cm(-1)].
      Comparisons indicate that Bodega Bay A. ceratodes maintain V(III) in a more
      acidic intracellular environment on average than do those from Monterey Bay,
      showing variation across populations. Blood cell vanadium thus noticeably
      diverges at all organismal levels among A. ceratodes.

PMID- 12620675
TI  - Association of anticancer drug mithramycin with H1-depleted chromatin: a
      comparison with native chromatin.
AB  - Depletion of histone H1 after covalent modification from chromatin is a key step
      in eukaryotic transcription initiation. We have studied the effect of depletion
      of linker histone H1 upon the association of transcription inhibitor,
      (mithramycin)(2):Mg(2+) complex, with chromatin. We have compared the binding
      characteristics of the above complex with native, H1-depleted chromatin and naked
      DNA. Binding site size (number of bases per ligand molecule) of the above complex
      to the chromosomal DNA increases upon removal of histone H1. It implies an
      increase in the accessibility of the ligand for the linker DNA. Spectroscopic
      data, and associated enthalpy and entropy values of the interaction of the
      complex with H1-depleted chromatin are similar to naked DNA rather than native
      chromatin. These results suggest that under in vivo conditions, depletion of
      histone H1 from transcriptionally inert native chromatin during gene activation
      would lead to an enhanced accessibility of linker DNA to the small ligands with
      the potential to inhibit transcription.

PMID- 12620676
TI  - EXAFS studies of the zinc sites of UDP-(3-O-acyl)-N-acetylglucosamine deacetylase
      (LpxC).
AB  - Extended X-ray absorption fine structure (EXAFS) spectroscopy has been used to
      determine the structure of the Zn(II) sites in UDP-(3-O-acyl)-N-acetylglucosamine
      deacetylase (LpxC) from Aquifex aeolicus and Pseudomonas aeruginosa. The active
      site Zn(II) is four coordinate, with exclusively low-Z (nitrogen and oxygen)
      ligation in both enzymes. The amplitude of the outer-shell scattering from the
      histidine ligands is best fit using two histidine ligands, suggesting a
      ZnO(2)(His)(2) site, where O most likely represents a conserved aspartate and a
      solvent molecule. The same structure was found for Co(II)-substituted A. aeolicus
      LpxC, although in this case it is possible that the coordination sphere may
      expand to include a fifth low-Z ligand. EXAFS data were also measured for the
      Escherichia coli LpxC enzyme. When a single Co(II) is substituted for Zn(II) in
      the active site of E. coli LpxC, EXAFS data show the same ligand environment as
      is found for the P. aeruginosa and A. aeolicus enzymes. However, the EXAFS data
      for E. coli LpxC with two zinc ions bound per protein, with the second Zn(II)
      acting as an inhibitory metal, demonstrates that the inhibitory metal is bound to
      at least two high-Z (sulfur, presumably thiolate, or chlorine) ligands. Results
      of the outer-shell scattering analysis, combined with previous studies of the
      LpxC enzyme, indicate a novel zinc binding motif not found in any previously
      studied zinc metalloproteins.

PMID- 12620677
TI  - Tissue and subcellular distribution of chromium picolinate with time after
      entering the bloodstream.
AB  - Chromium picolinate, [Cr(pic)(3)], is a popular nutritional supplement; however,
      the fate of the complex in vivo has not previously been established.
      Consequently, rats were administered [51Cr(pic)(3)] intravenously and the fate of
      the radiolabel in the urine, blood plasma, tissues, and subcellular components of
      hepatocytes was followed for the first 24 h after injection. The supplement
      leaves the blood stream rapidly appearing in the urine and entering tissue cells
      intact. Kidney, muscle, and liver possess most of the absorbed radiolabel. In
      hepatocytes, the radiolabel appears most rapidly in the nucleus and mitochondria,
      then in the cytosol, and finally in the lysosomes and microsomes. Thus, while the
      lifetime of the supplement in vivo is brief, it enters cells rapidly intact. The
      significance of the lifetime and distribution of [Cr(pic)(3)] in relationship to
      recent reported potential DNA damage from the supplement is discussed.

PMID- 12620678
TI  - Thermodynamic investigation of M-DNA: a novel metal ion-DNA complex.
AB  - The thermodynamics of formation of a novel divalent metal ion-DNA complex known
      as M-DNA have been investigated using an ethidium bromide (EB) fluorescence
      assay, and with isothermal titration calorimetry. The process of M-DNA formation
      was observed from the EB assay to be strongly temperature-dependent. The binding
      of Zn(2+) to calf thymus (42% GC content) and Escherichia coli (50% GC content)
      DNA at pH 8.5 exhibited an endothermic cooperative binding process at Zn(2+)
      concentrations of approximately 0.1 mM, indicating an entropy driven process.
      This binding process is consistent with a site-specific binding interaction,
      similar in nature to Z-DNA formation; however, the interaction occurs at much
      lower metal ion concentrations. The enthalpy of M-DNA formation for calf thymus
      DNA was determined to be 10.5+/-0.7 and 9+/-2 kJ/mbp at DNA concentrations of 100
      and 50 microg ml(-1), respectively. An enthalpy of 13+/-3 kJ/mbp was obtained for
      M-DNA formation for 50 microg ml(-1) E. coli DNA. No evidence of M-DNA formation
      was observed in either DNA at pH 7.5 with Zn(2+) or at either pH 7.5 or 8.5 with
      Mg(2+).

PMID- 12620680
TI  - Induced chirality of binary aggregates of oppositely charged water-soluble
      porphyrins on DNA matrix.
AB  - The induced chirality of achiral binary aggregates of meso-tetrakis(4-N
      methylpyridyl)porphyrine (TMPyP) and meso-tetrakis(4-sulfonatophenyl)porphyrine
      (TPPS) on a deoxyribonucleic acid (DNA) matrix was investigated. Although the
      negatively charged TPPS did not show induced chirality in DNA solution due to the
      electrostatic repulsion, induced chirality was obtained through the addition of a
      positively charged TMPyP. It was confirmed that the induced chirality was due to
      the binary complex formation between TPPS and TMPyP on the DNA matrix. Moreover,
      the induced chirality depended on the relative molar ratio of TPPS to TMPyP (r)
      and the binding modes of the complex to DNA. When r<1, induced circular dichroism
      (CD) spectrum of the ternary complex was similar to that of intercalated TMPyP
      into DNA. For r=1, the induced CD spectrum showed a reversed biphasic signal due
      to the complex of TMPyP and TPPS stacking along the DNA surface. At a higher r
      value (>1), there was an induced CD signal at 482 nm attributed to a lateral
      shifted arrangement of heteroaggregate of TPPS and TMPyP on DNA matrix where
      TMPyP acted as a spacer to mediate the growth of heteroaggregates. Increasing the
      concentration of sodium chloride in the solution would favor the formation of the
      lateral shifted arrangement of heteroaggregate of TPPS and TMPyP. The resonance
      light scattering (RLS) spectra confirmed the above results. Analysis of the CD
      spectral changes in DNA conformation showed that during the binary complex
      formation of TPPS and TMPyP, the intercalated TMPyP could be 'pulled out' from
      the base pairs of DNA, which might be useful in gene therapy. A model was
      proposed to account for these observations.

PMID- 12620679
TI  - Formation of the oxidative damage marker 8-hydroxy-2'-deoxyguanosine from the
      nucleoside 2'-deoxyguanosine: parameter studies and evidence of Fe(II) binding.
AB  - High-performance liquid chromatography (HPLC) with UV absorption detection was
      employed to measure the amounts of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) produced
      from the nucleoside 2'-deoxyguanosine (dG) under varying reaction conditions
      using iron and H(2)O(2). The results indicate that 8-OH-dG produced from the
      reaction of iron and H(2)O(2) with dG can undergo reaction with free (i.e.,
      unchelated) Fe(III) and that adding the chelating agent
      ethylenediaminetetraacetic acid (EDTA) after the reaction prevents this from
      occurring. It also appears that the free radical species generated by iron-EDTA
      chelates in pH 7.4 N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)
      (Hepes) buffer is either not formed or unstable in unbuffered aqueous solution.
      Finally, 8-OH-dG levels are significantly larger when Fe(II) is allowed to bind
      to the nucleoside dG prior to addition of H(2)O(2). However, production of 8-OH
      dG from unbound Fe(II) is also relevant. The results of this work show that
      differing reaction conditions in vivo, especially at the cellular level, will
      affect significantly the measured yields of 8-OH-dG. These results also have
      implications for studies involving DNA and the ability to distinguish between 8
      OH-dG produced from free iron and iron bound to both phosphate groups and the DNA
      base guanine.

PMID- 12620681
TI  - Binding of bismuth to serum proteins: implication for targets of Bi(III) in blood
      plasma.
AB  - Bismuth complexes have been widely used in clinical treatment as antiulcer drugs.
      However, different adverse effects have been observed and the diagnosis is
      generally confirmed by the detection of bismuth in blood or blood plasma. In this
      study, binding of bismuth to human serum albumin was studied by fluorescence
      spectroscopy with the binding constant logK(a) to be 11.2. Competitive binding of
      bismuth to human albumin and transferrin was carried out at pH 7.4 by FPLC and
      ICP-MS. It was found that over 70% of bismuth binds to transferrin even in the
      presence of a large excess of albumin (albumin/transferrin=13:1) at pH 7.4, 10 mM
      bicarbonate. The distribution of bismuth between the two proteins was almost
      unchanged when Cys(34) of albumin was blocked. However, all bismuth binds to
      albumin when iron-saturated transferrin was used. Almost all of the bismuth was
      distributed over the fractions containing transferrin (70%) and albumin (<30%) in
      serum. The percentage of bismuth associated with transferrin was further
      increased by 15% with elevated transferrin in serum. Binding of bismuth to
      transferrin is much stronger than human albumin. Transferrin is probably the
      major target of bismuth in blood plasma, and it may play a role in the
      pharmacology of bismuth.

PMID- 12620683
TI  - Spectroscopic study of a water-soluble iron(III) meso-tetrakis(4-N
      methylpyridiniumyl) porphyrin in aqueous solution: effects of pH and salt.
AB  - The equilibrium behavior of cationic iron(III) meso-tetrakis(4-N-methyl
      pyridiniumyl) porphyrin, Fe(III)TMPyP, in aqueous solution was studied as a
      function of pH by optical absorption, EPR and (1)H NMR spectroscopies. The
      presence of several Fe(III)TMPyP species in solution was unequivocally
      demonstrated: monomeric porphyrin species (a monoaqueous five-coordinated
      complex, a diaaqueous six-coordinated complex and a monoaqueous-hydroxo six
      coordinated complex), a micro-oxo dimer and a bis-hydroxo complex. The addition
      of salt to the porphyrin solution leads to a simplification of the equilibrium as
      a function of pH. In this case, only three species were observed in solution: a
      monomeric porphyrin species, a micro-oxo dimer and a bis-hydroxo complex. Optical
      absorption, EPR and (1)H NMR spectra contributed to the characterization of these
      species. Four critical pH values (pK) for Fe(III)TMPyP were obtained in pure
      buffer and only three pK values were observed in the presence of NaCl. The
      addition of salt favors the presence of the dimeric species in solution and
      simplifies the equilibrium in the acidic pH range.

PMID- 12620682
TI  - Photooxidation of DNA by a cobalt(II) tridentate complex.
AB  - [Co(bzimpy)(2)], where bzimpy is 2,6-bis(benzimidazol-2-yl)pyridine was
      synthesized and characterized by ESI-MS (electrospray ionization mass
      spectrometry), UV-visible and fluorescence spectra. Absorption titration and
      thermal denaturation experiments indicate that the complex binds to DNA with
      moderate strength. Viscosity measurement shows that the mode of binding could be
      surface binding. Fluorescence study shows that the fluorescence intensity of the
      complex decreases with increasing concentrations of DNA, which is due to the
      photoelectron transfer from guanine base to excited MLCT (metal to ligand charge
      transfer) state of the complex. Photoexcitation of the complex in the MLCT region
      in the presence of plasmid DNA has been found to give rise to nicking of DNA.

PMID- 12620684
TI  - DNA interactions of new mixed-ligand complexes of cobalt(III) and nickel(II) that
      incorporate modified phenanthroline ligands.
AB  - Four new mixed-ligand complexes, namely [Co(phen)(2)(qdppz)](3+),
      [Ni(phen)(2)(qdppz)](2+), [Co(phen)(2)(dicnq)](3+) and [Ni(phen)(2)(dicnq)](2+)
      (phen=1,10-phenanthroline, qdppz=naptho[2,3-a]dipyrido[3,2-H:2',3'-f]phenazine
      5,18-dione and dicnq=dicyanodipyrido quinoxaline), were synthesized and
      characterized by FAB-MS, UV/Vis, IR, 1H NMR, cyclic voltammetry and magnetic
      susceptibility methods. Absorption and viscometric titration as well as thermal
      denaturation studies revealed that each of these octahedral complexes is an avid
      binder of calf-thymus DNA. The apparent binding constants for the dicnq- and
      qdppz-bearing complexes are in the order of 10(4) and >10(6) M(-1), respectively.
      Based on the data obtained, an intercalative mode of DNA binding is suggested for
      these complexes. While both the investigated cobalt(III) complexes and also
      [Ni(phen)(2)(qdppz)](2+) affected the photocleavage of DNA (supercoiled pBR 322)
      upon irradiation by 360 nm light, the corresponding dicnq complex of nickel(II)
      was found to be ineffective under a similar set of experimental conditions. The
      physico-chemical properties as well as salient features involved in the DNA
      interactions of the cobalt(III) and nickel(II) complexes investigated here were
      compared with each other and also with the corresponding properties of the
      previously reported ruthenium(II) analogues.

PMID- 12620685
TI  - Organic and inorganic substrates as probes for comparing native bovine
      lactoperoxidase and recombinant human myeloperoxidase.
AB  - The interaction of native bovine lactoperoxidase (nbLPO) with four substrates has
      been studied and compared with that of recombinant human myeloperoxidase (rhMPO).
      Kinetic, spectroscopic and binding parameters extrapolated for each enzyme
      substrate adduct have been interpreted in the light of the structural data
      available for myeloperoxidase (X-ray structure) and lactoperoxidase (3D-model),
      respectively. The differences in the reactivity and affinity of nbLPO and rhMPO
      towards SCN(-), catechol, dopamine and 3,4-dihydroxyphenylpropionic acid are here
      discussed and related to a different structure of the organic substrate access
      channel as well as to a different accessibility of the heme pocket in the two
      enzymes.

PMID- 12620686
TI  - The effects of tungstophosphate and tungstosilicate on various stress promoters
      transformed in Escherichia coli.
AB  - Although tungsten is an important material in some industrial and chemical
      processes, the biological and biochemical effects, including the toxicity, of
      tungsten compounds are not known well. In this study, a reporter gene assay using
      special strains of Escherichia coli was performed to investigate the mode of
      action of two polyoxotungstates, i.e. undecatungstophosphate (PW(11)) and
      undecatungstosilicate (SiW(11)). When the bacterial cells were cultured with
      PW(11), osmY (a stress promoter gene sensitive to osmotic signals) was induced to
      some extent, while other stress promoters were expressed only slightly. SiW(11)
      gave similar results, but clpB (an analogue of human heat shock protein) was more
      strongly induced. It is possible that PW(11) and SiW(11) can produce an osmotic
      signal at lower concentrations without increasing ionic strength. Since the
      constituents of PW(11)/SiW(11) (i.e. HPO(4)(2-), SiO(3)(2-), WO(4)(2-)) showed
      almost no effect, a chemical feature unique to PW(11)/SiW(11) and originating
      from neither of their constituents, i.e. a polyanionic characteristic, may play
      an important role in their biological effects.

PMID- 12620687
TI  - Efficient biomimetic catalytic epoxidation of polyene polymers by manganese
      porphyrins.
AB  - Two polyene polymers, cis-polybutadiene and cis-polyisoprene, were transformed
      into polyepoxides under mild conditions. The epoxidation of these two polyene
      polymers is stereospecific, giving cis-epoxides as products. All factors
      controlling the reaction rate, such as the nature of the catalyst, the oxygen
      donor and the presence of bases as axial ligands, were studied. The optimum
      results were obtained when iodosylbenzene was used as the oxygen donor,
      Mn(TpFPP)Cl as the catalyst and imidazole as the axial ligand. Under these
      optimum conditions the turnover number was found to be 71. These results render
      this system promising for the epoxidation of polyene polymers in a more general
      way.

PMID- 12620688
TI  - Synthesis, crystal structure, and nuclease activity of planar mono-heterocyclic
      base copper(II) complexes.
AB  - A series of mononuclear copper(II) complexes having a 1:1 molar ratio of copper
      and the planar heterocyclic base like 1,10-phenanthroline (phen), dipyrido[3,2
      d:2',3'-f]quinoxaline (dpq) and dipyrido[3,2-a:2',3'-c]phenazine (dppz) are
      prepared from a reaction of copper(II) nitrate.trihydrate and the base (L) in
      ethanol or aqueous ethanol at different temperatures. The complexes
      [Cu(dpq)(NO(3))(2)] (2), [Cu(dpq)(NO(3))(H(2)O)(2)](NO(3)) (3),
      [Cu(dpq)(NO(3))(2)(H(2)O)(2)].2H(2)O (4.2H(2)O) and
      [Cu(dppz)(NO(3))(2)(H(2)O)].H(2)O (5.H(2)O) have been characterized by X-ray
      crystallography. The crystal structures show the presence of the heterocyclic
      base in the basal plane. The coordination geometries of the copper(II) centers
      are axially elongated square-pyramidal (4+1) in 2, 3 and 5, and octahedral (4+2)
      in 4. The nitrate anion in the coordination sphere displays unidentate and
      bidentate chelating bonding modes. The axial ligand is either H(2)O or NO(3) in
      these structures giving a Cu-L(ax) distance of approximately 2.4 A. The one
      electron paramagnetic complexes (mu approximately 1.8 mu(B)) exhibit axial EPR
      spectra in DMF glass at 77 K giving g(parallel)>g( perpendicular ) with an
      A(parallel) value of approximately 170G indicating a [d(x)2(-y)2](1) ground
      state. The complexes are redox active and display a quasireversible cyclic
      voltammetric response for the Cu(II)/Cu(I) couple near 0.0 V vs. SCE giving an
      order of the E(1/2) values as 5(dppz)>2-4 (dpq)>[Cu(phen)(2)(H(2)O)](2+)>1
      (phen). The complexes bind to calf thymus DNA giving an order 5 (dppz)>2
      (dpq)>[Cu(phen)(2)(H(2)O)](2+)>1 (phen). An effect of the extended planar ring in
      dpq and dppz is observed in the DNA binding. The complexes show nuclease activity
      with pUC19 supercoiled DNA in DMF/Tris-HCl buffer containing NaCl in presence of
      mercaptopropanoic acid as a reducing agent. The extent of cleavage follows the
      order: [Cu(phen)(2)(H(2)O)](ClO(4))(2)>5>2 approximately 3 approximately 4>1. The
      bis-phen complex is a better cleaver of SC DNA than 1-5 having mono-heterocyclic
      base. Mechanistic investigations using distamycin reveal minor groove biding for
      the phen, dpq complexes, and a major groove binding for the dppz complex 5. The
      cleavage reactions are found to be inhibited in the presence of hydroxyl radical
      scavenger DMSO and the reactions are proposed to proceed via sugar hydrogen
      abstraction pathway. The ancillary ligand is found to have less effect in DNA
      binding but are of importance in DNA cleavage reactions.

PMID- 12620689
TI  - Preparation, characterization, and antitumor activity of new cisplatin analogues
      with 1-methyl-4-(methylamino)piperidine: crystal structure of [PtII(1-methyl-4
      (methylamino) piperidine)(oxalate)].
AB  - A series of new platinum(II) complexes of the type [Pt(II)(mmap)X] (where mmap, 1
      methyl-4-(methylamino)piperidine and X, 1,1-cyclobutanedicarboxylato (CBDCA),
      oxalato, malonato, methylmalonato, dimethylmalonato, ethylmalonato,
      diethylmalonato or 2,3-naphthalene dicarboxylato (NDCA)) have been synthesized
      and characterized by elemental analysis, infrared (IR), and 13C and 195Pt nuclear
      magnetic resonance (NMR) spectroscopy. The crystal structure of the analogue
      [Pt(II)(mmap)(oxalate)] was determined using the single crystal X-ray diffraction
      method. Based upon a total of 4964 collected reflections, we determined that the
      compound crystallizes in the monoclinic space group P2(1)/c (with a=11.890(2) A,
      b=9.6695(19) A, c=9.875(2) A, beta=102.03(3) degrees, Z=4, and R=0.0428). In this
      complex, platinum has a slightly distorted square planar geometry with the two
      adjacent corners being occupied by two nitrogen atoms of the mmap ligand, whereas
      the remaining cis positions are occupied by two oxygen atoms of the oxalate
      molecule. The mmap ligand is in a boat conformation and forms six-membered
      chelating rings as well as the oxalate molecule forms five-membered chelating
      rings with platinum. The complexes were evaluated for their cytotoxic potential
      against the sensitive A2780 tumor model and cisplatin-resistant clone derived in
      vitro from potential cells.

PMID- 12620690
TI  - 5-Fluorouracil-cisplatin adducts with potential antitumor activity.
AB  - Using 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum(II) (cisplatin,
      CDDP) as starting compounds, 5-FU-cisplatin adducts cis-[Pt(NH(3))(2)(HFU)Cl] (1)
      and cis-[Pt(NH(3))(2)(HFU)(2)] (2) were prepared. The obtained complexes were
      characterized by IR, ES-MS and 1H NMR spectroscopy. Complex 1 reacted with
      guanosine-5'-monophosphate (5'-GMP) and gave rise to a stable mixed-ligand
      complex cis-[Pt(NH(3))(2)(HFU)(GMP)] (3), whereas 2 did not undergo a similar
      reaction. In vitro cell growth inhibition tests of complexes 1 and 2 exhibited
      moderate antitumor activities against the melanoma B16-BL6 cell line. This work
      provides the basis for a potential alternative for the combinational use of 5-FU
      and CDDP in cancer therapy.

PMID- 12620691
TI  - Zinc mediated methyl transfer from trimethyl phosphate to chelating and non
      chelating alkyl thiols. Model for Zn-dependent methyltransferases.
AB  - The methyl transfer from trimethyl phosphate to alkyl thiols was investigated in
      the presence of zinc ions and in the absence of strong base. The chelating thiol
      N-(2-mercaptoethyl)picolylamine (MEPAH) was methylated by trimethyl phosphate, in
      MeOH, in the presence of Zn salts whereas the reaction did not take place in the
      absence of Zn(2+). The pre-formed complex (MEPA)(2)Zn was methylated faster than
      the MEPAH in the presence of zinc ions The methyl transfer also took place in
      chloroform with similar yields at room temperature. When non-chelating
      hexanethiol was the methyl acceptor, a slower reaction took place in the presence
      of pyridine which was independent of Zn(2+). Kinetic studies of the methyl
      transfer from trimethyl phosphate to (MEPA)(2)Zn gave a second-order rate
      constant of 5.0 x 10(-5) M(-1) s(-1) as measured by 1H NMR spectroscopy in MeOH.
      The results obtained suggest that the methyl transfer to MEPA-Zn involves a zinc
      bound thiolate.

PMID- 12620692
TI  - The Cu(II) acetate complex of the heteroscorpionate ligand (2-hydroxy-3-t-butyl
      methylphenyl)bis(3,5-dimethylpyrazolyl)methane: a structural model for copper
      substituted serralysin and astacin.
AB  - Reaction of Cu(II) acetate with the deprotonated ligand (2-hydroxy-3-t-butyl
      methylphenyl)bis(3,5-dimethylpyrazolyl)methane (L1O(-)) in methanol produced the
      complexes [(L1O)Cu(OAc)], a=9.275(2), b=11.641(5), c=13.532(3) A, alpha=69.62(1)
      degrees, beta=89.49(2) degrees, gamma=87.12(1) degrees, P1. The Cu adopts a
      distorted five-coordinate geometry where the two pyrazole nitrogen ligands and a
      bidentate acetate occupy the pseudoequatorial plane with the phenoxy oxygen in an
      apical position. This complex has a number of features in common with galactose
      oxidase and the copper-substituted endopeptidases serralysin and astacin.

PMID- 12620693
TI  - Characterization of a Cu(II) complex of sulfadimethoxine.
AB  - The molecular structure of [Cu(sulfadimet)(2)].SO(CH(3))(2)
      (sulfadimet=sulfadimethoxine=4-p-aminobenzenesulfonamido-2,6-dimethoxypyrimidine)
      was determined by single crystal X-ray diffractometry. It crystallizes in the
      monoclinic space group P2(1)/c with Z=4. The Cu(II) cation is in a distorted
      CuN(5) square pyramidal coordination, involving four sulfadimethoxine molecules,
      one of them acting as a bidentate ligand. The infrared spectrum is briefly
      discussed on the basis of the structural peculiarities of the complex.

PMID- 12620694
TI  - Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart
      mitochondrial superoxide production.
AB  - BACKGROUND: The present study was designed to investigate whether the effects of
      dietary supplementation with alpha-lipoic acid could prevent the increase in
      mitochondrial superoxide production in the heart as well as the enhanced
      formation of advanced glycation end-products (AGE) that are associated with the
      development of hypertension and insulin resistance in chronically glucose-fed
      rats. METHODS: Sprague Dawley rats were either given or not given a 10% D-glucose
      solution to drink during 4 weeks, combined either with a normal chow diet or with
      alpha-lipoic acid supplemented diet. The oxidative stress was evaluated by
      measuring the heart mitochondrial superoxide production using the lucigenin
      chemiluminescence method. The formation of AGE was also assessed in plasma and
      aorta. RESULTS: Chronic administration of glucose resulted in a 29% increase in
      blood pressure, 30% increase in glycemia, 286% increase in insulinemia, and 408%
      increase in insulin resistance index. Chronic glucose feeding also resulted in a
      22% greater mitochondrial superoxide anion production in heart and in an increase
      of 63% in AGE content in aorta. Increases in blood pressure, aorta AGE content
      and heart mitochondrial superoxide production were prevented in the rats fed
      glucose supplemented with lipoic acid. The simultaneous treatment with lipoic
      acid also attenuated the rise in insulin levels as well as in insulin resistance
      in the glucose fed rats. CONCLUSIONS: These findings demonstrate that alpha
      lipoic acid supplementation prevents development of hypertension and
      hyperglycemia, presumably through its antioxidative properties, as reflected by
      prevention of an increase in heart mitochondrial superoxide anion production and
      in AGE formation in the aorta of chronically glucose treated rats.

PMID- 12620695
TI  - Left ventricular mass regression in the LIFE study: effect of previous
      antihypertensive treatment.
AB  - BACKGROUND: Whether to include only those patients who have not had prior
      hypertension treatment in clinical trials of left ventricular (LV) mass reduction
      is controversial. Accordingly, our aim was to study the relationship between
      prior treatment and both baseline and 1-year echocardiographic LV mass in
      subjects enrolled in the Losartan Intervention For Endpoint reduction (LIFE)
      study. METHODS: We studied clinical and baseline echocardiographic data on 960
      patients with electrocardiographically confirmed left ventricular hypertrophy
      enrolled in the electrocardiographic substudy of the LIFE study, 847 of whom had
      LV mass remeasured after 1 year of blinded treatment. The majority (75%) of these
      patients had prior medical treatment for hypertension. RESULTS: In multivariable
      regression analysis, controlling for age, sex, blood pressure (BP), body mass
      index, and indices of pump and myocardial function, prior antihypertensive
      treatment was not associated with either greater LV mass or relative wall
      thickness on the baseline study. Moreover, there was no significant difference
      between the 637 subjects who were previously treated and the 210 who were not
      treated with regard to the mean reduction in systolic or diastolic pressures (-25
      +/- 17 v -24 +/- -16 and -13 +/- 9 mm Hg v -12 +/- 9 mm Hg), LV mass (-27 +/- 38
      v -29 +/- 34 g), or LV mass/body surface area (-14 +/- 20 v -15 +/- 18 g/m(2)),
      all P >.05. CONCLUSIONS: Prior treatment is not associated with either greater LV
      mass or greater relative wall thickness when age, body mass index, sex, systolic
      BP, heart rate, or indices of LV volume load and systolic function are taken into
      account. In addition, prior treatment is not associated with lesser degrees of LV
      mass reduction. For design of future clinical trials, restriction of inclusion
      criteria to only previously untreated patients does not appear to be necessary
      when the selection criterion is electrocardiographically determined left
      ventricular hypertrophy.

PMID- 12620696
TI  - Effectiveness of furosemide in uncontrolled hypertension in the elderly: role of
      renin profiling.
AB  - BACKGROUND: Despite many advances in the treatment of hypertension, adequate
      blood pressure (BP) control in elderly patients continues to be a challenge.
      Optimal control of BP remains elusive because of issues relating to drug dosage
      and proper choice of therapeutic agents, including questions regarding the role
      of diuretics. METHODS: We examined the effect of diuretic treatment on BP in 12
      elderly hypertensive patients whose hypertension was poorly controlled on
      previous drug regimens. We also evaluated the relationship of systolic,
      diastolic, and mean arterial BP (SBP, DBP, MAP, respectively) to changes in
      plasma renin activity (PRA), serum aldosterone (SA), atrial natriuretic peptide
      (ANP), and serum chemistries both before and after adding furosemide to the prior
      antihypertensive agents. RESULTS: At baseline, 83% of patients had low PRA (< 1
      ng/mL/h). After furosemide, in 67% of patients, decreases in SBP (166 +/- 5 to
      134 +/- 5 mm Hg; P <.001), DBP (82 +/- 4 to 71 +/- 4 mm Hg; P =.004), and MAP
      (111 +/- 3 to 92 +/- 3 mm Hg; P <.001), were associated with increases in PRA
      (2.1 +/- 1.2 to 5.1 +/- 1.8 ng/mL/h; P =.01) and SA (4.8 +/- 1.0 to 9.4 +/- 1.4
      ng/dL; P =.01) and with decreases in ANP (101 +/- 28 to 58 +/- 11 pg/mL; P =.01)
      and body weight (77.5 +/- 3.6 to 76.4 +/- 3.3 kg; P =.02), findings consistent
      with volume mediated/salt sensitive hypertension. In the remaining 33% of
      patients, BP also decreased significantly, but there was no increase in PRA (0.15
      +/- 0.05 to 0.10 +/- 0 ng/mL/h) or SA (9.2 +/- 2.2 to 7.0 +/- 0.8 ng/dL) and no
      decrease in ANP (66 +/- 5 to 75 +/- 18 pg/mL) (P = ns for all), suggesting
      alternate mechanisms for their responses. CONCLUSIONS: Many of the elderly
      hypertensive patients in our study had decreased PRA levels and showed
      significant reductions in BP after furosemide administration. Despite the
      associated increases in PRA and SA and decreases in ANP in 67% of patients,
      diuretic use remains important in the control of hypertension in this population.

PMID- 12620697
TI  - The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and
      preeclampsia.
AB  - BACKGROUND: It is unclear whether pregnancy-induced hypertension (PIH) and
      preeclampsia (PE) are separate conditions or represent opposite ends of a
      spectrum of a single disease entity. Sympathetic hyperactivity exists in both PIH
      and PE; however, only the latter is characterized by multiorgan involvement,
      particularly renal impairment. As there is evidence in hypertension that target
      organ damage is associated with increased sympathetic drive, this study was
      designed to test the hypothesis that the magnitude of sympathetic hyperactivity
      in PE is greater than that in PIH. METHODS: Microneurography was used to compare
      peripheral sympathetic neural discharge, its reflex control and end-organ effect
      (plethysmographic measurement of calf blood flow) in 33 women with PIH, PE, and
      normal pregnancy (NP) who were matched for age, body weight, and gestation.
      RESULTS: As expected, patients with PIH and PE had higher levels of mean arterial
      pressure than those with NP. The frequency of sympathetic neural discharge was
      greater in the hypertensive disorders of pregnancy compared with NP; however, it
      was not increased in PE compared with PIH as might be expected. CONCLUSIONS:
      Based on the study results, PE is not associated with greater sympathetic
      hyperactivity than PIH, suggesting that any renal impairment in PE involves
      mechanisms that are not solely dependent on sympathetic hyperactivity.

PMID- 12620698
TI  - Differences in circadian blood pressure variability during gestation between
      healthy and complicated pregnancies.
AB  - BACKGROUND: Changes in circadian variation of blood pressure (BP) could be used
      either to predict preeclampsia or to assess its severity. We examined and
      compared characteristics of circadian variability in BP in women with both
      healthy and complicated pregnancies who were systematically monitored throughout
      gestation. METHODS: We analyzed 2430 BP series sampled by ambulatory monitoring
      for 48 h once every 4 weeks from the first obstetric visit until delivery in 235
      women with uncomplicated pregnancies, 128 with gestational hypertension, and 40
      with preeclampsia. The circadian pattern of BP variation for each group and
      trimester of gestation was established by population multiple-components
      analysis. RESULTS: The differences in 24-h mean and amplitude between healthy and
      complicated pregnancies were highly significant in all trimesters (P < 0.001).
      Results further indicated similar circadian characteristics between gestational
      hypertension and preeclampsia in the first trimester of pregnancy. The difference
      between these two groups in 24-h mean was statistically significant for systolic
      (P =.002) and diastolic BP (P =.038) in the second trimester and, to a larger
      extent, in the third trimester (P < 0.001). CONCLUSIONS: The differences in BP
      between healthy and complicated pregnancies that can be observed as early as in
      the first trimester of pregnancy are found when both systolic and diastolic BP
      for women with a later diagnosis of gestational hypertension or preeclampsia are
      well within the accepted range of normotension. These differences offer new end
      points that may lead to an early identification of hypertensive complications in
      pregnancy as well as to the establishment of prophylactic intervention.

PMID- 12620699
TI  - Impact of abnormal nocturnal blood pressure fall on vascular function.
AB  - BACKGROUND: It is well known that nondipping pattern of arterial hypertension has
      a harmful effect on target organs such as the brain, heart, and kidneys. However,
      it remains uncertain whether abnormal dipping patterns of nocturnal blood
      pressure (BP), such as extreme and reverse dipping, influence vascular function.
      METHODS: This study comprised consecutive 2800 individuals (1554 men and 1246
      women). All were nondiabetic and had uncomplicated, untreated essential sustained
      hypertension based on office measurements. After a 2-week wash-out period, 24-h
      ambulatory BP recordings were obtained and patients were classified by their
      nocturnal systolic BP fall (132 extreme dippers with >20% nocturnal systolic BP
      fall; 1235 dippers with >10% but <20% fall; 1146 nondippers with >0% but <10%
      fall; and 287 reverse dippers with <0% fall). Microalbumin, ACR
      (albumin/creatinine ratio), and microglobulin values were measured in all groups.
      RESULTS: Extreme dippers did not differ from dippers with regard to microalbumin,
      microglobulin excretion, or ACR. On the contrary, reverse dippers had
      significantly (P <.0001) higher values, compared with nondippers, for
      microalbumin (49.5 v 37.2 mg/dL), microglobulin (10.33 v 8.71 mg/dL), ACR (104.9
      v 65.2), and percentages of abnormal values for these parameters. CONCLUSIONS:
      Microalbuminuria, an index of vascular function, differentiates reverse dippers
      from nondippers, but not extreme dippers from dippers among hypertensive
      patients.

PMID- 12620700
TI  - Differential regulation of osteopontin expression in the clipped and nonclipped
      kidney of two-kidney, one-clip hypertensive rats.
AB  - BACKGROUND: Osteopontin (Opn) is highly upregulated in many different animal
      models of renal disease, where it is suspected to participate in progression of
      the disease. In some models, angiotensin II (Ang II) seems to induce the elevated
      Opn production. Therefore, we examined the regulation of Opn in two-kidney, one
      clip (2K1C) hypertensive rats, in which Ang II mediates the elevated blood
      pressure. METHODS: At days 7, 14, and 28, the clipped and nonclipped kidneys of
      hypertensive or sham-operated rats were analyzed for osteopontin protein, mRNA
      expression and mononuclear cell infiltration by imumunohistochemistry, in situ
      hybridization, and Northern blot analysis. Rats were treated with the Ang II type
      1 receptor antagonist Valsartan starting 14 days after clipping. RESULTS: In sham
      operated rats, Opn was mainly localized to cells of the thin ascending limbs of
      the outer medulla. No significant Opn staining was observed in cortical tubules.
      Focally defined tubular cortical Opn staining was observed in clipped and
      contralateral kidneys of hypertensive animals at days 14 and 28. Osteopontin
      protein expression correlated with the mRNA expression detected by in situ
      hybridization and Northern blot. Treatment with Valsartan reduced osteopontin
      staining by 51%, mRNA by 47%, and mononuclear cell number by 97% in nonclipped
      kidneys compared to untreated two-kidney, one-clip animals. In clipped kidneys,
      however, Opn protein and mRNA expression was not reduced, but a 240% increase in
      interstitial mononuclear cell number was observed. CONCLUSIONS: Osteopontin is
      involved in the induction of nephrosclerosis in renovascular hypertension,
      probably by a mechanism augmenting monocyte infiltration. Angiotensin II appears
      to be an important inducer of Opn in the nonclipped kidney. Ischemic conditions
      may regulate Opn expression in the clipped kidney.

PMID- 12620701
TI  - Role of endothelin-1 induced by insulin in the regulation of vascular cell
      growth.
AB  - Insulin is not only a growth factor for vascular cells, but also an inducer of
      other vasoactive substances such as endothelin-1 (ET-1) in vascular cells. The
      aim of the present study was to assess the role of endothelial cells (EC) in
      insulin mediated vascular smooth muscle cell (VSMC) proliferation. Cultured human
      aortic EC and VSMC were separately incubated. EC were stimulated with insulin (0
      to 1000 microU/mL) for 24 h, in the presence or absence of anti-insulin-growth
      factor-1 (anti-IGF-1) receptor antibody (alphaIR(3)) or a nonselective ET-1
      receptor antagonist (TAK044). Cell proliferation was measured by determining (3)H
      thymidine uptake. Although 10 microU/mL insulin did not affect ET-1 production in
      the EC culture medium, a higher concentration of insulin stimulated it.
      Production of ET-1 in EC was activated by insulin via the IGF-1 receptor,
      inasmuch as alphaIR(3) blocked insulin mediated upregulation of ET-1. There was
      no significant difference in (3)H-thymidine incorporation in the presence of
      insulin (up to 1000 microU/mL) or TAK044. Culture medium from EC stimulated with
      insulin enhanced VSMC proliferation, which was almost totally suppressed by
      TAK044. Insulin induced VSMC growth dose dependently when VSMC were cultured
      alone. In contrast, insulin at concentrations of 100 microU/mL or lower failed to
      stimulate growth of co-cultured VSMC, but only at 330 microU/mL or higher
      concentrations stimulated VSMC growth in this system. Of interest, VSMC
      proliferation was greatest when L-NAME was added and co-cultured with EC. In
      summary, a severely hyperinsulinemic state may regulate VSMC and EC proliferation
      via activation of vasoactive substances such as ET-1 and nitric oxide induced by
      insulin.

PMID- 12620702
TI  - Spurious systolic hypertension of youth: fit young men with elastic arteries.
AB  - BACKGROUND: We examined the role of high pulse pressure (PP) amplification in
      spurious systolic hypertension (SSH). METHODS: We recorded demographic
      characteristics, brachial blood pressure (BP) (Omron Model HEM-705 CP, Vernon
      Hills, IL), aortic BP, and arterial wave reflection (Sphygmocor, AtCor Medical,
      version 6.2, NSW, Australia) and PP amplification in 174 healthy medical students
      (87 male) and 22 young male hypertensive subjects. RESULTS: Eleven subjects had
      SSH (147 +/-2 v control 114 +/-1 mm Hg, mean +/- SEM,), normal aortic and
      brachial diastolic BP with an aortic pressure waveform that was normal in contour
      and amplitude. All were male, tall, nonsmokers, and active in sports, with slower
      heart rate, reduced arterial wave reflection (-8 +/- 3 v -0.7 +/-1) and enhanced
      PP amplification (31 +/-1 v 18 +/-1 mm Hg, P <.01. In contrast, male hypertensive
      subjects had reduced amplification (14 +/-0.9 mm Hg) and enhanced arterial wave
      reflection (17 +/-1.9). CONCLUSIONS: The SSH of youth, with raised brachial but
      normal aortic systolic BP, is commonly seen in tall men who are active in sports
      and are nonsmokers. It may be explained by the exaggerated first systolic peak in
      the brachial artery pressure waveform, which is due to very high PP amplification
      and low arterial wave reflection due to elastic arteries.

PMID- 12620703
TI  - Relationship between bone mineral density and angiotensin converting enzyme
      polymorphism in hypertensive postmenopausal women.
AB  - BACKGROUND: The purpose of this study was to assess the relationship between bone
      mineral density and insertion/deletion (I/D) angiotensin converting enzyme
      polymorphism (ACE) in hypertensive postmenopausal women. METHODS: Blood and urine
      samples from the study subjects were analyzed for calcium metabolism related
      parameters. Densitometry studies were conducted in the lumbar spine (L2 to L4).
      The ACE polymorphism was analyzed by polymerase chain reaction. RESULTS: Women
      with II genotype showed a higher intact parathyroid hormone (76 +/- 33 v 55 +/-
      27 pg/mL and 52 +/- 26 pg/mL, P =.034) without a decrease in calciuria, and
      higher bone mineral density than women with ID and homozygotus deletion genotype
      (1.138 +/- 0.08 v 1.051 +/- 0.16 pg/mL and 1.053 +/- 0.16 pg/mL). CONCLUSIONS:
      The ACE polymorphism could be one of the factors causing bone mass variations.

PMID- 12620704
TI  - Diastolic blood pressure is the first to rise in association with early
      subclinical obstructive sleep apnea: lessons from periodic examination screening.
AB  - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with long-term
      cardiovascular morbidity. Little is known about these relations at early stages.
      We conducted a case-control study in which we analyzed the clinical
      characteristics of young adults who underwent a periodic health examination and
      were screened for, and eventually found to experience, OSAS. METHODS: We
      identified 121 subjects newly diagnosed in a sleep study as having OSAS, and 229
      matched control subjects in which screening for OSAS was negative. All had a
      medical interview, physical examination, and routine laboratory tests. RESULTS:
      Subjects who had OSAS had a higher, body mass index (3-kg/m(2) difference) and a
      higher diastolic blood pressure (4-mm Hg difference) value, without elevation in
      systolic blood pressure. There was no metabolic difference (lipids profile and
      fasting glucose levels) between groups. CONCLUSIONS: Diastolic blood pressure is
      higher early in the course of OSAS. Long term follow-up may determine effects of
      prevention and early intervention in OSAS and associated hypertension.

PMID- 12620705
TI  - Correlates of myocardial oxygen demand measured by positron emission tomography
      in the hypertrophied left ventricle.
AB  - BACKGROUND: The aim of this study was to identify the best correlate of
      myocardial oxygen demand (MVO(2)) in patients with hypertension induced left
      ventricular hypertrophy (LVH), and to examine whether relationships between these
      surrogates and MVO(2) differed between patients with LVH and control subjects.
      METHODS: We measured MVO(2) by positron emission tomography using carbon-11
      acetate in 20 patients and 10 normotensive control subjects, and compared the
      relationships between commonly used surrogates and MVO(2). RESULTS: With the
      exception of diastolic blood pressure, the same variables correlated with resting
      MVO(2) in the patients and control subjects. CONCLUSIONS: The best correlate of
      resting MVO(2) in the patients with hypertension induced LVH was the stress-mass
      heart rate product.

PMID- 12620706
TI  - Nitric oxide is a determinant of membrane fluidity of erythrocytes in
      postmenopausal women: an electron paramagnetic resonance investigation.
AB  - In the present study, to determine a possible role of nitric oxide (NO) in the
      regulation of membrane functions, we examined the relationship between plasma NO
      level and membrane fluidity of erythrocytes in postmenopausal women. We evaluated
      the membrane fluidity of erythrocytes obtained from hypertensive and normotensive
      postmenopausal women by means of an electron paramagnetic resonance (EPR) and
      spin labeling method. The EPR study revealed that the order parameter (S) for 5
      nitroxide stearate in erythrocyte membranes was significantly greater in
      hypertensive postmenopausal women than in normotensive postmenopausal women. The
      finding indicated that the membrane fluidity of erythrocytes was decreased in
      hypertensive postmenopausal women compared with normotensive postmenopausal
      women. The plasma level of the NO metabolites (nitrite and nitrate) while fasting
      was significantly lower in hypertensive postmenopausal women than in normotensive
      postmenopausal women. In addition, the order parameter (S) in the EPR spectra of
      erythrocyte membranes was inversely correlated with the plasma NO metabolite
      level, which indicated that the lower membrane fluidity of erythrocytes was
      associated with the lower plasma NO level in postmenopausal women. These results
      are consistent with the hypothesis that NO may have a crucial role in the
      regulation of membrane fluidity of erythrocytes in postmenopausal women.

PMID- 12620707
TI  - Factors influencing arterial stiffness in systolic hypertension in the elderly:
      role of sodium and the renin-angiotensin system.
AB  - The mechanism(s) of systolic hypertension in the elderly imply structural and
      functional alterations of the large artery wall. Clinical and experimental
      studies have shown that, in the long term, the renin-angiotensin system may act
      on the geometry and stiffness of the large artery wall independently of blood
      pressure level through alterations of the extracellular matrix of vascular smooth
      muscle cells. In humans, gene polymorphisms related to angiotensin type I
      receptors, sodium, or alterations of endothelial function may modulate the age
      related increase in pulse pressure and aortic rigidity, the two main predictors
      of cardiovascular risk in the elderly. Based on this approach to the renin
      angiotensin system, it is suggested that antihypertensive drugs may be developed
      that attenuate the increase of aortic rigidity with age, acting on the hormonal
      environment as well as the secretory properties of vascular smooth muscle cells.

PMID- 12620708
TI  - Membrane fluidity and hypertension.

PMID- 12620709
TI  - Pseudo hypertension of youth: too much of a good thing?

PMID- 12620710
TI  - Reduced corticomotor excitability with cyclic passive movement: a study using
      transcranial magnetic stimulation.
AB  - Human voluntary movement involves the integration of kinaesthetic information
      with efferent motor activity during the planning and execution stages of
      movement. While much is known of the inhibitory and excitatory effects resulting
      from activation of specific kinaesthetic sensory receptors, in the present study
      we employed cyclic passive movement of the index finger in order to activate a
      range of kinaesthetic receptors in a manner that was intended to correspond to
      how these receptors might be active during a comparable voluntary movement. We
      intended to identify how this passive movement protocol might affect the
      excitability of the corticomotor pathway. During 1 Hz cyclic passive movement of
      the index finger there was an approximately 60% reduction in the amplitude of the
      motor evoked response from the first dorsal interosseous muscle. The results of
      the present study demonstrate that passive movement can have a profound effect on
      the excitability of the corticomotor pathway.

PMID- 12620711
TI  - Effects of nonconscious perception on motor response.
AB  - The present study reviews the literature on the empirical evidence for the
      dissociation between perception and action. We first review several key studies
      on brain-damaged patients, such as those suffering from blindsight and
      visual/tactile agnosia, and on experimental findings examining pointing movements
      in normal people in response to a nonconsciously perceived stimulus. We then
      describe three experiments we conducted using simple reaction time (RT) tasks
      with backward masking, in which the first (weak) and second (strong) electric
      stimuli were consecutively presented with a 40-ms interstimulus interval (ISI).
      First, we compared simple RTs for three stimulus conditions: weak alone, strong
      alone, and double, i.e., weak plus strong (Experiment 1); then, we manipulated
      the intensity of the first stimulus from the threshold (T) to 1.2T and 2T, with
      the second stimulus at 4T (Experiment 2); finally, we tested three different ISIs
      (20, 40, and 60 ms) with the stimulus intensities at 1.2T and 4T for the first
      and second stimuli (Experiment 3). These experiments showed that simple RTs were
      shorter for the double condition than for the strong-alone condition, indicating
      that motor processes under the double condition may be triggered by sensory
      inputs arising from the first stimulus. Our results also showed that the first
      stimulus was perceived without conscious awareness. These findings suggested that
      motor processes may be dissociated from conscious perceptual processes and that
      these two processes may not take place in a series but, rather, in parallel. We
      discussed the likely mechanisms underlying nonconscious perception and motor
      response to a nonconsciously perceived stimulus.

PMID- 12620712
TI  - Lateralized effects of target location on reaction times when preparing for
      manual aiming at a visual target.
AB  - To elucidate the temporal characteristics of information processing for motor
      action differing in complexity in relation to both perceptual and cognitive
      information processing, we investigated whether the reaction times (RTs) to a
      visual target would be affected by task complexity (finger lifting or manual
      aiming), pre-cueing (with a pre-cue or without a pre-cue), or target location
      (five horizontal positions). Using the right hand, seven right-handed subjects
      performed two tasks, finger lifting and manual aiming at a target, with or
      without a pre-cue. The pre-cue announced the location of the target to be
      presented. An ANOVA showed significant interactions between task and location and
      between pre-cue and location with no significant interaction between task and pre
      cue, indicating that the task-location interaction does not depend on whether or
      not a pre-cue is given. The manual-aiming RTs were longer than the finger-lifting
      RTs, and the effects of the target location on the RTs differed for finger
      lifting and manual aiming. It can be assumed that the longer RTs of manual aiming
      reflect the time for information processing that is needed when preparing for the
      aiming action per se, which is an extra movement performed in addition to the
      simple initiation of finger lifting. Differential RTs (DRTs) calculated by
      subtracting the finger-lifting RTs from the aiming RTs were therefore examined.
      The DRTs significantly differed for target locations (i.e., a lateralized
      effect), with the DRTs for an ipsilateral target appearing to be significantly
      shorter than those for contralateral and central targets. The lateralized effect
      appearing on the DRTs may be mediated by the processing of visual-spatial
      information about visual targets as motor preparations are made for manual
      aiming.

PMID- 12620713
TI  - Differences in postural control and movement performance during goal directed
      reaching in children with developmental coordination disorder.
AB  - Poor upper-limb coordination is a common difficulty for children with
      developmental coordination disorder (DCD). One hypothesis is that deviant muscle
      timing in proximal muscle groups results in poor postural and movement control.
      The relationship between muscle timing, arm motion and children's upper-limb
      coordination deficits has not previously been studied. The aim of this study was
      to investigate the relationship between functional difficulties with upper-limb
      motor skills and neuromuscular components of postural stability and coordination.
      Sixty-four children aged 8-10 years, 32 with DCD and 32 without DCD, participated
      in the study. The study investigated timing of muscle activity and resultant arm
      movement during a rapid, voluntary, goal-directed arm movement. Results showed
      that compared to children without DCD, children with DCD took significantly
      longer to respond to visual signals and longer to complete the goal-directed
      movement. Children with DCD also demonstrated altered activity in postural
      muscles. In particular, shoulder muscles, except for serratus anterior, and
      posterior trunk muscles demonstrated early activation. Further, anterior trunk
      muscles demonstrated delayed activation. In children with DCD, anticipatory
      function was not present in three of the four anterior trunk muscles. These
      differences support the hypothesis that in children with DCD, altered postural
      muscle activity may contribute to poor proximal stability and consequently poor
      arm movement control when performing goal-directed movement. These results have
      educational and functional implications for children at school and during
      activities of daily living and leisure activities and for clinicians assessing
      and treating children with DCD.

PMID- 12620714
TI  - Visuoperceptual and visuomotor deficits in developmental stutterers: an
      exploratory study.
AB  - Although the cause of stuttering is unknown, there is strong evidence for it
      being a neuromotor disorder characterised by an abnormality of higher control
      encompassing not only speech but other motor systems. The aim of this exploratory
      study was to look for the presence of non-speech/language deficits--in
      particular, visuomotor and visuoperceptual deficits--in persons who stutter.
      Twelve moderate to severe developmental stutterers were compared with a group of
      fluent speakers, matched for age and sex, on a range of computerized sensory
      motor tasks. These tasks covered various aspects of visuomotor function-
      ballistic movement, dynamic steadiness, and several types of tracking--and
      visuoperceptual function--acuity, static perception, and dynamic perception. A
      novel technique was used to remove the visuospatial component from tracking
      performance. Stutterers had slower reaction times, less accurate random tracking,
      and impaired dynamic visual perception. Severity of stuttering correlated with
      reaction time and dynamic perception. Removal of the visuoperceptual component
      from tracking performance indicated that the impaired tracking in the stutterers
      was predominantly due to reduced dynamic perception. This is the first study to
      provide preliminary evidence for the presence of non-linguistic visuoperceptual
      and upper-limb visuomotor tracking deficits in people with moderate to severe
      stuttering. These findings support a neurogenic aetiology for stuttering and are
      compatible with evidence of an overactive dopamine system in stutterers.

PMID- 12620715
TI  - Limb and gender differences in the development of coordination in early infancy.
AB  - Young infants produce a variety of spontaneous arm and leg movements in the first
      few months of life. Coordination of leg joints has been extensively investigated,
      whereas arm joint coordination has mainly been investigated in the sitting
      position in the context of early reaching and grasping. The current study
      investigated arm and leg joint coordination of movements produced in the supine
      position in 10 fullterm infants aged 6, 12 and 18 weeks. Longitudinal comparisons
      within limbs (intralimb) as well as between limbs (interlimb, ipsilateral and
      contralateral) were made as well as an exploration of differences in the
      development for boys and girls. The relationship between the joint angles was
      examined by measuring pair-wise cross-correlation functions for the angular
      displacement curves of the leg (hip, knee and ankle) and arm (shoulder, elbow and
      wrist) joints of both the right and left side. Both the arms and legs were found
      to follow a similar pattern of intralimb coordination, although the leg joints
      were more tightly coupled than the arm joints, particularly the proximal with the
      middle joint. In support of earlier findings, differences in the development of
      the right and left side were identified. In addition, gender differences in joint
      coordination were found for both intralimb and interlimb coordination. This
      contrasts with the view that gender differences in motor development may be
      primarily a result of environmental influences.

PMID- 12620716
TI  - Intentional and attentional dynamics of speech-hand coordination.
AB  - Interest is rapidly growing in the hypothesis that natural language emerged from
      a more primitive set of linguistic acts based primarily on manual activity and
      hand gestures. Increasingly, researchers are investigating how hemispheric
      asymmetries are related to attentional and manual asymmetries (i.e., handedness).
      Both speech perception and production have origins in the dynamical generative
      movements of the vocal tract known as articulatory gestures. Thus, the notion of
      a "gesture" can be extended to both hand movements and speech articulation. The
      generative actions of the hands and vocal tract can therefore provide a basis for
      the (direct) perception of linguistic acts. Such gestures are best described
      using the methods of dynamical systems analysis since both perception and
      production can be described using the same commensurate language. Experiments
      were conducted using a phase transition paradigm to examine the coordination of
      speech-hand gestures in both left- and right-handed individuals. Results address
      coordination (in-phase vs. anti-phase), hand (left vs. right), lateralization
      (left vs. right hemisphere), focus of attention (speech vs. tapping), and how
      dynamical constraints provide a foundation for human communicative acts.
      Predictions from the asymmetric HKB equation confirm the attentional basis of
      functional asymmetry. Of significance is a new understanding of the role of
      perceived synchrony (p-centres) during intentional cases of gestural
      coordination.

PMID- 12620717
TI  - The acquisition of bimanual coordination is mediated by anisotropic coupling
      between the hands.
AB  - The present study was designed to test two predictions from the coupled
      oscillator model of multifrequency coordination. First, it was predicted that
      multifrequency tasks that match the inherent manual asymmetry (i.e., the
      preferred hand assigned to the faster tempo) would be easier to learn than tasks
      that do not match the inherent dynamics (i.e., the non-preferred hand assigned to
      the faster tempo). Second, in the latter case acquisition of the multifrequency
      coordination would involve a reorganisation of the coupling dynamics such that
      the faster hand would exert a greater influence on the slower hand than vice
      versa. Sixteen right-handed volunteers received extensive training on a 2:1
      coordination pattern involving a bimanual forearm pronation-supination task.
      Participants were randomly assigned to one of two groups: 1L:2R in which the
      preferred right hand performed the higher frequency, or 2L:1R in which the non
      preferred left hand performed the higher frequency. The dynamic stability of the
      patterns was assessed by the ability of participants to maintain the coordination
      pattern as movement frequency was increased. Changes in the directional coupling
      between the hands was assessed by transition pathways and lead-lag relationship
      evident in a 1:1 anti-phase frequency-scaled coordination task performed prior to
      and following three practice sessions of the 2:1 task. The predicted differential
      stability between the multifrequency patterns was evident in the initial
      acquisition sessions but by the end of training the two patterns evidenced
      equivalent stability. Unexpectedly, for both groups the fast hand displayed
      greater variability in amplitude and movement frequency than the slow hand
      perhaps reflecting anchoring afforded to the slow hand by synchronising movement
      endpoints with the auditory pacing metronome. Analysis of pre- to post-training
      changes to the coupling dynamics in the 1:1 anti-phase task support the
      hypothesis that acquisition of the 2L:1R pattern involved reorganisation of the
      inherent dynamics.

PMID- 12620718
TI  - Anisotropic tracking: evidence for automatic synergy formation in a bimanual
      task.
AB  - Investigation of interlimb synergy has become synonymous with the study of
      coordination dynamics and is largely confined to periodic movement. Based on a
      computational approach this paper demonstrates a method of investigating the
      formation of a novel synergy in the context of stochastic, spatially asymmetric
      movements. Nine right-handed participants performed a two degrees of freedom (2D)
      "etch-a-sketch" tracking task where the right hand controlled the horizontal
      position of the response cursor on the display while the left hand controlled the
      vertical position. In a pre-practice 2D tracking task, measures of phase lag
      between the irregularly moving target and the response showed that participants
      controlled left and right hands independently, performance of the right hand
      being slightly superior to the left. Participants then undertook 4 h 16 min
      distributed practice of a one degree of freedom etch-a-sketch task where the
      target was constrained to move irregularly in only the 45 degrees direction on
      the display. To track such a target accurately participants had to make in-phase
      coupled stochastic movements of the hands. In a post-practice 2D task, measures
      of phase lag showed anisotropic improvement in performance, the amount of
      improvement depending on the direction of motion on the display. Improvement was
      greatest in the practised 45 degrees and least in the orthogonal 135 degrees
      direction. Best and worst performances were no longer in the directions
      associated with right and left hands independently, but in directions requiring
      coupled movements of the two hands. These data support the proposal that the
      nervous system can establish a model of novel coupling between the hands and
      thereby form a task-dependent bimanual synergy for controlling the stochastic
      coupled movements as an entity.

PMID- 12620719
TI  - Stability and skill in driving.
AB  - Two experiments addressed the relation between postural stability, perceptual
      sensitivity, and stability of driving performance. A vehicle was fitted with
      differential GPS for measuring position and speed, position sensors for measuring
      brake and accelerator depression, force transducers for measuring door, console
      and footrest bracing forces, and an accelerometer for measuring the 3D
      accelerations of the vehicle. In Experiment 1, we investigated whether the
      initiation of deceleration and the control of braking might be due to sensitivity
      to the perceptual variable tau, which specifies time-to-contact (TTC), and in
      particular, whether its first derivative, tau-dot, is used to maintain a constant
      deceleration profile. Using both untrained experienced drivers (EDs) and trained
      driving instructors from the Holden Performance Driving Centre (HPDC), results
      confirmed that, regardless of skill level, tau-dot was maintained at a value
      close to 0.5 and, as predicted by Lee [Perception 5 (1976) 437], braking was
      initiated when TTC approximately 5 s. In Experiment 2, we wished to quantify the
      purported differences in driving behaviour between EDs and HPDC instructors
      during a variety of everyday manoeuvres. Results indicated that instructors
      utilised a different cornering trajectory, a different emergency braking
      strategy, and were able to perform a high-speed swerve and recovery task more
      effectively than the EDs. In general, the instructors applied greater bracing
      forces using the door and console compared with EDs. The instructors also applied
      greater footrest forces during emergency braking than did the EDs. The greater
      use of bracing by instructor drivers to resist g-forces represents a strategy of
      active stabilisation that enhances both postural stability, as well as overall
      stability and consistency of driving performance. Results are discussed with
      regard to the dynamics of perceptual-motor coordination, and how increased
      stability might improve sensitivity to relevant perceptual information. We
      conclude that driver-training programmes that focus on increasing driver
      stability (as a pre-requisite for increased control) show great promise as a
      means to improving one's attention during driving, and hence have the potential
      to dramatically improve road safety in general.

PMID- 12620720
TI  - Are transitions in human gait determined by mechanical, kinetic or energetic
      factors?
AB  - It is currently unclear whether it is the need to maintain metabolic efficiency,
      the need to keep skeletal loading below critical force levels, or simple
      mechanical factors that drive the walk-to-run (W-R) and run-to-walk (R-W)
      transitions in human gait. Eighteen adults (9 males and 9 females) locomoted on
      an instrumented treadmill using their preferred gait. Each completed 2 ascending
      (W-R) and 2 descending (R-W) series of trials under three levels of loading (0%,
      15% and 30% body weight). For each trial, participants locomoted for 60 s at each
      of 9 different speeds--4 speeds both above and below their preferred transition
      speed (PTS) plus their PTS. Evidence was sought for critical levels of key
      kinetic (maximum vertical force, impulse, first peak force, time to first peak
      force and maximum loading rate), energetic (oxygen consumption, transport cost)
      and mechanical variables (limb lengths, strength) predictive of the gait
      transition. Analyses suggested the kinetic variables of time to first peak force
      and loading rate as the most likely determinants of the W-R and R-W transitions.

PMID- 12620721
TI  - Practice effects on coordination and control, metabolic energy expenditure, and
      muscle activation.
AB  - One defining characteristic of skilled motor performance is the ability to
      complete the task with minimum energy expenditure. This experiment was designed
      to examine practice effects on coordination and control, metabolic energy
      expenditure, and muscle activation. Participants rowed an ergometer at 100 W for
      ten 16-min sessions. Oxygen consumption and perceived exertion (central and
      peripheral) declined significantly with practice and movement economy improved
      (reliably) by 9%. There was an associated but non-significant reduction in heart
      rate. Stroke rate decreased significantly. Peak forces applied to the ergometer
      handle were significantly less variable following practice and increased
      stability of the post-practice movement pattern was also revealed in more tightly
      clustered plots of hip velocity against horizontal displacement. Over practice
      trials muscle activation decreased, as revealed in integrated EMG data from the
      vastus lateralis and biceps brachii, and coherence analysis revealed the muscle
      activation patterns became more tightly coordinated. The results showed that
      practice reduced the metabolic energy cost of performance and practice-related
      refinements to coordination and control were also associated with significant
      reductions in muscle activation.

PMID- 12620722
TI  - Freezing degrees of freedom under stress: kinematic evidence of constrained
      movement strategies.
AB  - The present study investigated the effect of psychological stress imposed on
      movement kinematics in a computer-simulated batting task involving a backward and
      forward swing of the forearm. The psychological stress was imposed by a mild
      electric stimulus following poor performance. Fourteen participants hit a moving
      ball with a horizontal lever and aimed at a distant target with as much accuracy
      as possible. The kinematic characteristics appearing under stress were delay of
      movement initiation, small amplitude of movement and low variability of spatial
      kinematic events between trials. These features were also found in previous
      studies in which the experimental task required high accuracy. The characteristic
      kinematics evident in the present study suggested that the movement strategies
      adopted by the stressed participants were similar to those that appear under high
      accuracy demand. Moreover, a correlation analysis between the onset times of
      kinematic events revealed that temporally consistent movements were reproduced
      under stress. Taken together, the present findings demonstrated that, under
      psychological stress, movement strategies tend to shift toward the production of
      more constrained trajectories, as is seen under conditions of high accuracy
      demand, even though the difficulty of the task itself does not change.

PMID- 12620723
TI  - Evidence for internal representation of a static nonlinearity in a visual
      tracking task.
AB  - A group of 24 participants was given over 3 h practice at a visual pursuit
      tracking task with a pronounced static nonlinearity between movement of the
      joystick and the resulting deflection of the response cursor. The aim was
      twofold: (1) to determine whether or not participants compensated for the
      nonlinearity and (2) to show that any such compensation involved the formation of
      an internal representation of the nonlinear relationship between movement of the
      joystick as sensed kinaesthetically and/or visually and movement of the response
      cursor as sensed visually. Results show that participants introduce partial
      compensation for the static nonlinearity. Furthermore, partial compensation was
      present even during open-loop tracking when participants were deprived of visual
      feedback of the position of the response cursor. This implies that participants
      are able to form an internal representation of the nonlinear relationship between
      movement of the joystick and the resulting movement of the response cursor.

PMID- 12620724
TI  - A simulation study of the degrees of freedom of movement in reaching and
      grasping.
AB  - The question of independently controlled components in the act of reaching and
      grasping has attracted interest experimentally and theoretically. Data from 35
      studies were recently found consistent with simulated kinematic finger and thumb
      trajectories optimised for minimum jerk. The present study closely reproduces
      those trajectories using a discrete-time model based on minimum acceleration.
      That model was further used to generate two-dimensional trajectories for finger
      and thumb to reach and grasp an elliptical object with varying position and/or
      orientation. Orthogonalisation of these four trajectories revealed one degree of
      freedom when direction of reach was constant and two degrees of freedom when
      direction of reach varied, irrespective of object distance and orientation. These
      simulations indicate that reach and grasp movements contain redundancy that is
      removable by formation of task-dependent synergies. As skilled movement can be
      planned and executed in a low dimension workspace, control of these independent
      components lessens central workload.

PMID- 12620725
TI  - Developmental coordination disorder: associated problems in attention, learning,
      and psychosocial adjustment.
AB  - This study investigated the problems of attention, learning and psychosocial
      adjustment evidenced by children with developmental coordination disorder (DCD).
      Forty-five children identified with DCD, 51 children identified as being suspect
      for DCD and 78 comparison children without motor problems on standardized tests
      of motor function participated in this study. Results revealed that both children
      with DCD and children suspect for DCD obtained significantly poorer scores on
      measures of attention and learning (reading, writing and spelling) than
      comparison children. Children with DCD and those suspect for DCD were also found
      to evidence a relatively high level of social problems and display a relatively
      high level of somatic complaints based on parent report. These findings indicate
      that all children with movement problems are at risk for problems in attention,
      learning and psychosocial adjustment. Assessment of children with movement
      problems, regardless of the degree or severity of these problems should examine a
      wide range of functions in addition to motor functioning. Such an approach, would
      assist in determining the types of intervention that would provide the most
      benefit to these children.

PMID- 12620726
TI  - Timing and force control in boys with attention deficit hyperactivity disorder:
      subtype differences and the effect of comorbid developmental coordination
      disorder.
AB  - This study examined the motor and performance outcomes of boys with subtypes of
      attention deficit hyperactivity disorder (ADHD) (DSM-IV, [American Psychiatric
      Association, Diagnostic and statistical manual of mental disorders, 4th ed.,
      Washington, DC, 1994]). It also examined the differences between boys with a
      single diagnosis of ADHD versus those who have the dual categorisation of ADHD
      and developmental coordination disorder (DCD). The participants were 157 boys,
      aged 7.70-12.98 years recruited from a community sample. Parent report was used
      to classify 143 boys into either a comparison group or one of the three DSM-IV
      ADHD subtypes. Participants were given a battery of tests that included the
      Movement Assessment Battery for Children [Movement Assessment Battery for
      Children, Psychological Corporation/Harcourt Brace-Jovanovich, New York, 1992],
      the Wechsler Intelligence Scales for Children--Third Edition [Manual for the
      Wechsler Intelligence Scale for Children, Psychological Corporation, New York,
      1992] and a finger tapping task targeting motor processing, preparation, and
      execution. Boys with subtypes that included inattentive symptomatology had
      significant difficulties with timing, force output and showed greater variability
      in motor outcomes. Boys with the comorbid condition (i.e., ADHD and DCD) had
      particular difficulty with force control. These outcomes identify a need for
      increased recognition of the clinical and research implications of the
      relationship between ADHD and motor dysfunction. This potentially impacts on
      assessment, intervention, theoretical modelling and the general interpretation of
      cognitive abilities research with children with ADHD.

PMID- 12620728
TI  - Ageing effects on the attention demands of walking.
AB  - Attention demands of walking were determined in six male and six female young
      adults (mean 26.3 yr) and 12 gender-matched healthy, active older adults (mean
      71.1 yr) using a dual task procedure with a reaction time (RT) secondary task. In
      three conditions an auditory stimulus, a visual stimulus and both stimuli
      (auditory/visual) were presented. Relative to no-walking baselines, increased RT
      was found in all conditions revealing an attentional cost of normal walking. When
      participants traversed the laboratory walkway and also positioned one of their
      feet within a target area on the ground, attention demands were greater than in
      unconstrained walking. In the targeting task, RTs to the visual stimulus were
      longer than for the auditory stimulus due to the interference associated with
      viewing both the stimulus monitor and the foot-target. Older participants' RTs in
      the visual and auditory/visual conditions, but not in the auditory condition,
      were significantly longer than for the young group in both walking tasks but RTs
      for young and older adults were not different in no-walking baseline trials.
      Inspection of mean RT functions at time intervals following gait initiation (0
      3000 ms from the first step) suggested a fluctuating attentional cost of walking
      with increased demands associated with contingencies requiring step length
      regulation. The findings have applied significance in demonstrating the
      possibility of increased falls and pedestrian accident risk in older individuals
      in dual task situations such as road crossing.

PMID- 12620727
TI  - The effects of different instructions for preparatory muscle tension on simple
      reaction time.
AB  - The effects of preparatory weak muscular contraction (pre-tension) have been
      investigated in a number of previous studies using tasks with either simple or
      choice responses to measure the reaction time (RT). These studies suggested that
      optimal pre-tension performed prior to a motor response tends to shorten the RTs.
      Using a simple RT task in which participants performed a grip response to a
      visual stimulus, the present study compared the RTs between two pre-tension
      conditions (self-selection and constraint) to investigate the effects of
      different instructions for pre-tension. Under the self-selection condition,
      participants were asked to determine their optimal pre-tension levels while
      attempting to give responses as fast as possible. Under the constraint condition,
      the participants developed a pre-tension at a target force determined by the
      experimenter. The target force was set at the same level as the pre-tension level
      maintained under the self-selection. Despite the fact that the pre-tension level
      manipulated was the same for both conditions, the RTs were significantly shorter
      under self-selection than under constraint. Moreover, the present study showed a
      positive correlation coefficient between the proportion of shortening in RT and
      the variation of pre-tension level. This indicated a performance trade-off
      between the stability of pre-tension and RTs. The result suggests that shorter
      RTs that occur under self-selection are primarily mediated by mental factors,
      such as attention allocation, rather than by the effects of peripheral muscular
      preparation.

PMID- 12620730
TI  - Goodbye Dolly...leader and friends?

PMID- 12620731
TI  - Medical journals: evidence of bias against the diseases of poverty.

PMID- 12620732
TI  - MRI for neonatal encephalopathy in full-term infants.

PMID- 12620733
TI  - To treat or not to treat? Implementation of DOTS in Central Asia.

PMID- 12620734
TI  - Complementary strategies for efficient use of knowledge for better health.

PMID- 12620735
TI  - Effectiveness and costs of interventions to lower systolic blood pressure and
      cholesterol: a global and regional analysis on reduction of cardiovascular
      disease risk.
AB  - BACKGROUND: Cardiovascular disease accounts for much morbidity and mortality in
      developed countries and is becoming increasingly important in less developed
      regions. Systolic blood pressure above 115 mm Hg accounts for two-thirds of
      strokes and almost half of ischaemic heart disease cases, and cholesterol
      concentrations exceeding 3.8 mmol/L for 18% and 55%, respectively. We report
      estimates of the population health effects, and costs of selected interventions
      to reduce the risks associated with high cholesterol concentrations and blood
      pressure in areas of the world with differing epidemiological profiles. METHODS:
      Effect sizes were derived from systematic reviews or meta-analyses, and the
      effect on health outcomes projected over time for populations with differing age,
      sex, and epidemiological profiles. Incidence data from estimates of burden of
      disease were used in a four-state longitudinal population model to calculate
      disability-adjusted life years (DALYs) averted and patients treated. Costs were
      taken from previous publications, or estimated by local experts, in 14 regions.
      FINDINGS: Non-personal health interventions, including government action to
      stimulate a reduction in the salt content of processed foods, are cost-effective
      ways to limit cardiovascular disease and could avert over 21 million DALYs per
      year worldwide. Combination treatment for people whose risk of a cardiovascular
      event over the next 10 years is above 35% is also cost effective leading to
      substantial additional health benefits by averting an additional 63 million DALYs
      per year worldwide. INTERPRETATION: The combination of personal and non-personal
      health interventions evaluated here could lower the global incidence of
      cardiovascular events by as much as 50%.

PMID- 12620736
TI  - An objective case definition of lipodystrophy in HIV-infected adults: a case
      control study.
AB  - BACKGROUND: Lipodystrophy (peripheral lipoatrophy, central fat accumulation, and
      lipomatosis) is a common and disfiguring problem in adult patients with HIV-1
      infection on antiretrovirals. However, an objective, validated definition of the
      disorder does not exist. We aimed to develop an objective, sensitive, specific,
      and broadly applicable case definition of HIV lipodystrophy. METHODS: In a case
      control study, 1081 consecutive, HIV-infected, adult outpatients (261 [15%]
      women) without active AIDS were recruited from 32 sites worldwide. We classed
      patients with at least one moderate or severe subjective lipodystrophic feature,
      identified by lipodystrophy-specific physical examination and patient
      questionnaire, and apparent to both doctor and patient as cases (n=417). We
      classed patients with no such feature as controls (n=371), and patients without a
      clear diagnosis as non-assigned. We used objective clinical, metabolic, and body
      composition measurements to construct a logistic regression model with a subset
      of randomly selected cases and controls. The model was validated in the remaining
      patients. FINDINGS: A model including age, sex, duration of HIV infection, HIV
      disease stage, waist to hip ratio, anion gap, serum HDL cholesterol
      concentration, trunk to peripheral fat ratio, percentage leg fat, and intra
      abdominal to extra-abdominal fat ratio had 79% (95% CI 70-85) sensitivity and 80%
      (95% CI 71-87) specificity for diagnosis of lipodystrophy. Models that
      incorporated only clinical, or only clinical and metabolic variables had lower
      sensitivity and specificity than the inclusive model. Models for lipoatrophy, fat
      accumulation, and lipomatosis could not be developed since pure phenotypes
      occurred in fewer than 10% of patients with clinical diagnoses of these
      disorders. INTERPRETATION: Our objective case definition of HIV-associated
      lipodystrophy should improve assessment of lipodystrophy prevalence, risk
      factors, and pathogenesis; prevention and treatment approaches; and assist in
      diagnosis.

PMID- 12620737
TI  - Thrombocytopenia or giant platelets?

PMID- 12620738
TI  - Origin and timing of brain lesions in term infants with neonatal encephalopathy.
AB  - BACKGROUND: The role of intrapartum asphyxia in neonatal encephalopathy and
      seizures in term infants is not clear, and antenatal factors are being implicated
      in the causal pathway for these disorders. However, there is no evidence that
      brain damage occurs before birth. We aimed to test the hypothesis that neonatal
      encephalopathy, early neonatal seizures, or both result from early antenatal
      insults. METHODS: We used brain MRI or post-mortem examination in 351 fullterm
      infants with neonatal encephalopathy, early seizures, or both to distinguish
      between lesions acquired antenatally and those that developed in the intrapartum
      and early post-partum period. We excluded infants with major congenital
      malformations or obvious chromosomal disorders. Infants were divided into two
      groups: those with neonatal encephalopathy (with or without seizures), and
      evidence of perinatal asphyxia (group 1); and those without other evidence of
      encephalopathy, but who presented with seizures within 3 days of birth (group 2).
      FINDINGS: Brain images showed evidence of an acute insult without established
      injury or atrophy in 197 (80%) of infants in group 1, MRI showed evidence of
      established injury in only 2 infants (<1%), although tiny foci of established
      white matter gliosis, in addition to acute injury, were seen in three of 21 on
      post-mortem examination. In group 2, acute focal damage was noted in 62 (69%) of
      infants. Two (3%) also had evidence of antenatal injury. INTERPRETATION: Although
      our results cannot exclude the possibility that antenatal or genetic factors
      might predispose some infants to perinatal brain injury, our data strongly
      suggest that events in the immediate perinatal period are most important in
      neonatal brain injury.

PMID- 12620740
TI  - Aching joints and jaundice.

PMID- 12620739
TI  - Genome sequence of Vibrio parahaemolyticus: a pathogenic mechanism distinct from
      that of V cholerae.
AB  - BACKGROUND: Vibrio parahaemolyticus, a gram-negative marine bacterium, is a
      worldwide cause of food-borne gastroenteritis. V parahaemolyticus strains of a
      few specific serotypes, probably derived from a common clonal ancestor, have
      lately caused a pandemic of gastroenteritis. The organism is phylogenetically
      close to V cholerae, the causative agent of cholera. METHODS: The whole genome
      sequence of a clinical V parahaemolyticus strain RIMD2210633 was established by
      shotgun sequencing. The coding sequences were identified by use of Gambler and
      Glimmer programs. Comparative analysis with the V cholerae genome was undertaken
      with MUMmer. FINDINGS: The genome consisted of two circular chromosomes of
      3288558 bp and 1877212 bp; it contained 4832 genes. Comparison of the V
      parahaemolyticus genome with that of V cholerae showed many rearrangements within
      and between the two chromosomes. Genes for the type III secretion system (TTSS)
      were identified in the genome of V parahaemolyticus; V cholerae does not have
      these genes. INTERPRETATION: The TTSS is a central virulence factor of diarrhoea
      causing bacteria such as shigella, salmonella, and enteropathogenic Escherichia
      coli, which cause gastroenteritis by invading or intimately interacting with
      intestinal epithelial cells. Our results suggest that V parahaemolyticus and V
      cholerae use distinct mechanisms to establish infection. This finding explains
      clinical features of V parahaemolyticus infections, which commonly include
      inflammatory diarrhoea and in some cases systemic manifestations such as
      septicaemia, distinct from those of V cholerae infections, which are generally
      associated with non-inflammatory diarrhoea.

PMID- 12620741
TI  - Deaths from variant Creutzfeldt-Jakob disease in the UK.
AB  - In 2002, 17 people died from variant CJD (vCJD) in the UK, compared with 20 in
      2001 and 28 in 2000. We analysed data for deaths from vCJD since 1995 and
      estimated the underlying trend in mortality. The trend had a quadratic component
      (p=0.005), suggesting that the increase was not exponential, and that the
      previously increasing trend is slowing down. The death rate peaked in 2000. These
      findings are encouraging, but mortality might increase again in the future.

PMID- 12620742
TI  - Flow limitation in infants with bronchopulmonary dysplasia and respiratory
      function at school age.
AB  - Bronchopulmonary dysplasia is associated with abnormalities in lung function
      during infancy, yet many infants recover with no respiratory problems in the long
      term. We therefore did a longitudinal study of pulmonary function in 18 children
      with moderate to severe bronchopulmonary dysplasia. Forced expiratory volume in 1
      s (FEV1) and forced mid-expiratory flow (FEF25-75) at school age were lower than
      normal in 15 of 18 children, and both showed a significant positive correlation
      with the maximal flow at functional residual capacity (Vmax(FRC)) at 24 months of
      age (r=0.68 and 0.85, respectively). Our results suggest that assessment of
      respiratory function during infancy can help to identify children with
      bronchopulmonary dysplasia at risk of incomplete recovery of respiratory function
      during childhood.

PMID- 12620743
TI  - HIV vaccine fails in phase 3 trial.

PMID- 12620746
TI  - Infant mortality is falling in Russia, latest figures suggest.

PMID- 12620749
TI  - North Korea's stance unravels years of work by relief agencies.

PMID- 12620750
TI  - Supreme court sets showdown on affirmative action.

PMID- 12620751
TI  - Measles: not just another viral exanthem.
AB  - Measles is the most frequent cause of vaccine-preventable childhood deaths.
      Infants younger than the recommended age for vaccination are susceptible to the
      disease, and in developing countries they have a high risk of complications and
      mortality. Vaccine coverage in excess of 95% interrupts endemic transmission of
      measles in many countries, but achievement of such coverage almost always
      requires coordinated supplementary mass vaccination campaigns. There are
      substantial health gains if countries improve measles vaccine coverage,
      irrespective of whether or not high coverage is achieved; these gains include
      much lower measles complication and case fatality rates, long-term interepidemic
      duration, and possibly non-specific improvements in survival of children.
      Investigation into the cost-effectiveness of different strategies for measles
      control, including mass campaigns, two-dose schedules, and young-infant doses,
      would help countries to formulate control policies appropriate to their setting.
      Pneumonia is the most common fatal complication associated with measles, and at
      least 50% of measles-related pneumonias are due to bacterial superinfection. WHO
      has developed standard case management programmes for measles, but there are
      several unresolved clinical issues, including optimum indications for antibiotic
      treatment, the importance of intravenous immunoglobulin, the role of viral
      coinfection, and the risk of tuberculosis after measles. The priority in
      worldwide efforts to control measles is to lend support to poor countries,
      helping them to increase vaccine coverage and sustain improvements to vaccination
      infrastructure, and to address technical issues with respect to optimum
      vaccination schedules. Measles represents a specific challenge, whereby
      partnerships between high-income and developing nations would reduce child
      mortality in developing countries; such partnerships are not without incentive
      for high-income countries, since without them imported measles cannot be
      prevented.

PMID- 12620752
TI  - Polycystic kidney disease--the ciliary connection.
AB  - CONTEXT: "Cystic degeneration" of the kidneys was first described pathologically
      in 1841 and "polycystic kidneys" as a clinical syndrome in 1888. The heritable
      nature in some families was noted in 1899, and autosomal dominant and recessive
      patterns of inheritance of polycystic kidney disease (PKD) were later recognised.
      Autosomal dominant PKD is one of the most common human genetic diseases and
      results from mutations in PKD1 or PKD2. These genes encode two proteins,
      polycystin-1 and polycystin-2. STARTING POINT: Primary cilia are cellular
      organelles previously thought by some to be vestigial. New findings from several
      species, including algae, nematodes, and mice, implicate defects in structure or
      function of primary cilia as a possible common mechanism central to the
      development of some forms of recessive PKD. Two recent reports propose a causal
      link between ciliary dysfunction and autosomal dominant PKD. B Yoder and
      colleagues (J Am Soc Nephrol 2002; 13:2508-16) show that polycystin-1 and
      polycystin-2 are localised to primary cilia in cultured renal epithelial cells. S
      Nauli and colleagues (Nat Genet 2003; 33:129-37) show that polycystin-1 and
      polycystin-2 function as flow-sensitive mechanosensors in the same signal
      transduction pathway. WHERE NEXT? Cystic epithelial cells show many altered
      cellular properties, including changes in proliferation, apoptosis, adhesion,
      differentiation, polarity, extracellular matrix synthesis, and fluid transport.
      The next important steps in PKD research will be to define the physiological
      roles of primary renal cilia and how defects in ciliary structure and function
      lead to the development of a cystic phenotype in different forms of PKD.

PMID- 12620753
TI  - Apolipoproteins versus lipids as indices of coronary risk and as targets for
      statin treatment.

PMID- 12620754
TI  - Transparency at the International Agency for Research on Cancer (IARC).

PMID- 12620755
TI  - Transparency at the International Agency for Research on Cancer (IARC).

PMID- 12620756
TI  - Comments on the common cold.

PMID- 12620758
TI  - Comments on the common cold.

PMID- 12620759
TI  - Comments on the common cold.

PMID- 12620760
TI  - Basic ideas of medicine.

PMID- 12620763
TI  - Nestle in Ethiopia.

PMID- 12620761
TI  - More on ISAT.

PMID- 12620764
TI  - Shigella dysenteriae type 1 with reduced susceptibility to fluoroquinolones.

PMID- 12620765
TI  - Need for a true placebo for vaginal microbicide efficacy trials.

PMID- 12620766
TI  - Preparedness of London hospitals for a chemical weapons attack.

PMID- 12620767
TI  - Humanitarian effects of war on Iraq.

PMID- 12620768
TI  - Use of weapons of mass destruction.

PMID- 12620770
TI  - Pre-Medline evidence of stroke mortality trends.

PMID- 12620771
TI  - Relation between sulphur dioxide concentration and all-cause mortality.

PMID- 12620772
TI  - Use of mobile phones in hospital: time to lift the ban?

PMID- 12620774
TI  - Strangers in a strange land.

PMID- 12620777
TI  - A urinous tale.

PMID- 12620779
TI  - Assessment of trunk function in single and multi-level spinal stenosis: a
      prospective clinical trial.
AB  - OBJECTIVE: To clarify the biomechanical indicators of single- and multi-level
      stenosis and to determine the biomechanical outcome of selective conservative
      decompression. DESIGN: This study is a prospective clinical trial examining trunk
      function in spinal stenosis patients operated using a conservative procedure in
      an orthopaedic clinic. BACKGROUND: Although several clinical studies have
      examined the instability and motion characteristics of operated lumbar spinal
      canal stenosis, few if any studies have prospectively examined the biomechanical
      outcome of lumbar spinal canal stenosis surgery. METHODS: Comprehensive pre- and
      post-operative trunk dynamometer strength and motion analysis tests were
      performed on 36 patients operated for lumbar canal stenosis. Surgical treatment
      efficacy was evaluated within a three variable crossed factorial design
      considering stenosis classification, number of operative levels, and changes in
      several trunk biomechanical outcomes from pre- to post-operative assessment.
      Patients were evaluated after a minimum one-year follow-up. RESULTS: Pre
      operatively there were no differential effects associated with stenosis
      classification or number of operated levels. There was a significant post
      operative increase in isometric trunk extension torque and flexion-extension
      power and a return to a more normal trunk extension-flexion torque ratio.
      Patients with mixed, single level stenosis demonstrated greater trunk extension
      power both pre- and post-operatively compared to other patients. CONCLUSIONS:
      Conservative surgical treatment of lumbar spinal stenosis produced a marked
      improvement in the functional mechanical status of the low back. RELEVANCE: This
      study assists clinicians and researchers to understand trunk function following
      conservative surgical treatment of lumbar spinal stenosis.

PMID- 12620780
TI  - The effect of cyclic compression on the mechanical properties of the inter
      vertebral disc: an in vivo study in a rat tail model.
AB  - OBJECTIVE: To assess the changes in the mechanical properties of inter-vertebral
      discs in vivo following static and cyclic compressive loading of different
      frequencies. DESIGN: An in vivo biomechanical study using a rat-tail model of the
      inter-vertebral disc.Background. Mechanical loading has been suggested as playing
      a major role in the etiology of disc degeneration, but the relationship is still
      not fully understood. METHODS: Sixty Sprague-Dawley rats were subject to daily
      compressive stress via pins inserted in the 6th and 7th caudal vertebrae over a
      two-week loading period. Animals were randomly divided into a sham group (pin
      insertion, no loading), a static loading group, or cyclic loading groups of 0.5,
      1.5, or 2.5 Hz. Loading was applied for 1 h each day from the 3rd to 17th day
      following pin insertion, and the angular compliance, angular laxity, and inter
      pin distance were measured in vivo at days 0, 3, 10 and 17. RESULTS: Changes in
      the inter-vertebral disc height depended on the frequency of loading, with the
      decrease in disc height in the static compression group significantly greater
      than that in all other groups, whereas the decrease in the 1.5 Hz cyclic
      compression group was significantly smaller than that in all other compression
      groups. CONCLUSIONS: Changes in disc properties depend on both the total load
      exposure and the frequency of loading. Cyclic loading in general produced less
      marked changes than static loading, but loading at particular frequencies may
      result in more severe changes. RELEVANCE: Previous studies have shown the in vivo
      changes in the mechanical properties of inter-vertebral discs to depend on the
      magnitude and duration of loading. In this study, a frequency dependent response
      to cyclic loading is also demonstrated.

PMID- 12620781
TI  - The effect of age and movement speed on maximum forward reach from an elevated
      surface: a study in healthy women.
AB  - OBJECTIVE: To test the hypotheses (1) that the maximum distance reached by young
      or older women when standing on a raised platform is independent of movement
      speed, and (2) the maximum forward momentum generated at comfortable and fast
      reaching speeds is independent of age. DESIGN: Repeated measures case-control
      study in a university laboratory setting.Background. Maximum forward reach
      distance is often part of a geriatric mobility assessment. The effect of movement
      speed, and hence momentum, on forward reaching behavior is unknown in young or
      older subjects, despite the fact that excess momentum might increase the risk of
      fall-related injuries, especially from an elevated surface. METHODS: Ten healthy
      young women (mean age 23.7 years) and 10 healthy older women (mean age 70.5
      years) participated. Subjects stood on an instrumented force platform and forward
      reach body segment kinematics were measured optoelectronically. Whole-body center
      of reaction and center of mass trajectories were calculated during six maximum
      forward reach trials: three performed "at a comfortable speed", and three
      performed "as fast as possible". RESULTS: Subjects reached slightly further at a
      comfortable speed than when reaching as fast as possible (P=0.016). Fast reaches
      were associated with a 25% increase in momentum (P<0.001; however, under both
      speed conditions, older women developed less whole-body momentum than did young
      controls (for example, 4.1 vs. 6.1 kgm/s at comfortable speed, P<0.05). Three
      young and one older women lost their balance in at least one trial. CONCLUSIONS:
      Independent of age, these women reached further when reaching slowly than when
      reaching rapidly, and older women restricted peak forward momentum under both
      speed conditions when standing on the elevated surface. RELEVANCE: Interventions
      designed to reduce falls from raised surfaces might utilize the insights gained
      from these women that (1) at any age, one cannot expect to reach as far when
      reaching fast as one can when reaching slowly; and (2) comfortable reaching speed
      is reduced in older individuals.

PMID- 12620782
TI  - Joint torques during sit-to-stand in healthy subjects and people with Parkinson's
      disease.
AB  - OBJECTIVES: To compare lower limb joint torques during sit-to-stand in normal
      elderly subjects and people with Parkinson's disease, using a developed
      biomechanical model simulating all phases of sit-to-stand.Design. A cross
      sectional study utilizing a Parkinsonian and a control group. BACKGROUND:
      Subjects with Parkinson's disease were observed to experience difficulty in
      performing sit-to-stand. The developed model was used to calculate the lower limb
      joint torques in normal elderly subjects and subjects with Parkinson's disease,
      to delineate possible causes underlying difficulties in initiating sit-to-stand
      task. METHODS: Six normal elderly subjects and seven age-matched subjects with
      Parkinson's disease performed five sit-to-stand trials at their self-selected
      speed. Anthropometric data, two-dimensional kinematic and foot-ground and thigh
      chair reactive forces were used to calculate, via inverse dynamics, the joint
      torques during sit-to-stand in both before and after seat-off phases. The
      difference between the control and Parkinson's disease group was analysed using
      independent t-tests. RESULTS: Both control and Parkinson's disease groups had a
      similar joint kinematic pattern, although the Parkinson's disease group
      demonstrated a slower angular displacement. The latter subjects produced
      significantly smaller normalized hip flexion torque and presented a slower torque
      build-up rate than the able-bodied subjects (P<0.05). CONCLUSION: Slowness of sit
      to-stand in people with Parkinson's disease could be due to a reduced hip flexion
      joint torque and a prolonged rate of torque production.

PMID- 12620783
TI  - A comparison of the gaits of Chinese and Caucasian women with particular
      reference to their heelstrike transients.
AB  - OBJECTIVE: To examine the hypothesis that the differences reported in incidence
      of osteoarthrosis in Chinese and Caucasians could be associated with differences
      in habitual gait. DESIGN: The effects of race and age on walking speed and
      heelstrike transient were examined.Background. The relatively low incidence of
      gonarthrosis in Chinese populations compared to Caucasians remains unexplained.
      Repetitive impulsive loading exhibited at heel strike in the walking process has
      been linked to the development of gonarthrosis, while the gait characteristics of
      people at different risk levels for gonarthrosis have not been compared
      quantitatively. METHODS: The gait of 117 healthy women, 76 Chinese and 41
      Caucasians, was studied with an optometric system and two force plates in an 8-m
      walkway. Natural walking speed, stride length, cadence and maximum loading rate
      at heelstrike were collected. RESULTS: The Caucasian women over age 45 walked
      significantly faster with significantly higher maximal loading rate than age
      matched Chinese women (P<0.005). Age effects on most gait parameters measured
      were found significant in the Chinese group (P<0.01) but not in the Caucasian
      group. CONCLUSIONS: Chinese women slow down their walking speed and reduce the
      cadence of their gait earlier in their life span and, thus, lower their
      heelstrike transients. Significant racial differences in gait might explain the
      lower prevalence of gonarthrosis reported in Chinese women. RELEVANCE:
      Significantly larger heelstrike transients and significantly faster walking speed
      were seen in the population at higher risk for gonarthrosis. Walking slowly with
      lower heelstrike transients might be an effective preventive measure against
      gonarthrosis.

PMID- 12620784
TI  - Lower-extremity biomechanics during forward and lateral stepping activities in
      older adults.
AB  - OBJECTIVE: To characterize the lower-extremity biomechanics associated with
      stepping activities in older adults. DESIGN: Repeated-measures comparison of
      kinematics and kinetics associated with forward step-up and lateral step-up
      activities. BACKGROUND: Biomechanical analysis may be used to assess the
      effectiveness of various 'in-home activities' in targeting appropriate muscle
      groups and preserving functional strength and power in elders. METHODS: Data were
      analyzed from 21 participants (mean 74.7 yr (standard deviation, 4.4 yr)) who
      performed the forward and lateral step-up activities while instrumented for
      biomechanical analysis. Motion analysis equipment, inverse dynamics equations,
      and repeated measures ANOVAs were used to contrast the maximum joint angles, peak
      net joint moments, angular impulse, work, and power associated with the
      activities. RESULTS: The lateral step-up resulted in greater maximum knee flexion
      (P<0.001) and ankle dorsiflexion angles (P<0.01). Peak joint moments were similar
      between exercises. The forward step-up generated greater peak hip power (P<0.05)
      and total work (P<0.001); whereas, the lateral step-up generated greater impulse
      (P<0.05), work (P<0.01), and power (P<0.05) at the knee and ankle. CONCLUSIONS:
      In older adults, the forward step-up places greater demand on the hip extensors,
      while lateral step-up places greater demand on the knee extensors and ankle
      plantar flexors. RELEVANCE: Clinicians may use data from biomechanical analyses
      of in-home exercises to more effectively target specific lower-extremity muscle
      groups when prescribing exercise activities for older adults. The forward step-up
      is recommended for maintaining or improving hip extensor performance; whereas,
      the lateral step-up is recommended when targeting the knee extensors and ankle
      plantar flexors.

PMID- 12620785
TI  - Neuromuscular disorder in response to anterior cruciate ligament creep.
AB  - OBJECTIVE: To determine the effect of creep developed in the anterior cruciate
      ligament and other viscoelastic knee structures on the function of the flexor and
      extensor muscles of males and females. DESIGN: Static load applied to the
      proximal tibia of young healthy male and female subjects in a laboratory setting
      with maximal voluntary knee flexion and extension performed before and after the
      load application. BACKGROUND: Static loads applied to various joints during
      occupational and sports activities are epidemiologically linked to higher than
      normal rates of disability reports. The physiological and biomechanical processes
      active in the development of such a neuromuscular disorder are not known. We
      hypothesize that creep developed in the anterior cruciate ligament due to
      prolonged static load will have pronounced impact on the reflexive activation of
      the associated musculature in a manner that may increase the risk of injury.
      Females are expected to be exposed to higher risk than males. METHODS: Male and
      female groups performed maximal voluntary knee flexion and extension before and
      after applying 200 and 150 N, respectively, to the proximal tibia for a 10 min
      period. Flexion and extension forces as well as electromyograph from agonist and
      antagonist muscles were measured at 35 degrees and 90 degrees knee flexion. Data
      was analyzed through repeated measures of analysis of variance. RESULTS: It was
      found that in extension, quadriceps electromyographic activity increased
      significantly after anterior cruciate ligament creep while hamstrings co
      activation did not change. There was also a trend towards increased extension
      force after creep was developed, with significant effect of gender (larger
      increase in females). Similarly, significant increase in hamstrings
      electromyographic activity and a trend towards increased force during knee
      flexion was observed but with no effect of gender. Electromyographic spasms from
      the flexors and extensors were recorded in 30% of the subjects during the 10 min
      static loading period at 90 degrees angle and from the flexors only at 35
      degrees. Creep in the ligament was marginally greater in females than in males
      with a significant effect of angle, being greater at 35 degrees than in 90
      degrees knee flexion. CONCLUSIONS: The results suggest that ligament creep may
      develop a neuromuscular disorder consisting of spasms, increased electromyography
      and force in the agonist muscles without compensation from the antagonist. Static
      loading of a joint, therefore, may develop a neuromuscular disorder compounded
      with laxity of the ligaments and subject the individual to increased risk of
      injury. RELEVANCE: The data provides evidence that prolonged static loads applied
      to the anterior cruciate ligament and associated viscoelastic structures results
      in unbalanced muscular activation which puts individuals at increased exposure to
      injury. Work and sports activities should be scheduled while minimizing periods
      of static joint loading and emphasizing sufficient rest periods to allow recovery
      of creep and return to balanced muscular activation and co-activation.

PMID- 12620786
TI  - The influence of surgical malalignment on the contact pressures of fixed and
      mobile bearing knee prostheses--a biomechanical study.
AB  - OBJECTIVE: To investigate the effect of surgical malalignment on contact
      pressures of fixed and mobile bearing knee prostheses. DESIGN: An experimental
      set-up was used to measure contact pressure on the tibial component of fixed and
      mobile bearing knee prostheses subjected to a compression load and surgical
      malalignment situations were simulated. BACKGROUND: Mobile bearing knee
      prostheses were designed to decrease tibiofemoral contact pressure by providing
      both high congruity and mobility. It was also assumed to accommodate surgical
      malalignment. However, few studies have reported the effect of malalignment of
      the tibiofemoral joint on contact pressure of fixed and mobile bearing knee
      prostheses. METHODS: Surgical malalignment situations were simulated to evaluate
      contact characteristics of tibial component of fixed and mobile bearing knee
      prostheses. The simulated malalignment conditions include the medial-lateral
      translation (0.5 and 1 mm), anterior-posterior translation (2 and 4 mm) and
      internal-external rotation (1 degrees, 3 degrees, 5 degrees and 10 degrees ) of
      the femoral component relative to the tibial component. Fuji pressure sensitive
      film was used to measure the contact pressure. RESULTS: The greatest increase of
      maximum contact pressure in the anterior-posterior maltranslation was 7.63% and
      7.62% relative to the neutral contact situation in the fixed and mobile bearing
      designs respectively. In the medial-lateral maltranslation, there was 23.3% in
      the fixed bearing design and was 22.0% in the mobile bearing design. In the
      internal/external malrotation, the greatest increase of maximum contact pressure
      in the fixed bearing design was 27.1%, which was much higher than the mobile
      bearing design (22.4%). CONCLUSIONS: The mobile bearing design can reduce maximum
      contact pressure more significantly than the fixed bearing design when
      malalignment conditions of the tibiofemoral joint occurs, especially in the
      internal/external malrotation. The mobile bearing design offers the advantage of
      self-adjusting over the fixed bearing design to accommodate surgical
      malalignment. RELEVANCE: This study revealed that the mobile bearing design has
      smaller maximum contact pressures than the fixed bearing design in knee
      prosthesis under malalignment biomechanical tests. This result indicates that
      there is an advantage for a mobile bearing design over a fixed bearing design to
      accommodate malalignment conditions caused by surgical technique or soft tissues
      imbalance in total knee arthroplasty.

PMID- 12620787
TI  - Stump/socket pressure profiles of the pressure cast prosthetic socket.
AB  - OBJECTIVE: The aim was to evaluate stump/socket interface pressure in amputees
      wearing a socket developed by a pressure casting system.Design. Five unilateral
      transtibial amputees wore a pressure cast socket and walked at a self-selected
      speed. BACKGROUND: The socket produces equally distributed pressure at the
      stump/socket interface, deviating from the conventional belief that pressure
      varies in proportion to the pain threshold of different tissues in the stump.
      METHODS: The socket was fabricated while the subject placed his stump in a
      pressure chamber. Pressure was applied while he adopted a normal standing
      position. A specially built strain gauged type pressure transducer was used for
      measuring pressure distribution. Pressure and gait parameters were measured
      simultaneously while the subjects were standing and walking. RESULTS AND
      CONCLUSION: The pressure cast technique was able to provide comfortable fitting
      sockets. A hydrostatic pressure profile was not evident during standing or gait.
      Results also showed that no standard pressure profile for the pressure cast
      socket was observed. This was expected as no rectifications were done on the
      pressure cast socket. Pressure profiles at 10%, 25% and 50% of gait cycle did not
      correlate with the pressure profiles previously proposed. RELEVANCE: The
      hydrostatic theory is an attractive concept in socket design as it produces a
      stump/socket pressure profile that is evenly distributed. Furthermore, it is a
      method that is easily implemented, independent of a prosthetist's skill and
      experience and reduces manufacturing time. However, there is still controversy
      surrounding the efficacy of this hydrostatic theory.

PMID- 12620788
TI  - Finite element analysis of the initial stability of ankle arthrodesis with
      internal fixation: flat cut versus intact joint contours.
AB  - OBJECTIVE: Qualitative comparison of the initial stability provided by two joint
      preparation techniques and various screw configurations in ankle arthrodesis,
      using the finite element method.Design. A three-dimensional model of a healthy
      ankle was developed from computed tomography images. Two groups of models were
      built, one with the joint contours resected to produce flat surfaces, and the
      second with the joint contours preserved. In each case, a variety of screw
      orientations were examined. BACKGROUND: Despite the improved results of ankle
      arthrodesis, failure rates due to non-union are still reported. The initial
      stability of the arthrodesis construct seems important in the final outcome of
      the fusion. METHODS: Non-linear contact finite element analyses were performed in
      the arthrodesis constructs subjected to internal/external torsion and
      dorsiflexion. Micromotions at the bone-to-bone interface were calculated for
      frictionless and Coulomb friction contact, and compared for the two joint
      preparation techniques and screw configurations. RESULTS: Overall lower peak
      micromotions were predicted when preserving the joint contours both in torsion
      and dorsiflexion. For both preparation techniques, the lowest micromotions tended
      to occur with the screws inserted at 30 degrees with respect to the long axis of
      the tibia, crossing above the fusion site. Inclusion of friction in the models
      caused a general decrease on the magnitude of the micromotions as compared to the
      frictionless case, but did not affect the ranking of the models. CONCLUSIONS: The
      finite element method can be used as a qualitative tool to study the initial
      stability of ankle arthrodesis, overcoming the difficulties of measuring bone-to
      bone interface micromotions experimentally. Better initial stability was
      predicted for ankle arthrodesis when the joint contours were preserved rather
      than resected. Crossing the screws above the fusion site at a steeper angle also
      tended to increase the stability at the fusion site. RELEVANCE: Finite element
      analyses can help during the pre-operative planning of ankle arthrodesis. When
      bone density is not compromised, preserving the joint contour and inserting the
      screws at less than 45 degrees to the long axis of the tibia, crossing over the
      arthrodesis site, may offer better initial stability.

PMID- 12620790
TI  - Three-dimensional analysis of active head and cervical spine range of motion:
      effect of age in healthy male subjects. By Sforza C et al.

PMID- 12620789
TI  - Foot orthotics affect lower extremity kinematics and kinetics during running.
AB  - OBJECTIVE: To quantify the effects of posting and custom-molding of foot
      orthotics on lower extremity kinematics and kinetics during running. DESIGN:
      Repeated measures.Background. Several kinematic and kinetic factors have been
      suggested to increase a runner's risk for injuries. It has been speculated that
      foot orthotics can be used to reduce injury related complaints or even prevent
      running injuries by affecting these factors. METHODS: Twenty one volunteers
      participated in this study. Kinematic and kinetic variables obtained during
      overground running for medial posting, custom-molding, and the combination of
      medial posting and custom-molding of foot orthotics were compared to a control
      condition. Repeated measures ANOVA and student t-tests were used to detect
      significant differences (alpha=0.05). RESULTS: Posting of foot orthotics reduced
      maximum foot eversion and ankle inversion moment and increased vertical loading
      rate and maximum knee external rotation moment (P<0.05). Molding and posting and
      molding reduced vertical loading rate and ankle inversion moment and increased
      maximum foot inversion and maximum knee external rotation moment (P<0.05).
      CONCLUSIONS: The effects of posting and molding of foot orthotics are extremely
      different and when combining posting and molding, the effects of molding appear
      to be dominant. It yet remains to be determined whether posting or molding is
      more beneficial with respect to overuse running injuries. RELEVANCE: The
      potential of foot orthotics for reducing pain and injuries is convincing. The
      current study provides valuable information about the role of specific structural
      components of foot orthotics and contributes to the knowledge about the mechanism
      underlying the effect of foot orthotics in running.

PMID- 12620791
TI  - Production, purification and preliminary X-ray crystallographic studies of adeno
      associated virus serotype 4.
AB  - Adeno-associated virus (AAV) serotypes 1 to 5 are currently under development as
      clinical gene delivery vectors for the treatment of human diseases. However, the
      ubiquitous nature of their cell surface receptors, heparin sulfate (AAV2 and 3)
      and sialic acids (AAV4 and 5), can preclude specific tissue targeting in vivo.
      Structural studies of AAV4 were initiated to characterize its capsid surface for
      re-targeting manipulations. Crystals obtained diffracted synchrotron radiation to
      3.2 A resolution. The unit cell is body-centered orthorhombic, I222, with a =
      339.6, b = 319.2 and c = 285.0 A. The virus particle orientation and position
      have been determined.

PMID- 12620792
TI  - Influenza B virus BM2 protein is an oligomeric integral membrane protein
      expressed at the cell surface.
AB  - The influenza B virus BM2 protein contains 109 amino acid residues and it is
      translated from a bicistronic mRNA in an open reading frame that is +2
      nucleotides with respect to the matrix (M1) protein. The amino acid sequence of
      BM2 contains a hydrophobic region (residues 7-25) that could act as a
      transmembrane (TM) anchor. Analysis of properties of the BM2 protein, including
      detergent solubility, insolubility in alkali pH 11, flotation in membrane
      fractions, and epitope-tagging immunocytochemistry, indicates BM2 protein is the
      fourth integral membrane protein encoded by influenza B virus in addition to
      hemagglutinin (HA), neuraminidase (NA), and the NB glycoprotein. Biochemical
      analysis indicates that the BM2 protein adopts an N(out)C(in) orientation in
      membranes and fluorescence microscopy indicates BM2 is expressed at the cell
      surface. As the BM2 protein possesses only a single hydrophobic domain and lacks
      a cleavable signal sequence, it is another example of a Type III integral
      membrane protein, in addition to M(2), NB, and CM2 proteins of influenza A, B,
      and C viruses, respectively. Chemical cross-linking studies indicate that the BM2
      protein is oligomeric, most likely a tetramer. Comparison of the amino acid
      sequence of the TM domain of the BM2 protein with the sequence of the TM domain
      of the proton-selective ion channel M(2) protein of influenza A virus is
      intriguing as M(2) protein residues critical for ion selectivity/activation and
      channel gating (H(37) and W(41), respectively) are found at the same relative
      position and spacing in the BM2 protein (H(19) and W(23)).

PMID- 12620794
TI  - Identification of a nonconventional motif necessary for the nuclear import of the
      human parvovirus B19 major capsid protein (VP2).
AB  - Human parvovirus B19 replicates and encapsidates its genome in the nucleus of
      erythroid progenitors in vivo and in vitro. We wanted to understand the
      determinants necessary for the nuclear transport of the major coat protein, VP2,
      which makes up about 96% of the viral capsid proteins. A nonconsensus basic
      motif, KLGPRKATGRW, necessary for the nuclear localization of VP2 was identified
      and shown to be able to import reporter proteins into the nucleus. The sequence
      is conserved among the VP2 C-terminal region of erythroviruses. This newly
      identified sequence will facilitate the understanding of the replication of these
      viruses.

PMID- 12620793
TI  - Multiple amino acid residues confer temperature sensitivity to human influenza
      virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60.
AB  - FluMist influenza A vaccine strains contain the PB1, PB2, PA, NP, M, and NS gene
      segments of ca A/AA/6/60, the master donor virus-A strain. These gene segments
      impart the characteristic cold-adapted (ca), attenuated (att), and temperature
      sensitive (ts) phenotypes to the vaccine strains. A plasmid-based reverse
      genetics system was used to create a series of recombinant hybrids between the
      isogenic non-ts wt A/Ann Arbor/6/60 and MDV-A strains to characterize the genetic
      basis of the ts phenotype, a critical, genetically stable, biological trait that
      contributes to the attenuation and safety of FluMist vaccines. PB1, PB2, and NP
      derived from MDV-A each expressed determinants of temperature sensitivity and the
      combination of all three gene segments was synergistic, resulting in expression
      of the characteristic MDV-A ts phenotype. Site-directed mutagenesis analysis
      mapped the MDV-A ts phenotype to the following four major loci: PB1(1195)
      (K391E), PB1(1766) (E581G), PB2(821) (N265S), and NP(146) (D34G). In addition,
      PB1(2005) (A661T) also contributed to the ts phenotype. The identification of
      multiple genetic loci that control the MDV-A ts phenotype provides a molecular
      basis for the observed genetic stability of FluMist vaccines.

PMID- 12620795
TI  - Turnip crinkle virus coat protein mediates suppression of RNA silencing in
      Nicotiana benthamiana.
AB  - All of the protein products of Turnip crinkle virus (TCV; Tombusviridae,
      Carmovirus) were tested for their ability to suppress RNA silencing of a reporter
      gene after transient expression in Agrobacterium-infiltrated Nicotiana
      benthamiana leaves. Only the capsid protein, P38, showed suppression activity,
      although this was not obvious when P38 was expressed as part of a TCV infection
      of the same tissues. When P38 was expressed from a PVX vector, symptoms with
      enhanced severity that correlated with increased PVX RNA accumulation were
      observed. This contradiction between ectopic expression of P38 and TCV infection
      could be accounted for if the active determinant of suppressor activity within
      P38 was sequestered within the capsid protein structure. The N-terminal 25 amino
      acids were shown to be important for this activity. This region forms part of the
      unexposed R-domain that interacts with the RNA within the virus particle. This
      observation throws light on some of the complex biology exhibited by TCV.

PMID- 12620796
TI  - Functional analysis of the grapevine virus A genome.
AB  - Grapevine virus A (GVA) carries five open reading frames (ORFs). Only the coat
      protein ORF has been experimentally identified as such; the roles of some of the
      other ORFs have been deduced by sequence homology to known genes (Minafra et al.,
      1997). The construction of a full-length, infectious clone of GVA has been
      previously reported. In an attempt to experimentally define the role of the
      various genes of GVA, we utilized the infectious clone, inserted mutations in
      every ORF, and studied the effect on viral replication, gene expression, symptoms
      and viral movement. Mutations in ORF 1 abolished RNA replication. Mutations in
      ORF 2 did not affect any of the aforementioned parameters. Mutations in ORFs 3
      and 4 restricted viral movement. Mutations in ORF 5 rendered the virus
      asymptomatic, and partially restricted its movement.

PMID- 12620797
TI  - Modulation of interferon expression by hepatitis C virus NS5A protein and human
      homeodomain protein PTX1.
AB  - Hepatitis C virus (HCV) NS5A protein transcriptionally modulates a number of
      cellular genes. Since there is no evidence of binding of NS5A protein to DNA, it
      is likely to exert its activity in concert with cellular factor(s). In this
      study, we have identified a specific interaction of HCV NS5A with homeodomain
      protein PTX1 of human origin by a yeast two-hybrid interacting cloning system.
      The authenticity of this interaction was verified by mammalian two-hybrid assay,
      in vivo co-immunoprecipitation analysis, and from a colocalization study.
      Recently, murine PTX1 (mPTX1) has been shown to repress virus-induced murine
      interferonA4 promoter activity. Interferon-a alone or together with ribavirin is
      the only available therapy for HCV-infected patients. Therefore, we examined
      whether coexpression of NS5A and human PTX1 (hPTX1) proteins modulate human IFN-a
      promoter activity. An in vitro reporter assay by transfection of HepG2 cells with
      NS5A suggested an activation of IFN-a promoter to approximately 20-fold upon
      Newcastle disease virus (NDV) infection. Under similar experimental conditions,
      hPTX1-activated IFN-a prompter to approximately sevenfold, unlike mPTX1. However,
      cotransfection of NS5A and hPTX1 displayed a lower interferon promoter activity,
      probably for physical association between these two proteins. Subsequent study
      demonstrated that activation of IFN promoter by NS5A is associated with an
      increased expression of IRF-3. Further analysis revealed that ectopic expression
      of NS5A in HepG2 cells enhances endogenous IFN-a secretion and MxA expression
      upon induction with NDV. However, exogenous expression of hPTX1 did not
      significantly alter NS5A-mediated function in the stable transfectants. Taken
      together, these results suggested that the level of endogenous hPTX1 is not
      sufficient to block the function of NS5A for augmentation of virus-mediated IFN
      activity in HepG2 cells.

PMID- 12620798
TI  - Binding of HTLV-1 tax oncoprotein to the precursor of interleukin-16, a T cell
      PDZ domain-containing protein.
AB  - HTLV-1 Tax oncoprotein interacts with various cellular factors and modulates
      transcription and the cell cycle. In that role it is sufficient to create T cell
      malignancies in the absence of HTLV-1 infection. HTLV-1 Tax protein has been
      reported to bind to cellular proteins containing PDZ domains in vitro. The
      precursor of human interleukin 16, pro-IL-16, is an abundant cellular protein
      present in human peripheral blood T cells. Pro-IL-16 contains three PDZ domains.
      It has been shown that expression of pro-IL-16 in pro-IL-16 negative cells
      induces a G(0)/G(1) arrest in the cell cycle. The current studies demonstrate
      that Tax binds to pro-IL-16 in HTLV-1 infected human T cells. We mapped the Tax
      binding site to the first PDZ domain of pro-IL-16. Over-expression of Tax in COS
      cells resulted in fewer cells in G(0)/G(1) consistent with its activity to induce
      G(1)- to S-phase progression in lymphocytes, while over-expression of pro-IL-16
      in COS cells resulted in G(0)/G(1) arrest. Co-expression of wild type Tax with
      pro-IL-16 in COS cells negated the effects of pro-IL-16, an effect not observed
      with Tax mutated at its PDZ binding C-terminus. These results suggest that one of
      the effects of Tax on growth deregulation in HTLV-1 infected T cells might be
      mediated by its binding to pro-IL-16.

PMID- 12620799
TI  - Chromatin repression by COUP-TFII and HDAC dominates activation by NF-kappaB in
      regulating major histocompatibility complex class I transcription in adenovirus
      tumorigenic cells.
AB  - In adenovirus type 12 transformed cells, the down-regulation of MHC class I
      transcription contributes to the tumorigenic phenotype and is solely mediated by
      Ad12 E1A. Previous in vitro studies with class I enhancer sequences have
      indicated that there is an increased binding of repressor COUP-TFII and its
      associated HDAC and a decreased binding of activator NF-kappaB. In this study, we
      used chromatin immunoprecipitation (ChIP) assay in order to determine in vivo
      whether these proteins regulate class I transcription by affecting chromatin. The
      ChIP assay revealed that there is lack of chromatin histone acetylation in the
      region of the class I enhancer in Ad12-transformed cells. This is regulated by
      histone deacetylation as it was further demonstrated in vivo that COUP-TFII and
      HDAC are associated with the class I enhancer chromatin. In agreement with in
      vitro studies, NF-kappaB could be recruited to the class I enhancer following
      induction by TNF-alpha. However, this enhancer-bound NF-kappaB failed to up
      regulate class I expression because the class I enhancer chromatin remained
      repressed as a result of histone deacetylation by HDAC in association with COUP
      TFII. Thus, we have demonstrated for the first time that repression of chromatin
      through histone deacetylation is a major mechanism in down-regulating class I
      transcription in Ad12-transformed cells. Finally, Ad12 E1A, a non-DNA binding
      protein, was shown to be present in the natural protein complex bound to the
      class I enhancer.

PMID- 12620800
TI  - RNA recombination between cucumoviruses: possible role of predicted stem-loop
      structures and an internal subgenomic promoter-like motif.
AB  - We previously analyzed hybrids of Cucumber mosaic virus (CMV) and Tomato aspermy
      virus (TAV) that contained CMV RNA2 with the 3'-terminal sequence from TAV RNA2.
      In this article, we scrutinized the RNA3 molecules in these hybrid viruses by
      Northern hybridization and RT-PCR and found some recombinant CMV RNA3 molecules
      and various recombinant RNA4 molecules whose 3'-termini were derived from TAV
      RNA1 or 2. Sequence analyses revealed that most of the crossover sites for
      recombination were located near putative stem-loop structures and an internal
      subgenomic promoter-like motif. We inoculated in vitro transcripts synthesized
      from cDNA clones of the recombinant RNA3 onto N. benthamiana along with either
      CMV RNA1 and 2 or TAV RNA1 and 2. Although all of the hybrids were infectious,
      many sequence deletions and nucleotide substitutions were found when RNA1 and 2
      from TAV were used, which suggests that fidelity of TAV replicase was lower than
      that of CMV replicase. The possible role of secondary structures and an internal
      subgenomic promoter-like motif in RNA recombination is discussed.

PMID- 12620801
TI  - Requirement of E6AP and the features of human papillomavirus E6 necessary to
      support degradation of p53.
AB  - E6 oncoproteins from human papillomavirus type 16 (16E6) and Bovine
      Papillomavirus type 1 (BE6) bind to leucine rich peptides (called charged
      leucine, LXXLL, or signature peptides) found on target cellular proteins. BE6 and
      16E6 both bind the product of the UBE3A gene called E6AP on a charged leucine
      peptide, LQELL. E6AP is an E3 ubiquitin ligase that together with 16E6 interacts
      with p53 to target p53 degradation. Although both BE6 and 16E6 bind the LQELL
      peptide of E6AP, only 16E6 acts as an adapter to then bring p53 to E6AP. In order
      to determine how E6 proteins function as adapters, 16E6, p53, and E6AP were
      expressed in yeast, and were shown to form a tri-molecular complex. 16E6 mutants
      were selected that retained interactions with E6AP yet were defective for
      interaction with p53. Such 16E6 mutations were typically within the amino
      terminus of 16E6. Through the use of E6AP null cells, transfected E6AP was shown
      to be necessary and sufficient for the degradation of p53 in the presence of
      16E6. However, the interaction of 16E6 with E6AP was complex. While BE6 interacts
      only with the LQELL motif of E6AP, an intact LQELL motif is not necessary either
      for interaction of 16E6 with E6AP or for p53 degradation. In addition, 16E6
      mutants that fail to bind the LQELL motif of E6AP can support p53 degradation.
      These results indicate that 16E6 may have multiple modes of interaction with E6AP
      and that assembly of p53 containing complexes for targeted degradation by E6AP
      may occur in more than one way. These results have implications for potential
      targeting of the interaction of 16E6 and E6AP in the therapy of HPV-induced
      cancer.

PMID- 12620802
TI  - Simian immunodeficiency virus Nef gene regulates the production of 2-LTR circles
      in vivo.
AB  - The replication dynamics of simian immunodeficiency virus (SIVmac32H-C8),
      attenuated through discrete genetic disruption of the nef gene, were compared
      with the wild-type parental clone (SIVmac32H-J5) using quantitative molecular
      methods. The primary viraemia of both infections were similar during the first
      week, but peaked on Day 10 at higher levels for wild-type virus. Viral RNA levels
      differed most markedly at Day 14. The frequency and levels of viral DNA species,
      detectable as gag provirus or circular 2-LTR episomes, differed depending on the
      virus and the lymphoid compartment sampled. 2-LTR circles persisted for prolonged
      periods in the peripheral blood but were never detected in any SIVmac32H C8
      infected tissue, even if positive by gag PCR. Paradoxically, the converse was
      observed following wild-type infection. 2-LTR circles disappeared from the
      peripheral blood by Day 42 postinfection but persisted in lymphoid tissues. These
      findings are discussed in terms of nef and the role and stability of 2-LTR circle
      forms in vivo.

PMID- 12620803
TI  - Evidence for specificity of psittacine beak and feather disease viruses among
      avian hosts.
AB  - Beak and feather disease is a major avian disease of both captive and wild parrot
      and cockatoo populations. Clinical signs include beak elongation and abnormal
      growth, together with weight loss and in some individuals the disease is fatal.
      We investigated the relationship between viral genotypes and their hosts in order
      to test for a positive association between distinct viral genomes and avian
      species. Specifically, we used the polymerase chain reaction (PCR) to amplify and
      sequence a 605-nucleotide (nt) segment of a coding region in the Beak and Feather
      Disease Virus (BFDV) genome. Feather and blood samples from 25 caged birds
      representing 10 species were assayed and the BFDV was detected in 21 samples from
      New Zealand. A phylogenetic analysis of DNA sequences from 17 specimens together
      with previously published sequences from Australian "isolates" revealed three
      lineages present in New Zealand. One viral lineage was found in six cockatoos
      representing two species (designated CT), a second lineage was detected in a
      budgerigar (designated BG), and a third was found in 10 lorikeets representing
      seven species (designated LK). This distinctive clustering pattern of viral
      sequences with groups of psittacine species indicates a genotypic association
      between the virus and these hosts.

PMID- 12620804
TI  - Prime-boost vaccination with plasmid DNA encoding caprine-arthritis encephalitis
      lentivirus env and viral SU suppresses challenge virus and development of
      arthritis.
AB  - This study evaluated the efficacy of prime-boost vaccination for immune control
      of caprine arthritis-encephalitis virus (CAEV), a macrophage tropic lentivirus
      that causes progressive arthritis in the natural host. Vaccination of Saanen
      goats with pUC-based plasmid DNA expressing CAEV env induces T helper type 1
      (Th1) biased immune responses to vector-encoded surface envelope (SU), and the
      plasmid-primed Th1 response is expanded following boost with purified SU in
      Freund's incomplete adjuvant (SU-FIA) (J. C. Beyer et al., 2001, Vaccine 19, 1643
      1651). Four goats vaccinated with env expression plasmids and boosted with SU-FIA
      were challenged intravenously with 1 x 10(4) TCID(50) of CAEV at 428 days after
      SU-FIA boost and evaluated by immunological, virological, and disease criteria.
      Controls included two goats primed with pUC18 and eight unvaccinated goats. Goats
      receiving prime-boost vaccination with CAEV env plasmids and SU-FIA became
      infected but suppressed postchallenge virus replication, provirus loads in lymph
      node, and development of arthritis for at least 84 weeks.

PMID- 12620805
TI  - Molecular evolution and phylogeny of dengue type 4 virus in the Caribbean.
AB  - We sequenced the E gene and adjacent prM/M and NS1 junctions (1940 bp) of 48
      Dengue-4 (DEN-4) isolates collected between 1981 and 1999 from 8 Caribbean
      islands and from 7 South and Central American countries. Phylogenetic analysis
      confirms a single introduction in the early 1980s and a high degree of gene flow
      resulting in a pattern of evolution defined more by time period than geographic
      origin, especially within the Caribbean basin. A modern Caribbean clade
      consisting of four distinct lineages has arisen, comprised of isolates from
      Caribbean islands and nearby regions of South America. This clade is defined by
      three amino acid substitutions in the E (aa 163 and 351) and NS1 (aa 52)
      proteins. These findings highlight the importance of migration and gene flow in
      dengue viral change and suggest that efforts to understand disease dynamics in
      the Caribbean basin need to focus at regional, rather than local scales.

PMID- 12620806
TI  - Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1
      phosphorylation and association of viral accessory proteins, C and V, with
      interferon-alpha receptor complex.
AB  - To establish infections, viruses use various strategies to suppress the host
      defense mechanism, such as interferon (IFN)-induced antiviral state. We found
      that cells infected with a wild strain of measles virus (MeV) displayed nearly
      complete suppression of IFN-alpha-induced antiviral state, but not IFN-gamma
      induced state. This phenomenon is due to the suppression of IFN-alpha-inducible
      gene expression at a transcriptional level. In the IFN-alpha signal transduction
      pathway, Jak1 phosphorylation induced by IFN-alpha is dramatically suppressed in
      MeV-infected cells; however, phosphorylation induced by IFN-gamma is not. We
      performed immunoprecipitation experiments using antibodies against type 1 IFN
      receptor chain 1 (INFAR1) and antibody against RACK1, which is reported to be a
      scaffold protein interacting with type I IFN receptor chain 2 and STAT1. These
      experiments indicated that IFNAR1 forms a complex containing the MeV-accessory
      proteins C and V, RACK1, and STAT1 in MeV-infected cells but not in uninfected
      cells. Composition of this complex in the infected cells altered little by IFN
      alpha treatment. These results indicate that MeV suppresses the IFN-alpha, but
      not IFN-gamma, signaling pathway by inhibition of Jak1 phosphorylation. Our data
      suggest that functional disorder of the type I IFN receptor complex is due to
      "freezing" of the receptor through its association with the C and/or V proteins
      of MeV.

PMID- 12620807
TI  - Human immunodeficiency virus type-1 integrase containing a glycine to serine
      mutation at position 140 is attenuated for catalysis and resistant to integrase
      inhibitors.
AB  - L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In
      this report, the effects of a glycine to serine mutation at position 140 (G140S)
      on HIV IN and its effects on IN inhibitor resistance are described. HIV
      containing the G140S mutation showed a delay in replication. Using real-time
      polymerase chain reaction, the delay was secondary to a failure in integration.
      The mutant protein (IN(G140S)) was attenuated approximately four-fold for
      catalysis under equilibrium conditions compared to wild-type IN (IN(WT)) and
      attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty
      percent inhibitory concentration assays were performed with IN inhibitors against
      both IN proteins in disintegration and strand transfer reactions. IN(G140S) was
      resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation
      was resistant to both inhibitors as well. The G140S mutation attenuates IN
      activity and confers resistance to IN inhibitors, suggesting that diketoacids and
      L-CA interact with a similar binding site on HIV IN.

PMID- 12620808
TI  - The L1 major capsid protein of human papillomavirus type 11 interacts with Kap
      beta2 and Kap beta3 nuclear import receptors.
AB  - We have previously shown that the L1 major capsid protein of low-risk HPV11 binds
      to the Kap alpha2 adapter and enters the nucleus via a Kap alpha2beta1-mediated
      pathway. In this study, we discovered that HPV11 L1 capsomeres bind to Kap beta2
      import receptor, known to mediate nuclear import of hnRNP A1 via interaction with
      its nuclear localization signal termed M9. Significantly, binding of HPV11 L1
      capsomeres to Kap beta2 inhibited the nuclear import of Kap beta2, and its
      specific M9-containing cargo. Interestingly, HPV11 L1 capsomeres also interacted
      with Kap beta3 import receptor and inhibited Kap beta3 nuclear import. Moreover,
      the L1 capsomeres of high-risk HPV-16 shared these activities. These data suggest
      that HPV L1 major capsid proteins interact with Kap beta2 and Kap beta3, and they
      may inhibit the Kap beta2- and Kap beta3-mediated nuclear import pathways during
      the productive phase of the viral life cycle when the virions are assembled and
      released.

PMID- 12620809
TI  - Enhancing biosynthesis and secretion of premembrane and envelope proteins by the
      chimeric plasmid of dengue virus type 2 and Japanese encephalitis virus.
AB  - We have constructed a series of plasmids encoding premembrane (prM) and envelope
      (E) protein genes of dengue virus type 2 (DEN-2). These plasmids included an
      authentic DEN-2 prM-E construct (pCBD2-14-6), and two chimeric constructs, 90%
      DEN-2 E-10% Japanese encephalitis (JE) virus E (pCB9D2-1J-4-3) and 80% DEN-2 E
      20% JE E (pCB8D2-2J-2-9-1). Monoclonal antibody (MAb) reactivity indicated that
      all three plasmids expressed authentic DEN-2 virus E protein epitopes
      representative of flavivirus domains 1, 2, and 3. However, only the pCB8D2-2J-2-9
      1 construct secreted high levels of prM, M (membrane), and E proteins into the
      culture fluid of plasmid-transformed COS-1 cells. The major portion of the prM
      and E proteins expressed by COS-1 cells transformed by pCBD2-14-6 or pCB9D2-4-3
      plasmids remained membrane-bound. The results supported the notion that an
      unidentified membrane retention sequence is located between E-397 and E-436 of
      DEN-2 virus E protein. Replacing the carboxyl-terminal 20% of DEN-2 E (397-450)
      with the corresponding JE sequence had no effect on anti-DEN-2 MAb reactivity,
      indicating that this region is antigenically inert, although it is required for
      antigen secretion. Plasmid pCBD2-2J-2-9-1, which expressed secreted forms of
      prM/M and E that have the potential to form subviral particles, was superior to
      other constructs in stimulating an antibody response. Ninety percent
      neutralization titers ranging from 1:40 to >1:1000 were observed in seven of nine
      serum specimens from pCB8D2-2J-2-9-1-immunized mice. Eleven of twelve 2-day-old
      neonatal mice, derived from a pCB8D2-2J-2-9-1 immunized female mouse, survived
      intraperitoneal challenge of DEN-2 New Guinea C virus.

PMID- 12620810
TI  - Four-gene-combination DNA vaccine protects mice against a lethal vaccinia virus
      challenge and elicits appropriate antibody responses in nonhuman primates.
AB  - Two major infectious forms of vaccinia virus (VACV) have been described: the
      intracellular mature virion (IMV), and the extracellular enveloped virion (EEV).
      Due to their stability in the environment, IMVs play a predominant role in host
      to-host transmission, whereas EEVs play an important role in dissemination within
      the host. In a previous report, we demonstrated that mice vaccinated with VACV
      L1R (IMV immunogen) and A33R (EEV immunogen) were protected from a lethal
      poxvirus challenge. Vaccination with a combination of both genes conferred
      greater protection than either gene alone, suggesting that an immune response
      against both IMV and EEV is advantageous. Here, we report that in mice
      individually administered DNA vaccines with two different VACV immunogens, A27L
      (IMV immunogen) or B5R (EEV immunogen), failed to significantly protect; however,
      vaccination with a combination of both genes conferred a high level of
      protection. Mice were completely protected when vaccinated with a combination of
      four VACV genes (A27L + A33R + L1R + B5R). Rhesus macaques vaccinated with this
      four-gene-combination developed appropriate antibody responses to each protein.
      Antibody responses elicited by this vaccine cross-reacted with monkeypox virus
      orthologous proteins. These data indicate that a gene-based vaccine comprised of
      the VACV A27L + A33R + L1R + B5R genes may be a useful candidate to protect
      against other orthopoxviruses, including those that cause monkeypox and smallpox.

PMID- 12620811
TI  - Rho GTPases show differential sensitivity to nucleotide triphosphate depletion in
      a model of ischemic cell injury.
AB  - Rho GTPases are critical for actin cytoskeletal regulation, and alterations in
      their activity may contribute to altered cytoskeletal organization that
      characterizes many pathological conditions, including ischemia. G protein
      activity is a function of the ratio of GTP-bound (active) to GDP-bound (inactive)
      protein, but the effect of altered energy metabolism on Rho protein activity has
      not been determined. We used antimycin A and substrate depletion to induce
      depletion of intracellular ATP and GTP in the kidney proximal tubule cell line
      LLC-PK10 and measured the activity of RhoA, Rac1, and Cdc42 with GTPase effector
      binding domains fused to glutathione S-transferase. RhoA activity decreased in
      parallel with the concentration of ATP and GTP during depletion, so that by 60
      min there was no detectable RhoA-GTP, and recovered rapidly when cells were
      returned to normal culture conditions. Dissociation of the membrane-actin linker
      ezrin, a target of RhoA signaling, from the cytoskeletal fraction paralleled the
      decrease in RhoA activity and was augmented by treatment with the Rho kinase
      inhibitor Y27632. The activity of Cdc42 did not decrease significantly during
      depletion or recovery. Rac1 activity decreased moderately to a minimum at 30 min
      of depletion but then increased from 30 to 90 min of depletion, even as ATP and
      GTP levels continued to fall. Our data are consistent with a principal role for
      RhoA in cytoskeletal reorganization during ischemia and demonstrate that the
      activity of Rho GTPases can be maintained even at low GTP concentrations.

PMID- 12620812
TI  - Modulation of smooth muscle phenotype in vitro by homologous cell substrate.
AB  - We have developed a novel cell culture system that supports the shortening of
      smooth muscle cells. Primary rat airway smooth muscle cells were plated on an
      ethanol-fixed, confluent monolayer of homologous smooth muscle cells (homologous
      cell substrate, HCS). Cells grown on HCS exhibited morphological and functional
      characteristics consistent with a differentiated phenotype. Cells on HCS were
      spindle shaped with a well-defined long axis, whereas cells grown on glass were
      larger and irregularly shaped. Smooth muscle-specific alpha-actin immunostained
      diffusely in cells on HCS, whereas it appeared as stress fibers in cells on
      glass. Agonists recruited a greater fraction of HCS cells to contract, resulting
      in greater changes in cell area or length on average, but the maximal capacity of
      shortening of individual cells was similar between the groups. Unlike cells on
      glass, cells on HCS shortened to methacholine. HCS was reversible and persisted
      over several passages. Agonists stimulated intracellular Ca(2+) oscillations in
      cells on HCS, whereas they elicited biphasic peak and plateau transients in cells
      on glass. HCS modulates smooth muscle cell phenotype in vitro.

PMID- 12620813
TI  - Inositol 1,4,5-trisphosphate receptors modulate Ca2+ sparks and Ca2+ store
      content in vas deferens myocytes.
AB  - Spontaneous Ca2+ sparks were observed in fluo 4-loaded myocytes from guinea pig
      vas deferens with line-scan confocal imaging. They were abolished by ryanodine
      (100 microM), but the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) blockers
      2-aminoethoxydiphenyl borate (2-APB; 100 microM) and intracellular heparin (5
      mg/ml) increased spark frequency, rise time, duration, and spread. Very prolonged
      Ca2+ release events were also observed in approximately 20% of cells treated with
      IP3R blockers but not under control conditions. 2-APB and heparin abolished
      norepinephrine (10 microM; 0 Ca2+)-evoked Ca2+ transients but increased caffeine
      (10 mM; 0 Ca2+) transients in fura 2-loaded myocytes. Transients evoked by
      ionomycin (25 microM; 0 Ca2+) were also enhanced by 2-APB. Ca2+ sparks and
      transients evoked by norepinephrine and caffeine were abolished by thimerosal
      (100 microM), which sensitizes the IP3R to IP3. In cells voltage clamped at -40
      mV, spontaneous transient outward currents (STOCs) were increased in frequency,
      amplitude, and duration in the presence of 2-APB. These data are consistent with
      a model in which the Ca2+ store content in smooth muscle is limited by tonic
      release of Ca2+ via an IP3-dependent pathway. Blockade of IP3Rs elevates
      sarcoplasmic reticulum store content, promoting Ca2+ sparks and STOC activity.

PMID- 12620814
TI  - Microbial populations stimulated for hexavalent uranium reduction in uranium mine
      sediment.
AB  - Uranium-contaminated sediment and water collected from an inactive uranium mine
      were incubated anaerobically with organic substrates. Stimulated microbial
      populations removed U almost entirely from solution within 1 month. X-ray
      absorption near-edge structure analysis showed that U(VI) was reduced to U(IV)
      during the incubation. Observations by transmission electron microscopy, selected
      area diffraction pattern analysis, and energy-dispersive X-ray spectroscopic
      analysis showed two distinct types of prokaryotic cells that precipitated only a
      U(IV) mineral uraninite (UO(2)) or both uraninite and metal sulfides. Prokaryotic
      cells associated with uraninite and metal sulfides were inferred to be sulfate
      reducing bacteria. Phylogenetic analysis of 16S ribosomal DNA obtained from the
      original and incubated sediments revealed that microbial populations were changed
      from microaerophilic Proteobacteria to anaerobic low-G+C gram-positive
      sporeforming bacteria by the incubation. Forty-two out of 94 clones from the
      incubated sediment were related to sulfate-reducing Desulfosporosinus spp., and
      23 were related to fermentative Clostridium spp. The results suggest that, if in
      situ bioremediation were attempted in the uranium mine ponds, Desulfosporosinus
      spp. would be a major contributor to U(VI) and sulfate reduction and Clostridium
      spp. to U(VI) reduction.

PMID- 12620815
TI  - Biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by a rabbit
      liver cytochrome P450: insight into the mechanism of RDX biodegradation by
      Rhodococcus sp. strain DN22.
AB  - A unique metabolite with a molecular mass of 119 Da (C(2)H(5)N(3)O(3))
      accumulated during biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine
      (RDX) by Rhodococcus sp. strain DN22 (D. Fournier, A. Halasz, J. C. Spain, P.
      Fiurasek, and J. Hawari, Appl. Environ. Microbiol. 68:166-172, 2002). The
      structure of the molecule and the reactions that led to its synthesis were not
      known. In the present study, we produced and purified the unknown metabolite by
      biotransformation of RDX with Rhodococcus sp. strain DN22 and identified the
      molecule as 4-nitro-2,4-diazabutanal using nuclear magnetic resonance and
      elemental analyses. Furthermore, we tested the hypothesis that a cytochrome P450
      enzyme was responsible for RDX biotransformation by strain DN22. A cytochrome
      P450 2B4 from rabbit liver catalyzed a very similar biotransformation of RDX to 4
      nitro-2,4-diazabutanal. Both the cytochrome P450 2B4 and intact cells of
      Rhodococcus sp. strain DN22 catalyzed the release of two nitrite ions from each
      reacted RDX molecule. A comparative study of cytochrome P450 2B4 and Rhodococcus
      sp. strain DN22 revealed substantial similarities in the product distribution and
      inhibition by cytochrome P450 inhibitors. The experimental evidence led us to
      propose that cytochrome P450 2B4 can catalyze two single electron transfers to
      RDX, thereby causing double denitration, which leads to spontaneous hydrolytic
      ring cleavage and decomposition to produce 4-nitro-2,4-diazabutanal. Our results
      provide strong evidence that a cytochrome P450 enzyme is the key enzyme
      responsible for RDX biotransformation by Rhodococcus sp. strain DN22.

PMID- 12620816
TI  - Purification and characterization of brochocin A and brochocin B(10-43), a
      functional fragment generated by heterologous expression in Carnobacterium
      piscicola.
AB  - Brochothrix campestris ATCC 43754 produces a heat-stable, two-component,
      nonlantibiotic, class IIb bacteriocin, brochocin C (BrcC), that is active against
      a broad range of gram-positive bacteria, including spores of Clostridium
      botulinum. An improved purification method was developed for BrcC, in which n
      butanol and chloroform extraction are used. Mass spectral characterization of the
      two components, brochocin A (BrcA) and brochocin B (BrcB), showed that both
      components are excreted into the medium by B. campestris as mature peptides
      consisting of 59 and 43 amino acids, respectively. Separate expression clones of
      BrcA and BrcB were constructed previously in Carnobacterium piscicola LV17C, but
      the products were not chemically characterized. Purification by the new protocol
      showed that BrcA is expressed as the mature 59-amino-acid peptide but that BrcB
      is produced by C. piscicola as a fragment, BrcB(10-43), which is cleaved at an
      internal Gly-Gly site. This fragment is not antimicrobial by itself, but in
      combination with BrcA it displays the full activity of the BrcC complex. Circular
      dichroism measurements revealed a high beta-sheet content in the secondary
      structure of both BrcA and BrcB(10-43), as well as in a 1:1 BrcA-BrcB(10-43)
      mixture. Separate expression clones of brcA and brcB were also constructed in
      Escherichia coli, but these clones only produced multiple fragments of the
      desired peptides with little or no activity.

PMID- 12620817
TI  - Community structure of ammonia-oxidizing bacteria within anoxic marine sediments.
AB  - The potential for oxidation of ammonia in anoxic marine sediments exists through
      anaerobic oxidation by Nitrosomonas-like organisms, utilizing nitrogen dioxide,
      coupling of nitrification, manganese reduction, and anaerobic oxidation of
      ammonium by planctomycetes (the Anammox process). Here we describe the presence
      of microbial communities with the potential to carry out these processes in a
      natural marine sediment system (Loch Duich, Scotland). Natural microbial
      communities of Planctomycetales-Verrucomicrobia and beta- and gamma
      proteobacterial ammonia-oxidizing bacteria were characterized by analysis of 16S
      rRNA genes amplified using group-specific primers by PCR- and reverse
      transcription-PCR amplification of 16S rDNA and RNA, respectively. Amplification
      products were analyzed by sequencing of clones and by denaturant gradient gel
      electrophoresis (DGGE). Amplification of primers specific for Planctomycetales
      Verrucomicrobia and beta-proteobacterial ammonia-oxidizing bacteria generated
      products at all sampling sites and depths, but no product was generated using
      primers specific for gamma-proteobacterial ammonia-oxidizing bacteria. 16S rDNA
      DGGE banding patterns indicated complex communities of beta-proteobacterial
      ammonia-oxidizing bacteria in anoxic marine sediments. Phylogenetic analysis of
      sequences from clones and those excised from DGGE gels suggests dominance of
      Nitrosospira cluster 1-like organisms and of strains belonging to a novel cluster
      represented in dominant bands in 16S rRNA DGGE banding patterns. Their presence
      indicates a group of organisms closely related to recognized beta-proteobacterial
      ammonia-oxidizing bacteria that may be selected in anoxic environments and may be
      capable of anoxic ammonia oxidation. Sequence analysis of planctomycete clone
      libraries and sequences excised from DGGE gels also demonstrated a diverse
      microbial community and suggested the presence of new subdivisions, but no
      sequence related to recognized Anammox organisms was detected.

PMID- 12620818
TI  - Expression of chlorocatechol 1,2-dioxygenase and chlorocatechol 2,3-dioxygenase
      genes in chlorobenzene-contaminated subsurface samples.
AB  - In order to evaluate the in situ degradative capabilities of microorganisms in an
      underground reactor facility housing two flowthrough columns filled with aquifer
      soil, we examined the distribution and phylogeny of gene transcripts encoding
      enzymes capable of catalyzing the cleavage of the chlorinated aromatic ring
      during transformation of the main pollutant, chlorobenzene. Initial
      biostimulation of the autochthonous bacteria in the originally anaerobic reactor
      columns was achieved by injecting nitrate and oxygen in the form of H(2)O(2). Two
      broad-range primer pairs were used for reverse transcriptase PCR (RT-PCR) of
      partial subunit genes of chlorocatechol 1,2-dioxygenase and catechol 2,3
      dioxygenase from RNA directly extracted from different groundwater and aquifer
      samples. Samples retrieved from the lowermost sections of the reactor columns,
      which were operated in upflow mode, were positive for the presence of
      chlorocatechol 1,2-dioxygenase and catechol 2,3-dioxygenase mRNA. On the other
      hand, chlorocatechol 1,2-dioxygenase RT-PCR products were detected in a larger
      part of each reactor column, up to a zone 5.5 m above the bottom. Phylogenetic
      analyses of these chlorocatechol 1,2-dioxygenase sequences clearly separated them
      into two main clusters, one of which was closely affiliated with the broad
      spectrum chlorocatechol 1,2-dioxygenase from Pseudomonas chlororaphis RW71.
      Analysis of sequences obtained from RT-PCR products amplified with catechol 2,3
      dioxygenase primers revealed that their closest relative was the chlorocatechol
      2,3-dioxygenase gene cbzE from Pseudomonas putida GJ31 (A. E. Mars, J. Kingma, S.
      R. Kaschabek, W. Reineke, and D. B. Janssen, J. Bacteriol. 181:1309-1318, 1999),
      with sequence similarities between 97.8 and 99.0%.

PMID- 12620819
TI  - New thermosensitive delivery vector and its use to enable nisin-controlled gene
      expression in Lactobacillus gasseri.
AB  - Derivatives of a cryptic plasmid from Lactobacillus curvatus showed temperature
      sensitive replication in thermophilic lactobacilli. The thermosensitive replicon
      was used to construct the new delivery vector pTN1, which allows site-specific
      replacement of chromosomal DNA sequences. pTN1 carries an erythromycin resistance
      marker suitable for selection of single-copy integrants and replicates readily at
      35 degrees C, whereas replication is efficiently shut down at 42 degrees C. To
      demonstrate the functionality of pTN1, the signal transduction genes (nisRK) of
      the nisin-controlled expression system were integrated downstream of the pepN
      gene into the chromosome of Lactobacillus gasseri. In the resulting strain,
      UKLbg1, expression of nisRK was likely driven by cotranscription with pepN and
      enabled nisin-dependent induction of a fusion of a reporter gene (pepI) to the
      nisA promoter. The induction rates were correlated with the amount of nisin used,
      and maximum pepI expression was achieved with nisin concentrations (above 25
      ng/ml) at which growth of the bacteria was already inhibited.

PMID- 12620820
TI  - A real-time PCR assay for the detection of Campylobacter jejuni in foods after
      enrichment culture.
AB  - A real-time PCR assay was developed for the quantitative detection of
      Campylobacter jejuni in foods after enrichment culture. The specificity of the
      assay for C. jejuni was demonstrated with a diverse range of Campylobacter
      species, related organisms, and unrelated genera. The assay had a linear range of
      quantification over six orders of magnitude, and the limit of detection was
      approximately 12 genome equivalents. The assay was used to detect C. jejuni in
      both naturally and artificially contaminated food samples. Ninety-seven foods,
      including raw poultry meat, offal, raw shellfish, and milk samples, were enriched
      in blood-free Campylobacter enrichment broth at 37 degrees C for 24 h, followed
      by 42 degrees C for 24 h. Enrichment cultures were subcultured to Campylobacter
      charcoal-cefoperazone-deoxycholate blood-free selective agar, and presumptive
      Campylobacter isolates were identified with phenotypic methods. DNA was extracted
      from enrichment cultures with a rapid lysis method and used as the template in
      the real-time PCR assay. A total of 66 samples were positive for C. jejuni by
      either method, with 57 samples positive for C. jejuni by subculture to selective
      agar medium and 63 samples positive in the real-time PCR assay. The results of
      both methods were concordant for 84 of the samples. The total time taken for
      detection from enrichment broth samples was approximately 3 h for the real-time
      PCR assay, with the results being available immediately at the end of PCR
      cycling, compared to 48 h for subculture to selective agar. This assay
      significantly reduces the total time taken for the detection of C. jejuni in
      foods and is an important model for other food-borne pathogens.

PMID- 12620821
TI  - Detection and typing of Campylobacter jejuni and Campylobacter coli and analysis
      of indicator organisms in three waterborne outbreaks in Finland.
AB  - Waterborne outbreaks associated with contamination of drinking water by
      Campylobacter jejuni are rather common in the Nordic countries Sweden, Norway,
      and Finland, where in sparsely populated districts groundwater is commonly used
      without disinfection. Campylobacters, Escherichia coli, or other coliforms have
      rarely been detected in potential sources. We studied three waterborne outbreaks
      in Finland caused by C. jejuni and used sample volumes of 4,000 to 20,000 ml for
      analysis of campylobacters and sample volumes of 1 to 5,000 ml for analysis of
      coliforms and E. coli, depending on the sampling site. Multiple samples obtained
      from possible sources (water distribution systems and environmental water
      sources) and the use of large sample volumes (several liters) increased the
      chance of detecting the pathogen C. jejuni in water. Filtration of a large volume
      (1,000 to 2,000 ml) also increased the rate of detection of coliforms and E.
      coli. To confirm the association between drinking water contamination and
      illness, a combination of Penner serotyping and pulsed-field gel electrophoresis
      (digestion with SmaI and KpnI) was found to be useful. This combination reliably
      verified similarity or dissimilarity of C. jejuni isolates from patient samples,
      from drinking water, and from other environmental sources, thus confirming the
      likely reservoir of an outbreak.

PMID- 12620822
TI  - Optimization strategies for DNA microarray-based detection of bacteria with 16S
      rRNA-targeting oligonucleotide probes.
AB  - The usability of the DNA microarray format for the specific detection of bacteria
      based on their 16S rRNA genes was systematically evaluated with a model system
      composed of six environmental strains and 20 oligonucleotide probes. Parameters
      such as secondary structures of the target molecules and steric hindrance were
      investigated to better understand the mechanisms underlying a microarray
      hybridization reaction, with focus on their influence on the specificity of
      hybridization. With adequate hybridization conditions, false-positive signals
      could be almost completely prevented, resulting in clear data interpretation.
      Among 199 potential nonspecific hybridization events, only 1 false-positive
      signal was observed, whereas false-negative results were more common (17 of 41).
      Subsequent parameter analysis revealed that this was mainly an effect of reduced
      accessibility of probe binding sites caused by the secondary structures of the
      target molecules. False-negative results could be prevented and the overall
      signal intensities could be adjusted by introducing a new optimization strategy
      called directed application of capture oligonucleotides. The small number of
      false-positive signals in our data set is discussed, and a general optimization
      approach is suggested. Our results show that, compared to standard hybridization
      formats such as fluorescence in situ hybridization, a large number of
      oligonucleotide probes with different characteristics can be applied in parallel
      in a highly specific way without extensive experimental effort.

PMID- 12620823
TI  - Construction and screening of metagenomic libraries derived from enrichment
      cultures: generation of a gene bank for genes conferring alcohol oxidoreductase
      activity on Escherichia coli.
AB  - Enrichment of microorganisms with special traits and the construction of
      metagenomic libraries by direct cloning of environmental DNA have great potential
      for identifying genes and gene products for biotechnological purposes. We have
      combined these techniques to isolate novel genes conferring oxidation of short
      chain (C(2) to C(4)) polyols or reduction of the corresponding carbonyls. In
      order to favor the growth of microorganisms containing the targeted genes,
      samples collected from four different environments were incubated in the presence
      of glycerol and 1,2-propanediol. Subsequently, the DNA was extracted from the
      four samples and used to construct complex plasmid libraries. Approximately
      100,000 Escherichia coli strains of each library per test substrate were screened
      for the production of carbonyls from polyols on indicator agar. Twenty-four
      positive E. coli clones were obtained during the initial screen. Sixteen of them
      contained a plasmid (pAK101 to pAK116) which conferred a stable carbonyl-forming
      phenotype. Eight of the positive clones exhibited NAD(H)-dependent alcohol
      oxidoreductase activity with polyols or carbonyls as the substrates in crude
      extracts. Sequencing revealed that the inserts of pAK101 to pAK116 encoded 36
      complete and 17 incomplete presumptive protein-encoding genes. Fifty of these
      genes showed similarity to sequenced genes from a broad collection of different
      microorganisms. The genes responsible for the carbonyl formation of E. coli were
      identified for nine of the plasmids (pAK101, pAK102, pAK105, pAK107 to pAK110,
      pAK115, and pAK116). Analyses of the amino acid sequences deduced from these
      genes revealed that three (orf12, orf14, and orf22) encoded novel alcohol
      dehydrogenases of different types, four (orf5, sucB, fdhD, and yabF) encoded
      novel putative oxidoreductases belonging to groups distinct from alcohol
      dehydrogenases, one (glpK) encoded a putative glycerol kinase, and one (orf1)
      encoded a protein which showed no similarity to any other known gene product.

PMID- 12620825
TI  - Population dynamics of male-killing and non-male-killing spiroplasmas in
      Drosophila melanogaster.
AB  - The endosymbiotic bacteria Spiroplasma spp. are vertically transmitted through
      female hosts and are known to cause selective death of male offspring in insects.
      One strain of spiroplasma, NSRO, causes male killing in Drosophila species, and a
      non-male-killing variant of NSRO, designated NSRO-A, has been isolated. It is not
      known why NSRO-A does not kill males. In an attempt to understand the mechanism
      of male killing, we investigated the population dynamics of NSRO and NSRO-A
      throughout the developmental course of the laboratory host Drosophila
      melanogaster by using a quantitative PCR technique. In the early development of
      the host insect, the titers of NSRO were significantly higher than those of NSRO
      A at the first- and second-instar stages, whereas at the egg, third-instar, and
      pupal stages, the titers of the two spiroplasmas were almost the same. Upon adult
      emergence, the titers of the two spiroplasmas were similar, around 2 x 10(8) dnaA
      copy equivalents. However, throughout host aging, the two spiroplasmas showed
      strikingly different population growth patterns. The titers of NSRO increased
      exponentially for 3 weeks, attained a peak value of around 4 x 10(9) dnaA copy
      equivalents per insect, and then decreased. In contrast, the titers of NSRO-A
      were almost constant throughout the adult portion of the life cycle. In adult
      females, consequently, the titer of NSRO was significantly higher than the titer
      of NSRO-A except for a short period just after emergence. Although infection of
      adult females with NSRO resulted in almost 100% male killing, production of some
      male offspring was observed within 4 days after emergence when the titers of NSRO
      were as low as those of NSRO-A. Based on these results, we proposed a threshold
      density hypothesis for the expression of male killing caused by the spiroplasma.
      The extents of the bottleneck in the vertical transmission through host
      generations were estimated to be 5 x 10(-5) for NSRO and 3 x 10(-4) for NSRO-A.

PMID- 12620824
TI  - Isolation and characterization of thermophilic bacilli degrading cinnamic, 4
      coumaric, and ferulic acids.
AB  - Thirty-four thermophilic Bacillus sp. strains were isolated from decayed wood
      bark and a hot spring water sample based on their ability to degrade vanillic
      acid under thermophilic conditions. It was found that these bacteria were able to
      degrade a wide range of aromatic acids such as cinnamic, 4-coumaric, 3
      phenylpropionic, 3-(p-hydroxyphenyl)propionic, ferulic, benzoic, and 4
      hydroxybenzoic acids. The metabolic pathways for the degradation of these
      aromatic acids at 60 degrees C were examined by using one of the isolates, strain
      B1. Benzoic and 4-hydroxybenzoic acids were detected as breakdown products from
      cinnamic and 4-coumaric acids, respectively. The beta-oxidative mechanism was
      proposed to be responsible for these conversions. The degradation of benzoic and
      4-hydroxybenzoic acids was determined to proceed through catechol and gentisic
      acid, respectively, for their ring fission. It is likely that a non-beta
      oxidative mechanism is the case in the ferulic acid catabolism, which involved 4
      hydroxy-3-methoxyphenyl-beta-hydroxypropionic acid, vanillin, and vanillic acid
      as the intermediates. Other strains examined, which are V0, D1, E1, G2, ZI3, and
      H4, were found to have the same pathways as those of strain B1, except that
      strains V0, D1, and H4 had the ability to transform 3-hydroxybenzoic acid to
      gentisic acid, which strain B1 could not do.

PMID- 12620826
TI  - Evaluation of genetic diversity among Pseudomonas citronellolis strains isolated
      from oily sludge-contaminated sites.
AB  - The diversity among a set of bacterial strains that have the capacity to degrade
      total petroleum hydrocarbons (TPH) in soil contaminated with oily sludge
      (hazardous hydrocarbon waste from oil refineries) was determined. TPH is composed
      of alkane, aromatics, nitrogen-, sulfur-, and oxygen-containing compound, and
      asphaltene fractions of crude oil. The 150 bacterial isolates which could degrade
      TPH were isolated from soil samples obtained from diverse geoclimatic regions of
      India. All the isolates were biochemically characterized and identified with a
      Biolog microbial identification system and by 16S rDNA sequencing. Pseudomonas
      citronellolis predominated among the 150 isolates obtained from six different
      geographically diverse samplings. Of the isolates, 29 strains of P. citronellolis
      were selected for evaluating their genetic diversity. This was performed by
      molecular typing with repetitive sequence (Rep)-based PCR with primer sets ERIC
      (enterobacterial repetitive intergenic consensus), REP (repetitive extragenic
      palindromes), and BOXAIR and PCR-based ribotyping. Strain-specific and unique
      genotypic fingerprints were distinguished by these molecular typing strategies.
      The 29 strains of P. citronellolis were separated into 12 distinguishable
      genotypic groups by Rep-PCR and into seven genomic patterns by PCR-based
      ribotyping. The genetic diversity of the strains was related to the different
      geoclimatic isolation sites, type of oily sludge, and age of contamination of the
      sites. These results indicate that a combination of Rep-PCR fingerprinting and
      PCR-based ribotyping can be used as a high-resolution genomic fingerprinting
      method for elucidating intraspecies diversity among strains of P. citronellolis.

PMID- 12620827
TI  - Isolation of novel ultramicrobacteria classified as actinobacteria from five
      freshwater habitats in Europe and Asia.
AB  - We describe the first freshwater members of the class Actinobacteria that have
      been isolated. Nine ultramicro-size (<0.1 microm(3)) strains were isolated from
      five freshwater habitats in Europe and Asia. These habitats represent a broad
      spectrum of ecosystems, ranging from deep oligotrophic lakes to shallow
      hypertrophic lakes. Even when the isolated strains were grown in very rich media,
      the cell size was <0.1 microm(3) and was indistinguishable from the cell sizes of
      bacteria belonging to the smaller size classes of natural lake bacterioplankton.
      Hybridization of the isolates with oligonucleotide probes and phylogenetic
      analysis of the 16S rRNA gene sequences of the isolated strains revealed that
      they are affiliated with the class Actinobacteria and the family
      Microbacteriaceae. The previously described species with the highest levels of
      sequence similarity are Clavibacter michiganensis and Rathayibacter tritici, two
      phytopathogens of terrestrial plants. The 16S rRNA gene sequences of the nine
      isolates examined are more closely related to cloned sequences from uncultured
      freshwater bacteria than to the sequences of any previously isolated bacteria.
      The nine ultramicrobacteria isolated form, together with several uncultured
      bacteria, a diverse phylogenetic cluster (Luna cluster) consisting exclusively of
      freshwater bacteria. Isolates obtained from lakes that are ecologically different
      and geographically separated by great distances possess identical 16S rRNA gene
      sequences but have clearly different ecophysiological and phenotypic traits.
      Predator-prey experiments demonstrated that at least one of the ultramicro-size
      isolates is protected against predation by the bacterivorous nanoflagellate
      Ochromonas sp. strain DS.

PMID- 12620828
TI  - Survival of bacterial indicator species and bacteriophages after thermal
      treatment of sludge and sewage.
AB  - The inactivation of naturally occurring bacterial indicators and bacteriophages
      by thermal treatment of a dewatered sludge and raw sewage was studied. The sludge
      was heated at 80 degrees C, and the sewage was heated at 60 degrees C. In both
      cases phages were significantly more resistant to thermal inactivation than
      bacterial indicators, with the exception of spores of sulfite-reducing
      clostridia. Somatic coliphages and phages infecting Bacteroides fragilis were
      significantly more resistant than F-specific RNA phages. Similar trends were
      observed in sludge and sewage. The effects of thermal treatment on various phages
      belonging to the three groups mentioned above and on various enteroviruses added
      to sewage were also studied. The results revealed that the variability in the
      resistance of phages agreed with the data obtained with the naturally occurring
      populations and that the phages that were studied were more resistant to heat
      treatment than the enteroviruses that were studied. The phages survived
      significantly better than Salmonella choleraesuis, and the extents of
      inactivation indicated that naturally occurring bacteriophages can be used to
      monitor the inactivation of Escherichia coli and Salmonella.

PMID- 12620829
TI  - Use of a packed-column bioreactor for isolation of diverse protease-producing
      bacteria from antarctic soil.
AB  - Seventy-five aerobic heterotrophs have been isolated from a packed-column
      bioreactor inoculated with soil from Antarctica. The column was maintained at 10
      degrees C and continuously fed with a casein-containing medium to enrich protease
      producers. Twenty-eight isolates were selected for further characterization on
      the basis of morphology and production of clearing zones on skim milk plates.
      Phenotypic tests indicated that the strains were mainly psychrotrophs and
      presented a high morphological and metabolical diversity. The extracellular
      protease activities tested were optimal at neutral pH and between 30 and 45
      degrees C. 16S ribosomal DNA sequence analyses showed that the bioreactor was
      colonized by a wide variety of taxons, belonging to various bacterial divisions:
      alpha-, beta-, and gamma-Proteobacteria; the Flexibacter-Cytophaga-Bacteroides
      group; and high G+C gram-positive bacteria and low G+C gram-positive bacteria.
      Some strains represent candidates for new species of the genera Chryseobacterium
      and Massilia. This diversity demonstrates that the bioreactor is an efficient
      enrichment tool compared to traditional isolation strategies.

PMID- 12620830
TI  - A Synechococcus PglnA::luxAB fusion for estimation of nitrogen bioavailability to
      freshwater cyanobacteria.
AB  - In contrast to extensive studies of phosphorus, widely considered the main
      nutrient limiting phytoplankton biomass in freshwater ecosystems, there have been
      few studies on the role of nitrogen in controlling phytoplankton populations.
      This situation may be due partly to the complexity in estimating its utilization
      and bioavailability. In an attempt to provide a novel tool for this purpose, we
      fused the promoter of the glutamine synthetase-encoding gene, P glnA, from
      Synechococcus sp. strain PCC7942 to the luxAB luciferase-encoding genes of the
      bioluminescent bacterium Vibrio harveyi. The resulting construct was introduced
      into a neutral site on the Synechococcus chromosome to yield the reporter strain
      GSL. Light emission by this strain was dependent upon ambient nitrogen
      concentrations. The linear response range of the emitted luminescence was 1 mM to
      1 micro M for the inorganic nitrogen species tested (ammonium, nitrate, and
      nitrite) and 10- to 50-fold lower for glutamine and urea. When water samples
      collected from along a depth profile in Lake Kinneret (Israel) were exposed to
      the reporter strain, the bioluminescence of the reporter strain mirrored the
      total dissolved nitrogen concentrations determined for the same samples and was
      shown to be a sensitive indicator of the concentration of bioavailable nitrogen.

PMID- 12620831
TI  - Effects of light on the microcystin content of Microcystis strain PCC 7806.
AB  - Many cyanobacteria produce microcystins, hepatotoxic cyclic heptapeptides that
      can affect animals and humans. The effects of photosynthetically active radiation
      (PAR) on microcystin production by Microcystis strain PCC 7806 were studied in
      continuous cultures. Microcystis strain PCC 7806 was grown under PAR intensities
      between 10 and 403 micro mol of photons m(-2) s(-1) on a light-dark rhythm of 12
      h -12 h. The microcystin concentration per cell, per unit biovolume and protein,
      was estimated under steady-state and transient-state conditions and on a diurnal
      timescale. The cellular microcystin content varied between 34.5 and 81.4 fg cell(
      1) and was significantly positively correlated with growth rate under PAR-limited
      growth but not under PAR-saturated growth. Microcystin production and PAR showed
      a significant positive correlation under PAR-limited growth and a significant
      negative correlation under PAR-saturated growth. The microcystin concentration,
      as a ratio with respect to biovolume and protein, correlated neither with growth
      rate nor with PAR. Adaptation of microcystin production to a higher irradiance
      during transient states lasted for 5 days. During the period of illumination at a
      PAR of 10 and 40 micro mol of photons m(-2) s(-1), the intracellular microcystin
      content increased to values 10 to 20% higher than those at the end of the dark
      period. Extracellular (dissolved) microcystin concentrations were 20 times higher
      at 40 micro mol of photons m(-2) s(-1) than at 10 micro mol of photons m(-2) s(
      1) and did not change significantly during the light-dark cycles at both
      irradiances. In summary, our results showed a positive effect of PAR on
      microcystin production and content of Microcystis strain PCC 7806 up to the point
      where the maximum growth rate is reached, while at higher irradiances the
      microcystin production is inhibited.

PMID- 12620832
TI  - Relationship between spatial and genetic distance in Agrobacterium spp. in 1
      cubic centimeter of soil.
AB  - The spatial and genetic unit of bacterial population structure is the clone.
      Surprisingly, very little is known about the spread of a clone (spatial distance
      between clonally related bacteria) and the relationship between spatial distance
      and genetic distance, especially at very short scale (microhabitat scale), where
      cell division takes place. Agrobacterium spp. Biovar 1 was chosen because it is a
      soil bacterial taxon easy to isolate. A total of 865 microsamples 500 microm in
      diameter were sampled with spatial coordinates in 1 cm(3) of undisturbed soil.
      The 55 isolates obtained yielded 42 ribotypes, covering three genomic species
      based on amplified ribosomal DNA restriction analysis (ARDRA) of the intergenic
      spacer 16S-23S, seven of which contained two to six isolates. These clonemates
      (identical ARDRA patterns) could be found in the same microsample or 1 cm apart.
      The genetic diversity did not change with distance, indicating the same habitat
      variability across the cube. The mixing of ribotypes, as assessed by the spatial
      position of clonemates, corresponded to an overlapping of clones. Although the
      population probably was in a recession stage in the cube (10(3) agrobacteria g(
      1)), a high genetic diversity was maintained. In two independent microsamples
      (500 microm in diameter) at the invasion stage, the average genetic diversity was
      at the same level as in the cube. Quantification of the microdiversity landscape
      will help to estimate the probability of encounter between bacteria under
      realistic natural conditions and to set appropriate sampling strategies for
      population genetic analysis.

PMID- 12620833
TI  - Solar UV-B radiation inhibits the growth of Antarctic terrestrial fungi.
AB  - We tested the effects of solar radiation, and UV-B in particular, on the growth
      of Antarctic terrestrial fungi. The growth responses to solar radiation of five
      fungi, Geomyces pannorum, Phoma herbarum, Pythium sp., Verticillium sp., and
      Mortierella parvispora, each isolated from Antarctic terrestrial habitats, were
      examined on an agar medium in the natural Antarctic environment. A 3-h exposure
      to solar radiation of >287 nm reduced the hyphal extension rates of all species
      relative to controls kept in the dark. Pythium sp. cultures exposed to solar
      radiation for 1.5 h on five consecutive days were most sensitive to radiation of
      >287 nm, but radiation of >313 nm also inhibited growth to a lesser extent.
      Radiation of >400 nm had no effect on hyphal growth relative to controls kept in
      the dark. Short-wave solar UV-B radiation of between 287 and 305 nm inhibited the
      growth of Pythium sp. hyphae on and below the surface of the agar medium after 24
      h, but radiation of > or =345 nm only reduced the growth of surface hyphae.
      Similar detrimental effects of UV-B on surface and, to a lesser extent, submerged
      hyphae of all five fungi were shown in the laboratory by using artificial UV-B
      from fluorescent lamps. A comparison of growth responses to solar radiation and
      temperature showed that the species that were most resistant to UV radiation grew
      fastest at higher temperatures. These data suggest that solar UV-B reduces the
      growth of fungi on the soil surface in the Antarctic terrestrial environment.

PMID- 12620834
TI  - Luminescence resonance energy transfer-based high-throughput screening assay for
      inhibitors of essential protein-protein interactions in bacterial RNA polymerase.
AB  - The binding of sigma factors to core RNA polymerase is essential for the specific
      initiation of transcription in eubacteria and is thus critical for cell growth.
      Since the responsible protein-binding regions are highly conserved among all
      eubacteria but differ significantly from eukaryotic RNA polymerases, sigma factor
      binding is a promising target for drug discovery. A homogeneous assay for sigma
      binding to RNA polymerase (Escherichia coli) based on luminescence resonance
      energy transfer (LRET) was developed by using a europium-labeled sigma70 and an
      IC5-labeled fragment of the beta' subunit of RNA polymerase (amino acid residues
      100 through 309). Inhibition of sigma binding was measured by the loss of LRET
      through a decrease in IC5 emission. The technical advances offered by LRET
      resulted in a very robust assay suitable for high-throughput screening, and LRET
      was successfully used to screen a crude natural-product library. We illustrate
      this method as a powerful tool to investigate any essential protein-protein
      interaction for basic research and drug discovery.

PMID- 12620836
TI  - Development and evaluation of PCR assays for the detection of Paenibacillus
      larvae in honey samples: comparison with isolation and biochemical
      characterization.
AB  - PCR assays were developed for the direct detection of Paenibacillus larvae in
      honey samples and compared with isolation and biochemical characterization
      procedures. Different primer pairs, designed from the 16S rRNA and the
      metalloproteinase precursor gene regions, and different DNA extraction methods
      were tested and compared. The sensitivity of the reactions was evaluated by
      serial dilutions of DNA extracts obtained from P. larvae cultures. The
      specificity of the primers was assessed by analyzing related Paenibacillus and
      Bacillus strains isolated from honey. The PCR assays also amplified these related
      bacteria, but at lower sensitivity. In the next step, the PCR assays were applied
      to contaminated honey and other bee products originating from 15 countries.
      Lysozyme treatment followed by proteinase K digestion was determined to be the
      best DNA extraction method for P. larvae spores. The most sensitive primer pair
      detected P. larvae in 18 of 23 contaminated honey samples, as well as in pollen,
      wax, and brood. Honey specimens containing saprophyte bacilli and paenibacilli,
      but not P. larvae, were PCR negative. Although the isolation and biochemical
      identification method (BioLog) showed higher sensitivity and specificity, PCR
      proved to be a valuable technique for large-scale screening of honey samples for
      American foulbrood, especially considering its rapidity and moderate costs.

PMID- 12620835
TI  - Ethanol tolerance in the yeast Saccharomyces cerevisiae is dependent on cellular
      oleic acid content.
AB  - In this investigation, we examined the effects of different unsaturated fatty
      acid compositions of Saccharomyces cerevisiae on the growth-inhibiting effects of
      ethanol. The unsaturated fatty acid (UFA) composition of S. cerevisiae is
      relatively simple, consisting almost exclusively of the mono-UFAs palmitoleic
      acid (Delta(9)Z-C(16:1)) and oleic acid (Delta(9)Z-C(18:1)), with the former
      predominating. Both UFAs are formed in S. cerevisiae by the oxygen- and NADH
      dependent desaturation of palmitic acid (C(16:0)) and stearic acid (C(18:0)),
      respectively, catalyzed by a single integral membrane desaturase encoded by the
      OLE1 gene. We systematically altered the UFA composition of yeast cells in a
      uniform genetic background (i) by genetic complementation of a desaturase
      deficient ole1 knockout strain with cDNA expression constructs encoding insect
      desaturases with distinct regioselectivities (i.e., Delta(9) and Delta(11)) and
      substrate chain-length preferences (i.e., C(16:0) and C(18:0)); and, (ii) by
      supplementation of the same strain with synthetic mono-UFAs. Both experimental
      approaches demonstrated that oleic acid is the most efficacious UFA in overcoming
      the toxic effects of ethanol in growing yeast cells. Furthermore, the only other
      UFA tested that conferred a nominal degree of ethanol tolerance is cis-vaccenic
      acid (Delta(11)Z-C(18:1)), whereas neither Delta(11)Z-C(16:1) nor palmitoleic
      acid (Delta(9)Z-C(16:1)) conferred any ethanol tolerance. We also showed that the
      most ethanol-tolerant transformant, which expresses the insect desaturase
      TniNPVE, produces twice as much oleic acid as palmitoleic acid in the absence of
      ethanol and undergoes a fourfold increase in the ratio of oleic acid to
      palmitoleic acid in response to exposure to 5% ethanol. These findings are
      consistent with the hypothesis that ethanol tolerance in yeast results from
      incorporation of oleic acid into lipid membranes, effecting a compensatory
      decrease in membrane fluidity that counteracts the fluidizing effects of ethanol.

PMID- 12620837
TI  - Bioaugmentation as a tool to protect the structure and function of an activated
      sludge microbial community against a 3-chloroaniline shock load.
AB  - Bioaugmentation of bioreactors focuses on the removal of xenobiotics, with little
      attention typically paid to the recovery of disrupted reactor functions such as
      ammonium-nitrogen removal. Chloroanilines are widely used in industry as a
      precursor to a variety of products and are occasionally released into wastewater
      streams. This work evaluated the effects on activated-sludge reactor functions of
      a 3-chloroaniline (3-CA) pulse and bioaugmentation by inoculation with the 3-CA
      degrading strain Comamonas testosteroni I2 gfp. Changes in functions such as
      nitrification, carbon removal, and sludge compaction were studied in relation to
      the sludge community structure, in particular the nitrifying populations.
      Denaturing gradient gel electrophoresis (DGGE), real-time PCR, and fluorescent in
      situ hybridization (FISH) were used to characterize and enumerate the ammonia
      oxidizing microbial community immediately after a 3-CA shock load. Two days after
      the 3-CA shock, ammonium accumulated, and the nitrification activity did not
      recover over a 12-day period in the nonbioaugmented reactors. In contrast,
      nitrification in the bioaugmented reactor started to recover on day 4. The DGGE
      patterns and the FISH and real-time PCR data showed that the ammonia-oxidizing
      microbial community of the bioaugmented reactor recovered in structure, activity,
      and abundance, while the number of ribosomes of the ammonia oxidizers in the
      nonbioaugmented reactor decreased drastically and the community composition
      changed and did not recover. The settleability of the activated sludge was
      negatively influenced by the 3-CA addition, with the sludge volume index
      increasing by a factor of 2.3. Two days after the 3-CA shock in the
      nonbioaugmented reactor, chemical oxygen demand (COD) removal efficiency
      decreased by 36% but recovered fully by day 4. In contrast, in the bioaugmented
      reactor, no decrease of the COD removal efficiency was observed. This study
      demonstrates that bioaugmentation of wastewater reactors to accelerate the
      degradation of toxic chlorinated organics such as 3-CA protected the nitrifying
      bacterial community, thereby allowing faster recovery from toxic shocks.

PMID- 12620838
TI  - Seasonal abundance of total and pathogenic Vibrio parahaemolyticus in Alabama
      oysters.
AB  - Recent Vibrio parahaemolyticus outbreaks associated with consumption of raw
      shellfish in the United States focused attention on the occurrence of this
      organism in shellfish. From March 1999 through September 2000, paired oyster
      samples were collected biweekly from two shellfish-growing areas in Mobile Bay,
      Ala. The presence and densities of V. parahaemolyticus were determined by using
      DNA probes targeting the thermolabile hemolysin (tlh) and thermostable direct
      hemolysin (tdh) genes for confirmation of total and pathogenic V.
      parahaemolyticus, respectively. V. parahaemolyticus was detected in all samples
      with densities ranging from <10 to 12,000 g(-1). Higher V. parahaemolyticus
      densities were associated with higher water temperatures. Pathogenic strains were
      detected in 34 (21.8%) of 156 samples by direct plating or enrichment. Forty-six
      of 6,018 and 31 of 6,992 V. parahaemolyticus isolates from enrichments and direct
      plates, respectively, hybridized with the tdh probe. There was an apparent
      inverse relationship between water temperature and the prevalence of pathogenic
      strains. Pathogenic strains were of diverse serotypes, and 97% produced urease
      and possessed a tdh-related hemolysin (trh) gene. The O3:K6 serotype associated
      with pandemic spread and recent outbreaks in the United States was not detected.
      The efficient screening of numerous isolates by colony lift and DNA probe
      procedures may account for the higher prevalence of samples with tdh(+) V.
      parahaemolyticus than previously reported.

PMID- 12620839
TI  - Fnr is involved in oxygen control of Herbaspirillum seropedicae N-truncated NifA
      protein activity in Escherichia coli.
AB  - Herbaspirillum seropedicae is an endophytic diazotroph belonging to the beta
      subclass of the class Proteobacteria, which colonizes many members of the
      Gramineae. The activity of the NifA protein, a transcriptional activator of nif
      genes in H. seropedicae, is controlled by ammonium ions through its N-terminal
      domain and by oxygen through mechanisms that are not well understood. Here we
      report that the NifA protein of H. seropedicae is inactive and more susceptible
      to degradation in an fnr Escherichia coli background. Both effects correlate with
      oxygen exposure and iron deprivation. Our results suggest that the oxygen
      sensitivity and iron requirement for H. seropedicae NifA activity involve the Fnr
      protein.

PMID- 12620840
TI  - Synergistic degradation of linuron by a bacterial consortium and isolation of a
      single linuron-degrading variovorax strain.
AB  - The bacterial community composition of a linuron-degrading enrichment culture and
      the role of the individual strains in linuron degradation have been determined by
      a combination of methods, such as denaturing gradient gel electrophoresis of the
      total 16S rRNA gene pool, isolation and identification of strains, and
      biodegradation assays. Three strains, Variovorax sp. strain WDL1, Delftia
      acidovorans WDL34, and Pseudomonas sp. strain WDL5, were isolated directly from
      the linuron-degrading culture. In addition, subculture of this enrichment culture
      on potential intermediates in the degradation pathway of linuron (i.e., N,O
      dimethylhydroxylamine and 3-chloroaniline) resulted in the isolation of,
      respectively, Hyphomicrobium sulfonivorans WDL6 and Comamonas testosteroni WDL7.
      Of these five strains, only Variovorax sp. strain WDL1 was able to use linuron as
      the sole source of C, N, and energy. WDL1 first converted linuron to 3,4
      dichloroaniline (3,4-DCA), which transiently accumulated in the medium but was
      subsequently degraded. To the best of our knowledge, this is the first report of
      a strain that degrades linuron further than the aromatic intermediates.
      Interestingly, the rate of linuron degradation by strain WDL1 was lower than that
      for the consortium, but was clearly increased when WDL1 was coinoculated with
      each of the other four strains. D. acidovorans WDL34 and C. testosteroni WDL7
      were found to be responsible for degradation of the intermediate 3,4-DCA, and H.
      sulfonivorans WDL6 was the only strain able to degrade N,O-dimethylhydroxylamine.
      The role of Pseudomonas sp. strain WDL5 needs to be further elucidated. The
      degradation of linuron can thus be performed by a single isolate, Variovorax sp.
      strain WDL1, but is stimulated by a synergistic interaction with the other
      strains isolated from the same linuron-degrading culture.

PMID- 12620841
TI  - 2,4,6-trinitrotoluene reduction by an Fe-only hydrogenase in Clostridium
      acetobutylicum.
AB  - The role of hydrogenase on the reduction of 2,4,6-trinitrotoluene (TNT) in
      Clostridium acetobutylicum was evaluated. An Fe-only hydrogenase was isolated and
      identified by using TNT reduction activity as the selection basis. The formation
      of hydroxylamino intermediates by the purified enzyme corresponded to expected
      products for this reaction, and saturation kinetics were determined with a K(m)
      of 152 micro M. Comparisons between the wild type and a mutant strain lacking the
      region encoding an alternative Fe-Ni hydrogenase determined that Fe-Ni
      hydrogenase activity did not significantly contribute to TNT reduction.
      Hydrogenase expression levels were altered in various strains, allowing study of
      the role of the enzyme in TNT reduction rates. The level of hydrogenase activity
      in a cell system correlated (R(2) = 0.89) with the organism's ability to reduce
      TNT. A strain that overexpressed the hydrogenase activity resulted in maintained
      TNT reduction during late growth phases, which it is not typically observed in
      wild type strains. Strains exhibiting underexpression of hydrogenase produced
      slower TNT rates of reduction correlating with the determined level of
      expression. The isolated Fe-only hydrogenase is the primary catalyst for reducing
      TNT nitro substituents to the corresponding hydroxylamines in C. acetobutylicum
      in whole-cell systems. A mechanism for the reaction is proposed. Due to the
      prevalence of hydrogenase in soil microbes, this research may enhance the
      understanding of nitroaromatic compound transformation by common microbial
      communities.

PMID- 12620842
TI  - Electricity production by Geobacter sulfurreducens attached to electrodes.
AB  - Previous studies have suggested that members of the Geobacteraceae can use
      electrodes as electron acceptors for anaerobic respiration. In order to better
      understand this electron transfer process for energy production, Geobacter
      sulfurreducens was inoculated into chambers in which a graphite electrode served
      as the sole electron acceptor and acetate or hydrogen was the electron donor. The
      electron-accepting electrodes were maintained at oxidizing potentials by
      connecting them to similar electrodes in oxygenated medium (fuel cells) or to
      potentiostats that poised electrodes at +0.2 V versus an Ag/AgCl reference
      electrode (poised potential). When a small inoculum of G. sulfurreducens was
      introduced into electrode-containing chambers, electrical current production was
      dependent upon oxidation of acetate to carbon dioxide and increased
      exponentially, indicating for the first time that electrode reduction supported
      the growth of this organism. When the medium was replaced with an anaerobic
      buffer lacking nutrients required for growth, acetate-dependent electrical
      current production was unaffected and cells attached to these electrodes
      continued to generate electrical current for weeks. This represents the first
      report of microbial electricity production solely by cells attached to an
      electrode. Electrode-attached cells completely oxidized acetate to levels below
      detection (<10 micro M), and hydrogen was metabolized to a threshold of 3 Pa. The
      rates of electron transfer to electrodes (0.21 to 1.2 micro mol of electrons/mg
      of protein/min) were similar to those observed for respiration with Fe(III)
      citrate as the electron acceptor (E(o)' =+0.37 V). The production of current in
      microbial fuel cell (65 mA/m(2) of electrode surface) or poised-potential (163 to
      1,143 mA/m(2)) mode was greater than what has been reported for other microbial
      systems, even those that employed higher cell densities and electron-shuttling
      compounds. Since acetate was completely oxidized, the efficiency of conversion of
      organic electron donor to electricity was significantly higher than in previously
      described microbial fuel cells. These results suggest that the effectiveness of
      microbial fuel cells can be increased with organisms such as G. sulfurreducens
      that can attach to electrodes and remain viable for long periods of time while
      completely oxidizing organic substrates with quantitative transfer of electrons
      to an electrode.

PMID- 12620843
TI  - Evaluation of potential indicators of viral contamination in shellfish and their
      applicability to diverse geographical areas.
AB  - The distribution of the concentration of potential indicators of fecal viral
      pollution in shellfish was analyzed under diverse conditions over 18 months in
      diverse geographical areas. These microorganisms have been evaluated in relation
      to contamination by human viral pathogens detected in parallel in the analyzed
      shellfish samples. Thus, significant shellfish-growing areas from diverse
      countries in the north and south of Europe (Greece, Spain, Sweden, and the United
      Kingdom) were defined and studied by analyzing different physicochemical
      parameters in the water and the levels of Escherichia coli, F-specific RNA
      bacteriophages, and phages infecting Bacteroides fragilis strain RYC2056 in the
      shellfish produced, before and after depuration treatments. A total of 475
      shellfish samples were studied, and the results were statistically analyzed.
      According to statistical analysis, the presence of human viruses seems to be
      related to the presence of all potential indicators in the heavily contaminated
      areas, where E. coli would probably be suitable as a fecal indicator. The F-RNA
      phages, which are present in higher numbers in Northern Europe, seem to be
      significantly related to the presence of viral contamination in shellfish, with a
      very weak predictive value for hepatitis A virus, human adenovirus, and
      enterovirus and a stronger one for Norwalk-like virus. However, it is important
      to note that shellfish produced in A or clean B areas can sporadically contain
      human viruses even in the absence of E. coli or F-RNA phages. The data presented
      here will be useful in defining microbiological parameters for improving the
      sanitary control of shellfish consumed raw or barely cooked.

PMID- 12620844
TI  - Prokaryotic homologs of the eukaryotic 3-hydroxyanthranilate 3,4-dioxygenase and
      2-amino-3-carboxymuconate-6-semialdehyde decarboxylase in the 2-nitrobenzoate
      degradation pathway of Pseudomonas fluorescens strain KU-7.
AB  - The 2-nitrobenzoic acid degradation pathway of Pseudomonas fluorescens strain KU
      7 proceeds via a novel 3-hydroxyanthranilate intermediate. In this study, we
      cloned and sequenced a 19-kb DNA locus of strain KU-7 that encompasses the 3
      hydroxyanthranilate meta-cleavage pathway genes. The gene cluster, designated
      nbaEXHJIGFCDR, is organized tightly and in the same direction. The nbaC and nbaD
      gene products were found to be novel homologs of the eukaryotic 3
      hydroxyanthranilate 3,4-dioxygenase and 2-amino-3-carboxymuconate-6-semialdehyde
      decarboxylase, respectively. The NbaC enzyme carries out the oxidation of 3
      hydroxyanthranilate to 2-amino-3-carboxymuconate-6-semialdehyde, while the NbaD
      enzyme catalyzes the decarboxylation of the latter compound to 2-aminomuconate-6
      semialdehyde. The NbaC and NbaD proteins were overexpressed in Escherichia coli
      and characterized. The substrate specificity of the 23.8-kDa NbaC protein was
      found to be restricted to 3-hydroxyanthranilate. In E. coli, this enzyme oxidizes
      3-hydroxyanthranilate with a specific activity of 8 U/mg of protein. Site
      directed mutagenesis experiments revealed the essential role of two conserved
      histidine residues (His52 and His96) in the NbaC sequence. The NbaC activity is
      also dependent on the presence of Fe(2+) but is inhibited by other metal ions,
      such as Zn(2+), Cu(2+), and Cd(2+). The NbaD protein was overproduced as a 38.7
      kDa protein, and its specific activity towards 2-amino-3-carboxymuconate-6
      semialdehyde was 195 U/mg of protein. Further processing of 2-aminomuconate-6
      semialdehyde to pyruvic acid and acetyl coenzyme A was predicted to proceed via
      the activities of NbaE, NbaF, NbaG, NbaH, NbaI, and NbaJ. The predicted amino
      acid sequences of these proteins are highly homologous to those of the
      corresponding proteins involved in the metabolism of 2-aminophenol (e.g.,
      AmnCDEFGH in Pseudomonas sp. strain AP-3). The NbaR-encoding gene is predicted to
      have a regulatory function of the LysR family type. The function of the product
      of the small open reading frame, NbaX, like the homologous sequences in the
      nitrobenzene or 2-aminophenol metabolic pathway, remains elusive.

PMID- 12620845
TI  - Bacterial rRNA genes associated with soil suppressiveness against the plant
      parasitic nematode Heterodera schachtii.
AB  - The goal of this study was to identify bacteria involved in soil suppressiveness
      against the plant-parasitic nematode Heterodera schachtii. Since H. schachtii
      cysts isolated from the suppressive soil can transfer this beneficial property to
      nonsuppressive soils, analysis of the cyst-associated microorganisms should lead
      to the identification of the causal organisms. Our experimental approach was to
      identify bacterial rRNA genes (rDNA) associated with H. schachtii cysts obtained
      from soil mixtures with various levels of suppressiveness. We hypothesized that
      we would be able to identify bacteria involved in the suppressiveness by
      correlating population shifts with differing levels of suppressiveness. Soil
      treatments containing different amounts of suppressive and fumigation-induced
      nonsuppressive soils exhibited various levels of suppressiveness after two
      nematode generations. The 10%-suppressive-soil treatment contained numbers of
      eggs per gram of soil similar to those of the 100%-suppressive-soil treatment,
      indicating that the suppressive factor(s) had been transferred. Bacterial rDNA
      associated with H. schachtii cysts were identified using a culture-independent
      method termed oligonucleotide fingerprinting of rRNA genes. Bacteria from five
      major taxonomic groups (Actinobacteria, Cytophaga-Flexibacter-Bacteroides, alpha
      Proteobacteria, beta-Proteobacteria, and gamma-Proteobacteria) were identified.
      Three bacterial rDNA groups contained clones that were more prevalent in the
      highly suppressive soil treatments than in the less suppressive treatments,
      indicating a potential involvement in the H. schachtii suppressiveness. When
      these three groups were examined with specific PCR analyses performed on H.
      schachtii cysts that developed in soils treated with three biocidal compounds,
      only one bacterial rDNA group with moderate to high sequence identity to rDNA
      from several Rhizobium species and uncultured alpha-proteobacterial clones was
      consistently associated with the highly suppressive treatments. A quantitative
      PCR analysis confirmed the association of this Rhizobium-like rDNA group with the
      H. schachtii suppressiveness.

PMID- 12620846
TI  - Conidial hydrophobins of Aspergillus fumigatus.
AB  - The surface of Aspergillus fumigatus conidia, the first structure recognized by
      the host immune system, is covered by rodlets. We report that this outer cell
      wall layer contains two hydrophobins, RodAp and RodBp, which are found as highly
      insoluble complexes. The RODA gene was previously characterized, and DeltarodA
      conidia do not display a rodlet layer (N. Thau, M. Monod, B. Crestani, C.
      Rolland, G. Tronchin, J. P. Latge, and S. Paris, Infect. Immun. 62:4380-4388,
      1994). The RODB gene was cloned and disrupted. RodBp was highly homologous to
      RodAp and different from DewAp of A. nidulans. DeltarodB conidia had a rodlet
      layer similar to that of the wild-type conidia. Therefore, unlike RodAp, RodBp is
      not required for rodlet formation. The surface of DeltarodA conidia is granular;
      in contrast, an amorphous layer is present at the surface of the conidia of the
      DeltarodA DeltarodB double mutant. These data show that RodBp plays a role in the
      structure of the conidial cell wall. Moreover, rodletless mutants are more
      sensitive to killing by alveolar macrophages, suggesting that RodAp or the rodlet
      structure is involved in the resistance to host cells.

PMID- 12620847
TI  - Identification and characterization of two novel clostridial bacteriocins,
      circularin A and closticin 574.
AB  - Two novel antibacterial peptides of clostridial species were purified, N
      terminally sequenced, and characterized. Moreover, their structural genes were
      identified. Closticin 574 is an 82-amino-acid bacteriocin produced by Clostridium
      tyrobutyricum ADRIAT 932. The supernatant of the producing strain showed a high
      level of activity against the indicator strain C. tyrobutyricum. The protein is
      synthesized as a preproprotein that is possibly secreted via the general
      secretion pathway, after which it is hydrolyzed at an Asp-Pro site. Circularin A
      is produced by Clostridium beijerinckii ATCC 25752 as a prepeptide of 72 amino
      acids. Cleavage of the prepeptide between the third leucine and fourth valine
      residues followed by a head-to-tail ligation between the N and C termini creates
      a circular antimicrobial peptide of 69 amino acids. The unusually small
      circularin A leader peptide of three amino acids is cleaved off in this process.
      The supernatant of C. beijerinckii ATCC 25752 showed a broad antibacterial
      activity range.

PMID- 12620849
TI  - Tri1 encodes the cytochrome P450 monooxygenase for C-8 hydroxylation during
      trichothecene biosynthesis in Fusarium sporotrichioides and resides upstream of
      another new Tri gene.
AB  - Many Fusarium species produce one or more agriculturally important trichothecene
      mycotoxins, and the relative level of toxicity of these compounds is determined
      by the pattern of oxygenations and acetylations or esterifications on the core
      trichothecene structure. Previous studies with UV-induced Fusarium
      sporotrichioides NRRL 3299 trichothecene mutants defined the Tri1 gene and
      demonstrated that it was required for addition of the oxygen at the C-8 position
      during trichothecene biosynthesis. We have cloned and characterized the Tri1 gene
      from NRRL 3299 and found that it encodes a cytochrome P450 monooxygenase. The
      disruption of Tri1 blocks production of C-8-oxygenated trichothecenes and leads
      to the accumulation of 4,15-diacetoxyscirpenol, the same phenotype observed in
      the tri1 UV-induced mutants MB1716 and MB1370. The Tri1 disruptants and the tri1
      UV-induced mutants do not complement one another when coinoculated, and the Tri1
      gene sequence restores T-2 toxin production in both MB1716 and MB1370. The DNA
      sequence flanking Tri1 contains another new Tri gene. Thus, Tri1 encodes a C-8
      hydroxylase and is located either in a new distal portion of the trichothecene
      gene cluster or in a second separate trichothecene gene cluster.

PMID- 12620848
TI  - Transcriptional cross-regulation of the catechol and protocatechuate branches of
      the beta-ketoadipate pathway contributes to carbon source-dependent expression of
      the Acinetobacter sp. strain ADP1 pobA gene.
AB  - Transcriptional control of carbon source preferences by Acinetobacter sp. strain
      ADP1 was assessed with a pobA::lacZ fusion during growth on alternative
      substrates. The pobA-encoded enzyme catalyzes the first step in the degradation
      of 4-hydroxybenzoate, a compound consumed rapidly as a sole carbon source. If
      additional aromatic carbon sources are available, 4-hydroxybenzoate consumption
      is inhibited by unknown mechanisms. As reported here, during growth on aromatic
      substrates, pobA was not expressed despite the presence of 4-hydroxybenzoate, an
      inducer that normally causes the PobR regulator to activate pobA transcription.
      Growth on organic acids such as succinate, fumarate, and acetate allowed higher
      levels of pobA expression. In each case, pobA expression increased at the end of
      the exponential growth phase. Complex transcriptional regulation controlled 4
      hydroxybenzoate catabolism in multisubstrate environments. Additional studies
      focused on the wild-type preference for benzoate consumption prior to 4
      hydroxybenzoate consumption. These compounds are degraded via the catechol and
      protocatechuate branches of the beta-ketoadipate pathway, respectively. Here,
      mutants were characterized that degraded benzoate and 4-hydroxybenzoate
      concurrently. These mutants lacked the BenM and CatM transcriptional regulators
      that normally activate genes for benzoate catabolism. A model is presented in
      which BenM and CatM prevent pobA expression indirectly during growth on benzoate.
      These regulators may affect pobA expression by lowering the PcaK-mediated uptake
      of 4-hydroxybenzoate. Consistent with this model, BenM and CatM bound in vitro to
      an operator-promoter fragment controlling the expression of several pca genes,
      including pcaK. These studies provide the first direct evidence of
      transcriptional cross-regulation between the distinct but analogous branches of
      the beta-ketoadipate pathway.

PMID- 12620850
TI  - Respiration of 13C-labeled substrates added to soil in the field and subsequent
      16S rRNA gene analysis of 13C-labeled soil DNA.
AB  - Our goal was to develop a field soil biodegradation assay using (13)C-labeled
      compounds and identify the active microorganisms by analyzing 16S rRNA genes in
      soil-derived (13)C-labeled DNA. Our biodegradation approach sought to minimize
      microbiological artifacts caused by physical and/or nutritional disturbance of
      soil associated with sampling and laboratory incubation. The new field-based
      assay involved the release of (13)C-labeled compounds (glucose, phenol, caffeine,
      and naphthalene) to soil plots, installation of open-bottom glass chambers that
      covered the soil, and analysis of samples of headspace gases for (13)CO(2)
      respiration by gas chromatography/mass spectrometry (GC/MS). We verified that the
      GC/MS procedure was capable of assessing respiration of the four substrates added
      (50 ppm) to 5 g of soil in sealed laboratory incubations. Next, we determined
      background levels of (13)CO(2) emitted from naturally occurring soil organic
      matter to chambers inserted into our field soil test plots. We found that the
      conservative tracer, SF(6), that was injected into the headspace rapidly diffused
      out of the soil chamber and thus would be of little value for computing the
      efficiency of retaining respired (13)CO(2). Field respiration assays using all
      four compounds were completed. Background respiration from soil organic matter
      interfered with the documentation of in situ respiration of the slowly
      metabolized (caffeine) and sparingly soluble (naphthalene) compounds.
      Nonetheless, transient peaks of (13)CO(2) released in excess of background were
      found in glucose- and phenol-treated soil within 8 h. Cesium-chloride separation
      of (13)C-labeled soil DNA was followed by PCR amplification and sequencing of 16S
      rRNA genes from microbial populations involved with (13)C-substrate metabolism. A
      total of 29 full sequences revealed that active populations included relatives of
      Arthrobacter, Pseudomonas, Acinetobacter, Massilia, Flavobacterium, and
      Pedobacter spp. for glucose; Pseudomonas, Pantoea, Acinetobacter, Enterobacter,
      Stenotrophomonas, and Alcaligenes spp. for phenol; Pseudomonas, Acinetobacter,
      and Variovorax spp. for naphthalene; and Acinetobacter, Enterobacter,
      Stenotrophomonas, and Pantoea spp. for caffeine.

PMID- 12620851
TI  - Improved anaerobic use of arginine by Saccharomyces cerevisiae.
AB  - Anaerobic arginine catabolism in Saccharomyces cerevisiae was genetically
      modified to allow assimilation of all four rather than just three of the nitrogen
      atoms in arginine. This was accomplished by bypassing normal formation of
      proline, an unusable nitrogen source in the absence of oxygen, and causing
      formation of glutamate instead. A pro3 ure2 strain expressing a PGK1 promoter
      driven PUT2 allele encoding Delta(1)-pyrroline-5-carboxylate dehydrogenase
      lacking a mitochondrial targeting sequence produced significant cytoplasmic
      activity, accumulated twice as much intracellular glutamate, and produced twice
      as much cell mass as the parent when grown anaerobically on limiting arginine as
      sole nitrogen source.

PMID- 12620852
TI  - Infectivity of RNA from inactivated poliovirus.
AB  - During inactivation of poliovirus type 1 (PV-1) by exposure to UV, hypochlorite,
      and heat (72 degrees C), the infectivity of the virus was compared with that of
      its RNA. DEAE-dextran (1-mg/ml concentration in Dulbecco's modified Eagle medium
      buffered with 0.05 M Tris, pH 7.4) was used to facilitate transfecting PV-1 RNA
      into FRhK-4 host cells. After interaction of PV-1 RNA with cell monolayer at room
      temperature (21 to 22 degrees C) for 20 min, the monolayers were washed with 5 ml
      of Hanks balanced salt solution. The remainder of the procedure was the same as
      that for the conventional plaque technique, which was also used for quantifying
      the PV-1 whole-particle infectivity. Plaque formation by extracted RNA was
      approximately 100,000-fold less efficient than that by whole virions. The slopes
      of best-fit regression lines of inactivation curves for virion infectivity and
      RNA infectivity were compared to determine the target of inactivation. For UV and
      hypochlorite inactivation the slopes of inactivation curves of virion infectivity
      and RNA infectivity were not statistically different. However, the difference of
      slopes of inactivation curves of virion infectivity and RNA infectivity was
      statistically significant for thermal inactivation. The results of these
      experiments indicate that viral RNA is a primary target of UV and hypochlorite
      inactivations but that the sole target of thermal inactivation is the viral
      capsid.

PMID- 12620853
TI  - The genes coding for enterocin EJ97 production by Enterococcus faecalis EJ97 are
      located on a conjugative plasmid.
AB  - Enterococcus faecalis EJ97 produces a cationic bacteriocin (enterocin EJ97) of
      low molecular mass (5,327.7 Da). The complete amino acid sequence of enterocin
      EJ97 was elucidated after automated microsequencing of oligopeptides generated by
      endoproteinase GluC digestion and cyanogen bromide treatment. Transfer of the 60
      kb conjugative plasmid pEJ97 from the bacteriocinogenic strain E. faecalis EJ97
      to E. faecalis OG1X conferred bacteriocin production and resistance on the
      recipient. The genetic determinants of enterocin EJ97 were located in an 11.3-kb
      EcoRI-BglII DNA fragment of pEJ97. This region was cloned and sequenced. It
      contains the ej97A structural gene plus three open reading frames (ORFs) (ej97B,
      ej97C, and ej97D) and three putative ORFs transcribed in the opposite direction
      (orfA, orfB, and orfC). The gene ej97A translated as a 44-amino-acid residue
      mature protein lacking a leader peptide with no homology to other bacteriocins
      described so far. The product of ej97B (Ej97B) shows strong homology in its C
      terminal domain to the superfamily of bacterial ATP-binding cassette
      transporters. The products of ej97C (Ej97C) and ej97D (Ej97D) could be proteins
      with 71 and 64 residues, respectively, of unknown functions and with no
      significant similarity to known proteins. There are two additional ORFs (ORF1 and
      ORF6) flanking the ej97 module, which have been identified as a transposon-like
      structure (tnp). ORF1 shows similarities to transposase of the Lactococcus lactis
      element ISS1 and is up to 50% identical to IS1216. This is flanked by two 18-bp
      inverted repeats (IRs) that are almost identical to those of ISS1 and IS1216.
      ORF6 (resEJ97) shows strong homology to the resolvase of plasmid pAM373 and up to
      40 to 50% homology with the recombinase of several multiresistant plasmids and
      transposons from Staphylococcus aureus and E. faecalis. These data suggest that
      EJ97 could represent a new class of bacteriocins with a novel secretion mechanism
      and that the whole structure could be a composite transposon. Furthermore, two
      additional gene clusters were found: one cluster is probably related to the
      region responsible for the replication of plasmid pEJ97, and the second cluster
      is related to the sex pheromone response. These regions showed a high homology to
      the corresponding regions of the conjugative plasmids pAM373, pPD1, and pAD1 of
      E. faecalis, suggesting that they have a common origin.

PMID- 12620854
TI  - Enterotoxigenicity and genetic relatedness of Clostridium perfringens isolates
      from retail foods in the United States.
AB  - Clostridium perfringens is a leading cause of bacterial food-borne illness in
      countries where consumption of meat and poultry is high. For example, each year
      in the United States, this organism is the second or third most common cause of
      confirmed cases of food-borne illness. Surveys of the incidence of this organism
      in retail foods were done in the 1960s without regard to whether isolates were
      enterotoxigenic. It is now known that not all strains of this organism possess
      the enterotoxin gene responsible for illness. We examined the incidence of this
      organism in 131 food samples from retail food stores in an area of the
      northeastern United States. Forty isolates were obtained by using the iron milk
      method at 45 degrees C, with confirmation by use of motility nitrate and lactose
      gelatin media. The presence of the C. perfringens enterotoxin (cpe) and alpha
      toxin (cpa) genes was determined by PCR using previously published primer
      sequences. All isolates possessed cpa. None of the isolates were identified as
      carrying the cpe gene by this method or by another method using a digoxigenin
      labeled gene probe. Consistent with these results, none of the sporulating-cell
      extracts contained enterotoxin as determined by reverse passive latex
      hemagglutination. Pulsed-field gel electrophoresis was used to determine the
      genetic relatedness of the isolates. About 5% of the isolates were considered to
      be closely related (2- to 3-band difference). The others were considered to be
      unrelated to one another. The results demonstrate the rarity of cpe(+) strains in
      retail foods and the genetic diversity among nonoutbreak strains.

PMID- 12620855
TI  - Characterization of the Streptomyces sp. strain C5 snp locus and development of
      snp-derived expression vectors.
AB  - The Streptomyces sp. strain C5 snp locus is comprised of two divergently oriented
      genes: snpA, a metalloproteinase gene, and snpR, which encodes a LysR-like
      activator of snpA transcription. The transcriptional start point of snpR is
      immediately downstream of a strong T-N(11)-A inverted repeat motif likely to be
      the SnpR binding site, while the snpA transcriptional start site overlaps the ATG
      start codon, generating a leaderless snpA transcript. By using the aphII reporter
      gene of pIJ486 as a reporter, the plasmid-borne snpR-activated snpA promoter was
      ca. 60-fold more active than either the nonactivated snpA promoter or the melC1
      promoter of pIJ702. The snpR-activated snpA promoter produced reporter protein
      levels comparable to those of the up-mutated ermE* promoter. The SnpR-activated
      snpA promoter was built into a set of transcriptional and translational fusion
      expression vectors which have been used for the intracellular expression of
      numerous daunomycin biosynthesis pathway genes from Streptomyces sp. strain C5 as
      well as the expression and secretion of soluble recombinant human endostatin.

PMID- 12620856
TI  - N2O-producing microorganisms in the gut of the earthworm Aporrectodea caliginosa
      are indicative of ingested soil bacteria.
AB  - The main objectives of this study were (i) to determine if gut wall-associated
      microorganisms are responsible for the capacity of earthworms to emit nitrous
      oxide (N(2)O) and (ii) to characterize the N(2)O-producing bacteria of the
      earthworm gut. The production of N(2)O in the gut of garden soil earthworms
      (Aporrectodea caliginosa) was mostly associated with the gut contents rather than
      the gut wall. Under anoxic conditions, nitrite and N(2)O were transient products
      when supplemental nitrate was reduced to N(2) by gut content homogenates. In
      contrast, nitrite and N(2)O were essentially not produced by nitrate-supplemented
      soil homogenates. The most probable numbers of fermentative anaerobes and
      microbes that used nitrate as a terminal electron acceptor were approximately 2
      orders of magnitude higher in the earthworm gut than in the soil from which the
      earthworms originated. The fermentative anaerobes in the gut and soil displayed
      similar physiological functionalities. A total of 136 N(2)O-producing isolates
      that reduced either nitrate or nitrite were obtained from high serial dilutions
      of gut homogenates. Of the 25 representative N(2)O-producing isolates that were
      chosen for characterization, 22 isolates exhibited >99% 16S rRNA gene sequence
      similarity with their closest cultured relatives, which in most cases was a soil
      bacterium, most isolates were affiliated with the gamma subclass of the class
      Proteobacteria or with the gram-positive bacteria with low DNA G+C contents, and
      5 isolates were denitrifiers and reduced nitrate to N(2)O or N(2). The initial
      N(2)O production rates of denitrifiers were 1 to 2 orders of magnitude greater
      than those of the nondenitrifying isolates. However, most nondenitrifying nitrate
      dissimilators produced nitrite and might therefore indirectly stimulate the
      production of N(2)O via nitrite-utilizing denitrifiers in the gut. The results of
      this study suggest that most of the N(2)O emitted by earthworms is due to the
      activation of ingested denitrifiers and other nitrate-dissimilating bacteria in
      the gut lumen.

PMID- 12620857
TI  - The earthworm gut: an ideal habitat for ingested N2O-producing microorganisms.
AB  - The in vivo production of nitrous oxide (N(2)O) by earthworms is due to their gut
      microbiota, and it is hypothesized that the microenvironment of the gut activates
      ingested N(2)O-producing soil bacteria. In situ measurement of N(2)O and O(2)
      with microsensors demonstrated that the earthworm gut is anoxic and the site of
      N(2)O production. The gut had a pH of 6.9 and an average water content of
      approximately 50%. The water content within the gut decreased from the anterior
      end to the posterior end. In contrast, the concentration of N(2)O increased from
      the anterior end to the mid-gut region and then decreased along the posterior
      part of the gut. Compared to the soil in which worms lived and fed, the gut of
      the earthworm was highly enriched in total carbon, organic carbon, and total
      nitrogen and had a C/N ratio of 7 (compared to a C/N ratio of 12 in soil). The
      aqueous phase of gut contents contained up to 80 mM glucose and numerous
      compounds that were indicative of anaerobic metabolism, including up to 9 mM
      formate, 8 mM acetate, 3 mM lactate, and 2 mM succinate. Compared to the soil
      contents, nitrite and ammonium were enriched in the gut up to 10- and 100-fold,
      respectively. The production of N(2)O by soil was induced when the gut
      environment was simulated in anoxic microcosms for 24 h (the approximate time for
      passage of soil through the earthworm). Anoxia, high osmolarity, nitrite, and
      nitrate were the dominant factors that stimulated the production of N(2)O.
      Supplemental organic carbon had a very minimal stimulatory effect on the
      production of N(2)O, and addition of buffer or ammonium had essentially no effect
      on the initial N(2)O production rates. However, a combination of supplements
      yielded rates greater than that obtained mathematically for single supplements,
      suggesting that the maximum rates observed were due to synergistic effects of
      supplements. Collectively, these results indicate that the special
      microenvironment of the earthworm gut is ideally suited for N(2)O-producing
      bacteria and support the hypothesis that the in situ conditions of the earthworm
      gut activate ingested N(2)O-producing soil bacteria during gut passage.

PMID- 12620858
TI  - Synthesis of imidazol-2-yl amino acids by using cells from alkane-oxidizing
      bacteria.
AB  - Sixty-one strains of alkane-oxidizing bacteria were tested for their ability to
      oxidize N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide to imidazol-2-yl amino
      acids applicable for pharmaceutical purposes. After growth with n-alkane, 15
      strains formed different imidazol-2-yl amino acids identified by chemical
      structure analysis (mass and nuclear magnetic resonance spectrometry). High
      yields of imidazol-2-yl amino acids were produced by the strains Gordonia
      rubropertincta SBUG 105, Gordonia terrae SBUG 253, Nocardia asteroides SBUG 175,
      Rhodococcus erythropolis SBUG 251, and Rhodococcus erythropolis SBUG 254.
      Biotransformation occurred via oxidation of the alkyl side chain and produced 1
      acetylamino-4-phenylimidazol-2-yl-6-aminohexanoic acid and the butanoic acid
      derivative. In addition, the acetylamino group of these products and of the
      substrate was transformed to an amino group. The product pattern as well as the
      transformation pathway of N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide
      differed in the various strains used.

PMID- 12620859
TI  - Biogeochemical evidence that thermophilic archaea mediate the anaerobic oxidation
      of methane.
AB  - Distributions and isotopic analyses of lipids from sediment cores at a
      hydrothermally active site in the Guaymas Basin with a steep sedimentary
      temperature gradient revealed the presence of archaea that oxidize methane
      anaerobically. The presence of strongly (13)C-depleted lipids at greater depths
      in the sediments suggests that microbes involved in anaerobic oxidation of
      methane are present and presumably active at environmental temperatures of >30
      degrees C, indicating that this process can occur not only at cold seeps but also
      at hydrothermal sites. The distribution of the membrane tetraether lipids of the
      methanotrophic archaea shows that these organisms have adapted their membrane
      composition to these high environmental temperatures.

PMID- 12620860
TI  - Prevalence of bacteria of division TM7 in human subgingival plaque and their
      association with disease.
AB  - Members of the uncultivated bacterial division TM7 have been detected in the
      human mouth, but little information is available regarding their prevalence and
      diversity at this site. Human subgingival plaque samples from healthy sites and
      sites exhibiting various stages of periodontal disease were analyzed for the
      presence of TM7 bacteria. TM7 ribosomal DNA (rDNA) was found in 96% of the
      samples, and it accounted for approximately 0.3%, on average, of all bacterial
      rDNA in the samples as determined by real-time quantitative PCR. Two new
      phylotypes of this division were identified, and members of the division were
      found to exhibit filamentous morphology by fluorescence in situ hybridization.
      The abundance of TM7 rDNA relative to total bacterial rDNA was higher in sites
      with mild periodontitis (0.54% +/- 0.1%) than in either healthy sites (0.21% +/-
      0.05%, P < 0.01) or sites with severe periodontitis (0.29% +/- 0.06%, P < 0.05).
      One division subgroup, the I025 phylotype, was detected in 1 of 18 healthy
      samples and 38 of 58 disease samples. These data suggest that this phylotype, and
      the TM7 bacterial division in general, may play a role in the multifactorial
      process leading to periodontitis.

PMID- 12620861
TI  - Early events in the Fusarium verticillioides-maize interaction characterized by
      using a green fluorescent protein-expressing transgenic isolate.
AB  - The infection of maize by Fusarium verticillioides can result in highly variable
      disease symptoms ranging from asymptomatic plants to severe rotting and wilting.
      We produced F. verticillioides green fluorescent protein-expressing transgenic
      isolates and used them to characterize early events in the F. verticillioides
      maize interaction that may affect later symptom appearance. Plants grown in F.
      verticillioides-infested soil were smaller and chlorotic. The fungus colonized
      all of the underground parts of a plant but was found primarily in lateral roots
      and mesocotyl tissue. In some mesocotyl cells, conidia were produced within 14 to
      21 days after infection. Intercellular mycelium was detected, but additional
      cells were not infected until 21 days after planting. At 25 to 30 days after
      planting, the mesocotyl and main roots were heavily infected, and rotting
      developed in these tissues. Other tissues, including the adventitious roots and
      the stem, appeared to be healthy and contained only a small number of hyphae.
      These results imply that asymptomatic systemic infection is characterized by a
      mode of fungal development that includes infection of certain tissues,
      intercellular growth of a limited number of fungal hyphae, and reproduction of
      the fungus in a few cells without invasion of other cells. Development of visibly
      rotted tissue is associated with massive production of fungal mycelium and much
      less organized growth.

PMID- 12620862
TI  - Mass transport of macromolecules within an in vitro model of supragingival
      plaque.
AB  - The aim of this study was to examine the diffusion of macromolecules through an
      in vitro biofilm model of supragingival plaque. Polyspecies biofilms containing
      Actinomyces naeslundii, Fusobacterium nucleatum, Streptococcus oralis,
      Streptococcus sobrinus, Veillonella dispar, and Candida albicans were formed on
      sintered hydroxyapatite disks and then incubated at room temperature for defined
      periods with fluorescent markers with molecular weights ranging from 3,000 to
      900,000. Subsequent examination by confocal laser scanning microscopy revealed
      that the mean square penetration depths for all tested macromolecules except
      immunoglobulin M increased linearly with time, diffusion coefficients being
      linearly proportional to the cube roots of the molecular weights of the probes
      (range, 10,000 to 240,000). Compared to diffusion in bulk water, diffusion in the
      biofilms was markedly slower. The rate of diffusion for each probe appeared to be
      constant and not a function of biofilm depth. Analysis of diffusion phenomena
      through the biofilms suggested tortuosity as the most probable explanation for
      retarded diffusion. Selective binding of probes to receptors present in the
      biofilms could not explain the observed extent of retardation of diffusion. These
      results are relevant to oral health, as selective attenuated diffusion of
      fermentable carbohydrates and acids produced within dental plaque is thought to
      be essential for the development of carious lesions.

PMID- 12620863
TI  - Role of Rhodobacter sp. strain PS9, a purple non-sulfur photosynthetic bacterium
      isolated from an anaerobic swine waste lagoon, in odor remediation.
AB  - Temporal pigmentation changes resulting from the development of a purple color in
      anaerobic swine waste lagoons were investigated during a 4-year period. The major
      purple photosynthetic bacterium responsible for these color changes and the
      corresponding reductions in odor was isolated from nine photosynthetic lagoons.
      By using morphological, physiological, and phylogenetic characterization methods
      we identified the predominant photosynthetic bacterium as a new strain of
      Rhodobacter, designated Rhodobacter sp. strain PS9. Rhodobacter sp. strain PS9 is
      capable of photoorganotrophic growth on a variety of organic compounds, including
      all of the characteristic volatile organic compounds (VOC) responsible for the
      odor associated with swine production facilities (J. A. Zahn, A. A. DiSpirito, Y.
      S. Do, B. E. Brooks, E. E. Copper, and J. L. Hatfield, J. Environ. Qual. 30:624
      634, 2001). The seasonal variations in airborne VOC emitted from waste lagoons
      showed that there was a 80 to 93% decrease in the concentration of VOC during a
      photosynthetic bloom. During the height of a bloom, the Rhodobacter sp. strain
      PS9 population accounted for 10% of the total community and up to 27% of the
      eubacterial community based on 16S ribosomal DNA signals. Additional observations
      based on seasonal variations in meteorological, biological, and chemical
      parameters suggested that the photosynthetic blooms of Rhodobacter sp. strain PS9
      were correlated with lagoon water temperature and with the concentrations of
      sulfate and phosphate. In addition, the photosynthetic blooms of Rhodobacter sp.
      strain PS9 were inversely correlated with the concentrations of protein and
      fluoride.

PMID- 12620864
TI  - Natural genetic transformation in monoculture Acinetobacter sp. strain BD413
      biofilms.
AB  - Horizontal gene transfer by natural genetic transformation in Acinetobacter sp.
      strain BD413 was investigated by using gfp carried by the autonomously
      replicating plasmid pGAR1 in a model monoculture biofilm. Biofilm age, DNA
      concentration, and biofilm mode of growth were evaluated to determine their
      effects on natural genetic transformation. The highest transfer frequencies were
      obtained in young and actively growing biofilms when high DNA concentrations were
      used and when the biofilm developed during continuous exposure to fresh medium
      without the presence of a significant amount of cells in the suspended fraction.
      Biofilms were highly amenable to natural transformation. They did not need to
      advance to an optimal growth phase which ensured the presence of optimally
      competent biofilm cells. An exposure time of only 15 min was adequate for
      transformation, and the addition of minute amounts of DNA (2.4 fg of pGAR1 per h)
      was enough to obtain detectable transfer frequencies. The transformability of
      biofilms lacking competent cells due to growth in the presence of cells in the
      bulk phase could be reestablished by starving the noncompetent biofilm prior to
      DNA exposure. Overall, the evidence suggests that biofilms offer no barrier
      against effective natural genetic transformation of Acinetobacter sp. strain
      BD413.

PMID- 12620865
TI  - Comparative genomic analyses of the vibrio pathogenicity island and cholera toxin
      prophage regions in nonepidemic serogroup strains of Vibrio cholerae.
AB  - Two major virulence factors are associated with epidemic strains (O1 and O139
      serogroups) of Vibrio cholerae: cholera toxin encoded by the ctxAB genes and
      toxin-coregulated pilus encoded by the tcpA gene. The ctx genes reside in the
      genome of a filamentous phage (CTXphi), and the tcpA gene resides in a vibrio
      pathogenicity island (VPI) which has also been proposed to be a filamentous phage
      designated VPIphi. In order to determine the prevalence of horizontal transfer of
      VPI and CTXphi among nonepidemic (non-O1 and non-O139 serogroups) V. cholerae,
      300 strains of both clinical and environmental origin were screened for the
      presence of tcpA and ctxAB. In this paper, we present the comparative genetic
      analyses of 11 nonepidemic serogroup strains which carry the VPI cluster. Seven
      of the 11 VPI(+) strains have also acquired the CTXphi. Multilocus sequence
      typing and restriction fragment length polymorphism analyses of the VPI and
      CTXphi prophage regions revealed that the non-O1 and non-O139 strains were
      genetically diverse and clustered in lineages distinct from that of the epidemic
      strains. The left end of the VPI in the non-O1 and non-O139 strains exhibited
      extensive DNA rearrangements. In addition, several CTXphi prophage types
      characterized by novel repressor (rstR) and ctxAB genes and VPIs with novel tcpA
      genes were found in these strains. These data suggest that the potentially
      pathogenic, nonepidemic, non-O1 and non-O139 strains identified in our study most
      likely evolved by sequential horizontal acquisition of the VPI and CTXphi
      independently rather than by exchange of O-antigen biosynthesis regions in an
      existing epidemic strain.

PMID- 12620866
TI  - Quorum-sensing system and stationary-phase sigma factor (rpoS) of the onion
      pathogen Burkholderia cepacia genomovar I type strain, ATCC 25416.
AB  - Bacterial strains belonging to Burkholderia cepacia can be human opportunistic
      pathogens, plant pathogens, and plant growth promoting and have remarkable
      catabolic activity. B. cepacia consists of several genomovars comprising what is
      now known as the B. cepacia complex. Here we report the quorum-sensing system of
      a genomovar I onion rot type strain ATCC 25416. Quorum sensing is a cell-density
      dependent regulatory response which involves the production of N-acyl homoserine
      lactone (HSL) signal molecules. The cep locus has been inactivated in the
      chromosome, and it has been shown that CepI is responsible for the biosynthesis
      of an N-hexanoyl HSL (C(6)-HSL) and an N-octanoyl HSL (C(8)-HSL) and that the cep
      locus regulates protease production as well as onion pathogenicity via the
      expression of a secreted polygalacturonase. A cep-lacZ-based sensor plasmid has
      been constructed and used to demonstrate that CepR responded to C(6)-HSL with
      only 15% of the molar efficiency of C(8)-HSL, that a cepR knockout mutant
      synthesized 70% less HSLs, and that CepR responded best towards long-chain HSLs.
      In addition, we also report the cloning and characterization of the stationary
      phase sigma factor gene rpoS of B. cepacia ATCC 25416. It was established that
      quorum sensing in B. cepacia has a negative effect on rpoS expression as
      determined by using an rpoS-lacZ transcriptional fusion; on the other hand, rpoS
      null mutants displayed no difference in the accumulation of HSL signal molecules.

PMID- 12620867
TI  - In situ accessibility of small-subunit rRNA of members of the domains Bacteria,
      Archaea, and Eucarya to Cy3-labeled oligonucleotide probes.
AB  - Low accessibility of the rRNA is together with cell wall impermeability and low
      cellular ribosome content a frequent reason for failure of whole-cell
      fluorescence hybridization with fluorescently labeled oligonucleotide probes. In
      this study we compare accessibility data for the 16S rRNA of Escherichia coli
      (gamma Proteobacteria, Bacteria) with the phylogenetically distantly related
      organisms Pirellula sp. strain 1 (Planctomycetes, Bacteria) and Metallosphaera
      sedula (Crenarchaeota, Archaea) and the 18S rRNA accessibility of Saccharomyces
      cerevisiae (Eucarya). For a total of 537 Cy3-labeled probes, the signal
      intensities of hybridized cells were quantified under standardized conditions by
      flow cytometry. The relative probe-conferred fluorescence intensities are shown
      on color-coded small-subunit rRNA secondary-structure models. For Pirellula sp.,
      most of the probes belong to class II and III (72% of the whole data set),
      whereas most of the probes targeting sites on M. sedula were grouped into class V
      and VI (46% of the whole data set). For E. coli, 45% of all probes of the data
      set belong to class III and IV. A consensus model for the accessibility of the
      small-subunit rRNA to oligonucleotide probes is proposed which uses 60 homolog
      target sites of the three prokaryotic 16S rRNA molecules. In general, open
      regions were localized around helices 13 and 14 including target positions 285 to
      338, whereas helix 22 (positions 585 to 656) and the 3' half of helix 47
      (positions 1320 to 1345) were generally inaccessible. Finally, the 16S rRNA
      consensus model was compared to data on the in situ accessibility of the 18S rRNA
      of S. cerevisiae.

PMID- 12620868
TI  - DNA microarray analyses of the long-term adaptive response of Escherichia coli to
      acetate and propionate.
AB  - In its natural environment, Escherichia coli is exposed to short-chain fatty
      acids, such as acetic acid or propionic acid, which can be utilized as carbon
      sources but which inhibit growth at higher concentrations. DNA microarray
      experiments revealed expression changes during exponential growth on complex
      medium due to the presence of sodium acetate or sodium propionate at a neutral
      external pH. The adaptive responses to acetate and propionate were similar and
      involved genes in three categories. First, the RNA levels for chemotaxis and
      flagellum genes increased. Accordingly, the expression of chromosomal fliC'-'lacZ
      and flhDC'-'lacZ fusions and swimming motility increased after adaptation to
      acetate or propionate. Second, the expression of many genes that are involved in
      the uptake and utilization of carbon sources decreased, indicating some kind of
      catabolite repression by acetate and propionate. Third, the expression of some
      genes of the general stress response increased, but the increases were more
      pronounced after short-term exposure for this response than for the adaptive
      response. Adaptation to propionate but not to acetate involved increased
      expression of threonine and isoleucine biosynthetic genes. The gene expression
      changes after adaptation to acetate or propionate were not caused solely by
      uncoupling or osmotic effects but represented specific characteristics of the
      long-term response of E. coli to either compound.

PMID- 12620869
TI  - Evaluation of a rapid, quantitative real-time PCR method for enumeration of
      pathogenic Candida cells in water.
AB  - Quantitative PCR (QPCR) technology, incorporating fluorigenic 5' nuclease
      (TaqMan) chemistry, was utilized for the specific detection and quantification of
      six pathogenic species of Candida (C. albicans, C. tropicalis, C. krusei, C.
      parapsilosis, C. glabrata and C. lusitaniae) in water. Known numbers of target
      cells were added to distilled and tap water samples, filtered, and disrupted
      directly on the membranes for recovery of DNA for QPCR analysis. The assay's
      sensitivities were between one and three cells per filter. The accuracy of the
      cell estimates was between 50 and 200% of their true value (95% confidence
      level). In similar tests with surface water samples, the presence of PCR
      inhibitory compounds necessitated further purification and/or dilution of the DNA
      extracts, with resultant reductions in sensitivity but generally not in
      quantitative accuracy. Analyses of a series of freshwater samples collected from
      a recreational beach showed positive correlations between the QPCR results and
      colony counts of the corresponding target species. Positive correlations were
      also seen between the cell quantities of the target Candida species detected in
      these analyses and colony counts of Enterococcus organisms. With a combined
      sample processing and analysis time of less than 4 h, this method shows great
      promise as a tool for rapidly assessing potential exposures to waterborne
      pathogenic Candida species from drinking and recreational waters and may have
      applications in the detection of fecal pollution.

PMID- 12620870
TI  - Kinetics and strain specificity of rhizosphere and endophytic colonization by
      enteric bacteria on seedlings of Medicago sativa and Medicago truncatula.
AB  - The presence of human-pathogenic, enteric bacteria on the surface and in the
      interior of raw produce is a significant health concern. Several aspects of the
      biology of the interaction between these bacteria and alfalfa (Medicago sativa)
      seedlings are addressed here. A collection of enteric bacteria associated with
      alfalfa sprout contaminations, along with Escherichia coli K-12, Salmonella
      enterica serotype Typhimurium strain ATCC 14028, and an endophyte of maize,
      Klebsiella pneumoniae 342, were labeled with green fluorescent protein, and their
      abilities to colonize the rhizosphere and the interior of the plant were
      compared. These strains differed widely in their endophytic colonization
      abilities, with K. pneumoniae 342 and E. coli K-12 being the best and worst
      colonizers, respectively. The abilities of the pathogens were between those of K.
      pneumoniae 342 and E. coli K-12. All Salmonella bacteria colonized the interiors
      of the seedlings in high numbers with an inoculum of 10(2) CFU, although
      infection characteristics were different for each strain. For most strains, a
      strong correlation between endophytic colonization and rhizosphere colonization
      was observed. These results show significant strain specificity for plant entry
      by these strains. Significant colonization of lateral root cracks was observed,
      suggesting that this may be the site of entry into the plant for these bacteria.
      At low inoculum levels, a symbiosis mutant of Medicago truncatula, dmi1, was
      colonized in higher numbers on the rhizosphere and in the interior by a
      Salmonella endophyte than was the wild-type host. Endophytic entry of M.
      truncatula appears to occur by a mechanism independent of the symbiotic
      infections by Sinorhizobium meliloti or mycorrhizal fungi.

PMID- 12620871
TI  - Enhanced accumulation of Cd2+ by a Mesorhizobium sp. transformed with a gene from
      Arabidopsis thaliana coding for phytochelatin synthase.
AB  - We expressed the Arabidopsis thaliana gene for phytochelatin synthase (PCS(At))
      in Mesorhizobium huakuii subsp. rengei B3, a microsymbiont of Astragalus sinicus,
      a legume used as manure. The PCS(At) gene was expressed under the control of the
      nifH promoter, which regulates the nodule-specific expression of the nifH gene.
      The expression of the PCS(At) gene was demonstrated in free-living cells under
      low-oxygen conditions. Phytochelatin synthase (PCS) was expressed and catalyzed
      the synthesis of phytochelatins [(gamma-Glu-Cys)(n)-Gly; PCs] in strain B3. A
      range of PCs, with values of n from 2 to 7, was synthesized by cells that
      expressed the PCS(At) gene, whereas no PCs were found in control cells that
      harbored the empty plasmid. The presence of CdCl(2) activated PCS and induced the
      synthesis of substantial amounts of PCs. Cells that contained PCs accumulated 36
      nmol of Cd(2+)/mg (dry weight) of cells. The expression of the PCS(At) gene in M.
      huakuii subsp. rengei B3 increased the ability of cells to bind Cd(2+)
      approximately 9- to 19-fold. The PCS protein was detected by immunostaining
      bacteroids of mature nodules of A. sinicus containing the PCS(At) gene. When
      recombinant M. huakuii subsp. rengei B3 established the symbiotic relationship
      with A. sinicus, the symbionts increased Cd(2+) accumulation in nodules 1.5-fold.

PMID- 12620872
TI  - Strong synergy between a eukaryotic antimicrobial peptide and bacteriocins from
      lactic acid bacteria.
AB  - The antimicrobial effect obtained upon combining the prokaryotic antimicrobial
      peptides (AMPs; more commonly referred to as bacteriocins) pediocin PA-1, sakacin
      P, and curvacin A (all produced by lactic acid bacteria [LAB]) with the
      eukaryotic AMP pleurocidin (from fish) has been investigated. The three LAB AMPs
      alone were active against gram-positive Listeria ivanovii bacteria at nanomolar
      concentrations, whereas they were inactive against gram-negative Escherichia coli
      bacteria. Pleurocidin alone was active against both of these types of bacteria at
      micromolar concentrations. Little if any synergy between the LAB AMPs and
      pleurocidin against the gram-positive L. ivanovii strain was obtained. In
      contrast, the LAB AMPs and pleurocidin acted highly synergistically against the
      gram-negative E. coli strain. Nanomolar concentrations of LAB AMPs increased the
      growth inhibitory potency of pleurocidin by about fourfold. When micromolar
      concentrations of LAB AMPs were combined with 2 micro g of pleurocidin/ml, 100%
      growth inhibition was attained, whereas pleurocidin alone at a concentration of 2
      micro g/ml gave no growth inhibition. Most noteworthy, when high concentrations
      (128 micro g/ml) of pleurocidin in the absence of LAB AMPs were used over a long
      period of incubation (1 week), some growth of E. coli was observed, whereas 16
      micro g of pleurocidin/ml completely abolished growth in the presence of 64 to
      128 ng of LAB AMPs/ml over the same period of time. The results clearly
      demonstrate that combining eukaryotic and prokaryotic AMPs can greatly increase
      the specific activity and broaden the target-cell range of these peptides.

PMID- 12620873
TI  - Soil type is the primary determinant of the composition of the total and active
      bacterial communities in arable soils.
AB  - Degradation of agricultural land and the resulting loss of soil biodiversity and
      productivity are of great concern. Land-use management practices can be used to
      ameliorate such degradation. The soil bacterial communities at three separate
      arable farms in eastern England, with different farm management practices, were
      investigated by using a polyphasic approach combining traditional soil analyses,
      physiological analysis, and nucleic acid profiling. Organic farming did not
      necessarily result in elevated organic matter levels; instead, a strong
      association with increased nitrate availability was apparent. Ordination of the
      physiological (BIOLOG) data separated the soil bacterial communities into two
      clusters, determined by soil type. Denaturing gradient gel electrophoresis and
      terminal restriction fragment length polymorphism analyses of 16S ribosomal DNA
      identified three bacterial communities largely on the basis of soil type but with
      discrimination for pea cropping. Five fields from geographically distinct soils,
      with different cropping regimens, produced highly similar profiles. The active
      communities (16S rRNA) were further discriminated by farm location and, to some
      degree, by land-use practices. The results of this investigation indicated that
      soil type was the key factor determining bacterial community composition in these
      arable soils. Leguminous crops on particular soil types had a positive effect
      upon organic matter levels and resulted in small changes in the active bacterial
      population. The active population was therefore more indicative of short-term
      management changes.

PMID- 12620874
TI  - PCR detection of virulence genes in Yersinia enterocolitica and Yersinia
      pseudotuberculosis and investigation of virulence gene distribution.
AB  - PCR-based assays were developed for the detection of plasmid- and chromosome
      borne virulence genes in Yersinia enterocolitica and Yersinia pseudotuberculosis,
      to investigate the distribution of these genes in isolates from various sources.
      The results of PCR genotyping, based on 5 virulence-associated genes of 140
      strains of Y. enterocolitica, were compared to phenotypic tests, such as
      biotyping and serotyping, and to virulence plasmid-associated properties such as
      calcium-dependent growth at 37 degrees C and Congo red uptake. The specificity of
      the PCR results was validated by hybridization. Genotyping data correlated well
      with biotype data, and most biotypes resulted in (nearly) homogeneous genotypes
      for the chromosomal virulence genes (ystA, ystB, and ail); however, plasmid-borne
      genes (yadA and virF) were detected with variable efficiency, due to
      heterogeneity within the bacterial population for the presence of the virulence
      plasmid. Of the virulence genes, only ystB was present in biotype 1A; however,
      within this biotype, pathogenic and apathogenic isolates could not be
      distinguished based on the detection of virulence genes. Forty Y.
      pseudotuberculosis isolates were tested by PCR for the presence of inv, yadA, and
      lcrF. All isolates were inv positive, and 88% of the isolates contained the
      virulence plasmid genes yadA and lcrF. In conclusion, this study shows that
      genotyping of Yersinia spp., based on both chromosome- and plasmid-borne
      virulence genes, is feasible and informative and can provide a rapid and reliable
      genotypic characterization of field isolates.

PMID- 12620875
TI  - Inactivation of gacS does not affect the competitiveness of Pseudomonas
      chlororaphis in the Arabidopsis thaliana rhizosphere.
AB  - Quorum-sensing-controlled processes are considered to be important for the
      competitiveness of microorganisms in the rhizosphere. They affect cell-cell
      communication, biofilm formation, and antibiotic production, and the GacS-GacA
      two-component system plays a role as a key regulator. In spite of the importance
      of this system for the regulation of various processes, strains with a Gac(-)
      phenotype are readily recovered from natural habitats. To analyze the influence
      of quorum sensing and the influence of the production of the antibiotic phenazine
      1-carboxamide on rhizosphere colonization by Pseudomonas chlororaphis, a
      gnotobiotic system based on Arabidopsis thaliana seedlings in soil was
      investigated. Transposon insertion mutants of P. chlororaphis isolate SPR044
      carrying insertions in different genes required for the production of N-acyl
      homoserine lactones and phenazine-1-carboxamide were generated. Analysis of
      solitary rhizosphere colonization revealed that after prolonged growth, the
      population of the wild type was significantly larger than that of the homoserine
      lactone-negative gacS mutant and that of a phenazine-1-carboxamide-overproducing
      strain. In cocultivation experiments, however, the population size of the gacS
      mutant was similar to that of the wild type after extended growth in the
      rhizosphere. A detailed analysis of growth kinetics was performed to explain this
      phenomenon. After cells grown to the stationary phase were transferred to fresh
      medium, the gacS mutant had a reduced lag phase, and production of the stationary
      phase-specific sigma factor RpoS was strongly reduced. This may provide a
      relative competitive advantage in cocultures with other bacteria, because it
      permits faster reinitiation of growth after a change to nutrient-rich conditions.
      In addition, delayed entry into the stationary phase may allow more efficient
      nutrient utilization. Thus, GacS-GacA-regulated processes are not absolutely
      required for efficient rhizosphere colonization in populations containing the
      wild type and Gac(-) mutants.

PMID- 12620876
TI  - The competitiveness of Pseudomonas chlororaphis carrying pJP4 is reduced in the
      Arabidopsis thaliana rhizosphere.
AB  - The effect of the large catabolic IncP plasmid pJP4 on the competitiveness of
      Pseudomonas chlororaphis SPR044 and on its derivatives SPR244 (GacS deficient),
      SPR344 (phenazine-1-carboxamide overproducer), and SPR644 (phenazine-1
      carboxamide deficient) in the Arabidopsis thaliana rhizosphere was assessed.
      Solitary rhizosphere colonization by the wild type, SPR244, and SPR644 was not
      affected by the plasmid. The size of the population of SPR344 carrying pJP4,
      however, was significantly reduced compared to the size of the population of the
      plasmid-free derivative. The abiotic stress caused by phenazine-1-carboxamide
      overproduction probably resulted in a selective disadvantage for cells carrying
      pJP4. Next, the effect of biotic stress caused by coinoculation of other bacteria
      was analyzed. Cells carrying pJP4 had a selective disadvantage compared to
      plasmid-free cells in the presence of the efficient colonizer Pseudomonas
      fluorescens WCS417r. This effect was not observed after coinoculation with a
      variety of other bacteria, and it was independent of quorum sensing and phenazine
      1-carboxamide production. Thus, the presence of large catabolic plasmids imposes
      a detectable metabolic burden in the presence of biotic stress. Plasmid transfer
      in the A. thaliana rhizosphere from P. chlororaphis and its derivatives to
      Ralstonia eutropha was determined by using culture-dependent and culture
      independent techniques. With the cultivation-independent technique we detected a
      significantly higher portion of exconjugants, but pJP4 transfer was independent
      of the quorum-sensing system and of phenazine-1-carboxamide production.

PMID- 12620877
TI  - Evidence for the existence of psychrophilic methanogenic communities in anoxic
      sediments of deep lakes.
AB  - In order to obtain evidence for the existence of psychrophilic methanogenic
      communities in sediments of deep lakes that are low-temperature environments (4
      to 5 degrees C), slurries were first incubated at temperatures between 4 and 60
      degrees C for several weeks, at which time they were amended, or not, with an
      additional substrate, such as cellulose, butyrate, propionate, acetate, or
      hydrogen, and further incubated at 6 degrees C. Initial methane production rates
      were highest in slurries preincubated at temperatures between 4 and 15 degrees C,
      with maximal rates in slurries kept at 6 degrees C. Hydrogen-amended cultures
      were the only exceptions, with the highest methane production rates at 6 degrees
      C after preincubation at 30 degrees C.

PMID- 12620878
TI  - Comparison of ribotyping and repetitive extragenic palindromic-PCR for
      identification of fecal Escherichia coli from humans and animals.
AB  - This report compares the performances of two popular genotypic methods used for
      tracking the sources of fecal pollution in water, ribotyping and repetitive
      extragenic palindromic-PCR (rep-PCR). The rep-PCR was more accurate,
      reproducible, and efficient in associating DNA fingerprints of fecal Escherichia
      coli with human and animal hosts of origin.

PMID- 12620879
TI  - Antigenic hepatitis A virus structures may be produced in Escherichia coli.
AB  - The synthesis of 14S pentamers and 70S empty capsids of hepatitis A virus (HAV)
      has been accomplished by expressing the viral genome for periods of time longer
      than 4 h in Escherichia coli. HAV pentamers (14S) self-assembled into capsids
      (70S) in vitro. The antibodies induced by these structures recognized and
      neutralized HAV.

PMID- 12620880
TI  - Comparison of methods for DNA isolation from food samples for detection of Shiga
      toxin-producing Escherichia coli by real-time PCR.
AB  - In this study, food samples were intentionally contaminated with Escherichia coli
      O157:H7, and then DNA was isolated by using four commercial kits. The isolated
      DNA samples were compared by using real-time PCR detection of the Shiga toxin
      genes. The four kits tested worked similarly.

PMID- 12620881
TI  - Cr(VI) reduction by sulfidogenic and nonsulfidogenic microbial consortia.
AB  - In time course experiments, bacterial community compositions were compared
      between a sulfidogenic and two nonsulfidogenic Cr(VI)-reducing consortia enriched
      from metal-contaminated sediments. The consortia were subjected to 0 and 0.85 mM
      or 1.35 mM Cr(VI), and Cr(VI) reduction, growth, and denaturing gradient gel
      electrophoresis profiles of PCR products of small-subunit (16S) ribosomal genes
      were compared. Results showed that although Cr(VI) was completely reduced by the
      three consortia, Cr(VI) inhibited cell growth, with sulfate-reducing bacteria
      being particularly sensitive to Cr(VI) toxicity relative to other bacteria in the
      consortia.

PMID- 12620882
TI  - A pediocin-producing Lactobacillus plantarum strain inhibits Listeria
      monocytogenes in a multispecies cheese surface microbial ripening consortium.
AB  - The growth of Listeria monocytogenes WSLC 1364, originating from a cheese-borne
      outbreak, was examined in the presence and in the absence of a pediocin AcH
      producing Lactobacillus plantarum strain on red smear cheese. Nearly complete
      inhibition was observed at 10(2) CFU of L. monocytogenes per ml of salt brine
      solution, while contamination with Listeria mutants resistant to pediocin
      resulted in high cell counts of the pathogen on the cheese surface. The
      inhibition was due to pediocin AcH added together with the L. plantarum culture
      to the brine solution but not to bacteriocin production in situ on cheese.
      Pediocin resistance developed in vitro at different but high frequencies in all
      12 L. monocytogenes strains investigated, and a resistant mutant remained stable
      in a microbial surface ripening consortium over a 4-month production process in
      the absence of selection pressure. In conclusion, the addition of a L. plantarum
      culture is a potent measure for combating Listeria in a contaminated production
      line, but because of the potential development of resistance, it should not be
      used continuously over a long time in a production line.

PMID- 12620883
TI  - An improved enrichment broth for isolation of Escherichia coli O157, with
      specific reference to starved cells, from radish sprouts.
AB  - An enrichment broth was developed for the efficient isolation of Escherichia coli
      O157 from radish sprouts. The broth was buffered peptone water containing 0.5%
      sodium thioglycolate (STG-BPW), which was designed to allow growth of E. coli
      O157 in starved and unstarved states. However, this medium suppressed the growth
      of non-carbohydrate-fermenting obligate aerobes whose colonial appearance on
      sorbitol MacConkey agar containing cefixime and tellurite (CT-SMAC) resembled
      that of E. coli O157. Both starved and unstarved cells of E. coli O157
      experimentally inoculated into radish sprouts were successfully recovered with
      STG-BPW enrichment in all cases, most of which showed marked disappearance of E.
      coli O157-like colonies on CT-SMAC.

PMID- 12620884
TI  - Heterologous expression of the Saccharomyces cerevisiae PGU1 gene in
      Schizosaccharomyces pombe yields an enzyme with more desirable properties for the
      food industry.
AB  - The Saccharomyces cerevisiae PGU1 gene was successfully expressed in
      Schizosaccharomyces pombe. The optimum pH and temperature for the recombinant
      enzyme were 5 and 40 degrees C, respectively, these being around 0.5 U higher and
      5 degrees C lower than those shown by the native enzyme. The K(m) value was about
      fourfold higher than that of the S. cerevisiae enzyme. The recombinant
      endopolygalacturonase was more efficient in reducing the viscosity of
      polygalacturonic acid and was also more stable at different pHs and temperatures
      than the native enzyme.

PMID- 12620885
TI  - Anaerobic mineralization of quaternary carbon atoms: isolation of denitrifying
      bacteria on pivalic acid (2,2-dimethylpropionic acid).
AB  - The degradability of pivalic acid was established by the isolation of several
      facultative denitrifying strains belonging to Zoogloea resiniphila, to Thauera
      and Herbaspirillum, and to Comamonadaceae, related to [Aquaspirillum] and
      Acidovorax, and of a nitrate-reducing bacterium affiliated with Moraxella
      osloensis. Pivalic acid was completely mineralized to carbon dioxide. The
      catabolic pathways may involve an oxidation to dimethylmalonate or a carbon
      skeleton rearrangement, a putative 2,2-dimethylpropionyl coenzyme A mutase.

PMID- 12620886
TI  - Biodegradation of the nitramine explosive CL-20.
AB  - The cyclic nitramine explosive CL-20 (2,4,6,8,10,12-hexanitro-2,4,6,8,10,12
      hexaazaisowurtzitane) was examined in soil microcosms to determine whether it is
      biodegradable. CL-20 was incubated with a variety of soils. The explosive
      disappeared in all microcosms except the controls in which microbial activity had
      been inhibited. CL-20 was degraded most rapidly in garden soil. After 2 days of
      incubation, about 80% of the initial CL-20 had disappeared. A CL-20-degrading
      bacterial strain, Agrobacterium sp. strain JS71, was isolated from enrichment
      cultures containing garden soil as an inoculum, succinate as a carbon source, and
      CL-20 as a nitrogen source. Growth experiments revealed that strain JS71 used 3
      mol of nitrogen per mol of CL-20.

PMID- 12620887
TI  - Regulation of the epithelial Ca2+ channels in small intestine as studied by
      quantitative mRNA detection.
AB  - The epithelial Ca2+ channels TRPV5 and TRPV6 are localized to the brush border
      membrane of intestinal cells and constitute the postulated rate-limiting entry
      step of active Ca2+ absorption. The aim of the present study was to investigate
      the hormonal regulation of these channels. To this end, the effect of 17beta
      estradiol (17beta-E2), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and dietary Ca2+
      on the expression of the duodenal Ca2+ transport proteins was investigated in
      vivo and analyzed using realtime quantitative PCR. Supplementation with 17beta-E2
      increased duodenal gene expression of TRPV5 and TRPV6 but also calbindin-D9K and
      plasma membrane Ca2+-ATPase (PMCA1b) in ovariectomized rats. 25-Hydroxyvitamin D3
      1alpha-hydroxylase (1alpha-OHase) knockout mice are characterized by
      hyperparathyroidism, rickets, hypocalcemia, and undetectable levels of
      1,25(OH)2D3 and were used to study the 1,25(OH)2D3-dependency of the stimulatory
      effects of 17beta-E2. Treatment with 17beta-E2 upregulated mRNA levels of
      duodenal TRPV6 in these 1alpha-OHase knockout mice, which was accompanied by
      increased serum Ca2+ concentrations from 1.69 +/- 0.10 to 2.03 +/- 0.12 mM (P <
      0.05). In addition, high dietary Ca2+ intake normalized serum Ca2+ in these mice
      and upregulated expression of genes encoding the duodenal Ca2+ transport proteins
      except for PMCA1b. Supplementation with 1,25(OH)2D3 resulted in increased
      expression of TRPV6, calbindin-D9K, and PMCA1b and normalization of serum Ca2+.
      Expression levels of duodenal TRPV5 mRNA are below detection limits in these
      1alpha-OHase knockout mice, but supplementation with 1,25(OH)2D3 upregulated the
      expression to significant levels. In conclusion, TRPV5 and TRPV6 are regulated by
      17beta-E2 and 1,25(OH)2D3, whereas dietary Ca2+ is positively involved in the
      regulation of TRPV6 only.

PMID- 12620888
TI  - Muscarinic receptors couple to modulation of nicotinic ACh receptor
      desensitization in myenteric neurons.
AB  - Signaling mechanisms coupled to activation of different neurotransmitter
      receptors interact in the enteric nervous system. ACh excites myenteric neurons
      by activating nicotinic ACh receptors (nAChRs) and muscarinic receptors expressed
      by the same neurons. These studies tested the hypothesis that muscarinic receptor
      activation alters the functional properties of nAChRs in guinea pig small
      intestinal myenteric neurons maintained in primary culture. Whole cell patch
      clamp techniques were used to measure inward currents caused by ACh (1 mM) or
      nicotine (1 mM). Currents caused by ACh and nicotine were blocked by
      hexamethonium (100 microM) and showed complete cross desensitization. The rate
      and extent of nAChR desensitization was greater when recordings were obtained
      with ATP/GTP-containing compared with ATP/GTP-free pipette solutions. These data
      suggest that ATP/GTP-dependent mechanisms increase nAChR desensitization. The
      muscarinic receptor antagonist scopolamine (1 microM) decreased desensitization
      caused by ACh but not by nicotine, which does not activate muscarinic receptors.
      Phorbol 12,13-dibutyrate (10-100 nM), an activator of protein kinase C (PKC), but
      not 4-alpha-phorbol 12-myristate 13-acetate (a PKC inactive phorbol ester),
      increased nAChR desensitization caused by ACh and nicotine. Forskolin (1 microM),
      an activator of adenylate cyclase, increased nAChR desensitization, but this
      effect was mimicked by dideoxyforskolin, an adenylate cyclase inactive forskolin
      analog. These data indicate that simultaneous activation of nAChRs and muscarinic
      receptors increases nAChR desensitization. This effect may involve activation of
      a PKC-dependent pathway. These data also suggest that nAChRs and muscarinic
      receptors are coupled functionally through an intracellular signaling pathway in
      myenteric neurons.

PMID- 12620889
TI  - ANG II stimulates PKC-dependent ERK activation, DNA synthesis, and cell division
      in intestinal epithelial cells.
AB  - PKC, a major target for the tumor-promoting phorbol esters, has been implicated
      in the signal transduction pathways that mediate important functions in
      intestinal epithelial cells, including proliferation and carcinogenesis. With the
      use of IEC-18 cells arrested in G0/G1, addition of phorbol esters resulted in a
      modest increase in [3H]thymidine incorporation and a slight shift toward the S
      and G2/M phases of the cell cycle, whereas the combination of EGF and phorbol
      12,13-dibutyrate (PDB) synergistically stimulated DNA synthesis. To investigate
      the effects of receptor-mediated PKC activation on mitogenesis, we demonstrated
      that ANG II induced ERK activation, a response completely blocked by pretreatment
      with mitogen/extracellular signal-regulated kinase inhibitors or specific PKC
      inhibitors. Furthermore, ANG II stimulated an over threefold increase in
      [3H]thymidine incorporation that was corroborated by flow cytometric analysis of
      the cell cycle to levels comparable to that achieved by the combination of EGF
      and PDB. Taken together, our results indicate that receptor-mediated PKC
      activation, as induced by ANG II, transduces mitogenic signals leading to DNA
      synthesis and cell proliferation in IEC-18 cells.

PMID- 12620890
TI  - Role of IGF system of mitogens in the induction of fibroblast proliferation by
      keloid-derived keratinocytes in vitro.
AB  - Keloids are proliferative dermal growths representing a pathological wound
      healing response. We report high proliferation rates in normal (NF) and keloid
      derived fibroblasts (KF) cocultured with keloid-derived keratinocytes (KK). IGF
      binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were
      increased in NF cocultured with KK compared with NF but markedly reduced in KF
      cocultured with KK or normal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels
      were elevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KK or NK.
      Significant increases in IGFBP-2 and -4 mRNA in KF cocultured with KK did not
      correlate with protein secretion. Downstream IGF signaling cascade components,
      phospho-Raf, phospho-MEK1/2, phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho
      Elk-1, were elevated in KF cocultured with KK. Addition of recombinant human
      IGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibited
      proliferation of KF. The bioavailability of IGF-I may be related to the levels of
      IGFBP-3 produced, which in turn influences KF proliferation, suggesting that
      modulation of IGF-I, IGF-IR, and IGFBP-3, individually or in combination, may
      represent novel approaches to the treatment of keloids.

PMID- 12620891
TI  - Activation of gene expression in human neutrophils by high mobility group box 1
      protein.
AB  - High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes
      nucleosomes and facilitates transcription, was recently identified as a late
      mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis
      are associated with increased mortality, and administration of HMGB1 produces
      acute inflammation in animal models of lung injury and endotoxemia. Neutrophils
      occupy a critical role in mediating the development of endotoxemia-associated
      acute lung injury, but previously it was not known whether HMGB1 could influence
      neutrophil activation. In the present experiments, we demonstrate that HMGB1
      increases the nuclear translocation of NF-kappaB and enhances the expression of
      proinflammatory cytokines in human neutrophils. These proinflammatory effects of
      HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3
      kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil
      activation are distinct from endotoxin-induced signals, because HMGB1 leads to a
      different profile of gene expression, pattern of cytokine expression, and
      kinetics of p38 activation compared with LPS. These findings indicate that HMGB1
      is an effective stimulus of neutrophil activation that can contribute to
      development of a proinflammatory phenotype in diseases characterized by
      excessively high levels of HMGB1.

PMID- 12620892
TI  - Functional analysis of gap junctions in ovarian granulosa cells: distinct role
      for connexin43 in early stages of folliculogenesis.
AB  - Ovarian granulosa cells are coupled via gap junctions containing connexin43 (Cx43
      or alpha-1 connexin). In the absence of Cx43, granulosa cells stop growing in an
      early preantral stage. However, the fact that granulosa cells of mature follicles
      express multiple connexins complicated interpretation of this finding. The
      present experiments were designed to clarify the role of Cx43 vs. these other
      connexins in the earliest stages of folliculogenesis. Dye injection experiments
      revealed that granulosa cells from Cx43 knockout follicles are not coupled, and
      this was confirmed by ionic current injections. Furthermore, electron microscopy
      revealed that gap junctions are extremely rare in mutant granulosa cells. In
      contrast, mutant granulosa cells were able to form gap junctions with wild-type
      granulosa cells in a dye preloading assay. It was concluded that mutant granulosa
      cells contain a population of connexons, composed of an unidentified connexin,
      that do not normally contribute to gap junctions. Therefore, although Cx43 is not
      the only gap junction protein present in granulosa cells of early preantral
      follicles, it is the only one that makes a significant contribution to
      intercellular coupling.

PMID- 12620893
TI  - Confocal ratiometric voltage imaging of cultured human keratinocytes reveals
      layer-specific responses to ATP.
AB  - Recent evidence suggests that changes in membrane potential influence the
      proliferation and differentiation of keratinocytes. To further elucidate the role
      of changes in membrane potential for their biological fate, the electrical
      behavior of keratinocytes needs to be studied under complex conditions such as
      multilayered cultures. However, electrophysiological recordings from cells in the
      various layers of a complex culture would be extremely difficult. Given the high
      spatial resolution of confocal imaging and the availability of novel voltage
      sensitive dyes, we combined these methods in an attempt to develop a viable
      alternative for recording membrane potentials in more complex tissue systems. As
      a first step, we used confocal ratiometric imaging of fluorescence resonance
      energy transfer (FRET)-based voltage-sensitive dyes. We then validated this
      approach by comparing the optically recorded voltage signals in HaCaT
      keratinocytes with the electrophysiological signals obtained by whole cell
      recordings of the same preparation. We demonstrate 1) that optical recordings
      allow precise multisite measurements of voltage changes evoked by the
      extracellular signaling molecules ATP and bradykinin and 2) that responsiveness
      to ATP differs in various layers of cultured keratinocytes.

PMID- 12620894
TI  - Altered muscle force and stiffness of skeletal muscles in alpha-sarcoglycan
      deficient mice.
AB  - Alpha-sarcoglycan (ASG) is a transmembrane protein of the dystrophin-associated
      complex, and absence of ASG causes limb-girdle muscular dystrophy. We hypothesize
      that disruption of the sarcoglycan complex may alter muscle extensibility and
      disrupt the coupling between passive transverse and axial contractile elements in
      the diaphragm. We determined the length-tension relationships of the diaphragm of
      young ASG-deficient mice and their controls during uniaxial and biaxial loading.
      We also determined the isometric contractile properties of the diaphragm muscles
      from mutant and normal mice in the absence and presence of passive transverse
      stress. We found that the diaphragm muscles of the null mutants for the protein
      ASG show 1) significant decrease in muscle extensibility in the directions of the
      muscle fibers and transverse to fibers, 2) significant reductions in force
      generating capacity, and 3) significant reductions in coupling between
      longitudinal and transverse properties. Thus these findings suggest that the
      sarcoglycan complex serves a mechanical function in the diaphragm by contributing
      to muscle passive stiffness and to the modulation of the contractile properties
      of the muscle.

PMID- 12620895
TI  - Cholinergic agonists transactivate EGFR and stimulate MAPK to induce goblet cell
      secretion.
AB  - Conjunctival goblet cells are the primary source of mucins in the mucous layer,
      the innermost layer of the tear film. Conjunctival goblet cell mucin secretion is
      under neural control because exogenous addition of parasympathetic agonists
      stimulates goblet cell secretion. To elucidate the intracellular signal pathways
      used by cholinergic agonists to stimulate goblet cell mucin secretion, we
      determined whether p42/p44 mitogen-activated protein kinase (MAPK) is activated
      during cholinergic agonist-stimulated mucin secretion. Rat conjunctiva was
      removed, preincubated with or without antagonists, and stimulated with the
      cholinergic agonist carbachol (10(-4) M). Carbachol statistically significantly
      stimulated the phosphorylation of MAPK in a time- and concentration-dependent
      manner. U-0126, an inhibitor of MAPK activation, completely inhibited both the
      activation of MAPK and goblet cell secretion stimulated by carbachol. The M(1)
      muscarinic antagonist pirenzepine, the M(2) muscarinic antagonist gallamine, and
      the M(1)/M(3) muscarinic receptor antagonist N-(3-chloropropyl)-4-piperidinyl
      diphenylacetate (4-DAMP) also inhibited carbachol-stimulated MAPK activation.
      Increasing the intracellular Ca(2+) concentration with a Ca(2+) ionophore
      increased MAPK activation, and chelation of extracellular Ca(2+) inhibited
      carbachol-stimulated activation. Carbachol also increased tyrosine
      phosphorylation of Pyk2, p60Src, and the epidermal growth factor receptor (EGFR).
      The Src inhibitor PP1 and the EGFR inhibitor AG-1478 completely inhibited
      carbachol-stimulated MAPK activation. AG-1478 also inhibited goblet cell
      secretion. We conclude that carbachol transactivates the EGFR to activate MAPK,
      leading to conjunctival goblet cell secretion. In addition, carbachol also
      activates Pyk2 and p60Src that could play a role in the transactivation of the
      EGFR.

PMID- 12620896
TI  - IkappaBalpha-dependent regulation of low-shear flow-induced NF-kappa B activity:
      role of nitric oxide.
AB  - We have investigated the role of inhibitor kappaBalpha (IkappaBalpha) in the
      activation of nuclear factor kappaB (NF-kappaB) observed in human aortic
      endothelial cells (HAEC) undergoing a low shear stress of 2 dynes/cm(2). Low
      shear for 6 h resulted in a reduction of IkappaBalpha levels, an activation of NF
      kappaB, and an increase in kappaB-dependent vascular cell adhesion molecule 1
      (VCAM-1) mRNA expression and endothelial-monocyte adhesion. Overexpression of
      IkappaBalpha in HAEC attenuated all of these shear-induced responses. These
      results suggest that downregulation of IkappaBalpha is the major factor in the
      low shear-induced activation of NF-kappaB in HAEC. We then investigated the role
      of nitric oxide (NO) in the regulation of IkappaBalpha/NF-kappaB. Overexpression
      of endothelial nitric oxide synthase (eNOS) inhibited NF-kappaB activation in
      HAEC exposed to 6 h of low shear stress. Addition of the structurally unrelated
      NO donors S-nitrosoglutathione (300 microM) or sodium nitroprusside (1 mM) before
      low shear stress significantly increased cytoplasmic IkappaBalpha and
      concomitantly reduced NF-kappaB binding activity and kappaB-dependent VCAM-1
      promoter activity. Together, these data suggest that NO may play a major role in
      the regulation of IkappaBalpha levels in HAEC and that the application of low
      shear flow increases NF-kappaB activity by attenuating NO generation and thus
      IkappaBalpha levels.

PMID- 12620897
TI  - Potassium channel expression level is dependent on the proliferation state in the
      GH3 pituitary cell line.
AB  - Previously, we showed that the peak density of the transient outward K(+) current
      (I(to)) expressed in GH3 cells was different in the S phase than in other phases
      of the cell cycle. Using cell synchronization, we show here that I(to) drops
      precisely at the quiescent (G(0) phase)/proliferating transition. This change is
      not due to a modification in the voltage dependence of I(to), but rather to a
      modification in its inactivation kinetics. Molecular determination of K(+)
      channel subunits showed that I(to) required the expression of Kv1.4, Kv4.1, and
      Kv4.3. We found that the increase in I(to) density during the quiescent state was
      accompanied by an increase in Kv1.4 protein expression, whereas Kv4.3 expression
      remained unchanged. We further demonstrate that the link between I(to) expression
      and cell proliferation is not mediated by variations in cell excitability. These
      results provide new evidence for the cell cycle dependence of I(to) expression,
      which could be relevant in understanding the mechanisms leading to pituitary
      adenomas.

PMID- 12620898
TI  - Colocalization but differential regulation of neuronal NO synthase and nicotinic
      acetylcholine receptor in C2C12 myotubes.
AB  - In mammalian skeletal muscle, neuronal-type nitric oxide synthase (nNOS) is found
      to be enriched at neuromuscular endplates. Here we demonstrate the colocalization
      of the nicotinic acetylcholine receptor (nAChR, stained with alpha-bungarotoxin)
      and nNOS (stained with a specific antibody) in murine C(2)C(12) myotubes.
      However, coimmunoprecipitation experiments demonstrated no evidence for a direct
      protein-protein association between the nAChR and nNOS in C(2)C(12) myotubes. An
      antibody to the alpha(1)-subunit of the nAChR did not coprecipitate nNOS, and an
      nNOS-specific antibody did not precipitate the alpha(1)-subunit of the nAChR.
      Treatment of mice with bacterial LPS downregulated the expression of nNOS in
      skeletal muscle, and treatment of C(2)C(12) cells with bacterial LPS and
      interferon-gamma markedly decreased nNOS mRNA and protein expression. In
      contrast, mRNA and protein of the nAChR (alpha-, gamma-, and epsilon-subunits)
      remained unchanged at the mRNA and protein levels. These data demonstrate that
      nNOS and the nAChR are colocalized in murine skeletal muscle and C(2)C(12) cells
      but differ in their expressional regulation.

PMID- 12620899
TI  - Oncologic safety of skin-sparing mastectomy.

PMID- 12620900
TI  - Nipple discharge: more than pathologic.

PMID- 12620901
TI  - Risks of the uncontrolled retroperitoneum.

PMID- 12620902
TI  - Skin involvement in invasive breast carcinoma: safety of skin-sparing mastectomy.
AB  - BACKGROUND: There is concern about the oncological safety of preserving most of
      the breast skin in skin-sparing mastectomy (SSM). Most supportive evidence for
      SSM evaluates the local recurrence rate on clinical follow-up. METHODS: The skin
      and 10 mm of the subcutaneous tissue of 30 total mastectomy specimens were
      studied with a step-serial sectioning technique. The incidence and mode of
      involvement of the skin and subcutaneous tissue were recorded in detail. This was
      correlated with other clinical and pathologic parameters. RESULTS: The incidence
      of skin involvement outside the nipple-areola complex was 20% (6 of 30). This was
      significantly related to the clinical T stage, site of the tumor, skin tethering,
      pathologic tumor size, and perineural infiltration. When the effects of both skin
      and subcutaneous tissue involvement were considered, the incidence of skin-flap
      involvement outside the nipple-areola complex was 23% (7 of 30). The significant
      parameters related to skin-flap involvement were skin tethering (75% vs. 15%; P
      <.05), pathologic tumor size (P <.03), and perineural infiltration (63% vs. 9%; P
      <.01). CONCLUSIONS: It would be oncologically safe to perform SSM in T1 and T2
      tumors, because the chance of skin involvement is small. It is safe to preserve
      the skin overlying the tumor if there is no skin tethering.

PMID- 12620903
TI  - Local recurrence after skin-sparing mastectomy: tumor biology or surgical
      conservatism?
AB  - BACKGROUND: Long-term follow-up of the use of skin-sparing mastectomy (SSM) in
      the treatment of breast cancer is presented to determine the impact of local
      recurrence (LR) on survival. METHODS: A total of 539 patients were treated for
      565 cases of breast cancer by SSM and immediate breast reconstruction from
      January 1, 1989 to December 31, 1998. The American Joint Committee on Cancer
      pathological staging was stage 0 175 (31%), stage I 135 (23.9%), stage II 173
      (30.6%), stage III 54 (9.6%), stage IV 8 (1.4%), and recurrent 20 (3.5%). The
      mean follow-up was 65.4 months (range, 23.7-86.3 months). Five patients were lost
      to follow-up. RESULTS: Thirty-one patients developed a LR during the follow-up
      including five who received adjuvant radiation. The distribution of LR stratified
      by cancer stage was stage 0 1, stage I 5, stage II 17, stage III 6, and recurrent
      2. The overall LR was 5.5%. Twenty-four patients (77.4%) developed a systemic
      relapse and 7 (22.6%) patients remained free of recurrent disease at a mean
      follow-up of 78.1 months. The cancer stage of those remaining disease free was
      stage 0 1 (100%), stage I 4 (80%), and stage II 2 (11.8%). CONCLUSIONS: LR of
      breast cancer after SSM is not always associated with systemic relapse.

PMID- 12620904
TI  - Nonsurgical evaluation of pathologic nipple discharge.
AB  - BACKGROUND: Nipple discharge is a common breast complaint. Because most nipple
      discharge is a result of benign processes, less-invasive, nonsurgical diagnostic
      modalities have been explored to reduce the need for surgical intervention.
      METHODS: Between September 1994 and December 2000, 108 female patients aged 25 to
      77 years underwent duct excision for bloody or clear nipple discharge. Results of
      various preoperative studies were compared with surgical pathology to determine
      the sensitivity, specificity, positive predictive value, and negative predictive
      value of these tests in detecting malignant ductal pathology. RESULTS: Of the 108
      surgical histopathology specimens, 90 of 108 patients were benign, 5 of 108
      patients were atypical, and 13 of 108 patients were malignant. The sensitivity of
      mammography was 57.1%, specificity was 61.5%, positive predictive value was
      16.7%, and negative predictive value was 91.4%. Hemoccult sensitivity was 50%,
      specificity was 0%, positive predictive value was 20%, and negative predictive
      value was 0%. The sensitivity of ductography was 0%, specificity was 90%,
      positive predictive value was 0%, and negative predictive value was 81.8%. The
      sensitivity of cytology was 11.1%, specificity was 96.3%, positive predictive
      value was 50%, and negative predictive value was 76.5%. CONCLUSIONS: Preoperative
      evaluations by mammography, Hemoccult, ductography, and cytology are poor
      predictors of histological diagnosis. These data suggest that patients with
      pathologic nipple discharge should undergo surgical biopsy for accurate
      diagnosis.

PMID- 12620905
TI  - Clinical relevance of reverse transcriptase-polymerase chain reaction for the
      detection of axillary lymph node metastases in breast cancer.
AB  - BACKGROUND: The mammary sentinel lymph node procedure can increase the detection
      of axillary metastases by 45% compared with standard axillary dissection. Some
      investigators have reported that reverse transcriptase-polymerase chain reaction
      (RT-PCR) increases metastasis detection even more, but it is uncertain whether a
      positive RT-PCR test in the face of a negative histological evaluation is
      clinically meaningful. METHODS: RT-PCR for epithelial glycoprotein 2 and
      cytokeratin 19 was performed on sentinel and pooled nonsentinel axillary lymph
      nodes from 108 women with clinical stage I or II breast cancer who were followed
      up for a median of 40 months. RESULTS: Axillary metastases were detected on
      standard tissue sections in 26% and by RT-PCR in 30%. Results for the two tests
      were concordant for 80% of the cases. RT-PCR upstaged 16%. Tumors from women
      whose lymph nodes were positive only by RT-PCR were phenotypically similar to
      those from women with no metastases detected by any method. Moreover, 4-year
      actuarial distant disease-free survival was 100% for women with metastases
      detected by RT-PCR only, as compared with 74% for those with metastases detected
      by routine histology (P =.03) and 93% for those with no metastases detected by
      either method (P =.04). CONCLUSIONS: Analysis of sentinel lymph nodes by RT-PCR
      for epithelial glycoprotein 2 and cytokeratin 19 is unlikely to provide
      clinically useful information.

PMID- 12620906
TI  - Preliminary outcome analysis in patients with breast cancer and a positive
      sentinel lymph node who declined axillary dissection.
AB  - BACKGROUND: This retrospective study was designed to provide a preliminary
      outcome analysis in patients with positive sentinel nodes who declined axillary
      dissection. METHODS: A review was conducted of patients who underwent lumpectomy
      and sentinel lymph node excision for invasive disease between January 1998 and
      July 2000. Those who were found to have sentinel lymph node metastasis without
      completion axillary dissection were selected for evaluation. Follow-up included
      physical examination and mammography. RESULTS: Thirty-one patients were
      identified who met inclusion criteria. Primary invasive cell types included
      infiltrating ductal carcinoma, infiltrating lobular carcinoma, and mixed
      cellularity. Most primary tumors were T1. Nodal metastases were identified by
      hematoxylin and eosin stain and immunohistochemistry. Twenty-seven of the
      metastases were microscopic (<2 mm), and the remaining four were macroscopic. All
      patients received adjuvant systemic therapy. With a mean follow-up of 30 months,
      there have been no patients with axillary recurrence on physical examination or
      mammographic evaluation. CONCLUSIONS: We have presented patients with sentinel
      lymph nodes involved by cancer who did not undergo further axillary resection and
      remain free of disease at least 1 year later. This preliminary analysis supports
      the inclusion of patients with subclinical axillary disease in trials that
      randomize to observation alone.

PMID- 12620907
TI  - Non-germ cell malignancy in residual or recurrent mass after chemotherapy for
      nonseminomatous testicular germ cell tumor.
AB  - BACKGROUND: After chemotherapy for nonseminomatous testicular germ cell tumor
      (NSTGCT), residual masses or recurrent disease may contain a non-germ cell
      malignancy (NGCM). METHODS: Over 20 years, 369 patients with disseminated NSTGCT
      were treated with cisplatin-based polychemotherapy at the University Medical
      Center Groningen. Residual tumor masses were resected in 244 patients and
      recurrent tumor masses in 37 patients. Histology was reviewed, focusing on the
      presence of NGCM. RESULTS: Nine patients developed an NGCM. Four patients had an
      NGCM in the resected residual tumor mass after chemotherapy: three patients had a
      sarcoma, and one patient had both a sarcoma and an adenocarcinoma. Five patients
      developed a late recurrence with an NGCM after 39, 40, 72, 72, and 84 months. One
      patient had a primitive neuroectodermal tumor, one had a sarcoma, and three had
      an adenocarcinoma in the resected recurrent tumor mass. A complete surgical
      resection was achieved in five (56%) of the nine patients. After a median follow
      up of 48 months (range, 3-271 months), five patients had no evidence of disease
      (56%), three patients were dead of disease (33%), and one patient was alive with
      disease (11%). CONCLUSIONS: Sarcoma, adenocarcinoma, or both in residual or
      recurrent tumor masses after combined-modality NSTGCT treatment are rare.
      Complete surgical resection of the tumor mass is the only curative treatment
      option.

PMID- 12620908
TI  - Fine mapping of Wilms' tumors with 16q loss of heterozygosity localizes the
      putative tumor suppressor gene to a region of 6.7 megabases.
AB  - BACKGROUND: The aim of this study was to more precisely map the region of 16q
      loss of heterozygosity (LOH) in Wilms' tumors and to examine the expression of
      putative tumor suppressor. METHODS: We performed polymerase chain reaction-based
      LOH analysis on the 185 sample pairs from 21 to 80 megabases (Mb) on chromosome
      16q. Expression of two candidate tumor suppressor genes located within the
      identified consensus region of 16q LOH was examined by immunohistochemistry.
      RESULTS: We identified 16q LOH in 7 (4%) of 185 Wilms' tumors not previously
      thought to demonstrate such genetic loss. The smallest common region of genetic
      loss was located between 67.3 and 74.0 Mb on chromosome 16. Within this 6.7-Mb
      region, there reside only three recognized tumor suppressor genes: E-cadherin, P
      cadherin, and E2F4. E-cadherin demonstrates statistically significantly reduced
      expression in Wilms' tumors with 16q LOH. CONCLUSIONS: We have localized the
      consensus region of 16q LOH in Wilms' tumor to a 6.7-Mb locus and have identified
      three candidate Wilms' tumor suppressor genes within this narrowed region. Our
      data support E-cadherin as a candidate tumor suppressor gene in Wilms' tumor;
      however, further studies are needed to definitively prove its role as the tumor
      suppressor gene associated with 16q LOH.

PMID- 12620909
TI  - Quality of life in patients with colorectal metastasis and intrahepatic
      chemotherapy.
AB  - BACKGROUND: Liver metastasis from colorectal cancer remains an oncological
      challenge. Hepatic chemotherapy has been used; however, rigorous quality of life
      (QOL) measurements are lacking. The aim of this study was to describe unique QOL
      issues to formulate a specific tool for this population. METHODS: A purposive
      sample was identified of patients treated with intrahepatic chemotherapy.
      Consenting patients completed a demographic tool and the City of Hope QOL
      Scale/Cancer Patient survey. An in-depth interview on QOL concerns was conducted,
      taped, and transcribed verbatim. The data from the interviews were coded to
      identify recurrent themes. RESULTS: Sixteen patients participated. Physical well
      being was maintained. Significantly lower subscale scores were noted for
      psychological, social, and spiritual domains compared with nonpatient norms (City
      of Hope volunteers; n = 169). Patients found intrahepatic chemotherapy convenient
      but were unable to pursue vigorous activity, and their sleep habits changed.
      Psychologically, patients felt reassured to receive specific therapy to their
      liver. CONCLUSIONS: Pilot evaluation of QOL in this population revealed changes
      in physical, psychological, social, and spiritual dimensions. Both disease- and
      treatment-specific concerns were identified, and the results provide evidence for
      items to include in a QOL questionnaire specific to this population.

PMID- 12620910
TI  - Cancer antigen 125 associated with multiple benign and malignant pathologies.
AB  - BACKGROUND: Cancer antigen (CA) 125 tumor-associated antigen is a high molecular
      glycoprotein used for follow-up of epithelial ovarian cancer. The test is often
      requested as a differential diagnosis in patients with pleural or peritoneal
      fluid. This study analyzes the prevalence of CA-125 increases in a population of
      patients attending a general hospital and discusses the possible clinical
      implications of increased levels. METHODS: On 4 different days, 380 CA-125 assays
      were performed in randomly selected patients attending our hospital. Serum CA-125
      was measured with a commercial enzyme immunoassay, and clinical records were
      reviewed for assessment of clinical parameters. RESULTS: Sixty-one patients (16%)
      had increased CA-125. The pathologies of these patients were heart failure in 9
      (14.7%), lung disease 11 (18%), hepatic cirrhosis in 7 (11.4%), malignant tumors
      in 9 (14.7%), intra-abdominal nonhepatic disease in 6 (10%), previous surgery in
      17 (27.8%), and miscellaneous in 2 (3%). Effusions were seen in 34 patients
      (55.7%). CONCLUSIONS: Our data confirm the variety of benign and malignant
      pathologies coursing with increased CA-125. Cardiovascular and chronic liver
      disease were the most frequent diagnoses in patients with increased CA-125; this
      supports the opinion that CA-125 lacks utility as a marker for malignancy. CA-125
      could have a role in the follow-up of cardiovascular, hepatic, and tumoral
      diseases with serosal involvement.

PMID- 12620911
TI  - Long-term survivorship and quality of life after cytoreductive surgery plus
      intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis.
AB  - BACKGROUND: Cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy
      with mitomycin C for peritoneal carcinomatosis is used as a palliative treatment
      for a variety of malignancies. The purpose of this study was to measure the
      quality of life (QOL) of survivors (>3 years) after treatment. METHODS: Patients
      were interviewed by telephone with the following tools: (1) the Functional
      Assessment of Cancer Therapy-Colon (FACT-C), (2) the Short Form of the Medical
      Outcomes Study Questionnaire, (3) the Center for Epidemiologic Studies-Depression
      scale, (4) the Life Appreciation scale, (5) the Psychosocial Concerns
      Questionnaire, and (6) performance status rating. RESULTS: Seventeen (10
      appendix, 5 large intestine, 1 ovarian, and 1 peritoneum) of 109 patients were
      interviewed from 3.1 to 8.0 years after treatment. Ten patients (62.5%) described
      their health as excellent or very good. No limitations on moderate activity were
      reported in 94% of cases. Paired t-tests were used to compare 10 patients who had
      baseline QOL data. FACT mean difference scores and P values (positive difference
      scores indicate improved QOL) were functional well-being: 4.9, P =.01; physical
      well-being: 3.3, P =.05; and FACT total: 14.3, P =.02. CONCLUSIONS: Long-term
      survival with good QOL is possible for selected patients with peritoneal
      carcinomatosis after cytoreductive surgery plus intraperitoneal hyperthermic
      chemotherapy.

PMID- 12620912
TI  - Distal intramural spread is an independent prognostic factor for distant
      metastasis and poor outcome in patients with rectal cancer: a multivariate
      analysis.
AB  - BACKGROUND: The aim of this study was to clarify the prognostic value of distal
      intramural spread of tumor for survival and recurrence in patients with rectal
      cancer. METHODS: Microscopic distal intramural spread was examined in 134
      consecutive specimens of resected rectal cancer. Correlations among distal
      intramural spread, established clinicopathologic factors, and patients' prognoses
      were examined by univariate and multivariate analyses. American Joint Committee
      on Cancer classification and stage groupings were used for tumor assessment.
      RESULTS: Thirty-three patients (24.6%) had distal intramural spread. Multivariate
      logistical regression analysis revealed that T3/T4 and M1 were independent
      predictive variables for the presence of distal intramural spread. Patients with
      distal intramural spread had a shorter disease-specific or disease-free survival
      time after curative surgery than those without distal intramural spread (P =.0003
      and P =.0006, respectively). Most patients with distal intramural spread
      developed distant recurrence. Cox's regression with multiple covariates showed
      that distal intramural spread is an independent factor in predicting distant
      recurrence and worse outcomes after curative surgery in patients with rectal
      cancer. CONCLUSIONS: Distal intramural spread is an independent risk factor for
      distant metastasis and poor prognosis in patients with rectal cancer.

PMID- 12620913
TI  - Detection of bone marrow micrometastasis in gastric cancer patients by
      immunomagnetic separation.
AB  - BACKGROUND: Micrometastasis to the bone marrow can predict widespread disease and
      a poor prognosis of cancer patients after surgery. The purpose of this study was
      to evaluate the clinical significance of detecting micrometastasis in the bone
      marrow of gastric cancer patients. METHODS: Bone marrow and peripheral blood
      samples were obtained from 53 gastric cancer patients at the time of surgery.
      These samples were enriched by immunomagnetic separation and immunostained with
      an anti-cytokeratin antibody. Expression of vascular endothelial growth factor
      and erbB-2/HER2 was examined in the primary tumors. RESULTS: Cytokeratin-positive
      cancer cells were observed in the bone marrow of 16 (30%) of 53 patients. Among
      them, two patients also had cancer cells in the peripheral blood. The presence of
      bone marrow micrometastasis was correlated with the depth of invasion and lymph
      node metastasis but was not associated with peritoneal dissemination. Detection
      of bone marrow micrometastasis was not correlated with vascular endothelial
      growth factor or HER2 expression in the primary tumors. Four patients with
      micrometastasis had recurrence in the liver or lungs, but this did not occur in
      patients without micrometastasis. CONCLUSIONS: Detection of cancer cells in the
      bone marrow might be an indicator of postoperative hematogenous metastasis in
      gastric cancer patients.

PMID- 12620914
TI  - Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic
      chemotherapy for stage I malignant pleural mesothelioma.
AB  - BACKGROUND: Malignant pleural mesothelioma (MPM) is a disease mostly confined to
      the thoracic cavity. Untreated, the median survival is <1 year. Cytoreductive
      surgery combined with intraoperative hyperthermic intrathoracic chemotherapy is
      used to kill residual tumor cells on the surface of the thoracic cavity while
      having limited systemic side effects. METHODS: From August 1998 to August 2001,
      22 patients with stage I MPM were included in this study. Two patients were
      irresectable at operation because of extrathoracic tumor growth. Twenty
      procedures were performed. After cytoreduction, a perfusion was performed with
      cisplatin and doxorubicin at 40 degrees C to 41 degrees C for 90 minutes.
      Adjuvant radiotherapy was given to surgical scars and drainage tracts. RESULTS:
      There was no perioperative mortality, but significant morbidity was seen in 13
      patients (65%), including bronchopleural fistula, diaphragm rupture, wound
      dehiscence, persistent air leakage, and chylous effusion. No hair loss or
      leucopenia was noticed. The median follow-up was 14 months. The median survival
      (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable
      pharmacokinetic ratio was observed for both cisplatin and doxorubicin.
      CONCLUSIONS: Cytoreductive surgery combined with hyperthermic intrathoracic
      chemotherapy for stage I MPM is feasible. However, this treatment is accompanied
      by considerable morbidity. Survival data were less encouraging.

PMID- 12620915
TI  - The role of staging laparoscopy in hepatobiliary malignancy: prospective analysis
      of 401 cases.
AB  - BACKGROUND: Patients with potentially resectable hepatobiliary malignancy are
      frequently found to have unresectable tumors at laparotomy. We prospectively
      evaluated staging laparoscopy in patients with resectable disease on preoperative
      imaging. METHODS: Staging laparoscopy was performed on 410 patients with
      potentially resectable hepatobiliary malignancy. The preoperative likelihood of
      resectability was recorded. Data on preoperative imaging, operative findings, and
      hospital course were analyzed. RESULTS: Laparoscopic inspection was complete in
      291 (73%) patients. In total, 153 patients (38%) had unresectable disease, 84 of
      whom were identified laparoscopically, increasing resectability from 62% to 78%.
      On multivariate analysis, a complete examination, preoperative likelihood of
      resection, and primary diagnosis were significant predictors of identifying
      unresectable disease at laparoscopy. The highest yield was for biliary cancers,
      and the lowest was for metastatic colorectal cancer. In patients with
      unresectable disease identified at laparoscopy, the mean hospital stay was 3
      days, and postoperative morbidity was 9%, compared with 8 days and 27%,
      respectively, in patients found to have unresectable disease at laparotomy.
      CONCLUSIONS: Laparoscopy spared one in five patients a laparotomy while reducing
      hospital stay and morbidity. Targeting laparoscopy to patients at high risk for
      unresectable disease requires consideration of disease-specific factors; however,
      the surgeons' preoperative impression of resectability is also important.

PMID- 12620916
TI  - Expression of p53 and proliferation index as prognostic factors in
      gastrointestinal sarcomas.
AB  - BACKGROUND: Sarcomas arising in the gastrointestinal (GI) tract are rare tumors.
      Molecular markers could be associated with prognosis in these types of tumors.
      METHODS: We performed a retrospective analysis of adult patients with sarcomas
      arising in the GI tract at the National Institute of Medical Sciences in Mexico
      City and the University of Alabama at Birmingham Hospital. All histological types
      were included. Patient, tumor, and treatment factors were analyzed, with overall
      survival as the main outcome variable. Expression of p53 and cellular
      proliferation antigen Ki-67 was also analyzed. Statistical analysis was performed
      by log-rank test and Cox regression. Significance was defined as P <.05. RESULTS:
      Forty-seven patients were analyzed. The median patient age was 53 years (range,
      16-82 years). Twenty-five patients (53%) were women. The stomach was the most
      common site of presentation. The mean tumor size was 14 cm (2-45 cm). A complete
      resection was achieved in 40 patients. With a median follow-up of 30 months, the
      actuarial 3-year survival was 68%. Univariate analysis identified overexpression
      of p53 and Ki-67, high tumor grade, tumor size >10 cm, and incomplete resection
      as significant negative prognostic factors. Hispanic race and good performance
      status were significantly associated with prolonged survival. On multivariate
      analysis, overexpression of p53 was the only independent negative prognostic
      factor. CONCLUSIONS: Overexpression of p53 is the strongest predictor of poor
      prognosis in patients with sarcomas of the GI tract.

PMID- 12620917
TI  - Delayed harvesting of sentinel lymph nodes after previous wide local excision of
      extremity melanoma.
AB  - BACKGROUND: Harvesting the sentinel lymph node (SLN) is important in the
      management of patients with primary cutaneous melanoma. Selective sentinel
      lymphadenectomy (SSL) is generally performed at the time of wide local excision
      (WLE). The aim of our study was to determine whether delayed SSL is useful in
      detecting micrometastasis to the regional basin in patients with previous WLE of
      an extremity melanoma. METHODS: Of 203 patients with a primary melanoma site
      located on the upper or lower extremity seen at the University of California, San
      Francisco/Mount Zion Melanoma Center from May 17, 1994, to March 23, 1999, 24
      patients had a WLE of their extremity melanoma with adequate margins before
      referral. SSL was performed to assess micrometastasis in the regional lymph node
      basin after preoperative lymphoscintigraphy. RESULTS: At least 1 SLN was
      identified in all 24 patients. At a median follow-up of 3 years, two patients
      showed micrometastasis in the SLNs. One of these two patients developed
      recurrence, and all remaining patients showed no evidence of disease.
      CONCLUSIONS: Although it is generally advised that WLE should be performed
      simultaneously with SSL, delayed SSL after WLE of an extremity melanoma can still
      provide valuable staging information, which is critical for management of the
      patient.

PMID- 12620918
TI  - New approaches to genetic manipulation of mice: tissue-specific expression of
      ACE.
AB  - The renin-angiotensin system (RAS) plays a central role in body physiology,
      controlling blood pressure and blood electrolyte composition. ACE.1 (null) mice
      are null for all expression of angiotensin-converting enzyme (ACE). These mice
      have low blood pressure, the inability to concentrate urine, and a maldevelopment
      of the kidney. In contrast, ACE.2 (tissue null) mice produce one-third normal
      plasma ACE but no tissue ACE. They also have low blood pressure and cannot
      concentrate urine, but they have normal indices of renal function. These mice,
      while very informative, show that the null approach to creating knockout mice has
      intrinsic limitations given the many different physiological systems that no
      longer operate in an animal without a functioning RAS. To investigate the fine
      control of body physiology by the RAS, we developed a novel promoter swapping
      approach to generate a more selective tissue knockout of ACE expression. We used
      this to create ACE.3 (liver ACE) mice that selectively express ACE in the liver
      but lack all ACE within the vasculature. Evaluation of these mice shows that
      endothelial expression of ACE is not required for blood pressure control or
      normal renal function. Targeted homologous recombination has the power to create
      new strains of mice expressing the RAS in selected subsets of tissues. Not only
      will these new genetic models be useful for studying blood pressure regulation
      but also they show great promise for the investigation of the function of the RAS
      in complicated disease models.

PMID- 12620919
TI  - Cell death induced by acute renal injury: a perspective on the contributions of
      apoptosis and necrosis.
AB  - In humans and experimental models of renal ischemia, tubular cells in various
      nephron segments undergo necrotic and/or apoptotic cell death. Various factors,
      including nucleotide depletion, electrolyte imbalance, reactive oxygen species,
      endonucleases, disruption of mitochondrial integrity, and activation of various
      components of the apoptotic machinery, have been implicated in renal cell
      vulnerability. Several approaches to limit the injury and augment the
      regeneration process, including nucleotide repletion, administration of growth
      factors, reactive oxygen species scavengers, and inhibition of inducers and
      executioners of cell death, proved to be effective in animal models.
      Nevertheless, an effective approach to limit or prevent ischemic renal injury in
      humans remains elusive, primarily because of an incomplete understanding of the
      mechanisms of cellular injury. Elucidation of cell death pathways in animal
      models in the setting of renal injury and extrapolation of the findings to humans
      will aid in the design of potential therapeutic strategies. This review evaluates
      our understanding of the molecular signaling events in apoptotic and necrotic
      cell death and the contribution of various molecular components of these pathways
      to renal injury.

PMID- 12620920
TI  - Sodium and calcium transport pathways along the mammalian distal nephron: from
      rabbit to human.
AB  - The final adjustment of renal sodium and calcium excretion is achieved by the
      distal nephron, in which transepithelial ion transport is under control of
      various hormones, tubular fluid composition, and flow rate. Acquired or inherited
      diseases leading to deranged renal sodium and calcium balance have been linked to
      dysfunction of the distal nephron. Diuretic drugs elicit their effects on sodium
      balance by specifically inhibiting sodium transport proteins in the apical plasma
      membrane of distal nephron segments. The identification of the major apical
      sodium transport proteins allows study of their precise distribution pattern
      along the distal nephron and helps address their cellular and molecular
      regulation under various physiological and pathophysiological settings. This
      review focuses on the topological arrangement of sodium and calcium transport
      proteins along the cortical distal nephron and on some aspects of their
      functional regulation. The availability of data on the distribution of
      transporters in various species points to the strengths, as well as to the
      limitations, of animal models for the extrapolation to humans.

PMID- 12620921
TI  - Glucose-induced changes in integrins and matrix-related functions in cultured
      human glomerular epithelial cells.
AB  - In cultured human glomerular epithelial cells (HGEC), 25 mM glucose resulted in
      decreased expression of alpha(3)-, alpha(2)-, and beta(1)-integrins and increased
      expression of alpha(5)- and alpha(v)beta(3)-integrins. This change was
      accompanied by decreased binding of HGEC to type IV collagen. In the presence of
      normal (5 mM) glucose concentration, cell binding to type IV collagen was
      primarily mediated by alpha(2)beta(1)- and alpha(5)beta(1)-integrins, as
      indicated by experiments in which cell adhesion to type IV collagen was competed
      by specific anti-integrin monoclonal antibodies. In the presence of high (25 mM)
      glucose, the upregulated alpha(5)- and alpha(v)beta(3)-integrins were mainly
      involved in cell binding to type IV collagen. Furthermore, high glucose decreased
      expression of matrix metalloproteinase-2 (MMP-2), a collagenase regulated in part
      by alpha(3)beta(1)-integrin, as suggested by the use of ligand-mimicking
      antibodies against these integrins, which resulted in release of increased
      amounts of MMP-2 in the culture medium. Finally, tissue inhibitor of
      metalloproteinase-2, the specific inhibitor of MMP-2, was upregulated in high
      glucose and could contribute to matrix accumulation. These changes could help
      explain basement membrane thickening in diabetes.

PMID- 12620923
TI  - Comparative analysis of ontogenic changes in renal and intestinal biotin
      transport in the rat.
AB  - Biotin, an essential water-soluble micronutrient, cannot be synthesized by
      mammals; rather, it is obtained from exogenous sources via uptake by intestinal
      epithelia. Renal epithelia reclaim the vitamin that is filtered in the glomeruli.
      Both epithelia take up biotin via the sodium-dependent multivitamin transporter
      (SMVT). Little is known about ontogenic regulation of the renal and intestinal
      biotin transport processes and about the mechanism(s) involved in any such
      regulation. In this study, we sought to examine and compare ontogenic aspects of
      the renal and intestinal biotin uptake processes using purified brush-border
      membrane vesicles (BBMV) isolated from the kidney cortex and jejunum of suckling
      and adult rats. Clear ontogenic changes were observed in the intestinal biotin
      uptake process, which were mediated via changes in V(max) and apparent K(m).
      Parallel changes were also seen in protein, mRNA, and transcription rate of SMVT
      as indicated by results of Western blotting, RT-PCR, and nuclear run-on assays,
      respectively. In contrast, biotin uptake by renal BBMV did not show ontogenic
      changes; i.e., it was similar in suckling and adult rats. Also, the levels of
      SMVT protein and mRNA were similar in the kidneys of both age groups. These data
      show that biotin uptake by renal and intestinal epithelial cells responds
      differently to ontogenic regulation. In addition, the ontogenic changes observed
      in the intestinal biotin uptake process involve the entry step of the vitamin at
      the BBM and appear to be mediated via a transcriptional mechanism(s).

PMID- 12620922
TI  - Contribution of quinolinic acid in the development of anemia in renal
      insufficiency.
AB  - Quinolinic acid (QA) is a potent endogenous excitotoxin; elevation of its
      concentration in an organism has been implicated in the pathogenesis of various
      disorders. The purpose of this study was the assessment of QA impact on the
      process of erythropoiesis. Marked increase of QA concentration was observed in
      plasma and peripheral tissues of uremic rats. These changes were proportional to
      the amount of the removed renal tissue and positively correlated with the
      concentration of creatinine but negatively correlated with hematological
      parameters, i.e., hematocrit and Hb red blood cells count. The changes were
      accompanied by a slight decrease in the concentration of endogenic erythropoietin
      (EPO) in the plasma of animals with uremia. Chronic treatment with QA diminished
      the increase in EPO concentration after introduction of cobalt in rats. These
      changes were associated with the decrease in all hematological parameters after
      QA administration. The in vitro study in the conditions of hypoxia showed that QA
      inhibited the EPO release from HepG2 cells to the culture base. Additionally, in
      HepG2 cells QA had a dose-dependent inhibitory effect on hypoxia- and cobalt
      induced EPO gene expression without any cell toxicity. In conclusion, the
      erythropoiesis in chronic renal failure could be attributed to the influence of
      QA on EPO synthesis. Thus we propose that QA can be a uremic toxin responsible
      for anemia in animals or patients with renal failure.

PMID- 12620924
TI  - HCaRG is a novel regulator of renal epithelial cell growth and differentiation
      causing G2M arrest.
AB  - We recently identified a novel calcium-regulated gene, HCaRG, that is highly
      expressed in the kidney and maps to a chromosomal locus determining kidney weight
      in rats. The mRNA levels of HCaRG negatively correlate with the proliferative
      status of the kidney cells. To investigate its role in renal epithelial cellular
      growth directly, we studied the human embryonic kidney cell line (HEK-293) stably
      transfected with either plasmid alone or plasmid containing rat HCaRG.
      [(3)H]thymidine incorporation was significantly lower in HCaRG clones. Although
      HCaRG clones exhibited some enhanced susceptibility to cell death, this was not
      the primary mechanism of reduced proliferation. Cell cycle analysis revealed a
      G(2)M phase accumulation in HCaRG clones that was associated with upregulation of
      p21(Cip1/WAF1) and downregulation of p27(Kip1). HCaRG clones had a greater
      protein content, larger cell size, and released 4.5- to 8-fold more of an atrial
      natriuretic peptide-like immunoreactivity compared with controls. In addition,
      HCaRG clones demonstrated the presence of differentiated junctions and a lower
      incidence of mitotic figures. Genistein treatment of wild-type HEK-293 cells
      mimicked several phenotypic characteristics associated with HCaRG
      overexpresssion, including increased cell size and increased release of atrial
      natriuretic peptide. Taken together, our results suggest that HCaRG is a
      regulator of renal epithelial cell growth and differentiation causing G(2)M cell
      cycle arrest.

PMID- 12620925
TI  - Substance P via NK1 receptor facilitates hyperactive bladder afferent signaling
      via action of ROS.
AB  - We explored whether substance P (SP) via neurokinin (NK) receptor facilitates
      bladder afferent signaling and reactive oxygen species (ROS) formation in bladder
      in association with neurogenic inflammation. We evaluated ROS activity and
      cystometrograms as well as pelvic nervous activity in anesthetized rat bladder
      with SP stimulation. Our results showed that endogenous SP via NK(1), not NK(2),
      receptor mediated a micturition reflex. An increase in SP by electrical
      stimulation of the pelvic nerve or an increase in exogenous SP by intra-arterial
      or intrathecal administration can facilitate myogenic and neurogenic bladder
      contractions. Furthermore, exaggerated SP release increased ROS in the bladder
      and whole blood via increased mast cell degranulation, intercellular adhesion
      molecule expression, and leukocyte adhesion, a primary source of ROS in the
      inflamed bladder. Treatment with NK(1)-receptor antagonists or ROS scavengers
      reduced bladder intercellular adhesion molecule expression and ROS and
      ameliorated the hyperactive bladder response. Our study indicates that the
      mechanism by which SP participates in the neurogenic bladder may be complicated
      by its proinflammatory activity and its ability to stimulate ROS generation.

PMID- 12620926
TI  - ADF/cofilin mediates actin cytoskeletal alterations in LLC-PK cells during ATP
      depletion.
AB  - Ischemic injury induces actin cytoskeleton disruption and aggregation, but
      mechanisms affecting these changes remain unclear. To determine the role of actin
      depolymerizing factor (ADF)/ cofilin participation in ischemic-induced actin
      cytoskeletal breakdown, we utilized porcine kidney cultured cells, LLC-PK(A4.8),
      and adenovirus containing wild-type (wt), constitutively active, and inactive
      Xenopus ADF/cofilin linked to green fluorescence protein [XAC(wt)-GFP] in an ATP
      depletion model. High adenoviral infectivity (70%) in LLC-PK(A4.8) cells resulted
      in linearly increasing XAC(wt)-GFP and phosphorylated (p)XAC(wt)-GFP (inactive)
      expression. ATP depletion rapidly induced dephosphorylation, and, therefore,
      activation, of endogenous pcofilin as well as pXAC(wt)-GFP in conjunction with
      the formation of fluorescent XAC(wt)-GFP/actin aggregates and rods. No
      significant actin cytoskeletal alterations occurred with short-term ATP depletion
      of LLC-PK(A4.8) cells expressing GFP or the constitutively inactive mutant
      XAC(S3E)-GFP, but cells expressing the constitutively active mutant demonstrated
      nearly instantaneous actin disruption with aggregate and rod formation. Confocal
      image three-dimensional volume reconstructions of normal and ATP-depleted LLC
      PK(A4.8) cells demonstrated that 25 min of ATP depletion induced a rapid increase
      in XAC(wt)-GFP apical and basal signal in addition to XAC-GFP/actin aggregate
      formation. These data demonstrate XAC(wt)-GFP participates in ischemia-induced
      actin cytoskeletal alterations and determines the rate and extent of these ATP
      depletion-induced cellular alterations.

PMID- 12620927
TI  - Renal fluid and electrolyte handling in BKCa-beta1-/- mice.
AB  - Large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) are composed of pore
      forming alpha-subunits and one of four accessory beta-subunits. The beta1
      subunit, found predominantly in smooth muscle, modulates the Ca(2+) sensitivity
      and pharmacological properties of BK(Ca). BK(Ca)-beta1 null mice (Mbeta1(-/-))
      are moderately hypertensive, consistent with the role of BK(Ca) in modulating
      intrinsic vascular tone. Because BK(Ca) are present in various renal cells
      including the mesangium and cortical collecting ducts, we determined whether
      fluid or electrolyte excretion was impaired in Mbeta1(-/-) under euvolemic,
      volume-expanded, or high-salt diet conditions. Under euvolemic conditions, no
      differences in renal function were found between Mbeta1(-/-) and Mbeta1(+/+).
      However, glomerular filtration rate (GFR) and fractional K(+) excretion were
      significantly impaired in Mbeta1(-/-) in response to acute volume expansion. In
      contrast, Mbeta1(-/-) exhibited enhanced Na(+) excretion and fractional Na(+)
      excretion responses to acute volume expansion. Differences in renal function
      between Mbeta1(+/+) and Mbeta1(-/-) were not observed when chronically treated
      with a high-salt diet. These observations indicate that the beta1-subunit of
      BK(Ca) contributes to the increased GFR that accompanies an acute salt and volume
      load and raises the possibility that it is also involved in regulating K(+)
      excretion under these conditions.

PMID- 12620929
TI  - Glomerular filtration rate dependence of sieving of albumin and some neutral
      proteins in rat kidneys.
AB  - The size and charge-selective properties of the glomerular barrier are partly
      controversial. Glomerular sieving coefficients (theta) for proteins have rarely
      been determined noninvasively before in vivo. Therefore, theta was assessed vs.
      glomerular filtration rate (GFR; (51)Cr-EDTA clearance) in intact rats for
      radiolabeled myoglobin, kappa-dimer, neutral horseradish peroxidase (nHRP),
      neutral human serum albumin (nHSA), and native albumin (HSA). To obtain theta,
      glomerular tracer clearance, assessed from the 7- to 8-min kidney uptake of
      protein, was divided by the GFR. The data were fitted with a two-pore model of
      glomerular permeability, where the small-pore radius was 37.35 +/- 1.11 (SE) A,
      and the "unrestricted pore area over diffusion path length" (A(0)/DeltaX) 1.84 +/
      0.43 x 10(6) cm. Although seemingly horizontal for nHRP and nHSA, the log theta
      vs. GFR curves showed slightly negative slopes for the proteins investigated in
      the GFR interval of 2-4.5 ml/min. Strong negative (linear) correlations between
      (log) theta and GFR were obtained for myoglobin (P = 0.002) and HSA (P = 0.006),
      whereas they were relatively weak for nHRP and nHSA and nonsignificant for kappa
      dimer. Theta for nHSA was markedly higher than that for HSA. In conclusion, there
      were no indications of increases in theta vs. GFR, as indicative of concentration
      polarization, for the proteins investigated at high GFRs. Furthermore, the
      glomerular small-pore radius assessed from endogenous (neutral) protein sieving
      data was found to be smaller than previously determined using dextran or Ficoll
      as test molecules.

PMID- 12620928
TI  - Functional evidence that vascular endothelial growth factor may act as an
      autocrine factor on human podocytes.
AB  - Vascular endothelial growth factor (VEGF) is expressed by renal glomerular
      epithelial cells (podocytes) and is thought to be protective against nephrotoxic
      agents. VEGF has been shown to be an autocrine survival factor in neuropilin-1
      positive, VEGF receptor-negative breast carcinoma cells. Normal human podocytes
      are also known to express neuropilin-1, VEGF, and are VEGF-R2 negative. Here, we
      investigated whether a similar VEGF autocrine loop may exist in podocytes.
      Podocyte cytosolic calcium concentration ([Ca(2+)](i)) was analyzed in primary
      cultured and conditionally immortalized podocytes using ratiometric fluorescence
      measurement. Cytotoxicity was determined by lactate dehydrogenase assay,
      proliferation by [(3)H]-thymidine incorporation, and cell counts by
      hemocytometric assay. VEGF decreased [Ca(2+)](i) in primary podocytes (from 179
      +/- 36 to 121 +/- 25 nM, P < 0.05) and conditionally immortalized podocytes (from
      95 +/- 10 to 66 +/- 8 nM, P < 0.02) in the absence of extracellular calcium. The
      type III receptor tyrosine-kinase inhibitor PTK787/ZK222584 abolished this
      reduction. VEGF increased podocyte [(3)H]-thymidine incorporation (3,349 +/- 283
      cpm, control 2,364 +/- 301 cpm, P < 0.05) and cell number (4.5 +/- 0.7 x
      10(4)/ml, control 2.6 +/- 0.5 x 10(4)/ml, P < 0.05) and decreased cytotoxicity
      (5.9 +/- 0.7%, control 12 +/- 3%, P < 0.05), whereas a monoclonal antibody to
      VEGF increased cytotoxicity. Electron microscopy of normal human glomeruli
      demonstrated that the glomerular VEGF is mostly podocyte cell membrane
      associated. These results indicate that one of the functions of VEGF secreted
      from podocytes may be to act as an autocrine factor on calcium homeostasis and
      cell survival.

PMID- 12620930
TI  - Interleukin-5 transgene expression and eosinophilia are associated with retarded
      mammary gland development in mice.
AB  - Eosinophils are prevalent in the female reproductive tract, where they may
      contribute to regulation of development and maintenance of epithelial integrity.
      The present study examined the effects of constitutive interleukin-5 (IL-5)
      expression and overabundance of eosinophils on the development and function of
      the mammary gland, uterus, and ovary in mice. Eosinophils were up to 13-fold and
      4-fold more abundant in the uterus and mammary gland, respectively, in female IL
      5 transgenic (IL-5Tg) mice than in wild-type (Wt) animals. Eosinophils were
      present in large numbers in regressing corpora lutea in IL-5Tg mice but not in
      ovaries from Wt mice. Postpubertal mammary gland development was retarded in IL
      5Tg mice, with impaired terminal end bud formation and an altered pattern of
      epithelial cell proliferation across the mammary fat pad coincident with
      disrupted ductal branching and extension. By 10 wk of age, the ductal tree was
      complete in both genotypes. Onset of first estrus was also delayed in IL-5Tg
      mice, but once IL-5Tg mice reached puberty, serum estrogen content across the
      cycle and estrous cycle duration were normal. The histology of uterine tissue and
      epithelial cell turnover were unchanged. Capacity to mate and achieve pregnancy
      was not affected by maternal IL-5 transgene expression, although at Day 18 of
      gestation, a modest decrease in the fetal:placental weight ratio was observed.
      Furthermore, parturition and ability to lactate and nurture postnatal pup
      development were not compromised. These data demonstrate an effect of IL-5
      overexpression on ductal morphogenesis during postpubertal mammary gland
      development that is consistent with a direct regulatory role for eosinophils in
      these events, but these data also show that eosinophil excess does not have long
      term consequences for adult reproductive function.

PMID- 12620931
TI  - A differential mechanism is involved during heparin- and cryopreservation-induced
      capacitation of bovine spermatozoa.
AB  - After ejaculation, mammalian spermatozoa must undergo capacitation to fertilize.
      Capacitation of bovine spermatozoa occurs in vitro in medium supplemented with
      heparin. Semen cryopreservation is an important tool for assisted reproduction,
      although the fertility of frozen-thawed spermatozoa is reduced, possibly due to
      precocious capacitation-like changes that are known to occur. Our purpose was to
      clarify the mechanisms involved in bull sperm cryocapacitation induced by
      cryopreservation. Our general hypothesis is that the signaling pathways that lead
      to capacitation are triggered by the cryopreservation procedure. Ejaculated
      bovine semen was divided into two aliquots and diluted in extender; one was then
      kept fresh, whereas the second was cryopreserved. Western blots of extracted
      sperm proteins with anti-phosphotyrosine antibody showed that capacitation,
      induced by either heparin in fresh sperm or cryopreservation (cryocapacitation),
      is associated with a differential profile of phosphotyrosine-containing proteins.
      Immunolocalization of phosphotyrosine-containing proteins in the fresh and
      cryopreserved spermatozoa showed that, after thawing, cryocapacitated sperm
      displayed labeling over the acrosomal region, whereas for fresh sperm, this
      labeling appeared after 5-h incubation with heparin. The chlortetracycline assay
      and the ability of the sperm to undergo the lysophosphatidylcholine-induced
      acrosome reaction were used to confirm that a subpopulation of cryopreserved
      sperm is capacitated at thawing, irrespective of heparin inclusion. Since glucose
      is known to inhibit heparin-induced capacitation, the semen extender was modified
      to include glucose as a means of inhibiting cryocapacitation; however,
      cryocapacitation was not prevented according to the chlortetracycline assay and
      profile of phosphotyrosine-containing sperm proteins.

PMID- 12620932
TI  - Expression of hyaluronan synthases and corresponding hyaluronan receptors is
      differentially regulated during oocyte maturation in cattle.
AB  - In response to the gonadotropin surge, the compact cumulus-oocyte complex (COC)
      undergoes expansion by synthesis of the mucopolysaccharide hyaluronan (HA)
      accompanying oocyte maturation. The objective of the present study was to
      quantify mRNA transcripts of the HA synthase (HAS) 1, HAS2, and HAS3 and the HA
      receptors CD44 and RHAMM (receptor for HA-mediated motility). Additionally, we
      determined the histological localization of HA and its receptor, CD44, in
      maturing bovine COCs and cultured granulosa cells (GCs). Full-length transcript
      of bovine HAS2 and a part of the bovine RHAMM sequence has been made available.
      Real-time reverse transcriptase-polymerase chain reaction was used for individual
      mRNA expressions of bovine COCs in comparison to follicular GC gonadotropin
      treatment. Localization of CD44 and HA were done by immunohistochemistry and
      biotinylated HA-binding protein, respectively. Gonadotropins caused a rapid, 120
      fold increase of HAS2 mRNA, whereas a delayed, 2-fold up-regulation of HAS3 mRNA
      was observed. The HAS1 transcripts were barely detected. Expression of CD44 mRNA
      greatly increased during in vitro maturation of COCs, indicating an important
      role when compared to an unchanged, steady-state RHAMM expression. As a
      consequence, HA was locally enriched after COC expansion, but only limited change
      was observed in the GCs. In cultured GCs, HAS2 expression was stimulated through
      FSH application, followed by the effective treatments of FSH+LH and LH. Treatment
      with LH induced the highest increase of the CD44 receptor, followed by FSH and
      FSH+LH treatments. These results suggest that HAS2 is mainly responsible for
      rapid HA synthesis in bovine COCs and GCs. In bovine COCs, the transcriptional up
      regulation of both HAS2 and the receptor CD44 appear to be important
      prerequisites for initiating HA-mediated effects during final oocyte development
      and sperm-egg interaction.

PMID- 12620933
TI  - Temporal regulation of the expression of syncytin (HERV-W), maternally imprinted
      PEG10, and SGCE in human placenta.
AB  - Maternally imprinted PEG10 and SGCE, separated by approximately 2.15 Mb from
      Syncytin (HERV-W) gene at 7q21.3, are implicated in choriocarcinoma and Silver
      Russell syndrome. Here we have analyzed the temporal regulation of mRNA
      expression of these genes in placenta and demonstrate that Syncytin gene
      activation is highest in term placenta, PEG10, downregulated at early hypoxic
      phase, and highly activated at 11-12 wk of gestation. In contrast, transcription
      from SGCE remained unchanged throughout pregnancy, suggesting two neighboring
      imprinted genes are differentially regulated at very early pregnancy.
      Additionally, accumulation of two major species of mRNA (8 kb and 3.1 kb) encoded
      by HERV-W in placenta is regulated: 3.1 kb mRNA level remained unchanged
      throughout pregnancy, whereas the production of 8 kb species was highest in term
      placenta. Western blot and immunohistochemical staining of placental tissues with
      monoclonal antibodies revealed a marked reduction of syncytin glycoprotein
      synthesis in late pregnancy. Therefore, the relative levels of 3.1 kb and 8 kb
      mRNAs in trophoblasts could regulate syncytin protein synthesis, possibly by
      competition of the two mRNA species for translational apparatus.

PMID- 12620934
TI  - Ischemia-reperfusion of the murine testis stimulates the expression of
      proinflammatory cytokines and activation of c-jun N-terminal kinase in a pathway
      to E-selectin expression.
AB  - Ischemia-reperfusion (IR) of the testis results in germ cell-specific apoptosis
      and can lead to aspermatogenesis. Germ cell-specific apoptosis after IR of the
      testis has been shown to be correlated with and dependent on neutrophil
      recruitment to the testis after IR. Studies that used E-selectin-deficient mice
      have demonstrated that E-selectin expression is critical for neutrophil
      recruitment to subtunical venules in the testis after IR and for the resultant
      germ cell-specific apoptosis. The present study investigates the in vivo
      signaling pathway that exists after IR that leads to neutrophil recruitment in
      the murine testis. Mice were subjected to a 2-h period of testicular ischemia
      followed by reperfusion. Results demonstrate that the proinflammatory cytokines,
      tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta), are
      stimulated after IR as is the phosphorylation of c-jun N-terminal kinase (JNK).
      The downstream transcription factors of JNK, ATF-2 and c-jun are also
      phosphorylated at specific times after IR of the testis. Activation of the JNK
      stress-related kinase pathway is correlated with an increase in E-selectin
      expression and neutrophil recruitment to the testis after IR. Intratesticular
      injection of IL-1beta also caused JNK phosphorylation and neutrophil recruitment
      to the testis. These results suggest that testicular IR injury stimulates IL
      1beta expression, which leads to activation of the JNK signaling pathway and
      ultimately E-selectin expression and neutrophil recruitment to the testis. This
      provides the first evidence of a cytokine/stress-related kinase signaling pathway
      to E-selectin expression in vivo.

PMID- 12620935
TI  - Infertility observed in reproductive toxicity study of N-acetyl-L-cysteine in
      rats.
AB  - The toxic effects of i.v. administration of N-acetyl-l-cysteine (NAC), a
      component of parenteral nutrition solutions, on fertility and embryonic
      development were investigated in SD male and female rats at doses of 100, 300,
      and 1000 mg kg-1 day-1. Infertility was observed in females in the 1000-mg/kg
      group throughout the period from before mating to embryogenesis. No effect of NAC
      on the reproductive ability of the male rats was seen. The oocytes and embryos
      were assessed morphologically to clarify the cause of the effects of NAC. The
      unfertilized oocytes (UO) recovered from the ampullae of the uterine tubes and
      Gestational Day (GD) 1 and 2 embryos recovered from the oviducts or uterus of the
      rats that received NAC i.v. at a dosage of 1000 mg kg-1 day-1 for more than 1 wk
      before mating were assessed morphologically by stereomicroscopy. In addition, the
      thickness of the zona pellucida (ZP) was calculated by morphometric evaluation of
      the UO. Fewer UO were collected in the NAC group than in the control
      (nontreatment) group. Interestingly, ZP-lacking or partially ZP-lacking oocytes
      were observed in the NAC group, and the morphometric evaluation of the UO showed
      thinning of the ZP. The number of embryos in each animal was markedly decreased
      on GD1, and no embryos were recovered on GD2 in the NAC group. The oocytes that
      had ZP affected by NAC treatment were abnormal or nonviable. The findings of the
      present study suggest that changes in the ZP are related to the infertility
      associated with NAC.

PMID- 12620936
TI  - Role of prostaglandin H2 synthase 2 in murine parturition: study on ovariectomy
      induced parturition in prostaglandin F receptor-deficient mice.
AB  - To determine the prostaglandin (PG) H2 synthase (generally referred to as
      cyclooxygenase [COX]) isozyme responsible for producing uterotonic PGs during
      parturition, we used PGF2alpha receptor-deficient mice, which exhibit parturition
      failure due to impaired withdrawal of serum progesterone at term. On ovariectomy
      induced parturition in these mice, uterine COX-2 mRNA expression was drastically
      induced in the myometrium, whereas COX-1 mRNA expression in the endometrial
      epithelium decreased. The concomitant administration of progesterone with
      ovariectomy resulted in a delay in parturition and the disappearance of both the
      increase in COX-2 mRNA and the decrease in COX-1 mRNA. Thus, the expression of
      myometrial COX-2 and the occurrence of parturition are closely associated in this
      model. Furthermore, administration of the COX-nonselective inhibitor,
      indomethacin, or the COX-2-selective inhibitor, Dup-697 or JTE-522, effectively
      delayed ovariectomy-induced parturition in these mice. These findings suggest
      that COX-2-derived PGs contribute to the onset of parturition after the decrease
      in serum progesterone level.

PMID- 12620937
TI  - Endovascular trophoblast invasion: implications for the pathogenesis of
      intrauterine growth retardation and preeclampsia.
AB  - Maternal uteroplacental blood flow increases during pregnancy. Altered
      uteroplacental blood flow is a core predictor of abnormal pregnancy. Normally,
      the uteroplacental arteries are invaded by endovascular trophoblast and remodeled
      into dilated, inelastic tubes without maternal vasomotor control. Disturbed
      remodeling is associated with maintenance of high uteroplacental vascular
      resistance and intrauterine growth restriction (IUGR) and preeclampsia. Herein,
      we review routes, mechanisms, and control of endovascular trophoblast invasion.
      The reviewed data suggest that endovascular trophoblast invasion involves a side
      route of interstitial invasion. Failure of vascular invasion is preceded by
      impaired interstitial trophoblast invasion. Extravillous trophoblast synthesis of
      nitric oxide is discussed in relation to arterial dilation that paves the way for
      endovascular trophoblast. Moreover, molecular mimicry of invading trophoblast
      expressing endothelial adhesion molecules is discussed in relation to replacement
      of endothelium by trophoblast. Also, maternal uterine endothelial cells actively
      prepare endovascular invasion by expression of selectins that enable trophoblast
      to adhere to maternal endothelium. Finally, the mother can prevent endovascular
      invasion by activated macrophage-induced apoptosis of trophoblast. These data are
      partially controversial because of methodological restrictions associated with
      limitations of human tissue investigations and animal studies. Animal models
      require special care when extrapolating data to the human due to extreme species
      variations regarding trophoblast invasion. Basal plates of delivered placentas or
      curettage specimens have been used to describe failure of trophoblast invasion
      associated with IUGR and preeclampsia; however, they are unsuitable for these
      kinds of studies, since they do not include the area of pathogenic events, i.e.,
      the placental bed.

PMID- 12620938
TI  - Mouse round spermatids developed in vitro from preexisting spermatocytes can
      produce normal offspring by nuclear injection into in vivo-developed mature
      oocytes.
AB  - It has been shown that mature oocytes injected with nuclei from round spermatids
      collected from mouse testis can generate normal offspring and that round
      spermatids can develop in vitro. An undetermined issue is whether spermatids
      developed in vitro are capable of generating fertile offspring by nuclear
      injection into oocytes. Herein, we report the production of normal and fertile
      offspring by nuclear injection using haploid spermatid donors derived from mouse
      primary spermatocyte precursors cocultured with Sertoli cells. Cocultured
      spermatogonia and spermatocytes were characterized by their nuclear
      immunoreactive patterns determined by an antibody to phosphorylated histone H2AX
      (gamma-H2AX), a marker for DNA double-strand breaks. Cocultured round spermatid
      progenies display more than one motile flagellum, whose axonemes were recognized
      by antitubulin immunostaining. Flagellar wavelike movement and flagellar-driven
      propulsion of round spermatids developed in vitro were documented by
      videomicroscopy (http://www.sci.ccny.cuny.edu/ approximately kier). We also show
      that breeding of male and female mouse offspring generated by spermatid nuclear
      injection produced fertile offspring. In addition to their capacity to produce
      fertile offspring, cocultured, flagellated round spermatids can facilitate the
      analysis of the mechanisms of centriolar polarity, duplication, assembly, and
      flagellar growth, including the intraflagellar transport of cargo proteins.

PMID- 12620939
TI  - Protamine 2 deficiency leads to sperm DNA damage and embryo death in mice.
AB  - Cytokinesis is incomplete in spermatogenic cells, and the descendants of each
      stem cell form a clonal syncytium. As a result, a heterozygous mutation in a gene
      expressed postmeiotically affects all of the haploid spermatids within a
      syncytium. Previously, we have found that disruption of one copy of the gene for
      either protamine 1 (PRM1) or protamine 2 (PRM2) in the mouse results in a
      reduction in the amount of the respective protein, abnormal processing of PRM2,
      and inability of male chimeras to transmit either the mutant or wild-type allele
      derived from the 129-genotype embryonic stem cells to the next generation.
      Although it is believed that protamines are essential for compaction of the sperm
      nucleus and to protect the DNA from damage, this has not been proven
      experimentally. To test the hypothesis that failure of chimeras to transmit the
      129 genotype to offspring was due to alterations in the organization and
      integrity of sperm DNA, we used the single-cell DNA electrophoresis (comet)
      assay, ultrastructural analysis, and the intracytoplasmic sperm injection (ICSI)
      procedure. Comet assay demonstrated a direct correlation between the fraction of
      sperm with haploinsufficiency of PRM2 and the frequency of sperm with damaged
      DNA. Ultrastructural analysis revealed reduced compaction of the chromatin. ICSI
      with PRM2-deficient sperm resulted in activation of most metaphase II-arrested
      mouse eggs, but few were able to develop to the blastocyst stage. These findings
      suggest that development fails because of damage to paternal DNA and that PRM2 is
      crucial for maintaining the integrity of sperm chromatin.

PMID- 12620940
TI  - Current equipment alarm sounds: friend or foe?

PMID- 12620941
TI  - Arrhythmogenic potential of antiemetics: perspectives on risk-benefits.

PMID- 12620942
TI  - The perceived urgency of auditory warning alarms used in the hospital operating
      room is inappropriate.
AB  - PURPOSE: To examine the perceived urgency of 13 auditory warning alarms commonly
      occurring in the hospital operating room. METHODS: Undergraduate students, who
      were naive with respect to the clinical situation associated with the alarms,
      judged perceived urgency of each alarm on a ten-point scale. RESULTS: The
      perceived urgency of the alarms was not consistent with the actual urgency of the
      clinical situation that triggers it. In addition, those alarms indicating patient
      condition were generally perceived as less urgent than those alarms indicating
      the operation of equipment. Of particular interest were three sets of alarms
      designed by equipment manufacturers to indicate specific priorities for action.
      Listeners did not perceive any differences in the urgency of the 'information
      only', 'medium' and 'high' priority alarms of two of the monitors with all judged
      as low to moderate in urgency. In contrast, the high priority alarm of the third
      monitor was judged as significantly more urgent than its low and medium urgency
      counterparts. CONCLUSION: The alarms currently in use do not convey the intended
      sense of urgency to naive listeners, and this holds even for two sets of alarms
      designed specifically by manufacturers to convey different levels of urgency.

PMID- 12620943
TI  - Atrial fibrillation after ondansetron for the prevention and treatment of
      postoperative nausea and vomiting: a case report.
AB  - PURPOSE: Even though clinical safety has been established in large studies,
      ondansetron has been reported to cause adverse cardiovascular events. We present
      a case of atrial fibrillation in association with ondansetron in the
      postoperative period. CLINICAL FEATURES: A 47-yr-old, 81 kg female presented with
      a benign lump in her left breast for lumpectomy. Her past medical history was
      unremarkable. Physically she was very active, non-smoker and had no allergies.
      She underwent the procedure under general anesthesia. She received 4 mg of
      ondansetron intravenously for postoperative nausea and vomiting prophylaxis at
      the end of the procedure and an additional 4 mg in the recovery room for nausea.
      Within 15 min after the second dose she was noted to be in atrial fibrillation
      that required admission to the hospital and procainamide infusion for conversion
      to normal sinus rhythm. She did not have any evidence of myocardial ischemia,
      valvular abnormality or pulmonary embolism. CONCLUSION: The 5-hydroxytryptamine 3
      receptor (5-HT(3)) antagonist ondansetron has been reported to cause myocardial
      ischemia, supraventricular and ventricular tachycardia. Postulated mechanism
      includes inhibition of Bezold-Zarisch cardiac reflex and coronary
      vasoconstriction. Inhibition of 5-HT(3) receptors in the heart could lead to
      unopposed action of other serotonin receptors leading to atrial fibrillation or
      other tachyarrhythmias described in the literature.

PMID- 12620944
TI  - Dexamethasone prevents postoperative nausea and vomiting more effectively in
      women with motion sickness.
AB  - PURPOSE: To evaluate the antiemetic effect of iv dexamethasone for preventing
      postoperative nausea and vomiting (PONV) in women with and without a history of
      motion sickness. METHODS: This randomized, double-blinded, placebo-controlled
      study was carried out in 168 female patients with (n = 84) and without (n = 84) a
      history of motion sickness undergoing gynecological laparoscopy. Patients
      received 8 mg dexamethasone or saline immediately before induction of anesthesia.
      Postoperatively patients were assessed for 24 hr for nausea, vomiting, and
      complete response (no vomiting, no need for rescue antiemetics). RESULTS: The
      complete response for patients with a history of motion sickness was 80.5% and
      37.5% for recipients of dexamethasone and saline, respectively [P < 0.001; number
      needed-to-treat (NNT) = 2.3]; with corresponding incidences of 83.3% and 53.7%
      when there was no such history (P = 0.009; NNT = 3.4). Calculation of the
      efficacy of dexamethasone for the different subgroups shows that dexamethasone
      was 45.3% more effective in patients with motion sickness than in those without
      it. CONCLUSIONS: Prophylactic administration of dexamethasone is effective in
      reducing PONV in patients with and without a history of motion sickness. The
      results of this study were more favourable in patients with a history of motion
      sickness, demonstrating a higher effectiveness of dexamethasone for preventing
      PONV in this subgroup of patients.

PMID- 12620945
TI  - General anesthesia does not impair simulator driving skills in volunteers in the
      immediate recovery period - a pilot study.
AB  - PURPOSE: The current recommendations to refrain from driving for 24 hr after
      general anesthesia (GA) lack evidence. Our objective was to measure impairment of
      driving performance at various time intervals after anesthesia using driving
      impairment at different blood alcohol concentrations (BAC) as a gold standard for
      comparison. METHODS: Institutional Review Board approval was obtained. A cross
      over design, within subject comparison was used. Twelve volunteers were
      randomized to three treatments: GA, alcohol, and no drug. Psychomotor recovery
      was assessed by Digit Symbol Substitution Test (DSST) and Trieger Dot Test (TDT).
      On the anesthetic day, GA was induced with propofol 2.5 mg x kg(-1) and fentanyl
      l micro g x kg(-1) and maintained with N(2)O-O(2) 50:50 and approximately one
      minimum alveolar concentration of desflurane by spontaneous ventilation for 30
      min. Driving simulator test runs occurred at two, three, four, and 24 hr
      postanesthesia. On the alcohol treatment day, a vodka and orange juice beverage
      was administered to reach the legal limit for BAC in the province of Ontario,
      Canada (BAC 0.08%). On the control day, no drug was given. Driving simulator test
      runs corresponded to the same time of day as the postanesthetic test runs. Two
      way analysis of variance for dependent samples (ANOVA) was performed using the
      SAS program. P values of less than 0.05 were considered significant. RESULTS:
      There was no significant difference in postanesthetic driving skills at two,
      three, and four hours postanesthesia, and the corresponding control sessions.
      There was no significant difference among the three sessions with respect to pen
      and paper tests of psychomotor performance. Performance during the alcohol
      session differed significantly from that during the control and postanesthetic
      sessions. CONCLUSION: Certain driving skills return by two hours after one half
      hour of GA of propofol, desflurane, and fentanyl in a group of young volunteers.

PMID- 12620947
TI  - Sevoflurane degradation by carbon dioxide absorbents may produce more than one
      nephrotoxic compound in rats.
AB  - PURPOSE: Degradation of sevoflurane by carbon dioxide absorbents produces
      compound A, a vinyl ether. In rats, compound A can produce renal corticomedullary
      necrosis. We tested whether other compounds produced by sevoflurane degradation
      also could produce corticomedullary necrosis. METHODS: Two groups of rats were
      exposed for four hours to sevoflurane 2.5% delivered through a container filled
      with fresh Sodasorb and heated to 30 degrees C or to 50 degrees C, respectively.
      Compound A was added to produce an average concentration of 120 ppm in both
      groups. A third (control) group received 2.5% sevoflurane that did not pass
      through absorbent, and no compound A was added. RESULTS: As determined by gas
      chromatography, the higher temperature produced more volatile breakdown products,
      including compound A. Median necrosis of the corticomedullary junction in the 50
      degrees C group [10% (quartiles 1.0%-7.8%); n = 20] exceeded that in the 30
      degrees C group [5% (6.5%-15%); n = 18; P < 0.02], and both exceeded the median
      necrosis in the control group [0% (0.0%-0.2%); n = 10; P < 0.02]. The respective
      mean +/- SD values for these three studies were: 12.8 +/- 16.7%, 5.3 +/- 4.4%,
      and 0.3 +/- 0.5%. CONCLUSION: Degradation products of sevoflurane other than
      compound A can cause or augment the renal injury in rats produced by compound A.

PMID- 12620948
TI  - The infraclavicular brachial plexus block by the coracoid approach is clinically
      effective: an observational study of 150 patients.
AB  - PURPOSE: To evaluate the sensory distribution, motor block and the clinical
      efficacy of the infraclavicular block by the coracoid approach. METHODS: In this
      prospective descriptive study, 150 patients received an infraclavicular block by
      the coracoid approach performed by a single anesthesiologist. Neurostimulation
      was used and 40 mL of mepivacaine 1.5% with adrenaline were injected. Block
      performance time, sensory distribution, motor block and tourniquet tolerance were
      evaluated. RESULTS: Time to perform the block was 5 +/- 2 min (mean +/- SD).
      Success rate defined as analgesia in the five nerves distal to the elbow
      (musculocutaneous, median, ulnar, radial and medial cutaneous nerve of the
      forearm) was 91% (137 patients). A proximal block of the axillary nerve was
      present in 98.5% of the patients and of the medial cutaneous nerve of the arm in
      60%. An arm tourniquet ( 250 mmHg of pressure ) was applied to 115 of the 137
      patients with a successful block and all tolerated the tourniquet for a duration
      of 37 +/- 21 min ( mean +/- SD). CONCLUSION: Infraclavicular block by the
      coracoid approach provides an extensive sensory distribution with an excellent
      tourniquet tolerance. We conclude that this approach provides highly consistent
      brachial plexus anesthesia for upper extremity surgery.

PMID- 12620946
TI  - Elimination of routine testing in patients undergoing cataract surgery allows
      substantial savings in laboratory costs. A brief report.
AB  - PURPOSE: To evaluate the possible cost savings when routine preoperative testing
      is discontinued in ambulatory cataract surgery patients. METHODS: A policy was
      introduced at our hospital to stop routine testing in ambulatory cataract
      patients. Consecutive patients' medical records were analyzed in a four-month
      period pre- and a four-month period post-discontinuation of routine laboratory
      tests. Ambulatory cataract surgery is performed under topical (and sometimes
      retrobulbar block) anesthesia with iv sedation. Co-morbidities, perioperative
      events, frequency and cost of tests ordered were compared for the two groups.
      Average costs per patient pre- and post-discontinuation of routine tests, and
      total possible cost savings were calculated. RESULTS: One thousand two hundred
      and thirty-one patients were studied; 636 had routine laboratory tests and 595
      had no routine laboratory tests. The ratios of gender, co-morbidities and
      perioperative events were similar in the two groups. There was a significant
      reduction in the number of tests ordered after the new policy was introduced,
      from 5.8 tests per patient to 0.4 tests per patient. The cost of tests per
      patient was reduced from Can $39.67 to $4.01. CONCLUSION: In ambulatory cataract
      surgery, over 90% savings in laboratory costs is possible after elimination of
      routine tests.

PMID- 12620949
TI  - Patient-controlled epidural analgesia reduces analgesic requirements compared to
      continuous epidural infusion after major abdominal surgery.
AB  - PURPOSE: To compare the quality of pain relief and incidence of side effects
      between 24-hr postoperative continuous epidural infusion (CEI) and subsequent
      patient-controlled epidural analgesia (PCEA) with different analgesics after
      major abdominal surgery. METHODS: Twenty-eight women undergoing extended
      gynecological tumour surgery received postoperative CEI with 0.15 mL x kg(-1) x
      hr(-1) 0.2% ropivacaine (R: n = 14) or 0.125% bupivacaine plus 0.5 micro g x mL(
      1) sufentanil (BS: n = 14) during 24 postoperative hours. Twenty-four hours
      later, postoperative pain management was switched to PCEA without background
      infusion and 5 mL single bolus application of R or BS every 20 min at most.
      Visual analogue scales (VAS; 1-100 mm) were assessed by patients at rest and on
      coughing after 24 hr of CEI and PCEA. Side effects, doses of local anesthetics
      and opioids were recorded and plasma concentrations of total and unbound
      ropivacaine and bupivacaine were measured. RESULTS: Patients required lower doses
      of each respective analgesic medication with PCEA (R: 108 +/- 30 mL; BS: 110 +/-
      28 mL) than with CEI (R: 234 +/- 40; BS: 260 +/- 45; P < 0.01). Ropivacaine
      plasma concentrations were lower 24 hr after PCEA when compared with CEI (P <
      0.01). No patient after PCEA but two after CEI (n = 4; NS) presented motor block.
      PCEA with R provided better postoperative pain relief than CEI (37 +/- 32 vs 59+/
      27, P < 0.05). No difference in parenteral opioid rescue medication between CEI
      and PCEA was seen. CONCLUSION: PCEA in comparison to preceding CEI provides
      equivalent analgesia with lower local anesthetic doses and plasma levels, and
      without motor blocking side effects, irrespective of the applied drug regimen.

PMID- 12620950
TI  - The difficulties of ambulatory interscalene and intra-articular infusions for
      rotator cuff surgery: a preliminary report.
AB  - PURPOSE: Rotator cuff repair may result in severe postoperative pain. We compared
      a continuous intra-articular infusion to a continuous interscalene block with
      ropivacaine for patients undergoing outpatient rotator cuff repair. METHODS:
      Seventeen patients were randomized to one of two groups: 1) interscalene block
      with 0.5% ropivacaine (40 mL) followed by a postoperative intra-articular
      infusion or; 2) interscalene block with 0.5% ropivacaine (40 mL) followed by a
      postoperative continuous interscalene infusion. Infusions were 0.2% ropivacaine
      at 10 mL x hr(-1) for both groups. Infusions were maintained for 48 hr. Patients
      were discharged on the day of surgery. Verbal analogue pain scores (VAS) and
      postoperative oxycodone consumption were measured for 48 hr. RESULTS: Eight
      patients (47%; four in each group) had side effects or logistical problems
      complicating care. The mean VAS scores at rest and with movement in the
      postanesthesia care unit and at 12 hr, 24 hr, and 48 hr were not different (P >
      0.1). Inadequate analgesia was reported in 50-75% of all study patients. Time
      until first oxycodone use was similar between groups 829 min +/- 432
      (interscalene) and 999 min +/- 823 (intra-articular; P = 0.6). Total oxycodone
      consumption was also similar 49 mg +/- 48 and 59 mg +/- 51 (P = 0.7),
      respectively. CONCLUSIONS: This study demonstrates the difficulties of ambulatory
      interscalene and intra-articular infusion for rotator cuff surgery. The high VAS
      scores and need for additional medical care suggest that intra-articular
      administration may not be reasonable for this magnitude of surgery. Further
      refinement of the perineural local anesthetic infusion is necessary to
      consistently provide analgesia after ambulatory rotator cuff surgery.

PMID- 12620951
TI  - Remifentanil induces consistent and sustained controlled hypotension in children
      during middle ear surgery.
AB  - PURPOSE: To determine in children whether remifentanil combined with sevoflurane,
      could induce controlled hypotension, reduce middle ear blood flow (MEBF) measured
      by laser-Doppler, and provide a satisfactory operative field. METHODS: Forty
      children undergoing middle ear surgery and anesthetized with sevoflurane were
      randomly assigned to receive either 1 micro g x kg(-1) remifentanil iv followed
      by a continuous infusion of 0.2 to 0.5 micro g x kg(-1) x min(-1) or 0.25 micro g
      x kg(-1) x min(-1) nitroprusside iv and alfentanil iv (n = 20 in each group).
      RESULTS: Controlled hypotension was achieved at the target mean arterial pressure
      (MAP) of 50 mmHg (P < 0.01) within 121 +/- 21 and 62 +/- 9 sec for remifentanil
      and nitroprusside respectively. MEBF decreased by 22 +/- 4 and 20 +/- 6% and
      preceded the decrease in MAP within 20 +/- 7 and 10 +/- 3 sec for remifentanil
      and nitroprusside respectively. Remifentanil, and nitroprusside decreased MEBF
      autoregulation (0.41 +/- 0.2 and 0.37 +/- 0.3 respectively). Controlled
      hypotension was sustained in both groups throughout surgery, and the surgical
      field rating was good. Nitroprusside increased PaCO(2) slightly, and there were
      no postoperative circulatory, neurological or metabolic complications in any of
      the groups. CONCLUSION: Remifentanil combined with sevoflurane in children
      enabled controlled hypotension, reduced MEBF and provided good surgical
      conditions for middle ear surgery with no need for additional use of a specific
      hypotensive agent.

PMID- 12620952
TI  - Bronchodilator premedication does not decrease respiratory adverse events in
      pediatric general anesthesia.
AB  - PURPOSE: Upper respiratory infections (URI) presage perioperative respiratory
      complications, but thresholds to cancel surgery vary widely. We hypothesized that
      autonomically-mediated complications seen during emergence from anesthesia would
      be predicted by capnometry and reduced with preoperative bronchodilator
      administration. METHODS: Afebrile outpatient tertiary-care children (age two
      months to 18 yr, n = 109) without lung disease or findings, having non-cavitary,
      non-airway surgery for under three hours, were randomized to bronchodilator
      premedication vs placebo and had preoperative capnometry. After halothane via
      mask, laryngeal mask airway, or endotracheal tube, and regional anesthesia as
      appropriate, patients recovered breathing room air while cough, wheeze, stridor,
      laryngospasm, and cumulative desaturations were recorded for 15 min. RESULTS: In
      this specific population, there was no association between adverse events and
      either URI within six weeks (n = 76) or URI within seven days (n = 21). Neither
      albuterol nor ipratropium premedication decreased adverse events. Endotracheal
      intubation was associated with increased emergence desaturations and placebo
      nebulized saline increased emergence coughing. Neither anesthesiologists nor
      preoperative capnometry predicted adverse events. CONCLUSIONS: Adverse events
      were neither predicted nor prevented. In afebrile outpatient ASA I and II
      children with no lung disease or findings, having non-cavitary, non-airway
      surgery for under three hours, there was no association between either recent URI
      or active URI and desaturation, wheeze, cough, stridor, or laryngospasm causing
      desaturation (all P > 0.05). In this highly selected population of afebrile
      patients, the results suggest that anesthesiologists may proceed with surgery
      using specific criteria in the presence of a URI.

PMID- 12620953
TI  - Diltiazem may preserve renal tubular integrity after cardiac surgery.
AB  - PURPOSE: To evaluate the influence of dopamine and diltiazem on renal function
      and markers for acute renal failure, including urinary alpha-glutathion s
      transferase (alpha-GST), alpha-1-microglobulin (alpha(1)-MG) and N-acetyl-ss
      glucosaminidase (ss-NAG) after extracorporeal circulation. METHODS: In a
      randomized, placebo-controlled, double-blind trial we evaluated the efficacy of
      dopamine (2.5 micro g x kg(-1) x min(-1)), diltiazem (2 micro g x kg(-1) x min(
      1)) or placebo administered over 48 hr postoperatively to maintain renal tubular
      integrity in 60 elective cardiac surgery patients. alpha-GST, alpha(1)-MG, ss
      NAG, and creatinine clearance were measured from urine collected during surgery
      (T0), the first four hours (T1), 24 hr (T2) and 48 hr (T3) postoperatively.
      RESULTS: Cumulative urine output in the diltiazem group (9.0 +/- 2.8 L) increased
      significantly compared with placebo (7.0 +/- 1.6 L), but not compared with
      dopamine (7.8 +/- 1.8 L). Creatinine clearance showed no significant intergroup
      differences. In all groups alpha(1)-MG increased from T0 to T3, but we found no
      significant intergroup differences. alpha-GST increased significantly from T0 to
      T3 in the placebo (2.1 +/- 1.8 to 11.4 +/- 8.6 micro g x L(-1)) and in the
      dopamine groups (2.7 +/- 1.8 to 13.6 +/- 14.9 micro g x L(-1)), but not in the
      diltiazem group (1.8 +/- 1.4 to 3.2 +/- 3.2 micro g x L(-1)). Forty-eight hours
      postoperatively alpha-GST was significantly lower in the diltiazem group than in
      both other groups. CONCLUSIONS: Diltiazem stimulates urine output, reduces
      excretion of alpha-GST and ss-NAG and may be useful to maintain tubular integrity
      after cardiac surgery.

PMID- 12620954
TI  - Usefulness of intraoperative epiaortic echocardiography to resolve discrepancy
      between transthoracic and transesophageal measurements of aortic valve gradient -
      a case report.
AB  - PURPOSE: Intraoperative measurement of the aortic valve (AV) gradient in patients
      undergoing cardiac surgery is routinely performed using transesophageal
      echocardiography (TEE). In patients with severe aortic stenosis (AS), TEE Doppler
      beam alignment with the blood flow through the stenotic valve may be inaccurate,
      resulting in an underestimation of the AV gradient. We describe here the use of
      epiaortic echocardiography as an alternative to TEE for the intraoperative
      evaluation of AS. CLINICAL FEATURES: A patient diagnosed with severe AS (peak
      pressure gradient by transthoracic echocardiography: 108 mmHg) was undergoing AV
      replacement. In contrast, intraoperative TEE examination performed prior to
      bypass showed only a mild pressure gradient across the AV (peak pressure
      gradient: 38 mmHg). In order to resolve the conflicting information, epiaortic
      echocardiography was used to measure the AV gradient, confirming severe AS (peak
      pressure gradient: 98 mmHg). Most likely, Doppler beam alignment through the
      stenotic valve was more parallel to blood flow using epiaortic echocardiography,
      thus revealing the true pressure gradient. CONCLUSION: Intraoperative epiaortic
      measurement of AV gradients can be successfully performed in patients where TEE
      may be inaccurate due to difficulty in aligning a Doppler beam with the
      transvalvular blood flow.

PMID- 12620955
TI  - Salbutamol, beclomethasone or sodium chromoglycate suppress coughing induced by
      iv fentanyl.
AB  - PURPOSE: Fentanyl, a synthetic opioid, is a popular choice amongst
      anesthesiologists in the operating room. Preinduction iv fentanyl bolus is
      associated with coughing in 28-45% of patients. Coughing due to fentanyl is not
      always benign and at times may be explosive requiring immediate intervention. We
      have studied the role of aerosol inhalation of salbutamol, beclomethasone and
      sodium chromoglycate in preventing fentanyl induced coughing and have compared
      their efficacy. METHODS: Two hundred patients aged 18-60 yr, undergoing elective
      laparoscopic cholecystectomy were randomized into four groups of 50 each. Group I
      served as control, while Groups II, III and IV received an aerosol inhalation of
      salbutamol, beclomethasone or sodium chromoglycate 15 min prior to entering the
      operating room. Following iv fentanyl (2 micro g x kg(-1)) the incidence of cough
      was recorded and graded as mild (1-2), moderate (3-5) and severe (> 5) depending
      on the number of coughs observed. Results were analyzed using 'z' and Fischer's
      Exact test. A P value of < or = 0.05 was considered significant. RESULTS: The
      incidence of cough was 28% in the control group, 6%, 0% and 4% in the salbutamol,
      beclomethasone and sodium chromoglycate groups respectively. Occurrence of cough
      was significantly low (P < or = 0.05) in the treatment groups, however the
      difference amongst the groups was not significant (P >/= 0.05). CONCLUSION: The
      use of salbutamol, beclomethasone or sodium chromoglycate aerosol 15 min prior to
      iv fentanyl administration minimizes fentanyl-induced coughing.

PMID- 12620956
TI  - Volatile anesthetics regulate pulmonary vascular tension through different
      potassium channel subtypes in isolated rabbit lungs.
AB  - BACKGROUND: The effects of volatile anesthetics on subtypes of K(+) channels
      located on pulmonary vessels remain largely unexplored. METHODS: To investigate
      whether or not potassium channels play a role in the effect of volatile
      anesthetic on pulmonary vessels, isolated and perfused rabbit lungs were divided
      into four groups (n = 7 each): a control group without treatment, a glibenclamide
      (Glib) group treated with adenosine triphosphate-sensitive K(+) (K(ATP)) channel
      inhibitor, a 4-aminopyridine (4-AP) group treated with voltage-sensitive K(+)
      (K(V)) channel inhibitor, and an iberiotoxin (IbTX) group treated with high
      conductance calcium-activated K(+) (K(Ca)) channel inhibitor. After inhibitor
      administration and stabilization, two minimum alveolar concentration (MAC) of
      halothane, enflurane, isoflurane, or 1.8 MAC of sevoflurane were randomly
      administered for 15 min followed by eight minutes of fresh gas mixture after each
      agent inhalation. RESULTS: Isoflurane did not change pulmonary vascular tension
      in the control group but instead constricted the pulmonary vessels when K(V)
      channels were inhibited with 4-AP; constrictive effects of enflurane and
      halothane were observed on pulmonary vessels, and were enhanced by K(V) channel
      inhibition with 4-AP, but they were inhibited by K(Ca) channel inhibition with
      IbTX; the dilation effect of sevoflurane was observed on pulmonary vessels but
      was not significantly affected by any of the K(+) channel inhibitors. CONCLUSION:
      Halothane, enflurane and isoflurane, but not sevoflurane, regulate pulmonary
      vascular tension through K(V) and/or K(Ca) channels in isolated rabbit lungs.

PMID- 12620958
TI  - Intratracheal kinking of endotracheal tube.

PMID- 12620957
TI  - Transthoracic echocardiography does not improve prediction of outcome over APACHE
      II in medical-surgical intensive care.
AB  - PURPOSE: To examine the hypothesis that transthoracic echocardiographic findings
      predict mortality in critically ill patients. METHODS: A retrospective analysis
      of concurrently collected data for consecutive patients from May 1996 to May 1998
      who had transthoracic echocardiography on or within six months of admission to
      the medical surgical intensive care (MSICU). We examined the role of physiologic,
      clinical, and echocardiography variables in predicting the mortality of patients
      admitted to the MSICU. Three logistic regression models were developed: 1)
      clinical; 2) echocardiographic; and 3) combined clinical with echocardiographic.
      Univariate and multivariate analyses were performed and the relative strength of
      clinical and echocardiographic predictors was compared using odds ratio (OR) and
      receiver-operator-characteristic (ROC). RESULTS: Of 4,070 MSICU patient
      admissions, 1,093 patients had transthoracic echocardiography; the study group
      comprised 942 patients with complete clinical and echocardiographic data. The
      MSICU mortality was 28%. For the combined model, analyses identified left
      ventricular systolic function (LVSF), [OR 1.26; confidence interval (CI) 1.01
      1.57], severe tricuspid regurgitation (TR) (OR 3.72; CI 1.04-13.24), medical
      diagnosis (OR 1.91; CI 1.15-3.19), and acute physiology and chronic health
      evaluation (APACHE) II score (OR 1.27; CI 1.23-1.31), as predictors of MSICU
      mortality. The combined model yielded an area under ROC curve of 0.913. For the
      clinical model, analyses identified age (OR 1.04; CI 1.02-1.05) and APACHE II (OR
      1.32; 1.26-1.35) as predictors of mortality with an area under ROC curve of
      0.917. For the echocardiography model, TR (OR 2.40; 1.08-5.38), severe aortic
      insufficiency (AI) (OR 4.13; CI 1.17-16.29) and pulmonary hypertension (OR 2.05;
      1.01-4.09) were identified as predictors of outcome with an ROC curve of 0.536
      for this model. CONCLUSION: Statistical models utilizing clinical variables are
      predictive of mortality in MSICU. Models that include diagnostic transthoracic
      echocardiography variables do not provide incremental value to predict ICU
      mortality. These findings may have implications for non-invasive hemodynamic
      assessment of critically ill patients, and raise the hypothesis that
      echocardiography-guided interventions may not alter outcome in ICU.

PMID- 12620959
TI  - Anesthesia for a child with a congenital antithrombin deficiency.

PMID- 12620960
TI  - Epidural analgesia for a laparotomy in a morbidly obese patient with a history of
      difficult intubation.

PMID- 12620961
TI  - A probable CO2 embolus during laparoscopic cholecystectomy.

PMID- 12620962
TI  - Streptococcal meningitis after spinal anesthesia: report of a case.

PMID- 12620963
TI  - Evaluation of the stability and efficacy of a propofol-rocuronium mixture.

PMID- 12620964
TI  - A dominant mutation within the DNA-binding domain of the bZIP transcription
      factor Maf causes murine cataract and results in selective alteration in DNA
      binding.
AB  - The murine autosomal dominant cataract mutants created in mutagenesis experiments
      have proven to be a powerful resource for modelling the biological processes
      involved in cataractogenesis. We report a mutant which in the heterozygous state
      exhibits mild pulverulent cataract named 'opaque flecks in lens', symbol Ofl. By
      molecular mapping, followed by a candidate gene approach, the mutant was shown to
      be allelic with a knockout of the bZIP transcription factor, Maf. Homozygotes for
      Ofl and for Maf null mutations are similar but a new effect, renal tubular
      nephritis, was found in Ofl homozygotes surviving beyond 4 weeks, which may
      contribute to early lethality. Sequencing identified the mutation as a G-->A
      change, leading to the amino-acid substitution mutation R291Q in the basic region
      of the DNA-binding domain. Since mice heterozygous for knockouts of Maf show no
      cataracts, this suggests that the Ofl R291Q mutant protein has a dominant effect.
      We have demonstrated that this mutation results in a selective alteration in DNA
      binding affinities to target oligonucleotides containing variations in the core
      CRE and TRE elements. This implies that arginine 291 is important for core
      element binding and suggests that the mutant protein may exert a differential
      downstream effect amongst its binding targets. The cataracts seen in Ofl
      heterozygotes and human MAF mutations are similar to one another, implying that
      Ofl may be a model of human pulverulent cortical cataract. Furthermore, when bred
      onto a different genetic background Ofl heterozygotes also show anterior segment
      abnormalities. The Ofl mutant therefore provides a valuable model system for the
      study of Maf, and its interacting factors, in normal and abnormal lens and
      anterior segment development.

PMID- 12620965
TI  - cDNA microarray analysis of individual Duchenne muscular dystrophy patients.
AB  - We have developed a novel cDNA microarray encompassing 3500 genes expressed in
      skeletal muscle. With this system, we have performed the first study of gene
      expression in samples from individual patients. We analyzed muscle specimen from
      individuals with Duchenne muscular dystrophy to identify differences among
      patients. Among the variably expressed genes, we focused on the expression of the
      genes encoding HLA-related proteins, myosin light chains and troponin Ts as
      markers of muscle necrosis and regeneration. The expression patterns of these
      genes correlated with the severity of dystrophic changes on histological
      examination. Our cDNA microarray provides a new tool to investigate molecular
      muscle pathology.

PMID- 12620966
TI  - The dystrophin associated protein complex in zebrafish.
AB  - Many cases of muscular dystrophy in humans are caused by mutations in members of
      the dystrophin associated protein complex (DAPC). Zebrafish are small vertebrates
      whose bodies are composed predominantly of skeletal muscle, making them
      attractive models for studying mammalian muscle disorders. Potential orthologs to
      most of the human DAPC proteins have been found in zebrafish by database
      screening. Expression of the sarcoglycans, dystroglycan and dystrophin has been
      confirmed by western blotting. Immunohistochemical and biochemical techniques
      localize these proteins to the muscle cell membrane in adult zebrafish.
      Morpholino (MO) experiments designed to inhibit the translation of dystrophin
      mRNA produce juvenile zebrafish that are less active than zebrafish injected with
      control morpholinos. Western blot analysis of the dystrophin morpholino-injected
      zebrafish shows concurrent reduction of dystrophin and the sarcoglycans,
      suggesting that these proteins, like those in mammals, are part of a complex
      whose integrity is dependent on dystrophin expression. These results indicate
      that the zebrafish is an excellent animal model in which to approach the study of
      dystrophin and its associated proteins.

PMID- 12620967
TI  - Transgenic rat model of Huntington's disease.
AB  - Huntington's disease (HD) is a late manifesting neurodegenerative disorder in
      humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units
      in a gene of unknown function. Several mouse models have been reported which show
      rapid progression of a phenotype leading to death within 3-5 months (transgenic
      models) resembling the rare juvenile course of HD (Westphal variant) or which do
      not present with any symptoms (knock-in mice). Owing to the small size of the
      brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid
      progression of the disease in the transgenic models limits their usefulness for
      neurotransplantation. We therefore generated a rat model transgenic of HD, which
      carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of
      the native rat huntingtin promoter. This is the first transgenic rat model of a
      neurodegenerative disorder of the brain. These rats exhibit adult-onset
      neurological phenotypes with reduced anxiety, cognitive impairments, and slowly
      progressive motor dysfunction as well as typical histopathological alterations in
      the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo
      imaging demonstrates striatal shrinkage in magnetic resonance images and a
      reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron
      emission tomography studies. This model allows longitudinal in vivo imaging
      studies and is therefore ideally suited for the evaluation of novel therapeutic
      approaches such as neurotransplantation.

PMID- 12620968
TI  - Atopy, respiratory function and HLA-DR in Aboriginal Australians.
AB  - The Class II genes of the MHC represent a major locus with quantified effects on
      atopic (allergic) phenotypes in many studies of westernized Caucasians. Although
      asthma is considered a disease of western societies, typical components of the
      asthma phenotype, such as elevations of the IgE, are seen with parasitic
      infestation. We have therefore investigated the effects of the HLA-DRB1 locus on
      asthma and its intermediate phenotypes in Aboriginal people from the Kimberly
      region of Australia who were suffering from endemic hookworm infection.
      Recognizable correlates of allergic asthma were present in the subjects,
      including skin test positivity to house dust mite (HDM), specific IgE responses
      to HDM, and the total serum IgE. HLA-DRB1 alleles did not predict the presence of
      asthma, but multi-allelic tests of association showed the locus accounted for
      approximately 33% of the variance of the total serum IgE concentration and 17% of
      the variance of the specific IgE titres to HDM. Genetic admixture was excluded as
      a cause of the results. These effects of the MHC on IgE levels were an order of
      magnitude greater than that seen in Caucasians, consistent with the hypothesis
      that the genetic predisposition to allergic disease may be driven by adaptation
      to helminth infection. The results further suggest that parasitism per se is not
      protective against asthma.

PMID- 12620969
TI  - LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and
      peripheral neuropathy in mice.
AB  - In previous overexpression studies we revealed a role for the lysosomal membrane
      protein LIMP-2/LGP85 in lysosomal biogenesis. LIMP-2-deficient mice show an
      increased postnatal mortality which is associated with a development of a uni- or
      bilateral hydronephrosis caused by an obstruction of the ureteropelvic junction.
      An accumulation of lysosomes in epithelial cells of the ureter adjacent to the
      ureteral lumen and a disturbed apical expression of uroplakin was observed,
      suggesting an impairment of membrane transport processes. Serious hearing
      impairment in LIMP-2-deficient animals was indicated by deficits in acoustic
      startle responses, in brainstem evoked auditory potentials and a reduced
      endochondral potential. LIMP-2-deficient mice suffer from a massive decline of
      spiral ganglia in the cochlea concomitant with that of the inner and outer hair
      cells. These pathological changes begin at the age of 3 months and are probably
      secondary to a degeneration of the stria vascularis. LIMP-2-deficient mice are
      also characterized by a peripheral demyelinating neuropathy. Demyelinization was
      found to be associated with a massive loss of peripheral myelin proteins and an
      increased activity and expression of lysosomal proteins highlighting a hitherto
      unknown role of the lysosomal compartment in the development of this myelination
      disorder. The phenotype of LIMP-2-deficient mice stimulates the search for
      mutations in human disorders associated with degeneration of the stria vascularis
      and/or demyelinization of peripheral nerves.

PMID- 12620970
TI  - Haplotype-specific linkage disequilibrium patterns define the genetic topography
      of the human MHC.
AB  - Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite
      for population-based disease gene mapping. Variable patterns across the human
      genome are now recognized, both between regions and populations. Here, we
      demonstrate that LD may also vary within a genomic region in a haplotype-specific
      manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD
      patterns across the human MHC by the construction of gene-specific allelic
      haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found
      across both common and rare haplotypes, suggesting that haplotype structure is
      influenced by factors other than genetic drift, including both selection and
      differential haplotype recombination. Knowledge of haplotype-specific LD in the
      HLA may explain the apparent discrepant data from previous studies of global LD,
      help delineate key areas in mapping HLA-associated diseases and, together with
      recombination data, provide valuable information about a population's demographic
      history and the selective pressures operating on it.

PMID- 12620971
TI  - On noxious desmin: functional effects of a novel heterozygous desmin insertion
      mutation on the extrasarcomeric desmin cytoskeleton and mitochondria.
AB  - Recent studies in desmin (-/-) mice have shown that the targeted ablation of
      desmin leads to pathological changes of the extrasarcomeric intermediate filament
      cytoskeleton, as well as structural and functional abnormalities of mitochondria
      in striated muscle. Here, we report on a novel heterozygous single adenine
      insertion mutation (c.5141_5143insA) in a 40-year-old patient with a distal
      myopathy. The insertion mutation leads to a frameshift and a truncated desmin
      (K239fs242). Using transfection studies in SW13 and BHK21 cells, we show that the
      K239fsX242 desmin mutant is incapable of forming a desmin intermediate filament
      network. Furthermore, it induces the collapse of a pre-existing desmin
      cytoskeleton, alters the subcellular distribution of mitochondria and leads to
      abnormal cytoplasmic protein aggregates reminiscent of desmin-immunoreactive
      granulofilamentous material seen in the ultrastructural analysis of the patient's
      muscle. Analysis of mitochondrial function in isolated saponin-permeablized
      skeletal muscle fibres from our patient showed decreased maximal rates of
      respiration with the NAD-dependent substrate combination glutamate and malate, as
      well as a higher amytal sensitivity of respiration, indicating an in vivo
      inhibition of complex I activity. Our findings suggest that the heterozygous
      K239fsX242 desmin insertion mutation has a dominant negative effect on the
      polymerization process of desmin intermediate filaments and affects not only the
      subcellular distribution, but also biochemical properties of mitochondria in
      diseased human skeletal muscle. As a consequence, the intermediate filament
      pathology-induced mitochondrial dysfunction may contribute to the
      degeneration/regeneration process leading to progressive muscle dysfunction in
      human desminopathies.

PMID- 12620972
TI  - Genomic convergence: identifying candidate genes for Parkinson's disease by
      combining serial analysis of gene expression and genetic linkage.
AB  - We present a multifactorial, multistep approach called genomic convergence that
      combines gene expression with genomic linkage analysis to identify and prioritize
      candidate susceptibility genes for Parkinson's disease (PD). To initiate this
      process, we used serial analysis of gene expression (SAGE) to identify genes
      expressed in two normal substantia nigras (SN) and adjacent midbrain tissue. This
      identified over 3700 transcripts, including the three most abundant SAGE tags,
      which did not correspond to any known genes or ESTs. We developed high-throughput
      bioinformatics methods to map the genes corresponding to these tags and
      identified 402 SN genes that lay within five large genomic linkage regions,
      previously identified in 174 multiplex PD families. These genes represent
      excellent candidates for PD susceptibility alleles and further genomic
      convergence and analyses.

PMID- 12620973
TI  - BMP2 exposure results in decreased PTEN protein degradation and increased PTEN
      levels.
AB  - The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that
      recognizes protein and phosphatidylinositiol substrates and modulates cellular
      functions such as migration and proliferation. Germline mutations of PTEN have
      been shown to cause Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome and
      Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the
      type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare
      families with Cowden syndrome, suggesting that there may be a link between BMP
      signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters
      PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to
      BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The
      increase in PTEN protein was rapid and was not due to an increase in new protein
      synthesis, as cycloheximide treatment did not inhibit BMP2-induced PTEN
      accumulation, suggesting that BMP2 stimulation inhibited PTEN protein
      degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the
      association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9.
      These data indicate that BMP2 exposure can regulate PTEN protein levels by
      decreasing PTEN's association with the degradative pathway. This opens up a new
      mode of regulating PTEN activity to be investigated further and may explain why
      BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden
      syndrome.

PMID- 12620974
TI  - PKHDL1, a homolog of the autosomal recessive polycystic kidney disease gene,
      encodes a receptor with inducible T lymphocyte expression.
AB  - Autosomal-recessive polycystic kidney disease (ARPKD) is caused by mutation to a
      large gene, PKHD1, encoding a putative receptor protein, fibrocystin. We have
      identified, through analysis of human genomic sequence, a PKHD1 homolog, PKHDL1,
      in chromosome region 8q23. The PKHDL1 transcript of 13081 bp was amplified as 16
      fragments and sequenced; the sequence of the murine ortholog, Pkhdl1 (chromosome
      region 15B3) was also determined. PKHDL1 contains 78 exons, covers a genomic
      region of approximately 168 kb and encodes a large protein, fibrocystin-L.
      Screening PKHDL1 in ARPKD patients with no PKHD1 mutations revealed several
      sequence variants but no clear mutations, making it unlikely that it is ARPKD
      associated. Human fibrocystin-L is predicted to be a large receptor protein (4243
      aa; 466 kDa) with a signal peptide, single transmembrane domain and short
      cytoplasmic tail. Fibrocystin-L is homologous to fibrocystin throughout most of
      the extracellular region with overall identity of 25.0% and similarity of 41.5%.
      Fibrocystin-L has extracellular domains similar to fibrocystin with 14 copies of
      the TIG domain and two regions of significant homology to the protein TMEM2.
      Genomic sequence analysis identified no other full-length fibrocystin homologs in
      humans, mice or other sequenced organisms. The Fugu fish has a fibrocystin-L
      ortholog but no fibrocystin, suggesting that the newly identified protein may be
      the ancestral form. PKHDL1 and Pkhdl1 are widely expressed at a low level in most
      tissues but only detected in blood-derived cell-lines. Low level expression was
      detected in many primary immune cell subtypes but up-regulated specifically in T
      lymphocytes, following activation signals, suggesting a role in cellular
      immunity.

PMID- 12620975
TI  - BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin
      specificity during sensory nervous system development.
AB  - Neurotrophins have multiple functions during peripheral nervous system
      development such as controlling neuronal survival, target innervation and
      synaptogenesis. Neurotrophin specificity has been attributed to the selective
      expression of the Trk tyrosine kinase receptors in different neuronal
      subpopulations. However, despite overlapping expression of TrkB and TrkC in many
      sensory ganglia, brain-derived neurotrophic factor (BDNF) and neurotrophin 3
      (NT3) null mutant mice display selective losses in neuronal subpopulations. In
      the present study we have replaced the coding part of the BDNF gene in mice with
      that of NT3 (BDNF(NT3/NT3)) to analyse the specificity and selective roles of
      BDNF and NT3 during development. Analysis of BDNF(NT3/NT3) mice showed striking
      differences in the ability of NT3 to promote survival, short-range innervation
      and synaptogenesis in different sensory systems. In the cochlea, specificity is
      achieved by a tightly controlled spatial and temporal ligand expression. In the
      vestibular system TrkB or TrkC activation is sufficient to promote vestibular
      ganglion neuron survival, while TrkB activation is required to promote proper
      innervation and synaptogenesis. In the gustatory system, NT3 is unable to replace
      the actions of BDNF possibly because of a temporally selective expression of TrkB
      in taste neurons. We conclude that there is no general mechanism by which
      neurotrophin specificity is attained and that specificity is achieved by (i) a
      tightly controlled spatial and temporal expression of ligands, (ii) different Trk
      receptors playing distinct roles within the same neuronal subpopulation, or (iii)
      selective receptor expression in sensory neuron subpopulations.

PMID- 12620976
TI  - HASTY, the Arabidopsis ortholog of exportin 5/MSN5, regulates phase change and
      morphogenesis.
AB  - Loss-of-function mutations of HASTY (HST) affect many different processes in
      Arabidopsis development. In addition to reducing the size of both roots and
      lateral organs of the shoot, hst mutations affect the size of the shoot apical
      meristem, accelerate vegetative phase change, delay floral induction under short
      days, adaxialize leaves and carpels, disrupt the phyllotaxis of the
      inflorescence, and reduce fertility. Double mutant analysis suggests that HST
      acts in parallel to SQUINT in the regulation of phase change and in parallel to
      KANADI in the regulation of leaf polarity. Positional cloning demonstrated that
      HST is the Arabidopsis ortholog of the importin beta-like nucleocytoplasmic
      transport receptors exportin 5 in mammals and MSN5 in yeast. Consistent with a
      potential role in nucleocytoplasmic transport, we found that HST interacts with
      RAN1 in a yeast two-hybrid assay and that a HST-GUS fusion protein is located at
      the periphery of the nucleus. HST is one of at least 17 members of the importin
      beta family in Arabidopsis and is the first member of this family shown to have
      an essential function in plants. The hst loss-of-function phenotype suggests that
      this protein regulates the nucleocytoplasmic transport of molecules involved in
      several different morphogenetic pathways, as well as molecules generally required
      for root and shoot growth.

PMID- 12620977
TI  - The dead ringer/retained transcriptional regulatory gene is required for
      positioning of the longitudinal glia in the Drosophila embryonic CNS.
AB  - The Drosophila dead ringer (dri, also known as retained, retn) gene encodes a
      nuclear protein with a conserved DNA-binding domain termed the ARID (AT-rich
      interaction domain). We show here that dri is expressed in a subset of
      longitudinal glia in the Drosophila embryonic central nervous system and that dri
      forms part of the transcriptional regulatory cascade required for normal
      development of these cells. Analysis of mutant embryos revealed a role for dri in
      formation of the normal embryonic CNS. Longitudinal glia arise normally in dri
      mutant embryos, but they fail to migrate to their final destinations. Disruption
      of the spatial organization of the dri-expressing longitudinal glia accounts for
      the mild defects in axon fasciculation observed in the mutant embryos. Consistent
      with the late phenotypes observed, expression of the glial cells missing (gcm)
      and reversed polarity (repo) genes was found to be normal in dri mutant embryos.
      However, from stage 15 of embryogenesis, expression of locomotion defects (loco)
      and prospero (pros) was found to be missing in a subset of LG. This suggests that
      loco and pros are targets of DRI transcriptional activation in some LG. We
      conclude that dri is an important regulator of the late development of
      longitudinal glia.

PMID- 12620978
TI  - Dally regulates Dpp morphogen gradient formation in the Drosophila wing.
AB  - Decapentaplegic (Dpp), a Drosophila TGF beta/bone morphogenetic protein homolog,
      functions as a morphogen to specify cell fate along the anteroposterior axis of
      the wing. Dpp is a heparin-binding protein and Dpp signal transduction is
      potentiated by Dally, a cell-surface heparan sulfate proteoglycan, during
      assembly of several adult tissues. However, the molecular mechanism by which the
      Dpp morphogen gradient is established and maintained is poorly understood. We
      show evidence that Dally regulates both cellular responses to Dpp and the
      distribution of Dpp morphogen in tissues. In the developing wing, dally
      expression in the wing disc is controlled by the same molecular pathways that
      regulate expression of thick veins, which encodes a Dpp type I receptor. Elevated
      levels of Dally increase the sensitivity of cells to Dpp in a cell autonomous
      fashion. In addition, dally affects the shape of the Dpp ligand gradient as well
      as its activity gradient. We propose that Dally serves as a co-receptor for Dpp
      and contributes to shaping the Dpp morphogen gradient.

PMID- 12620979
TI  - Regulation of motor neuron subtype identity by repressor activity of Mnx class
      homeodomain proteins.
AB  - In the developing spinal cord, motor neurons acquire columnar subtype identities
      that can be recognized by distinct profiles of homeodomain transcription factor
      expression. The mechanisms that direct the differentiation of motor neuron
      columnar subtype from an apparently uniform group of motor neuron progenitors
      remain poorly defined. In the chick embryo, the Mnx class homeodomain protein
      MNR2 is expressed selectively by motor neuron progenitors, and has been
      implicated in the specification of motor neuron fate. We show here that MNR2
      expression persists in postmitotic motor neurons that populate the median motor
      column (MMC), whereas its expression is rapidly extinguished from lateral motor
      column (LMC) neurons and from preganglionic autonomic neurons of the Column of
      Terni (CT). The extinction of expression of MNR2, and the related Mnx protein
      HB9, from postmitotic motor neurons appears to be required for the generation of
      CT neurons but not for LMC generation. In addition, MNR2 and HB9 are likely to
      mediate the suppression of CT neuron generation that is induced by the LIM HD
      protein Lim3. Finally, MNR2 appears to regulate motor neuron identity by acting
      as a transcriptional repressor, providing further evidence for the key role of
      transcriptional repression in motor neuron specification.

PMID- 12620980
TI  - Regulation of Wingless and Vestigial expression in wing and haltere discs of
      Drosophila.
AB  - In the third thoracic segment of Drosophila, wing development is suppressed by
      the homeotic selector gene Ultrabithorax (Ubx) in order to mediate haltere
      development. Previously, we have shown that Ubx represses dorsoventral (DV)
      signaling to specify haltere fate. Here we examine the mechanism of Ubx-mediated
      downregulation of DV signaling. We show that Wingless (Wg) and Vestigial (Vg) are
      differentially regulated in wing and haltere discs. In wing discs, although Vg
      expression in non-DV cells is dependent on DV boundary function of Wg, it
      maintains its expression by autoregulation. Thus, overexpression of Vg in non-DV
      cells can bypass the requirement for Wg signaling from the DV boundary. Ubx
      functions, at least, at two levels to repress Vestigial expression in non-DV
      cells of haltere discs. At the DV boundary, it functions downstream of
      Shaggy/GSK3 beta to enhance the degradation of Armadillo (Arm), which causes
      downregulation of Wg signaling. In non-DV cells, Ubx inhibits event(s) downstream
      of Arm, but upstream of Vg autoregulation. Repression of Vg at multiple levels
      appears to be crucial for Ubx-mediated specification of the haltere fate.
      Overexpression of Vg in haltere discs is enough to override Ubx function and
      cause haltere-to-wing homeotic transformations.

PMID- 12620981
TI  - Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for
      gli genes in vertebrate development.
AB  - Gli proteins regulate the transcription of Hedgehog (Hh) target genes. Genetic
      studies in mouse have shown that Gli1 is not essential for embryogenesis, whereas
      Gli2 acts as an activator of Hh target genes. In contrast, misexpression studies
      in Xenopus and cultured cells have suggested that Gli1 can act as an activator of
      Hh-regulated genes, whereas Gli2 might function as a repressor of a subset of Hh
      targets. To clarify the roles of gli genes during vertebrate development, we have
      analyzed the requirements for gli1 and gli2 during zebrafish embryogenesis. We
      report that detour (dtr) mutations encode loss-of-function alleles of gli1. In
      contrast to mouse Gli1 mutants, dtr mutants and embryos injected with gli1
      antisense morpholino oligonucleotides display defects in the activation of Hh
      target genes in the ventral neuroectoderm. Mutations in you-too (yot) encode C
      terminally truncated Gli2. We find that these truncated proteins act as dominant
      repressors of Hh signaling, in part by blocking Gli1 function. In contrast,
      blocking Gli2 function by eliminating full-length Gli2 results in minor Hh
      signaling defects and uncovers a repressor function of Gli2 in the telencephalon.
      In addition, we find that Gli1 and Gli2 have activator functions during somite
      and neural development. These results reveal divergent requirements for Gli1 and
      Gli2 in mouse and zebrafish and indicate that zebrafish Gli1 is an activator of
      Hh-regulated genes, while zebrafish Gli2 has minor roles as a repressor or
      activator of Hh targets.

PMID- 12620982
TI  - A novel function for Hedgehog signalling in retinal pigment epithelium
      differentiation.
AB  - Sonic hedgehog is involved in eye field separation along the proximodistal axis.
      We show that Hh signalling continues to be important in defining aspects of the
      proximodistal axis as the optic vesicle and optic cup mature. We show that two
      other Hedgehog proteins, Banded hedgehog and Cephalic hedgehog, related to the
      mouse Indian hedgehog and Desert hedgehog, respectively, are strongly expressed
      in the central retinal pigment epithelium but excluded from the peripheral
      pigment epithelium surrounding the ciliary marginal zone. By contrast, downstream
      components of the Hedgehog signalling pathway, Gli2, Gli3 and X-Smoothened, are
      expressed in this narrow peripheral epithelium. We show that this zone contains
      cells that are in the proliferative state. This equivalent region in the adult
      mammalian eye, the pigmented ciliary epithelium, has been identified as a zone in
      which retinal stem cells reside. These data, combined with double labelling and
      the use of other retinal pigment epithelium markers, show that the retinal
      pigment epithelium of tadpole embryos has a molecularly distinct peripheral to
      central axis. In addition, Gli2, Gli3 and X-Smoothened are also expressed in the
      neural retina, in the most peripheral region of the ciliary marginal zone, where
      retinal stem cells are found in Xenopus, suggesting that they are good markers
      for retinal stem cells. To test the role of the Hedgehog pathway at different
      stages of retinogenesis, we activated the pathway by injecting a dominant
      negative form of PKA or blocking it by treating embryos with cyclopamine. Embryos
      injected or treated at early stages display clear proximodistal defects in the
      retina. Interestingly, the main phenotype of embryos treated with cyclopamine at
      late stages is a severe defect in RPE differentiation. This study thus provides
      new insights into the role of Hedgehog signalling in the formation of the
      proximodistal axis of the eye and the differentiation of retinal pigment
      epithelium.

PMID- 12620983
TI  - A Balbiani body and the fusome mediate mitochondrial inheritance during
      Drosophila oogenesis.
AB  - Maternally inherited mitochondria and other cytoplasmic organelles play essential
      roles supporting the development of early embryos and their germ cells. Using
      methods that resolve individual organelles, we studied the origin of oocyte and
      germ plasm-associated mitochondria during Drosophila oogenesis. Mitochondria
      partition equally on the spindle during germline stem cell and cystocyte
      divisions. Subsequently, a fraction of cyst mitochondria and Golgi vesicles
      associates with the fusome, moves through the ring canals, and enters the oocyte
      in a large mass that resembles the Balbiani bodies of Xenopus, humans and diverse
      other species. Some mRNAs, including oskar RNA, specifically associate with the
      oocyte fusome and a region of the Balbiani body prior to becoming localized.
      Balbiani body development requires an intact fusome and microtubule cytoskeleton
      as it is blocked by mutations in hu-li tai shao, while egalitarian mutant
      follicles accumulate a large mitochondrial aggregate in all 16 cyst cells.
      Initially, the Balbiani body supplies virtually all the mitochondria of the
      oocyte, including those used to form germ plasm, because the oocyte ring canals
      specifically block inward mitochondrial transport until the time of nurse cell
      dumping. Our findings reveal new similarities between oogenesis in Drosophila and
      vertebrates, and support our hypothesis that developing oocytes contain specific
      mechanisms to ensure that germ plasm is endowed with highly functional
      organelles.

PMID- 12620984
TI  - bHLH transcription factor Her5 links patterning to regional inhibition of
      neurogenesis at the midbrain-hindbrain boundary.
AB  - The midbrain-hindbrain (MH) domain of the vertebrate embryonic neural plate
      displays a stereotypical profile of neuronal differentiation, organized around a
      neuron-free zone ('intervening zone', IZ) at the midbrain-hindbrain boundary
      (MHB). The mechanisms establishing this early pattern of neurogenesis are
      unknown. We demonstrate that the MHB is globally refractory to neurogenesis, and
      that forced neurogenesis in this area interferes with the continued expression of
      genes defining MHB identity. We further show that expression of the zebrafish
      bHLH Hairy/E(spl)-related factor Her5 prefigures and then precisely delineates
      the IZ throughout embryonic development. Using morpholino knock-down and
      conditional gain-of-function assays, we demonstrate that Her5 is essential to
      prevent neuronal differentiation and promote cell proliferation in a medial
      compartment of the IZ. We identify one probable target of this activity, the
      zebrafish Cdk inhibitor p27Xic1. Finally, although the her5 expression domain is
      determined by anteroposterior patterning cues, we show Her5 does not
      retroactively influence MH patterning. Together, our results highlight the
      existence of a mechanism that actively inhibits neurogenesis at the MHB, a
      process that shapes MH neurogenesis into a pattern of separate neuronal clusters
      and might ultimately be necessary to maintain MHB integrity. Her5 appears as a
      partially redundant component of this inhibitory process that helps translate
      early axial patterning information into a distinct spatiotemporal pattern of
      neurogenesis and cell proliferation within the MH domain.

PMID- 12620986
TI  - Global analysis of dauer gene expression in Caenorhabditis elegans.
AB  - The dauer is a developmental stage in C. elegans that exhibits increased
      longevity, stress resistance, nictation and altered metabolism compared with
      normal worms. We have used DNA microarrays to profile gene expression differences
      during the transition from the dauer state to the non-dauer state and after
      feeding of starved L1 animals, and have identified 1984 genes that show
      significant expression changes. This analysis includes genes that encode
      transcription factors and components of signaling pathways that could regulate
      the entry to and exit from the dauer state, and genes that encode components of
      metabolic pathways important for dauer survival and longevity. Homologs of C.
      elegans dauer-enriched genes may be involved in the disease process in parasitic
      nematodes.

PMID- 12620985
TI  - Developmental defects observed in hypomorphic anaphase-promoting complex mutants
      are linked to cell cycle abnormalities.
AB  - In C. elegans, mutants in the anaphase-promoting complex or cyclosome (APC/C)
      exhibit defects in germline proliferation, the formation of the vulva and male
      tail, and the metaphase to anaphase transition of meiosis I. Oocytes lacking
      APC/C activity can be fertilized but arrest in metaphase of meiosis I and are
      blocked from further development. To examine the cell cycle and developmental
      consequences of reducing but not fully depleting APC/C activity, we analyzed
      defects in embryos and larvae of mat-1/cdc-27 mutants grown at semi-permissive
      temperatures. Hypomorphic embryos developed to the multicellular stage but were
      slow to complete meiosis I and displayed aberrant meiotic chromosome separation.
      More severely affected embryos skipped meiosis II altogether and exhibited
      striking defects in meiotic exit. These latter embryos failed to produce normal
      eggshells or establish normal asymmetries prior to the first mitotic division. In
      developing larvae, extended M-phase delays in late-dividing cell lineages were
      associated with defects in the morphogenesis of the male tail. This study reveals
      the importance of dosage-specific mutants in analyzing molecular functions of a
      ubiquitously functioning protein within different cell types and tissues, and
      striking correlations between specific abnormalities in cell cycle progression
      and particular developmental defects.

PMID- 12620987
TI  - On the turning of Xenopus retinal axons induced by ephrin-A5.
AB  - The Eph family of receptor tyrosine kinases and their ligands, the ephrins, play
      important roles during development of the nervous system. Frequently they exert
      their functions through a repellent mechanism, so that, for example, an axon
      expressing an Eph receptor does not invade a territory in which an ephrin is
      expressed. Eph receptor activation requires membrane-associated ligands. This
      feature discriminates ephrins from other molecules sculpturing the nervous system
      such as netrins, slits and class 3 semaphorins, which are secreted molecules.
      While the ability of secreted molecules to guide axons, i.e. to change their
      growth direction, is well established in vitro, little is known about this for
      the membrane-bound ephrins. Here we set out to investigate--using Xenopus laevis
      retinal axons--the properties of substratum-bound and (artificially) soluble
      forms of ephrin-A5 (ephrin-A5-Fc) to guide axons. We find--as expected on the
      basis of chick experiments - that, when immobilised in the stripe assay, ephrin
      A5 has a repellent effect such that retinal axons avoid ephrin-A5-Fc-containing
      lanes. Also, retinal axons react with repulsive turning or growth cone collapse
      when confronted with ephrin-A5-Fc bound to beads. However, when added in soluble
      form to the medium, ephrin-A5 induces growth cone collapse, comparable to data
      from chick. The analysis of growth cone behaviour in a gradient of soluble ephrin
      A5 in the 'turning assay' revealed a substratum-dependent reaction of Xenopus
      retinal axons. On fibronectin, we observed a repulsive response, with the turning
      of growth cones away from higher concentrations of ephrin-A5. On laminin, retinal
      axons turned towards higher concentrations, indicating an attractive effect. In
      both cases the turning response occurred at a high background level of growth
      cone collapse. In sum, our data indicate that ephrin-As are able to guide axons
      in immobilised bound form as well as in the form of soluble molecules. To what
      degree this type of guidance is relevant for the in vivo situation remains to be
      shown.

PMID- 12620988
TI  - A hedgehog homolog regulates gut formation in leech (Helobdella).
AB  - Signaling by the hedgehog (hh)-class gene pathway is essential for embryogenesis
      in organisms ranging from Drosophila to human. We have isolated a hh homolog (Hro
      hh) from a lophotrochozoan species, the glossiphoniid leech, Helobdella robusta,
      and examined its expression by reverse transcription polymerase chain reaction
      (RT-PCR) and whole-mount in situ hybridization. The peak of Hro-hh expression
      occurs during organogenesis (stages 10-11). No patterned expression was detected
      within the segmented portion of the germinal plate during the early stages of
      segmentation. In stage 10-11 embryos, Hro-hh is expressed in body wall, foregut,
      anterior and posterior midgut, reproductive organs and in a subset of ganglionic
      neurons. Evidence that Hro-hh regulates gut formation was obtained using the
      steroidal alkaloid cyclopamine, which specifically blocks HH signaling.
      Cyclopamine induced malformation of both foregut and anterior midgut in
      Helobdella embryos, and no morphologically recognizable gonads were seen. In
      contrast, no gross abnormalities were observed in the posterior midgut. Segmental
      ectoderm developed normally, as did body wall musculature and some other
      mesodermal derivatives, but the mesenchymal cells that normally come to fill most
      of the coelomic cavities failed to develop. Taken with data from Drosophila and
      vertebrates, our data suggest that the role of hh-class genes in gut formation
      and/or neural differentiation is ancestral to the bilaterians, whereas their role
      in segmentation evolved secondarily within the Ecdysozoa.

PMID- 12620989
TI  - Knock-in of integrin beta 1D affects primary but not secondary myogenesis in
      mice.
AB  - Integrins are extracellular matrix receptors composed of alpha and beta subunits
      involved in cell adhesion, migration and signal transduction. The beta1 subunit
      has two isoforms, beta 1A ubiquitously expressed and beta 1D restricted to
      striated muscle. They are not functionally equivalent. Replacement of beta 1A by
      beta 1D (beta 1D knock-in) in the mouse leads to midgestation lethality on a 50%
      Ola/50% FVB background [Baudoin, C., Goumans, M. J., Mummery, C. and Sonnenberg,
      A. (1998). Genes Dev. 12, 1202-1216]. We crossed the beta 1D knock-in line into a
      less penetrant genetic background. This led to an attenuation of the midgestation
      lethality and revealed a second period of lethality around birth. Midgestation
      death was apparently not caused by failure in cell migration, but rather by
      abnormal placentation. The beta 1D knock-in embryos that survived midgestation
      developed until birth, but exhibited severely reduced skeletal muscle mass.
      Quantification of myotube numbers showed that substitution of beta 1A with beta
      1D impairs primary myogenesis with no direct effect on secondary myogenesis.
      Furthermore, long-term primary myotube survival was affected in beta 1D knock-in
      embryos. Finally, overexpression of beta 1D in C2C12 cells impaired myotube
      formation while overexpression of beta 1A primarily affected myotube maturation.
      Together these results demonstrate for the first time distinct roles for beta1
      integrins in primary versus secondary myogenesis and that the beta 1A and beta 1D
      variants are not functionally equivalent in this process.

PMID- 12620990
TI  - Incomplete reactivation of Oct4-related genes in mouse embryos cloned from
      somatic nuclei.
AB  - The majority of cloned animals derived by nuclear transfer from somatic cell
      nuclei develop to the blastocyst stage but die after implantation. Mouse embryos
      that lack an Oct4 gene, which plays an essential role in control of developmental
      pluripotency, develop to the blastocyst stage and also die after implantation,
      because they lack pluripotent embryonic cells. Based on this similarity, we
      posited that cloned embryos derived from differentiated cell nuclei fail to
      establish a population of truly pluripotent embryonic cells because of faulty
      reactivation of key embryonic genes such as Oct4. To explore this hypothesis, we
      used an in silico approach to identify a set of Oct4-related genes whose
      developmental expression pattern is similar to that of Oct4. When expression of
      Oct4 and 10 Oct4-related genes was analyzed in individual cumulus cell-derived
      cloned blastocysts, only 62% correctly expressed all tested genes. In contrast to
      this incomplete reactivation of Oct4-related genes in somatic clones, ES cell
      derived cloned blastocysts and normal control embryos expressed these genes
      normally. Notably, the contrast between expression patterns of the Oct4-related
      genes correlated with efficiency of embryonic development of somatic and ES cell
      derived cloned blastocysts to term. These observations suggest that failure to
      reactivate the full spectrum of these Oct4-related genes may contribute to
      embryonic lethality in somatic-cell clones.

PMID- 12620992
TI  - Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ
      cell production.
AB  - The tumor suppressor gene PTEN, which is frequently mutated in human cancers,
      encodes a lipid phosphatase for phosphatidylinositol 3,4,5-triphosphate
      [PtdIns(3,4,5)P3] and antagonizes phosphatidylinositol 3 kinase. Primordial germ
      cells (PGCs), which are the embryonic precursors of gametes, are the source of
      testicular teratoma. To elucidate the intracellular signaling mechanisms that
      underlie germ cell differentiation and proliferation, we have generated mice with
      a PGC-specific deletion of the Pten gene. Male mice that lacked PTEN exhibited
      bilateral testicular teratoma, which resulted from impaired mitotic arrest and
      outgrowth of cells with immature characters. Experiments with PTEN-null PGCs in
      culture revealed that these cells had greater proliferative capacity and enhanced
      pluripotent embryonic germ (EG) cell colony formation. PTEN appears to be
      essential for germ cell differentiation and an important factor in testicular
      germ cell tumor formation.

PMID- 12620991
TI  - Defective somite patterning in mouse embryos with reduced levels of Tbx6.
AB  - During vertebrate embryogenesis, paraxial mesoderm gives rise to somites, which
      subsequently develop into the dermis, skeletal muscle, ribs and vertebrae of the
      adult. Mutations that disrupt the patterning of individual somites have dramatic
      effects on these tissues, including fusions of the ribs and vertebrae. The T-box
      transcription factor, Tbx6, is expressed in the paraxial mesoderm but is
      downregulated as somites develop. It is essential for the formation of posterior
      somites, which are replaced with ectopic neural tubes in Tbx6-null mutant
      embryos. We show that partial restoration of Tbx6 expression in null mutants
      rescues somite development, but that rostrocaudal patterning within them is
      defective, ultimately resulting in rib and vertebral fusions, demonstrating that
      Tbx6 activity in the paraxial mesoderm is required not simply for somite
      specification but also for their normal patterning. Somite patterning is
      dependent upon Notch signaling and we show that Tbx6 genetically interacts with
      the Notch ligand, delta-like 1 (Dll1). Dll1 expression, which is absent in the
      Tbx6-null mutant, is restored at reduced levels in the partially rescued mutants,
      suggesting that Dll1 is a target of Tbx6. We also identify the spontaneous
      mutation rib-vertebrae as a hypomorphic mutation in Tbx6. The similarity in the
      phenotypes we describe here and that of some human birth defects, such as
      spondylocostal dysostosis, raises the possibility that mutations in Tbx6 or
      components of this pathway may be responsible for these defects.

PMID- 12620993
TI  - An I47L substitution in the HOXD13 homeodomain causes a novel human limb
      malformation by producing a selective loss of function.
AB  - The 5' members of the Hoxa and Hoxd gene clusters play major roles in vertebrate
      limb development. One such gene, HOXD13, is mutated in the human limb
      malformation syndrome synpolydactyly. Both polyalanine tract expansions and
      frameshifting deletions in HOXD13 cause similar forms of this condition, but it
      remains unclear whether other kinds of HOXD13 mutations could produce different
      phenotypes. We describe a six-generation family in which a novel combination of
      brachydactyly and central polydactyly co-segregates with a missense mutation that
      substitutes leucine for isoleucine at position 47 of the HOXD13 homeodomain. We
      compared the HOXD13(I47L) mutant protein both in vitro and in vivo to the wild
      type protein and to an artificial HOXD13 mutant, HOXD13(IQN), which is completely
      unable to bind DNA. We found that the mutation causes neither a dominant-negative
      effect nor a gain of function, but instead impairs DNA binding at some sites
      bound by wild-type HOXD13. Using retrovirus-mediated misexpression in developing
      chick limbs, we showed that wild-type HOXD13 could upregulate chick EphA7 in the
      autopod, but that HOXD13(I47L) could not. In the zeugopod, however, HOXD13(I47L)
      produced striking changes in tibial morphology and ectopic cartilages, which were
      never produced by HOXD13(IQN), consistent with a selective rather than
      generalised loss of function. Thus, a mutant HOX protein that recognises only a
      subset of sites recognised by the wild-type protein causes a novel human
      malformation, pointing to a hitherto undescribed mechanism by which missense
      mutations in transcription factors can generate unexpected phenotypes.
      Intriguingly, both HOXD13(I47L) and HOXD13(IQN) produced more severe shortening
      in proximal limb regions than did wild-type HOXD13, suggesting that functional
      suppression of anterior Hox genes by more posterior ones does not require DNA
      binding and is mediated by protein:protein interactions.

PMID- 12620994
TI  - HIF1alpha is a critical regulator of secretory differentiation and activation,
      but not vascular expansion, in the mouse mammary gland.
AB  - During pregnancy the mammary epithelium and its supporting vasculature rapidly
      expand to prepare for lactation, resulting in dramatic changes in the micro
      environment. In order to investigate the role of oxygenation and metabolism in
      these processes, the oxygen-responsive component of the hypoxia-inducible factor
      (HIF) 1 complex, HIF1alpha, was deleted in the murine mammary gland. Although
      vascular density was unchanged in the HIF1alpha null mammary gland, loss of HIF
      alpha impaired mammary differentiation and lipid secretion, culminating in
      lactation failure and striking changes in milk composition. Transplantation
      experiments confirmed that these developmental defects were mammary epithelial
      cell autonomous. These data make clear that HIF1alpha plays a critical role in
      the differentiation and function of the mammary epithelium.

PMID- 12620995
TI  - Exercise-induced electrocardiographic changes in patients with chronic
      respiratory diseases: differential diagnosis by 99mTc-tetrofosmin SPECT.
AB  - Evaluation of possible cardiac complications is essential for safe and effective
      respiratory rehabilitation of patients with chronic respiratory diseases (CRDs).
      The aim of this study is to clarify the pathophysiology of electrocardiographic
      (ECG) changes during exercise and the prevalence of coronary artery disease (CAD)
      in CRD patients without a history of myocardial ischemia. METHODS: We studied 42
      CRD patients with exercise-induced ST depression by cardiopulmonary exercise
      testing (CPET). They were selected from 249 consecutive CRD patients without any
      history of CAD who underwent CPET between January 1999 and December 2001. Thirty
      three patients without respiratory diseases who had positive ST depression during
      exercise were selected as disease control subjects. Exercise myocardial SPECT was
      performed to evaluate myocardial ischemia and right ventricular (RV) overload as
      measured by increased RV uptake. RESULTS: Among the 249 consecutive CRD patients
      without any history of CAD, positive ST depression during exercise was found in
      42 (16.9%). Only 2 of the 42 patients (4.8%) had an ST depression other than in
      II, III, or aVF leads. The incidence of myocardial ischemia by perfusion SPECT
      was significantly lower in CRD patients (26.2%) than in disease control subjects
      (78.8%). The most common finding in the CRD patients during exercise was RV
      overload but without ischemia (26 cases; 61.9%). Ischemia was found in 11
      patients (26.2%), with 10 of these patients also having RV overload. Neither
      ischemia nor RV overload was found in 5 patients (11.9%); these patients were
      eventually diagnosed as normal. CONCLUSION: The incidence of myocardial ischemia
      as determined by perfusion SPECT was low in CRD patients with positive exercise
      induced ECG changes. On the other hand, RV overload was observed in most such
      cases. Cardiac perfusion SPECT is a useful technique to evaluate cardiac ischemia
      and RV overload simultaneously. CPET with 12-lead ECG monitoring is necessary in
      CRD patients before respiratory rehabilitation. Further examination for ischemia
      should be done if positive ST depression is found.

PMID- 12620996
TI  - Preoperative staging of pelvic lymph nodes in prostate cancer by 11C-choline PET.
AB  - Prostate cancer is known for its difficulties in preoperative staging of pelvic
      lymph nodes by conventional imaging techniques. Thus, a histopathologic
      examination of the pelvic lymphadenectomy specimen is mandatory for patients at
      risk for metastatic disease. The aim of this study was to evaluate the strength
      and accuracy of (11)C-choline PET in preoperative noninvasive staging of pelvic
      lymph nodes in prostate cancer. METHODS: In a prospective study we examined 67
      consecutive patients with histologically proven prostate cancer with (11)C
      choline PET. The results of PET were compared with the results of histology of
      the pelvic lymph nodes and with the follow-up data. Conventional axial imaging
      was routinely performed using MRI or CT. The sensitivity, specificity, and
      accuracy of (11)C-choline PET were calculated. RESULTS: Fifteen patients had
      histologically proven lymph node metastases. (11)C-Choline PET was true-positive
      in 12 of 15 patients and false-negative in 3 patients. Fifty-two patients had no
      lymph node metastases. (11)C-Choline PET was true-negative in 50 of 52 patients
      and false-positive in 2 patients. We calculated a sensitivity of (11)C-choline
      PET for staging metastatic lymph node disease of 80%, a specificity of 96%, and
      an accuracy of 93%. Next, (11)C-choline PET detected solitary extraregional lymph
      node metastases in 5 of 12 patients with nodal metastases. CONCLUSION: This study
      showed that (11)C-choline PET is sensitive and accurate in preoperative staging
      of pelvic lymph nodes in prostate cancer.

PMID- 12620997
TI  - Use of a dual-head coincidence camera and 18F-FDG for detection and nodal staging
      of non-small cell lung cancer: accuracy as determined by 2 independent observers.
AB  - The accurate detection of lung carcinoma and the determination of its stage
      remain significant clinical problems. (18)F-FDG PET has been shown to improve
      detection and staging of lung cancer and to prevent unnecessary invasive
      procedures. Positron imaging with dual-head gamma cameras may not be as sensitive
      as PET, but recent studies have shown good results with these cameras. METHODS:
      In the present study, we investigated 100 patients, 76 of whom were male and 24
      female (mean age +/- SD, 60.7 +/- 9.4 y), with suspected non-small cell lung
      cancer. (18)F-FDG scanning was performed using a dual-head coincidence camera 1 h
      after the intravenous injection of 185 MBq of (18)F-FDG. For 46 patients,
      attenuation correction was also performed. Two independent observers unaware of
      clinical status analyzed all imaging studies. TNM classification was assigned
      after surgical staging. RESULTS: In 44 patients with clinically suspected
      bronchogenic carcinoma, no evidence of malignancy was found. However, in 56
      patients a pulmonary neoplasm was demonstrated. At interobserver analysis, a
      kappa value of 0.94 (P < 0.0001) was found for detection of the primary tumor and
      a kappa value of 0.63 (P < 0.0001) was found for mediastinal staging. A
      sensitivity of 96%, a specificity of 93%, and an accuracy of 95% were found for
      detection of pulmonary neoplasm. Assessment of lymph node involvement showed a
      sensitivity of 50%, a specificity of 92%, and an accuracy of 77%. The sensitivity
      of CT in assessing lymph node involvement was 36%, the specificity was 86%, and
      the accuracy was 67%. Attenuation correction provided more anatomic information,
      but no differences were seen between attenuation-corrected and non-attenuation
      corrected images for detecting lesions or lymph node involvement. CONCLUSION: The
      present study confirms earlier data showing that (18)F-FDG scans obtained with
      dual-head coincidence cameras are useful in the detection of non-small cell lung
      cancer and less suitable for staging of lymph node involvement, with accuracy
      comparable to that of CT.

PMID- 12620998
TI  - L-1-11C-tyrosine PET in patients with laryngeal carcinomas: comparison of
      standardized uptake value and protein synthesis rate.
AB  - PET with L-1-(11)C-tyrosine (TYR) can measure and quantify increased protein
      synthesis in tumor tissue in vivo. For quantification of the protein synthesis
      rate (PSR), arterial cannulation with repeated blood sampling to obtain the
      plasma input function and a dynamic TYR PET study to calculate a time-activity
      curve are necessary. In most PET studies the standardized uptake value (SUV)
      method is used to quantify tumor activity. The SUV can be calculated without
      repeated arterial blood sampling and prolonged scanning time, as required for
      determination of the PSR. The relationship between PSR and SUV is largely unknown
      and different factors can cause wide variability in the SUV. Therefore, the
      comparison of the absolute quantification method (PSR) with the SUV method is
      obligatory to determine the possible use of noninvasive PET in head and neck
      oncology. METHODS: Twenty-four patients with proven squamous cell carcinomas of
      the larynx (T1-T4) were studied using dynamic TYR PET. The PSRs of tumor and
      nontumor (background) regions were determined. Four different methods were used
      to calculate the SUV: uncorrected SUV (SUV(BW)); and SUVs corrected for body
      surface area (SUV(BSA)), for lean body mass (SUV(LBM)), and for the Quetelet
      index (SUV(QI)). Correlations between PSR values and SUVs were calculated.
      RESULTS: The PSR of all tumors was significantly higher (P < 0.001) than the PSR
      of nontumor tissue. The correlations of SUV(BW), SUV(BSA), SUV(LBM), and SUV(QI)
      with the quantitative values of the PSR were high (r = 0.84-0.90). The best
      correlation was observed with the SUV based on the LBM (SUV(LBM)). CONCLUSION:
      High correlation between the quantitative values (PSR) and the SUVs offers the
      possibility to use noninvasive TYR PET for detection and reliable quantification
      of primary head and neck tumors.

PMID- 12620999
TI  - Detection of early recurrence with 18F-FDG PET in patients with cervical cancer.
AB  - This study investigated the feasibility of PET with (18)F-FDG to evaluate
      retrospectively early recurrence in patients with cervical cancer. METHODS: From
      September 1997 to March 2000, 249 patients with no evidence of cervical cancer
      after treatment were investigated with (18)F-FDG PET. (18)F-FDG PET scanning,
      beginning 50 min after injection of 370-555 MBq (18)F-FDG, was performed. (18)F
      FDG uptake other than physiologic uptake was evaluated with the standardized
      uptake value and was analyzed by 2 observers who were unaware of CT or MRI data.
      CT or MRI and needle biopsies were performed to evaluate the positive lesions on
      (18)F-FDG PET, and all patients were monitored closely for 6 mo for recurrence.
      RESULTS: Of the 249 patients, 80 patients (32.1%) showed positive lesions with
      (18)F-FDG PET, and 28 patients (11.2%) were clinically or histologically
      confirmed as having recurrences. Eighty-two percent of recurrence was detected
      within 6-18 mo after diagnosis, and 89% of recurrence occurred in Federation
      Internationale de Gynecologie et d'Obstetrique (FIGO) stage IIb and stage III
      patients. The sensitivity and specificity of (18)F-FDG PET for detection of early
      recurrence were 90.3% and 76.1%, respectively. The sensitivity of (18)F-FDG PET
      was high in mediastinal, hilar, and scalene lymph nodes, spine, and liver;
      however, the sensitivity was relatively low in lung, retrovesical lymph nodes,
      and paraaortic lymph nodes. Three false-negative cases were detected in lung,
      retrovesical lymph nodes, and paraaortic lymph nodes. CONCLUSION: (18)F-FDG PET
      was effective in detecting early recurrences in cervical cancer patients with no
      evidence of disease. (18)F-FDG PET may be a useful follow-up method for cervical
      cancer, thereby providing the patients with early opportunities for sophisticated
      treatments.

PMID- 12621000
TI  - Evaluation of 18F-FDG PET with bladder irrigation in patients with uterine and
      ovarian tumors.
AB  - The purpose of this study was to evaluate PET using (18)F-FDG for gynecologic
      lesions with continuous bladder irrigation to eliminate artifacts from the (18)F
      FDG activity in the bladder. METHODS: Forty-one patients were studied. They had
      23 cervical uterine lesions (15 cases of cancer, 5 recurrences, 3
      nonrecurrences); 8 cases of uterine corpus cancer, including 2 recurrences; and
      10 ovarian masses (6 malignant, 4 nonmalignant). All cases of cancer were
      histologically proven; however, 2 cases of nonrecurrent uterine cervical
      carcinomas were diagnosed by clinical course. Continuous bladder irrigation was
      performed 35-55 min after intravenous administration of 185-370 MBq (18)F-FDG,
      and an emission scan was obtained 40-55 min after intravenous administration.
      Standardized uptake value (SUV) was used to estimate the degree of (18)F-FDG
      uptake quantitatively. RESULTS: After bladder irrigation, the (18)F-FDG activity
      in the urinary tract was eliminated in 33 patients, so that detection of tumor
      (18)F-FDG accumulation was easy. Two patients showed residual activity in the
      urinary bladder, and 6 patients showed activity in the ureter. An artifact was
      seen in 1 patient with residual activity in the urinary bladder caused by
      insufficient irrigation. However, these residual activities had no influence on
      detecting (18)F-FDG accumulation in tumor. The mean (+/-SD) of SUVs of malignant
      lesions was 6.04 +/- 3.22, that of nonmalignant lesions was 1.71 +/- 1.12, and
      the difference was significant (P = 0.0002). SUVs of all malignant lesions were
      greater than 2.0, and SUVs of all nonmalignant lesions, except the 1 case of
      ovarian fibroma, were less than 2.0. CONCLUSION: (18)F-FDG PET with continuous
      bladder irrigation is useful for eliminating (18)F-FDG activity in the bladder
      and for differentiating between malignant and nonmalignant uterine or ovarian
      masses.

PMID- 12621001
TI  - Somatostatin receptor scintigraphy in liver metastasis detection from
      gastroenteropancreatic neuroendocrine tumors.
AB  - In patients with gastroenteropancreatic (GEP) neuroendocrine tumors, we
      investigated the usefulness of somatostatin receptor scintigraphy (SRS) in the
      detection of liver metastasis, which represents the most important prognostic
      factor in these tumors, and in the management of affected patients. METHODS: We
      enrolled 149 patients with GEP tumors, 69 during initial staging and 80 in follow
      up. All patients underwent whole-body scanning at 4 and 24 h, followed by
      abdominal planar and SPECT imaging after intravenous injection of 250 MBq (111)In
      pentetreotide. The patients had previously been submitted to 2 of 3 conventional
      imaging procedures (CIP), such as CT, MRI, and ultrasound of the abdomen within 1
      mo before SRS; on the basis of liver CIP data, the patients had been classified
      into 3 groups as follows: no evidence of liver metastases, the presence of
      resectable metastases, or the presence of nonresectable metastases. RESULTS:
      Liver metastases were histologically proven in 65 cases. SPECT identified
      malignant lesions in 60 of 65 patients with metastases (sensitivity, 92.3%),
      planar imaging identified malignant lesions in 38 of 65 patients (sensitivity,
      58.5%), and CIP identified malignant lesions in 52 of 65 patients (sensitivity,
      80%). Only SPECT demonstrated liver involvement in 13 patients, whereas CIP
      showed liver involvement in 5 other cases. Moreover, SPECT was significantly more
      sensitive than planar imaging and CIP in identifying patients with single
      lesions. Neither SPECT nor planar imaging showed false-positive results in
      patients with no evidence of liver metastases, including 21 patients with
      hemangiomas (specificity, 100%), 12 of which were false-positive on CIP
      (specificity, 85.7%). SPECT per-lesion sensitivity (92.4%) was significantly
      higher than that of planar imaging (52.4%) and CIP (79.4%). Moreover, SPECT
      correctly changed patient classification and, thus, management in 28 of 149
      patients (18.8%), whereas planar imaging changed classification in 13 patients
      (8.7%), identifying new or additional metastases not evident on CIP or excluding
      metastases on CIP of patients with false-positive findings, thus avoiding
      unnecessary surgery; however, SPECT classification was incorrect in 3.3% of
      patients, and planar imaging was incorrect in 17.4%. CONCLUSION: (111)In
      Pentetreotide SRS is a useful diagnostic tool in the detection of liver
      metastases in GEP tumor patients. In particular, SPECT proved to be significantly
      more sensitive and accurate than both planar imaging and CIP. Moreover, SPECT was
      also the most reliable procedure to obtain correct patient classification, thus
      guiding the most appropriate therapeutic strategy.

PMID- 12621002
TI  - Predicting the outcome of distraction osteogenesis by 3-phase bone scintigraphy.
AB  - Distraction osteogenesis is an effective method for lengthening long bones and
      filling bone defects that result from bone resection. Insufficiency of bone
      consolidation in the distraction segment is problematic. In this study, we
      examined whether 3-phase bone scintigraphy can predict the outcome of distraction
      osteogenesis. We also investigated the effects of chemotherapy and surgical
      treatment on distraction osteogenesis. METHODS: We performed 3-phase bone
      scintigraphy on 60 patients (9 high-grade malignant bone tumors as group A, 11
      low-grade malignant or benign tumors as group B, 40 nontumoral conditions as
      group C) with distraction osteogenesis at the lengthening phase of the long
      bones. By setting the region of interest on the distraction segment and
      contralateral normal area, we calculated the perfusion index (PI), the uptake
      ratio of the blood-pool image (BPR), and the uptake ratio of the delayed image
      (DR). Patients were classified into poor and good consolidation groups from the
      radiographic findings of the distraction segment. RESULTS: Good to fair
      correlations were obtained between the PI and BPR, the PI and DR, and the BPR and
      DR (r = 0.65, 0.45, and 0.57, respectively). The PI and BPR indicated no
      significant differences among group A-C (1.7 +/- 0.6, 2.1 +/- 0.7, and 1.8 +/-
      0.8 in PI, respectively; 1.8 +/- 1.1, 1.9 +/- 0.5, and 2.0 +/- 0.7, in BPR,
      respectively). The DR of group A (2.4 +/- 1.2) was significantly lower than that
      of group B (6.3 +/- 1.8; P = 0.001) and group C (5.9 +/- 2.8; P < 0.001). Eleven
      patients were classified in the poor consolidation group. The other 49 patients
      showed good consolidation. The poor consolidation group showed lower values in
      all indices obtained by 3-phase bone scintigraphy than the good consolidation
      group. The optimal cutoff levels, sensitivity, specificity, and accuracy of each
      index for detection of patients with poor consolidation were as follows: 1.1,
      36%, 90%, and 80% in the PI, respectively; 1.2, 55%, 94%, and 87% in the BPR,
      respectively; and 2.2, 82%, 96%, and 93% in the DR, respectively. CONCLUSION:
      Three-phase bone scintigraphy is a promising method for the assessment of
      distraction osteogenesis. The delayed image of 3-phase bone scintigraphy,
      especially, is an excellent modality for predicting the outcome of distraction
      osteogenesis.

PMID- 12621003
TI  - Long-term effects of "ecstasy" use on serotonin transporters of the brain
      investigated by PET.
AB  - Alterations of the serotonergic system due to ecstasy consumption have been
      extensively documented in recent literature. However, reversibility of these
      neurotoxic effects still remains unclear. To address this question, PET was
      performed using the serotonin transporter (SERT) ligand (11)C-(+)-McN5652 in a
      total of 117 subjects subdivided into 4 groups: actual ecstasy users (n = 30),
      former ecstasy users (n = 29), drug-naive control subjects (n = 29), and subjects
      with abuse of psychoactive agents other than ecstasy (n = 29). METHODS: About 500
      MBq (11)C-(+)-McN5652 were injected intravenously. Thirty-five scans were
      acquired according to a dynamic scan protocol of 90 min using a full-ring whole
      body PET system. Transaxial slices were reconstructed using an iterative method.
      Individual brains were transformed to a template defined earlier. Distribution
      volume ratios (DVRs) were derived by application of a reference tissue approach
      for reversible binding. Gray matter of the cerebellum served as reference. SERT
      rich brain regions--mesencephalon, putamen, caudate, and thalamus--were selected
      for the evaluation of SERT availability using volumes of interest predefined in
      the template. RESULTS: Compared with drug-naive control subjects, the DVR in
      actual ecstasy users was significantly reduced in the mesencephalon (P = 0.004)
      and the thalamus (P = 0.044). The DVR in former ecstasy users was very close to
      the DVR in drug-naive control subjects in all brain regions. The DVR in polydrug
      users was slightly higher than that in the drug-naive control subjects in all
      SERT-rich regions (not statistically significant). CONCLUSION: Our findings
      further support the hypothesis of ecstasy-induced protracted alterations of the
      SERT. In addition, they might indicate reversibility of the availability of SERT
      as measured by PET. However, this does not imply full reversibility of the
      neurotoxic effects.

PMID- 12621004
TI  - Preoperative risk stratification using stress myocardial perfusion scintigraphy
      with electrocardiographic gating.
AB  - This study was designed to assess the prognostic value of stress myocardial
      perfusion SPECT with electrocardiographic (ECG) gating in patients undergoing
      noncardiac surgical treatment. METHODS: The study included 481 consecutive
      patients who underwent noncardiac surgery and had been referred for preoperative
      myocardial perfusion scintigraphy. Myocardial scintigraphy used (99m)Tc-labeled
      perfusion agents and dipyridamole stress with ECG gating, permitting qualitative
      and quantitative analyses of both myocardial perfusion and cardiac function.
      Reconstructed perfusion images were analyzed qualitatively and
      semiquantitatively. The Quantitative Gated SPECT (QGS) program was used for gated
      SPECT analysis to calculate global left ventricular ejection fraction and
      estimate regional wall motion. We assessed the relationships between
      perioperative cardiac events and various predictors, including clinical risk
      factors, radionuclide perfusion, and functional variables. RESULTS: Univariate
      analysis indicated that age (P < 0.001), diabetes mellitus (P < 0.01), history of
      heart failure (P < 0.05) or perfusion imaging (P < 0.0001), and QGS analysis (P <
      0.0001) yielded significant risk stratification. According to multivariate
      analysis, age, diabetes mellitus, perfusion imaging, and QGS analysis were
      independent predictors of perioperative cardiac events. The event rate was
      correlated with quantitative scintigraphic indices of perfusion images (rest
      perfusion and ischemic scores) and QGS analysis (global ejection fraction and the
      number of hypokinetic segments). Although QGS functional data offered no
      significant incremental prognostic value in patients with abnormal perfusion, it
      classified patients with normal perfusion into 2 risk groups (P < 0.0001). A
      combination of clinical risk factors, scintigraphic perfusion results, and
      functional data allowed further detailed risk stratification. CONCLUSION: Stress
      myocardial perfusion SPECT with ECG gating has an incremental prognostic value
      over conventional nongated stress perfusion imaging in predicting perioperative
      cardiac events.

PMID- 12621005
TI  - In vivo detection of cell death in the area at risk in acute myocardial
      infarction.
AB  - Annexin A5 is a phospholipid binding protein with high affinity for phosphatidyl
      serine, which is externalized by cells undergoing programmed cell death. An
      increased programmed cell death rate has been reported in the heart after
      myocardial infarction (MI). The aim of this study was to correctly localize
      annexin A5 uptake in vivo and to determine the area at risk in humans with acute
      MI. METHODS: Nine patients were studied. Before reperfusion was achieved, (99m)Tc
      sestamibi was injected intravenously. Myocardial (99m)Tc-sestamibi perfusion
      scintigraphy was performed after reperfusion. Thereafter, (99m)Tc-labeled annexin
      A5 was administered intravenously, followed by scintigraphic imaging of the
      heart. Myocardial (99m)Tc-sestamibi scintigraphy was repeated 1-3 wk after the MI
      onset. (99m)Tc-Annexin uptake was also studied in the subacute phase of the MI in
      2 patients. RESULTS: All patients clearly showed perfusion defects on (99m)Tc
      sestamibi scintigraphy in concordance with the infarct location. Furthermore, all
      patients showed accumulation of (99m)Tc-annexin A5 at the infarct site,
      indicating that cardiomyocytes with externalized phosphatidyl-serine are present
      in the infarct area. (99m)Tc-sestamibi defects determined 1-3 wk after the MI
      onset were significantly smaller than the defects in the acute phase. (99m)Tc
      annexin uptake was absent in the 2 patients studied in the subacute phase.
      CONCLUSION: In acute MI, an increase of programmed cell death can be correctly
      localized in vivo in the area at risk. Furthermore, the decrease in (99m)Tc
      sestamibi defect size in the subacute phase of the MI further suggests that in
      parts of the area at risk, reversible myocardial damage rather than necrosis is
      present in cardiomyocytes.

PMID- 12621006
TI  - Invited commentary: P.S.* I love you: implications of phosphatidyl serine (PS)
      reversal in acute ischemic syndromes.

PMID- 12621007
TI  - Pretargeted radioimmunotherapy of cancer: progress step by step.
AB  - To enhance the therapeutic efficacy of radioimmunotherapy of cancer, several
      pretargeting strategies have been developed. In pretargeted radioimmunotherapy,
      the tumor is pretargeted with an antibody construct that has affinity for the
      tumor-associated antigen on the one hand and for a radiolabeled hapten on the
      other. The radiolabeled hapten is administered in a later phase, preferably after
      the antibody construct has cleared from the circulation. In pretargeted
      radioimmunotherapy, 2 main approaches can be distinguished: pretargeting
      strategies based on the avid interaction between streptavidin (SA) or avidin and
      biotin, and pretargeting strategies based on the use of bispecific antibodies. In
      pretargeting strategies based on biotin and SA or avidin, the use of a clearing
      agent that could remove the pretargeting construct from the circulation markedly
      improved the targeting of the radiolabeled biotin to the tumor. Thus, multistep
      injection schemes in which 3-5 different agents are subsequently injected were
      developed. In bispecific antibody-based pretargeting strategies, the use of
      bivalent haptens improved the efficacy of the tumor targeting, and a 2-step
      pretargeted radioimmunotherapy strategy is now being tested in cancer patients.
      Preclinical studies as well as studies on cancer patients have shown that these
      pretargeting strategies can result in higher radiation doses to the tumor than
      can directly radiolabeled antitumor antibodies. Here, the development and state
      of the art of the most effective approaches for pretargeted radioimmunotherapy
      are reviewed.

PMID- 12621008
TI  - Initial experience with oral contrast in PET/CT: phantom and clinical studies.
AB  - The aims of the study were to evaluate the effects of oral contrast on apparent
      tracer activity measured with PET/CT when using CT attenuation correction and to
      report our initial experience in the use of oral contrast with PET/CT. METHODS:
      Phantom studies with (18)F activity and saline bags or syringes filled with
      barium or gastrografin of varying densities were performed using a PET/CT scanner
      (CT attenuation correction). In the study, 91 clinical patients received dilute
      oral contrast and were evaluated by whole-body (18)F-FDG PET. RESULTS: A phantom
      experiment with CT contrast (1.3% weight/volume [w/v] barium) showed a "cold"
      area in the cold stomach whereas a phantom with high-density barium (98% w/v)
      showed an artifactual focus of intense "activity" in the cold stomach. In
      clinical studies, stomach and right colon were opacified by CT contrast. Maximal
      measured contrast density was 239 Hounsfield units. CONCLUSION: High-density
      barium causes overestimation of tissue (18)F-FDG concentration. Low-density
      barium does not cause significant artifacts and appears suitable for clinical
      use.

PMID- 12621009
TI  - Simple analytic method of 11C-flumazenil metabolite in blood.
AB  - 11C-Flumazenil ((11)C-FMZ) is useful to estimate central benzodiazepine receptors
      by PET. The binding potential (BP) can be calculated with dynamic PET and
      continual blood sampling. Because conventional metabolite analysis of plasma
      samples is complicated and time consuming, a simple method is required to obtain
      an input function. In this article, a whole blood solvent extraction method was
      evaluated using data of 13 subjects. METHODS: The plasma solvent extraction
      method was estimated in comparison with the thin-layer chromatography (TLC)
      method. Then, the whole blood solvent extraction method was evaluated in
      comparison with the plasma solvent extraction method. RESULTS: Metabolite data
      analyzed by the plasma extraction method were well correlated with those by the
      TLC method (r = 0.99). The BP was calculated using both the whole blood
      extraction data and the plasma extraction data. No difference was observed in all
      brain regions. CONCLUSION: This simple whole blood solvent extraction method can
      be applied to clinical BP estimation using (11)C-FMZ.

PMID- 12621010
TI  - Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid
      tissues and B cell tumors in mice.
AB  - B lymphocyte stimulator (BLyS) protein is a member of the tumor necrosis factor
      (TNF) superfamily of cytokines that binds to B lineage cells, but not T cells,
      monocytes, natural killer cells, or granulocytes. BLyS protein binding to B cells
      is restricted to immunoglobulin-positive cells and is not evident on pro- or pre
      B cell populations. This unique binding profile suggests that a radiolabeled form
      of BLyS protein may be a useful treatment for B cell neoplasias such as B cell
      lymphoma and multiple myeloma. Here, we report the biodistribution of
      radiolabeled recombinant human BLyS after intravenous injection into normal mice
      and mice bearing BCL1 tumor in the spleen or J558 tumor in the subcutaneous
      space. We also report the use of these data to estimate human dosimetry. METHODS:
      (125)I-Labeled BLyS protein (50 micro g/kg, 0.185-0.37 MBq per mouse) was
      injected intravenously into BALB/c mice, and biodistribution was measured by
      direct counting of radioactivity in dissected tissues and by quantitative whole
      body autoradiography (QWBA). RESULTS: The half-life of radiolabeled BLyS protein
      in blood was approximately 2.7 h in both normal and tumor-bearing mice. The
      spleen showed the highest uptake of BLyS protein in both normal and tumor-bearing
      mice, with a maximum concentration (C(max)) of 35-45 percentage injected dose per
      gram (%ID/g) occurring between 1 and 3 h after injection. In lymph nodes, C(max)
      was approximately 20 %ID/g in normal and J558 tumor-bearing mice and 8-15 %ID/g
      in BCL1 tumor-bearing mice. Limited biodistribution data from the J558 tumors
      showed a C(max) of approximately 15 %ID/g. By contrast, C(max) was only
      approximately 5 %ID/g for both kidney and liver. QWBA confirmed high
      radioactivity in spleen, lymph nodes, and stomach contents and low radioactivity
      in kidney and liver. After 24 h, spleen and lymph nodes were still positive in
      QWBA images, whereas liver and kidney no longer had observable levels.
      CONCLUSION: Radiolabeled BLyS showed specific and rapid targeting to lymphoid
      tissues and B cell tumors in mice. Unlike monoclonal antibodies, which have long
      plasma half-lives and considerable liver uptake, BLyS has distinct
      pharmacokinetic and biodistribution properties that may offer advantages compared
      with antibody-based radioimmunotherapy.

PMID- 12621011
TI  - Invited commentary: targeting of 125I-labeled B lymphocyte stimulator.

PMID- 12621012
TI  - Comparison of immunoscintigraphy, efficacy, and toxicity of conventional and
      pretargeted radioimmunotherapy in CD20-expressing human lymphoma xenografts.
AB  - Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated
      antibodies before radiolabeled-biotin is a promising approach to improve absorbed
      dose ratios and achieve high durable remission rates with diminished systemic
      toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic
      efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody.
      METHODS: Athymic mice bearing Ramos human Burkitt's lymphoma xenografts were
      injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a
      galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by
      (111)In- or (90)Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
      acid (DOTA)-biotin. The comparison groups consisted of mice injected with
      conventional, directly labeled (111)In- or (90)Y-1F5. RESULTS: Rapid tumor uptake
      of radioactivity within 2 h was observed with the pretargeting approach,
      resulting in high-contrast tumor images at 24 h with minimal blood-pool
      radioactivity. Although conventional radiolabeled antibodies produced clear tumor
      images at 24 h, a large amount of radioactivity was present in the blood pool.
      The tumor-to-blood ratio was 3.5:1 with pretargeting compared with 0.4:1 with
      conventional (111)In-1F5. Pretargeted RIT with 29.6 MBq (800 micro Ci) (90)Y-DOTA
      biotin cured 100% of mice with tolerable toxicity, whereas conventional RIT with
      (90)Y-1F5 at a dose of 14.8 MBq (400 micro Ci) produced no cures, induced
      profound pancytopenia, and was lethal to all mice. CONCLUSION: These results
      suggest that anti-CD20 pretargeted RIT may be superior to conventional
      radiolabeled antibodies in terms of radioimmunoscintigraphy, toxicity, and
      therapeutic efficacy for treatment of B-cell lymphomas.

PMID- 12621013
TI  - Quantitative cholescintigraphy: selection of random dose for CCK-33 and
      reproducibility of abnormal results.
AB  - Dynamic cholescintigraphy (DCG) is a valid technique for evaluating gallbladder
      emptying. Cholecystokinin (CCK) as a slow infusion is recommended as a
      contraction stimulus. The normal ejection fraction (EF) has been shown to be
      reproducible, although the reproducibility of abnormal results has not been
      investigated. The aims of the present study were to standardize the CCK
      administration method (phase 1), obtain EF normality values (phase 2), and
      evaluate the reproducibility of abnormal results in patients with clinically
      suspected gallbladder dysfunction (phase 3). METHODS: Phase 1 included 40 healthy
      volunteers divided into 4 groups (n = 10) and subjected to intravenous CCK
      infusion according to 4 different regimens (0.25, 0.30, 0.40, and 0.60 Ivy dog
      units [IDU]/kg). Phase 2 comprised 33 healthy volunteers for determining DCG
      normality values, and phase 3 evaluated the reproducibility of abnormal results
      in 44 patients having clinical manifestations compatible with gallbladder
      dysfunction and showing an abnormal EF in a previous study. RESULTS: The most
      effective CCK infusion regimen was 0.40 IDU/kg (3.07 ng/kg) over 20 min, because
      it afforded the least variability and a high EF. When this regimen was applied to
      the healthy population, the EF was found to be 74.2% +/- 17.1% (mean +/- SD); the
      inferior normality limit was estimated to be 40%. Abnormal results were recorded
      in 77% (95% confidence interval, 62%-89%) of the patients. When the 2 DCG studies
      of phase 3 were compared, the EF correlation coefficient between them was 0.439
      (P = 0.003). CONCLUSION: Slow CCK infusion is the best regimen for stimulating
      gallbladder contraction; an EF of less than 40% is estimated to represent
      abnormality. The abnormal results for the EF in patients with clinically
      suspected gallbladder dysfunction proved to be reproducible.

PMID- 12621014
TI  - Dosimetry-guided radioactive iodine treatment in patients with metastatic
      differentiated thyroid cancer: largest safe dose using a risk-adapted approach.
AB  - This study is a retrospective analysis of 124 differentiated thyroid cancer
      patients who underwent dosimetric evaluation using MIRD methodology over a period
      of 15 y. The objectives of the study were to demonstrate the clinical use of
      dosimetry-guided radioactive iodine ([RAI] (131)I) treatment and the safe and
      effective application of a 3-Gy bone marrow (BM) dose in patients with
      differentiated thyroid cancer. METHODS: Tumor and BM dose estimates were
      obtained. The administered activity that would deliver a maximum safe dose to the
      organ at risk (red BM or lungs) was determined as well as the resulting doses to
      the metastases. The clinical benefit of an individual RAI treatment was predicted
      on the basis of the dose estimates and the expected therapeutic response. Each
      patient's response to treatment was assessed clinically and by monitoring the
      hematologic profile. RESULTS: One hundred twenty-four patients underwent 187
      dosimetric evaluations. One hundred four RAI treatments were performed. A
      complete response at metastatic deposits was attained with absorbed doses of >100
      Gy. No permanent BM suppression was observed in patients who received absorbed
      doses of <3 Gy to BM. The maximum administered dose was 38.5 GBq (1,040 mCi) with
      the BM dose limitation. CONCLUSION: Dosimetry-guided RAI treatment allows
      administration of the maximum possible RAI dose to achieve the maximum
      therapeutic benefit. Estimation of tumor dose rates helps to determine the
      curative versus the palliative intent of the therapy.

PMID- 12621015
TI  - Update on hybrid conjugate-view SPECT tumor dosimetry and response in 131I
      tositumomab therapy of previously untreated lymphoma patients.
AB  - A study of the use of (131)I-labeled tositumomab, preceded by an unlabeled
      tositumomab predose, for therapy of 76 previously untreated non-Hodgkin's
      lymphoma patients has been completed at the University of Michigan. Fifty-two of
      the 76 treated patients were imaged once during therapy with SPECT to assist in
      dosimetric estimation. In this article, the patient's average tumor dose,
      estimated by a hybrid method using that SPECT, is compared with the same
      statistic estimated by pretherapy conjugate views. METHODS: The SPECT activity
      quantification procedure used 3-dimensional CT-to-SPECT image registration. Daily
      pretherapy conjugate-view images provided the shape of the time-activity curve
      for the hybrid dose estimation. RESULTS: With the hybrid method, the mean of the
      patient's average tumor dose over 8 patients using only their axillary tumors
      (162 cGy) was very significantly lower (P < 0.0001) than the mean over 47
      patients using only their evaluated chest, abdominal, and pelvic tumors (624 cGy)
      for unknown reasons. Excluding axillary tumors as a best case for prediction,
      there still was considerable overlap in the distribution of a patient's average
      tumor dose over 38 patients who went on to a complete response (CR) and that from
      9 patients who went on to a partial response (PR) using either method. However, a
      high value of the patient's average tumor dose was correctly associated with a CR
      for 15 of 16 patients (94%) with hybrid SPECT and for 9 of 12 patients (75%) with
      conjugate views. Also, the mean of the patient's average tumor dose for the CR
      patients was larger than the mean for PR patients; the P value was 0.18 with
      hybrid SPECT and 0.25 with conjugate views. A multiple logistic regression
      analysis combining the dose, tumor burden, and level of lactate dehydrogenase as
      explanatory variables for response did not yield statistical significance with
      either method. CONCLUSION: Patients with evaluated tumors that receive the
      highest tumor radiation dose are most likely to achieve a CR. Dosimetry based on
      a combination of pretherapy conjugate views and intratherapy SPECT provides
      somewhat better correspondence between the patient's average tumor dose and his
      or her degree of response compared with dosimetry from pretherapy conjugate views
      alone. Statistical significance for the correspondence is not reached either with
      the dosimetric method or with either method in combination with the tumor burden
      and level of lactate dehydrogenase.

PMID- 12621016
TI  - Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan
      radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined
      data from 4 clinical trials.
AB  - Ibritumomab tiuxetan is an anti-CD20 murine IgG1 kappa monoclonal antibody
      (ibritumomab) conjugated to the linker-chelator tiuxetan, which securely chelates
      (111)In for imaging or dosimetry and (90)Y for radioimmunotherapy (RIT).
      Dosimetry and pharmacokinetic data from 4 clinical trials of (90)Y-ibritumomab
      tiuxetan RIT for relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) were
      combined and assessed for correlations with toxicity data. METHODS: Data from 179
      patients were available for analysis. Common eligibility criteria included <25%
      bone marrow involvement by NHL, no prior myeloablative therapy, and no prior RIT.
      The baseline platelet count was required to be > or = 100,000 cells/mm(3) for the
      reduced (90)Y-ibritumomab tiuxetan administered dose (7.4-11 MBq/kg [0.2-0.3
      mCi/kg]) or > or = 150,000 cells/mm(3) for the standard (90)Y-ibritumomab
      tiuxetan administered dose (15 MBq/kg [0.4 mCi/kg]). Patients were given a tracer
      administered dose of 185 MBq (5 mCi) (111)In-ibritumomab tiuxetan on day 0,
      evaluated with dosimetry, and then a therapeutic administered dose of 7.4-15
      MBq/kg (0.2-0.4 mCi/kg) (90)Y-ibritumomab tiuxetan on day 7. Both ibritumomab
      tiuxetan administered doses were preceded by an infusion of 250 mg/m(2) rituximab
      to clear peripheral B-cells and improve ibritumomab tiuxetan biodistribution.
      Residence times for (90)Y in blood and major organs were estimated from (111)In
      biodistribution, and the MIRDOSE3 computer software program was used, with
      modifications to account for patient-specific organ masses, to calculate
      radiation absorbed doses to organs and red marrow. RESULTS: Median radiation
      absorbed doses for (90)Y were 7.42 Gy to spleen, 4.50 Gy to liver, 2.11 Gy to
      lung, 0.23 Gy to kidney, 0.62 Gy (blood-derived method) and 0.97 Gy (sacral image
      derived method) to red marrow, and 0.57 Gy to total body. The median effective
      blood half-life was 27 h, and the area under the curve (AUC) was 25 h. No patient
      failed to meet protocol-defined dosimetry safety criteria and all patients were
      eligible for treatment. Observed toxicity was primarily hematologic, transient,
      and reversible. Hematologic toxicity did not correlate with estimates of red
      marrow radiation absorbed dose, total-body radiation absorbed dose, blood
      effective half-life, or blood AUC. CONCLUSION: Relapsed or refractory NHL in
      patients with adequate bone marrow reserve and <25% bone marrow involvement by
      NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a
      fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do
      not correlate with toxicity.

PMID- 12621017
TI  - Functional mapping of regional liver asialoglycoprotein receptor amount from
      single blood sample and SPECT.
AB  - The objective of this study was to validate a method for estimating regional
      liver asialoglycoprotein (ASGP) receptor amount from single blood samples using
      static SPECT with (99m)Tc-diethylenetriaminepentaacetic acid galactosyl human
      serum albumin ((99m)Tc-GSA). METHODS: Based on a 2-compartment nonlinear model,
      regional ASGP receptor amount could be calculated from total liver ASGP receptor
      amount (Ro) and regional GSA uptake at a specific time. Because Ro could be
      estimated from single blood samples using an empiric formula, regional GSA uptake
      obtained as a SPECT voxel count could be converted to regional ASGP receptor
      amount by solving a nonlinear model equation. To validate this method, data from
      62 patients with chronic liver disease underwent dynamic SPECT (30 rotations per
      30 min) and simultaneous multiblood sampling and were analyzed by this method. Ro
      was calculated as the sum of voxel values of parametric receptor images generated
      from plasma concentration of GSA at 20 min and of static SPECT images generated
      by merging dynamic SPECT data (12-20 min). Ro was also estimated by fitting time
      activity curves (4-30 min) of plasma and whole liver to the nonlinear model using
      the nonlinear regression method. Ro obtained from the receptor image was compared
      with that from curve fitting in relation to the results of hepatic function tests
      (indocyanine green test, hepaplastin test, and branched-chain amino
      acids/tyrosine plasma concentration ratio) and Child's classification. RESULTS:
      Ros from the 2 methods showed a significant linear correlation (r(2) = 0.938; P <
      0.0001; slope = 0.90; y-intercept = 1.5). Both Ros had significant correlations
      with the results of hepatic function tests (P < 0.001) and differed significantly
      among the 3 groups of Child's classification (P < 0.0001). CONCLUSION: The
      present method could provide a quantitative ASGP receptor image without dynamic
      data acquisition. This approach could be useful for quantitative evaluation of
      regional liver function and estimation of residual liver function in hepatectomy.

PMID- 12621018
TI  - PET imaging of pulmonary fibrosis.

PMID- 12621019
TI  - Motionlike artifacts in myocardial SPECT.

PMID- 12621020
TI  - PET detection of melanoma metastases in lymph nodes.

PMID- 12621021
TI  - The cellular protein level of parkin is regulated by its ubiquitin-like domain.
AB  - Parkin is a ubiquitin-protein isopeptide ligase (E3) involved in
      ubiquitin/proteasome-mediated protein degradation. Mutations in the parkin gene
      cause a loss-of-function and/or alter protein levels of parkin. As a result, the
      toxic build-up of parkin substrates is thought to lead to autosomal recessive
      juvenile Parkinsonism. To identify a role for the ubiquitin-like domain (ULD) of
      parkin, we created a number of hemagglutinin (HA)-tagged parkin constructs using
      mutational and structural information. Western blotting and immunocytochemistry
      showed a much stronger expression level for HA-parkin residues 77-465 (without
      ULD) than HA-parkin full-length (with ULD). The deletion of ULD in Drosophila
      parkin also caused a sharp increase in expression of the truncated form,
      suggesting that the function of the ULD of parkin is conserved across species. By
      progressive deletion analysis of parkin ULD, we found that residues 1-6 of human
      parkin play a crucial role in controlling the expression levels of this gene. HA
      parkin residues 77-465 showed ubiquitination in vivo, demonstrating that the ULD
      is not critical for parkin auto-ubiquitination; ubiquitination seemed to cluster
      on the central domain of parkin (residues 77-313). These effects were specific
      for the ULD of parkin and not transfection-, toxic-, epitope tag-, and/or vector
      dependent. Taken together, these data suggest that the 76 most NH(2)-terminal
      residues (ULD) dramatically regulate the protein levels of parkin.

PMID- 12621022
TI  - A novel alternative spliced chondrolectin isoform lacking the transmembrane
      domain is expressed during T cell maturation.
AB  - Chondrolectin (CHODL) is a novel type I transmembrane protein containing one
      carbohydrate recognition domain (CRD) of C-type lectins. Recently, data base
      searching revealed a variant of CHODL (AK022689) with a different 5' leader
      sequence derived from a new putative upstream alternative promoter (P2). The P2
      promoter gives rise to at least three additional alternatively spliced isoforms,
      designated as CHODLf, CHODLf Delta E, and CHODL Delta E. Of all variants, the
      alternative exon E-splicing isoforms (CHODLf Delta E/CHODL Delta E) are expressed
      exclusively in the T lymphocyte lineage and are regulated during T lymphopoiesis.
      Peripheral T lymphocytes demonstrated a unique exon E-splicing pattern in
      comparison with end maturation stage thymocytes, suggesting its association with
      the post-thymic maturation of T cells. Since exon E encodes the transmembrane
      domain of CHODL, the exon E-skipping variant results in a non-transmembrane
      domain-containing isoform (CHODLf Delta E/CHODL Delta E) terminating in the QDEL
      sequence, thus suggesting different functional attributes of CHODL isoforms
      during the development of T cells. Double label immunofluoresence experiments
      demonstrated that the transmembrane-containing isoform (CHODLf) colocalizes with
      rBet1 to the endoplasmic reticulum-Golgi apparatus. In summary, this study
      describes the molecular characterization of novel members of the chondrolectin
      family associated with T cell maturation and a subcellular localization of CHODLf
      in the endoplasmic reticulum-Golgi apparatus.

PMID- 12621023
TI  - The small nuclear RNA-activating protein 190 Myb DNA binding domain stimulates
      TATA box-binding protein-TATA box recognition.
AB  - Human U6 small nuclear RNA (snRNA) gene transcription by RNA polymerase III
      requires cooperative promoter binding involving the snRNA-activating protein
      complex (SNAP(c)) and the TATA-box binding protein (TBP). To investigate the role
      of SNAP(c) for TBP function at U6 promoters, TBP recruitment assays were
      performed using full-length TBP and a mini-SNAP(c) containing SNAP43, SNAP50, and
      a truncated SNAP190. Mini-SNAP(c) efficiently recruits TBP to the U6 TATA box,
      and two SNAP(c) subunits, SNAP43 and SNAP190, directly interact with the TBP DNA
      binding domain. Truncated SNAP190 containing only the Myb DNA binding domain is
      sufficient for TBP recruitment to the TATA box. Therefore, the SNAP190 Myb domain
      functions both to specifically recognize the proximal sequence element present in
      the core promoters of human snRNA genes and to stimulate TBP recognition of the
      neighboring TATA box present in human U6 snRNA promoters. The SNAP190 Myb domain
      also stimulates complex assembly with TBP and Brf2, a subunit of a snRNA-specific
      TFIIIB complex. Thus, interactions between the DNA binding domains of SNAP190 and
      TBP at juxtaposed promoter elements define the assembly of a RNA polymerase III
      specific preinitiation complex.

PMID- 12621024
TI  - HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein
      complex with HSP90 in vivo.
AB  - Heat shock factor 1 (HSF1) regulates the rapid and transient expression of heat
      shock genes in response to stress. The transcriptional activity of HSF1 is
      tightly controlled, and under physiological growth conditions, the HSF1 monomer
      is in a heterocomplex with the molecular chaperone HSP90. Through unknown
      mechanisms, transcriptionally repressed HSF1.HSP90 heterocomplexes dissociate
      following stress, which triggers HSF1 activation and heat shock gene
      transcription. Using a yeast two-hybrid screening system, we have identified Ral
      binding protein 1 (RalBP1) as an additional HSF1-interacting protein. We show
      that RalBP1 and HSF1 interact in vivo, and transient cotransfection of HSF1 and
      RalBP1 into hsf1(-/-) mouse embryo fibroblasts represses HSP70 expression.
      Furthermore, transient cotransfection of HSF1 and the constitutively active form
      of RalA (RalA23V), an upstream activator of the RalBP1 signaling pathway,
      increases the heat-inducible expression of HSP70, whereas the dominant negative
      form (RalA28N) suppresses HSP70 expression. We further find that alpha-tubulin
      and HSP90 are also present in the RalBP1.HSF1 heterocomplexes in unstressed
      cells. Upon heat shock, the Ral signaling pathway is activated, and the resulting
      RalGTP binds RalBP1. Concurrently, HSF1 is activated, leaves the RalBP1 x HSF1 x
      HSP90 x alpha-tubulin heterocomplexes, and translocates into the nucleus, where
      it then activates transcription. In conclusion, these observations reveal that
      the RalGTP signal transduction pathway is critical for activation of the stress
      responsive HSF1 and perhaps HSP90 molecular chaperone system.

PMID- 12621025
TI  - Inhibition of the mitochondrial permeability transition by creatine kinase
      substrates. Requirement for microcompartmentation.
AB  - Mitochondria from transgenic mice, expressing enzymatically active mitochondrial
      creatine kinase in liver, were analyzed for opening of the permeability
      transition pore in the absence and presence of creatine kinase substrates but
      with no external adenine nucleotides added. In mitochondria from these transgenic
      mice, cyclosporin A-inhibited pore opening was delayed by creatine or
      cyclocreatine but not by beta-guanidinopropionic acid. This observation
      correlated with the ability of these substrates to stimulate state 3 respiration
      in the presence of extramitochondrial ATP. The dependence of transition pore
      opening on calcium and magnesium concentration was studied in the presence and
      absence of creatine. If mitochondrial creatine kinase activity decreased (i.e. by
      omitting magnesium from the medium), protection of permeability transition pore
      opening by creatine or cyclocreatine was no longer seen. Likewise, when creatine
      kinase was added externally to liver mitochondria from wild-type mice that do not
      express mitochondrial creatine kinase in liver, no protective effect on pore
      opening by creatine and its analog was observed. All these findings indicate that
      mitochondrial creatine kinase activity located within the intermembrane and
      intercristae space, in conjunction with its tight functional coupling to
      oxidative phosphorylation, via the adenine nucleotide translocase, can modulate
      mitochondrial permeability transition in the presence of creatine. These results
      are of relevance for the design of creatine analogs for cell protection as
      potential adjuvant therapeutic tools against neurodegenerative diseases.

PMID- 12621026
TI  - Overexpression of the 78-kDa glucose-regulated protein/immunoglobulin-binding
      protein (GRP78/BiP) inhibits tissue factor procoagulant activity.
AB  - Previous studies have demonstrated that overexpression of GRP78/BiP, an
      endoplasmic reticulum (ER)-resident molecular chaperone, in mammalian cells
      inhibits the secretion of specific coagulation factors. However, the effects of
      GRP78/BiP on activation of the coagulation cascade leading to thrombin generation
      are not known. In this study, we examined whether GRP78/BiP overexpression
      mediates cell surface thrombin generation in a human bladder cancer cell line
      T24/83 having prothrombotic characteristics. We report here that cells
      overexpressing GRP78/BiP exhibited significant decreases in cell surface-mediated
      thrombin generation, prothrombin consumption and the formation of thrombin
      inhibitor complexes, compared with wild-type or vector-transfected cells. This
      effect was attributed to the ability of GRP78/BiP to inhibit cell surface tissue
      factor (TF) procoagulant activity (PCA) because conversion of factor X to Xa and
      factor VII to VIIa were significantly lower on the surface of GRP78/BiP
      overexpressing cells. The additional findings that (i) cell surface factor Xa
      generation was inhibited in the absence of factor VIIa and (ii) TF PCA was
      inhibited by a neutralizing antibody to human TF suggests that thrombin
      generation is mediated exclusively by TF. GRP78/BiP overexpression did not
      decrease cell surface levels of TF, suggesting that the inhibition in TF PCA does
      not result from retention of TF in the ER by GRP78/BiP. The additional
      observations that both adenovirus-mediated and stable GRP78/BiP overexpression
      attenuated TF PCA stimulated by ionomycin or hydrogen peroxide suggest that
      GRP78/BiP indirectly alters TF PCA through a mechanism involving cellular Ca(2+)
      and/or oxidative stress. Similar results were also observed in human aortic
      smooth muscle cells transfected with the GRP78/BiP adenovirus. Taken together,
      these findings demonstrate that overexpression of GRP78/BiP decreases thrombin
      generation by inhibiting cell surface TF PCA, thereby suppressing the
      prothrombotic potential of cells.

PMID- 12621027
TI  - Targeting presenilin-type aspartic protease signal peptide peptidase with gamma
      secretase inhibitors.
AB  - Presenilin is implicated in the pathogenesis of Alzheimer's disease. It is
      thought to constitute the catalytic subunit of the gamma-secretase complex that
      catalyzes intramembrane cleavage of beta-amyloid precursor protein, the last step
      in the generation of amyloidogenic Abeta peptides. The latter are major
      constituents of amyloid plaques in the brain of Alzheimer's disease patients.
      Inhibitors of gamma-secretase are considered potential therapeutics for the
      treatment of this disease because they prevent production of Abeta peptides.
      Recently, we discovered a family of presenilin-type aspartic proteases. The
      founding member, signal peptide peptidase, catalyzes intramembrane cleavage of
      distinct signal peptides in the endoplasmic reticulum membrane of animals. In
      humans, the protease plays a crucial role in the immune system. Moreover, it is
      exploited by the hepatitis C virus for the processing of the structural
      components of the virion and hence is an attractive target for anti-infective
      intervention. Signal peptide peptidase and presenilin share identical active site
      motifs and both catalyze intramembrane proteolysis. These common features let us
      speculate that gamma-secretase inhibitors directed against presenilin may also
      inhibit signal peptide peptidase. Here we demonstrate that some of the most
      potent known gamma-secretase inhibitors efficiently inhibit signal peptide
      peptidase. However, we found compounds that showed higher specificity for one or
      the other protease. Our findings highlight the possibility of developing
      selective inhibitors aimed at reducing Abeta generation without affecting other
      intramembrane-cleaving aspartic proteases.

PMID- 12621028
TI  - c-Src regulation of fibroblast growth factor-induced proliferation in murine
      embryonic fibroblasts.
AB  - Activated fibroblast growth factor receptor 1 (FGFR1) propagates FGF signals
      through multiple intracellular pathways via intermediates FRS2, PLCgamma, and
      Ras. Conflicting reports exist concerning the interaction between FGFR1 and Src
      family kinases. To address the role of c-Src in FGFR1 signaling, we compared
      proliferative responses of murine embryonic fibroblasts (MEF) deficient in c-Src,
      Yes, and Fyn to MEF expressing either endogenous levels or overexpressing c-Src.
      MEF with endogenous c-Src had significantly greater FGF-induced DNA synthesis and
      proliferation than cells lacking or overexpressing c-Src. This was related
      directly to c-Src expression by analysis of c-Src-deficient cells transfected
      with and sorted for varying levels of a c-Src expression vector. This suggests an
      "optimal" quantity of c-Src expression for FGF-induced proliferation. To
      determine if this was a general phenomenon for growth factor signaling pathways
      utilizing c-Src, responses to epidermal growth factor (EGF), platelet-derived
      growth factor (PDGF), and lysophosphatidic acid (LPA) were examined. As for FGF,
      responses to EGF were clearly inhibited when c-Src was absent or overexpressed.
      In contrast, varying levels of c-Src had little effect on responses to PDGF or
      LPA. The data show that mitogenic pathways activated by FGF-1 and EGF are
      regulated by c-Src protein levels and appear to differ significantly from those
      activated by PDGF and LPA.

PMID- 12621029
TI  - Evidence that the wzxE gene of Escherichia coli K-12 encodes a protein involved
      in the transbilayer movement of a trisaccharide-lipid intermediate in the
      assembly of enterobacterial common antigen.
AB  - The assembly of many bacterial cell surface polysaccharides requires the
      transbilayer movement of polyisoprenoid-linked saccharide intermediates across
      the cytoplasmic membrane. It is generally believed that transverse diffusion of
      glycolipid intermediates is mediated by integral membrane proteins called
      translocases or "flippases." The bacterial genes proposed to encode these
      translocases have been collectively designated wzx genes. The wzxE gene of
      Escherichia coli K-12 has been implicated in the transbilayer movement of Fuc4NAc
      ManNAcA-GlcNAc-P-P-undecaprenol (lipid III), the donor of the trisaccharide
      repeat unit in the biosynthesis of enterobacterial common antigen (ECA). Previous
      studies (Feldman, M. F., Marolda, C. L., Monteiro, M. A., Perry, M. B., Parodi,
      A. J., and Valvano, M. (1999) J. Biol. Chem. 274, 35129-35138) provided indirect
      evidence that the wzx(016) gene product of E. coli K-12 encoded a translocase
      capable of mediating the transbilayer movement of N
      acetylglucosaminylpyrophosphorylundecaprenol (GlcNAc-P-P-Und), an early
      intermediate in the synthesis of ECA and many lipopolysaccharide O antigens.
      Therefore, genetic and biochemical studies were conducted to determine if the
      putative Wzx(O16) translocase was capable of mediating the transport of N
      acetylglucosaminylpyrophosphorylnerol (GlcNAc-P-P-Ner), a water-soluble analogue
      of GlcNAc-P-P-Und. [(3)H]GlcNAc-P-P-Ner was transported into sealed, everted
      cytoplasmic membrane vesicles of E. coli K-12 as well as a deletion mutant
      lacking both the wzx(016) and wzxC genes. In contrast, [(3)H]GlcNAc-P-P-Ner was
      not transported into membrane vesicles prepared from a wzxE-null mutant, and
      metabolic radiolabeling experiments revealed the accumulation of lipid III in
      this mutant. The WzxE transport system exhibited substrate specificity by
      recognizing both a pyrophosphoryl-linked saccharide and an unsaturated alpha
      isoprene unit in the carrier lipid. These results support the conclusion that the
      wzxE gene encodes a membrane protein involved in the transbilayer movement of
      lipid III in E. coli.

PMID- 12621030
TI  - Lipid binding inhibits alpha-synuclein fibril formation.
AB  - Parkinson's disease is the second most common neurodegenerative disorder, and the
      cause is unknown; however, substantial evidence implicates the aggregation of
      alpha-synuclein as a critical factor in the etiology of the disease. alpha
      Synuclein is a relatively abundant brain protein of unknown function, and the
      purified protein is intrinsically unfolded. The amino acid sequence has seven
      repeats with an apolipoprotein lipid-binding motif, which are predicted to form
      amphiphilic helices. We have investigated the interaction of alpha-synuclein with
      lipid vesicles of different sizes and properties by monitoring the effects on the
      conformation of the protein and the kinetics of fibrillation. The nature of the
      interaction of alpha-synuclein with vesicles was highly dependent on the
      phospholipid composition, the ratio of alpha-synuclein to phospholipid, and the
      size of the vesicles. The strongest interactions were between alpha-synuclein and
      vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphate/1,2-dipalmitoyl-sn
      glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phospho-RAC-(1
      glycerol)/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and involved formation of
      helical structure in alpha-synuclein. A strong correlation was observed between
      the induction of alpha-helix in alpha-synuclein and the inhibition of fibril
      formation. Thus, helical, membrane-bound alpha-synuclein is unlikely to
      contribute to aggregation and fibrillation. Given that a significant fraction of
      alpha-synuclein is membrane-bound in dopaminergic neurons, this observation has
      significant physiological significance.

PMID- 12621031
TI  - SIC, a secreted protein of Streptococcus pyogenes that inactivates antibacterial
      peptides.
AB  - Some isolates of the significant human pathogen Streptococcus pyogenes, including
      virulent strains of the M1 serotype, secrete protein SIC. This molecule, secreted
      in large quantities, interferes with complement function. As a result of natural
      selection, SIC shows a high degree of variation. Here we provide a plausible
      explanation for this variation and the fact that strains of the M1 serotype are
      the most frequent cause of severe invasive S. pyogenes infections. Thus, protein
      SIC was found to inactivate human neutrophil alpha-defensin and LL-37, two major
      antibacterial peptides involved in bacterial clearance. This inactivation
      protected S. pyogenes against the antibacterial effect of the peptides. Moreover,
      SIC isolated from S. pyogenes of the M1 serotype was more powerful in this
      respect than SIC variants from strains of M serotypes 12 and 55, serotypes rarely
      connected with invasive infections.

PMID- 12621032
TI  - Early events in the anoikis program occur in the absence of caspase activation.
AB  - Adhesion of many cell types to the extracellular matrix is essential to maintain
      their survival. In the absence of integrin-mediated signals, normal epithelial
      cells undergo a form of apoptosis termed anoikis. It has been proposed that the
      activation of initiator caspases is an early event in anoikis, resulting in Bid
      cleavage and cytochrome c release from mitochondria. We have previously
      demonstrated that the loss of integrin signaling in mammary epithelial cells
      results in apoptosis and that this is dependent upon translocation of Bax from
      the cytosol to the mitochondria. In this paper, we ask whether caspases are
      required for Bax activation and the associated changes within mitochondria. We
      show that Bax activation occurs extremely rapidly, within 15 min after loss of
      integrin-mediated adhesion to extracellular matrix. The conformational changes
      associated with Bax activation are independent of caspases including the
      initiator caspase-8. We also examined downstream events in the apoptosis program
      and found that cytochrome c release occurs after a delay of at least 1 h, with
      subsequent activation of the effector caspase-3. This delay is not due to a
      requirement for new protein synthesis, since cycloheximide has no effect on the
      kinetics of Bax activation, cytochrome c release, caspase-3 cleavage, or
      apoptosis. Together, our data indicate that the cellular decision for anoikis in
      mammary epithelial cells occurs in the absence of caspase activation. Moreover,
      although the conformational changes in Bax are rapid and synchronous, the
      subsequent events occur stochastically and with considerable delays.

PMID- 12621034
TI  - Relationships of ligand binding, redox properties, and protonation in Coprinus
      cinereus peroxidase.
AB  - The pH dependence of the redox potentials and kinetics for CO association and
      dissociation was determined between pH 3.0 and 13.0 at 25 degrees C for the wild
      type Coprinus cinereus fungal peroxidase and for a site-directed mutant in which
      Asp245, which is H-bonded to N delta of the imidazole of the proximal His183, was
      substituted with Asn. The determination of these functional properties allowed
      this information to be merged in a self-consistent fashion and to formulate for
      the first time a complete scheme employing the minimum number of groups required
      to describe the whole proton-linked behavior of both redox and ligand binding
      properties. The overall pH dependence can be accounted for by four redox- and
      ligand-linked groups. The proximal H-bond, which is strictly conserved in all
      peroxidases, will still be present in the site-specific mutant, but will no
      longer have an ionic character, and this event will bring about an alteration of
      redox equilibria and CO binding kinetics, envisaging a relevant role played by
      this H-bond also in modulating redox properties and ligand binding equilibria.

PMID- 12621033
TI  - The hepatitis C virus non-structural NS5A protein inhibits activating protein-1
      function by perturbing ras-ERK pathway signaling.
AB  - The hepatitis C virus nonstructural 5A (NS5A) protein is a pleiotropic
      phosphoprotein that has been shown to associate with a wide variety of cellular
      signaling proteins. Of particular interest is the observation that a highly
      conserved C-terminal Class II polyproline motif within NS5A mediated association
      with the Src homology 3 domains of members of the Src family of tyrosine kinases
      and the mitogenic adaptor protein Grb2 (A. Macdonald, K. Crowder, A. Street, C.
      McCormick, and M. Harris, submitted for publication). In this study, we analyzed
      the consequences of NS5A expression on mitogenic signaling pathways within a
      variety of cell lines. Utilizing a transient luciferase reporter system, we
      observed that NS5A inhibited the activity of the mitogenic and stress-activated
      transcription factor activating protein-1 (AP1). This inhibition was dependent
      upon a Class II polyproline motif within NS5A. Using a combination of dominant
      active and negative mutants of components of the MAPK signaling pathways,
      selective inhibitors, together with immunoblotting with phospho-specific and
      phosphorylation-independent antibodies, we determined the signaling pathways
      targeted by NS5A to inhibit AP1. These studies demonstrated that in both stable
      NS5A-expressing cells and Huh-7-derived cells harboring subgenomic hepatitis C
      virus (HCV) replicons, this inhibition was mediated through the ERK signaling
      pathway. Importantly, a comparable inhibition of AP1 reporter activity was
      observed in hepatocyte-derived cell lines transduced with a baculovirus vector
      driving expression of full-length HCV polyprotein. In conclusion, these data
      strongly suggest a role for the NS5A protein in the perturbation of mitogenic
      signaling pathways in HCV-infected hepatocytes.

PMID- 12621035
TI  - Stimulation of beta 2-adrenergic receptor increases cystic fibrosis transmembrane
      conductance regulator expression in human airway epithelial cells through a
      cAMP/protein kinase A-independent pathway.
AB  - PSD-95/Dlg-A/ZO-1 (PDZ) domains play an essential role in determining cell
      polarity. The Na(+)/H(+) exchanger regulatory factor (NHERF), also known as
      EBP50, contains two PDZ domains that mediate the assembly of transmembrane and
      cytosolic proteins into functional signal transduction complexes. Moreover, it
      has been shown that cystic fibrosis transmembrane conductance regulator (CFTR)
      and beta(2)-adrenergic receptor (beta(2)AR) bind equally well to the PDZ1 domain
      of EBP50. We hypothesized that beta(2)AR activation may regulate CFTR protein
      expression. To verify this, we evaluated the effects of a pharmacologically
      relevant concentration of salmeterol (2.10(-7) m), a long acting beta(2)AR
      agonist, on CFTR expression in primary human airway epithelial cells (HAEC).
      beta(2)AR stimulation induced a time-dependent increase in apical CFTR protein
      expression, with a maximal response reached after treatment for 24 h. This effect
      was post-transcriptional, dependent upon the beta(2)AR agonist binding to
      beta(2)AR and independent of the known beta(2)AR agonist-mediated cAMP/PKA
      pathway. We demonstrated by immunohistochemistry that CFTR, beta(2)AR, and EBP50
      localize to the apical membrane of HAEC. Analyses of anti-EBP50 protein
      immunoprecipitate showed that salmeterol induced an increase in the amount of
      CFTR that binds to EBP50. These data suggest that beta(2)AR activation regulates
      the association of CFTR with EBP50 in polarized HAEC.

PMID- 12621036
TI  - Syntaxin 1A binds to the cytoplasmic C terminus of Kv2.1 to regulate channel
      gating and trafficking.
AB  - Voltage-gated K(+) (Kv) 2.1 is the dominant Kv channel that controls membrane
      repolarization in rat islet beta-cells and downstream insulin exocytosis. We
      recently showed that exocytotic SNARE protein SNAP-25 directly binds and
      modulates rat islet beta-cell Kv 2.1 channel protein at the cytoplasmic N
      terminus. We now show that SNARE protein syntaxin 1A (Syn-1A) binds and modulates
      rat islet beta-cell Kv2.1 at its cytoplasmic C terminus (Kv2.1C). In HEK293 cells
      overexpressing Kv2.1, we observed identical effects of channel inhibition by
      dialyzed GST-Syn-1A, which could be blocked by Kv2.1C domain proteins (C1: amino
      acids 412-633, C2: amino acids 634-853), but not the Kv2.1 cytoplasmic N terminus
      (amino acids 1-182). This was confirmed by direct binding of GST-Syn-1A to the
      Kv2.1C1 and C2 domains proteins. These findings are in contrast to our recent
      report showing that Syn-1A binds and modulates the cytoplasmic N terminus of
      neuronal Kv1.1 and not by its C terminus. Co-expression of Syn-1A in Kv2.1
      expressing HEK293 cells inhibited Kv2.1 surfacing, which caused a reduction of
      Kv2.1 current density. In addition, Syn-1A caused a slowing of Kv2.1 current
      activation and reduction in the slope factor of steady-state inactivation, but
      had no affect on inactivation kinetics or voltage dependence of activation. Taken
      together, SNAP-25 and Syn-1A mediate secretion not only through its participation
      in the exocytotic SNARE complex, but also by regulating membrane potential and
      calcium entry through their interaction with Kv and Ca(2+) channels. In contrast
      to Ca(2+) channels, where these SNARE proteins act on a common synprint site, the
      SNARE proteins act not only on distinct sites within a Kv channel, but also on
      distinct sites between different Kv channel families.

PMID- 12621037
TI  - Microarray profiling of human skeletal muscle reveals that insulin regulates
      approximately 800 genes during a hyperinsulinemic clamp.
AB  - Insulin action in target tissues involved precise regulation of gene expression.
      To define the set of insulin-regulated genes in human skeletal muscle, we
      analyzed the global changes in mRNA levels during a 3-h hyperinsulinemic
      euglycemic clamp in vastus lateralis muscle of six healthy subjects. Using 29,308
      cDNA element microarrays, we found that the mRNA expression of 762 genes,
      including 353 expressed sequence tags, was significantly modified during insulin
      infusion. 478 were up-regulated and 284 down-regulated. Most of the genes with
      known function are novel targets of insulin. They are involved in the
      transcriptional and translational regulation (29%), intermediary and energy
      metabolisms (14%), intracellular signaling (12%), and cytoskeleton and vesicle
      traffic (9%). Other categories consisted of genes coding for receptors, carriers,
      and transporters (8%), components of the ubiquitin/proteasome pathways (7%) and
      elements of the immune response (5.5%). These results thus define a
      transcriptional signature of insulin action in human skeletal muscle. They will
      help to better define the mechanisms involved in the reduction of insulin
      effectiveness in pathologies such as type 2 diabetes mellitus, a disease
      characterized by defective regulation of gene expression in response to insulin.

PMID- 12621038
TI  - Actions and interactions of extracellular potassium and kainate on expression of
      13 gamma-aminobutyric acid type A receptor subunits in cultured mouse cerebellar
      granule neurons.
AB  - Cerebellar granule neurons in culture are a popular model for studying neuronal
      signaling and development. Depolarizing concentrations of K(+) are routinely used
      to enhance cell survival, and kainate is sometimes added to eliminate GABAergic
      neurons. We have investigated the effect of these measures on expression of mRNA
      for gamma-aminobutyric acid type A (GABA(A)) receptor alpha1-6, beta1-3, gamma1
      3, and delta subunits in cultures of mouse cerebellar granule neurons grown for 7
      or 12 days in vitro (DIV) using semiquantitative reverse transcription-PCR. We
      detected mRNA for the alpha1, alpha2, alpha5, alpha6, beta2, beta3, gamma2, and
      delta subunits in all the cell cultures, but the expression levels of the alpha5
      , alpha6-, and beta2-subunit mRNAs were significantly dependent on the
      composition of the culture medium. Both an increase of the extracellular K(+)
      concentration from 5 to 25 mm and the addition of 50 microm kainate immediately
      depolarized the neurons but prolonged exposure (7-8 DIV)-induced compensatory
      hyperpolarization. 25 mm K(+) caused a shift from alpha6 to alpha5 expression
      measured at 7 and 12 DIV, which was mimicked by kainate in 12 DIV cultures. The
      expression of beta2 was decreased by 25 mm K(+) in 7 DIV cultures and by kainate
      in 12 DIV cultures. The effects on beta2 expression could not be ascribed to
      depolarization. Alterations of alpha6 mRNA expression were reflected in altered
      sensitivity to GABA and furosemide of the resulting receptors. Our study has
      shown that a depolarizing K(+) concentration as well as kainate in the culture
      medium significantly disturbs maturation of GABA(A) receptor subunit expression.

PMID- 12621039
TI  - Critical regions for activation gating of the inositol 1,4,5-trisphosphate
      receptor.
AB  - To understand the molecular mechanism of ligand-induced gating of the inositol
      1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)/Ca(2+) release channel, we analyzed
      the channel properties of deletion mutants retaining both the IP(3)-binding and
      channel-forming domains of IP(3)R1. Using intrinsically IP(3)R-deficient cells as
      the host cells for receptor expression, we determined that six of the mutants,
      those lacking residues 1-223, 651-1130, 1267-2110, 1845-2042, 1845-2216, and 2610
      2748, did not exhibit any measurable Ca(2+) release activity, whereas the mutants
      lacking residues 1131-1379 and 2736-2749 retained the activity. Limited trypsin
      digestion showed that not only the IP(3)-gated Ca(2+)-permeable mutants lacking
      residues 1131-1379 and 2736-2749, but also two nonfunctional mutants lacking
      residues 1-223 and 651-1130, retained the normal folding structure of at least
      the C-terminal channel-forming domain. These results indicate that two regions of
      IP(3)R1, viz. residues 1-223 and 651-1130, are critical for IP(3)-induced gating.
      We also identified a highly conserved cysteine residue at position 2613, which is
      located within the C-terminal tail, as being essential for channel opening. Based
      on these results, we propose a novel five-domain structure model in which both N
      terminal and internal coupling domains transduce ligand-binding signals to the C
      terminal tail, which acts as a gatekeeper that triggers opening of the activation
      gate of IP(3)R1 following IP(3) binding.

PMID- 12621040
TI  - Structural basis of fosmidomycin action revealed by the complex with 2-C-methyl-D
      erythritol 4-phosphate synthase (IspC). Implications for the catalytic mechanism
      and anti-malaria drug development.
AB  - 2-C-Methyl-d-erythritol 4-phosphate synthase (IspC) is the first enzyme committed
      to isoprenoid biosynthesis in the methylerythritol phosphate pathway, which
      represents an alternative route to the classical mevalonate pathway. As it is
      present in many pathogens and plants, but not in man, this pathway has attracted
      considerable interest as a target for novel antibiotics and herbicides.
      Fosmidomycin represents a specific high-affinity inhibitor of IspC. Very
      recently, its anti-malaria activity in man has been demonstrated in clinical
      trials. Here, we present the crystal structure of Escherichia coli IspC in
      complex with manganese and fosmidomycin at 2.5 A resolution. The (N-formyl-N
      hydroxy)amino group provides two oxygen ligands to manganese that is present in a
      distorted octahedral coordination, whereas the phosphonate group is anchored in a
      specific pocket by numerous hydrogen bonds. Both sites are connected by a spacer
      of three methylene groups. The substrate molecule, 1-d-deoxyxylulose 5-phosphate,
      can be superimposed onto fosmidomycin, explaining the stereochemical course of
      the reaction.

PMID- 12621041
TI  - Activation of transforming growth factor-beta signaling by SUMO-1 modification of
      tumor suppressor Smad4/DPC4.
AB  - Smads are important intracellular effectors in signaling pathways of the
      transforming growth factor-beta (TGF-beta) superfamily. Upon activation by TGF
      beta, receptor-phosphorylated Smads form a complex with tumor suppressor
      Smad4/DPC4, and the Smad complexes then are imported into the nucleus. Although
      diverse pathways regulate the activity and expression of receptor-phosphorylated
      and inhibitory Smads, cellular factors modulating the activity of the common
      Smad4 remain unidentified. Here we describe the involvement of the small
      ubiquitin-like modifier-1 (SUMO-1) conjugation pathway in regulating the growth
      inhibitory and transcriptional responses of Smad4. The MH1 domain of Smad4 was
      shown to associate physically with Ubc9, the ubiquitin carrier protein (E2)
      conjugating enzyme in sumoylation. In cultured cells, Smad4 is modified by SUMO-1
      at the endogenous level. The sumoylation sites were identified as two
      evolutionarily conserved lysine residues, Lys-113 and Lys-159, in the MH1 domain.
      We found that the mutations at Lys-113 and Lys-159 did not alter the ability of
      Smad4 to form a complex with Smad2 and FAST on the Mix.2 promoter. Importantly,
      SUMO-1 overexpression enhanced TGF-beta-induced transcriptional responses. These
      findings identify sumoylation as a unique mechanism to modulate Smad4-dependent
      cellular responses.

PMID- 12621042
TI  - The C-terminal domain of the measles virus nucleoprotein is intrinsically
      disordered and folds upon binding to the C-terminal moiety of the phosphoprotein.
AB  - The nucleoprotein of measles virus consists of an N-terminal moiety, N(CORE),
      resistant to proteolysis and a C-terminal moiety, N(TAIL), hypersensitive to
      proteolysis and not visible as a distinct domain by electron microscopy. We
      report the bacterial expression, purification, and characterization of measles
      virus N(TAIL). Using nuclear magnetic resonance, circular dichroism, gel
      filtration, dynamic light scattering, and small angle x-ray scattering, we show
      that N(TAIL) is not structured in solution. Its sequence and spectroscopic and
      hydrodynamic properties indicate that N(TAIL) belongs to the premolten globule
      subfamily within the class of intrinsically disordered proteins. The same
      epitopes are exposed in N(TAIL) and within the nucleoprotein, which rules out
      dramatic conformational changes in the isolated N(TAIL) domain compared with the
      full-length nucleoprotein. Most unstructured proteins undergo some degree of
      folding upon binding to their partners, a process termed "induced folding." We
      show that N(TAIL) is able to bind its physiological partner, the phosphoprotein,
      and that it undergoes such an unstructured-to-structured transition upon binding
      to the C-terminal moiety of the phosphoprotein. The presence of flexible regions
      at the surface of the viral nucleocapsid would enable plastic interactions with
      several partners, whereas the gain of structure arising from induced folding
      would lead to modulation of these interactions. These results contribute to the
      study of the emerging field of natively unfolded proteins.

PMID- 12621043
TI  - NMR solution structure and dynamics of an exchangeable apolipoprotein, Locusta
      migratoria apolipophorin III.
AB  - We report here the NMR structure and backbone dynamics of an exchangeable
      apolipoprotein, apoLp-III, from the insect Locusta migratoria. The NMR structure
      adopts an up-and-down elongated five-helix bundle, which is similar to the x-ray
      crystal structure of this protein. A short helix, helix 4', is observed that is
      perpendicular to the bundle and fully solvent-exposed. NMR experimental
      parameters confirm the existence of this short helix, which is proposed to serve
      as a recognition helix for apoLp-III binding to lipoprotein surfaces. The L.
      migratoria apoLp-III helix bundle displays several characteristic structural
      features that regulate the reversible lipoprotein binding activity of apoLp-III.
      The buried hydrophilic residues and exposed hydrophobic residues readily adjust
      the marginal stability of apoLp-III, facilitating the helix bundle opening.
      Specifically, upon lipoprotein binding the locations and orientations of the
      buried hydrophilic residues modulate the apoLp-III helix bundle to adopt a
      possible opening at the hinge that is opposite the recognition short helix, helix
      4'. The backbone dynamics provide additional support to the recognition role of
      helix 4' and this preferred conformational adaptation of apoLp-III upon lipid
      binding. In this case, the lipid-bound open conformation contains two lobes
      linked by hinge loops. One lobe contains helices 2 and 3, and the other lobe
      contains helices 1, 4, and 5. This preferred bundle opening is different from the
      original proposal on the basis of the x-ray crystal structure of this protein
      (Breiter, D. R., Kanost, M. R., Benning, M. M., Wesenberg, G., Law, J. H., Wells,
      M. A., Rayment, I., and Holden, H. M. (1991) Biochemistry 30, 603-608), but it
      efficiently uses helix 4' as the recognition short helix. The buried interhelical
      H-bonds are found to be mainly located between the two lobes, potentially
      providing a specific driving force for the helix bundle recovery of apoLp-III
      from the lipid-bound open conformation. Finally, we compare the NMR structures of
      Manduca sexta apoLp-III and L. migratoria apoLp-III and present a united scheme
      for the structural basis of the reversible lipoprotein binding activity of apoLp
      III.

PMID- 12621044
TI  - The crystal structure and stereospecificity of levodione reductase from
      Corynebacterium aquaticum M-13.
AB  - The (6R)-2,2,6-trimethyl-1,4-cyclohexanedione (levodione) reductase (LVR) of the
      soil isolate bacterium Corynebacterium aquaticum M-13 is a NAD(H)-linked enzyme
      that catalyzes reversible oxidoreduction between (4R)-hydroxy-(6R)-2,2,6
      trimethylcyclohexanone (actinol) and levodione. Here the crystal structure of a
      ternary complex of LVR with NADH and its inhibitor 2-methyl-2,4-pentanediol has
      been determined by molecular replacement and refined at 1.6-A resolution with a
      crystallographic R factor of 0.199. The overall structure is similar to those of
      other short-chain alcohol dehydrogenase/reductase enzymes. The positions of NADH
      and 2-methyl-2,4-pentanediol indicate the binding site of the substrate and
      identify residues that are likely to be important in the catalytic reaction.
      Modeling of the substrate binding in the active site suggests that the
      specificity of LVR is determined by electrostatic interactions between the
      negatively charged surface of Glu-103 of LVR and the positively charged surface
      on the re side of levodione. Mutant LVR enzymes in which Glu-103 is substituted
      with alanine (E103A), glutamine (E103Q), asparagines (E103N), or aspartic acid
      (E103D) show a 2-6-fold increase in Km values as compared with wild-type LVR and
      a much lower enantiomeric excess of the reaction products (60%) than the wild
      type enzyme (95%). Together, these data indicate that Glu-103 has an important
      role in determining the stereospecificity of LVR.

PMID- 12621045
TI  - Maturation processing and characterization of streptopain.
AB  - Streptopain is a cysteine protease expressed by Streptococcus pyogenes. To study
      the maturation mechanism of streptopain, wild-type and Q186N, C192S, H340R, N356D
      and W357A mutant proteins were expressed in Escherichia coli and purified to
      homogeneity. Proteolytic analyses showed that the maturation of prostreptococcal
      pyrogenic exotoxin B zymogen (pro-SPE B) involves eight intermediates with a
      combination of cis- and trans-processing. Based on the sequences of these
      intermediates, the substrate specificity of streptopain favors a hydrophobic
      residue at the P2 site. The relative autocatalytic rates of these mutants
      exhibited the order Q186N > W357A > N356D, C192S, H340R. Interestingly, the N356D
      mutant containing protease activity could not be converted into the 28-kDa form
      by autoprocessing. This observation suggested that Asn(356) might involve the cis
      processing of the propeptide. In addition, the maturation rates of pro-SPE B with
      trypsin and plasmin were 10- and 60-fold slower than that with active mature
      streptopain. These findings indicate that active mature streptopain likely plays
      the most important role in the maturation of pro-SPE B under physiological
      conditions.

PMID- 12621046
TI  - Resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and abnormal liver
      development in mice carrying a mutation in the nuclear localization sequence of
      the aryl hydrocarbon receptor.
AB  - The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar
      aromatic chemicals. Essential steps in this adaptive mechanism include AHR
      binding of ligand in the cytosol, translocation of the receptor to the nucleus,
      dimerization with the Ah receptor nuclear translocator, and binding of this
      heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream
      of promoters that regulate the expression of genes involved in xenobiotic
      metabolism. The AHR is also involved in other aspects of mammalian biology, such
      as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as
      regulation of normal liver development. In an effort to test whether these
      additional AHR-mediated processes require a nuclear event, such as DRE binding,
      we used homologous recombination to generate mice with a mutation in the AHR
      nuclear localization/DRE binding domain. These Ahr(nls) mice were found to be
      resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that
      we examined, including hepatomegaly, thymic involution, and cleft palate
      formation. Moreover, aberrations in liver development observed in these mice were
      identical to that observed in mice harboring a null allele at the Ahr locus.
      Taken in sum, these data support a model where most, if not all, of AHR-regulated
      biology requires nuclear localization.

PMID- 12621047
TI  - Enzymatic cyclization of a potent bowman-birk protease inhibitor, sunflower
      trypsin inhibitor-1, and solution structure of an acyclic precursor peptide.
AB  - The most potent known naturally occurring Bowman-Birk inhibitor, sunflower
      trypsin inhibitor-1 (SFTI-1), is a bicyclic 14-amino acid peptide from sunflower
      seeds comprising one disulfide bond and a cyclic backbone. At present, little is
      known about the cyclization mechanism of SFTI-1. We show here that an acyclic
      permutant of SFTI-1 open at its scissile bond, SFTI-1[6,5], also functions as an
      inhibitor of trypsin and that it can be enzymatically backbone-cyclized by
      incubation with bovine beta-trypsin. The resulting ratio of cyclic SFTI-1 to SFTI
      1[6,5] is approximately 9:1 regardless of whether trypsin is incubated with SFTI
      1[6,5] or SFTI-1. Enzymatic resynthesis of the scissile bond to form cyclic SFTI
      1 is a novel mechanism of cyclization of SFTI-1[6,5]. Such a reaction could
      potentially occur on a trypsin affinity column as used in the original isolation
      procedure of SFTI-1. We therefore extracted SFTI-1 from sunflower seeds without a
      trypsin purification step and confirmed that the backbone of SFTI-1 is indeed
      naturally cyclic. Structural studies on SFTI-1[6,5] revealed high heterogeneity,
      and multiple species of SFTI-1[6,5] were identified. The main species closely
      resembles the structure of cyclic SFTI-1 with the broken binding loop able to
      rotate between a cis/trans geometry of the I7-P8 bond with the cis conformer
      being similar to the canonical binding loop conformation. The non-reactive loop
      adopts a beta-hairpin structure as in cyclic wild-type SFTI-1. Another species
      exhibits an iso-aspartate residue at position 14 and provides implications for
      possible in vivo cyclization mechanisms.

PMID- 12621048
TI  - Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA
      reductase.
AB  - Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in the
      current clinical treatment of hypercholesterolemias with specific inhibitors of
      the "statin" family. Statins are excellent inhibitors of the class I (human)
      enzyme but relatively poor inhibitors of the class II enzymes of important
      bacterial pathogens. To investigate the molecular basis for this difference we
      determined the x-ray structure of the class II Pseudomonas mevalonii HMG-CoA
      reductase in complex with the statin drug lovastatin. The structure shows
      lovastatin bound in the active site and its interactions with residues critically
      involved in catalysis and substrate binding. Binding of lovastatin also displaces
      the flap domain of the enzyme, which contains the catalytic residue His-381.
      Comparison with the structures of statins bound to the human enzyme revealed a
      similar mode of binding but marked differences in specific interactions that
      account for the observed differences in affinity. We suggest that these
      differences might be exploited to develop selective class II inhibitors for use
      as antibacterial agents against pathogenic microorganisms.

PMID- 12621049
TI  - APPL suppresses androgen receptor transactivation via potentiating Akt activity.
AB  - APPL may function as an adapter protein to modulate the phosphatidylinositol 3
      kinase (PI3K)/Akt pathway. Although we have previously proven that the PI3K/Akt
      pathway can suppress androgen receptor (AR) transactivation, the potential
      linkage from APPL to the AR remains unclear. Here we demonstrated that APPL could
      suppress AR-mediated transactivation in a dose-dependent manner in LNCaP and PC-3
      cells. This suppressive effect could be blocked by either dominant-negative Akt
      or dominant-negative PI3K or LY294002, suggesting that the APPL-mediated
      suppression of AR transactivation is dependent on the PI3K/Akt pathway. We also
      observed that APPL could further enhance the Akt-mediated suppression of AR
      transactivation and AR target gene using the reporter gene and Northern blot
      assay. APPL was able to enhance insulin-like growth factor (IGF-1)-mediated Akt
      activation. The abrogation of IGF-1-mediated Akt activation by the dominant
      negative PI3K or LY294002 or antisense APPL suggests that APPL may function as an
      important adapter protein in controlling the IGF-1 --> Akt signal pathway. Co
      immunoprecipitation and glutathione S-transferase pull-down assays suggest that
      APPL, Akt, and AR may exist in a complex and Akt may serve as an important bridge
      factor for the association of APPL with AR. Together, our data indicate that APPL
      may suppress AR transactivation via potentiating Akt activity.

PMID- 12621050
TI  - Decreased CCA-addition in human mitochondrial tRNAs bearing a pathogenic A4317G
      or A10044G mutation.
AB  - Pathogenic point mutations in mitochondrial tRNA genes are known to cause a
      variety of human mitochondrial diseases. Reports have associated an A4317G
      mutation in the mitochondrial tRNA(Ile) gene with fatal infantile cardiomyopathy
      and an A10044G mutation in the mitochondrial tRNA(Gly) gene with sudden infant
      death syndrome. Here we demonstrate that both mutations inhibit in vitro CCA
      addition to the respective tRNA by the human mitochondrial CCA-adding enzyme.
      Structures of these two mutant tRNAs were examined by nuclease probing. In the
      case of the A4317G tRNA(Ile) mutant, structural rearrangement of the T-arm
      region, conferring an aberrantly stable T-arm structure and an increased T(m)
      value, was clearly observed. In the case of the A10044G tRNA(Gly) mutant, high
      nuclease sensitivity in both the T- and D-loops suggested a weakened interaction
      between the loops. These are the first reported instances of inefficient CCA
      addition being one of the apparent molecular pathogeneses caused by pathogenic
      point mutations in human mitochondrial tRNA genes.

PMID- 12621051
TI  - Age-related changes in the proteoglycans of human skin. Specific cleavage of
      decorin to yield a major catabolic fragment in adult skin.
AB  - Dramatic changes occur in skin as a function of age, including changes in
      morphology, physiology, and mechanical properties. Changes in extracellular
      matrix molecules also occur, and these changes likely contribute to the overall
      age-related changes in the physical properties of skin. The major proteoglycans
      detected in extracts of human skin are decorin and versican. In addition, adult
      human skin contains a truncated form of decorin, whereas fetal skin contains
      virtually undetectable levels of this truncated decorin. Analysis of this
      molecule, herein referred to as decorunt, indicates that it is a catabolic
      fragment of decorin rather than a splice variant. With antibody probes to the
      core protein, decorunt is found to lack the carboxyl-terminal portion of decorin.
      Further analysis by matrix-assisted laser desorption/ionization time-of-flight
      mass spectrometry shows that the carboxyl terminus of decorunt is at Phe(170) of
      decorin. This result indicates that decorunt represents the amino-terminal 43% of
      the mature decorin molecule. Such a structure is inconsistent with alternative
      splicing of decorin and suggests that decorunt is a catabolic fragment of
      decorin. A neoepitope antiserum, anti-VRKVTF, was generated against the carboxyl
      terminus of decorunt. This antiserum does not recognize intact decorin in any
      skin proteoglycan sample tested on immunoblots but recognizes every sample of
      decorunt tested. The results with anti-VRKVTF confirm the identification of the
      carboxyl terminus of decorunt. Analysis of collagen binding by surface plasmon
      resonance indicates that the affinity of decorunt for type I collagen is 100-fold
      less than that of decorin. This observation correlates with the structural
      analysis of decorunt, in that it lacks regions of decorin previously shown to be
      important for interaction with type I collagen. The detection of a catabolic
      fragment of decorin suggests the existence of a specific catabolic pathway for
      this proteoglycan. Because of the capacity of decorin to influence collagen
      fibrillogenesis, catabolism of decorin may have important functional implications
      with respect to the dermal collagen network.

PMID- 12621053
TI  - Essential steps in the ppGpp-dependent regulation of bacterial ribosomal RNA
      promoters can be explained by substrate competition.
AB  - Transcription of stable RNA genes is known to be dramatically reduced in the
      presence of guanosine tetraphosphate (ppGpp), the mediator of the stringent
      response. Using in vitro transcription systems with ribosomal RNA P1 promoters,
      we have analyzed which step of the initiation cycle is inhibited by the effector
      ppGpp. We show that formation of the ternary transcription initiation complex
      consisting of RNA polymerase holoenzyme, the promoter DNA, and the first
      initiating nucleotide triphosphate is the major step at which ppGpp exerts its
      regulation. Neither primary binding of RNA polymerase to the promoter nor
      isomerization to the open binary complexes or the subsequent promoter clearance
      steps contributes notably to the observed inhibition. The effect of ppGpp
      dependent inhibition in the formation of the ternary transcription initiation
      complex could be mimicked by nucleotide derivatives known to bind to the RNA
      polymerase active center. Using these model compounds, almost identical
      inhibition characteristics were observed as seen with ppGpp. The results support
      the previously published model, which suggests that ppGpp-dependent inhibition is
      based on competition between the inhibitor molecules and NTP substrates for
      access to the active center of RNA polymerase.

PMID- 12621052
TI  - Signal recognition particle binds to ribosome-bound signal sequences with
      fluorescence-detected subnanomolar affinity that does not diminish as the nascent
      chain lengthens.
AB  - The binding of signal recognition particle (SRP) to ribosome-bound signal
      sequences has been characterized directly and quantitatively using fluorescence
      spectroscopy. A fluorescent probe was incorporated cotranslationally into the
      signal sequence of a ribosome.nascent chain complex (RNC), and upon titration
      with SRP, a large and saturable increase in fluorescence intensity was observed.
      Spectral analyses of SRP and RNC association as a function of concentration
      allowed us to measure, at equilibrium, K(d) values of 0.05-0.38 nm for SRP.RNC
      complexes with different signal sequences. Competitive binding experiments with
      nonfluorescent RNC species revealed that the nascent chain probe did not alter
      SRP affinity and that SRP has significant affinity for both nontranslating
      ribosomes (K(d) = 71 nm) and RNCs that lack an exposed signal sequence (K(d) = 8
      nm). SRP can therefore distinguish between translating and nontranslating
      ribosomes. The very high signal sequence-dependent SRP.RNC affinity did not
      decrease as the nascent chain lengthened. Thus, the inhibition of SRP-dependent
      targeting of RNCs to the endoplasmic reticulum membrane observed with long
      nascent chains does not result from reduced SRP binding to the signal sequence,
      as widely thought, but rather from a subsequent step, presumably nascent chain
      interference of SRP.RNC association with the SRP receptor and/or translocon.

PMID- 12621054
TI  - Calcium plays a critical role in determining the acetylcholine receptor
      clustering activities of alternatively spliced isoforms of Agrin.
AB  - Neural agrin, an extracellular matrix protein secreted by motor neurons, plays a
      key role in clustering of nicotinic acetylcholine receptors (AChR) on
      postsynaptic membranes of the neuromuscular junction. The action of agrin is
      critically dependent on an eight-amino acid insert (z8 insert) in the third of
      three consecutive laminin-like globular (G3) domains near the C terminus of
      neural agrin. Alternatively spliced agrin isoforms in non-neural tissue including
      muscle lack the z8 insert and are biologically inactive. Extracellular calcium
      has been shown to be imperative for the AChR-clustering activity of neural agrin.
      It is unclear, however, whether calcium preferentially interacts with the neural
      isoform or whether it acts solely as an intracellular messenger that mediates
      agrin signaling. Here, we report the G3 domain of rat neural agrin (AgG3z8)
      expressed in Pichia pastoris promoted AChR clustering on surface of C2C12
      myotubes in a calcium-dependent manner. Direct binding of calcium to AgG3z8 was
      demonstrated by trypsin digestion and thermal denaturation experiments. Moreover,
      calcium induced a significant change in the conformation of AgG3z8, and the
      effect was correlated with an enhanced binding affinity of the protein to muscle
      receptor. Mutation of calcium-binding residues in the G3 domain diminished the
      conformational change of neural agrin, reduced its binding affinity to muscle
      membrane, and inhibited AChR-clustering activity. Conversely, the G3 domain of
      muscle agrin (AgG3z0) displayed little structural change in the presence of
      calcium, bound poorly to muscle surface, and was inactive in AChR-clustering
      assays. We conclude that distinct interactions of the G3 domain with calcium
      determine the biological activities of alternatively spliced agrin isoforms
      during synapse formation.

PMID- 12621055
TI  - Rescue of light responses in the Drosophila "null" phospholipase C mutant,
      norpAP24, by the diacylglycerol kinase mutant, rdgA, and by metabolic inhibition.
AB  - Light responses in Drosophila are reportedly abolished in severe mutants of the
      phospholipase C (PLC) gene, norpA. However, on establishing the whole-cell
      recording configuration in photoreceptors of the supposedly null allele,
      norpAP24, we detected a small ( approximately 15 pA) inward current that
      represented spontaneous light channel activity. The current decayed during
      approximately 20 min, after which tiny residual responses (<2 pA) were elicited
      by intense flashes. Both spontaneous currents and light responses appeared to be
      mediated by residual PLC activity, because they were enhanced by impairing
      diacylglycerol (DAG) kinase function by mutation (rdgA) or by restricting ATP but
      were reduced or abolished by a mutation of the PLC-specific Gq alpha subunit. It
      was reported recently that metabolic inhibition activated the light-sensitive
      transient receptor potential and transient receptor potential-like channels, even
      in norpAP24, leading to the conclusion that this action was independent of PLC
      (Agam, K., von Campenhausen, M., Levy, S., Ben-Ami, H. C., Cook, B., Kirschfeld,
      K., and Minke, B. (2000) J. Neurosci. 20, 5748-5755). However, we found that
      channel activation by metabolic inhibitors in norpAP24 was strictly dependent on
      the residual PLC activity underlying the spontaneous current, because the
      inhibitors failed to activate any channels after the spontaneous current had
      decayed. By contrast, polyunsaturated fatty acids invariably activated the
      channels independently of PLC. The results strongly support the obligatory
      requirement for PLC and DAG in Drosophila phototransduction, suggest that
      activation by metabolic inhibition is primarily because of the failure of
      diacylglycerol kinase, and are consistent with the proposal that polyunsaturated
      fatty acids, which are potential DAG metabolites, act directly on the channels.

PMID- 12621056
TI  - A winged helix forkhead (FOXD2) tunes sensitivity to cAMP in T lymphocytes
      through regulation of cAMP-dependent protein kinase RIalpha.
AB  - Forkhead/winged helix (FOX) transcription factors are essential for control of
      the cell cycle and metabolism. Here, we show that spleens from Mf2-/- (FOXD2-/-)
      mice have reduced mRNA (50%) and protein (35%) levels of the RIalpha subunit of
      the cAMP-dependent protein kinase. In T cells from Mf2-/- mice, reduced levels of
      RIalpha translates functionally into approximately 2-fold less sensitivity to
      cAMP-mediated inhibition of proliferation triggered through the T cell receptor
      CD3 complex. In Jurkat T cells, FOXD2 overexpression increased the endogenous
      levels of RIalpha through induction of the RIalpha1b promoter. FOXD2
      overexpression also increased the sensitivity of the promoter to cAMP. Finally,
      co-expression experiments demonstrated that protein kinase Balpha/Akt1 work
      together with FOXD2 to induce the RIalpha1b promoter (10-fold) and increase
      endogenous RIalpha protein levels further. Taken together, our data indicate that
      FOXD2 is a physiological regulator of the RIalpha1b promoter in vivo working
      synergistically with protein kinase B to induce cAMP-dependent protein kinase
      RIalpha expression, which increases cAMP sensitivity and sets the threshold for
      cAMP-mediated negative modulation of T cell activation.

PMID- 12621057
TI  - The cell surface expression of SAP-binding receptor CD229 is regulated via its
      interaction with clathrin-associated adaptor complex 2 (AP-2).
AB  - CD229 (Ly9) is a cell surface receptor selectively expressed on T and B
      lymphocytes, and it belongs to the CD150 receptor family. Like other receptors of
      this family, CD229 interacts with SAP/SH2D1a protein, mutation of which is
      responsible for the fatal X-linked lymphoproliferative disease. Receptors of the
      CD150 family function as costimulatory molecules, regulating cytokine production
      and cytotoxicity. Thus, their signaling and regulation in lymphocytes may be
      critical to an understanding of the pathogenesis of the X-linked
      lymphoproliferative disease. Here we show that CD229 interacts with the mu(2)
      chain of the AP-2 adaptor complex that links transmembrane proteins to clathrin
      coated pits. CD229 was the only member of the CD150 family associated with AP-2.
      We also show that the mu(2) chain interacts with the Y(470)EKL motif of CD229.
      The integrity of this site was necessary for CD229 internalization, but it was
      not involved in SAP recruitment. Moreover, CD229 binds to the AP-2 complex in T
      and B cell lines, and it is internalized rapidly from the cell surface on T cells
      after antibody ligation. In contrast, cross-linking of CD229 receptors with
      intact antibody inhibited CD229 internalization on B cells. However, when
      F(ab')(2) antibodies were used, CD229 internalization was similar on T and B
      cells, suggesting that Fcgamma receptors control CD229 cell surface expression.
      Furthermore, CD229 was regulated by T cell receptor and B cell receptor signaling
      because coligation with antibodies against anti-CD3 and anti-IgM increased the
      rate of CD229 endocytosis. These data suggest that CD229 cell surface expression
      on lymphocytes surface is strongly and differentially regulated within the CD150
      family members.

PMID- 12621059
TI  - The transmembrane domain and PXXP motifs of ApoE receptor 2 exclude it from
      carrying out clathrin-mediated endocytosis.
AB  - The low density lipoprotein (LDL) receptor family comprises several proteins with
      similar structures including the LDL receptor and apoE receptor 2 (apoER2). The
      human brain expresses two major splice variants of apoER2 mRNA, one of which
      includes an additional exon that encodes 59 residues in the cytoplasmic domain.
      This exon is absent from the LDL receptor and contains three proline-rich (PXXP)
      motifs that may allow apoER2 to function as a signal transducer. To investigate
      the role of this insert, we took advantage of the well characterized low density
      lipoprotein receptor pathway. Chimeras comprising the ectodomain and
      transmembrane domain of the LDL receptor fused to the cytoplasmic domain of
      apoER2 lacking the PXXP-containing residues are able to mediate clathrin
      dependent endocytosis of LDL as effectively as cells expressing the LDL receptor
      but not if the PXXP insert is present in the protein. Although expressed on the
      cell surface, the PXXP-containing chimeric receptor is excluded from clathrin
      vesicles as judged by its failure to co-localize with adaptor protein-2 possibly
      due to interaction with intracellular adaptors or scaffolding proteins. Chimeras
      with the transmembrane domain of apoER2, predicted to be longer than that of the
      LDL receptor by several residues, fail to mediate endocytosis of LDL or to co
      localize with adaptor protein-2 regardless of the presence or absence of the PXXP
      insert. Thus features of apoER2 that distinguish it as a signaling receptor,
      rather than as an endocytosis receptor like the LDL receptor, reside in or near
      the transmembrane domain and in the proline-rich motifs.

PMID- 12621058
TI  - Characterization of growth factor-induced serine phosphorylation of tumor
      necrosis factor-alpha converting enzyme and of an alternatively translated
      polypeptide.
AB  - Tumor necrosis factor-alpha converting enzyme (TACE) is a prototype member of the
      adamalysin family of transmembrane metalloproteases that effects ectodomain
      cleavage and release of many transmembrane proteins, including transforming
      growth factor-alpha. Growth factors that act through tyrosine kinase receptors,
      as well as other stimuli, induce shedding through activation of the Erk mitogen
      activated protein (MAP) kinase pathway without the need of new protein synthesis.
      How MAP kinase regulates shedding by TACE is not known. We now report that the
      cytoplasmic domain of TACE is phosphorylated in response to growth factor
      stimulation. We also identified a naturally expressed smaller polypeptide
      corresponding to most of the cytoplasmic domain of TACE. This protein, which we
      named SPRACT, is derived through alternative translation of the TACE-coding
      sequence and is, similarly to TACE, phosphorylated in response to growth factor
      and phorbol 12-myristate 13-acetate stimulation. Phosphoamino acid analysis
      revealed that growth factor-induced phosphorylation of TACE occurs only on serine
      and not on threonine or tyrosine. Tryptic mapping experiments coupled with site
      directed mutagenesis identified Ser(819) as the major target of growth factor
      induced phosphorylation, whereas Ser(791) undergoes dephosphorylation in response
      to growth factor stimulation. The phosphorylation of Ser(819), but not the
      dephosphorylation of Ser(791), depends on activation of the Erk MAP kinase
      pathway. Increased SPRACT expression or mutation of the TACE cytoplasmic domain
      to inactivate growth factor-induced phosphorylation did not detectably affect
      growth factor-induced shedding of transmembrane transforming growth factor-alpha
      by TACE. The roles of SPRACT and the cytoplasmic phosphorylation of TACE remain
      to be defined.

PMID- 12621060
TI  - Synthesis and phorbol ester binding of the cysteine-rich domains of
      diacylglycerol kinase (DGK) isozymes. DGKgamma and DGKbeta are new targets of
      tumor-promoting phorbol esters.
AB  - Diacylglycerol kinase (DGK) and protein kinase C (PKC) are two distinct enzyme
      families associated with diacylglycerol. Both enzymes have cysteine-rich C1
      domains (C1A, C1B, and C1C) in the regulatory region. Although most PKC C1
      domains strongly bind phorbol esters, there has been no direct evidence that DGK
      C1 domains bind phorbol esters. We synthesized 11 cysteine-rich sequences of DGK
      C1 domains with good sequence homology to those of the PKC C1 domains. Among
      them, only DGKgamma-C1A and DGKbeta-C1A exhibited significant binding to phorbol
      12,13-dibutyrate (PDBu). Scatchard analysis of rat-DGKgamma-C1A, human-DGKgamma
      C1A, and human-DGKbeta-C1A gave K(d) values of 3.6, 2.8, and 14.6 nm,
      respectively, suggesting that DGKgamma and DGKbeta are new targets of phorbol
      esters. An A12T mutation of human-DGKbeta-C1A enhanced the affinity to bind PDBu,
      indicating that the beta-hydroxyl group of Thr-12 significantly contributes to
      the binding. The K(d) value for PDBu of FLAG-tagged whole rat-DGKgamma (4.4 nm)
      was nearly equal to that of rat-DGKgamma-C1A (3.6 nm). Moreover, 12-O
      tetradecanoylphorbol 13-acetate induced the irreversible translocation of whole
      rat-DGKgamma and its C1B deletion mutant, not the C1A deletion mutant, from the
      cytoplasm to the plasma membrane of CHO-K1 cells. These results indicate that 12
      O-tetradecanoylphorbol 13-acetate binds to C1A of DGKgamma to cause its
      translocation.

PMID- 12621061
TI  - Signal transduction pathways regulated by prolactin and Src result in different
      conformations of activated Stat5b.
AB  - Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor
      tyrosine kinases, such as Src. In this study, the DNA binding properties of the
      two closely related Stat5 proteins, Stat5a and Stat5b, induced either by
      prolactin (Prl) or by Src were analyzed by electrophoretic mobility shift assays
      using several different Stat5 binding sites. Src-induced Stat5b-DNA binding
      complexes consistently displayed a slightly faster mobility than those induced by
      Prl, as well as differences in their ability to be supershifted by anti-Stat5
      antibodies. IP-Westerns performed using specific antibodies directed at the N and
      C termini of Stat5b suggested that depending on the activating stimulus, Stat5b
      exhibited different conformations, which influenced antibody accessibility at its
      C terminus. These conformational differences may in part be due to differential
      effects of Prl and Src on Stat5b tyrosine phosphorylation, since Src induced
      several additional sites of tyrosine phosphorylation of Stat5b at residues other
      than Tyr-699, including Tyr-724 and Tyr-679. The latter Tyr-679 is conserved in
      all mammalian Stat5bs, but is not present in Stat5a. A Stat 5bY679F mutant
      induced by Src kinase exhibited an altered pattern of nuclear localization as
      compared with wild-type Stat5b. Furthermore, this mutation inhibited v-Src
      induced cyclin D1-luciferase reporter activity in transient transfection assays
      performed in Stat5a/b-deficient MEFs, suggesting that Tyr-679 phosphorylation may
      play a role in v-Src induced proliferation. Thus, depending on the signal
      transduction pathway responsible for activation, different conformations of
      activated Stat5 may result in selective biological responses.

PMID- 12621063
TI  - MGAT2, a monoacylglycerol acyltransferase expressed in the small intestine.
AB  - Acyl CoA:monoacylglycerol acyltransferase (MGAT) catalyzes the synthesis of
      diacylglycerol, a precursor of triacylglycerol. In the intestine, MGAT plays a
      major role in the absorption of dietary fat by catalyzing the resynthesis of
      triacylglycerol in enterocytes. This resynthesis is required for the assembly of
      lipoproteins that transport absorbed fat to other tissues. Despite intense
      efforts, a gene encoding an intestinal MGAT has not been found. Previously, we
      identified a gene encoding MGAT1, which in mice is expressed in the stomach,
      kidney, adipose tissue, and liver but not in the intestine. We now report the
      identification of homologous genes in humans and mice encoding MGAT2. Expression
      of the MGAT2 cDNA in either insect or mammalian cells markedly increased MGAT
      activity in cell membranes. MGAT activity was proportional to the level of MGAT2
      protein expressed, and the amount of diacylglycerol produced depended on the
      concentration of MGAT substrates (fatty acyl CoA or monoacylglycerol). In humans,
      the MGAT2 gene is highly expressed in the small intestine, liver, stomach,
      kidney, colon, and white adipose tissue; in mice, it is expressed predominantly
      in the small intestine. The discovery of the MGAT2 gene will facilitate studies
      to determine the functional role of MGAT2 in fat absorption in the intestine and
      to determine whether blocking MGAT activity in enterocytes is a feasible approach
      to inhibit fat absorption and treat obesity.

PMID- 12621062
TI  - Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of
      the pocket proteins pRb, p107, and p130.
AB  - Oxidative stress induces cell death and growth arrest. In this study, the
      regulation and the functional role of the retinoblastoma family proteins pRb,
      p107, and p130 in the cellular response to oxidative stress were investigated.
      Treatment of endothelial cells with H2O2 induced rapid hypophosphorylation of the
      retinoblastoma family proteins. This event did not require p53 or
      p21Waf1/Cip1/Sdi1 and was not associated with cyclin/cyclin-dependent kinase down
      modulation. Four lines of evidence indicate that H2O2-induced hypophosphorylation
      of pRb, p107, and p130 was because of the activity of protein phosphatase 2A
      (PP2A). First, cell treatment with two phosphatase inhibitors, okadaic acid and
      calyculin A, prevented the hypophosphorylation of the retinoblastoma family
      proteins, at concentrations that specifically inhibit PP2A. Second, SV40 small t,
      which binds and inhibits PP2A, when overexpressed prevented H2O2-induced
      dephosphorylation of the retinoblastoma family proteins, whereas a SV40 small t
      mutant unable to bind PP2A was totally inert. Third, PP2A core enzyme physically
      interacted with pRb and p107, both in H2O2-treated and untreated cells. Fourth, a
      PP2A phosphatase activity was co-immunoprecipitated with pRb, and the activity of
      pRb-associated PP2A was positively modulated by cell treatment with H2O2. Because
      DNA damaging agents inhibit DNA synthesis in a pRb-dependent manner, it was
      determined whether the PP2A-mediated dephosphorylation of the retinoblastoma
      family proteins played a role in this S-phase response. Indeed, it was found that
      inhibition of PP2A by SV40 small t over-expression prevented DNA synthesis
      inhibition induced by H2O2.

PMID- 12621064
TI  - Induction of endoreduplication by topoisomerase II catalytic inhibitors.
AB  - The striking phenomenon of endoreduplication has long attracted attention from
      cytogeneticists and researchers into cell cycle enzymology and dynamics alike.
      Because of the variety of agents able to induce endoreduplication and the various
      cell types where it has been described, until now no clear or unique mechanism of
      induction of this phenomenon, rare in animals but otherwise quite common in
      plants, has been proposed. Recent years, however, have witnessed the unfolding of
      a number of essential physiological roles for DNA topoisomerase II, with special
      emphasis on its major role in mitotic chromosome segregation after DNA
      replication. In spite of the lack of mammalian mutants defective in topoisomerase
      II as compared with yeast, experiments with inhibitors of the enzyme have
      supported the hypothesis that this crucial untangling of daughter DNA molecules
      by passing an intact helix through a transient double-stranded break carried out
      by the enzyme, when it fails, leads to aberrant mitosis that results in
      endoreduplication, polyploidy and eventually cell death. Anticancer drugs that
      interfere with topoisomerase II can be classified into two groups. The classical
      poisons act by stabilizing the enzyme in the so-called cleavable complex and
      result in DNA damage, which represents a problem in the study of
      endoreduplication. The true catalytic inhibitors, which are not cleavable complex
      stabilizers, allow us to use doses efficient in the induction of
      endoreduplication while eliminating high levels of DNA and chromosome damage.
      This review will discuss the basic and applied aspects of this as yet scarcely
      explored field.

PMID- 12621065
TI  - Antimutagenic activity of extracts of natural substances in the
      Salmonella/microsome assay.
AB  - Scientific information regarding plants used in folk medicine in the form of teas
      and their effect on human health or on genetic material has been the subject of
      many different types of investigation. The antimutagenic activity of two plants
      Maytenus ilicifolia and Peltastes peltatus, both rich in compounds of the
      flavonoid and tannin groups and frequently employed in folk medicine, was
      studied. Antimutagenicity was determined against known mutagenic substances (4
      oxide-1-nitroquinoline, sodium azide, 2-nitrofluorene, aflatoxin B(1), 2
      aminofluorene and 2-aminoanthracene), using the Salmonella/microsome assay.
      Infusions of P.peltatus showed high cytotoxicity and a co-mutagenic effect for
      induction of base pair substitution mutations with 4-oxide-1-nitroquinoline (-S9
      mix). Infusions of M.ilicifolia produced similar effects for frameshift and base
      pair substitution mutations. With the mutagens 2-nitrofluorene (TA98) and sodium
      azide (TA100) no significant enhancement effects (co-mutagenic effects) were
      observed and inhibition of mutagenic activity and cytotoxicity were also
      diminished. In assays evaluating antimutagenic activity in the presence of
      metabolic activation utilizing S9 mix, high and significant inhibition of
      aflatoxin B(1)-, 2-aminofluorene- and 2-aminoanthracene-induced mutagenicity was
      observed in the presence of the infusions using both TA98 and TA100 and employing
      doses ranging from 25 to 500 mg/plate. Seventy-five percent of the doses tested
      exhibited a significant or suggestive decrease in induced mutagenicity with the
      infusion of M.ilicifolia. With the infusion of P.peltatus significant or
      suggestive antimutagenic responses were observed with 50% of the doses evaluated.
      Complexity was clearly noted in the responses observed in the interaction of
      aqueous extracts of M.ilicifolia and P.peltastes with the genetic material and
      metabolites generated by the S9 mix played an important role in the protection of
      DNA.

PMID- 12621066
TI  - The principal phenolic and alcoholic components of wine protect human lymphocytes
      against hydrogen peroxide- and ionizing radiation-induced DNA damage in vitro.
AB  - We have tested the hypothesis that the alcoholic and phenolic components of wine
      are protective against the DNA-damaging and cytotoxic effects of hydrogen
      peroxide and gamma-radiation in vitro. The components of wine tested were
      ethanol, glycerol, a mixture of the phenolic compounds catechin and caffeic acid
      and tartaric acid, all at concentrations that were 2.5 or 10.0% of the
      concentration in a typical Australian white wine (Riesling). These components
      were tested individually or combined as a mixture and compared to a white wine
      stripped of polyphenols, as well as a Hanks balanced salt solution control, which
      was the diluent for the wine components. The effect of the components was tested
      in lymphocytes, using the cytokinesis-block micronucleus assay, after 30 min
      incubation in plasma or whole blood for the hydrogen peroxide or gamma-radiation
      challenge, respectively. The results obtained showed that ethanol, glycerol, the
      catechin-caffeic acid mixture, the mixture of all components and the stripped
      white wine significantly reduced the DNA-damaging effects of hydrogen peroxide
      and gamma-radiation (P = 0.043-0.001, ANOVA). The strongest protective effect
      against DNA damage by gamma-irradiation was observed for the catechin-caffeic
      acid mixture and the mixture of all components (30 and 32% reduction,
      respectively). These two treatments as well as ethanol produced the strongest
      protective effects against DNA damage by hydrogen peroxide (24, 25 and 18%,
      respectively). The protection provided by the mixture did not account for the
      expected additive protective effects of the individual components. Ethanol was
      the only component that significantly increased baseline DNA damage rate,
      however, this effect was negated in the mixture. In conclusion, our results
      suggest that the main phenolic and alcoholic components of wine can reduce the
      DNA-damaging effects of two important oxidants, i.e. hydrogen peroxide and
      ionizing radiation, in this physiologically relevant in vitro system.

PMID- 12621068
TI  - Induction of genetic instability and chromosomal instability by nickel sulfate in
      V79 Chinese hamster cells.
AB  - Nickel compounds are known to be carcinogenic to humans and show genotoxicity,
      including the ability to induce chromosome aberrations and neoplastic
      transformation in vitro. The mutagenicity of nickel compounds is, however,
      equivocal and the mechanisms of carcinogenesis are still not clear. In this
      study, the possibility that nickel compounds induce genetic or chromosomal
      instability was examined, because recent studies in cancer research show that
      these conditions are critically involved in carcinogenesis. V79 Chinese hamster
      cells were treated with 320 microM nickel sulfate for 24 h at low cell density
      (100 cells/100 mm diameter dish) and clones derived from single cells surviving
      Ni treatment were isolated. When cells grew up to 23-25 population doublings post
      treatment, mutation frequency at the HPRT locus and the chromosome aberration
      frequency of each clone were examined. Five out of 37 clones (13.5%) derived from
      Ni-treated cells showed a remarkably increased frequency of HPRT mutations (>or=1
      x 10(-4)), while only one out of 37 control clones (2.7%) showed this high
      mutation rate. In addition, 17 out of 37 clones (45.9%) from Ni-treated cells
      showed structural chromosomal aberrations in 10% or more of cells (up to 45.5%),
      while only three out of 31 control clones (9.7%) showed this high aberration
      rate. Out of 37 clones derived from Ni-treated cells, eight (21.6%) and 11
      (29.7%) clones showed an increased frequency (>or=5%) of aneuploid and polyploid
      cells, respectively, while only a few control clones showed such an increase in
      aneuploid and polyploid cells. These results indicate that nickel sulfate can
      induce genetic and chromosomal instability in V79 cells.

PMID- 12621067
TI  - The role of oxidative stress in the in vitro induction of micronuclei by
      pesticides in mouse lung fibroblasts.
AB  - The involvement of the antioxidant enzymes catalase and glutathione peroxidase
      (both at 0.1 mg/ml) in defence against the genotoxicity of phosphamidon (80
      microg/ml) and dieldrin (25 microM) was investigated in order to demonstrate that
      the two pesticides damage DNA through the generation of reactive oxygen species
      and therefore of oxidative stress. The pesticide genotoxicity was determined by
      the cytokinesis-block micronucleus test performed on primary mouse lung
      fibroblast cultures. Also, 3-aminotriazole (40 mM) and mercaptosuccinate (0.5
      mM), inhibitors of catalase and glutathione peroxidase, respectively, were added
      to the cultures. Data indicate that catalase causes a decrease only in the damage
      induced by phosphamidon, while glutathione peroxidase protects against damage
      induced by both phosphamidon and dieldrin. Simultaneous treatment with
      antioxidant inhibitors and pesticides results in a decrease in micronucleus
      frequency and cell number, due to apoptotic death. Our results indicate that
      clastogenic DNA damage produced by the two pesticides is modulated by antioxidant
      enzymes and their inhibitors and thus could be due to oxidative stress induction.

PMID- 12621069
TI  - A study on the effects of seasonal solar radiation on exposed populations.
AB  - In the present study the effects of seasonal solar radiation (summer and winter)
      on exposed populations of two different age groups (20-25 and 40-55 years old)
      were investigated. In addition, the effects of external factors, such as hydrogen
      peroxide (H(2)O(2)) and gamma-irradiation, as well as the repair efficiency of
      human lymphocytes from these populations, was also evaluated. Our results show
      that the amount of DNA damage appears to be influenced by the exposure to solar
      radiation, with the summer exposure being the most damaging. Age was also found
      to be a significant factor, with the older population being more susceptible to
      solar radiation than the younger one. Season does not appear to affect the
      sensitivity to external DNA-damaging agents, while age does. Age was also found
      to have an effect on the DNA repair capacity of the examined populations.

PMID- 12621070
TI  - Effects of black tea theafulvins on aflatoxin B(1) mutagenesis in the Ames test.
AB  - Black tea theafulvins, a fraction of thearubigins isolated from black tea aqueous
      infusions, potentiated the mutagenic activity of the mycotoxin aflatoxin B(1) in
      the Ames test, in the presence of a hepatic S9 activation system derived from
      Aroclor 1254-treated rats. In contrast, when the S9 activation system was
      replaced with isolated microsomes, theafulvins suppressed the mutagenicity of the
      mycotoxin. When microsomal metabolism was terminated after metabolic activation
      of the mycotoxin, incorporation of the theafulvins into the activation system
      reduced the mutagenic activity, whereas if it was added before termination of
      microsomal activity a potentiation of mutagenic response was observed. In in
      vitro studies, theafulvins inhibited epoxide hydrolase and glutathione S
      transferase activities in a concentration-dependent manner. Finally, the
      mutagenicity of aflatoxin B(1) was much more pronounced in bacteria that were pre
      exposed to theafulvins but from which they were subsequently washed off. It may
      be inferred from the above studies that the genotoxic synergy between aflatoxin
      B(1) and black tea theafulvins does not occur during the bioactivation of the
      carcinogen, but may partly be due to decreased deactivation of the reactive
      intermediate, aflatoxin B(1) 8,9-oxide, by conjugation with glutathione.

PMID- 12621071
TI  - Environmental factors affecting transcription of the human L1 retrotransposon.
      II. Stressors.
AB  - Retrotransposons have clearly molded the structure of the human genome. The
      reverse transcriptase coded for by long interspersed nuclear elements (LINEs)
      accounts for 35% of the human genome, with 8-9 x 10(5) copies of the most common
      human LINE element, L1Hs. Retrotransposons cycle through an RNA intermediate with
      transcription as the rate limiting step. Because various retrotransposons have
      been demonstrated to be induced by environmental stimuli, we investigated the
      response of the L1Hs promoter to various agents. L1Hs promoter activity was
      analyzed by transfecting an L1Hs-expressing cell line with plasmids containing
      one of two L1Hs promoters fused to the LacZ reporter gene. L1Hs promoter activity
      was then monitored with a beta-galactosidase assay. Treatment with UV light and
      heat shock resulted in a small increase in beta-galactosidase activity from one
      promoter, while treatment with tetradecanoylphorbol 13-acetate resulted in small
      increases in beta-galactosidase activity from both promoters. No increase in beta
      galactosidase activity was observed after exposure to X-rays or hydrogen
      peroxide.

PMID- 12621072
TI  - Statistics of the Comet assay: a key to discriminate between genotoxic effects.
AB  - The alkaline Comet assay is a widely used single cell gel electrophoresis
      technique for the quantification of DNA strand breaks, crosslinks and alkali
      labile sites induced by a series of physical and chemical agents. DNA migration
      in an electric field, supposed proportional to strand breakage, is a proposed
      estimation of genotoxicity. Breaks are quantified from geometric and fluorescence
      measurements by image analysis of comet-shaped DNA, often reported parameters
      being tail DNA and tail moment. Although a variety of statistical approaches have
      been used in the literature, most of these do not take into account the
      distribution patterns of comet data. In order to investigate a methodology for
      statistically demonstrating a comet effect, two different experiments, a
      reproducibility study and a trend analysis, were undertaken on a murine lymphoma
      cell line (P388D1) photodynamically stressed after induction of porphyrins with
      delta-aminolaevulinic acid. This treatment results in significant heterogeneity
      of DNA damage, producing values ranging from 0 to 100% tail DNA in the same
      sample. The comparison of distribution curves for stressed and non-stressed
      samples shows that none of the application conditions are verified, either for
      parametric tests (which require normal distributions), or non-parametric tests
      (which assume essentially similar distributions). Meaningful statistics (median
      and 75th percentile) were consequently extracted from repeated experiments and
      found suitable for comparing stress conditions in an ANOVA and in a trend
      analysis; the 75th percentile is theoretically more sensitive but tends to more
      rapidly saturate at extensive stress levels. We conclude that a trend analysis of
      median comet metrics from repeated experiments at different stress levels is
      certainly an efficient way to statistically demonstrate a genotoxic effect.
      Whether the considered comet parameter is tail DNA or tail moment had no
      influence on the conclusions of our experiments, which were carried up to stress
      levels leading to a median 70% tail DNA.

PMID- 12621073
TI  - Aspects of design and statistical analysis in the Comet assay.
AB  - Some aspects of the statistical design and analysis of the Comet (single cell gel
      electrophoresis) assay have been evaluated by means of a simulation study. The
      tail length and tail moment were selected for the quantification of DNA
      migration. Results from the simulation study showed that the choice of measure to
      summarize the cells on each slide is extremely important in order to facilitate
      an efficient analysis. For tail moment, the mean of log transformed data is
      clearly superior to the other evaluated measures, whereas using the mean of raw
      data without transformation can lead to very inefficient analyses. The 90th
      percentile, capturing the upper tail of the distribution, performs well for the
      tail length, with a slight improvement obtained by applying a log transformation
      prior to calculations. Furthermore, the simulation study has been used to assess
      the appropriateness of some models for statistical analysis and to address the
      issue of design (i.e. number of cultures or animals in each group, number of
      slides per animal/culture and number of cells scored per slide). Combining the
      results from the simulations with practical experience from the pharmaceutical
      industry, we conclude the paper by providing concise recommendations regarding
      the design and statistical analysis in the Comet assay.

PMID- 12621074
TI  - In vitro genotoxic effects of different combinations of cobalt and metallic
      carbide particles.
AB  - Occupational exposure to hard metal dust, consisting of tungsten carbide (WC) and
      metallic cobalt particles (Co), is associated with an increased risk of lung
      cancer, while no increased risk was observed in workers exposed to Co alone. In
      vitro, in human peripheral blood mononucleated cells (PBMC), we previously
      demonstrated that WC-Co is more genotoxic than Co and WC alone. A possible
      mechanism underlying this higher genotoxicity is a specific physicochemical
      interaction between Co and WC particles leading to the enhanced short-term
      formation of active oxygen species. The aim of this study was to evaluate the in
      vitro genotoxicity of other combinations of Co with metal carbide particles in
      comparison with WC-Co. The ability of Cr(3)C(2), Mo(2)C and NbC and of their
      powder mixtures with Co to induce DNA strand breaks and alkali-labile sites was
      assessed by the alkaline Comet assay and their potential to induce
      chromosome(/genome) mutations by the cytokinesis-block micronucleus test on human
      PBMC from two donors. PBMC were treated in vitro for 15 min, 24 h after the onset
      of PHA stimulation. In the micronucleus test, while the metal carbides alone did
      not increase the micronucleus frequency, Co alone and the four tested carbide-Co
      mixtures induced a statistically significant concentration-dependent increase in
      micronucleated binucleates. In addition to WC, NbC and Cr(3)C(2) particles were
      able to interact with Co, producing a higher mutagenic effect than the individual
      metal particles. Mo(2)C particles did not display interactive mutagenicity with
      Co in the micronucleus test, possibly related to their small specific surface
      area, compactness and/or spherical shape. With the Comet assay, applied directly
      at the end of the treatment, less clear results, due to inter-experimental and
      inter-donor variation, were obtained. These data indicate that particular
      interaction of a metal carbide with Co leading to enhanced mutagenicity is not
      specific for WC.

PMID- 12621075
TI  - Nucleoplasmic bridges are a sensitive measure of chromosome rearrangement in the
      cytokinesis-block micronucleus assay.
AB  - We have performed experiments using the WIL2-NS human B lymphoblastoid cell line
      and primary human lymphocytes to: (i). determine the importance of including
      measurements of nucleoplasmic bridges (NPB) in the cytokinesis-block micronucleus
      (CBMN) assay; (ii). provide evidence that NPB originate from dicentric
      chromosomes and centric ring chromosomes. In addition, we describe theoretical
      models that explain how dicentric chromosomes and centric ring chromosomes may
      result in the formation of NPB at anaphase. The results with WIL2-NS showed that
      it was possible to distinguish genotoxic effects induced by different oxidizing
      agents in terms of the NPB/micronucleus frequency ratio. The results with
      lymphocytes indicated a strong correlation: (i). between NPB, centric ring
      chromosomes and dicentric chromosomes in metaphases (r > 0.93, P < 0.0001); (ii).
      between micronuclei (MNi), acentric chromosome fragments and acentric ring
      chromosomes (r > 0.93, P < 0.0001). The dose-response curves with gamma-rays were
      very similar for NPB, ring chromosomes and dicentric chromosomes, as were the
      dose-response curves for MNi, acentric rings and fragments. However, not all
      acentric chromosomes and dicentric chromosomes/centric rings were converted to
      MNi and NPB respectively, depending on the dose of radiation. Preliminary data,
      using FISH, suggest that NPB often represent DNA from a structural rearrangement
      involving only one or two homologous chromosomes. The results from this study
      validate the inclusion of NPB in the CBMN assay which provides a valuable measure
      of chromosome breakage/rearrangement that was otherwise not available in the
      micronucleus assay. The CBMN assay allows NPB measurement to be achieved reliably
      because inhibition of cytokinesis prevents the loss of NPB that would otherwise
      occur if cells were allowed to divide.

PMID- 12621077
TI  - Evaluation of genetic damage in workers employed in pesticide production
      utilizing the Comet assay.
AB  - The use of pesticides has been increasing in recent years, resulting in the need
      for increased production of pesticides. However, some pesticides may represent a
      hazard to human health, especially by causing cancer. Genotoxicity tests form an
      important part of cancer research and risk assessment of potential carcinogens.
      Therefore, in the current study the potential DNA damage associated with exposure
      to pesticides of Indian pesticide production workers was assessed using the
      single cell gel electrophoresis assay or Comet assay. Blood leukocytes of a group
      of 54 pesticide workers and an equal number of control subjects were examined for
      genotoxicity in this study. The two groups had similar mean ages and smoking
      prevalences. The mean comet tail length was used to measure DNA damage. The
      exposed workers had significantly greater mean comet tail lengths than those of
      controls (mean +/- SD 19.17 +/- 2.467 versus 8.938 +/- 2.889, P < 0.001). Smokers
      had significantly larger mean tail lengths than non-smokers (19.75 +/- 2.52
      versus 18.26 +/- 2.13, P = 0.024). Analysis of covariance showed that
      occupational exposure (P < 0.05) and smoking (P < 0.05) had significant effects
      on mean tail length, whereas age and gender had no effect on DNA damage. The
      present study suggests that occupational exposure to pesticides and smoking can
      cause DNA damage. This investigation confirms the sensitivity of the Comet assay.

PMID- 12621076
TI  - Conjugated linoleic acid inhibits mutagenesis by 2-amino-1-methyl-6
      phenylimidazo[4,5-b]pyridine in the prostate of Big Blue rats.
AB  - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent mutagen and
      carcinogen formed at high temperature during the cooking of meat. PhIP induces
      tumors in the colon and prostate of male rats and in the mammary gland of female
      rats and has been associated with the etiology of human cancers. We have recently
      demonstrated that PhIP induces mutations in the prostate in Big Blue transgenic
      rats. In the current study we have examined the effect of a dietary anti
      carcinogen, conjugated linoleic acid (CLA), on PhIP-induced mutagenesis in the
      prostate. CLA is a mixture of positional and geometric isomers of linoleic acid
      and has been reported to inhibit various chemical-induced cancers in rodent
      models. Fifty day old male Big Blue rats were fed a standard diet containing 100
      p.p.m. PhIP for 47 days, which induced a mutation frequency of 14.6 x 10(-5) in
      the prostate, 5.1-fold higher than that of controls. The addition of 1% CLA (w/w)
      in the diet starting 1 week prior to exposure to PhIP decreased PhIP-induced
      mutagenesis by 38% (P = 0.03). The predominant class of mutation induced by PhIP
      is -1 frameshifts involving the loss of G:C base pairs, followed by G:C-->T:A
      transversions and G:C-->A:T transitions. Addition of CLA to the diet
      significantly changed the PhIP-induced mutation spectrum; notably, -1 frameshifts
      and G:C-->A:T transitions were selectively inhibited, suggesting involvement of
      mismatch repair. This is the first report to show the protective effect of CLA
      against PhIP-induced mutagenesis in the prostate on both mutation frequency and
      mutational spectrum. The inhibitory effect of CLA against PhIP-induced
      mutagenicity suggests a possibility for its application in human chemoprevention
      studies.

PMID- 12621078
TI  - Simultaneous detection of the exon 10 polymorphism and a novel intronic single
      base insertion polymorphism in the XPD gene using single strand conformation
      polymorphism.
AB  - We developed a new method based on the single strand conformation polymorphism
      (SSCP) technique for the detection of a G23591A (Asp312Asn) polymorphism in exon
      10 of the XPD gene. In the process we also identified a novel polymorphism 23623C
      ins (IVS10+17C-ins) in intron 10 of the same gene. With this newly developed SSCP
      based method of genotyping we could detect both polymorphisms in the same assay
      and thus consequently determine the haplotype. In order to determine the
      population frequency of the novel polymorphism and the haplotype frequency, 302
      healthy individuals were genotyped. The allelic frequency of the 23623C-ins
      intronic polymorphism was 0.16, whereas the frequency of the variant allele for
      the G23591A polymorphism was 0.39. Forty-three individuals (14%) were
      heterozygous for both polymorphisms but none carried polymorphic variants for
      both G23591A and 23623C-ins on the same allele. The effect of the novel intronic
      insertion polymorphism, which is located 16 nt downstream of the 3'-end of exon
      10 of the XPD gene and involves a mononucleotide C repeat sequence, on expression
      remains to be determined.

PMID- 12621079
TI  - Infection of rats with Taenia taeniformis metacestodes increases hepatic CYP450,
      induces the activity of CYP1A1, CYP2B1 and COH isoforms and increases the
      genotoxicity of the procarcinogens benzo[a]pyrene, cyclophosphamide and aflatoxin
      B(1).
AB  - Infection of rat liver by Taenia taeniformis metacestodes produced an increase in
      total CYP450 content and induced activity of the CYP1A1, CYP2B1 and COH isoforms.
      Variations in activity and p450 total content were found with increasing time of
      infection. During increased activity of p450 isoforms, rats were challenged with
      carcinogens metabolized by the mentioned isozymes and an increased amount of
      genotoxic damage was found when benzo[a] pyrene, cyclophosphamide and aflatoxin
      B(1) were used. No change was seen in CYP2E1 activity. These results support
      previous findings regarding an increased susceptibility to genotoxic damage of
      infected organisms.

PMID- 12621080
TI  - Wortmannin enhances the induction of micronuclei by low and high LET radiation.

PMID- 12621083
TI  - Chlamydia trachomatis-induced death of human spermatozoa is caused primarily by
      lipopolysaccharide.
AB  - Elementary bodies (EBs) of Chlamydia trachomatis serovar E are more toxic to
      sperm than those from serovar LGV. In this study, lipopolysaccharide (LPS) was
      prepared from the EBs of both serovars and incubated with human spermatozoa at
      concentrations that matched the LPS concentration of EBs. The effects of EBs and
      LPS on sperm motility, viability and acrosomal status were then determined. Sperm
      motility was measured by computer-assisted sperm analysis and the hypo-osmotic
      swelling test was used to determine the proportion of dead cells. Acrosomal
      status was examined using a standard mAb assay. Over a 6 h incubation, LPS from
      both serovars resulted in a marked reduction in sperm motility (and a concomitant
      increase in the proportion of dead spermatozoa) in a manner similar to that seen
      in response to EBs of serovar E. In addition, when sperm were incubated with a
      range of doses of EBs and LPS, probit analysis revealed that the greater
      spermicidal effects of EBs from serovar E (when compared with serovar LGV) were
      not observed when sperm were incubated with LPS from the two serovars. This
      suggests that the more potent effect of EBs of serovar E cannot be explained
      entirely by differences in the composition of LPS. Interestingly, Escherichia
      coli LPS was required in doses 500 times more concentrated than chlamydial LPS in
      order to kill a similar proportion of sperm, suggesting that bacterial LPSs may
      differ in their spermicidal properties. However, that chlamydial LPS was
      spermicidal was demonstrated by the use of polymyxin B (a polycationic antibiotic
      known to neutralize LPS effects), confirming that the effects observed were
      primarily a result of LPS activity.

PMID- 12621084
TI  - Protein kinase antagonists inhibit invasion of mammalian cells by Fonsecaea
      pedrosoi.
AB  - The phosphorylation process is an important mechanism of cell signalling and
      regulation. It has been implicated recently in defence strategies against a
      variety of pathogens that alter host signalling pathways in order to facilitate
      their invasion and survival within host cells. In this study, the involvement of
      protein kinases (PKs) has been investigated in attachment and invasion by the
      pathogenic fungus Fonsecaea pedrosoi within epithelial cells and macrophages. The
      use of the PK inhibitors staurosporine, genistein and calphostin C prior to
      infection provided significant information about the role played by PKs in the F.
      pedrosoi-host cell interaction. All three PK inhibitors could reduce cell
      invasion by F. pedrosoi significantly. Pre-treatment of macrophages, epithelial
      cells or conidia with PK inhibitors decreased fungus invasion, and this effect
      could be overcome by okadaic acid, a phosphatase inhibitor. Immunofluorescence
      assays showed that tyrosine residues were phosphorylated in the first step of the
      interaction, while serine residues were phosphorylated in the subsequent step of
      entry of the parasite into the host cell. These results suggest that both host
      cell and conidium PK activities are important in the interaction process, playing
      a significant role in cell invasion.

PMID- 12621086
TI  - Identification of immunodominant Helicobacter pylori proteins with reactivity to
      H. pylori-specific egg-yolk immunoglobulin.
AB  - The importance of hens eggs as a source of specific antibodies (IgY) is well
      recognized. The protective effect of IgY obtained from hens immunized with
      Helicobacter pylori whole-cell lysate has been reported for the control of H.
      pylori infection. However, IgY produced by whole-cell lysates presents the
      possibility of cross-reactivity with other bacteria, including the normal human
      flora, and this could decrease the efficiency of IgY. In the present study, the
      immunodominant proteins of H. pylori with reactivity to H. pylori-specific IgY
      (IgY-Hp) were identified. IgY obtained from hens immunized with various fractions
      of H. pylori proteins was isolated and purified, titres of IgY-Hp against H.
      pylori were determined and cross-reactivity between IgY-Hp and normal human
      bacteria was examined by Western blot analysis. Finally, immunodominant H. pylori
      proteins were identified by LC/MS analysis. IgY obtained 2 months after
      immunization with H. pylori whole-cell lysate showed the highest antibody titre.
      Five immunodominant proteins were identified that were strongly reactive to IgY
      Hp: urease beta-subunit (62 kDa), heat-shock protein 60 (60 kDa), urease alpha
      subunit (26 kDa), probable peroxiredoxin (22 kDa) and probable thiol peroxidase
      (18 kDa). Immunization of hens with the immunodominant proteins identified would
      produce a more specific IgY against H. pylori.

PMID- 12621085
TI  - Medium pH-dependent redistribution of the urease of Helicobacter pylori.
AB  - Helicobacter pylori is an aetiological agent of gastric disease. Although the
      role of urease in gastric colonization of H. pylori has been shown, it remains
      unclear as to where urease is located in this bacterial cell. The purpose of this
      study was to define the urease-associated apparatus in the H. pylori cytoplasm.
      H. pylori was incubated at both a neutral and an acidic pH in the presence or
      absence of urea and examined by double indirect immunoelectron microscopy. The
      density of gold particles for UreA was greatest in the inner portion of the wild
      type H. pylori cytoplasm at neutral pH but was greatest in the outer portion at
      acidic pH. This difference was independent of the presence of urea and was not
      observed in the ureI-deletion mutant. Also, the eccentric shift of urease in
      acidic pH was not observed in UreI. After a 2 day incubation period at acidic pH,
      it was observed that the urease gold particles in H. pylori assembled and were
      associated with UreI gold particles. Urease immunoreactivity shifted from the
      inner to the outer portion of H. pylori as a result of an extracellular decrease
      in pH. This shift was urea-independent and UreI-dependent, suggesting an
      additional role of UreI in urease-dependent acid resistance. This is the first
      report of the intracellular transport of molecules in bacteria in response to
      changes in the extracellular environment.

PMID- 12621088
TI  - Detection of seven Candida species using the Light-Cycler system.
AB  - Due to the limitations of classical methods for the detection of systemic fungal
      infections and the high mortality rates associated with these infections, it has
      become essential to develop a quick, sensitive and specific detection assay. By
      using the Idaho Technologies Light-Cycler system, a qualitative real-time PCR
      system has been developed for the detection of the leading causes of systemic
      infection within the genus Candida. The sensitivity of the assay was comparable
      to previously described PCR methods (1-5 c.f.u. ml(-1)) and, by the use of a
      single Candida probe, it was able to detect, but not differentiate between, seven
      species of Candida (Candida albicans, Candida dubliniensis, Candida glabrata,
      Candida kefyr, Candida krusei, Candida parapsilosis and Candida tropicalis).
      Single-round amplification on the Light-Cycler allowed rapid turn-around of
      clinical samples (within one working day) and it was shown to be more sensitive
      than classical procedures, exposing 39 possible systemic infections that were not
      detected by blood culture.

PMID- 12621087
TI  - Enhancement of DNA vaccine potency against herpes simplex virus 1 by co
      administration of an interleukin-18 expression plasmid as a genetic adjuvant.
AB  - In this study, the immune-modulatory and vaccine effects of using an interleukin
      (IL)-18 expression plasmid as a genetic adjuvant to enhance DNA vaccine-induced
      immune responses were investigated in a mouse herpes simplex virus 1 (HSV-1)
      challenge model. BALB/c mice were immunized by three intramuscular inoculations
      of HSV-1 glycoprotein D (gD) DNA vaccine alone or in combination with a plasmid
      expressing mature IL-18 peptide. Both the serum IgG2a/IgG1 ratio and T helper 1
      type (Th1) cytokines [IL-2 and interferon (IFN)-gamma] were increased
      significantly by the co-injection of the IL-18 plasmid compared with the
      injection of gD DNA alone. However, the production of IL-10 was inhibited by IL
      18 plasmid co-injection. Furthermore, IL-18 plasmid co-injection efficiently
      enhanced antigen-specific lymphocyte proliferation and the delayed-type
      hypersensitivity response. When mice were challenged with HSV-1 at the cornea, co
      injection of IL-18 plasmid with gD DNA vaccine showed significantly better
      protection, manifested as lower corneal lesion scores and faster recovery. These
      experiments indicate that co-injection of an IL-18 plasmid with gD DNA vaccine
      efficiently induces Th1-dominant immune responses and improves the protective
      effect against HSV-1 infection.

PMID- 12621089
TI  - Characterization of rifampicin-resistant Mycobacterium tuberculosis in Taiwan.
AB  - Sixty-three rifampicin-resistant (Rif(r)) isolates of Mycobacterium tuberculosis
      from Kaohsiung, Taiwan, were analysed for mutations in the core region (69 bp,
      codons 511-533) of the rpoB gene. Some 84.1 % (53/63) of the resistant isolates
      showed mutations in this region, especially in codons 531 (41.5 %), 526 (18.9 %),
      516 (15.1 %) and 533 (7.5 %). Five novel alleles of a total of 16 different types
      of mutations were identified in Rif(r) isolates. Ten Rif(r) isolates (15.9 %)
      exhibited no mutations in the core region of rpoB. Also, they did not show
      mutations in another 365 bp fragment (codons 99-220) of rpoB. The agar proportion
      method was used to determine the relationship between the degree of rifampicin
      resistance and alterations in the core region of rpoB. The results revealed that
      the mean MIC was 92.38 micro g ml(-1) for the 53 isolates with a mutation in the
      core region, whereas the mean MIC of the other 10 isolates without mutations was
      only 24.8 micro g ml(-1). This indicates that the isolates with mutations in the
      core region had higher levels of resistance than those without mutations in this
      region. IS6110 restriction fragment length polymorphism (RFLP) was used for
      typing of 55 Rif(r) M. tuberculosis isolates. Isolates contained two to 19 copies
      of IS6110, with sizes ranging from 600 to 16 000 bp. The majority (85 %)
      contained six to 16 copies. No strains lacking IS6110 were found. A total of 54
      of 55 RFLP types were defined at the 90 % similarity level. The observation of
      varied IS6110-associated banding patterns indicates that an outbreak of drug
      resistant tuberculosis did not occur in this area.

PMID- 12621090
TI  - Effect of antimycotic agents on the activity of aspartyl proteinases secreted by
      Candida albicans.
AB  - The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors
      amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole,
      amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by
      Candida albicans was tested in an in vitro spectophotometric assay. As expected,
      both HIV proteinase inhibitors showed a significant inhibitory effect on Sap
      activity, which was comparable to that of the classical aspartyl proteinase
      inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole,
      terbinafine and amphotericin B had no, or only minor, inhibitory effects on
      proteolytic activity. In contrast, a significant reduction in Sap activity could
      be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P <
      0.001). These results point to a multiple effect of this antimycotic agent and
      might explain the reduced adherence of C. albicans to human epithelial cells at
      subinhibitory doses.

PMID- 12621091
TI  - Antimicrobial susceptibility patterns and genomic diversity in strains of
      Streptococcus pyogenes isolated in 1978-1997 in different Brazilian cities.
AB  - Penicillin has been the antimicrobial of choice for the treatment of
      Streptococcus pyogenes infections for almost six decades. Although penicillin
      resistant isolates have not been described to date, clinical failures have been
      reported after treatment with beta-lactams. In this study, we analysed the
      antimicrobial susceptibility and genetic diversity of S. pyogenes isolates
      obtained from healthy carriers or patients in different cities in the south and
      south east of Brazil. The MICs were determined for penicillin and seven other
      antimicrobials. Penicillin tolerance was also investigated. Genetic diversity was
      analysed by PFGE after SmaI fragmentation of the genomic DNA. All 211 isolates
      tested were susceptible to penicillin (MIC 0.0025-0.02 mg l(-1)). Four isolates
      were moderately penicillin-tolerant (MBC/MIC = 16 mg l(-1)). Most of the other
      drugs tested were very active against the strains examined, except for
      tetracycline, to which 50 % of strains were resistant. We also found extensive
      genetic diversity, in that 60 different patterns were recognized in the 96
      strains studied. Indeed, we found no correlation between tetracycline resistance
      and clonality. Despite this diversity, some PFGE patterns persisted for up to 18
      years and specific clone types were spread over different geographical locations

PMID- 12621092
TI  - Changes in sensitivity patterns to selected antibiotics in Clostridium difficile
      in geriatric in-patients over an 18-month period.
AB  - Clostridium difficile-associated disease continues to be a major problem in
      hospitals and long-term care facilities throughout the developed world.
      Administration of certain antibiotics such as amoxycillin, oral cephalosporins
      and clindamycin is associated with the greatest risk of developing C. difficile
      disease. The two antibiotics used for treatment of C. difficile disease are
      vancomycin and metronidazole, to which there is currently very little resistance.
      Randomly selected isolates (186) from 90 patients being investigated during an 18
      month epidemiological study into the disease were tested for their susceptibility
      to vancomycin, metronidazole, amoxycillin, clindamycin, cefoxitin and ceftriaxone
      by the NCCLS agar dilution method. There was a narrow range of MIC for the two
      treatment agents (vancomycin and metronidazole), from 0.5 to 4 microg ml(-1),
      with no evidence of resistance. All strains were resistant to cefoxitin (MIC 64
      256 microg ml(-1)), the antibiotic used in most selective media. All strains were
      of similar sensitivity to amoxycillin (MIC(90)= 4 microg ml(-1)). Most strains
      were resistant to ceftriaxone (MIC > or = 64 microg ml(-1)) or of intermediate
      resistance (MIC > or = 32 microg ml(-1)), with only two sensitive strains (MIC 16
      microg ml(-1)). Clindamycin resistance was common, with 67 % of strains resistant
      (MIC > or = 8 microg ml(-1)), 25 % with intermediate resistance (MIC > or = 4
      microg ml(-1)) and only 8 % sensitive (MIC < or = 2 microg ml(-1)). Twelve
      isolates from six different patients had very high resistance to clindamycin (MIC
      > or = 128 microg ml(-1)). Multiple isolates from the same patient, taken at
      different times, showed changes in susceptibility patterns over time. The only
      major change in susceptibility over the time-period was in clindamycin
      resistance; some strains appeared to become more resistant while others became
      less resistant. No differences were seen in the MIC(50) and MIC(90) of the
      different S-types of C. difficile identified, although some S-types were present
      in very small numbers. There was no correlation between the antibiotics
      prescribed and susceptibility.

PMID- 12621093
TI  - Chlamydia pneumoniae infection in adult patients with persistent cough.
AB  - Chlamydia pneumoniae is a frequent causative agent of acute respiratory disease.
      To assess whether C. pneumoniae plays a role in persistent cough, the prevalence
      of C. pneumoniae infection in adult patients with persistent cough was
      investigated. Nasopharyngeal swabs and serology samples from 366 adult patients
      with a persistent cough lasting in excess of 2 weeks and 106 control subjects
      were analysed for bacterial isolation and by PCR. C. pneumoniae was isolated from
      two patients and from none of the controls and was detected by PCR in 20 patients
      and one control. Serological evidence of acute C. pneumoniae infection was
      present in 24 patients but in none of the controls. Of these 20 patients who were
      positive by culture and/or PCR, three were still positive by PCR after 2 weeks of
      treatment with clarithromycin and symptoms either continued or relapsed. However,
      when patients were treated with clarithromycin for 5-6 weeks, their symptoms
      disappeared completely and the results of their cultures and/or PCR for C.
      pneumoniae became negative. These data suggest that C. pneumoniae infection may
      cause persistent cough in adults. Furthermore, these data also indicate that it
      may be necessary to eradicate the organism when C. pneumoniae is detected by
      culture and/or PCR in patients with persistent cough.

PMID- 12621095
TI  - Usefulness of a new Doppler index for assessing both ventricular functions and
      pulmonary circulation in newborn piglet with hypoxic pulmonary hypertension.
AB  - Persistent pulmonary hypertension of the newborn is a clinical syndrome
      associated with a variety of cardiopulmonary diseases. Serial evaluation of
      pulmonary circulation and cardiac function is important, but available imaging
      techniques have been limited. A new Doppler index combining systolic and
      diastolic time intervals (the Tei index, which is a simple and noninvasive
      measurement) has been reported to be useful for the assessment of global cardiac
      function in adults and children. The purpose of this study was to test the
      effectiveness of the Tei index in prospectively assessing ventricular function
      and pulmonary circulation in a newborn piglet model with hypoxic pulmonary
      hypertension. One-day-old piglets (1.1-1.6 kg) were intubated and prepared for
      the experiments under room air and hypoxia. A complete two-dimensional Doppler
      echocardiographic examination was performed. Common hemodynamic variables were
      measured continuously throughout the study. The right ventricle (RV) Tei index
      under hypoxia (fraction of inspired oxygen = 0.10) was significantly higher than
      the value under air ventilation (medians, 0.38 versus 0.56; p < 0.05). Moreover,
      there was a significant correlation between RV Tei index and mean pulmonary
      artery pressure and positive linear correlation between individual changes in RV
      Tei index and changes in mPAP (r2 = 0.799, p < 0.05). We conclude that the Tei
      index is useful for assessing the function of the RV and the left ventricle and
      pulmonary circulation in a newborn piglet model with hypoxic pulmonary
      hypertension. These results suggest that the Tei index will become an objective
      method of assessing patients with persistent pulmonary hypertension of the
      newborn.

PMID- 12621094
TI  - Disseminated cryptococcosis in an AIDS patient caused by a canavanine-resistant
      strain of Cryptococcus neoformans var. grubii.
AB  - A case of disseminated cryptococcosis caused by Cryptococcus neoformans var.
      grubii is presented in a male diabetic who had AIDS. The diagnosis was based upon
      the isolation and identification of the aetiological agent from a lymph-node
      biopsy, cerebrospinal fluid and sputum. The isolate formed spherical,
      encapsulated yeast cells, produced cherry-brown colonies on niger-seed agar, grew
      on canavanine-glycine-bromothymol blue (CGB) medium, changing its colour from
      greenish yellow to blue, and hydrolysed urea weakly in the presence of 100 microM
      EDTA. The strain was unable to assimilate D-proline and, serologically, it was
      untypable. The identity of the isolate as C. neoformans var. grubii, serotype A,
      possessing a mating-type allele A alpha, was confirmed by crossing with standard
      laboratory test strains and by performing PCR with the mating-type alpha allele
      specific primer of the STE12 gene and with serotype (A and D)- and mating type (a
      and alpha)-specific primers of the STE20 gene. To the best of our knowledge, this
      is the first report of disseminated cryptococcosis in an AIDS patient caused by a
      canavanine-resistant strain of C. neoformans var. grubii, serotype A, possessing
      mating type allele A alpha; the strain is probably a hybrid. The report suggests
      that, in the absence of a clear-cut serotyping result, a positive CGB reaction
      alone is not sufficient for intervarietal discrimination and additional
      confirmatory evidence is required.

PMID- 12621096
TI  - Circadian and sleep development in preterm infants occurs independently from the
      influences of environmental lighting.
AB  - This study investigated the effect of intermediate nursery illumination on
      circadian rhythm and sleep development of preterm infants. Preterm infants were
      randomly assigned to one of two intermediate nursery rooms: a dimly lighted room,
      the dim (control) group, or a day-night lighted room, the cycled (intervention)
      group. Continuous rectal temperature and sleep were recorded at 36 wk
      postconceptional age (before discharge) and at 1 and 3 mo corrected age at home.
      Forty infants, 21 in the dim group and 19 in the cycled group, were recorded. The
      clinical demographic data and neonatal scores were similar between groups before
      the intervention. Circadian rhythms and sleep showed significant development with
      age, but there was no environmental lighting effect. Circadian and sleep
      organization seems to develop endogenously in preterm infants.

PMID- 12621097
TI  - Glutamate transport by Rcho-1 cells derived from rat placenta.
AB  - Marginal giant cells within the rodent placenta are important sources of
      androgens, critical to maintenance of pregnancy. Androgen synthesis requires
      NADPH, a by-product of glutamate oxidation. We examined the uptake of glutamate
      into rat choriocarcinoma cells, which have been shown to maintain many of the
      characteristics of marginal giant cells in culture. Na+-dependent, d-aspartate
      inhibitable uptake consistent with System XAG- mediated transport was present, as
      were proteins capable of System XAG- activity, EAAC1, GLAST1, and GLT1. Glutamate
      uptake in rat choriocarcinoma cells was up-regulated by amino acid deprivation-a
      response that was not reversed by the addition of glutamate to the media.
      Inhibition data suggested up-regulation of transport activity mediated by either
      EAAC1 or GLAST1 at 6 h, whereas at 24 and 48 h, up-regulation of GLT1 plays an
      increasing role. Levels of EAAC1 immunoreactive protein increased with time under
      amino acid depleted conditions, whereas those of GLAST1 and GLT1 remained stable
      or declined but not significantly.

PMID- 12621098
TI  - Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced
      hydrocephalus.
AB  - Hydrocephalus causes damage to periventricular white matter at least in part
      through chronic ischemia. Magnesium sulfate (MgSO4) has been shown to be
      protective in various models of neurologic injury. We hypothesized that this
      agent would ameliorate the effects of experimental childhood-onset hydrocephalus.
      Hydrocephalus was induced in 3- and 4-wk-old rats by injection of kaolin into the
      cisterna magna. Tests of cognitive and motor function were performed on a weekly
      basis. In a blinded and randomized manner, MgSO4 was administered in two separate
      experiments (s.c. injection 0.85, 4.1, or 8.2 mM/kg/d), supplemented by osmotic
      minipump infusion (0.03 mM/d) to prevent low trough levels for 2 wk, beginning 2
      wk after induction of hydrocephalus. The brains were then subjected to
      histopathological and biochemical analyses. With the 4.1 mM/kg/d dose, serum Mg++
      levels were elevated transiently from 1.3 to approximately 7 mM/L. We observed
      statistically significant improvement in gait performance and reduced astroglial
      reaction. There was also a trend to improved memory performance, but no evidence
      of increased myelin or synaptic protein content. The 8.2 mM/kg/d dose was
      associated with sedation and there was no evidence of improvement in any
      parameter. We conclude that MgSO4 might be mildly protective in experimental
      hydrocephalus.

PMID- 12621099
TI  - Transient intrauterine hypotension causes apoptosis in fetal rat brain and
      affects learning.
AB  - Hypotensive episodes are frequent during pregnancy, and their functional effect
      on fetal brain has not been studied. We produced systemic hypotension for 30 min
      during mid-gestation in pregnant rats and examined their offspring on postnatal
      days 1 and 28. When compared with sham controls, the brain of the hypotensive
      group contained more TUNEL-positive cells in the hippocampal and periventricular
      regions on both time points. Spatial learning assessed by water milk maze test
      was impaired in 28-day-old pups of the hypotensive mothers. According to these
      results, transient maternal hypotension can induce apoptotic cell death in fetal
      brain and affect learning. Similar mechanisms may be considered and investigated
      in the pathogenesis of human learning disorders.

PMID- 12621100
TI  - The effects of bilirubin on evoked potentials and long-term potentiation in rat
      hippocampus in vivo.
AB  - Neonatal jaundice is a common condition that could potentially lead to severe
      neurotoxicity. In this electrophysiological study we observed the effects of a
      short-term bilirubin injection on evoked potentials (population spike, PS) and
      long-term potentiation (LTP) in the hippocampal CA3 region of Sprague Dawley rats
      in vivo. The animal received a bolus i.v. injection of either 60 mg/kg, or 30
      mg/kg of bilirubin, or an equivalent volume of bilirubin-free vehicle in 5 min.
      The results showed that both bilirubin-treated groups had a dose-independent
      prolongation of peak latencies and decrease of slopes of the PS at all measured
      time points following injection (1, 3, 5, 10, 15, 30, 45, 60, 90, 120 min), while
      the amplitudes of the PS did not change significantly. The peak latency, slope,
      and the amplitude of PS stayed unchanged in the control group. Furthermore, while
      LTP could be induced by high-frequency stimulation in control animals, this
      phenomenon was absent in both bilirubin-treated groups. The amplitudes of the PS
      in the two treated groups after stimulation were also smaller than those of the
      control animals at every time points. These findings are in accordance with
      previous observations showing significant depressive effects of bilirubin on the
      nervous system. Our novel finding that short-term exposure to bilirubin can
      inhibit the induction of LTPs in the hippocampus, is compatible with the
      suggestion that neonatal hyperbilirubinemia can impact on learning and memory.

PMID- 12621101
TI  - Cardiac hypertrophy and altered hemodynamic adaptation in growth-restricted
      preterm infants.
AB  - The objective was to elucidate hemodynamic adaptation in very low birth weight
      (<1500 g) infants after intrauterine growth retardation. 31 growth-retarded (SGA,
      birth weight <-2 SD) and 32 appropriate for gestational age (AGA, birth weight
      within +/- 1 SD range) infants were enrolled. In SGA infants, the diastolic
      diameters of the interventricular septum and the left ventricle were increased,
      and serum brain natriuretic peptide (BNP) was elevated. Left ventricular output
      (LVO) of the AGA infants increased from 150 +/- 28 to 283 +/- 82 mL/kg/min during
      the study (p < 0.01). The SGA infants had a higher initial LVO than the AGA
      infants (243 +/- 47 versus 150 +/- 28 mL/kg/min, p < 0.05), but did not show
      further LVO increase during the study period. Red cell (RCV) and blood (BV)
      volume were assessed by Hb subtype analysis, when packed donor red cells were
      transfused. RCV and BV did not differ between the groups initially, but RCV
      increased by 18% and BV by 29% in the AGA group during the first 3 d. On day 3,
      AGA infants had larger BV than the SGA infants (88 +/- 5 versus 73 +/- 12 mL/kg,
      p < 0.05). In conclusion, cardiac hypertrophy, elevated initial LVO and BNP of
      the SGA infants suggest increased cardiac workload after intrauterine growth
      retardation. Based on the BV and RCV data, blood volume regulation may also be
      impaired. The data suggest that SGA preterm infants may be exposed to an
      increased risk of circulatory failure during early adaptation.

PMID- 12621102
TI  - Insights into the genetic and molecular basis of primary pulmonary hypertension.
AB  - The pathogenesis of primary pulmonary hypertension (PPH) remains poorly
      understood. Molecular genetic studies have identified that mutations within the
      gene BMPR2 on the long arm of chromosome 2 underlie familial PPH. This review
      explores the significance of the PPH gene identification and examines additional
      genetic determinants, emphasizing the immediate implications for assessment and
      management of patients and their relatives.

PMID- 12621103
TI  - Plasminogen activator inhibitor-1 in patients with Kawasaki disease: diagnostic
      value for the prediction of coronary artery lesion and implication for a new mode
      of therapy.
AB  - Kawasaki disease (KD) in children takes the form of acute systemic vasculitis,
      which causes coronary artery dilation and aneurysm formation in 10% to 15% of the
      patients. We have recently shown that matrix metalloproteinases (MMPs) are
      intimately involved in coronary arterial wall destruction and the resultant
      formation of coronary artery lesions (CALs) in this disease. Plasminogen
      activators (PAs) are known to be a major pathway of MMP activation, and this
      suggests that their inhibitor, plasminogen activator inhibitor-1 (PAI-1), also
      plays important roles in the development of CALs in KD. The present study was
      conducted to test the hypothesis that circulating levels of PAI-I are related to
      CAL formation in KD. Plasma levels of PAI-1 were measured by enzyme-linked
      immunoassay in 37 KD patients without CALs (group 1) and 7 KD patients with CALs
      (group 2). Blood samples were obtained before and after i.v. gammaglobulin
      therapy (IVGG), and in the convalescent stage. Levels of PAI-1 were significantly
      higher in KD patients before IVGG than in 18 age-matched healthy control subjects
      (p < 0.01). More importantly, both pre-IVGG and post-IVGG levels of PAI-1 were
      significantly higher in group 2 than in group 1 (p < 0.01). Furthermore, PAI-1
      levels of 9 patients from group 1 who showed pre-IVGG PAI-1 levels higher than
      the minimum PAI-1 level in group 2 significantly decreased after IVGG, whereas
      PAI-1 levels of group 2 patients remained persistently elevated, further
      suggesting a close association between PAI-1 and CAL development in KD. Thus, PAI
      1 may be useful as a predictive marker for CAL development in KD. Studies of the
      effects of PA inhibition on coronary outcome may provide evidence that PA is a
      viable therapeutic target for the prevention of KD-related CALs.

PMID- 12621104
TI  - Hypothyroidism increases osmotic water permeability (Pf) in the developing renal
      brush border membrane.
AB  - The osmotic water permeability (Pf) of the rabbit proximal tubule brush border
      membrane vesicles (BBMV) increases during maturation and is mediated by an
      increase in aquaporin-1 (AQP1) protein expression. Serum thyroid hormone levels
      increase after birth and have been shown to play a role in the maturation of
      other renal transport functions. We examined the hypothesis that thyroid hormone
      plays a role in the maturational increase in osmotic water permeability.
      Hypothyroidism was induced by addition of 0.1% propylthiouracil (PTU) to the
      drinking water of pregnant rabbits (starting 9 d before delivery) and was
      continued until the rabbits were studied as adults (9-11 wk). Some animals
      received thyroid hormone replacement by daily injection with triiodothyronine
      (T3; 10 microg/100 g body weight) for three days before study. Pf was found to be
      higher in BBMV from hypothyroid (82.7 +/- 5.5 microm/s) than from euthyroid (60.6
      +/- 4.0 microm/s) and T3-replacement rabbits (69.0 +/- 5.0 microm/s) (p < 0.05).
      The activation energy (Ea; in kcal/deg.mol) of Pf was not different among the
      three experimental groups (euthyroid 5.6 +/- 0.9, hypothyroid 4.9 +/- 0.8, T3
      replacement 5.0 +/- 1.0; p = NS), nor was the percentage mercury inhibition of Pf
      (euthyroid 66.5 +/- 5.3, hypothyroid 74.2 +/- 3.2 and T3-replacement 73.1 +/-
      4.3; p = NS). AQP1 expression, measured by immunoblotting, was highest in BBMV
      from hypothyroid rabbits (p < 0.05). Membrane fluidity, measured as steady-state
      generalized polarization (GP) of Laurdan, which is inversely related to membrane
      fluidity, was significantly different between the three groups (GP: euthyroid
      0.307 +/- 0.004, hypothyroid 0.271 +/- 0.004 and T3-replacement 0.287 +/- 0.003;
      for all p < 0.05). These data demonstrate that the maturational increase in
      thyroid hormone levels is not responsible for the maturational increase in water
      transport. Surprisingly, congenital hypothyroidism in rabbits is associated with
      an increased Pf when rabbits are studied as adults. The higher Pf in hypothyroid
      adult rabbits is due to a higher expression of AQP1 protein as well as a greater
      membrane fluidity than in euthyroid rabbits.

PMID- 12621105
TI  - Changes in neurotrophin levels in umbilical cord blood from infants with
      different gestational ages and clinical conditions.
AB  - Apoptotic neuronal loss may be responsible for altered brain development
      associated with prematurity and perinatal insults. Neurotrophins play crucial
      roles in protecting neurons from entering or progressing along an apoptotic
      pathway. The present study examined levels of neurotrophins in human umbilical
      cord blood from infants at different gestational ages and clinical conditions. We
      collected 60 samples of cord blood and categorized them accordingly into three
      gestational age groups: group A (24-28 wk), group B (29-35 wk), and group C
      (>/=36 wk). Neurotrophin levels were determined by using brain-derived
      neurotrophic factor (BDNF) and neurotrophin 3 (NT3) ELISA. Clinical data were
      obtained by medical chart analysis. The BDNF levels were 884 +/- 386, 1421 +/-
      616, and 2190 +/- 356 pg/mL in group A, group B, and group C, respectively.
      Significant differences were found between groups A and B (p = 0.038), groups A
      and C (p = 0.0001), and groups B and C (p = 0.001). Infants with severe
      intraventricular hemorrhage had significantly lower cord blood BDNF levels (925
      +/- 513 pg/mL) compared with their normal counterparts (1650 +/- 674 pg/mL; p =
      0.021). NT3 levels did not show significant change either across gestational ages
      or with the presence of intraventricular hemorrhage. Cord blood levels of BDNF
      may reflect the degree of neural maturity in premature infants. Interestingly,
      when a complete course of antenatal steroids was given, BDNF and NT3 cord blood
      levels were higher than when no steroid was given. Increased neurotrophins levels
      may also mediate improved neurodevelopmental outcome in infants who received
      antenatal steroids.

PMID- 12621107
TI  - Etiology of congenital diaphragmatic hernia: the retinoid hypothesis.
AB  - Congenital diaphragmatic hernia (CDH) is a major life-threatening cause of
      respiratory failure in the newborn. Although significant efforts have been
      undertaken to unravel the pathophysiology of CDH, our current understanding of
      the etiology remains spare. Here we outline recent evidence suggesting that
      abnormalities linked with the retinoid signaling pathway early in gestation may
      contribute to the etiology of CDH. These studies include 1) the effect of
      altering the retinoid system in vitamin A deficient and transgenic animals; 2)
      disruption of the retinoid system in teratogen-induced CDH in rodents, 3) the
      effect of co-administration of retinoids in nitrofen-induced CDH on lung and
      diaphragm development, and 4) clinical evidence suggesting decreased markers of
      vitamin A status in human CDH. Given the substantial mortality and morbidity
      associated with this serious developmental anomaly, advancements in this area
      will be critical. We feel that there is now sufficient circumstantial and direct
      experimental evidence to warrant further testing of the retinoid-CDH etiology
      hypothesis, including examination of retinoid-regulated target genes that could
      be candidates for involvement in CDH.

PMID- 12621106
TI  - Catecholamine response to exercise in children with attention deficit
      hyperactivity disorder.
AB  - The objective of this study was to examine differences in catecholamine (CA)
      response to exercise between children who had received a diagnosis of attention
      deficit/hyperactivity disorder (ADHD) and age- and gender-matched controls. On
      the basis of the notion of a CA dysfunction in ADHD, we reasoned that the normal
      robust increase in circulating CA seen in response to exercise would be blunted
      in children with ADHD. To test this, we recruited 10 treatment-naive children
      with newly diagnosed ADHD and 8 age-matched controls (all male) and measured CA
      response to an exercise test in which the work was scaled to each subject's
      physical capability. After exercise, epinephrine and norepinephrine increased in
      both control and ADHD subjects (p = 0.006 and p = 0.002, respectively), but the
      responses were substantially blunted in the ADHD group (p = 0.018) even though
      the work performed did not differ from controls. Circulating dopamine increased
      significantly in the control subjects (p < 0.016), but no increase was noted in
      the subjects with ADHD. Finally, a significant attenuation in the lactate
      response to exercise was found in ADHD (between groups, p < 0.005). Our data
      suggest that CA excretion after exercise challenges in children with ADHD is
      deficient. This deficiency can be detected using a minimally invasive,
      nonpharmacologic challenge.

PMID- 12621112
TI  - Genetics and the pathophysiology of obesity.
AB  - Obesity is a complex disease that involves interactions between environmental and
      genetic factors. Obesity results from an imbalance between food intake and energy
      expenditure over several years. The genetic approach both in animal models and in
      humans has allowed immense progress in the understanding of body weight
      regulation. Monogenic forms of obesity in humans have been characterized and
      result from mutations in genes involved in the central pathways of food intake
      regulation. However, these cases are extremely rare and generally obesity must be
      considered as a complex polygenic disease involving interactions between multiple
      genes and the environment. Numerous studies, including studies in children, have
      tried to identify "susceptibility" genes. At present, the results are not
      conclusive inasmuch as they are highly variable between studies and because the
      relative risk associating a specific gene allele and obesity remains low. Thus,
      it seems highly premature to genotype obese patients on a large scale for
      predictive testing. When specific pharmacological treatments based on recent
      discoveries become available, however, genetic testing could help discriminate
      between the subtypes of obesity that may respond differentially to treatment.

PMID- 12621113
TI  - Neonatal blood plasma is less susceptible to oxidation than adult plasma owing to
      its higher content of bilirubin and lower content of oxidizable Fatty acids.
AB  - Newborn infants are susceptible to a range of problems attributed to excessive
      production of free radicals. Because of a higher content of antioxidants, above
      all bilirubin, and a lower content of oxidizable lipids, newborn plasma should be
      better protected against oxidation than adult plasma. To test this hypothesis, we
      measured the susceptibility of plasma to in vitro oxidation in microsamples (7
      microL) from 57 healthy newborns and 18 adults. Heparin plasma was diluted 150
      fold and oxidized by 50 microM Cu2+. Oxidation was monitored as an increase in
      sample absorbance at 234 nm. Plasma oxidizability was found to be significantly
      lower in newborns than in adults. Accordingly, the level of bilirubin, an
      important antioxidant, was significantly higher, and the level of polyunsaturated
      fatty acids, a major substrate of lipid peroxidation, was significantly lower in
      newborn plasma. In addition, plasma oxidizability correlated positively with the
      level of polyunsaturated fatty acids and negatively with that of bilirubin. These
      data indicate that plasma is better protected against oxidative stress in
      newborns than in adults, owing to its higher content of antioxidants like
      bilirubin and its lower content of oxidizable lipids.

PMID- 12621115
TI  - Chronic prenatal nicotine exposure alters enkephalin mRNA regulation in the
      perinatal rat adrenal medulla.
AB  - Prenatal exposure to nicotine significantly increases enkephalin mRNA levels in
      the rat adrenal medulla prenatally, and postnatally the normal up-regulation is
      obliterated. This may lead to a disturbed modulation or regulation of
      catecholamine release in the adrenal and may be one factor contributing to the
      attenuated capacity of nicotine-treated pups to survive severe hypoxia. We
      speculate that this may be part of the mechanism underlying the relation between
      maternal smoking and sudden infant death syndrome.

PMID- 12621114
TI  - Perinatal bone turnover in term human neonates and the influence of maternal
      smoking.
AB  - Bone turnover in neonates appears independently of the comparably low maternal
      bone turnover, but there is only sparse information on the effect of the in utero
      environment on fetal bone turnover. Postnatally, the resuming growth velocity and
      alterations in mineral homeostasis affect neonatal bone turnover. This study
      evaluated the relationship of bone marker concentrations to maternal and fetal
      auxological variables as well as maternal smoking and assessed the short-term
      change in bone markers during the first days of life. Serum markers of bone
      formation [osteocalcin and bone-specific alkaline phosphatase (BALP)] and bone
      resorption (C-terminal telopeptide of type I collagen) were measured in cord
      blood and at discharge (median d 3) in 69 healthy term neonates. Concentrations
      of BALP were significantly lower in neonates of smokers (n = 16) compared with
      nonsmokers (n = 53), both at birth (p = 0.013) and at discharge (p = 0.036). Both
      cord osteocalcin and BALP were negatively related to maternal weight and maternal
      body mass index. Maternal smoking and pregnancy weight gain were the predictors
      of cord BALP (r2 = 0.24; p < 0.001), whereas the mode of delivery best predicted
      cord C-terminal telopeptide of type I collagen levels (r2 = 0.19; p < 0.001). C
      terminal telopeptide of type I collagen and osteocalcin increased significantly
      (p < 0.001) from birth to discharge, whereas BALP levels did not change
      significantly during the same period. Our results suggest that maternal smoking
      during pregnancy and maternal obesity may have a negative impact on fetal bone
      formation. The significant increase of osteocalcin and C-terminal telopeptide of
      type I collagen may result either from an increase in bone turnover or altered
      renal clearance.

PMID- 12621116
TI  - Differential effect of DCA treatment on the pyruvate dehydrogenase complex in
      patients with severe PDHC deficiency.
AB  - Dichloroacetate (DCA) is a structural analog of pyruvate that has been
      recommended for the treatment of primary lactic acidemia, particularly in
      patients with pyruvate dehydrogenase (PDHC) deficiency. Recent reports have
      demonstrated that the response to DCA may depend on the type of molecular
      abnormality. In this study, we investigated the response to DCA in various PDHC
      deficient cell lines and tried to determine the mechanism involved. The effect of
      chronic 3-d DCA treatment on PDHC activity was assessed in two PDHC-deficient
      cell lines, each with a different point mutation in the E1alpha subunit gene
      (R378C and R88C), and one cell line in which an 8-bp tandem repeat was deleted
      (W383 del). Only two (R378C and R88C) of the three PDHC-deficient cell lines with
      very low levels of PDHC activity and unstable polypeptides were sensitive to
      chronic DCA treatment. In these cell lines, DCA treatment resulted in an increase
      in PDHC activity by 125 and 70%, respectively, with concomitant increases of 121
      and 130% in steady-state levels of immunoreactive E1alpha. DCA treatment reduced
      the turnover of the E1alpha subunit in R378C and R88C mutant cells with no
      significant effect on the E1beta subunit. Chronic DCA treatment significantly
      improved the metabolic function of PDHC in digitonin-permeabilized R378C and R88C
      fibroblasts. The occurrence of DCA-sensitive mutations suggests that DCA
      treatment is potentially useful as an adjuvant to ketogenic and vitamin treatment
      in PDHC-deficient patients.

PMID- 12621117
TI  - Effect of L-carnitine supplementation on cardiac carnitine palmitoyltransferase
      activities and plasma carnitine concentrations in adriamycin-treated rats.
AB  - Adriamycin (ADR) inhibits the carnitine palmitoyl transferase (CPT) system and
      consequently the transport of long-chain fatty acids across mitochondrial
      membranes. l-Carnitine (CARN) plays a major role in fatty acid oxidation by
      translocating activated long-chain fatty acids into the matrix of mitochondria.
      CARN has been shown to be of benefit in certain cardiac conditions including
      cardiomyopathy and myocardial infarction. This study was devised to investigate
      the effect of CARN on altered CPT I and CPT II activity in the cardiomyopathy
      associated with ADR therapy. We also assessed the effect of CARN on the plasma
      free, total, and acylcarnitine concentrations. Four groups, each consisting of
      four male Sprague-Dawley rats, were studied: group 1(n = 4) was not given either
      ADR or CARN; group 2 (n = 4) was given ADR (15 and 20 mg/kg, respectively,
      cumulative dose) by i.p. injections for 1 and 2 wk; group 3 (n = 4) was given the
      same dose of ADR with CARN (200 mg/kg); and group 4 (n = 4) was given CARN (200
      mg/kg). The activities of CPT I and CPT II in heart were significantly decreased
      in the ADR-treated rats (p < 0.05) in a dose-dependent manner. The reduced
      activities of CPT I and CPT II, inhibited by ADR, were not normalized by
      supplementation with CARN (p < 0.05). In rats supplemented with CARN alone, the
      activities of CPT I and CPT II were elevated approximately 50% above those of the
      control rats (p < 0.05). ADR treatment resulted in elevation of plasma free and
      total CARN concentrations (p < 0.05). Supplementation with CARN did not effect
      the increased plasma CARN concentrations resulting from ADR treatment (p < 0.05).
      This study supports the concept that ADR toxicity results from the inhibition of
      both CPT I and CPT II activities and that one of the causes of ADR-induced
      cardiomyopathy is a result of globally impaired fatty acid oxidation.

PMID- 12621118
TI  - Increased fibronectin expression in sturge-weber syndrome fibroblasts and brain
      tissue.
AB  - Sturge-Weber syndrome (SWS) is a neurocutaneous disorder that presents with a
      facial port-wine stain and a leptomeningeal angioma. Fibronectin expression
      regulates angiogenesis and vasculogenesis and participates in brain tissue
      responses to ischemia and seizures. We therefore hypothesized that abnormal gene
      expression of fibronectin and other extracellular matrix genes would be found in
      SWS brain tissue and SWS port-wine skin fibroblasts. Fibronectin gene and protein
      expression from port-wine-derived fibroblasts were compared with that from normal
      skin-derived fibroblasts of four individuals with SWS using microarrays, reverse
      transcriptase-PCR, Western analysis, and immunocytochemistry. Fibronectin gene
      and/or protein expression from eight SWS surgical brain samples was compared with
      that in two surgical epilepsy brain samples and six postmortem brain samples
      using microarrays, reverse transcriptase-PCR, and Western analysis. The gene
      expression of fibronectin was significantly increased (p < 0.05) in the SWS port
      wine-derived fibroblasts compared with that of fibroblasts from SWS normal skin.
      A trend for increased protein levels of fibronectin in port-wine fibroblasts was
      found by Western analysis. No difference in the pattern of fibronectin staining
      was detected. The gene expression of fibronectin was significantly increased (p <
      0.05), and a trend for increased fibronectin protein expression was found in the
      SWS surgical brain samples compared with the postmortem controls. These results
      suggest a potential role for fibronectin in the pathogenesis of SWS and in the
      brain's response to chronic ischemic injury in SWS. The reproducible differences
      in fibronectin gene expression between the SWS port-wine-derived fibroblasts and
      the SWS normal skin-derived fibroblasts are consistent with the presence of a
      hypothesized somatic mutation underlying SWS.

PMID- 12621120
TI  - Carbenoxolone accelerates maturation of rat intestine.
AB  - The rat undergoes profound maturational changes in the intestinal structure and
      function during the third week of its life. To investigate the role of peripheral
      glucocorticoid metabolism in this process, we studied the postnatal maturation of
      intestinal structure and function. The peripheral metabolism of glucocorticoids
      depends on enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), which is
      responsible for the interconversion of corticosterone to 11-dehydrocorticosterone
      and thus for the modulation of glucocorticoid access to corticosteroid receptors.
      The pups were treated with carbenoxolone (CBX), an inhibitor of 11betaHSD, for 10
      d during the suckling (days 8-18) or weaning period (days 14-24 or days 20-30),
      and we determined the parameters of intestinal growth and activities of sucrase,
      alkaline phosphatase, and Na,K-ATPase. The CBX treatment increased plasma
      concentrations of corticosterone as a result of a significant reduction of
      peripheral degradation of corticosterone catalyzed by 11betaHSD. This also
      stimulated intestinal growth without changing somatic growth. The mucosal cell
      mass was significantly higher in CBX-treated suckling rats, whereas the effect of
      this treatment was less obvious in weanling animals. CBX increased the crypt
      depth and villus height in 18- and 24-d-old pups but not in 30-d-old animals. The
      small intestinal activities of sucrase, alkaline phosphatase, and Na,K-ATPase
      were not influenced by CBX. In contrast, colonic Na,K-ATPase was stimulated by
      CBX. We conclude that the administration of CBX results in acceleration of
      intestinal growth and structural maturation without any influence on the
      developmental pattern of brush-border hydrolases. The results indicate an
      important role of peripheral glucocorticoid metabolism in the regulation of
      intestinal growth during early postnatal life.

PMID- 12621121
TI  - Effect of human breast milk on urinary 8-hydroxy-2'-deoxyguanosine excretion in
      infants.
AB  - During the perinatal period, oxidative stress is intimately involved in
      pathologic processes of serious diseases. Although breast milk contains many
      antioxidants, it is not clear whether breast milk can act as an antioxidant in
      infants in vivo. We compared the oxidative stress levels in total of 41 healthy 1
      mo-old infants by measuring urinary 8-hydroxy-2'-deoxyguanosine, which is one of
      the biomarkers of oxidative DNA damage. These infants were divided into four
      groups according to the type of feeding. Urinary 8-hydroxy-2'-deoxyguanosine
      excretion of the breast-fed group was significantly lower than those of the
      artificial milk dominant mixed-fed group or the bottle-fed group. Our data
      suggest that breast milk, not artificial formula, acts as an antioxidant during
      infancy.

PMID- 12621119
TI  - Iron deficiency alters iron regulatory protein and iron transport protein
      expression in the perinatal rat brain.
AB  - Iron plays an important role in numerous vital enzyme systems in the perinatal
      brain. The membrane proteins that mediate iron transport [transferrin receptor
      (TfR) and divalent metal transporter 1 (DMT-1)] and the iron regulatory proteins
      (IRP-1 and IRP-2) that stabilize their mRNAs undergo regional developmental
      changes in the iron-sufficient rat brain between postnatal day (P) 5 and 15.
      Perinatal iron deficiency (ID) affects developing brain regions nonhomogeneously,
      suggesting potential differences in regional iron transporter and regulatory
      protein expression. The objective of the study was to determine the effect of
      perinatal ID on regional expression of IRP-1, IRP-2, TfR, and DMT-1 in the
      developing rat brain. Gestationally iron-deficient Sprague Dawley rat pups were
      compared with iron-sufficient control pups at P10. Serial 12-mu coronal sections
      of fixed frozen brain from pups on P10 were assessed by light microscopy for IRP
      1, IRP-2, DMT-1, and TfR localization. ID did not change the percentage of cells
      with positive staining for the four proteins in the choroid epithelium, ependyma,
      vascular endothelium, or neurons of the striatum. ID increased the percentage of
      neurons expressing the four proteins in the hippocampus and the cerebral cortex.
      Increased numbers of TfR- and DMT-1-positive cells were always associated with
      increased IRP-positive cells. The P10 rat responds to perinatal ID by selectively
      increasing the number of neurons expressing IRP-regulated transporters in brain
      regions that are rapidly developing, without any change at transport surfaces or
      in regions that are quiescent. Brain iron distribution during ID seems to be
      locally rather than globally regulated.

PMID- 12621122
TI  - Intracisternal application of endotoxin enhances the susceptibility to subsequent
      hypoxic-ischemic brain damage in neonatal rats.
AB  - Perinatal brain damage is associated not only with hypoxic-ischemic insults but
      also with intrauterine inflammation. A combination of antenatal inflammation and
      asphyxia increases the risk of cerebral palsy >70 times. The aim of the present
      study was to determine the effect of intracisternal (i.c.) administration of
      endotoxin [lipopolysaccharides (LPS)] on subsequent hypoxic-ischemic brain damage
      in neonatal rats. Seven-day-old Wistar rats were subjected to i.c. application of
      NaCl or LPS (5 microg/pup). One hour later, the left common carotid artery was
      exposed through a midline neck incision and ligated with 6-0 surgical silk. After
      another hour of recovery, the pups were subjected to a hypoxic gas mixture (8%
      oxygen/92% nitrogen) for 60 min. The animals were randomized to four experimental
      groups: 1) sham control group, left common carotid artery exposed but not ligated
      (n = 5); 2) LPS group, subjected to i.c. application of LPS (n = 7); 3) hypoxic
      ischemic study group, i.c. injection of NaCl and exposure to hypoxia after
      ligation of the left carotid artery (n = 17); or 4) hypoxic-ischemic/LPS study
      group, i.c. injection of LPS and exposure to hypoxia after ligation of the left
      carotid artery (n = 19). Seven days later, neonatal brains were assessed for
      neuronal cell damage. In a second set of experiments, rat pups received an i.c.
      injection of LPS (5 microg/pup) and were evaluated for tumor necrosis factor
      alpha expression by immunohistochemistry. Neuronal cell damage could not be
      observed in the sham control or in the LPS group. In the hypoxic-ischemic/LPS
      group, neuronal injury in the cerebral cortex was significantly higher than in
      animals that were subjected to hypoxia/ischemia after i.c. application of NaCl.
      Injecting LPS intracisternally caused a marked expression of tumor necrosis
      factor-alpha in the leptomeninges. Applying LPS intracisternally sensitizes the
      immature rat brain to a subsequent hypoxic-ischemic insult.

PMID- 12621123
TI  - Meconium aspiration stimulates cyclooxygenase-2 and nitric oxide synthase-2
      expression in rat lungs.
AB  - To study the impact of meconium aspiration on the biosynthesis of prostaglandins
      and nitric oxide, we investigated the effects of intratracheal meconium
      instillation on the expression of cyclooxygenase-1 (COX-1) and -2 (COX-2) and
      endothelial (NOS-3) and inducible (NOS-2) nitric oxide synthase in rat lungs.
      Anesthetized, tracheotomized, and ventilated rats received 3 mL/kg human meconium
      suspension intratracheally (n = 19), and 14 control rats received an equal volume
      of saline. Ten rats were pretreated with indomethacin, and 13 rats were
      pretreated with dexamethasone. The lungs were ventilated with 70% oxygen for 3 h
      after the insult, and the level of COX-1, COX-2, NOS-2, and NOS-3 mRNA in lung
      tissue was analyzed by Northern blot hybridization. Furthermore, the expression
      and localization of the enzyme proteins was analyzed by immunohistochemistry. COX
      1 and NOS-3 were clearly expressed in the lungs of control rats, whereas the
      level of COX-2 and NOS-2 expression was minimal. Meconium administration did not
      affect the expression of COX-1, but COX-2 expression was up-regulated in the
      respiratory epithelium and alveolar macrophages. Meconium also induced up
      regulation of NOS-2 in the pulmonary epithelium, vascular endothelium, and
      macrophages. Indomethacin pretreatment did not affect the enzyme expressions,
      whereas dexamethasone administration significantly inhibited the meconium-induced
      COX-2 and NOS-2 up-regulation. Our data thus indicate that intrapulmonary
      meconium up-regulates lung COX-2 and NOS-2 gene expression, suggesting an
      important role for prostaglandins and nitric oxide in the meconium aspiration
      induced pulmonary inflammation and hemodynamic changes.

PMID- 12621124
TI  - Decreased functional caspase-3 expression in umbilical cord blood neutrophils is
      linked to delayed apoptosis.
AB  - Resolution of inflammatory processes depends on the efficient removal of aging
      neutrophils by the reticuloendothelial system. Neutrophil apoptosis is key to
      this process, and its impairment may contribute to the pathogenesis of chronic
      inflammation. We recently discovered that Fas-mediated apoptosis in umbilical
      cord blood neutrophils was significantly delayed as compared with those of
      adults. Because execution of apoptosis relies on caspases, we used reverse
      transcription PCR, immunoblots, and enzymatic assays to study the integrity of
      several members of those proteases known to mediate Fas-induced apoptosis in
      neutrophils. Our results indicate that diminished expression of caspase-3 mRNA
      and the precursor form of the protein, as well as a lower functional enzymatic
      activity of caspase-3, correlates with delayed apoptosis in umbilical cord blood
      neutrophils. Our data suggest that functional expression of caspase-3 in
      neutrophils may be regulated during ontogeny.

PMID- 12621125
TI  - Accumulation of 3-hydroxy-fatty acids in the culture medium of long-chain L-3
      hydroxyacyl CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein
      deficient skin fibroblasts: implications for medium chain triglyceride dietary
      treatment of LCHAD deficiency.
AB  - Dietary management of long-chain l-3-hydroxyacyl CoA dehydrogenase (LCHAD)
      deficiency involves a regimen that contains adequate carbohydrate, protein, and
      essential lipids, and supplementation with medium-chain fatty acids in the form
      of medium-chain triglycerides, providing energy from fats that bypasses the long
      chain metabolic block. This study analyzes the effects of dietary treatment of
      LCHAD deficiency in an in vitro model. Cultured skin fibroblasts from LCHAD
      deficient and normal individuals were grown in media supplemented with
      physiologic combinations of medium-chain fatty acids octanoate and decanoate, and
      the long-chain palmitate. Medium was removed from the cells after various
      incubation times, and assayed for 3-hydroxy-intermediates of fatty acid
      oxidation. The 3-hydroxy-fatty acids were measured by stable-isotope dilution gas
      chromatography/mass spectrometry. We found that the addition of medium-chain
      fatty acids caused a decrease in the accumulation of long-chain fatty acid
      oxidation intermediates in LCHAD-deficient cells when the cells were incubated in
      untreated medium, and also when they were incubated in this medium with palmitate
      added. Medium with decanoate alone was better at achieving this effect than
      medium with only octanoate added. A 1:3 ratio of octanoate to decanoate worked
      best over an extended time period in LCHAD-deficient cells in untreated medium,
      whereas a 1:1 ratio of octanoate to decanoate worked best in the same cells
      incubated in medium containing palmitate. In all dietary medium-chain
      triglyceride preparations, the ratio of octanoate was greater than that of
      decanoate. Our results suggest that a medium-chain triglyceride preparation that
      is higher in decanoate may be more effective in reducing the accumulation of
      potentially toxic long-chain 3-hydroxy-fatty acids in LCHAD deficiency.

PMID- 12621127
TI  - Clinical, genetic, and biophysical characterization of a homozygous HERG mutation
      causing severe neonatal long QT syndrome.
AB  - Previous studies have identified mutations in five ion channel genes as a cause
      of long QT syndrome, a heterogeneous disorder characterized by prolongation of
      the QT interval, multiform ventricular tachycardia (torsades de pointes),
      seizures, syncope, and sudden death. However, in these studies, the average age
      of initial symptoms is in the third decade of life or later, and few reports have
      described the genetic causes of long QT syndrome presenting in the prenatal or
      neonatal period. We used a candidate gene approach to identify the genetic cause
      of long QT syndrome in an infant whose initial manifestations were detected in
      utero. Direct bidirectional sequencing of long QT syndrome genes identified a
      previously unreported HERG missense mutation (R752Q). Three asymptomatic family
      members were heterozygous for R752Q, and the proband, who manifested ventricular
      tachycardia in utero, was homozygous. R752Q was not found in 100 normal unrelated
      chromosomes. Paternal DNA was unavailable for testing. Transient transfection of
      HERG generated robust IKr, but no current was observed for the mutant HERG. The
      HERG mutant, R752Q, is associated with a mild phenotype, inasmuch as family
      members with a heterozygous mutation appear unaffected. The homozygous mutation
      results in absence of functional IKr, causing a profound loss of HERG channel
      function, creating the equivalent of a "HERG knockout" and leading to a severe
      phenotype.

PMID- 12621128
TI  - Distribution of Poly(ADP-ribosyl)ation and cell death after cerebral ischemia in
      the neonatal rat.
AB  - The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is a key component of
      molecular mechanisms leading to cell death or survival after an ischemic insult.
      Oxidative stress damages DNA, and breaks in the DNA strands activate PARP enzyme,
      leading to poly(ADP-ribosyl)ation of nuclear proteins. In this study, we
      investigated PARP activation using immunodetection of PAR polymers in the brain
      of neonatal rat pups subjected to unilateral focal ischemia with reperfusion.
      PARP activation was detected in the ischemic core between 2 and 18 h, and in the
      penumbra between 24 and 48 h in the middle cerebral artery (MCA) territory but
      also in territories of the anterior and posterior cerebral artery, and in white
      matter tracts. The intranuclear accumulation of PAR in cells preceded a positive
      terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end
      labeling, suggesting that PARP activation may actually contribute to delayed cell
      death. Pretreatment with 3-aminobenzamide (3-AB, 10 mg/kg) strongly reduced PARP
      activation and cell death. These data suggest that PARP activation represents, in
      the immature brain, the early sign of ischemic cell death. This raises the
      possibility of the use of PARP inhibitors not only immediately postischemia but
      perhaps also later to reduce ischemic lesion in the MCA territory and its
      connected structures.

PMID- 12621126
TI  - CCR5 expression and beta-chemokine production during placental neonatal monocyte
      differentiation.
AB  - The stage of maturation of monocytes affects their susceptibility to HIV
      infection. The beta-chemokines and their receptor CCR5 play a crucial role in
      inflammatory reactions and HIV infection. We therefore examined the correlation
      between the expression of CCR5 and beta-chemokine production and the
      susceptibility to HIV infection during cord monocyte (CM) differentiation into
      macrophages. CM and CM-derived macrophages (CMDM) were examined for beta
      chemokine and CCR5 expression. The susceptibility of the CM cultured in vitro at
      different time points to HIV infection was also determined. Although the levels
      of CCR5 mRNA expression in freshly isolated CM are comparable to those in CMDM,
      CM had significantly lower levels of CCR5 protein on the cell surface than CMDM
      did. Steady increase of CCR5 protein expression on the cell surface was observed
      during CM differentiation into macrophages. The CCR5 expression correlated with
      the increased susceptibility to HIV infection by CMDM. Although there was no
      significant difference in endogenous beta-chemokine production between CM and
      CMDM, HIV infection of CMDM significantly enhanced production of macrophage
      inflammatory protein-1alpha and -1beta. CCR5 receptor plays a critical role in
      HIV infection of neonatal blood monocyte/macrophages.

PMID- 12621129
TI  - Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright
      hereditary osteodystrophy and pseudohypoparathyroidism.
AB  - Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH
      resistance and classified as types Ia, Ib, Ic, and II, according to its different
      pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH
      resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous
      mutations in the GNAS1 gene encoding the Gsalpha protein have been identified
      both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with
      isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP
      in the same family when inherited from the maternal and the paternal allele,
      respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether
      molecular diagnosis is a useful tool to characterize AHO and PHP when testing for
      Gsalpha activity and PTH resistance is not available, we have performed GNAS1
      mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of
      the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP
      patients, eight of which have not been reported previously. Inheritance was
      ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were
      inherited from the mothers, who had AHO (PPHP), consistent with the proposed
      imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia
      and PPHP in the mutated patients. Our results stress the usefulness of this
      approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and
      illustrate the wide mutation heterogeneity of PHP and PHP-Ia.

PMID- 12621130
TI  - Aspirin and the prevention of colorectal cancer.

PMID- 12621131
TI  - Computer crash--lessons from a system failure.

PMID- 12621132
TI  - A randomized trial of aspirin to prevent colorectal adenomas in patients with
      previous colorectal cancer.
AB  - BACKGROUND: Experimental studies in animals and observational studies in humans
      suggest that regular aspirin use may decrease the risk of colorectal adenomas,
      the precursors to most colorectal cancers. METHODS: We conducted a randomized,
      double-blind trial to determine the effect of aspirin on the incidence of
      colorectal adenomas. We randomly assigned 635 patients with previous colorectal
      cancer to receive either 325 mg of aspirin per day or placebo. We determined the
      proportion of patients with adenomas, the number of recurrent adenomas, and the
      time to the development of adenoma between randomization and subsequent
      colonoscopic examinations. Relative risks were adjusted for age, sex, cancer
      stage, the number of colonoscopic examinations, and the time to a first
      colonoscopy. The study was terminated early by an independent data and safety
      monitoring board when statistically significant results were reported during a
      planned interim analysis. RESULTS: A total of 517 randomized patients had at
      least one colonoscopic examination a median of 12.8 months after randomization.
      One or more adenomas were found in 17 percent of patients in the aspirin group
      and 27 percent of patients in the placebo group (P=0.004). The mean (+/-SD)
      number of adenomas was lower in the aspirin group than the placebo group (0.30+/
      0.87 vs. 0.49+/-0.99, P=0.003 by the Wilcoxon test). The adjusted relative risk
      of any recurrent adenoma in the aspirin group, as compared with the placebo
      group, was 0.65 (95 percent confidence interval, 0.46 to 0.91). The time to the
      detection of a first adenoma was longer in the aspirin group than in the placebo
      group (hazard ratio for the detection of a new polyp, 0.64; 95 percent confidence
      interval, 0.43 to 0.94; P=0.022). CONCLUSIONS: Daily use of aspirin is associated
      with a significant reduction in the incidence of colorectal adenomas in patients
      with previous colorectal cancer.

PMID- 12621133
TI  - A randomized trial of aspirin to prevent colorectal adenomas.
AB  - BACKGROUND: Laboratory and epidemiologic data suggest that aspirin has an
      antineoplastic effect in the large bowel. METHODS: We performed a randomized,
      double-blind trial of aspirin as a chemopreventive agent against colorectal
      adenomas. We randomly assigned 1121 patients with a recent history of
      histologically documented adenomas to receive placebo (372 patients), 81 mg of
      aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to
      the protocol, follow-up colonoscopy was to be performed approximately three years
      after the qualifying endoscopy. We compared the groups with respect to the risk
      of one or more neoplasms (adenomas or colorectal cancer) at least one year after
      randomization using generalized linear models to compute risk ratios and 95
      percent confidence intervals. RESULTS: Reported adherence to study medications
      and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up
      colonoscopy was performed at least one year after randomization in 1084 patients
      (97 percent). The incidence of one or more adenomas was 47 percent in the placebo
      group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in
      the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative
      risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg
      group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group
      (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas
      measuring at least 1 cm in diameter or with tubulovillous or villous features,
      severe dysplasia, or invasive cancer), the respective relative risks were 0.59
      (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence
      interval, 0.55 to 1.23). CONCLUSIONS: Low-dose aspirin has a moderate
      chemopreventive effect on adenomas in the large bowel.

PMID- 12621134
TI  - Urinary incontinence after vaginal delivery or cesarean section.
AB  - BACKGROUND: It is uncertain whether women who deliver by cesarean section have an
      increased risk of urinary incontinence as compared with nulliparous women and
      whether women who deliver vaginally have an even higher risk. METHODS: We studied
      15,307 women enrolled in the Epidemiology of Incontinence in the County of Nord
      Trondelag (EPINCONT) study, which involved a community-based cohort. The data
      base for this study was linked to data from the Medical Birth Registry of Norway.
      We included women who answered questions related to urinary incontinence, were
      younger than 65 years of age, and had had no deliveries, cesarean sections only,
      or vaginal deliveries only. RESULTS: The prevalence of any incontinence was 10.1
      percent in the nulliparous group; age-standardized prevalences were 15.9 percent
      in the cesarean-section group and 21.0 percent in the vaginal-delivery group.
      Corresponding figures for moderate or severe incontinence were 3.7 percent, 6.2
      percent, and 8.7 percent, respectively; figures for stress incontinence were 4.7
      percent, 6.9 percent, and 12.2 percent, respectively; figures for urge
      incontinence were 1.6 percent, 2.2 percent, and 1.8 percent, respectively; and
      figures for mixed-type incontinence were 3.1 percent, 5.3 percent, and 6.1
      percent, respectively. As compared with nulliparous women, women who had cesarean
      sections had an adjusted odds ratio for any incontinence of 1.5 (95 percent
      confidence interval, 1.2 to 1.9) and an adjusted odds ratio for moderate or
      severe incontinence of 1.4 (95 percent confidence interval, 1.0 to 2.1). Only
      stress and mixed-type incontinence were significantly associated with cesarean
      sections. The adjusted odds ratio for any incontinence associated with vaginal
      deliveries as compared with cesarean sections was 1.7 (95 percent confidence
      interval, 1.3 to 2.1), and the adjusted odds ratio for moderate or severe
      incontinence was 2.2 (95 percent confidence interval, 1.5 to 3.1). Only stress
      incontinence (adjusted odds ratio, 2.4; 95 percent confidence interval, 1.7 to
      3.2) was associated with the mode of delivery. CONCLUSIONS: The risk of urinary
      incontinence is higher among women who have had cesarean sections than among
      nulliparous women and is even higher among women who have had vaginal deliveries.
      However, these findings should not be used to justify an increase in the use of
      cesarean sections.

PMID- 12621135
TI  - Treatment with a luteinizing hormone-releasing hormone agonist in adolescents
      with short stature.
AB  - BACKGROUND: Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist
      increases adult height in children with LHRH-dependent precocious puberty and is
      prescribed by some practitioners to augment height in short adolescents. We
      performed a randomized clinical trial to determine whether treatment with an LHRH
      agonist increases adult height in short adolescents with normally timed puberty.
      METHODS: Fifty short adolescents (18 boys and 32 girls) with low predicted adult
      height (mean [+/-SD], 3.3+/-1.2 SD below the population mean) received either
      placebo (24 subjects) or an LHRH agonist (26 subjects). The mean (+/-SD) duration
      of treatment was 3.5+/-0.9 years in the LHRH-agonist group and 2.1+/-1.2 years in
      the placebo group (P<0.001). Adult height was measured when bone age exceeded 16
      years in girls and 17 years in boys and when the rate of growth was less than 1.5
      cm per year. RESULTS: Forty-seven adolescents (94 percent) were followed until
      they attained adult height. At the time adult height was achieved, the subjects
      who had been treated with an LHRH agonist were older than those who had received
      placebo (20.5+/-2.1 years vs. 18.0+/-2.5 years, P=0.01) and were taller (standard
      deviation score, -2.2+/-1.1 vs. -3.0+/-1.2; P=0.01). Analysis of covariance
      showed that LHRH-agonist treatment resulted in an increase of 0.6 (95 percent
      confidence interval, 0.2 to 0.9) in the standard-deviation score for height, or
      an increase of 4.2 cm (95 percent confidence interval, 1.7 to 6.7), over the
      initially predicted adult height (P=0.01). Treatment with an LHRH agonist
      resulted in significantly greater adult height than did placebo in boys and
      girls, in adolescents with idiopathic short stature, and in those who had a
      growth-limiting syndrome. The principal adverse event in the LHRH-agonist group
      was decreased accretion of bone mineral density (mean lumbar vertebral bone
      mineral density at the time adult height was achieved, 1.6+/-1.2 SD below the
      population mean, vs. 0.3+/-1.2 SD below the population mean in the placebo group;
      P<0.001). CONCLUSIONS: Treatment with an LHRH agonist for 3.5 years increases
      adult height by 0.6 SD in adolescents with very short stature but substantially
      decreases bone mineral density. Such treatment cannot be routinely recommended to
      augment height in adolescents with normally timed puberty.

PMID- 12621136
TI  - Images in clinical medicine. Calcified left ventricular aneurysm.

PMID- 12621137
TI  - Hereditary colorectal cancer.

PMID- 12621138
TI  - Use of the electrocardiogram in acute myocardial infarction.

PMID- 12621139
TI  - Is treatment with a luteinizing hormone-releasing hormone agonist justified in
      short adolescents?

PMID- 12621140
TI  - Elective primary cesarean delivery.

PMID- 12621141
TI  - Dexamethasone in adults with bacterial meningitis.

PMID- 12621142
TI  - Treatment of asymptomatic bacteriuria in diabetic women.

PMID- 12621143
TI  - Insurance coverage and outcomes of in vitro fertilization.

PMID- 12621144
TI  - Analgesics for the treatment of pain in children.

PMID- 12621145
TI  - Case 29-2002: antiphospholipid-antibody syndrome.

PMID- 12621146
TI  - Five years of legal physician-assisted suicide in Oregon.

PMID- 12621147
TI  - Images in clinical medicine. Impending rupture of the myocardial wall.

PMID- 12621148
TI  - Focus issue: aging--a multifaceted issue.

PMID- 12621149
TI  - Physiologic and pathologic events mediated by intramembranous and juxtamembranous
      proteolysis.
AB  - Intramembranous proteolysis (IP) is a recently recognized mechanism for
      transmembrane signal transduction that involves proteolysis of transmembrane
      proteins within their membrane-spanning domains. Juxtamembranous proteolysis (JP)
      is similar, but proteolytic cleavage of a transmembrane protein occurs at a site
      close to, but not within, the transmembrane domain of the target protein. In both
      IP and JP, a soluble domain of a transmembrane protein is released from its
      membrane tether. This domain can then transmit a signal either locally or at some
      distance from the site of cleavage. In certain signaling pathways, JP and IP are
      linked. JP on one side of the membrane results in secondary IP, which then
      releases a signaling domain from the membrane. Whereas well-characterized
      proteases such as caspases, the proteasome, and metalloprotease disintegrins,
      have been implicated in JP, three families of multipass membrane proteases
      (MpMPs) have now been shown to carry out IP. Recent studies of events mediated by
      IP and JP indicate that they regulate key cellular signaling events including
      pathways involved in sterol regulation, cell fate selection, and growth
      regulation. Moreover, IP and JP have important roles in certain diseases such as
      Alzheimer's disease. Because some of the proteases mediating IP and JP can be
      selectivity inhibited, inhibitors targeting these proteases are likely to alter
      both physiologic and pathologic events triggered by IP and JP.

PMID- 12621150
TI  - The many forks in FOXO's road.
AB  - The FOXO family of transcription factors constitute an evolutionarily conserved
      subgroup within the larger family known as winged helix or Forkhead
      transcriptional regulators. Building upon work in the nematode, researchers have
      uncovered a role for these proteins in a diverse set of cellular responses that
      include glucose metabolism, stress response, cell cycle regulation, and
      apoptosis. At the organismal level, FOXO transcription factors are believed to
      function in various pathological processes ranging from cancer and diabetes to
      organismal aging. A number of studies have also shed light on the signaling
      pathways that regulate FOXO activity in response to external stimuli and have
      identified multiple FOXO target genes that mediate this varied set of biological
      responses.

PMID- 12621151
TI  - The 1.6-A crystal structure of the class of chaperones represented by Escherichia
      coli Hsp31 reveals a putative catalytic triad.
AB  - Heat shock proteins (Hsps) play essential protective roles under stress
      conditions by preventing the formation of protein aggregates and degrading
      misfolded proteins. EcHsp31, the yedU (hchA) gene product, is a representative
      member of a family of chaperones that alleviates protein misfolding by
      interacting with early unfolding intermediates. The 1.6-A crystal structure of
      the EcHsp31 dimer reveals a system of hydrophobic patches, canyons, and grooves,
      which may stabilize partially unfolded substrate. The presence of a well
      conserved, yet buried, triad in each two-domain subunit suggests a still unproven
      hydrolytic function of the protein. A flexible extended linker between the A and
      P domains may play a role in conformational flexibility and substrate binding.
      The alpha-beta sandwich of the EcHsp31 monomer shows structural similarity to
      PhPI, a protease belonging to the DJ-1 superfamily. The structure-guided sequence
      alignment indicates that Hsp31 homologs can be divided in three classes based on
      variations in the P domain that dramatically affect both oligomerization and
      catalytic triad formation.

PMID- 12621152
TI  - Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart
      function.
AB  - The heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is
      a member of the EGF family of growth factors that binds to and activates the EGF
      receptor (EGFR) and the related receptor tyrosine kinase, ErbB4. HB-EGF-null mice
      (HB(del/del)) were generated to examine the role of HB-EGF in vivo. More than
      half of the HB(del/del) mice died in the first postnatal week. The survivors
      developed severe heart failure with grossly enlarged ventricular chambers.
      Echocardiographic examination showed that the ventricular chambers were dilated
      and that cardiac function was diminished. Moreover, HB(del/del) mice developed
      grossly enlarged cardiac valves. The cardiac valve and the ventricular chamber
      phenotypes resembled those displayed by mice lacking EGFR, a receptor for HB-EGF,
      and by mice conditionally lacking ErbB2, respectively. HB-EGF-ErbB interactions
      in the heart were examined in vivo by administering HB-EGF to WT mice. HB-EGF
      induced tyrosine phosphorylation of ErbB2 and ErbB4, and to a lesser degree, of
      EGFR in cardiac myocytes. In addition, constitutive tyrosine phosphorylation of
      both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts. It was
      concluded that HB-EGF activation of receptor tyrosine kinases is essential for
      normal heart function.

PMID- 12621154
TI  - Discrete two-terminal single nanocluster quantum optoelectronic logic operations
      at room temperature.
AB  - Readily formed at nanoscale break junctions, arrays of individual spatially
      isolated, strongly electroluminescent Ag(2)-Ag(8) nanoclusters perform complex
      logic operations within individual two-terminal nanoscale optoelectronics
      devices. Simultaneous electrical excitation of discrete room-temperature
      nanocluster energy levels directly yields AND, OR, NOT, XOR, and even full
      addition logic operations with either individual nanoclusters or nanocluster
      pairs as the active medium between only two electrodes. Imaged in parallel,
      noncontact electroluminescent readout obviates the need for electrically
      isolating individual features. This gated, pulsed, two-terminal device operation
      will likely drive future nano and molecular electronics advances without
      complicated nanofabrication.

PMID- 12621153
TI  - Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP
      dependent protein kinase pathway in vascular regeneration.
AB  - Natriuretic peptides (NPs), which consist of atrial, brain, and C-type
      natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as
      cardiac or vascular hormones that elicit their biological effects by activation
      of the cGMPcGMP-dependent protein kinase (cGK) pathway. We recently reported that
      adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed
      neointimal formation but also accelerated reendothelialization, a required step
      for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we
      investigated the therapeutic potential of the NPscGMPcGK pathway for vascular
      regeneration. In transgenic (Tg) mice that overexpress BNP in response to
      hindlimb ischemia, neovascularization with appropriate mural cell coating was
      accelerated without edema or bleeding, and impaired angiogenesis by the
      suppression of nitric oxide production was effectively rescued. Furthermore, in
      BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular
      superoxide production were suppressed compared with control mice. Ischemia
      induced angiogenesis was also significantly potentiated in cGK type I Tg mice,
      but attenuated in cGK type I knockout mice. NPs significantly stimulated
      capillary network formation of cultured endothelial cells by cGK stimulation and
      subsequent Erk12 activation. Furthermore, gene transfer of CNP into ischemic
      muscles effectively accelerated angiogenesis. These findings reveal an action of
      the NPscGMPcGK pathway to exert multiple vasculoprotective and regenerative
      actions in the absence of apparent adverse effects, and therefore suggest that
      NPs as the endogenous cardiovascular hormone can be used as a strategy of
      therapeutic angiogenesis in patients with tissue ischemia.

PMID- 12621156
TI  - Link between immune response and parasite synchronization in malaria.
AB  - Anti-malaria vaccines and drugs could be greatly improved if we knew which phases
      of Plasmodium falciparum development in red blood cells are major inducers and
      which are major targets of natural immune responses. This information should
      focus attention on relevant immunogens and prove useful in developing immune
      based therapies. Here we explore the hypothesis that innate immune responses
      mediate synchronization between the replication cycles of parasites in different
      red blood cells which is reflected in periodic fevers. Based on a recently
      developed, rather general mathematical model, we find that periodicity is highly
      sensitive to the position of both the inducing phase interval and the target
      phase interval in the parasite replication cycle. In addition, the degree of
      variability in the length of the replication cycle also strongly affects
      periodicity. To produce synchronization, the inducing and the target phase
      intervals must be developmentally distant from each other. We developed a
      computer program which prompts for information based on measurements of the
      numbers of erythrocytes in two replication cycle intervals chosen by the
      researcher, tests our model, and predicts the two phase intervals most critical
      to the synchronizing immune response. The program can be obtained from the
      authors.

PMID- 12621155
TI  - Neuroglobin protects the brain from experimental stroke in vivo.
AB  - Neuroglobin (Ngb) is an O(2)-binding protein localized to cerebral neurons of
      vertebrates, including humans. Its physiological role is unknown but, like
      hemoglobin, myoglobin, and cytoglobin/histoglobin, it may transport O(2),
      detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported
      recently that hypoxia stimulates transcriptional activation of Ngb in cultured
      cortical neurons and that antisense inhibition of Ngb expression increases
      hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to
      hypoxia. These findings are consistent with a role for Ngb in promoting neuronal
      survival after hypoxic insults in vitro. Here we report that in rats,
      intracerebroventricular administration of an Ngb antisense, but not sense,
      oligodeoxynucleotide increases infarct volume and worsens functional neurological
      outcome, whereas intracerebral administration of a Ngb-expressing adeno
      associated virus vector reduces infarct size and improves functional outcome,
      after focal cerebral ischemia induced by occlusion of the middle cerebral artery.
      We conclude that Ngb acts as an endogenous neuroprotective factor in focal
      cerebral ischemia and may therefore represent a target for the development of new
      treatments for stroke.

PMID- 12621157
TI  - Advanced glycation end products (AGE) inhibit scavenger receptor class B type I
      mediated reverse cholesterol transport: a new crossroad of AGE to cholesterol
      metabolism.
AB  - Advanced glycation end products (AGE) -modified proteins behave as active ligands
      for several receptors belonging to the scavenger receptor family. Scavenger
      receptor class B type I (SR-BI) was identified as the first high density
      lipoprotein (HDL) receptor that mediates selective uptake of HDL-cholesteryl
      esters (HDL-CE). This study investigated whether AGE proteins serve as ligands
      for SR-BI and affect SR-BI-mediated cholesterol transport using Chinese hamster
      ovary (CHO) cells overexpressing hamster SR-BI (CHO-SR-BI cells). [125I] AGE
      bovine serum albumin (AGE-BSA) underwent active endocytosis and subsequent
      lysosomal degradation by CHO-SR-BI cells, indicating that SR-BI serves as an AGE
      receptor. SR-BI-mediated selective uptake of HDL-CE by CHO-SR-BI cells was
      efficiently inhibited by AGE-BSA although AGE-BSA had no effect on HDL binding to
      CHO-SR-BI cells. In addition, AGE-BSA significantly inhibited the efflux of [3H]
      cholesterol from CHO-SR-BI cells to HDL. These findings suggest the possibility
      that AGE proteins in the circulation interfere with the functions of SR-BI in
      reverse cholesterol transport by inhibiting the selective uptake of HDL-CE, as
      well as cholesterol efflux from peripheral cells to HDL, thereby accelerating
      diabetes-induced atherosclerosis.

PMID- 12621158
TI  - Ascorbic acid augments cytotoxicity induced by oxidized low-density lipoprotein.
AB  - Although ascorbic acid (ASA) is known as a water-soluble antioxidant, we found
      that it accelerated the cytotoxicity induced by oxidized low-density lipoprotein
      (OxLDL) in vitro. This suggests that ASA may enhance the oxidation of LDL to
      augment the atherogenic activities of OxLDL under certain conditions. Thus, this
      study was designed to investigate the underlying mechanism that ASA enhances
      OxLDL-induced cytotoxicity. ASA enhanced the cytotoxicity of macrophage cell line
      (J774) induced by OxLDL in a dose-dependent manner, whose effect was more
      apparent in high glucose concentration in the medium. The ASA-induced enhancement
      in cytotoxicity was inhibited by the presence of lipid-soluble antioxidants, such
      as alpha-tocopherol and probucol, suggesting that the pro-cytotoxic effect by ASA
      is likely due to its pro-oxidant property. We also investigated the effects of
      ASA at different time points on the Cu2+-mediated oxidation of LDL. ASA decreased
      the rate of conjugated dienes formation when added at the early phase of
      oxidation, whereas it increased when added at the late phase of oxidation. These
      data suggest that ASA may act as a pro-oxidant under the condition of extensive
      LDL oxidation. To prevent oxidation stress, ASA would be better used together
      with lipid-soluble antioxidants for antioxidant therapies.

PMID- 12621159
TI  - Changes in carotid atherosclerosis patterns detected by ultrasonography in
      Japanese elderly patients with aortic aneurysm.
AB  - To clarify current changes in the patterns of carotid atherosclerosis in Japan,
      carotid ultrasonographic findings in Japanese male patients with aortic aneurysm
      were compared between two groups examined in different periods. The first group
      was recruited from 42 consecutively examined patients in 1997, while the second
      group consisted of 40 consecutive patients from September, 2001 to January, 2002.
      Carotid lesions were analyzed by computer, and classified into three types based
      on the texture: echolucent, hyperechoic, and heterogeneous types. The mean age of
      the first group was 72 years, similar to that of the second group. In the first
      group, cigarette smoking was frequently noted, while the mean BMI was greater and
      IHD and CVD were frequent in the second group. Fifty carotid lesions were seen in
      each group. Severe stenosis and hypoechoic type lesions were more frequent in the
      second group than in the first group. These findings indicated that hypoechoic
      type lesions, which are considered to be lipid deposition, hemorrhage, or loose
      fibrous tissue, and severe stenosis, were increased in the more recent group.
      This predicted that circulatory disturbance due to unstable atherosclerotic
      lesions may increase in the future among the elderly because carotid lesions
      reflect vascular change in other organs.

PMID- 12621160
TI  - Related factors of meeting National Cholesterol Education Program-recommended
      goals with atorvastatin.
AB  - The aim of this study was to observe the efficacy of atorvastatin and the related
      factors of meeting the National Cholesterol Education Program (NCEP)-recommended
      low-density lipoprotein (LDL) cholesterol levels in patients with
      hypercholesterolemia. A total of 107 patients were treated with atorvastatin 10
      mg/day for 12 weeks. Eighty % of the patients achieved the target goals. There
      was a significant difference in the initial body mass index (BMI) between
      patients achieving the target goals and those not achieving the target goals (p <
      0.05). In multiple stepwise logistic regression analysis, initial BMI and
      complications correlated with reaching the NCEP-recommended target goals (p <
      0.05). A great number of patients treated with atorvastatin, including those
      previously poorly controlled with other therapies, reached the target goals at
      the starting dose 10 mg/day. BMI may be a useful index of achieving the NCEP
      recommended target goals with atorvastatin.

PMID- 12621161
TI  - Preventing angiographic progression of coronary atherosclerosis with pravastatin.
AB  - We conducted a prospective study to investigate the relationship between the
      decrease of serum lipid levels during pravastatin therapy and changes of coronary
      angiography parameters in Japanese patients with coronary atherosclerosis. The
      patients were predominantly male, aged between 18 and 75 years (mean: 58 years),
      had at least 25% stenosis of one or more major coronary arteries, and had a serum
      total cholesterol ( TC) level > or = 200 mg/dl (5.18 mM/l). Treatment with
      pravastatin (10 mg/day) was continued for 3 years. Coronary angiography was
      performed before and 3 years after the start of pravastatin therapy to assess the
      relationship between the mean segment diameter (MSD), the minimal lumen diameter
      (MLD), and the annual changes of percent stenosis and TC levels. of 265 patients
      who were initially registered, 129 were followed for an average of 35 months.
      Consequently, second angiograms were only obtained in 68 patients for various
      reasons, so this group was used for analysis. During pravastatin therapy, the TC
      level significantly decreased from 239 mg/dl (6.19 mM/l) to 210 mg/dl (5.44 mM/l)
      (a 12% reduction; p<0.001). In addition, HDL-cholesterol increased by 5%
      (p=0.007), but the triglyceride level did not show a significant change. Both MSD
      and MLD were significantly improved on follow-up angiography, increasing from
      2.67 mm to 2.76 mm and from 2.09 mm to 2.13 mm, respectively. However, no change
      of percent stenosis was observed. The mean TC level during treatment did not show
      any significant correlation with the changes of angiography parameters. However,
      a significant correlation was observed between the percent reduction of TC and
      the annual change of MSD (r=-0.272, p=0.027). A similar relationship was also
      found between the change of MLD and the percent reduction of TC (r=-0.260,
      p=0.035). In conclusion, the percent decrease of serum cholesterol may be a
      better indicator of clinical efficacy than the absolute cholesterol level during
      pravastatin therapy.

PMID- 12621162
TI  - Effects of a new single-nucleotide polymorphism in the Acyl-CoA:cholesterol
      acyltransferase-2 gene on plasma lipids and apolipoproteins in patients with
      hyperlipidemia.
AB  - Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes cholesterol esterification
      in mammalian cells. Two isoforms of ACAT have been reported to date (ACAT-1 and
      ACAT-2). ACAT-1 protein is ubiquitously expressed in tissues, including
      macrophages, hepatocytes, adrenal glands, and intestines. In contrast, ACAT-2 is
      expressed mainly in the intestine in humans. However, the roles of ACAT-1 and
      ACAT-2 in lipoprotein metabolism in humans have not yet been reported. This study
      was carried out to clarify the relationship between ACAT-2 gene mutations and
      hyperlipidemia in humans. To identify gene mutations, we screened 30 subjects
      with hyperlipidemia (TC > 220 mg/dl or TG >150 mg/dl) by direct sequencing. As a
      result, we found a new single-nucleotide polymorphism (SNP; a point mutation in
      intron 1, IVS1 -8 G-->C) in the ACAT-2 gene. To investigate the relationship
      between this SNP and both plasma lipids and apolipoproteins, 91 unrelated
      hyperlipidemic subjects (40 males and 51 females), and 92 unrelated
      normolipidemic subjects (46 males and 46 females) were screened by direct
      sequencing. The frequencies of the IVS1 - 8G-->C allele in normolipidemic and
      hyperlipidemic subjects were 0.131 and 0.125, respectively. IVS1 -8 G-->C did not
      affect plasma concentrations of lipids or apolipoproteins in either
      normolipidemic or hyperlipidemic subjects. Although further studies are needed,
      our data suggest that the ACAT-2 gene may not affect lipid levels in humans.

PMID- 12621163
TI  - Pitavastatin inhibits vascular smooth muscle cell proliferation by inactivating
      extracellular signal-regulated kinases 1/2.
AB  - We recently reported that lysophosphatidylcholine (lysoPC) acts on vascular
      smooth muscle cells ( VSMCs ) to produce a mitogenic response through the
      activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In this study,
      we examined the role of HMG-CoA reductase inhibitors on lysoPC-induced VSMC
      proliferation. Pitavastatin, a new HMG-CoA reductase inhibitor, suppressed lysoPC
      induced DNA synthesis in primary cultured rat VSMCs. Since lysoPC-induced ERK1/2
      activation contributes to smooth muscle cell proliferation, we explored the
      effect of pitavastatin on ERK1/2 activation. Pitavastatin inhibited lysoPC
      induced ERK1/2 phosphorylation and ERK1/2 activation. The other HMG-CoA reductase
      inhibitors, atrovastatin and fluvastatin, also inhibited lysoPC-induced ERK1/2
      phosphorylation. Pitavastatin also inhibited lysoPC-induced c-fos mRNA
      expression. To gain insight into the mechanism of the inhibitory effect of
      pitavastatin on ERK1/2 activation by lysoPC, we examined the role of the
      mevalonate pathways. Mevalonate and farnesylpyrophosphate reduced the inhibition
      of ERK1/2 phosphorylation by pitavastatin. These studies demonstrate that
      pitavastatin may inhibit lysoPC-induced VSMC proliferation, at least in part, by
      inactivating ERK1/2, which is linked to mevalonate metabolism.

PMID- 12621164
TI  - The relationship between insulin resistance and polymorphisms of the endothelial
      nitric oxide synthase gene in patients with coronary artery disease.
AB  - Nitric oxide (NO) regulates endothelial function and is believed to prevent
      atherogenesis. In endothelial cells, endothelial nitric oxide synthase (eNOS) is
      expressed constitutively, and regulates NO synthesis. A mutation of the eNOS gene
      has been associated with the development of coronary artery disease (CAD). The
      development of CAD is also influenced by insulin resistance, and recent studies
      suggest that NO might affect cellular insulin activity. We investigated the
      association between eNOS polymorphisms and insulin resistance in patients with
      CAD. We screened 45 patients with a history of myocardial infarction (MI), angina
      pectoris (AP), or coronary spasm. Genotypes were determined by polymerase chain
      reaction-restriction fragment-length polymorphism analysis. We examined two
      polymorphisms of the eNOS gene (The T(-786)-->C variant and the missense
      Glu298Asp variant). Insulin resistance was measured by determining the plasma
      immunoreactive insulin concentration at the 120 min time point (IRI 120) of a 75
      g oral glucose tolerance test. The IRI 120 of the T(-786)-->C variant group was
      higher than that for the control group (p<0.05). This finding demonstrates that
      the T(-786)-->C mutation in the eNOS gene decreases insulin sensitivity.

PMID- 12621165
TI  - Characterization of an in vitro model of calcification in retinal pigmented
      epithelial cells.
AB  - Little is known about the relationship at the molecular and cellular levels
      between vascular calcification and elastic fibers essential for elasticity. To
      gain a better understanding of the physiological function of elastin in vascular
      calcification, we developed a calcification model on cultured bovine retinal
      pigmented-epithelial cells (RPEs) that do not express endogenous tropoelastin.
      The addition of inorganic phosphate (NaH2PO4; Pi) induced calcium deposition in
      RPEs. The Pi-induced calcification, as assessed by the o-cresolphthalein
      complexone method, Goldenbergs method, and von Kossa staining, was completely
      inhibited by treatment with clodronate (DMDP) and phosphonoformic acid (PFA) and
      was weakly suppressed by treatment with levamisole. Moreover, the osteopontin
      mRNA expression was upregulated in the Pi-induced calcification of RPEs. These
      reactions in RPEs were characteristically consistent with those already
      established in cultured bovine aortic smooth muscle cells (BASMCs). Furthermore,
      bacterially expressed tropoelastin inhibited calcium deposition in RPEs as well
      as in BASMCs. Finally, Pi-induced calcification was partially suppressed after
      the addition of tropoelastin due to elastic fiber formation. In conclusion, we
      suggest that this calcification model in RPEs is useful for analyzing the
      relation between elastic fibers and vascular calcification, and that tropoelastin
      and elastic fibers may contribute to the inhibition of vascular calcification.

PMID- 12621166
TI  - R192Q paraoxonase gene variant is associated with a change in HDL-cholesterol
      level during dietary caloric restriction in nondiabetic healthy males.
AB  - Paraoxonase (PON), an HDL- associated enzyme, may protect against the development
      of atherosclerosis. Single nucleotide polymorphisms of PON have been reported to
      be associated with an incidence of coronary heart diseases. We investigated the
      effect of PON R192Q variants on serum lipid profile after caloric restriction in
      nondiabetic healthy males. After caloric restriction for 12 weeks, the levels of
      high-density lipoprotein cholesterol (HDL-C) increased in the subjects carrying
      RR genotype, but not in the QR and QQ genotypes. The changes in HDL-C from the
      baseline values in the RR genotype were significantly different from those in the
      QR and QQ genotypes. Although the changes in lipoprotein lipase activity were not
      different among three genotypes, we observed a significant difference in the
      changes in hepatic lipase (HL) activity after caloric restriction, namely, a
      decrease in the RR genotype and an increase in the subjects carrying the Q
      allele. In addition, the changes in fasting insulin levels significantly
      correlated with those in HDL-C levels in the RR genotype, not in the QR and QQ
      genotypes. PON R192Q polymorphism could affect HDL-C levels after caloric
      restriction presumably due to decreased HL activity and altered insulin
      resistance.

PMID- 12621167
TI  - Factors determining the ultimate fate of a plastic surgery applicant.
AB  - Plastic surgery residency program directors are frequently interested in
      predictors of future career direction in their applicants. Many programs strive
      to train leaders in academic plastic surgery. To determine what factors may
      predict the ultimate fate of graduating plastic surgery residents, the authors
      reviewed the application files of 33 former residents from a single, major
      plastic surgery training program. The data from 29 residents were available for
      analysis. Nearly half of the residents graduating from the plastic surgery
      training program went into private practice. Two factors, the number of years
      taken off for research before entering the plastic surgery residency and the
      presence of children, were found to be indicative of a candidate's future career
      path. Of particular note, there was no difference between academic graduates and
      nonacademic graduates with regard to their intentions in their letters of
      recommendation and personal statements. This information is useful to both
      academic program directors and resident applicants.

PMID- 12621168
TI  - Orbitoblepharophimosis syndrome: a 16-year perspective.
AB  - The orbitoblepharophimosis syndrome is a congenital malformation of the
      orbitopalpebral region. It is an autosomal-dominant condition typified by
      palpebral and orbital phimosis, ptosis, epicanthus inversus with telecanthus, and
      enophthalmia. It has three forms: minor, major, and extreme. It is a rare
      malformation affecting both sexes. The gene responsible is 3q21-24. Surgical
      treatment involves three to four operations: orbital remodeling by burring and
      grafting (intraorbital and extraorbital), epicanthus correction, and ptosis
      operation. Results varied depending on the severity of the form and the quality
      of the tissues. The authors present a series of 50 patients who were treated for
      this syndrome over the past 16 years.

PMID- 12621169
TI  - Binderoid complete cleft lip/palate.
AB  - A small subset of infants with complete cleft lip/palate look different because
      they have nasolabiomaxillary hypoplasia and orbital hypotelorism. The authors'
      purpose was to define the clinical and radiographic features of these patients
      and to comment on operative management, classification, and terminology. The
      authors reviewed 695 patients with all forms of incomplete and complete cleft
      lip/palate and identified 15 patients with nasolabiomaxillary hypoplasia and
      orbital hypotelorism. All 15 patients had complete labial clefting (5 percent of
      320 patients with complete cleft lip/palate), equally divided between bilateral
      and unilateral forms. The female-to-male ratio was 2:1. Of the seven infants with
      unilateral complete cleft lip/palate, one had an intact secondary palate and all
      had a hypoplastic septum, small alar cartilages, narrow basilar columella,
      underdeveloped contralateral philtral ridge, ill-defined Cupid's bow, thin
      vermilion-mucosa on both sides of the cleft, and a diminutive premaxilla. Of the
      eight infants with bilateral complete cleft lip, one had an intact secondary
      palate. The features were the same as in patients with unilateral cleft, but with
      a more severely hypoplastic nasal tip, conical columella, tiny prolabium,
      underdeveloped lateral labial elements, and small/mobile premaxilla. Central
      midfacial hypoplasia and hypotelorism did not change during childhood and
      adolescence. Intermedial canthal measurements remained 1.5 SD below normal age
      matched controls. Skeletal analysis (mean age, 10 years; range, 4 months to 19
      years) documented maxillary retrusion (mean sagittal maxillomandibular
      discrepancy, 13.7 mm; range, 3 to 17 mm), absent anterior nasal spine, and a
      class III relationship. The mean sella nasion A point (S-N-A) angle of 74 degrees
      (range, 65 to 79 degrees) and sella nasion B point (S-N-B) angle of 81 degrees
      (range, 71 to 90 degrees) were significantly different from age-matched norms ( =
      0.0007 and = 0.004, respectively). The ipsilateral central and lateral incisors
      were absent in all children with unilateral cleft, whereas a single-toothed
      premaxilla was typically found in the bilateral patients. Several modifications
      were necessary during primary nasolabial repair because of the diminutive bony
      and soft-tissue elements. All adolescent patients had Le Fort I maxillary
      advancement and construction of an adult nasal framework with costochondral or
      cranial graft. Other often-used procedures were bony augmentation of the anterior
      maxilla; cartilage grafts to the nasal tip and columella; and dermal grafting to
      the median tubercle, philtral ridge, and basal columella. Infants with complete
      unilateral or bilateral cleft lip/palate in association with nasolabiomaxillary
      hypoplasia and orbital hypotelorism do not belong on the holoprosencephalic
      spectrum because they have normal head circumference, stature, and intelligence,
      nor should they be referred to as having Binder anomaly. The authors propose the
      term cleft lip/palate for these children. Early recognition of this entity is
      important for counseling parents and because alterations in standard operative
      methods and orthodontic protocols are necessary.

PMID- 12621170
TI  - Hemifacial microsomia: use of the OMENS-Plus classification at the Royal
      Children's Hospital of Melbourne.
AB  - Hemifacial microsomia is the most common facial congenital disability after cleft
      lip and palate, but as yet its pathogenesis remains unknown. Clinical
      classification systems have evolved over the last 30 years from those classifying
      only single components of the disorder, to those classifying according to the
      combination of deformities, to the most recent systems that grade each anatomical
      component separately, such as the Orbit, Mandible, Ear, Nerve, and Soft tissue
      (OMENS) system. The aim of the present study was to review the classification of
      patients with hemifacial microsomia treated by the Melbourne Craniofacial Unit at
      the Royal Children's Hospital using the OMENS-Plus system of classification and
      to correlate the findings with data from other centers. Records of patients
      treated by the craniofacial unit were reviewed and included in the study if
      adequate clinical records, photographs, and radiographs (anteroposterior,
      lateral, basal cephalometry, panoramic views) were available. The data were
      entered into a database file developed for this purpose. Seventy-one patients
      were identified from the hospital database, of which six were excluded because of
      incomplete data. Of the 65 patients, there were 31 (48 percent) with right-sided
      microsomia, 25 (38 percent) with left-sided microsomia, and nine (14 percent)
      with bilateral microsomia, with an overall male-to-female ratio of 1.2:1. The
      majority of patients had a normal orbit (77 percent), mildly hypoplastic
      mandibular ramus-condyle with functioning temporomandibular joint (57 percent
      with type M1 or M2a), normal facial nerve (76 percent), and mild soft-tissue
      hypoplasia (73 percent). There was a similar proportion of patients with mild ear
      anomalies (53 percent with grade 0 or 1) compared with those with more severe
      anomalies (47 percent with grade 2 or 3). Correlative analysis demonstrated a
      slight but positive correlation between the severity gradings of the five
      individual components. The correlation was lowest between the grading of the
      nerve and ear and that of the mandible and nerve. The data demonstrate the
      phenotypic variability of hemifacial microsomia and suggest a degree of
      relationship among the components of hemifacial microsomia. The OMENS-Plus system
      has provided a major advancement in the classification of hemifacial microsomia.
      The authors suggest refinements to the grading of the orbit and nerve components.

PMID- 12621171
TI  - Dual midfacial distraction osteogenesis: Le Fort III minus I and Le Fort I for
      syndromic craniosynostosis.
AB  - Midfacial hypoplasia has been corrected by Le Fort III or monobloc forward
      advancement in one stage in syndromic craniosynostosis, but recently developed
      distraction osteogenesis has been in use. Whereas the amount of forward
      mobilization in Le Fort III conventional osteotomy is determined by the
      preplanned fabricated interdental splint, that in Le Fort III distraction is
      determined by the positions of the inferior orbital rim, malar complex, and nose.
      Therefore, the forward mobilization of the upper part of the midface may
      sometimes be insufficient when one focuses on the final occlusion, and the
      occlusion might not be satisfied when the forward mobilization is sufficient.
      Correction of the midfacial hypoplasia should be considered differently in the
      upper and lower portions of the midface. The upper portion contains the inferior
      orbit and nose, and the lower portion contains the occlusal structure of the
      maxillary dentoalveolar portion with the mandible. Separating the midface into
      two portions and conducting the distraction osteogenesis in both portions
      separately in different amounts and vectors of distraction is described in this
      article. Although distraction of the upper portion of the midface can be
      conducted in one direction with an internal device, distraction of the lower
      portion of the midface is preferred for conduction by a controllable device
      because of the need to obtain the preferred occlusion. To obtain better
      functional and aesthetic results in midfacial distraction in adults and
      adolescents with syndromic craniosynostosis, dual Le Fort III minus I and Le Fort
      I midfacial distraction osteogenesis was performed in four cases (in two patients
      with Crouzon syndrome and in two patients with Apert syndrome). Two females and
      two males are described (age range, 13 to 26 years). An internal device was used
      for the upper portion of the midface and an external device was used for the
      lower portion. The amount of distraction ranged from 14 to 21 mm in the upper
      portion of the midface and from 11 to 18 mm in the lower portion. No particular
      complications were noticed over a follow-up period of 10 to 38 months (average
      follow-up, 19.8 months).

PMID- 12621172
TI  - Nine-year experience with extended use of the commissure-based buccal
      musculomucosal flap.
AB  - This study reports on the extended use of the commissure-based buccal
      musculomucosal (CBMM) flap. Large lip defects and medium-size intraoral defects
      have the general problem of being too large for primary closure to avoid a major
      functional and aesthetic impairment. Elaborate free flaps, such as axial flaps,
      although excellent in large defects, may not provide mucosa-equivalent
      sensitivity, motility, volume, and texture to replace lost tissue with a similar
      kind of tissue. A total of 60 flap procedures were performed with bilateral and
      unilateral flaps up to 7.5 x 4 cm in size. The partial and total upper and lower
      vermilion, gingivobuccal sulcus, floor of the mouth, lateral tongue margin,
      oropharynx, and hard and soft palates were reconstructed. Partial necrosis was
      seen in four flaps; all patients recovered with good oral function in speech and
      swallowing, good aesthetics, and prosthetic rehabilitation if necessary. The
      donor site could be closed primarily. In flaps with dorsal advancement, the
      mucosal excess above and below was closed, creating two small dog-ears. Facial
      expression and mouth opening returned to normal after less than 2 months. The
      parotid duct had to be marsupialized in large flap preparations, but this did
      never provoke stasis or infection. The two-point sensitivity of the flaps was, on
      average, equal to that of the nonoperated mucosa in intraindividual correlation,
      and the flaps lost, on average, 15 percent of their original size. In the
      authors' estimation, the results indicate a reliable and technically easy option
      for intraoral, medium-size defect reconstruction that yields sensitivity and
      facilitates the rehabilitation of oral function in speaking and ingestion.

PMID- 12621173
TI  - Surgical management of the cutaneous manifestations of linear nevus sebaceus
      syndrome.
AB  - Linear nevus sebaceus syndrome is characterized by the association of nevus
      sebaceus covering extensive areas on the head and scalp with abnormalities of the
      central nervous system, ophthalmologic and skeletal changes, and malignancies.
      The incidence is approximately one per 10,000 live births, and there is no sexual
      predilection reported. The original description of this syndrome was followed by
      extensive literature describing the dermatologic, neurologic, and ophthalmologic
      manifestations of this disease. The objective of this report is to describe the
      surgical approach for the excision and reconstruction of giant sebaceous nevi of
      the face and scalp in children with linear nevus sebaceus syndrome on the basis
      of a consecutive series of five patients treated over 10 years in the same
      institution. To the authors' knowledge, this report represents the largest
      surgical series and suggests a reliable approach to the treatment of the
      cutaneous manifestations of this syndrome.

PMID- 12621174
TI  - Women who wish breast reconstruction: characteristics, fears, and hopes.
AB  - The aims of the present study were to identify the characteristics of a
      consecutive series of women with newly diagnosed breast cancer and to evaluate
      the perceived benefits and disadvantages of breast reconstruction. A consecutive
      series of 125 women completed the Breast Reconstruction Questionnaire, the
      Hospital Anxiety and Depression Scale, and the Eysenck Personality Questionnaire.
      The median age was 48 years (range, 28 to 75 years). A total of 49.6 percent (n =
      62) indicated that, if it were possible, they would like breast reconstruction.
      Logistic regression (simultaneous entry) revealed that younger women (p = 0.0001)
      and more depressed women (p = 0.026) were more likely to wish reconstruction.
      Marital status, tumor size, extroversion, neuroticism, and tough-mindedness did
      not independently predict the desire for reconstruction. If given a choice of
      reconstruction at 3 months or 6 months after mastectomy, of the women who wished
      reconstruction, 74 percent would prefer it at 3 months. Of the women who wished
      reconstruction and expressed a preference, 63 percent were afraid reconstruction
      might mask recurrence, 39 percent were afraid that reconstruction might cause the
      cancer to return, and 89 percent thought they would be concerned with their
      appearance after the operation. Positively, 94 percent considered that
      reconstruction would be beneficial in terms of their self-esteem, 86 percent
      indicated that reconstruction would give greater freedom to wear any clothing,
      and 86 percent thought that the cosmetic appearance of breast reconstruction was
      better than that of a prosthesis. Concerns about recurrence were common. A better
      understanding of the concerns of women with regard to reconstruction would allow
      more informed preoperative discussion.

PMID- 12621175
TI  - The psychological effect of mastectomy with or without breast reconstruction: a
      prospective, multicenter study.
AB  - A multicenter, prospective study ( = 103) examined the psychological implications
      of women's decisions for or against breast reconstruction. Recognized measures of
      anxiety, depression, body image, and quality of life were completed before the
      operation, and 6 and 12 months later. A reduction in psychological distress over
      the year following the operation was evident in each surgical group (mastectomy
      alone or immediate or delayed reconstruction), indicating that reconstructive
      surgery can offer psychological benefits to some women; however, others report
      improved psychological functioning without this surgical procedure. In contrast
      to existing retrospective research, the prospective design enabled the process of
      adjustment during the first year after the operation to be examined. The results
      indicate that breast reconstruction is not a universal panacea for the emotional
      and psychological consequences of mastectomy. Women still reported feeling
      conscious of altered body image 1 year postoperatively, regardless of whether or
      not they had elected breast reconstruction. Health professionals should be
      careful of assuming that breast reconstruction necessarily confers psychological
      benefits compared with mastectomy alone.

PMID- 12621176
TI  - Technical aspects and outcome after prophylactic mastectomy and immediate breast
      reconstruction in 30 consecutive high-risk patients.
AB  - The purpose of this study was to evaluate a consecutive series of patients
      operated on with prophylactic mastectomy and immediate breast reconstruction with
      implants, focusing on preoperative assessment, technical aspects of surgical
      outcome, and number of postoperative complications on a short-term basis. Thirty
      consecutive healthy women with an increased risk of breast cancer who were
      therefore operated on with bilateral prophylactic mastectomy and immediate breast
      reconstruction are reported. A multidisciplinary approach with a geneticist,
      general surgeon, plastic surgeon, specially trained nurse, psychologist,
      gynecologist, and oncologist was used preoperatively, with thorough information
      provided to the patient about the surgery. Eleven patients had gene mutations,
      and in all patients, the geneticist had performed a risk assessment. The mean age
      of the patients was 41 years. The technique was modified over time with smaller
      or special incisions and tailor-made adjustments for each patient. Great care was
      taken to remove all breast tissue. The tops of the breast nipples were regrafted
      for cosmetic purposes, and the base was sent for histopathologic examination. In
      most cases, permanent expander prostheses with detachable valves were used. The
      areolas were tattooed, if they were not left in place. No patient had occult
      cancer or carcinoma in situ. Four postoperative complications occurred, including
      two hematomas, one infection (treated with antibiotics), and one pneumothorax in
      a patient with severe asthma. All reconstructions were fulfilled. The mean
      hospital stay was 5.7 days. The time from mastectomy to the final tattooing of
      the areolas was 260 days. All patients returned to normal daily activities after
      fulfilled reconstruction.

PMID- 12621177
TI  - Surgical treatment of breast cancer in previously augmented patients.
AB  - The incidence of breast cancer is increasing each year. Concomitantly, cosmetic
      breast augmentation has become the second most often performed cosmetic surgical
      procedure. As the augmented patient population ages, an increasing number of
      breast cancer cases among previously augmented women can be anticipated. The
      surgical treatment of these patients is controversial, with several questions
      remaining unanswered. Is breast conservation therapy feasible in this patient
      population and can these patients retain their implants? A retrospective review
      of all breast cancer patients with a history of previous augmentation mammaplasty
      who were treated at the Revlon/UCLA Breast Center between 1991 and 2001 was
      performed. During the study period, 58 patients were treated. Thirty patients (52
      percent) were treated with a modified radical mastectomy with implant removal.
      Twenty-eight patients (48 percent) underwent breast conservation therapy, which
      consisted of lumpectomy, axillary lymph node dissection, and radiotherapy. Twenty
      two of the patients who underwent breast conservation therapy initially retained
      their implants. Eleven of those 22 patients (50 percent) ultimately required
      completion mastectomies with implant removal because of implant complications
      (two patients), local recurrences (five patients), or the inability to obtain
      negative margins (four patients). Nine additional patients experienced
      complications resulting from their implants, including contracture, erosion,
      pain, and rupture. The data illustrate that breast conservation therapy with
      maintenance of the implant is not ideal for the majority of augmented patients.
      Breast conservation therapy with explantation and mastopexy might be appropriate
      for rare patients with large volumes of native breast tissue. Mastectomy with
      immediate reconstruction might be a more suitable choice for these patients.

PMID- 12621178
TI  - Salvage of infected expander prostheses in breast reconstruction.
AB  - Periprosthetic infection is a devastating complication following breast
      reconstruction with prostheses. Traditional surgical principles dictate removal
      of the prosthesis to control infection. Although successful salvage of prostheses
      in the presence of periprosthetic infections has been reported in the plastic and
      other surgical literature, salvage procedures remain seldom practiced. Reports in
      the plastic surgery literature have been limited to implant salvage following
      cosmetic breast augmentation and subcutaneous mastectomy with implants. Salvage
      of saline-filled expander prostheses used in breast reconstruction following
      mastectomy for cancer has not been previously reported. The authors review their
      experience with implant salvage in patients with periprosthetic infections
      following breast reconstruction for a 6-year period. Fourteen patients (13 with
      saline-filled expander prostheses and one with silicone prosthesis) underwent
      implant salvage. Salvage of the breast reconstruction was successful in nine
      patients. Staphylococcus aureus infection was associated with poorer salvage rate
      (p = 0.023). Previous radiotherapy to the chest wall did not affect the salvage
      outcome (p = 0.50). In selected patients, immediate salvage of a breast
      reconstruction in the presence of prosthesis-related infection remains an
      alternative to implant removal followed by delayed reconstruction.

PMID- 12621179
TI  - Modified free paraumbilical perforator flap: the next logical step in breast
      reconstruction.
AB  - The free paraumbilical perforator flap that was developed with only the
      perforator penetrating the rectus abdominis muscle seems nearly ideal from the
      donor-site perspective, because it reduces morbidity virtually to that of an
      abdominoplasty. However, it requires "supermicrosurgery" skills for suturing of
      vessels with diameters of 0.7 mm or less, making the procedure technically
      demanding and risky. Another significant disadvantage of that technique is that
      the flap has very short vascular pedicles. To overcome the disadvantages of the
      free paraumbilical perforator flap, a minor modification in flap harvesting that
      improves the vessel size and length is described. Results for a total of 15
      patients who underwent breast reconstruction with modified free paraumbilical
      perforator flaps are presented, and the advantages and disadvantages of this flap
      are discussed.

PMID- 12621180
TI  - Experience with reduction mammaplasty combined with breast conservation therapy
      in the treatment of breast cancer.
AB  - As the inclusion criteria for breast conservation therapy have continued to
      evolve to include lower quadrant tumors, very large breasts, and central tumors,
      the potential for significant disfigurement after breast conservation therapy has
      also increased. This has led some centers to develop coordinated oncology-plastic
      surgery approaches to ensure both adequate cancer resection and aesthetic
      appearance to the breasts. The authors applied this principle to a specific group
      of breast cancer patients--women with macromastia--who would benefit from
      reduction mammaplasty. Eleven women were identified from the senior author's
      (S.L.S.) reconstructive practice who underwent breast conservation therapy
      followed by breast reconfiguration and bilateral reduction mammaplasty.
      Preoperative brassiere sizes ranged from 34D to 46D. All women had immediate
      reduction after frozen sections from the lumpectomy/partial mastectomy margins
      were determined to be negative. A total of 22 reduction mammaplasties were
      performed (eight free-nipple grafts, five inferior pedicle flaps, seven
      superomedial pedicle flaps, and two superolateral flaps) and an average of 1085 g
      was removed per breast. All patients underwent radiation therapy postoperatively.
      There were eight minor complications in six patients (one hematoma, one keloid,
      one radiation burn, two cases of nipple hypopigmentation, and three cases of fat
      necrosis). After an average of 24 months' follow-up, there were no local
      recurrences and one death from distant metastasis. Seven of the 11 patients were
      available and agreed to rate their aesthetic satisfaction on the basis of a scale
      from 1 to 4, with 4 being the best. The mean satisfaction score was 3.3.
      Aesthetic outcomes before radiation therapy and after radiation therapy were
      evaluated by a panel of plastic surgery residents blinded to the purpose of the
      study. Using a scale of 1 to 4, the aesthetic mean before radiation therapy was
      2.9 and the aesthetic mean after radiation therapy was 3.03. By combining breast
      conservation therapy with breast reconfiguration or reduction in large-breasted
      women, multiple benefits are derived. Larger segmental or partial mastectomies
      can be performed without disfigurement risk, ensuring adequate surgical margins.
      Immediate reconfiguration of the breast with reduction of the contralateral side
      creates symmetric, aesthetically pleasing breasts; allows contralateral breast
      tissue to be evaluated; and spares women from undergoing a second operative
      procedure. Such a coordinated program gives women an important boost, both
      physically and psychologically, during management of their breast cancer.

PMID- 12621181
TI  - Breast reconstruction in older women: advantages of autogenous tissue.
AB  - As the population ages, the treatment of breast cancer among elderly women is
      becoming increasingly common. Decisions with regard to breast reconstruction
      require not only consideration of patient age and comorbidities but also a need
      to balance life expectancy with quality of life. Although it is often assumed
      that implant-based breast reconstruction is the least disruptive method,
      especially among patients who may be facing limited survival times, it was
      hypothesized that autogenous tissue breast reconstruction is a well-tolerated and
      perhaps preferable means of reconstruction for older women who choose to undergo
      reconstruction following mastectomy. No large series of autogenous tissue
      reconstructions in this age group has been presented. A retrospective study of 84
      postmastectomy reconstructions (66 unilateral and 18 bilateral; 78.6 percent
      immediate) performed at the authors' institution for 81 women 65 years of age or
      older, between April of 1987 and December of 2000, was undertaken.
      Reconstructions were implant-based ( = 26), latissimus dorsi flap-based ( = 24),
      or transverse rectus abdominis myocutaneous (TRAM) flap-based ( = 34). Of the 34
      TRAM flaps, 21 were free or supercharged. Breast complications were more frequent
      ( < 0.05) among recipients of implant-based reconstructions (76.9 percent) than
      among recipients of latissimus dorsi flap (41.7 percent) or TRAM flap (35.3
      percent) reconstructions. In multivariate logistic regression analyses,
      comorbidities, smoking, radiotherapy, and body mass index had no effect. Medical
      complications without long-term sequelae were observed for two patients who
      underwent latissimus dorsi flap reconstructions and two patients who underwent
      free TRAM flap reconstructions; the difference in the rates of medical
      complications was not significant. At the mean follow-up time of 4.2 years, 92.8
      percent of all study patients exhibited no evidence of disease. Notably, despite
      being free of disease, seven of the 26 patients (27 percent) who underwent
      implant-based reconstructions abandoned further reconstructive efforts after
      complications necessitated implant removal. It was concluded that age alone
      should not determine the type of breast reconstruction and that autogenous tissue
      breast reconstruction can be a safe successful alternative for women 65 years of
      age or older.

PMID- 12621182
TI  - Reduction mammaplasty and correction of ptosis: dermal bra technique.
AB  - A new technique for reduction mammaplasty or mastopexy techniques is presented,
      which the authors call the dermal bra. The surgical steps are described point by
      point. A series of 36 patients underwent reduction mammaplasty or mastopexy by
      means of this technique from January of 1998 to April of 2001. Thirty-two
      patients were followed; 28 presented satisfactory results, including a good
      mammary appearance, invisible scar, good and stable breast projection, and
      lasting results. Nipple-areola complex sensitivity was unchanged in all 32
      patients. The overall complication rate was 12.5 percent (one patient suffered
      purse-string suture exposure, and three had a cutaneous rend). The advantages and
      disadvantages of this technique are discussed.

PMID- 12621183
TI  - Tissue oxygenation and perfusion in inferior pedicle reduction mammaplasty by
      near-infrared reflection spectroscopy and color-coded duplex sonography.
AB  - Near-infrared reflection spectroscopy has been used in various experimental and
      clinical settings to investigate tissue perfusion and oxygenation noninvasively.
      Its application in plastic surgery has only recently been reported. The current
      study used near-infrared reflection spectroscopy to monitor cutaneous
      microcirculation in breast skin flaps after inferior pedicle reduction
      mammaplasty. Thirty patients underwent bilateral reduction mammaplasty by a
      modified Robbins technique. Near-infrared reflection spectroscopy measurements
      were performed preoperatively and postoperatively at several defined positions of
      the breast. The reflection spectroscopy system was capable of detecting absolute
      values of total hemoglobin in milligrams per milliliter of tissue and tissue
      hemoglobin oxygen saturation in percent. Color-coded duplex sonography was used
      to visualize nutrient vessels of the inferior dermoglandular pedicle and to
      measure systolic peak flow in the arteries supplying the nipple-areola complex.
      Reflection spectroscopy values were examined for changes during the postoperative
      course. Reflection spectroscopy and duplex sonography values were analyzed for
      differences between patients with normal and compromised skin flap perfusion and
      wound healing, which was assessed clinically and by ultrasound. Preoperative
      reflection spectroscopy values demonstrated local, regional, and interindividual
      variations. Postoperatively, characteristic changes of tissue hemoglobin oxygen
      saturation and total hemoglobin were observed in all patients during the 2-week
      follow-up. Reflection spectroscopy values differed significantly between breast
      and nipple-areola skin. Tissue hemoglobin oxygen saturation was significantly
      lower, and total hemoglobin significantly higher, in patients with impaired wound
      healing compared with patients having normal wound healing. However, systolic
      peak flow in arteries of the inferior dermoglandular pedicle did not reveal
      differences between patients with impaired or normal wound healing of the nipple
      areola complex. Near-infrared reflection spectroscopy allows the detection of
      hemoglobin content and oxygenation in skin flaps. Changes in tissue hemoglobin
      oxygen saturation and total hemoglobin reflect hemodynamic changes in skin flaps
      during normal and pathological wound healing. Because of considerable
      intraindividual and interindividual variations, trend values seem to be superior
      to single measurements. Although in this study, near-infrared reflection
      spectroscopy was capable of distinguishing between normal and impaired perfusion
      in skin flaps in a clinical model, its future implication may be the early
      detection of vascular compromise in free flaps.

PMID- 12621184
TI  - The role of muscle flaps in pulmonary aspergillosis.
AB  - Pulmonary invades the lung parenchyma and vessels, causing necrotizing pneumonia
      and massive hemoptysis in immunocompromised patients. Medical treatment alone
      often fails to clear the organism. Early surgical intervention is advocated in
      localized disease to remove infection near pulmonary vessels. The resection is
      limited in an attempt to preserve as much lung function as possible. However,
      preexisting cavitations and lung disease predispose to postoperative space
      problems, including prolonged air leak, bronchopleural fistula, and empyema.
      Muscle flaps provide a solution to these problems by obliterating residual space
      and providing protective coverage to the bronchial stump. The authors present
      four cases of pulmonary aspergillosis treated by multimodality therapy and
      extrathoracic muscle flap transposition. Factors that may contribute to
      successful treatment include underlying condition of the host and history of
      cancer, radiation therapy, and great vessel involvement. Despite aggressive
      medical and surgical therapy, pulmonary aspergillosis has a poor prognosis.

PMID- 12621185
TI  - Significance of venous anastomosis in fingertip replantation.
AB  - Adequate venous outflow is the most important factor for successful fingertip
      replantation. The authors have attempted venous anastomosis in all cases of
      fingertip replantation to overcome postoperative congestion. In this article, the
      significance of venous repair for fingertip replantation is described from the
      authors' results of 64 complete fingertip amputations in 55 consecutive patients,
      which were replanted from January of 1996 to June of 2001. The overall survival
      rate was 86 percent. Of the 44 replantations in zone I, 37 survived, and the
      success rate was 84 percent. Of the 20 replantations in zone II, 18 survived, and
      the success rate was 90 percent. Venous anastomosis was attempted in all cases,
      but it was possible in 39 zone I and in all zone II replantations. For arterial
      repair, vein grafts were necessary in 17 of the 44 zone I and in one of the 20
      zone II replantations; for venous repair, they were necessary in six zone I
      replantations and one zone II replantation. Postoperative vascular complications
      occurred in 15 replantations. There were five cases of arterial thrombosis and 10
      cases of venous congestion. Venous congestion occurred in nine zone I and one
      zone II replantations. In five of these 10 replantations, venous anastomosis was
      not possible. In another five replantations, venous outflow was established at
      the time of surgery, but occlusion occurred subsequently. Except for the five
      failures resulting from arterial thrombosis, successful venous repair was
      possible in 49 of 59 replantations (83 percent). Despite the demand for skillful
      microsurgical technique and longer operation time, the authors' results using
      venous anastomosis in successful fingertip replantations are encouraging. By
      performing venous anastomosis, external bleeding can be avoided and a higher
      survival rate can be achieved. Venous anastomosis for fingertip replantation is a
      reliable and worthwhile procedure.

PMID- 12621186
TI  - Arterial reconstruction using the basilic vein from the zone of injury in
      pediatric supracondylar humeral fractures: a clinical and radiological series.
AB  - The authors describe the advantages of using the basilic vein as an arterial
      conduit in the management of children with supracondylar humeral fractures
      requiring vascular repair. Eight children, aged 3 to 10 years, presented with
      supracondylar humeral fractures and vascular injury. In all eight children, the
      arteries were successfully reconstructed with a reversed, interposition basilic
      vein graft harvested from the ipsilateral arm. The basilic vein was anatomically
      consistent with few side branches and was an excellent size match for the
      brachial artery. There were no postoperative thromboses. At a minimum follow-up
      of 1 year, all children had palpable radial pulses and the vein grafts were
      patent with no anastomotic or other focal stenoses. This series confirms the
      safety of using a donor vein from within the zone of injury for arterial
      reconstruction, after a supracondylar humeral fracture. Benefits include a single
      surgical wound on the less conspicuous medial side of the arm, reduced operating
      time, and preservation of donor veins that may be subsequently required for the
      management of atherosclerotic disease.

PMID- 12621187
TI  - The free thoracoumbilical flap for resurfacing large soft-tissue defects of the
      lower extremity.
AB  - Both cadavers and living patients were studied regarding a method to resolve
      large skin defects with bone exposure in the leg, with long-distance thrombosis
      of the anterior tibial vessels or posterior tibial vessels resulting from
      traumatic lesions. Forty-six casting mold specimens of cadaveric legs were
      investigated. There were rich communication branches among the anterior tibial
      artery, posterior tibial artery, and fibular artery in the foot and ankle, which
      complemented each other well. Twenty-six patients with large skin defects with
      bone exposure in the proximal or middle segment of the leg were admitted to the
      authors' hospital. Among those patients, 19 demonstrated long-distance thrombosis
      of the anterior tibial vessels or posterior tibial vessels resulting from
      traumatic lesions. During treatment, a thoracoumbilical flap based on the
      inferior epigastric vessels was anastomosed to the distal stump of the anterior
      tibial vessels or the posterior tibial vessels, with reversed flow. All defects
      were successfully repaired, with good color and texture matches of the flaps.
      This method can be used for patients with normal anterior tibial vessels or
      posterior tibial vessels, normal distal stumps of the injured blood vessels, and
      good reversed flow. The method has the advantages of dissecting blood vessels in
      the recipient area during the debridement, not affecting the blood circulation of
      the injured leg, not sacrificing blood vessels of the opposite leg, and not
      fixing the patient in a forced posture. The muscles are less bulky in the distal
      one-third of the leg, and the blood vessels are shallow and can be dissected and
      anastomosed easily. When the flap is used for reconstruction in the proximal two
      thirds of the leg, the blood vessel pedicle of the free flap is at a straight
      angle, without kinking.

PMID- 12621188
TI  - Cavernous nerve reconstruction to preserve erectile function following non-nerve
      sparing radical retropubic prostatectomy: a prospective study.
AB  - Erectile dysfunction following radical prostatectomy for treatment of clinically
      localized prostate cancer remains a problem that deters many men from seeking
      surgical treatment. Sparing the cavernous nerves has been popularized as a method
      of preserving potency, but men with locally advanced disease may be at increased
      risk for positive margins with this technique. In this study, sural nerve
      grafting of the cavernous nerve bundles, to preserve postoperative potency while
      potentially maximizing cancer control, was examined. Thirty men were enrolled in
      this prospective phase I study and underwent non-nerve-sparing radical
      prostatectomy performed by one of two protocol surgeons. Preoperative erectile
      function was assessed both objectively, using a RigiScan (Timm Medical
      Technologies, Inc., Eden Prairie, Minn.), and subjectively. The cavernous nerves
      were identified and resected during the operation with the use of an
      intraoperative mapping device (CaverMap; Alliant Medical Technologies, Norwood,
      Mass.). Bilateral autologous sural nerve grafting to the cavernous nerve stumps
      was performed by one of two protocol plastic surgeons. Postoperative erectile
      dysfunction therapy, using intracorporeal injection, a vacuum pump, and/or oral
      sildenafil therapy, was instituted 6 weeks after the operation. Spontaneous
      erectile activity was subjectively and objectively measured every 3 months after
      the operation. Follow-up periods ranged from 13 to 33 months (mean, 23 months).
      Overall, 18 of 30 patients (60 percent) demonstrated both objective and
      subjective evidence of spontaneous erectile activity. Of those 18 men, 13 (72
      percent) were able to have intercourse (seven unassisted and six with the aid of
      sildenafil). No disease or biochemical recurrences have been noted in this group
      of patients with locally advanced disease. In conclusion, autologous sural nerve
      grafting after non-nerve-sparing radical prostatectomy is an effective means of
      preserving spontaneous erectile activity after the operation while maximizing
      cancer control potential.

PMID- 12621189
TI  - Pseudo-iatrogenic hypospadias: the megameatus intact-prepuce hypospadias variant.
AB  - This article presents the authors' experience with 21 patients with the
      megameatus variant of hypospadias who were treated during an 8-year period. In
      nine of the cases, the parents were convinced that the defect was a complication
      of circumcision, and the patients were examined in consultations in preparation
      for litigation. Seven of those nine patients had been previously examined by
      either a plastic surgeon or a urologist, who failed to recognize this variant.
      The typical appearance of the defect and how to differentiate this congenital
      deformity from true iatrogenic hypospadias are described. The features of the
      megameatus intact-prepuce variant of hypospadias include a wide spatulated glans,
      a deep groove, a large wide patulous meatus at the subglanular groove, an intact
      prepuce before circumcision, no evidence of glanular scarring, and no history of
      bleeding at the time of circumcision.

PMID- 12621190
TI  - Increasing the volume of vascularized tissue formation in engineered constructs:
      an experimental study in rats.
AB  - The authors have previously described a model of in vivo tissue generation based
      on an implanted, microsurgically created vessel loop in a plastic chamber
      (volume, 0.45 ml) containing a poly(DL-lactic-co-glycolic acid) (PLGA) scaffold.
      Tissue grew spontaneously in association with an intense angiogenic sprouting
      from the loop and almost filled the chamber, resulting in a mean amount of tissue
      in chambers of 0.23 g with no added matrix scaffold and 0.33 g of tissue in PLGA
      filled chambers after 4 weeks of incubation. The aim of the present study was to
      investigate whether a greater volume of tissue could be generated when the same
      size vessel loop was inserted into a larger (1.9 ml) chamber. In four groups of
      five rats, an arteriovenous shunt sandwiched between two disks of PLGA, used as a
      scaffold for structural support, was placed inside a large polycarbonate growth
      chamber. Tissue and PLGA weight and volume, as well as histological
      characteristics of the newly formed tissue, were assessed at 2, 4, 6, and 8
      weeks. Tissue weight and volume showed a strong linear correlation. Tissue weight
      increased progressively from 0.13 +/- 0.04 g at 2 weeks to 0.57 +/- 0.06 g at 6
      weeks (p < 0.0005). PLGA weight decreased progressively from 0.89 +/- 0.07 g at 2
      weeks to 0.20 +/- 0.09 g at 8 weeks (p < 0.0005). Histological examination of the
      specimens confirmed increased tissue growth and maturation over time. It is
      concluded that larger quantities of tissue can be grown over a longer period of
      time by using larger-size growth chambers.

PMID- 12621191
TI  - Acceleration of healing, reduction of fibrotic scar, and normalization of tissue
      architecture by an angiotensin analogue, NorLeu3-A(1-7).
AB  - Angiotensin peptides have been demonstrated to modulate cellular proliferation,
      angiogenesis, and dermal repair. In this report, the effects of an analogue of
      the active angiotensin peptide angiotensin(1-7), namely norLeu3-angiotensin(1-7)
      (NorLeu3-A(1-7)), on the healing of epithelial wounds are presented. Three models
      were used to evaluate the normal (rats) and delayed (diabetic mice) healing
      responses of full-thickness excision wounds and the healing responses of full
      thickness incision wounds (rats). NorLeu3-A(1-7) was superior to the naturally
      occurring angiotensin peptide angiotensin(1-7) and to Regranex (Ortho McNeil,
      Somerville, N.J.) (a formulation of recombinant platelet-derived growth factor
      used clinically for the treatment of diabetic ulcers) in accelerating tissue
      repair. By day 9 (normal rats) and day 11 (diabetic mice), the differences in the
      rates of closure of full-thickness excision wounds between NorLeu3-A(1-7) and
      Regranex were statistically significant (n = 5 per group). Full healing was
      observed for 60 percent of the diabetic mice treated topically with NorLeu3-A(1
      7) by day 18 after injury, at which time full healing of wounds on placebo
      treated or Regranex-treated diabetic mice was not observed. In the rat incision
      model, accelerated healing and reduced gross appearance of scarification were
      observed. Administration of NorLeu3-A(1-7) reduced fibrosis and scarring in the
      healing wounds. This action was more pronounced with longer administration of the
      peptide after injury. In fact, if systemic administration of the peptide (NorLeu3
      A(1-7)) was continued during the remodeling phase, then the formation of new
      adnexal structures at the center of full-thickness excision wounds was observed,
      with an increase in the appearance of small immature hair follicles at the sites
      of the excision wounds. The action of this peptide was blocked by the AT receptor
      antagonist d-Ala7-angiotensin(1-7), which suggests that this receptor is involved
      in the healing responses to exogenous NorLeu3-A(1-7). These data suggest that
      this novel angiotensin peptide has the potential to be of benefit in accelerating
      wound repair and reducing scar formation.

PMID- 12621192
TI  - Improved dorsal random-pattern skin flap survival in rats with a topically
      applied combination of nonivamide and nicoboxil.
AB  - The effects of a topically applied combination of nonivamide and nicoboxil in
      improving skin perfusion and preventing distal flap necrosis were tested in a
      random-pattern dorsal skin flap model. Forty male Wistar rats were randomized
      into two groups (n = 20), and a standardized dorsal random-pattern skin flap was
      raised on each rat. Animals in the experimental group were treated with the
      topically applied drug combination four times per day for 6 days, whereas in the
      control group only a placebo ointment was applied each time. Skin flap viability
      was evaluated on day 7, and the extent of skin flap necrosis was compared between
      the two groups. The topically applied combination of nonivamide and nicoboxil
      resulted in a statistically significant decrease in skin flap necrosis, compared
      with the control group (mean percentage of skin flap necrosis in the
      nonivamide/nicoboxil-treated group, 22.6 +/- 6.0 percent; control group, 36.8 +/-
      4.3 percent; p< 0.05). The topical combination of nonivamide and nicoboxil was
      effective in reducing ischemic necrosis in failing random-pattern skin flaps in
      this rat model. The results of this study suggest that such a topical drug
      application might have significant effects in the reduction of ischemic necrosis
      in the distal parts of skin flaps, and this treatment might also have
      applications as prophylactic therapy for risky skin flaps.

PMID- 12621193
TI  - Effect of vascular endothelial growth factor-induced angiogenesis on TRAM flap
      harvesting after abdominoplasty.
AB  - In this study, the effect of intramuscular injection of human vascular
      endothelial growth factor (hVEGF) on neovascularization following abdominoplasty
      was investigated. Twenty-four Sprague-Dawley rats were divided into four groups
      (n = 6). Two control groups and two experimental groups were established.
      Abdominoplasty was performed in all rats, with division of all the perforator
      vessels. In the control groups, normal saline was injected into the rectus
      abdominis muscle, and in the experimental groups, 100 microg of VEGF and normal
      saline were injected into the rectus muscle. A transverse rectus abdominis
      musculocutaneous (TRAM) flap was harvested on day 20 and day 40 in both the
      control and experimental groups. The range of viability of the TRAM flap was,
      respectively, 0 to 20 percent (mean, 6.7 percent) and 0 to 25 percent (mean, 14.2
      percent) in both short-term and long-term control groups (no VEGF injected). The
      study (VEGF) group demonstrated a viability of 50 to 80 percent (mean, 70
      percent) for the short-term group and 50 to 85 percent (mean, 72.5 percent) in
      the long-term group. No wound infection was documented, and there were no deaths
      during the study period. There was no statistically significant difference
      between the short-term and long-term divisions of the groups (p < 0.01); however,
      significant differences were observed between the control and experimental groups
      (p < 0.01). The authors concluded that VEGF injection after abdominoplasty
      improved the percentage of TRAM flap viability. This method of
      delay/revascularization could be used for the difficult problem of flap viability
      following abdominoplasty and for high-risk patients.

PMID- 12621194
TI  - Nape of neck eyebrow reconstruction.

PMID- 12621195
TI  - Superior cheiloplasty by occipital scalp island flap in male patients.

PMID- 12621196
TI  - Schwannoma of the hand and wrist.

PMID- 12621197
TI  - Prefabricated alloplastic implants for cranial defects.

PMID- 12621198
TI  - Distraction osteogenesis of free osteocutaneous flap for treatment of severe
      facial asymmetry.

PMID- 12621199
TI  - Cutaneous neovaginoplasty using the Malaga flap (vulvoperineal fasciocutaneous
      flap): a 12-year follow-up.

PMID- 12621200
TI  - Regional isolated perfusion of extremities for melanoma: now a 26-year experience
      with drugs other than L-phenylalanine mustard.

PMID- 12621201
TI  - As I remember: becoming a plastic surgeon and my three years (1943 to 1946) with
      the Vilray P. Blair group.

PMID- 12621202
TI  - Risks associated with "components separation" for closure of complex abdominal
      wall defects.
AB  - The reconstruction of complex abdominal wall defects can often pose a significant
      challenge to surgeons and their patients. Complex ventral hernias may result from
      large tumor resections, trauma from gunshot wounds, or infections following
      routine abdominal surgery. "Components separation" of the abdominal musculature
      uses advancement of local autologous tissue, when available, to close large
      ventral wall defects. The authors report on a retrospective chart review of 30
      patients who underwent components separation for the closure of complex abdominal
      defects. The study group was 50 percent female, with a mean age of 45 years, body
      mass index of 33.2 kg/m2, and abdominal defect size of 240 cm2. On average, 20
      percent of patients had preoperative wound infections, 30 percent had
      intraoperative bowel enterotomies, and 33 percent required prosthetic mesh for
      closure. Total surgery time averaged 4.8 hours, with a mean postoperative stay of
      12.5 days and follow-up of 9.5 months. The recurrence rate was 10 percent;
      postoperative complications included midline ischemia, infection, and dehiscence
      occurring at rates of 20, 40, and 43 percent, respectively. This study provides a
      comprehensive review of the risks and complications associated with the treatment
      of complex ventral hernias and those associated with abdominal "components
      separation."

PMID- 12621203
TI  - The making of a plastic surgeon: present and future.

PMID- 12621204
TI  - Carbon dioxide laser resurfacing and thin skin grafting in the treatment of
      "stable and recalcitrant" vitiligo.
AB  - Various surgical methods have been used in the treatment of small stable
      vitiliginous areas, but there is no established surgical approach for larger
      vitiligo areas and therapy-resistant anatomic sites, such as the hands. Two years
      ago, we successfully treated large burn scar depigmentation areas at different
      anatomic sites using carbon dioxide laser resurfacing and thin (0.2 to 0.3 mm)
      skin grafting. The purpose of this study was to investigate the effectiveness of
      our method in treating large, stable, and recalcitrant vitiligo areas. Thirteen
      anatomic sites of seven male patients, whose ages ranged from 20 to 22 years,
      were treated. The locations of the treated areas were as follows: seven areas on
      the dorsum of the hands, two areas on the forearms, two areas in the pretibial
      region, one area on the lateral thigh, and one area in the presternal region. The
      surface area of treated vitiligo sites ranged from 0.5 to 6 percent of total body
      surface area (mean, 2.5 percent). Skin graft take was excellent in all patients
      except for one. The follow-up period for these patients ranged from 6 to 18
      months, with an average follow-up period of 14 months. Early and complete
      repigmentation was achieved and the color match was good or excellent in all
      patients. No depigmentation occurred again in the treated areas or graft donor
      sites. In conclusion, with careful patient selection and delicate surgical
      technique, our method was effective in treating large areas of vitiligo over the
      extremities and dorsum of hands, which were refractory to other therapies and
      could not be hidden.

PMID- 12621205
TI  - Lower eyelid blepharoplasty: analysis of indications and the treatment of 100
      patients.
AB  - Traditionally, lower lid blepharoplasty has been confined to a choice of skin or
      skin-muscle flap transcutaneous blepharoplasty. In the past decade, in
      particular, various new techniques and technologies have emerged, altering our
      ability to treat the lower eyelids. These techniques include transconjunctival
      blepharoplasty, a variety of canthopexy procedures, fat-conserving or fat
      replacing methods, wedge excision, and laser resurfacing techniques, and they
      allow a more individualized approach based on variations in anatomical features
      and patient goals. A retrospective review of data for 100 consecutive patients
      (ranging in age from 30 to 80 years) who underwent lower eyelid procedures during
      a 12-month period is presented. Procedures were categorized as follows: lower lid
      blepharoplasty, 35 cases; lower lid transconjunctival blepharoplasty, 27 cases;
      lower lid transconjunctival blepharoplasty with laser resurfacing, 17 cases;
      lower lid laser resurfacing, 16 cases; tarsorrhaphy with lower lid operation,
      three cases; tarsorrhaphy with laser resurfacing, two cases. Two complications of
      retained fat pads (one medial and one lateral) were encountered and were
      addressed with a secondary operation using a transconjunctival blepharoplasty
      approach. The results indicate that laser treatment has become the predominant
      form of lower eyelid resurfacing and that transconjunctival blepharoplasty is now
      the most common surgical procedure for the lower eyelid. All of our tarsorrhaphy
      procedures were performed for patients who had previously undergone surgical
      treatment of the lower eyelids. An algorithm based on physical findings and these
      techniques has been developed, for appropriate tailoring of the procedure to each
      patient's specific concerns. With the availability of a variety of techniques, an
      individualized approach based on variations in anatomical features is feasible.

PMID- 12621206
TI  - Nasal augmentation with Surgicel-wrapped diced cartilage: a review of 67
      consecutive cases.
AB  - Cartilage grafting has been used extensively to correct both the functional and
      aesthetic aspects of the nasal framework. The technique described by Erol ( 105:
      2229, 2000) uses Surgicel-wrapped diced cartilage grafts in rhinoplasties. The
      advantages include its ease of preparation, the large volume of graft substrate
      available for use, and the avoidance of contour irregularities in the areas of
      placement. A retrospective case review of 67 consecutive patients who were
      treated with a Surgicel-wrapped diced cartilage graft as part of an aesthetic
      and/or functional rhinoplasty, in a 5-year period between 1995 and 2000, was
      performed in this study. All cases of congenital nasal deformities or deformities
      caused by trauma or tumors in which the technique was used were excluded. The
      charts were reviewed to determine demographic variables, the surgical procedures
      performed, prior operations, the rhinoplasty approach used, and the graft donor
      and recipient sites. Preoperative and postoperative photographs were examined,
      and the results were assessed. Data on the donor and recipient sites,
      complications, and the necessity for revisionary procedures were tabulated. There
      were two complications, namely, an infection, which resolved with aspiration and
      oral antibiotic therapy, and a recurrence of a dorsal depression, which
      necessitated repeated augmentation within 6 months. The technique of using
      Surgicel-wrapped diced cartilage proved to be effective for the augmentation of
      various areas of the nose. The complication and revision rates were acceptable
      and comparable to those of other techniques. Patient satisfaction with the
      aesthetic results was rated highly, with no reports of graft extrusion or contour
      irregularities. This technique is recommended for nasal augmentation and
      contouring for selected rhinoplasty patients.

PMID- 12621207
TI  - Rhinoplasty in the African-American patient.
AB  - Because of the increasing popularity of rhinoplasty in the African-American
      patient, we delineate how a rhinoplasty surgeon can perform this challenging
      technique to obtain uniform and consistent results. First, we address how one can
      appreciate and analyze the various aesthetic concepts of beauty and the unique
      anatomic characteristics of the African-American nose. Second, we present a
      pragmatic, systematic analysis of the African-American nose. Last, we describe
      the techniques consistently used to modify the African-American nose while
      achieving or maintaining facial harmony using the open approach to rhinoplasty.
      Specific case analyses are presented to demonstrate utilization of the technique.

PMID- 12621208
TI  - Cervicoplasty: nonexcisional anterior approach. A 10-year follow-up.

PMID- 12621209
TI  - The media and plastic surgery: on being what you want to become.

PMID- 12621210
TI  - "What's in a name?".

PMID- 12621211
TI  - Just stop.

PMID- 12621212
TI  - The caudal trapezius musculocutaneous flap.

PMID- 12621213
TI  - The tendon pin: a modified safety pin for tendon surgery.

PMID- 12621214
TI  - Protective rat vest for a tail suspension model.

PMID- 12621216
TI  - The re-usable medicinal leech.

PMID- 12621215
TI  - Safe drainage by puncture of postmastectomy seroma in a patient with immediate
      reconstruction using an expander.

PMID- 12621217
TI  - Management of soft-tissue problems in leg trauma in conjunction with application
      of the Ilizarov fixator assembly.

PMID- 12621218
TI  - Reconstruction of a perianal defect after basal cell carcinoma using bilateral V
      Y advancement fasciocutaneous flaps.

PMID- 12621219
TI  - Reduction mammaplasty using inferior pedicle technique combined with dermal
      suspension.

PMID- 12621220
TI  - Silicone implants, granulomas, and chronic infection: a causal relationship?

PMID- 12621221
TI  - The new bilaterally pedicled V-Y advancement flap for face reconstruction.

PMID- 12621222
TI  - Another reason for the choice of horizontal incision: a geometric illusion.

PMID- 12621223
TI  - Vaginal reconstruction after pelvic exenteration.

PMID- 12621224
TI  - A role for the anesthesiologist in elective cosmetic surgery.

PMID- 12621225
TI  - Upper eyelid ptosis repair after cataract extraction and the importance of
      Hering's test.

PMID- 12621226
TI  - Digital photography for rhinoplasty.

PMID- 12621227
TI  - Chin augmentation with nasal osteocartilaginous graft.

PMID- 12621228
TI  - Hammock flap.

PMID- 12621230
TI  - Inappropriate suction dressings.

PMID- 12621229
TI  - Stafne's bone cyst.

PMID- 12621231
TI  - Prefabricated fascial flap for hand and forearm defects.

PMID- 12621232
TI  - Hair removal technology.

PMID- 12621234
TI  - Comments from the editor-in-chief. Infectious complications of cancer treatment.
      Survivorship and treatment-related toxicities: how well are we doing?

PMID- 12621235
TI  - Hepatitis B and C infection in children undergoing chemotherapy or bone marrow
      transplantation.
AB  - Despite preventive measures, patients who have cancer or who undergo bone marrow
      transplantation remain at higher risk of viral infection since they often receive
      multiple blood products. This category of patients also includes subjects from
      countries that are highly endemic for hepatitis B virus and hepatitis C virus
      infection and who travel to developed countries for specialized treatment. This
      review discusses the current opinions concerning the diagnostic, clinical, and
      therapeutic aspects of hepatitis B and C virus infection in different groups of
      patients: children with chronic infection before chemotherapy, children infected
      during chemotherapy or bone marrow transplantation, and patients with chronic
      infection after the end of treatment.

PMID- 12621236
TI  - Summary of the 12th Nikolas Symposium dendritic cell differentiation: signals,
      signaling and functional consequences as clues to possible therapy.

PMID- 12621237
TI  - Medulloblastomas with systemic metastases: evaluation of tumor histopathology and
      clinical behavior in 23 patients.
AB  - PURPOSE: To review the clinical behavior and histopathologic features of
      medulloblastomas that metastasize outside the central nervous systems (CNS).
      PATIENTS AND METHODS: The authors studied 23 cases of medulloblastomas that
      metastasized outside the CNS. The patients included 15 males and 8 females, ages
      1 to 40 years at initial diagnosis (median 8.5). Five of the patients were over
      20 years of age at diagnosis. The histologic grade of anaplasia was determined
      for each case. RESULTS: Extra-CNS metastases were identified at initial
      presentation in four individuals and up to 11 years later in the remaining cases.
      Metastatic sites included bone/bone marrow (21 cases), soft tissue/lymph nodes (3
      cases), and lung (1 case). In seven cases, multiple extra-CNS metastatic sites
      were documented. Of the patients with available clinical follow-up after
      metastasis, 10 died of their disease 1 to 39 months after detection of extra-CNS
      metastases (median 9 months), while 5 are alive 16 to 120 months after extra-CNS
      metastasis (median 45 months). Moderate or severe anaplasia was detected in 8 of
      20 intracranial specimens (40%) and in 4 of 6 extra-CNS metastases (66%); these
      frequencies are higher than observed in medulloblastomas overall. Tissue from
      both the initial resection and subsequent recurrence or metastasis was available
      in six cases. The anaplasia grade was higher upon recurrence or metastasis in
      four of these six, consistent with tumor progression. CONCLUSIONS: Metastasis of
      medulloblastomas outside the CNS can occur after long periods of clinical
      remission and is associated with anaplasia in some cases. Medulloblastomas can
      show histologic progression on recurrence or metastasis.

PMID- 12621238
TI  - Prognostic significance of the TEL-AML1 fusion gene in pediatric acute
      lymphoblastic leukemia in Turkey.
AB  - PURPOSE: The t(12;21) translocation is the most common reciprocal chromosomal
      rearrangement in pediatric acute lymphoblastic leukemia (ALL). This translocation
      fuses two genes, TEL and AML1, and results in the production of the TEL-AML1
      fusion protein. The authors investigated the incidence and prognostic
      significance of the TEL-AML1 fusion gene in patients with ALL in Turkey. METHODS:
      The authors analyzed 219 children with ALL using the reverse transcription
      polymerase chain reaction. RESULTS: The TEL-AML1 fusion transcript was detected
      in 20.1% (44/219) of newly diagnosed children with ALL. -positive patients had
      precursor B-cell ALL and were 3 to 10 years old at diagnosis. -positive patients
      had a significantly lower rate of relapse compared with -negative patients. 
      positive patients have a higher overall survival rate than -negative patients.
      CONCLUSIONS: These data support that the presence of at diagnosis is an
      independent favorable prognostic indicator in patients with ALL in Turkey.

PMID- 12621239
TI  - Impaired tubular excretory function as a late renal side effect of chemotherapy
      in children.
AB  - PURPOSE: Renal drug excretion is variously influenced by nephrotoxic drugs. This
      study was designed to evaluate renal function as a late renal side effects in
      children receiving combination chemotherapy for malignancy. PATIENTS AND METHODS:
      Follow-up studies of 30 newly diagnosed patients were performed a median of 12
      months after completion of chemotherapy. The glomerular filtration rate (GFR) was
      measured using sodium thiosulfate. The following were also assessed: urinary high
      molecular-weight fraction (urinary albumin/urinary creatinine ratio); para
      aminohippurate (PAH) clearance; urinary low-molecular-weight fraction (urinary
      beta2-microglobulin/urinary creatinine ratio); and routine serum and urinary
      parameters. RESULTS: Serum and urinary electrolytes were normal in most patients.
      GFR was low in four patients (13%). Urinary high-molecular-weight fraction was
      elevated in two patients. Urinary low-molecular-weight fraction was elevated in
      one patient. PAH clearance was below the referenced normal value in 73% of the
      patients. CONCLUSIONS: This report demonstrates decreased PAH clearance as a late
      renal side effect of chemotherapy and suggests disturbed function of the organic
      anion transport system. The unexpected high serum concentration of drugs excreted
      through the organic anion transport system may induce severe side effects.
      Elucidation of the mechanism and clinical relevance of decreased PAH clearance is
      warranted.

PMID- 12621240
TI  - Effects of therapy on dentofacial development in long-term survivors of head and
      neck rhabdomyosarcoma: the memorial sloan-kettering cancer center experience.
AB  - PURPOSE: To describe potential effects of multimodality therapy on dental and
      facial development in long-term survivors of head and neck rhabdomyosarcoma.
      PATIENTS AND METHODS: The medical records of all patients aged 20 years or less
      presenting between 1985 and 1996 with a diagnosis of rhabdomyosarcoma and treated
      by protocol were reviewed. Head and neck rhabdomyosarcoma patients who were
      followed in the Dental Service and were alive and free of disease with at least a
      5-year follow-up were included in the review. Ten patients satisfied the
      inclusion criteria and form the basis of this report. The median age at diagnosis
      of the 10 patients was 4.3 years (range 10 months to 19.5 years). All patients
      were treated with chemotherapy, two patients underwent surgery, and all but one
      patient received external beam radiation therapy. RESULTS: Clinical or
      radiographic dentofacial abnormalities were observed in 8 of the 10 (80%)
      patients. Abnormalities included enamel defects, bony hypoplasia/facial
      asymmetry, trismus, velopharyngeal incompetency, tooth/root agenesis, and
      disturbance in root development. Bony hypoplasia and disturbance in root
      formation were the most common findings. CONCLUSIONS: Multimodality therapy for
      head and neck rhabdomyosarcoma can result in dentofacial abnormalities that
      affect the patient's quality of life. The care of the long-term survivor requires
      a multidisciplinary approach, including early involvement of the dental team.

PMID- 12621241
TI  - Psychosocial needs of families with a child with cancer.
AB  - PURPOSE: The aims of this study were to map the problems and needs of children
      with cancer and their families with regard to possible psychosocial
      interventions, and to do an acceptability study of different ways to provide
      support. METHODS: The authors performed a cross-sectional structured telephone
      interview with 56 parents of children with cancer and 13 adolescents from these
      families. On 0 to 10 analog scales, parents and adolescents rated the importance
      of different needs, how these needs had been met, the acceptability of different
      ways of providing supportive interventions, how often these ways had been used,
      and comfort using them. RESULTS: Parents' mean rating of importance of
      information needs was 9.42, peer social support 7.84, and self-management therapy
      9.21. The ratings of how well these needs had been met were 8.05, 5.30, and 7.13,
      respectively. Both parents and adolescents ranked getting information written on
      paper highest, preferred to communicate in a face-to-face support group for peer
      social support, and preferred a therapist for self-management therapy. The
      comfort ratings for using different ways to provide the interventions were all
      high, as was access; 89% of families had computers in their homes, 76% had
      Internet access. CONCLUSIONS: The needs for information, peer social support, and
      self-management therapy are all high. There is still room to meet these needs
      better. Using paper-based, telephone, computer CD, or an interactive Web-based
      intervention package all seem to be acceptable and accessible ways to meet the
      needs and might reduce the risk of families developing psychosocial problems.

PMID- 12621242
TI  - Combination therapy for refractory idiopathic thrombocytopenic purpura in
      adolescents.
AB  - PURPOSE: To investigate combined immunosuppressive therapy with vincristine,
      methylprednisolone, and prolonged cyclosporine in adolescents with refractory
      idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Ten adolescent
      patients with ITP refractory to previous medical management, including gluco
      corticosteroid, intravenous immunoglobulin or anti-Rh (D) IgG, or splenectomy,
      were treated with combination immunosuppressive therapy at the University of
      Michigan between 1997 and 2001. Therapy consisted of weekly doses of vincristine
      1.5 mg/m intravenous push (IVP) (maximum dose 2 mg), weekly methylprednisolone
      100 mg/m IVP, and cyclosporine (CSA) 5 mg/kg orally twice daily (goal: CSA trough
      of 100-200 mg/mL). Vincristine and methylprednisolone were given weekly until the
      platelet count was greater than 50,000/mm for a minimum of 2 doses and a maximum
      of 4 doses. CSA was continued until the platelet count was normal for 3 to 6
      months. RESULTS: Seven patients had continuous complete responses (platelet count
      normal after cessation of CSA), a median of 13 months (9-37 months) since
      completion of therapy. One patient had a partial response (platelet count 80-120
      x 10 /L off CSA for 3 months). Two patients were nonresponders (platelet count
      <40 x 10 /L), one of whom had all therapy discontinued after 2 weeks due to
      peripheral neuropathy. The median time to response was 7 days (range 7-67 days).
      CSA was administered for a median of 4 months (range 0.5-19 months). CONCLUSIONS:
      A combination immunosuppressive approach that includes prolonged cyclosporine
      therapy may be promising for refractory ITP and is associated with sustained
      disease remissions in some patients.

PMID- 12621243
TI  - Reversible posterior leukoencephalopathy syndrome in children with cancers.
AB  - We report three cases of reversible posterior leukoencephalopathy syndrome (RPLS)
      in children with cancers. All patients presented with sudden confusional state,
      visual disturbance, and transient mild hypertension under the treatment of
      childhood cancers. Magnetic resonance imaging of the brain demonstrated cortical
      and subcortical lesions predominantly in the occipital region, which showed high
      intensity signal on fluid-attenuated inversion recovery images. All patients
      completely recovered from their neuropsychologic deficits only with
      antihypertensive therapy or discontinuation of the possible offending drugs.
      Early recognition of RPLS as a complication during cancer therapy in childhood
      may facilitate precise diagnosis and appropriate treatment.

PMID- 12621244
TI  - Congenital acute myelogenous leukemia presenting as palpable renal masses in a
      neonate.
AB  - Our report concerns a neonate who was noted to have palpable kidneys soon after
      birth. Her clinical and radiologic findings were compatible with the diagnosis of
      autosomal recessive polycystic kidney disease. The patient eventually died of
      sepsis-related multiorgan failure, and on autopsy, surprisingly, was found to
      have leukemic infiltrates in the kidney. Healthcare providers need to be aware
      that congenital acute myelogenous leukemia, although rare, can present in the
      newborn period with nephromegaly.

PMID- 12621245
TI  - Atypical presentation and progression of glioblastoma multiforme in a 6-year-old
      girl: multidisciplinary case report.
AB  - Glioblastoma multiforme is the most common adult malignant brain tumor but is
      notably less common in children. The authors describe the case of a child who
      presented for evaluation and treatment of neurologic signs caused by a brain stem
      glioma. Response to radiotherapy and chemotherapy with temozolomide was initially
      positive, but later extensive leptomeningeal metastasis developed. Biopsy proved
      the lesion to be glioblastoma multiforme. During salvage irradiation to the spine
      and unirradiated brain, the patient complained of hip and femur pain. Subsequent
      radiographs demonstrated multiple bony metastases. This pattern of spread is
      uncharacteristic and emphasizes the importance of adequate metastatic evaluation.

PMID- 12621246
TI  - Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage
      syndrome.
AB  - A 3-year-old child with microcephaly, facial dysmorphism, growth retardation, and
      developmental delay was diagnosed with medulloblastoma. Craniospinal irradiation
      resulted in severe radiation-induced dermatitis and gastroesophagitis,
      unresponsive to further medical therapy. Colony survival assay on the patient's
      transformed lymphocytes revealed a high degree of radiosensitivity ex vivo. The
      presence of radiation sensitivity, both clinically and ex vivo, in association
      with microcephaly and growth retardation, prompted a diagnostic workup for
      Nijmegen breakage syndrome. The patient was confirmed to have a compound
      heterozygote genotype for the common founder mutation of NBS1 675del5 in exon 6,
      and 1142delC in exon 10. Because irradiation is an important component of therapy
      for brain tumors, caution should be exercised in cancer patients with associated
      microcephaly and growth retardation, as they may turn out to have the rare
      diagnosis of Nijmegen breakage syndrome.

PMID- 12621247
TI  - Successful treatment of invasive aspergillosis in two patients with acute
      myelogenous leukemia.
AB  - Invasive aspergillosis is a severe, devastating fungal infection that is seen in
      patients with hematologic malignancies and profound neutropenia. Despite
      aggressive treatment, the outcome is poor without neutrophil recovery. The
      authors describe two children with acute myelogenous leukemia (AML) with
      extensive invasive aspergillosis who were successfully treated both for their
      infection and the underlying malignancy. These patients were treated aggressively
      for their infections and simultaneously were able to complete treatment of their
      AML. Currently both patients are alive without evidence of fungal infection or
      AML. Patients with hematologic malignancies can survive severe, invasive
      aspergillosis during prolonged periods of neutropenia with a combination of
      antifungal and growth factor therapies, donor granulocyte infusions, and surgical
      debridement.

PMID- 12621248
TI  - Resolution of chronic hepatic sequestration in a patient with homozygous sickle
      cell disease receiving hydroxyurea.
AB  - Hepatic sequestration is an uncommon complication in patients with homozygous
      sickle cell disease. Although transfusion therapy has been effective for the
      acute condition, no definitive treatment of chronic hepatic sequestration has
      been identified. We describe a 17-year-old male patient with hemoglobin SS and
      chronic hepatic sequestration who was treated with long-term (60 months)
      hydroxyurea. After 36 months of HU therapy, the patient had both an excellent
      hematologic response and a resolution of hepatic sequestration, as evidenced by
      disappearance of clinical hepatomegaly, normalization of liver volume on serial
      computed tomography scans, as well as decreased sinusoidal dilatation and
      congestion and red blood cell sickling on liver biopsy. The findings in this case
      suggest that hydroxyurea may benefit patients who have unusual complications of
      sickle cell disease, such as chronic erythrocyte sickling in the liver.

PMID- 12621249
TI  - Homozygous hemoglobin Tak causes symptomatic secondary polycythemia in a Thai
      boy.
AB  - Secondary polycythemia caused by high-oxygen-affinity hemoglobin is rare in
      children. Most patients with this condition have asymptomatic erythrocytosis. In
      this article the authors describe a young boy from Thailand with plethora,
      hypoxemia, and aggravated respiratory distress following a chest infection.
      Hematological and molecular studies revealed that the boy is homozygous for Hb
      Tak, an extended beta-globin variant with high oxygen affinity. This report of a
      patient who is homozygous for high-oxygen-affinity hemoglobin highlights the
      clinical significance of this hemoglobin disorder, which has been previously
      reported in several unrelated families from Southeast Asia.

PMID- 12621250
TI  - CD62 expression during thrombus formation.
AB  - A large right atrial mass was discovered in a 16-year-old female patient
      receiving chemotherapy treatment for Hodgkin disease. The patient was
      participating in a platelet function research study. During laboratory
      examination of platelet activation, increasing CD62 and CD63 expression were
      found to mirror the clot formation. Further investigation of platelet expression
      of CD62 and CD63 by flow cytometry might reveal it to be a valuable tool in
      predicting impending thrombus formation.

PMID- 12621251
TI  - Congenital self-healing langerhans cell histiocytosis with atrophic recovery of
      the skin: clinical correlation of an immunologic phenomenon.
AB  - The pathophysiology and pathogenesis of congenital self-healing Langerhans cell
      histiocytosis (CSHLCH) as well as that of the other types of Langerhans cell
      histiocytosis is not well understood. Some authors postulate deregulated
      immunologic mechanisms that result in overproduction of cytokines. We examined a
      neonate with disseminated papulonodular eruptions containing lymphoid aggregates
      of B lymphocytes in the chorial layer. The diagnosis of a CSHLCH was made and the
      follow-up showed a complete involution of the eruptions, leaving atrophic lesions
      in the sites corresponding to the initial findings. We discuss a possible
      imbalance of the immune response as a pathogenetic mechanism.

PMID- 12621252
TI  - Alpha-1 antitrypsin deficiency: an overlooked cause of late hemorrhagic disease
      of the newborn.

PMID- 12621253
TI  - Hypoparathyroidism in beta-thalassemic patients.

PMID- 12621255
TI  - Physeal fractures of the distal radius and ulna: long-term prognosis.
AB  - OBJECTIVES: The long-term prognosis of injuries to the distal physis of forearm
      bones, including complications such as radioulnar length discrepancy and styloid
      nonunion, has not been extensively studied. Reliable radiographic prognostic
      criteria to predict physeal disturbance at trauma are also lacking. The aim of
      this study is to investigate both issues. DESIGN: Retrospective study. SETTING:
      University hospital. PATIENTS/PARTICIPANTS: One hundred sixty-three lesions to
      the distal physis of the forearm bones in 157 patients were available for a long
      term follow-up. Seventy-seven injuries of the distal radial physis were
      radiographically isolated, 54 were associated with a fracture of the ulnar
      styloid, and 26 with a fracture of the distal ulnar metaphysis. Of the six
      injuries of the distal ulnar physis, five were associated with a fracture of the
      distal radial metaphysis, and one was an isolated injury of the distal ulnar
      physis. INTERVENTION: Treatment consisted of wrist immobilization in a long-arm
      plaster cast for 6 weeks. Dorsal or volar displacement was reduced using general
      anesthesia. MAIN OUTCOME MEASUREMENTS: All patients had both clinical and
      radiographic evaluation, with an average follow-up of 25.5 years (range 14-46
      years). The average age of the patients at injury was 11.6 years (range 5-17
      years), whereas their average age at follow-up was 35.5 years (range 22-56
      years). Both the Salter and Harris and the Ogden classifications were used to
      classify physeal injuries. RESULTS: According to Salter and Harris, of the 157
      radial lesions, 18 were type 1 and 139 type 2. According to Ogden, 14 were type
      1A, 4 type 1C, 84 type 2A, 13 type 2B, 17 type 2C, and 25 type 2D. Of the 6 ulnar
      lesions, 2 were Salter and Harris type 1 (Ogden type 1A), 3 type 2 (Ogden type
      2A), and 1 type 4 (Ogden type 4A). Fifty-four radiographically evident fractures
      of the ulnar styloid associated with injuries of the distal radial physis were
      classified as Ogden type 7A. At follow-up, all of our patients were fully
      asymptomatic, except for those who had forearm bone growth failure of more than 1
      cm. Shortening of the previously injured forearm bones ranging from 1 to 6.5 cm
      was observed in 2 open and subsequently infected lesions as well as in 5
      uncomplicated lesions of the 157 distal radial physeal injuries (4.4%), and in 3
      of the 6 distal ulnar physeal injuries (50%). Shortening of 1 cm or more was
      observed in the uncomplicated lesions of radial physeal injury with Ogden type
      1C, 2B, and 2D lesions, and in ulnar physeal injuries Ogden type 1A, 2A, and 4A.
      Thirty-eight additional patients had radioulnar length discrepancy that ranged
      from 2 to 9 mm, and 53 patients had styloid nonunion, but all of them were
      asymptomatic. CONCLUSIONS: None of the patients reviewed at follow-up, including
      those with radioulnar length discrepancy of less than 1 cm and those with styloid
      nonunion, complained of any symptom related to their previous injury, not even
      those engaged in heavy manual labor. Of the 10 patients with either radial or
      ulnar shortening of more than 1 cm, only 2 with radial growth arrest and marked
      radioulnar length discrepancy had severe functional problems. Growth disturbances
      of more than 1 cm following distal radial physeal injury occurred only in Ogden
      type 1C, 2B, and 2D lesions, whereas in distal ulnar physeal injuries, growth
      disturbances occurred regardless of the Ogden classification type.

PMID- 12621257
TI  - Prognostic factors in prosthetic replacement for acute proximal humerus
      fractures.
AB  - OBJECTIVES: To investigate the effect of some epidemiological and radiologic
      factors on the outcome of prosthetic replacement in acute proximal humerus
      fractures. DESIGN: Retrospective clinical study. PATIENTS: Thirty-two patients
      [mean age 58 (range 37-83 years)] with a mean follow-up period of 35 months
      (range 8-80 months). Fifteen cases had Neer type IV, 2 had type III, and 15
      patients had fracture-dislocations. MAIN OUTCOME MEASUREMENTS: Neer's criteria,
      Constant score, and elevation degree were used. Radiological parameters were
      union and position of the tuberosities, bone stock, and position of the
      prosthesis. RESULTS: Excellent or good results according to Neer's criteria were
      obtained in 24 of the 32 cases (75%), and unsatisfactory results in 8 cases
      (25%). Mean Constant score was 68 (range 19-98) and mean elevation degree 113
      (range 30-180). Thirty-one cases (97%) had no or mild pain. Cases operated within
      14 days following injury had a better general outcome (p = 0.005). The humeral
      offset was directly correlated to the elevation degree (p = 0.011) and Constant
      score (p = 0.002), whereas the head height was inversely correlated to the same
      parameters (p = 0.001 for both). The cutoff point for the humeral offset-general
      outcome correlation was calculated as 23 mm using ROC curve analysis. The most
      common complications were problems concerning the tuberosities (50%), and they
      adversely affected the clinical outcome (p = 0.002). CONCLUSIONS: Preoperative
      delay, problems of tuberosity fixation, and position of the tuberosities were
      parameters influencing the clinical outcome. Lateralization of the tuberosities
      results in better scores, whereas their distal transfer can be related to a
      poorer outcome.

PMID- 12621259
TI  - Late outcome of nonoperative management of thoracolumbar vertebral wedge
      fractures.
AB  - OBJECTIVES: To study the medical and social outcome of nonoperative management of
      traumatic thoracolumbar vertebral wedge fractures in the absence of neurologic
      damage. DESIGN: Retrospective review of data, as elicited from records and from
      patients. SUBJECTS AND METHODS: We retrieved the hospital records of 85
      consecutive patients who conformed to the foregoing definition and whose
      admission for fracture had taken place at least 3 years earlier. The current
      status of each patient was inquired into by a mailed questionnaire designed to
      determine: 1) presence and severity of back pain; 2) presence and magnitude of
      overall disability; and 3) current work capacity, postinjury employment history,
      and history of litigation concerning the injury. Using the last radiographs of
      the spine, measurements were taken of anterior column deformity (Willen formula)
      and degree of local, fracture-related kyphosis (lateral angle of Cobb).
      Correlations between paired variables and group comparisons with respect to means
      of pain indices were analyzed statistically by analysis of variance (chi 2) and
      regression analysis. RESULTS: Chronic pain predominant in the lower lumbar area
      was reported in 69.4% of subjects. Mean pain index was 2.94 +/- 2.67 on a scale
      of 1 to 10. The mean overall disability score was 56.3 +/- 14.2 on a scale of 1
      to 100. Pain intensity was correlated with angle of local kyphosis (p = 0.04) but
      not with magnitude of anterior column deformity. Twenty-five percent of the
      subjects had changed jobs, mostly from full- to part-time employment. Forty-eight
      percent of patients who filed lawsuits concerning their injury versus 11% of
      those who did not (p = 0.04) were absent from work for > or = 6 months.
      CONCLUSIONS: Traumatic, uncomplicated thoracolumbar wedge fractures of the
      vertebral body, below given limits of local kyphosis and anterior column
      deformity, are adequately managed by a limited period of bed rest alone. Surgery,
      bracing, and intensive physiotherapy are not indicated.

PMID- 12621260
TI  - Primary total hip arthroplasty with a Burch-Schneider antiprotrusion cage and
      autologous bone grafting for acetabular fractures in elderly patients.
AB  - OBJECTIVES: To investigate the clinical and functional outcome in an elderly
      population with acetabular fractures after low-energy trauma treated acutely with
      a total hip arthroplasty supported by a reinforcement ring (Burch-Schneider
      antiprotrusion cage) and autologous bone grafting of the acetabulum. SETTING:
      University hospital. DESIGN: Retrospective clinical study. PATIENTS: Ten patients
      (7 males) available for follow-up, with a mean age at the time of surgery of 73
      years (range 57-87). The mean time to follow-up was 38 months (range 11-84).
      INTERVENTION: Primary total hip arthroplasty supported by a reinforcement ring
      (Burch-Schneider Antiprotrusion Cage) and autologous bone grafting of the
      acetabulum. MAIN OUTCOME MEASUREMENTS: Surgical data, complications, radiographic
      assessment, pain, walking ability, Harris Hip Score, activities of daily living,
      health-related quality of life according to EuroQol (EQ-5D). RESULTS: The mean
      operating time was 159 minutes (range 125-185). The mean intraoperative blood
      loss was 1100 mL (700-1600 mL). The reinforcement ring was stable and there were
      no signs of loosening of the acetabular component or stem in any of the patients.
      The bone graft was completely incorporated in all cases. Four patients presented
      slight (Brooker I-II) heterotopic bone formation. All patients were still
      independent walkers at follow-up but with a slightly increased need for walking
      aids. The mean Harris Hip Score was 85 (range 69-99). The mean EQ-5D(index) score
      was 0.62. CONCLUSION: Primary total hip replacement with a reinforcement ring and
      bone grafting of the socket seems to be a promising treatment alternative in
      displaced acetabular fractures in elderly patients with osteoporotic bone, except
      in those with an increased risk of dislocation.

PMID- 12621261
TI  - Knee dislocations: where are the lesions? A prospective evaluation of surgical
      findings in 63 cases.
AB  - OBJECTIVE: To evaluate soft-tissue injury patterns in a large series of patients
      with knee dislocations to identify frequency and associations that may aid in
      surgical planning. DESIGN: Prospective clinical study. SETTING: Two institutions,
      both level I trauma centers. PATIENTS: Sixty patients with 63 dislocatable knees.
      RESULTS: Cause of injury was motor vehicle injury in 34 patients, sports in 23
      patients, and falls in 3 patients; 71% of knees studied had bicruciate injuries.
      Eight knees had associated major intraarticular fractures. Vascular disruption
      occurred in 14% of knees. Peroneal nerve palsies occurred in 14% of knees. All
      injured knees with complete peroneal nerve palsies had anterior cruciate
      ligament, posterior cruciate ligament, and lateral collateral ligament
      disruptions. The incidence of vascular injury was the same for patients injured
      in sports as for those injured in road trauma. Reattachable ligamentous avulsions
      occurred in 19% for anterior cruciate ligament, 51% for posterior cruciate
      ligament, 64% for medial collateral ligament, and 84% for lateral collateral
      ligament injuries. Certain injury patterns also had a high association of tendon
      and capsule avulsions. Proximal lateral collateral ligament injuries were
      commonly associated with popliteus tendon avulsions and seldom with distal biceps
      avulsions. Distal lateral collateral ligament injuries were commonly associated
      with distal biceps avulsions and seldom with popliteus tendon avulsions.
      Reattachable meniscal capsular avulsions off the tibia occurred predominantly
      when the collateral ligament injury was a distal avulsion. CONCLUSIONS: This
      study showed a wide variety of injury patterns. Knees had to have at least two
      ligaments injured to be dislocatable but not necessarily both cruciate ligaments.
      Sports injuries have the same pattern of injury as motor vehicle accidents,
      suggesting similar forces of injury. The study demonstrates a high incidence of
      reattachable avulsion injuries to ligaments and soft tissues in dislocatable
      knees. These may not be as easily dealt with if surgery is delayed beyond 3-4
      weeks.

PMID- 12621262
TI  - Comparison of internal bone transport and vascularized fibular grafting for
      femoral bone defects.
AB  - OBJECTIVE: To compare results between vascularized fibular grafting and internal
      bone transport for large bone defects of the femur. DESIGN: Retrospective review
      of patients. SETTING: University teaching hospitals. PATIENTS: This study
      included 37 patients with femoral bone loss: 20 patients were treated with
      internal bone transport and seventeen patients were treated with vascularized
      fibular grafting. MAIN OUTCOME MEASUREMENTS: The outcomes investigated were
      external fixation time, external fixation index, bone results (union, infection,
      deformity, leg length discrepancy), and functional results. RESULTS: The mean
      amount of filled defect was 8.4 cm with internal bone transport and 8.9 cm with
      vascularized fibular grafting. The external fixation index was 1.4 months/cm with
      internal bone transport and 1 month/cm with vascularized fibular grafting. The
      bone results and functional results of the internal bone transport were excellent
      in 65% and 0%, good in 5% and 45%, fair in 5% and 40%, poor in 25% and 15%,
      respectively, whereas those of the vascularized fibular grafting were excellent
      in 35% and 0%, good in 25% and 47%, fair in 5% and 35%, and poor in 35% and 18%.
      CONCLUSION: With vascularized fibular grafting, careful monitoring of circulation
      and early intervention surgery is necessary to avoid vascular failure. With
      internal bone transport, repeated radical debridement until control of infection
      is achieved, bone grafting at the docking site for early union, and avoiding
      stress fracture are recommended to improve bone results.

PMID- 12621264
TI  - Hyphenated history: the Bohler-Braun frame.
AB  - Throughout the history of medicine, many great physicians have originated or
      popularized ideas that have resulted in their names being attached to a device,
      procedure, or disease process. Hyphenated eponyms are especially interesting, for
      there are always underlying stories that explicate how people became associates
      in history. This paper will describe a bit of hyphenated history regarding
      orthopaedic trauma, specifically, the development of the Bohler-Braun frame. The
      lives of two great surgeons associated with this device, Lorenz Bohler, the
      "father of traumatology," and Heinrich Braun, the "father of local anesthesia,"
      will also be reviewed.

PMID- 12621263
TI  - Gentamicin may have an adverse effect on osteogenesis.
AB  - OBJECTIVE: To investigate the toxic effect of gentamicin at the high
      concentrations that can be achieved by local administration in the management of
      bone infection. DESIGN: Randomized, prospective study in cultured cells, with
      drug exposure duration of 4 days. SETTING: Cell culture in Dulbecco's
      modification of Eagle's minimal essential medium with supplements at 37 degrees C
      in air:CO2 (v:v, 95:5). MATERIALS: Human osteoblastlike cells derived from
      cancellous bone collected from four adult patients without systemic disease
      during total hip replacement were cultured in antibiotic-free medium for 4 weeks.
      INTERVENTION: The cultured cells were exposed to media containing various
      concentrations of gentamicin (0-1000 microg/mL) for 4 days. MAIN OUTCOME
      MEASUREMENTS: Alkaline phosphatase activity, total DNA, and 3H-thymidine
      incorporation. RESULT: Alkaline phosphatase activity was significantly decreased
      (p < 0.05) in all of the cultures at gentamicin concentrations of 100 microg/mL
      and above. 3H-thymidine incorporation was also decreased (p < 0.05) in three out
      of four cultures at 100 microg/mL and above. Total DNA was significantly
      decreased (p < 0.05) at 700 microg/mL and above. CONCLUSION: Gentamicin, at high
      concentrations, as achieved following topical application, inhibits cell
      proliferation in vitro and, therefore, may be detrimental to the repair process
      in vivo.

PMID- 12621265
TI  - Fine wire frame-assisted intramedullary nailing of the tibia.
AB  - Intramedullary nailing is accepted as the technique of choice for treatment of
      unstable tibial diaphyseal fractures. Indirect closed reduction must first be
      obtained to allow passage of the guide wire and reamers. We describe the use of a
      simple frame that allows precise reduction, control of rotation and easy imaging
      access, without increasing operating or screening time.

PMID- 12621266
TI  - Subtrochanteric fracture after cannulated screw fixation of femoral neck
      fractures: a report of four cases.
AB  - Subtrochanteric fractures after screw or pin fixation of femoral neck fractures
      are a recognized complication. No literature is available on this complication
      after fixation using the recently popularized cannulated screws. We present our
      experience in treating four of these complications. The common denominator for
      all four patients seemed to be an entry point in the lateral cortex below the
      level of the most inferior edge of the lesser trochanter.

PMID- 12621267
TI  - Osteochondral flap fracture of the olecranon with dislocation of the elbow in a
      child: a case report.
AB  - An osteochondral intraarticular fracture of the ulnotrochlear joint in a child is
      rare. The author reports on a 12-year-old child with an osteochondral
      intraarticular flap fracture of the proximal ulna associated with a dislocation
      of the elbow joint. Three-dimensional reconstruction computerized tomogram
      imaging revealed the direction of displacement and the origin of the detached
      flap. This fracture has been previously described by Rang (1974), but no
      illustration was provided. To date, only one other case in a child was reported
      by Blasier (1989), but it did not confirm an exact correlation between the
      osteochondral intraarticular fracture with dislocation of the elbow, which would
      have suggested the mechanism of injury.

PMID- 12621269
TI  - The Institute of Medicine's "Quality Chasm" Report: implications for ECT care.

PMID- 12621268
TI  - Nonunion as a complication of an open reduction of a distal radial fracture in a
      healthy child: a case report.
AB  - Nonunion of a distal radial fracture is rare in children. We report one referred
      case of a nonunion of the distal radius after an open reduction. The patient is a
      10-year-old healthy male with a displaced bicortical fracture of the distal
      radius and an undisplaced ulnar fracture. This fracture was initially treated by
      the referring orthopedist with open reduction and single Kirschner wire fixation,
      as closed reduction was thought to be difficult to achieve. The patient was seen
      with a distal radius nonunion at 14 months following the initial procedure. A
      complete workup revealed a healthy child with no general or local pathologies. He
      was treated with open reduction of the nonunion site, correction of angular
      deformity, and plate fixation. This resulted in bony union with no limitation of
      motion. Potential reasons for the development of nonunion and suggestions to
      avoid this complication are discussed.

PMID- 12621270
TI  - Long-term maintenance ECT: a retrospective review of efficacy and cognitive
      outcome.
AB  - Continuation and maintenance electroconvulsive therapy (ECT) are used to prevent
      relapse of depression after a successful course of index ECT. Such a course of
      treatment is typically extended for as long as a year. However, some patients
      seem to require longer courses of maintenance ECT. Little is known about the
      outcomes of long-term use (> 1 year) of maintenance ECT. We reviewed our
      maintenance ECT practice for the year 2000 and found that 43 patients had been
      receiving maintenance ECT for more than a year. This retrospective study reviews
      the outcomes of these patients. All patients had depression associated with
      either unipolar or bipolar disorder or schizoaffective disorder. These patients
      had multiple medication or psychotherapy trials or both and multiple
      hospitalizations before receiving maintenance ECT. Effects on depressive
      symptoms, level of functioning, health care use, frequency of hospitalizations,
      and cognition are discussed. We conclude that extended maintenance ECT is
      efficacious and well tolerated and reduces hospital use for a population of
      chronically depressed patients refractory to medication.

PMID- 12621271
TI  - Continuation and maintenance ECT in treatment-resistant bipolar disorder.
AB  - Continuation and maintenance electroconvulsive therapy (c/mECT) is a treatment
      alternative for the long-term management of mood and psychotic disorders,
      especially in chronic, recurring, medication-resistant illnesses and in patients
      who are medication-intolerant, are non-compliant, and have a high risk of suicide
      with medications. A MEDLINE search was performed with maintenance
      electroconvulsive therapy (ECT), continuation ECT, and prophylactic ECT as
      keywords. The relevant literature was obtained and reviewed. Despite methodologic
      flaws, the overwhelming majority of the studies report the effectiveness of
      c/mECT in bipolar mood disorder. We also reviewed the charts of 13 patients with
      mood disorder receiving maintenance ECT in the ECT service of a Veterans
      Administration medical center. Despite good results, c/mECT is underused in the
      treatment of bipolar mood disorder. More research with better study design is
      needed to define the predictors of response to c/mECT and to develop c/mECT
      treatment protocols for treatment-resistant bipolar patients.

PMID- 12621272
TI  - Impact of ECT on duration of hospitalizations for mania.
AB  - OBJECTIVE: To assess the impact of the use of electroconvulsive therapy (ECT) on
      the length of hospital stay of manic patients. MATERIALS AND METHODS: We reviewed
      425 consecutive admissions of 269 patients with manic or mixed affective episodes
      in a Brazilian private psychiatric hospital. Lengths of stay (LOSs) were compared
      for admissions in which ECT versus exclusive pharmacologic treatment was
      administered. A mixed model for repeated measures was developed to control for
      intraindividual correlations and potential demographic, clinical, and treatment
      confounder variables. The analyses were repeated using LOS minus the time until
      ECT was first given in each admission (LOS-tECT) as the response variable.
      RESULTS: Use of ECT was associated with longer LOS than exclusive pharmacologic
      treatment (18.78 versus 12.51 days; p < 0.001). This effect disappeared when
      using LOS-tECT as the response variable (11.57 versus 12.16 days; p = 0.530).
      Violent behavior and in-hospital use of antipsychotics and benzodiazepines were
      also associated with longer LOS, whereas being married was associated with
      shorter LOS. CONCLUSION: The use of ECT during hospitalizations for mania was
      associated with longer lengths of stay. This effect was caused mostly by delays
      in commencing ECT treatments rather than by the duration of treatment itself.

PMID- 12621273
TI  - Cardiac arrhythmias induced by ECT in elderly psychiatric patients: experience
      with 48-hour Holter monitoring.
AB  - Serious adverse events associated with electroconvulsive therapy (ECT) are
      uncommon and consist mostly of cardiovascular complications, mainly arrhythmias.
      The risk of complications is increased in elderly and physically ill patients. In
      the current study, a 24-hour pre-ECT and 24-hour post-ECT Holter recording was
      performed on 26 elderly patients during their first ECT treatment. ECT caused a
      significant increase in bigeminy/trigeminy and supraventricular tachycardia, but
      did not increase other arrhythmias. Pre-ECT arrhythmias correlated with post-ECT
      arrhythmias. All patients in the current study completed the ECT course. Thus,
      the clinical significance of arrhythmias remains uncertain. The present findings
      support the usual practice of continuous electrocardiogram monitoring during ECT
      and recovery.

PMID- 12621274
TI  - End-tidal carbon dioxide monitoring stabilized hemodynamic changes during ECT.
AB  - Accumulation of carbon dioxide (CO2) can disturb systemic and cerebral
      hemodynamics in patients receiving electroconvulsive therapy (ECT). The purpose
      of this study was to identify the effects of end-tidal CO2 monitoring on
      hemodynamic changes in patients who received ECT under propofol anesthesia. ECT
      was prescribed to 40 patients under propofol anesthesia. Ventilation was assisted
      using a face mask and 100% oxygen, with or without end-tidal CO2 monitoring.
      Heart rate was significantly increased in patients without end-tidal CO2
      monitoring at 1 to 5 minutes after electrical stimulation (p < 0.01). Mean
      arterial blood pressure and middle cerebral artery blood flow velocity in the
      group without end-tidal CO2 monitoring were significantly larger than the values
      in the group with the monitor at 1 to 5 minutes after electrical stimulation.
      Arterial CO2 tension in the group without end-tidal CO2 monitoring was larger
      than the value in the group with the monitoring at 1 minute (45+/-5 mm Hg with
      the monitor and 56+/-8 without the monitor) and 5 minutes (37+/-4 mm Hg with the
      monitor and 51+/-8 without the monitor) after electrical stimulation (p < 0.01).
      Application of end-tidal CO2 monitoring is considered beneficial for safe and
      effective anesthesia management of patients undergoing ECT, especially patients
      with an intracranial disorder or ischemic heart disease.

PMID- 12621275
TI  - ECS seizure threshold: normal variations, and kindling effects of subconvulsive
      stimuli.
AB  - BACKGROUND: The efficacy and adverse effects of electroconvulsive therapy are
      generally believed to depend upon the extent to which an administered stimulus is
      suprathreshold. The seizure threshold is therefore an important biologic marker.
      We sought to examine the variability of the electroconvulsive shock (ECS) seizure
      threshold in rats, and to identify factors influencing the threshold, to guide
      future research using animal models. MATERIALS AND METHODS: We administered once
      daily subconvulsive stimuli to Wistar rats beginning at a charge of either 1 mC
      (n = 25) or 5 mC (n = 25) and titrated the dose upward in 1-mC steps until the
      baseline seizure threshold was identified. Two weeks later, we divided each group
      into two subgroups and administered stimuli that were either at or 2 mC below the
      baseline threshold, and titrated the dose upward, again in 1-mC steps once daily,
      until the final threshold was identified. RESULTS: The mean baseline seizure
      threshold was 3.8 mC when upward titration was begun at 1 mC, and 6.7 mC when
      upward titration was begun at 5 mC (p < 0.001). Two weeks later, titration from
      baseline-subthreshold stimuli was associated with a lower final threshold in the
      5-mC group, while titration from baseline-threshold stimuli was associated with a
      higher final threshold in the 1-mC group (p < 0.006). CONCLUSIONS: The ECS
      seizure threshold ranged from 3 to 7 mC in this sample of rats; since the twofold
      variation is very small relative to clinical contexts, it is unlikely that ECS
      research needs to be threshold-based. The administration of low-dose, once-daily
      subconvulsive stimuli significantly lowered the seizure threshold; while this
      kindling effect wore off within 2 weeks, thresholds otherwise identified remained
      stable at the 2-week time point.

PMID- 12621276
TI  - Effects of animal-assisted therapy on patients' anxiety, fear, and depression
      before ECT.
AB  - OBJECTIVE: To determine whether animal-assisted therapy (AAT) is associated with
      reductions in fear, anxiety, and depression in psychiatric patients before
      electroconvulsive therapy (ECT). MATERIALS AND METHODS: Before their scheduled
      ECT treatment, 35 patients were assigned on alternate days to the treatment
      condition, consisting of a 15-minute AAT session, and the standard (comparison)
      condition, consisting of 15 minutes with magazines. Visual analogue scales were
      used to measure anxiety, fear, and depression before and after treatment and
      standard conditions. RESULTS: The effect of AAT on fear was significant in both
      the mixed-model, repeated-measures analysis of covariance (ANCOVA) (p = 0.0006)
      and the secondary analysis (p = 0.0050), which covaried out all of the
      demographic conditions (gender, race, marital status, pet ownership, age),
      condition order, and the pretest rating. The effect of AAT on anxiety approached
      significance in the ANCOVA (p = 0.0982), but in the secondary analysis, the
      effect was not significant (p = 0.6498). The AAT effect on depression was not
      significant in ANCOVA (p = 0.7665) or in the secondary analysis (p = 0.9394). A
      least squares mean analysis showed that AAT reduced fear by 37% and anxiety by
      18%. There was no demonstrated effect of AAT on depression. CONCLUSIONS: Animal
      assisted therapy may have a useful role in psychiatric and medical therapies in
      which the therapeutic procedure is inherently fear-inducing or has a negative
      societal perception.

PMID- 12621277
TI  - Successful use of ECT as the sole modality of treatment in a case of motility
      psychosis.
AB  - Episodic psychoses characterized by predominant abnormalities of movement are
      called motility psychoses in Leonhard's classification of endogenous psychoses.
      They have been treated with a variety of methods, including ECT and lithium. Here
      we describe a case of motility psychosis that was successfully managed with ECT
      as the only modality of treatment.

PMID- 12621279
TI  - Remission of major depression and obsessive-compulsive disorder after a single
      unilateral ECT.

PMID- 12621280
TI  - Cochlear Implant and ECT.

PMID- 12621281
TI  - The incisor war: declaring the winner today, but will it really end one day?

PMID- 12621282
TI  - Recent developments in orofacial cleft genetics.
AB  - Nonsyndromic cleft of the lip and/or palate (CLP or orofacial cleft) derives from
      an embryopathy with consequent failure of the nasal process and/or palatal
      shelves fusion. This severe birth defect is one of the most common malformations
      among live births. Nonsyndromic CLP is composed of two separate entities: cleft
      lip and palate (CL+/-P) and cleft palate only (CPO). Both have a genetic
      background, and environmental factors probably disclose these malformations. In
      CL+/-P, several loci have been identified, and, in one case, a specific gene has
      also been found. In CPO, one gene has been identified, but many more are probably
      involved. Because of the complexity of the genetics of nonsyndromic CLP as a
      result of the difference between CL+/-P and CPO, heterogeneity of each group
      caused by the number of involved genes, type of inheritance, and interaction with
      environmental factors, we discuss the more sound results obtained with different
      approaches: epidemiological studies, animal models, human genetic studies, and in
      vitro studies.

PMID- 12621283
TI  - Clinical outcome in cranioplasty: critical review in long-term follow-up.
AB  - Various materials have been proposed for cranial reconstruction. Bone autograft
      and alloplasts such as polymethylmethacrylate (PMMA) and hydroxyapatite (HA)
      cement are most commonly used at the present time. Patients submitted for
      cranioplasty were evaluated. The prognostic factors influencing the results and
      the outcome were analyzed. Three hundred twelve patients who had 449 procedures
      performed by a single surgeon to reconstruct a calvarial deformity between 1981
      and 2001 were studied. Post-tumor resection deformity was the main reason for
      cranioplasty (32.4%). Bone graft was the material of choice (69.5%). The main
      surgical site was the frontal bone (53.2%). Complications were observed in 23.6%
      of cases and were responsible for the least satisfactory results (P > 0.001),
      with infection and material exposure being the most critical complications. The
      eventual outcome was considered good in 91.8% of cases. The use of HA cement was
      associated with the worst results (P > 0.001). Bone grafts showed a high grade of
      partial resorption and required further surgery for correction. Multiple surgical
      procedures were correlated with a high rate of complications and an
      unsatisfactory outcome. Bone graft and PMMA are still the best materials in
      calvarial reconstruction. Even though HA cement is an osteoconductive material,
      it seems to induce what appears to be an immunoguided delayed inflammatory
      reaction that leads to thinning of the skin and exposure of the material, making
      secondary repair difficult. Before deciding which reconstructive option to use, a
      careful evaluation of the patient in terms of diagnosis, number of previous
      surgeries, and surgical site should be undertaken. If this is adopted, good
      results and a satisfactory outcome can be achieved on long-term follow-up.

PMID- 12621284
TI  - Relation between anthropometric and cephalometric measurements and proportions of
      the face of healthy young white adult men and women.
AB  - The specific aim of this study was to determine the differences between 6
      anthropometric (taken from the surface) and cephalometric (taken from x-rays)
      measurements and 12 proportion indices formed by the measurements obtained from
      the face of 51 healthy Caucasoid young adult males and females. The z-score
      analysis revealed negligible differences in frequency of normal values, in
      surface measurements 97.4% (298 of 306) versus 96.7% (296 of 306) in
      cephalometric ones. The optimal normal measurements dominated, in males in 76.8%
      and in females in 80.8%. The mean values of the 6 linear measurements, taken from
      the surface and the cephalogram of the face were in equal number similar and
      significantly dissimilar in both sexes (Table 1). Comparison of the mean
      anthropometric and cephalometric proportion indices did not show significant
      differences in the two sexes (Table 2). For males 50% of the 12 proportions the
      indices were similar and 50% were significantly different. For females the
      frequency of similar proportions was seen in 33.3% and in 66.7% moderately
      severely differing, statistically not significant. The z-score analysis
      identified subnormal measurements on the facial surface in 2.6% (8 of 306) and in
      cephalometric ones in 3.3% (10 of 306). The subnormal measurements of mild and
      moderate degree disclosed on the skeleton were not detected on the surface and
      some of the severely subnormal ones became mild-moderate on the skin surface. The
      study showed that the vertical anthropometric and cephalometric measurements in
      the facial profile were in highly significant percentage normal when compared
      with their normative data established for healthy populations. Generally, the
      cephalometric normal measurements were smaller than those of the anthropometric
      ones, some of them significantly. The significant differences between the
      proportions on the surface and skeleton in healthy subjects advice to be cautious
      in clinical practice, to judge the morphological changes of the face separately
      on the surface and on the skeleton of the patient.

PMID- 12621285
TI  - The accuracy of stereolithography in planning craniofacial bone replacement.
AB  - Stereolithography can be used to produce physical models of the craniofacial
      skeleton from three-dimensional computed tomography (CT) data. The purpose of
      this study was to assess its accuracy for modeling osseous defects of the
      midface. Maxillary resections simulating unilateral maxillectomy (N = 3),
      bilateral maxillectomy (N = 3), and unilateral orbitomaxillectomy (N = 3) were
      performed as for sinus tumor resection on nine fresh cadaver skulls.
      Stereolithographic models (SLMs) were made from the specimen's CT data. The
      accuracy of SLMs was determined by comparing distances between key landmarks on
      the skulls and SLMs. Each SLM was grossly accurate with some loss of thin
      delicate structures. The mean differences in overall dimensions between the SLMs
      and skull specimens were 1.5 mm (range: 0-5.5 mm) for craniofacial measures, 1.2
      mm (range: 0-4.8 mm) for skull base measures, 1.6 (range: 0-5.8 mm) for midface
      measures, 1.9 mm (range: 0-7.9 mm) for maxilla measures, and 1.5 mm (range: 0-5.7
      mm) for orbital measures. The mean differences in defect dimensions were 1.9 mm
      (range: 0.1-5.7 mm) for unilateral maxillectomy, 0.8 mm (range: 0.2-1.5 mm) for
      bilateral maxillectomy, and 2.5 mm (range: 0.2-7.0 mm) for orbitomaxillectomy
      defects. Midface SLMs may be more prone to error than those of other craniofacial
      regions because of the presence of thin walls and small projections. Thus, one
      should consider designing midface bone replacements that are larger in critical
      dimensions than those predicted by preoperative modeling. These findings have
      important implications for the planning of current surgical methods as well as
      future applications of tissue-engineered bone replacement.

PMID- 12621286
TI  - Holding power of bioabsorbable self-reinforced poly-L/DL-lactide 70/30 tacks and
      miniscrews in human cadaver bone.
AB  - Several bioabsorbable internal fixation systems are currently in use in the field
      of bone surgery. To test the mechanical properties of recently developed
      amorphous self-reinforced poly-L/DL-lactide [SR-P(L/DL)LA] 70/30 tacks in
      comparison with commercially available SR-P(L/DL)LA 70/30 (BioSorbFX; Bionx
      Implants Ltd) miniscrews, SR-P(L/DL)LA miniscrews (length = 6.0 mm, core diameter
      = 1.5 mm, thread diameter = 2.0 mm) and tacks (length = 5.4 mm, core diameter =
      1.5 mm, thread diameter = 2.0 mm) were applied to human cadaveric metatarsal (MT)
      bones (6 pairs of fourth MT bones and 6 pairs of fifth MT bones from donors who
      were from 29 to 56 years of age at the time of death). Pullout force was measured
      using a mechanical testing machine. Forty-eight pullout tests were carried out
      for each implant type. The Student test, Mann-Whitney test, and Spearman
      coefficient were used for statistical evaluation. The pullout force of tacks was
      135.0 +/- 26.1 N, and that of the miniscrews was 119.3 +/- 26.1 N ( = 0.04,
      statistically significant difference). Accordingly novel SR-P(L/DL)LA 70/30 tacks
      have a statistically better pullout strength than the SR-P(L/DL)LA 70/30
      miniscrews when tested in cadaver MT bones.

PMID- 12621287
TI  - The influence of temperature on the degradation rate of LactoSorb copolymer.
AB  - Heat is one of the fundamental forces that influence the rates of chemical
      reactions. The hydrolysis of an absorbable polymer is a function of many factors,
      both material-related and implant-site-related, including temperature. There is
      variance in temperature among patients as well as among various animals in which
      degradation studies are performed. This study investigated the influence of
      temperature on hydrolysis and found that a variance from 37 degrees C to as
      little as 2 degrees C can affect the rate of hydrolysis of a PGA/PLLA copolymer
      about 25-30%, with the rate increasing with increasing temperature. As most
      animals of biomedical interest have a body temperature on the order of 1-3
      degrees C greater than that of humans, it is possible that animal testing may be
      "worst case"; that is, strength loss may be accelerated in animals relative to
      that in human patients. Also, variation of body temperature within the human
      population may contribute to some variance in the rate of hydrolysis from person
      to person; however, other influences may minimize this effect and make it
      difficult to observe clinically.

PMID- 12621288
TI  - Intracapsular fractures of mandibular condyle: diagnosis, treatment, and
      anatomical and pathological evaluations.
AB  - The aim of this study was to attempt to establish a correlation between condylar
      localized fracture, onset of anatomicopathological lesions of the articular
      structures, and determination of ankylosis so as to define appropriate diagnostic
      and therapeutic procedures. Clinical, arthroscopic, and histological studies were
      carried out in two patients with a severe temporomandibular joint disorder after
      a condylar localized fracture. Treatment included removal of the displaced
      fragments, condylar surface remodeling, suture of retrodiskal perforations, and
      diskal repositioning. The histological study of the condylar specimens revealed
      signs of osteoarthrosis of the articular surface and chondroid metaplasia of the
      bilaminar zone with early onset of ankylosis. Results of this study confirmed the
      presence of causal relations between condylar localized fracture and ankylosis
      with alterations in retrodiskal tissue. These relations are found in 1) tissue
      damage caused by bony fragments remaining in the articular cavity (underestimated
      and poorly treated fractures), 2) the lesion that occurs in association with
      mechanical trauma; and, particularly, c) the disk and retrodiskal impairments
      caused by catabolic and degenerative osteoarthrotic changes secondary to condylar
      marrow damage. Thus, timeliness and accuracy of the diagnosis of condylar
      localized fracture are most important, as are correct diagnosis and treatment
      before the onset of degenerative anatomicopathological lesions.

PMID- 12621289
TI  - Parietal bone agenesis and associated multiple congenital anomalies.
AB  - Congenital defects of the calvaria in general and the parietal bones in
      particular are rare diseases. The latter are of three kinds: 1) cranioschisis, 2)
      craniodysostosis, and 3) foramina parietalia permagna (FPP). Here, we describe an
      exceptional anomaly, namely, complete absence of one parietal bone and dysplasia
      of the other. Agenesis has been reported twice before in the literature. In these
      cases, the calvarial defect was the only congenital anomaly. In contrast, the
      patient described in this article exhibited many other congenital deformities,
      namely, iris coloboma, facial dysmorphism, a large ventricular septal defect of
      the heart, and a horseshoe kidney. Some of these deformities are associated with
      neural crest development. Chromosomal analysis was normal in both blood and
      fibroblasts, and fluorescent in situ hybridization analysis failed to demonstrate
      a 22q11 deletion as seen in DiGeorge syndrome, a neural crest-related disease
      complex. Since 2000, the third group of congenital defects of the parietal bones,
      FPP, has been associated with mutations of the MSX-2 gene. In our case, a genetic
      analysis of this gene was performed, but no mutations or deletions of MSX-2 were
      detected.

PMID- 12621290
TI  - Severe granulomatous allergic tissue reaction after hyaluronic acid injection in
      the treatment of facial lines and its surgical correction.
AB  - Hyaluronic acid is considered to be nonimmunogenic. Frequently, it is used for
      the correction of facial lines. It is believed that hyaluronic acid injection
      fillers are safe and have no occurrence of serious adverse reactions or allergic
      reactions. Nevertheless, recent publications have documented the rate of
      intermittent swelling and severe granulomatous allergic reactions that evolved
      into abscesses. A clinical case of a 54-year-old patient is presented. After
      injection of hyaluronic acid in the treatment of nasolabial folds elsewhere, she
      developed palpable painful erythematous nodules evolving into abscesses several
      month after injection. Surgical treatment and correction of these lesions after
      hyaluronic acid injection of the nasolabial folds and the histological findings
      of these erythematous nodules are described. Histological and clinical
      examination documented intermittent swelling and severe granulomatous allergic
      reactions that may render the use of hyaluronic acid unacceptable. Patients
      should be informed of the potential complications when treating facial lines with
      hyaluronic acid gel.

PMID- 12621291
TI  - Cherubism: clinical evidence and therapy.
AB  - Cherubism is a hereditary childhood disease of autosomal dominant inheritance
      that is more common in the male sex. Some cases have also revealed a mutation of
      the gene FGF-RIII (fibroblast growth factor receptor III). The clinical picture
      of cherubism is characterized by painless symmetrical swelling of the mandible
      and polycystic destruction of the mandibular bone structure. Complications
      include delayed dentition, dental root resorption, malalignment of teeth, and
      impacted teeth. The disease progression comes to a halt of its own accord at the
      end of puberty. Spontaneous recoveries have been observed. Histologically,
      multinuclear giant cells with osteoclastic activity, which correspond to a giant
      cell granuloma, are found in fibrous stroma. It is generally agreed that
      decisions about surgical intervention should be considered carefully. A case
      report describes the course of the disease and therapy of a female patient with a
      periorbital manifestation of cherubism. The latero-orbital enlargement of the
      intraorbital and latero-orbital region of the zygomatic bone resulted in
      displacement of the orbital contents with a motility disorder of the eyes. The
      motility disorder was eliminated by reduction of the diseased hard tissue as well
      as by carrying out a modeling orbitotomy and by reconstructing an anatomically
      correct localized and irregular bilateral osseous structure of the zygomatic bone
      in the intraorbital and latero-orbital region.

PMID- 12621292
TI  - Hydroxyapatite cranioplasty: 2. Clinical experience with a new quick-setting
      material.
AB  - A clinical series of 62 patients who underwent cranioplasty using a new quick
      setting hydroxyapatite (HA) material was done over a 2-year period. The majority
      of procedures (69%) were performed for secondary reconstruction of frontal,
      temporal, and supraorbital deficiencies after primary repair of a
      craniosynostosis. The frontal sinus was obliterated as part of the cranioplastic
      procedure in 5 cases (8%) in older patients. The material set effectively in
      approximately 5 minutes with a good working time. Infection occurred in 3
      patients (5%) which was treated by removing the HA cranioplastic material. This
      faster-setting HA material offers similar cranioplastic benefits as other
      materials but with an accelerated intraoperative set time.

PMID- 12621293
TI  - Multimodality imaging for precise localization of craniofacial osteomyelitis.
AB  - Functional imaging identifies areas of abnormal bone turnover, providing a useful
      adjunct in the treatment of osteomyelitis and bone tumors. The low resolution and
      lack of anatomical detail limit the application of bone scans in craniofacial
      surgery, however. Multimodality image registration addresses this problem by
      fusing functional images (single photon emission computed tomography [SPECT]) to
      high-resolution structural images (computed tomography [CT]) for precise
      anatomical delineation of bone activity. This article describes a technique for
      spatial registration of CT and SPECT images to provide precise anatomical
      delineation of abnormal bone turnover, thereby guiding the extent of resection in
      the management of craniofacial osteomyelitis. Standard CT and SPECT imaging
      protocols were used in imaging the skull from the vertex to the mentum. Image
      data were imported into Analyze (Biomedical Imaging Resource; Mayo Foundation,
      Rochester, MN) on a dedicated Windows NT (Microsoft Corporation, Redmond, WA)
      workstation. Using the CT data, the craniofacial skeleton, osteotomy segments,
      and bone grafts were interactively mapped out. Consecutive axial slices were then
      reconstructed to form a three-dimensional volume of interest. The CT-derived
      volume of interest was registered to the technetium Tc 99m-methylene
      diphosphonate SPECT scan using the Analyze program to provide a fused
      multimodality image. The imaging technique was used to localize osteomyelitis in
      a complex craniofacial reconstruction. The fused images guided the extent of
      resection during surgery, and postoperative microbiological and histological
      testing confirmed the diagnosis. Multimodality image registration provides a
      readily available method to relate facial skeletal anatomy and physiology. This
      technique is valuable in planning and monitoring therapeutic interventions in
      clinical conditions in which bone turnover is abnormal.

PMID- 12621294
TI  - Use of radial forearm free flap with palmaris longus tendon in reconstruction of
      total maxillectomy with sparing of orbital contents.
AB  - Nasal paragangliomas are extremely rare. The most adequate treatment is total
      excision. After surgical excision requiring total maxillectomy, there has been no
      ideal technique for reconstruction. A 47-year-old man was admitted to our clinic
      because of recurrent epistaxis, which lasted for 2 months. He was also suffering
      from nasal airway obstruction. The physical examination revealed a mass
      originating from the medial aspect of the middle turbinate of the right nasal
      cavity. It invaded the anterior maxillary wall and hard and soft palate.
      Endoscopic examination showed that the mass pushed the nasal septum to the left
      side and protruded into the nasopharynx. The mass was fleshy and had a rich
      capillary network. Conventional paranasal sinus radiographs were normal.
      Computerized tomography of the skull showed the mass protruding into the
      nasopharynx. A total maxillectomy was performed. Histopathological evaluation
      showed neoplastic tissue consisting of round, oval, or slightly elongated cells,
      altogether of a rather monomorphous appearance, tending to arrange themselves in
      clusters adjacent to or around capillary blood vessels. The blood vessels were
      numerous and branched. Reticulum staining showed a typical Zellballen arrangement
      of the neoplastic cells to provide a firmer basis for the diagnosis of
      paraganglioma. To reconstruct the total maxillectomy defect, a radial forearm
      free flap with the palmaris longus tendon was elevated to inlay the nasal cavity
      and the oral cavity and to suspend the ocular globe. The flap was placed into the
      defect, and the palmaris longus tendon was medially and laterally anchored to the
      periosteum of the frontal bone to suspend the ocular globe in the orbital cavity.
      One part of the skin island was used to close the defect of the nasal mucosal
      cavity, and the other part was used to repair the oral mucosal defect of the
      palate. Consequently, speech was considered near normal; the patient was able to
      eat an unrestricted diet and to retain both solid and liquid food inside the oral
      cavity without drooling, and there was no diplopia or enophthalmos. Six months
      later, porous polyethylene was inserted and fixed to the zygomatic bone with a
      miniplate and miniscrews to restore malar contour. No further procedure was
      believed to be necessary later on. Two years later, a satisfactory and functional
      esthetic result was obtained, providing an acceptable suspension of the ocular
      globe and filling of the total maxillectomy defect. We believe that a total
      maxillectomy is indicated if it is needed in nasal paragangliomas and that
      microsurgical repair with the composite radial forearm-palmaris longus free flap
      has several advantages: 1) it can offer en bloc reconstruction of the entire
      defect after a total maxillectomy in terms of good function and cosmesis; 2) it
      can repair mucosal defects; and 3) it can anchor and suspend the ocular globe in
      its original anatomical location, protecting against gravity through the sling
      effect of the palmaris longus tendon. The composite radial forearm-palmaris
      longus free flap has not been described previously for suspension of the ocular
      globe.

PMID- 12621296
TI  - Clinical implications of the innervation of the temporomandibular joint.
AB  - The successful management of temporomandibular joint (TMJ) pain remains elusive.
      Often, the initial relief of pain is complicated by recurrence of the symptoms.
      This time frame suggests that the pain may be related to neuromas of the nerves
      that innervate the TMJ. The current study attempted to define the innervation
      pattern of the TMJ as identified in 16 embalmed and 8 fresh-frozen specimens. In
      each specimen, the auriculotemporal nerve, a branch of the mandibular portion
      (V3) of the trigeminal nerve, was found to innervate the lateral capsule of the
      TMJ. In 75% of the specimens, the masseteric nerve, a branch of the maxillary
      portion (V2) of the trigeminal nerve, was found to innervate the anteromedial
      capsule of the TMJ. In 33% of the specimens, there was a branch coming through
      the mandibular notch to innervate the anteromedial capsule that was not from the
      masseteric nerve; this nerve is believed to have passed through the lateral
      pterygoid muscle after leaving V2. These consistent patterns of innervation of
      the TMJ suggest that diagnostic nerve blocks can be done to determine the pain
      pathway in these patients. It is suggested that if the nerve blocks are
      successful, TMJ denervation may be a future method of pain relief in patients
      with recalcitrant or recurrent TMJ pain.

PMID- 12621295
TI  - Auricular composite graft for skin defect of the philtrum dimple.
AB  - Our method of performing an auricular composite graft for a skin defect of the
      philtrum dimple in a patient whose lip is not damaged and has retained its
      original softness and elasticity is presented. After resecting the lesion, an
      auricular composite graft is harvested from the conchal region. The size of the
      graft is almost the same as the size of the resected lesion, although the
      cartilage is harvested in an elliptical shape, and its size is approximately 60%
      in area of the overriding skin of the graft. The graft is harvested from the
      site, which has a similar curvature to the defect. The cartilage is sutured
      tightly to the graft bed at a minimum of four points with 6-0 absorbable suture.
      The transversal axis of the harvested cartilage is sutured as vertically as
      possible so as to fit the direction of the wrinkle line of the upper lip. The
      skin is sutured to the defect margin using 5-0 nylon suture. The graft donor site
      is closed primarily. This method has been used for the closure of six
      comparatively large skin defects after resecting a skin lesion (pigmented nevus
      in three cases and hypertrophic scar in three cases) in the philtrum dimple in
      six patients. In all cases, the upper lip was not damaged and retained its
      original softness and elasticity. The "take" of the graft was complete in all
      patients, and the donor site healed without any problem. In all cases,
      postoperative shrinkage of the graft was not significant during the follow-up
      period, and the graft had a smooth surface. In addition, no patients suffered
      from a feeling of discomfort in moving the mouth, and an acceptable shape of the
      philtrum dimple was achieved in all cases. There were no deformational changes in
      the graft donor site. In conclusion, our method is valid in the patient whose lip
      is not damaged and has retained its original softness and elasticity and in whom
      a full-thickness skin graft is selected as the covering method for a skin defect
      of the philtrum dimple.

PMID- 12621297
TI  - Traumatic carotid-cavernous fistula: pathophysiology and treatment.
AB  - Traumatic carotid-cavernous fistulae are rare yet potentially lethal vascular
      anomalies in the skull base seen after craniomaxillofacial trauma. This aberrant
      vascular communication has been extensively evaluated and classified, with a
      number of treatment modalities available to clinicians. The ultimate and
      definitive treatment of carotid-cavernous fistulae falls beyond the scope of
      craniomaxillofacial surgery. Nevertheless, clinicians treating patients with
      craniofacial injuries should have a complete understanding of this pathological
      entity, because urgent intervention may improve patient outcome.

PMID- 12621298
TI  - Spotlight on naturally absorbable osteofixation devices.
AB  - The practice of using implants is growing day by day, and more foreign materials
      are being inserted for various indications. The field of implantology thus
      deserves intensive research and careful evaluation of results. Solutions to
      overcome current problems and risks are necessary. It has taken a long time to
      arrive at where we are now. Bioabsorbable devices were explored in the 1960s for
      surgical bone fixation. Failures were followed by changes in ways of thinking and
      innovations. Improvements in the strength properties and biocompatibility were
      achieved. Bioabsorbable polymeric materials such as high-molecular-weight
      polymers were used and also reinforced with other material or, more recently, by
      self-reinforcement to produce small yet strong devices. New generations of
      implants include those that contain bioactive substances such as antibiotics and
      growth factors. Developments in bioabsorbable materials continue to accommodate
      the new way of thinking brought about by the emergence of the field of tissue
      engineering. Surgeons, conversely, are also inventing new surgical techniques and
      methods to exploit the plastic and bioabsorbability properties of these materials
      for the better future of our patients. Such a multidisciplinary approach that
      involves surgeons and materials scientists should help to find solutions to the
      current limitations of these devices.

PMID- 12621302
TI  - Bcl-XL maintains mitochondrial function in murine astrocytes deprived of glucose.
AB  - Bcl-XL is a protein that blocks both apoptotic and necrotic cell death. The
      authors have previously shown that it is effective in maintaining mitochondrial
      membrane potential during glucose deprivation in cultured astrocytes. To further
      investigate the mechanism involved, the authors studied mitochondrial function
      and cytochrome c release. Oxygen consumption was monitored to assess oxidative
      respiration. State III respiration decreased significantly as early as 3 h after
      removal of glucose. At this time mitochondria hyperpolarize but cytochrome c is
      not yet released. Damage to the electron transport chain is not responsible for
      this change because uncoupled respiration was unchanged at this time point. At 5
      h of glucose deprivation, when mitochondrial depolarization was observed, state
      IV respiration increased significantly, cytochrome c began to be released, and
      mitochondrial morphology changed from elongated to punctate. When Bcl-XL was
      overexpressed normal state III respiration and mitochondrial morphology were
      maintained and cytochrome c release was inhibited in the face of glucose
      deprivation stress.

PMID- 12621301
TI  - Oligodendrocytes and ischemic brain injury.
AB  - Oligodendrocytes, myelin-forming glial cells of the central nervous system, are
      vulnerable to damage in a variety of neurologic diseases. Much is known of
      primary myelin injury, which occurs in settings of genetic dysmyelination or
      demyelinating disease. There is growing awareness that oligodendrocytes are also
      targets of injury in acute ischemia. Recognition of oligodendrocyte damage in
      animal models of ischemia requires attention to their distinct histologic
      features or use of specific immunocytochemical markers. Like neurons,
      oligodendrocytes are highly sensitive to injury by oxidative stress, excitatory
      amino acids, trophic factor deprivation, and activation of apoptotic pathways.
      Understanding mechanisms of oligodendrocyte death may suggest new therapeutic
      strategies to preserve or restore white matter function and structure after
      ischemic insults.

PMID- 12621303
TI  - In vivo measurement of receptor density and affinity: comparison of the routine
      sequential method with a nonsequential method in studies of dopamine D2 receptors
      with [11C]raclopride.
AB  - Positron emission tomography with the dopamine D(2/3) receptor ligand raclopride
      was used to compare sequential (studies on 1 day) and nonsequential (different
      days) approaches to in vivo measurement of the density and affinity of receptors.
      The choice of temporal sequence of radiotracer injection over a range of specific
      activities might result in bias because of diverse factors. A strong concordance
      is reported between the outcomes of the sequential and nonsequential methods.
      This suggests that the characteristics of the dopamine D(2/3) receptors are
      relatively stable within physiologic boundaries and can be reproducibly and
      reliably measured in stable conditions.

PMID- 12621304
TI  - Imaging human mesolimbic dopamine transmission with positron emission tomography.
      Part II: amphetamine-induced dopamine release in the functional subdivisions of
      the striatum.
AB  - The human striatum is functionally organized into limbic, associative, and
      sensorimotor subdivisions, which process information related to emotional,
      cognitive, and motor function. Dopamine projections ascending from the midbrain
      provide important modulatory input to these striatal subregions. The aim of this
      study was to compare activation of dopamine D2 receptors after amphetamine
      administration in the functional subdivisions of the human striatum. D2 receptor
      availability (V3") was measured with positron emission tomography and
      [11C]raclopride in 14 healthy volunteers under control conditions and after the
      intravenous administration of amphetamine (0.3 mg/kg). For each condition,
      [11C]raclopride was administered as a priming bolus followed by constant
      infusion, and measurements of D2 receptor availability were obtained under
      sustained binding equilibrium conditions. Amphetamine induced a significantly
      larger reduction in D2 receptor availability (DeltaV3") in limbic (ventral
      striatum, -15.3 +/- 11.8%) and sensorimotor (postcommissural putamen, -16.1 +/-
      9.6%) regions compared with associative regions (caudate and precommissural
      putamen, -8.1 +/- 7.2%). Results of this region-of-interest analysis were
      confirmed by a voxel-based analysis. Correction for the partial volume effect
      showed even greater differences in DeltaV3" between limbic (-17.8 +/- 13.8%),
      sensorimotor (-16.6 +/- 9.9%), and associative regions (-7.5 +/- 7.5%). The
      increase in euphoria reported by subjects after amphetamine was associated with
      larger DeltaV3" in the limbic and sensorimotor regions, but not in the
      associative regions. These results show significant differences in the dopamine
      response to amphetamine between the functional subdivisions of the human
      striatum. The mechanisms potentially accounting for these regional differences in
      amphetamine-induced dopamine release within the striatum remain to be elucidated,
      but may be related to the asymmetrical feed-forward influences mediating the
      integration of limbic, cognitive, and sensorimotor striatal function via dopamine
      cell territories in the ventral midbrain.

PMID- 12621305
TI  - Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the
      relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and
      the [18F]fluorodopa plasma input uptake rate constant Ki.
AB  - Parkinson disease is characterized by the loss of dopaminergic neurons, thus
      decreasing the system's ability to produce and store dopamine (DA). Such ability
      is often investigated using 18F-fluorodopa (FD) positron emission tomography. A
      commonly used model to investigate the DA synthesis and storage rate is the
      modified Patlak graphical approach. This approach allows for both plasma and
      tissue input functions, yielding the respective uptake rate constants K(i) and
      K(occ). This method requires the presence of an irreversible compartment and the
      absence of any nontrapped tracer metabolite. In the case of K(occ), this last
      assumption is violated by the presence of the FD metabolite 3-O-methyl
      [18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a
      downward bias. It was found that both K(i) and K(occ) are influenced by DA loss
      and thus are not pure measures of DA synthesis and storage. In the case of
      K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus
      introducing a disease-dependent bias in the K(occ) determination. These findings
      imply that K(i) and K(occ) provide different assessments of disease severity and
      that, as disease progresses, K(i) and especially K(occ) become more related to DA
      storage capacity and less to the DA synthesis rate.

PMID- 12621306
TI  - Blood genomic expression profile for neuronal injury.
AB  - This study determined whether stroke and other types of insults produced a gene
      expression profile in blood that correlated with the presence of neuronal injury.
      Adult rats were subjected to ischemic stroke, intracerebral hemorrhage, status
      epilepticus, and insulin-induced hypoglycemia and compared with untouched, sham
      surgery, and hypoxia animals that had no brain injury. One day later, microarray
      analyses showed that 117 genes were upregulated and 80 genes were downregulated
      in mononuclear blood cells of the "injury" (n = 12) compared with the "no injury"
      (n = 9) animals. A second experiment examined the whole blood genomic response of
      adult rats after global ischemia and kainate seizures. Animals with no brain
      injury were compared with those with brain injury documented by TUNEL and PANT
      staining. One day later, microarray analyses showed that 37 genes were
      upregulated and 67 genes were downregulated in whole blood of the injury (n = 4)
      animals compared with the no-injury (n = 4) animals. Quantitative reverse
      transcription-polymerase chain reaction confirmed that the vesicular monoamine
      transporter-2 increased 2.3- and 1.6-fold in animals with severe and mild brain
      injury, respectively, compared with no-injury animals. Vascular tyrosine
      phosphatase-1 increased 2.0-fold after severe injury compared with no injury. The
      data support the hypothesis that there is a peripheral blood genomic response to
      neuronal injury, and that this blood response is associated with a specific blood
      mRNA gene expression profile that can be used as a marker of the neuronal damage.

PMID- 12621307
TI  - Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for
      cerebral vascular protection by erythropoietin.
AB  - Erythropoietin (EPO) plays a prominent role in the regulation of the
      hematopoietic system, but the potential function of this trophic factor as a
      cytoprotectant in the cerebral vascular system is not known. The authors examined
      the ability of EPO to modulate a series of death-related cellular pathways during
      free radical-induced injury in cerebral microvascular endothelial cells (ECs).
      Endothelial cell injury was evaluated by trypan blue, DNA fragmentation, membrane
      phosphatidylserine exposure, apoptotic protease-activating factor-1 (Apaf-1), and
      Bcl-XL expression, mitochondrial membrane potential, cytochrome c release, and
      cysteine protease activity. They show that constitutive EPO is present in ECs but
      is insufficient to prevent cellular injury. Signaling through the EPO receptor,
      however, remains biologically responsive to exogenous EPO administration to offer
      significant protection against nitric oxide-induced injury. Exogenous EPO
      maintains both genomic DNA integrity and cellular membrane asymmetry through
      parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial
      membrane potential in conjunction with enhanced Bcl-XL expression. Consistent
      with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits
      the activation of caspase-9 and caspase-3-like activities. Identification of
      novel cytoprotective pathways used by EPO may serve as therapeutic targets for
      cerebral vascular disease.

PMID- 12621308
TI  - Temporal profile of stem cell division, migration, and differentiation from
      subventricular zone to olfactory bulb after transient forebrain ischemia in
      gerbils.
AB  - The stage of neurogenesis can be divided into three steps: proliferation,
      migration, and differentiation. To elucidate their detailed relations after
      ischemia, the three steps were comprehensively evaluated, in the subventricular
      zone (SVZ) through the rostral migratory stream (RMS) to the olfactory bulb (OB),
      in adult gerbil brain after 5 minutes of transient forebrain ischemia.
      Bromodeoxyuridine (BrdU), highly polysialylated neural cell adhesion molecule
      (PSA-NCAM), neuronal nuclear antigen (NeuN), and glial fibrillary acidic protein
      (GFAP) were used as markers for proliferation, migration, and differentiation,
      respectively. The number of BrdU-labeled cells that coexpressed PSA-NCAM and the
      size of PSA-NCAM-positive cell colony increased in the SVZ with a peak at 10 d
      after transient ischemia. In the RMS, the number of BrdU-labeled cells that
      coexpressed PSA-NCAM increased, with a delayed peak at 30 d, when the size of RMS
      itself became larger and the number of surrounding GFAP-positive cells increased.
      In the OB, BrdU + NeuN double positive cells were detected at 30 and 60 d. NeuN
      staining and terminal deoxynucleotidyl dUTP nick-end labeling staining showed no
      neuronal cell loss around the SVZ, and in the RMS and the OB after transient
      ischemia. These findings indicate that transient forebrain ischemia enhances
      neural stem cell proliferation in the SVZ without evident neuronal cell loss, and
      has potential neuronal precursor migration with activation of GFAP-positive cells
      through the RMS to the OB.

PMID- 12621309
TI  - Novel diketopiperazine enhances motor and cognitive recovery after traumatic
      brain injury in rats and shows neuroprotection in vitro and in vivo.
AB  - The authors developed a novel diketopiperazine that shows neuroprotective
      activity in a variety of in vitro models, as well as in a clinically relevant
      experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA
      35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing
      hormone (TRH) analog, significantly reduced cell death associated with necrosis
      (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal-glial
      cocultures. Rats subjected to lateral fluid percussion-induced TBI and then
      treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed
      significantly improved motor recovery and spatial learning compared with vehicle
      treated controls. Treatment also significantly reduced lesion volumes as shown by
      magnetic resonance imaging, and decreased the number of TUNEL-positive neurons
      observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b
      treatment did not change mean arterial pressure, body temperature, or thyroid
      stimulating hormone release, and did not have analeptic activity. Moreover, in
      contrast to TRH or typical TRH analogs, 35b administration after TBI did not
      alter free-magnesium concentration or cellular bioenergetic state. Receptor
      binding studies showed that 35b did not act with high affinity at 50 classical
      receptors, channels, or transporters. Thus, 35b shows none of the typical
      physiologic actions associated with TRH, but possesses neuroprotective actions in
      vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell
      death.

PMID- 12621310
TI  - Neuroprotective and nootropic actions of a novel cyclized dipeptide after
      controlled cortical impact injury in mice.
AB  - 1-ARA-35b (35b) is a cyclized dipeptide that shows considerable neuroprotective
      activity in vitro and improves neurologic recovery after fluid percussion-induced
      traumatic brain injury in rats. The authors evaluated the effects of treatment
      with 35b in mice subjected to controlled cortical impact brain injury. Animals
      treated with intravenous 35b after traumatic injury showed significantly enhanced
      recovery of beam walking and place learning functions compared with vehicle
      treated controls, in addition to reduced lesion volumes. Beneficial effects were
      dose related and showed an inverted U-shaped dose-response curve between 0.1 and
      10 mg/kg. Protective actions were found when the drug was administered initially
      at 30 minutes or 1, 4, or 8 hours, but not at 24 hours, after trauma. In separate
      experiments, rats treated with 35b on days 7 through 10 after injury showed
      remarkably improved place learning in comparison with injured controls. These
      studies confirm and extend the neuroprotective effects of this diketopiperazine
      in traumatic brain injury. In addition, they show that 35b has a relatively wide
      therapeutic window and improves cognitive function after both acute and chronic
      injury.

PMID- 12621311
TI  - Cholecystokinin induces cerebral vasodilatation via presynaptic CCK2 receptors:
      new implications for the pathophysiology of panic.
AB  - The authors report that cholecystokinin (CCK), via its subtype 2 receptor (CCK2R)
      located presynaptically on cerebral arteries, mediates the release of nitric
      oxide (NO), which induces vasodilatation. Whereas CCK octapeptide and its
      fragment CCK tetrapeptide (CCK-4) lack a direct effect on the smooth muscle of
      pial vessels, the authors showed that both CCK peptides modulate the neurogenic
      responses in bovine cerebral arteries. The neurogenic vasodilatation induced by
      CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal
      NO synthase (nNOS) inhibitors, but was independent of the endothelium. In whole
      mount arteries, CCK2Rs were detected in nerve fibers and colocalized with nNOS
      and synaptophysin. The findings provide, for the first time, a neural mechanism
      by which CCK may increase cerebral blood flow.

PMID- 12621312
TI  - Normalization of endothelial and inducible nitric oxide synthase expression in
      brain microvessels of spontaneously hypertensive rats by angiotensin II AT1
      receptor inhibition.
AB  - Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the
      cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify
      the mechanism, spontaneously hypertensive rats (SHR) and normotensive control
      Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist
      candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that
      which protected SHR from brain ischemia, and the authors studied middle cerebral
      artery (MCA) and common carotid morphology, endothelial nitric oxide synthase
      (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and
      protein expression in cerebral microvessels, principal arteries of the Willis
      polygon, and common carotid artery. The MCA and common carotid artery of SHR
      exhibited inward eutrophic remodeling, with decreased lumen diameter and
      increased media thickness when compared with WKY rats. In addition, there was
      decreased eNOS and increased iNOS protein and mRNA in common carotid artery,
      circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both
      remodeling and alterations in eNOS and iNOS expression in SHR were completely
      reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and
      biochemical alterations in hypertension associated with increased vulnerability
      to brain ischemia are fully reversed by AT1 receptor blockade, indicating that
      AT1 receptor activation is crucial for the maintenance of the pathologic
      alterations in cerebrovascular circulation during hypertension, and that their
      blockade may be of therapeutic advantage.

PMID- 12621313
TI  - Role of P2X7 receptors in ischemic and excitotoxic brain injury in vivo.
AB  - Purinergic P2X7 receptors may affect neuronal cell death through their ability to
      regulate the processing and release of interleukin-1beta (IL-1beta), a key
      mediator in neurodegeneration. The authors tested the hypothesis that ATP, acting
      at P2X7 receptors, contributes to experimentally induced neuronal death in
      rodents in vivo. Deletion of P2X7 receptors (P2X7 knockout mice) did not affect
      cell death induced by temporary cerebral ischemia, which was reduced by treatment
      with IL-1 receptor antagonist (IL-1RA). Treatment of mice with P2X7 antagonists
      did not affect ischemic or excitotoxic cell death, suggesting that P2X7 receptors
      are not primary mediators of experimentally induced neuronal death.

PMID- 12621314
TI  - Psychiatric symptomatology and prodromal Alzheimer's disease.
AB  - The aim of this study was to determine the prevalence of psychiatric symptoms
      among nondemented individuals with memory changes and whether such symptoms
      predict progression of functional decline or diagnosis of Alzheimer disease (AD).
      A semi-structured interview was administered at baseline to controls (n = 32) and
      to nondemented subjects with memory changes (n = 112) and to each subject's
      collateral source. The interview assessed the impact of cognition on functional
      abilities in daily life and a variety of psychiatric symptoms, including symptoms
      of psychosis, depression, and personality change. Participants were followed
      annually for 3 years to determine who had progressive functional decline and who
      progressed to meet clinical criteria for AD. Those diagnosed with AD on follow-up
      had more symptoms of personality change, such as agitation and passivity, at
      baseline than those who did not progress to meet clinical criteria for AD. Mild
      depressive symptoms were also more common among individuals at baseline who
      subsequently 'converted' to AD. Symptoms of personality change were associated
      with a more rapid increase in functional difficulty over time, whereas depressive
      symptoms were not. Changes in personality are more common among subjects with
      memory changes who go on to develop AD. Particular types of personality change,
      such as agitation and passivity, are related to progression of functional
      difficulty over time. Depressive symptoms, although common in prodromal AD, are
      not associated with a more rapid functional decline.

PMID- 12621315
TI  - Identifying dementia in high-risk community samples: the memory and medical care
      study.
AB  - The Memory and Medical Care Study (MMCS) is a community-based, longitudinal study
      of elders at risk for dementia. This paper describes the study methods for
      identifying subjects with dementia or mild cognitive impairment (MCI) and the
      validation of these methods. The MMCS cohort was established by identifying
      subjects at risk for dementia in three previous studies of randomly ascertained
      samples. Neuropsychologic test score criteria were established to identify MMCS
      subjects with dementia or MCI. These criteria were validated using a fourth
      community-based sample of at-risk elders in which dementia was identified by a
      clinical adjudication panel. Of the 498 MMCS subjects, 70% had dementia and 27%
      had MCI by the MMCS criteria. In the validation sample, the MMCS dementia
      classification method was in agreement with the clinical adjudication panel for
      81% of cases (kappa = 0.62, 95% confidence interval = 0.45-0.78). The methods
      used in the MMCS are efficient and reasonably valid for establishing a cohort of
      subjects to investigate how dementia is assessed, diagnosed, and treated in the
      community.

PMID- 12621316
TI  - Differences between African Americans and whites in their perceptions of
      Alzheimer disease.
AB  - To design optimal health services and education programs for Alzheimer disease
      (AD), it is important to understand cultural differences in perceptions of the
      disorder. In this study, we investigated differences between African Americans
      and whites in their beliefs, knowledge, and information sources regarding AD. We
      distributed a written questionnaire through lay and professional organizations
      and meetings in the southeastern United States, yielding a sample of 452 adults
      (61% white, 39% African American; 78% female; mean age 47 years; 33% with family
      history of AD). The questionnaire assessed the following: (1) illness beliefs,
      (2) factual knowledge, (3) sources of information, and (4) perceived subjective
      threat of AD. African Americans and whites were generally similar in their
      beliefs about common symptoms, prominent risk factors, and the effectiveness of
      treatments for AD (although whites expressed greater certainty in these beliefs
      than African Americans). In comparison to whites, African Americans showed less
      awareness of facts about AD, reported fewer sources of information, and indicated
      less perceived threat of the disorder. These preliminary findings suggest
      important distinctions between African Americans and whites in their knowledge
      about, and conceptualization of, AD. Follow-up studies with more representative
      samples and more fully validated measures will be necessary to confirm these
      differences. Health psychologic research suggests that such differences in
      illness perceptions could shape response to disease burden, assessment and
      diagnosis, and available health care options.

PMID- 12621317
TI  - Identifying driving impairment in Alzheimer disease: a comparison of self and
      observer reports versus driving evaluation.
AB  - This study examined the relationship between driving behaviors and awareness of
      deficit in patients with Alzheimer's disease (AD). Fifteen mildly impaired AD
      patients and 15 healthy elderly controls with valid drivers' licenses were
      administered a series of questionnaires concerning daily functioning and driving
      performance, and all 30 subjects were evaluated on a standardized road test. Self
      report and caregiver/informant responses were compared with determine levels of
      discrepancy in ratings, while comparisons of AD and healthy elderly controls
      revealed group differences. Actual driving performance was considered the
      standard by which to determine accuracy of perceptions. Drivers with AD were
      rated as significantly worse than healthy elderly drivers on nine of 10 driving
      behaviors by an independent evaluator. AD patients' self-reports of driving
      ability were significantly better than the evaluator's ratings on seven of the 10
      items, whereas the healthy elderly drivers rated themselves better than did the
      evaluator on one item. Although caregivers were likely to acknowledge a general
      concern with their AD patients' driving, they underreported specific driving
      problems when their ratings were compared with those of an independent evaluator.
      These findings have implications for the development of caregiver-based
      modifications of driving behavior.

PMID- 12621318
TI  - Brain correlates of performance in a free/cued recall task with semantic encoding
      in Alzheimer disease.
AB  - The goal of this study was to explore in patients with Alzheimer's disease (AD)
      the brain correlates of free and cued recall performance using an adaptation of
      the procedure developed by Grober and Buschke (1987). This procedure, which
      ensures semantic processing and coordinates encoding and retrieval, has been
      shown to be very sensitive to an early diagnosis of AD. Statistical parametric
      mapping (SPM 99) was used to establish clinicometabolic correlations between
      performance at free and cued verbal recall and resting brain metabolism in 31
      patients with AD. Results showed that patient's score on free recall correlated
      with metabolic activity in right frontal regions (BA 10 and BA 45), suggesting
      that performance reflected a strategic retrieval attempt. Poor retrieval
      performance was tentatively attributed to a loss of functional correlation
      between frontal and medial temporal regions in patients with AD compared with
      elderly controls. Performance on cued recall was correlated to residual metabolic
      activity in bilateral parahippocampal regions (BA 36), suggesting that
      performance reflected retrieval of semantic associations, without recollection in
      AD. In conclusion, this study demonstrates that the diagnostic sensitivity for
      Alzheimer's disease of the cued recall performance in the Grober and Buschke
      procedure (1987) depends on the activity of parahippocampal regions, one of the
      earliest targets of the disease. Moreover, the results suggest that the poor
      performance of patients with AD during free and cued recall is related to a
      decreased connectivity between parahippocampal regions and frontal areas.

PMID- 12621319
TI  - The efficacy of pentoxifylline in the treatment of vascular dementia: a
      systematic review.
AB  - This systematic review seeks to (1) summarize the pharmacologic effects of
      pentoxifylline on the cerebrovasculature and (2) review critically the studies
      evaluating pentoxifylline in the treatment of vascular dementia. To retrieve all
      relevant published and unpublished studies, we performed with no language
      restrictions computer keyword searches of MEDLINE, EMBASE, and Cochrane Library
      databases; reviewed bibliographies; and contacted the pharmaceutical
      manufacturer. We included pertinent articles if they met three quality criteria:
      randomized, double-blinded, and placebo-controlled study design; objective
      diagnostic criteria for vascular dementia; and reported original data. The
      literature search identified a total of 20 articles; however, only four studies
      met the quality criteria for inclusion in this systematic review. All four
      studies suggested a trend toward improved cognitive function in patients treated
      with pentoxifylline. Three of the studies performed a subgroup analysis using a
      stricter definition for vascular dementia. In these secondary analyses, the
      studies noted statistically significant differences in cognitive function between
      placebo and treatment groups. In conclusion, this systematic review suggested a
      potential therapeutic role for pentoxifylline in vascular dementia. However, few
      studies met the quality criteria for inclusion in this systematic review, and
      most of these studies were small and had methodologic limitations.

PMID- 12621320
TI  - White matter lesions, dementia, and ischemic axonopathy.

PMID- 12621322
TI  - Mastoid obliteration: autogenous cranial bone pAte reconstruction.
AB  - OBJECTIVE: To review the outcome in consecutive patients who have undergone
      complete epitympanic and mastoid obliteration and concurrent tympanic membrane
      reconstruction over a 53-month period. STUDY DESIGN: Retrospective review.
      SETTING: Tertiary referral center. PATIENTS: Sixty-two ears in 56 sequential
      patients undergoing mastoid obliteration with major indications including
      recurrent infection, debris trapping in the canal wall-down cavity, intolerance
      of water exposure, calorically induced vertigo in an existing cavity, a
      semicircular canal fistula, and inability to wear a hearing device. Thirty-six
      ears in 33 patients who underwent second-stage surgery for ossicular
      reconstruction during the same time period are also reviewed. INTERVENTION:
      Transplanted autogenous cranial bone is used to induce osteoneogenesis resulting
      in complete obliteration of the epitympanic and mastoid spaces while maintaining
      a mesotympanic space. MAIN OUTCOME MEASURES: Success of obliteration, incidence
      of symptoms prompting intervention, hearing outcome, incidence of recurrent
      cholesteatoma, and incidence of eustachian tube dysfunction necessitating
      treatment and need for revision surgical procedures.RESULTS Complete take of the
      bony obliteration occurs in over 95% of cases; 90% of treated patients enjoy
      complete absence of original symptoms, whereas symptoms improved in the
      remainder. For over 95% of patients, existing eustachian tube function has been
      adequate after obliteration. To date, no patient has required revision surgical
      intervention. CONCLUSION: Mastoid obliteration with autogenous cranial bone is a
      safe and extremely effective option for treatment of problematic canal wall-down
      mastoid cavities. Surgical techniques that include sterile harvest of the cranial
      bone graft mixed with antibiotic, revision of the cavity to expose viable native
      bone, inclusion of the epitympanic spaces in the obliteration, and complete
      coverage of the pAte with autogenous fascia have proven critical to successful
      outcome.

PMID- 12621323
TI  - Sensorineural hearing loss in chronic otitis media.
AB  - OBJECTIVE: To determine whether chronic suppurative otitis media may cause
      sensorineural hearing loss. METHODS: The files of 121 patients with unilateral
      chronic suppurative otitis media were reviewed in a retrospective study. Air
      conduction and bone conduction threshold averages were calculated over the speech
      frequencies (500 Hz, 1,000 Hz, and 2,000 Hz). Thresholds at 4 kHz were examined
      separately but in a similar way. Multiple linear regression models were used to
      clarify the relationships between sensorineural hearing loss and chronic otitis
      media. RESULTS: Chronic suppurative otitis media was seen to be associated with
      sensorineural hearing loss. When age and normal side were corrected for, pure
      tone threshold and bone conduction threshold at either the speech frequencies or
      at 4 kHz increased gradually according to the duration of the chronic suppurative
      otitis media. The threshold shift was more accentuated as age increased. The
      sensorineural hearing loss at 4 kHz seemed to be higher than that at the speech
      frequencies. CONCLUSIONS: The inner ear is vulnerable against chronic suppurative
      otitis media. Older age increases this vulnerability. The proximity of the
      sensory cells to the potential source of harm (inflamed middle ear) may mean
      higher exposure, as reflected by the fact that sensory cells processing higher
      frequencies are more seriously damaged.

PMID- 12621324
TI  - Lateralization of the tympanic membrane as a complication of canal wall down
      tympanoplasty: a report of four cases.
AB  - OBJECTIVE: To describe the pathophysiology and treatment of the lateralized
      tympanic membrane that occurs after canal wall down tympanoplasty. STUDY DESIGN:
      Retrospective case review. SETTING: Tertiary referral hospital. PATIENTS: Four
      patients in whom lateralization of the tympanic membrane developed as a
      complication of canal wall down tympanoplasty. RESULTS: The patients had
      undergone middle ear surgery 20 to 34 years before their first visit to the
      authors. A Bondy operation with soft-wall reconstruction of the ear canal had
      been performed in three patients and a modified radical mastoidectomy in one
      patient. They all had severe conductive hearing loss. Common findings were
      anterior canal sulcus blunting, good tubal function, normal middle ear mucosa,
      and mobile stapes. At revision surgery, the lateralized tympanic membrane was
      removed, and the temporalis fascia was grafted medial to the malleus manubrium.
      The exposed bony surface in the ear canal was covered with a split-thickness skin
      graft, and the ear canal and the mastoid cavity were tightly packed to secure the
      graft. All the patients regained good hearing after the revision. Although
      deterioration of the anterior tympanic ring was presumed to be the primary cause
      of the graft lateralization, the lack of a posterior bony ear canal might have
      facilitated this condition. CONCLUSION: Lateralization of the tympanic membrane
      can occur even in an ear with a radicalized mastoid cavity, especially when the
      anterior tympanic ring is torn and the posterior ear canal is reconstructed with
      soft tissue.

PMID- 12621325
TI  - Early results with titanium ossicular implants.
AB  - OBJECTIVE: To report the efficacy of titanium middle ear prosthesis for ossicular
      reconstruction. STUDY DESIGN: Retrospective chart reviews were performed for 25
      patients who had undergone titanium ossicular implants between January 1, 1999,
      and June 1, 20001. SETTING: Tertiary otology referral center. PATIENTS: All
      patients had a minimum of 6 months of postoperative follow-up and no evidence of
      recurrent otologic disease. INTERVENTION: All patients had undergone
      ossiculoplasty using titanium middle ear implants. MAIN OUTCOME MEASURES:
      Comparisons of preoperative and postoperative pure tone averages were performed.
      Air-bone gap closures and implant extrusion rates were measured. RESULTS Overall
      mean pure tone averages improved 22.2 dB with air-bone gap improvement at 20.9
      dB. Fifty-six percent of patients achieved air-bone gap less than 20 dB
      postoperatively. The overall extrusion rate was 4%. However, with the placement
      of cartilage graft interposed between the prosthesis and the tympanic membrane,
      no extrusion was observed. CONCLUSION: Titanium implants provide comparable
      hearing improvement compared with other materials. The extrusion rate seems quite
      low if cartilage interposition graft is inserted. Its ease of handling,
      biocompatible properties, and sound conducting properties improve its efficacy as
      an ossicular implant.

PMID- 12621326
TI  - Prolonged middle ear ventilation with the cartilage shield T-tube tympanoplasty.
AB  - BACKGROUND: In 1994, the favorable experience with composite cartilage shield
      tympanoplasty was reported to the American Otological Society. On that occasion,
      the technical question regarding the concomitant placement of a ventilating tube
      was posed. In response, the authors proposed that the tympanostomy tube be
      incorporated in the cartilage graft. Moreover, they proposed that this marriage,
      when used to reverse atelectasis and to repneumatize the middle ear, should offer
      the advantage of both procedures while reducing the incidence of tube extrusion
      and other complications of prolonged intubation. Although attractive in theory,
      this supposition could be validated only after prolonged follow-up, reported
      here. OBJECTIVE: To describe an effective means to secure prolonged middle ear
      ventilation in a patient population prone to atelectasis and chronic middle ear
      effusion and to establish the incidence of favorable and unfavorable outcomes
      after 6 years of observation. STUDY DESIGN: Retrospective case series. SETTING:
      Tertiary referral center. PATIENTS: Forty patients (28 adults and 12 children)
      who underwent tympanic membrane reconstruction with a composite cartilage shield
      T-tube "unit."RESULTS The overall retention rate was 62.5% over 6 years. Sixty
      five percent of retained tubes were maintained for a minimum of 4 years in adult
      patients. Extrusion and permanent perforation rates were 0%. CONCLUSION: The
      cartilage shield T-tube tympanoplasty can effectively reverse atelectasis and
      provide prolonged middle-ear ventilation. The technique can be used safely and
      minimizes the risk of tympanic membrane perforation and other complications
      associated with prolonged middle ear intubation.

PMID- 12621327
TI  - Adipose graft: an original option in myringoplasty.
AB  - OBJECTIVE: To describe the fat graft as a reconstructive material in
      myringoplasty. METHOD: In a review of 45 patients conducted between 1993 and
      1999, the authors analyzed their patients' outcomes after having myringoplasties
      with fat graft. Median follow-up was 2.5 years (range, 6 mo-6 yr). RESULTS: We
      achieved a success rate of 91.1%. Different features of the patient and the
      tympanic perforation were studied to demonstrate their role in the quality of the
      surgical closing. A review of the literature was done to compare our results with
      the results of other series using this type of graft as well as with studies of
      the temporalis fascia as a graft material. CONCLUSION: The high reliability of
      the fat graft and the technical simplicity of this procedure in anterior
      perforations, especially with the use of intraoperative endoscopy, make it an
      attractive technique.

PMID- 12621328
TI  - Diagnostic utility of laser-Doppler vibrometry in conductive hearing loss with
      normal tympanic membrane.
AB  - HYPOTHESIS: It was hypothesized that laser-Doppler vibrometry measurements of
      umbo velocity in aerated middle ears with conductive loss can differentiate
      ossicular interruptions, stapes fixations, and mallear fixations. More generally,
      we hypothesize that laser-Doppler vibrometry measurements of umbo velocity can
      give information about how differences in the impedance that the ossicles work
      against affect middle-ear function. BACKGROUND: Laser-Doppler vibrometry is a
      well-established research tool for exploring middle-ear function. The authors
      wished to investigate its potential as a clinical tool for differential diagnosis
      of the cause of conductive hearing loss. METHODS: Laser-Doppler vibrometry was
      used to investigate the relationship between the sound-induced velocity of the
      tympanic membrane at the umbo and the cause of conductive hearing loss when the
      tympanic membrane was normal and the middle ear was aerated. The results of
      measurements in 17 adult ears before exploratory tympanotomy were compared with
      the surgically determined cause of the hearing loss. The authors also measured
      the motion of the umbo in 10 patients who had undergone successful small-fenestra
      stapedectomy procedures. In all the studied ears, pure-tone audiograms were
      measured at the time of laser-Doppler vibrometry testing. RESULTS: There were
      clear statistical differences between the umbo velocity in normal ears and in
      ears with different ossicular pathologic conditions. There was also a clear
      separation of the results between ears with ossicular interruptions and ossicular
      fixation. The pattern of laser-Doppler vibrometry measurements in
      poststapedectomy ears approximated the pattern in ears with ossicular
      interruptions. CONCLUSION: Comparison of laser-Doppler vibrometry results and
      audiometry may be a sensitive and selective indicator of ossicular pathologic
      conditions as well as a useful tool for investigating middle ear function.

PMID- 12621329
TI  - Middle-ear mechanics of Type III tympanoplasty (stapes columella): I.
      Experimental studies.
AB  - OBJECTIVE: To investigate the mechanics of Type III tympanoplasty by developing a
      cadaveric temporal bone model. BACKGROUND: Type III stapes columella
      tympanoplasty involves the placement of a tympanic membrane graft, usually made
      of temporalis fascia, directly onto the stapes head. The procedure is usually
      done in conjunction with a canal wall down mastoidectomy. Postoperative hearing
      results vary widely, with air-bone gaps of 10 to 60 dB. The structural features
      responsible for the wide range in hearing results have not been systematically
      investigated. METHODS: Canal wall down Type III procedures were performed in
      eight cadaveric temporal bones. Acoustic stimuli were presented in the ear canal,
      and round window velocity VRW (used as an index of hearing) was measured, while
      systematically varying stapes mobility, mechanical properties of tympanic
      membrane graft, and tightness of connection between tympanic membrane graft and
      stapes. The effect of interposing a thin cartilage disc between the tympanic
      membrane graft and stapes head was also assessed. RESULTS: When the middle ear
      was aerated and the stapes was mobile, VRW was 15 to 30 dB lower than in an
      intact, normal ear. Stapes fixation led to a significant reduction in VRW;
      reduction was greatest at low frequencies. There was little effect of varying the
      tightness of connection between the tympanic membrane graft and stapes head.
      Sound energy was transmitted from the graft to the stapes as long as the graft
      was in physical contact with the stapes head. Different tympanic membrane graft
      materials with a range of mechanical properties (stiffness and mass) resulted in
      little variation in VRW. Interposing a thin cartilage disc between the tympanic
      membrane graft and stapes improved VRW in the lower frequencies by 5 to 10 dB.
      The authors hypothesize that the disc acted to increase the effective vibrating
      area of the graft. CONCLUSIONS: The feasibility of using a cadaveric temporal
      bone model to study the mechanics of Type III tympanoplasty was demonstrated. A
      mobile stapes and aerated middle ear were essential for a successful Type III
      tympanoplasty. There was little effect of varying the mechanical properties of
      the tympanic membrane graft or changing the tightness of connection between the
      graft and stapes head. Improved results were achieved by interposing a thin
      cartilage disc between the graft and stapes head to increase the effective
      vibrating area of the graft.

PMID- 12621330
TI  - Middle ear mechanics of Type III tympanoplasty (stapes columella): II. Clinical
      studies.
AB  - OBJECTIVES: To determine the structural features that are responsible for the
      large variation in postoperative hearing results after Type III stapes columella
      tympanoplasty, to compare the clinical results after Type III tympanoplasty with
      predictions based on experimental investigations using a temporal bone model, and
      to investigate the effectiveness of a modification in surgical technique for Type
      III reconstruction. STUDY DESIGN: Retrospective case review. SETTING: Tertiary
      referral center. INCLUSION CRITERIA: The ear was healed with an intact tympanic
      membrane graft; the status of the stapes was known, whether mobile or fixed; and
      the postoperative status of aeration of the middle ear was known, whether aerated
      or not. MAIN OUTCOME MEASURE: Air-bone gap at frequencies 250, 500, 1,000, 2,000
      and 4,000 Hz. RESULTS: In ears with temporalis fascia graft onto stapes head:
      mobile stapes and aerated middle ear (n = 34), mean air-bone gaps at audiometric
      frequencies were 15 to 30 dB, consistent with predictions of the experimental
      model; mobile stapes and nonaerated middle ear (n = 16), large air-bone gaps of
      35 to 55 dB; fixed stapes and aerated middle ear (n = 4), large air-bone gaps of
      30 to 50 dB; fixed stapes and nonaerated middle ear (n = 2), large air-bone gaps
      of 30 to 70 dB. In ears with a fascia-cartilage graft onto stapes head, where a
      thin disc of meatal cartilage, 0.3 to 0.5 mm thick and 4 to 6 mm in diameter was
      interposed between the fascia graft and the stapes head: mobile stapes and
      aerated middle ear (n = 9), mean air-bone gaps at audiometric frequencies were 10
      to 25 dB, about 5 dB better at 250, 500, and 2,000 Hz than in ears with only a
      fascia graft ( <0.05), improvement consistent with that observed experimentally
      when a thin cartilage disc was used in the temporal bone model, hypothesis that
      the cartilage increased the effective vibrating area of the graft; mobile stapes
      and nonaerated middle ear (n = 2), air-bone gaps were 40 to 50 dB. CONCLUSIONS:
      Large air-bone gaps of 30 to 70 dB occurred as a result of stapes fixation,
      nonaeration of the middle ear, or both. When the stapes was mobile and the middle
      ear was aerated, a fascia graft resulted in air-bone gaps of 15 to 30 dB.
      Interposing a thin disc of cartilage between the fascia graft and stapes head to
      improve the effective vibrating graft area gave better hearing, with air-bone
      gaps of 10 to 25 dB. The clinical Type III results were consistent with
      predictions based on experimental investigations of mechanics of the Type III
      procedure in a temporal bone model.

PMID- 12621331
TI  - Persistent inner ear injury after diving.
AB  - OBJECTIVE: The purpose of this multiple case report was to discuss the occurrence
      and cause of sudden sensorineural hearing loss after diving. STUDY DESIGN: The
      study design was a retrospective case review. SETTING: The study was conducted at
      an academic tertiary referral center. PATIENTS: In this multiple case report, two
      teenagers with unilateral sudden sensorineural hearing loss after diving, one
      from a starting block and one from a 1-m board, while performing school
      swimsports were included. INTERVENTION: The patients underwent diagnostic
      tympanotomy with sealing of the round and oval window membranes and a vasoactive
      rheologic therapy combined with corticosteroid treatment. MAIN OUTCOME MEASURES:
      The average pure-tone bone-conduction thresholds were calculated. The appearance
      of nystagmus, vertigo, and tinnitus was analyzed. RESULTS: Both patients
      experienced unilateral sudden deafness after performing a headfirst pike-type
      dive into a swimming pool. None of the patients contacted with the bottom of the
      pool. In one patient, a rupture of the round window was found intraoperatively.
      In the other patient, no rupture of the round or oval window was seen
      intraoperatively. In spite of sealing of the round window and application of
      vasoactive rheologic therapy, hearing did not improve significantly in either of
      the patients. CONCLUSION: Rupture of the round window may occur after diving even
      if the dive is performed from a low height into the water and the bottom of the
      pool is not contacted. Besides direct contusion to the external ear and
      barotrauma, other causes such as whiplash mechanism have to be considered.

PMID- 12621332
TI  - The utility of positron emission tomography in the evaluation of autoimmune
      hearing loss.
AB  - OBJECTIVE: To evaluate positron emission tomography as an imaging tool in the
      diagnosis, evaluation, and management of autoimmune inner ear disease.
      BACKGROUND: Autoimmune inner ear disease is a form of cochleovestibular disease
      associated with variable hearing loss and vertigo for which no reliable
      diagnostic tests are available. METHODS: Pilot study of 10 patients with
      autoimmune inner ear disease and 5 sex-matched and age-matched control subjects
      without any history of autoimmune inner ear disease, who underwent limited
      positron emission tomography of the inner ear. Five patients with new or active
      autoimmune inner ear disease underwent serial positron emission tomography before
      and after 4 to 6 weeks of a high-dose tapering course of prednisone. The subjects
      had cranial magnetic resonance imagining, audiometric and vestibular studies, and
      heat-shock protein (HSP-70) measurements. Reading of the positron emission
      tomography scans was blinded. RESULTS: Positron emission tomography was normal in
      4 of 5 normal control subjects and abnormal in 1 with normal audiometric and
      vestibular studies and positive HSP-70. Of patients with established and stable
      autoimmune inner ear disease, 4 of 5 had no positron emission tomography
      abnormalities and negative HSP-70, and the one with abnormal positron emission
      tomography shortly thereafter manifested clinically active disease. Of the 5
      patients with active autoimmune inner ear disease monitored serially, 4 had an
      initial abnormal positron emission tomography in at least one ear, which became
      normal in all but 1 patient after therapy. HSP-70 correlated with disease
      activity. Only 1 patient with clinically active autoimmune inner ear disease had
      a normal positron emission tomography before and after therapy (the HSP-70 was
      positive before therapy and negative after the therapy). CONCLUSIONS: Positron
      emission tomography, especially when combined with HSP-70 determination, may be a
      useful technique for assessing disease in patients with autoimmune inner ear
      disease.

PMID- 12621333
TI  - Macrothrombocytopenia and progressive deafness is due to a mutation in MYH9.
AB  - BACKGROUND: In 1992, a family with hereditary macrothrombocytopenia and
      progressive sensorineural hearing impairment without renal dysfunction was
      described. Recently, mutations in MYH9, a nonmuscle myosin heavy chain, have been
      found in several forms of hereditary macrothrombocytopenia. HYPOTHESIS: The
      hereditary macrothrombocytopenia and hearing loss in the previously reported
      family is due to a mutation in MYH9 gene. METHODS: Genomic DNA was extracted from
      the affected proband. Mutation screening of all MYH9 coding exons was carried out
      using denaturing high-performance liquid chromatography. Abnormal results were
      followed by direct sequencing of the exon and comparison of the sequence with the
      normal MYH9 sequence. RESULTS: The results of denaturing high-performance liquid
      chromatography suggested a potential sequence alteration in exon 30 of MYH9.
      Direct sequence analysis of this exon in the affected individual identified a G
      to A single base pair transition at nucleotide 4270 altering codon 1424. This
      mutations leads to an amino acid change from aspartate (D) to asparagine (N) in
      the highly conserved coiled-coil domain. CONCLUSIONS: A single base pair
      transition in MYH9, resulting in an amino acid substitution D1424N, is
      responsible for macrothrombocytopenia and hearing loss in the kindred under
      study. The presence of hearing impairment and the absence of renal symptoms, as
      reported in other families with the same mutation MYH9, further highlights the
      role of genetic background in expression and modification of the affected
      phenotype.

PMID- 12621334
TI  - Characterization of a stapes ankylosis family with a NOG mutation.
AB  - OBJECTIVE: To characterize the otologic phenotype in a family with autosomal
      dominant stapes ankylosis, hyperopia, and skeletal abnormalities caused by a
      mutation in the noggin gene (NOG). STUDY DESIGN: Case series. SETTING: Academic
      tertiary care center. PATIENTS: Eight affected and 3 unaffected family members.
      MAIN OUTCOME MEASURES: History, physical and radiologic examination, and surgical
      outcomes. RESULTS: Although affected members were initially presumed to have
      typical nonsyndromic otosclerosis, the clinical data were most consistent with an
      autosomal dominant congenital stapes ankylosis syndrome. Eight of eight affected
      family members had bilateral low-frequency conductive hearing loss. Six of eight
      underwent fenestration procedures and/or stapedectomies. All members with initial
      postoperative closure of the air-bone gap returned to their baseline conductive
      loss within 2 years. Two affected family members had documented maximal
      conductive hearing loss by age 4, and two members without previous otologic
      surgery have not experienced sensorineural hearing loss. High-resolution temporal
      bone computed tomography showed stapes ankylosis and indistinction of the
      incudomalleal junction bilaterally and bony regrowth over the stapedotomy for
      those with stapedectomies. Detailed physical and radiologic examination
      identified multiple other skeletal abnormalities. CONCLUSIONS: Although this
      phenotype may present as classic otosclerosis to the otolaryngologist, detailed
      investigation revealed a congenital stapes ankylosis syndrome. Because is
      essential in regulating normal bone development and maturation, mutations in this
      gene may be associated with excessive bony overgrowth and refixation of the
      stapes footplate after initial successful surgery. Patients with hereditary
      conductive hearing loss should be assessed to rule out subtle features of a
      skeletal syndrome.

PMID- 12621336
TI  - Technical report: modification of a cochlear implant electrode for drug delivery
      to the inner ear.
AB  - OBJECTIVE: To investigate the possibility of modifying a cochlear implant
      electrode for the purpose of drug delivery to the cochlea. BACKGROUND: Animal
      experiments suggest that local therapy of the inner ear could be a promising new
      approach to the interventional treatment of inner ear disease, and that
      pharmacologic intervention could possibly enhance cochlear implant performance.
      One of the key aspects is the deployment of a means of drug delivery to the human
      inner ear. METHODS: The tip of the Contour electrode array was cut to open the
      lumen of the array, and a connecting piece was developed to connect the electrode
      to a pump. The feasibility of using the array for drug delivery was tested using
      both an Alzet mini-osmotic pump and a mechanical pump. The connection was tested
      for its stability in terms of leakage and resistance to tractive forces. The
      system was also applied to temporal bones to evaluate its applicability to the
      human cochlea. RESULTS: The modified Contour electrode is easy to handle in
      temporal bones and can be used to simulate drug delivery to the inner ear. The
      connection to the pump was sealed for all tested pump rates and resisted tractive
      forces up to 50 N. CONCLUSIONS: The described modified electrode could provide a
      safe and easy-to-handle means of combining electrical stimulation with the
      beneficial effects of a local drug therapy applied to the inner ear.

PMID- 12621335
TI  - Usher syndrome and cochlear implantation.
AB  - OBJECTIVE: To evaluate the symptoms leading to diagnosis and the quality of
      rehabilitation after cochlear implantation in Usher syndrome. STUDY DESIGN:
      Retrospective cohort study. SETTING: ENT department of a tertiary referral
      hospital. PATIENTS: Among 210 patients given an implantation in the Ear, Nose,
      and Throat department, 185 were congenitally deaf and 13 had Usher syndrome
      (7.0%). Five had a family history of Usher, and eight were sporadic cases. Eleven
      cases were Usher type I, one was Usher type III, and one was not classified. The
      age at implantation ranged from 18 months to 44 years (mean, 6 years 1 month).
      The mean follow-up was 52 months (range, 9 months to 9 years). MAIN OUTCOME
      MEASURES: All patients had audiophonological and clinical examination, computed
      tomography scan of the temporal bones, ophthalmologic examination with
      fundoscopy, and an electroretinogram. Cerebral magnetic resonance imaging and
      vestibular examination were performed in 9 of 13 and 10 of 13 cases,
      respectively. Logopedic outcome measured preimplant and postimplant closed- and
      open-set word recognition and oral expression at follow-up. RESULTS: The most
      frequent initial sign of Usher syndrome was delayed walking, with a mean age of
      20 months. Among the 172 other congenitally deaf children with implants, when
      deafness was not associated with other neurologic disorders, the mean age at
      walking was 14 months (p < 0.001). The fundoscopy was always abnormal after the
      age of 5 years, and the electroretinogram was abnormal in all cases. Vestibular
      function was abnormal in all but one case (nonclassified). The computed
      tomography scan and the magnetic resonance imaging were always normal. Logopedic
      results with cochlear implants showed good perception skills in all but one case.
      The best perceptive results were obtained in children implanted before the age of
      9 years. Oral language had significantly progressed in 9 of 13 at follow-up.
      There was no relation between the visual acuity and the logopedic results.
      CONCLUSION: The earliest clinical sign associated with deafness evoking Usher
      syndrome is late walking. The electroretinogram is the only reliable examination
      to enable the diagnosis. When severe profound deafness is associated with late
      walking, the electroretinogram should be systematically proposed. Logopedic
      results are linked to precocity of implantation, and early Usher's diagnosis
      contributes to optimize speech therapy.

PMID- 12621337
TI  - Speech coding strategies and revised cochlear implant candidacy: an analysis of
      post-implant performance.
AB  - OBJECTIVE: Technological advances in cochlear implant systems on which a sequence
      of speech coding strategies have been implemented seem to have resulted in
      improved speech perception. However, changing selection criteria for implantation
      have coincided with evolving technology and may confound post-implantation speech
      perception performance. This study compares speech coding strategy with speech
      perception performance in severe and profound postlingually deafened adults using
      one of three successive generations of Nucleus Cochlear Implant speech processors
      (i.e., Mini Speech Processor, Spectra 22, and SPrint) implementing three speech
      coding strategies (i.e., MPEAK, SPEAK, and Advanced Combination Encoders;
      Cochlear Corporation, Englewood, CO, U.S.A.). STUDY DESIGN: Four cohorts of
      patients were retrospectively reviewed. SETTING: Multicenter, tertiary referral
      cochlear implant programs in Ontario, Canada. METHODS: Four cohorts of patients
      (n = 139) were identified based on preimplant audiological measures, duration of
      deafness, device type, and speech coding strategy. Word and sentence recognition
      scores at 12 months after implantation were compared using MPEAK with SPEAK22
      implemented on the Nucleus 22 speech processors (Mini Speech Processor and
      Spectra22, respectively) and SPEAK24 as well as Advanced Combination Encoders
      implemented on the Nucleus 24 SPrint processor. RESULTS: Open-set speech
      recognition batteries revealed significant improvements in word and sentence
      scores as advancing technology implemented new speech coding strategies. Subgroup
      analysis of profoundly deafened patients supported this. Analysis of covariance
      confirmed that the measured differences could not be accounted for by changing
      selection criteria for implantation. CONCLUSION: Improvements in performance can
      be attributed to evolving speech coding strategies and speech processors rather
      than to differences in preimplant candidacy.

PMID- 12621338
TI  - Vestibular dysfunction after cochlear implantation.
AB  - OBJECTIVE: To determine the prevalence, symptom characteristics, and potential
      risk factors for vestibular symptoms after cochlear implantation. STUDY DESIGN:
      Case-control study design embedded within an ongoing cohort of patients
      undergoing implantation. SETTING: Academic medical center cochlear implant
      research program funded by the National Institutes of Health. PATIENTS: Seventy
      five eligible consecutive patients undergoing cochlear implantation.
      INTERVENTION: Medical record review. MAIN OUTCOME MEASURE: Recorded symptoms of
      vestibular symptoms after cochlear implantation. Subjects with vestibular
      symptoms were considered case subjects; those without vestibular symptoms were
      considered control subjects. RESULTS: Twenty-nine of 75 (39%) patients
      experienced dizziness postoperatively. Four patients experienced a single,
      transient acute vertigo attack occurring less than 24 hours after surgery. The
      majority, 25 patients, experienced delayed, episodic onset of vertigo. The median
      (interquartile range) time of delayed onset was 74 (26-377) days after
      implantation. Delayed dizziness manifested as spontaneous episodic or positional
      vertigo. Preoperative dizziness, age at implantation, and age at onset of hearing
      loss were significantly greater in the dizzy group. Preoperative
      electronystagmography did not differentiate between groups. CONCLUSIONS: Thirty
      nine percent (29/75) of subjects with implants were dizzy after implantation. The
      majority of subjects experienced dizziness in a delayed episodic fashion.
      Dizziness was not related to implant activation. It seemed that delayed dizziness
      was not related to immediate surgical intervention but could result from chronic
      changes occurring in the inner ear; there was some suggestion this could take the
      form of endolymphatic hydrops.

PMID- 12621339
TI  - Coding of sounds in the auditory system and its relevance to signal processing
      and coding in cochlear implants.
AB  - OBJECTIVE: To review how the properties of sounds are "coded" in the normal
      auditory system and to discuss the extent to which cochlear implants can and do
      represent these codes. DATA SOURCES: Data are taken from published studies of the
      response of the cochlea and auditory nerve to simple and complex stimuli, in both
      the normal and the electrically stimulated ear. REVIEW CONTENT: The review
      describes: 1) the coding in the normal auditory system of overall level (which
      partly determines perceived loudness), spectral shape (which partly determines
      perceived timbre and the identity of speech sounds), periodicity (which partly
      determines pitch), and sound location; 2) the role of the active mechanism in the
      cochlea, and particularly the fast-acting compression associated with that
      mechanism; 3) the neural response patterns evoked by cochlear implants; and 4)
      how the response patterns evoked by implants differ from those observed in the
      normal auditory system in response to sound. A series of specific issues is then
      discussed, including: 1) how to compensate for the loss of cochlear compression;
      2) the effective number of independent channels in a normal ear and in cochlear
      implantees; 3) the importance of independence of responses across neurons; 4) the
      stochastic nature of normal neural responses; 5) the possible role of across
      channel coincidence detection; and 6) potential benefits of binaural
      implantation. CONCLUSIONS: Current cochlear implants do not adequately reproduce
      several aspects of the neural coding of sound in the normal auditory system.
      Improved electrode arrays and coding systems may lead to improved coding and, it
      is hoped, to better performance.

PMID- 12621340
TI  - The use of full-thickness skin grafts for the skin-abutment interface around bone
      anchored hearing aids.
AB  - OBJECTIVE: To review the complication rate encountered with the use of full
      thickness skin grafts to establish the skin-abutment interface around bone
      anchored hearing aid implants. STUDY DESIGN: Retrospective chart review. SETTING:
      Tertiary referral center. PATIENTS: Fifteen patients who underwent bone-anchored
      hearing aid placement over a 4-year period. INTERVENTION: Each percutaneous
      titanium implant and abutment was placed into the temporal bone following the
      standard Branemark technique. Eight procedures were performed in two stages, and
      seven were performed as single-stage procedures. In all cases, the skin-abutment
      interface was established by use of a full-thickness skin graft inset around the
      implant. MAIN OUTCOME MEASURES: The incidence of complications resulting in skin
      graft loss, time from implantation to bone-anchored hearing aid use, additional
      procedures for revision of the interface, and complicating medical factors in the
      patient population. RESULTS: Seven patients (46.7%) experienced loss of the full
      thickness skin graft around the abutment. Four of these seven had complicating
      medical factors associated with impaired wound healing: two with diabetes
      mellitus, one of whom was also a smoker, and two patients who were receiving
      inhaled steroids for treatment of asthma. Of the seven patients who lost skin
      grafts, two healed by secondary intention, two underwent repeated full-thickness
      skin grafting, and three underwent galeal rotation flaps with split-thickness
      skin grafting, one of which eventually required a scalp flap. No patient
      experienced loss of the implant. CONCLUSION: The use of full-thickness skin
      grafts for establishment of the skin-abutment interface around bone-anchored
      hearing aid implants is associated with a high rate of graft loss. Although
      salvage techniques can successfully establish the interface after skin graft
      failure, alternative methods should be considered, especially in high-risk
      patients.

PMID- 12621341
TI  - Round window atresia and its effect on sound transmission.
AB  - OBJECTIVE: To document isolated round window atresia and to discuss its impact on
      current theories of inner ear function. PATIENTS AND STUDY DESIGN: Retrospective
      analysis of isolated round window atresia suggesting an autosomal dominant
      inheritance pattern and review of current concepts of cochlear macromechanics.
      SETTING: Tertiary referral center. RESULTS: The unexpected finding of isolated
      round window atresia in two female patients of the same family was confirmed
      intraoperatively as well as postoperatively using high-resolution computed
      tomography. The current audiograms and the review of the literature highlight a
      mixed, but predominantly conductive, hearing impairment with thresholds at 30 to
      40 dB. Implying that there is no pressure release mechanism for inner ear fluid
      displaced by the stapes footplate, a total conductive hearing loss would be
      expected. CONCLUSIONS: The rare finding of round window atresia can be overlooked
      at surgery because of insufficient exposure of the round window niche. High
      resolution computed tomography confirms the round window obliteration. It seems
      that an alternative way of cochlear stimulation takes place besides the concept
      of fluid bulk shifting. Surgery seems not to guarantee favorable results.

PMID- 12621342
TI  - Cartilage tympanoplasty for posterosuperior retraction pockets of the pars tensa
      in children.
AB  - OBJECTIVE: To assess the functional and anatomic results of cartilage grafting in
      children with a severe retraction pocket of the posterosuperior part of the pars
      tensa and operated on by pocket excision and cartilage grafting. STUDY DESIGN:
      Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Fifty six
      children (60 ears) with severe posterosuperior retraction pockets. INTERVENTION:
      Excision of the pocket and tympanic reinforcement with a tragal or conchal
      cartilaginous graft. MAIN OUTCOME MEASURES: Postoperative anatomic (otoscopy,
      computed tomography) and functional (pure tone audiometry thresholds) outcome.
      The follow-up time was 27 +/- 18 months (mean +/- SD). RESULTS: Retraction
      recurrences requiring additional surgery occurred in 5 cases (8%). The risk of
      recurrence was lower in children older than 10 years and when the whole surface
      of the pars tensa was reinforced (chi(2) test, p< 0.05 for both factors).
      Functionally, hearing was improved even when the ossicular chain was intact. In
      case of disrupted ossicular chain, direct contact between the graft and eroded
      incudostapedial joint gave good hearing results. CONCLUSIONS: Cartilage
      reinforcement of the whole surface of the pars tensa is probably the best
      treatment of a severe posterosuperior retraction pocket. The flexibility and
      thinness of cartilage from the cymba conchae makes it particularly suitable in
      this indication.

PMID- 12621343
TI  - Dehiscence of bone overlying the superior canal as a cause of apparent conductive
      hearing loss.
AB  - OBJECTIVE: To identify patients with superior semicircular canal dehiscence and
      apparent conductive hearing loss and to define the cause of the air-bone gap.
      STUDY DESIGN: Prospective study of patients with superior canal dehiscence.
      SETTING Tertiary referral center. PATIENTS: Vestibular and/or auditory findings
      indicative of canal dehiscence and demonstration of superior canal dehiscence on
      computed tomography of the temporal bone. INTERVENTION: Vestibular-evoked
      myogenic potentials, three-dimensional eye movement recordings, and surgical
      resurfacing of the superior canal. OUTCOME MEASURE: Association of superior canal
      dehiscence with an air-bone gap on audiometry. RESULTS: Four patients with
      dehiscence of bone overlying the superior canal were found to have air-bone gaps
      in the affected ears that were greatest at lower frequencies and averaged 24 +/-
      7 dB over the frequency range of 250 to 4,000 Hz. Three of these patients had
      undergone stapedectomy before the identification of superior canal dehiscence.
      The air-bone gap was unchanged postoperatively. Each patient had an intact
      vestibular-evoked myogenic potential (VEMP) response from the affected ear, a
      finding that would not have been expected based on a middle ear cause of
      conductive hearing loss. One patient underwent resurfacing of the superior canal
      through a middle fossa approach. Postoperatively, his vestibular symptoms were
      relieved, and his air conduction thresholds were improved by 20 dB. CONCLUSIONS:
      Superior canal dehiscence can result in apparent conductive hearing loss. The
      third mobile window created by the dehiscent superior canal results in
      dissipation of acoustic energy and is a cause of inner ear conductive hearing
      loss.

PMID- 12621344
TI  - Development of autoimmune sensorineural hearing loss after endolymphatic sac
      decompression: two case reports.
AB  - OBJECTIVE: To present two case reports that the authors believe demonstrate the
      creation of autoimmune hearing loss in a healthy ear in response to endolymphatic
      sac surgery in an opposite ear felt to be afflicted with Meniere's Disease. In
      both cases, unexpected trama was incurred in performing the original surgery for
      endolymphatic sac decompression. STUDY DESIGN: Two case reports. SETTING:
      Ambulatory office and hospital in a tertiary referral center. PATIENTS: Two
      patients selected for their unique development of autoimmunity in the ear that
      was not operated on. INTERVENTIONS: Surgical intervention (endolymphatic sac
      surgery) for Meniere's Disease. MAIN OUTCOME MEASURES: Audiometry and clinical
      assessment. RESULTS: Audiometric results of two patients believed to have
      developed autoimmune sensorineural hearing loss as the result of surgical trauma
      delivered to the patient's opposite ear. CONCLUSION: It is believed that the two
      patients presented developed autoimmune sensorineural hearing loss in an opposite
      nonsurgical ear in response to surgical intervention (believed to be traumatic)
      in their original Meniere's Disease ear.

PMID- 12621345
TI  - Furosemide loading vestibular evoked myogenic potential for unilateral Meniere's
      disease.
AB  - OBJECTIVE: To investigate whether endolymphatic hydrops in Meniere's Disease
      could be diagnosed by comparing vestibular evoked myogenic potential (VEMP)
      before and after furosemide administration (F-VEMP). STUDY DESIGN: Retrospective
      study. SETTING: University hospital. INTERVENTION: Furosemide administration.
      PATIENTS: Twenty-five affected ears of patients with unilateral Meniere's Disease
      were studied. The patients had received confirmed diagnoses Meniere's Disease;
      thus, the presence of endolymphatic hydrops was suggested. For the control, 22
      ears of 11 normal healthy volunteers who had never had vertigo or hearing
      disturbance were used. MAIN OUTCOME MEASURE: The amplitude of the p13-n23
      biphasic wave before and after furosemide administration. RESULTS: The amplitude
      of the p13-n23 biphasic wave was significantly enlarged in 7 of 18 cases in which
      it could be detected before diuretic loading. The biphasic waves appeared after
      diuretic loading in 3 of 7 cases in which it could not be recorded before
      loading. Thus, the positive ratio of F-VEMP for unilateral Meniere's Disease was
      considered to be 40% (10 of 25). The ratio was similar to that of the
      conventional examinations for endolymphatic hydrops such as the glycerol test,
      furosemide test, and electrocochleogram. CONCLUSION: The F-VEMP test may be
      useful in the diagnosis of endolymphatic hydrops.

PMID- 12621346
TI  - Dual-task study of cognitive and postural interference in patients with
      vestibular disorders.
AB  - OBJECTIVE: To study the relation between a mental task (silent backward counting)
      and posture in patients with vestibular deficits and to study the role of
      attention. STUDY DESIGN: In Experiment 1, postural sway and performance on the
      mental task were measured in a 2 x 2 dual-task design (with or without mental
      task and calf stimulation). In Experiment 2 a similar design was used, the only
      difference being that during trials without the mental task, patients were
      instructed to focus on their balance and provide a rating of body sway. SETTING:
      The study was carried out at a tertiary referral outpatient audiology clinic.
      PATIENTS: The first experiment included 20 patients and the second experiment 10
      patients seen consecutively at the clinic on account of vertigo and dizziness.
      MAIN OUTCOME MEASURES: Performance on a mental task and on a force platform for
      measurement of anterior-posterior and lateral sway. RESULTS: Results showed no
      effect of the balance conditions on the cognitive task in Experiments 1 and 2.
      The mental task led to less body sway during calf stimulation in Experiment 1. In
      Experiment 2, when attention was focused on body sway, an opposite result was
      found, with more sway during the mental task in the condition of no calf
      stimulation. CONCLUSIONS: Control of body sway and cognitive functioning are to
      some extent related, most likely because of postural stability being prioritized
      in dual-task conditions.

PMID- 12621347
TI  - Gentamicin perfusion vestibular response and hearing loss.
AB  - OBJECTIVE: To compare hearing results as a function of vestibular ablation in the
      treatment of Meniere's Disease, using gentamicin perfusion. STUDY DESIGN: A
      retrospective review of patients with Meniere's Disease treated by gentamicin
      perfusion of the inner ear via the MicroWick device. SETTING: A tertiary otologic
      referral center. PATIENTS AND INTERVENTIONS: The charts of patients treated with
      gentamicin perfusion via the MicroWick between the years 1998 and 2000 were
      reviewed. The results for patients with functional hearing in the affected ear
      were analyzed and were compared with the results in patients without functional
      hearing. MAIN OUTCOME MEASURES: Audiologic and vestibular test results as well as
      subjective symptoms. RESULTS: There were 45 patients who met the inclusion
      criteria. The averages for speech discrimination score and pure tone average
      before treatment were 92% and 38 dB, and after treatment were 82% and 47 dB.
      Patients were divided into two groups: Group 1 (20 patients), less than 75% ice
      air caloric reduced vestibular response (RVR); Group 2 (25 patients), those who
      reached greater than 75% ice air caloric RVR. There were 8 patients (17.6%) with
      persistent vertigo; 7 were from Group 1, and 1 was from Group 2, which was
      statistically significant (p = 0.007)wwww. The pure tone average dropped an
      average of 3 dB for Group 1 and 15 dB for Group 2. The difference in hearing loss
      between the two groups was statistically significant (p = 0.01). CONCLUSION: This
      study suggests that there is a correlation between the degree of vestibular
      ablation, the control of vertigo, and the risk of hearing loss. Patients with
      functional hearing seem to have a similar success rate for vertigo control,
      compared with patients who already had lost functional hearing before treatment.
      Future investigation may determine if less than 100% RVR, but greater than 75%
      RVR, is an alternative end point with adequate vertigo control and reduced risk
      of hearing loss.

PMID- 12621348
TI  - Intralabyrinthine schwannomas.
AB  - OBJECTIVE: To describe the patient presentation, radiographic findings, and
      treatment results in a series of eight patients with a diagnosis of
      intralabyrinthine schwannoma, and to review the presentation of other cases of
      intralabyrinthine schwannoma in the English otolaryngologic literature. METHODS:
      Retrospective review of patient records, operative reports, and radiologic
      studies, and review of the literature. RESULTS: Eight patients with a variety of
      otologic symptoms including progressive hearing loss, episodic vertigo, and
      tinnitus were found to have a schwannoma involving the vestibule or cochlea.
      Surgery was performed to remove the tumors from four patients with nonserviceable
      hearing. The patients experienced significant improvement in their vertigo and
      tinnitus after surgery. Observation and serial magnetic resonance imaging were
      adequate treatment of the four patients with serviceable hearing. In the
      literature review, 447 cases of intralabyrinthine schwannoma were identified, and
      the presentations were similar to those in the cases described here. CONCLUSION:
      Intralabyrinthine schwannomas are rare tumors that arise from the distal portion
      of either the vestibular nerve or the cochlear nerve. Consequently, the cochlea,
      the semicircular canals, the vestibule, or a combination of these structures may
      become involved with these lesions. Transmastoid labyrinthectomy or a transotic
      approach can be used to remove intralabyrinthine tumors from patients with
      nonserviceable hearing and severe vertigo or tinnitus. In addition, these
      surgical approaches should be used if the tumor grows to involve the internal
      auditory canal. Observation is an appropriate option for patients who have
      serviceable hearing.

PMID- 12621349
TI  - Preservation of the saccular nerve and of the vestibular evoked myogenic
      potential during vestibular schwannoma surgery.
AB  - OBJECTIVE: The aim of the study was to present a case report demonstrating that
      vestibular evoked myogenic potentials originate from the saccular nerve. STUDY
      DESIGN: Retrospective case review. SETTING: Tertiary referral center.
      INTERVENTION: Vestibular evoked myogenic potentials are shown before and after
      operation in a patient with a surgically confirmed superior vestibular schwannoma
      (1.3 cm). MAIN OUTCOME MEASURES: Preoperative and postoperative audiometry,
      auditory brainstem response, caloric test, vestibular evoked myogenic potentials,
      and magnetic resonance imaging outcomes. RESULTS On preoperative audiometry,
      slight sensorineural hearing loss with normal auditory brainstem response could
      be detected. Caloric tests showed a reduced response of the right labyrinth.
      Vestibular evoked myogenic potentials were normal. The tumor was removed via a
      combined retrosigmoid and partial labyrinthectomy approach with the removal of
      the posterior semicircular canal. The facial, auditory, and inferior semicircular
      nerves were anatomically preserved. Postoperative audiometry revealed
      preservation of hearing and vestibular evoked myogenic potentials; caloric
      responses were now absent. CONCLUSION: The combined retrosigmoid and partial
      labyrinthectomy approach represents an ideal condition to study the influence of
      the saccular nerve on the origin of the vestibular evoked myogenic potentials.
      The maintenance of the vestibular evoked myogenic potential responses in our
      patient supports the concept that the vestibular evoked myogenic potential
      originates in the saccule and is transmitted in the saccular nerve.

PMID- 12621350
TI  - Management of intratemporal facial nerve schwannoma.
AB  - OBJECTIVE: The aim of this study was to report a series of 18 facial nerve
      schwannomas, including 2 infantile cases. STUDY DESIGN: Retrospective case
      review. SETTING: Tertiary referral center. PATIENTS: Eighteen patients with
      facial nerve schwannoma, operated on between 1980 and 2000. INTERVENTION:
      Surgical treatments were performed in all cases. MAIN OUTCOME MEASURES: The
      presenting symptoms and facial nerve function were graded using the House
      Brackmann scale and eye closure. RESULTS Facial nerve paralysis was the most
      common symptom, presenting in 94% of cases, followed by hearing loss and mass
      lesion. In one case, the tumor was shaved, leaving the facial nerve intact. In
      the other cases, the facial nerve reconstruction with hypoglossal-facial
      anastomosis or interposition graft was performed. The postoperative facial
      function was House-Brackmann grade IV in most cases (88.2%). In terms of the
      functional recovery classified by complete or incomplete eye closure, the
      moderate preoperative facial nerve palsy group showed a better functional outcome
      than severe group. CONCLUSION: In cases with good facial nerve function, it would
      be better to consider an alternative method for preserving the facial nerve.
      Furthermore, when facial nerve paralysis has developed to more than House
      Brackmann grade III, an immediate operation is recommended to obtain a good
      postoperative facial functional recovery.

PMID- 12621351
TI  - Fascicle preservation surgery for facial nerve neuromas involving the posterior
      cranial fossa.
AB  - OBJECTIVE: To assess facial nerve function after fascicle preservation surgery in
      cases of facial nerve neuroma involving the cerebellopontine angle. STUDY DESIGN:
      Retrospective case series and literature review. SETTING: Tertiary referral
      center. PATIENTS: Seven patients with facial nerve neuroma involving the
      posterior cranial fossa were reviewed from a single neurotologist's practice and
      combined with a review of 648 cases reported in the literature. INTERVENTIONS:
      Translabyrinthine resection was used in all patients for complete tumor removal.
      Nerve reconstruction was accomplished with fascicle preservation (three cases),
      cable nerve interposition grafting (three cases, one of which involved using
      cranial nerve VIII as the graft), or direct anastomosis (one case). MAIN OUTCOME
      MEASURE: Facial nerve function as measured by the House-Brackmann grading system.
      RESULTS A postoperative facial nerve (House-Brackmann) grade of II/VI was
      obtained in two of our three patients who underwent fascicle preservation
      reconstruction and in two of eight cases reported by other authors. One case
      reported elsewhere resulted in grade I/VI, and four other cases reported
      elsewhere achieved grade III/VI; only two cases were grade V/VI. There were no
      tumor recurrences at 5 to 19 years of follow-up. CONCLUSION: Most cases of facial
      nerve neuroma require facial nerve resection. In rare cases, these tumors can be
      dissected away from the nerve fascicles, allowing the surgeon to preserve the
      facial nerve. This method resulted in better long-term postoperative facial nerve
      function (House-Brackmann grade II/VI vs. grade III/VI) compared with other
      techniques for patients in this small series, and no tumor recurrence.

PMID- 12621352
TI  - Regional spread of nonneurogenic tumors to the skull base via the facial nerve.
AB  - OBJECTIVE: This study examined the clinical and pathologic features of regional
      spread of nonneurogenic neoplastic disease to the intratemporal segments of the
      facial nerve. STUDY DESIGN: Retrospective review.SETTING Three tertiary referral
      centers. PATIENTS: Six patients with neoplastic disease of nonneurogenic origin
      involving segments of the facial nerve within the temporal bone. INTERVENTIONS:
      All patients underwent surgery with curative intent. Five patients received
      adjuvant radiation, and two received adjuvant radiation and chemotherapy. MAIN
      OUTCOME MEASURES: Histopathology, site of primary tumor, intratemporal location
      of regional spread along the facial nerve, degree of facial paralysis, and
      presence of residual disease. RESULTS: Five cases of malignancy were reported:
      one case of parotid adenoid cystic carcinoma, one case of parotid mucoepidermoid
      carcinoma, two cases of squamous cell carcinoma of the skin, and one case of an
      unidentified carcinoma. Perineural spread was histologically found in all cases
      of malignant disease. In addition, one case of benign pleomorphic adenoma of the
      parotid gland that circumferentially involved an intratemporal segment of the
      facial nerve was reported. Facial paralysis was present in five of six (83%) of
      cases. Four patients had unresectable malignant disease, and two died despite
      multimodality therapy. CONCLUSIONS: The facial nerve provides a route for the
      spread of neoplastic disease into the temporal bone, and perineural invasion is
      an important mechanism of invasion and motility of malignant disease.
      Nonneurogenic intratemporal tumors of the facial nerve are a rare but significant
      cause of facial paralysis.

PMID- 12621353
TI  - To what extent do evaluations of facial paralysis by physicians coincide with
      self-evaluations by patients: comparison of the Yanagihara method, the House
      Brackmann method, and self-evaluation by patients.
AB  - OBJECTIVES: To understand to what extent evaluations of facial paralysis by
      physicians coincide with self-evaluations by patients. STUDY DESIGN: Prospective
      clinical study. PATIENTS: One hundred thirty-one patients (68 male patients and
      63 female patients) with facial paralysis were included in the study.
      INTERVENTIONS: The relationship between the evaluation of facial paralysis using
      the Yanagihara system, the House-Brackmann grading system, and self-evaluation by
      patients was studied. MAIN OUTCOME MEASURES: The paralysis scores and grade
      determined by physicians using the above two systems were well correlated with
      the self-evaluations by patients. RESULTS The evaluation of subjective symptoms
      differed among individuals. Even patients who were evaluated as either completely
      paralyzed or cured according to the Yanagihara and House-Brackmann methods did
      not always rate their subjective symptoms as being consistent with these scores.
      CONCLUSION: Evaluations with the two systems correlated significantly with self
      evaluations by patients on the whole. These two methods of evaluation are
      considered appropriate not only for physicians but also for patients. In
      contrast, some discrepancies were observed. This point should be taken into
      account in routine patient care.

PMID- 12621354
TI  - Morphologic changes in round window membrane after topical hydrocortisone and
      dexamethasone treatment.
AB  - HYPOTHESIS: Are all glucocorticoids supposed to have the same effect on the round
      window membrane? BACKGROUND: Interest in glucocorticoids for topical treatment of
      inner ear diseases is increasing. The safety of such treatment should therefore
      be an important consideration before clinical use. METHODS: In this study the
      authors investigated the morphology of the round window membrane after topical
      instillation of dexamethasone or hydrocortisone into the middle ear. Twenty
      Sprague-Dawley rats were used. Five rats received 5 doses, and five rats 10
      doses, of 1 microg (20 microl) dexamethasone in the right ear, and five others
      were given 5 doses, and five rats 10 doses, of 2% (20 microl) hydrocortisone
      solution, also in the right ear. Membrane morphology was studied in both light
      microscopy and transmission electron microscopy. The thickness of exposed
      membranes was measured and compared with that of control membranes. RESULTS:
      Thickening and microscopically signs of inflammation were observed in
      hydrocortisone-exposed membranes but not in dexamethasone-exposed membranes,
      which did not differ morphologically from those in control ears. CONCLUSION:
      Although hydrocortisone has anti-inflammatory properties, it seems to provoke
      inflammation in the round window membrane after topical instillation.
      Dexamethasone had no such effects, however.

PMID- 12621355
TI  - Mesenchymal chondrosarcoma presenting as an external auditory canal mass.

PMID- 12621356
TI  - Malignant external otitis: temporal bone histopathology case of the month.

PMID- 12621357
TI  - Cochlear malformations, meningitis, and cochlear implants: what have we learned?

PMID- 12621358
TI  - Cartilage palisade tympanoplasty, diving and eustachian tube function.

PMID- 12621359
TI  - [Growth hormone secretion in heart failure].
AB  - Growth hormone is a pituitary polypeptide hormone regulating growth in paediatric
      age as well as inducing anabolic actions directly or IGF-I mediated in adult age.
      Particularly, in many animals GH and IGF-I receptors were observed in cardiac
      myocyte membrane. GH modifies left ventricle structure and function. As concerns
      spontaneous GH secretion, some data suggest that pituitary gland can have a
      compensatory role on endocrine response to heart failure. Heart failure stage was
      directly correlated to nocturnal GH levels. All GH spontaneous night secretion
      parameters as well as IGF-I levels showed a range between normal people and very
      high spontaneous secretion. Therefore in these patients there are either a GH
      peripheric resistance or a reduction of the activity of GH/IGF-I axis. Anyhow in
      our patients, GH 24 hour infusion was inducing a 5 fold increase in GH
      concentration and a 50% increase in basal IGF-I levels. Anker et al. suggested to
      evaluate nutritional state in heart failure patients, observing no differences in
      non-cachectic patients vs controls, while cachectic patients presented a typical
      GH resistance syndrome. Interestingly, cardiovascular effects of GH
      administration seem to be only marginally correlated to hemodynamic basal state.
      On the other hand basal hormonal setting of the patient seems to correlate to the
      GH-induced cardiovascular response. In fact, low basal IGF-I but high basal GH
      patients presented the worst endocrine and cardiovascular response to GH
      infusion. In literature there are controversial data about GH treatment in
      patients with chronic heart failure. The heterogeneity of the population could be
      the reason for this discrepancy. Besides very different IGF-I responses to GH
      have been reported. Therefore, as there is good clinical evidence that GH acute
      infusion can improve heart failure, it seems to be necessary firstly to evaluate
      the basal endocrine status of the patients. Particularly attention should be
      given to those patients that present a peripheric GH resistance. On the other
      hand, those patients with a reduced pituitary GH reserve are supposed to have
      very beneficial effects from GH treatment.

PMID- 12621360
TI  - Effects of adult growth hormone deficiency and growth hormone replacement on
      circadian rhythmicity.
AB  - In health, growth hormone (GH) is secreted in a circadian rhythm with
      superimposed pulsatility. Temporal fluctuations of hormone concentrations are
      essential for physiological action, and loss of diurnal rhythm is important in
      the development of disease. GH feedback occurs through the hypothalamus and
      involves neuropeptides such as somatostatin, GH-releasing hormone, GH-releasing
      peptides and neuropeptide Y. In addition, the same neuropeptides are involved in
      the regulation of other hormone axes and biological systems, thus, establishing a
      link through which regulation by GH may occur. Clinical features of adult growth
      hormone deficiency (AGHD) include abnormal body composition, reduction in quality
      of life, osteoporosis and increased risk of cardiovascular mortality. In health,
      many of the factors which regulate these features demonstrate circadian
      rhythmicity and pulsatility. Furthermore, AGHD is associated with abnormalities
      in the periodic variation of such controlling factors. GH replacement therapy,
      administered in the form of timed, intermittent subcutaneous injections, results
      in improvement of many of the clinical effects of AGHD, and is associated with
      normalization of the temporal fluctuations. Currently, there remains scope for
      further investigation of the effects of AGHD and subsequent GHR on the circadian
      rhythmicity of many hormones and systems; and additional studies are required to
      understand the physiological significance of the changes observed to date.

PMID- 12621361
TI  - [Genetic changes in human pituitary adenomas].
AB  - In the last few years molecular biology technologies have provided important
      insights into mechanisms possibly involved in pituitary tumor formation. Several
      evidences indicate that the majority of pituitary adenomas is monoclonal, thus
      implying that they derive from the replication of a single mutant cell. In about
      30-40% of GH-secreting adenomas mutations at codon 201 and 227 of GNAS1 gene that
      codes for the Gs alpha subunit have been identified. These mutations, named gsp
      for Gs protein, cause the constitutive, hormone-independent, activation of
      adenylyl cyclase and consequent overproduction of cAMP, that is mitogenic in
      somatotropes. Screening studies carried out on large series of acromegalic
      patients carrying tumors with or without gsp oncogene failed to detect clinical
      differences between the two groups. The existence of mechanisms induced by gsp
      mutations and able to counteract the mitogenic potential of this oncogene has
      been hypothesized. In particular, several events including the low expression of
      mutant Gs, the induction of phosphodiesterases, that are involved in cAMP
      degradation, and of the inducible cAMP early repressor (ICER) that represses cAMP
      induced gene expression, together with a high sensitivity to somatostatin have
      been characterized in gsp positive tumors. As far as the loss of oncosuppressors
      is concerned, no mutations of these genes have been so far reported, while they
      are frequently expressed at low levels in pituitary tumors. However, the nature
      of initiating and promoting events involved in tumor formation remains to be
      clarified in the majority of pituitary tumors.

PMID- 12621362
TI  - [The role of somatostatin analogues in the treatment of hypophyseal adenomas].
AB  - Somatostatin analogues are widely employed in the treatment of hypophyseal
      adenomas. The most widely used analogues at the present time are octreotide and
      lanreotide. Both are available in slow release formulations using the parenteral
      route and show a preferential affinity for the sst(2) receptor of somatostatin.
      Both octreotide and lanreotide have proved their effectiveness in the treatment
      of GH- and TSH-secretory hypophyseal adenomas. In those patients who respond to
      pharmacological treatment we often achieve not only the control of hormonal
      hypersecretion, but also a reduction in the volume of hypophyseal neoplasia. In
      the other types of hypophyseal adenoma, on the other hand, somatostatin analogues
      have proved to have little effect: apart from isolated cases of effectiveness in
      non-functioning adenomas, the administration both of octreotide and lanreotide to
      patients with Cushing's disease or prolactinoma did not significantly modify the
      hormonal hypersecretion or tumoural volume. The side-effects of somatostatin
      analogues are comparatively rare and of moderate entity: only a small percentage
      of patients requires the treatment to be suspended owing to the occurrence of
      side-effects. New analogues are currently under study. These have a different
      receptor profile and they could therefore find new applications in hypophyseal
      pathology. Octreotide, bound to radioactive substances or to toxins, has also
      been utilised for the selective destruction of neoplastic tissues expressing the
      sst(2) receptor of somatostatin.

PMID- 12621363
TI  - Regulation of insulin-like growth factor-I in skeletal muscle and muscle cells.
AB  - Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are potent
      regulators of muscle mass. Transgenic mice that over-express these proteins
      exhibit dramatically enlarged skeletal muscles. In contrast, malnutrition,
      critical illness, sepsis, and aging are all associated with a dramatic reduction
      in muscle mass and function. The circulating concentration of IGF-I and the
      expression of IGF-I in skeletal muscle are also reduced during catabolic states.
      Consequently, GH has been used clinically to increase lean body mass in patients
      with muscle wasting. Likewise, delivery of IGF-I specifically into muscle has
      been proposed as a genetic therapy for muscle disorders. A better understanding
      of the regulation of IGF-I expression in skeletal muscle and muscle cells is
      therefore of importance. Yet, our knowledge in this area has been limited by a
      lack of GH responsive muscle cells. In addition the IGF-I gene spans over 90 kb
      of genomic DNA and it exhibits a very complex regulatory pattern. This review
      will summarize our knowledge of the control of muscle mass by GH, IGF-I, anabolic
      steroids, exercise and other growth enhancing hormones. We will also highlight
      recent advances in the regulation of IGF-I and signal transducers and activators
      of transcription (Stats) by GH. A special emphasis will be placed on the
      interaction of IGF-I and proinflammatory cytokines in skeletal muscle and muscle
      cells.

PMID- 12621366
TI  - Purchasing that new helicopter, Part 2: Writing the RFP.

PMID- 12621364
TI  - Growth hormone and mannan-binding lectin: emerging evidence for hormonal
      regulation of humoral innate immunity.
AB  - An increasing number of studies in animals and humans indicate that growth
      hormone (GH) and insulin-like growth factor-I (IGF-I) modulate immune function.
      It was recently reported that, surprisingly, GH therapy increased the mortality
      in critically ill patients. The excessive mortality was almost entirely due to
      septic shock or multi-organ failure, which could suggest that a GH-induced
      modulation of immune function was involved. Mannan-binding lectin (MBL) is a
      plasma protein that plays an important role in innate immunity through activation
      of the complement cascade and inflammation following binding to carbohydrate
      structures. The serum concentration of MBL is subject to large between-subjects
      differences, which primarily are caused by genetic factors. However, mounting
      evidence supports a significant influence from growth hormone on MBL levels. In
      the present review, we focus on the function of MBL, on the influence of growth
      hormone on MBL levels, and on the possible clinical consequences of this new link
      between the endocrine and the immune system.

PMID- 12621368
TI  - Lost child.

PMID- 12621367
TI  - Extracorporeal life support: a transcontinental transport experience.

PMID- 12621370
TI  - 2002 air medical transport industry awards.

PMID- 12621373
TI  - The haves and the have-nots.

PMID- 12621374
TI  - Five with twenty: five air medical services celebrate 20-plus years in business.

PMID- 12621375
TI  - A flight orientation curriculum for emergency medicine resident physicians.

PMID- 12621376
TI  - EMS provider level does not impact use of air medical transport.
AB  - INTRODUCTION: The local emergency medical services (EMS) provider level within a
      nearby EMS system changed from EMT-I to paramedic. This increase in level of care
      was expected to decrease utilization of air medical transport and increase acuity
      of patients flown. SETTING: Semirural, mountainous area with an annual volume of
      2800 transports. METHODS: Retrospective review of the EMS database performed for
      the 24-month period before and after the change in local provider level. The
      number and acuity of patients flown was recorded. Data analysis was performed
      using chi-square with significance at P <.05. RESULTS: A total of 53 flights with
      an EMS call volume of 2544 were flown in the 24-month period before the change in
      EMS provider level, and 54 flights with a call volume of 2842 in the following 24
      month period (P >.05). The number of patients with abnormal vital signs or injury
      severity markers was not different between the 2 periods (P >.05). CONCLUSION:
      The change in EMS provider level from EMT-I to paramedic in this semirural area
      had no impact on the number of air medical transports. The acuity of patients
      flown after the change in EMS provider level remained similar based on common
      hemodynamic and injury severity markers.

PMID- 12621377
TI  - Ultrasound in HEMS: its role in differentiating shock states.

PMID- 12621379
TI  - Use of healthy children as volunteers in drug studies: the ethical debate.

PMID- 12621380
TI  - An evaluation of the suitability of intravenous midazolam as an in vivo marker
      for hepatic cytochrome P4503A activity.

PMID- 12621381
TI  - Steady-state pharmacokinetic interaction of modified-dose indinavir and
      rifabutin.
AB  - BACKGROUND: Combined administration of the human immunodeficiency virus protease
      inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin
      (300 mg daily) results in a significant decrease in indinavir concentrations with
      subsequent risk of treatment failure, as well as a significant increase in
      rifabutin concentrations with increased toxicity. Therefore this study was
      designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy
      volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg
      indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given
      at 8 am or noon in a randomized crossover sequence for 14 days. Ten human
      immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours
      for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily
      at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at
      the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours,
      coadministered with 150 mg rifabutin daily produced an area under the
      concentration-time curve similar to that of 800 mg indinavir every 8 hours. The
      mean area under the concentration-time curve values of rifabutin and 25-desacetyl
      rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously
      with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg
      rifabutin daily alone. Drug concentrations were not different when rifabutin and
      indinavir were administered simultaneously at 8 am or staggered by 4 hours.
      CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when
      coadministered with rifabutin at a reduced dose of 150 mg daily compensates for
      rifabutin induction of indinavir metabolism. Rifabutin concentrations were still
      higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which
      is the current recommendation when these 2 drugs are combined. The clinical
      significance of the increase in rifabutin and 25-desacetyl rifabutin
      concentrations is not known.

PMID- 12621382
TI  - Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy
      volunteers.
AB  - BACKGROUND AND OBJECTIVES: Duloxetine, a potent dual reuptake inhibitor of
      serotonin and norepinephrine currently undergoing clinical investigation for
      treatment of depression and stress urinary incontinence, has the potential to act
      as both a substrate and an inhibitor of cytochrome P4502D6 (CYP2D6). Our
      objectives were to determine the effect of duloxetine on the pharmacokinetics of
      desipramine, a tricyclic antidepressant metabolized by CYP2D6 (study 1), and the
      effect of paroxetine, a potent CYP2D6 inhibitor, on duloxetine pharmacokinetics
      (study 2). METHODS: Subjects were healthy men and women between 21 and 63 years
      old. All subjects were genotypically CYP2D6 extensive metabolizers. In study 1,
      50 mg of desipramine was administered as a single dose alone and in the presence
      of steady-state duloxetine 60 mg twice daily. In study 2, steady-state
      pharmacokinetics of duloxetine 40 mg once daily were determined in the presence
      and absence of steady-state paroxetine 20 mg once daily. RESULTS: Duloxetine
      increased the maximum plasma concentration of desipramine 1.7-fold and the area
      under the concentration-time curve 2.9-fold. Paroxetine increased the maximum
      plasma concentration of duloxetine and the area under the concentration-time
      curve at steady state 1.6-fold. Reports of adverse events were similar whether
      duloxetine was administered alone or in combination with desipramine or
      paroxetine. CONCLUSION: Duloxetine 60 mg twice daily is a moderately potent
      CYP2D6 inhibitor, intermediate between paroxetine and sertraline. The potent
      CYP2D6 inhibitor paroxetine has a moderate effect on duloxetine concentrations.
      The results of these 2 studies suggest that caution should be used when CYP2D6
      substrates and inhibitors are coadministered with duloxetine.

PMID- 12621383
TI  - Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its
      metabolites.
AB  - BACKGROUND AND OBJECTIVES: Atomoxetine is a treatment for attention
      deficit/hyperactivity disorder and is primarily eliminated via cytochrome P4502D6
      (CYP2D6). The pharmacokinetics of atomoxetine and its primary metabolites were
      investigated in 10 adults with hepatic impairment (6 moderate, 4 severe) and 10
      age- and sex-matched control subjects, all being genotyped as CYP2D6 extensive
      metabolizers. METHODS: A single oral 20-mg dose of atomoxetine was given.
      Multiple blood samples were collected for 48 hours in healthy subjects and for
      120 hours in patients. Urine was collected up to 24 hours. Before atomoxetine
      administration (10-20 days), sorbitol clearance and debrisoquin (INN,
      debrisoquine) metabolic ratio were determined as markers of hepatic blood flow
      and CYP2D6 activity, respectively. RESULTS: The systemic clearance of atomoxetine
      was significantly reduced in those with hepatic impairment compared with
      controls, thereby resulting in increased exposure (area under the concentration
      time curve from time 0 to infinity, 1.58 versus 0.85 microg. h(-1). mL(-1); P
      =.035) but no change in maximum concentration. Mean 4-hydroxyatomoxetine area
      under the concentration-time curve from time 0 to time t and maximum
      concentration were increased approximately 7-fold and 2-fold, respectively (P
      =.0001 and P =.0056, respectively). For the glucuronide conjugate of 4
      hydroxyatomoxetine, the mean half-life was longer and the mean area under the
      concentration-time curve from time 0 to infinity and the maximum concentration
      were lower (P =.0028, P =.003, and P =.0001, respectively). The sorbitol
      clearance was lower and the debrisoquin metabolic ratio was higher, reflecting
      reduced hepatic blood flow and decreased CYP2D6 activity, respectively. Decreased
      atomoxetine clearance in patients with hepatic impairment was clearly correlated
      with decreased CYP2D6 activity and decreased hepatic blood flow. Mean atomoxetine
      plasma protein binding was lower in patients with hepatic impairment compared
      with controls (96.5% versus 98.7%, P =.0008). Atomoxetine was well tolerated in
      the 2 populations. CONCLUSION: For patients with attention-deficit/hyperactivity
      disorder who have hepatic impairment, dosage adjustment is recommended. Initial
      target doses should be reduced to 25% and 50% of the normal dose for patients
      with severe and moderate hepatic impairment, respectively.

PMID- 12621384
TI  - Itraconazole increases but grapefruit juice greatly decreases plasma
      concentrations of celiprolol.
AB  - OBJECTIVES: Our objective was to evaluate the effects of itraconazole and
      grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking
      agent celiprolol in healthy volunteers. METHODS: In a randomized 3-phase
      crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo
      twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning
      of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice,
      each subject ingested 100 mg celiprolol with 200 mL of water (placebo and
      itraconazole phases) or grapefruit juice. In addition, 200 mL of water or
      grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma
      concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the
      excretion of celiprolol into urine were measured up to 33 hours after dosing.
      Systolic and diastolic blood pressures and heart rate were recorded with subjects
      in a sitting position before the administration of celiprolol and 2, 4, 6, and 10
      hours later. RESULTS: During the itraconazole phase, the mean area under the
      plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was
      80% greater (P <.05) than in the placebo phase. During the grapefruit juice
      phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were
      reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase
      values. The cumulative excretion into urine of celiprolol was increased by 59% by
      itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001).
      Hemodynamic variables did not differ between the phases. CONCLUSIONS:
      Itraconazole almost doubles but grapefruit juice greatly reduces plasma
      concentrations of celiprolol. The itraconazole-celiprolol interaction most likely
      resulted from increased absorption of celiprolol possibly as a result of P
      glycoprotein inhibition in the intestine. The reduced celiprolol concentrations
      during the grapefruit juice phase were probably caused by physicochemical factors
      that interfered with celiprolol absorption, although other mechanisms cannot be
      excluded. The grapefruit juice-celiprolol interaction is probably of clinical
      relevance.

PMID- 12621385
TI  - Disposition and miotic effects of oral alfentanil: a potential noninvasive probe
      for first-pass cytochrome P4503A activity.
AB  - BACKGROUND AND OBJECTIVES: Systemic clearance of the opioid alfentanil after
      intravenous administration is an excellent in vivo probe for hepatic cytochrome
      P4503A (CYP3A) activity and drug interactions. Alfentanil effect (miosis) is a
      surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics
      may be a suitable noninvasive probe for hepatic CYP3A. Oral alfentanil might be a
      probe for first-pass CYP3A activity; however, it is not used clinically, and oral
      alfentanil disposition is unknown. This investigation evaluated the disposition
      and miotic effects of oral alfentanil. METHODS: Ten healthy volunteers were
      studied in a dose-escalation fashion, receiving 23, 30, 43, and 75 microg/kg oral
      alfentanil on different days. Dark-adapted pupil diameter was measured at the
      time of venous blood sampling. Alfentanil was quantified by liquid chromatography
      mass spectrometry. Plasma concentrations of alfentanil and pupil diameter change
      versus time data were analyzed by noncompartmental modeling. RESULTS: Alfentanil
      was rapidly absorbed (time to maximum concentration [T(max)], 0.7 +/- 0.5 hour).
      Mean values for area under the plasma concentration-time curve extrapolated to
      infinity (AUC( infinity )) (27 +/- 14, 38 +/- 22, 57 +/- 31, and 105 +/- 59 ng x
      h x mL(-1)) and maximum concentration (16 +/- 8, 23 +/- 16, 31 +/- 18, and 50 +/-
      22 ng/mL) were linear with dose, although there was considerable interindividual
      variability. T(max), elimination half-life (1.0 +/- 0.2 hours), total body
      clearance after oral administration (20 +/- 18 mL x kg(-1) x min(-1)), and dose
      normalized AUC(infinity ) were independent of dose. Dose-dependent alfentanil
      disposition was mirrored by commensurate changes in clinical effect, although
      miosis was variable and not detectable in all subjects at the lowest dose. Mean
      miosis AUC (AUEC) and peak miosis were log-dose linear. Effect half-life (1.3 +/-
      0.9 hours) was similar to plasma half-life. CONCLUSION: Oral alfentanil is
      rapidly absorbed, exhibits linear and dose-independent kinetics, and undergoes
      substantial first-pass metabolism. Oral alfentanil may be a suitable probe for
      first-pass CYP3A activity. Alfentanil effect (miosis) may be an acceptable
      surrogate for plasma alfentanil concentrations. Oral alfentanil effect may be a
      noninvasive surrogate for conventional pharmacokinetics. Further studies are
      warranted to determine whether oral alfentanil and alfentanil effect kinetics may
      be a suitable noninvasive in vivo probe for first-pass CYP3A activity.

PMID- 12621386
TI  - Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in
      vivo.
AB  - OBJECTIVES: Cisapride was compared with midazolam in vivo to determine its
      potential applicability as a cytochrome P450 (CYP) 3A4 "probe." As well, we
      evaluated whether cisapride was transported by P-glycoprotein. METHODS:
      Bidirectional transport assays were conducted in LLC-PK1 cells and the derivative
      cell line L-MDR1 to determine whether cisapride was a substrate for P
      glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n
      = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15
      mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma
      concentrations were quantitated from repeated after-dosing blood samples by HPLC
      with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry
      detection for cisapride and norcisapride. Pharmacokinetic parameters were
      determined by noncompartmental methods. Both linear and nonlinear regression
      analyses were used to examine the association between the apparent plasma
      clearance of midazolam and cisapride and the cisapride/norcisapride plasma
      concentration ratios. RESULTS: Although not a substrate for P-glycoprotein,
      cisapride inhibited P-glycoprotein with an apparent inhibition constant (K(i)) of
      16.1 micromol/L. Linear correlations between cisapride clearance and both
      intravenous and oral midazolam clearance (P =.01, r(2) = 0.43 and P =.001, r(2) =
      0.46, respectively) were found. Cisapride/norcisapride plasma concentration
      ratios at 8 hours (P =.001, r(2) = 0.90) and 12 hours (P =.001, r(2) = 0.96), as
      well as cisapride plasma concentrations at these time points, were shown to
      accurately predict the area under the plasma concentration versus time curve for
      cisapride. CONCLUSIONS: CYP3A4 activity reflected by the total body clearance
      after oral administration of cisapride should be independent of transport by P
      glycoprotein. Concordance between the pharmacokinetics for cisapride and
      midazolam support the applicability of oral cisapride as a pharmacologic
      substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration
      ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a
      single-point determination to reflect the area under the plasma concentration
      versus time curve and the plasma clearance of cisapride and, as well, total
      CYP3A4 activity in vivo.

PMID- 12621387
TI  - P-glycoprotein-mediated intestinal and biliary digoxin transport in humans.
AB  - BACKGROUND AND AIMS: Intestinal transport by P-glycoprotein is a recently
      recognized determinant of drug disposition. However, direct measurements of
      transporter-mediated drug elimination into isolated segments of human small
      intestine are lacking. METHODS: Using a recently developed intestinal perfusion
      catheter, we perfused in healthy volunteers two 20-cm jejunal segments with and
      without the P-glycoprotein inhibitor quinidine before and during administration
      of the P-glycoprotein inducer rifampin (INN, rifampicin). RESULTS: Within 3 hours
      after intravenous administration of digoxin (1 mg), perfusate samples were
      collected. We found that 0.45% +/- 0.24% and 0.83% +/- 0.60% of the digoxin dose
      were eliminated into a jejunal segment and into bile, respectively. Perfusion of
      the isolated segment with quinidine reduced intestinal digoxin elimination (0.23%
      +/- 0.08%, P =.031). During rifampin, intestinal digoxin elimination was 0.80 +/-
      0.59 (P =.383). Enterocyte P-glycoprotein content correlated with the area under
      the plasma concentration-time curve of digoxin (Spearman nonparametric
      correlation coefficient [r(S)] = -0.73, P =.003) and digoxin nonrenal clearance
      (r(S) = 0.52, P =.056), as well as with intraluminal and plasma concentrations of
      quinidine (r(S) = 0.55, P =.041 and r(S) = -0.67, P =.009, respectively).
      CONCLUSION: Using segmental intestinal perfusion, we provide direct evidence that
      intestinal P-glycoprotein mediates substantial drug elimination after intravenous
      administration from the systemic circulation into the gut lumen and prevents
      entry of luminally administered P-glycoprotein substrates into the enterocytes.
      These data also highlight the relative importance of direct intestinal drug
      secretion in comparison with drug elimination through bile.

PMID- 12621388
TI  - Clopidogrel but not aspirin reduces P-selectin expression and formation of
      platelet-leukocyte aggregates in patients with atherosclerotic vascular disease.
AB  - Formation of platelet-leukocyte aggregates via the CD62 ligand represents an
      important mechanism by which leukocytes contribute to thrombotic events. In a
      cross-sectional study, we investigated platelet-leukocyte aggregate formation and
      markers indicative for platelet, leukocyte, and endothelial activation (CD62,
      activated fibrinogin receptor glycoprotein IIb/IIIA [PAC-1], CD11b/CD18 [MAC-1],
      and soluble intercellular adhesion molecule 1) in 44 patients with
      atherosclerotic vascular disease and peripheral occlusions receiving clopidogrel
      (n = 12), aspirin (n = 17), their combination (n = 8), or no treatment (n = 7),
      as well as in a group of healthy subjects (n = 9). Whole-blood flow cytometry was
      performed before (baseline) and after stimulation with thrombin receptor
      activating peptide or adenosine diphosphate. Both at baseline and after
      stimulation, untreated patients and those receiving aspirin monotherapy exhibited
      significantly higher levels of platelet CD62 expression (baseline CD62:
      untreated, 22% [median]; with aspirin, 16%) and had higher rates of platelet
      leukocyte aggregate formation (monocyte-platelet-leukocyte aggregates at
      baseline: untreated, 27%; with aspirin, 16%) when compared with patients
      receiving clopidogrel alone (baseline CD62: 10% [P <.05]; monocyte-platelet
      leukocyte aggregates: 13% [P <.05]) or combined with aspirin (baseline CD62: 5%
      [P <.05]; monocyte-platelet-leukocyte aggregates: 7% [P <.05]). Up-regulation of
      MAC-1 on monocytes after stimulation with thrombin receptor-activating peptide
      and adenosine diphosphate was significantly lower in patients treated with
      clopidogrel and aspirin. Plasma levels of soluble intercellular adhesion molecule
      1 were significantly lower in the group of healthy subjects (median, 186 ng/mL)
      when compared with those in untreated patients (median, 352 ng/mL) (P <.05),
      whereas intercellular adhesion molecule 1 levels in treated patients were similar
      for any antiplatelet regimen (aspirin, 262 ng/mL; clopidogrel, 274 ng/mL;
      combination therapy, 273 ng/mL) but significantly lower than those in untreated
      patients. This is the first report showing that platelet-leukocyte aggregate
      formation is enhanced in atherosclerotic vascular disease but was found to be
      reduced in patients receiving clopidogrel.

PMID- 12621389
TI  - Effect of single and repeated oral doses of telithromycin on cardiac QT interval
      in healthy subjects.
AB  - BACKGROUND: Telithromycin is the first member of a new class of antimicrobials
      the ketolides. The main objective of this study was to assess the effect of
      various oral doses of telithromycin on QT interval during single and repeated
      administrations. METHODS: Seventeen men and 17 women participated in double
      blind, placebo-controlled, crossover studies. Of these subjects, 18 (9 men and 9
      women) received single and repeated oral doses of telithromycin (800 mg daily),
      clarithromycin (500 mg twice daily), or placebo (protocol 1). The other 16
      subjects received a single oral dose (800 mg, 1600 mg, and 2400 mg) of
      telithromycin or placebo (protocol 2). At the time of expected telithromycin
      maximum concentration, several electrocardiographic recordings were obtained at
      rest and during the course of a submaximal exercise test. QT intervals were
      measured within a wide range of R-R intervals in each subject. RESULTS: ANOVA
      showed that telithromycin did not increase QT interval at any dose compared with
      placebo. The greatest effect observed during any study period was a mean (+/-SD)
      change in QT-interval duration of 4.2 +/- 15.2 ms (ie, +1.2% +/- 4.0%, P not
      significant) at R-R = 1000 ms after repeated doses of 800 mg telithromycin.
      Outlier values (change in Bazett QTc from baseline >60 ms) from resting 12-lead
      electrocardiograms did not differ across treatment groups, including placebo.
      CONCLUSIONS: Telithromycin administered as repeated doses of 800 mg (recommended
      doses) or as single doses of up to 3 times this recommended dose did not increase
      the QT interval at any heart rate at rest and during effort. Telithromycin did
      not prolong QT-interval duration when administered to healthy young male and
      female subjects.

PMID- 12621390
TI  - Population differences in S-warfarin metabolism between CYP2C9 genotype-matched
      Caucasian and Japanese patients.
AB  - OBJECTIVE: Our objective was to investigate population differences in the
      metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically matched
      Caucasian and Japanese patients by using the unbound oral clearance of S-warfarin
      as an in vivo phenotypic trait measure. METHODS: Ninety Japanese and 47 Caucasian
      patients receiving maintenance warfarin therapy were studied. Steady-state plasma
      unbound concentrations of S-warfarin were measured by a chiral HPLC method
      coupled with an ultrafiltration technique, and unbound oral clearance for S
      warfarin was estimated. By combining plasma unbound concentrations of S-warfarin
      with the urinary excretion rates of S-7-hydroxywarfarin, the formation clearance
      of S-7-hydroxywarfarin was also determined. Genotyping of CYP2C9 was performed
      for 6 distinct alleles (CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, and a
      T/C transition in intron 2). RESULTS: The frequency distribution of unbound oral
      clearance for S-warfarin obtained from Japanese patients was shifted toward
      higher values as compared with that in Caucasian patients. Japanese patients had
      lower allelic frequencies for the 5 variants than Caucasian patients. When
      interpopulation comparisons of CYP2C9 activity were made for genotype-matched
      subjects, Japanese patients with the homozygous CYP2C9*1 (wild-type) genotype (n
      = 85) had significantly (P <.01) greater median values for unbound oral clearance
      and formation clearance than Caucasian patients with the corresponding genotype
      (n = 26), 10.4 mL x min(-1) x kg(-1) versus 4.25 mL x min(-1) x kg(-1) and 0.015
      mL x min(-1) x kg(-1) versus 0.010 mL x min(-1) x kg(-1), respectively. In
      addition, Japanese patients heterozygous for the CYP2C9*3 genotype (n = 4) showed
      a significantly (P <.05) reduced unbound oral clearance for S-warfarin, by 63%,
      as compared with Japanese patients possessing the homozygous CYP2C9*1 genotype.
      By contrast, in Caucasian patients, no significant differences were observed in
      this parameter between CYP2C9(*)1 homozygous subjects and those with heterozygous
      CYP2C9(*)2 or CYP2C9(*)3 genotypes. CONCLUSIONS: These findings indicate that
      population differences in the frequencies of known variant CYP2C9 alleles account
      only in part for the variability observed in in vivo CYP2C9 activity in different
      populations. In addition, a gene-dose effect of defective CYP2C9 alleles on the
      in vivo CYP2C9 activity is evident in Japanese patients but not in Caucasian
      patients. Further studies are required to identify currently unknown factor(s)
      (eg, transcriptional regulation) responsible for the large intrapopulation and
      interpopulation variability in CYP2C9 activity.

PMID- 12621391
TI  - Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy
      subjects.
AB  - OBJECTIVE: This study was designed to define the effect of low-dose aspirin
      administration on the activity of cytochrome P450 (CYP) in normal human subjects.
      METHODS: Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy
      male volunteers. A modified 5-drug cocktail procedure consisting of caffeine,
      mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to
      simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and
      CYP3A, respectively. The activities were assessed on 4 occasions including at
      baseline, after 7 and 14 daily doses of aspirin, and at 7 days after
      discontinuation of aspirin. Concentrations of parent drugs and corresponding
      metabolites in biologic samples were assayed by reversed-phase HPLC. RESULTS:
      Both 7-day and 14-day aspirin intake increased the activity of CYP2C19
      significantly, as indicated by 4-hydroxymephenytoin urinary recovery (P <.001).
      Induction of low-dose aspirin on CYP2C19 was time-dependent. CYP3A activity
      indices increased moderately but significantly by both 7-day and 14-day aspirin
      treatment (P <.05), but the percentage changes in CYP3A activity indices were not
      significant. Low-dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo
      activity by either 7-day or 14-day treatment. CONCLUSIONS: The effect of low-dose
      aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin
      induced the in vivo activities of CYP2C19 but did not affect the activities of
      CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity
      awaits further confirmation. When low-dose aspirin is used in combination with
      drugs that are substrates of CYP2C19, doses of the latter should be adjusted to
      ensure their efficacy.

PMID- 12621392
TI  - Influence of willow bark extract on cyclooxygenase activity and on tumor necrosis
      factor alpha or interleukin 1 beta release in vitro and ex vivo.

PMID- 12621393
TI  - Concern about similarity of manuscripts.

PMID- 12621394
TI  - Retractions' realities.

PMID- 12621395
TI  - Yes, we have no energy policy.

PMID- 12621396
TI  - Astronomers urge NASA not to cut corners on Hubble successor.

PMID- 12621397
TI  - 'Revolutionary' telescope gets green light.

PMID- 12621398
TI  - Climate studies hold key to future of desalination plant.

PMID- 12621399
TI  - Agency 'ignoring its advisers' over Bt maize.

PMID- 12621401
TI  - India budgets for boost in research.

PMID- 12621400
TI  - Vaccine sought as bird flu infects humans.

PMID- 12621403
TI  - Coal-fired power plant to bury issue of emissions.

PMID- 12621402
TI  - Cancer risk prompts US to curb gene therapy.

PMID- 12621405
TI  - Archaeology: The coast road.

PMID- 12621406
TI  - Crime prevention: The lab arm of the law.

PMID- 12621407
TI  - No strings attached to 225m dollars sponsorship.

PMID- 12621408
TI  - The subtle beauty of art in the service of science.

PMID- 12621409
TI  - India: A champion of new technologies.

PMID- 12621416
TI  - Cosmology: Filling in the background.

PMID- 12621415
TI  - Evolutionary biology: Speciation reversal.

PMID- 12621417
TI  - Immunology: Fast and feel good?

PMID- 12621418
TI  - Microfluidics: DNA amplification moves on.

PMID- 12621419
TI  - Climate change: The earlier bird.

PMID- 12621420
TI  - Planetary science: Kuiper-belt interlopers.

PMID- 12621421
TI  - Plant biology: Mobile plastid genes.

PMID- 12621424
TI  - Inbreeding: Disease susceptibility in California sea lions.

PMID- 12621425
TI  - Psychophysics: Is subliminal learning really passive?

PMID- 12621426
TI  - Regulated portals of entry into the cell.
AB  - The plasma membrane is the interface between cells and their harsh environment.
      Uptake of nutrients and all communication among cells and between cells and their
      environment occurs through this interface. 'Endocytosis' encompasses several
      diverse mechanisms by which cells internalize macromolecules and particles into
      transport vesicles derived from the plasma membrane. It controls entry into the
      cell and has a crucial role in development, the immune response,
      neurotransmission, intercellular communication, signal transduction, and cellular
      and organismal homeostasis. As the complexity of molecular interactions governing
      endocytosis are revealed, it has become increasingly clear that it is tightly
      coordinated and coupled with overall cell physiology and thus, must be viewed in
      a broader context than simple vesicular trafficking.

PMID- 12621427
TI  - Three-dimensional imaging of atomic four-body processes.
AB  - To understand the physical processes that occur in nature we need to obtain a
      solid concept about the 'fundamental' forces acting between pairs of elementary
      particles. It is also necessary to describe the temporal and spatial evolution of
      many mutually interacting particles under the influence of these forces. This
      latter step, known as the few-body problem, remains an important unsolved problem
      in physics. Experiments involving atomic collisions represent a useful testing
      ground for studying the few-body problem. For the single ionization of a helium
      atom by charged particle impact, kinematically complete experiments have been
      performed since 1969 (ref. 7). The theoretical analysis of such experiments was
      thought to yield a complete picture of the basic features of the collision
      process, at least for large collision energies. These conclusions are, however,
      almost exclusively based on studies of restricted electron-emission geometries.
      Here, we report three-dimensional images of the complete electron emission
      pattern for the single ionization of helium by the impact of C6+ ions of energy
      100 MeV per a.m.u. (a four-body system) and observe features that have not been
      predicted by any published theoretical model. We propose a higher-order
      ionization mechanism, involving the interaction between the projectile and the
      target nucleus, to explain these features.

PMID- 12621428
TI  - Ordering and manipulation of the magnetic moments in large-scale superconducting
      pi-loop arrays.
AB  - The phase of the macroscopic electron-pair wavefunction in a superconductor can
      vary only by multiples of 2pi when going around a closed contour. This results in
      quantization of magnetic flux, one of the most striking demonstrations of quantum
      phase coherence in superconductors. By using superconductors with unconventional
      pairing symmetry, or by incorporating pi-Josephson junctions, a phase shift of pi
      can be introduced in such loops. Under appropriate conditions, this phase shift
      results in doubly degenerate time-reversed ground states, which are characterized
      by the spontaneous generation of half quanta of magnetic flux, with magnitude 1/2
      Phi(0)(Phi(0) = h/2e = 2.07 x 10(-15) Wb) (ref. 7). Until now, it has only been
      possible to generate individual half flux quanta. Here we report the realization
      of large-scale coupled pi-loop arrays based on YBa2Cu3O7-Au-Nb Josephson
      contacts. Scanning SQUID (superconducting quantum interference device) microscopy
      has been used to study the ordering of half flux quanta in these structures. The
      possibility of manipulating the polarities of individual half flux quanta is also
      demonstrated. These pi-loop arrays are of interest as model systems for studying
      magnetic phenomena--including frustration effects--in Ising antiferromagnets.
      Furthermore, studies of coupled pi-loops can be useful for designing quantum
      computers based on flux-qubits with viable quantum error correction capabilities.

PMID- 12621429
TI  - Superconductivity in two-dimensional CoO2 layers.
AB  - Since the discovery of high-transition-temperature (high-T(c)) superconductivity
      in layered copper oxides, many researchers have searched for similar behaviour in
      other layered metal oxides involving 3d-transition metals, such as cobalt and
      nickel. Such attempts have so far failed, with the result that the copper oxide
      layer is thought to be essential for superconductivity. Here we report that
      Na(x)CoO2*yH2O (x approximately 0.35, y approximately 1.3) is a superconductor
      with a T(c) of about 5 K. This compound consists of two-dimensional CoO2 layers
      separated by a thick insulating layer of Na+ ions and H2O molecules. There is a
      marked resemblance in superconducting properties between the present material and
      high-T(c) copper oxides, suggesting that the two systems have similar underlying
      physics.

PMID- 12621430
TI  - Dynamical coupling of wind and ocean waves through wave-induced air flow.
AB  - Understanding the physical mechanisms behind the generation of ocean waves by
      wind has been a longstanding challenge. Previous studies have assumed that ocean
      waves induce fluctuations in velocity and pressure of the overlying air that are
      synchronized with the waves, and numerical models have supported this assumption.
      In a complex feedback, these fluctuations provide the energy for wave generation.
      The spatial and temporal structure of the wave-induced airflow therefore holds
      the key to the physics of wind-wave coupling, but detailed observations have
      proved difficult. Here we present an analysis of wind velocities and ocean
      surface elevations observed over the open ocean. We use a linear filter to
      identify the wave-induced air flow from the measurements and find that its
      structure is in agreement with 'critical-layer' theory. Considering that the wave
      induced momentum flux is then controlled by the wave spectrum and that it varies
      considerably in vertical direction, a simple parameterization of the total air
      sea momentum flux is unlikely to exist.

PMID- 12621431
TI  - Iron-silica interaction at extreme conditions and the electrically conducting
      layer at the base of Earth's mantle.
AB  - The boundary between the Earth's metallic core and its silicate mantle is
      characterized by strong lateral heterogeneity and sharp changes in density,
      seismic wave velocities, electrical conductivity and chemical composition. To
      investigate the composition and properties of the lowermost mantle, an
      understanding of the chemical reactions that take place between liquid iron and
      the complex Mg-Fe-Si-Al-oxides of the Earth's lower mantle is first required.
      Here we present a study of the interaction between iron and silica (SiO2) in
      electrically and laser-heated diamond anvil cells. In a multianvil apparatus at
      pressures up to 140 GPa and temperatures over 3,800 K we simulate conditions down
      to the core-mantle boundary. At high temperature and pressures below 40 GPa, iron
      and silica react to form iron oxide and an iron-silicon alloy, with up to 5 wt%
      silicon. At pressures of 85-140 GPa, however, iron and SiO2 do not react and iron
      silicon alloys dissociate into almost pure iron and a CsCl-structured (B2) FeSi
      compound. Our experiments suggest that a metallic silicon-rich B2 phase, produced
      at the core-mantle boundary (owing to reactions between iron and silicate), could
      accumulate at the boundary between the mantle and core and explain the
      anomalously high electrical conductivity of this region.

PMID- 12621432
TI  - A Middle Miocene hominoid from Thailand and orangutan origins.
AB  - The origin of orangutans has long been debated. Sivapithecus is considered to be
      the closest ancestor of orangutans because of its facial-palatal similarities,
      but its dental characteristics and postcranial skeleton do not confirm this
      phylogenetic position. Here we report a new Middle Miocene hominoid, cf.
      Lufengpithecus chiangmuanensis n. sp. from northern Thailand. Its dental
      morphology relates it to the Pongo clade, which includes Lufengpithecus,
      Sivapithecus, Gigantopithecus, Ankarapithecus and possibly Griphopithecus. Our
      new species displays striking dental resemblances with living orangutans and
      appears as a more likely candidate to represent an ancestor of this ape. In
      addition, it originates from the geographic area of Pleistocene orangutans. But
      surprisingly, the associated flora shows strong African affinities, demonstrating
      the existence of a temporary floral and faunal dispersal corridor between
      southeast Asia and Africa during the Middle Miocene, which may have played a
      critical role in hominoid dispersion.

PMID- 12621433
TI  - Species interactions can explain Taylor's power law for ecological time series.
AB  - One of the few generalities in ecology, Taylor's power law, describes the species
      specific relationship between the temporal or spatial variance of populations and
      their mean abundances. For populations experiencing constant per capita
      environmental variability, the regression of log variance versus log mean
      abundance gives a line with a slope of 2. Despite this expectation, most species
      have slopes of less than 2 (refs 2, 3-4), indicating that more abundant
      populations of a species are relatively less variable than expected on the basis
      of simple statistical grounds. What causes abundant populations to be less
      variable has received considerable attention, but an explanation for the
      generality of this pattern is still lacking. Here we suggest a novel explanation
      for the scaling of temporal variability in population abundances. Using
      stochastic simulation and analytical models, we demonstrate how negative
      interactions among species in a community can produce slopes of Taylor's power
      law of less than 2, like those observed in real data sets. This result provides
      an example in which the population dynamics of single species can be understood
      only in the context of interactions within an ecological community.

PMID- 12621434
TI  - Engineering evolution to study speciation in yeasts.
AB  - The Saccharomyces 'sensu stricto' yeasts are a group of species that will mate
      with one another, but interspecific pairings produce sterile hybrids. A
      retrospective analysis of their genomes revealed that translocations between the
      chromosomes of these species do not correlate with the group's sequence-based
      phylogeny (that is, translocations do not drive the process of speciation).
      However, that analysis was unable to infer what contribution such rearrangements
      make to reproductive isolation between these organisms. Here, we report
      experiments that take an interventionist, rather than a retrospective approach to
      studying speciation, by reconfiguring the Saccharomyces cerevisiae genome so that
      it is collinear with that of Saccharomyces mikatae. We demonstrate that this
      imposed genomic collinearity allows the generation of interspecific hybrids that
      produce a large proportion of spores that are viable, but extensively aneuploid.
      We obtained similar results in crosses between wild-type S. cerevisiae and the
      naturally collinear species Saccharomyces paradoxus, but not with non-collinear
      crosses. This controlled comparison of the effect of chromosomal translocation on
      species barriers suggests a mechanism for the generation of redundancy in the S.
      cerevisiae genome.

PMID- 12621435
TI  - Optimal transsaccadic integration explains distorted spatial perception.
AB  - We scan our surroundings with quick eye movements called saccades, and from the
      resulting sequence of images we build a unified percept by a process known as
      transsaccadic integration. This integration is often said to be flawed, because
      around the time of saccades, our perception is distorted and we show saccadic
      suppression of displacement (SSD): we fail to notice if objects change location
      during the eye movement. Here we show that transsaccadic integration works by
      optimal inference. We simulated a visuomotor system with realistic saccades,
      retinal acuity, motion detectors and eye-position sense, and programmed it to
      make optimal use of these imperfect data when interpreting scenes. This optimized
      model showed human-like SSD and distortions of spatial perception. It made new
      predictions, including tight correlations between perception and motor action
      (for example, more SSD in people with less-precise eye control) and a graded
      contraction of perceived jumps; we verified these predictions experimentally. Our
      results suggest that the brain constructs its evolving picture of the world by
      optimally integrating each new piece of sensory or motor information.

PMID- 12621436
TI  - Monoclonal antibodies inhibit prion replication and delay the development of
      prion disease.
AB  - Prion diseases such as Creutzfeldt-Jakob disease (CJD) are fatal, neuro
      degenerative disorders with no known therapy. A proportion of the UK population
      has been exposed to a bovine spongiform encephalopathy-like prion strain and are
      at risk of developing variant CJD. A hallmark of prion disease is the
      transformation of normal cellular prion protein (PrP(C)) into an infectious
      disease-associated isoform, PrP(Sc). Recent in vitro studies indicate that anti
      PrP monoclonal antibodies with little or no affinity for PrP(Sc) can prevent the
      incorporation of PrP(C) into propagating prions. We therefore investigated in a
      murine scrapie model whether anti-PrP monoclonal antibodies show similar
      inhibitory effects on prion replication in vivo. We found that peripheral PrP(Sc)
      levels and prion infectivity were markedly reduced, even when the antibodies were
      first administered at the point of near maximal accumulation of PrP(Sc) in the
      spleen. Furthermore, animals in which the treatment was continued remained
      healthy for over 300 days after equivalent untreated animals had succumbed to the
      disease. These findings indicate that immunotherapeutic strategies for human
      prion diseases are worth pursuing.

PMID- 12621437
TI  - Apolipoprotein L-I is the trypanosome lytic factor of human serum.
AB  - Human sleeping sickness in east Africa is caused by the parasite Trypanosoma
      brucei rhodesiense. The basis of this pathology is the resistance of these
      parasites to lysis by normal human serum (NHS). Resistance to NHS is conferred by
      a gene that encodes a truncated form of the variant surface glycoprotein termed
      serum resistance associated protein (SRA). We show that SRA is a lysosomal
      protein, and that the amino-terminal alpha-helix of SRA is responsible for
      resistance to NHS. This domain interacts strongly with a carboxy-terminal alpha
      helix of the human-specific serum protein apolipoprotein L-I (apoL-I). Depleting
      NHS of apoL-I, by incubation with SRA or anti-apoL-I, led to the complete loss of
      trypanolytic activity. Addition of native or recombinant apoL-I either to apoL-I
      depleted NHS or to fetal calf serum induced lysis of NHS-sensitive, but not NHS
      resistant, trypanosomes. Confocal microscopy demonstrated that apoL-I is taken up
      through the endocytic pathway into the lysosome. We propose that apoL-I is the
      trypanosome lytic factor of NHS, and that SRA confers resistance to lysis by
      interaction with apoL-I in the lysosome.

PMID- 12621438
TI  - Retraction: Superconductivity in CaCuO2 as a result of field-effect doping.

PMID- 12621439
TI  - Retraction: Superconductivity in single crystals of the fullerene C70.

PMID- 12621440
TI  - Retraction: Self-assembled monolayer organic field-effect transistors.

PMID- 12621441
TI  - Retraction: Gate-induced superconductivity in a solution-processed organic
      polymer film.

PMID- 12621442
TI  - Retraction: Superconductivity at 52 K in hole-doped C60.

PMID- 12621443
TI  - Retraction: Superconductivity in molecular crystals induced by charge injection.

PMID- 12621444
TI  - Retraction: Efficient organic photovoltaic diodes based on doped pentacene.

PMID- 12621446
TI  - Recruitment blueprint.

PMID- 12621447
TI  - Access delayed.

PMID- 12621449
TI  - Progress and prospects: naked DNA gene transfer and therapy.
AB  - Increases in efficiency have made naked DNA gene transfer a viable method for
      gene therapy. Intravascular delivery results in effective gene delivery to liver
      and muscle, and provides in vivo transfection methods for basic and applied gene
      therapy and antisense strategies with oligonucleotides and small interfering RNA
      (siRNA). Delivery via the tail vein in rodents provides an especially simple and
      effective means for in vivo gene transfer. Electroporation methods significantly
      enhance direct injection of naked DNA for genetic immunization. The availability
      of plasmid DNA expression vectors that enable sustained high level expression,
      allows for the development of gene therapies based on the delivery of naked
      plasmid DNA.

PMID- 12621450
TI  - Doxycycline-regulated lentiviral vector system with a novel reverse
      transactivator rtTA2S-M2 shows a tight control of gene expression in vitro and in
      vivo.
AB  - Regulated expression of therapeutic genes is required for long-term gene therapy
      applications for many disorders. Here we describe a doxycycline (dox)-regulated
      lentiviral vector system consisting of two HIV-1-based self-inactivating viruses.
      One of the vectors is constitutively expressing a novel improved version of the
      tetracycline reverse transactivator rtTA2(S)-M2 and the other has a rtTA
      responsive promoter driving the expression of beta-galactosidase gene (lacZ). The
      rtTA2(S)-M2 has highly improved properties with respect to specificity, stability
      and inducibility. Functionality of the system by dox was confirmed after in vitro
      cotransduction of Chinese hamster ovary and human endothelial hybridoma (EAhy926)
      cells. Regulation of the system showed tight control of the gene expression. Dose
      dependence for dox was seen with concentrations that can be obtained in vivo with
      doses normally used in clinical practice. LacZ expression could be switched
      on/off during long-term (3 months) culturing of cotransduced cells. The system
      was next tested in vivo after cotransduction into rat brain and studying
      expression of the lacZ gene in dox-treated and control rats. Nested RT-PCR
      confirmed that the tight control of the gene expression was achieved in vivo.
      Also, X-gal staining showed positive cells in the dox-treated rats, but not in
      the controls 10 days after cotransduction with 4 days preceding treatment with
      dox. It is concluded that our doxycycline-regulated vector system shows
      significant potential for long-term gene therapy treatments.

PMID- 12621451
TI  - HIV-1 proprotein processing as a target for gene therapy.
AB  - The central role of endoconvertases and HIV-1 protease (HIV-1 PR) in the
      processing of HIV proproteins makes the design of specific inhibitors important
      in anti-HIV gene therapy. Accordingly, we tested native alpha(1) antitrypsin
      (alpha(1)AT) delivered by a recombinant simian virus-40-based vector, SV(AT), as
      an inhibitor of HIV-1 proprotein maturation. Cell lines and primary human
      lymphocytes were transduced with SV(AT) without selection and detectable
      toxicity. Expression of alpha(1)AT was confirmed by Northern blotting,
      immunoprecipitation and immunostaining. SV(AT)-transduced cells showed no
      evidence of HIV-1-related cytopathic effects when challenged with high doses of
      HIV-1(NL4-3). As measured by HIV-1 p24 assay, SV(AT)-transduced cells were
      protected from HIV-1(NL4-3) at challenge dose of 40 000 TCID(50) (MOI = 0.04). In
      addition, peripheral blood lymphocytes treated with SV(AT) were protected from
      HIV doses challenge up to 40 000 TCID(50) (MOI = 0.04). By Western blot analyses,
      the delivered alpha(1)AT inhibited cellular processing of gp160 to gp120 and
      decreased HIV-1 virion gp120. SV(AT) inhibited processing of p55(Gag) as well.
      Furthermore, high levels of uncleaved p55(Gag) protein were detected in HIV virus
      particles recovered from SV(AT)-transduced cells lines and primary lymphocytes.
      Thus, delivering alpha(1)AT using SV(AT) to human lymphocytes strongly inhibits
      replication of HIV-1, most likely by inhibiting the activities both of the
      cellular serine proteases involved in processing gp160 and of the aspartyl
      protease, HIV-1 PR, which cleaves p55(Gag). alpha(1)AT delivered by SV(AT) may
      represent a novel and effective strategy for gene therapy to interfere with HIV
      replication, by blocking a stage in the virus replicative cycle that has until
      now been inaccessible to gene therapeutic intervention.

PMID- 12621452
TI  - A neovascularized organoid derived from retrovirally engineered bone marrow
      stroma leads to prolonged in vivo systemic delivery of erythropoietin in
      nonmyeloablated, immunocompetent mice.
AB  - Marrow stromal cells (MSCs) are postnatal progenitor cells that can be easily
      cultured ex vivo to large amounts. This feature is attractive for cell therapy
      applications where genetically engineered MSCs could serve as an autologous
      cellular vehicle for the delivery of therapeutic proteins. The usefulness of MSCs
      in transgenic cell therapy will rely upon their potential to engraft in
      nonmyeloablated, immunocompetent recipients. Further, the ability to deliver MSCs
      subcutaneously - as opposed to intravenous or intraperitoneal infusions - would
      enhance safety by providing an easily accessible, and retrievable, artificial
      subcutaneous implant in a clinical setting. To test this hypothesis, MSCs were
      retrovirally engineered to secrete mouse erythropoietin (Epo) and their effect
      was ascertained in nonmyeloablated syngeneic mice. Epo-secreting MSCs when
      administered as 'free' cells by subcutaneous or intraperitoneal injection, at the
      same cell dose, led to a significant - yet temporary - hematocrit increase to
      over 70% for 55+/-13 days. In contrast, in mice implanted subcutaneously with
      Matrigel trade mark -embedded MSCs, the hematocrit persisted at levels >80% for
      over 110 days in four of six mice (P<0.05 logrank). Moreover, Epo-secreting MSCs
      mixed in Matrigel elicited and directly participated in blood vessel formation de
      novo reflecting their mesenchymal plasticity. MSCs embedded in human-compatible
      bovine collagen matrix also led to a hematocrit >70% for 75+/-8.9 days. In
      conclusion, matrix-embedded MSCs will spontaneously form a neovascularized
      organoid that supports the release of a soluble plasma protein directly into the
      bloodstream for a sustained pharmacological effect in nonmyeloablated recipients.

PMID- 12621453
TI  - Function of a genetically modified human liver cell line that stores, processes
      and secretes insulin.
AB  - An alternative approach to the treatment of type I diabetes is the use of
      genetically altered neoplastic liver cells to synthesize, store and secrete
      insulin. To try and achieve this goal we modified a human liver cell line, HUH7,
      by transfecting it with human insulin cDNA under the control of the
      cytomegalovirus promoter. The HUH7-ins cells created were able to synthesize
      insulin in a similar manner to that which occurs in pancreatic beta cells. They
      secreted insulin in a regulated manner in response to glucose, calcium and
      theophylline, the dose-response curve for glucose being near-physiological.
      Perifusion studies showed that secretion was rapid and tightly controlled.
      Removal of calcium resulted in loss of glucose stimulation while addition of
      brefeldin A resulted in a 30% diminution of effect, indicating that constitutive
      release of insulin occurred to a small extent. Insulin was stored in granules
      within the cytoplasm. When transplanted into diabetic immunoincompetent mice, the
      cells synthesized, processed, stored and secreted diarginyl insulin in a rapid
      regulated manner in response to glucose. Constitutive release of insulin also
      occurred and was greater than regulated secretion. Blood glucose levels of the
      mice were normalized but ultimately became subnormal due to continued
      proliferation of cells. Examination of the HUH7-ins cells as well as the parent
      cell line for beta cell transcription factors showed the presence of NeuroD but
      not PDX-1. PC1 and PC2 were also present in both cell types. Thus, the parent
      HUH7 cell line possessed a number of endocrine pancreatic features that reflect
      the common endodermal ancestry of liver and pancreas, perhaps as a result of
      ontogenetic regression of the neoplastic liver cell from which the line was
      derived. Introduction of the insulin gene under the control of the CMV promoter
      induced changes in these cells to make them function to some extent like
      pancreatic beta cells. Our results support the view that neoplastic liver cells
      can be induced to become substitute pancreatic beta cells and become a therapy
      for the treatment of type I diabetes.

PMID- 12621454
TI  - High-efficiency plasmid gene transfer into dystrophic muscle.
AB  - The efficiency of plasmid gene transfer in skeletal muscle is significantly
      enhanced by pretreatment with hyaluronidase and the application of an electrical
      field to the muscle following the injection of plasmid DNA, a process referred to
      as electrotransfer. However, the presence of increased levels of connective
      tissue in muscular dystrophies, such as Duchenne muscular dystrophy (DMD), may
      affect the efficiency of this process. Here we demonstrate that the efficiency of
      electrotransfer is not affected by increased levels of connective tissue in the
      mdx mouse model of DMD and that any damage induced by the electrotransfer process
      is not exacerbated in the dystrophic phenotype. However, increasing the
      concentration of hyaluronidase does not improve transfection efficiencies
      further. Unlike direct injection of plasmid DNA, the efficiency of
      electrotransfer is not dependent upon the sex and age of mice used. The combined
      treatment of hyaluronidase and electrotransfer results in highly efficient gene
      transfer in dystrophic muscle with limited muscle damage.

PMID- 12621455
TI  - Targeted regulation of imprinted genes by synthetic zinc-finger transcription
      factors.
AB  - Epigenetic control of transcription is essential for mammalian development and
      its deregulation causes human disease. For example, loss of proper imprinting
      control at the IGF2-H19 domain is a hallmark of cancer and Beckwith-Wiedemann
      syndrome, with no targeted therapeutic approaches available. To address this
      deficiency, we engineered zinc-finger transcription proteins (ZFPs) that
      specifically activate or repress the IGF2 and H19 genes in a domain-dependent
      manner. Importantly, we used these ZFPs successfully to reactivate the
      transcriptionally silent IGF2 and H19 alleles, thus overriding the natural
      mechanism of imprinting and validating an entirely novel avenue for
      'transcription therapy' of human disease.

PMID- 12621456
TI  - Intraocular gene delivery of ciliary neurotrophic factor results in significant
      loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal
      degeneration.
AB  - Intraocular delivery of a variety of neurotrophic factors has been widely
      investigated as a potential treatment for retinal dystrophy (RD). The most
      commonly studied factor, ciliary neurotrophic factor (CNTF), has been shown to
      preserve retinal morphology and to promote cell survival in a variety of models
      of RD. In order to evaluate CNTF as a potential treatment for RD, we used the
      Prph2(Rd2/Rd2) mouse. CNTF was expressed intraocularly using AAV-mediated gene
      delivery either by itself or, in a second treatment group, combined with AAV
      mediated gene replacement therapy of peripherin2, which we have previously shown
      to improve photoreceptor structure and function. We confirmed in both groups of
      animals that CNTF reduces the loss of photoreceptor cells. Visual function,
      however, as assessed over a time course by electroretinography (ERG), was
      significantly reduced compared with untreated controls. Furthermore, CNTF gene
      expression negated the effects on function of gene replacement therapy. In order
      to test whether this deleterious effect is only seen when degenerating retina is
      treated, we recorded ERGs from wild-type mice following intraocular injection of
      AAV expressing CNTF. Here a marked deleterious effect was noted, in which the b
      wave amplitude was reduced by at least 50%. Our results demonstrate that
      intraocular CNTF gene delivery may have a deleterious effect on the retina and
      caution against its application in clinical trials.

PMID- 12621457
TI  - Hematopoietic cell transplantation for inherited metabolic diseases: an overview
      of outcomes and practice guidelines.
AB  - For the past two decades, hematopoietic cell transplantation (HCT) has been used
      as effective therapy for selected inherited metabolic diseases (IMD) including
      Hurler (MPS IH) and Maroteaux-Lamy (MPS VI) syndromes, childhood-onset cerebral X
      linked adrenoleukodystrophy (X-ALD), globoid-cell leukodystrophy (GLD),
      metachromatic leukodystrophy (MLD), alpha-mannosidosis, osteopetrosis, and
      others. Careful pre-HCT evaluation is critical and coordinated, multidisciplinary
      follow-up is essential in this field of transplantation. The primary goals of HCT
      for these disorders have been to promote long-term survival with donor-derived
      engraftment and to optimize the quality of life. Guidelines for HCT and
      monitoring are provided; a brief overview of long-term results is also presented.

PMID- 12621458
TI  - Clinical application of hematopoietic progenitor cell expansion: current status
      and future prospects.
AB  - In the past decade, we have witnessed significant advances in ex vivo
      hematopoietic stem cell culture expansion, progressing to the point where
      clinical trials are being designed and conducted. Preclinical milestone
      investigations provided data to enable expansion of portions of hematopoietic
      grafts in a clinical setting, indicating safety and feasibility of this approach.
      Data derived from current clinical trials indicate successful reconstitution of
      hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo
      expanded perfusion cultures. Future avenues of exploration will focus upon
      refining preclinical and clinical studies in which cocktails of available
      cytokines, novel molecules and sophisticated expansion systems will explore
      expansion of blood, marrow and umbilical cord blood cells.

PMID- 12621459
TI  - Low-intensity conditioning and hematopoietic stem cell transplantation in
      patients with renal and colon carcinoma.
AB  - We have evaluated whether allogeneic hematopoietic stem cell transplantation
      (HSCT) could induce an antitumor effect in patients with metastatic solid tumors.
      A total of 12 HLA-identical siblings and 6 HLA-A-, -B- and -DR beta 1-compatible
      unrelated grafts were used. Diagnoses were adenocarcinoma of kidney (n=10), colon
      (n=6), breast (n=1) and cholangiocarcinoma (n=1). Conditioning was fludarabine 30
      mg/m(2)/day for 3 days and 2 Gy of total body irradiation. Recipients of
      unrelated HSCT were also given thymoglobuline and two additional days of
      fludarabine. The median CD34+ cell dose was 7.5 x 10(6)/kg. Immunosuppression was
      mycophenolate mofetil and cyclosporin. Among all, 12 patients became complete
      donor chimeras within a median of 28, 29 and 65 days for B, myeloid and T cells,
      respectively. Two patients rejected the grafts, one developed marrow aplasia and
      three were mixed chimeras. The probability of grades II-IV acute graft-versus
      host-disease (GVHD) was 57%. Regression of all tumor metastases was seen in one
      patient with colon carcinoma. Another patient with colon and two with renal
      carcinoma had regression of lung metastases, but progression of metastases in the
      liver and/or bone. Necrosis of lung metastasis was found in one further patient
      with renal carcinoma who died of graft-versus-host-disease (GVHD). In all, 10
      patients died; four of transplant-related complications, one of trauma and five
      of progressive disease. Thus, progression was common after allogeneic HSCT in
      unselected patients with advanced solid tumors. However, the regression of some
      metastases associated with GVHD provides suggestive evidence that the GVHD effect
      may occur in renal and colon adenocarcinoma using reduced intensity conditioning.

PMID- 12621460
TI  - Large volume leukapheresis in small children: safety profile and variables
      affecting peripheral blood progenitor cell collection.
AB  - Large volume leukapheresis (LVL) has been proposed as a simplified single
      apheresis approach to collect the target number of CD34(+) cells. We
      retrospectively analyzed results of LVL in cytokine-mobilized patients weighing
      less than 20 kg to evaluate adverse events and variables affecting the yield. The
      only major adverse event recorded was transient and reversible systolic
      hypotension (three episodes). All the other adverse events were mild and did not
      require treatment. In multivariate analysis leukocyte count (P=0.001) and younger
      age (P=0.009) affected the CD34(+) cell number in the peripheral blood before
      apheresis. The number of CD34(+) cells before the apheresis was the only variable
      affecting CD34(+) cell yield in multivariate analysis (P=0.0001). In all, 77% of
      patients achieved the target CD34(+) cell dose of 2 x 10(6)/kg in their first
      apheresis. Recruitment was seen in 72% of the procedures, and this was related to
      the total blood volume processed (P=0.0005).

PMID- 12621461
TI  - Comparison between two strategies for umbilical cord blood collection.
AB  - The use of cord blood (CB) for transplantation has increased greatly in recent
      years. The collection strategy is the first step in collecting good-quality CB
      units. There are two main techniques for collecting CB from the umbilical vein:
      in the delivery room while the placenta is still in the uterus by midwives and
      obstetricians or in an adjacent room after placental delivery by CB bank trained
      personnel. In this study, the benefits and disadvantages between the two
      different CB collection strategies were evaluated, in order to improve CB bank
      methodology. Valencia CB bank maintains the two different collection strategies.
      CB was obtained from 569 vaginal and 70 caesarean deliveries and obstetrical and
      clinical charts were reviewed. Before processing CB units, volume was calculated
      and samples were drawn for cell counts. After processing and before
      cryopreservation samples were drawn for cell counts, CD34+cell analysis,
      viability, clonogenic assays and microbiology were drawn directly from the bags.
      We compared the efficiency of the two collection techniques. Obstetric data and
      umbilical CB were obtained from 569 vaginal (264 collected in utero and 305
      collected ex utero) and 70 caesarean deliveries. The proportion of excluded CB
      units before processing was 33% for vaginal ex utero, 25% for vaginal in utero
      and 46% for caesarean deliveries. Differences were statistically significant. For
      vaginal deliveries a larger volume and a higher number of nucleated cells,
      percentage of CD34+ cells and colony-forming units (CFUs) were harvested in the
      in utero collection group. There was no statistical difference between CB
      collected after placental expulsion from vaginal and caesarean deliveries.
      Comparison between all vaginal and caesarean deliveries did not show any
      difference. We conclude that the mode of collection influences the haematopoietic
      content of CB donations. Collection before placental delivery is the best
      approach to CB collection and allows optimisation of CB bank methodology.
      Caesarean deliveries seem to contain similar progenitor content to vaginal
      deliveries.

PMID- 12621462
TI  - High-dose consolidation chemotherapy with Idarubicin and alkylating agents
      following induction with gemcitabine-epirubicin-paclitaxel in metastatic breast
      cancer: a dose finding study.
AB  - Preliminary randomized studies have failed to show a survival benefit of high
      dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an
      active agent in breast cancer and is suitable for dose escalation. We designed a
      dose finding study with escalating high-dose idarubicin (HD-Ida) followed by
      fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells
      (PBPC) in MBC patients with stable disease or in partial response after six
      courses of induction chemotherapy with gemcitabine 1000 mg/m(2) days 1 and 4,
      epirubicin 90 mg/m(2) day 1, taxol 175 mg/m(2) day 1 (GET). Aims of the study
      were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the
      cardiac safety and activity of HD-Ida and HD-TM after GET and to study the
      pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients
      were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at
      the following dose levels: 40 mg/m(2) (three patients), 50 mg/m(2) (three
      patients), 60 mg/m(2) (five patients) and 70 mg/m(2) (three patients). Mucositis
      was the dose-limiting toxicity and the MTD was 60 mg/m(2). C(max) of Idarubicin
      and idarubicinol were 7.7+/-2.0 and 26.3+/-9.7 ng/ml at 40 mg/m(2) and increased
      to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m(2). AUCt(0-264) of idarubicin and
      idarubicinol increased from 423.2+/-111.6 and 2581+/-606 hng/ml at 40 mg/m(2) to
      732.8+/-140.2 and 4590+/-1258 hng/ml at 70 mg/m(2). Conversion rates after HD-Ida
      and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were
      observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of
      cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing
      regimen suggests incomplete cross-resistance between the two drugs.

PMID- 12621463
TI  - High-dose chemotherapy with autologous stem cell rescue in children with
      retinoblastoma.
AB  - Children with metastatic retinoblastoma are considered to have a poor prognosis
      after conventional chemotherapy. We used high-dose chemotherapy (HDC) with
      peripheral hematopoietic stem cell transplantation in such patients in an attempt
      to improve their survival. Four patients with bone marrow metastases and one
      child with extraorbital disease were treated with HDC after achieving complete
      remission by enucleation and conventional chemotherapy. The child with
      extraorbital tumor was the only one to receive local irradiation. The
      conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and
      carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)),
      cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child.
      Hematologic recovery occurred without delay in all patients. The main toxicities
      were diarrhea, mucositis and infectious complications. No toxic deaths or any
      major late toxicities were observed. The child treated with the BCNU regimen
      developed a meningeal relapse 10 months after HDC, which was partially resected
      and treated with conventional chemotherapy, but not with radiotherapy. He is in
      complete remission (CR) 105 months off treatment. The other patients are in CCR
      for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and
      carboplatin may represent a curative option for children with extrabulbar or
      disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS
      disease. The necessity to irradiate these children and the curative potential of
      this strategy for patients with bulky CNS disease remain to be determined.

PMID- 12621464
TI  - Rapid immune reconstitution following autologous hematopoietic stem cell
      transplantation in children: a single institution experience.
AB  - In this retrospective study, we review the immune reconstitution of children
      undergoing autologous hematopoietic stem cell transplantation. A total of 125
      patients underwent autologous transplantation between 1992 and 2000. The report
      includes data on 58 patients. Data were not available on the remaining patients
      who either died before testing or data were not obtained. The parameters
      evaluated include: (a) immunophenotype by flow cytometry to quantify lymphocyte
      subpopulations (b) mitogen stimulation assays, and (c) quantitative
      immunoglobulins. The analysis reveals that CD3+ cells did not reach the normal
      range during the first year post-transplant. The median percentage of CD4+ cells
      was below normal up to 6 months post-transplant, while the absolute number remain
      low throughout the first year. The CD8+ percentage and absolute numbers remain
      normal at all times post-transplant. The CD19+ cells were also normal post
      transplantation. The mitogen lymphocyte stimulation was normal in 27 out of 31
      patients tested after 6 months post-transplant. Our analysis of immune
      reconstitution shows a similar pattern to previous studies with a faster recovery
      of the CD4/CD8 ratio, especially in those patients who did not receive TBI. In
      conclusion, the observed deficiencies are transient and have very little clinical
      significance because, historically, the rate of serious infections is low despite
      prolonged immune suppression. The recovery post-autologous transplant is fast.

PMID- 12621465
TI  - Treating refractory chronic graft-versus-host disease with extracorporeal
      photochemotherapy.
AB  - Extracorporeal photochemotherapy (ECP; photopheresis), an immunomodulatory
      therapy, has previously demonstrated promising results in treating chronic graft
      versus-host disease (cGvHD). We treated six patients (ages 33-54 years) with long
      standing refractory extensive-stage cGvHD. ECP was performed thrice weekly
      initially in all patients. Concomitant therapies included prednisone (n=6),
      tacrolimus (n=5), cyclosporin A (n=2), hydroxychloroquine (n=2), mycophenolate
      mofetil (n=1), and psoralen plus ultraviolet A radiation (n=1). After an average
      of 7.2 months (range, 2-13 months) of ECP, all patients experienced either
      improvement or stabilization in sclerodermatous skin changes, as well as partial
      improvements in liver enzyme levels. Skin softening occurred in four patients and
      was noted as early as 3-8 weeks into treatment. Two patients were able to taper
      steroid therapy, and two patients were able to taper ECP to twice weekly. ECP was
      well tolerated. Our results support those of previous studies, suggesting that
      ECP may be beneficial in patients with refractory cGvHD.

PMID- 12621467
TI  - Cyclic recovery of adenovirus in a stem cell transplant recipient: an inverse
      association with graft-versus-host disease.
AB  - Adenovirus (AdV) infections have been increasingly recognized as significant
      pathogens that may cause severe morbidity and mortality among stem cell
      transplant (SCT) recipients. AdV can cause localized infections such as
      hemorrhagic cystitis (HC), pneumonia, hepatitis and also disseminated disease
      that can lead to death. We report a case of severe hemorrhagic cystitis in a SCT
      recipient who died 83 days after transplant. In this patient, AdV recovery was
      not constantly detected. In fact, fluctuations of the AdV detection in leukocytes
      and urine were observed by culture and PCR. When analyzing this viral cyclic
      recovery with different signs or symptoms in the patient, we observed an inverse
      association with the presence of acute graft-versus-host disease (GVHD). Whether
      these fluctuations represent donor-derived reactivity, indirectly manifested by
      the presence of GVHD, requires further study. This is the first case describing a
      dynamic pattern of AdV replication in leukocytes and urine samples from a patient
      with severe HC and the temporal correlation with GVHD.

PMID- 12621466
TI  - Hepatitis reactivation and liver failure in haemopoietic stem cell transplants
      for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a
      retrospective study by the Italian group for blood and marrow transplantation.
AB  - Hepatitis B virus/hepatitis C virus (HBV/HCV) positive patients undergoing
      haemopoietic stem cell transplantation (HSCT) are at risk of hepatitis
      reactivation and fatal liver failure: we have conducted a retrospective study to
      assess the risk in 20 Italian transplant centres. A total of 90 patients infected
      with HBV (n=33) or HCV (n=57) receiving allogeneic (n=36) or autologous (n=54)
      haemotopoietic stem cell transplant (HSCT) between 1996 and 2000 were reviewed.
      The biochemical profiles and outcomes of infection-related liver disease were
      also analysed. The risk of death at 2 years was comparable when considering type
      of infection (3% for HBV vs 8% for HCV, P=0.6) or type of HSCT (7% for allogeneic
      vs 5% for autologous HHSCT, P=0.34). Hepatitis reactivation followed by
      resolution was more frequent in HCV+ than in HBV+ patients receiving an allograft
      (100% vs 16%, P=0.004). In HBV+ cases, risk of reactivation was comparable after
      autologous or allogeneic transplantation (66 vs 81%, P=0.3), but liver disease
      was more severe and occurred earlier in the autologous group. Our results
      indicate that HBV and HCV infection should not be taken as an absolute
      contraindication for HSCT and the risk of life-threatening liver complications
      are similar after allogeneic or autologous transplants.

PMID- 12621468
TI  - Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell
      transplantation did not compromise engraftment and resulted in cytogenetic
      remission in a patient with chronic myeloid leukemia in blast crisis.
AB  - The main obstacles to successful hematopoietic stem cell transplantation for
      patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased
      post-transplant relapse and high treatment-related mortality. We report a patient
      with CML in BC who was treated initially with imatinib mesylate and was then
      concurrently treated with a nonmyeloablative stem cell transplant. Successful
      engraftment of donor cells followed by complete cytogenetic remission was
      achieved in the absence of severe therapy-related toxicities. This case
      demonstrates that imatinib mesylate given through nonmyeloablative transplant is
      a minimally toxic therapeutic approach, which does not compromise engraftment and
      may result in a favorable outcome in patients with CML in BC.

PMID- 12621469
TI  - Human metapneumovirus in a haematopoietic stem cell transplant recipient with
      fatal lower respiratory tract disease.
AB  - Respiratory viruses are increasingly recognized as a cause of pneumonitis
      following haematopoietic stem cell transplantation (HSCT). However, frequently,
      no pathogen is identified in cases of suspected viral pneumonia. Recently, a
      previously undescribed paramyxovirus, designated 'human metapneumovirus' (hMPV),
      was isolated from children with respiratory illness. We have detected hMPV as the
      sole pathogen in the nasopharyngeal aspirate of an HSCT recipient who succumbed
      to progressive respiratory failure following an upper respiratory prodrome. This
      report highlights the importance of further studies to elucidate the role of hMPV
      in causing respiratory illnesses in the HSCT population.

PMID- 12621470
TI  - Does adding ATG to the GVHD prophylaxis regimen help reduce its incidence?

PMID- 12621472
TI  - Severe neurotoxicity because of dimethyl sulphoxide following peripheral blood
      stem cell transplantation.

PMID- 12621473
TI  - May primary liver cancer induce a graft-versus-tumor effect?

PMID- 12621474
TI  - Post-transplant lymphoproliferative disorder: a review.
AB  - Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of
      Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis
      like illness to a fulminant non-Hodgkin's lymphoma. In the setting of
      hematopoietic stem cell transplantation, PTLD is an often-fatal complication
      occurring relatively early after transplant. Risk factors for the development of
      PTLD are well established, and include HLA-mismatching, T-cell depletion, and the
      use of antilymphocyte antibodies as conditioning or treatment of graft-versus
      host disease. Early recognition of PTLD is particularly important in the SCT
      setting, because PTLD in these patients tends to be rapidly progressive.
      Familiarity with the clinical features of PTLD and a heightened level of
      suspicion are critical for making the diagnosis. Surveillance techniques with EBV
      antibody titers and/or polymerase chain reaction (PCR) may have a role in some
      high-risk settings. Immune-based therapies such as monoclonal anti-B-cell
      antibodies, interferon-alpha, and EBV-specific donor T cells, either as treatment
      for PTLD or as prophylaxis in high-risk patients, represent promising new
      directions in the treatment of this disease.

PMID- 12621475
TI  - Allogeneic transplantation for multiple myeloma: late relapse may occur as
      localised lytic lesion/plasmacytoma despite ongoing molecular remission.
AB  - Allogeneic SCT for myeloma may be curative for young patients, but its role
      remains controversial because of a reported high TRM in some series. Since 1991,
      we have performed 25 allografts for myeloma using fully matched sibling donors.
      Of the 18 evaluable patients, 13 achieved CR at a median time of 2.5 months post
      transplant. The five patients who were not in CR when assessed at 3 months
      received a short course of alpha-interferon and four subsequently achieved CR
      with this approach at a median of 82 days. One patient who failed to respond to
      IFN went on to achieve CR after four doses of DLI therapy, thus giving an overall
      CR rate of 72%. Seven patients have relapsed at a median of 4.7 years post
      transplant (range 1.38-7.7 years) including two patients who had received IFN
      therapy. In five of these cases, relapse has been as a localised area of bone
      disease or isolated plasmacytoma with no evidence of marrow involvement by
      trephine biopsy or molecular analysis. All patients with localised relapse were
      treated with local radiotherapy +/-DLI and four are currently disease free
      despite two patients having had further treatment for a second localised lesion.
      Six patients died of TRM (24%) and the OS at 8 years is currently 69% with an EFS
      of 26%. These results suggest that allogeneic SCT for myeloma can be carried out
      with an acceptable TRM and a high CR rate. However, late relapses as localised
      disease may be a frequent finding and may represent foci of myeloma not
      eradicated by the conditioning. The use of pretransplant MRI scanning and top-up
      radiotherapy to involved areas may be useful in preventing this type of relapse.

PMID- 12621476
TI  - Autologous stem cell transplantation in multiple myeloma: improved survival in
      nonsecretory multiple myeloma but lack of influence of age, status at transplant,
      previous treatment and conditioning regimen. A single-centre experience in 127
      patients.
AB  - High-dose therapy with autologous stem cell transplantation (ASCT) has become the
      treatment of choice for symptomatic eligible patients with multiple myeloma (MM).
      We report our centre experience and analyse retrospectively the prognostic
      influence of pretransplant characteristics and transplant modalities on response
      and survival. A total of 127 MM patients (median age: 55.2 years) were
      transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light
      chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients
      were in complete remission (CR), 73% in partial remission (PR), 12% showed minor
      response to previous treatment and 9% had stable or refractory disease. Prior to
      autograft, 79% of cases had received only one line of chemotherapy and 21% two or
      more lines. All patients received PBSC support after conditioning with 200
      mg/m(2) melphalan alone (100 patients) or melphalan and TBI (27 patients). We
      evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65
      years), type of MM, status pre- and post-ASCT, number of lines of previous
      regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+
      cells, plasma cell infiltration and beta(2)-microglobulin at diagnosis on overall
      (OS) and progression-free survivals (PFS) to define patients with better
      prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only
      two patients progressed. Median OS and PFS from transplantation were 50.4 and
      23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant
      related mortality was 2.3%. Low levels of beta(2)-microglobulin and the
      achievement of CR post-transplant correlated with longer PFS (P<0.03 and P<0.01,
      respectively). The median PFS was 36.1, 23.9, 21.1 and 16.4 months for
      nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an
      important prognostic factor at a cutoff value of 55 or 60 years. We conclude that
      ASCT is a safe and effective procedure even in resistant cases. The outcome was
      independent of age, time from diagnosis, previous treatment and conditioning
      regimen, but there was a tendency for better survival in the nonsecretory
      patients.

PMID- 12621477
TI  - Peripheral blood stem cell collection in 24 low-weight infants: experience of a
      single centre.
AB  - Peripheral blood stem cells (PBSC) harvest may be difficult in young children.
      Extracorporeal separator line priming by red blood cells is usually required to
      improve haemodynamic tolerance and efficacy of collection. We present our
      experience with 24 children weighing less than 15 kg treated between January 1997
      and September 1999, in whom we tried to avoid systematic blood priming. The
      median age and weight at the time of apheresis were 2.4 years and 12 kg,
      respectively. A total of 48 PBSC were performed. When haemoglobin was less than
      12 g/dl, packed red cells were transfused before collection (40% of aphereses).
      The median cell yield per apheresis was 7.1 (2.2-30.6)x10(6)/kg CD34(+) cells and
      16.0 (3.3-44.3)x10(5) CFU-GM/kg. Initial collection failed in three cases. Four
      children required an additional haematopoietic progenitor mobilization. This
      procedure allowed PBSC collection without transfusion in 37.5% of children, and
      was safe (two serious and five mild transient side effects) and effective (median
      CD34(+) cells collected per child: 7.1 x 10(6)/kg (4.6-30.6) and CFU-GM: 15.1 x
      10(5)/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter
      was avoided in 43% of children.

PMID- 12621478
TI  - Graft-versus-leukaemia effect in children: chronic GVHD has a significant impact
      on relapse and survival.
AB  - To examine whether graft-versus-host-disease (GVHD) is associated with a graft
      versus-leukaemia (GVL) effect that also influences the outcome of allogeneic stem
      cell transplantation (SCT) in childhood acute leukaemia, we evaluated all
      consecutive (n=169) children who had undergone SCT for ALL and AML at our centre.
      Median follow-up was 7 years. The 5-year probability of chronic GVHD was 34%.
      Median time to relapse was 24 months in children with chronic GVHD and 6 months
      in those without. The corresponding 5-year probabilities of relapse were 30 and
      45% (P=0.01). The 5-year probability of survival was 54%. Patients with chronic
      GVHD had a significantly better survival, 77 vs 51% (P=0.01). In a Cox regression
      model, chronic GVHD independently decreased the risk of relapse (RR 0.44) and
      further predicted an increased chance of relapse-free survival (RR 1.7) and
      survival (RR 2.6). The impact of chronic GVHD on survival was most apparent in
      late-stage disease and in ALL. Acute GVHD was not an independent predictor for
      relapse or death in this study. This study is in support of a GVL effect in
      childhood leukaemia related to chronic GVHD, reducing the risk of relapse and
      improving survival.

PMID- 12621479
TI  - Increased levels of immune transcript in patients with acute GVHD after
      allogeneic stem cell transplantation.
AB  - After allogeneic stem cell transplantation (SCT), donor T-cells are primarily
      responsible for the antihost activity, resulting in graft-versus-host disease
      (GVHD). Three effector pathways have been described for T-cell cytotoxicity:
      perforin/granzyme B; Fas/Fas ligand (FasL) and secreted molecules such as TNF
      alpha. The goal of this pilot study was to utilize competitive reverse
      transcription (RT)-PCR to evaluate the pattern of granzyme B, perforin, FasL and
      TNF-alpha gene expression in peripheral blood in patients after SCT. Protein
      levels of granzyme B, soluble FasL (sFasL) and TNF-alpha in plasma were also
      analyzed. Eight patients who underwent allogeneic SCT were included; five were
      diagnosed with acute GVHD. In the patients diagnosed with acute GVHD, we found
      increased levels of granzyme B, perforin and FasL mRNA, although this did not
      correlate with the clinical severity. However, patients with increasing levels of
      gene expression during acute GVHD treatment may have an increased risk of
      developing severe acute GVHD, as two out of three patients with increasing immune
      transcript levels during GVHD therapy developed life-threatening acute GVHD. In
      conclusion, the quantitative RT-PCR of granzyme B, perforin and FasL may serve as
      a guide to the clinician in diagnosing acute GVHD and monitoring treatment.

PMID- 12621480
TI  - Central nervous system aspergillosis in allogeneic stem cell transplant
      recipients.
AB  - Invasive aspergillosis (IA) is relatively common in allogeneic stem cell
      transplant (SCT) recipients. Although lungs are the most common site, central
      nervous system (CNS) involvement is also observed in this setting. We have
      retrospectively studied 14 cases of CNS aspergillosis found in a cohort of 455
      allogeneic SCT recipients (incidence 3%). All patients, except one, had
      experienced acute graft-versus-host disease treated with high-dose
      methylprednisolone, and eight patients (57%) had also received ATG. The median
      time to the diagnosis of CNS aspergillosis was 124 days (range 49-347 days) from
      SCT. Pulmonary aspergillosis had been diagnosed earlier in four patients (29%).
      The most common initial symptoms of CNS aspergillosis were convulsions,
      hemiparesis, and mental alteration. Neuroradiological studies revealed single
      (two patients) or multiple (seven patients) focal lesions of 0.2-9 cm in
      diameter. Despite clinical suspicion in many patients, a confirmed diagnosis of
      CNS aspergillosis was made during life in only one patient. A total of 12
      patients (86%) received amphotericin B. Despite therapy, all patients died 0-27
      days (median seven days) after the initial CNS symptoms. CNS aspergillosis is not
      uncommon in allogeneic SCT recipients. Clinical manifestations are usually
      dramatic and progress quickly. Earlier and more effective treatment of IA is
      needed to prevent dissemination of infection into the CNS.

PMID- 12621481
TI  - Alteration of pharmacokinetics of cyclophosphamide and suppression of the
      cytochrome p450 genes by ciprofloxacin.
AB  - Recently, it has been reported that prophylactic administration of ciprofloxacin
      during cyclophosphamide (CY) conditioning was a high-risk factor for relapse in
      patients undergoing allogeneic BMT. In the present study, we investigated the
      possible mechanisms of this interaction in male Sprague-Dawley rats. The kinetics
      of CY and its active 4-OH-CY metabolite were determined, after 3 days
      pretreatment with ciprofloxacin (200 mg/kg) and compared to control rats without
      treatment. CY was administered as a high or low single intravenous dose (150 and
      90 mg/kg, respectively). The expression of the CYP2B1, CYP2B2, CYP2C11, CYP3A1
      and CYP3A2 genes was evaluated by SYBR Green I Dye real-time PCR for
      quantification of mRNA. The administration of ciprofloxacin resulted in a
      significant increase in the AUC (P=0.007) and a significant decrease in clearance
      (P=0.007) when CY was given as a high dose. In accordance, the metabolic ratio
      (AUC4-OH-CY/AUCCY) was significantly lower (P=0.007) compared to that found in
      the control group. Ciprofloxacin significantly suppressed gene expression of
      CYP2C11 (P=0.01) and CYP3A1 (P=0.04); however, no effect was observed on the gene
      expression of CYP3A2, CYP2B1 and CYP2B2. Our study revealed that ciprofloxacin
      interacts with CY and suppressed relevant cytochromes p450 at the transcriptional
      level. This study may have a great clinical impact when ciprofloxacin is used in
      therapy.

PMID- 12621482
TI  - Economic analysis of conventional-dose chemotherapy compared with high-dose
      chemotherapy plus autologous hematopoietic stem-cell transplantation for
      metastatic breast cancer.
AB  - We performed an economic analysis of data from 180 women in a clinical trial of
      conventional-dose chemotherapy vs high-dose chemotherapy plus stem-cell
      transplantation for metastatic breast cancer responding to first-line
      chemotherapy. Data on resource use, including hospitalizations, medical
      procedures, medications, and diagnostic tests, were abstracted from subjects'
      clinical trial records. Resources were valued using the Medicare Fee Schedule for
      inpatient costs at one academic medical center and average wholesale prices for
      medications. Monthly costs were calculated and stratified by treatment group and
      clinical phase. Mean follow-up was 690 days in the transplantation group and 758
      days in the conventional-dose chemotherapy group. Subjects in the transplantation
      group were hospitalized for more days (28.6 vs 17.8, P=0.0041) and incurred
      higher costs (US dollars 84055 vs US dollars 28169) than subjects receiving
      conventional-dose chemotherapy, with a mean difference of US dollars 55886 (95%
      CI, US dollars 47298-US dollars 63666). Sensitivity analyses resulted in cost
      differences between the treatment groups from US dollars 36528 to US dollars
      75531. High-dose chemotherapy plus stem-cell transplantation resulted in
      substantial additional morbidity and costs at no improvement in survival. Neither
      the survival results nor the economic findings support the use of this procedure
      outside of the clinical trial setting.

PMID- 12621483
TI  - Lymphoid blast crisis of chronic myelogenous leukemia occurring more than 11
      years after receiving an allogeneic bone marrow transplant for chronic
      myelogenous leukemia in myeloid blast crisis at onset.
AB  - A 25-year-old male developed lymphoid blast crisis (BC) of chronic myelogenous
      leukemia (CML) more than 11 years after receiving an allogeneic bone marrow
      transplant (alloBMT) for CML with myeloid BC at presentation from his HLA
      identical brother. The lymphoid BC of CML probably occurred without a preceding
      chronic phase of CML. This case illustrates the difficulties involved in
      determining the appropriate length of follow-up after alloBMT.

PMID- 12621484
TI  - Richter's syndrome after allogeneic stem cell transplantation for chronic
      lymphocytic leukaemia successfully treated by withdrawal of immunosuppression,
      and donor lymphocyte infusion.
AB  - Development of high-grade non-Hodgkin's lymphoma is a possible complication of
      chronic lymphocytic leukaemia/small lymphocytic lymphoma, known as Richter's
      syndrome (RS). Treatment for RS includes systemic chemotherapy and, recently,
      allogeneic stem cell transplantation (SCT). We describe a patient with B-chronic
      lymphocytic leukaemia who developed RS 4 months after allogeneic SCT from an HLA
      identical sibling. The RS presented with systemic symptoms, lymphadenopathy,
      pancytopenia and serum lactate dehydrogenase elevation. The patient was treated
      with immunosuppressive drug withdrawal and a donor lymphocyte infusion (DLI) of 1
      x 10(7) CD3/kg, leading to the disappearance of all symptoms and the attainment
      of complete donor chimerism. After 18 months of the therapeutic DLI, the patient
      continues in complete remission.

PMID- 12621485
TI  - Fatal EBV-related post-transplant lymphoproliferative disorder (LPD) after
      matched related donor nonmyeloablative peripheral blood progenitor cell
      transplant.
AB  - A 39-year-old male underwent a nonmyeloablative stem cell transplant (NMAPBPCT)
      from his HLA-matched sister for recurrent anaplastic large cell lymphoma in CR-2,
      receiving fludarabine, cyclophosphamide, and rabbit antithymocyte globulin for
      the preparative therapy. The patient was readmitted on day+33 for persistent
      culture-negative fevers. He rapidly developed marked elevations of alkaline
      phosphatase and bilirubin. Liver biopsy showed a periportal infiltrate of large
      immunoblastic appearing cells. The tumor cells did not stain for CD3/CD20/CD30
      and alk protein, but did stain for CD79a/LCA and CD43. In situ hybridization for
      Epstein-Barr virus (EBV) RNA (EBER 1) was strongly positive in the periportal
      infiltrating lymphocytes. Fluorescence in situ hybridization (FISH) studies
      revealed female (XX) cells in the tumor cells and male (XY) in the surrounding
      hepatic parenchymal cells. The patient developed severe lactic acidosis, oliguric
      renal failure and expired on day+44. Both donor and patient had positive IgG
      serologies for EBV VCA and EBNA pretransplant. The donor also had a positive IgM
      titer for EBV VCA in the pretransplant specimen. The LPD may have been related to
      the intense immunosuppression of the preparative therapy and the presence of
      recent EBV infection in the donor.

PMID- 12621486
TI  - Busulfan and cyclophosphamide as a preparative regimen for allogeneic blood and
      marrow transplantation in patients with non-Hodgkin's lymphoma.
AB  - This study reports on overall and recurrence-free survival (OS and RFS) of 37
      consecutive patients with low- and intermediate-grade NHL receiving a related
      donor allogeneic BMT using a nonradiation-containing preparative regimen. In
      addition, transplant-related toxicity and factors influencing outcome are
      discussed. The preparative regimen consisted of busulfan and cyclophosphamide.
      Median patient age was 44 years (range 20-55). In all, 18 were female. Median
      follow-up of surviving patients from BMT was 4.2 years. A total of 25 patients
      had low-grade, and 12 intermediate grade NHL. Most patients (89%) were treated
      with at least two different chemotherapy regimens prior to BMT. In all, 22
      patients (59%) were transplanted in partial remission, 15 (41%) in complete
      remission. OS at 12 months was 89% (95% confidence interval (CI) of 79-99%) and
      79% (64-93%) at 60 months. RFS at 12 months was 86% (75-97%) and at 5 years 70%
      (54-86%). Four patients (11%) relapsed. Seven patients (19%) died, six because of
      treatment-related toxicity and one with relapse. Univariate analysis showed
      improved OS for younger patients and patients of female gender, suggesting that
      allogeneic BMT using busulfan-cyclophosphamide as a preparative regimen can
      achieve disease control and possibly cure patients with NHL particularly younger
      ones.

PMID- 12621487
TI  - Successful allogeneic hematopoietic stem cell transplantation using triple agent
      immunosuppression in severe aplastic anemia patients.
AB  - Graft rejection in patients with severe aplastic anemia (SAA) following
      allogeneic hematopoietic stem cell transplantation (HSCT) is strongly associated
      with a large number of prior transfusions and with prolonged disease duration
      before transplant. We retrospectively analyzed the outcomes and the factor
      affecting these multitransfused SAA patients, who had received triple agent
      immunosuppression and high doses of stem cells to overcome rejection. In total,
      113 patients with SAA who had a median 16 months (range 1-216) of disease
      duration were transplanted using HLA-matched sibling donors after conditioning
      with cyclophosphamide (CY), procarbazine (PCB), and ATG. Graft failure occurred
      in 16 of the eligible 113 patients, and with a median follow-up of 30 months
      (range, 1-80), probability of overall rejection was 15%. Specifically, the
      multitransfused patients who received high doses of stem cells with T-cell
      depletion showed the lowest rejection rate, 5.6%, compared with 30.3% in
      multitransfused patients with bone marrow stem cells alone (P=0.0310). Disease
      duration (P=0.0338) and the number of infused CD34+cells (P=0.0101) were
      associated with a high risk of graft rejection on multivariate analysis. ABO
      mismatch and the number of CD34+ cells were significant factors in the incidence
      of acute graft-versus-host-disease (GVHD). The incidence of chronic GVHD among
      patients with sustained engraftment was 13/109 (11.9%). With the same follow-up
      period, probability of disease-free survival for the entire group of patients at
      6 years was 89% and the only factor associated with long-term survival was
      rejection (P=0.0241). These results suggest that allogeneic HSCT conditioned with
      triple agent immunosuppression, and specifically with high-dose stem cell return
      is probably an effective treatment for successful engraftment in SAA patients
      with a high risk of rejection.

PMID- 12621488
TI  - Radiation-free regimens result in similar outcomes of allogeneic hematopoietic
      progenitor cell transplantation in patients aged >or=50 years compared to younger
      adults with low-risk disease.
AB  - Age >or=50 years has been reported to be an adverse risk factor for allogeneic
      BMT, and consequently many of these patients are either not transplanted or
      treated on nonmyeloablative protocols. To study if older patients perform poorly
      relative to younger adults following myeloablative allogeneic transplants, we
      compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50
      years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for
      AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35
      (range 18-49) years for older and younger patients, respectively. Patients were
      low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia,
      or NHL in remission or sensitive relapse at the time of transplantation. All
      others were high-risk. In patients with low-risk disease, there was no
      significant difference in overall survival (OS) between older and younger adults
      (P=0.64), while older patients tended to have a shorter OS among high-risk
      patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95%
      CI, 50-69%) for older and younger patients with low-risk disease, respectively.
      The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%)
      for high-risk patients. In low-risk patients, the incidence of acute and chronic
      graft-versus-host disease, and treatment-related mortality were similar in older
      and younger patients, while older patients experienced more treatment-related
      deaths by day 100. On multivariable analysis, age >or=50 years was a significant
      adverse factor only when high-risk patients were considered. We conclude that
      when radiation-free conditioning is used, age >or=50 years is not a significant
      adverse risk factor for allogeneic BMT in patients with low-risk disease, and
      that such patients should not be excluded from conventional myeloablative
      approaches until the efficacy of nonmyeloablative transplantation is better
      established.

PMID- 12621489
TI  - Etoposide (VP-16) plus G-CSF mobilizes different dendritic cell subsets than does
      G-CSF alone.
AB  - Dendritic cells (DCs) are antigen-presenting cells that are critical to the
      generation of immunologic tumor responses. Myeloid DCs (DC1) express myeloid
      antigen CD11c; lymphoid DCs (DC2) express CD123(+) and are CD11c(-). Analysis of
      DC subsets from peripheral blood progenitor cells (PBPC) collected from normal
      donors mobilized with G-CSF shows a predominance of DC2 cells. Whether PBPCs
      mobilization by chemotherapy yields different subsets of DCs has not been
      studied. We analyzed DC subsets in apheresis products from 44 patients undergoing
      autologous stem cell transplantation from 6/00 to 5/01. Patients received either
      G-CSF alone (10 microg/kg per day, n=11) or etoposide (2 g/m(2)) plus G-CSF
      (n=33) for progenitor cell mobilization. The patients were apheresed for 2-10
      days (median 3) to reach a minimum of 2.0 x 10(6) CD34(+) cells/kg. Patients
      receiving G-CSF alone mobilized significantly more total DC2s than did those
      receiving etoposide plus G-CSF (median 6.2 x 10(6)/kg vs 2.9 x 10(6)/kg,
      P=0.001). The DC2/DC1 ratio was also significantly different in the two groups,
      with the G-CSF group having a higher ratio (median 1.2 vs 0.4, P<0.001). We
      conclude that the combination of chemotherapy plus G-CSF yields different
      mobilized dendritic cell subsets than does G-CSF alone.

PMID- 12621491
TI  - Unrelated bone marrow transplantation for Epstein-Barr virus-associated T/NK-cell
      lymphoproliferative disease.
AB  - Epstein-Barr virus (EBV)-associated T/NK-cell lymphoproliferative disease (LPD)
      has been linked to several different disorders, including chronic active EBV
      infection, EBV-associated hemophagocytic syndrome, hypersensitivity to mosquito
      bites, hydroa vacciniforme, aggressive NK-cell leukemia, and nasal/nasal-type NK
      cell lymphoma. In most instances, these disorders are refractory to conventional
      treatments and have a poor prognosis. Here, we report a new treatment strategy
      for EBV-associated T/NK-cell LPD, consisting of immunochemotherapy, intensive
      combination chemotherapy, and stem cell transplantation. The five patients
      studied, two with T-cell and three with NK-cell LPD, lacked a human leukocyte
      antigen-matched, related donor, and therefore received bone marrow grafts from
      HLA-matched, unrelated donors. The preconditioning regimen consisted of total
      body irradiation (12 Gy), etoposide (900 mg/m(2)), and cyclophosphamide (120
      mg/kg) or melphalan (210 mg/m(2)). All patients had residual LPD by a
      quantitative PCR technique prior to transplantation. After unrelated bone marrow
      transplantation (UBMT), four of the five patients remain in continuous complete
      remission at a median of 19 months, without detectable EBV-DNA in peripheral
      blood. Thus, UBMT appears to be a reasonable option for the treatment of patients
      with EBV-associated T/NK-cell LPD. Detection of EBV-DNA by PCR offers an
      important tool for assessing minimal residual disease in patients with EBV
      associated T/NK-cell LPD.

PMID- 12621490
TI  - Mobilization of peripheral blood progenitor cells with vinorelbine and
      granulocyte colony-stimulating factor in multiple myeloma patients is reliable
      and cost effective.
AB  - Cyclophosphamide with granulocyte colony stimulating factor (G-CSF) is commonly
      used to mobilize stem cells in multiple myeloma. Timing of collection is variable
      and incidence and severity of side effects is substantial. To optimize timing of
      collection, to reduce side effects and to limit costs of the procedure, we
      evaluated vinorelbine, a drug shown to have activity in multiple myeloma, in
      combination with G-CSF as mobilizing regimen. A total of 19 consecutive patients
      with advanced stage multiple myeloma received one dose of vinorelbine 35 mg/m(2)
      intravenously on day 1 in an outpatient setting and G-CSF 10 microg/kg/day from
      day 4 divided in two daily doses. Median CD34+ cell blood counts measured on day
      8 of mobilization were 142 x 10(6)/l (range 57-467). One 15-l apheresis on day 8
      resulted in sufficient stem cells (median 11.1 x 10(6) CD34+ cells/kg, range 6.2
      36.0 prior and median 7.5 x 10(6) CD34+ cells/kg, range 4.0-20.2 post-positive
      CD34+ cell selection) for transplantation. Hematopoietic recovery was swift with
      ANC >0.5 x 10(9)/l on day 11 median (range 10-15) and platelets >20 x 10(9)/l on
      day 12 median (range 10-15) after reinfusion of the stem cells on day 0. No
      episodes of febrile neutropenia were observed during mobilization. In our
      institutions cost reduction for the procedure was about 1700 euros compared to
      the mobilization with cyclophosphamide and G-CSF. Vinorelbine and G-CSF allow
      precise timing and harvesting of sufficient stem cells, and might be an
      alternative to cyclophosphamide in the mobilization of stem cells for autologous
      transplantation in multiple myeloma.

PMID- 12621493
TI  - Influence of intestinal decontamination using metronidazole on the detection of
      methanogenic Archaea in bone marrow transplant recipients.
AB  - Methane-forming microbes of the phylogenetic domain Archaea are part of the
      strictly anaerobic microflora of the human intestine. In bone marrow transplant
      (BMT) recipients, the regimen of intestinal decontamination with metronidazole is
      targeted to anaerobic bacteria. The effect on the anaerobic methanoarchaea,
      however, is unknown. Therefore, the faeces of patients undergoing BMT were
      investigated for methane production. The anoxic Hungate technique and an archaeal
      growth medium were used to culture faecal specimens. Methane production was
      measured in the head space of the culture bottles by gas chromatography using a
      thermal conductivity detector. In a testing serial specimen of 100 patients, 13
      patients were found to bear methanogens, and 11 of these patients received
      metronidazole. The methane-producing faecal specimens occurred before
      metronidazole use in three patients, during the first week in five patients, and
      after cessation in three patients. No specimen of the 11 patients that was
      obtained during the 2nd-5th week of gut decontamination showed methane
      production. It is concluded that use of metronidazole directed against faecal
      anaerobic bacteria also suppresses or eliminates faecal methanogenic Archaea.

PMID- 12621492
TI  - Engraftment syndrome after autologous hematopoietic stem cell transplant
      supported by granulocyte-colony-stimulating factor (G-CSF) versus granulocyte
      macrophage colony-stimulating factor (GM-CSF).
AB  - The engraftment syndrome (ES) is a phenomenon observed in some patients
      undergoing autologous hematopoietic stem cell transplant (AHSCT). ES is
      characterized by fever, rash, capillary leak, and pulmonary infiltrates occurring
      at the onset of engraftment. Prior studies have suggested that the administration
      of hematopoietic growth factors post-transplant results in the increased
      frequency of ES. However, the relative contribution of granulocyte colony
      stimulating factor (G-CSF) vs granulocyte-macrophage colony-stimulating factor
      (GM-CSF) to the development of ES remains unknown. A total of 152 consecutive
      patients who were treated with high-dose chemotherapy and AHSCT supported by
      either G-CSF or GM-CSF were analyzed retrospectively. In all, 20 patients
      developed ES, an incidence of 13%. ES was seen more frequently in patients who
      received GM-CSF (GM-CSF 24% vs G-CSF 4%, p=0.0001). The highest incidence of ES
      was observed in breast cancer patients (42% of breast cancer patients; 70% of all
      ES cases). Comparison of the incidence of ES by the priming regimen used
      comprising either of the growth factors revealed no significant association
      (p=0.8224). This study demonstrates that the incidence of ES is higher using GM
      CSF, particularly in patients with breast cancer. It suggests that it might be
      advantageous to administer only G-CSF in breast cancer patients undergoing AHSCT
      to reduce ES-related morbidity.

PMID- 12621494
TI  - Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation
      with CD3+ T-cell-depleted graft.
AB  - In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using
      unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and
      disease control has not been defined. In a study of 116 patients (92 matched, 24
      mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions
      of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were
      prospectively investigated. T cells were administered while patients were on
      cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had
      not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients
      before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%)
      patients without DLI and 44 of 72 (61%) patients who received DLI developed
      chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of
      chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were
      27 and 21%, respectively. The 2-year incidence of relapse was 14%. In
      multivariate analysis, only chronic GVHD was a good prognostic factor for both
      OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and
      chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9
      for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of
      transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two
      most common causes of 1-year non-GVHD death were viral infection (9%) and
      idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low,
      the study suggests that the current scheme of DLI in unrelated TCD-BMT would not
      improve survival unless TRM decreases significantly.

PMID- 12621495
TI  - Acute graft-versus-host disease (aGVHD) presenting with an acquired lupus
      anticoagulant.
AB  - There are few reports describing the association between antiphospholipid
      antibodies, including the lupus anticoagulant, and bone marrow or peripheral stem
      cell transplantation. Autoimmune syndromes and autoantibodies such as lupus
      anticoagulant and anticardiolipin antibodies have been described following
      allogeneic bone marrow or peripheral blood stem cell transplantation,
      particularly in patients who develop chronic graft-versus-host disease (GVHD).
      The association between Lupus anticoagulant and acute GVHD has not been
      previously described. We report a patient who developed a de novo lupus
      anticoagulant on day +34 after a matched-related allogeneic peripheral stem cell
      transplant. No clinical evidence of systemic thrombosis was observed and the
      lupus anticoagulant disappeared following immunosuppressive therapy with a
      combination of steroids and infliximab.

PMID- 12621496
TI  - Successful unrelated cord blood transplantation in two children with severe
      combined immunodeficiency syndrome.
AB  - We describe the successful unrelated cord blood transplantation in two patients
      affected by a Zap-70 deficiency and an Omenn-like syndrome, respectively. The
      patients were hospitalised for recurrent infections at the age of 13 and 2
      months, respectively. An unrelated cord blood unit was found for each. The
      conditioning regimen was cyclophosphamide, busulfan and antithymocyte globulin.
      The total number of infused cells was 15.1 x 10(7)/kg and 17 x 10(7)/kg,
      respectively. Neutrophil engraftment was achieved on days +15 and +23, and
      platelet count >50 x 10(9)/l was achieved on days +21 and +52, respectively. One
      patient presented acute Graft-versus-host disease (GVHD) grade I and the other
      grade III. Chimerism was mixed and full donor. Normal lymphoproliferative
      response to mitogens and alloantigens was detectable at 6 months for both. No
      chronic GVHD was observed in either. The patients are alive and well at 53 and 15
      months after transplantation. In conclusion, umbilical cord blood represents a
      valid alternative source of haemopoietic stem cells.

PMID- 12621497
TI  - Split chimerism after allogeneic bone marrow transplantation in Chediak-Higashi
      syndrome.
AB  - Chediak-Higashi Syndrome (CHS) is a hereditary multiorgan disease associated with
      a lymphoproliferative disorder termed 'accelerated phase' (AP). As AP is often
      life-threatening, hematopoietic stem cell transplantation has been proposed as
      the only curative treatment for CHS. Here, we report a 1-year-old Japanese boy
      with CHS who received an HLA-matched unrelated BMT at the AP stage, which
      resulted in split chimerism. We evaluated the chimerism status of isolated
      leukocytes and found that only a limited population of T and NK cells was of
      donor origin and the majority of these and other hematopoietic cells was of host
      origin. Clinical outcome was successful, and the patient is currently alive and
      well, free of AP and serious infections more than 18 months after BMT.

PMID- 12621498
TI  - Prolonged survival associated with early lymphocyte recovery after autologous
      hematopoietic stem cell transplantation for patients with metastatic breast
      cancer.

PMID- 12621500
TI  - Mucosal injury in patients undergoing hematopoietic progenitor cell
      transplantation: new approaches to prophylaxis and treatment.
AB  - Hematopoietic progenitor cell transplantation is often associated with severe
      mucosal toxicity. The need for parenteral analgesics and parenteral nutrition are
      evidence of the severity of the problem in individual patients. However, the
      increased risk for systemic infection related to bacteremia associated with the
      breakdown of mucosal barriers is a significant cause of morbidity and mortality
      as well. There is a multitude of grading scales, demonstrating the lack of
      consensus among clinicians in this area. Multiple agents have been used
      prophylactically and therapeutically to address mucositis. While efforts have
      been less successful in the past, the advent of newer agents including
      amifostine, keratinocyte growth factor, transforming growth factor beta and
      interleukin-11 provides hope that this toxicity will be significantly decreased
      in the near future.

PMID- 12621501
TI  - Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and
      maintains effective graft-versus-leukemia effect after allogeneic stem cell
      transplantation in murine lymphocytic leukemia.
AB  - Graft-versus-host disease (GVHD) is a severe disorder and despite therapeutic
      efforts to decrease its distressing clinical manifestations, treatment is still
      not optimal. Here we report the results of studies, in which the purine analogue,
      fludarabine phosphate, was used in an attempt to modify and decrease GVHD after
      stem cell transplantation, across major histocompatibility barriers for murine
      leukemia. B-cell leukemia (BCL-1) bearing (BALB/c x C57BL/6) F1 mice received two
      cycles of fludarabine (0.8 mg/kg) for 5 days every 2 weeks, followed by 400 mg/kg
      cyclophosphamide i.p. Animals were then transplanted with C57BL/6 precursor cells
      and the development of leukemia and extent of GVHD was monitored both clinically
      and histopathologically. In the fludarabine-treated group, only nine of 28 (32%)
      mice developed leukemia, compared to 25 of 33 (76%) of control animals (P=0.0006
      ). Mice treated with fludarabine-containing regimens prior to transplantation
      also had much less GVHD both clinically and at autopsy, while graft-versus
      leukemia appeared to be augmented in the same animals.

PMID- 12621502
TI  - Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral
      blood stem cells.
AB  - We have evaluated the feasibility of large-scale isolation of CD133+ progenitors
      from healthy mobilized adult donors for potential clinical use in autologous and
      allogeneic transplantation. A total of 11 healthy volunteer adult donors were
      mobilized with G-CSF. CD133+ stem cells were isolated from a single leukapheresis
      using the Clinimacs method. The median percentage of CD133 before positive
      selection was 0.75% (range 0.39-2.03%). After selection, the median purity and
      recovery was 94% (range 85.2-98.0%) and 69% (range 44-100%), respectively. The
      median log10 T-cell depletion obtained by CD133+ positive selection was 4.2
      (range 3.8-4.7). The CD133+ progenitors were highly enriched in colony-forming
      units (CFU) and transplantation into NOD/SCID mice resulted in a high engraftment
      rate. Transplantation of sorted CD133+/CD34+ cells into NOD/SCID mice showed a
      higher engraftment compared to CD133-/CD34+ cells. Mobilized peripheral CD133+
      stem cells can be purified in large scale for potential clinical use. The
      biological function of the cells is not impaired. The majority of the NOD/SCID
      repopulating cells are within the CD133+/CD34+ subpopulation. Therefore, clinical
      studies using purified CD133+ stem cells can be envisoned to further clarify the
      role of CD133+ stem cells in hematopoietic reconstitution after transplantation.

PMID- 12621504
TI  - Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells
      can affect the early reconstitution phase of naive T cells after autologous
      transplantation.
AB  - Transient T cell immunodeficiency is a common complication following
      hematopoietic stem cell transplantation. In breast cancer patients transplanted
      with autologous peripheral blood progenitor cells (PBPC) harvested after
      cytotoxic treatment with either cyclophosphamide or epirubicin plus paclitaxel,
      we evaluated T cells infused in grafts and in peripheral blood during the early
      reconstitution phase. We found that PBPC grafts harvested after treatment with
      epirubicin plus paclitaxel contained substantially larger numbers of T cells with
      less altered composition than after cyclophosphamide. Three months after high
      dose cytotoxic chemotherapy, the numbers and the kinetics of circulating naive T
      cells, but not of memory and CD28- T cells, correlated positively with the number
      of naive T cells infused PBPC grafts. Finally, retrospective analysis of two
      cohorts of patients transplanted in different clinical settings with PBPC grafts
      harvested following cyclophosphamide or epirubicin plus paclitaxel showed
      apparently different susceptibilities to develop endogenous varicella zoster
      virus reactivation in the first year after high-dose cytotoxic chemotherapy. On
      the whole, these data indicate that number and composition of T cells in PBPC
      grafts vary according to the former cytotoxic therapy, and suggest that
      autologous transfer of T cells may accelerate the early T cell reconstitution
      phase and possibly ameliorate immune competence in patients rendered lymphopenic
      by high-dose chemotherapy.

PMID- 12621503
TI  - Patients with acute lymphoblastic leukaemia allografted with a matched unrelated
      donor may have a lower survival with a peripheral blood stem cell graft compared
      to bone marrow.
AB  - We analysed data for 213 patients with ALL and AML who received either peripheral
      blood stem cells (PBSC) (n=74) or bone marrow (BM) (n=139) from an HLA-matched
      unrelated donor (EBMT acute leukaemia registry; January 1994 to January 1999).
      The two groups of patients (by cell source) were comparable with respect to age,
      sex, disease status, year at transplant and graft T cell depletion. Engraftment
      was achieved in about 90% regardless of stem cell source or leukaemia type.
      Kinetics of neutrophil and platelet recovery, similar for both sources in ALL
      patients, were faster for PBSC in AML patients. The incidence of acute graft
      versus-host disease was similar for both sources in AML patients, but higher for
      PBSC in ALL patients (74 vs 54%, P=0.05). The 1-year probability of chronic graft
      versus-host disease was 40 and 45% (P=0.66) in ALL patients compared to 49 and
      35% (P=0.13) in AML patients (PBSC vs BM). In AML patients, none of the following
      differed significantly with cell source: transplant-related mortality, relapse
      incidence, leukaemia-free survival and overall survival. In ALL patients, the
      transplant-related mortality for PBSC vs BM was 61 vs 47% (P=0.13), the relapse
      incidence was 47 vs 39% (P=0.17), the leukaemia-free survival was 21 vs 32%
      (P=0.04) and the overall survival was 24 vs 34% (P=0.04). These data suggest that
      the short-term outcome of allogeneic PBSC is not significantly different from
      that of BM in AML patients who underwent a transplant from a matched unrelated
      donor but, conversely, that survival with PBSC may be decreased in ALL patients.
      In conclusion, the source of transplant cells needs to be evaluated by disease,
      especially when dealing with unrelated donors.

PMID- 12621505
TI  - Donor lymphocyte infusions in adult haploidentical transplant: a dose finding
      study.
AB  - Haploidentical transplantation has become a clinical option for patients lacking
      a compatible donor. However, patients are still referred at advanced stages and
      are usually heavily pretreated. This results in a high risk of toxicity, relapses
      and infections. We therefore started a donor lymphocyte infusion (DLI) dose
      finding protocol, to try to improve both relapse rate and immunity
      reconstitution. In all, 12 consecutive patients were investigated. All had a
      refractory, some progressive, disease. Conditioning consisted of TBI, melphalan,
      ATG, fludarabine and CSA pretransplant. In four rapidly progressive patients, Ara
      C had to be given 1 week preconditioning. The graft was T- and B-cell depleted
      with a fixed reinfused CD3 dose of 5 x 10(4)/kg. All patients engrafted before
      day 20. G-CSF was given from day 5 post-transplant and replaced with GM-CSF in
      the last three patients. Nonrelapse related mortality was 0/12 at 1 year. DLI
      were started at day 28 (3 x 10(4) CD3/kg) in the two first patients. This
      resulted in acute graft-versus-host disease (aGVHD) and chronic graft-versus-host
      disease (cGVHD) in both, but they did not relapse. The next dose was 1 x 10(4)/kg
      monthly for 3 months. This was well tolerated with only one grade I GVHD. Given
      the high relapse rate, we escalated doses (1, 3 and 10 x 10(4)/kg). This produced
      GVHD in all. We next moved, to GM-CSF and 1 x 10(4) CD3/kg monthly. Overall, 6/12
      patients relapsed and received therapeutic DLI, starting at 1 x 10(5) CD3/kg with
      escalation every 2 weeks. We conclude that prophylactic DLI are feasible in adult
      haploidentical transplantation, without GVHD at a monthly dose of 1 x 10(4)
      CD3/kg. They result in faster CD4 recovery and a low rate of infections. The
      impact of GM-CSF remains to be further investigated. This scheme seems ideal for
      patients transplanted early in the course of their disease. In very bad prognosis
      patients, it remains insufficient to rapidly induce a GVL effect. Escalated doses
      are feasible but the price is aGVHD. Therapeutic DLI can be given at higher
      doses, depending on the time post-transplant. Haploidentical transplantation with
      low-dose DLI is a safe procedure that should be considered in all patients
      needing a transplant, but lacking a matched donor, early in the course of the
      disease.

PMID- 12621506
TI  - Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative
      transplantation for haematological malignancies.
AB  - Most bone marrow transplant recipients are infertile due to reversible or
      irreversible testicular failure. However, little is known about the gonadotoxic
      potential of the newly introduced nonmyeloablative transplants. We undertook a 24
      month longitudinal study in a cohort of 32 recipients of nonmyeloablative
      transplantation to test whether the combined regimen of fludarabine, melphalan
      and CAMPATH-1H can induce damage to germ cell (GC) and Leydig cell (LC)
      compartments. Testicular function was assessed immediately prior to
      transplantation and at four time points post-transplant to compare hormonal
      levels before and after the procedure. Two other groups treated with BEAM- and
      TBI-related regimes were also included in the study group for comparative
      purposes. GC function was assessed by measuring basal serum follicle stimulating
      hormone (FSH). LC function was assessed by measuring basal luteinising hormone
      (LH) and testosterone (T) levels. LC reserve was assessed by measuring the T/LH
      ratio. As a group, patients who received a non myeloablative transplant sustained
      severe damage to the GC compartment, as evident from a substantial elevation in
      the FSH level post-transplant (12 IU/l vs 18.4 IU/l, P<0.001). Similar to the GC
      injury, patients as a group sustained significant damage to the LC compartment
      following the transplant (5.4 IU/l vs 9.6 IU/l, P<0.001). In general, patients
      had reduced LC reserve post-BMT, as evident from a diminished T/LH ratio (2.6
      pretransplant vs 1.6 post-transplant P=0.05). Patients who received a
      nonmyeloablative transplant had a similar effect on the GC and LC compartments
      compared to those who had a BEAM autograft. On the other hand, patients who
      received a TBI-based transplant sustained more damage to their GC and LC
      compartments compared to those who received a nonmyeloblative transplant;
      however, this was not statistically significant (P=0.09). Our data suggest that
      this type of regimen is potentially gonadotoxic and consideration should be given
      to fertility counselling and testosterone replacement therapy post-transplant.

PMID- 12621507
TI  - Clinical utility of oral valacyclovir compared with oral acyclovir for the
      prevention of herpes simplex virus mucositis following autologous bone marrow
      transplantation or stem cell rescue therapy.
AB  - Oral acyclovir has been demonstrated to prevent reactivation of herpes simplex
      virus (HSV) infections when administered prophylactically to autologous bone
      marrow transplant (BMT) recipients or patients undergoing stem cell rescue
      therapy. Oral valacyclovir, which is converted in the body to acyclovir, has
      greater oral bioavailability than oral acyclovir and compared with oral acyclovir
      yields similar acyclovir plasma concentrations with less frequent (twice-daily)
      dosing. This study compared the efficacy of oral valacyclovir with that of oral
      acyclovir at preventing HSV mucositis in BMT recipients. A total of 60 HSV-1
      positive patients scheduled for BMT or stem cell rescue therapy were treated
      prophylactically with valacyclovir 500 mg twice daily until resolution of
      neutropenia. Data from these patients were compared with those of a historical
      control group of 60 patients who had received acyclovir 600 mg every 6 h until
      resolution of neutropenia or acyclovir 125 mg/m(2) intravenously every 6 h. The
      results show that none of the patients developed oral or oropharyngeal HSV
      infection while receiving either treatment. Of the 60 patients receiving
      valacyclovir, 38 (63%) completed treatment without the need for intravenous
      acyclovir compared with 12 of 60 (20%) patients in the acyclovir group.
      Additionally, the total number of doses of drug administered to the valacyclovir
      group was significantly less than the number received by patients in the
      acyclovir group. No serious adverse events occurred in either group of patients.
      This study demonstrates that oral valacyclovir and acyclovir are comparably
      effective and safe in preventing reactivation of HSV infections in autologous BMT
      and stem cell recipients. The less frequent dosing schedule with valacyclovir
      compared with acyclovir offers a potential advantage for patients undergoing BMT
      who frequently suffer with severe mucositis and have difficulty taking oral
      medications.

PMID- 12621508
TI  - Fatal chemotherapy-induced encephalopathy following high-dose therapy for
      metastatic breast cancer: a case report and review of the literature.
AB  - Chemotherapy-induced encephalopathies occur in a variety of clinical settings and
      the most detailed accounts have been described following combination methotrexate
      and radiation therapy. The case described herein developed severe encephalopathy
      following a high-dose chemotherapy protocol used in the treatment of metastatic
      carcinoma of the breast. Visual symptoms developed 3 weeks after completing high
      dose chemotherapy and peripheral blood hematopoietic stem cell transplantation.
      Over the next several weeks, additional neurologic deficits developed and
      continued to progress despite various treatment interventions. Diffuse deep gray
      matter damage was identified on MR imaging and a brain biopsy revealed
      pathological findings similar in many respects to those described for
      methotrexate/radiation, cisplatin, BCNU and/or 5 FU/levamisole-related
      leukoencephalopathy. The patient succumbed to complications resulting from the
      CNS disorder, 8 weeks after the onset of symptoms. This case is unusual for two
      reasons. First, the patient developed severe encephalopathy following a high-dose
      chemotherapy protocol commonly used in the treatment of metastatic breast
      carcinoma and second, the encephalopathy involved primarily deep gray matter
      structures rather than white matter.

PMID- 12621509
TI  - Central and extrapontine myelinolysis following allogeneic peripheral
      haematopoietic progenitor cell transplantation. Favourable outcome in a patient
      with chronic myeloid leukaemia.
AB  - A 48-year-old-man in the first chronic phase of chronic myeloid leukaemia
      developed a central nervous system complication on day +57 after HLA-identical
      peripheral blood progenitor cell (PBPC) transplantation. The clinical picture
      evolved to a reversible pseudobulbar palsy requiring mechanical ventilation. MRI
      examination disclosed lesions typical of central and extrapontine myelinolysis
      (CEPM), which disappeared on a repeat examination 20 days later. The patient had
      received cyclosporine A (CsA) as GVHD prophylaxis and severe hyponatremia was
      detected 7 days after the first neurological sign. CEPM has been described in
      alcohol-induced liver disease, following rapidly corrected hyponatremia and
      associated with CsA in orthotopic liver transplantation. This is the first
      reported case of CEPM in PBPC transplantation, and CsA seems to have played a
      role in the development of this very serious complication.

PMID- 12621510
TI  - Successful treatment of meningoencephalitis caused by methicillin-resistant
      Staphylococcus aureus with intrathecal vancomycin in an allogeneic peripheral
      blood stem cell transplant recipient.
AB  - Methicillin-resistant Staphylococcus aureus (MRSA) is a common infectious
      pathogen during stem cell trans-plantation. We report a case of
      meningoencephalitis with multiple abscess formation caused by MRSA, which
      occurred in a 4-year-old boy soon after allogeneic peripheral blood stem cell
      transplantation. We successfully cured the infection with a combination of
      intravenous and intrathecal vancomycin.

PMID- 12621511
TI  - Granulocyte transfusion as a treatment for enterococcal meningoencephalitis after
      allogeneic bone marrow transplantation from an unrelated donor.
AB  - Bacterial meningoencephalitis occurring in the pre-engraftment period after bone
      marrow transplantation (BMT) is a rare complication, and the feasibility of
      granulocyte transfusion (GTX) in such cases remains to be elucidated. A 37-year
      old man developed enterococcal meningoencephalitis during a severely
      granulocytopenic pre-engraftment period after BMT. Despite therapy with
      appropriate antibiotics, cultures of blood and cerebro-spinal fluid (CSF)
      continued to grow Enterococcus faecalis, and he developed rapid mental
      deterioration and seizure. Granulocytes were collected from his HLA-mismatched,
      ABO-matched sibling with subcutaneous injection of granulocyte colony-stimulating
      factor (G-CSF) and oral dexamethazone. Transfusion of 4.4 x 10(10) granulocytes
      resulted in a 12-h post-transfusion granulocyte increment of 2.0 x 10(9)/l, and
      maintained peripheral blood granulocyte counts above 0.5 x 10(9)/l for 3 days. A
      rapid increase of granulocytes in CSF was also observed, and cultures of blood
      and CSF became negative after GTX. A transient worsening of seizure was observed
      as a potential side effect of GTX. The patient subsequently developed septic
      shock because of Pseudomonas aeruginosa and died. Further studies are warranted
      to evaluate the clinical efficacy of GTX for the treatment of uncontrolled
      infections in granulocytopenic stem cell transplant recipients.

PMID- 12621512
TI  - Toxicology and Carcinogenesis Studies of g-Butyrolactone (CAS No. 96-48-0) in
      F344/N Rats and B6C3F1 Mice (Gavage Studies).
AB  - g-Butyrolactone is an intermediate in the synthesis of polymers used as film
      formers in hair sprays, blood plasma extenders, and clarifying agents in beer and
      wine. Toxicology and carcinogenesis studies were conducted by administering g
      butyrolactone (greater than 97% pure) in corn oil by gavage to groups of F344/N
      rats and B6C3F1 mice of each sex, 5 days per week for 16 days, 13 weeks, and 2
      years. Genetic toxicology studies were conducted in Salmonella typhimurium,
      Drosophila melanogaster, and Chinese hamster ovary cells. 16-Day Studies: Groups
      of five rats of each sex received doses of 0, 75, 150, 300, 600, or 1,200 mg of g
      butyrolactone per kg of body weight and groups of five mice of each sex received
      doses of 0, 87, 175, 350, 700, or 1,400 mg/kg. All male and female rats given
      1,200 mg/kg and one male rat given 600 mg/kg died within 3 days. The mean body
      weight gain of female rats given 600 mg/kg was significantly lower than that of
      the controls. Mean body weight gains of the other female dose groups and all male
      dose groups were similar to those of the controls. All of the male and four
      female mice receiving 1,400 mg/kg died during the studies. Mean body weight gains
      of dosed mice were generally similar to those of the controls. Rats receiving 600
      or 1,200 mg/kg and mice receiving 350 mg/kg or more became inactive or recumbent
      with irregular respiration following dosing. 13-Week Studies: Groups of 10 rats
      of each sex received doses of 0, 56, 112, 225, 450, or 900 mg of g-butyrolactone
      per kg of body weight and groups of 10 mice of each sex received doses of 0, 65,
      131, 262, 525, or 1,050 mg/kg. One female and all male rats given 900 mg/kg died
      during the studies. The final mean body weight and mean body weight gain of male
      rats receiving 450 mg/kg were significantly lower than those of the controls;
      final mean body weights and body weight gains of all female rat dose groups were
      similar to those of the controls. There was an increased incidence of focal
      inflammation of the nasal mucosa in rats administered g-butyrolactone. Three male
      mice and one female receiving 1,050 mg/kg died from g-butyrolactone toxicity
      during the studies. The mean body weight gain and final mean body weight of high
      dose male mice were lower than those of the controls; the mean body weight gains
      and final mean body weights of dosed female mice were similar to those of the
      controls. No lesions related to the administration of g-butyrolactone occurred in
      mice of either sex. 2-Year Studies: The doses administered to groups of 50
      animals per sex were 0, 112, and 225 mg ofg-butyrolactone per kg of body weight
      for male rats; 0, 225, and 450 mg/kg for female rats; and 0, 262, and 525 mg/kg
      for male and female mice. Body Weight and Survival in the 2-Year Studies: The
      mean body weights of male rats administered g-butyrolactone were similar to those
      of the controls throughout the study. The mean body weight of high-dose females
      was lower than that of the controls after week 5 and was 10% to 20% lower than
      that of the controls throughout the second year. The survival of high-dose male
      rats was slightly higher than that of the controls (control, 24/50; low-dose,
      27/50, high-dose, 32/50) due primarily to a lower incidence of mononuclear cell
      leukemia in the high-dose group (16/50, 15/50, 9/50). The survival of dosed
      females was similar to that of the controls (28/50, 27/50, 28/50). The mean body
      weights of dosed male mice were lower than those of the controls throughout the
      study, but the differences in mean body weights decreased when male mice were
      housed individually at week 67. The final mean body weights of dosed male mice
      were 6% lower than that of the controls. Mean body weights of dosed female mice
      were also lower than those of the controls throughout the study, and the final
      mean body weights were from 14% to 17% lower than that of the controls. The
      survival in high-dose male mice was significantly lower than that of the controls
      (35/50, 30/50, 12/50) due to bite wounds and fighting in high-dose males
      recovering from the sedative effects of g-becovering from the sedative effects of
      g-butyrolactone. The survival of female dosed mice was similar to that of the
      controls (38/50, 34/50, 38/50). Neoplasms and Nonneoplastic Lesions in the 2-Year
      Studies: No increased incidences of neoplasms or nonneoplastic lesions in male
      rats were related to the administration of g-butyrolactone for 2 years. In female
      rats, negative trends were observed in the incidences of cysts (42/50, 35/50,
      23/50) and fibroadenomas of the mammary gland (22/50, 14/50, 6/50) and in cysts
      of the pituitary pars distalis (25/49, 13/37, 11/48). These decreases were
      considered to be related to g-butyrolactone administration. Increased incidences
      of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low
      dose male mice were associated with g-butyrolactone administration
      (pheochromocytoma, benign or malignant: 2/48, 6/50, 1/50; hyperplasia: 2/48,
      9/50, 4/50). The incidence of hepatocellular neoplasms in both dose groups of
      male mice was lower than the incidence in the controls (hepatocellular adenoma or
      carcinoma: 24/50, 8/50, 9/50). Genetic Toxicology: g-Butyrolactone was not
      mutagenic, with or without exogenous metabolic activation (S9), in Salmonella
      typhimurium strains TA98, TA100, TA1535, and TA1537, nor did it induce sex-linked
      recessive lethal mutations in germ cells of male Drosophila melanogaster when
      administered in feed or by injection. Positive results were obtained, however, in
      cytogenetic tests with Chinese hamster ovary cells; g-butyrolactone induced
      sister chromatid exchanges and chromosomal aberrations in trials conducted in the
      presence of S9 activation. Conclusions: Under the conditions of these 2-year
      gavage studies, there was no evidence of carcinogenic activity of g-butyrolactone
      in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or
      450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of g
      butyrolactone in male B6C3F1 mice based on marginally increased incidences of
      adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The
      sensitivity of the study in male mice to detect a carcinogenic effect was reduced
      by the low survival of the high-dose group associated with fighting. There was no
      evidence of carcinogenic activity of g-butyrolactone in female B6C3F1 mice given
      262 or 525 mg/kg in corn oil. A decreased incidence of hepatocellular neoplasms
      in dosed male mice and decreased incidences of mammary gland fibroadenomas and
      cysts and pituitary cysts in female rats were associated with the administration
      of g-butyrolactone. Synonyms: Dihydro-2(3H)-furanone (8CI) (9CI), 1,2-butanolide,
      butyrolactone, 1,4-butanolide, 4-butyrolactone, 4-hydroxybutanoic acid lactone, g
      hydroxybutyric acid cyclic ester, g-hydroxybutyric acid lactone, g-lactone 4
      hydroxy-butanoic acid, butyric acid lactone, butyryl lactone, 4-hydroxybutyric
      acid lactone, tetrahydro-2-furanone, 4-butanolide, 4-deoxytetronic acid, g
      hydroxybutyrolactone

PMID- 12621513
TI  - Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in
      F344/N Rats (Drinking Water Studies).
AB  - C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year
      carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye
      Initiative. This Initiative was designed to evaluate representative benzidine
      congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid
      Red 114 was nominated for study because of the potential for human exposure
      during production of bisazobiphenyl dyes and because benzidine, a structurally
      related chemical, is a known human carcinogen. Toxicology and carcinogenesis
      studies were conducted by administering desalted, industrial grade C.I. Acid Red
      114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks,
      9 or 15 months, or 2 years. These studies were performed only in rats because
      studies of benzidine congeners were being performed in mice at the National
      Center for Toxicological Research (NCTR). Genetic toxicology studies were
      conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila
      melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking
      water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats
      survived except one male rat in the 20,000 ppm dose group. Final mean body
      weights in the three dosed groups were 94%, 83%, or 77% of controls for males and
      92%, 88%, or 80% of controls for females. Water consumption declined with
      increased dose. Clinical findings included red stained fur, ears, and tail in all
      test animals. On gross necropsy, organs and tissues were also stained red. 13
      Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0,
      600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived
      until the end of the study. Final mean body weights in the five dosed groups were
      97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89%
      of controls for females. Water consumption was decreased in dosed animals. As was
      seen in the 13-day studies, major organs and tissues from treated animals were
      stained red. Kidney toxicity characterized by regeneration and karyomegaly of
      tubule epithelial cells with chronic inflammation was observed in female rats at
      doses of 1,200 ppm or above. Treatment-related increases in relative liver
      weights and elevated liver enzyme levels were seen in males and females,
      centrilobular pallor in the liver was seen in all male dose groups. Because of
      these body weight differences, decreases in water consumption, and organ
      toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for
      males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses
      of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150,
      300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in
      the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated
      from the control and high-dose groups at 9 months, and ten animals from all dose
      groups were evaluated at 15 months. The average amount of compound consumed per
      day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival
      and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or
      300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300
      ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died
      by week 89. The decreased survival in treated groups was due primarily to the
      development of chemical-related neoplasms. Of the surviving animals, the final
      mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control
      and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight
      differences began in the second year of the studies and were attributed in part
      to the development of neoplasms in the dosed groups. Histopathologic Effects in
      the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver,
      lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and
      large intestine, and the number of neoplasms at these sites increased as gland,
      skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and
      the number of neoplasms at these sites increased as the studies progressed. At 2
      years, there was a clear carcinogenic response in the skin, Zymbal's gland, and
      liver of male and female rats, and in the clitoral gland, oral cavity epithelium,
      small and large intestine, and lung in female rats. Treatment-related increases
      were also seen in the incidence in neoplasms of the oral cavity epithelium,
      adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in
      neoplasms of the mammary gland and adrenal gland in female rats. The incidence of
      these neoplasms was generally lower, but was significant and considered to be
      marginally related to chemical treatment. The same neoplastic effects have been
      previously observed in some or all of the NTP studies with dimethoxybenzidine,
      dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard
      preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium
      strain TA98 in the presence of induced hamster liver S9, and an equivocal
      response was noted in strain TA100 with hamster liver S9. However, no significant
      mutagenic activity was noted in strains TA1535 or TA1537 with or without S9
      activation. In a modified S. typhimurium gene mutation test which employed
      reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I.
      Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not
      induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster
      ovary cells with or without S9 activation; reductive metabolism was not used in
      these cytogenetic tests. No increase in sex-linked recessive lethal mutations was
      observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red
      114 by feeding or injection. Conclusions: Under the conditions of these 2-year
      drinking water studies, there was clear evidence of carcinogenic activity of C.I.
      Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms
      of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the
      oral cavity epithelium, adrenal gland, and lung may have been related to chemical
      administration. There was clear evidence of carcinogenic activity for female
      F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's
      gland, clitoral gland, liver, oral cavity epithelium, small and large intestines,
      and lung. Increased incidences of mononuclear cell leukemia, mammary gland
      adenocarcinoma, and adrenal gland pheochromocytomas may have been related to
      chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'
      dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4
      yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid
      Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635,
      Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol
      Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI
      C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R,
      Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG,
      Tertracid Milling Red B, Vondamol Fast Red RS

PMID- 12621514
TI  - Toxicology and Carcinogenesis Studies of 5,5-Diphenylhydantoin (CAS No. 57-41-0)
      (Phenytoin) in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - 5,5-Diphenylhydantoin and its sodium salt are primarily used in the treatment of
      grand mal and psychomotor seizures, often in combination with other
      anticonvulsants, including phenobarbital. 5,5-Diphenylhydantoin is a suspected
      human carcinogen and was one of three compounds selected by the NTP to
      investigate the potential value of perinatal exposures in assessing chemical
      carcinogenicity. Chronic toxicity and carcinogenicity studies of 5,5
      diphenylhydantoin were conducted in male and female F344/N rats and B6C3F1 mice.
      The studies were designed to determine the following: a) the effects of 5,5
      diphenylhydantoin in the diet given to rats and mice during the adult (F1) period
      only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of
      5,5-diphenylhydantoin in rats and mice receiving perinatal (F0) exposure only
      (dietary exposure of dams prior to breeding and throughout gestation and
      lactation), and c) the effects of combined perinatal and adult exposure to 5,5
      diphenylhydantoin. Genetic toxicology studies were conducted in Salmonella
      typhimurium, mouse Iymphoma cells, cultured Chinese hamster ovary cells,
      Drosophila melanogaster, and mouse bone marrow cells. STUDIES IN F344/N RATS: A
      13-week toxicity study was conducted to select the exposure levels for adults in
      the 2-year study. The exposure levels for the 13-week study ranged from 300 to
      4,800 ppm 5,5-diphenylhydantoin in the diet. The final mean body weights of males
      and females exposed to 2,400 or 4,800 ppm were significantly decreased. All
      groups showed a net weight gain over the study period, although the mean body
      weight gain of females in the 4,800 ppm group was only one-half that of the
      controls. Feed consumption also decreased with increasing exposure level. No
      chemical-related gross lesions were present in the tissues of exposed rats.
      Microscopically, centrilobular hypertrophy of hepatocytes was observed in the
      liver of rats in the 4,800 ppm groups. Based on these results, 2,400 ppm was
      selected as the highest exposure for the adult-only portion of the 2-year
      carcinogenicity study. A gestational study was performed to select the exposure
      levels for the perinatal portion of the 2-year study. The exposure levels ranged
      from 80 to 2,400 ppm 5,5-diphenylhydantoin in the diet of the dams. The 2,400 ppm
      exposure level was found to have reproductive and embryotoxic effects, as none of
      the sperm-positive females delivered litters. In the 800 ppm group, a greater
      number of pups died between postnatal day 1 and day 28 than in the control group.
      No gross external malformations were observed among fetuses or pups surviving to
      term in any exposure group, and no gross or histopathologic lesions were observed
      in the animals exposed to 800 ppm for 4 weeks following weaning. Based on these
      results, 630 ppm was selected as the highest exposure level for the perinatal
      portion of the 2-year carcinogenicity study. The eight F0:F1 exposure
      combinations selected for the 2-year study are listed in the table (contained in
      full report - page 6). In the 2-year study, male and female rats in the 630:2,400
      ppm groups evaluated at 9 months had increased relative liver weights.
      Hematologic evaluations indicated mild but consistent chemical-related increases
      in erythrocyte and platelet counts in male and female rats. Mild decreases in
      triglyceride concentrations and alanine aminotransferase enzyme activity were
      seen generally in the high-exposure groups. In the 2-year study, the survival of
      exposed rats was similar to that of the controls. However, body weights of
      exposed rats were lower than those of the controls, and body weights were 11% to
      35~ lower in rats receiving adult exposure of 2,400 ppm 5,5-diphenylhydantoin.
      Feed consumption was similar for exposed and control groups. Hepatocellular
      neoplasms, primarily adenomas, occurred with a positive trend in male rats fed
      5,5-diphenylhydantoin only as adults (0:0 ppm, 0/50; 0:800 ppm, 2/50; 0:2,400
      ppm, 4/50). There were no increased neoplasm incidences at other sites in exposed
      males or at any site in exposed females.emales. Perinatal-only or combined
      perinatal and adult exposure to 5,5-diphenylhydantoin did not enhance the overall
      incidences of liver neoplasms in male or female rats. However, the finding of
      5/49 hepatocellular adenomas in the 630:2,400 male rat group was consistent with
      the marginally elevated liver neoplasm rate observed in the 0:2,400 group.
      Decreased incidences of a number of different neoplasms in exposed groups were
      most likely related to the lower body weights. STUDIES IN B6C3F1 MICE: A 13-week
      toxicity study was conducted to select the exposure levels for adults in the 2
      year study. The exposure levels for the 13-week study ranged from 75 to 1,200 ppm
      5,5-diphenylhydantoin in the diet. With the exception of one male, all mice
      exposed to 1,200 ppm died before the end of the study. No other chemical-related
      deaths occurred. All groups of mice except the 1,200 ppm groups gained weight
      over the 13-week period; however, an exposure related decrease in body weight
      gain was seen in males and females. Feed consumption by exposed and control
      groups was generally similar. Chemical related histomorphologic lesions were
      present in the liver of exposed mice, particularly 600 ppm males, and consisted
      of centrilobular hypertrophy of hepatocytes. Females appeared to be less
      sensitive than males to the effects of 5,5-diphenylhydantoin on growth and on
      histomorphologic liver lesions. Based on these results, 300 ppm (males) and 600
      ppm (females) were selected as the highest exposure levels for the adult-only
      portion of the 2-year carcinogenicity study. A gestational study was performed to
      select the exposure levels for the perinatal portion of the 2-year study. The
      exposure levels for males and females ranged from 20 to 600 ppm 5,5
      diphenylhydantoin in the diet. In general, reproductive performance and maternal
      care were poor in all groups, including the controls, thus restricting the sample
      size and sensitivity of this evaluation. There were no litters in the 600 ppm
      group, and maternal weight gain was depressed. There were no gross external
      malformations among pups surviving to term, and no gross or histopathologic
      lesions were observed in any mice exposed for 4 weeks following weaning. Based on
      these results, 210 ppm was selected as the highest exposure level for the
      perinatal portion of the 2-year carcinogenicity study. The F0:F1 exposure
      combinations selected for the 2-year study are listed in the following table
      (contained in full report - page 7). For mice evaluated at 9 months, males and
      females receiving the highest F0:F1 exposure levels had increased relative liver
      weights. In the 2-year study, the survival of exposed animals was similar to that
      of the controls; however, body weights were lower for exposed groups, and
      decreased body weights were most severe in adult females receiving 600 ppm 5,5
      diphenylhydantoin. Feed consumption was similar for exposed and control groups.
      The incidences of hepatocellular neoplasms were increased in female mice
      receiving adult-only exposure (0:0 ppm, 5/48; 0:200 ppm, 14/49; 0:600 ppm, 30/50)
      or combined perinatal and adult exposure (210:200 ppm, 16/50; 210:600 ppm,
      34/50). A marginally increased incidence of liver neoplasms (12/49) occurred in
      females in the perinatal-only (210:0) exposure group. There were no chemical
      related increased incidences of liver neoplasms in males receiving adult-only or
      perinatal-only exposure. However, males receiving the high-exposure combined
      perinatal and adult exposure regimen (210:300 ppm) had an increased incidence of
      liver neoplasms (41/50) compared to the 0:0 (29/50), 0:300 (26/49), and 210:0
      (33/50) groups. As a result, there was a significant enhancement (interaction)
      associated with combined perinatal and adult exposure. Such enhancement of
      neoplasia did not occur in female mice. Decreased incidences of malignant
      neoplasms in exposed groups were most likely related to the lower body weights.
      GENETIC TOXICOLOGY: In general, tests for genotoxic activity of 5,5
      diphenylhydantoin were negative. All in vitro testing was performed in the
      presence and the absence of exogenous metabolic activation (S9). 5,5
      Diphenylhydantoin did not induce mutations in Salmonella typhimurium, in L5178Y
      mouse Iymphoma cells, or in germ cells of male Drosophila melanogaster, nor did
      it induce chromosomal aberrations in cultured Chinese hamster ovary cells. A
      small but statistically significant increase was obtained in the cultured Chinese
      hamster ovary cell test for induction of sister chromatid exchanges in the
      presence of S9; without S9, no increase in sister chromatid exchanges was
      observed. In vivo, 5,5-diphenylhydantoin did not induce micronuclei polychromatic
      erythrocytes or chromosomal aberrations in bone marrow cells of male mice;
      equivocal results were obtained in an in vivo test for induction of sister
      chromatid exchanges in mouse bone marrow cells. CONCLUSIONS: Adult-Only Exposure:
      Under the conditions of these 2-year, adult-only, dietary exposure studies, there
      was equivocal evidence of carcinogenic activity of 5,5-diphenylhydantoin in male
      F344/N rats based on marginally increased incidences of hepatocellular neoplasms.
      There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in female
      F344/N rats given 240, 800, or 2,400 ppm. There was no evidence of carcinogenic
      activity of 5,5-diphenylhydantoin in male B6C3F1 mice given 30,100, or 300 ppm.
      There was clear evidence of carcinogenic activity of 5,5-diphenylhydantoin in
      female B6C3F1 mice based on increased incidences of hepatocellular neoplasms.
      Perinatal-Only Exposure: Perinatal exposure alone (through dietary administration
      of 210 ppm 5,5-diphenylhydantoin during the perinatal period) caused a marginal
      increase in the incidences of hepatocellular neoplasms in female B6C3F1 mice
      evaluated 2 years after cessation of exposure. In male and female F344/N rats,
      exposure to 630 ppm during the perinatal period did not influence the incidences
      of hepatocellular or other neoplasms. Similarly, exposure of male B6C3F1 mice to
      dietary levels of 210 ppm 5,5-diphenylhydantoin during the perinatal period did
      not affect neoplasm incidences. No teratologic effects were observed. Combined
      Perinatal and Adult Exposure: Combined perinatal and adult dietary exposure to
      5,5-diphenylhydantoin confirmed the findings of the increased incidences of
      hepatocellular neoplasms for adult-only exposures in male F344/N rats and female
      B6C3F1 mice, although combined exposure did not enhance these neoplastic effects.
      However, in male B6C3F1 mice, combined perinatal and adult exposure resulted in
      increased incidences of hepatocellular neoplasms (hepatocellular carcinomas and
      multiple adenomas) that were not seen when dietary exposure was limited to the
      adult exposure period only. Synonyms: Diphenylhydantoin; 5,5-diphenyl-2,4
      imidazolidinedione Trade names: Difhydan; Dihycon; Di-Hydan; Di-Lan; Dilabid;
      Dilantin; Ekko; Hydantol; Lehydan; Zentropil

PMID- 12621515
TI  - Toxicology and Carcinogenesis Studies of Resorcinol (CAS No. 108-46-3) in F344
      Rats and B6C3F1 Mice (Gavage Studies).
AB  - Resorcinol is used in the manufacture of adhesives and dyes and as an ingredient
      in pharmaceutical preparations for the topical treatment of skin conditions.
      Toxicity and carcinogenicity studies were conducted by administering resorcinol
      (>99% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each
      sex for 17 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted
      in Salmonella typhimurium, Chinese hamster ovary cells, mouse lymphoma cells, and
      Drosophila melanogaster. 17-Day Studies: Groups of five rats of each sex were
      administered 0, 27.5, 55, 110, 225, or 450 mg/kg resorcinol and groups of five
      mice of each sex were administered 0, 37.5, 75, 100, 300, or 600 mg/kg resorcinol
      in deionized water by oral gavage. No rats died during the studies. All female
      and four male mice receiving 600 mg/kg and one male receiving 300 mg/kg died as a
      result of resorcinol administration. Final mean body weights of dosed rats and
      mice were similar to those of the control groups. No gross or microscopic lesions
      attributable to resorcinol administration were observed. 13-Week Studies: Groups
      of 10 rats of each sex were administered 0, 32, 65, 130, 260, or 520 mg/kg
      resorcinol and groups of 10 mice of each sex were administered 0, 28, 56, 112,
      225, or 420 mg/kg resorcinol in deionized water by oral gavage. All female and
      eight male rats receiving 520 mg/kg and eight mice of each sex receiving 420
      mg/kg resorcinol died of chemical-related toxicity during the studies. The final
      mean body weights of dosed rats and mice were similar to those of the control
      groups. No chemical-related gross or microscopic lesions were observed. 2-Year
      Studies: Doses were selected for the 2-year studies based on the decreased
      survival observed in the 13-week studies. Groups of 60 male rats and male and
      female mice were administered 0, 112, or 225 mg/kg resorcinol in deionized water
      by gavage, five days per week for up to 104 weeks. Groups of 60 female rats were
      initially administered the same doses as male rats, but by week 22 of the study
      16 of the high-dose females had died. Consequently, the female rat study was
      restarted using doses of 0, 50, 100, or 150 mg/kg. After 15 months of exposure
      interim evaluations were performed on 10 animals from each group. No chemical
      related changes in clinical pathology parameters or incidence of neoplasms or
      nonneoplastic lesions were found during the 15-month interim evaluations. Body
      Weights and Survival in the 2-Year Studies: Mean body weights of high-dose male
      rats were 10% to 15% lower than those of the controls from week 87 to study
      termination. Mean body weights of high-dose female rats were 11% to 14% lower
      than those of controls from week 95 to study termination. Mean body weights of
      other dosed rat groups were similar to those of controls. Survival of high-dose
      male and female rats was significantly lower than controls. Decreased survival in
      high-dose groups was attributed to chemical-related toxicity. Mean body weights
      of high-dose female mice were 10% to 15% lower than those of controls from week
      85 to study termination, whereas those of the remaining dosed mouse groups were
      similar to those of the controls. Survival of dosed mice was similar to that of
      controls. Clinical signs suggestive of a chemical-related effect on the central
      nervous system, including ataxia, recumbency, and tremors, were observed in rats
      and mice in the 2-year studies. Neoplasms and Nonneoplastic Lesions in the 2-Year
      Studies: There were no treatment-related increased incidences of neoplasms or
      nonneoplastic lesions in rats or mice administered resorcinol for 2 years.
      Mammary gland fibroadenomas occurred at significantly reduced incidences in all
      exposed groups of female rats (25/50, 14/50, 12/50, 9/50). The incidence of
      subcutaneous fibroma or sarcoma in high-dose male mice was significantly lower
      than for the controls (8/50, 6/50, 1/50). Genetic Toxicity: Resorcinol was not
      mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with
      or without exogenous metabolic activation (S9). Induor without exogenous
      metabolic activation (S9). Induction of trifluorothymidine resistance was
      observed in mouse L5178Y lymphoma cells treated with resorcinol in the absence of
      S9 activation; this test was not performed with S9. Resorcinol induced sister
      chromatid exchanges in Chinese hamster ovary cells with and without S9.
      Resorcinol was positive for induction of chromosomal aberrations in Chinese
      hamster ovary cells in the presence of S9; an equivocal response was obtained in
      this test in the absence of S9. No induction of sex-linked recessive lethal
      mutations was observed in the germ cells of male Drosophila melanogaster when
      resorcinol was administered in the feed, but an equivocal response was observed
      when the chemical was administered by injection. Conclusions: Under the
      conditions of these 2-year gavage studies, there was no evidence of carcinogenic
      activity of resorcinol in male F344/N rats given 112 or 225 mg/kg or female
      F344/N rats given 50, 100, or 150 mg/kg. There was no evidence of carcinogenic
      activity of resorcinol in male or female B6C3F1 mice given 112 or 225 mg/kg.
      Clinical signs suggestive of a chemical-related effect on the central nervous
      system, including ataxia, recumbency, and tremors, were observed in rats and mice
      in the 2-year studies. Synonyms: 1,3-benzenediol; m-dihydroxybenzene; resorcin

PMID- 12621516
TI  - Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats
      and B6C3F1 Mice(Gavage Studies).
AB  - Furan serves as an intermediate in the synthesis and preparation of numerous
      linear polymers used to prepare temperature-resistant structural laminates and to
      prepare copolymers used in machine dishwashing products as alternatives to
      phosphorus- and nitrogen-containing detergents. Toxicology and carcinogenesis
      studies were conducted by administering furan (purity > 99%) in corn oil by
      gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13
      weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella
      typhimurium, Drosophila melanogaster, mouse bone marrow cells, mouse L5178Y
      lymphoma cells, and Chinese hamster ovary cells. 16-Day Studies: Groups of five
      male rats received doses of 0, 5, 10, 20, 40, or 80 mg of furan per kg of body
      weight and groups of five female rats and five mice of each sex received doses of
      0, 10, 20, 40, 80, and 160 mg/kg in corn oil by gavage. All male and female mice
      and female rats that received 160 mg/kg, all male and female rats and all male
      and four female mice that received 80 mg/kg, and three male mice that received 40
      mg/kg died by day 8. Final mean body weights of male rats that received 20 mg/kg
      and of male and female rats that received 40 mg/kg were significantly lower than
      controls. Final mean body weights of male mice that received 10 or 20 mg/kg were
      significantly greater than controls. Mottled and enlarged livers were observed at
      necropsy in male rats that received 20, 40, or 80 mg/kg and in females that
      received 40, 80, or 160 mg/kg. No lesions were observed at necropsy that were
      considered related to furan administration in mice. 13-Week Studies: Groups of 10
      rats of each sex and groups of 10 female mice received doses of 0, 4, 8, 15, 30,
      or 60 mg of furan per kg of body weight, and groups of 10 male mice received
      doses of 0, 2, 4, 8, 15, or 30 mg/kg in corn oil by gavage. Nine male and four
      female rats that received 60 mg/kg died before the end of the studies. There were
      no chemical-related deaths in mice. Final mean body weights of male rats that
      received 15 or 30 mg/kg and female rats that received 60 mg/kg were significantly
      lower than controls. Final mean body weights of male mice that received 60 mg/kg
      were significantly lower than controls. Relative and absolute liver weights in
      both sexes of rats and mice were increased in groups that received furan, as were
      relative and absolute kidney weights in female rats that received furan. Thymus
      weights were decreased in all groups of rats that received furan. Toxic lesions
      of the liver (bile duct hyperplasia, cholangiofibrosis, cytomegaly and
      degeneration of hepatocytes, and nodular hyperplasia of hepatocytes) were
      associated with furan administration in all dose groups of rats; the severity of
      the lesions increased with dose. Kidney lesions (tubule dilatation and necrosis
      of tubule epithelium) were present in rats that received 30 or 60 mg/kg. Thymic
      atrophy and testicular or ovarian atrophy were also observed in rats exposed to
      60 mg/kg furan. Toxic liver lesions (cytomegaly, degeneration, and necrosis of
      hepatocytes) were also present in all groups of furan-exposed mice. Bile duct
      hyperplasia and cholangiofibrosis were observed in groups of mice receiving 30 or
      60 mg/kg. Doses selected for the 2-year studies of rats and mice were based on
      the hepatotoxicity associated with exposure to furan. 2-Year Studies: Groups of
      70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in
      corn oil by gavage 5 days per week for 2 years. After 9 and 15 months of chemical
      exposure, 10 rats per group were evaluated for the presence of treatment
      associated lesions. Groups of 50 mice of each sex received doses of 8 or 15 mg/kg
      furan 5 days per week for 2 years. Body Weight and Survival: Mean body weights of
      male rats that received 8 mg/kg furan were lower than controls from approximately
      week 73 to the end of the study. Survival of male and female rats that received 8
      mg/kg was lower than controls from approximately week 85 to the end of the
      studies as a result of moribund condition associatedassociated with liver and
      biliary tract neoplasms and mononuclear cell leukemia. Mean body weights of male
      and female mice that received 15 mg/kg furan were lower than controls during the
      studies. Survival of low- and high-dose male and high-dose female mice was lower
      than controls from approximately week 80 to the end of the studies as a result of
      moribund condition associated with liver neoplasms. Neoplastic and Nonneoplastic
      Lesions: Cholangiocarcinoma of the liver occurred in all groups of dosed rats
      (males: control, 0/50; low dose, 43/50; mid dose, 48/50; high dose, 49/50;
      females: 0/50; 49/50; 50/50; 48/50) and was present in many rats of each sex at
      the 9- and 15-month interim evaluations (9-month: males - 0/10, 5/10, 7/10,
      10/10; females - 0/10, 4/10, 9/10, 10/10; 15-month: males - 0/10, 7/10, 9/10,
      6/10; females - 0/10, 9/10, 9/10, 7/10). Hepatocellular adenomas or carcinomas
      (combined) were significantly increased in male rats after 2 years of chemical
      administration (1/50, 5/50, 22/50, 35/50) and hepatocellular adenomas were
      significantly increased in female rats (0/50, 2/50, 4/50, 7/50); hepatocellular
      neoplasms were not observed at the 9- or 15-month interim evaluations. Increased
      incidences of numerous nonneoplastic liver lesions were present in rats
      administered furan. These lesions included biliary tract fibrosis, hyperplasia,
      chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic
      vacuolization, degeneration, nodular hyperplasia, and necrosis. The incidence of
      mononuclear cell leukemia was increased in male and female rats that received 4
      or 8 mg/kg furan (males: 8/50, 11/50, 17/50, 25/50; females: 8/50, 9/50, 17/50,
      21/50); the incidence in the 8 mg/kg groups of each sex exceeded the historical
      control ranges for corn oil gavage studies. The severity of nephropathy increased
      with dose and the incidence was significantly increased in all groups of dosed
      rats; this increased severity was accompanied by an associated increased
      incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism). The
      incidence of forestomach hyperplasia was increased in male and female rats
      (males: 1/50, 4/49, 7/50, 6/50; females: 0/50, 2/50, 5/50, 5/50) and the
      incidence of subacute inflammation of the forestomach was increased in female
      rats (0/50, 1/50, 5/50, 6/50). No forestomach neoplasms were observed in males; a
      squamous papilloma was present in one low-dose female. The incidences of
      hepatocellular adenomas and carcinomas were significantly increased in mice
      receiving furan (males: adenoma - 20/50, 33/50, 42/50; carcinoma - 7/50, 32/50,
      34/50; females: adenoma - 5/50, 31/50, 48/50; carcinoma - 2/50, 7/50, 27/50). The
      incidences of numerous nonneoplastic hepatocellular lesions were increased in
      dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis,
      multifocal hyperplasia, and cytoplasmic vacuolization and biliary tract
      dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign
      pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in
      low- and high-dose male and in high-dose female mice (benign pheochromocytoma:
      males - 1/49, 6/50, 10/50; females - 2/50, 1/50, 6/50). The incidences of
      squamous papilloma, focal inflammation, and papillary hyperplasia of the
      forestomach were increased in male mice (squamous papilloma: 0/49, 1/50, 3/50;
      focal inflammation: 9/49, 13/50, 21/50; papillary hyperplasia: 7/49, 14/50,
      22/50). Stop-Exposure Study: A separate 2-year study was conducted in which 50
      male rats were administered 30 mg/kg furan in corn oil by gavage 5 days per week
      for 13 weeks and then maintained for the remainder of the 2 years without
      additional furan administration. Groups of 10 animals were evaluated for the
      presence of treatment-related lesions at the end of the 13-week period of furan
      administration and at 9 and 15 months. Neoplastic and Nonneoplastic Lesions:
      Cholangiocarcinoma of the liver occurred with an overall incidence of 100&percnt;
      (40/40) and hepatocellular carcinoma occurred with an overall incidence of
      15&percnt; (6/40) in stop-exposure male rats that survived at least 9 months.
      Cholangiocarcinoma was observed in all 10 males at both the 9-month and 15-month
      interim evaluations. Hepatocellular carcinoma was first observed in 2 males at
      the 15-month interim evaluation. Genetic Toxicology: Furan was negative for
      induction of gene mutations in Salmonella typhimurium strains TA100, TA1535,
      TA1537, and TA98 in the presence and the absence of exogenous metabolic
      activation (S9). Furan was negative for the induction of sex-linked recessive
      lethal mutations in germ cells of male Drosophila melanogaster when administered
      either by feeding or by injection. In vitro tests for genotoxicity in mammalian
      cells, however, were positive. Furan induced trifluorothymidine resistance in
      mouse L5178Y lymphoma cells in the absence of S9, and sister chromatid exchanges
      and chromosomal aberrations in Chinese hamster ovary cells, with and without S9.
      Furan administered to male B6C3F1 mice by intraperitoneal injection induced
      chromosomal aberrations but not sister chromatid exchanges in bone marrow cells.
      Conclusions: Under the conditions of these 2-year gavage studies there was clear
      evidence of carcinogenic activity of furan in male and female F344/N rats based
      on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the
      liver and on increased incidences of mononuclear cell leukemia. There was clear
      evidence of carcinogenic activity of furan in male and female B6C3F1 mice based
      on increased incidences of hepatocellular neoplasms of the liver and benign
      pheochromocytomas of the adrenal gland. Nonneoplastic liver lesions associated
      with furan administration in rats and mice included biliary tract fibrosis,
      hyperplasia, inflammation, and proliferation, as well as hepatocellular
      cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats,
      increased severity of nephropathy with an associated increased incidence of
      parathyroid hyperplasia was associated with exposure to furan. Synonyms:
      Divinylene oxide, tetrole, furfuran, oxole, 1,4-epoxy-1,3-butadiene, axole,
      oxacyclopentadiene

PMID- 12621517
TI  - NTP Technical Report on the Toxicology and Carcinogenesis Studies of 2,4
      Diaminophenol Dihydrochloride (CAS NO. 137-09-7) in F344/N Rats and B6C3F1 Mice
      (Gavage Studies).
AB  - 2,4-Diaminophenol dihydrochloride is used in the manufacture of dyes and as a
      color accelerator in photographic developers. Toxicology and carcinogenesis
      studies were conducted by administering 2,4-diaminophenol dihydrochloride
      (greater than 97% pure) in corn oil by gavage to F344/N rats and B6C3F1 mice for
      16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in
      Salmonella typhimurium, mouse lymphoma cells, Drosophila melanogaster, and
      Chinese hamster ovary cells. 16-Day Studies: Groups of five rats of each sex
      received doses of 0, 6, 13, 25, 50, or 100 mg/kg and groups of five mice of each
      sex received doses of 0, 13, 25, 50, 100, or 200 mg/kg of 2,4-diaminophenol
      dihydrochloride in corn oil by gavage. There were no deaths among rats during the
      16-day studies and chemical exposure had no effect on final mean body weights.
      Organ weight differences were unrelated to chemical exposure. Renal tubule
      necrosis was present in male and female rats in the 25, 50, and 100 mg/kg dose
      groups. All male and four female mice that received 200 mg/kg, all males and
      three females that received 100 mg/kg, and two female mice that received 50 mg/kg
      died before the end of the studies. Final mean body weights of surviving dosed
      mice were similar to controls. Absolute liver weights were increased in female
      mice that received 50 and 100 mg/kg and relative liver weights were increased in
      all female dose groups. Renal tubule necrosis was present in the 100 mg/kg male
      and female dose groups. 13-Week Studies: Groups of ten male and female rats
      received doses of 0, 12, 25, 50, 100, or 200 mg/kg and groups of ten male and
      female mice received doses of 0, 5, 9, 19, 38, or 75 mg/kg of 2,4-diaminophenol
      dihydrochloride in corn oil by gavage. All female and nine male rats that
      received 200 mg/kg and four males and one female in the 100 mg/kg rat groups died
      before the end of the studies. Final mean body weights of male rats that received
      50 or 100 mg/kg were significantly lower than controls. Relative kidney weights
      were significantly increased in all male dose groups; absolute and relative
      kidney and liver weights were significantly increased in females that received 50
      and 100 mg/kg. Lesions in rats associated with chemical exposure included renal
      tubule necrosis in males that received 25 mg/kg and above and in females that
      received 100 or 200 mg/kg. Forestomach ulcers with acanthosis and hyperkeratosis
      were present at 50 mg/kg and above in both sexes. Pigment, presumably 2,4
      diaminophenol dihydrochloride or a metabolite, was present in the duodenum and
      within the renal tubule epithelium of all dose groups. Splenic lymphoid depletion
      was present in both sexes and bone marrow hyperplasia was present in groups of
      males that received 100 or 200 mg/kg. Hemosiderin was present in Kupffer cells of
      males that received 100 or 200 mg/kg. The severity of splenic extramedullary
      hematopoiesis increased with dose in males. There were no deaths among mice
      attributed to chemical exposure. Final mean body weight of male mice that
      received 75 mg/kg was 8% lower than for the controls. Absolute and relative liver
      weights were increased in males that received 9 mg/kg or above and in all female
      dose groups. Absolute and relative kidney weights of 38 and 75 mg/kg male mice
      and all dosed female mice were significantly increased. Absolute heart weights
      were increased in the 19, 38, and 75 mg/kg female groups. Lesions in 75 mg/kg
      mice included increased incidences of renal tubule regeneration; forestomach
      acanthosis and hyperkeratosis occurred in 38 and 75 mg/kg groups. Hemosiderin was
      present in the spleen of mice from all dose groups and in hepatic Kupffer cells
      of female mice that received 38 or 75 mg/kg. Pigment was present in the duodenum
      of males and females that received 9 mg/kg and above and in the renal tubule
      epithelium of both sexes that received 75 mg/kg. 2-Year Studies: The 2-year
      studies were conducted by administering 2,4-diaminophenol dihydrochloride in corn
      oil by gavage to groups of 60 male and 60 female F344/N rats and B6C3F1 mice.
      Tence. Ten animals from each dose group were evaluated after 15 months. Rats
      received doses of 0, 12.5, or 25 mg/kg; mice received doses of 0, 19, or 38
      mg/kg. Body Weight and Survival in the 2-Year Studies: Mean body weights of high
      dose male and female rats and of high-dose male mice were lower than those of the
      respective controls. Survival of dosed rats and mice was similar to controls
      throughout the 2-year studies. Neoplastic and Nonneoplastic Effects in the 2-Year
      Studies: The severity of nephropathy increased in high-dose male rats. The
      incidence of renal tubule cell hyperplasia was increased in rats that received
      2,4-diaminophenol dihydrochloride; however, there were no renal tubule cell
      neoplasms attributed to chemical exposure. Renal tubule cell hyperplasia was
      present in three high-dose male mice and a renal tubule adenoma was present in
      one of the high-dose males with hyperplasia; two additional high-dose males also
      had renal tubule adenomas. These are uncommon neoplasms in male mice and were
      considered related to chemical exposure. In a supplemental review of step
      sectioned kidneys, six additional hyperplasia were seen in high-dose male mice
      and adenomas in three other high-dose males. A tubule cell carcinoma was present
      in one low-dose female mouse. The incidences of several nonneoplastic kidney
      lesions, including necrosis and renal tubule regeneration, were also increased in
      male and female mice. Pigment was observed in the lamina propria of the duodenum,
      the submucosa of the forestomach, and in pancreatic and mesenteric lymph nodes in
      dosed rats. Hemosiderin was present in the renal tubule epithelial cells of low-
      and high-dose rats. The incidence of forestomach acanthosis was increased in
      dosed male mice and pigment was present in liver Kupffer cells, in the lamina
      propria of the duodenum, and in the mesenteric lymph nodes of male and female
      mice. Pigment and hemosiderin were also present in the renal tubule epithelium of
      dosed mice. Genetic Toxicology: 2,4-Diaminophenol dihydrochloride was mutagenic
      in the Salmonella typhimurium strain TA98 in the presence of exogenous metabolic
      activation (S9); it was not mutagenic in strain TA98 in the absence of S9, nor
      was it mutagenic in strains TA100, TA1535, or TA1537 with or without S9. 2,4
      Diaminophenol dihydrochloride was positive in the mouse lymphoma assay for
      induction of trifluorothymidine resistance in L5178Y cells without S9; it was not
      tested with S9. No induction of sister chromatid exchanges or chromosomal
      aberrations was observed in Chinese hamster ovary cells treated with 2,4
      diaminophenol dihydrochloride with and without S9. In the Drosophila melanogaster
      sex-linked recessive lethal assay, 2,4-diaminophenol dihydrochloride gave
      equivocal results when administered in the feed and negative results when
      administered by injection. Conclusions: Under the conditions of these 2-year
      gavage studies, there was no evidence of carcinogenic activity of 2,4
      diaminophenol dihydrochloride in male or female F344/N rats that received 12.5 or
      25 mg/kg. There was some evidence of carcinogenic activity of 2,4-diaminophenol
      dihydrochloride in male B6C3F1 mice based on increased incidences of renal tubule
      adenomas; there was no evidence of carcinogenic activity of 2,4-diaminophenol
      dihydrochloride in female B6C3F1 mice that received 19 or 38 mg/kg.
      Administration of 2,4-diaminophenol dihydrochloride to rats was associated with
      increased severity of nephropathy in males and females, increased incidence of
      nephropathy in females, and focal renal tubule hyperplasia in males and females.
      In mice, chemical exposure was associated with renal tubule necrosis and
      regeneration in males and females and forestomach acanthosis in males. Synonyms:
      Acrol, amidol, dianol

PMID- 12621518
TI  - Toxicology and Carcinogenesis Studies of 4,4'-Diamino-2,2'-Stilbenedisulfonic
      Acid Disodium Salt (CAS No. 7336-20-1) in F344 Rats and B6C3F1 Mice (Feed
      Studies).
AB  - 4,4'-Diamino-2,2'-stilbenedisulfonic acid, disodium salt, is used in the
      synthesis of dyes and optical brighteners or fluorescent whitening agents.
      Toxicology and carcinogenesis studies were conducted by administering the
      chemical (approximately 14% water, 6% sodium chloride, 4% impurities, and 76%
      4,4'-diamino-2,2'-stilbenedisulfonic acid) in feed to groups of F344/N rats and
      B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology
      studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells.
      14-Day Studies: Groups of five rats and five mice of each sex were given 0,
      6,250, 12,500, 25,000, 50,000, or 100,000 ppm 4,4'-diamino-2,2'
      stilbenedisulfonic acid, disodium salt, in feed for 14 days. All rats and mice
      survived to the end of the studies. The mean body weight gain of male rats
      receiving 50,000 or 100,000 ppm and of female rats and male and female mice
      receiving 100,000 ppm was significantly lower than those of the respective
      controls. Clinical findings included diarrhea in the rats and mice receiving
      100,000 ppm. There were no chemical-related changes in absolute or relative organ
      weights in rats or mice. There were no gross or microscopic lesions related to
      chemical administration in rats or mice. 13-Week Studies: Groups of 10 rats and
      10 mice of each sex were given 0, 6,250, 12,500, 25,000, 50,000, or 100,000 ppm
      4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for 13 weeks.
      One female rat, six male mice, and one female mouse in the 100,000 ppm dose
      groups died during the studies. Mean body weight gain was significantly decreased
      in male rats and female mice receiving 50,000 or 100,000 ppm, in male mice
      receiving 25,000, 50,000, or 100,000 ppm, and in female rats receiving 100,000
      ppm. Clinical findings in rats that received 50,000 or 100,000 ppm and in mice
      that received 100,000 ppm included diarrhea, emaciation, and hyperemia of the
      perineum. There were no biologically significant changes in absolute or relative
      organ weights or clinical pathology results in rats or mice. Histopathologic
      lesions present in rats receiving 100,000 ppm were bone marrow hypercellularity
      and chronic inflammation of the anus and rectum. Ulcerative inflammation of the
      anus and rectum was observed in mice receiving 25,000 ppm and above. Female mice
      in the 6,250, 12,500, 25,000, and 50,000 ppm dose groups had increased incidences
      of cystic endometrial hyperplasia. 2-Year Studies: Doses selected for the 2-year
      studies were based on mortality, decreased body weight gains, and the presence of
      diarrhea and chronic inflammation of the anus/rectum in rats and mice during the
      13-week studies. Groups of 60 rats of each sex were given 0, 12,500 or 25,000 ppm
      and groups of 60 mice of each sex were given 0, 6,250, or 12,500 ppm 4,4'-diamino
      2,2'-stilbenedisulfonic acid, disodium salt, in feed for up to 103 weeks. Interim
      evaluations were performed on 10 rats and 10 mice from each dose group at 15
      months. There were no biologically significant absolute or relative organ weight,
      clinical pathology, or histopathology findings in rats or mice administered 4,4'
      diamino-2,2'-stilbenedisulfonic acid, disodium salt, in feed for 15 months. Body
      Weight, Feed Consumption, Survival, and Clinical Findings in the 2-Year Studies:
      Mean body weights were marginally decreased for high-dose male and female rats
      and female mice. Feed consumption by dosed rats and mice was similar to feed
      consumption by the controls throughout the studies. Survival was similar among
      control and treated groups of rats and mice. No clinical findings related to
      chemical administration were observed in rats or mice. Nonneoplastic and
      Neoplastic Effects in the 2-Year Studies: There were no chemical-related
      increased incidences of neoplasms at any site in rats. Ulcers of the forestomach
      or glandular stomach occurred in dosed rats (males: 1/50, 5/50, 4/50; females:
      0/50, 1/50, 4/50), and may have been related to the administration of 4,4'
      diamino-2,2'-stilbenedisulfonic acid, disodium salt. There were no chemical
      related incidences ohemical-related incidences of neoplasms, nonneoplastic
      lesions, or other toxic effects in mice in the 2-year studies. Although the
      animals might have been able to tolerate slightly higher doses, results of the 13
      week studies indicate that a doubling of the highest doses could not have been
      tolerated. Genetic Toxicology: 4,4'-Diamino-2,2'-stilbenedisulfonic acid was not
      mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with
      or without S9 metabolic activation. 4,4'-Diamino-2,2'-stilbenedisulfonic acid did
      not induce sister chromatid exchanges or chromosomal aberrations in Chinese
      hamster ovary cells in the presence or absence of S9. Conclusions: Under the
      conditions of these 2-year feed studies, there was no evidence of carcinogenic
      activity of 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium salt, in male or
      female F344/N rats receiving 12,500 or 25,000 ppm. There was no evidence of
      carcinogenic activity of 4,4'-diamino-2,2'-stilbenedisulfonic acid, disodium
      salt, in male or female B6C3F1 mice receiving 6,250 or 12,500 ppm. Synonyms:
      Amsonic acid; diaminostilbene disulphonate (DASD); 2,2'-(1,2-ethenediyl)bis[5
      amino-benzenesulfonic acid]; 2,2'-disulfo-4,4'-stilbenediamine; 2,2'
      stilbenedisulfonic acid; 4,4'-diamino-2,2'-benzenesulfonic acid; 2,2'-(1,2
      ethenediyl)bis(5-amino-) diaminostilbenedisulfonic acid; flavonic acid; p,p'
      diaminostilbene-o,o'-disulfonic acid; 4,4'-diaminostilbene-2,2'-disulfonic acid

PMID- 12621519
TI  - Toxicology and Carcinogenesis Studies of C.I. Pigment Red 23 (CAS No. 6471-49-4)
      in F344 Rats and B6C3F1 Mice (Feed Studies).
AB  - C.I. Pigment Red 23 is a bluish red commercial dye used as a coloring agent in
      paints, inks, rubber, plastics, lacquers, and paper. Toxicology and
      carcinogenicity studies were conducted by feeding groups of rats and mice diets
      containing C.I. Pigment Red 23 (greater than 96% pure) for 17 days, 13 weeks, and
      2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and
      in Chinese hamster ovary cells. 17-Day Studies: Groups of five rats and five mice
      of each sex were fed diets containing 0, 6,000, 12,500, 25,000, 50,000, or
      100,000 ppm C.I. Pigment Red 23 for 15 to 17 days. All rats and all female mice
      lived until the end of the studies. Two male mice in the 12,500 ppm dose group
      died accidentally. No other deaths occurred among male mice. Final mean body
      weights of rats and mice receiving C.I. Pigment Red 23 were within 10% of those
      of the controls. Feed consumption by exposed animals was similar to that of the
      controls. Hematocrit value, hemoglobin concentration, and erythrocyte count were
      decreased in the 50,000 and 100,000 ppm groups of rats. A corresponding decrease
      was not seen in mice. Absolute and relative organ weights of exposed animals were
      generally similar to those of the controls. No chemical-related gross lesions
      were seen in rats or mice. 13-Week Studies: Groups of 10 rats and 10 mice of each
      sex were fed diets containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I.
      Pigment Red 23 for 13 weeks. All rats and mice lived until the end of the
      studies. Final mean body weights of rats and mice receiving C.I. Pigment Red 23
      were within 10% of those of the controls. Feed consumption by exposed animals was
      similar to that of the controls. In 50,000 ppm male rats, hematocrit and
      hemoglobin concentrations and erythrocyte counts were significantly less than
      those of the controls. In female rats receiving 3,000, 6,000 and 50,000 ppm C.I.
      Pigment Red 23, lymphocyte counts were significantly higher than the control
      values. Leukocyte counts in 3,000 ppm females were also significantly increased.
      Female mice in the 6,000 ppm dose group had significantly lower hematocrit and
      hemoglobin concentrations than did untreated females. Hematology parameters in
      exposed males were similar to those of untreated males. There were no
      biologically significant differences in organ weights among dosed and control
      rats. Absolute and relative liver weights of male mice receiving 12,500 ppm C.I.
      Pigment Red 23 were significantly increased compared to those of the controls.
      Absolute and relative thymus weights for all but 12,500 ppm female mice were
      significantly lower than those of the controls. No chemical-related gross or
      histopathologic lesions occurred in rats or mice. 2-Year Studies: Survival, Body
      Weights, Feed Consumption, and Clinical Findings Because levels of C.I. Pigment
      Red 23 as high as 50,000 or 100,000 ppm in the feed did not adversely affect
      survival and mean body weights in the 17-day and 13-week studies, nor cause any
      chemical- related lesions, doses of 0, 10,000, 25,000, or 50,000 ppm were
      selected for the 2-year studies. Doses higher than 50,000 ppm (5%) are not used
      in 2-year studies because they may lead to excessive dilution of nutrients in
      feed which in turn could produce nutritional deficiencies. Survival rates of mid-
      and high-dose male and of high-dose female rats were significantly greater than
      those of the controls, due primarily to a chemical related decreased incidence of
      mononuclear cell leukemia in these groups (survival in male rats: control, 22/50,
      low-dose, 29/50, mid-dose, 36/50, high-dose, 35/51; female rats: 29/50, 34/50,
      33/50, 40/50). Survival of mice was not affected by the administration of C.I.
      Pigment Red 23, although survival of low-dose male mice was significantly lower
      than that of controls (male mice: 29/51, 17/53, 27/52, 30/51; female mice: 35/50,
      34/49, 36/50, 35/49). The decreased survival in the low- dose males was
      associated with evidence of body trauma and secondary septicemia caused by
      fighting. From approximately week 20 of the study, the group mean body weight,
      the group mean body weights of exposed female rats were consistently lower than
      those of controls; at week 101, mean body weights of mid- dose (25,000 ppm) and
      high-dose (50,000 ppm) females were 6&percnt; and 8&percnt; less, respectively.
      The final mean body weights of exposed male rats and male and female mice were
      similar to those of controls. Feed consumption values for exposed male and female
      rats and mice were similar to those of the controls and there were no clinical
      signs associated with the administration of C.I. Pigment Red 23. Pathology
      Findings: Renal tubule adenomas occurred in two high- dose male rats. Renal
      tubule carcinomas occurred in one high-dose male and one mid-dose male rat. No
      renal tubule neoplasms were seen in the controls. Renal tubule neoplasms are
      uncommon and have occurred in 8/499 (1.6&percnt;) untreated historical controls
      with a range of 0&percnt; to 6&percnt;. The residual halves of kidneys from
      control and high-dose males were step sectioned and examined; renal tubule
      adenomas were observed in a control male and in two additional high- dose males.
      Because of the low numbers of renal neoplasms, it is uncertain if they were
      related to chemical administration. The incidence of renal tubule hyperplasia
      (3/50, 6/48, 5/50, 8/50) and the mean severity of nephropathy were also slightly
      increased in high-dose male rats. The incidence of mononuclear cell leukemia
      occurred with a significant negative trend in exposed male and female rats. No
      chemical-related increases in the incidence of neoplasms were observed in mice of
      either sex. There was a chemical-related increase in the incidence of hyperplasia
      (male mice: 0/49, 1/48, 1/50, 7/48; female mice: 6/49, 14/49, 43/50, 47/49) and
      hyperkeratosis of the forestomach epithelium attributed to chemical
      administration. Genetic Toxicology: C.I. Pigment Red 23 was mutagenic in
      Salmonella typhimurium strains TA100, TA1537, and TA98 with and without exogenous
      metabolic activation (S9), but it was not mutagenic in strain TA1535. C.I.
      Pigment Red 23 induced sister chromatid exchanges in Chinese hamster ovary cells
      in the absence of S9, but not with S9 activation. The pigment was negative for
      the induction of chromosomal aberrations in Chinese hamster ovary cells both in
      the presence and absence of S9. Conclusions: Under the conditions of these 2-year
      feed studies, there was equivocal evidence of carcinogenic activity of C.I.
      Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence
      of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of
      C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or
      50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male
      and female rats receiving C.I. Pigment Red 23. There was no evidence of
      carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed
      diets containing 10,000, 25,000 or 50,000 ppm. The severity of kidney nephropathy
      was increased in exposed male rats. In mice, C.I. Pigment Red 23 caused an
      increase in hyperkeratosis and epithelial hyperplasia of the fore- stomach.
      Synonyms: 2-Naphthalenecarboxamide; 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-N
      (3- nitrophenyl); 3-hydroxy-4-((2-methoxy-5- nitrophenyl)azo)-3 -2-naphthanilide;
      Alkali Resistant Red Dark; Calcotone Red 3B; Carnation Red Toner B; CI 12355;
      Congo Red R- 138; Fenalac Red FKB Extra; Malta Red X2284; Naphthol Red B;
      Naphthol Red T Toner 35- 6001; Naphthol Red Deep 10459; Pigment Red BH;
      Rubescence Red MT-21; Sanyo Fast Red 10B; Sapona Red Lake RL-6280; Sengale Light
      Rubin RG; Textile Red WD-263

PMID- 12621520
TI  - Toxicology and Carcinogenesis Studies of Naphthalene (CAS No. 91-20-3) in B6C3F1
      Mice (Inhalation Studies).
AB  - Naphthalene, a white, crystalline powder, is used as a moth repellent and in the
      manufacture of phthalic and anthranilic acids, naphthylamines, and synthetic
      resins. The 2-year studies were conducted by exposing groups of male and female
      B6C3F1 mice to naphthalene (>99% pure) vapor for 6 hours daily, 5 days per week,
      for 104 weeks. Genetic toxicology studies were conducted in Salmonella
      typhimurium and Chinese hamster ovary cells. 2-Year Studies: Groups of male and
      female mice were exposed to atmospheres containing 0 (75 mice per group), 10 (75
      mice per group), or 30 ppm (150 mice per group) naphthalene. Mice from each group
      were included for 14-day hematology evaluations (male: 0 ppm, 5 animals; 10 ppm,
      4; 30 ppm, 10; female: 0 ppm, 4; 10 ppm, 5; 30 ppm, 10). Mean body weights of
      exposed mice were slightly lower than those of controls throughout the studies.
      Survival of male control mice was significantly less than that of exposed mice;
      the lower survival was the result of wound trauma and secondary infections
      related to fighting among the group-housed mice (0 ppm, 26/70, 37%; 10 ppm,
      52/69, 75%; 30 ppm, 118/133, 89%). Survival of exposed female mice was similar to
      that of controls (59/69, 86%; 57/65, 88%; 102/135, 76%). Neoplastic and
      Nonneoplastic Effects in the 2-Year Studies: No increase in tumor incidence
      related to naphthalene administration was observed in male mice. In females, the
      incidence of pulmonary alveolar/bronchiolar adenomas was significantly greater in
      the high-dose group than in the controls (5/69, 7%; 2/65, 3%; 28/135, 21%). One
      other high-dose female had an alveolar/bronchiolar carcinoma. The combined
      incidence of alveolar/ bronchiolar adenomas and carcinomas in the high-dose
      females was above those for control female B6C3F1 mice from NTP feed, water, and
      inhalation studies (91/1,166, 7.8%, range 0%-16%). These lung tumors were
      attributed to naphthalene exposure. Nonneoplastic lesions attributed to
      naphthalene exposure were observed in the nose and lungs of mice of both sexes.
      In the nose, naphthalene exposure was associated with an increase in the
      incidence and severity of chronic inflammation, metaplasia of the olfactory
      epithelium, and hyperplasia of respiratory epithelium. Chronic inflammation in
      the lung was associated with chemical exposure. Genetic Toxicology: Naphthalene
      was negative for the induction of gene mutations in Salmonella typhimurium
      strains TA100, TA1535, TA1537, and TA98 with and without exogenous metabolic
      activation (S9). In cytogenetic tests with Chinese hamster ovary cells,
      naphthalene induced sister chromatid exchanges with and without S9 activation.
      Exposure to naphthalene induced a significant increase in chromosomal aberrations
      in Chinese hamster ovary cells in the presence of S9. Conclusions: Under the
      conditions of these 2-year inhalation studies, there was no evidence of
      carcinogenic activity of naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm.
      There was some evidence of carcinogenic activity of naphthalene in female B6C3F1
      mice, based on increased incidences of pulmonary alveolar/ bronchiolar adenomas.
      In both male and female mice, naphthalene caused increased incidences and
      severity of chronic inflammation, metaplasia of the olfactory epithelium, and
      hyperplasia of the respiratory epithelium in the nose and chronic inflammation in
      the lungs. Synonyms: Naphthalin, Naphthene, Tar Camphor

PMID- 12621521
TI  - Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344
      Rats (Feed Studies).
AB  - Quercetin is a member of a group of naturally occurring compounds, the
      flavonoids, which have a common flavone nucleus composed of two benzene rings
      linked through a heterocyclicpyrone ring. Quercetin is found in various plants,
      food products, and dyes of natural origin. The estimated average daily intake of
      quercetin by an individual in the United States is 25 mg. The Food and Drug
      Administration nominated quercetin for toxicity and carcinogenicity studies in
      the rat because it is a chemical that is widely distributed in foods. Quercetin
      was administered to rats by dosed feed since human exposure is by dietary
      consumption. Information in the literature showed that quercetin administered in
      the diet to rats at levels up to approximately 4% caused a minor body weight
      effect, whereas higher dose levels produced greater than 10% reduction in body
      weight gains relative to controls. Based on this information, the NTP 2-year
      studies were conducted by administering 0, 1,000, 10,000, or 40,000 ppm quercetin
      (>95% pure) in feed to groups of 50 male and female rats for 104 weeks. Ten
      additional animals per dose group were evaluated at 6 and 15 months. Body Weight,
      Survival, and Clinical Findings in the 2-Year Studies: Body weights of exposed
      male and female rats given 1,000 and 10,000 ppm were within 5% of controls
      throughout the studies. Reduced body weight gain in male and female rats
      receiving 40,000 ppm was observed by week 15 and the final mean body weights were
      87% of controls at week 104. Survival and feed consumption were similar among
      exposed and control groups throughout the studies. The average amounts of
      quercetin consumed per day by the 1,000, 10,000 and 40,000 ppm dose groups after
      week 52 were 40, 400, and 1,900 mg/kg of body weight. Nonneoplastic and
      Neoplastic Effects in the 2-Year Studies: In male rats, the principal toxic
      effects associated with the dietary administration of quercetin for 2 years were
      observed in the kidney. There were dose-related increases in the severity of
      chronic nephropathy (control, 2.7; low-dose, 2.7; mid-dose, 3.0; high-dose, 3.2)
      and a slight increased incidence in focal hyperplasia of the renal tubule
      epithelium (1/50; 2/50; 3/50; 4/50). Parathyroid hyperplasia, indicative of renal
      secondary hyperparathyroidism, also increased incidence in dosed male rats (1/43,
      6/45, 6/43, 17/43). The evaluation of single sections from the left and right
      kidneys revealed renal tubule adenomas in three male rats and adenocarcinomas in
      another male rat receiving 40,000 ppm quercetin; none were seen in the controls.
      Examination of additional step sections of the male rat kidney identified
      additional hyperplasia and adenomas in all dose groups (hyperplasia: 2/50, 2/50,
      6/50, 8/50; adenoma: 1/50, 2/50, 7/50, 6/50). The overall incidence of renal
      tubule adenoma or adenocarcinoma combined in male rats was 1/50 in controls and
      9/50 in the high-dose group. There was no apparent effect of quercetin on the
      kidney of female rats. A single renal tubule adenoma was seen in a female
      receiving 10,000 ppm; this neoplasm was not considered biologically significant.
      There was a statistically significant, dose-related decrease in the incidence of
      mammary gland fibroadenomas in exposed female rats (29/50, 27/50, 16/50, 9/50),
      which may in part be attributed to lower body weight gains. There was a treatment
      related accumulation of yellow-brown granular pigment adsorbed to or absorbed by
      the epithelial cells of the glandular stomach, ileum, jejunum, and, to a lesser
      extent, the duodenum and colon. The severity of the pigmentation in these tissues
      increased with increased length of exposure. There were no other lesions
      considered to be related to chemical administration. Genetic Toxicology:
      Quercetin induced gene mutations in Salmonella typhimurium strains TA100 and TA98
      with and without exogenous metabolic activation (S9). Positive results were also
      obtained in tests with and without S9 for induction of sister chromatid exchanges
      and chromosomal aberrations in Chinese hamster ovary cells. Conclusions: Under
      the conditionslls. Conclusions: Under the conditions of these 2-year feed studies
      there was some evidence of carcinogenic activity of quercetin in male F344/N rats
      based on an increased incidence of renal tubule cell adenomas. There was no
      evidence of carcinogenic activity of quercetin in female F344/N rats receiving
      1,000, 10,000 or 40,000 ppm. The incidence of renal tubule hyperplasia and the
      severity of nephropathy were increased in exposed male rats. Synonyms: C.I.
      Natural Yellow 10; C.I. 75670; Cyanidelonon 1522; Flavin Meletin; Quercetine;
      Quercetol; Quertin; Quertine; Sophoretin; Xanthaurine; 3,3',4',5,7
      Pentahydroxyflavone; 3,5,7,3',4'-Pentahydroxyflavone; 2-(3,4-Dihydroxyphenyl)
      3,5,7-trihydroxy-4H-1-benzopyran-4-one

PMID- 12621522
TI  - Toxicology and Carcinogenesis Studies of Mercuric Chloride (CAS No. 7487-94-7) in
      F344 Rats and B6C3F1 Mice (Gavage Studies).
AB  - Mercuric chloride is an inorganic compound that has been used in agriculture as a
      fungicide, in medicine as a topical antiseptic and disinfectant, and in chemistry
      as an intermediate in the production of other mercury compounds. The widespread
      use of mercury has resulted in increased levels of mercury in rivers and lakes.
      Mercuric chloride was evaluated in toxicity and carcinogenicity studies because
      of its extensive use and its occurrence as an environmental pollutant, and
      because of the lack of adequate long-term rodent studies. Toxicology and
      carcinogenesis studies were conducted by administering mercuric chloride (greater
      than 99% pure) in deionized water by gavage to groups of F344 rats or B6C3F1 mice
      for 16 days, 6 months, and 2 years. Genetic toxicology studies were conducted in
      Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537), in mouse
      lymphoma L5178Y cells, in Chinese hamster ovary cells, and in Drosophila
      melanogaster. 16-DAY STUDIES: Groups of five rats of each sex received 0, 1.25,
      2.5, 5, 10, or 20 mg mercuric chloride/kg body weight and groups of five mice of
      each sex received 0, 5, 10, 20, 40, or 80 mg/kg in deionized water by gavage for
      12 dose days. Two male rats in the 20 mg/kg group died in the first week, as did
      all male and four female mice from the 80 mg/kg group and one male mouse from the
      40 mg/kg group. The final mean body weight of male rats receiving 20 mg/kg was
      10% lower than that of the controls; the final mean body weight of 20 mg/kg
      females was 9% lower than that of the controls. Final mean body weights and body
      weight gains of dosed mice were similar to those of the controls. Absolute and
      relative kidney weights of male rats receiving 2.5 mg/kg or greater doses and of
      female rats administered 5 mg/kg or more were significantly greater than those of
      the controls. Absolute kidney weights of mice were significantly increased in all
      male dose groups and in the 40 mg/kg female dose group; relative kidney weights
      of dosed male and female mice were significantly greater than the controls.
      Analysis of kidney, liver, and brain tissues for mercury residues revealed that
      the highest mercury concentration was in the kidneys of rats and mice. Acute
      renal tubule nephropathy occurred in dosed rats and was slightly more severe in
      males than in females. Chemical-related lesions in mice included renal tubule
      necrosis, inflammation and necrosis of the forestomach, and necrosis of the
      glandular stomach. 6-MONTH STUDIES: Groups of 10 rats of each sex received 0,
      0.312, 0.625, 1.25, 2.5, or 5 mg mercuric chloride/kg body weight in deionized
      water by gavage for 26 weeks. Groups of 10 mice of each sex received 0, 1.25,
      2.5, 5, 10, or 20 mg/kg in deionized water by gavage for 26 weeks (males) or 27
      weeks (females). No deaths related to mercuric chloride administration occurred
      in rats or mice. Mean body weight gains of male rats that received 5 mg/kg and
      all female rat dose groups that received 0.625 mg/kg or greater were
      significantly lower than the controls. The final mean body weight and body weight
      gain of male mice in the 20 mg/kg group were significantly lower than those of
      the controls; final mean body weights and body weight gains of other dosed male
      mice and all dosed female mice were similar to those of the controls. Absolute
      and relative kidney weights of all dosed male rats and of female rats that
      received 0.625 mg/kg or greater were significantly greater than those of the
      controls. In male mice, absolute kidney weights in the three highest dose groups
      were significantly increased; no biologically significant differences in organ
      weights occurred in female mice. Analysis of kidney, liver, and brain tissues for
      mercury residues revealed the highest mercury concentration in the kidneys of
      rats and mice. The severity of chronic nephropathy increased with dose in male
      rats. Cytoplasmic vacuolation of renal tubule epithelial cells was observed in
      male mice in the 5, 10, and 20 mg/kg groups. No histopathologic changes in female
      mice were related to chemical exposure. 2-YEAR STUDIES: Groups YEAR STUDIES:
      Groups of 60 rats of each sex received 0, 2.5, or 5 mg mercuric chloride/kg body
      weight and groups of 60 mice of each sex received 0, 5, or 10 mg/kg in deionized
      water by gavage 5 days per week for 2 years. The doses were based on decreased
      weight gains in rats receiving 10 and 20 mg/kg and the decreased weight in male
      mice receiving 40 mg/kg during the 16-day studies, and on the decreased weight
      gains and toxicity results seen in the 6-month studies. Increased absolute and
      relative kidney weights in rats and male mice in the 6-month studies and
      degenerative renal changes suggested that higher dose levels would result in
      inadequate survival rates for a 2-year study. 15-Month Interim Evaluations:
      Relative kidney weights were significantly increased in dosed rats and female
      mice. The severity of nephropathy was increased in male rats, but not in females.
      High-dose male and female rats had minimal to mild hyperplasia of the basal cell
      layer in the forestomach epithelium (diagnosed as acanthosis); this lesion was
      not found in control or low-dose rats. Male mice had an increased severity of
      vacuolation of the renal tubule epithelium; no chemical-related lesions occurred
      in the kidneys of females. The incidence of inflammation of the olfactory
      epithelium lining the nasal cavity increased in male and female high-dose mice.
      Survival, Body Weights, and Clinical Signs: Survival of dosed male rats was lower
      than that of the controls (26/50, 10/50, 5/50); survival of dosed female rats was
      similar to that of the controls (35/50, 28/49, 30/50). Although more than
      60&percnt; of the mice in each dose group survived to study end, survival rates
      of high-dose male mice and dosed female mice were lower than those of the
      controls (males: 36/50, 36/50, 31/50; females: 41/50, 35/50, 31/50). The final
      mean body weights of high-dose male and female rats were 15&percnt; and
      14&percnt; lower than controls, respectively. The mean body weight of low-dose
      female rats was generally similar to controls throughout the 2-year study; the
      mean body weight of low-dose male rats was similar to that of the control through
      week 89. In mice, mean body weights of all male and female dose groups were
      similar to those of the controls throughout the studies. Pathology Findings:
      Chronic nephropathy appeared to develop at an accelerated rate and led to
      decreased survival in both dosed male rat groups. Secondary effects of renal
      dysfunction in dosed male rats resulted in increased incidences of fibrous
      osteodystrophy of the bone, mineralization of various tissues, and parathyroid
      gland hyperplasia. Based on evaluations of single and step sections, the
      incidence of renal tubule hyperplasia was increased in high-dose male rats
      (control, 3/50; high-dose, 10/50), but the incidences of renal tubule adenoma in
      high-dose and control males were similar (4/50, 5/50). Renal tubule hyperplasia
      was also slightly increased in high-dose female rats (2/50, 5/50) and adenomas
      were seen in high-dose females, but not in controls (0/50, 2/50). Incidences of
      forestomach hyperplasia in rats were markedly increased in dosed males (3/49,
      16/50, 35/50) and high-dose females (5/50, 5/49, 20/50). Squamous cell papillomas
      of the forestomach were found in 3 low-dose and 12 high-dose males and in 2 high
      dose females. No squamous cell carcinomas were found. The incidence of thyroid
      follicular cell carcinoma was marginally increased in high-dose male rats (1/50,
      2/50, 6/50). However, a corresponding increased incidence in follicular cell
      adenomas (1/50, 4/50, 0/50) or hyperplasia (2/50, 4/50, 2/50) in males did not
      occur, and the overall incidence of follicular cell neoplasms was not
      significantly increased (2/50, 6/50, 6/50). The incidence of nasal mucosa
      inflammation in male and female rats was increased in the high-dose groups (male:
      9/50, 8/47, 18/50; female: 0/49, 5/49, 15/50) and may have been related to
      chemical administration. The incidences of mammary gland fibroadenomas were
      significantly decreased in dosed female rats (15/50, 5/48, 2/50). The incidence
      and severity of nephropathy were increased in dosed mice; secondary effects of
      renal dysfunction did not occur. Renal tubule hyperplasia was found in one
      control and two high-dose male mice. Two renal tubule adenomas and one renal
      tubule adenocarcinoma were seen in high-dose male mice. Additional step sections
      revealed focal hyperplasia in another control male; no additional renal tubule
      neoplasms were found in high-dose or control males. Proliferative lesions of the
      renal tubule epithelium were not found in female mice. The incidence of
      metaplasia of the olfactory epithelium increased with dose in male and female
      mice. No other biologically significant lesions were found. GENETIC TOXICOLOGY:
      Mercuric chloride was not mutagenic in Salmonella typhimurium strains TA100,
      TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9).
      Induction of sex-linked recessive lethal mutations in germ cells of male
      Drosophila melanogaster did not occur when mercuric chloride was administered in
      feed or by injection. However, positive results were obtained in mutagenicity
      tests with mammalian cells. In the absence of S9, mercuric chloride induced
      trifluorothymidine resistance in mouse L5178Y cells and chromosomal aberrations
      in Chinese hamster ovary cells. In the Chinese hamster ovary cell test for
      induction of sister chromatid exchanges, mercuric chloride produced a negative
      response without S9 and a weakly positive response in the presence of S9.
      CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some
      evidence of carcinogenic activity of mercuric chloride in male F344 rats based on
      the increased incidence of squamous cell papillomas of the forestomach.
      Marginally increased incidences of thyroid follicular cell adenomas and
      carcinomas may have been related to mercuric chloride exposure. There was
      equivocal evidence of carcinogenic activity of mercuric chloride in female F344
      rats based on two squamous cell papillomas of the forestomach. There was
      equivocal evidence of carcinogenic activity of mercuric chloride in male B6C3F1
      mice based on the occurrences of two renal tubule adenomas and one renal tubule
      adenocarcinoma. There was no evidence of carcinogenic activity of mercuric
      chloride in female B6C3F1 mice receiving 5 or 10 mg/kg. Nonneoplastic lesions
      associated with exposure to mercuric chloride included increased severity of
      nephropathy in male rats and male and female mice. There was an increased
      incidence of renal tubule hyperplasia in male rats. The incidence of forestomach
      hyperplasia was increased in dosed male and female rats. Increased incidences of
      nasal mucosa inflammation were associated with mercuric chloride administration
      in rats. Increased incidences of olfactory epithelial metaplasia in mice were
      also associated with mercuric chloride administration. Synonyms: Abavit B,
      calochlor, corrosive sublimate, dichloromercury, mercuric bichloride, mercury
      chloride, mercury (II) chloride, mercury bichloride, mercury perchloride,
      sublimate, sulem, bichloride of mercury, corrosive mercury chloride, perchloride
      of mercury, mercury dichloride Trade name: Fungchex

PMID- 12621523
TI  - Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 (CAS No. 2425-85-6)
      in F344/N Rats and B6C3F1 Mice (Feed Studies).
AB  - C.I. Pigment Red 3, a yellowish red solid, is widely used for coloring paints,
      inks, plastics, and rubber, and in textile printing. It is used in a wide range
      of consumer items such as wallpaper, typewriter ribbons, carbon paper, and art
      materials. Toxicology and carcinogenicity studies were conducted by feeding
      groups of F344/N rats and B6C3F1 mice of each sex diets containing C.I. Pigment
      Red 3 (97% pure) for 2 weeks, 13 weeks, and 2 years. Genetic toxicology studies
      were conducted in Salmonella typhimurium and cultured Chinese hamster ovary
      cells. 2-Week Studies: Groups of five rats and five mice of each sex were given
      feed containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red
      3 for 2 weeks. No chemical-related deaths occurred in rats or mice. Final mean
      body weights of exposed rats and male mice were lower than controls; female mice
      that received 6,000 and 50,000 ppm had significantly increased final mean body
      weights compared to that of the controls. The feed consumption of treated rats
      and mice was slightly greater than that of the controls, suggesting that C.I.
      Pigment Red 3 had no adverse effects on the feed palatability. Dose-related
      decreases in erythrocyte counts and hematocrit values and an increase in
      reticulocyte counts were observed in rats. Changes in these parameters were
      observed in mice, but there were no clear, dose-related trends. 13-Week Studies:
      Groups of ten rats and ten mice of each sex were given feed containing 0, 3,000,
      6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 3 for 13 weeks. No chemical
      related deaths were observed in rats or mice. The final mean body weights of
      exposed female rats were significantly lower than that of the controls; the final
      mean body weights of exposed male rats and exposed mice were similar to controls.
      There were significant increases in relative liver and kidney weights of exposed
      male rats. Increases in the relative liver weights in mice did not occur with a
      dose-related trend and thus they were not considered related to chemical
      administration. Sites for the toxicity of C.I. Pigment Red 3 were the bone
      marrow, kidney, liver, and spleen in rats. Lesions observed in rats included bone
      marrow hyperplasia, congestion and hematopoietic cell proliferation of the
      spleen, and iron-positive pigmentation of the spleen, kidney, and liver. Sites
      for the toxicity of C.I. Pigment Red 3 in mice were the liver, kidney, and spleen
      in males and the liver and spleen in females. Lesions noted among mice in the
      spleen were hematopoietic cell proliferation and iron-positive pigmentation. In
      the liver, there was hematopoietic cell proliferation in male and female mice.
      Cytomegaly occurred in the renal tubule epithelium of the male mouse kidney. 2
      Year Studies: Doses selected for the 2-year feed studies were 0, 6,000, 12,500,
      and 25,000 ppm for rats and 0, 12,500, 25,000, and 50,000 ppm for mice. The dose
      selection for rats was based on body weight changes observed for females that
      received 50,000 ppm; the dose selection for mice was based on the lack of body
      weight depression or death at the doses tested during the 13-week studies.
      Concentrations higher than 50,000 ppm in the feed were not used because higher
      levels might have adversely affected the nutritional value of the diet during the
      2-year studies. Body Weight, Feed Consumption, Clinical Findings, and Survival in
      the 2-Year Studies: Final mean body weights for male rats that received 25,000
      ppm, female rats that received 12,500 and 25,000 ppm, and male and female mice
      that received 50,000 ppm were more than 10% lower than those of the controls.
      Feed consumption of exposed rats and mice was similar to that of the controls. No
      clinical findings indicative of toxicity were observed in rats or mice. The
      survival of low-dose male rats was greater than that of the controls (0 ppm,
      28/50; 6,000 ppm, 40/50; 12,500 ppm, 28/50; 25,000 ppm, 20/50). Survival of
      exposed female rats and exposed male mice was similar to the controls; the
      survival of high-dose female mice was significantly decreased compared to
      thcompared to that of the controls (39/50, 37/50, 31/50, 25/50). The reduced
      survival in this dose group may have been due to the increased incidence of
      ovarian abscesses. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies:
      Benign adrenal pheochromocytomas were significantly increased in the 12,500 and
      25,000 ppm groups of male rats compared to the controls (22/50, 29/50, 35/50,
      34/50). However, malignant neoplasms were not increased in incidence (6/50, 7/50,
      10/50, 4/50). The incidence of adrenal pheochromocytomas in dosed groups exceeded
      the range for NTP historical controls for feed studies (22&percnt;-48&percnt;),
      and the increased incidence of this neoplasm was attributed to C.I. Pigment Red 3
      administration. Squamous cell papillomas of the skin occurred with a positive
      trend in male rats (0/50, 4/50, 2/50, 6/50), and the incidence in the high-dose
      group was significantly greater than that of the controls. A poorly
      differentiated squamous cell carcinoma (diagnosed as carcinoma) was observed in a
      control male. The historical control rate for squamous cell papillomas in NTP
      feed studies is low (16/800 or 2&percnt;, range 0&percnt;-4&percnt;), and the
      higher incidence of this tumor in male rats may have been caused by the
      administration of C.I. Pigment Red 3. Hepatocellular adenomas occurred with a
      positive trend in female rats, with a significantly greater incidence in the high
      dose group than in the control group (0/50, 0/50, 1/50, 10/50). This neoplasm has
      occurred in only one historical control group in NTP feed studies (3/800, range
      0&percnt;-6&percnt;), and the increase in hepatocellular adenomas in female rats
      was attributed to chemical administration. Chemical-related nonneoplastic lesions
      observed in the livers of male and female rats included eosinophilic or mixed
      type foci of cellular alteration. Foci were often accompanied by angiectasis and
      cystic degeneration in males and by granulomas and cholesterol pigmentation in
      females. Chronic nephropathy occurred with increased severity in exposed male and
      female rats. The lesions were more severe in males than in females. Other lesions
      considered secondary to renal disease included parathyroid gland hyperplasia,
      fibrous osteodystrophy of the bone, and mineralization of various organs
      (stomach, intestine, heart, and blood vessels). The increased incidence of
      hyperplasia of the transitional epithelium of the renal papilla observed in
      treated rats was considered to be part of the chronic nephropathy. Zymbal's gland
      carcinoma incidences were marginally increased in the mid- and high-dose male
      rats (0/50, 0/50, 2/50, 3/50). The incidence in the high-dose group was outside
      the NTP historical control range (0&percnt;-4&percnt;), and the Zymbal's gland
      carcinomas may have been related to C.I. Pigment Red 3 administration.
      Mononuclear cell leukemias, mammary gland fibroadenomas, and preputial
      gland/clitoral gland adenomas occurred at lower incidences in exposed male and
      female rats. The decrease in mononuclear cell leukemia was attributed to the
      direct effect of C.I. Pigment Red 3 or its metabolites on the mechanism
      responsible for inducing leukemias in aging rats, while the decreased incidence
      of mammary gland fibroadenomas might be attributed to decreased body weights in
      female rats. The cause of the decreased incidences of preputial and clitoral
      gland tumors is unknown. Tubule adenomas of the renal cortex occurred at a
      significantly higher incidence in high-dose male mice than in controls (0 ppm,
      0/50; 12,500 ppm, 0/50; 25,000 ppm, 0/50; 50,000 ppm, 6/50). Because this tumor
      occurred only in exposed males and was outside the range for NTP historical
      controls in feed studies (0&percnt;-2&percnt;), renal cortical tubule adenomas in
      male mice were considered to be related to the administration of C.I. Pigment Red
      3. Follicular cell adenoma of the thyroid gland occurred with a positive trend in
      male mice (0/50, 0/49, 1/50, 5/50). Theincidence in the high-dose group was
      significantly greater than that in the controls. This chemical-related effect is
      supported by the increased incidence of follicular cell hyperplasia. Because the
      incidence of this tumor exceeded the range of the historical controls from NTP
      feed studies (0&percnt;-4&percnt;), the increase of follicular cell adenoma was
      attributed to chemical administration. Female mice receiving C.I. Pigment Red 3
      had a significant increase in follicular cell hyperplasia but showed no increase
      in tumor incidence at this site. Focal renal tubule hyperplasia and cystic
      hyperplasia occurred in exposed male mice but not in the controls. Cytomegaly
      (karyomegaly) of the renal tubule epithelium was seen in all treated male mice.
      The severity of the accompanying chronic nephropathy was increased in both male
      and female mice. Genetic Toxicology: C.I. Pigment Red 3 was mutagenic in
      Salmonella typhimurium strains TA100 and TA98 in the presence of exogenous
      metabolic activation (S9); no increases in gene mutation were observed in strains
      TA1535 and TA1537, with or without S9. C.I. Pigment Red 3 did not induce sister
      chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in
      either the presence or the absence of S9. Conclusions: Under the conditions of
      these 2-year feed studies, there was some evidence of carcinogenic activity of
      C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of
      benign pheochromocytomas of the adrenal gland. The marginal increase in the
      incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas
      may have been related to C.I. Pigment Red 3 administration. There was some
      evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as
      indicated by the increased incidence of hepatocellular adenomas. There was some
      evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as
      exhibited by the increased incidences of tubule adenomas of the renal cortex and
      follicular cell adenomas of the thyroid gland. There was no evidence of
      carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received
      12,500, 25,000, or 50,000 ppm. The incidences of mononuclear cell leukemia and
      preputial gland tumors in male rats and mononuclear cell leukemia, mammary gland
      fibroadenoma, and clitoral gland tumors in female rats were lower in the exposed
      groups. The incidences of liver foci were markedly increased in exposed male and
      female rats. The severity of chronic nephropathy was increased in male rats and
      to a lesser extent in female rats given C.I. Pigment Red 3. An increase in the
      severity of nephropathy was observed in male and female mice; cytomegaly
      (karyomegaly) of renal tubule epithelium was observed in male mice. Thyroid
      follicular cell hyperplasia occurred with an increased incidence in male and
      female mice receiving C.I. Pigment Red 3. Synonyms: 2-Naphthalenol, 1-((4-methyl
      2-nitrophenyl)azo)-; Calcotone Toluidine Red YP; Fast Red A; Pigment Scarlet R;
      Recolite Fast Red RBL; Sengale Light Red B

PMID- 12621524
TI  - Red cell pulmonary transit times through the healthy human lung.
AB  - It has previously been postulated that rapid red cell capillary transit through
      the human lung plays a role in the mechanism of diffusion limitation in some
      endurance athletes. Methodological limitations currently prevent researchers from
      directly measuring pulmonary capillary transit times in humans during exercise;
      however, first pass radionuclide cardiography allows direct measurement of red
      blood cell (RBC) transit times through the whole lung at various exercise
      intensities. We examined the relationship between mean whole lung red cell
      pulmonary transit times (cardiopulmonary transit times or CPTT) and different
      levels of flow in 88 healthy humans (76 males, 12 females) from several studies
      (mean age 31 years). The pooled data suggest that the relationship between CPTT
      and cardiac index (CI), beginning at rest and progressing through to maximum
      exercise demonstrates that CPTT reaches its minimum value when CI is about 8.1 l
      m2 x min(-1) (2.5-3 times the CI value at rest), and does not significantly
      change with further increases in CI. Cardiopulmonary blood volume (CPBV) index
      also does not change significantly until CI reaches 2.5 to 3 times the CI value
      at rest and then increases roughly linearly after that point. Consequently, the
      systematic increase in CPBV index with increasing pulmonary blood flow between
      8.1 and 20 l m2 x min(-1) displays an adaptive response of the cardiopulmonary
      system by augmenting CPBV (and perhaps pulmonary capillary blood volume through
      distension and recruitment) to offset the reduction in CPTT, as no significant
      difference in mean CPTT is observed between these levels of flow (P > 0.05).
      Therefore, these data demonstrate that CPBV does not reach maximum capacity
      during strenuous or maximum exercise. This does not support the principle of
      quarter-power allometric scaling for flow when explaining modifications during
      exercise. Therefore, we speculate that the observed relationships between CPTT,
      CBPV index and flow may prevent mean CPTT (and perhaps mean pulmonary capillary
      transit times) from decreasing below the threshold time required for oxygenation.

PMID- 12621525
TI  - Effects of endotoxin exposure on cationic amino acid transporter function in
      ovine peripheral blood mononuclear cells.
AB  - Rodent models of sepsis differ from clinical human disease in that humans make
      substantially less whole-body nitric oxide and have different cellular responses
      to endotoxin. Sheep, when exposed to endotoxin, behave in a manner more similar
      to humans. Many studies of rodent peripheral blood mononuclear cells (PBMCs)
      exposed to endotoxin demonstrate increased cationic amino acid transporter
      function (particularly through the y+ transporter) to supply arginine substrate
      to upregulated nitric oxide synthase. Whether this is true in sheep is not known.
      We have studied cationic amino acid transport in sheep PBMCs stimulated with
      endotoxin, using labelled lysine. PBMCs stimulated both in vitro and in vivo show
      an initial reduction in total and y+ lysine transport (after 1-2 h exposure to
      endotoxin): a previously undescribed effect of endotoxin. In in vitro activated
      cells, the reduction in y+ transport was prevented by the lipoxygenase inhibitor,
      nordihydroguaretic acid (NDGA), and the phospholipase inhibitor 4-bromophenacyl
      bromide (4-BPAB), but not cyclohexamide or a number of other inhibitors of
      intracellular second-messenger pathways. In contrast after 14 h incubation, the
      expected increase in total and y+ lysine transport was seen. The increase in y+
      transport could be prevented by cyclohexamide, dexamethasone, ibuprofen, the
      protein kinase C inhibitor sphingosine, NDGA and 4-BPAB. These results suggest
      that in response to endotoxin exposure there is an initial decrease in y+
      activity mediated by a lipoxygenase product, followed by a substantial increase
      in y+ activity mediated by the products of either cyclo-oxygenase or
      lipoxygenase. Cyclo-oxygenase and/or lipoxygenase inhibition might be useful in
      reducing arginine transport, and hence nitric oxide production, in these cells.

PMID- 12621526
TI  - Hyperglycaemia inhibits thymidine incorporation and cell growth via protein
      kinase C, mitogen-activated protein kinases and nitric oxide in human umbilical
      vein endothelium.
AB  - An elevated extracellular concentration of D-glucose (i.e. hyperglycaemia)
      inhibits cell proliferation and incorporation of the endogenous nucleoside
      thymidine into DNA in human umbilical vein endothelial cells (HUVECs). Cells in
      their log-phase of growth (3.7 +/- 0.3 days, n = 27) incubated for 30 min with 25
      mM D-glucose, but not with equimolar concentrations of L-glucose or D-mannitol,
      exhibited reduced [3H]thymidine incorporation and cell growth rate, with no
      change in cell viability (> 98 %), total DNA, protein content or cell volume.
      Incubation with D-glucose activated protein kinase C (PKC), endothelial NO
      synthase (eNOS), p42 and p44 mitogen-activated protein kinases (p42/44(mapk)),
      but inhibited superoxide dismutase (SOD). Incubation with D-glucose also
      increased cGMP and cAMP levels. The effect of D-glucose was blocked by the PKC
      inhibitor calphostin C, the MAP kinase kinase 1/2 (MEK1/2) inhibitor PD-98059,
      the eNOS inhibitor L-NAME, the protein kinase G (PKG) inhibitor KT-5823 and the
      protein kinase A (PKA) inhibitor KT-5720. In the presence of 5 mM D-glucose,
      [3H]thymidine incorporation and cell growth were reduced by the PKC activator
      phorbol 12-myristate 13-acetate (PMA), the NO donor S-nitroso-N-acetyl-L,D
      penicillamine (SNAP), dibutyryl cGMP, dibutyryl cAMP and the Ca2+ ionophore A
      23187. The effect of A-23187 was blocked by calphostin C and PD-98059. D-Glucose
      dependent inhibition of thymidine incorporation and cell proliferation is
      associated with increased PKC, eNOS, and MEK1/2, but decreased SOD activity, and
      higher intracellular levels of cGMP, cAMP and Ca2+ in HUVECs. These are cellular
      mechanisms which may reduce endothelial cell growth in pathological conditions
      such as in diabetes mellitus or hyperglycaemia.

PMID- 12621527
TI  - The effect of isoprenaline infusion on renal renin and angiotensinogen gene
      expression in the anaesthetised rat.
AB  - In this study, we investigated the ability of acute infusions of isoprenaline to
      alter renin and angiotensinogen gene expression in the kidney of rats
      anaesthetised with chloralose-urethane. Groups of rats received I.V. infusions of
      either saline or the beta-adrenoceptor agonist isoprenaline at 400 ng x kg(-1) x
      min(-1) for 4 h. The isoprenaline infusion caused a sustained decrease in mean
      blood pressure of approximately 20 mmHg (P < 0.01), an increase in heart rate of
      50 beats x min(-1) (P < 0.01) and reductions in urine flow and sodium excretion
      of 80-90 % (both P < 0.01). Renal blood flow and glomerular filtration rate were
      transiently reduced by 21 % (P < 0.01) and 61 % (P < 0.001), respectively, in the
      first hour, recovering to baseline levels after 4 h of infusion. At the end of
      the study, plasma renin activity was raised approximately 6-fold (P < 0.01) while
      renal renin and angiotensinogen mRNA levels were 1.8- and 1.5-fold higher (both P
      < 0.05) compared to the control group (saline infusion). The isoprenaline-induced
      renin secretion could have been mediated via the activation of beta-adrenoceptors
      resulting in the exocytosis of renin-containing granules, with a smaller
      contribution being due to reduced renal haemodynamics. The increase in renal
      renin gene expression in response to isoprenaline was probably due primarily to
      the intracellular signalling processes acting directly on nuclear mechanisms.
      Similarly, the increased renal angiotensinogen gene expression most probably
      reflected a direct action of the isoprenaline. These findings provide evidence
      that catecholamines are involved in mechanisms that rapidly alter the expression
      of the genes of the renin-angiotensin system within the kidney.

PMID- 12621528
TI  - Interactions between neural and hormonal mediators of renal vascular tone in
      anaesthetized rabbits.
AB  - We investigated how sympathetic nerve activity and vasoactive hormones interact
      in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. Renal
      blood flow was progressively reduced by electrical stimulation (0.5-3 Hz) of the
      renal nerves, during renal arterial infusion of saline, vasoconstrictors
      (angiotensin II and [Phe2,Ile3,Orn8]-vasopressin), or vasodilators
      (acetylcholine, adrenomedullin and the nitric oxide donor methylamine
      hexamethylene NONOate (MAHMA NONOate). A frequency-rich stimulus was also applied
      to test whether the vasoactive agents affect the dynamic control of renal blood
      flow by sympathetic nerve activity. The vasodilators tended to increase renal
      blood flow, but only the effect of MAHMA NONOate was statistically significant.
      [Phe2,Ile3,Orn8]-vasopressin reduced medullary perfusion (by 61 +/- 12 %) but not
      renal blood flow or cortical perfusion. Angiotensin II reduced renal blood flow
      (33 +/- 3 %) and cortical perfusion (14 +/- 5 %) but not medullary perfusion.
      Steady-state responses of renal blood flow and cortical perfusion during renal
      nerve stimulation were attenuated during infusion of acetylcholine and
      [Phe2,Ile3,Orn8]-vasopressin, while angiotensin II attenuated responses of
      medullary perfusion, and MAHMA NONOate and adrenomedullin had no significant
      effects. The dynamic response to sympathetic nerve activity (renal blood flow
      responded as a low pass filter with a pure time delay of ~664 ms) was not altered
      by the vasoactive agents. We conclude that some vasoactive agents can modulate
      steady-state renal haemodynamic responses to sympathetic nerve activity in a
      regionally specific manner, independent of their effects on baseline renovascular
      tone. However, they have little impact on the dynamic response of renal blood
      flow to sympathetic nerve activity.

PMID- 12621529
TI  - Chronic blockade of neuronal nitric oxide synthase does not affect long-term
      control of blood pressure in normal, saline-drinking or deoxycorticosterone
      treated rats.
AB  - It has been reported that long-term selective inhibition of neuronal nitric oxide
      synthase (nNOS) produces elevated blood pressure (BP) in normal rats. The present
      study was designed to analyse the possible influences of the sodium-retaining
      hormone deoxycorticosterone acetate (DOCA) and of an increased sodium intake on
      BP effects induced by the chronic blockade of nNOS with 7-nitroindazole (7NI).
      Two experiments were performed using 7NI at a dose of either 10 mg x kg(-1) x
      day(-1) (experiment 1) or 30 mg x kg(-1) x day(-1) (experiment 2). The following
      groups were used in both experiments: control rats, and rats that received either
      1 % saline drinking water (Salt), deoxycorticosterone acetate (DOCA), 7NI, 7NI
      plus 1 % saline (7NI + Salt) or 7NI plus DOCA (7NI + DOCA). The tail systolic BP
      (SBP) was measured in all rats once a week. At the end of the experimental
      period, the mean arterial pressure (MAP) and metabolic, morphological and renal
      variables were measured. There were no significant differences in the tail SBP,
      final MAP or glomerular filtration rate between the experimental groups and the
      control group. In both experiments, the plasma renin activity (PRA) was
      significantly inhibited in the Salt groups and suppressed in the DOCA groups. The
      PRA significantly increased in the 7NI groups, whereas the 7NI + Salt and 7NI +
      DOCA groups showed a significant inhibition in PRA, especially compared to the
      7NI groups in the two experiments. We conclude that chronic nNOS blockade is
      unable to increase BP in normal, saline-drinking or DOCA-treated rats.
      Furthermore, the nNOS blockade does not interfere with the counterbalance between
      renin and an increased sodium intake or retention.

PMID- 12621530
TI  - Effect of brain serotoninergic stimulation on sodium appetite of euthyroid and
      hypothyroid rats.
AB  - The aim of the present work was to investigate the role of the serotoninergic
      system in the control of sodium appetite of hypothyroid rats (HTR) by
      administering drugs that affect the serotoninergic activity, and to compare the
      same homeostatic behaviour in euthyroid rats (ETR) also given these drugs.
      Fenfluramine (FEN; 5.0 mg x kg(-1), I.P.), which releases serotonin in the brain,
      significantly reduced the intake of 1.8 % NaCl in HTR subjected to water and
      sodium depletion (depleted) or water, sodium and food deprivation (deprived) by
      31 and 45 %, respectively, 120 min after FEN injection, compared to HTR that
      received vehicle alone. Similarly, administration of FEN to ETR reduced 1.8 %
      NaCl intake in depleted and deprived rats by 64 and 46 %, respectively. The
      presynaptic serotonin reuptake inhibitor fluoxetine (20.0 mg x kg(-1), I.P.) led
      to the inhibition of sodium appetite in HTR during the initial 30 min in depleted
      rats and for up to 60 min post-injection in deprived rats, while sodium appetite
      inhibition persisted for longer periods in ETR. The 5HT2C receptor agonist mCPP
      (5.0 mg x kg(-1), I.P.) caused a drastic reduction in sodium appetite in HTR and
      ETR in depleted and deprived rats, respectively, after 120 min. Prior
      administration of the 5HT2C receptor antagonist LY53857 (5.0 mg x kg(-1), I.P.)
      completely blocked the inhibitory action of mCPP on sodium appetite in both HTR
      and ETR. In summary, our results suggest that the recruitment of serotoninergic
      neurons involved in the modulation of sodium appetite seems to be decreased in
      hypothyroidism due to a probable deficiency in the cerebral signalling pathway.

PMID- 12621531
TI  - Keratinocyte growth factor and epidermal growth factor can reverse the intestinal
      atrophy associated with elemental diets in mice.
AB  - Elemental diets are associated with intestinal atrophy and reduced intestinal
      integrity. Growth factors such as keratinocyte growth factor (KGF) and epidermal
      growth factor (EGF) have considerable potential for the therapeutic reversal of
      such atrophy and may have greater actions if given in combination. We examined
      the effects of recombinant human KGF (rHuKGF), EGF and their combination on
      tissue mass, cell proliferation and crypt fission throughout the intestine of
      mice fed elemental diets. rHuKGF significantly increased the relative wet weight
      of the intestine, with EGF having a lesser effect. Cell proliferation of the
      stomach, small intestine and colon were significantly increased by rHuKGF, but
      EGF only increased proliferation in the small intestine. Crypt fission in the
      small intestine and colon was significantly decreased by rHuKGF. An interactive
      effect of rHuKGF and EGF on the weight of stomach and the proliferation of the
      fundus and antrum was observed. Moreover, an interactive effect of the agents was
      also seen on crypt fission in the colon. We concluded that (1) rHuKGF and EGF
      have significant trophic effects on the stomach, small intestine and colon, (2)
      these actions vary between different sites in the gastrointestinal tract, and (3)
      interactive effects occur.

PMID- 12621532
TI  - Apoptosis-dependent acute lung injury and repair after intratracheal instillation
      of noradrenaline in rats.
AB  - Earlier work in this laboratory showed that noradrenaline (NA) induces apoptosis
      in primary cultures of alveolar epithelial cells (AECs). Apoptosis of alveolar
      epithelial cells may promote the collapse of lung barrier function. On this basis
      we hypothesized that exogenous NA, administered by intratracheal (I.T.)
      instillation, might induce AEC apoptosis in vivo followed by acute lung injury.
      Delivery of NA (10 microM) I.T. into male Wistar rats increased labelling of both
      fragmented DNA, measured by in situ end labelling (ISEL), and the active form of
      caspase 3 (anti-Casp3) 6 and 20 h after administration (P < 0.05), but
      instillation of the vehicle alone (PBS) had no effect. Both ISEL and anti-Casp3
      labelling were attenuated by concurrent I.T. delivery of the broad-spectrum
      caspase inhibitor ZVADfmk. After 6 h, most ISEL- and Casp3-positive cells were
      located in the surfaces of alveolar walls, but after 20 h more were found in
      alveolar spaces (P < 0.05). Instillation of NA also increased the bronchoalveolar
      lavage (BAL) content of fluorescent albumin (BODIPY-alb), which had previously
      been injected intravenously; the increase was reversed by concurrent ZVADfmk
      administration. These data suggest that NA-induced apoptosis of AECs in vivo is
      sufficient to invoke transient collapse of AEC barrier function that is rapidly
      repaired.

PMID- 12621533
TI  - G protein-coupled receptor kinases 2 and 5 are differentially expressed in rat
      skeletal muscle and remain unchanged following beta2-agonist administration.
AB  - Chronic stimulation of beta2-receptors with beta2-agonists causes
      desensitisation, which in skeletal muscle is accompanied by myosin heavy chain
      (MHC) remodelling, similar to that observed in heart failure patients. However,
      the mechanisms for this skeletal muscle remodelling are not well established. G
      protein-coupled receptor kinases (GRKs) specifically phosphorylate and
      desensitise G protein-coupled receptors during periods of agonist activation.
      However, desensitisation associated with prolonged agonist activation alters beta
      adrenergic signalling, and downstream affects gene expression. We hypothesised
      that skeletal muscle remodelling induced by beta2-agonist administration could be
      regulated by GRK expression. Therefore the aim of this study was firstly to
      characterise which, if any, of the six known isoforms of GRK were expressed in
      skeletal muscle and then secondly to determine whether remodelled skeletal muscle
      induced by chronic beta2-agonist administration was accompanied by altered
      expression of GRK isoforms. Male Wistar rats were administered a beta2-agonist
      daily for 8 weeks, and the expression of MHC and GRKs examined in gastrocnemius
      and soleus muscles. Treatment with beta2-agonist caused a change in MHC in soleus
      from types I to IIA, and in gastrocnemius from MHC types IIA/IIX to IIB. Western
      blotting revealed that GRK2 and GRK5 were expressed in skeletal muscle.
      Furthermore, despite changes in MHC and differential muscle-specific expression
      of GRK isoforms, there was no significant change in expression of GRK2 and GRK5
      in soleus or gastrocnemius following beta2-agonist administration. In conclusion
      the level of GRK expression is unlikely to be responsible for MHC switching
      following chronic beta2-receptor stimulation.

PMID- 12621534
TI  - Static fusimotor action during locomotion in the decerebrated cat revealed by
      cross-correlation of spindle afferent activity.
AB  - Cross-correlation of the discharges of muscle spindle afferents in ankle extensor
      and flexor muscles has been used to reveal the activity of static gamma (gammaS)
      motoneurones innervating chain intrafusal muscle fibres during locomotion. In the
      anaesthetised cat, the cross-correlation of spindle afferents, jointly innervated
      by a gammaS-efferent with chain fibre contacts, showed short duration synchrony
      (2-8 ms) when the efferent was stimulated repetitively. In pre-mammillary
      decerebrated cats, the cross-correlograms of discharges of some pairs of spindle
      afferents showed similar short duration peaks of synchronisation and these were
      interpreted as being due to a common gammaS drive to chain intrafusal muscle
      fibres. The incidence of synchrony was low, and was similar at rest (5 % of
      pairs) and during treadmill locomotion (7 % of pairs). Phase dependence of
      synchrony was evident during locomotion in the flexor muscle. The synchrony of
      muscle spindle afferent discharge is discussed in relation to estimates of the
      numbers of spindles contacted by individual gammaS-efferents.

PMID- 12621535
TI  - Cerebral metabolism is influenced by muscle ischaemia during exercise in humans.
AB  - Maximal exercise reduces the cerebral metabolic ratio (O2/(glucose + 1/2
      lactate)) to < 4 from a resting value close to 6, and only part of this decrease
      is explained by the 'intent' to exercise. This study evaluated whether sensory
      stimulation of brain by muscle ischaemia would reduce the cerebral metabolic
      ratio. In 10 healthy human subjects the cerebral arterial-venous differences (a-v
      differences) for O2, glucose and lactate were assessed before, during and after
      three bouts of 10 min cycling with equal workload: (1) control exercise at light
      intensity, (2) exercise that elicited a high rating of perceived exertion due to
      a 100 mmHg thigh cuff, and (3) exercise followed by 5 min of post-exercise muscle
      ischaemia that increased blood pressure by approximately 20 %. Control exercise
      did not significantly affect the a-v differences. However, during the recovery
      from exercise with thigh cuffs the cerebral metabolic ratio decreased from a
      resting value of 5.4 +/- 0.2 to 4.0 +/- 0.4 (mean +/- S.E.M.; P < 0.05) as a
      discrete lactate efflux from the brain at rest shifted to a slight uptake. Also,
      following post-exercise muscle ischaemia, the cerebral metabolic ratio decreased
      to 4.5 +/- 0.3 (P < 0.05). The results support the hypothesis that during
      exercise, cerebral metabolism is influenced both by the mental effort to exercise
      and by sensory input from skeletal muscles.

PMID- 12621536
TI  - The ECG: what is 'normal'?

PMID- 12621537
TI  - Ageing of ex-sportsmen: ergonometric parameters of ex-elite athletes.
AB  - After the cessation of physical activity for six or more years, processes start
      to occur in previously active sportsmen that cause aerobic capacity to reach the
      values observed in people of the same age who have never participated in sport.
      However, the physical capacity of these people remains above the average level
      for the same age group. The important factors related to the aerobic capacity of
      ex-elite sportsmen are the age, current physical activity and body weight. There
      is no relationship between their maximal aerobic capacity and the type of sport
      discipline practiced by the ex-athlete in the past.

PMID- 12621538
TI  - Typical electrocardiographic deviations after cessation of physical activities in
      elite sportsmen.
AB  - We observed that ECG changes associated with high levels of sporting activity are
      reversible in the majority of cases after cessation of the sports career. This is
      probably related to the normalization of the raised vagal tone and diminution of
      the effort-related heart hypertrophy and chamber dilatation in ex-sportsmen. The
      persistent ECG changes observed in some of the ex-sportsmen could be related to
      the ageing processes observed in the general population as well. It is important
      that all ECG deviations in ex-sportsmen be considered seriously and interpreted
      in the context of the ECGs obtained during the active sports career.

PMID- 12621539
TI  - Physical inactivity as a risk factor for cardiovascular disease in communities
      undergoing rural to urban transition: the THUSA study.
AB  - BACKGROUND: Coronary heart disease (CHD) remains uncommon among South African
      blacks. Habitual physical activity contributes to the low prevalence of CHD in
      this population. The aim of this study was to determine the physical activity
      levels of black South Africans in the North West Province and to assess the
      relationship between physical activity and the prevalence of risk factors for
      cardiovascular disease in a cross-sectional study. SUBJECTS AND METHODS:
      Apparently healthy volunteers (n = 946) were recruited from randomly selected
      sites in the North West Province, South Africa. Measurements were made in
      community halls. Demographic data, anthropometric measurements and physical
      activity were determined. Blood pressures were measured, blood was drawn and
      serum and plasma samples were prepared. Biochemical variables were determined
      using standardised methodology. RESULTS: Men were significantly more active than
      women, with mean physical activity index (PAI) scores of 3.66 +/- 1.78 and 2.75
      +/- 1.04 respectively (P = 0.0001). Subjects in the deep rural areas were more
      inactive than more urbanized subjects. With multivariate tests in men, no
      statistically significant differences in CHD risk could be found with increasing
      physical activity, except for fasting insulin, which was significantly lower in
      the moderately active group than in the inactive group. In women, the most active
      group had a significantly higher mean high-density lipoprotein (HDL)-cholesterol
      concentration than the most inactive group and also a significantly lower mean
      triglyceride concentration. The most active group of women also had a
      significantly higher mean fasting serum glucose than the less active group. Among
      both men and women, inactive overweight subjects had the highest mean systolic
      blood pressure, total serum cholesterol and low-density lipoprotein (LDL)
      cholesterol. CONCLUSIONS: In men, only fasting serum insulin was significantly
      associated with physical inactivity, but in woman, a number of cardiovascular
      disease risk factors were significantly associated with physical inactivity
      especially in overweight subjects.

PMID- 12621540
TI  - Autopsy-determined causes of death following organ transplantation in 25 patients
      aged 20 years or younger.
AB  - AIM: This study aims to examine the autopsy-determined principal and proximate
      causes of death in 25 patients aged 20 years or younger who died during the 10
      year period from 1990 to 1999 after receiving an organ transplant at the
      University of Minnesota/Fairview-University Medical Center. METHODS: The autopsy
      records of this institution were examined for organ transplant recipients who
      were aged 20 years or younger at the time of their death. In each case, after
      review of the clinical and pathological data, the principle cause of death
      (PCOD), as well as the proximate cause of death (PXCOD) were noted. RESULTS: A
      total of 25 recipient patients were identified (five heart, five lung, five
      kidney and 10 liver transplants). Seven patients died 30 days or less post
      operatively and 18 died thereafter. The following categories of PCOD were
      encountered: operative/technical complications 28%, most (6/7) being associated
      with liver transplantation. Infection (24%) and chronic rejection (12%) were
      other important PCOD. Respiratory complications accounted for 47% of the PCOD.
      The following categories of PXCOD were noted: technical problems 16%, pulmonary
      pathology 24%, miscellaneous 32%, acute rejection 4% and nil 20%. CONCLUSIONS:
      This study revealed that technical problems in liver transplants were an
      important PCOD; respiratory complications and chronic rejection were additional
      major causes of mortality in this young age group of transplant recipients.
      Pulmonary pathology and technical problems were the commonest specific groups
      contributing to the PXCOD.

PMID- 12621541
TI  - Chronic idiopathic effusive pericarditis in a patient with 'cor pulmonale'.
AB  - Chronic idiopathic pericarditis is a diagnosis of exclusion that is estimated to
      occur in 3.5% of primary pericardial disease. It is possible that many of these
      cases are secondary to unrecognised viral infections. The natural history is
      variable and treatment should be individualised, although chronic colchicines
      administration may hold promise as a newer therapeutic modality in symptomatic
      recurrent pericarditis. This case presentation illustrates the diagnostic and
      therapeutic difficulties that may arise in such patients.

PMID- 12621542
TI  - Are all statins created equal?

PMID- 12621543
TI  - The jury is still out on oestrogens and oestrogen/progestin and the heart.

PMID- 12621544
TI  - Monomeric B27 Lys destripeptide insulin: semisynthesis, characterization and
      biological activity.
AB  - In this paper, we report the semisynthesis of B27 Lys destripeptide insulin (B27
      Lys DTrI), i.e. destetrapeptide insulin with an additional Lys residue at the C
      terminus of B-chain. B27 Lys DTrI is also monomeric as shown by gel filtration.
      Its in vivo biological activity is 80% in comparison with that of native insulin.
      The addition of a Lys residue at the C-terminus of B-chain makes it possible to
      obtain monomeric B27 Lys DTrI from a precursor expressed in Saccharomyces
      cerevesiae by tryptic hydrolysis instead of the less efficient tryptic
      transpeptidation.

PMID- 12621545
TI  - Purification, characterization and biological activity of an L-amino acid oxidase
      from Trimeresurus mucrosquamatus venom.
AB  - An L-amino acid oxidase (TM-LAO) from the venom of Hunan Trimeresurus
      mucrosquamatus was purified to homogeneity by three steps including DEAE Sephadex
      A-50 ion-exchange chromatography, Sephadex G-75 gel filtration and Resource Q ion
      exchange chromatography. TM-LAO is composed of two identical subunits with a
      molecular weight of 55 kD by SDS-polyacrylamide gel electrophoresis. The
      molecular weight was different with that of LAO purified from the same species
      distributed in Taiwan that was 70 kD. The 24 N-terminal amino acid sequence of TM
      LAO is ADNKNPLEECFRETNYEEFLEIAR, which shares high similarity with other Viperid
      snake venom LAOs and has moderate similarity with Elapid snake venom LAOs.
      Further studies found that TM-LAO inhibited the growth of E. coli, S. aurues and
      B. dysenteriae. TM-LAO also showed cytotoxicity and platelet aggregation
      activity. All the biological activities were eliminated by catalase, a H(2)O(2)
      scavenger. It was shown that these biological effects were possibly due to the
      formation of H(2)O(2) produced by TM-LAO.

PMID- 12621546
TI  - [An insertion mutant of LeuRS with 116 amino acid residues has full activity].
AB  - Escherichia coli leucyl-tRNA synthetase (LeuRS) belongs to class I aminoacyl-tRNA
      synthetases. It consists of 860 amino acid residues and catalyzes the leucylation
      of tRNA(Leu). An insertion of its 253-368 peptide fragment between 368 to 369 in
      CP1 domain of this enzyme was shown to maintain the activity of the enzyme, and
      the insertion mutant was named as LeuRS-C. Because the insertion mutant of LeuRS
      was sensitive to operation of the purification, a plasmid containing the gene
      encoding LeuRS with His(6)-tag at its N-terminus was constructed to facilitate
      the purification of His(6)-LeuRS-C through one-step affinity chromatography on
      Ni(2+)-NTA column. The purified His(6)-LeuRS-C had full activity as the native
      LeuRS with His-tag at the N-terminus (His(6)-LeuRS), although the mutant enzyme
      had an insertion of 116 amino acid residues. The kinetic parameters of His(6)
      LeuRS-C were determined. The secondary structure estimated by CD spectrum and
      thermal stability of the insertion mutant was compared with those of His(6)
      LeuRS, respectively.

PMID- 12621547
TI  - Identification of a novel human zinc finger protein gene ZNF313.
AB  - A novel human zinc finger protein gene that contains both ring finger and
      C(2)H(2) domain was first isolated by mRNA differential display between the
      testes of fertile adults and azoospermic patients followed by rapid amplification
      of cDNA ends (RACE). Total 6 exons of the human gene span a 17,484 bp genomic DNA
      sequence that was mapped to chromosome 20q13 by fluorescence in situ
      hybridization. The mature processed mRNA encodes a 228-amino acid protein with a
      C(3)HC(4) ring finger and three C(2)H(2) domains. Genomic analysis of the human
      gene identified two polyadenylation signals in exon 6 resulting in alternative 3'
      untranslated regions. Results of Northern blot and RT-PCR of RNAs extracted from
      multiple tissues revealed that the gene has two transcripts of which the shorter
      transcript was expressed abundantly in fertile adult testes, but much less in
      testes of azoospermic patient, fetus as well as other human tissues. These data
      suggest that the gene may play a role in human spermatogenesis and male
      fertility.

PMID- 12621548
TI  - [RNA interference in three ES cell lines from different mouse strains].
AB  - RNA interference phenomenon in three different murine ES cell lines (MESPU13, B3,
      and R1) is reported. A vector(pdsGFP) was used that transcribed hairpin double
      stranded RNA of GFP gene to transfect ES cells by using lipofectin. The transient
      transcription of dsRNA induced RNAi (RNA interference) in the ES cells. That is,
      the double-stranded RNA of GFP gene potently turned down the expression of the
      GFP gene. On the hand, the linearized plasmid pdsGFP-puro was electroporated into
      MESPU13 ES cells, and the expression level of GFP after puromycin screening was
      turned down obviously in about 30% ES cell clones; and in a few clones, the
      expression level of GFP was not observed under the fluorescence microscope and
      GFP mRNA was not detectable by RT-PCR. Further more, another vector (pdsOCT4) was
      constructed that transcribed double-stranded RNA of OCT-4 gene which is
      specifically expressed in ES cells. ES cell clones that stably integrated the
      vector were screened after the electrotransfection of the cells with the above
      construct. 51 random-selected clones were amplified and 48 of them were checked
      by semi-quantitative RT-PCR. In 11 of them the mRNA of OCT-4 was undetectable by
      RT-PCR. This means that RNAi can be used to study mammal and human gene's
      function in ES cell lines from different strain mice.

PMID- 12621549
TI  - [Functions of neutrophil gelatinase-associated lipocalin in the esophageal
      carcinoma cell line SHEEC].
AB  - Neutrophil gelatinase-associated lipocalin (NGAL) is a novel member of the
      lipocalin family and may be a new human oncogene product, but function of NGAL is
      not clear in the cancer. It was recently found that NGAL was overexpressed in the
      progression of malignant transformation from human immortalized esophageal
      epithelial cell line SHEE to esophageal carcinoma cell line SHEEC. This indicated
      that cell line SHEEC was a good model for exploring functions of NGAL in the
      carcinogenesis. The effects of blocking transcription of NGAL gene on invasion,
      division and proliferation of SHEEC cells were studied by antisense blocking RNA
      technique and tumor formation in nude mice. The results showed that the antisense
      blocking of transcription of NGAL gene not only decreased effectively the
      activity of MMP-9 and MMP-2 secreted by SHEEC cells, but suppressed significantly
      also the invasion of these cells in nude mice. However, the telomere length, the
      content of the cellular topoisomerase II-alpha and cellular proliferation index
      (PI) of the SHEEC cells have not been changed markedly. These results indicate
      that NGAL is possibly involved in invasion of tumor cells by regulating activity
      of MMP-9 and MMP-2, but is not apparently related with division and proliferation
      of tumor cells in SHEEC.

PMID- 12621550
TI  - [Subcellular localization of basic Kruppel-like factor].
AB  - To understand the function of basic Kruppel-like factor (BKLF), it was confirmed
      by direct fluorescence and indirect fluorescence observation that hBKLF was
      localized in nucleus, and distributed throughout nucleoplasm in a speckled
      pattern, except the nucleoli. This pattern is similar to many but not all
      transcription factors. To clarify the specific sequence responsible for its
      nuclear localization, a series of deletion mutants of GFP/hBKLF were constructed.
      By observing their subcellular localization, it was found that the three zinc
      fingers of hBKLF and the N-terminal aside from the fingers all served as nuclear
      localization signals (NLS); the sub-NLS of hBKLF was located in the N-terminus,
      including the CtBP-binding motif and the proline rich domain. These results
      provided a basis for further clarifying the function of BKLF.

PMID- 12621551
TI  - [Construction and function analysis of a CTAR-2 region mutant of the Epstein-Barr
      virus-encoded latent membrane protein-1].
AB  - To investigate the activating sites and functional mechanism of Epstein-Barr
      virus(EBV)-latent membrane protein-1(LMP1), a mutant type LMP1(mt-LMP1) was made
      by PCR methods, replacing the amino acid residues YYD with ID in carboxy terminal
      activating region-2 (CTAR-2) at position 384-386 codons. The mt-LMP1 and wild
      type LMP1 (wt-LMP1) were cotransfected with transcription factor NF-kappa B or AP
      1 luciferase reporter into 293 cells, respectively, and their actions in
      activating transcription factors were compared by results of luciferase activity
      assay. Moreover, mt-LMP1 and wt-LMP1 were transfected into Rat-1 cells to compare
      their transforming effects by contact inhibition assay. The results showed that
      (1) Compared with wt-LMP1, mt-LMP1 was 80% defective in NF-kappa B activation and
      100% defective in AP-1 activation. (2) Colony formation number (CFN) of Rat-1
      cells expressing mt-LMP1 was significantly decreased compared with CFN of Rat-1
      cells expressing wt-LMP1 [(23+/-3)/well vs. (357+/-19)/well; (64+/-8)/well vs.
      (408+/-40)/well. n=3, P>0.001]. These results suggested that amino acid residues
      384-386 in CTAR-2 may be one of the most important function sites of LMP1 and the
      activation of NF-kappa B and AP-1 might be closely related to LMP1-mediated cell
      transformation and tumorigenesis.

PMID- 12621552
TI  - [Enhancement by an in vivo-activated promoter of immunogenicity of recombinant
      attenuated Salmonella typhimurium expressing hepatitis C virus core antigen].
AB  - The promoter of phoP-activated gene C (P(pagC)) of Salmonella typhimurium was
      cloned and used as transcriptionally regulating element for a plasmid that
      expresses hepatitis C virus core antigen. The resultant plasmid was transformed
      into attenuated Salmonella typhimurium SL7207 and its expression activity in
      vitro was determined. Mg(2+) inhibited the recombinant bacteria to express HCV
      core antigen in a dose-dependent manner. This recombinant strain, and another
      bacterial strain that constitutively expresses HCV core antigen were orally
      inoculated BALB/c mice respectively. The stability of the plasmid in the bacteria
      and the immune responses was analyzed. The results showed that the in vivo
      activated P(pagC) promoter could stabilize the plasmid in the bacteria and
      enhance the humoral and cellular immune responses greatly, showing a novel way to
      produce effective, cheap oral vaccine against hepatitis C.

PMID- 12621553
TI  - [Transcriptional regulation of gamma- and epsilon-globin genes by basic Kruppel
      like factor].
AB  - To study the transcription regulatory function of basic Kruppel-like factor
      (BKLF)on gamma- and epsilon-globin genes, recombinant expression vectors
      containing the full-length human BKLF gene, and a deletion mutant that lost N
      terminal 40 amino acids, were constructed and used, respectively, to transiently
      transfect COS7 cells in order to assay their reporter activities. Results showed
      that hBKLF was able to repress the activity of gamma- and epsilon-globin gene
      promoters, while the antisense nucleic acid specific for hBKLF activated the
      transcription of these promoters. Deleting 40 amino acids from N-terminus did not
      influence the transcriptional repression of hBKLF. The stimulatory function of
      FKLF on gamma- and epsilon-globin gene promoters was also significantly reduced
      by hBKLF. In addition, BKLF bound the CACCC element in the SHP1 (SH2-containing
      protein tyrosine phosphatase 1) gene promoter. These results suggest that gamma-
      and epsilon-globin genes may be transcriptional targets of BKLF, providing
      evidence for further studies on the role of BKLF in participating the
      transcriptional regulation of haemocyte-specific genes.

PMID- 12621554
TI  - [Enhancement by FK506 of triptolide-induced inhibition of expression of COX-2 and
      iNOS in human rheumatoid arthritis synovial fibroblasts].
AB  - To explore the effects of FK506 on the inhibition by triptolide (TP) of cell
      proliferation and expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide
      synthase (iNOS) and their inducing products PGE2, NO in human rheumatoid
      arthritis synovial fibroblasts (RASF), and to study the mechanisms of combination
      of FK506 and TP in RA therapy, RASF used in the experiments were obtained from
      synovial tissue of patients with RA and were cultured. RASF were pretreated with
      FK506(10-1000 nmol/L)for 2 h, then the cells were stimulated with TNF alpha(20
      microg/L) in the presence or absence of TP (10 microg/L). The RASF proliferation
      was determined by [(3)H]-TdR incorporation, and the productions of PGE2 and NO in
      culture supernatants of RASF were detected with competitive ELISA and enzyme
      reduction of nitrate. Expression of COX-2 and iNOS mRNA in RASF were analyzed by
      semi quantitative RT-PCR. Expressions of COX-2 and iNOS protein were estimated by
      Western blot method and cellular enzyme immunoassay in synovial fibroblasts. NF
      kappa B activity in whole-cell extract of RASF was also measured by an ELISA
      based method. Results showed that neither FK506 nor TP at lower concentration (10
      microg/L) alone affected TNF alpha-induced COX-2, iNOS expression and production
      of PGE2, NO in synovial cells. Combined treatment of FK506 and a lower
      concentration of TP (10 microg/L) down-regulated COX-2 and iNOS mRNA and protein
      expression, and their inducing products PGE2 and NO of synovial fibroblasts. This
      effect was positively correlated with FK506 concentrations (10-1000 nmol/L). NF
      kappa B activity in TNF alpha-stimulated synovial cells was suppressed more
      profoundly by FK506 plus TP (10 microg/L) treatment than those with TP (10
      microg/L) alone. No change was observed in inhibition of proliferation of
      synovial cells after combined treatment of FK506 and TP. In conclusion, FK506
      enhanced TP-mediated down-regulation of COX-2, iNOS and their inducing products
      PGE2, NO in human RASF by suppressing the activity of NF-kappa B.

PMID- 12621555
TI  - [Cloning of cDNA of TSARG4, a human spermatogenesis related gene].
AB  - To understand molecular mechanism of spermatogenesis, two ESTs BG720564 and
      AI700454, were found from SPAG4 (sperm antigen 4), a gene related to dense fiber
      protein of outer membrane of the human sperm and mouse spermatocytes gene
      AK006225. The gap was filled by polymerase chain reaction, and a 1252 bp fragment
      was obtained. This 1252 bp fragment was named TSARG4 (testis and spermatogenesis
      related gene 4 (GenBank accession number AF401350). Its opening reading frame was
      94-1233 bp, as was proved by RT-PCR in human testis. TSARG4 gene was located in
      20q11.2, and the putative protein was 379 amino acid with a theoretical molecular
      weight of 43 081 and isoelectric point of 8.61. The homologies of amino acid
      sequences were 74% between TSARG4 and AK006225 gene and 45% between TSARG4 and
      SPAG4 gene, respectively. The human TSARG4 mRNA is expressed in a wide range of
      adult tissues, including testis, whereas the homologous mouse spermatocytes gene
      AK006225 is expressed specifically in the testis.

PMID- 12621556
TI  - [Detection of 2'-O-ribose Methylation Sites on Rice 25 S rRNA].
AB  - Ribose methylation is a widespread type of nucleotide modification in rRNA. In
      order to map the methylation sites of rice 25 S rRNA, a series of primers
      complementary to both yeast 28 S and rice 25 S rRNA simultaneously were
      synthesized. Primer extensions at different dNTP concentrations were carried out
      to detect the methylation sites of both yeast and rice rRNAs. The data showed
      that over 80% of the methylation sites in yeast 28 S rRNA was also detected in
      rice. In addition, compared with the known methylation sites of Arabidopsis 25 S
      rRNA, other 54 sites probably methylated in rice were found in Arabidopsis. Thus,
      there are 85 methylation sites detected altogether; the distribution of the
      methyl sites in rice 25 S rRNA was determined. The results show that most of the
      sites are conserved among different species, especially between closely related
      species. And remarkably, there are much more ribose methylation sites in plant
      rRNA, and the propinquous methylation sites in plants are more frequent than
      those in other eukaryotes. Moreover, the data provide the most important clue for
      searching new box C/D snoRNAs.

PMID- 12621557
TI  - Real-time detection of nitric oxide in cultured rat aorta endothelial cells
      induced by shear stress.
AB  - To establish a stable and real-time method to detect the production of
      intracellular nitric oxide (NO) of endothelial cells under different shear
      stresses. After the cultured endothelial cells were loaded with DAF-FM, the
      relative NO production was determined by fluorescence intensity, which was
      detected using Zeiss Axioskop 2 fluorescence microscope and ICCD-camera. The
      fluorescence of DAF-FM can reflect NO production. Shear stress can induce a dose
      dependent increase of NO production, and the increase can be totally inhibited by
      L-NAME and partly inhibited by Ca(2+)-free buffer. The method can be used to
      detect the change of NO production in real time, and it can also be used to study
      the mechanism related to NO increase induced by shear stress.

PMID- 12621558
TI  - [Adriamycin or adriamycin-Fe3+ induced bovine serum albumin damage].
AB  - ESR spectroscopy was used to investigate the production of reactive oxygen
      radicals in adriamycin (ADM) and its iron complex. The results showed that ADM
      Fe(3+) induced the production of oxygen radicals more efficiently than ADM. The
      damage of BSA mediated by ADM or ADM-Fe(3+) was investigated by measuring the
      increase of reactive carbonyl content and the decrease of the fluorescence
      intensity of the Trp residue. It was shown that the damage of bovine serum
      albumin (BSA) was dependent on the time and on the concentration of ADM or ADM
      Fe(3+). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that
      BSA was not cross-linked nor fragmented by the effect of ADM or ADM-Fe(3+). It
      was also found that oxygen radical scavengers could inhibit the damage of BSA
      induced by ADM or ADM-Fe(3+), suggesting that ADM or ADM-Fe(3+) induced protein
      damage via the oxygen radicals produced in the reaction.

PMID- 12621559
TI  - Mandibular symphyseal contouring in mild mandibular prognathism.
AB  - Kolle's mandibular segmental osteotomy, with extraction of the bilateral first
      bicuspids, is often used in cases of mild mandibular prognathism. While
      mandibular prognathism is usually corrected by mandibular ramus osteotomy and the
      mandible is set back en bloc, the premolar region alone is set back by segmental
      osteotomy, retaining the protruding mental area. In Asians, particularly, the
      protruding chin is not preferred by our concepts of beauty. In mandibular
      segmental osteotomy, the entire mandibular symphyseal shape should be considered.
      Mandibular symphyseal contouring constitutes setting back the premolar region by
      segmental osteotomy, recession genioplasty, and chiseling out the protruding
      middle portion of the protruding chin. In 18 series of mild manibular prognathism
      in Asians patients, this procedure was used and satisfactory aesthetic results
      were obtained.

PMID- 12621561
TI  - Unilateral osteotomies for externally deviated noses.
AB  - Despite the many methods described for correction of the deviated nose, it still
      continues to be one of the most challenging problems in rhinoplasty. It is
      obvious from the literature that the deformities present in the deviated nose can
      be quite different from patient to patient and that there is no one method that
      should be used for every deviated nose. Although unilateral osteotomy technique
      is not a new concept, so far it has not received the interest of plastic
      surgeons. Shorter operation time, lessened surgical trauma to the nose, lessened
      intraoperative bleeding, lessened postoperative edema, and lessened recurrence of
      the deviation are distinct features of the unilateral osteotomy technique that
      should be considered when planning surgery on such a complex deformity. We
      present our experiences with unilateral osteotomy and recommend it for patients
      who have a deviation related to only one side of the nose.

PMID- 12621560
TI  - The use of lower turbinate bone grafts in the treatment of saddle nose
      deformities.
AB  - Saddle nose reconstruction is based on the use of support grafts to manage
      aesthetic and functional problems. Bone (calvarial, iliac crest, costal, nasal
      hump, ulnar, and heterogeneous origin), cartilage (septal, costal,
      heterogeneous), and synthetic materials (silicon, silastic, polyethylene) were
      used as support grafts. Three patients have been included in this study to define
      the surgical management and long-term aesthetic and functional results of
      patients undergoing rhinoplasty with support grafts for a saddle nose deformity.
      Open rhinoplasty was employed. Both the lower turbinates were excised and the
      bone dissected from the soft tissues in two cases and in one case, only mucosa
      was removed. The amount of support needed was measured by using bone wax. The
      bone was used shaped in layers, according to the defect, and sutured to each
      other by vycril suture, and wrapped around by surgicell. The graft was then
      inserted in its place and fixed with external prolene sutures. Results were
      satisfactory in both function and aesthetics. Ten to 16-month follow-ups had no
      complications. Saddle nose surgery basically requires the use of a support graft
      to repair the nasal dorsum. A lower turbinate bone graft procedure has some
      advantages: it is cheap and safe, it is ready to use and not time-consuming,
      there is no donor area and no additional donor site morbidity, and it enlarges
      the airway and the passage to prevent nasal airway obstruction.

PMID- 12621562
TI  - Free temporoparietal fascial flaps and full-thickness skin grafts in aesthetic
      restoration of the nose.
AB  - Free tissue transfers have been rapidly replacing distant flaps for use in nasal
      reconstruction. The temporoparietal fascial flap is a thin, broad, pliable, and
      well-vascularized flap. It can be used to drape over the cartilaginous and bony
      framework of the nasal skeleton and nourish the underlying primary cartilage
      grafts as well as the overlying full-thickness skin graft. The thin contour of
      the flap is aesthetically superior to thicker skin flaps and eliminates the need
      for secondary defatting or touch-up procedures. A large, single sheet of full
      thickness skin graft, harvested from the supraclavicular region, can be applied
      over the fascial flap in the same session and provide a quite acceptable color
      match. The authors present a case whose alar margins and atrophic nasal skin were
      restored in one session by primary conchal cartilage grafts, a free
      temporoparietal fascial flap, and a full-thickness supraclavicular skin graft.

PMID- 12621563
TI  - An unusual complication of a Medpor implant in nasal reconstruction: a case
      report.
AB  - There are few implant materials which have been successfully used for nasal
      reconstruction. Of these, the medpor implant is the most accepted alloplastic
      material for reconstruction of the nasal framework. Here, an unusual complication
      of a medpor implant in nasal reconstruction is presented. A 24-year-old medical
      student suffering from a saddle nose deformity after a primary rhino plasty was
      admitted to our department. The medpor nasal implant was used to restore the
      nasal dorsum. The surgical result was appreciated by the patient. No problem was
      encountered during two years after surgery. Recently, the patient suffered from
      an asymmetry of the nasal dorsum. The physical examination revealed a step on the
      nasal dorsum with caudal mobility of the implant. The nasal implant was suspected
      to be broken. Multislice CT scan and ultrasonographic imaging of the implant were
      obtained. The radiologic evaluation of the region confirmed the fracture of the
      medpor nasal implant. Nasal reconstruction with a medpor implant is a good choice
      with low complication rates. This is the first case in the literature reporting a
      broken medpor nasal implant. Moreover, in this study a new method is described
      for imaging the medpor implant material.

PMID- 12621564
TI  - Functional lower lip reconstruction with bilateral cheek advancement flaps:
      revisitation of Webster method with a minor modification in the technique.
AB  - Major defects of the lower lip have been repaired in many ways. Of these, some
      employed flaps from the chin, cheek or upper lip. Some of these procedures
      employed flaps without regard for the facial grooves or landmarks. Some methods
      required incisions through nerves supplying the orbicularis oris and the flaps
      used for the lower lip reconstruction. Of the many methods of reconstruction that
      have been reported, we believe that the Webster technique should be considered as
      the first choice for lower lip defects larger than 80% of the total. Because this
      technique interferes minimally with the sensation of the lower lip and a
      satisfactory cosmetic outcome with a functional lower lip is achieved, the
      sensation and muscle function of the upper lip are unaffected. In addition to
      discussing the advantages of the Webster method, in this paper we present a minor
      modification in the dissection of the orbicularis oris muscle in an attempt to
      improve the motor innervation and to provide adequate oral competence and labial
      functioning in expression and speaking. Motor function and innervation of the
      lips after reconstruction was documented by clinical findings as well as
      electrophysiological methods.

PMID- 12621565
TI  - Aesthetic breast reconstruction.
AB  - Breast reconstruction is fully justified only from an aesthetic perspective. A
      reconstructed breast, therefore, should be as aesthetically natural and similar
      to the contralateral one as possible, even if this means reproducing some little
      defects. The breast's profile (projection, ptosis, sulcus location, and
      superficial unevenness), symmetry, areola, and nipple are the characterizing
      aesthetic factors. The authors present their experience in prosthetic breast
      reconstruction seen with an aesthetic eye and an artistic touch, illustrating
      personal tips and technical adjustments: use of anatomical prostheses, pectoralis
      muscle treatment, sulcus stabilization or reconstruction, superficial
      irregularities correction, and nipple-areola complex reconstruction. Results are
      evaluated by both the surgeon and the patient using a score system, validating
      the method.

PMID- 12621566
TI  - Importance of pedicle length in inferior pedicle technique and long-term outcome
      of areola-to-fold distance.
AB  - Various techniques are being used to perform reduction mammaplasty. One of the
      most widely used techniques is the inferior pedicle technique. To our knowledge,
      there are not many studies on long-term changes in areola-to-fold distance,
      distribution of pedicle length, and its importance. Therefore, in this study,
      breast volume, suprasternal notch-to-nipple distance, and nipple-to-inframammary
      fold distance were analyzed and the movement range of the nipple-areola complex
      was determined. In addition, the degree of benefit derived from the technique and
      the degree of long-term ptosis were investigated. The desired transposition of
      the nipple can be achieved by the inferior pedicle technique. The most serious
      complication of reduction mammaplasty is impairment of the blood supply to the
      nipple. However, the inferior pedicle technique has a slight possibility of
      causing the above complications. The most important criterion in deciding whether
      to perform free nipple technique or inferior pedicle technique is the pedicle
      length. This is a detailed study on the pedicle length and its statistical
      analysis.

PMID- 12621567
TI  - Double-pedicle TRAM flap breast reconstruction: following Bostwick's principles.
AB  - After using various techniques with various results, Bostwick's principles for
      breast reconstruction were used in mastectomy cases and their early results are
      presented. The breast reconstructions were performed to 12 cases, of which eight
      patients had one or two risk factors and four had more. The double-pedicle
      technique was used in the former and vascular delay preceding double-pedicle
      technique was used in the latter. No vascular compromises, arterial or venous,
      were observed on the flaps in the acute phase and no fat necrosis ensued lately.
      All patients were satisfied with these principles and we did not observe any
      problems with the flaps. We have concluded that Bostwick's principles offered a
      reliable and minimal risk basis for breast reconstructive surgeons.

PMID- 12621568
TI  - The use of the ipsilateral versus contralateral pedicle and vertical versus
      horizontal flap inset models in TRAM flap breast reconstruction: the aesthetic
      outcome.
AB  - The use of an ipsilateral or a contralateral rectus abdominis muscle as a pedicle
      and comparison of their advantages and disadvantages in TRAM flap breast
      reconstruction have been reported in the literature. In our clinical experience
      with 22 pedicled TRAM flap breast reconstructions, the use of either an
      ipsilateral or contralateral pedicle was found to be equivocal regarding the flap
      viability and the aesthetic outcome. Thus, it seems better to decide their use
      according to the needs of an individual patient. In our series, the contralateral
      pedicled TRAM flap with a vertical flap inset was preferred in patients with a
      small opposite breast or in patients with infraclavicular tissue losses (four
      patients). The ipsilateral pedicled TRAM flap reconstruction with a horizontal
      flap inset was preferred in patients with a full and attractive opposite breast,
      unless they received adjuvant radiotherapy (six patients). In patients who
      received adjuvant radiotherapy the contralateral pedicle was used regardless of
      the inset model preferred (10 patients). Bilateral TRAM flap breast
      reconstruction was applied in one of our cases, which is not included in the
      three categories above mentioned. The aesthetic outcome was determined by
      analyzing a patient satisfaction questionnaire. Overall satisfaction was achieved
      in 17 patients. Four patients were dissatisfied. We think that choosing the
      correct flap inset model is one of the most important factors in achieving a
      satisfactory aesthetic outcome. Choosing the correct pedicle regarding the type
      of the flap inset model is equally important to facilitate technical ease during
      flap transposition and to improve flap survival.

PMID- 12621569
TI  - Free nipple reduction mammaplasty with a horizontal scar in high-risk patients.
AB  - Women with extremely large and ptotic breasts have many complaints and
      difficulties during daily life. Conventional reduction mammaplasty techniques are
      not convenient because the presence of excess tissue beneath and over a long
      pedicle may cause nipple-areola complex necrosis. These patients mostly have
      systemic health problems so they benefit from a shorter operative procedure. The
      amputation method is an option providing rapid surgical operation time and little
      blood loss but it may lead to a flat, unaesthetic breast with poor projection. In
      this paper we present an alternative amputation with the use of a backfolded
      dermoglandular flap and free nipple graft. The inferior pole is amputated. The
      deepithelialized breast tissue is left on the superior pedicle extending below
      the 7-cm vertical limb mark. This deepithelialized tissue is tucked to give more
      central mound projection. The aesthetic outcomes, such as well-rounded breasts
      with good projection and a hidden scar at the submammary sulcus, have led us to
      perform this technique, which was first described by the Mansteins in 1997.

PMID- 12621570
TI  - The double pocket technique: aesthetic breast augmentation.
AB  - A subglandular versus a subpectoral pocket for breast prostheses has been a
      subject of discussion over the past quarter century. In 1994, in order to
      increase the volume, enhance the shape, and improve the breast projection, the
      authors [1,2,3][1-3] used a procedure that took advantage of the virtual spaces
      found in the breast anatomy, simultaneously utilizing the subglandular and
      subpectoral areas by locating the prostheses in a double pocket on both sides of
      the pectoral muscle, joined through a gentle muscle buttonhole.

PMID- 12621571
TI  - Cryopreservation of hair follicles at 20 degrees C: can it work in staged hair
      transplantation.
AB  - Androgenic alopecia is a serious problem for a large proportion of the
      population, especially males, and causes them to seek medical help. Many methods
      have been described for treatment of androgenic alopesia. Among them are punch
      grafts, strip grafts, scalp grafts, scalp reductions, tissue expanders, and flap
      combinations, and hair transplantations with minigrafts and micrografts. The
      latter has become popular in the last two to three decades and has been
      investigated extensively. Improvements in hair replacement with minigrafts and
      micrografts may allow an ideal result with a nearly normal appearance. However,
      hair replacement with these grafts has important disadvantages. It requires a
      long operational time and only a limited number of grafts can be placed in one
      session. In this study, we investigated morphological structures of micrografts
      stored at 4 degrees C and those stored at -20 degrees C. We found that
      morphological structures of the grafts stored at 4 degrees C started to be
      impaired in the fifth day, but that the morphological structures of the grafts
      stored at -20 degrees C remained unaltered for 15 days. If this method is put
      into practice, the use of minigrafts and micrografts available will not only
      obviate the second graft harvesting, but also allow reconstruction of a large
      area in a short period of time.

PMID- 12621572
TI  - Improving scar quality: a prospective clinical study.
AB  - Following traumatic or surgical injury to the skin, wounds do not heal by tissue
      regeneration but rather by scar formation. Though healing is definitely a
      welcomed event, the resultant scar, very often, is not aesthetically pleasing,
      and not infrequently, may be pathologic causing serious deformities and
      contractures. Management of problematic scars continues to be a frustrating
      endeavor with less than optimal results. Prophylactic methods of wound management
      to minimize serious scarring are being developed. In a previously published
      study, we have demonstrated improved healing of split thickness skin graft donor
      sites following treatment with Moist Exposed Burn Ointment (MEBO, Julphar Gulf
      Pharmaceutical Industries, Ras Al-Khaimah, UAE). At present, we are reporting the
      results of a comparative clinical prospective study evaluating scar quality
      following primary healing of elective surgical and traumatic facial wounds with
      prophylactic MEBO application, topical antibiotic ointment application, and no
      topical therapy at all. Scars were evaluated according to the Visual Analogue
      Scale for scar assessment. Statistical analysis of scar assessment scores
      demonstrated marked prevention of unfavorable scars with improved cosmetic
      results following MEBO prophylactic therapy.

PMID- 12621573
TI  - If you continue to smoke, we may have a problem: smoking's effects on plastic
      surgery.
AB  - Smoking causes various aero-digestive neoplasms, some cardiovascular diseases,
      respiratory pathologies, and cardiovascular disorders. Surgeons have observed an
      association between impaired wound healing and smoking. In plastic surgery,
      cigarette smoking should be forbidden before and after surgery to prevent poor
      surgical results. In this retrospective study, we presented four major
      complications related with continuous smoking immediately after surgery. Although
      we have strongly forbidden smoking for every patient, 4 patients did not follow
      our advice and continued to smoke. One of them had a breast reconstruction with a
      pedicled transverse rectus abdominis musculocutaneous flap. Another patient had
      an abdominoplasty. The third and fourth patients had digital replantation and
      they were chronic smokers. After their poor surgical outcomes, these heavy
      smokers received close supervision, but managed to smoke, anyway. Education,
      psychologic consultation, and sometimes refusing to perform aesthetic or
      reconstructive surgery are required to minimize postoperative complications.

PMID- 12621574
TI  - Complications of minor cutaneous surgery in patients under anticoagulant
      treatment.
AB  - Anticoagulant use is common in the elderly population. The role of these
      medications in the postoperative period is not well defined. We designed a
      prospective study to evaluate the incidence of postoperative complications in
      patients taking aspirin and warfarin. A prospective study was performed on 102
      patients undergoing minor cutaneous plastic surgery. The number of subjects using
      regular aspirin, warfarin, and that of the patients with no anticoagulant
      medication were 37, 21, and 44, respectively. Complications were defined as
      minor, moderate, or major based on predetermined criteria. Of patients taking
      warfarin, 57% had some complication, significantly more than complications in the
      control group. The number of major complications in the warfarin group was
      significantly higher than those of the control and aspirin groups (p = 0.02).
      Also, the total number of complications in the warfarin group was significantly
      higher than the control group, but there was no significant difference between
      aspirin and control groups (p > 0.05). Cutaneous surgery in patients who receive
      warfarin is associated with a risk of major complication, but this risk does not
      exist in the patients receiving chronic aspirin treatment.

PMID- 12621575
TI  - A case report of cutis laxa in one of identical twins.
AB  - A 29-year-old man with cutis laxa presented requesting surgery to improve his
      appearance. The patient had an unaffected identical twin brother which allowed us
      to compare how he had changed over the years in relation to his sibling and this
      also provided us with a gold standard for any surgery performed. The patient
      underwent staged surgery including upper lid blepharoplasties and two facelifts.

PMID- 12621576
TI  - Aesthetic calf augmentation with silicone implants.
AB  - So-called "skinny legs" are commonly held to be aesthetically negative in both
      men and women. Taking care of one's body in terms of aesthetics is a practice
      that is continuously spreading and being refined to the smallest details. Indeed,
      a leg with underdeveloped muscles, lacking a sculptured look is considered to be
      unattractive and therefore deserving of surgical correction. The present article
      illustrates a surgical technique for correcting this marginal, yet valid,
      aesthetic complaint as well as the relative indications, methods, and preliminary
      results that have been obtained in 11 patients.

PMID- 12621577
TI  - Pseudocorrection of deviated orthostatic axes on lipodystrophic legs.
AB  - reproducible Some lipodystrophies can visually exaggerate the deviation from the
      axes of the legs. The objective of this work is to demonstrate how an aesthetic
      operation, such as liposuction, can be used not only to slenderize the leg,
      bearing in mind the proportions, but also to visually improve the deviations from
      the referred axis. In other words: aesthetic surgery can be used to pseudocorrect
      the axis of the legs. The median line of the leg is calculated preoperatively and
      postoperatively and these curved lines are compared with the axis of the leg.
      This way, the grade of visual correction can be quantified. This is an easy and
      reproducible method. Eighty-three cases have been studied with both deviated and
      lipodystrophic legs.

PMID- 12621578
TI  - Rehabilitation of wounded Civil War veterans.

PMID- 12621579
TI  - A safe and effective technique.

PMID- 12621581
TI  - Coblation in aesthetic facial rejuvenation.

PMID- 12621583
TI  - Refinement of a 400-kb critical region allows genotypic differentiation between
      isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to
      deletions of 17p13.3.
AB  - Deletions of 17p13.3, including the LIS1 gene, result in the brain malformation
      lissencephaly, which is characterized by reduced gyration and cortical
      thickening; however, the phenotype can vary from isolated lissencephaly sequence
      (ILS) to Miller-Dieker syndrome (MDS). At the clinical level, these two
      phenotypes can be differentiated by the presence of significant dysmorphic facial
      features and a more severe grade of lissencephaly in MDS. Previous work has
      suggested that children with MDS have a larger deletion than those with ILS, but
      the precise boundaries of the MDS critical region and causative genes other than
      LIS1 have never been fully determined. We have completed a physical and
      transcriptional map of the 17p13.3 region from LIS1 to the telomere. Using
      fluorescence in situ hybridization, we have mapped the deletion size in 19
      children with ILS, 11 children with MDS, and 4 children with 17p13.3 deletions
      not involving LIS1. We show that the critical region that differentiates ILS from
      MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids
      from selected patients, we have identified eight genes that are consistently
      deleted in patients classified as having MDS. In addition, deletion of the genes
      CRK and 14-3-3 epsilon delineates patients with the most severe lissencephaly
      grade. On the basis of recent functional data and the creation of a mouse model
      suggesting a role for 14-3-3 epsilon in cortical development, we suggest that
      deletion of one or both of these genes in combination with deletion of LIS1 may
      contribute to the more severe form of lissencephaly seen only in patients with
      MDS.

PMID- 12621584
TI  - An ethical dilemma in rheumatology: should the eponym Reiter's syndrome be
      discarded?

PMID- 12621585
TI  - The physician Hans Reiter as prisoner of war in Nuremberg: a contextual review of
      his interrogations (1945-1947).
AB  - OBJECTIVE: Crimes against humanity by Nazi Germany led to the codification of
      procedures for trying medical professionals. The principles detailed in the
      Nuremberg Code formulated by the Allies represented their effort to prevent
      future excesses and embody today's Institutional Review Boards. Reactive
      arthritis is often termed Reiter's syndrome, after Hans Reiter, who was
      incarcerated at Nuremberg. METHODS: The authors reviewed Dr Hans Reiter's
      Nuremberg file at the National Archives in Washington, DC, and present
      chronologic excerpts of his interrogations between 1945 and 1947, with
      interpretative commentary. RESULTS: Reiter was involved with or knowledgeable of
      involuntary sterilization and euthanasia undertaken by the Nazi regime. He also
      played an active role in the design of a study that inoculated concentration camp
      internees at Buchenwald with an experimental typhus vaccine, which resulted in
      hundreds of deaths. CONCLUSIONS: A brilliant investigator and erudite
      intellectual, the career of Hans Reiter shows the importance and the relevance of
      scientific inquiry to adhere to principles enumerated in the Nuremberg Code.
      Because he was not the first to describe reactive arthritis, and in view of the
      above, Reiter's syndrome should only be used to cite an older reference that uses
      the term or in a historical context.

PMID- 12621586
TI  - The tainted legacy of Hans Reiter.
AB  - There is more than ample evidence that Hans Reiter, whose name has been
      eponymously linked to a rheumatologic syndrome, was a Nazi war criminal. He was
      responsible for heinous atrocities that violated the precepts of humanity,
      ethics, and professionalism. The authors suggest that Reiter's legacy is
      sufficiently tainted that the professional and ethical position of the medical
      community should be to no longer afford him this recognition. He should be
      remembered symbolically to remind us of our moral and professional
      responsibilities to prevent the kind of "experiments" he perpetrated as Director
      of the Nazi office for such matters. Medicine is a moral enterprise. Physicians
      serve to promote the welfare of their patients. Hans Reiter and others like him
      who have behaved in such a manner have acted beyond the pale of acceptable human
      behavior. These crimes by Reiter and others like him were transcendently aberrant
      and evil. We regard Reiter and others like him as tainted. We see no acceptable
      rationale to preserve any professional memory of Reiter and others like him
      within our medical culture except as a symbol of what our societal values
      obligate us to reject. We suggest reverting to or substituting other terms for
      the syndrome (such as spondyloarthropathy, spondyloarthritis, oligoarthritis,
      inflammatory oligoarthritis, reactive arthritis, [oligo-] arthritis with
      conjunctivitis/urethritis/diarrhea, etc) until pathophysiologic or other insights
      lead to better ones. (It should be noted that the description of this syndrome
      was not original to Reiter and that current nomenclature is probably in need of
      revision in any case because the terminology and classification is outdated and
      clinically imprecise.) We offer these recommendations because we cannot forget.
      We cannot forget that Reiter and others like him represented an abhorrent evil.
      We cannot forget that Reiter and others like him desecrated the traditions of our
      civilization. We cannot forget that Reiter and others like him violated the
      precepts of the Hippocratic oath. The legacy of Hans Reiter should be that we
      remember only this and resolve that such transgressions never again occur.

PMID- 12621587
TI  - Hans Reiter and the politics of remembrance.

PMID- 12621588
TI  - Changing the name of Reiter's syndrome: a psychiatric perspective.

PMID- 12621589
TI  - Dr Reiter: the "Third" and "Fourth" Reich.

PMID- 12621590
TI  - A systematic analysis of sequences of human antiphospholipid and anti-beta2
      glycoprotein I antibodies: the importance of somatic mutations and certain
      sequence motifs.
AB  - OBJECTIVE: Previous studies have suggested the importance of somatic mutations
      and certain residues in the complementarity determining regions (CDRs) of
      antiphospholipid antibodies (aPL) implicated in the pathogenesis of
      antiphospholipid antibody syndrome (APS). The authors tested this hypothesis by
      carrying out a systematic analysis of all published aPL sequences. METHODS: Each
      aPL variable region sequence was aligned to the closest germline counterpart in
      the VBASE Sequence Directory by using DNAPLOT software, allowing analysis of
      nucleotide homology and distribution of somatic mutations. The probability that
      this distribution arose as a result of antigen-driven accumulation of replacement
      mutations in the CDRs was tested statistically. RESULTS: There was no
      preferential gene or family use in the 36 aPL sequences identified.
      Immunoglobulin (Ig) M aPL had few somatic mutations compared with IgG. Of the IgG
      aPL, 9 of 14 showed evidence of antigen-driven accumulation of replacement
      mutations in the CDRs. Multinomial analysis allowed a clearer statistical
      identification of sequences that had been subject to antigen drive. The more
      specific IgM aPL and some IgG aPL displayed an accumulation of arginine,
      asparagine, and lysine residues in CDRs. CONCLUSIONS: High-specificity binding in
      IgG aPL, but not in more specific IgM aPL, is conferred by antigen-driven somatic
      mutation. This may in part be caused by an accumulation of arginine, asparagine,
      and lysine residues in the CDRs, which are germlines encoded in the more specific
      IgM aPL, but often arise because of somatic mutation in IgG aPL. RELEVANCE: An
      understanding of the role of arginine, asparagine, and lysine residues in the
      binding of pathogenic aPL to phospholipids, and to beta(2)-glycoprotein I, may
      eventually help in the development of drugs to interfere with those interactions,
      and thereby improve the treatment of antiphospholipid antibody syndrome.

PMID- 12621591
TI  - Hypothalamic-pituitary-adrenocortical axis function in patients with polymyalgia
      rheumatica and giant cell arteritis.
AB  - BACKGROUND: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are 2
      closely related syndromes affecting elderly people. One of the most striking
      features of these conditions is the development of the disease in an almost
      exclusive manner in people older than 50 years. Despite this close association
      with age, the pathogenic mechanisms that could explain this age-related
      predisposition are unknown. Aging is accompanied by a number of quantitative and
      qualitative changes in the endocrine system that may predispose to several
      pathologic conditions that occur in the elderly. OBJECTIVE: To explore the
      hypothalamic-pituitary-adrenal axis in PMR and GCA. METHODS: Basal levels of
      adrenal hormones as well as the response to low-dose adrenocorticotropin hormone
      (ACTH) were investigated in 20 patients with active untreated disease and
      compared with levels in 16 healthy age-matched controls. RESULTS: Male patients
      with active disease had low basal levels of androstenedione compared to the
      controls. After low-dose ACTH challenge, cortisol and dehydroepiandrosterone
      reached higher levels in patients than in healthy subjects, indicating that the
      adrenal gland function was not suppressed. Furthermore, the authors did not find
      a clear relationship between the levels of acute phase reactants and adrenal
      hormones in the patient population. CONCLUSIONS: The authors' findings are
      probably more compatible with the hypothesis that the abnormalities found in the
      patient group are the consequences of chronic illness rather than a crucial
      factor contributing to the pathogenesis of the disease.

PMID- 12621592
TI  - Panic disorder in public sector primary care: clinical characteristics and
      illness severity compared with "mainstream" primary care panic disorder.
AB  - The prevalence of anxiety disorders is increased among low-income individuals,
      who are more likely to seek mental health care in medical as opposed to specialty
      settings because of limited insurance access and restricted availability of
      public sector mental health resources. However, little is known about the
      clinical characteristics and illness severity of anxiety disorders in this
      setting. We studied the clinical characteristics of low-income compared with
      middle-income primary care panic patients. Clinical, functional, and service use
      measures obtained at baseline interview in 39 panic disorder patients seen in one
      public sector medical clinic were compared with 76 patients seen in two middle
      income clinics. All patients were participants in a randomized effectiveness
      pharmacotherapy trial [Roy Byrne et al., Arch Gen Psychiatry 2001;58:869-876].
      Public sector patients were more often older, male, single, unemployed, of lower
      income, and non-Caucasian ethnicity. They had more severe clinical symptoms, more
      medical comorbidity, worse physical and role health status, and more emergency
      room visits. Low income and unemployment accounted for most of the differences in
      non-anxiety-related measures. However, type of clinic still contributed
      independently to the greater severity of specific measures of panic/anxiety
      (Panic Disorder Severity Scale and Marks Fear Scale scores), suggesting that the
      increased stress and limited social resources associated with low-income and
      disadvantaged status may have more specific effects on anxiety than other aspects
      of psychopathology.

PMID- 12621593
TI  - Review of the long-term effectiveness of cognitive behavioral therapy compared to
      medications in panic disorder.
AB  - Panic disorder is a recurrent and disabling illness. It is believed that
      Cognitive Behavioral Therapy (CBT) has a long-term protective effect for this
      disorder. This would offer CBT considerable advantage over medication management
      of panic disorder, as patients often relapse when they are tapered off their
      medications. This is a review of the literature about the long-term effectiveness
      of CBT. We searched for follow-up studies of panic disorder using CBT. Of the 78
      citations produced in the initial search, most had major methodological flaws,
      including ignoring losses to follow-up, not accounting for interval treatment,
      and unclear reporting. Three papers met strict methodological criteria, and two
      of these demonstrated a modest protective effect of CBT in panic disorder
      patients. We make recommendations for well-designed studies involving comparisons
      of medications and cognitive behavior therapy.

PMID- 12621594
TI  - Prevalence and relationship to delusions and hallucinations of anxiety disorders
      in schizophrenia.
AB  - We investigated the prevalence of anxiety disorders in a sample of individuals
      with chronic schizophrenia, controlling for anxiety symptoms that may be related
      to delusions and hallucinations, and the possible differences in clinical
      variables between the groups. Individuals with a diagnosis of schizophrenia and
      able to give informed consent were recruited from the community. The Mini
      International Neuropsychiatric Interview (MINI) was administered to both confirm
      the DSM-IV diagnosis of schizophrenia and screen for comorbid anxiety disorders.
      If a comorbid anxiety disorder was found, its relation to the individual's
      delusions and hallucinations was examined. Clinical rating scales for
      schizophrenia were administered as well as rating scales for specific anxiety
      disorders where appropriate. Overall, anxiety disorders ranged from 0% [ for Post
      Traumatic Stress Disorder (PTSD)] to 26.7% [ for generalized anxiety disorder
      (GAD) and agoraphobia without panic] with lower rates when controlled for anxiety
      symptoms related to delusions and hallucinations. In investigating clinical
      variables, the cohort was initially divided into schizophrenics with no anxiety
      disorders and those with an anxiety disorder; with further analyses including
      schizophrenics with anxiety disorders related to delusions and hallucinations and
      those with anxiety disorders not related to delusions and hallucinations. The
      most consistent difference between all the groups was on the PANSS-G subscale. No
      significant differences were found on the remaining clinical variables. Comorbid
      anxiety disorders in schizophrenia can be related to the individual's delusions
      and hallucinations, though anxiety disorders can occur exclusive of these
      positive symptoms. Clinicians must be aware that this comorbidity exists in order
      to optimize an individual's treatment.

PMID- 12621595
TI  - Group behavioral therapy for adolescents with tic-related and non-tic-related
      obsessive-compulsive disorder.
AB  - Prior research supports the distinction between tic-related and non-tic-related
      obsessive-compulsive disorder (OCD) based on phenomenologic, etiologic, and
      neurobehavioral data. The present study examines whether response to psychosocial
      treatment differs in adolescents, depending on the presence of comorbid tics.
      Nineteen adolescents, 12-17 years of age, participated in 7-week, uncontrolled
      trial of group cognitive-behavioral treatment (CBT) for OCD. Eight of the
      patients had tic-related and eleven had non-tic-related OCD. The group CBT
      program included psycho-education, exposure and response prevention, cognitive
      strategies, and family involvement. Significant improvement was observed for all
      subjects on the Yale-Brown Obsessive Compulsive Scale ratings of obsessions,
      compulsions, and total OCD symptoms. Outcomes were similar for subjects with tic
      related and non-tic-related OCD. These preliminary results suggest that the
      presence of comorbid tic disorders may not attenuate response to behavioral group
      treatment among adolescents.

PMID- 12621596
TI  - Panic-related responses to pentagastrin, flumazenil, and thyrotropin-releasing
      hormone in healthy volunteers.
AB  - Thyrotropin-releasing hormone ( TRH) induces some somatic symptoms that resemble
      those of a panic attack, without being considered to be a laboratory panicogen in
      panic disorder (PD) patients. This study aimed to identify doses of TRH and the
      laboratory panicogens, pentagastrin and flumazenil, that would produce a similar
      intensity of panic-related somatic symptoms in healthy volunteers because
      comparison of the effects of these doses in PD patients could be used to test the
      hypothesis that these agents have specific panicogenic effects that are not
      explained solely by cognitively mediated reactions to somatic symptoms. Nine
      subjects were administered pentagastrin (0.2 micro g/kg) and TRH (600 or 1,200
      micro g) in a double-blind, randomized order, within-subjects design. Fifteen
      subjects received pentagastrin (0.1 micro g/kg), TRH (600 or 1200 micro g) and
      flumazenil (2 mg) in a double-blind, randomized order within-subjects design.
      Although low dose pentagastrin (0.1 micro g/kg) induced comparable
      cardiorespiratory responses to those of TRH, it induced greater anxiety,
      suggesting that TRH would not be a credible comparator for pentagastrin in
      challenge studies in PD. However, TRH produced equal or greater symptom and
      physiological responses compared with flumazenil, suggesting that flumazenil may
      act as a panicogen in PD via a GABAergic mechanism rather than via a cognitively
      mediated response to somatic symptoms. This now requires confirmation in PD
      patients.

PMID- 12621597
TI  - The effect of pharmacotherapist characteristics on treatment outcome in panic
      disorder.
AB  - A large number of studies suggest that individual characteristics of
      psychotherapists affect the outcome of psychosocial treatments for psychiatric
      illness, but little work has been done to see if this is also the case for
      pharmacotherapy. In the context of a multicenter study that compared psychosocial
      and medication treatments for panic disorder, we assessed whether such
      characteristics as age of the psychiatrist, number of years of experience, and
      gender influence the outcome of treatment with the antipanic drug imipramine.
      Data were examined by multiple and logistic regression analyses for eight
      psychiatrists who treated a total of 57 patients with panic disorder. More
      physician experience, measured as years since completing residency, was
      associated with better response to imipramine on one of two main dichotomous
      measures (the Clinical Global Impression-Improvement Scale) and on six of nine
      continuous measure rating scales. Associations between psychiatrist age and
      outcome and between psychiatrist gender and outcome were also present but on
      fewer measures. Although these are post-hoc analyses that were not planned when
      the multicenter study was originally designed and therefore there are limitations
      in the information available about the psychiatrists' characteristics, the
      findings suggest that even in the context of a clinical trial that employs a
      specific protocol and single medication, physician experience may influence
      patient outcome. Depression and Anxiety 17:88-93, 2003.

PMID- 12621598
TI  - In search of social phobia subtypes: similarity of feared social situations.
AB  - The existence of subtypes of social phobia has been questioned. Although cluster
      analytic methods have been used to support various subtype models, a continuous
      model based on total number of feared social situations seems equally plausible.
      In a community sample, we calculated mean similarity measures for combinations of
      item pairs of feared social situations. Speaking fear items were significantly
      more similar to each other than to other items. There was also a trend for
      interaction fear items to be more similar to each other than to other items.
      These findings suggest that fear of speaking and interactional situations may
      represent distinct domains of socially feared situations. They should be
      considered separately in delineation of treatment response and may, if replicated
      in clinical samples, help identify meaningful subtypes of social phobia.

PMID- 12621599
TI  - Predictors and outcomes in people told that they have panic attacks.
AB  - We sought to identify predictors of being told the diagnosis of panic by health
      care providers and to assess whether being told affected outcomes. We collected
      data about care-seeking behavior, panic and family characteristics, psychiatric
      comorbidity, and illness behaviors. Outcomes included psychiatric symptomatology,
      disability, substance use, and control. Presentation to an emergency department
      and the number of mental health sites used predicted being told. Patient
      predictors centered on symptom severity. Being told was not associated with
      outcomes. Hence, care-seeking from emergency departments and mental health sites
      as well as symptom severity predicted being told but not better outcomes.

PMID- 12621600
TI  - Serotonergic modulation of the balance system in panic disorder: an open study.
AB  - Experimental evidence suggests that panic disorder is characterized by
      abnormalities in the balance system function and that these abnormalities might
      be related to the severity of agoraphobic avoidance. Since the balance system can
      be modulated by the serotonergic system, we investigated the effect of a 6-week
      treatment with citalopram on the balance system function in patients with panic
      disorder. Fifteen patients with panic disorder with/without agoraphobia underwent
      static posturography on days 0 and 42. Static posturography and clinical
      assessments were carried out by different investigators who were blind to each
      other. Static posturography showed high percentages of abnormal scores. Patients
      with no or low agoraphobic avoidance showed less abnormal posturographic measures
      than those with moderate to severe agoraphobia. After 6 weeks of treatment with
      citalopram there was a significant decrease of four out of six posturography
      measures in eyes-closed and neck extension conditions, whereas no significant
      effect was found in the eyes-open condition. This is the first report that
      suggests that the modulation of the serotonergic system can improve the balance
      system function in patients with panic disorder, particularly when visual
      information is lacking. In addition, our findings confirm the observation that
      many patients with panic disorder have abnormalities in their balance system
      function, supporting the idea that these abnormalities are mainly related to
      agoraphobic avoidance.

PMID- 12621601
TI  - Dental variation of Ryukyu islanders: a comparative study among Ryukyu, Ainu, and
      other Asian populations.
AB  - The presence or absence of 24 nonmetric dental traits was examined to investigate
      the inter- and intraregional variation of Ryukyu Islanders. We compared the
      dentition of the Kadena sample from the central district of Okinawa Island in the
      Ryukyu Island chain to those of samples from Nakijin from the northern district
      of the same Okinawa Island, Tokunoshima, another island of the Ryukyu Island
      chain, main-island Japanese in Kagoshima and Tokyo, Hokkaido Ainu, Atayal in
      Taiwan, and Pashtuns and Tajiks in Afghanistan. Many traits of the Ryukyu
      Islanders were found to be close to those of the main-island Japanese; however,
      several were intermediate between those of the main-island Japanese and the Ainu
      or Atayal. The intraregional variation in the Ryukyu Islanders was comparable to
      that in the main-island Japanese. This result supports the influence of a complex
      gene flow to the Ryukyu Islanders, as suggested by some genetic studies. Among
      the populations compared here, that closest to the Ainu was the population of
      Tokunoshima.

PMID- 12621602
TI  - Center of body mass and the evolution of female body shape.
AB  - Among primates, the genus Homo has a unique sexual dimorphism in general body
      shape. The stenotypic female "hourglass figure" has often been attributed to
      sexual selection. Sexual dimorphism both in shape and in position of the center
      of body mass (CoM) emerges during puberty and is related to hormonal influences.
      These are only the proximal and not the ultimate causes of this feature. This
      article explores the hypothesis that the evolutionary (i.e., ultimate) reason for
      female body shape and male preference for a lower waist-to-hip ratio (WHR) is due
      to the acquisition of bipedal locomotion and different biomechanical constraints
      on each sex. The demands of pregnancy and subsequently carrying infants may have
      more tightly constrained CoM in females than in males. A lower-position of CoM
      relative to height (RCoM=(CoM/height)*100%) would contribute to better stability
      during pregnancy and infant carrying. Using body measurements from 119 female
      students, we show that RCoM correlates negatively with only maximal thigh
      circumference and positively with only WHR and shoulder width. The relationship
      between RCoM and traits that best characterize female body shape seems to confirm
      a hypothesis of biomechanical selection pressure that may have acted on Homo
      female morphology, thus contributing to sexual dimorphism.

PMID- 12621603
TI  - Genetic structure and affinities of the Corsican population (France): classical
      genetic markers analysis.
AB  - The frequencies of 19 classical genetic markers for a total of 54 alleles were
      studied in a sample of 1,164 individuals born and residing in five different
      regions of Corsica. The results, which are also discussed in the context of the
      Mediterranean populations, show the existence within Corsica of a certain genetic
      differentiation between north and south which follows the linguistic subdivision
      differentiation. Compared to the other Mediterranean populations, Corsica also
      appears to be greatly differentiated from the populations of regions such as
      France and Tuscany, regions which have had great political and cultural
      influence. The Mediterranean population most comparable to Corsica is Sardinia.
      Despite their common origin, however, they do not prove to be absolutely
      identical. The genetic characteristics of Corsica and their relationship with the
      Mediterranean populations are interpreted in terms of demographic and matrimonial
      structure, isolation, and genetic drift.

PMID- 12621604
TI  - Childhood overweight problem in a selected school district in Hawaii.
AB  - Anthropometric measurements were collected from 1,437 public school students in a
      selected school district in Hawaii every year from 1992 to 1996. Results showed
      that boys and girls of Hawaiian ancestry (HA) are generally taller in stature and
      somewhat heavier in weight than their non-Hawaiian counterparts (Non-HA). Also,
      there are no clear differences between the two groups in BMI, sums of skinfolds,
      waist and hip circumferences, and waist/hip circumference ratios. When compared
      to data from NHANES III (Centers for Disease Control and Prevention), the median
      statures of HA boys and girls are very close to the median statures of NHANES
      III, but the body weights of HA are heavier at most ages. Also, the BMI values of
      HA are distinctly higher and their medians are closer to the 75th percentile of
      NHANES III. In addition, the values of the sums of skinfolds and the waist and
      hip circumferences of HA are also higher at most ages than NHANES III. These
      multiple anthropometric indicators suggest that there might be more overweight
      children and adolescents of HA. When compared to the statistics in NHANES III,
      there are twice as many HA and Non-HA boys and girls classified as obese.
      Clearly, a serious childhood problem exists among the children in this selected
      school district in Hawaii. More research is needed in other school districts in
      Hawaii. Also, it is suggested in this study that using multiple anthropometric
      indicators, rather than a single one, may be more accurate and appropriate in
      determining overweight problems in a youth population.

PMID- 12621605
TI  - Mixed-longitudinal analysis of growth data from Malian adolescent girls: evidence
      for compensatory gain?
AB  - Cross-sectional data have previously indicated poor growth and development among
      adolescent girls in Mali. These data have shown that Malian girls are shorter and
      lighter than their United States female counterparts. Many studies suggest that
      this evidence of poor growth and development is due to a combination of poor
      nutrient intake, high-energy expenditure, and poor access to health care. At
      adolescence, individuals rarely follow a standard pattern of growth due to
      different biological timetables and expressions of pubertal growth. By examining
      velocity of growth, researchers can recognize developmental patterns such as
      compensatory gain. This study examines the growth rates of Malian girls over a 6
      month period. Anthropometric data were collected from a total of 1,045 adolescent
      girls ages 10-17 years. Height and weights were collected twice from the Segou
      Coura community in the town of Segou and from the Dioro Arrondissement in 1997.
      From these data, mixed longitudinal analyses were conducted. Both the height and
      weight velocity data showed patterns of delayed growth rates when compared with
      American girls. Although Malian girls are similar to American girls in that they
      tend to reach their peak height velocity at age 12, the Malian girls demonstrate
      a longer growth spurt than the American girls. This evidence of greater height
      velocity may be an indication of compensatory growth, or compensatory gain, and
      is partially supported from cross-sectional data. While these Malian data do not
      show much evidence that certain stressors are relieved during adolescence, only
      more extensive longitudinal data can more fairly examine the issue.

PMID- 12621606
TI  - BMI in the Trois-Rivieres study: child-adult and child-parent relationships.
AB  - This study evaluated intraindividual child-adult and interindividual child-parent
      relationships of body mass index (BMI) using data from the Trois-Rivieres
      semilongitudinal study of growth and development. Intraindividual correlations
      between age 12 and 35 years were substantial (r(2) = 36% of variance in women,
      30% of variance in men). Interindividual child-parent correlations for mothers
      and fathers age 36.6 +/- 0.4 and 39.5 +/- 0.4 years, respectively, were very low
      to low for daughters age 12 years (r = 0.09, NS and 0.34, P < 0.001 vs. father
      and mother, respectively) but all very low for sons age 12 years (r = 0.07, NS
      and 0.16, NS vs. father and mother, respectively). A multiple regression analysis
      predicted adult BMI from the individual's BMI at 10, 11, 12 years plus the
      maternal and paternal BMIs as calculated from self-reported heights and weights.
      The BMI at age 12 years was a better predictor of adult BMI than the parental BMI
      in both men and women (P < 0.001) and multivariate analysis revealed that this
      index at age 12 years was the sole significant predictor of adult BMI for both
      men and women. The results from our study do not support the hypothesis that
      parental BMI is a stronger predictor of adult BMI than childhood BMI. However,
      useful information for the prediction and prevention of adult overweight can be
      obtained from the BMI at age 12 years. Our results suggest that environmental
      influences may be the major factor in the present obesity epidemic.

PMID- 12621607
TI  - Comparative survival advantage of males with Down syndrome.
AB  - In virtually all countries life expectancy is longer in females than in males. A
      multigeneration, population-based dataset was used to investigate whether a
      gender-specific difference in life expectancy could be determined in a large
      cohort (n = 1,332) of people with Down syndrome resident in Western Australia.
      Contrary to the established pattern of longevity in the general population, and
      in most people with intellectual disability, males with Down syndrome had a
      significantly greater life expectancy than females with the same disorder. The
      reasons for this atypical finding are discussed in terms of the patterns of
      morbidity experienced by people with Down syndrome, especially at early and late
      stages of their lifespan.

PMID- 12621608
TI  - Modeling growth and senescence in physical performance among the ache of eastern
      Paraguay.
AB  - This article seeks to partially fill a paucity of available data on physical
      performance in hunter-gatherer societies. Quantitative data are presented on
      various physical performance measures conducted on the Ache of eastern Paraguay,
      hunter-gatherers up to the 1970s and now part-time foragers and horticulturists.
      The performance battery was conducted on most individuals over 10 years of age,
      allowing for cross-sectional examination of growth and senescence patterns across
      the lifespan for both sexes. These measures tend to display steep ascents and
      peak in the early 20s with slight declines thereafter with age for males, whereas
      females demonstrate peaks in performance earlier in life, with lower or no
      senescence rates thereafter. The result is a convergence in physical performance
      between men and women at later ages. We suggest that the female physiology faces
      reproductive constraints to performance early in life but shifts allocation to
      increased work output later in life during the long human postmenopausal stage.
      In contrast, the male physiology maximizes work output in early adult life. These
      schedules of physical performance are contrasted with schedules of food
      production ability, which tend to occur later in life, and therefore imply that
      skill rather than strength alone is an important component of the human foraging
      niche.

PMID- 12621609
TI  - Coliforms in the water and hemoglobin concentration are predictors of
      gastrointestinal morbidity of Bangladeshi children ages 1-10 years.
AB  - The presence of pathogens in the water and children's poor nutritional status are
      likely to increase morbidity in developing countries. Understanding the
      interactions between the environmental and nutritional factors is important from
      the standpoint of improving child health. In this study, we analyzed the effects
      of fecal and total coliforms in the water available at the source and that stored
      in the household on the spells of gastrointestinal morbidity of 99 Bangladeshi
      children at three time points in an 8-month period. Fecal and total coliforms in
      the stored water were significant predictors (P < 0.05) of morbidity that was
      modeled using dynamic random effects models. Moreover, children with better
      hemoglobin status experienced lower morbidity. An empirical model for the
      proximate determinants of hemoglobin concentration showed significant negative
      associations between children's hookworm loads and hemoglobin. While the
      children's intakes of bioavailable iron, iron from meat, fish, and poultry, and
      iron from animal sources were not significant predictors of hemoglobin status in
      this population, the need for broader interventions for improving child health
      was apparent.

PMID- 12621610
TI  - Impact of maternal age and maternal somatic characteristics on newborn size.
AB  - Pregnancies during early adolescence were commonly thought to represent special
      risks, such as preterm delivery or low-weight newborns, resulting in increased
      mortality and morbidity of mother and child. An important biopsychosocial
      interaction can be assumed. In the present study the impact of maternal age and
      maternal somatic characteristics such as prepregnancy weight, stature, or
      pregnancy weight gain on newborn somatometric features (birth weight, birth
      length, head circumference, and arcomial circumference) using a dataset of 8,011
      single term births were analyzed. The offspring of 215 extremely young mothers
      ages 12-16 years were significantly (P < 0.0001) lighter and smaller in all body
      dimensions than the offspring of older adolescent mothers, ages 17-19 years, and
      the offspring of adult gravida, ages 20-29 years, although no increased incidence
      of low-weight newborns (<2,500 g) could be observed. As expected, the youngest
      mothers were also significantly smaller and lighter than their older,
      biologically more mature counterparts, although the relative weight gain during
      pregnancy was highest in the youngest age group (23.4% vs. 22.9 and 22.1%,
      respectively). In general, age but also pregnancy weight gain and prepregnancy
      weight status were significantly associated with pregnancy outcome. Within term
      births taking place under sufficient psychosocial support, maternal somatic
      features had an important impact on newborn size.

PMID- 12621611
TI  - High-throughput cytochrome p450 inhibition assays by ultrafast gradient liquid
      chromatography with tandem mass spectrometry using monolithic columns.
AB  - A generic method employing ultrafast liquid chromatography with tandem mass
      spectrometry (LC/MS/MS) was developed and employed for routine screening of drug
      candidates for inhibition of five major human cytochrome p450 (CYP) isozymes,
      CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2. The method utilized a monolithic
      silica rod column to allow fast flow rates to significantly reduce
      chromatographic run time. The major metabolites of six CYP-specific probe
      substrates for the five p450 isoforms were monitored and quantified to determine
      IC(50) values of five drug compounds against each p450 isozyme. Human liver
      microsomal incubation samples at each test compound concentration were combined
      and analyzed simultaneously by the LC/MS/MS method. Each pooled sample containing
      six substrates and an internal standard was separated and detected in only 24
      seconds. The combination of ultrafast chromatography and sample pooling
      techniques has significantly increased sample throughput and shortened assay
      turnaround time, allowing a large number of compounds to be screened rapidly for
      potential p450 inhibitory activity, to aid in compound selection and optimization
      in drug discovery.

PMID- 12621612
TI  - Simple and sensitive liquid chromatography/tandem mass spectrometry method for
      the determination of diazepam and its major metabolites in rat cerebrospinal
      fluid.
AB  - Diazepam (DZP) is one of the most commonly prescribed drugs for treating status
      epilepticus (SE). A simple, sensitive and selective LC/MS/MS method with a wide
      linear calibration range was developed to quantify DZP and its major metabolites,
      N-desmethyldiazepam (DMDZP), temazepam (TZP), and oxazepam (OZP), in rat
      cerebrospinal fluid (CSF). The method was used to simultaneously determine the
      concentrations of all analytes in a small sample volume (as little as 25 microL)
      of rat CSF. The lower limits of quantification (LLOQ) of the method are 0.04
      ng/mL for DZP and 0.1 ng/mL for its metabolites. The calibration range is 0.04
      200 ng/mL for DZP and 0.1-200 ng/ml for the metabolites. All intra- and inter
      assay coefficients of variation (%CV) and mean percent errors of the method are
      less than 12%. This method successfully addresses the need to determine low
      therapeutic drug concentrations in small physiological samples, namely rat CSF.
      Moreover, it can be used to investigate the distribution of the drug and its
      metabolites among blood plasma, brain tissue, and CSF in pharmacokinetic and
      pharmacodynamic studies in a variety of laboratory animals. With respect to
      animal experiments involving assays in CSF, this method addresses two of the
      three criteria of Russell and Bruch (Principles of Humane Experimental
      Techniques, 1959, Methuen and Co., London) for minimizing animal use, namely
      refinement and reduction.

PMID- 12621613
TI  - Investigation by solid-phase microextraction and gas chromatography/mass
      spectrometry of secondary metabolites in lichens deposited on stone monuments.
AB  - Lichens are ubiquitous organisms formed by symbiotic associations of fungal
      hyphas and algae that also grow under often extreme environmental conditions.
      They produce secondary metabolites, the so-called lichen substances, whose
      structural characterization can give an important contribution to lichen
      taxonomy. Lichens are also widely employed as biomonitors of atmospheric
      pollution; being epiphyte organisms they tend, in fact, to accumulate exogenous
      compounds. Moreover, it could be questioned if the environmental stress alters
      their secondary metabolites production. Therefore, a new strategy for the
      analysis of the organic substances absorbed or metabolized by lichens has been
      developed. This method exploits the dry solid-phase microextraction (SPME)
      headspace technique coupled with gas chromatography/mass spectrometry (GC/MS).
      Lichens coating the stone surfaces of monuments, located in small towns between
      high mountains and far away from urban environments, have been investigated. In
      the field of cultural heritage, this study can contribute to the knowledge of the
      state of conservation of outdoor exposed historical monuments.

PMID- 12621615
TI  - Quantification of [Dmt1]DALDA in ovine plasma by on-line liquid
      chromatography/quadrupole time-of-flight mass spectrometry.
AB  - The synthetic peptide [Dmt(1)]DALDA (Dmt-D-Arg-Phe-Lys-NH(2); Dmt = 2',6'
      dimethyltyrosine; 'super-DALDA') is a mu opioid-receptor agonist. On-line liquid
      chromatography/quadrupole time-of-flight mass spectrometry and the corresponding
      stable isotope-incorporated synthetic peptide internal standard were used to
      quantify [Dmt(1)]DALDA that had been extracted from ovine plasma samples. The
      [M+2H](2+) ion was used to construct the calibration curve, and the product ion
      was used for verification of the peptide. The detection sensitivity for the
      [Dmt(1)]DALDA [M+2H](2+) ion was 12.5 fmol and 50 fmol for the m/z 432.3 product
      ion. The concentration profile of [Dmt(1)]DALDA was determined from a set of
      ovine plasma samples. The molecular specificity of the peptide quantification was
      confirmed by tandem mass spectrometry (MS/MS).

PMID- 12621614
TI  - Matrix-assisted laser desorption/ionization detection of polymerase chain
      reaction products by utilizing the 5'-3' exonuclease activity of Thermus
      aquaticus DNA polymerase.
AB  - The 5'-3' exonuclease activity of DNA polymerase was utilized in the polymerase
      chain reaction system to generate a specific signal concomitant with
      amplification. These signals were detected by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). This method
      obviates the need to perform extensive DNA purification of reaction products that
      is often necessary for detecting larger DNA molecules by mass spectrometry.
      Oligonucleotides complementary to the internal region of the amplicon are
      degraded by the 5'-3' exonuclease activity and the degradation products are
      analyzed by MALDI mass spectrometry. We refer to this assay as the Exo-taq assay
      or probe degradation assay. This method should be amenable to automation.

PMID- 12621616
TI  - Differentiation of isomeric sulfur heterocycles by electron ionization mass
      spectrometry: 1,4-dithiins, 1,4-dithiafulvenes and their analogues
      tetrathianaphthalenes, tetrathiafulvalenes and tetrathiapentalenes.
AB  - The electron ionization mass spectra of the title compounds have been studied
      along with the product ion spectra of their metastable or collisionally activated
      molecular ions. The relative abundances of ions in the spectra allow unambiguous
      isomer differentiation. Isomerization of the molecular ions was observed in the
      metastable ion spectra of tetrathianaphthalenes and tetrathiafulvalenes. This
      isomerization reaction parallels the electrochemical or base-induced
      isomerization observed in solution. The studied tetrathiapentalene derivative
      does not rearrange to the corresponding tetrathiafulvalene or
      tetrathianaphthalene isomers.

PMID- 12621617
TI  - Ionic matrices for matrix-assisted laser desorption/ionization time-of-flight
      detection of DNA oligomers.
AB  - Salts with low melting points, also termed room-temperature ionic liquids, can be
      used as matrices in matrix-assisted laser desorption/ionization time-of-flight
      (MALDI-TOF). They have great vacuum stability, and can dissolve polar and apolar
      solutes including carbohydrates, biological oligomers and proteins. The ionic
      liquids give much more homogeneous sample solutions compared with solid matrices.
      We demonstrate the usefulness of using ionic matrices to determine the molecular
      weight of DNA oligomers by direct TOF mass spectrometric analysis. Three
      oligonucleotides were tested, (d(pT)(10), d(pC)(11), and d(pC)(12)), with several
      ionic matrices synthesized from different bases associated to two acids (3
      hydroxypicolinic acid and 2,5-dihydroxybenzoic acid). The results obtained show
      that the best ionic matrices enhance the ion peak intensity of the
      oligonucleotides with respect to conventional molecular matrices under our
      experimental conditions. In one case, an ionic matrix provided a signal-to-noise
      ratio ten times higher than the corresponding molecular matrix. Several of the
      tested ionic matrices were liquids. However, all working ionic matrices were
      solids.

PMID- 12621618
TI  - Accurate mass measurement at enhanced mass-resolution on a triple quadrupole mass
      spectrometer for the identification of a reaction impurity and collisionally
      induced fragment ions of cabergoline.
AB  - In this study, accurate mass measurements were made by electrospray ionization
      (ESI) on a triple quadrupole mass spectrometer operating in enhanced mass
      resolution mode (peak width = 0.1 u FWMH), to give qualitative information
      relating to the pharmaceutical, cabergoline. Accurate mass determinations by ESI
      MS were performed on a protonated impurity formed during cabergoline storage. The
      accurate mass measurement resulted in only one proposed elemental composition for
      the impurity, using reasonable elemental limits and mass tolerance for the
      calculation. This information was sufficient to propose a structure for the
      impurity where ESI-MS/MS proved consistent. The difference between the accurate
      mass measurement and the exact mass calculated for the proposed structure was 0.8
      mmu, with a standard deviation of 0.7 mmu for replicate accurate mass
      determinations. Accurate mass determinations in ESI-MS/MS provided information on
      cabergoline fragment ions formed through collisionally-induced dissociation.
      Since the potential formation of isobaric ions exists for two major cabergoline
      fragment ions, accurate mass measurement allowed for the determination of the
      most probable fragment ion structures. The differences between the accurate mass
      measurements and exact masses calculated for the proposed fragment ions were 1.9
      and 2.1 mmu, with standard deviations of 0.4 and 0.8 mmu, respectively, for
      replicate determinations.

PMID- 12621619
TI  - Enantioselective trace analysis of amphetamine in human plasma by gas
      chromatography/negative ion chemical ionization mass spectrometry.
AB  - A method for the quantitative enantioselective analysis of amphetamine in human
      plasma by gas chromatography/negative ion chemical ionization mass spectrometry
      (GC/NICI-MS) is presented. Five-fold deuterated analogues of both enantiomers
      were used as internal standard. Plasma sample preparation was performed by a
      rapid liquid-liquid extraction using n-hexane. Derivatization with (S)-(-)-N
      (heptafluorobutyryl)prolyl chloride was accomplished directly in the n-hexane
      extract to avoid loss of amphetamine during sample concentration. The method was
      validated in the expected concentration range of 0.006 for a pharmacokinetic
      study. Calibration curves were linear within a range 0.006-50 ng/mL plasma.
      Precision and accuracy were acceptable over the entire calibration range.
      Baseline separation of the enantiomers was easily achieved on a 15-m nonchiral
      apolar column. The method is simple and robust, and has been applied to the batch
      analysis of amphetamine enantiomers.

PMID- 12621620
TI  - Identification of hyaluronic acid oligosaccharides by direct coupling of
      capillary electrophoresis with electrospray ion trap mass spectrometry.
AB  - A new method for the identification of oligosaccharides obtained by enzymatic
      digestion of hyaluronic acid (HA) with bacterial hyaluronidase (HA lyase, E.C.
      4.2.2.1, from Streptococcus agalactiae) using online capillary
      electrophoresis/electrospray mass spectrometry (CE/ESI-MS) is presented. A fused
      silica capillary coated with polyacrylamide was used with a 40 mM ammonium
      acetate buffer at pH 9.0 and a separation voltage of +30 kV applied to the inlet.
      Separation was achieved for oligosaccharides containing 4-16 monomers. The
      migration behavior follows the chain length of the oligomers, regardless of
      charge state. However, no linear relationship was found for the relation between
      mobility and chain length. Using an ion trap mass analyzer, complementary
      structural information was obtained by MS/MS and MS(n) experiments.

PMID- 12621621
TI  - Liquid chromatography with electrospray ion-trap mass spectrometry for the
      determination of anatoxins in cyanobacteria and drinking water.
AB  - Anatoxin-a (AN) and homoanatoxin-a (HMAN) are potent neurotoxins produced by a
      number of cyanobacterial species. A new, sensitive liquid chromatography/multiple
      tandem mass spectrometry (LC/MS(n)) method has been developed for the
      determination of these neurotoxins. The LC system was coupled, via an
      electrospray ionisation (ESI) source, to an ion-trap mass spectrometer in
      positive ion mode. The [M+H](+) ions at m/z 166 (anatoxin-a) and m/z 180
      (homoanatoxin-a) were used as the precursor ions for multiple MS experiments.
      MS(2)bond;MS(4) spectra displayed major fragment ions at m/z 149 (AN), 163
      (HMAN), assigned to [Mbond;NH(3)+H](+); m/z 131 (AN), 145 (HMAN), assigned to
      [Mbond;NH(3)bond;H(2)O+H](+), and m/z 91 [C(7)H(7)](+). Although the
      chromatographic separation of these neurotoxins is problematic, reversed-phase
      LC, using a C(18) Luna column, proved successful. Calibration data for anatoxin-a
      using spiked water samples (10 mL) in LC/MS(n) modes were: LC/MS (25-1000
      microg/L), r(2) = 0.998; LC/MS(2) (5-1000(microg/L), r(2) = 0.9993; LC/MS(3) (2.5
      1000 microg/L), r(2) = 0.9997. Reproducibility data (% RSD, N = 3) for each
      LC/MS(n) mode ranged between 2.0 at 500 microg/L and 7.0 at 10 microg/L. The
      detection limit (S/N = 3) for AN was better than 0.03 ng (on-column) for LC/MS(3)
      which corresponded to 0.6 microg/L.

PMID- 12621622
TI  - Post-column infusion study of the 'dosing vehicle effect' in the liquid
      chromatography/tandem mass spectrometric analysis of discovery pharmacokinetic
      samples.
AB  - It has become increasingly popular in drug development to conduct discovery
      pharmacokinetic (PK) studies in order to evaluate important PK parameters of new
      chemical entities (NCEs) early in the discovery process. In these studies, dosing
      vehicles are typically employed in high concentrations to dissolve the test
      compounds in dose formulations. This can pose significant problems for the liquid
      chromatography/tandem mass spectrometric (LC/MS/MS) analysis of incurred samples
      due to potential signal suppression of the analytes caused by the vehicles. In
      this paper, model test compounds in rat plasma were analyzed using a generic fast
      gradient LC/MS/MS method. Commonly used dosing vehicles, including poly(ethylene
      glycol) 400 (PEG 400), polysorbate 80 (Tween 80), hydroxypropyl beta
      cyclodextrin, and N,N-dimethylacetamide, were fortified into rat plasma at 5
      mg/mL before extraction. Their effects on the sample analysis results were
      evaluated by the method of post-column infusion. Results thus obtained indicated
      that polymeric vehicles such as PEG 400 and Tween 80 caused significant
      suppression (> 50%, compared with results obtained from plasma samples free from
      vehicles) to certain analytes, when minimum sample cleanup was used and the
      analytes happened to co-elute with the vehicles. Effective means to minimize this
      'dosing vehicle effect' included better chromatographic separations, better
      sample cleanup, and alternative ionization methods. Finally, a real-world example
      is given to illustrate the suppression problem posed by high levels of PEG 400 in
      sample analysis, and to discuss steps taken in overcoming the problem. A simple
      but effective means of identifying a 'dosing vehicle effect' is also proposed.

PMID- 12621623
TI  - Improved detection of higher molecular weight proteins by matrix-assisted laser
      desorption/ionization time-of-flight mass spectrometry on polytetrafluoroethylene
      surfaces.
AB  - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
      (MALDI-TOFMS) of proteins was performed on a range of polytetrafluoroethylene
      (PTFE) surfaces. Sinapinic acid and alpha-cyano-4-hydroxycinnamic acid matrices
      were compared and the order of application varied to identify the best
      combination for each surface. It is demonstrated that the use of a PTFE surface
      improves the intensity of signals obtained for higher molecular weight proteins.

PMID- 12621624
TI  - Derivatisation for liquid chromatography/electrospray mass spectrometry:
      synthesis of pyridinium compounds and their amine and carboxylic acid
      derivatives.
AB  - A simple method has been developed for the pre-column derivatisation of low
      molecular weight primary and secondary amines and carboxylic acids using
      quaternary nitrogen compounds to enhance their detection by liquid
      chromatography/electrospray ionisation mass spectrometry (LC/ESI-MS). The
      synthesis of seven novel quaternary nitrogen reagents is described. The
      derivatives are designed to be relatively small molecules to avoid some of the
      steric hindrance problems that may be associated with larger derivatisation
      reagents. The compounds have amine and carboxylic acid functional groups with
      which to derivatise carboxylic acids and amines, respectively. Two of the
      compounds contain a bromine atom in order to assess the advantages of a bromine
      isotope pattern in the mass spectra. This acts as a simple marker for
      derivatisation and enables data processing by cluster analysis. Activation of the
      carboxylic acid group was achieved by the use of either 1-chloro-4
      methylpyridinium iodide (CMPI) or the more reactive 1-fluoro-4-methylpyridinium p
      toluenesulphonate (FMP).1 Using both of these active reagents, the degree of
      nucleophilic substitution was investigated for the derivatisation of a variety of
      small molecules. Whilst giving some increase in the ESI-MS response for the
      derivatised compounds, the FMP itself acted as a derivatising reagent in a
      competing reaction. In the light of this finding, FMP was reacted with the test
      compounds separately and gave positive results as a derivatising reagent.
      Detection of the 'pre-charged' derivatives of amines and carboxylic acids by
      LC/ESI-MS was investigated with respect to their ESI response and chromatography.

PMID- 12621625
TI  - Formation, growth mechanism and packing sequences of binary alloy cluster anions
      from laser ablation of mixtures of lead and transition metals.
AB  - By using laser ablation of the mixtures of a transition metal (M: Ti, Cr, Mn, Fe,
      Co, Ni, Cu, Zn, Pd, Ag) plus lead, M/Pb binary cluster anions were observed
      except for Zn, and the number of transition metal atoms contained in the binary
      clusters is at most 4. This behavior is different from that reported previously
      for M/Ge binary clusters. The experiments indicate that it is also very difficult
      to form Al/Pb clusters. The distribution patterns of M/Pb binary alloy cluster
      anions are remarkably similar to those of pure Pb clusters, consistent with a
      formation mechanism in which transition metal atoms are sequentially attached to
      [M(x-1)Pb(y)](-) clusters and thus form [M(x)Pb(y)](-) clusters by a simple
      condensation process. As the number of transition metal atoms increases, the
      intensities of binary clusters gradually decrease. It is proposed that [MPb(4)](
      ) and [MPb(5)](-) cluster anions might be the unit building blocks of M/Pb binary
      cluster anions, and the layer packing sequences for magic clusters are predicted
      on this basis. The [M(x)Pb(y)](-) binary clusters containing 13 atoms (x + y =
      13; x not equal 0) are proposed to have an icosahedral structure.

PMID- 12621626
TI  - Sensorimotor integration in movement disorders.
AB  - Although current knowledge attributes movement disorders to a dysfunction of the
      basal ganglia-motor cortex circuits, abnormalities in the peripheral afferent
      inputs or in their central processing may interfere with motor program execution.
      We review the abnormalities of sensorimotor integration described in the various
      types of movement disorders. Several observations, including those of
      parkinsonian patients' excessive reliance on ongoing visual information during
      movement tasks, suggest that proprioception is defective in Parkinson's disease
      (PD). The disturbance of proprioceptive regulation, possibly related to the
      occurrence of abnormal muscle-stretch reflexes, might be important for generating
      hypometric or bradykinetic movements. Studies with somatosensory evoked
      potentials (SEPs), prepulse inhibition, and event-related potentials support the
      hypothesis of central abnormalities of sensorimotor integration in PD. In
      Huntington's disease (HD), changes in SEPs and long-latency stretch reflexes
      suggest that a defective gating of peripheral afferent input to the brain might
      impair sensorimotor integration in cortical motor areas, thus interfering with
      the processing of motor programs. Defective motor programming might contribute to
      some features of motor impairment in HD. Sensory symptoms are frequent in focal
      dystonia and sensory manipulation can modify the dystonic movements. In addition,
      specific sensory functions (kinaesthesia, spatial-temporal discrimination) can be
      impaired in patients with focal hand dystonia, thus leading to a "sensory
      overflow." Sensory input may be abnormal and trigger focal dystonia, or defective
      "gating" may cause an input-output mismatch in specific motor programs.
      Altogether, several observations strongly support the idea that sensorimotor
      integration is impaired in focal dystonia. Although elemental sensation is normal
      in patients with tics, tics can be associated with sensory phenomena. Some
      neurophysiological studies suggest that an altered "gating" mechanism also
      underlies the development of tics. This review underlines the importance of
      abnormal sensorimotor integration in the pathophysiology of movement disorders.
      Although the physiological mechanism remains unclear, the defect is of special
      clinical relevance in determining the development of focal dystonia.

PMID- 12621627
TI  - Changes of GABA receptors and dopamine turnover in the postmortem brains of
      parkinsonians with levodopa-induced motor complications.
AB  - Brain samples from 14 Parkinson's disease patients, 10 of whom developed motor
      complications (dyskinesias and/or wearing-off) on dopaminomimetic therapy, and 11
      controls were analyzed. Striatal 3beta-(4-(125)I-iodophenyl)tropane-2beta
      carboxylic acid isopropyl ester ([(125)I]RTI-121) -specific binding to dopamine
      transporter and concentration of dopamine were markedly decreased, but no
      association between level of denervation and development of motor complications
      was observed. The homovanillic acid/dopamine ratio of concentrations was higher
      in putamen of patients with wearing-off compared to those without. Striatal (35)S
      labeled t-butylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam
      binding to GABA(A) receptors were unchanged in patients with Parkinson's disease,
      whereas [(125)I]CGP 64213 -specific binding to GABA(B) receptors was decreased in
      the putamen and external segment of the globus pallidus of parkinsonian patients
      compared with controls. [(3)H]Flunitrazepam binding was increased in the putamen
      of patients with wearing-off compared to those without. [(35)S]TBPS-specific
      binding was increased in the ventral internal globus pallidus of dyskinetic
      subjects. These data suggest altered dopamine metabolism and increased GABA(A)
      receptors in the putamen related to the pathophysiology of wearing-off. The
      present results also suggest that an up-regulation of GABA(A) receptors in the
      internal globus pallidus is linked to the pathogenesis of levodopa-induced
      dyskinesias.

PMID- 12621628
TI  - Effects of dopaminergic cell degeneration on electrophysiological characteristics
      and GAD65/GAD67 expression in the substantia nigra: different action on GABA cell
      subpopulations.
AB  - The motor disturbances occurring in Parkinson's disease have been partially
      attributed to a hyperactivity of gamma-aminobutyric acid (GABA)-ergic nigral
      cells largely in the substantia nigra pars reticulata (SNr) secondary to the
      degeneration of dopaminergic nigrostriatal neurons. However, some aspects of this
      response remain unclear. In this work, different electrophysiological and
      neurochemical parameters were studied in GABAergic cells of the SN after
      unilateral nigrostriatal dopaminergic lesion using 6-hydroxydopamine injection in
      rats. Our data showed that 1) the SN under normal conditions contains different
      subsets of GABAergic cells according to their firing pattern and glutamic acid
      decarboxylase mRNA levels, and 2) the response of these GABAergic cell subgroups
      was different after the ipsi- and contralateral dopaminergic cell degeneration.
      These findings indicate a complex regulation of nigral GABAergic activity after
      nigrostriatal dopaminergic degeneration that probably involves local mechanisms,
      the nigro-striato-nigral loop, as well as interhemispheric mechanisms whose
      anatomical basis remains unstudied.

PMID- 12621629
TI  - Prevalence of PD and other types of parkinsonism in three elderly populations of
      central Spain.
AB  - The prevalence of Parkinson's disease (PD) and other types of parkinsonism in
      three elderly populations of central Spain was investigated using a door-to-door,
      two-phase approach. This design called for the administration of a brief
      questionnaire to subjects 65 years of age or older taken from the census of one
      urban municipality of Greater Madrid (Margaritas, Getafe), one rural site
      (Arevalo County, Avila), and one urban district of Madrid (Lista) in Spain (N =
      5,278). Study neurologists extensively investigated those subjects who screened
      positively. The diagnoses, based on specified criteria, were reviewed to increase
      reliability across neurologists. We found 118 subjects with parkinsonism: 81
      affected by PD (68.6%), 26 drug-induced parkinsonism (22.0%), 6 parkinsonism in
      dementia (5.1%), 3 vascular parkinsonism (2.5%), and 2 unspecified parkinsonism
      (1.7%). The prevalence was 2.2% (95% confidence interval [CI], 1.8-2.6) for all
      types of parkinsonism and 1.5% (95% CI, 1.2-1.8) for PD. The prevalence estimates
      of parkinsonism and PD increased with age, declining at 85 years and over. Age
      prevalence ratios were higher for men. Twenty-three subjects (28.4%) of the
      subjects with PD were detected through the screening and had not been diagnosed
      previously. Overall prevalence estimates of PD and other types of parkinsonism in
      central Spain rank at levels similar to those recently reported for other
      European and non-European elderly populations. Despite improvement in access to
      health services, an important proportion of PD patients may never seek
      neurological attention.

PMID- 12621630
TI  - Reliability of reported age at onset for Parkinson's disease.
AB  - An individual's age at onset of Parkinson disease (PD) can be collected through a
      variety of sources, including medical records, family report, and clinical
      observation. The most common source of PD age at onset information in the
      research setting is family-report, which is then typically used to classify a
      subject as juvenile, young, or late age at onset. The reliability of the family
      reported age at onset of PD has not been rigorously examined. The present study
      used data from individuals diagnosed with PD to evaluate the reliability of age
      at onset information by comparing data obtained from three sources: 1) the
      subject's medical records, 2) a Family History Questionnaire, and 3) a Subject
      History Questionnaire. Among the 149 subjects with data for all three age at
      onset sources, the estimated reliability was R = 0.94. Similar reliability was
      observed when the sample was stratified based on gender, age at examination,
      disease duration, first symptom of PD, and years of education. The three measures
      of age at onset of PD show excellent agreement, strengthening confidence in the
      reliability of the reported age of clinical onset for PD.

PMID- 12621631
TI  - Pallidotomy in Parkinson's disease improves single-joint, repetitive, ballistic
      movements, but fails to modify multijoint, repetitive, gestural movements.
AB  - We studied 12 non-demented PD patients in on state before and 3 months after
      posteroventral pallidotomy (PVP), in order to evaluate the effects of surgery
      upon an unconstrained, multijoint skilled movement as well as a single joint,
      repetitive, ballistic movement. A Selspot II System was used for three
      dimensional data acquisition, processing and reconstruction of limb trajectories.
      Specific wrist kinematic features of spatial accuracy (linearity and planarity),
      temporal attributes (acceleration and velocity), spatiotemporal relationships
      (velocity-curvature coupling), and joint kinematic variables (relationships
      between wrist and elbow velocities and relative arm angle amplitudes) for each
      cycle of movement were graphically and numerically analysed. QMC was applied to
      single joint, repetitive, ballistic movements. QMC significantly improved after
      PVP (P < 0.0006). However, wrist as well as joint kinematic variables of the
      gestural movements failed to change significantly after PVP. The lack of
      improvement of the kinematic abnormalities of the gestural movement in PD
      patients would indicate that they are unrelated to the basic motor deficit; most
      likely they are the result of a disruption of a complex of sensorimotor
      integration processes due to abnormal parieto-frontal basal ganglia interaction.

PMID- 12621632
TI  - Randomized trial of modafinil for treating subjective daytime sleepiness in
      patients with Parkinson's disease.
AB  - We assessed the safety and efficacy of modafinil for the treatment of excessive
      daytime sleepiness in patients with Parkinson's disease (PD). This was a single
      site, randomized, double-blind, placebo-controlled crossover study of 21 PD
      patients having an Epworth Sleepiness Scale (ESS) score > or =10. They received
      either placebo or modafinil 200 mg/day for 3 weeks, followed by a washout week,
      then the alternate treatment for 3 weeks. The ESS data demonstrated a carryover
      effect, so the changes from baseline ESS scores were compared between the two
      treatments for period 1 only. The ESS scores for the placebo group went from 16.0
      +/- 4.2 (mean +/- SD) to 17.0 +/- 5.1 and for the modafinil group went from 17.8
      +/- 4.2 to 14.4 +/- 5.7 (P = 0.039). There was no significant carryover effect
      for any other measure. The patient Clinical Global Impression of Change (+3 to 
      3) improved by 0.75 on modafinil compared with 0.15 for placebo (P = 0.07). A
      total of 7 of 20 (35%) of the patients reported some improvement on modafinil but
      not placebo. There was no significant improvement or worsening of the UPDRS
      subscores I-III, Timed Tap test, or time on. Vital signs, electrocardiograms, and
      lab tests were unchanged. Modafinil was very well tolerated. Our data demonstrate
      that, in a small sample size, administration of 200 mg/day of modafinil was
      associated with few side effects and was modestly effective for the treatment of
      excessive daytime sleepiness in patients with PD.

PMID- 12621633
TI  - Neurodegenerative disease and the evolution of art: the effects of presumed
      corticobasal degeneration in a professional artist.
AB  - Production of art is a complex process involving a combination of technical skill
      and a unique talent. Changes in artistic ability may accompany neurodegenerative
      disorders when they occur in an artist. The nature of these changes in the
      context of definable regional neuropathological disturbances may provide insight
      into the structural basis of the creative process. We describe a professional
      artist in whom presumed corticobasal degeneration (CBD) was associated with an
      alteration of his artistic judgement and production. Disinhibition,
      perseveration, and left hemispatial neglect, features of his cognitive profile
      were readily discernible in his work. The differences in his style are examined
      with respect to his main neuroanatomic abnormalities, namely right cerebral
      hemiatrophy as defined by magnetic resonance and single-photon emission computed
      tomography imaging. Cognitive deficits, including visuoconstructive and motor
      neglect, apathy, perseveration, and disinhibition as determined by
      neuropsychological testing, contributed to the dissolution of his artistic
      skills. Our case study adds to the growing literature on the effects of brain
      damage on artistic expression in the graphic arts.

PMID- 12621634
TI  - Rating scales for dystonia: a multicenter assessment.
AB  - The evaluation of dystonia requires a reliable rating scale. The widely used Fahn
      Marsden Scale (F-M) has not been sufficiently tested across multiple centers and
      investigators. The Dystonia Study Group developed the Unified Dystonia Rating
      Scale (UDRS) and a Global Dystonia Rating Scale (GDS) to serve as instruments to
      assess dystonia severity. In this study, 25 dystonia experts evaluated the UDRS,
      F-M, and GDS for internal consistency and reliability. One hundred dystonia
      patients were videotaped using a standardized videotape protocol. Each examiner
      rated 20 patients using the UDRS, F-M, and GDS in random order. The examiner then
      assessed each scale for ease of use. Statistical analysis used Cronbach's alpha,
      intraclass correlation coefficients (ICC), generalized weighted kappa statistic,
      and Kendall's coefficient of concordance. The UDRS, F-M, and GDS showed excellent
      internal consistency (Cronbach's alpha 0.89-0.93) and good to excellent
      correlation among the raters (ICC range from 0.71-0.78). Inter-rater agreement
      was fair to excellent (Kendall's 0.54-0.87; kappa 0.37-0.91) being lowest for
      eyes, jaw, face, and larynx. The modifying ratings (Duration in the UDRS and
      Provoking Factor in the F-M) showed less agreement than the motor severity
      ratings. Among scales, the total scores correlated (Pearson's r, 0.977-0.983).
      Overall, 74% of raters found the GDS the easiest to apply. The GDS with its
      simplicity and ease of application may be the most useful dystonia rating scale.

PMID- 12621635
TI  - Burden of parkinsonism: a population-based study.
AB  - Parkinson's disease (PD) is associated with a significant burden of illness and
      cost to society, which has been difficult to quantify. Our objective was to use
      linked administrative databases from the population of Ontario, Canada, to assess
      the prevalence of parkinsonism, physician- and drug-related costs, and hospital
      utilization for parkinsonian patients compared with age/sex matched controls. An
      inception cohort of parkinsonian cases from 1993/1994 was age and sex matched
      (1:2) to controls and followed for 6 years. Patients were identified by the
      diagnostic code for PD, the use of specific PD drugs, or a combination. The
      parkinsonian case cohort (15,304) was matched to (30,608) controls that did not
      have parkinsonism. The age-adjusted prevalence rates were 3.63 for men and for
      3.24 women per 1,000 (increased by 5.4% for men and 9.8% for women). Physician
      costs were 1.4 times more, there were 1.44 times more hospital admissions,
      admissions were on average 1.19 times longer, and drug costs were 3.0 times more
      for parkinsonian cases. We conclude that the substantially higher physician and
      drug costs as well as hospitalization rates compared with controls clearly
      suggest that parkinsonism is associated with large direct costs to society.

PMID- 12621636
TI  - Increased daytime sleepiness in Parkinson's disease: a questionnaire survey.
AB  - We evaluated the frequency and severity of excessive daytime sleepiness in an
      outpatient population with Parkinson's disease in comparison to age-matched
      controls and examined its relationship with antiparkinsonian drug therapy and
      sleep history. Increased daytime sleepiness and involuntary sleep episodes have
      been described in Parkinson's disease, but the etiology is not completely
      understood. The Epworth Sleepiness Scale (ESS), a validated questionnaire for
      daytime sleepiness, was prospectively administered to 99 consecutive outpatients
      with Parkinson's disease and 44 age-matched controls. In addition, a short sleep
      screening questionnaire was used. The ESS revealed significantly increased
      daytime sleepiness in PD patients compared to controls (7.5 +/- 4.6 vs. 5.8 +/-
      3.0, P = 0.013). The ESS score was abnormally high (10 or more) in 33 % of PD
      patients and 11.4% of controls (P = 0.001). ESS was not different between PD
      patients on levodopa monotherapy and those on levodopa and dopamine agonists, or
      between patients taking ergoline or non-ergoline dopamine agonists. In PD
      patients and in controls, sleepiness was significantly associated with reported
      heavy snoring. Increased daytime sleepiness is more frequent in patients with PD
      than in elderly controls. Similar to controls, increased daytime sleepiness in PD
      patients is correlated with heavy snoring.

PMID- 12621637
TI  - Cognitive effects of unilateral posteroventral pallidotomy: a 4-year follow-up
      study.
AB  - We assessed the long-term neuropsychological effects of unilateral posteroventral
      pallidotomy in Parkinson's disease. Eleven Parkinson's disease patients, from an
      original cohort of 15 consecutive patients who underwent pallidotomy, were
      evaluated. A neuropsychological battery was administered to each patient before
      (3 days) and after (3 months and 4 years) surgery during the effects of levodopa.
      The following tests were administered: Rey's Auditory-Verbal Learning Test,
      Visual Associative Learning test from the Wechsler Memory Scale-Revised, Luria's
      motor alternation, Benton's Judgment of Line Orientation, Trail Making, phonetic
      verbal fluency, Stroop test, Petrides' working memory tasks, Beck's depression
      questionnaire and the Maudsley obsessional-compulsive inventory. In the 3-month
      postoperative assessment, there was a significant worsening in phonetic verbal
      fluency and an improvement in Benton's Judgment of Line Orientation test. In the
      4-year follow-up assessment, phonetic verbal fluency and Benton's Judgment of
      Line Orientation test returned to baseline scores. Although there was no
      significant difference between pre- and postsurgical scores for long-term visual
      associative memory, there was a significant deterioration between 3-month and 4
      year follow-up performances. Our results suggest that unilateral posteroventral
      pallidotomy may produce transient changes in prefrontal and visuospatial
      functions, but there is no evidence of permanent neuropsychological effects.

PMID- 12621638
TI  - Chemotherapy-induced parkinsonism responsive to levodopa: an underrecognized
      entity.
AB  - Parkinsonism is a rare neurological complication of cancer treatment. Although
      individual case reports of this syndrome have been reported, the clinical
      features and prevalence of this syndrome are unknown. We present 3 patients,
      encountered over 6 months at one institution, who developed parkinsonism after
      treatment with various chemotherapeutic agents. Parkinsonism was severe in 2
      patients, affecting postural reflexes, speech, and swallowing. All 3 patients
      responded dramatically to treatment with levodopa, and parkinsonism spontaneously
      improved or remitted over months. This unusual complication of cancer therapy is
      treatable and may be underappreciated.

PMID- 12621639
TI  - Cerebral amyloid angiopathy and motor neurone disease presenting with a
      progressive supranuclear palsy-like syndrome.
AB  - We describe a 68-year-old woman who presented with falls, mild limb bradykinesia,
      axial rigidity, and a severe supranuclear gaze palsy, which failed to benefit
      from levodopa. She subsequently developed severe apraxia, progressive dysarthria,
      dysphagia, and a frontal cognitive impairment. Pyramidal weakness with
      fasciculations and widespread chronic partial denervation appeared shortly before
      her death from bronchopneumonia, 6 months after disease onset. A severe cerebral
      amyloid angiopathy diffusely involving the cerebral hemispheres and cerebellum
      was present at autopsy as well as a second pathological condition indicative of
      motor neurone disease. Cerebral amyloid angiopathy may rarely present with a
      progressive supranuclear palsy-like phenotype.

PMID- 12621640
TI  - HLA typing does not predict REM sleep behaviour disorder and hallucinations in
      Parkinson's disease.
AB  - HLA-DR2 haplotype and DQ1 DNA alleles, characterizing 90 to 100% of all
      narcoleptic patients, were found to be equally distributed in 20 Parkinson's
      disease (PD) patients with early hallucinations, rapid eye movement (REM) sleep
      related behaviour disturbances (RBD), and sleep onset in REM (SOREM), and in 20
      PD patients without hallucinations, despite 10 to 15 years of treatment, and no
      RBD or SOREM.

PMID- 12621641
TI  - Parkinsonism associated with Addison's disease.
AB  - We describe a 35-year-old woman who developed parkinsonism in association with
      Addison's disease. The parkinsonism disappeared following treatment for Addison's
      disease without the use of antiparkinsonian drugs. This association stands unique
      although the pathophysiology remains unclear.

PMID- 12621642
TI  - Decreased striatal dopamine transporter binding in a patient with extrapontine
      myelinolysis.
AB  - We describe the case of a 61-year-old woman who developed extrapontine
      myelinolysis (EPM) with parkinsonism. Decreased striatal dopamine transporter
      binding assessed by [(123)I]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4
      chlorophenyl) tropane and single photon emission computed tomography
      ([(123)I]IPT) SPECT) were observed in the patient, suggesting that osmotic injury
      causes the demyelination of nigrostriatal dopaminergic neurons and that such
      injury may be involved in the pathogenesis of EPM with parkinsonism.

PMID- 12621643
TI  - Primary orthostatic tremor associated with a persistent cerebrospinal fluid
      monoclonal IgG band.
AB  - Primary orthostatic tremor is of unknown aetiology and is believed to be a
      distinct entity rather than a subtype of essential tremor. We describe the first
      patient with a typical phenotype of primary orthostatic tremor who has a
      persistent isolated monoclonal immunoglobulin G band in the cerebrospinal fluid.

PMID- 12621644
TI  - Late delayed postradiation spinal myoclonus or psychogenic movement disorder?
AB  - We describe a patient with intermittent, at times rhythmic trunk flexion
      movements. Neurophysiological assessment excluded a psychogenic movement
      disorder. The segmental spinal myoclonus occurred 6 years after radiation therapy
      of the brain and entire spinal cord, and we suggest this patient to be the first
      case of a late-delayed sequela of spinal cord irradiation presenting as segmental
      spinal myoclonus.

PMID- 12621645
TI  - Unsuccessful deep brain stimulation in the subthalamic nucleus for advanced
      Parkinson's disease.

PMID- 12621646
TI  - Corticobasal degeneration syndrome with basal ganglia calcification: Fahr's
      disease as a corticobasal look-alike?

PMID- 12621649
TI  - Influence of parental deprivation on the behavioral development in Octodon degus:
      modulation by maternal vocalizations.
AB  - Repeated separation from the family during very early stages of life is a
      stressful emotional experience which induces a variety of neuronal and synaptic
      changes in limbic cortical areas that may be related to behavioral alterations.
      First, we investigated whether repeated parental separation and handling, without
      separation from the family, leads to altered spontaneous exploratory behavior in
      a novel environment (open field test) in 8-day-old Octodon degus. Second, we
      tested whether the parentally deprived and handled animals display different
      stimulus-evoked exploratory behaviors in a modified open field version, in which
      a positive emotional stimulus, the maternal call, was presented. In the open
      field test a significant influence of previous emotional experience was found for
      the parameters of running, rearing, and vocalization. Parentally deprived degus
      displayed increased horizontal (running) and vertical (rearing) motoric
      activities, but decreased vocalization, compared to normal and handled controls.
      The presentation of maternal vocalizations significantly modified running,
      vocalization, and grooming activities, which in the case of running activity was
      dependent on previous emotional experience. Both deprivation-induced locomotor
      hyperactivity together with the reduced behavioral response towards a familiar
      acoustic emotional signal are similar to behavioral disturbances observed in
      human attachment disorders.

PMID- 12621648
TI  - Enduring maternal influences in a precocial rodent.
AB  - The guinea pig is highly developed at birth and requires little active maternal
      care. Yet the mother and other social figures markedly influence biobehavioral
      processes of the offspring. Here, responses of guinea pigs and nonhuman primates
      to maternal and other social separation procedures are compared, and influences
      of social partners on endocrine responses and behavior in periadolescent guinea
      pigs are described.

PMID- 12621650
TI  - Effects of the presence of the father on pup development in California mice
      (Peromyscus californicus).
AB  - Pup development and behavior in California mice were studied in litters housed
      with single mothers, or with fathers and mothers living together. Behavior of
      pups was recorded during a 15-min session every 2 days from 10 to 30 days of age.
      Physical contact, locomotion, grooming, and physical development indicators were
      recorded. It was found that the physical contact between siblings was greater and
      there was a tendency to have more contact between pup and either parent in the
      group in which the father was present. Finally, it was noted that the presence of
      the father did not affect either the first appearance of pup behavior during
      development or physical growth. In conclusion, the results indicate that the
      presence of the father had a greater influence on social contact between the
      different members of the litter than on pup behavioral development and physical
      growth.

PMID- 12621651
TI  - Ethanol consumption by rat dams during gestation, lactation and weaning increases
      ethanol consumption by their adolescent young.
AB  - In two experiments, we examined effects of ethanol consumption in rat dams during
      gestation, lactation, and weaning on voluntary ethanol consumption by their
      adolescent young. We found that exposure to an ethanol-ingesting dam throughout
      gestation, lactation, and weaning enhanced voluntary ethanol consumption by 26-
      to 33-day-old adolescents. We systematically examined effects on adolescent
      ethanol intake or requiring dams to drink ethanol during various periods in their
      pups' development. We found that exposure to an ethanol-consuming dam during
      weaning enhanced adolescent ethanol consumption and exposure to a dam drinking
      ethanol during either gestation or while nursing enhanced adolescents' ethanol
      consumption only if pups also had access to ethanol during the weaning period.

PMID- 12621652
TI  - Latent inhibition of conditioned odor potentiation of startle: a developmental
      analysis.
AB  - We conducted a two-part study of age and latent inhibition in the rat. In the
      first part of the study, rats given odor-shock pairings at 23 or 75 days of age
      exhibited a potentiated startle response in the presence of the odor the
      following day. This effect did not occur in rats trained at 16 or 20 days of age.
      Odor pre-exposure on the day prior to conditioning markedly reduced the odor
      potentiation of startle effect in 23- and 75-day-old rats but had no effect in 16
      and 20-day-olds. In the second part of the study, rats were pre-exposed to the
      odor at 16 or 20 days of age and then conditioned at 23 days of age. When tested
      the day after conditioning, these pre-exposed rats exhibited a disruption in the
      odor potentiation of startle effect. We compare our results with other studies of
      latent inhibition, and with recent studies on whether conditioned responses are
      appropriate to the animal's age at training or their age at test.

PMID- 12621653
TI  - Reinstatement maintains a memory in human infants for 1(1/2) years.
AB  - This study tested the proposition of Campbell and Jaynes (1966) that
      reinstatement is the mechanism by which early memories are maintained over a
      significant period of development. In four progressive replications, 6-month-old
      human infants learned to move a miniature train around a track by lever-pressing.
      They received a brief reinstatement at 7, 8, 9, 12, and 18 months of age and a
      final retention test at 2 years of age. Although 6-month-olds usually remember
      this task for only 2 weeks, after five reinstatements they exhibited significant
      retention 1(1/2) years later. Untrained yoked controls that received the same
      reinstatement regimen exhibited no retention after any delay. These findings
      reveal that the immaturity of the brain at the time of encoding is not the rate
      limiting step in whether infants remember over the long term. Rather, as long as
      infants periodically encounter a nonverbal reminder, they can maintain early
      memories over a significant period of development.

PMID- 12621654
TI  - Does infant memory expression reflect age at encoding or age at retrieval?
AB  - Do human infants express a memory acquired earlier in ontogeny in a manner
      appropriate to their age at encoding or their age at the time of retrieval? To
      answer this, we exploited the fact that retention is highly context dependent at
      6 months but not at 8-9 months of age. Six-month-olds learned an operant response
      in one context, and their memory was maintained by monthly reinstatements in the
      original context. At 8 or 9 months of age, 1 month after the last (or only)
      reinstatement, infants were tested in either the same or a different context.
      During testing, infants' retention was no longer context dependent; rather, they
      responded robustly in both test contexts. These results revealed that infants
      expressed a memory acquired when they were younger in a manner appropriate to
      their test age. They were interpreted in terms of changes in the functional
      significance of context before and after infants self-locomote.

PMID- 12621656
TI  - Behavioral inhibition and behavioral activation in young children: relations with
      self-regulation and adaptation to preschool in children attending Head Start.
AB  - We examine a parent-report version of the measure of behavioral inhibition and
      behavioral activation of Carver and White (1994), the BIS/BAS scales.
      Participants included 42 children (mean age = 4 years, 9 months) attending Head
      Start programs. Information was collected on aspects of physiological and
      cognitive regulation, temperamental emotionality, BIS/BAS sensitivity, and
      teacher report of social competence and on-task behavior in the classroom.
      Physiological regulation was assessed by cardiac vagal tone and was measured
      during a baseline period and during the administration of a mildly effortful
      cognitive task. Cognitive regulation was assessed by executive function and was
      measured using two tasks that require children to inhibit a prepotent response
      while remembering and executing the rule for correct responding. Parents reported
      on behavioral inhibition and behavioral activation and aspects of child negative
      emotionality associated with fear and anger. Results indicated that the BIS scale
      was positively related to teacher reported social competence but negatively
      related to on-task behavior. Associations between the BIS and each of the outcome
      variables were independent of relations of physiological and cognitive regulation
      to outcomes and were present when relations between fearful emotionality and the
      outcomes were not. No relations were observed between any of the BAS scales and
      the outcome measures. Results recommend the application of neurobiological and
      psychophysiological approaches to the study of children's adaptation to
      preschool.

PMID- 12621655
TI  - Attention during looking and reaching as assessed by heart rate in 7(1/2)-month
      old infants.
AB  - Attention mediates the acquisition and encoding of information about the world
      and is central to motor action. Heart rate deceleration and behavioral inhibition
      are sensitive indices of the attentional process, but it is unknown whether these
      indices are valid in the context of overt action. The current study investigated
      the relationship between visual attention, action, and heart rate during reaching
      in 7(1/2)-month-old infants. We found that infants showed prolonged looking and
      large heart rate decelerations on reaching and looking trials. We conclude that
      overt action itself does not prevent the autonomic and behavioral changes that
      are also seen in attention to simple visual displays and that attention is
      maintained throughout the act of reaching.

PMID- 12621657
TI  - Changing determinants of crying termination in 6- to 12-week-old human infants.
AB  - Developmental change in human infant crying termination was studied in 60 infants
      who were 6, 9, and 12 weeks of age. They qualified by spontaneously crying for at
      least 30 s during the study's first minute. Infants then received either 0.8 ml
      sucrose (12% w/v) by syringe or sucked a pacifier dipped in the 12% solution for
      a total of 3.5 min. Crying was substantially reduced by pacifier-sucking at all
      three ages tested. Sucrose too was effective at 6 and 9 weeks of age but did not
      reduce crying in 12-week-olds. These data suggest different schedules in the
      decline of sweet taste and pacifier sucking as agents of crying termination.
      These differential rates argue for multiple systems that govern crying reduction
      and argue against a single central target that changes ontogenetically in
      sensitivity and control. Whether the continuation of sucking effectiveness is
      sustained by infant sucking experience or reflects a slower rate of decline
      cannot be determined at present.

PMID- 12621658
TI  - Quiz page. Proliferative glomerulonephritis.

PMID- 12621659
TI  - Mercury exposure and malaria prevalence among gold miners in Para, Brazil.
AB  - Economic development, including resource extraction, can cause toxic exposures
      that interact with endemic infectious diseases. Mercury is an immunotoxic metal
      used in the amalgamation of gold, resulting in both occupational exposures and
      environmental pollution. A cross-sectional medical survey was conducted in 1997
      on 135 garimpeiros in Para, Brazil, because of their risks of both mercury
      exposure and malaria transmission. Mean levels of blood and urine mercury were
      well above non-exposed background levels. Twenty-six subjects had malaria
      parasitemia: Health symptoms consistent with mercury exposure were reported, but
      neither symptoms nor signs correlated with mercury levels in blood or urine. We
      did not find a dose response relationship between mercury exposure and likelihood
      of prevalent malaria infection, but there was a possible reduction in acquisition
      of immunity that may be associated with conditions in gold mining, including
      mercury exposure.

PMID- 12621661
TI  - [Presence of human papillomavirus in malignant oral lesions].
AB  - The purpose of this study was to investigate the prevalence of human
      papillomavirus 6/11 and 16/18 in patients, with oral lesions clinically diagnosed
      as leucoplakia, attending the School of Dentistry, University of Sao Paulo
      State/UNESP, Brazil. After paraffin embedded process, in the sections staining
      with H&E, 30 biopsies were screened and separated on 3 groups: 10 oral lesions
      without dysplasia, 10 with dysplasia, and 10 with invasive squamous cell
      carcinoma. The lesions with dysplasia were classified in agreement with Van Der
      Wall's histopathological standard method. Oral lesions were investigated for the
      presence of human papillomavirus (HPV) by in situ hybridization with wide
      spectrum, 6/11 and 16/18 biotinylated probes. HPV 16/18 was found in 20% (n = 2)
      of the leucoplakia with severe-degree dysplasia. The presence of HPV 16/18 in
      malignant lesions suggests its importance as a risk factor for oral
      carcinogenesis.

PMID- 12621660
TI  - [Phlebotominae (Diptera: Psychodidae) in area of transmission of american
      tegumentar leishmaniasis in the north coast of the State of Sao Paulo, Brazil].
AB  - Fourteen, 30 and 104 cases of American tegumentary leishmaniasis were recorded
      respectively, in 1993, 1994 and 1995, in the coast region of Sao Paulo State.
      Aiming to characterize the fauna and seasonal and hourly distributions of the
      phlebotominic species, adult specimens were captured fortnightly between
      November/95 and December/96. CDC light traps were used as of dusk
      intradomiciliarly, peridomiciliarly and in the forest for 12 hours. From the same
      moment on but only during 6 hours Shannon traps were set in the peridomicile 100
      meters from the house. Quarterly this trap was used for 12 hours. The population
      density fluctuation as well as the occurrence of intra and extradomiciliarly
      predominant species were observed. In the different traps used and environments
      investigated Lutzomyia intermedia was the most abundant species.

PMID- 12621662
TI  - [Epidemiological and clinical study of 332 cases of cutaneous leishmaniasis in
      the north of Parana State from 1993 to 1998].
AB  - Cases of cutaneous leishmaniasis (CL) in northern Parana State have been reported
      since the 1950's, but towards the end of the 1980's there has been an increase in
      the number of human infections. From 1993 to 1998, a study was carried out in an
      attempt to define the epidemiological profile of leishmaniasis in this region. A
      total of 316 cases of CL were reported from 35 municipal districts and 16
      imported cases. Most cases of CL notified (70.8%) were in the age group of 15 to
      49 years old and most of these were males (61.2%). Of the 332 positive patients,
      66.8% presented single classic lesions and 31.1% multiple lesions. Most of these
      lesions were located in the lower limbs (47.7%) while 26.7% were in the arms and
      16% on the face. Thirty-two Leishmania stocks were isolated and identified by
      isoenzymatic characterization using 13 enzymatic systems as Leishmania (Viannia)
      braziliensis.

PMID- 12621664
TI  - Outbreak of aggressions and transmission of rabies in human beings by vampire
      bats in northeastern Brazil.
AB  - Outbreaks of attacks upon human beings by vampire bats seems to be a common
      phenomenon in several regions of Latin America, but the occurrence of rabies
      infection among humans bled by vampires, is relatively low. In the present study,
      two outbreaks of human rabies transmitted by common vampire bats (Desmodus
      rotundus) are described from Bahia State, Northeastern Brazil, in 1991 and 1992.
      The first was recorded in Apora where 308 people were bled by vampires bats and
      three of these die from this zoonosis. The 2nd outbreak occurred in Conde where
      only five people were bled by vampires, and two deaths by rabies were registered.
      Our data suggest that rabies transmitted by bats basically depends on the
      presence of virus in the vampire bat population and not on the number of humans
      bled by them.

PMID- 12621663
TI  - [Adverse effects of multidrug therapy in leprosy patients: a five-year survey at
      a Health Center of the Federal University of Uberlandia].
AB  - The introduction of multidrug therapy (WHO/MDT)-composed by the drugs dapsone,
      clofazimine and rifampicin has enabled the cure of Hansen's disease, however, the
      adverse effects of these drugs were not given priority by the health team. Aiming
      to determine MDT's adverse effects' magnitude and relate them to the non-adhesion
      of patients to the treatment, a study of 187 charts of patients treated with MDT
      from January of 1995 to May 2000, was carried out at a Health Center of the
      Federal University of Uberlandia. Side effects were recorded in 71 patients'
      charts. Among the 113 side effects found, 80 (70.7%) were related to dapsone, 7
      (6.2%) were caused by rifampicin and 26 (20.5%) were attributed to clofazimine.
      These effects induced 28 (14.9%), patients to change the therapeutic scheme,
      representing 39.4% from the 71 patients with adverse effects. Throughout this
      study, the importance is discussed of considering MDT's adverse effects when
      training the health team to heighten the patient's adhesion to the treatment and
      thereby collaborating to eliminate Hansen's disease as a public health problem.

PMID- 12621665
TI  - [Frequency and implications of autoantibodies in acute viral hepatitis].
AB  - There are interactions between hepatotropic viruses and the host immune system,
      which could contribute to liver damage in viral hepatitis. The aim of this study
      was to investigate the frequency of autoantibodies in patients with acute viral
      hepatitis and their relationship with biochemical activity, severity of acute
      illness and chronicity rate. From 1992 to 2000, 156 patients with acute viral
      hepatitis were enrolled in a prospective study. Among these, hepatitis A was
      detected in 32%, hepatitis B in 31%, hepatitis C in 8%, hepatitis E in 3% and 24%
      were considered non A-E hepatitis. During the acute phase, 20.5% of patients
      presented ANA and 14.8% anti-smooth muscle antibody positive. During
      convalescence, 6.4% of patients showed ANA and 3.9% anti-smooth muscle positive.
      Comparison between autoantibodies-positive and negative groups showed no
      differences regarding ALT and bilirubin levels. In conclusion, autoantibodies can
      occur in acute viral hepatitis but there are no prognostic consequences.

PMID- 12621667
TI  - An intermittent schedule is better than continuous regimen of antimonial therapy
      for cutaneous leishmaniasis in the municipality of Rio de Janeiro, Brazil.
AB  - This study reviews a series of cutaneous leishmaniasis cases diagnosed and
      treated in outpatient units in the municipality of Rio de Janeiro, where the
      intermittent schedule of antimonial therapy was replaced by the continuous
      regimen. Both schedules were based on daily intramuscular injections of
      pentavalent antimonial. Forty-nine subjects received the intermittent regimen,
      consisting of three ten-day series alternated with ten-day rest intervals whereas
      seventy-one patients received the continuous regimen during 20 consecutive days.
      The study groups had similar composition regarding age, sex and clinical
      condition. The cure rate was significantly higher in the group receiving the
      intermittent schedule than in the group receiving continuous therapy (89.8% vs
      63.3%). Moreover, loss to follow-up was significantly more frequent in the group
      receiving continuous therapy (19.7% vs 4.1% in the intermittent therapy). Under
      field conditions, the intermittent regimen provided higher effectiveness and
      adherence than the continuous schedule.

PMID- 12621666
TI  - Molecular epidemiology of HIV-1 in Rio Grande, RS, Brazil.
AB  - We conducted a molecular epidemiological study to investigate HIV-1 strains in
      Rio Grande, southern Brazil, searching for an association with transmission mode
      and risk behavior. Patients (185) identified at an AIDS treatment reference
      Hospital, from 1994 to 1997, were included; from which 107 blood samples were
      obtained. Nested PCR was realized once for each sample; for amplified samples
      (69) HIV subtypes were classified using the heteroduplex mobility assay. Subtypes
      identified were B (75%), C (22%) and F (3%). All infections with C were diagnosed
      after 1994. Comparing patients with B and C, no differences were detected
      regarding demographic, clinical and laboratory characteristics; survival analysis
      did not reveal differences in HIV to AIDS evolution. A higher proportion of
      injecting drug users, IDU (not significant, p < .07) was found among those with
      C. This suggests that C may have been introduced in this area through IDU, and is
      being spread, probably by their sexual partners, to persons with other risk
      practices.

PMID- 12621668
TI  - Acute liver failure in children: observations in Vitoria, Espirito Santo State,
      Brazil.
AB  - In this communication we report 46 cases of acute liver failure in children
      diagnosed at the Hospital Infantil Nossa Senhora da Gloria in Vitoria, E Santo.
      Serology for IgM anti-HAV, IgM anti-HBc, HbsAg, anti-HCV and biochemical tests
      were performed in all cases in a routine laboratory. The M/F ratio was 1.1:1 and
      the mean age was 4.7 +/- 3.2 years, without gender difference. Anti-HAV IgM+ in
      38 (82.6%) cases, anti-HbcIgM+ in two (4.3%) cases and 6 (13.1%) cases were
      negative for all viral markers investigated. Anti-HCV+ in one anti-HAV IgM+ case.
      HbsAg+ in two anti-HbcIgM+ and in two HAVIgM+ cases. Among the six A, B and C
      negative cases, four (8.6%) did not have the suspected exogenous intoxication.
      Mortality was 50%, without gender or age differences. These results demonstrate
      that HAV infection is the main etiology of acute liver failure in children in
      Brazil, confirming that, although it is a self limited, relatively mild illness,
      it can cause serious and even fatal disease. The observation of four cases
      without A, B and C viral markers and no history of exogenous intoxication, agree
      with the observation of non A-E acute sporadic hepatitis in Northeastern Brazil.

PMID- 12621669
TI  - Sensitivity of polymerase chain reaction for detection of known aliquots of
      Trypanosoma cruzi in the blood of mice: an in vitro study.
AB  - To evaluate the sensitivity of polymerase chain reaction (PCR) to reveal known
      number of trypomastigote in the blood of mice, three separate experiments were
      done. First: To eight samples of 500 microliters of normal mice blood, one
      aliquot of 1, 2, 3, 4, 5, 10, and 50 trypomastigotes respectively, were added.
      Second and third: 10 aliquots with 1 and 10 with 2 trypomastigotes were added to
      samples of 500 microliters of normal mice blood. Positive control: 500
      microliters of blood containing 100,000 trypomastigotes. For kDNA minicircles
      amplification by PCR the primers: S35 and S36 were used. PCR revealed products of
      330 b.p in the positive controls. When only one sample with the aliquots of 1 or
      2 trypomastigotes was examined, results were negative; results were positive with
      aliquots of 3 to 50 trypomastigotes. In the 2nd and 3rd experiments, 9/10
      aliquots with one parasite and 9/10 with 2 trypomastigotes were positive
      revealing a high sensitivity of this reaction. In conclusion, the presence of one
      single parasite in 500 microliters of blood, is enough for a positive PCR. This
      method could be used as a complement to the various parasitological cure tests in
      treated mice, when low volumes of blood are individually examined.

PMID- 12621670
TI  - [Mortality due to infectious and parasitic diseases in Salvador, Bahia: evolution
      and intra-urban differences according to living conditions].
AB  - The evolution of mortality due to infectious and parasitic diseases (IPD) and its
      intra-urban distribution in Salvador (Bahia) during the 1990's was analyzed in a
      study of time series and spatial aggregation. This data was obtained from DATASUS
      and from death certificates. Proportional mortality, mortality rate and
      standardized mortality ratio (SMR) were used for the temporal analysis. Mortality
      rates due to IPD stratified by a living conditions index (LCI) were analyzed in
      the spatial study. Between 1991 and 1995, the proportional mortality for IPD was
      8.3% and the risk of dying varied between 55.9 and 34.0/100,000 inhabitants.
      After 1995 the variation was between 52.8 and 41.1/100,000 inhabitants. The
      standardized mortality ratio for infectious and parasitic diseases in 1998 was
      1.3. Infectious intestinal diseases continue to be one of the principal causes of
      death in this group. The highest rates of mortality from IPD were concentrated in
      the areas of the city where the living conditions were poor. Despite the observed
      decline, there is still an excessive mortality rate from IPD in Salvador. The
      developmental model of the Country and re-emergence of some diseases could be
      contributing towards this pattern.

PMID- 12621671
TI  - [Infection and disease caused by the human T cell lymphotropic viruses type I and
      II in Brazil].
AB  - HTLV-I/II infection is present in all regions of Brazil, but its prevalence
      varies according to the geographical area, being higher in Bahia, Pernambuco and
      Para. It has been estimated that Brazil has the highest absolute number of
      infected individuals in the world. Blood donors screening and research conducted
      with special groups (indigenous population of Brazil, IV drug users and pregnant
      women) are the major sources of information about these viruses in our Country.
      HTLV-I causes adult T cell leukemia/lymphoma (ATLL), HTLV associated
      myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV associated uveitis (HAU),
      dermatological and immunological abnormalities. HTLV-II is not consistently
      associated with any disease. Diagnosis is established using screening (enzymatic
      assays, agglutination) and confirmatory (Western blot, PCR) tests. The viruses
      are transmitted by blood and contaminated needles, by sexual relations and from
      mother to child, especially by breast feeding. Prevention efforts should focus on
      education of positive blood donors, infected mothers and IV drug users.

PMID- 12621672
TI  - [Schistosomiasis in Brazil after one century of research].
AB  - An attempt to evaluate the importance of scientific research on Schistosomiasis
      in Brazil, since 1908 until now, reveals the difficulties and uncertainties of
      such a task, when current criteria for measuring scientific impact are employed.
      However, with due respect to the contribution of international research, the data
      originated from Brazilian research on schistosomiasis, during almost a century,
      now appear sufficient for dealing with all our practical and scientific needs in
      this area.

PMID- 12621673
TI  - [Visceral leishmaniasis and B fulminant hepatitis association: case report].
AB  - The case of a 20-year-old man with hepatoesplenomegaly, fever and severe hepatic
      insufficiency is reported. Histopathological and immunohistochemical studies of
      tissue specimens obtained at autopsy led to diagnosis of visceral leishmaniasis
      and fulminant hepatitis B. The authors pointed out a possible influence of
      immunological response related with visceral leishmaniasis in development of
      severe hepatic involvement by hepatitis B virus.

PMID- 12621674
TI  - [A case of parasitism by Rhabditis sp in a child from Goiania, Goias, Brazil].
AB  - We report a case of parasitism by Rhabditis sp in a five-month-old child, from
      Goias State, Brazil. He had a history of diarrhea with liquid and green faeces
      which later became bloody. Parasitological examination revealed the presence of
      larvae and adult female of Rhabditis sp. We used thiabendazole in this case after
      which the child improved. The authors suggest a better differential diagnostic
      between Strongyloides and Rhabditis.

PMID- 12621675
TI  - Brazilian spotted fever: description of a fatal clinical case in the State of Rio
      de Janeiro.
AB  - We describe a case of Brazilian spotted fever in a previously healthy young woman
      who died with petechial rash associated to acute renal and respiratory
      insufficiency 12 days following fever, headache, myalgia, and diarrhea. Serologic
      test in a serum sample, using an immunofluorescence assay, revealed reactive
      IgM/IgG.

PMID- 12621676
TI  - Genetic diversity and differentiation in natural Plasmodium falciparum
      populations inferred by molecular typing of the merozoite surface proteins 1 and
      2.
AB  - Genetic diversity and differentiation, inferred by typing the polymorphic genes
      coding for the merozoite surface proteins 1 (Msp-1) and 2 (Msp-2), were compared
      for 345 isolates belonging to seven Plasmodium falciparum populations from three
      continents. Both loci yielded similar estimates of genetic diversity for each
      population, but rather different patterns of between-population differentiation,
      suggesting that natural selection on these loci, rather than the transmission
      dynamics of P. falciparum, determines the variation in allele frequencies among
      populations.

PMID- 12621678
TI  - Intestinal nematodes and pulmonary tuberculosis.
AB  - We report a significantly higher prevalence of intestinal nematodes in patients
      with pulmonary tuberculosis (TB) compared to a matched control group: 33/57
      (57.8%) in patients with TB and 18/86 (20.9%) in the control group; OR = 5.19;
      95% CI = 2.33-11.69; p = 0.000). When TB patients eosinophilia was also
      significantly higher among those with intestinal parasites (69.8%) compared to
      those without this condition (45.6%). We hypothesized that the immune modulation
      induced by nematodes is a factor that enhances TB infection/progression and that
      eosinophilia seen in TB patients is a consequence of helminth infection.

PMID- 12621677
TI  - [Intestinal helminthiasis in street population of Rio de Janeiro city].
AB  - Stool examination by sedimentation method in 82 homeless individuals living in
      the streets of Rio de Janeiro City, revealed Ascaris lumbricoides eggs in 40
      (48.85%), Trichuris trichiura in 27 (32.9%) and hookworm in 7 (8.5%).

PMID- 12621679
TI  - Cryptococcus neoformans causing meningitis in AIDS patients.
AB  - Cryptococcus neoformans causes meningitis in AIDS patients. In the Sao Jose
      Hospital, reference center for patients with AIDS in Fortaleza--Ceara State-
      Brazil, 54 samples of the cerebrospinal fluid were analyzed from January 1st
      through December 31st 2000. Direct examination with India ink and culture in
      Sabouraud's agar at 37 degrees C were done. Of the specimens studied 5(9.25%)
      were positive.

PMID- 12621680
TI  - Overdose of yellow fever vaccine: a preventable error?

PMID- 12621682
TI  - ["Current aspects of stroke"].

PMID- 12621681
TI  - Cervical spinal cord schistosomiasis.

PMID- 12621683
TI  - [Epidemiology of stroke].
AB  - In spite of the decrease in stroke mortality in industrialized western countries
      an increase of stroke incidence is expected especially in developing countries.
      Thus, within the next years, stroke will lead to a growing global health burden.
      In Austria, mortality has decreased between 1970 and 1994 by half and has now
      reached a rate of 100 per 100,000 inhabitants per year. Incidence rates amount to
      200-300 per 100,000 inhabitants per year. Recurrent stroke rates are estimated to
      occur at a rate of 6-12% within the first year and 5-8% within the following
      years. Data from the Austrian Stroke Unit Registry comprise data compiled in 15
      stroke units and show that the 3 month mortality is 11.7% and 40% show pronounced
      or moderate residual disabilities.

PMID- 12621684
TI  - [Prevention of stroke].
AB  - In the past years, research on cardiovascular prevention was among the fields
      with the most pronounced medical progress. Actually, a substantial proportion of
      strokes could be avoided given a strict consideration of the currently available
      prevention guidelines. The current review summarizes the most compelling studies
      and meta-analyses on this issue and depicts the main consequences and resulting
      recommendations. Apart from classic risk factors there is a special focus on new
      risk concepts including toxic effects of homocystine, the 'iron hypothesis' and
      the intriguing issues of inflammation and chronic infection. In addition, there
      will be a dispute on challenges regarding carotid surgery and optimal drug
      therapy as well as on dietary guidelines.

PMID- 12621685
TI  - [Diagnosis of stroke--an update].
AB  - In practical day-to-day terms, most patients have one of the common causes of
      stroke: ischemic stroke caused by the complications of atherothrombosis,
      intracranial small Vessel disease, embolism from the heart, primary intracerebral
      hemorrhage caused by hypertension, or subarachnoid hemorrhage as a result of a
      ruptured saccular aneurysm. There are three issues to be considered in assessing
      the reliability of the clinical diagnosis of stroke: the diagnosis of stroke
      itself: is it a stroke or not; whether the stroke is caused by an infarct or a
      hemorrhage and particular in ischemic stroke the site and size of the lesion
      (anterior vs. posterior circulation, lacunar vs. cortical, etc.) No clinical
      scoring method can differentiate with absolute reliability ischemic stroke from
      primary intracerebral hemorrhage. To do this brain computed tomography or
      magnetic resonance imaging is required. For vascular diagnosis ultrasound and
      magnetic resonance angiography are ideal and complementary non-invasive
      techniques. Both have no risks and are reasonably sensitive. Catheterangiography
      is only reserved for patients with subarachnoid hemorrhage with a view to
      surgical or endovascular treatment or in exceptional cases to establish a more
      firm prognosis. The diagnosis of ischemic stroke caused by embolism from the
      heart can only be considered at all if there is an identifiable cardioembolic
      source which is the case in about 30% of ischemic stroke, a higher proportion in
      recent studies using transoesophageal echocardiography. It is not clear that
      transoesophageal echocardiography provides much more information for clinical
      decision-making than transthoracic echocardiography, although it certainly
      provides more anatomical information in selected patients. This article
      summarises the diagnostic armamentarium which is used for the diagnosis of stroke
      and gives an overview of clinically reliable and relevant measures.

PMID- 12621687
TI  - [Neurorehabilitation after stroke].
AB  - After stroke most patients need to undergo extensive neurological and
      neuropsychological rehabilitation (neurorehabilitation). It is important to have
      an individual treatment programme that takes into account that the stroke patient
      is impaired in terms of his receptive skills, his capacity to act and his
      personal integrity. Based on the "phase model" of the Austrian Society for
      Neurological Rehabilitation (OGNR) individual goals have to be agreed and
      measures have to be taken. After maintaining the vital functions and a stable
      vegetative state, the remaining abilities have to be stimulated, functions have
      to be regained and deficits have to be compensated. An interdisciplinary
      neurological rehabilitation team has, for example, the following
      responsibilities: treatment of impaired motor skills and balance, treatment of
      swallowing and breathing impairments, training of activities of daily living, and
      special concepts for the treatment of cognitive deficits and impaired behaviour.
      A decisive factor for rehabilitation success is the relationship between
      therapists and patients and their relatives/carers. Preparation for independent
      or care-managed life after inpatient rehabilitation is of paramount importance,
      this means organization of continuing out-patient treatment, out-patient care
      management, as well as measurement and documentation of rehabilitation success.
      Regaining quality of life is an active process of analysing and working on the
      remaining activity limitations and participation restrictions in society. The
      work of the interdisciplinary neurological rehabilitation team contributes
      decisively to this process.

PMID- 12621686
TI  - [Acute therapy of ischemic stroke].
AB  - Thrombolysis was used in 3.7% of stroke patients who were admitted to the
      Neurological Departments of Vienna. High doses of heparin were associated with an
      increased risk of secondary symptomatic hemorrhage (OR 10.3; 95% CI 2.4-43.2).
      But none of the patients with TIA or minor stroke who received high dosages of
      heparin suffered from secondary symptomatic hemorrhage. Spontaneous or
      therapeutically induced decrease of the diastolic blood pressure by more than 20
      mmHg was associated with a three-fold risk of an unfortunate functional outcome.
      Complications following stroke are frequent and most likely to occur within the
      first 5 days. Pneumonia was found to be an independent risk factor for an
      unfortunate functional outcome after three months. A main field of activity of
      stroke units should be to prevent or to early recognize and treat complications.

PMID- 12621688
TI  - [Stroke in nursing care--regarding the need for a neurogeriatric management
      process].
AB  - In Austria every year approximately 15,000 people are suffering the fate of
      stroke. A permanent handicap remains in about 60 percents. Many of the patients
      need permanent assistance and admittance to a nursing home is often required. The
      clinical picture of stroke makes it necessary that even in nursing homes a
      qualified and professional care is offered to the patients to satisfy their
      needs. In such stroke care specialized nursing homes an extensive
      multiprofessional assessment is useful to determine and to quantify the deficits
      but even the abilities of stroke victims. The results are the basis for further
      treatment and planning of nursing care. More and more modern and progressive
      nursing concepts are used emphasizing the special clinical situation. The goal is
      to establish an extensive concept of stroke care that is realized not only in
      stroke units but even in long term care institutions. A modern long term
      management of stroke patients exceeds the term "Pflegefall" by far. It is a
      multiprofessional challenge.

PMID- 12621689
TI  - [Minimally invasive funnel chest correction: initial experiences and critical
      evaluation of this fascinating technique].
AB  - The discussion about the surgical correction of funnel chest deformities enjoys a
      great renaissance since D. Nuss presented a new, minimal invasive technique.
      Although his method has gained wide acceptance among patients and pediatric
      surgeon the question arises, whether it can be considered as the Golden Standard'
      already. In 2000-2001 a total of 14 patients were corrected by transthoracic
      implantation of the pectus bar and subsequent elevation of the deformity. Results
      (mean data): age 14.3 years body weight 54 kg, height 170 cm, operative time 57
      min, minimal blood loss, no intraoperative complications. The cosmetic result was
      considered as very good by all patients on the day of dismission. As a late
      complication one bar dislocated and had to be repositioned surgically. The
      minimal invasive approach for funnel chest corrections is a fascinating
      technique, which demonstrates striking advantages for the children: reduced
      operative trauma (no rib resections), shorter recovery, small incisions. However
      only few studies validate the long-term benefit of this procedure. Consequently,
      the minimal invasive method should not be advocated as the new Golden Standard',
      until these results meet the high quality of the conventional technique.

PMID- 12621690
TI  - [Therapy of head injuries caused by animal slaughter guns].
AB  - Slaughterer's guns ("humane killers") are powder-activated cattle skull impacting
      tools. Today mechanical stunning is typical for country like regions, because in
      the municipal slaughter-houses electrical stunning of pigs and ruminants is
      preferred. In rare cases these weapons are used for suicide. They then cause
      penetrating brain lesions and if the victim survives the brain-damage, an
      encephalitis caused by the impacted material results. The neurosurgical treatment
      is to revise the gunshot canal and to remove impacted fragments of bone and
      contaminated skin (imprimat) under antibiotic cover. A psychiatric treatment of
      the mostly underlying depression and a rehabilitative treatment should complete
      therapy. So treatment of slaughterer's gun injury should have a multidisciplinary
      approach.

PMID- 12621691
TI  - Serum concentrations of sCD30 and sCD40L in patients with malignant bone tumours.
AB  - The aim of this study was to evaluate serum levels of both soluble CD30 (sCD30)
      and soluble CD40 ligand (sCD40L) in patients with malignant bone tumours and to
      determine their ability to serve as serum markers. Sera of 31 patients were taken
      at the time of diagnosis, analysed by ELISA, and the results were correlated with
      clinical features and compared with healthy controls. Soluble CD30 and sCD40L
      levels were significantly higher in all patient groups than in the healthy
      controls. Soluble CD30 levels showed statistically significant differences
      between high malignant osteosarcoma and Ewing sarcoma (P = 0.015), whereas no
      statistically significant correlation was seen between different types of tumours
      and sCD40L levels. Soluble CD30 and sCD40L seem to be of diagnostic value in
      osteosarcoma and Ewing sarcoma.

PMID- 12621692
TI  - [Elephantiasis of the thoracic wall within the scope of von Recklinghausen
      neurofibromatosis, case report].
AB  - Neurofibromas are benign tumors arising from neuroectodermal tissues. They may
      occur as solitary lesions, or multiple, in which case they are referred to as
      neurofibromatosis, or von Recklinghausen's disease. We report about a 17-year-old
      patient with neurofibromatous elephantiasis located in the lateral aspect of the
      left hemithorax. CT showed massive chest wall infiltration and retroperitoneal
      tumor growth, but no abnormalities of the cranium. Our surgical treatment
      consisted of a two-stage, palliative tumor debulking and defect coverage with a
      splitthickness skin graft. The operative and postoperative course was uneventful.

PMID- 12621693
TI  - Recurrent syncope in a young patient with long QT syndrome: possible relationship
      of atrioventricular nodal re-entrant tachycardia with neurally mediated spells?
AB  - This is a case of a 15-year-old woman with long QT syndrome (LQTS) and a history
      of 14 events of syncope, demonstrating that the underlying mechanism for any
      symptomatic episode is not necessarily based on torsades de pointes. The need for
      careful distinction between true ventricular tachyarrhythmia and other forms of
      supraventricular tachycardia in the LQTS is the subject of the article. To the
      knowledge of the authors, this is the first reported case of an association of
      LQTS with AV nodal re-entrant tachycardia.

PMID- 12621695
TI  - [Admission and management of patients from different ethnic groups in a
      cardiology service].

PMID- 12621697
TI  - [In whom do we implant a pacemaker?].

PMID- 12621698
TI  - [Automatic implantable defibrillators].

PMID- 12621696
TI  - [Patient education before a coronary angiography].

PMID- 12621699
TI  - [Experience of Paris firefighter brigade with semi-automatic defibrillation].

PMID- 12621700
TI  - [Education of the myocardial insufficiency patient].

PMID- 12621701
TI  - [Nurses' role in the prevention and cessation of smoking in the hospital].

PMID- 12621702
TI  - [Cardiology according to Galen].

PMID- 12621703
TI  - Gearing up for the new accreditation process. Revised Joint Commission standards
      for 2004.

PMID- 12621704
TI  - Performance improvement in long-term care (PI).

PMID- 12621705
TI  - [What future for personalized autonomy allocation in the home?].

PMID- 12621707
TI  - [Elderly persons in the family environment, the new deal].

PMID- 12621708
TI  - [Home care, a choice for the elderly and his family?].

PMID- 12621709
TI  - [Family and institution, an impossible understanding?].

PMID- 12621710
TI  - [Role of self help groups for families in institutions].

PMID- 12621711
TI  - [Educating family nursing aides].

PMID- 12621712
TI  - [Mediation, education and systematic nutritional after-care in the elderly in
      nursing homes].

PMID- 12621713
TI  - [Management of Alzheimer's disease. 2/6-incontinence and sexual behavior].

PMID- 12621714
TI  - [The elderly person at home and his relation to money].

PMID- 12621715
TI  - [Money, a mediation in the relations between nurses and elderly persons].

PMID- 12621716
TI  - [The quality charter of nurses' aides].

PMID- 12621717
TI  - Evaluation of the Florida coordinated school health program pilot schools
      project.
AB  - The Florida Department of Education, with CDC funding, designed the Florida
      Coordinated School Health Program Pilot Schools Project (PSP) to encourage
      innovative approaches to promote coordinated school health programs (CSHP) in
      Florida schools. Each of eight pilot schools received $15,000 in project funding,
      three years of technical assistance including on-site and off-site assistance, a
      project office resource center, mailings of resource materials, needs assessment
      and evaluation assistance, and three PSP Summer Institutes. Project evaluators
      created a context evaluation, approaching each school independently as a "case
      study" to measure the school's progress in meeting goals established at baseline.
      Data were collected using the How Healthy is Your School? needs assessment
      instrument, a School Health Portfolio constructed by each school team, a Pilot
      Schools Project Team Member Survey instrument, midcourse team interviews, final
      team interviews, and performance indicator data obtained from pilot and control
      schools. The PSP posed two fundamental questions: "Can financial resources,
      professional training, and technical assistance enable individual schools to
      create and sustain a coordinated school health program?" and "What outcomes
      reasonably can one expect from a coordinated school health program, assuming
      programs receive adequate support over time?" First, activities at the eight
      schools confirmed that a coordinated school health programs can be established
      and sustained. Program strength and sustainability depend on long-term resources,
      qualified personnel, and administrative support. Second, though coordinated
      school health programs may improve school performance indicators, the PSP yielded
      insufficient evidence to support that belief. Future projects should include
      robust measurement and evaluation designs, thereby producing conclusive evidence
      about the influence of a coordinated school health program on such outcomes.

PMID- 12621718
TI  - Elementary school teachers' techniques of responding to student questions
      regarding sexuality issues.
AB  - Fifth- and sixth-grade elementary school teachers' (n = 277) techniques of
      responding to students' human sexuality-related questions were assessed. Few
      teachers (34%) reported receiving formal training in sexuality education. The
      most commonly asked student questions dealt with STDs, puberty, homosexuality,
      pregnancy, and abortion. Teachers' willingness to answer sexually-related
      questions in front of the class varied (73% to 14%) by content of the question.
      There were no questions on the questionnaire in which more than one in five
      teachers would choose not to answer. The most common questions the teachers
      identified they would not respond to dealt with topics such as abortion,
      masturbation, homosexuality, and issues about the male genitals. Finally, none of
      the questions was perceived by more than one in eight of the teachers as
      questions they would not be allowed to answer.

PMID- 12621719
TI  - The adolescent health review: test of a computerized screening tool in school
      based clinics.
AB  - This study tested the viability of a stand-alone screening process in school
      based health centers, and gauged its acceptance by patients and providers. The
      study also examined the prevalence of a variety of health risks disclosed in
      response to a new screening instrument and the relationship between these health
      risks and the stated purpose for the clinic visit. Seven school-based clinics
      located in six high schools and one alternative school in an urban school
      district participated in the study; 692 patients (83% female, 67% minority)
      completed the Adolescent Health Review (AHR), a multidimensional screening
      instrument that addressed 14 risk domains. The AHR was computerized for
      administration, scoring, and report generation. Females reported risk in
      significantly more domains than males (4.2 vs. 3.2; t = 4.5, p < .0001),
      including higher risk in family interaction problems, a history of physical or
      sexual abuse, emotional distress, suicidal behavior, marijuana use, and sexual
      activity. Significantly more males than females reported violent behavior. Risk
      rates were high regardless of stated purpose for the clinic visit. According to
      clinic staff, use of the AHR increased routine screening and the process was well
      accepted by patients and providers. Providers benefited from the opportunity to
      discuss risks with patients by using the printed reports to facilitate
      conversation and develop health care plans.

PMID- 12621720
TI  - Reporting of validity from school health promotion studies published in 12
      leading journals, 1996-2000.
AB  - A targeted review was conducted of school-based, controlled intervention studies
      that promoted good nutrition, physical activity, or smoking cessation/prevention,
      and were published in one of 12 leading health behavior journals between 1996 and
      2000. The RE-AIM framework was used to evaluate the extent to which each paper
      reported on elements of reach, efficacy, adoption, implementation, and
      maintenance. Thirty-two publications were reviewed. Reporting rates across the RE
      AIM dimensions varied substantially: Reach = 59.3%; Efficacy = 100%; Adoption =
      14.8%; Implementation = 37%; Maintenance = 25.9% for individuals, 0% for schools.
      Few studies reported if characteristics of the study sample were representative
      of those found in the broader population of students or schools. Among studies
      reporting on the RE-AIM dimensions, participation rates generally were high
      (median 82%), adoption rates were moderate (median 72.5%), and reports of
      implementation were high (87%). To increase the potential to translate controlled
      research to "real-world" practice conditions, a stronger emphasis should be
      placed on reporting the representativeness of the sample of students and schools.

PMID- 12621721
TI  - Reliability and validity of the School Health Policies and Programs Study 2000
      questionnaires.
AB  - To help assess the quality of the questionnaires developed for the School Health
      Policies and Programs Study (SHPPS) 2000, the Centers for Disease Control and
      Prevention (CDC) conducted a data quality substudy in conjunction with SHPPS
      2000. The substudy assessed validity of the state- and district-level
      questionnaires through telephone interviews with a subsample of the original
      state- and district-level respondents, and the test-retest reliability of the
      school- and classroom-level questionnaires through computer-assisted repeat
      interviews with a subsample of the school- and classroom-level respondents.
      Results indicated that although a few threats to the validity of responses to the
      state- and district-level questionnaires were identified, the questionnaires
      generally produced valid data. Among the school- and classroom-level
      questionnaires, some questions demonstrated poor reliability, but most exhibited
      moderate or substantial reliability, and some exhibited almost perfect
      reliability. CDC will use these results to revise the SHPPS 2000 questionnaires
      and will consider alternative methods of data collection to improve the quality
      of data collected in future versions of SHPPS.

PMID- 12621722
TI  - A hidden epidemic: dental disparities among children.

PMID- 12621723
TI  - Exploring gender-based communication styles.

PMID- 12621724
TI  - How one school district decided on a carpet policy.

PMID- 12621726
TI  - Drying phenomenon of Moroccan natural phosphates under microwave irradiation.
      Part I: Thermal and kinetic aspects.
AB  - In this paper, the use of microwave energy in a drying problem is examined. The
      purpose of this work is the investigation of the effect of incident microwave
      power to a material during drying and in particular the research of the
      experimental conditions which can be used to accelerate the drying phenomenon in
      order to save energy in the industrial processes. We describe, in the first
      instance, the experimental apparatus used and the results of kinetic and thermal
      aspects of drying induced by microwave heating. These results lead to the role of
      different parameters (microwave power, initial sample mass and diameter of the
      reactor) on the kinetic and the thermal aspects of the drying. In the second
      instance, the experimental results are presented and discussed taking into
      account the dielectric proprieties of the material, the literature and the use of
      the heterogeneous kinetic models. These studies point out important kinetic and
      thermal aspects allowing a better understanding of drying under microwave
      irradiation.

PMID- 12621728
TI  - [Bacteria isolated from surgical infections and their susceptibilities to
      antimicrobial agents. Special references to bacteria isolated between April 1999
      and March 2000].
AB  - The annual multicenter studies on isolated bacteria from infections in general
      surgery and their antimicrobial susceptibility have been conducted in Japan since
      July 1982. In this paper, the results obtained in the academic year 1999 (from
      April 1999 to March 2000) have been summarized. Two hundred seven cases were
      investigated, and 411 strains were isolated from 169 cases (81.6%). Of those
      strains, 184 and 227 strains were from primary infections and postoperative
      infections, respectively. In primary infections, the isolation rates of
      anaerobes, Streptococcus spp., and Escherichia coli were higher than in
      postoperative infections, while in postoperative infections, those of Gram
      positive aerobes were higher than in primary infections. Staphylococcus aureus
      were most frequently isolated among Gram-positive aerobes, Peptostreptococcus
      prevotii among Gram-positive anaerobes, E. coli among Gram-negative aerobes, and
      Bacteroides fragilis among Gram-negative anaerobes. In primary infections, the
      percentage of Gram-negative aerobes, which gradually increased by the year 1998,
      decreased in the year 1999. The percentage of Gram-negative anaerobes increased,
      while that of Gram-negative bacteria was equivalent to that in the last year. In
      postoperative infections, the percentage of Gram-negative anaerobes, which
      continuously increased after the year 1990, decreased, while that of Gram
      positive aerobes, which decreased in the last year, increased. Methicillin
      resistant S. aureus accounted for 70.7% of S. aureus (41 strains). Either the
      number of strain or the percentage of MRSA decreased. The susceptibilities of E.
      coli and Klebsiella pneumoniae decreased against third and forth generation
      cephems, oxacephems, and monobactams. The susceptibilities of P. aeruginosa to
      carbapenems tend to decrease after the year 1997. S. aureus showed good
      susceptibilities to the tested drugs including arbekacin, vancomycin, and
      teicoplanin.

PMID- 12621730
TI  - [Survey of susceptibility of methicillin-resistant Staphylococcus aureus to
      antimicrobial agents in Hokusetsu General Hospital].
AB  - We examined the annual isolation rate, susceptibility to antimicrobial agents and
      coagulase types of methicillin-resistant Staphylococcus aureus (MRSA) isolated
      from inpatients in Hokusetsu General Hospital to ascertain the situation of MRSA
      isolates between 1992 and 2001. The isolation rate of MRSA in S. aureus increased
      annually from 1992, reaching 65.3% in 2001. The isolation rates of MRSA in the
      inpatients were 3.2 times greater than those in the outpatients. In the clinical
      specimens the isolation rate of MRSA from sputum was the highest, i.e., 32.9%. In
      respect of the coagulase types, type II accounted for 85.7% of the all types.
      MIC90 values of arbekacin, sulfmethoxazole-trimethoprin, vancomycin, teicopranin
      and minocycline were 4.0, 2.0, 2.0, 2.0, and 8.0 micrograms/ml, respectively.

PMID- 12621729
TI  - [Bacteria isolated from surgical infections and their susceptibilities to
      antimicrobial agents--special references to bacteria isolated between April 2000
      and March 2001].
AB  - Tendency of isolated bacteria from infections in general surgery and their
      antimicrobial susceptibilities during the period from April 2000 to March 2001
      were investigated in a multicenter study in Japan, and the following results were
      obtained. The number of cases investigated as objectives was 234 for one year. A
      total of 388 strains (136 strains from primary infections and 252 strains from
      postoperative infections) were isolated from 165 cases (70.5% of total cases). In
      primary infections, anaerobic Gram-positive bacteria were predominant, while from
      postoperative infections, aerobic Gram-positive bacteria were predominant. Among
      aerobic Gram-positive bacteria, the isolation rate of Enterococcus faecalis was
      the highest, followed by that of Staphylococcus aureus from postoperative
      infections. Among anaerobic Gram-positive bacteria, the isolation rate of
      Peptostreptococcus spp. was the highest from both types of infections. Among
      aerobic Gram-negative bacteria, Escherichia coli was the most predominantly
      isolated from primary infections, followed by Klebsiella pneumoniae and
      Pseudomonas aeruginosa in this order, and from postoperative infections, P.
      aeruginosa was the most predominantly isolated, followed by Enterobacter spp. and
      Klebsiella spp. Among anaerobic Gram-negative bacteria, the isolation rate of
      Bacteroides fragilis group was the highest from both types of infections. There
      was no vancomycin-resistant S. aureus nor Enterococcus spp. Among anaerobic
      bacteria, there were many resistant strains against penicillins and cephems with
      MICs higher than 100 micrograms/ml, and the same trend was observed among other
      Bacteroides spp. and Prevotella spp.

PMID- 12621731
TI  - [Comparative in vitro activities of several antimicrobial agents against
      Helicobacter pylori].
AB  - Comparative in vitro activities of several antimicrobial agents against
      Helicobacter pylori were evaluated. Minimum inhibitory concentrations against 41
      strains of H. pylori were determined by using E test. All 41 strains were
      isolated from gastric mucosa of patients suspected to have gastric ulcer. The
      ranges of MIC of amoxicillin was from 0.016 microgram/ml and less to 0.064
      microgram/ml. The ranges of MIC of clarithromycin, erythromycin, and azithromycin
      were from 0.016 microgram/ml and less to 64 micrograms/ml, from 0.016
      microgram/ml and less to more than 256 micrograms/ml, from 0.064 to more than 256
      micrograms/ml, respectively. The ranges of MIC of ciprofloxacin, sparfloxacin,
      levofloxacin, norfloxacin were from 0.016 microgram/ml and less to 32
      micrograms/ml, from 0.002 microgram/ml and less to more than 32 micrograms/ml,
      from 0.002 microgram/ml and less to more than 32 micrograms/ml, from 0.064 to
      more than 32 micrograms/ml, respectively.

PMID- 12621732
TI  - [In vitro antibacterial activity of prulifloxacin, a new oral fluoroquinolone].
AB  - We compared antibacterial activity of NM394, which is the active metabolite of a
      prodrug of new fluoroquinolone prulifloxacin (PUFX), against clinical isolates of
      bacteria with those of ciprofloxacin (CPFX), levofloxacin (LVFX), gatifloxacin
      (GFLX), tosufloxacin (TFLX) and fleroxacin (FLRX). 1. NM394 showed a broad
      spectrum antibacterial activity against both Gram-positive and Gram-negative
      bacteria. 2. MIC80 of NM394 for methicillin-sensitive Staphylococcus aureus,
      Streptococcus pneumoniae and Enterococcus faecalis were 0.5 microgram/ml, 2
      micrograms/ml and 4 micrograms/ml, respectively. MIC80 of NM394 for Escherichia
      coli, Klebsiella pneumoniae and Enterobacter cloacae was lower than 0.06
      microgram/ml. MIC80 of NM394 for Serratia marcescens and Pseudomonas aeruginosa
      were 0.25 microgram/ml and 2 micrograms/ml, respectively. 3. Short-time
      bactericidal activity of NM394 against P. aeruginosa was stronger than those of
      CPFX, GFLX, LVFX and TFLX. 4. Short-time bactericidal activity of NM394 at Cmax
      concentration against 12 strains of P. aeruginosa was stronger than those of
      CPFX, LVFX, GFLX and TFLX.

PMID- 12621734
TI  - [Antibacterial activity of gatifloxacin against various fresh clinical isolates
      in 2002].
AB  - Antibacterial activities of gatifloxacin (GFLX) and other antibacterial drugs
      against various fresh clinical strains (800 isolates) isolated from specimens of
      patients in 2002 were compared. GFLX was more active than levofloxacin and
      ciprofloxacin against Gram-positive bacteria such as methicillin susceptible
      Staphylococcus aureus and Streptococcus pneumoniae. For these isolates,
      clarithromycin and azithromycin were less active (MIC90; > 16- > 64
      micrograms/mL), GFLX was more active than cefdinir. For Escherichia coli,
      Klebsiella pneumoniae, Acinetobacter species, Haemophilus influenzae and
      Moraxella (Branhamella) catarrhalis, three quinolones including GFLX were
      potently active (MIC90; < or = 0.06-0.5 microgram/mL). Pseudomonas aeruginosa
      isolated from urinary tract infections were resistant to three quinolones
      including GFLX (MIC90; 32-64 micrograms/mL), however P. aeruginosa isolated from
      respiratory and otolaryngological infections were more susceptible (MIC90; 0.5-2
      micrograms/mL). Quinolones were less active against Neisseria gonorrhoeae as
      compared with the cephem antibiotics tested, but GFLX was the most active against
      N. gonorrhoeae among the quinolones tested. In this study, we investigated
      activity of GFLX against fresh clinical strains isolated early in 2002, GFLX is
      widely and potently active against S. aureus, S. pneumoniae and various Gram
      negative bacteria.

PMID- 12621736
TI  - [Antibacterial activity of cefpodoxime against clinical isolates in 2000 and
      2001].
AB  - As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of
      cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22
      species from 15 medical institutions all over Japan from June 2000 to March 2001
      were measured using the broth microdilution method approved by the Japanese
      Society of Chemotherapy and compared with those of oral cephem antibacterials,
      cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change
      in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus
      influenzae compared with the susceptibility in the studies before Banan was
      launched. This cause is considered to be the increase in the incidence of the
      following resistant strains: penicillin-intermediate S. pneumoniae (47.3%),
      penicillin-resistant S. pneumoniae (PRSP, 15.1%), and beta-lactamase-negative
      ampicillin-resistant (BLNAR) H. influenzae (24.0%), which were scarcely isolated
      in 1989 when Banan was launched. Other tested drugs also exhibited low activity
      against these resistant strains. However, CPDX showed comparatively good activity
      with MIC90 of 2 micrograms/mL against PRSP. Against methicillin-susceptible
      Staphylococcus spp., Streptococcus pyogenes, Streptococcus agalactiae, and
      Moraxella catarrhalis, CPDX also showed comparatively good activity with MIC90 of
      < or = 4 micrograms/mL, which was almost equal to that in the studies before its
      marketing. Against quinolones-resistant Neisseria gonorrhoeae, CPDX showed
      excellent activity with MIC90 of 0.5 microgram/mL. Against members of the family
      Enterobacteriaceae except for Citrobacter freundii, Enterobacter spp., Proteus
      vulgaris, and Morganella morganii, CPDX showed good activity. However, in
      Escherichia coli, Klebsiella spp. Proteus spp., and Providencia spp., there are
      some high-resistant strains to all tested drugs including CPDX. Against
      Peptostreptococcus spp., MIC90 of CPDX was 8 micrograms/mL and its MIC range was
      widely distributed from 0.03 to 32 micrograms/mL, which were similar to those in
      the studies before its marketing. In this study, CPDX showed the decrease in the
      activity against several species as did other drugs tested, but against most of
      species tested, CPDX maintained good activity. Furthermore, it is necessary to
      pay much attention to the trend of resistant strains.

PMID- 12621735
TI  - [Antibacterial activity of panipenem against clinical isolates in 2000 and 2001].
AB  - As the post-marketing surveillance of panipenem/betamipron (Carbenin), MICs of
      panipenem (PAPM) against 1355 clinical isolates of 28 species from 15 medical
      institutions all over Japan from June 2000 to March 2001 were measured using the
      broth microdilution method approved by the Japanese Society of Chemotherapy and
      compared with those of parenteral carbapenem antibacterials, imipenem (IPM) and
      meropenem (MEPM), and parenteral cephem antibacterials, cefozopran, cefepime, and
      sulbactam/cefoperazone. The activity of PAPM was comparable to that of IPM
      against almost all species tested. Compared with MEPM, PAPM was more active
      against Gram-positive bacteria and Bacteroides spp., and less active against Gram
      negative bacteria. Compared with the parenteral cephems, PAPM was more active
      against most of species tested and its MIC ranges were narrower than those of the
      cephems as were those of other carbapenems. In this surveillance study, the
      incidence of resistance in various species were as follows: 39.3% for methicillin
      resistant Staphylococcus aureus, 47.3% for penicillin-intermediate Streptococcus
      pneumoniae (PISP), 15.1% for penicillin-resistant S. pneumoniae (PRSP), 0.9% for
      extended-spectrum beta-lactamase (ESBL) producing Escherichia coli, 3.4% for ESBL
      producing Klebsiella pneumoniae, 19.2% for beta-lactamase producing Haemophilus
      influenzae, 24.0% for beta-lactamase-negative ampicillin-resistant (BLNAR) H.
      influenzae, and 1.0% for metallo-beta-lactamase producing Pseudomonas aeruginosa.
      Against these resistant strains, carbapenems including PAPM showed generally more
      potent activity than cephems. It was noted that PAPM showed the most potent
      activity against PISP and PRSP, which showed high incidence of 62.4% totally,
      among tested drugs. Metallo-beta-lactamase producing P. aeruginosa exhibited high
      resistance and BLNAR H. influenzae also exhibited low susceptibility against all
      tested drugs. But no remarkable change in the activity of PAPM against other
      species was observed in this study compared with that in the studies before the
      marketing of Carbenin. Furthermore, it is necessary to pay much attention to the
      trend of resistant strains such as PRSP, metallo-beta-lactamase producing
      bacteria, and BLNAR H. influenzae.

PMID- 12621733
TI  - [In vitro short-term bactericidal activity and accumulation of NM394, the active
      metabolite of prulifloxacin, for Staphylococcus aureus, Escherichia coli and
      Pseudomonas aeruginosa: comparison with ciprofloxacin, levofloxacin, and
      gatifloxacin].
AB  - The in vitro short-term bactericidal activity and accumulation of NM394, the
      active metabolite of prulifloxacin, was compared with those of ciprofloxacin
      (CPFX), levofloxacin (LVFX) and gatifloxacin (GFLX), using Staphylococcus aureus,
      Escherichia coli and Pseudomonas aeruginosa. Of the 4 fluoroquinolones examined,
      NM394 accumulated to the highest concentration in all three strains. The order of
      concentration of the fluoroquinolones accumurated in S. aureus 209P JC-1, E. coli
      NIHJ JC-2 and P. aeruginosa PAO1 were NM394 >> CPFX > GFLX > or = LVFX. The
      accumulation of fluoroquinolones into bacterial cells correlated with their MICs
      of the drugs for E. coli and P. aeruginosa, whereas there was no correlation
      between the accumulation and MICs of the drugs for S. aureus. We also studied the
      reduction of viable cells after addition of each fluoroquinolones to clarify
      relationship between the short-term bactericidal activity and the accumulation of
      the quinolones. The short-term bactericidal activity of NM394 against S. aureus
      209P JC-1, E. coli NIHJ JC-2 and P. aeruginosa PAO1 were stronger than those of
      CPFX, LVFX and GFLX when compared at the same concentration. In conclusion, the
      strong short-term bactericidal activity of NM394 may be attributed to its high
      accumulation in bacterial cells.

PMID- 12621737
TI  - [Antibacterial activities of fosfomycin against several fresh clinical isolates-
      comparison of the test methods for antibacterial activity].
AB  - In vitro antibacterial activity of fosfomycin was evaluated by various methods.
      Strains of methicillin-sensitive Staphylococcus aureus, methicillin-sensitive
      coagulase-negative Staphylococci and Escherichia coli were much more susceptible
      when glucose-6-phosphate was added to the test medium, but strains of Serratia
      marcescens and Pseudomonas aeruginosa were not affected. Nutrient agar instead of
      Mueller-Hinton agar allowed to exhibiting the higher activity of fosfomycin
      against all the species tested. The activity of fosfomycin was as equivalent or
      superior to those of cefazolin, cefmetazole, cefotiam and piperacillin. The
      susceptibility of strains isolated during 2000 to 2001 to fosfomycin was almost
      the same as that of the isolates reported in 1975. Fosfomycin was considered to
      show high efficacy in several infections, since it has maintained its favorable
      antibacterial activities against several bacterial species for more than 20 years
      after the first application to clinical practice.

PMID- 12621738
TI  - [A questionnaire survey on antimicrobial chemotherapy for acute peritonitis].
AB  - A questionnaire survey on antimicrobial chemotherapy for acute peritonitis was
      conducted to obtain the consensus among abdominal surgeons in Japan in the period
      from January to March 2002. Forty-one of the 58 surgeons replied, and the
      following consensus was obtained. Antibiotics should be given as soon as possible
      the diagnosis of infection in the abdominal cavity is established. When the
      perforated viscus is demonstrated at operation, giving antibiotic should be
      reconfirmed whether it covers organisms in the perforated site or not. The
      ascites obtained at operation should be sent for bacterial culture. When
      postoperative course is eventful, considering WBC, body temperature and CRP, the
      drainage fluid should be sent for culture on 4 to 7 days postoperatively. Most
      commonly used antibiotic for perforation of duodenal ulcer is cefotiam, and it is
      given 4.1 +/- 1.2 days postoperatively. Target organisms at the perforation of
      the lower digestive tract were E. coli, Bacteroides spp., Klebsiella pneumoniae
      and Enterobacter spp. Carbapenems were likely given agents for the perforation of
      the colon, and they were given 5.0 +/- 1.4 days postoperatively.

PMID- 12621739
TI  - [Meropenem was effective to the bacterial meningitis due to beta-lactamase
      negative ampicillin-resistant Haemophilus influenzae; case report].
AB  - We experienced a case in the infant of the bacterial meningitis due to beta
      lactamase negative ampicillin-resistant Haemophilus influenzae (BLNAR) which has
      increased in recent years. In the present condition, the sensitivity of the
      bacteria to the antibacterial-drug used as the initial treatment for the
      bacterial meningitis is sometimes inadequate. If it takes into consideration that
      BLNAR participates in H. influenzae meningitis, it will be one of the choice to
      use meropenem with other antibacterial-drug concomitantly.

PMID- 12621740
TI  - Levofloxacin for prophylaxis in breast cancer surgery compared with ofloxacin.
AB  - BACKGROUND: We found that once-daily use of ofloxacin is beneficial from the
      standpoints of economy and patient compliance. Levofloxacin, has twice the
      antimicrobial activity and same toxicity of ofloxacin. We investigated the
      clinical usefulness of levofloxacin compared with ofloxacin in breast surgery.
      METHOD: Between July, 1996 and April, 1999, 199 consecutive patients hospitalized
      in our department for treatment of breast cancer were enrolled in this study with
      their informed consent and 181 patients were evaluated. RESULTS: Four (4%) of the
      99 patients in the levofloxacin group had wound infections, as did 5 (6%) of the
      82 patients in the ofloxacin group. The median times needed for wound care, with
      25th and 75th percentiles, were 13 [9, 16] days in the levofloxacin group and 11
      [9, 16] days in the ofloxacin group. From infected wound three strains of
      Staphylococcus aureus were detected from the levofloxacin group and two strains
      were from ofloxacin group, but no methicillin-resistant strains were isolated.
      Multiple regression analysis showed that only wound dehiscence was a significant
      factor in the occurrence of wound infection and the period of wound care. No
      signs or symptoms suggesting levofloxacin or ofloxacin toxicity were observed.
      Laboratory test changes before and after treatment were similar in the two
      groups. CONCLUSION: It appears that levofloxacin is not superior to ofloxacin in
      prophylactic efficacy for postoperative wound infection after breast surgery.

PMID- 12621741
TI  - [Investigation on administration method of carbapenems].
AB  - Seventy-two women diagnosed as parametritis were enrolled in this study and
      examined on the effective administration method of carbapenems,
      imipenem/cilastatin (IPM/CS), panipenem/betamipron (PAPM/BP) and meropenem
      (MEPM). The total dosage of each carbapenem was 1.5 g/day, and administration
      frequency was twice a day (0.75 g x 2) or three times a day (0.5 g x 3). We
      reviewed the highest body temperature, white blood cell count and CRP value,
      before treatment and the fourth day after the start of treatment. Three times a
      day method was statistically superior to twice a day method in the highest body
      temperature, and CRP value. When we use carbapenem antimicrobial agents, the
      basis of PK/PD of time above MIC would lead to the increasing clinical effects.

PMID- 12621742
TI  - [Inhibitory activity of NM394, the active form of prodrug prulifloxacin against
      type II topoisomerase from Pseudomonas aeruginosa].
AB  - The inhibitory activity of NM394, the active form of the prodrug prulifloxacin,
      against type II topoisomerase from Pseudomonas aeruginosa was compared with those
      of ciprofloxacin (CPFX), levofloxacin (LVFX) and gatifloxacin (GFLX). The 50%
      inhibitory concentrations (IC50S) of NM394 for supercoiling activity of DNA
      gyrase and the decatenation activity of topoisomerase IV were 1.21 and 21.1
      micrograms/ml, respectively. The IC50 of NM394 was equal to that of CPFX and
      lower than those of LVFX and GFLX. The inhibitory activity of the four drugs for
      DNA gyrase was also corresponding to the antimicrobial activity of the drugs for
      P. aeruginosa PAO1. The IC50S of the drugs tested for the decatenation activity
      of topoisomerase IV were from 17.4 to 24.2 times higher than those for the
      supercoiling activities of DNA gyrase. These results show that DNA gyrase is more
      sensitive to quinolones than is topoisomerase IV and may be a primary target of
      quinolones in P. aeruginosa. We concluded that NM394 exerts the potent
      antimicrobial activity through its strong inhibitory activity for DNA gyrase.

PMID- 12621743
TI  - Mandibular symphyseal distraction osteogenesis.

PMID- 12621744
TI  - Evidence for the efficacy of various methods of treating white-spot lesions after
      debonding of fixed orthodontic appliances.

PMID- 12621745
TI  - Distalization of maxillary molars with a midpalatal miniscrew.

PMID- 12621746
TI  - Jumbo separators for partial molar impactions.

PMID- 12621747
TI  - A new fixed interarch device for Class II correction.

PMID- 12621748
TI  - A fixed reverse labial bow for moderate Class III interceptive treatment.

PMID- 12621749
TI  - [Urinalysis in renal diseases: strategy not appreciated enough in clinical
      practice].
AB  - This review refers to the critical analysis of clinical usefulness of traditional
      and new strategies of urinalysis proposed in the literature. Special attention
      was paid to tubular proteinuria as well as enzymuria.

PMID- 12621750
TI  - [Spiral computed tomography in evaluation of arteriovenous fistula for
      hemodialysis. Preliminary report].
AB  - Failure of arteriovenous fistula (AVFf) still remains the "Achilles'heel" of
      chronic haemodialysis (HD) programme. Therefore, early, potentially non-invasive
      diagnosis and prompt surgical correction of AVFf are needed. For these purposes
      spiral computed tomographic angiography (SCTA) was used for evaluation of
      clinically suspected AVFf in 19 patients (10M/9F, aged 58.6 +/- 14.6 years, on HD
      for 34.4 +/- 29.3 months). SCTA was performed using Marconi MX8000 scanner
      covering whole AVF. After intravenous administration to the peripheral vein of
      the other leg of 100 ml of non-ionic lomeron 350 contrast (3 ml/s), axial CT
      images were obtained helically covering whole surface of AVF. Time delay was
      measured by Trigger function. Maximum Intensity Projections (MIP), 4D-Angio and
      virtual endoscopy (VE) techniques were used for reconstruction. MIP images
      demonstrated contrast-enhanced vascular structures and other high-density tissues
      (calcifications). VE enabled non-invasive simulation of endoscopic procedures and
      interactive intravascular navigation. Total number of 24 SCTA were performed. We
      found normal patency of AVF in 5 patients. In the remaining 14 subjects, the
      following abnormalities were found: stenosis of AVF at the site of anastomosis or
      in distal segment of efferent vein in 6 SCTA examinations, dilatation in 7 SCTA,
      acute or chronic thrombosis of AVF in 9 SCTA procedures including total occlusion
      of AVF in 2 cases. In 2 cases pseudoaneurysms of AVF were found. In 7 SCTA
      examinations more than one reason of AVFf was found. Photographs of every AVF
      complication are presented. We noted only one complication of SCTA-rupture of
      venous vessel on the opposite arm during contrast injection. There were no
      hypersensitivity reactions to the contrast.

PMID- 12621751
TI  - [Influence of parathormone level on the doses of human recombinant erythropoietin
      in haemodialysed patients].
AB  - The purpose of the study was to determine the doses of rHuEPO, which are
      necessary to obtain the same correction of renal anaemia in chronically
      haemodialysed patients with different levels of iPTH. 25 haemodialysed patients
      with stable values of iPTH for at least 6 months (mean age 58 +/- 15.6 years; 6
      females and 19 males on haemodialysis from 1 to 126 months) were divided into 3
      groups: group 1 (7 patients) with iPTH < 100 pg/ml, group 2 (12 patients) with
      iPTH 100-300 pg/ml and group 3 (6 patients) with iPTH > 300 pg/ml. In all groups
      adequacy of haemodialysis (HD) measured by Kt/V was similar. Every month the
      following data were determined: Ca, P, CaxP product, HCT, HGB, Fe, transferrin
      saturation (TSAT) and weekly dose of rHuEPO. Patients with chronic infections,
      neoplastic diseases or those after blood transfusions were excluded from the
      study. Significantly higher weekly dose of rHuEPO was needed in patients with
      iPTH > 300 pg/ml to obtain similar correction of renal anaemia in comparison with
      patients with iPTH from 100 to 300 pg/ml. There were no statistically significant
      differences between the groups with respect to other data except significantly
      higher values of Cas in the group with iPTH > 300 pg/ml. CONCLUSION: Higher doses
      of rHuEPO to obtain the same correction of renal anaemia are necessary only in
      patients with iPTH > 300 pg/ml.

PMID- 12621752
TI  - [Mood and illness-related stress in dialysed patients].
AB  - The aim of the paper was to evaluate the mood and attitude to the illness-related
      stress and correlations between them among patients treated with haemodialysis
      (HD) or continuous ambulatory peritoneal dialysis (CAPD). The following
      psychological questionnaires were used: the Cognitive Stress Appreciation
      Questionnaire (CSAQ), the Social Appreciation Questionnaire and the Profile of
      Mood States. The total of 26 HD (17M, 9F) and 28 CAPD (17M, 11F) patients were
      studied. The control group (CONTR) consisted of 48 (26M, 22F) healthy volunteers
      who filled the questionnaires as if they had a "bad cold". The dispositional
      attitude to the stress was similar in the studied groups. The dialysed patients
      evaluated their disease-related stress mainly as a threat as compared to the
      healthy volunteers (p < 0.01). Additionally, HD patients evaluated their disease
      as a loss as compared to the CAPD group and CONTR group (p < 0.05). In HD and
      CAPD patients Confusion-Bewilderment had significantly higher values in
      comparison to the healthy group (p < 0.01), whereas only HD group had higher
      values of Fatigue-Inertia as compared to CAPD and control groups (p < 0.01).
      Additionally our results showed a significant correlation between evaluation of
      renal disease as a loss and Fatigue--Inertia emotion in the HD group (r = 0.89; p
      < 0.01). From the psychological point of view CAPD seems to be better than HD,
      since the patients treated by this method evaluated better their mood and illness
      related stress, similarly as the healthy volunteers suffering from acute
      infectious disease.

PMID- 12621753
TI  - [Chlamydia pneumoniae antibodies and other atherosclerosis risk factors in
      haemodialysed patients. Preliminary report].
AB  - Nowadays, it is considered that viral or bacterial infections can influence
      atherosclerosis development rate. One of them is infection by Chlamydia
      pneumoniae. The aim of the study was to assess the occurrence of anti-Chlamydia
      pneumoniae antibodies (AChPA) and their relationship with biochemical and
      clinical atherosclerosis risk factors in haemodialysed patients. There were 38
      patients (24M, 14F) at the mean age 63.3 +/- 14.5 years, haemodialysed for 30.9
      +/- 26.1 months. Previous Ch. Pneumoniae infection was assessed based on AchPA
      IgA and IgG concentrations determined using SIMPLE INDEX. The following risk
      factors for atherosclerosis were checked in the study group: total cholesterol.
      CRP and iPTH. AChPA indicative for Ch. pneumoniae infection in the past were
      detected in 28 patients (74%). The study group was divided into two subgroups; A-
      (n = 28 patients) with serological features of previous Ch. pneumoniae infection
      and B- (n = 10 patients) without serological features of Ch. pneumoniae
      infection. We found no statistical difference between the groups in the studied
      biochemical factors. We found no correlation between AChPA and other
      atherosclerosis risk factors. Our preliminary report does not confirm the
      prognostic value of AChPA presence as an atherosclerosis risk factor in
      haemodialysed patients.

PMID- 12621754
TI  - [Mathematical analysis of the possibilities of automated peritoneal dialysis
      optimization].
AB  - The aim of the study was assessment of theoretical possibilities of the Automated
      Peritoneal Dialysis (APD) optimization. The analysis of influence of dwells
      number modification and peritoneal transport character on Nightly Intermittent
      Peritoneal Dialysis (NIPD) efficacy and adequacy was performed. 20 patients were
      included in the study. The velocity of urea peritoneal transport expressed as
      SMTR (solute mass transport rate) was calculated according to the formula: SMTR =
      delta (CDVD)/delta t, where: delta (CDVD)--change of urea mass in dialysate
      during delta t time (CD-urea concentration in dialysate, VD-intraperitoneal
      volume of dialysate). VD was estimated from dilution of volume marker (RISA). On
      the basis of SMTR, the dialysis efficacy expressed as total dialysed urea and
      dialysis adequacy expressed as Kt/V were estimated. The values of listed
      parameters were calculated for the different NIPD schedules (4-9 dwells during 8
      hours session). It was revealed that the shortening of dwell time with
      simultaneous multiplying of dwell numbers resulted in increase of dialysis
      efficacy and adequacy. However, this improvement was non-proportional to the
      increase of dialysis solution volume and it did not provide the optimum of
      dialysis nor recommended level of adequacy even during the session consisting of
      9 dwells. There were no significant differences of Kt/V values between subgroups
      of patients with different character of peritoneal transport assessed according
      to PET test. The tendency to achieve the recommended values of Kt/V was observed
      in high transporters group. The results of the study indicate the large
      capabilities of APD optimization. The direct measurement of peritoneal transport
      velocity allows to provide better individualization of PD program. The prediction
      of APD efficacy and adequacy on the base of presented method seams to be an
      interesting alternative.

PMID- 12621755
TI  - [Comparison of peritoneal transport of solutes and water during CAPD with glucose
      or amino acids solutions. Preliminary report].
AB  - The aim of the study was the comparison of peritoneal transport of solutes and
      water during dialysis with presently used 1.1% amino acid solution in relation to
      1.36% glucose solution. 20 clinically stable patients on CAPD for 50.0 +/- 27.6
      months were enrolled into the study. On the basis of blood and dialysate samples
      taken during 4-hour CAPD, intraperitoneal dialysate volume and diffusive mass
      transport coefficients (KBD) for: glucose, creatinine, urea, sodium, potassium
      and total protein were calculated. Intraperitoneal dialysate volume was higher in
      the case of amino acid solution in comparison to glucose solution. The KBD values
      for the investigated solutes were higher when amino acid solution was used, but
      for glucose and sodium the KBD values were statistically significantly higher. In
      conclusion, the differences in transperitoneal transport of solutes and water
      between both solutions found in our study suggest better clinical usefulness of
      amino acid solution than standard glucose solution for achieving adequate
      ultrafiltration.

PMID- 12621756
TI  - [New look at the scintigraphic visualization of peritoneal cavity in the course
      of the peritoneal dialysis].
AB  - Development of peritoneal dialysis treatment in the world as well as in Poland
      followed by prolongation of patients' survival calls for imaging of peritoneal
      cavity in the course of non-complicated programme as well as complicated CAPD
      programme. Retrospective analysis was performed of the clinical utility of
      peritoneal scintigraphy applied in our centre since 1982. According to the aim of
      the study 125 scans of the peritoneal cavity performed in 67 patients treated by
      CAPD/APD method in the years 1982-2002 were subjected to analysis. Among the
      detected pathologies adhesions (69% scans) and dialysate extraperitoneal leakages
      (17% scans) predominated. Special attention was paid to the character of the
      intraperitoneal adhesions which, if multilocular, were the reason of dropping-out
      from the peritoneal dialysis programme.

PMID- 12621757
TI  - [Empirical therapy of peritonitis in peritoneal dialysis patients--it is
      reasonable to use a new therapeutic schedule?].
AB  - The Ad Hoc Advisory Committee on Peritonitis Management recommended in the year
      2000 a new protocol of empirical peritonitis therapy in patients on peritoneal
      dialysis with preserved residual renal function (RRF). This protocol comprises
      1st and 3rd generation cephalosporins. According to these recommendations the old
      protocol of therapy, comprising 1st generation cephalosporin and aminoglycoside
      may be used only in patients with diuresis lower than 100 ml/day. The aim of the
      study was a retrospective assessment of the efficacy and cost of peritonitis
      therapy using "old" and "new" protocols. The analysed episodes of peritonitis
      were divided into two groups. Group 1 included 22 episodes of peritonitis in 13
      patients treated with the old protocol, in whom RRF was lower than 100 ml/day.
      Group 2 included 6 episodes of peritonitis in 4 patients with preserved RRF
      treated with the new protocol. The efficacy of the treatment according to the old
      protocol was 64% and according to the new protocol--33%. The average cost of 14
      day therapy with the old and new schedule was 67.1 and 247.2 Euro, respectively.
      In our studied population a considerably lower efficacy and higher cost were
      revealed of the new empirical schedule of peritonitis treatment in comparison to
      the old schedule. The results of the study indicate the need of further
      estimation of the usefulness of the new peritonitis empirical treatment protocol.

PMID- 12621758
TI  - [Pseudoaneurysm of arteriovenous fistula for haemodialysis].
AB  - On the basis of two cases of haemodialysed patients we present the usefulness of
      spiral computed tomography in the diagnosis of pseudoaneurysm as a complication
      of arteriovenous fistula for haemodialysis.

PMID- 12621759
TI  - [Usefulness of ultrasonographic renal resistive index in monitoring efficacy of
      hypotensive in haemodialysed patients--case report].
AB  - On the basis of a 29-year-old haemodialysed male patient with poorly controlled
      hypertension refractory to multidrug hypotensive therapy, we present the
      usefulness of ultrasonographic evaluation of the renal resistive index in the
      monitoring of hypotensive therapy efficacy.

PMID- 12621760
TI  - [Sterile peritonitis associated with the use of icodextrin solution. Case
      report].
AB  - Sterile peritonitis after dialysis with the use of icodextrin-containing solution
      is a rare complication of peritoneal dialysis programme. On the basis of the case
      of hypersensitivity to icodextrin accompanied by peritonitis, the diagnostic
      problems were described and a review of literature on this complication is
      presented.

PMID- 12621761
TI  - [Diverticulosis as a background of "abdominal catastrophe" in the course of
      peritoneal dialysis. Care Report].
AB  - Peritonitis complicating peritoneal dialysis (PD) may represent a difficult
      diagnostic and therapeutic problem if it coexists with surgical pathology of
      intra-abdominal organs defined as "abdominal catastrophe". The illustration of
      this problem is the case of 70-year-old patient treated with automated PD, in
      whom recurrent episodes of peritonitis (Escherichia coli) were typical of
      "abdominal catastrophe" and were probably caused by microperforations of the
      colon in the course of diverticulosis.

PMID- 12621763
TI  - [Immunomodulatory effect of blood components transfusions].
AB  - In this paper the authors have described basic mechanisms of immunomodulation
      caused by blood transfusion and its clinical consequences. Transfusions of blood
      and blood components can induce cell interaction changing the immunological
      response of a recipient. Two phenomena--immunisation and immunosuppression result
      from post-transfusion immunological changes. The factors causing these two
      phenomena are not fully known. Immunomodulation observed as a consequence of
      blood transfusion is probably associated with a decrease of cell mediated
      immunity and at the same time an increase of humoral immunity. The observed
      effects of transfusion include a shift of lymphocyte subpopulations from Th1 to
      Th2, a reduction of natural cytotoxic cell activity, CD4/CD8 ratio and
      blastogenesis of lymphocytes. Animal studies suggest that the mechanisms of
      immunomodulation are stimulated by leukocytes present in blood components. Animal
      data show that pre-storage leukoreduction is more effective than post-storage
      leukodepletion.

PMID- 12621762
TI  - [Universalistic medicine in relation to diabetes as a chronic disease at the turn
      of 20th and 21st centuries].
AB  - This paper is devoted to the ideas and purposes of universalistic medicine as a
      knowledge of restoring, preserving and improving health state and making possible
      to evaluate individual human being as an integrated subject of creative
      evolution. The illustration of the problem are own experiences with educational
      programmes for patients with diabetic nephropathy at end-stage renal failure,
      prepared for renal replacement therapy with continuous ambulatory peritoneal
      dialysis.

PMID- 12621764
TI  - [Hepatorenal syndrome in view of experimental studies].
AB  - Hepatorenal syndrome is still one of the most important challenges of medicine in
      the 21st century. In spite of many years of experimental and clinical studies, it
      failed to discover precise pathomechanisms leading from hepatic damage to
      functional renal failure. Among many directions and types of present scientific
      researches, experimental studies play a great role. In the paper most often used
      and most commonly accepted experimental models of hepatorenal syndrome are
      presented. The technique is described of conducting the experiments and the signs
      and biochemical and histopathological disorders occurring in experimental animals
      are discussed. Individual models are compared with respect to their value and
      usefulness in experimental studies of hepatorenal syndrome and at the same time
      attempt has been made to answer the question whether we have any ideal
      experimental model of this important, yet not fully elucidated clinical syndrome.

PMID- 12621765
TI  - [Quality of life in dialysed patients--methodological issues].
AB  - The aim of this review was to present problems emerging during the study of the
      Quality of Life in patients with end-stage renal disease on renal replacement
      therapy. Special attention was paid to the psychological tools that are used for
      assessment of the Quality of Life, including medical history, structured history,
      questionnaires and psychological tests. The NECOSAD (Netherlands Cooperative
      Study on Adequacy of Dialysis) study was analysed as an example of the current
      trends in the studies on Quality of Life.

PMID- 12621766
TI  - [Calcimimetics as a new chance for effective treatment of calcium metabolism
      disturbances].
AB  - Physiological principles are presented of calcium receptor (CaR) as well as
      agents affecting the receptor, defined as calcimimetics. Positive influence of
      type 1 and type 2 calcimimetics on calcium metabolism is discussed. The clinical
      indications for calcimimetics, especially type 2, in the future, seem to be
      hypercalcemia in the course of primary and secondary hyperparathyroidism as well
      as hypercalcemia in patients with parathyroid carcinoma.

PMID- 12621767
TI  - [Diagnosis of haematuria in phase-contrast microscopy--current knowledge].
AB  - Haematuria present in 4% of adult population is not always connected with
      clinical symptoms. This article presents the current state of the art of using
      phase-contrast microscopy in examination of urinary sediment in differential
      diagnosis of haematuria.

PMID- 12621768
TI  - [Enoxaparin in haemodialysis].
AB  - Using of low-molecular-weight heparins (LMWH) in haemodialysis therapy
      significantly reduced the incidence of haemorrhagic complications with the same
      clinical efficacy in comparison to standard unfractionated heparins. Taking
      enoxaparin as example, we present the mechanisms of action of LMWH paying special
      attention to efficacy in haemodialysis and adverse effects.

PMID- 12621770
TI  - [The First World Congress of Nephrology, San Francisco, October 13-17, 2001].
AB  - This report describes the progress in the field of prevention, diagnosis and
      treatment of renal diseases including renal replacement therapy with special
      reference to chronic peritoneal dialysis.

PMID- 12621769
TI  - [Spiral computed tomography angiography--advantages and limitations in nephrology
      and dialysotherapy].
AB  - This review is devoted to imaging techniques of kidney and renal vasculature
      including evaluation of renal artery stenosis, parenchymal renal diseases, living
      related renal donor candidates and preoperative evaluation of abnormal renal
      masses for nephron sparing surgery. Special interest is paid to the advantages of
      spiral CT in naphrology and transplantology.

PMID- 12621771
TI  - [Report from the XXVIII Congress of ERA-EDTA, Vienna, June, 2001].
AB  - This paper refers to selected reports on nephrology and renal dialysis therapy
      presented on the XXXVIII Congress of European Renal Association--European
      Dialysis and Transplant Association (ERA-EDTA), held in 2001 in Vienna. Special
      attention was paid to diagnosis and therapy of renal anaemia, calcium-phosphate
      metabolism, Fabry's disease and vascular access in hemodialysed patients.

PMID- 12621772
TI  - [Report on the Second International Course of Critical Care Nephrology, Vicenza,
      Italy, May 22-25, 2001].
AB  - This report is devoted to the Second International Course of Critical Care
      Nephrology with special interest to epidemiology, pathogenesis, diagnosis and
      intensive renal replacement therapy of acute renal failure in patients
      hospitalised in intensive care units.

PMID- 12621773
TI  - [Advances in the therapy of hypertension].

PMID- 12621774
TI  - [Treatment of dyslipidemia].

PMID- 12621775
TI  - [Angioplasty of renal artery stenosis in patients with renal failure and
      renovascular hypertension].

PMID- 12621776
TI  - [Treatment of diabetes mellitus in patients after renal transplantation].
AB  - Diabetes mellitus (DM) is the most common metabolic disease, an independent risk
      factor of coronary disease, and shortens lifetime in all populations of patients,
      including kidney transplant recipients. Patients after kidney transplantation are
      exceptionally predisposed to develop or to exacerbate the preexisting DM. Age, DM
      in family, CMV infections, genetic factor (HLA A26 and B27), immunosuppressive
      treatment with steroids or calcineurin inhibitors belong to the major risk
      factors of diabetes. We analyzed 1300 renal transplant recipients in our center.
      Out of them 153 suffered from DM. DM de novo revealed 80 pts. Mean age in type I
      pts was 44.88 years and in type II pts was 57.27 years. De novo diabetics were
      56.41 years old in average. CMV infection, potentially pathogenic in development
      of DM de novo, coexisted in 7.5% of these cases as frequently as in whole TPN
      population. Most frequently detected HLA antigens were: A2, B8 and DR5. Use of
      cyclosporine and tacrolimus promoted incidence of DM. We conclude, that low
      percentage of de novo DM in patients after renal transplantation may result from
      flexibility in administration of immunosuppressive regimens. Cyclosporine and
      tacrolimus treatment was switched to sirolimus or mycophenolate mofetil when the
      glucose intolerance was detected to prevent development of DM.

PMID- 12621777
TI  - [Noninvasive monitoring of chronic glomerulonephritides progression].
AB  - Progression to end-stage renal failure is the final common pathway of many forms
      of glomerular diseases, independent of the type of initial insult.
      Tubulointerstitial fibrosis is tis near invariable finding and significant
      prognostic feature. We have reviewed immunological (cytokines, inflammatory
      cells) and nonimmunological factors (extracellular matrix proteins and
      proteolytic enzymes), being involved in mechanisms leading from glomerular
      disease to tubulointerstitial scarring, from the point of view of potential
      clinical usefulness of measuring its urine activities and levels to noninvasive
      diagnostic of kidney diseases.

PMID- 12621778
TI  - [Cytokines in noninvasive diagnostics of diabetic nephropathy progression].
AB  - Diabetic nephropathy is major long-term complication of diabetes mellitus a
      social and civilization-related disease. At present, the most sensitive and non
      invasive indicator of the progression of diabetic nephropathy is
      microalbuminuria. Morphological features such as accumulation of extracellular
      matrix proteins, thickening of glomerules' basement membranes are prior to
      microalbuminuria. The aim of our clinical study was to establish whether urine
      and serum TGF-beta 1 and IL-6 levels may be significant in prognosing and
      evaluating a risk for developing diabetic nephropathy. The trial was carried out
      in 68 patients with type II diabetes mellitus and a group of 10 healthy subjects
      served as control. Urine and serum TGF-beta 1 concentrations were evaluated, as
      well as, basic laboratory parameters. After one-year-observation serum creatinine
      level and microalbuminuria value were investigated in 60 patients with type II
      diabetes mellitus. In patients with type II diabetes mellitus both urine and
      serum TGF-beta 1 and IL-6 were elevated. After one-year-observation of patients
      with type II diabetes mellitus it was established that the increase of serum
      creatinine concentrations values were higher in those patients, whose initial TGF
      beta 1 levels exceeded normal values. A positive correlation between urine TGF
      beta 1 level and the progression of renal failure measured by the increase of
      serum creatinine level was observed. In conclusion, our findings indicate that
      urine TGF-beta 1 and IL-6 levels may be a good prognostic factor of the
      development of diabetic nephropathy in the course of diabetes mellitus.

PMID- 12621779
TI  - [Expression of mRNA for growth factors and cytokines in the renal artery wall of
      chronically rejected renal allograft].
AB  - The vascular hallmark of chronic rejection (CR), as well as of atherosclerosis,
      is initial hyperplasia. It results from migration and proliferation of vascular
      smooth muscle cell and increased deposition of extracellular matrix proteins. A
      possible mechanism responsible for formation of neointima is the release of
      growth factors and cytokines, such as: transforming growth factor beta (TGF
      beta), tumour necrosis factor alfa (TNF-alpha), interleukin 1 (IL-1) and
      interleukin 6 (IL-6). The expression of these factors in the renal artery wall of
      chronically rejected allografts was quantified. The renal artery samples were
      obtained from patients with chronic renal allograft rejection, undergoing
      graftectomy (n = 11) and patients with autosomal dominant polycystic kidney
      disease (ADPKD), undergoing nephrectomy (n = 4). Total RNA was isolated and the
      expression of mRNA for TGF-beta, TNF-alpha, IL-1 and IL-6 was measured using a
      real time PCR. In patients with CR the expression levels of TGF-beta, TNF-alpha
      and IL-1 mRNA were higher than in control group. No difference between groups was
      detected for IL-6. In both groups a correlation was detected between age and TGF
      beta expression. The increased expression of TGF-beta, TNF-alpha and IL-1 may be
      a key factor in the neointimal formation and pathogenesis of CR. The increase in
      the TGF-b expression with age might be a protective mechanism in atherosclerosis.

PMID- 12621780
TI  - [Effect of immunosuppressive treatment on diurnal profile of blood pressure].
AB  - Prevalence of arterial hypertension suddenly rose in patients after renal
      transplantation since cyclosporine A was introduced. Arterial hypertension is now
      diagnosed in 67-90% of patients after renal transplantation. It has not only
      negative effect on cardiovascular system but also shortens survival of renal
      graft. Ambulatory blood pressure monitoring (ABPM) enables evaluation of diumal
      profile of BP and efficacy of treatment. This diagnostic tool is very useful in
      the management of these patients. Nocturnal hypertension was 2.5 times more
      frequent than daytime elevation of BP in the group of 58 consecutive renal
      transplant patients treated with calcineurin inhibitors who were assessed by ABPM
      at our department. Lack of nocturnal dip of BP was observed in most of the
      patients. Conversion from calcineurin inhibitors (cyclosporine A, tacrolimus) to
      sirolimus or mycophenolate mofetil may improve BP profile in this group of
      patients.

PMID- 12621781
TI  - [Polymorphism of angiotensin II type 1 receptor in terminal renal failure].

PMID- 12621782
TI  - [Influence of hemodialysis on the homogenicity of repolarization phase of action
      potential of myocardium].

PMID- 12621783
TI  - [Influence of ultrafiltration on urea sequestration during hemodialysis].

PMID- 12621784
TI  - [The prevalence of renal failure in Polish population--epidemiological study].

PMID- 12621785
TI  - [Role of renin-angiotensin system genes in the development of renal failure].

PMID- 12621786
TI  - [Role of other than renin-angiotensin system genes in the development of renal
      failure].

PMID- 12621787
TI  - Clinical resistance of recurrent Candida albicans vulvovaginitis to fluconazole
      in the presence and absence of in vitro resistance.
AB  - OBJECTIVE: To determine if failure of recurrent Candida albicans vulvovaginitis
      to respond clinically to fluconazole is related to in vitro mycologic resistance.
      STUDY DESIGN: We compared clinical response to fluconazole with culture and
      sensitivity data in all cases of recurrent C albicans vulvovaginitis referred to
      our clinic over an 18-month period. RESULTS: Of 52 patients referred to us with
      recurring vulvovaginitis, 10 were C albicans culture positive. All 10 had
      previously responded to fluconazole but subsequently failed fluconazole therapy.
      All were euglycemic and HIV negative. In 3 of the 10 isolates, the mean
      inhibitory concentration for fluconazole was > 64 micrograms/mL. The history of
      response to fluconazole in the 7 patients with susceptible isolates was
      indistinguishable from that of the 3 with resistant isolates. Five of the 10
      patients were given multiagent antifungal therapy. Of 4 patients available for
      long-term follow-up in this group, all had negative fungal cultures. In contrast,
      4 evaluable patients who received maintenance azole therapy were C albicans
      culture positive at long-term follow-up. CONCLUSION: Recurrent C albicans
      vulvovaginitis can display clinical resistance to fluconazole that correlates
      with in vitro resistance in only some cases. We postulate that aberrant host
      response may play a role in the failure to control fungal colonization with a
      single fungistatic agent.

PMID- 12621788
TI  - Use of packing in obstetric hemorrhage of uterine origin.
AB  - OBJECTIVE: To determine the safety and effectiveness of uterine packing to stop
      hemorrhage in obstetric patients following delivery and pregnancy termination.
      STUDY DESIGN: A review of obstetric records at Children's Hospital of Buffalo in
      a 9-year period was undertaken. Patients with uterine packing were identified.
      Indications, additional medical and surgical procedures, estimated blood loss,
      postoperative complications and packing material used were reviewed. RESULTS: A
      total of 9 patients were identified among 34,071. Five patients had hemorrhage
      during cesarean section. Two patients had hemorrhage after vaginal delivery; 1
      case of which had failure with packing and resulted in postpartum hysterectomy.
      The remaining 2 patients had hemorrhage after dilation and evacuation. Uterine
      atony unresponsive to oxytocics was the most common indication for uterine
      packing (44%). The average hematocrit decrease was 10.4% (average total blood
      loss, 2,200 mL), and all patients received transfusion except 1. The only
      immediate postoperative complications occurred in a patient with postpartum
      hysterectomy after failed packing; she developed a pelvic abscess but did well
      after drainage. CONCLUSION: Uterine packing may be a reasonable alternative to
      further surgical intervention in patients with intractable obstetric hemorrhage
      who wish to preserve fertility.

PMID- 12621789
TI  - The effort to increase breast-feeding. Do obstetricians, in the forefront, need
      help?
AB  - OBJECTIVE: To assess the knowledge, training and attitudes of obstetricians
      concerning management of breast-feeding. STUDY DESIGN: A survey was sent to 1,200
      fellows of the American College of Obstetricians and Gynecologists; 397
      practicing obstetricians responded. RESULTS: Obstetricians who were satisfied
      with their patients' behavior (69.5%) estimated that on average > 70% of their
      patients planned to breast-feed, while those who were unsatisfied (21.4%)
      estimated that < 60% of their patients planned to breast-feed. African American
      race and eligibility for Medicaid both appear to predict low rates of breast
      feeding among patients. Most physicians considered that they were very well
      qualified to treat mastitis, prescribe maternal medications and advise their
      patients regarding contraception. They were less certain of their qualifications
      regarding educating their patients about breast-feeding and aiding them in
      solving breast-feeding problems. Personal breast-feeding experience was a
      significant predictor of female physician confidence. Four of 10 physicians
      regarded their residency training as inadequate in terms of breast-feeding
      management. CONCLUSION: The perceptions of obstetricians regarding breast-feeding
      practices of their patients appear consistent with national surveys.
      Obstetricians consider counseling their patients and managing breast-feeding care
      to be important parts of their clinical responsibilities, but further training
      and educational materials are warranted.

PMID- 12621790
TI  - Effect of an oral contraceptive containing ethinyl estradiol and drospirenone on
      premenstrual symptomatology and health-related quality of life.
AB  - OBJECTIVE: To evaluate the effect of the oral contraceptive Yasmin (drospirenone,
      3 mg, and ethinyl estradiol, 30 micrograms) (Berlex Laboratories, Wayne, New
      Jersey) on premenstrual symptomatology and health-related quality of life
      (HRQoL). STUDY DESIGN: Participating health care providers received 11,260 self
      administered surveys for distribution to women initiating use of Yasmin. Of
      these, 1,932 (17.2%) baseline surveys and 1,104 follow-up surveys (57.1%) were
      returned, with 858 (44.4%) of the returns evaluated as suitable for analysis.
      RESULTS: Premenstrual symptomatology, as measured with the negative affect and
      water retention domains of the Moos Menstrual Distress Questionnaire (MDQ),
      significantly improved from baseline in all phases of the menstrual cycle (P =
      .000). All individual MDQ items improved significantly in the late luteal phase
      and during menses (P = .000), and the majority (76.9%) improved significantly in
      the remainder of the cycle (P < .05). Improvements were also observed in general
      sense of well-being (P < .05), impairment in usual activities due to premenstrual
      symptomatology (P < .05) and Mental Component Summary scale (P = .000) but not
      the Physical Component Summary scale of the Short Form-12 generic HRQoL
      instrument. CONCLUSION: These data support the effectiveness of Yasmin in
      reducing premenstrual symptomatology and improving HRQoL and general sense of
      well-being.

PMID- 12621791
TI  - Maternal dietary intake and pregnancy outcome.
AB  - OBJECTIVE: To study the relationship between maternal diet and infant
      anthropometric measurements in 56 women, aged 28 +/- 5.1 years, with singleton
      pregnancies. STUDY DESIGN: The overall quality of the diet (three 24-hour
      recalls), including supplementation, was evaluated at 34 +/- 1.3 weeks using a
      total mean adequacy ratio (TMAR) of 12 nutrients. Specific interviewing
      techniques were used to minimize social desirability bias. Anthropometric
      measurements of both parents and maternal lifestyle practices were also obtained.
      Infant weight, crown-heel length and head circumference were measured 14.6 +/-
      4.4 days after birth. RESULTS: Stepwise multiple regression analysis revealed
      that maternal diet quality (TMAR) was significantly related to infant weight (r =
      .039, P = .036) and crown-heel length (r = .071, P = .007). Other significant
      predictors included gestational age, maternal height, sex, smoking and physical
      activity. CONCLUSION: Maternal diet was positively associated with infant weight
      and crown-heel length.

PMID- 12621792
TI  - Evaluating prognostic parameters in women with uterine leiomyosarcoma. A
      clinicopathologic study.
AB  - OBJECTIVE: To evaluate the prognostic impact of different clinicopathologic
      parameters in patients with uterine leiomyosarcoma. STUDY DESIGN: Twenty-one
      patients with histologically proven uterine leiomyosarcoma were included in the
      analysis. Leiomyosarcomas were defined as uterine smooth muscle tumors with > or
      = 5 mitoses per 10 high-power fields and nuclear atypia and/or necrosis. RESULTS:
      The median follow-up time was 47 months; 5-year overall survival was 41%. A
      univariate Cox model revealed that early tumor stage (P = .00001), age at
      diagnosis < 50 years (P = .02), absence of vascular space involvement (P = .04),
      low myometrial invasion (P = .006) and low histologic grade (P = .04) were
      associated with lengthened overall survival. Adjuvant radiotherapy and/or
      chemotherapy (P = .1) did not influence overall survival. CONCLUSION: Early tumor
      stage, age at diagnosis < 50 years, absence of vascular space invasion, low
      myometrial invasion and low histologic grade were parameters of a good prognosis
      in women with uterine leiomyosarcoma. Adjuvant chemotherapy and/or radiotherapy
      showed no benefit in these patients.

PMID- 12621793
TI  - Outcomes and surgical therapeutic index of Burch colposuspension in stress
      urinary incontinence.
AB  - OBJECTIVE: To apply the new concept of a surgical therapeutic index to patients
      who suffer from stress urinary incontinence using the cure rate and complication
      rates of Burch colposuspension and to develop a preoperative counseling tool and
      objective comparison tool for the many surgical procedures that have been
      described. STUDY DESIGN: We reviewed the case histories of 22 patients between
      March 1999 and March 2000 who had stress urinary incontinence and underwent Burch
      colposuspension and in whom the diagnosis of stress urinary incontinence was made
      using urodynamic studies and the cotton-tipped-swab test. The surgical
      therapeutic index was then calculated using the median percentage cure rate and
      complication rate. RESULTS: The surgical cure rates were 81.8%, 81.8%, 90.9%,
      90.9%, 95.4% and 95.4% at postoperative 1st, 3rd, 5th, 7th, 9th and 12th month,
      respectively, and the surgical complication rates were 69%, 36%, 31.5%, 27%,
      22.5% and 27%. The surgical therapeutic indices for each postoperative period
      were 1.19, 2.27, 2.89, 3.37, 4.24 and 3.53, respectively. The surgical cure rate
      for Burch colposuspension in stress urinary incontinence was 95.4% 1 year after
      surgery, and the surgical therapeutic index 1 month and 1 year after surgery was
      1.19 and 3.53, respectively. CONCLUSION: Burch colposuspension is a relatively
      effective and safe surgical procedure for managing stress urinary incontinence.

PMID- 12621794
TI  - Limitations of the obstetric group B Streptococcus protocol.
AB  - OBJECTIVE: To assess compliance with the Centers for Disease Control and
      Prevention (CDC) screening-based protocol for obstetric group B Streptococcus
      (GBS) and to determine an acceptable threshold for protocol failure. STUDY
      DESIGN: A retrospective chart review was carried out for all deliveries performed
      through the resident-run community clinic from January through June 1999.
      Compliance with the CDC protocol was assessed by reviewing collected data from
      patient charts and comparing it to CDC requirements. Data were collected
      regarding patient demographics, antenatal GBS status, gestational age at
      screening, time of rupture of the membranes, time the antibiotic was given and
      time of delivery. RESULTS: A total of 248 charts were reviewed. Elective cesarean
      deliveries were excluded (25 charts). Unknown culture status was found for 22
      (9.9%) patients. Cultures were collected before 35 weeks' gestation in 39 (17.5%)
      patients and at > 37 weeks' gestation in 28 (12.6%) patients. Of those with known
      positive GBS status, 4 (7.0%) were not treated, and antibiotics were given less
      than four hours before delivery in 13 (24.5%) patients. Of those with unknown
      status, six (27.2%) were not treated. Overall, there was 70% compliance with the
      culture collection arm of the protocol and 87% compliance with the treatment arm.
      CONCLUSION: Fulfillment of CDC guidelines in this community setting is imperfect.
      There are several areas beyond physician control, including precipitous delivery
      and patient non-compliance. However, perhaps an acceptable threshold for
      limitations of adherence to the protocol can be reached.

PMID- 12621795
TI  - Recombinant vs. urinary follicle-stimulating hormone in couples undergoing
      intrauterine insemination. A randomized study.
AB  - OBJECTIVE: To compare the results of ovulation induction in couples undergoing
      intrauterine insemination (IUI) with a standard daily dose of 100 IU of
      recombinant follicle-stimulating hormone (rFSH) vs. 150 IU of urinary follicle
      stimulating hormone (uFSH). STUDY DESIGN: Prospectively, 118 cycles were
      randomized to rFSH and 106 cycles to uFSH. Ovarian response was compared on the
      human chorionic gonadotropin administration day by serum estradiol (E2) levels
      and number of ovarian follicles produced. RESULTS: In the rFSH group a
      significantly lower dose of FSH was administered (799.1 vs. 1,293.0 IU, P <
      .001), and a lower number of follicles > or = 12 mm (2.9 vs. 3.7, P < .001) and
      lower number of midsized follicles (12-16 mm) were observed (0.7 vs. 1.7, P <
      .001) as compared to the uFSH group. No difference was found between groups in
      the number of follicles > or = 17 mm or in serum E2 levels obtained. The E2/FSH
      dose ratio was significantly higher in the rFSH group (0.9 vs. 0.6, P < .001),
      and the ratio of E2/follicles > or = 17 mm was significantly lower in the rFSH
      group (308.9 vs. 406.5, P < .001). CONCLUSION: A standard daily dose of 100 IU of
      rFSH is more effective than uFSH in women undergoing IUI treatment since a more
      symmetric response is obtained.

PMID- 12621796
TI  - Leiomyoma remaining after vaginal hysterectomy for symptomatic leiomyomas. A case
      report.
AB  - BACKGROUND: A remaining leiomyoma, an uncommon postoperative complication of
      vaginal hysterectomy for symptomatic leiomyomas, occurred. CASE: A second vaginal
      operation for a remaining leiomyoma was necessary 1 month after a vaginal
      hysterectomy for a myomatous uterus. CONCLUSION: Checking the pelvic cavity
      during hysterectomy may avoid this complication.

PMID- 12621797
TI  - Spontaneous pregnancy in a woman with 45,X/47,XXX mosaicism in both serum and
      germ cell lines. A case report.
AB  - BACKGROUND: This is the first published case report of pregnancy in a women with
      45, X/47, XXX mosaicism in both blood and germ cell lines. CASE: The patient
      conceived, and analysis of ovarian tissue confirmed a karyotype of 45, X/47, XXX.
      CONCLUSION: Women with a 45, X/47, XXX karyotype in the germ cell line can
      conceive, as this case demonstrates.

PMID- 12621798
TI  - Postoperative vomiting causing esophageal rupture after antiemetic use. A case
      report.
AB  - BACKGROUND: Antiemetic medications are commonly used in the postoperative
      patient. Despite the lack of evidence-based data, these medications have also
      been increasingly used in the management of postoperative ileus. This practice is
      dangerous and increases the risk for morbidity and mortality. CASE: A 77-year-old
      woman underwent an uneventful total abdominal hysterectomy and bilateral salpingo
      oophorectomy. The patient developed abdominal distention and vomiting, which were
      managed with antiemetic medication. The patient continued to vomit, developed
      esophageal rupture (Boerhaave's syndrome) and died of sepsis and multiorgan
      failure. CONCLUSION: Despite no scientific evidence for it, the practice of using
      antiemetic medications and prokinetic agents in the management of postoperative
      ileus continues. This places the patient at increased risk for completely
      preventable morbidity, including aspiration, pneumonia, esophageal perforation,
      prolonged hospital stay and death.

PMID- 12621799
TI  - Hyperreactio luteinalis in a woman with high-risk factors. A case report.
AB  - BACKGROUND: Hyperreactio luteinalis is a rare condition characterized by
      multicystic and bilateral ovarian enlargement associated with high maternal human
      chorionic gonadotropin serum levels. CASE: A case of spontaneous twin pregnancy,
      polycystic kidney and thyrotoxicosis was treated conservatively. CONCLUSION: In
      this case, hyperreactio luteinalis was associated with twin pregnancy in a woman
      with preexisting renal failure. The association of other endocrinopathies, such
      as hyperthyroidism and diabetes mellitus, creates a clinical problem that could
      be quite hazardous in pregnancy if this association is not detected.

PMID- 12621800
TI  - Methotrexate for cervical pregnancy. A case report.
AB  - BACKGROUND: The incidence of cervical pregnancy is 1:1,000-95,000 pregnancies and
      represents < 1% of all ectopic pregnancies. Evacuation of the pregnancy by
      curettage does not always stop the bleeding because there is little contractile
      muscle in the cervix. If there is uncontrollable bleeding, hysterectomy is
      necessary. In selected cases, nonsurgical management offers high success rates.
      Among medical treatments, the most common is systemic or local administration of
      methotrexate. CASE: A 36-year-old woman, gravida 2, para 2, presented with
      vaginal bleeding and subacute pain in the lower abdomen. The patient was 7 weeks'
      pregnant according to her last menstrual period. Transvaginal ultrasonography
      showed a gestational sac of approximately 5 weeks' gestational age implanted in
      the wall of the cervix. Fifty milligrams of methotrexate was injected into the
      gestational sac and another 50 mg administered intramuscularly. The hCG level
      decreased continuously and was no longer detectable after 35 days. CONCLUSION:
      The use of methotrexate for cervical pregnancy is safe and effective and
      preserves fertility.

PMID- 12621801
TI  - Key developments in dermatology.

PMID- 12621802
TI  - Managing facial redness and rashes.

PMID- 12621803
TI  - Malignant and premalignant skin conditions.

PMID- 12621804
TI  - Recent advances in topical treatments.

PMID- 12621805
TI  - The patient with hair loss.

PMID- 12621806
TI  - Modulation by enteral nutrition of the acute phase response and immune functions.
AB  - To use nutrition in order to limit the negative consequences of physical and
      mental stress is not new. Recent advances in immunology and particularly in the
      understanding of the chemical language used to communicate both by eukarytic and
      prokarotic cells has made it easier to objectively evaluate effects of various
      immunomodulating efforts including the use of nutrients, vitamins and
      antioxidants in preventing or limiting the development of disease and its late
      consequences.

PMID- 12621807
TI  - [Assessment of the nutritional status of elderly patients treated at a home
      hospital unit].
AB  - GOALS: To establish the nutritional status of our elderly patients, assess the
      usefulness of the various anthropometric and biochemical parameters as markers of
      malnutrition and to determine which of the variables studied have the greatest
      correlation with malnutrition. SCOPE: Home Hospital Unit of the Arnau de Vilanova
      Teaching Hospital in Lerida. PATIENTS: 57 patients > or = 60 years. Mean
      admission to our unit: 12.1 days. VARIABLES: Age, sex, groups by treatment
      complexity, associated pathology, diagnosis, reason for admission, duration of
      stay in hospital, surgery performed, complications during the stay at the Home
      Hospital Unit, weight, height, PCT, AC, BMI, albumin, haemoglobin and RTL.
      RESULTS: Patients of great age present lower levels of serum albumin (p < 0.005),
      total proteins (p < 0.001), transferrin (p < 0.03), haemoglobin (p < 0.02) and
      RTL (p < 0.04) than "younger" elderly patients. Serum albumin and haemoglobin are
      lower in patients in a complicated post-surgical condition (p < 0.04 and p <
      0.02, respectively) and this group is the one with the longest stays (p < 0.001).
      Those patients with hypoalbuminaemia (74.1%) present lower PCT and RTL (p < 0.02)
      and a longer stay in hospital (p < 0.01) than those with normal levels of albumin
      in blood. Patients with anaemia (63.3%) present a lower RTL (p < 0.01) and a
      greater hospitalization time than those without anaemia. Total proteins (p <
      0.0001), albumin (p < 0.004), transferrin (p < 0.003) and RTL (p < 0.005)
      correlate negatively with age. Albumin (p < 0.001), haemoglobin (p < 0.006) and
      RTL (p < 0.0001) present a negative correlation with length of hospital stay.
      CONCLUSION: The prevalence of global malnutrition is high (51% moderate-severe).
      The nutritional status worsens with age. The length of hospitalization increases
      gradually with age, with deteriation in the nutritional status and with
      complexity of the treatment provided.

PMID- 12621808
TI  - [Feeding and assessment of nutritional status of spanish adolescents (AVENA
      study). Evaluation of risks and interventional proposal. I.Methodology].
AB  - BACKGROUND: Adolescence is a decisive period in human life due to the multiple
      physiological and psychological changes that take place. These changes will
      condition both nutritional requirements and eating/physical activity behavior. It
      has been demonstrated that these "adolescence" factors are of significant
      influence in health status during adult life. Due to its importance and adequate
      development the project has been granted by the Fondo de Investigacion Sanitaria
      of the Institute of Health Carlos III. OBJECTIVE: To develop a methodology to
      evaluate the health and nutritional status of a representative population of
      Spanish adolescents. Specific attention is paid to three specific health
      problems: obesity, anorexia nervosa/bulimia, dislipidemia. METHODOLOGY: The
      following magnitudes will be studied: 1) dietary intake, food habits and
      nutrition knowledge; 2) daily physical activity and personal approach; 3)
      physical condition; 4) anthropometry and body composition; 5) hematobiochemical
      study: plasma lipid phenotypic and metabolic profile, blood cell counts; 6)
      genotipic profile of cardiovascular risk lipid factors; 7) immune function
      profile related to nutritional status; 8) psychological profile. CONCLUSION: This
      project includes the co-ordinate activity of five Spanish centers of five
      different cities (Granada, Madrid, Murcia, Santander, Zaragoza). Each center is
      specialized in a specific area and will be responsible for the corresponding part
      of the study. From the data obtained, we will elaborate a specific intervention
      program in order to improve nutrition and neutralize the risk for nutritional
      related problems in adolescence. By this, we will contribute to improve the
      health status of the Spanish population in the new millennium.

PMID- 12621809
TI  - [Parenteral nutrition at home: NADYA register for the year 2000].
AB  - AIM: We analyze the registered data of home parenteral nutrition (HPN) in our
      country during the year 2000. METHOD: The data were collected through a
      previously designed questionnaire. Apart from epidemiological information, the
      form includes the disease to prescribe this treatment, the specific nutritional
      treatment used and its duration, access path, complications and readmission rate
      in hospital, follow-up of the treatment, and progress. All data were processed
      and analysed by the co-ordinating team. RESULTS: Fourteen hospitals participated,
      and 67 patients were enrolled. Middle age was 5 +/- 4 years for patients < 14
      years old, and 48 +/- 15 years for those > or = 14 years old. The more prevalent
      diagnosis were: ischemic bowel (28.4%), neoplasm (16.4%), radiation enteritis
      (13.4%), motility disorders (7.5%), Crohn's disease (2.9%), and other. The mean
      time on HPN was 7.5 +/- 4.4 months. Tunelized catheter was the preferential route
      (77.6%), followed by the implantated one (20.9%). The intermittent method
      (nocturnal) was preferential (91.0%). Patients receive the formula from hospital
      pharmacy more frequently than from Nutriservice (71.5% versus 19.4%). The
      complications related to nutrition (0.32/100 days of HPN) included the infections
      (0.12 catheter sepsis/100 d of HPN), metabolic (0.06/100 d of HPN), mechanic
      (0.03/100 d of HPN) and electrolitic disorders (0.03/100 d of HPN). The
      readmission rate, for nutritional problems, was 0.3 hospitalizations/100 d of
      HPN. At the end of the year, 61.2% of the patients remained in the HPN program,
      37.3% abandoned the treatment (due to death (40%), to progress to oral feeding
      (48%), and to progress to enteral nutrition (4%); and 1.5% of the patients were
      not follow up. CONCLUSIONS: This review illustrates that there is an increment in
      the registration of HPN patients in our country (1997: 0.7 patients/10(6)
      habitants, 2000: 1.9 patients/10(6) habitants), that vascular pathology is the
      more frequent diagnoses in HPN patients, and the rate of readmission and
      complications and the behaviour is similar to other series making this as a safe
      treatment in our place.

PMID- 12621810
TI  - [Enteral nutrition at home: National register for the year 2000].
AB  - GOAL: Once again, the NADYA-SENPE Working Group analysed the registered data of
      Home Enteral Nutrition (HEN) in our country, during the year 2000. MATERIAL AND
      METHODS: The data were collected through a closed questionnaire included on our
      web site (www.nadya-senpe.com). Apart from epidemiological information, the form
      includes the indication to prescribe this treatment, the specific nutritional
      treatment used and its duration, access path, complications and readmission rate
      in hospital, follow-up of the treatment, patient's quality of life and progress.
      All data were processed and analysed by the co-ordinating team. RESULTS: Twenty
      two hospital participated and 2,986 patients, aged 65.1 +/- 19.7 years, were
      enrolled. Of these patients, 41.2% were diagnosed with neurological diseases and
      33.3% with cancer. The mean time on HEN was 6.3 +/- 4.4 months. Oral nutrition
      was the preferential route (50.8%), followed by nasoenteral tube (30.5%), and in
      17.4% ostomy tubes were placed. Polymeric was the formula composition mainly used
      (83.2%). Patients were followed (70.1%) by the hospital reference Nutritional
      Support Unit. The complications related to nutrition included the
      gastrointestinal (0.25 complications/patient), the mechanical one (0.19
      complications/patient), and the metabolic (0.007 complications/patient). Feeding
      tube need to be replaced 0.3 times/patient/year. The readmission rate, for
      nutritional problems, was observed in 0.03 patients. At the end of the year,
      54.9% of the patients were in the HEN program, and in 30.3% HEN was finish due to
      different reasons. In 21.9% of the patients no, o light, discapacity degree was
      found. CONCLUSIONS: Related to previous years, there is an increment in the
      number of enrolled patients. Neurological diseases and cancer were the more
      frequent diagnoses in HEN patients. Oral access was the higher feeding route due,
      probably, to the high prevalence of cancer patients. In spite of the elevated
      prevalence of neurological diseases, a few number of patients were feed with
      ostomy tube. Finally, due to the few readmission rate and complications, HEN is a
      safe treatment in our country.

PMID- 12621812
TI  - [Cardiac Tamponade after on a guide changing of a central venous catheter for
      total parenteral nutrition. Could it be avoided?].
AB  - Catheterization of central veins is a routine process, especially in severely-ill
      patients. It is a technique associated with multiple potential complications,
      fortunately infrequent, depending on the skill with which it is performed.
      Cardiac blockade is one of these infrequent complications with a high mortality.
      We describe a case in which suspicion, early diagnosis, and immediate
      manipulative treatment allowed a successful recovery of the patient. In addition,
      the literature is reviewed and possible mechanisms involved in these episodes are
      discussed.

PMID- 12621811
TI  - [Evaluation of diet and biochemical parameters for minerals in a group of elderly
      subjects in the province of Leon (Spain)].
AB  - The population of the elderly people is increasing in our society, and it is very
      frequently affected by undernutrition problems. It is mainly due to an inadequate
      intake of micronutrients, as well as to a higher incidence of chronic diseases,
      which negatively affect the nutritional status. The aim of this study is to
      assess the levels, in terms of minerals (Ca, Fe, I, Zn, Mg, Na and K), of a
      population of 124 elderly persons (60 males and 64 females), aged between 65 and
      98 years, who are institutionalized in five institutions for elderly people in
      the province of Leon (Spain). The dietetics study was carried out recording the
      food intake throughout 7 days by the precise weighting method. Blood
      concentration in Mg, Fe, Ca and ferritin was determined for the biochemical
      study. Calcium intake was 813 +/- 182 mg in males and 792 +/- 173 mg in females,
      which are lower values than those of reference that are being discussed at
      present. Regarding the values of serum calcium, no significant differences were
      found between males and females (9.2 +/- 0.4 mg/dL vs 9.1 +/- 0.6 mg/dl,
      respectively), but all these individuals are situated at the lower limit of range
      of normality. Iron intake was high, and there were 98% of males and 89% of
      females whose iron intakes were higher than the recommendations. Iron serum
      concentration was 89.6 +/- 37.9 micrograms/dl vs 79.3 +/- 24.2 micrograms/dl, and
      blood ferritin concentration was 107 +/- 64 ng/ml vs 64 +/- 48 ng/ml, in males
      and females respectively. Despite the fact that there is a very high percentage
      of elderly people whose iodine intake is lower than the 80% of the recommended
      intake (96% in males and 75% in females), no old person participating in this
      study was diagnosed of hypothyroidism. In relation to zinc intake, no significant
      differences are found between sexes, recording in both cases very low mean intake
      values compared to the dietetic recommendation (61 +/- 10% I/RD).

PMID- 12621813
TI  - [Pathogenesis and clinical significance of atrial fibrillation].
AB  - The authors review the current knowledge relating to the epidemiology,
      classification and pathogenesis of atrial fibrillation, and then discuss those
      cardiac electrophysiological changes that play roles in the initiation and/or
      maintenance of atrial fibrillation. They draw attention to the fact that atrial
      fibrillation is the most common cardiac arrhythmia in humans, its prevalence
      increasing continuously with the increase in average lifespan of the population.
      Atrial fibrillation doubles all-cause mortality, it gives rise to considerable
      haemodynamic alterations and clinical symptoms, and it is responsible for almost
      half of the cases of hospitalizations attributable to arrhythmia. Because of the
      great pathogenetic variety, the most important diagnostic task is to establish
      the nature of the underlying disease, the arrhythmia substrate, and the
      predisposing and triggering factors; this permits selection of the therapeutic
      procedure that is optimum for the given patient. The results of the most recent
      prospective randomized clinical trials indicate that, in certain groups of
      patients, it will no longer be absolutely necessary in the future to strive to
      restore and maintain sinus rhythm: effective oral anticoagulant treatment in
      combination with pharmacological ventricular rate control ensures the same
      survival chances and the same quality of life for the patient as those achieved
      in earlier years with the preferred sinus rhythm-preserving treatment strategy
      based on pharmacological and/or electrical cardioversions and prophylactic
      antiarrhythmic drug therapy.

PMID- 12621814
TI  - [Therapy of diabetic nephropathy].
AB  - It appears to be confirmed by international studies that the development of end
      stage nephropathy, cardiovascular mortality and morbidity can be reduced to a
      large extent by achieving a target blood pressure of 130/85 mmHg in diabetes
      hypertension and 125/75 mmHg in diabetic nephropathy. Diuretics, beta-blockers,
      ACE inhibitors and calcium antagonists are all recommended agents with evidence
      "A" according to both international and national recommendations. The most
      efficient nephroprotection and simultaneous intensive and efficient blood
      pressure reduction can be achieved by ACE inhibitors and AT1 receptor blockers as
      basic agents. It is often required to use combination treatment to achieve the
      target blood pressure. In the predialysis stage, tight blood pressure control
      should be completed with balanced glucose metabolism, restricted protein intake,
      controlled salt and water metabolism, early treatment of metabolic acidosis and
      preparation for kidney substitution treatment. The patient and the treating
      physicians should work together in a coordinated way during the complex
      nephrology, diabetes, cardiology care to slow down the progress of the disease.

PMID- 12621815
TI  - [Adult-onset Still-disease: survey of 18 cases].
AB  - INTRODUCTION: Adult onset Still's disease (juvenile rheumatoid arthritis with
      septic appearance) is rare, leading to clinical signs similar to those seen in
      bacterial sepsis, lymphomas, rheumatological, or systemic autoimmune diseases.
      The disease can present with a fever of unknown origin, and can cause
      difficulties in the diagnosis. It is based upon, partly, the exclusion of other
      diseases and on diagnostic criteria. Its characteristic feature is the rise of
      acute phase proteins. Exanthemata are temporary. The basis of treatment is
      immunosuppression, however relapses can occur. AIM: The aim of the authors was to
      evaluate on the most characteristic clinical signs and laboratorical data of
      their patients, and to examine the revealing parameters of the course of the
      disease. METHOD: Retrospective epidemiological survey of the data obtained from
      18 patients. RESULTS: The characteristic signs of the disease were, fever, sore
      throat, arthritis, joint pain, exanthemata, hepato-splenomegaly,
      lymphadenomegaly, pleurisy. The typical laboratorical data were: elevated CRP,
      low PCT, negative Waaler-Rose and ANA test, low serum iron level, leukocytosis,
      thrombocytosis, elevated alkalic phosphatase activity, high LDH, positive bone
      scintigraphy. The fever was steroid dependent. Generally, the illness was
      recognised after 2-3 months, and relapses were frequent. CONCLUSIONS: Still's
      disease has an important role in the differential diagnosis of fever of unknown
      origin. The diagnosis is based upon the evaluation of clinical signs and
      laboratorical data together. Prolonged immunosuppressive therapy is required.

PMID- 12621816
TI  - [Results of scanning and flying spot technologies in photorefractive keratectomy
      (PRK) for hypermetropia].
AB  - AIM OF THE STUDY: To compare the results of scanning and flying spot laser beam
      technologies of photorefractive keratectomy (PRK) in eyes with hypermetropic
      refractive error. PATIENTS AND METHODS: In Group I (n = 800) eyes were treated
      with scanning technology (Aesculap-Meditec MEL 60), in Subgroup I/1 (n = 482)
      those eyes, which had a preoperative refractive error between +1.0 and +3.5 D; in
      Subgroup I/2 (n = 318) the eyes between +3.75 and +6.5 D. In Group II (n = 200)
      eyes treated with flying spot technology (Aesculap-Meditec MEL 70 G-Scan) were
      evaluated; in Subgroup II/1 (n = 106) eyes between +1.0 and +3.5 D; in subgroup
      II/2 (n = 94) eyes between +3.75 and +7.5 D. Follow-up time was 12 months.
      RESULTS: The preoperative correction need decreased in Group I/1 from +2.88 +/-
      1.34 D to +1.26 +/- 1.24 D; in Group I/2 from 64 +/- 2.96 D to +2.46 +/- 1.84 D;
      in Group II/1 from +2.94 +/- 1.42 D to +0.42 +/- 0.14 D and in Group II/2 from 48
      +/- 2.62 D to +0.86 +/- 0.6 D 12 months after PRK. Postoperative uncorrected
      visual acuity (UCVA) was 1.0 or better in 75.7% within the eyes of Group I/1; it
      was 22.3% in Group I/2; 80% in Group II/1 and 64.8% in Group II/2. The percentage
      of the eyes within +/- 1.0 D of targeted refraction was: In Group I/1 86.1%, in
      Group I/2 45.3%, in Group II/1 92.4% and in Group II/2 78.7%. The best spectacle
      corrected visual acuity (BSCVA) decreased by 2 or more Snellen lines among the
      eyes of Group I/1 in 12%; in Group I/2 in 21%; in Group II/1 in 2.8% and in Group
      II/2 in 9.6%. In Group I/1 2%, in Group II/1 3.8% of the treated eyes gained 2 or
      more lines of BSCVA. Among the eyes treated with the scanning model (Group I/2) a
      central bump-like opacity was observed in 4 eyes (1.2%); among the eyes treated
      with the flying spot model no similar complication occurred. The postoperative
      increase of intraocular pressure was observed in 7.5% in Group I/1; in 6.8% in
      Group I/2; in 7.0% in Group II/1; and in 6.4% in Group II/2. CONCLUSIONS: Flying
      spot technology was superior to scanning method in each treatment group,
      difference was greatest in eyes treated with a preoperative refractive error
      higher than +3.75 D. The upper limit of hypermetropic treatments has increased to
      +6.0 D in case of flying spot treatments from the previous +3.5 D upper limit of
      scanning technology.

PMID- 12621817
TI  - [Liver cirrhosis. 1953].

PMID- 12621818
TI  - [Dentist's opinion about their dental education in Nijmegen, the Netherlands from
      1990-1997].
AB  - A questionnaire was sent to 328 dentists graduated from the University of
      Nijmegen in the period 1990-1998, to ask their opinion concerning the way they
      were prepared by dental education for their professional career. Comparison with
      similar data from Amsterdam Academic Centre for Dentistry has been carried out.
      The results show unanimity among graduates that they have been adequately
      prepared for the requirements in general dental practice as far as knowledge is
      concerned related to cariology, periodontology, crown and bridgework and dental
      radiology. They also have a positive assessment regarding other dental cognitive
      domains, except implantology. There is positive unanimity regarding their skills
      in various clinical areas. Shortcomings in dental education have been experienced
      in practice management and infection prevention, treatment of medically
      compromised patients, treatment of anxious patients and handicapped patients.
      Almost all responders have the opinion that they gained enough experience
      throughout their dental education to be competent to start their dental career
      independently. In general the Nijmegen graduates have a positive opinion
      concerning their dental education, although preparation for professional life
      could be strengthened in some specific areas. Comparison with ACTA-graduates
      shows that in both programmes the weakest areas are implantology and practice
      management.

PMID- 12621819
TI  - [Choking phobia: symptomatology, diagnosis and treatment].
AB  - Clinically significant forms of choking fear (i.e., choking phobia) are
      characterized by fear and avoidance of objects and situations that may lead to
      choking such as ingestion of food or pills. During dental treatment patients may
      also be confronted with situations that give rise to extreme fear of suffocating
      or being choked (mouth full of water, the making of dental radiographs and dental
      impressions). Choking phobia often develops following an episode of choking on
      food. The paper shortly reviews relevant literature, medical and psychiatric
      differential diagnosis, as well as possible treatment approaches to individuals
      suffering from choking fear.

PMID- 12621820
TI  - [Syndromes 17. Hypohidrotic ectodermal dysplasia].
AB  - The X-linked hypohidrotic ectodermal dysplasia (HED) is characterized by
      hypohidrosis, hypotrichosis and hypodontia. Sebaceous and salivary glands ar also
      affected. Recognition of the syndrome usually comes from affected man, although
      female carriers may show symptoms. Dental treatment is complicated and should be
      coordinated by a dentist in a centre for special dental care. Cooperation with an
      orthodontist and an oral and maxillofacial surgeon is advocated.

PMID- 12621821
TI  - [Dental equipment in the twentieth century 1. Preventive dentistry].

PMID- 12621822
TI  - [Examine everything, keep the best].

PMID- 12621823
TI  - [Accredited, but also competent?].

PMID- 12621824
TI  - [Visiting report of dentistry].

PMID- 12621825
TI  - [Sulfur smell after placing of implants].

PMID- 12621826
TI  - [Helicobacter pylori and the stomach].

PMID- 12621827
TI  - [Trends in Vienna radiology--from roentgen laboratory to university clinic for
      radiodiagnosis].
AB  - In Vienna/Austria, with leading representatives of the so-called second Viennese
      medical school at the turn of the 19th to the 20th century, the detection of x
      rays by W. C. Rontgen was observed with special interest. In the general hospital
      of Vienna, where still today the medical school of the university of Vienna is
      hosted, high research activities to understand the origin and the effects of X
      rays were performed. Guido Holzknecht (1872-1931) was the first chairman of the
      central roentgen laboratory. Today, the scientific and the clinical activities at
      the department of diagnostic radiology are manifold and virtually all fields of
      imaging are covered.

PMID- 12621828
TI  - [Organ specific MRI contrast media in general practice].
AB  - Conventional MR imaging with non-specific gadolinium contrast agents is useful in
      the detection and staging of malignancies. With the development of organ-specific
      MR contrast agents, MR imaging is assuming an even larger role in body imaging.
      Two different classes of liver-specific agents, hepato-biliary agents targeted to
      the hepatocytes, and reticulo-endothelial agents (or Kupffer cell agents)
      targeted to the reticuloendothelial system in the liver and spleen, have been
      developed. MRI with liver-specific contrast agents is superior to helical CT for
      detection of liver metastases. Mangafodipir, which was originally developed as a
      liver-specific agent, has been shown to accumulate in the pancreas as well.
      Recent studies have revealed that mangafodipir-enhanced MRI is at least equal to
      spiral CT in the staging of pancreatic cancer and may be superior to CT in the
      detection of small cancers. Blood-pool contrast agents with a long blood half
      life, such as ultrasmall iron oxide particles (USPIO), have been developed for MR
      angiography. After the clearance from the vascular system, USPIO are taken up by
      phagocytes and accumulate in normal lymph, but not in metastatic nodes. This
      effect can be exploited to increase the accuracy of MRI in lymph node staging of
      cancer of head-neck, lung or pelvis. In conclusion, various organ-specific MR
      contrast agents with a wide range of clinical applications have been developed.
      Future studies will demonstrate the role of contrast-enhanced MRI in comparison
      with multi-detector array CT.

PMID- 12621829
TI  - [Flat panel detector systems in skeletal radiology].
AB  - Implementation of flatpanel detectors and digital integration of the technique
      instead of the use of conventional radiographs leads to a shortening of the work
      process. With flatpanel technology the image production process is shortened by
      25-30%. Major advantages in the implementation of integrated RIS, PACS and
      flatpanel detector-system are increases in quality because most errors in picture
      labeling can be avoided, easier handling, without the need for cassettes and the
      possibility of image post-processing. The diagnostic quality of the images in the
      field of musculoskeletal radiology is, in comparison to conventional radiographs,
      at least adequate and in most cases markedly improved.

PMID- 12621830
TI  - [Measuring perfusion and diffusion in neuroradiology].
AB  - Neuroradiology should be regarded as a discipline with a strong focus on integral
      diagnosis of morphology and function of the central nervous system. With
      perfusion magnetic resonance imaging (P-MRI) and diffusion-weighted magnetic
      resonance imaging (DWI) the functional micro-structural analysis of the central
      nervous system has been made possible. So, disease processes may be characterised
      on a molecular level and P-MRI as well as DWI are now integrated in clinical
      routine diagnosis to improve therapy planning.

PMID- 12621831
TI  - [From morphology to function: progress in integrated lung imaging using
      computerized tomography and magnetic resonance tomography].
AB  - During the last two decades diagnostic imaging of the pulmonary system has been
      improved dramatically with computed tomography (CT). Especially with high
      resolution computed tomography techniques it has become possible to document the
      various forms of interstitial lung disease in detail. Magnetic resonance imaging
      (MRI) has been accepted for investigating abnormalities of the Mediastinum and of
      the chest wall. Magnetic resonance imaging of the lung parenchyma, however, is
      performed in experimental settings and is not yet used routinely in clinical
      practice.

PMID- 12621832
TI  - [3 Tesla magnetic resonance tomography--clinical applications].
AB  - With high-field magnetic resonance a better signal-to-noise ratio can be gained
      with the possibility of higher spatial resolution or shorter scan times. Clinical
      applications are especially in the field of spectroscopy of the brain, the liver,
      and the muscles as well as in with functional imaging of the brain. It can be
      expected that cerebral diffusion and perfusion studies will be significantly
      improved. Other applications include cardiac, abdominal, and musculo-skeletal
      diseases with the early diagnosis of cartilage diseases being of high interest.

PMID- 12621833
TI  - [Molecular imaging].
AB  - The disclosure of the human genoma, the progress in understanding of diseases on
      molecular and cellular levels, the discovery of new disease-specific targets, and
      the development of new medications will revolutionize our understanding of the
      etiology and the treatment of many disease entities. Radiologists are faced with
      a paradigm shift from unspecific to specific molecular imaging techniques as well
      as with enormous speed in the development of new methods and should be enrolled
      actively in this field of medicine.

PMID- 12621834
TI  - [Digital radiography: from storage phosphor plates to direct detector systems].
AB  - All three currently commercially available systems for digital radiography of the
      chest such as the selenium drum, storage phosphor plates and the flat panel
      direct detector systems provide an excellent image quality that is at least
      equivalent or superior to that of conventional film. Reasons for that are the
      continuously improved detective or dose efficiency of the detector systems and an
      improved image processing. The new direct detector systems have the largest
      potential for dose reduction while storage phosphor and selenium radiographs are
      usually obtained with a dose comparable to that of a 400 speed system. Improved
      image processing algorithms allow for the production of digital images that are
      adapted to the conventional image characteristics within the lung regions
      combined with an increased transparency of the high absorption areas such as the
      retrocardial and retrodiaphragmatic regions.

PMID- 12621835
TI  - [Virtual multislice computed tomographic colonoscopy].
AB  - Virtual colonoscopy or computed tomographic (CT) colonography is a rapidly
      evolving technique for imaging the entire colon and detection of colorectal
      polyps. It uses standard helical computed tomography images of the colon and
      advanced imaging software to produce reformatted two- and three-dimensional views
      of the entire colorectum. Multi-detector row helical computed tomography has
      several technical advantages over single-detector row computed tomographic,
      including faster imaging times with the acquisition of thinner sections. The
      improved speed and spatial resolution of multislice computed tomography promises
      an increase of sensitivity and specificity, especially for the detection of
      colorectal lesions.

PMID- 12621836
TI  - [Computer-assisted radiologic quantification of hand and foot changes in
      rheumatoid arthritis].
AB  - Driven by the increasing implementation of electronical picture archiving and
      communications system (PACS) into every days practice a fully operative Java
      application software was developed to support the efficacy of the scoring process
      in rheumatoid arthritis. This software, namely the "Rheuma-Coach" offers the
      possibility to use the Larsen- or the Ratingen-Score. We measured time savings of
      approximately 20% per case if this computer assistance was used. The lack of a
      standard for the positioning of limbs was confirmed.

PMID- 12621837
TI  - [High resolution magnetic resonance tomography and ultrasound imaging of the
      Achilles tendon].
AB  - Increasing sporting activities of high-ranking athletes as well as of the general
      population have led to a higher number of lesions of the Achilles tendon.
      Radiological investigations of this tendon are requested more often and the
      resolution of MR and ultrasound images has been improved significantly.
      Intratendinous lesions can be detected and may be differentiated from normal
      collagen fibers.

PMID- 12621838
TI  - [Middle field and low field magnetic resonance tomography in wrist injuries].
AB  - PURPOSE: To evaluate the diagnostic value of magnet resonance imaging in
      comparison of a dedicated 0.2-T unit and a 1.0-T unit in patients with clinically
      suspected scaphoid fractures and other wrist fractures. MATERIAL AND METHODS: In
      20 patients (14 m/6 f) with clinically suspected scaphoid fractures and a normal
      six view radiographic exam, magnet resonance imaging was performed first with the
      dedicated 1.0-T unit and afterwards with the 0.2-T unit within 7 days after
      trauma. T1 weighted spin-echo, STIR and T2-weighted 3D GRE sequences were
      performed. RESULTS: The 0.2 Tesla dedicated system is inferior to the 1.0 Tesla
      unit concerning the outcome of the 3 examiners. Especially the areas of bone
      bruise showed different results: each examiner detected at least two more cases
      of bone bruise with the 1.0 Telsa unit, which could not be defined with the 0.2
      Tesla unit. CONCLUSIONS: This study shows, how utmost sensitive magnet resonance
      imaging is referring to unremoved fractures of the scaphoid and to other wrist
      abnormalities. Results with the 0.2 Tesla dedicated system was inferior compared
      to the 1.0 Tesla unit.

PMID- 12621839
TI  - [Temporary and permanent vena cava filter for prevention of pulmonary embolism].
AB  - Inferior vena cava filters have been used for prophylaxis of pulmonary embolism
      since the end of the sixties. Complication rates depend on the types of filters
      used and are reported to be 2% with the Guenther-Filter and 21% with the Titanium
      Greenfield-Filter. Depending on the exact indication both filter types are useful
      instruments for the prevention of pulmonary embolism.

PMID- 12621840
TI  - [Radiologic progression of rheumatoid arthritis in early basic drug therapy].
AB  - For therapy and follow-up control in early disease modifying antirheumatic drug
      (DMARD) treated rheumatoid arthritis (RA), objective quantification is still
      lacking. Therefore, radiological analyses are considered the most appropriate
      method. One aim of this study was to retrospectively determine the time-dependent
      progression of joint damage in RA patients on DMARDs. Outpatient records and
      radiographs from hands and feet of 54 RA patients on DMARDs were evaluated.
      Radiographs were quantified by using the original Larsen score and a newly
      developed computer-assisted quantification software. Our observations showed that
      radiologically-detectable damage in all patients, regardless of their treatment,
      is most pronounced during the first year of disease, being mitigated and
      generally progressing linearly in the subsequent years. Cumulative ESR correlated
      with RA progression, and its reduction with therapeutic efficacy.

PMID- 12621841
TI  - [Dose classification in digital roentgen diagnosis: clinical applications].
AB  - Technological improvements in digital radiography and computed tomography have
      led to a substantial increase of radiation dose that subjectively cannot be
      detected. In order to reduce dose in a form that may be used in clinical
      practise, the quality of digital radiograms and computed tomography images should
      be classified in three classes. Low-dose investigations are indicated in
      children, in case of therapy control and for imaging organs with high differences
      in tissue contrast. High-dose investigations are scarcely indicated and middle
      dose investigations should be performed in all other remaining clinical
      situations. Dose recommendations given by vendors in radiology should be viewed
      critically.

PMID- 12621842
TI  - [Kinematic magnetic resonance tomography in functional disorders of joints and
      vertebral articulations].
AB  - Imaging studies of peripheral joints and of vertebral junctions are of major
      importance in the diagnosis of many degenerative diseases of the musculoskeletal
      system. Radiograms with flexion and extension views are regarded as standard for
      diagnosing abnormalities of the spine, the patello-femoral joint, and other
      articulations. With magnetic resonance imaging (MRI), kinematic studies can be
      performed analogously. With high gradient field strengths and in-phase and
      opposed-phase gradient echo sequences it is possible to study the motion of
      joints continuously. First results show that this technique may be added to
      static magnetic resonance imaging sequences in certain cases with hypermobility
      or instability of the knee and other major joints.

PMID- 12621843
TI  - [CT angiography (CTA)].
AB  - Computed tomography angiography (CTA) is today a well-established diagnostic
      technique for non-invasive vascular imaging and has replaced diagnostic intra
      arterial angiography. Especially since the implementation of multi detector-row
      computed tomography (MDCT) the acquisition of isotropic data sets is possible,
      thus widening the spectrum of clinical application of multi detector-row computed
      tomography. Compared to intra-arterial angiography computed tomography
      angiography is less invasive and cheaper.

PMID- 12621844
TI  - [Noninvasive vascular diagnosis with magnetic resonance angiography].
AB  - Currently contrast medium-enhanced, 3D magnetic resonance angiography enables
      fast and non-invasive depiction of the arterial vessels in the neck, thorax,
      abdomen, and limbs, which allows high sensitivity and specificity in the
      diagnostically evaluation of aneurysms, dissection and arterial stenosis.
      Intravenous bolus administration of a paramagnetic contrast medium is performed
      after timing of the bolus arrival time, thus enabling rapid acquisition of 3D
      datasets with high contrast between vessel lumen and surrounding soft tissue.
      Thorax and abdomen are examined within one breath-hold, the periphery of the
      extremities and the supra-aortal vessels can be imagined with longer sequences
      and even increased spatial resolution. Fast contrast-enhanced 3D magnetic
      resonance angiography--in combination with flow measurements--carries the
      potential to replace the additional functional information obtained by
      conventional digital subtraction angiography.

PMID- 12621845
TI  - [Early recognition of bronchial carcinoma with computerized tomography].
AB  - Bronchial carcinoma is the most common cause of tumor induced death worldwide.
      Because of the lack of clinical symptoms and signs the diagnosis of this tumor is
      generally established in advanced stages. With computed tomography (CT) pulmonary
      nodules can be detected with high sensitivity. Nodules are, because they are
      surrounded by aerated lung tissue, high-contrast objects and can be investigated
      with low-dose computed tomography technique. The reduction of mortality is the
      central issue in the ongoing discussion about early diagnosis of bronchial
      carcinoma with computed tomography. To date, no medical society or governmental
      body has expressed recommendations because randomized controlled trials have not
      been performed yet. It is expected that such trials are started in the near
      future in the USA and in several European countries.

PMID- 12621846
TI  - [Pancreatic carcinoma: state of the art imaging].
AB  - In view of the bad prognosis of pancreatic carcinoma the exact pre-surgical
      staging is essential for curative therapy. The rapid development of multi
      detector computed tomography with the clinical implementation of 16 row scanners
      allow for almost isotropic pixel size and high-resolution multiplanar
      reconstruction. Sensitivity and specificity of magnetic resonance imaging are
      similar to those of computed tomography with lower values in the detection of
      vessel wall infiltration. Ultrasound may be a valuable modality for primary
      diagnosis.

PMID- 12621847
TI  - [In situ ductal carcinoma of the breast: a diagnostic challenge].
AB  - Ductal carcinoma in situ (DCIS) represents a heterogenous group of lesions
      nowadays most commonly detected by mammography. The biological behaviour of
      ductal carcinoma in situ ranges from clinically occult, indolent, essentially
      benign lesions to precursors of invasive carcinoma. This work gives a review on
      the natural history of this disorder, and focuses on its imaging features. Stress
      is laid on the pivotal role of mammography in the management of ductal carcinoma
      in situ. The recent literature is reviewed.

PMID- 12621848
TI  - [Magnetic resonance imaging of brain tumors].
AB  - Investigating intracranial tumors, different MR-related methods permit not only
      morphological visualization of lesions but also give insights into their
      metabolism, resulting in information about the biological qualities of the
      respective tumor. Magnetic resonance protocols are selected based on the type and
      timing of onset of clinical signs. Combined information from imaging studies and
      spectroscopy facilitates the differential diagnosis between blastomatous and non
      blastomatous lesions before and after therapy.

PMID- 12621849
TI  - [Mammography referral center combined with breast cancer center].
AB  - Carcinoma of the breast is, with 26.7% of all malignancies, the most commonly
      diagnosed tumour in women, every eighth female Austrian suffers from this
      disease. Similar figures are reported from other European countries. Following
      recommendations of scientific societies like the European School of Mastology
      (ESOMA) or the British Breast Group, breast diseases should be treated by
      interdisciplinary teams in dedicated breast centers. Many such institutions exist
      in Austria and international, but only few of them are organized optimally and
      fulfill the requirements of an internationally accredited breast cancer centre.

PMID- 12621850
TI  - [Lymph node staging and diagnostic imaging--status quo and future prospects].
AB  - Exact lymph node staging is crucial to tumor staging and outcome, as well as
      therapy planning. Due to the low specificity and sensitivity of current imaging
      methods, invasive, expansive and uncomfortable diagnostic procedures are still
      widely used, often in conjunction with imaging. This brief overview is intended
      to summarize current imaging strategies and to give an outlook on new
      experimental imaging strategies which may play an important role in lymph node
      staging.

PMID- 12621851
TI  - [Prostatic carcinoma: current status of diagnostic imaging].
AB  - Prostate carcinoma showed a strong increase in industrial countries and today it
      is the second common cause of cancer related death. Prostate specific antigen
      allows early detection of prostate cancer, US-guided biopsy is employed for proof
      of diagnosis. The role of imaging has been discussed very contrarily. However,
      different options for treatment of prostate cancer and last but not least
      technological advances of different imaging modalities seem to reassess the role
      of imaging in prostate cancer.

PMID- 12621853
TI  - [Value of roentgen diagnosis in recognition of primary and potentially malignant
      bone tumors].
AB  - To assess the efficiency of plain radiographs for the detection of primary and
      potentially malignant bone tumors a retrospective study in 70 patients with
      histologically proven bone sarcomas was performed. Plain radiographs were the
      first imaging modality in most cases and for many patients the basic step leading
      to further diagnostic investigations. With young patients suffering from bone
      pain imaging work-up was obtained immediately, whereas older patients showed
      significant delay until radiographs were performed. The findings of this study
      suggest that radiography is an effective tool for the diagnosis of primary and
      potentially malignant bone tumors and that physicians should think of bone tumors
      also when patients beyond the adolescence have focal bone pain.

PMID- 12621852
TI  - [Bone metastases: new trends in diagnostic imaging].
AB  - Skeletal metastases are common in patients with cancers of the breast, lung,
      kidneys, prostate, and thyroid gland. Two main aspects have to be considered in
      diagnostic imaging. Screening in patients with known primary tumor. Triphasic
      Sczintigraphy is the imaging modality of choice for this purpose, however, whole
      body-magnetic resonance imaging seems to be a potential alternative. Evaluation
      of suspicious skeletal lesions, which is currently dominated by magnetic
      resonance imaging. New perspectives for preoperative staging as well as for
      reconstruction- and implant-surgery are made available by multidetector-row
      computed tomography. Non-invasive techniques, such as diffusion weighted imaging,
      positron emission tomography and positron emission tomography/computed tomography
      are now available, which seem to have potential for reliable tissue
      characterization. This feature is critical for monitoring treatment response in
      oncology.

PMID- 12621854
TI  - Risk assessment of dental unit waterline contamination.
AB  - Biofilms form rapidly on dental unit waterlines. The majority of the organisms in
      the biofilm are harmless environmental species, but some dental units may harbour
      opportunistic respiratory pathogens. This paper describes a risk assessment
      approach to analysing the hazard from biofilm organisms contaminating dental unit
      waterlines on the respiratory health of both the dental team and patients. The
      health risk from the respiratory pathogens Legionella spp, Mycobacterium spp and
      Pseudomonads was found to be low. Nevertheless, in order to satisfy water
      regulations and comply with health and safety legislation dentists should
      institute infection-control measures to maintain the dental unit water at the
      standard of less than 200 colony-forming units per ml of aerobic bacteria.

PMID- 12621855
TI  - Rotational path of insertion for removable partial dentures with an anterior
      saddle.
AB  - The provision of removable partial dentures remains a viable treatment modality
      for many partially dentate patients. Replacing missing anterior teeth with a
      removable partial denture using a rotational path of insertion provides improved
      retention and appearance. The use of a rotational path of insertion also provides
      additional retention for a removable partial denture restoring combined anterior
      and posterior bounded saddles. Two case reports demonstrate the use of the
      rotational path of insertion for partial denture design.

PMID- 12621856
TI  - Dentistry for those requiring special care.
AB  - Individuals with special needs, namely those whose dental care is complicated by
      a physical, mental or social disability, often have a higher level of unmet
      dental need and poorer oral hygiene than the general population, and offer unique
      challenges to the dental practitioner. This paper outlines the dental management
      of the three most common groups of individuals with special needs.

PMID- 12621857
TI  - Occupational exposures occurring among dental assistants in a UK dental school.
AB  - PURPOSE: The cross-infection risks for dentists have been well recognised, and
      much has been published regarding the incidence of occupational exposures to
      patient body fluids. Less has been reported regarding the risks to dental
      assistants. The purpose of this study was to evaluate the incidence of
      occupational exposures to patient body fluids among dental assistants, to assess
      the rate of reporting of such incidents, and to evaluate the association of
      various factors with these exposures. METHOD: All 84 dental assistants working at
      Birmingham Dental Hospital were asked to complete a confidential questionnaire to
      provide retrospective information regarding the nature and incidence of any
      occupational exposures they had experienced. RESULTS: An overall response rate of
      94% was achieved. Dental nurses experienced fewer occupational exposures than
      dental students at the same institution, and reported incidents more frequently.
      More injuries occurred after the treatment session. Handling local anaesthetic
      syringes was associated with more injuries, and percutaneous injuries
      predominated. Trainee nurses had experienced more occupational injuries in the
      preceding six months than their qualified colleagues. There was no significant
      association with any of the other factors evaluated. CONCLUSIONS: The general
      incidence of occupational exposures among the dental assistants in this survey
      was low in comparison to dental students at the same institution. A further
      reduction may be possible by increasing the training of unqualified nurses with
      particular regard to post-treatment handling of sharp dental instruments and
      equipment.

PMID- 12621858
TI  - An audit of the hepatitis B vaccination status of staff in general dental
      practices in Lancashire.
AB  - PURPOSE OF THE STUDY: To audit compliance, by general dental practitioners
      working in two health authorities in Lancashire, with the British Dental
      Association recommendations on vaccination against hepatitis B. BASIC PROCEDURE:
      A postal questionnaire to dental practices. MAIN FINDINGS: Replies were received
      from 85% of practices. The respondents consisted of 187 dentists, 270 dental
      nurses and 132 non-clinical staff. Totals of 98.9% of dentists, 96.7% of nurses
      and 72.7% of the non-clinicians reported that they had been vaccinated but fewer
      had undergone a blood test in the past five years. The poorest compliance was in
      having written evidence of immune status, with only 46.5% of dentists, 51.0% of
      nurses and 62.5% of non-clinical staff having this. PRINCIPAL CONCLUSIONS:
      Greater publicity about the BDA recommendations is needed to improve compliance.
      An extension of the occupational health services currently being set up for
      general medical practitioners and their staff to dental practices would also
      help.

PMID- 12621859
TI  - Lifelong learning.
AB  - This article looks at the theory behind lifelong learning as a concept and
      applies it to many aspects of the dentist's professional life.

PMID- 12621860
TI  - Protein dynamics studied by neutron scattering.
AB  - This review of protein dynamics studied by neutron scattering focuses on data
      collected in the last 10 years. After an introduction to thermal neutron
      scattering and instrumental aspects, theoretical models that have been used to
      interpret the data are presented and discussed. Experiments are described
      according to sample type, protein powders, solutions and membranes. Neutron
      scattering results are compared to those obtained from other techniques. The
      biological relevance of the experimental results is discussed. The major
      conclusion of the last decade concerns the strong dependence of internal dynamics
      on the macromolecular environment.

PMID- 12621861
TI  - What vibrations tell us about proteins.
AB  - This review deals with current concepts of vibrational spectroscopy for the
      investigation of protein structure and function. While the focus is on infrared
      (IR) spectroscopy, some of the general aspects also apply to Raman spectroscopy.
      Special emphasis is on the amide I vibration of the polypeptide backbone that is
      used for secondary-structure analysis. Theoretical as well as experimental
      aspects are covered including transition dipole coupling. Further topics are
      discussed, namely the absorption of amino-acid side-chains, 1H/2H exchange to
      study the conformational flexibility and reaction-induced difference spectroscopy
      for the investigation of reaction mechanisms with a focus on interpretation
      tools.

PMID- 12621862
TI  - Helicase mechanisms and the coupling of helicases within macromolecular machines.
      Part I: Structures and properties of isolated helicases.
AB  - Helicases are proteins that harness the chemical free energy of ATP hydrolysis to
      catalyze the unwinding of double-stranded nucleic acids. These enzymes have been
      much studied in isolation, and here we review what is known about the mechanisms
      of the unwinding process. We begin by considering the thermally driven
      'breathing' of double-stranded nucleic acids by themselves, in order to ask
      whether helicases might take advantage of some of these breathing modes. We next
      provide a brief summary of helicase mechanisms that have been elucidated by
      biochemical, thermodynamic, and kinetic studies, and then review in detail recent
      structural studies of helicases in isolation, in order to correlate structural
      findings with biophysical and biochemical results. We conclude that there are
      certainly common mechanistic themes for helicase function, but that different
      helicases have devised solutions to the nucleic acid unwinding problem that
      differ in structural detail. In Part II of this review (to be published in the
      next issue of this journal) we consider how these mechanisms are further modified
      to reflect the functional coupling of these proteins into macromolecular
      machines, and discuss the role of helicases in several central biological
      processes to illustrate how this coupling actually works in the various processes
      of gene expression.

PMID- 12621863
TI  - The Un-Peel Report (Walton 2003)!

PMID- 12621864
TI  - Scottish plan to network maternity services.

PMID- 12621865
TI  - Baby milk manufacturers violate the international code.

PMID- 12621867
TI  - Don't take it lying down! The NCT calls on UK midwives to help mums get active.

PMID- 12621866
TI  - Theories surrounding waterbirth.

PMID- 12621868
TI  - Compare and contrast.... Three births in one day.

PMID- 12621869
TI  - TENS--a marketing triumph.

PMID- 12621870
TI  - Antenatal care--antenatal screening for fetal abnormality.
AB  - JOANNA IS NOW 24 WEEKS pregnant. She is feeling very well and finding that now
      her energy has returned, she is really enjoying being preganant. She still
      proudly shows her precious scan picture to interested friends and takes the
      occasional glance herself during quiet moments. Joanna, has a cousin, Susan, who
      has Down's syndrome. Susan is  a happy and loving child who has brought  a lot of
      joy, as well as heartache, to the extended family. Although Joanna has no
      delusions about the hard work and continuing care that her cousin requires, she
      would not herself  contemplate terminating  a pregnancy if her baby had the
      condition.

PMID- 12621871
TI  - To feel, or not to feel? Checking the nuchal cord.

PMID- 12621872
TI  - It's a bloody risk. Midwives' attitudes, perceptions and practices regarding
      wearing goggles on delivery suite.

PMID- 12621873
TI  - Teamwork and the code of professional conduct.

PMID- 12621874
TI  - The National Childbirth Trust breastfeeding counsellor training.

PMID- 12621875
TI  - Nipple shields--never a good thing?

PMID- 12621876
TI  - [Levels of organochlorine insecticides in Polish women's breast adipose tissue,
      in years 1997-2001].
AB  - Although manufacture and use of chlorinated insecticides was banned or severely
      restricted in most of countries in the 1970s, the residues of these compounds are
      still detected in various environmental matrices all over the world. Their
      highest levels are found in adipose tissue of beings at the top of food chain,
      including humans. Levels of persistent organochlorine compounds in human
      specimens are monitored by numerous scientific organizations in various
      countries, including Poland. The purpose of the study was to survey the current
      levels of selected organochlorine insecticides (isomers alpha-, beta-, gamma-,
      delta-HCH, o,p'- and p,p'-DDT, DDE i DDE, oxy-chlordane and heptachlor) in
      women's breast adipose tissue which can be an indicator of body burden. A total
      of 67 samples of adipose breast tissue collected between 1997 and 2001 from non
      cancer patients, aged from 15 to 74 years have been analyzed. The analytical
      procedure included extraction, clean-up and analysis by means of GC-ECD with GC
      MS confirmation. In all the samples analyzed p,p'-DDE, p,p'-DDT and beta-HCH were
      present (mean values, expressed as mg/kg of fat: 0.7700, 0.0720, and 0.0635
      respectively) with p,p'-DDE, found to be dominant analyte. The levels of the
      remaining compounds, were usually about or below the method quantification limits
      (from 0.0025 to 0.0060 mg/kg of fat). The results for DDTs and beta-HCH for the
      oldest group (above 50 years) were 2.1 to 3.6 times higher than the youngest
      group (below 39 years). The results obtained in this study are similar to those
      reported in analogous samples collected from women living in other European
      countries with similar climate and history or organochlorines usage as well as in
      the USA. The presence of some organo-chlorine insecticide residues in women's
      adipose tissue, even those, who were born even 10-15 years after most countries
      introduced severe restrictions or banned the use of these compounds may be cause
      for anxiety. That is due to the potential of these compounds to promote toxic
      effects, including disrupting the human endocrine system.

PMID- 12621877
TI  - [The occurrence of polycyclic aromatic hydrocarbons (PAHs) in infusion of natural
      coffee, coffee substitute and cocoa].
AB  - The content of polycyclic aromatic hydrocarbons (PAHs) in chosen condiments
      commercially available was investigated. The concentration of these compounds in
      infusion of natural coffee, coffee ersatz and cocoa was determined by gas
      chromatography. Fluoranthene, pyrene and benz(a)anthracene were the PAHs, which
      the most frequently were present in infusions of unfiltered natural coffee.
      Assuming the extraction of PAHs into infusion of natural coffee of about several
      percent, obtained results are in good agreement with the amount of those
      compounds in coffee beans. These compounds were found at similar concentration in
      infusions of ersatz coffee. The highest concentrations of investigated PAHs were
      found in cocoa and their amount was 0.82 mg per litre of beverage. The content of
      these compounds in cocoa was several times higher then the content of those in
      infusion of unfiltered natural coffee.

PMID- 12621878
TI  - [The content of fat and fatty acids in selected snack products (nuts and seeds)].
AB  - The content of fat and fatty acids in 13 selected snack products (nuts and seeds)
      purchased on the marked in Warsaw region in 2000 have been investigated. The
      content of fat in examined products varied from 41% to 68%. The fat of nuts and
      seeds was rich in unsaturated fatty acids, except cocoa product.

PMID- 12621879
TI  - [Changes in vitamins intake in overweight and obese adults after low-energy
      diets].
AB  - Dietary modification is indispensable part of obesity treatment. PURPOSE:
      Assessment of vitamins supply in overweight and obese adults in habitual diet and
      during consuming a low-energy diet (about 1000 kcal/d). The studied group
      consisted of 67 women and 29 men, aged 20-68, with BMI above 25 kg/m2. Dietary
      assessment were carried out by 24-hours dietary recall. Intake of vitamin A, E,
      B1, B2, C, PP were evaluated. At baseline in men the lowest intake was found for
      vitamin A-87.6% of RDA, in women for vitamin B1--82.8% of RDA and for vitamin PP-
      90.2% of RDA, respectively. Low percentage of participants met the requirements
      for assessed vitamins. After 18 weeks of the low-energy diet the mean supply of
      assessed nutrients was below RDA. Only in subjects with baseline intake covering
      the requirement supply of nutrients on the low-energy diet was above the RDA
      level. Implementation of the low-energy diet can resulted in mean low supply of
      assessed vitamins. It is necessary to provide information for patients on energy
      value as well as nutritional value of food products. Subjects need consistent
      evaluation of realization of the low-energy diet.

PMID- 12621880
TI  - [Impact of of school children's nutrition education program on the knowledge and
      nutritional behavior of their parents].
AB  - The aim of the work was to present the analysis of the influence of school
      children's nutrition education program on the knowledge and nutritional behavior
      of their parents (110 persons). The program was realized during 10 lessons. The
      interview with the parents concerning their knowledge and nutritional behavior
      was carried before and after realization of educational program at school. One
      can state that changes of parents nutritional behavior was connected with the
      educational materials getting by children, for example higher consumption of
      vegetables, fruits, milk and its products were observed. An increased level of
      knowledge especially on sources of selected nutrients: calcium, dietary fiber was
      found. Education of children and youth can be seen as one of the effective
      educational method of their parents.

PMID- 12621881
TI  - [Evaluation of the usefulness of spectrophotometric method based on the reaction
      of formation of silic-molybdenum blue for determination of silica in hydrogenated
      fat].
AB  - The spectrophotometric method based on the reaction of formation of silic
      molybdenum blue for determination of silica (silicon dioxide) in hydrogenated fat
      was developed. Determination limit of silica in this method was 15.6 mg/kg and
      average recovery 77.77%. Using this method the content of silica in the edible
      fat (margarine) taken from the market was determined. The samples of margarine
      before determination of silicon dioxide were mineralised and than the analyte was
      concentrated. The silica was not found in the margarine samples at levels above
      the determination limit of spectrophotometric method i.e. 15.6 mg/kg.

PMID- 12621882
TI  - [Keratinolytic fungi in an acidic petroleum waste lagoon at a petroleum
      refinery].
AB  - The incidence of keratinolytic fungi in an acidic petroleum waste lagoon (before
      bioremediation) at a petroleum refinery situated within a highly populated area
      was examined. High concentrations of petroleum hydrocarbons (aliphatics and PAHs)
      made the growth of keratinolytic fungi in clay and litter collected from the
      lagoon impossible. The natural self-purification process considerably decreased
      the hydrocarbon contamination, increased the pH and caused the abundant growth of
      Trichophyton ajelloi in organic soil that contained the root-adjacent material
      from the grass growing in green oases at the lagoon. Ecological and
      epidemiological aspects of the data were discussed.

PMID- 12621883
TI  - [The evaluation of thermophilic fungi in raw coffee beans].
AB  - The purpose of the study was the attempt of the isolation of the thermophilic
      fungi from raw coffee beans. The material constituted of 24 coffee beans samples
      came from 12 countries. The isolation and the identification of the thermophilic
      fungi was conducted according to Bilaj [2], Bilaj and Zacharczenko [3]. The study
      proved, that raw coffee beans were the rich source of the thermophilic mycoflora.
      From all tested samples 270 species were isolated. The most refused sample came
      from Ecuador--81% coffee beans were infected. The most of species (90% from among
      isolated) were species belonged to the Thermomyces lanuginosus.

PMID- 12621884
TI  - [Assessment of the alkaline (ALP) and acid phosphatase (ACP) in the blood serum
      of rats during experimental postmenopausal osteoporosis].
AB  - The aim of this study was to evaluate the activity of alkaline (ALP) and acid
      (ACP) phosphatase in the blood serum of rats after ovariectomy and with estrogen
      replacement therapy. The relationship between mandible and spine bone mineral
      density (BMD) and parameters of bone remodeling was also estimated. The
      concentration of serum total alkaline and acid phosphatase was higher in the rats
      with estrogen deficiency, and statistically lower in rats administering 17 beta
      estradiol. ALP and ACP levels were correlated significantly negative with
      mandible and spine BMD. Carried out examinations confirmed increasing bone
      resorption during experimental postmenopausal osteoporosis.

PMID- 12621885
TI  - [Flame retardants--use and hazards for human].
AB  - Flame retardants (FRs) are chemicals which added to materials during or after
      manufacture, inhibit or even suppress the combustion process due to their thermal
      stability. Large quantities of FRs are added to the plastic material (resins) in
      variety of electrical and electronic appliances including television and computer
      casing. The other uses of these compounds include production of building
      materials, upholstered furniture, textiles, wall covering, carpets, hydraulic
      fluids as well as vehicles and aircraft. Taking into account the chemical
      structure, there are five main groups of FRs: brominated, chlorinated,
      phosphorous-containing, nitrogen-containing (i.e. melamines) and inorganic
      compounds. Halogenated compounds, especially polybrominated diphenyl ethers
      (PBDEs), a class of brominated flame retardants, due to their lipophilic
      characteristics and persistence have become ubiquitous environmental
      contaminants. There are indications that PBDEs may affect hormone function acting
      as endocrine disruption and may be toxic for developing brain. These compounds
      have been associated with non-Hodgkin's lymphoma in humans, a variety of cancers
      in rodents and disruption of thyroid hormones balance. Similarly to other
      persistent halogenated compounds they are also able to affect the xenobiotic
      metabolizing enzymes activity. PBDEs are now found as residues in sediments,
      wildlife and human (milk, serum adipose tissue) samples. The predominant
      congeners in environmental samples, including human specimens are two congeners:
      47 and 99. Currently, the estimated daily intake of PBDEs by adult humans is
      equal 51 ng x day-1 while by breast-fed infants equals 110 ng x day-1.

PMID- 12621886
TI  - [Emission volatile organic compounds from new textile floor coverings].
AB  - The emission of formaldehyde and the other volatile organic compounds (toluene,
      styrene, 4-PC) and total volatile organic compounds (VOCs) from new textile floor
      coverings was measured with the use of environmental chamber (0.6 m3 capacity) in
      the following conditions: temperature 23 degrees C, relative humidity 45%, 1
      exchange/hour and factor loading 1 m2 m-3. The formaldehyde was determined by
      using colorimetric method, VOCs by GC method. The tested carpets did not emit
      formaldehyde. The emission of other volatile organic compounds was very low and
      fulfill known requirements.

PMID- 12621887
TI  - Will new education costs drive nurses away?

PMID- 12621888
TI  - Excelling at inspections.

PMID- 12621889
TI  - The ethical implications and legal aspects of patient restraint.
AB  - Restraint can be applied in a physical way, via medication or by more subtle
      means. An attempt by an individual to restrain another is legally justifiable in
      limited situations, for example to prevent a person committing a crime. In other
      circumstances, restraint is unjustifiable. It is important, from a legal and
      moral perspective, to ensure that nursing practice does not involve unjustifiable
      restraint. This article focuses on restraint within a care setting for older
      people and highlights the complexity of situations in which restraint may be
      required and the ethics governing its use.

PMID- 12621890
TI  - What you need to know about... fibroids.

PMID- 12621891
TI  - Enema administration.

PMID- 12621892
TI  - National directives on managing 'violent' patients: a critique.
AB  - The incidence and nature of patient aggression and violence in health care has
      been a neglected area of investigation. However, since the 1980s there has been
      an increase in the amount of research examining the problem of patients who are
      aggressive and violent in a multitude of health care settings. A critique of
      three initiatives highlights the problems associated with aggression and violence
      in healthcare. They fail, however, to make the distinction between aggression and
      violence, and as aggression is more common, inappropriate, restrictive care for
      patients will continue at the expense of developing therapeutic relationships.

PMID- 12621893
TI  - The benefits of a fast-track, staff nurse development programme.
AB  - In line with other professions, nursing should offer a range of career paths to
      suit the differing needs of its members. There should be opportunities for nurses
      who have both the ability and the commitment to make rapid career progress. This
      article describes a fast-track, staff nurse D-E grade development programme for
      junior nurses. The programme has been introduced in an acute teaching trust with
      the aim of improving career opportunities and contributing to the delivery of
      quality care for patients.

PMID- 12621894
TI  - 'We offer hope to people'.

PMID- 12621895
TI  - Making patient leaflets work.

PMID- 12621896
TI  - A family-friendly nursing specialty.

PMID- 12621897
TI  - Home hygiene: a risk approach.
AB  - The need to place "prevention through hygiene" at the core of strategies for
      infection prevention has been emphasised by recent events. Indications are that
      re-evaluation of current practice and the promotion of improved hygiene in the
      domestic setting could have a significant impact in reducing infectious disease.
      If the public are to play a part however they must be properly informed.
      Encouraging the concept of the home as a setting in which the whole range of
      activities occur, including food hygiene, personal hygiene and hygiene related to
      medical care, provides the opportunity for a rational approach to home hygiene
      based on risk assessment. In the home surfaces (including hand surfaces) and
      other sites play an important part in the transmission of infection, especially
      food-borne infections. From an assessment of the frequency of occurrence of
      pathogens and potential pathogens at reservoirs, disseminators and hand and food
      contact sites together with the potential for transfer within the home, the risks
      of exposure can be assessed. This can be used to develop a rational approach in
      which effective hygiene procedures involving cleaning and disinfection as
      appropriate are targeted at these sites to reduce risks of cross contamination.
      This approach is consistent with the view that good home hygiene is not about
      "getting rid of household germs" but about targeting hygiene measures
      appropriately to reduce exposure to germs and thereby prevent cross infection. In
      motivating change, education programmes must take account of concerns related to
      antimicrobial resistance, the environment and the "health" of the immune system.

PMID- 12621898
TI  - A first approach to estimate the internal exposure to acrylamide in smoking and
      non-smoking adults from Germany.
AB  - Since the formation of acrylamide (AA) in the heating process of starch
      containing food could be demonstrated and high contents of this substance were
      found in commercial food products, there is a great discussion about the possible
      human health risks connected with this dietary exposure. In order to determine
      the body burden of the general population in Germany caused by this uptake, we
      investigated the internal exposure to acrylamide and acrylonitrile in a group of
      72 persons using haemoglobin adducts as parameters of biochemical effects. The
      collective was subdivided into non-smokers and smokers basing on the results of
      the smoking-specific acrylonitrile adduct (N-cyanoethylvaline, CEV). The median
      value for the adduct of AA (N-2-carbamoylethylvaline, AAV) in 25 non-smokers was
      21 pmol/g globin (approximately 0.6 microgram/l blood) with a 95 percentile of 46
      pmol/g globin (approximately 1.3 micrograms/l) (LOD: 12 pmol/g globin). The
      median level for AAV in smokers (n = 47) was found to be 85 pmol/g globin
      (approximately 2.3 micrograms/l blood) with a 95 percentile of 159 pmol/g globin
      (approximately 4.3 micrograms/l blood). Based on these results about 60
      micrograms AA/d are taken up by adult non-smoking persons. According to
      calculations of WHO and US EPA this background exposure would lead to a cancer
      risk between 6 x 10(-4) and 3.6 x 10(-3). Our results confirm a body burden to AA
      even in persons from the non-smoking general population in Germany that is most
      probably caused by dietary uptake. Smoking habits considerably contribute to the
      level of this adduct.

PMID- 12621899
TI  - German Environmental Survey 1998 (GerES III): environmental pollutants in the
      urine of the German population.
AB  - The German Environmental Survey (GerES) is a cross-sectional probability study to
      determine the exposure of the general population to environmental contaminants.
      The study was repeated for the third time in 1998 (GerES III). Again, a
      stratified random procedure was used to select the study population taking into
      account the parameters gender, age, community size and place of residence (West-
      or East-Germany). A total of 4822 persons between 18 and 69 years of age from 120
      localities participated in GerES III. Human biomonitoring comprised the
      determination of arsenic, cadmium, mercury, metabolites of polycyclic aromatic
      hydrocarbons (PAH), pentachlorophenol (PCP), other chlorophenols, precious metals
      (gold, platinum, iridium), nicotine, and cotinine in urine.

PMID- 12621900
TI  - Health risk for children from lead and cadmium near a non-ferrous smelter in
      Bulgaria.
AB  - In an interdisciplinary approach the exposure to lead and cadmium of the
      population living in the vicinity of a Bulgarian non-ferrous metallurgical plant
      was studied to determine the routes of exposure. Two exposed villages situated 4
      and 6 km SW and W, respectively,--in the plume of the plant's emissions--and a
      village for comparison situated 14 km SE of the plant were selected for the
      study. The blood of children aged 3-13 years from the exposed villages (n = 111)
      and the village for comparison (n = 18) was analyzed for lead (PbB) and cadmium
      (CdB) as well as for free erythrocyte protoporphyrin (FEP) and haematological
      parameters. A personal questionnaire concerning nutrition habits and life-style
      was filled in by interviewers of the children's parents. The cadmium levels in
      blood were within the variation range stated for Bulgaria. The exposed children
      had a mean CdB of 0.38 +/- 0.18 microgram/l (range 0.10-0.90 microgram/l) and the
      comparison group 0.31 +/- 0.35 microgram/l (0.06-1.42 micrograms/l). The mean PbB
      value measured in the exposed children was 240 +/- 96 micrograms/l (77-631
      micrograms/l), while the mean value of PbB for the reference group was 149 +/- 57
      micrograms/l (63-285 micrograms/l). Individual PbB levels > 150 and > 200
      micrograms/l were found in 85% and 62%, respectively, of the exposed children and
      FEP > 80 micrograms/dl erythrocytes was detected in 21%. There was a
      concentration-response and a concentration-effect relationship (r = 0.51, D >
      0.001) between PbB and FEP. According to the questionnaire only 10.3% of the
      interviewed families in the two exposed villages buy all food from the market,
      the others produce a significant part of their food themselves. The PbB levels of
      children who consume certain foods of local production (cabbage, cereals,
      poultry, and beef) were significantly higher compared to the PbB values of
      children whose families purchase these foods from the market. No significant
      relationship between lead in children's blood and the use of tin and ceramic
      utensils, drinking and irrigation water, hygiene habits, family tobacco smoking
      habits, playgrounds and traffic intensity were revealed. There was a
      significantly higher incidence of prematurely born babies in the exposed
      population. The proven relationship between lead intake via the food chain and
      existing significant health risks is the basis for risk communication. Measures
      aimed at healthier nutrition and life-style intend to contribute to decreasing
      the risk of the population living in the smelter region.

PMID- 12621901
TI  - DNA damage in a human population affected by chronic psychogenic stress.
AB  - The effects of chronic psychogenic stress on the expression of DNA damage and
      cellular response to the damage were investigated. Using the comet assay, basal
      DNA damage was found to be similar in lymphocytes of both affected and non
      affected populations (n = 30 in both groups). The induction of DNA damage in
      lymphocytes by external factors (H2O2 and gamma-irradiation), was also
      investigated. In these studies, cells were treated with 50, 100 and 150 microM
      H2O2 for 5 minutes or with 0.8, 2.5 and 4.2 Gy gamma-rays. A significant
      difference was found between the chronically stressed and the control
      populations, indicating the enhanced sensitivity of the former population. Cells
      were also held for 2 hours after the treatment, allowing time for the cells to
      deal with the induced DNA damage. Based on the level of residual DNA strand
      breaks, cells from the stressed population had more breaks than the controls.
      Gender does not alter these findings. In conclusion, our data indicate that cells
      from the stressed population were more sensitive to the induction of DNA damage
      and had higher level of residual damage. Therefore, stress conditions may cause
      the affected individuals to be susceptible to environmental mutagenic agents.

PMID- 12621903
TI  - Pattern of Salmonella excretion in amphibians and reptiles in a vivarium.
AB  - During a period of about three years the faeces of five species of amphibians (35
      individuals) and of 23 species of reptiles (103 individuals) living in one
      vivarium with terrariums imitating different types of ecosystems were examined
      for salmonellae. From 54 out of 376 faecal samples Salmonella spp. was isolated
      (= 14%). Twenty-one different Salmonella strains were found. Salmonellae could be
      isolated about twice as often from animals kept under arid or mesic conditions
      than from animals living in humid or aquatic environments although this was not
      statistically significant. Statistically significant for the rate of Salmonella
      excretion was the animals' diet and the class the animals are belonging to.
      Animals feeding on mice (p = 0.04) and reptiles in general (p = 0.04) were more
      commonly excreting Salmonella. Duration of stay was also a significant factor (p
      = 0.0005), whereby the relative risk for Salmonella excretion increased with the
      factor 2.91 per year during the investigation period. Salmonella strains were not
      necessarily transferred among animals living in the same terrarium or among the
      inhabitants of different terrariums. The pattern of Salmonella excretion was
      generally fragmentary. The outsides as well as the insides of the walls of the
      terrariums were also tested for salmonellae several times, but salmonellae have
      never been isolated.

PMID- 12621902
TI  - Dracunculiasis in the north eastern border of Ebonyi State, south eastern
      Nigeria.
AB  - Between January and August 2000, a house-to-house survey of dracunculiasis was
      conducted in 15 communities along the north eastern border of Ebonyi State, south
      eastern Nigeria. Of the 3,777 subjects examined, 192 (5.1%) had active cases of
      guinea worm comprising 109 males (5.5%) and 83 females (4.6%). Infections were
      observed in all age groups. Of the 3,777 persons examined, 2,092 (55.4%) had ever
      been infected in the area. Protruding adult female Dracunculus medinensis worms
      were found predominantly on the lower limbs (80.2%), but also on the scrotum
      (9.4%), umbilicus (3.1%) groin (2.6%), buttocks (20.8%) and chest (1.6%).
      Prevalence of dracunculiasis had no significant sex, age and occupation related
      differences (P > 0.1). All the 47 stagnant ponds in the area were infested with
      cyclops while the 6 streams and 13 newly constructed community wells were free of
      cyclops. Of the five species of cyclopoid copepods found in the stagnant ponds,
      only Thermocyclops oblongatus nigerianus and Mesocyclops aequatorialis harboured
      guinea worm larvae. The efforts of the endemic communities, government and
      international organizations in guinea worm eradication in these areas are
      discussed.

PMID- 12621904
TI  - Ranking and frequency of somatic symptoms in residents near composting sites with
      odor annoyance.
AB  - The presented study reports the prevalence of somatic symptoms in three study
      samples living in the vicinity of composting plants. Microorganisms were measured
      in the air of the residential areas closest to the plants at the same time an
      epidemiological investigation was performed in the neighborhood near (150 to
      1,500 m) to three plants and in corresponding control residential areas of the
      same district. Nine hundred and seventy-nine residents were questioned about the
      odor annoyance in their vicinity. An instrument measuring somatic complaints
      (SOMS 2 acc. Rief et al., 2001) was used to determine the unexplained somatic
      symptoms of the past two years and a gender-independent Total Complaint Index
      (TCI) was calculated. The percentages of study population reporting somatic
      symptoms were higher in all six samples in comparison with the German population
      (Rief et al., 2001) and in samples living near composting sites compared to the
      corresponding control samples. The study sample living close to site A (exposed
      to bioaerosols and odor annoyance) had the highest rates of complaints. A
      difference could be seen in comparison to the corresponding control sample (TCI:
      p[Anear vs. Acontrol] = 0.001; Mann-Whitney). In this group breathlessness was
      reported more than twice as often as in the other three samples. Out of the five
      most frequently reported symptoms four corresponded to the five complaints the
      German population reports most frequently in all groups. Nausea was the fifth
      most reported symptom in both samples reporting annoying residential odors (Anear
      and Bnear). The type of somatic symptoms reported most often was influenced
      little by environmental odors and medically relevant bioaerosol concentrations,
      except for nausea in context with annoying residential odors. As expected
      frequency of reporting general somatic symptoms was influenced by the perceived
      environment near the three composting sites. Concerning the sum of bodily
      complaints (TCI) though, this was only significant in the group exposed to
      medically relevant concentrations of residential outdoor bioaerosols, which was
      accompanied by high rates for breathlessness. The SOMS2 was able to mirror
      measurable, medically relevant environmental exposures in study groups and showed
      fewer changes concerning annoying or presumed environmental exposures.

PMID- 12621905
TI  - Profiles of microfungi--Penicillium chrysogenum and P. expansum.

PMID- 12621906
TI  - Commentary regarding the article by Gottwald et al.: "Amalgam disease"-
      poisoning, allergy, or psychic disorder? Int. J. Hyg. Environ. Health 204, 223
      229 (2001).

PMID- 12621907
TI  - [What is your diagnosis? Pulmonary edema in acute left heart failure].

PMID- 12621908
TI  - [Manual lymph drainage as therapy of edema in the head and neck area].
AB  - Depending on its genesis, edema must be treated by medication or diet.
      Simultaneous application of lymph drainage may be beneficial in some cases,
      especially in combined edema. The manual lymphdrainage is a special method of
      massage. In some kinds of edema, in particular lymphedema, only therapeutic lymph
      drainage introduced into medicine by Vodder, Asdonk and Kuhnke can attain an
      improvement, since there is no drug which acts on the lymphatic system. We report
      about primary and secondary lymphedemas of the face and head. Secondary
      lymphedemas are a result of surgical therapy, cancer therapy, irradiation or are
      caused of tumors or their metastases respectively. Depending on the state of the
      edema a lymphatic drainage treatment is indicated palliatively.

PMID- 12621909
TI  - [Prostatic carcinoma: from morphology to molecular biology].

PMID- 12621910
TI  - [Weight loss cures advertised in the media: only quackery?].
AB  - Obesity is a multifactorial disease that afflicts a growing number of people in
      Europe and throughout the world. Both commercial and medical treatment programs
      are characterized by high rates of long-term recidivism. A cultural preoccupation
      with slimness has created a profitable industry serving millions of people who
      are attempting continually to reduce weight. This review summarizes the major
      areas of consensus and controversy concerning the health implications of obesity
      and weight loss and suggests novel directions for treatment.

PMID- 12621912
TI  - [Sudden onset of left-sided epigastric pain].

PMID- 12621911
TI  - [Elevated liver values of uncertain origin].
AB  - A 31-year old Egyptian was referred to evaluate the etiology of elevated liver
      enzymes. The patient had been suffering from diabetes type 1 for three years and
      complained about episodes of light diarrhea. Laboratory investigation revealed a
      moderate elevation of cholestatic enzymes. Ultrasound examination and computed
      tomography did not show mechanical biliary obstruction. Drug-induced cholestasis,
      viral hepatitis and primary biliary cirrhosis could be excluded as well. Finally,
      schistosomiasis mansoni was diagnosed by microscopic stool examination as well as
      histological evaluation of biopsy specimens obtained during colonoscopy. This
      parasitic disease may cause slowly progressive liver injury by the release of
      schistosome eggs into the portal vein system. Histological evaluation of liver
      specimens of this patient showed portal inflammation and the presence of
      pigmented macrophages. This pattern, though unspecific, was consistent with the
      diagnosis of schistosomiasis mansoni. Treatment with praziquantel resulted in
      regression of diarrhea episodes and normalization of cholestatic enzymes within
      three months.

PMID- 12621913
TI  - [65-year-old patient with headache of 3 months duration].

PMID- 12621914
TI  - A negative myocardial perfusion scintigram after coronary angioplasty confers
      benign long-term prognosis.
AB  - BACKGROUND: Myocardial perfusion SPECT is often used to exclude late restenosis
      or disease progression after coronary angioplasty (PTCA), but few studies have
      been published regarding the prognostic value of a negative study. AIM: To
      examine the long-term prognostic value of a non-ischemic SPECT result after
      successful PTCA. METHODS: We retrospectively reviewed 783 patients (pts) who
      underwent scintigraphy 3 months to 3 years after successful PTCA. In 118 no
      significant myocardial ischemia (moderate or severe) was observed. There was a
      history of myocardial infarction (MI) in 38.1%, multivessel disease in 36.8% and
      LVEF < 50% in 15.3%. Referral for SPECT was chronic angina in 50.5% and acute
      coronary syndrome in 32.2%. SPECT was performed using a treadmill exercise test
      in 72%, adenosine in 21%, dipyridamole in 3% and dobutamine in 4%. Fifty-three
      percent of pts were under anti-ischemic medication. Patients were divided into
      two groups according to the SPECT result: group A pts (n = 70) had mild or no
      ischemia and group B pts (n = 48) had non-reversible defects of small or moderate
      size. The endpoint was the combined occurrence of death, MI, unstable angina (UA)
      and repeated revascularization. RESULTS: There were one MI, 2 UA episodes and 4
      repeated PTCAs (1 for UA). Event-free survival rate at two-year follow-up was
      slightly lower in patients from group B compared with group A, respectively 91.7%
      versus 97.1% (p = 0.16, log rank test). CONCLUSIONS: This study suggests an
      excellent prognosis for patients with no or mild ischemia as assessed by SPECT
      performed more than 3 months after coronary angioplasty. Those patients with mild
      persistent defects did not present a significantly worse outcome.

PMID- 12621915
TI  - Can myocardial perfusion scintigraphy predict the future for patients after
      percutaneous coronary intervention?

PMID- 12621916
TI  - Regional myocardial function by tissue Doppler in hypertrophic cardiomyopathy:
      the impact of obstruction.
AB  - BACKGROUND: The conventional echocardiographic assessment of myocardial function
      in patients with obstructive hypertrophic cardiomyopathy (HOCM) is complex,
      because of the load dependency of this method. Tissue Doppler imaging (TDI) may
      improve this evaluation. AIM: To compare regional myocardial function with TDI,
      between patients with hypertrophic obstructive cardiomyopathy (HOCM) and with non
      obstructive forms of the disease (NOHCM). METHODS: 26 patients with HOCM and 23
      with NOHCM were studied with pulsed TDI. We studied longitudinal (8 left
      ventricular segments, apical views) and radial regional function (2 segments,
      short axis view), and analyzed velocities, time intervals, velocity-time
      integrals and heterogeneity and asynchrony indices and the meridional (basal
      medial segments) velocity gradient in each wall. Data were compared within each
      group and between groups. RESULTS: Compared to NOHCM, HOCM patients showed:
      systolic functions: a) longitudinal: similar velocities, time intervals and
      integrals; b) radial: higher meridional gradient, lower velocity-time integrals.
      Diastolic function: a) longitudinal: lower a, higher e and e/a tendency; lower e
      meridional gradient, higher percentage of septal and anterior wall segments with
      e/a > or = 1; b) radial: lower a velocities and integrals, shorter diagnostic
      time. CONCLUSIONS: This study shows that in HOCM patients, the presence of
      obstruction and its associated load conditions have a different impact on
      systolic and diastolic regional myocardial function, in long and short axis,
      assessed with TDI. So, in HOCM patients: 1-Long axis regional systolic function
      is similar to the non-obstructive forms, suggesting relative load independence. 2
      Long and short axis regional diastolic function is, in specific segments and
      parameters, different from the non-obstructive forms. These data should be taken
      into account in the assessment of regional myocardial function with TDI in HOCM.

PMID- 12621917
TI  - Balloon mitral valvuloplasty during pregnancy--our experience.
AB  - INTRODUCTION: Mitral stenosis is the most common valvular heart lesion found in
      pregnancy. When severe, it leads to significant maternal and fetal morbidity and
      mortality, since the hemodynamic adaptations to pregnancy are badly tolerated.
      Pregnancy can lead to development of heart failure in patients with asymptomatic
      or even unknown mitral stenosis, as a result of the increased mitral valve
      pressure gradient caused by the physiologic increase in heart rate and blood
      volume in pregnancy. When symptoms persist despite optimal medical therapy, the
      poor prognosis justifies the correction of mitral stenosis during pregnancy.
      OBJECTIVE: To present our experience in treating severe mitral stenosis in women
      who develop severe heart failure during pregnancy, using percutaneous balloon
      mitral valvuloplasty. PATIENTS: From 1996 to March 2002, in our department, 47
      balloon mitral valvuloplasties were successfully performed in women, three of
      them pregnant. These were patients with congestive heart failure, New York Heart
      Association (NYHA) functional class III or IV, at the end of the second trimester
      of pregnancy, who did not respond positively to drug treatment with diuretics and
      digitalis. INTERVENTIONS: We performed percutaneous balloon mitral valvuloplasty
      using the Inoue technique in the three pregnant patients, with success, at around
      25 weeks of gestation. RESULTS: After the procedure, the patients showed clinical
      improvement, returning to the NYHA functional class that they were in before
      becoming pregnant (I-II). The previous mitral valve area was 0.9-1.2 cm2, nearly
      doubling after valvuloplasty. Mean left atrial pressure decreased on average by
      42%, and the maximum pressure (V wave) decreased on average by 40%. The mitral
      valve pressure gradient decreased from 15, 10 and 28 mmHg to 7, 5 and 5 mmHg
      after valvuloplasty. During the procedure there were no maternal or fetal
      complications. All patients were discharged 24 to 48 h after valvuloplasty,
      continuing their pregnancies without complications. One woman had vaginal
      delivery, and the other two had cesarean sections at 35 weeks of gestation, all
      without complications with healthy newborns that developed normally. In follow
      up, one patient who had moderate mitral regurgitation after valvuloplasty
      developed severe mitral regurgitation, requiring surgical correction after two
      years. CONCLUSION: In pregnant patients who have severe mitral stenosis and
      persistent congestive heart failure symptoms despite conventional medical
      treatment, when feasible, percutaneous balloon mitral valvuloplasty is the best
      treatment.

PMID- 12621918
TI  - Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and
      xantine oxidase--what role in myocardial ischemia and reperfusion?
AB  - OBJECTIVES: The cardioprotective effects of carvedilol (CV) may be explained in
      part by interactions with heart mitochondria. The objective of this work was to
      study the protection afforded by CV against oxidative stress induced in isolated
      heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known
      source of reactive oxygen species (ROS) in the cardiovascular system. METHODS:
      Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with
      HX/XO in the presence and in the absence of calcium. Several methods were used to
      assess the protection afforded by CV: evaluation of mitochondrial volume changes
      (by measuring changes in the optical density of the mitochondrial suspension),
      calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and
      mitochondrial respiration (with a Clark-type oxygen electrode). RESULTS: CV
      decreased mitochondrial damage associated with ROS production by HX and XO, as
      verified by the reduction of mitochondrial swelling and increase in mitochondrial
      calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial
      respiration in the active phosphorylation state and prevented decrease in the
      respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative
      efficiency (p < 0.001). CONCLUSIONS: The data indicate that CV partly protected
      heart mitochondria from oxidative damage induced by HX and XO, which may be
      useful during myocardial ischemia and reperfusion. It is also suggested that
      mitochondria may be a priority target for the protective action of some
      compounds.

PMID- 12621919
TI  - Do patients with intraventricular gradients during dobutamine stress
      echocardiography have intraventricular gradients with exercise testing?
AB  - The development of intraventricular gradients during dobutamine stress
      echocardiography has been widely reported and this finding is commonly associated
      with symptoms during stress testing. In a previous study, we investigated the
      incidence of intraventricular gradients during dobutamine stress echocardiography
      in 46 patients and concluded that they occur frequently (43%). In another study
      we looked for the same phenomenon in 50 other consecutive patients during
      exercise stress echocardiography and only found a small gradient in one patient
      (2%). The purpose of the present study was to look for the development of
      intraventricular gradients during exercise echocardiography, in patients in whom
      this phenomenon occurred during dobutamine stress echocardiography. We studied 10
      patients who developed a significant intraventricular gradient in a negative or
      inconclusive dobutamine stress echocardiography study. Five of the patients were
      male, mean age was 63 +/- 15.9 years (34-79). Three patients had previously
      undergone coronary angioplasty. The presence of intraventricular gradients was
      evaluated in all patients by color, pulsed and continuous wave Doppler
      echocardiography during dobutamine and exercise stress testing. An
      intraventricular gradient was considered significant when the intraventricular
      flow velocity increased by more than 1 m/s at the end of systole. The mean
      intraventricular gradient developed during dobutamine stress echocardiography was
      101.7 +/- 68 mmHg (47-270). Only one of these patients developed a small
      intraventricular gradient during exercise stress echocardiography. CONCLUSION: In
      a small population of patients who developed significant intraventricular
      gradients during dobutamine stress echocardiography, this finding was not
      reproduced with exercise echocardiography.

PMID- 12621920
TI  - Leiomyosarcoma of the inferior vena cava--a very rare case report.
AB  - The authors present a case report of a patient with abdominal pain that began 6
      months before hospital admission. Ambulatory abdominal echography and computed
      tomography (CT) revealed partial thrombosis of the inferior vena cava (IVC) with
      right atrial extension. During hospitalization, magnetic resonance imaging (MRI)
      revealed aspects suggesting a tumoral lesion of the right atrium, rather than a
      thrombus, with tumoral extension to the IVC. The echocardiogram showed images
      suggesting a right atrial tumor. Transesophageal echocardiography confirmed the
      diagnosis. During surgery, an IVC tumor was found invading the right atrium,
      which histopathology confirmed as a leiomyosarcoma. The authors present this case
      because this type of tumor is rare (21 cases worldwide at this anatomic site), it
      is difficult to diagnose, and its management has not been adequately described.
      The authors review the literature relevant to this case.

PMID- 12621922
TI  - Familial dilated cardiomyopathy.
AB  - Dilated cardiomyopathy is a disorder affecting heart muscle, characterized by
      ventricular dilation and reduced systolic function. It represents the most common
      cause of heart failure. Until recently, dilated cardiomyopathy was considered an
      exclusively sporadic and idiopathic disease. Now, as defined by the World Health
      Organization, cardiomyopathy includes not only the idiopathic form, but secondary
      ones such as ischemic or hypertensive. It is estimated that familial occurrence
      accounts for 30% of cases of idiopathic dilated cardiomyopathy. The most common
      mode of inheritance is the autosomal dominant type. The X-linked, autosomal
      recessive and mitochondrial forms are less common. Different genes or loci are
      responsible for the cardiac dilatation, and code for sarcomeric, cytoskeleton and
      nuclear lamina proteins. The molecular interactions of the mutated proteins with
      factors such as infectious agents or alcohol could explain the variety of
      presenting signs and symptoms of this type of cardiomyopathy. Recently the
      European Society of Cardiology published a definition and a protocol for the
      study of familial dilated cardiomyopathies. Genetic research in the field of
      dilated cardiomyopathy can increase our understanding of its pathogenesis and
      lead to new treatment modalities for the disease.

PMID- 12621921
TI  - Chronic left ventricular pseudoaneurism.
AB  - We present the case of a 70-year-old white male presenting with an abnormal
      cardiac silhouette on the chest X-ray and complaining of fatigue in the week
      before hospital admission. Four months before admission he had a single prolonged
      ischemic chest pain episode. The ECG revealed an old true posterior myocardial
      infarction. The transthoracic echocardiogram showed a large left ventricular
      pseudoaneurysm and surgical resection was performed successfully. The etiology,
      diagnosis and treatment of left ventricular pseudoaneurysm are reviewed.

PMID- 12621923
TI  - Prevention and screening. Part I: General principles.
AB  - Currently, a substantial part of clinical practice is involved with health
      maintenance and disease prevention. However, there continue to be deficiencies in
      the delivery of preventive care, and it is sometimes difficult to identify which
      interventions are effective--for lack of randomized clinical trials--and the
      theoretical basis of this approach is not always clear. In this paper, the first
      in a series of two, we will present the general conceptual principles of
      preventive medicine, starting with levels of prevention and followed by the
      criteria for selecting a preventive intervention. Regarding the latter, the
      characteristics of the disease to be screened and the respective screening test
      will be discussed, as well as therapy for positive cases. Finally, we will
      discuss the possible consequences of screening for disease. In our second paper,
      to be published in the next issue, we will present guidelines for the critical
      appraisal of an article about screening.

PMID- 12621924
TI  - Tetralogy of Fallot: two ways out of the right ventricle.

PMID- 12621925
TI  - Characterization of coronary anatomy with a single angiography in patients with
      transposition of the great arteries.

PMID- 12621926
TI  - [17th. Presidency of the Portuguese Society of Cardiology (1981-83)].

PMID- 12621927
TI  - Global status of immunization safety: a report based on the WHO/UNICEF joint
      reporting form.

PMID- 12621928
TI  - Moving cultural diversity toward cultural competence in health care.

PMID- 12621929
TI  - An ecological analysis of racial differences in low birthweight: implications for
      maternal and child health social work.
AB  - This study attempted to gain a better understanding of the effect of ecological
      and individual risk factors on infant health for black and white women in a large
      metropolitan city. The study examined the association among neighborhood economic
      indicators, neighborhood quality, access to prenatal care, and individual
      perinatal risk factors and subsequent birthweight among 78,415 black and 60,346
      white residents of New York City in 1991 and 1992. Multivariate analyses
      indicated the continuing importance of factors such as smoking and being
      uninsured as individual-level risk factors for low-birthweight babies,
      particularly among black women. The implications of these findings emphasize the
      need for socially and ecologically focused policies that can reduce individual
      level risks for low birthweight in the future.

PMID- 12621930
TI  - Functional impairment as a predictor of depressive symptomatology: the role of
      race, religiosity, and social support.
AB  - The study discussed in this article examined the relationship between depression
      symptomatology and functional impairment among white and African American elderly
      people and investigated the effect of race, religiosity, and social support on
      this relationship. Study results indicate that although African American elderly
      people were more impaired in the performance of activities of daily living (ADL)
      and instrumental activities of daily living (IADL) than white elderly people,
      they did not experience higher levels of depression. However, African Americans
      did report significantly higher levels of religiosity and social support.

PMID- 12621931
TI  - Psychosocial factors and ethnic disparities in diabetes diagnosis and treatment
      among older adults.
AB  - This study examined diabetes awareness, diagnosis, and social support among
      Mexican Americans, African Americans, other Hispanic people, and white people
      living in the United States. Using a national sample of people age 60 and older,
      three groups were formed based on serum glucose level and diagnosis of diabetes:
      those who were unaware that their serum glucose level was greater than 115 mg/dl
      (no diagnosis), those with a diabetes diagnosis, and those with normal glucose
      (no diagnosis). Mexican Americans were the most likely to have a diagnosis, had
      the highest mean glucose levels, and, together with white people, were most
      likely to be classified as unaware. Mexican Americans and other Hispanic people
      had the lowest levels of social support and affiliation on four out of five
      measures.

PMID- 12621932
TI  - Use and implications of ethnomedical health care approaches among Central
      American immigrants.
AB  - Although Latinos in the United States often share similar cultural values and
      health beliefs, there are differences among Central American, South American,
      Mexican, and Caribbean Latinos. Central American health beliefs and practices are
      largely influenced by religious and indigenous worldviews. Health care providers
      in the United States may fail to recognize or accept the many ethnomedical
      approaches to treatment. This descriptive study assesses the use of ethnomedical
      approaches and the illnesses for which these approaches are used among 76 Central
      Americans in the District of Columbia. The results indicate the importance of
      understanding and integrating cultural and spiritual influences on health-related
      schemata and their effect on health care use and delivery.

PMID- 12621933
TI  - Notions of HIV and medication among multiethnic people living with HIV.
AB  - To help understand why people of ethnic minority groups tend to be less likely
      than European Americans to take medication for HIV, narratives from 62
      multiethnic HIV-positive individuals were coded for mention of taking medication
      for HIV and reasons for not doing so. Respondents viewed HIV/AIDS and medication
      in terms of other illnesses and drugs, including colds, cancer, and street drugs.
      Some recovering drug users expressed concern about ingesting synthetic medication
      or considered medical regimens as constraining as a drug addiction. Some in the
      sample also thought antiretroviral medications were toxic, especially when taken
      in combination. Others thought they should wait to take medication to prevent
      opportunistic infection until they felt ill. Implications for providers are
      discussed.

PMID- 12621934
TI  - Health care needs of foreign-born Asian Americans: an overview.
AB  - Asian Americans are one of the fastest growing groups in the United States. A
      majority of them are foreign born, which makes their health-related situation
      very complex. Many still have the diseases they brought with them from their
      native lands. In addition, they acquire new diseases attributed to the changes in
      their living conditions and lifestyle. They are vulnerable to the physical
      effects of acculturation-related stress as well. The health care needs of these
      new Americans are not being adequately met. This article describes the barriers
      to their ability to use health care services and analyzes the reasons for the
      health care system's inability to respond to their needs. Finally, it urges
      social work to contribute to the system's responsiveness and suggests approaches
      to social work intervention with and on behalf of Asian Americans.

PMID- 12621936
TI  - A call to action: patients' access to clinical trials.

PMID- 12621937
TI  - [Seafood poisoning through marine biotoxins].

PMID- 12621935
TI  - Reach out and I'll be there: mental health crisis intervention and mobile
      outreach services to Urban African Americans.

PMID- 12621938
TI  - [History of hepatitis.2. Identification of epidemic hepatitis].

PMID- 12621939
TI  - [The organization of burn care].
AB  - In 2002, the organisation of burn care is confronted to a great deficiency in
      burn epidemiological datas. The main mechanisms of hospitalized burns are somehow
      wellknown in industrialized countries: about 60% scalds and 30% flame burns; as
      well as the place of occurrence (60% at home, and 20% at work), and the risk
      groups (3 times more important for the age group 0-4 years old). The incidence of
      burns needing medical care (all levels) (250/100,000 inh/yr) or hospitalization
      (15-20/100,000 inh/yr) is much more uncertain. The statistics of Diagnosis
      Related Groups (DRG), for hospitalized patients will allow in France very shortly
      to know more about the most rational ways of dispatching and treating them. They
      already show that only 30% of hospitalized burned patients are treated in
      specialized facilities.

PMID- 12621940
TI  - [Evaluation and first aid of burned patients].
AB  - First cares of burned patients depend of an accurate evaluation of the injury
      severity. Total body surface area burned can be estimated taking into account the
      fact that the area of one hand face is equivalent to 1% of the total body surface
      (TBS) of the individual. Second-degree burns are characterized by the occurrence
      of phlyctena, third-degree burns appear like adhering necrosis without any
      sensibility. Smoke inhalation injuries are frequent and can be recognized on the
      presence of tare deposits inside the mouse and on the respiratory conducts.
      Taking care of the patient begins with making the victim safe from the thermal
      aggression. Then, cooling the burn is to be performed. The emergency medical care
      consists in securing respiratory function, and, as early as possible, in
      beginning perfusions of Ringer Lactate Lavoisier exceeding 20 mL/kg during the
      first post-burn hours for patient suffering of burns exceeding 10% of the total
      body area. Pain must be controlled using preferentially morphine or related
      products. Transport to the specialized unit, in case of severe injury, will be
      performed assuring thermal comfort, wound protection and vital function
      monitoring.

PMID- 12621941
TI  - [Chemical and electrical burns].
AB  - Chemical burns are less frequent in routine practice, but could be very serious
      owing to the complexity and severity of their actions. Influx of casualty after a
      civil disaster (industrial explosion) or military (war or terrorism) is possible.
      The action of these agents could be prolonged and deep. In addition to the skin,
      respiratory lesions and general intoxication could be observed. The urgent local
      treatment rely essentially on prolonged washing. Prevention and adequate
      emergency care could limit the serious consequences of these accidents. Accidents
      (thermal burns or electrisations) due to high or low voltage electricity are
      frequent. The severity is linked with the affected skin but especially with
      internal lesions, muscular, neurological or cardiac lesions. All cases of
      electrisation need hospital care. Locally, the lesions are often deep with
      difficult surgical repairs and often require amputation. Aesthetic and functional
      sequela are therefore frequent. Secondary complications could appear several
      months after the accident: cataract, dysesthesia and hypotonia.

PMID- 12621942
TI  - [Intensive care for burn patients].
AB  - Improvement in intensive care procedures allowed patients with extensive burns to
      survive, leading to develop new technics for cutaneous coverage. During initial
      stage of burn, internal fluid shifts can impair hemodynamic function and lead to
      large fluid infusion which has to be monitored. Afterwards, nutritional care by
      artificial nutrition, and prevention of infection, especially cutaneous infection
      by antibacterial topical creams, are the principal factors which improve vital
      prognosis.

PMID- 12621943
TI  - [Surgery of burns].
AB  - The surgical treatment of burns must provide the best conditions that assure re
      epidermalisation of the burn. Two imperatives must be respected during the
      initial management: encourage rapid scarring of the burn as the loss of the
      protection of the cutaneous barrier leads to a significant risk of contamination
      of the burn and of generalised infection, and the quality of the burn scar
      (minimal retraction or hypertrophic reaction) is directly related to the duration
      of the scarring process; utilisation of the technique that will give the best
      aesthetic and functional results in treating firstly the exposed zones (face and
      hands) and the functional zones (flexural folds, articular regions). The surgical
      treatment should respect the areas that can spontaneously re-epidermalise
      (superficial or intermediate burns), however in the deeper lesions (second-degree
      or third-degree burns) the destruction of the basal layer capable of providing
      keratinisation and re-epidermalisation renders the recourse to skin
      transplantation indispensable, which must be performed before the fifteenth day
      in order to best avoid complications.

PMID- 12621944
TI  - [Skin substitutes and skin culture].
AB  - Ideal skin substitutes would reproduce normal skin in its various functions. Even
      in the absence of such ultimate products, the ones in use today represent a major
      part in local burn care as agents promoting wound healing and minimising the long
      term consequences after burn injuries. They originate from natural structures as
      well as (bio)engineering concepts. The application fields cover all depth of
      burns as well as skin donors' areas and even secondary surgery. Among other
      techniques, skin allografts followed by autografts or autologous keratinocytes
      cultures especially over the integrated dermis and artificial skin Integra then
      subsequently grafted with very thin autografts are significant methods in
      treating extensive injuries when utilised according to clinical status accurately
      defined. However further advances are essential for improving the life of burn
      survivors.

PMID- 12621945
TI  - [The lung of the thermally injured patient].
AB  - Severely burned patients are at high risk for developing respiratory failure at
      any time during their treatment. The lung of a thermally injured patient may
      sustain many injuries such as smoke inhalation, physical forces, inflammation and
      infection. The knowledge of the mechanisms of burn injury, physical exam
      findings, laboratory studies, relevant radiologic examinations, and fiberoptic
      bronchoscopy allow an early and accurate diagnosis of pulmonary damage. The
      treatment consists of oxygenation, mechanical ventilation, surgical treatment of
      burn wounds and trauma, and possible therapy for poisoning. The respiratory
      injuries are one of the main factors responsible for high mortality in burned
      patients. Better understanding of the pathophysiology and inflammatory response
      will lead to future therapeutic advances.

PMID- 12621946
TI  - [Burn scars: rehabilitation and skin care].
AB  - Burn rehabilitation main goal is to minimize the consequences of hypertrophic
      scars and concomitant contractures. The treatment principles rely on the
      association of joint posture, continuous pressure completed with range of motion
      to prevent joint fusion (which happens to adults but not to children). Throughout
      the different treatment phases and wound evolution, reassessment is necessary to
      review rehabilitation goals and activities. During the acute phase the alternance
      of positioning is prioritized in order to keep the affected extremities in
      antideformity position using splint or other devices. At the rehabilitation
      phase, treatment is focussed on active/passive range of motion (skin posture)
      strengthening exercises and use of dynamic splint is introduced to correct
      contractures. After their discharge home, patients benefit from outpatient rehab
      until scar maturation (approximately 18 months). The treatment consists mainly on
      active/passive range of motion, scar massage, strengthening exercise and
      endurance retraining. Also modalities (such as thermal bath and high pressure
      water spray) are used to address itching problems and for scar softening.
      Finally, reconstructive surgery can be performed to correct excessive scarring or
      joint contracture for better functional or cosmetic outcome.

PMID- 12621947
TI  - [Network: quality, formation and economics].

PMID- 12621948
TI  - [Breastfeeding and complications].

PMID- 12621949
TI  - [Multiple kidney cysts].

PMID- 12621950
TI  - [Multidisciplinary palliative care to patients at the end of life. Support to
      dying ones and their families].

PMID- 12621951
TI  - [Orodental development and anomalies].

PMID- 12621952
TI  - [Cardiovascular risk factors and their prevention].

PMID- 12621953
TI  - [ Myelodysplastic syndrome].

PMID- 12621954
TI  - [Pleural effusion. Diagnosis].

PMID- 12621955
TI  - Generic drug perspectives.

PMID- 12621956
TI  - Atypical antipsychotic induced mild hypothermia.
AB  - Atypical antipsychotic induced hypothermia is a rare adverse effect that may
      present with mild to severe symptoms. This is a case report of subtle, mild
      hypothermia in a 54-year old female patient receiving risperidone for
      schizophrenia. A mild decrease in the temperature (33.4-34.7 degrees C) along
      with delusions and feeling slightly chilly was part of the initial presentation.
      The diagnosis of hypothermia was delayed until it was apparent for several days
      but resolved with the discontinuation of risperidone and continuation of
      clozapine. Evaluation of hypothermia with psychiatric patients should include
      primary accidental hypothermia, central nervous system disorders, metabolic
      disorders, infections, and medications.

PMID- 12621957
TI  - [The 80th anniversary of the journal "Urologiia"].

PMID- 12621958
TI  - [Results of a 5-year screening for prostatic cancer].
AB  - The results of 5-year screening (1996-2000) for prostatic cancer in 1129 males 40
      to 80 years of age are presented. The examination included: measurement of blood
      levels of prostate-specific antigen (PSA), finger rectal examination, transrectal
      ultrasonic examination (TRUE) and, on demand, biopsy of the prostatic gland.
      Prostatic cancer was diagnosed in 1.5, 2.2 and 16% patients having PSA levels of
      0-4.0, 4.0-10.0 and 10.0-30.0% ng/ml, respectively. At finger rectal examination
      prostatic cancer was suspected in 8% examinees, only in 33% of them the diagnosis
      was verified morphologically. By TRUE evidence 7% examinees were suspected and in
      44.3% of them prostatic cancer was confirmed. Thus, biopsy proved necessary in
      172 cases of 1129 examinees. In 64 (5.7%) males prostatic cancer was diagnosed
      and confirmed. Early prostatic cancer in the screened men and those consulted in
      the outpatient department of the National Cancer Research Center was detected in
      77.7 and 22% men, respectively. The conclusion is made that men over 50 years of
      age should undergo prophylactic examination of the prostatic gland once a year.

PMID- 12621959
TI  - [Screening for prostatic cancer].
AB  - The discussion covers different aspects of application of programs of early
      prostatic cancer diagnosis. Arguments for and against the screening are
      presented. The existing methods of early prostatic cancer diagnosis are reviewed.
      How to improve the technique of taking prostatic biopsy is shown.

PMID- 12621960
TI  - [Results of treatment of irritative symptoms and urinary retention in patients 1
      year after radical retropubic prostatectomy].
AB  - AIM: To assess function of urinary retention and irritative symptoms from the
      lower urinary tracts in patients after radical prostatectomy for local prostatic
      cancer. MATERIAL AND METHODS: From November 1997 to May 2001 radical
      prostatectomy was performed in 181 patients. One year after the operation 86
      patients with pT1c-T2b filled in the questionnaire on urinary retention (UR) and
      irritative symptoms. RESULTS: One year after radical prostatectomy complete UR
      was registered in 76% of the patients, partial UR in 20.5% and unsatisfactory UR
      in 3.5%. Uroflowmetrical and ultrasound investigations, urine seeding made
      possible to select 16 patients with irritative symptoms. 11 patients of this
      group received alpha-adrenoblocker terazosin with a good response. CONCLUSION:
      One year after radical prostatectomy UR (complete or partial) was observed in
      96.5% patients. Irritative symptoms unrelated to stricture of vesicourethral
      anastomosis and inflammation can be climinated by administration of terazosin.

PMID- 12621961
TI  - [Urinary tract occlusion: a principal cause of some complications of
      urolithiasis].
AB  - Urinary tract occlusion in urolithiasis is a serious complication which provokes
      an attack of acute obstructive pyelonephritis. The infected urine aggravates this
      infectious-inflammatory process and endangers bacterial shock. Etiopathogenesis
      of this shock is outlined and modern approaches to its management are described.

PMID- 12621962
TI  - [Residual kidney stones and their treatment].
AB  - 416 case histories of patients with different forms of urolithiasis aged 6 to 70
      years who had undergone sectional nephrolithotomy (83, 19.9%),
      pyelonephrolithotomy (24, 5.8%), pyelolithotomy (146, 35.1%), percutaneous
      nephrolithotomy (163, 39.9%) were analysed. Residual nephroliths occurred in 108
      (25.9%) patients. 98 of them were subjected to extracorporeal lithotripsy (ELT).
      To determine minimal possible interval between the operation and ELT, changes in
      the levels of lipid peroxidation products and concentration of alpha-glutathione
      S-aminotransferase were studied. The results allowed the authors to optimize ELT
      after operative interventions for uroliths. In the course of 206 ELT sessions the
      residual uroliths were destroyed in 96 (97.9%) patients. After one session a
      complete fragmentation was achieved in 19 (19.4%) patients, after two sessions-
      in 64 (65.3%) patients, after three sessions and more--in 15 (15.3%).
      Pyoinflammatory complications developed in 8 (8.2%) patients while
      retrospectively such complications were encountered in 16 of 50 patients (32%).
      One month after ELT, the control examination found neither nephroliths nor their
      fragments in 85 (86.7%) patients, in patients with large and multiple stones
      elimination rate 1.5 months after the treatment was 69.5%. It is inferred that
      ELT is an effective method of residual uroliths elimination and is a method of
      choice in the treatment of such patients.

PMID- 12621963
TI  - [Some features of recovery of upper urinary tract urodynamics after surgical
      treatment of vesicoureteral dysplasia in children].
AB  - Urodynamics of the upper urinary tract (UUT) was examined in 327 children aged
      1.5 months to 15 years with congenital vesicoureteral reflux (VUR) dysplasia
      treated surgically. 230 patients were followed up for 1 to 20 years. Staging of
      chronic disorders of UUT urodynamics is thought to be the key criterion of
      objective assessment of VUR effective surgical treatment. The better long-term
      treatment outcomes are the earlier the disease was diagnosed and corrected. Early
      defects of urodynamics in the absence of marked dilatation of the ureter are
      better corrected by Lich-Gregoir operation which is physiological, low traumatic,
      technically available and most effective (97% of favourable long-term outcomes).
      Ureterocystoneostomy by Politano-Leadbetter (in modification of the authors) is
      indicated in urodynamic disorders stage III and marked ureteral dilatation as
      providing improvement of urodynamics or stabilization in 93.7% patients.

PMID- 12621964
TI  - [Effectiveness of levofloxacin (Tavanik, "Aventis Pharma") in the treatment of
      complicated infections of the urogenital organs].

PMID- 12621965
TI  - [Structural-functional damage to cellular membranes in deficiency of vitamins A,
      E, B2, B6, PP in children with calculous pyelonephritis].
AB  - Lipids were studied in 150 patients with nephrolithiasis, calculous
      pyelonephritis; enzymes, LPO products, phospholipase in 111 patients; vitamins A
      and E in 136 patients, vitamins B2, B6 and PP in 146 patients in the course of
      the disease, at admission and after treatment. In acute purulent and aggravated
      chronic calculous pyelonephritis lysophospholipids levels rose manifolds.
      Activation of LPO products, phospholipase, organ-specific enzymes is closely
      associated with low provision of vitamins A, E, B2, B6, PP. Deficiency of these
      vitamins ranged from 76.8 to 94.6% in acute purulent calculous pyelonephritis in
      all the patients.

PMID- 12621966
TI  - [Use of pyelo-cystic anastomosis in ureteral obliteration after kidney
      transplantation].
AB  - Reconstruction of the urinary tract because of ureteral stricture after kidney
      transplantation is a serious problem. In development of obliteration of the
      recipient's ureter near anastomosis and in the absence of own ureters
      reconstruction is made by pyelocystoanastomosis. A case is reported of a
      successful use of this method in reconstruction of the urinary tract.
      Preoperative preparation includes transcutaneous nephrostomy. Sometimes Boary
      flap is used. The arising reflux had insignificant effect on the transplant's
      function.

PMID- 12621967
TI  - [Long-term use of ovestin by postmenopausal women with urinary incontinence].
AB  - The aim of the study was to improve diagnosis and treatment of women suffering
      from clinical manifestations of urogenital atrophy in menopause: stress and
      urgent urine incontinence, disturbances of urination, recurrent infections of the
      lower urinary tracts. A total of 237 menopausal women were treated for urogenital
      atrophy for four years. The age of the patients ranged from 51 to 78 years (mean
      age 64.5 years). after treatment with ovestin they were followed up for 1 to 2.1
      years. It was found that stress incontinence is more common in young women, older
      females suffer more frequently from urgent and imperative incontinence. Ovestin,
      as a local replacement therapy, relieved symptoms within the first several days
      of treatment, the complaints disappeared completely after 25 days of ovestin
      intake. Side effects (nausea, head ache, breast discomfort) occurred rarely, were
      mild and disappeared within the first two weeks of the treatment. The conclusion
      is made that urogenital atrophy is a common disease of postmenopausal women
      arising as a result of lacking estrogenization of the vagina and adjacent
      tissues. Urogenital atrophy manifests as stress and urgent urinary incontinence,
      disurea and recurrent infection of the lower urinary tracts. Ovestin therapy
      should be given for at least 1.5 months. In positive effect the duration of the
      treatment is not limited.

PMID- 12621968
TI  - [Treatment of stable dysuria in women].
AB  - The authors analyse treatment results for 88 women suffering from stable dysuria
      (SD). 44 of them with diagnosis "proliferative cystitis" underwent TUR of the
      bladder mucosa. The rest were treated conventionally. Biopsy of the bladder was
      made in all the patients. It is shown that mechanisms of SD development lies in
      that developing metaplasia of the squamous epithelium prevents close contacts
      between the surface cells leading to urine penetration into the submucous layer.
      This provokes frequent and painful micturition. The area of the bladder triangle
      contains vaginal epithelium (embryological) which changes according to the
      menstrual phases. Dysuria is more pronounced in the premenstrual period, i.e. in
      the period of marked desquamation of the squamous epithelial. Desquamation of the
      surface layer of metaplastic squamous epithelium cells and its thinning ease
      urine diffusion via intercellular space to the nerves and muscles of the bladder
      detrusor, thus deteriorating clinical symptoms. Thus, pain in full bladder
      results from functional failure of metaplastic multilayer squamous epithelium. To
      eradicate SD in such a situation, TUR of the bladder is recommended.

PMID- 12621969
TI  - [Dehydroepiandrosterone and sexual function in men with chronic prostatitis].
AB  - The aim of this study was to determine relationships between the level of DHEA
      sulfate (DHEA-S), an erectile function and libido in men with chronic
      prostatitis. 53 patients (mean age 44.6 +/- 12.0; range 21-68 years) with chronic
      prostatitis were studied. Libido and erection were estimated and patients were
      divided into two groups according to their sexual dysfunction: 21 patients with
      severe sexual dysfunction (SSD) and 32 patients with mild sexual dysfunction
      (MSD). Testosterone, prolactin and DHEA-S were detected by ELISA. SSD patients
      had a lower testosterone level than patients with MSD (11.8 +/- 4.6 vs 14.8 +/-
      5.9 nmol/l, respectively, p = 0.04) and DHEA-S (1.7 +/- 0.8 vs 2.5 +/- 1.2
      microg/ml, respectively, p = 0.01). There was a negative correlation between the
      age of the patients and an erectile function (r = -0.70; p < 0.001), age and
      libido (r = -0.57; p < 0.001). The negative correlation was revealed between DHEA
      S and age (r = -0.59; p < 0.001). A positive correlation was between DHEA-S and
      an erectile function (r = 0.45, p = 0.001). There was no correlation between DHEA
      S and serum testosterone level (r = 0.10; p = 0.5). Multiple regression analysis
      showed an independent positive correlation between DHEA-S and erectile function
      in patients with chronic prostatitis (beta = 0.28; p = 0.02; R2 = 0.40). The
      findings show that erectile dysfunction independently from age is associated with
      a lower level of serum DHEA-S in patients with chronic prostatitis.

PMID- 12621970
TI  - [Sex correction in testicular feminization syndrome].
AB  - From 1993 to 2000 the authors observed 10 patients with testicular feminization.
      In spite of existent highly informative methods, early diagnosis of the genesis
      of abnormal sexual differentiation is not easy, it requires time. Treatment
      policy varied with the form of testicular feminization. In a complete form (6
      patients), bilateral ventrofixation of the gonads (ovotestis) was made, in
      incomplete form (4 patients) male gonads were removed with subsequent replacement
      hormonotherapy. Correction of the external genitalia consisted in amputation of
      the hypertrophic clitoris with creation of the female-type external genitalia. It
      is emphasized that in incomplete testicular feminization surgical correction
      should be started before the appearance of secondary sexual characters to raise
      effectiveness of hormone treatment in formation of a female genotype.

PMID- 12621971
TI  - [Urogenital chlamydia infection: treatment with wilprafen].
AB  - Antibiotic wilprafen (josamycin) was given in a dose 500 mg per os two times a
      day for 15 days to 30 male patients with a long history of chronic Chlamydia
      trachomatis infection (CTI) treated ineffectively. The control examination has
      not detected Chlamydia in 29 (96.5%) patients. The results demonstrate high
      efficacy of the drug wilprafen in the treatment of patients with urogenital CTI.

PMID- 12621972
TI  - [An increase in the active oxygen forms as a cause of metabolic disorders in
      renal tubular cells in patients with acute and chronic pyelonephritis].

PMID- 12621973
TI  - [Memorable and anniversary dates in the history of urology in 2003].

PMID- 12621974
TI  - [Three toddlers with a swelling in the neck].
AB  - Three children, a girl aged 2.5 years and two boys aged 2 and 3 years
      respectively, presented with unilateral cervical lymphadenitis. The first patient
      had acute bacterial lymphadenitis due to group A Streptococcus, characterised by
      a painful cervical swelling of acute onset. The second patient had painless
      cervical lymphadenitis caused by Mycobacterium avium-intracellulare, which
      drained spontaneously. The third patient developed a non-tender, cervical
      swelling within a day. He too was systemically ill with fever and a headache. The
      lymphadenitis was caused by Bartonella henselae. After drainage, dissection
      and/or antibiotic therapy, all three recovered. A cervical mass in a young child
      is most frequently caused by an infectious lymphadenopathy. It rarely represents
      a malignant or other systemic disease. In many cases the diagnosis of infectious
      lymphadenitis can be made on the basis of the case history and clinical
      characteristics. However, when malignancy cannot be excluded tissue examination
      is always indicated.

PMID- 12621975
TI  - [The contribution of clinical research to improved patient care].
AB  - In a simplistic view, clinicians eagerly await the publication of new research
      results which they can incorporate into their patient care. However, the transfer
      of research findings into patient care is complex and it is not always possible
      to detect the effects of individual studies in improved diagnostic and
      therapeutic routines. Consequently, the relevance of clinical research is
      undervalued. There are several examples from across the field of medicine and
      surgery, which illustrate the importance of clinical studies for the quality of
      patient care. Clinical research must be closely related to clinical care to
      ensure that the research aims formulated reflect clinical dilemmas within the
      setting of patient care. Yet, it is even more important to understand the impact
      which the participation of physicians and their patients in studies has on the
      quality of care provided. The standardisation of diagnostic and therapeutic
      procedures in the preparation of clinical studies may yield an effect on the
      health status of patients; this might be more substantial than the effect of the
      actual intervention studied. Clinicians and researchers should acknowledge the
      importance of medical science for the quality of patient care.

PMID- 12621976
TI  - [Quality assessment of medical-scientific research: in the future it should also
      be assessed on the basis of social impact].
AB  - Clinical research is the basis for the improvement of clinical care, yet
      assessments of the quality of research output in terms of the consequences for
      patient care are seldom acknowledged. However, contributions to guidelines,
      educational programmes and other products for clinicians indicate the clinical
      relevance of research and researchers. A recent report from the Royal Netherlands
      Academy of Arts and Science (Dutch acronym: KNAW) proposes a method to measure
      these aspects in addition to the scientific value of the output from research
      programmes. The transfer of research findings into clinical practice requires an
      implementation process. Measurements of the societal impact of research may lead
      to a better understanding of this process.

PMID- 12621977
TI  - [Inherited metabolic diseases and pregnancy: consequences for mother and child].
AB  - The prevalence of individual hereditary metabolic diseases is low, but together
      they constitute an important group in which pregnancy is of growing interest
      because patients more often reach adulthood and consider progeny. Hereditary
      metabolic diseases of the woman, such as hyperhomocystinemia or urea cycle
      defect, can present during or directly after pregnancy for the first time with
      thrombosis or coma, respectively. Other hereditary metabolic diseases of the
      woman, such as glycogen storage disease type I or III, can progress during
      pregnancy and may result in renal insufficiency or cardiomyopathy. Maternal
      hereditary metabolic diseases, such as poorly controlled hyperhomocystinemia or
      phenylketonuria, can deleteriously affect the foetus. Hereditary metabolic
      diseases of the foetus may have implications for the foetus itself, e.g.,
      lysosomal storage diseases of the foetus may cause hydrops foetalis,
      cardiomyopathy, or foetal demise. In addition, hereditary defects of long chain
      fatty acid oxidation of the foetus may result in severe haemolysis and elevated
      liver enzymes and low platelets, or acute fatty liver of pregnancy in the mother.

PMID- 12621978
TI  - [Salt sensitivity and hypertension].
AB  - For many years there has been ongoing controversy concerning the presumed
      relationship between salt intake and population blood pressure. In addition, in
      light of the availability of many efficient antihypertensive drugs and the
      frequent difficulty to motivate patients to maintain prolonged salt restriction,
      clinicians often doubt the importance of salt restriction in the individual
      treatment of hypertension. Accumulating data now underline the importance of a
      restriction of salt intake on a population level. This is expressed in a recent
      advice of the Dutch Health Council (Gezondheidsraad) and governmental
      intervention in some other countries. However, it is not the level of salt intake
      but salt sensitivity of blood pressure which predicts the effect of salt
      restriction in the individual treatment of essential hypertension. It should be
      noted that salt restriction or depletion will increase the sensitivity to other
      antihypertensive drugs in each form of hypertension. Recent data suggest that
      salt sensitivity per se should be viewed as an independent risk factor for
      cardiovascular morbidity and mortality. Therefore, identification and aggressive
      treatment of salt-sensitive hypertension, including salt restriction, is
      indicated. Demographic and racial characteristics as well as additional
      laboratory investigation may help identifying potential 'salt-sensitive'
      subjects, who form part of a high-risk population.

PMID- 12621980
TI  - [Diagnostic image (125). A man with Bechterew's disease and dysfunctional
      defecation, micturition and erection. Cauda equina syndrome].
AB  - A 62-year-old man suffering from long-standing ankylosing spondylitis had a 5
      year history of progressive difficulty of defecation, micturition and erection,
      due to complication by a cauda equina syndrome.

PMID- 12621979
TI  - [From gene to disease; SLC3A1, SLC7A9 and cystinuria].
AB  - In total, 1-2% of adults and 6-8% of children suffering from kidney stones have
      cystinuria, a defect in the transport of amino acids, which leads to high
      concentrations of cystine in the urine. Two genes have been implicated, solute
      carrier family 3 (cystine, basic and) neutral amino acid transporter, member 1
      (SLC3A1) coding for the protein related to the system bo,+ amino-acid
      transporter, and solute carrier family 7, member 9 (SLC7A9), coding for the
      protein bo,+AT. There are three clinically defined types of cystinuria. Type I
      (autosomal recessive) is characterised by mutations in the SLC3A1 gene; carriers
      have normal cystine levels in urine. In total 80% of non-type-I patients have a
      detectable mutation in the SLC7A9 gene. First-degree relatives of a patient with
      type 2 (dominant) or type 3 (incomplete recessive) cystinuria may have slightly
      elevated cystine levels in the urine. The early recognition and treatment of
      cystinuria is important because recurrent stone formation may lead to urinary
      tract infection and, eventually, renal failure.

PMID- 12621981
TI  - [Arthralgia and rash from Australia caused by Ross river virus].
AB  - A 58-year-old entomologist presented with disabling arthralgia after a recent
      visit to the Northern Territory of Australia. A faint maculopapular rash was
      noticed on the trunk and limbs. The presumptive diagnosis of RRV disease was
      confirmed by the finding of IgM and IgG antibodies against RRV in serum. RRV, a
      mosquito-transmitted alpha virus, is the most common cause of arboviral disease
      in Australia. This disease, initially referred to as epidemic polyarthritis, is
      characterised by joint pain, rash and constitutional manifestations. The
      reservoir of RRV are marsupials, other mammals and birds, but mosquitoes may also
      transmit the disease between humans. The diagnosis is mainly based on RRV
      specific serology. In case of arthritis viral RNA sometimes can be detected in
      synovium biopsies by PCR. No specific therapy is available; the prognosis is
      favourable. Prevention is based on protection against mosquito bites by wearing
      clothes to protect the skin, and by using insect repellents.

PMID- 12621982
TI  - [A child with peculiar movements: Sydenham chorea].
AB  - An 11-year-old girl with Sydenham chorea presented with a rapid onset of serious
      restlessness of mainly the right side of the body. Additional laboratory
      investigations revealed no abnormalities, yet this is not unusual for such cases.
      Valproic acid and pimozide were then successively prescribed because of the
      chorea. For secondary prevention she received long-term oral penicillin. Sydenham
      chorea is a manifestation of rheumatic fever and occurs after a throat infection
      by group A streptococci. The disease is characteristic and consists of a
      combination of choreic movements, hypotonia and emotional lability. The clinical
      course is diverse. Improvement usually occurs over a period of several months,
      although a significant proportion of patients exhibit little recovery.

PMID- 12621983
TI  - [Anticoagulant treatment of patients with atrial fibrillations: dependent on age
      and other risk factors for thromboembolism].

PMID- 12621984
TI  - ['Necessity' determined on the basis of disease severity when prioritising health
      care interventions].

PMID- 12621985
TI  - [Pulmonary thromboendarterectomy: an effective surgical treatment for cor
      pulmonale due to chronic pulmonary emboli].

PMID- 12621986
TI  - [The disc prosthesis: myths and facts].

PMID- 12621987
TI  - Vascular stents in congenital heart disease.

PMID- 12621988
TI  - Transcatheter closure of atrial septal defects.

PMID- 12621989
TI  - Balloon dilatation of the aortic valve.

PMID- 12621990
TI  - Balloon dilatation of coarctation and recoarctation.

PMID- 12621991
TI  - Percutaneous closure of a patent arterial duct.

PMID- 12621992
TI  - Very late embolization of a ductal occlusion device.

PMID- 12621993
TI  - Balloon pulmonary valvuloplasty.

PMID- 12621994
TI  - Pulmonary valve perforation.

PMID- 12621995
TI  - Therapeutic embolization in congenital heart disease.

PMID- 12621996
TI  - [Lasers in dentistry. 9. Safety in laser use].
AB  - The laser has become an effective new tool in dentistry. Besides the positive
      effects for which it is applied, the laser is also capable of causing damage to
      the patient, the user and the bystanders. In this paper the different types of
      laser-specific hazards are explained. The concept of the nominal hazard distance
      is introduced and used to analyse the practical risks and suggest safety measures
      to be taken.

PMID- 12621997
TI  - [Lasers in dentistry. Epilogue].
AB  - Laser use in the dental clinic requires scientifically demonstrated improvement
      for patient and/or dentist, easily obtainable equipment, adequate training and
      safety. These aspects are summarized for all laser applications. Improvement has
      not been shown for all applications. In the Netherlands manufacturer-independent
      training is little available. Safety requires care, but not a large investment.
      Economical aspects include an adequate compensation for the necessary investment.
      For only a few applications laser treatment leads to decreased cost or time of
      treatment. However, also increased compensation by insurers or patients may be
      possible; some patients will be willing to pay more when laser treatment is less
      unpleasant than traditional treatment or, in the case of diagnosis, leads to
      better information.

PMID- 12621998
TI  - [Simulation of pigmented mucosa in complete dentures: development of an oral
      pigment index].
AB  - In the non-Caucasian population the skin and oral tissues show pigmentation to a
      variable degree, but much more than in Caucasian. When a person becomes
      edentulous, the tissues containing oral pigmentation disappear. The patient's
      ethnic background gives no information to predict the characteristics of
      individual oral pigmentation; other sources have to be found. The mucosal
      pigmentation of 106 non-Caucasian, dentate people in Amsterdam and Los Angeles
      was investigated; a classification-chart of oral pigmentation with six types was
      designed. This tool makes it possible to help patient, dentist and dental
      technician to choose an accurate simulation of the contour of oral pigmentation
      in a denture. It is recommended to document the individual pigmentation before
      extractions are performed.

PMID- 12621999
TI  - [Oral surgery in hemophilia patients].
AB  - Oral surgery in hemophilia patients requires special arrangements in close
      collaboration with a hemotologist. Minor oral surgeries in not complicated cases
      can be done by a dentist or an oral surgeon with aid and assistance of a
      hemotologist. All major oral surgeries in hemophilia patients with antibodies
      counteracting coagulation agents should occur in a hemophilia treatment centre.

PMID- 12622000
TI  - [Ankylosis after frontal trauma].

PMID- 12622001
TI  - [Smallpox].

PMID- 12622002
TI  - [Hemifacial spasms caused by neurovascular compression].
AB  - Three patients, one woman aged 52 years and two men aged 63 and 71 years,
      respectively, had involuntary movement on one side of their face due to
      hemifacial spasms. The first patient's spasms were misdiagnosed as a tic, the
      second patient had received injections of botulinum A toxin which gave no
      improvement and the third patient suffered from persistent symptoms after a first
      neurovascular decompression without intraoperative EMG monitoring. All three
      patients underwent microvascular decompression of the facial nerve with
      intraoperative EMG monitoring. All three patients were cured. Hemifacial spasm is
      a curable illness if appropriately diagnosed and treated. Oral medications have
      no effect on the disease. Local injection of botulinum A toxin is indicated when
      the spasm is mild or when surgery is contraindicated. The primary causative
      factor is vascular compression of the facial nerve at its exit zone. Therefore,
      decompressive surgery is the logical treatment, and the best results are obtained
      with intraoperative EMG monitoring.

PMID- 12622003
TI  - [Diagnostic significance of human papillomavirus overestimated].
AB  - Human papillomavirus (HPV) is a group of oncogenic viruses, of which some are
      known to cause cervical cancer in women. The causal relation between infection
      and cervical cancer is well established. There is however a discrepancy between
      the rate of infection and the incidence of (pre)neoplastic lesions of the cervix.
      Cohort studies of the natural history of this virus show that many, if not most,
      young females become infected, but that the infection usually clears without any
      consequences. This high infection rate precludes the use of HPV diagnosis for
      primary screening for cervical cancer. The low specificity precludes its use for
      triage of borderline cervical lesions. Critical appraisal of different diagnostic
      approaches using a direct or indirect molecular detection method of HPV does not
      show a convincing advantage over 'conservative' diagnostic cytological regiments.
      Perhaps the absence of the virus is more significant than its presence.

PMID- 12622004
TI  - [Nutrition and health--obesity].
AB  - About 12% of the adult Dutch population is obese (Quetelet Index > or = 30
      kg/m2). The prevalence has roughly doubled over the past 20 years. Obesity is
      strongly associated with a number of chronic diseases, such as type 2 diabetes
      mellitus, increased healthcare costs and a loss of productivity. Obesity is
      always the result of a mismatch between energy intake and energy expenditure.
      Foods with a high percentage of energy derived from fat are associated with
      weight gain, particularly when the rest of the energy is obtained from products
      containing little dietary fibre. Foods with a high content of refined added
      sugars or starch might be unfavourable with respect to the energy balance and the
      risk for type 2 diabetes mellitus and cardiovascular diseases. Slimming diets
      should aim for a gradual and sustained weight loss of about 10% of the initial
      weight over a period of six months, followed by weight maintenance over the next
      two years. Physical activity is an essential component of a weight loss strategy.
      Moderate sustained weight loss is associated with a strong reduction in the risk
      of type 2 diabetes mellitus in people with impaired glucose tolerance.

PMID- 12622005
TI  - [Dislocation of total hip prostheses; risk factors and treatment].
AB  - Primary hip prostheses dislocate in 0.4 to 8.7% of the cases. Revision hip
      prostheses dislocate in 5 to 20% of the cases. High age, female sex, co-morbidity
      and alcoholism increase the risk of dislocation. The surgical approach of the hip
      and the experience of the surgeon are important factors in the operation
      technique. The anterior approach causes the least dislocations, but a
      disadvantage of this approach is that patients are more likely to walk with a
      limp afterwards. The selected implant also influences the dislocation risk. The
      smaller the head, the narrower the neck must be. Furthermore, the femur must not
      come to be too close to the pelvis. If necessary, a cup can be used with a raised
      anterior edge. Treatment of a primary dislocation is usually conservative and is
      based on providing the patient with guidelines. An abduction brace can be
      prescribed if a patient is not able or willing to comply with these rules. If
      dislocation is a recurring problem, revision of the prosthesis is often the only
      solution.

PMID- 12622006
TI  - [Three newly registered drugs in the Netherlands for the treatment and
      chemoprophylaxis of malaria: atovaquone-proguanil, artemether-lumefantrine and
      artemotil].
AB  - Three new antimalarial drugs have recently been registered in the Netherlands:
      atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are
      effective against parasites with multiple resistance. Atovaquone-proguanil and
      artemether-lumefantrine seem in practice to be equivalent for the treatment of
      non-severe Plasmodium falciparum infections for respectively persons of more than
      11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular
      injection) is registered for the treatment of severe malaria in children up to 17
      years of age. Atovaquone-proguanil is also registered for prophylactic use in
      adults. The intravenous administration of quinine is preferable in the case of
      seriously ill patients. In patients with non-severe malaria for whom parenteral
      treatment is indicated, artemotil is a good alternative for quinine.

PMID- 12622007
TI  - [Diagnostic image (126). A man with progressive icterus and an abdominal
      swelling. Pseudoaneurysm of the A. gastroduodenalis as complication of chronic
      pancreatitis].
AB  - A 39-year-old man presented with jaundice and an abdominal mass. Ultrasound and
      CT showed an A. gastroduodenalis pseudoaneurysm complicating chronic
      pancreatitis.

PMID- 12622008
TI  - [Wait-and-see policy versus loop excision after two consecutive Pap-2 cervical
      smears: over time less surgery and an equivalent outcome; no substantial
      contribution to be expected from the detection of high risk human
      papillomavirus].
AB  - OBJECTIVE: To determine the number interventions and outcomes in patients
      referred with two consecutive Pap 2 cervical smear results who were managed
      either by a wait-and-see policy or aggressively, and to determine whether triage
      with high-risk human papillomavirus (hr-HPV) detection, resulting in the referral
      of only hr-HPV positive patients, would lead to the detection of all patients
      with cervical intraepithelial neoplasia (CIN). DESIGN: Retrospective comparison
      and retrospective cohort study. METHOD: 282 patients referred in 1997/'99 with 2
      consecutive Pap 2 cervical smears in the screening program were included.
      Patients referred to the UMC St Radboud Hospital (n = 140; mean age: 45 years)
      underwent a colposcopy during which only lesions suggestive for CIN 3 were
      treated. All other colposcopic lesions (CIN 2 or less) were not treated but
      followed prospectively. Patients referred to the Canisius Wilhelmina Hospital
      (CWZ) (n = 142; mean age: 44 years) underwent colposcopy during which all
      colposcopic lesions (including CIN 2 or less) were treated directly. The two
      groups were compared in terms of the final cytological follow-up, the number of
      loop excisions, and the number of patients with CIN. The mean follow up was 40
      months. In the first group, the effect of triage using hr-HPV detection was also
      investigated retrospectively. RESULTS: With the wait-and-see approach,
      statistically significantly fewer diathermic loop excisions were done: 13 versus
      124. After the follow-up period there was no statistically significant difference
      between the two groups in terms of the number of patients with persisting Pap 2:
      16 (11%) versus 12 (8%). Triage with hr-HPV detection would identify all patients
      with CIN 3, 50% of the patients with CIN 2, and none of the patients with CIN 1;
      of the 48 hr-HPV-positive women, 1 had a CIN 3 lesion and 3 had a CIN 2 lesion;
      of the remaining 92 women, 2 had a CIN 1 lesion and 3 had a CIN 2 lesion.
      CONCLUSION: The wait-and-see approach led to fewer interventions, while the
      number of women with persisting Pap 2 smears was not higher than with the
      aggressive approach. Triage with hr-HPV may reduce the number of referrals and
      colposcopies, but follow-up remains necessary in all women regardless of hr-HPV
      status.

PMID- 12622009
TI  - [Acute renal failure following treatment with intravenously administered
      immunoglobulins].
AB  - A 74-year-old woman with insulin-dependent diabetes mellitus type 2 developed
      severe, reversible renal failure due probably to the administration of high doses
      of intravenous immunoglobulins (IVIG) for Guillain-Barre syndrome. The
      preparation administered did not contain sucrose or mannitol as adjuvants. The
      risk factors for the development of acute renal failure include pre-existent
      diabetes mellitus, reduced renal function and advanced age. In approximately 150
      case reports in the literature, acute renal failure developed mainly after the
      use of sucrose-containing IVIG preparations. The course of both the onset of and
      the recovery from the renal failure and the histopathological findings in the
      described patient were in accordance with these findings. Since other causes were
      unlikely and in view of the supportive finding of elevated colloid osmotic
      pressure, it was concluded that the renal failure in this case was probably
      mediated by the oncotic effect of the macromolecular immunoglobulin itself.

PMID- 12622010
TI  - [Schizophrenia and the 22q11 deletion syndrome].

PMID- 12622011
TI  - [Continuous subcutaneous infusion in palliative care, an undervalued method].

PMID- 12622012
TI  - [Continuous subcutaneous infusion in palliative care, an undervalued method].

PMID- 12622013
TI  - [Psychosis following treatment with topiramate].

PMID- 12622014
TI  - [Diagnostic image (108). A boy with malaise and pain above one eye].

PMID- 12622015
TI  - Interpretation of dental and maxillofacial radiographs: a comparative study using
      an X-ray viewing box and window.
AB  - AIM: To ascertain if interpretation of radiographs by holding them up to a window
      rather than using a light viewing box has led to underdetection of clinically
      significant radiographic abnormalities. MATERIALS AND METHODS: Twenty members of
      staff were selected randomly. They were divided into two group i.e., ten house
      offers (Group 1), five specialist registrars and five demonstrators (Group 2).
      They interpreted 10 radiographs by first holding them up against a window, and
      then by using a light viewing box. A score out of 10 was obtained at each time
      (one for each film). RESULTS: A mean score of 6.6 (6 per cent) was obtained for
      Group 1 and a mean score of 8 (80 per cent) was obtained for Group 2 when
      radiographs were interpreted using a window. The mean score for both groups was
      10 when a light viewing box was used. CONCLUSION: Important radiographic
      abnormalities went undetected when the light box was not used. Awareness should
      be raised among hospital staff with regard to the importance of using light
      viewing boxes for the interpretation of radiographs.

PMID- 12622016
TI  - Surgical management of pleomorphic adenoma of the palate.
AB  - OBJECTIVES: The purpose of this article is to present an intraoral technique,
      which allows a wide local excision of pleomorphic adenoma of the palate with
      adequate mucosal and periosteal margins. STUDY DESIGN: Between September 1992 and
      May 1994 ten patients with pleomorphic adenoma of the palate were treated by one
      surgeon at the Oral and Maxillofacial Surgery Unit of the Jordan University of
      Science and Technology. A surgical technique, which was particularly useful for
      tumours extending into the soft palate, is described. RESULTS: Nine patients were
      aged between 15 and 25 years (mean age 20.1 years) and one patient was aged 50
      years. Six of the patients were males. The tumour was removed from all ten
      patients by wide local excision with adequate margins, and after a follow-up
      period from 5 to 7 years (mean 6.3 years) there were no recurrences. CONCLUSION:
      This study has shown that wide local excision used for the treatment of
      pleomorphic adenoma of the palate is to be recommended. A close follow-up is
      necessary postoperatively.

PMID- 12622017
TI  - Control of denture plaque and mucosal inflammation in denture wearers.
AB  - The aims of this study were to collect data about the popular methods and
      materials used for cleaning dentures among complete and partial denture wearers
      in Jordan and to discuss the relationship between denture base plaque and mucosal
      inflammation under dentures. A questionnaire consisting of six questions
      regarding denture hygiene practices and cleaning products was completed by 321
      patients who attended two prosthodontic clinics for replacement or adjustment of
      their dentures. Following careful oral examination and examination of dentures,
      the relationship between denture hygiene and inflammation under the denture base
      was investigated. In this study there were 615 dentures and 321 patients. The
      mean age of patients was 65 years and it ranged from 18 to 100 years (s.d. =
      10.1). The mean age of their dentures was 7.3 years (s.d. = 5.6) ranging from one
      to 27 years. The most popular method of cleaning dentures was brushing. Ninety
      four (29 per cent) of the denture wearers had denture stomatitis. There was a
      statistically significant relationship between poor denture hygiene and denture
      stomatitis (P = 0.0001). There was also a significant relationship between
      continuous wearing of the dentures, day and night, and denture stomatitis (P <
      0.0001). The presence of bacterial and yeast plaque on the fitting surface of the
      denture base appeared to be of critical importance for development and
      maintenance of denture stomatitis. It is necessary, therefore, that dentists
      should give instructions to denture wearers on how to clean their denture
      surfaces properly so as to maintain good hygiene and prevent denture stomatitis.

PMID- 12622018
TI  - Infant with high arched palate, bell-shaped chest, joint contractures, and
      intrauterine fractures.
AB  - A case is presented of a female newborn infant delivered with an Apgar Score of
      1, who could not be resuscitated. There was a high arched palate, bell-shaped
      chest, contractures of writes inflexion, ankles and knees in extension, and
      intrauterine fractures. Clinical discussion led to a diagnosis of arthrogryposis
      secondary to fetal akinesia syndrome caused by nemaline myopathy. Pathology and
      pathologic discussion confirmed this diagnosis.

PMID- 12622019
TI  - FMEA (failure mode analysis): a new QI tool to help improve case management
      processes.

PMID- 12622020
TI  - CMs, social workers collaborate for better care.

PMID- 12622021
TI  - Team care management = lower lengths of stay.

PMID- 12622022
TI  - Ventilator education program reduces VAP (ventilator-associated pneumonia).

PMID- 12622023
TI  - Computer technology improves operations.

PMID- 12622024
TI  - How will you measure up to new CARF standards?

PMID- 12622025
TI  - Wait of expectation.

PMID- 12622026
TI  - Back to the drawing board.

PMID- 12622027
TI  - Retirement. Into extra time.

PMID- 12622028
TI  - First person. Good of small things.

PMID- 12622029
TI  - Capacity planning. Figures you can count on.

PMID- 12622030
TI  - Integrated care. The skin trade.

PMID- 12622032
TI  - [Computed tomography in the diagnosis of periodontal changes].
AB  - The paper shows how volumetric reconstruction of jaw images can be used and
      analyzes the plots of planar characteristics of cortical plates in different
      forms of periodontitis. Clinical and X-ray parallels in this disease are
      discussed.

PMID- 12622031
TI  - [Proton magnetic resonance spectroscopy in diagnostics of epilepsy].
AB  - Present paper presents proton MRS investigation results. The investigation was
      carried out with Magnetom Vision device. Twenty-five patients in the age of 20-44
      years suffering with generalization epileptic fits validated by EEG (no visible
      changes on MRT) were examined. In all cases independently on the localization of
      the changes, decreasing of NAA and increasing of Cho were recorded. At one side
      temporal lobe injury recorded by EEG at the damaged part decreasing of NAA/Cr and
      NAA/Cho + Cr ratios were registered. Patients with bilateral changes registered
      by EEG showed non-equal changes of metabolite concentration on both sides.
      Examination of patients suffering with distinct symptoms of temple epileptics has
      shown ipsilaterality decrease of NAA and Cr concentration. But on the injured
      side NAA/Cr ratio decrease was more distinct. In general, the laterality was
      recorded in 14 patients out of 22 with pathological changes registered by proton
      MRS and in 10 patients out of 14 the above mentioned changes corresponds to the
      side of the fit initiation. In the patients with bilaterality changes NAA/Cr
      ratio asymmetry was recorded in all cases, but the most distinctly in the medium
      part of the temple lobe. Comparison of data recorded in 8 patients suffering with
      one side fit complex has shown significant asymmetry of metabolites which was
      observed in ipsilaterality and contra laterality NAA ratio obtained in
      hippocampal areas. Difference in NAA ratio obtained between left and right sides
      are 19-25%. Left-right ratio of other metabolites corresponded to that ratio in
      the control group and was symmetrical.

PMID- 12622033
TI  - [Immediate and long-term outcomes of coronary stenting in relation to stent
      implantation pressure in patients with coronary heart disease].
AB  - The paper evaluates the pressure impact of implantation of intracoronary stents
      of different designs on the immediate and long-term outcomes of stenting. A
      retrospective study included 192 patients. Matrix and wire stents were implanted
      in 97 (50.5%) and 95 (49.5%) patients, respectively. In one part of the patients,
      the coronary stent was implanted under nominal pressure, in the other, the stent
      after implantation was extended with a balloon by using high pressure. Good
      immediate angiographic and clinical results were obtained in all 192 patients.
      Thirty three (17.2%) patients were found to have coronary spasm at the site of a
      stent. There was no significant difference in the development of coronary spasm,
      which was associated with the type of an implanted (matrix or wire) stent and
      with the pattern of its implantation (under high or nominal pressure). Dissection
      along the stent edges developed in 17 of the 192 patients, which amounted to
      8.8%. It significantly more frequently developed in patients from Subgroup IA
      than in those from Subgroup IB. There was no significant difference in the
      development of restenosis in patients after implantation of matrix or wire stents
      and in the relation to the stent implantation pressure.

PMID- 12622034
TI  - [Radiation diagnosis of venous angiodysplasias].
AB  - The paper proposes an original procedure for diagnosing venous dysplasias of
      different sites. The procedure is based on the analysis of the capacities of
      currently used invasive and noninvasive techniques of radiation visualization.
      The practical aspects of conduct of routine studies, their potentialities and
      shortcomings are outlined. The principle of the proposed procedure is a result of
      a complex use of the capacities of ultrasound visualization and interventional X
      ray contrast studies of the vascular system. The procedure has been successfully
      used in 8 patients. It is concluded that it is promising to examine venous
      angiodysplasias by means of direct puncture made under ultrasound guidance,
      followed by mass contrasting and angiography which may be supplemented by
      sclerosing therapy.

PMID- 12622035
TI  - [MRI as a diagnostic technique in examination of the shoulder joint].
AB  - The paper presents the results of examination of 95 patients with shoulder joint
      abnormality to define the capacities of MR imaging in the evaluation of the
      anatomic structures of this joint. It details the MR anatomic features of the
      shoulder joint. Some conditions should be adhered to while performing MRI of the
      joint, namely: to obtain high-quality images by correctly choosing pulse
      sequences and scanning planes and to know the anatomic variants of the structure
      of the shoulder joint.

PMID- 12622036
TI  - [The necessity of complex use of radiation and endoscopic techniques in the
      differential diagnosis of gastric ulcerations].
AB  - The results of examination of 156 patients were used to consider whether
      radiation and endoscopic techniques might be used in the differential diagnosis
      of gastric ulcerations. The necessity of their complex use is shown. Evidence is
      provided for that the understanding of intramural changes at the site of
      ulceration should underlie the interpretation of visual changes in the gastric
      mucosa. An algorithm has been developed for the rational and effective use of
      radiation and endoscopic techniques in the differential diagnosis of gastric
      ulcerations. The algorithm is shown to be highly effective in the correct
      interpretation of the pattern of an identified ulceration (98.4% specificity).
      Ultrasound and computed tomographic semiotics of benign and malignant gastric
      ulcerations is presented.

PMID- 12622037
TI  - [Ultrasound study in the diagnosis of small and large intestinal obstruction].
AB  - The results of ultrasound study were analyzed in 148 and 26 patients with acute
      small and intestinal obstruction, respectively, the causes of the latter included
      different diseases of the intestine and abdominal organs. The commonest
      ultrasound symptoms based on the diameter of the bowel, on the thickness and
      structure of the intestinal wall, on the status of mucosal motility folds of
      intestinal loops and on the pattern of motility were defined. They enable one to
      differentiate large and small intestinal obstruction and to define its degree
      with a high degree of validity. Abdominal ultrasonography used in the emergency
      surgical setting may rapidly solve problem in the diagnosis of abnormal changes,
      differential mechanical and functional ileus in most cases. Dynamic ultrasound
      monitoring allows the efficiency of the treatment performed to be evaluated.

PMID- 12622038
TI  - [Algorithms of diagnostic radiation methods in current urological pathology].
AB  - Based on the results of 3600 studies using all basic methods of modern radiation
      diagnosis, the authors show it necessary to develop diagnostic algorithms
      applicable to certain groups of urological diseases (urolithiasis, inflammatory
      processes and bulky masses in the kidney). This necessity has recently stemmed
      from the advent of new technologies of radiation diagnosis and from the
      expediency of using a certain method at the specific stage of examination. At the
      same time, the authors underline the importance of using standardized examination
      programmes (algorithms) in practice, which is also due to the fact that
      unreasonable use of the whole set of new radiation techniques that are of highly
      diagnostic value may bear great material costs.

PMID- 12622039
TI  - [A case of extraabdominal desmoid].

PMID- 12622040
TI  - [Computed tomography in planning reparative operations after craniocerebral and
      maxillofacial injuries].

PMID- 12622041
TI  - [Mammological service in the Russian Federation].

PMID- 12622042
TI  - Prostate cancer treatment offers growth opportunities.

PMID- 12622044
TI  - Outlook for hospital credit ratings stable in 2003, Moody's says.

PMID- 12622045
TI  - Hospitals' ED needs to be evaluated in achieving facilities' overall goals.

PMID- 12622043
TI  - Tenet Healthcare's lapse in execution.

PMID- 12622046
TI  - IOM offers five recommendations to mend ailing health care system.

PMID- 12622047
TI  - Study finds varying levels of awareness regarding hospitals, services.

PMID- 12622048
TI  - Death and hospitals: an inquiry into the body count.

PMID- 12622049
TI  - The power of community.

PMID- 12622050
TI  - Relationships among older patients, CAM practitioners, and physicians: the
      advantages of qualitative inquiry.
AB  - Older patients are increasingly likely to be under the simultaneous care of both
      physicians and alternative practitioners, often for treatment of the same
      condition. In the majority of cases, however, alternative care is not integrated
      with biomedical care; indeed, most patients do not inform their physicians of
      their concurrent use of complementary and alternative medicine (CAM). Because of
      the increased use of CAM in recent years, this is a critical juncture at which to
      study healthcare relationships in which the patient is treated by practitioners
      from different medical systems who are usually not in contact with and often not
      aware of one another. The purpose of this paper is to (a) review the limited
      literature that addresses healthcare relationships among patients, physicians,
      and alternative practitioners; (b) suggest that understanding all 3 sides of the
      patient-physician CAM practitioner triangle creates a more comprehensive and
      realistic view of current healthcare practices; and (c) propose that qualitative
      research methodologies can provide unique and essential understandings of these
      emerging healthcare relationship configurations. An ongoing qualitative research
      study of older women with breast cancer and their interactions with their
      physicians and alternative practitioners is described as an example.

PMID- 12622051
TI  - A holistic approach to health: The Scripps Center for Integrative Medicine.

PMID- 12622052
TI  - Photothermal analysis of polymeric dye laser materials excited at different pump
      rates.
AB  - The photothermal properties and heat diffusion of polymeric lasers, made up from
      solutions of Rhodamine 6G in solid matrices of poly(2-hydroxyethyl methacrylate)
      with different amounts of the cross-linking monomer ethylene glycol
      dimethacrylate and copolymers of 2-hydroxyethyl methacrylate and methyl
      methacrylate have been studied through photothermal deflection spectroscopy. The
      heat load that is due to the pumping process was quantified as a function of the
      pump excitation repetition frequency (0.25-10 Hz), determining the time-dependent
      temperature changes at different locations within the laser matrix. A theoretical
      model, which reproduces these changes with high accuracy, was developed on the
      basis of the heat-diffusion equation of optically dense fluids. The observed
      thermal effects became important for impairing the laser stability at pump
      repetition frequencies higher than 1 Hz. In addition, the irreversible optical
      changes produced in the laser matrices at high pump fluence values (>1 J/cm2)
      were also analyzed. These effects originate, most likely, from a two-step
      photothermal mechanism.

PMID- 12622053
TI  - Computed tomography wire localisation-assisted operative retrieval of a migrated
      symphysis pubis plate from the ischiorectal fossa.
AB  - We report an unusual case of migration of a metal plate from the symphysis pubis
      to the left ischiorectal fossa, and a technique of using pre-operative CT guided
      wire localisation of the plate as a successful method of assisting plate
      retrieval.

PMID- 12622054
TI  - Patient information. Safe sexual positions for hip surgery patients.

PMID- 12622055
TI  - Enhancement of medication recall using medication pictures and lists in telephone
      interviews.
AB  - PURPOSE: To determine the effect of reading medication lists and providing
      medication pictures on recall of non-aspirin non-steroidal anti-inflammatory
      drugs (NANSAIDs) during telephone interviews in a case-control study. METHODS:
      After a series of indication-specific questions, a list of all available NANSAIDs
      was read to study participants and a series of pictures was reviewed when
      available. Recall was defined as enhanced if a participant recalled NANSAID use
      only after the memory aids. RESULTS: Among the 1484 participants who reported
      NANSAID use, 94 (6.3%) recalled their NANSAID use only after the memory aids.
      Several groups demonstrated enhanced recall following the memory aids: men (odds
      ratio (OR): 1.73; 95% confidence interval (CI): 1.11, 2.69), users of non
      prescription versus prescription NANSAIDs (OR 2.28; 95% CI: 1.21, 4.30), those
      using > 2 other medications (OR 1.69; 95% CI: 1.06, 2.69), those who did not have
      all of their medication containers available during the interview (OR 1.58; 95%
      CI: 1.03, 2.42) and cases versus controls (OR 1.90; 95% CI: 1.11, 3.28).
      CONCLUSION: The reading of medication names with the availability of medication
      photographs enhanced recall by approximately 6%. The use of this type of memory
      aid may reduce recall bias in case-control studies that rely on medication
      recall, depending on the overall prevalence of medication use and the effect size
      of the drug on the outcome.

PMID- 12622056
TI  - Agreement between patient self-report and a Veterans Affairs national pharmacy
      database for identifying recent exposures to antibiotics.
AB  - PURPOSE: The dramatic rise in antibiotic drug resistance among community
      pathogens has stimulated interest in the epidemiological relationship between
      antibiotic exposure and drug resistance. In assessing the strength of this
      relationship, studies are hampered by the lack of data on the accuracy of subject
      self-report of antibiotic exposure. The authors compared self-report with
      pharmacy dispensing data to determine the accuracy of self-reported antibiotic
      exposure. METHODS: The study design was a cross-sectional survey of veterans seen
      at the Philadelphia Veterans Affairs (VA) Medical Center in 1999 and 2000.
      Subjects reported exposures to antibiotics, antihypertensive drugs and
      nonsteroidal anti-inflammatory drugs through a structured telephone interview.
      The instrument included open-ended questions, condition-specific prompts and drug
      specific prompts. Subject responses were linked to a national VA pharmacy
      database that served as the reference standard for evaluating self-reported
      exposures. RESULTS: The authors found that the sensitivity of self-report of
      antibiotic exposure increased with increasing use of prompts. A comprehensive
      assessment of antibiotic exposure identified 73% of antibiotic exposures,
      compared to 73% of antihypertensive drug exposures and 92% of nonsteroidal anti
      inflammatory drug exposures. CONCLUSIONS: Assessment of antibiotic exposure
      appears to be comparable to assessment of other chronic and episodic drugs.
      Multistep assessment of exposure improves the sensitivity of assessment.

PMID- 12622057
TI  - Calculation of dose components in head phantom for boron neutron capture therapy.
AB  - Application of neutrons to cancer treatment has been a subject of considerable
      clinical and research interest since the discovery of the neutron by Chadwick in
      1932 (3). Boron neutron capture therapy (BNCT) is a technique of radiation
      oncology which is used in treating brain cancer (glioblastoma multiform) or
      melanoma and that consists of preferentially loading a compound containing 10B
      into the tumor location, followed by the irradiation of the patient with a beam
      of neutron. Dose distribution for BNCT is mainly based on Monte Carlo
      simulations. In this work, the absorbed dose spatial distribution resultant from
      an idealized neutron beam incident upon ahead phantom is investigated using the
      Monte Carlo N-particles code, MCNP 4B. The phantom model used is based on the
      geometry of a circular cylinder on which sits an elliptical cylinder capped by
      half an ellipsoid representing the neck and head, both filled with tissue
      equivalent material. The neutron flux and the contribution of individual absorbed
      dose components, as a function of depths and of radial distance from the beam
      axis (dose profiles) in phantom model, is presented and discussed. For the
      studied beam the maximum thermal neutron flux is at a depth of 2 cm and the
      maximum gamma dose at a depth of 4 cm.

PMID- 12622058
TI  - Current awareness on yeast.

PMID- 12622059
TI  - Debate needed on disguising medication.

PMID- 12622060
TI  - Should line managers be supervisors?

PMID- 12622061
TI  - Ergonomics enquiry.

PMID- 12622062
TI  - The dentist's role.

PMID- 12622063
TI  - Student attitudes.

PMID- 12622064
TI  - Restoring deciduous teeth.

PMID- 12622065
TI  - Mandible pain.

PMID- 12622066
TI  - Caring from afar: expanding our concept of care in the profession.

PMID- 12622067
TI  - Cognitive development and minors: implications for health care providers.

PMID- 12622069
TI  - The breast and cervical cancer treatment program: accepting inequality for
      undocumented women?

PMID- 12622070
TI  - Expression of heat shock protein after +Gz exposure and its protective effects on
      +Gz-induced brain injury.
AB  - Objective. To investigate the rule of intensity and duration of HSP70 expression
      in rat brain and its relationship with brain injury after repeated +Gz exposures.
      Method. SD male rats were arranged into control group, +2 Gz, +4 Gz, +6 Gz, and
      +10 Gz exposure groups. Rat brains were taken 6 h, 10 h, 1 d, 2 d, 4 d or 6 d
      after +Gz exposure for histopathologic and immunohistochemic or in situ
      hybridization studies. The expression of HSP70 and HSP70 mRNA or morphology of
      neurons were observed. Result. The intensity and duration of HSP70 expression
      were weak and brief at +2 Gz exposure, but was relatively extensive. There was a
      middling reaction of HSP70 only in hippocampal area after +10 Gz exposure. The
      duration, extension and intensity of HSP70 expression were wide, long and strong
      after +4 Gz and +6 Gz exposures. After 1 or 3-5 times exposures, the HSP70
      expression reached its peak on the first day after +4 Gz exposures, and dropped
      obviously on the second day. However the expression of HSP70 maintained a high
      level after 2 d and was still higher than normal on the 6 d after 3-5 times
      repeated +4 Gz exposures. The distribution of HSP70 mRNA expression was as same
      as that of the HSP70 expression but the peak appeared much earlier (10 h) and its
      duration was shorter. After +10 Gz/5 min exposure, degenerated neurons were found
      in cortex, hippocampus and thalamus regions while the number of degenerated
      neurons were obviously decreased in such areas in pre-exposure groups with
      repeated +4 Gz/3 min for 3-5 times. Conclusion. The intensity and duration of
      HSP70 and HSP70 mRNA expression after +4 Gz and +6 Gz exposure were stronger and
      longer than +2 Gz and +10 Gz exposure. The degree of neuron damage after +10 Gz/5
      min exposure in pre-exposure groups with repeated +4 Gz/3 min 3-5 times was
      obviously slight comparing with that of single +10 Gz exposure group.

PMID- 12622071
TI  - The limits of law at the limits of life: lessons from cannibalism, euthanasia,
      abortion, and the court-ordered killing of one conjoined twin to save the other.

PMID- 12622072
TI  - Analysis of human two-dimension target-aiming movement.
AB  - Objective. To study the problem of human movement characteristics of target
      aiming movement. Method. The authors first analyzed the essentials of target
      aiming movement on the basis of previous research results, then designed and made
      a two-dimension experiment of target-aiming movement. Result. After theoretical
      consideration and analysis of experimental results, a new model of human two
      dimension target-aiming movement was proposed, and the coefficients are
      determined experimentally. Conclusion. The model was verified by experimental
      data. It was demonstrated that the new model has an excellent suitability, and is
      applicable for evaluations of target-aiming movements of one and two dimensions.

PMID- 12622073
TI  - [Study on anti +Gx respiratory maneuver and its training method].
AB  - Objective. To study the anti +Gx respiratory maneuver and its training method.
      Method. Seven young male subjects undertook the anti +Gx respiratory maneuver
      training. Their +Gx tolerances were examined on human centrifuge before and after
      training. The change of respiratory type, breath rate, electrocardiogram, heart
      rate, arterial oxygen saturation (SaO2), subjective symptom and vision were real
      time monitored during the +Gx tolerance examination. Result. Compared with pre
      training, the +Gx tolerance increased after training (P<0.05). Dyspnea and chest
      pain disappeared or obviously lightened and the magnitude of decrease of SaO2
      decreased significantly (P<0.05). Conclusion. The above results suggested that
      the anti +Gx respiratory maneuver can effectively eliminate or alleviate dyspnea
      and chest pain induced by +Gx stress and increase human +Gx tolerance.

PMID- 12622074
TI  - [Effects of +Gx load on energy metabolism of brain tissue in rats].
AB  - Objective. To observe the changes of energy metabolism of brain tissue in rats
      under +Gx loads, and to explore its possible role in changes of brain function
      and work efficiency induced by +Gx stress. Method. Forty-five male Wistar rats
      were randomly divided into control, +5 Gx, +10 Gx, +15 Gx and +20 Gx group. Each
      group was exposed to the corresponding G value for 3 min. After that, cortical
      adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine
      monophosphate (AMP) and lactic acid (LA) content, lactate dehydrogenase (LDH)
      activity were measured. Result. Compared with the control group, the cortical
      (LA) content increased significantly after +5 Gx, +10 Gx, +15 Gx and +20 Gx
      exposure (P<0.01). Cortical ADP content and ratio of ADP/AMP and AMP/ATP
      increased significantly after +10 Gx, +15 Gx and +20 Gx exposure (P<0.01),
      whereas ATP content, energy charge and LDH activity decreased significantly
      (P<0.05 or 0.01). Cortical AMP content increased significantly after +15 Gx and
      +20 Gx exposure (P<0.05 and 0.01). Conclusion. It is suggested that +Gx load can
      result in obvious depression of brain energy metabolism, which could be an
      important reason for the change of brain function and work efficiency induced by
      +Gx stress.

PMID- 12622075
TI  - Sensorimotor control of movement and posture. Proceedings of a conference.
      Cairns, Australia, September 3-6, 2001.

PMID- 12622076
TI  - [Effects of simulated weightlessness on pressure-volume relationships of femoral
      vein of New Zealand Rabbits].
AB  - Objective. To observe the changes of pressure-volume relationships of rabbit
      femoral veins and their structural changes caused by simulated weightlessness.
      Method. Head-Down Tilt (HDT) -20 degrees rabbit model was used to simulate
      weightlessness. Twenty four healthy male New Zealand Rabbits were randomly
      divided into 21 d HDT group,10 d HDT group and control group, (8 in each group).
      Pressure-volume (P-V) relationship of rabbits femoral veins was measured and the
      microstructure of the veins was observed. Result. The femoral vein P-V
      relationship curves of HDT groups showed a larger volume change ratio than that
      of control group. This change was that 21 d HDT group was even more obvious than
      that of HDT-10 d group. B1 and B2 in quadratic equations of 21 d HDT group were
      significantly higher than the values of both 10 d HDT group and control group
      during expansion (inflow) and collapse (outflow) (P<0.01). The result of
      histological examination showed that the contents and structure of femoral vein
      wall of HDT-rabbits changed significantly. Endothelial cells of femoral vein
      became short and columnar or cubic, some of which fell off. Smooth muscle layer
      became thinner. Conclusion. Femoral venous compliance increased after
      weightlessness-simulation and the femoral venous compliance in 21 d-HDT rabbits
      increased more obviously than that in 10 d-HDT rabbits. The structure of femoral
      vein wall had changed obviously.

PMID- 12622077
TI  - [Construction of a cDNA subtractive library of rat brain after repeated +Gz
      exposure].
AB  - Objective. To construct a cDNA subtractive library of rat brain after repeated +
      Gz exposures with suppression subtractive hybridization (SSH). Method. Wistar
      [correction of Wister] rats were randomly divided into control group and repeated
      +Gz exposure group. Using an animal centrifuge, control rats were exposed to +1
      Gz and exposure rats were exposed to +10 Gz for three times, each for 1 min with
      30 min interval in between. Brains were taken 6 h after the last centrifuge run
      and Poly (A) + RNA were isolated. Moreover, single-strand cDNAs and double-strand
      cDNAs were synthesized in turn. After Rsa I enzyme restriction, +Gz exposure rat
      brain cDNAs were divided into two groups and ligated to the specific adaptor 1
      and adaptor 2R, respectively. Then +Gz exposure rat brain cDNAs were hybridized
      with the control rat brain cDNA twice and underwent nested PCR twice. The PCR
      product was ligated with T/A plasmid vectors to set up the subtractive library.
      Result. The cDNA subtractive library of rat brain after repeated +Gz exposures
      with high subtractive efficiency was set up successfully. Conclusion. The highly
      efficient cDNA subtractive library may provide a solid foundation for screening
      and cloning differentially expressed genes in rat brain after repeated exposures
      to +Gz.

PMID- 12622078
TI  - [Effects of head down tilt on intra-ocular pressure, near vision, and visual
      field and the protection effect of Chinese herbs].
AB  - Objective. To observe the influences of 21 d head down tilt (HDT) bed rest on the
      intra-ocular pressure, visual field and near vision in human and to study the
      countermeasure of Chinese herb against weightlessness. Method. Ten subjects were
      randomly divided into control group and Chinese herb group. -6 degrees HDT was
      used to simulate weightlessness. Intra-ocular pressure, near vision and vision
      field were measured before, during and after bed rest in both groups. Result.
      Intra-ocular pressure and near vision showed a wave-like decrease change during
      bed rest, and there exists a certain coherence between them. Visual field showed
      no obvious changes. Taking Chinese herb was able to antagonize the decreasing of
      intra-ocular pressure and near vision during various phases of bed rest.
      Conclusion. 1) Bed rest could lead to the decreasing of intra-ocular pressure and
      near vision; 2) Taking Chinese herb was able to antagonize the negative
      influences of bed rest on visual function.

PMID- 12622079
TI  - Breast cancer and the language of risk, 1750-1950.
AB  - The language of risk, in relation to disease, is usually viewed as having
      developed in the post-war era, but in fact it has a much longer history. Focusing
      on the period from the mid-eighteenth century to the mid-twentieth century, this
      article examines evolving beliefs about what makes women vulnerable to breast
      cancer and traces the history of certain 'risk factors', such as the presence of
      benign breast disease, the experience of injury to the breast, the influence of
      unhappy emotions, the onset of menopause, and a family history of cancer. It
      situates beliefs about breast cancer within their social and cultural contexts,
      examining ideas concerning the relationship between mind and body, the impact of
      new medical knowledge, the social meanings of cancer, definitions of femininity
      and images of the female body, and women's own views on what places them at risk.
      It concludes that an historical perspective adds an important dimension to our
      contemporary understanding of the concept of medical risk.

PMID- 12622080
TI  - [Overall design and proof-test of an integrated environmental control and life
      support system (ECLSS) for demonstration and verification].
AB  - Objective. To test and demonstrate embryonic form of our future space station
      ECLSS, which will also form an advanced research and test ground facility.
      Method. The following functions of the system were tested and demonstrated:
      integrated solid amine CO2 collection and concentration, Sabatier CO2 reduction,
      urine processing thermoelectric integrated membrane evaporation, solid polymer
      water electrolysis O2 generation, concentrated ventilation, temperature and
      humidity control, the measurement and control system, and other non-regenerative
      techniques. All of these were demonstrated in a sealed adiabatic module, and
      passed the proof-tests. Result. The principal technical requirements of the
      system and each regenerative subsystem were met. The integration of system
      general and each subsystem was successful, and the partial closed loop of the
      system's integration has been realized basically. Conclusion. The reasonableness
      of the project design was verified, and the major system technical requirements
      were satisfied. The suitability and harmonization among system general and each
      subsystem were good, the system operated normally, and the parameters measured
      were correct.

PMID- 12622082
TI  - [Design and application of a circuit for measuring frequency & duty cycle of
      stimulated bioelectrical signal].
AB  - Objective. To design a new type of circuit for measuring frequency & duty cycle
      of stimulated bioelectrical signal for the project of "the map of neuron
      threshold in human brain and its clinical application". Method. This circuit was
      designed according to the character of stimulated bioelectrical signals. It was
      tested and improved and then used in the neuron-threshold stimulator. Result. The
      circuit was found to be very accurate for measuring frequency and the error for
      measuring duty cycle was below 0.2%. Conclusion. This circuit is well-designed,
      simple, easy to use, and can be applied in many systems.

PMID- 12622081
TI  - [A vertical vibration model of human body in supine position].
AB  - Objective. To establish the models of head, abdomen, and chest of supine human
      body respectively under vertical vibration. Method. The mechanical impedance of
      12 healthy volunteers aged 24-56 was measured under vertical white noise stimulus
      in the frequency range of 2-35 Hz. To explain these findings, the model of head
      was proposed, the models of abdomen and chest were computed by way of an
      optimization procedure. Result. The models of abdomen and chest are three-degree
      of-freedom and the head is rigid. Conclusion. The mechanical impedance of the
      supine human body is linear and sole. The established models of head, abdomen and
      chest of supine human body when subjected to vertical vibration are useful for
      calculating and evaluating the comfort of supine human body under whole-body
      vibration.

PMID- 12622083
TI  - [A study for time-history waveform synthesis of algorithm in shock response
      spectrum (SRS)].
AB  - Objective. To present an effective on-line SRS time-history waveform synthesis
      method for simulating pyrotechnic shock environment with electrodynamic shakers.
      Method. A procedure was developed for synthesizing a SRS time-history waveform
      according to a general principle. The effect of three main parameters to
      waveform's shape, amplitude of acceleration and duration were investigated. A
      modification method of SRS's amplitude and an optimal algorithm of time-history
      waveform were presented. Result. The algorithm was used to generate a time
      history waveform that could satisfy SRS's accuracy requirement and electrodynamic
      shaker's acceleration limitation. Conclusion. The numerical example indicates
      that the developed method is effective. The synthesized time-history waveform can
      be used to simulate pyrotechnic shock environment using electrodynamic shakers.

PMID- 12622084
TI  - [Application of adaptive canceling methods in temperature control in ultrasonic
      therapeutical treatment].
AB  - Objective. To improve the quality of ultrasonic therapeutical treatment by
      improving the accuracy of temperature control. Method. Adaptive canceling methods
      were used to reduce the noise of temperature signal gained, and enhance signal-to
      noise ratio. Result. The test's result corresponds basically to the theoretical
      curve. Conclusion. Adaptive canceling methods can be applied to clinic treatment.

PMID- 12622085
TI  - Sporadic late onset paroxysmal cerebellar ataxia.

PMID- 12622086
TI  - Cerebrovascular reactivity in patients with a recent lacunar infarction.

PMID- 12622087
TI  - [Study on sensitivity of event-related EEG sychronization and desychronization
      visual memory load].
AB  - Objective. To examine the effect of visual working memory load on the event
      related EEG synchronization and desynchronization. Method. EEG was recorded when
      12 normal participants were performing the visual spatial matching task and the
      abstract geometrical figure matching task in the n-back paradigm in which the
      memory load varied from 1 to 3. Result. Theta ERS was observed along with alpha
      ERD. As the memory load increased, the 6-8 Hz ERS decreased and the alpha ERD
      increased. The theta ERS and alpha ERD elicited by the figure matching task were
      larger than those in the visual spatial matching task. The fact that most of the
      differences were observed in the CZ and FZ electrodes was in line with the view
      that the activation of attention and working memory was often found in prefrontal
      and parietal regions. Conclusion. The event-related EEG synchronization and
      desynchronization varies with the visual memory load and therefore are good
      indicators of memory load.

PMID- 12622089
TI  - Pregnancy associated quadriparesis in a patient with Von-Hippel Lindau disease.

PMID- 12622088
TI  - [Circadian expression of mPER1 in cultured murine myocardiocytes and effects of
      melatonin on it].
AB  - Objective. To investigate the mechanism of beating in cultured myocardiocytes
      through analyzing mPER1 expression and effect of melatonin on it. Method.
      Immunohistochemistry and melatonin interference test were employed. Result. mPER1
      expression in cultured myocardiocytes showed circadian pattern, its acrophase was
      15:20, its three consecutive daily average period length was approximately 23 h.
      Melatonin had little effects on its amplitude and period, but results in its
      phase delayed. The observation in this study was similar to those that we
      previously observed in cultured murine myocardiocytes beating. Conclusion.
      Oscillation of mPER1 gene is one of the important reasons which cause murine
      myocardiocytes circadian beating. Melatonin acts as "Zeitgeber" regulating mPER1
      gene expression.

PMID- 12622090
TI  - Evoked potentials in a case of progressive multifocal leukoencephalopathy.

PMID- 12622092
TI  - Recurrent nonhemorrhagic mass lesion due to cerebral amyloid angiopathy.

PMID- 12622091
TI  - [Study on mechanical factors involved in sports muscle injury].
AB  - Objective. To investigate the effect of eccentric strengthening (EC) exercise on
      muscular structure, plasma CK and biomechanical behavior under different
      mechanical loadings and to study the mechanical factors involved in sports muscle
      injury. Method. We developed an apparatus to do eccentric strength training with
      male SD rats under different mechanical loadings and to measure the biomechanical
      behavior. Result. No significant difference (P>0.05) of muscular structure,
      plasma CK and biomechanical behavior were found between high and low force
      groups. Conclusion. Skeletal muscle injury after cyclic EC with different
      mechanical loadings suggested that muscle damage is not simply a function of peak
      muscle force.

PMID- 12622093
TI  - Severe heart failure in a young multiple sclerosis patient.

PMID- 12622094
TI  - [A dynamic model of the extravehicular (correction of extravehicuar) activity
      space suit].
AB  - Objective. To establish a dynamic model of the space suit base on the particular
      configuration of the space suit. Method. The mass of the space suit components,
      moment of inertia, mobility of the joints of space suit, as well as the suit
      generated torques, were considered in this model. The expressions to calculate
      the moment of inertia were developed by simplifying the geometry of the space
      suit. A modified Preisach model was used to mathematically describe the
      hysteretic torque characteristics of joints in a pressurized space suit, and it
      was implemented numerically basing on the observed suit parameters. Result. A
      dynamic model considering mass, moment of inertia and suit-generated torques was
      established. Conclusion. This dynamic model provides some elements for the
      dynamic simulation of the astronaut extravehicular activity.

PMID- 12622095
TI  - Serial gadolinium-enhanced MRI in acute attack of multiple sclerosis treated with
      plasma exchange.

PMID- 12622096
TI  - An Unusual Headache: Lemierre's Syndrome.

PMID- 12622097
TI  - [Review of influence of landing impact on human body (correction of boby) and its
      medical evaluation].
AB  - Landing impact is the dynamic factor that manned spaceship will inevitably meet
      after the mission has been completed, and impact force may cause damages to human
      tissues [correction of tissuses] and organs, even death. This paper described the
      characteristics of pathological and dynamic response of human body to landing
      impact, and discussed various related factors such as impact angle, fetters,
      design of cushion, harness and terrain condition. Medical evaluation of +Gx, +Gz,
      +/- Gy impacts were summarized.

PMID- 12622098
TI  - The effect of Bacille Calmette-Guerin on the evolution of new enhancing lesions
      to hypointense T1 lesions in relapsing remitting MS.

PMID- 12622099
TI  - Article Highlights Importance of Clinical Trial Nurses.

PMID- 12622100
TI  - [Advances in monoclonal antibody researches].
AB  - Monoclonal antibody techniques are very important tools in modern life science
      research. Despite extensive research efforts paid in recent years, and promising
      results yielded in the study on the structure and function of genes and proteins,
      there is still a great need for further researches on the definition, principle
      and applicability of some immunological methods. This review gives an overview of
      the advances in immunological researches, including DNA immunization, cellular
      immunization and preparation of monoclonal antibodies. Using methods of modem
      molecular immunology, such as genetic immunization, cellular immunization,
      subtractive immunization and repetitive immunization multiple sites (RIMMS), to
      construct eukaryotic expression vector and to prepare high-affinity monoclonal
      antibodies in short time, the conventional method which is time-consuming and
      laborious could be improved. It is meaningful to the field of basic research and
      application, such as proteomics, biochip, clinical medicine and diagnosis and
      therapy of diseases.

PMID- 12622101
TI  - Alfred Walter Campbell (1868-1937).

PMID- 12622102
TI  - [Effects of weightlessness on baroreflex function].
AB  - The declination of baroreceptor reflex function is one of the important factor
      causing orthostatic intolerance after space flight. The change of baroreceptor
      reflex function during weightlessness and simulated weightlessness is introduced,
      and the influence of elevatory upper body blood pressure and electrolyte changes
      caused by weightlessness on baroreflex function are analyzed.

PMID- 12622103
TI  - Motor co-ordination in humans is guided by optimal feedback control.

PMID- 12622104
TI  - Current awareness in prenatal diagnosis.

PMID- 12622105
TI  - The need for a regional weaning centre, a one-year survey of intensive care
      weaning delay in the Northern Region of England.
AB  - Over a period of one year, a weekly telephone survey identified 161 stable
      patients with weaning delay (defined as patients ventilated for at least 6 h per
      day for more than 2 weeks) in intensive care units in the Northern Region of
      England. Their median age was 69 years (range 21-88 years). Sixty patients (37%)
      were admitted with medical conditions, 89 (55%) were postoperative patients,
      whereas 12 (8%) were surgical but required non-operative admission. One hundred
      and thirty (89%) were weaned and discharged from the intensive care unit during
      the year. Twenty-two (14%) died and two were transferred to the home ventilation
      service. Seven patients remained ventilated in intensive care at the end of the
      study period. Twenty patients (12%) required more than 28 days of respiratory
      support. These patients occupied on average 6.0% of available intensive care unit
      beds in the region. This study suggests that in the Northern Region of England
      there are a significant number of stable but ventilator-dependent patients
      occupying intensive care beds.

PMID- 12622106
TI  - A comparison of target-controlled therapy with patient-controlled administration
      of propofol combined with midazolam for sedation during dental surgery.
AB  - Forty anxious day case patients undergoing extraction of third molar teeth under
      local anaesthesia with sedation, were studied in a randomised double-blind
      controlled trial. A target-controlled infusion of propofol was compared with
      patient-controlled propofol for sedation, combined with a small dose of midazolam
      to improve amnesia. The objectives of the study were to measure the total dose of
      propofol used by the two groups and assess recovery and patient satisfaction. The
      mean dose of propofol used in the patient-controlled sedation group was
      significantly less than the target-controlled group (p < 0.00007). Five patients
      became over-sedated in the target-controlled group compared with none in the
      patient-controlled group. Only one of the three tests of performance showed that
      the target-controlled patients were more sedated. Patient satisfaction was high
      in both groups despite a greater recollection of events in the patient-controlled
      group.

PMID- 12622107
TI  - White cell count and intensive care unit outcome.
AB  - A high white cell count on admission to the intensive care unit (ICU) is
      generally perceived to be associated with severe illness and poor outcome, but
      the implications of a low white cell count are less well recognised. We
      retrospectively analysed data on 4,165 patients. The white cell count on
      admission was split into four categories, leucopenic (< 4.0 x 10(9).l(-1)),
      normal (4.001-10.0 x 10(9).l(-1)), leucemoid (10.001-25.0 x 10(9).l(-1)) and an
      exaggerated leucemoid response (> 25.001 x 10(9).l(-1)). The mortality of
      patients with leucopenia on admission to the intensive care unit was higher than
      those with normal or moderately raised white cell count (37.5% vs. 18.9% and
      23.9%, respectively). A leucopenic response, as well as an exaggerated leucemoid
      response, is associated with an increased mortality.

PMID- 12622109
TI  - Reversing the Cardiovascular Disease Epidemic Among Ethnic Minority Populations:
      Translating Strategies into Success. 17th Annual International Interdisciplinary
      Conference on Hypertension and Related Risk Factors in Ethnic Populations. June 8
      12, 2002, Miami, Florida, USA. Proceedings and abstracts.

PMID- 12622108
TI  - A comparison of total intravenous with balanced anaesthesia for middle ear
      surgery: effects on postoperative nausea and vomiting, pain, and conditions of
      surgery.
AB  - We compared postoperative nausea and vomiting (PONV), pain and conditions for
      surgery in patients scheduled for middle ear surgery. In a double-blind study,
      100 patients were randomly allocated to receive either balanced anaesthesia
      (group A) using fentanyl, propofol and isoflurane, or total intravenous
      anaesthesia (group B) using propofol and remifentanil infusions. Pain scores,
      nausea/vomiting scores, conditions for surgery and analgesic requirements were
      recorded for 18 h post operatively. In the recovery ward, patients in group B
      suffered significantly less PONV (p = 0.026) with a reduced requirement for anti
      emetic medication (p = 0.023); however, this difference was not maintained on the
      ward. The overall incidence of PONV was 34% and 17% in groups A and B,
      respectively. Initial pain scores were higher in group B in the recovery ward (p
      = 0.003) and patients required more morphine administration (p = 0.002); however,
      pain scores were similar on the ward. Conditions for surgery were found to be
      better in group B.

PMID- 12622110
TI  - Mayhem and medical students: image, conduct, and control in the Victorian and
      Edwardian London teaching hospital.
AB  - In exploring how the image of the medical student was created and modified during
      the nineteenth century, this article suggests that stereotypes first put forward
      in the 1820s were in part a product of the trend towards institutional medical
      education. They quickly acquired a cultural resonance that reflected concerns
      about the nature of medicine and fears of the urban. By the late nineteenth
      century, however, the medical student was being reinvented as part of doctors'
      efforts to improve the status of medicine and rework stereotypes so that they
      reflected the values associated with the professional gentlement. At the same
      time, student conduct had started to alter, giving some substance to a new set of
      stereotypes being put forward by doctors. By locating the transformation within
      the culture of London's medical schools, the article shifts attention away from
      the changes that were occurring in the structure of medical education to look at
      the role of the medical school in regulating the student. A focus on the
      experiences of St Bartholomew's, the largest medical school in London, provides a
      case study through which these changes are discussed.

PMID- 12622111
TI  - [Nasal tuberculosis].

PMID- 12622112
TI  - [Long-term progression of a Lasthenie de Ferjol syndrome].

PMID- 12622114
TI  - Renal targeting of captopril selectively enhances the intrarenal over the
      systemic effects of ACE inhibition in rats.

PMID- 12622113
TI  - [Meningococcemia following chemotherapy for bronchial cancer].

PMID- 12622115
TI  - This mysterious and intangible enemy: health and disease amongst the early UMCA
      missionaries, 1860-1918.
AB  - From the first moment of the UMCA's incursion into the African interior, the
      greatest challenge it faced was the problem of mortality and morbidity. Between
      1860 and 1918, over one-third of the mission staff were lost to death, or
      invalided out due to ill-health. This article tracks the institutional response
      to the problems of death and disease, and seeks to explain why, from the mid
      1890s, there was a notable downward shift, both in the numbers of missionaries
      dying, and in the numbers forced to retire through sickness. For the first 35
      years of the UMCA's existence, it paid little attention to establishing and
      enforcing a disease-management strategy. Health issues were left to the
      individual missionaries, and medical policy (in as much as the UMCA can be said
      to have had a 'policy' before the mid-1890s) was driven by the periphery. A
      mortality crisis in the 1890s refocused the attention of the Mission authorities
      on the need to establish more rigorous procedures for overcoming the impact of
      disease. Control over medical policy was centralized, and structures established
      for the better enunciation and enforcement of this policy. This institutional
      response ensured an improvement in the health environment of the missionaries,
      and consequent reductions in the impact of disease upon the UMCA.

PMID- 12622116
TI  - Building national medicine: leprosy and power in Colombia, 1870-1910.
AB  - As imperialist nations rediscovered leprosy in their colonial world in the late
      nineteenth century, Colombian physicians found endemic leprosy in their own
      country. The medical community was interested in constructing a national medicine
      to conform to 'universal' science. To medicalize leprosy, doctors provoked fears
      through exaggerating the number of leprosy sufferers to demonstrate that charity
      was incapable of dealing with the problem. The government approved laws of
      compulsory segregation of leprosy patients in the 1890s, while the 1897
      international conference on leprosy held in Berlin gave international sanction to
      isolation. Lepers actively resisted segregation as a violation of their
      individual rights. Dr Juan de Dios Carrasquilla studied the disease, experimented
      with sero-therapy to cure it, and claimed that the flea was its agent of
      transmission. He combatted segregation and proposed instead a hygienic programme
      to improve environmental living conditions, but his approach was defeated. When
      the early twentieth century saw the consolidation of the Colombian state,
      modernization of the country became a national priority. The government started
      to take control of lazarettos, enforcing segregation of lepers, who were confined
      within an area circumscribed by a sanitary cordon. This strategy was a failure,
      since patients resisted segregation.

PMID- 12622117
TI  - State publishes acute infection guidelines.

PMID- 12622118
TI  - Rapid AIDS test approved.

PMID- 12622119
TI  - Measles, mumps, and rubella vaccination and autism.

PMID- 12622120
TI  - Sexual addiction being studied.

PMID- 12622121
TI  - New hepatitis treatment decreases injections.

PMID- 12622122
TI  - Measles, mumps, and rubella vaccination and autism.

PMID- 12622123
TI  - Measles, mumps, and rubella vaccination and autism.

PMID- 12622124
TI  - Measles, mumps, and rubella vaccination and autism.

PMID- 12622125
TI  - Dexamethasone in adults with bacterial meningitis.

PMID- 12622126
TI  - Dexamethasone in adults with bacterial meningitis.

PMID- 12622127
TI  - Dexamethasone in adults with bacterial meningitis.

PMID- 12622128
TI  - Dexamethasone in adults with bacterial meningitis.

PMID- 12622129
TI  - Health of children of immigrants.

PMID- 12622131
TI  - Treatment of opiate dependence in hands of primary care providers.

PMID- 12622130
TI  - Survey finds decrease in use of certain drugs by nation's youth.

PMID- 12622132
TI  - [Wound infections, adhesions, late fistulas. Are you equipped to deal  with the
      possible sequelae of abdominal operations?].

PMID- 12622133
TI  - Glioneuronal tumors of the central nervous system.
AB  - Advances in the immunohistochemical detection of neuron-specific and neuronal
      associated antigens have resulted in the discovery of neuronal elements in
      certain primary human brain tumors. The results have been not only to expand what
      neuropathologists commonly recognize as gangliogliomas, including the tumors now
      known as glioneurocytic tumor with neuropil rosettes and papillary
      ganglioneuroma, but also to expand the spectrum of tumor types to now include
      tumors such as central neurocytoma, dysembryoplastic neuroepithelial tumor, and
      desmoplastic infantile ganglioglioma. These discoveries have helped us to better
      understand the biology of these tumors and to refine our classification of them.
      Distinctions among these tumors include sites of predilection, such as the
      temporal lobe with the dysembryoplastic neuroepithelial tumors, and a spectrum of
      clinical aggressiveness that spans indolent "quasi-hamartomatous" lesions, such
      as the dysembryoplastic neuroepithelial tumor, to high-grade, highly aggressive
      tumors, such as the supratentorial primitive neuroectodermal tumor (World Health
      Organization Grade IV). Many of these tumors also commonly exhibit a glial
      component, as determined by both their histologic appearance and their
      immunoreactivity for glial fibrillary acidic protein. This review covers these
      recently described lesions, including the desmoplastic infantile ganglioglioma,
      the dysembryoplastic neuroepithelial tumor, the papillary glioneuronal tumor, the
      glioneuronal tumor with neuropil rosettes, and the mixed glioblastoma-cerebral
      neuroblastoma (supratentorial primitive neuroectodermal tumor), as well as the
      known tumors, ganglioglioma, medulloepithelioma, and medulloblastoma. For
      pathologists confronted by this growing array of tumors and subtypes, it is
      appropriate to focus on them and understand the differential diagnosis to be
      considered when confronted by them.

PMID- 12622134
TI  - Major vault protein/lung resistance-related protein (MVP/LRP) expression in
      nervous system tumors.
AB  - Lung resistance-related protein (LRP) was identified as the major vault protein
      (MVP), the main component of multimeric vault particles. It functions as a
      transport-associated protein that can be associated with multidrug resistance. In
      previous studies, expression of MVP/LRP has been documented in tumors of various
      types. In general, good correlations have been reported for expression of MVP/LRP
      and decreased sensitivity to chemotherapy and poor prognosis. MVP/LRP expression
      has been documented in glioblastomas, but its expression in nervous system tumors
      in general has not been well characterized. Immunohistochemistry using anti-human
      MVP/LRP antibody (LRP-56) was performed on formalin-fixed, paraffin-embedded
      archival tissue from 69 primary central nervous system tumors. Expression of
      MVP/LRP was observed in 81.2% (56/69) of primary nervous system tumors, including
      astrocytomas (11/13), oligodendrogliomas (1/2), oligoastrocytomas (5/5),
      ependymoma (1/1), meningiomas (35/45), schwannomas (2/2), and neurofibroma (1/1).
      Various degrees and distributions of immunoreactivity to MVP/ LRP were observed.
      Neither the presence nor the degree of immunoreactivity to MVP/LRP showed any
      correlation with either tumor grade or the presence of brain invasion.

PMID- 12622135
TI  - Intrasellar gangliocytomas associated with acromegaly.
AB  - The present study was designed to investigate the immunohistochemical
      characteristics of gangliocytomas associated with growth hormone (GH)-secreting
      pituitary adenomas. In our surgical collection of 476 GH-secreting adenoma cases,
      we examined tumor tissue from 6 patients (1.3%). All 6 patients were women,
      ranging from 29 to 52 years (mean, 40.3 +/- 9.5 SD) of age. Among 470 patients
      with GH-secreting adenomas without gangliocytoma, there were 255 female and 215
      male patients. The preponderance of female patients with gangliocytomas was
      striking. Histological examination of the resected specimens showed areas of
      ganglion cells and adenomatous cells. Ganglion cell lesions were stained
      positively for synaptophysin (4 of 4; 100%) and neurofilament (4 of 4; 100%) as
      well as GH-releasing hormone (5 of 6; 83.3%). Subtypes of GH cell adenomas
      included 4 cases of sparsely granulated type and 2 cases of mixed GH and
      prolactin (PRL) cell adenomas. Based on these findings, we hypothesized that the
      intrasellar gangliocytoma promoted the growth of the pituitary adenoma by chronic
      overstimulation from excess GH-releasing hormone.

PMID- 12622136
TI  - Tracking cell invasion of human glioma cells and suppression by anti-matrix
      metalloproteinase agent in rodent brain-slice model.
AB  - Persistent expression of green fluorescent protein (GFP) in human malignant
      glioma cell clones (U87MG, U251MG, and U373MG) was established using the pEGFP-Cl
      vector. Tumor spheroid was implanted into the caudate nucleus-putamen of a
      severely compromised immunodeficient (SCID) mouse brain slice. To allow
      quantitative assessment of tumor cell invasion, the invasion area index was
      measured on days 1, 3, 5, and 7 by a fluorescence stereomicroscope and an image
      analyzer in the presence of varying concentrations of SI-27. In the control group
      (0 microg/ml), all glioma cell lines invaded in a fingerlike fashion, reaching
      the contralateral hemisphere via the corpus callosum. SI-27 at concentrations of
      10, 50, or 100 microg/ml significantly suppressed the index on days 5 and 7 in a
      dose-dependent manner, whereas 1 microg/ml had no effect. Laser confocal
      microscopy indicated that the tumor cells penetrated through the brain slice.
      This model enabled unequivocal periodic tracking of individual invading tumor
      cells in the normal brain. The significant suppression of glioma cell invasion by
      SI-27 indicates that anti-matrix metalloproteinase (MMP) treatment may represent
      an important future therapeutic strategy for malignant cerebral neoplasms.

PMID- 12622137
TI  - Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit
      vascular endothelial growth factor (VEGF) secretion from human glioblastoma
      cells.
AB  - We investigated the effects of histone deacetylase (HDAC) inhibitors such as
      sodium butyrate (SB) and trichostatin A (TSA) on the expression of vascular
      endothelial growth factor (VEGF) by human glioblastoma T98G, U251MG, and U87MG
      cells. The glioblastoma cells secreted three VEGF isoforms, VEGF (189), (165),
      and (121), although the expression levels of VEGF differed between the cell
      types. Treatment with either 5mM SB or 100 ng/ml TSA reduced VEGF secretion in
      conditioned media and reduced VEGF mRNA expression. We also studied the
      expression of VEGF-B, -C, and -D mRNA in human glioblastoma cells and their
      modulation by HDAC inhibitors. The PCR products of VEGF-B (357bp), VEGF-C
      (501bp), and VEGF-D (484bp) were amplified in all glioblastoma cells examined.
      Treatment with SB reduced the expression of VEGF-D mRNA in U251MG cells and the
      expression of VEGF-B mRNA in U87MG cells. TSA treatment reduced the expression of
      VEGF-D in U251MG cells. These results suggest that HDAC inhibitors reduce VEGF
      secretion and modulate the expression of the other VEGF family members, and
      therefore may inhibit angiogenesis in glioblastoma tissues.

PMID- 12622138
TI  - Radiological response and histological changes in malignant astrocytic tumors
      after stereotactic radiosurgery.
AB  - Stereotactic radiosurgery is an encouraging approach to deliver higher doses of
      radiation boost for malignant gliomas safely and precisely. The purpose of this
      study was to investigate the radiation response and histological changes of
      malignant astrocytic tumors after stereotactic linac radiosurgery (SLRS). We
      studied an autopsy case of recurrent glioblastoma multiforme (GBM) and two
      surgical cases with gross total removal of recurrent GBM and anaplastic
      astrocytoma transformed from fibrillary astrocytoma treated with SLRS.
      Destructive changes, such as the disappearance of viable cells, coagulation
      necrosis, and fibrinoid degeneration of vascular walls, were observed in the
      center of the target of SLRS, which showed histologically similar radiobiological
      reactions to well-known delayed central nervous system radiation necrosis caused
      by conventional radiotherapy. The region showing such radiation necrosis was
      within the area irradiated with approximately 15-20Gy or more by SLRS; however,
      dense viable tumor cells remained in the periphery that was irradiated with less
      than 15Gy. In a comparative immunohistochemical study of the tumors before and
      after SLRS, neither MIB-1 and p53 labeling indices nor immunoreactivity for GFAP
      represented any persistent tendencies. There were very few TUNEL-positive cells
      in either tumor before and after SLRS. These results showed that radiosurgery for
      malignant gliomas leads to earlier radiation necrosis than conventional radiation
      and that it is useful in eradicating tumor cells in the center of the target.
      However, some viable tumor cells may remain in the periphery irradiated with an
      insufficient dose for cell death and may be partly transformed in character by
      DNA damage due to radiation. Proton magnetic resonance spectroscopy (MRS) was
      suggested to characterize the radiation response in radiosurgery tumor targets
      for correlation with histological findings.

PMID- 12622139
TI  - A melanotic desmoplastic medulloblastoma: report of a rare case and review of the
      literature.
AB  - A 28-year-old man had a desmoplastic medulloblastoma in the vermis and left
      cerebellum. This tumor was composed of nodular, reticulin-free zones (pale
      islands) surrounded by densely packed, highly proliferative cells that produced a
      dense intercellular reticulin network. Some of the cells were heavily pigmented,
      and this pigment proved to be melanin. Adult age, desmoplastic nature, and
      melanin pigmentation are some of the rare features of this tumor that need
      documentation. Further, this pigment was in the primitive cells, unlike in the
      published cases, in which it was present in the tubular or tubulopapillary
      component. To the best of our knowledge, this is the first published case of
      desmoplastic pigmented medulloblastoma, and the patient is the oldest reported to
      have this tumor.

PMID- 12622140
TI  - Dysembryoplastic neuroepithelial tumor of the midbrain tectum: a case report.
AB  - Dysembryoplastic neuroepithelial tumor (DNT) is a relatively new nosologic
      entity. First described in 1988, it is now included in the "neuronal and mixed
      neuronal-glial tumours" category in the revised 2000 World Health Organization
      (WHO) Classification of Tumours of the Nervous System. The collective experience
      of more than 300 reported cases indicates that, with only rare exceptions, DNTs
      are cerebral cortical lesions. At present, the actual incidence of extracortical
      DNT is unknown. We describe, the clinicopathologic features of the first tectal
      DNT. The patient was a 51-year-old man with a 2-month history of pulsatile
      headaches. On neurologic examination, the only abnormality was gait ataxia.
      Magnetic resonance imaging (MRI) demonstrated a midbrain tumor involving the
      tectum. It was hypointense on T1-weighted images and featured an iso- to
      hyperintense nodule at its center. The nodule showed enhancement upon contrast
      administration. No aqueductal obstruction or intraventricular extension of tumor
      was detected. The tumor was approached supratentorially and removed completely.
      The mucoid tumor was well demarcated from neural tissue. Histopathologically, it
      was a typical DNT, exhibiting a nodular pattern of growth with a "specific
      glioneuronal component." This case report documents the first DNT to arise in the
      midbrain tectum and focuses on the problem of diagnosing this uncommon tumor at
      extracortical sites.

PMID- 12622141
TI  - Extensive and dense calcification in the core of a ventrally exophytic brainstem
      glioma.
AB  - The first case of a ventrally exophytic pontine glioma with extensive and dense
      calcification is reported. A 10-year-old boy presented with a generalized
      seizure. The skull radiogram and CT scan showed a dense area of calcification,
      revealed by MRI as the core of a ventrally exophytic tumor. The pathologic
      diagnosis was fibrillary astrocytoma.

PMID- 12622142
TI  - Two cases of atypical central neurocytomas.
AB  - Central neurocytomas (CNs) are usually considered benign; however, some subsets
      of these tumors with histologic atypia and elevated proliferation potential have
      been reported to have a poor outcome. It has been proposed that those CNs
      exhibiting a MIB-1 labeling index (LI) greater than 2% and/or vascular
      proliferation be defined as atypical central neurocytoma (ACN). Two cases of ACN
      are reported here. Case 1 was a 13-year-old male who complained of headache. An
      MRI showed an enhancement of the tumor in the third ventricle and left lateral
      ventricle. The tumor was completely removed transcortically by a left
      frontotemporal craniotomy. The tumor showed anaplastic features, including
      microvascular proliferation, mitosis, and necrosis. The MIB-1 LI was 7.8%. The
      patient received 50Gy of focal irradiation. After 16 months of follow-up, no
      recurrence was observed. Case 2 was a 17-year-old female who presented with
      headache. An MRI showed an enhancement of the tumor in the right lateral
      ventricle. To preserve the internal cerebral vein, the tumor was partially
      removed by the transcingulate approach after a bifrontal craniotomy.
      Histologically, the tumor displayed the typical features of a CN. The MIB-1 LI
      was 7.0%. Complete remission was achieved through 50Gy of focal irradiation.
      After 15 months of follow-up, there was no recurrence. The differences in the
      histopathological findings in these two cases indicate the presence of a variety
      of histopathological features among ACNs.

PMID- 12622143
TI  - A case of angioglioma composed of astrocytoma with a papillary growth pattern:
      immunohistochemical and ultrastructural studies.
AB  - We report a case of a large cystic astrocytoma associated with arteriovenous
      malformation in the right cerebral hemisphere of a 16-year-old boy. Neuroimaging
      showed large abnormal vessels with flow voids and arteriovenous shunt around the
      cystic lesion. Histologically, the cyst wall was formed by abnormal vasculature
      and clusters of glial cells forming a papillary growth pattern. The abnormal
      vasculature consisted of dilated vein-like vessels and medium-sized arteries with
      incomplete media, and was diagnosed as an arteriovenous malformation.
      Immunohistochemically, glial fibrillary acidic protein (GFAP) decorated both the
      perikaryon and the processes of the glial tumor cells. They were negative for
      epithelial membrane antigen (EMA), cytokeratin, and S-100 protein.
      Ultrastructurally, the tumor cells were rich in intermediate filaments, and
      neither cilia, microvilli, nor ependymal rosettes were verified. Based on these
      morphological features and the low MIB-1 labeling index of 0.8%, the glial tumor
      was diagnosed as astrocytoma, Grade II, according to the World Health
      Organization (WHO) tumor classification. An association of glioma with various
      types of vascular anomalies has been designated as angioglioma. A unique feature
      of the present case, however, is a papillary growth pattern, which is not listed
      in the current WHO classification of brain tumors. The recognition of the
      occurrence of such cases would be important in differential diagnosis of
      papillary ependymoma and choroid plexus papilloma.

PMID- 12622144
TI  - Brain metastasis from small-cell neuroendocrine carcinoma of the urinary bladder:
      a case report.
AB  - Eight months after radical surgery for small-cell neuroendocrine carcinoma (SCNC)
      of the urinary bladder, a 69-year-old man was admitted with a brain tumor in the
      left frontal lobe. The tumor, about 5 cm in diameter, was intensely but
      heterogeneously enhanced on computed tomography and magnetic resonance imaging.
      The tumor was subtotally removed, leaving only the portion adjacent to the
      anterior horn of the left lateral ventricle. Microscopically, the tumor was
      composed of diffuse sheets of small tumor cells with round to spindle-shaped
      nuclei, indistinct nucleoli, scant or absent cytoplasm, and indistinct cell
      margins. Immunohistochemically, the tumor cells were positive for synaptophysin,
      neuron-specific enolase, chromogranin A, and keratin. Ultrastructurally, the
      tumor cells showed classic neurosecretory granules and microvilli in the
      cytoplasm. The tumor was diagnosed as a brain metastasis from SCNC of the urinary
      bladder. After surgery, whole-brain radiation therapy of 40 Gy was performed,
      which succeeded in controlling the residual tumor. However, 4 months after
      surgery, the patient died of meningeal carcinomatosis. To our knowledge, this is
      the first report focusing on brain metastasis from SCNC of the urinary bladder.
      The clinicopathological features and pathological diagnosis of this tumor are
      discussed.

PMID- 12622145
TI  - Fluorescence: basic concepts, practical aspects, and some anecdotes.
AB  - We hope that we have conveyed information of interest and value to present and
      future fluorescence practitioners. Those readers with a sustaining interest in
      this topic may wish to consult more comprehensive sources such as Molecular
      Fluorescence: Principles and Applications, an excellent text by Valeur, or
      Principles of Fluorescence Spectroscopy by Lakowicz. Many specialized
      fluorescence topics are covered in the series Topics in Fluorescence Spectroscopy
      (Volumes 1-6), and several volumes of Methods in Enzymology (e.g., Volumes 246
      and 278) have dealt with issues in fluorescence spectroscopy. Proceedings from
      the International Conference on Methods and Applications of Fluorescence
      Spectroscopy, 1997 (MAFS 97) and MAFS 98 (in press) also present fluorescence
      work on many different topics in biological and chemical fields. The Molecular
      Probes Handbook and web site (www.probes.com) are also rich sources of useful
      information. Finally, any reader with a question or seeking advice on some topic
      related to fluorescence is welcome to e-mail D.M.J. at djameson@hawaii.edu.

PMID- 12622146
TI  - Fluorescence-sensing methods.
AB  - Novel approaches to sensor design, based on the use of an internal standard with
      appropriate spectral properties, provide new possibilities for designing simple
      devices for fluorescence sensing. Detection of combined emission from the
      reference and an analyte-sensitive fluorophore has been achieved in numerous
      measurements in cuvettes, tissues, and high-throughput formats. These methods
      have been used with a long-lifetime reference to measure pH, O2, pCO2, glucose,
      and calcium by means of modulation-sensing methods as well as by the use of
      oriented films as the reference for polarization sensing of glucose, pH, oxygen,
      and lactate. Polarization sensing has also been developed with visual detection
      to measure the concentration of rhodamine B and pH. Modulation and polarization
      sensing was found to be effective in highly scattering media such as Intralipid
      or tissue. The applicability of these technologies to transdermal diagnostics
      depends on the availability of red fluorophores that can be used in vivo. One dye
      that could possibly be used is indocyanine green (IcG), which absorbs and emits
      at wavelengths above 700 nm. Furthermore, IcG has already been approved for use
      in humans for monitoring burn severity and it has been detected through the skin.
      It appears likely that modern optics and electronic technology will allow the
      development of practical devices for biomedical use as shown in Scheme 1.

PMID- 12622147
TI  - Bioluminescence and chemiluminescence.

PMID- 12622148
TI  - Fluorescent amino acid analogs.

PMID- 12622149
TI  - Fluorescent nucleotides: synthesis and characterization.

PMID- 12622150
TI  - Photophysics of green and red fluorescent proteins: implications for quantitative
      microscopy.

PMID- 12622151
TI  - Development of genetically encoded fluorescent indicators for calcium.

PMID- 12622152
TI  - Development and application of caged calcium.
AB  - Several caged calciums have been synthesized since 1986, and three are
      commercially available: DM-nitrophen, NP-EGTA, and nitr-5. Each of these caged
      compounds has uniquely useful properties, making the choice of which cage to use
      dependent on the specific experiment (i.e., the cell type and divalent cation
      requirements of the experiments within purview). Significantly, methods have been
      developed for all three cages that permit their quantitative use inside many cell
      types, including those with some of the most demanding of requirements for
      experiments with caged calcium, namely, in relating presynaptic [Ca] to
      postsynaptic function. The success of such experiments using DM-nitrophen and NP
      EGTA suggests that caged calcium is now a mature tool for cellular physiology and
      neurobiology.

PMID- 12622153
TI  - Application of fluorescent probes to study mechanics and dynamics of Ca2+
      triggered synaptotagmin C2 domain-membrane interactions.

PMID- 12622154
TI  - Caging proteins through unnatural amino acid mutagenesis.
AB  - The caging of specific residues of proteins is a powerful tool. This discussion
      attempts to alert the reader to the considerations that must be made in preparing
      and analyzing a caged protein through nonsense suppression. Although the
      suppression methodology is conceptually straightforward, it not possible to
      provide a failsafe "cook book" method for using caged unnaturals. We have
      emphasized the preparation of caged receptors expressed in Xenopus oocytes, but
      these approaches can clearly be adapted to many other systems.

PMID- 12622155
TI  - Preparation and light-directed activation of caged proteins.

PMID- 12622156
TI  - Bioluminescence resonance energy transfer: monitoring protein-protein
      interactions in living cells.

PMID- 12622157
TI  - Structure-function relationships in metalloproteins.

PMID- 12622158
TI  - Spectroscopy and microscopy of cells and cell membrane systems.

PMID- 12622159
TI  - Photonics for biologists.

PMID- 12622160
TI  - Imaging at low light levels with cooled and intensified charge-coupled device
      cameras.

PMID- 12622161
TI  - Filters and mirrors for applications in fluorescence microscopy.

PMID- 12622162
TI  - Resolution in optical microscopy.

PMID- 12622163
TI  - Video-rate confocal microscopy.
AB  - The CLSM described here can be built with relatively little electronic or optical
      experience and with a budget of approximately $20,000-$30,000 (excluding
      microscope and table). This cost is substantially less than that of commercial
      counterparts. However, this CLSM has excellent spatial and temporal resolution
      and the convenience of digital recording and playback. By building the CLSM, the
      investigator ensures long-term support and reliability of the instrument as well
      as the potential for future modifications and improvements. Finally, the sense of
      accomplishment of building your own instrument should not to be underestimated.

PMID- 12622164
TI  - Giant vesicles, Laurdan, and two-photon fluorescence microscopy: evidence of
      lipid lateral separation in bilayers.

PMID- 12622165
TI  - Biological near-field microscopy.

PMID- 12622166
TI  - Fluorescence lifetime-resolved imaging: measuring lifetimes in an image.
AB  - We have given an overview of what one can gain by lifetime-resolved imaging and
      reviewed the major issues concerning lifetime-resolved measurements and FLI
      instrumentation. Instead of giving diverse selected examples, we have discussed
      the underlying basic pathways of deexcitation available to the molecules in the
      excited state. It is by traversing these pathways that compete kinetically with
      the fluorescence pathway of deactivation--and therefore affect the measured
      fluorescence lifetime--that we gain the information that lifetime-resolved
      fluorescence provides. It is hoped that being aware of the diversity, of pathways
      available to an excited fluorophore will facilitate potential users to recognize
      the value of FLI measurements and inspire innovative experiments using lifetime
      resolved imaging. FLI gives us the ability within a fluorescence image of
      measuring and quantifying dynamic events taking place in the immediate
      surroundings of fluorophores as well as locating the fluorescent components
      within the image. Just as measurements in cuvettes, lifetime-resolved imaging
      extends considerably the potential information that can be derived from a
      fluorescence experiment. Our purpose has been to arouse an appreciation for the
      broad application of fluorescence lifetime-resolved measurements in imaging. We
      have given only general design characteristics of the instrumentation and
      discussed the characteristics that distinguish imaging from the single channel
      lifetime-resolved measurements. We have not provided details of the
      instrumentation or the presented many examples. These are available in the
      literature, and given in the references, and they are continually and rapidly
      growing.

PMID- 12622167
TI  - Fluorescence resonance energy transfer imaging microscopy.

PMID- 12622168
TI  - Fluorescence resonance energy transfer imaging microscopy and fluorescence
      polarization imaging microscopy.

PMID- 12622169
TI  - Homo-FRET versus hetero-FRET to probe homodimers in living cells.

PMID- 12622170
TI  - Spinning disk confocal microscope system for rapid high-resolution, multimode,
      fluorescence speckle microscopy and green fluorescent protein imaging in living
      cells.

PMID- 12622171
TI  - Single-particle tracking image microscopy.
AB  - The techniques of single particle tracking (SPT) and optical force microscopy
      (OFM) as described above allow direct imaging of the motion of molecules in the
      membrane of live cells, and provide a means of controlling the movement by an
      almost noninvasive method. Combination of these techniques with other single
      molecule methods, such as single-fluorophore imaging, allows direct comparison of
      motion at video rate (because faster than video rate imaging of fluorophore is
      still not generally feasible) to determine any effect due to the attached
      colloidal gold particle. Also, simultaneous use of the two techniques allows for
      monitoring two molecules, one at high time resolution. As such, the system can
      then be used in conjunction with green fluorescent protein (GFP) transfection to
      watch simultaneously the motion of an internal component of, say, a signaling
      pathway while seeing the motion of the transmembrane signaling receptor.

PMID- 12622172
TI  - Diffusion in cells measured by fluorescence recovery after photobleaching.

PMID- 12622173
TI  - Fluorophore-assisted light inactivation for multiplex analysis of protein
      function in cellular processes.

PMID- 12622174
TI  - Phospholipase A2-activating protein--an important regulatory molecule in
      modulating cyclooxygenase-2 and tumor necrosis factor production during
      inflammation.
AB  - Inflammation is a complex multifactorial process and a hallmark of many
      inflammatory diseases. Most of the tissue destruction that occurs in these
      diseases is the result of an aberrant or often uncontrolled immune response.
      Factors that play an important role in such diseases include pro-inflammatory
      cytokines, complement, and eicosanoids. This review focuses on eicosanoids and
      their regulation via phospholipase A2-activating protein, which could be targeted
      as a new therapeutic tool to control inflammatory diseases.

PMID- 12622175
TI  - Peripheral nerve connections influence the appearance of neurosecretary material
      in neural sheath of ventral ganglion of the fly Sarcophaga bullata: an
      immunocytochemical study.
AB  - This study examined the role of the brain and peripheral connections with the
      target organs in the appearance of neurosecretary material within the dorsal
      neural sheath of the ventral ganglion of the fly S. bullata. Specifically, the
      accumulation of the neuropeptide FMRFamide (the neurosecretary material) was
      examined by immunocytochemistry. Immunoreactions were performed on: (1) a normal
      intact ventral ganglion, (2) an isolated ventral ganglion that was cultured in
      vivo, and (3) a ventral ganglion that was isolated by transection from the brain,
      but retained its peripheral nerve connections. The results demonstrate that (a)
      the neurons of the ganglia survive and exhibit FMRFamide immune reaction
      independent of their peripheral connections, and (b) the accumulation of
      neuropeptide in the dorsal neural sheath is controlled by intact peripheral nerve
      connections with the ganglion. It is suggested that in the absence of their
      peripheral connections, the axons of FMRFamide immunoreactive neurons fail to
      invade the neural sheath resulting in the accumulation of neurosecretary
      material.

PMID- 12622176
TI  - Induced liver tumour further support to a genetic marker with its high
      correlation with chorioallantoic membrane phenotypes in selected layer lines.
AB  - The conventional chorioallantoic membrane (CAM) phenotype assay was conducted
      using 11-day-old embryonatic eggs of white Leghorn strains, each inoculated with
      0.2 ml of subgroup A Rous sarcoma virus (RSV) and subgroup C RSV separately
      containing 10(3)pfu ml(-1). Eggs were further incubated for hatching. Harvesting
      of CAMs for counting of pocks and monitoring chicks for liver tumour (LT)
      mortality during 4 weeks of post-hatching period were followed. The conversely
      associated phenotype (CAP) incidence i.e. CAM(+) LT(-) and CAM(-) LT(+) was
      observed in all three lines for both subgroup A and C virus infection. The LT
      deaths of chicks in all strains occurred within 21 days post-hatch irrespective
      of virus subgroups. The regression analysis of %LT death (transformed data)
      distributed within pock count range (PCR) basis was performed. The regression
      coefficients (b(i)'s) were found to be non-significant, indicating that %LT death
      did not correlate with number of particles that entered the cells because the
      chicks that had at least 25 pock counts in CAMs died with few exceptions. This
      study upheld the view that the CAM phenotypes (S and R) under the control of a
      pair of alleles, a(s) and a(r) at the tva locus and c(s) and c(r) at the tvc
      locus as reported extensively. Because of a high correlation coefficients between
      CAM and LT phenotypes [S and LT(+)] in respect of subgroup A (r = 0.72) and
      subgroup C (r = 0.81) infection, it is obvious that one could postulate a
      pleiotropic control of the two traits by the tva and tvc genes, respectively.
      Indeed fitting a 4-allele model in both tva and tvc locus, suggesting that CAPs
      are the indicator for nullifying the conventional 2-allele model proposed for the
      induced tumour expression phenotypes by leukosis sarcoma viruses.

PMID- 12622177
TI  - Protein mediated cholesterol absorption in locusts Schistocerca gregaria
      (Forskal) and Locusta migratoria (Linn).
AB  - Absorption and transport of 3H cholesterol from the midgut to hemolymph and other
      tissues was studied in the locusts Schistocerca gregaria and Locusta migratoria.
      S. gregaria are able to absorb dietary cholesterol in the midgut and release into
      the hemolymph in vivo and into the incubation medium in virto. Certain proteins
      of midgut origin are involved in the absorption and release of cholesterol. The
      proteins designated as cholesterol binding proteins (CBP's) were fractionated by
      gel filtration chromatography using Sepharose CL-6B-200 column. Presence of a
      protein and its binding with cholesterol is confirmed by TCA precipitation after
      subsequent incubation of midgut in the incubation medium. Cholesterol binding
      with the proteins was also confirmed in native polyacrylamide gel
      electrophoresis. Biosynthesis of this protein takes place in the midgut which is
      inhibited by a protein synthesis inhibitor, cycloheximide. It also inhibits
      absorption and release of cholesterol from the midgut. The cholesterol binding
      activity was associated with a peak containing proteins ranging from molecular
      weights of 17-32 kDa in SDS-PAGE gels. Treatment of midgut with cycloheximide
      resulted in reduced cholesterol binding activity. Dilipidation of mucin and
      transport in presence of bile salts yielded a higher cholesterol binding
      activity. Although the absorption and release of cholesterol was observed in the
      hemolymph of both sexes, the ovary exhibited higher cholesterol binding as
      compared to testis.

PMID- 12622178
TI  - Acute and sub-acute effects of 2-butenoic acid-3-(diethoxy phosphinothioyl)
      methyl ester (RPR-II) on testis of albino rat.
AB  - Acute and sub-acute toxic effects of a novel phosphorothionate coded as RPR-II on
      testis of albino rats were studied. In acute study rats received a single dose of
      12.3 mg/kg of RPR-II and sacrificed after 24 hr. For sub-acute study 0.58
      mg/kg/day was administered orally to rats for 10 and 21 days. Acute exposure of
      rats to RPR-II brought no change either in the gonadosomatic index (GSI) or in
      the structure of testis or in the serum levels of testosterone. Testis
      glutathione (GSH) level and glutathione S-transferase (GST) activity was
      significantly decreased whereas, acid phosphatase (AcP) levels increased
      significantly at 24 hr post-treatment. On 7th day (withdrawal period) after the
      cessation of the treatment the GSH, GST, AcP, and AkP levels reached to near
      control. The sub-acute study revealed a significant decrease in GSI on 10th and
      21st day of the treatment. In contrast, a time-dependent and significant
      increased in GSH level and GST activity was observed on 100th and 21st day of
      post-treatment, except GSH level on 10th day, which was declined. Due to RPR-II
      treatment the testis AcP and alkaline phosphatase (AkP) levels were significant
      at both 10th and 21st day of medication but AcP levels were increased whereas AkP
      levels decreased. The histopathological studies on day 10th showed considerable
      loss of spermatozoids in testis and at 21st day complete derangement of cellular
      organization was observed. Testosterone levels decreased significantly on 10th
      day and remained significantly low at 21st day. However, withdrawal studies
      showed a recovery in testis of rat treated with RPR-II. GST, GSH, GSI, AcP and
      AkP values recovered, testosterone levels were also well recovered but recovery
      in testis structure remained at a low profile. The present study suggests that
      RPR-II may cause testicular toxicity in rats affecting the normal functioning of
      testis and it also gave some new information in withdrawal studies.

PMID- 12622179
TI  - Effects of short-term treatment of solasodine on cauda epididymis in dogs.
AB  - Oral administration (80 mg/kg body wt/day for 30 days) of solasodine (extracted
      and isolated from the berries of the Solanum xanthocarpum) to intact dogs
      significantly decreased the epithelial cell height of cauda epididymides. The
      cells became atrophic and the lumen was devoid of spermatozoa. Castration
      followed by the adminstration of solasodine further reduced the epithelial cell
      height in comparison to castrated controls. Concurrent treatment of solasodine
      along with testosterone propionate was unable to restore the normal epithelial
      lumen parameters. Total protein, sialic acid, glycogen and acid phosphatase
      activities were significantly reduced in solasodine treated cauda epididymides.
      These result suggest antiandrogenic potency of solasodine.

PMID- 12622180
TI  - 5-HT3 receptors in selective animal models of cognition.
AB  - Role of 5-HT3 receptors in cholinergic hypofunctional models of cognitive
      impairment in the elevated plus maze model and a passive avoidance model is
      studied. Cognitive impairment was caused by scopolamine (1 mg/kg, ip) in mice and
      5-HT3 ligands mCPBG (1 and 5 mg/kg, ip) and ondansetron (0.5 and 5 mg/kg, ip)
      were administered before the pre-learning phase to study the effects on
      acquisition, while post-learning administration was used to determine the effects
      on consolidation. Ondansetron improved acquisition and retention in cholinergic
      hypofunctional models while mCPBG potentiated selected impaired cognitive
      indices. The results indicate the role of 5-HT3 receptors in cognition and that
      an ideal evaluation of 5-HT3 ligands in cognition should distinguish true
      cognitive effects from locomotor, motivational and emotional effects.

PMID- 12622181
TI  - Protective effect of N-acetylcysteine against gamma ray induced damages in rats-
      biochemical evaluations.
AB  - The effect of N-acetylcysteine (NAC) (Ig/kg body weight in saline for 7 days)
      against the damages induced by gamma ray was studied. Whole body exposure of rats
      to gamma-rays (3.5 Gy) caused increases in lipid peroxides (P < 0.01). Reduced
      glutathione (GSH) (P < 0.01) and total sulphydryl groups (TSH) (P < 0.05), were
      found to be increased probably to counteract the damages produced by the lipid
      peroxides. The plasma antioxidant vitamins E, C and A were reduced. The
      activities of antioxidant enzymes, superoxide dismutase (SOD), catalase and
      glutathione peroxidase (GPx) were enhanced, which might be to eliminate the
      superoxide radical and H2O2 and accompanied by a fall in glutathione-s
      transferase (GST) and glutathione reductase (GR) activity. The excessive
      production of free radicals and lipid peroxides might have caused the leakage of
      cytosolic enzymes such as aminotransferases (AST and ALT), lactate dehydrogenase
      (LDH), creatine kinase (CK) and phosphatases. Membrane damage is quite evident
      from histological studies undertaken in the intestinal tissue, which is
      susceptible to radiation damage. Intragastric pretreatment of NAC (1g/kg body
      weight in saline for 7 days) prevented the radiation induced damage to an
      appreciable extent. From the results it may be concluded that NAC is effective in
      protecting from the damages caused by gamma-ray radiations and its prospects as
      an adjuvant to radiotherapy should be considered.

PMID- 12622182
TI  - Inhibition of endocytotic functions in Dictyostelium discoideum treated with a
      carbamate pesticide.
AB  - Administration of a carbamate pesticide carbaryl (1-Naphthyl-N-methyl carbamate)
      at a concentration of 60 and 100 ppm greatly inhibits the endocytotic functions
      during growth of the cellular slime mold D. discoideum. The ingestion of
      fluorescien isothiocynate (FITC) labeled E. coli is reduced between 30 and 40% in
      the treated cells as compared to controls. Similarly, the uptake of FITC-labeled
      dextran, which has been used as fluid-phase marker for pinocytosis also show 40
      50% inhibition in the treated cells. 3H-leucine uptake and incorporation are also
      inhibited in the treated cells. SDS-PAGE analysis of cytoskeletal proteins shows
      a higher actin association with the membrane of treated cells. The results
      demonstrate the detrimental effects of Carbamate on the soil microbe even at a
      very low concentration and the efficacy of the slime mold cells as a biosensor
      for the carbamate-induced cytotoxicity.

PMID- 12622184
TI  - Induction of metabolic shocks in source and sink of two cucurbits by molybdenum
      stress.
AB  - Different concentrations of ammonium molybdate (10(-7) to 10(-4)M) affected the
      levels of metabolites in the source and sink organs of the seedlings of C. melo
      and C. vulgaris and data were recorded at 7, 14 and 21 days after treatment (DAT)
      of molybdenum (Mo). Reducing and non reducing sugars declined with an increase in
      concentration of ammonium molybdate from 10(-7) to 10(-4) M. Soluble protein and
      dry weight of seedlings increased in source at lower concentration (10(-7) M) and
      gradually decreased in all other concentrations (10(-6), 10(-5) and 10(-4) M).
      Starch was slightly accumulated in hypocotyl and fresh weight constantly declined
      with an increase in ammonium molybdate concentration from 10(-7) to 10(-4) M in
      all the parts of seedlings viz. cotyledon, hypocotyl and roots. Thus molybdenum
      at higher concentration induced decline in the metabolite levels in source and
      sink as well as in transporting organs.

PMID- 12622183
TI  - Native state, energetic interaction of chlorophyll precursors and intraplastid
      location of S-adenosyl-L-methionine: Mg-protoporphyrin IX methyltransferase in
      etiolated leaves.
AB  - Low temperature fluorescence spectra (FS) and fluorescence excitation spectra
      (FES) of protoporphyrin IX (Proto), Mg-protoporphyrin IX and its monomethyl ester
      (MgProto-ME) and protochlorophyllide (Pchlide) in etiolated barley leaves treated
      with 5-aminolevulinic acid and/or 2,2'-dipyridyl were studied. The spectra of
      Proto and MgProto-ME showed a little dependence on temperature of registration
      and exhibited similarity to low temperature spectra in diluted organic and buffer
      solutions. However, a red wavelength shift for Soret bands of Proto and MgProto
      ME was observed due to porphyrin interaction with bovine serum albumin in 0.05 M,
      Na2HPO4 solution at room temperature. Disaggregating treatments had no effect on
      Proto and MgProto-ME spectra in plants. These results suggested that in etiolated
      leaves Proto and MgProto-ME molecules were in a monomer state. The spectral
      properties of these molecules were determined by interaction of porphyrins with
      proteins and other plastid membrane components. The spectral analyses indicated
      an efficient energy migration from Proto and MgProto-ME molecules to active form
      of Pchlide which emitted at 656nm, and no energy transfer from carotenoids to
      porphyrins in vivo. These findings suggested that Proto and MgProto-ME from
      carotenoids, and close location of these porphyrins and photoactive Pchlide in
      etioplast membranes. The latter conclusion was strongly supported by an
      observation that in etiolated leaves, S-adenosyl-L-methionin:Mg-protoporphyrin IX
      methyltransferase, which converts MgProto into MgProtoME, were located not only
      in prothylakoids but also in prolamellar bodies containing photoactive Pchlide.

PMID- 12622185
TI  - RAPD based DNA markers linked to anthracnose disease resistance in Sorghum
      bicolor ( L.) Moench.
AB  - Anthracnose caused by Colletotrichum graminicola is one of the major diseases of
      sorghum. The locus for disease resistance in sorghum [Sorghum biocolor (L.)
      Moench] accession G73 was found to segregate as a simple recessive trait in a
      cross to susceptible cultivar HC136. In order to identify molecular markers
      linked to the locus for disease resistance, random amplified polymorphic DNA
      (RAPD) analysis was coupled with bulk segregant analysis. DNA from the parental
      cultivars and the bulks were, screened by PCR amplification with 114 RAPD
      primers. Three RAPD primers amplified a sequence that consegregated with the
      recessive resistance allele, while another three amplified a band linked to the
      susceptible allele. The six disease linked markers were screened with individual
      resistant and susceptible genotypes to observe degree of linkage of identified
      RAPD markers with the gene for resistance. Two primer sequences (OPI 16 and OPD
      12) were found to be closely linked to the locus for disease resistance.

PMID- 12622186
TI  - In vitro propagation of Lagerstromia parviflora Roxb. from adult tree.
AB  - A micropropagation protocol based on axillary bud proliferation has been
      developed from mature Lagerstromia parviflora adult tree. Nodal segments cultured
      on woody plant medium supplemented with 5.0 microl. BAP and 0.25 microm IAA gave
      maximum (86.9%) morphogenetic response. Proliferated shoots (10.7 per explants)
      were elongated to 3.9 cm within 6 weeks. In vitro produced micro-shoots were
      subjected to an IBA treatment (500 ppm for 2 min. dip) and placed under misting
      conditions for rooting. Misting beds were prepared with sand: soil (3:1) for
      80.6% rooting and was acclimatized. Shoot length seems to be important to induce
      adventitious roots. The highest (91.7%) rooting was recorded on shoots ranging a
      length between 3.1-4.0 cm. Rooted and hardened plants were later transferred to
      poly bags and maintained in shadenet house. The protocol has the realizes
      capacity to produce 260 plants from a single explants within 10 months
      multiplication cycle.

PMID- 12622187
TI  - Impact of copper application on soil metabolism, energy budget and formation of
      stable aggregates by anecic earthworm in tea plantations.
AB  - The preparation of daily energy budget of earth worm Lampito mauritii showed (i)
      decrease in consumption by about 66%, (ii) decrease of egestion 97%, (iii)
      decrease in growth by 80%, and (iv) enhancement in maintenance cost by about
      31.5% on exposure to 8 ppm copper in comparison to zero level exposure. The
      stable aggregate formations also decreased by 67.6% at 8 ppm copper as compared
      to zero level exposure. Two way ANOVA showed significant decrease in stable
      aggregate formation and biomass at 5% level of significance on exposure to 8 ppm
      copper. The soil metabolism also increased under the negative impact of copper.

PMID- 12622188
TI  - Potentiality of a new compound for in vitro differentiation between halophilic
      and non-halophilic vibrios.
AB  - Sensitivity of 21 halophilic vibrios and 16 clinical isolates of non-halophilic
      vibrios was determined against a new possible antivibrio agent, a pyrimidine
      analogue, 4, 6-dimethylpyrimidine -2-thiol (4,6-DMPT). It appeared to be a
      vibriocidal agent, having a mean MIC and MBC of 32 microg/ml for halophilic
      strains and 64 microg/ml for non-halophilic strains and an LD50 of 300 mg/Kg body
      weight of mice. Thus, 4,6-DMPT may help an in vitro distinction between
      halophilic and non-halophilic vibrios. Sensitivity of these strains was also
      studied with respect to pteridine, crystal violet and Tween 80 hydrolysis as
      further markers distinguishing between these 2 groups which could also be
      differentiated by their growth on TCBS or/and CLED media.

PMID- 12622189
TI  - Assessment of performance of UV sterilizer for room air bacteria.
AB  - Paper presents a technique for performance of UV sterilizer for room air
      bacteria. Patterns of decay of room air bacteria concentration during
      sterilization and build-up there after as a function of time is studied. Decay
      process seems to follow exponential pattern. Half-lives during decay are
      estimated. For single sterilizer unit with a dose of 16 W the decay half-life is
      around 8.6 min. For the dose of 32 W (2 sterilizers), half-life is estimated to
      be 6.18 min. The removal rates of room air bacteria due to sterilizer are
      compared with the natural decay of aerosols at steady state. The importance of
      decay half-life in the assessment has been stated. The bacteria concentration
      buildup process after putting off the sterilizers seems to be sigmoidal in
      nature. The buildup half-life is estimated to be around 53 min for present
      experimental conditions.

PMID- 12622190
TI  - Reversibility of oxygen induced inactivation of nitrogenase in some
      enterobacteria.
AB  - Aerobic and microaerobic diazotrophs possess numerous oxygen restriction
      strategies to protect nitrogenase from inactivation by oxygen without interfering
      with energy generation through oxidative phosphorylation. Protection by
      conformational change in nitrogenase was first detected and described in
      Azotobacter. This strategy once considerd unique for Azotobacter has been shown
      in this study to occur in Citrobacterfreundii (Braak) Werkman and Gillen and
      Klebsiella pneumoniae subspecies rhinoscleromatis (Trevisan) Migula also.
      However, in these enteric bacteria the entire enzyme is not protected probably
      due to the absence of any respiratory protection similar to that found in the
      aerobe, Azotobacter.

PMID- 12622191
TI  - High frequency in vitro production of microrhizomes of Curcuma amada.
AB  - Microrhizomes were induced at the base of the in vitro derived shoots of Curcuma
      amada grown in the liquid MS medium supplemented with BA (5 mg/l), sucrose (80
      g/l) and incubated under 16 hr photoperiod. They were produced year round in
      culture, harvested after 90 days of growth in medium, and could be used as seeds
      and germinated to plantlets showing normal growth.

PMID- 12622192
TI  - Partial molecular characterization of some kiwi fruit cultivars by RAPD markers.
AB  - Molecular variability among seven cultivars of A. deliciosa var. deliciosa was
      investigated through RAPD markers. Thirty four decamer primers were screened
      generating polymorphic patterns of amplified DNA for these cultivars. Twenty one
      selected primers gave clear and reporducible patterns. A total of 430 bands were
      produced and 29.37% of them were polymorphic. The patterns distinguished between
      the cultivars and their analysis established an approach to classification within
      A. deliciosa var. deliciosa based on RAPD markers. The dendrogram clearly
      differentiated male from female cultivars. While abbot and allison female
      cultivars were closely related, bruno and abbot female cultivars showed maximum
      dissimilarity.

PMID- 12622193
TI  - Symposium on 'challenges in clinical pharmacology.'.

PMID- 12622194
TI  - Identification and isolation of insect pheromone gene: a model worth
      experimentation.

PMID- 12622195
TI  - Programmed cell death and its clinical implications.
AB  - Cell death is a highly regulated process that is ubiquitous in all eukaryotes.
      Programmed cell death (PCD) is an integral part of both animal and plant
      development. Studies on apoptosis, the well characterized form of programmed cell
      death led to the identification of a central tripartite death switch i.e.
      apoptosome consisting of Apaf-1, Apaf-2 and Apaf-3. The caspases, a family of
      cysteine-dependent aspartate directed-proteases, constitute the central
      executioners of apoptosis. Much of the attention on programmed cell death is
      focused on caspases, however, cell death can still occur even when the caspase
      cascade is blocked, revealing the existence of nonapoptotic alternative
      pathway(s) of cell death. The mitochondrial release of cytochrome C following a
      PCD inducing stimulus in both plants and animals suggests the evolutionary
      conservation of death pathways. Dysregulation of apoptosis may be related to the
      development of several disease states as well as ageing. Excessive apoptosis is
      associated with neurodegenerative disorders, AIDS etc., whereas deficient
      apoptosis is associated with cancer, auto-immunity, viral infections etc.
      Understanding the regulation of programmed cell death would throw light in
      designing drugs and gene therapies that can target specific molecules in the
      apoptotic pathway opening the vistas for new therapeutic endeavors in many areas
      of medicine.

PMID- 12622197
TI  - Development of biological tissue-equivalent phantoms for optical imaging.
AB  - Optical characteristics of freshly isolated tissues depend on their color and
      composition. The surface backscattered profile, which account for the tissue
      compositional variation in fresh excised sheep's heart, lungs, bone and muscle,
      were measured by multi-probe reflectometer. Optical phantoms were prepared from
      paraffin wax by mixing a specific combination of wax color materials till the
      surface backscattered profile of these matched with that of the biological
      tissues. The optical parameters absorption coefficient (micro(a)), reduced
      scattering coefficient (micro(s)) and anisotropy factor (g) of these phantoms,
      are the same as that of biological tissues and are obtained by matching their
      surface backscattered profiles with that as simulated by Monte Carlo procedure.
      The maximum and minimum values of absorption coefficient are for the phantoms of
      lungs (1.0 cm(-1)) and muscle (0.02 cm(-1)), whereas, for scattering coefficient
      these values are for muscle (21.2 cm(-1)) and bone (13.08 cm(-1)).

PMID- 12622196
TI  - Protective effect of RH-3 with special reference to radiation induced micronuclei
      in mouse bone marrow.
AB  - Effect of pre-irradiation administration of different doses of RH-3, the herbal
      preparation of an Indian medicinal plant Hippophae rhamnoides, 30 min before 10
      Gy whole body gamma irradiation was studied. Doses between 25 to 35 mg/kg body
      wt. were found to render > 80 % survival in mice. In order to investigate whether
      RH-3 protected against radiation induced genotoxicity, mice were administered
      different doses of RH-3, 30 min before 2 Gy dose and compared with untreated, RH
      3 treated and irradiated controls. The bone marrow cells were collected at
      different time intervals following various treatments and processed for scoring
      micronuclei (MN). Administration of RH-3 alone did not enhance the MN frequency
      as compared to the control, and radiation dose of 2 Gy significantly enhanced the
      MN frequency (3.1 %, P < 0.01). Pre-irradiation treatment with RH-3, however,
      reduced the radiation induced MN frequency in a drug dose dependent manner
      suggesting its radioprotective efficacy. The protective effect of RH-3 on
      radiation induced perturbations in cell cycle progression was studied
      flowcytometrically in mouse bone marrow cells. RH-3 treatment (30 mg/kg body wt.)
      enhanced DNA synthesis (S-phase) in unirradiated controls and also countered
      radiation induced depression of S-phase to facilitate replenishment of cells lost
      due to radiation injury.

PMID- 12622198
TI  - Alteration of ingestive behaviours by nucleus accumbens in normal and
      streptozotocin-induced diabetic rats.
AB  - Twenty-four hour basal food and water intakes were recorded in Wistar rats.
      Diabetes was produced in a group of rats by injecting streptozotocin (STZ, 75
      mg/kg, b.w., IP) and their post-diabetic basal food and water intakes were
      recorded. Noradrenaline (2 microg) and dopamine (2 microg) were injected
      separately into the nucleus accumbens through the implanted cannula in non
      diabetic and diabetic animals and their 24 hr food and water intakes were
      recorded. Food and water intakes were also recorded following bilateral
      electrolytic lesions of nucleus accumbens in both the groups of rats. In diabetic
      rats, basal food and water intakes were significantly increased in comparison to
      basal intakes of non-diabetic rats. Following injection of noradrenaline, a
      significant increase in water intake but not food intake was seen in non-diabetic
      rats, whereas food and water intakes remained unchanged in diabetic rats.
      Following injection of dopamine, a significant increase in food and water intakes
      was observed in non-diabetic rats, whereas dopamine-induced increase in food
      intake was absent in diabetic rats. The bilateral lesions of nucleus accumbens
      resulted in a significant inhibition of food and water intakes in non-diabetic
      rats, whereas inhibition of water intake without change in food intake observed
      in diabetic rats. However, no difference was observed in the pattern of change in
      water intake following lesions or dopamine injections between non-diabetic and
      diabetic rats, whereas difference was observed for food intake. The results
      suggest that nucleus accumbens activity changes for food intake, but not for
      water intake in diabetes.

PMID- 12622199
TI  - Vestibulo-cerebellar participation in protection of duodenal mucosa: possible
      role of neurotransmitters.
AB  - Vestibulo cerebellar lesion in rats produced a decrease in the intracellular
      presecreted mucus together with a decrease in the norepinephrine (NE) and
      serotonin (5HT) content of the duodenal tissue. Whereas vestibulo cerebellar
      stimulation by rotation produced an increase in the intracellular presecreted
      mucus and an increase in the NE content of the duodenal tissue but very little
      increase in 5HT content of the duodenum. The results suggest that the vestibulo
      cerebellum by modulating the tissue content of the neurotransmitter NE and 5HT
      has a direct influence in the protective mechanism through the intracellular
      mucus content.

PMID- 12622200
TI  - Neurotoxicity of fluoride: neurodegeneration in hippocampus of female mice.
AB  - Light microscopic study of hippocampal sub-regions demonstrated significant
      number of degenerated nerve cell bodies in the CA3, CA4 and dentate gyrus(Dg)
      areas of sodium fluoride administered adult female mice. Ultrastructural studies
      revealed neurodegenrative characteristics like involution of cell membranes,
      swelling of mitochondria, clumping of chromatin material etc, can be observed in
      cell bodies of CA3, CA4 and dentate gyrus (Dg). Fluoride intoxicated animals also
      performed poorly in motor co-ordination tests and maze tests. Inability to
      perform well increased with higher fluoride concentration in drinking water.

PMID- 12622201
TI  - Effect of preservative, antioxidant and viscolizing agents on in vitro
      transcorneal permeation of ketorolac tromethamine.
AB  - The influence of formulation additives, e.g. preservative, antioxidant and
      viscolizing agents on in vitro transcorneal permeation of ketorolac tromethamine
      from 0.5%(w/v) aqueous drop was studied using goat cornea. Permeation
      characteristics of drug, from selected formulations, through excised rabbit
      cornea were also evaluated. Aqueous solution of ketorolac tromethamine (0.5%
      w/v), pH 6.5 or 7.0 having ionic strength 0.2, was prepared. To this solution
      perservatives either alone or in combination with other additives were added to
      have drops of various composition. Permeation studies with goat cornea showed
      maximum permeation of ketorolac tromethamine from formulation containing
      benzalkonium chloride and disodium edetate. Increase in viscosity of drop
      resulted in decreased permeation of drug. Formulation containing benzalkonium
      chloride and disodium edetate also increased permeation of drug through rabbit
      cornea. Cumulative permeation of drug through rabbit cornea was found to be 2.3
      2.4 fold higher than that observed with goat cornea.

PMID- 12622202
TI  - Effect of honey on carbamazepine kinetics in rabbits.
AB  - The study was undertaken to determine the effect of honey on carbamazepine
      kinetics in rabbits. The study was done on three occasions in each animal. Study
      1 was carried out after single dose administration of carbamazepine (80 mg/kg,
      po), along with saline (2.34 ml/kg, po). After a wash out period of one week, the
      second study was carried out by co-administration of carbamazepine with honey
      (2.34ml/kg, po). After this, the animals continued to receive honey (2.34ml/kg,
      po), once daily, for 7 days. On the eighth day of honey treatment, the
      carbamazepine kinetics was studied again. Pharmacokinetic analysis revealed that
      single as well as multiple dose honey treatment showed a significant decrease in
      area under the plasma time concentration curve (AUC) when compared with saline
      treated control. A significant increase in the clearance (CL/F) rate of
      carbamazepine was observed only after multiple dose honey treatment. Both single
      and multiple dose honey treatment did not show any significant effect on other
      pharmacokinetic parameters like t1/2, Cmax, Tmax and Vd when compared with saline
      treated group. Data thus obtained suggested that honey decreases the
      bioavailability of carbamazepine.

PMID- 12622203
TI  - Modulation of acute cadmium toxicity by Emblica officinalis fruit in rat.
AB  - The efficacy of Emblica officinalis in modifying the acute cytotoxicity of
      cadmium in male rats was evaluated. Oral administration of Emblica fruit juice
      (500 mg/kg, b.w.) for 8 days followed by a single toxic dose of Cd as CdCl2 (3
      mg/kg,b.w. ip), considerably reduced the mortality in rats as well as prevented
      to some extent the cadmium induced histopathological damage in testis, liver and
      kidneys. Biochemical investigation also revealed reduced levels of Cd induced
      serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and
      gamma glutamyltranspeptidase. The enhanced levels of Cd and lipid peroxidation in
      liver, kidney, and testes and metallothionein and total sulphydryl in liver and
      kidney by Cd were significantly reduced by Emblica pretreatment. These results
      suggest cytoprotective potential of Emblica fruit in acute cadmium toxicity which
      could be due to its multiple role in biological system.

PMID- 12622204
TI  - Effect of the aqueous extract of African mistletoe, Tapinanthus sessilifolius (P.
      Beauv) van Tiegh leaf on gastrointestinal muscle activity.
AB  - Effects of the aqueous extract of T. sessilifolius on the gastrointestinal muscle
      were investigated on smooth muscle preparations isolated from rabbit jejunum,
      guinea pig ileum and on gastrointestinal transit in mice. Elemental analysis of
      the extract was also carried out. The aqueous extract of T. sessilifolius evoked
      a concentration dependent contraction of the rabbit jejunum and guinea pig ileum.
      The contractions evoked by the extract were not attenuated either by atropine or
      mepyramine, but they were completely blocked by verapamil. The elemental analysis
      revealed the presence of Mg, Zn, Fe, Cu, and very high concentration of Ca. The
      intraperitoneal LD50 in mice was found to be 1500 mg/kg. The aqueous extract of
      T. sessilifoliius possesses active components that may be mediating the observed
      biological activity through calcium mobilization.

PMID- 12622205
TI  - Role of chelating agents and antioxidants in beryllium induced toxicity.
AB  - The present study was conducted to evaluate the therapeutic effectiveness of
      chelating agents [glutathione, 2,3 dimercapto propane sulfonic acid (DMPS) and D
      penicillamine (DPA)] in combination with antioxidant (sodium selenite) in
      beryllium induced toxicity in female rats. A bolus dose of 50mg/kg-beryllium
      nitrate was administered singly followed by chelation therapy with GSH, DMPS + Se
      and DPA + Se at various durations of 1,3 and 7 days respectively. Results
      revealed a significant fall in the glycogen content, whereas, a marginal fall in
      the protein was also observed. The enzymatic activity of alkaline phosphatase and
      adenosine triphosphatase was depleted; on the contrary, there was a significant
      rise in the acid phosphatase and glucose-6-phosphatase pattern. A rise in the
      hepatic lipid peroxidation activity is a direct indication of oxidative damage
      resulting in free radical generation. The distribution of the metal by atomic
      absorption spectrophotometry revealed an increased concentration of beryllium in
      liver and kidney, followed by lung and uterus. The relative ability of three
      chelating agents to act as antagonists, for acute beryllium poisoning, have been
      examined in liver, kidney, lungs and uterus. The appreciable change in the
      beryllium concentration in various organs is duration dependent during the entire
      period being highly significant at 7 days regimen. Biochemical and distribution
      studies reveal that DPA + Se was the most effective therapeutic agent followed by
      DMPS + Se and GSH.

PMID- 12622206
TI  - Role of esterases and monooxygenase in the deltamethrin resistance in Anopheles
      stephensi Giles (1908), at Mysore.
AB  - Field collected An. stephensi larvae were colonized in the laboratory for 15
      generations and acclimatized. An isofemale line was raised from this colony and
      the larvae were subjected to continuous deltamethrin selection pressure. LC50 and
      LC90 values were calculated at every generation. The values indicated that at the
      end of seventh generation the larvae have developed 87 fold tolerance in terms of
      LC50 value compared with the first generation. The reason for this kind of
      resistance was analyzed on the basis of differential activity of A-esterase, B
      esterase, glutathione s-transferase (GST) and glucose 6-phosphate dehydrogenase
      (G6PD). A significant correlation (P < 0.05) was observed with B-esterase and
      G6PD activity with the rise in the LC50 and LC90 values. However no significant
      rise were observed in the other enzymes tested such as A-esterase and GST. The
      isozyme analysis of the A-esterase and B-esterase using polyacrylamide gel
      electrophoresis (PAGE) have shown differential profiles.

PMID- 12622207
TI  - Sublethal temperature stress in juvenile Labeo rohita (Ham-Buch.) and Rita rita
      (Ham.): some physiological changes.
AB  - Juveniles of fish L. rohita and R. rita subjected to a rapid (5 min) sublethal
      temperature increase from 28 to 35 degrees C showed significant increase in
      cortisol and decrease in interrenal ascorbic acid. Hypercholesterolemia,
      hyperglycemia and hyperlactemia were also evident accompanied by increased blood
      haemoglobin and haematocrit and stable protein levels. Compensatory responses
      were initiated within 72 hr in both the fishes. R. rita recovered more quickly
      indicating it to be more resistant to the heat stress than L. rohita. Hence
      fishes subjected to sublethal temperature stress should be given a metabolic
      recovery period of 72 hr prior to further stress being applied.

PMID- 12622208
TI  - Physiological and biochemical alterations in Anabaena 7120 under iron stress.
AB  - Various physiological and biochemical process like growth, NO3- -uptake, nitrate
      reductase, glutamine synthetase and ATPases (Mg2+ and Ca2+ dependent) in the
      cyanobacterium Anabaena 7120 were observed under iron stress. Growth was found to
      be maximum in 50 microM Fe3+ added cells however, 20 microM Fe3+ (the Fe3+
      concentration generally used for routine culturing of cyanobacterial cell in Chu
      10 medium) incubation resulted in lower growth. Fe3+ starvation on the other hand
      showed very poor growth up to 4th day but once the growth started it reached at
      significant level on 7th day. Higher Fe3+ concentration reflected reduced growth
      with lethality at 500 microM Fe3+. Chlorophyll a fluorescence under Fe3+ stress
      reflected almost the similar results as in case of growth. However, the pigment
      was found to be more sensitive as compared to protein under Fe3+ stress. Similar
      results have been observed in case of NO3-uptake with only 80% reduction in
      nutrient uptake in 500 microM Fe3+ incubated cells. Nitrate reductase activity
      was lower in Fe3+ starved cells as compared to significant enzyme activity in 20
      and 50 microM Fe3+ incubated cells. Similar to nitrate reductase, glutamine
      synthetase also showed maximum level in 50 microM Fe3+ added cells, however,
      higher Fe3+ concentration (300-500 microM ) resulted in reduced enzymatic
      activity. Glutamine synthetase activity was less sensitivity as compared to
      nitrate reductase activity under Fe3+ stress. ATPase (Mg2+ and Ca2+ dependent)
      always showed higher level with increasing Fe3+ concentration.

PMID- 12622209
TI  - Efficient protocol for in vitro direct plant regeneration in chickpea Cicer
      arietinum L.
AB  - An efficient plant regeneration system was developed for two important Indian
      chickpea cultivars, C-235 and HC-1. Immature cotyledons (7-8 mm) directly formed
      shoots without an intervening callus phase on MS medium containing B5 vitamins,
      BAP (2.0 mg/l), IBA (0.125 mg/l), AgNO3 (1.69 mg/l) and phytagel (2.5 g/l). The
      regenerated shoots had normal morphology and were successfully rooted in half
      strength MS medium under partial dark conditions. Regenerated plants were
      transferred to potted soil. However, the survival rate of pot house transferred
      plants was 17.6 per cent.

PMID- 12622210
TI  - A new assembly and technique for testing insecticides.
AB  - A new design of insecticide testing assembly has been devised that is highly
      versatile in testing the efficacy, potency and interaction of insecticides and
      other test chemicals. The merits of the assembly and technique have been
      explained.

PMID- 12622211
TI  - Establishment of asymptomatic Leishmania donovani infection in Indian langurs
      (Presbytis entellus) through intradermal route.
AB  - Indian langurs, which were previously reported to be highly susceptible, were
      infected intradermally using variable numbers of promastigotes along with
      different doses, 1/2 pair, 5 pairs and 10 pairs respectively of salivary gland
      lysate (SGL). Although, all the monkeys developed mild infection and remained
      subclinically infected throughout the observation period, which later resolved,
      none of them could develop the classical disease. No marked antigen specific
      antibody or lymphoproliferative response was noticed throughout the experimental
      period. However, a late IFN-gamma response (by day 90 pi.) was demonstrated in
      monkeys infected with 2 x 10(6) promastigotes +10 pairs SGL. It seems that a
      single intradermal dose of promastigotes with or without SGLs had a vaccines like
      effect. Perhaps, multiple frequent inoculations, as happens in the natural
      situation, may be necessary for the development of full-blown disease.

PMID- 12622212
TI  - Ovary specific immune response during Plasmodium yoelii yoelii infection in
      malaria vector Anopheles stephensi (Diptera:Insecta).
AB  - Innate immune related polypeptides expression during three gonotrophic cycles in
      the ovaries of major disease vector mosquito A. stephensi has been analyzed
      following infection by malaria parasite, P. yoelii yoelii. Seventeen polypeptides
      were induced in the ovaries of various stages due to parasitic infection. Most of
      proteins were induced systemically during early stages of infection suggesting
      the possibility of immune related signalling process. The reduction in the
      quantity of protein contents in infected mosquitoes has been ascribed to the
      repression of seven polypeptides and in turn correlated with the fecundity
      reduction. The mechanism of these responses and their significance for malaria
      transmission and fecundity reduction are discussed.

PMID- 12622213
TI  - R-factor in Proteus vulgaris from ulcerative disease of fish, Channa punctatus.
AB  - A Proteus vulgaris isolated from external ulcers of the fresh water fish Channa
      punctatus showed multidrug resistance and heavy metal tolerance. The isolate from
      the ulcer showed resistance to chloramphenicol (Ch), nalidixic acid (Nx),
      streptomycin (Str) and tetracycline (Tet) with minimum inhibitory concentration
      (MIC) values of 750, 150, 75 and 125 microg/ml, respectively. The isolate showed
      growth in medium containing cadmium (Cd2+), up to a concentration of 2.5 mM
      indicating its heavy metal tolerance. Resistance to Ch, Str, Tet and Cd2+ of the
      isolate was lost after plasmid curing. Presence of plasmid DNA in the wild type
      and its absence in the cured P. vulgaris suggested that the resistance were
      plasmid mediated.

PMID- 12622214
TI  - Effect of vitamin C on endothelial dysfunction during N-alpha-tosyl L-arginine
      methyl ester [TAME]-esterase induced contractions in rat aorta in vitro.
AB  - Contractions induced by TAME-esterase on rat aorta strips mounted in vitro were
      significantly inhibited in presence of Vitamin C. The work lends support to the
      role of ascorbic acid in preventing endothelial dysfunction through release of
      nitric oxide. It is suggested that conclusions TAME-esterase could be an
      important biological marker associated with onset of vascular discases such as
      hypertension.

PMID- 12622215
TI  - In vitro propagation of Dendrobium macrostachyum Lindl.--a threatened orchid.
AB  - In vitro propagation of Dendrobium macrostachyum, a threatened and endemic
      species was achieved through nodal explants. The nodal explants were cultured on
      Murashige and Skoog (MS) basal medium and MS medium supplemented with N6
      benzyladenine (BA-2.22, 4.44 and 8.88 microM), Kinetin (KN-2.32, 4.65, and 9.29
      microM) and Coconut water (CW, 5, 10 and 15%) individually or in combination with
      2.69 microM alpha-naphthalene acetic acid (NAA). Axillary shoots were induced
      directly from nodal explants in medium containing BA, KN or CW. Optimal shoot
      induction (6 shoots/explant) was attained from nodal explants cultured on medium
      supplemented with 15% CW. Well developed shoots rooted at an average 5 roots per
      shoot in half strength MS medium devoid of any growth regulators.

PMID- 12622216
TI  - Somatic embryogenesis and plant regeneration from immature embryo explant of
      papaya (Carica papaya L. cv. washington and honey dew).
AB  - Immature zygotic embryo explants of Carica papaya were cultured on MS medium
      supplemented with 2,4-D (2.0 mg/l) and formed globular embryos on explants
      without callus formation in 4-6 weeks. Maturation and conversion of somatic
      embryos was also achieved on the same medium. Cotyledonary stage embryos
      germinated to 63.66 and 68.33% in cv. honey dew and washington respectively in MS
      basal medium supplemented ABA (0.5 microm/l). Robust development and
      proliferation of plantlet roots in vitro was obtained on MS basal medium.
      Hardened plantlets have 60% survival rate.

PMID- 12622217
TI  - New, simple and cheap alternative to troponin test for diagnosis of acute
      myocardial infarction.
AB  - Acute myocardial infarction (AMI) is often a fatal disorder in humans seen
      throughout the world. It was earlier diagnosed with some serum enzymes like
      aspartate transaminase, creatine phosphokinase and its isoenzyme CPK-MB and
      lactate dehydrogenase which were shown to be increased in AMI. However, in the
      last few years importance has been given to measuring serum troponins released
      from the injured myocardium to confirm an AMI. Troponin estimation involves
      immunological technique, which is expensive with other associated problems like
      shelf life of reagents, number of samples to be analysed and availability of the
      kit itself, used for estimation. Under these circumstances the present work
      involves the measurement of total salt soluble proteins which are proteins
      associated with troponins also released from myocardium of a patient with AMI.
      This new test overrules all the disadvantages of the troponin test but seems
      equally viable and useful for diagnosis of AMI.

PMID- 12622218
TI  - The pyoverdin of Pseudomonas fluorescens G173, a novel structural type
      accompanied by unexpected natural derivatives of the corresponding ferribactin.
AB  - The siderophores produced by Pseudomonas fluorescens G173 are unusual in several
      respects. So far all pyoverdins with a C-terminal cyclopeptidic substructure have
      in common that the epsilon-amino group of an in-chain Lys is bound amidically to
      the carboxyl group of a C-terminal Ser or Thr and that N5-formyl-N5-hydroxy Orn
      (FoOHOrn) is the next amino acid after Lys. FoOHOrn may (cyclotetrapeptidic
      structures) be or may not (cyclotripeptidic structures) be followed by a further
      amino acid. In the pyoverdin described here Orn instead of Lys is the amino acid
      forming the cycle, FoOHOrn is replaced by AcOHOrn which does not follow the
      branching Orn but is the penultimate amino acid and finally the last amino acid
      is Asp. The producing strain which had been classified as Pseudomonas fluorescens
      may well be a new species. Pyoverdins are frequently accompanied by ferribactins
      which are considered to be their biogenetic precursors. They always have the same
      amino acid chain as the co-occurring pyoverdins but the pyoverdin chromophore is
      replaced by a condensation product of L-Dab and D-Tyr with the amino group of Tyr
      bound to the gamma-carboxyl group of Glu. A ferribactin having these structural
      characteristics is produced by the investigated strain, but it is accompanied by
      derivatives where the alpha-amino group of Glu is partially or completely
      transformed into a hydroxamic acid by substitution with a hydroxyl and/or acetyl
      group.

PMID- 12622219
TI  - Flavonoids from Achillea nobilis L.
AB  - The detailed investigation of a methanolic extract of aerial parts of Achillea
      nobilis resulted in the isolation of 10 flavonoids. A new C-glycosylflavone,
      luteolin-6-C-apiofuranosyl-(1'''-->2'')-glucoside, was isolated besides orientin,
      isoorientin, vitexin, isoschaftoside, luteolin-7-O-beta-glucuronide, luteolin-4'
      O-beta-glucoside and quercetin-3-O-methyl ether and two rare flavonolglycosides,
      quercetin-3-O-alpha-arabinosyl-(1'''-->6'')-glucoside and quercetin-3-O
      methylether-7-O-beta-glucoside. The structures were established either by
      comparison with authentic substances or by UV, 1H NMR and 13C NMR spectroscopic
      methods including 2D-NMR techniques and ESI-MS.

PMID- 12622220
TI  - Cytotoxic hydroazulene diterpenes from the brown alga Dictyota dichotoma.
AB  - Two new hydroazulenoid (prenyl guaiane) diterpenes, dictyone acetate (2) and 3,4
      epoxy 13-hydroxy pachydictyol A (4) were isolated from the petroleum ether
      fraction of the alcoholic extract of the brown alga, Dictyota dichotoma (Hudson)
      Lamouroux, which was collected from the Red Sea coasts at Hurgada, Egypt,
      together with three known ones, pachydictyol A (1), dictyone (3) and 11
      hydroxypachydictyol A (dictyol E) (5). In addition, the steroidal compound,
      stigmasta-5,(E)-24(28)-dien-3-beta-ol (fucosterol) (6) was also isolated. The
      structures of the isolated compounds have been determined on the basis of
      spectroscopic evidences as well as physical and chemical correlation with known
      compounds. Compounds 1, 2, 3 and 5 showed moderate cytotoxic activity.

PMID- 12622221
TI  - New erythroxane-type diterpenoids from Fagonia boveana (Hadidi) Hadidi & Graf.
AB  - The aerial parts of Fagonia boveana afforded two new erythroxane-type diterpenes,
      3beta,15,16-trihydroxy-erythrox-4(18)-ene (2) and 15,16-dihydroxy-cis-ent
      erythrox-3-ene (fagonene) (3) together with two known ones; 16-O-acetylfagonone
      (1) and 7beta-hydroxy fagonene (8). Also a new guaiane sesquiterpene alcohol,
      6,10-epoxy-4alpha-hydroxy guaiane type sesquiterpene (4) has been isolated. In
      addition three 8-methoxy flavonols, 8-methoxy-quercetin-3,7,3'-trimethyl ether
      (ternatin) (5), gossypetin, 3,8,3',4' tetramethyl ether (6) and herbacetin-3,8
      dimethyl ether (7) were also isolated. The structures of the isolated compounds
      have been determined on the basis of spectroscopic evidences as well as physical
      and chemical correlation with known compounds. On performing different assays for
      biological activities, 6 displayed significant cytotoxic activity against KA3IT
      and NIH3T3 cell lines, 8 was the most active antiviral against Herpes simplex
      type 1 while 7 was the most active cancer-preventive agent using protein-tyrosine
      kinase inhibitory method.

PMID- 12622222
TI  - Cytotoxic hydroazulene diterpenes from the brown alga Cystoseira myrica.
AB  - Cytotoxicity-guided fractionation of the alcohol extract of the brown alga,
      Cystoseira myrica, afforded four new cytotoxic hydroazulene diterpenes, dictyone
      acetate (2), dictyol F monoacetate (4), isodictytriol monoacetate (6), and
      cystoseirol monoacetate (8), together with two known cytotoxic hydroazulene
      diterpenes, pachydictyol A (1) and dictyone (3). The constitution of each
      isolated compound has been determined on the basis of spectroscopic and chemical
      evidence.

PMID- 12622224
TI  - Alkaloid spectrum in diploid and tetraploid hairy root cultures of Datura
      stramonium.
AB  - Hairy root cultures were obtained from diploid and induced tetraploid plants of
      Datura stramonium and analyzed by gas chromatography/mass spectrometry. Twenty
      alkaloids (19 for diploid and 9 for tetraploid hairy root cultures) were
      identified. A new tropane ester 3-tigloyloxy-6-propionyloxy-7-hydroxytropane was
      identified on the basis of mass spectral data. Hyoscyamine was the main alkaloid
      in both diploid and tetraploid cultures. In contrast to diploid hairy roots, the
      percentage contributions of the alkaloids, with exceptions for hyoscyamine and
      apoatropine, were higher in the total alkaloid mixture of tetraploid hairy roots.

PMID- 12622225
TI  - Chemical constituents from the infusion of Zollernia ilicifolia Vog. and
      comparison with Maytenus species.
AB  - The new flavonoid glycoside kaempferol-3-O-alpha-L-rhamnopyranosyl(1-->2)-O
      [alpha-L-rhamnopyranosyl(1-->6)]-O-beta-D-galactopyranoside-7-O-alpha-L
      rhamnopyranoside was isolated together with (S)-zierin from the leaves of
      Zollernia ilicifolia (Fabaceae), a medicinal plant used as analgesic and
      antiulcerogenic effects in Brazilian Tropical Atlantic Rain Forest. The
      structures were established on the basis of 1H, 13C NMR and 2D NMR (COSY, HMBC,
      HMQC), UV, MS and IV spectra. The infusion of Zollernia ilicifolia was
      qualitatively compared to the infusion of the espinheiras-santas (Maytenus
      aquifolium and Maytenus ilicifolia) by HPLC-DAD.

PMID- 12622223
TI  - New caffeic acid esters from Plazia daphnoides.
AB  - Two new 3,4 dihydroxycinnamic acid esters have been isolated from Plazia
      daphnoides. The structures were elucidated by NMR spectroscopy.

PMID- 12622226
TI  - The mis-identification of the major antioxidant flavonoids in young barley
      (Hordeum vulgare) leaves.
AB  - Several papers have appeared in the literature since 1992 which refer to a major
      "isoflavonoid" antioxidant in young green barley leaves (Hordeum vulgare) as 2''
      O-glucosylisovitexin. In the present paper the original NMR data supporting this
      structural assignment are examined and found to have been misinterpreted. HPLC
      and NMR data are used to prove that the major flavonoid antioxidants in young
      green barley leaves are in fact the flavone-C-glycosides, saponarin and
      lutonarin.

PMID- 12622227
TI  - Interpopulation congruence in Chinese Primula ovalifolia revealed by chemical and
      molecular markers using essential oils and ISSRs.
AB  - The chemical composition of the essential oils of five natural populations of P.
      ovalifolia from central and southwest China and their interpopulation variability
      were first analyzed by using GC-MS. Twenty-two essential oil compounds were
      obtained, in which eighteen ones were identified and characterized representing
      95%-96% of the oil composition. Three main chemotypes, i.e., the methyl-acetyl
      hydroquinone-rich, hydroquinone-rich, and acetyl-hydroquinone-rich chemotypes,
      were then differentiated, corresponding to the three groups obtained from the
      cluster analysis based on the essential oil composition percentages. Genetic
      variations among the five populations were also investigated using the Inter
      Simple Sequence Repeats (ISSR) markers. Finally, the Mantel test showed that
      there was a significant correlation between two distance matrices based on the
      chemical compounds of essential oils and ISSR markers, confirming the congruence
      of interpopulation relationships in the P. ovalifolia revealed by the chemical
      and molecular markers

PMID- 12622228
TI  - Production and purification of statins from Pleurotus ostreatus (Basidiomycetes)
      strains.
AB  - Pleurotus ostreatus strains were cultured in liquid medium and on wheat straw.
      The yields of lovastatin were compared.

PMID- 12622229
TI  - Antifungal activity of biflavones from Taxus baccata and Ginkgo biloba.
AB  - Bilobetin and 4'''-O-methylamentoflavone were isolated and identified in the
      needles of Taxus baccata, for the first time in this species. The antifungal
      activity of biflavones from T. baccata and Ginkgo biloba, namely amentoflavone, 7
      O-methylamentoflavone, bilobetin, ginkgetin, sciadopitysin and 2,3
      dihydrosciadopitysin towards the fungi Alternaria alternata, Fusarium culmorum,
      Cladosporium oxysporum was determined employing computer-aided image analysis
      couplet to a microscope. Bilobetin exhibited a significant antifungal activity
      with values of ED50 14, 11 and 17 microM respectively. This compound completely
      inhibited the growth of germinating tubes of Cladosporium oxysporum and Fusarium
      culmorum at a concentration 100 microM. Activity of ginkgetin and 7-O
      methylamentoflavone towards Alternaria alternata was stronger than that of
      bilobetin. Moreover, slight structural changes in the cell wall of Alternaria
      alternata exposed to ginkgetin at concentration of 200 microM were observed.

PMID- 12622231
TI  - Spirulina platensis growth in open raceway ponds using fresh water supplemented
      with carbon, nitrogen and metal ions.
AB  - To investigate the feasibility of using fresh water from Mangueira Lagoon (Rio
      Grande do Sul, Brazil) for biomass production in open raceway ponds (0.7 m long,
      0.18 m wide, 0.075 m deep) we studied the influence of nutrient addition (carbon
      as sodium bicarbonate, nitrogen as urea, phosphate, sulfate, ferric iron,
      magnesium and potassium) on the growth rate of the cyanobacteria Spirulina
      platensis using a 22 factorial design. In unsupplemented lagoon water production
      of S platensis was 0.78 +/- 0.01 g/l (dry weight basis) while the addition of
      2.88 g/l of sodium bicarbonate (without added urea, phosphate, sulfate or metal
      ions) resulted in 0.82 +/- 0.01 g/l after 400 hours of culture. The further
      addition of phosphate and metal ions resulted in growth for up to 750 h and a
      final S. platensis biomass of 1.23 +/- 0.04 to 1.34 +/- 0.03 g/l.

PMID- 12622230
TI  - Constituents of antibacterial extract of Caesalpinia paraguariensis Burk.
AB  - The Argentinean legume Caesalpinia paraguariensis Burk. (Fabaceae) was selected
      for further fractionation work based on the strong antimicrobial activity of its
      CH2Cl2-MeOH (1:1 v/v) extract against a host of clinically significant
      microorganisms, including antibiotic resistant strains. 1D and 2D NMR enabled the
      identification of the novel benzoxecin derivative caesalpinol along with the
      known compounds bilobetin, stigma-5-en-3-O-beta-6'-stearoylglucopyranoside,
      stigma-5-en-3-beta-6'-palmitoylglucopyranoside, stigma-5-en-3-beta
      glucopyranoside, oleanolic acid, 3-O-(E)-hydroxycinnamoyl oleanolic acid,
      betulinic acid, 3-O-(E)-hydroxycinnamoyl betulinic acid, and lupeol from the
      active fractions. Oleanolic acid was found active against Bacillus subtilis and
      both methicillin-sensitive and -resistant Staphylococcus aureus with MICs of 8
      (17.5 microM), 8 and 64 (140 microM) microg/ml, respectively. The rest of the
      compounds, however, did not show activity.

PMID- 12622232
TI  - Light-dependent changes in the leaflet movement rhythm of the plant Desmodium
      gyrans.
AB  - The movements of the lateral leaflets of the Indian telegraph plant Desmodium
      gyrans (L. F.) DC, have earlier been studied in detail with regards to the
      effects of chemicals, DC currents, and static magnetic fields. In the present
      paper we have discussed the oscillation of the lateral leaflets under the
      influence of white light of various light levels (0-75 micromol x m(-2) x s(-1)),
      produced by an array of LEDs (light emitting diodes). LEDs were used in contrast
      to fluorescense tubes as in earlier studies in order to minimize changes of
      wavelength when light intensity was decreased or increased. Furthermore, care was
      taken to ensure that the temperature in the experimental chamber was constant.
      When the oscillations were first monitored in bright light, the oscillations were
      found to be very rapid and with decreasing light intensity the oscillations
      slowed down. For light levels lower than about 20 micromol x m(-2) x s(-1) the
      period of the oscillation of the lateral leaflets was almost constant (or even
      decreased slightly towards complete darkness). We also show that the oscillations
      could completely stop under prolonged darkness (for longer than about 6 h) and
      that such halted oscillations could be restarted in most of the leaflets when he
      light was turned back on. Such stopping of the oscillation of the lateral
      leaflets in prolonged darkness suggests that these short period oscillations of
      the lateral leaflets could have a daily component and in natural environment
      these oscillations could serve the purpose of optimising the amount of light
      falling on the leaflets or/and facilitating transpiration of water through
      stomata. Such a finding could have an implication for the answer to the long
      standing question of adaptive significance of short period oscillation of the
      Indian telegraph plant Desmodium gyrans (L. F.) DC.

PMID- 12622233
TI  - Hydrolytic enzymes and surfactants of bacterial isolates from lubricant
      contaminated wastewater.
AB  - Fifteen bacterial monocultures were isolated from lubricant-contaminated
      wastewater of an electric power station in Sofia. Six isolates showed best growth
      in liquid media with 1.5% hexadecane, and on mineral salt agar plates
      supplemented with one of the following hydrocarbons: n-hexadecane, paraffin,
      kerosene and samples of wastewater. The ability of all isolates to produce
      extracellular hydrolytic enzymes and surface-active glycolipids was assessed on
      the basis of their growth on hydrocarbons. The study of this relatively closed
      micro-ecosystem revealed the existence of well-balanced microbial consortium
      where different members have their own role and support each other. On this
      basis, an alternative approach is proposed for bioaugmented clean up of
      wastewater contaminated with hydrocarbons and organic polymers using a mixed
      culture of indigenous bacteria that combines the best producers of glycolipids
      and hydrolytic enzymes.

PMID- 12622234
TI  - Dependence of the flash-induced oxygen evolution pattern on the chemically and
      far red light-modulated redox condition in cyanobacterial photosynthetic electron
      transport.
AB  - Flash-induced photosynthetic oxygen evolution was measured in cells and thylakoid
      preparations from the coccoid cyanobacteria Synechocystis sp. PCC 6803 and
      Synechococcus sp. PCC 7942 and from the filamentous cyanobacterium Oscillatoria
      chalybea. The resulting characteristic flash patterns from these cyanobacteria
      can be chemically altered by addition of exogenously added substances like CCCP,
      DCPiP and inorganic salts. Potassium chloride, manganese sulfate and calcium
      chloride affected the sequences by specific increases in the flash yield and/or
      effects on the transition parameters. Chloride appeared to exert the strongest
      stimulatory effect on the oxygen yield. In comparison to chloride, both manganese
      and calcium did not significantly stimulate the flash amplitudes as such, but
      improved the functioning of the oxygen evolving complex by decreasing the miss
      parameter alpha. Particular effects were observed with respect to the time
      constants of the relaxation kinetics of the first two flash signals Y1/Y2 of the
      cyanobacterial patterns. In the presence of the investigated chemicals the
      amplitudes of the first two flash signals (Y2 in particular) were increased and
      the relaxation kinetics were enhanced so that the time constant became about
      identical to the conditions of steady state oxygen flash amplitudes. The results
      provide further evidence against a possible participation of either PS I or
      respiratory processes to Y1/Y2 of cyanobacterial flash patterns. Dramatic effects
      were observed when protoplasts from Oscillatoria chalybea or cells from
      Synechocystis sp. PCC 6803 and Synechococcus sp. PCC 7942 were exposed to weak
      far red background illumination. Under these conditions, Y2 (and to a smaller
      extent Y1) of otherwise unchanged flash sequences were specifically modified. Y2
      was substantially increased and again the relaxation kinetics were accelerated
      making the signal indistinguishable from a Y(SS) signal. From the mathematical
      fit of the sequences we conclude that S2 contributes to 10-20% of the S-state
      distribution (in comparison to 0% in the control). Thus, far red background
      illumination might represent a valuable means for photosynthetic investigations
      where high amounts of S2 are required like e. g. EPR measurements. In such
      experiments the corresponding EPR signals appeared substantially enhanced
      following far red preillumination (Ahrling and Bader, unpublished observations).
      Our results clearly show that the 'controversial results' from parts of the
      literature suggesting the participation of different mechanisms (net oxygen
      evolution, inhibited uptake processes etc.) are not required to explain the flash
      induced oxygen evolution in cyanobacteria: the seemingly 'incompatible'
      conditions and conformations can be perfectly interconverted by different
      modulation techniques (chemicals, far red) of the respective redox condition
      within the water oxidation complex of photosynthesis.

PMID- 12622235
TI  - Synthesis and cytotoxicity of platinum(II) complexes of 3-aminocyclopentanespiro
      5-hydantoin and 3-aminocycloheptanespiro-5-hydantoin.
AB  - Four new platinum(II) complexes of 3-aminocyclopentanespiro-5-hydantoin (acpsh)
      and 3-aminocycloheptanespiro-5-hydantoin (achpsh) were synthesized and
      characterized by elemental analysis, IR and 1NMR spectra. The spectral analyses
      indicated a cis-square planar structure of the complexes with ligands coordinated
      via the NH2 group. The complexes were evaluated for in vitro cytotoxicity in
      murine erythroleukemia (MEL) cells, clone F4N, using cell-growth and
      macromolecular synthesis assay. The compounds, with exception of
      [Pt(NH3)(achpsh)Cl2] (IV), exhibited much lower cytotoxicity than that of
      cisplatin (DDP). Compound IV was nearly as cytotoxic as DDP. The new complexes
      exerted low antibacterial activity as assessed by seven bacterial strains.

PMID- 12622236
TI  - Biomimetic conversion of (3S)-(-)-neodictyoprolenol to optically pure (1S,2R)-(-)
      dictyopterene B, marine algal sex pheromone.
AB  - Both enantiomers of (3S)-(-)- and (3R)-(+)-Neodictyoprolenol [(3S,5Z,8Z)-(-)
      1,5,8-undecatrien-3-ol] were successfully converted to the algal sex pheromone,
      (1S,2R)-(-)-dictyopterene B and (1R,2S)-(+)-dictyopterene B in high enantiomeric
      purities (e. e. > 99%), respectively, by the biomimetic reaction involving
      phosphorylation and elimination under a mild condition.

PMID- 12622237
TI  - Roles of alpha-farnesene in the behaviors of codling moth females.
AB  - Reproduction and olfactory behavioral responses of codling moth, Cydia pomonella
      (L.), females to synthetic alpha-farnesene were observed in the laboratory as
      well as their reproduction behaviors in an apple orchard. Calling levels were
      lifted and ovipositional peaks were advanced in codling moth females at presence
      of 1 microg and 0.1 microg of alpha-farnesene, respectively. Mated females of
      codling moth more actively responded to 0.01 microg alpha-farnesene with walking
      and wing-fanning while walking than to other doses (0.001, 0.1, 1, 10 microg) and
      control. The results show that alpha-farnesene plays important roles in the
      behaviors of codling moth females. However, the differences between responses to
      alpha-farnesene and those to apple volatiles by codling moth females indicate
      that components other than alpha-farnesene in apple volatiles also have
      biological activities.

PMID- 12622238
TI  - Attenuation of blood parameters in smokers and non-smokers after intake of a
      complex food additive.
AB  - This report describes an intervention study with healthy volunteers (20 smokers,
      28 non-smokers) taking a food additive mainly containing vitamin C (ascorbic
      acid), vitamin E (alpha-tocopherol), ubiquinone (Q10), vitamin A and zinkoxide
      for four weeks in a double blind, randomized and placebo controlled manner.
      Before and after the intervention blood was withdrawn and general blood
      parameters were analyzed. In addition, lipid soluble antioxidants were analyzed
      in blood plasma by HPLC and the water soluble antioxidative properties were
      tested with the enzymic xanthin/xanthinoxidase-reaction. In summary the results
      show that the smoker-verum group exhibit a significant down regulation of the
      leukocyte counts. The test for antioxidants show the following significant
      differences after intervention: Smokers exhibit an increase of both vitamin E and
      coenzyme Q10 and an attenuation of their (before intervention) clearly increased
      water soluble-antioxidative potential, non-smokers showed only an increase of
      vitamin E and trends of an increase of Q10 and water soluble-antioxidative
      potential. These results may contribute to the discussion of the intrinsic
      deficiency brought about by smoking and the possible attenuation of part of these
      deficiency by increasing the intake of certain vitamins or food additives.

PMID- 12622239
TI  - Effect of a fungal Cu/Zn superoxide dismutase on the cell-mediated immune
      response in Graffi tumor bearing hamsters.
AB  - The antibody-dependent cell cytotoxicity (ADCC) of spleen lymphocytes, isolated
      from hamsters with progressing myeloid Graffi tumor, was studied. The effect of
      the application of Cu/Zn superoxide dismutase, isolated from the fungal strain
      Humicola lutea (HL SOD), before and during tumor transplantation on the
      lymphocyte ADCC was examined. Myeloid Graffi tumor cells as target cells were
      used. Antibodies from a rabbit hyper-immune anti-tumor Graffi cells serum, or
      from tumor-bearing hamsters serum were used in the test. The leukocyte adherence
      inhibition (LAI) in the presence of tumor antigen was examined also during tumor
      progression. ADCC of the spleen lymphocytes, determined by both, rabbit and
      hamster anti-tumor antibodies, decreased during tumor progression. The optimum
      treatment of the animals by HL SOD induced a 20-30% increase of lymphocyte
      cytotoxicity against myeloid Graffi tumor cells. Cytotoxicity in presence of
      tumor bearing hamsters serum was twofold lower as compared to that one determined
      in the presence of rabbit hyper-immune anti-myeloid Graffi tumor cells serum.
      Leukocyte adherence inhibition (LAI) index in the presence of tumor antigen
      increased during tumor development in the groups of treated and untreated
      animals. The LAI indices of HL SOD-treated tumor-bearing hamsters were lower than
      that of untreated animals with tumors, what can be explained by a higher
      adherence ability of leukocytes induced by HL SOD treatment (in formula for
      calculation of LAI index the adherence value is in the denominator). The results
      show the beneficial effect of HL SOD on the cell-mediated immune response of
      myeloid Graffi tumor bearing hamsters, what is probably due to the participation
      of the enzyme in the host's oxidant-antioxidant balance.

PMID- 12622240
TI  - Relationship between structure and permeability of tryptophan derivatives across
      human intestinal epithelial (Caco-2) cells.
AB  - L-Trp and its derivatives were used as model compounds to clarify structural
      factors which influence the intestinal epithelial permeation and metabolism of
      amino-acid derivatives. Permeability of model compounds through Caco-2 cells was
      used as an in vitro absorption model for human intestinal epithelial cells. The
      influence of compound concentration, the effects of various transporter
      substrates on permeability coefficients, and pH dependency of permeability
      coefficients were investigated. The transcellular permeability of Trp and Trp-NH2
      in the direction from the apical side to the basolateral side, in which nutrients
      and drugs were ordinarily absorbed, declined with increasing concentration and
      saturated at more than 1 and 0.4 mM, respectively. The permeability coefficients
      for N-terminal protected Trp derivatives and Ac-Trp-NH2 showed similar and
      constant values in both from the apical-to-basolateral and basolateral-to-apical
      directions. In addition, significant inhibition of the apical-to-basolateral
      permeation of Trp by Leu and Phe was observed. The permeability coefficient ratio
      at pH 6.3 to that at pH 7.3 was explained by the ratio of the ionic form to the
      neutral form of the compounds. Based upon these results and the partition
      coefficients in the 1-octanol/water system, possible absorption mechanism of Trp
      and its derivatives across Caco-2 cells was proposed.

PMID- 12622241
TI  - Determination of selenium in Teucrium species by hydride generation atomic
      absorption spectrometry.
AB  - Hydride generation atomic absorption spectrometry (HGAAS) was applied for
      determination of selenium content in dried aerial parts of wild and cultivated
      Teucrium species (Lamiaceae) growing in Croatia: T. arduini L., T. chamaedrys L.,
      T. flavum L., T. montanum L., T. polium L., and T. scordium L. subsp. scordioides
      Schreb. Special attention was paid to the wet oxidation procedure for the sample
      dissolution. The proposed procedure involved microwave-assisted sample digestion
      using a mixture of HNO3/H2O2. Wild specimens generally had a higher content of
      selenium, with concentrations of 0.030-0.095 mg/kg of the dry drug. Cultivated
      plants contained 0.020-0.055 mg Se/kg.

PMID- 12622242
TI  - Comparative analysis of the composition of the volatile oils of two forms of
      Achillea crithmifolia W. et. K.--diploid and tetraploid.
AB  - The genus Achillea L. includes more than 100 species and is a polyploid complex
      of di-, tetra-, hexa- and octaploids, individuals.

PMID- 12622243
TI  - Clusterin overexpression is responsible for the anti-apoptosis effect in a mouse
      neuroblastoma cell line, B103.
AB  - The functional role of clusterin in apoptosis was examined using flow cytometry.
      Clusterin cDNA was transfected into the mouse neuroblastoma cell line, B103, in
      order to determine if clusterin overexpression inhibits apoptosis. The increased
      clusterin expression level in the B103 cells tended to suppress the apoptotic
      index. This suggests an association of clusterin gene expression with apoptosis
      inhibition. These results support the conclusion that clusterin expression in
      B103 cells has an anti-apoptotic influence.

PMID- 12622244
TI  - An overview on the advances of Gymnema sylvestre: chemistry, pharmacology and
      patents.
AB  - Chemistry and pharmacology of Gymnema sylvestre is reviewed relying on research
      papers and patent literature. Extracts of this plant are widely used in
      Australian, Japananese, Vietnamese and Indian folk medicine. Gymnema preparations
      have a profound action on the modulation of taste, particularly suppressing sweet
      taste sensations. It is used in the treatment of diabetes mellitus and in food
      additives against obesity and caries. Anti-allergic, antiviral, lipid lowering
      and other effects are also reported. From a technological point of view,
      muchefforts have been made to mask the biter taste of Gymnema preparations.

PMID- 12622245
TI  - New series of N-substituted phenyl ketone oxime ethers: synthesis and bovine
      beta3-adrenergic agonistic activities.
AB  - A series of ten novel phenyl ketone oxime ethers substituted on the terminal
      nitrogen by either 1,3 benzodioxole, alkyl, aralkyl or aryl moiety were
      synthesized and tested for their activity at bovine beta3-adrenoceptors. The best
      compound, which was the benzodioxole dicarboxylate derivative, showed potent
      beta3-adrenergic agonistic activities in Chinese hamster ovary cells expressing
      the bovine beta3-adrenoceptors with Kact and Ki values better than compound CL
      316,243 used as reference (14 +/- 6 nM and 203 +/- 71 nM, respectively). In this
      series three compounds showed an antagonistic activity. Structure-activity
      relationships in these ketone oxime ethers are discussed.

PMID- 12622246
TI  - Synthesis and pharmacological evaluation of novel potential ultrashort-acting
      beta-blockers.
AB  - The basic relationship between chemical structure and pharmacological activity of
      eight newly developed potential ultrashort-acting beta-adrenergic blockers was
      evaluated. The compounds studied are derivatives of arylcarbonyloxyaminopropanols
      and were prepared by four-step synthesis. All the compounds evaluated showed weak
      antiisoprenaline (beta-adrenergic receptor blocking) activity and antiarrhythmic
      (antiouabain) activity.

PMID- 12622248
TI  - Chemically prepared silver electrode for determination of N-acetyl-L-cysteine by
      flow-injection potentiometry.
AB  - This paper describes the use of the silver electrode by means of chemical
      pretreatment of the electrode surface with mercuric(II) chloride solution and
      potassium iodide solution in flow injection analysis (FIA). The electrode is used
      as a potentiometric sensor for the indirect determination of NAC in a carrier
      stream containing iodine. A one-channel flow system that consists of a
      peristaltic pump, injection valve, a silver wire electrode and a saturated
      calomel reference electrode (SCE) was used. Some typical FIA parameters such as
      flow rate, tube length and composition of the carrier stream were varied. The
      electrode is further characterised by a constant linear response within the
      concentration range for NAC between 4.0 x 10(-6) and 1.0 x 10(-3) M at the slope
      of 60.6 +/- 1.0 mV/p(NAC). Some pharmaceutical products containing NAC were also
      tested. These results can be compared to the results obtained by the direct
      potentiometric titrations with silver nitrate and are also in good agreement with
      values declared by pharmaceutical manufacturers.

PMID- 12622247
TI  - Determination of nabumetone in pharmaceutical formulation by flow injection
      analysis (FIA) with UV-detection.
AB  - A precise and accurate FIA method for the quantification of nabumetone (NAB) in
      pharmaceuticals is described. The best suitable carrier solvent system consisted
      of ethanol: water (30:70 v/v). Sample solution (4.7 x 10(-6) M NAB) was prepared
      in this solvent and injected to the instrumental system at a flow rate of 1.2 ml
      x min(-1). The signals were detected by a UV detector at 228.8 nm. The
      calibration curves of NAB was linear in the concentration range of 1.4 x 10(-6) M
      2.8 x 10(-5) M. The intra- and inter-assay precision were less than 2.6%. The
      method exhibited a good linearity with the correlation coefficients. The LOD and
      LOQ values were found to be 4.4 x 10(-7) and 1.3 x 10(-6) M, respectively. The
      effects of the tablet excipients were insignificant at the 95% probability level.
      The calculated tablet content was 99% which is agreement with the ranges stated
      by pharmacopoeias.

PMID- 12622249
TI  - Determination of diclofenac in pharmaceutical preparations using a novel PVC
      membrane sensor.
AB  - A novel potentiometric PVC membrane sensor for determination of diclofenac in
      pharmaceutical preparations has been developed. The sensor is based on the use of
      the 2,4,6-tri(2-pyridyl)-s-triazine iron(II) diclofenac complex [diclofenac-TPTZ
      Fe(II)] as an electroactive material in a plasticized PVC membrane matrix. The
      sensor exhibits fast, stable and near Nernstian response for diclofenac over the
      concentration range 10(-2)-10(-6) M and pH 5.5-9.5. Application to quality
      control analysis of diclofenac in various dosage forms shows an average recovery
      of 99% with a mean standard deviation of 0.2%. No significant interferences are
      caused by inorganic and organic anions and various drug excipients and diluents.

PMID- 12622250
TI  - Effects of hydroxypropyl-beta-cyclodextrin on the chemical stability of a
      naphthoquinone in aqueous solutions.
AB  - 2-Hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (1), an
      antibacterial agent, was shown to form inclusion complexes with HP-beta-CD in
      aqueous solution. In the present work the kinetics of 1 degradation in aqueous
      buffer solution was investigated as a function of pH (2.34-3.95), HP-beta-CD
      concentration (0%-28% (w/v)) and temperature (60-90 degrees C). A second-order
      derivative spectroscopic methodology was developed for the kinetic
      investigations. The degradation showed to follow pseudo-first-order kinetics.
      Also, an specific acid catalysis was found and the introduction of up to 28%
      (w/v) HP-beta-CD to the reaction medium did not change this kinetic behaviour.
      The obtained results indicated that HP-beta-CD stabilises 1 against degradation
      in aqueous solutions.

PMID- 12622251
TI  - Formulation and evaluation of sustained release floating capsules of nicardipine
      hydrochloride.
AB  - Nicardipine hydrochloride, a calcium channel blocker with significant
      vasodilating and antihypertensive activities, was formulated in this work as
      sustained release floating capsules. A hydrocolloid of high viscosity grade was
      used for the floating systems. The inclusion of sodium bicarbonate to allow
      evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release
      were included as coprecipitates with the drug and/or as additives in the
      formulated capsules. Both simple powder mixing of the ingredients and granule
      preparation via wet granulation were used. Seven capsule formulae were prepared.
      The prepared capsules were evaluated in vitro by testing drug dissolution,
      floating time and the kinetics of drug release. In vitro evaluation of a
      commercially available conventional 20 mg capsule of nicardipine hydrochloride,
      "Micard", was carried out for comparison. The hydrocolloid used succeeded in
      effecting capsule buoyancy. Floating time increased with increasing the
      proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased
      buoyancy. All of the seven floating capsule formulae prepared proved efficient in
      controlling drug release. The sustained release floating capsule formulation of
      choice was evaluated in vivo in comparison to "Micard" capsules using rabbits.
      Reversed phase HPLC with UV detection was used for drug determination in rabbit
      plasma. Plasma concentration time curves revealed a longer drug duration for
      administration in the sustained release formula than the conventional "Micard"
      capsule being 16 h in the former versus 8 h for the latter.

PMID- 12622252
TI  - Effect of monovalent cations on the binding of amino acids to cholesterol.
AB  - The nature of the interaction between amino acids and cholesterol was shown by
      reversed-phase thin-layer chromatography (RP-TLC) in the presence of monovalent
      cations of different concentration. The degree of interaction between amino acids
      and cholesterol was affected by different salt solutions and by applying
      cholesterol to the chromatographic plates at higher concentration. The relative
      strength of interaction was determined by statistical evaluation of the results
      in each case. The objectives of the investigations were to study the retention
      behaviour of biologically active amino acids on alumina supports impregnated with
      cholesterol and to characterize the effects of monovalent cations on the
      interaction between amino acids and cholesterol.

PMID- 12622253
TI  - Glycaemic control by Casearia esculenta--a short duration study in albino rats.
AB  - An aqueous extract of Casearia esculenta was found to lower blood glucose in
      basal conditions and after a glucose load in normal rats. Maximum reduction in
      blood glucose was observed between 2-3 h at a dose level of 200 and 300 mg/kg
      body weight. C. esculenta extract was also found to reduce the blood sugar level
      in streptozotocin--induced diabetic rats. Oral administration of the extract
      significantly reduced the blood sugar in streptozotocin induced diabetic rats for
      15 days. The extract was also found to reduce the increased plasma thiobarbituric
      acid reactive substances (TBARS), blood urea and improvement in body weight
      reduction induced by streptozotocin injection. These results indicate that C.
      esculenta extracts are able to ameliorate biochemical changes induced by
      streptozotocin in diabetic rats.

PMID- 12622254
TI  - Influenza virus variants with reduced susceptibility to inhibition by a
      polyphenol extract from Geranium sanguineum L.
AB  - A polyphenol extract obtained from the Bulgarian medicinal plant Geranium
      sanguineum L. (PC) inhibited influenza virus reproduction in vitro, in ovo and in
      vivo. The inhibitory activity of the plant preparation was proved to be selective
      and specific. Two variants of the virus A/chicken/Germany/34, strain Rostock
      (H7N1) (A/Rostock) with reduced drug sensitivity were selected by following
      passages in chicken embryo fibroblast (CEF) cells in the presence of inhibitory
      concentrations of the substance and by subsequent purification of resistant
      plaques (A/Rostock-R). PC affected to a lesser extent the biological activity and
      the infectivity of the resistant variants compared to the sensitive parent. The
      lower susceptibility of the variants was consistently observed in contact assay,
      ELISA, cytopathogenic effect reduction, plaque reduction and infectious virus
      yield reduction assays. Virus-specific protein synthesis in CEF cells infected
      with the resistant variants, determined by 35S-labelling and following SDS-PAGE,
      was also less sensitive to inhibition with PC.

PMID- 12622255
TI  - Effect of magnetic field on the biosynthesis of neomycin by Streptomyces
      marinensis.
AB  - The effect of 30, 70, 90, 100, 110 and 150 gauss permanent magnetic field
      strength on the growth and neomycin titre of Streptomyces marinensis was studied.
      Maximum growth was attained in 120 h at all magnetic strengths. Gradual increase
      in neomycin titre was observed with increase of magnetic field strength up to 110
      gauss.

PMID- 12622256
TI  - Argyroside from Argyreia nervosa seeds.
AB  - The phytochemical investigation of the seeds of Argyreia nervosa has resulted in
      the isolation of a new steroidal glycoside, (24R)-ergost-5-en-11-oxo-3beta-ol
      alpha-D-glucopyranoside, designated as argyroside. The structure has been
      elucidated by spectroscopic and chemical methods.

PMID- 12622257
TI  - Separation of enzymes from polyenzyme mixture used in medicine and pharmacy. II.
      Purification and characterization of extracellular beta-glycosidases with high
      transglycosylation activities from Aspergillus oryzae.
AB  - Three extracellular beta-glycosidases with different substrate specificities have
      been isolated from Aspergillus oryzae (Luizym) and purified to electrophoretic
      homogeneity by molecular-sieve and ion-exchange chromatographic methods. The
      enzymes were characterized as monomeric glycoproteins with an estimated molecular
      mass of 95 kDa by SDS-PAGE and 92 kDa by gel-permeation chromatography on
      Superose 12 HR 10/30. beta-glycosidase I (pHopt 4.8; Topt 40 degrees C, pl 4.5)
      was able to catalyze the hydrolysis of aryl-beta-galactopyranosides (o- and p-),
      where as gamma-glycosidase II and III were found to be active towards aryl-beta
      gluco- and xylopyranosides. The specific chemical modifications of different
      amino acid residues showed that tryptophyl and carboxyl residues play an
      important role for the enzyme activity. The isolated beta-glycosidases exhibited
      high levels of transglycosylation activities and were used for the production of
      tri- and tetrasaccharides from lactose and whey permeate.

PMID- 12622259
TI  - Cytotoxic activity of physalins possessing modified skeletal structures against
      HeLa cells.

PMID- 12622258
TI  - Anti-malarial activity of some 7-chloro-2-quinoxalinecarbonitrile-1,4-di-N-oxide
      derivatives.

PMID- 12622260
TI  - Pharmacokinetic and bloequivalence studies of generic clarithromycin tablets in
      healthy male volunteers.

PMID- 12622261
TI  - Meloxicam complexation with beta-cyclodextrin: influence on the anti-inflammatory
      and ulcerogenic activity.

PMID- 12622262
TI  - Two new diterpene quinones from the roots of Salvia lanigera Poir.

PMID- 12622263
TI  - Nosporins A and B, new metabolites from a filamentous fungus, VKM-3750.

PMID- 12622264
TI  - Acute oral ulcers.
AB  - In general, a detailed history and examination of the patient provides sufficient
      information for diagnosis. The pattern, frequency, and natural history of ulcer
      episodes are helpful. The presence or absence of associated features and the site
      of oral involvement guides most physicians accurately in the diagnosis.
      Additional investigations, including blood tests, and occasionally the use of
      oral cultures or biopsy, are needed to make a definitive diagnosis. A
      multispecialty approach is often necessary to evaluate patients with other
      systemic features. Most acute oral ulcers heal spontaneously without specific
      therapy being necessary, but an understanding of the cause of the ulcer is
      reassuring to the patient and guides the clinician in management to prevent
      recurrent episodes of oral ulceration, or chronicity of ulcers.

PMID- 12622265
TI  - Viral diseases of the oral mucosa.
AB  - A wide variety of both DNA and RNA viruses affect the oral cavity. When
      considered in conjunction with cutaneous features, careful examination of the
      oral mucosa and oropharynx aids the clinician in making a diagnosis. Examination
      of the oral cavity should be incorporated as a regular component of the
      dermatologic examination because diagnostic clues are readily available to assist
      in the evaluation of infectious processes.

PMID- 12622266
TI  - Recurrent aphthous stomatitis.
AB  - Recurrent aphthous stomatitis remains a commonly occurring cause of oral pain and
      ulceration. Although the ulcerations of RAS are multifactorial and of unknown
      cause, recognition of the role of patient and environmental factors may be
      helpful in developing recommendations for treatment and prevention of future
      ulcers.

PMID- 12622267
TI  - Complex aphthosis and Behcet's disease.
AB  - Complex aphthosis is a disorder in which patients develop recurrent oral and
      genital aphthous ulcers or almost constant, multiple oral aphthae, without
      manifestations of systemic disease. Behcet's disease is a multisystem disease
      characterized clinically by oral and genital aphthae, arthritis, cutaneous
      lesions, and ocular, gastrointestinal, and neurologic manifestations. This
      article reviews both disorders, including their clinical and histologic
      presentations, factors in pathogenesis, and includes an overview of therapeutic
      modalities.

PMID- 12622268
TI  - Pseudo-Behcet's disease.
AB  - The conditions of complex aphthosis, EM, MMP, and the VVG variant of erosive oral
      LP may be confused by clinicians who refer patients for diagnosis and management
      of BD (Table 8). The mucocutaneous presentations or the presence of complex
      aphthosis, the hallmark of BD, can be confusing and lead to the referral of the
      patient for a diagnosis of BD. The astute clinician evaluating patients for BD
      considers pseudo-BD in the differential diagnosis of the mucocutaneous
      manifestations of BD.

PMID- 12622269
TI  - White lesions of the oral cavity.
AB  - White lesions are frequently found during the examination of the oral cavity.
      Although some benign physiologic entities may present as white lesions, systemic
      conditions, infections, and malignancies may also present as white oral lesions.
      An appreciation of the many clinical entities that white lesions may represent is
      necessary if a differential diagnosis of white lesions is to be elucidated. The
      appreciation of subtle clinical findings associated with white lesions of the
      oral cavity permits clinicians to better care for their patients.

PMID- 12622270
TI  - The clinical manifestations and treatment of oral lichen planus.
AB  - The progress in research on OLP and other autoimmune diseases has been
      significant. Coupled with a growing recognition of the clinical features and
      treatment options by dentists and physicians and fueled by the advances in
      immunosuppressive therapies, research will undoubtedly provide new insights into
      this complex disorder. It is likely that what is learned will enhance the
      understanding not only of OLP but also of many other mucocutaneous diseases.

PMID- 12622271
TI  - Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival
      syndrome and the peno-gingival syndrome.
AB  - Lichen planus is an inflammatory mucocutaneous disorder that may involve mucosal
      surfaces, such as the oral, genital, and other mucosae, and the skin including
      the scalp and the nails. Ocular, esophageal, bladder, nasal, laryngeal, otic,
      gastric, and anal involvement may occur. This article describes patients with the
      unique chronic orogenital variant of erosive oral lichen planus in both women and
      men. Although treatment of genital Lichen planus is quite challenging,
      therapeutic benefit in this painful, protracted condition can be obtained.

PMID- 12622272
TI  - Oral psoriasis.
AB  - It is strange that the existence of oral psoriasis seems so rare. Other
      papulosquamous disorders, such as lichen planus, are frequently associated with
      oral manifestations, yet oral psoriasis is rare given the prevalence of cutaneous
      disease. One explanation is that oral lesions are asymptomatic and do not come to
      the clinician's attention. Other explanations, however, are necessary. Epithelial
      turnover time is significantly increased in psoriatic plaques and may be as rapid
      as 3 to 7 days, whereas normal epithelial turnover is 28 days. Some have
      suggested that this abnormally increased turnover time in psoriasis approximates
      that of the normal regenerative time of the oral epithelium, and this possibility
      may account for the apparent lack of changes in the oral mucosa of patients with
      psoriasis [1]. It is also possible that oral lesions of psoriasis are altered
      both clinically and histologically by other factors within the oral
      microenvironment and are not recogized. Although controversy has appeared in the
      literature about whether lesions of oral psoriasis exist, there is sufficient
      evidence that a subset of patients have oral lesions in association with skin
      disease. This occurrence is more common in patients with the severe forms of
      psoriasis, such as generalized pustular psoriasis. The diagnosis of oral
      psoriasis should be based on good clinical and histologic evidence, and, in
      general, the clinical course of the oral lesions should parallel that of the skin
      disease. Exclusion of other causes is important, particularly if cutaneous
      lesions are absent and a diagnosis of isolated oral psoriasis is entertained.
      Because neither the clinical nor the histologic changes are absolutely specific
      for psoriasis, the patient requires holistic evaluation. That being said, in day
      to-day practice it is most likely not practical to obtain a biopsy of
      asymptomatic oral lesions for definitive histologic or immunofluorescence
      studies. The clinician, however, must have a high degree of awareness and pay
      close attention to the oral mucosa in patients with psoriasis. A thorough
      examination is imperative, because asymptomatic oral lesions may be found more
      frequently in patients with psoriasis if clinicians habitually check mucous
      membranes during the generalized skin examination. Conversely, in patients with
      troublesome oral lesions, a cutaneous examination that reveals subtle changes
      suggestive of psoriasis may provide clues to the oral diagnosis. A detailed
      history remains the cornerstone of diagnosis, because a family history of
      psoriasis or a history of psoriasis now in remission may guide physicians when
      they note oral lesions.

PMID- 12622273
TI  - Contact stomatitis.
AB  - Contact stomatitis is inflammation or pain of the oral mucosa due to both
      irritant and allergic substances. Irritants include heat, frictional trauma, and
      chemicals. Oral flavorings, preservatives, and dental materials are common
      allergens. Simplification of oral care and avoidance of contactants is the
      primary mode of therapy. Patch testing to a broad series of antigens may be
      required to identify specific causes of allergic contact stomatitis.

PMID- 12622274
TI  - Denture sore mouth.
AB  - The majority of the lesions associated with DSM are preventable and can be
      managed successfully by the dental professional. The hyperplastic tissue response
      seen in denture wearing patients generally requires surgical excision and follow
      up. Health care providers should be encouraged to ask patients to remove their
      prostheses during a thorough examination of the oral tissues. In addition,
      patients should be asked about the fit and comfort of their dentures, and
      referred to their dental health care team for appropriate follow-up when
      required.

PMID- 12622275
TI  - Glossitis and other tongue disorders.
AB  - Patients frequently present complaining of tongue abnormalities. Knowledge of
      normal tongue anaomy an d architecture enable the clinician t odifferentiate
      variations of normal from abnormal conditions. Many tongue conditions are benign
      and. require reassurance and explanation, with little to no treatment. Others can
      signify systemic disorders. Examination of the tongue is an integral part of a
      complete physical examination. Recognizing the disorders of the tongue that are
      benign and do not require treatment or further evaluation prevents unnecessary
      testing for the patient. Careful evaluation of the tongue may provide valuable
      clues to a systemic disorder.

PMID- 12622276
TI  - Burning mouth syndrome.
AB  - Burning mouth syndrome is the occurrence of oral pain in a patient with a normal
      oral mucosal examination. It can be caused by both organic and psychologic or
      psychiatric factors, which can be broken down into local, systemic. psychologic
      or psychiatric, and idiopathic causes. The most frequently associated conditions
      are psychiatric (depression, anxiety, or cancerphobia); xerostomia; nutritional
      deficiency; allergic contact dermatitis; candidiasis; denture-related pain: and
      parafunctional behavior. Multiple different factors contributing to the oral pain
      are common, and a systematic approach to the evaluation is important.
      Identification of correctable causes of BMS should be emphasized and psychiatric
      causes should not be invoked without thorough evaluation of the patient. A
      directed history and careful oral examination must be completed to exclude local
      diseases and identify clues to potential causes. Assessment of medications,
      psychiatric history and background, and selected laboratory and patch tests may
      help identify the etiologies of these symptoms. Treatment should be tailored to
      each patient and may best be managed in a multidisciplinary approach with input
      from dermatologists, dentists, psychiatrists. otorhinolaryngologists, and primary
      care providers. A thoughtful and structured evaluation of the patient with BMS
      has been associated with improvement in about 70% of patients. The remaining
      patients may benefit from empiric therapy with a chronic pain protocol and
      continued supportive interactions.

PMID- 12622277
TI  - Halitosis.
AB  - Halitosis (oral malodor, bad breath) is a condition affecting millions of
      Americans and is a major concern to the general public. In healthy individuals
      complaining of bad breath, the mouth is the main source of their oral malodor,
      more specifically the posterior dorsum of the tongue. Halitosis may also indicate
      an underlying medical condition that necessitates treatment. In a patient with
      oral malodor for whom an underlying systemic problem has been ruled out, improved
      oral hygiene, removal of tongue plaque, and, if necessary, antibacterial mouth
      rinses are advised.

PMID- 12622278
TI  - Pediatric oral medicine.
AB  - A thorough examination of the oral mucosa can provide helpful clues toward making
      a diagnosis in a number of developmental, neoplastic, inflammatory, and
      infectious conditions. A number of oral lesions seen in infants and children are
      benign and of no medical significance. In these instances, the ability of the
      physician to confidently identify the diagnosis, and reassure parents that a
      lesion is not worrisome, carries significant value. Likewise, the ability to
      recognize an underlying systemic illness or genetic disease based on an oral
      examination can also be of tremendous value, particularly when oral involvement
      is the presenting feature.

PMID- 12622279
TI  - Oral manifestations of systemic disease.
AB  - Most systemic diseases can affect the oral cavity. Some oral changes are
      nonspecific, whereas others directly lead to the diagnosis of a particular
      disorder. A systems approach is used here to catalog these oral changes. In some
      instances it is difficult to separate the oral manifestations of pharmacotherapy
      for a particular disease from that entity. The oral manifestations of
      pharmacotherapy are presented for selected disease processes. This article
      introduces the most common oral manifestations of systemic disease.

PMID- 12622280
TI  - Oral manifestations of genodermatoses.
AB  - Many genodermatoses have distinct oral features that may help identify or confirm
      a genetic diagnosis. Oral features of the disorders described here are summarized
      in Table 1. These conditions provide clear examples of rapid progress in the
      field of genetic technology relevant to patient care. Less than a decade ago, the
      exact genetic locus of most of these disorders was unknown. Today, for many of
      these disorders, the exact location of the disease-causing mutation is known and
      clinical genetic testing is available for patients. This information has impact
      not only for genetic counseling and anticipatory medical care, but also provides
      insight into the mechanisms of disease. How this rapid progress will impact care,
      and ultimately treatment of patients, remains to be seen.

PMID- 12622281
TI  - Oral manifestations of erythema multiforme.
AB  - Erythema multiforme is a reactive mucocutaneous disorder in a disease spectrum
      that comprises a self-limited, mild, exanthematic, cutaneous variant with minimal
      oral involvement (EM minor) to a progressive, fulminating, severe variant with
      extensive mucocutaneous epithelial necrosis (SJS and TEN). Significant
      differences exist among EM minor, EM major, SJS, and TEN with regards to severity
      and clinical expression; however, all variants share two common features: typical
      or less typical cutaneous target lesions and satellite-cell or more widespread
      necrosis of the epithelium. These features are considered to be sequelae of a
      cytotoxic immunologic attack on keratinocytes expressing non-self-antigens. These
      antigens are primarily microbial (viruses) or drugs and in rare instances
      histocompatibility antigens [5]. Although the precise pathogenesis is unknown,
      there is a tendency to consider EM both minor and major as part of one spectrum
      that is most often triggered by viral infections, and SJS and TEN as a separate
      one most often elicited by drugs with EM major and SJS representing a bridge in
      the continuum of EM. The oral manifestations of the spectrum of EM range from
      tender superficial erythematous and hyperkeratotic plaques to painful deep
      hemorrhagic bullae and erosions. Other mucosal surfaces including ocular, nasal,
      pharyngeal, laryngeal, upper respiratory, and anogenital may be involved.
      Scarring sequelae from ocular and pharyngeal involvement cause morbidity. The
      oral EM variant is an underrecognized form of EM. Most patients have chronic or
      recurrent oral lesions only, but one third have oral and lip lesions and one
      quarter have oral, lip, and skin lesions. This variant is a reaction pattern
      similar to EM minor, EM major, SJS, and TEN. The diagnosis of oral EM is one of
      exclusion. Careful clinical evaluation for other chronic mucocutaneous diseases,
      such as pemphigus, paraneoplastic pemphigus, mucous membrane pemphigoid, and
      lichen planus, is a necessary component of the diagnosis. The value of a biopsy
      specimen studied by both routine histopathologic and immunopathologic methods is
      fundamental to excluding the other causes for this variant of EM.

PMID- 12622282
TI  - Important drug interactions and reactions in dermatology.
AB  - A constantly expanding pharmacological armamentarium increases the concern for
      serious drug interactions. This article discusses drug metabolism and how the
      cytochrome P-450 family facilitates drug biotransformation. Clinically
      significant drug interactions involving antifungal drugs, antibiotics, retinoids,
      and immunosuppressive agents, as well as topical anesthetics and various foods,
      are included.

PMID- 12622283
TI  - RCVS seeks views on a new Veterinary Surgeons Act.

PMID- 12622284
TI  - Developing a strategy for veterinary surveillance.

PMID- 12622285
TI  - Studies of serum total immunoglobulin E concentrations in atopic and non-atopic
      dogs.
AB  - The serum total immunoglobulin E (IgE) concentrations of two groups of atopic
      dogs and three groups of non-atopic dogs were compared. There was a wide range of
      concentrations with a high degree of overlap between the groups. The serum total
      IgE concentrations of a group of 15 non-atopic racing greyhounds were
      significantly higher than those of all the other groups. Atopic and non-atopic
      dogs receiving stringent parasite control treatments could not be differentiated
      on the basis of their serum total IgE concentrations. In the non-atopic dogs
      there was no correlation between their serum total IgE concentrations and the
      number of allergen-specific positive results obtained in an ELISA, or between
      their serum total IgE concentrations and their age.

PMID- 12622286
TI  - Morphological, histological and histochemical studies of the gonads of ovine
      freemartins.
AB  - Freemartins are XX/XY chimaeras that develop as a result of the fusion of the
      placental circulation of at least one male and one female fetus. Of 19 freemartin
      ewes, 13 had testis-like structures, seven of them in an abdominal position and
      six in an inguinal position. Histologically, their gonads had structures
      resembling seminiferous tubules and interstitial cells, and grossly, most had
      structures derived from the mesonephric ducts (vasa deferentia, epididymides and
      vesicular glands). The other six freemartin ewes had small, undifferentiated
      gonads that lacked either follicles or seminiferous tubule-like structures. They
      also lacked any structures derived from the mesonephric ducts. No derivatives of
      the paramesonephric ducts were detectable in any of the freemartin ewes. The
      gonads of the male-type freemartins stained immunocytochemically for 3beta
      hydroxysteroid dehydrogenase (3beta-HSD) and histochemically for alkaline
      phosphatase (AP) in a similar way to, but more extensively and intensely than,
      the gonads of normal rams, and the staining was confined to interstitial cell
      like structures. The staining in the undifferentiated-type freemartins was weak,
      but both 3beta-HSD and AP were present in unidentified cell types.

PMID- 12622287
TI  - Percutaneous puncture technique for treating persistent retropharyngeal lymph
      node infections in seven horses.
AB  - Between 1999 and 2001, seven horses with fever, dysphagia and a history of
      chronic upper respiratory tract infection lasting between three weeks and three
      months were examined. They had been treated unsuccessfully with a variety of
      antibiotics for three to four weeks. A deep abscess in a retropharyngeal lymph
      node was diagnosed in each case by clinical examination, endoscopy and
      echographic examination of the retropharyngeal region. The infected
      retropharyngeal lymph node of each horse was punctured with a spinal needle under
      ultrasound guidance. Pus was aspirated from four of the horses, and their
      abscesses were then rinsed with 0.9 per cent saline solution, and antibiotics
      (sodium ceftiofur or penicillin) were injected. In the other three horses the pus
      was too viscous to be aspirated, and the enlarged lymph node was opened along the
      tract of the needle and rinsed with chlorhexidine. All the horses were treated
      with penicillin for two weeks and in six of them the clinical signs gradually
      disappeared. The other horse continued to show fever and the penicillin treatment
      was continued for another 10 days, after which the signs gradually disappeared
      over a period of two months.

PMID- 12622288
TI  - Pathology of sporotrichosis in 10 cats in Rio de Janeiro.
AB  - Ten cats with sporotrichosis were examined clinically and pathologically. They
      were in very poor general condition, and had widespread ulcerated cutaneous
      lesions and respiratory signs. Gross internal abnormalities were found only in
      the lungs and lymph nodes. Histologically, an inflammatory infiltrate and yeast
      like structures were observed in the skin, lungs, liver and lymph nodes. The
      spleen was congested and contained fungal elements. No microscopical changes were
      observed in the pancreas, kidneys and heart. Sporothix schenckii was isolated
      from all the skin samples and nasal swabs obtained in vivo, and from all the
      samples of lung, liver, spleen, lymph nodes, heart and kidney taken postmortem.

PMID- 12622289
TI  - Review of exotic infectious diseases in small animals entering the United Kingdom
      from abroad diagnosed by PCR.

PMID- 12622290
TI  - Efficacy of an ivermectin-praziquantel combination in equids against bots and
      tapeworms.

PMID- 12622291
TI  - Incidence of Campylobacter species in hobby birds.

PMID- 12622292
TI  - Sarcoptic mange in foxes.

PMID- 12622293
TI  - Sarcoptic mange in foxes.

PMID- 12622294
TI  - Hip dysplasia in dogs.

PMID- 12622295
TI  - Forensic veterinary medicine.

PMID- 12622296
TI  - Veterinary practice in the future.

PMID- 12622297
TI  - Paraphimosis/priapism in rabbits.

PMID- 12622298
TI  - Methodological aspects of randomized controlled trials of psychotherapy in
      primary care.

PMID- 12622299
TI  - Costs, correlates and consequences of fatigue in children and adults.

PMID- 12622300
TI  - The clinical effectiveness of counselling in primary care: a systematic review
      and meta-analysis.
AB  - BACKGROUND: Counselling is frequently used in the management of common mental
      disorders (such as anxiety and depression) in primary care. However, there are
      concerns over the clinical effectiveness of counselling, both in comparison with
      usual general practitioner care, and with other treatments such as alternative
      psychological therapies and antidepressant treatment. This study used systematic
      review methodology to assess the current evidence-base. METHOD: A systematic
      literature review located seven trials of relevance, comparing counselling with
      usual general practitioner care, cognitive-behaviour therapy and antidepressant
      medication. Data on internal and external validity were examined using a
      standardized quality rating scheme. Data concerning the impact of counselling on
      symptoms of anxiety and depression were pooled using meta-analytical procedures.
      RESULTS: The main analyses showed significantly greater clinical effectiveness of
      counselling compared with usual general practitioner care in the short-term
      (standardized mean difference -0.28, 95% CI -0.43 to -0.13, N=741, six trials)
      but not the long-term (standardized mean difference -0.07, 95% CI -0.26 to 0.12,
      N=447, four trials). Sensitivity analyses were undertaken to test the robustness
      of the results. CONCLUSION: Counselling is associated with modest improvement in
      short-term outcome compared with usual general practitioner care, and thus may be
      a useful addition to mental health services in primary care.

PMID- 12622301
TI  - Computerized, interactive, multimedia cognitive-behavioural program for anxiety
      and depression in general practice.
AB  - BACKGROUND: Cognitive-behavioural therapy (CBT) brings about significant clinical
      improvement in anxiety and depression, but therapists are in short supply. We
      report the first phase of a randomized controlled trial of an interactive
      multimedia program of cognitive-behavioural techniques, Beating the Blues (BtB),
      in the treatment of patients in general practice with anxiety, depression or
      mixed anxiety/depression. METHOD: One hundred and sixty-seven adults suffering
      from anxiety and/or depression and not receiving any form of psychological
      treatment or counselling were randomly allocated to receive, with or without
      medication, BtB or treatment as usual (TAU). Measures were taken on five
      occasions: prior to treatment, 2 months later, and at 1, 3 and 6 months follow-up
      using the Beck Depression Inventory, Beck Anxiety Inventory and Work and Social
      Adjustment Scale. RESULTS: Patients who received BtB showed significantly greater
      improvement in depression and anxiety compared to TAU by the end of treatment (2
      months) and to 6 months follow-up. Symptom reduction was paralleled by
      improvement in work and social adjustment. There were no interactions of BtB with
      concomitant pharmacotherapy or duration of illness, but evidence, on the Beck
      Anxiety Inventory only, of interaction with primary care practice. Importantly,
      there was no interaction between the effects of BtB and baseline severity of
      depression, from which we conclude that the effects of the computer program are
      independent of starting level of depression. CONCLUSIONS: These results
      demonstrate that computerized interactive multimedia cognitive-behavioural
      techniques under minimal clinical supervision can bring about improvements in
      depression and anxiety, as well as in work and social adjustment, with and
      without pharmacotherapy and in patients with pre-treatment illness of durations
      greater or less than 6 months. Thus, our results indicate that wider
      dissemination of cognitive-behavioural techniques is possible for patients
      suffering from anxiety and/or depression.

PMID- 12622302
TI  - A randomized controlled trial to evaluate the effectiveness and cost
      effectiveness of psychodynamic counselling for general practice patients with
      chronic depression.
AB  - BACKGROUND: Counsellors have been employed in general practice with little
      evidence of effectiveness. This study examined the effectiveness and cost
      effectiveness of short-term counselling in general practice for patients with
      chronic depression either alone or combined with anxiety. METHOD: A randomized
      controlled trial with an economic evaluation was carried out in Derbyshire. One
      hundred and forty-five patients were recruited at seven GP practices by screening
      using the Beck Depression Inventory. Both the experimental and control group
      received routine GP treatment but the experimental group were also referred to
      the practice counsellor. Depression, anxiety and other mental health symptoms,
      social and interpersonal functioning and social support were measured at
      baseline, 6 months and 12 months. Comprehensive costs were also estimated.
      RESULTS: There was an overall significant improvement in the actual scores over
      time, but there were no significant differences between the two groups on any of
      the measures at either 6 or 12 months. However fewer experimental group patients
      were still 'cases' on the BDI than controls at 12 months. There were no
      significant differences in the mean total costs, aggregate costs of services, or
      any service-group costs except for primary care, between the experimental and
      control groups over time. CONCLUSIONS: This trial demonstrates only very limited
      evidence of improved outcomes in those referred to counselling and increased
      primary care treatment costs in the short-term. Stricter referral criteria to
      exclude the more severely depressed in the group (BDI > or = 24) might have
      yielded more conclusive results.

PMID- 12622303
TI  - Patient-practitioner agreement: does it matter?
AB  - BACKGROUND: Good communication is a crucial clinical skill. Previous research
      demonstrated better clinical outcomes when practitioners and patients agree about
      the nature of patients' core presenting complaints. We investigated the nature of
      this agreement and its impact on outcome among depressed primary care patients.
      METHOD: We compared presenting problem formulations completed by patients, GPs
      and therapists in a primary care randomized controlled trial of cognitive
      behavioural therapy and non-directive counselling for depression. Participants
      compiled formulations from a list of 13 potential problems of self-completed
      questionnaires. Subjects scored at least 14 on the Beck Depression Inventory
      (BDI) at baseline. Outcome measure for this study included BDI at 4 and 12
      months, failure to attend for therapy when referred, dropout from therapy and
      patient satisfaction. RESULTS: Among 464 trial patients, 395 received therapy.
      Patient baseline problem formulations included significantly more items than GPs,
      who identified significantly more items than therapists. Agreement levels varied
      according to a range of patient and professional variables. While patients in
      complete agreement with their therapists about their main problem after
      assessment had lower average BDI scores at 12 months (9.7 v. 12.8, P=0.03); we
      found no other significant associations between the extent of agreement and
      clinical outcome. There were significant (but relatively weak) associations
      between agreement and aspects of patient satisfaction. CONCLUSION: Our results
      suggest that detailed mutual understanding of the presenting complaints may be
      less important than agreement that the core problem is psychological, and that
      referral for psychological therapy is appropriate.

PMID- 12622304
TI  - The economic cost of chronic fatigue and chronic fatigue syndrome in UK primary
      care.
AB  - BACKGROUND: Chronic fatigue and chronic fatigue syndrome are most often
      encountered in primary care settings. Given the disabling nature of chronic
      fatigue it may have a substantial impact on service use and costs as well as on
      employment. This study estimates this impact. METHOD: Patients presenting to
      general practitioners with unexplained chronic fatigue were recruited to the
      study. Service use over a 3 month period was measured and lost employment
      recorded. These data were used to estimate economic costs. Patients with chronic
      fatigue syndrome were compared to patients with only chronic fatigue using a
      multiple regression model with sample differences controlled. RESULTS: The mean
      total cost of services and lost employment across the sample was Pound
      Sterling1906 for the 3-month period with formal services accounting for 9.3% of
      this figure. Service use was higher for patients with chronic fatigue syndrome
      compared to those with chronic fatigue alone. Total 3-month costs were on average
      higher for chronic fatigue syndrome (Pound Sterling3515 v. Pound Sterling1176)
      but when sample differences were taken account of the mean difference was reduced
      to Pound Sterling1406 (P = 0.086). Over 90% of the cost was accounted for by care
      provided by friends and family members and by lost employment. Patients with
      dependants had significantly higher costs than those with none and costs were
      also significantly higher for greater levels of functional impairment.
      CONCLUSION: Chronic fatigue imposes substantial economic costs on society, mainly
      in the form of informal care and lost employment. Treatments need to be developed
      which recognize these impacts.

PMID- 12622305
TI  - Fatigue in a community sample of twins.
AB  - BACKGROUND: Fatigue is a complex symptom associated with many physiological,
      psychological and pathological processes. Its correlates and typology remain
      inadequately understood. METHOD: These data were from two large, longitudinal
      twin studies. Trained interviewers enquired as to the presence of a > or = 5 day
      period in the previous year of fatigue or tiredness that interfered with daily
      activities. A range of potential correlates was assessed in a structured
      interview: demography; health beliefs; the presence of nine physical disorders;
      mood, anxiety and addictive disorders; neuroticism and extraversion;
      recollections of parental rearing; and nine stressful life events. Statistical
      analyses included logistic regression, CART, MARS, latent class analysis and
      univariate twin modelling. RESULTS: Data were available for interfering fatigue
      (IF) on 7740 individual twins (prevalence 9.9% in the previous year). IF was
      significantly associated with 42 of 52 correlates (most strongly with major
      depression, generalized anxiety disorder, reported major health problems and
      neuroticism). Multivariate analyses demonstrated that IF is a highly complex
      construct with different sets of correlates in its subtypes. There were two broad
      clusters of correlates of IF: (a) major depression, generalized anxiety disorder
      and neuroticism; and (b) beliefs of ill health coexisting with alcoholism and
      stressful life events. Twin analyses were consistent with aetiological
      heterogeneity--genetic effects may be particularly important in women and shared
      environmental effects in men. CONCLUSIONS: IF is a complex and common human
      symptom that is highly heterogeneous. More precise understanding of the
      determinants of IF may lead to a fuller understanding of more extreme conditions
      like chronic fatigue syndrome.

PMID- 12622306
TI  - Predictors of outcome in a fatigued population in primary care following a
      randomized controlled trial.
AB  - BACKGROUND: The objective of this study was to examine factors that predicted
      outcome in a chronically fatigued group of patients who were randomized to
      cognitive behaviour therapy or counselling in primary care. METHOD: Illness
      perceptions, attributions, fatigue, disability and demographic variables were
      recorded at assessment and levels of fatigue and disability were measured at 6
      months post randomization. Logistic regression was used to examine associations.
      RESULTS: Factors that predicted a poor outcome (four or more on the fatigue
      questionnaire) were: poor social adjustment at assessment; the patients self
      report that they had never seen the GP for an emotional reason; a physical
      illness attribution; and, a long perceived future illness duration. CONCLUSIONS:
      Patients who are more psychologically minded are more likely to improve with
      psychological treatments in primary care. General practitioners need to assess
      this before referring to an appropriate therapist.

PMID- 12622307
TI  - Psychiatric adjustment in chronic fatigue syndrome of childhood and in juvenile
      idiopathic arthritis.
AB  - BACKGROUND: High rates of psychopathology and of personality problems have been
      reported in children and adolescents with chronic fatigue syndrome (CFS). It is
      not clear whether this is consequent on the experience of chronic physical ill
      health. We compare psychiatric adjustment in children with CFS and in children
      suffering from another chronic physical disorder (juvenile idiopathic arthritis
      or JIA). METHOD: Our sample consisted of 28 children with CFS and 30 with JIA
      attending tertiary paediatric centres (age range, 11 to 18 years, mean 15, S.D.
      2.3). In order to assess psychiatric status and functioning, we used the K-SADS
      psychiatric interviews, CGAS and Harter Self-Esteem Questionnaire with child
      subjects; behavioural questionnaires (CBCL) and child personality assessment
      interviews (PAS) with parent informants. RESULTS: Psychiatric disorders in the
      year prior to interview had been present significantly more commonly in the CFS
      group (72% v. 34% in JIA) and were more impairing to them (CGAS scores of 45 v.
      77). Most common diagnoses in both groups were depressive and anxiety disorders.
      Personality problems were also significantly more frequent in CFS subjects (48%
      disorder and 26% difficulty v. 11% and 11% in JIA). There were few differences
      between the two groups in self-esteem. CONCLUSIONS: Psychopathology and
      personality problems are common in children and adolescents with severe forms of
      CFS and cannot be explained strictly through the experience of chronic physical
      illness.

PMID- 12622308
TI  - Social precursors to onset and recovery from episodes of common mental illness.
AB  - BACKGROUND: Social disadvantage and lack of social support have been identified
      as important risk factors for the onset and continuance of episodes of common
      mental illness. This study aimed to identify the social precursors to episodes of
      and recovery from common mental illness in a large, general population sample
      over eight yearly intervals. METHOD: The analytical samples were drawn from those
      aged > or = 16 in the British Household Panel Survey from 1991 to 1998. The
      samples were: (1) onset--over 42,000 paired years from 10,204 persons; (2)
      recovery--over 10,000 paired years from 4878 persons; and (3) 1812 spells with
      observed onset and recovery. Markov and discrete-time complementary log-log
      models were used. Common mental illness was measured using the 12-item General
      Health Questionnaire. RESULTS: Sex, age, changes in marital and employment
      status, physical health, family care and social support were all associated with
      differential rates of onset and recovery. Severity of disorder was associated
      with less likelihood of recovery and longer time to recovery. CONCLUSIONS: The
      study confirms many previous findings concerning social factors associated with
      onset and recovery. Low social support acted as expected by increasing chances of
      onset and decreasing chances of recovery. Other social factors such as separation
      or divorce, becoming and remaining unemployed, health limiting daily activities,
      caring for a sick relative all decreased chances of recovery. The chances of
      observing a change in state (either onset or recovery) decreased with the number
      of prior observations in that state. Reduced rates of recovery with increasing
      degrees of severity of distress was expected, but not previously demonstrated.

PMID- 12622309
TI  - Social support networks and type of neurotic symptom among adults in British
      households.
AB  - BACKGROUND: Current knowledge about associations between psychosocial factors and
      non-psychotic symptoms provide little information about their relationship to
      specific types of neurotic symptoms such as symptoms of fatigue, worry, phobic
      anxiety and obsessional symptoms. METHOD: The British National Survey of
      Psychiatric Morbidity was based on a cross-sectional random sample of 10,108
      householders. Neurotic symptoms were established by lay interviewers using the
      revised fully structured Clinical Interview Schedule (CIS-R). Subjects were asked
      about perceived social support, the size of their close primary social network
      and sociodemographic attributes. To assess possible associations between specific
      types of neurotic symptoms and psychosocial risk factors multivariate Huber
      logistic models (a modified form of repeated measures design modelling) was used
      taking account of correlation between symptom types and sampling design including
      clustering. RESULTS: After controlling for sociodemographic factors the risk of
      having a high total CIS-R score (> or = 12) was approximately doubled for both
      types of poor social functioning. Specific types of neurotic symptoms were
      associated both with a small primary group and with inadequate perceived social
      support. Depression, depressive ideas and panic symptoms had a higher prevalence
      in multivariate models. Poverty was associated with low support. CONCLUSIONS:
      Associations with deficiencies in social support and self-reported neurotic
      symptoms are better explained by symptom type and in particular by depression
      than by the total number of symptoms. If confirmed by longitudinal study findings
      this knowledge could be used to inform the development of interventions to
      improve social support in order to reduce specific neurotic symptom types.

PMID- 12622310
TI  - Association between organizational inequity and incidence of psychiatric
      disorders in female employees.
AB  - BACKGROUND: Prior research on work-related factors in the aetiology of
      psychiatric disorders has been concentrated on job control, job demands and
      social support. To broaden the view to managerial procedures, we examined whether
      the extent to which employees are treated with equity in the workplace predicts
      their mental health. Organizational equity refers to decision-making procedures,
      which are consistently applied, open, correctable and include input from affected
      parties (procedural justice). It also refers to respectful and considerate
      treatment of individuals by supervisors (relational justice). METHOD: A cohort of
      1786 female hospital employees with no psychiatric disorder at baseline responded
      to a questionnaire on organizational equity. From the responses, both an
      individual score and a work unit mean score were assigned to each participant.
      The outcome was new reports of doctor-diagnosed psychiatric disorders during the
      2-year follow-up. Odds ratios and 95% confidence intervals were corrected for
      clustering of the data. RESULTS: After adjustment for age and salary, odds ratio
      of new psychiatric disorders for self-reported low procedural justice was 1.9
      (95% CI 1.1 to 3.2). Corresponding odds ratio for low procedural justice, as
      assessed with work unit mean scores, was 1.7 (95% CI 1.5 to 2.0). These
      associations remained statistically significant after additional adjustment for
      mental distress at baseline and job control, job demands and social support.
      Relational justice did not predict psychiatric disorders. CONCLUSION: Research on
      organizational equity provides new information about potential work-related
      determinants of mental health. Low procedural justice seems to be an independent
      risk factor for psychiatric disorders in female employees.

PMID- 12622311
TI  - Do life events have their effect on psychosis by influencing the emotional
      reactivity to daily life stress?
AB  - BACKGROUND: Life events (LE) have consistently been found to influence course and
      outcome of psychotic disorders. However, the mechanism through which they operate
      is not known. The present study investigated whether LE have their effect by
      impacting on the emotional sensitivity for daily hassles. METHOD: Patients with
      clinically remitted psychotic illness (N=42) were studied with the Experience
      Sampling Method (a structured diary technique assessing current context and mood
      in daily life) to assess: (1) appraised subjective stress related to daily events
      and activities; and (2) emotional reactivity conceptualized as changes in both
      negative affect (NA) and positive affect (PA). LE were assessed with the Brown &
      Harris Life Event and Difficulties Schedule. RESULTS: Multilevel regression
      analyses showed that previous exposure to LE influenced the appraised
      stressfulness of neither daily events nor the activities in which the subjects
      were involved. However, a history of LE did modify the emotional reaction to
      daily life stress, both in models predicting NA and in models predicting PA.
      CONCLUSIONS: By their cumulative effect on emotional reactivity to daily
      activities and events, LE may render individuals more vulnerable to the onset or
      persistence of psychotic experiences.

PMID- 12622312
TI  - Learning disability and epilepsy in an epidemiological sample of individuals with
      tuberous sclerosis complex.
AB  - BACKGROUND: Intellectual impairments are a recognized feature of tuberous
      sclerosis complex (TSC), but the frequency and degree of intellectual impairments
      has not been systematically studied in large epidemiological samples using
      standardized measures. As such, the form of the IQ distribution (uni- or bi
      modal) has not been established and the relationship between IQ and other
      features (e.g. epilepsy history) is poorly delineated. To address these
      shortcomings, we assessed the intellectual abilities of a large epidemiological
      sample of individuals with TSC, drawn from the 'Wessex' area of SW England and
      compared them with the abilities of their unaffected siblings. METHOD:
      Standardized tests were used to estimate the abilities of 108 (56 males, 52
      females, median age = 25, range = 4-75) individuals with TSC and 29 unaffected
      siblings (14 males, 15 females, median age = 18, range = 6-55). Seizure history
      was obtained from informants and medical records. RESULTS: Estimated IQ was bi
      modally distributed: 55.5% had an IQ in the normal range; 14% had mild to severe
      impairments: and 30.5% had profound disability (IQ < 21). Forty-four per cent of
      the individuals with TSC had an IQ < 70. In the subset of normally intelligent
      individuals with TSC, IQ was normally distributed with a mean of 93.6. This mean
      was significantly lower than the mean IQ of unaffected siblings (IQ = 105.6). All
      individuals with learning disability had a history of seizures that usually
      commenced before 12 months of age and that often presented as infantile spasms.
      Multivariate analyses indicated that a history of seizures as well as a history
      of infantile spasms was predictive of the degree of intellectual impairment.
      CONCLUSIONS: Intellectual abilities were bi-modally distributed in a
      representative sample of individuals with TSC. The likelihood of impairment was
      associated with a history of seizures, particularly infantile spasms. The genetic
      and brain basis of these findings requires further investigation.

PMID- 12622313
TI  - Pattern of cognitive dysfunction in depressive patients during maintenance
      electroconvulsive therapy.
AB  - BACKGROUND: Objective data regarding adverse cognitive deficits associated with
      maintenance electroconvulsive therapy (M-ECT) are lacking. This study examined
      the cognitive state of depressive patients during M-ECT. METHOD: A cross
      sectional study was carried out in 11 depressive patients in remission, all with
      a DSM-IV diagnosis of major depressive disorder. The mean number of previous ECT
      sessions was 36.1, and the mean intersession interval was 52.7 days. A group of
      11 patients who had not received ECT was selected for comparison and matched for
      diagnosis, sex, age and years of schooling. All subjects were assessed using a
      complete neuropsychological battery including memory, attention and frontal
      function tests. RESULTS: Groups did not present differences in long delay verbal
      recall. Encoding of new information and results on the frontal function tests
      were significantly lower in the M-ECT patients. CONCLUSION: Depressed patients
      preserve long-term memory, but suffer short-term memory impairment and frontal
      function alteration during M-ECT. Further longitudinal studies are necessary to
      determine the influence of M-ECT on non-memory functions and different memory
      subtypes.

PMID- 12622314
TI  - The internal and external validity of the Major Depression Inventory in measuring
      severity of depressive states.
AB  - BACKGROUND: We have developed the Major Depression Inventory (MDI), consisting of
      10 items, covering the DSM-IV as well as the ICD-10 symptoms of depressive
      illness. We aimed to evaluate this as a scale measuring severity of depressive
      states with reference to both internal and external validity. METHOD: Patients
      representing the score range from no depression to marked depression on the
      Hamilton Depression Scale (HAM-D) completed the MDI. Both classical and modern
      psychometric methods were applied for the evaluation of validity, including the
      Rasch analysis. RESULTS: In total, 91 patients were included. The results showed
      that the MDI had an adequate internal validity in being a unidimensional scale
      (the total score an appropriate or sufficient statistic). The external validity
      of the MDI was also confirmed as the total score of the MDI correlated
      significantly with the HAM-D (Pearson's coefficient 0.86, P < or = 0.01, Spearman
      0.80, P < or = 0.01). CONCLUSION: When used in a sample of patients with
      different states of depression the MDI has an adequate internal and external
      validity.

PMID- 12622315
TI  - The performance of the K6 and K10 screening scales for psychological distress in
      the Australian National Survey of Mental Health and Well-Being.
AB  - BACKGROUND: Two new screening scales for psychological distress, the K6 and K10,
      have been developed but their relative efficiency has not been evaluated in
      comparison with existing scales. METHOD: The Australian National Survey of Mental
      Health and Well-Being, a nationally representative household survey, administered
      the WHO Composite International Diagnostic Interview (CIDI) to assess 30-day DSM
      IV disorders. The K6 and K10 were also administered along with the General Health
      Questionnaire (GHQ-12), the current de facto standard of mental health screening.
      Performance of the three screening scales in detecting CIDI/DSM-IV mood and
      anxiety disorders was assessed by calculating the areas under receiver operating
      characteristic curves (AUCs). Stratum-Specific Likelihood Ratios (SSLRs) were
      computed to help produce individual-level predicted probabilities of being a case
      from screening scale scores in other samples. RESULTS: The K10 was marginally
      better than the K6 in screening for CIDI/DSM-IV mood and anxiety disorders (K10
      AUC: 0.90, 95%CI: 0.89-0.91 versus K6 AUC: 0.89, 95%CI: 0.88-0.90), while both
      were significantly better than the GHQ-12 (AUC: 0.80, 95%CI: 0.78-0.82). The
      SSLRs of the K10 and K6 were more informative in ruling in or out the target
      disorders than those of the GHQ-12 at both ends of the population spectrum. The
      K6 was more robust than the K10 to subsample variation. CONCLUSIONS: While the
      K10 might outperform the K6 in screening for severe disorders, the K6 is
      preferred in screening for any DSM-IV mood or anxiety disorder because of its
      brevity and consistency across subsamples. Precision of individual-level
      prediction is greatly improved by using polychotomous rather than dichotomous
      classification.

PMID- 12622317
TI  - The epidemiology of murder-suicide in England and Wales.

PMID- 12622318
TI  - Translating worldwide calcium-channel blocker experience into clinical practice.

PMID- 12622316
TI  - Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces
      personnel.
AB  - BACKGROUND: In both psychiatrically ill and psychiatrically healthy adults, the
      connection between health and individuals' height and weight has long been
      examined. Specifically, research on the idea that individuals with certain body
      types were prone to particular psychiatric diseases has been explored
      sporadically for centuries. The hypothesis that psychiatrically ill individuals
      were shorter and weighed less than psychiatrically healthy counterparts would
      correspond with the neurodevelopmental model of psychiatric disease. METHOD: To
      evaluate possible links between psychiatric illness and physique, the height,
      weight and BMI of 7514 patients and 85,940 controls were compared. All subjects
      were part of the National Collaborative Study of Early Psychosis and Suicide
      (NCSEPS). Patients were US military active duty personnel hospitalized for either
      bipolar disorder, major depressive disorder, or schizophrenia and controls were
      psychiatrically-healthy US military active duty personnel matched for date of
      entry into the service. RESULTS: No consistent differences in height, weight or
      BMI were found between patients and controls, or between patient groups. Some
      weak ANOVA differences were found between age at the time of entering active duty
      and weight, as well as BMI, but not height. CONCLUSIONS: Unlike most previous
      studies that have looked at the links between height and psychiatric illness,
      this study of the NCSEPS cohort found that, at entry into the US Armed Forces,
      there were no consistent decreases in height for patients with bipolar disorder,
      major depressive disorder or schizophrenia compared with a large control group.
      Furthermore, there were no consistent differences for weight or BMI.

PMID- 12622319
TI  - Getting to goal in complex patients.
AB  - Traditionally, the term complex hypertension has been applied to patients who
      have clinical evidence of target organ damage. However, this definition can be
      expanded to include many hypertensive patients who either present without
      manifest disease but harbor silent concomitant organ damage, or belong to a high
      risk group and are likely to develop such damage. Thus, the number of patients
      who deserve special consideration as complex patients is considerable. Various
      factors may contribute toward classifying a patient as having complex
      hypertension. These include severe hypertension, concomitant conditions such as
      diabetes, chronic renal insufficiency, coronary artery disease, orcongestive
      heart failure; and high-risk populations such as the elderly and African
      Americans. Recent evidence demonstrates that aggressive goal blood pressure (BP)
      lowering therapy is the key toward halting the progression of vascular disease.
      Although the choice of initial therapy seems less important than achieving goal
      BP, the drug selected must impart efficacy, organ protection, and tolerability.
      Combination therapy consisting of calcium-channel blockers and angiotensin
      converting enzyme inhibitors seems to achieve these desirable effects. Several
      clinical trials have demonstrated these agents to have favorable effects on BP
      and organ protection even in complex hypertension, particularly when used in
      combination.

PMID- 12622321
TI  - Evolution of calcium antagonists: past, present, and future.
AB  - Calcium antagonists were originally introduced as fast-acting vasodilators
      exhibiting powerful antihypertensive properties. They have now evolved into
      agents exhibiting a smooth onset and a long duration of action. Early agents,
      because of their rapid onset of action, were associated with a host of
      compensatory hemodynamic adverse effects including cardioacceleration and
      sympathetic stimulation. In contrast, the newer agents appear to retain the
      antihypertensive properties, but with an improved tolerability profile. Across
      the cardiovascular disease continuum, the presence of diabetes adds to the risk
      forcardiovascular events. In diabetic patients with hypertension, multiple drug
      therapy is clearly indicated. Agents such as calcium antagonists that normalize
      hemodynamics in this patient population might be expected to demonstrate
      beneficial effects on mortality. Evidence from the Systolic Hypertension in
      Europe and the Systolic Hypertension in China trials demonstrated over a 50%
      reduction in total mortality in the diabetic subgroup in patients treated with
      calcium antagonists. Among the calcium antagonists, particularly among the
      dihydropyridine subclasses, the efficacy of the drugs has been accompanied by
      some side effects, in particular pedal edema. The incidence of pedal edema is
      dose dependent and is the result of vasodilation and intracapillary hypertension.
      Newer calcium antagonists demonstrate antihypertensive efficacy similar to that
      of their predecessors but appear to have a reduced propensity to cause edema.

PMID- 12622320
TI  - Clinical trial experience around the globe: focus on calcium-channel blockers.
AB  - Although certain classes of drugs appear to possess benefits apart from their
      blood-pressure lowering capability, reduction of blood pressure remains the
      single most important action of antihypertensive therapy. Calcium-channel
      blockers (CCBs) have long been recognized as potent agents for hypertension
      therapy. This is especially true for the prevention of stroke in hypertensive
      patients as evidenced from the Systolic Hypertension in Europe (Syst-Eur) and
      Systolic Hypertension in China (Syst-China) trials with a long acting
      dihydropyridine CCB. The same can be said for beta blockers in patients post
      myocardial infarction. However, most recent clinical trials have underscored the
      necessity of multiple drug therapy to achieve the goals of blood pressure
      reduction coupled with outcomes reduction. For example, the many recent large
      scale clinical trials have required an average of three or more agents to achieve
      goal. Thus, the paradigm for hypertension management has been altered to
      determine the best treatment regimen rather than the best initial agent. While
      response rates to individual agents across a wide spectrum of patients vary
      little, not all drugs are equally suited as companion products. In this article,
      we discuss the most recent outcome trials with the long acting CCBs alone or in
      combination with other drugs. The evidence shows that calcium antagonists remain
      an important part of hypertension management, including in those individuals at
      risk of cardiac and cerebrovascular events.

PMID- 12622322
TI  - Emerging data on calcium-channel blockers: the COHORT study.
AB  - Multiple studies have demonstrated dihydropyridine calcium-channel blocker (CCB)
      therapy to be appropriate for the treatment of hypertension, as is reflected in
      treatment guidelines such as the Sixth Report of the Joint National Committee on
      Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in the
      United States and the 1999 World Health Organization-International Society of
      Hypertension report. As with any drug class, successful treatment with CCBs
      depends on good patient compliance, which often hinges on drug tolerability. The
      differing characteristics among the various generations of CCBs may contribute to
      some compounds demonstrating superior tolerability. To test this hypothesis, the
      COHORT trial (named for the large group of participants) was undertaken in 828
      elderly hypertensive patients aged > or = 60 years. This trial investigated the
      possible differences in patient tolerability between the third-generation agent
      amlodipine and the latest-generation agents lercanidipine and lacidipine. The
      primary endpoint of the study was the percentage of patients reporting edema, the
      most common side effect associated with CCB therapy. The study results indicated
      that while all three treatments were similarly efficacious in lowering blood
      pressure, lercanidipine and lacidipine were much better tolerated than amlodipine
      whether they were used as single agents or as initial therapy combined with other
      antihypertensive drugs. These newest-generation dihydropyridine CCBs offer the
      potential to reduce side effects, improve patient compliance, and ultimately help
      patients reach target blood pressures as recommended by the aforementioned
      guidelines.

PMID- 12622323
TI  - Hypertension is not all alike nor are its treatments: where would a better
      calcium-channel blocker fit in a modern treatment system?

PMID- 12622324
TI  - Measuring immune selection.
AB  - Immune responses that kill pathogens or reduce their reproductive rate are
      generally important in protecting hosts from infection and disease. Pathogens
      that escape the full impact of such responses will survive, and any heritable
      genetic basis of this evasion will be selected. Due to the memory component of
      vertebrate immune responses, pathogens with rare alleles of a target antigen can
      have an advantage over those with common alleles, leading to the maintenance of a
      polymorphism. At the genetic level, there ought to be detectable signatures of
      balancing selection in the genes encoding these antigens. Here, methods for
      identifying these selective signatures are reviewed. Their practical utility for
      identifying which antigens are targets of protective immune responses is
      discussed.

PMID- 12622325
TI  - A perspective on clonal phenotypic (antigenic) variation in protozoan parasites.
AB  - Intra-clonal phenotypic (antigenic) variation is used by many pathogens to evade
      the consequences of immune-mediated killing by mammalian hosts. In this
      substantially theoretical article, I emphasise that antigenic variation (sensu
      stricto) involves no change in genotype; its importance as a mechanism for
      promoting pathogen transmission and its polyphyletic origin. From a functional
      perspective, antigenic variation is constrained by the requirement to meet five
      conditions. These are: capability to express several antigens against which
      functional immunity predominates; capability to interact with the environment;
      mutually exclusive expression of variable antigens in each cell within an
      infection; mutually exclusive expression in the within-host pathogen population
      and the capability for population growth within a host. Meeting these conditions
      leads to chronicity of infection and high rates of hierarchical and reversible
      switching of expression between variable antigens. The organisation of
      hierarchical expression is discussed in some detail.

PMID- 12622326
TI  - Variation and polymorphism in helminth parasites.
AB  - There are strong biological, evolutionary and immunological arguments for
      predicting extensive polymorphism among helminth parasites, but relatively little
      data and few instances from which the selective forces acting on parasite
      diversity can be discerned. The paucity of information on intraspecific variation
      stands in contrast to the fine detail with which helminth species have been
      delineated by morphological techniques, accentuating a trend towards considering
      laboratory strains as representative of a relatively invariant organism. However,
      in the fast-moving evolutionary race between host and parasite one would predict
      a monomorphic species would be driven to extinction. We review the arena of
      intraspecific variation for the major helminth parasites, ranging from biological
      properties such as host or vector preference, to biochemical and immunological
      characteristics, as well as molecular markers such as DNA sequence variants.
      These data are summarized, before focusing in more detail on polymorphisms within
      protein-coding genes of potential relevance to the host-parasite relationship,
      such as vaccine candidates. In particular, we discuss the available data on a
      number of major antigens from the filarial nematode Brugia malayi. Information is
      currently too sparse to answer the question of whether there is antigenic
      variation in filariasis, but the indications are that proteins from the blood
      borne microfilarial stage show significant intraspecific variability. Future work
      will define whether polymorphisms in these antigens may be driven by exposure to
      the host immune response or reflect some other facet of parasite biology.

PMID- 12622327
TI  - Variation and immunity to intestinal worms.
AB  - Genetically determined variation in host capacity to express resistance to a
      given parasite plays a major role in determining the outcome of infection. It can
      be assumed that the same is true of variation in parasites, but very much less is
      known of its influence on the host-parasite relationship. Phenotypic and
      genotypic variation within species of intestinal worms is now well documented,
      detailed studies having been made of parasites such as Ascaris in humans and
      trichostrongyles in domestic animals. However, the extent to which this variation
      affects the course of infection or the host immune response in these hosts is
      limited. Of the nematodes used as experimental models in laboratory rodents,
      detailed data on phenotypic or genotypic variation are limited to Strongyloides
      and Trichinella. Parasite variation is known to be subject to host-mediated
      selection, the emergence of anthelmintic resistance being a good example.
      Repeated passage has been used to select lines of parasite that survive in
      abnormal hosts or which show adaptation to host immunity. Experimental studies
      with Trichinella genotypes in mice have demonstrated the extent to which parasite
      variation influences the nature and degree of the host's immune and inflammatory
      responses, the complex interplay between immunogenicity and pathogenicity
      influencing both partners in the relationship. Recent studies with isolates of
      Trichuris muris have shown how parasite variation influences the capacity of mice
      to express the T helper cell responses necessary for resistance. Molecular
      differences between T. muris isolates have been shown in their excreted/secreted
      products as well as at the level of their DNA. Knowledge of the functional
      consequences of parasite variation will add to our understanding of host-parasite
      evolution as well as providing a rational basis for predicting the outcome of
      controls strategies that rest on the improvement of host resistance through
      vaccination or selective breeding.

PMID- 12622328
TI  - Schistosome genetic diversity: the implications of population structure as
      detected with microsatellite markers.
AB  - Blood flukes in the genus Schistosoma are important human parasites in tropical
      regions. A substantial amount of genetic diversity has been described in
      populations of these parasites using molecular markers. We first consider the
      extent of genetic variation found in Schistosoma mansoni and some factors that
      may be contributing to this variation. Recently, though, attempts have been made
      to analyze not only the genetic diversity but how that diversity is partitioned
      within natural populations of schistosomes. Studies with non-allelic molecular
      markers (e.g. RAPDs and mtVNTRs) have indicated that schistosome populations
      exhibit varying levels of gene flow among component subpopulations. The recent
      characterization of microsatellite markers for S. mansoni provided an opportunity
      to study schistosome population structure within a population of schistosomes
      from a single Brazilian village using allelic markers. Whereas the detection of
      population structure depends strongly on the type of analysis with a
      mitochondrial marker, analyses with a set of seven microsatellite loci
      consistently revealed moderate genetic differentiation when village boroughs were
      used to define parasite subpopulations and greater subdivision when human hosts
      defined subpopulations. Finally, we discuss the implications that such strong
      population structure might have on schistosome epidemiology.

PMID- 12622329
TI  - The epidemiological consequences of optimisation of the individual host immune
      response.
AB  - We present a simple unscaled, quantitative framework that addresses the optimum
      use of resources throughout a host's lifetime based on continuous exposure to
      parasites (rather than evolutionary, genetically explicit trade-offs). The
      principal assumptions are that a host's investment of resources in growth
      increases its survival and reproduction, and that increasing parasite burden
      reduces survival. The host reproductive value is maximised for a given
      combination of rates of parasite exposure, host resource acquisition and
      pathogenicity, which results in an optimum parasite burden (for the host).
      Generally, results indicate that the optimum resource allocation is to tolerate
      some parasite infection. The lower the resource acquisition, the lower the
      proportion of resources that should be devoted to immunity, i.e. the higher the
      optimum parasite burden. Increases in pathogenicity result in reduced optimum
      parasite burdens, whereas increases in exposure result in increasing optimum
      parasite burdens. Simultaneous variation in resource acquisition, pathogenicity
      and exposure within a community of hosts results in overdispersed parasite
      burdens, with the degree of heterogeneity decreasing as mean burden increases.
      The relationships between host condition and parasite burden are complicated, and
      could potentially confound data analysis. Finally, the value of this approach for
      explaining epidemiological patterns, immunological processes and the
      possibilities for further work are discussed.

PMID- 12622330
TI  - Costs of resistance in insect-parasite and insect-parasitoid interactions.
AB  - Most, if not all, organisms face attack by natural enemies and will be selected
      to evolve some form of defence. Resistance may have costs as well as its obvious
      benefits. These costs may be associated with actual defence or with the
      maintenance of the defensive machinery irrespective of whether a challenge
      occurs. In this paper, the evidence for costs of resistance in insect-parasite
      and insect-parasitoid systems is reviewed, with emphasis on two host-parasitoid
      systems, based on Drosophila melanogaster and pea aphids as hosts. Data from true
      insect-parasite systems mainly concern the costs of actual defence; evidence for
      the costs of standing defences is mostly circumstantial. In pea aphids, the costs
      of standing defences have so far proved elusive. Resistance amongst clones is not
      correlated with life-time fecundity, whether measured on good or poor quality
      plants. Successful defence by a D. melanogaster larva results in a reduction in
      adult size and fecundity and an increased susceptibility to pupal parasitoids.
      Costs of standing defences are a reduction in larval competitive ability though
      these costs only become important when food is limited. It is concluded that
      costs of resistance can play a pivotal role in the evolutionary and population
      dynamic interactions between hosts and their parasites.

PMID- 12622331
TI  - Getting published in the Journal of Nursing Education.

PMID- 12622332
TI  - Due process rights of nursing students in cases of misconduct.

PMID- 12622333
TI  - Bearing witness to suffering: the lived experience of nursing students.
AB  - This study explored the meanings of the lived experience of nursing students as
      they care for patients who are suffering. In this interpretive phenomenological
      study, 13 nursing students participated in conversational interviews and wrote
      narratives about their experiences of being with someone who was suffering.
      Embedded in the students' stories are the ways they came to understand suffering
      in the context of learning to practice nursing. The metatheme of bearing witness
      to suffering emerged from the analysis of the students' reflections. Bearing
      witness was exemplified with the subthemes of grappling with suffering,
      struggling with the ineffable, getting through, being with suffering patients,
      embodying the experience of suffering, and seeing possibilities in suffering.
      Bearing witness to suffering patients called students to an awareness of their
      own vulnerability. A concern for learning amid suffering was present throughout
      the students' texts. The call to care can be sustained through a pedagogy of
      suffering that acknowledges the need for support through a caring community.

PMID- 12622334
TI  - Faculty support and student retention.
AB  - A study was conducted to explore the relationship between nursing students'
      perceived faculty support and nursing student retention. The 458 associate degree
      nursing students who participated were categorized according to their persistence
      those who had persisted continuously throughout a nursing program, those who had
      withdrawn voluntarily at some time during a program, and those who had been
      required to withdraw because of academic failure. Perceived faculty support was
      measured by scores on the Perceived Faculty Support Scale, an instrument
      developed by the researcher for this study. A factor analysis of the instrument
      revealed two factors-psychological support, directed at promoting a sense of
      competency and self-worth, and functional support, directed at the achievement of
      tasks to reach the goals of persistence and academic success. Analysis of
      variance revealed persistence group differences in perceived faculty support.
      Students who reported greater perceived faculty support were more likely to
      persist throughout a nursing program than students who withdrew either
      voluntarily or because of academic failure. To promote retention of nursing
      students, faculty need to provide the caring atmosphere of a mentoring
      relationship and direct assistance to facilitate student learning.

PMID- 12622335
TI  - "I was actually a nurse": the meaning of professionalism for baccalaureate
      nursing students.
AB  - An important process in any profession is the development of professional
      identity. Understanding how students experience professionalism is important to
      provide appropriate educational experiences to foster this aspect of professional
      socialization. Therefore, this study investigated baccalaureate student nurses'
      perspectives of what it means to be professional. This qualitative study was
      based on Pollio, Henley, and Thompson's interpretive framework, an existential
      phenomenological approach. The purpose of the interpretation was to recognize
      patterns or themes in an experience. Figural experiences in one's life emerge
      against a backdrop, or ground. Sixty-nine baccalaureate nursing students at
      different educational levels participated. They described specific experiences in
      which they felt professional. The student experience of being professional was
      one grounded in a world of self and others. Three interrelated themes emerged
      from this ground-belonging, knowing, and affirmation. The ground of self and
      others provides the backdrop of the experience. It is through self and others
      that the figural themes are experienced. The themes are inherently inter-related.
      For example, the experiences of belonging and knowing were affirming to students,
      and affirmation enhanced their sense of knowing and belonging. Implications of
      the findings are explored.

PMID- 12622336
TI  - The values profile of nursing undergraduate students: implications for education
      and professional development.
AB  - This study examined the values profile of 152 nursing undergraduate students, as
      measured by the 20 life and work values from the Values Scale, and compared their
      profiles to those from a comparable sample of 111 management undergraduate
      students. Results showed that Personal Development and Altruism are the most
      important values for this sample of nursing students. There also were several
      significant age effects related to six of the values. The results of the t tests
      showed that the nursing sample had a significantly higher mean on the Altruism
      value and lower means on the Life Style, Advancement, Autonomy, Authority,
      Creativity, Economic, and Risk values, compared to the management sample.
      Recommendations are offered for nurse educators and managers. Inevitably, values
      compel individuals to be and to act, both personally and professionally.

PMID- 12622337
TI  - Physician-assisted dying: are education and religious beliefs related to nursing
      students' attitudes?

PMID- 12622338
TI  - Amphetamine-like discriminative stimulus effects of ephedrine and its
      stereoisomers in pigeons.
AB  - This study assessed the discriminative stimulus effects of (+/-)-ephedrine and
      its stereoisomers in pigeons discriminating 1.0 mg/kg of amphetamine from saline.
      Amphetamine, (+/-)-, (-)-, and (+)-ephedrine, and cocaine occasioned greater than
      80% drug-key responding with the following rank order of potency: amphetamine >
      cocaine > (-)-ephedrine > or = (+/-)-ephedrine > or = (+)-ephedrine. Neither the
      alpha-adrenergic antagonist, phentolamine, nor the beta-adrenergic antagonist,
      propranolol, antagonized the effects of amphetamine or (+/-)-ephedrine. In
      contrast, the dopamine receptor antagonist, haloperidol, antagonized the
      discriminative stimulus effects of amphetamine and (+/-)-ephedrine as well as
      those of (-)- and (+)-ephedrine. These results indicate that, like cocaine, (+/-)
      ephedrine and its stereoisomers share discriminative stimulus effects with
      amphetamine. Moreover, these effects appear to be the result of increased
      activity in dopaminergic systems.

PMID- 12622339
TI  - Alcohol tolerance in humans is enhanced by prior caffeine antagonism of alcohol
      induced impairment.
AB  - The author tested the hypothesis that a history of drug-induced antagonism of
      alcohol impairment would enhance alcohol tolerance in humans. Groups of
      participants (N = 21) repeatedly performed a psychomotor task under different
      drug treatments: 0.65 g/kg alcohol, 4 mg/kg caffeine, or both drugs combined.
      Tolerance to a 0.65 g/kg alcohol dose challenge was then tested. Results showed
      that a history of combined alcohol and caffeine administrations increased alcohol
      tolerance compared with an exposure history to either drug alone. The findings
      contribute to the understanding of the complexities of polydrug use history and
      provide a useful model to examine how alcohol tolerance might be affected by a
      history of coadministration with other drugs (e.g., cocaine and nicotine).

PMID- 12622340
TI  - Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine
      dependent individuals.
AB  - In this study, crack/cocaine-dependent (CD) and non-drug-using matched control
      (MC) participants were presented with hypothetical immediate and delayed rewards,
      with 16 delay conditions ranging from 5 min to 25 years. All participants were
      presented with hypothetical monetary rewards; however, the CD group was also
      presented with hypothetical crack/cocaine rewards. The objective value of the
      rewards ranged from $1 to $1,000. Hyperbolic discounting functions provided a
      good fit of the data. The CD group discounted monetary rewards at a higher rate
      than the MC group did, and the CD group discounted crack/cocaine rewards at a
      higher rate than it did monetary rewards. Moreover, scores on self-report
      measures indicated greater impulsivity in the CD group when compared with the MC
      group.

PMID- 12622341
TI  - The Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokers.
AB  - In trying to better understand why individuals begin and continue to smoke
      despite the obvious health consequences, researchers have become interested in
      identifying relevant personality variables, such as risk taking. In this study,
      the authors compared the ability of 2 behavioral measures of risk taking, the
      Bechara Gambling Task (BGT) and the Balloon Analogue Risk Task (BART), to
      differentiate smokers and nonsmokers. Self-report measures of impulsivity and
      sensation seeking were taken for comparison with the 2 behavioral risk-taking
      tasks. Results indicate that behavior on the BART, and not the BGT, was related
      to smoking status. Further, when considered in a logistic regression analysis,
      only the Sensation Seeking total score and the BART score contributed uniquely to
      the differentiation of smokers and nonsmokers.

PMID- 12622342
TI  - The neuropsychological test performance of drug-abusing patients: an examination
      of latent cognitive abilities and associated risk factors.
AB  - The purpose of this study was to examine the latent structure of
      neuropsychological abilities of drug-abusing patients. Four factors were
      identified in an exploratory factor analysis (N = 329) and a subsequent
      confirmatory factor analysis (N = 258): Executive Functioning, Verbal Ability,
      Memory, and Speed, Education, years of regular alcohol use, number of substance
      use dependence disorders, percentage of days of heavy drinking in the previous
      year, depression, familial alcoholism, premorbid level of cognitive functioning,
      liver functioning, and previous head injuries were identified as risk factors to
      these latent abilities.

PMID- 12622343
TI  - Effects of reinforcer magnitude on data-entry productivity in chronically
      unemployed drug abusers participating in a Therapeutic Workplace.
AB  - The Therapeutic Workplace is a substance abuse treatment wherein patients are
      hired and paid to work in a job contingent on daily drug-free urine samples. The
      present study examined data-entry productivity of 6 unemployed methadone patients
      who demonstrated relatively variable and low data-entry response rates. A within
      subject reversal design was used to determine whether increasing reinforcement
      magnitude tenfold could increase response rates. Four of the 6 participants
      showed the highest rates of responding in the high magnitude reinforcement
      condition. Two participants, who had the lowest overall response rates, showed
      less robust changes to the magnitude manipulation. The results suggest that
      reinforcement magnitude can be used to improve productivity in Therapeutic
      Workplace participants.

PMID- 12622345
TI  - The feasibility of using cellular phones to collect ecological momentary
      assessment data: application to alcohol consumption.
AB  - The limitations of paper-and-pencil self-monitoring (PM) are leading to the use
      of more sophisticated techniques. PM was compared with cellular phone monitoring
      (CM) to collect ecological momentary assessment data on alcohol use. Twenty
      social drinkers were randomly assigned to the 2 groups, and their drinking was
      monitored for 14 days. PM participants recorded data on cards. CM participants
      carried telephones and responded to an interactive voice response system. The
      authors found few significant group differences in alcohol use, compliance with
      the self-monitoring, and satisfaction. However, CM had useful advantages,
      including instantaneous entry of data into a central database, date and time
      stamping of data, and easy integration into daily life. Although preliminary,
      this study suggests that CM is a promising alternative to PM.

PMID- 12622344
TI  - Lorazepam and scopolamine: A single-dose comparison of effects on human memory
      and attentional processes.
AB  - This placebo-controlled, double-blind, double-dummy, independent groups study
      directly compared effects of the benzodiazepine, lorazepam (2.0 mg/70 kg orally
      administered), and the anticholinergic scopolamine (0.6 mg/70 kg subcutaneously
      administered) on memory and attentional measures hypothesized to differentiate
      the drugs. At the studied doses, lorazepam and scopolamine produced similar
      decrements in psychomotor performance, free recall, and overall sensitivity in
      distinguishing between studied and nonstudied items on a recognition memory test.
      However, the drugs differed with respect to effects on working memory, response
      bias, metacognition, subjective awareness, and selective attention. In addition
      to providing information about the cognitive psychopharmacological profiles of
      drugs with distinct neurochemical and pharmacological mechanisms of action, this
      study also informs the understanding of memory and attentional processes.

PMID- 12622346
TI  - Repeated spatial acquisition: effects of NMDA antagonists and morphine.
AB  - Effects of morphine and 2 N-methyl-D-aspartate (NMDA) receptor antagonists,
      phencyclidine and LY235959, were studied using a within-subject, repeated
      acquisition/performance procedure adapted to the Morris Swim Task. In the
      performance component, subjects swam to a hidden platform that was always in the
      same location in the pool. In the acquisition component, the platform was moved
      to a different place for each session. Baseline training produced rapid and
      direct swims to the platform in the performance component and steep within
      session learning curves in the acquisition component. All 3 compounds increased
      swim distances, escape latencies, and slowed swim speed in a dose-dependent
      manner, but only morphine consistently produced selective impairments on
      acquisition. NMDA antagonists generally affected acquisition only at doses that
      also disrupted performance, although phencyclidine produced selective effects in
      some animals. These outcomes were different than those from studies of response
      chains in primates, suggesting that task and species variables may be important
      determinants of drug effects on acquisition.

PMID- 12622347
TI  - Variations in affect following amphetamine and placebo: markers of stimulant drug
      preference.
AB  - Variations in affect following d-amphetamine and placebo were examined in healthy
      young adults who subsequently preferred d-amphetamine (choosers; n = 61) or
      placebo (nonchoosers; n = 48) in a drug preference procedure. Affect was assessed
      before and 1, 3, and 6 hr after participants received the placebo and 10 mg d
      amphetamine. Following amphetamine as compared with placebo, choosers' ratings
      increased on scales measuring energy, cognitive efficiency, and well-being, and
      decreased on scales measuring fatigue and sedation. Nonchoosers reported no
      effects, sedative effects, and dysphoric effects of amphetamine. Following
      placebo, ratings of energy, efficiency, and well-being decreased, and ratings of
      sedation increased in choosers but not in nonchoosers. Variations in affect
      following placebo and amphetamine may constitute markers of risk for drug use.

PMID- 12622348
TI  - Sensitization to cocaine in pigeons: interaction with an operant contingency.
AB  - A 2-part study with pigeons investigated the role of an explicit operant
      contingency in determining how cocaine interacts with locomotor activity. In Part
      1, pigeons pecked on a fixed-ratio-20 schedule of food presentation. In Part 2,
      different pigeons were studied without opportunity to peck for food. After
      determination of cocaine's initial effects, pigeons were exposed to daily
      administrations of a locomotion-increasing dose of cocaine. Locomotor
      sensitization was evident in the pigeons of Part 2, and tolerance developed to
      cocaine's effects on key pecking in the pigeons of Part 1. Locomotor
      sensitization was generally not evident in the pigeons of Part 1. These results
      suggest that explicitly conditioned operant behavior may compete with behavior
      sensitized by prolonged exposure to cocaine.

PMID- 12622349
TI  - Preresponse cues reduce the impairing effects of alcohol on the execution and
      suppression of responses.
AB  - The present study examined the effects of alcohol on the ability to execute and
      inhibit behavior in a context in which preliminary information signaled the
      likelihood that a response should be executed or suppressed. Social drinkers (N =
      12) performed a cued go/no-go task that required quick responses to go targets
      and suppression of responses to no-go targets. Performance was tested under 3
      doses of alcohol: 0.65 g/kg, 0.45 g/kg, and 0.0 g/kg (placebo). Alcohol had no
      effect on inhibition and execution when cues correctly signaled these actions. By
      contrast, alcohol impaired inhibition and execution in a dose-dependent manner
      when cues incorrectly signaled actions. These findings are consistent with a
      resource limitation account of alcohol impairment.

PMID- 12622351
TI  - Failure to convince osteopathic medical students of OMT's worth increases risk of
      subspecialization.

PMID- 12622350
TI  - Exploring the benefit of semantics in the osteopathic profession.

PMID- 12622352
TI  - Somatic dysfunction during carisoprodol cessation: evidence for a carisoprodol
      withdrawal syndrome.
AB  - Carisoprodol is a commonly used skeletal muscle relaxant with potential for abuse
      because of its active metabolite, meprobamate, and several reports have suggested
      that patients abruptly stopping intake of carisoprodol may have a withdrawal
      syndrome. The authors studied changes in the occurrence of somatic dysfunctions
      in five patients during an 8-day period following discontinuation from large
      doses of carisoprodol. Results showed that the number of somatic dysfunctions
      changed significantly during the withdrawal period. Each patient had an increase
      in the number of somatic dysfunctions during the first 3 days after cessation of
      carisoprodol with return to at or near baseline by the eighth day. This was
      reflected statistically in a significant-within-subjects effect for time. Results
      of supplemental analyses revealed a significant component of the effect and a
      trend for the quadratic component to be significant. Increases in the number of
      somatic dysfunctions during carisoprodol discontinuation support the existence of
      a carisoprodol withdrawal syndrome.

PMID- 12622353
TI  - Characteristics of physicians disciplined by the State Medical Board of Ohio.
AB  - Although physicians have been disciplined for a variety of offenses by state
      medical boards across the United States, limited information is available about
      the characteristics of these physicians. To assess the characteristics of,
      offenses committed by, and resulting disciplinary actions taken against a
      consecutive series of disciplined physicians in the state of Ohio, the authors
      conducted a case-control study of all 308 physicians publicly disciplined by the
      State Medical Board of Ohio (SMBO) from January 1997 to June 1999. Subjects were
      matched with two groups of control physicians--one matched by location only, and
      the second matched for location, gender, practice type, and self-designated
      specialty. The main outcomes measured were disciplinary actions, offenses leading
      to state medical board actions, and the characteristics of disciplined
      physicians. Of 340 physicians disciplined during these 30 months (approximately
      0.37% per year), 308 committed 477 offenses requiring 409 actions by the SMBO.
      The most common offenses were impairment due to alcohol and/or drug use (21%),
      inappropriate prescribing or drug possession (14%), previous state actions (15%),
      negligence or incompetence (7%), and drug-related charges (7%). Although
      offenders were significantly less likely to be women (P < .05; odds ratio [OR],
      0.46; 95% confidence interval [CI], 0.28-0.75), the authors found no difference
      in the severity of disciplinary action taken against offenders by gender (OR,
      1.23; 95% CI, 0.54-2.82) or by type of medical training, ie, between osteopathic
      physicians and allopathic physicians (OR, 0.70; 95% CI, 0.39-1.26). Compared with
      controls matched for location, gender, practice type, and self-designated
      specialty, offenders were significantly less likely to be board certified (OR,
      0.65; CI, 0.46-0.92) and significantly more likely to have been in practice 20 or
      fewer years (OR, 1.51; 95% CI, 1.08-2.13). Disciplinary actions in Ohio were more
      frequent, more severe, and more often in response to impairment due to alcohol
      and/or drug use and previous state actions than previously reported. No
      difference in the severity of disciplinary action was noted between men and women
      or between osteopathic and allopathic physicians.

PMID- 12622354
TI  - Validity and reliability of the Osteopathic Survey of Health Care in America
      (OSTEOSURV).
AB  - The osteopathic medical profession has lacked research instruments to measure and
      characterize the use of osteopathic physicians and to assess public awareness and
      perceptions of osteopathic medicine. In the 1990s, the Osteopathic Survey of
      Health Care in America (OSTEOSURV) was developed to fill this void. Data from
      OSTEOSURV-I and OSTEOSURV-II, random national telephone surveys administered
      during 1998 and 2000, respectively, were used to test the validity and
      reliability of OSTEOSURV as a longitudinal survey instrument for osteopathic
      medicine. A total of 12 survey items were found to contribute to the "Perceptions
      of osteopathic medicine" construct. Within this construct, an osteopathic
      medicine scale emerged that consists of three distinct dimensions termed
      conventional medicine, manual medicine, and somato/visceral medicine.

PMID- 12622355
TI  - Sickle cell episode manifesting as superficial thrombophlebitis of the penis.
AB  - In 1955, the first reported case of Mondor's disease (superficial
      thrombophlebitis) of the penis was published. Since then, there have been
      scattered reports of penile Mondor's disease in the literature. Most studies
      suggest sexual trauma or neoplasm as the most frequent etiologic factor. The
      authors report a case of a sickle cell episode presenting with superficial
      thrombophlebitis of the penis. The patient was treated with an antiinflammatory
      agent and reassured that this is a self-limiting process. Resolution of symptoms
      occurred within 6 weeks.

PMID- 12622356
TI  - Fabrication of a reversible protein array directly from cell lysate using a
      stimuli-responsive polypeptide.
AB  - We report a new method to reversibly bind proteins to a surface in a functionally
      active orientation directly from cell lysate by exploiting a thermodynamically
      reversible hydrophilic-hydrophobic lower critical solution temperature (LCST)
      transition exhibited by a recombinant, stimuli-responsive elastin-like
      polypeptide (ELP). An ELP is covalently micropatterned on a glass surface against
      an inert BSA background. The ELP-patterned surface is incubated with the soluble
      fraction of E. coli lysate containing an expressed ELP fusion protein, which is
      appended with the same ELP as on the surface. The LCST transition of the grafted
      ELP and the ELP fusion protein is simultaneously triggered by an external
      stimulus. The LCST transition results in capture of the ELP fusion protein from
      solution onto the immobilized ELP by hydrophobic interactions between the grafted
      ELP and the ELP fusion protein. The captured ELP fusion protein is oriented such
      that the fusion partner is accessible to binding of its target from solution. We
      also demonstrate that TRAP is reversible; the bound protein-ligand complex is
      released from the surface by reversing the LCST transition. The triggered control
      of interfacial properties provided by an immobilized stimuli-responsive
      polypeptide at the solid-water interface is an enabling technology that allows
      reversible and functional presentation of ELP fusion proteins on a surface
      directly from cell lysate without the necessity of intermediate purification
      steps and subsequent recovery of the protein-ligand complex for downstream
      analysis by other analytical techniques. TRAP has application in lab-on-a-chip
      bioanalytical devices as well as in the fabrication of peptide and protein
      arrays.

PMID- 12622357
TI  - Identification of pigments in paint cross sections by reflection visible light
      imaging microspectroscopy.
AB  - A setup for reflection visible light imaging microspectroscopy (VIS-imaging) as
      well as its evaluation and application is described and tested. The spatial
      resolution of the system is approximately 1 microm at a spectral resolution of 4
      nm. The optical contrast between different colored particles in the surface of a
      sample is optimized with a new image processing method for mapping of the
      distribution of the identified pigment particles. The potential of VIS-imaging in
      the study of paint cross sections obtained from paintings is explored. Spectra
      obtained from pigment particles in these cross sections result in classification
      or identification of several pigments. The investigated paint samples are
      challenging test cases, as they contain several colored materials with a very
      fine distribution. VIS-imaging can identify and map the most common traditional
      blue pigments, i.e., smalt, azurite, ultramarine, and indigo in 17th century oil
      paintings. Smalt can be identified even after complete discoloration. VIS-imaging
      analysis assisted in the identification and mapping of modern synthetic red and
      yellow pigments in a 20th century painting.

PMID- 12622358
TI  - Combination of high-performance liquid chromatography and microplate
      scintillation counting for crop and animal metabolism studies: a comparison with
      classical on-line and thin-layer chromatography radioactivity detection.
AB  - Samples from crop or animal metabolism studies of pesticides were used to
      evaluate the performance of the combination of analytical or narrow-bore HPLC and
      microplate scintillation counting (TopCount). Samples with extreme matrix content
      such as grain and tomato extracts from crop metabolism studies as well as
      extracts from hen excreta or goat urine from farm animal metabolism studies could
      be injected, analyzed, and quantified directly without any sample pretreatment.
      The minimum amount of radioactivity injected was approximately 1 Bq (60 dpm).
      Counting times from 5 to 60 min were used for detection and quantification. These
      results were compared with those from classical on-line radioactivity detection
      and with radioactivity detection on thin-layer chromatography plates.The
      combination of analytical or narrow-bore HPLC and microplate scintillation
      counting (TopCount) offers high sensitivity and high resolution power at the same
      time. It could be clearly demonstrated that the combination of HPLC with
      microplate scintillation counting is superior to the classical on-line
      radioactivity detection and at least equivalent to the classical thin-layer
      radiochromatography regarding performance and sensitivity.

PMID- 12622359
TI  - Trace analysis of peroxide-based explosives.
AB  - The first method for quantitative trace analysis of peroxide-based explosives is
      described. A reversed-phase high-performance liquid chromatography method with
      post-column UV irradiation and fluorescence detection for the analysis of
      triacetone triperoxide (TATP) and hexamethylene triperoxide diamine (HMTD) has
      been developed. After separation, the analytes are degraded photochemically to
      hydrogen peroxide, which is subsequently determined on the basis of the
      peroxidase-catalyzed oxidation of p-hydroxyphenylacetic acid to the fluorescent
      dimer. This two-step reaction scheme in combination with the respective blanks
      (photochemical reactor switched off) provides for high selectivity. The limits of
      detection were 2 x 10(-6) mol/L for both TATP and HMTD, respectively. The method
      has been applied to the analysis of real samples.

PMID- 12622360
TI  - Helical sorbent microtrap for continuous sampling by a membrane and trap
      interface for on-line gas chromatographic monitoring of volatile organic
      compounds.
AB  - A helical sorbent microtrap consisting of a helical sorbent fixed inside a
      silicosteel capillary tube is presented. The main parameters that affect the safe
      sampling time of the helical sorbent microtrap in continuous sampling by a
      membrane and trap interface for on-line gas chromatographic monitoring of organic
      volatiles in gaseous samples are examined, taking into account the helical
      configuration of the sorbent, the presence of the membrane in system, and the
      properties of the analytes. Thermal desorption of analytes from the helical
      sorbent trap was also examined having regard to the influence of the turbulent
      flow generated by the helical sorbent in the heat transfer and the effect of
      thermal backward flow on the peak shape. The practical application of the helical
      sorbent microtrap in a membrane and trap interface was demonstrated by on-line
      gas chromatographic monitoring of four volatile organic compounds in the fume
      hood air and of volatile organic compounds from a diesel engine exhaust. The
      limit of detection was in the picogram per milliliter range, depending on the
      time of trapping and the parameters that affect the permeation through the
      membrane.

PMID- 12622361
TI  - Vibrational spectroscopic analysis of silicones: a Fourier transform-Raman and
      inelastic neutron scattering investigation.
AB  - An inelastic neutron scattering spectrum of a poly(dimethylsiloxane) (PDMS) is
      reported, and a spectrum simulated using a monomer molecular unit as a model for
      comparison. FT-Raman spectra of a series of PDMS derivatives are reported and
      structure spectra correlations are shown to exist for the estimation of (a) PDMS
      average chain length, (b) ratio of the number of monofunctional units to
      quadrifunctional units in silicone resins, and (c) the percentage weight of PDMS
      in silicone emulsions.

PMID- 12622362
TI  - Elemental fractionation studies in laser ablation inductively coupled plasma mass
      spectrometry on laser-induced brass aerosols.
AB  - Previous investigations on laser-induced aerosols of brass samples showed that
      preferential vaporization of zinc occurs during the ablation process leading to
      elemental fractionation and limited possibilities for non matrix matched
      calibration. In a variety of experiments carried out within this study it is
      shown that multiple effects are complicating the quantification of brass using IA
      ICPMS. It is shown that the ablated copper and zinc is not homogeneously
      distributed within the laser-produced aerosol. Copper was found enriched up to
      100% in particles larger than 100 nm as shown from EDX measurements (electron
      excited) on individual particles, and zinc was enriched by over 40% in the
      particles smaller than the lowest measurable particle size (below 100 nm or in
      the vapor phase). Solution nebulization analysis on digested filter-collected
      aerosols results in a higher Cu/Zn ratio than the certified value for the brass
      sample. ESEM pictures with analysis of the electron excited X-rays measured on
      the filter-collected material support the results showing copper enrichment.
      However, online LA-ICPMS measurements carried out under the same operating
      conditions as for filtering show a copper depletion within the ICP, which leads
      to the conclusion of partial vaporization and ionization of the aerosol particles
      in the ICP. The larger particles containing more or exclusively copper are not
      completely ionized. Within this study, three sources of elemental fractionation
      can be distinguished and described: (A) The ablation process leads to no
      measurable copper enrichment at the ablation crater rim. (B) Zinc deposition
      between the ablation site and the aerosol collection on filters leads to an up to
      37% higher Cu/Zn ratio on the filter in comparison to the certified value. (C) On
      line laser ablation aerosols measured within the ICPMS lead to significantly
      lower Cu/Zn ratios in comparison to the certified value. (D) Combination of the
      various studied sources of fractionation can finally lead to an agreement between
      measured and certified values due to inverse overlapping of various fractionation
      sources.

PMID- 12622363
TI  - Development and validation of a near-infrared method for the quantitation of
      caffeine in intact single tablets.
AB  - A near-infrared spectroscopic method was developed and validated for determining
      the caffeine concentration of single and intact tablets in a Finnish
      pharmaceutical product containing 58.82% (m/m) caffeine.The spectral region of
      interest contained a total of 474 data points. The second derivative of Savitsky
      Golay, a standard normal variate, and mean centering were used as spectral
      preprocessing options. The feasibility study showed nonuniformity of caffeine
      repartition within each tablet. Thus, spectra were recorded from both faces of
      the tablets, and the analysis result for a single tablet was reported as the
      average of both face determinations. Precision of the method was validated
      because the relative standard deviations from repeatability and intermediate
      precision tests were below 0.75% (m/m). Accuracy validation proved that the NIR
      results were not significantly different (P = 0.09, n = 12) from the results
      obtained with the reference HPLC method. The limit of quantification for caffeine
      was 13.7% (m/m) in the tablets. The method was found to be unaffected by NIR
      source replacement, but the repeatability of the results was affected if the
      sample holder was not placed in the correct position in the light beam. Routine
      NIR analysis of caffeine in tablet form was found to be more flexible and much
      faster than that performed with the HPLC method.

PMID- 12622364
TI  - Effect of metal ions on the molecular weight distribution of humic substances
      derived from municipal compost: ultrafiltration and size exclusion chromatography
      with spectrophotometric and inductively coupled plasma-MS detection.
AB  - The effect of metal ions (Co, Cu, Ni, Pb, Zn) on the molecular weight
      distribution of humic substances (HSs) obtained from compost is studied. We
      believe this is the first of this type of study applied in this way to humic
      substances. Size exclusion chromatography is coupled with two on-line detection
      systems (spectrophotometric and ICPMS) to study the binding of metal ions by
      humic substances leached from compost. ICPMS provided highly specific, sensitive,
      and multielement analytical information that enabled obtaining direct
      experimental evidence for the participation of metal ions in molecular size
      distributions of humic compounds. The compost extract or its high molecular
      weight fraction (>5,000) was put in contact with EDTA or citrate ions, thereby
      competing with HSs for binding metals. The experiments were carried out by
      varying the pH maintained by Tris-HCl or CAPS buffer (pH 8.0 and 10.3) and
      keeping the ionic strength constant. The elution profile of humic substances
      using UV/ visible detection was compared with those from ICPMS detection of Co,
      Cu, Ni, Pb, and Zn in the same chromatographic runs. The results obtained
      suggested that both bridging between small molecules and complexation/ chelation
      by individual molecules are involved in metal ion binding to humic substances.
      The use of ICPMS to study the role of metal ions in aggregation/disassociation of
      humic substances proposed in this work is promising. Coupling element-specific
      detection with SEC or other separation systems allows better understanding of the
      mobility and bioaccessibility of elemental species in the environment and further
      elucidation of the dissolved humic structure.

PMID- 12622365
TI  - A method for assessing the statistical significance of mass spectrometry-based
      protein identifications using general scoring schemes.
AB  - This paper investigates the use of survival functions and expectation values to
      evaluate the results of protein identification experiments. These functions are
      standard statistical measures that can be used to reduce various protein
      identification scoring schemes to a common, easily interpretably representation.
      The relative merits of scoring systems were explored using this approach, as well
      as the effects of altering primary identification parameters. We would advocate
      the widespread use of these simple statistical measures to simplify and
      standardize the reporting of the confidence of protein identification results,
      allowing the users of different identification algorithms to compare their
      results in a straightforward and statistically significant manner. A method is
      described for measuring these distributions using information that is being
      discarded by most protein identification search engines, resulting in accurate
      survival functions that are specific to any combination of scoring algorithms,
      sequence databases, and mass spectra.

PMID- 12622366
TI  - Development and evaluation of an isotope dilution LC/MS method for the
      determination of total homocysteine in human plasma.
AB  - Elevated plasma homocysteine has been identified as a strong and independent risk
      factor for cardiovascular diseases, and recently, it has been associated with the
      development of dementia in older adults. Selected ion-monitoring isotope-dilution
      LC/MS (electrospray) has been developed and evaluated as a reference method for
      the accurate determination of total homocysteine in human plasma. Homocysteine is
      quantitatively isolated from plasma via the use of anion-exchange resins and then
      detected and quantified in stabilized plasma extracts with selected ion
      monitoring LC/MS. This method is shown to be highly comparable to LC/MS/MS
      determinations in terms of its analytical accuracy and precision, yet this
      alternative measurement approach does not necessitate the enhanced
      instrumentation or added expense required of tandem MS/MS determinations. LC/MS
      detection of homocysteine was linear (standard error of the estimate for the
      regression line was 0.0323) over 3 orders of magnitude, and the calculated limits
      of detection and quantification were 0.06 micromol/L (0.12 ng on column) and 0.6
      micromol/L (1.2 ng on column), respectively. Independent calibration curves
      showed excellent linearity (r2 > or = 0.996) between 0 and 25 micromol/L
      homocysteine over a 3-day period. The accuracy and precision of total
      homocysteine measurements for patient samples and quality control pools using
      LC/MS were compared to total homocysteine measurements using LC/MS/MS, GC/MS,
      FPIA, and LC-FD. LC/MS performed well in relation to the other homocysteine
      methods in terms of its capability to accurately quantify plasma homocysteine
      over the normal range (5-15 micromol/L).

PMID- 12622367
TI  - On-line liquid chromatography-accurate radioisotope counting coupled with a
      radioactivity detector and mass spectrometer for metabolite identification in
      drug discovery and development.
AB  - A novel detection method combining on-line liquid chromatography-accurate
      radioisotope counting (LC-ARC, advanced stop flow controller) coupled with a
      radioactivity detector and mass spectrometer has been developed. One of the major
      benefits of this method is that this system enhances the sensitivity of
      radioisotope measurement for metabolite identification in drug metabolism
      studies. Another advantage to this system is the easy interface with the mass
      spectrometer, which allows acquisition of mass spectrometric data on-line. For
      purposes of evaluating this system, in vitro microsomal incubations with
      [3Hlpropranolol were conducted. On-line separation and identification of
      [3H]propranolol metabolites was achieved without intensive sample preparation,
      concentration, or fraction collection. Mass spectrometric analysis showed the
      presence of propranolol major metabolites formed by hydroxylation, correlating
      with previously published results. Further evaluations of this system also were
      conducted using two 14C compounds, which are herein labeled X and Y. As our
      results show, 14C peaks were detected down to 6 cpm, which is approximately 20
      times more sensitive than commercially available flow through radioactivity
      detectors. The overall results suggest that the combination of LC-ARC with
      radioactivity detection and mass spectrometry has great potential as a powerful
      tool for improving the sensitivity of radioisotope measurement in metabolite
      identification studies during drug discovery and development.

PMID- 12622368
TI  - Capillary liquid chromatography/electrospray mass spectrometry for analysis of
      steroid sulfates in biological samples.
AB  - A new procedure for capillary liquid chromatography-electrospray (CLC-ES) mass
      spectrometry is described. Using this procedure, coupling of a CLC column to a
      low-flow-rate ES interface is made simple. A 5-cm precolumn and a 35-cm
      analytical column, both fused-silica capillaries with an i.d. of 100 microm and
      packed with 3-microm octadecylsilane-bonded material, are coupled in series to a
      sheathless ES emitter. One solvent splitter is positioned between the loop
      injector and the precolumn, and a second, between the precolumn and the
      analytical column. By opening and closing the splitters in the appropriate order,
      this arrangement permits the injection of 1-20 microL of sample solution with
      analyte focusing onto the top of the precolumn, followed by isocratic or gradient
      elution at a flow rate of 0.2-0.3 microL/min through the analytical column. The
      relative standard deviation of the retention times of reference compounds was
      <3.5% (n = 5). The potential of the system in metabolome analysis, in which
      numerous isomeric compounds will require identification, is illustrated by the
      application of the system to the analysis of steroid sulfates in plasma.

PMID- 12622369
TI  - LC-atmospheric pressure chemical ionization-MS/ MS analysis of multiple illicit
      drugs, methadone, and their metabolites in oral fluid following protein
      precipitation.
AB  - A quantitative LC-APCI-MS/MS method for simultaneous determination of multiple
      illicit drugs, methadone, and their metabolites in oral fluid was developed and
      validated. Sample pretreatment was limited to acetonitrile protein precipitation.
      LC separation was performed in 25.5 min, with a total analysis time of 35 min.
      Identification and quantitation were based on selected reaction monitoring.
      Calibration by linear regression analysis utilized deuterated internal standards
      and a weighing factor 1/x. Limits of detection and lower limits of quantitation
      (LOQ) were established between 0.25 and 5 ng/ mL and 0.5-10 ng/mL, respectively.
      linearity was obtained with an average correlation coefficient (R2) of >0.99,
      over a dynamic range from the LOQ up to maximum 500 ng/mL The method demonstrated
      good accuracy, intra- and interbatch precision, recovery, and stability for all
      compounds. No oral fluid matrix effect was observed throughout the
      chromatographic run. Protein precipitation provided a fast and simple sample
      pretreatment, while LC-APCI-MS/MS proved to be a sensitive and rugged
      quantitative method for multiple illicit and legal drugs in oral fluid. The
      method proved to be suitable for the evaluation of oral fluid as an alternative
      matrix to urine for monitoring illicit drug use and for determining oral fluid
      methadone concentrations in pregnant opiate and/or cocaine addicts.

PMID- 12622370
TI  - Demonstration of direct bioanalysis of drugs in plasma using nanoelectrospray
      infusion from a silicon chip coupled with tandem mass spectrometry.
AB  - Quantitative bioanalysis by direct nanoelectrospray infusion coupled to tandem
      mass spectrometry has been achieved using an automated liquid sampler integrated
      with an array of microfabricated electrospray nozzles allowing rapid, serial
      sample introduction (1 min/ sample). Standard curves prepared in human plasma for
      verapamil (r2 = 0.999) and its metabolite norverapamil (r2 = 0.998) were linear
      over a range of 2.5-500 ng/ mL. Based on the observed precision and accuracy, a
      lower limit of quantitation of 5 ng/mL was assigned for both analytes. Sample
      preparation consisted of protein precipitation with an organic solvent containing
      the structural analogue gallopamil as an internal standard. Protein precipitation
      was selected both to maximize throughput and to test the robustness of direct
      nanoelectrospray infusion. Aliquots of supernatant (10 pL) were transferred to
      the back plane of the chip using disposable, conductive pipet tips for direct
      infusion at a flow rate of 300 nL/min. Electrospray ionization occurred from the
      etched nozzles (30-microm o.d.) on the front of the chip, initiated by a voltage
      applied to the liquid through the pipet tip. The chip was positioned near the API
      sampling orifice of a triple quadrupole mass spectrometer, which was operated in
      selected reaction monitoring mode. Results are presented that document the
      complete elimination of system carry-over, attributed to lack of a redundant
      fluid path. This technology offers potential advantages for MS-based screening
      applications in drug discovery by reducing the time for methods development and
      sample analysis.

PMID- 12622371
TI  - Quantitative analysis of lycopene isomers in human plasma using high-performance
      liquid chromatography-tandem mass spectrometry.
AB  - An analytical method for the determination of the concentrations of total
      lycopene and its cis and all-trans isomers in human plasma has been developed
      using high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS).
      This method was based on the observation that, during negative ion atmospheric
      pressure chemical ionization with collision-induced dissociation, a unique
      fragment of m/z 467 was formed from the molecular ion of m/z 536 by elimination
      of a terminal isoprene group. The use of multiple reaction monitoring facilitated
      the selective detection of lycopene isomers and an internal standard without
      interference from the isobaric carotenoids a-carotene and beta-carotene, which
      are also abundant in human plasma. Measurement of total lycopene was carried out
      using a C18 high-performance liquid chromatography (HPLC) column and an isocratic
      mobile phase consisting of acetonitrile/methyl tert-butyl ether (95:5) so that
      all lycopene isomers eluted as a single chromatographic peak. all-trans-Lycopene
      was separated from its various cis isomers by using a C30 carotenoid column and a
      gradient solvent system from methanol to methyl tert-butyl ether. The effects of
      sample preparation and handling parameters on the stability of lycopene were
      evaluated such as the stability of lycopene in the HPLC autosampler and the
      effect of saponification upon lycopene isomerization. For example, the half-life
      of all-trans-lycopene in the HPLC mobile phase in the autosampler at 4 degrees C
      was determined to be approximately 16 h. Also, saponification of plasma samples
      was determined to cause lycopene degradation and isomerization so that lycopene
      recovery was reduced. The accuracy and interassay precision of this LC-MS-MS
      assay for lycopene showed a standard deviation of less than 10% over the range of
      5-500 pmol injected on-column. The limit of detection was 11.2 fmol injected on
      column, and the limit of quantitation was 22.8 fmol.

PMID- 12622372
TI  - Mechanism of microbial aggregation during capillary electrophoresis.
AB  - We studied the aggregation of a rod-shaped bacteria, Bifidobacterium infantis,
      during capillary electrophoresis (CE). A microscope with an intensified CCD
      camera was employed to monitor the migration and aggregation of bacteria, which
      are labeled with fluorescent dye Syto 9 and excited with a 488-nm argon ion
      laser. A collision-based aggregation mechanism is proposed, in which collisions
      between microbes result from different mobilities and migration directions in the
      electric field. Individual microbes are aligned differently with respect to the
      direction of the electric field and exhibit different drag coefficients. The long
      range forces include van der Waals attraction and electrostatic repulsion as
      qualitatively described by DLVO theory. Collisions in CE produce sufficient
      energy to overcome electrostatic repulsion, thus improving the efficiency of
      aggregation. This is supported by the fact that higher electric fields always
      resulted in faster aggregation. Also, when sodium phosphate buffer was used,
      increasing the ionic strength resulted in faster aggregation. However, when Tris
      boric acid-EDTA (TBE, pH 9.1) buffer was used, the aggregation speed decreased
      when the ionic strength increased. We attribute this to the change of the surface
      of the bacteria at high borate and EDTA concentration, such as the loss of
      polysaccharides or the presence of complexation. This reduces the hydrophobicity
      of the surface and, thus, the short-range attractive forces. The addition of
      0.05% poly(ethylene oxide) (PEO) into high ionic strength TBE buffer increased
      the aggregation rate. This can be attributed to the bridging effect of PEO
      between microbes. Further increase in the concentration of polymer reduced the
      aggregation rate, especially when the electric field was low, due in part to the
      increase in viscosity. The decrease in migration velocity produced lower
      collision energies and lower aggregation efficiencies as well.

PMID- 12622373
TI  - Electrophoretic behavior and potency assessment of boar sperm using a capillary
      electrophoresis-laser induced fluorescence system.
AB  - The assessment of mammalian fertility, and the agents that affect it, is of
      increasing concern in medicinal, environmental, and agricultural science. The
      viability, integrity, and overall state of the male gamete (sperm) is an
      essential factor that must be considered in such studies. Traditional potency
      evaluations tend to be labor intensive and often are not precise. A CE-LIF
      technique for determining the viability of boar sperm was developed using the
      fluorescent stains SYBER-14 and propidium iodide. The buffer type, pH, ionic
      strength, applied voltage, and polymer additive must be optimized in order to
      obtain sharp peaks and accurate results. Extender solutions that are widely used
      in artificial insemination programs were found to be compatible and even
      beneficial for these CE-LIF experiments. A single viability assay takes less than
      10 min, which is significantly faster than most other procedures. The compaction
      or focusing of the sample zone seems to be similar to that reported previously
      for microorganisms in CE.

PMID- 12622375
TI  - A correlation for the pressure drop in monolithic silica columns.
AB  - To gain insight into how the pressure drop in monolithic silica columns is
      determined by the microscopic details of the pore structure, a series of well
      validated computational fluid dynamics simulations has been performed on a
      simplified model structure, the so-called tetrahedral skeleton column. From these
      simulations, a direct correlation between the pressure drop and two main
      structural properties (skeleton thickness and column porosity) of the monolithic
      skeleton could be established. The correlation shows good agreement with the
      experimental pressure-drop data available from the literature on silica
      monoliths, especially when a correction for the flow-through pore size
      heterogeneity is made. The established correlation also yields a much more
      accurate representation of the relation between the flow resistance and the bed
      porosity than does the Kozeny-Carman model, making it much better suited for
      porosity optimization calculations.

PMID- 12622374
TI  - Comparative study of IgG binding to proteins G and A: nonequilibrium kinetic and
      binding constant determination with the acoustic waveguide device.
AB  - The aim of this work was to measure and compare the binding constants of antibody
      immunoglobulin G (IgG) to bacterial cell wall proteins, streptococcal protein G
      and Staphylococcus aureus protein A, using an acoustic wave sensor. Devices,
      which used shear-horizontal acoustic waves propagating in a waveguide
      configuration at 108 and 155 MHz, were employed in the detection of apparent IgG
      binding constants at the solid-liquid interface in the range of 6.7-667 nM IgG.
      Real-time data during IgG-protein G and IgG-protein A binding yielded apparent
      association constants of 3.29 x 10(4) and 8.02 x 10(3) M(-1) s(-1) leading to
      equilibrium constants of 1.13 x 10(8) and 2.90 x 10(7) M(-1), respectively. The
      measured apparent rate constants are consistent with literature reports of higher
      affinity of protein G for IgG. Furthermore, protein binding through the Fc region
      of IgG is suggested to occur below 333 nM, while different mechanisms are
      suggested to occur above 333 nM. For the first time, nonequilibrium studies of
      IgG-protein G and A binding at a solid-liquid interface has yielded valuable
      quantitative kinetic information about binding mechanisms. The promise of this
      detection method is shown by providing quick determination of binding constants
      with low sample volumes.

PMID- 12622376
TI  - A Monte Carlo program for quantitative electron-induced X-ray analysis of
      individual particles.
AB  - A versatile Monte Carlo program for quantitative particle analysis in electron
      probe X-ray microanalysis is presented. The program includes routines for
      simulating electron-solid interactions in microparticles lying on a flat surface
      and calculating the generated X-ray signal. Simulation of the whole X-ray
      spectrum as well as phi(z) curves is possible. The most important facility of the
      program is the reverse Monte Carlo quantification of the chemical composition of
      microparticles, including low-Z elements, such as C, N, O, and F. This
      quantification method is based on the combination of a single scattering Monte
      Carlo simulation and a robust successive approximation. An iteration procedure is
      employed; in each iteration step, the Monte Carlo simulation program calculates
      characteristic X-ray intensities, and a new set of concentration values for
      chemical elements in the particle is determined. When the simulated X-ray
      intensities converge to the measured ones, the input values of elemental
      concentrations used for the simulation are determined as chemical compositions of
      the particle. This quantification procedure was evaluated by investigating
      various types of standard particles, and good accuracy of the methodology was
      demonstrated. A methodology for heterogeneity assessment of single particles is
      also described.

PMID- 12622377
TI  - Determination of the nature of naphthenic acids present in crude oils using
      nanospray Fourier transform ion cyclotron resonance mass spectrometry: the
      continued battle against corrosion.
AB  - Recent research has shown that the corrosivity of naphthenic acids is related to
      their molecular mass and that the "total acid number" (TAN), traditionally used
      as an indicator of the naphthenic acid content of an oil, is not as reliable as
      first believed. The presence of naphthenic acids in crude oils leads to the
      corrosion of oil refinery equipment, with the oil industry incurring costs that
      will ultimately be passed on to the consumer. With regard to these concerns, mass
      spectrometry has been increasingly applied to the investigation of the naphthenic
      acid content of crude oils. To ascertain the nature of the species present,
      however, it is necessary to utilize an ionization technique that does not result
      in fragmentation, ensuring the detection only of molecular species which provide
      useful information about the sample constitution. In the following investigation,
      negative ion mode nanospray Fourier transform ion cyclotron resonance (FTICR)
      mass spectrometry has been applied to the analysis of crude oil samples,
      providing insight into the different acidic species that were present. Use of the
      negative ion mode to allow the selective observation of the naphthenic acids and
      the inherent high mass accuracy and ultrahigh resolution of FTICR mass
      spectrometry ensure that this technique is very well suited to the
      characterization of naphthenic acids within a crude oil sample. Determination of
      the nature of the naphthenic acids present provides vital information, such as
      the acids' sizes and composition, which may be used in the battle against
      corrosion and also used to fingerprint samples from different oil fields.

PMID- 12622378
TI  - Abundance ratio-dependent proteomic analysis by mass spectrometry.
AB  - The goal of quantitative proteomics is to determine the identity and relative
      quantity of each protein present in two or more complex protein samples. Here we
      describe a novel approach to quantitative proteomics. It is based on a highly
      accurate algorithm for the automated quantification of chromatographically
      fractionated, isotope-coded affinity-tagged peptides and MALDI quadrupole time-of
      flight tandem mass spectrometry for their identification. The method is capable
      of detecting and selectively identifying those proteins within a complex mixture
      that show a difference in relative abundance. We demonstrate the effectiveness
      and the versatility of this approach in the analysis of a standard protein
      mixture, protein expression profiling in a human prostate cancer cell line model,
      and identification of the specific components of the multiprotein transcriptional
      machinery in S. cerevisiae.

PMID- 12622379
TI  - High-throughput protein sequencing.
AB  - We have designed and implemented an autosampler that provides additional sample
      capacity on a commercial protein sequencer. The autosampler attaches to a
      standard ABI Procise sequencer, enabling a single-sample cartridge to hold up to
      six separate samples. The autosampler is used in combination with faster Edman
      cycles and a rapid 12-min PTH separation to significantly increase the speed of
      automated protein sequencing. We also describe Edman chemistry modifications that
      improve coupling efficiency and prevent internal cleavage that can occur when
      samples are sequenced in the standard glass cartridges.

PMID- 12622380
TI  - High-throughput measurement of pKa values in a mixed-buffer linear pH gradient
      system.
AB  - A procedure is described for measuring pKa values in a short time, e.g., 4
      min/assay. Samples, as 10 mM solutions, are prepared in DMSO in 96-well plates. A
      flowing pH gradient is produced by mixing two buffer solutions containing
      mixtures of weak acids and bases that do not absorb significantly in the UV above
      250 nm. The sample solution is diluted with water and then injected directly into
      the flowing gradient, which then passes through a diode array spectrophotometer
      measuring in the UV wavelength range. The buffer has been formulated so that its
      acid-base titration curve is linear over a wide pH range, such that the pH of the
      gradient is a linear function of time. The solution pH in the measurement flow
      cell is therefore proportional to the time elapsed since the start of gradient
      generation. The sample's pKa values are calculated from the change in UV
      absorbance at multiple wavelengths as a function of pH. The pKa values of 71
      drugs have been measured, and results compare well with values measured by pH
      metric or traditional UV methods. Rules are suggested for the rapid inspection of
      data and the choice of method for the calculation of pKa from the data.

PMID- 12622381
TI  - Theoretical and analytical characterization of a flow-through permeation liquid
      membrane with controlled flux for metal speciation measurements.
AB  - Speciation measurements with the permeation liquid membrane (PLM) technology
      require necessarily a good control of the flux of the analyte. In this
      perspective, a PLM-based multichannel flow-through cell has been designed. The
      first objective of this study has been to adapt the classical Levich model
      commonly used for electrochemical flow devices to the characteristic geometry of
      the PLM cell. In the latter case and contrary to the Levich model, the effects of
      the channel lateral walls on the flux of active species through the membrane have
      to be taken into account. The problem was solved by considering the existence of
      two parabolic Poiseuille profiles perpendicular to each other and developing
      along the fluid motion. The theoretical results obtained match satisfactorily
      with experimental data. The analytical study of this PLM system has been
      performed with copper(II) ions as test species and has shown that the
      preconcentration factor is (1) linear at least for preconcentration times of < or
      = 120 min, (2) reproducible on the same membrane as well as on different
      membranes, and (3) independent of the initial test metal ion concentration in the
      sample solution. The capabilities of this cell to determine metal speciation by
      considering lability of complexes and the flux of metal at variable flow rates of
      the test solution is also discussed by means of Cu(II)/sulfosalicylic complexes.

PMID- 12622382
TI  - Electroosmotic dispersion in microchannels with a thin double layer.
AB  - Dispersion of a nonelectrolyte solute due to the electroosmotic flow in long
      straight microchannels was analyzed theoretically. A version of the Aris-Taylor
      procedure was employed to predict the dispersion coefficient for arbitrary
      geometry of the microchannel cross section. The analysis was conducted using a
      thin double-layer approximation, which is valid when the Debye length is much
      smaller than the characteristic dimensions of the cross section. For thin double
      layers, the obtained results describe the electroosmotic dispersion for arbitrary
      surface potential, electrolyte type, and cross-section geometry. Dispersion for
      several cases of the cross-section geometries was discussed. It was shown that,
      for given values of the surface potential and the Debye length, both the cross
      section geometry and the electrolyte content of the driven solution substantially
      affect the dispersion of a nonelectrolyte solute. In the relevant particular
      cases, the obtained results agree with predictions of the previous theories.

PMID- 12622383
TI  - Electrical communication between glucose oxidase and electrodes mediated by
      phenothiazine-labeled poly(ethylene oxide) bonded to lysine residues on the
      enzyme surface.
AB  - A series of glucose oxidase (GOx) hybrids (GOx-phe-nothiazine-labeled
      poly(ethylene oxide) (PT-PEO)) capable of direct electrical communication with
      electrodes is synthesized by covalently modifying PT-PEO to lysine residues on
      the enzyme surface. The length of the PEO chain and the number of PT groups are
      systematically altered. After the PT-PEO modification, all the hybrids maintain
      more than 50% of enzyme activity relative to that of native GOx, although loss of
      the activity becomes greater with increasing PEO chain length. The catalytic
      current, i(cat), is observed at a potential more positive than 0.55 V after the
      addition of glucose, due to the intramolecular electron transfer (El) from
      reduced forms of flavin adenine dinucletide (FADH2/FADH) to PT+ that are
      electrogenerated at the electrode. The i(cat) value increases with the number of
      PT groups, indicating that most of the modified PT groups act as mediators. The
      magnitude of the i(cat) increase depends on the PEO chain length and reveals a
      maximum for PT-PEO with the molecular weight of 3,000. In contrast, the i(cat) is
      almost constant for GOx-2-(10-phenothiazyl)propionic acid (PT-PA) hybrids with
      more than two PT groups synthesized by covalently modifying PT-PA to surface
      lysines, indicating that only a few key PT groups function as mediators. The
      maximum rate constant (130 s(-1)) for the ET from FADH2/FADH to PT+ is obtained
      for the GOx hybrid modified with five PT-PEO groups with the molecular weight of
      3,000.

PMID- 12622384
TI  - A biosensing system based on extracellular potential recording of ligand-gated
      ion channel function overexpressed in insect cells.
AB  - We have used outer cell potential measurement to record agonist-dependent
      cellular responses in cells engineered to express ligand-gated ion channels and
      grown on a microelectrode surface. Application of glutamate, a natural agonist,
      induced a complex and robust potentiometric response in cells expressing
      homomeric GluR-D glutamate receptor, but not in nonexpressing control cells. The
      response consisted of an initial decrease in outer potential followed by a
      transient increase and was not obtained for other amino acids devoid of agonist
      activity at glutamate receptors. Furthermore, the pharmacological agonist of the
      GluR-D receptor, kainate, also produced the potentiometric response whereas 6
      cyano-7-nitroquinoxaline-2,3-dione, a competitive antagonist, was not active in
      itself but attenuated the responses to glutamate. The time course of the measured
      changes was slow, which may be partially due to the ligand being applied by free
      diffusion but may also reflect a contribution by secondary changes in the
      behavior of the cells. This novel approach should be applicable to other ligand
      gated ion channels and holds promise as a cell-based biosensor for high
      throughput drug screening and other applications.

PMID- 12622385
TI  - Liquid chromatography with on-line electrochemical derivatization and
      fluorescence detection for the determination of phenols.
AB  - A new methodological approach for the determination of monosubstituted phenols is
      described. After liquid chromatographic separation of the analytes, an on-line
      electrochemical derivatization is carried out and the reaction products are
      detected fluorometrically. Phenols are oxidized in the electrochemical cell to
      form fluorescent dimers and higher oligomers, which were identified by on-line
      electrochemistry/mass spectrometry. Major advantages of the proposed method
      include enhanced selectivity and sensitivity. Without prior enrichment of the
      analytes, limits of detection down to 2 x 10(-9) M (20 fmol) may be reached for
      selected phenols, e.g., for 4-octylphenol, 4-ethylphenol, and 4-(1
      indanyl)phenol. Only readily available instrumentation is required for these
      measurements.

PMID- 12622386
TI  - Development of a flow amperometric enzymatic method for the determination of
      total glucosinolates in real samples.
AB  - The first amperometric flow analyzer, based on the biosensor concept, capable of
      determining total glucosinolates in real samples, is described. Myrosinase was
      immobilized on aminopropyl-modified controlled pore glass, which was then used
      for the construction of a packed-bed reactor. Myrosinase catalyzes the hydrolysis
      of glucosinolates (sinigrin) to glucose (among the other products), which is then
      oxidized by the action of glucose oxidase to produce hydrogen peroxide. The
      glucose enzyme electrode is based on a multimembrane architecture and was mounted
      on an amperometric flow cell (hydrogen peroxide detection at a platinum anode
      poised at +0.65 V vs Ag/AgCl/3M KCl). Different membrane types and different
      activation procedures were tested. The system was optimized to various working
      parameters, either as a glucose electrode or as a glucosinolate analyzer. The
      interference effect of various compounds was also investigated. Application of
      the method to real samples was carried out using glucose/glucose, hydrolyzed
      sinigrin and glucose/sinigrin solution as calibrators of the glucose electrode
      and the glucosinolate analyzer. Deviations due to the enantioselectivity of
      glucose oxidase to the beta-glucose anomer were observed, and a data elaboration
      protocol is proposed. The possibility of the simultaneous determination of
      glucose and glucosinolates is also demonstrated.

PMID- 12622387
TI  - Microchip capillary electrophoresis coupled with a boron-doped diamond electrode
      based electrochemical detector.
AB  - The attractive behavior and advantages of a diamond electrode detector for a
      micromachined capillary electrophoresis (CE) system are discussed. A chemically
      vapor-deposited boron-doped diamond (BDD) film band (0.3 x 6.0 mm) electrode is
      used for end-column amperomettic detection. The favorable performance of the
      diamond electrode microchip detector is indicated from comparison to a commonly
      used thick-film carbon detector. The diamond electrode offers enhanced
      sensitivity, lower noise levels, and sharper peaks for several groups of
      important anaytes (nitroaromatic explosives, organophosphate nerve agents,
      phenols). The favorable signal-to-background characteristics of the BDD-based CE
      detector are coupled with a greatly improved resistance to surface fouling and
      greater isolation from high separation voltages. The enhanced stability is
      indicated from a RSD of 0.8% for 60 repetitive measurements of 5 ppm 2,4,6
      trinitrotoluene (vs RSD of 10.8% at the thick-film carbon electrode). A highly
      linear response is obtained for the explosives 1,3-dinitrobenzene and 2,4
      dinitrotoluene over the 200-1,400 ppb range, with detection limits of 70 and 110
      ppb, respectively. Factors influencing the performance of the BDD detector are
      assessed and optimized. The attractive properties of BDD make it very promising
      material for electrochemical detection in CE microchip systems and other
      micromachined flow analyzers.

PMID- 12622388
TI  - Electrogenerated chemiluminescence derivatization reagent, 3-isobutyl-9,10
      dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylamine, for
      carboxylic acid in high-performance liquid chromatography using tris(2,2'
      bipyridine)ruthenium(II).
AB  - 3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2
      ylamine (IDHPIA) was found to be a selective and highly sensitive derivatization
      reagent for carboxylic acid by high-performance liquid chromatography (HPLC) with
      electrogenerated chemiluminescence detection using tris(2,2'
      bipyridine)ruthenium(II). Free fatty acids and phenylbutylic acid were used as
      model compounds of carboxylic acids, and the derivatization conditions were
      optimized with myristic acid. Under the mild reaction conditions of room
      temperature for 45 min in acetonitrile containing 2-bromo-1-ethylpyridinium
      tetrafluoroborate and 9-methyl-3,4-dihydro-2H-pyridol1,2-a]pyrimidin-2-one, all
      the fatty acids tested were reacted with IDHPIA to produce highly sensitive
      derivatives. The chemiluminescence intensity was essentially the same for all
      fatty acids. The derivatives obtained from 10 free fatty acids were completely
      separated by reversed-phase chromatography under isocratic elution conditions.
      The on-column detection limit (signal-to-noise ratio of 3) with proposed HPLC
      separation and chemiluminescence detection was 0.5 and 0.6 fmol for myristic acid
      and phenylbutylic acid, respectively. IDHPIA was 100-fold more sensitive than
      previously developed reagents (Morita, H.; Konishi, M. AnaL Chem. 2002, 74, 1584
      1589). The free fatty acids in human serum were successfully determined using the
      present method.

PMID- 12622389
TI  - Three-electrode electrochemical detector and platinum film decoupler integrated
      with a capillary electrophoresis microchip for amperometric detection.
AB  - This article demonstrates that a three-electrode electrochemical (EC) detector
      and an electric decoupler could be fabricated in the same glass chip and
      integrated with an O2-plasma-treated PDMS layer using microfabrication techniques
      to form the capillary electrophoresis (CE) microchip. The platinized decoupler
      could mostly decouple the electrochemical detection circuit from the interference
      of an separation electric field in 10 mM 2-(N-morpholino)ethanesulfonic acid
      (MES, pH 6.5) solution. The baseline offset of background current recorded from
      the working electrode with and without application of a separation electric field
      was maintained at less than 0.05 pA in 10 mM MES. In addition, the platinized
      pseudoreference electrode was demonstrated to offer a stable potential in
      electrochemical detection. As a consequence, the limit of detection of dopamine
      was 0.125 microM at a S/N = 4. The responses for dopamine to different
      concentrations were found to be linear between 0.25 and 50 microM with a
      correlation coefficient of 0.9974 and a sensitivity of 11.76 pA/microM. The
      totally integrated CE-EC microchip should be able to fulfill the ideal of
      miniaturization and commercialization.

PMID- 12622390
TI  - High-performance taste sensor made from Langmuir-Blodgett films of conducting
      polymers and a ruthenium complex.
AB  - A sensor array made up of nanostructured Langmuir-Blodgett (LB) films is used as
      an electronic tongue capable of identifying sucrose, quinine, NaCl, and HCl at
      the parts-per-billion (ppb) level, being in some cases 3 orders of magnitude
      below the human threshold. The sensing units comprise LB films from conducting
      polymers and a ruthenium complex transferred onto gold interdigitated electrodes.
      Impedance spectroscopy is used as the principle of detection, and the importance
      of using nanostructured films is confirmed by comparing results from LB films
      with those obtained from cast films.

PMID- 12622391
TI  - Micromixer-based time-resolved NMR: applications to ubiquitin protein
      conformation.
AB  - Time-resolved NMR spectroscopy is used to studychanges in protein conformation
      based on the elapsed time after a change in the solvent composition of a protein
      solution. The use of a micromixer and a continuous-flow method is described where
      the contents of two capillary flows are mixed rapidly, and then the NMR spectra
      of the combined flow are recorded at precise time points. The distance after
      mixing the two fluids and flow rates define the solvent-protein interaction time;
      this method allows the measurement of NMR spectra at precise mixing time points
      independent of spectral acquisition time. Integration of a micromixer and a
      microcoil NMR probe enables low-microliter volumes to be used without losing
      significant sensitivity in the NMR measurement. Ubiquitin, the model compound,
      changes its conformation from native to A-state at low pH and in 40% or higher
      methanol/water solvents. Proton NMR resonances of the His-68 and the Tyr-59 of
      ubiquitin are used to probe the conformational changes. Mixing ubiquitin and
      methanol solutions under low pH at microliter per minute flow rates yields both
      native and A-states. As the flow rate decreases, yielding longer reaction times,
      the population of the A-state increases. The micromixer-NMR system can probe
      reaction kinetics on a time scale of seconds.

PMID- 12622392
TI  - Rare-earth glass reference materials for near-infrared spectrometry: correcting
      and exploiting temperature dependencies.
AB  - Quantitative descriptions of the location of seven near-infrared absorption bands
      as functions of temperature 5-50 degrees C are presented here for three recently
      introduced wavelength/wavenumber Standard Reference Materials (SRMs): SRM 2035,
      SRM 2065, and SRM 2036. For all bands in all three SRMs, locations are well
      described as linear models parametrized with the location at 0 degrees C
      (intercept) and the rate of location change per degrees C (slope). Since these
      materials were produced from compositionally similar melts, the slopes for each
      band are identical within measurement imprecision in all three SRMs; only minor
      differences are observed in the intercepts. Because the direction of change in
      location differs among the bands, it is possible to use the measured band
      locations to reliably estimate sample temperature. Two approaches to estimating
      temperature are evaluated: slope and measurement uncertainty-weighted means.
      While both methods work well with measurements made under well-characterized and
      stable environmental conditions, the more complex uncertainty-weighted analysis
      becomes relatively more predictive as the total measurement uncertainties
      increase.

PMID- 12622393
TI  - Flow injection analysis in a microfluidic format.
AB  - A microfluidic flow injection analysis system has been designed and evaluated.
      The system incorporates within a single two-layer poly(dimethylsiloxane) monolith
      multiple pneumatically driven peristaltic pumps, an injection loop, a mixing
      column, and a transparent window for fluorescence detection. Central to this
      device is an injection system that mimics the operation of a standard six-port,
      two-way valve used in conventional liquid chromatography and flow injection
      experiments. Analyte and carrier solutions continuously flow through this
      injection system allowing for measurements and sample changes to be performed
      rapidly and simultaneously. Injection volumes of 1.25 nL generated peak area
      reproducibility of better than 3% relative standard deviation. The flow injection
      device was evaluated with fluorescent dyes and demonstrated a detection limit of
      400 zmol for fluorescein. A rudimentary sample selection system allowed
      calibration curves to be rapidly produced, often in less than 10 min. The
      hydrolysis of fluorescein diphosphate by alkaline phosphatase demonstrates that
      chemical assays can be carried out with this device in a manner characterized by
      short analysis times and low sample consumption.

PMID- 12622394
TI  - Combined electrospray ionization-atmospheric pressure chemical ionization source
      for use in high-throughput LC-MS applications.
AB  - Fast and accurate analytical methods are essential to keep pace with sample
      libraries produced from combinational chemistry and high-throughput biological
      screening. Many laboratories now use a combination of ionization techniques for
      the characterization of these samples, including atmospheric pressure chemical
      ionization (APCI), electrospray ionization (ESI), and photoionization (PI). Data
      are shown here from the analysis of a compound collection plate containing a
      variety of sample structures. ESI will normally analyze around 80% of these
      samples, necessitating a source change to analyze a further 10%. In this work, we
      have developed a new combined ESI-APCI source (ESCi) for use in on-line HPLC
      applications. The combined source allows alternate on-line ESI and APCI scans
      with polarity switching within a single analysis. The ESCi source has been
      designed to be a simple replacement for the existing mass spectrometer
      interfaces. Each ionization method is optimized independently using separate
      tuning parameters. Instrument electronics can readily switch between the two
      ionization methods and polarities within normal interscan time periods. The new
      source has reduced the analysis time of sample plates by eliminating the need for
      a source hardware change, source optimization, and repeat analyses.

PMID- 12622395
TI  - On-line multibed sorption trap and injector for the GC analysis of organic vapors
      in large-volume air samples.
AB  - A capillary-dimension on-line sorption trap is used to preconcentrate organic
      vapors from large-volume air samples and inject the organic compounds into the
      separation column as a relatively narrow vapor plug. The multibed trap is made
      from a Co-Ni alloy for resistive heating during sample desorption and uses four
      different carbon-based adsorption materials that are graded from weakest to
      strongest in the direction of the sample gas flow during sample preconcentration.
      The flow direction then is reversed for sample injection. The multibed design and
      the flow direction reversal during thermal desorption prevents the higher-boiling
      point compounds in the sample from reaching the strongest adsorbing material,
      from which they would be difficult to desorb as a sufficiently narrow vapor plug.
      A relatively high current pulse is used to rapidly achieve trap temperatures in
      the 200-400 degrees C temperature range, and a lower current is used to maintain
      the maximum temperature for several seconds in order to ensure injection of the
      entire trapped sample. A temperature of 350 degrees C is reached after degrees
      1.5 s, and injection plug widths are typically in the range of 0.6-1.3 s. Plots
      of peak area versus sample collection time show excellent linearity and shot-to
      shot relatively standard deviations of about +/- 5%. Performance data are
      presented for a mixture of 42 volatile compounds spanning a volatility range from
      n-C5 to n-C12. Data are presented for injection plug width and shape for both
      polar and nonpolar compounds. Decomposition of thermally labile compounds is
      observed for injection temperatures above 300 degrees C.

PMID- 12622397
TI  - Improved sensitivity and characterization of high-speed ion chromatography of
      inorganic anions.
AB  - In this work, a reversed-phase monolithic column was permanently coated with
      didodecyldimethylammonium bromide (DDAB) to perform ultrafast separations of
      iodate, chloride, nitrite, bromide, nitrate, phosphate, and sulfate in as little
      as 30 s. Separations were performed using 6 mM o-cyanophenol (pH 7.0) at flow
      rates up to 10 ml/min and suppressed conductivity detection. Detection limits in
      the parts-per-billion range were observed for all anions studied (e.g., ranging
      from 30 ppb for phosphate to 4 ppb for sulfate). The reproducibility was 0.7 and
      0.4% RSD for retention time and peak area, respectively. Coated columns were
      stable for up to 12 h of continuous use at 5 mL/min (i.e., 1-min separations).

PMID- 12622396
TI  - Hydroxypropyl cellulose as an adsorptive coating sieving matrix for DNA
      separations: artificial neural network optimization for microchip analysis.
AB  - Effective DNA separations in microelectrophoretic systems are complicated by the
      need to passivate the surface dynamically or covalently. We describe the
      optimization and utilization of a novel buffer system for fast DNA separations by
      capillary and microchip electrophoresis without the need for any surface
      modification or conditioning prior to separation. At concentrations as high as
      5%, hydroxypropyl cellulose (HPC) has a relatively low viscosity, allowing for
      microchip channel filling to be performed with ease. A MES/TRIS buffer system at
      pH 6.1 eliminates the need for surface preconditioning procedures due to the
      promotion of hydrogen bonding of HPC with the wall. An additional benefit with
      this buffer system is the low current observed at high fields when compared to
      other common DNA separation buffers. An artificial neural network (ANN) was used
      to model the data and to predict the optimum conditions. Utility of the ANN
      optimized system for molecular diagnostic testing was demonstrated by performing
      microchip separations on DNA samples from patients suspected of having genetic
      mutations associated with Duchenne muscular dystrophy (DMD). Microchip analysis
      easily allowed for the patient samples positive for DMD mutations to be
      distinguished from patient samples negative for the disease.

PMID- 12622398
TI  - Thin-film microextraction.
AB  - The properties of a thin sheet of poly(dimethylsiloxane) (PDMS) membrane as an
      extraction phase were examined and compared to solid-phase microextraction (SPME)
      PDMS-coated fiber for application to semivolatile analytes in direct and
      headspace modes. This new PDMS extraction approach showed much higher extraction
      rates because of the larger surface area to extraction-phase volume ratio of the
      thin film. Unlike the coated rod formats of SPME using thick coatings, the high
      extraction rate of the membrane SPME technique allows larger amounts of analytes
      to be extracted within a short period of time. Therefore, higher extraction
      efficiency and sensitivity can be achieved without sacrificing analysis time. In
      direct membrane SPME extraction, a linear relationship was found between the
      initial rate of extraction and the surface area of the extraction phase. However,
      for headspace extraction, the rates were somewhat lower because of the resistance
      to analyte transport at the sample matrix/headspace barrier. It was found that
      the effect of this barrier could be reduced by increasing either agitation,
      temperature, or surface area of the sample matrix/headspace interface. A method
      for the determination of PAHs in spiked lake water samples was developed based on
      the membrane PDMS extraction coupled with GC/MS. A linearity of 0.9960 and
      detection limits in the low-ppt level were found. The reproducibility was found
      to vary from 2.8% to 10.7%.

PMID- 12622399
TI  - Polar polymeric stationary phases for normal-phase HPLC based on monodisperse
      macroporous poly(2,3-dihydroxypropyl methacrylate-co-ethylene dimethacrylate)
      beads.
AB  - The effect of variables such as shape template size, porogen composition and
      percentage, content of cross-linking monomer, and polymerization temperature on
      the properties of uniformly sized 3-microm porous poly(glycidyl methacrylate-co
      ethylene dimethacrylate) beads prepared by the staged templated suspension
      polymerization technique has been studied. The porous properties of the beads
      including surface morphology, pore size distribution, and specific surface area
      have been optimized to obtain highly efficient stationary phases for normal-phase
      HPLC. A column packed with diol stationary phase obtained by hydrolysis of
      poly(glycidyl methacrylate-co-ethylene dimethacrylate) beads affords an
      efficiency of 67,000 plates/m for toluene using THF as the mobile phase. The
      retention properties and selectivity of the diol beads are easily modulated by
      changes in the composition of the mobile phase. The performance of these beads is
      demonstrated with the separations of a variety of polar compounds including
      positional isomers, aniline derivatives, and basic tricyclic antidepressant
      drugs.

PMID- 12622400
TI  - On-column electrochemical reactions accompanying the electrospray process.
AB  - It is well-established that electrochemical reactions can occur within the
      capillary of an electrospray (ES) devise coupled to a mass spectrometer. In fact,
      such reactions must occur to maintain charge balance during the ES process.
      However, electrochemical reactions occurring distal to the capillary as a result
      of the high potential applied to the capillary have not been thoroughly
      investigated. In the present communication, we show that electrochemical
      processes can occur on a high performance liquid chromatography (HPLC) column
      coupled to an ES capillary. On-column solvent electrolysis is proposed to
      generate free radicals, which can subsequently initiate analyte oxidation.
      Oxidation of steroid sulfates possessing a reactive double bond between C-5 and C
      6 is demonstrated. The possibility of similar reactions occurring within peptides
      possessing a site of unsaturation is also considered.

PMID- 12622401
TI  - Miniaturized electrochemical flow cells.
AB  - Several novel types of miniaturized electrochemical flow cells are described. The
      flow cells are fabricated in fluorinated ethylene propylene using a novel
      technique where channels with inner diameters down to 13 microm are integrated
      with electrodes. The channel is formed by shrinking and simultaneous melting of a
      heat shrink/melt tubing around a channel template (a tungsten wire) and
      electrodes followed by removal of the channel template. The technique allows
      incorporation of different electrode materials of different sizes. The electrode
      configuration consists of one or two working electrodes inside the channel and a
      counter electrode located in the channel outlet reservoir. Electrode
      configurations with different channel and working electrode sizes, different
      electrode materials including carbon fibers, glassy carbon rods,
      poly(tetrafluoroethylene)/carbon composite material, and platinum wires, and
      different arrangements have been assembled. Hydrodynamic voltammograms in dual
      electrode (generator-collector) experiments indicate good potential control for
      cells with 25-microm channels, while there is some iR drop in cells with 13
      microm channels. Cells prepared with a cylindrical working electrode tangent and
      perpendicular to a flow channel show a flow rate dependence consistent with thin
      layer cell behavior. Electrode areas can be made in the range of 10(-10)-10(-8)
      m2.

PMID- 12622403
TI  - Family-based association study of the serotonin-2A receptor gene (5-HT2A) and
      bipolar disorder.
AB  - OBJECTIVES: The serotonin 2A receptor gene (5-HT2A) is of great interest for
      research in neuropsychiatric disorders based on the observation that various
      neuroleptic agents and antidepressants bind with relatively high affinity at 5
      HT2A receptors, and the fact that the receptor density in platelets tends to
      increase in depression. To test for the presence of association between 5-HT2A
      and bipolar disorder (BP), we studied a large number of triad families having
      probands affected with DSM-IV bipolar I (BPI), bipolar II (BPII) or
      schizoaffective disorder, bipolar type. METHODS: Two polymorphisms of 5-HT2A,
      102T/C, and His452Tyr were analyzed in the 274 bipolar triad families. Both the
      transmission disequilibrium test (TDT) and haplotype TDT were performed on the
      genotype data. We also calculated the maternal transmission and paternal
      transmission for each allele and compared the mean ages of onset across probands
      grouped by genotype at each of the two markers. RESULTS: No significant
      transmission disequilibrium between the alleles of 5-HT2A and BP was found.
      Separate studies of the sub-phenotypes also failed to demonstrate significant
      association. However, we found a trend towards transmission disequilibrium with
      the haplotype 102C.His452 (p = 0.0504). This trend may become more significant
      with a larger sample size. SIGNIFICANCE: At present, results of this study
      suggest that the 5-HT2A is unlikely to play a major role in the genetic
      susceptibility to BP. Future studies will be directed towards increasing sample
      size, focusing on subtypes of BP or biochemical measures as phenotypes, and
      investigating other polymorphisms of 5-HT2A to provide more information at the
      DNA level.

PMID- 12622402
TI  - Stem cell and precursor cell therapy.
AB  - Strategies for cell replacement therapy have been guided by the success in the
      hematopoietic stem cell field. In this review, we discuss the basis of this
      success and examine whether this stem cell transplant model can be replicated in
      other systems where stem cell therapy is being evaluated. We conclude that
      identifying the most primitive stem cell and using it for transplant therapy may
      not be appropriate in all systems. We suggest alternative strategies such as
      progenitor cell replacement, inductive factors, bioengineering organs, in utero
      transplants, or any approach that takes advantage of the unique properties of the
      tissue and the stem cell type which, are more likely to provide effective
      functional replacement.

PMID- 12622404
TI  - PTEN regulates Akt kinase activity in hippocampal neurons and increases their
      sensitivity to glutamate and apoptosis.
AB  - The tumor suppressor phosphatase PTEN can promote apoptosis of mitotic cells by
      inhibiting activation of the cell survival kinase Akt. PTEN is essential for
      normal embryonic development, PTEN expression is associated with neuronal
      differentiation, and deletion of PTEN in the mouse brain results in seizures,
      ataxia, and other abnormalities. However, the possible roles of PTEN in
      regulating neuronal survival are not known. We provide evidence that PTEN
      sensitizes hippocampal neurons to excitotoxic death in culture and in vivo.
      Overexpression of wild-type PTEN decreased, while a dominant-negative PTEN
      increased, levels of activated Akt in cultured hippocampal neurons. Wild-type
      PTEN promoted, while dominant-negative PTEN prevented, apoptotic death of neurons
      exposed to the excitatory amino acid neurotransmitter glutamate. Hippocampal
      neurons of mice with reduced PTEN levels were more resistant to seizure-induced
      death compared to wild-type littermates. These findings demonstrate a cell death
      function of PTEN in hippocampal neurons and identify PTEN as a potential
      therapeutic target for neurodegenerative disorders that involve excitotoxicity
      and apoptosis. The ability of PTEN to modify neuronal sensitivity to glutamate
      also suggests possible roles for PTEN in regulating developmental and synaptic
      plasticity.

PMID- 12622405
TI  - Neuroprotection against excitotoxicity by N-alkylglycines in rat hippocampal
      neurons.
AB  - Excessive activation of glutamate receptors of the N-methyl-D-aspartate (NMDA)
      subtype is considered a relevant initial step underlying different
      neurodegenerative diseases. Recently, with the approval of memantine to treat
      Alzheimer dementia, NMDA receptors have regained clinical interest. Accordingly,
      the development and validation of NMDA receptor antagonists is being
      reconsidered. We recently identified a family of trialkylglycines that act as
      channel blockers of the NMDAreceptor. Their neuroprotective activity against
      excitotoxic insults remains elusive. To address this issue, we first
      characterized the contribution of glutamate receptor subtypes to hippocampal
      death in culture as a function of days in culture in vitro (DIV). Whereas at 7
      DIV neither NMDA nor glutamate produced a significant neuronal death, at 14 and
      21 DIV, NMDA produced the death of 40% of the neurons exposed to this receptor
      agonist that was fully protected by MK-801. Similar results were obtained for L
      glutamate at 14 DIV. In contrast, when neurons at 21 DIV were used, glutamate
      killed 51.1 +/- 4.9% of the neuronal population. This neuronal death was only
      partially prevented by MK-801, and fully abrogated by a combination of MK-801 and
      6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Glucose deprivation injured 37.1 +/-
      9.2% of the neurons through a mechanism sensitive to MK-801. The family of
      recently identified N-alkylglycines tested protected neurons against NMDA and
      glucosedeprivation toxicity, but not against glutamate toxicity. Noteworthy, N
      alkylglicines with a moderate protection against NMDA-induced toxicity strongly
      protected from beta-amyloid toxicity. Collectively, these findings imply both
      NMDA and non-NMDA receptors in excitotoxicity of hippocampal neurons, and suggest
      that blockade of NMDA receptors alone may not suffice to efficiently abrogate
      neurodegeneration.

PMID- 12622406
TI  - A drosophila model for attention deficit hyperactivity disorder (ADHD): No
      evidence of association with PRKG1 gene.
AB  - Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric
      condition in children and follow up studies have indicated that 22-33% of
      patients continue to suffer from ADHD during late adolescence and adulthood. The
      action of psychostimulant drugs may be determined by additional mechanisms beyond
      the dopamine transporter and receptors. We are exploring new methodology for
      discovering these mechanisms. For example, in Drosophila, such an additional
      determinant of psychostimulant action could be protein kinase G (PKG) that
      affects food-search behavior. Here we initiated studies with the human homologue
      of PKG, the PRKG1 gene. The aim of this study was to investigate for the presence
      of linkage disequilibrium between the protein kinase G gene (PRKG1) and adult
      ADHD in a sample of nuclear families. Genotyping data for the C2276T polymorphism
      were analyzed using the Transmission Disequilibrium Test (TDT). Sixty three
      nuclear families were informative for the TDT on C2276T polymorphism, which
      showed no preferential transmission of either allele (chi-square = 0.778, df = 1,
      p = 0.316). These findings exclude a direct involvement of this genetic marker of
      the Protein kinase G gene in the pathogenesis of ADHD.

PMID- 12622407
TI  - First evidence to show the topological change of DNA from B-dNA to Z-DNA
      conformation in the hippocampus of Alzheimer's brain.
AB  - Alzheimer's disease (AD) is a complex neurodegenerative disorder. Our studies for
      the first time showed evidence for altered DNA conformation in the hippocampus of
      Alzheimer's disease affected brain. The Circular dichroism spectra of severely
      affected AD DNA showed a typical left-handed Z-DNA conformation, whereas normal,
      young, and aged brain DNA have the usual B-DNA conformation. Moderately affected
      AD DNA has modified B-DNA conformation (probable B-Z intermediate form). The
      ELISA, ethidium bromide binding pattern to DNA and melting temperature (Tm)
      profiles also revealed the conformational transition from B to Z DNA in AD brain
      DNA. The altered conformation of DNA will have tremendous implications in gene
      expressions.

PMID- 12622409
TI  - Emerging cellular and molecular themes in pancreatic cancer research.

PMID- 12622408
TI  - Stimulus-dependent activation of NF-kappaB specifies apoptosis or neuroprotection
      in cerebellar granule cells.
AB  - Oxidative stress is believed to play an important role in neuronal cell death
      associated with several neurodegenerative diseases (e.g., Alzheimer disease,
      Parkinson disease, and cerebral ischemia). Neuronal cell death might be one of
      the crucial mediators of these diseases. The transcription factor NF-kappaB is
      well-known for its roles in preventing apoptotic cell death. Data indicated that
      NF-kappaB activation by pre-conditioning is part of a general brain tolerance
      program. Here we show that pre-conditioning leading to NF-kappaB activation also
      protects against oxidative insults generated by Fe2+ ions. Protection was
      accompanied by a long-lasting (more than 24 h) NF-kappaB activation. Using this
      paradigm of oxidative insult, we analyzed the effect of hypericin, one of the
      active principles of St. John's Wort. Hypericin alone was able to induce short
      time activation of NF-kappaB, which declined to basal levels after 24 h. Cell
      death was induced by hypericin at a concentration of 10 microM. A profound
      synergistic action in inducing apoptosis was detected in co-treatment of
      hypericin together with FeSO4. In contrast, hypericin in low concentrations was
      able to partly prevent cell death induced by amyloid-beta-peptide (Abeta).
      Hypericin (10 microM) synergistically enhanced Abeta neurotoxicity. Since
      hypericin is a described inhibitor of protein kinase C, we compared its action to
      staurosporine, another natural neuronal death-promoting PKC inhibitor.
      Staurosporine induced cell death and activates NF-kappaB. Molecular inhibition of
      NF-kappaB activation with a transdominant negative IkappaB-alpha protected
      against staurosporine-induced cell death. In summary, the data describe NF-kappaB
      in the same primary neuronal culture as stimulus-dependent, anti-apoptotic, or
      pro-apoptotic factor.

PMID- 12622411
TI  - Novel protein kinases in pancreatic cell growth and cancer.
AB  - The network of enzymes that contribute to the signal transduction of
      extracellular factors in pancreatic cancer is ever increasing. The classical Raf
      MEK-ERK signaling cascade plays a crucial role in the regulation of apoptosis,
      proliferation, and metastasis of pancreatic cancer. Phosphatidylinositide-3
      kinase also contributes to growth and prevents apoptosis in pancreatic cancer
      cells, acting in part via its downstream targets, PKB/AKT and the FRAP/p70s6k
      signaling complex. Recently, members of the PKC family of serine threonine
      kinases have emerged as novel modulators of transformation and cell cycle
      progression of pancreatic cancers. The novel PKD family of serine threonine
      kinases has just been detected in pancreatic cancer and awaits its functional
      characterization in these tumors.

PMID- 12622410
TI  - Cell growth and metastasis in pancreatic cancer: is Vav the Rho'd to activation?
AB  - The best-known family of low molecular weight GTP-binding proteins is Ras, owing
      to their high incidence of gain of function mutations in a variety of human
      cancers including pancreatic cancer. Unlike Ras, no activating mutations have
      been observed thus far for Rho family GTP-binding proteins in cancer, yet there
      is increasing evidence that overexpression of Rho family members and/or
      dysregulation of the GDP-->GTP cycle play an important role in cancer development
      and progression. The activation of Rho family GTPases downstream of cell surface
      receptors results in the induction of several intracellular signaling cascades
      that have been shown to impact on such diverse cellular responses as
      reorganization of the actin cytoskeleton, gene transcription, cell survival, and
      cell proliferation. One family of guanine nucleotide exchange factors (GEFs) that
      have the potential to couple the activation of Rho family members to upstream
      growth factor receptor tyrosine kinases (RTKs) is the Vav family of proto
      oncogenes. Recent experimental evidence has implicated Vav in the regulation of
      numerous Rho-mediated pathways downstream of RTKs and other cell surface
      receptors. In this review, we will discuss our current understanding of how Vav
      proteins are regulated, and how Vav and their target GTP-binding proteins
      participate in tumorigenesis.

PMID- 12622412
TI  - Chemokines: new, key players in the pathobiology of pancreatic cancer.
AB  - The chemokines are a family of peptide hormones that regulate cellular adhesion,
      migration, proliferation, and survival. Accumulating evidence indicates critical
      regulatory roles for chemokines during the development of hyperplasias and
      metastatic tumors. Chemokines promote tumor metastasis, growth, survival, and
      angiogenesis. In addition, by regulating immunity, chemokines critically regulate
      anti-tumor immune responses and chronic inflammation such as that associated with
      various neoplasias. Since chemokine receptors are G-protein coupled receptors
      that are ideal drug targets, these discoveries presage the development of new and
      potent anti-cancer drugs that target chemokine receptors. Here, I review the
      chemokine system and chemokine regulation of neoplasias, with a special emphasis
      on pancreatic cancer.

PMID- 12622413
TI  - Signaling from novel splice variants of hormone receptors in cancer.
AB  - A number of splice variants of hormone receptors have recently been described in
      malignant neoplasms. Signaling by these novel receptor isoforms differ from their
      wild type counterparts, raising interesting questions as to possible roles in the
      initiation, progression, and metastatic potential of various tumors. This review
      summarizes recent findings on the signaling of novel variants of hormone
      receptors, including human HER-2/neu, the secretin receptor, the CCK-B/gastrin
      receptor and fibroblast growth factor receptor-2.

PMID- 12622414
TI  - TGFbeta-induced fibrogenesis of the pancreas.
AB  - The biological cause of fibrosis is the accumulation of excessive amounts of
      extracellular matrix (ECM) which leads to tissue dysfunction and organ failure. A
      strong correlation can be found between pancreatic diseases and fibrotic
      processes, in particular chronic pancreatitis and pancreatic cancer. There is
      growing evidence that pancreatic fibrosis represents a dysregulation of the
      normal repair processes after injury. This concept is based on the findings that
      fibrosis and tissue repair involve similar biological reactions regulated by the
      same group of molecules. The best characterized example for these regulatory
      molecules are the members of the transforming growth factor beta family
      (TGFbeta). TGFbeta1 represents the prototype of this family of highly similar
      growth factors, with the unique ability to stimulate the expression and
      deposition of extracellular matrix and to inhibit its degradation. Growth factor
      induced fibrotic events are targeted by a myofibroblast-like cell called
      pancreatic stellate cell (PSC). These cells show enhanced expression of all
      important ECM proteins after TGFbeta stimulation including collagen, fibronectin
      and proteoglycans. At the same time TGFbeta inhibits the degradation of ECM by
      blocking the secretion of proteases and stimulating the production of naturally
      occurring protease inhibitors.

PMID- 12622415
TI  - Smad4 transcriptional pathways and angiogenesis.
AB  - Smad4/DPC4 is a tumor suppressor gene frequently inactivated in gastrointestinal
      carcinomas. Smad4 encodes a key intracellular transmitter for signals of the TGF
      beta superfamily of cytokines. TGF-beta potently inhibits the growth of normal
      epithelial cells but tumor cells are frequently resistant; thus, it has been
      assumed that loss of Smad4 during tumor progression relieves this inhibition.
      Mediating TGF-beta responses is only one of the many putative functions of Smad4
      as a signaling molecule. Smad proteins are versatile transcriptional co
      modulators whose activities depend on the genetic makeup of a cell. We have used
      restoration of Smad4 in deficient cancer cells as an unbiased approach to
      decipher Smad4's tumor suppressor functions. Stable reexpression of Smad4 in
      human colon and pancreatic cancer cells potently suppressed tumor growth in vivo
      in nude mice. Surprisingly, it was not adequate to suppress tumor cell growth in
      vitro, nor did it restore TGF-beta responsiveness. Rather, Smad4 restoration
      influenced angiogenesis, decreasing expression of vascular endothelial growth
      factor and increasing expression of thrombospondin-1. These findings suggest that
      the acquisition of TGF-beta resistance and loss of Smad4 may be independent
      consecutive events in the tumorigenic process. They define the control of an
      angiogenic switch as a novel alternative mechanism of tumor suppression for
      Smad4.

PMID- 12622416
TI  - TGFbeta-regulated transcriptional mechanisms in cancer.
AB  - Transforming growth factor-beta (TGFbeta) has been implicated in oncogenesis for
      many years. The multifunctional activities of TGFbeta endow it with both tumor
      suppressor and tumor promoting activities, depending on the stage of
      carcinogenesis and the responsivity of the tumor cell. In early tumor stages,
      TGFbeta inhibits epithelial cell growth through induction of apoptosis and cell
      cycle arrest. During tumor development, however, many tumor cells lose their
      growth-inhibitory responses to TGFbeta owing to genetic alterations or signaling
      perturbations such as oncogenic Ras signaling. Loss of TGFbeta-growth inhibition
      is commonly associated with increased tumor cell invasion and metastasis of tumor
      cells that undergo an epithelial-mesenchymal transition. Interestingly, the tumor
      promoting effects of TGFbeta on the tumor cells are observed particularly in
      cells in which TGFbeta-signaling remains functional despite loss of growth
      control by TGFbeta. New insights into transcriptional mechanisms activated by
      TGFbeta are providing a better understanding of the cellular changes involved in
      the switch of TGFbeta from a tumor suppressor to a tumor promotor.

PMID- 12622417
TI  - NF-kappaB/Rel transcriptional pathway: implications in pancreatic cancer.
AB  - Despite considerable efforts in understanding the cellular mechanisms
      contributing to pancreatic cancer, the prognosis of this malignant disease is
      still extremely poor. Although pancreatic cancer is the fifth common cause of
      cancer death in Western countries, current options in treatment enable a 5-yr
      survival rate for all stages of less than 5%. In the face fo the fatal outcome,
      new approaches to the therapy have been established. Based on its role in
      malignant transformation, apoptosis, and cell proliferation, the transcription
      factor NF-kappaB/Rel has gained the attention of many laboratories. This review
      provides basic information for the understanding of the biology of NF-kappaB and
      aims at presenting experimental data illustrating the involvement of NF
      kappaB/Rel in pancreatic cancer.

PMID- 12622418
TI  - Regulation of epithelial cell growth by ZBP-89: potential relevance in pancreatic
      cancer.
AB  - ZBP-89 (ZNF148) is a Zinc finger Binding Protein of 89 kDa that binds GC-rich DNA
      elements. Originally, it was expression cloned using a DNA element mediating EGF
      regulation of the gastrin promoter. ZBP-89 functions as both a transcriptional
      activator and repressor. A variety of extracellular regulators including TGFbeta,
      retinoic acid and butyrate stimulate ZBP-89 gene expression. Butyrate activation
      of p21WAF1 is potentiated by ZBP-89 through the recruitment of the co-activator
      p300, while chronic stimulation by butyrate increases ZBP-89 gene expression
      correlating with cell differentiation. ZBP-89 stimulates growth arrest and
      apoptosis through its ability to bind the p21WAF1 promoter or its ability to form
      protein-protein interactions with p53. ZBP-89 protein is elevated in a variety of
      gastrointestinal cancers as well as the pancreas. In particular, ZBP-89 is
      normally expressed in pancreatic islets and ducts and in about 30% of pancreatic
      adenocarcinomas.

PMID- 12622419
TI  - Expression of the stress-associated protein p8 is a requisite for tumor
      development.
AB  - We identified a new gene, called p8, because its expression was strongly induced
      during the acute phase of pancreatitis. Further experiments have shown that p8
      mRNA is activated in response to several stresses and that its activation is not
      restricted to pancreatic cells. p8 is a nuclear protein and biochemical and
      biophysical studies have shown that p8 was very similar in many structural
      aspects to the HMG proteins, although sharing only low amino acid sequence
      homology. Also, p8 was found overexpressed in many human cancers. Therefore, we
      wondered whether the p8-mediated response to cellular stress was necessary for
      tumor establishment. Subcutaneous or intraperitoneal injections of transformed p8
      expressing fibroblasts led to tumor formation in nude mice, but no tumor was
      observed with transformed p8-deficient cells. Restoring p8 expression in
      transformed p8-deficient fibroblasts led to tumor formation, demonstrating that
      p8 expression is crucial for tumor development and suggesting that the stress
      response mechanisms governed by p8 are required for tumor establishment.

PMID- 12622420
TI  - BRCA2 and pancreatic cancer.
AB  - Many factors, including a family history of cancer, have been implicated in the
      development of pancreatic cancer. Among these factors, germline BRCA2 mutations
      have been clearly associated with the development of this disease, while
      mutations in BRCA1 appear to have a limited role. Patients with pancreatic cancer
      and germline BRCA2 mutations tend to be Ashkenazi Jewish, have a younger than
      average age of onset, and in many cases, lack family history for breast, ovarian,
      or pancreatic cancers. In addition, somatic mutations of BRCA2 appear to be rare
      in tumors of the pancreas. The mechanism by which mutant BRCA2 contributes to
      development of pancreatic cancers is not well understood. However, it appears
      that inactivation of several independent functions of BRCA2 including regulation
      of gene transcription, chromatin remodeling, cell growth, DNA damage repair, and
      chromosomal instability may provide a pathophysiological basis for the
      association of BRCA2 mutations and pancreatic cancer.

PMID- 12622423
TI  - The specificity of amylin for the diagnosis of pancreatic adenocarcinoma.
AB  - BACKGROUND: Diabetes mellitus or impaired glucose tolerance occurs in up to 80%
      of patients with pancreatic cancer at the time of cancer diagnosis. It has been
      reported that plasma amylin (islet amyloid polypeptide [IAPP]) levels are
      elevated in all patients with pancreatic cancer who are diabetic, and even
      moderately elevated in pancreatic cancer patients with normal glucose tolerance.
      AIM: To determine the specificity of elevated amylin levels for pancreatic
      cancer. METHODS: Plasma amylin levels were determined in 168 patients with one or
      more of the following medical conditions: benign and malignant biliary
      obstruction, pancreatic cancer, chronic pancreatitis, acute pancreatitis, other
      gastrointestinal (GI) malignancies, and newly diagnosed type II diabetes.
      RESULTS: Elevated levels of plasma amylin were detected in several disorders
      other than pancreatic cancer--particularly chronic pancreatitis, other GI
      malignancies, and biliary obstruction from benign causes. No statistical
      differences in amylin levels were detected for any of the tested medical
      conditions when compared to pancreatic adenocarcinoma. CONCLUSION: These results
      suggest that elevated plasma amylin is not specific for pancreatic cancer,
      thereby limiting its role as a tumor marker. Further studies are needed to
      determine whether amylin, if used in conjunction with other biological markers,
      could be useful for the diagnosis of pancreatic cancer.

PMID- 12622421
TI  - Translational control of protein synthesis in pancreatic acinar cells.
AB  - Translational control of protein synthesis in the pancreas is important in
      regulating growth and the synthesis of digestive enzymes. Regulation of
      translation is primarily directed at the steps in initiation and involves
      reversible phosphorylation of initiation factors (eIFs) and ribosomal proteins.
      Major sites include the assembly of the eIF4F mRNA cap binding complex, the
      activity of guanine nucleotide exchange factor eIF2B, and the activity of
      ribosomal S6 kinase. All of these involve phosphorylation by different regulatory
      pathways. Stimulation of protein synthesis in acinar cells is primarily mediated
      by the phosphatidylinositol 3-kinase-mTOR pathway and involves both release of
      eIF4E (the limiting component of eIF4F) from its binding protein and
      phosphorylation of ribosomal S6 protein by S6K. eIF4E is itself phosphorylated by
      a distinct pathway. Inhibition of acinar protein synthesis can be mediated by
      inhibition of eIF2B following phosphorylation of eIF2alpha.

PMID- 12622422
TI  - Successful pre-operative diagnosis of malignant intraductal papillary mucinous
      tumor of the pancreas by detecting telomerase activity.
AB  - BACKGROUND: Pre-operative differential diagnosis between benign and malignant
      intraductal papillary mucinous tumor (IPMT) of the pancreas is markedly difficult
      by imaging examination. In recent years, telomerase activity has been reported to
      be detected only in malignant tumors. METHODS: A 52-yr-old man with abdominal
      pain was diagnosed with a IPMT through imaging examination. Telomerase activity
      of the pure pancreatic juice, which was obtained pre-operatively by endoscopic
      retrograde pancreatic juice aspiration (ERPJA), was analyzed by telomeric repeat
      amplification protocol (TRAP) assay. RESULTS: Telomerase activity was detected in
      the pure pancreatic juice of the patient, who was diagnosed with a malignant
      IPMT. A pylorus-preserving pancreatoduodenectomy was performed, and subsequent
      pathological findings revealed the tumor to be adenocarcinoma in adenoma with
      papillary growth. CONCLUSION: Detection of telomerase activity of the pure
      pancreatic juice might be useful to distinguish benign from malignant IPMT pre
      operatively.

PMID- 12622424
TI  - Clinical implication of anti-p53 antibodies and p53-protein in pancreatic
      disease.
AB  - p53 gene mutations play an important role in the pathogenesis of pancreatic
      carcinomas. Anti-p53 antibodies and p53 protein have been detected in the sera of
      patients with pancreatic carcinomas. However, very little is known about the
      clinical significance of these p53 antibodies. We investigated the relationship
      between anti-p53 antibodies and the presence of p53 protein in cancer cells and
      the serum, as well as other clinical factors. Anti-p53 antibodies were detected
      in 19 (23%) of 82 pancreatic-duct-cell carcinomas, and in one (5%) of 21 cases of
      chronic pancreatitis. However, no antibodies were detected in mucin-producing
      tumors or in islet-cell tumors of the pancreas. The anti-p53 antibodies were
      detected in both early and advanced stages. In those patients undergoing surgical
      resection for pancreatic duct-cell carcinomas, the prognosis of patients who were
      negative for the anti-p53 antibodies was better than patients who were positive.
      Of the 11 cases that were positive for anti-53 antibodies, 8 (73%) were also
      positive for the immunohistochemical expression of p53 protein in cancer cells.
      However, there was no significant correlation between the presence of anti-p53
      antibodies and the serum p53 protein levels. These results suggest that the
      benefits of measuring the anti-p53 antibody titier as a screening test to detect
      pancreatic carcinoma are limited, but the presence of anti-p53 antibodies
      predicts a poor prognosis for postoperative pancreatic carcinoma patients.

PMID- 12622425
TI  - Ethnic disparity of pancreatic cancer in New Zealand.
AB  - BACKGROUND: The etiology of pancreatic cancer remains elusive. Identification of
      high-risk groups may enable targeted study to identify new markers and risk
      factors. AIM: To review the epidemiology of pancreatic cancer in New Zealand and
      identify any differences between ethnic groups. METHODS: All cases notified with
      pancreatic cancer between 1988 and 1997 were identified from the New Zealand
      Cancer Registry. Age-specific and age-standardized incidence rates (ASR) of
      pancreatic cancer were calculated for the total sample and the ethnic subgroups
      (Maori, Pacific, and Other, which was predominantly European). Data on the site,
      morphology, stage of tumors, and survival times were also reviewed. RESULTS:
      There were 3004 cases over the 10-yr period. Ethnic ASR comparisons demonstrated
      higher rates in Maori (7.3/100,000) compared with Pacific (6.4/100,000) and the
      Other (5.6/100,000) ethnic group. Males had higher incidence rates than females
      in Pacific and Other, but not in Maori because of the unusually high rate among
      Maori women (7.2/100,000). The most commonly identified site, morphological type,
      and stage at presentation were the head of the pancreas (80.9% of site-specified
      cases), adenocarcinoma (44.3% of histologically confirmed cases), and diffuse +/-
      metastases (69.2% of staged cases), respectively. The median survival time was 92
      d, and this did not differ significantly for the Maori and Other ethnic groups.
      CONCLUSION: The Maori have higher rates of pancreatic cancer than other ethnic
      groups in New Zealand, and do not show the expected male predominance. Maori
      women currently have one of the highest reported female rates in the world, and
      are a population that should be further investigated for disease markers and
      modifiable risk factors.

PMID- 12622426
TI  - Expression of cyclooxygenase-2 protein in colorectal carcinomas.
AB  - BACKGROUND: Overexpression of cyclooxygenase-2 (COX-2) has been demonstrated in
      various human cancers, including colorectal cancer. Thus, overexpression of COX-2
      may be involved in the growth and progression of cancer, and this may have
      prognostic significance. AIM: The aim of our study is to evaluate the expression
      of COX-2 in colorectal cancer tissue, and to examine the relationship of its
      expression to various clinicopathological parameters and patient survival.
      METHODS: Formalin-fixed, paraffin-embedded tissue blocks were obtained from 60
      patients who underwent surgery for colorectal carcinoma in 1995 at the Chonnam
      National University Hospital in Gwangju, Korea. We have used an
      immunohistochemical technique to localize COX-2 in colorectal carcinoma tissues.
      RESULTS: Immunohistochemical staining of the colorectal cancer specimens
      demonstrated that COX-2 expression was localized to the carcinoma cells and was
      not detectable in the stromal compartment of the cancers. The COX-2
      immunostaining pattern was predominantly homogenous, and perinuclear cytoplasmic
      within the tumors. Normal colonic epithelium adjacent to the tumor showed no
      staining for COX-2. The COX-2 protein was detected in 70% (42/60) of colorectal
      carcinoma tissues. However, no significant correlation was found between COX-2
      expression and various clinicopathological parameters, including histologic
      grade, tumor size, depth of invasion, lymph node metastasis, distant metastasis,
      or stage. Furthermore, COX-2 expression did not correlate with patient survival
      (p = 0.401). CONCLUSION: These results suggest that COX-2 expression may play an
      important role in the evolution of colon carcinogenesis. However, further studies
      are needed to determine the prognostic relevance of COX-2.

PMID- 12622427
TI  - Differences in plasma gastrin, CEA, and CA 19-9 concentration in patients with
      proximal and distal colorectal cancer.
AB  - AIM: We investigated whether there are differences in plasma gastrin, as compared
      with carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 between patients
      with proximal and distal colorectal cancer. Gastrin concentration has also been
      analyzed, dependent on the tumor stage, in order to evaluate the possible
      prognostic role of this measurement. METHODS: In 50 patients with colon cancer
      fasting gastrin, CA 19-9 and CEA levels were evaluated. RESULTS: Mean plasma
      gastrin level in patients with distal tumor yielded 105.31 +/- 12.5 microU/L and
      was significantly higher than in patients with the proximal tumor site (42.2 +/-
      3.1 microU/L) as well as in controls (p < 0.001). No significant difference was
      observed between mean plasma gastrin in patients with proximal tumors and the
      control group. The mean CEA plasma level was significantly higher (p < 0.01) in
      patients with distal tumors (9.1 +/- 1.1 ng/mL) than in those with proximal
      tumors (1.48 +/- 0.1 ng/mL). Similarly, the mean CA 19-9 plasma level was
      significantly higher (p < 0.01) in patients with distal tumor (19.9 +/- 2.1 U/mL)
      than in those with proximal tumor: 1.8 +/- 0.2 U/mL. The mean gastrin plasma, CA
      19-9, and CEA level was significantly higher in group of Duke's stage C and D as
      compared to A and B. CONCLUSION: We speculate that observed differences in
      gastrin concentration in patients with distal and proximal tumors may contribute
      to the distinct pathogenesis and biological properties of those cancers. The
      significance of gastrin as a marker for diagnostic or prognostic purposes in
      colorectal cancer requires further study.

PMID- 12622429
TI  - EUS may have limited impact on the endoscopic management of gastric carcinoids.
AB  - Background. Carcinoids are occasionally found during gastroscopy. Endoscopic
      ultrasonography (EUS) can determine the depth of invasion and vascularity of
      submucosal tumors, including carcinoid tumors. Thus, EUS can lead to an informed
      decision as to whether to attempt endoscopic or surgical excision of a carcinoid.
      The three cases described here were found by EUS to be amenable to endoscopic
      resection of submucosal carcinoid tumors. In each case, the margin of the
      specimen obtained led to uncertainty regarding the completeness of gastroscopic
      excision of the tumor. Guidelines for follow-up of gastric carcinoid are few. The
      incompleteness of endoscopic resection of submucosal tumors, with tumor found at
      the specimen margin, indicates that careful follow-up and/or consideration of
      other means of excision are indicated.

PMID- 12622428
TI  - Bacterial antigen-induced release of white cell- and platelet-derived bioactive
      substances in vitro.
AB  - OBJECTIVES: Poor prognosis after resection of primary colorectal cancer may be
      related to the combination of perioperative blood transfusion and subsequent
      development of infectious complications. Various white cell- and platelet-derived
      cancer-growth substances may be involved in this process. Therefore, we studied
      the in vitro release of substances from white cells and platelets stimulated by
      bacterial antigens and supernatants from stored red-cell components. METHODS:
      Eight units of whole blood (WB) and 8 U of buffy-coat-depleted red-cell (SAGM)
      blood were donated by healthy blood donors. Subsequently, one-half of each unit
      was leucocyte-depleted by filtration, and all 32 half-units were stored under
      standard conditions for 35 d. Just after storage, and on d 7, 21, and 35 during
      storage, aliquots of the supernatants were removed from the units and frozen at 
      80 degrees C. WB from other healthy donors was stimulated for 2 h with sodium
      chloride (controls), with Escherichia coli (E. coli) lipopolysaccharide (LPS)
      alone, or with LPS plus supernatants from the WB units (diluted 1:10), or from
      the SAGM units (diluted 1:20) stored for 0, 7, 21, or 35 d, respectively. Similar
      assays were performed using Staphylococcus aureus-derived protein A as a
      stimulatory antigen. The concentration of eosinophil cationic protein (ECP),
      myeloperoxidase (MPO), histamine (HIS), and plasminogen-activator inhibitor-1
      (PAI-1) were determined in supernatants from the stored blood and in assay
      supernatants by using enzyme-linked immunosorbent assay (ELISA) and
      radioimmunoassay (RIA) methods. RESULTS: The extracellular concentration of ECP,
      MPO, and HIS increased significantly in a storage-time-dependent manner in
      nonfiltered WB and SAGM blood, and the increase was abrogated by prestorage
      leukofiltration. Similarly, PA-1 increased significantly in nonfiltered WB, and
      the increase was abrogated by prestorage leukofiltration. The supernatant
      concentrations of the four substances were significantly increased in LPS
      stimulated (0.5-4 fold) and in protein A-stimulated (0.5-13.5-fold) assays
      compared with controls. The addition of supernatants from stored nonfiltered WB
      or SAGM blood significantly increased the assay supernatant of ECP, MPO, HIS, and
      PAU-1 concentrations storage-time-dependently in LPS-stimulated assays.
      Prestorage leukofiltration abrogated the additional effect of supernatants from
      stored blood. Similar results were observed for ECP and HIS through the addition
      of supernatants from stored blood to protein A-stimulated assays. Protein A
      stimulation did not lead to increased PA-1 release in assays diluted by
      supernatants from stored blood. However, the MPO concentrations were
      significantly (p = 0.004), and independent of storage time and leukofiltration,
      increased in protein A-stimulated assays diluted by supernatants from stored
      blood compared with sodium chloride dilution. CONCLUSION: Extracellular ECP, MPO,
      HIS, and PA-1 accumulate during storage of nonfiltered red-cell components, but
      the accumulation can be prevented by prestorage leukofiltration. In addition,
      bacterial antigens appear to induce significant release of the substances from
      white cells and platelets. Addition of supernatants from stored, nonfiltered WB
      and SAGM blood may increase the substance levels in a storage-time-dependent
      manner, and prestorage leukofiltration may prevent further increase by
      supernatants, except for MPO.

PMID- 12622430
TI  - Pedunculated early carcinoma of supra-ampullary duodenum presenting as acute
      pancreatitis.
AB  - Background. A 43-yr-old man was admitted to our hospital after sudden onset of
      epigastric pain. He was diagnosed with acute pancreatitis by clinical,
      laboratory, and radiographic signs. Examinations for the etiology of acute
      pancreatitis revealed a duodenal tumor arising at the proximal portion of the
      descending limb, extending by a long stalk, and coming into contact with Vater's
      papilla. The tumor was snare-resected endoscopically. Histological examination
      showed an early carcinoma. Extra-ampullary carcinoma of the duodenum should be
      considered an unusual cause of acute pancreatitis secondary to obstruction of the
      major duodenal papilla. Endoscopic polypectomy is effective because of the
      difficulty in making a precise diagnosis by endoscopic biopsy.

PMID- 12622432
TI  - Serial analyses of ventricular late potentials in patients with reciprocal ST
      segment changes during acute myocardial infarction.
AB  - The aim of this study was to determine whether successful reperfusion may alter
      substrate that is responsible for late potentials in the presence or absence of
      reciprocal ST segment changes (RC). The study population consisted of 50 patients
      (27 with RC and 23 without RC) with anterior acute myocardial infarction (AMI)
      undergoing successful thrombolytic therapy (TT). The presence of reciprocal
      changes was defined as ST-segment depression >1 mm, measured 80 ms after the J
      point in at least 2 leads other than those reflecting the infarct on admission
      ECG. All patients were evaluated with coronary angiography at predischarge.
      Signal averaged ECG (SAECG) recordings were obtained before and 10 days after TT.
      Baseline characteristics, SAECG findings, and angiographic data were similar
      between the groups. The only different baseline finding was the time from symptom
      onset to TT (204 +/- 150 minutes for patients with RC vs 312 +/- 174 minutes for
      patients without RC. P = 0.021). After TT, RMS values improved in patients with
      RC (from 35 +/- 17 microV to 43 +/- 14 microV, P = 0.038) and LAS and RMS were
      significantly better in this group. However, patients without RC did not show any
      changes in SAECG parameters after TT. LV ejection fraction (10th day) was better
      in patients with RC (45 +/- 11% vs 39 +/- 6%, P = 0.014). The frequency of
      ventricular arrhythmias during the hospitalization period was also similar
      between the groups. Reciprocal ST depression that regresses simultaneously with
      the infarction related ECG changes after TT in anterior AMI seems to be related
      to the time that has elapsed since the symptom onset. The improvement in SAECG
      parameters after TT in these patients is probably the result of earlier
      reperfusion leading to less myocardial damage.

PMID- 12622431
TI  - Minute invasive ductal carcinoma of the residual pancreas after distal
      pancreatectomy for intraductal papillary-mucinous tumor.
AB  - Our report describes a 66-yr-old man who underwent surgical resection of the
      pancreas twice within a period of 3 yr for primary and recurrent intraductal
      papillary mucinous tumors (IPMTs). During the second operation, a minute invasive
      ductal carcinoma (IDC) was accidentally discovered in the resected specimen of
      the residual pancreas. The similarity and continuity between this IDC and
      recurrent IPMT were not recognized histologically. A solid tumor was found in the
      hepatoduodenal ligament 3 mo after the second operation. We performed a third
      operation, performing laparotomy and intra-operative radiotherapy, but could not
      extirpate the tumor. A biopsy specimen obtained from the tumor during this third
      operation revealed adenocarcinoma, and the patient later died because of tumor
      progression. We immunohistochemically analyzed the expression of HER-2/neu,
      Smad4, p16, p21, p53, mucin immunophenotypes and the Ki-67 labeling index in this
      series of pancreatic-duct neoplasias. Overexpression of HER-2/neu and loss of
      Smad4 were detected in the minute IDC, which was very different from the
      immunohistochemical features of both the primary and recurrent IPMTs. The IDC
      also showed a MUC1-positive/MUC2-negative phenotype. Therefore, we suggest that
      de novo IDC may occur in IPMT patients, especially those with multiple tumor
      recurrence. The present case may be helpful in understanding the pathogenesis of
      pancreatic duct lesions.

PMID- 12622434
TI  - Differential effect of aspirin on platelet aggregation in patients with coronary
      artery disease in relation with associated risk factors.
AB  - Platelets play a key role in the pathogenesis of atherosclerosis and acute
      coronary syndromes and antiplatelet therapy offers a clinical benefit. Although
      aspirin is the most widely used agent, there are several conditions in which
      aspirin may fail to provide a full antithrombotic benefit. Furthermore, data
      concerning the relationship between platelet function, aspirin, and the
      associated risk factors are limited. In the present study. ADP and collagen
      induced platelet aggregation of 200 consecutive patients with suspected coronary
      artery disease (CAD) who underwent coronary angiography were evaluated. The
      patients were classified into three groups according to the number of stenotic
      vessels. One hundred and eight patients were using 300 mg/day of aspirin. The
      associated cardiovascular risk factors were also considered. The collagen-induced
      platelet aggregation of smokers was significantly higher than non-smokers (P <
      0.05). Although platelet aggregation was higher in diabetic and hypertensive
      patients, the difference was not statistically significant. No significant
      correlation was found between platelet aggregation and other risk factors. The
      collagen-induced platelet aggregation of the subjects with non-stenotic vessels
      was reduced by aspirin (P < 0.05). Aspirin did not sufficiently inhibit ADP and
      collagen-induced aggregation in patients with CAD. This finding supports the idea
      that the nonplatelet-mediated effects of aspirin could be more important than its
      antiplatelet effect in clinical use and the use of new potent antiplatelet drugs
      may complete its antiplatelet effect.

PMID- 12622433
TI  - In-hospital outcome in octogenarians with acute coronary syndrome undergoing
      emergent coronary angiography.
AB  - Very elderly patients have higher mortality rates than younger patients after
      acute coronary syndrome (ACS). However, the mechanism by which increasing age
      contributes to such mortality remains unclear. In addition, the efficacy and
      safety of invasive coronary procedures for octogenarians with ACS have not been
      well established. We compared the clinical characteristics and in-hospital
      outcome of 193 octogenarians (mean age, 83 years) with those of 1,462 younger
      patients (mean age, 64 years) with ACS who underwent emergent coronary
      angiography. Octogenarians included a greater number of females, had higher rates
      of cerebrovascular disease and multivessel disease, a higher Killip class, a
      higher Forrester class, and lower rates of smoking, diabetes, and
      hypercholesterolemia than the younger subjects. Interventions, including
      percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass
      grafting (CABG), were performed less frequently in octogenarians than in younger
      patients (88.0% versus 90.8%). The procedural success rate in octogenarians did
      not differ from that in younger patients. However, the in-hospital mortality rate
      for the octogenarians was about three times higher than for the younger patients
      (19.2% versus 6.9%). Multivariate analysis revealed that the predictors of in
      hospital mortality in the octogenarians were a higher Killip class and a higher
      Forrester class. Octogenarians with ACS had fewer coronary risk factors and a
      similar success rate for the intervention, but had more greatly impaired
      hemodynamics and higher in-hospital mortality than the younger patients.
      Therefore, impaired myocardial reserve may contribute to a large portion of in
      hospital deaths in octogenarians with ACS.

PMID- 12622435
TI  - Five-year angiographic outcome in patients without restenosis following coronary
      balloon angioplasty: a comparison between non diabetic and diabetic lesions.
AB  - Few studies have investigated the long-term angiographic outcome of successful
      coronary balloon angioplasty (CBA) among diabetic and nondiabetic dilated
      lesions. The purpose of this study was to evaluate and compare the long-term (>5
      years) outcomes of diabetic and nondiabetic CBA lesions which had remained patent
      3-12 months after intervention. Twenty-five patients (45 lesions) with diabetes
      mellitus and 79 patients (138 lesions) without diabetes mellitus were enrolled as
      subjects. All patients who underwent CBA without restenosis within 3-12 months of
      the initial CBA based on follow-up angiographic evaluation were included.
      Quantitative coronary angiograms performed before, immediately after CBA, during
      the 3-12-month period (mean 4.1 +/- 1.0 months), and at or after 5 years (mean
      6.4 +/- 2.0 years) were compared. There was no significant difference in the
      reference diameter between nondiabetic and diabetic lesions at any of the four
      time points studied. The minimum lumen diameter before and immediately after the
      procedure and at the 3-12-month follow-up did not differ significantly between
      the two groups. At >5-year follow-up. the minimum lumen diameter was
      significantly (P = 0.005) decreased in diabetic lesions. Total occlusion occurred
      in 9% (4/45) of the diabetic lesions compared to only 1%, (1/138) in the
      nondiabetic lesions (P = 0.007). Diabetic lesions showed significant (P = 0.049)
      narrowing between the 3-12 month period and >5-year follow-up. Fifty-one percent
      (18/35) of the nondiseased vessels in the diabetic patients at the time of
      enrollment had new stenosis during the follow-up periods. In conclusion, compared
      to nondiabetic lesions, patients with diabetic lesions who underwent CBA were
      more predisposed to have stenotic progression and total occlusion.

PMID- 12622436
TI  - The feasibility and safety of early discharge for low risk patients with acute
      myocardial infarction after successful direct percutaneous coronary intervention.
AB  - There is a lack of consensus among cardiologists regarding the length of time
      patients should be hospitalized after an uncomplicated acute myocardial
      infarction (AMI) and successful direct percutaneous coronary intervention (d
      PCI). The purpose of this study was to evaluate the feasibility and safety of
      early discharge (discharge <4 days after the procedure) for low risk patients
      with AMI who underwent successful d-PCI. From May 1996 through December 2001, d
      PCI was performed in 898 consecutive patients with AMI. Of these 898 patients,
      463 (51.6%) were stratified to be at low risk. Lower risk was defined as: (1)
      Killip classification < or = 2 on admission; (2) the infarct-related artery
      achieved normal blood flow without recurrent ischemia or reinfarction in the
      first 24 hours; (3) no mechanical or electrical complications after d-PCI. (4) no
      acute renal failure, acute stroke, or major bleeding complication; (5) no
      advanced congestive heart failure (defined as > or = New York Heart Association
      functional class 3); and (6) no sepsis. Patients who were discharged <4 days
      after undergoing the procedure were enrolled in group 1 (n = 266). Patients who
      were discharged > or = 4 days after undergoing the procedure were enrolled in
      group 2 (n = 197). Univariate analysis demonstrated that group 2 patients had a
      significantly longer hospital stay (P = 0.0001) than group 1 patients. At the
      first 30-day follow-up examination, there were no significant differences in the
      combined major cardiac events (death, recurrent isehemia, reinfarction,
      revascularization. or advanced congestive heart failure) between the group 1 and
      group 2 patients (1.50% vs 1.52%, P = 0.92). There were also no significant
      differences in the combined major noncardiac complications (acute stroke, acute
      renal failure, bleeding complications requiring blood transfusion, vascular
      sequelae, or sepsis) between the group 1 and group 2 patients (1.13% vs 0.51%. P
      = 0.89). Early discharge was feasible in a majority of the patients who
      experienced AMI and were at lower risk 24 hours after successful d-PCI. Thus, the
      patients had a shortened hospital stay and no increased risk.

PMID- 12622437
TI  - The safety and feasibility of transradial cutting balloon angioplasty: immediate
      results, benefits, and limitations.
AB  - Cutting balloon angioplasty can reduce the restenosis rate more than conventional
      balloon angioplasty, but is traditionally performed through a femoral artery.
      However, it is not clear how useful a transradial approach would be for cutting
      balloon angioplasty. This study was conducted to examine the safety, feasibility,
      and limitations of transradial as opposed to transfemoral cutting balloon
      angioplasty. From November 1999 to August 2001, 177 patients underwent cutting
      balloon coronary angioplasty. We compared the success rate, angiographic results,
      and complication rates of two groups of patients, those undergoing transradial
      (168 lesions from 153 patients) and those undergoing transfemoral (24 lesions
      from 24 patients) cutting balloon angioplasty. In both groups of patients who had
      similar clinical and target lesion characteristics. the percentage of lesions
      that required balloon predilation (27.4% vs 29.2%). stenting (7.7% vs 4.2%), and
      adjunct balloon dilation (28.0% vs 33.3%) due to dissection (35.7% vs 33.3%) or
      suboptimal results were comparable. Both approaches achieved a 100% primary
      success rate with similar acute gain (2.02 +/- 0.68 mm vs 1.94 +/- 0.70 mm),
      residual (luminal) diameter stenosis (19.2 +/- 11.7% vs 17.0 +/- 12.7%).
      proportion of lesions that achieved TIMI 3 flow (98.8% vs 100%), and clinical
      success rate (98.8% vs 95.8%). However, patients undergoing transradial cutting
      balloon angioplasty had earlier ambulation and a significantly shorter hospital
      stay than those undergoing a transfemoral approach (2.80 +/- 2.67 days vs 4.75 +/
      5.44 days, P = 0.005). We conclude that the transradial approach is a feasible
      and safe alternative to the transfemoral approach for cutting balloon
      angioplasty. In addition, it offers patients early ambulation and a short
      hospital stay.

PMID- 12622438
TI  - Effects of smoking on pulmonary functions and arterial blood gases following
      coronary artery surgery in Turkish patients.
AB  - The effects of smoking on postoperative lung volumes, arterial blood gas
      tensions, and pulmonary complications were studied prospectively in 213
      consecutive Turkish patients undergoing elective coronary artery bypass graft
      surgery. One hundred and seventeen patients were current smokers (19 females, 98
      males, mean age. 59.0 +/- 6.1 years. group 1) and 96 were nonsmokers (40 females,
      56 males mean age. 59.6 +/- 5.8 years, group 2). Demographic data and the
      anesthesia and surgical methods were similar in both groups. Pulmonary function
      tests, arterial blood gas analyses, and chest radiographs were done
      preoperatively and postoperatively. Pulmonary complications were recorded.
      Postoperative partial arterial oxygen tension values in both groups revealed
      moderate hypoxemia which was more intense in smokers (decreased from preop. 82.0
      +/- 7.8 mmHg to postop. 66.1 +/- 8.0 mmHg). Mean partial carbon dioxide tension
      increased significantly, remaining within acceptable limits (from 32.5 +/- 2.2
      mmHg to 38.6 +/- 3.6 mmHg) in smokers following surgery. The postoperative
      pulmonary function test values decreased significantly in both groups but the
      deterioration in the smoking group was highly significant, except for FMFT. In
      the smokers, the preoperative mVC/pFVC (%) value was at the lower normal limit
      which indicates slight restrictive respiratory problems. Patients in both groups
      developed a severe restrictive ventilatory defect after coronary artery surgery
      (P < 0.0001 for both), but this restriction was also statistically significant in
      the smoking group compared to nonsmokers after surgery (mVC/pFVC from 74.7 +/-
      12.6% to 52.3 +/- 10.0% and 80.8 +/- 13.5% to 63.2 +/- 10.7%. in the smokers and
      nonsmokers, respectively). Also, the significantly greater decrease in the
      FEV1/FVC ratio in the smokers (from 75.4 +/- 12.2% to 72.2 +/- 11.5%) (P = 0.037)
      was indicative of greater airway obstruction. Pulmonary complications developed
      in 20.5% (24 people) of the smokers and 10.4% (10 people) of the nonsmokers. The
      mean time to extubation, intensive care unit stay, and hospital stay for groups
      1/2 were 19.9 +/- 11.5/14.1 +/- 4.3 hours (P < 0.0001) 3.2 +/- 1.3/2.4 +/- 0.6
      days (P < 0.0001), and 14.1 +/- 4.4/12.5 +/- 2.4 days (P = 0.0013), respectively.
      For the male group, we obtained results similar to those for the whole (males +
      females) study population and concluded that the observed differences in various
      parameters between smokers and nonsmokers were not due to gender. As a result. we
      revealed that cigarette smoking affects pulmonary functions by causing
      obstructive type respiratory problems and by worsening existing restrictive type
      respiratory problems postoperatively. The postoperative deterioration in blood
      gas measurements of smokers was also statistically significant compared with
      nonsmokers. In addition, the incidence of pulmonary complications in smokers was
      2-fold greater than in nonsmokers and was related to the number of cigarettes
      consumed daily, leading to prolongation of the postoperative intubation period,
      and ICU and hospital stays.

PMID- 12622439
TI  - Restoring sinus rhythm improves excessive heart rate response to exercise in
      patients with atrial fibrillation.
AB  - The aim of this study was to investigate improvement in the cardiovascular
      response to isometric and isotonic exercises after reverting rhythm to sinus in
      patients with atrial fibrillation. Twenty seven cases with nonvalvular paroxysmal
      atrial fibrillation were included in the study. Sinus rhythm could not be
      restored in two cases so they were excluded. The remaining cases were divided
      into two groups according to the existence of cardiac diseasc. Group 1 (n:14,
      mean age. 60.8 +/- 14.9 years) included cases with cardiac diseases (8 of the
      patients had hypertension in addition to the cardiac disease) and group 2 (n:11,
      mean age. 64.8 +/- 13.9 years) included those without cardiac disease (patients
      with hypertension and diabetes mellitus). Isometric and isotonic exercise tests
      were performed in all of the patients before and 48 hours after the rhythm was
      reverted to sinus and the values in atrial fibrillation were compared with those
      in sinus rhythm (following cardioversion). The isotonic exercise period increased
      significantly in only group 1 patients following cardioversion (P = (0.0061). In
      both groups, the increase in heart rate during atrial fibrillation was
      significantly higher compared to those after being reverted to sinus, at all
      stages of the isotonic exercise (in groups 1 and 2, heart rate in patients with
      atrial fibrillation increased from 96.5 +/- 19.3 to 173.3 +/- 19.3 beats/min and
      96.1 +/- 12.6 to 185.0 +/- 12.1 beats/ min, respectively; and in sinus rhythm, it
      ranged from 85.1 +/- 11.4 to 164.6 +/- 9.1 beats/min and 81.3 +/- 11.4 to 157.6
      +/- 15.1 beats/min, respectively). Systolic arterial pressure increased
      significantly during atrial fibrillation in group 1, at the 2nd stage of the
      isotonic exercise test (P = 0.0070). In group 2, systolic arterial pressure
      increased significantly at the 3rd stage in sinus rhythm and at the 4th stage
      when in rhythm in atrial fibrillation. Also, diastolic arterial pressure
      increased significantly during atrial fibrillation only at the 3rd stage of the
      exercise. As a result, restoring sinus rhythm by cardioversion improves excessive
      heart rate responses to exercise significantly in patients with atrial
      fibrillation during both isometric and isotonic exercises. Also, we have revealed
      that the exercise time increased significantly by restoring sinus rhythm in
      patients with heart disease.

PMID- 12622440
TI  - Single photon emission computed tomography of technetium-99m tetrofosmin
      myocardial perfusion imaging in patients with systemic lupus erythematosus--a
      preliminary report.
AB  - The purpose of this study was to evaluate the utility of single-photon emission
      computed tomography (SPECT) of technetium-99m tetrofosmin (Tc-99m TF) myocardial
      perfusion imaging to detect myocardial involvement in patients with systemic
      lupus erythematosus (SLE). Three groups of subjects-group 1: 25 SLE female
      patients with non-specific cardiac symptoms and signs, group 2: 25 female SLE
      patients without any cardiac symptoms and signs, and group 3: 25 female healthy
      controls-were evaluated by comparing rest and dipyridamole-stress Tc-99m TF
      myocardial perfusion SPECT. Tc-99m TF myocardial perfusion SPECT revealed
      perfusion defects in 88% and 40% of the cases in groups 1 and 2. respectively.
      However, no cases in group 3 demonstrated myocardial perfusion defects. Tc-99m TF
      myocardial perfusion SPECT is a useful noninvasive imaging modality to detect
      cardiac involvement in SLE patients with or without cardiac symptoms and signs.

PMID- 12622441
TI  - Effect of cervical vagal nerve stimulation on defibrillation energy: a possible
      adjunct to efficient defibrillation.
AB  - The efficacy of electrical defibrillation is considered to be related to the
      autonomic status. In search of a possible adjunct to enhance the therapeutic
      performance of an implantable cardioverter-defibrillator. we investigated whether
      parasympathetic manipulation by cervical vagal nerve stimulation (VNS) increases
      defibrillation efficacy. The effects of VNS on transcardiac defibrillation
      threshold (DFT) were assessed in 55 anesthetized dogs. In neurally intact dogs,
      right and left unilateral VNS at 10 mA for 7 seconds significantly decreased the
      DFT after 10 seconds of ventricular fibrillation (control: 3.1 +/- 0.9 J, right:
      2.1 +/- 0.9 J [delta-35 +/- 12%, P < 0.0001], left: 2.2 +/- 0.8 J [delta-31 +/-
      11%, P < 0.0005]), while bilateral VNS did not (2.8 +/- 1.0 J). In dogs with
      decentralized vagus nerves, both unilateral and bilateral VNS decreased the DFT.
      The extent of the VNS-induced decrease in DFT was dependent on the current and
      the duration of stimulation. We conclude that unilateral VNS decreases the DFT,
      while bilateral VNS paradoxically has no effect on the DFT unless the vagi are
      decentralized.

PMID- 12622442
TI  - Different gene expression of potassium channels by thyroid hormone and an
      antithyroid drug between the atrium and ventricle of rats.
AB  - Thyroid hormone has been shown to modulate the gene expression of cardiac
      potassium channels, however, it is not known if gene expression is different
      between the atrium and the ventricle. The long-term effects of thyroid hormone on
      nuclear thyroid hormone receptors are also not known. Triiodothyronine (T3) at 25
      microg/100 g of body weight or propylthiouracil (PTU) at 4 mg/100 g of body
      weight was given to adult rats via a gastric tube for 14 days. The levels of mRNA
      of Kv1.2. Kv1.4, Kv1.5, Kv2.1, Kv4.2, erg, LQT1, and minK were assayed by RNase
      protection assay. The mRNA of nuclear T3-receptor-al and T3-receptor-beta1 were
      also assayed for 15 days. After T3 (or PTU), plasma free T3 and free T4 increased
      (or decreased) significantly. The mRNA levels of Kv1.2 and Kv1.4 were reduced
      after T3 in the atrium and the ventricle. while PTU increased the levels in both
      chambers. Kv1.5 was significantly up-regulated by T3 in the atrium and the
      ventricle (P < 0.02 for both) and PTU decreased its expression in the ventricle
      (P < 0.02). Kv2.1 and Kv4.2 were not affected by T3 or PTU. mRNA of erg was not
      affected by T3 in the atrium but decreased in the ventricle (P < 0.01). After
      PTU, erg mRNA was decreased in the atrium (P < 0.02) but increased in the
      ventricle (P < 0.01). LQT1 was decreased by T3 in both chambers (P < 0.01) and
      not affected by PTU. minK was not detectable in the control state and was up
      regulated only in the atrium: a peak on the 4th day followed by a decline to the
      undetectable level on the 10-15th days. During T3 treatment, nuclear T3-receptor
      alpha1 and beta1 mRNA were decreased in the initial 3 days but returned to
      control levels thereafter. CONCLUSIONS: Between the atrium and ventricle of the
      adult rat heart, the responses of gene expression of voltage-gated potassium
      channels to T3 or PTU were quantitatively or qualitatively different and the
      differential responses may explain cardiac manifestations of hyperthyroidism,
      which is a frequent complication of supraventricular arrhythmia.

PMID- 12622443
TI  - Altered microvasculature is involved in remodeling processes in cardiomyopathic
      hamsters.
AB  - The cardiomyopathic hamster (BIO TO2) is a well-established model of heart
      failure. Deterioration of cardiac function in BIO TO2 is attributed to a defect
      in delta-sarcoglycan, whereas cardiac dysfunction in delta-sarcoglycan knockout
      mice is caused by microvascular abnormalities. We examined the relation between
      cardiac function and the microvasculature, including angiogenic factors, in BIO
      TO2. METHODS AND RESULTS: At the age of 5 weeks, percent fractional shortening
      (%FS) and positive rate of change in left ventricular pressure over time (dP/dt
      max) were lower in BIO TO2 than in age-matched F1B controls. Capillary density,
      capillary/myocyte (CM) ratio, capillary domain area (CDA), and myocyte density
      were similar between BIO TO2 and F1B controls. At the ages of 13 and 20 weeks,
      BIO had significantly lower capillary and myocyte densities and a significantly
      higher CM ratio and CDA. Myocyte density positively correlated with %FS and dP/dt
      max. There were no significant differences in mRNA expression for VEGF, Flt-1,
      angiopoietin-1, or angiopoietin-2 between BIO TO2 and F1B control. CONCLUSION:
      Progressive myocyte loss is responsible for deterioration of cardiac function in
      BIO TO2. The impaired neovascularization may be involved in the progress of
      cardiac remodeling in cardiomyopathic hamsters.

PMID- 12622444
TI  - Role of nitric oxide in the progression of cardiovascular remodeling induced by
      carotid arterio-venous shunt in rabbits.
AB  - Despite a variety of biological roles for nitric oxide (NO) in the cardiovascular
      system, little is known about whether NO is involved in cardiac hypertrophy. We
      hypothesized that NO production following a sustained increase in shear stress by
      volume-overload modifies the level of cardiac hypertrophy independent of
      hemodynamic changes. Volume-overload was induced by shunt formation between the
      left common carotid artery and the external jugular vein in 21 rabbits. These
      shunt rabbits were randomly assigned to 3 groups: shunt with no treatment (n =
      8), shunt treated with a low dose of N(G)-nitro-L-arginine methyl ester (L-NAME.
      0.5 g/L in drinking water, n=8), and shunt with a high dose of L-NAME (1.5 g/L, n
      = 5). Eight sham operated rabbits were used as controls. Treatments were started
      immediately after operation and were continued for 6 weeks. Chronic volume
      overload by shunt formation caused left ventricular dilatation and arterial
      enlargement proximal to the fistula. The relative wall thickness of the left
      ventricle was decreased, indicating eccentric cardiac hypertrophy. L-NAME
      elevated mean arterial blood pressure (P < 0.01) and reduced the increment of
      cardiac output (P < 0.05). L-NAME attenuated ventricular weight (P < 0.01)
      ventricular cavity dilatation (P < 0.01). and arterial enlargement (P < 0.05).
      The re-capitulation of atrial natriuretic factor mRNA in the hypertrophied left
      ventricular myocardium by volume-overload was attenuated with L-NAME. In this
      model with chronic volume-overload, NO plays a pivotal role in the progression of
      cardiovascular remodeling by regulating the loading conditions of the heart.

PMID- 12622445
TI  - Exacerbation of Lambert-Eaton myasthenic syndrome caused by an L-type Ca2+
      channel antagonist.
AB  - A 74 year-old Japanese woman, who had suffered from Lambert-Eaton myasthenic
      syndrome (LEMS), Sjoegren's syndrome, and discoid lupus erythematosus for 10
      years and had been successfully controlled by 3,4-diaminopyridine and
      prednisolone, began to suffer from chest discomfort at night. Stress-induced
      myocardial ischemia in the left ventricular anterior septum was detected by
      thallium-201 scintigraphy. After diltiazem was prescribed, she began to feel
      systemic malaise and weakness in both thighs. She stopped taking diltiazem and
      the symptoms improved. Coronary angiography revealed 75% stenosis with
      calcification in the middle of the left anterior descending artery. After
      atherectomy with a lotablator and coronary stenting, diltiazem was prescribed.
      She felt malaise again, but continued taking diltiazem. After three months a
      follow-up coronary angiography showed no restenosis in the lesion and diltiazem
      was stopped. The weakness and malaise disappeared and her muscle strength
      recovered. LEMS is an autoimmune disorder of peripheral cholinergic transmission
      in which autoantibodies to the presynaptic P/Q-type voltage-gated calcium
      channels (VGCC) decrease the release of acetylcholine at the neuromuscular
      junction resulting in muscle weakness. P/Q-type VGCC regulates most of the
      neurotransmitter release and L-type VGCC regulates the remainder. L-type VGCC
      blockers are thought to have little effect on the neuromuscular junction. but
      they should be used very carefully. even in the remission stage of LEMS, because
      of preexisting neuromuscular blocking in transmission.

PMID- 12622446
TI  - Modulation of oxidative stress in response to gamma-radiation in human glioma
      cell lines.
AB  - Radiation therapy is routinely used in the management of primary central nervous
      system malignancies. However, the efficacy of this therapeutic modality is
      limited by the occurrence of resistance. In the present study, we investigated
      whether modulation of oxidative stress might underlie glioma cell
      radioresistance. Superoxide dismutase activity in irradiated M059J cells was two
      fold higher than that in untreated controls, but did not significantly change in
      U-87 and U-138 cells. This is accompanied by an increase in reactive oxygen
      species content and decreases in cells viability. Pharmacological or genetic
      modulation of oxidative stress could be associated with an enhancement in the
      susceptibility of tumor cells to radiation therapy.

PMID- 12622447
TI  - Deregulation of the p14ARF/Mdm2/p53 pathway and G1/S transition in two
      glioblastoma sets.
AB  - Sixty-one glioblastomas have been studied, subdivided into the categories of
      classic glioblastomas (GBM) and glioblastomas with astrocytic (GBA) and
      oligodendroglial (GBO) differentiated areas. On surgical samples, TP53, Mdm2,
      CDKN2A/p16-p14 alterations were studied by molecular biology techniques and by
      immunohistochemistry. It has been found that Mdm2 amplification was more frequent
      in GBM than in GBA and GBO, that p14ARF was inactivated in a high percentage of
      cases in the three tumor categories. Both these and other alterations did not
      reach a statistical significance, with the exception of CDKN2A/p16 homozygous
      deletion which showed the highest frequency in GBO. The latter finding could be
      in line with the observation that CDKN2A/p16 inactivation is a step in the
      molecular pathway to tumor progression in oligodendrogliomas. TP53 mutations and
      Mdm2 amplifications were mutually exclusive, whereas TP53 mutations and
      CDKN2A/p14 inactivation coexisted in 5 cases. The alterations of the
      p53/Mdm2/p14ARF pathway occurred in 73% of cases and in 80% of cases if CDKN2A
      homozygous deletions were associated. All glioblastomas with gemistocytic areas
      showed p14ARF inactivation. Immunohistochemistry showed higher percentages of
      positivity in comparison with molecular genetics, but with similar variations.

PMID- 12622448
TI  - In vitro and in vivo growth inhibition of human malignant astrocytoma cells by
      the farnesyltransferase inhibitor B1620.
AB  - p21-Ras, the protein product of the proto-oncogene Ras is overactivated in
      malignant astrocytomas despite the absence of mutation. It is known that p21-Ras
      participates in signaling events from membrane tyrosine kinase receptors and a
      variety of intracellular biochemical pathways to downstream targets. Signal
      transduction inhibition by targeting against Ras is now thought to be a promising
      therapeutic strategy for malignant astrocytomas. This study demonstrates that Ras
      pathway inactivation by a farnesyltransferase inhibitor, B1620, effectively
      inhibits in vitro and in vivo growth of human astrocytoma cells, although normal
      human astrocytes (NHA) derived from fetal brain are resistant to B1620. Anti
      proliferative effect of B1620 on in vitro growth of astrocytoma cells was
      examined by MTT assays and soft agar colony formation assay. B1620 inhibited
      anchorage-dependent growth of six astrocytoma cell lines with a median effective
      dose (IC50) ranging from 2.0 to 20.7 microM. However, growth of NHA was not
      significantly affected by B1620 even at the concentration of 100 microM. All
      astrocytoma cells showed apoptotic figures after Hoechst 33258 staining, when
      treated for 5 days at each IC50 concentration against B1620. Anchorage
      independent growth of these astrocytoma cell lines was inhibited at a much lower
      concentration than that of anchorage-dependent growth. Daily treatment of U87
      xenograft-bearing athymic mice with B1620 at 100 or 50 mg kg(-1) resulted in
      significant inhibition of tumor growth. A histological study of the B1620-treated
      tumor tissue showed decreased vascularity with numerous TUNEL-positive apoptotic
      cells. These results suggest that the mechanism of the growth-inhibitory effect
      of B1620 is anti-angiogenesis, apoptosis induction and reversion of the
      transformed phenotype. The potential clinical use of B1620 could be expanded to
      malignant astrocytomas.

PMID- 12622449
TI  - Primary intraspinal primitive neuroectodermal tumor: report of two cases and
      review of the literature.
AB  - BACKGROUND: Primary intraspinal primitive neuroectodermal tumor (PNET) is a very
      rare tumor entity. The optimal therapeutic approach is not known yet. We report
      on two women with primary intraspinal PNETs and review the literature. We
      describe the typical course of the disease, compare our patients to the other 17
      cases reported until today, and discuss therapeutic options. PATIENTS AND METHOD:
      Case A: In a 49-year-old woman with an intraspinal PNET at L2, laminectomy and a
      gross tumor removal was accomplished. Postoperative radiation was performed from
      T12 to L3 to a dose of 50.4 Gy. Subsequently she was treated with chemotherapy
      containing vincristine, cisplatinum and lomustine. Case B: A 29-year-old woman
      presented with intramedullary PNET lesions at T1-3 and T10-11. Due to the
      multifocal location, she received a primary craniospinal axis irradiation to a
      dose of 35.2 Gy plus a boost to the tumor region to a total dose of 53.2 Gy.
      RESULTS: Both patients developed multilocular intraspinal relapses with
      meningeosis neoplastica 17 and 6 months from radiation therapy and underwent
      palliative chemotherapy. Case A died 23 months, case B 17 months after primary
      diagnosis. CONCLUSION: Despite modern treatment with microsurgery, irradiation
      and chemotherapy in primary intraspinal PNETs, local relapse or dissemination in
      most cases lead to death within a few months. An improvement of treatment outcome
      can only be achieved by intensification through multidisciplinary treatment.

PMID- 12622452
TI  - Rosai-Dorfman disease. Extranodal sinus histiocytosis in three co-existing sites.
      A case report.
AB  - A 73-year-old woman presented with mild anterior uveitis, ipsilateral optic
      neuropathy, and ipsilateral skin nodules. A compressive mass at the level of the
      orbital apex and sphenoid wing was found on cranial magnetic resonance imaging.
      Biopsy of the skin nodules revealed histopathologic evidence of sinus
      histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease (RDD).
      Systemic investigations failed to show any massive lymphadenopathy, making this a
      case of extranodal RDD. This is a salient case in that it proposes three
      simultaneous and separate sites of involvement by extranodal RDD. It also
      exemplifies that RDD should be a suspect diagnosis even in the absence of
      lymphadenopathy.

PMID- 12622450
TI  - Primary malignant rhabdoid tumors of the central nervous system: considerations
      about two cases of adulthood presentation.
AB  - Malignant rhabdoid tumors (MRT) are aggressive neoplasms generally of the infant
      kidney, although a few extrarenal, central nervous system-located, were reported.
      We describe two cases of such tumors arising intracerebrally in patients aged 16
      and 31 years, hence older than the usually reported, with survival times of 16
      and 4 months, respectively. Besides, in the youngest, the mass seemed to have
      developed from a low grade glioma, an occurrence not reported earlier, although
      the coexistence of morphological features of glioma and rhabdoid tumor is well
      known. The broad immunoprofile spectrum found in these two tumors seems to
      reflect the lack of specific differentiation of MRTs. As in the case of other
      MRTs, our patients had short survivals despite the aggressive post-surgical
      treatment. In conclusion, MRTs should be suspected also in intracerebral
      neoplasms of adult patients, and the medical treatment remains disappointing.

PMID- 12622451
TI  - Quantitative measurement of quality outcome in malignant glioma patients using an
      independent living score (ILS). Assessment of a retrospective cohort.
AB  - PURPOSE: Although a number of tools have been developed to measure 'quality of
      life' in patients with malignant glioma, there remains no completely satisfactory
      technique that incorporates a quality of life measure into survival analysis. We
      propose that a patient's ability to maintain independent activity offers a way to
      accomplish this goal. PATIENTS AND METHODS: An independent living score (ILS) is
      generated by awarding points on a monthly basis based on Karnofsky score and
      weighing the score based on the particular month of the clinical course. The ILS
      has a large range for any given survival, and can discriminate important
      treatment effects to which standard survival analyses are completely insensitive.
      Using this score and several variations, we were able to retrospectively analyze
      a patient cohort to assess what correlated with ILS. RESULTS: We found a strong
      correlation with survival of all the measures tested. Interestingly, we found
      that patients for whom a total resection was performed and those who were most
      intensively treated had significantly higher ILS values, suggesting that not only
      did more aggressive treatment improve survival but that it did not simply
      increase survival at the expense of the time a patient remained independent.
      CONCLUSION: Since the general course for patients with malignant glioma is one of
      increasing disability and loss of independence, we feel that these measures can
      serve as a way to distinguish between those therapies that increase survival at
      the expense of quality of life versus those that do not. Consideration should be
      given to incorporating these measures into prospective trials.

PMID- 12622453
TI  - Prospective study of stereotactic radiosurgery without whole brain radiotherapy
      in patients with four or less brain metastases: incidence of intracranial
      progression and salvage radiotherapy.
AB  - This prospective study was conducted to evaluate the treatment outcome after
      stereotactic radiosurgery (SRS) alone with special attention to its influence on
      intracranial freedom from progression (FFP), local control, time to whole brain
      radiotherapy (WBRT), and survival. Forty-one patients with brain metastases who
      met the inclusion criteria were enrolled in this prospective cohort and treated
      by SRS alone between January 1998 and September 2001. The overall local control
      rate was 76%. The one year actuarial intracranial FFP was 33%. Ten patients (24%)
      had relapse at treated site. Twenty-three patients (56%) had intracranial
      progression with a median time of 4.25 months (1-24.6). Salvage radiotherapy was
      given in 21 patients (51%). Only 12 (29%) patients required WBRT with the median
      time to WBRT after SRS of 4.85 months. Nine patients (22%) underwent additional
      SRS at the median time of 5 months after the first procedure. The median survival
      was 10 months. At the time of follow up, 16 patients (39%) were still alive with
      a range of 6-31 months. This prospective study suggests that the omission of WBRT
      in the initial treatment of patients with SRS for four or less brain metastases
      may allow up to 70% of patients to avoid WBRT.

PMID- 12622454
TI  - Baseline levels of glucose metabolites, glutamate and glycerol in malignant
      glioma assessed by stereotactic microdialysis.
AB  - The metabolism of high grade astrocytoma was studied in 15 patients using intra
      tumoural microdialysis. Two catheters were implanted during a stereotactic biopsy
      procedure: one in the tumour and one in the peri-tumoural tissue. The patients
      were fully mobilized the same day as the operation. Microdialysis samples were
      collected the next day and subsequently analysed for glucose, lactate, pyruvate,
      glutamate and glycerol. The main objective was to establish base-line levels of
      the studied substances. In addition, an in vitro experiment was performed in
      order to estimate recovery for the flow rates and catheters used. Glucose showed
      a tendency to be lower in tumour than in peri-tumoural tissue, indicating a high
      energy demand of the tumour. Lactate was significantly higher in tumour tissue.
      This supports previous reports that high grade astrocytomas use glycolysis rather
      than respiration to meet their energy demand. The tumours were also classified
      into necrotic and non-necrotic, according to the radiological finding. The
      necrotic tumours showed significantly higher levels of glutamate. They also
      presented a tendency to higher levels of glycerol than the non-necrotic tumours.
      These findings might be explained by the release of intracellular glutamate and
      of cell-membrane glycerol by cell destruction. We believe that microdialysis in
      awake and mobilized patients will prove to be a valuable tool in investigating
      metabolic events in malignant brain tumours especially during therapy.

PMID- 12622455
TI  - A phase II study of radiotherapy after hyperbaric oxygenation combined with
      interferon-beta and nimustine hydrochloride to treat supratentorial malignant
      gliomas.
AB  - Hypoxic cells play a key role in the radioresistance of malignant glioma.
      Interferon-beta, ACNU as nimustine hydrochloride and radiotherapy (IAR) is a
      common therapy for malignant glioma in Japan. Since hyperbaric oxygenation (HBO)
      increases oxygen pressure in glioma tissue, we applied a modified IAR therapy,
      radiotherapy after HBO combined with interferon-beta and ACNU (HBO/IAR therapy),
      for supratentorial malignant gliomas. Daily radiation therapy was completed
      within 15 min after HBO. We assessed HBO/IAR with respect to toxicity, response
      rates and the time of tumor progression (TTP). We also examined the incidence of
      responses by some prognostic factors before HBO/IAR, namely, age, Karnofsky
      performance scale (KPS), histological type, tumor size, tumor site and operation
      type. Of 39 patients who participated in this study, 35 underwent a complete
      schedule of HBO/IAR therapy in which toxicity was permissible. Thirty patients
      (76.9%) either maintained or increased KPS during HBO/IAR with a mean duration of
      68 +/- 14 days. The response rates (CR + PR%) for glioblastoma, anaplastic
      astrocytoma and overall were 50%, 30% and 43%, respectively. The incidence of
      therapeutic responses among all prognostic factors before HBO/IAR did not
      significantly differ. Median TTP for patients with glioblastoma, patients with
      anaplastic astrocytoma, and overall were 38, 56 and 43 weeks, respectively. The
      present study suggested that HBO/IAR therapy could be applied to especially
      patients with poor prognostic factors, because of its short treatment period, its
      permissible toxicity and identical response to patients with good prognostic
      factors.

PMID- 12622456
TI  - Treatment of low-grade diffuse astrocytomas by surgery and human fibroblast
      interferon without radiation therapy.
AB  - Low-grade diffuse astrocytomas are slowly growing tumors with a relatively long
      overall survival. However, a substantial proportion undergoes dedifferentiation
      to a more malignant phenotype. Considerable controversy exists as to the best
      therapeutic management for patients with such tumors. Over the past decade, we
      have applied human fibroblast interferon (HFIF) therapy without radiation therapy
      to low-grade astrocytomas. We investigated 28 patients with WHO grade II
      astrocytomas of the cerebral hemispheres treated by surgery plus HFIF therapy.
      The overall response rate to the HFIF therapy was 36%. All side-effects of HFIF
      were transient, tolerable and manageable. The 5-year progression free survival
      and overall survival probabilities were 65% and 96%, respectively. Although our
      data from small cohort of patients may have modest value, our results suggest
      that HFIF may be useful in treating low-grade diffuse astrocytomas.

PMID- 12622457
TI  - Efficacy and tolerability of Boswellia serrata extract in treatment of
      osteoarthritis of knee--a randomized double blind placebo controlled trial.
AB  - Osteoarthritis is a common, chronic, progressive, skeletal, degenerative
      disorder, which commonly affects the knee joint. Boswellia serrata tree is
      commonly found in India. The therapeutic value of its gum (guggulu) has been
      known. It posses good anti-inflammatory, anti-arthritic and analgesic activity. A
      randomized double blind placebo controlled crossover study was conducted to
      assess the efficacy, safety and tolerability of Boswellia serrata Extract (BSE)
      in 30 patients of osteoarthritis of knee, 15 each receiving active drug or
      placebo for eight weeks. After the first intervention, washout was given and then
      the groups were crossed over to receive the opposite intervention for eight
      weeks. All patients receiving drug treatment reported decrease in knee pain,
      increased knee flexion and increased walking distance. The frequency of swelling
      in the knee joint was decreased. Radiologically there was no change. The observed
      differences between drug treated and placebo being statistically significant, are
      clinically relevant. BSE was well tolerated by the subjects except for minor
      gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of
      the knee with possible therapeutic use in other arthritis.

PMID- 12622458
TI  - Investigation of the pharmaceutical and pharmacological equivalence of different
      Hawthorn extracts.
AB  - Seven Hawthorn extracts were tested in isolated guinea pig aorta rings. The
      effect on noradrenaline- (10 microM) induced contraction was investigated. The
      extracts were prepared using ethanol (40 to 70% v/v), methanol (40 to 70% v/v),
      and water as the extraction solvents. The aqueous-alcoholic extracts displayed
      similar spectra of constituents. They were characterised by similar procyanidin,
      flavonoid, total vitexin and total phenols content and by similar TLC fingerprint
      chromatograms. The aqueous extract, however, showed a different fingerprint and a
      noticeably lower concentration of procyanidins, flavonoids and total phenols but
      a similar total vitexin content. All 7 extracts had a relaxant effect on the
      aorta precontracted by noradrenaline and led to relaxations to 44 until 29% of
      the initial values. The EC50 values of the aqueous-alcoholic extracts varied
      between 4.16 and 9.8 mg/l. The aqueous extract produced a similarly strong
      maximal relaxation as the other extracts, but the EC50, at 22.39 mg/l, was
      markedly higher. The results show that Hawthorn extracts with comparable quality
      profiles were obtained by using aqueous-alcoholic extraction solvents (40 to 70%
      ethanol or methanol). The extracts exerted comparable pharmacological effects.
      When using water as the extraction solvent, both, the spectrum of constituents
      and the pharmacological effect, deviated remarkably. It is thus possible to
      obtain bioequivalent extracts with comparable effect profiles by using 40 to 70%
      ethanol or methanol as the extraction solvent.

PMID- 12622459
TI  - The effects of Coptidis Rhizoma extract on a hypercholesterolemic animal model.
AB  - The serum cholesterol (total, free, esterified, low density lipoprotein (LDL) and
      oxidized LDL) levels of rats fed a diet containing, by weight, 1% cholesterol and
      0.5% cholic acid increased, as compared with those of rats fed a normal diet. The
      levels, especially of total cholesterol, LDL and oxidized LDL, were reduced
      significantly in a dose-dependent manner, in rats given Coptidis Rhizoma extract
      orally at doses of 50 and 100 mg/kg body wt./day for 30 days. These results
      indicate that Coptidis Rhizoma extract is effective in reducing the pathological
      damage caused by hypercholesterolemia, through lowering of serum cholesterol
      levels. In addition, Coptidis Rhizoma extract reduced the level of liver
      cholesterol, but it did not reduce that of fecal cholesterol, suggesting that the
      cholesterol level-lowering effect resulted from the reduction of cholesterol
      synthesis, not the enhancement of its excretion. Furthermore, the serum
      thiobarbituric acid-reactive substance level decreased after oral administration
      of Coptidis Rhizoma extract, indicating that Coptidis Rhizoma could prevent
      hypercholesterolemic disease through reducing lipid peroxidation. This study
      demonstrates that Coptidis Rhizoma may be a useful therapy for
      hypercholesterolemia through reducing oxidative stress and cholesterol levels.

PMID- 12622460
TI  - C-Med 100, a hot water extract of Uncaria tomentosa, prolongs lymphocyte survival
      in vivo.
AB  - Water extracts of the bark of Uncaria tomentosa, a vine indigenous to South
      America, has been used for generations as an "immuno modulator". To understand
      the basis of this immuno modulatory effect we fed mice in their drinking water
      with C-Med 100, which is a commercially available water extract from Uncaria
      tomentosa. We found a dose-dependent increase in spleen cell numbers in the
      supplemented mice, but the proportions of B cells, T cells, NK cells,
      granulocytes, and memory lymphocytes were normal. However, there were no
      detectable changes of the lymphoid architecture of the spleen even after long
      term treatment. Further, when C-Med 100 treatment was interrupted the cellularity
      returned to normal level within four weeks. The increased number of lymphocytes
      was most likely not due to increased production because C-Med 100 did not have
      any significant effect on precursor cells nor on the accumulation of recent
      thymic emigrants in the spleen. We conclude that accumulation is most likely due
      to prolonged cell survival, because adoptive transfer experiments demonstrated
      that C-Med 100 treatment significantly prolonged lymphocyte survival in
      peripheral lymphoid organs, without increasing their proliferation rate. Since
      the accumulation was reversible and without detectable pathological effects,
      these results suggest the use of C-Med 100 as a potential agent for clinically
      accelerating the recovery of patients from leukopenia.

PMID- 12622461
TI  - Inhibition of Propionibacterium acnes-induced mediators of inflammation by Indian
      herbs.
AB  - Propionibacterium acnes, an anaerobic pathogen, plays an important role in the
      pathogenesis of acne by inducing certain inflammatory mediators. These mediators
      include reactive oxygen species (ROS) and pro-inflammatory cytokines. In the
      present study, ROS, interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF
      alpha) were used as the major criteria for the evaluation of anti-inflammatory
      activity. To prove the anti-inflammatory effects of herbs, polymorphonuclear
      leukocytes (PMNL) and monocytes were treated with culture supernatant of P. acnes
      in the presence or absence of herbs. It was found that Rubia cordifolia, Curcuma
      longa, Hemidesmus indicus, and Azadirachta indica caused a statistically
      significant suppression of ROS from PMNL. Sphaeranthus indicus caused a smaller,
      still significant suppression of ROS. Aloe vera had no effect on ROS production.
      In the case of proinflammatory cytokine-induced monocytes, maximum suppression
      was shown by Azadirachta indica and Sphaeranthus indicus, followed by Hemidesmus
      indicus, Rubia cordifolia, and Curcuma longa. Aloe vera showed insignificant
      inhibitory activity. Thus, these herbs shows anti-inflammatory activity by
      suppressing the capacity of P. acnes-induced ROS and pro-inflammatory cytokines,
      the two important inflammatory mediators in acne pathogenesis.

PMID- 12622462
TI  - Effects of aqueous extracts of Halimeda incrassata (Ellis) Lamouroux and
      Bryothamnion triquetrum (S.G.Gmelim) Howe on hydrogen peroxide and methyl mercury
      induced oxidative stress in GT1-7 mouse hypothalamic immortalized cells.
AB  - The current investigation focuses attention on the neuroprotective and
      antioxidant properties of aqueous extracts from Halimeda incrassata (Hi) and
      Bryothamniom triquetrum (Bt) in the mouse immortalized hypothalamic GT1-7 cell
      line. Under basal oxidative conditions, Hi extract reduces intracellular reactive
      oxygen species production, as assessed by 2',7'-dichlorofluorescein fluorescence,
      while Bt extract does not contribute to basal ROS generation. Both extracts, at
      concentrations higher than 0.20 mg/ml, exert protection against hydrogen peroxide
      mediated cell death, although only Hi extract can additionally prevent hydrogen
      peroxide-induced ROS production. The two seaweed aqueous extracts, at
      concentrations higher than 0.05 mg/ml, also display protection against neuronal
      death induced by methyl mercury chloride, as well as against methyl mercury
      chloride-mediated ROS generation. None of the extracts increase GSH intracellular
      pools, in basal conditions, after depleting its levels with either hydrogen
      peroxide or methyl mercury chloride. Some comments on the probable targets of the
      neuroprotection exerted by these two extracts are included in this paper.

PMID- 12622463
TI  - Toxicological evaluations of long-term consumption of Solanum lycocarpum St. Hill
      fruits in male and female adult rats.
AB  - Solanum lycocarpum St. Hill is a common plant in the Brazilian savanna. This
      plant contains an alkaloid with stereospecific configuration to the synthesis of
      steroid hormones. Because the plant may be consumed long-term, the present study
      was undertaken to determine the possible toxic effects of S. lycocarpum fruit
      ingestion (3% added to the diet) on male (60 days of administration) and female
      (37 days) adult rats. Few significant differences in body weight and consumption
      of food and water, no significant differences in male and female weight gain or
      estrous cycle were detected. Female treated rats showed a significant reduction
      in uterus and liver weights; however, no significant differences were observed in
      other organ (adrenal, liver, seminal vesicle, testicle and ovary) weights in
      either sex. Additionally blood enzymes and proteins evaluated were not affected
      by treatment with 3% S. lycocarpum added to the diet. The present data, however,
      show sex-related differences in S. lycocarpum toxicity. Thus, other studies have
      to be conducted to better investigate female toxicity and other toxic effects of
      higher levels of exposure to this plant.

PMID- 12622464
TI  - Ethanolic extracts of Euphorbia and other ethnobotanical species as inhibitors of
      human tumour cell growth.
AB  - Ethanolic extracts of 20 plant species, selected from the ethnobotanical
      literature, were analysed for their pharmacological potential as antineoplastic
      agents against the HEp-2 cell line. Psoralea corylifolia and E. grandidens were
      the most efficacious species eliciting IC50 values of 22 microg/ml and 57
      microg/ml respectively. Psoralea corylifolia, additionally tested against lung
      carcinoma (A549) cells gave an IC50 value of 68 microg/ml. Such data would
      justify a search for active compounds from this species.

PMID- 12622465
TI  - Antimicrobial activity of various extracts and carvacrol from Lippia multiflora
      leaf extract.
AB  - This study examines the antimicrobial activity of the hexane, dichloromethane and
      methanol extracts of Lippia multiflora and carvacrol isolated from the hexane
      extract. The result shows the hexane extract to be the most active, while the
      methanol extract exhibited no antimicrobial activity. The isolated carvacrol from
      the hexane fraction showed tremendous antimicrobial activity. These results
      confirm the traditional uses of Lippia multiflora in the treatment of disease
      conditions due to microbes.

PMID- 12622466
TI  - The effect of an extract of Salvadora persica (Meswak, chewing stick) on
      fertility of male and female mice.
AB  - This study investigated the toxic effects of an extract of Meswak from Salvadora
      persica for 30 days on the reproductive system of the mouse. The results showed
      that exposure to Meswak extract did not have much effect on female mouse
      fertility, although it caused a significant decrease in the relative weights of
      the ovary and an increase in uterine weights. Exposure of male mice to Meswak
      extract resulted in a 72% reduction in pregnancies in untreated females
      impregnated by test males. The relative weights of the testes and preputial
      glands were significantly increased and that of the seminal vesicles was
      significantly decreased in test males. The results indicate that Meswak has
      adverse effects on male and female reproductive system and fertility.

PMID- 12622467
TI  - Medicinal properties of Echinacea: a critical review.
AB  - Preparations from Echinacea purpurea are among the most widely used herbal
      medicines. Most uses of E. purpurea are based on the reported immunological
      properties. A series of experiments have demonstrated that E. purpurea extracts
      do indeed demonstrate significant immunomodulatory activities. Among the many
      pharmacological properties reported, macrophage activation has been demonstrated
      most convincingly. Phagocytotic indices and macrophage-derived cytokine
      concentrations have been shown to be Echinacea-responsive in a variety of assays.
      Activation of polymorphonuclear leukocytes and natural killer cells has also been
      reasonably demonstrated. Changes in the numbers and activities of T- and B-cell
      leukocytes have been reported, but are less certain. Despite this cellular
      evidence of immunostimulation, pathways leading to enhanced resistance to
      infectious disease have not been described adequately. Several dozen human
      experiments--including a number of blind randomized trials--have reported health
      benefits. The most robust data come from trials testing E. purpurea extracts in
      the treatment for acute upper respiratory infection. Although suggestive of
      modest benefit, these trials are limited both in size and in methodological
      quality. Hence, while there is a great deal of moderately good-quality scientific
      data regarding E. purpurea, effectiveness in treating illness or in enhancing
      human health has not yet been proven beyond a reasonable doubt.

PMID- 12622468
TI  - What is your diagnosis? Perirenal abscess and pyelonephritis.

PMID- 12622469
TI  - Use of computed tomography in the diseased feline thorax.
AB  - Computed tomography (CT) scanning of the thorax is gaining more attention in
      veterinary medicine as therapeutic possibilities increase. Plain and contrast
      enhanced CT images of the thorax of five referred cats with signs of respiratory
      disease were evaluated using soft tissue (pleural) and lung windows. The common
      CT pattern in all cats was involvement of the lung lobes, either as a homogeneous
      or heterogeneous single lobe hyperdensity. It involved the main bronchus, invaded
      the cranial or caudal mediastinum, and crossed the border to the opposite lung.
      Right lung atelectasis and mediastinal shift caused left lung overinflation.
      Bronchial lymph node enlargement was found unilaterally or bilaterally. CT-guided
      percutaneous fine needle aspiration biopsy of the lobar lung lesion was performed
      in four cats; in three cases it revealed carcinoma and in one inflammation,
      although the cat with suspected inflammation was subsequently found to have a
      carcinoma on lung lobectomy. Histopathology confirmed lung metastasis in one case
      and bronchial adenocarcinoma in four cases. A protocol for systematic examination
      of thoracic CT images is proposed.

PMID- 12622470
TI  - Assessment of acid-base status of cats with naturally occurring chronic renal
      failure.
AB  - Metabolic acidosis is reported to be a common complication of feline chronic
      renal failure (CRF) but acid-base status of feline patients with this disease is
      rarely assessed by general practitioners. A cross-sectional study involving 59
      cases of naturally occurring feline CRF was conducted to determine the prevalence
      of acid-base disturbances. Cases were categorised on the basis of their plasma
      creatinine concentrations as mild, moderate or severe. A group of 27 clinically
      healthy, age-matched cats was assessed for comparison. A low venous blood pH
      (<7.270) was found in 10 of the 19 severe cases (52.6 per cent), three of the 20
      moderate cases (15 per cent) and none of the 20 mild cases. Acidaemia was
      associated with an increased anion gap contributed to by both low plasma
      bicarbonate and low chloride ion concentrations. Biochemical analysis of urine
      samples showed urine pH to decrease with increasing severity of renal failure.
      Urinary loss of bicarbonate was not associated with the occurrence of acidaemia
      and there was a tendency for urinary ammonium ion excretion to decrease as the
      severity of renal failure increased. Cats with naturally occurring CRF do not
      show plasma biochemical evidence of acid-base disturbances until the disease is
      advanced.

PMID- 12622471
TI  - Evaluation of fipronil spot-on in the treatment of flea allergic dermatitis in
      dogs.
AB  - The purpose of this study was to evaluate the effectiveness of treatment with 10
      per cent fipronil solution for controlling signs of flea allergic dermatitis in
      dogs under field conditions. Thirty-one client-owned dogs with flea allergic
      dermatitis were treated with three monthly applications of 10 per cent fipronil
      solution. Flea counts and pruritus were significantly reduced at all post
      treatment visits. At the final visit, on day 90, flea counts were reduced by 98
      per cent, and pruritus was reduced or eliminated in 84 per cent of the study
      dogs. Dermatological lesion scores for erythema, crusts, scales and papules were
      also significantly improved by the final visit. The overall assessment of
      efficacy on day 90 was 'excellent' to 'good' for 87 per cent of the study dogs.
      The results demonstrate that treatment with monthly topical applications of 10
      per cent fipronil solution is effective in reducing the prevalence and severity
      of signs of flea allergic dermatitis in dogs.

PMID- 12622472
TI  - Fibrocartilaginous embolism in 75 dogs: clinical findings and factors influencing
      the recovery rate.
AB  - The records of 75 dogs with fibrocartilaginous embolism of the spinal cord were
      evaluated retrospectively. The diagnosis was confirmed histopathologically in 21
      dogs (group A) and remained suspected in 54 patients (group B). The two groups
      were compared. Particular emphasis was placed on the description of physiotherapy
      procedures, recovery rates and prognostic criteria. Results demonstrated that
      fibrocartilaginous embolism affected mainly middle-aged, large- or giant-breed
      dogs. Clinical signs were peracute in onset, non-progressive and often
      asymmetric. Cerebrospinal fluid analysis was normal in the majority of dogs.
      Intramedullary swelling was the only abnormality detected on myelograms of these
      patients. A positive correlation was found between a poor prognosis and the
      involvement of intumescences, symmetrical clinical signs and decreased deep pain
      sensation. However, physio/hydrotherapy instituted immediately after the
      diagnostic work-up seemed to have a major influence on the recovery rate.

PMID- 12622473
TI  - Mixed germ cell tumour of the spinal cord in a young dog.
AB  - A spinal cord mixed germ cell tumour was identified in a two-year-old, female
      Airedale terrier with a history of progressive paraplegia. At necropsy, a
      discrete pale pink spinal cord mass was identified at the L5 vertebra, which
      extensively invaded the associated spinal cord segments L6 and L7.
      Histologically, the tumour was located within the subarachnoid space and invaded
      the spinal cord. It was composed of three different types of cells: small round
      cells, forming clusters or islands, similar to germ cells identified in
      testicular germinomas; large cells with eosinophilic or amphophilic cytoplasm,
      forming trabeculae; and a third, rarer type of well differentiated epithelial
      cells, forming acinar or tubular structures. Immunohistochemical examination
      revealed reactivity to antibodies against alpha-fetoprotein and broad spectrum
      cytokeratins. The composition, cytological features and immunohistochemical
      staining of this neoplasm are similar to germ cell tumours previously reported in
      the suprasellar region and in the eye of dogs.

PMID- 12622475
TI  - BSAVA welcomes the Government's response to Marsh recommendations.

PMID- 12622474
TI  - Diagnosis and management of hepatic copper accumulation in a Skye terrier.
AB  - A one-year-old, neutered female Skye terrier presented with anorexia, vomiting,
      seizures and ascites. Portal venography demonstrated the presence of multiple
      acquired portosystemic shunts. Hepatic biopsy confirmed the presence of copper
      accumulation and fibrosis. Treatment included ursodeoxycholic acid therapy,
      colchicine and oral zinc. To the authors' knowledge, this is the first case
      report detailing successful management of Skye terrier hepatopathy.

PMID- 12622476
TI  - Electronic training devices: a behavioural perspective.

PMID- 12622477
TI  - Moving forward on liver pathology.

PMID- 12622478
TI  - Lumbar spinal stenosis: anatomy and pathogenesis.
AB  - This article reviews the history, classification, and pathoanatomy of lumbar
      spinal stenosis. An understanding of the pathoanatomy of lumbar spinal stenosis
      is essential for the clinician to treat the patient with clinically symptomatic
      lumbar spinal stenosis more effectively.

PMID- 12622479
TI  - Pathogenesis of lumbar spinal stenosis pain: why does an asymptomatic stenotic
      patient flare?
AB  - This article discusses the pathogenesis of lumbar spinal stenosis pain and
      presents a theory on why asymptomatic stenotic patients flare.

PMID- 12622481
TI  - Imaging of spinal stenosis.
AB  - Imaging has an important role in the diagnosis of canal and neuroforaminal
      stenosis when correlated with clinical symptoms. MR and CT myelography have the
      best correlation because of multiplanar reformatting. Special techniques to load
      the spine such as an upright MR increase sensitivity in detecting canal stenosis.

PMID- 12622480
TI  - Spinal stenosis: history and physical examination.
AB  - The history and physical examination are an essential component in the assessment
      of patients with lumbar spinal stenosis. The differential diagnosis is broad, and
      many conditions may be ruled out with a thorough office evaluation. Peripheral
      neuropathy, arteriovascular disease, and hip arthrosis are common entities with
      similar symptoms. Imaging studies provide poor specificity. Clinical decision
      making should be based on a collection of data, including the history and
      physical findings, functional status, imaging and electrodiagnostic studies, and
      other adjunctive studies.

PMID- 12622482
TI  - Electrodiagnostic challenges in the evaluation of lumbar spinal stenosis.
AB  - Taken together, the most common electromyographic finding in lumbar spinal
      stenosis is bilateral multilevel radiculopathy. The sensitivity of
      electrodiagnostic testing for radiculopathy is difficult to quantify because
      there is no criterion standard. Differentiating peripheral neuropathy and lumbar
      spinal stenosis on electromyography and routine nerve-conduction studies can be
      clinically challenging, especially when the two entities may be present
      simultaneously in older patients.

PMID- 12622483
TI  - Dermatomal somatosensory-evoked potentials in the evaluation of lumbosacral
      spinal stenosis.
AB  - DSEPs are very useful in determining which patients with degenerative lumbar
      spine disease have the added component of neurogenic compromise. Based on sound
      physiologic principles, level-by-level prolongation of DSEP latencies, reduction
      of amplitude, asymmetry, or a complete absence of response is associated with
      dysfunction in that particular neurologic pathway. This result does not
      necessarily correspond to the exact level of stenosis noted on MRI, because the
      rootlets in the lumbar and sacral regions pass through multiple spinal segments
      as they course through the spinal canal. Given that LSSS develops typically over
      time, it is not unlikely that the degree of abnormality will be variable between
      different levels. The pattern of abnormality will correspond to the physiologic
      slowing occurring in the multiple rootlets of the cauda equina. These recordings
      are not easy to perform and interpret; but, when done correctly, they provide the
      best evidence for the type of neurophysiologic dysfunction in LSSS that responds
      favorably to surgical decompression.

PMID- 12622484
TI  - Nonsurgical management of patients with lumbar spinal stenosis: a literature
      review and a case series of three patients managed with physical therapy.
AB  - This article critically reviews the available literature regarding nonsurgical
      management for lumbar spinal stenosis (LSS) and presents a case series of three
      patients managed with manual physical therapy. This case series uses a well
      defined, impairment-based, noninvasive, outpatient treatment program for patients
      with LSS and provides patient-centered, long-term outcome information. The
      outpatient treatment program focuses on patients' individualized, prioritized
      impairments identified on initial examination, and emphasizes manual physical
      therapy techniques targeting each patient's impairments, specific exercises to
      either reinforce the manual physical therapy treatment or strengthen specific
      muscles, and a walking program. The results demonstrate that patients with LSS
      can make significant gains in disability, symptoms, and function in relatively
      short periods of time and that these gains can be maintained for up to 18 months.
      Under this physical therapy program, patients experienced significant
      improvements, and the potential adverse effects of invasive therapies or
      pharmacologic management strategies, which often are included in other
      "nonsurgical" treatment programs, were avoided.

PMID- 12622485
TI  - Manual therapy for lumbar spinal stenosis: a comprehensive physical therapy
      approach.
AB  - A physical therapy approach to lumbar spinal stenosis involves techniques
      directed at opening up the neurovascular spaces in the lumbar spine to reduce the
      stenosis. This entails manual therapy techniques for improving intervertebral
      motion, regaining neural mobility, and restoring muscle function, followed by an
      active exercise program that often involves flexion exercises. Techniques for
      unloading the spine and patient education are included in this physical therapy
      approach. A successful functional outcome requires a comprehensive and
      individualized approach to the patient with spinal stenosis.

PMID- 12622486
TI  - Functional rehabilitation for degenerative lumbar spinal stenosis.
AB  - Nonoperative treatment for lumbar spinal stenosis must address anatomic and
      biomechanical factors. The entire functional kinetic chain and patient specific
      goals must be considered. In addition to passive modalities, manual therapy, and
      patient education, an active program consisting of flexion-based lumbar
      stabilization exercises, hip mobilization, proprioceptive training, and general
      conditioning should be initiated. More studies are needed to establish the
      benefit of a comprehensive, multifaceted treatment approach and to prove its
      clear benefit over the natural history of lumbar spinal stenosis.

PMID- 12622488
TI  - Surgical management of spinal stenosis.
AB  - Proper patient selection is the key to successful surgical management. The
      presence of the appropriate symptoms, signs and imaging findings--along with the
      individual psychologic and socioeconomic factors--play a significant role in the
      selection process. Patient education is important so that the patient's
      expectations from surgery are aligned with the surgeon's expectations. When the
      patient has been properly selected, and there has been adherence to the decision
      making principles, along with meticulous surgical technique, good outcomes can be
      expected with surgical management of patients with spinal stenosis.

PMID- 12622487
TI  - Lumbar epidural steroid injections in the patient with lumbar spinal stenosis.
AB  - Epidural steroid injections seem to be a useful component of a comprehensive and
      functionally oriented rehabilitation program for the patient with LSS. Review of
      the literature indicates the injections seem to be effective and are safe when
      performed with proper technique.

PMID- 12622489
TI  - Neural nets and prediction of the recovery rate from neuromuscular block.
AB  - BACKGROUND AND OBJECTIVE: The aim was to train artificial neural nets to predict
      the recovery of a neuromuscular block during general anaesthesia. It was assumed
      that the initial/early neuromuscular recovery data with the simultaneously
      measured physical variables as inputs into a well-trained back-propagation neural
      net would enable the net to predict a rough estimate of the remaining recovery
      time. METHODS: Spontaneous recovery from neuromuscular block (electrically evoked
      electromyographic train-of-four responses) were recorded with the following
      variables known to affect the block: multiple minimum alveolar concentration, end
      tidal CO2 concentration, and peripheral and central temperature. RESULTS: The
      mean prediction errors, mean absolute prediction errors, root-mean-squared
      prediction errors and correlation coefficients of all the nets were significantly
      better than those of average-based predictions used in the study. The root-mean
      squared prediction error of the net - employing minimum alveolar concentrations
      from the whole recovery period (the recovery time from E2/E1 = 0.30 to E4/E1 =
      0.75; E1 = first response of train-of-four, E2 = second response of train-of
      four, etc.)--were significantly smaller than those of other nets, or the same net
      employing minimum alveolar concentrations only from the initial recovery period
      (from E2/E1 = 0.30 to E4/E1 = 0.25). CONCLUSIONS: Neural nets could predict
      individual recovery times from the neuromuscular block significantly better than
      the average-based method used here, which was supposed to be more accurate than
      guesses by any clinician. The minimum alveolar concentration was the only
      monitored variable that influenced the recovery rate, but it did not aid neural
      net prediction.

PMID- 12622490
TI  - Effects of repeated anaesthesia on central cholinergic function in the rat
      cerebral cortex.
AB  - BACKGROUND AND OBJECTIVE: General anaesthesia may contribute to postoperative
      cognitive decline in the elderly. The aim was to determine the effects of
      repeated pentobarbital anaesthesia throughout life on central cholinergic
      function in the rat. METHODS: Young Lewis rats were randomly allocated to two
      groups. The anaesthesia group (n = 15) was anaesthetized with pentobarbital 20 mg
      kg(-1) intraperitoneally at 6, 8.5, 11, 13.5, 16, 18.5, 21 and 23.5 months of
      age. The control group (n = 12) was treated identically, apart from the
      anaesthesia. At 26 months of age, the animals were killed and the brain dissected
      and stored for analysis. Central cholinergic function in the cortex and
      hippocampus was assessed by measuring [3H]-epibatidine and [125I]alpha
      bungarotoxin binding to nicotinic receptors and choline acetyltransferase (ChAT)
      activity. RESULTS: Tissue from nine rats in the anaesthesia group and eight in
      the control group was available for analysis. There was a significant reduction
      in alpha-bungarotoxin binding in the anaesthetized compared with the control
      group in the superior cortex (P < 0.0002) and molecular cortex (P < 0.04). There
      were no significant differences between the groups for epibatidine binding or
      ChAT. CONCLUSIONS: Repeated anaesthesia in rat reduces central nicotinic
      cholinergic binding in the cortex. The findings may have implications for
      postoperative cognitive function studies.

PMID- 12622491
TI  - Effects of xenon on mesenteric blood flow.
AB  - BACKGROUND AND OBJECTIVE: The effects of xenon on mesenteric vascular resistance
      have not been investigated. Because human beings anaesthetized with xenon show
      good cardiovascular stability, we believed that the agent would have little or no
      effect on vascular resistance in the splanchnic bed. We determined the effects of
      different inhaled xenon concentrations on mesenteric blood flow and mesenteric
      oxygen consumption in pigs sedated with intravenous propofol. METHODS: Twenty
      three minipigs were instrumented with transit time flow probes around the
      pulmonary and superior mesenteric arteries as well as with pulmonary artery and
      portal venous catheters. A 14 h recovery was allowed followed by recordings of
      baseline values. Xenon was then randomly administered in 0.30, 0.50, and 0.70 end
      tidal fractions. RESULTS: The administration of xenon resulted in an 8% (not dose
      dependent) decrease in mean arterial pressure (from 99 +/- 15 to 91 +/- 19 mmHg;
      P < 0.05), a 20% decrease in calculated systemic oxygen consumption (from 0.23 +/
      0.07 to 0.19 +/- 0.04L min(-1); P < 0.01), a 20% reduction in mesenteric oxygen
      delivery (from 41 +/- 12 to 33 +/- 11 mL min; P < 0.001), a 37% reduction in
      mesentericmetabolic rate of oxygen (from 11.3 +/- 3.6 to 7.1 +/- 3.2 mL min(-1);
      P < 0.01) and an 8% decrease in mesenteric artery blood flow (0.22 +/- 0.07 to
      0.20 +/- 0.07 L min(-1); P < 0.05) in a dose-dependent fashion. Heart rate,
      cardiac output, systemic vascular resistance, mesenteric vascular resistance,
      mesenteric oxygen extraction fraction and portal lactate concentration were not
      significantly altered by xenon. CONCLUSIONS: Xenon inhalation in the propofol
      sedated pig had no measurable effects on mesenteric vascular resistance. This
      finding may partly explain the well-known cardiovascular stability observed in
      patients anaesthetized with xenon. Although mesenteric artery blood flow and
      mesenteric oxygen delivery decreased during xenon administration, unchanged
      mesenteric oxygen extraction fraction and portal lactate suggest that metabolic
      regulation of the splanchnic circulation remained unaltered.

PMID- 12622492
TI  - Effects of ropivacaine on human neutrophil function: comparison with bupivacaine
      and lidocaine.
AB  - BACKGROUND AND OBJECTIVE: Neutrophils are important both for the immunological
      defence system and for the inflammatory tissue autoinjury mechanism. However,
      many local anaesthetics impair certain neutrophil functions. The aim was to
      assess the effects of ropivacaine, bupivacaine and lidocaine on human neutrophils
      from adult volunteers. METHODS: Chemotaxis, phagocytosis, reactive oxygen species
      production, intracellular calcium ion ([Ca2+]i) concentrations and protein kinase
      C activity were measured in the absence and presence of ropivacaine, bupivacaine
      or lidocaine. The lowest concentrations of the local anaesthetics were similar to
      those clinically observed in the plasma. RESULTS: Bupivacaine did not affect any
      neutrophil function (P > 0.05). Ropivacaine failed to change chemotaxis or
      phagocytosis, while lidocaine suppressed both these neutrophil functions.
      Ropivacaine (15, 150 microg mL(-1)) and lidocaine (20, 200 microg mL(-1))
      impaired neutrophil production of O2-, H2O2 and OH- (P < 0.05) at similar rates
      (by 7-10%). These same concentrations of ropivacaine and lidocaine suppressed
      [Ca2+1i elevation. Finally, neither ropivacaine nor bupivacaine inhibited protein
      kinase C activity, while lidocaine did. CONCLUSIONS: Suppression of the [Ca2+]i
      response in neutrophils by ropivacaine may represent one of the mechanisms
      responsible for the impairment of neutrophil functions. It should be emphasized
      that the inhibitory effects of ropivacaine are minor and are attained only at
      high concentrations, which may minimize the clinical implication of ropivacaine
      associated impairment of reactive oxygen species production. Further studies
      using in vivo systems are required to identify the inhibitory effects of
      ropivacaine on reactive oxygen species production in clinical settings.

PMID- 12622493
TI  - Effect of sevoflurane on human neutrophil apoptosis.
AB  - BACKGROUND AND OBJECTIVE: Both chronic occupational exposure to volatile
      anaesthetic agents and acute in vitro exposure of neutrophils to isoflurane have
      been shown to inhibit the rate of apoptosis of human neutrophils. It is possible
      that inhibition of neutrophil apoptosis arises through delaying mitochondrial
      membrane potential collapse. We assessed mitochondrial depolarization and
      apoptosis in unexposed neutrophils and neutrophils exposed to sevoflurane in
      vivo. METHODS: A total of 20 mL venous blood was withdrawn pre- and postinduction
      of anaesthesia, the neutrophils isolated and maintained in culture. At 1, 12 and
      24 h in culture, the percentage of neutrophil apoptosis was assessed by dual
      staining with annexin V-FITC and propidium iodide. Mitochondrial depolarization
      was measured using the dual emission styryl dye JC-1. RESULTS: Apoptosis was
      significantly inhibited in neutrophils exposed to sevoflurane in vivo at 24
      (exposed: 38 (12)% versus control: 28 (11)%, P = 0.001), but not at 1 or 12 h, in
      culture. Mitochondrial depolarization was not delayed in neutrophils exposed to
      sevoflurane. CONCLUSIONS: The most important findings are that sevoflurane
      inhibits neutrophil apoptosis in vivo and that inhibition is not mediated
      primarily by an effect on mitochondrial depolarization.

PMID- 12622494
TI  - Sevoflurane but not isoflurane can reduce prostacyclin production of endothelial
      cells.
AB  - BACKGROUND AND OBJECTIVE: Little is known about the interaction of newer volatile
      anaesthetics with endothelial eicosanoid production. Sevoflurane may possibly
      reduce prostacyclin formation. Thus, we compared the influences of sevoflurane
      and isoflurane on endothelial prostacyclin production. METHODS: Production of
      prostacyclin of human umbilical vein endothelial cells was measured by the ELISA
      technique under basal conditions and after stimulation with calcium ionophore A
      23187 10 micromol or histamine 0.1 micromol in the absence and presence of 1 and
      2 minimal alveolar concentrations (MAC) of sevoflurane or isoflurane. RESULTS:
      The basal production of prostacyclin was unaffected by the volatile anaesthetics.
      Stimulation of endothelial cells increased prostacyclin formation 3-5-fold.
      Sevoflurane at 2 MAC, but not at 1 MAC, could reduce stimulated prostacyclin
      production by about half (P < 0.05). Isoflurane had no inhibitory effect.
      Inhibition of cyclo-oxygenase function by acetylsalicylic acid abolished the
      induced burst of prostacyclin formation completely. CONCLUSIONS: Sevoflurane, but
      not isoflurane, can reduce stimulated endothelial prostacyclin production in a
      concentration-dependent manner. Because at least 2 MAC of sevoflurane were
      required, this effect should be of minor importance under clinical conditions of
      balanced anaesthesia.

PMID- 12622495
TI  - Dopamine stabilizes milrinone-induced changes in heart rate and arterial pressure
      during anaesthesia with isoflurane.
AB  - BACKGROUND AND OBJECTIVE: Phosphodiesterase-III inhibitors and dobutamine
      effectively improve cardiac function in patients with cardiac failure, but they
      are limited by possible hypotensive effects. We tested the hypothesis that
      dopamine contributes to stabilizing milrinone-induced haemodynamic changes.
      METHODS: Nine patients undergoing major surgery were anaesthetized using nitrous
      oxide and oxygen supplemented with isoflurane 1-2%. After baseline haemodynamics
      were recorded, milrinone (25 or 50 microg kg(-1)) was administered over 10min,
      followed by a continuous infusion (0.5 microg kg(-1) min(-1). The second set of
      haemodynamic values was measured 50 min after beginning the continuous infusion
      of milrinone. Dopamine (4 microg kg(-1) min(-1)) was then administered with
      milrinone. RESULTS: Milrinone significantly increased the heart rate from 81 +/-
      8 to 102 +/- 16beats min(-1), but it decreased the mean arterial pressure from 83
      +/- 10 to 66 +/- 10 mmHg and systemic vascular resistance (P < 0.05 for each).
      The pulmonary capillary wedge pressure, cardiac index and pulmonary vascular
      resistance did not change significantly. The addition of dopamine to the
      milrinone infusion significantly decreased the heart rate (94 +/- 12 beats min(
      1)) and increased the mean arterial pressure (82 +/- 11 mmHg). Dopamine and
      milrinone, but not milrinone alone, significantly increased the cardiac index and
      the rate-pressure product. CONCLUSIONS: The combination regimen of milrinone and
      dopamine improved cardiac function, and changes in heart rate and mean arterial
      pressure induced by milrinone were attenuated by dopamine. The results suggest
      that a combination regimen of milrinone and dopamine rather than milrinone alone
      should be used to maintain arterial pressure.

PMID- 12622496
TI  - Adsorption of sufentanil to epidural filters and catheters.
AB  - BACKGROUND AND OBJECTIVE: Stable drug concentrations must be administered to
      provide adequate patient-controlled epidural analgesia. This study investigated
      the stability of sufentanil after the epidural delivery system had been flushed
      with solutions containing the drug. METHODS: Sufentanil citrate, 5 microg mL(-1)
      was injected through an epidural catheter system into a glass container. The
      concentrations of the drug leaving the system, in 1 mL aliquots (1-5 mL) were
      measured using high-performance liquid chromatography. In the same manner,
      sufentanil samples were analysed after flushing the filter, as well as after
      priming the filter and catheter. RESULTS: ANOVA for repeated measurements
      demonstrated that sufentanil concentrations remained constant as long as the
      catheter had been adequately flushed. However, the concentration of sufentanil in
      the solution exiting the filter was reduced significantly. Hardly any sufentanil
      could be detected (0.09 +/- 0.01 microg mL(-1), P < 0.001) in the first 1 mL
      aliquot (probe) leaving the filter. Altogether, 3 mL sufentanil solution was
      needed to pass through the filter before the baseline values were restored (P >
      0.05). The greatest decrease occurred when the whole epidural delivery apparatus
      (catheter and filter) was primed; to regain baseline values, as much as 4 mL
      solution was needed to flush the system. CONCLUSIONS: Sufentanil citrate is
      adsorbed by the materials used to manufacture systems (catheters, filters) used
      in epidural anaesthesia. Hence, the epidural catheter system should be primed
      with sufentanil before connecting it to the patient so as to deliver reliable
      concentrations.

PMID- 12622497
TI  - Opioid-induced respiratory depression is associated with increased tidal volume
      variability.
AB  - BACKGROUND AND OBJECTIVE: mu-agonistic opioids cause concentration-dependent
      hypoventilation and increased irregularity of breathing. The aim was to quantify
      opioid-induced irregularity of breathing and to investigate its time-course
      during and after an opioid infusion, and its ability to predict the severity of
      respiratory depression. METHODS: Twenty-three patients breathing spontaneously
      via a continuous positive airway pressure (CPAP) mask received an intravenous
      (i.v.) infusion of alfentanil (2.3 microg kg(-1) min(-1), 14 patients) or
      pirinitramide (piritramide) (17.9 microg kg(-1) min(-1), nine patients) until
      either a cumulative dose of 70 microg kg(-1) for alfentanil or 500 microg kg(-1)
      for pirinitramide had been achieved or the infusion had to be stopped for safety
      reasons. Tidal volumes (VT) and minute ventilation were measured with an
      anaesthesia workstation. For every 20 breaths, the quartile coefficient was
      calculated (Qeff20V(T)). RESULTS: Both the decrease of minute volume and the
      increase of Qeff20V(T) during and after opioid infusion were highly significant
      (P < 0.001, ANOVA). Patients in which the alfentanil infusion had to be
      terminated prematurely had lower minute volumes (P = 0.002, t-test) and higher
      Qeff20V(T) (P = 0.034, t-test) than those who received the complete dose. Changes
      in the regularity of breathing measured as Qeff20V(T) parallel those of minute
      ventilation during and after opioid infusion. CONCLUSIONS: Opioids cause a more
      complicated disturbance of the control of respiration than a mere resetting to
      higher PCO2. Furthermore, Qeff20V(T) appears to predict the severity of opioid
      induced respiratory depression.

PMID- 12622498
TI  - Induced arterial hypotension for interventional thoracic aortic stent-graft
      placement: impact on intracranial haemodynamics and cognitive function.
AB  - BACKGROUND AND OBJECTIVE: The study investigated the impact of induced arterial
      hypotension for the facilitation of endovascular stent-graft placement in
      patients with thoracic aortic aneurysm on cerebral blood flow velocity and
      neurological/neurocognitive outcome. METHODS: In 27 ASA III patients, cerebral
      blood flow velocity was recorded during induced arterial hypotension for
      endovascular stent-graft placement using transcranial Doppler sonography and the
      Folstein Mini Mental State Examination and the National Institute of Health
      Stroke Scale were performed before and after the intervention. RESULTS: Mean
      arterial pressure was decreased <50 mmHg, and in 22 patients it was <40 mmHg.
      Diastolic cerebral blood flow velocity decreased by 59%. Postoperatively, six of
      21 patients exhibited changes in the Folstein Mini Mental State Examination and
      four of these six patients in the National Institute of Health Stroke Scale as
      indices of new-found neurocognitive dysfunction, but there were no signs of
      stroke. Loss of the diastolic blood flow profile was detected in two of six
      patients with new-found neurocognitive dysfunctions and in 18 of 21 patients with
      no new-found neurocognitive dysfunction. Changes in the Folstein Mini Mental
      State Examination on postoperative day 1 were correlated to the pre-procedural
      Folstein Mini Mental State Examination, but not to the time spent with a mean
      arterial pressure <50 mmHg, <40 mmHg or with a loss of diastolic blood flow
      profile. CONCLUSIONS: Transcranial Doppler sonography visualizes the individual
      effect of induced hypotension and the period of intracranial circulatory arrest
      during aortic stent-graft placement. However, transient new-found neurocognitive
      dysfunctions occur independently of the transcranial Doppler data, and are in
      close correlation to the neurocognitive state before the procedure. The results
      suggest that induced arterial hypotension is not the major factor for
      postoperative new-found neurocognitive dysfunction.

PMID- 12622499
TI  - Intravenous patient-controlled analgesia after thoracotomy: a comparison of
      morphine with tramadol.
AB  - BACKGROUND AND OBJECTIVE: This study examined the quality of analgesia together
      with the side-effects produced by tramadol compared with morphine using
      intravenous patient-controlled analgesia during the first 24 h after thoracotomy.
      METHODS: Forty-four patients scheduled for thoracotomy were included in the
      study. Morphine 0.3 mg kg(-1) was given interpleurally 20 min before a standard
      general anaesthetic. In the postanaesthetic care unit, the patients were randomly
      allocated to one of two groups to self-administer tramadol or morphine using a
      patient-controlled analgesia device throughout a 24 h period. The patient
      controlled analgesia device was programmed to deliver tramadol 20 mg as an
      intravenous bolus or morphine 2 mg with a lockout time of 10 min. RESULTS: Mean
      cumulative morphine and tramadol consumption were 48.13 +/- 30.23 and 493.5 +/-
      191.5 mg, respectively. There was no difference in the quality of analgesia
      between groups. Five (26.3%) patients in the tramadol group and seven (33%) in
      the morphine group had nausea, and three of the latter patients vomited. The
      incidence rate of vomiting with tramadol was 5.2%. All vital signs were within
      safe ranges. Sedation was less in the tramadol group, but not statistically
      significant. CONCLUSIONS: In this clinical setting, which includes interpleural
      morphine pre-emptively, postoperative analgesia provided by tramadol was similar
      to that of morphine at rest and during deep inspiration. Side-effects were slight
      and comparable between the patients receiving morphine and tramadol.

PMID- 12622500
TI  - Gastric mucosal-to-end-tidal PCO2 difference during major abdominal surgery:
      influence of the arterial-to-end-tidal PCO2 difference?
AB  - BACKGROUND AND OBJECTIVE: Because gastric mucosal PCO2 must be referenced to
      arterial values via a gastric-to-arterial PCO2 gap (Pg-aCO2), the gastric-to-end
      tidal PCO2 difference (Pg-ETCO2) may be proposed as a surrogate method to monitor
      Pg-aCO2. However, the influence of arterial-to-end-tidal PCO2 (Pa-ETCO2) on its
      value remains unknown. Pa-ETCO2 may be enhanced by a low cardiac output and
      subsequent reduced perfusion of the lungs. This study was designed to compare
      such gaps observed during abdominal surgery in patients with or without
      preoperative cardiac dysfunction. METHODS: Haemodynamic, metabolic and tonometric
      variables were measured in seven patients with Crohn's disease and in five
      patients with chronic heart failure scheduled for abdominal surgery. Data were
      collected before skin incision (T0); at extractor placement (T1), 30 (T2) and 60
      (T3) min later; at organ extraction (T4), 30 (T5) and 60 (T6) min later, and at
      the end of surgery (T7). RESULTS: Gradients appeared larger in the cardiac group.
      The difference was significant for Pg-ETCO2 during the whole study period, while
      it was only reached at T1-T2 for Pa-ETCO2 and at T5-T6 for Pg-aCO2. Gaps did not
      change significantly over the peroperative time points in either group. No major
      haemodynamic variations were registered in either group. CONCLUSIONS: In patients
      with preoperative chronic heart failure, Pg-ETCO2 remained constant throughout a
      major general surgical procedure and was only moderately influenced by the Pa
      ETCO2 gap. In these patients, Pg-ETCO2 may be used as a reliable index of
      gastrointestinal perfusion after control of PaCO2.

PMID- 12622501
TI  - Ondansetron disintegrating tablets of 8 mg twice a day for 3 days did not reduce
      the incidence of nausea or vomiting after laparoscopic surgery.
AB  - BACKGROUND AND OBJECTIVE: Although many antiemetic drugs are available for
      intravenous use in the hospital setting, few are available after patient
      discharge. Consequently, nausea and vomiting are frequent complaints from
      patients at home after ambulatory surgery. We tested the hypothesis that the new
      8 mg ondansetron disintegrating tablets will decrease the rate of nausea and
      vomiting at home after laparoscopic surgery. METHODS: Ninety-six patients were
      studied in a randomized double-blind study. Starting the first evening after
      operation and continuing every 12 h for 3 days, patients received either placebo
      or ondansetron 8 mg disintegrating tablets orally. The patients returned a
      questionnaire about postoperative nausea and vomiting, other side-effects, e.g.
      dizziness, headache, nightmare, anxiety and pain, as well as their overall
      satisfaction at 24 and 72 h after completion of surgery. RESULTS: The rates of
      nausea and vomiting were similar in the two groups, both during the first 24 h
      (28 versus 48%, placebo and ondansetron, respectively (ns) and during the 24-72 h
      (21 versus 35% (ns)). The incidence rate of vomiting was 8% (placebo) versus 12%
      (ondansetron) during the first 24 h (ns) and 9 versus 13% respectively in the 24
      72 h (ns). No difference between groups was observed in overall satisfaction,
      incidence of postoperative pain or other side-effects. CONCLUSIONS: The use of
      ondansetron disintegrating tablets of 8 mg twice a day for 3 days did not reduce
      the incidence of nausea and vomiting in patients undergoing outpatient
      laparoscopic surgery.

PMID- 12622502
TI  - Nitrous oxide/oxygen mixture and the prevention of pain during injection of
      propofol.
AB  - BACKGROUND AND OBJECTIVE: The incidence of pain associated with the injection of
      propofol still remains a problem. This study sought to examine the analgesic
      effects of inhaled nitrous oxide in oxygen on the prevention of propofol
      injection pain. METHODS: Nitrous oxide in oxygen was compared with a lidocaine
      (20 mg)-propofol mixture and with propofol alone (control) in a prospective,
      randomized, observer-blinded study. ASA I and II patients (n = 135) scheduled for
      elective surgical procedures were studied. A standard propofol injection
      technique and scoring system to measure the pain on injection was used. RESULTS:
      Demographic variables were similar between the study groups. Without analgesia
      (control) 26 of 45 patients (58%) reported pain on injection compared with 11 of
      45 patients (24%) in both the nitrous oxide (95% CI: 14-52%, P = 0.001) and
      lidocaine groups (95% CI: 14-52%, P = 0.001). CONCLUSIONS: The inhalation of a
      nitrous oxide/oxygen mixture significantly reduces the incidence of pain during
      propofol injection. This therapeutic stratagem was as effective as a lidocaine
      propofol mixture.

PMID- 12622503
TI  - Subcutaneous emphysema at the site of central line placement due to the
      haematogenous spread of Clostridium septicum.

PMID- 12622504
TI  - Efficacy of epidural analgesia during labour and delivery: a comparison between
      singleton vertex presentation, singleton breech presentation and twin
      pregnancies.

PMID- 12622505
TI  - Survey of antibiotic prophylaxis in cardiac surgery.

PMID- 12622506
TI  - Fentanyl-mediated reduction in the bispectral index and 95% spectral edge
      frequency is age-dependent.

PMID- 12622507
TI  - Anaphylaxis after rocuronium.

PMID- 12622508
TI  - Alternative application site of transdermal nitroglycerin and the reduction of
      pain on propofol injection.

PMID- 12622509
TI  - Fractionated stereotactic radiotherapy: a short review.
AB  - Currently, optimally precise delivery of intracranial radiotherapy is possible
      with stereotactic radiosurgery and fractionated stereotactic radiotherapy. We
      present in this article a review of the underlying basic physical and
      radiobiological principles of fractionated stereotactic radiotherapy and review
      the clinical experience for ateriovenus malformations, pituitary adenomas,
      mengiomas, vestibular schwanomas, low grade astrocytomas, malignant gliomas, and
      brain metastases.

PMID- 12622510
TI  - Image guided stereotactic radiosurgery for lesions in proximity to the anterior
      visual pathways: a preliminary report.
AB  - The incidence of optic neuropathy after stereotactic radiosurgery (SRS) is
      related to the total dose, fraction size, and treatment volume. Theoretically,
      fractionated SRS can decrease this risk. In this paper, we report our technique
      for fractionated SRS and assess its potential role in the management of tumors
      located adjacent to the anterior visual pathways. Since 1997, thirteen patients
      (median age: 50, range 21-76) with lesions in close proximity to the anterior
      visual pathways were treated on the CyberKnife image guided SRS system (Accuray,
      Inc., Sunnyvale, CA). The CyberKnife is a 6MV linear accelerator mounted on a
      robotic arm which can monitor and adjust to changes in the target position in
      real time thus eliminating skeletal frame immobilization and allowing for
      convenient multi-fraction SRS treatments. Magnetic Resonance Imaging (MRI) and
      computerized tomography (CT) imaging for treatment planning were obtained with
      the patients head immobilized in an aquaplast mask. After image fusion, the
      target and critical structures were delineated. Two to five fractions were
      prescribed with approximately a 24-hour interfraction interval. The patients
      received 25 Gy in 5 fractions (n=5), 21 Gy in 3 fractions (n=5), or 20 Gy in 2
      fractions (n=3) to the 75-95% isodose line. Ten of the thirteen patients had good
      pretreatment vision. In nearly all instances, the volume of the optic nerve that
      received 80% of the prescribed dose was < 0.05 cm3. In all instances, the volume
      of the optic nerve that received 50% of the prescribed dose was </= 0.5 cm3. Only
      one patient received more than a 5 Gy daily dose to > 0.03 cm3 of optic nerve.
      With median follow up of 18 months (range 12 to 54), four patients have had
      improvement in their vision. No visual deterioration has been observed in any of
      the other patients. In addition, there has been no tumor progression within the
      treated field. Fractionated SRS using the CyberKnife is technically feasible and
      may decrease the risk of optic neuropathy. Greater patient accrual and longer
      follow up will be necessary to further determine the clinical benefit of this
      approach.

PMID- 12622511
TI  - Enhanced anatomic visualization with ultrasound-assisted intracranial image
      guidance in neurosurgery.
AB  - Anatomical comparisons between ultrasound images and magnetic resonance imaging
      (MRI)/computed tomography (CT) preoperative images were performed in four
      ultrasound-assisted image-guided intracranial surgeries. An ultrasound scanner
      connected to a surgical navigation system allowed the neurosurgeon to acquire
      useful views from that integration, offering an improved method for
      visualization. This surgical navigation device and associated ultrasound provides
      real-time brain shift correction. The accuracy of navigation depends on the
      identification of the anatomic structures. Despite some limitations of the
      ultrasound images, the ability to compare preoperative MRI and intraoperative
      ultrasound proved useful to the surgeon.

PMID- 12622512
TI  - Molecular and functional imaging technology for the development of efficient
      treatment strategies for gliomas.
AB  - Gliomas are the most common types of brain tumors, which invariably lead to death
      over months or years. Before new and potentially more effective treatment
      strategies, such as gene therapy, can be effectively introduced into clinical
      application the following goals must be reached: (1) the determination of
      localization, extent and metabolic activity of the glioma; (2) the assessment of
      functional changes within the surrounding brain tissue; (3) the identification of
      genetic changes on the molecular level leading to disease; and in addition (4) a
      detailed non-invasive analysis of both endogenous and exogenous gene expression
      in animal models and in the clinical setting. Non-invasive imaging of endogenous
      gene expression by means of positron emission tomography (PET) may reveal insight
      into the molecular basis of pathogenesis and metabolic activity of the glioma and
      the extent of treatment response. When exogenous genes are introduced to serve
      for a therapeutic function, PET imaging techniques may reveal the assessment of
      the location, magnitude and duration of therapeutic gene expression and its
      relation to the therapeutic effect. Here, we review the main principles of PET
      imaging and its key roles in neurooncology research.

PMID- 12622513
TI  - Effect of electrically mediated intratumor and intramuscular delivery of a
      plasmid encoding IFN alpha on visible B16 mouse melanomas.
AB  - Interferon alpha may be used as a single agent therapy for metastatic malignant
      melanoma or as an adjuvant to chemotherapy. Delivery of interferon alpha by gene
      therapy offers an alternative to recombinant protein therapy. Electrically
      mediated delivery enhances plasmid expression in a number of tissues, for
      instance skin, liver, muscle and tumors including melanomas. Here we compare the
      effect of delivery of a plasmid encoding mouse interferon alpha on growth of
      visible B16 mouse melanomas following electrically mediated delivery to muscle or
      directly to the tumor. Intratumoral delivery of interferon alpha plasmid not only
      slows melanoma growth, but induces complete, long term, regression. This effect
      was not observed after intramuscular delivery.

PMID- 12622514
TI  - Computer-aided diagnosis of breast cancer in mammography: evidence and potential.
AB  - Computer-aided diagnosis (CAD) methods are being developed to help radiologists
      improve the interpretation of mammograms for the detection of breast cancer. We
      review several laboratory observer performance studies of computer-aided
      diagnosis of malignant and benign breast lesions. These studies show that CAD can
      improve radiologist diagnostic performance by increasing the number of their
      biopsy recommendations for actual malignant lesions while reducing the number of
      their biopsy recommendations for suspicious but actually benign lesions, and by
      reducing the variability in their interpretation of mammograms. These results
      indicate a potential clinical role of CAD in mammography for the detection of
      breast cancer.

PMID- 12622516
TI  - Very high energy electrons (50-250 MeV) and radiation therapy.
AB  - High energy electron beams in the range 150-250 MeV are investigated to evaluate
      their feasibility for radiotherapy. Monte Carlo simulation results from PENELOPE
      code are used to determine lateral spread and penetration of these beams. It is
      shown that dose distribution of electron beams compare favorably with photon
      beams. Electromagnetic control of electron beams enables scanned intensity
      modulation not possible with photon beams.

PMID- 12622515
TI  - The potential role of Fourier transform infrared spectroscopy and imaging in
      cancer diagnosis incorporating complex mathematical methods.
AB  - Infrared spectroscopy and imaging technology can provide new diagnostic
      capabilities for cancer research applications and to physicians directly involved
      in patient treatment. A methodology that permits the phenotypical description of
      cells and tissues is introduced, as well as a variety of new evaluation
      techniques that allow researchers and physicians to evaluate the infrared data at
      different levels of sophistication. The detection of cell alterations in the case
      of Chronic Lymphocytic Leukemia (CLL) demonstrates the capability of infrared
      spectroscopy to identify and stage this type of cancer, providing new prospects
      for diagnosis and treatment. The pathological study of oral tissue affected by
      Squamous Cell Carcinoma (SCC) illustrates the potential of Infrared Spectroscopy
      and Imaging for tissue diagnosis and cancer staging based in altered cell
      biochemistry, without using stains or any other marker technology. An example of
      combined fluid, cell and tissue analysis of thyroid cancers based on infrared
      technology is introduced to demonstrate the possibility of earlier detection of
      gland abnormalities and biochemical alterations in cell extracts using fine
      needle aspirates. Simple statistical techniques such as bivariate histogram
      analysis can distinguish between normal and altered cells and tissues when
      applied to infrared spectra and images. More complex mathematical techniques such
      as Principal Component Analysis (PCA) or Artificial Neural Networks (ANN) provide
      additional evaluation capabilities that can relate spectra of an unknown sample
      to an infrared reference database of known cell states. It is documented how this
      new infrared technology could enhance the diagnoses, treatment decisions and
      prognoses of patients in the field of cancer medicine.

PMID- 12622517
TI  - X-ray optics for better diagnostic imaging.
AB  - Polycapillary x-ray optics provide an innovative new way to control x-ray beams.
      Placing these optics after the object to be imaged provides very efficient
      rejection of Compton scatter, while allowing image magnification without loss of
      resolution, image demagnification, or image shaping to match with digital
      detectors. Measured scatter rejection optics had primary transmissions greater
      than 50% and scatter transmission of less than 1%. For a 5-cm thick Lucite
      phantom, this resulted in a contrast enhancement of nearly a factor of two at 20
      keV and three at 40 keV. The magnification from the tapered capillary optics
      improved the MTF at all frequencies out to 1.8 times the original system
      resolution. Increases below the system resolution are most important because
      clinically relevant structures generally occupy lower spatial frequencies.
      Alternatively, placing a collimating optic and diffracting crystal before the
      patient provides sufficient monochromatic beam intensity for medical imaging.
      Contrast, resolution, and intensity measurements were performed with both high
      and low angular acceptance crystals. At 8 keV, contrast enhancement was a factor
      of 5 relative to the polychromatic case, in good agreement with theoretical
      values. At 17.5 keV, monochromatic subject contrast was more than a factor of 2
      times greater than the conventional polychromatic contrast. An additional factor
      of two increase in contrast, for a total factor of four, is expected from the
      removal of scatter in a large beam clinical system. The measured angular
      resolution after the crystal was 0.4 mrad for a silicon crystal.

PMID- 12622518
TI  - Historical technical developments in mammography.
AB  - In mammography it is most important to consistently produce high-contrast, high
      resolution images at the lowest radiation dose consistently with high image
      quality. Today it is possible to obtain mammograms with higher image quality that
      require significantly lower radiation dose compared to mammograms dating back to
      the 1970's and early 1980's. Some of the technical developments due to x-ray
      equipment and image receptors and quality control programs that have let to
      todays high quality mammographic images are discussed in this article.

PMID- 12622519
TI  - Breast cancer screening: potential role of computer-aided detection (CAD).
AB  - Four separate studies conducted as blinded retrospective radiologist reviews of
      screening mammograms where cancer subsequently developed found lesions requiring
      work-up or biopsy in 25% to 41% of cases. Three non-blinded retrospective reviews
      by radiologists identified 57% to 75% of cancers. Among breast cancers detected
      by radiologists on blinded retrospective review in one study, computer aided
      detection (CAD) would have found 77%. These studies suggest that improved cancer
      detection rates could result if radiologists who interpret screening mammography
      were aided by computers. One prospective study initiated on that premise found
      that CAD increased the screening detection rate by 19.5%. At the current state-of
      the-art, CAD performs best for cancers presenting as calcifications, less well
      for cancers appearing as spiculated masses, and least well for cancers appearing
      as circumscribed masses. CAD does not seem to increase false positive call back
      rates for additional imaging work-up or to increase false positive biopsy rates.

PMID- 12622520
TI  - A phase II study of concomitant hyperfractionated radiation therapy and double
      dose intra-arterial cisplatin for squamous cell carcinoma of the head and neck.
AB  - This successor phase II study evaluates the tolerability and efficacy of
      concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra
      arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma
      of the head and neck (SCCHN). In doing so, this study represents further
      resurgence of the potential use of IA chemotherapy in the management of SCCHN.
      This has been enabled by the evolution of angiographic catheter/microcatherter
      technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN
      were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high
      dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment
      [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%)
      N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3
      (79%) mucosal events; and single grade 3 hematologic, infectious and skin events.
      Eight patients (33%) were unable to receive the second planned dose of IA
      cisplatin. Twenty-two patients had complete response (92%) at the primary site.
      Among 17 patients with positive neck disease 12 (71%) achieved complete response
      in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14
      patients alive without disease, 2 alive with disease, 7 dead of disease and 1
      dead of intercurrent disease. While concomitant HFX-RT and double dose IA
      cisplatin as used in this study is associated with encouraging response rates in
      this highly unfavorable subset of patients with locally advanced SCCHN it was not
      feasible. Future investigation of this novel treatment strategy utilizing modern
      angiographic catheter/microcatherter technology will involve a single dose of IA
      cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.

PMID- 12622521
TI  - The impact of TNF-alpha induction on therapeutic efficacy following high dose
      spatially fractionated (GRID) radiation.
AB  - A variety of cytokines especially TNF-alpha and TGF-beta are known to be released
      in response to high dose radiation of tumors. However, these are not normally
      measurable in systemic circulation unless high levels of these cytokines are
      produced by tumor cells. This study was undertaken to see if circulating levels
      of these cytokines could be measured in the serum of patients treated with high
      dose spatially fractionated (GRID) radiation and to correlate the finding of
      these cytokines with clinical response to treatment. Thirty-four patients (31
      patients had single treatment site and 3 patients had 2 treatment sites) treated
      with spatially fractionated (GRID) radiation were entered in this study. Serum
      samples were collected before treatment and at 24, 48 and 72 hours after GRID
      radiation. Sandwich enzyme linked immunosorbent assay (ELISA) was performed to
      estimate the levels of TNF-alpha and activated TGF-beta1 proteins. Seven of 37
      patients studied had no TNF-alpha protein before treatment but showed induction
      of TNF-alpha after GRID radiation. Three patients showed faint basal level of TNF
      alpha protein before treatment and these levels were induced after treatment.
      Three patients showed a basal level of TNF-alpha protein before treatment and
      these levels decreased after treatment. In 21 cases no TNF-alpha protein was
      detected before or after treatment at the time points measured. In the case of
      TGF-beta1 protein, 2 patients showed no TGF-beta1 protein before GRID radiation
      and an induction of TGF-beta1 protein was observed after treatment. Seven
      patients showed basal level of TGF-beta1 protein prior to treatment and these
      levels were induced after treatment. Seventeen patients showed a basal level of
      TGF-beta1 protein before treatment and these levels decreased after treatment. In
      8 cases no TGF-beta1 protein was detected before or after treatment. Complete
      clinical response (CR) to GRID therapy was seen in 12/37 (32%) treatment sites
      and partial response (PR) in 18/37 (49%) treatment sites. A strong correlation
      was observed between clinical CR rate and TNF-alpha induction. The rate of CR was
      6/10 (60%) in patients where TNF-alpha was induced as compared to 6/27 (23%)
      treatment sites in patients where TNF-alpha induction was not seen (p = 0.029).
      No significant correlation with CR rate and TGF-beta1 induction (44% vs. 28%, p =
      0.36) was observed. High dose spatially fractionated (GRID) radiation results in
      significant induction of TNF-alpha that can be measured in serum of some patients
      24 72 hours after radiation. Complete tumor response strongly correlated with the
      induction of TNF-alpha levels in the serum.

PMID- 12622522
TI  - Plasmid DNA electrotransfer: a new non viral method for gene therapy in oncology.
AB  - With some defined conditions, electric pulses delivery to tissue in vivo can
      greatly enhance DNA transfection. We here describe the application in oncology of
      intratumoral or intramuscular DNA electrotransfer by using muscle as a secretory
      tissue of transgenic proteins displaying anticancer properties.

PMID- 12622523
TI  - Research brief: some data concerning the reporting of participants' gender in the
      mental retardation literature.
AB  - The gender of participants in articles published from 1991 through 2000 in eight
      journals relevant to mental retardation was determined. Overall, participants
      were used in 65% of the articles; gender was not reported in 26% of them. When
      gender was reported, 6%, 8%, and 60% of the investigators used females only,
      males only, and both sexes, respectively. Unless gender is reported, one cannot
      ascertain to whom results should generalize or whether gender affects the
      variable under investigation. For these and other reasons, we recommend that
      researchers routinely specify how many of their participants are males and how
      many are females. This information requires little space and in most cases is
      easy to obtain.

PMID- 12622524
TI  - Health care decision-making by adults with mental retardation.
AB  - Abilities of adults with mild, moderate, or no mental retardation to understand
      hypothetical treatments was investigated using the Assessment of Consent Capacity
      Treatment developed for this study based on Appelbaum and Roth's psycholegal
      consent standards. Performance in all groups decreased with increasing
      psycholegal complexity of consent decision-making. Most adults with mild and no
      mental retardation and almost half of adults with moderate mental retardation
      were able to make and justify treatment choices and fully or partially understand
      treatment information. Most adults without mental retardation, 50% with mild, and
      18% with moderate mental retardation were able to partially appreciate relevance
      of treatment choice to patient's situation and weigh treatment risks against
      benefit. Implications of findings for patient rights are discussed.

PMID- 12622525
TI  - Psychometric properties of the Beck Depression Inventory and the Zung Self Rating
      Depression Scale in adults with mental retardation.
AB  - The psychometric properties of the Beck Depression Inventory and the Zung Self
      Rating Depression Scale were examined. Both tests were administered to 120 adults
      with mental retardation. Results were analyzed, correlated, and examined with
      principle component analysis. Findings suggest that the tests have good clinical
      utility with these persons and that depression may be more severe in people with
      mental retardation. Characteristics that can be employed in building other
      behavioral measures of depression for persons with mental retardation were also
      identified. Results show that there may be a tendency for persons with mental
      retardation to minimize distress report, further complicating the depression
      diagnostic process for these persons.

PMID- 12622526
TI  - Best and worst ways to motivate staff in community agencies: a brief survey of
      supervisors.
AB  - Supervisors in community agencies were surveyed regarding the best and worst ways
      to motivate staff to work diligently and enjoy work. Most respondents (88%)
      reported that it was very or extremely important for supervisors to motivate
      their staff, although only 53% reported that supervisors performed well in this
      regard. Concerning the best way to motivate staff, the most common response
      category was interacting positively and providing positive feedback for work
      performance. Regarding the worst way to motivate, the most common response
      category was interacting negatively with staff and providing negative feedback.
      Results are discussed in terms of emphasizing positive interaction styles and
      feedback by supervisors to help ensure that community support staff experience a
      motivating work environment.

PMID- 12622527
TI  - Cost comparisons of community and institutional residential settings: historical
      review of selected research.
AB  - A review of the literature on cost comparisons between community settings and
      institutions for persons with mental retardation and developmental disabilities
      was conducted. We selected literature for review that was published in peer
      reviewed journals and had either been cited in the area of cost comparisons or
      provided a novel approach to the area. Methodological problems were identified in
      most studies reviewed, although recent research employing multivariate methods
      promises to bring clarity to this research area. Findings do not support the
      unqualified position that community settings are less expensive than are
      institutions and suggest that staffing issues play a major role in any cost
      differences that are identified. Implications are discussed in light of the
      findings.

PMID- 12622528
TI  - Let's focus on the real issues.

PMID- 12622529
TI  - Preserving oral histories: example of the institutional experience.

PMID- 12622530
TI  - Parents who moved against the tide.

PMID- 12622531
TI  - The editor's perspective on institutional and community costs.

PMID- 12622534
TI  - Wages of non-state direct-support professionals lag far behind those of public
      direct-support professionals and the general workforce.

PMID- 12622535
TI  - Prevention of meningitis: cochlear implants and inner ear abnormalities.

PMID- 12622536
TI  - Genomewide linkage analysis to presbycusis in the Framingham Heart Study.
AB  - OBJECTIVE: To identify chromosomal regions that show evidence of linkage to age
      associated hearing impairment (presbycusis) in humans. DESIGN: We evaluated the
      genetic linkage between quantitative measures from audiometric examinations and
      markers from a genomewide scan in a population-based sample ascertained without
      respect to hearing status. PARTICIPANTS: Audiometric examinations were conducted
      on 2263 original cohort members and 2217 offspring cohort members of the National
      Heart, Lung, and Blood Institute's Framingham Heart Study. Of these, 1789
      individuals were members of 328 extended pedigrees used for linkage analysis. The
      outcome traits for linkage analysis were pure-tone average at medium (0.5, 1.0,
      and 2.0 kHz) and low (0.25, 0.5, and 1.0 kHz) frequencies adjusted for cohort,
      sex, age, age squared, and age cubed. RESULTS: We found heritability (proportion
      of variance due to genes) of age-adjusted pure-tone average at medium and low
      frequencies to be 0.38 and 0.31, respectively. Genomewide linkage analysis
      identified several locations with suggestive evidence of linkage. Of particular
      interest are the regions 11p (maximum multipoint logarithm of odds [MLOD], 1.57),
      11q13.5 (MLOD, 2.10), and 14q (MLOD, 1.55), which overlap with genes known to
      cause congenital deafness. CONCLUSIONS: There is evidence that genetic and
      environmental factors contribute to hearing loss in the mature human population.
      Several of the chromosomal locations identified overlap with loci known to cause
      congenital hearing loss. Further studies are needed to determine whether the same
      genes cause presbycusis and congenital hearing loss.

PMID- 12622537
TI  - Incidence of and risk factors for additional tympanostomy tube insertion in
      children.
AB  - OBJECTIVE: To determine the incidence and risk factors that account for
      additional tympanostomy tube placement among children who have undergone an
      initial placement of ventilation tubes. DESIGN: Retrospective case review of
      consecutive patients. SETTING: A tertiary care pediatric hospital. PATIENTS: Five
      year consecutive series of 2121 children cared for in a hospital-based, tertiary
      care pediatric otolaryngology practice. INTERVENTION: Subsequent need for
      additional ventilation tube surgery. RESULTS: Four hundred twenty-three (19.9%)
      of the 2121 children who underwent initial placement of bilateral myringotomy
      tubes (BMTs) between April 20, 1995, and May 25, 1998, subsequently had a second
      set of tubes placed by May 25, 2000. Children 18 months or younger at the time of
      initial BMT placement were nearly twice as likely (26.3% vs 15.9%) to undergo a
      second BMT procedure when compared with children who were older than 18 months at
      initial surgery (P<.005). The probability of having a second BMT procedure was
      reduced if adenoidectomy was performed at the first BMT procedure (0.08 vs 0.24,
      P<.001). Adenoidectomy status, craniofacial deformities, and a family history of
      adenoidectomy or tonsillectomy with or without BMTs were independent risk factors
      for multiple BMTs. CONCLUSIONS: Epidemiologic analysis of this consecutive series
      of patients who underwent BMT placement in a tertiary care pediatric
      otolaryngology practice suggests that 1 in 5 patients will subsequently require a
      second set of ventilation tubes. Age younger than 18 months at the time of the
      initial BMT procedure is associated with an increased risk for additional surgery
      but is not an independent risk factor. Adenoidectomy reduces the incidence of
      subsequent BMTs following initial surgery.

PMID- 12622538
TI  - The cost-effectiveness of hearing-aid fitting in the Netherlands.
AB  - OBJECTIVE: To determine the cost-effectiveness of hearing-aid fitting. DESIGN:
      Cost-effectiveness analysis using a Markov model based on aggregate data and
      results from a prospective intervention study. SETTING: The cost-effectiveness
      study was based in the general community. The prospective study was hospital
      based, as 85% of the first-time hearing-aid users attend a hospital in the
      process of hearing-aid fitting. PATIENTS: The prospective intervention study
      included adult first-time hearing-aid users with no contraindications for hearing
      aid use. INTERVENTION: The usual process of hearing-aid fitting in the
      Netherlands. MAIN OUTCOME MEASURE: Costs per quality-adjusted life-year (QALY).
      The QALYs were based on EuroQol scores. We included direct and indirect costs in
      the analysis. RESULTS: The mean improvement on the EuroQol measure was 0.03 (95%
      confidence interval [CI], -0.03 to 0.08), and on the hearing-specific visual
      analog scale, 0.27 (95% CI, 0.22-0.31). The base-case outcome based on the
      EuroQol was 15 807/QALY (US dollars 17 072/QALY) (CI, -24 239/QALY to 3718/QALY).
      CONCLUSIONS: On the basis of this base-case estimate, fitting of hearing aids is
      considered a cost-effective health care intervention. The CI indicates that the
      result is not unambiguously positive, probably because the EuroQol lacked
      sensitivity for the evaluation of hearing-aid fitting. Until now, no study has
      found an effect of hearing-aid fitting on generic quality of life. Therefore,
      measures are needed that are suitable for the evaluation of the effects of
      interventions for sensory disabilities, such as the fitting of hearing aids, on
      generic quality of life.

PMID- 12622540
TI  - Synchrony of laryngeal muscle activity in persons with vocal tremor.
AB  - OBJECTIVE: To determine if the tremor activity in laryngeal muscles is
      synchronous, which would indicate a single central source of tremor. DESIGN: Six
      persons with vocal tremor participated in this study. Laryngeal muscle activity
      was recorded from 2 intrinsic and 2 extrinsic laryngeal muscles during production
      of a sustained ?i? sound. Correlations were computed between electromyographic
      activity in pairs of laryngeal muscles to measure the degree to which
      electromyographic activity in one muscle was synchronous with electromyographic
      activity in another laryngeal muscle. In addition, correlations were computed
      between each of the 4 laryngeal muscles and the voice signal to determine which
      muscle had activity that was most highly related to amplitude modulations in the
      voice. Multiple samples from each subject were analyzed to obtain measures of the
      consistency and strength of the correlations. RESULTS: In most subjects, the
      bursts of electromyographic activity in one muscle were not consistently related
      to tremor activity in other affected muscles. Half the subjects exhibited
      moderate to strong correlations between thyroarytenoid muscle activity and the
      amplitude of the voice signal. Although the thyroarytenoid and cricothyroid
      muscles were always active during sustained phonation, half of the subjects did
      not activate either the thyrohyoid or the sternothyroid muscle during this task.
      CONCLUSIONS: The results of this study did not support the hypothesis that
      essential voice tremor is generated by a single central oscillator. Differences
      in the presence and timing of modulations in laryngeal muscle activity, as
      described in this study, may reflect clinically in the variable regularity and
      severity of vocal tremor.

PMID- 12622539
TI  - The role of airway fluoroscopy in the evaluation of stridor in children.
AB  - OBJECTIVE: To determine the role of airway fluoroscopy in comparison with other
      diagnostic modalities in diagnosing the site of partial airway obstruction in
      children with stridor. DESIGN: Prospective study comparing direct laryngoscopy
      and bronchoscopy with nasopharyngoscopy, airway fluoroscopy, and plain films.
      Children with stridor or partial airway obstruction were evaluated by the
      Department of Otolaryngology at Columbus Children's Hospital, Columbus, Ohio. A
      history review and physical examination, including flexible fiberoptic
      laryngoscopy, plain films, airway fluoroscopy, and direct laryngoscopy and
      bronchoscopy, were performed for all children. SETTING: Tertiary care children's
      hospital. PATIENTS: From November 1996 to September 1999, 64 children aged 1 week
      to 12 years, with a mean age of 1.8 years and male-female ratio of 3:2, were
      evaluated for stridor. MAIN OUTCOME MEASURES: The sensitivity and specificity of
      airway fluoroscopy in diagnosing the site of partial airway obstruction in
      comparison with nasopharyngoscopy and plain films. RESULTS: Airway fluoroscopy
      had a sensitivity of 80% for subglottic, 73% for tracheal, and 80% for bronchial
      sites of obstruction. It was less sensitive for supraglottic and glottic sites
      33% and 14%, respectively. Nasopharyngoscopy was more sensitive for supraglottic
      and glottic sites of obstruction. Overall, airway fluoroscopy was far more
      sensitive than plain films for diagnosing site of obstruction. CONCLUSIONS:
      Airway fluoroscopy is a quick, noninvasive, and dynamic study of the entire
      airway that provides important additional information to the history review and
      physical examination and is a valuable adjunct to flexible fiberoptic
      laryngoscopy. It was far superior to plain films and may serve as a cost
      effective screening tool in the evaluation of stridor in children, especially for
      lesions of the lower airway.

PMID- 12622541
TI  - Tracheoesophageal shunt method with omohyoid muscle loop for voice restoration.
AB  - OBJECTIVE: To decrease the aspiration rate of the previously reported simple
      mucodermal tracheoesophageal (TE) shunt method for voice restoration after total
      laryngectomy with the use of omohyoid muscle loop. DESIGN: Retrospective clinical
      analysis. SETTING: Department of Otorhinolaryngology, Fukui Medical University,
      Fukui, Japan. PATIENTS: Ten male patients underwent total laryngectomy and
      received TE shunt by the omohyoid muscle loop method for voice restoration. There
      were 5 patients with glottic laryngeal cancer, 2 with supraglottic laryngeal
      cancer, and 3 with hypopharyngeal cancer. Patients' age ranged from 46 to 66
      years. INTERVENTION: The dermal incision on the neck was U-shaped with a
      superiorly pedicled, small U-shaped dermal flap. This small flap was used to form
      the anterior wall of the shunt. Bilateral omohyoid muscles were preserved at the
      total laryngectomy site with or without neck dissection. After creating a TE
      shunt directly on the posterior wall of the tracheal stump, the bilateral
      omohyoid muscles were looped through each other beneath the TE shunt. MAIN
      OUTCOME MEASUREMENTS: Maximum phonation time, maximum phonation intensity, and
      rating scales of shunt voice, aspiration rate, and survival time. RESULTS: Mean
      maximum phonation time was 20 seconds, while mean maximum phonation intensity was
      83 dB. The first voice was obtained on postoperative day 29 on average. Of the 10
      patients, 9 could phonate, with 1 case (10%) of slight aspiration 3 months after
      the surgery. CONCLUSIONS: Although this omohyoid muscle loop method needs to
      preserve the hyoid bone with those muscles, aspiration was prevented more
      effectively compared with the former, direct mucodermal TE shunt method. The
      indication for this method is preferably glottic laryngeal cancer.

PMID- 12622542
TI  - Obesity as a risk factor for primary spontaneous rhinoliquorrhea.
AB  - OBJECTIVE: To determine whether obesity is a potential risk factor of primary
      spontaneous cerebrospinal fluid rhinorrhea (CSFR). DESIGN: Retrospective study.
      SETTING: University hospital. PATIENTS AND METHODS: The clinical data of 79
      patients diagnosed with CSFR who had been treated at our hospital between 1991
      and 2001 were assessed. The data of 61 (77%) of 79 cases were complete and could
      be used for this study. Patients were segregated according to the cause of their
      CSFR: 21 (34%) due to head trauma, 14 (23%) due to previous surgery, 7 (11%) due
      to congenital malformation, and 2 (3%) due to tumor adjacent to the anterior
      cranial fossa. Of the 61 subjects, 17 (28%) had CSFR without any detectable
      reason. This group was therefore designated as primary spontaneous CSFR. The body
      mass indexes (BMIs) of all patients were compared and statistically evaluated.
      RESULTS: The mean BMI (calculated as weight in kilograms divided by the square of
      height in meters) of the 17 patients with primary spontaneous CSFR was 34.87,
      which was significantly higher (P<.001) than the mean BMI of the other 44
      patients (28.53). The mean BMI of the group of patients with CSFR due to previous
      surgery or trauma was significantly lower than the BMI of the group with primary
      spontaneous CSFR (P<.003), whereas in relation to the group afflicted with tumors
      and malformations, only a tendency (P<.28) was found. CONCLUSION: Our data
      suggest that obese patients are at an increased risk to develop primary
      spontaneous CSFR.

PMID- 12622543
TI  - Endolacrimal KTP laser-assisted dacryocystorhinostomy.
AB  - OBJECTIVE: To describe our experience with potassium-titanyl-phosphate (KTP)
      laser-assisted dacryocystorhinostomy, controlled via endolacrimal and endonasal
      endoscopy. The development of miniendoscopes enables endoscopy of the lacrimal
      drainage system via the lacrimal puncta to visualize the exact site of a
      stenosis. DESIGN: A case series of 78 patients, with 1-year postoperative follow
      up. SETTINGS: A university medical center. PATIENTS: Consecutive sample of 78
      adult patients who required surgery for dacryostenosis. INTERVENTION:
      Endolacrimal use of a KTP laser to perform a bony osteotomy of the lacrimal sac
      into the nasal cavity. The position for the perforation was controlled by
      endonasal endoscopy. The procedure was performed under either general or local
      anesthesia. RESULTS: One year after surgery, 65 (83%) of the 78 patients were
      free of symptoms. Seven patients experienced intermittent tearing, and 6 had
      revision surgery because of restenosis. CONCLUSIONS: The success rate of 83%
      achieved with KTP laser-assisted dacryocystorhinostomy, using miniendoscopes for
      lacrimal endoscopy to visualize the exact site of obstruction, is better compared
      with that of prior studies without the use of miniendoscopes (with success rates
      of 47%-85%). The advantages of this technique are that it is a minimally invasive
      procedure, requires a short operating time, and avoids use of an external
      incision.

PMID- 12622544
TI  - Survival and staging characteristics for non-squamous cell malignancies of the
      maxillary sinus.
AB  - OBJECTIVE: To characterize the clinical behavior of non-squamous cell cancer of
      the maxillary sinus. METHODS: Cases of non-squamous cell maxillary sinus
      malignancy during 1988 through 1998 were extracted from the Surveillance,
      Epidemiology, and End Results database. Data for histologic type of tumor, tumor
      stage, and survival were analyzed using the Kaplan-Meier method to determine
      mean, median, and 5-year survival statistics for the overall cohort and for
      individual histologic types of tumor. The effect of tumor stage on overall
      survival was assessed. To determine relative survival, the non-squamous cell
      group was compared with a second group of patients with squamous cell carcinoma,
      matched according to age at diagnosis, year of diagnosis, and T stage. RESULTS:
      One hundred eighty-eight cases of non-squamous cell malignancy were identified.
      The mean patient age was 57.8 years, and 143 patients (76%) presented with T3 or
      T4 tumors. There were 31 adenocarcinomas, 64 adenoid cystic carcinomas, 15
      mucoepidermoid carcinomas, 22 melanomas, 45 sarcomas, and 11 undifferentiated
      carcinomas. The overall mean survival was 63.4 months, and 5-year survival was
      45.6%. Adenoid cystic carcinoma exhibited the best mean survival (79 months),
      whereas melanoma and undifferentiated carcinoma exhibited poor mean survivals
      (30.3 and 12.8 months, respectively). T stage did not statistically affect
      overall survival (P =.86). Survival for patients with non-squamous cell cancer
      was substantially better than survival for the matched group with squamous cell
      carcinomas (mean survival, 41.5 months; 5-year survival, 27.4%). CONCLUSIONS:
      Patients with non-squamous cell carcinoma of the maxillary sinus typically
      present with advanced T stage but have significantly better survival than
      patients with similar-stage squamous cell carcinoma of the maxillary sinus. T
      stage has less effect than histologic type of tumor on prognosis in non-squamous
      cell carcinoma of the maxillary sinus.

PMID- 12622545
TI  - Detection of Epstein-Barr virus in metastatic lymph nodes of patients with
      nasopharyngeal carcinoma and a primary unknown carcinoma.
AB  - BACKGROUND: Nasopharyngeal carcinoma is often associated with neck lymph node
      (LN) metastases, which in many cases is the only manifestation of this disease.
      The submucosal and infiltrative characteristics of nasopharyngeal carcinoma make
      this type of cancer difficult to diagnose. Nasopharyngeal carcinoma has also been
      reported to be strongly associated with the Epstein-Barr virus. METHODS: We
      examined 36 nasopharyngeal carcinomas (from 30 primary sites and from 6
      metastasized LNs), 13 metastasized LNs of other head and neck cancers, and 12
      primary unknown neck metastases using an in situ hybridization technique.
      RESULTS: In the nasopharyngeal carcinomas, in situ hybridization with an Epstein
      Barr virus-encoded small RNA identified the Epstein-Barr virus in 20 (67%) of the
      30 primary sites and in 3 (50%) of the 6 metastasized LNs. Epstein-Barr virus was
      not detected in metastasized LNs of other head and neck cancers, but was detected
      in 1 of the primary unknown neck metastases. CONCLUSION: In situ hybridization
      using a digoxigenin-labeled Epstein-Barr virus-encoded small RNA probe is useful
      for the differential diagnosis of metastasized LNs when the primary site is
      unknown.

PMID- 12622546
TI  - Management of nontuberculous mycobacterial cervical lymphadenitis.
AB  - OBJECTIVE: To review the treatment and outcome of patients with nontuberculous
      mycobacterial (NTM) cervical lymphadenitis. DESIGN: Retrospective chart review.
      SETTING: Tertiary care children's hospital. PATIENTS: Thirty consecutive
      immunocompetent patients (median age, 32 months; age range, 11-147 months)
      diagnosed as having NTM cervical lymphadenitis over a 77-month period.
      INTERVENTIONS: Primary therapy for 34 foci of NTM cervical lymphadenitis in 30
      children consisted of excisional biopsy (n = 8), incision and drainage procedures
      (n = 14), fine-needle aspiration biopsy (n = 7), observation only (n = 4), and
      antimycobacterial chemotherapy only (n = 1). MAIN OUTCOME MEASURES: (1) Time to
      cure, (2) recurrent adenitis, and (3) complications associated with therapy were
      determined for each therapeutic option. The average duration of follow-up was 32
      months (range, 6-78 months). RESULTS: Nearly all patients (97%) were cured of
      their disease regardless of which therapeutic option was used. Excisional biopsy,
      while associated with transient marginal mandibular nerve injury in 1 patient,
      typically resulted in the most rapid resolution of disease. Observation alone did
      result in eventual cure, although the disease course was protracted. Simple
      incision and drainage without curettage was associated with prolonged
      postoperative wound discharge and hypertrophic scarring. CONCLUSIONS: A variety
      of therapeutic options were used in children with NTM cervical lymphadenitis.
      Resolution of infection was an eventual outcome regardless of treatment option,
      although duration of disease, potential for facial nerve injury, and incidence of
      hypertrophic scarring varied among the different treatments. An individualized
      management approach is recommended, with excisional biopsy as the preferred
      option when feasible.

PMID- 12622547
TI  - Impact of transplanted fibroblasts on rabbit skin wounds.
AB  - OBJECTIVES: To determine the effect of injected fibroblasts on full-thickness
      cutaneous wounds and to distinguish between the properties of fetal vs adult
      fibroblasts. DESIGN: Full-thickness cutaneous wounds were created by incision in
      the skin of adult New Zealand white rabbits and treated with fluorescently
      labeled autogenic, allogenic, and xenogenic fetal and adult fibroblasts. Wound
      healing was evaluated by histologic analysis and tensiometry over time. SUBJECTS:
      A total of 9 New Zealand white rabbits with 24 wounds per animal were examined in
      this study. Groups of 3 animals were treated with different fibroblasts and
      euthanized at 7, 14, and 28 days after manipulation. INTERVENTION: Fibroblasts
      were labeled with a fluorescent dye (CM-DiI) and suspended in a hyaluronic acid
      gel. The cell-gel mix was used to treat full-thickness incisional wounds in
      rabbit skin. Imaging of CM-DiI determined the quantity and the migratory patterns
      of the transplanted fibroblasts present in the wounds. Tensiometry characterized
      the mechanical properties of the healed connective tissue. RESULTS: Transplanted
      fibroblasts exhibited good survival and migration patterns. Cell therapy
      increased the tensile strength of the wounds. Allogenic fetal and autogenic adult
      fibroblasts achieved similar effects. CONCLUSIONS: Cell therapy is a viable
      approach to significantly affect the course of normal cutaneous wound healing,
      and cell lines from genetically unrelated donors do not appear to be
      disadvantaged by a host immune response compared with autogenic cell lines.

PMID- 12622548
TI  - Anatomical variations of the facial nerve in first branchial cleft anomalies.
AB  - OBJECTIVE: To review our experience with branchial cleft anomalies, with special
      attention to their subtypes and anatomical relationship to the facial nerve.
      STUDY DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: Ten patients
      who underwent resection for anomalies of the first branchial cleft, with at least
      1 year of follow-up, were included in the study. The data from all cases were
      collected in a prospective fashion, including immediate postoperative diagrams.
      INTERVENTION: Complete resection of the branchial cleft anomaly was performed in
      all cases. Wide exposure of the facial nerve was achieved using a modified Blair
      incision and superficial parotidectomy. Facial nerve monitoring was used in every
      case. MAIN OUTCOME MEASURES: The primary outcome measurements were facial nerve
      function and incidence of recurrence after resection of the branchial cleft
      anomaly. RESULTS: Ten patients, 6 females and 4 males,with a mean age of 9 years
      at presentation, were treated by the senior author (P.J.K.) between 1989 and
      2001. The lesions were characterized as sinus tracts (n = 5), fistulous tracts (n
      = 3), and cysts (n = 2). Seven lesions were medial to the facial nerve, 2 were
      lateral to the facial nerve, and 1 was between branches of the facial nerve.
      There were no complications related to facial nerve paresis or paralysis, and
      none of the patients has had a recurrence. CONCLUSIONS: The successful treatment
      of branchial cleft anomalies requires a complete resection. A safe complete
      resection requires a full exposure of the facial nerve, as the lesions can be
      variably associated with the nerve.

PMID- 12622549
TI  - Silent internal sinus of the pyriform fossa: a rare adult manifestation of a
      branchial anomaly.
AB  - Branchial anomalies present with a wide range of pathologic characteristics,
      including cysts, fistulas, and sinuses of the head and neck region. Branchial
      cysts are most commonly diagnosed during the second through fourth decades of
      life, while branchial sinuses and fistulas are diagnosed almost exclusively in
      children with infection episodes. Only rarely has an internal sinus of a third or
      fourth branchial anomaly manifested in adults as a noninfectious swelling in the
      neck during swallowing. In this report, we describe our experience treating a 21
      year-old man with a left-sided swallowing-induced neck protrusion of 10 years'
      duration. Findings of physical examination, videolaryngoscopy, and a
      pharyngoesophagogram confirmed the diagnosis of internal sinus of the pyriform
      fossa, with uncertain origin of a third or fourth branchial anomaly. The patient
      underwent regular follow-up as an outpatient and experienced no further
      infectious episodes.

PMID- 12622550
TI  - Myoepithelial neoplasia of the submandibular gland: case report and therapeutic
      considerations.
AB  - Tumors of the submandibular gland typically arise from the seromucinous acini,
      which make up the majority of the gland. The most common benign tumor of this
      structure is the pleomorphic adenoma, whereas the most common malignancy of the
      submandibular gland is adenoid cystic carcinoma. We describe an unusual case of a
      neoplastic process of the myoepithelial cells of the submandibular gland in a
      middle-aged woman. This rare tumor is most commonly diagnosed in the parotid
      gland and in the minor salivary glands of the hard palate; a review of the
      literature uncovered only 5 previous reports of myoepithelioma of the
      submandibular gland. Distinguishing myoepithelioma from benign pleomorphic
      adenoma and malignant myoepithelial carcinomas can be challenging.
      Immunohistochemical staining can help to distinguish between the benign
      neoplasms, but histologic features remain the "gold standard" for diagnosing the
      malignant tumors. Increasing use of immunohistochemistry panels to assess parotid
      neoplasms also suggests that myoepithelioma may be underrecognized.

PMID- 12622551
TI  - The use of genetic markers in the clinical care of patients with head and neck
      cancer.

PMID- 12622552
TI  - Genetic markers of head and neck cancer: identifying new molecular targets.

PMID- 12622553
TI  - Genetic markers in the clinical care of head and neck cancer: slow in coming.

PMID- 12622554
TI  - Pathology quiz case 1. Hairy polyp.

PMID- 12622555
TI  - Pathology quiz case 2. Lymphoepithelial carcinoma (LEC) with a focal conventional
      squamous cell carcinoma (SCC) component.

PMID- 12622556
TI  - Radiology quiz case 1. Allergic fungal sinusitis (AFS) with bacterial
      superinfection of frontal ethmoid mucoceles caused by AFS.

PMID- 12622557
TI  - Radiology quiz case 2. Nasolabial (nasoalveolar) cyst.

PMID- 12622558
TI  - Colon cancer screening guidelines stress initial test's importance.

PMID- 12622559
TI  - The siren song of disease eradication: is it out of tune with the times?

PMID- 12622560
TI  - Effort launched to study stem cell lines, train researchers how to nurture them.

PMID- 12622561
TI  - From the Centers for Disease Control and Prevention. Smallpox Vaccine Adverse
      Events Monitoring and Response System for the first stage of the smallpox
      vaccination program.

PMID- 12622562
TI  - From the Centers for Disease Control and Prevention. Pneumococcal conjunctivitis
      at an elementary school--Maine, September 20-December 6, 2002.

PMID- 12622564
TI  - From the Centers for Disease Control and Prevention. Progress toward
      poliomyelitis eradication--Ethiopia, Somalia, and Sudan, January 2001-October
      2002.

PMID- 12622567
TI  - Estrogen replacement and risk of Alzheimer disease.

PMID- 12622568
TI  - Estrogen replacement and risk of Alzheimer disease.

PMID- 12622569
TI  - Estrogen replacement and risk of Alzheimer disease.

PMID- 12622570
TI  - Estrogen replacement and risk of Alzheimer disease.

PMID- 12622571
TI  - Antihypertensive drugs and renal protection.

PMID- 12622573
TI  - Pharmacist care for reactive airway disease.

PMID- 12622574
TI  - Pharmacist care for reactive airway disease.

PMID- 12622576
TI  - Pharmacist care for reactive airway disease.

PMID- 12622577
TI  - Pharmacist care for reactive airway disease.

PMID- 12622578
TI  - Pharmacist care for reactive airway disease.

PMID- 12622579
TI  - Osseous Kaposi sarcoma.

PMID- 12622580
TI  - Incidence and preventability of adverse drug events among older persons in the
      ambulatory setting.
AB  - CONTEXT: Adverse drug events, especially those that may be preventable, are among
      the most serious concerns about medication use in older persons cared for in the
      ambulatory clinical setting. OBJECTIVE: To assess the incidence and
      preventability of adverse drug events among older persons in the ambulatory
      clinical setting. DESIGN, SETTING, AND PATIENTS: Cohort study of all Medicare
      enrollees (30 397 person-years of observation) cared for by a multispecialty
      group practice during a 12-month study period (July 1, 1999, through June 30,
      2000), in which possible drug-related incidents occurring in the ambulatory
      clinical setting were detected using multiple methods, including reports from
      health care providers; review of hospital discharge summaries; review of
      emergency department notes; computer-generated signals; automated free-text
      review of electronic clinic notes; and review of administrative incident reports
      concerning medication errors. MAIN OUTCOME MEASURES: Number of adverse drug
      events, severity of the events (classified as significant, serious, life
      threatening, or fatal), and whether the events were preventable. RESULTS: There
      were 1523 identified adverse drug events, of which 27.6% (421) were considered
      preventable. The overall rate of adverse drug events was 50.1 per 1000 person
      years, with a rate of 13.8 preventable adverse drug events per 1000 person-years.
      Of the adverse drug events, 578 (38.0%) were categorized as serious, life
      threatening, or fatal; 244 (42.2%) of these more severe events were deemed
      preventable compared with 177 (18.7%) of the 945 significant adverse drug events.
      Errors associated with preventable adverse drug events occurred most often at the
      stages of prescribing (n = 246, 58.4%) and monitoring (n = 256, 60.8%), and
      errors involving patient adherence (n = 89, 21.1%) also were common.
      Cardiovascular medications (24.5%), followed by diuretics (22.1%), nonopioid
      analgesics (15.4%), hypoglycemics (10.9%), and anticoagulants (10.2%) were the
      most common medication categories associated with preventable adverse drug
      events. Electrolyte/renal (26.6%), gastrointestinal tract (21.1%), hemorrhagic
      (15.9%), metabolic/endocrine (13.8%), and neuropsychiatric (8.6%) events were the
      most common types of preventable adverse drug events. CONCLUSIONS: Adverse drug
      events are common and often preventable among older persons in the ambulatory
      clinical setting. More serious adverse drug events are more likely to be
      preventable. Prevention strategies should target the prescribing and monitoring
      stages of pharmaceutical care. Interventions focused on improving patient
      adherence with prescribed regimens and monitoring of prescribed medications also
      may be beneficial.

PMID- 12622581
TI  - Outcome of elderly patients with chronic symptomatic coronary artery disease with
      an invasive vs optimized medical treatment strategy: one-year results of the
      randomized TIME trial.
AB  - CONTEXT: The risk-benefit ratio of invasive vs medical management of elderly
      patients with symptomatic chronic coronary artery disease (CAD) is unclear. The
      Trial of Invasive versus Medical therapy in Elderly patients (TIME) recently
      showed early benefits in quality of life from invasive therapy in patients aged
      75 years or older, although with a certain excess in mortality. OBJECTIVE: To
      assess the long-term value of invasive vs medical management of chronic CAD in
      elderly adults in terms of quality of life and prevention of major adverse
      cardiac events. DESIGN: One-year follow-up analysis of TIME, a prospective
      randomized trial with enrollment between February 1996 and November 2000. SETTING
      AND PARTICIPANTS: A total of 282 patients with Canadian Cardiac Society class 2
      or higher angina despite treatment with 2 or more anti-anginal drugs who survived
      for the first 6 months after enrollment in TIME (mean age, 80 years [range, 75-91
      years]; 42% women), enrolled at 14 centers in Switzerland. INTERVENTIONS:
      Participants were randomly assigned to undergo coronary angiography followed by
      revascularization (if feasible) (n = 140 surviving 6 months) or to receive
      optimized medical therapy (n = 142 surviving 6 months). MAIN OUTCOME MEASURES:
      Quality of life, assessed by standardized questionnaire; major adverse cardiac
      events (death, nonfatal myocardial infarction, or hospitalization for acute
      coronary syndrome) after 1 year. RESULTS: After 1 year, improvements in angina
      and quality of life persisted for both therapies compared with baseline, but the
      early difference favoring invasive therapy disappeared. Among invasive therapy
      patients, later hospitalization with revascularization was much less likely (10%
      vs 46%; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.11-0.32;
      P<.001). However, 1-year mortality (11.1% for invasive; 8.1% for medical; HR,
      1.51; 95% CI, 0.72-3.16; P =.28) and death or nonfatal myocardial infarction
      rates (17.0% for invasive; 19.6% for medical; HR, 0.90; 95% CI, 0.53-1.53; P
      =.71) were not significantly different. Overall major adverse cardiac event rates
      were higher for medical patients after 6 months (49.3% vs 19.0% for invasive;
      P<.001), a difference which increased to 64.2% vs 25.5% after 12 months (P<.001).
      CONCLUSIONS: In contrast with differences in early results, 1-year outcomes in
      elderly patients with chronic angina are similar with regard to symptoms, quality
      of life, and death or nonfatal infarction with invasive vs optimized medical
      strategies based on this intention-to-treat analysis. The invasive approach
      carries an early intervention risk, while medical management poses an almost 50%
      chance of later hospitalization and revascularization.

PMID- 12622582
TI  - Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the
      outcome of extremely low-birth-weight infants at 18 months: results from the
      trial of indomethacin prophylaxis in preterms.
AB  - CONTEXT: Despite more than 2 decades of outcomes research after very preterm
      birth, clinicians remain uncertain about the extent to which neonatal morbidities
      predict poor long-term outcomes of extremely low-birth-weight (ELBW) infants.
      OBJECTIVE: To determine the individual and combined prognostic effects of
      bronchopulmonary dysplasia (BPD), ultrasonographic signs of brain injury, and
      severe retinopathy of prematurity (ROP) on 18-month outcomes of ELBW infants.
      DESIGN: Inception cohort assembled for the Trial of Indomethacin Prophylaxis in
      Preterms (TIPP). SETTING AND PARTICIPANTS: A total of 910 infants with birth
      weights of 500 to 999 g who were admitted to 1 of 32 neonatal intensive care
      units in Canada, the United States, Australia, New Zealand, and Hong Kong between
      1996 and 1998 and who survived to a postmenstrual age of 36 weeks. MAIN OUTCOME
      MEASURES: Combined end point of death or survival to 18 months with 1 or more of
      cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness.
      RESULTS: Each of the neonatal morbidities was similarly and independently
      correlated with a poor 18-month outcome. Odds ratios were 2.4 (95% confidence
      interval [CI], 1.8-3.2) for BPD, 3.7 (95% CI, 2.6-5.3) for brain injury, and 3.1
      (95% CI, 1.9-5.0) for severe ROP. In children who were free of BPD, brain injury,
      and severe ROP the rate of poor long-term outcomes was 18% (95% CI, 14%-22%).
      Corresponding rates with any 1, any 2, and all 3 neonatal morbidities were 42%
      (95% CI, 37%-47%), 62% (95% CI, 53%-70%), and 88% (64%-99%), respectively.
      CONCLUSION: In ELBW infants who survive to a postmenstrual age of 36 weeks, a
      simple count of 3 common neonatal morbidities strongly predicts the risk of later
      death or neurosensory impairment.

PMID- 12622583
TI  - Antithymocyte globulin and cyclosporine for severe aplastic anemia: association
      between hematologic response and long-term outcome.
AB  - CONTEXT: In most patients, aplastic anemia results from T-cell-mediated immune
      destruction of bone marrow. Aplastic anemia can be effectively treated by stem
      cell transplantation or immunosuppression. OBJECTIVE: To assess long-term
      outcomes after immunosuppressive therapy. DESIGN, SETTING, AND PATIENTS: Cohort
      of 122 patients (31 were < or =18 years and 91 were >18 years) with severe
      aplastic anemia, as determined by bone marrow cellularity and blood cell count
      criteria, were enrolled in a single-arm interventional research protocol from
      1991 to 1998 at a federal government research hospital. INTERVENTIONS: A dose of
      40 mg/kg per day of antithymocyte globulin administered for 4 days, 10 to 12
      mg/kg per day of cyclosporine for 6 months (adjusted for blood levels), and a
      short course of corticosteroids (1 mg/d of methylprednisolone for about 2 weeks).
      MAIN OUTCOME MEASURES: Survival, improvement of pancytopenia and transfusion
      independence, relapse, and evolution to other hematologic diseases. RESULTS:
      Response rates were 60% at 3 months after initiation of treatment, 61% at 6
      months, and 58% at 1 year. The blood cell counts of patients who responded no
      longer satisfied severity criteria and they were transfusion-independent. Overall
      actuarial survival at 7 years was 55%. Survival was associated with early
      satisfaction of response criteria (86% vs 40% at 5 years; P<.001) and by blood
      counts at 3 months (reticulocyte count or platelet count of >50 x 10(3)/ microL
      predicted survival at 5 years of 90% [64/71] vs 42% [12/34] for patients with
      less robust recovery [P<.001 by log-rank test]). There were no deaths among
      responders more than 3 years after treatment. Relapse was common, but severe
      pancytopenia usually did not recur. Relapse did not influence survival. Thirteen
      patients showed evolution to other hematologic diseases, including monosomy 7.
      CONCLUSIONS: Approximately half of patients with severe aplastic anemia treated
      with antithymocyte globulin and cyclosporine have durable recovery and excellent
      long-term survival. These outcomes were related to the quality of hematologic
      recovery.

PMID- 12622584
TI  - Preliminary assessment of inhaled nitric oxide for acute vaso-occlusive crisis in
      pediatric patients with sickle cell disease.
AB  - CONTEXT: Vaso-occlusion is central to the painful crises and acute and chronic
      organ damage in sickle cell disease. Abnormal nitric oxide-dependent regulation
      of vascular tone, adhesion, platelet activation, and inflammation contributes to
      the pathophysiology of vaso-occlusion. Nitric oxide may have promise as a
      mechanism-of-disease-based therapy for treatment of vaso-occlusion. OBJECTIVE: To
      explore the efficacy and safety of inhaled nitric oxide (INO) for treatment of
      vaso-occlusive crisis in pediatric patients. DESIGN: Prospective, double-blind,
      placebo-controlled, randomized clinical trial with enrollment between September
      1999 and October 2001. SETTING: Urban, tertiary care children's hospital in the
      United States. PARTICIPANTS: Twenty patients aged 10 to 21 years with sickle cell
      disease and severe acute vaso-occlusive crisis. INTERVENTION: Patients were
      randomly assigned to receive INO (80 ppm with 21% final concentration of inspired
      oxygen; n = 10), or placebo (21% inspired oxygen; n = 10) for 4 hours. MAIN
      OUTCOME MEASURES: Change in pain at 4 hours of inhalation compared with
      preinhalation pain, measured on a 10-cm visual analog scale (VAS); secondary
      outcome measures were pain over 6 hours, parenteral narcotic use over 24 hours,
      duration of hospitalization, blood pressure, oxygen saturation, and methemoglobin
      concentration. RESULTS: Preinhalation VAS pain scores were similar in the INO and
      placebo groups (P =.80). The decrease in VAS pain scores at 4 hours was 2.0 cm in
      the INO group and 1.2 cm in the placebo group (P =.37). Repeated-measures
      analysis of variance for hourly pain scores showed a 1-cm/h greater reduction in
      the INO group than the placebo group (P =.02). Morphine use over 6 hours was
      significantly less in the INO group (mean cumulative use, 0.29 vs 0.44 mg/kg; P
      =.03) but was not different over 4 hours (0.26 vs 0.32 mg/kg; P =.21) or 24 hours
      (0.63 vs 0.91 mg/kg; P =.15). Duration of hospitalization was 78 and 100 hours in
      the INO and placebo groups, respectively (P =.19). No INO toxicity was observed.
      CONCLUSIONS: Results of this exploratory study suggest that INO may be beneficial
      for acute vaso-occlusive crisis. These preliminary results warrant further
      investigation.

PMID- 12622585
TI  - The consequences of premature abandonment of affirmative action in medical school
      admissions.
AB  - The US Supreme Court recently accepted on appeal 2 cases from the University of
      Michigan regarding the constitutionality of race-conscious decision making in
      higher education admissions. The consequences of the Court's decision will
      directly affect the future of medicine in the United States. Medical schools have
      a societal obligation to select and educate the physician workforce of the
      future. To outlaw the use of affirmative action in the admissions process would
      cripple the profession's ability to achieve racial and ethnic diversity.
      Preserving this diversity in medical school admissions programs is important for
      4 major reasons (1) adequate representation among students and faculty of the
      diversity in US society is indispensable for quality medical education; (2)
      increasing the diversity of the physician workforce will improve access to health
      care for underserved populations; (3) increasing the diversity of the research
      workforce can accelerate advances in medical and public health research; and (4)
      diversity among managers of health care organizations makes good business sense.
      This article explores these reasons in detail, reviews the history and
      effectiveness of affirmative action in medical school admissions programs, and
      explains why alternatives to affirmative action are unworkable.

PMID- 12622586
TI  - Acute pericarditis: current concepts and practice.

PMID- 12622587
TI  - Medication safety: moving from illusion to reality.

PMID- 12622588
TI  - Patient-centered cardiac care for the elderly: TIME for reflection.

PMID- 12622590
TI  - MSJAMA: Do the Math.

PMID- 12622591
TI  - MSJAMA: A historical survey of national health movements and public opinion in
      the United States.

PMID- 12622592
TI  - MSJAMA: Government share of health care expenditures.

PMID- 12622593
TI  - MSJAMA: Incremental approaches to increasing health care coverage.

PMID- 12622594
TI  - MSJAMA: The Latino disparity in health coverage.

PMID- 12622597
TI  - JAMA patient page. Pericarditis.

PMID- 12622598
TI  - Continuous positive airway pressure: placebo power, or does it really work?

PMID- 12622599
TI  - High blood pressure in African Americans.

PMID- 12622600
TI  - Management of high blood pressure in African Americans: consensus statement of
      the Hypertension in African Americans Working Group of the International Society
      on Hypertension in Blacks.

PMID- 12622601
TI  - A comprehensive evidence-based approach to fever of unknown origin.
AB  - BACKGROUND: Fever of unknown origin (FUO) is defined as a temperature higher than
      38.3 degrees C on several occasions and lasting longer than 3 weeks, with a
      diagnosis that remains uncertain after 1 week of investigation. METHODS: A
      systematic review was performed to develop evidence-based recommendations for the
      diagnostic workup of FUO. MEDLINE database was searched (January 1966 to December
      2000) to identify articles related to FUO. Articles were included if the patient
      population met the criteria for FUO and they addressed the natural history,
      prognosis, or spectrum of disease or evaluated a diagnostic test in FUO. The
      quality of retrieved articles was rated as "good," "fair," or "poor," and
      sensitivity, specificity, and diagnostic yield of tests were calculated.
      Recommendations were made in accordance with the strength of evidence. RESULTS:
      The prevalence of FUO in hospitalized patients is reported to be 2.9%. Eleven
      studies indicate that the spectrum of disease includes "no diagnosis" (19%),
      infections (28%), inflammatory diseases (21%), and malignancies (17%). Deep vein
      thrombosis (3%) and temporal arteritis in the elderly (16%-17%) were important
      considerations. Four good natural history studies indicate that most patients
      with undiagnosed FUO recover spontaneously (51%-100%). One fair-quality study
      suggested a high specificity (99%) for the diagnosis of endocarditis in FUO by
      applying the Duke criteria. One fair-quality study showed that computed
      tomographic scanning of the abdomen had a diagnostic yield of 19%. Ten studies of
      nuclear imaging revealed that technetium was the most promising isotope, showing
      a high specificity (94%), albeit low sensitivity (40%-75%) (2 fair-quality
      studies). Two fair-quality studies showed liver biopsy to have a high diagnostic
      yield (14%-17%), but with risk of harm (0.009%-0.12% death). Empiric bone marrow
      cultures showed a low diagnostic yield of 0% to 2% (2 fair-quality articles).
      CONCLUSIONS: Diagnosis of FUO may be assisted by the Duke criteria for
      endocarditis, computed tomographic scan of the abdomen, nuclear scanning with a
      technetium-based isotope, and liver biopsy (fair to good evidence). Routine bone
      marrow cultures are not recommended.

PMID- 12622602
TI  - Risk for myopathy with statin therapy in high-risk patients.
AB  - Emerging data suggest that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
      reductase inhibitors (statins) offer important benefits for the large population
      of individuals at high risk for coronary heart disease. This population
      encompasses a sizable portion of individuals who are also at high risk for drug
      drug interactions due to their need for multiple medications. In general, statins
      are associated with a very small risk for myopathy (which may progress to fatal
      or nonfatal rhabdomyolysis); however, the potential for drug-drug interactions is
      known to increase this risk in specific high-risk groups. The incidence of
      myopathy associated with statin therapy is dose related and is increased when
      statins are used in combination with agents that share common metabolic pathways.
      Of particular concern is the potential for interactions with other lipid-lowering
      agents such as fibrates and niacin (nicotinic acid), which may be used in
      patients with mixed lipidemia, and with immunosuppressive agents, such as
      cyclosporine, which are commonly used in patients after transplantation.
      Clinicians should be alert to the potential for drug-drug interactions to
      minimize the risk of myopathy during long-term statin therapy in patients at high
      risk for coronary heart disease.

PMID- 12622603
TI  - Continuous positive airway pressure therapy for treating sleepiness in a diverse
      population with obstructive sleep apnea: results of a meta-analysis.
AB  - BACKGROUND: Although continuous positive airway pressure (CPAP) has become the
      standard of care in the treatment of obstructive sleep apnea (OSA), 2 systematic
      reviews have questioned its utility. Since the publication of these reviews,
      several randomized controlled trials have been reported. We, therefore, performed
      a meta-analysis to assess the effect of CPAP on subjective and objective
      sleepiness. METHODS: We conducted a thorough literature search to identify all
      published randomized controlled trials of CPAP in patients with OSA. Meta
      analyses were performed using a random-effects model. Statistical heterogeneity
      was assessed using the Q statistic. RESULTS: Twelve trials of CPAP in patients
      with OSA meeting our inclusion criteria were found. The Epworth Sleepiness Scale
      score was reported in 11 studies (706 patients). A meta-analysis found that CPAP
      reduced the Epworth Sleepiness Scale score an average of 2.94 points more than
      placebo (P<.001). The heterogeneity (Q10 = 57.7, P<.001) between studies could
      not be explained by differences in sex composition, mean age, mean body mass
      index, or country of study. Trials recruiting subjects with severe OSA plus
      sleepiness (mean apnea-hypopnea index, > or =30 events per hour; and mean Epworth
      Sleepiness Scale score, > or =11) had a greater decrease in the Epworth
      Sleepiness Scale score than the other studies (4.75 vs 1.10; P<.001). Objective
      measures of sleepiness were reported in 8 trials (482 subjects). Continuous
      positive airway pressure increased sleep onset latency by 0.93 minute (P =.04)
      more than placebo. CONCLUSIONS: Continuous positive airway pressure therapy
      significantly improves subjective and objective measures of sleepiness in
      patients with OSA across a diverse range of populations. Patients with more
      severe apnea and sleepiness seem to benefit the most.

PMID- 12622604
TI  - Genetic counseling and testing in families with hereditary nonpolyposis
      colorectal cancer.
AB  - BACKGROUND: Genetic testing to refine cancer risk is available. However, little
      is known about factors affecting the uptake of testing for the most common
      hereditary colon cancer, hereditary nonpolyposis colorectal cancer. This study
      investigated attitudes, intentions, and uptake of genetic testing within newly
      identified families with hereditary nonpolyposis colorectal cancer. METHODS:
      Cohort study conducted at the National Institutes of Health between April 15,
      1996, and November 20, 1999. Data were collected through questionnaires before
      semistructured education sessions, individual counseling sessions, and the offer
      of genetic testing. RESULTS: Of the 111 eligible first-degree relatives, 51%
      chose to participate in education and individual counseling sessions.
      Participation was associated with greater numbers of first-degree relatives with
      cancer; no association was found between participation and personal history of
      cancer. Before education and individual counseling sessions, 64% of participants
      had heard little about genetic testing for cancers; however, most (97%) stated
      intentions to pursue testing. Fifty-one percent identified learning about their
      children's risks as the most important reason to consider testing. Thirty-nine
      percent identified the potential effect on their health insurance as the most
      important reason to not undergo testing. Of the 111 eligible first-degree
      relatives, 51% chose to undergo genetic testing. Participants' intentions to
      pursue genetic testing were significantly affected by concerns regarding the
      ability to handle the emotional aspects of testing and the psychosocial effect on
      family members. CONCLUSIONS: Genetic counseling and testing offers the potential
      to focus cancer screening resources in individuals truly at increased risk,
      thereby reducing mortality and morbidity. Fears of discrimination and concerns
      about psychological and psychosocial issues may present barriers to the use of
      current cancer prevention strategies, including genetic counseling and testing.

PMID- 12622605
TI  - Reduction of hospital utilization in patients with chronic obstructive pulmonary
      disease: a disease-specific self-management intervention.
AB  - BACKGROUND: Self-management interventions improve various outcomes for many
      chronic diseases. The definite place of self-management in the care of chronic
      obstructive pulmonary disease (COPD) has not been established. We evaluated the
      effect of a continuum of self-management, specific to COPD, on the use of
      hospital services and health status among patients with moderate to severe
      disease. METHODS: A multicenter, randomized clinical trial was carried out in 7
      hospitals from February 1998 to July 1999. All patients had advanced COPD with at
      least 1 hospitalization for exacerbation in the previous year. Patients were
      assigned to a self-management program or to usual care. The intervention
      consisted of a comprehensive patient education program administered through
      weekly visits by trained health professionals over a 2-month period with monthly
      telephone follow-up. Over 12 months, data were collected regarding the primary
      outcome and number of hospitalizations; secondary outcomes included emergency
      visits and patient health status. RESULTS: Hospital admissions for exacerbation
      of COPD were reduced by 39.8% in the intervention group compared with the usual
      care group (P =.01), and admissions for other health problems were reduced by
      57.1% (P =.01). Emergency department visits were reduced by 41.0% (P =.02) and
      unscheduled physician visits by 58.9% (P =.003). Greater improvements in the
      impact subscale and total quality-of-life scores were observed in the
      intervention group at 4 months, although some of the benefits were maintained
      only for the impact score at 12 months. CONCLUSIONS: A continuum of self
      management for COPD patients provided by a trained health professional can
      significantly reduce the utilization of health care services and improve health
      status. This approach of care can be implemented within normal practice.

PMID- 12622606
TI  - Drug intolerance due to nonspecific adverse effects related to psychiatric
      morbidity in hypertensive patients.
AB  - BACKGROUND: Poor adherence to antihypertensive drug regimens is common and may
      increase the risk for cardiovascular morbidity and mortality. Adverse effects of
      the drugs can contribute to poor adherence, but some patients who discontinue
      several different antihypertensive drugs may misinterpret nonspecific symptoms as
      adverse effects of the drug because of psychiatric morbidity. We examined the
      relationship between intolerance to antihypertensive drugs and the presence of
      panic disorder, panic attacks, anxiety, and depression. METHODS: We included all
      patients with hypertension who attended a hospital hypertension clinic during 1
      year with at least 2 episodes of intolerance (resulting in reduction of the
      dosage or stopping an antihypertensive drug) recorded on standardized problem
      lists and a similar number of patients with no recorded episodes of intolerance.
      Psychiatric morbidity, assessed by self-administered questionnaires, was analyzed
      against the number of episodes of nonspecific and drug-specific intolerance,
      verified by means of individual case-note scrutiny, and scored independently by 2
      assessors masked to patient identity. RESULTS: Analyzable questionnaires were
      returned by 233 (84%) of 276 patients who had experienced 576 (85%) of 679
      episodes of intolerance assessed. Five hundred thirty-two episodes (92%) were
      subjective (patient was symptomatic); of these, 284 were judged to be drug
      specific; 248, nonspecific. Having more episodes of nonspecific intolerance was
      associated with significantly higher diastolic blood pressure (P =.003). Episodes
      of nonspecific intolerance were associated with panic attacks (P =.008), anxiety
      (Hospital Anxiety and Depression Scale score, P =.04), and depression (Hospital
      Anxiety and Depression Scale score, P =.005). Drug-specific intolerance was not
      associated with psychiatric morbidity. CONCLUSIONS: Intolerance to multiple
      antihypertensive drugs, particularly non-drug-specific intolerance, is strongly
      associated with psychiatric morbidity. Physicians treating hypertensive patients
      need to recognize and manage the psychiatric aspects of intolerance to multiple
      antihypertensive drugs.

PMID- 12622607
TI  - Fluoroquinolone utilization in the emergency departments of academic medical
      centers: prevalence of, and risk factors for, inappropriate use.
AB  - BACKGROUND: Resistance to fluoroquinolone (FQ) antibiotics has risen markedly in
      recent years and has been associated with increasing FQ use; however, few data
      exist regarding FQ use patterns. Designing strategies to limit FQ resistance by
      optimizing FQ use depends on identifying patterns of inappropriate FQ use. Use of
      FQs in emergency departments (EDs) has not been studied. METHODS: We studied 100
      consecutive ED patients who received an FQ and were subsequently discharged.
      Appropriateness of the indication for use was judged according to existing
      institutional guidelines. A case-control study was conducted to identify the
      prevalence of, and risk factors for, inappropriate FQ use. RESULTS: Of 100 total
      patients, 81 received an FQ for an inappropriate indication. Of these cases, 43
      (53%) were judged inappropriate because another agent was considered first line,
      27 (33%) because there was no evidence of infection based on the documented
      evaluation, and 11 (14%) because of inability to assess the need for
      antimicrobial therapy. Although the prevalence of inappropriate use was similar
      across various clinical scenarios, there was a borderline significant association
      between the hospital in which the ED was located and inappropriate FQ use. Of the
      19 patients who received an FQ for an appropriate indication, only 1 received
      both the correct dose and duration of therapy. CONCLUSIONS: Inappropriate FQ use
      in EDs is extremely common. Efforts to limit emergence of FQ resistance must
      address the high level of inappropriate FQ use in EDs. Future studies should
      evaluate the impact of interventions designed to reduce inappropriate FQ use in
      this setting.

PMID- 12622608
TI  - The value of disease severity in predicting patient readiness to address end-of
      life issues.
AB  - BACKGROUND: Although patient-physician discussion is the most important tool for
      end-of-life planning, less than 30% of seriously ill patients have held these
      discussions. While physicians use objective disease severity and recent clinical
      events to trigger end-of-life discussions, it is not known if such findings
      predict patient readiness. We evaluated the ability of disease severity measures
      and recent clinical events to predict patient readiness for end-of-life
      discussions in patients with chronic lung disease. METHODS: The desire for
      discussion about end-of-life care was evaluated in 100 outpatients with a
      diagnosis of chronic lung disease presenting for pulmonary function testing.
      Objective disease severity was indicated by the percentage of the predicted
      forced expiratory volume, use of oral corticosteroids, a functional status score,
      frequency of recent hospitalizations, and required use of mechanical ventilation.
      RESULTS: In multivariate analysis, patient desire for an end-of-life discussion
      with the physician was not associated with percentage of predicted forced
      expiratory volume in 1 second (odds ratio [OR], 0.99; 95% confidence interval
      [CI], 0.96-1.03), oral corticosteroid use (OR, 1.34; 95% CI, 0.40-4.54),
      functional status score (OR, 1.37; 95% CI, 0.34-5.56), hospitalizations in the
      past year (OR, 0.33; 95% CI, 0.09-1.20), or previous mechanical ventilation (OR,
      1.37; 95% CI, 0.34-5.56). CONCLUSIONS: Patients appear no more or less interested
      in end-of-life discussions at later stages of chronic lung disease. Physicians
      cannot use disease severity measures or recent clinical events to accurately
      predict when patients desire end-of-life discussions. Focusing on physician skill
      in using specific communication strategies for patients at all stages of illness
      may be the most promising approach to increasing end-of-life discussions.

PMID- 12622609
TI  - Role of liver function tests in detecting methotrexate-induced liver damage in
      sarcoidosis.
AB  - BACKGROUND: Methotrexate has become a standard second-line agent for the
      treatment of sarcoidosis. Because sarcoidosis has a high frequency of liver
      involvement, we routinely perform a liver biopsy after each cumulative gram of
      methotrexate therapy in patients with sarcoidosis in whom we plan to continue
      therapy. METHODS: Following a previously described protocol for methotrexate
      therapy, we have performed 100 liver biopsies on 68 patients with chronic
      sarcoidosis at our institution. On the basis of the liver biopsy results, we
      identified the following 4 groups: sarcoidosis (47 cases), toxic effects of
      methotrexate (14 cases), hepatitis C (2 cases), and normal liver tissue (37
      cases). RESULTS: We found no difference among the groups in terms of age, weight
      at time of biopsy, the number of patients receiving corticosteroids at the time
      of biopsy, cumulative dose of methotrexate, race, or sex. The 14 cases of toxic
      reactions to methotrexate included 5 patients who had undergone 1 or more
      previous liver biopsies in which the results did not show toxic effects. We found
      a significant difference between groups for levels of alkaline phosphatase and
      asparate aminotransferase at the time of starting (or restarting) methotrexate
      therapy (analysis of variance, P<.05). This finding was also true for the liver
      function tests performed at the time of the biopsy (analysis of variance, P<.05).
      The highest values were for those whose biopsy findings showed sarcoidosis.
      CONCLUSIONS: Toxic reactions to methotrexate eventually occurred in more than 10%
      of patients with sarcoidosis treated for more than 2 years with methotrexate.
      Because of hepatic involvement owing to sarcoidosis, results of serial liver
      function tests were not useful in determining which patients would have this
      reaction to methotrexate.

PMID- 12622610
TI  - Challenges to the effective use of unfractionated heparin in the hospitalized
      management of acute thrombosis.
AB  - BACKGROUND: Unfractionated heparin therapy is care intensive because of dose
      response variability, and because of the necessity of constant intravenous
      infusion and frequent monitoring. We sought to assess the real-world course of
      transition from heparin to warfarin in hospitalized patients undergoing
      anticoagulation therapy for acute venous or arterial thrombosis at our medical
      center. METHODS: Patients were retrospectively identified from July 1998 to
      December 1998. Data collected included initiation and maintenance doses of
      heparin, frequency of monitoring and dose adjustments, time to the therapeutic
      range, complications and interruptions of therapy, and characteristics of heparin
      to-warfarin transition. RESULTS: Of the 311 patients who met the study criteria
      during the 6-month period, 134 had venous thromboembolism, 122 had cerebral
      arterial thrombosis, and 55 had peripheral arterial thrombosis. Groups differed
      in use and magnitude of initial heparin bolus, frequency of monitoring, and time
      to the therapeutic range. Dose response to intravenous heparin was highly
      variable. Even when the activated partial thromboplastin time reached the
      therapeutic range of 55 to 85 seconds, the next 2 consecutive measurements
      remained in this range in only 29% of the patients. Patients received an average
      of 4 different heparin doses over the first 3 days of treatment, and the
      therapeutic range was maintained on each of 4 sequential days in only 7% of them.
      During the course of therapy, 54% of the patients had at least 1 prolonged
      interruption in heparin infusion, and 4.8% sustained a major hemorrhage. Overall,
      20% of the patients met the currently recommended treatment guideline of 4 days
      or more of heparin and warfarin overlap, until the international normalized ratio
      is greater than 2.0 for 2 consecutive days. CONCLUSIONS: Multiple challenges to
      effective anticoagulation treatment with unfractionated heparin exist in the
      hospital setting. Strategies are needed to improve the overall quality of
      anticoagulant care, including the substitution of low-molecular-weight heparin
      for unfractionated heparin, where appropriate.

PMID- 12622611
TI  - More than 7 years of consistent neuropathic pain relief in geriatric patients.

PMID- 12622612
TI  - Captopril renal scans for detecting renal artery stenosis.

PMID- 12622614
TI  - Cancer survival in US racial/ethnic groups: heterogeneity among Asian ethnic
      subgroups.

PMID- 12622616
TI  - Topical imiquimod in the treatment of metastatic melanoma to skin.

PMID- 12622617
TI  - The scars of smallpox.

PMID- 12622618
TI  - The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: a
      population-based estimate.
AB  - BACKGROUND: Moles, or melanocytic nevi, are both markers of an increased risk of
      cutaneous melanoma and direct precursor lesions. Recent strategies to reduce the
      burden of advanced disease have focused on early detection and ongoing
      surveillance of moles for malignant degeneration. Inherent in this approach is
      the notion that moles exhibit a certain risk of transformation into melanoma;
      however, this risk is unknown. OBJECTIVE: To estimate the risk of moles
      transforming into cutaneous melanoma. DESIGN: We first constructed a model of
      transformation based on the assumption that the minimal number of moles turning
      into cutaneous melanoma per year is roughly equivalent to the number of melanomas
      diagnosed each year with associated nevic components. The annual risk was then
      calculated as the number of mole-associated melanomas diagnosed in 1 year
      (stratified by 10-year age groups) divided by the number of moles in a the same
      10-year age group. We also estimated the cumulative risk during the lifetime of
      an individual mole by using a modification of the standard life table method.
      RESULTS: The annual transformation rate of any single mole into melanoma ranges
      from 0.0005% or less (ie, </=1 in 200,000) for both men and women younger than 40
      years to 0.003% (about 1 in 33,000) for men older than 60 years. The rate is
      similar between men and women younger than 40 years but becomes substantially
      higher for men older than 40 years. For a 20-year-old individual, the lifetime
      risk of any selected mole transforming into melanoma by age 80 years is
      approximately 0.03% (1 in 3,164) for men and 0.009% (1 in 10,800) for women.
      CONCLUSIONS: The risk of any particular mole becoming melanoma is low, especially
      in younger individuals. However, since moles can disappear, ones that persist
      into old age have an increased risk of malignant degeneration. For young people
      with innumerable moles and no other associated risk factors, systematic excision
      of benign-appearing lesions would be of limited benefit.

PMID- 12622619
TI  - Analysis of heterogeneity of atypia within melanocytic nevi.
AB  - BACKGROUND: Incisional biopsy of clinically atypical nevi continues to be a
      common practice. Questions can arise as to the adequacy of these partial
      biopsies. OBJECTIVE: To determine whether incisional (partial) biopsy specimens
      may be considered representative of the entire lesion, atypical nevi submitted to
      our dermatopathology laboratory were examined for the presence or absence of
      heterogeneity of atypia within the individual nevi. DESIGN: The study included
      250 histologically atypical nevi that were selected consecutively from pigmented
      lesions that were submitted to our dermatopathology laboratory by community and
      academic dermatologists for histopathologic analysis. Also, 23 moderately to
      severely atypical and 25 severely atypical nevi from consecutive submissions were
      added for statistical reasons. Lesions with both clear and involved margins were
      used. Lesions were considered homogeneous if the atypia involved the entire
      lesion or heterogeneous if either the atypia was focal or if different degrees of
      atypia occurred within the same lesion. Atypia was defined by the usual
      parameters of architectural and cytologic atypia and host response. Also, the
      degree of atypia in relationship to heterogeneity and to patient age was
      determined. SETTING: The Dermatopathology Laboratory, University of California,
      Irvine. MAIN OUTCOME MEASURES: Outcome measures included the percentage of nevi
      exhibiting heterogeneity of atypia, heterogeneity of atypia in relation to
      patient age, degree of atypia in relation to patient age, and degree of atypia in
      relation to the presence of heterogeneity of atypia. RESULTS: Of the 298 nevi
      examined, 107 (35.9%) were heterogeneous in atypia and 191 (64.1%) were
      homogeneous in atypia. There was no significant difference in age between
      patients with heterogeneous lesions and those with homogeneous lesions. There was
      a statistically significant correlation between the degree of atypia and patient
      age. The average age of patients with a lesser degree of atypia was 36.9 years,
      while the average age of patients with a greater degree of atypia was 44.8 years
      (P<.005). There was no significant correlation between degree of atypia and
      heterogeneity of atypia (correlation coefficient, 0.1). CONCLUSIONS: A clinically
      significant proportion of atypical nevi exhibited heterogeneity of atypia. Also,
      there was a significant relationship between the degree of atypia and increasing
      age (P<.005). Therefore, if a clinically atypical nevus warrants a biopsy, these
      results give additional support for complete excisional biopsy (which can include
      shave or punch) to assure adequate histopathologic sampling of the lesion.

PMID- 12622620
TI  - Preoperative melanoma thickness determination by 20-MHz sonography and digital
      videomicroscopy in combination.
AB  - OBJECTIVE: To identify accurately thick melanomas preoperatively by means of a
      combined approach based on sonography and clinical-videomicroscopic evaluation.
      DESIGN: Ultrasonographic thickness measurement, obtained by means of a 20-MHz B
      scanner, and identification of clinical and videomicroscopic variables useful in
      distinguishing between thick and thin melanomas were performed on a training set
      of 40 melanomas. An algorithm based on echographic, clinical, and
      videomicroscopic criteria was constructed to develop a method for preoperative
      evaluation of melanoma thickness and was validated on a test set of 48 melanomas.
      SETTING: University medical department. PATIENTS: Eighty-eight patients affected
      by primary cutaneous melanoma. MAIN OUTCOME MEASURES: Sensitivity and specificity
      of the algorithm, with the use of sonographic, clinical, and videomicroscopic
      data, in thick melanoma identification. RESULTS: Echographic thickness was
      calculated for each lesion. On the training set, 2 clinical and 7
      videomicroscopic features were identified for distinction between thick and thin
      melanomas: nonpalpability, central pigment network, central brown globules, and
      blotches were characteristic of thin melanomas; clinical regression, localized
      peripheral pigment network, veil, grayish polygonal areas, and blood vessels were
      characteristic of thick ones. A coefficient was attributed to each variable and a
      score was obtained for each lesion. The algorithm, developed for preoperative
      thickness prediction, was validated on the test set, enabling the distinction of
      thick melanomas with an 86.7% sensitivity and a 100% specificity. CONCLUSION: The
      correct classification of all thin melanomas as such renders this approach
      suitable in clinical practice.

PMID- 12622621
TI  - Defining the clinical course of metastatic skin cancer in organ transplant
      recipients: a multicenter collaborative study.
AB  - OBJECTIVE: To evaluate the demographic characteristics, clinical course, and
      outcome in organ transplant recipients with metastatic skin cancer. DESIGN AND
      SETTING: An international, multicenter, Internet-coordinated collaborative group
      retrospectively analyzed data from 68 organ transplant recipients with 73
      distinct metastatic skin cancers. MAIN OUTCOME MEASUREMENTS: The Kaplan-Meier
      method was used to estimate the cumulative incidence of relapse, overall
      survival, and disease-specific survival after metastatic skin cancer. Univariate
      Cox proportional hazards models were fit to evaluate factors for an association
      with survival. RESULTS: Metastasis from skin cancer in organ transplant
      recipients most commonly consisted of squamous cell carcinoma in regional nodal
      basins. It was predominantly treated with a combination of surgery and
      irradiation. By 1 year after metastasis, the cumulative incidence of relapse was
      29%, and the 3-year disease-specific survival was 56%. Patients whose initial
      metastases were distant or systemic had a significantly poorer disease-specific
      survival than those whose initial metastases were in-transit or regional (risk
      ratio, 6.5; P<.001). CONCLUSIONS: Metastatic skin cancer in organ transplant
      recipients has a poor prognosis. Preventive, early, and aggressive therapeutic
      interventions are required to minimize this serious complication of transplant
      associated immunosuppression.

PMID- 12622623
TI  - The frequency of common skin conditions in preschool-aged children in Australia:
      seborrheic dermatitis and pityriasis capitis (cradle cap).
AB  - OBJECTIVE: To determine the prevalence and severity of seborrheic dermatitis and
      pityriasis capitis in Australian preschool-aged children. DESIGN: A stratified
      cross-sectional skin survey using cluster sampling of centers throughout
      Victoria, Australia. SETTING: The study population included children attending
      child care centers, preschools, and Maternal and Child Health Centers, with the
      reference population being Australian children 5 years and younger. PARTICIPANTS:
      Of the 1,634 children in the original sample, 1.116 children aged 11 days to 5
      years 11 months were included in the study. INTERVENTION: Parents completed a
      questionnaire recording demographic information and personal and family history
      of skin problems and related diseases. A dermatologist performed a total skin
      examination, including the diaper area for children younger than 12 months. MAIN
      OUTCOME MEASURE: The age- and sex-specific prevalence rates and site and severity
      of seborrheic dermatitis and pityriasis capitis were measured. RESULTS: The
      overall age- and sex-adjusted prevalence of seborrheic dermatitis was 10.0% (95%
      confidence interval [CI], 8.2%-11.7%): 10.4% (95% CI, 7.8%-12.9%) in boys and
      9.5% (95% CI, 7.0%-12.0%) in girls. This was highest in the first 3 months of
      life, decreasing rapidly by the age of 1 year, after which it slowly decreased
      over the next 4 years. Most (71.9%) had disease classified as minimal to mild.
      Pityriasis capitis occurred in 41.7% (95% CI, 38.8%-44.6%) of the 1,116 children
      examined, with 85.8% categorized as minimal to mild only. CONCLUSIONS: Seborrheic
      dermatitis and pityriasis capitis are common in early childhood. Most children
      have minimal to mild disease that would require little if any treatment.
      Education programs directed at those caring for preschool-aged children are
      needed to provide information on simple preventative measures and treatment, if
      necessary, that could easily reduce the morbidity associated with these very
      common conditions.

PMID- 12622622
TI  - Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria
      cutanea tarda.
AB  - OBJECTIVE: To examine the role of hemochromatosis (HFE) gene mutations, which are
      associated with porphyria cutanea tarda (PCT), in the therapeutic response to
      chloroquine. DESIGN: We retrospectively analyzed a database (Excel version 2001
      [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine
      treated patients with PCT on whether HFE mutations (C282Y and H63D) might have
      influenced the clinical response, urinary porphyrin excretion, liver enzyme
      activities, and serum iron markers. Serum samples and corresponding complete sets
      of data before and after therapy were available in 62 of 207 patients with PCT
      who were treated exclusively with chloroquine. SETTINGS: Academic teaching
      hospital. INTERVENTION: For treatment, low-dose chloroquine diphosphate, 125 to
      250 mg twice weekly, was used during a median time of 16 months (range, 12-26
      months). RESULTS: Of the 62 German patients with PCT, 37 (60%) carries HFE
      mutations. Chloroquine therapy was accompanied by clinical remission and reduced
      urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type
      as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum
      iron markers following chloroquine therapy were limited to patients with PCT and
      HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had
      high serum iron, ferritin, and transferrin saturation and failed to respond to
      chloroquine treatment. CONCLUSIONS: The therapeutic response to chloroquine was
      not compromised by C282Y heterozygosity and compound heterozygosity of HFE
      mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and
      a decrease in serum iron concentration was limited to patients with PCT and HFE
      wild type, phlebotomy should be first-line therapy in patients with PCT and HFE
      mutations.

PMID- 12622624
TI  - Narrowband UV-B (TL-01) phototherapy vs oral 8-methoxypsoralen psoralen-UV-A for
      the treatment of chronic plaque psoriasis.
AB  - OBJECTIVE: To compare the efficacy of narrowband UV-B (TL-01) phototherapy with
      oral 8-methoxypsoralen photochemotherapy (8-MOP psoralen-UV-A [PUVA]) in patients
      with chronic plaque psoriasis (CPP). DESIGN: Open, randomized, controlled study.
      SETTING: Phototherapy unit in a dermatology hospital. PATIENTS: Fifty-four
      patients with CCP. INTERVENTIONS: Patients received whole-body threshold
      erythemogenic dose of either 3-times weekly TL-01 or twice-weekly oral 8-MOP
      PUVA, based on minimal erythema or phototoxic doses. Patients were treated until
      completely clear. OUTCOME MEASURES: Number of treatments to clear, number of days
      in treatment, number of days in remission, and adverse effects of both therapies
      were assessed. RESULTS: Forty-five patients completed the study. Those in the
      PUVA group required significantly fewer treatments to clear (P =.03). There was
      no significant difference in the number of days to clear or number of days in
      remission. A similar percentage of patients in the TL-01 and PUVA groups
      developed minimal perceptible erythema, showing that the regimens were equally
      erythemogenic. Asymptomatic, well-defined erythema occurred only in the PUVA
      group. Pruritus and polymorphic light eruption occurred equally in both groups,
      but only patients in the PUVA group developed nausea. CONCLUSION: Narrowband UV-B
      phototherapy, used 3 times weekly, is as effective for the treatment of CPP as
      oral 8-MOP PUVA used twice weekly.

PMID- 12622625
TI  - The time course of topical PUVA erythema following 15- and 5-minute methoxsalen
      immersion.
AB  - BACKGROUND: Limited data exist in the literature concerning the characteristics
      of erythema following psoralen UV-A (PUVA) treatment using topical methoxsalen.
      To optimize the phototherapeutic regimen and reduce short- and long-term risks,
      knowledge of such basic information is essential. OBSERVATIONS: The
      characteristics of PUVA erythema following 15- and 5-minute immersion in
      methoxsalen was determined. The PUVA erythema after 15-minute methoxsalen
      immersion exhibited a broad peak, with the lowest median minimal phototoxic dose
      (MPD) at 96, 120, and 144 hours after UV-A irradiation. Seventy-three percent of
      subjects experienced peak erythema at 120 hours compared with only 45% at 72
      hours. From the dose-response data, an increase in the erythema index of 0.025
      (equivalent to the MPD) was significantly lower when determined at 120 hours
      after UV-A irradiation than at 72 hours (P =.03). The median maximum slope of the
      dose-response curve occurred at 144 hours. After 5-minute immersion, PUVA
      erythema displayed a broad peak from 72 hours. Erythema summation scores followed
      a trend similar to that of 15-minute immersion, but the intensity was
      significantly reduced. CONCLUSIONS: Methoxsalen-UV-A erythema exhibited a broad
      plateau between 96 and 144 hours, with most subjects at peak erythema at 120
      hours. Reduction of methoxsalen immersion time significantly lowered the
      erythemal intensity. Minimum phototoxic dose reading at 72 hours underestimates
      the phototoxic effect of topical methoxsalen PUVA, and a change in the MPD
      assessment time should be considered.

PMID- 12622626
TI  - Flagellate hyperpigmentation following intralesional bleomycin treatment of
      verruca plantaris.
AB  - BACKGROUND: Flagellate hyperpigmentation is a well-documented complication of
      systemic bleomycin sulfate therapy when using doses of 100 U or more as an
      antineoplastic agent. Two cases occurred after using systemic doses from 15 to 30
      U injected intravenously or intrapleurally; however, it has not been described as
      a complication following intralesional treatment of verruca plantaris.
      OBSERVATIONS: We report a case of flagellate hyperpigmentation after
      intralesional injection of 14 U of bleomycin for verrucae plantaris and review
      the literature associated with this cutaneous complication. CONCLUSIONS:
      Flagellate hyperpigmentation from extremely low doses of intralesional bleomycin
      is a previously undescribed complication. Although the mechanisms of reaction are
      not clearly understood, the clinician should be mindful of this uncommon
      complication.

PMID- 12622627
TI  - Delayed-type hypersensitivity to lidocaine.
AB  - BACKGROUND: Lidocaine hydrochloride is the preferred anesthetic agent used in
      outpatient surgical procedures. While type I hypersensitivity reactions to
      lidocaine are uncommon, type IV hypersensitivity is reported even less
      frequently. OBSERVATIONS: Between January 1, 2001, and December 31, 2001, 183
      patients were patch tested at the Penn State Milton S. Hershey Medical Center
      (Hershey, Pa) to the North American Contact Dermatitis Group tray. All patients
      who had a positive patch test reaction to lidocaine were challenged with 0.1 mL
      of preservative-free 1% lidocaine intradermally. Of the 183 patients patch
      tested, 4 had positive reactions to lidocaine, 2 of whom had histories of
      sensitivity to local injections of lidocaine manifested by dermatitis.
      CONCLUSIONS: Delayed-type hypersensitivity to lidocaine may occur more frequently
      than previously thought. In cases of suspected lidocaine contact type IV
      sensitivity, patients should be patch tested to lidocaine. Positive patch test
      reactions should be confirmed by intradermal challenge with lidocaine. To provide
      the patient with alternative local anesthetics, patch testing should be performed
      with other injectable anesthetics. If positive patch test results occur,
      intradermal testing should follow.

PMID- 12622628
TI  - Histopathologic correlation in dermoscopy: a micropunch technique.
AB  - BACKGROUND: Dermoscopy is a simple-to-use, in vivo method for the diagnosis of
      malignant melanoma and the differential diagnosis of pigmented skin lesions. It
      uses an immersion technique and optical magnification to visualize structures not
      visible to the naked eye. The anatomoclinical correlation of dermoscopic with
      histopathologic findings is important, and while many articles have described
      different techniques to achieve this goal, no direct correlation with a visual
      control has been described. We recently developed a micropunch technique that
      allows for the first time this direct correlation. OBSERVATIONS: After applying
      local anesthesia, the physician makes a superficial round incision using a 1-mm
      micropunch in the area of interest and leaves the punch in place. The lesion is
      documented using digital dermoscopy before and after surgery. Using these images,
      the laboratory technicians can easily visualize the precise site of the punch and
      its correlation with the initial dermoscopic image, and the sections are chosen
      in a way that they pass through the punch incision. The punch incision can be
      easily identified in the histopathologic slides because of its clear-cut borders.
      Since the punch always stays in place, this technique does not interfere with the
      interpretation of the slides (eg, measurement of the Breslow thickness).
      CONCLUSIONS: The advantages of our technique are that it is easy to perform by
      any clinician in any setting after a short setup and training period for the
      clinician and the laboratory technicians. Unlike with other techniques, the
      physician need not be present at the laboratory at the moment of the step
      sectioning. It can be performed in private practice and for many other
      indications besides pigmented skin lesions. Finally, since this technique allows
      for the first time a direct correlation between dermoscopic and histopathologic
      findings, the clinician will be able to "guide" the pathologist and indicate the
      precise areas of interest or suspicion.

PMID- 12622629
TI  - Performance of the self-administered psoriasis area and severity index in
      evaluating clinical and sociodemographic subgroups of patients with psoriasis.
AB  - BACKGROUND: There is a need to evaluate severity of psoriasis with a simple,
      patient-assessed instrument. OBJECTIVE: To investigate whether the self
      administered Psoriasis Area and Severity Index (SAPASI) could be used as a
      measure of severity in different clinical types of psoriasis. DESIGN: Hospital
      based cross-sectional study, with measures of clinical severity collected
      separately by dermatologists (PASI) and patients with psoriasis (SAPASI).
      SETTING: Part of a large project on clinical, epidemiological, emotional, and
      quality-of-life aspects of psoriasis (the IDI Multipurpose Psoriasis Research on
      Vital Experiences study), performed between February 21 and August 31, 2000, at
      the inpatient wards of the Istituto Dermopatico dell'Immacolata-Istituto di
      Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), Rome, Italy. PATIENTS: The
      study population comprised 351 eligible patients with complete sets of
      information on PASI and SAPASI hospitalized at IDI-IRCCS with a diagnosis of
      psoriasis. MAIN OUTCOME MEASURES: Correlation between PASI and SAPASI scores and
      analysis of variance on the difference between PASI and SAPASI scores in subsets
      of patients based on clinical and sociodemographic characteristics. RESULTS: A
      high correlation between the 2 measures was observed (overall Pearson correlation
      coefficient, r = 0.69). The SAPASI values were higher and had a wider scattering
      than PASI values, and SAPASI was able to discriminate properly between clinical
      types and global severity as assessed by dermatologists. CONCLUSIONS: The SAPASI
      scoring system is well understood and accepted by patients in different
      populations than previously tested, adding confidence in the validity of the
      instrument. It could be used as a severity measure for psoriasis even for "at
      distance" follow-up. Some caution, though, is needed when using SAPASI strictly
      to estimate PASI measurements, especially for guttate psoriasis.

PMID- 12622631
TI  - Accuracy of computer diagnosis of melanoma: a quantitative meta-analysis.
AB  - BACKGROUND: Recent developments in computer technology have raised expectations
      that fully automated diagnostic instruments will become available to diagnose
      cutaneous melanoma without the need of human expertise. OBJECTIVES: To critically
      review the contemporary literature on computer diagnosis of melanoma, evaluate
      the accuracy of such computer diagnosis, analyze the influence of study
      characteristics, and compare the accuracy of computer diagnosis of melanoma with
      human diagnosis. METHODS: Quantitative meta-analysis of published reports. DATA
      SOURCES: Eligible studies were identified by a MEDLINE search covering the period
      from January 1991 to March 2002, by manual searches of the reference lists of
      retrieved articles, and by direct communication with experts. RESULTS: Thirty
      studies with substantial differences in methodological quality were deemed
      eligible for meta-analysis. Five of these complied with the predetermined list of
      "good quality" requirements, but none met all methodological quality
      requirements. Ten of these studies compared the performance of computer diagnosis
      with human diagnosis. The diagnostic accuracy achieved with computer diagnosis
      was statistically not different from that of human diagnosis (log odds ratios,
      3.36 vs 3.51; P =.80). The diagnostic performance of the computer diagnosis was
      better for studies that used dermoscopic images than for studies that used
      clinical images (log odds ratios, 4.2 vs 3.4; P =.08). Other study
      characteristics did not significantly influence the accuracy of the computer
      diagnosis. CONCLUSIONS: The computer diagnosis of melanoma is accurate under
      experimental conditions, but the practical value of automated diagnostic
      instruments under real-world conditions is currently unknown. We suggest minimum
      requirements for methodological quality in future experimental studies or,
      ideally, randomized controlled trials.

PMID- 12622633
TI  - Assessing evidence-based dermatology and evidence-based internal medicine
      curricula in US residency training programs: a national survey.
AB  - OBJECTIVES: To examine attitudes toward evidence-based medicine and evidence
      based dermatology and to assess evidence-based training in US internal medicine
      and dermatology residency programs. METHODS: A 1-page self-administered
      questionnaire was mailed to residency training directors and chief residents at
      104 dermatology and 103 internal medicine residency programs from the same or
      affiliated medical centers. RESULTS: Questionnaires were returned by respondents
      from 70 (68%) of 103 internal medicine programs and 86 (83%) of 104 dermatology
      programs. Most respondents (91% internal medicine and 70% dermatology) strongly
      agreed or agreed that evidence-based internal medicine/dermatology is valuable
      and should be included in residency training (93% internal medicine and 70%
      dermatology). Respondents from internal medicine programs agreed more strongly
      with both statements than respondents from dermatology programs (P =.001).
      Dedicated evidence-based curricula were in place at significantly more internal
      medicine programs (50 [71%] of 70) than dermatology programs (20 [23%] of 86)
      (P<.001). Curricula at internal medicine programs offered significantly more
      evidence-based medicine training sessions (24 vs 6; P<.001) and biostatistics
      sessions (10 vs 2.3; P =.03), and internal medicine programs more frequently
      evaluated the curricula using clinical question applications (56% vs 30%; P
      =.04). CONCLUSION: Despite favorable attitudes toward evidence-based dermatology,
      compared with internal medicine programs, dedicated evidence-based training is
      underdeveloped in dermatology programs.

PMID- 12622635
TI  - Antibiotic prophylaxis for Lyme disease: how the way of reporting a clinical
      trial can alter the perception of effectiveness.

PMID- 12622638
TI  - New reasons for an archaic treatment: phlebotomy in sporadic porphyria cutanea
      tarda.

PMID- 12622636
TI  - Taking advantage of a side effect of isotretinoin.

PMID- 12622639
TI  - Asymptomatic nodule on the upper lip.

PMID- 12622640
TI  - Brownish reticulate maculopapular eruption on the flexures.

PMID- 12622641
TI  - An asymptomatic preauricular subcutaneous nodule in a 65-year-old woman.

PMID- 12622642
TI  - Plaque on the thigh of a renal transplant recipient.

PMID- 12622643
TI  - Nodular melanoma is not a distinct entity.

PMID- 12622646
TI  - Metastasizing thin melanoma or multiple primary melanomas?

PMID- 12622647
TI  - Surgilube as a replacement for oil during dermoscopic examination.

PMID- 12622648
TI  - Melanoma simulating seborrheic keratosis: a major dermoscopy pitfall.

PMID- 12622650
TI  - Combination of narrowband UV-B and topical calcipotriene in vitiligo.

PMID- 12622654
TI  - The Wood of the Self-Murderers: the Harpies and the Suicides.

PMID- 12622649
TI  - Leg ulcers associated with cryoglobulinemia: clinical study of 15 patients and
      response to treatment.

PMID- 12622655
TI  - Childhood head injury and expression of schizophrenia in multiply affected
      families.
AB  - BACKGROUND: The etiology of schizophrenia is believed to include genetic and
      nongenetic factors, with the pathogenesis involving abnormal neurodevelopment. We
      investigated whether mild head injury during brain maturation plays a role in the
      expression of schizophrenia in multiply affected families. METHODS: We compared
      the history and severity of head injuries in childhood (age, < or =10 years) and
      through adolescence (age, < or =17 years) in 67 subjects with narrowly defined
      schizophrenia and 102 of their unaffected siblings from 23 multiply affected
      families. In subjects with schizophrenia, only head injuries preceding the onset
      of psychosis were considered. RESULTS: Subjects in the schizophrenia group (n =
      16 [23.9%]) were more likely than the unaffected siblings group (n = 12 [11.8%])
      to have a history of childhood head injury (P =.04; odds ratio, 2.35 [95%
      confidence interval, 1.03-5.36]). Subjects in the schizophrenia group with a
      history of childhood head injury had a significantly younger median age at onset
      of psychosis (20 years) compared with those with no such history (25 years; z = 
      2.98; P =.003). The severity of head injury ranged from minimal to mild,
      including concussions, but within this narrow range, severity was correlated with
      younger age at onset (r(s) = -0.66; P =.005). Head injury occurred a median of 12
      years before the onset of psychosis. Results were similar if head injuries during
      adolescence were included, but did not achieve statistical significance.
      CONCLUSIONS: Mild childhood head injury may play a role in the expression of
      schizophrenia in families with a strong genetic predisposition. Prospective
      studies of mild head injury should consider genetic predisposition for possible
      long-term neurobehavioral sequelae.

PMID- 12622656
TI  - Impairments in perceptual competency and maintenance on a visual delayed match-to
      sample test in first-episode schizophrenia.
AB  - BACKGROUND: Deficits in working memory (WM) have been reported in patients with
      schizophrenia, but WM is a complex construct dependent on several subprocesses,
      including input representation (perceptual competency) and holding stimuli on
      line (maintenance). A visual delayed match-to-sample task (DMST) was developed to
      isolate perceptual competency from maintenance during delays. It was hypothesized
      that patients in the first episode of schizophrenia would exhibit dissociable
      deficits in both WM domains. METHODS: Performance on the DMST was assessed in 57
      patients in the first episode of schizophrenia or schizoaffective disorder and 22
      healthy comparison subjects. In phase 1 of the DMST, a complex visual stimulus
      (target) was followed immediately by a forced choice between 2 test stimuli, and
      item difficulty (differences between the test stimuli) was titrated until each
      subject achieved a consistent accuracy (80%-90%) in this no-delay condition. In
      phase 2, a delay of 4 or 8 seconds with a mask of randomly illuminated pixels was
      introduced between target and test stimuli; test stimuli were fixed in difficulty
      level based on phase 1 titration. Main outcome measures were mean item difficulty
      attained in the no-delay condition and mean accuracy in matching after delay.
      RESULTS: Compared with controls, patients attained a lower level of difficulty in
      the no-delay condition (P =.001) and significantly lower accuracy with delay (P
      =.002). CONCLUSIONS: Deficits in both domains of WM suggest abnormality in the
      posterior and prefrontal cortexes. These deficits can be observed in a task
      involving complex visual pattern stimuli using only a brief delay and are present
      even in unmedicated patients in the first episode of illness.

PMID- 12622657
TI  - Compounded brain volume deficits in schizophrenia-alcoholism comorbidity.
AB  - BACKGROUND: Schizophrenia and alcoholism are characterized by brain volume
      abnormalities. Despite the frequent comorbidity of these conditions, the
      potentially compounded effects of comorbidity on brain structure have seldom been
      rigorously assessed. METHODS: To determine the compounding effect of
      schizophrenia and alcoholism on regional brain volumes, we performed
      retrospective quantitative analysis of magnetic resonance images from men who
      participated in research protocols at the Veterans Affairs Palo Alto Health Care
      System, Palo Alto, Calif. Participants were selected on the basis of diagnostic
      criteria, yielding 4 comparison groups: 35 men comorbid for DSM-III-R
      schizophrenia or schizoaffective disorder and lifetime alcohol abuse or
      dependence; 64 men with DSM-III-R schizophrenia or schizoaffective disorder; 62
      men with Research Diagnostic Criteria alcoholism; and 62 healthy men screened to
      exclude any Axis I diagnosis or heavy alcohol use. The comorbid group matched the
      schizophrenia group on age and illness severity but was younger and drank 5 times
      less alcohol in their lifetimes than the alcoholism group. Gray and white matter
      volumes from 6 cortical regions were expressed as age- and head size-corrected z
      scores and were subjected to multivariate profile analyses. RESULTS: Gray matter
      volume deficits were present in all 3 patient groups but were greatest in the
      comorbid group. In the comorbid group, the most prominent volume deficits were in
      the prefrontal and anterior superior temporal regions. CONCLUSIONS: Despite lower
      alcohol exposure than in pure alcoholism, the comorbidity of schizophrenia with
      alcoholism has a particularly profound effect on prefrontal gray matter volume,
      compounding the prominent prefrontal deficits present independently in
      schizophrenia and alcoholism.

PMID- 12622658
TI  - Severity, chronicity, and timing of maternal depression and risk for adolescent
      offspring diagnoses in a community sample.
AB  - BACKGROUND: Risk for depression and other disorders is known to be high among
      children of depressed mothers, but little is known about the parameters of
      severity, chronicity, and timing of depression and its effects on children. The
      study addresses these issues, disaggregating their overlapping effects. METHODS:
      A sample of 816 women and their 15-year-old children in an Australian community
      were selected from a large birth cohort study to represent variation in maternal
      depression history during the child's first 10 years of life. Quantification of
      maternal depression severity and duration, and dates of occurrence, permitted
      analyses of youth depression and nondepressive disorders as a function of
      relative severity, chronicity, and timing of maternal depression. RESULTS:
      Diagnosable depression in children as old as 15 years was twice as likely among
      offspring of depressed, as compared with never-depressed mothers. After controls
      for demographic factors, severity of maternal depression contributed more to
      children's risk for depression than did chronicity. Children exposed even to 1 to
      2 months of maternal major depression, or to more than 12 months of mild
      depression had elevated risks of depression; however, chronicity of maternal
      depression was associated more with nondepressive outcomes than was severity.
      Timing of exposure did not differentially predict risk for the disorder in
      children when separated from confounding chronicity and severity parameters.
      CONCLUSIONS: Even relatively brief maternal major depression, but more prolonged
      mild depression, predicted children's risk for depressive disorders by age 15
      years in a community sample. Nondepressive outcomes were more complex to predict,
      which was due in part to difficulty dating disorder onset in relation to maternal
      depression. Exposure to maternal depression at any period in the first 10 years
      equally predicted youth depression if the mother was depressed only once. Further
      studies are needed to shed light on the mechanisms by which maternal depression
      has its effects.

PMID- 12622659
TI  - A prospective investigation of the natural history of the long-term weekly
      symptomatic status of bipolar II disorder.
AB  - BACKGROUND: This is the first prospective longitudinal study, to our knowledge,
      of the natural history of the weekly symptomatic status of bipolar II disorder
      (BP-II). METHODS: Weekly affective symptom status ratings for 86 patients with BP
      II were based on interviews conducted at 6- or 12-month intervals during a mean
      of 13.4 years of prospective follow-up. Percentage of weeks at each symptom
      severity level and the number of shifts in symptom status and polarity were
      examined. Predictors of chronicity for BP-II were evaluated using new chronicity
      measures. Chronicity was also analyzed in relation to the percentage of follow-up
      weeks with different types of somatic treatment. RESULTS: Patients with BP-II
      were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of
      weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed
      (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms
      combined were 3 times more common than major depressive symptoms. Longer intake
      episodes, a family history of affective disorders, and poor previous social
      functioning predicted greater chronicity. Prescribed somatic treatment did not
      correlate significantly with symptom chronicity. Patients with BP-II of brief (2
      6 days) vs longer (> or =7 days) hypomanias were not significantly different on
      any measure. CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic
      and is dominated by depressive rather than hypomanic or cycling/mixed symptoms.
      Symptom severity fluctuates frequently within the same patient over time,
      involving primarily symptoms of minor and subsyndromal severity. Longitudinally,
      BP-II is expressed as a dimensional illness involving the full severity range of
      depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II
      seems to be part of the same disease process.

PMID- 12622660
TI  - Abnormal expression and functional characteristics of cyclic adenosine
      monophosphate response element binding protein in postmortem brain of suicide
      subjects.
AB  - BACKGROUND: Cyclic adenosine monophosphate response element binding protein
      (CREB) is a transcription factor that, on phosphorylation by protein kinases, is
      activated, and in response, regulates the transcription of many neuronally
      expressed genes. In view of the recent observations that catalytic properties
      and/or expression of many kinases that mediate their physiological responses
      through the activation of CREB are altered in the postmortem brain of subjects
      who commit suicide (hereafter referred to as suicide subjects), we examined the
      status of CREB in suicidal behavior. METHODS: These studies were performed in
      Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20
      nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron
      specific enolase were determined in total RNA by means of quantitative reverse
      transcriptase-polymerase chain reaction. Protein levels and the functional
      characteristics of CREB were determined in nuclear fractions by means of Western
      blot and cyclic adenosine monophosphate response element (CRE)-DNA binding
      activity, respectively. In the same nuclear fraction, we determined the catalytic
      activity of cyclic adenosine monophosphate-stimulated protein kinase A by means
      of enzymatic assay. RESULTS: We observed a significant reduction in messenger RNA
      and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic
      adenosine monophosphate-stimulated protein kinase A activity in BA 9 and
      hippocampus of suicide subjects, without any change in messenger RNA levels of
      neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in
      CREB expression and CRE-DNA binding activity were present in all suicide
      subjects, irrespective of diagnosis. These changes were unrelated to postmortem
      intervals, age, sex, or antidepressant treatment. CONCLUSIONS: Given the
      significance of CREB in mediating various physiological functions through gene
      transcription, our results of decreased expression and functional characteristics
      of CREB in postmortem brain of suicide subjects suggest that CREB may play an
      important role in suicidal behavior.

PMID- 12622661
TI  - Physiologic responses to sudden, loud tones in monozygotic twins discordant for
      combat exposure: association with posttraumatic stress disorder.
AB  - BACKGROUND: Larger heart rate responses to sudden, loud (startling) tones
      represent one of the best-replicated psychophysiologic markers for posttraumatic
      stress disorder (PTSD). This abnormality may be a pretrauma vulnerability factor,
      ie, it may have been present prior to the event's occurrence and increased the
      individual's likelihood of developing PTSD on traumatic exposure. Alternately, it
      may be an acquired PTSD sign, ie, it may have developed after the traumatic
      exposure, along with the PTSD. Studying identical twins discordant for traumatic
      exposure offers an opportunity to resolve these competing origins. METHODS:
      Subjects included pairs of Vietnam combat veterans and their non-combat-exposed,
      monozygotic twins. Combat veterans were diagnosed as having current PTSD (n = 50)
      or non-PTSD (ie, never had) (n = 53). All subjects listened to a series of 15
      sudden, loud tone presentations while heart rate, skin conductance, and
      orbicularis oculi electromyogram responses were measured. RESULTS: Consistent
      with previous reports, averaged heart rate responses to the tones were larger in
      Vietnam combat veterans with PTSD. These larger responses were not shared by
      their non-combat-exposed co-twins, whose responses were similar to those of the
      non-PTSD combat veterans and their non-combat-exposed co-twins. This result
      remained significant after adjusting for a number of potentially confounding
      factors. CONCLUSIONS: The results suggest that larger heart rate responses to
      sudden, loud tones represent an acquired sign of PTSD rather than a familial
      vulnerability factor.

PMID- 12622662
TI  - Posttraumatic stress disorder and the incidence of nicotine, alcohol, and other
      drug disorders in persons who have experienced trauma.
AB  - BACKGROUND: We examine whether exposure to traumatic events increases the risk
      for nicotine dependence or alcohol or other drug use disorders, independent of
      posttraumatic stress disorder (PTSD). METHODS: Data come from a longitudinal
      epidemiologic study of young adults in southeast Michigan. Prospective data
      covering a 10-year period and retrospective lifetime data gathered at baseline
      were used to estimate the risk for onset of substance use disorders in persons
      with PTSD and in persons exposed to trauma without PTSD, compared with persons
      who have not been exposed to trauma. The National Institute of Mental Health
      Diagnostic Interview Schedule for DSM-III-R was used. Logistic regression was
      used to analyze the prospective data, and Cox proportional hazards survival
      analysis with time-dependent variables was applied to the lifetime data. RESULTS:
      The prospective and retrospective data show an increased risk for the onset of
      nicotine dependence and drug abuse or dependence in persons with PTSD, but no
      increased risk or a significantly (P =.004) lower risk (for nicotine dependence,
      in the prospective data) in persons exposed to trauma in the absence of PTSD,
      compared with unexposed persons. Exposure to trauma in either the presence or the
      absence of PTSD did not predict alcohol abuse or dependence. CONCLUSIONS: The
      findings do not support the hypothesis that exposure to traumatic events per se
      increases the risk for substance use disorders. A modestly elevated risk for
      nicotine dependence might be an exception. Posttraumatic stress disorder might be
      a causal risk factor for nicotine and drug use disorders or, alternatively, the
      co-occurrence of PTSD and these disorders might be influenced by shared risk
      factors other than traumatic exposure.

PMID- 12622663
TI  - Deep brain stimulation of the subthalamic nucleus enhances emotional processing
      in Parkinson disease.
AB  - BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a
      new and highly effective therapy for complications of long-term levodopa therapy
      and motor symptoms in advanced Parkinson disease (PD). Clinical observations
      indicate additional influence on emotional behavior. METHODS: Electrical
      stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a
      reversible, lesioning-like effect. Here, the effect of deep brain stimulation of
      the subthalamic nucleus on emotional, cognitive, and motor performance in
      patients with PD (n = 12) was examined. The results were compared with the
      effects of a suprathreshold dose of levodopa intended to transiently restore
      striatal dopamine deficiency. Patients were tested during medication
      off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and
      during the best motor state after taking levodopa without deep brain stimulation
      (MED). RESULTS: More positive self-reported mood and an enhanced mood induction
      effect as well as improvement in emotional memory during STIM ON were observed,
      while during STIM OFF, patients revealed reduced emotional performance.
      Comparable effects were revealed by STIM ON and MED. Cognitive performance was
      not affected by the different conditions and treatments. CONCLUSIONS: Deep brain
      stimulation of the subthalamic nucleus selectively enhanced affective processing
      and subjective well-being and seemed to be antidepressive. Levodopa and deep
      brain stimulation had similar effects on emotion. This finding may provide new
      clues about the neurobiologic bases of emotion and mood disorders, and it
      illustrates the important role of the basal ganglia and the dopaminergic system
      in emotional processing in addition to the well-known motor and cognitive
      functions.

PMID- 12622664
TI  - A twin study of the neuropsychological consequences of stimulant abuse.
AB  - BACKGROUND: Previous studies document neuropsychological deficits associated with
      stimulant abuse, but findings are inconsistent. METHODS: We identified 50 twin
      pairs in which only 1 member had heavy stimulant abuse (cocaine and/or
      amphetamines) ending at least 1 year before the evaluation. The co-twin control
      research design controls for familial vulnerability and makes it easier to
      identify neuropsychological deficits that are consequences of stimulant abuse.
      Subjects were administered an extensive neuropsychological test battery organized
      into the following 5 functions: attention, executive functioning, motor skills,
      intelligence, and memory. RESULTS: Multivariate tests showed that abusers
      performed significantly worse than nonabusers on functions of attention and motor
      skills. Within each of these functions, univariate tests showed that abusers
      performed significantly worse on certain tests of motor skills and attention. In
      contrast, abusers performed significantly better on one test of attention
      measuring visual vigilance. Within the abuser group, higher levels of stimulant
      use were largely uncorrelated with neuropsychological test scores, although a few
      significant correlations indicated better functioning with more stimulant use.
      CONCLUSIONS: With ideal controls, this study demonstrates that deficits in
      attention and motor skills persist after 1 year of abstinence from stimulant use
      and raises hypotheses regarding relative strengths on a vigilance task among
      abusers.

PMID- 12622667
TI  - Primary care and specialty care for US children: what is the right mix?

PMID- 12622665
TI  - Up-regulation of the D1 dopamine receptor-interacting protein, calcyon, in
      patients with schizophrenia.
AB  - BACKGROUND: The dopamine hypothesis remains a prominent influence on research
      into the pathogenesis of schizophrenia, yet the presence of consistent
      schizophrenia-linked abnormalities in the presynaptic components of the dopamine
      system or in dopamine receptors still remains a matter of debate. The present
      study focuses on a recently recognized group of dopamine receptor-interacting
      proteins as possible novel sites of dysfunction in schizophrenia. Specifically,
      we examined whether the D1 dopamine receptor-interacting protein calcyon and the
      D2 dopamine receptor-interacting proteins filamin-A and spinophilin are affected
      in the dorsolateral prefrontal cortex of patients with schizophrenia. METHODS:
      Slot blots of dorsolateral prefrontal cortical tissue were used to compare the
      levels of the 3 proteins of interest in control, schizophrenic, bipolar, and
      major depression groups (n = 15 per group). The nonschizophrenic psychiatric
      groups were included to determine the specificity of the detected abnormalities.
      RESULTS: The dorsolateral prefrontal cortex in schizophrenic patients displayed
      nearly twice the normal levels of calcyon, whereas filamin-A and spinophilin
      levels were unaltered. Patients with bipolar disorder or major depression showed
      no changes in all 3 proteins examined. CONCLUSION: Our findings provide the first
      evidence that abnormalities in the dopamine system of patients with schizophrenia
      may lie in altered levels of dopamine receptor-interacting proteins.

PMID- 12622668
TI  - Caring for parents vs caring for children: is there a difference?

PMID- 12622669
TI  - On the standard gamble.

PMID- 12622670
TI  - Danny's mother: a lesson in humility.

PMID- 12622671
TI  - Effect of an intervention standardization system on pediatric dosing and
      equipment size determination: a crossover trial involving simulated resuscitation
      events.
AB  - BACKGROUND: Pediatric medication dosing has been recognized as a high-error
      activity with the potential to cause serious harm. Few studies assess systems
      approaches to error reduction in pediatrics. OBJECTIVE: To estimate the decrease
      in deviation from recommended medication doses associated with use of a pediatric
      intervention standardization system in the acute setting. DESIGN: Two-period, 2
      treatment crossover trial with data collected between December 1, 1999, and
      February 29, 2000. SETTING: Tertiary, academic medical center. PARTICIPANTS:
      Convenience sample of 28 resident physicians, representing 69% of pediatrics and
      50% of medicine-pediatrics residents. INTERVENTION: Each resident participated in
      4 simulated pediatric resuscitations. The Broselow Pediatric Emergency Tape and
      color-coded materials were available in either the first or second 2 scenarios.
      Traditional dosing references were available in all scenarios. MAIN OUTCOME
      MEASURE: Median difference between deviation from recommended dose range (DRDR)
      in scenarios where color coding was used (intervention) and DRDR in scenarios
      where color coding was not available (control). RESULTS: Median DRDR in
      intervention scenarios was 25.4% lower than in control scenarios (95% confidence
      interval [CI], 19.1%-32.5%; P<.001). In 4 medication prescriptions in
      intervention scenarios and in 54 prescriptions in control scenarios, DRDRs
      exceeded 100%. Median deviation from recommended equipment sizes in intervention
      scenarios was 0.12 size lower than in control scenarios (95% CI, 0.03-0.22 size;
      P<.001). Deviations in equipment size of 2 or more sizes were noted in 1 size
      determination in intervention scenarios and in 21 size determinations in control
      scenarios. CONCLUSIONS: Color coding was associated with a significant reduction
      in deviation from recommended doses in simulated pediatric emergencies. Numerous
      potentially clinically significant deviations from recommended doses and
      equipment sizes were avoided. Future studies should measure impact in the real
      clinical setting.

PMID- 12622672
TI  - Breastfeeding and the risk of hospitalization for respiratory disease in infancy:
      a meta-analysis.
AB  - OBJECTIVE: To examine breastfeeding and the risk of hospitalization for lower
      respiratory tract disease in healthy full-term infants with access to modern
      medical care. DATA SOURCES: MEDLINE, personal communication with researchers, the
      OVID databases, Dissertation Abstracts Online, and BIOSIS. STUDY SELECTION: The
      titles, abstracts, and text of studies from developed countries were explored for
      breastfeeding exposure measures and lower respiratory tract disease
      hospitalization rates. For summary statistics, we required 3 inclusion criteria:
      (1) a feeding contrast of a minimum of 2 months of exclusive breastfeeding (no
      formula supplementation) vs no breastfeeding and (2) study populations that
      excluded sick, low birth weight or premature infants and (3) reflected affluent
      regions; 27% of studies met these criteria. DATA EXTRACTION: We abstracted data
      from all relevant reports. DATA SYNTHESIS: Data from all primary material (33
      studies) indicated a protective association between breastfeeding and the risk of
      respiratory disease hospitalization. Nine studies met all inclusion criteria, and
      7 cohort studies were pooled. The feeding contrasts in these 7 studies were 4 or
      more months of exclusive breastfeeding vs no breastfeeding. The summary relative
      risk (95% confidence interval) was 0.28 (0.14-0.54), using a random-effects
      model. This effect remained stable and statistically significant after adjusting
      for the effects of smoking or socioeconomic status. CONCLUSION: Among generally
      healthy infants in developed nations, more than a tripling in severe respiratory
      tract illnesses resulting in hospitalizations was noted for infants who were not
      breastfed compared with those who were exclusively breastfed for 4 months.

PMID- 12622673
TI  - Disparities in the prevalence of disability between black and white children.
AB  - OBJECTIVES: To examine disparities in the prevalence of the limitation of
      activity caused by chronic conditions or disability for black and white non
      Hispanic children and to examine trends over time in the prevalence of
      disability. DESIGN: We analyzed data on 419,843 children (22,758 with a
      disability) younger than 18 years included in 14 annual editions of the National
      Health Interview Survey spanning the period 1979-2000. SETTING:
      Noninstitutionalized population in the United States. INTERVENTIONS: None. MAIN
      OUTCOME MEASURE: Prevalence of disability. RESULTS: The prevalence of disability
      increased markedly for both black and white children between 1979 and 2000.
      Bivariate analysis demonstrated racial differences that fluctuated through time,
      but persisted through 2000, with black children experiencing a higher prevalence
      of disability than white children. Multivariate analyses conducted on the 1999
      2000 data indicated that the black-white difference in disability prevalence
      could be explained entirely by differences in poverty status. CONCLUSION: Black
      children have higher rates of disability primarily owing to their increased
      exposure to poverty.

PMID- 12622674
TI  - Barriers to HAART adherence among human immunodeficiency virus-infected
      adolescents.
AB  - OBJECTIVES: To investigate the barriers to highly active antiretrovial therapy
      (HAART) adherence among human immunodeficiency virus (HIV)-infected adolescents
      and to explore the association of barriers and nonadherence. DESIGN: Structured
      interviews were conducted to determine the barriers associated with adherence;
      principal component factor analysis was performed on scores of the 19 barrier
      variables. SETTING: Human immunodeficiency virus-infected adolescents were
      recruited from 13 US cities into the REACH (Reaching for Excellence in Adolescent
      Care and Health) Project, the first large-scale disease progression study of HIV
      positive adolescents infected through sexual behavior or injection drug use.
      PATIENTS: Human immunodeficiency virus-infected adolescents in the REACH cohort
      who were prescribed HAART (N = 114) were included in the analyses. MAIN OUTCOME
      MEASURES: The main outcome measures were self-report of adherence and barriers to
      adherence and viral load (HIV-1 RNA level in plasma). RESULTS: Viral load was
      significantly associated with self-report of adherence to HAART (P =.02). Only
      28.3% of adolescents reported taking all of their prescribed antiretroviral
      medications in the previous month. Factor analysis of the barriers to adherence
      indicates there are 2 factors accounting for the largest proportion of the
      variance: (1) medication-related adverse effects (both physical and
      psychological) and (2) complications in day-to-day routines. CONCLUSIONS:
      Adherence was tied closely with daily routine, which supports the assumption that
      working closely with adolescents to improve their organizational skills may be
      necessary to improve adherence. Patient-level intervention, provider-level
      intervention, and health care system modification may all be necessary to improve
      HIV-infected adolescents' adherence to HAART.

PMID- 12622675
TI  - Influence of the news media on diagnostic testing in the emergency department.
AB  - OBJECTIVE: To examine the association between mass media attention regarding
      invasive group A streptococcal (GAS) disease and testing for GAS in a pediatric
      emergency department (ED). DESIGN, SETTING, AND PARTICIPANTS: An observational
      analysis was performed of patients who had GAS tests done in a pediatric ED
      between December 1, 1999, and November 30, 2001. Data were analyzed by dividing
      each of the 2 years into 4 consecutive 90-day intervals. Data including age, date
      of the visit, presenting complaint, primary discharge diagnosis, whether a GAS
      test was obtained, and the results were collected from an electronic data
      repository. The date of the news stories, the station, and the duration of the
      broadcast were collected from electronic archives of the local newspaper and a
      broadcast monitoring service. MAIN OUTCOME MEASURE: The rate of GAS tests done
      per 1000 ED visits and the rate of positive tests per 1000 ED visits. RESULTS: An
      average of 103 GAS tests were performed per 1000 ED visits in the December
      through February period in year 2 compared with 55 GAS tests per 1000 ED visits
      in a similar period in year 1. This difference was statistically significant
      (difference, 48 tests; 95% confidence interval, 24-72 tests; P<.001). There were
      no significant differences in the proportion of positive tests (32% in year 1 vs
      20% in year 2; mean difference, -11%; 95% confidence interval, -23% to 1%; P
      =.07). There were a total of 16 newspaper articles and 34 television stories on
      GAS during the 2-year study period. The peak in GAS tests and the peak in media
      events were concomitant. CONCLUSION: A surge in news stories regarding GAS
      disease was associated with an increase in testing for GAS in a pediatric ED.

PMID- 12622676
TI  - Stability of maternal preferences for pediatric health states in the perinatal
      period and 1 year later.
AB  - BACKGROUND: We have previously shown that parents of premature children provided
      relatively high valuation of their children's health state in adolescence.
      However, stability of parental preferences for future pediatric health states is
      unknown during the antenatal and neonatal periods and infancy. OBJECTIVE: To
      determine whether preference-based, health-related quality-of-life scores
      obtained serially from 2 cohorts (women with high-risk pregnancies [antenatal
      cohort] and mothers of very low-birth-weight newborns [VLBW cohort]) are stable
      during the first year after birth. DESIGN AND METHODS: Longitudinal cohort study.
      Participants included 80 high-risk pregnant women recruited at 24 +/- 2 weeks of
      gestation, and 75 mothers of VLBW infants recruited within 1 week of delivery. We
      conducted 2 to 3 standardized interviews (antenatally, at 1 week after delivery,
      and at the 12-month corrected age visit) using the Standard Gamble technique to
      elicit preferences for 5 pediatric hypothetical health states with varying
      disabilities. RESULTS: Seventy-three mothers with high-risk pregnancies (91%) and
      72 mothers of VLBW infants (96%) completed all scheduled interviews. As expected,
      preference scores were affected by the level of severity of the hypothetical
      health states (antenatal cohort, F(4,288) = 87.0 [P<.001]; VLBW cohort, F(4,284)
      = 64.2 [P<.001]). At each assessment, at least 38% of mothers rated 1 or more
      health states as worse than death. Repeated-measures analysis showed no change in
      preference scores over time (antenatal cohort, F(2,144) = 1.3 [P =.29]; VLBW
      cohort, F(1,71) = 0.7 [P =.42]). Maternal socioemotional factors, infant severity
      of illness at birth, and global health at 12 months did not affect preference
      scores. CONCLUSION: In our population, maternal preference scores for disabling
      health states appear to be stable during the first year of life and are
      unaffected by key maternal and infant variables.

PMID- 12622677
TI  - Identification of children with special health care needs within a managed care
      setting.
AB  - OBJECTIVE: To assess 2 established methods of identifying children with special
      health care needs (CSHCN) within a health plan population for intensified service
      coordination. METHODS: The tools tested were the Questionnaire for Identifying
      Children With Chronic Conditions (QuICCC) and the Clinical Risk Grouper (CRG)
      software. The QuICCC was administered by telephone to the parents of 517
      children. The CRG software tool was then applied to the health plan database. The
      accuracy of identifying the target population was assessed by a single trained
      reviewer by comparison with the comprehensive medical record. RESULTS: According
      to the QuICCC, 37.1% of the parents surveyed had CSHCN. According to the CRG, 11%
      of the health plan's pediatric population was categorized as CSHCN. The medical
      record review agreed with overall QuICCC findings in 53% to 61% of cases and
      overall CRG findings in 66% to 73% of cases. CONCLUSIONS: Administering the
      QuICCC was a time- and labor-intensive endeavor with a relatively low overall
      level of sensitivity. The CRG was less labor intensive with slightly higher
      sensitivity. Identifying the target population in an effective and efficient
      manner remains a challenge for health plans.

PMID- 12622678
TI  - Referral of children to specialists in the United States and the United kingdom.
AB  - OBJECTIVE: To compare the rates and patterns of children's specialty referrals in
      the United States (US) and the United Kingdom (UK). DESIGN: Retrospective cohort
      analysis of health care claims/encounter data obtained in 1996 (US) and 1997
      (UK). SETTING: Children in the US were selected from 5 managed health plans that
      used primary care physicians as gatekeepers: 2 health maintenance organizations
      and 3 point-of-service plans. Point-of-service plans allow patient self-referral
      at increased out-of-pocket costs. In the UK, the General Practice Research
      Database provided data from 211 general practices. PARTICIPANTS: Children, from
      birth to the age of 17 years, with no cost sharing for physician services in the
      US (n = 135,092) and who were registered with general practitioners, all of whom
      authorize patients' access to specialty care, in the UK (n = 221,312). MAIN
      OUTCOME MEASURE: Annual percentage of children referred to a specialist. RESULTS:
      Across the 5 US plans, 18.6% to 28.8% of the patients per year were referred vs
      8.7% of the patients per year in the UK sample. Referral rates were not
      significantly different between a health maintenance organization and a point-of
      service plan administered by a single insurer. Compared with patients in the UK
      sample, those in the US plans were 1.9 times more commonly referred to medical
      specialists and 3.2 times more commonly referred to surgical specialists. There
      was considerable cross-national variation in specialty-specific referral rates
      for children with selected conditions. CONCLUSIONS: Children in US managed care
      plans are between 2 and 3 times as likely to be referred to specialists compared
      with counterparts in the UK. Although these referral rate differences are
      substantial, our findings cannot be construed to mean that the US referral rates
      are too high or that the UK rates are too low. The greater supply of specialists
      and higher expectations for direct access to specialty care in the US, compared
      with the UK, are likely explanations for these differences in children's
      specialty referral rates.

PMID- 12622679
TI  - Defining the sudden infant death syndrome.
AB  - Sudden infant death syndrome (SIDS) is a term that was first proposed in 1969 for
      a distinctive subgroup of unexpected infant deaths that occur during the
      postneonatal period with relatively consistent clinical, epidemiological, and
      pathological features. This term played an important role by focusing attention
      on a major category of postneonatal infant death, providing support to grieving
      families, and diminishing the guilt and blame characteristic of these deaths.
      Unfortunately, the application of this term has become increasingly
      controversial. Some have applied it too liberally, and others not at all.
      According to the definition proposed in 1969, despite slight changes suggested in
      1989, SIDS remains a diagnosis of exclusion. Although this syndrome has several
      distinctive features, including age distribution and apparent occurrence during
      sleep, there has been reluctance to include these features in the definition. The
      problems created by the lack of an adequate definition are discussed. A 2-tiered
      approach is suggested, with a more general definition intended primarily for case
      management and death administration, and a more restrictive one intended
      primarily for research purposes, which distinguishes those deaths closely fitting
      the classic SIDS profile from those with one or more less typical features.

PMID- 12622680
TI  - I agree with Beckwith.

PMID- 12622681
TI  - Reflections on redefining SIDS.

PMID- 12622682
TI  - An international perspective.

PMID- 12622683
TI  - New Challenges for SIDS Research.

PMID- 12622684
TI  - Sudden infant death syndrome: need for simple definition but detailed diagnostic
      criteria.

PMID- 12622685
TI  - SIDS: permissive or privileged "diagnosis"?

PMID- 12622686
TI  - Pediatric-based smoking cessation intervention for low-income women: a randomized
      trial.
AB  - BACKGROUND: Continued high rates of smoking among socioeconomically disadvantaged
      women lead to increases in children's health problems associated with exposure to
      tobacco smoke. The pediatric clinic is a "teachable setting" in which to provide
      advice and assistance to parents who smoke. OBJECTIVE: To evaluate a smoking
      cessation intervention for women. DESIGN: Two-arm (usual care vs intervention)
      randomized trial. SETTING: Pediatric clinics serving an ethnically diverse
      population of low-income families in the greater Seattle, Wash, area.
      INTERVENTION: During the clinic visit, women received a motivational message from
      the child's clinician, a guide to quitting smoking, and a 10-minute motivational
      interview with a nurse or study interventionist. Women received as many as 3
      outreach telephone counseling calls from the clinic nurse or interventionist in
      the 3 months following the visit. PARTICIPANTS: Self-identified women smokers (n
      = 303) whose children received care at participating clinics. MAIN OUTCOME
      MEASURE: Self-reported abstinence from smoking 12 months after enrollment in the
      study, defined as not smoking, even a puff, during the 7 days prior to
      assessment. RESULTS: Response rates at 3 and 12 months were 80% and 81%. At both
      follow-ups, abstinence rates were twice as great in the intervention group as in
      the control group (7.7% vs 3.4% and 13.5% vs 6.9%, respectively). The 12-month
      difference was statistically significant. CONCLUSIONS: A pediatric clinic smoking
      cessation intervention has long-term effects in a socioeconomically disadvantaged
      sample of women smokers. The results encourage implementation of evidence-based
      clinical guidelines for smoking cessation in pediatric practice.

PMID- 12622691
TI  - Non-genomic progesterone receptors in the mammalian ovary: some unresolved
      issues.
AB  - In addition to their well-documented genomic effects, steroid hormones may also
      exert actions that are: (i) rapid, (ii) insensitive to inhibitors of
      transcription, (iii) mimicked by steroids coupled to cell membrane-impermeant
      molecules, and (iv) demonstrable in cells that do not express the classic genomic
      progesterone receptor (gPR). Such 'non-genomic' effects have been described for
      all the major classes of steroids (progesterone, oestrogens, androgens and
      corticoids), as well as for thyroid hormones, retinoids and vitamin D(3). Rapid,
      membrane-mediated effects of progesterone have been studied most intensively in
      human spermatozoa and in the Xenopus oocyte. However, similar non-genomic actions
      of progesterone and other steroids have now been described in a wide variety of
      different tissues in many species. The first putative membrane steroid receptor
      to be cloned was that for the pig membrane progesterone receptor (mPR).
      Subsequently, similar genes were cloned from rats and cattle, and two related
      mPRs have been described in humans. Despite accumulating evidence for cell
      surface membrane actions of steroids, a number of uncertainties remain as to the
      properties and identity of such 'receptors' and their cellular actions.
      Furthermore, some rapid steroid effects may be mediated through membrane
      associated 'classical' steroid receptors, and steroid receptors may be capable of
      activating other signalling pathways non-classically. This review focuses on some
      of these unresolved issues, taking as its model the actions of progesterone in
      the mammalian ovary.

PMID- 12622692
TI  - Protein phosphorylation in mammalian spermatozoa.
AB  - Spermatozoa undergo a series of changes before and during egg binding to acquire
      the ability to fuse with the oocyte. These priming events are regulated by the
      activation of compartmentalized intracellular signalling pathways, which control
      the phosphorylation status of sperm proteins. Increased protein tyrosine
      phosphorylation is associated with capacitation, hyperactivated motility, zona
      pellucida binding, acrosome reaction and sperm-oocyte binding and fusion. The
      main tyrosine phosphorylated proteins during the course of capacitation and
      fertilization are localized to the flagellum, although tyrosine phosphorylation
      of less abundant proteins may also be regulated in the sperm head. Spermatozoa
      bound to the zona pellucida and fusing with the oocyte plasma membrane are
      characterized by a tyrosine phosphorylated flagellum. Protein phosphorylation in
      the flagellum is linked to hyperactivated motility in spermatozoa, but may also
      regulate additional functions involved in sperm-oocyte fusion. Factors involved
      in the appearance of phosphorylation more likely arise from the milieu
      surrounding the spermatozoa, but their uptake and processing are likely to be
      regulated differentially at specific steps within the female genital tract and
      during penetration of the egg vestments. One of these factors is glucose, the
      metabolic products of which (ATP and NADPH) appear to participate in signalling
      pathways by supporting a precise onset of tyrosine phosphorylation in the sperm
      flagellum leading to successful fertilization.

PMID- 12622689
TI  - Haem and nitric oxide: synergism in the modulation of the endothelial haem
      oxygenase-1 pathway.
AB  - NO potently up-regulates vascular haem oxygenase-1 (HO-1), an inducible defensive
      protein that degrades haem to CO, iron and the antioxidant bilirubin. Since
      several pathological states are characterized by increased NO production and
      liberation of haem from haem-containing proteins, we examined how NO influences
      HO-1 induction mediated by haemin. Aortic endothelial cells treated with S
      nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (SNP) or
      diethylenetriamine-NONOate (DETA/NO) and haemin exhibited higher levels of haem
      oxygenase activity compared with cells exposed to NO donors or haemin alone. This
      was accompanied by a marked increase in bilirubin production and, notably, by a
      strong magnification of cellular haem uptake. A role for haem metabolites in
      modulating HO-1 expression by NO was assessed by exposing cells to SNAP, SNP or
      DETA/NO in medium derived from cells treated with haemin, which contained
      increased bilirubin levels. This treatment considerably potentiated HO-1
      expression and haem oxygenase activity mediated by NO and the use of a haem
      oxygenase inhibitor abolished this effect. Both iron liberated during haem
      breakdown and the formation of nitroxyl anion from NO appeared to partially
      contribute to the amplifying phenomenon; in addition, medium from haemin-treated
      cells significantly augmented the release of NO by NO donors. Thus we have
      identified novel mechanisms related to the induction of HO-1 by NO indicating
      that the signalling actions of NO vary significantly in the presence of haem and
      haem metabolites, ultimately increasing the defensive abilities of the
      endothelium to counteract oxidative and nitrosative stress.

PMID- 12622693
TI  - Role of tumour necrosis factor stimulated gene 6 (TSG-6) in the coupling of inter
      alpha-trypsin inhibitor to hyaluronan in human follicular fluid.
AB  - Binding of the plasma proteinase inhibitor inter-alpha-trypsin inhibitor (ITI) to
      hyaluronan is necessary for normal expansion of the cumulus-oocyte complex. Lack
      of ITI causes severe infertility. Binding of ITI to hyaluronan depends on calcium
      ions and coupling activity present in follicular fluid (Odum et al., 2002). The
      complexes formed by this process contain ITI heavy chains bound to hyaluronan,
      and bikunin is detached from ITI during the coupling reaction. In the present
      study, an electrophoretic technique by which hyaluronan-bound ITI is immobilized
      was used to demonstrate that tumour necrosis factor stimulated gene 6 (TSG-6) is
      necessary for the coupling reaction. Thus, immunoprecipitation of TSG-6 in human
      follicular fluid eliminates the coupling reaction and re-addition restores the
      activity. However, it appears that components other than hyaluronan, ITI, calcium
      ions and TSG-6 are involved in the coupling reaction, as in vitro incubation of
      these components does not generate stable complexes between ITI heavy chains and
      hyaluronan unless some follicular fluid is added. In conclusion, TSG-6 is
      necessary for the coupling of ITI to hyaluronan, but at least one additional
      component in follicular fluid is essential.

PMID- 12622694
TI  - Immunohistochemical localization of inhibin/activin alpha, betaA and betaB
      subunits and follistatin in bovine oocytes during in vitro maturation and
      fertilization.
AB  - The aim of this study was to evaluate the distribution of inhibin/activin alpha,
      beta(A) and beta(B) subunits and follistatin in immature oocytes and in matured
      oocytes before and after IVF. Denuded oocytes were submitted to a whole-mount
      immunofluorescence procedure. Specimens were imaged and fluorescent intensities
      quantified by scanning laser confocal microscopy. Immunoreactivity for inhibin
      alpha subunit (both alpha(C) and pro-alpha regions), abundant in the ooplasm of
      immature oocytes, decreased after maturation (a 68% and 88% decrease,
      respectively; P < 0.001), but increased after IVF by 2- and 5.7-fold,
      respectively (P < 0.01). Intense staining for beta(A) was detected in immature
      oocytes (predominantly in the outer ooplasm and zona pellucida) but after
      maturation and fertilization it was localized mainly in the zona pellucida,
      perivitelline space and oolemma. Immunoreactivity for beta(A) in the ooplasm
      decreased by 58% after maturation (P < 0.001) but increased again by 75% after
      fertilization (P < 0.01). Immunoreactivity for beta(B) was localized mainly in
      the zona pellucida and did not change after maturation. However, immunoreactivity
      for beta(B) was not detected in the zona pellucida after fertilization, but
      remained unchanged in unfertilized oocytes. Immunoreactivity for follistatin was
      detected in the ooplasm and zona pellucida of immature oocytes but decreased
      progressively in the ooplasm after maturation (a 63% decrease; P < 0.001) and did
      not change after IVF. Examination of partially denuded cumulus-oocyte complexes
      confirmed abundant expression of alpha(C), pro-alpha, beta(A) and follistatin
      immunoreactivity in cumulus cells, whereas beta(B) subunit staining was weak or
      absent in cumulus cells, but intense in the zona pellucida. In conclusion, the
      present study shows that qualitative and quantitative changes in the distribution
      of inhibin/activin subunits and follistatin accompany oocyte maturation and
      fertilization. The possibility, indicated by these observations, that activin A
      and activin B may play distinct roles in bovine oocyte maturation and
      fertilization warrants further study.

PMID- 12622695
TI  - Changes in flagellar bending during the course of hyperactivation in hamster
      spermatozoa.
AB  - The motility pattern of mammalian spermatozoa changes during migration in the
      female genital tract and during incubation in vitro. This change in motility is
      termed hyperactivation. Hyperactivated spermatozoa swim vigorously in 'whiplash',
      'figure-8' or 'small circle' trajectories. In this study, a quantitative analysis
      was carried out of the changes in the motility pattern of hamster spermatozoa
      during incubation to investigate the mechanism regulating hyperactivation. In the
      culture system used in this study, hyperactivation occurred 4 h after incubation.
      Several parameters in the analysis of sperm movement pattern were examined.
      Curvilinear velocity, average path velocity and straightness abruptly increased
      between 2 and 4 h. However, linearity, amplitude of lateral head displacement,
      beat cross frequency and average wavelength gradually changed with time. In the
      analysis of flagellar bending, the bend angles were measured after dividing
      images of the flagellum into short lengths. Flagellar bending changed in
      different manners in each region during incubation. The asymmetry in the
      direction of the curve of the head gradually increased with time in the first
      half of the flagellum. The flexibility, which was determined using the amplitude
      of bending and the rate of change in bend angles, abruptly decreased between 10
      min and 1 h, and then increased between 2 and 4 h in the first half of flagellum.
      These results indicate that complex physiological changes occur before
      hyperactivation.

PMID- 12622696
TI  - Cloning of pig prostaglandin F2alphaFP receptor cDNA and expression of its mRNA
      in the corpora lutea.
AB  - Changes in the expression and localization of luteal mRNA for PGF(2alpha) (FP)
      receptors may be critical in determining the luteolytic action of PGF(2alpha) in
      pig corpora lutea. In this study, a full-length FP receptor (FPr) cDNA was
      isolated and cloned from pig corpora lutea. This isolate (GenBank accession no.
      U91520) contains an open reading frame of 1086 bases coding for a protein of 362
      amino acids with seven potential transmembrane domains. The predicted amino acid
      sequence of this isolate was 83% identical to the FPr amino acid sequence of
      other species including sheep, cattle and humans. Northern blot analysis showed
      the presence of an FPr message of about 5 kb in mRNA from pig corpora lutea.
      Relatively weak FPr mRNA expression was detected on day 4 and day 7 of the
      oestrous cycle. The expression was greater (P < 0.05) on days 10, 13 and 15 than
      on days 4 and 7. In situ hybridization analysis revealed that mRNA for FPr was
      expressed predominantly in the steroidogenic large luteal subtype of cell,
      although there was some expression in small luteal cells, with histological
      appearance of steroidogenic small cells. Localization of hybridization signals of
      FPr was observed in luteal tissue at all stages examined. These data demonstrate
      that FPr is expressed in pig corpora lutea throughout the oestrous cycle and that
      upregulation of the FPr mRNA occurs when the corpora lutea becomes sensitive to
      PGF(2alpha). Direct luteal targets of PGF(2alpha) appear to be primarily large
      steroidogenic cells in this species.

PMID- 12622697
TI  - Species differences in the ovarian distribution of 3beta-hydroxysteroid
      dehydrogenase/delta5-->4 isomerase (3beta-HSD) in two marsupials: the brushtail
      possum Trichosurus vulpecula and the grey, short-tailed opossum Monodelphis
      domestica.
AB  - The ovarian distribution of the steroidogenic enzyme 3beta-hydroxysteroid
      dehydrogenase/delta(5-->4) isomerase (3beta-HSD) was investigated by
      immunocytochemistry in two marsupial species throughout the reproductive cycle,
      using a rabbit polyclonal antibody raised against human placental 3beta-HSD. In
      the polyoestrous and polyovular South American opossum Monodelphis domestica,
      immunostaining was positive for 3beta-HSD in the adrenal cortex, the ovarian
      interstitial tissue, the corpus luteum and the granulosa cells of antral and
      atretic follicles. The theca interna was weakly positive for 3beta-HSD, but only
      in late preantral to early antral stages of follicular development. The adrenal
      medulla and smaller preantral follicles were completely negative for 3beta-HSD.
      In contrast, in the polyoestrous and monovular Australian brushtail possum
      Trichosurus vulpecula, immunostaining showed a strong positive reaction for 3beta
      HSD in the theca, whereas the granulosa layer remained predominantly negative for
      3beta-HSD except in the largest follicles. The atretic follicles were completely
      negative for 3beta-HSD. The ovaries of pregnant animals contained grossly
      enlarged, persistent, antral follicles, which reacted positively for 3beta-HSD.
      The function of these follicles in T. vulpecula and the 3beta-HSD-positive
      atretic follicles in M. domestica has not been determined. The differences
      between the two marsupials represent species variations. The situation in M.
      domestica does not represent a marsupial-eutherian dichotomy as previously
      conjectured.

PMID- 12622699
TI  - Effects of reduction of the number of primordial follicles on follicular
      development to achieve puberty in female rats.
AB  - Effects of reduction of the number of primordial follicles on follicular
      development and concentrations of circulating hormones were examined in immature
      female rat offspring of dams given busulfan intraperitoneally on day 14 of
      gestation. The offspring of dams treated with 5 mg busulfan kg(-1) showed vaginal
      opening at an age comparable with the offspring of dams treated with 2.5 mg
      busulfan kg(-1) or with corn oil as a control, although they exhibited an
      irregular oestrous cycle until week 14 after birth. The serum concentrations of
      immunoreactive inhibin and FSH on day 26 after birth of the offspring treated
      with 5 mg busulfan kg(-1) were similar to those of age-matched controls. On day
      15 after birth, however, the concentration of their immunoreactive inhibin was
      markedly lower than that of controls, whereas the concentration of their FSH was
      increased inversely. Comparison of the numbers of ovarian follicles in the
      controls and groups treated with 2.5 mg busulfan kg(-1) and 5 mg busulfan kg(-1)
      revealed that prenatal treatment with busulfan reduced the number of follicles in
      the primordial or primary phase and in the preantral phase on day 7 after birth.
      Although the increase of the ratio of the number of preantral follicles during
      days 7-13 after birth tended to vary with the prenatal dose of busulfan, the
      number of preantral follicles in the group treated with 5 mg busulfan kg(-1) was
      still smaller than in the controls. The concentration of serum immunoreactive
      inhibin of the offspring treated with busulfan was reduced on day 7 after birth
      without alteration of the concentration of gonadotrophin. On day 13 after birth,
      the concentration of serum immunoreactive inhibin was reduced only in the
      offspring treated with 5 mg busulfan kg(-1), and the concentration of serum FSH
      of the offspring was increased inversely as found on day 15 after birth. These
      results indicate that a reduction in the number of primordial follicles decreases
      the number of follicles that enter the growing phase, a major source of
      circulating inhibin in the neonatal and infantile ovary, and that consequently
      increased circulating FSH may accelerate follicular development to achieve
      puberty.

PMID- 12622698
TI  - Expression of insulin, insulin-like growth factor I and glucocorticoid receptor
      in rat uterus and embryo during decidualization, implantation and organogenesis.
AB  - The significance of insulin, insulin-like growth factor I (IGF-I) and
      glucocorticoids to the early mammalian embryo is clear in that they are key
      regulators of both mitogenic and metabolic effects during development. In the
      present study, the temporal sequence of expression of the respective receptor
      proteins was investigated for the first time in the developing rat utero
      embryonic unit between conception and day 12 of gestation using
      immunocytochemistry. Insulin, IGF-I and glucocorticoid receptor were expressed in
      embryonic tissues after the start of implantation, and were co-localized in the
      primary ectoderm, extraembryonic ectoderm as well as in the ectoplacental cone.
      The parietal endoderm was devoid of glucocorticoid receptor staining, whereas IGF
      I receptor was absent in visceral endoderm. After completion of basic
      organogenesis, the neural tube, notochord, otic placode, Wolffian duct,
      mesonephros and intestinal tube expressed insulin, IGF-I and glucocorticoid
      receptor. The glucocorticoid receptor was not expressed in heart tube and dorsal
      aortae. Considerable amounts of insulin receptor were detected in trophoblast
      derived giant cells. In the uterus, luminal epithelium, endometrial stromal and
      myometrial smooth muscle cells immunoreacted with antisera against insulin, IGF-I
      and glucocorticoid receptor. Endometrial glands remained negative for the
      glucocorticoid receptor throughout the gestational period investigated. Uterine
      hormone receptor expression reached a peak at days 4 and 5 of gestation in
      endometrial stromal cells and decidua, respectively. In conclusion, the
      demonstrated ontogenetic pattern of insulin, IGF-I and glucocorticoid receptor
      expression indicates the potential sites of biological action of the respective
      ligands, providing supportive evidence for their critical importance during the
      course of embryogenesis in rats.

PMID- 12622700
TI  - The fundamental role of increased production of nitric oxide in
      lipopolysaccharide-induced embryonic resorption in mice.
AB  - Nitric oxide (NO) fulfils important functions during pregnancy and has a role in
      implantation, decidualization, vasodilatation and myometrial relaxation. However,
      at high concentrations, such as those that are produced in sepsis, NO has toxic
      effects as it is a free radical. The aim of this study was to characterize
      uterine and decidual NO production in lipopolysaccharide (LPS)-induced embryonic
      resorption in mice and to determine which isoforms of nitric oxide synthase (NOS)
      take part. LPS produced 100% embryonic resorption at 24 h, with complete fetus
      expulsions at 48 h. Decidual and uterine NO production were increased by LPS,
      with maximum production at 6 h. This increase was due to the induction of
      expression of inducible nitric oxide synthase (iNOS) isoform in the decidua and
      uterus, and neuronal nitric oxide synthase (nNOS) isoform in the decidua, as
      detected by western blot analysis and immunohistochemistry. LPS increased iNOS
      expression in decidual and myometrial cells and increased nNOS expression in
      decidual cells. In addition, LPS caused fibrinolysis and infiltration of
      mesometrial decidua by macrophages positive for iNOS and CD14 (LPS receptor).
      Endothelial nitric oxide synthase (eNOS) was found in decidual and uterine
      arteries but LPS did not modify its expression. LPS induced CD14 expression in
      endometrial glands, and this could have amplified the inflammatory response.
      Aminoguanidine, an inhibitor of iNOS activity, totally reversed the LPS-induced
      embryonic resorption. This result could be explained by an inhibition of the
      increase in NO production but also by an inhibition of the cellular infiltration
      and fibrinolysis. These results show that NO fulfils a fundamental role in LPS
      induced embryonic resorption.

PMID- 12622701
TI  - Inositol transport in mouse oocytes and preimplantation embryos: effects of mouse
      strain, embryo stage, sodium and the hexose transport inhibitor, phloridzin.
AB  - The uptake of myo-inositol by mouse oocytes and preimplantation embryos of a
      crossbred (DBA x C57BL/6) and a purebred outbred strain (MF1) was measured using
      [2-(3)H]myo-inositol. Uptake in crossbred embryos increased about 15-fold between
      the one- and two-cell stages and increased again by about sixfold at the
      blastocyst stage compared with the morula stage. Uptake in purebred embryos
      increased about 42-fold between the one- and two-cell stages and increased more
      than threefold at the blastocyst stage compared with the morula stage. In all
      stages examined, except two-cell crossbred embryos, inositol uptake was,
      depending on the stage, either largely or partly sodium dependent and could be
      inhibited by the sodium-dependent hexose transport inhibitor, phloridzin. This is
      consistent with the hypothesis that transport occurs via a sodium myo-inositol
      transporter (SMIT) protein. In addition, there was strong evidence that a sodium
      independent mechanism of uptake, possibly a channel, was switched on at the two
      cell stage coincident with zygotic gene activation which resulted in 141-fold and
      71-fold increases in sodium-independent uptake from the one-cell to two-cell
      stages in crossbred and purebred embryos, respectively. This mechanism was either
      abolished or drastically downregulated at the blastocyst stage, whereas sodium
      dependent uptake was markedly upregulated. In two-cell crossbred embryos, there
      was a complete abolition of sodium-dependent uptake, again possibly regulated by
      zygotic gene activation. The hypothesis that the changes in mechanism of inositol
      uptake at about the two-cell stage are due to zygotic gene activation was
      supported by the finding that these changes did not occur in parthenogenetic two
      cell embryos.

PMID- 12622702
TI  - Immunohistochemical localization and expression of the hyaluronan receptor CD44
      in the epithelium of the pig oviduct during oestrus.
AB  - Hyaluronan is related to essential reproductive processes in pigs. Hyaluronan
      produced by cumulus cells builds, via specific cell surface receptors, an
      extracellular matrix responsible for cumulus cell cloud expansion during final
      oocyte maturation, a preparatory event for ovulation and fertilization. In
      addition, hyaluronan that has been localized in the pig oviduct both in the
      intraluminal fluid and on the surface of the lining epithelium of the
      preovulatory sperm reservoir, has proven beneficial during in vitro fertilization
      and embryo culture, thus indicating that it has a role in vivo. This study
      monitored the immunolocalization, protein determination and gene expression of
      the major cell surface hyaluronan receptor CD44 in the epithelial lining of the
      pig oviduct during selected stages of standing oestrus, in relation to
      spontaneous ovulation. The CD44 immunostaining in the lining epithelium was
      localized to the surface membrane and the supranuclear domain of mainly the
      secretory cells, particularly in the sperm reservoir of both treatment
      (inseminated) and control (non-inseminated) specimens. Up to four hyaluronan
      binding protein (HABP) bands (60, 90, 100 and 200 kDa) were detected in the tubal
      epithelium, and the 200 kDa band was determined as CD44 by immunoblotting. The
      expression of CD44 mRNA was higher before than after ovulation (P < 0.05), most
      conspicuously in the uterotubal junction (UTJ). In addition, CD44 expression in
      the preovulatory UTJ and the ampullary-isthmic junction (AIJ) of control animals
      was higher than in those that were inseminated (P < 0.05 and P < 0.01 for UTJ and
      AIJ, respectively). The results demonstrate for the first time that the specific
      hyaluronan receptor CD44 is expressed by the oviduct epithelial cells during
      spontaneous oestrus, and is particularly abundant in the sperm reservoir before
      ovulation. Presence of spermatozoa in this segment seemed to downregulate the
      receptor. The variation in the expression of CD44 in relation to spontaneous
      ovulation and the presence of spermatozoa indicate that the hyaluronan CD44
      signalling pathway may play a role in oviduct function during sperm storage and
      fertilization in pigs.

PMID- 12622703
TI  - Effect of sperm preparation method on in vitro fertilization in pigs.
AB  - This study was designed to determine the effect of different sperm preparation
      treatments before IVF on the acrosome reaction, oocyte penetration time, early
      embryo development and timing of female and male pronucleus formation. Pooled
      sperm-rich fractions were (i) washed in PBS, (ii) left unwashed, or (iii) layered
      in a Percoll gradient. In Expt 1, the proportion of acrosome-reacted spermatozoa,
      determined by staining with fluorescein isothyocyanate-labelled peanut agglutinin
      lectin and propidium iodide, was highest after treatment with Percoll (P <
      0.001). In Expt 2, oocytes matured in vitro were co-cultured with spermatozoa for
      2, 4 or 6 h. Attached spermatozoa were then removed and the oocytes were cultured
      in fresh IVF medium for 16 h. Both sperm treatment and co-culture time were found
      to affect penetrability and monospermy rates (P < 0.001); spermatozoa treated
      with Percoll showed fastest oocyte penetration and highest penetrability. In Expt
      3, matured oocytes were co-incubated with spermatozoa pretreated by the three
      above mentioned procedures (i, ii, iii) for 2, 6 and 2 h respectively. Putative
      zygotes were then washed and transferred to medium NCSU-23 until the blastocyst
      stage. In this experiment, sperm treatment had a significant effect on the
      cleavage rate (P < 0.001) and rate of blastocyst formation (P < 0.05); the group
      treated with Percoll showed the highest rate of blastocyst formation. Finally, in
      Expt 4, timing of female and male pronucleus formation for each sperm treatment
      was determined 4, 6 and 8 h after insemination. The time of female and male
      pronucleus formation was affected by the sperm treatment and was faster for the
      Percoll group (P < 0.05). The findings of the present study indicate that
      treatment with Percoll yields the best results in this in vitro pig embryo
      production system.

PMID- 12622704
TI  - Structural studies on the reaction of isopenicillin N synthase with the substrate
      analogue delta-(l-alpha-aminoadipoyl)-l-cysteinyl-d-alpha-aminobutyrate.
AB  - Isopenicillin N synthase (IPNS) is a non-haem iron(II) oxidase which catalyses
      the biosynthesis of isopenicillin N from the tripeptide delta-(L-alpha
      aminoadipoyl)-L-cysteinyl-D-valine (ACV). Herein we report crystallographic
      studies to investigate the reaction of IPNS with the truncated substrate analogue
      delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-alpha-aminobutyrate (ACAb). It has
      been reported previously that this analogue gives rise to three beta-lactam
      products when incubated with IPNS: two methyl penams and a cepham. Crystal
      structures of the IPNS-Fe(II)-ACAb and IPNS-Fe(II)-ACAb-NO complexes have now
      been solved and are reported herein. These structures and modelling studies based
      on them shed light on the diminished product selectivity shown by IPNS in its
      reaction with ACAb and further rationalize the presence of certain key residues
      at the IPNS active site.

PMID- 12622706
TI  - Comparison of outcomes of three different surgical techniques performed for
      stress urinary incontinence.
AB  - BACKGROUND: The aim was to compare the efficacy of Burch colposuspension,
      transvaginal four-corner bladder neck suspension (FCBNS) and the vaginal wall
      sling (VWS) procedures in patients with stress urinary incontinence. METHODS: A
      retrospective analysis was performed on 88 patients who underwent Burch
      colposuspension (n = 20), FCBNS (n = 29) and VWS (n = 39) for stress urinary
      incontinence. Objective and subjective cure rates at 3 months and annually after
      the operation were the primary outcome measures. RESULTS: The patients were
      similar in age, parity, menopausal status, grade of cystocel and preoperative
      residual urine volumes. Fourteen out of 20 (70%) patients showed improvement in
      the group undergoing Burch colposuspension, 29 out of 39 (74.4%) patients showed
      improvement in the FCBNS group, and 28 out of 29 (96.6%) patients showed
      improvement in the VWS group. The mean length of follow up was 3.8 years (range 3
      5). CONCLUSION: In this study, the VWS procedure had a higher long-term cure rate
      of stress urinary incontinence when compared with the Burch colposuspension and
      the FCBNS procedures.

PMID- 12622705
TI  - Postoperative morbidity, functional results and quality of life of patients
      following orthotopic neobladder reconstruction.
AB  - AIM: To evaluate postoperative morbidity, functional results and health-related
      quality of life of patients with an orthotopic neobladder. METHODS: A total of 37
      patients with orthotopic neobladder (modified Studer method: 35 cases; Hautmann
      method: one case; sigmoid neobladder: one case) were included in the present
      study. Postoperative morbidity and neobladder function were analyzed. To
      determine quality of life, the Sickness Impact Profile questionnaire was used.
      The quality of life of patients who underwent orthotopic neobladder was compared
      with that of patients who underwent ileal conduit. RESULTS: In 37 consecutive
      patients with neobladder reconstruction, early complications included 10 cases of
      pyelonephritis (27.0%) and one of stenosis of ureterointestinal anastomosis
      (2.7%). Two patients died of ARDS and sepsis following peritonitis and pneumonia
      in the perioperative period. Late complications included pyelonephritis in three
      patients (8.6%). In 32 cases, except for an early postoperative case and those
      that died, complete daytime and night-time continence was achieved in 31 patients
      (96.9%) and 16 patients (50.0%), respectively. Concerning health-related quality
      of life, the mean sum scores per category of the Sickness Impact Profile were
      calculated for 32 patients with orthotopic neobladder and 30 patients with ileal
      conduit. There were no significant differences in overall satisfaction, however,
      the scores for patients with orthotopic neobladder reconstruction were
      significantly higher than those for patients with ileal conduit in the three
      categories of emotions, feelings and sensation, social interaction and
      recreation. CONCLUSION: Orthotopic neobladder reconstruction exhibited good
      functional results with acceptable complications. Patients who underwent
      neobladder reconstruction were satisfied with their voiding. Assessment of
      quality of life using the Sickness Impact Profile questionnaire demonstrated that
      orthotopic neobladder improved their quality of life better than ileal conduit,
      especially with regard to mental, physical and social functioning in daily life.

PMID- 12622709
TI  - Preliminary results of a monitoring system to confirm the preservation of
      cavernous nerves.
AB  - BACKGROUND: It is important to preserve the neurovascular bundle (NVB) during
      nerve-sparing surgery. This article presents the preliminary results of our
      monitoring system for the postoperative preservation of erectile function.
      METHODS: In 15 patients undergoing radical prostatectomy and 20 patients
      undergoing radical cystoprostatectomy, intraoperative electrical stimulation
      along the NVB was performed to measure changes in intracavernous pressure before
      and after prostate removal. Seven of the radical prostatectomy patients and eight
      of the radical cystoprostatectomy patients underwent nerve-sparing surgery.
      Postoperative erectile function was evaluated in 25 patients not receiving
      adjuvant hormonal therapy. RESULTS: The NVB was judged to be preserved at least
      on one side electrophysiologically in 14 of 15 patients. Pathologically, three
      patients had pT3 cancer. Postoperatively, sufficient erectile function was
      demonstrated using the International Index of Erectile Function 5 in three
      patients, nocturnal penile tumescence in three patients, and a questionnaire or
      an interview in three patients. The other patients were incompletely erectile.
      None of the 11 patients not receiving adjuvant hormonal therapy, in whom NVB was
      not preserved, were erectile. CONCLUSION: If the successful criterion of nerve
      sparing surgery is defined as a change in intracavernous pressure of 4 cm H2O or
      more being observed at least unilaterally, and the successful criteria of
      erectile function preservation includes being sufficiently erectile as revealed
      by an interview, the sensitivity of our system was 69.2% (9/13) and the
      specificity was 100% (12/12). Neither adverse reactions to the measurement, nor
      inadequacy of cancer excision accompanying NVB sparing, were observed. These
      results suggest that our system can predict postoperative erectile function
      fairly accurately.

PMID- 12622708
TI  - Tension-free vaginal tape for surgical treatment of stress urinary incontinence:
      two years follow-up.
AB  - BACKGROUND: The objective was to study prospectively the effectiveness of tension
      free vaginal tape as an ambulatory and minimal invasive operation for the
      treatment of female stress incontinence. METHODS: The tension-free vaginal tape
      procedure was performed in 25 patients with genuine stress incontinence and they
      were followed for a 2-year period. All patients were diagnosed with urodynamics
      to have genuine stress incontinence. Pad tests, cough stress test and quality-of
      life assessments were carried out in all patients, both preoperatively and
      postoperatively. The majority of the women were discharged the morning after the
      surgical procedure. RESULTS: Twenty of 25 (80%) patients were found to be cured 2
      years after the operation. The vaginal tape was spontaneously dropped out from
      the vagina in one patient 2 weeks after the procedure. We did not see such a
      complication in previous studies. CONCLUSION: We conclude that the tension-free
      vaginal tape procedure is both a safe and effective method to cure genuine female
      stress incontinence. Furthermore, it can be performed as an ambulatory procedure
      under local anesthesia with a short operative time.

PMID- 12622710
TI  - Topographic anatomy of the male perineal structures with special reference to
      perineal approaches for radical prostatectomy.
AB  - AIM: Although perineal approaches for radical prostatectomy have recently gained
      renewed attention as excellent methods for minimally invasive surgery, the most
      commonly used techniques, Belt's and Young's approaches, have inadequacies
      regarding the topographical relationship between the rectourethral and levator
      ani muscles. METHODS: Using macroscopic observations of sagittal slices of 27
      male pelvises and smooth muscle immunohistochemical staining of semiserial
      sections of another eight pelvises, we investigated the topographical anatomy of
      the perineal structures and their interindividual variations in elderly Japanese
      men. RESULTS: The inferomedial edge of the levator ani was located 5-15 mm
      lateral to the midsagittal plane in an area between the urethra and the rectum.
      The rectourethral smooth muscle had a superoinferior thickness of 5-10 mm and
      occupied a space between the right and left levator slings. The levator was
      adjacent to, or continuous with, the striated anal sphincters. A thick connective
      tissue septum, composed of smooth muscle, was evident between the rectal smooth
      muscle and the anal sphincter-levator ani complex. CONCLUSION: Because the
      connective tissue septum guides the surgeon's finger upwards towards the
      rectoprostatic space, Belt's approach appears relatively easy; however, rectal
      injury can sometimes occur if the surgeon loses this guidance. In contrast, if
      the levator edge is identified as the first step in Young's approach, the
      rectourethral muscle can be precisely divided, leaving a 3-5-mm margin from the
      rectum and sphincter-levator complex. Clinical investigations are now required to
      modify Young's approach based on the present results.

PMID- 12622711
TI  - Predicting disease outcome of non-invasive transitional cell carcinoma of the
      urinary bladder using an artificial neural network model: results of patient
      follow-up for 15 years or longer.
AB  - BACKGROUND: Patients with non-invasive (Ta/T1) transitional cell carcinoma (TCC)
      of the urinary bladder are often observed without progression in the long-term
      follow-up period, although many of them experience recurrence of disease. It is
      difficult to accurately predict the disease outcome of each patient with Ta/T1
      TCC using conventional prognostic criteria. In this study, we examined the
      usefulness of artificial neural networks (ANNs) to predict the long-term disease
      outcome of patients with TCC of the urinary bladder. METHODS: A retrospective,
      prognostic study of 90 patients with Ta/T1 TCC of the urinary bladder, diagnosed
      by transurethral resection of the bladder tumor between April 1981 and March
      1985, and then followed up for 15 years or longer, was carried out. Data were
      analyzed using the Bayesian network tool of SPSS Neural Connection 2.1. The input
      neural data consisted of tumor stage, grade, tumor number, age, gender, tumor
      architecture and estimates of mean nuclear volume. The data set was randomly
      divided into 68 training and 22 testing examples for the prediction of disease
      progression and tumor recurrence within 15 years. RESULTS: During 15 years follow
      up, tumor recurrence was noted in 42/90 (47%) Ta/T1 tumors. The ANN model could
      not predict tumor recurrence. Conversely, disease progression was noted in 17/90
      (19%) Ta/T1 tumors, and, in the test set, 4/22 (18%) Ta/T1 tumors underwent
      disease progression. The sensitivity of the ANN model to predict progression was
      100% (specificity 67%; positive predictive value 40%; negative predictive value
      100%). Patients who were judged to have a favorable prognosis using ANN analysis
      did not progress within the 15-year follow-up period. CONCLUSION: The results of
      the ANN study indicate that long-term progression-free survival of patients with
      non-invasive TCC of the urinary bladder can be precisely predicted. A favorable
      prognosis using ANNs would be one of the exclusion criteria for immediate or
      future total cystectomy.

PMID- 12622712
TI  - Telomerase activity in renal cell carcinoma by modified telomeric repeat
      amplification protocol assay.
AB  - BACKGROUND: Previous assessments by the conventional telomeric repeat
      amplification protocol have not been reliable for the quantitation of telomerase
      activity. We, therefore, determined telomerase activity in renal cell carcinoma
      (RCC) tissue by the modified sensitive telomeric repeat amplification protocol
      assay. METHODS: Telomerase activity was examined in 23 cases of RCC and in the
      adjacent normal kidney tissue, and assessed for associations with clinical and
      pathological variables of the disease. RESULTS: The linearity and quantitation of
      the modified method was confirmed. Mean telomerase activity of RCC (1987.889 +/-
      1232.801 units) was significantly greater than that of normal renal tissue
      (173.467 +/- 241.893 units) (P = 0.0001). Telomerase activity in RCC was,
      however, not associated with clinical or pathological variables such as clinical
      stage (P = 0.8941), grade (P = 0.8043) or pathological subtype (P = 0.9739).
      CONCLUSION: The results suggest that telomerase might play a crucial role in an
      initial step of the development of RCC, but not in the progression of the
      disease.

PMID- 12622713
TI  - Preventive effects of urinary bladder tumors induced by N-butyl-N-(4
      hydroxybutyl)-nitrosamine in rat by green tea leaves.
AB  - BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied
      in sites other than the urinary tract. Although the incidence of bladder cancer
      has increased, responses to therapy have been limited. The present work examined
      the preventive effects of green tea against bladder tumors induced in rats by the
      carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine(BBN). METHODS: From week 5 to
      week 9, all the groups were exposed to 0.05% BBN in the drinking water for 5
      weeks. Rats were divided into four groups. Group 1 was fed a CE-2 diet and tap
      water for the entire experimental period and served as the control group. Group 2
      was fed the green tea leaves after carcinogen exposure. Groups 3 and 4 received
      green tea leaves before carcinogen exposure. All rats were killed and examined at
      44 weeks. RESULTS: Green tea leaves prevented the growth of BBN-induced urinary
      bladder tumors when given before the carcinogen. CONCLUSION: Green tea may
      inhibit tumor initiation in the bladder.

PMID- 12622714
TI  - N-acetyltransferase-2 gene polymorphism as a possible biomarker for prostate
      cancer in Japanese men.
AB  - BACKGROUND: The purpose of this study was to determine the frequency of a
      polymorphism of the candidate metabolic enzyme N-acetyltransferase-2 (NAT2) in
      Japanese prostate cancer patients and Japanese non-cancer controls, in order to
      determine if an association exists between NAT2 genotype and the occurrence,
      clinical stage and grade of prostate cancer. METHODS: In the present case-control
      study, 111 patients with prostate cancer and 152 controls were genotyped for the
      NAT2 polymorphism using the polymerase chain reaction-based restriction fragment
      length polymorphism method. The NAT2 genotypes (slow or rapid acetylator
      genotype) were determined by the combination of three known NAT2 mutant alleles
      (M1, M2, M3) and the wild-type allele. RESULTS: The NAT2 slow acetylator genotype
      was statistically higher among prostate cancer patients (17.1%) compared with
      controls (8.6%) (Odds ration (OR) = 2.21; 95% confidence interval (CI), 1.04
      4.69; P = 0.0289). In addition, there was a statistically increased risk of
      prostate cancer among smokers with the NAT2 slow genotype (OR = 3.78: 95% CI,
      1.48-9.66; P = 0.0041). Furthermore, the NAT2 slow acetylator genotype was
      significantly higher among prostate cancer patients with locally advanced and
      metastatic disease (22.7%) compared with controls (8.6%) (OR = 3.14; 95% CI, 1.40
      7.06; P = 0.0051). Lastly, the NAT2 slow acetylator genotype was significantly
      higher among prostate cancer patients with high-grade tumors (31.4%) compared
      with controls (8.6%) (OR = 4.90; 95% CI, 1.97-12.20; P = 0.0010). CONCLUSION:
      These data demonstrate that the NAT2 slow acetylator genotype plays an important
      role in determining the risk of developing prostate cancer in Japanese men and is
      also associated with more clinically advanced and pathologically aggressive
      disease. Furthermore, a possible interaction between the NAT2 slow acetylator
      genotype and smoking status was suggested.

PMID- 12622715
TI  - Infected urachal cyst ruptured during medical palliation.
AB  - Since most cases of urachal cyst are asymptomatic, they are frequently detected
      after complication by infection. Ruptured urachal cysts are frequently detected
      after complication by severe infections such as sepsis. We report on a 31-year
      old man who was diagnosed preoperatively as having an infected urachal cyst and
      the decision was made to follow the patient because primary excision was
      scheduled to be performed a few days later. Symptoms were transiently relieved,
      but the cyst ruptured during medical palliation. We treated this case with a two
      stage surgical procedure.

PMID- 12622716
TI  - Prostate cancer in patients with Hansen's disease.
AB  - Hansen's disease causes testicular failure secondarily, and because of this, it
      has been considered that prostate cancer would not be found in association. Three
      of 14 patients with chronic leprosy in Suruga National Sanatorium Hansen's
      Disease Hospital were found to have prostate cancer. A 72-year-old with
      lepromatous leprosy was diagnosed with stage T3a prostate cancer and treated with
      radical prostatectomy after hormonal therapy, plus irradiation. An 80-year-old
      with lepromatous leprosy was diagnosed with stage T2 prostate cancer and treated
      with irradiation and follow up only without hormone therapy and surgery because
      of his low testosterone level and old age. An 82-year-old with borderline leprosy
      was diagnosed with stage T1c prostate cancer and because of the pathological
      finding of low Gleason score and his old age, he was treated with hormonal
      therapy only. Two of the three cases had elevated concentrations of follicle
      stimulating hormone and luteinizing hormone, which suggests that their prostatic
      cancers might have been equivalent to be under the influence of hormone therapy.
      Therefore, in aged male patients with Hansen's disease, the follicle-stimulating
      hormone, luteinizing hormone and testosterone concentrations should be measured,
      as well as that of prostate-specific antigen, and a prostate biopsy should be
      also considered if the prostate-specific antigen concentration is increased, even
      with hypogonadism.

PMID- 12622717
TI  - Simple correction of ureteral stomal stenosis for cutaneous ureterostomy.
AB  - Cutaneous ureterostomy is a simple procedure to perform, but has some morbidity
      owing to stomal stenosis. We describe a new and simple technique applied to the
      stomal stenosis for cutaneous ureterostomy.

PMID- 12622718
TI  - Comparative analysis of the self-incompatibility (S-) locus region of Prunus
      mume: identification of a pollen-expressed F-box gene with allelic diversity.
AB  - BACKGROUND: Self-incompatibility (SI) in the Solanaceae, Rosaceae and
      Scrophulariaceae is gametophytically controlled by a single polymorphic locus,
      termed the S-locus. To date, the only known S-locus product is a polymorphic
      ribonuclease, termed S-RNase, which is secreted by stylar tissue and thought to
      act as a cytotoxin that degrades the RNA of incompatible pollen tubes. However,
      understanding how S-RNase causes S-haplotype specific inhibition of pollen tubes
      has been hampered by the lack of a cloned pollen S-determinant gene. RESULTS: To
      identify the pollen S-determinant gene, we investigated the genomic structure of
      the S-locus region of the S1- and S7-haplotypes of Prunus mume (Japanese
      apricot), and identified 13 genes around the S-RNase gene. Among them, only one F
      box gene, termed SLF (S-locus F-box), fulfilled the conditions for a pollen S
      determinant gene: (i) together with the S-RNase gene, it is located within the
      highly divergent genomic region of the S-locus, (ii) it exhibits S-haplotype
      specific diversity among three analysed S-haplotypes, and (iii) it is
      specifically expressed in pollen, but not in the styles or leaves. CONCLUSION:
      The results indicate that SLF is a prime candidate for the pollen S-determinant
      gene of SI.

PMID- 12622719
TI  - Mechanism of H-8 inhibition of cyclin-dependent kinase 9: study using inhibitor
      immobilized matrices.
AB  - BACKGROUND: Positive transcription elongation factor b (P-TEFb), which
      phosphorylates the carboxyl-terminal domain (CTD) of RNA polymerase II (RNAPII),
      is comprised of the catalytic subunit cyclin-dependent kinase 9 (CDK9) and the
      regulatory subunit cyclin T. The kinase activity and transcriptional activation
      potential of P-TEFb is sensitive to various compounds, including H-8, 5,6
      dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), and flavopiridol. RESULTS: We
      investigated the molecular mechanism of the H-8 inhibition of CDK9 using matrices
      to which H-9, an amino derivative of H-8, was immobilized. CDK9 bound
      specifically to H-9, and this interaction was competitively inhibited by ATP and
      DRB, but not by flavopiridol. Mutational analyses demonstrated that the central
      region of CDK9, which encompasses the T-loop region, was important for its
      binding to H-9. CONCLUSIONS: H-9-immobilized latex beads are useful for trapping
      CDK9 and a subset of kinases from crude cell extracts. The flavopiridol-binding
      region of CDK9 is most likely different from its H-9-binding region. These
      biochemical data support previously reported observations which were based on
      crystallographic data.

PMID- 12622720
TI  - Matrix metalloproteinase-12 gene expression in human vascular smooth muscle
      cells.
AB  - BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in smooth
      muscle cell (SMC) migration and proliferation during vascular remodelling. To
      investigate the expression of MMP-12 by SMCs, we examined the protein secretion
      and mRNA expression of MMP-12 by cultured medial SMCs and intimal SMCs derived
      from human aortic atherosclerotic lesions. To further elucidate the molecular
      mechanism for MMP-12 expression in SMCs, we determined the sequence requirements
      for MMP-12 gene transcriptional activity. RESULTS: Cultured medial SMCs and
      intimal SMCs showed substantial MMP-12 expression at both the protein and mRNA
      levels. A series of 5'-deletion and site-directed mutants of the human MMP-12
      promoter demonstrated that an AP-1 site spanning -81 to -75 bp was critical for
      the MMP-12 promoter activity in SMCs. An electrophoretic mobility shift assay
      confirmed the AP-1 binding activity in SMCs and showed that the protein bound to
      the AP-1 site consisted predominantly of c-Jun, JunD and Fra-1. Two structurally
      different inhibitors of phosphatidylinositol 3-kinase, wortmannin and LY294002,
      inhibited MMP-12 transcriptional activity and AP-1 binding. CONCLUSION: These
      results indicated the expression of MMP-12 in vascular SMCs and showed that the
      MMP-12 gene expression was dependent on the AP-1 binding activity.
      Phosphatidylinositol 3-kinase signalling may be involved in MMP-12
      transcriptional activation through AP-1 binding activity.

PMID- 12622722
TI  - ATPase/helicase motif mutants of Escherichia coli PriA protein essential for
      recombination-dependent DNA replication.
AB  - BACKGROUND: PriA protein, a DEXH-type helicase with C2C2 zinc-finger motifs,
      plays essential roles in RecA-dependent modes of Escherichia coli chromosomal DNA
      replication, namely inducible and constitutive stable DNA replication (iSDR and
      cSDR respectively, which may be initiated from a D-loop or R-loop structure), and
      in repair of double-stranded DNA breaks generated by various genotoxic agents or
      spontaneously during the course of DNA replication. However, the roles of
      ATPase/DNA helicase activities in functions of PriA are not well understood.
      RESULTS: We have generated and characterized mutants of PriA protein carrying
      amino acid substitutions in its conserved ATPase/DNA helicase motifs, namely the
      Walker A, B and QXXGRXGR motifs. All these mutants were deficient in ATP
      hydrolysis and DNA helicase activities, but showed wild-type levels of D-loop DNA
      binding, except for the Walker B mutant which showed reduced DNA binding
      activity, suggesting that the helicase motifs are not directly involved in the
      DNA binding activity of PriA protein. They also rescued the low viability and UV
      sensitivity of priA null cells. However, they did not rescue iSDR or cSDR
      alternative modes of chromosomal DNA replication of the E. coli genome dependent
      on recombination functions-to the full extent. CONCLUSIONS: ATPase/DNA helicase
      activities of PriA protein are required for full-level DNA synthesis in
      recombination-dependent modes of DNA replication in E. coli.

PMID- 12622721
TI  - The upstream regulator, Rsr1p, and downstream effectors, Gic1p and Gic2p, of the
      Cdc42p small GTPase coordinately regulate initiation of budding in Saccharomyces
      cerevisiae.
AB  - BACKGROUND: Cdc42p, a Rho family small GTPase, is essential for budding
      initiation in the yeast Saccharomyces cerevisiae. The homologous proteins Gic1p
      and Gic2p (Gic1/2p) are effectors of Cdc42p, but their precise functions remain
      unknown. Rsr1p/Bud1p is a Ras family small GTPase that controls the selection of
      the budding site. Previous observations suggested that Rsr1p-GTP recruits Cdc24p,
      a GDP/GTP exchange factor for Cdc42p, at the incipient bud site. However, this
      model only addresses how Rsr1p determines the budding site, because the rsr1
      mutant normally initiates budding. RESULTS: Here we show that a rsr1 gic1 gic2
      mutant fails to initiate budding, resulting in unbudded, large, and
      multinucleated cells. Expression of a dominant active or dominant negative mutant
      of RSR1 also inhibited the growth of the gic1 gic2 mutant, suggesting that
      cycling of Rsr1p between the GTP- and GDP-bound forms is required for budding
      initiation in the gic1 gic2 mutant. Among the mutations in effectors of CDC42,
      only the gic1 gic2 mutation demonstrated a synthetic lethal interaction with
      rsr1. Increased gene dosage of CDC42 suppressed defects in budding initiation of
      rsr1 gic1 gic2 mutants containing additional mutations in other effectors of
      CDC42, including BNI1, CLA4 or STE20. The polarized localization of Bni1p-GFP
      (green fluorescent protein) and Cla4p-GFP was lost after depletion of Gic1p in
      the rsr1 gic2 mutant. CONCLUSION: We propose that Gic1/2p may stabilize or
      maintain a complex consisting of Cdc42p-GTP and its effectors at the budding
      site, which are assembled by the action of the Rsr1p-Cdc24p system.

PMID- 12622723
TI  - Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway.
AB  - BACKGROUND: ERK5 is the newest subfamily member of the mitogen-activated protein
      kinase (MAPK) family, and is activated by various extracellular signals including
      growth factors. MEK5 is a specific activator of ERK5. c-Fos and Fra-1, well-known
      immediate early gene products, are members of the AP-1 family. We previously
      reported that activation of the MEK5-ERK5 pathway is able to induce expression of
      c-Fos. RESULTS: We have found that activation of the MEK5-ERK5 pathway causes the
      phosphorylation and stabilization of c-Fos and Fra-1. Phosphorylation of c-Fos
      appears to be mediated by ERK5 and a kinase(s) lying downstream of ERK5, and the
      MEK5-ERK5 pathway-dependent phosphorylation sites on c-Fos are different from the
      ERK1/2 pathway-dependent ones. Interestingly, activation of the MEK5-ERK5
      pathway, but not that of the ERK1/2 pathway, is found to markedly increase the
      transactivation activity of c-Fos. Furthermore, our results show that the C
      terminal half of ERK5 is necessary for the maximal activation of the
      transactivation activity of c-Fos and Fra-1. CONCLUSION: These results reveal a
      role of the MEK5-ERK5 pathway in modulating the function of the Fos family
      proteins which is different from the role of the ERK1/2 pathway.

PMID- 12622724
TI  - PML-nuclear bodies are involved in cellular serum response.
AB  - BACKGROUND: Serum stimulation leads to the activation of various signal
      transduction pathways in cells, and the resultant signals are integrated into the
      serum response factor (SRF)-dependent transcription of immediate-early genes such
      as c-fos. RESULTS: To further characterize this response, we investigated the
      mechanism which controls serum response transcription in cultured human cells.
      Frequency of PML (promyelocytic leukaemia)-nuclear bodies (NBs) formation
      increases shortly after serum stimulation, probably facilitating the interaction
      of SRF and CBP acetyltransferase at the NBs. PML modulates SRF-mediated c-fos
      promoter activities upon addition of serum to cells or expression of
      constitutively active Rho family GTPases. We mapped the region in the SRF that
      interacts with PML to the C-terminal transactivation domain. An SRF mutant
      deleted of the transactivation domain neither co-localizes with CBP in NBs nor
      fulfills its transcriptional role. Under conditions of serum stimulation, the
      formation of NBs coincides with the immediate-early expression of the endogenous
      c-fos gene in fibroblasts and in all-trans retinoic acid-treated acute
      promyelocytic leukaemia NB4 cells. CONCLUSION: These data provide an insight into
      the involvement of NBs in modulating the transcription of serum-induced immediate
      early genes.

PMID- 12622725
TI  - ATP-induced hexameric ring structure of the cyanobacterial circadian clock
      protein KaiC.
AB  - BACKGROUND: KaiA, KaiB and KaiC are cyanobacterial circadian clock proteins. KaiC
      contains two ATP/GTP-binding Walker's motif As, and mutations in these regions
      affect the clock oscillations. RESULTS: ATP induced the hexamerization of KaiC.
      The Km value for the ATP for the hexamerization was 1.9 micro m. Triphosphate
      nucleotides bound to the two Walker's motif As, and their binding functioned
      cooperatively for the hexamerization. An unhydrolysable substrate, 5'
      adenylylimidodiphosphate (AMPPNP), also induced the hexamerization, indicating
      that nucleotide binding, but not its hydrolysis, is essential for the
      hexamerization. Mutations in each of the two Walker's motif As that affect the
      clock phenotype increased the Km value for ATP and inhibited the hexamerization.
      Thus, the KaiC hexamerization seems to be necessary for its clock function. The
      KaiC hexamer has the shape of a hexagonal pot with a diameter and height of
      approximately 100 A and with a relatively large cavity (73 A deep and 18-34 A
      wide) inside. This pot-shaped structure suggests that KaiC functions in a similar
      manner to F1-ATPase, helicase or ATP-dependent protease/chaperon, all of which
      have dynamic activities inside the central cavity of their hexameric rings.
      CONCLUSION: ATP-induced KaiC hexamerization is necessary for the clock function
      of KaiC.

PMID- 12622727
TI  - Developmental constraint and natural selection.

PMID- 12622728
TI  - The difficulty of agreeing about constraints.

PMID- 12622729
TI  - Early differentiation and migration of cranial neural crest in the opossum,
      Monodelphis domestica.
AB  - Marsupial mammals are born at a highly altricial state. Nonetheless, the neonate
      must be capable of considerable functional independence. Comparative studies have
      shown that in marsupials the morphogenesis of many structures critical to
      independent function are advanced relative to overall development. Many skeletal
      and muscular elements in the facial region show particular heterochrony. Because
      neural crest cells are crucial to forming and patterning much of the face, this
      study investigates whether the timing of cranial neural crest differentiation is
      also advanced. Histology and scanning electron microscopy of Monodelphis
      domestica embryos show that many aspects of cranial neural crest differentiation
      and migration are conserved in marsupials. For example, as in other vertebrates,
      cranial neural crest differentiates at the neural ectoderm/epidermal boundary and
      migrates as three major streams. However, when compared with other vertebrates, a
      number of timing differences exist. The onset of cranial neural crest migration
      is early relative to both neural tube development and somite formation in
      Monodelphis. First arch neural crest cell migration is particularly advanced and
      begins before any somites appear or regional differentiation exists in the neural
      tube. Our study provides the first published description of cranial neural crest
      differentiation and migration in marsupials and offers insight into how shifts in
      early developmental processes can lead to morphological change.

PMID- 12622730
TI  - Protochordate Zic genes define primitive somite compartments and highlight
      molecular changes underlying neural crest evolution.
AB  - The vertebrate Zic gene family encodes C2H2 zinc finger transcription factors
      closely related to the Gli proteins. Zic genes are expressed in multiple areas of
      developing vertebrate embryos, including the dorsal neural tube where they act as
      potent neural crest inducers. Here we describe the characterization of a Zic
      ortholog from the amphioxus Branchiostoma floridae and further describe the
      expression of a Zic ortholog from the ascidian Ciona intestinalis. Molecular
      phylogenetic analysis and sequence comparisons suggest the gene duplications that
      formed the vertebrate Zic family were specific to the vertebrate lineage. In
      Ciona maternal CiZic/Ci-macho1 transcripts are localized during cleavage stages
      by asymmetric cell division, whereas zygotic expression by neural plate cells
      commences during neurulation. The amphioxus Zic ortholog AmphiZic is expressed in
      dorsal mesoderm and ectoderm during gastrulation, before being eliminated first
      from midline cells and then from all neurectoderm during neurulation. After
      neurulation, expression is reactivated in the dorsal neural tube and dorsolateral
      somite. Comparison of CiZic and AmphiZic expression with vertebrate Zic
      expression leads to two main conclusions. First, Zic expression allows us to
      define homologous compartments between vertebrate and amphioxus somites, showing
      primitive subdivision of vertebrate segmented mesoderm. Second, we show that
      neural Zic expression is a chordate synapomorphy, whereas the precise pattern of
      neural expression has evolved differently on the different chordate lineages.
      Based on these observations we suggest that a change in Zic regulation,
      specifically the evolution of a dorsal neural expression domain in vertebrate
      neurulae, was an important step in the evolution of the neural crest.

PMID- 12622731
TI  - Comparison of even-skipped related gene expression pattern in vertebrates shows
      an association between expression domain loss and modification of selective
      constraints on sequences.
AB  - The even-skipped related genes (evx) encode homeodomain-containing transcription
      factors that play key roles in body patterning and neurogenesis in a wide array
      of Eumetazoa species. It is thought that the genome of the last common ancestor
      of Chordata contained a unique evx gene linked to a unique ancestral Hox complex.
      During subsequent evolution, two rounds of whole genome duplication followed by
      individual gene losses gave rise to three paralogs: evx1, evx2, and eve1. Then,
      eve1 was maintained in Actinopterygii lineage but not in Tetrapoda. To explain
      this discrepancy, we examined the expression patterns of the evx1 homologue,
      Xhox3, in Xenopus laevis and that of evx1 and eve1 in Danio rerio. We show here
      that Xhox3 is expressed in a manner that closely reflects the inferred expression
      pattern of the evx1 gene in the last common ancestor of Vertebrata (i.e., in
      gastrula, the central nervous system, the posterior gut, and the tip of the
      growing tail). Zebrafish evx1 and Xenopus Xhox3 are expressed in homologous cell
      lineages of the central nervous system and of the posterior gut, but evx1 was
      undetectable in the gastrula and the tail bud. Strikingly, eve1 is the only evx
      gene of zebrafish to be expressed in these two latter regions. Thus, the
      ancestral expression pattern of evx1 in vertebrates appears to have been
      distributed between evx1 and eve1 in zebrafish. We propose that evx1 and eve1
      underwent a complementary loss of expression domain in zebrafish that allowed the
      maintenance of the two paralogs in accordance with the duplication-degeneration
      complementation model. It is important to note that, in zebrafish, Evx1 and Eve1
      have lost most of the protein domain upstream of the homeodomain. In addition,
      Eve1 has accumulated substitutions in positions that are highly conserved in all
      other Evx proteins. Thus, the reduction of the expression domain of both evx1 and
      eve1 in zebrafish appears to be associated with the modification of constraints
      on the protein sequences, allowing the shortening of both genes and an
      accelerated substitution rate in eve1.

PMID- 12622732
TI  - Comparative expression analysis of Adh3 during arthropod, urochordate,
      cephalochordate, and vertebrate development challenges its predicted housekeeping
      role.
AB  - Gene and genome duplications in the vertebrate lineage explain the complexity of
      extant gene families. Among these, the medium-chain alcohol dehydrogenase (ADH),
      which expanded by tandem duplications after the cephalochordate-vertebrate split,
      is a good model with which to analyze the evolution of gene function. Although
      the ancestral member of this family, ADH3, has been strictly conserved throughout
      animal evolution, its physiological role is still controversial. Previous
      evidence indicates that it contributes to formaldehyde cytoprotection, retinoic
      acid metabolism, and nitric oxide homeostasis. We performed in situ hybridization
      during Drosophila, ascidian (Ciona intestinalis), and zebrafish (Danio rerio)
      development. We showed that Adh3 expression was restricted to the fat body in
      Drosophila embryos at stage 17 and to the anterior endoderm in C. intestinalis
      tail bud, whereas in the zebrafish 2.5-day larvae the signal appeared widespread.
      A more comprehensive expression analysis including amphioxus and mice revealed
      that ancestral Adh3 was tissue specific, whereas a widespread expression was
      later attained in vertebrates. These variations occurred concomitantly with the
      expansion of the ADH family and the acquisition of new functions but were
      unlinked to the genomic changes that led to the transition from fractional to
      global methylation in vertebrates. Our data challenge the housekeeping role of
      ADH3 and question its involvement in the prevertebrate retinoic acid pathway.

PMID- 12622733
TI  - Developmental flexibility and the effect of social environment on fertility and
      fecundity in parthenogenetic reproduction.
AB  - One specialized environment that can influence development arises in the context
      of social interactions, including the environment contributed by a sexual partner
      during sexual reproduction. It is often difficult, however, to separate out the
      effect of mating (fertilization) from the effect of social environment. In the
      study reported here we examine the effect of social environment mediated by a
      pheromonal signal on the fertility and fecundity of the facultatively
      parthenogenetic cockroach Nauphoeta cinerea. By examining parthenogenetically
      reproducing females, we isolate the effects of social environment in the absence
      of mating or fertilization. Females exposed to male odors are more likely to
      produce parthenogenetic offspring. Further, increased exposure to the male
      pheromone increases the number of offspring produced. Variation in timing of
      reproduction is also dependent on the male. Thus, social environments are a
      mechanism by which males contribute to the development of their offspring,
      resulting in variation in development. This study illustrates the potential
      evolutionary importance of social environments in development, because a
      requirement for male-contributed environments may be a constraint to evolving
      asexual reproduction from a sexually reproducing species.

PMID- 12622734
TI  - Concerted evolution and developmental integration in modular butterfly wing
      patterns.
AB  - Developing organisms are thought to be modular in organization so that traits in
      different modules evolve independently whereas traits within a module change in a
      concerted manner. The eyespot pattern in Bicyclus anynana butterflies provides an
      ideal system where morphological modularity can be dissected and different levels
      of genetic integration analyzed. Several lines of evidence show that all eyespots
      in an individual butterfly are genetically integrated, suggesting that the whole
      pattern, rather than the separate eyespots, should be considered as a single
      character. However, despite the strong genetic correlations between the two
      eyespots on the dorsal forewing of B. anynana, there is great potential for
      independent changes. Here we use laboratory lines selected in different
      directions for the size of those eyespots to study correlated responses in the
      whole eyespot pattern. We show clear changes in eyespot size across all wing
      surfaces, which depend on eyespot position along the anterior-posterior axis.
      There are also changes in the number of extra eyespots and in eyespot color
      composition but no changes in eyespot position relative to wing margin. Our
      analysis of eyespot pattern modularity is discussed in the light of what is known
      about the cellular and genetic mechanisms of eyespot formation and the great
      potential for evolutionary diversification in butterfly wing patterns.

PMID- 12622735
TI  - Mutants highlight the modular control of butterfly eyespot patterns.
AB  - The eyespots on butterfly wings are thought to be serially homologous pattern
      elements. Yet eyespots differ greatly in number, shape, color, and size, within
      and among species. To what extent do these serially homologues have separate
      developmental identities, upon which selection acts to create diversity? We
      examined x-ray-induced mutations for the eyespots of the nymphalid butterfly
      Bicyclus anynana that highlight the modular control of these serially homologous
      wing pattern elements. These mutations reduce or eliminate individual eyespots,
      or groups of eyespots, with no further effect on the wing color pattern. The
      collection of mutants highlights a greater potential developmental repertoire
      than that observed across the genus Bicyclus. We studied in detail one such
      mutation, of codominant effect, that causes the elimination of two adjacent
      eyespots on the ventral hindwing. By analyzing the expression of genes known to
      be involved in eyespot formation, we found an alteration in the differentiation
      of the "organizing" cells at the eyespot's center. No such cells differentiate in
      the wing subdivisions lacking the two eyespots in the mutants. We propose several
      developmental models, based on wing compartmentalization in Drosophila, that
      provide the first framework for thinking about the molecular evolution of
      butterfly wing pattern modularity.

PMID- 12622736
TI  - Critical weight in the development of insect body size.
AB  - Body size is one of the most important life history characters of organisms, yet
      little is known of the physiological mechanisms that regulate either body size or
      variation in body size. Here, we examined one of these mechanisms, the critical
      weight, which is defined as the minimal mass at which further growth is not
      necessary for a normal time course to pupation. The critical weight occurred at
      55% of peak larval mass in laboratory-reared larvae of the tobacco hornworm
      Manduca sexta. We examined the effects of genetic and environmental variation in
      the critical weight on body size. As in many other insects, Manduca larvae reared
      on poor diets were smaller and those reared at lower temperatures were larger
      than control animals. We demonstrated that the critical weight was lower on low
      quality diets but did not change with temperature. There was significant genetic
      variation for body size, for plasticity of body size, and for critical weight,
      but not for plasticity of critical weight. Variation in the critical weight
      accounted for 73% of between-family variance in peak larval size, whereas
      plasticity of critical weight was not significantly correlated with plasticity of
      body size. Our results suggest that although critical weight is an important
      factor in determining body size and enabling the evolution of body size, it may,
      at the same time, act as a constraint on the evolution of plasticity of body
      size. Thus, the determinants of body size and the determinants of plasticity of
      body size do not need to be identical.

PMID- 12622737
TI  - The pattern of segment formation, as revealed by engrailed expression, in a
      centipede with a variable number of segments.
AB  - Arthropods vary enormously in segment number, from less than 20 to more than 200.
      This between-species variation must have originated, in evolution, through
      divergent selection operating in ancestral arthropod species with variable
      segment numbers. Although most present-day arthropod species are invariant in
      this respect, some are variable and so can serve as model systems. Here, we
      describe a study based on one such species, the coastal geophilomorph centipede
      Strigamia maritima. We investigate the way in which segments are formed using in
      situ hybridization to demonstrate the expression pattern of the engrailed gene
      during embryogenesis. We also analyze segment number data in mother-offspring
      broods and thereby demonstrate a significant heritable component of the
      variation. We consider how natural selection might act on this intraspecific
      developmental variation, and we discuss the similarities and differences in
      segment formation between the geophilomorphs and their phylogenetic sister-group.

PMID- 12622738
TI  - Why is limb regeneration possible in amphibians but not in reptiles, birds, and
      mammals?
AB  - The capacity to regenerate limbs is very high in amphibians and practically
      absent in other tetrapods despite the similarities in developmental pathways and
      ultimate morphology of tetrapod limbs. We propose that limb regeneration is only
      possible when the limb develops as a semiautonomous module and is not involved in
      interactions with transient structures. This hypothesis is based on the following
      two assumptions: To an important extent, limb development uses the same
      developmental mechanisms as normal limb development and developmental mechanisms
      that require interactions with transient structures cannot be recapitulated
      later. In amniotes limb development is early, shortly after neurulation, and
      requires inductive interactions with transient structures such as somites. In
      amphibians limb development is delayed relative to amniotes and has become
      decoupled from interactions with somites and other transient structures that are
      no longer present at this stage. The limb develops as a semi-independent module.
      A comparison of the autonomy and timing of limb development in different
      vertebrate taxa supports our hypothesis and its assumptions. The data suggest a
      good correlation between self-organizing and regenerative capacity. Furthermore,
      they suggest that whatever barriers amphibians overcame in the evolution of
      metamorphosis, they are the same barriers that need to be overcome to make limb
      regeneration possible in other taxa.

PMID- 12622739
TI  - Transcriptional regulation of COX-2: a key mechanism in the pathogenesis of nasal
      polyposis in aspirin-sensitive asthmatics?

PMID- 12622740
TI  - Food allergy in adulthood.

PMID- 12622741
TI  - Difficult asthma.

PMID- 12622742
TI  - Nuclear factor-kappaB activity is down-regulated in nasal polyps from aspirin
      sensitive asthmatics.
AB  - BACKGROUND: We examined whether a decreased activity of nuclear factor(NF)
      kappaB), a transcriptional regulator of cyclooxygenase-2 (COX-2), could account
      for down-regulation of COX-2 in nasal polyps of aspirin-sensitive asthmatics.
      METHODS: Nasal polyps were obtained from 17 aspirin-intolerant asthma/rhinitis
      patients (AIAR; 7 men, mean age 48 +/- 12 years) and 23 aspirin-tolerant
      asthma/rhinitis patients (ATAR; 12 men, mean age 65 +/- 11 years). COX-2 mRNA
      expression was measured using semiquantitative reverse transcriptase competitive
      polymerase chain reaction (RT-PCR), and the results were expressed as mean +/-
      standard error of 106 molecules of mRNA/ micro g of total RNA. NF-kappaB binding
      was measured with 32P-labeled oligonucleotides and electrophoretic mobility shift
      assay (EMSA), and the results were expressed as a percentage with respect to the
      mean EMSA obtained in 19 healthy nasal mucosa. RESULTS: The mean levels of COX-2
      mRNA expression (0.25 +/- 0.06) and NF-kappaB activity (89 +/- 13) in nasal
      polyps from AIAR were significantly lower than in polyps from ATAR (COX-2 = 1.58
      +/- 0.50, and NF-kappaB = 143 +/- 12, P < 0.01 and P < 0.05, respectively).
      Levels of COX-2 mRNA and NF-kappaB activity in polyps from patients on
      corticosteroid therapy did not differ statistically from those who were not on
      this therapy before polypectomy. CONCLUSION: This study shows that the low
      expression of COX-2 mRNA in nasal polyps from aspirin-sensitive patients is
      associated with a down-regulation of NF-kappaB activity.

PMID- 12622743
TI  - Beef allergy: a review of 12 cases.
AB  - BACKGROUND: Although beef allergy has long been considered a rare condition, the
      number of studies regarding the nature, epidemiology, and symptoms of beef
      allergy has been increasing. We aimed to describe the results of allergy work-up
      of 12 patients who have a convincing history of acute allergic symptoms following
      beef ingestion. METHODS: Detailed histories of 10 children and two adult
      relatives were obtained and patients underwent skin prick tests with commercial
      beef extract, raw beef and cooked beef. Serum total and beef-specific IgE were
      measured. Labial, and in selected cases, open food challenges were undertaken.
      RESULTS: Interestingly, the rate of family history of beef allergy was 67%
      (8/12). Three patients (two with commercial extract, and one with cooked beef)
      had positive skin test responses to beef. Ten (83%) patients had elevated serum
      IgE concentrations (median 316.5 kU/l, range 9-1321 kU/l) and the beef-specific
      IgE was positive in all patients (median 6.23 kUA/l, range 0.83-36.6 kUA/l).
      Labial food challenge was positive in four (30%) patients. Of the five patients
      who underwent open food challenges, three were positive and two tolerated the
      beef administered. CONCLUSIONS: We conclude that skin prick tests do not
      accurately diagnose IgE-mediated sensitization to beef. Thus, patients with
      suspected beef allergy should be screened additionally for beef-specific IgE
      antibodies, and in selected cases oral food challenge should be carried out to
      verify the diagnosis.

PMID- 12622744
TI  - Roasted hazelnuts--allergenic activity evaluated by double-blind, placebo
      controlled food challenge.
AB  - BACKGROUND: Allergy to hazelnuts is a common example of birch pollen related food
      allergy. Symptoms upon ingestion are often confined to the mouth and throat, but
      severe systemic reactions have been described in some patients. The aim of the
      study was to evaluate the reduction in allergenicity by roasting of the nuts.
      METHODS: Double-blind, placebo-controlled food challenges (DBPCFC) with roasted
      hazelnuts (140 degrees C, 40 min) were performed in 17 birch pollen allergic
      patients with DBPCFC-confirmed food allergy to raw hazelnuts. The effect of
      roasting was further evaluated by skin prick test (SPT), histamine release (HR),
      measurement of specific IgE, and IgE-inhibition experiments. RESULTS: In 5/17
      patients the DBPCFC with the roasted nuts were positive. The symptoms were
      generally mild and included OAS (oral allergy syndrome) in all patients. Roasting
      of the nuts significantly reduced the allergenic activity evaluated by SPT, HR,
      specific IgE, and IgE-inhibition. Immunoblotting experiments with recombinant
      hazelnut allergens showed sensitization against Cor a 1.04 in 16/17 patients and
      against Cor a 2 in 7/17 patients. None of the patients were sensitized to Cor a
      8. Challenge-positive patients did not differ from the rest in IgE-binding
      pattern. CONCLUSIONS: All the applied methods indicated that roasting of
      hazelnuts reduces the allergenicity, but since 5/17 birch pollen allergic
      patients were DBPCFC-positive to the roasted nuts, ingestion of roasted hazelnuts
      or products containing roasted hazelnuts can not be considered safe for a number
      of hazelnut allergic consumers. For patients with a history of severe allergic
      symptoms upon ingestion of hazelnuts, thorough and conscientious food labelling
      of hazelnuts and hazelnut residues is essential.

PMID- 12622745
TI  - A mouse model of the atopic eczema/dermatitis syndrome by repeated application of
      a crude extract of house-dust mite Dermatophagoides farinae.
AB  - BACKGROUND: We cultured Dermatophagoides farinae (Df), one of the most common
      mites in house dust and the most important allergen among natural allergens. With
      this material, we attempted to produce an animal model of the atopic
      eczema/dermatitis syndrome (AEDS). METHODS: We cultured Df mites in high density
      and prepared a crude extract of Df (DfE) together with the culture medium. We
      applied the extract to the back skin of NC/Nga and BALB/c mice three times per
      week for 8 weeks. RESULTS: In the NC/Nga group, dryness or scaling appeared on
      the skin, and scratching behavior increased at the second week in the DfE-treated
      group. Skin erosion and hemorrhage occurred at the fourth week. The epidermis
      thickened and deepened into the upper dermis, in which mast cells were highly
      accumulated, corresponding with the skin lesion of AEDS patients. Specific IgE
      and IgG to DfE and total IgE were elevated in the sera. Mice treated with an
      extract of mite culture medium did not develop skin lesions. In the BALB/c group,
      mice developed specific IgE and IgG to DfE, however, no typical skin lesions
      appeared. Mast cells in the upper dermis did not increase. CONCLUSIONS: Repeated
      painting of Dermatophagoides extract produced IgE-associated AEDS-like lesions on
      the skin of NC mice.

PMID- 12622746
TI  - Limpet anaphylaxis: cross-reactivity between limpet and house-dust mite
      Dermatophagoides pteronyssinus.
AB  - BACKGROUND: Limpet is a mollusc that is frequently found along the shores of warm
      seas. Few allergic reactions to limpet have been described, and cross-reactivity
      with house-dust mites has not been established. METHODS: We report five patients
      with anaphylactic reactions due to limpet ingestion. A limpet extract was
      prepared and skin prick tests (SPT), radioallergosorbent assays (RAST), sodium
      dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), and IgE
      immunoblotting were performed. In order to evaluate cross-reactivity, an
      immunoblotting inhibition assay with Dermatophagoides pteronyssinus was also
      done. RESULTS: All patients were asthmatics sensitized to house-dust mites. In
      each case, severe bronchospasm was evidenced, and three required mechanical
      ventilation. Positive SPT with limpet extract was found in the four patients
      tested. RAST showed specific IgE on each patient's sera. Immunoblotting showed
      several allergenic fractions with a wide molecular weight range (15-250 kDa). D.
      pteronyssinus inhibited IgE-binding molecules above 50 kDa in the limpet extract,
      particularly one molecule of 75 kDa. CONCLUSIONS: We describe five patients with
      IgE-mediated limpet allergy. Severe bronchospasm was the most important symptom.
      Cross-reactivity with D. pteronyssinus was demonstrated.

PMID- 12622749
TI  - Acute urticaria due to dental eugenol.

PMID- 12622747
TI  - The effect of storage on allergen and microbial agent levels in frozen house
      dust.
AB  - BACKGROUND: House dust samples collected for exposure studies are often stored
      for variable time periods until analysis. However, there is currently no
      information on the effects of dust storage on the content of biocontaminants.
      Therefore, associations were analysed between the levels of mite allergens (Der p
      1, Der f 1), cat allergen (Fel d 1) and microbial components (endotoxin, beta(1-
      >3)-glucan) on the one hand and the storage duration of dust samples at -20
      degrees C on the other hand. METHODS: Within the framework of a study on the
      influences of INdoor factors and Genetics on Asthma (INGA), dust samples were
      collected from living room floors between June 1995 and August 1998 and extracted
      according to a standardized protocol. The concentrations of Der p 1, Der f 1, Fel
      d 1 and beta(1-->3)-glucan were determined with specific enzyme immunoassays.
      Endotoxin content was quantified using a chromogenic kinetic Limulus amoebocyte
      lysate (LAL) test. All concentrations were expressed per gram of dust RESULTS:
      Dust samples (n = 1236) were obtained from 655 homes in Hamburg, Hettstedt,
      Zerbst and Bitterfeld. Storage duration (range 8-298 days) was grouped into four
      categories (<or= 60 d; 61-90 d; 91-120 d; > 120 d). After adjustment for city of
      residence and season of dust sampling, means ratios comparing categories 2-4 to
      the first category were not statistically significant for Der p 1, Der f 1,
      endotoxin and beta(1-->3 glucan). However, Fel d 1 concentrations significantly
      declined with increased storage times of dust samples. CONCLUSIONS: Storage of
      house dust at -20 degrees C for up to 10 months has no effect on mite allergen,
      endotoxin and beta(1-->3)-glucan levels. A potential loss of Fel d 1 during
      storage of frozen dust samples needs further investigations by repeated
      measurements of allergen in identical dust samples.

PMID- 12622748
TI  - Health impacts of second-hand exposure to cat allergen Fel d 1 in infants.
AB  - BACKGROUND: Recent cross-sectional studies suggested that highest sensitization
      prevalences occur with moderate cat allergen exposures. We aimed to assess the
      impact of moderate levels of second-hand cat allergen exposure on the incidence
      of specific sensitization and wheezing in the framework of a birth cohort study.
      Therefore we restricted our analysis to infants without a cat at home since
      birth. METHODS: At infant's age 3 months, cat allergen levels were measured in
      the mattress dust of 1840 families without cats. At age 2 years, serum IgE
      specific to Fel d 1 was analyzed. Incidence of wheezing apart from respiratory
      infection was assessed by questionnaire. Logistic regression models were used to
      calculate adjusted odds ratios (OR) for the association between second-hand cat
      allergen exposure and health outcomes. RESULTS: Until age 2 years, 13 of 1301
      infants (1%) were sensitized to cat allergen and 56 of 1492 infants (4%) had ever
      wheezing without infection. Early exposure to second-hand cat allergen levels
      >or= 1 microg/g dust increased substantially the risk for specific sensitization
      to Fel d 1 (OR 10.9, 95% CI 3.4-35.0) and ever-wheeze without infection (OR 2.0,
      95% CI 1.1-3.9) at age 2 years. CONCLUSIONS: Second-hand exposure to cat allergen
      in homes without cats is detrimental in terms of allergy development in infants.

PMID- 12622750
TI  - Anaphylaxis during negative penicillin skin prick testing confirmed by elevated
      serum tryptase.

PMID- 12622751
TI  - Aspirin intolerance in boy with primary ciliary dyskinesia.

PMID- 12622752
TI  - Double allergy to the same drug in the same patient.

PMID- 12622753
TI  - Meat allergy and cross-reactivity with hamster epithelium.

PMID- 12622754
TI  - Treatment of bullous pemphigoid with a leukotriene receptor antagonist.

PMID- 12622755
TI  - Winging of the scapula--an unusual cause.

PMID- 12622756
TI  - Review article: Esomeprazole--enhanced bio-availability, specificity for the
      proton pump and inhibition of acid secretion.
AB  - Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor
      available for clinical use as a single isomer. It demonstrates pharmacological
      and clinical benefits beyond those seen with the racemic omeprazole. Esomeprazole
      has higher and more consistent bio-availability than omeprazole, which results in
      a greater area under the plasma concentration-time curve. It is the area under
      the plasma concentration-time curve of omeprazole and esomeprazole that
      determines how much of each reaches the parietal cell, and thus the control of
      gastric acid secretion that is achieved. Esomeprazole, like other proton pump
      inhibitors, has a high specificity for the acidic environment of the parietal
      cell, where it is accumulated, activated and covalently inhibits the proton pump.
      Proton pumps elsewhere in the body do not achieve the level of acidity needed for
      accumulation and activation. Esomeprazole, 40 mg once daily, provides more
      effective control of gastric acid secretion than omeprazole, 20 or 40 mg once
      daily, and all other proton pump inhibitors given at their standard doses. This
      translates into greater clinical effect compared with omeprazole, 20 mg once
      daily, and lansoprazole, 30 mg once daily, in the management of reflux disease.
      Esomeprazole therapy is well tolerated, with a low adverse events profile,
      similar to that seen with omeprazole.

PMID- 12622757
TI  - Review article: The pharmacological properties and clinical use of valdecoxib, a
      new cyclo-oxygenase-2-selective inhibitor.
AB  - Cyclo-oxygenase-2-selective inhibitors produce less gastric damage than
      conventional non-steroidal anti-inflammatory drugs. Valdecoxib is a new orally
      administered cyclo-oxygenase-2-selective inhibitor, recently approved for use in
      osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea in the USA. The
      drug has been evaluated in more than 60 clinical studies involving more than 14
      000 patients and healthy volunteers. The analgesic efficacy of valdecoxib at a
      dose of 10 mg once daily in both osteoarthritis and rheumatoid arthritis is
      superior to that of placebo and similar to that of traditional non-steroidal anti
      inflammatory drugs. Valdecoxib is effective in single doses of up to 40 mg for
      the alleviation of acute menstrual pain and has a rapid onset of action (within
      30 min) and a long duration of analgesia (up to 24 h). Valdecoxib is well
      tolerated and has safety advantages compared with traditional non-steroidal anti
      inflammatory drugs in terms of less gastrointestinal toxicity and a lack of an
      effect on platelet function. The incidence of adverse effects involving the
      kidney (fluid retention, oedema and hypertension) is similar to that of non
      selective, non-steroidal anti-inflammatory drugs.

PMID- 12622758
TI  - 6-thioguanine--efficacy and safety in chronic active Crohn's disease.
AB  - BACKGROUND: : Azathioprine and mercaptopurine are commonly used in chronic active
      Crohn's disease. They share the disadvantage of a delayed onset of action and
      potentially serious side-effects, and are metabolized to thioguanine nucleotides
      which are thought to be the active metabolites. The direct use of 6-thioguanine
      may offer a more rapid and safer alternative. We conducted an open prospective
      study to investigate the efficacy and safety of 6-thioguanine in chronic active
      Crohn's disease. METHODS: : Thirty-seven patients with chronic active Crohn's
      disease and a Crohn's disease activity index of > 150 were enrolled in this
      study. Inclusion criteria were steroid dependence (n = 19), steroid
      refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to
      azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks;
      a dose escalation to 80 mg was allowed at week 12. Remission was defined as a
      Crohn's disease activity index of < 150 associated with a decrease of > 70
      points; response was defined as a decrease of > 70 points in the Crohn's disease
      activity index. RESULTS: : In the intention-to-treat analysis, 13 of 37 patients
      achieved remission (35%). Twelve of these 13 patients achieved remission after 4
      weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean
      Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6
      Thioguanine was more effective in azathioprine-intolerant than in azathioprine
      refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6
      thioguanine. Adverse events included phototoxicity, pancreatitis, headache,
      nausea, alopecia, arthralgia, minor infections and reversible elevation of
      transaminases. Six patients required discontinuation of medication, two because
      of leucopenia. CONCLUSIONS: : In this patient group with chronic active Crohn's
      disease, 6-thioguanine appeared to be effective with acceptable short-term
      toxicity, but long-term controlled trials are clearly needed to further define
      its role.

PMID- 12622759
TI  - Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation and microbial
      flora.
AB  - BACKGROUND: Preliminary trials of probiotics in preventing recurrent chronic
      pouchitis have been encouraging. AIM: To investigate the efficacy of
      Lactobacillus GG supplementation as primary therapy for ileal pouch inflammation,
      and its effect on the microbial flora. METHODS: Twenty patients, with a previous
      history of pouchitis and endoscopic inflammation, were recruited for a
      prospective, randomized, double-blind, placebo-controlled trial of Lactobacillus
      GG supplementation (10 LGG, 10 placebo) in two gelatine capsules [(0.5-1) x
      10(10) colony-forming units/capsule] b.d. for 3 months. Quantitative bacterial
      culture of fresh faecal samples and biopsies taken from the pouch and afferent
      limb was performed before and after supplementation. RESULTS: Lactobacillus GG
      supplementation changed the pouch intestinal flora by increasing the ratio of
      total faecal lactobacilli to total faecal anaerobes (P = 0.03) and enhancing the
      frequency of lactobacilli-positive cultures in the pouch and afferent limb
      mucosal biopsy samples. However, only 40% of patients were colonized with
      Lactobacillus GG. No differences were observed between the groups with regard to
      the mean pouchitis disease activity index or the total anaerobes or aerobes of
      faecal or tissue biopsy samples. CONCLUSIONS: A single-strain probiotic bacterium
      supplement of Lactobacillus GG changed the pouch intestinal bacterial flora, but
      was ineffective as primary therapy for a clinical or endoscopic response. More
      clinical trials are needed to evaluate the right placement and dosage of
      probiotics within a treatment regimen for pouchitis.

PMID- 12622760
TI  - Two mesalazine regimens in the prevention of the post-operative recurrence of
      Crohn's disease: a pragmatic, double-blind, randomized controlled trial.
AB  - BACKGROUND: The role of mesalazine in preventing the clinical recurrence of
      Crohn's disease after surgery has been shown in a meta-analysis of all published
      studies. No clear relationship, however, has been shown between dosage and
      response. AIM: To evaluate whether 4.0 g/day of mesalazine may offer therapeutic
      advantages over 2.4 g/day in the prevention of both endoscopic and clinical post
      operative recurrence of Crohn's disease. METHODS: The study was a double-blind,
      randomized, multi-centre, prospective, controlled clinical trial. Two hundred and
      six patients, submitted to first or second intestinal resection for Crohn's
      disease limited to the terminal ileum, with or without involvement of the
      caecum/ascending colon, were enrolled. Of these, 101 were randomly allocated to
      receive 4.0 g/day of mesalazine (Asacol, Giuliani SpA, Milan, Italy) and 105 to
      receive 2.4 g/day, starting 2 weeks after surgery. The primary outcome was
      endoscopic recurrence, at 12 months after surgery. Three different degrees of
      endoscopic recurrence were evaluated (endoscopic scores: > 0, > 1 and > 2). The
      secondary outcome was clinical recurrence, defined as a Crohn's disease activity
      index of more than 150 points or an increase in the Crohn's disease activity
      index of 100 points or more. For statistical analysis, chi-square, Wilcoxon and
      Cox regression model tests were used, when appropriate. RESULTS: Eighty-four
      patients in the 4.0 g/day group and 81 patients in the 2.4 g/day group were
      evaluable by endoscopy. Endoscopic recurrence of > 0 was significantly higher in
      the 2.4 g/day group than in the 4.0 g/day group (62% vs. 46%; P < 0.04). No
      difference was observed between the two groups with regard to the other two
      endoscopic outcomes (> 1 and > 2) or clinical recurrence. CONCLUSIONS: A 4.0
      g/day regimen of mesalazine does not offer a clinically significant advantage
      over a 2.4 g/day regimen in the prevention of post-operative endoscopic and
      clinical recurrence of Crohn's disease at 1 year of follow-up.

PMID- 12622761
TI  - A pharmacoscintigraphic evaluation of oral budesonide given as controlled-release
      (Entocort) capsules.
AB  - AIMS: To investigate the gastrointestinal pharmacokinetics of controlled-release
      (Entocort) and standard budesonide capsules. METHODS: Six Crohn's disease
      patients and eight healthy controls were given controlled-release capsules
      containing budesonide and an inert 111In label, following breakfast. In the
      patients, a standard capsule containing deuterium-labelled budesonide was given
      simultaneously. In the controls, on a separate occasion, the controlled-release
      capsules were given in the fasting state. Gastrointestinal transit was recorded
      by a gamma camera. Plasma budesonide and deuterium-labelled budesonide were used
      to estimate drug release, and urine cortisol was used to assess systemic effects.
      RESULTS: Budesonide delivery to the ileo-colonic region was significantly greater
      after the intake of the controlled-release capsules [69%; 95% confidence interval
      (CI), 54-84] than after the standard capsules (30%; 95% CI, 15-45) (P = 0.005).
      Fasting had little impact on uptake. The transit and pharmacokinetics of
      budesonide were similar in both subject groups, although systemic availability
      was higher in patients (21%; 95% CI, 13-33) than in controls (12%; 95% CI, 10-14)
      (P = 0.009). Urinary cortisol was, however, similar in both groups. CONCLUSIONS:
      A major fraction of budesonide is released in the ileum and throughout the colon,
      the intended target for the controlled-release formulation. The prandial state
      has little effect on budesonide uptake.

PMID- 12622762
TI  - Non-erosive reflux disease (NERD)--acid reflux and symptom patterns.
AB  - BACKGROUND: Recent reports suggest that patients with non-erosive reflux disease
      (NERD) treated with anti-reflux medications show lower symptom improvement rates
      than patients with erosive oesophagitis treated with the same medications. AIM:
      To determine the acid reflux and symptom patterns of patients with NERD in
      comparison with those with erosive oesophagitis and Barrett's oesophagus, and to
      identify different NERD subgroups. METHODS: One hundred and forty-nine
      consecutive patients seen for classic heartburn symptoms were evaluated for the
      study. Oesophageal mucosal injury was assessed by upper endoscopy and classified
      by Hetzel-Dent criteria. Patients with Hetzel-Dent grades 0-1 were considered to
      have NERD. The extent of oesophageal acid exposure was determined by ambulatory
      24-h oesophageal pH monitoring. RESULTS: Seventy-one patients were found to have
      NERD, 36 erosive oesophagitis and 42 Barrett's oesophagus. Compared with patients
      with erosive oesophagitis (75%) and Barrett's oesophagus (93%), those with NERD
      (45%) were significantly less likely to have an abnormal pH test (P = 0.0001).
      Patients with Barrett's oesophagus had the highest mean number of acid reflux
      events (210 +/- 17.7), compared with those with erosive oesophagitis (139.7 +/-
      15.2) and NERD (95.3 +/- 9.4) (P = 0.0001); however, the rate of perceived acid
      reflux events was similar and very low in all groups (NERD, 3.6%; erosive
      oesophagitis, 2.9%; Barrett's oesophagus, 2.17%). NERD-positive patients
      (abnormal pH test) had a similar extent of oesophageal acid exposure to those
      with erosive oesophagitis. NERD-positive patients were more likely to demonstrate
      a symptom index greater than 75% than NERD-negative patients (normal pH test)
      (61.9% vs. 10.5%; P = 0.0001). In the NERD-negative group, those with a negative
      symptom index reported having heartburn at pH < 4 only 12.7% of the time,
      compared with 70.7% of the time in those with a positive symptom index, despite a
      similar mean number of heartburn episodes. CONCLUSIONS: Patients with NERD
      commonly demonstrate a negative pH test. Acid reflux characteristics and symptom
      patterns suggest a heterogeneous group of patients.

PMID- 12622763
TI  - Reflux and Barrett's oesophagitis after gastric surgery--long-term follow-up and
      implications for the roles of gastric acid and bile in oesophagitis.
AB  - BACKGROUND: The role of gastric acid is difficult to separate from that of bile
      in oesophageal reflux, and the complications of this can take many years to
      develop. Gastric surgery patients provide a good model for both significant bile
      reflux and marked gastric acid inhibition. AIM: To study the oesophageal
      abnormalities in gastric surgery patients undergoing long-term follow-up,
      compared with patients with intact stomachs. METHODS: Two hundred and forty adult
      patients were endoscoped regardless of their age, sex or type of surgical
      procedure. Oesophageal damage was graded on a scale of 0-5, and biopsies were
      taken to exclude neoplasia, to diagnose Barrett's oesophagus and to identify
      Helicobacter pylori. RESULTS: Of the 240 patients studied, 140 had undergone
      gastric surgery 27 years (19-31 years) [median (interquartile range)] prior to
      endoscopy, and these patients had milder oesophageal scores and fewer cases of
      Barrett's oesophagitis. Of the 119 patients with post-surgical bile reflux
      gastritis, 31 (26%) had oesophagitis, two (1.7%) had Barrett's oesophagitis and
      oesophageal scores of 0 (0-1) were found. These results compared with
      corresponding values of 37 (37%; P = 0.11), 11 (11%; P = 0.007) and 0 (0-2) (P =
      0.046), respectively, in 100 patients with intact stomachs. In addition, of the
      83 patients with vagotomy, 19 had oesophagitis (23%; P = 0.05), none had
      Barrett's oesophagitis and lower oesophageal scores (P = 0.02) were found.
      CONCLUSIONS: The prevalence and severity of reflux and Barrett's oesophagitis are
      not increased in patients with a long history of gastric surgery, particularly
      after vagotomy, and despite being at risk of bile reflux.

PMID- 12622764
TI  - Randomized controlled study of rabeprazole, levofloxacin and rifabutin triple
      therapy vs. quadruple therapy as second-line treatment for Helicobacter pylori
      infection.
AB  - AIM: To test the efficacy of rabeprazole, levofloxacin and rifabutin triple
      therapy vs. quadruple therapy for the second-line treatment of Helicobacter
      pylori infection. METHODS: One hundred and nine patients who had failed previous
      H. pylori eradication were randomized to receive: (i) rabeprazole, 20 mg b.d.,
      rifabutin, 300 mg once daily, and levofloxacin, 500 mg once daily, for 7 days
      (triple therapy); or (ii) rabeprazole, 20 mg b.d., metronidazole, 400 mg t.d.s.,
      bismuth subcitrate, 120 mg q.d.s., and tetracycline, 500 mg q.d.s., for 7 days
      (quadruple therapy). Endoscopy and culture were performed before treatment.
      RESULTS: The clarithromycin (79% vs. 21%, P < 0.001) and metronidazole (89% vs.
      40%, P < 0.001) resistance rates were significantly higher in patients with
      previous exposure than in those with no previous exposure. The intention-to-treat
      and per protocol eradication rates were 91%/91% for the triple therapy group and
      91%/92% for the quadruple therapy group. For patients with double resistance to
      metronidazole and clarithromycin, the eradication rates were 85% (17/20) in the
      triple therapy group and 87% (13/15) in the quadruple therapy group. Compliance
      was greater than 95% for both regimens. CONCLUSION: Rabeprazole, levofloxacin and
      rifabutin-based triple therapy and quadruple therapy were equally effective as
      second-line treatments for H. pylori infection.

PMID- 12622765
TI  - Gallstones--an increasing problem: a study of hospital admissions in England
      between 1989/1990 and 1999/2000.
AB  - BACKGROUND: The number of operations for cholelithiasis increased from the 1950s
      to the 1990s. AIMS: To determine the time trends in cholelithiasis for hospital
      admissions, operations and in-hospital case fatalities in England between
      1989/1990 and 1999/2000, and population mortality rates between 1979 and 1999.
      METHODS: Hospital Episode Statistics for admissions were obtained from the
      Department of Health and mortality data were obtained from the Office for
      National Statistics. RESULTS: Between 1989/1990 and 1999/2000, age-standardized
      hospital admission rates for cholelithiasis increased by 30% for males and 64%
      for females. The proportions of admissions undergoing an operation declined
      progressively over the study period. In 1999/2000, the frequency of operation was
      approximately 50-60% for most age groups, but decreased progressively with
      advancing age at > or = 65 years. The proportions of admissions undergoing
      therapeutic endoscopy increased several-fold, especially amongst older
      individuals. Case fatality rates declined. Mortality rates declined from 1979 to
      1988, but showed no further change from 1989 to 1999. CONCLUSIONS: There has been
      a steady increase in admission rates for cholelithiasis over the study period.
      Whilst the frequency of operation has declined, the proportion of patients
      undergoing therapeutic endoscopy has increased.

PMID- 12622766
TI  - Use of unlicensed and off-label medications in paediatric gastroenterology with a
      review of the commonly used formularies in the UK.
AB  - BACKGROUND: Use of unlicensed and off-label medications is common in hospital
      based paediatric practice. Whilst inpatient prescription can be closely monitored
      within the hospital setting, it is subspecialties like paediatric
      gastroenterology, caring for chronically ill children on an outpatient basis that
      require administration of regular medications in the community. Local
      practitioners rely on available paediatric formularies or information provided by
      the tertiary unit for monitoring and dispensing further prescriptions. AIM: To
      assess the proportion of unlicensed and off-label medications prescribed in a
      paediatric gastroenterology unit to children discharged to the community and
      assess adequacy of information about these medications in commonly used British
      formularies. METHODS: All prescriptions prescribed over a six-month period (Jan
      Jul 2002) either in the paediatric gastroenterology outpatient department or for
      children discharged home after an inpatient stay, were retrieved from the
      pharmacy database. The main outcome measures were to assess the proportion of
      medications prescribed for unlicensed or off-label use. RESULTS: 308 patients
      received 777 prescriptions of which 384 (49%) were for unlicensed or off-label
      use. Of these 291 (76%) were off-label; 208 in relation to indication and 83 to
      child's age. 93 of the prescribed medications were unlicensed; 37 were due to
      manipulation of formulation. Of the commonly used formularies in the UK, only
      'Medication for Children(R)' contained dosage information on more than half
      (9/13) of the most often prescribed off-label/unlicensed medications in
      paediatric gastroenterology. CONCLUSIONS: Use of unlicensed and off-label
      medications remains a problem in paediatric practice. Until licensing laws change
      and more drugs are licensed in children, paediatric gastroenterologists remain
      responsible for provision of information to families, local practitioners, nurses
      and pharmacists. Of the commonly used formularies, 'Medicines for Children' is
      the most detailed and comprehensive, and should be available to all general
      practitioners and pharmacists in the UK. Clear communication between specialist
      units and local practitioners is imperative to ensure safe and effective
      prescribing to children.

PMID- 12622767
TI  - Tegaserod, a 5-HT4 receptor partial agonist, decreases sensitivity to rectal
      distension in healthy subjects.
AB  - BACKGROUND: Tegaserod reduces the symptoms associated with irritable bowel
      syndrome, and anti-nociceptive effects have been demonstrated in animals. Its
      effect on the rectal sensitivity in humans has not been delineated clearly. AIM:
      To evaluate the action of tegaserod on rectal sensitivity in response to
      distension by means of a reflexological technique based on electrophysiological
      recordings of the RIII nociceptive reflex. METHODS: A randomized, double-blind,
      placebo-controlled study, performed in 20 healthy women, quantified the effects
      of slow or rapid rectal distensions on the RIII reflex at baseline and on day 8
      following treatment with either placebo or tegaserod (6 mg b.d.). RESULTS: At
      baseline, slow distensions performed up to the pain threshold induced gradual
      inhibitions of the RIII reflex. On day 8, these inhibitory effects were
      significantly reduced in the tegaserod group, but not in the placebo group (P =
      0.0001). The effects of rapid distensions were not significantly modified by
      tegaserod or placebo. The intensity of subjective pain perception and rectal
      compliance were not altered by either treatment. CONCLUSION: These results
      suggest that tegaserod reduces the sensitivity to rectal distension in healthy
      subjects and interacts with the processing of sensory visceral information.

PMID- 12622768
TI  - Wheat-starch-based gluten-free products in the treatment of newly detected
      coeliac disease: prospective and randomized study.
AB  - BACKGROUND: The safety of wheat-starch-based gluten-free products in the
      treatment of coeliac disease is debatable. Prospective studies are lacking. AIM:
      : To compare the clinical, histological and serological response to a wheat
      starch-based or natural gluten-free diet in patients with newly detected coeliac
      disease. METHODS: Fifty-seven consecutive adults with untreated coeliac disease
      were randomized to a wheat-starch-based or natural gluten-free diet. Clinical
      response, small bowel mucosal morphology, CD3+, alphabeta+ and gammadelta+ intra
      epithelial lymphocytes, mucosal human leucocyte antigen-DR expression and serum
      endomysial, transglutaminase and gliadin antibodies were investigated before and
      12 months after the introduction of the gluten-free diet. Quality of life
      measurements were performed by standardized questionnaires and the bone mineral
      density was analysed. RESULTS: In both groups, abdominal symptoms were alleviated
      equally by a strict diet. There were no differences between the groups in mucosal
      morphology, the density of intra-epithelial lymphocytes, serum antibodies, bone
      mineral density or quality of life tests at the end of the study. Four patients
      on a natural gluten-free diet and two on a wheat-starch-based gluten-free diet
      had dietary lapses; as a result, inadequate mucosal, serological and clinical
      recovery was observed. CONCLUSIONS: The dietary response to a wheat-starch-based
      gluten-free diet was as good as that to a natural gluten-free diet in patients
      with newly detected coeliac disease.

PMID- 12622769
TI  - Moderate coffee consumption increases plasma glutathione but not homocysteine in
      healthy subjects.
AB  - BACKGROUND: The consumption of unfiltered coffee, containing bioactive
      diterpenes, causes an increase in plasma homocysteine concentration. A slight
      increase in plasma homocysteine is also caused by large quantities of filtered
      coffee. Coffee terpenes also raise plasma glutathione in mice. AIM: To verify the
      effect of Italian-style coffee consumption on the plasma concentration of
      glutathione and homocysteine in healthy subjects. METHODS: Twenty-two volunteers
      consumed five cups of coffee per day for 1 week and maintained their usual diet.
      Five subjects were enrolled as controls. The intervention trial was preceded and
      followed by seven coffee-free days. RESULTS: Plasma glutathione increased by 16%
      (P < 0.05) on coffee consumption, and returned to the original concentration
      after the washout period. The increase in plasma homocysteine concentration (13%
      after 1 week of coffee intake) was not significant. No differences in glutathione
      or homocysteine concentration were observed in the control group. No variation of
      plasma hydroperoxide concentration was detectable. CONCLUSIONS: A coffee intake
      regimen, representing the average consumption of coffee drinkers in Italy,
      increased the plasma concentration of glutathione, but no significant increase in
      the plasma homocysteine concentration was detected.

PMID- 12622770
TI  - Influence of the selective serotonin re-uptake inhibitor, paroxetine, on gastric
      sensorimotor function in humans.
AB  - BACKGROUND: The role of 5-hydroxytryptamine in the control of gastric fundus tone
      in humans is still unknown. Selective 5-hydroxytryptamine re-uptake inhibitors
      act both centrally and peripherally to enhance the availability of
      physiologically released 5-hydroxytryptamine. AIM: To study the influence of a
      selective 5-hydroxytryptamine re-uptake inhibitor, paroxetine, on gastric fundus
      tone, on the perception to gastric distension and on gastric accommodation to a
      meal. METHODS: Sixteen healthy volunteers underwent a gastric barostat study on
      two occasions, after pre-treatment with placebo or paroxetine, 20 mg/day. Graded
      isobaric and isovolumetric distensions were performed and perception was scored
      by a questionnaire. Subsequently, the amplitude of the gastric accommodation to a
      mixed liquid meal was also measured. RESULTS: Pre-treatment with paroxetine did
      not alter the thresholds for perception and discomfort during isobaric (4.7 +/-
      2.3 vs. 4.0 +/- 2.0 mmHg and 13.3 +/- 3.1 vs. 12.7 +/- 2.3 mmHg above the minimum
      intragastric distending pressure, N.S.) and isovolumetric (307 +/- 90 vs. 417 +/-
      114 mL and 772 +/- 74 vs. 750 +/- 76 mL, N.S.) distensions. Paroxetine
      significantly enhanced the amplitude of the meal-induced fundus relaxation (136
      +/- 51 vs. 255 +/- 43 mL, P < 0.05). CONCLUSIONS: Pre-treatment with paroxetine
      enhances gastric accommodation to a meal. These data suggest that the release of
      5-hydroxytryptamine, probably at the level of the enteric nervous system, is
      involved in the control of the accommodation reflex in humans, and that
      paroxetine may be beneficial to patients with impaired post-prandial fundus
      relaxation.

PMID- 12622771
TI  - Regular medication and paracetamol overdose.

PMID- 12622772
TI  - Tissue typing in support of unrelated hematopoietic cell transplantation.
AB  - The success of unrelated hematopoietic cell transplantation (HCT) for the
      treatment of hematologic malignancies has closely paralleled development of
      robust typing methods for comprehensive and precise donor-recipient matching. The
      application of molecular methods in clinical research has led to a more complete
      understanding of the immunogenetic barriers involving host-vs-graft (HVG) and
      graft-vs-host (GVH) reactions. Along with the development of less toxic
      transplant regimens, advances in the prevention and treatment of graft-vs-host
      disease (GVHD) and in the supportive care of the transplant recipient, improved
      HLA matching of potential unrelated donors has led to clinical results that begin
      to compare favorably with that of HLA-identical sibling transplants.

PMID- 12622773
TI  - Population of the HLA ligand database.
AB  - We have established an HLA ligand database to provide scientists and clinicians
      with access to Major Histocompatibility Complex (MHC) class I and II motif and
      ligand data. The HLA Ligand Database is available on the world wide web at
      http://hlaligand.ouhsc.edu and contains ligands that have been published in peer
      reviewed journals. HLA peptide datasets prove useful in several areas: ligands
      are important as targets for various immune responses while algorithms built upon
      ligand datasets allow identification of new peptides without time-consuming
      experimental procedures. A review of the HLA class I ligands in the database
      identifies strengths and deficiencies in the database and, therefore, the utility
      of the dataset for identifying new peptides. For instance, 212 HLA-A phenotypes
      exist of which 23 have a motif determined and 43 have peptides characterized. In
      terms of number of ligands, HLA-A*0201 has 258 characterized ligands, A*1101 has
      25 peptides, while the remaining two-thirds of the HLA-A phenotypes have less
      than 10 associated peptide sequences. Characterization of ligands and motifs
      remains roughly the same at the HLA-B locus while the peptides of the HLA-C locus
      tend to be less characterized. These data show that 74% of HLA class I molecules
      do not have ligands represented in the database and thus algorithms based on the
      dataset could not predict ligands for a majority of the US population. Building
      upon this dataset and knowledge of HLA allelic frequencies, it is possible to
      plan a systematic expansion of the HLA class I ligand database to better identify
      ligands useful throughout the population.

PMID- 12622774
TI  - Cloning and sequencing full-length HLA-B and -C genes.
AB  - Currently most available HLA-A, -B and -C DNA sequences cover exons 2 and 3 with
      a limited number extending to include other exons and introns. We have developed
      a method for the accurate determination of full-length genomic DNA sequences for
      HLA-A, -B and -C alleles. The method involves cloning of PCR amplified full
      length HLA genes to separate alleles at heterozygous loci. The approach avoids
      any ambiguities from sequencing heterozygous PCR products directly and also
      avoids ambiguities from sequencing overlapping PCR products to achieve full
      length sequence. To date we have sequenced full-length genomic sequences from
      representatives of all the major HLA-B and -C allele groups.

PMID- 12622775
TI  - Monoclonal antibodies to denatured human ACE (CD 143), broad species specificity,
      reactivity on paraffin sections, and detection of subtle conformational changes
      in the C-terminal domain of ACE.
AB  - Two new mouse monoclonal antibodies (mAbs) were generated to denatured human
      angiotensin-converting enzyme (ACE, CD143). The clones 2E2 and 3C5, each of the
      IgG1 kappa chain isotype, detect ACE with high sensitivity, respectively, at 20
      ng and 2 ng of protein per lane in Western blotting. They both recognize
      different epitopes on the C-domain of ACE located between amino acid residues 740
      and 992. In formalin-fixed and paraffin-embedded human tissues,
      immunohistochemistry revealed all known expression sites of ACE, e.g. the
      epithelial brush borders of proximal kidney tubules, epithelial cells of
      epididymis, endothelial cells, activated macrophages as well as germ cells during
      spermatogenesis. In contrast to other mAbs to denatured human ACE, mAbs 2E2 and
      3C5 demonstrate cross-reactivity with a broad spectrum of animal species such as
      monkey, rat, rabbit, cattle, dog, cat, and guinea pig. In addition, mAb 2E2
      recognized mouse ACE in Western blotting and on paraffin sections. Our findings
      suggest that mAbs 2E2 and 3C5 are useful for identifying even subtle changes in
      ACE conformation resulting from denaturation. These mAbs are also sensitive tools
      for the detection of minimal amounts of ACE in biological fluids and tissues
      using proteomics approaches. Their reactivity in routinely processed tissues of
      various species may prove useful for correlation of ACE expression in animal
      models to human diseases.

PMID- 12622776
TI  - Cluster of TRIM genes in the human MHC class I region sharing the B30.2 domain.
AB  - The major histocompatibility complex (MHC), a region of high gene density,
      contains a large number of genes relevant to the immune response, belonging to
      different multigenic families. We studied the genomic organization and
      polymorphism of a set of genes in the MHC class I region containing the
      tripartite motif (TRIM), consisting of a RING domain, B-box and coiled coil
      region, and a B30.2-like domain. A cluster of seven genes at 6p21.33 and two
      related family members telomeric of the cluster were characterized. All MHC
      encoded TRIM-B30.2 genes showed moderate levels of polymorphism, affecting
      predominantly the RING and B-box domains. In terms of structure, the genes varied
      by the loss of partial and, in some cases, complete domains. They were strongly
      conserved in exons 2, 3 and 4, which form the coiled-coil region. The last exon,
      encoding the B30.2-like domain, is shared with the otherwise unrelated
      butyrophilin-like (BTN) genes, located 4.3 Mb telomeric of the TRIM-B30.2
      cluster. The data are consistent with multiple, ancient duplications giving rise
      to a set of related genes.

PMID- 12622777
TI  - TNFA-TNFB haplotypes modify susceptibility to type I diabetes mellitus
      independently of HLA class II in a Moroccan population.
AB  - The contribution of single nucleotide polymorphisms in tumor necrosis factors
      (TNF) alpha and beta to autoimmune diseases, and to type 1 diabetes mellitus
      (T1DM) in particular, is not well established, and may be confounded by linkage
      disequilibrium to class II HLA genes. At least two polymorphisms seem to have
      functional relevance in the respective genes: TNFA-307 and TNFB+252. We have
      typed these two polymporphisms in samples of Moroccan T1DM patients and controls
      for which class II HLA genes had already been typed. Tumor necrosis factors and
      compound TNF-class II HLA haplotypes were inferred; it was the first time that
      such a design had been implemented. Independent of linkage disequilibrium with
      class II HLA, TNF haplotype TNFA-307*2 - TNFB+252*2 showed a significant
      protective effect (OR = 0.031), partly exacerbated by partial linkage to
      protective class II haplotypes. Such effect could be detected because Morocco
      shows the highest frequency of the TNFA-307*2 allele yet reported. This
      highlights the possible population differences in alleles contributing to
      autoimmune diseases.

PMID- 12622778
TI  - An additional susceptibility gene for juvenile idiopathic arthritis in the HLA
      class I region on several DR-DQ haplotypes.
AB  - Juvenile idiopathic arthritis (JIA) is an HLA-associated rheumatic disease with
      onset in childhood. We recently reported that allele 5 at microsatellite D6S265
      in the HLA class I region is associated with JIA, independent of linkage
      disequilibrium with the high risk DR8-DQ4 haplotype. In the present study, we
      investigated whether alleles at D6S265, or other markers in this region, also
      modify the risk for JIA on other haplotypes, i.e., DRB1*1301-DQB1*0603 or
      DRB1*1101/4-DQB1*0301. We observed a significant association with allele 6 at
      D6S265 on the DRB1*1301-DQB1*0603 haplotype. We also noted an association with
      allele 3 at D6S265, when carried on the DRB1*1101/4-DQB1*0301 haplotype. Our
      results further support an additional JIA susceptibility gene in the HLA class I
      region in linkage disequilibrium with alleles at D6S265.

PMID- 12622779
TI  - Mutations in the gene for toll-like receptor 4 and multiple sclerosis.
AB  - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central
      nervous system with heterogeneous pathological features, disease courses and
      genetical backgrounds. In this study we determined whether genetic variants of
      toll-like receptor (TLR) 4, which confer substantial differences in the
      inflammation elicited by bacterial lipopolysaccharide, are related to the
      development of MS. We found no differences in the frequencies of the
      cosegregating TLR4 Asp299Gly and Thr399Ile polymorphisms between Austrian MS
      patients (11.6%) and age-matched controls (13.7%). Furthermore, we could not
      detect any influence of these mutations on clinical parameters and serum levels
      of soluble adhesion molecules of MS patients. Our data indicate that these TLR4
      polymorphisms have no influence on the incidence, progression and inflammatory
      parameters of MS.

PMID- 12622780
TI  - Identification of a new HLA-B*40 variant, B*4035.
AB  - In this report, the novel allele B*40351 is presented. The allele was identified
      in a Caucasian individual by sequence-based typing. B*4035 is identical to B*4002
      in exon 2, but differs in exon 3 at position 463, where it has an A in stead of a
      C. This results in an amino acid change from arginine to serine at codon 131 of
      the mature protein. The haplotype carrying the B*4035 was A3 B*4035 Cw2 DR11 DQ3.

PMID- 12622781
TI  - HLA-B phenotype modifies the course of Behcet's disease in Moroccan patients.
AB  - In Moroccan patients, predisposition to Behcet's disease is associated with HLA
      B*51, mostly in males with young age at disease onset. In addition, the disease
      is associated with B*15 both in females and in males with late disease onset. We
      analyzed the clinical presentation, the severity and the course of the disease in
      86 Moroccan patients according to their HLA-B phenotype. The presence of the B*51
      or B*15 did not predispose to a particular clinical manifestation, nor to a more
      severe presentation of the disease. By contrast, outcome of the disease
      significantly differed depending on HLA-B phenotype, with an increase of symptoms
      in most B*51+ patients and in half of B*15 patients, and a remission or a
      decrease of symptoms in all B*51-B*15- patients. This variable course was mostly
      observed for ocular lesions, skin lesions, articular symptoms, and neurological
      symptoms. These data may suggest that treatment should be given early in the
      course of the disease in B*51 or B*15-positive patients in order to stabilize the
      inflammatory process.

PMID- 12622782
TI  - HLA-B*5130, a new HLA-B allele carrying a rare nucleotide substitution in exon 4.
AB  - We report herein the identification of a new HLA-B*51 allele in a Spanish
      Caucasoid organ donor. The novel allele, designated B*5130, differs from B*51011
      by one nucleotide change at position 787 (A to G) in exon 4, leading to an amino
      acid change from Arg (AGA) to Gly (GGA) at codon 239 in the alpha3 domain. This
      substitution is present in most classical and nonclassical HLA class I loci (A,
      C, E, and G) but not in any of the HLA-B alleles reported so far, except for
      B*7301. Although the frequency of the new variant seems to be low, its existence
      makes mandatory the analysis of exon 4 before assigning a B*5101 type.

PMID- 12622783
TI  - Association of HLA-DR and type II collagen autoimmunity with Meniere's disease.
AB  - To investigate HLA-associated genetic susceptibility to Meniere's disease in
      relation to type II collagen (CII) autoimmunity status, HLA-DRB1 genotyping and
      ELISA measurement of anti-CII antibody were performed in 41 Korean patients with
      Meniere's disease. In the anti-CII positive subgroup (20%) of patients, the
      frequency of HLA-DRB1*0405 was significantly increased (uncorrected) compared
      with both controls (63% vs 16%) and anti-CII negative patients (63% vs 12%). In
      the anti-CII negative subgroup, HLA-DRB1*1201 was significantly increased
      (uncorrected) (27% vs 10%) and DRB1*13 was decreased (6% vs 24%) compared with
      controls; these alleles appeared to confer susceptibility and resistance to the
      development of the disease. Association of HLA-DRB1*0405 with anti-CII positive
      Meniere's disease in this study suggests that it shares a specific HLA-DR
      sequence, QRRAA, as a genetic susceptibility factor with the anti-CII positive
      rheumatoid arthritis. In conclusion, whilst type II collagen autoimmunity may
      have a partial role in Meniere's disease, different HLA-DR alleles may also be
      associated with either susceptibility or resistance to the development of the
      disease in relation to anti-CII antibody status.

PMID- 12622786
TI  - Chemical and instrumental approaches to treat hyperpigmentation.
AB  - Many modalities of treatment for acquired skin hyperpigmentation are available
      including chemical agents or physical therapies, but none are completely
      satisfactory. Depigmenting compounds should act selectively on hyperactivated
      melanocytes, without short- or long-term side-effects, and induce a permanent
      removal of undesired pigment. Since 1961 hydroquinone, a tyrosinase inhibitor,
      has been introduced and its therapeutic efficacy demonstrated, and other
      whitening agents specifically acting on tyrosinase by different mechanisms have
      been proposed. Compounds with depigmenting activity are now numerous and the
      classification of molecules, based on their mechanism of action, has become
      difficult. Systematic studies to assess both the efficacy and the safety of such
      molecules are necessary. Moreover, the evidence that bleaching compounds are
      fairly ineffective on dermal accumulation of melanin has prompted investigations
      on the effectiveness of physical therapies, such as lasers. This review which
      describes the different approaches to obtain depigmentation, suggests a
      classification of whitening molecules on the basis of the mechanism by which they
      interfere with melanogenesis, and confirms the necessity to apply standardized
      protocols to evaluate depigmenting treatments.

PMID- 12622785
TI  - Evidence for an autoimmune pathogenesis of vitiligo.
AB  - Vitiligo is a depigmenting disorder characterized by the development of white
      patches in various distributions, which are due to the loss of melanocytes from
      the epidermis. A variety of arguments from clinical observations to research
      findings in human and animal models support the hypothesis of autoimmunity and
      are reviewed in this article. The association with autoimmune diseases and organ
      specific autoantibodies is well known. Various effective treatment options have
      an immunosuppressive effect. Today the autoimmune pathogenesis of the disease has
      become a rapidly evolving field of research. Detection of circulating melanocyte
      antibodies in human and animal models implicates a possible role of humoral
      immunity. Histological and immunohistochemical studies in perilesional skin
      suggest the involvement of cellular immunity in vitiligo. Recently, T-cell
      analyses in peripheral blood further support this hypothesis. Interestingly, new
      insights in the association of vitiligo and melanoma may help to clarify the role
      of autoimmunity in the development of vitiligo.

PMID- 12622787
TI  - Catecholamines increase in the urine of non-segmental vitiligo especially during
      its active phase.
AB  - Neural factors appear to play a major role in the pathogenesis of vitiligo. To
      investigate the possible correlation between vitiligo and peripheral
      monoaminergic system activity, we used high-pressure liquid chromatography and
      electrochemical detector methods to evaluate the basal urine excretion values of
      catecholamines [norepinephrine (NE), epinephrine and dopamine (DA)], their
      relative metabolites [3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine
      (NMN), metanephrine (MN), vanilmandelic acid (VMA) and homovanillic acid], as
      well as 5-hydroxyindoleacetic acid (5-HIAA), in 35 healthy subjects and in 70
      patients, suffering from non-segmental vitiligo at different stages of the
      disease. Levels of NE, DA, NMN, MN, MHPG, VMA and 5-HIAA were found to be
      significantly higher in patients than in controls. The patients with progressive
      vitiligo (n = 56) presented increased urinary excretion values for all parameters
      (in particular, NE levels) than other patients. Interestingly, in patients at its
      more recent vitiligo onset (<1 yr), NE values were different to those of subjects
      affected from 1 to 5 yr and from 6 to 10 yr. This result was confirmed by the
      significant negative relationship detected between NE excretion values and
      disease duration. In both vitiligo and control groups, significant correlations
      were found between monoamines as well as between these monoamines and their
      metabolites. The increase in catecholamine turnover, mainly occurring at the
      onset of the disease, is probably due to the stress associated with the
      appearance of lesions. Moreover, considering that these compounds readily produce
      toxic free-radicals and that vitiliginous subjects have a defective free radical
      defence mechanism, they may also contribute to the disappearance of melanocytes
      in the early phases of vitiligo.

PMID- 12622788
TI  - Expression analysis of a tyrosinase promoter sequence in zebrafish.
AB  - Sequence comparisons and functional analysis of the 5' upstream regions of
      tyrosinase genes have revealed the importance of cis-regulatory elements acting
      to control the spatiotemporal expression of tyrosinase in the melanocytes and
      retinal pigmented epithelium of developing embryos. To date there are no reports
      addressing the control of tyrosinase gene transcription in zebrafish, a
      vertebrate model organism of increasing importance. To exploit the tyrosinase
      gene as a marker in zebrafish we set out to clone its promoter and analyse its
      regulation during embryogenesis. Amplification of a zebrafish tyrosinase
      complementary DNA fragment by reverse transcriptase polymerase chain reaction
      allowed us to isolate and sequence a 1041 nt genomic DNA fragment that includes a
      transcription initiation site and 73 nt of the open reading frame. Bioinformatic
      analysis of this genomic sequence revealed five E-box motifs, including one
      CATGTG type E-box present in a putative initiation region. These are conserved
      positive regulatory elements in vertebrate tyrosinase promoters. We show that a
      region of 814 nt upstream from the translation start site of the zebrafish
      tyrosinase gene can drive expression in retinal pigmented epithelium in
      transiently transgenic zebrafish embryos but that its activity is not restricted
      to melanin-producing cells. This region is unable to drive transcription in human
      melanoma cell lines. Ectopic expression from this zebrafish tyrosinase promoter
      fragment is probably due to the absence of positive and negative cis-regulatory
      elements, such as a tyrosinase distal element, which is known to function as a
      pigment cell-specific enhancer.

PMID- 12622789
TI  - Melanin has a role in Ca2+ homeostasis in human melanocytes.
AB  - We have examined whether melanin affects Ca2+ homeostasis in cultured normal
      human melanocytes. Intracellular Ca2+ concentrations ([Ca2+]i), were measured in
      four Caucasian and in three Negroid melanocyte cultures. Under resting conditions
      [Ca2+]i was around 100 nM in all cultures, but differences between cells within
      cultures were observed. All cultures responded to endothelin-1 (ET-1) with
      increases in [Ca2+]i and there were no differences between Caucasian and Negroid
      cultures. However, large differences in responses between cells within cultures
      were observed, indicating that melanocyte cultures are very heterogeneous. The
      addition of 2.5 mM CaCl2 to melanocytes kept in Ca2+-free medium resulted in
      rapid and transient increases in [Ca2+]i of up to 1500 nM. These increases were
      on average more than two times smaller in melanocyte cultures established from
      Negroid donors compared with Caucasian cultures. In addition, well melanized
      Caucasian melanocytes, cultured in the presence of 400 microM tyrosine and 10 mM
      NH4Cl, showed a reduced increase in cytoplasmic Ca2+ concentration upon the
      addition of extracellular Ca2+. The difference in maintaining Ca2+ homeostasis
      between poorly and well melanized melanocytes may be the result of the clearance
      of cytoplasmic Ca2+ into melanosomes and the greater capacity for this in the
      more pigmented melanocytes.

PMID- 12622790
TI  - Tyrosinase gene correction using fluorescent oligonucleotides.
AB  - Gene therapy and production of mutated cell lines or animal models should be
      improved significantly once efficient controlled gene targeting strategies are
      developed. We used short single-stranded oligodeoxynucleotides (ODN), in some
      cases coupled to the fluorescent dye fluorescein isothiocyanate (FITC), to
      correct an endogenic natural point mutation in melanocytes in culture. The
      addition of the FITC molecule to the 5' extremity of the ODN did not interfere
      with the efficiency of the reversion of the mutation and did not have any
      deleterious side-effects. The use of fluorescent ODN could lead to great
      improvement in the technique. In particular, it may facilitate sorting of the
      transfected cells in the treated population, and thereby significantly increase
      the percentage of corrected cells.

PMID- 12622791
TI  - The cAMP signaling pathway has opposing effects on Rac and Rho in B16F10 cells:
      implications for dendrite formation in melanocytic cells.
AB  - A hallmark of melanocytic cells is their ability to form dendrites in response to
      growth factors and to ultraviolet irradiation. It is known that the cyclic
      adenosine monophosphate (cAMP) second messenger pathway stimulates melanocyte
      dendrite formation because agents that increase cAMP such as forskolin and
      dibutyrl cAMP induce dendrite formation in normal human and murine melanocytes
      and melanoma cell lines. The Rho family of guanosine triphosphate (GTP)-binding
      proteins regulates cytoskeletal reorganization in all cells tested and Rac and
      Rho have both been shown to regulate melanocyte dendrite formation. In this
      report, we analyzed the effect of cAMP on the activation of Rac and Rho and show
      that elevation of cAMP stimulates Rac and inhibits Rho in B16F10 cells. The Rho
      GTP-binding proteins have also been shown to either cross-activate or inhibit
      each other and in this report we show that Rac activates Rho in B16F10 cells.
      Microinjection of C3 botulinum exoenzyme toxin, an agent that specifically
      inactivates Rho or microinjection of constitutively active mutant Rac protein
      induced dendricity in human melanocytes and in B16F10 and B16F1 murine melanoma
      cell lines. We conclude that cAMP-mediated dendrite formation in melanocytic
      cells is mediated through upregulation of Rac activity and downregulation of Rho
      activity.

PMID- 12622793
TI  - Co-culture of mouse epidermal cells for studies of pigmentation.
AB  - Interactions between melanocytes and keratinocytes in the skin suggest bi
      directional interchanges between these two cell types. Thus, melanocytes cultured
      alone may not accurately reflect the physiology of the skin and the effects of
      physiological regulators in vivo, because they do not consider possible
      interactions with keratinocytes. As more and more pigment genes are identified
      and cloned, the characterization of their functions becomes more of a challenge,
      particularly with respect to their roles in the processing and transport of
      melanosomes and their transfer to keratinocytes. Immortalized melanocytes mutant
      at these loci are now being routinely generated from mice, but interestingly,
      successful co-culture of murine melanocytes and keratinocytes is very difficult
      compared with their human counterparts. Thus, we have now optimized co-culture
      conditions for murine melanocytes and keratinocytes so that pigmentation and the
      effects of specific mutations can be studied in a more physiologically relevant
      context.

PMID- 12622792
TI  - Accumulation of tyrosinase in the endolysosomal compartment is induced by
      U18666A.
AB  - The 3beta-(2-diethylaminoethoxy)-androstenone HCl (U18666A), progesterone and
      several cationic amphiphilic drugs have been shown to alter the trafficking of a
      number of intracellular membrane proteins including CD63/Lamp-3, insulin growth
      factor 2/mannose 6-phosphate receptor (IGF2/MPR), and the Niemann-Pick C1 gene
      product (NPC1) as well as ganglioside GM1. We have examined the effects of these
      compounds on cultured melanocytes at concentrations that have been shown to
      effectively alter intracellular trafficking. Treatment of melanocytes with
      U18666A (2.5 micro M) or progesterone (15 micro M) for 96 h decreased melanin
      content an average of 67% as compared with control without lowering the total
      cellular tyrosinase activity. Steroidal alkaloids that preferentially act on the
      Sonic Hedgehog signaling pathway showed no related specificity in their ability
      to decrease pigmentation. In melanocytes treated with U18666A, tyrosinase
      accumulates in a compartment that contains both lysosome-associated membrane
      protein-1 (Lamp 1) and MPR, and stains with filipin, consistent with cholesterol
      laden late endosomes/lysosomes. Our results suggest that tyrosinase, like the
      NPC1 gene product, traverses a U18666A-sensitive trafficking pathway.

PMID- 12622798
TI  - Servants of the state: nurses caught between professional ethics and deathwork.

PMID- 12622799
TI  - Killing for the state: the darkest side of American nursing.
AB  - The aim of this article is to bring to the attention of the international nursing
      community the discrepancy between a pervasive 'caring' nursing discourse and a
      most unethical nursing practice in the United States. In this article, we present
      a duality: the conflict in American prisons between nursing ethics and the
      killing machinery. The US penal system is a setting in which trained healthcare
      personnel practice the extermination of life. We look upon the sanitization of
      deathwork as an application of healthcare professionals' skills and knowledge and
      their appropriation by the state to serve its ends. A review of the states' death
      penalty statutes shows that healthcare workers are involved in the capital
      punishment process and shielded by American laws (and to a certain extent by
      professional boards through their inaction). We also argue that the law's
      language often masks that involvement; and explain how states further that
      duplicity behind legal formalisms. In considering the important role healthcare
      providers, namely nurses and physicians, play in administering death to the
      condemned, we assert that nurses and physicians are part of the states' penal
      machinery in America. Nurses and physicians (as carriers of scientific knowledge,
      and also as agents of care) are intrinsic to the American killing enterprise.
      Healthcare professionals who take part in execution protocols are state
      functionaries who approach the condemned body as angels of death: they constitute
      an extension of the state which exercises its sovereign power over captive
      prisoners.

PMID- 12622800
TI  - Breastfeeding policies and the production of motherhood: a historical-cultural
      approach.
AB  - This paper revisits some of the aspects that allow us to situate historically the
      process that has been called the 'politicization of women's breasts'. It is part
      of a broader research project being undertaken in Rio Grande do Sul, Brazil,
      which is studying information from the educational material used in the National
      Campaign for the Incentive of Breastfeeding. The methodological approach used is
      cultural analysis, and its theoretical basis is informed by feminist studies and
      cultural studies, from a poststructuralist perspective. Knowledges and practices
      that produce notions of maternity are problematized to argue that current
      political and economic arrangements have necessitated a redefinition of
      motherhood. This re-signification of motherhood has transferred to women the duty
      of solving an array of problems that were previously considered government's
      responsibility, in particular those related to the physical and emotional
      development of infants.

PMID- 12622801
TI  - Meanings of living at home on a ventilator.
AB  - Nine adults were interviewed in order to illuminate the meanings of being
      dependent on a ventilator and living at home. The data were analysed using a
      phenomenological-hermeneutic method inspired by the philosophy of Ricoeur. Five
      main themes emerged through the analysis: experiencing home as a safe and
      comfortable space from which to reach out, experiencing the body as being frail,
      brave and resilient, striving to live in the present, surrendering oneself to and
      trusting others, and experiencing technology as a burden and a relief to the
      lived body. Meanings of being home on a ventilator were interpreted as
      maintaining autonomy and persistence in interaction with the ventilator and other
      human beings and being able to rise above yourself and your personal boundaries
      in order to live a good life. These meanings indicate that aesthetic and ethical
      values impact on the lived body. They are bound up with experiencing a vital
      force and interdependency, bringing safety and courage into daily life.

PMID- 12622802
TI  - Clerical frames for nursing practice: missionary nurses at Rehoboth.
AB  - This paper presents a discourse analysis of publications of the Christian
      Reformed Church regarding its Rehoboth Mission near Gallup, New Mexico, among the
      Navajo. All issues of The Banner, Acts of Synod of the Christian Reformed Church,
      the Rehoboth Hospital Bulletin, and the Annual Report of the Rehoboth Mission
      from 1880 to the present were reviewed for references to health-care at Rehoboth
      from 1903 to 1943. Four religiously framed discourses were identified: discourses
      justifying provision of health-care at the mission, discourses of the Navajos as
      immature and potentially dangerous, needing to be civilized, discourses of
      cleanliness, and discourses of calling. This paper adds to a growing body of
      knowledge about religious frames within which nurses have practiced in North
      America.

PMID- 12622803
TI  - Exploring the dynamics of power: a Foucauldian analysis of care planning in
      learning disabilities services.
AB  - This paper draws upon a study completed in 2000 that focused upon health and
      welfare provision for people with learning disabilities in one English county.
      This study drew upon the theoretical insights of Michel Foucault to provide an
      analysis of the micro politics of care planning. This involved the analysis of
      text from two sources: the academic literature and interview material gained from
      a number of professionals working in health and welfare services for people with
      learning disabilities. Drawing upon this research material, the first part of
      this paper briefly explores the relationship between policy, professional
      practice and the people who are the subjects of that practice. The discussion
      then moves on to consider Foucault's five methodological precautions and the way
      power produces a localised web of activity that identifies specific targets for
      management. In this process power draws into the web a range of informal and
      formal practices that initially lie outside of the web. The discourse produced
      through the activity surrounding care planning provides the evidence of this flow
      of power. This discourse then takes on the status of science (truth), which
      reproduces this activity.

PMID- 12622804
TI  - Nurses' bodywork: is there a body of work?
AB  - The work that many nurses do involves the use of their own body as one of the
      tools of their occupation. Being a nurse, in many cases, means controlled,
      purposeful use of her or his own body oriented to the patient. This paper
      discusses some of the ways in which nurses' bodies and the work that those bodies
      do are represented in professional and academic research accounts and made
      relevant in literature. Using instances of bodies and bodily activity mentioned
      in a variety of literature, the paper discusses three categories of accounts of
      nursing bodywork: those which are problematised and where the nurse's body is
      seen as a topic for investigation, and those which are unproblematised either
      explicitly discussing bodily activity (for example, touch) or implicitly dealing
      with bodywork (for example, taking blood pressure). Four ways in which nurses'
      bodies are made relevant in accounts are proposed: relational, corporate,
      instrumental and human. The paper discusses the prominence (or not) nurses'
      bodies are given in professional and academic accounts, as a contribution to
      preliminary work of generating a topic for investigation and concludes with some
      suggestions as to how this investigative project might be taken forward, focusing
      primarily on an examination of methodic practices, or how bodywork is brought off
      and executed as a skilled but taken-for-granted activity.

PMID- 12622805
TI  - 'Patient satisfaction': knowledge for ruling hospital reform--an institutional
      ethnography.
AB  - Driven by funding restraint, Canadian health-care has undergone over a decade of
      significant reform. Hospitals are being restructured, as text-based practices of
      accountability bring a new business-orientation into hospital and clinical
      management. New forms of knowledge, generated through records of various sorts,
      are a necessary resource for managing care in the new environment. This paper's
      research uses Canadian sociologist Dorothy E. Smith's institutional ethnographic
      methodology to critically analyse one instance of text-based management. I
      analyse information about 'patient satisfaction' as it is generated through a
      patient survey (in which I was implicated through my involvement with a
      hospitalized family member). Subsequently, I have studied the management
      environment into which that information would be entered. I argue that in the
      instance analysed, the information becomes part of a dominant consumer oriented
      healthcare discourse that subordinates concerns about 'what actually happened' as
      a professional caregiver would have known it. On this basis, I contend that this
      sort of taken-for-granted approach to making decisions about quality care in
      hospitals may be seriously, even dangerously, flawed.

PMID- 12622806
TI  - Men's passage to fatherhood: an analysis of the contemporary relevance of
      transition theory.
AB  - This paper presents a theoretical analysis of men's experiences of pregnancy,
      birth and early fatherhood. It does so using a framework of ritual transition
      theory and argues that despite its earlier structural-functionalist roots,
      transition theory remains a valuable framework, illuminating contemporary
      transitions across the life course. The paper discusses the historical
      development of transition or ritual theory and, drawing upon data generated
      during longitudinal ethnographic interviews with men undergoing the transition to
      fatherhood, analyses its relevance in understanding contemporary experiences of
      fatherhood.

PMID- 12622807
TI  - Mechanisms of iron regulation in mycobacteria: role in physiology and virulence.
AB  - The role of iron in mycobacteria as in other bacteria goes beyond the need for
      this essential cofactor. Limitation of this metal triggers an extensive response
      aimed at increasing iron acquisition while coping with iron deficiency. In
      contrast, iron-rich environments prompt these prokaryotes to induce synthesis of
      iron storage molecules and to increase mechanisms of protection against iron
      mediated oxidative damage. The response to changes in iron availability is
      strictly regulated in order to maintain sufficient but not excessive and
      potentially toxic levels of iron in the cell. This response is also linked to
      other important processes such as protection against oxidative stress and
      virulence. In bacteria, iron metabolism is regulated by controlling transcription
      of genes involved in iron uptake, transport and storage. In mycobacteria, this
      role is fulfilled by the iron-dependent regulator IdeR. IdeR is an essential
      protein in Mycobacterium tuberculosis, the causative agent of human tuberculosis.
      It functions as a repressor of iron acquisition genes, but is also an activator
      of iron storage genes and a positive regulator of oxidative stress responses.

PMID- 12622808
TI  - An integrated analysis of the genome of the hyperthermophilic archaeon Pyrococcus
      abyssi.
AB  - The hyperthermophilic euryarchaeon Pyrococcus abyssi and the related species
      Pyrococcus furiosus and Pyrococcus horikoshii, whose genomes have been completely
      sequenced, are presently used as model organisms in different laboratories to
      study archaeal DNA replication and gene expression and to develop genetic tools
      for hyperthermophiles. We have performed an extensive re-annotation of the genome
      of P. abyssi to obtain an integrated view of its phylogeny, molecular biology and
      physiology. Many new functions are predicted for both informational and
      operational proteins. Moreover, several candidate genes have been identified that
      might encode missing links in key metabolic pathways, some of which have unique
      biochemical features. The great majority of Pyrococcus proteins are typical
      archaeal proteins and their phylogenetic pattern agrees with its position near
      the root of the archaeal tree. However, proteins probably from bacterial origin,
      including some from mesophilic bacteria, are also present in the P. abyssi
      genome.

PMID- 12622809
TI  - Demonstration of a sensory rhodopsin in eubacteria.
AB  - We report the first sensory rhodopsin observed in the eubacterial domain, a green
      light-activated photoreceptor in Anabaena (Nostoc) sp. PCC7120, a freshwater
      cyanobacterium. The gene encoding the membrane opsin protein of 261 residues (26
      kDa) and a smaller gene encoding a soluble protein of 125 residues (14 kDa) are
      under the same promoter in a single operon. The opsin expressed heterologously in
      Escherichia coli membranes bound all-trans retinal to form a pink pigment (lambda
      max 543 nm) with a photochemical reaction cycle of 110 ms half-life (pH 6.8, 18
      degrees C). Co-expression with the 14 kDa protein increased the rate of the
      photocycle, indicating physical interaction with the membrane-embedded rhodopsin,
      which we confirmed in vitro by affinity enrichment chromatography and Biacore
      interaction. The pigment lacks the proton donor carboxylate residue in helix C
      conserved in known retinylidene proton pumps and did not exhibit detectable
      proton ejection activity. We detected retinal binding to the protein in Anabaena
      membranes by SDS-PAGE and autofluorography of 3H-labelled all-trans retinal of
      reduced membranes from the organism. We conclude that Anabaena rhodopsin
      functions as a photosensory receptor in its natural environment, and suggest that
      the soluble 14 kDa protein transduces a signal from the receptor. Therefore,
      unlike the archaeal sensory rhodopsins, which transmit signals by transmembrane
      helix-helix interactions with membrane-embedded transducers, the Anabaena sensory
      rhodopsin may signal through a soluble cytoplasmic protein, analogous to higher
      animal visual pigments.

PMID- 12622810
TI  - Stage-specific gene expression of Candida albicans in human blood.
AB  - The pathogenic fungus Candida albicans commonly causes mucosal surface
      infections. In immunocompromised patients, C. albicans may penetrate into deeper
      tissue, enter the bloodstream and disseminate within the host causing life
      threatening systemic infections. In order to elucidate how C. albicans responds
      to the challenge of a blood environment, we analysed the transcription profile of
      C. albicans cells exposed to human blood using genomic arrays and a cDNA
      subtraction protocol. By combining data obtained with these two methods, we were
      able to identify unique sets of different fungal genes specifically expressed at
      different stages of this model that mimics bloodstream infections. By removing
      host cells and incubation in plasma, we were also able to identify several genes
      in which the expression level was significantly influenced by the presence of
      these cells. Differentially expressed genes included those that are involved in
      the general stress response, antioxidative response, glyoxylate cycle as well as
      putative virulence attributes. These data point to possible mechanisms by which
      C. albicans ensures survival in the hostile environment of the blood and how the
      fungus may escape the bloodstream as an essential step in its systemic
      dissemination.

PMID- 12622811
TI  - Nucleotide sequence, functional characterization and evolution of pFKN, a
      virulence plasmid in Pseudomonas syringae pathovar maculicola.
AB  - Pseudomonas syringae pv. maculicola strain M6 (Psm M6) carries the avrRpm1 gene,
      encoding a type III effector, on a 40 kb plasmid, pFKN. We hypothesized that this
      plasmid might carry additional genes required for pathogenesis on plants. We
      report the sequence and features of pFKN. In addition to avrRpm1, pFKN carries an
      allele of another type III effector, termed avrPphE, and a gene of unknown
      function (ORF8), expression of which is induced in planta, suggesting a role in
      the plant-pathogen interaction. The region of pFKN carrying avrRpm1, avrPphE and
      ORF8 exhibits several features of pathogenicity islands (PAIs). Curing of pFKN
      (creating Psm M6C) caused a significant reduction in virulence on Arabidopsis
      leaves. However, complementation studies using Psm M6C demonstrated an obvious
      virulence function only for avrRpm1. pFKN can integrate and excise from the
      chromosome of Psm M6 at low frequency via homologous recombination between
      identical sequence segments located on the chromosome and on pFKN. These segments
      are part of two nearly identical transposons carrying avrPphE. The avrPphE
      transposon was also detected in other strains of P. s. pv. maculicola and in P.
      s. tomato strain DC3000. The avrPphE transposon was found inserted at different
      loci in different strains. The analysis of sequences surrounding the avrPphE
      transposon insertion site in the chromosome of Psm M6 indicates that pFKN
      integrates into a PAI that encodes type III effectors. The integration of pFKN
      into this chromosomal region may therefore be seen as an evolutionary process
      determining the formation of a new PAI in the chromosome of Psm M6.

PMID- 12622812
TI  - Linear plasmid SLP2 of Streptomyces lividans is a composite replicon.
AB  - SLP2 is a 50 kb linear plasmid in Streptomyces lividans that contains short (44
      bp) terminal inverted repeats and covalently bound terminal proteins. The
      nucleotide sequence of SLP2 was determined. The rightmost 15.4 kb sequence is
      identical to that of the host chromosome, including the Tn4811 sequence at the
      border, which is interrupted by an insertion sequence (IS) element in SLP2.
      Examination of the flanking target sequences of Tn4811 suggests a previous
      recombinational event there. The 43 putative protein coding sequences contained
      many involved in replication (including two terminal protein homologues),
      partitioning, conjugal transfer and intramycelial spread. The terminally located
      helicase-like gene ttrA was necessary for conjugal transfer. The two telomeres
      diverge significantly in primary sequence, while preserving similar secondary
      structures. Mini-linear plasmids containing these telomeres replicated in S.
      lividans using the chromosomally encoded terminal protein. In addition, two
      pseudotelomere sequences are present near the left telomere. The G+C content and
      GC or AT skew profiles exhibit complex distributions. These, plus the inferred
      recombination at the right arm, indicate that SLP2 has evolved through rounds of
      exchanges involving at least three replicons.

PMID- 12622813
TI  - The MAPKK kinase SteC regulates conidiophore morphology and is essential for
      heterokaryon formation and sexual development in the homothallic fungus
      Aspergillus nidulans.
AB  - Environmental signals can be transduced into intracellular responses by the
      action of MAP kinase cascades. Sequential phosphorylation results in the
      transient activation of a MAP kinase, which in turn activates certain
      transcription factors and thus a set of pathway-specific genes. Many steps in
      this cascade are conserved, and homologues have been discovered from yeast to
      human. We have characterized the MAPKK kinase, SteC, a homologue of Saccharomyces
      cerevisiae Ste11, in the filamentous fungus Aspergillus nidulans. The 886-amino
      acid-long protein shares the highest similarity to Neurospora crassa Nrc-1.
      Deletion of the gene in A. nidulans results in a slower growth rate, the
      formation of more branched hyphae, altered conidiophore morphology, an inhibition
      of heterokaryon formation and a block of cleistothecium development. The gene is
      transcriptionally activated during asexual development and controls the
      phosphorylation of two putative MAP kinases.

PMID- 12622814
TI  - Streptococcus dysgalactiae-derived mitogen (SDM), a novel bacterial superantigen:
      characterization of its biological activity and predicted tertiary structure.
AB  - A mitogenic substance, designated Streptococcus dysgalactiae-derived mitogen
      (SDM), was purified from S. dysgalactiae culture supernatant, and the gene
      encoding the mitogen was cloned. Both native and recombinant SDM expressed in
      Escherichia coli significantly activated human V beta 1+ and V beta 23+ T cells
      in association with major histocompatibility complex (MHC) class II molecules on
      accessory cells, indicating that SDM possesses superantigenic properties. The sdm
      gene consists of two segments encoding a signal peptide and a mature 25 kDa
      protein composed of 212 amino acids. Three of 34 S. dysgalactiae strains but none
      of 28 Streptococcus pyogenes strains examined carried sdm. Phylogenetic analysis
      indicated that SDM belongs to a family distinct from established bacterial
      superantigens. SDM showed around 30% homology with other superantigens at the
      amino acid sequence level. The tertiary structure of SDM was predicted by
      modelling onto streptococcal pyrogenic exotoxin C and streptococcal mitogenic
      exotoxin Z-2, both of which share highly homologous structure-determining
      regions. SDM showed overall structural similarity to both these superantigens.
      This is the first study to characterize fully a bacterial superantigen from S.
      dysgalactiae.

PMID- 12622815
TI  - The glyoxylate cycle is required for temporal regulation of virulence by the
      plant pathogenic fungus Magnaporthe grisea.
AB  - We describe the isolation and characterization of ICL1 from the rice blast fungus
      Magnaporthe grisea, a gene that encodes isocitrate lyase, one of the principal
      enzymes of the glyoxylate cycle. ICL1 shows elevated expression during
      development of infection structures and cuticle penetration, and a targeted gene
      replacement showed that the gene is required for full virulence by M. grisea. In
      particular, we found that the prepenetration stage of development, before entry
      into plant tissue, is affected by loss of the glyoxylate cycle. There is a delay
      in germination, infection-related development and cuticle penetration in Delta
      icl1 mutants. Recent reports have shown the importance of the glyoxylate cycle in
      the virulence of the human pathogenic fungus Candida albicans and the bacterial
      pathogen Mycobacterium tuberculosis. Our results indicate that the glyoxylate
      cycle is also important in this plant pathogenic fungus, demonstrating the
      widespread utility of the pathway in microbial pathogenesis.

PMID- 12622816
TI  - Transcriptome analysis of Listeria monocytogenes identifies three groups of genes
      differently regulated by PrfA.
AB  - PrfA is the major regulator of Listeria virulence gene expression. This protein
      is a member of the Crp/Fnr family of transcription regulators. To gain a deeper
      understanding of the PrfA regulon, we constructed a whole-genome array based on
      the complete genome sequence of Listeria monocytogenes strain EGDe and evaluated
      the expression profiles of the wild-type EGDe and a prfA-deleted mutant (EGDe
      Delta prfA). Both strains were grown at 37 degrees C in brain-heart infusion
      broth (BHI) and BHI supplemented with either activated charcoal, a compound known
      to enhance virulence gene expression, or cellobiose, a sugar reported to
      downregulate virulence gene expression in spite of full expression of PrfA. We
      identified three groups of genes that are regulated differently. Group I
      comprises, in addition to the 10 already known genes, two new genes, lmo2219 and
      lmo0788, both positively regulated and preceded by a putative PrfA box. Group II
      comprises eight negatively regulated genes: lmo0278 is preceded by a putative
      PrfA box, and the remaining seven genes (lmo0178-lmo0184) are organized in an
      operon. Group III comprises 53 genes, of which only two (lmo0596 and lmo2067) are
      preceded by a putative PrfA box. Charcoal addition induced upregulation of group
      I genes but abolished regulation by PrfA of most group III genes. In the presence
      of cellobiose, all the group I genes were downregulated, whereas group III genes
      remained fully activated. Group II genes were repressed in all conditions tested.
      A comparison of the expression profiles between a second L. monocytogenes strain
      (P14), its spontaneous mutant expressing a constitutively active PrfA variant
      (P14prfA*) and its corresponding prfA-deleted mutant (P14 Delta prfA) and the
      EGDe strain revealed interesting strain-specific differences. Sequences strongly
      similar to a sigma B-dependent promoter were identified upstream of 22 group III
      genes. These results suggest that PrfA positively regulates a core set of 12
      genes preceded by a PrfA box and probably expressed from a sigma A-dependent
      promoter. In contrast, a second set of PrfA-regulated genes lack a PrfA box and
      are expressed from a sigma B-dependent promoter. This study reveals that PrfA can
      act as an activator or a repressor and suggests that PrfA may directly or
      indirectly activate different sets of genes in association with different sigma
      factors.

PMID- 12622817
TI  - The spa-box for transcriptional activation of subtilin biosynthesis and immunity
      in Bacillus subtilis.
AB  - The subtilin gene cluster (spa) of Bacillus subtilis ATCC 6633 is organized in
      transcriptional units spaBTC, spaS, spaIFEG and spaRK. Specific binding of the
      response regulator protein SpaR to spaB, spaS and spaI DNA promoter fragments was
      shown by means of electromobility shift assays. A repeated pentanucleotide
      sequence spaced by six nucleotides was identified as SpaR binding motif (spa
      box). Saturating mutational analysis of the spa-box by single- and multiple-base
      pair substitutions revealed the consensus motif (A/T)TGAT for optimal SpaR
      binding with the second, third and fifth position being absolutely conservative.
      Variations in the spacer size between the two pentanucleotide repeats revealed a
      strong conservation of their relative location. Only DNA with a proximal
      arrangement of two pentanucleotide repeats showed affinity to SpaR. A 2:1
      stoichiometry between SpaR and DNA was obtained by optical biosensor analyses,
      which corresponds to the binding of two SpaR proteins per spa-box.

PMID- 12622818
TI  - Candida albicans binds human plasminogen: identification of eight plasminogen
      binding proteins.
AB  - Several microbial pathogens augment their invasive potential by binding and
      activating human plasminogen to generate the proteolytic enzyme plasmin. Yeast
      cells and cell wall proteins (CWP) of the human pathogenic fungus Candida
      albicans bound plasminogen with a K(d) of 70 +/- 11 nM and 112 +/- 20 nM
      respectively. Bound plasminogen could be activated to plasmin by mammalian
      plasminogen activators; no C. albicans plasminogen activator was detected.
      Binding of plasminogen to CWP and whole cells was inhibited by epsilon ACA,
      indicating that binding was predominantly to lysine residues. Candida albicans
      mutant strains defective in protein glycosylation did not show altered
      plasminogen binding, suggesting that binding was not mediated via a surface
      lectin. Binding was sensitive to digestion by basic carboxypeptidase, implicating
      C-terminal lysine residues in binding. Proteomic analysis identified eight major
      plasminogen-binding proteins in isolated CWP. Five of these (phosphoglycerate
      mutase, alcohol dehydrogenase, thioredoxin peroxidase, catalase, transcription
      elongation factor) had C-terminal lysine residues and three (glyceraldehyde-3
      phosphate dehydrogenase, phosphoglycerate kinase and fructose bisphosphate
      aldolase) did not. Activation of plasminogen could potentially increase the
      capacity of this pathogenic fungus for tissue invasion and necrosis. Although
      surface-bound plasmin(ogen) degraded fibrin, no direct evidence for a role in
      invasion of endothelial matrix or in penetration and damage of endothelial cells
      was found.

PMID- 12622819
TI  - Expression of cnf1 by Escherichia coli J96 involves a large upstream DNA region
      including the hlyCABD operon, and is regulated by the RfaH protein.
AB  - Examination of 55 clinical isolates of uropathogenic Escherichia coli producing
      the CNF1 toxin demonstrated that the cnf1 gene is systematically associated with
      a hly operon via a highly conserved hlyD-cnf1 intergenic region (igs, 943 bp) as
      shown in the J96 UPEC strain. We examined if this association could reflect a co
      regulation of the production of these toxins. Translation of cnf1 from an
      immediately upstream promoter has been shown to be controlled by means of an anti
      Shine-Dalgarno sequence present in the cnf1 coding sequence [fold-back inhibition
      (cnf1 fbi)]. The cnf1 fbi was not regulated by elements present in the igs. An
      RNA covering the full hlyD sequence, the igs and extending on the cnf1 gene, was
      then detected in the J96 strain. This RNA could be part of a HlyCABD mRNA.
      Transcription of the haemolysin operon requires RfaH antitermination activity.
      Inactivation of rfaH in J96 resulted in a 100-fold reduction of the CNF1 content
      of bacteria. The production of CNF1 from a plasmidic igscnf1 DNA was not
      sensitive to RfaH, indicating that this factor acted on cnf1 transcription via
      the hly promoter. This way the cnf1 fbi mechanism might be overcome by
      transcription of cnf1 from the haemolysin promoter and antitermination by RfaH.
      This constitutes a novel system of bacterial virulence factors co-regulation.

PMID- 12622820
TI  - SeqA-mediated stimulation of a promoter activity by facilitating functions of a
      transcription activator.
AB  - It was demonstrated recently that the SeqA protein, a main negative regulator of
      Escherichia coli chromosome replication initiation, is also a specific
      transcription factor. SeqA specifically activates the bacteriophage lambda pR
      promoter while revealing no significant effect on the activity of another lambda
      promoter, pL. Here, we demonstrate that lysogenization by bacteriophage lambda is
      impaired in E. coli seqA mutants. Genetic analysis demonstrated that CII-mediated
      activation of the phage pI and paQ promoters, which are required for efficient
      lysogenization, is less efficient in the absence of seqA function. This was
      confirmed in in vitro transcription assays. Interestingly, SeqA stimulated CII
      dependent transcription from pI and paQ when it was added to the reaction mixture
      before CII, although having little effect if added after a preincubation of CII
      with the DNA template. This SeqA-mediated stimulation was absolutely dependent on
      DNA methylation, as no effects of this protein were observed when using
      unmethylated DNA templates. Also, no effects of SeqA on transcription from pI and
      paQ were observed in the absence of CII. Binding of SeqA to templates containing
      the tested promoters occurs at GATC sequences located downstream of promoters, as
      revealed by electron microscopic studies. In contrast to pI and paQ, the activity
      of the third CII-dependent promoter, pE, devoid of neighbouring downstream GATC
      sequences, was not affected by SeqA both in vivo and in vitro. We conclude that
      SeqA stimulates transcription from pI and paQ promoters in co-operation with CII
      by facilitating functions of this transcription activator, most probably by
      allowing more efficient binding of CII to the promoter region.

PMID- 12622821
TI  - Characterization of Cu,Zn superoxide dismutase (SOD1) gene knock-out mutant of
      Cryptococcus neoformans var. gattii: role in biology and virulence.
AB  - The pathogenic yeast Cryptococcus neoformans (Cn) var. gattii causes
      meningoencephalitis in healthy individuals, unlike the better known Cn varieties
      grubii and neoformans, which are common in immunocompromised individuals. The
      virulence determinants and mechanisms of host predilection are poorly defined for
      var. gattii. The present study focused on the characterization of a Cu,Zn
      superoxide dismutase (SOD1) gene knock-out mutant constructed by developing a DNA
      transformation system. The sod1 mutant was highly sensitive to the redox cycling
      agent menadione, and showed fragmentation of the large vacuole in the cytoplasm,
      but no other defects were seen in growth, capsule synthesis, mating, sporulation,
      stationary phase survival or auxotrophies for sulphur-containing amino acids. The
      sod1 mutant was markedly attenuated in virulence in a mouse model, and it was
      significantly susceptible to in vitro killing by human neutrophils (PMNs). The
      deletion of SOD1 also resulted in defects in the expression of a number of
      virulence factors, i.e. laccase, urease and phospholipase. Complementation of the
      sod1 mutant with SOD1 resulted in recovery of virulence factor expression and
      menadione resistance, and in restoration of virulence. Overall, these results
      suggest that the antioxidant function of Cu,Zn SOD is critical for the
      pathogenesis of the fungus, but is dispensable in its saprobic life. This report
      constitutes the first instance in which superoxide dismutase has been directly
      implicated in the virulence of a fungal pathogen.

PMID- 12622822
TI  - Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus.
AB  - Several members of the two-component signal transduction family have been
      implicated in the control of polar development in Caulobacter crescentus: PleC
      and DivJ, two polarly localized histidine sensor kinases; and the response
      regulators DivK and PleD. The PleD protein was shown previously to be required
      during the swarmer-to-stalked cell transition for flagellar ejection and
      efficient stalk biogenesis. Here, we present data indicating that PleD also
      controls the onset of motility and a cell density switch immediately preceding
      cell division. Constitutively active alleles of pleD or wspR, an orthologue from
      Pseudomonas fluorescens, almost completely suppressed C. crescentus motility and
      inhibited the increase in swarmer cell density during cell differentiation. The
      observation that these alleles also had a dominant-negative effect on motility in
      a pleC divJ and a pleC divK mutant background indicated that PleD is located
      downstream of the other components in the signal transduction cascade, which
      controls the activity of the flagellar motor. In addition, the presence of a
      constitutive pleD or wspR allele resulted in a doubling of the average stalk
      length. Together, this is consistent with a model in which the active form of
      PleD, PleD approximately P, negatively controls aspects of differentiation in the
      late predivisional cell, whereas it acts positively on polar development during
      the swarmer-to-stalked cell transition. In agreement with such a model, we found
      that DivJ, which localizes to the stalked pole during cell differentiation,
      positively controlled the in vivo phosphorylation status of PleD, and the swarmer
      pole-specific PleC kinase modulated this status in a negative manner.
      Furthermore, domain switch experiments demonstrated that the WspR GGDEF output
      domain from P. fluorescens is active in C. crescentus, favouring a more general
      function for this novel signalling domain over a specific role such as DNA or
      protein interaction. Possible roles for PleD and its C-terminal output domain in
      modulating the polar cell surface of C. crescentus are discussed.

PMID- 12622823
TI  - Regulation of the central glycolytic genes in Bacillus subtilis: binding of the
      repressor CggR to its single DNA target sequence is modulated by fructose-1,6
      bisphosphate.
AB  - Glycolysis is one of the best and widely conserved general metabolic pathways.
      Bacillus subtilis enzymes catalysing the central part of glycolysis, gathering
      the steps of interconversion of the triose phosphates from dihydroxyacetone
      phosphate to phosphoenolpyruvate, are encoded by five genes, gapA, pgk, tpi, pgm
      and eno. They are transcribed in a hexacistronic operon together with cggR, the
      first cistron, encoding the repressor of this gapA operon. Using deletion
      analysis, we have localized the CggR operator between the promoter and the first
      gene of the operon. CggR was purified and used in gel mobility shift assays and
      DNase I footprinting experiments to delimit its target sequence. Site-directed
      mutagenesis and in vivo tests demonstrated that it consists of two direct-repeats
      (CGGGACN6TGTCN4CGGGACN6TG TC). Sequence analysis and transcriptome comparison of
      a wild-type and a cggR mutant strain strongly suggested that CggR regulates only
      the gapA operon. The presence of glycolytic carbon sources induces expression of
      the gapA operon. Genetic experiments allowed us to identify the metabolic steps
      required for the formation of the CggR effector. In vitro experiments with the
      suggested candidates allowed us to demonstrate that fructose-1,6-biphosphate
      (FBP) acts as an inhibitor of CggR DNA-binding activity (10 mM for full
      inhibition). FBP is thus the major signal for both CcpA-dependent catabolite
      repression (or activation) and activation of the central glycolytic genes.
      Genomic sequence comparisons suggest that these results can apply to numerous low
      G+C, Gram-positive bacterial species.

PMID- 12622824
TI  - Association of mycothiol with protection of Mycobacterium tuberculosis from toxic
      oxidants and antibiotics.
AB  - Mycothiol, MSH or 1D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D
      glucopyranoside, is an unusual conjugate of N-acetylcysteine (AcCys) with 1D-myo
      inosityl 2-acetamido-2-deoxy-alpha-D-glucopyranoside (GlcN-Ins), and is the major
      low-molecular-mass thiol in mycobacteria. Mycothiol has antioxidant activity as
      well as the ability to detoxify a variety of toxic compounds. Because of these
      activities, MSH is a candidate for protecting Mycobacterium tuberculosis from
      inactivation by the host during infections as well as for resisting
      antituberculosis drugs. In order to define the protective role of MSH for M.
      tuberculosis, we have constructed an M. tuberculosis mutant in Rv1170, one of the
      candidate MSH biosynthetic genes. During exponential growth, the Rv1170 mutant
      bacteria produced approximately 20% of wild-type levels of MSH. Levels of the
      Rv1170 substrate, GlcNAc-Ins, were elevated, whereas those of the product, GlcN
      Ins, were reduced. This establishes that the Rv1170 gene encodes for the major
      GlcNAc-Ins deacetylase activity (termed MshB) in the MSH biosynthetic pathway of
      M. tuberculosis. The Rv1170 mutant grew poorly on agar media lacking catalase and
      oleic acid, and had heightened sensitivities to the toxic oxidant cumene
      hydroperoxide and to the antibiotic rifampin. In addition, the mutant was more
      resistant to isoniazid, suggesting a role for MSH in activation of this prodrug.
      These data indicate that MSH contributes to the protection of M. tuberculosis
      from oxidants and influences resistance to two first-line antituberculosis drugs.

PMID- 12622826
TI  - The Leopoldina international symposium on parasitism, commensalism and symbiosis-
      common themes, different outcome.
AB  - The development of new methods, including genomics, which can even be applied to
      unculturable microorganisms, has significantly increased our knowledge about
      bacterial pathogenesis and symbiosis and, in consequence, is profoundly modifying
      our views on the evolution and the genetic and physiological basis of bacteria
      host interactions. The presentations at this symposium revealed conceptual links
      between bacterial pathogenesis and symbiosis. The close co-operation of experts
      in both fields will result in significant synergy and new insights into basic
      mechanisms of bacteria-host interactions and their evolution. The meeting
      provided fascinating news about the genetic and metabolic consequences that the
      change in their lifestyle had for bacteria that developed from free-living to
      permanent host-associated organisms exemplified by intracellular pathogens or
      symbionts. In addition, surprising similarities but also striking differences
      between the strategies involved in the establishment of a symbiotic versus a
      parasitic lifestyle can be noted. In the long run, the characterization of such
      differences might lead to lifestyle prediction or to an evaluation of the
      pathogenic potential of newly isolated bacteria via the definition of genetic
      and/or metabolic signatures characteristic for pathogenic or symbiotic organisms.
      Moreover, it is expected that these investigations will lead to new strategies
      for the treatment or prevention of bacterial infections, or the avoidance of
      pathogen transmission.

PMID- 12622825
TI  - Clinical isolates of Enterococcus faecium exhibit strain-specific collagen
      binding mediated by Acm, a new member of the MSCRAMM family.
AB  - A collagen-binding adhesin of Enterococcus faecium, Acm, was identified. Acm
      shows 62% similarity to the Staphylococcus aureus collagen adhesin Cna over the
      entire protein and is more similar to Cna (60% and 75% similarity with Cna A and
      B domains respectively) than to the Enterococcus faecalis collagen-binding
      adhesin, Ace, which shares homology with Acm only in the A domain. Despite the
      detection of acm in 32 out of 32 E. faecium isolates, only 11 of these (all
      clinical isolates, including four vancomycin-resistant endocarditis isolates and
      seven other isolates) exhibited binding to collagen type I (CI). Although acm
      from three CI-binding vancomycin-resistant E. faecium clinical isolates showed
      100% identity, analysis of acm genes and their promoter regions from six non-CI
      binding strains identified deletions or mutations that introduced stop codons
      and/or IS elements within the gene or the promoter region in five out of six
      strains, suggesting that the presence of an intact functional acm gene is
      necessary for binding of E. faecium strains to CI. Recombinant Acm A domain
      showed specific and concentration-dependent binding to collagen, and this protein
      competed with E. faecium binding to immobilized CI. Consistent with the adherence
      phenotype and sequence data, probing with Acm-specific IgGs purified from anti
      recombinant Acm A polyclonal rabbit serum confirmed the surface expression of Acm
      in three out of three collagen-binding clinical isolates of E. faecium tested,
      but in none of the strains with a non-functional pseudo acm gene. Introduction of
      a functional acm gene into two non-CI-binding natural acm mutant strains
      conferred a CI-binding phenotype, further confirming that native Acm is
      sufficient for the binding of E. faecium to CI. These results demonstrate that
      acm, which encodes a potential virulence factor, is functional only in certain
      infection-derived clinical isolates of E. faecium, and suggest that Acm is the
      primary adhesin responsible for the ability of E. faecium to bind collagen.

PMID- 12622829
TI  - Expression of mCLOCK and other circadian clock-relevant proteins in the mouse
      suprachiasmatic nuclei.
AB  - Circadian timing in mammals is based upon the cell-autonomous clockwork located
      in the suprachiasmatic nuclei (SCN) of the hypothalamus. It is thought to involve
      interlocked feedback loops in which periodic transcriptional drive to core clock
      genes is mediated by CLOCK/BMAL1 heterodimers. Negative-feedback actions of the
      encoded proteins PER and CRY terminate this phase of the cycle. In lower species,
      rhythmic abundance of the mCLOCK homologue initiates the subsequent cycle. By
      contrast, it is proposed that the new circadian cycle in mammals is triggered by
      indirect, positive transcriptional actions leading to a subsequent surge in
      BMAL1. The aim of this study was to test predictions made by this model
      concerning the behaviour of the native clock factor mCLOCK in the mouse SCN.
      Using in situ hybridization, immunocytochemistry, Western blotting and
      immunoprecipitation, we demonstrate constitutive expression of mCLOCK as a
      nuclear antigen in the SCN. mCLOCK forms alternating, periodic associations with
      either mBMAL1 or the negative regulators mPER and mCRY. The results confirm
      predictions made by the "two-loop" model of the mouse clock, and further
      highlight the role of interlocked cycles of positive and negative transcriptional
      regulatory complexes at the heart of the circadian clockwork.

PMID- 12622830
TI  - An essential role for peptidergic signalling in the control of circadian rhythms
      in the suprachiasmatic nuclei.
AB  - Two structurally related neuropeptides, pituitary adenylate cyclase-activating
      polypeptide (PACAP), colocalized with glutamate in neurones of the
      retinohypothalamic tract, and vasoactive intestinal peptide (VIP), present in
      light-responsive cells of the suprachiasmatic nuclei (SCN), appear to play
      distinct and important roles in the control of mammalian circadian rhythms. Mice
      deficient in the PACAP-selective PAC1 receptor exhibit altered responsiveness of
      the SCN clock to light-induced phase-shifts, but display robust circadian
      patterns of wheel-running behaviour. By contrast, our studies of mice lacking the
      VPAC2 receptor, which responds to both PACAP and VIP, indicate that this receptor
      plays a critical role in rhythm generation in the SCN. The predominant factor
      determining wheel-running activity in VPAC2 receptor null (Vipr2-/-) mice is
      "masking" by light. Mutant animals re-entrain immediately to advances or delays
      in the light/dark cycle and do not exhibit robust circadian rhythms of behaviour
      when in constant darkness. The mice do not exhibit circadian expression of core
      clock genes (mPer1, mPer2, mCry1), or of the clock-controlled gene arginine
      vasopressin (AVP), in the SCN. We propose that VIP signalling between SCN
      neurones provides a paracrine reinforcing signal that is essential for sustained
      rhythm generation. The presence of VIP signalling in the SCN may explain why SCN
      neurones are capable of generating long-lasting self-sustained oscillations,
      whereas rhythmic clock gene expression in other tissues is dependent on periodic
      reinforcement by neural or hormonal signals.

PMID- 12622831
TI  - The circadian clock: a manager of biochemical processes within the organism.
AB  - The periodic succession of night and day has influenced life on earth for
      millions of years. Many organisms have "internalized" this periodic change in the
      form of the circadian clock. Its main function is to organize the time course of
      biochemical, physiological and behavioural processes thereby optimizing an
      organism's performance in anticipating changing environmental conditions.
      Therefore, it is important to understand the underlying mechanisms that connect
      the core pacemaker, which is located in the suprachiasmatic nuclei (SCN) of the
      hypothalamus, with peripheral organs. Several laboratories set out to identify
      genes that are under the influence of the circadian clock. It appears that the
      circadian clock coordinates transcription of key metabolic pathways thereby
      orchestrating the time course of physiological and behavioural processes. We
      review these investigations and put our experiments, the comparison of gene
      expression in SCN tissue of Per2 mutant and wild-type mice, in the context of
      these findings.

PMID- 12622832
TI  - Flies and fish: birds of a feather.
AB  - The identification of specific clock-containing structures has been a major
      endeavour of the circadian field for many years. This has lead to the
      identification of many key components of the circadian system, including the
      suprachiasmatic nucleus in mammals, and the eyes and pineal glands in lower
      vertebrates. However, the idea that these structures represent the only clocks in
      animals has been challenged by the discovery of peripheral pacemakers in most
      organs and tissues, and even a number of cell lines. In Drosophila, and
      vertebrates such as the zebrafish, these peripheral clocks appear to be highly
      autonomous, being set directly by the environmental light/dark cycle. However, a
      hierarchy of clocks may still exist in mammals. In this review, we examine some
      of the current views regarding peripheral clocks, their organization and how they
      are entrained.

PMID- 12622833
TI  - Molecular control of Xenopus retinal circadian rhythms.
AB  - Vertebrate retinas contain endogenous circadian clocks that control many aspects
      of retinal physiology. Our work has focused on studying the molecular mechanism
      of this clock and the way in which it controls the many cellular rhythms within
      the retina. These studies focus on the retina of Xenopus laevis, a well
      established model system extensively used for the study of both retinal
      physiology and circadian function. We have cloned Xenopus homologues of the genes
      thought to be critical for vertebrate clock function, including Clock, Bmal1,
      cryptochromes and period, as well as other rhythmic genes such as nocturnin. We
      have used these genes to manipulate the clock within different subsets of retinal
      photoreceptors via cell-specific promoters, in order to study the location of the
      clock within the retina. These in vivo experiments have shown that photoreceptor
      cells contain clocks that are necessary for the rhythmic production of melatonin.
      We have also used biochemical approaches to further investigate the molecular
      events that drive specific rhythmic outputs, such as circadian regulation of
      nocturnin gene transcription and control of post-transcriptional events within
      these clock-containing cells.

PMID- 12622834
TI  - The photoreceptive capacity of the developing pineal gland and eye of the golden
      hamster (Mesocricetus auratus).
AB  - Anatomical and physiological studies have suggested that the pineal gland of
      neonatal mammals has a photoreceptive capacity. Using the golden hamster
      (Mesocricetus auratus) as our model, we applied biochemical approaches to look
      for a functional photopigment within the pineal during early development.
      Immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) were used to
      localize and quantify opsin, and high-performance liquid chromatography (HPLC) to
      identify photopigment chromophore (11-cis and all-trans retinaldehyde) in the
      developing eye and pineal. For HPLC analysis, retinaldehydes were converted to
      their corresponding retinoid oximes. Eluted retinoids were identified by
      comparison with standard vitamin A1 retinoid oxime isomers on the basis of
      relative elution sequence and characteristic absorbance spectra. Both
      immunocytochemistry and ELISA suggested an increase in the opsin content of the
      pineal during the first week of life. In the eye, 11-cis retinaldehyde was first
      detected between days 3 and 5 after birth. In three separate extractions, and
      using a considerable excess of pineal tissue, we failed to identify chromophore
      within the pineal during the first week of postnatal development. The appearance
      of 11-cis retinaldehyde within the eye between postnatal days 3-5 is consistent
      with the hypothesis that retinol isomerase activity is coordinated with outer
      segment development. The failure to identify chromophore within the neonatal
      pineal suggests that this gland lacks a functional opsin-based photopigment.
      These data contradict physiological evidence suggesting that the neonatal pineal
      of mammals contains photoreceptors.

PMID- 12622835
TI  - Photic and circadian regulation of retinal melatonin in mammals.
AB  - Several studies have established that melatonin synthesis occurs in the retina of
      vertebrates, including mammals. In mammals, a subpopulation of photoreceptors
      (probably the cones) synthesize melatonin. Melatonin synthesis in the retina is
      elevated at night and reduced during the day in a fashion similar to events in
      the pineal gland. Both the MT1 and MT2 melatonin receptors are present in the
      retina and retinal melatonin does not contribute to circulating levels,
      suggesting that retinal melatonin acts locally as a neurohormone and/or
      neuromodulator. Melatonin synthesis in the retina of mammals is under the control
      of a circadian oscillator, and circadian rhythms in melatonin synthesis and/or
      release have been described for several species of mammals. These rhythms are
      present in vivo, persist in vitro, are entrained by light and are temperature
      compensated. The cloning of the gene responsible for the synthesis of the enzyme
      arylalkylamine N-acetyltransferase (the key enzyme in the melatonin biosynthetic
      pathway) has allowed studies of the molecular mechanisms responsible for the
      generation of retinal melatonin rhythmicity. The present review focuses on the
      cellular and molecular mechanisms that regulate melatonin synthesis. In
      particular, we discuss how the photic environment and the circadian clock
      interact in determining melatonin levels, in addition to the role that melatonin
      plays in retinal physiology.

PMID- 12622836
TI  - 14-3-3 proteins in pineal photoneuroendocrine transduction: how many roles?
AB  - Recent studies suggest that a common theme links the diverse elements of pineal
      photoneuroendocrine transduction--regulation via binding to 14-3-3 proteins. The
      elements include photoreception, neurotransmission, signal transduction and the
      synthesis of melatonin from tryptophan. We review general aspects of 14-3-3
      proteins and their biological function as binding partners, and also focus on
      their roles in pineal photoneuroendocrine transduction.

PMID- 12622837
TI  - Genetic, temporal and developmental differences between melatonin rhythm
      generating systems in the teleost fish pineal organ and retina.
AB  - Complete melatonin rhythm generating systems, including photodetector, circadian
      clock and melatonin synthesis machinery, are located within individual
      photoreceptor cells in two sites in Teleost fish: the pineal organ and retina. In
      both, light regulates daily variations in melatonin secretion by controlling the
      activity of arylalkylamine N-acetyltransferase (AANAT). However, in each species
      examined to date, marked differences exist between the two organs which may
      involve the genes encoding the photopigments, genes encoding AANAT, the times of
      day at which AANAT activity and melatonin production peak and the developmental
      schedule. We review the fish pineal and retinal melatonin rhythm generating
      systems and consider the evolutional pressures and other factors which led to
      these differences.

PMID- 12622838
TI  - Melatonin: a clock-output, a clock-input.
AB  - In mammals, the circadian system is comprised of three major components: the
      lateral eyes, the hypothalamic suprachiasmatic nucleus (SCN) and the pineal
      gland. The SCN harbours the endogenous oscillator that is entrained every day to
      the ambient lighting conditions via retinal input. Among the many circadian
      rhythms in the body that are driven by SCN output, the synthesis of melatonin in
      the pineal gland functions as a hormonal message encoding for the duration of
      darkness. Dissemination of this circadian information relies on the activation of
      melatonin receptors, which are most prominently expressed in the SCN, and the
      hypophyseal pars tuberalis (PT), but also in many other tissues. A deficiency in
      melatonin, or a lack in melatonin receptors should therefore have effects on
      circadian biology. However, our investigations of mice that are melatonin
      proficient with mice that do not make melatonin, or alternatively cannot
      interpret the melatonin message, revealed that melatonin has only minor effects
      on signal transduction processes within the SCN and sets, at most, the gain for
      clock error signals mediated via the retino-hypothalamic tract. Melatonin
      deficiency has no effect on the rhythm generation, or on the maintenance of the
      oscillation. By contrast, melatonin is essential for rhythmic signalling in the
      PT. Here, melatonin acts in concert with adenosine to elicit rhythms in clock
      gene expression. By sensitizing adenylyl cyclase, melatonin opens a temporally
      restricted gate and thus lowers the threshold for adenosine to induce cAMP
      sensitive genes. This interaction, which determines a temporally precise
      regulation of gene expression, and by endocrine-endocrine interactions possibly
      also pituitary output, may reflect a general mechanism by which the master clock
      in the brain synchronizes clock cells in peripheral tissues that require unique
      phasing of output signals.

PMID- 12622839
TI  - Clock genes and the long-term regulation of prolactin secretion: evidence for a
      photoperiod/circannual timer in the pars tuberalis.
AB  - Prolactin secretion is regulated by photoperiod through changes in the 24-h
      melatonin profile and displays circannual rhythmicity under constant photoperiod.
      These two processes appear to occur principally within the pituitary gland,
      controlled by the pars tuberalis. This is evident because: (i) hypothalamic
      pituitary disconnected (HPD) sheep show marked changes in prolactin secretion in
      response to switches in photoperiod and manipulations of melatonin, similar to
      brain-intact controls; (ii) HPD sheep also show photoperiod-specific, long-term
      cycles in prolactin secretion under constant long or short days, with the timing
      maintained even when prolactin secretion is blocked for 2-3 months; and (iii)
      pars tuberalis cells, but not lactotrophs, express high concentrations of
      melatonin (MT1) receptor, and exhibit a duration-sensitive, cAMP-dependant,
      inhibitory response to physiological concentrations of melatonin. This suggests
      the existence of an intrinsic, reversible photoperiod-circannual timer in pars
      tuberalis cells. A full complement of clock genes (Bmal1, Clock, Per1, Per2, Cry1
      and Cry2) are expressed in the ovine pars tuberalis, and undergo 24-h cyclical
      expression as observed in a cell autonomous, circadian clock. Activation of Per
      genes occurs in the early day (melatonin off-set), while activation of Cry genes
      occurs in the early night (melatonin on-set). This temporal association is
      evident under both long and short days, thus the Per-Cry interval varies directly
      with photoperiod. Because, PER : CRY, protein : protein interactions affect
      stability, nuclear entry and gene transcription based on rodent data, the change
      in phasing of Per/Cry expression provides a potential mechanism for decoding the
      long day/short day melatonin signal. A speculative, but testable, extension of
      this hypothesis is that intrinsically regulated changes in the phase of Per/Cry
      rhythms, regulates both photorefractoriness and the generation of circannual
      rhythms in prolactin secretion.

PMID- 12622840
TI  - Encoding time of day and time of year by the avian circadian system.
AB  - The most important zeitgeber for seasonal rhythmicity of physiology and behaviour
      in birds is the annual cycle of photoperiod. Regulatory mechanisms are less well
      understood in birds than in mammals since photic information can be perceived by
      photoreceptors in the retina and the pineal gland, as well as in the brain, and
      photoperiodic time measurement might be performed with reference to at least
      three autonomous circadian systems, the retina, the pineal gland and a
      hypothalamic oscillator. In many bird species, the pineal melatonin rhythm plays
      a central role in circadian organization. Durations of elevated melatonin in the
      blood reflect night length when animals are kept under natural photoperiodic
      conditions, as well as under different light/dark schedules in the laboratory. In
      the house sparrow, time of year is encoded in a particular melatonin signal,
      being short in duration and high in amplitude in long photoperiods and being long
      in duration and low in amplitude in short photoperiods, independent of whether
      the light zeitgeber is natural or artificial or varies in strength. Specific
      features of the melatonin signal are retained in vivo as well as in vitro when
      birds or isolated pineal glands are transferred to constant conditions. To
      regulate daily and seasonal changes of behaviour and physiology, melatonin may
      act at various target sites, including a complex hypothalamic oscillator that,
      unlike that in mammals, is not confined to a single cell group in the house
      sparrow. There is increasing evidence that interactions between two or more
      components of the songbird circadian pacemaking system are essential to encode
      and store biologically meaningful information about time, and thus provide the
      basis for photoperiodic time measurements and after effects in birds.

PMID- 12622841
TI  - Melatonin action in the pituitary: neuroendocrine synchronizer and developmental
      modulator?
AB  - Melatonin inhibits the gonadotropin-releasing hormone (GnRH)-stimulated secretion
      of luteinizing hormone and follicle-stimulating hormone from the pars distalis
      region of the neonatal rat pituitary gland. Over the initial weeks of postnatal
      life, this response to melatonin declines in parallel with a loss of iodo
      melatonin binding sites. Although neonatal gonadotrophs have since been
      extensively used to study melatonin receptor signalling pathways, the mechanisms
      driving this phenomenon, together with its physiological significance, remain
      unknown. Melatonin receptors are expressed in the foetal pars distalis before
      activation of the GnRH system. Furthermore, the MT1 melatonin receptor promoter
      contains response elements for transcription factors involved in both pituitary
      differentiation and gonadotroph regulation. These data, coupled with the known
      ability of melatonin to regulate rhythmical gene expression in adult pars
      tuberalis cells, leads us to propose that melatonin acts in the developing animal
      as a regulator of internal synchrony between tissues.

PMID- 12622842
TI  - Leptin and seasonal mammals.
AB  - Seasonal mammals commonly exhibit robust annual cycles of adiposity, food intake
      and energy metabolism. These cycles are driven by changes in the external
      daylength signal, which generates a diurnal melatonin profile and acts on
      neuroendocrine pathways. The white adipose tissue hormone leptin reflects overall
      adiposity in seasonal mammals, and consequently undergoes significant seasonal
      fluctuations in secretion. The seasonally breeding Siberian (Djungarian) hamster
      is a convenient laboratory model to study the effect of a seasonal time-keeping
      clock on energy metabolism, appetite regulation and the control of adiposity. We
      have shown that administration of exogenous leptin at physiological doses induces
      significant loss of adipose tissue for short-day housed winter-like hamsters in
      which endogenous adipose tissue and leptin concentrations are already low. By
      contrast, long-day housed hamsters with high adipose tissue reserves are
      refractory to the effects of leptin. This phenomenon of seasonal leptin
      resistance appears to be a general feature of other seasonally breeding mammals,
      and may reflect the operation of an annual timer controlling leptin uptake and/or
      action on central nervous system signal transduction pathways. The mobilization
      of fat by leptin in short-day housed hamsters is not associated with changes in
      expression in either anorexic or anabolic peptides expressed in leptin-receptor
      rich structures in the arcuate region of the hypothalamus, and suggests that
      leptin may target other structures. These data contrast with studies, which show
      that homeostatic mechanisms in response to feed-restriction induce changes in
      hypothalamic peptides in a similar manner to nonphotoperiodic species. Thus, the
      long-term seasonal regulation of body weight set point and leptin feedback may
      operate through separate pathways to those responsible for acute responses to
      food restriction.

PMID- 12622843
TI  - Sensitization: a mechanism for melatonin action in the pars tuberalis.
AB  - Sensitization of adenylate cyclase is a recently discovered phenomenon. Melatonin
      can induce a sensitized response of adenylate cyclase in ovine pars tuberalis
      cells where the receptor for melatonin is endogenously expressed. Although the
      mechanism is not fully understood, sensitization of adenylate cyclase may be an
      important part of the mechanism by which melatonin encodes daylength in the pars
      tuberalis of sheep and other animals. We used this as a hypothesis to search for
      a natural ligand that would activate adenylate cyclase in ovine pars tuberalis
      cells. The approach revealed pituitary adenylate cyclase activating polypeptide
      to be an indirect activator of adenylate cyclase in the ovine pars tuberalis. We
      discuss this in relation to the mechanism and importance of sensitization to the
      function to the pars tuberalis.

PMID- 12622844
TI  - Melatonin: from seasonal to circadian signal.
AB  - In mammals, the role of melatonin in the control of seasonality is well
      documented, and the sites and mechanisms of action involved are beginning to be
      identified. The exact role of the hormone in the circadian timing system remains
      to be determined. However, exogenous melatonin has been shown to affect the
      circadian clock. Identification of the molecular and cellular mechanisms involved
      in this well characterized chronobiotic effect will allow clarification of the
      role of endogenous melatonin in circadian organization.

PMID- 12622845
TI  - Importance and relevance of melatonin to human biological rhythms.
AB  - The pineal hormone melatonin is a remarkable molecule, with a conserved time
      keeping function across species. It is extensively used as a self-administered
      remedy for sleep disturbance in countries where it is freely available, and to
      some extent when it is available on prescription, as in the UK. In some
      circumstances, notably free-running sleep disorder of the blind, it is the
      treatment of choice. It is also the marker rhythm of choice for the determination
      of circadian phase and period. This review outlines the current state of
      knowledge within a physiological perspective with emphasis on human biological
      rhythms.

PMID- 12622846
TI  - Role of melatonin in the regulation of human circadian rhythms and sleep.
AB  - The circadian rhythm of pineal melatonin is the best marker of internal time
      under low ambient light levels. The endogenous melatonin rhythm exhibits a close
      association with the endogenous circadian component of the sleep propensity
      rhythm. This has led to the idea that melatonin is an internal sleep
      "facilitator" in humans, and therefore useful in the treatment of insomnia and
      the readjustment of circadian rhythms. There is evidence that administration of
      melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is
      insufficient; (ii) to inhibit the drive for wakefulness emanating from the
      circadian pacemaker; and (iii) induce phase shifts in the circadian clock such
      that the circadian phase of increased sleep propensity occurs at a new, desired
      time. Therefore, exogenous melatonin can act as soporific agent, a
      chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the
      regulation of sleep, and the use of exogenous melatonin to treat sleep or
      circadian rhythm disorders.

PMID- 12622847
TI  - Optimization of light and melatonin to phase-shift human circadian rhythms.
AB  - Both light and melatonin, appropriately timed, have been shown to phase-shift
      human circadian rhythms. In addition, both light and melatonin have acute
      physiological and behavioural effects. Depending on the dose, melatonin can
      reduce core body temperature and induce sleepiness. Conversely, light at night
      increases body temperature and enhances alertness and performance. The acute and
      phase-shifting effects of light and melatonin have justified their investigation
      and use in the treatment of circadian rhythm sleep disorders. Melatonin is the
      treatment of choice for blind people with non-24 h sleep/wake disorder. Current
      research is directed towards optimizing these therapies with respect to time of
      administration, dose and formulation of melatonin, intensity, duration and
      spectral composition of light. Our studies in totally blind people with non-24 h
      sleep/wake disorder have shown that, in addition to improving sleep, daily
      administration of melatonin can entrain their free-running circadian rhythms. The
      ability of melatonin to entrain free-running rhythms depends, in part, on the
      time of melatonin administration relative to the subject's circadian phase.
      Subjects who were entrained by melatonin began their treatment in the phase
      advance portion (CT 6-18) of the published melatonin phase-response curves
      (PRCs), whereas those who failed to entrain began their melatonin treatment in
      the delay portion of the PRC. Whether the effect of light on the human circadian
      axis can be optimized by altering its spectral composition has been investigated.
      Recently, it was demonstrated that light-induced melatonin suppression in humans
      is sensitive to short wavelength light (420-480 nm; lambda(max) approximately 460
      nm), a response very different to the classical scotopic and photopic visual
      systems. Whether other nonvisual light responses (e.g. circadian phase resetting)
      show a similar spectral sensitivity is currently being studied.

PMID- 12622848
TI  - Therapeutic perspectives for melatonin agonists and antagonists.
AB  - Melatonin is a neurohormone synthesized in the pineal gland during the dark
      period in all species, including humans. The diversity and differences in
      melatonin receptor distribution in the brain and extracerebral organs suggest
      multiple functional roles for melatonin. Administration of melatonin agonists
      reduces neophobia and treatment with a melatonin antagonist during the dark
      period reverses the anxiolytic-like effect of endogenous melatonin. Chronic
      treatment with agonists prevents various perturbations induced by chronic mild
      stress. Melatonin in vivo directly constricts cerebral arterioles in rats and
      decreases the lower limit of cerebral blood flow autoregulation, suggesting that
      melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At
      the extracerebral level, melatonin regulates intestinal motility in rats. The
      intestinal postprandial motor response is shorter in the dark phase than in the
      light phase and this reduction is reversed in animals pretreated with a melatonin
      antagonist. Moreover, melatonin reduces the duration of cholecystokinin
      excitomotor effect. Endogenous melatonin may modulate intestinal motility to
      coordinate intestinal functions such as digestion and transit and control the
      metabolism of the animal. An adipocyte melatonin binding site may also
      participate in this control. Melatonin is involved in a wide range of
      physiological functions. The question remains as to whether evolution, adaptation
      and diurnal life have modified the physiological role of melatonin in humans.
      Moreover, the functional role of each of the receptor subtypes has to be
      characterized to design selective ligands to treat specific diseases.

PMID- 12622849
TI  - Ultrasonic dental scaler: associated hazards.
AB  - BACKGROUND: The ultrasonic dental scaler is a valuable tool in the prevention of
      periodontal disease; however, this equipment has a number of hazards with which
      it is associated. These include heating of the tooth during scaling, vibrational
      hazards causing cell disruption, possible platelet damage by cavitation,
      associated electromagnetic fields that can interrupt pacemakers, auditory damage
      to patient and clinician and the release of aerosols containing dangerous
      bacteria. OBJECTIVE: To collate the research reported on the various hazards
      associated with the ultrasonic dental scaler and discuss possible future research
      areas. DATA SOURCES: The scientific literature was searched using Web of Science,
      EMBASE and Medline, and the results of these were then hand-searched to eliminate
      nonrelevant papers. CONCLUSIONS: This review outlines some of the research
      conducted into these areas of associated hazard in order to assess their
      significance in the clinical situation, and discusses ideas for future research.
      Suggestions of recommendations are given, which have been previously investigated
      for their aid in reducing possible hazards, to ensure the safe working of
      ultrasonic scalers in the dental practice.

PMID- 12622850
TI  - Interleukin-1 gene polymorphisms and experimental gingivitis.
AB  - BACKGROUND: Recently, an association between the severity of periodontitis and
      specific variations in the interleukin-1 (IL1) alpha and beta genes has been
      demonstrated. AIM: : The purpose of this study was to evaluate the relationship
      of the IL1 genotype to the development of experimental gingivitis. MATERIALS AND
      METHODS: Twenty young adult subjects presenting with healthy gingival conditions
      participated after giving their informed consent. The group included 10 risk
      genotype positive (P+) and 10 risk genotype negative (P-) individuals. The IL1
      genotypes were determined on DNA samples from peripheral blood using PCR-RFLP
      analyses for the IL1alpha and IL1beta polymorphisms. Experimental gingivitis was
      allowed to develop in two posterior sextants per subject. Bleeding on probing
      (BOP%) and gingival crevicular fluid volume (GCF) were assessed at baseline and
      days 2, 7, 9, 14, 16 and 21. The day 21 results for BOP and GCF as well as the
      rate of increase of these parameters - mean area under the curve (AUC) and mean
      increase per day (slope) - were evaluated using risk analyses for IL1 genotype,
      smoking status and gender. RESULTS: Experimental gingivitis developed with a
      gradual increase in BOP scores and GCF values (expressed as Periotron units=PU)
      from baseline to day 21 (BOP, P+: 0.5 to 26.0%; P-: 1.0 to 28.1%; GCF, P+: 36.8
      to 138.5 PU, P-: 43.1 to 143.4 PU). No significant risk was associated with P+
      and P- for day 21 results, AUC or slope. CONCLUSION: The results of this study
      failed to provide evidence that the IL1 risk genotype was associated with higher
      GCF volume and percentage BOP during the development of experimental gingivitis.

PMID- 12622851
TI  - Tobacco smoking and risk for periodontal disease.
AB  - OBJECTIVE: The magnitude of risk for periodontal disease associated with smoking
      was investigated by exploring the interrelationships between definition of
      disease, prevalence and relative risk in a population of dentally aware
      individuals. MATERIALS AND METHODS: A total of 133 smokers and 242 non-smokers in
      the age range 20-69 years served as the database. Criteria based on clinical
      probing of pocket depth and radiographic measurement of bone height were used for
      the purpose of disease definition. Various pocket frequency cutoff points for two
      probing depth levels, > or =5 and > or =6 mm, and, in addition, the 30th, 25th,
      and 20th percentiles of the bone height distribution were alternately selected as
      criteria. RESULTS: Disease definition had an impact on the prevalence, and the
      relative risk varied as a function of the prevalence. For a broad definition of
      disease such as 1% of pockets > or =5 mm, the prevalence for smokers was
      approximately twice the prevalence for non-smokers and the odds ratio (OR) was
      3.0. A narrower definition such as 15% of pockets > or =5 mm resulted in
      decreased prevalences for both smokers and non-smokers and an OR of 12.1.
      Increasing exposures correlated with greater magnitudes of risk. Heavy exposure
      was associated with greater risk than light exposure. For the combination of a
      narrow disease definition and heavy exposure, the relative risk was considerable
      (OR 9.8-20.3). CONCLUSION: Smoking-associated relative risk is dependent on
      definition of disease and prevalence. Given other factors, a narrow definition
      will result in a low prevalence and a high risk and, vice versa, for a broader
      definition, prevalence will be high and the risk moderate.

PMID- 12622852
TI  - In vitro calibration and validation of a digital subtraction radiography system
      using scanned images.
AB  - OBJECTIVES: To calibrate and validate a digital subtraction radiography system
      using scanned images for quantification of alveolar bone changes by means of
      computer-assisted densitometric image analysis (CADIA) in vitro. MATERIALS AND
      METHODS: Noise levels were determined using 10 standardized periapical
      radiographs of the same lower molar region in a human dry skull. For validation
      of the system, radiographs were taken before and after bovine bone particles in
      measures with increments of 2 mg weighing from 2 to 20 mg were added into each
      socket of three dry skulls. Radiographs were developed and scanned into a
      computer with a flatbed scanner. After digitization, the images were subjected to
      alignment, normalization and subtraction. Appropriate regions of interest (ROIs)
      were selected and their CADIA values were calculated for the determination of
      noise levels, and correlations between the CADIA values and the actual bone mass
      were performed. RESULTS: When the threshold value was 7, the percentage of pixels
      deviating from the set threshold value was small (0-11.3%). There were
      statistically significant correlations between the actual bone mass and the CADIA
      value for anterior sockets (p<0.001, r2=0.89) and posterior sockets (p<0.001,
      r2=0.9). For pooled data of both anterior and posterior sockets, the correlation
      was also statistically significant (p<0.001, r2=0.88). CONCLUSIONS: A high and
      statistically significant correlation between the actual bone mass and CADIA
      value was obtained, which suggests that the system could be suitable for the
      detection of small alveolar bone changes.

PMID- 12622854
TI  - Effects of enamel matrix protein application on the viability, proliferation, and
      attachment of human periodontal ligament fibroblasts to diseased root surfaces in
      vitro.
AB  - OBJECTIVES: The purpose of this research was to examine the influence of enamel
      matrix proteins (EMP) on the viability, proliferation, and attachment of
      periodontal ligament fibroblasts (PDLF) to diseased root surfaces. MATERIALS AND
      METHODS: Primary cell cultures of PDFL were obtained from clinically healthy
      third molars or premolar teeth. Viability and proliferation rates were carried
      out over a 10-day period. A total of 80,000 cells were plated in 24-well plates
      followed by EMEM with 10% FBS (positive control) and EMEM plus EMP at 25, 50, 75,
      and 100 micro g/ml. Cells were harvested on days 1, 3, 5, 7, and 10 and viability
      was performed utilizing an MTS assay. PDLF proliferation rates were assessed by a
      CyQUANT GR dye assay. SEM analysis was used to examine the qualitative effects of
      cellular attachment to diseased root surfaces following EMP compared to
      nontreated controls. RESULTS: The results indicated that viability was negatively
      affected for higher doses over time while lower doses displayed viability effects
      similar to control. Proliferation, however, appeared to be ameliorated following
      exposure to EMP. The SEM analysis suggests that cellular attachment to diseased
      dentin was enhanced following EMP application. CONCLUSION: These in vitro studies
      support the concept that EMP may act as a suitable matrix for PDLF.

PMID- 12622853
TI  - A modification to the experimental gingivitis protocol to compare the antiplaque
      properties of two toothpastes.
AB  - BACKGROUND AND AIMS: Randomised, blind, controlled experimental gingivitis and
      home-use study protocols are used to evaluate the efficacy of oral hygiene
      products. The present methodological study combined the two clinical trial
      designs to compare the preventive and therapeutic potentials of two toothpastes.
      MATERIAL AND METHODS: The study was a parallel group, randomised, double-blind
      design, initially involving 73 healthy dentate subjects. A 21-day experimental
      gingivitis protocol was combined with a 6-week (42 days) home-use protocol. At
      baseline, modified gingival index (MGI), gingival index (GI) and gingival
      bleeding (GB) were recorded. A dental prophylaxis was then performed. Subjects
      were allocated to either control fluoride or stannous fluoride toothpaste based
      on gender and GI. During the first 21-day period, subjects applied the allocated
      toothpaste, for 1 min twice a day, to a group of teeth in a plastic shield and
      brushed the remaining teeth with the same paste. From day 21 the shield was not
      placed, and subjects brushed all teeth with the toothpaste for 1 min twice per
      day up to day 42. MGI, GB and a plaque index (PI) were recorded on days 21 and
      42. RESULTS: Sixty-nine and 67 subjects completed to days 21 and 42,
      respectively. For shielded teeth, PI, MGI and GB increased to day 21 and then
      after ceasing the use of the shield decreased to day 42. At day 21, PI favoured
      the stannous fluoride toothpaste, but differences did not achieve statistical
      significance for any parameter at days 21 or 42. For unshielded teeth, there were
      no significant differences between the toothpastes for any parameter at either
      time point. CONCLUSION: : The feasibility of combining two gingivitis clinical
      trial methodologies appears proven, and data on both the preventive and
      therapeutic chemical and mechanical efficacy of toothpastes can be obtained
      through such protocols. Specifically from the present study and consistent with
      some other reports, the plaque inhibitory properties of the stannous fluoride
      product are limited and do not always translate into an antiplaque/antigingivitis
      effect.

PMID- 12622855
TI  - The effects of cigarette smoking on the periodontal condition of young Jordanian
      adults.
AB  - BACKGROUND: Several studies have reported an association between smoking and
      periodontal destruction in young adults. AIMS: To investigate the effects of
      cigarette smoking on the periodontal condition of young Jordanian adults.
      METHODS: A case-control study of young adults between the ages of 20 and 35 years
      who were attending a dental hospital in Jordan for routine dental treatment. A
      group of 100 subjects who had smoked for at least 2 years were compared with 100
      age- and sex-matched never smokers. Clinical measurements of plaque, bleeding on
      probing and probing depth were recorded and interproximal bone levels related to
      molar teeth were assessed from bitewing radiographs. RESULTS: The smokers had
      higher levels of plaque, more sites which bled in response to probing and a
      greater mean probing depth than never smokers. The unadjusted odds ratio for
      smoking to be associated with the presence of more than 10 pockets which were >
      or =4 mm was 3.08 (95% confidence interval 1.58-6.03). The proportion of
      measurable surfaces in smokers (22.7%) which had bone levels > or =3 mm below the
      cementoenamel junction was significantly higher (P<0.0001) than in never smokers
      (7.4%). Independent predictors of reduced bone levels in multivariate analysis
      were infrequent interdental cleaning (P=0.03), age of 30 or older (P=0.03) and
      smoking (P<0.0001). Within the multivariate analysis the adjusted odds ratio for
      smoking to be associated with reduced molar bone levels was 4.95 (confidence
      interval 2.48-9.88). CONCLUSIONS: It is concluded that cigarette smoking was a
      major environmental factor associated with accelerated periodontal destruction in
      the young adult Jordanians investigated.

PMID- 12622856
TI  - Plaque removal with a novel manual toothbrush (X-Active) and the Braun Oral-B 3D
      Plaque Remover.
AB  - OBJECTIVES: The study was designed to test the efficacy in plaque removal of
      three toothbrushes: two manual brushes, the Butler GUM 311 and the Dr Best X
      Active, and one electric toothbrush the Braun Oral-B 3D Plaque Remover (3D).
      METHOD: The study was a split-mouth, single-blind, randomized clinical study
      consisting of three identical experiments testing three combinations of
      toothbrushes (experiment 1: 3D versus Butler; experiment 2: 3D versus Dr Best;
      experiment 3: Butler versus Dr Best), in which the teeth of the panellists were
      brushed by a dental hygienist. In a fourth experiment, the panellists brushed
      their own teeth (3D versus Dr Best). Thirty-five subjects participated in the
      study and received a professional prophylaxis prior to the first experiment. They
      were requested to refrain from brushing their teeth for 48 h prior to each
      experiment. Plaque was assessed according to the Silness & Loe plaque index at
      six sites per tooth. Next, the dental hygienist (experiments 1-3) or the
      panellist (experiment 4) brushed for 60 s with their first assigned brush in two
      randomly selected contralateral quadrants. Brushing was repeated (60 s) with the
      second brush in the opposing two contralateral quadrants. Prior to experiment 4,
      panellists were given two thorough hands-on professional instructions in the use
      of the 3D and the Dr Best toothbrushes. RESULTS: In experiment 1, the 3D showed a
      mean plaque reduction of 72% compared to 63% with the Butler (P<0.01). In
      experiment 2, the 3D showed a mean plaque reduction of 79% and the Dr Best 76%
      (P<0.05). In experiment 3, the Butler showed a mean plaque reduction of 81% and
      the Dr Best 85% (P=0.01). In the hands of the panellists (experiment 4), the 3D
      showed a mean plaque reduction of 88% and the Dr Best 84% (P<0.05). CONCLUSIONS:
      A 5-week training period with repeated hands-on instruction gives panellists the
      skill to perform brushing with efficacy comparable to that of professional
      brushing. In agreement with a previous study, the 3D was more effective than a
      flat-trimmed manual toothbrush (Van der Weijden et al. 1994). Brushing with the
      criss-cross resulted in small statistical differences with the 3D and the flat
      trimmed manual toothbrush. The clinical relevance of these statistically
      significant results should be the subject of a longitudinal study.

PMID- 12622857
TI  - Effect of inflammation, smoking and stress on gingival crevicular fluid cytokine
      level.
AB  - BACKGROUND: Recent studies have shown that cytokines are pivotal to the
      pathogenesis of periodontal diseases and may be used as markers in diagnosis.
      AIM: The aim of the present study was to determine the levels of interleukin (IL)
      1beta, IL-4, IL-6 and IL-8 in gingival crevicular fluid of periodontally healthy
      and diseased individuals and to study their association to smoking, stress and
      clinical periodontal parameters. MATERIAL AND METHODS: A total of 80 patients
      were included in the study : 20 patients with early onset or aggressive
      periodontitis (EOP), 20 with chronic adult periodontitis (AP), 20 with gingivitis
      (G) and 20 patients with healthy periodontium (H). GCF was collected by means of
      Durapore strips, from four sites per patient, randomly selected in each quadrant.
      The contents of IL- 1beta, IL-4, IL-6 and IL-8 were measured in 320 samples by
      use of commercially available sandwich enzyme-linked immunoadsorbent assays.
      RESULTS: In periodontally diseased subjects the total amounts of IL-1beta, IL-6
      and IL-8 were significantly elevated as compared to healthy subjects, whereas IL
      4 showed an inverse relationship to periodontal status and higher amounts were
      found in the healthy group. The amounts of all four cytokines were positively
      correlated with probing depths. IL-4, IL-6 and IL-8 were significantly correlated
      to smoking while stress was associated with IL-1beta, IL-6 and IL-8 levels.
      CONCLUSIONS: The present data suggest that crevicular IL-1beta, IL-6 and IL-8
      reflect the activity of periodontal destruction, whereas IL-4 shows an inverse
      correlation to it. The enhanced production of inflammatory cytokines in the
      presence of smoking and stress may have clinical consequences.

PMID- 12622858
TI  - MMP-1 promoter polymorphism: association with chronic periodontitis severity in a
      Brazilian population.
AB  - BACKGROUND: A single nucleotide polymorphism was described in the promoter region
      of the human MMP-1 gene, and this polymorphism has been associated with risk of
      cancer metastasis and inflammatory diseases. In this paper, we studied the
      possible relationship between the MMP-1 promoter polymorphism and the severity of
      chronic periodontitis. METHODS: Genomic DNA from oral mucosa was amplified by PCR
      and analyzed by restriction endonuclease. The alleles were separated by
      polyacrylamide gel electrophoresis. The significance of the differences in
      observed frequencies of polymorphism in moderate and severe disease and healthy
      groups was assessed by Chi-squared test. RESULTS: In the healthy group, the 2G
      allele was observed with a frequency of 48.7%, while in severely diseased
      patients the 2G allele was seen in 69.2% (P = 0.0344). The genotype 2G/2G was
      found in 46.15% of the group with severe periodontitis, and 24.3% and 25.0%,
      respectively, of the healthy and moderate groups (P = 0.0647). CONCLUSION: These
      results show that a polymorphism in the promoter region of MMP-1 gene is
      associated with the severe chronic periodontitis phenotype in non-smokers.

PMID- 12622859
TI  - Treatment of gingivitis with hyaluronan.
AB  - OBJECTIVES: Hyaluronic acid (hyaluronan) is a glycosaminoglycan with anti
      inflammatory and antiedematous properties. It was evaluated in a gel formulation
      for its effect in the treatment of plaque-induced gingivitis. METHOD: In a
      randomised double-blind study, 50 male subjects with plaque-induced gingivitis
      were divided into two groups and used a verum or placebo gel twice daily
      additionally to oral hygiene for a 3-week treatment period. Clinical indices
      (API, Turesky index, PBI) and crevicular fluid variables (peroxidase, lysozyme)
      were determined at baseline and after 4, 7, 14 and 21 days, respectively.
      RESULTS: Significant improvements could be found for all clinical variables in
      both groups. The verum group showed significant improvement in the study area for
      the plaque indices beginning with day 4 (P = 0.011) and the PBI beginning with
      day 7 (P = 0.001) in comparison with the placebo group. The crevicular fluid
      variables were significantly improved in the centre of the studied inflammation
      area in the verum group. Here all studied sites had significant decreases in
      peroxidase (176.72-128.75 and 188.74-128.75 U/L) and lysozyme (1.27-0.27 and 1.30
      0.33 mg/L) activities after 7, 14 and 21 days (P between 0.034 and < 0.001),
      whereas in the placebo group only one site showed a significant decrease for
      lysozyme (1.74-0.75 mg/L) after 7 and 21 days (P = 0.048 and 0.025). CONCLUSIONS:
      These data suggest that a hyaluronan containing gel has a beneficial effect in
      the treatment of plaque-induced gingivitis.

PMID- 12622862
TI  - Doing practice differently: solution-focused nursing.
AB  - BACKGROUND: Critical thinking and reasoning take many forms; however, a problem
      orientation remains the favoured approach in health care. PURPOSE: This paper
      considers the effects of a problem-orientation and argues that a solution
      orientation fits nursing's interests more closely and represents an exciting way
      forward in both education and practice. DISCUSSION: Whilst a problem-focus is
      criticized by some, it remains largely unchallenged as the guiding light for
      nursing practice. A major reason is that the problem focused approach has strong
      cultural roots. It is deeply embedded in our thinking, and has become taken-for
      granted and not often recognized or debated. Whilst problem-solving has an
      important place in helping to diagnose disorder and overcome difficulties,
      nursing needs to move beyond its borders because the role also concerns problem
      free issues such as health and well-being. Creativity, imagination and focusing
      on strengths not problems are also important cognitive processes. CONCLUSION: A
      problem-orientated approach in nursing has had a constraining rather than
      enabling influence. By refocusing on a solution-focused approach, we could show
      how we are different from medicine, and how we aim to do nursing differently
      through using skills such as engagement, resilience-building, community
      development, primary health care and health education.

PMID- 12622860
TI  - Root defects following air polishing.
AB  - AIM: Air-polishing devices (APDs) are highly effective in removing plaque and
      extrinsic staining. Their application on root surfaces, however, may result in
      clinically relevant substance removal, limiting the use in patients with
      periodontitis, where denuded root surfaces are frequently found. Therefore, the
      purpose of the study was to assess the influence of different working parameters
      on root damage and to identify those minimizing root damage. MATERIAL AND
      METHODS: Defect depth and defect volume after instrumentation of roots with an
      APD (Dentsply Prophy-Jet) using conventional NaHCO3 powder at instrumentation
      times of 5, 10 and 20 s, combinations of low, medium and high powder and water
      settings, distances of 2, 4 and 6 mm, and angulations of 45 degrees and 90
      degrees were quantified laseroptically. A total of 297 roots were instrumented
      and parameter combinations were performed in triplicate. The influence of each
      working parameter on substance loss was determined by multiple regression
      analysis. RESULTS: Time had the greatest influence on defect volume and depth
      (beta-weights 0.6 and 0.57, respectively), when compared with powder setting
      (beta-weights 0.49 and 0.3) and water setting (beta-weights 0.28 and 0.3).
      Variations in distance affected defect depth (beta-weight 0.44), but not volume
      (beta-weight 0.04). No major differences were found at 45 degrees and 90 degrees.
      Various parameter combinations led to maximal defect depths of 473.5 +/- 26.2
      micro m within 20 s. CONCLUSION: Root damage varies among combinations of working
      parameters. Using the APD with the assessed NaHCO3 powder, all parameter
      combinations led to substantial root damage. Thus, APDs using NaHCO3 may not be
      safely utilized on exposed root surfaces.

PMID- 12622863
TI  - Systematic review of patient handling activities starting in lying, sitting and
      standing positions.
AB  - BACKGROUND: Over the last 20 years a number of methods have been recommended in
      professional guidelines for moving patients. This review was undertaken as it was
      recognized that there was a need for clinical work involving handling patients
      (systems of work and equipment) to be based on scientific evidence. AIMS: The aim
      of this paper is to report the methodology, search strategy and results relating
      to work involving the care, treatment and transfer of patients starting in lying,
      sitting and standing positions. METHODS: An unusual philosophical stance has been
      taken by appraising studies within a study type rather than comparatively. This
      facilitated the inclusion of a wide range of study designs (quantitative and
      qualitative). A string search was run on eight databases and supplemented by
      other search strategies. A published checklist was selected and inter-rater
      reliability established before the main review commenced. A systematic process
      for inclusion, exclusion, appraisal, extraction and synthesis was undertaken.
      RESULTS: Thirty-two studies were included: nine for activities with the patient
      starting in a lying position and 23 for the sitting position. No studies were
      found with respect to patient handling activities starting in a standing
      position. These data were synthesized into evidence statements. CONCLUSIONS: The
      evidence statements support the use of hoists (for nonweight bearing patients),
      standaids, sliding sheets (double thickness rollers), lateral transfer boards,
      walking belts and adjustable height beds and baths. It is suggested that these
      items should constitute a minimum equipment list for any clinical environment
      where patient handling takes place on a regular basis. The lack of research
      relating to patient handling in standing is of particular concern and it is
      recommended that this area should be a high research priority to address concerns
      about patient handling in rehabilitation activities.

PMID- 12622864
TI  - Nursing care of dead bodies: a discursive analysis of last offices.
AB  - BACKGROUND: Nurses care for patients before they are born, after they have died
      and during the lifetime in between. This paper explores nursing care of the
      patient after they have died including the actions by nurses in preparation of
      the body, the covering with a shroud, and the transfer to the mortuary. AIMS: The
      analysis of a procedure manual excerpt Last Offices, which directs care of the
      dead patient aims to explore nursing care practices in regard to dead patients,
      as well as the impact of the health care institution and society at large on
      these care practices. METHOD: An acute care teaching hospital located in a major
      Australian city was approached and permission was granted to access their
      procedure and policy manuals. The Last Offices excerpt of the procedure manual
      was discursively analysed. FINDINGS: It is the contention of this paper that,
      through their care, nurses enact the transition between life and death, and from
      person to corpse. Furthermore, nurses mediate the move from embodied person to
      becoming dead, and in so doing traverse the cultural, ontological and
      epistemological breaks that death entails.

PMID- 12622865
TI  - Exploring nursing outcomes for patients with advanced cancer following
      intervention by Macmillan specialist palliative care nurses.
AB  - BACKGROUND: Little information exists about the outcomes from nursing
      interventions, and few studies report new approaches to evaluating the complex
      web of effects that may result from specialist nursing care. AIMS: The aim of
      this study was to explore nursing outcomes for patients with advanced cancer that
      may be identified as resulting from the care of a Macmillan specialist palliative
      care nurse. METHODS/INSTRUMENTS: Seventy-six patients referred to 12 United
      Kingdom Macmillan specialist palliative care nursing services participated in a
      longitudinal study of their care over 28 days. Patients were interviewed and
      completed the European Organization for Research on Treatment of Cancer Quality
      of Life Scale and the Palliative Care Outcomes Scale at referral, and 3, 7 and 28
      days following referral to a Macmillan specialist palliative care nursing
      service. A nominated carer was interviewed at baseline and 28 days. Notes
      recorded by Macmillan specialist palliative care nurses in relation to each
      patient case were analysed. FINDINGS: Significant improvements in emotional (P =
      0.03) and cognitive functioning (P = 0.03) were identified in changes in
      patients' European Organization for Research on Treatment of Cancer Quality of
      Life Scale scores, and in Palliative Care Outcomes Scale patient anxiety scores
      (P = 0.003), from baseline to day 7. Analysis of case study data indicated that
      overall positive outcomes of care from Macmillan specialist palliative care
      nursing intervention were achieved in 42 (55%) cases. STUDY LIMITATIONS: Sample
      attrition due to patients' deteriorating condition limited the value of data from
      the quality of life measures. The method developed for evaluating nursing
      outcomes using data from patient and carer interviews and nursing records was
      limited by a lack of focus on outcomes of care in these data sources.
      CONCLUSIONS: A method was developed for evaluating outcomes of nursing care in
      complex situations such as care of people who are dying. Positive outcomes of
      care for patients that were directly attributable to the care provided by
      Macmillan specialist palliative care nurses were found for the majority of
      patients. For a small number of patients, negative outcomes of care were
      identified.

PMID- 12622866
TI  - Older people in persistent pain: nursing and paramedical staff perceptions and
      pain management.
AB  - BACKGROUND: Persistent pain is a common problem for older people. Knowledge about
      how nursing and paramedical staff perceive these people and what they do to
      relieve the pain seems scarce. AIM: To explore nursing and paramedical staff
      perceptions of older people in persistent pain and their day-to-day management of
      pain. METHODS: Interviews in Swedish with 52 nursing auxiliaries, Registered
      Nurses, physiotherapists and occupational therapists were collected from February
      to May 2000. The analysis was based on their stories (n = 150) about older people
      in persistent pain who received help in their own homes or in special
      accommodation. A typology of staff perceptions of pain in older people was
      developed. Activities to manage pain were examined using content analysis.
      RESULTS: Respondents perceived the pain as real, exaggerated, trivial, care
      related, endured, concealed, self-caused or inarticulate. Older people perceived
      as exaggerating the pain, those with care-related and self-caused pain evoked
      frustration in the staff, while those perceived as enduring their pain evoked
      satisfaction. Various strategies to manage pain were used: no activity,
      medication, mediating contacts, distracting activities, physical therapies,
      mobility, work in a gentle way, rest or relieving pressure on body part, and
      communication concerning pain. The activities differed between the types, as well
      as between staff with different professional backgrounds. CONCLUSION: Care and
      treatment provided by staff should be based on older people's needs rather than
      on staff attitudes and preferences. The typology revealed that staff perceived
      older people in pain as a heterogeneous group and that their perceptions affected
      the pain-relieving activities that were offered. It seems urgent to address how
      to handle pain in older people who never complain and those who complain a great
      deal, as well as how to handle pain in people with impaired communicative
      ability. Reflective discussions on feelings related to different individuals are
      needed.

PMID- 12622868
TI  - Early support needs of Finnish families with small children.
AB  - AIMS: This study describes the early needs for support that families with small
      children have in the context of their own life situations. The study population
      consisted of Finnish families (n = 551) who participated in a project titled
      'Families with Children' (1996-2001). The project supplemented the existing
      public services. The information provided by the study was utilized in supporting
      families and developing family work in seven experimental areas. METHODS: The
      data were collected between 1997 and 2000 using family service plans and client
      reports. The data were analysed with inductive content analysis and using the
      SPSS software (version 7.5). FINDINGS: The families needed support in the areas
      of parenthood, upbringing and child care, marital problems and social support
      networks. The need for early support was also connected to health problems of the
      children or the parents, problems with work or studies, unemployment, problems in
      economic or living conditions, or family crises. In addition to support, the
      families searched for help from family workers in disputes over child custody and
      visitation rights, intoxicant abuse and violence, and problems in adjusting to
      society. Each family had 4-5 needs for early support. CONCLUSIONS: The results
      demonstrate that families with small children have many needs for which they seek
      help when there are available services supplementing the existing public
      services. The information provided by the study can be utilized in maternity and
      child welfare clinics, in social services and in family work provided by civic
      organizations to define the early needs of families for support and to develop
      services.

PMID- 12622867
TI  - Pain and anxiety management in the postoperative gastro-surgical setting.
AB  - BACKGROUND: Despite increasing knowledge and technological advances, patients
      continue to experience pain and anxiety in the postoperative setting. AIM OF THE
      STUDY: The aim of this study was to examine how nurses managed patients' pain and
      anxiety within the gastro-surgical hospital setting. METHODS: An observational
      design was selected to examine nurses' management of postoperative patients' pain
      and anxiety. Six nurses who were involved in direct patient care in one of two
      gastro-surgical wards in a public teaching hospital in Melbourne, Australia, were
      randomly selected to participate. The observation period comprised a fixed 2-hour
      segment, and each nurse was observed on three different occasions. FINDINGS:
      Patient assessment was a major concern for participants, which was influenced by
      the modes of assessment used, patients' medical condition and operation
      procedure, and their self-reports of pain or anxiety. Communication with health
      care professionals and policy and protocol concerns also affected nurses' pain
      and anxiety management decisions. Formal communication through the
      multidisciplinary ward round tended to be somewhat fragmented, as the medical
      consultant did not seek out the bedside nurse. Nurses had good knowledge of unit
      policies and protocols and, while attempting to enforce them, spent considerable
      time encouraging medical colleagues to abide by these guidelines. Finally, nurses
      made complex clinical judgements which extended beyond the administration of
      analgesics or antianxiety drugs. STUDY LIMITATIONS: It is possible that nurses
      demonstrated a raised awareness of how they managed patients' pain and anxiety
      during observation periods. CONCLUSIONS: The study confirmed the importance of
      examining the complexities of the clinical context in determining how nurses
      manage pain and anxiety in the postoperative setting.

PMID- 12622869
TI  - Nurse cadet schemes in the British NHS - challenges and opportunities.
AB  - RATIONALE: Nurse cadet schemes are locally developed initiatives which prepare
      participants for entry to preregistration nurse education. The paper discusses
      the political context in which modern day nurse cadet schemes have developed in
      the British National Health Service and explores the diversity of schemes
      currently operating in the United Kingdom (UK). BACKGROUND: Nursing recruitment
      is a high priority for the National Health Service in the UK which, in common
      with many countries, is facing a nursing shortage. In addition, the government is
      committed to increasing flexibility in the education and recruitment of staff.
      The entry gate to health professional education needs to be widened to improve
      access for hitherto under-represented groups. METHODS: The paper provides a
      critical commentary on key issues in the development of nurse cadet schemes as
      discussed in a range publications, together with information gathered from 'grey'
      literature and personal contacts in nurse education. A wide range of health care
      and social science databases was used to collect material for the discussion.
      FINDINGS: Approximately 800 cadets are currently engaged in around 60 cadet
      schemes in a number of localities in Britain, and it is proposed that these will
      be expanded to over 2000 nurse cadets by 2004. Nurse cadet schemes have developed
      to meet local needs and priorities and, in the absence of a strong national
      framework, a wide diversity of participants, curricula and funding arrangements
      have emerged. CONCLUSIONS: Serious consideration needs to be given to further
      standardization in the structure and funding of schemes to reduce the degree of
      inequality which currently exists for cadets, together with development of
      national benchmarks to ensure that a set of minimum standards is met. Any future
      development must be built on a systematic evaluation of current schemes, which
      has yet to be undertaken.

PMID- 12622870
TI  - Nurse supervisors' actions in relation to their decision-making style and ethical
      approach to clinical supervision.
AB  - AIM: The aim of the study was to explore the decision-making style and ethical
      approach of nurse supervisors by focusing on their priorities and interventions
      in the supervision process. BACKGROUND: Clinical supervision promotes ethical
      awareness and behaviour in the nursing profession. METHODS: A focus group
      comprised of four clinical nurse supervisors with considerable experience was
      studied using qualitative hermeneutic content analysis. FINDINGS: The essence of
      the nurse supervisors' decision-making style is deliberations and priorities. The
      nurse supervisors' willingness, preparedness, knowledge and awareness constitute
      and form their way of creating a relationship. The nurse supervisors' ethical
      approach focused on patient situations and ethical principles. The core
      components of nursing supervision interventions, as demonstrated in supervision
      sessions, are: guilt, reconciliation, integrity, responsibility, conscience and
      challenge. The nurse supervisors' interventions involved sharing knowledge and
      values with the supervisees and recognizing them as nurses and human beings.
      CONCLUSION: Nurse supervisors frequently reflected upon the ethical principle of
      autonomy and the concept and substance of integrity. The nurse supervisors used
      an ethical approach that focused on caring situations in order to enhance the
      provision of patient care. They acted as role models, shared nursing knowledge
      and ethical codes, and focused on patient related situations. This type of
      decision-making can strengthen the supervisees' professional identity. The
      clinical nurse supervisors in the study were experienced and used evaluation
      decisions as their form of clinical decision-making activity. The findings
      underline the need for further research and greater knowledge in order to improve
      the understanding of the ethical approach to supervision.

PMID- 12622872
TI  - Low self-esteem and psychiatric patients: Part II - The relationship between self
      esteem and demographic factors and psychosocial stressors in psychiatric
      patients.
AB  - BACKGROUND: The objective of the present study was to identify the effects and
      relative importance of demographic factors and psychosocial stressors on self
      esteem of psychiatric patients. METHOD: The present study was carried out on a
      consecutive sample of 1,190 individuals attending an open-access psychiatric
      outpatient clinic. Patients were diagnosed according to DSM III-R diagnostic
      criteria following detailed assessments. At screening, patients and controls
      completed two self-esteem questionnaires, the Rosenberg self-esteem scale and the
      Janis and Field Social Adequacy scale. In addition, a large amount of demographic
      and psychosocial data was collected on all patients. RESULTS: Significantly
      increased self-esteem was observed with an increase in age, educational
      achievement and income. Employed patients showed significantly higher self-esteem
      compared to unemployed patients. Female patients had a significantly lower self
      esteem compared to male patients. The self-esteem of psychiatric patients did not
      vary significantly with their marital status. No relationship was detected
      between acute stressors and the self-esteem of psychiatric patients, although
      severe enduring stressors were associated with lower self-esteem in psychiatric
      patients. CONCLUSION: The results of this large study demonstrate that the self
      esteem of adult psychiatric patients is affected by a number of demographic and
      psychosocial factors including age, sex, educational status, income, employment
      status, and enduring psychosocial stressors.

PMID- 12622874
TI  - Use of zinc phosphate cement as a luting agent for Denzir trade mark copings: an
      in vitro study.
AB  - BACKGROUND: The clinical success rate with zinc phosphate cemented Procera crowns
      is high. The objective with this study was to determine whether CADCAM processed
      and zinc phosphate cemented Denzir copings would perform as well as zinc
      phosphate cemented Procera copings when tested in vitro in tension. METHODS:
      Twelve Procera copings and twenty-four Denzir copings were made. After the
      copings had been made, twelve of the Denzir copings were sandblasted on their
      internal surfaces. All copings were then cemented with zinc phosphate cement to
      carbon steel dies and transferred to water or artificial saliva. Two weeks after
      cementation, half of the samples were tested. The remaining samples were tested
      after one year in the storage medium. All tests were done in tension and
      evaluated with an ANOVA. RESULTS: Sandblasted and un-sandblasted Denzir copings
      performed as well as Procera copings. Storage in water or artificial saliva up to
      one year did not decrease the force needed to dislodge any of the coping groups.
      Three copings fractured during testing and one coping developed a crack during
      testing. The three complete fractures occurred in Procera copings, while the
      partly cracked coping was a Denzir coping. CONCLUSION: No significant differences
      existed between the different material groups, and the retentive force increased
      rather than decreased with time. Fewer fractures occurred in Denzir copings,
      explained by the higher fracture toughness of the Denzir material. Based on good
      clinical results with zinc phosphate cemented Procera crowns, we foresee that
      zinc phosphate cement luted Denzir copings are likely to perform well clinically.

PMID- 12622871
TI  - Advances in understanding the regulation of apoptosis and mitosis by peroxisome
      proliferator activated receptors in pre-clinical models: relevance for human
      health and disease.
AB  - Peroxisome proliferator activated receptors (PPARs) are a family of related
      receptors implicated in a diverse array of biological processes. There are 3 main
      isotypes of PPARs known as PPARalpha, PPARbeta and PPARgamma and each is
      organized into domains associated with a function such as ligand binding,
      activation and DNA binding. PPARs are activated by ligands, which can be both
      endogenous such as fatty acids or their derivatives, or synthetic, such as
      peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin
      sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene
      transcription. The different isotypes differ in their expression patterns,
      lending clues on their function. PPARalpha is expressed mainly in liver whereas
      PPARgamma is expressed in fat and in some macrophages. Activation of PPARalpha in
      rodent liver is associated with peroxisome proliferation and with suppression of
      apoptosis and induction of cell proliferation. The mechanism by which activation
      of PPARalpha regulates apoptosis and proliferation is unclear but is likely to
      involve target gene transcription. Similarly, PPARgamma is involved in the
      induction of cell growth arrest occurring during the differentiation process of
      fibroblasts to adipocytes. However, it has been implicated in the regulation of
      cell cycle and cell proliferation in colon cancer models. Less in known
      concerning PPARbeta but it was identified as a downstream target gene for
      APC/beta-catenin/T cell factor-4 tumor suppressor pathway, which is involved in
      the regulation of growth promoting genes such as c-myc and cyclin D1. Marked
      species and tissue differences in the expression of PPARs complicate the
      extrapolation of pre-clinical data to humans. For example, PPARalpha ligands such
      as the hypolipidaemic fibrates have been used extensively in the clinic over the
      past 20 years to treat cardiovascular disease and side effects of clinical
      fibrate use are rare, despite the observation that these compounds are rodent
      carcinogens. Similarly, adverse clinical responses have been seen with PPARgamma
      ligands that were not predicted by pre-clinical models. Here, we consider the
      response to PPAR ligands seen in pre-clinical models of efficacy and safety in
      the context of human health and disease.

PMID- 12622873
TI  - Identifying barriers and tailoring interventions to improve the management of
      urinary tract infections and sore throat: a pragmatic study using qualitative
      methods.
AB  - BACKGROUND: Theories of behaviour change indicate that an analysis of factors
      that facilitate or impede change is helpful when trying to influence professional
      practice. The aim of this study was to identify barriers to implementing evidence
      based guidelines for urinary tract infection and sore throat in general practice
      in Norway, and to tailor interventions to address these barriers. METHODS: We
      used a checklist to identify barriers and possible interventions to address these
      in an iterative process that included a review of the literature, brainstorming,
      focus groups, a pilot study, small group discussions and interviews. RESULTS: We
      identified at least one barrier for each category. Both guidelines recommended
      increased use of telephone consultations and reduced use of laboratory tests, and
      the barriers and the interventions were similar for the two guidelines. The
      complexity of changing routines involving patients, general practitioners and
      general practitioner assistants, loss of income with telephone consultations,
      fear of overlooking serious disease, perceived patient expectations and lack of
      knowledge about the evidence for the guidelines were the most prominent barriers.
      The interventions that were tailored to address these barriers included support
      for change processes in the practices, increasing the fee for telephone
      consultations, patient information leaflets and computer-based decision support
      and reminders. CONCLUSION: A systematic approach using qualitative methods helped
      identify barriers and generate ideas for tailoring interventions to support the
      implementation of guidelines for the management of urinary tract infections and
      sore throat. Lack of resources limited our ability to address all of the barriers
      adequately.

PMID- 12622875
TI  - Atherosclerotic ischemic renal disease. Diagnosis and prevalence in an
      hypertensive and/or uremic elderly population.
AB  - BACKGROUND: Atherosclerotic ischemic renal disease is a frequent cause of end
      stage renal failure leading to dialysis among the elderly; Its prevalence is
      inferred from autopsy or retrospective arteriographic studies. This study has
      been conducted on 269 subjects over 50 with hypertension and/or CRF, unrelated to
      other known causes of renal disease. METHODS: All 269 patients were studied
      either by color-flow duplex sonography (n = 238) or by renal scintigraphy (n =
      224), and 199 of the 269 patients were evaluated using both of these techniques.
      40 patients, found to have renal artery stenosis (RAS), were subjected to 3D
      contrast enhancement Magnetic Resonance Angiography (MRA) and/or Selective
      Angiography (SA). An additional 23 cases, negative both to scintigraphy and to
      ultrasound study, underwent renal angiography (MRA and/or SA). RESULTS: Color
      duplex sonography, carried out in 238 patients, revealed 49 cases of RAS. MR or
      SA was carried out in 35 of these 49 patients, and confirmed the diagnosis in 33.
      Color-duplex sonography showed a PPV value of 94.3% and NPV of 87.0% while renal
      scintigraphy, carried out in 224 patients, had a PPV of 72.2% and a NPV of 29.4%.
      Patients with RAS showed a higher degree of renal insufficiency compared to non
      stenotic patients while there were no differences in proteinuria. RAS, based on
      color-duplex sonography studies, was present in 11% of patients in the age group
      50-59, 18% in the 60-69 and 23% at age 70 and above. CONCLUSIONS: A relatively
      large percentage of the elderly population with renal insufficiency and/or
      hypertension is affected by RAS and is at risk of developing end-stage renal
      failure. Color-duplex ultrasonography is a valid routine method of investigation
      of population at risk for renal artery stenosis.

PMID- 12622877
TI  - Clinical presentation and differential diagnosis of nasolabial cyst.
AB  - Nasolabial cyst is a rare non-odontogenic, soft-tissue, developmental cyst
      occurring inferior to the nasal alar region. The patient usually presents with a
      slowly enlarging asymptomatic swelling, typically without radiographic
      abnormalities. This paper documents the presentation and management of a 46-year
      old woman with a nasolabial cyst. The histopathologic features, differential
      diagnosis, treatment and prognosis are discussed.

PMID- 12622876
TI  - Somatization in response to undiagnosed obsessive compulsive disorder in a
      family.
AB  - BACKGROUND: Somatization is a common problem in primary care and often presents
      puzzling problems for the family physician. A family or contextual approach is
      often useful in investigating and treating refractory symptoms. CASE
      PRESENTATION: A 63 year-old patient presented to his family physician with
      recurrent episodes of syncope, weakness and various other somatic symptoms.
      Lengthy clinical investigations found no organic pathological findings but a
      brief family assessment by the family physician revealed that the patient's wife
      was the "hidden" patient. Successful treatment of the patient's wife led to full
      recovery for both. CONCLUSIONS: Exploration and treatment of the family context
      may often hold the key to the solution of difficult problems in somatizing
      patients.

PMID- 12622878
TI  - Cherubism in siblings: a case report.
AB  - Cherubism is a non-neoplastic bone disease characterized by clinically evident
      bilateral, painless enlargements of the jaws that are said to give the patient a
      cherubic appearance. Cherubism may appear in solitary cases or in many members of
      the same family, often in multiple generations. On radiography, the lesions
      exhibit bilateral multilocular radiolucent areas. Histopathologic evaluation
      reveals proliferating fibrous connective tissue containing numerous
      multinucleated giant cells. Since the first description of this condition in
      1933, almost 200 cases have been reported. We describe cherubism in 2 siblings
      and briefly review the literature on this subject.

PMID- 12622879
TI  - A promising periodontal procedure for the treatment of adjacent gingival
      recession defects.
AB  - Various clinical reports on the reconstruction of gingival recession defects have
      been published in the past decade. Several techniques have been used to achieve
      root coverage, including creation of free gingival grafts, laterally positioned
      flaps or semilunar coronally positioned flaps, as well as guided tissue
      regeneration and connective tissue grafting. This article focuses on the
      importance of connective tissue grafting, combined with a recent approach known
      as the tunnel procedure, in managing gingival recession defects with a single
      operation. This procedure originated in 1985 with an envelope design and a
      subepithelial connective tissue graft for single gingival recession defects and
      is used today for coverage of multiple adjacent gingival recession defects.
      Histological evaluation of such connective tissue grafts demonstrates periodontal
      regeneration in human subjects. Clinical trials have yielded good results,
      including early tissue healing because of increased blood supply, good esthetic
      results, excellent patient cooperation and avoidance of secondary periodontal
      plastic surgery. These benefits underline the appropriateness of this technique,
      which improves the success rate of connective tissue grafting and increases the
      amount of root coverage.

PMID- 12622882
TI  - Mechanism by which IL-16 generated by mast cells mediates allergic inflammation.

PMID- 12622880
TI  - Emergency management of acute apical periodontitis in the permanent dentition: a
      systematic review of the literature.
AB  - OBJECTIVE: To perform a systematic literature review and meta-analysis on the
      effectiveness of interventions used in the emergency management of acute apical
      periodontitis in the permanent dentition. METHODS: Electronic databases were
      searched from their inception to 2001. These searches, combined with manual
      searching, yielded 1,097 citations, of which 92 were relevant. Independent
      application of inclusion criteria by 2 teams of reviewers yielded 15 eligible
      randomized controlled trials. Data on population, interventions, outcomes (pain
      relief or change in intensity of pain as reported by patients or clinicians) and
      methodological quality were determined by independent duplicate review.
      Disagreements were resolved by consensus. RESULTS: Meta-analysis showed that pre
      emptive analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs]) in conjunction
      with pulpectomy provided a significant benefit (weighted mean difference -11.70,
      95% confidence interval -22.84 to -0.56). Three interventions did not show
      significant benefit: systemic antibiotics, intracanal treatment with a steroid
      antibiotic combination, and trephination through attached gingiva. CONCLUSIONS:
      In the management of pain associated with acute apical periodontitis, there is
      strong evidence to support the use of systemic NSAIDs in conjunction with
      nonsurgical endodontics. The use of antibiotics is not recommended.

PMID- 12622881
TI  - Evaluation of proximal contacts of posterior composite restorations with 4
      placement techniques.
AB  - BACKGROUND: Contrary to the situation for amalgam restorations, obtaining
      acceptable proximal contacts with posterior composite restorations can be
      difficult. Proximal contacts that are less than ideal may permit food impaction
      and subsequent caries formation and periodontal problems. PURPOSE: The aim of
      this study was to assess the quality of proximal contacts of posterior composite
      restorations placed with 4 restorative techniques. METHODS: Seventy-five mounted
      ivorine teeth with large, standardized MOD cavities were divided into 5 groups of
      15 teeth each. The teeth in 4 of these groups were restored with a resin
      composite and those in the remaining group were restored with amalgam. The
      restorative techniques for the 4 composite groups were traditional wedge and
      matrix (Group 1), use of a light-tip attachment (Group 2), use of the Contact Pro
      hand instrument (Group 3) and use of Beta Quartz glass-ceramic inserts (Group 4).
      All restorations were completed under simulated clinical conditions. Standards
      for evaluating proximal contacts were set by preparing 4 dental study models,
      each model having one type of proximal contact (open, not tight enough, ideal and
      too tight). All restored teeth were carefully painted with opaque nail polish,
      except at the contact areas, to conceal restoration type and hence to ensure
      unbiased evaluation by assessors. Three experienced clinicians independently
      assessed the quality of the proximal contacts of all restored teeth (total of 150
      contacts) relative to the 4 types of contacts exemplified by the dental study
      models. In cases of disagreement, the clinicians reassessed the disputed contact
      collectively. RESULTS: Amalgam restorations had 5 contacts that were not tight
      enough, 20 that were ideal and 5 that were too tight. The Group 1 composite
      restorations had a total of 25 open contacts and 5 contacts that were not tight
      enough; the Group 2 composite restorations had 3 open contacts, 13 contacts that
      were not tight enough and 14 that were ideal; the Group 3 composite restorations
      had 11 contacts that were not tight enough and 19 that were ideal; and the Group
      4 composite restorations had 3 contacts that were not tight enough and 27 that
      were ideal. None of the composite contacts was judged too tight. CONCLUSIONS: The
      use of inserts (Group 4) resulted in a better rate of acceptable proximal
      contacts in posterior composite restorations than the 3 other techniques (90% vs.
      0%, 47% and 63% for Group 1, Group 2 and Group 3, respectively).

PMID- 12622883
TI  - Effect of TNF-alpha on the induction of apoptosis in murine macrophages: role of
      interleukin-1 beta converting enzyme.
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces apoptosis in
      various cell types via its binding to TNF-receptors (TNF-R). Involvement of ICE
      like protease in the induction of TNF-alpha mediated apoptosis in murine
      macrophage was investigated using ICE inhibitor YVAD-cmk (Tetrapeptide-Acetyl-Try
      Val Ala-Asp-Chloromethyl ketone). Macrophages treated with TNF showed a time
      dependent decrease in cell viability with a simultaneous increase in the percent
      of cells showing apoptotic morphology and an increase in percent DNA
      fragmentation, a quantitative measure of apoptosis. However, incubation of
      macrophage in medium containing TNF and YVAD-cmk had inhibitory effect on the TNF
      induced apoptosis of macrophage. This finding suggests that ICE-like protease may
      be involved in the induction of apoptosis in macrophage by TNF-alpha.

PMID- 12622884
TI  - Chronic fatigue syndrome: circadian rhythm and hypothalamic-pituitary-adrenal
      (HPA) axis impairment.
AB  - Chronic Fatigue Syndrome (CFS) is a clinical condition characterized by a
      persistent or relapsing debilitating fatigue at rest, lasting more than 6 months,
      and made worse by exercise. At the present moment, there are three potential
      etiopathogenic factors: immunologic, viral and neuroendocrine. The purpose of our
      study was to evaluate possible alterations of the hypothalamic-pituitary-adrenal
      (HPA) axis in our CFS patients by studying the circadian rhythms of prolactin
      (PRL), thyrotropic hormone (TSH), adrenocorticotropic hormone (ACTH), and
      cortisol (CS). A total of 36 patients were enrolled according to the Centers for
      Disease Control and Prevention case-definition criteria. Twenty healthy subjects
      were included as controls. Blood samples were taken every 4 hours during a single
      24-hour period. We performed a fluorometric enzyme immunoassay with serum PRL,
      cortisol and TSH, and an immunoradiometric assay with plasma ACTH. The circadian
      rhythms of PRL, TSH, ACTH and CS were statistically significant in both CFS and
      control groups. At 24:00 and 04:00 hrs the CFS patients showed lower ACTH levels
      than healthy subjects (p &#x003C; 0.001); the PRL levels were higher at 04.00 h
      in CFS patients than in healthy subjects.

PMID- 12622885
TI  - Toxocarosis as zoonosis. A review of literature and the prevalence of Toxocara
      canis antibodies in 511 serum samples.
AB  - A total of 511 serum samples from children aged between 6 months to 15 years old,
      with different clinical signs-living in the region of Northern Greece - were
      tested by ELISA (enzyme links immunosorbent assay) technique, for the detection
      of specific IgG and IgM antibodies against T. canis antigen. The reason IgM was
      detected was because IgM levels are elevated in the acute phase of toxocara
      infection, in spite of their notorious non-specificity. In this seroepidemiologic
      survey of children, a remarkably high percentage (12.5&#x0025;) reacted
      positively to this method. Sixteen (3.1&#x0025;) out of 511 sera showed IgG
      antibodies, 43 (8.4&#x0025;) showed IgM, while 5 (1&#x0025;) showed both IgG and
      IgM antibodies against T. canis E/S (excretory - secretory) antigen. Females were
      significantly more infected than males. Seropositivity rate was highest in
      children over the age of 10.

PMID- 12622886
TI  - Angiotensin II: a regulator of inflammation during renal disease?
AB  - It has been recently recognized that besides its vasoactive actions Angiotensin
      II (Ang II) exerts various immunomodulatory effects that may contribute to renal
      injury and to the progression of renal disease. Consistent with this concept, Ang
      II facilitates macrophage recruitment into the kidney either directly or through
      the-upregulation of different chemotactic molecules such as RANTES (Regulated on
      Activation Normal T Expressed and Secreted), monocyte chemoattractant protein-1
      (MCP-1) and osteopontin. Infiltrating macrophages not only produce a number of
      cytokines, growth factors and proinflammatory Mediators, but also synthesize Ang
      II intacellularly which increases tissue levels of the hormone within the kidney.
      Finally, specific binding sites for Ang II have been demonstrated on macrophages
      and increasing evidence indicates that Ang II directly modulates many of the
      cellular functions of these cells during the course of renal disease. Together
      these data suggest that Ang II plays an important role in modulating inflammatory
      responses in the kidney.

PMID- 12622887
TI  - Non insulin-dependent diabetes mellitus (type 2) secondary failure. Metformin
      glibenclamide treatment.
AB  - The goal of sulphonylurea (S) treatment in Non-Insulin-Dependent Diabetes
      Mellitus (NIDDM - type 2 diabetes) subjects should be to obtain a satisfactory
      glycemic control (fasting glycemic levels &#x003C; 140 mg&#x0025;). The loss of
      an adequate blood glucose control after an initial variable period of S is known
      as secondary failure (SF). The number of SF are extremely variable among
      different trials for many reasons, some of which are patient-related: increased
      food intake, weight gain, non-compliance, poor physical activity, stress,
      diseases and&#x00F7;or impaired pancreatic beta cell function, desensitization
      after S chronic therapy, reduced absorption, concomitant therapies. Many
      therapeutic strategies have been proposed to achieve an adequate metabolic
      control in type 2 diabetes patients: switch to intensive insulin therapy and
      subsequent return to S therapy; association with insulin; association with
      sulphonylureas plus biguanides. The association biguanides and S, in particular
      glibenclamide plus metformin, is now widely used by diabetologists in SF since
      glibenclamide improves insulin secretion while metformin exerts its antidiabetic.

PMID- 12622888
TI  - Early detection and treatment of altered growth and puberty in children and
      adolescents with vertically-acquired HIV-1 infection: It's time to think about
      it.

PMID- 12622889
TI  - [Comparison between the severity criteria of the Chinese guidelines for community
      acquired pneumonia and Fine's risk classes].
AB  - OBJECTIVE: To validate the Chinese guidelines for community-acquired pneumonia
      (CAP) in evaluating severe pneumonia and hospitalization criteria for the
      implementation of the Chinese guidelines accordingly. METHODS: The medical
      records of 137 inpatients with CAP in the hospital from September 1, 2001 to
      March 31, 2002 were retrospectively studied and analyzed with SPSS 10.0. Chi
      square test and ANOVA were used to compare severity criteria of the Chinese
      guidelines with Fine's risk classes. Statistical differences in age, duration of
      hospitalization, cost, duration of intravenous therapy, number of risk factors,
      and the mortality of the three subgroups stratified by the severity criteria of
      the Chinese guidelines were also analyzed. RESULTS: (1) The correlation was
      significant between the severity criteria of the Chinese guidelines and Fine's
      risk classes (P < 0.001, Pearson coefficient 0.601); (2) The differences in age,
      duration of hospitalization, cost, duration of intravenous therapy, number of
      risk factors and mortality were statistically significant between patients who
      met the hospitalization criteria and patients who did not base on the severity
      criteria of the Chinese guidelines (P < 0.001). The number of risk factors and
      the mortality in patients with severe pneumonia were significantly higher than
      those in other groups (P < 0.01). CONCLUSIONS: The severity criteria of the
      Chinese CAP guidelines can differentiate patients with different risks. Fine's
      risk classification is useful for evaluating Chinese patients with CAP. The
      current Chinese guidelines for the management of CAP should be implemented.

PMID- 12622890
TI  - [Surveillance of drug resistant tuberculosis in Hubei, China].
AB  - OBJECTIVES: To establish a surveillance system for antituberculous drug
      resistance according to WHO and IUATLD guidelines, to collect the data of initial
      and acquired drug resistance, and to evaluate the efficacy of ongoing
      tuberculosis control strategies. METHODS: Thirty counties (or cities or
      districts) were randomly selected as surveillance points by cluster sampling.
      Thirty new cases of smear positive pulmonary tuberculosis in each cluster were
      enrolled consecutively. Bacterial typing and susceptibility tests (proportion
      method for SM, INH, RFP and EMB) were done in all culture positive samples.
      Laboratory quality control was implemented by Korean Super-country Reference
      Laboratory. Data were analyzed by WHO SDRTB2 software. RESULTS: 1,136 patients
      with pulmonary tuberculosis were enrolled in 30 clusters, among them 1,097 were
      culture positive. Smear-positive culture-positive rate was 96.6% and the
      contamination rate was 0.4%. The total drug resistance rate was 23.3%, the
      initial drug resistance being 17.5% and the acquired drug resistance being 44.5%.
      The initial multi-drug resistance rate (H + R) was 2.1% and the acquired multi
      drug resistance rate (H + R) was 21.8%. CONCLUSIONS: Laboratory methods for
      surveillance of drug resistant tuberculosis and quality control were established,
      and reliable data on the status of antituberculous drug resistance in Hubei
      province were collected. The results showed that implementation of DOTS and
      regular surveillance were very important.

PMID- 12622891
TI  - [The relationship between drug sensitivity and expression of drug resistance gene
      mutations in non-small cell lung cancer].
AB  - OBJECTIVE: To study the relationship between the expression of drug resistance
      genes and the results of drug sensitivity test. METHODS: Surgical or biopsy
      specimens from 48 patients with non-small cell lung cancer (NSCLC) were measured
      for drug sensitivity by Annexin V combined with PI using flow cytometry. The drug
      resistance genes MDR(1), GST-pi and MPR were measured by RT-PCR. The relationship
      between expression of drug resistance gene mutations and the drug sensitivity of
      lung cancer was analyzed. RESULTS: The anti-tumor cytotoxicity of MMC, DDP, VDS,
      NVB, TAX, GEM, VP-16 and VCR were measured, and their respective tumor inhibition
      rates were (10.3 +/- 17.1)%, (20.7 +/- 22.2)%, (5.6 +/- 14.9)%, (7.9 +/- 16.2)%,
      (15.7 +/- 21.8)%, (11.2 +/- 13.8)%, (9.7 +/- 20.1)%, and (4.7 +/- 8.7)%. The
      positive rates of MDR(1), MRP and GST-pi expression were 67% (32/48), 42%
      (20/48), and 48% (23/48) respectively. There was no association between the
      expression of drug resistance genes MRP and GST-pi and the pathology or the stage
      of lung cancer. Interestingly, the over-expression of MRP was related to drug
      resistance to NVB, VDS and MMC; while the over-expression of GST-pi was related
      to resistance to DDP. No relationship was found between MDR(1) over-expression
      and drug resistance. CONCLUSION: The expression of some drug resistance genes is
      related to drug sensitivity test. The detection of the genes may be clinically
      useful in the administration of chemotherapy.

PMID- 12622892
TI  - [The value of specific neuronal anti-Hu antibody in the early diagnosis of small
      cell lung cancer].
AB  - OBJECTIVE: To evaluate the value of specific neuronal anti-Hu antibody in the
      early diagnosis of small cell lung cancer (SCLC). METHODS: Ninety-eight patients
      with SCLC were included in the study. Specific neuronal anti-Hu antibody was
      detected by immunohistochemistry (the ABC method) and Western blot. RESULTS: The
      sera from 40% (32/80) of the patients in group A (without paraneoplastic syndrome
      of the nervous system) reacted with the frozen sections of human cerebra and were
      stained by indirect immunoperoxidase method at final dilutions of 1:1,000 to
      1:8,000, while the sera from 89% of the patients (16/18) in group B (with
      paraneoplastic syndrome of the nervous system) reacted at final dilutions of
      1:1,000 to 1:64,000. Western blot analysis revealed that the specific neuronal
      anti-Hu antibody was identified at several bands of approximately 35,000
      approximately 40,000 with nuclear extracts, and at 40,000 with HuD clonal
      protein. The anti-Hu antibody was detected in only two patients from group A, but
      in 16 patients from group B. The antibody was not detected in sera from 32 normal
      human subjects. CONCLUSIONS: Specific neuronal anti-Hu antibody at high titers
      was detected in patients with SCLC not complicated with paraneoplastic syndrome
      of the nervous system. This antibody may be useful in the early diagnosis of
      SCLC.

PMID- 12622893
TI  - [The establishment of a guinea pig model of inflammatory pleural effusion and the
      effect of batroxobin in the prevention of pleural encapsulation].
AB  - OBJECTIVE: To establish an animal model of inflammatory pleural effusion and to
      investigate the role of batroxobin in preventing encapsulation of pleural
      effusion. METHODS: (1) Forty guinea pigs were divided into two groups: the animal
      model group received injection of 1% carrageenan (0.8 approximately 1.0 ml) in
      the right chest cavity; the control animals received injection of normal saline
      (1 ml). (2) Sixty guinea pigs were injected with 1% carrageenan (0.8
      approximately 1.0 ml) in the right chest cavity, and then divided into a
      treatment group and a control group. Batroxobin (3 BU) was injected into the
      right chest cavity of the animals in the treatment group, while normal saline was
      used in the control group. The animals were killed at different time points.
      RESULTS: In the animal model group, pleural effusion appeared in 24 hours and
      reached maximum amount within 2 approximately 3 days. Neutrophils accumulated in
      the effusion and pleural inflammation intensified at the same time. Fibrosis and
      pleural adhesion appeared by the seventh day, became prominent by the tenth day,
      and encapsulated pleurisy was evident by the fourteenth day. With batroxobin
      treatment, pleural effusion and inflammation attenuated. The fibrinogen (Fbg)
      level decreased, and the levels of tissue plasminogen activator (t-PA) and D
      dimer increased in the effusion. No pleural encapsulation was observed.
      CONCLUSIONS: Carrageenan was successfully used to establish an animal model of
      inflammatory pleural effusion in guinea pigs. Batroxobin was effective in
      reducing inflammation and pleural effusion and in preventing pleural fibrosis and
      encapsulation.

PMID- 12622894
TI  - [Symptom correlation between asthma and gastroesophageal reflux].
AB  - OBJECTIVE: To study the symptom correlation between gastroesophageal reflux (GER)
      and asthma, the significance of 24 hour esophageal pH monitoring in the diagnosis
      of GER and the efficacy of anti-reflux therapy in asthmatics with GER. METHODS:
      Twenty-six patients with asthma, who presented with refractory respiratory
      symptoms despite of regular anti-asthmatic treatment, were enrolled in the study.
      24 hour ambulatory esophageal pH monitoring was performed and symptoms, such as
      cough, chest tightness and pyrosis were recorded. Peak expiratory flow (PEF) was
      performed hourly. GER was defined by DeMeester score > or = 14.72 or SAP (cough
      with reflux) > or = 95%. Patients with diagnosed GER were divided into two
      groups, one of which was given anti-reflux therapy. RESULTS: DeMeester score > or
      = 14.72 was found in 58% (15/26) of the patients. Symptom association probability
      (SAP) with cough > or = 95% was found in 2 patients with a DeMeester score <
      14.72. Taken together, GER was diagnosed in 17 patients. After anti-reflux
      therapy, symptoms such as cough, chest tightness and pyrosis improved
      significantly, and the 24 hour PEF variability decreased significantly as
      compared to that before therapy [(38 +/- 8)% versus (16 +/- 3%, P < 0.05].
      CONCLUSION: The incidence of GER was 58% in this group of moderate to severe
      asthmatic patients. 24 hour esophageal pH monitoring was of great value in
      diagnosing GER in asthmatic patients, and anti-reflux therapy was effective in
      improving symptoms induced by GER in those patients.

PMID- 12622896
TI  - [Loss of heterozygosity on chromosome loci 2, 3, 5, 11, 17, and 18 in aberrant
      crypt foci of human colon].
AB  - OBJECTIVE: To study the genetic basis of aberrant crypt foci (ACF), which serve
      as a very early morphological alteration during the development of carcinogenesis
      by analyzing the loss of heterozygosity (LOH). METHODS: DNA from 35 colorectal
      carcinomas (CRC) and 34 matched ACF were isolated by microdissection. LOH of
      microsatellite loci at 18q12, 18q21, 5q12, 5q21, 3p21, 2p16, 17q21, 17q11 and
      11p13 was detected by means of ABI-SEQUENCER and GeneScan software was applied
      for analysis. RESULTS: The rate of LOH in ACF (41.18%) was less than that in
      carcinoma (68.57%) (P < 0.05). The profile of LOH rates at loci 18q12, 5q12,
      3p21, 17q21, 17q11, 11p13 and 2p16 in ACF was similar to that in carcinoma. The
      LOH frequencies on 18q12, 18q21, 5q12, 5q21, and 3p21 were higher than that on
      17q11 and 11p13. However the rate at 18q21 and 5q21 in ACF was much lower than
      that in the carcinoma (P < 0.05). The co-existing carcinomas displayed more
      polypoid growth pattern and located more at the sigmoid colon and rectum. LOH in
      carcinomas did not correlate with the location, size, type of the carcinoma and
      Duke's stage. CONCLUSIONS: ACF are putative preneoplastic lesions that might
      represent the earliest morphological lesion with the alteration at molecular
      genetic level. Our study provides further genetic evidence in the pathogenesis of
      colorectal carcinomas.

PMID- 12622895
TI  - [Hepatic injury induced by acute lung injury in aging rats].
AB  - OBJECTIVE: To investigate the induction of hepatic function damage by acute lung
      injury (ALI) in aging rats and the effect of Ginkgo Biloba extract (GBE) on this
      process. METHODS: Thirty male Wistar rats were used to produce the aging animal
      model. Aging rats were randomly divided into three groups: the control group, the
      lipopolysaccharide (LPS, intravenous injection) group, and the GBE + LPS group
      (GBE given 7 days before experiment, once a day, via the esophagus). Samples from
      the blood, the lung and the liver were collected 2 and 6 h after LPS or saline
      administration. RESULTS: ALI was induced by intravenous injection of LPS in aging
      rats. Compared with the aging control, the total bilirubin content and the
      glutamic pyruvic transaminase (GPT) activity in serum did not change at 2 h after
      LPS administration. But at 6 h, they were increased, respectively from (10.9 +/-
      0.6) mg/L and (26 +/- 3) U in the control group to (30.1 +/- 2.1) mg/L and (88 +/
      12) U in the LPS group (P < 0.001). MDA content increased in the blood and the
      lung tissue at 2 has compared to the control group, from (15.9 +/- 1.8) micro
      mol/L and (18.8 +/- 2.1) nmol/mg protein to (22.1 +/- 1.9) micro mol/L and (28.8
      +/- 3.1) nmol/mg protein (all P < 0.001), respectively. SOD activity in the lung
      tissue was decreased significantly, from (25.5 +/- 2.6) mU/L and (36.1 +/- 2.4)
      U/mg protein to (20.6 +/- 1.9) mU/L and (32.0 +/- 2.7) U/mg protein, respectively
      (P < 0.05, P < 0.001). The GSH-P(X) activity and the Na(+)-K(+)-ATPase activity
      in the lung tissue at 2 hours after LPS administration were decreased markedly,
      from (28.2 +/- 2.8) U/mg protein and (4.9 +/- 0.5) micromol Pi x mg(-1) protein x
      h(-1). to (21.1 +/- 2.7) U/mg protein and (3.1 +/- 0.3) micromol Pi x mg(-1)
      protein x h(-1). These changes lasted 6 h after LPS administration. These
      parameters did not change significantly in the hepatic tissue at 2 h after LPS
      administration. But after 6 h, MDA content was increased from (7.9 +/- 0.9)
      nmol/mg protein to (10.9 +/- 0.7) nmol/mg protein; while the GSH-P(X) and the
      Na(+)-K(+)-ATPase activities were decreased markedly, from (59.0 +/- 3.9) U/mg
      protein and (0.87 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) to (49.2 +/-
      3.0) U/mg protein and (0.77 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) (P <
      0.001, P < 0.01). There was no obvious change in the SOD activity. All the
      changes were significantly attenuated in the GBE + LPS group (P < 0.05, P <
      0.01). CONCLUSION: Hepatic function damage could be induced by ALI in aging rats.
      GBE showed a protective effect on ALI and hepatic function damage in this animal
      model.

PMID- 12622897
TI  - [The influence of heat-induced epitope retrieval on endogenous avidin-binding
      activity (EABA) and blocking of EABA in immunohistochemistry].
AB  - OBJECTIVE: To study the influence of heat-induced epitope retrieval (HIER) on
      endogenous avidin-binding activity (EABA) and to establish an effective way to
      block EABA in immunohistochemistry. METHODS: Systematically screening EABA in 164
      (679 samples) formalin-fixed and paraffin-embedded human tissues including 76
      (102 samples) normal tissues and 88 (577 samples) tumor tissues as well as 4 (80
      samples) formalin-fixed and paraffin-embedded rat normal tissues using tissue
      array (tissue chip), HIER, immunohistochemistry and egg white solution blocking.
      In addition, EABA was also examined in 9 (15 samples) human frozen tissues.
      RESULTS: (1) EABA was detected in frozen tissues. (2) No staining for EABA was
      seen in formalin-fixed and paraffin-embedded tissues. (3) EABA was revealed after
      the tissues treated with microwave HIER. (4) The density of signal for EABA was
      variable from tissue to tissue and cell to cell. (5) The signals of EABA
      expressed in scatter or diffuse in tissues and in granular form in cytoplasm. (6)
      EABA was found in a wide range of epithelial tissues, especially in gland
      epithelia of normal and tumor tissues. These included kidney, adrenal cortex,
      liver, C cells of thyroid gland, oxyphil cells of parathyroid, fundal gland of
      stomach, sebaceous gland of skin, duct of salivary; oncocytoma and papillary
      adenocarcinoma of kidney and thyroid gland, adenolymphoma of parotid, carcinoma
      of liver cell, adenocarcinoma of stomach, colon, prostate, gall bladder and
      endometrium, and so on. (7) EABA was easier revealed by higher pH value buffer
      (EGTA pH 9.0) than that with lower pH value (EDTA pH 8.0 and citrate pH 6.0). (8)
      The revealed EABA could be effectively blocked using 20% egg white solution.
      CONCLUSIONS: HIER could unmask EABA in formalin-fixed and paraffin-embedded
      tissues. The unmasked EABA present in a wide range of human normal and tumor
      tissues as well as in rat normal tissues. The EABA could influence routine
      immunohistochemistry staining when using (strept)avidin-horseradish peroxidase
      detective system. The egg white solution could effectively block EABA and
      eliminate the influence of EABA on immunohistochemistry.

PMID- 12622898
TI  - [Primitive study of the cell lineage and Epstein-Barr virus infection in so
      called malignant histiocytosis with tissue microarray technique].
AB  - OBJECTIVE: To investigate the cell lineage and Epstein-Barr virus infection in
      previously diagnosed cases of malignant histiocytosis (MH) with tissue microarray
      technique. METHODS: Using tissue-chips, immunohistochemical staining, in situ
      hybridization and PCR to analyze 5 autopsy cases of MH. RESULTS: (1) In all 5
      cases, positive reactions of CD45RO, CD3 epsilon, TIA-1, Granzyme B were detected
      in the neoplastic cells, whereas negative reactions were found with CD30, CD20,
      CD56. (2) All cases revealed EBER1/2 positivity in neoplastic cells. CONCLUSION:
      Previously diagnosed malignant histiocytosis is an EBV-associated aggressive NK/T
      cell lymphoma.

PMID- 12622899
TI  - [Impairment of signal transduction pathway on neuronal survival in brains of
      Alzheimer's disease].
AB  - OBJECTIVES: To explore the mechanisms of neuronal loss and apoptosis in the
      brains of Alzheimer's disease (AD) patients, through studying the expression of
      proteins related to signal transduction pathways, which are important for neuron
      survival. METHODS: (1) Immunohistochemistry: Sections were double stained with
      Tunel and NSE antibodies. (2) The hippocampal tissue taken from 6 cases of AD and
      6 cases of non-AD brains was homogenized. Protein estimation was done by Lowry
      method. Equal amounts of protein were taken from each specimen and
      immunoprecipitation was performed and analyzed by Western blot; color development
      was done by alkaline phosphatase method or luminol reagent. RESULTS: (1) Tunel
      positive neurons were found in both AD and non-AD brains, but the number in the
      former was more than the latter. (2) The AD hippocampal tissue showed diminished
      expression of Akt/PKB, CREB, P-CREB, increased expression of apoptosis-related
      protein apoptosis-inducing factor, and diminished expression of apoptosis-related
      protein bcl-2. The expression of bax did not change. CONCLUSIONS: Diminished
      expression of CREB, P-CREB, bcl-2 in AD hippocampus indicates that the neuron
      survival signal transduction pathway in AD brains is impaired. Neurons are in
      apoptotic or pro-apoptotic state. In addition, increased expression of apoptosis
      inducing factor, diminished expression of bcl-2, which is an anti-apoptotic
      factor, promotes further neuron apoptosis.

PMID- 12622901
TI  - [The nature of calcifying odontogenic cysts of the jaws].
AB  - OBJECTIVE: To clarify the clinicopathological and behavioral spectrum of the so
      called calcifying odontogenic cysts (COC). METHODS: Retrospective analysis of 21
      cases previously diagnosed as COC was undertaken to evaluate their clinical,
      radiographic, pathological and behavioral features. RESULTS: The lesions of this
      series were divided into three groups, including simple cysts, benign and
      malignant tumors. The cyst group was composed of 16 cases (9 men, 7 women). The
      age of the patients peaked at the second decade, with a predilection for the
      premolar region of the jaws. The clinicopathological features of this group were
      consistent with that of developmental odontogenic cysts. Follow-up of the 13
      patients treated by enucleation revealed no recurrence. The benign tumor group
      consisted of 4 cases with variable clinicopathologic features. Two cases were
      solid tumors containing ameloblastomatous epithelium, ghost cells and
      calcification foci. The other two cases had lesions that contained typical areas
      of COC and other types of odontogenic tumors (1 ameloblastoma and 1 odontogenic
      fibromyxoma). All the 4 cases occurred in the mandible with a relative large
      size. Two of which had a history of multiple recurrences. Only one case was
      identified as malignant tumor based on its infiltrative growth pattern and
      histological features. CONCLUSIONS: The so-called COC, previously recognized as a
      pathologic entity, can show extreme diversity in its clinical and
      histopathological features as well as in its biological behavior. Thus, the
      subgroups as simple cyst, benign and malignant tumors should be clarified and
      treated accordingly. Their terminology and classification should be reconsidered.

PMID- 12622900
TI  - [Expression of glutathione S-transferase, P-glycoprotein, and multidrug
      resistance-associated protein in neuroblastoma and its clinical significance].
AB  - OBJECTIVE: To detect expression of p-glycoprotein (P-gp), multidrug resistance
      associated protein (MRP), and glutathione S-transferase (GST-pi), and to evaluate
      its clinical significance in neuroblastoma (NB). METHODS: SP immunohistochemical
      technique was used to investigate expression of P-gp, MRP, and GST-pi in 70 cases
      of NB. RESULTS: The frequency of expression of P-gp, MRP, and GST-pi was 61.4%,
      38.6%, and 51.4%, respectively. The coexpression rate of P-gp and MRP, P-gp and
      GST-pi, MRP and GST-pi, P-gp, MRP and GST-pi was 32.9%, 35.7%, 27.1%, and 24.3%,
      respectively. Significant positive correlation was observed between P-gp and MRP
      expression (P = 0.001), and between MRP and GST-pi expression (P = 0.012), but no
      correlation was found between P-gp and GST-pi expression. The expression of P-gp
      and MRP was higher in tumors from patients over 1 year old compared with those
      less than 1 year old at diagnosis (P = 0.01, 0.018, respectively). MRP expression
      was higher in tumors from the metastatic than the non metastatic groups (P =
      0.015). All tested proteins showed significant relationship to the
      differentiation of the tumor (P = 0.006, 0.000, 0.019, respectively), but no
      correlation was found to the stage of NB or sex of the patients. MRP expression
      was significantly related to the reduction of both median survival time and the
      two-year cumulative survival (P = 0.02). In contrast, P-gp and GST-pi expression
      had no correlation with survival. CONCLUSIONS: The intrinsic multidrug resistance
      of NB involves the combined effects of P-gp, MRP, and GST-pi. MRP expression may
      be an important parameter in predicting the prognosis of patients with NB.

PMID- 12622902
TI  - [Pathologic diagnosis and histogenesis of primary signet ring cell carcinoma of
      the prostate].
AB  - OBJECTIVE: To study the histogenesis, pathologic features and differential
      diagnosis of prostatic primary signet ring cell carcinoma. METHODS: 10 cases of
      the primary signet ring cell carcinoma were detected from 262 cases of prostate
      carcinomas diagnosed on needle biopsy were investigated by routine pathological,
      immunohistochemical and histochemical methods, and then compared with 10 cases of
      signet ring cell carcinomas of the stomach and colon. 3 cases were studied with
      electron microscopy. RESULTS: 9 cases of prostate signet ring cell carcinoma were
      associated with concurrent high-grade conventional prostatic carcinoma, but at
      least 25% of the neoplasm consisted of signet ring cells. Only one case was pure
      signet ring cell carcinoma. Neoplastic signet ring cells may be divided into two
      types: the first type showed formation of intracytoplasmic lumina or vacuole, and
      the second type had intracytoplasmic accumulation of excess PSA and/or PAP. Both
      types of signet ring cells were negative for mucin staining (AB/PAS and
      mucicarmine). Therefore they differed from signet ring cell carcinomas of the
      stomach and colon. CONCLUSIONS: Primary prostate signet ring cell carcinoma is a
      low-differentiated adenocarcinoma of a special histologic type, which arises from
      the epithelial cells of the prostate acinus. They can be distinguished from
      metastatic signet ring cell carcinoma of the stomach and colon and also from
      vacuolate degeneration of conventional carcinoma after endocrine or radiation
      therapy.

PMID- 12622903
TI  - [Research on the relationship between pathological features of the uveal melanoma
      and prognosis].
AB  - OBJECTIVE: To study the pathological features of uveal melanoma and to evaluate
      their influence on patients' prognosis. METHODS: Paraffin embedded uveal melanoma
      tissues of 115 cases were examined using routine pathologic methods. Three
      histological types were classified according to the modified Callender system and
      patients were followed clinically. The data were done regression and survival
      analysis by SPSS statistic soft. RESULTS: The patient with epithelial cell type,
      mixed type, and spindle cell type uveal melanoma have different life times, the
      average life time is 35.6 +/- 21.5 months, 63.7 +/- 37.0 months, 69.5 +/- 36.5
      months in turn, patients with epithelial uveal melanoma had shorter survival time
      than other two types. The survival time was negatively related to the largest
      diameter of contact area with the sclera, the largest height and the depth of
      tumor invasion to the sclera. CONCLUSIONS: Epithelial uveal melanoma is more
      malignant than the other two types. Histological classification of this tumor
      combined with other pathologic features can indicate the patient's prognosis.

PMID- 12622904
TI  - [Pseudomyxoma peritonei: report of 11 cases with a literature review].
AB  - OBJECTIVE: The clinicopathologic and immunohistochemical features of 11
      pseudomyxoma peritonei (PMP) cases were studied to determine pathologic
      diagnosis, site of origin and prognosis. METHODS: Clinical files of 11 cases of
      PMP were reviewed with follow up. The changes in mucinous tumors of peritoneum
      and primary tumors under microscope and immunostaining were reviewed. RESULTS:
      Eleven cases (8 women, 3 men) are reported. The patients age ranged from 36 to 76
      (average 56). One died 2 years after operation, and one case was lost. The
      remaining 8 cases were alive 1 to 60 months postoperatively. Of the 11 cases, 8
      cases had appendiceal mucinous neoplasm of the 11 cases, and 5 women had
      synchronous ovarian mucinous tumors; colon mucinous adenocarcinoma was present in
      one case with synchronous ovarian mucinous tumor; simple ovarian mucinous tumors
      were present in two cases. Immunostainings were consistent on mucinous tumors of
      appendix, ovary and peritoneum in the same case. CONCLUSIONS: To diagnose the
      PMP, the type of tumor should be considered whether it is benign, low malignant
      or malignant. The appendix neoplasm is closely related to PMP. The prognosis
      depends greatly on the growth speed of the mucinous neoplasm.

PMID- 12622905
TI  - [Primary breast lymphoma: a clinical, pathological and immunophenotypic study of
      eight cases].
AB  - OBJECTIVE: To study the clinical, pathological and immunophenotypic
      characteristics of the primary breast lymphoma (PBL). METHODS: Analyses of
      clinical history, preoperative findings, histological and immunohistochemical
      features of eight patients with PBL were performed. RESULTS: Malignant lymphoma
      was difficult to diagnose preoperatively. All patients were women. The age range
      was from 34 approximately 65 years (mean 46.4 years). The right breast was
      involved initially in three patients, the left in four. One patient presented
      bilateral involvement. Seven patients were assessed at stage IE, one with
      ipsolateral axillary lymph nodes involvement at stage IIE. According to the WHO
      classification, five patients were diagnosed as diffuse large B-cell lymphoma
      (4/5 centroblast, 1/5 immunoblast); the other three patients as MALT lymphoma,
      all with lymphoepithelial lesions. The paraffin-embedded tissues of all cases
      showed immunoreactivity for B-cell markers CD20, CD45RA. CD5 and CD10 were
      negative in all cases. Follow-up data were obtained in six patients, none
      recurred or died within 8 to 108 months after diagnosis. CONCLUSIONS: This study
      indicates that most PBL are diffuse large B-cell lymphoma and MALT lymphoma and
      have a better prognosis after comprehensive therapy.

PMID- 12622906
TI  - [Timeliness of 5,979 surgical pathology reports].
AB  - OBJECTIVE: To analyze the influence of prelaboratory and intralaboratory factors
      on the turnaround time of the reports in order to develop a reference database
      for continuous quality improvement, a retrospective study of the timeliness was
      reported. METHODS: Using cluster sampling of a total of 5,979 pathology reports
      selected by sampling a single month's reports from each quarter of the year 2000,
      of which there were 5,250 cases from routine biopsy and 729 cases from operative
      specimen. The timeliness and the factors that influence the turnaround time of
      the two types of surgical pathology reports were analyzed. RESULTS: 4,872
      pathology reports of 5,250 routine biopsy cases were completed in 3 working days,
      and 613 of 729 cases of the operative specimens were completed in 4 working days.
      The percentage was 92.8% and 84.1% respectively. Factors that significantly
      contributed to the increase in turnover time of biopsy reports included request
      of immunohistochemical staining, delayed arrival of the operative specimen at the
      laboratory after frozen section, additional recutting, intradepartment
      consultation and decalcification etc. As for the operative cases, several factors
      were associated with delayed report: second day arrival of the operative specimen
      at the laboratory after frozen section, lack of the adequate clinical history,
      request for immunohistochemical staining etc. CONCLUSIONS: The majority of
      surgical pathology reports in the department can be completed timely and the
      timeliness meets the general standard. Only about 10 percent of the reports were
      delayed because of some prelaboratory and intralaboratory factors, for which
      there were 33.5% and 66.5% respectively for routine biopsy, and 50.9% and 49.1%
      respectively for operative specimen.

PMID- 12622907
TI  - [The effect of transmembrane- and secreted-tumor necrosis factor-alpha on shock
      liver].
AB  - OBJECTIVE: To observe the dynamic expression of transmembrane (TM)-tumor necrosis
      factor (TNF)-alpha and secreted (S)-TNF-alpha in the development of endotoxic
      shock and explore the actions and mechanism of TM-TNF-alpha in liver of the rat
      with endotoxic shock. METHODS: Endotoxic shock in rats was induced by intravenous
      injection of dead gram negative bacteria E. Coli; the kinetics of TM-TNF-alpha on
      peritoneal macrophages and S-TNF-alpha in serum of these rats were determined.
      Pretreatment with TNF alpha converting enzyme antisense oligonucleotide (5 mg/kg)
      30 minutes before rats were administrated dead bacteria inhibited enzymatic
      cleavage of TM-TNF-alpha into S-TNF-alpha. Six hours after bacteria injection, TM
      TNF-alpha and S-TNF-alpha were also detected respectively. The pathological
      injury in the livers of rats with endotoxin shock was examined, and artery
      pressure was constantly measured. RESULTS: The kinetics of TM-TNF-alpha
      expression in the development of endotoxic shock was different from that of S-TNF
      alpha expression in serum. The expression of TM-TNF-alpha began to increase on
      the surface of peritoneal macrophages and liver within 30 min, after bacteria
      challenge and peaking within a period of 4.5 hours followed by a gradual decrease
      to a relatively high level which was maintained for at least 24 hours. The TACE
      antisense oligonucleotide pretreated rats showed remarkable increase in TM-TNF
      alpha expression by peritoneal macrophages and liver (P < 0.001), and their
      arterial blood pressure were maintained within normal levels and there were no
      detectable pathological changes in their livers. CONCLUSIONS: These findings
      suggested that TM-TNF-alpha may be a potent endogenous regulator involved in anti
      inflammatory responses to maintain normal arterial pressure and protect liver
      tissue from pathological injury in during endotoxin shock. This study confirmed
      the important role of TNF-alpha in endotoxic shock which is not only of important
      theoretical significance, but also of practical interest in providing
      experimental basis for clinical treatment of endotoxin shock.

PMID- 12622908
TI  - [Study on the relationship between human leucocyte antigen and parents' antigen
      sharing rate and the incidence of pregnancy induced hypertension].
AB  - OBJECTIVE: To study the relationship between human leucocyte antigen (HLA),
      parents' sharing rate and the incidence of pregnancy induced hypertension (PIH),
      and investigate its immunopathogenetic roles to severe PIH. METHODS: Newborn's
      and their parents' peripheral blood DNA was extracted and HLA phenotypes were
      studied by sequence-specific primers polymerase chain reaction (SSP-PCR) in 57
      with PIH and 46 normal pregnancy. RESULTS: The frequency of DRB1 * 0306, DRB1 *
      0405, DRB1 * 0315, DRB1 * 0403, DRB1 * 1304, QB1 * 03032/33, DQB1 * 0502 in women
      with PIH was increased significantly and the frequency of DRB1 * 0407, DRB1 *
      0317, DQB1 * 05031 were lower than controls. And the risk to PIH of women with
      DRB1 * 0306, DRB1 * 0405, DQB1 * 0502 were higher than others (RR: 9.76, 6.34,
      4.20), and its gene-frequency was higher than controls (P < 0.01). Frequency of
      DQB1 * 0502, DRB1 * 0405 in PIH's newborns were higher than controls (P < 0.05),
      but DRB1 * 1304, DQB1 * 05031 were lower than controls, with significant
      difference (P < 0.05); The gene-frequency of fathers of the two groups weren't
      different. The HLA sharing rate of mothers or fathers of the two groups weren't
      different. But that of mother-fetus was higher in PIH than controls. Two locus
      alleles of PIH group constructed haplotype, and the DRB1 * 0315-DQB1 * 0502, DRB1
      * 0405-DQB1 * 06012 antibody was positive with hypertension and protenuria (P <
      0.05). CONCLUSION: PIH is associated with HLA, and the over expression of HLA
      genes was a severe cause of PIH.

PMID- 12622909
TI  - [Comparison study on transvaginal ultrasonographic measurement and cytokine in
      prediction of the cervical ripening and the onset time of term labor].
AB  - OBJECTIVE: To compare the level of interleukin-6 (IL-6), interleukin-8 (IL-8),
      human chorionic gonadotropin (hCG) with transvaginal ultrasonographic measurement
      in prediction of the cervix ripening and the time of term labor. METHODS: The 79
      cases of primiparous women of term pregnancy were chosen as the research
      subjects. The maternal level of IL-6, IL-8, hCG in cervicovaginal secretions were
      measured. The cervical length, internal cervical os wedge width and forebag
      length were measured by transvaginal ultrasonography. The cervical Bishop score
      was also determined. RESULTS: (1) The levels of IL-6, IL-8, hCG in cervicovaginal
      secretions were significantly higher in women they are in labor than that of
      women at term not in labor (782 +/- 508) ng/L, (10,539 +/- 8 680) ng/L, (114 +/-
      86) IU/L, versus (155 +/- 75) ng/L, (7,113 +/- 6 050) ng/L, (35 +/- 21) IU/L,
      respectively. (2) The levels of cervicovaginal secretions IL-6, IL-8, hCG and the
      length of cervical, forebag were significant correlation with the cervical Bishop
      score (P < 0.05, r = 0.42, 0.24, 0.44, -0.56, 0.35) respectively. (3) The levels
      of cervicovaginal secretions IL-6, IL-8, the length of cervical, forebag measured
      by transvaginal ultrasonography and the cervical Bishop score were significant
      correlation to the onset time of term labor (P < 0.01, r = -0.42, -0.46, 0.64, 
      0.52, -0.41) respectively, and all these markers also could predict the onset of
      term labor in < or = 7 days, The predictive value on onset labor within < or = 7
      days by cervical length < or = 30 mm: the sensitivity, specificity, positive
      values and negative value are 0.83, 0.89, 0.91 and 0.81 respectively. (4) Among
      the several markers in predicting cervix ripening and onset of labor, the best
      one was the transvaginal ultrasonographic measurement of cervical length.
      CONCLUSIONS: The levels of cervicovaginal secretions IL-6, IL-8, the length of
      cervical and forebag measured by transvaginal ultrasonography and the Bishop
      score are valuable in prediction of cervix ripening and onset of labor. The
      cervical length measured by transvaginal ultrasonography is the best one.

PMID- 12622910
TI  - [Study on the outcome of pregnancy after transcervical resection of endometrium].
AB  - OBJECTIVE: To evaluate the outcome and management of pregnancy after
      transcervical resection of endometrium (TCRE). METHOD: Retrospective study on the
      pregnant complication and outcome after TCRE of 26 patients (32 pregnancies).
      RESULTS: There were two case of spontaneous abortion, in which one case of
      cervical pregnancy combined with huge bleeding when the gestational sac was
      extracted. There were 27 cases of artificial abortion. Among them one case of
      intrauterine adhesion and narrow which was resected by resectoscope and
      gestational sac was aspirated completely. One case encountered profuse bleeding
      about 700 ml just after aspiration ended which was irresponsible to general
      treatment. Finally the bleeding was stopped by pressure from intrauterine
      balloon. One case pregnancy on the right uterine corner, which was treated by
      subtotal hysterectomy because of the suctioned abortion failed. There are two
      cases of fallopian tube pregnancy. One case of term pregnancy and placenta
      increta, a low birth weight girl was born by cesarean section and subtotal
      hysterectomy was performed simultaneously. CONCLUSIONS: Pregnancy is possible
      after TCRE and which can complicate with difficulties of abortion, abnormal
      insertion of placenta, fetal growth restriction and abnormal third labor course
      etc. Therefore pregnancies after TCRE are high-risk, which have to be monitored
      intensively and treated appropriately.

PMID- 12622911
TI  - [Detect maternal serum fetal DNA for prenatal diagnosis].
AB  - OBJECTIVE: To detect maternal serum fetal DNA for prenatal diagnosis of fetal
      sex. METHODS: Five to ten ml maternal serum was obtained from 24 pregnant women
      with 16 male fetuses and 8 female fetuses (including 4 carriers with X-linked
      diseases). The fetal sex was detected by analyzing the karyotype from amniotic
      fluid and villus. Serum DNA was extracted, nested polymerase chain reaction was
      employed the male fetal DNA. RESULTS: The sensitivity of the first polymerase
      chain reaction was 62.5%. The sensitivity of the first and the second reaction
      was 100%. There was no false positive. Fetal sex of 4 X-linked disease carriers
      was diagnosed. The determinate rate was 100%. CONCLUSION: Using fetal DNA from
      maternal serum and nested polymerase chain reaction was a quick, simple and
      accurate method for prenatal diagnosis of the fetal sex.

PMID- 12622912
TI  - [Study on the relationship between endogenous opioid peptides and fetal
      distress].
AB  - OBJECTIVE: To evaluate the role of endogenous opioid peptides (EOP) in the fetal
      distress. METHODS: Forty three patients with fetal distress (fetal distress
      group) and 40 healthy pregnant women (control group) in their third trimester
      were studied. The concentrations of plasma EOP (beta-endorphin, dorphin A(1 - 13)
      and leu-enkephalin) were measured by radioimmunoassay. Umbilical artery pH, PO(2)
      and PCO(2) were also measured. RESULTS: The levels of umbilical artery plasma EOP
      (beta-endorphin, dorphin A(1 - 13) and leu-enkephalin) in fetal distress group
      were (453 +/- 68) ng/L, (242 +/- 33) ng/L, and (498 +/- 68) ng/L, respectively.
      In control group, the levels of EOP were (251 +/- 39) ng/L, (103 +/- 22) ng/L,
      and (322 +/- 40) ng/L, respectively. The levels of umbilical artery plasma EOP
      (beta-endorphin, dorphin A(1 - 13) and leu-enkephalin) in fetal distress group
      were significantly higher than that in the control group (P < 0.01,P < 0.05). The
      umbilical artery blood gas analysis: pH was (7.0 +/- 0.1), PO(2) was (1.7 +/-
      0.6) kPa, PCO(2) was (8.9 +/- 0.7) kPa; the levels of beta-endorphin and dorphin
      A(1 - 13) were negatively correlated to pH and PO(2) in umbilical artery plasma
      (P < 0.01; P < 0.05), significant correlation was found between the EOP and
      PCO(2) (P < 0.05). In fetal distress group, the levels of maternal plasma EOP
      were (40 +/- 13) ng/L, (64 +/- 16) ng/L and (219 +/- 40) ng/L respectively. In
      control group, the levels were (37 +/- 9) ng/L, (59 +/- 15) ng/L and (199 +/- 37)
      ng/L respectively. There was no statistical difference in the levels of maternal
      plasma EOP between the control group and fetal distress group (P > 0.05).
      CONCLUSIONS: The fetal distress was associated with EOP, the changes of EOP
      levels in umbilical artery plasma may play an important role in the
      pathophysiological changes in fetal distress.

PMID- 12622913
TI  - [Role of placental apoptosis in fetal growth restriction].
AB  - OBJECTIVE: To determine the relationship of placental cellular apoptosis and
      pathophysiology of fetal growth restriction (FGR). METHODS: Placental samples
      were obtained from 18 pregnancies complicated by FGR and 14 normal pregnancies.
      Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end
      labeling (TUNEL) and transmission electron microscopy were used to confirm the
      occurrence of apoptosis. RESULTS: In FGR group the placental apoptosis rate was
      (n = 18) 12.1 per thousand, the average placental weight was (236 +/- 24) g, the
      average birth weight was (2,071 +/- 428) g; In normal group (n = 14), the
      placental apoptosis rate was 7.3 per thousand, the average placental weight was
      (354 +/- 63) g, the average birth weight was (3,411 +/- 588) g (P < 0.05). The
      incidence of apoptosis was significantly higher in placental samples from
      pregnancies with FGR compared with normal placental samples (P < 0.05). Under
      transmission election microscopy, apoptosis was obviously compact and the
      chromatins were formed as mass. CONCLUSION: These results suggest that apoptosis
      may play a role in the pathophysiologic mechanisms of FGR.

PMID- 12622914
TI  - [Relationship between trophoblast cell's human leukocyte antigen G expression and
      early embryo development].
AB  - OBJECTIVE: To study the expression of soluble human leukocyte antigen G (sHLA-G)
      in trophoblast cells of spontaneous abortion after in vitro fertilization and
      embryo transfer (IVF-ET) and choriocarcinoma, and explore the relationship
      between sHLA-G expression in trophoblast cells and the early embryo development.
      METHODS: 14 cases of trophoblast cells of spontaneous abortion after IVF-ET and 6
      cases of choriocarcinoma tissue has been detected, and which were compared with
      the 10 cases of trophoblast cells of normal villus. RESULTS: (1) One case (1/14)
      has positive sHLA-G expression in IVF-ET group, and other cases in this group are
      negative or faint sHLA-G expression; ALL cases in choriocarcinoma group are
      strong positive sHLA-G expression; All cases in normal villous group are positive
      sHLA-G expression. (2) sHLA-G is expressed on the cytotrophoblast cells,
      especially on the extravillus cytotrophablast. The expression level of HLA-G is
      obviously decreased in the spontaneous abortion group compared with normal group.
      For single cells, the staining on the choriocarinoma cells are stronger than that
      of the normal villus cells. CONCLUSION: High expression of sHLA-G in
      choriocarcinoma trophoblast cells and in trophoblast cells of normal villus and
      low expression in spontaneous abortion trophoblast cells indicating sHLA-G in
      trophoblast cells has some relationship with the early embryo development.

PMID- 12622915
TI  - [Changes of plasma serotonin precursor metabolite concentrations in
      postmenopausal women with hot flushes].
AB  - OBJECTIVE: To investigate the relationship between changes of serotonin
      metabolism and hot flushes in climacteric women. METHODS: Ninety seven
      climacteric women, aged 40 - 60 were enrolled and divided into 4 groups, group A:
      early menopausal transition 20 cases, group B: late menopausal transition, 26
      cases with skip of periods 3 - 12 months, group C: early postmenopause (1 - 3
      years) 28 cases, group D: late postmenopause (> 3 - 6 years) 24 cases. Twelve
      normal women of reproductive age were served as young controls. Fifty two
      postmenopausal women were subdivided into 3 groups according to presence or
      absence of hot flushes. (1) postmenopausal controls without hot flush, 17 cases,
      (2) mild hot flushes group fewer < or = 5 times/day. (3) severe hot flushes group
      more than 5 times/day. Plasma concentrations of tryptophan (TP), 5
      hydroxytryptophane (5-HTP), 5-hydroxytryptamine (5-HT or serotonin) and 5
      hydroxyindoleacetic acid (5-HIAA) were measured in all participants by high
      pressure liquid chromatography-fluorescence spectrophotometer. Plasma level
      luteinizing hormone (LH) was measured in postmenopausal women by radioimmuno
      assay. The relationship between serotonin metabolic parameters and menopause, hot
      flushes and LH level were analysed. RESULTS: (1) Mean 5-HT and 5-HIAA
      concentrations in plasma were significantly higher in climacteric women than
      those in young controls, especially in the group B. Mean 5-HTP and 5-HT levels
      were higher and 5-HIAA lower in group D as compared with those of young controls.
      (2) Plasma 5-HT levels was positively correlated to luteinizing hormone
      concentration in postmenopausal women (P < 0.001). (3) In the mild hot flushes
      group, only plasma 5-HTP levels was significantly higher than that in the
      postmenopausal control group. In severe hot flushes group, plasma 5-HT and 5-HTP
      contents were significantly higher and 5-HIAA/5-HT ratio lower than those in the
      postmenopausal control groups. CONCLUSION: Our results suggest that the catabolic
      disorder of serotonin may involve in the underlying mechanism of hot flushes in
      postmenopausal women.

PMID- 12622917
TI  - [Transitional cell carcinoma of the ovary: one kind of uncommon type of ovarian
      epithelial carcinoma].
AB  - OBJECTIVE: To evaluated clinico-biologic behavior, prognosis and relative
      prognostic factors of transitional cell carcinoma of the ovary. METHODS: The
      clinical records of 58 patients with transitional cell carcinoma of the ovary,
      who received treatment in the department of Obstetrics and Gynecology, Peking
      Union Medical College Hospital in 20 years, were reviewed retrospectively. The
      data were analyzed statistically by SPSS 10.0. RESULTS: Among 58 cases, the
      median age was 55 +/- 10 (35 - 75) years old. 31% of them had bilateral ovary
      involvement, and the median level of CA(125) was (687 +/- 365) U/L. All patients
      received cytoreductive surgery in our hospital, 69% of them got optimal
      cytoreduction. Pathologic results showed that G(1), G(2), G(3) were 7%, 45% and
      48% respectively, 40% were demonstrated lymph node metastasis. Nearly 80% of
      patients were classified to International Federation of Gynecology and Obstetrics
      (FIGO) stage III and IV. Different courses of chemotherapy were given to all
      patients. The recurrence occurred in 45% of cases and the death rate was 53%. The
      Cox hazards regression model was used to analyze the possible prognostic factors
      and revealed that tumor residuals (P < 0.01), preoperative level of CA(125) (P <
      0.01), bilateral ovary involvement (P < 0.05) and lymph node metastasis (P <
      0.05) were the most important prognostic factors. CONCLUSIONS: Transitional cell
      carcinoma of ovary is an uncommon type of ovarian cancer. It usually behaves
      better prognosis when compared with papillary serous cystadenocarcinoma of the
      ovary.

PMID- 12622916
TI  - [Expression of vascular endothelial growth factor and its receptors, flt-1 and
      kinase insert domain-containing receptor in normal human endometrium during
      menstrual cycle].
AB  - OBJECTIVE: To detect the expression of the vascular endothelial growth factor
      (VEGF) and its receptors, the fms-like tyrosine (flt-1), kinase insert domain
      containing receptor (KDR) in normal human endometrium during menstrual cycle and
      investigate the functions of VEGF and its receptors for development and
      differentiation of human endometrium. METHODS: Immunohistochemistry and in situ
      hybridization techniques were used to measure the level of VEGF, flt-1 and KDR
      protein and mRNA in normal endometrium from 50 women. Few samples of endometrium
      respectively in the proliferative and secretory phase were homogenized for
      Western Blot analysis of VEGF subtypes. The blood vessel density was estimated by
      counting staining with a endothelial marker VIII factor. RESULTS: The VEGF and
      its receptors mainly expressed in endometrial endothelial cells and gland
      epithelium. The level of VEGF, protein and mRNA, as well as flt-1 in mid
      secretory and menstrual phase were highest (P < 0.05). The expression in early
      proliferative phase was lowest. KDR was with more intense expression from mid
      proliferative phase to westrual phase. The acreage of the blood vessel wall and
      cavity was larger in the secretory than that in proliferative phase (P < 0.05),
      but those number of the blood vessels didn't alter through the menstrual cycle (P
      > 0.05). Western Blot analysis showed stained VEGF bands in 34,000 (VEGF(121)),
      46,000 (VEGF(165)), 54,000 (VEGF(189)), 68,000 (VEGF(206)), predominantly in
      34,000 and 46,000. CONCLUSIONS: VEGF, flt-1 and KDR, including both protein and
      mRNA, showed a pronounced menstrual cycle-dependent expression in cycling
      endometrium. VEGF and its receptors expressing higher in secretory phase and
      menstruation probably be involved in embryonic implantation and endometrial
      shedding.

PMID- 12622918
TI  - [Umbilical metastasis from malignant neoplasms of pelvic and abdominal cavity
      with 3 cases analysis].
AB  - OBJECTIVE: To study the incidence, spreading path, prognosis and treatment of the
      umbilical metastasis Sister Mary Joseph nodule (SMJN) from malignancies. METHODS:
      To analyse the clinical feature from 3 cases of SMJN and to review pertinent
      literatures. RESULTS: Three cases SMJN were come from advanced primary peritoneal
      carcinoma in case 1, recurrent mucinous ovarian papillary adenocarcinoma in case
      2 after primary cytoreductive surgery and systemic chemotherapy and case 3 with
      recurrent endometrial carcinoma. All patients received umbilical resection and
      the umbilical metastasis was confirmed pathologically, while case 3 was diagnosed
      adenocarcinoma spreading by fine needle respiration before the surgery. The mean
      survival was 63 months following surgery or chemotherapy or radiotherapy, case 1
      died of advanced malignancy, while case 2 and case 3 were still alive 58 and 44
      months, respectively. CONCLUSIONS: Although the incidence being low, SMJN was the
      important sign of one of the vast metastatic malignancy and has grave prognosis.
      Umbilical resection should be performed on some patients of SMJN with relative
      good condition, and chemotherapy or radiotherapy should also performed
      accordingly.

PMID- 12622919
TI  - Experimental studies on the treatment and pathological basis of combined
      radiation and burn injury.
AB  - OBJECTIVE: To investigate therapeutics for and the pathological basis of combined
      radiation and burn injuries. METHODS: Combined radiation and burn injuries on
      mice and rats were inflicted by gamma ray irradiation from a (60)Co source and
      thermal radiation from a 5 kW bromotungsten lamp. RESULTS: The dysfunction of
      myocardium played an important role in the development of early stage shock.
      Transfusion of irradiated (in vitro, 20 Gy) or stored (4 degrees C, 7 days) blood
      after irradiation was done to promote the success of allo-transplantation of bone
      marrow. Decrease of IL-4 mRNA expression was the molecular basis of depression of
      intestinal mucosa immune and intervention of IL-4 showed an antagonistic effect
      on enterogenic infection. A new lipid component extracted from burn eschar was
      documented for the first time and its toxic effects were elucidated. The survival
      rate of alloskin grafts after removal of burn eschar from the recipient animals
      was obviously increased in combined injury due to reduction of immune rejection
      activity by the radiation effect. In contrast, in animal models with simple burn,
      the alloskin grafts were all rejected within ten days after the procedure. A
      successful therapeutic result (survival rate: 92% for 30 days and 67% for 100
      days) was obtained by comprehensive management of treated animals, while the
      untreated control animals all died within 3 - 7 days after injury. CONCLUSION:
      The pathogenesis of injury caused by simultaneous radiation and burn is extremely
      complicated and the treatment is very difficult. A comprehensive management
      program consisting of several therapeutic measures aimed at key links of the
      pathogenesis may achieve significantly improved results.

PMID- 12622920
TI  - TNF-alpha gene-modified dendritic cells act as more potent adjuvants for peptide
      delivery to induce specific antitumor immunity in mice.
AB  - OBJECTIVE: To investigate the antitumor immune efficiency of mouse dendritic
      cells (mDCs) by using adenovirus-mediated tumor necrosis factor-alpha (AdV-TNF
      alpha) gene transfer. METHODS: MDCs infected with AdV-TNF-alpha and AdV-pLpA (no
      gene insert) at 100 multiplicity of infection (MOI) were analyzed by RNase
      protection assay for their cytokine secretion. Mixed lymphocyte reactions were
      also performed to analyze their capacity for alloantigen-presentation. C57BL/6
      mice were challenged with R3LL tumor cells (Lewis lung carcinoma line) 10 days
      after vaccination with different engineered DCs and regular DCs as well. RESULTS:
      Compared to AdV-pLpA and mock-infected DCs, AdV-TNF-alpha-infected DCs displayed
      up-regulated expression of alpha tumor necrosis factor, interleukin-12 (IL-12),
      interleukin-18 (IL-18) and granulocyte macrophage colony stimulation factor (GM
      CSF), and indicated stronger allogeneic T cell proliferative responses.
      Furthermore, vaccination of mice with dendritic cell tumor necrosis factor-alpha
      (DCTNF-alpha) pulsed with Mut1 peptide induced more efficient tumor-specific
      cytotoxic T lymphocyte (CTL) cytotoxicity against R3LL tumor cells in vitro and
      with efficient antitumor immunity in vivo. CONCLUSION: This type of engineered
      DCs could be applied in clinical settings of DC-based cancer vaccines.

PMID- 12622921
TI  - Adaptive alterations of elastic fibers in the bilaminar zone of rabbit
      temporomandibular joint following disc displacement.
AB  - OBJECTIVE: To study the adaptive alterations of elastic fibers in the bilaminar
      zone (BZ) of rabbit temporomandibular joint (TMJ) following disc displacement.
      METHODS: Twenty-eight Japanese white rabbits were used in this study. The right
      temporomandibular joints of 20 of 28 rabbits were subjected to the surgical
      procedure of anterior disc displacement (ADD). Four rabbits in the surgical group
      were sacrificed at 2, 4, 6, 8 and 12 weeks after operation. Their
      temporomandibular joints were studied histochemically. RESULTS: Elastic fibers
      were reduced in number and ran irregularly in the superior lamina of BZ from ADD
      rabbits. The jungly elastic fibers (EFs) could still be seen at 2 weeks after
      operation. At 4 weeks, the number of EFs decreased significantly; EFs lost their
      jungly arrangement and were shaped like rough dots, of which the arrangement and
      the lengths were different. Six weeks after operation, many EFs were replaced by
      distorted, uneven, non-oriented fine EFs, distributed unevenly and some thick or
      fine EFs that ran irregularly. The number of EFs decreased further and their
      arrangement was more deranged at 8 weeks. At 10 and 12 weeks, EFs in the superior
      lamina of BZ were similar to those at 8 weeks. CONCLUSION: Our results show that
      EFs lost their function as well as their distribution and arrangement after disc
      displacement.

PMID- 12622922
TI  - Zinc is a potent heat shock protein inducer during liver cold preservation in
      rats.
AB  - OBJECTIVE: A simple liver cold preservation model was established to study the
      synthesis of heat shock protein 70 (HSP70) induced by zinc (ZnSO(4), i.p.) and
      its protection during liver cold preservation in rat. METHODS: Male Wistar rats
      were divided into 5 groups (n = 6). In control group rat received no
      pretreatment; in Zn-1 group, Zn-2 group, and Zn-3 group rats were pretreated with
      zinc sulfate at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg respectively; and in H
      group rat received heat shock preconditioning (42.5 degrees C x 15 min). Livers
      were preserved in UW solution for 6, 12 and 24 h, respectively. HSP70 was
      analyzed by Western blot. Aspartate transaminase (AST) and lactate dehydrogenase
      (LDH) values of the perfusion solution and the histology of the liver were
      evaluated. RESULTS: HSP70 expression was markedly elevated after pretreatment
      with zinc and heat shock. AST and LDH values in the Zn-1, Zn-2 and H groups were
      significantly lower than those in the control group, respectively (P < 0.05).
      There was no significant difference among the three groups (P > 0.05), whereas
      the AST and LDH values in the Zn-3 group were much higher than those in the
      control group. Histology results showed that liver injury in the Zn-1, Zn-2 and H
      groups were minimal, while it was severe in the Zn-3 group. CONCLUSIONS: Zn(2+)
      is a potent and feasible inducer of HSP expression and is able to protect liver
      from cold preservation injury. The proper inducing dosage of Zn(2+) ranged from 5
      mg/kg to 10 mg/kg. The dosage of 15 mg/kg for Zn(2+) as a HSP inducer is not
      indicated for its severe toxicity to the liver.

PMID- 12622923
TI  - Genetic polymorphisms of CYP2D6 in Chinese mainland.
AB  - OBJECTIVE: To observe the significant differences in the frequencies of the
      cytochrome P450 2D6 (CYP2D6) alleles in Chinese popoulations. METHODS: Tetra
      primer polymerase chain reaction (PCR), allele specific amplification (ASA) PCR
      and multiplex long PCR were developed to detect the CYP2D6 alleles * 2, * 3, * 4,
      * 5, * 6, * 8, * 10 and * 14 in 223 subjects from Chinese mainland. RESULTS: The
      CYP2D6 * 5 allele was the most frequent poor metabolizer (PM) allele in Chinese
      (7.2%), followed by CYP2D6 * 14 (2.0%) which was only detected in orientals.
      There was only 0.2% CYP2D6 * 4, and no CYP2D6 * 3, * 6 and * 8 were detected. In
      contrast to the Caucasians, the most frequent allele in Chinese was the * 10
      allele with a frequency of 51.6%. CONCLUSION: The frequencies of PM alleles,
      CYP2D6 * 5 and CYP2D6 * 14, were higher; but the frequency of CYP2D6 * 10 was
      lower in mainland Chinese population than that in other orientals.

PMID- 12622924
TI  - High-level expression of foreign genes via multiple joined operons and a new
      concept regarding the restricted constant of total amount of plasmid DNA per
      Escherichia coli cell.
AB  - OBJECTIVE: To examine the feasibility of linking operons in tandem to enhance
      expression of heterologous genes in Escherichia coli (E. coli) and clarify the
      potential control mechanism of the total plasmid DNA amount in each host cell.
      METHODS: Two series of expression plasmids, CW11 and CW12, containing 1 to 4 and
      1 to 3 heterologous gene operon(s) respectively, were constructed. The molecular
      size of the CW11 series varied from 5.47 kb to 12.26 kb in 2.25 kb increments.
      The CW12 series varied from 5.40 kb to 9.72 kb in 2.16 kb increments. The
      expression level of desired protein was assayed by SDS-PAGE and laser density
      scanning. Plasmid copy number was determined by incorporation with (3)H-thymidine
      ((3)H-TdR). RESULTS: No influence of the tandem-joined operons on host growth and
      plasmid stability was observed. Upon induction, the desired protein accumulations
      in the CW11 series were 44.9% +/- 3.9%, 51.3% +/- 4.1%, 54.8% +/- 3.3% and 58.2%
      +/- 3.4% of total cell protein. In the CW12 series, the yields were 32.2% +/-
      5.0%, 42.8% +/- 4.1% and 46.9% +/- 4.0% of total cell protein. As size increased,
      the plasmid copy number decreased, but target gene dosage increased significantly
      (P < 0.01). Further calculation showed that the total amount of plasmid DNA per
      cell was not significantly different in each series (P > 0.05) and restricted to
      some extent. CONCLUSIONS: Increasing the target gene dosage by tandem linking of
      operons may enhance the expression level of a desired protein. Although the size
      (kb) and the copy number of each plasmid are negatively interrelated, for certain
      plasmids in each series, their total DNA amount per cell seems to be a restricted
      constant for specific E. coli strains under identical incubation condition.

PMID- 12622925
TI  - Percutaneous estrogen in prevention of early postmenopausal bone loss in Chinese
      women.
AB  - OBJECTIVE: To identify the optimal dosage of 17beta-estradiol gel + oral
      progestin for preventing bone loss in postmenopausal Chinese women. METHODS: A 3
      year open label, randomized, prospective clinical trial was conducted. Sixty
      healthy women who had been postmenopausal for 1 to 5 years were recruited and
      divided into following 4 groups: group 1, percutaneous gel 17beta-estradiol
      (E(2)) 1.5 mg/d plus micronized progesterone (MP) 100 mg/d; group 2, percutaneous
      gel 17beta-estradiol (E(2)) 1.5 mg/d plus medroxyprogesterone acetate (MPA) 2
      mg/d; group 3, percutaneous gel 17beta-estradiol (E(2)) 0.75 mg/d plus micronized
      progesterone (MP) 100 mg/d; and group 4, percutaneous gel 17beta-estradiol (E(2))
      0.75 mg/d plus medroxyprogesterone acetate (MPA) 2 mg/d. Estrogen and progestin
      were given continuously for 25 days per month. Bone mineral density (BMD) was
      measured using quantitative computed tomography (QCT) for trabecular bone of L2-5
      and dual energy X-ray absorptiometry (DEXA) for L2-4 and hip 5 times during the
      trial at baseline and at the 6-, 12-, 18-, 24- and 36-month visits. RESULTS:
      Fifty-nine patients (98.3%, 59/60) stayed in the study for 1 year, 56 patients
      (93.3%, 56/60) for 2 years, and 51 (85%, 51/50) for 3 years. On average,
      menopausal symptoms were relieved by 80% after 6 months of treatment. By the 24th
      month, the mean increase in BMD ranged from 4.3% to 7.5% in trabecular bone; and
      by the 36th month, it ranged from 4.2% to 6.2% in L2-4 and 1.61% to 3.77% in the
      neck. There were significant difference after treatment (P < 0.05). Among the
      four groups, no significant difference (P > 0.05) was found in improvement of
      symptoms, levels of bone markers or BMD. CONCLUSION: A daily dose of estradiol
      gel, either 0.75 mg or 1.5 mg, is effective in preventing early postmenopausal
      bone loss and relieving menopausal symptoms. After 3-year treatment, spinal BMD
      could increase steadily, so does hip BMD, especially in the first 2 years.

PMID- 12622926
TI  - Paclitaxel-induced apoptosis in osteosarcoma cell line U-2 OS.
AB  - OBJECTIVE: To observe the in vitro growth inhibitory and apoptosis-inducing
      effects of paclitaxel on the human osteosarcoma cell line U-2 OS. METHODS: U-2 OS
      cells were treated with various concentrations of paclitaxel. Proliferation was
      determined by cell count in a neubauer cytometer chamber. Viability was assessed
      by trypan blue dye exclusion. Paclitaxel-induced morphologic alterations were
      visualized using light and transmission electron microscopy. The extent of
      paclitaxel-induced apoptosis was determined by flow cytometry and
      immunohistochemical detection (TdT-mediated dUTP nick end labeling technique,
      TUNEL). RESULTS: The cells treated with paclitaxel initially showed G(2)/M
      arrest, which was followed by apoptosis. The characteristic apoptotic changes,
      including nuclear disintegration and chromatin agglomeration, were displayed.
      Large amounts of micronuclei cells appeared, something not observed in those
      cells treated with cisplatin and adriamycin for contrast. Also, extensive DNA
      cleavage was detected using TUNEL. CONCLUSION: This study demonstrates that
      paclitaxel has an apoptotic-inducing effect on osteosarcoma cells through the
      initiation of G(2)/M arrest and inhibiting mitosis in both a time-dependent and
      dose-dependent manner.

PMID- 12622927
TI  - Primary cutaneous CD30-positive anaplastic large cell lymphoma analysis.
AB  - OBJECTIVE: To examine 10 cases with primary cutaneous CD30-positive anaplastic
      large cell lymphoma (ALCL), analyze their clinical manifestations and
      pathological and immunohistochemical features, and improve early diagnosis of
      this disease. METHODS: We studied the morphological characteristics of primary
      cutaneous CD30-positive ALCL using histopathological methods. Leukocyte common
      antigen (LCA), CD20, CD30, CD45RO, CD68, epithelial membrane antigen (EMA),
      cytokeratin (CK) and HMB45 antibodies were used to determine the expression of
      their respective antigens from routine paraffin samples of the patients. RESULTS:
      Ten patients (7 men and 3 women, aged 31 to 84 years) complained of subcutaneous
      masses or papular eruptions over their lower trunks and extremities.
      Histopathologically, the lesions were composed of numerous large round or oval
      pleomorphic cells. The cytoplasm was usually abundant, amphophilic or basophilic,
      and finely vacuolated. Nuclei were commonly eccentrically localized and lobated
      or horseshoed in shape, and multinucleated giant cells and Reed-Sternberg-like
      cells were seen. Nucleoli were generally multiple and large. Of the 10 patients,
      tumor cells displayed positive antigen expression of CD30 in all cases, positive
      CD45RO in 6 cases, positive CD20 in only 1 case, but negative CD45RO and CD20
      expressions in 3 cases. Two patients died at 7 weeks and 3.4 years of follow-up,
      respectively. CONCLUSION: Our study highlights the importance of histopathologic
      features and positive CD30 staining for differentiation of this disease from
      other malignant skin tumors.

PMID- 12622928
TI  - Expression of adrenomedullin and its receptor in lungs of rats with hypoxic
      pulmonary hypertension.
AB  - OBJECTIVE: To investigate the role of adrenomedullin (AM) in the development of
      hypoxic pulmonary hypertension (HPH), and to assess the expression of AM and
      adrenomedullin receptor (AMR) in the lungs of rats with HPH. METHODS: We exposed
      10 rats to normobaric hypoxic conditions for 3 weeks to establish rat model of
      pulmonary hypertension; and 10 other rats were used as normoxic controls. Mean
      pulmonary arterial pressure (mPAP) was measured by a right cardiac
      catheterization. The thickness of pulmonary arterioles was measured by a
      computerized image analyzer. We used the reverse transcription-polymerase chain
      reaction (RT-PCR) to assess the change of expression of AM and AMR in lung of HPH
      rat model. RESULTS: Compared with the control group, hypoxic rats developed
      remarkable pulmonary hypertension, increment in the thickness of pulmonary
      arterioles and right ventricular hypertrophy (P < 0.01). Chronic hypoxia elicited
      a considerable increment in expression of AM and AMR in the lungs of rats, and
      the ratio of AM/beta-actin and AMR/beta-actin in lungs of rats treated with
      hypoxia were significantly higher (P < 0.01). CONCLUSIONS: The AM plays an
      important role in regulating pulmonary vascular tone and can ameliorate the
      development of hypoxic pulmonary hypertension in rats.

PMID- 12622929
TI  - Clinical efficacy of albendazole emulsion in treatment of 212 cases of liver
      cystic hydatidosis.
AB  - OBJECTIVE: To evaluate the clinical efficacy of a new formulation of albendazole
      emulsion (AbzE) in cases of liver cystic hydatidosis. METHODS: Two regimens of
      AbzE (10 mg.kg(-1).d(-1) and 12.5 mg.kg(-1).d(-1)) were given to 212 patients
      with liver cystic hydatidosis in courses ranging from 3 months to more than one
      year. Assessment of drug efficacy was essentially based on imaging signs with
      ultrasonography as the main tool. Assessments were performed at the end of
      different courses and in the follow-up study of 1 - 4 years after the cessation
      of therapy. RESULTS: At the end of therapeutic courses, the overall cure rate of
      the 212 cases was 74.5%, with a 99.1% effective rate. In the follow-up study, the
      cure rate was 83.1%, effective rate was 89.3%, ineffective rate was 0.6%, and
      recurrence rate was 10.2%. The highest cure rate was observed in cases receiving
      AbzE 12.5 mg.kg(-1).d(-1) for 9 months. Retreatment of recurrent cases with AbzE
      obtained satisfactory results. CONCLUSIONS: AbzE surpassed other currently used
      antihydatidosis drugs or formulations with its promising efficacy and mild side
      effects, and could be recommended as a drug of choice in the treatment of cystic
      hydatidosis.

PMID- 12622930
TI  - An extended two-year trial of lamivudine in Chinese patients with chronic
      hepatitis B.
AB  - OBJECTIVE: To evaluate the long-term efficacy and safety of lamivudine therapy
      for the treatment of chronic hepatitis B and the clinical influence of emergence
      of tyrosine methionine aspartic acid (YMDD) motif mutation of hepatitis B virus
      (HBV). METHODS: This multicenter, double-blind, randomized, placebo controlled
      trial began in 1996. A total of 429 patients with HBsAg, HBeAg and HBV CNA
      positives were enrolled. They were randomized to receive either lamivudine 100 mg
      daily (n = 322) or placebo (n = 107) on 3 : 1 ratio for the first 12 weeks.
      Thereafter all patients were offered open label lamivudine treatment and assessed
      every 4 weeks for a total of 104 weeks. RESULTS: After 1 year treatment 72.7%
      patients (285/392) had a sustained serum HBV DNA response. HBV DNA continued to
      be substantially suppressed at the second year, except in patients with the
      emergence of YMDD mutation whose mean HBV DNA levels increased to 86 Meq/ml (bDNA
      assay) but were much more lower than that of pre-treatment baseline level.
      lamivudine therapy resulted in increased HBeAg loss and HBeAg/anti-HBe
      seroconversion, which were correlated with both baseline alanine transaminase
      (ALT) levels and also with duration of lamivudine treatment. HBeAg loss was
      achieved in 26.8% of patients with ALT > 1-fold upper limit of normal at 2 yeas
      and in 35.6% and 55.6% of patients with ALT > 2-fold upper limit of normal and
      ALT > 5-fold upper limit of normal, respectively. For HBeAg seroconversion, these
      figures were 17.4%, 22.2%, and 33.3% respectively. By the end of 2 years, ALT
      levels were remained in normal ranges in 50.3% whose ALT were abnormal before
      treatment, and in 83% whose ALT were mormal before treatment. YMDD mutation were
      developed in 49.7% of the patients. Their serum HBV DNA levels were slightly
      increased to bDNA median level 86 Meq/ml and 15% of the patients they were ALT
      exceeded baseline levels. Four patients clinically flared-up and recovered after
      stop treatment. The adverse drug reactions (ADRs) of lamivudine were mild to
      moderate, only two patients were reported as drug related severe ADR. CONCLUSION:
      Sustained HBV replication and clinical improvement could be obtained by the long
      term lamivudine therapy with good tolerance and safety.

PMID- 12622931
TI  - Long-term mortality of ultrasound structure in patients with venous leg ulcers
      healed from one week to twenty years.
AB  - OBJECTIVE: To obtain information about the quality of scars of healed venous leg
      ulcers compared with intact skin on the opposite leg by using high-frequency
      ultrasound. METHODS: Twenty-eight patients (16 women, 12 men, aged 31 - 89 years)
      whose venous ulcers had healed and scars formed were included in this study. The
      echogenicities of scars were measured with a 20 MHz high-frequency ultrasound
      Dermascan. The thickness of epidermis and dermis was assessed and the number of
      low echogenic pixels (LEPs) in the papillary dermis and reticular dermis were
      counted using image analysis software. RESULTS: The average epidermal thickness
      of the scars after 1 week to 20 years of healing was significantly increased
      compared to those of the control (P < 0.01), whereas the average dermal thickness
      of scars after healing was significantly decreased compared to the control (P <
      0.01). The numbers of LEPs and the distributions of LEPs between scars and
      controls had no statistically significant differences. There were no correlations
      among scar echogenicities, age of healed venous ulcers, initial ulcer areas, age
      of venous ulcers or age of patients. In the control skin samples, the young group
      aged 31 - 69 years had fewer LEPs than did the elderly group aged 70 - 89 years.
      CONCLUSION: Our study demonstrates that after the healing of venous leg ulcers,
      there are significant differences in the thickness of the epidermis and dermis,
      but no significant alterations in water content and distribution in the dermis
      when compared to the controls.

PMID- 12622932
TI  - A pilot study on the combined therapy of granulocyte-macrophage colony
      stimulating factor and hepatitis B vaccine on chronic hepatitis B virus carrier
      children.
AB  - OBJECTIVE: To observe the efficacy of treating intrauterine infected chronic
      hepatitis B virus (HBV) carrier children with a combination of granulocyte
      macrophage colony-stimulating factor (GM-CSF) or hepatitis B immunoglobulin
      (HBIG) plus recombinant hepatitis B vaccine (rHBvac). METHODS: A total of 27
      chronic HBV infected children, who were born to HBV carrier mothers and received
      hepatitis B immunoprophylaxis at birth, were randomized into 2 groups: one
      receiving a combined therapy of 50 micro g of GM-CSF plus 10 micro g of rHBvac
      injected intramuscularly at the same location (GM-CSF group, 14 children) or 200
      IU HBIG and 10 micro g rHBvac in different muscles (HBIG group, 13 children) on a
      monthly four-dose schedule. HBV-DNA quantification and other HBV serological
      markers were tested before and after the four-dose therapy. RESULTS: Twelve
      children in each group completed the study. Of them, 3 children in the GM-CSF
      group and 4 in the HBIG group had elevated serum alanine transaminase (ALT)
      before the trial, and then 2 in each group became ALT normal after the treatment.
      Before the therapy, hepatitis B e antigen (HBeAg) positivity was found in nine
      children in the GM-CSF group and 10 in the HBIG group. One from each group had an
      HBeAg/anti-HBe seroconversion after the treatment. The quantity of HBV-DNA was
      significantly lower after the treatment (P = 0.023) in GM-CSF group, but was not
      significantly reduced in HBIG group. No subjects were found to be negative for
      hepatitis B surface antigen (HBsAg) after the treatment, and no serious adverse
      events occurred in either group. CONCLUSION: Combined GM-CSF and rHBvac therapy
      inhibit HBV replication in carrier children who were not protected after
      treatment with immunoprophylaxis.

PMID- 12622933
TI  - Relationship between sleep apnea hypopnea syndrome and cardiovascular events in
      elderly Chinese snorers.
AB  - OBJECTIVE: To investigate the relationship between sleep apnea hypopnea syndrome
      (SAHS) and some cardiovascular abnormalities in elderly snorers, as well as the
      effectiveness of nasal continuous positive airway pressure on those with SAHS.
      METHODS: With the use of polysomnography, 73 elderly snorers (older than 60
      years) were examined and placed into either the SAHS group or the control group.
      Using ambulatory electrocardiogram (ECG) and blood pressure measurement, daily
      nocturnal rhythm of blood pressure, hypertension, heart rate variability, some
      arrhythmia and angina pectoris of coronary heart disease (CHD) were monitored and
      compared between the two groups before and after 5 - 7 days of treatment with
      nasal continuous positive airway pressure on the SAHS group. RESULTS: This study
      indicated a higher incidence (47.9%) of sleep apnea syndrome in elderly snorers
      and demonstrated that there was a significantly higher incidence of hypertension,
      disappearance in daily nocturnal rhythm of blood pressure, poor effectiveness of
      nitrate on angina pectoris of coronary heart disease, decreased heart rate
      variability during sleep, increased arrhythmia and lower pulse oxygen saturation
      (SpO(2)) levels in the SAHS group than in the control group. After nasal
      continuous positive airway pressure treatment during sleep, snoring control,
      significantly higher SpO(2) levels and lower index of apnea/hypopnea were
      achieved in the SAHS group; heart rate variability (HRV) and blood pressure day
      nocturnal rhythm were returned to normal levels. CONCLUSION: This research
      suggests that there is a close relationship between the development of sleep
      apnea syndrome and some cardiovascular diseases. Continuous positive nasal airway
      pressure is effective not only on SAHS but also on coexisting cardiovascular
      disorders.

PMID- 12622934
TI  - Hypoxia-inducible factor 1 alpha upregulates the expression of inducible nitric
      oxide synthase gene in pulmonary arteries of hyposic rat.
AB  - OBJECTIVE: To investigate the expression of hypoxia-inducible factor 1 alpha (HIF
      1alpha) and inducible nitric oxide synthase (iNOS) genes in rats' pulmonary
      arteries in different phases of hypoxia-induced pulmonary hypertension
      development. METHODS: Models of chronic hypoxic pulmonary hypertension rat were
      duplicated by intermittent hypoxia. Mean pulmonary arterial pressure (mPAP) was
      measured by right-heart catheterization. HIF-1alpha and iNOS messenger
      ribonucleic acid (mRNA) were detected by in situ hybridization. HIF-1alpha and
      iNOS protein were measured by immunohistochemical analysis. RESULTS: Expression
      of HIF-1alpha protein was upregulated in pulmonary arterial tunica intimae of all
      hypoxic rats. In pulmonary arterial tunica media, the level of HIF-1alpha protein
      was markedly upregulated at days 3 and 7 of hypoxia (P < 0.01), then tended to
      restore at 14 days and 21 days. HIF-1alpha mRNA levels in pulmonary arteries of
      rats began to increase significantly at day 14 of hypoxia (P < 0.01). Expression
      of iNOS mRNA and protein in pulmonary arteries of rats were upregulated by
      hypoxia for 3 days (P < 0.01), then reached its peak and maitained the same level
      while the extension of hypoxia. Linear correlation analysis showed that iNOS
      protein was associated with both mean pulmonary arterial pressure (r = 0.74, P <
      0.01) and hypoxic pulmonary vascular remodeling (r = 0.78, P < 0.01), whereas the
      inverse was associated with HIF-1alpha protein (r = -0.52, P < 0.01).
      CONCLUSIONS: HIF-1alpha and iNOS are both involved in the pathogenesis of hypoxia
      induced pulmonary hypertension in rat. HIF-1alpha protein may upregulate the
      expression of iNOS gene by transcriptional activation; in addition, iNOS protein
      may inhibit the expression of HIF-1alpha protein.

PMID- 12622935
TI  - Shear stress induces interleukin-8 mRNA expression and transcriptional activation
      in human vascular endothelial cells.
AB  - OBJECTIVE: To examine interleukin-8 (IL-8) mRNA expression induced by flow shear
      stress in human umbilical vein endothelial cells (HUVECs) and investigate its
      transcriptional activation. METHODS: Flow laminar shear stress 4.2 dyne/cm(2) was
      used for the stimulating experiments. The flow shear stress-induced IL-8 mRNA
      expression was detected by reverse transcription-polymerase chain reaction (RT
      PCR). pEGFP1 was used to construct IL-8 reporter gene pEGFP1-IL8USCS for
      determining IL-8 gene transcriptional activation through gene transfer and flow
      cytometric analysis. NF-kappaB nuclear translocation was observed by
      immunocytofluorescent staining. Western blot was used to examine IkappaB
      phosphorylation and degradation. RT-PCR, Northern blot, immunocytofluorescent
      staining and laser confocal microscopy were used to determine Toll-like receptor
      4 (TLR-4) expression at mRNA and protein levels in the cells. RESULTS: There was
      a marked increase in IL-8 mRNA expression in HUVECs after 120 min of exposure to
      laminar flow shear stress. When exposed to shear stress for 180 min, there was an
      increase in enhanced green fluorescent protein expression in pEGFP1-IL8USCS
      transfected endothelial cells. NF-kappaB p65 immunocytofluorescent staining of
      HUVECs showed that when exposed to the same flow shear stress for 30 or 60 min,
      the cell nuclei became stained; after 90 or 120 min, the staining became much
      more pronounced. A significant increase in P-IkappaB in the cell lysates occurred
      after 10 min of exposure while blot density dramatically dropped after 60 min of
      exposure. The density of the IkappaB blot dropped with increasing exposure time
      after 30 min. TLR-4 was present on the surface of HUVECs. HUVECs constitutively
      expressed TLR-2 and TLR-4 mRNA; when exposed to flow shear stress for 60 min, TLR
      4 mRNA expression increased. CONCLUSION: NF-kappaB activation is involved in flow
      shear stress-induced IL-8 mRNA expression in human umbilical vein endothelial
      cells. TLR-4 receptor for innate immunity most likely mediate these events.

PMID- 12622936
TI  - Inhibition of phosphoenolpyruvate carboxykinase gene expression by metformin in
      cultured hepatocytes.
AB  - OBJECTIVE: To investigate the effect and mechanism of the antihyperglycemic agent
      metformin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) gene in
      hepatocytes and to determine whether the effects of metformin in hepatocytes are
      transmitted throughout the known insulin signaling pathways. METHODS: Confluent
      H4IIE rat heptoma cells were cultured for 16 h with 0.1 mmol/L metformin either
      in absence or presence of 0.1 nmol/L insulin, and then stimulated with various
      agents. The expression of PEPCK gene was examined by Northern blot analysis.
      RESULTS: Therapeutic concentrations of metformin significantly inhibited basal
      PEPCK mRNA expression and also decreased cAMP and dexamethasone induced PEPCK
      gene expression through interaction with insulin. In the presence of insulin
      signaling pathway inhibitors wortmannin and UO126, metformin reduced PEPCK mRNA
      levels, but wortmannin blocked inhibitory regulation of insulin on PEPCK gene
      expression. CONCLUSION: Metformin inhibits PEPCK gene expression via either an
      insulin-independent or an interacting-with-insulin manner. The results suggest
      that a possible mechanism by which metformin reduces gluconeogenesis could be
      associated with the inhibition of PEPCK gene expression.

PMID- 12622937
TI  - A randomized, controlled clinical trial on meropenem versus imipenem/cilastatin
      for the treatment of bacterial infections.
AB  - OBJECTIVE: To evaluate the efficacy and safety of meropenem in Chinese patients,
      we conducted a study for the treatment of patients with lower respiratory tract
      infections, urinary tract infections and other infections. METHODS: A total of
      182 hospitalized patients were enrolled in the study. 90 patients received 500 mg
      meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients
      received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours
      if necessary) by intravenous infusion. The duration of treatment was 7 - 14 days
      for both groups. RESULTS: Seventy of 90 cases receiving meropenem and 70 of 92
      cases receiving imipenem/cilastatin were assessable for clinical efficacy. The
      overall efficacy rates were 90% for the meropenem group and 87% for the
      imipenem/cilastatin group, and the bacterial eradication rates were 86% in both
      groups. 93 (76%) of 123 strains isolated from patients produced beta-lactamases.
      Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70
      cases in the imipenem/cilastatin group. The adverse drug reaction rates were 9.7%
      and 8.6%, respectively. The results showed that there were no statistical
      differences between these two groups (P > 0.05). CONCLUSION: Meropenem is
      effective and safe for the treatment of bacterial infections caused mainly by
      beta-lactamase-producing strains.

PMID- 12622938
TI  - Polysaccharide sulfate 916 inhibits neutrophil-endothelial adhesion.
AB  - OBJECTIVE: To study the effect of polysaccharide sulfate 916 (PS916) on
      neutrophil-endothelial cell adhesion. METHODS: Cell adhesion was evaluated by
      testing neutrophil myeloperoxidase activity. Expression of adhesion molecule in
      human umbilical vein endothelial cell (HUVEC) was measured by ELISA. The
      neutrophil activation rate induced by N-formyl-methionyl-leucyl-phenylalanine
      (fMLP) was tested by nitroblue tetrazolium (NBT) reduction. RESULTS: Tumor
      necrosis factor alpha (TNFalpha, 50 - 800 U/ml) increased the adherence of
      neutrophil to TNFalpha-stimulated HUVEC in a concentration and time dependent
      manner. PS916 (0.01 - 1.0 mg/ml) dose-dependently inhibited the adherence of
      neutrophils to TNFalpha-stimulated HUVEC. fMLP increased the activation rate of
      neutrophils independent of concentration. PS916 also inhibited the adherence of
      fMLP-activated neutrophils to HUVEC. Moreover, PS916 inhibited adhesion molecule
      expression in TNFalpha-stimulated HUVEC. CONCLUSIONS: PS916 inhibited neutrophil
      endothelial adhesion. The mechanism of its action was partially related to
      suppressing the expressions of intercellular adhesion molecule-1 (ICAM-1) and
      vascular adhesion molecule-1 (VCAM-1).

PMID- 12622939
TI  - Aloin, cinnamic acid and sophorcarpidine are potent inhibitors of tyrosinase.
AB  - OBJECTIVE: To evaluate the effects of aloin, cinnamic acid and 15 other kinds of
      natural chemicals on the activity of tyrosinase, in order to provide lightening
      agents in the treatment of hyperpigmentation disorders and cosmetic additives.
      METHODS: Tyrosinase activity was estimated by measuring the oxidation rate of L
      dopa. Inhibition of the enzyme was deduced according to the Lineweaver-Burk plots
      compared to the control. RESULTS: Cadabine, paeonal, farrerol, evodin, cinnamic
      acid, aloin and sophorcarpidine had different levels of inhibition of tyrosinase.
      The inhibitory rates of cinnamic acid (2 mmol/L, 0.5 mmol/L), aloin (2 mmol/L)
      and the rest were significantly higher than that of hydroquinone (0.5 mmol/L) (P
      < 0.05). CONCLUSIONS: Tyrosinase activity can be greatly inhibited by cinnamic
      acid, aloin and sophorcarpidine, of which sophorcarpidine functions as an
      uncompetitive inhibitor, compared to aloin and cinnamic acid, which are mixed
      type inhibitors.

PMID- 12622940
TI  - Mandibular functional reconstruction using internal distraction osteogenesis.
AB  - OBJECTIVE: To study the potential and advantages of internal distraction
      osteogenesis in mandibular functional reconstruction. METHODS: Three types of
      mandibular distractors were used in eight patients with various mandibular
      defects due to tumor or cyst resection. The average age of the patients was 31.5
      years old (ages ranged from 8 to 54 years). For two patients with ramus defects,
      specially designed distractors were used to restore the normal ramus height. In
      two other patients, specially designed trifocal distractors were used. In three
      patients, vertical distractors were used. RESULTS: All the mandibles were
      successfully reconstructed in accordance with the direction and distance designed
      before operation except in one patient. In that patient the distal 23 mm defect
      failed to be corrected because of loosening of transport block fixation screws.
      CONCLUSIONS: Mandibular defects can be successfully corrected using internal
      distraction osteogenesis. Performing mandibular reconstruction using distraction
      osteogenesis is best done at the time of tumor or cyst resection.

PMID- 12622941
TI  - MRI and magnetic resonance angiography in evaluating simultaneous pancreas-kidney
      transplantation.
AB  - OBJECTIVE: To evaluate the value of magnetic resonance imaging (MRI) and three
      dimensional (3D) contrast magnetic resonance angiography (MRA) in the diagnosis
      of complications of simultaneous pancreas-kidney transplantation (SPKT), as
      confirmed by biopsy and digital subtraction angiography (DSA). METHODS: Five MR
      examinations of five patients were performed within 28 days to 2 years after
      surgery on GE 1.5T MR system. Imaging techniques included axial and sagittal
      chemical fat-suppressed T1-weighted image (T1WI) and T2-weighted image (T2WI),
      additional contrast axial or saggital chemical fat-suppressed T1WI were obtained
      after 3D contrast MRA for calculating the mean percentage of the parenchymal
      enhancement (MPPE) of the pancreas and kidney. 3D contrast MRA was performed with
      Smartprep technique. MRA data were analyzed with maximum intensity projection
      (MIP) and multi-planner reformat (MPR). RESULTS: In five cases of transplant
      pancreases, MRI found two normal pancreas grafts, one case of acute rejection,
      one case of chronic rejection with 70% fibrosis and one case of late
      pancreatitis. In five transplant kidneys, MRI detected four normal kidney grafts
      and one case of acute rejection with infarction. MPPE could distinguish
      infarction from other complications. 3D contrast MRA could display vascular
      complications of SPKT, such as stenosis or occlusion, aneurysm formation of
      transplanted vessels and narrowing at the site of anastomosis, as confirmed by
      DSA. CONCLUSION: With combined application of MRI and 3D contrast MRA,
      complications of SPKT can be clearly identified.

PMID- 12622942
TI  - Changes in gap junctional intercellular communication in rabbits lens epithelial
      cells induced by low power density microwave radiation.
AB  - OBJECTIVE: To demonstrate the changes in gap junctional intercellular
      communication (GJIC) mediated by low power density microwave radiation in rabbits
      lens epithelial cells (LECs) and its mechanisms. METHODS: Rabbits' eyes were
      exposed to 5 mW/cm(2) and 10 mW/cm(2) power densities of microwave radiation for
      3 hours. The fluorescence-recovery-after-photobleaching (FRAP) method was used to
      determine the GJIC. The localization and function of connexin 43 in LECs was
      detected by laser scanning confocal microscopy. RESULTS: The GJIC of rabbits LECs
      was inhibited by microwave radiation especially in the 10 mW/cm(2) irradiated
      samples. A decrease in connexin 43-positive staining was seen in 5 mW/cm(2) x 3 h
      treated LECs. Intracellular space accumulation and cytoplasmic internalization
      were clearly demonstrated in 10 mW/cm(2) group. CONCLUSIONS: Low power densities
      microwave radiation (5 mW/cm(2) and 10 mW/cm(2)) induces damage to connexin 43
      and inhibits the GJIC of rabbits LECs. These changes result in an osmotic
      imbalance within the lens and induce early cataract. 5 mW/cm(2) or 10 mW/cm(2)
      microwave radiation is cataractogenic.

PMID- 12622943
TI  - Reconstruction of mandible with fibular flap and dental implant distractor: a new
      approach.
AB  - OBJECTIVE: To study the application of dental implant distractor (DID) in
      mandibular functional reconstruction. METHODS: We designed a new device named
      DID, which includes the permanent dental implant and the temporary distractor in
      itself. It is specially designed for fibula wider distraction in mandible
      reconstruction. Twenty-five sets of DID devices were put into 8 patients (6 men
      and 2 women) during operation. Two patients suffered from ameloblastoma of the
      mandible, 2 from odontogenic cyst of the mandible, 1 from fibrous dysplasia, and
      the other 3 from malignant tumor of the mandible. The age of 8 patients ranged
      from 19 to 67 (mean 46.8) years. RESULTS: During postoperative 2 - 15 months
      follow up, 7 patients were found to be successful. The clinical examination and X
      ray film showed the normal shape of the mandible and the osteointegration of the
      implants were solid enough to withstand the denture force. Others had the DID
      removed because of inflammation. Two of the patients successfully worn the fixed
      dental prosthesis. The outcomes was satisfying. CONCLUSION: The DID device
      specially designed for mandibular reconstruction with fibular flap can help to
      simplify convenient procedures to a single surgery.

PMID- 12622944
TI  - Genotype identification of Orientia tsutsugamushi isolated from Nan Peng Lie
      Islands in China.
AB  - OBJECTIVE: To identify genotype of eight strains of Orientia tsutsugamushi (O.
      tsutsugamushi) isolated from Nan Peng Lie Islands in China and establish
      tsutsugamushi disease nature foci for this region. METHODS: The nested polymerase
      chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used.
      Three primers were selected from the DNA sequence of the gene encoding type
      specific 56-kDa protein of the Karp strain. The positive products were digested
      by Hine II and Pst I, meanwhile profiles specific to each strain were analyzed.
      RESULTS: Three genotypes of O. tsutsugamushi including Karp, Kato and a new
      strain existed on Nan Peng Lie Islands. CONCLUSION: Nan Peng Lie Islands is
      tsutsugamushi disease nature foci.

PMID- 12622945
TI  - Interventional and synthetic therapy of advanced hepatocellular carcinoma.
AB  - OBJECTIVE: To evaluate the clinical efficacy of interventional therapy in the
      treatment of hepatocellular carcinoma (HCC). METHODS: Thirty-three patients with
      HCC were synthetically treated by systematic measures. Among them, percutaneous
      port-catheter system (PCS) implantation via the femoral artery was performed in
      21 cases. Patients with haemorrhage were treated with prothrombin complex
      concentrate and fibroraas, and patients with hepatic encephalopathy by branched
      chain amino acids and arginine. RESULTS: All indwelling catheters of PCS were
      patent and no catheter tip dislocations were observed. Of 33 patients with
      advanced HCC, the mean survival rate was 20.1 months and 12 (36%) patients
      survived more than 2 years. CONCLUSION: Patients with advanced HCC were treated
      by synthetic measures. Survival was prolonged, quality of life was improved
      significantly, and the effectiveness of interventional therapy was further
      improved.

PMID- 12622946
TI  - Insulin sensitivity and the diffuseness of coronary artery disease in humans.
AB  - OBJECTIVE: To study the relationship between insulin sensitivity and diffuse
      coronary artery disease. METHODS: Ninety-two consecutive patients underwent
      coronary angiography were enrolled in the study. Relationships between the
      results of angiograms and both glucose tolerance and blood lipids were analyzed.
      RESULTS: The mean age of the 92 patients (70 males, 22 females) was 65.4 +/- 6.3
      y. In the 78 patients diagnosed by angiography as coronary artery disease,
      diffuse lesion was more common in diabetic patients than in those without a
      diabetes history (12/13 vs 24/65, P = 0.00026). Fasting glucose [(6.06 +/- 2.43)
      x 10(-3) mol/L vs (4.80 +/- 1.47) x 10(-3) mol/L, P = 0.009], glucose levels at
      one hour [(12.37 +/- 4.38) x 10(-3) mol/L vs (9.10 +/- 3.97) x 10(-3) mol/L, P =
      0.001], two hours [(11.12 +/- 5.64) x 10(-3) mol/L vs (7.49 +/- 4.29) x 10(-3)
      mol/L, P = 0.003] and three hours [(8.11 +/- 5.51) x 10(-3) mol/L vs (5.56 +/-
      3.46) x 10(-3) mol/L, P = 0.020] after food were higher in patients with diffuse
      coronary disease than in those with non-diffuse coronary disease. Differences in
      the insulin sensitivity index (ISI) between the two groups was statistically
      significant (-4.36 +/- 0.52 vs -3.89 +/- 0.69, P = 0.003). The incidence of
      multiple-vessel disease in diabetic patients was higher than that in non-diabetic
      patients (12/13 vs 33/65, P = 0.00565). Glucose levels at two hours [(10.22 +/-
      5.57) x 10(-3) mol/L vs (7.67 +/- 4.43) x 10(-3) mol/L, P = 0.034] and three
      hours [(7.90 +/- 5.47) x 10(-3) mol/L vs (5.22 +/- 2.79) x 10(-3) mol/L, P =
      0.007] after food were higher in patients with multiple-vessel disease than in
      those with single-vessel disease. Impaired insulin sensitivity without a history
      of diabetes mellitus was commonly seen in patients with coronary artery disease.
      CONCLUSIONS: The diffuseness of coronary artery disease is associated with
      insulin sensitivity and blood glucose levels. Insulin resistance is a common
      phenomenon in non-diabetic patients.

PMID- 12622947
TI  - A new echocardiographic system for assessment of epicardial and intramyocardial
      coronary flow in a swine model.
AB  - OBJECTIVE: To visualize epicardial and intramyocardial coronary blood flow by
      using a noninvasive echocardiography system. METHODS: In five juvenile swines,
      coronary flow imaging was used to visualize the different segments of epicardial
      coronary and intramyocardial arteries. Pulsed-Doppler spectrums were recorded and
      analyzed. The left anterior descending artery (LAD) and intramyocardial coronary
      blood flow signals were recorded at baseline and during dipyridamole
      administration. RESULTS: Epicardial and intramyocardial coronary arteries could
      be visualized by coronary flow imaging. The systolic component of coronary flow
      in the right coronary artery (RCA) was greater than in the LAD. The
      intramyocardial blood flow was characterized by persistent retrograde blood flow
      velocity during systole. Vasodilation with dipyridamole produced exaggerated
      differences in the phasic pattern of coronary blood flow in epicardial and
      intramyocardial vessels. CONCLUSION: Color Doppler coronary flow imaging provides
      a noninvasive method to study the coronary blood flow.

PMID- 12622948
TI  - Clinical blood routine and bone marrow smear manifestations of disseminated
      penicilliosis marneffei.
AB  - OBJECTIVE: To investigate the manifestation of clinical, blood routine and bone
      marrow smear of disseminated penicilliosis marneffei. METHODS: There were 13
      cases of penicilliosis marneffei whose peripheral blood had been drawn for
      routine tests, as well as blood and bone marrow aspiration for smears. Wright's
      Giemsa stain, Gomori's methenamine-silver stain (GMS) and periodic acid Schiff's
      reaction (PAS) were performed for light microscopy in consultation with
      pathologic diagnosis and fungi culture for precise diagnosis. RESULTS: Seven
      cases of bone marrow and 2 peripheral blood smears were found positive for
      penicillium marneffei in the test group. The morphology of penicillium marneffei
      was extremely similar to that of histoplasma capsulatum. However, the observation
      of sausage cells and central cross wall, which are signs of dividing by fission
      and not by budding, aided in differential diagnosis. CONCLUSION: Bone marrow
      smear or occasional blood smear examination play an important role in the
      diagnosis of disseminated penicilliosis marneffei.

PMID- 12622949
TI  - Detection of Epstein-Barr virus DNA in plasma/serum: a useful serological
      indicator for diagnosis of nasopharyngeal carcinoma.
AB  - OBJECTIVE: To compare the detection rates of Epstein-Barr virus (EBV) DNA in the
      serum/plasma between apparently healthy adults (AHAs) and nasopharyngeal
      carcinoma (NPC) patients in attempt to evaluate the efficiency of EBV DNA assay
      for serodiagnosis of NPC. METHODS: The plasma and serum were obtained from 58
      AHAs and 66 untreated NPC patients. EBV DNA W-fragment was detected using nested
      ploymerase chain reaction (PCR). Immunoenzymatic assay for titration of IgA-VCA
      was also adopted. RESULTS: EBV DNA detection rate (84.85%) in the plasma/serum of
      66 NPC patients was significantly higher than that (10.34%) in 58 AHAs. The
      sensitivity of plasma/serum EBV DNA assay (0.8485) was higher than that (0.8030)
      of titrating IgA-VCA (positive criterion >/= 1:40) though the specificities of
      these two tests were the same (0.8966). The correct rate, predictive value of a
      positive test, and Odds ratio of dual positivity (0.8387, 0.9792 and 141.0,
      respectively) were higher than those of single positivity either to plasma/serum
      EBV assay (0.5242, 0.7333 and 1.1423, respectively) or to IgA-VCA >/= 1:40 test
      (0.4839, 0.5385 and 1.0480, respectively). CONCLUSION: The EBV DNA detection in
      the plasma/serum using nested PCR may be a useful indicator for serodiagnosis of
      NPC.

PMID- 12622950
TI  - [Let's improve coronary risk prediction in Spain].

PMID- 12622952
TI  - [Ten years' experience in continuous intravenous epoprostenol therapy in severe
      pulmonary arterial hypertension].
AB  - INTRODUCTION: Primary pulmonary hypertension and its associated forms is a
      progressive and often fatal disease, the course of which has been favourably
      modified by prostacyclin therapy in the last decade. OBJECTIVE: The aim of this
      study is to analize retrospectively the efficacy of continuous intravenous
      epoprostenol (synthetic prostacyclin) therapy in pulmonary arterial hypertension,
      and to compare it with conventional therapy (anticoagulants, digoxin and
      diuretics). METHODS: Between 1990-2000, 31 patients with severe precapillary
      pulmonary hypertension in functional class III or IV went on continuous
      intravenous epoprostenol therapy, administered by a portable infusion pump
      through a Hickman catheter. We compared their survival with a group of 16
      patients treated with conventional therapy alone. RESULTS: Time of follow-up was
      33.25 months in the prostacyclin group and 20 months in the conventional group.
      The one- three- and five- year survival rates were 86%, 50% and 38% respectively
      for patients treated with epoprostenol compared with 40%, 40% and 8% survival
      rates at idetical periods for patients treated conventionally (p = 0,02).
      Functional class and the mean distance walked in the 6 minutes test were improved
      in patients treated with prostacyclin (p < 0,01). Serious complications
      attributable to the delivery system included 3 deaths, mainly due to infection.
      CONCLUSION: Continuous intravenous epoprostenol therapy improves survival and
      exercise capacity in patients with severe pulmonary arterial hypertension despite
      potentially serious complications attributable to the delivery system.

PMID- 12622951
TI  - [Hopes and experiences in the treatment of severe pulmonary hypertension].

PMID- 12622953
TI  - [Value of NTproBNP concentration in an out-of-hospital adult population].
AB  - INTRODUCTION: The diagnosis of chronic heart failure (CHF) is based on
      demonstrating the cardiac origin of clinical manifestations. Echocardiography is
      the method of choice for the detection of left ventricular systolic dysfunction
      (LVSD). Brain natriuretic peptide (BNP) rises during LVSD. OBJECTIVES: To analyze
      the plasma concentration of N-terminal brain natriuretic propeptide (NTproBNP) in
      a general adult population in relation to different spontaneous circumstances and
      to study its capacity for identifying patients with LVSD.Methods. A cardiological
      examination was made and plasma NTproBNP levels were measured in a randomized
      group of 203 people (49-81 years old) from the Community of Valencia. RESULTS:
      The average NTproBNP concentration was 52.2 98.2 pmol/l. NTproBNP levels varied
      with age, gender and functional stage (NYHA). The highest NTproBNP values were
      observed in people who had previously suffered from acute pulmonary edema or who
      had an ejection fraction (EF) of less than 40%. There was also a significant
      elevation in patients with nocturnal dyspnea, orthopnea, atrial fibrillation, EF
      < or = 50%, angina, and ankle edema. The best concentration of NTproBNP for
      differentiating EF < or = 50% was 37.7 pmol/l, with 92% sensitivity and 68%
      specificity. CONCLUSIONS: The elevation of NTproBNP concentration indicates the
      cardiac origin of clinical manifestations and serves to select patients for
      echocardiographic examination. Low NTproBNP concentrations help to rule out LVSD.

PMID- 12622954
TI  - [Biventricular pacing as a treatment for advanced heart failure. Preliminary
      experience in a series of 22 consecutive patients].
AB  - BACKGROUND AND OBJECTIVES: Recent data suggest that biventricular pacing may play
      an important role in treating advanced heart failure in the presence of a
      significant interventricular and/or intraventricular conduction disorder by
      correcting cardiac dysynchrony. In this article, we review the initial technical
      and clinical experience with cardiac resynchronization therapy in an
      electrophysiology laboratory. METHODS: The first 22 consecutive patients with
      severe congestive heart failure, ejection fraction < 0.35, NYHA functional class
      III or IV, and QRS duration > 120 ms who were implanted biventricular pacemakers
      were studied. Clinical, electrocardiographic, and echocardiographic evaluations
      were made before and three months after pacemaker implantation. Acute functional
      capacity testing with peak oxygen uptake was measured during biventricular pacing
      and during intrinsic rhythm or right ventricular pacing three months after the
      implantation procedure. RESULTS: The success rate of pacemaker implantation was
      95%. Pre-discharge left ventricular pacing was achieved in 91%, with an average
      pacing threshold of 1.53 (1.04) volts. NYHA functional class improved (p = 0.039)
      from 3.4 (0.7) to 2.3 (0.78). The rate of hospitalization for heart failure
      decreased from an average of 3.12 (0.58) three months before the procedure to
      1.38 (0.34) three months after the procedure. Peak oxygen uptake was
      significantly greater (p = 0.028) during biventricular pacing: 14.89 (2.1)
      ml/min/kg, than during intrinsic rhythm or right ventricular pacing: 12.65 (2.3)
      ml/min/kg. CONCLUSIONS: Cardiac resynchronization therapy can be performed safely
      and with a high success rate in the electrophysiology laboratory. Biventricular
      pacing seems to improve the symptoms of congestive heart failure in patients with
      evidence of atrioventricular and/or interventricular/intraventricular
      dysynchrony. An acute benefit in peak oxygen uptake was associated with
      biventricular pacing after the implantation procedure.

PMID- 12622955
TI  - [Coronary risk estimation in Spain using a calibrated Framingham function].
AB  - INTRODUCTION AND OBJECTIVES: The Framingham coronary heart disease (CHD)
      functions overestimate the risk of CHD in countries with a low incidence.
      Consequently, these functions should be calibrated for the purpose of primary
      prevention. Calibrated Framingham function charts of overall CHD risk for the
      Spanish population are presented. Patients and methods. The Framingham functions
      were calibrated by substituting the prevalence of CHD risk factors and incidence
      found in Framingham with the same values for Spain. The Framingham function that
      included high-density lipoprotein (HDL) cholesterol was used. The 10-year
      probability of developing a CHD event was estimated for several combinations of
      risk factors and HDL levels ranging from 35 to 59 mg/dl. Color-coded charts were
      prepared that show the exact probability of CHD corresponding to each combination
      of risk factors, shown in separate cells on the chart. RESULTS: The event rate
      and prevalence of CHD risk factors differed considerably between Girona and
      Framingham. HDL < 35 mg/dL increased risk by approximately 50% and HDL > 60 mg/dL
      reduced it by 50%. The proportion of cells in which the 10-year probability of
      developing a CHD event was > 9% was 2.3 times higher and that of cells with a
      probability > 19% was 13 times lower in the chart calibrated for Spain than in
      the original Framingham charts. CONCLUSIONS: The calibrated Framingham function
      may help to more accurately estimate the overall risk of CHD in the Spanish
      population for primary prevention purposes. The calibrated function should be
      validated, and the development of functions for the Spanish population should be
      promoted.

PMID- 12622956
TI  - [Clinical characteristics, management, and prognosis of patients with acute
      myocardial infarction not admitted to the coronary care unit. Usefulness of an
      intermediate care unit as the initial admission site].
AB  - INTRODUCTION AND OBJECTIVES: There is little information about the management and
      prognosis of patients with acute myocardial infarction (AMI) who are not admitted
      to coronary care units (CCU) because of the lack of available beds. The aim of
      this study was to evaluate the characteristics and prognosis of the patients who
      were admitted to the intermediate care unit (INTCU) of a cardiology department.
      METHODS: We compared the clinical profile, management, and 12-month prognosis of
      the patients admitted to the INTCU or general ward (Ward) instead of the CCU.
      RESULTS: Out of 242 patients with AMI, 62 (23%) were not admitted to the CCU due
      to the lack of available beds. Of these, 29 (12%) were admitted to the INTCU and
      26 (11%) to the Ward after being monitored for at least 24 h in the emergency
      room. Patients admitted to the CCU arrived at the hospital early, were younger,
      less frequently female, and had a lower prevalence of diabetes. ST-segment
      elevation AMI was more frequent in patients admitted to the CCU than in patients
      admitted to the INTCU or Ward (67 vs 17 and 23%, respectively; p < 0.0001), and
      non-Q wave AMI was less frequent (30 vs 76 and 81%; p < 0.0001). No differences
      were found between groups in the number of stress tests or revascularization
      procedures performed after the first 24 h, the duration of the hospital stay
      (median 8 days), or in-hospital mortality. The 12-month survival was 82, 80, and
      64% in the patients admitted to the CCU, INTCU, or Ward (p < 0.05), respectively.
      These differences ceased to be significant after adjusting for the patients'
      baseline clinical profile and treatment received at admission. CONCLUSION:
      Compared to patients with AMI admitted to the CCU, patients admitted to the INTCU
      or Ward after being monitored at least 24 h had non-ST elevation and non-Q wave
      AMI more frequently, but a less favorable risk profile for long-term mortality.
      The different types of AMI were managed similarly and had a similar 12-month
      prognosis. Intermediate care units may be useful for palliating the lack of CCU
      beds and care for some patients with AMI.

PMID- 12622957
TI  - [Angiographic results of thrombectomy performed with two new devices in lesions
      with intracoronary thrombus].
AB  - INTRODUCTION AND OBJECTIVE: The presence of intracoronary thrombus is associated
      with less favorable results of percutaneous coronary interventions. In recent
      years, new devices have been designed to improve the outcome of these procedures
      when an intracoronary thrombus is present. The results of two new systems of
      thrombectomy used in a single center are analyzed. METHODS: Prospective
      observational registry of the use of two thrombectomy devices, X-SIZER (EndiCOR
      Medical Inc., San Clemente, California, USA) and RESCUE (Boston Scientific
      Scimed, Inc., Maple Grove, Minnesota, USA), between 1 June 2000 and 15 February
      2002. RESULTS. One hundred thirty-nine devices were used in 137 patients (112
      RESCUE and 27 X-SIZER). The main indication was primary angioplasty for acute
      myocardial infarction (80%). In 7 patients (5%), unscheduled thrombectomy was
      performed for unexpected complications that appeared during the procedure. In 75%
      of patients, IIb/IIIa inhibitors were given. In 10 cases (7%) the device did not
      reach the lesion. Complications derived from the use of the device were recorded
      in 3 cases (2.1%). TIMI flow improved from 1.28 1.1 before thrombectomy to 2.31
      1.2 after the procedure. Improvement in the thrombus image was observed in 86%.
      The intervention was successful in 86%. CONCLUSIONS: Thrombectomy with X-Sizer
      and Rescue improved the angiographic thrombus image in most cases and was
      associated to a low complication rate. Its efficacy compared to the conventional
      technique should be assessed in future trials.

PMID- 12622958
TI  - [Value of gated-SPECT in defining the post-revascularization prognosis of
      patients with ischemic cardiomyopathy].
AB  - INTRODUCTION AND OBJECTIVES: Gated-SPECT simultaneously evaluates perfusion and
      ventricular function and could provide important prognostic information in
      ischemic cardiomyopathy. Our aim was to study the value of gated-SPECT performed
      before revascularization in a cardioischemic population to predict the outcome of
      revascularization. METHODS: One hundred and ten patients who had undergone
      percutaneous (n = 100) or surgical revascularization were included. Patients
      underwent sestamibi gated-SPECT before revascularization. After
      revascularization, they were followed-up for at least 12 months (mean 23.7
      months, maximum 44 months). We recorded deaths and a combined clinical event of
      death, non-fatal infarction, and hospital re-admission for cardiac reasons. We
      analyzed the prognostic value of clinical, angiographic, and gated-SPECT
      variables. RESULTS: During follow-up, there were 14 deaths (6.4%/ year) and 36
      cases of combined events (16.5%/year). Multivariate analysis showed that
      depressed gated-SPECT ejection fraction (threshold 0.30) was the only variable
      independently related to death (OR = 4.8; 95%CI, 1.6-14.6) and combined event (OR
      = 2.5; 95%CI, 1.2-4.8). Survival analysis showed that patients with ejection
      fraction < or = 0.30% had a significantly shorter period of time free of death
      (33 months [28-38] versus 42 months [40-44]; p = 0.002) and combined events (28
      months [23-32] versus 36 months [33-39]; p = 0.007). CONCLUSIONS: Gated-SPECT,
      due to the information it provides about left ventricular function, predicts the
      prognosis of patients after coronary revascularization.

PMID- 12622959
TI  - [Proteomics and cardiovascular disease].
AB  - The description of the human genome has opened new venues for the study and
      understanding of pathophysiological phenomena. In the 20th century, individual
      cell components were studied. The 21st century began with a global analysis of
      cell components. Thanks to the development of new technologies such as DNA chips,
      or two-dimensional electrophoresis, we can now study the expression of thousands
      of genes, or the proteins they encode, in a few hours. Genomics has opened the
      way for proteomics. Improved knowledge of genes does not provide information
      about cell functions, because any cell expresses all genes simultaneously.
      Instead, there is selective gene expression depending on the cell type and the
      stimuli to which it is exposed. The result of this is the proteome, an ensemble
      of proteins that are responsible for cell functions at any given moment, which
      are the object of the study of proteomics. The description of the proteome of
      cardiac cells has begun and some new proteins have been found to be dysregulated
      in different cardiomyopathies. These proteins are involved either in energy
      production or in the stress response, or belong to the cell proteasome or
      cytoskeleton. They may be potential risk markers or new therapeutic targets in
      the future. In this sense, chemogenomics is a new methodology for the development
      of new drugs using genomic and proteomic data.

PMID- 12622960
TI  - [Risk stratification after acute myocardial infarction].
AB  - In recent years, the characteristics of patients who suffer acute myocardial
      infarction without complications during hospitalization have changed. In
      addition, the range of non-invasive studies available for evaluating left
      ventricular systolic function, residual myocardial ischemia, and myocardial
      viability in these patients has improved. Left ventricular systolic function and
      residual ischemia should be evaluated in all patients before release. The non
      invasive technique used (exercise test, echocardiography, nuclear cardiology,
      magnetic resonance imaging) depends on availability, experience, and results at
      each institution. Coronary arteriography should be performed in patients with
      significant ischemia or severe left ventricular systolic dysfunction in non
      invasive studies. In these cases coronary angiography must be performed to
      determine if coronary arteries are suitable for revascularization before
      performing a test of myocardial viability.

PMID- 12622961
TI  - [Penetrating atherosclerotic ulcer of the descending aorta].

PMID- 12622962
TI  - [Could fractional flow reserve guide therapeutic strategy in acute coronary
      syndrome?].
AB  - Fractional flow reserve, as determined with a pressure-wire, was validated in the
      assessment of the functional severity of intermediate lesions in a population
      with stable ischemic cardiopathy. The value of pressure-wire analysis in acute
      coronary syndrome is unknown. We report two patients with acute coronary
      syndrome, in which the therapeutic approach was guided by the fractional flow
      reserve. We discuss the utility of this tool in this context.

PMID- 12622963
TI  - [Multiple coronary embolisms in a woman with risk factors for thromboembolic
      disease].
AB  - We report the case of a 33-years-old woman, smoker and taking oral
      contraceptives, who presented to the emergency room with an anterior ST-elevation
      myocardial infarction. Thrombolytic treatment was initiated and a few minutes
      after, chest pain returned and an inferior ST-segment-elevation infarction was
      diagnosed at that moment. Catheterization revealed multiple embolic occlusion of
      coronary branches. We discuss tests performed and pathophysiology of myocardial
      infarction in this patient.

PMID- 12622964
TI  - [Usefulness of magnetic resonance imaging in the assessment of endomyocardial
      disease].
AB  - Endomyocardial disease is a restrictive cardiomyopathy that includes Loffler
      endocarditis, which is characterized by hypereosinophilia, and endomyocardial
      fibrosis, which is not. Echocardiography enables cardiac function and anatomy to
      be assessed and the differential diagnosis of other causes of restrictive
      disease, but magnetic resonance imaging provides information about the tissue
      itself. Furthermore, paramagnetic contrast agents are useful in detecting
      myocardial abnormalities. We report three cases of endomyocardial disease and the
      typical findings of magnetic resonance imaging.

PMID- 12622965
TI  - [Coronary stent infection: case report and definition].

PMID- 12622966
TI  - [Pneumococcus and quinolone resistance].

PMID- 12622967
TI  - [Pneumonia in the patient with chronic obstructive pulmonary disease. Levels of
      severity and risk classification].
AB  - OBJECTIVES: To analyze the severity, clinical course and mortality in patients
      with community-acquired pneumonia and COPD. METHOD: Retrospective study of
      patients admitted with pneumonia over a period of 12 months. From records, we
      gathered information related to patient characteristics, signs and symptoms and
      concomitant disease and classified each patient according to risk. RESULTS: One
      hundred twenty-nine patients with a mean age of 71.13 (SD 17) were identified; 43
      (33.3%) had COPD with severe airflow obstruction (FEV1 937 mL, SD 309), although
      there were no differences from one risk classification to another. No significant
      differences were found in mortality, as 8 patients (18.6%) with COPD died and 9
      patients (10.7%) without COPD. The length of hospital stay was similar in both
      groups. Patients with COPD suffered more severe pneumonia and were at higher risk
      (classes IV and V). The percentage of COPD patients using chronic domiciliary
      oxygen therapy who died (75%) was different from the percentage of such patients
      who lived (37%); percent mortality also differed by level of risk. Patients
      receiving oxygen therapy had greater obstruction and greater respiratory
      insufficiency upon admission (PaO2/FiO2: 216.9, SD 41.92). CONCLUSIONS: The
      mortality rates and mean hospital stays of patients with and without COPD who are
      admitted with community-acquired pneumonia are similar, but patients with COPD
      suffer more severe pneumonia. Mortality is higher in patients with community
      acquired pneumonia and COPD who are receiving domiciliary oxygen therapy and have
      greater airflow obstruction and respiratory deterioration upon admission.

PMID- 12622968
TI  - [Nasal resistance and continuous positive airway pressure treatment for sleep
      apnea/hypopnea syndrome].
AB  - OBJECTIVE: To evaluate the relation between nasal resistance and tolerance and
      compliance with continuous positive airway pressure (CPAP) in patients with
      obstructive sleep apnea/hypopnea syndrome (SAHS). MATERIAL AND METHOD: One
      hundred twenty-five patients with a mean apnea/hypopnea index (AHI) of 53 21 were
      assessed for nasal resistance by active anterior rhinometry before starting CPAP
      treatment. Airflow (cm3/s) at 150 Pa was measured at each nostril. Tolerance for
      and compliance with CPAP was assessed at 2 weeks, 6 months and one year after
      start of treatment. RESULTS: The mean CPAP prescribed was 9 2 cmH2O. Rhinometry
      findings were considered pathological for 70 patients (56%). We observed no
      correlation between nasal flow and the CPAP established (r = 0.018). The
      treatment compliance objective in the first year was 5 1.5 hours/day. The most
      common nasal side effects during this period were runny nose, itching and
      sneezing (24%), oronasal dryness (21%) and subjective nasal obstruction (6%).
      There were no significant differences in tolerance of or compliance with CPAP
      treatment between patients with normal or abnormal rhinometry. CONCLUSIONS: Nasal
      resistance assessed by anterior rhinometry is unrelated to optimum CPAP and does
      not affect either tolerance or compliance among patients with SAHS.

PMID- 12622969
TI  - [Emergency lung transplantation].
AB  - INTRODUCTION: Lung donors are scarce and lung transplantation resources limited,
      leading to a need to look at transplants in terms of efficiency. Because
      emergency transplants (C-0) are assumed to yield poor results, most countries do
      not perform them on a regular basis. Spain, however does accept the concept of
      emergency lung transplantation for patients who are on waiting lists. We assess
      outcome for our patients who have received scheduled and emergency transplants.
      MATERIAL AND METHOD: The survival of patients receiving lung transplants in our
      service from 1992 through 2001 was studied using, Kaplan-Meier, Cox regression
      and chi-squared statistical analyses. We compared outcome and perioperative
      mortality (over 30 days) for scheduled versus C-0 procedures, analyzing the
      influence of certain variables (age, sex, emergency status, type of transplant,
      mechanical ventilation and use of extracorporeal membrane oxygenation). RESULTS:
      Eleven of 183 lung transplants were C-0 and 172 were scheduled. Forty-one were
      single-lung and 142 were double-lung transplants. Perioperative mortality was
      36.4% for emergency procedures and 8.7% for scheduled procedures (p = 0.0035).
      Survival was significantly better for scheduled patients than for C-0 patients (p
      = 0.0032), although outcome was similar when perioperative mortality was not
      taken into account (58.16% vs. 57.14% at 5 years for scheduled and C-0 patients,
      respectively). CONCLUSIONS: Long-term survival after lung transplantation shows
      that the procedure is effective and efficient in C-0 patients, in spite of
      perioperative risk, provided the patient has been adequately monitored.

PMID- 12622970
TI  - [Histopathological changes in sympathetic ganglia of patients treated surgically
      for palmar-axillary hyperhidrosis. A study of 55 biopsies].
AB  - INTRODUCTION: Primary palmar hyperhidrosis (PPH) mainly affects the sympathetic
      ganglia. This study aims to analyze the histopathological changes in the
      sympathetic ganglia of patients with PPH. MATERIAL AND METHOD: We studied 55
      tissue samples from 35 patients with PPH who underwent T2-T3 gangliectomy for
      definitive treatment of their disease, analyzing the presence of inflammation,
      chromatolysis and lipofuscin accumulation. Findings were analyzed in relation to
      age, compensatory sweating and type of surgery: unilateral, synchronic bilateral
      or sequential bilateral. RESULTS: We found inflammation in 5.5%, chromatolysis in
      61.8% and lipofuscin accumulation in 41.8% of the samples. Chromatolysis and
      lipofuscin were found without inflammation in 32.1%. Chromatolysis and lipofuscin
      accumulation were each found in 60% of the samples from synchronic bilateral
      sympathectomies. However, those percentages decreased between the first and
      second sympathectomies in sequential procedures, such that chromatolysis was
      found in 71.4% of first-procedure samples and 42.8% of second-procedure samples;
      the rates for lipofuscin accumulation changed from 64.2% to 14.2%. Although
      findings were unrelated to age, they did correlate with compensatory sweating,
      which was found in 79.7% of patients undergoing synchronic bilateral
      sympathectomy, 78.5% of sequential bilateral sympathectomy patients and only
      56.25% of unilateral sympathectomy patients. CONCLUSIONS: Neuronal death and
      lipofuscin accumulation unrelated to inflammation are evident in sympathetic
      ganglia from patients with PPH. Such changes are atypical for a group of patients
      whose mean age is 29 years, unless such lesions are the result of functional
      hyperstimulation. Surgery performed sequentially does not lead to overloading of
      contralateral T2-T3 ganglia; on the contrary, decreased injury is evident.

PMID- 12622971
TI  - [Protocol to evaluate automatic continuous positive airway pressure. Assessment
      of the usefulness of the Autoset-T device to determine optimal pressure for
      treating sleep apnea/hypopnea syndrome].
AB  - INTRODUCTION: Given the high prevalence of sleep apnea/hypopnea syndrome (SAHS)
      and great demand for conventional polysomnography (PSG) and long waiting lists,
      alternative means for diagnosing SAHS and titrating continuous positive airway
      pressure (CPAP) are needed. Automatic CPAP may play a role in meeting the last
      objective, not only for treatment but also for suggesting the optimum CPAP
      setting. OBJECTIVES: a) To define a protocol to assess the functioning of an
      automatic CPAP device by means of a mechanical model; b) to determine the
      behavior of automatically adjusted CPAP during PSG; c) to define the usefulness
      of automatic CPAP for indicating optimal CPAP pressure for patients with SAHS; d)
      to evaluate the efficacy of the automatically indicated pressure setting against
      conventional PSG. METHODS: Four protocols were carried out using the Autoset-T
      (AT) device. 1. Apneas, hypopneas, flow limitation, snoring and normal flow were
      simulated in a laboratory using a mechanical model in order to check AT
      functioning. 2. The behavior of the automatically adjusted CPAP was observed in
      real time during PSG in 12 patients with severe SAHS. 3. The agreement of CPAP
      titrated with the AT and with PSG was checked in a group of 39 patients with
      SAHS. 4. The efficacy of the CPAP pressure recommended by the AT was checked by
      PSG in a group of 14 patients with SAHS. RESULTS: With the AT, CPAP increased
      rapidly in response to apneas or snoring in the mechanical model and during
      conventional PSG; it took only a mean 2.8 3.1 min to rise from a baseline
      pressure of 4 cm H2O to a near-optimum pressure of 11 1 cm H2O. Once normal flow
      was reached CPAP slowly decreased, responding with great sensitivity to the
      slightest abnormality, especially snoring, but not changing in response to
      certain types of flow limitation. The pressure read visually on the AT was
      similar to the one recommended by PSG in most of the 39 patients (71%). The PSG
      performed after one month of using AT-recommended CPAP titration confirmed that
      the number of apneas, hypopneas (apnea/hypopnea index 6(1) and arousals (8 2) was
      normal for these SAHS patients. CONCLUSIONS: The AT increases pressure rapidly in
      the presence of respiratory events and maintains a normal breathing pattern in
      most patients. Visual reading of the AT pressure allows correct identification of
      the optimal CPAP setting for SAHS treatment.

PMID- 12622972
TI  - [Stress testing and lung resection surgery].

PMID- 12622973
TI  - [Lipoid pneumonia related to workplace exposure to paint].
AB  - A 49-year-old man with no known history of pulmonary disease was treated at our
      hospital after observation of an interstitial pattern on a chest film. The
      patient was a smoker and professional painter. Computed tomography of the chest
      showed a diffuse bilateral ground-glass pattern. The lung biopsy showed intra
      alveolar lipid accumulation in the form of vacuoles of varying sizes surrounded
      by numerous focally multinucleated macrophages, establishing a definitive
      diagnosis of exogenous lipoid pneumonia. Given the patient's profession, he was
      recommended to avoid workplace exposure to paraffins and oily sprays. The
      clinical course was favorable after exposure was stopped, with improved lung
      function and symptoms.

PMID- 12622974
TI  - [Primary pulmonary synovial sarcoma: a report and diagnosis of 2 cases].
AB  - Synovial sarcoma is an extremely rare primary pulmonary tumor whose description
      is based on a limited number of cases. We report two cases diagnosed by
      thoracotomy. One patient was initially treated surgically, and a later recurrence
      was controlled by combined chemotherapy and a second operation after three years
      of monitoring. In the second case, surgery was imperative to treat massive
      hemoptysis and was followed by combined chemotherapy after diagnosis of lesions
      consistent with extrapulmonary metastasis.

PMID- 12622975
TI  - [A word against increasing the number of chest surgeons].

PMID- 12622976
TI  - [The distribution of thoracic surgeons in Spain. Scarcity or plethora].

PMID- 12622978
TI  - [Rigid bronchoscopy and foreign bodies in the airway].

PMID- 12622979
TI  - [semFYC and the third sector: more than just a society in society].

PMID- 12622980
TI  - [Effectiveness of medical counseling for alcoholic patients and patients with
      excessive alcohol consumption seen in primary care].
AB  - AIM: To determine the effectiveness of medical counseling for alcohol abuse, when
      it is provided in primary care centers. DESIGN: Quasi-experimental, open,
      multicenter before-after study.Setting. 14 primary care physician's practices (7
      rural, 7 urban) in the province of Cordoba (Spain). PARTICIPANTS: 306 patients of
      both sexes, recruited with a case-finding strategy, who consumed >=35 (men) or
      >=21 (women) IU per week, or who had alcohol dependence syndrome (ADS) (MALTS
      score O>=11). Interventions. All patients were offered brief counseling to reduce
      drinking, and all were followed to evaluate their status 3 months, 1 year and 2
      years later. MAIN MEASURES: The response variable was self-reported alcohol
      consumption together with normal GGT values or confirmation of alcohol
      consumption by a relative. The results were subjected to intention-to-treat
      analysis. RESULTS: Of the 306 patients included in the study, 95.1% were men and
      78.4% had ADS. After 2 years 38.89% (95% CI, 32.2%-44.3%) had attained their
      treatment goal: 23.85% were in complete abstinence, and 15.0% consumed moderate
      amounts of alcohol below the limit considered to indicate risk. Starting
      excessive consumption at less than 16 years of age (odds ratio [OR], 3.0885),
      living in a slum (OR, 3.2103), smoking (OR, 1.7187), and a positive CAGE test
      (OR, 1.9949) were associated with failure of the intervention (P<.05).
      CONCLUSIONS: Counseling provided by the family doctor was highly effective under
      the usual conditions of general practice, both for patients with excessive
      alcohol consumption and for patients with con ADS.

PMID- 12622981
TI  - [Editorial commentary: primary care intervention for at-risk drinking].

PMID- 12622982
TI  - [Detection of cardiovascular risk factors in the reformed primary care network in
      Catalonia. Comparison between the years 1995 and 2000].
AB  - OBJECTIVES: To know if much the detection and control of cardiovascular risk
      factors (FRCV) have been incorporated in primary care settings (PCS) on 2000 and
      compare them with 1995 results. Design and participants. A descriptive cross
      sectional study of a random sample of 5,875 of clinical histories (CH) of
      patients aged 15 and over attended during 2000 in PCS, which had been in
      operation for over three years. MEASUREMENTS AND MAIN RESULTS: Whether were
      recorded values, levels, diagnoses and control related to: blood pressure,
      cholesterol, glucose, weight, size, tobacco and alcohol consumption, in order to
      compare 1995 and 2000 results obtained with the same methodology. Cholesterol
      levels (57.3%), blood pressure values (52.9%) and glucose levels (51.3%) are the
      most recorded variables in CH. Obese diabetics and high blood pressure patients
      are the most studied with a mean of 3.6 records in the CH related others CRF.
      Smoking (41.7%) and hypertension (32.9%) are the most frequents diagnoses. The
      32.3% of the high blood pressure patients have optimum control and 42.9%
      acceptable control. The 31.2% hyperlipaemia and the 34.1% diabetic patients are
      controlled. Compared with 1995, the main variations observed are: an increase of
      the records of cholesterol levels and glucose levels and a decrease of the
      others, especially in tobacco and alcohol consumption screening. Diabetes and
      obesity diagnosis decrease and smoking and excessive alcohol consumption increase
      have been also observed. Screening age and sex group differences are maintained.
      CONCLUSIONS: The results suggest that may be a change in CRF screening
      performance is happening and the influencial factors would be study.

PMID- 12622983
TI  - [Effectiveness of combined therapy at set doses in a cohort of hypertense
      patients not controlled by single therapy].
AB  - OBJECTIVE: To evaluate the effectiveness of the fixed dose of a lisinopril
      hydrochlorothiazide combination treatment in the control of blood pressure, in
      poorly controlled high blood pressure people, treated with monotherapy.Design.
      Prospective observational study.Setting. Primary care frame.Participants. 931
      patients (56.7% women) with an average age of 62.0+/-3 years, were included by
      199 primary care physicians. 915 patients (98%) ended the study and finally they
      were included for the statistical analysis. MAIN MEASUREMENTS: OMS/SIH
      recommendations on blood pressure measurement and diagnose of poor control were
      followed. Pulse pressure, body mass index and basic clinical analyses were
      assessed. Four continuation visits were made during six months. RESULTS:
      Lisinopril-hidrochlorothiazide (20/12.5 mg) reduced significantly SBP (24.6 +/-
      3.5 mm Hg) and DBP (14,3 +/- 0.7 mm Hg) (P<.001). Blood pressure control was only
      influenced by age (OR, 0.81; 95% CI, 0.71-0.92; P=.001). Pulse pressure was
      reduced in 10.4 +/- 4.3 mm Hg (P<.001). After 24 weeks of treatment, glycemic and
      lipidic profiles showed an improvement, as well as HbA1c in diabetic people.
      CONCLUSIONS: In Primary care, a 52.8% of poorly controlled with monotherapy high
      blood pressure people were controlled by a combination of lisinopril
      hydrochlorothiazide (20/12.5 mg). In addition, pulse pressure was decreased and
      both lipid and glucose blood profiles improved.

PMID- 12622984
TI  - [Views of primary care users concerning generic medicines and the cost of
      medication].
AB  - OBJECTIVES: To assess primary care users' views on generic drugs, approach to
      them and degree of understanding of them; and to find the importance they attach
      to the economic cost of medication. DESIGN: Transversal, descriptive study.
      SETTING: Primary care. PARTICIPANTS: A sample of 231 patients was selected from
      all the people over 18 who attended the health centre for medical consultation
      during 2001. RESULTS: 60% (95% CI, 55.22%-67.42%) of those surveyed said they had
      heard of generic medicines. The communications media were the main source of
      information, accounting for 78.4% of cases (95% CI, 69.19%-83.96%). 48.04% (95%
      CI, 38.04%-58.16%) of those who had heard of generic medicines had taken them on
      some occasion; and 32.4% (95% CI, 23.42%-42.34%) normally took them. 76.47% (95%
      CI, 67.04%-84.30%) did not mind or, where appropriate, would not mind if their
      doctor changed a medicine they normally took for a generic one. The mean age of
      those who did not mind was significantly lower than that of those who did. 50%
      (95% CI, 42.25%-52.75%) of those questioned were very interested in the cost of
      drugs prescribed by their doctors: people still working were more interested than
      those on a pension. 67.6% (95% CI, 60.06%-74.61%) believed that doctors should
      try to prescribe the cheapest drugs, as long as they were equally efficacious.
      78.8% of those questioned (95% CI, 71.91%-84.70%) would choose the cheaper of two
      drugs which were the same bar the cost. CONCLUSIONS: Most patients in our study
      were aware of generic drugs and were not against the replacement of a medicine
      they were already taking by a generic one. They did not relate drugs' cost to
      their quality.

PMID- 12622985
TI  - [Primary care and eating disorders: our attitude towards them (I)].

PMID- 12622986
TI  - [Report on passive smoking].

PMID- 12622987
TI  - [Glycaemic risk and contribution of post-prandial glucaemia to glycosylated
      haemoglobin (HbA 1c )].

PMID- 12622988
TI  - [Advances and controversies in medical treatment of depression].

PMID- 12622989
TI  - [Immunisation: leaps into the future: a new concept: therapeutic immunisation].

PMID- 12622990
TI  - [Do we in primary care carry out properly procedures for early detection of
      cervical cancer?].

PMID- 12622991
TI  - [Convulsive episode secondary to bupropion in a patient not included in a risk
      group].

PMID- 12622992
TI  - [Is satisfaction with ones own weight relevant in primary care?].

PMID- 12622993
TI  - [Inadequate analysis casts doubt on the benefits of health education in
      fibromyalgia].

PMID- 12622994
TI  - [Causes of mortality at a primary care centre].

PMID- 12622996
TI  - [Scapulo-humeral luxation and convulsive crises].

PMID- 12622997
TI  - [Clinical use of transcranial Doppler in critical neurological patients. Results
      of a multicenter study].
AB  - BACKGROUND AND OBJECTIVE: We aimed to determine the clinical usefulness of
      transcranial Doppler (TCD) in critical neurological patients. PATIENTS AND
      METHOD: Prospective, multicenter study of 66 patients (44 men) with acute
      neurologic disorders (16 brain injury, 25 subarachnoid hemorrhage, 15
      intracerebral hemorrhage, 2 ischemic stroke, 2 metabolic encephalopaty, 5 brain
      ischemia after cardiac arrest, and another pathology), admitted to 7 intensive
      care units. Data collection was performed during one month from 8 AM to 5 PM. An
      ultrasonographic study was performed in every patient every day; 234 studies were
      performed with 227 medium cerebral artery (MCA) blood flow determinations.
      Several patterns of cerebral blood flow were established: normal, hyperhemia,
      vasospasm, intracranial hypertension and brain death. RESULTS: Intracranial
      hypertension was found during 109 determinations (48%), a normal pattern was
      found in 104 (45.5%), hyperhemia in 9 (4%) and brain death in 5 (2.2%) patients.
      Doppler determinations meant that, in 195 cases (86%) no change in the clinical,
      diagnostic or therapeutic approach was necessary, in 18 cases (8%) medical
      treatment was changed, in 8 cases (3.5%) it was suggested to perform a CT scan
      and in 2 cases (0.9%) it was suggested to perform an EEG. Moreover, an
      intracranial pressure monitoring was indicated after one Doppler determination
      (0.4%) and in 3 cases (1.3%) a brain death diagnosis was done. CONCLUSIONS: The
      use of transcranial Doppler in critical neurological patients modified the
      management in 36% of them.

PMID- 12622998
TI  - [Prevalence of iodine deficiency and related factors in 4 year-old
      schoolchildren].
AB  - BACKGROUND AND OBJECTIVE: Iodine deficiency in early years of life can cause
      important disorders in body growth and development. The aim of this study was to
      determine the prevalence of iodine deficiency in 4 year-old schoolchildren from
      the town of Mataro (Barcelona, Spain) and to know the factors associated with
      this nutritional deficiency. PATIENTS AND METHOD: A population-based cross
      sectional study was designed, which included all 4 year-old schoolchildren of
      this town. A physicians team performed a basic physical examination and collected
      urine samples for iodine determination. Parents were asked to answer a
      nutritional habits questionnaire. RESULTS: Eight hundred and sixty urine samples
      were obtained from 987 participants. Mean urinary iodine levels were 214.1 g/l
      (SD = 103.3 g/l) and the median was 189.0 g/l. Prevalence of iodine deficiency
      was 7.8% at a 100 g/l cut-off point and 1.2% at a 50 g/l cut-off point.
      Statistical differences in the prevalence of iodine deficiency were observed
      between ethnic groups: while natives had a prevalence of 7.0%, in Magrebins it
      was 18.4%, Subsaharians 20.0% and other ethnical groups 14.3% (p = 0.016).
      CONCLUSIONS: Schoolchildren in Mataro have adequate urinary iodine levels
      according to WHO recommendations with a relatively low prevalence of iodine
      deficiency. However, even after adjustments for the knowledge of the existence of
      iodized salt, iodine deficiency correlates with the child's ethnic origin (native
      or immigrant).

PMID- 12622999
TI  - [Effect of renal revascularization techniques on renal function and blood
      pressure control].
AB  - BACKGROUND AND OBJECTIVE: Our objective was to assess the effect of renal
      revascularization on renal function and blood pressure control. PATIENTS AND
      METHOD: Retrospective analysis of primary renal revascularization procedures
      performed during a 6-year period. Parameters of renal function and blood pressure
      control were assessed before and after the procedure. RESULTS: Forty consecutive
      renal artery revascularizations were performed in 36 patients (12 aorto-renal
      bypasses and 28 percutaneous transluminal angioplasties, 4 bilateral). At the
      first month, the renal function improved in 50% cases, but at the mean follow-up
      it improved only in 26%. At the first month, blood pressure control improved in
      50% patients, but at the mean follow-up, it only improved in 28%. CONCLUSIONS:
      Renal revascularization does not offer a medium-term benefit in most patients.

PMID- 12623001
TI  - [Topic calcineurin inhibitors].

PMID- 12623000
TI  - [Infection due to Mycobacterium kansasii in Elche, Spain].
AB  - BACKGROUND AND OBJECTIVE: Our goal was to determine the incidence of infection
      due to Mycobacterium kansasii in Elche, Spain over the last 10 years and to study
      the activity of new antibiotics against the strains isolated. MATERIAL AND
      METHODS: A retrospective study of patients and study of antibiotic susceptibility
      in vitro. RESULTS: The annual incidence of infection by this microorganism was
      2.66 cases/ 1,000,000 inhabitants per year. In patients with AIDS, the incidence
      increased to 571.4 cases/1,000,000 inhabitants per year. Gatifloxacin and
      moxifloxacin exhibit better in vitro activity than levofloxacin; in some strains,
      a synergism exists between rifampi cin/fluoroquinolones and rifampicin/linezolid.
      CONCLUSION: In Elche, infections due to M. kansasii are uncommon. It is necesary
      to continue evaluating the activity of fluoroquinolones and linezolid.

PMID- 12623002
TI  - [Committees on Ethics and Clinical Research over 10 years: risks of complacency].

PMID- 12623003
TI  - [About Spanish continued medical training certification].

PMID- 12623004
TI  - [Growth factors, cell damage, cyclin-dependent kinases and their inhibitors:
      relevance in molecular pathology of human cancer].

PMID- 12623005
TI  - [Pseudovasculitic syndromes].

PMID- 12623006
TI  - [Internal jugular vein thrombosis after cocaine inhalation in a woman with factor
      V Leiden].

PMID- 12623007
TI  - [Erosive seronegative arthritis associated with monoclonal gammopathy].

PMID- 12623008
TI  - Binding platforms for Rab prenylation and recycling: Rab escort protein, RabGGT,
      and RabGDI.

PMID- 12623009
TI  - The bacteriophage PRD1 uses a pseudo-beta propeller to bind to its cellular
      receptor.

PMID- 12623010
TI  - A new kinase fold.

PMID- 12623011
TI  - Conformational evolution: the wiggling of peptides into amyloid.

PMID- 12623012
TI  - The unfolding story of three-dimensional domain swapping.
AB  - Three-dimensional domain swapping is the event by which a monomer exchanges part
      of its structure with identical monomers to form an oligomer where each subunit
      has a similar structure to the monomer. The accumulating number of observations
      of this phenomenon in crystal structures has prompted speculation as to its
      biological relevance. Domain swapping was originally proposed to be a mechanism
      for the emergence of oligomeric proteins and as a means for functional
      regulation, but also to be a potentially harmful process leading to misfolding
      and aggregation. We highlight experimental studies carried out within the last
      few years that have led to a much greater understanding of the mechanism of
      domain swapping and of the residue- and structure-specific features that
      facilitate the process. We discuss the potential biological implications of
      domain swapping in light of these findings.

PMID- 12623013
TI  - Nucleotide-induced conformational changes in an isolated Escherichia coli DNA
      polymerase III clamp loader subunit.
AB  - Sliding clamps are loaded onto DNA by ATP-driven clamp loader complexes. The
      structure of the E. coli clamp loader in a nucleotide-free state has been
      determined previously. We now report crystal structures of a truncated form of
      the isolated gamma-ATPase subunit, gamma(1-243), of the E. coli clamp loader, in
      nucleotide-free and bound forms. The gamma subunit adopts a defined conformation
      when empty, in which the nucleotide binding site is blocked. The binding of
      either ATPgammaS or ADP, which are shown to bind with equal affinity to gamma(1
      243), induces a change in the relative orientation of the two domains such that
      nucleotides can be accommodated. This change would break one of the gamma:gamma
      interfaces seen in the empty clamp loader complex, and may represent one step in
      the activation process.

PMID- 12623015
TI  - The 2.2 A crystal structure of a pocilloporin pigment reveals a nonplanar
      chromophore conformation.
AB  - Reef-building corals contain host pigments, termed pocilloporins, that function
      to regulate the light environment of their resident microalgae by acting as a
      photoprotectant in excessive sunlight. We have determined the crystal structure
      of an intensely blue, nonfluorescent pocilloporin to 2.2 A resolution and a
      genetically engineered fluorescent variant to 2.4 A resolution. The pocilloporin
      chromophore structure adopts a markedly different conformation in comparison with
      the DsRed chromophore, despite the chromophore sequences (Gln-Tyr-Gly) being
      identical; the tyrosine ring of the pocilloporin chromophore is noncoplanar and
      in the trans configuration. Furthermore, the fluorescent variant adopted a
      noncoplanar chromophore conformation. The data presented here demonstrates that
      the conformation of the chromophore is highly dependent on its immediate
      environment.

PMID- 12623014
TI  - Crystal structure of human riboflavin kinase reveals a beta barrel fold and a
      novel active site arch.
AB  - Riboflavin kinase (RFK) is an essential enzyme catalyzing the phosphorylation of
      riboflavin (vitamin B(2)) to form FMN, an obligatory step in vitamin B(2)
      utilization and flavin cofactor synthesis. The structure of human RFK revealed a
      six-stranded antiparallel beta barrel core structurally similar to the riboflavin
      synthase/ferredoxin reductase FAD binding domain fold. The binding site of an
      intrinsically bound MgADP defines a novel nucleotide binding motif that
      encompasses a loop, a 3(10) helix, and a reverse turn followed by a short beta
      strand. This active site loop forms an arch with ATP and riboflavin binding at
      the opposite side and the phosphoryl transfer appears to occur through the hole
      underneath the arch. The invariant residues Asn36 and Glu86 are implicated in the
      catalysis.

PMID- 12623016
TI  - Pyruvoyl-dependent arginine decarboxylase from Methanococcus jannaschii: crystal
      structures of the self-cleaved and S53A proenzyme forms.
AB  - The three-dimensional structure of pyruvoyl-dependent arginine decarboxylase from
      Methanococcus jannaschii was determined at 1.4 A resolution. The pyruvoyl group
      of arginine decarboxylase is generated by an autocatalytic internal serinolysis
      reaction at Ser53 in the proenzyme resulting in two polypeptide chains. The
      structure of the nonprocessing S53A mutant was also determined. The active site
      of the processed enzyme unexpectedly contained the reaction product agmatine. The
      crystal structure confirms that arginine decarboxylase is a homotrimer. The
      protomer fold is a four-layer alphabetabetaalpha sandwich with topology similar
      to pyruvoyl-dependent histidine decarboxylase. Highly conserved residues Asn47,
      Ser52, Ser53, Ile54, and Glu109 are proposed to play roles in the self-processing
      reaction. Agmatine binding residues include the C terminus of the beta chain
      (Ser52) from one protomer and the Asp35 side chain and the Gly44 and Val46
      carbonyl oxygen atoms from an adjacent protomer. Glu109 is proposed to play a
      catalytic role in the decarboxylation reaction.

PMID- 12623017
TI  - Dissecting the assembly of Abeta16-22 amyloid peptides into antiparallel beta
      sheets.
AB  - Multiple long molecular dynamics simulations are used to probe the
      oligomerization mechanism of Abeta(16-22) (KLVFFAE) peptides. The peptides, in
      the monomeric form, adopt either compact random-coil or extended beta strand-like
      structures. The assembly of the low-energy oligomers, in which the peptides form
      antiparallel beta sheets, occurs by multiple pathways with the formation of an
      obligatory alpha-helical intermediate. This observation and the experimental
      results on fibrillogenesis of Abeta(1-40) and Abeta(1-42) peptides suggest that
      the assembly mechanism (random coil --> alpha helix --> beta strand) is universal
      for this class of peptides. In Abeta(16-22) oligomers both interpeptide
      hydrophobic and electrostatic interactions are critical in the formation of the
      antiparallel beta sheet structure. Mutations of either hydrophobic or charged
      residues destabilize the oligomer, which implies that the 16-22 fragments of
      Arctic (E22G), Dutch (E22Q), and Italian (E22K) mutants are unlikely to form
      ordered fibrils.

PMID- 12623018
TI  - The receptor binding protein P2 of PRD1, a virus targeting antibiotic-resistant
      bacteria, has a novel fold suggesting multiple functions.
AB  - Bacteriophage PRD1 is unusual, with an internal lipid membrane, but has striking
      resemblances to adenovirus that include receptor binding spikes. The PRD1 vertex
      complex contains P2, a 590 residue monomer that binds to receptors on antibiotic
      resistant strains of E. coli and so is the functional counterpart to adenovirus
      fiber. P2 structures from two crystal forms, at 2.2 and 2.4 A resolution, reveal
      an elongated club-shaped molecule with a novel beta propeller "head" showing
      pseudo-6-fold symmetry. An extended loop with another novel fold forms a long
      "tail" containing a protruding proline-rich "fin." The head and fin structures
      are well suited to recognition and attachment, and the tail is likely to trigger
      the processes of vertex disassembly, membrane tube formation, and subsequent DNA
      injection.

PMID- 12623019
TI  - Crystal structure of the E. coli Hsp100 ClpB N-terminal domain.
AB  - E. coli Hsp100 ClpB can disaggregate denatured polypeptides by employing ATP
      hydrolysis. The ClpB N-terminal domain (ClpBN) has been proposed to play
      important roles in ClpB molecular chaperone activities. We have determined the
      crystal structure of ClpBN to 1.95 A resolution by MAD methods. The ClpBN monomer
      contains two subdomains that have similar folds. The crystal structure revealed a
      hydrophobic groove on the molecular surface. We have constructed ClpB mutants in
      which the hydrophobic residues within the putative peptide binding groove were
      replaced by glutamine. These ClpB mutants exhibited severe defects in molecular
      chaperone activity but retained the wild-type ATPase activity.

PMID- 12623020
TI  - Structural basis for the antibiotic activity of ketolides and azalides.
AB  - The azalide azithromycin and the ketolide ABT-773, which were derived by chemical
      modifications of erythromycin, exhibit elevated activity against a number of
      penicillin- and macrolide-resistant pathogenic bacteria. Analysis of the crystal
      structures of the large ribosomal subunit from Deinococcus radiodurans complexed
      with azithromycin or ABT-773 indicates that, despite differences in the number
      and nature of their contacts with the ribosome, both compounds exert their
      antimicrobial activity by blocking the protein exit tunnel. In contrast to all
      macrolides studied so far, two molecules of azithromycin bind simultaneously to
      the tunnel. The additional molecule also interacts with two proteins, L4 and L22,
      implicated in macrolide resistance. These studies illuminated and rationalized
      the enhanced activity of the drugs against specific macrolide-resistant bacteria.

PMID- 12623021
TI  - Collagen stabilization at atomic level: crystal structure of designed
      (GlyProPro)10foldon.
AB  - In a designed fusion protein the trimeric domain foldon from bacteriophage T4
      fibritin was connected to the C terminus of the collagen model peptide
      (GlyProPro)(10) by a short Gly-Ser linker to facilitate formation of the three
      stranded collagen triple helix. Crystal structure analysis at 2.6 A resolution
      revealed conformational changes within the interface of both domains compared
      with the structure of the isolated molecules. A striking feature is an angle of
      62.5 degrees between the symmetry axis of the foldon trimer and the axis of the
      triple helix. The melting temperature of (GlyProPro)(10) in the designed fusion
      protein (GlyProPro)(10)foldon is higher than that of isolated (GlyProPro)(10,)
      which suggests an entropic stabilization compensating for the destabilization at
      the interface.

PMID- 12623023
TI  - Stage-dependent hatching responses of rohu (Labeo rohita) embryos to different
      concentrations of cryoprotectants and temperatures.
AB  - Hatching performances of three embryonic stages of postfertilization rohu (Labeo
      rohita) (9-, 12-, and 15-h) were examined after treatment with various
      concentrations (0.5-4.5M) of two cryoprotectants (methanol and propylene glycol)
      supplemented with 0.1M trehalose. Different lengths of storage (1-48 h) and
      temperature (-4 degrees C to ambient) were studied. Of the three stages of
      embryonic development, the 12-h stage proved to be the most suitable stage for
      low temperature storage, showing the highest percentage of hatch out (72+/-2%)
      with 2.0M methanol and 0.1M trehalose. Methanol was more useful for storage at
      higher temperatures and propylene glycol at subzero temperatures. The maximum
      possible duration of effective storage of 12-h embryos was 31h in 2.0M methanol
      at 0 degrees C. No hatch out was found beyond 31h of storage with all
      concentrations of methanol at 0 degrees C. The results of interactions was that
      the optimal concentration of methanol was 3.0M at 4 degrees C, 2.0M at 0 degrees
      C, and 1.5M at 4 degrees C. Among three embryonic stages 12-h stage showed better
      results in trehalose treatment than sucrose. Among all concentrations of
      trehalose tested 0.1M gave the maximal survival rate of the rohu embryos.

PMID- 12623022
TI  - Geranylgeranyl switching regulates GDI-Rab GTPase recycling.
AB  - Rab GTPases, key regulators of membrane targeting and fusion, require the
      covalent attachment of geranylgeranyl lipids to their C terminus for function. To
      elucidate the role of lipid in Rab recycling, we have determined the crystal
      structure of Rab guanine nucleotide dissociation inhibitor (alphaGDI) in complex
      with a geranylgeranyl (GG) ligand (H(2)N-Cys-(S-GG)-OMe). The lipid is bound
      beneath the Rab binding platform in a shallow hydrophobic groove. Mutation of the
      binding pocket in the brain-specific alphaGDI leads to mental retardation.
      Strikingly, lipid binding acts through a conserved allosteric switching mechanism
      to promote release of the GDI-Rab[GDP] complex from the membrane.

PMID- 12623024
TI  - Effects of glycine and alanine on short-term storage and cryopreservation of
      striped bass (Morone saxatilis) spermatozoa.
AB  - Three experiments were designed to examine the effects of the amino acids glycine
      and alanine on short-term storage and cryopreservation of striped bass
      spermatozoa. In the first experiment, the effect of glycine on post-equilibration
      motility was evaluated. In the presence of 2.5 or 5.0% Me(2)SO, glycine
      treatments (25, 50, and 75 mM) yielded higher (P<0.05) post-equilibration
      motility at all equilibration times examined compared to the control. There was
      no difference (P>0.05) among these three glycine treatments. In the second
      experiment, glycine and alanine at concentrations of 25, 50, 75, or 100mM were
      evaluated for post-thaw motility in the presence of 2.5 or 5% Me(2)SO. When
      compared to the control, both the glycine and alanine treatments showed positive
      effects on post-thaw motility at all concentrations tested. The highest (P<0.05)
      post-thaw motility was achieved with 50mM glycine or 75 mM alanine using 5%
      Me(2)SO. No interaction (P>0.05) between Me(2)SO and glycine or alanine was
      observed, indicating that the effect of glycine or alanine was independent of the
      concentrations of Me(2)SO. In the third experiment, glycine was evaluated for
      sperm motility, after short-term refrigerated storage and after cryopreservation
      of the same refrigerated semen. Sperm motility decreased after 24h of
      refrigerated storage in 50mM glycine treatment and the control, when compared to
      fresh sperm motility. However, 50mM glycine treatment yielded higher (P<0.01)
      sperm motility after both 24 and 48 h of storage as well as higher (P<0.01) post
      thaw motility when compared to the control. An average of 30+/-2.9% and 16+/-2.4%
      post-thaw motility was achieved with the 50mM glycine treatment after 24 and 48 h
      of refrigerated semen, respectively.

PMID- 12623025
TI  - Cryoanalgesia: electrophysiology at different temperatures.
AB  - Somatosensory evoked potentials (SEP) and sensory conduction velocity (SCV) were
      measured in rabbit sciatic nerves following graded cold lesioning. The SEP
      disappeared when injury was induced at temperatures below -60 degrees C, but
      returned on day 41+/-4 (mean+/-SD). SEP returned on day 56+/-11 days when the
      lesion was induced at 100 to -180 degrees C. The SEP latency was prolonged after
      creating lesions at -100 to -180 degrees C, compared with both the sham operated
      and the -20 degrees C groups. These experiments suggest the cryolesions produced
      at temperatures between -60 and -100 degrees C are most suitable for altering the
      electrophysiological conduction of the nerve, and may result in suitable post
      operative analgesia.

PMID- 12623026
TI  - Influence of cooling rate on Saccharomyces cerevisiae destruction during
      freezing: unexpected viability at ultra-rapid cooling rates.
AB  - The purpose of this work was to study cell viability as a function of cooling
      rate during freezing. Cooling rate strongly influences the viability of cells
      during cold thermal stress. One of the particularities of this study was to
      investigate a large range of cooling rates and particularly very rapid cooling
      rates (i.e., faster than 20000 degrees C min (-1)). Four distinct ranges of
      cooling rates were identified. The first range (A(')) corresponds to very slow
      cooling rates (less than 5 degrees C min (-1)), and results in high cell
      mortality. The second range (A) corresponds to low cooling rates (5-100 degrees C
      min (-1)), at which cell water outflow occurs slowly and does not damage the
      cells. The third range (B) corresponds to rapid cooling rates (100-2000 degrees C
      min (-1)), at which there is competition between heat flow and water flow. In
      this case, massive water outflow, which is related to the increase in
      extracellular osmotic pressure and the membrane-lipid phase transition, can cause
      cell death. The fourth range (C) corresponds to very high cooling rates (more
      than 5000 degrees C min (-1)), at which the heat flow is very rapid and partially
      prevents water exit, which seems to preserve cell viability.

PMID- 12623027
TI  - Detrimental effects of cryopreservation of loach (Misgurnus fossilis) sperm on
      subsequent embryo development are reversed by incubating fertilised eggs in
      caffeine.
AB  - Cryopreservation can cause changes to the genetic material of cells, but the
      mechanism and significance of these changes are still unknown. It has been
      suggested that some damage to the sperm genome could be repaired by the DNA
      repair system of the oocyte after fertilisation. Caffeine has been reported to be
      an inhibitor of such repair processes. In this study the effect of caffeine on
      the repair system of Loach (Misgurnus fossilis) oocytes was investigated. Loach
      eggs were fertilised using cryopreserved sperm. Embryos derived from
      cryopreserved sperm were exposed to 2.6mM caffeine for 1h after fertilisation.
      The experiments were carried out using 32313 embryos from four females and eight
      males. Embryo survival was evaluated for 46 h until the hatching stage. Reduction
      in embryo survival after 20th stage is generally believed to result from the
      failure in the genome function of embryos. Cryopreservation of sperm
      significantly decreased embryo survival (53.4+/-2.8% compared to 68.4+/-2.8% of
      control) after the 20th stage. However, the addition of caffeine to the embryos
      derived from cryopreserved sperm, in contrast to our expectation, significantly
      increased survival of loach embryos (70.9+/-2.8% compared to 53.4+/-2.8% of
      embryos derived from cryopreserved sperm in the absence of caffeine). The effect
      of individual donors of sperm and eggs on overall embryo survival was also
      studied. Whilst no significant differences were observed between males, the
      effect of individual females on embryo survival was significant. The analysis of
      embryo survival at different developmental stages showed that embryo survival
      both before and after 20th stage decreased with embryo development. When fresh
      sperm were used the decline of embryo survival with development was more
      pronounced compared with those embryos derived from cryopreserved sperm. Possible
      explanations of these effects are presented.

PMID- 12623028
TI  - Oxygenated machine perfusion mitigates surface antigen expression and improves
      preservation of predamaged donor livers.
AB  - The aim of the present study was to evaluate the potential benefit of machine
      preservation with the Belzer MPS or HTK solution, compared to standard cold
      storage, after procurement of marginal livers from non-heart beating donors in an
      experimental pilot study. Livers from male Wistar rats (250-300 g bw) were
      harvested after 60 min of cardiac arrest, flushed via the portal vein and cold
      stored submerged in HTK for 24 h at 4 degrees C while other organs were subjected
      to oxygenated machine perfusion with HTK or Belzer's MPS at 5 ml/min at 4 degrees
      C. Cold perfusion of livers with the non-colloidal HTK was not compromised by the
      lack of oncotic agents and there was no rise in vascular resistance during the 24
      h of machine preservation with HTK or the colloidal Belzer MPS. Viability of the
      livers was assessed after the cold preservation period by warm reperfusion in
      vitro. Oxygenated machine perfusion was found to significantly increase viability
      of the livers vs simple cold storage with respect to portal vascular resistance
      upon reperfusion, enzyme release as well as functional recovery of oxygen
      utilization or bile production. Moreover, tissue antigen expression of ICAM-1 or
      histocompatibility antigen class II could be markedly reduced by oxygenated
      perfusion preservation as compared to cold storage. It is concluded that
      predamaged organs should preferably be preserved by oxygenated machine perfusion
      thus minimizing functional alterations and immunogenicity of the graft. In this
      setup HTK appeared equally effective as Belzer's MPS for machine preservation.

PMID- 12623029
TI  - Cryopreservation of umbilical cord blood: 1. Osmotically inactive volume,
      hydraulic conductivity and permeability of CD34(+) cells to dimethyl sulphoxide.
AB  - Umbilical cord blood (UCB) is an accepted treatment for the reconstitution of
      bone marrow function following myeloablative treatment predominantly in children
      and juveniles. Current cryopreservation protocols use methods established for
      bone marrow and peripheral blood progenitors cells that have largely been
      developed empirically. Such protocols can result in losses of up to 50% of the
      nucleated cell population: losses unacceptable for cord blood. The design of
      optimal cryopreservation regimes requires the development of addition and elution
      protocols for the chosen cryoprotectant; protocols that minimise damaging osmotic
      transients. The biophysical parameters necessary to model the addition and
      elution of dimethyl sulphoxide to and from cord blood CD34(+) cells have been
      established. An electronic particle counting method was used to establish the
      volumetric response of CD34(+) cells to changes in osmolality of the suspending
      medium. The non-osmotic volume of the cell was 0.27 of the cells isotonic volume.
      The permeation kinetics of CD34(+) cells to water and dimethyl sulphoxide were
      investigated at two temperatures, +1.5 and +20 degrees C. Values for the
      hydraulic conductivity were 3.2 x 10(-8) and 2.8 x 10(-7)cm/atm/s, respectively.
      Values for the permeability of dimethyl sulphoxide at these temperatures were 4.2
      x 10(-7) and 7.4 x 10(-6)cm/s, respectively. Clonogenic assays indicated that the
      ability of CD34(+) cells to grow and differentiate was significantly impaired
      outside the limits 0.6-4x isotonic. Based on the Boyle van't Hoff plot, the
      tolerable limits for cell volume excursion were therefore 45-140% of isotonic
      volume. The addition and elution of cryoprotectant was modelled using a two
      parameter model. Current protocols for the addition of cryoprotectant based on
      exposure at +4 degrees C would require additional time for complete equilibration
      of the cryoprotectant. During the elution phase current protocols are likely to
      cause CD34(+) cells to exceed tolerable limits. The addition of a short holding
      period during elution reduces the likelihood of this occurring.

PMID- 12623030
TI  - Cryopreservation of umbilical cord blood: 2. Tolerance of CD34(+) cells to
      multimolar dimethyl sulphoxide and the effect of cooling rate on recovery after
      freezing and thawing.
AB  - Cryopreservation protocols for umbilical cord blood have been based on methods
      established for bone marrow (BM) and peripheral blood stem cells (PBSC). The a
      priori assumption that these methods are optimal for progenitor cells from UCB
      has not been investigated systematically. Optimal cryopreservation protocols
      utilising penetrating cryoprotectants require that a number of major factors are
      controlled: osmotic damage during the addition and removal of the cryoprotectant;
      chemical toxicity of the cryoprotectant to the target cell and the
      interrelationship between cryoprotectant concentration and cooling rate. We have
      established addition and elution protocols that prevent osmotic damage and have
      used these to investigate the effect of multimolar concentrations of Me(2)SO on
      membrane integrity and functional recovery. We have investigated the effect of
      freezing and thawing over a range of cooling rates and cryoprotectant
      concentrations. CD34(+) cells tolerate up to 60 min exposure to 25% w/w (3.2M)
      Me(2)SO at +2 degrees C with no significant loss in clonogenic capacity. Exposure
      at +20 degrees C for a similar period of time induced significant damage. CD34(+)
      cells showed an optimal cooling range between 1 degrees C and 2.5 degrees C/min.
      At or above 1 degrees C/min, increasing the Me(2)SO concentration above 10% w/w
      provided little extra protection. At the lowest cooling rate tested (0.1 degrees
      C/min), increasing the Me(2)SO concentration had a statistically significant
      beneficial effect on functional recovery of progenitor cells. Our findings
      support the conclusion that optimal recovery of CD34(+) cells requires serial
      addition of Me(2)SO, slow cooling at rates between 1 degrees C and 2.5 degrees
      C/min and serial elution of the cryoprotectant after thawing. A concentration of
      10% w/w Me(2)SO is optimal. At this concentration, equilibration temperature is
      unlikely to be of practical importance with regard to chemical toxicity.

PMID- 12623031
TI  - Ice nucleation in nature: supercooling point (SCP) measurements and the role of
      heterogeneous nucleation.
AB  - In biological systems, nucleation of ice from a supercooled aqueous solution is a
      stochastic process and always heterogeneous. The average time any solution may
      remain supercooled is determined only by the degree of supercooling and
      heterogeneous nucleation sites it encounters. Here we summarize the many and
      varied definitions of the so-called "supercooling point," also called the
      "temperature of crystallization" and the "nucleation temperature," and exhibit
      the natural, inherent width associated with this quantity. We describe a new
      method for accurate determination of the supercooling point, which takes into
      account the inherent statistical fluctuations of the value. We show further that
      many measurements on a single unchanging sample are required to make a
      statistically valid measure of the supercooling point. This raises an interesting
      difference in circumstances where such repeat measurements are inconvenient, or
      impossible, for example for live organism experiments. We also discuss the effect
      of solutes on this temperature of nucleation. Existing data appear to show that
      various solute species decrease the nucleation temperature somewhat more than the
      equivalent melting point depression. For non-ionic solutes the species appears
      not to be a significant factor whereas for ions the species does affect the level
      of decrease of the nucleation temperature.

PMID- 12623032
TI  - Percutaneous cryoablation of colorectal liver metastases: potentiated by two
      consecutive freeze-thaw cycles.
AB  - Cryoablation may be beneficial for selected patients with liver tumours. Two
      freeze-thaw cycles at the same location have been recommended during treatment as
      this potentiate the effect of ablation in experimental studies. However, single
      freeze ablations are used by some as double freeze procedures are time-consuming
      and have been associated with increased risk of complications. Estimation of ice
      ball volume is difficult using regularly used monitoring techniques. Magnetic
      resonance imaging, however, allows excellent and multiplanar visualisation of the
      frozen region during ablation. We comment on the effect of double freeze cycles
      in regard to ice-ball volume as estimated from magnetic resonance imaging during
      percutaneous cryoablation of colorectal liver metastases. The ice-ball volume at
      the end of the second freeze cycle was median 42% larger than the volume at the
      end of the first freeze. Double freeze cycles may thus facilitate tumour
      destruction.

PMID- 12623036
TI  - The interventional radiological management of cholangiocarcinoma.
AB  - The successful management of cholangiocarcinoma requires the collaboration of
      several clinical disciplines. Modern imaging can demonstrate the liver and the
      surrounding structures in exquisite detail. Complete surgical resection offers
      the only potential for cure. The judgement of whether resection is feasible
      requires precise staging of the tumour. Unfortunately, in most cases, imaging
      delineates an advanced and inoperable tumour, requiring non-surgical palliative
      treatment, usually by means of endoscopic or percutaneous radiological
      techniques. The management of hilar lesions can be problematic requiring
      substantial experience and skill.

PMID- 12623037
TI  - Radiology and the Cancer Services Collaborative--an opportunity awaits.
AB  - The principles and methodologies used by the Cancer Services Collaborative (CSC)
      are particularly relevant for radiology departments. A radiology project looking
      at the provision of barium enema examinations is used to highlight how the
      principles can be applied to a radiology department. Advice on how to access
      available CSC literature is offered. The CSC principles and methodologies are an
      important part of the NHS modernization agenda, and offer an exciting vehicle to
      improve patient care. It is important that radiologists understand the
      opportunities offered and the challenges posed by the modernization agenda.

PMID- 12623038
TI  - Paget's disease of the spine: unusual features and complications.
AB  - Paget's disease of bone is a common disorder, with the spine being involved in
      over 50% of cases. This pictorial review illustrates unusual features and
      complications of the disease as related to the spine. Unusual features include
      location in the atlanto-axial region, lytic vertebral Paget's disease and Pagetic
      ankylosis. Complications related to the spine are mainly neurological due to
      spinal stenosis, compression fractures and sarcomatous degeneration

PMID- 12623039
TI  - MR-guided laser thermal ablation of primary and secondary liver tumours.
AB  - AIM: To test the hypothesis that magnetic resonance (MR)-guided hepatic tumour
      ablation is (i) safe and feasible, (ii) is associated with favourable patient
      survival, and (iii) decreases viable tumour. MATERIALS AND METHODS: One hundred
      and twenty-five MR-guided laser thermal ablations (LTA) were performed on 35
      patients with hepatocellular carcinoma (HCC, n=19), hepatic metastases (n=11,
      mainly colorectal) and carcinoid liver tumours (n=5). RESULTS: Mean overall
      survival was 14.8 months (HCCs 14.6 months, metastases 15.2 months). Near real
      time T1-weighted colourized thermal maps correlated moderately with follow-up
      gadolinium-enhanced MR imaging in predicting ablated tumour area (Pearson
      correlation coefficient=0.5). There was a significant difference in percentage
      enhancing pre- and post-LTA (Wilcoxon signed ranks test=0.0001). An average of
      50.7% of tumour was ablated by each treatment. In patients with multiple liver
      tumours ablated tumours grew significantly less than untreated tumours
      (108%compared with 196% growth, follow-up period 5.8 months, WSRTp=0.07).
      CONCLUSION: MR- guided LTA of primary and secondary liver tumours is safe,
      feasible, and significantly decreased amount of enhancing or viable tumour. MR
      guided LTA produces a better survival in patients with HCC than would be expected
      in untreated patients, and has a mean survival in patients with metastases at
      least equal to the longest median survival in untreated patients.

PMID- 12623040
TI  - Sedations and analgesia in patients undergoing percutaneous transhepatic biliary
      drainage.
AB  - AIM: To present our experience using intravenous sedoanalgesia for percutaneous
      biliary drainage. MATERIALS AND METHODS: This study comprised 100 patients, all
      of whom were continuously monitored [electrocardiogram (ECG), blood pressure,
      pulse oxymetry] and received an initial dose of 2mg midazolam followed by 0.02 mg
      fentanyl. Before every anticipated painful procedure, a maintenance dose of 0.01
      mg fentanyl was administered. If the procedure continued and the patient became
      aware, another 1mg midazolam was given. This was repeated if patients felt pain.
      A total dose of 0.08 mg fentanyl and 7 mg midazolam was never exceeded.
      Immediately after the procedure, the nurse was asked to evaluate patients' pain
      score. The patients were asked 3h later to complete a visual 10-degree pain score
      scale. RESULTS: The average dose of fentanyl and midazolam was 0.042 mg (0.03
      0.08 mg) and 4.28 mg (2-7 mg), respectively. Only one patient recorded the
      procedure as painful. The scores given by the attending nurse (1-7 points, mean
      2.9) correlated well with those given by the patients (1-6 points, mean 2.72). No
      complications were noted. CONCLUSION: According to our experience, interventional
      radiologists practising biliary procedures can administer low doses of midazolam
      and minimize the doses of fentanyl, without loss of adequate sedation and
      analgesia.

PMID- 12623041
TI  - Radiology review of the UKCCCR Breast Screening Frequency Trial: potential
      improvements in sensitivity and lead time of radiological signs.
AB  - AIM: To review all previous mammograms of breast cancer cases diagnosed during a
      randomized trial comparing 3 yearly to annual mammographic screening with a view
      to identifying and quantifying cases that might potentially have been diagnosed
      earlier. METHODS: Mammograms of 602 breast cancer cases (399 screen-detected and
      203 interval cases) were reviewed in chronological order and suspicious
      radiological features noted for each mammogram, up to and including the
      diagnostic mammogram. RESULTS: Of the 602 cases, 79 (13%) had features at
      diagnosis that were visible on previous mammograms, suggesting a sensitivity of
      interpretation of 87%. A similar proportion of screen-detected (14%) and interval
      cancers (11%) had signs at diagnosis that were visible on previous mammograms.
      The potential for improvement was particularly noted for asymmetric density
      (sensitivity = 77%, average time visible before diagnosis 14 months) and
      parenchymal deformity/stellate lesion (sensitivity = 81%, average time visible
      before diagnosis 12 months). CONCLUSION: The highest sensitivity was observed for
      comedo-type microcalcifications (sensitivity = 97%, average time visible before
      diagnosis 5 months). By improvements in sensitivity to asymmetric density and
      parenchymal deformity/stellate lesion, 4% of tumours could have their time of
      diagnosis advanced substantially.

PMID- 12623042
TI  - Clinical performance of computer-assisted detection (CAD system in detecting
      carcinoma in breasts of different densities.
AB  - OBJECTIVES: To determine the clinical performance of a computer-assisted
      detection (CAD) system in detecting carcinoma in breasts of different densities.
      MATERIALS AND METHODS: A total of 264 sets of bilateral screening mammograms
      taken in craniocaudal and medial-lateral oblique projections during the year 1997
      were divided into four groups according to the BI-RADS density classification:
      fatty (pattern 1), scattered fibroglandular (pattern 2), heterogeneously dense
      (pattern 3) and extremely dense (pattern 4). Each group contained about 60%
      normal and 40% biopsy-proven cancer cases. Of the malignant cases, there were a
      mixture of mammographic findings including focal masses (<2.5 cm), asymmetrical
      density, architectural distortion or microcalcifications. Films with artefacts
      and obvious masses>2.5 cm were not included. The chosen cases were then digitized
      and analysed by the CAD system. Sensitivity was calculated as detection of cancer
      by at least one marker in at least one view. Specificity was calculated as the
      number of false-positive marks per image on normal cases. Statistical tests of
      significance were performed by using contingency tables and Chi square test.
      RESULTS: The CAD system detected 14 out of the total 15 cancer cases in totally
      fatty breasts with a sensitivity of 93.3% at a specificity of 1.3 false-positive
      marks per image. In breasts with scattered fibroglandular pattern, the
      sensitivity was 93.9% (31/33) and the specificity was 1.6 false-positive marks
      per image while in heterogeneously dense breasts, the sensitivity of the CAD
      system fell to 84.8% at a specificity of 1.6 false-positive marks per image. The
      sensitivity of the CAD system further dropped to 64.3% in markedly dense breasts
      while maintaining a specificity of 1.2 false-positive marks per image. The
      decrease in sensitivity in dense breast was found to be significant (p=0.046).
      CONCLUSION: The sensitivity of the CAD system deteriorated significantly as the
      density of the breast increased while the specificity of the system remained
      relatively constant.

PMID- 12623043
TI  - CT detection of hydronephrosis in resected colorectal cancer: a predictor of
      recurrent disease.
AB  - AIM: To investigate the causes and significance of hydronephrosis in follow-up of
      colorectal cancer. METHODS AND MATERIALS: Case notes and serial computed
      tomography (CT) examinations were reviewed of 75 patients (250 CT examinations)
      after resection for colorectal cancer in whom hydronephrosis developed on follow
      up. RESULTS: The most common cause of hydronephrosis was a focal plaque-like mass
      centred on the peritoneum, demonstrated in 37 cases (49%). Patients with R1
      (microscopic residual tumour) or R2 (macroscopic residual tumour) disease
      developed hydronephrosis at a median time of 13 months (90% CI: 9-18 months)
      compared with 22 months (90% CI: 17-26 months) for those having (R0) curative
      resection. Patients with pT4 invasion of peritoneum or adjacent organs developed
      hydronephrosis at a median of 14 months (90% CI: 6-16 months) compared with a
      median of 22 months in patients with pT3 tumours (90% CI: 11-27 months). Of 26
      patients without an obvious cause of hydronephrosis on initial CT examination,
      follow-up CT demonstrated a definite mass lesion in 50%. Median survival after
      the onset of hydronephrosis was 6 months (range 1-34 months) with a 1-year
      mortality of 62%. CONCLUSIONS: Hydronephrosis is an important early indicator of
      colorectal cancer recurrence, even in the absence of a mass.

PMID- 12623044
TI  - CT-guided biopsy with cutting-edge needle for the diagnosis of malignant
      lymphoma: experience of 267 biopsies.
AB  - AIM: We performed a retrospective study of 267 core needle aspiration biopsies in
      order to estimate the accuracy of CT-guided aspiration core needle biopsies for
      the diagnosis and subsequent treatment of malignant lymphoma. MATERIALS AND
      METHODS: Between 1989 and 1999, 267 CT-guided core needle biopsies were performed
      in 241 patients with either primary or recurrent malignant lymphoma. Patients age
      ranged from 4--88 years. One hundred and sixty-six (62.2%) nodal and 101 (37.8%)
      extranodal aspiration biopsies were performed using either 18G or 20G Turner
      needles. Statistical method used was Chi-square analysis. RESULTS: An accurate
      histological diagnosis was made in 199 (82.5%) patients, the remaining 42 (17.4%)
      patients had non-diagnostic CT biopsies. Thirty-seven of them were diagnosed by a
      surgical biopsy, four by bone marrow biopsy and in one patient by paracentesis.
      One hundred and seventy-nine patients had non-Hodgkin's lymphoma (NHL) and 62 had
      Hodgkin's disease (HD); 23 (9.54%) patients underwent repeated CT biopsy which
      was diagnostic in 17 (73.9%) and non-diagnostic in six (26%). CONCLUSION: CT
      guided aspiration core biopsies were sufficient to establish a diagnosis in
      lymphoproliferative disorders in 82.5% of cases. In the light of this experience
      we suggest that imaging-guided core needle biopsy be used as the first step in
      the work up of many patients with lymphoma.

PMID- 12623046
TI  - CT in the diagnosis of isolated cysticercal infestation of extraocular muscle.
AB  - AIM: To evaluate the use of computed tomography (CT) and ultrasound (US) to
      diagnose orbital cysticercosis, and present the diagnostic features. METHOD: US
      and CT were used to evaluate patients with proptosis. Four patients were
      diagnosed as having orbital myocysticercosis and treated with oral albendazole
      and corticosteroid. Follow-up was undertaken with US and CT. RESULT: US features
      were confirmatory of myocysticercosis in two eyes where as CT was effective in
      diagnosing the condition in all four eyes. In two patients the medial rectus was
      involved, in one the superior rectus and, in the other, the inferior rectus
      muscles. Serial US and CT revealed complete resolution of the lesions in 3
      months. CONCLUSION: CT is useful method in diagnosing isolated orbital
      myocysticercosis. Our report demonstrated that ophthalmic signs and symptoms in
      the presence of proptosis, especially in an endemic region, should alert the
      clinician to the possibility of myocysticercosis. Though CT is superior, US can
      be used as a economical follow-up investigation.

PMID- 12623045
TI  - Magnetic resonance spectroscopic abnormalities in sporadic and variant
      Creutzfeldt-Jakob disease.
AB  - AIM: To study the proton MR spectroscopic findings in Creutzfeldt-Jakob disease
      (CJD) (sporadic and variant). MATERIALS AND METHODS: MR imaging and proton MR
      spectra were acquired in two patients with sporadic CJD (biopsy proven) and one
      patient with variant CJD. RESULTS: The two patients with sporadic CJD
      demonstrated MR signal change within the basal ganglia and thalami and reduced N
      acetylaspartate (NAA):creatine ratios. The patient with variant CJD showed
      characteristic signal change within the pulvinar of the thalami and a markedly
      reduced N-acetylaspartate:creatine ratio. CONCLUSION: All three patients with CJD
      demonstrated evidence of reduced N-acetylaspartate: creatine ratios on MR
      spectroscopy. These changes imply that neuronal loss and/or dysfunction is a
      consistent finding in established CJD.

PMID- 12623047
TI  - Imaging features of aggressive angiomyxoma.
AB  - AIM: To describe the imaging features of aggressive angiomyxoma in a rare benign
      mesenchymal tumour most frequently arising from the perineum in young female
      patients. MATERIALS AND METHODS: We reviewed the computed tomography (CT) and
      magnetic resonance (MR) imaging features of patients with aggressive angiomyxoma
      who were referred to our hospital. The imaging features were correlated with
      clinical information and pathology in all patients. RESULTS: Four CT and five MR
      studies were available for five patients (all women, mean age 39, range 24-55).
      Three patients had recurrent tumour at follow-up. CT and MR imaging demonstrated
      a well-defined mass-displacing adjacent structures. The tumour was of low
      attenuation relative to muscle on CT. On MR, the tumour was isointense relative
      to muscle on T1-weighted image, hyperintense on T2-weighted image and enhanced
      avidly after gadolinium contrast with a characteristic "swirled" internal
      pattern. MR imaging demonstrates the extent of the tumour and its relation to the
      pelvic floor. Recurrent tumour has a similar appearance to the primary lesion.
      CONCLUSION: The MR appearances of aggressive angiomyxomas are characteristic, and
      the diagnosis should be considered in any young woman presenting with a well
      defined mass arising from the perineum.

PMID- 12623048
TI  - Pregnancy after treatment for Hodgkin's lymphoma: inadvertent diagnosis by CT.

PMID- 12623049
TI  - Imaging strategy in young patients with malignancy.

PMID- 12623050
TI  - Severe underestimation of lumbar spinal stenosis by supine imaging.

PMID- 12623051
TI  - Fibroblastic osteosarcoma arising in chronic osteomyelitis.

PMID- 12623052
TI  - A rare form of supracardiac total anomalous pulmonary venous drainage--evaluation
      by computed tomography and magnetic resonance imaging.

PMID- 12623053
TI  - Stenting of carotid artery false aneurysms.

PMID- 12623054
TI  - The effect of storage at different temperatures on the stability of Hepatitis C
      virus RNA in plasma samples.
AB  - One important issue related to Hepatitis C virus (HCV) RNA nucleic acid
      amplification testing (NAT) is the storage conditions of plasma samples in order
      to obtain reliable results. Many authors have reported that the storage
      conditions could affect the RNA stability and, hence, HCV RNA detection. We have
      studied HCV RNA stability in plasma samples after storage at different
      temperatures (-70, -20, 5 and 25 degrees C). Samples containing different HCV
      titres were stored and analysed by qualitative or quantitative NAT techniques at
      defined time points. At -20 degrees C, samples containing high HCV RNA titres
      were followed-up during approximately 2.6-2.7 years, samples with intermediate
      concentrations during approximately 1 year and samples with 100 International
      Units/millilitre (IU/ml) during 2.5 years. Independently of the HCV RNA
      concentration, the results show absence of decay in HCV RNA detectability.
      Samples stored at 25 degrees C maintain their HCV RNA titre during 14 days and
      samples at 5 degrees C were stable for at least 3 months.

PMID- 12623055
TI  - Inactivated rabies vaccine control and release: use of an ELISA method.
AB  - Quality control of human rabies vaccines performed by National Control
      Laboratories (NCLs) prior to marketing vaccines batches requires in vivo and in
      vitro potency assays as requested by the relevant European Pharmacopoeia
      monographs, OMCLs guidelines and WHO technical recommendations. The aim of the
      present study was to check the suitability of an enzyme-linked immunosorbent
      assay (ELISA) using a virus neutralizing monoclonal antibody, directed to the
      rabies virus glycoprotein, to monitor the consistency of the lot to lot rabies
      vaccines production. Furthermore, this work was implemented to establish in house
      specifications for the glycoprotein content.

PMID- 12623056
TI  - Evaluation of a botulinum fragment C-based ELISA for measuring the humoral immune
      response in primates.
AB  - An enzyme-linked immunosorbent assay (ELISA) using botulinum neurotoxin serotype
      B recombinant fragment C (rBoNTB(HC)) was developed to measure specific humoral
      immune responses of monkeys vaccinated with a vaccine consisting of rBoNTB(HC).
      Several fundamental parameters for a bioassay were evaluated. The evaluation
      results demonstrated that using BoNTB(HC) as the capture antigen led to a
      specific and sensitive ELISA for botulinum type B antibody with excellent
      precision, accuracy, and linearity. There was a good correlation (r=0.91) between
      ELISA titers and neutralization bioassay titers. Experimental results suggested
      that the ELISA could be useful for detecting botulinum type B antibody levels and
      may supplement mouse neutralization bioassays during planned clinical
      manufacturing and clinical trials of rBoNTB(HC) vaccine.

PMID- 12623058
TI  - Identification and characterization by 16S rDNA analysis of viable bacterial
      colonies isolated from oral medicines based on inactivated or lysed pathogenic
      bacteria.
AB  - Oral bacterial immunomodulators are based on inactivated or lysed pathogenic
      bacterial cells. The safety of these products for consumers critically depends on
      the effectiveness of procedures used for pathogen inactivation. In a market
      survey in Switzerland we tested 26 lots of three different immunomodulators for
      the presence of any remaining culturable cells. Dissolved stimulants were plated
      on Eugon agar for the unspecific cultivation of bacteria (including most of the
      pathogenic bacteria in the modulator) and on Chocolate+PolyViteX agar for the
      cultivation of Haemophilus influenzae. A total of 16 colonies were grown on
      either Eugon agar or Chocolate+PolyViteX agar. These colonies were characterized
      by amplifying and sequencing a 16S rDNA fragment using unspecific screening
      primers. None of the sequenced fragments could be associated with the inactivated
      or lysed pathogenic bacteria present in the modulator. These data indicate that
      the pathogen inactivation procedures used for all tested products are effective.
      They also demonstrate full compliance of all products with pharmacopoeial
      requirements regarding microbial purity. Finally, the spectrum of germs isolated
      confirms the notion that man is the primary source of microbial contamination in
      pharmaceutical products.

PMID- 12623057
TI  - Collaborative study for the establishment of a European Phamacopoeia Biological
      reference preparation for Bordetella pertussis mouse antiserum for serological
      potency testing of acellular pertussis vaccines.
AB  - A collaborative study was organised by the European Directorate For the Quality
      of Medicines (EDQM) to assess the suitability of a candidate mouse antiserum as a
      European Pharmacopoeia Biological reference preparation (BRP) for acellular
      pertussis vaccine potency testing. The candidate antiserum was obtained by
      immunising mice with a five-component acellular pertussis vaccine: pertussis
      toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and Fimbrial
      2/Fimbrial 3 (Fim 2&3). The study has been divided into two separate phases.
      Phase I was a pre-qualification study including three laboratories. This phase
      was aimed at pre-qualifying the candidate BRP (cBRP) and at documenting the
      impact of differences in the antibody detection methodology enzyme linked
      immunosorbent assay (ELISA) procedures on results of pertussis antisera
      calibration versus the currently used standard US standard pertussis antiserum
      (mouse) Lot 1 (SPAM-1) (United States Food and Drug Administration (USFDA)
      reference serum) and the cBRP. As no significant difference between the antibody
      titres determined by using the different ELISA methodologies was found, a large
      scale study enrolling 13 laboratories (Phase II) was carried out, each
      participant performing its in-house methodology. Its aim was to calibrate the
      cBRP (in terms of the SPAM-1 reference) and to demonstrate its equivalence or
      superiority to internal references. The study showed that there was no difference
      in positive sera titres expressed relative to their corresponding internal
      reference (homologous situation) or the proposed standard (heterologous
      situation) reference. The cBRP can, therefore, reliably act as replacement for
      the in-house reference preparations. Further analysis of the outcome of this
      study enabled to assign to the cBRP a potency of 39, 138, 34 and 56 ELISA unit
      per millilitre, respectively, to its anti-PT, anti-FHA, anti-PRN and anti-Fim 2&3
      antibody contents. The cBRP has been adopted by the European Pharmacopoeia
      Commission at its June 2000 session as Bordetella pertussis mouse anti-serum Ph
      Eur. BRP batch 1.

PMID- 12623060
TI  - Validation of a nested PCR assay UMELOSA HCV CUALITATIVO for the detection of
      Hepatitis C virus.
AB  - An analysis of the performance characteristics of the UMELOSA HCV CUALITATIVO
      assay for the detection of Hepatitis C virus (HCV) RNA in human serum or plasma
      is presented. This qualitative in vitro diagnostic test is performed in three
      steps: (a) extraction of viral RNA, (b) reverse transcription of target RNA to
      generate complementary DNA followed by a polymerase chain reaction assay coupled
      with a second round of amplification, and finally (c) fluorescent detection of
      the amplified DNA by hybridization in a solid phase of an ultramicroplate coated
      with a complementary to amplified DNA probe. Considering the assay as a limit
      test for the control of impurities, the following analytical performance
      parameters were evaluated: specificity, detection limit and robustness. A
      comparative evaluation of the clinical performance and detection limit of our kit
      and the commercial AMPLICOR HCV test, version 2.0, was also included in the
      validation protocol. The assay had a good specificity and did not cross-react
      with the non-HCV analyzed positive samples. The 95% detection limit was of
      101.7IU/ml with 95% confidence interval from 81.0 to 162.8IU/ml. The UMELOSA HCV
      CUALITATIVO meets the minimal sensitivity requirements for a single unit blood
      testing of 5000 and 1250IU/ml, defined by the Paul-Ehrlich-Institute in Germany
      and the Food and Drug Administration in USA, respectively. Compared with the
      commercial AMPLICOR, the test gave identical results for all analyzed positive
      and negative samples. In robustness studies there was no cross-contamination
      between negative samples and these same samples spiked with 10000IU/ml of HCV
      RNA.

PMID- 12623059
TI  - Production of neutralizing human monoclonal antibody directed to tetanus toxin in
      CHO cell.
AB  - By the fusion of lymphocytes from hyperimmunized people with heteromyeloma cells,
      600 human hybridoma cell lines were generated. Even though seven cell lines
      produced antibodies against tetanus toxoid, only two antibodies from hybrid CH8
      and CH5 only neutralized the tetanus toxin and completely protected the mice that
      had been challenged with the toxin even at the level of 90 mean lethal dose. The
      cDNA of light (L) chain and heavy (H) chain variable region was isolated, and
      then inserted into expression vectors containing human IgG constant regions.
      After transfection of the recombinant human IgG gene into Chinese Hamster Ovary
      (CHO) cells, transformants secreting the complete human antibody were selected.
      The recombinant human antibodies produced from CHO cells possessed neutralizing
      activity against tetanus toxin just like the original human antibodies produced
      from human hybridoma cell lines. Western blot analysis showed that rCH8 and rCH5
      antibodies recognized the H chain of tetanus toxin and did not bind to its L
      chain. The neutralizing test showed that HmAb rCH5 had 4.55IU and HmAb rCH8 had
      1.09IU/100 micro g of IgG, respectively. Mixing of the two HmAbs resulted in
      synergistic effects. On a weight basis (IU/100 micro g IgG), the highest potency
      values were obtained when the two HmAbs were combined in equal quantity. The
      neutralizing activity of rCH8 and rCH5 mixture was 6.94IU/100 micro g IgG.

PMID- 12623062
TI  - Virus inactivation in bone tissue transplants (femoral heads) by moist heat with
      the 'Marburg bone bank system'.
AB  - Several virus inactivation procedures like heat treatment, gamma irradiation and
      chemical sterilization are used to increase the safety of bone tissue
      transplants. In this study we present data on the virus-inactivating effect of
      heat disinfection on human femoral heads, using the Marburg bone bank system
      'Lobator sd-2'. Three enveloped viruses (human immunodeficiency virus type 2 [HIV
      2], bovine viral diarrhoea virus as a model for Hepatitis C virus [HCV], and the
      herpesvirus pseudorabies virus), and three non-enveloped viruses (hepatitis A
      virus, poliomyelitis virus, and bovine parvovirus) were investigated. In a model
      system the central part of human femoral heads was contaminated with the
      respective cell-free virus suspension, establishing a direct contact between
      virus and native bone tissue. The core temperature in the femoral heads during
      the sterilization process was determined in additional model experiments. A
      temperature of 82.5 degrees C, given by the manufacturer as the effective
      temperature for virus inactivation, was maintained for at least 15 min in
      decartilaged femoral heads with a diameter of < or = 56 mm. Heat treatment using
      the Lobator sd-2 inactivated all viruses in human femoral heads below the
      detection limit (at least by a factor of > or =4 log(10)). By combining a well
      focussed anamnesis of the donors and serological testing for relevant infection
      markers (anti-HIV-1/2, HBsAg, anti-HBcore, anti-HCV, TPHA) with heat treatment of
      femoral heads in the Lobator sd-2 system, a high safety level is achieved. To
      further increase virus safety of cadaveric bone transplants, it is recommended
      that multi-organ donors are tested by nucleic acid testing (i.e. polymerase chain
      reaction) for HIV, HBV and HCV genome.

PMID- 12623061
TI  - Simian cytomegalovirus and contamination of oral poliovirus vaccines.
AB  - In the 1950s the use of primary rhesus macaque kidney cultures to propagate
      poliovirus for vaccine production led to the contamination of vaccines with
      simian virus 40 (SV40). African green monkey kidney (AGMK) cultures free of SV40
      were used as an alternative cell substrate for vaccine manufacture. In this study
      we evaluate oral poliovirus seeds, vaccine bulks and vaccines themselves for the
      presence of a common contaminant of AGMK cultures, simian cytomegalovirus (SCMV).
      Using sensitive polymerase chain reaction (PCR) techniques, nearly half of the
      samples analysed were found to be contaminated with SCMV sequences. However,
      vaccine bulks, positive by PCR for SCMV failed to show any evidence of infectious
      virus in these studies. One poliovirus vaccine and one seed, propagated on rhesus
      macaque kidney cultures were found to be positive for the rhesus monkey CMV by
      PCR.

PMID- 12623063
TI  - Stability of the prion protein-encoding (PRNP) gene in HeLa cells.
AB  - To assess the risk of the de novo emergence of the agent of transmissible
      spongiform encephalopathies in cultured cells, we examined the stability of the
      prion protein-encoding (PRNP) gene in HeLa cells and in cultures contaminated
      with HeLa cells that have been passaged extensively for over 50 years. Various
      sub-lineages of HeLa cells showed that some contained a mixture of a truncated
      PRNP gene (R3-R4 deletion) and a full-length PRNP gene, while others were
      homozygous for the R3-R4 deletion. That finding suggests that the progenitor of
      several popular sub-lineages of HeLa must have lost part or all of chromosome 20
      early in the history of HeLa cells. No mutations were found in the PRNP genes. We
      conclude that the spontaneous appearance of mutations leading to expression of
      abnormal prion proteins in continuously passaged heteroploid cell lines is
      unlikely to pose a substantial risk for the safe production of biologicals in
      such cells.

PMID- 12623065
TI  - Identification of the changes in phospholipase C isozymes in ischemic-reperfused
      rat heart.
AB  - Phospholipase C (PLC) influences cardiac function. This study examined PLC
      isozymes of the cardiac sarcolemma (SL) membrane and in the cytosol compartment
      in isolated perfused rat hearts subjected to global ischemia for 30 min followed
      by up to 30 min of reperfusion. Although the total SL PLC activity was decreased
      in ischemia and increased upon reperfusion, differential changes in PLC isozymes
      were detected. PLC beta(1) mRNA and SL protein abundance and activity were
      increased in ischemia, with concomitant decreases in activity and protein level
      in the cytosol. On the other hand, upon reperfusion, PLC beta(1) activity was
      decreased, but remained higher than control values. Although no change in the PLC
      delta(1) mRNA level in ischemia was detected, SL PLC delta(1) activity and
      content were depressed. Furthermore, in the cytosol, PLC delta(1) activity was
      increased, but the protein level decreased. SL PLC gamma(1) activity was
      decreased, independent of gene expression and protein content; however, decreases
      in the activity and protein abundance were detected in the cytosol. Increases in
      PLC gamma(1) and delta(1) activities occurred upon reperfusion, but were not
      accounted for by altered mRNA and protein levels. The results indicate that
      ischemia-reperfusion induces differential changes in PLC isozymes.

PMID- 12623064
TI  - Homozygous deletion of the CRABPI gene in AB1 embryonic stem cells results in
      increased CRABPII gene expression and decreased intracellular retinoic acid
      concentration.
AB  - The cellular retinoic acid (RA) binding proteins I and II (CRABPI and CRABPII),
      intracellular proteins which bind retinoic acid with high affinity, are involved
      in the actions of RA, though their exact roles are not fully understood. We have
      generated several genetically engineered AB1 cell lines in which both alleles of
      the CRABPI gene have been deleted by homologous recombination. We have used these
      CRABPI knockout cell lines to examine the consequences of functional loss of
      CRABPI on RA-induced gene expression and RA metabolism in the murine embryonic
      stem cell line, AB1, which undergoes differentiation in response to RA. Complete
      lack of CRABPI results in decreased intracellular [3H]RA concentrations under
      conditions in which external concentrations of [3H]RA are low (1-10nM) and in an
      altered distribution of [3H] polar metabolites of [3H]RA in the cell and in the
      medium. Fewer [3H] polar metabolites are retained within the CRABPI(-/-) cells
      compared to the wild-type cells. These data suggest that CRABPI functions to
      regulate the intracellular concentrations of retinoic acid and to maintain high
      levels of oxidized retinoic acid metabolites such as 4-oxoretinoic acid within
      cells.

PMID- 12623066
TI  - Pyruvate:NADP+ oxidoreductase is stabilized by its cofactor, thiamin
      pyrophosphate, in mitochondria of Euglena gracilis.
AB  - Pyruvate:NADP(+) oxidoreductase (PNO) is a thiamin pyrophosphate (TPP)-dependent
      enzyme that plays a central role in the respiratory metabolism of Euglena
      gracilis, which requires thiamin for growth. When thiamin was depleted in Euglena
      cells, PNO protein level was greatly reduced, but its mRNA level was barely
      changed. In addition, a large part of PNO occurred as an apoenzyme lacking TPP in
      the deficient cells. The PNO protein level increased rapidly, without changes in
      the mRNA level, after supplementation of thiamin into its deficient cells. In the
      deficient cells, in contrast to the sufficient ones, a steep decrease in the PNO
      protein level was induced when the cells were incubated with cycloheximide.
      Immunofluorescence microscopy indicated that most of the PNO localized in the
      mitochondria in either the sufficient or the deficient cells. These findings
      suggest that PNO is readily degraded when TPP is not provided in mitochondria,
      and consequently the PNO protein level is greatly reduced by thiamin deficiency
      in E. gracilis.

PMID- 12623067
TI  - Molecular cloning and 3D structure prediction of the first raw-starch-degrading
      glucoamylase without a separate starch-binding domain.
AB  - Raw-starch-degrading glucoamylases have been known as multidomain enzymes
      consisting of a catalytic domain connected to a starch-binding domain (SBD) by an
      O-glycosylated linker region. A molecular genetics approach has been chosen to
      find structural differences between two related glucoamylases, raw-starch
      degrading Glm and nondegrading Glu, from the yeasts Saccharomycopsis fibuligera
      IFO 0111 and HUT 7212, respectively. We have found that Glm and Glu show a high
      primary (77%) and tertiary structure similarity. Glm, although possessing a good
      ability for raw starch degradation, did not show consensus amino acid residues to
      any SBD found in glucoamylases or other amylolytic enzymes. Raw starch binding
      and digestion by Glm must thus depend on the existence of a site(s) lying within
      the intact protein which lacks a separate SBD. The enzyme represents a
      structurally new type of raw-starch-degrading glucoamylase.

PMID- 12623068
TI  - Domain swapping of Citrus limon monoterpene synthases: impact on enzymatic
      activity and product specificity.
AB  - Monoterpene cyclases are the key enzymes in the monoterpene biosynthetic pathway,
      as they catalyze the cyclization of the ubiquitous geranyl diphosphate (GDP) to
      the specific monoterpene skeletons. From Citrus limon, four monoterpene synthase
      encoding cDNAs for a beta-pinene synthase named Cl(-)betaPINS, a gamma-terpinene
      synthase named ClgammaTS, and two limonene synthases named Cl(+)LIMS1 and
      Cl(+)LIMS2 were recently isolated [J. Lucker et al., Eur. J. Biochem. 269 (2002)
      3160]. The aim of our work in this study was to identify domains within these
      monoterpene synthase enzymes determining the product specificity. Domain swapping
      experiments between Cl(-)betaPINS and ClgammaTS and between Cl(+)LIMS2 and
      ClgammaTS were conducted. We found that within the C-terminal domain of these
      monoterpene synthases, a region comprising 200 amino acids, of which 41 are
      different between Cl(-)betaPINS and ClgammaTS, determines the specificity for the
      formation of beta-pinene or gamma-terpinene, respectively, while another region
      localized further downstream is required for a chimeric enzyme to yield products
      in the same ratio as in the wild-type ClgammaTS. For Cl(+)LIMS2, the two domains
      together appear to be sufficient for its enzyme specificity, but many chimeras
      were inactive probably due to the low homology with ClgammaTS. Molecular modeling
      was used to further pinpoint the amino acids responsible for the differences in
      product specificity of ClgammaTS and Cl(-)betaPINS.

PMID- 12623070
TI  - Increased level of glycoxidation product N(epsilon)-(carboxymethyl)lysine in rat
      serum and urine proteins with aging: link with glycoxidative damage accumulation
      in kidney.
AB  - Accumulation of carboxymethylated proteins (CML-proteins) is taken as a biomarker
      of glycoxidative stress which is thought to contribute to the age-related
      impairment in tissue and cell function. To investigate the occurrence and extent
      of glycoxidative damage with aging in rat kidney, serum and urine, we have
      prepared a polyclonal antibody against CML-modified bovine serum albumin. We
      subsequently used it for immunolocalization and in enzyme-linked immunosorbent
      assays to evaluate CML-protein content. In the serum, CML-protein level was
      1.43+/-0.14 pmol CML/micrograms protein at 3 months and significantly increased
      by 50% from 10 to 27 months (1.50+/-0.14 pmol CML/micrograms protein vs 2.27+/
      0.26 pmol CML/micrograms protein), albumin and transferrin being the main
      modified proteins. In the urine, CML-protein level was 2.50+/-0.14 pmol
      CML/micrograms protein at 3 months and markedly increased from 10 months (2.99+/
      0.24 pmol CML/micrograms protein) to 27 months (3.76+/-0.25 pmol CML/micrograms
      protein), with albumin as the main excreted modified protein. Immunolocalization
      of CML-proteins in kidney provided evidence for an age-dependent increased
      accumulation in extracellular matrices. Intense staining of the glomerular
      basement membrane (GBM), Bowman's capsule, and the tubular basement membrane was
      found. Additionally, the CML content for collagen from GBM was 195.85+/-28.95
      pmol CML/microgrms OHPro at 3 months and significantly increased from 10 months
      (187.61+/-21.99 pmol CML/micrograms OHPro) to 27 months (334.55+/-62.21 pmol
      CML/micrograms OHPro). These data show that circulating CML-protein level in
      serum and urine and CML accumulation in nephron extracellular matrices with aging
      are increasing in parallel. The CML-protein measurement in serum and urine may
      thus be used as an index for the assessment of age-associated glycoxidative
      kidney damage.

PMID- 12623069
TI  - Human transcobalamin II receptor binds to Staphylococcus aureus protein A:
      implications as to its structure and function.
AB  - Purified human placental transcobalamin II receptor (TC II-R) dimer of molecular
      mass 124 kDa bound to Sepharose-linked bacterial immunoglobulin (IgG) binding
      proteins protein A, protein G, and protein A/G. TC II-R dimer was detected
      directly, by blotting human placental and rabbit and rat kidney membrane proteins
      with 125I-protein A, or indirectly, using antiserum to TC II-R or IgG-Fc region
      and 125I-protein. TC II-R antiserum, but not protein A, protein G, protein A/G,
      or antiserum to the IgG-Fc region, when added to culture medium of human
      intestinal epithelial Caco-2 cells or umbilical vein endothelial cells, inhibited
      ligand binding. However, protein A, protein G, protein A/G, or antiserum to the
      Fc region inhibited the internalization of the ligand TC II-[57Co]cyanocobalamin.
      Taken together, these studies strongly suggest TC II-R is an IgG-like molecule
      that contains an Fc-like region which is important in ligand internalization but
      not binding.

PMID- 12623071
TI  - Identification and regulation of a new vertebrate cytochrome P450 subfamily, the
      CYP2Ps, and functional characterization of CYP2P3, a conserved arachidonic acid
      epoxygenase/19-hydroxylase.
AB  - Three genes cloned from Fundulus heteroclitus (killifish) define a new P450
      subfamily, CYP2P. Structurally, the CYP2Ps are related to fish CYP2Ns and
      mammalian CYP2Js. CYP2P transcripts are expressed predominantly in liver and
      intestine. CYP2P3 coexpressed with P450 oxidoreductase in a baculovirus system
      catalyzed benzphetamine-N-demethylation and arachidonic acid oxidation, forming
      14,15-, 11,12-, and 8,9-epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic
      acid. CYP2P3 regio- and enantioselectivities with arachidonic acid were
      remarkably similar to human CYP2J2 and rat CYP2J3. Epoxyeicosatrienoic acids and
      their corresponding hydration products, the dihydroxyeicosatrienoic acids, were
      detected in killifish liver and intestine, indicating metabolism of arachidonic
      acid by killifish P450s in vivo. Levels of these products in killifish intestine
      were higher than those in mammalian intestine. 12-O-Tetradecanoyl phorbol 13
      acetate suppressed expression of CYP2P2 and CYP2P3 in killifish intestine;
      fasting itself suppressed expression of CYP2P2/3 but not CYP2P1. In rat intestine
      fasting similarly depressed the levels of CYP2J proteins. The CYP2Ps and the
      CYP2Js appear to be derived from a common ancestral gene, likely a fatty acid
      monooxygenase.

PMID- 12623072
TI  - N-linked oligosaccharide processing, but not association with
      calnexin/calreticulin is highly correlated with endoplasmic reticulum-associated
      degradation of antithrombin Glu313-deleted mutant.
AB  - Previously we showed that two antithrombin mutants were degraded through an
      endoplasmic reticulum (ER)-associated degradation (ERAD) pathway [F. Tokunaga et
      al., FEBS Lett. 412 (1997) 65]. Here, we examined the combined effects of
      inhibitors of glycosidases, protein synthesis, proteasome, and tyrosine
      phosphatase on ERAD of a Glu313-deleted (DeltaGlu) mutant of antithrombin. We
      found that kifunensine, an ER mannosidase I inhibitor, suppressed ERAD,
      indicating that specific mannose trimming plays a critical role. Cycloheximide
      and puromycin, inhibitors of protein synthesis, also suppressed ERAD, the effects
      being cancelled by pretreatment with castanospermine. In contrast, kifunensine
      suppressed ERAD even in castanospermine-treated cells, suggesting that
      suppression of ERAD does not always require the binding of lectin-like ER
      chaperones-like calnexin and/or calreticulin. These results indicate that,
      besides proteasome inhibitors, inhibitors of ER mannosidase I and protein
      synthesis suppress ERAD of the antithrombin deltaGlu mutant at different stages,
      and processing of N-linked oligosaccharides highly correlated with the efficiency
      of ERAD.

PMID- 12623073
TI  - Characterization of multidrug resistance-associated protein 2 in the
      hepatocellular disposition of 4-hydroxynonenal.
AB  - 4-hydroxynonenal (4HNE) is a major product of peroxidative membrane lipid
      destruction and exerts a variety of deleterious actions through formation of
      covalent adducts with cellular nucleophiles. Consequently, a number of cellular
      enzyme systems exist that are capable of detoxifying this reactive aldehyde by
      oxidation, reduction, or conjugation with glutathione. In this investigation we
      characterize the multidrug resistance-associated protein 2 (MRP2) as the primary
      transmembrane transport protein in hepatocytes responsible for extracellular
      export of 4HNE-glutathione conjugate (HNE-SG) from the intracellular site of its
      formation. Suspensions of freshly isolated hepatocytes (10(6) cells/ml) prepared
      from either wild-type (WT) Wistar rats or TR(-) rats possessing a mutated Mrp2
      gene were incubated with 4HNE (50 nmol/10(6) cells). The formation of 4HNE
      metabolites, 4-hydroxynonenoic acid (HNA) and HNE-SG, was quantified in the
      intracellular and extracellular fractions. These studies demonstrated that
      freshly isolated hepatocytes from both WT and TR(-) rats formed and exported the
      oxidized metabolite (HNA) to similar extents. Likewise, both populations of
      hepatocytes displayed nearly identical rates of glutathione conjugation with
      4HNE. However, the rate of HNE-SG export from TR(-) hepatocytes was approximately
      fourfold less than that of WT hepatocytes. In TR(-) hepatocytes, HNE-SG
      accumulated and remained predominantly intracellular throughout the time course,
      suggesting an absence of compensatory export by other hepatocellular
      transporters. In conclusion, these data demonstrate that although WT and TR(-)
      hepatocytes are similar in their conjugative and oxidative metabolism of 4HNE,
      export of 4HNE-SG is mediated by the MRP2 transporter, a transport system
      distinct from that involved in HNA efflux.

PMID- 12623074
TI  - Glucuronidation of catechols by human hepatic, gastric, and intestinal microsomal
      UDP-glucuronosyltransferases (UGT) and recombinant UGT1A6, UGT1A9, and UGT2B7.
AB  - The substrate specificity of human gastric and intestinal UDP
      glucuronosyltransferases (UGTs) toward catechols was investigated and compared to
      that of liver UGTs. Small catechols were efficiently glucuronidated by stomach
      (0.8-10.2 nmol/mgprotein x min) and intestine (0.9-7.7 nmol/mgprotein x min) with
      activities in a range similar to those found in liver (2.9-19 nmol/mgprotein x
      min). Large interindividual variations were observed among the samples.
      Immunoblot analysis demonstrated the presence of UGT1A6 and UGT2B7 in stomach and
      throughout the intestine. Recombinant human UGT1A6, 1A9, and 2B7, stably
      expressed in mammalian cells, all effectively catalyzed catechol glucuronidation.
      K(m) values (0.09-13.6mM) indicated low affinity for UGTs and V(max) values
      ranged from 0.51 to 64.0 nmol/mgprotein x min. These results demonstrate for the
      first time glucuronidation of catechols by gastric and intestinal microsomal UGTs
      and three human recombinant UGT isoforms.

PMID- 12623075
TI  - Reciprocal effects between spermine and Mg2+ on their movements across the
      mitochondrial membrane.
AB  - Mg(2+) competitively inhibits spermine transport in energized rat liver
      mitochondria (RLM) and exhibits a K(i) of 0.1mM on the initial rate and an I(50)
      of 0.6mM on total spermine accumulation after 20 min. Addition of 2mM Mg(2+)
      after spermine accumulation induces release of the polyamine. In view of the fact
      that spermine cycles across the inner membrane under physiological conditions,
      these results demonstrate that Mg(2+) inhibits spermine influx but does not
      affect the efflux pathway of the polyamine; the inhibitory effect occurs via an
      interaction with the specific site responsible for spermine transport. Instead,
      spermine inhibits Mg(2+) binding without affecting the rate of Mg(2+) transport,
      suggesting that both cations bind to the same site, which, however, is not used
      for Mg(2+) transport. Spermine also inhibits Mg(2+) efflux from RLM induced under
      conditions of the "low conductance state," a preliminary step preceding
      permeability transition pore opening.

PMID- 12623076
TI  - cDNA isolation, functional expression, and characterization of (+)-alpha-pinene
      synthase and (-)-alpha-pinene synthase from loblolly pine (Pinus taeda):
      stereocontrol in pinene biosynthesis.
AB  - The complex mixture of monoterpenes, sesquiterpenes, and diterpenes that
      comprises oleoresin provides the primary defense of conifers against bark beetles
      and their associated fungal pathogens. Monoterpene synthases produce the
      turpentine fraction of oleoresin, which allows mobilization of the diterpene
      resin acid component (rosin) and is also toxic toward invading insects; this is
      particularly the case for alpha-pinene, a prominent bicyclic monoterpene of pine
      turpentine. The stereochemistry of alpha-pinene is a critical determinant of host
      defense capability and has implications for host selection, insect pheromone
      biosynthesis, and tritrophic-level interactions. Pines produce both enantiomers
      of alpha-pinene, which appear to arise through antipodal reaction mechanisms by
      distinct enzymes. Using a cDNA library constructed with mRNA from flushing
      needles of loblolly pine (Pinus taeda), we employed a homology-based cloning
      strategy to isolate, and confirm by functional expression, the genes encoding (+)
      (3R:5R)-alpha-pinene synthase, (-)-(3S:5S)-alpha-pinene synthase, and several
      other terpene synthases. The pinene synthases, which produce mirror-image
      products, share only 66% amino acid identity (72% similarity) but are similar in
      general properties to other monoterpene synthases of gymnosperms. The
      stereochemical control of monoterpene cyclization reactions, the evolution of
      "antipodal" enzymes, and the implications of turpentine composition in ecological
      interactions are discussed.

PMID- 12623078
TI  - Geographic variations, cloning, and functional analyses of the venom acidic
      phospholipases A2 of Crotalus viridis viridis.
AB  - Geographic venom samples of Crotalus viridis viridis were obtained from South
      Dakota, Wyoming, Colorado, Oklahoma, Texas, New Mexico, and Arizona. From these
      samples, the phospholipases A(2) (PLA(2)s) were purified and their N-terminal
      sequences, precise masses, and in vitro enzymatic activities were determined. We
      purified two to four distinct acidic PLA(2)s from each sample; some of them
      displayed different inhibition specificities toward mammalian platelets. One of
      the acidic PLA(2)s induced edema, but had no anti-platelet activity. There was
      also a common basic PLA(2) myotoxin in all the samples. We have cloned five
      acidic PLA(2)s and several hybrid-like nonexpressing PLA(2)s. Molecular masses
      and N-terminal sequences of the purified PLA(2)s were matched with those deduced
      from the cDNA sequences, and the complete amino acid sequences of five novel
      acidic PLA(2)s were thus solved. They share 78% or greater sequence identity, and
      a cladogram based on the sequences of many venom acidic PLA(2)s of New World pit
      vipers revealed at least two subtypes. The results contribute to a better
      understanding of the ecogenetic adaptation of rattlesnakes and the structure
      activity relationships and evolution of the acidic PLA(2)s in pit viper venom.

PMID- 12623079
TI  - Visual preferences of students with profound mental retardation and healthy, full
      term infants.
AB  - Thirty students with profound mental retardation (age range: 3-5 to 19-11) and 30
      healthy, full-term infants (5-8 months) were shown 12 stimuli, three times each.
      Four patterned stimuli were presented one to a card and each pattern appeared in
      black-and-white, black-and-yellow, and red-and-yellow. Both groups looked
      significantly longer at face patterns than other patterns. Students with profound
      mental retardation looked longer at black-and-white patterns than other color
      combinations. Infants looked longer at red and yellow cards than did students
      with profound mental retardation. The measurement method was practical, reliable,
      and sensitive to both within and between group differences. Results from this
      assessment method may help determine the most salient visual stimuli for evoking
      active-alert states for students with profound mental retardation. Individual
      variability was evident in the data, which demonstrates the importance of
      examining preferences for each individual when planning intervention.
      Implications for future research and intervention are discussed.

PMID- 12623077
TI  - Isolation and characterization of 27-O-demethylrifamycin SV methyltransferase
      provides new insights into the post-PKS modification steps during the
      biosynthesis of the antitubercular drug rifamycin B by Amycolatopsis mediterranei
      S699.
AB  - The gene rif orf14 in the rifamycin biosynthetic gene cluster of Amycolatopsis
      mediterranei S699, producer of the antitubercular drug rifamycin B, encodes a
      protein of 272 amino acids identified as an AdoMet: 27-O-demethylrifamycin SV
      methyltransferase. Frameshift inactivation of rif orf14 generated a mutant of A.
      mediterranei S699 that produces no rifamycin B, but accumulates 27-O
      demethylrifamycin SV (DMRSV) as the major new metabolite, together with a small
      quantity of 27-O-demethyl-25-O-desacetylrifamycin SV (DMDARSV). Heterologous
      expression of rif orf14 in Escherichia coli yielded a 33.8-kDa polyhistidine
      tagged polypeptide, which efficiently catalyzes the methylation of DMRSV to
      rifamycin SV, but not that of DMDARSV or rifamycin W. 27-O-Demethylrifamycin S
      was methylated poorly, if at all, by the enzyme to produce rifamycin S. The
      purified enzyme does not require a divalent cation for catalytic activity. While
      Ca(2+) or Mg(2+) inhibits the enzyme activity slightly, Zn(2+), Ni(2+), and
      Co(2+) are strongly inhibitory. The K(m) values for DMRSV and S-adenosyl-L
      methionine (AdoMet) are 18.0 and 19.3 microM, respectively, and the K(cat) is
      87s(-1). The results indicate that DMRSV is a direct precursor of rifamycin SV
      and that acetylation of the C-25 hydroxyl group must precede the methylation
      reaction. They also suggest that rifamycin S is not the precursor of rifamycin SV
      in rifamycin B biosynthesis, but rather an oxidative shunt-product.

PMID- 12623080
TI  - Self-regulatory behaviors in children with Down syndrome and typically developing
      children measured using the Goodman Lock Box.
AB  - Self-regulation has been identified as an area of difficulty for those with
      mental retardation. The Goodman Lock Box provides measures of two critical
      aspects of self-regulation-planfulness and maintenance of goal-directed behavior.
      In this study, the Lock Box performance of 25 children with Down syndrome was
      compared with that of 43 typically developing children, matched for mental age
      (24-36 months). Children in both groups showed similar levels of competence,
      planfulness and distractibility. However, children with Down syndrome displayed
      more task-avoidant behavior. Some issues related to the measurements obtained
      from the Lock Box are raised.

PMID- 12623081
TI  - Parent's perceptions of interactions with health professionals in the pathway to
      gaining a diagnosis of tuberous sclerosis (TS) and beyond.
AB  - This paper presents selected findings from a qualitative study on the lived
      experience of young people with tuberous sclerosis (TS) and their families. In
      depth interviews with 109 participants from 40 families were undertaken. This
      paper presents the findings in relation to parents' interactions with health
      professionals before, during and after a diagnosis of TS was given. The majority
      of parents recalled examples of both positive and negative experiences with
      health professionals. Negative experiences included having to 'fight' for the
      recognition of symptoms and the reluctance of doctors to move on beyond a
      diagnosis of epilepsy. Attributes valued by parents pre-diagnosis included health
      professionals showing understanding at diagnosis, flexibility, support,
      accessibility, time and attention, honesty, reliability, sensitivity and post
      diagnosis a willingness to find out and share information and to consult
      colleagues and other professionals. The interviews indicated that these were not
      always demonstrated by professionals.

PMID- 12623082
TI  - Efficacy of behavioral interventions for reducing problem behavior in persons
      with autism: a quantitative synthesis of single-subject research.
AB  - The efficacy of behavioral interventions for problem behavior in persons with
      autism was reviewed. One hundred and seventeen published articles representing
      181 individuals with autism were examined. Articles were selected from 15
      journals. Participant, treatment, and experimental variables were evaluated.
      Three effect sizes were calculated for each article. Behavioral treatments are
      effective in reducing problematic behaviors in individuals with autism. Type of
      target behavior and type of treatment did not moderate the average effect of
      treatment. As measured by percentage of zero data (PZD), three variables were
      predictive of behavioral suppression beyond that accounted for by behavioral
      topography and treatment type. Reliability of observation and number of treatment
      data points were positively related to PZD scores. Treatments based on
      experimental functional analysis (EFA) produced higher average PZD scores than
      treatments that did not include an EFA. The implications of the findings, study
      limitations, and suggestions for future research are discussed.

PMID- 12623083
TI  - Extending microswitch-based programs for people with multiple disabilities: use
      of words and choice opportunities.
AB  - This study assessed a microswitch-based program in which three request and one
      choice microswitches were used for two participants with multiple disabilities.
      The program was then transferred into the participants' daily contexts. Each
      request microswitch was linked to different stimulation opportunities. Every
      activation of the microswitch triggered the verbal announcement of one such
      opportunity that the participant could choose or bypass. The request
      microswitches were introduced individually and then combined. During the last
      part of the intervention and the post-intervention checks, all three request
      microswitches plus the choice microswitch were simultaneously available. Both
      participants learned to use the microswitches very rapidly. Responding levels
      were high during intervention and the post-intervention checks carried out in the
      participants' daily contexts. Implications of the findings for advanced
      microswitch-based programs and vocal recognition technology are discussed.

PMID- 12623084
TI  - Predicting the heating value of MSW with a feed forward neural network.
AB  - The influence of the heating value of municipal solid waste (MSW) is very
      important on the combustion efficiency of MSW incinerators. The heating value of
      MSW is determined by the elementary chemical composition of its various
      components. Commonly, calorimetric measurement and empirical methods are
      available for this determination. In this analysis, the relationship between the
      physical composition and the low heating value (LHV) was studied. A feed forward
      neural network (FFNN) can be very helpful in predicting the heating value of MSW
      from its physical composition. The results of this analysis show that the
      prediction of LHV of MSW with FFNN is much better than conventional models.

PMID- 12623085
TI  - Environmental evaluation of reuse of by-products as road construction materials
      in Sweden.
AB  - Reuse of by-products in road construction is most often environmentally evaluated
      from the narrow perspective of the material itself, i.e. the material level. In
      this article, we argue that the current mainstream environmental evaluation of
      reuse of by-products in road construction should use wider system boundaries. In
      order to illustrate the importance of system boundaries to the final result,
      three additional levels that complement the material level, are applied to the
      environmental evaluation of reuse of by-products. In total these four levels of
      evaluation are, firstly, the material itself, mainly studied by leaching tests,
      secondly, the road environment studied by substance flow analysis, furthermore, a
      narrow life-cycle perspective and, finally, the industrial system level that
      addresses the reuse of by-products in a broader sense. Methods and tools applied
      to different levels emphasise different environmental aspects and consequently
      they are appropriate for addressing different questions. However, especially for
      the evaluation of environmental aspects on the industrial system level, there is
      a need to develop the methods. To apply these four levels to the evaluation would
      broaden the knowledge about the environmental impacts of the reuse of by
      products. We argue that current leaching tests have to be complemented by the
      broader system boundaries used in substance flow studies and in life-cycle
      assessments in order to discuss the use of resources and environmental impacts
      from a wider perspective.

PMID- 12623086
TI  - Behaviour of Cd, Cr, Mn, Ni, Pb, and Zn in sewage sludge incineration by
      fluidised bed furnace.
AB  - Cd, Cr, Mn, Ni, Pb, and Zn behaviour during sewage sludge incineration was
      investigated in seven pilot tests using a circulating fluidised bed furnace.
      Dewatered sludge at a solids concentration of 15-18% was fed to the furnace
      either alone (two tests) or spiked with chlorinated organic compounds (five
      tests). The behaviour of metals in the fluidised bed furnace was studied by
      comparing metal concentrations in the two main ash streams: ash separated from
      the cyclone immediately following the fluidised bed furnace, and fly ash
      recovered in the final bag filter. A metal enrichment factor was defined as the
      ratio of metal concentration between filter ash and cyclone ash. Only Cd and Pb
      showed any significant enrichment. Their enrichment factors were mainly affected
      by chlorine concentration in the feed sludge. To check whether simple equilibrium
      models may explain and predict metal behaviour, experimental data were compared
      with percentage of the metal vaporisation in the combustion chamber predicted
      using a thermodynamic model. Discrepancies between model predictions and
      experimental results are accounted for by considering that kinetics may be a
      limiting factor in the formation of metal chloride gaseous species. Due to the
      very short sludge residence time in the fluidised bed furnace, the gaseous
      compounds have little chance to evolve completely.

PMID- 12623088
TI  - Accumulation and fate of selected heavy metals in a biological wastewater
      treatment system.
AB  - The aim of this research was to study the accumulation and removal of heavy
      metals (Cd, Cu, Pb, Zn) by a biological wastewater treatment system. Heavy metal
      contents in the influent and effluent wastewater were compared. Also, the heavy
      metal contents in the sludge before and after anaerobic digestion were compared.
      The results showed: (1) more pronounced variations in the contents of Cu and Zn
      than that of Cd and Pb, which showed that at 0.02 for Cd and 0.05 mg/l for Pb,
      the reduction in their contents was insignificant; (2) that removal of heavy
      metals was directly proportional to their initial contents in the influent
      wastewater. Corresponding to the influent contents, in increasing order, the
      reduction in heavy metal contents was: Cd<Pb<Cu<Zn; and (3) that anaerobic
      stabilization of sludge caused an increase in heavy metal contents on dry weight
      basis. The order of increase in heavy metal contents in digested sludge
      (Zn<Pb<Cu<Cd) was opposite to that of their contents removal from influent
      wastewater.

PMID- 12623087
TI  - Chemical changes in different types of coal ash during prolonged, large scale,
      contact with seawater.
AB  - In this study, we followed the chemical changes occurring in coal ash exposed to
      prolonged (300 days), large scale, contact with running seawater. Four major
      components (Al, Ca, Mg, Fe) and seven minor and trace elements (Cd, Cr, Cu, Mn,
      Zn, Pb, Hg) were measured in four coal ash types: fly and bottom ash freshly
      obtained from coal-fired power plant, and old ash (crushed and blocks) recovered
      from the sea after 3-5 years contact with seawater. Changes occurred in the
      chemical composition of the coal ash along the experiment: Fe increased in fresh
      ash, Al increased in old ash and Ca increased in all ash types except old ash
      blocks. Cu and Hg decreased in fresh fly ash while Cr increased, Cd decreased in
      all ash types except bottom ash, and Mn decreased in bottom ash. Most of the
      changes occurred in the fresh fly ash, and not in the old ash, indicating
      equilibrium after prior exposure to seawater. In addition, more changes occurred
      in fresh fly ash than in bottom ash, emphasizing the differences between the two
      ash types. While the changes in the concentrations of the major elements may be
      an indication of the integrity of the ash matrix, the only elements of
      environmental significance released to the environment were Hg and Cd. However,
      calculated seawater concentrations were much lower than seawater quality criteria
      and therefore the coal ash was considered suitable for marine applications
      concerning seawater quality.

PMID- 12623089
TI  - Physical and mechanical properties of cement-based products containing
      incineration bottom ash.
AB  - This paper presents the results of a wider experimental programme conducted in
      the framework of the NNAPICS ("Neural Network Analysis for Prediction of
      Interactions in Cement/Waste Systems") project funded by the European Commission
      and a number of industrial partners under Brite-EuRamIII. Based on the fact that
      bottom ashes from waste incineration are classified as non-hazardous wastes
      according to the European Waste Catalogue, the aim of the present work was to
      investigate the feasibility of addressing the potential use of such residues in
      cement-based mixtures. This issue was suggested by the analysis of the properties
      of different bottom ashes coming from Italian municipal and hospital solid waste
      incinerators, which showed a chemical composition potentially suitable for such
      applications. Different mixes were prepared by blending bottom ash with ordinary
      Portland cement in different proportions and at different water dosages. The
      solidified products were tested for setting time and bulk density, unconfined
      compressive strength and evaporable water content at different curing times. The
      results of the experimental campaign were analysed through a statistical
      procedure (analysis of variance), in order to investigate the effect of mixture
      composition (waste replacement level and water dosage) on the product properties.

PMID- 12623090
TI  - Development of guidelines on best practices for the slaughter of animals in
      Cyprus.
AB  - Cyprus is one of the candidate countries to become a full member of the European
      Union. In order to access formally to the EU, Cyprus has to follow an
      implementation process and take into account all the obligations that the fifteen
      Member States have to respect. A large number of obligations derive from the
      European Integrated Pollution Prevention and Control (IPPC) Directive 96/61/EC,
      which intends to result in the protection of the environment as a whole and the
      public health as well. This will be the outcome of determining ways of pollution
      prevention and control for several industrial sectors, which are covered by the
      IPPC Directive and then taking action so that all operators act according to the
      Directive's demands. In this framework, the National Technical University of
      Athens, after thorough examination of a large number of documents relevant to the
      Best Available Techniques (BATs), developed guidelines for the application of
      BATs for 14 categories of the industry of Cyprus. This paper concerns the
      developed guidelines for slaughterhouses.

PMID- 12623091
TI  - Microbial degradation of pyridine using Pseudomonas sp. and isolation of plasmid
      responsible for degradation.
AB  - Pseudomonas (PI2) capable of degrading pyridine was isolated from the mixed
      population of the activated sludge unit which was being used for treating complex
      effluents, the strain was characterized. Aerobic degradation of pyridine was
      studied with the isolated strain and the growth parameters were evaluated.
      Pyridine degradation was further conformed by chromatography (HPLC) analysis. The
      process parameters like biomass growth and dissolved oxygen consumption were
      monitored during pyridine degradation. In order to conform with the plasmid
      capability to degrade pyridine, the requisite plasmid was isolated and
      transferred to DH 5alpha Escherichia coli. The subsequent biodegradation studies
      revealed the ability of the transformed plasmid capability to degrade the
      pyridine.

PMID- 12623092
TI  - Preparation of aluminium-magnesium alloys and some valuable salts from used
      beverage cans.
AB  - The purpose of this work is to recover standard aluminium-magnesium alloy(s) and
      some valuable salts from used beverage cans (UBCs). The suggested method updated
      the current recycling technology by augmenting removal of the coating paint,
      decreasing magnesium loss during melting process and improving hydrochloric acid
      leaching of the formed slag. Iron impurity present in the leaching solution, was
      removed by oxidation using oxygen gas or hydrogen peroxide and filtered as
      goethite. Results obtained revealed that a mixture of methyl ethyl
      ketone/dimethyl formamide entirely removes the paint coating at room temperature.
      The process compares favorably to the current methods involving firing or swell
      peeling. The coating decomposes to titanium dioxide by heating at 750 degrees C
      for 30 min. Standard compositions of Al-Mg alloys are formulated using secondary
      magnesium. The extent of recovery (R) of these alloy(s) is a function of the
      melting time and temperature and type of the flux. The maximum (R) value amounts
      to 94.4%. Sodium borate/chloride mix decreases magnesium loss to a minimum. The
      extent of leaching valuable salts from the slag increases with increasing the
      molarity, stoichiometric ratio and leaching temperature of the acid used. Removal
      of iron is a function of the potential of the oxidation process. Stannous
      chloride has been recovered from the recovered and dried salts by distillation at
      700-750 degrees C.

PMID- 12623093
TI  - Destruction of cyanide waste solutions using chlorine dioxide, ozone and titania
      sol.
AB  - Increasingly, there are severe environmental controls in the mining industry.
      Because of lack of technological advances, waste management practices are
      severely limited. Most of the wastes in the milling industrial effluents are
      known to contain cyanides and it is recognized that after extraction and recovery
      of precious metals, substantial amounts of cyanide are delivered to tailings
      ponds. The toxicity of cyanide creates serious environmental problems. In this
      paper we describe several methods for the treatment of cyanide solutions. These
      include: (1) cyanide destruction by oxidation with chlorine dioxide (ClO(2)) in a
      Gas-Sparged Hydrocyclone (GSH) reactor; (2) destruction of cyanide by ozone
      (O(3)) using a stirred batch reactor, and finally, (3) the photolysis of cyanide
      with UV light in presence of titania sol. In all cases excellent performance were
      observed as measured by the extent and of the destruction.

PMID- 12623096
TI  - Improving our ability to manage risks.

PMID- 12623097
TI  - Energy from gasification of solid wastes.
AB  - Gasification technology is by no means new: in the 1850s, most of the city of
      London was illuminated by "town gas" produced from the gasification of coal.
      Nowadays, gasification is the main technology for biomass conversion to energy
      and an attractive alternative for the thermal treatment of solid waste. The
      number of different uses of gas shows the flexibility of gasification and
      therefore allows it to be integrated with several industrial processes, as well
      as power generation systems. The use of a waste-biomass energy production system
      in a rural community is very interesting too. This paper describes the current
      state of gasification technology, energy recovery systems, pre-treatments and
      prospective in syngas use with particular attention to the different process
      cycles and environmental impacts of solid wastes gasification.

PMID- 12623099
TI  - Waste paper and clinoptilolite as a bulking material with dewatered anaerobically
      stabilized primary sewage sludge (DASPSS) for compost production.
AB  - Environmental problems associated with sewage sludge disposal have prompted
      strict legislative actions over the past few years. At the same time, the
      upgrading and expansion of wastewater treatment plants have greatly increased the
      volume of sludge generated. The major limitation of land application of sewage
      sludge compost is the potential for high heavy metal content in relation to the
      metal content of the original sludge. Composting of sewage sludge with natural
      zeolite (clinoptilolite) can enhance its quality and suitability for agricultural
      use. However, the dewatered anaerobically stabilized primary sewage sludge
      (DASPSS) contained a low concentration of humic substances (almost 2%), and the
      addition of the waste paper was necessary in order to produce a good soil
      conditioner with high concentrations of humics. The final results showed that the
      compost produced from DASPSS and 40-50% w/w of waste paper was a good soil
      fertilizer. Finally, in order to estimate the metal leachability of the final
      compost product, the generalized acid neutralization Capacity (GANC) procedure
      was used, and it was found that by increasing the leachate pH, the heavy metal
      concentration decreased. The application of the sequential chemical extraction
      indicated that metals were bound to the residual fraction characterized as a
      stabilize fractions.

PMID- 12623098
TI  - Investigation and optimization of composting processes-test systems and practical
      examples.
AB  - To determine the optimal course of composting it is useful to carry out
      experiments. The selection of the right experimental set-up depends on the
      question of concern. Each set-up is useful for a particular application and has
      its limits. Two test systems of different scales (up to 1500 ml; up to 100 l) are
      introduced. The purpose and importance of each system design shall be highlighted
      by application examples: (1). Suitability of a liquid industrial residue as
      composting accelerator; (2). Determination of the compost maturity; (3).
      Behaviour of odor-reducing additives during waste collection and composting; (4).
      Production of tailor-made compost with respect to Nitrogen (5). Suitability of
      O(2)-enriched air for acceleration of composting. Small-scale respiration
      experiments are useful to optimize parameters which have to be adjusted during
      substrate pre-treatment and composting, with the exception of particle size and
      temperature, and to reduce the number of variants which have to be investigated
      in greater detail in larger scale experiments. As all regulation possibilities
      such as aeration, moistening, turning can be simulated with the technical scale
      set-up, their complex cooperation can be taken into consideration. Encouraging
      composting variants can be tested, compared and optimized.

PMID- 12623101
TI  - A comparison of small-scale, pilot-scale and large-scale tests for predicting
      leaching behaviour of landfilled wastes.
AB  - Landfills generate emissions over long periods, often longer than a lifetime. The
      longest lasting emission is leachate. In order to estimate the future
      requirements for leachate treatment, different kinds of leaching tests may be
      applied. In this paper, shaking leaching tests (SLT), landfill-simulator leaching
      tests and a field-cell leaching test performed with ash, municipal solid waste
      (MSW) and MSW+ash are evaluated. The tests are compared and the factors
      influencing leaching are identified and discussed. The factors are: liquid to
      solid (L/S) ratio, water withdrawal, recirculation rate, presence or absence of
      biological processes, size of particles, duration of experiment, temperature and
      pre-treatment of the waste. The presence of biological processes has the greatest
      impact on leaching and is the main reason why SLT is less useful for long-term
      predictions. The landfill simulator tests were found to be useful for several
      different kinds of predictions. However, they are not reliable for predicting the
      L/S required for reaching a certain concentration. The possibilities for reliable
      long-term predictions would be facilitated by a better knowledge of the influence
      of various factors on leaching. Such an increased knowledge would make it
      possible to enhance waste stabilisation in leaching tests as well as in full
      scale landfills.

PMID- 12623100
TI  - The PAF model: an integrated approach for landfill sustainability.
AB  - Lab-scale tests were set up to investigate different options for achieving
      sustainability by reducing long-term landfill emissions. The options which have
      been studied and compared with the traditional anaerobic landfill for unprocessed
      refuse were: mechanical-biological pretreatment, landfill aeration with forced
      and with natural advective air flow (semi-aerobic), flushing. Combination of
      different options have been experimented. The combination of mechanical
      biological Pretreatment, Aeration by the semi-aerobic method and Flushing (PAF
      model) seems to synergize the advantages of the individual options. The research
      is ongoing and further studies are necessary in order to assess the full-scale
      applicability of the model.

PMID- 12623102
TI  - Management of municipal solid waste incineration residues.
AB  - The management of residues from thermal waste treatment is an integral part of
      waste management systems. The primary goal of managing incineration residues is
      to prevent any impact on our health or environment caused by unacceptable
      particulate, gaseous and/or solute emissions. This paper provides insight into
      the most important measures for putting this requirement into practice. It also
      offers an overview of the factors and processes affecting these mitigating
      measures as well as the short- and long-term behavior of residues from thermal
      waste treatment under different scenarios. General conditions affecting the
      emission rate of salts and metals are shown as well as factors relevant to
      mitigating measures or sources of gaseous emissions.

PMID- 12623103
TI  - Evidence of Al-Cr interactions affecting Cr-leaching from waste incineration
      ashes.
AB  - Leaching tests on flue gas ashes from waste incineration showed low leaching of
      Cr from ashes that under moist anaerobic conditions also produced hydrogen gas.
      In some cases, also the redox levels (aerobic/anaerobic conditions) during the
      leaching test affected Cr leaching. Aerobic ashes tested in an open batch
      leaching test leached Cr up to 2-3 orders of magnitude more than the ashes kept
      moist under anaerobic conditions and tested in a closed leaching test. Model
      experiments showed that metallic Al could reduce Cr and at the same time produce
      H(2). The hydrogen gas per se could not reduce Cr. Laboratory experiments with
      ashes provided evidence that metallic Al, present naturally in the ashes or
      amended, could reduce Cr under moist anaerobic, but not under aerobic storage.
      Significant Cr reduction was linked to, but not caused by hydrogen formation. The
      reduced Cr seemed to be partially reoxidizable upon aeration or drying. The
      observations presented provide a basis for understanding the complexity of Cr
      leaching from waste incineration ashes, as for example, why some chemical
      stabilization methods increase Cr leaching, and point out the need for
      standardizing leaching test conditions with respect to Cr.

PMID- 12623104
TI  - Report: waste management in Portugal between 1996 and 2002.

PMID- 12623106
TI  - Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of
      the norepinephrine transporter.
AB  - The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine
      (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific
      activity. These radiotracers are close analogues of reboxetine, a potent and
      selective ligand for the norepinephrine transporter (NET). They were examined as
      potential ligands for imaging NET in vivo by positron emission tomography (PET).
      The in vivo brain distribution of both [(11)C]-labeled enantiomers were evaluated
      in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain
      uptake and washout of radioactivity was homogeneous at all time points examined
      (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a
      heterogeneous distribution of radioactivity in brain with highest uptake in the
      hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain
      region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved
      at 60 min post injection of (S,S)-[(11)C]-MeNER. Pre-injection of the
      norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced
      hypothalamus to striatum ratios to near unity while reuptake inhibitors of
      dopamine and serotonin had no significant effect on binding. In vitro
      autoradiography studies (rat brain slices) with (S,S)-[(11)C]-MeNER produced a
      regional distribution pattern that was consistent with the reported distribution
      of NET. (S,S)-[(11)C]-MeNER has the potential to be the first successful PET
      ligand to image NET.

PMID- 12623107
TI  - A novel method for determining hepatic sinusoidal oxygen permeability in the
      isolated perfused rat liver using [15O]O2.
AB  - Measurement of hepatic sinusoidal permeability of oxygen and other substrates may
      help elucidate the mechanisms responsible for impaired liver function in
      cirrhosis. However studies of sinusoidal oxygen permeability in normal liver and
      various disease states have been limited due to the considerable technical
      difficulties involved in the use of standard techniques. We have developed a new
      method for measuring sinusoidal oxygen permeability in the isolated perfused rat
      liver that overcomes the difficulties of previous methods by using [(15)O]O(2)
      and an in-line fluid monitor. This method uses data obtained from impulse
      response curves of radiolabelled red cells, albumin and oxygen that are fitted
      mathematically using the axial dispersion model to yield rate constants that
      describe oxygen transit through the liver. We have demonstrated the utility and
      reproducibility of this method by comparing multiple injections and permeability
      determinations in the same preparation. This approach could be used in isolated
      perfused organs to study oxygen permeability in a range of disease states.

PMID- 12623109
TI  - Effect of P-glycoprotein and multidrug resistance associated protein gene
      expression on Tc-99m MIBI imaging in hepatocellular carcinoma.
AB  - P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP)
      expressions as well as Tc-99m methoxisobutylisonitrile (MIBI) images were
      assessed in 25 patients hepatocellular carcinoma (HCC). Tc-99m MIBI imaging was
      performed 10 minutes after intravenous injection of 20 mCi Tc-99m MIBI. Using
      immunohistochemical staining, 60% of the HCC lesions showed positive for Pgp and
      64% showed positive for MRP. In 3 patients with MIBI uptake, immunohistochemical
      study of tumor tissue showed no Pgp stained cells. Nevertheless, they were all
      positive for MRP. The result of Tc-99m MIBI imaging is more related to the
      expression of Pgp than MRP gene. It is possible that other membrane transporters
      as well as Pgp and MRP are involved in the efflux of Tc-99m MIBI.

PMID- 12623108
TI  - Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in
      vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3
      human prostate cancer cells.
AB  - Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin
      releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and
      specificity. The GRPr is over expressed on a variety of human cancer cells
      including prostate, breast, lung, and pancreatic cancers. The specific aim of
      this study was to identify a BBN analogue that can be radiolabeled with (177)Lu
      and maintains high specificity for GRPr positive prostate cancer tumors in vivo.
      A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was
      designed to produce a DOTA-BBN (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N",N"'
      tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V
      G-H-L-M-(NH(2)), where the spacer group, X = omega-NH(2)(CH(2))(7)COOH (8-Aoc).
      The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray
      Mass Spectrometry (ES-MS) was used to characterize both metallated and non
      metallated BBN-conjugates. The new DOTA-conjugate was metallated with
      (177)Lu(III)Cl(3) or non-radioactive Lu(III)Cl(3). The (177)Lu(III)- and non
      radiolabeled Lu(III)-conjugates exhibit the same retention times under identical
      RP-HPLC conditions. The (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate was found to
      exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in
      vivo models demonstrated the ability of the (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2)
      conjugate to specifically target GRP receptors expressed on PC-3 human prostate
      cancer cells.

PMID- 12623110
TI  - Tumor detection using 18F-labeled matrix metalloproteinase-2 inhibitor.
AB  - Matrix metalloproteinase-2 (MMP-2) is a key enzyme involved in tumor
      invasiveness. (2R)-2- [4-(6-[(18)F]Fluorohex-1-ynyl)-benzenesulfonylamino]-3
      methylbutyric acid ([(18)F]SAV03), a new fluorine-18 labeled MMP-2 inhibitor
      developed for tumor imaging with PET, was biologically evaluated using in vivo
      tumor model. Enzymatic MMP-2 assay of SAV03 yielded an IC(50) value of 1.9
      microM. Biodistribution study of [(18)F]SAV03 using Ehrlich tumor bearing mice
      showed that the uptake in tumor was higher than in other organs, except for the
      liver, small intestine, and bone. When [(18)F]SAV03M, a methyl ester of
      [(18)F]SAV03, was used as a prodrug, the uptake in liver at 30 min after
      injection decreased by half and that in tumor increased by 2.4 times, compared
      with [(18)F]SAV03. Radio-thin-layer chromatographic analysis of [(18)F]SAV03M
      metabolites revealed that administered [(18)F]SAV03M was easily converted to the
      parent drug in vivo and accumulated in tumor tissue. Thus, [(18)F]SAV03M is
      suitable as the prodrug of [(18)F]SAV03 with potent efficacy. Whole body
      autoradiography using [(18)F]SAV03M also indicated tumor-specific accumulation of
      radioactivity, while higher accumulations in bone and intestinal contents were
      observed. Our results suggest that [(18)F]SAV03M could be potentially suitable
      for tumor imaging with PET.

PMID- 12623111
TI  - 99mTc-labeling studies of a modified metronidazole and its biodistribution in
      tumor bearing animal models.
AB  - A cysteine-based bifunctional chelating agent viz. N-(2'-hydroxybenzyl)-cysteine
      with a free carboxylic acid group (CAA) was synthesized. Bearing in mind the
      affinity of localization of nitroimidazoles in hypoxic tissues, this bifunctional
      chelating agent was coupled to metronidazole (MNZ). The (99m)Tc labeling studies
      of the novel agent (MNZCAA) thus obtained, was carried out and the radiolabeled
      product was subsequently purified. The complexation yield under optimized
      condition was approximately 85%. Biodistribution studies carried out in Swiss
      mice bearing 'barcl-95' tumors showed selective accumulation of the injected
      activity in the tumor (1.70%/g at 30 min p.i.) with renal as well as
      hepatobiliary clearance. High tumor/muscle ratio (14.7 at 3 h post-injection) of
      the novel agent indicates considerable promise towards further evaluation.

PMID- 12623112
TI  - Uptake of 153Sm-DTPA-bis-biotin and 99mTc-DTPA-bis-biotin in rat as-30D-hepatoma
      cells.
AB  - Labeled biotin has been used mainly for pretargeted therapy, an approach for
      increasing the amount of radioactivity delivered to a cancer cell. The aim of
      this investigation was to prepare (153)Sm-DTPA-bis-biotin and (99m)Tc-DTPA-bis
      biotin in order to study their in vitro and in vivo uptake in rat AS-30D hepatoma
      cells found in ascites and in implanted tumor. DTPA-bis-biotin (pH 8) was (153)Sm
      labeled with (153)SmCl(3) and (99m)Tc-DTPA-bis-biotin was prepared via SnCl(2)
      reduction. Radiochemical purity was >98% in both cases. AS-30D hepatoma cells
      were obtained from ascites of a rat with hepatoma and were propagated in the
      peritoneum cavity of normal rats. In vitro ascites cell (153)Sm-DTPA-bis-biotin
      uptake was compared with (153)SmCl(3) cell uptake. The ratio cell (153)Sm-DTPA
      bis-biotin/(153) SmCl(3) was 39.6 and when avidin was added it increased to 50.
      The ratio (99m)Tc-DTPA-bis-biotin/TcO(4)Na was 8.7. Concentration of (153)Sm-DTPA
      bis-biotin in tumor 2, 3 and 24 h after administration, was 5, 15 and 3 times
      higher than in normal muscle (T/nT). Biodistribution in a 0.083-24 h time period
      showed that (153)Sm-DTPA-bis-biotin was taken up only by ascites tumor cells and
      hepatoma cells. Two and 3 h ratio ascites/liver (As/Lv) was 6.4 and 6.0. For
      (99m)Tc-DTPA-bis-biotin 2 and 3 h T/nT was 15.7 and 4.7 and 2 h As/Lv was 1.4. In
      conclusion, both radiopharmaceuticals show high uptake in rat AS-30D hepatoma
      cells in ascites and in implanted tumor. Since lung, thyroid, kidney, liver or
      pancreas carcinomas are ascites producing cancers (153)Sm-DTPA-bis-biotin would
      be an adequate therapeutic radiopharmaceutical for these patients whose life
      quality would be enhanced with control of ascites, and a reduction of the primary
      tumor and its metastases.

PMID- 12623114
TI  - High radiochemical yield synthesis of 3'-deoxy-3'-[18F]fluorothymidine using (5'
      O-dimethoxytrityl-2'-deoxy-3'-O-nosyl-beta-D-threo pentofuranosyl)thymine and its
      3-N-BOC-protected analogue as a labeling precursor.
AB  - We prepared 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) from 3'-O-nosyl
      thymidine derivative 3 or its pyrimidine ring N-BOC-protected analogue 5 and
      optimized [(18)F]fluorination condition for a high radiochemical yield. The
      optimal condition for [(18)F]fluorination with precursor 3 was 30 mg (41.1
      micromol)/300 microl CH(3)CN at 130 degrees C for 5 min, while precursor 5
      required 34 mg (40 micromol)/300 microl CH(3)CN at 110 degrees C for 5 min. After
      HPLC purification at neutral pH, we achieved high radiochemical yields of 40 +/-
      5.2% and 42 +/- 5.4% (decay-corrected) within 60 min of preparation time with
      radiochemical purities of >97%.

PMID- 12623113
TI  - In vitro cell studies of technetium-99m labeled RGD-HYNIC peptide, a comparison
      of tricine and EDDA as co-ligands.
AB  - The level of alpha(V)beta(3) integrins on endothelial cells is elevated in
      angiogenesis. The high binding specificity to alpha(V)beta(3) integrins of
      peptides containing Arg-Gly-Asp (RGD) residues suggests that the radiolabeled RGD
      peptides may be useful as tumor specific imaging agents. In this research,
      cyclised peptides containing Arg-Gly-Asp (RGD) and Arg-Gly-Glu (RGE, as control)
      residues were conjugated with HYNIC and labeled with (99m)Tc. OBJECTIVE: The goal
      was to evaluate the influence of co-ligand, either tricine or ethylenediamine
      N,N'-diacetic acid (EDDA) on protein and integrin binding and on cellular uptake
      in culture. METHODS: The n-octanol/water partition coefficient, binding to bovine
      serum albumin (BSA) and human umbilical vein endothelial (HUVE) cells, and cell
      lysate distributions of the radiolabeled peptides were evaluated. RESULTS: The co
      ligands had a significant effect on the labeling efficiency of the HYNIC
      conjugates and on certain properties of the (99m)Tc complexes. The labeling
      efficiency with tricine was 10 fold higher and BSA binding was over 8 fold
      greater compared to EDDA. Both RGD labels showed higher (6 to 28 fold) binding to
      HUVE cells than that of the RGE labels, indicating binding specificity. After
      cell-lysis, only a small percentage of the total RGD label that accumulated in
      the cells was found bound to cellular proteins (9% of RGD/tricine and 5% of
      RGD/EDDA), implying that over 90% of the radiolabeled peptides were internalized
      for both radiolabeled RGDs. The number of the RGD molecules bound to proteins was
      estimated to be approximately three per cell, suggesting that only a small number
      of alpha(V)beta(3) integrin proteins are expressed on the cells. CONCLUSIONS:
      Apart from the differences in radiolabeling, the only important effect of
      substituting EDDA for tricine as co-ligand on the HYNIC-peptides was the lower
      degree of serum protein binding. In spite of the lower serum protein binding
      potential, in vivo tumor accumulation of the RGD/EDDA may not be improved
      compared to RGD/tricine since quantitation of the cell binding results suggests
      that the number of alpha(V)beta(3) integrin proteins per cell might be limited.

PMID- 12623115
TI  - [99mTc] liposomes for localizing experimental colitis in a rabbit model.
AB  - [(99m)Tc] liposomes (TL) and [(111)In]WBCs (WBCs) were compared for imaging
      colitis in rabbits. At 24 h, liver was the major organ of accumulation (7.8% TL
      vs 39.7% WBCs), besides blood (44.1% TL vs 24.4% WBCs) and spleen (0.3% TL vs 7%
      WBCs). The inflamed colon accumulated 37.1 times more of [(99m)Tc] liposomes than
      the normal colon whereas the ratio was only 15.2 in case of [(111)In] WBCs. The
      study demonstrates the usefulness of [(99m)Tc] liposomes for imaging inflammatory
      bowel diseases.

PMID- 12623117
TI  - Quantification of brain mu-opioid receptors with [11C]carfentanil: reference
      tissue methods.
AB  - [(11)C]Carfentanil (CFN) is a mu-opioid agonist used for in vivo positron
      emission tomography (PET) studies of mu-opioid receptors. Previously, a tissue
      ratio method was validated for the quantification of CFN binding. However, since
      that initial validation, several other blood independent (reference-tissue)
      methods have become available. To evaluate these methods, CFN PET studies with
      arterial blood sampling were acquired in six healthy male control subjects.
      Specific binding estimates obtained from reference-tissue methods were compared
      to those obtained with a more rigorous blood input modeling technique. It was
      determined that both a graphical method, and a simplified reference tissue model,
      were more accurate than the tissue-ratio method for quantification of CFN
      binding.

PMID- 12623116
TI  - 99mTc-alafosfalin: an antibiotic peptide infection imaging agent.
AB  - The radiolabeled antibiotic peptide (99m)Tc-alafosfalin was assessed as an
      infection imaging agent in a rat model by comparison with (99m)Tc-DTPA and
      (99m)Tc-leukocytes. (99m)Tc-alafosfalin was prepared via an instant cold kit and
      (99m)Tc-leukocytes were prepared using (99m)Tc-stannous fluoride colloid in an ex
      vivo labeling procedure of whole blood. In separate experiments, the three
      radiotracers were administered to rats infected with staphylococcus aureus.
      Quantitative biodistribution studies were performed as well as scintigraphic
      images and histopathology. (99m)Tc-alafosfalin is a stable product, obtained in
      high radiochemical purity (>95%). This agent was mainly renally excreted, with
      low liver, spleen and bone uptake, and resulted in a mean ratio of infected/non
      infected thighs of 4.3/1.0 at 4 hr post radiotracer injection. (99m)Tc-DTPA gave
      a corresponding ratio of 1.9/1.0 and (99m)Tc-leukocytes gave 20.0/1.0 at the same
      time point. An in vitro assay found the level of (99m)Tc-alafosfalin binding to
      staphylococcus aureas higher than (99m)Tc-DTPA (10% versus 1% respectively).
      (99m)Tc-alafosfalin accumulates at sites of infection in a rat model better than
      the perfusion molecule (99m)Tc-DTPA, yet less than (99m)Tc-leukocytes. The
      distribution characteristics of this (99m)Tc-antibiotic peptide would be an
      advantage in imaging abdominal and soft tissue infection.

PMID- 12623118
TI  - Evaluation of [3H]LY341495 for labeling group II metabotropic glutamate receptors
      in vivo.
AB  - New glutamatergic drugs are being developed as potential therapies for
      neurodegenerative disorders, anxiety disorders, and psychoses. The development of
      effective mGluR radiotracers would provide essential tools with which to probe
      these sites in living humans, providing critical information about certain
      disease processes involving the glutamaterigic system and its regulation in
      humans. As a first step towards this goal, the tritiated form of the high
      affinity group II metabotropic glutamate receptor (mGluR) antagonist LY341495
      [K(D) (mGluR(2)) = 1.67 +/- 0.20 nM, K(D) (mGluR(3)) = 0.75 +/- 0.43 nM] was
      evaluated to determine its potential to label mGluRs in vivo. Dissection analysis
      of the regional brain distribution over time of [(3)H]LY341495 in male rats
      revealed low brain uptake and no significant demonstrable saturable binding of
      this tracer. A group II mGluR tracer possessing higher affinity than
      [(3)H]LY341495 and an absence of carboxylic acid groups is likely required for in
      vivo PET imaging purposes.

PMID- 12623119
TI  - Pharmacological evaluation of (S)-8-[123I]iodobretazenil: a radioligand for in
      vivo studies of central benzodiazepine receptors.
AB  - In vitro studies on cortical membranes indicated (S)-8-[(123)I]iodobretazenil
      bound saturably to a single population of binding sites (B(max) = 2.33 pmol/mg
      protein) with a dissociation constant K(d) = 1.9 nM. (R)-8-[(123)I]Iodobretazenil
      displayed only non-specific binding. In vivo biodistribution of (S)-8
      [(123)I]iodobretazenil in rats indicated high accumulation in regions of high BZR
      density. Radioactivity was blocked by preadministration with iodobretazenil and
      flumazenil, while non-BZR drugs had no effect on the uptake of activity in any
      brain region. (S)-8-[(123)I]Iodobretazenil uptake was saturable in a dose
      dependent manner (ID(50) = 0.13 mg/kg) in all brain regions. With the (R)
      enantiomer no specific uptake was observed. Metabolite studies at 1-3 h p.i.
      indicated that greater than 95% of activity extracted from brain tissue
      corresponded to unchanged radiotracer while that in plasma was over 70%. (S)-8
      [(123)I]Iodobretazenil potently and selectively labels BZR in vivo and deserves
      further investigation as a possible SPECT radiotracer.

PMID- 12623120
TI  - The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to
      the acute phase reactant alpha1-acid glycoprotein: implications for the use of
      the ligand as a CNS inflammatory marker.
AB  - The peripheral benzodiazepine receptor ligand PK11195 has been used as an in vivo
      marker of neuroinflammation in positron emission tomography studies in man. One
      of the methodological issues surrounding the use of the ligand in these studies
      is the highly variable kinetic behavior of [(11)C]PK11195 in plasma. We therefore
      undertook a study to measure the binding of [(3)H]PK11195 to whole human blood
      and found a low level of binding to blood cells but extensive binding to plasma
      proteins. Binding assays using [(3)H]PK11195 and purified human plasma proteins
      demonstrated a strong binding to alpha1-acid glycoprotein (AGP) and a much weaker
      interaction with albumin. Immunodepletion of AGP from plasma resulted in the loss
      of plasma [(3)H]PK11195 binding demonstrating: (i) the specificity of the
      interaction and (ii) that AGP is the major plasma protein to which PK11195 binds
      with high affinity. PK11195 was able to displace fluorescein-dexamethasone from
      AGP with IC(50) of <1.2 microM, consistent with a high affinity interaction.
      These findings are important for understanding the behavior of the ligand in
      positron emission tomography studies for three reasons. Firstly, AGP is an acute
      phase protein and its levels will vary during infection and pathological
      inflammatory diseases such as multiple sclerosis. This could significantly alter
      the free plasma concentrations of the ligand and contribute to its variable
      kinetic behavior. Secondly, AGP and AGP-bound ligand may contribute to the access
      of [(11)C]PK11195 to the brain parenchyma in diseases with blood brain barrier
      breakdown. Finally, local synthesis of AGP at the site of brain injury may
      contribute the pattern of [(11)C]PK11195 binding observed in neuroinflammatory
      diseases.

PMID- 12623121
TI  - Radiolabeling morpholinos with 90Y, 111In, 188Re and 99mTc.
AB  - This laboratory is investigating morpholinos (MORF), a DNA analogue, for
      radiopharmaceutical applications. While we routinely radiolabel with (99m)Tc, we
      have now labeled MORFs with (111)In, (188)Re and (90)Y in anticipation of
      therapeutic studies. METHODS: A 25 mer MORF with a primary amine on the 3'
      equivalent end attached via a 10 member linker was conjugated with an
      isothiocyanate backbone derivative of DOTA (for labeling with (111)In and (90)Y)
      and with NHS-MAG(3) (for labeling with (188)Re and (99m)Tc). The in vitro
      stability of labeled MORFs were investigated and biodistribution was carried out
      in normal mice. RESULTS: As evident by size exclusion HPLC, ITLC and Sep-Pak
      analysis, all four radiolabeled MORFs were successfully radiolabeled. In each
      case, the labeled MORFs showed one sharp peak in HPLC that shifted completely to
      earlier retention times following addition of a polymer conjugated with the
      complementary MORF. In saline at room temperature and in 37 degrees C serum, the
      radioactivity profile of (111)In, (188)Re and (99m)Tc was unchanged over 48 h
      while over the same period, the (90)Y profile showed a pronounced lower molecular
      weight peak which did not shift and was shown to be most probably due to (90)Y
      DOTA resulting from radiolysis. In addition, the recovery of (188)Re on HPLC
      decreased as samples aged probably due to oxidation to perrhenate which was
      retained by the HPLC column. The biodistributions at 1, 3 and 6 h in normal mice
      showed no important differences among all four labels with the exception that
      levels of radioactivity in stomach and thyroid were higher in the case of (188)Re
      due to in vivo oxidation of the radiolabel to perrhenate. CONCLUSIONS: When
      radiolabeled with DOTA, (90)Y-labeled MORF showed increased instabilities
      relative to that of (111)In and when radiolabeled with MAG(3), (188)Re showed in
      vitro and in vivo instabilities compared to (99m)Tc, but all labels were still
      largely intact after 48 h in saline or serum. Possibly because of the rapid
      clearance of MORFs, no important differences in biodistribution among (90)Y,
      (111)In and (99m)Tc labels were evident in normal mice. These strategies for
      labeling MORF with (90)Y and (188)Re therefore appear to be suitable for
      therapeutic applications although both show some evidence of instabilities.

PMID- 12623122
TI  - Corticotropin-releasing hormone (CRH) and immunotolerance of the fetus.
AB  - The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced
      by several tissues of the female reproductive system, including the endometrial
      glands and decidualized stroma, as well as the trophoblast, syncytiotrophoblast,
      and placental decidua. CRH is also secreted at inflammatory sites and possesses
      potent pro-inflammatory properties influencing both innate and acquired immune
      processes. Recent experimental findings show that uterine CRH participates in
      local immune phenomena associated with early pregnancy, such as differentiation
      of endometrial stroma to decidua and protection of the fetus from the maternal
      immune system. CRH induces the expression of apoptotic Fas ligand (FasL) on
      invasive extravillous trophoblast and maternal decidual cells at the fetal
      maternal interface. Furthermore, CRH increases the apoptosis of activated T
      lymphocytes through FasL induction, participating in the processes of both
      implantation and early pregnancy tolerance.

PMID- 12623124
TI  - Assessment of sarcoplasmic reticulum Ca2+-uptake during the development of left
      ventricular hypertrophy.
AB  - Cardiac sarcoplasmic reticulum (SR) sequesters Ca(2+) and plays a crucial role in
      the regulation of intracellular Ca(2+). Its functional properties are central to
      the excitation-contraction cycle of cardiac muscle. In this study, we
      hypothesized that alterations in SR function occur during the development of left
      ventricular (LV) hypertrophy. LV hypertrophy was produced in Lewis rats by the
      one-kidney, one-clip (1K1C) procedure. LV tissues were obtained from 1K1C rats 1
      week (mild, N=7), 4 weeks (moderate, N=7), and 8 weeks (severe, N=7) post-surgery
      and from the corresponding age-matched, sham-operated controls (N=7 at each
      stage). In all of these rats, the ratio of LV weight (g) to body weight (kg) was
      determined and considered as an index for LV hypertrophy. In addition, the ratio
      of lung weight (g) to body weight (kg) was determined and considered as an index
      for pulmonary congestion and heart failure. In each LV specimen, SR Ca(2+)-uptake
      and tissue Ca(2+)-ATPase (CAA) level were determined. In 1K1C rats, LV
      hypertrophy increased by 21, 40, and 90% at 1, 4, and 8 weeks post-surgery,
      respectively, compared to the age-matched, sham-operated rats, whereas pulmonary
      congestion did not occur at 1 and 4 weeks but increased significantly by about
      21% at 8 weeks. Further, both SR Ca(2+)-uptake and immunodetectable CAA level did
      not change at 1 week, increased (54%) to the same extent at 4 weeks, and
      decreased (42%) by approximately the same extent at 8 weeks in 1K1C rats compared
      to the age-matched, sham-operated rats. In summary, as LV hypertrophy evolved,
      Ca(2+)-uptake and CAA expression did not change in the early, increased in the
      moderate, and then declined in the later stages of hypertrophy development. The
      increase in Ca(2+)-uptake and CAA expression suggests, at the cellular level, a
      compensatory response to LV hypertrophy, while the decline at later stages
      indicates the transition to heart failure.

PMID- 12623123
TI  - Tumor necrosis factor alpha-induced apoptosis in astrocytes is prevented by the
      activation of P2Y6, but not P2Y4 nucleotide receptors.
AB  - The physiological role of the uracil nucleotide-preferring P2Y(6) and P2Y(4)
      receptors is still unclear, although they are widely distributed in various
      tissues. In an effort to identify their biological functions, we found that
      activation by UDP of the rat P2Y(6) receptor expressed in 1321N1 human astrocytes
      significantly reduced cell death induced by tumor necrosis factor alpha (TNF
      alpha). This effect of UDP was not observed in non-transfected 1321N1 cells.
      Activation of the human P2Y(4) receptor expressed in 1321N1 cells by UTP did not
      elicit this protective effect, although both receptors were coupled to
      phospholipase C. The activation of P2Y(6) receptors prevented the activation of
      both caspase-3 and caspase-8 resulting from TNF alpha exposure. Even a brief (10
      min) incubation with UDP protected the cells against TNF alpha-induced apoptosis.
      Interestingly, UDP did not protect the P2Y(6)-1321N1 cells from death induced by
      other methods, i.e. oxidative stress induced by hydrogen peroxide and chemical
      ischemia. Therefore, it is suggested that P2Y(6) receptors interact rapidly with
      the TNF alpha-related intracellular signals to prevent apoptotic cell death. This
      is the first study to describe the cellular protective role of P2Y(6) nucleotide
      receptor activation.

PMID- 12623126
TI  - Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by
      peroxisome proliferators.
AB  - Peroxisome proliferators (PPs) regulate a battery of rodent P450 genes, including
      CYP2B, CYP2C, and CYP4A family members. We hypothesized that other components of
      the P450-metabolizing system are altered by exposure to PPs, including NADPH
      cytochrome P450 oxidoreductase (P450R), an often rate-limiting component in P450
      dependent reactions. In this study, we determined whether exposure to
      structurally diverse PPs alters the expression of P450R mRNA and protein.
      Increases in P450R mRNA levels were observed in male and female F-344 rat livers
      and in male rat kidneys after chronic exposure of the animals to PPs.
      Paradoxically, under the same treatment conditions in male rats, liver P450R
      protein levels decreased after exposure to the PPs Wy-14,643 ([4-chloro-6-(2,3
      xylidino)pyrimidynylthio]acetic acid) (WY) or gemfibrozil (GEM). The down
      regulation of the P450R protein was sex- and tissue-specific in that exposure to
      PPs led to increases in P450R protein in female rat livers [di-n-butyl phthalate
      (DBP) only] and male rat kidneys (WY, GEM, DBP). In male wild-type SV129 mice,
      P450R mRNA levels increased in livers after exposure to WY and diethylhexyl
      phthalate (DEHP) and in male kidneys after exposure to DEHP. Induction of mRNA by
      PPs was not observed in the liver or kidneys of mice, which lack a functional
      peroxisome proliferator-activated receptor alpha (PPAR alpha), the central
      mediator of the effects of PPs in the rodent liver. In wild-type male mice, P450R
      protein was decreased in liver after WY and DEHP treatment and in kidneys after
      WY treatment. The down-regulation of the P450R protein was not observed in PPAR
      alpha-null mice. These studies demonstrate the complex regulation of P450R
      expression by PPs at two different levels, both of which are dependent upon PPAR
      alpha: up-regulation of transcript levels in liver and kidneys and down
      regulation of protein levels in male rat and mouse liver by a novel
      posttranscriptional mechanism.

PMID- 12623125
TI  - P23 enhances the formation of the aryl hydrocarbon receptor-DNA complex.
AB  - The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor
      that requires heterodimerization with its partner, the Ah receptor nuclear
      translocator (Arnt), for activation of transcription. The heterodimer
      specifically recognizes the dioxin response element (DRE), which contains a core
      sequence (5'-TNGCGTG-3'). This AhR/Arnt/DRE complex has been well characterized
      and can be observed readily by the gel shift assay. Human AhR and Arnt with a C
      terminal histidine tag have been expressed functionally using a baculovirus
      expression system. However, after purification of these proteins using the metal
      resin, they are not able to bind the response element in a ligand-dependent
      manner unless crude extracts, such as the rabbit reticulocyte lysate (RRL), are
      reconstituted with these proteins. Proteins in the RRL are responsible for this
      restoration of the gel shift complex because the activity is sensitive to both
      heat and proteolytic treatments. We have examined whether hsp90 and p23 are among
      the protein factors in the RRL that are responsible for this activity. By
      performing fractionation studies using filtration devices and immunodepletion
      studies, we have selectively fractionated these proteins. Among all the
      fractions, the centricon-10 retentate, which contains 100% of p23 but no hsp90,
      possessed the most enriched activity. Purified bacterial-expressed p23 restored
      the gel shift complex; the mechanism was mediated at the heterodimerization step
      and was hsp90-dependent.

PMID- 12623127
TI  - Peptide G protein agonists from a phage display library.
AB  - G proteins may serve as targets for pharmacological activation of signaling
      pathways bypassing the regulatory events that may counteract the effect of the
      external stimulus on the level of receptors. We sought to identify peptides as
      lead structures interacting with G proteins utilizing a commercially available
      phage-display library. The heptapeptide library was screened for binding to human
      G alpha(i1) which was modified with a hexahistidine tag and immobilized on a
      Ni(2+)-coated surface. After several rounds of phage selection a number of phage
      clones with consensus sequences were found. Peptides with such sequences were
      chemically synthesized and their effect on [35S]GTP gamma S binding to G
      alpha(i1) and other G protein alpha subunits was determined. Through this process
      two peptide 'families' with the capability to activate G proteins were
      identified. The peptides showed no structural similarity to known peptide or
      nonpeptide G protein activators with a cationic amphiphilic structure like
      mastoparan or alkylamines. The functional relevance of the peptide-G protein
      interaction was shown by an increased sensitivity for guanine nucleotides of high
      affinity agonist binding to A(1) adenosine receptors. The peptide G protein
      activators may, therefore, serve as novel tools for further investigation of
      receptor-independent activation of G proteins.

PMID- 12623128
TI  - Kinetic analysis of fluorescein and dihydrofluorescein effluxes in tumour cells
      expressing the multidrug resistance protein, MRP1.
AB  - Multidrug resistance (MDR) in tumour cells is often caused by the overexpression
      of two transporters the P-glycoprotein (P-gp) and the multidrug resistance
      associated protein (MRP1) which actively pump out multiple chemically unrelated
      substrates across the plasma membrane. A clear distinction in the mechanism of
      translocation of substrates by MRP1 or P-gp is indicated by the finding that, in
      most of cases, the MRP1-mediated transport of substrates is inhibited by
      depletion of intracellular glutathione (GSH), which has no effect on their P-gp
      mediated transport. The aim of the present study was to quantitatively
      characterise the transport of anionic compounds dihydrofluorescein and
      fluorescein (FLU). We took advantage of the intrinsic fluorescence of FLU and
      performed a flow cytometric analysis of dye accumulation in the wild-type drug
      sensitive GLC4 that do not express MRP1 and its MDR subline which display high
      level of MRP1. The measurements were made in real time using intact cells. The
      kinetics parameters, k(a)=V(M)/K(m), which is a measure of the efficiency of the
      transporter-mediated efflux of a substrate, was very similar for the two FLU
      analogues. They were highly comparable with values for k(a) of other negatively
      charged substrates, such as GSH and calcein. The active efflux of both FLU
      derivatives was inhibited by GSH depletion.

PMID- 12623129
TI  - Regulation of cyclooxygenase-2 expression by iloprost in human vascular smooth
      muscle cells. Role of transcription factors CREB and ICER.
AB  - Prostaglandin-endoperoxide synthase-2 (PGH-synthase) or cyclooxygenase-2 (COX-2)
      is inducible by a variety of stimuli, e.g. inflammatory mediators, growth factors
      and hormones and is believed to be responsible for the majority of inflammatory
      prostanoid production. Moreover, it has been demonstrated that COX-2 contributes
      substantially to prostacyclin-synthesis in patients with atherosclerosis. In this
      study, we demonstrate an up-regulation of COX-2 mRNA, protein and product
      formation by the prostacyclin-mimetic iloprost in human vascular smooth muscle
      cells (hSMC). COX-2 mRNA expression was induced transiently between 1 and 6 hr
      and returned to basal levels after 16 hr of iloprost stimulation. COX-2 protein
      was induced concomitantly between 3 and 6 hr of iloprost stimulation. This was
      accompanied by an increase in PGI(2) formation. Forskolin, a direct activator of
      adenylyl cyclase, and dibutyryl cAMP, a cell-permeable cAMP analogue-induced COX
      2 mRNA, suggesting a cAMP-dependent COX-2 expression in hSMC. Iloprost-induced
      COX-2 protein expression and PGI(2) formation was synergistically elevated by co
      stimulation with the phorbolester PMA (phorbol-12-myristate-13-acetate). It is
      concluded, that the observed up-regulation of COX-2 with subsequent release of
      newly synthesized PGI(2) and the synergistic effect of iloprost and phorbolester
      on PGI(2) formation provide a positive feedback of prostaglandins on their own
      synthesizing enzyme. This might be important for control of hSMC proliferation,
      migration and differentiation as well as inhibition of platelet aggregation.

PMID- 12623130
TI  - Expression of acetoacetyl-CoA synthetase, a novel cytosolic ketone body-utilizing
      enzyme, in human brain.
AB  - Acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) is a
      ketone body-utilizing enzyme, the physiological role of which remains unclear yet
      in mammals, particularly has never been studied in human. In order to investigate
      the tissue distribution of AACS in human, cDNA encoding AACS was isolated from
      HepG2 cells. Amino acid sequence of human AACS deduced from the open reading
      frame showed high homology (89.3%) with that of rat AACS and much less homology
      (43.7%) with that of bacterial AACS. The expression level of the AACS mRNA was
      high in kidney, heart and brain, but low in liver, and the expression profile of
      AACS in the human brain was quite similar to that of 3-hydroxy-3-methylglutaryl
      CoA reductase.

PMID- 12623131
TI  - Expression profiles of three isoforms of inositol 1,4,5-trisphosphate receptor in
      brown adipose tissue of the rat.
AB  - The thermogenic function of brown adipose tissue (BAT) is known to be mainly
      regulated by a signal transduction cascade via beta-adrenoceptor. However, recent
      studies indicated that the alpha-adrenoceptor and its downstream signal
      transduction cascade, causing elevation of the cellular Ca(2+) level, are also
      important for the regulation of this function of BAT. In the present study,
      expression profiles of 3 isoforms of the inositol 1,4,5-trisphosphate (IP(3))
      receptor, known as one of the major components of the machinery regulating the
      intracellular Ca(2+) concentration in the BAT of rats, were investigated by
      Northern analysis. Of these three IP(3) receptor isoforms, the type 2 one was
      found to be the most abundant of the three in BAT. Furthermore, when rats were
      exposed to the cold, under which condition the thermogenic function of BAT is
      known to be stimulated, the expression levels of types 1 and 2 isoforms of IP(3)
      receptor were remarkably elevated. The results of Western analysis supported the
      predominant expression of the type 2 isoform in BAT. However, different from the
      results of Northern analysis, the expression levels of types 1 and 2 isoforms of
      IP(3) receptor protein in BAT were not influenced by exposure of the animals to
      the cold.

PMID- 12623132
TI  - Trypanosoma cruzi: effect and mode of action of nitroimidazole and nitrofuran
      derivatives.
AB  - With the aim of determining the actual target(s) of nitro-group bearing compounds
      considered as possible leads for the development of drugs against Chagas'
      disease, we studied in parallel nitrofurans and nitroimidazoles. We investigated
      nine representative compounds for the following properties: efficacy on different
      Trypanosoma cruzi strains, redox cyclers, inhibition of respiration, production
      of corresponding nitroso derivatives and intracellular thiol scavengers. Our
      results indicate that nifurtimox and related compounds act as redox cyclers,
      whereas the most active in the series, the 5-nitroimidazole megazol essentially
      acts as thiol scavenger particularly for trypanothione, the cofactor for
      trypanothione reductase, an essential enzyme in the detoxification process.

PMID- 12623133
TI  - The inhibition of mast cell activation by neutrophil lactoferrin: uptake by mast
      cells and interaction with tryptase, chymase and cathepsin G.
AB  - Inhibitors of mast cell tryptase and chymase can be effective as mast cell
      stabilising compounds. Lactoferrin has been reported to inhibit tryptase
      activity, but its actions on other serine proteases of mast cells and its
      potential to alter mast cell function are not known. We have examined the ability
      of lactoferrin to inhibit mast cell tryptase, chymase and cathepsin G, and
      investigated its potential to modulate the activation of human mast cells.
      Enzymatically dispersed cells from human skin, lung and tonsil were challenged
      with anti-IgE or calcium ionophore A23187, following incubation with recombinant
      human lactoferrin, and histamine release determined. IgE-dependent histamine
      release from skin mast cells was inhibited by up to 50% following incubation with
      lactoferrin (50 or 500 nM). Tonsil mast cells were also stabilised by
      lactoferrin, but not those from lung. Calcium ionophore A23187-induced histamine
      release was not altered by lactoferrin. A double-labelling immunocytochemical
      procedure revealed the presence of lactoferrin in 4-6% of mast cells, and this
      proportion increased to 40% following incubation with lactoferrin. Lactoferrin
      did not inhibit cleavage of synthetic substrates by tryptase and chymase
      directly, though it was able to diminish the ability of heparin to stabilise
      tryptase. Cathepsin G activity was inhibited by lactoferrin. The ability of
      lactoferrin to inhibit IgE-dependent activation of human mast cells and modulate
      protease activity suggests that the release of this neutrophil product may have a
      role in the downregulation of allergic inflammation.

PMID- 12623134
TI  - Down-regulation of bradykinin B2-receptor mRNA in the heart in pressure-overload
      cardiac hypertrophy in the rat.
AB  - To determine the potential role of the cardiac kallikrein-kinin system in the
      development of cardiac hypertrophy, we studied the expression patterns of
      kallikrein, kininogen, and bradykinin receptor mRNA in the heart by polymerase
      chain reaction during the development of pressure-overload-induced left
      ventricular hypertrophy (LVH) in rats. The abdominal aortic constriction produced
      LVH after 7, 14, and 28 days. Neither mRNA levels for high-molecular-weight (H-)
      or low-molecular-weight (L-) kininogens and T-kininogen, nor those for tissue
      kallikreins, changed during LVH. B(2)-receptor mRNA levels in the left ventricles
      decreased 4 and 7 days after aortic constriction, subsequently returning to the
      levels in sham-operated animals. B(2)-receptor densities in cardiac membrane
      preparations obtained 4 days after aortic constriction significantly decreased
      compared to preparations from sham-operated rats, whereas the receptor affinity
      was unchanged. Down-regulation of B(2)-receptor mRNA levels was abolished by oral
      administration of an angiotensin II type 1 (AT1) receptor antagonist,
      candesartan, for 4 days after aortic constriction. Both cardiomyocytes and
      nonmyocytes obtained from neonatal rat hearts expressed B(2)-receptor mRNA in
      vitro, and the levels were not changed in either cell type by culture with 1
      microM angiotensin II (Ang II). However, when a mixture of cardiomyocytes and
      nonmyocytes was cultured with 1 microM Ang II, B(2)-receptor mRNA levels
      decreased within 12 hr; this in vitro effect of Ang II was inhibited by the AT1
      receptor antagonist losartan. These results indicate that the mechanical load in
      the myocardium caused by pressure-overload rapidly produces a down-regulation of
      B(2)-receptor expression during the initial stage of LVH, probably mediated by
      activating the AT1-receptor.

PMID- 12623145
TI  - The effects of corticosteroids and vitamin A on the healing of tracheal
      anastomoses.
AB  - OBJECTIVE: This study investigates the deleterious effects of corticosteroids on
      tracheal anastomotic healing and the ability of vitamin A to reverse these
      effects in a rat model. METHODS: Forty-two adult Wistar rats were randomly
      divided into five groups. The animals underwent tracheal transection and primary
      anastomoses. The groups were assigned as follows: Group I, sham (N=6); Group II,
      control (N=6); Group III, dexamethasone, 0.1 mg/kg/day intramuscularly (N=10);
      Group IV, dexamethasone 0.1 mg/kg/day intramuscularly+vitamin A 10000 IU/kg/day
      by gavages (N=10); and Group V, vitamin A 10000 IU/kg/day by gavages for a week
      (N=10). After 7 days, anastomotic healing was assessed by measurement of bursting
      pressure, hydroxyproline content and subsequent histological grading using the
      modified Ehrlich/Hunt scale. RESULTS: Bursting pressures and hydroxyproline
      contents were as follows: Group I: 977+/-8 mmHg and 11.80+/-0.3 microg/mg (mean+/
      standard error of the mean); Group II: 890+/-55 mmHg and 9.93+/-0.6 microg/mg;
      Group III: 555+/-26 mmHg and 11.90+/-1.3 microg/mg; Group IV: 873+/-73 mmHg and
      10.24+/-2.2 microg/mg; Group V: 905+/-45 mmHg and 7.51+/-0.8 microg/mg,
      respectively. Bursting pressure of Group III was found to be significantly lower
      when compared to other groups (P<0.0001). However, statistical significance was
      not found among the study groups for the hydroxyproline content. Except for
      inflammatory cell infiltration, histological parameters including epithelial
      regeneration, fibroblast proliferation, collagen content, and angiogenesis
      demonstrated significant differences among the groups. CONCLUSION: The present
      study demonstrates that dexamethasone significantly impairs the healing of
      tracheal anastomoses in rats and postoperative administration of vitamin A
      appreciably reverses this inhibitory effect. Patients receiving corticosteroids
      may benefit from vitamin A when undergoing prolonged intubation and
      laryngotracheal reconstruction.

PMID- 12623146
TI  - Postinflammatorial stenoses of the pharynx in a child with Barth-syndrome.
AB  - We report about a boy with Barth-syndrome (X-chromosomal cardioskeletal myopathy,
      neutropenia and abnormal mitochondria) and postinflammatorial pharyngeal
      stenosis. After a pseudomembranous pharyngitis he developed a dyspnea and an
      inability to swallow with a resultant aspiration pneumonia. After endoscopic
      diagnosis of scarred pharyngeal stenoses the child required a tracheostomy and a
      percutaneous endoscopic gastrostomy tube. Then the boy underwent transoral
      pharyngoplastic surgery. Thirty five months after pharyngoplasty transoral
      nutrition was feasible. The tracheostomy was closed and the gastrostomy tube was
      removed. Throughout a 40 month period of observation the child had no more
      complaints relating to the minor residual pharyngeal stenoses.

PMID- 12623147
TI  - Pulmonary function tests in children with adenotonsillar hypertrophy.
AB  - OBJECTIVE: Adenotonsillar hypertrophy, a common malady in children may lead on to
      cardiopulmonary dysfunction in untreated cases. The present study was designed to
      see alteration in pulmonary function tests i.e. spirometric parameters and blood
      oxygen saturation consequent to adenotonsillar hypertrophy and subsequent changes
      after adenotonsillectomy. METHODS: Spirometry and pulse oximetry were carried out
      in 40 children with adenotonsillar hypertrophy of both sexes between the age of 7
      and 14 years and 40 age and sex matched healthy children. The test was repeated
      one and half months after surgery in study group and data was statistically
      analyzed using students' t-test. RESULTS: The flow volume plot was abnormal in
      all the patients along with hypoxia, reduced FIF50% and, increased FEF50%/FIF50%,
      FEV1/PEFR, FEV1/FEV0.5 ratios. There was statistically significant improvement in
      above parameters following surgery. CONCLUSIONS: Spirometry can prove an useful
      diagnostic tool in adenotonsillar hypertrophy for deciding early intervention to
      prevent cardio pulmonary complications.

PMID- 12623148
TI  - Depressive symptoms in children after tonsillectomy.
AB  - OBJECTIVE: Several cases of severe depression after tonsillectomy have been
      described in children, indicating psychological trauma after surgery and
      hospitalization. The actual prevalence of depressive symptoms after tonsillectomy
      is unknown and possibly underestimated. This study aims to quantify this problem
      by employing current diagnostic methods. METHODS: This is a prospective study of
      159 children who underwent tonsillectomy in a major Pediatric University
      Hospital. All patients stayed in the hospital overnight. Parents were sent
      questionnaires based on diagnostic criteria for depression (ICD-10) 3 weeks
      postoperatively. Whenever the criteria for a depressive episode were met, a
      telephone interview with the parents followed 3 months after the operation.
      RESULTS: Some 89 questionnaires were returned (56%), revealing that 15 patients
      (17%), 4-16 years old, developed depressive symptomatology compared with a 4%
      prevalence of depression in the general child population and 10-20% in the
      pediatric hospital populations. No children had persisting symptoms 3 months
      later. CONCLUSIONS: These results suggest that post-tonsillectomy morbidity can
      occasionally manifest with depressive symptoms, usually resolving spontaneously.
      A high index of suspicion is required by the otolaryngologist, nurses and primary
      care physician for early diagnosis and referral of persisting cases to a
      specialist. Emphasis is given to a structured preoperative psychological
      preparation of pediatric patients.

PMID- 12623149
TI  - Effects of trolox, locally applied on round windows, on cisplatin-induced
      ototoxicity in guinea pigs.
AB  - OBJECTIVE: Cisplatin (CDDP), an antitumor agent widely used in the treatment of
      pediatric solid tumors, has dose-limiting side effects such as ototoxicity and
      nephrotoxicity. Recently, evidence has been accumulated to demonstrate that these
      side effects are closely related to oxidative stress. In the present study, we
      attempted to suppress CDDP-induced ototoxicity in guinea pigs by administering
      trolox, a water-soluble analogue of alpha-tocopherol which is a natural lipid
      soluble antioxidant, locally on round windows. METHODS: Hartley albino guinea
      pigs (250-300 g) were treated with CDDP (0.3 mg/ml) in the presence or absence of
      a combined treatment of trolox (5 mM). Both drugs were administered locally on
      round windows. RESULTS: The combined treatment of trolox distinctly improved the
      ototoxic side effects induced by CDDP. These were: elevation of auditory brain
      stem response threshold at 4, 8 and 16 kHz and substantial losses of outer hair
      cells with the base-to-apex gradient. CONCLUSION: Trolox, locally applied on
      round windows, showed a suppression on CDDP-ototoxicity. The results obtained in
      the present study suggest that a local application of trolox in the tympanic
      cavity can be a promising candidate to prevent the CDDP-ototoxicity in the
      future.

PMID- 12623150
TI  - Health-service costs of pediatric cochlear implantation: multi-center analysis.
AB  - OBJECTIVE: Pediatric cochlear implantation (CI) entails surgery followed by
      lifetime maintenance, and hence incurs both initial and ongoing costs. Previous
      assessments of these costs were either undertaken early in the evolution of
      services, or were based on single hospitals, or estimated costs largely from
      hospital charges. The aim was to overcome these limitations by conducting a multi
      center evaluation of the costs of providing unilateral CI to children in the
      United Kingdom (UK). METHODS: Annual numbers of implantations in all UK pediatric
      CI programs were monitored prospectively from 1991. Resource use was measured in
      12 programs in 1998/1999 and retrospectively back to the year of inception of
      each program. The profile of outpatient and outreach visits was assessed in the
      12 programs. Together these variables were used to estimate health-service costs
      for four phases of management: pre-operative assessment, implantation, tuning,
      and subsequent maintenance, using economic micro-costing methods. Costs were
      subsequently estimated for all children implanted in 1998/1999 (N=199) and were
      aggregated over 1, 15, and 73 years following implantation. To assess the
      robustness of cost estimates, parameter values were varied over plausible ranges
      and costs re-estimated. Total UK health-service costs were also estimated. All
      costs are presented in euros (1=US dollars 0.98= pound 0.65, 1st July 2002),
      inflated to 2000/2001 financial-year levels, and discounted at 6% per annum.
      RESULTS: Per-child average costs were 42972 (1-year), 73763 (15-years), and 95034
      (73-years). Cost estimates were not overly sensitive to the value of any one cost
      component nor to the relative cost of outpatient and outreach visits. When these
      parameters were varied, costs ranged between 30000 and 47000 (1-year), 61000 and
      83000 (15-years), and 82000 and 108000 (73-years). The total UK health-service
      cost of unilateral pediatric CI was estimated to be 14 million in 2000/2001 and
      is predicted to rise to 23 million in 2015/2016, if the present model of service
      delivery continues. The cost of maintaining implanted children was estimated to
      account for 22% of the total in 2000/2001 and is predicted to rise to 63% by
      2015/2016. CONCLUSIONS: Ongoing costs of maintaining implanted children and their
      implant systems are significant and should be factored into resource-allocation
      decisions.

PMID- 12623151
TI  - Risk factors for adenotonsillar hypertrophy in children following solid organ
      transplantation.
AB  - OBJECTIVE: Post-transplantation lymphoproliferative disorder (PTLD), or its
      precursor, Epstein-Barr virus (EBV)-related lymphoid hyperplasia, may first
      present in the tonsils and adenoids in the pediatric solid organ transplant
      population. We sought to identify signs and symptoms of and risk factors for
      adenotonsillar hypertrophy (ATH), a potential precursor to PTLD in children
      following solid organ transplantation. METHODS: We performed a cross-sectional
      study of 132 consecutive pediatric solid organ transplant patients at our
      institution. Questionnaire, physical examination, and laboratory data collection
      were obtained. Correlation of signs and symptoms of ATH with objective laboratory
      data was conducted. RESULTS: 132 pediatric transplant recipients (64 renal, 68
      liver) were enrolled. Mean age at transplantation was 7.4 (S.D. 6.0) years with a
      mean follow-up of 49.0 (S.D. 48.4) months post-transplantation. The mean
      questionnaire score was 8.4 (S.D. 7.9) out of a maximum 65 and the mean physical
      examination score was 3.9 (S.D. 1.9) out of a maximum 8, with a statistically
      significant correlation between the two (Pearson's r=0.352, P<0.001). A
      multivariate linear regression model found recipient EBV seronegativity and
      younger age at transplantation to be statistically significant risk factors for
      development of ATH (P=0.024 and 0.035, respectively). CONCLUSIONS: Young age and
      EBV seronegativity confer increased risk for ATH in pediatric patients undergoing
      solid organ transplantation. As ATH may be the earliest sign of PTLD, long-term
      surveillance is required to determine the impact of ATH on quality of life and
      survival in these patients.

PMID- 12623152
TI  - Durability of the binding inhibition of albumin coating on tympanostomy tubes.
AB  - OBJECTIVE: Occlusion and prolonged otorrhea are typical problems associated with
      the use of middle-ear ventilation tubes. Albumin coating of ventilation tubes has
      been introduced to prevent tube occlusions by granulation tissue, blood clot, or
      pus. In this study, the durability of the binding inhibition (BI) of fibronectin
      was examined on the tube surface in albumin-coated tubes in different
      environments during an 8-month trial. METHODS: Human serum albumin (HSA) was used
      to coat silicone tympanostomy tubes. Fibronectin, a typical adhesive protein in
      serum and exudates, was used as a model representative of exudates of the ear.
      The durability of BI of this glue protein on the tube surface was tested in
      different time periods with radiolabelled fibronectin. Scanning electron
      microscopy (SEM) was performed on the tubes. RESULTS: The BI of fibronectin,
      achieved with the albumin coating, was still strong after 8 months of storage at
      +4 degrees C. A slight decline in BI was noted between the first and third months
      of storage at +37 degrees C. A significant difference between HSA-coated and
      uncoated tympanostomy tubes was noted in SEM. The uncoated surface generally
      appeared to be rougher than that of HSA-coated tubes when either titanium or
      silicone tubes were tested. CONCLUSIONS: Albumin coating markedly inhibits the
      binding of fibronectin on tube surfaces in vitro. A clear BI achieved by albumin
      coating on tube surfaces was shown to persist throughout an 8-month trial,
      although some reduction of the BI was seen over time. The result emphasizes the
      role of albumin coating in preventing the adherence of foreign material on
      tympanostomy tubes. No advantage was achieved by using a cross-linking chemical
      in the albumin coating.

PMID- 12623153
TI  - The symptoms and clinical course of acute bullous myringitis in children less
      than two years of age.
AB  - OBJECTIVE: the most characteristic symptom of acute bullous myringitis
      (inflammation of the tympanic membrane) is a sudden onset of severe ear pain.
      However, in infants and young children a precise symptom history is more
      difficult to obtain and the symptoms may be less specific. Our objective was to
      determine the occurrence of different symptoms, signs and the recovery of
      symptoms during the course of acute bullous myringitis in children less than 2
      years. We also evaluated whether there were any specific features in bullous
      myringitis in comparison with acute otitis media (AOM). METHODS: 2028 children
      (aged 7-24 months) at primary care level in a prospective longitudinal cohort
      study in the Finnish Otitis Media Vaccine Trial. RESULTS: during the follow-up
      there were 86 office visits with bullous myringitis in 92 ears and 1876 office
      visits with acute otitis media in 2683 ears. Middle ear fluid developed in 97% of
      cases of bullous myringitis during the course of disease. Earache was present in
      58% and fever (>or=38 degrees C) in 62% of cases of bullous myringitis. The
      symptoms of upper respiratory tract infection (rhinitis in 93% and cough in 73%
      of events) were present in a majority of cases. Earache, fever, rubbing of the
      ear, restless sleeping, excessive crying and poor appetite were present more
      often in bullous myringitis than in acute otitis media. The symptoms were
      relieved in 1-2 days in a majority of cases. There were no recognized cases of
      bullous myringitis in ears with patent tympanostomy tubes. CONCLUSIONS: acute
      bullous myringitis in children represents a special form of AOM with more severe
      symptoms. Earache and fever were more common in bullous myringitis than in AOM.
      However, the condition resolved rapidly and the short-term outcome was good.

PMID- 12623154
TI  - Effect of exposure to mitomycin C on cultured tympanic membrane fibroblasts.
AB  - OBJECTIVE: Recently, attempts have been made to prolong the patency of
      myringotomy site with topical use of mitomycin C (MMC). It has been shown that
      MMC inhibits mitosis and proliferation of ocular fibroblasts, however, there are
      no studies of MMC's effect on tympanic membrane fibroblasts. To investigate the
      effects of MMC on cultured human tympanic membrane fibroblasts and understand the
      cellular basis of MMC for maintain myringotomy patency, cultured fibroblasts were
      exposed to various concentrations of MMC for periods of 5-10 min. METHODS: Effect
      of MMC on cultured fibroblasts was assessed by microscopic observation and cell
      viability test. RESULTS: Dose-, time- dependent relationship of MMC on cultured
      fibroblasts was revealed. There was a significant difference between the
      inhibition effects of MMC at concentrations of 0.4 mg/ml and control following 5
      and 10 min exposure intervals. Phase-contrast microscopy showed consistency with
      the antiproliferative effect of MMC at higher concentration. CONCLUSIONS:
      Therefore, it would appear that intraoperative use of MMC could be effective in
      delaying the healing of the myringotomy site and extending the period of time for
      myringotomy patency.

PMID- 12623156
TI  - Endoscopic ablation of distal tracheal lesions using Nd:YAG contact laser.
AB  - Surgical lasers are an excellent tool for the treatment of airway lesions. Distal
      tracheal lesions offer a greater challenge in that they are less accessible to
      laser treatment relative to upper airway lesions yet retain the propensity to
      cause complete airway obstruction. The ideal treatment modality for the
      endoscopic ablation of distal tracheal lesions provides secure airway protection,
      excellent visualization of the lesion in question, and delivery of a safe and
      effective method of treatment. We have found that the use of a contact Nd:YAG
      fiberoptic delivery system through a rigid bronchoscope has performed very well
      in meeting these criteria.

PMID- 12623155
TI  - Chlamydia infection in children with acquired subglottic stenosis.
AB  - The purpose of the study was to find out the frequency of occurrence and the role
      of Chlamydia infection in the pathogenesis of acquired subglottic stenosis in
      children. Forty-nine patients of the age from 1 year 10 months to 15 years with
      acquired cicatricial laryngotracheal stenosis were examined. The
      immunofluorescent method was used to detect serum antibodies to the antigens of
      Chlamydia trachomatis and Chlamydia pneumoniae. Dilutions of 1:32 for C.
      trachomatis and 1:64 for C. pneumoniae were considered positive. The results of
      the study suggested both a high frequency (26.5%) of Chlamydia infection (C.
      pneumoniae) of the children with acquired subglottic stenosis, as well as 92% of
      infected children were either with tracheotomies or had been decannulated
      earlier. It reasonable to test children with a tracheostomy for the presence of
      Chlamydia infection to perform timely and specific antibiotic therapy.

PMID- 12623157
TI  - Nasogastric tube misplacement into Eustachian tube.
AB  - Paediatric nasogastric tube placement can occasionally be difficult to perform. A
      unique case in a child is described where the tip of the nasogastric tube managed
      to travel via the Eustachian tube through the attic and into the mastoid cavity
      of the middle ear. To the best of the authors' knowledge, this has never been
      reported in the literature before.

PMID- 12623159
TI  - Choristomatous polyps of the aural and pharyngeal regions: first simultaneous
      case.
AB  - The first known case of embryological development of a salivary gland choristoma
      of the middle ear and a hairy teratoid (choristomatous) mass of the pharynx
      arising in the same patient is reported. On the day after the patient, a female,
      was born, a posterior pharyngeal mass was discovered, resected, and diagnosed
      histopathologically as a hairy teratoid (choristomatous) polyp. At 10 months of
      age, the patient underwent myringotomy and tympanostomy tube placement, and
      another mass was found in the left middle ear. This mass was diagnosed as a
      salivary gland choristoma. Our review of the literature showed that, consistent
      with our case, choristomas are more prevalent in females, and those in the middle
      ear almost always occur on the left side. Both types of polyps are rare and are
      thought to be due to errors in development of the second and first branchial
      arches.

PMID- 12623158
TI  - Otolaryngological manifestations of ligneous conjunctivitis.
AB  - Ligneous conjunctivitis is a rare condition that can involve the mucous membranes
      of the upper and lower airways and temporal bone extensively. This can lead to
      life threatening airway obstruction. Involvement of the middle ear and mastoid
      may cause significant conductive hearing loss. This is the first reported case
      with temporal bone sections of ligneous conjunctivitis, and awareness of the
      associated obstructive hydrocephalus may prevent death in this condition.
      Evidence suggests that plasminogen deficiency may be a causative factor in
      ligneous conjunctivitis, and this finding may offer new prospects for management.

PMID- 12623161
TI  - Physiology and pathophysiology of K(ATP) channels in the pancreas and
      cardiovascular system: a review.
AB  - K(ATP) channels are present in pancreatic and extrapancreatic tissues such as
      heart and smooth muscle, and display diverse molecular composition. They contain
      two different structural subunits: an inwardly rectifying potassium channel
      subunit (Kir6.x) and a sulfonylurea receptor (SURX). Recent studies on
      genetically engineered Kir6.2 knockout mice have provided a better understanding
      of the physiological and pathophysiological roles of Kir6.2-containing K(ATP)
      channels. Kir6.2/SUR1 has a pivotal role in pancreatic insulin secretion.
      Kir6.2/SUR2A mediates the effects of K(ATP) channels openers on cardiac
      excitability and contractility and contributes to ischemic preconditioning.
      However, controversy remains on the physiological properties of the K(ATP)
      channels in vascular smooth muscle cells. Kir6.1 knockout mice exhibit sudden
      cardiac death due to cardiac ischemia, indicating that Kir6.1 rather than Kir6.2
      is critical in the regulation of vascular tone. This article summarizes current
      understanding of the physiology and pathophysiology of Kir6.1- and Kir6.2
      containing K(ATP) channels.

PMID- 12623162
TI  - Effects of sulfonylureas on K(ATP) channel-dependent vasodilation.
AB  - INTRODUCTION: Sulfonylureas are widely prescribed for the treatment of type 2
      diabetes. Their therapeutic efficacy resides in the ability to bind to
      sulfonylurea receptors (SURs) present on the beta-cell plasma membrane, to close
      the ATP-regulated potassium (K(ATP)) channel, and thereby to enhance glucose
      stimulated insulin secretion. These receptors are also found in a wide variety of
      extra-pancreatic tissues such as brain, peripheral nerves, heart, and vascular
      smooth muscle where they contribute to the regulation of the vascular tone.
      OBJECTIVE: The objective of the present study was to determine the potency of
      three sulfonylureas, glibenclamide, gliclazide, and glimepiride, in antagonizing
      the vasorelaxant action of diazoxide, an ATP-regulated K(+) channel (K(ATP))
      opener, in vivo, using the hamster cheek pouch preparation and evaluating the
      changes in mean internal diameter and blood flow of arterioles and venules.
      MATERIAL AND METHODS: Cheek pouches of anesthetized male hamsters superfused with
      a HEPES-supported HCO(3)(-)-buffered saline solution were placed under an
      intravital microscope coupled to a closed-circuit TV system. All substances were
      applied topically. MEASUREMENTS: Mean arteriolar and venular internal diameters
      using an image shearing device, red blood cell (RBC) velocity by the dual-slit
      photometric technique and microvessel volume flow was calculated from diameters
      and RBC velocities. RESULTS: The numbers are given in order, first diameter and
      then flow, always for the highest concentration of diazoxide tested, by itself or
      in combination with a given sulfonylurea: (1) diazoxide, used in doses of 0.01,
      1, and 100 microM, elicited a dose-dependent dilation and flow increase in
      arterioles [increase of 52.1% (P<.01) and 41.2% (P<.01)] and venules [37.9%
      (P<.05) and 57.6% (P<.01)]; (2) glibenclamide (0.81 microM)+diazoxide 29.3%
      (P=.172) and 25.0% (P=.064) for arterioles and 8% (P=.654) and 3.7% (P=.769) for
      venules; (3) gliclazide (12 microM)+diazoxide 51.0% (P<.01) and 46.7% (P<.01) for
      arterioles and 59.0% (P<.01) and 45.2% (P<.01) for venules; (4) glimepiride (0.82
      microM)+diazoxide 22.8% (P=.228) and 12.5% (P=.305) for arterioles and 15.6%
      (P=.415) and 16.0% (P=.291) for venules. CONCLUSION: These results suggest that,
      in contrast to glibenclamide and glimepiride, therapeutic concentrations of
      gliclazide produce no cross-reactivity with smooth muscle cell K(ATP) channels in
      the microvessels of the hamster cheek pouch. Previous studies have confirmed
      these results in isolated aortic rings of rats and guinea pigs.

PMID- 12623164
TI  - Pathophysiological mechanisms of diabetic angiopathy.
AB  - The sequelae of chronic hyperglycemia in diabetes of all phenotypes are divided
      into microvascular and macrovascular complications. Microvascular disease causes
      blindness, renal failure, and neuropathy, and diabetes-accelerated macrovascular
      disease causes excessive risk for myocardial infarction, stroke, and lower limb
      amputation. The link between chronic hyperglycemia and vascular damage has been
      established by four independent biochemical abnormalities: increased polyol
      pathway flux, increased formation of advanced glycation end-products (AGEs),
      activation of protein kinase C (PKC), and increased hexosamine pathway flux.
      These seemingly unrelated pathways have an underlying common denominator:
      overproduction of superoxide by the mitochondrial electron transport chain.
      Mitochondrial reactive oxygen species (ROS) partially inhibit the glycolytic
      enzymes glyceraldehyde-3-phosphate dehydrogenase, which diverts increased
      substrate flux from glycolysis to pathways of glucose overutilization.
      Preliminary experimental evidence in vivo suggests that this new paradigm
      provides a novel basis for research and drug development.

PMID- 12623163
TI  - Differential selectivity of insulin secretagogues: mechanisms, clinical
      implications, and drug interactions.
AB  - The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for
      several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in
      pancreatic beta-cells and are used to stimulate insulin release in type 2
      diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal
      agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The
      predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in
      cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs
      exhibit differences in tissue specificity, as the drugs interact to varying
      degrees with different types of SUR. Gliclazide and tolbutamide are beta-cell
      selective and reversible. Glimepiride, glibenclamide, and repaglinide, however,
      inhibit cardiac and smooth muscle K(ATP) channels in addition to those in beta
      cells and are only slowly reversible. Similar properties have been observed by
      recording K(ATP) channel activity in intact cells and in Xenopus oocytes
      expressing cloned K(ATP) channel subunits. While K(ATP) channels in cardiac and
      smooth muscle are largely closed under physiological conditions (but open during
      ischaemia), they are activated by antianginal agents such as nicorandil. Under
      these conditions, they may be inhibited by sulphonylureas that block SUR2-type
      K(ATP) channels (e.g., glibenclamide). Care should, therefore, be taken when
      choosing a sulphonylurea if potential interactions with cardiac and smooth muscle
      K(ATP) channels are to be avoided.

PMID- 12623165
TI  - Monocyte adhesion in diabetic angiopathy: effects of free-radical scavenging.
AB  - Increased interaction of monocytes with vascular cells is linked to the
      development and progression of atherosclerosis in patients with diabetes. One
      major determinant of increased monocyte binding to vascular cells could be
      oxidative stress. Given the free-radical scavenging properties of gliclazide, we
      evaluated the ex vivo and in vitro effects of this drug on human monocyte binding
      to endothelial cells and smooth muscle cells (SMCs). Short-term administration of
      gliclazide to patients with type 2 diabetes decreases plasma lipid peroxides and
      lowers the enhanced adhesion of diabetic monocytes to cultured endothelial cells
      observed before gliclazide treatment. Gliclazide (10 microg/ml) also reduces
      oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product
      (AGE)-induced monocyte adhesion to cultured endothelial cells. The suppressive
      effect of gliclazide on AGE-induced monocyte adhesion to endothelium involves a
      reduction of cell adhesion molecule mRNA and protein expression and an inhibition
      of NF-kappaB activation. Gliclazide also inhibits oxLDL-induced monocyte adhesion
      to cultured human aortic smooth muscle cells (HASMCs). Furthermore, treatment of
      HASMCs with gliclazide results in a marked decrease in oxLDL-induced monocyte
      chemoattractant protein-1 expression, both at the gene and protein levels. These
      results suggest that gliclazide, at concentrations in the therapeutic range (5-10
      microg/ml), by its ability to decrease monocyte-vascular cell interactions could
      reduce monocyte accumulation in the atherosclerotic plaque and thereby contribute
      to attenuate the sustained inflammatory process that occurs in the vessel wall.
      These findings suggest that treatment of diabetic patients with gliclazide may
      prevent or retard the development of vascular disturbances associated with
      diabetes.

PMID- 12623167
TI  - Interpretation of unexpected rocking curve asymmetry in LACBED patterns of
      semiconductors.
AB  - Transmission electron microscopy rocking curves diffracted from inclined planes
      in argon ion-thinned Si and III-V semiconductors display a significant asymmetry
      around the Bragg condition. Kinematical and dynamical calculations of the rocking
      curves show that such an asymmetry can be attributed to the dilation of coherent
      crystalline surface layers implanted with argon atoms. The surface layers are
      characterized with two parameters, their width h and the strain component epsilon
      (z) normal to the thin foil plane. The dark-field rocking curve asymmetry is
      shown, for sufficiently high values of h (> approximately 2 nm), to strongly
      depend on epsilon (z) which is directly related to the density of implanted argon
      atoms in the surface layers. Calculations also show that a significant rocking
      curve asymmetry is only observed for intermediate values of epsilon (z) of about
      a few percentage points.

PMID- 12623166
TI  - Diabetic endothelial dysfunction: effect of free radical scavenging in Type 2
      diabetic patients.
AB  - Diabetes mellitus is characterized by oxidative stress, which in turn determines
      endothelial dysfunction. It has been recently demonstrated that gliclazide, a
      second-generation sulfonylurea with antioxidant properties, is able to protect
      endothelial function in animal models of diabetes. In streptozotocin-induced
      diabetic rats, gliclazide prevented endothelial dysfunction when given orally and
      improved the impaired relaxations to exogenous nitric oxide (NO) when applied on
      aortic segments. Moreover, gliclazide was able to inhibit glycosylated
      oxyhemoglobin-induced endothelial dysfunction both in animal and human
      microvessels. All these effects were not shared by glibenclamide, but were
      mimicked by vitamin C or superoxide dismutase (SOD), thus suggesting that
      gliclazide's action on endothelium-dependent vasodilation is mediated by its
      antioxidant properties. Thus far, there are no clinical studies that describe the
      influence of gliclazide on both oxidative status and NO-mediated vasodilation. We
      therefore evaluated the effects of gliclazide on plasma lipid peroxides, plasma
      total radical trapping antioxidant parameter (TRAP), and NO-mediated vasodilation
      assessed by blood pressure modifications following intravenous L-arginine in 30
      subjects with Type 2 diabetes mellitus. The patients received glibenclamide
      (n=15) or gliclazide (n=15) in a 12-week, randomized, observer-blinded, parallel
      study, and were studied pre- and post-treatment. At 12 weeks, gliclazide-treated
      patients had lower plasma lipid peroxides (13.3+/-3.8 vs. 19.2+/-4.3 micromol/l;
      P=.0001, respectively) and higher plasma TRAP (1155.6+/-143.0 vs. 957.7+/-104.3
      micromol/l; P=.0001, respectively) than the glibenclamide-treated patients.
      Gliclazide, but not glibenclamide, significantly reduced the systolic and
      diastolic blood pressure (P=.0199 and P=.00199, respectively, two-way repeated
      measures analysis of variance) in response to intravenous L-arginine. In
      conclusion, our results demonstrate that glicazide treatment improves both
      antioxidant status and NO-mediated vasodilation in diabetic patients.

PMID- 12623168
TI  - Determination of the mean inner potential in III-V semiconductors by electron
      holography.
AB  - The mean inner potential of GaAs(14.18V), InAs(14.50V), GaP(14.35V) and
      InP(14.50V) has been measured by transmission electron holography using the phase
      shift of the (000)-beam of the first hologram sideband. To provide a defined
      specimen geometry we used 90 degrees wedges obtained by the cleavage technique.
      The exact excitation condition as well as the acceleration voltage of the
      electrons were determined from convergent beam electron diffraction images. The
      magnification is extracted from two-beam lattice fringe images and dynamical
      effects are taken into account by Bloch-wave calculations.

PMID- 12623169
TI  - A method for estimating the CTF in electron microscopy based on ARMA models and
      parameter adjustment.
AB  - In this work, a powerful parametric spectral estimation technique, 2D-auto
      regressive moving average modeling (ARMA), has been applied to contrast transfer
      function (CTF) detection in electron microscopy. Parametric techniques such as
      auto regressive (AR) and ARMA models allow a more exact determination of the CTF
      than traditional methods based only on the Fourier transform of the complete
      image or parts of it and performing some average (periodogram averaging).
      Previous works revealed that AR models can be used to improve CTF estimation and
      the detection of its zeros. ARMA models reduce the model order and the computing
      time, and more interestingly, achieve increased accuracy. ARMA models are
      generated from electron microscopy (EM) images, and then a stepwise search
      algorithm is used to fit all the parameters of a theoretical CTF model in the
      ARMA model previously calculated. Furthermore, this adjustment is truly two
      dimensional, allowing astigmatic images to be properly treated. Finally, an
      individual CTF can be assigned to every point of the micrograph, by means of an
      interpolation at the functional level, provided that a CTF has been estimated in
      each one of a set of local areas. The user need only know a few a priori
      parameters of the experimental conditions of his micrographs, for turning this
      technique into an automatic and very powerful tool for CTF determination, prior
      to CTF correction in 3D-EM. The programs developed for the above tasks have been
      integrated into the X-Windows-based Microscopy Image Processing Package (Xmipp)
      software package, and are fully accessible at www.biocomp.cnb.uam.es.

PMID- 12623170
TI  - Electrostatic interactions observed when imaging proteins with the atomic force
      microscope.
AB  - The atomic force microscope (AFM) is now an established and valuable tool for the
      study of biological macromolecules in aqueous environments. In this paper we form
      a patterned boundary via the microcontact printing of individually isolated
      proteins, covalently attached to a solid support. We use this boundary to
      investigate electrostatic interactions that can occur between an AFM tip and a
      protein surface during imaging in solution. The observed height variations of the
      protein film are found to be a combination of not only structural considerations
      and thickness of the protein film, but also the repulsive contribution from
      electrostatic interactions between the AFM tip and the sample. These variations
      in measured heights of the protein surface can be described by Derjaguin, Landau,
      Verway, Overbeek (DLVO) theory. Our experimental results show that height
      measurements can be manipulated either negatively or positively by adjusting the
      pH and concentration of the electrolyte buffer that is utilised.

PMID- 12623171
TI  - Lattice-resolution contrast from a focused coherent electron probe. Part I.
AB  - To develop a Bloch wave framework for lattice-resolution contrast derived from
      coherent or incoherent scattering of an electron probe focused onto a crystal,
      boundary conditions which influence the propagation of an arbitrarily distorted
      coherent electron probe are addressed. These boundary conditions are particularly
      relevant for a probe focused within a unit cell, and lead to a general theory
      which hinges on Bloch wave excitation amplitudes being written as a function of
      beam position and focus. Whereas antisymmetric Bloch states are not excited for
      an incident plane wave at an exact zone axis orientation, these states may be
      strongly excited depending on probe focus and position within the unit cell.
      Equations for both coherent and incoherent lattice image contrast in scanning
      transmission electron microscopy are derived for any detector configuration in
      the Bloch wave framework. An equivalent expression amenable to evaluation via
      multislice techniques is also described. It is shown explicitly how mixed dynamic
      form factors for incoherent scattering should be taken into account for annular
      dark field or backscattered electron detectors, as well as for characteristic
      losses detected by X-ray emissions or by electron energy loss spectroscopy. A
      background contribution from "absorbed" electrons is included in the theory. The
      contribution of cross-talk from neighbouring columns to incoherent contrast is
      examined within the context of this theoretical framework.

PMID- 12623172
TI  - Lattice-resolution contrast from a focused coherent electron probe. Part II.
AB  - In the previous paper, boundary conditions matching the probe to the crystal wave
      function in scanning transmission electron microscopy were applied by matching
      the whole wave function across the boundary. It is shown here how that approach
      relates to previous Bloch wave formulations using (phase-linked) plane wave
      boundary conditions for wave vectors implied by the range of transverse momentum
      components in the incident probe. Matching the whole wave function across the
      boundary, and including a suitably fine mesh in the reciprocal space associated
      with the crystal to allow matching of transverse momentum components within the
      probe, leads to a structure matrix A containing many elements which would
      normally be excluded for plane wave incidence. For perfect crystals, the A-matrix
      may be block diagonalised. This leads to a considerable increase in the
      computational efficiency of the model and yields important insights into the
      physics of convergent probes in perfect crystals-reciprocity in coherent imaging
      and the small aperture limit for coherent and incoherent contrast are considered.
      The numerical equivalence of the incoherent lattice contrast calculated in this
      Bloch wave method and the multislice method using mixed dynamic form factors will
      be demonstrated. Comparison between both these methods and the frozen phonon
      model, a prevalent multislice method for annular dark field simulation which has
      the theoretical advantage of handling double channelling, will be made.

PMID- 12623173
TI  - Interaction forces and conduction properties between multi wall carbon nanotube
      tips and Au(111).
AB  - We have studied the interaction forces and electrical conduction properties
      arising between multiwall carbon nanotube tips and the Au(111) surface in air, by
      means of amplitude modulation scanning force microscopy, also called intermittent
      contact. We have centered our work on tips with metallic electronic structure and
      for the specific parameters used we have found a preliminary interaction range
      where there is no contact between tip and surface. Stable imaging in this non
      contact range is possible with multiwall carbon nanotube tips. These tips have
      also been used to obtain simultaneous topographic and current maps of the
      surface. They show excellent properties as tips due to their high aspect ratio
      and durability, as a result of their elastic and non-reactive properties.
      Correspondingly, multiwall carbon nanotube tips allow high resolution local
      analysis of electrical conductivity on a nanometer scale.

PMID- 12623174
TI  - A Fourier approach to fields and electron optical phase-shifts calculations.
AB  - The Fourier method is applied to calculate fields and electron optical phase
      shifts in specimens having long-range electromagnetic fields, like reverse biased
      p-n junctions or stripe magnetic domains. It is shown that this approach not only
      allows to take into account rather easily the effect of the fringing fields
      protruding in the space around the specimen, but also to obtain solutions to
      interesting models in analytical form.

PMID- 12623175
TI  - A method to determine long-range order parameters from electron diffraction
      intensities detected by a CCD camera.
AB  - To determine long-range order parameters from electron diffraction intensities,
      the authors have developed a CCD camera system to detect precisely electron
      diffraction intensities, a method for quickly and precisely measuring specimen
      thickness, and a computer programming to calculate long-range order parameters
      from the ratio of superlattice and fundamental diffraction intensities. Thickness
      variation over a diffraction area is taken into consideration in the calculation
      of electron diffraction intensities on the basis of the multi-slice method, and
      long-range order parameters are calculated by the successive approximation
      method. The absorptive form factors are also calculated from experimental data of
      diffraction intensities by parameter fitting, and the effect of absorption on the
      calculation of long-range order parameters is examined. The values of Cu(3)Au
      alloys aged at 523 and 653 K that were obtained by averaging long-range order
      parameters determined for several diffraction areas with the developed method are
      close to the reported data obtained by the X-ray diffraction method. The main
      causes for the deviation of long-range order parameters determined for several
      diffraction areas are also discussed.

PMID- 12623176
TI  - Comparison of phase contrast transmission electron microscopy with optimized
      scanning transmission annular dark field imaging for protein imaging.
AB  - Henderson has already shown that electron microscopy should be superior to X-ray
      and neutron diffraction for determining protein structure with minimum radiation
      damage. Since the contrast for a molecule embedded in vitreous ice is very low,
      it is conceivable that dark field imaging would be superior to bright field phase
      contrast microscopy. A detailed analysis of contrast and signal/noise for both
      imaging modes is presented. Annular dark field scanning transmission microscopy
      gives improved contrast and equivalent signal/noise to phase contrast TEM when
      the molecule is the same thickness as a vitreous ice embedding medium. For a
      constant embedding medium thickness of 200 A the contrast is equivalent to phase
      contrast TEM but the signal/noise is 5 times worse. Even with an efficient
      detector that only excludes scattering less than 5 mrad there is insufficient
      signal at a dose of 5 electrons/A(2) to produce an image with more than 1
      electron/per pixel. For larger molecules (>100 A thick which corresponds to 420
      kDa for spherical molecules) the weak phase object approximation used to analyse
      a phase contrast image no longer applies at 100 kV. This limit could be extended
      to about 200 A (about 3 MDa) if a 400 kV microscope were used.

PMID- 12623177
TI  - Does training have consequences for the walk-run transition speed?
AB  - A number of authors when studying the walk-run transition phenomenon focused
      either on the mechanical or energy expenditure whilst only a few used both
      parameters concurrently. Moreover the literature demonstrates that the
      contribution of these variables changes along with the level and method of
      training. Consequently the purpose of this study is to find, by analyzing
      concurrently these two variables, if the walk-run transition speed is linked to
      the type of training. To this end we calculated two theoretical transition
      speeds: one based on the metabolic energy expenditure St(1) and the second one
      based on the internal work St(2). Subjects were divided into three groups
      (untrained, sprint and endurance-trained men) who were required to walk and run
      on a treadmill at increasing speeds. Firstly we show that the relationship
      between St(1) and St(2) differs depending on the groups. Sprinters have a
      significantly lower St(2) than St(1) whereas the opposite is found for untrained
      subjects. We also show that the transition speed is linked to the subject's type
      of training. To conclude it seems that acquiring running techniques through
      specific training has consequences for the walk-run transition phenomenon.

PMID- 12623178
TI  - On-line trajectory modifications of planar, goal-directed arm movements.
AB  - Sometimes a goal-directed arm movement has to be modified en route due to an
      unforeseen perturbation such as a target displacement or a hand displacement by
      an external force. In this paper several aspects of that modification process are
      addressed. Subjects had to perform a point-to-point movement task on a computer
      screen using a mouse-coupled pointer as the representation of the hand position.
      Trajectory modifications were imposed by unexpectedly changing the position of
      the target or by changing the relation between mouse and screen pointer. In the
      first series of experiments, we examined how often a trajectory is updated. Here,
      trajectory modifications were imposed by unexpectedly changing the normal
      relation between mouse and pointer to a shear-like relation, where a percentage
      of the forward/backward position of the hand was added to the pointer position in
      the left/right direction. Withdrawal of visual feedback during the movement
      revealed that trajectories were updated at interval times shorter than 200 ms.
      From the similarity with experiments where the original relation between mouse
      and pointer was restored during the movements, we conclude that motor plans are
      updated on-line to move the hand from its current perceived position to the
      target. In a second series of experiments, we studied whether a continuous change
      in target position yields similar trajectory modifications as a continuous hand
      displacement. To mimic the latter perturbation, we used the above-mentioned
      distortion of the mouse-pointer relation. We found that the resulting hand paths
      did not differ for the two visual perturbations and conclude that the perturbed,
      goal-directed movements are modified in a consistent way, irrespective of whether
      the position of the target or hand was perturbed. Simulations of the experimental
      data with a kinematic reaching model support this conclusion.

PMID- 12623179
TI  - Activation patterns in forearm muscles during archery shooting.
AB  - A contraction and relaxation strategy with regard to forearm muscles during the
      release of the bowstring has often been observed during archery, but has not well
      been described. The purpose of this study was to analyze this strategy in archers
      with different levels of expertise; elite, beginner and non-archers.
      Electromyography (EMG) activity of the M. flexor digitorum superficialis and the
      M. extensor digitorum were recorded at a sampling frequency of 500 Hz, together
      with a pulse synchronized with the clicker snap, for twelve shots by each
      subject. Raw EMG records, 1-s before and after the clicker pulse, were rectified,
      integrated and normalized. The data was then averaged for successive shots of
      each subject and later for each group. All subjects including non-archers
      developed an active contraction of the M. extensor digitorum and a gradual
      relaxation of the M. flexor digitorum superficialis with the fall of the clicker.
      In elite archers release started about 100 ms after the fall of the clicker,
      whereas in beginners and non-archers release started after about 200 and 300 ms,
      respectively. Non-archers displayed a preparation phase involving extensive
      extensor activity before the release of the bowstring, which was not observed in
      elite and beginner archers. In conclusion, archers released the bowstring by
      active contraction of the forearm extensors, whereas a clear relaxation of the
      forearm flexors affecting the release movement was not observed.

PMID- 12623180
TI  - Learning to coordinate redundant degrees of freedom in a dynamic balance task.
AB  - The present study investigated Bernstein's [The co-ordination and regulation of
      movements, 1967] proposal regarding the three stages of learning in the changing
      coordination and control of redundant joint-space degrees of freedom. Six
      participants practiced maintaining balance on a moving platform that was
      sinusoidally translated in the anterior-posterior direction for 30 trials on day
      1 and 10 trials on day 2. At the beginning of practice, the motion of the torso
      and limb segments was less coherent in the attempt to compensate for the movement
      of the support surface in retaining a balanced posture. However, with practice,
      the organization of a compensatory postural coordination mode became highly
      coherent and also progressively utilized the passive, inertial forces generated
      by the movement of the support surface. The findings support the propositions
      that: (a) the pathway of change over time in the coordination pattern of the
      torso and joint motions depends on the task goal and constraints to action and
      (b) the changes in limb and torso motion are in support of the learning of a
      global body center of mass/platform dynamic.

PMID- 12623181
TI  - Movement parameters that distinguish between voluntary movements and levodopa
      induced dyskinesia in Parkinson's disease.
AB  - It is well known that long-term use of levodopa by patients with Parkinson's
      disease causes dyskinesia. Several methods have been proposed for the automatic,
      unsupervised detection and classification of levodopa induced dyskinesia.
      Recently, we have demonstrated that neural networks are highly successful to
      detect dyskinesia and to distinguish dyskinesia from voluntary movements. The aim
      of this study was to use the trained neural networks to extract parameters, which
      are important to distinguish between dyskinesia and voluntary movements. Thirteen
      patients were continuously monitored in a home-like situation performing in about
      35 daily life tasks for a period of approximately 2.5 h. Behavior of the patients
      was measured using triaxial accelerometers, which were placed at six different
      positions of the body. A neural network was trained to assess the severity of
      dyskinesia. The neural network was able to assess the severity of dyskinesia and
      could distinguish dyskinesia from voluntary movements in daily life. For the
      trunk and the leg, the important parameters appeared to be the percentage of time
      that the trunk or leg was moving and the standard deviation of the segment
      velocity of the less dyskinetic leg. For the arm, the combination of the
      percentage of time, that the wrist was moving, and the percentage of time, that a
      patient was sitting, explained the largest part of the variance of the output.
      Dyskinesia differs from voluntary movements in the fact that dyskinetic movements
      tend to have lower frequencies than voluntary movements and in the fact that
      movements of different body segments are not well coordinated in dyskinesia.

PMID- 12623182
TI  - The influence of motor system degradation on the control of handwriting
      movements: a dynamical systems analysis.
AB  - The complex dynamics of the human hand/arm system need to be precisely controlled
      to produce fine movements such as those found in handwriting. This study employs
      dynamical systems analysis techniques to further understand how this system is
      controlled when it is functioning well and when it is compromised through motor
      function degradation (e.g. from tremor). Seven people with and 16 people without
      multiple sclerosis (MS) participated in this study. Tremor was assessed using
      spirography with participants being separated into "tremor" (6 people with and 1
      person without MS; 2 male, 5 female; age range 40-68) and control (1 person with
      and 15 people without MS; 5 male, 11 female, age range 18-59) groups.
      Participants wrote the pseudo-word "lanordam" six times on a digitizer, in a
      quiet as well as a noisy, mildly stressful environment. Velocity profiles of the
      pen tip for the best four trials were concatenated and analyzed to determine
      their dimensionality (a measure of the number of control variables) and Lyapunov
      exponents (a measure of predictability). Results indicate that the velocity
      profiles for people with tremor were lower dimensional and had less predictable
      dynamics than for controls, with no effect of sound condition. Interpreted in the
      context of related research, it was speculated that the lower dimensionality
      reflected the loss of control of variables related to the minimization of
      movement variability, resulting in less predictable movements.

PMID- 12623183
TI  - A common perceptual parameter for stair climbing for children, young and old
      adults.
AB  - In this paper we examine whether a common perceptual parameter is available for
      guiding old adults, young adults and children in climbing the highest stair
      mountable in a bipedal fashion. Previous works have shown that the ratio between
      the height of the stair and the hip height was the body-scaled invariance adopted
      as information for selecting the highest stair by young adults [Journal of
      Experimental Psychology: Human Perception and Performance 10 (1984) 683-703] but
      not by older adults [Journal of Experimental Psychology: Human Perception and
      Performance 3 (1992) 691-697]. Indeed, for older adults additional bio-mechanical
      parameters needed to be added to the model due to their decrease in leg strength
      and flexibility.Up to now, no perceptual invariant has been identified yet for
      determining the relevant information used for guiding the stair climbing action
      for normal healthy people. We propose a new parameter as the angle defined by the
      ratio between the height of the stair and the distance taken from the feet to the
      top edge of the stair before the initiation of the movement. We show that this
      angle is the same for children, young adults and older adults despite the
      different kinematics of the motion, the anthropometrics and the skill ability
      exhibit by the participants. In summary we show that even when the climbability
      judgments, based on the simple ratio leg length-stair height, are influenced by
      differences in age, participants use a common perceptual variable when they are
      coordinating their stair climbing action.

PMID- 12623184
TI  - Comments on "Sugawara, K., & Kasai, T. (2002). Facilitation of motor evoked
      potentials and H-reflexes of flexor carpi radialis muscle induced by voluntary
      teeth clinching. Human Movement Science, 21, 203-212".

PMID- 12623186
TI  - Microemulsions for topical delivery of estradiol.
AB  - Estradiol has been widely used for the treatment of hormonal insufficiencies. Due
      to its extensive first pass metabolism after oral administration, transdermal
      administration of estradiol in gels and emulsions has been used to improve its
      bioavailability, prolong activity and to optimize metabolic profile. The purpose
      of this study was to investigate microemulsions as delivery systems for
      estradiol. Various o/w microemulsions were used to deliver estradiol across human
      abdominal skin in vitro. Trasdermal flux of estradiol was determined using Franz
      type diffusion cells and the samples were analyzed by high-performance liquid
      chromatography (HPLC). The permeation data showed that microemulsion formulations
      increased estradiol flux 200-700-fold over the control, but permeability
      coefficients were decreased by 5-18 times. The superior transdermal flux of
      estradiol was due to 1500-fold improvement in solubilization of estradiol by
      microemulsions. The results suggest that microemulsions are potential vehicles
      for improved topical delivery of estradiol.

PMID- 12623187
TI  - Characterization of hydrophobized pullulan with various hydrophobicities.
AB  - In this study, we prepared self-assembling nanospheres of hydrophobized pullulan.
      Pullulan acetate (PA), as hydrophobized pullulan, was synthesized by the
      acetylation of pullulan. PA derivatives were synthesized by changing the degree
      of acetylation. PA was characterized by Fourier transform infrared (FT-IR), X-ray
      diffractometry (XRD), and differential scanning calorimetry (DSC). The particle
      size distribution of the PA was determined using photon correlation spectroscopy
      (PCS) and the number-average particle size was found to depend upon the degree of
      acetylation of PA. Morphology by transmission electron microscopy (TEM) and
      scanning electron microscopy (SEM) showed the PA nanospheres were spherical in
      shape. The fluorescence probe technique was used to study the self-association
      behavior of hydrophobized pullulans in water using pyrene as a hydrophobic probe.
      The critical association concentration (CAC) values were determined from the
      fluorescence excitation spectra, CAC values were dependent upon the degree of
      acetylation. Drug release studies using clonazepam (CNZ) as a hydrophobic model
      drug showed that the increased drug contents and increased degree of acetylation
      resulted in a slower release rate of drug from the nanospheres.

PMID- 12623189
TI  - Microcrystals for dissolution rate enhancement of poorly water-soluble drugs.
AB  - Slight dissolution rates related to poor water-solubility are one of the well
      known difficulties to be covered during the development of new drug substances.
      The poorly water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti
      inflammatory properties for oral administration, shows a poor dissolution rate.
      This study is intended to enhance the drug dissolution rate by using
      microcrystals. The common way for micronization is the milling of previously
      formed larger crystals. However, milling shows several disadvantages as the newly
      created surfaces are thermodynamically activated due to the high energy input and
      not naturally grown. In this study microcrystals were not produced using any
      cutting up techniques, but only by association. Naturally grown microcrystals
      were prepared by a precipitation method in the presence of stabilizing agents
      (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray
      drying of the formed dispersion. First the drug was dissolved in acetone and then
      precipitated by rapid pouring an aqueous solution of the stabilizer into the drug
      solution. Particularly, cellulose ethers were able to form stable and homogeneous
      dispersions of microcrystals (mean particle size = 1 microm) showing a tight
      particle size distribution. By spray-drying, the drug powder was obtained. The
      dissolution rate is significantly enhanced (common drug: 4% after 20
      min/microcrystals 93% after 20 min) due to the large surface, which is
      hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65
      and 30 degrees, respectively).

PMID- 12623188
TI  - The influence of drug type on the release profiles from Surelease-coated pellets.
AB  - The release of metoclopramide hydrochloride (a water-soluble cationic drug) and
      diclofenac sodium (a sparingly soluble anionic drug) from pellets coated with
      ethylcellulose from an aqueous ethylcellulose dispersion (Surelease) at different
      coating loads was investigated. The release rates of each drug decreased as the
      coating load of Surelease increased. However, despite its lower water solubility,
      diclofenac sodium was released slightly faster than metoclopramide hydrochloride
      at equivalent coating loads. Changes in the release rates after curing were more
      pronounced for metoclopramide hydrochloride and the release rates of diclofenac
      sodium were lower than those of metoclopramide hydrochloride after curing.
      Differences between the release behaviour of the two drugs were probably due to
      an interaction between the cationic metoclopramide and the anionic ammonium
      oleate present in the Surelease. The slower release of metoclopramide
      hydrochloride may be due to an in situ formation of a poorly soluble complex of
      the drug and the ammonium oleate. This complex, because of its large molecular
      size, may diffuse more slowly through the film, causing a reduction in the
      release rate of metoclopramide hydrochloride. This interaction may also account
      for the differences in release characteristics of the drugs after curing. During
      curing the surfactant, due to its unstable nature in heat, may be converted to
      its constituent components. The interaction of drug with the surfactant was
      reduced as the residue of the ammonium oleate decreased during curing. However, a
      relatively low volume flow rate of air, and therefore, slower removal of ammonia
      in the modified side-vented Manesty Accela-cota 10 may also have affected the
      coating process of the pellets.

PMID- 12623190
TI  - Influence of dissolution medium buffer composition on ketoprofen release from ER
      products and in vitro-in vivo correlation.
AB  - The purpose of this work was to investigate the influence of dissolution medium
      composition on the in vitro release of ketoprofen from a series of ER products
      and the impact of the different buffer media on the in vivo-in vitro (IVIV)
      relationship. The products investigated were coated micro bead preparations
      having increasing levels of coating to retard drug release. Four common
      dissolution media; USP phosphate buffers of pH 7.2 and 6.8, phosphate (modified
      isotonic) buffer pH 6.8 and a fasted state simulated intestinal fluid without
      lipid components (FaSSIFLF) of pH 6.5, were employed in the USP 2 apparatus.
      Release profiles were compared to the corresponding in vivo release profiles,
      obtained following deconvolution of the plasma level versus time profiles
      obtained from a 10-subject five-period cross-over study. Despite the relative
      similarity in composition of the media employed, significant differences in
      release profiles were observed reflecting media differences in buffer capacity,
      ionic strength and pH. As a consequence, the quality and shape of the IVIV
      relationship changed significantly, the only apparent IVIVC incorporating all
      four ER products, which was non-linear, was obtained using the phosphate
      (modified isotonic) buffer of pH 6.8. This data was fitted, using a non-linear
      least squares method, by the equation of Polli et al. [J. Pharm. Sci. 85 (1996)
      753] and gave an alpha parameter estimate of 2, consistent with initial
      dissolution being more rapid in vitro than in vivo. The systematic shift in
      profiles, particularly with buffer capacity, underlines the sensitivity of IVIV
      relationship to medium composition and hence the current difficulties in making a
      rational choice of an appropriate single dissolution medium.

PMID- 12623191
TI  - Effect of beta-sitosterol on precipitation of cholesterol from non-aqueous and
      aqueous solutions.
AB  - The aim of the present work was to study the solubility and phase behaviour of
      the beta-sitosterol-cholesterol mixed crystals in the presence and absence of
      water. Cholesterol, beta-sitosterol and 3:1, 1:1 and 1:3 mixtures of these were
      co-precipitated from acetone and acetone-water solutions. Precipitated crystals
      were analysed using powder X-ray diffraction (PXRD), differential scanning
      calorimetry (DSC), optical microscopy and Karl-Fischer titrimetry. The
      quantification of the sterols in solutions was preformed using GC-MS. The
      solubility of the sterols was mutually limiting. In the aqueous system, the
      solubility of both the sterols were significantly lower than in the absence of
      water, but the decrease in the solubility was considerably greater with the more
      hydrophobic beta-sitosterol. In the aqueous system, the total sterol solubility
      decreased with the increasing proportion of beta-sitosterol. The formation of new
      crystal structures, solid solutions of cholesterol and beta-sitosterol, was
      observed in non-aqueous as well as in aqueous environments except with the lowest
      cholesterol proportion in the system, in which case mixed crystals with eutectic
      behaviour were formed.

PMID- 12623192
TI  - Prediction of Setschenow constants.
AB  - The Setschenow (salting out) constant by sodium chloride is related to molar
      volume, aqueous solubility, and octanol-water partition coefficient, K(ow), of
      the drug solute. This study validates a previously proposed relationship between
      the salting out constant of a solute and its partition coefficient. It also shows
      that the partition coefficient is a better descriptor of salting out than either
      molar volume or solubility.

PMID- 12623193
TI  - Improvement of the dissolution rate of artemisinin by means of supercritical
      fluid technology and solid dispersions.
AB  - The purpose of this study was to enhance the dissolution rate of artemisinin in
      order to improve the intestinal absorption characteristics. The effect of: (1)
      micronisation and (2) formation of solid dispersions with PVPK25 was assessed in
      an in vitro dissolution system [dissolution medium: water (90%), ethanol (10%)
      and sodium lauryl sulphate (0.1%)]. Coulter counter analysis was used to measure
      particle size. X-ray diffraction and DSC were used to analyse the physical state
      of the powders. Micronisation by means of a jet mill and supercritical fluid
      technology resulted in a significant decrease in particle size as compared to
      untreated artemisinin. All powders appeared to be crystalline. The dissolution
      rate of the micronised forms improved in comparison to the untreated form, but
      showed no difference in comparison to mechanically ground artemisinin. Solid
      dispersions of artemisinin with PVPK25 as a carrier were prepared by the solvent
      method. Both X-ray diffraction and DSC showed that the amorphous state was
      reached when the amount of PVPK25 was increased to 67%. The dissolution rate of
      solid dispersions with at least 67% of PVPK25 was significantly improved in
      comparison to untreated and mechanically ground artemisinin. Modulation of the
      dissolution rate of artemisinin was obtained by both particle size reduction and
      formation of solid dispersions. The effect of particle size reduction on the
      dissolution rate was limited. Solid dispersions could be prepared by using a
      relatively small amount of PVPK25. The formation of solid dispersions with PVPK25
      as a carrier appears to be a promising method to improve the intestinal
      absorption characteristics of artemisinin.

PMID- 12623194
TI  - Analysis of Case II drug transport with radial and axial release from cylinders.
AB  - Analysis is presented for Case II drug transport with axial and radial release
      from cylinders. The previously reported [J. Control Release 5 (1987) 37]
      relationships for radial release from films and slabs are special cases of the
      general solution derived in this study. The widely used exponential relation
      M(t)/M(infinity) = kt(n) describes nicely the first 60% of the fractional release
      curve when Case II drug transport with axial and radial release from cylinders is
      operating.

PMID- 12623195
TI  - Effect of pH and sodium chloride on the strength and selectivity of the
      interaction of gamma [correction for tau] -cyclodextrin with some antisense
      nucleosides.
AB  - The influence of pH and the concentration of sodium chloride on the strength and
      selectivity of the interaction of twelve 8-substituted-2'-deoxyadenosine and
      sixteen 5-substituted-2'-deoxyuridine derivatives with gamma-cyclodextrin (GCD)
      have been studied by the spectral mapping technique (SPM). The potency values of
      the spectral map were regarded as indicators of the capability of antisense
      nucleosides and GCD to interact simultaneously taking into consideration all
      relevant data. It has been established that the strength of interaction is
      highest in acetic and lowest in alkaline solutions, and the selectivities of
      acidic, alkaline and salt solutions are markedly different. The length of
      hydrophobic alkyl substituents in antisense molecules influenced both the
      strength and selectivity of the interaction. The character of the base structure
      affected only the selectivity.

PMID- 12623196
TI  - Acyclovir permeation through rat skin: mathematical modelling and in vitro
      experiments.
AB  - The aim of this work is to characterise the skin permeation properties of a male
      rat by means of a purely diffusive mathematical model based on Fick's second law.
      Additionally, in the attempt of proposing a reliable tool allowing the skin
      permeability (or resistance) determination on the basis of experimental data, the
      model automatically accounts also for two typical experimental conditions. In
      particular, drug dissolution in the donor environment and receiver sampling
      technique (part of the receiver volume is withdrawn and immediately replaced by
      fresh solvent) are considered. The results of this characterisation are then
      compared with those coming from a common simplified approach. Acyclovir is chosen
      as model drug and a thermostatic (37 degrees C) Franz cell apparatus is used to
      perform permeation experiments. This study suggests that Acyclovir permeation
      through the rat skin can be well described by the proposed model and that some
      differences arise in the evaluation of the full-skin resistance performed by
      means of our model or the usual simpler approach.

PMID- 12623197
TI  - Release mechanism of insulin encapsulated in trehalose ester derivative
      microparticles delivered via inhalation.
AB  - The aim of this study was to evaluate properties of amorphous oligosaccharide
      ester derivative (OED) microparticles in order to determine drug release
      mechanisms in the lung. Trehalose OEDs with a wide range of properties were
      synthesised using conventional methods. The interaction of spray dried amorphous
      microparticles (2-3 microm) with water was investigated using attenuated total
      reflectance Fourier transform infra-red spectroscopy (ATR-FTIR) and dynamic
      vapour sorption (DVS). The in vivo performance of insulin/OED microparticles was
      assessed using a modified Higuchi kinetic model. A modified Hansen solvent
      parameter approach was used to analyse the interactions with water and in vivo
      trends. In water or high humidity, OED powders absorb water, lose relaxation
      energy and crystallise. The delay of the onset of crystallisation depends on the
      OED and the amount of water present. Crystallisation follows first order
      Arrhenius kinetics and release of insulin from OED microparticles closely matches
      the degree of crystallisation. The induction period depends on dispersive
      interactions between the OED and water while crystallisation is governed by
      polarity and hydrogen bonding. Drug release from OED microparticles is,
      therefore, controlled by crystallisation of the matrix on contact with water. The
      pulmonary environment was found to resemble one of high humidity rather than a
      liquid medium.

PMID- 12623198
TI  - The effects of hyaluronan and its fragments on lipid models exposed to UV
      irradiation.
AB  - The effects of hyaluronan and its degradation products on irradiation-induced
      lipid peroxidation were investigated. Liposomal skin lipid models with increasing
      complexity were used. Hyaluronan and its fragments were able to reduce the amount
      of lipid peroxidation secondary products quantified by the thiobarbituric acid
      (TBA) assay. The qualitative changes were studied by mass spectrometry. To
      elucidate the nature of free radical involvement electron paramagnetic resonance
      (EPR) studies were carried out. The influence of hyaluronan and its fragments on
      the concentration of hydroxyl radicals generated by the Fenton system was
      examined using the spin trapping technique. Moreover, the mucopolysaccharide's
      ability to react with stable radicals was checked. The quantification assay of
      2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) showed no concentration changes of
      the stable radical caused by hyaluronan. Hyaluronan was found to exhibit
      prooxidative effects in the Fenton assay in a concentration dependent manner. A
      transition metal chelation was proposed as a mechanism of this behavior.
      Considering human skin and its constant exposure to UV light and oxygen and an
      increased pool of iron in irradiated skin the administration of hyaluronan or its
      fragments in cosmetic formulations or sunscreens could be helpful for the
      protection of the human skin.

PMID- 12623199
TI  - Preparation of griseofulvin nanoparticles from water-dilutable microemulsions.
AB  - Nanoparticles of griseofulvin, a model drug with poor solubility and low
      bioavailability, were prepared from water dilutable microemulsions by the solvent
      diffusion technique. Solvent-in-water microemulsion formulations containing
      water, butyl lactate, lecithin, taurodeoxycholate sodium salt (TDC) or
      dipotassium glycyrrhizinate (KG), 1,2-propanediol or ethanol were used. The
      formation of macroscopically homogeneous, stable, fluid, optically transparent,
      isotropic solutions (microemulsions) was investigated by constructing pseudo
      ternary phase diagrams. In the presence of TDC or KG, microemulsion systems that
      remained transparent on water dilution could be obtained. The displacement of
      butyl lactate, with an excess of water, from the internal phase of the
      microemulsions containing the drug into the external phase, lead to successful
      fabrication of drug nanosuspensions. Nanoparticle size was dependent on
      microemulsion composition: using KG, griseofulvin nanoparticles below 100 nm with
      low polydispersity and an increased dissolution rate were obtained.

PMID- 12623201
TI  - Decomposition of solids accompanied by melting--Bawn kinetics.
AB  - The book "Chemistry of the Solid State", edited by W.E. Garner more than 50 years
      ago, contained a chapter (Chapter 10) by C.E.H. Bawn which dealt with the
      kinetics of the thermal decompositions of solids that are accompanied by some
      melting. Rate equations were derived and this model has become known as the Bawn
      model or as "Bawn kinetics". This kinetic model has proved particularly useful in
      pharmaceutical stability studies. The isothermal curves of extent of
      decomposition, alpha, against time for this model are sigmoidal and the problems
      of distinguishing this model from other sigmoidal models (Prout-Tompkins, Avrami
      Erofeev) have been examined. Under programmed temperature conditions,
      distinguishability becomes even more difficult.

PMID- 12623200
TI  - A system for the production and delivery of monodisperse salbutamol aerosols to
      the lungs.
AB  - An aerosol system is described for the generation and delivery of measured doses
      of monodisperse therapeutic drug particles to the human lungs. The system
      comprises a spinning top aerosol generator (STAG), aerosol chamber and inhalation
      control unit. Monodisperse aerosols allow drug particle size effects to be
      studied as the dose is within a narrow size distribution and when combined with
      controlled inhalation may lead to more precise targeting of therapeutic drug to
      the airways. Using the STAG, particles in the size range 1.5-12 microm were
      generated and their mass median aerodynamic diameter (MMAD) and concentration
      measured using an aerodynamic particle sizer (APS). The application and
      validation of the system with the bronchodilator drug salbutamol sulphate is
      described, and its potential use in the study of aerosol particle size effects is
      discussed.

PMID- 12623202
TI  - Comparative study of the lubricant performance of Compritol HD5 ATO and Compritol
      888 ATO: effect of polyethylene glycol behenate on lubricant capacity.
AB  - The aim of this paper is to study the lubricant capacity of Compritol HD5 ATO, a
      glyceryl and polyethylene glycol dibehenate, obtained by atomization. This
      material is compared to Compritol 888 ATO, constituted only by glyceryl
      dibehenate. First, this study verifies that Compritol HD5 ATO and Compritol 888
      ATO present the same granular characteristics and that their mixes with
      Lactopress present no structural differences. Secondly, in term of
      compressibility and cohesiveness, the use of Compritol 888 ATO or Compritol HD5
      ATO with Lactopress does not involve any significant modification. Finally, the
      minor difference of lubricant capacity between Compritol HD5 ATO and Compritol
      888 ATO has no consequence in compression practice. The presence of polyethylene
      glycol behenate does not decrease the glyceryl dibehenate compression
      functionality. This study concludes that Compritol HD5 ATO could be a very
      interesting excipient because it associates the glyceryl dibehenate lubricant
      capacity with the polyethylene glycol behenate-specific capacity in terms of
      dissolution enhancement.

PMID- 12623203
TI  - Transdermal iontophoresis of insulin. II. Physicochemical considerations.
AB  - Transdermal iontophoresis is one of the potential enhancement strategies for the
      delivery of large and charged molecules. Insulin, a polypeptide of 6 kDa was used
      as a model for large peptides to understand the influence of peptide
      concentration, NaCl concentration, buffer type and its concentration on the
      transport efficiency of iontophoresis. Maximum enhancement was found at 3 mg/ml
      (75 IU/ml). The permeation of insulin was found to increase up to 0.05 M NaCl and
      decreased at higher concentrations of NaCl. The glucose permeation studies showed
      that permeation of insulin increased in the presence of NaCl due to ion induced
      convective flow. The flux enhancement of insulin in the presence of phthalate
      buffer was higher in comparison to citrate buffer, but the enhancement in these
      two buffers was the same in the presence of 0.05 M NaCl, which was also supported
      by a similar trend in conductivity values. However, the solution conductivity
      values did not reflect the influence of co-ions and counter ions on the transport
      of large peptides across the skin. Overall the findings revealed that the
      transport efficiency of large peptides like insulin may be improved by the
      optimisation of competing ions in solution.

PMID- 12623204
TI  - Tablet surface characterisation by various imaging techniques.
AB  - The aim of this study was to characterise tablet surfaces using different imaging
      and roughness analytical techniques including optical microscopy, scanning
      electron microscopy (SEM), laser profilometry and atomic force microscopy (AFM).
      The test materials compressed were potassium chloride (KCl) and sodium chloride
      (NaCl). It was found that all methods used suggested that the KCl tablets were
      smoother than the NaCl tablets and higher compression pressure made the tablets
      smoother. Imaging methods like optical microscopy and SEM can give useful
      information about the roughness of the sample surface, but they do not provide
      quantitative information about surface roughness. Laser profilometry and AFM on
      the other hand provide quantitative roughness data from two different scales,
      laser profilometer from 1 mm and atomic force microscope from 90 microm scale.
      AFM is a powerful technique but other imaging and roughness measuring methods
      like SEM, optical microscopy and laser profilometry give valuable additional
      information.

PMID- 12623205
TI  - Clinical Sarcocystis neurona encephalomyelitis in a domestic cat following
      routine surgery.
AB  - Sarcocystis neurona is an important cause of equine protozoal myeloencephalitis
      (EPM) in horses in the Americas. An EPM-like neurological disease also has been
      reported from other mammals but it is difficult to induce this disease in the
      laboratory. A 4-month-old male domestic cat developed neurological signs 3 days
      following castration. The cat was euthanized 12 days later because of paralysis.
      Encephalomyelitis was the only lesion and was associated with numerous
      Sarcocystis schizonts and merozoites in the brain and spinal cord. The protozoa
      reacted positively with S. neurona-specific polyclonal rabbit antibody. Two
      unidentified sarcocysts were present in the cerebellum. It may be possible that
      stress of surgery triggered relapse of S. neurona infection in this cat.

PMID- 12623206
TI  - Anti-parasitic activity of depudecin on Neospora caninum via the inhibition of
      histone deacetylase.
AB  - Neospora caninum is an apicomplexan parasite associated with abortion in cattle
      worldwide. Apicidin, histone deacetylase (HDAC) inhibitor, has shown a broad
      spectrum of anti-protozoal activity against apicomplexan parasites. Cultured vero
      cells infected with N. caninum tachyzoites were treated with 0.5 microg/ml of
      depudecin, another known natural product isolated from Altermaria brassiciicola
      with anti-histone deacetylase activity, to examine the efficacy of depudecin
      against intracellular multiplication of N. caninum tachyzoite, using 15 ng/ml of
      apicidin as the control. Depudecin significantly inhibited the intracellular
      multiplication of N. caninum at a level similar to that of apicidin without
      exerting any cytotoxicity on the host vero cells. Acid/urea/Triton gel
      electrophoresis analysis show anti-parasitic activity of depudecin appears to be
      due to the inhibition of protozoal histone deacetylase, which induces
      hyperacetylation of histones in N. caninum.

PMID- 12623207
TI  - Prevalence and control of bovine cryptosporidiosis in German dairy herds.
AB  - In a 5-year survey regarding its prevalence and importance in five German state
      veterinary laboratories Cryptosporidium was diagnosed annually in 19-36% of
      faecal samples either submitted to the laboratories or taken post mortem. In
      approximately half of the cases no other enteropathogens were detected. However,
      only 73% of 30 laboratories participating in a questionnaire survey routinely
      tested for this parasite, and the majority of researchers considered
      cryptosporidiosis to be of minor importance. In a placebo-controlled field study
      152 suckling calves were treated daily against cryptosporidiosis either with
      sulfadimidine or with halofuginone (Halocur, Intervet) over 1 week. Treatment by
      oral drench started at the onset of diarrhoea in the herd. Oocyst excretion,
      faecal consistency and health status were recorded five times for a 3-week
      period. Oocyst excretion peaked 7-14 days in the placebo group after the onset of
      diarrhoea, and during that period prevalence and intensity of excretion were
      significantly lower in the halofuginone-treated group compared to the
      sulfadimidine and the placebo control groups. The health status (diarrhoea,
      dehydration) declined in all groups but was significantly (P<0.05-0.001) better
      in the halofuginone group in the first 2 weeks. Halofuginone effectively (P<0.05
      0.001) reduced oocyst excretion and improved the health status of the treated
      animals, while sulfadimidine had no effect against Cryptosporidium.

PMID- 12623208
TI  - Prevalence and genotyping of Giardia duodenalis from beef calves in Alberta,
      Canada.
AB  - Giardia infections in domestic cattle has come under increasing scrutiny owing to
      the potential contamination of surface and ground waters through manure
      distribution on fields and pasture runoff. The objective of the study was to
      determine the prevalence and genotypes of Giardia duodenalis in beef calves in
      major beef cow calf farms in Alberta, Canada. Fecal samples were collected from
      beef calves aged 2-10 weeks at nine farms in Alberta. Samples were examined for
      the presence of G. duodenalis cysts by immunofluorescent staining. Giardia cysts
      were found in 168 of the 495 fecal samples examined, with prevalence ranging from
      7 to 60% among farms. Genotypic analysis of positive isolates utilizing PCR and
      sequencing of a 292 bp fragment of the 16S-rRNA locus, revealed the hoofed
      livestock genotype in 41 of the 42 isolates. One isolate was identical to the
      Assemblage A genotype. The results of this study demonstrate that beef calves in
      this area are primarily infected with the livestock genotype which is thought to
      be specific to artiodactyl hosts and non-infective to humans. This suggests that
      the Giardia carried by beef cattle may be a minimal zoonotic threat.

PMID- 12623209
TI  - Co-feeding studies of ticks infected with Anaplasma marginale.
AB  - Ticks often cluster at preferred feeding sites on hosts, and the co-feeding of
      ticks at the same site has been shown to increase feeding success and the
      transmission of some pathogens. While the major route of infection of ticks with
      pathogens is via the bloodmeal during feeding on a parasitemic host, non-systemic
      transmission of viruses and spirochetes has been shown to occur from infected to
      uninfected ticks at common feeding sites on uninfected hosts. In this research,
      two separate studies were done using the tick-borne rickettsial pathogen of
      cattle, Anaplasma marginale. In one study we tested whether A. marginale could be
      transmitted non-systemically from infected to uninfected Dermacentor variabilis
      males while co-feeding on rabbits. Infection of ticks was determined by allowing
      them to transmission feed on susceptible cattle and by DNA probe and microscopy
      studies on salivary glands. In the second study, we tested whether the co-feeding
      of male and female ticks on parasitemic cattle would increase the acquisition and
      development of A. marginale in males. A. marginale infections in salivary glands
      were determined by quantitative PCR after the ticks were allowed to transmission
      feed on susceptible cattle. Non-systemic transmission of A. marginale did not
      occur from infected and uninfected ticks that fed at the same site on rabbits
      and, therefore, does not appear to be a means of A. marginale transmission. A.
      marginale infections in male ticks were not increased while co-feeding with
      females. Thus, co-feeding of adult Dermacentor spp. does not appear to influence
      the dynamics of A. marginale transmission.

PMID- 12623210
TI  - A longitudinal study of a natural lice infestation in growing cattle over two
      winter periods.
AB  - A group of 61 cattle which were naturally infested with lice was followed over
      two winter periods. Data were collected on the number of lice found at various
      body sites over this period. Summary statistics were produced and due to the
      repeated measured and hierarchical structure of the data, multi-level analysis
      was used to model the population dynamics of Bovicola bovis and assess the
      influence of the various hierarchical levels. A four level Poisson model was
      produced--level one, the individual number of lice at each parting; level two,
      the body site examined (shoulder, midline or rump); level three, the time of the
      inspection and level four, the animal. Seasonal fluctuation in lice numbers was
      modelled using a cosine function transformation of time. A seasonal pattern was
      seen in both year's with lice counts higher in the first than the second year.
      The midline area was the most sensitive to detection of B. bovis. Variance
      contributed by the individual animal was less than that contributed by the body
      site examined and the time of the inspection. The model suggested that lice
      numbers within the shoulder and rump sites were near random following a Poisson
      distribution, but aggregation of lice occurred at the midline site with the
      distribution between animals following a Negative Binomial Pattern. The midline
      site was the most sensitive site for detecting B. bovis. Infestation numbers were
      higher in the first winter when cattle were younger. In the second winter, there
      was no difference in lice numbers between cattle exposed to infection for the
      first or second time.

PMID- 12623211
TI  - Factors affecting the detachment rhythm of engorged Boophilus microplus female
      ticks (Acari: Ixodidae) from Charolais steers in New Caledonia.
AB  - As in most parts of the world where the cattle tick Boophilus microplus is
      established, resistance of ticks to acaricides occurs in New Caledonia. In order
      to implement laboratory resistance tests on larvae, engorged females collected in
      suspected farms are necessary. Investigations on the detachment schedule of the
      engorged females were conducted to explain certain field situations such as the
      lack or scarcity of engorged females on highly infested cattle driven from the
      pasture to the pen in the morning. Three experiments on Charolais steers
      naturally infested on pastures showed that: (1) engorged female burdens at
      sunrise are similar whether the steers spend the night in pasture or in a pen;
      (2) compared with steers maintained in a pen, morning detachment of females
      increases when the steers stay on the pasture or move from the pasture to the
      pen; (3) detachment rhythm of engorged females on steers staying the morning in a
      pen, is not influenced by feeding activity or exposition of steers to sun; (4)
      detachment occurs earlier for females attached on anatomical sites exposed to
      sun, and earlier from these sites for the steers in pasture or walking than for
      steers in a pen.

PMID- 12623212
TI  - Enhancement of moxidectin bioavailability in lamb by a natural flavonoid:
      quercetin.
AB  - Moxidectin is an antiparasitic drug widely used in cattle, sheep and companion
      animals. Due to the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A
      in the metabolism of moxidectin, we studied the influence of various P-gp
      interfering agents (ivermectin, quercetin and ketoconazole) on the metabolism of
      14C moxidectin in cultured rat hepatocytes over 72 h. This in vitro study allowed
      selection of compounds which are able to increase the moxidectin bioavailability
      in lambs. From this, the modulation of moxidectin pharmacokinetics in plasma of
      lambs was studied after co-administration of 0.2 mg kg(-1) moxidectin
      (subcutaneously (SC)) and 0.2 mg kg(-1) ivermectin (SC), or 10 mg kg(-1)
      quercetin (SC), or 10 mg kg(-1) ketoconazole (orally). Ivermectin and quercetin
      increased significantly the quantity of 14C moxidectin in the rat hepatocytes.
      Ketoconazole co-administration led to a higher concentration of moxidectin in the
      rat hepatocytes. In vivo, only quercetin was able to modify the pharmacokinetics
      of moxidectin in plasma of lambs by increasing significantly the area under the
      plasma concentration-time curve. This study allowed the use of a natural agent,
      quercetin, to improve the bioavailability of moxidectin.

PMID- 12623213
TI  - Determination of group I metabotropic glutamate receptor subtypes involved in the
      frequency of epileptiform activity in vitro using mGluR1 and mGluR5 mutant mice.
AB  - In mouse hippocampal slices, bicuculline elicited spontaneous epileptiform bursts
      with a duration of 200-300 ms and with a frequency of five to six events per
      minute. Application of group I metabotropic glutamate receptor agonist (RS)-3,5
      dihydroxyphenylglycine ((RS)-DHPG) increased the burst frequency up to 300% at
      concentrations of 50 to 100 microM, while it decreased the burst duration below
      100 ms. In slices of subtype I mGluR1 or subtype I mGluR5 knockout mice,
      bicuculline elicited spontaneous epileptiform bursts with similar duration and
      frequency as those measured in wild-type mice but without the previous effects
      seen following application of DHPG at concentrations up to 100 microM. Likewise,
      in slices of wild-type mice, preincubation with mGluR1 antagonist, 1-aminoindan
      1,5-dicarboxylic acid (AIDA) or mGluR5 receptor antagonist, 2-methyl-6
      (phenylethynyl)-pyridine (MPEP) blocked in both cases completely the increase in
      frequency following DHPG application. These findings suggest an interactive
      mechanism between mGluR1 and mGluR5 receptors in the modulation of epileptiform
      bursting activity by DHPG that could indicate a common intracellular signaling
      mechanism or possibly direct interaction between these two receptors.

PMID- 12623214
TI  - Dynamic pelvic-pudendal reflex plasticity mediated by glutamate in anesthetized
      rats.
AB  - Reflex plasticity between pelvic afferent nerve (PAN) and pudendal efferent nerve
      (PEN), as well as external-urethral sphincter (EUS) activity was examined in
      anesthetized rats. A progressive increase in the number of evoked action
      potentials per stimulus occurred in PEN and EUS activity when PAN was
      repetitively stimulated (1 Hz). This potentiation in pelvic-pudendal reflex (PPR)
      activity induced by repetitive stimulation was abolished by APV (D-2-amino-5
      phosphonoraleric acid, i.t. 100 microM, 2-5 microl) and attenuated by the NBQX
      (2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline, i.t. 20 microM, 2-5
      microl) but was not affected by the presence of bicuculline (i.t. 10 microM, 2-5
      microl). The duration of contraction wave of intra-urethral pressure (IUP)
      elicited by a single electric shock was elongated by potentiated PPR, while the
      peak pressure was not affected. Both intrathecal application of glutamate (i.t.
      0.1 mM, 2-5 microl) and NMDA (N-methyl-D-aspartic acid, i.t. 0.1 mM, 2-5 microl)
      induced spontaneous repetitive (0.31+/-0.02 Hz) burst discharges in PEN and EUSE
      and produced small contraction wave in IUP, which is similar to the high
      frequency oscillation phase during a voiding cycle of urinary bladder in rats.
      All these results demonstrate that repetitive stimulation of PAN can induce a
      distinct and long-lasting modulation in PPR activity and this change may be
      physiologically relevant in urinary continence.

PMID- 12623215
TI  - Metabotropic glutamate receptors activate phospholipase D in astrocytes through a
      protein kinase C-dependent and Rho-independent pathway.
AB  - Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that
      mediate phospholipase D (PLD) activation in brain, but the mechanism underlying
      this response remains unclear. Here we used primary cultures of astrocytes as a
      cell model to explore the mechanism that links mGluRs to PLD. Glutamate activated
      both phospholipase C (PLC) and PLD with equal potency and this effect was
      mimicked by L-cysteinesulfinic acid, a putative neurotransmitter previously shown
      to activate mGluRs coupled to PLD, but not PLC, in adult brain. PLD activation by
      glutamate was dependent on Ca(2+) mobilization and fully blocked by both protein
      kinase C (PKC) inhibitors and PKC down-regulation, suggesting that PLD activation
      is secondary to PLC stimulation. Furthermore, brefeldin A, an inhibitor of ADP
      ribosylation factor (ARF) activation, partially inhibited the activation of PLD
      by glutamate. By contrast, pretreatment of astrocytes with Clostridium difficile
      toxin B, which inactivates small G proteins of the Rho family (Rho, Rac, and
      Cdc42), had no effect on PLD stimulation by glutamate. Taken together, these
      results indicate that PLD activation by mGluRs in astrocytes is dependent on PKC
      and small G proteins of the ARF family, but does not require Rho proteins.

PMID- 12623216
TI  - Properties of GABA(A) receptor-mediated transmission at newly formed Golgi
      granule cell synapses in the cerebellum.
AB  - Cerebellar granule cells receive inhibitory synaptic input from Golgi cells,
      which is mediated by gamma-aminobutyric acid (GABA) acting on GABA(A) receptors.
      In the present study we examined the properties of GABAergic inhibitory
      postsynaptic currents (IPSCs) in granule cells of the rat at a time when they
      first receive synaptic contacts from Golgi cells. Our results demonstrate that
      granule cells receive functional GABAergic synaptic input as early as postnatal
      day three (P3). The kinetic properties of these early IPSCs and the single
      channel conductance of the synaptic receptors are similar to those seen at the
      end of the first postnatal week, suggesting a stable subunit composition during
      this initial period of development. However, at P3, unlike the situation at more
      mature synapses, two distinct patterns of synaptic activity are evident, with
      IPSCs occurring either regularly or in bursts. In addition we find that Golgi
      cells are spontaneously active during early development, and at P7 most IPSCs are
      action potential-dependent. Moreover, paired Golgi-granule cell recordings
      suggest a high level of connectivity and a high release probability at these
      early synapses.

PMID- 12623217
TI  - GABA(A) alpha 1 subunit knock-out mice do not show a hyperlocomotor response
      following amphetamine or cocaine treatment.
AB  - The GABA(A) receptor system provides the major inhibitory control in the CNS,
      with the alpha 1 beta 2 gamma 2 subunit combination being the most abundant and
      widely distributed form of the receptor. The alpha1 subunit knock-out (alpha1 KO)
      mice had a surprisingly mild overt phenotype, despite having lost approximately
      60% of all GABA(A) receptors. The alpha1 KO mice had normal spontaneous locomotor
      activity, but were more sensitive to the sedating/ataxic effects of diazepam than
      wildtype (WT) mice. Pharmacological modulation of dopamine and N-methyl-D
      aspartate (NMDA) receptors also produced altered responses in alpha1 KO mice
      compared with WT mice. As expected, the NMDA receptor antagonist MK801,
      amphetamine and cocaine increased locomotor activity in WT mice. Although MK801
      increased locomotor activity in alpha1 KO mice, amphetamine and cocaine induced
      stereotypy not hyperlocomotion. Binding studies showed no gross changes in the
      total number of D1, D2 or NMDA receptors. Furthermore, pre-pulse inhibition of
      acoustic startle and the effects of cocaine in conditioned place preference were
      similar in both alpha1 KO and WT mice, indicating selective rather that global
      changes in response to dopaminergic agents. These data demonstrate subtle changes
      in behaviours mediated by neurotransmitters other than GABA in alpha1 KO mice and
      suggest that compensation may have occurred beyond the GABAergic system.

PMID- 12623218
TI  - Scopolamine-induced convulsions in fasted mice after food intake: determination
      of blood glucose levels, [3H]glutamate binding kinetics and antidopaminergic drug
      effects.
AB  - The present study was performed to evaluate the role(s) of hypoglycemia, changes
      in [(3)H]glutamate binding kinetics and dopaminergic activity in the occurrence
      of scopolamine-induced convulsions in fasted mice after food intake. Plasma
      glucose levels and density (B(max)) and affinity (K(d)) of [(3)H]glutamate
      binding sites in whole brain synaptic membranes were determined in animals fed ad
      lib or fasted for 48 h and treated intraperitoneally (i.p.) with 3 mg/kg
      scopolamine or saline and allowed to eat for 5 min. Fasting for 48 h decreased
      plasma glucose levels. After refeeding, plasma glucose concentrations increased
      in saline treated animals, but remained unchanged in scopolamine treated animals
      which consumed less food. Fasting for 48 h also produced significant changes in
      the kinetics of [(3)H]glutamate binding. The B(max) and K(d) of the binding sites
      decreased in fasted animals. These changes were partially antagonized by
      scopolamine treatment and food intake. For the evaluation of the contribution of
      dopaminergic activity, another group of mice fasted for 48 h and pretreated
      (i.p.) with saline or dopamine antagonists, 2 mg/kg chlorpromazine or 2 or 4
      mg/kg haloperidol, were treated 10 min later with either saline or 3 mg/kg
      scopolamine. Then 20 min later, they were allowed to eat ad lib and were observed
      for 30 min for the incidence and onset of clonic convulsions. Pretreatment of
      both 2 mg/kg chlorpromazine and 4 mg/kg haloperidol markedly suppressed the
      convulsions. These results indicate that the decrease in the [(3)H]glutamate
      binding induced by fasting, its antagonism by scopolamine treatment and food
      intake, and the dopaminergic hyperactivity may be possible factors contributing
      to the occurrence of convulsions.

PMID- 12623219
TI  - Activation of 5-HT(1A) autoreceptors enhances the inhibitory effect of galanin on
      hippocampal 5-HT release in vivo.
AB  - The microdialysis technique was used to examine interactions between 5-HT(1A) and
      galanin receptors in the dorsal raphe nucleus (DRN), by measuring the
      extracellular levels of 5-HT in the ventral hippocampus of awake rats. The rats
      were pretreated with the 5-HT(1A) receptor agonist (R,S)-8-OH-DPAT (0.3 mg/kg,
      s.c.) or saline. 8-OH-DPAT caused a time-dependent reduction of basal 5-HT levels
      down to 43-48% at 40 min while at 140 min, the hippocampal 5-HT had returned to
      control values. At that time point, the rats received a second injection of 8-OH
      DPAT or galanin (0.15, 0.5 and 1.5 nmol/0.5 microl) infused into the lateral
      ventricle. The second injection of 8-OH-DPAT caused a significantly smaller
      reduction of hippocampal 5-HT levels. In contrast, galanin at all three doses in
      the 8-OH-DPAT-pretreated groups, was significantly more potent in reducing 5-HT
      levels (maximal reduction to 74%, 52% and 49%, respectively) than it was in
      saline-pretreated rats (maximal reduction to 96%, 85% and 69%, respectively). The
      inhibitory effect of galanin (1.5 nmol) on extracellular 5-HT levels in the rat
      hippocampus was significantly attenuated by co-administration of the 5-HT(1A)
      receptor antagonists WAY-100635 (0.3 and 0.6 mg/kg s.c.) and, to a lesser extent,
      with pindolol (20 mg/kg s.c.). These data provide direct in vivo evidence of
      agonistic 5-HT(1A)-galanin receptor interaction at the presynaptic level.
      Furthermore, the findings indicate that a down-regulation of the somato-dendritic
      5-HT(1A) autoreceptors, following their stimulation with 8-OH-DPAT and possibly
      also indirectly with 5-HT reuptake inhibitors, may be compensated by a subsequent
      'sensitization' of the inhibitory galanin receptors in the DRN. Thus, the
      enhanced galanin receptor-mediated inhibition of 5-HT neurotransmission may
      contribute to the pathophysiology of depression or to the reduced and delayed
      efficacy of antidepressant therapies.

PMID- 12623220
TI  - Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3
      receptors native to neuroblastoma cells.
AB  - The identification of a second 5-HT(3) (5-HT(3B)) subunit provides an explanation
      for 5-HT(3) receptor heterogeneity. We investigated whether introduction of
      recombinant 5-HT(3B) subunits would alter the functional properties of mouse
      neuroblastoma 5-HT(3) receptors. RT-PCR analysis revealed that NB41A3 cells
      contain mRNAs encoding 5-HT(3A) and 5-HT(3B) subunits. 5-HT increased
      intracellular Ca(2+) concentration ([Ca(2+)](i)) and caused the concentration
      dependent activation of inward currents recorded at -60 mV. Both actions of 5-HT
      were antagonized by ondansetron. The 5-HT concentration-response relationship of
      NB41A3 cells was indistinguishable from that of the related NG108-15 cell line.
      The selective 5-HT(3)-receptor agonist mCPBG also elevated [Ca(2+)](i) and
      activated inward currents. 2-M-5HT was less efficacious than 5-HT as an activator
      of 5-HT(3) receptors in NB41A3 cells and did not significantly increase
      [Ca(2+)](i). The 5-HT induced increase in [Ca(2+)](i) did not involve caffeine-
      or thapsigargin-sensitive intracellular Ca(2+) stores. The introduction of the 5
      HT(3B) subunit by transient transfection of NB41A3 cells caused 5-HT to become
      less potent as an activator of 5-HT(3) receptors and altered the kinetics of 5-HT
      activated currents so that they resembled currents mediated by 5-HT(3AB)
      receptors. The 5-HT(3B) subunit also abolished the 5-HT induced [Ca(2+)](i)
      increase seen in untransfected NB41A3 cells. These data are consistent with the
      hypothesis that NB41A3 cells predominantly express homomeric 5-HT(3A) receptors
      that become heteromeric 5-HT(3AB) receptors upon introduction of the recombinant
      5-HT(3B) subunit.

PMID- 12623221
TI  - Chronic nicotine treatment attenuates alpha 7 nicotinic receptor deficits
      following traumatic brain injury.
AB  - Traumatic brain injury (TBI) often causes a persistent and debilitating
      impairment of cognitive function. Although the neurochemical basis for TBI
      induced cognitive dysfunction is not well characterized, some studies suggest
      prominent involvement of the CNS cholinergic system. Previous studies from our
      laboratories have shown that alpha 7* nicotinic cholinergic receptors (nAChrs)
      are especially vulnerable to the pathophysiological effects of TBI. Hippocampal
      and cortical alpha-[(125)I]-bungarotoxin (BTX) expression of alpha 7* nAChrs is
      significantly decreased in many brain regions following TBI and this reduction
      persists for at least 3 weeks following injury. In the present study we evaluated
      whether chronic nicotine infusion could attenuate TBI-induced deficits in alpha
      7* nAChr expression. Male Sprague-Dawley rats were sham-operated, or subjected to
      mild or moderate unilateral cortical contusion injury. Immediately following
      brain injury, osmotic mini-pumps that delivered chronic saline or nicotine (0.125
      or 0.25 mg/kg/h) were implanted. The animals were euthanatized and the brains
      prepared for nAChr quantitative autoradiography, 7 days following surgery. Brain
      injury caused significant decreases in BTX binding in several regions of the
      hippocampus. TBI-induced deficits in alpha 7* nAChr density were reversed in four
      of the six hippocampal brain regions evaluated following chronic nicotine
      administration. If TBI-induced deficits in alpha 7* nAChr expression play a role
      in post-injury cognitive impairment, pharmacological treatments which restore
      nAChr binding to control levels may be therapeutically useful.

PMID- 12623222
TI  - Electroencephalographic characterisation of pentylenetetrazole-induced seizures
      in mice lacking the alpha 4 subunit of the neuronal nicotinic receptor.
AB  - Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) is associated in some
      kindreds with mutations in the genes encoding the alpha 4 or beta 2 subunits of
      the neuronal nicotinic acetylcholine receptor (nAChR). Functional
      characterisation of the described ADNFLE mutations in oocyte preparations has
      produced conflicting results, with some studies suggesting hypofunction but
      others showing increased ligand sensitivity or delayed desensitisation. Knockout
      mice were studied to investigate extreme hypofunction of alpha 4 nAChRs in vivo.
      Mutant (Mt) and control mice underwent epidural electroencephalographic (EEG)
      recording for 2 h in the untreated state and for 1 h following administration of
      the gamma-amino butyric acid (GABA) antagonist, pentylenetetrazole (PTZ, 80
      mg/kg). No spontaneous seizures occurred and no EEG differences were observed
      between the genotypes in drug naive mice. Following PTZ, however, Mt mice showed
      markedly increased mortality compared to controls (85 vs 30%, P<0.001). Mts also
      had a greater number of generalised clonic seizures in the first 40 min following
      injection. In the same period, the EEGs of Mt mice showed an excess of spikes
      (P=0.033), multi-spike complexes (P=0.002) and continuous fast activity (P=0.017)
      compared to controls. These findings demonstrate that intact alpha 4 nAChR
      subunits provide significant in vivo protection against the proconvulsant effects
      of GABA antagonism.

PMID- 12623223
TI  - Preservation of neurological functions by nitric oxide synthase inhibitors
      following hemorrhagic shock.
AB  - Excessive production of nitric oxide (NO) as result of inducible nitric oxide
      synthase (iNOS) induction has been implicated in the pathophysiology of
      hemorrhagic shock. Our aim was to study the effect of iNOS inhibitors, L
      canavanine (50mg/kg) and N(G)-nitro- L-arginine methyl (L-NAME, 10mg/kg) and a
      resuscitation fluid, lactated Ringer's solution (3 times amount of blood lost),
      on survivability and neurological functions in rodents subjected to hemorrhagic
      shock. L-canavanine-treated rats had significantly higher survival rates (75%)
      compared to L-NAME-treated rats (44%) and lactated Ringer's solution-treated rats
      (40%), 72 h following hemorrhagic shock. A marked increase in the neurological
      performance was observed in L-canavanine-treated rats over the three-day period.
      Histological examinations also showed a reduction of degenerating neurons in L
      canavanine-treated rats when compared to L-NAME-, lactated Ringer's solution- or
      un-treated rats. Mean arterial blood pressure (MABP), nitrate/nitrite level,
      glutamic oxalacetic transaminase (GOT) level, and blood gases were also
      significantly improved in L-canavanine-treated rats when compared to those of L
      NAME-, lactated Ringer's solution- or un-treated rats. In conclusion, L
      canavanine-treated rats were able to improve survivability, attenuate organ
      damage, and improve neurological outcome when compared to other treatment groups.
      It is therefore suggest that L-canavanine may be beneficial as a potentially
      useful therapeutic agent in treating neurological deficit as a result of
      hemorrhagic shock.

PMID- 12623224
TI  - Neuroprotection by aminoguanidine after lateral fluid-percussive brain injury in
      rats: a combined magnetic resonance imaging, histopathologic and functional
      study.
AB  - The present study examined the effects of a selective inducible nitric oxide
      synthase (iNOS) inhibitor, aminoguanidine (AG), on neuronal cell survival and
      post-traumatic recovery in rats following a lateral fluid percussive brain
      injury. Daily treatment of AG at the dosage of 100 mg/kg or normal saline was
      given intraperitoneally into rats starting 2 h before or 30 min after brain
      injury. Treatment with AG significantly reduced lesion volumes in the brains of
      rats after injury, as evaluated by high-resolution magnetic resonance imaging
      (MRI). Immunohistochemical analysis showed a marked induction of iNOS expression
      in brain macrophages ipsilateral to the injury. Apoptotic neurons were observed
      in the ipsilateral cerebral cortex by in situ terminal transferase d-UTP nick-end
      labelling (TUNEL) and caspase-3 immunohistochemistry. In rats receiving
      prophylactic or post-injury treatment of AG, the number of degenerating neurons
      was markedly reduced in the cerebrum compared to those receiving saline
      injection. The location and extent of these pathologic changes correlated with
      MRI findings. Neurobehavioral studies showed that rotametric performance, grip
      strength score, total and ambulatory locomotor responses and acoustic startle
      response were reduced in rats subjected to the injury but were significantly
      improved in AG-treated rats. It is suggested that inhibition of iNOS by AG may
      represent a potential therapeutic strategy for the treatment of traumatic brain
      injury.

PMID- 12623225
TI  - Regional differences in naloxone modulation of Delta(9)-THC induced Fos
      expression in rat brain.
AB  - Recent behavioral and pharmacological research shows extensive interplay between
      cannabinoid and opioid neurochemical systems. Here we examined the
      neuroanatomical basis of this interaction using c-fos immunohistochemistry. We
      compared Fos immunoreactivity in groups of male albino Wistar rats treated with
      vehicle, Delta(9)-tetrahydrocannabinol (THC, 10 mg/kg, i.p.), naloxone (10 mg/kg,
      i.p.) or THC and naloxone in combination. Locomotor activity was depressed in
      both THC treatment groups and moderately inhibited in rats given naloxone alone.
      Results showed that naloxone inhibited THC-induced Fos immunoreactivity in
      several key brain regions including the ventral tegmental area, ventromedial and
      dorsomedial hypothalamus, central caudate-putamen and ventrolateral
      periaqueductal grey. Conversely, naloxone and THC had an additive effect on Fos
      immunoreactivity in the central nucleus of the amygdala, the bed nucleus of the
      stria terminalis (lateral division), the insular cortex, and the paraventricular
      nucleus of the thalamus. These findings complement earlier pharmacological
      results showing potent modulation of cannabinoid-induced analgesia, appetite and
      reward by opioids. The inhibitory effects of naloxone on THC-induced ventral
      tegmentum, hypothalamic and periaqueductal grey Fos expression point to these
      structures as key sites involved in cannabinoid-opioid interactions.

PMID- 12623226
TI  - Neurons in the periaqueductal gray are critically involved in the neuronal
      network for audiogenic seizures during ethanol withdrawal.
AB  - The periaqueductal gray (PAG) is implicated in the network subserving audiogenic
      seizures (AGS). AGS are seen during ethanol withdrawal (ETX), and the present
      study examined effects of focal NMDA receptor blockade in PAG during ETX and PAG
      neuronal firing changes associated with ETX. Bilateral cannulae or microwire
      electrodes were chronically implanted into PAG. Ethanol was administered
      intragastrically at 8-h intervals for 4 days, resulting in AGS susceptibility
      during ETX. Microinjection of a competitive NMDA receptor antagonist, DL-2-amino
      7-phosphonoheptanoic acid (AP7) (2 and 5 but not 1 nmol/side), into the PAG
      suppressed AGS, in part, reversibly. In microwire experiments spontaneous and
      acoustically evoked PAG neuronal responses in behaving rats were reduced
      significantly 1 h after initial administration of ethanol. During ETX, when the
      animals were susceptible to AGS, significant increases in spontaneous and
      acoustically evoked PAG neuronal firing occurred. PAG neurons exhibited burst
      firing 2-4 s prior to the tonic-clonic phase of AGS and tonic repetitive firing
      during this seizure phase, which ceased during post-ictal depression. Increased
      NMDA receptor function in PAG may be important to the aberrant PAG neuronal
      firing in AGS, since previous studies observed upregulation of NMDA receptors
      during ETX, and the present study observed that focal microinjection of a NMDA
      antagonist into PAG blocked AGS.

PMID- 12623228
TI  - Of mouse and man--what is the value of the mouse in predicting gene expression in
      humans?
AB  - The mouse is the most commonly used mammalian species in biomedical research and
      is widely regarded as a human surrogate species. In this Editorial, Robert
      Coleman discusses the validity of this assumption and cautions against the
      unquestioning acceptance of the mouse an experimental model for drug discovery
      and development.

PMID- 12623229
TI  - New ligands for defective receptors.
AB  - Scientists are trying to create hormone analogues that will work more effectively
      with defective receptors than natural hormones do.

PMID- 12623227
TI  - Functional interaction between neuropeptide Y receptors and modulation of calcium
      channels in the rat hippocampus.
AB  - We investigated the functional interaction between neuropeptide Y (NPY) receptors
      using nerve terminals and cultured rat hippocampal neurons, and we evaluated the
      involvement of voltage-gated Ca(2+) channels (VGCCs) in NPY receptors-induced
      inhibition of Ca(2+) influx and glutamate release. The KCl-evoked release of
      glutamate from hippocampal synaptosomes was inhibited by 1 microM NPY and this
      effect was insensitive to either BIBP3226 (Y1 receptor antagonist) or L-152,804
      (Y5 receptor antagonist), but was sensitive to BIIE0246 (Y2 receptor antagonist).
      We could also pharmacologically dissect the NPY receptors activity by using Y1,
      Y2 and Y5 receptor agonists ([Leu(31),Pro(34)]NPY, NPY13-36, NPY (19-23)
      (Gly(1),Ser(3),Gln(4),Thr(6),Ala(31),Aib(32),Gln(34))-pancreatic polypeptide
      (PP), respectively), and in all the cases we observed that these agonists could
      inhibited the KCl-induced release of glutamate. However, the selective and
      specific co-activation of both Y1 and Y2 or Y2 and Y5 receptors resulted in non
      additive inhibition, and this effect was prevented in the presence of the Y2
      antagonist, but was insensitive to the Y1 or Y5 receptor antagonist. Moreover, as
      we previously showed for Y1 receptors, we also observed that the activation of Y5
      receptors inhibited the glutamate release in the dentate gyrus and CA3 subregion,
      without significant effect in the CA1 subregion of the hippocampus. The same
      qualitative results were obtained when we investigated the role of NPY Y1 and Y2
      receptors in modulating the changes in [Ca(2+)](i) due to KCl depolarisation in
      cultured hippocampal neurons. The inhibitory effect of nitrendipine (L-type VGCC
      blocker) or omega-conotoxin GVIA (omega-CgTx; N-type VGCC blocker) was not
      potentiated by the simultaneous activation of Y1 or Y2 receptors. Moreover, the
      exocytotic release of glutamate was inhibited by omega-agatoxin IVA (omega-Aga; P
      /Q-type VGCC blocker), and this VGCC blocker did not potentiate Y1, Y2 or Y5
      receptor-mediated inhibition of glutamate release. Also, the effect of ionomycin
      in inducing the exocytotic release of glutamate from hippocampal synaptosomes was
      insensitive to the activation of NPY receptors. In the present paper, we
      identified a role for NPY Y1, Y2 and Y5 receptors in modulating the exocytotic
      release of glutamate and the [Ca(2+)](i) changes in the rat hippocampus. In
      conditions of co-activation, there appears to exist a physiological cross-talk
      between Y1 and Y2 and also between Y2 and Y5 receptors, in which Y2 receptors
      play a predominant role. Moreover, we also show that Y1 and Y2 receptors exert
      their inhibitory action by directly modulating L-, N-, and P-/Q-type VGCCs,
      whereas the inhibition of glutamate release mediated by the Y5 receptors seems to
      involve P-/Q-type VGCCs.

PMID- 12623230
TI  - Nucleus 'hallowed ground' no more.
AB  - The proces of piecemeal microautophagy of the nucleus describes the way in which
      autophagy occurs in the nucleus, a realm of the cell once considered to be off
      limits for autophagy.

PMID- 12623231
TI  - Scientists expand the genetic code.
AB  - A bacterium has been created that synthesizes an unnatural amino acid and
      incorporates it into proteins with a fidelity and efficiency that rivals that of
      the 20 natural amino acids.

PMID- 12623234
TI  - A new model for drug discovery--meeting our societal obligation.
AB  - The development of new models that will enable and encourage drug discovery in
      disease areas that are neglected by the industry is urgently needed. Here, one
      model is described that has been established to find treatments for
      neurodegenerative diseases.

PMID- 12623235
TI  - Letting biology do the work.

PMID- 12623236
TI  - Nuclear transport as a target for cancer therapies.

PMID- 12623237
TI  - Systems biology unplugged.

PMID- 12623239
TI  - Cancer immunotherapy: an embarrassment of riches?
AB  - There is clear evidence that certain forms of immunotherapy can be successful
      against certain cancers. However, it would appear that cancerous cells of various
      origin are exceptionally adept at subverting the immune response. Consequently,
      it is probable that the most efficacious therapy will be one in which multiple
      responses of the immune system are activated. There is currently an embarrassment
      of riches with regard to multiple vaccine strategies in the clinic, although no
      single method seems to hold the solution. Here, we draw together several of the
      humoral- and cellular-activating strategies currently under clinical
      investigation.

PMID- 12623240
TI  - Peptide and protein drug delivery to and into tumors: challenges and solutions.
AB  - The potential of peptide and protein anticancer agents has yet to be realized
      owing to the many unresolved problems concerning their delivery to the site of a
      tumor and into tumor cells. However, our understanding of the mechanisms
      underlying the biological fate and biodistribution of protein and peptide drugs
      has advanced to the stage where methods that use or influence these mechanisms
      are now available. There are different approaches that can improve the stability,
      longevity and targeting of peptides and proteins in the body, such as their
      modification with various soluble polymers, incorporation into microparticular
      drug carriers, enhanced permeability and retention effect-based tumor targeting
      and the use of targeting moieties. Furthermore, new approaches to intracellular
      drug delivery, including the use of transduction proteins and peptides, are being
      developed. These advances promise the delivery of a new generation of anticancer
      drugs.

PMID- 12623241
TI  - The extended pharmaceutical enterprise.
AB  - The availability of widespread contractual services led to the birth of the
      virtual company in the 1990s. As the concept has matured, and the biotechnology
      sector diversified, interchange of intellectual property in the form of
      collaborative and license arrangements opens up still further the opportunities
      for outsourced forms of pharmaceutical R&D.

PMID- 12623244
TI  - Duodenal injuries.

PMID- 12623245
TI  - Traumatic rupture of the diaphragm: experience with 65 patients.
AB  - Traumatic diaphragmatic rupture is reported with increasing frequency and is
      associated with high morbidity and mortality. The purpose of this study was to
      present our experience with the management of this injury. Sixty-five patients
      with TDR were treated in our hospital between January 1989 and May 2000. They
      were 54 men (83%) and 11 women (17%). Mean age was 36.57 years (range 15-76
      years). Rupture of the diaphragm was left-sided in 43 patients (66%), right-sided
      in 21 (32%), and bilateral in 1 (1.5%). Blunt trauma accounted for the injuries
      of 52 patients (80%). Early diagnosis was obtained in 57 patients (88%). The
      diagnosis was established preoperatively in 17 patients (26%), and intra
      operatively in 48 (74%). Multiple associated injuries were observed in 62
      patients (95%). Postoperative complications were observed in seven patients
      (11%), and the overall mortality was 14%. Injury severity score (ISS) and
      haemorrhagic shock upon admission strongly influence the outcome. A high index of
      suspicion and a thorough examination of both hemi diaphragms during laparotomy is
      recommended in order to avoid early or late complications.

PMID- 12623246
TI  - Effects of in vivo freezing and mannitol in intestinal ischaemia-reperfusion
      injury.
AB  - PURPOSE: The main purpose of this study was to investigate whether in vivo
      freezing and mannitol administration can protect the small intestine against
      ischaemia-reperfusion (I-R) injury. METHODS: Fifty male Sprague-Dawley rats (200
      225 g) were divided into 5 groups each containing 10 rats; group SO, sham
      operation group; group I, mesenteric ischaemia group; group R, ischaemia
      reperfusion (I-R); group FR, I-R plus in vivo freezing; group MR, I-R plus
      mannitol treatment. Intestinal ischaemia for 30 min and reperfusion for 60 min
      were applied. Ileum specimens were obtained to determine the tissue levels of
      malondialdehyde (MDA) and histological changes. RESULTS: The mucosal injury
      scores of group R were significantly higher than those of the group I (P<0.0001).
      The mucosal injury scores in the groups FR and MR were significantly lower than
      the group R (P<0.0001 and P<0.0001, respectively). In the group FR, mucosal
      injury scores were not significantly different from those of group I (P=0.123).
      However, mucosal injury scores of group MR were significantly less when compared
      to those of group I (P=0.01). Mean MDA levels of group R were significantly
      higher than those of the group I (P<0.0001). Mean MDA levels of groups FR and MR
      were significantly lower than those of group R (P<0.0001 and P<0.0001,
      respectively). In addition, MDA levels of group FR were significantly higher than
      those of group MR (P<0.0001). CONCLUSION: In conclusion, these observations
      suggest that the in vivo freezing of SMA and the pre-treatment with mannitol
      before reperfusion period may be useful in preventing intestinal reperfusion
      injury.

PMID- 12623247
TI  - Blunt liver injury: from non-operative management to liver transplantation.
AB  - Therapeutic options for blunt hepatic trauma include both non-operative and
      operative management. We have reviewed our experience of the management of blunt
      hepatic trauma, from non-operative to liver transplantation. A total of 72
      patients with blunt hepatic injury observed at the first surgical unit of Padua
      in a 3-year period (1998-2000) were analysed; we also included a patient who had
      a liver transplant in 1993 for severe liver trauma. Twenty-nine patients (39.7%)
      were treated conservatively, with a 93% success rate; 60.3% were treated
      surgically. Suture hepatorraphy was the most common procedure performed (52.3%).
      Advantages of non-operative management in our experience were the reduced need
      for transfusion (1.1U versus 4.3U) with 92% of patients not needing transfusion,
      and a reduced stay in the intensive care unit; there was no liver-related
      mortality. The overall morbidity in surgical patients was 30%, with 16% liver
      related complications. Twelve surgical patients (27.2%) died, with a liver
      related mortality of 18.2%. A large number of patients may present with an
      associated endo-abdominal injury, even in low-grade liver trauma, requiring rapid
      laparotomy. In high-grade hepatic trauma, the evolution toward liver failure is
      an indication for liver transplantation.

PMID- 12623248
TI  - Reduction of time to definitive care in trauma patients: effectiveness of a new
      checklist system.
AB  - This study evaluated the feasibility of establishing a new trauma transfer
      checklist and assessed its impact on trauma-related interhospital transfers. A
      standard envelope with a printed checklist (N.E.W.S.) incorporating four key
      concepts in the care and transfer of trauma patients was used. A prospective
      comparison of consecutive interhospital trauma transfers to the major trauma
      service between July 1999-May 2000 (pre-N.E.W.S.) and August 2000-November 2000
      (post-N.E.W.S.) was made. Changes in management satisfaction were assessed by a
      Likert scale (1=poor to 5=excellent). Pre-N.E.W.S., 88 trauma patients were
      transferred and 20 trauma transfers were recorded post-N.E.W.S. The time to
      definitive care pre-N.E.W.S. was 443+/-322 min, and 339+/-108 min (P=0.014) post
      N.E.W.S. The time in the referring hospital was also reduced from 343+/-310 min
      pre-N.E.W.S. to 197+/-90 min post-N.E.W.S (P=0.0002). The checklist system
      prompted changes in the management of the trauma patient in 20% of the cases and
      there was a high level of satisfaction expressed by users of the checklist (4.6+/
      0.7). The N.E.W.S. checklist is effective in facilitating the interhospital
      transfer of trauma patients by shortening the time to definitive care.

PMID- 12623249
TI  - Trauma resuscitation time.
AB  - Documenting the timing and organisation of trauma resuscitation can be utilised
      to assess performance standards, and to ensure a high quality of trauma
      resuscitation procedures. Since there is no European literature available on
      trauma resuscitation time (TRT) in the emergency room, the aim of this
      descriptive study is to evaluate TRT in the Netherlands. The introduction of an
      ATLS-trained prehospital mobile medical team (MMT) in the Nijmegen area initiated
      the on-site advanced trauma life-support for the prehospital management of trauma
      patients. We studied TRT in two groups of patients, one with, the other without
      on-site care by a MMT. In the emergency room the use of videotape recording was
      chosen to document trauma resuscitation (22 actions) and TRT. A specially flow
      chart was used to define the TRT-procedures. We studied 43 patients; 27 without
      MMT treatment and 16 with MMT treatment. The activities were divided into the
      ABCDE's of trauma care. Significant more patients of the MMT group were intubated
      before arrival in the hospital (12/16 (75%) versus 2/27 (2%), P<0.05). Eleven
      definitive airway management interventions (intubation) and one thoracic drainage
      in the non-MMT group were demanded by the protocol, but not performed before
      arrival in the hospital. Sixteen out of 22 actions that were documented were
      carried out at an earlier stage in the MMT group. There was no significant
      difference between the resuscitation times; in both groups the recorded median
      time was approximately 43 min. This prospective analysis demonstrates the timing
      of resuscitation procedures in a resuscitation room and provides some insight
      into the timing of ATLS initial assessment.

PMID- 12623250
TI  - Consequences of road traffic accidents for different types of road user.
AB  - The study aimed to describe the immediate and later physical, social and
      psychological consequences of a road traffic accident for vehicle occupants,
      motorcyclists, cyclists and pedestrians amongst consecutive hospital attenders at
      an Accident and Emergency Department. Physical and accident details were collated
      from hospital records. Subjects completed questionnaires at hospital attendance,
      3 months, 1 and 3 years. There were 1148 respondents from 1441 consecutive
      attenders over a 1-year period. The main outcome measures were self-report
      physical status, standard measures of post-traumatic stress disorder, mood,
      travel anxiety and health status at 3 months, 1 and 3 years. There were marked
      differences in injury pattern and immediate reaction between road user groups.
      Pedestrians and motorcyclists suffer the most severe injuries and report more
      continuing medical problems and greater resource use, especially in the first 3
      months. There were few differences in psychological or social outcomes at any
      stage of follow-up. Despite differences between the road user groups in their
      injuries, immediate reactions and treatment, there were few longer-term
      differences. A third of all groups described chronic adverse consequences which
      were principally psychological, social and legal.

PMID- 12623251
TI  - All-terrain vehicles--unstable, unsafe and unregulated. A prospective study of
      ATV-related trauma in rural Ireland.
AB  - All-terrain vehicles (ATVs) are fast, powerful machines that pose a significant
      threat to public safety. In the USA, ATVs are responsible for 273 deaths and over
      68,000 injuries each year. As the incidence of ATV-related accidents in Britain
      and Ireland is unknown we carried out a prospective audit of all patients
      presenting to our Accident and Emergency Departments with ATV-related trauma over
      a 1-year period. Of 32 patients with ATV-associated injuries, 10 were under 16
      years of age and 23 had no previous experience of operating an ATV. We documented
      24 fractures (2 open) and 1 tension pneumothorax. Helmet usage was high and head
      injuries were few and not of a serious nature. Two-thirds of injuries occurred on
      commercial adventure sports courses. Since ATVs are off-road vehicles, they are
      exempt from safety regulations that apply to other forms of transport. As care
      providers to trauma victims, we must make prevention of these injuries a priority
      and campaign for both voluntary and legislative controls to make ATV use a safer
      leisure pursuit.

PMID- 12623252
TI  - Sports injury or trauma? Injuries of the competition off-road motorcyclist.
AB  - A prospective analysis of the injuries of off-road competition motorcyclist at
      four International Six Day Enduro (ISDE) events was performed utilizing the
      injury severity score (ISS) and the abbreviated injury scale (AIS). Of the 1787
      participants, approximately 10% received injuries that required attention from a
      medical response unit. The majority (85%) sustained a mild injury (mean ISS 3.9).
      Loss of control while jumping and striking immovable objects were important risk
      determinants for serious injury. Although seasoned in off-road experiences, mean
      15.3 years, 54% of those injured were first year rookies to the ISDE event.
      Speeds were below 50 km/h in the majority of accidents (80%), and were not
      statistically correlated with severity. The most frequently injured anatomical
      regions were the extremities (57%). The most common types of injury were
      ligamentous (50%). Seventy-seven percent of all fractures were AIS grades 1 and
      2. The most common fractures were those of the foot and ankle (36%). Multiple
      fractures involving different anatomical regions, or a combination of serious
      injuries was seen with only one rider. When compared to the injuries of the
      street motorcyclist, competition riders had lower AIS grades of head and limb
      trauma. Off-road motorcycle competition is a relatively safe sport with injury
      rates comparably less than those of contact sports such as American football and
      hockey.

PMID- 12623253
TI  - Parachuting: a sport of chance and expense.
AB  - This paper seeks to determine the cost to the NHS associated with treating
      parachute-related injuries. More specifically, it compares the training received
      by civilians to that received by military personnel together with the types of
      parachutes used or the type of jump. It also reviews the information given to
      civilian jumpers prior to their first jump. Fifty-three jumpers suffered injuries
      in the period under review. Of these, 32 cases with 41 injuries were transferred
      to Accident and Emergency Department for treatment. Injuries involved most of the
      musculoskeletal system. Twenty-six (n=32) patients were admitted for treatment,
      with an average length of hospital stay of 6.8 days. Post-discharge, the length
      of time lost from work was 42.8 days. The cost to the NHS was calculated at pound
      4026.50 per patient treated. This did not include time lost from work, subsequent
      follow up or any other secondary procedures. Civilian parachute jumpers were
      trained for 6.5h compared to 31.5h for military personnel. Twenty-seven patients
      used rectangular rather than circular parachutes. Thirty of the 41 injuries
      occurred during static line jumps, with 7 occurring during tandem jumps and only
      5 during free-fall jumps. Twenty-three of the 32 jumpers sustained the injury
      during their first jump. First-time civilian jumpers were given a minimum of
      information regarding risks and injuries prior to their jump and were
      inadequately insured against potential injuries. The cost of caring for these
      patients is substantial when compared to the money that is raised for charity
      during some of the jumps. Private insurance, with the NHS legally able to claim
      expenses would help to offset these medical costs. It is also possible that by
      increasing civilian training, there may be a reduction in the number of injuries
      sustained by first-time civilian jumpers from 1.1 to 1.2% (11% in charity jumps)
      to the military figures of 0.22-0.89%.

PMID- 12623254
TI  - Seasonal variation in the incidence of wrist and forearm fractures, and its
      consequences.
AB  - We have used the All Wales Injury Surveillance System (AWISS) in a population
      based study of wrist and forearm fractures. We examined seasonal variation in the
      incidence of these injuries, and looked at resulting pressures on outpatient and
      inpatient trauma services. AWISS collected data from eight Accident and Emergency
      (A&E) departments which between them serve a total of 1.2 million people in South
      Wales. During a single year, we identified all 5013 people who presented with a
      wrist or forearm fracture. Seasonal variation in wrist/forearm fracture incidence
      was apparent, but showed a different pattern in different age groups. Overall
      incidence figures were dominated by an increase in children's fractures in spring
      and summer. Children under the age of 15 suffered a total of 360 wrist and
      forearm fractures during the three winter months; an incidence of 5.9/1000 per
      year that was only about half that observed during the remainder of the year
      (10.7/1000 per year). In contrast, older people showed a higher incidence in the
      winter. During the winter months people aged over 75 sustained a total of 160
      wrist/forearm fractures; an incidence of 8.2/1000 per year, significantly higher
      than the incidence observed in other months (5.8/1000 per year). Seasonality of
      incidence was not apparent in other age groups. Children presenting during the
      spring and summer months were significantly more likely to need admission to
      hospital; 22.8% were admitted compared with just 10.3% of those presenting during
      the winter months (P<0.001, chi(2)-test). Other age groups showed no significant
      seasonal variation in the likelihood of hospital admission.

PMID- 12623255
TI  - Seasonal variation of proximal femoral fractures in the United Kingdom.
AB  - A prospective study including 3034 consecutive hip fracture patients admitted to
      a single unit in the United Kingdom over a 12-year period was performed. The
      daily incidence of hip fractures was compared between all four seasons throughout
      the year. Information was recorded for each patient including level of mobility,
      mental test score, type of residence, fracture type and total length of stay.
      Mortality rates at 30, 120 and 365 days were also calculated. More hip fractures
      occurred during the winter compared to summer (P=0.002). There was an increase in
      the number of extracapsular fractures (P=0.006) and tendency to a higher
      mortality for those patients admitted in the winter months. There was no
      significant difference in patient characteristics between the winter and summer
      seasons. Funding and resources within the health service may need to be adjusted
      to accommodate this variation in patient load.

PMID- 12623256
TI  - Iatrogenic nerve injury with the Russell-Taylor humeral nail.
AB  - The first consecutive 51 humeral shaft fractures treated with the Russell-Taylor
      intramedullary nail at Glasgow Royal Infirmary were reviewed in a retrospective
      study. There were eight iatrogenic nerve injuries- three to the radial nerve
      which settled spontaneously and five to the lateral cutaneous nerve of forearm of
      which three have failed to recover completely. The authors feel that the
      insertion of the distal interlocking screw in the antero-posterior direction puts
      this nerve at risk. We believe that iatrogenic injury to the lateral cutaneous
      nerve of forearm during humeral nailing has not been previously reported.

PMID- 12623257
TI  - An aid to femoral nail removal.
AB  - We describe a novel technique to aid the removal of a proximally inserted femoral
      nail by using a guide wire and the starter reamer. By reaming through the scar
      tissue, a cylindrical track is created and the threaded top end of the nail is
      exposed. The soft tissue dissection is therefore limited to the absolute minimum
      with no further damage to the hip abductors.

PMID- 12623258
TI  - Laparoscopic spleen preserving distal pancreatectomy after blunt abdominal
      trauma.

PMID- 12623259
TI  - Human injury as a result of the recent foot and mouth crisis.

PMID- 12623260
TI  - Perilymph fistula--a complication of penetrating injury to the ear not to be
      missed.

PMID- 12623261
TI  - The nail gun: injuries to the knee and chest.

PMID- 12623262
TI  - Trapped medial epicondyle of the humerus.

PMID- 12623263
TI  - Problems with Halder nail fixation of humeral fractures.

PMID- 12623267
TI  - Finding out where we are.

PMID- 12623265
TI  - Rectal perforation in unstable pelvic fractures: the use of flexible
      sigmoidoscopy.

PMID- 12623268
TI  - Pattern recognition technique in immunological antigenic tests to identify
      Mycobacterium tuberculosis infection.
AB  - The importance of a diagnostic test that is simple and quick to identify
      Mycobacterium tuberculosis infection needs no emphasis. The tuberculin skin test
      (TST - 1 TU RT23) is the diagnostic tool for identifying M. tuberculosis
      infection at present. The test reaction on the skin is measured after 48-72 h. It
      is observed that often multi-modes are seen, when the reactions are drawn as a
      graph and the bimodality is seen very feebly. Because of the difficulties in the
      administration of TST, several serological tests were developed over three
      decades, but none of the studies showed the desired results. One study to
      evaluate purified protein derivative (PPD) antigen resulted in a claim of 80%
      sensitivity and 4% false-positivity rate (14), while other researchers were not
      able to obtain similar results. In addition, several problems were encountered
      due to the non-availability of antigens, and data analyses from an ELISA-based
      diagnostic test showed considerable overlap of distributions of optical density
      (OD) values among patients and healthy individuals (10). Classical statistical
      techniques cannot explain the cause of these overlaps. Hence, an attempt is made
      in this article to resolve these difficulties by the pattern recognition
      technique (PRT). The technique lies in splitting the data into clusters using a
      supervised algorithm. The data set is normally split into a training set, a test
      set and a validation set. The PRT gets "trained" through the training data set
      until the infected and uninfected groups of individuals are correctly classified.
      The training occurs based on an algorithm on the training set. On successful
      completion of the training, this technique is further tested and validated in the
      respective data sets. SETTING: A total of 273 finger-prick specimens were
      collected from five categories (Al, A2, B, C, D, E) of subjects not vaccinated
      with (bacille Calmette Guerin) (BCG) from Trivellore BCG Trial area adopted by
      the Tuberculosis Research Center, Chennai, India. OBJECTIVE: The study was
      conducted with the primary aim of evaluating purified antigens--r38 kDa, PPD and
      30 kDa--for their usefulness as diagnostic tools and to test the applicability of
      the PRT in the evaluation of diagnostic tests. Individuals in two main categories
      (definitely not infected categories Al, A2 and D, and definitely infected
      categories B, E and C based on reaction to TST) were assembled for the purpose.
      RESULTS: The overall PRT performance of 30 kDa was 72.3% sensitivity and 90.9%
      specificity for identifying M. tuberculosis infection, while the r38 kDa antigen
      recorded a sensitivity of 73.8% and a specificity of 84.6%. In the case of PPD,
      the results were not promising. CONCLUSION: This paper on ELISA-based diagnostic
      tests attempts to implement an optimal decision support system through PRT that
      would identify the outcome (as infected or non-infected) based on the OD values.
      The PRT was able to predict the outcome for individual suspects. Further,
      Kullback-Leibler distance measurement has validated the PRT in distinguishing
      infected individuals from healthy subjects (based on the OD values).

PMID- 12623269
TI  - Dose of BCG does not influence the efficient generation of protective immunity in
      mice challenged with Mycobacterium tuberculosis.
AB  - It is generally agreed that BCG vaccination is relatively ineffective in adults
      exposed to tuberculosis infection. The reasons for this may well be multiple, and
      may include the possibility that higher doses of BCG may induce a mixed TH1 and
      TH2 response, which may lessen the protective effect of the vaccine. To test this
      hypothesis, mice were vaccinated with a range of doses of BCG and then challenged
      by the intravenous or aerogenic routes with virulent Mycobacterium tuberculosis.
      While the data support the hypothesis that a TH2 response is induced by higher
      doses of BCG, this was found to have no influence whatsoever on the capacity of
      the vaccinated mouse to express acquired specific resistance to the challenge
      infection.

PMID- 12623270
TI  - Aerosol delivery of virulent Mycobacterium bovis to cattle.
AB  - SETTING: Although animal models of aerosol inoculation of Mycobacterium
      tuberculosis and M. bovis have been reported using laboratory animals, a model of
      aerosol delivery of M. bovis to cattle has not been reported previously.
      OBJECTIVE: Develop and characterize a model of aerosol delivery of M. bovis to
      cattle, and compare the distribution of lesions in cattle infected with either of
      two different strains of M. bovis, one isolated from cattle (HC2005T), and the
      other isolated from white-tailed deer (1315). DESIGN: Cattle (n=20, female and
      castrated males) aged 4 months, were infected with 1 x 10(3) (n=5) or 1 x 10(5)
      (n=5) colony-forming units (CFU) of M. bovis 1315 or 1 x 10(3) (n=5) or 1x10(5)
      (n=5) CFU of M. bovis HC2005T. Calves were infected using a commercially
      available aerosol delivery system. One hundred fifty-five days after infection,
      calves were euthanized, examined and tissues collected for microscopic analysis
      and bacteriologic culture. RESULTS: Nineteen of 20 calves developed tuberculosis.
      Typical tuberculous lesions were most pronounced in the lungs and
      tracheobronchial and mediastinal lymph nodes. CONCLUSION: The system described
      provides a reliable method of aerosol delivery of M. bovis to cattle. Lesion
      distribution suggests that the aerosolized inoculum was delivered deep into
      pulmonary alveoli and thus represents true aerosol exposure. Disease was more
      severe in groups receiving the highest dose of either inoculum strain; however,
      differences between strains were not seen. Published by Elsevier Science Ltd.

PMID- 12623271
TI  - Expression of foreign genes in Mycobacterium bovis BCG strains using different
      promoters reveals instability of the hsp60 promoter for expression of foreign
      genes in Mycobacterium bovis BCG strains.
AB  - SETTING: Optimization of BCG as a vehicle for live recombinant vaccines requires
      improved strategies for stable antigen expression. OBJECTIVES: To investigate the
      effects of various combinations of post-translational signals and promoters on
      expression and stability in different BCG strains. DESIGN: Plasmids were
      constructed using mycobacterial promoters (hsp60, 19-kDa antigen, 85A antigen-
      from the Mycobacterium tuberculosis complex--and the 18-kDa antigen from
      Mycobacterium leprae) and post-translation signals (85A antigen secretion and 19
      kDa antigen acylation signals), coupled with reporter genes. RESULTS: The 19-kDa
      acylation signal had little effect on expression, while the 85A secretion signal
      enhanced markedly the levels of cell-associated product. Inclusion of the hsp60
      promoter caused plasmid instability; various deletions affecting the promoter
      region occurred during or soon after transformation, but not during subsequent
      growth of the transformants, nor with other promoters. BCG Moreau appeared to be
      more susceptible to deletions than other BCG strains. CONCLUSIONS: The 85A signal
      may prove useful in optimizing gene expression in BCG, irrespective of secretion
      of the product. Deletions associated with the hsp60 promoter may be due to a
      transient lethal induction of the hsp60 promoter associated with electroporation.
      With intact plasmid there was no marked difference in expression between BCG
      strains.

PMID- 12623273
TI  - Infection of human fibroblast-like synovial cells with Chlamydia trachomatis
      results in persistent infection and interleukin-6 production.
AB  - Recent studies have shown that the urogenital pathogen Chlamydia trachomatis to
      be a major bacterium triggering reactive arthritis (ReA), and is able to induce
      interleukin-6 (IL-6) production in human fibroblast-like synovial cells (FSC) in
      vitro. In the present study, we examined the correlation between IL-6 production
      and multiplication of chlamydia in FSC. All FSC from five patients secreted
      highly increased quantities of IL-6 in a dose-dependent and time-dependent
      fashion. Heat and UV inactivated chlamydia failed to enhance production of IL-6.
      When azithromycin was added to infected cultures of FSC at 0 or 48 h after
      infection, the level of IL-6 production was very low. Transmission electron
      microscopy of such infected cultures revealed many abnormal forms of chlamydia
      within the inclusions in FSC. From one step-growth curve experiments, it was
      suggested that C. trachomatis hardly multiplied in FSC. In contrast, in C.
      trachomatis infected HeLa 229 cells, chlamydia multiplied as usual, but little IL
      6 production were found. These observations indicated that live chlamydia and the
      persistence of chlamydia may be essential for stimulating the synthesis of IL-6
      in FSC.

PMID- 12623274
TI  - Cleavage of human fibronectin and other basement membrane-associated proteins by
      a Cryptococcus neoformans serine proteinase.
AB  - The interaction between the fungal pathogen Cryptococcus neoformans and human
      fibronectin (HFN) was examined in this study. Polypeptides from cryptococcal
      whole homogenates and cell wall with molecular masses of 25 and 35 kDa,
      respectively reacted with HFN. The relevance of the occurrence of these proteins
      in intact cells was uncertain, since yeast cells from different strains and
      serotypes of C. neoformans did not significantly adhere to soluble or solid
      phased HFN. In contrast, an exocellular proteolytic activity that cleaves HFN was
      suggested. Degradation of HFN by culture supernatant fluids was demonstrated by
      Western blotting using a monoclonal anti-HFN antibody. Several fragments of lower
      molecular weights were observed which reacted with the antibody. Proteolysis was
      mediated by a serine protease activity, since HFN cleavage was completely
      inhibited by phenylmethylsulfonyl fluoride (PMSF), aprotinin, and N-tosyl-L
      phenylalanyl chloromethylketone (TPCK), but not by inhibitors of metalo,
      cysteine, or aspartyl proteases. Similar results were obtained when the
      fluorogenic peptide carbobenzoxy-phenylalanyl-arginyl-7-amido-4-methylcoumarin
      (CBZ-Phe-Arg-NHmet-C) was used as substrate. The cryptococcal supernatant also
      cleaved laminin and type IV collagen, as demonstrated by polyacrylamide gel
      electrophoresis with co-polymerized proteins. The hydrolysis of these proteins
      was mediated by a single cryptococcal protease with a molecular mass of 75 kDa.
      The cleavage of key host components of the basement membrane and extracellular
      matrix by C. neoformans may be a relevant factor in the process of fungal
      invasion.

PMID- 12623272
TI  - Characterization of virulence, colony morphotype and the glycopeptidolipid of
      Mycobacterium avium strain 104.
AB  - SETTING: Members of the Mycobacterium avium complex (MAC) are responsible for
      mycobacterial disease in children, the aged and in immunocompromised individuals.
      The complex consists of different species, serovars and morphologic forms that
      vary in virulence. One isolate of the MAC is currently being sequenced (MAC 104)
      and was chosen based on its derivation from an AIDS patient and the fact that it
      could be genetically manipulated. OBJECTIVE: MAC 104 was therefore analyzed for
      virulence, colony morphotype and expression of the glycopeptidolipid (GPL)
      responsible for serotying differences and the rough to smooth morphological
      switch. RESULTS: The isolate was found to be virulent in the murine model of low
      dose aerosol infection in that it could colonize the lung, proliferate within the
      tissue and disseminate to other organs. MAC 104 expressed a variety of colony
      morphotypes, the most prevalent of which were smooth opaque, smooth transparent
      and rough. All three morphotypes could persist in the lung; however, the
      transparent and rough morphotypes grew more rapidlyinvivo. The rough morphotype
      was unusual in that it expressed an atypical form of the GPL usually absent from
      rough morphotypes. CONCLUSION: This characterization complements the genome data
      and confirms that MAC 104 behaves similarly to other MAC isolates.

PMID- 12623275
TI  - Virulence of a hemB mutant displaying the phenotype of a Staphylococcus aureus
      small colony variant in a murine model of septic arthritis.
AB  - Persistence of Staphylococcus aureus during invasive infections has been
      associated with a small-colony variant (SCV) phenotype. SCVs are frequently
      auxotrophic for menadione or hemin, two compounds involved in the biosynthesis of
      the electron transport chain. SCVs have been shown to be more resistant to
      antibiotics such as aminoglycosides, grow slowly and persist intracellularly. The
      aim of this study was to assess the virulence of an hemB mutant, which has been
      shown to display the typical characteristics of clinical SCVs, in a murine model
      of septic arthritis. NMRI mice were inoculated intravenously with either the wild
      type strain Newman or with its mutant displaying the SCV phenotype. The clinical,
      bacteriological, and histopathological progression of the disease was studied.
      Mice inoculated with the hemB mutant displayed a higher frequency and a
      significantly higher severity of arthritis than mice inoculated with the wild
      type Newman strain. Despite that, the mutant inoculated mice displayed
      significantly lower bacterial burden in their kidneys and joints compared with
      mice exposed to the wild parental strain. Notably, the hemB mutant produced
      almost 20 times more protease in vitro than the parental strain. We conclude that
      the small colony variants of S. aureus are more virulent on a per organism basis
      than its isogenic parental strain in the model of septic arthritis. This can at
      least in part be explained by the ability of SCV to produce high amounts of
      destructive proteases.

PMID- 12623276
TI  - Immunogenicity of a 16.7 kDa Mycobacterium paratuberculosis antigen.
AB  - Mycobacterium paratuberculosis (MPT), the agent of paratuberculosis is a slow
      growing mycobacteria that causes important economic losses mainly due to lower
      weight gains and drastic decrease in milk production. Existing paratuberculosis
      vaccines are not completely protective and induce antibodies/delayed type
      hypersensitivity (DTH) reaction that cannot be differentiated from those of
      naturally infected animals. New potent acellular vaccines that allow
      discrimination between infected and vaccinated animals are needed to improve the
      control of this disease. We have identified, expressed and purified a
      hypothetical thiol peroxidase of MPT (MPT-TP) in mice. We also characterized the
      immunogenicity of this antigen in mice. The recombinant MPT-TP (rMPT-TP) antigen
      induced a high production of IFNgamma, IL-6, and NO and a low production of IL-10
      by spleen cells of immunized mice. Addition of Ribi adjuvant to rMPT-TP resulted
      in lower IFNgamma secretion and higher NO production in spleen cells. A similar
      level of proliferation of spleen cells exposed to rMPT-TP was found in immunized
      groups (rMPT-TP and rMPT-TP emulsified in Ribi). DTH responses in mice footpads
      were observed only in mice immunized with rMPT-TP emulsified in Ribi. Addition of
      Ribi adjuvant clearly induced a significantly higher anti-rMPT-TP antibody
      production of all classes tested and decreased the IgG1/IgG2a ratio. MPT-TP
      demonstrated antigenic characteristics that make this antigen a potential
      component in the development of a future subunit vaccine against
      paratuberculosis.

PMID- 12623277
TI  - Uptake and cellular actions of mycolactone, a virulence determinant for
      Mycobacterium ulcerans.
AB  - Mycolactone is a macrolide secreted by Mycobacterium ulcerans. Experimental
      evidence suggests that mycolactone plays a prominent role in the pathogenesis of
      Buruli ulcer by causing both tissue destruction and immunosuppression. To
      understand the cell biology of mycolactone activity, we have synthesized the
      fluorescent mycolactone derivativebodipymycolactone. Although derivatization
      resulted in a modest decrease in cytopathic activity, the derivatized and native
      molecules produce identical phenotypes in cultured cells. Confocal microscopy of
      bodipymycolactone added to cultured fibroblasts, shows that it is localized to
      the cytosol. Bodipymycolactone fails to bind to the cell membrane and is excluded
      from the nucleus. Uptake is both nonsaturable and noncompetitive with excess
      mycolactone, consistent with passive diffusion of this toxin through the cell
      membrane. These facts, combined with the inability of signal transduction
      inhibitors to inhibit mycolactone cytopathicity point towards the presence of an
      cytosolic target for mycolactone.A dose dependent increase in intracellular
      calcium levels at occurs upon mycolactone exposure, but chelation of
      intracellular calcium alters neither the cytopathicity nor the caspase induction
      profile of treated cells. Mitochondrial polarization is maintained in treated
      cells for up to 3 days arguing that the rise in intracellular calcium levels may
      be a result of cytoskeletal remodeling.

PMID- 12623278
TI  - Role of complement C5 and T lymphocytes in pathogenesis of disseminated and
      mucosal candidiasis in susceptible DBA/2 mice.
AB  - The aims of the study were to compare the pathogenesis of Candida albicans
      infection in various organs and anatomical regions of C5-deficient (DBA/2) and C5
      sufficient (BALB/c) mice, and to evaluate the importance of complement C5 and T
      lymphocytes as factors that determine host susceptibility or resistance. The
      kidneys of DBA/2 mice showed higher colonisation and more severe tissue damage
      than those of BALB/c, but infection at other sites, including oral and vaginal
      mucosa, was generally similar in the two strains. Passive transfer of C5
      sufficient serum into DBA/2 mice decreased the fungal burden in the kidney, and
      prolonged survival of the reconstituted animals. Depletion of CD4(+) and/or
      CD8(+) cells did not exacerbate either systemic or mucosal infection when
      compared to controls, and passive transfer of splenocytes from infected donors
      caused only a small and transient reduction in numbers of yeasts recovered from
      the kidney of sub-lethally infected recipients. It is concluded that the acute
      susceptibility of the kidneys in this mouse strain is due to C5 deficiency
      expressed on a susceptible genetic background. T lymphocytes, however, appear to
      have minimal influence on recovery from systemic infection with this isolate of
      C. albicans.

PMID- 12623279
TI  - The hitchhiker's guide to altruism: gene-culture coevolution, and the
      internalization of norms.
AB  - An internal norm is a pattern of behavior enforced in part by internal sanctions,
      such as shame, guilt and loss of self-esteem, as opposed to purely external
      sanctions, such as material rewards and punishment. The ability to internalize
      norms is widespread among humans, although in some so-called "sociopaths", this
      capacity is diminished or lacking. Suppose there is one genetic locus that
      controls the capacity to internalize norms. This model shows that if an internal
      norm is fitness enhancing, then for plausible patterns of socialization, the
      allele for internalization of norms is evolutionarily stable. This framework can
      be used to model Herbert Simon's (1990) explanation of altruism, showing that
      altruistic norms can "hitchhike" on the general tendency of internal norms to be
      personally fitness-enhancing. A multi-level selection, gene-culture coevolution
      argument then explains why individually fitness-reducing internal norms are
      likely to be prosocial as opposed to socially harmful.

PMID- 12623280
TI  - Application of a single-solute non-steady-state phloem model to the study of long
      distance assimilate transport.
AB  - A mass-balanced, finite-difference solution to Munch's osmotically generated
      pressure-flow hypothesis is developed for the study of non-steady-state sucrose
      transport in the phloem tissue of plants. Major improvements over previous
      modeling efforts are the inclusion of wall elasticity, nonlinear functions of
      viscosity and solute potential, an enhanced calculation of sieve pore resistance,
      and the introduction of a slope-limiting total variation diminishing method for
      determining the concentration of sucrose at node boundaries. The numerical
      properties of the model are discussed, as is the history of the modeling of
      pressure-driven phloem transport. Idealized results are presented for a sharp,
      fast-moving concentration front, and the effect of changing sieve tube length on
      the transport of sucrose in both the steady-state and non-steady-state cases is
      examined. Most of the resistance to transport is found to be axial, rather than
      radial (via membrane transport), and most of the axial resistance is due to the
      sieve plates. Because of the sieve plates, sieve tube elasticity does not provide
      a significant enhancement to conductivity at high pressure, as previously
      suspected. The transit time of sucrose through a sieve tube is found to be
      inversely proportional to the square of the sieve tube's length; following that
      observation, it is suggested that 20 1-m-long sieve tubes could transport sucrose
      20 times faster than a single 20 m sieve tube. Short sieve tubes would be highly
      sensitive to differentials between loading and unloading rate, and would require
      close cooperation with adjacent companion cells for proper function.

PMID- 12623281
TI  - Characterization of a branch of the phylogenetic tree.
AB  - We use a combination of analytic models and computer simulations to gain insight
      into the dynamics of evolution. Our results suggest that certain interesting
      phenomena should eventually emerge from the fossil record. For example, there
      should be a "tortoise and hare effect": those genera with the smallest species
      death rate are likely to survive much longer than genera with large species birth
      and death rates. A complete characterization of the behavior of a branch of the
      phylogenetic tree corresponding to a genus and accurate mathematical
      representations of the various stages are obtained. We apply our results to
      address certain controversial issues that have arisen in paleontology such as the
      importance of punctuated equilibrium and whether unique Cambrian phyla have
      survived to the present.

PMID- 12623282
TI  - Chlorophyll a fluorescence rise induced by high light illumination of dark
      adapted plant tissue studied by means of a model of photosystem II and
      considering photosystem II heterogeneity.
AB  - Chlorophyll a fluorescence rise (FLR) measured in vivo in dark-adapted plant
      tissue immediately after the onset of high light continuous illumination shows
      complex O-K-J-I-P transient. The steps typically appear at about 400 micros (K),
      2 ms (J), 30 ms (I), and 200 - 500 ms (P) and a transient decrease of
      fluorescence to local minima (dips D) can be observed after the K, J, and I
      steps. As the FLR reflects a function of photosystem II (PSII) and to more
      understand the FLR, a PSII reactions model was formulated comprising equilibrium
      of excited states among all light harvesting and reaction centre pigments and
      P680, reversible radical pair formation and the donor and acceptor side
      functions. Such a formulated model is the most detailed and complex model of PSII
      reactions used so far for simulations of the FLR. By varying of selected model
      parameters (rate constants and initial conditions) several conclusions can be
      made as for the origin of and changes in shape of the theoretical FLR and compare
      them with in-literature-reported results. For homogeneous population of PSII and
      using standard in-literature-reported values of the model parameters, the
      simulated FLR is characterized by reaching the minimal fluorescence F(0) at about
      3 ns after the illumination is switched on lasting to about 1 micros, followed by
      fluorescence rise to a plateau located at about 2 ms and subsequent fluorescence
      rise to a global maximum that is reached at about 60 ms. Varying of the values of
      rate constants of fast processes that can compete for utilization of the excited
      states with fluorescence emission does not change qualitatively the shape of the
      FLR. However, primary photochemistry of PSII (the charge separation,
      recombination and stabilization), non-radiative loss of excited states in light
      harvesting antennae and excited states quenching by oxidized plastoquisnone (PQ)
      molecules from the PQ pool seem to be the main factors controlling the maximum
      quantum yield of PSII photochemistry as expressed by the F(V)/F(M) ratio. The
      appearance of the plateau at about 2 ms in the FLR is affected by several
      factors: the height of the plateau in the FLR increases when the fluorescence
      quenching by oxidized P680(+) is not considered in the simulations or when the
      electron transfer from Q(A)(-) to Q(B)((-)) is slowed down whereas the height of
      the plateau decreases and its position is shifted to shorter times when OEC is
      initially in higher S state. The plateau at about 2 ms is changed into the local
      fluorescence maximum followed by a dip when the fluorescence quenching by
      oxidized PQ molecules or the charge recombination between P680(+) and Q(A)(-) is
      not considered in the simulations or when all OEC is initially in the S(0) state
      or when the S -state transitions of OEC are slowed down. Slowing down of the S 
      state transitions of OEC as well as of the electron transfer from Q(A)(-) to
      Q(B)((-)) also causes a decrease of maximal fluorescence level. In the case of
      full inhibition of the S -state transitions of OEC as well as in the case of full
      inhibition of the electron donation to P680(+) by Y(Z), the local fluorescence
      maximum becomes the global fluorescence maximum. Assuming homogeneous PSII
      population, theoretical FLR curve that only far resembles experimentally measured
      O-J-I-P transient at room temperature can be simulated when slowly reducing PQ
      pool is considered. Assuming heterogeneous PSII population (i.e. the alpha/beta
      and the Q(B) -reducing/Q(B)-non-reducing heterogeneity and heterogeneity in size
      of the PQ pool and rate of its reduction) enables to simulate the FLR with two
      steps between minimal and maximal fluorescence whose relative heights are in
      agreement with the experiments but not their time positions. A cause of this
      discrepancy is discussed as well as different approaches to the definition of
      fluorescence signal during the FLR.

PMID- 12623283
TI  - Quasi-independence, homology and the unity of type: a topological theory of
      characters.
AB  - In this paper Lewontin's notion of "quasi-independence" of characters is
      formalized as the assumption that a region of the phenotype space can be
      represented by a product space of orthogonal factors. In this picture each
      character corresponds to a factor of a region of the phenotype space. We consider
      any region of the phenotype space that has a given factorization as a "type",
      i.e. as a set of phenotypes that share the same set of phenotypic characters.
      Using the notion of local factorizations we develop a theory of character
      identity based on the continuation of common factors among different regions of
      the phenotype space. We also consider the topological constraints on evolutionary
      transitions among regions with different regional factorizations, i.e. for the
      evolution of new types or body plans. It is shown that direct transition between
      different "types" is only possible if the transitional forms have all the
      characters that the ancestral and the derived types have and are thus compatible
      with the factorization of both types. Transitional forms thus have to go over a
      "complexity hump" where they have more quasi-independent characters than either
      the ancestral as well as the derived type. The only logical, but biologically
      unlikely, alternative is a "hopeful monster" that transforms in a single step
      from the ancestral type to the derived type. Topological considerations also
      suggest a new factor that may contribute to the evolutionary stability of
      "types". It is shown that if the type is decomposable into factors which are
      vertex irregular (i.e. have states that are more or less preferred in a random
      walk), the region of phenotypes representing the type contains islands of
      strongly preferred states. In other words types have a statistical tendency of
      retaining evolutionary trajectories within their interior and thus add to the
      evolutionary persistence of types.

PMID- 12623284
TI  - Bioinformatic principles underlying the information content of transcription
      factor binding sites.
AB  - Empirically, it has been observed in several cases that the information content
      of transcription factor binding site sequences (R(sequence)) approximately equals
      the information content of binding site positions (R(frequency)). A general
      framework for formal models of transcription factors and binding sites is
      developed to address this issue. Measures for information content in
      transcription factor binding sites are revisited and theoretic analyses are
      compared on this basis. These analyses do not lead to consistent results. A
      comparative review reveals that these inconsistent approaches do not include a
      transcription factor state space. Therefore, a state space for mathematically
      representing transcription factors with respect to their binding site recognition
      properties is introduced into the modelling framework. Analysis of the resulting
      comprehensive model shows that the structure of genome state space favours
      equality of R(sequence) and R(frequency) indeed, but the relation between the two
      information quantities also depends on the structure of the transcription factor
      state space. This might lead to significant deviations between R(sequence) and
      R(frequency). However, further investigation and biological arguments show that
      the effects of the structure of the transcription factor state space on the
      relation of R(sequence) and R(frequency) are strongly limited for systems which
      are autonomous in the sense that all DNA-binding proteins operating on the genome
      are encoded in the genome itself. This provides a theoretical explanation for the
      empirically observed equality.

PMID- 12623286
TI  - Criteria for selection and application of molecular markers for clinical studies
      of osteoarthritis.
AB  - OBJECTIVE: To develop criteria for the selection and application of molecular
      markers for the study of osteoarthritis (OA). METHODS: Statistical criteria for
      marker selection for OA are developed. RESULTS AND CONCLUSIONS: After studying
      more than 20 different molecular markers for monitoring OA, procedures for
      choosing markers for clinical studies have been developed. For a particular
      study, the process starts with the markers showing 'face-validity' for monitoring
      OA. They are next required to successfully distinguish OA patients from controls.
      This necessitates definition of the distribution of marker values in OA patients
      and controls. So far, they have been consistently log-normal. The difference
      (Delta) in marker values between OA and controls defines the opportunity for
      marker improvement. The between-visit standard deviation (S) in patients puts
      limits on the detection of marker changes. The two variables can be combined to
      estimate the practicality of a marker using a modified power analysis. The number
      of patients (N*) required to observe a 50% improvement with an alpha level of
      P=0.05 and with 80% certainty is estimated as 50(S/Delta)(2). N*, S and Delta
      should be used to characterize and compare markers. Marker efficiency can be
      refined by regressing on secondary variables, such as age, sex, BMI, severity,
      etc. Finally, the use of two or more markers may be required to improve marker
      prediction of clinical outcome. Correlated markers can be used to reinforce
      conclusions by essentially adding replicative data. Independent, complementary
      markers can be used to develop associations with clinical parameters, and perhaps
      diagnose and monitor disease status, activities that so far have not been
      possible with single markers.

PMID- 12623285
TI  - Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic
      dosing and its antiangiogenic basis.
AB  - The general utility of the maximum tolerated dose (MTD) paradigm, a strategy
      aimed at optimizing the chance of total tumor cell eradication, is here
      questioned. Evidence to date suggests that for many tumors the potential for
      eradication is in fact remote, with patients consistently demonstrating tumor
      cell presence subsequent to MTD treatments having eradicative intent. The failure
      to eradicate is attributed largely to the heterogeneous nature of the tumor.
      Heterogeneous cell populations demonstrate short-term refractoriness to up-front
      dose delivery, but "resensitize" as part of dose recovery, showing increased
      overall susceptibility to a given series of doses when delivered more evenly
      spaced. It is demonstrated: (1) that the minimization of total tumor burden,
      rather than complete eradication, may often be the more practical objective; and
      (2) that regularly spaced, "metronomic" dosing is the best way to achieve it. As
      a corollary, it is found that the more efficient ability of the tumor endothelial
      cells to resensitize following dosing predicts a targeting bias towards the
      endothelial compartment of a tumor when metronomic dosing is employed. This lends
      theoretical support to recent empirical studies showing that regularly spaced
      dosing schedules with no extended rest periods act more antiangiogenically,
      thereby delaying or avoiding the onset of acquired resistance.

PMID- 12623287
TI  - Malondialdehyde oxidation of cartilage collagen by chondrocytes.
AB  - OBJECTIVE: The damage to cartilage collagen is a central event in the
      pathogenesis of cartilage aging and osteoarthritis (OA). We have previously
      developed an in vitro model of cartilage degradation which shows that chondrocyte
      dependent lipid peroxidation mediates cartilage collagen degradation. The goal of
      our study was to investigate the role of vitamin C in this degradation model and
      to investigate effect of chondrocyte-dependent lipid peroxidation in the
      oxidation of cartilage collagen. METHODS: We studied primary articular
      chondrocytes. Effect of vitamin C was investigated in the previously described
      model. Serum-free stimulated and unstimulated chondrocyte-matrix extracts were
      subjected to SDS-PAGE and immunoblot analysis. Malondialdehyde (MDA)-protein
      oxidation of cartilage proteins was demonstrated by the reactivity of chondrocyte
      extracts to a monoclonal antibody, MDA2, which detects MDA-lysine adducts.
      RESULTS: Vitamin C treatment of chondrocyte cultures resulted in significant
      enhanced incorporation of 3H-proline label in cell-matrix. Cells treated with
      vitamin C, as compared to control untreated cells showed decreased spontaneous
      release of labeled matrix. Vitamin C treated or not treated chondrocytes
      responded comparably to stimulation with the agonist calcium ionophore A23187.
      The serum-free in vitro culture of chondrocytes resulted in MDA-protein
      oxidation. The treatment of chondrocytes with A23187 resulted in the enhancement
      of MDA-protein oxidation. The immunoblot reactivity pattern of extracts to MDA2
      antibody and to polyclonal anti-type II collagen antibody was somewhat similar,
      which suggests that these two different types of antisera exhibit a crossreaction
      to chondrocyte proteins. Chondrocyte extracts were pretreated both with and
      without pure collagenase, and then subjected to immunoblot analysis. Only
      collagenase treated extracts showed a disappearance, or significant reduction, of
      larger than 60 kDa size MDA2 immunoreactive proteins. This suggests that the
      proteins that disappeared after the enzyme treatment were collagen proteins and
      which had also been modified by MDA oxidation. CONCLUSIONS: These observations
      suggest that collagen hydroxylation of matrix by vitamin C does not play a role
      in this model of chondrocyte-dependent collagen degradation. Also, this study
      demonstrates that chondrocyte-derived lipid peroxidation product MDA mediates
      oxidation of cartilage collagens. Oxidative modification of cartilage collagen in
      vivo could result in alteration of biochemical and biophysical properties of
      cartilage collagen fibrils, making them prone to degradation, thus initiating the
      changes observed in aging and OA.

PMID- 12623288
TI  - TGF beta 1 and biglycan, decorin, and fibromodulin metabolism in canine
      cartilage.
AB  - OBJECTIVE: Small proteoglycans (PGs) may accumulate in late stage osteoarthritis
      even as aggrecan is lost. It is not clear what role transforming growth factor
      (TGF) beta has in this accumulation. Our goal was to investigate the ability of
      TGF beta 1 to modulate the synthesis and accumulation of decorin, biglycan, and
      fibromodulin in cartilage explants cultured under conditions in which aggrecan
      synthesis remains relatively constant. DESIGN: Articular cartilage was cultured
      in the presence or absence of 4 ng/ml TGF beta 1 for up to 16 days. Material
      extracted from cartilage was assayed for 35SO(4)-large and small PGs and for
      total endogenous decorin, biglycan and fibromodulin. RESULTS: The synthesis of
      35SO(4)-small PGs increased during the 16 days in culture in response to TGF beta
      1, but declined in control cultures. The difference in 35SO(4)-decorin between
      TGF beta 1 and control samples reached nine-fold after 16 days, while the
      difference in total endogenous decorin was less than 1.5-fold. 35SO(4)-decorin,
      which was present in TGF beta 1-treated cultures had an identical core protein,
      but a longer glycosaminoglycan chain than that of decorin in control cultures. No
      significant differences in endogenous biglycan were detected, but accumulation of
      fibromodulin in TGF beta 1 explants exceeded fibromodulin in controls, on
      average, by 3.8-fold. Fibromodulin was present in cartilage in both keratan
      sulfate- and non-sulfated oligosaccharide-substituted forms. CONCLUSIONS: The
      accumulation of each of the three small PGs was affected to a different extent in
      response to TGF beta 1. Of the three, fibromodulin content was most rapidly
      augmented in response to TGF beta 1.

PMID- 12623289
TI  - High molecular weight hyaluronan promotes repair of IL-1 beta-damaged cartilage
      explants from both young and old bovines.
AB  - OBJECTIVE: The addition of exogenous high molecular weight hyaluronic acid (HA)
      reverses cartilage damage caused by fibronectin fragments (Fn-fs) added to
      explant cultures of bovine and human cartilage and by Fn-fs in an experimental in
      vivo model of rabbit knee joint damage. Our objective was to test whether HA was
      also effective in an IL-1 damage model and whether this repair was stable and
      occurred in older bovine cartilage. DESIGN: Bovine cartilage explants from 18
      month-old or 6-year-old bovines in 10% serum/Dulbecco's modified Eagle's medium
      were exposed to Fn-f or to IL-1 and the ability of 1mg/ml HA of 800 kDa to block
      damage or promote restoration of proteoglycan (PG) after the damage was measured.
      The damage phase as well as the exposure to HA were varied. RESULTS: Exposure of
      exogenous HA decreased Fn-f-mediated damage, but did not decrease IL-1 beta
      induced cartilage damage. If explants from 18-month-old bovines were damaged by a
      7-day exposure to Fn-f or IL-1 beta and then exposed for 7 days to HA, PG was
      restored. This reparative activity persisted up to 4 weeks after the removal of
      HA from the culture medium. The restoration of PG did not occur in 0.1% serum
      free cultures, was less when the exposure to the Fn-f was doubled and failed when
      exposure to IL-1 beta was doubled. In explants from 6-year-old bovines damaged
      with IL-1 beta for 7 days, HA fully restored PG content to normal levels.
      CONCLUSIONS: The reparative activities of HA occur not only in a Fn-f damage
      model, but also in an IL-1 damage model and occur with older bovine cartilage.

PMID- 12623290
TI  - Hypo-osmotic stress induces calcium-dependent actin reorganization in articular
      chondrocytes.
AB  - OBJECTIVE: The aim of this study was to investigate the effects of hypo
      osmotically induced calcium (Ca(2+)) transients on the organization of the actin
      cytoskeleton in articular chondrocytes. The secondary hypothesis tested was that
      actin restructuring following hypo-osmotic stress is mediated by gelsolin.
      METHODS: Isolated porcine chondrocytes were exposed to hypo-osmotic stress, and
      [Ca(2+)](i)was monitored using laser scanning microscopy. Calcium transients were
      monitored using fluorescent ratiometric imaging. The intracellular distribution
      of actin was examined using fluorescent immunohistochemistry and transient
      transfection with the pEGFP-actin plasmid. The intracellular distribution of
      gelsolin was investigated using fluorescent immunohistochemistry. RESULTS:
      Osmotic stress induced transient increases in [Ca(2+)](i)caused reorganization of
      intracellular actin through a mechanism that required Ca(2+)in the extracellular
      media. Fluorescence microscopy revealed that gelsolin was colocalized with F
      actin immediately following hypo-osmotic stress but dissociated over time.
      CONCLUSION: These results indicate that hypo-osmotic stress induces a gelsolin
      mediated reorganization of actin through a transient increase in [Ca(2+)](i).

PMID- 12623291
TI  - Arthroscopic evaluation of potential structure-modifying drug in osteoarthritis
      of the knee. A multicenter, randomized, double-blind comparison of tenidap sodium
      vs piroxicam.
AB  - OBJECTIVE: To test the hypothesis that tenidap has a structure-modifying effect
      in human knee osteoarthritis. DESIGN:  STUDY: multicenter, prospective,
      randomized, double blind, 1 year duration. PATIENTS: primary painful knee
      osteoarthritis (ACR criteria) of the medial tibiofemoral compartment, medial
      joint space width > or =2mm, at least 10% of one cartilage surface of the medial
      compartment affected by superficial fibrillation or worse at baseline
      arthroscopy. STUDY MEDICATION: once daily dosage of either tenidap 40 mg, tenidap
      120 mg or piroxicam 20mg. STUDY ENDPOINTS: bilateral extended weight-bearing X
      rays and knee arthroscopy under local anaesthesia were done at entry and after 1
      year. Joint space width was measured in millimeters at the narrowest point of the
      medial compartment. Chondropathy was scored by using reader's overall assessment
      (VAS score, 100mm) and Societe Francaise d'Arthroscopie (SFA) score (0-100).
      RESULTS: Patients (665) were randomized and 494 completed the study. After 1
      year, intra-group radiological changes and radiological difference between both
      tenidap groups and the piroxicam group did not reach statistical significance.
      The intra-group arthroscopic deterioration of chondropathy was low, but
      statistically significant in the three study groups. However, there was no
      statistically significant difference between both tenidap groups and the
      piroxicam group. CONCLUSIONS: This study failed to demonstrate any difference
      between the treatment arms with regard to the structural progression of medial
      knee osteoarthritis as measured by radiography and arthroscopy. Arthroscopy did,
      however, appears to be more sensitive in detecting disease progression than the
      weight-bearing radiographs with fully extended knees. This study shows that it is
      possible to complete a large international trial using arthroscopy as an outcome
      measure of articular cartilage.

PMID- 12623293
TI  - Topographic and zonal distribution of tenascin in human articular cartilage from
      femoral heads: normal versus mild and severe osteoarthritis.
AB  - OBJECTIVE: The extracellular matrix glycoprotein tenascin (TN) is upregulated in
      articular cartilage with severe osteoarthritis (OA). This study gives a detailed
      description of TN expression in areas of articular cartilage from femoral heads
      with mild OA showing structural lesions and in structurally normal areas of the
      same femoral heads compared with normal cartilage and cartilage with severe OA.
      METHODS: Immunohistochemical evaluation was performed on cryosections stained
      with antibodies against TN. Sections were selected as follows: from each
      macroscopically normal femoral head (n=6) a normal central and peripheral biopsy;
      from each femoral head with macroscopically mild OA (n=8) a central biopsy that
      showed structural lesions and a peripheral normal biopsy; from each femoral head
      with severe OA (n=9) a central and a peripheral biopsy with structural lesions.
      Central biopsies represent load bearing areas, whereas peripheral biopsies are
      non-load bearing. RESULTS: Central cartilage with mild OA contains significantly
      higher levels of TN in the superficial zone than structurally normal, peripheral
      cartilage from the same femoral heads. Normal cartilage and cartilage with severe
      OA do not display this topographic variation. Central cartilage with mild OA
      shows significantly higher levels of TN than normal, central cartilage.
      Peripheral, normal cartilage with mild OA shows significantly less TN than
      peripheral cartilage with severe OA. CONCLUSIONS: In femoral heads with mild OA,
      TN is accumulated in areas displaying structural damage. This proposes mild OA to
      be a localized disorder. Extreme caution is necessary for sampling of articular
      cartilage, especially from joints with mild OA.

PMID- 12623292
TI  - The effect of hyaluronan on CD44-mediated survival of normal and hydroxyl radical
      damaged chondrocytes.
AB  - OBJECTIVE: To identify the CD44-receptor-mediated effects of 5-7 x 10(5)MW
      hyaluronan (HA, Hyalgan) on cell viability in normal and damaged human
      chondrocyte primary cultures isolated from articular cartilage. DESIGN: Primary
      cultures of human chondrocytes were established from normal articular biopsies
      and expanded to the second culture passage. The dose-response effects of HA on
      the viability of normal cultures were identified. Chondrocytes were then treated
      with either hypoxanthine (2 mM) and xanthine oxidase (20-60 mU), or with
      activated polymorphonuclear leukocytes (PMNs) to induce injury. Damaged and
      control cells were then treated with 5-7 x 10(5)HA in the previously identified
      optimal dose of 0.05 mg/ml. Viability was assessed at specific time periods for
      the chemically and PMN-damaged cells. To identify if HA effects were mediated by
      the CD44 receptor, chondrocytes were incubated with anti-CD44 antibody at
      saturating concentrations (5 microg/ml for 100,000 cells) to produce a maximum
      inhibition of HA binding. Cells were evaluated using the MTT viability assay,
      histology, electron microscopy and immunohistochemistry. RESULTS: Direct addition
      of HA (optimal dose, 0.5 mg/ml) significantly increased cell survival in normal
      chondrocyte primary cultures (P<0.05). Similarly, addition of this same dose of
      HA to cultures of free radical-damaged chondrocytes, restored the viability to
      baseline conditions. Cell viability rates dropped significantly (P<0.05) when
      CD44 receptor binding was inhibited, indicating that cell growth was mediated by
      the CD44 receptor. CONCLUSIONS: HA (0.5 mg/ml of 5-7 x 10(5)) significantly
      increased the viability of normal human chondrocytes in primary culture and
      restored cell viability to near normal levels after oxidative cell injury.

PMID- 12623294
TI  - Chondroitin sulfate and other sulfate containing chondroprotective agents may
      exhibit their effects by overcoming a deficiency of sulfur amino acids.

PMID- 12623295
TI  - Sulfhydryl modulation of K+ currents: a possible cross-link between oxidative
      stress and altered cardiovascular function.

PMID- 12623296
TI  - Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and
      failure.
AB  - Altered intracellular Na(+) ([Na(+)](i)) is a potentially important factor in the
      functional adaptation of the hypertrophied and failing heart. We review the
      currently reported changes in [Na(+)](i) and Na(+) transport in different models
      of cardiac hypertrophy and heart failure. Direct measurements are limited, but
      most of these indicate that there is a rise in [Na(+)](i), in particular in
      hypertrophy. In addition to these direct measurements, several studies report a
      rise in Na(+) influx or an upregulation of Na(+) influx transporters. The most
      extensive literature on Na(+) regulating pathways concerns the Na/K-ATPase. Total
      Na/K-ATPase activity decreases in most models of cardiac hypertrophy and failure,
      though few measurements were actually performed in intact cells. This decrease
      can been related to a selective reduction of high-affinity (for cardiac
      glycosides) Na/K pump alpha-isoforms, across many species and models, including
      human heart failure. We have used these data to predict changes of [Na(+)](i) in
      a simulation model, varying the contribution of total Na/K pump capacity and
      expression of isoforms with different Na(+)(i) affinities, and varying Na(+)
      influx. A rise in Na(+) in cardiac hypertrophy and failure may improve systolic
      contractile function, though at the cost of worsening of diastolic function and
      increased risk of ventricular arrhythmias. The benefit of further increasing
      [Na(+)](i,) e.g. with cardiac glycosides, is thus compromised. Future therapies
      may include selective isoform blockers, which could raise [Na(+)](i) in
      restricted subcellular compartments, drug associations that reduce the arrhythmic
      risk, or even drugs that lower [Na(+)](i) and thus interfere with the remodelling
      pathways.

PMID- 12623297
TI  - Structural determinants and biophysical properties of HERG and KCNQ1 channel
      gating.
AB  - The delayed rectifier K(+) currents, I(Kr) and I(Ks,) play a critical role in
      modulating the plateau phase of the cardiac action potential. HERG encodes the
      alpha-subunit of channels underlying I(Kr), while I(Ks) is composed of subunits
      encoded by KCNQ1 and KCNE1. Mutations in any of these genes cause the long QT
      syndrome, a disorder of myocellular repolarization that predisposes affected
      individuals to life-threatening arrhythmias. Elucidation of the molecular basis
      of these currents has led to significant advancements in our understanding of
      fundamental properties of channel function. This review summarizes the current
      state of knowledge regarding the structural determinants and biophysical
      properties of HERG and KCNQ1 channels.

PMID- 12623298
TI  - Ion channel macromolecular complexes in the heart.
AB  - The response to extracellular signals by ion channels requires the activity of
      several protein kinases and phosphatases to catalyze reversible
      phosphorylation/dephosphorylation events. The specificity of these events is
      governed in part, by subcellular targeting of distinct pools of kinases and
      phosphatases as well as their regulation by anchoring proteins. In several cases,
      multiple kinase and phosphatase anchoring proteins are bound to an ion channel,
      which permits rapid and specific regulation of the phosphorylation and
      dephosphorylation events. Recently, the role of kinase and phosphatase anchoring
      proteins has been elucidated in various tissues, including the brain and the
      heart. This review summarizes the recent findings related to the concept of ion
      channel phosphorylation modulatory targeting proteins in the heart through the
      formation of macromolecular complexes.

PMID- 12623299
TI  - Enhanced cell volume regulation: a key protective mechanism of ischemic
      preconditioning in rabbit ventricular myocytes.
AB  - Accumulation of osmotically active metabolites, which create an osmotic gradient
      estimated at ~60 mOsM, and cell swelling are prominent features of ischemic
      myocardial cell death. This study tests the hypothesis that reduction of ischemic
      swelling by enhanced cell volume regulation is a key mechanism in the delay of
      ischemic myocardial cell death by ischemic preconditioning (IPC). Experimental
      protocols address whether: (i) IPC triggers a cell volume regulation mechanism
      that reduces cardiomyocyte swelling during subsequent index ischemia; (ii) this
      reduction in ischemic cell swelling is sufficient in magnitude to account for the
      IPC protection; (iii) the molecular mechanism that mediates IPC also mediates
      cell volume regulation. Two experimental models with rabbit ventricular myocytes
      were studied: freshly isolated pelleted myocytes and 48-h cultured myocytes.
      Myocytes were preconditioned either by distinct short simulated ischemia
      (SI)/simulated reperfusion protocols (IPC), or by subjecting myocytes to a
      pharmacological preconditioning (PPC) protocol (1 microM calyculin A, or 1 microM
      N(6)-2-(4-aminophenyl)ethyladenosine (APNEA), prior to subjecting them to either
      different durations of long SI or 30 min hypo-osmotic stress. Cell death (percent
      blue square myocytes) was monitored by trypan blue staining. Cell swelling was
      determined by either the bromododecane cell flotation assay (qualitative) or
      video/confocal microscopy (quantitative). Simulated ischemia induced myocyte
      swelling in both the models. In pelleted myocytes, IPC or PPC with either
      calyculin A or APNEA produced a marked reduction of ischemic cell swelling as
      determined by the cell floatation assay. In cultured myocytes, IPC substantially
      reduced ischemic cell swelling (P < 0.001). This IPC effect on ischemic cell
      swelling was related to an IPC and PPC (with APNEA) mediated triggering of cell
      volume regulatory decrease (RVD). IPC and APNEA also significantly (P < 0.001)
      reduced hypo-osmotic cell swelling. This IPC and APNEA effect was blocked by
      either adenosine receptor, PKC or Cl(-) channel inhibition. The osmolar
      equivalent for IPC protection approximated 50-60 mOsM, an osmotic gradient
      similar to the estimated ischemic osmotic load for preconditioned and non
      preconditioned myocytes. The results suggest that cell volume regulation is a key
      mechanism that accounts for most of the IPC protection in cardiomyocytes.

PMID- 12623300
TI  - Chronic inhibition of Rho kinase blunts the process of left ventricular
      hypertrophy leading to cardiac contractile dysfunction in hypertension-induced
      heart failure.
AB  - The Gq-RhoA-Rho kinase pathway, activated by neurohormonal factors such as
      angiotensin II (Ang II), has been proposed to be one of the important signaling
      pathways involved in the progression of left ventricular (LV) hypertrophy to
      heart failure. We tested the hypothesis that chronic inhibition of Rho kinase
      prevents this process. Heart failure was induced in Dahl salt-sensitive (DS) rats
      fed an 8% NaCl diet from 8 until 17 weeks of age. Y-27632 (5 mg/kg per day), a
      selective Rho kinase inhibitor, was applied orally to DS rats starting at 10
      weeks of age for 7 weeks (DS/Y+). DS rats without Y-27632 (DS/Y-) and Dahl salt
      resistant (DR) rats fed the 8% NaCl diet were regarded as non-therapeutic and
      normotensive controls, respectively. At 17 weeks of age, there was no significant
      difference in the blood pressure of DS/Y- and DS/Y+ rats. DS/Y- rats exhibited:
      (1) increases in LV mass, cross-sectional area (CSA) of cardiomyocytes, and
      interstitial fibrosis; (2) contractile dysfunction, i.e. decreases in LV ejection
      fraction and % fractional shortening, and prolongation of time to peak tension as
      well as to 50% relaxation in the twitch contraction of isolated papillary muscle;
      and (3) increases in the protein expression of Galphaq and Rho kinase in the
      myocardial membrane fraction. In DS/Y+ rats, the degree of myocardial hypertrophy
      was significantly inhibited in association with improved contractile function,
      without a decrease in the degree of interstitial fibrosis. Our results suggest
      the possibility that the Gq-Rho kinase pathway plays an important role in the
      process of hypertension-induced LV hypertrophy leading to contractile
      dysfunction.

PMID- 12623301
TI  - Modulation of myocardial contractility by lysophosphatidic acid (LPA).
AB  - Lysophosphatidic acid (LPA) is a phospholipid messenger, which is released from
      activated platelets and leukocytes. This study examined the effects of LPA on
      myocardial contractility and characterized the signal transduction pathway
      involved in these effects. Functional effects of LPA were determined in isolated,
      electrically driven human myocardial preparations and rat cardiac myocytes. In
      human atrial and ventricular myocardial preparations, LPA (100 micromol/l)
      decreased isoprenaline (0.03 micromol/l) enhanced force of contraction by 17 +/-
      2% and 28 +/- 3%, respectively. The effect of LPA was attenuated by suramin (1
      mmol/l). In isolated rat cardiomyocytes, LPA (1-100 micromol/l) concentration
      dependently abolished isoprenaline (0.03 micromol/l) induced increase in cell
      shortening. This antiadrenergic effect was blunted after pretreatment with
      pertussis toxin (5 microg/ml, 12 h). Forskolin (10 micromol/l) stimulated
      adenylyl cyclase activity was inhibited by LPA in human myocardial membranes. PCR
      analysis of human atrial and ventricular cDNAs revealed the expression of two
      cognate LPA receptors: EDG-2 and EDG-7. Our results suggest that LPA exerts
      antiadrenergic effects on force of contraction in human and rodent myocardium via
      a Galpha(i/o) protein-mediated mechanism, most probably by LPA binding to the
      mammalian LPA receptors EDG-2 and/or EDG-7. This newly discovered action of LPA
      might be of pathophysiological importance in conditions like myocardial ischemia
      or inflammatory disorders when LPA release is enhanced.

PMID- 12623302
TI  - Role of cyclooxygenase 2, p38 and p42/44 MAPK in the secretion of prostacyclin
      induced by epidermal growth factor, endothelin-1 and angiotensin II in rat
      ventricular cardiomyocytes.
AB  - We studied the respective roles of cyclooxygenases (COX) isoforms as well as the
      p38 and p42/44 MAP kinase cascades in angiotensin II (AngII)-, endothelin-1 (ET
      1)- and epidermal growth factor (EGF)-induced prostacyclin (PGI(2)) secretion in
      neonatal rat ventricular cardiomyocytes. Exposure of these cells for 1 h to 100
      nM AngII, ET-1 or EGF resulted in an increase in prostacyclin formation which was
      abolished by the COX-2 specific inhibitor NS-398 (1 microM), while the COX-1
      inhibitor valeryl salicylate (5 microM) had no effect. Agonist-induced
      prostacyclin secretion was also abolished in the presence of cycloheximide (10
      microg/ml), indicating that newly synthesized proteins are necessary for this
      response. In this context, the COX-2 protein amount was significantly increased
      following 1 h incubation of cardiomyocytes, with AngII, ET-1 and EGF. These
      results indicate that in cardiomyocytes AngII, ET-1 and EGF induce both the
      synthesis and the activity of COX-2. Investigating the role of MAPK in the
      stimulation of prostacyclin induced by these three agonists, we found that both
      the p42/44 MAPK inhibitor PD 98059 (50 microM) and the p38 MAPK blocker SB 203580
      (5 microM) prevented agonist-induced PGI(2) secretion without affecting COX-2
      activity or synthesis. Our results show that p42/44 and p38 MAPK activation is at
      the basis of AngII-, ET-1- and EGF-induced prostacyclin secretion in
      cardiomyocytes. They further suggest that these MAPK act on a target(s) located
      upstream of COX-2.

PMID- 12623303
TI  - Myosin from failing and non-failing human ventricles exhibit similar contractile
      properties.
AB  - In non-failing human myocardium, V1 myosin comprises a small amount (<10%) of the
      total myosin content, whereas end-stage failing hearts contain nearly 100% V3
      myosin. It has been suggested that this shift in V1 myosin isoform content may
      contribute to the contractile deficit in human myocardial failure. To test this
      hypothesis, myosin was isolated from human failing and non-failing ventricles,
      and non-failing atria. Performance was assessed in in vitro motility and
      isometric force assays. Consistent with prior reports, a small amount of V1
      myosin was present in both non-failing (6.2 +/- 1.0%) and failing (3.5 +/- 1.4%)
      ventricular tissues. No difference in isometric force or unloaded shortening
      velocity was observed for failing and non-failing ventricular myosin irrespective
      of myosin isoform content. Atrial tissue expressing predominantly V1 myosin (66.7
      +/- 4.1%) generated half the force but greater velocity compared with ventricular
      tissue, expressing predominantly V3 myosin. In additional experiments, rabbit
      cardiac myosin was used in a calcium regulated assay system to determine if V1
      and V3 isoforms differentially affect thin filament activation. Half-maximal
      calcium activation was similar for the two cardiac isoforms. A 1:9 mixture of
      V1/V3 myosin, simulating isoform composition in non-failing human myocardium, was
      indistinguishable from 100% V3 myosin (simulating the failing state) with regard
      to velocity of shortening and average force. These data suggest that the myosin
      isoform shift reported in human myocardial failure does not significantly
      contribute to the contractile deficit of this disease.

PMID- 12623304
TI  - Transfection with 5-HT1A receptor gene and antisense directed against muscarinic
      M2 receptors reveal a mutual influence between Gi/o-coupled receptors in rat
      atrial myocytes.
AB  - A recently described reduction in sensitivity of G protein-activated inward
      rectifying K(+) (GIRK) channels to stimulation of muscarinic M(2) receptors
      (M(2)AChR) in atrial myocytes overexpressing purinergic A(1) receptors (A(1)AdoR)
      was further investigated by heterologous expression of a 5-HT(1A) receptor (5
      HT(1A)R) and by reducing the expression level of endogenous M(2)AChR receptors
      using antisense. In 5-HT(1A)R-expressing myocytes, in line with previous studies,
      sizable GIRK currents could be activated by 5-HT. In these cells, the mean
      current density and activation rate of M(2)AChR-activated current were
      significantly reduced, supporting the notion that signalling via this receptor is
      negatively regulated by other G protein-coupled receptors (GPCR) coupling to the
      same class (G(i/o)) of G proteins. To study if reducing M(2)AChR expression
      affects sensitivity of GIRK current to stimulation of A(1)AdoR, antisense
      oligodinucleotides (AsODN) against the M(2)AChR were used. Incubation of myocytes
      with M(2)AChR-specific AsODN resulted in a significant reduction in mean
      amplitude and activation rate of ACh-induced currents. This was paralleled by an
      increase in mean amplitude and activation rate of current activated by
      stimulation of A(1)AdoR. Plotting amplitudes of 5-HT- or Ado-induced currents
      from individual manipulated cells against the amplitude of ACh-induced current
      yielded a positive correlation between these data. Although difficult to
      interpret in mechanistic terms, this argues against a competition of receptors
      for a common pool of G(i/o). The mutual interaction between G(i/o)-coupled
      receptors depends on manipulation of the expression level, since long-term
      desensitization or down regulation of M(2)AChR by treatment with carbachol did
      not affect sensitivity of GIRK current to A(1)AdoR stimulation, despite a
      substantial reduction in amplitude and activation rate of M(2)AChR-activated
      currents. These data suggest a novel crosstalk between parallel receptors
      converging on the same class of G proteins.

PMID- 12623305
TI  - Effects of amlodipine, atorvastatin and combination of both on advanced
      atherosclerotic plaque in APOE*3-Leiden transgenic mice.
AB  - Combined treatment of statins and calcium channel blockers has been suggested to
      be superior to statin therapy alone. We quantified the anti-atherosclerotic
      potential of amlodipine, atorvastatin and their combination on existing
      atherosclerotic plaques in the aorta of APOE*3-Leiden transgenic mice. Sixty-two
      mice were fed a high cholesterol containing diet for 18 weeks. A subgroup of 10
      mice was then killed. All other mice received the diet for another 18 weeks,
      alone (late control group), along with 0.01% atorvastatin, 0.002% w/w amlodipine,
      or their combination (all groups, n = 13). Atherosclerotic lesions, collagen
      content and monocyte adherence were quantified using standard histology (aortic
      root). Raman spectroscopy was used to quantify the content of cholesterol and
      calcification (aortic arch). Compared to the late control group, treatment with
      amlodipine, atorvastatin or the combination, reduced atherosclerostic lesion area
      by, respectively, 25%, 39% and 46% in the aortic root (P < 0.01) and by 53%, 55%
      and 60% in the aortic arch (P < 0.05). Atorvastatin, but not amlodipine reduced
      the adherence of monocytes in the intima. Lesion severity and plaque contents of
      collagen, cholesterol and calcification were equal for all treatment groups.
      Neither treatment resulted in regression of atherosclerotic plaque size. In
      conclusion, both atorvastatin and amlodipine significantly retard the progression
      of existing atherosclerotic lesions. No additive effect of the combination of
      amlodipine and atorvastatin could be observed in this study.

PMID- 12623307
TI  - Strain-specific detection of introduced Beauveria bassiana in agricultural fields
      by use of sequence-characterized amplified region markers.
AB  - Field studies on the efficacy and persistence of an introduced strain of
      Beauveria bassiana for insect control require detection assays to differentiate
      the non-native strain from indigenous populations. In this study we developed
      strain-specific molecular markers based on polymerase chain reaction
      amplification of sequence-characterized amplified regions (SCAR) in combination
      with dilution plating on semi-selective medium to detect and estimate density of
      propagules of a commercial strain of B. bassiana (strain GHA) in field samples.
      Using random amplified polymorphic DNA (RAPD) analysis, unique fragments that
      distinguished GHA from other strains of B. bassiana were obtained. Three
      amplicons, OPA-14(0.44), OPA-15(0.44), and OPB-9(0.67), generated with RAPD
      primers were cloned and sequenced and used as bases for designing SCAR primers
      OPA14 F/R(445), OPA15 F/R(441), and OPB9 F/R(677), respectively. All three SCAR
      primers were highly sensitive, capable of detecting 100pg B. bassiana GHA genomic
      DNA, and thus could be used to detect varying levels of the fungus in the field.

PMID- 12623306
TI  - Ultrasound-targeted antisense oligonucleotide attenuates ischemia/reperfusion
      induced myocardial tumor necrosis factor-alpha.
AB  - Ultrasound contrast agents are now emerging as effective vehicles for delivering
      therapeutic agents to target tissues. In the present study, we used ultrasound
      targeted, contrast-bound antisense oligonucleotides to inhibit the expression of
      tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine with negative
      inotropic effects. We compared the efficacy of left ventricular vs. intravenous
      administration and determined the optimal time for delivery. WKY rats were
      treated with perfluorocarbon-exposed sonicated dextrose albumin (PESDA)
      microspheres incubated with 100 microg of antisense oligonucleotide directed
      against TNF-alpha. Contrast was infused into either the superior vena cava or the
      left ventricular cavity along with simultaneous application of ultrasound. Twenty
      four hours later, the animals underwent 15 min of ischemia and 2 h reperfusion.
      Control animals underwent sham operation only, ischemia/reperfusion only, or
      received PESDA only. A second group received treatment just prior to, or
      immediately after the onset of ischemia. At the end of the experimental period,
      hearts were removed and analyzed for TNF-alpha by northern and western blotting.
      While no TNF-alpha expression was detected in sham-operated animals, robust
      expression of TNF-alpha mRNA and protein was seen in controls treated with
      ultrasound and PESDA alone. In contrast, intravenous or left ventricular
      administration of antisense oligonucleotides significantly inhibited
      ischemia/reperfusion-induced TNF-alpha expression. Direct delivery into the left
      ventricular cavity was more effective than intravenous administration, and
      delivery just prior to ischemia was most effective in attenuating TNF-alpha
      expression. Furthermore, attenuation of TNF-alpha expression also significantly
      inhibited other post-ischemic inflammatory mediators including IL-1beta and
      intercellular adhesion molecule-1 (ICAM-1). Thus, ultrasound-targeted antisense
      oligonucleotides can effectively attenuate post-ischemic cytokine expression when
      delivered in a clinically relevant time frame, obviating the need for
      pretreatment.

PMID- 12623308
TI  - Effect of spatial heterogeneity on the role of Coccinella septempunctata as an
      intra-guild predator of the aphid pathogen Pandora neoaphidis.
AB  - The foraging behavior of starved and non-starved adult and larval Coccinella
      septempunctata on groups of plants in the presence of Pandora neoaphidis-infected
      Acyrthosiphon pisum, uninfected aphids or a mixture of these two prey types was
      compared. In general results of these studies confirmed the results of previous
      work comparing foraging behavior on a smaller spatial scale in Petri dishes.
      However, behaviors were modified in response to spatial complexity, prey quality,
      and the host plant. Starved C. septempunctata adults and larvae fed for longer
      and consumed more aphids than non-starved coccinellids. Both larvae and adults
      fed on infected aphids and in some cases entirely consumed them. This was thought
      to be due to the ease of capture of infected (dead) aphids and the feeding
      stimuli provided by the presence of the host plant and, where there was a choice
      of prey, uninfected aphids in the environment. Both larvae and adults spent the
      majority of the time foraging in the upper regions of plants and visited more
      plants when they were not starved or when they were in the presence of less
      suitable, infected aphid prey.

PMID- 12623309
TI  - Effects of long-term storage at -14 degrees C on the survival of Neozygites
      fresenii (Entomophthorales: Neozygitaceae) in cotton aphids (Homoptera:
      Aphididae).
AB  - Neozygites fresenii-infected Aphis gossypii cadavers, containing dormant hyphal
      bodies of N. fresenii, were stored in 4 ml glass vials at -14 degrees C in a
      standard consumer-type refrigerator/freezer for 1, 21, 30, 43, 51, and 68 months
      to determine the effect of storage on fungal survival. When the cadavers were
      removed from the freezer and placed in 25+/-1 degrees C, 100% relative humidity,
      and 12:12 (L:D) conditions, N. fresenii survival, as shown by fungal sporulation
      from the cadavers, was high at all storage periods. The average percentage of
      cadavers from which the fungus sporulated were 93, 47, 100, 100, 80, and 60% from
      1, 21, 30, 43, 51, and 68 months storage periods, respectively. The number of
      primary conidia discharged from each sporulating cadaver was estimated using a
      scale of 1 (low, ca. 1000 primary conidia), 2 (medium, ca. 2000 primary conidia)
      and 3 (high, ca. 3000 primary conidia). The median scores for the number of
      primary conidia produced per sporulating cadaver were 3, 2, 3, 3, 2.5, and 1 for
      1, 21, 30, 43, 51, and 68 months, respectively. Therefore, except for the longest
      storage period, most cadavers produced medium to high numbers of primary conidia.
      Mean germination of primary conidia produced from N. fresenii-infected-aphid
      cadavers from each time period varied significantly from 66.3 to 86.1% in the 21
      and 43 months categories, respectively. Infectivity of capilliconidia, produced
      from frozen N. fresenii, to live healthy cotton aphids varied significantly from
      16.7 to 68.7% from cadavers stored 68 months and 1 month, respectively. Overall
      N. fresenii survived well in dried frozen cotton aphid cadavers for up to 6 years
      with little reduction in sporulation, numbers of spores produced, germination of
      primary conidia, or infectivity.

PMID- 12623310
TI  - Inhibition of fungal growth in thermoregulating locusts, Locusta migratoria,
      infected by the fungus Metarhizium anisopliae var acridum.
AB  - The locust, Locusta migratoria, has the capacity to develop a behavioural fever
      which reduces fungal infection by Metarhizium anisopliae var acridum. We
      investigated hemocyte and blastospore kinetics in infected insects under
      conditions that did or did not allow thermoregulation. Hemocyte concentrations
      were severely reduced in inoculated insects that did not thermoregulate but
      remained similar to those of controls in inoculated insects that were allowed to
      thermoregulate. Reductions in hemocyte counts were accompanied by an increase in
      the concentration of blastospores. In non-thermoregulating insects, circulating
      blastospores were first observed two days post-inoculation and had heavily
      colonized the hemolymph by day 5; in contrast, no blastospores were recovered
      from hemolymph of inoculated-thermoregulating insects. We used fluorescein
      isothiocyanate (FITC)-labelled silica beads to examine in vivo phagocytosis in
      thermoregulating and non-thermoregulating locusts. In the absence of fungus, a
      greater proportion of beads were engulfed by hemocytes in thermoregulating than
      in non-thermoregulating locusts early (4 and 24h) after bead injection, but the
      proportions were similar thereafter. In infected locusts, phagocytosis in non
      thermoregulating insects was progressively impaired; such impairment, however,
      was not observed in challenged, thermoregulating insects. Our results suggest
      that thermoregulation helped keep fungal growth in check, apparently through the
      maintenance of hemocyte population levels and the direct inhibition of
      blastospore propagation by elevated temperatures.

PMID- 12623311
TI  - Impact of the host cadaver on survival and infectivity of entomopathogenic
      nematodes (Rhabditida: Steinernematidae and Heterorhabditidae) under desiccating
      conditions.
AB  - Entomopathogenic nematode species of Steinernema carpocapsae, Steinernema
      riobrave, or Heterorhabditis bacteriophora were used to compare survival and
      infectivity among infective juveniles (IJs) emerging in water from hosts in White
      traps (treatment a), emerging in sand from hosts placed in sand (treatment c),
      and emerging from hosts placed on a mesh suspended over sand (treatment m).
      Nematode survival and infectivity was recorded in sand at three-day intervals
      during 21 days of storage in desiccators at 75% relative humidity and 25 degrees
      C. Infectivity was measured by exposing 5 Galleria mellonella for 16 h to IJs.
      Treatment did not affect percent survival of H. bacteriophora IJs. Percent
      survival of S. riobrave and S. carpocapsae IJs was lowest in treatment a. Across
      all treatments, by 10 days after the beginning of the experiments, IJ survival
      declined to 93, 43, and 28% of levels on day 1 for H. bacteriophora, S. riobrave,
      and S. carpocapsae, respectively. For the three treatments, infection rate over
      time was described by a negative exponential function for S. riobrave and S.
      carpocapsae and by a sigmoid function for H. bacteriophora.

PMID- 12623312
TI  - Distribution and diversity of cry genes in native strains of Bacillus
      thuringiensis obtained from different ecosystems from Colombia.
AB  - Colombia is a tropical country located at the north of South America. It is
      considered to be one of the most important countries in terms of its biodiversity
      worldwide. One hundred and eight soil samples obtained from agricultural crops
      and wild ecosystems were evaluated in terms of the presence of Bacillus
      thuringiensis (Bt) native strains. One hundred and eight different Bt strains
      were isolated and characterized by the presence of crystal proteins by SDS-PAGE
      and a multiplex PCR with general and specific primers for cry1 and cry3, cry7,
      and cry8 gene detection. Most of the Bt strains (73%) reacted with the cry1
      general primers; 27.8% of the Bt strains reacted with cry3, cry7, and cry8
      general primers and 17.8% of strains did not react with any of these two sets of
      primers. Thirty different PCR profiles were found in the strains with cry1 genes
      when they were analyzed with specific primers (cry1A to cry1F). A high frequency
      of joint occurrence was observed for cry1Aa/cry1Ab, cry1Aa/cry1Ac, cry1Ab/cry1Ac,
      and cry1C/cry1D genes with a Pearson coefficient of 0.88, 0.74, 0.76, and 0.87,
      respectively. Other distinctive characteristics were found in the Colombian
      collection as the presence of 22.2% of native strains which presented, at the
      same time, lepidopteran and coleopteran active genes. Interesting relations were
      found as well between the cry gene distribution and the geographical areas
      sampled. Finally, some strains with moderate to high biopesticide activity
      against Spodoptera frugiperda (Lepidoptera) and Premnotrypes vorax (Coleoptera)
      insects were identified, this being important to explore future microbial
      strategies for the control of these crop pests in the region.

PMID- 12623313
TI  - Comparative susceptibilities of twelve insect cell lines to infection by three
      baculoviruses.

PMID- 12623314
TI  - Deletion of the Cry11A or the Cyt1A toxin from Bacillus thuringiensis subsp.
      israelensis: effect on toxicity against resistant Culex quinquefasciatus
      (Diptera: Culicidae).

PMID- 12623315
TI  - Vancomycin-resistant enterococci: 15 years and counting.
AB  - We review the history of vancomycin-resistant enterococci (VRE) and propose a
      causal model illustrating the roles of exposure to VRE reservoirs, patient
      characteristics, antimicrobial exposure, and prevalence of VRE in the progression
      from potential VRE reservoirs to active disease in hospitalized patients.
      Differences in VRE colonization and VRE infection are discussed with respect to
      hospital surveillance methodology and implications for interventions. We further
      document clonal transmission of VRE in a large, urban, teaching hospital and
      demonstrate VRE susceptibility to a wide array of antimicrobial agents. This
      model can guide the identification of mutable factors that are focal points for
      intervention.

PMID- 12623316
TI  - The role of clinical guidelines, policies and stewardship.
AB  - The purpose of guidelines is to improve the quality of care for patients and
      improve clinical effectiveness by implementation of evidence-based care in daily
      practice. However, the potential of guidelines for resolving clinical questions
      should not be overstated. Ideally, policy makers use input from research data, as
      well as current prescribing habits, when developing guidelines. Care has to be
      given to the quality of guidelines, as well as their effect on outcome.
      Prospective validation of the content and use of guidelines must be set up.
      Beside the quality of guidelines, efforts are necessary for an effective
      implementation into daily practice. Many studies have shown that a combination of
      different interventions is needed. Thereby, an investigation of possible barriers
      should be an essential part of any strategy.

PMID- 12623317
TI  - Impact of a multidisciplinary approach to the control of antibiotic prescription
      in a general hospital.
AB  - We examined the impact of a rational antibiotic prescription programme based on a
      multidisciplinary consultative approach in a 600-bed hospital. The programme
      involved four measures: (1). drawing up of a local prescribing consensus with all
      prescribers; (2). a restricted prescriptions policy for the most expensive
      antibiotics; (3.assessment of the prescription of these antibiotics by regular
      audits; and (4). institutional training and information for prescribers. The
      impact of the programme was assessed by comparing actual prescriptions with the
      criteria of the local consensus, compliance with the restrictive prescription
      policy, changes in the average daily cost of antibiotic therapy per inpatient and
      changes in the local ecology of methicillin-resistant Staphylococcus aureus
      (MRSA), Enterobacteriaceae producing extended-spectrum beta-lactamases (EPESB)
      and ceftazidime-resistant Pseudomonas species (CRP). Using a participatory
      consensual approach, 182 reference recommendations were established (104 for
      adults, 78 for children), corresponding to 85% of the clinical settings
      encountered in the hospital. Six audits, conducted since June 1997, show that the
      rate of unjustified prescriptions first fell significantly (from 6 to 0%,
      P<0.001), then increased significantly (from 0 to 3%, P<0.05) before stabilizing
      at 3%. The cost of antimicrobials per inpatient day fell significantly (from US
      dollars 13.8 in 1997 to US dollars 11 in 2000, P<0.001). The prevalence of MRSA
      and CRP remained stable, while that of EPESB fell significantly (P<0.001). This
      multidisciplinary consultative approach thus reduced antibiotic costs,
      contributed to infection control, and improved the quality of antibiotic
      prescription.

PMID- 12623319
TI  - Outbreak of Clostridium difficile-related diarrhoea in an adult oncology unit:
      risk factors and microbiological characteristics.
AB  - We describe the risk factors and microbiological findings of an outbreak of
      Clostridium difficile (CD)-related diarrhoea in the Medical Oncology Department
      of the Curie Institute. Screening for CD in stools was performed on 59 patients
      with diarrhoea and 146 patients without diarrhoea. Toxin secretion, serotyping
      (enzyme-linked immunosorbant assay) and genotyping (AP-polymerase chain reaction)
      were performed on 39 CD strains from 32 patients. The risk factors for toxigenic
      CD-positive diarrhoea were also investigated. Twenty-seven (46%) patients with
      diarrhoea and 12 (8%) patients without diarrhoea were CD-positive (P<0.001).
      Patients with diarrhoea were older (P=0.03). Chemotherapy was a risk factor for
      toxigenic CD-related diarrhoea (P=0.02) and antibiotic treatment was a risk
      factor only in those patients who were also receiving chemotherapy. Serotyping
      and genotyping showed that several strains were involved in this outbreak, with
      only two instances of patient-to-patient transmission, involving four and two
      patients.

PMID- 12623320
TI  - Nosocomial outbreak of diarrhoea by enterotoxigenic Escherichia coli among
      preterm neonates in a tertiary care hospital in India: pitfalls in healthcare.
AB  - An outbreak of watery diarrhoea accompanied by low-grade fever and weight loss in
      16 preterm neonates (age range 2-20 days) admitted to a neonatal intensive care
      unit (NICU) over four days in August 2000 is reported. Escherichia coli having
      similar antibiograms were identified on routine bacterial stool cultures in 14
      (87.5%) neonates and none of the other known enteropathogens were detected. An
      investigation was undertaken to trace the source of infection. Surveillance
      cultures of swabs from the utensils used to prepare milk feed, culture of the
      formula feed and all items handled by one particular cook yielded growth of E.
      coli as did culture of his hand swabs and faecal sample. The causative agent was
      identified as enterotoxigenic E. coli (ETEC) as toxin production could be
      demonstrated by reverse passive latex agglutination in all the strains of E. coli
      isolated both from the infected neonates and the source of infection. The
      outbreak was effectively controlled by appropriate therapy and institution of
      proper measures of hygiene after identification of the source of infection.

PMID- 12623321
TI  - Extended-spectrum beta-lactamase-producing Klebsiella pneumoniae in a neonatal
      intensive care unit: risk factors for infection and colonization.
AB  - An outbreak of extended spectrum beta-lactamase-producing Klebsiella pneumoniae
      (ESBLKp) infections in a neonatal intensive care unit (NICU) prompted a
      prospective investigation of colonization and infection with this pathogen. From
      August 1, 1997 to May 30, 1999, neonates admitted to the NICU for more than 24 h
      were screened for ESBLKp acquisition. Neonatal gastrointestinal screening was
      performed by means of faecal sampling within 48 h of admission and then weekly
      until discharge. Isolates were typed using pulsed-field gel electrophoresis
      (PFGE). Time-dependent proportional hazard models were used to identify
      independent effects of invasive procedures and antimicrobials after controlling
      for duration of stay at the NICU. During the study period, 464 neonates were
      admitted and 383 were regularly screened. Infections occurred in 13 (3.4%)
      neonates and 206 (53.8%) became colonized. Independent risk factors for
      colonization during the first nine days in the NICU were the antimicrobial
      combination cephalosporin plus aminoglycoside [hazard rate (HR)=4.60; 95% CI:
      1.48-14.31], and each NICU-day was associated with a 26% increase in the hazard
      rate for colonization (HR=1.26; 95% CI: 1.16-1.37). Previous colonization
      (HR=5.19; 95% CI: 1.58-17.08) and central vascular catheter use (HR=13.89; 95%
      CI: 2.71-71.3) were independent risk factors for infection. In an outbreak
      setting the proportion of neonates colonized with ESBLKp was observed to increase
      with the duration of stay and antimicrobial use, and once colonized, infants
      exposed to invasive devices may become infected.

PMID- 12623318
TI  - Correlation between candiduria and departmental antibiotic use.
AB  - The incidence of candiduria is increasing in teaching hospitals. We examined the
      hypothesis that this trend was correlated with the amount of departmental
      antibiotic consumption. In the setting of a large teaching hospital in Israel,
      the correlation coefficient between departmental intravenous antibiotic
      consumption (expressed as daily defined dose (DDD)/1000 patient-days) and the
      incidence of candiduria per 1000 patient-days was 0.47 (P=0.03). For broad
      spectrum antibiotics, the corresponding correlation coefficient was 0.66
      (P=0.001). The strongest correlation with candiduria was shown for the use of
      meropenem (r=0.79, P<0.001) and ceftazidime (r=0.66, P=0.001). This is the first
      time that departmental habits of antibiotic use have been shown to be strongly
      correlated with the incidence of candiduria in hospitalized patients. These
      results add an important new dimension to the strategy of restricting broad
      spectrum antibiotics.

PMID- 12623322
TI  - Hospital-acquired urinary tract infections in Turkey: a nationwide multicenter
      point prevalence study.
AB  - Hospital-acquired urinary tract infection (UTI) is the most common infection
      acquired in hospitals. The aim of the study was to determine the prevalence of
      UTIs in Turkey. A nationwide one day point-prevalence survey was conducted.
      Centers for Diseases Control and Prevention (CDC) standard definitions for
      nosocomial UTIs were used. Data were collected by detailed uniform questionnaires
      for each patient with UTI. A total of 13269 patients were investigated, the
      number of patients observed in each hospital varied from 21 to 1329 patients, an
      average of 458 patients per prevalence study per hospital. The overall prevalence
      of UTI was 1.7%. Fifty-eight (26.1%) of the patients had sepsis or septic shock.
      Twenty-five (11.3%) patients had culture-proven bloodstream infection. Over 60%
      (65.3%) of urinary tract infections were associated with urinary catheters.
      Overall, 78.4% of UTIs were culture-proven. Escherichia coli (32.4%) was the most
      common reported pathogen, followed by Klebsiella spp. (17.0%), Candida spp.
      (12.8%),Pseudomonas aeruginosa (11.7%) and enterococci 8.5%. The prevalence of
      ampicillin-resistant E. coli was 23.9% and accounted for 73.8% of all E. coli
      isolated from UTI 8.2%, and 24.6% of E. coli were resistant to quinolones and
      ceftriaxone, respectively. There were no resistance to carbapenems in E. coli but
      6.25, 40.6, 59.4% of Klebsiella spp. were resistant to carbapenems, quinolones
      and ceftriaxone, respectively. The results of this first national point
      prevalence study offers a reliable measure of the prevalence of nosocomial UTIs
      at hospitals in Turkey and provides a baseline for future studies which will
      enable the monitoring of trends over time.

PMID- 12623323
TI  - Antibacterial activity and endotoxin-binding capacity of Actisorb Silver 220.
AB  - Actisorb Silver 220 wound dressing demonstrated a high in vitro endotoxin-binding
      capacity combined with a marked bactericidal activity without releasing
      Pseudomonas aeruginosa endotoxins into the environment, and so may be beneficial
      in the treatment of infected wounds, particularly colonization by Gram-negative
      bacteria.

PMID- 12623324
TI  - Survey of nasal colonization by, and assessment of a novel multiplex PCR method
      for detection of biofilm-forming methicillin-resistant staphylococci in healthy
      medical students.
AB  - We surveyed the prevalence of nasal colonization by biofilm-forming methicillin
      resistant staphylococci in healthy medical students, who had never had contact
      with patients, using polymerase chain reaction (PCR) to detect themec A gene,
      production of penicillin-binding protein 2' (PBP2'), and quantitative assay of
      biofilm formation on polystyrene. Anterior nasal swabs from 90 students were
      cultured on mannitol salt and oxacillin salt screening agar plates. In total, 231
      staphylococcal isolates belonging to 10 species from 88 students were identified,
      of which 139 from 77 (88%) students were Staphylococcus epidermidis. The overall
      prevalences of methicillin-resistant and biofilm-forming staphylococci were 48%
      (43 of 90) and 59% (53 of 90) for the medical students, respectively. In total 30
      (33%) students carried biofilm-forming methicillin-resistant staphylococci in the
      nares, all of which were identified as S. epidermidis. For rapid detection of
      biofilm-forming methicillin-resistant S. epidermidis (MRSE), we devised a novel
      multiplex PCR method to assess a total of 243 staphylococcal isolates, including
      the 231 isolates from the students. The multiplex PCR assay used six primers to
      amplify atl E and ica ADB, which are responsible for the biofilm formation ofS.
      epidermidis, and mec A genes. The multiplex PCR assay revealed that 68 (96%)
      isolates were detectable in 71 biofilm-forming MRSE isolates, which corresponded
      to 93% (28 of 30) of biofilm-forming MRSE carriers. Surveillance of nasal
      colonization with biofilm-forming MRSE using this multiplex PCR in healthcare
      workers and patients, might provide useful information for the establishment of
      infection control procedures toward biofilm-forming MRSE.

PMID- 12623325
TI  - Isolation of non-tuberculous mycobacteria from hospital cockroaches (Periplaneta
      americana).
AB  - This study attempted to isolate mycobacteria from hospital and household
      cockroaches from 90 hospitals and 40 households in Kaohsiung City and Kaohsiung
      County, South Taiwan. Among 203 cockroaches (139 Periplaneta americana and 64
      Blattella germanica) collected from the hospitals, six Mycobacterium spp. were
      isolated and identified by polymerase chain reaction-restriction fragment length
      polymorphism analysis. In 12 cockroaches (P. americana): four Mycobacterium
      kansaii, three Mycobacterium xenopi, two Mycobacterium gordonae, one
      Mycobacterium hemophilium, one Mycobacterium fortuitum, and one Mycobacterium
      avium. However, no mycobacteria were obtained form the hospital B. germanica or
      226 household cockroaches (123 P. americana and 103 B. germanica). As cockroach
      infestation occurs commonly in the hospital environment, they may potentially be
      implicated as a cause of hospital-acquired infections due to non-tuberculous
      mycobacteria.

PMID- 12623326
TI  - Effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus
      in elderly patients in a hospital ward.
AB  - We investigated the effects of inhalation of tea catechin on MRSA in the 24
      elderly in patients, who were known to carry MRSA in sputum. The patients in the
      catechin group (N=12) were administered an inhalation of tea catechin extracts
      (in saline/bromhexine) (3.7 g/L catechins, 43% of them are composed of
      epigallocatechin gallate), three times daily with hand nebulizer for four weeks.
      The clinical effects were compared with the control group (N=12) who were given
      an inhalation of saline/bromhexine alone. After a week of the course, the numbers
      of the patients with decreased or disappearance of MRSA in their sputum was
      significantly higher in the catechin group, compared with that in the control
      group (seven vs. no patients; P<0.05). The number of patients discharged during
      the study was significantly increased, and the days of hospital stay were
      significantly decreased in the catechin group compared with those in the control
      group (six vs. one patient; P<0.05, 51+/-22 vs. 85+/-50 days, mean+/-S.D.;P
      <0.05, respectively). No adverse effects were observed in any patients during the
      study. Catechin inhalation seemed to be safe, and at least temporarily effective
      in the reduction of MRSA and shortening of hospitalization.

PMID- 12623327
TI  - External auditors for infection control.

PMID- 12623328
TI  - European guidelines-yes, but how?

PMID- 12623329
TI  - The endovascular management of ruptured abdominal aortic aneurysms.
AB  - Endovascular aneurysm repair (EVAR) is a controversial technique, which remains
      the subject of a number of prospective randomised trials. Although questions
      remain regarding its long-term durability objective evidence exists which
      demonstrates its reduced physiological impact compared with conventional open
      repair. If this technique could be used in patients with ruptured abdominal
      aortic aneurysm (AAA) it may reduce the high peri-operative mortality. A review
      of the literature identified a limited experience with EVAR of ruptured AAA. Only
      a small number of case series with selected patients exist. The majority of
      patients were haemodynamically stable. However, the selective use of aortic
      occlusion balloons allowed successful endovascular management in a small number
      of unstable cases. All investigators had access to an "off the shelf"
      endovascular stent-graft (EVG). Per-operative mortality ranged from 9 to 45% and
      may reflect increasing experience and patient selection. A number of patients who
      underwent successful EVAR were turned down for open repair. A number of important
      lessons have been learned from these studies but questions remain regarding
      patient suitability and staffing issues. If these difficulties can be surmounted
      then the technique may offer an alternative to open repair.

PMID- 12623330
TI  - Disease-specific quality of life assessment in intermittent claudication: review.
AB  - OBJECTIVES: intermittent claudication (IC) is a common condition that has a major
      impact on the patients' quality of life (QoL). Generic QoL instruments often lack
      sensitivity to detect small but clinically significant variation in QoL. Disease
      specific instruments may overcome this problem. This study aims to review various
      disease-specific QoL instruments available for use in IC and make recommendations
      for clinical utilization based on validity, reliability and responsiveness.
      METHODS: a detailed literature search and extensive bibliography review of all
      papers relating to disease-specific QoL and IC. RESULTS: several disease-specific
      QoL instruments are available for use in patients with IC. The most notable of
      these are the Claudication Scale (CLAU-S), Sickness Impact Profile - Intermittent
      Claudication (SIP(IC)) and the VascuQoL. The Walking Impairment Questionnaire
      (WIQ) is an objective measure of the patient's walking ability and not a QoL
      instrument. CONCLUSION: many of the questionnaires are new and have undergone
      only a limited validation process. More work is required in this field before any
      one disease-specific QoL instrument can be recommended for use in patients with
      IC.

PMID- 12623331
TI  - The prevalence of intermittent claudication. Sex-related differences have been
      eliminated.
AB  - OBJECTIVES: to investigate the prevalence of intermittent claudication (IC) in an
      unselected population of nearly 20000 individuals between 40 and 69 years of age.
      DESIGN: epidemiologic investigation of residents in Nord-Trondelag County,
      Norway. MATERIAL AND METHODS: between 1995 and 1997, all residents 20 years of
      age or older in Nord-Trondelag County, Norway, were invited to attend the HUNT
      Study. A total of 19748 participants between 40 and 69 years of age responded to
      questions related to the symptoms of intermittent claudication. We estimated the
      prevalence of IC based on these questions. RESULTS: the age-adjusted prevalence
      of intermittent claudication in the total population was 1.1% for men and 1.2%
      for women. We found an increase in the prevalence of IC by age, however, no sex
      differences were observed. CONCLUSION: the prevalence of intermittent
      claudication increased gradually by age. However, in contrast to previous
      reports, there was no difference by sex.

PMID- 12623332
TI  - Cost-effectiveness of diagnostic imaging work-up and treatment for patients with
      intermittent claudication in The Netherlands.
AB  - OBJECTIVE: to determine the societal cost-effectiveness of various management
      strategies, including both the diagnostic imaging work-up and treatment, for
      patients with intermittent claudication in The Netherlands. METHODS: a decision
      analytic model was used and included probability and quality of life data
      available from the literature. A cost-analysis was performed in a university
      setting in The Netherlands. Imaging work-up options included magnetic resonance
      angiography (MRA), color-guided duplex ultrasound, or intraarterial digital
      subtraction angiography (DSA) and treatment options were percutaneous
      transluminal angioplasty with selective stent placement if feasible or bypass
      surgery. Management strategies were defined as combinations of imaging work-up
      and treatment options. A conservative strategy with no imaging work-up and
      walking exercises was considered as reference. Main outcome measures were quality
      adjusted life years (QALYs), lifetime costs (euro), and incremental cost
      effectiveness (CE) ratios. The base-case analysis evaluated 60-year-old men with
      severe unilateral intermittent claudication of at least one year duration.
      RESULTS: the range in QALYs and costs across management strategies that
      considered angioplasty as only treatment option was small (maximum difference:
      0.0033 QALYs and 451 euros). Similarly, the range was small across management
      strategies that considered angioplasty if feasible otherwise bypass surgery
      (maximum difference: 0.0033 QALYs and 280 euros). MRA in combination with
      angioplasty (6.1487 QALYs and 8556 euros) had a CE ratio of 20,000 euros/QALY
      relative to the conservative strategy. The most effective strategy was DSA in
      combination with angioplasty if feasible otherwise bypass surgery (6.2254 QALYs
      and 18,583 euros) which had a CE ratio of 131,000 euros/QALY relative to MRA in
      combination with angioplasty. CONCLUSION: the results suggest that the imaging
      work-up with non-invasive imaging modalities can replace DSA for the work-up of
      patients with intermittent claudication without a substantial loss in
      effectiveness and a minimal cost-reduction. Management strategies including
      angioplasty are cost-effective in the Netherlands but although strategies
      including bypass surgery are more effective, their incremental costs are very
      high.

PMID- 12623333
TI  - Interobserver variation in duplex scanning of infrainguinal arterial bypass
      grafts.
AB  - OBJECTIVE: to determine the degree of interobserver variation of color-flow
      duplex scanning of infrainguinal arterial bypass grafts. METHODS: two experienced
      vascular technologists randomly assessed bypass grafts in 32 consecutive
      patients, using a color-flow duplex scan. In pre-defined segments the highest
      peak systolic velocity (PSV(max)) and end-diastolic velocity (EDV) were measured
      and a peak systolic velocity ratio (PSV ratio) was calculated. Results were
      analyzed as continuous variables (Bland and Altman plots and Intraclass
      Correlation Coefficient=ICC) and also as categorical data (weighted Kappa
      coefficient) for the PSV ratio 1-2.5, > or =2.5-4, > or =4.0. RESULTS: the ICC
      for the PSV(max), PSV ratio and EDV indicated "almost perfect" agreement for all
      three parameters. However, the Bland and Altman plots showed impressive
      interobserver variation for the higher values of all three parameters. For the
      PSV ratio categories a weighted kappa of 0.31 was calculated, indicating only
      fair agreement. Substantial variation was found for the categories with PSV
      ratios > or =2.5-4.0 and > or =4.0. CONCLUSION: though performing accurately for
      the lower values of the assessed parameters, duplex scanning shows considerable
      interobserver variation for the clinically significant higher values.
      Particularly in the PSV ratio interval > or =2.5-4.0, most relevant for clinical
      decision-making, the interobserver variability is unacceptable.

PMID- 12623334
TI  - Graft patency and clinical outcome of femorodistal arterial reconstruction in
      diabetic and non-diabetic patients: results of a multicentre comparative
      analysis.
AB  - OBJECTIVE: in diabetic patients with critical limb ischaemia (CLI) an inferior
      success rate following infrainguinal bypass surgery is quite often suggested. The
      aim of this retrospective analysis was, therefore, to evaluate the graft patency
      and, particularly, the clinical outcome at 1 year in diabetic compared with non
      diabetic patients. MATERIAL AND METHODS: two hundred and eleven patients
      (diabetics 94; non-diabetics 117) with femorodistal reconstruction for CLI were
      studied. Groups were comparable with regard to the Fontaine classification, the
      distribution of vascular risk factors, graft material, distal anastomosis site,
      and the angiographic runoff grading. RESULTS: diabetes did not adversely affect
      graft function. For diabetics and non-diabetics primary cumulative patency rate
      at 1 year was found to be 66 and 56%, respectively (p=0.10) and a virtually
      identical limb salvage rate of 85 and 83% was achieved (p=0.76). With regard to
      healing of ischaemic foot ulcers a trend against diabetics was noted with a
      healing rate of 81% compared to 96% in non-diabetics at 1 year (p=0.067);
      gangrenous foot lesions could be equally remedied in 94% and in 87% among
      patients with and without diabetes (p=0.44). The survival rate of diabetics,
      however, was significantly lower with 78% at 1 year compared with 95% in non
      diabetic patients (p=0.0004). CONCLUSIONS: our preliminary results support the
      view that infrainguinal bypass grafting can be safely done even in diabetics.
      Despite increased mortality in this group, liberal indication for reconstructive
      vascular surgery seems to be justified by favourable patency rates and clinical
      outcome in selected patients.

PMID- 12623335
TI  - The distaflo graft: a valid alternative to interposition vein?
AB  - INTRODUCTION: the rationale behind the Distaflo graft is inhibition of myointimal
      hyperplasia through optimisation of haemodynamic forces at the distal
      anastomosis. This prospective study reports our early clinical results. METHOD:
      patients with critical limb ischaemia, but no autologous vein, underwent
      infrainguinal bypass using Distaflo. Clinical and Duplex assessment provided
      prospective data from which one year cumulative patency, limb salvage and
      survival rates were calculated using Kaplan-Meier analysis. Log rank test enabled
      comparison with an historical control group of Miller cuff grafts. RESULTS: fifty
      Distaflo were inserted over 29 months into 46 patients, median age 68.5 years, 27
      male (59%), of which 27 (54%) were re-do procedures. Proximal anastomoses were to
      common femoral arteries in 40 cases (80%); distal anastomoses were to popliteal
      vessels in 20 (40%), and tibial vessels in 30 (60%). The Distaflo graft had
      patency, limb salvage and survival rates of 39, 50 and 82% respectively compared
      to 49, 56 and 85% respectively in the control group, with no statistical
      difference (p = 0.39; 0.65; 0.67 respectively; log rank). CONCLUSION: in this non
      randomised study, the Distaflo has similar one year patency, limb salvage and
      survival rates to the Miller cuff, potentially justifying its use an alternative
      in distal prosthetic arterial reconstruction for critical limb ischaemia.

PMID- 12623336
TI  - Ten-year experience in autogenous reconstruction with the femoral vein in the
      treatment of aortofemoral prosthetic infection.
AB  - OBJECTIVE: to study the short and long term effectiveness of in situ replacement
      of infected aortic grafts with the lower extremity deep veins. METHODS: forty
      nine patients operated on for infrarenal aortic graft infection since 1990 were
      studied. Diagnosis of infection was based on clinical signs, bacteriological
      tests and typical findings on CT scan and leukocyte scan. The surgical treatment
      consisted in harvesting the femoral vein, total graft excision, thorough
      debridement and in situ reconstruction with the femoral veins. After discharge,
      the patients were followed at 6 monthly intervals with clinical examination,
      duplex and/or CT scan. RESULTS: there were four in-hospital deaths (8%). One
      patient required above-knee amputation (2%) and there were two graft limb
      occlusions (4%). With a mean follow-up 41 months, another 13 patients died,
      unrelated to the operation (29%). There were no late amputations and only two
      late graft limb stenoses (4%). We have a 5 year survival rate of 60%, a 5 year
      limb salvage rate of 98%, and a 5 year primary patency rate of 91%. There were no
      cases of aneurysmal dilatation of vein grafts and no incidence of reinfection.
      CONCLUSION: in situ reconstruction with the lower extremity deep veins is in the
      long term a safe and attractive alternative in the treatment of infrarenal aortic
      graft infection.

PMID- 12623337
TI  - Steal phenomenon in radiocephalic arteriovenous fistula. In vitro haemodynamic
      and electrical resistance simulation studies.
AB  - OBJECTIVE: steal phenomenon following an arteriovenous fistula (AVF) creation is
      characterised by retrograde flow in the artery segment distal to the anastomosis
      and occurs in the majority of patients with radiocephalic AVF although this
      rarely leads to distal ischaemia. To investigate the local haemodynamics after
      the creation of an AVF, a simple electrical resistance model which assumes time
      independent flow was used. The applicability of this model to pulsatile flow
      conditions was verified using an in vitro flow circuit. The effects of stenoses
      in various artery segments were also investigated. DESIGN OF THE STUDY: the
      electrical analogue model consists of a pressure source, constant resistances
      that represent the resistance to flow of various arterial segments and the
      fistula. The stenosis was modelled by a resistor and a non-linear term is
      simulated by a current-controlled voltage source. In vitro experiments were
      performed in pulsatile and steady flow and the results were compared with
      electrical simulations. The effects of fistula flow and the presence and severity
      of a stenosis on flow distribution, particularly the direction of flow in the
      distal radial artery and flow into the hand were assessed. RESULTS: steady and
      pulsatile time-averaged flows measured in vitro compared well with the results of
      electrical circuit simulations for cases without a stenosis. When a stenosis was
      present comparisons were made only in steady flow and these show good agreement
      for stenoses of 75% area reduction. The direction of flow in the distal radial
      artery was antegrade (towards the hand) at low fistula flow and became retrograde
      as fistula flow increased. The presence of a severe stenosis in the brachial
      artery was found to have the strongest influence on flow to the hand.
      CONCLUSIONS: an electrical resistance model of a radiocephalic AVF has been
      validated with an in vitro pulsatile flow circuit. One of the benefits of this
      model is that it can be easily analysed using standard circuit simulation
      software. The model also provide insights into the possible haemodynamics
      consequences of creating an AVF with or without the presence of a stenosis in the
      arterial segments.

PMID- 12623338
TI  - Changes in TH1/TH2 immunity after endovascular and conventional infrarenal aortic
      aneurysm repair: its relevance for clinical practice.
AB  - OBJECTIVE: to evaluate local surgical trauma induced by endovascular (TPEG) and
      conventional infrarenal aortic aneurysm repair (AAA-C), the inflammatory response
      and changes in cell-mediated and antibody-mediated immunity as illustrated by the
      type-1/type-2 T-helper (TH1/TH2) cell balance were investigated. DESIGN:
      prospective study. PATIENTS AND METHODS: sixteen patients were included, eight
      patients underwent AAA-C and eight TPEG. Venous peripheral blood samples were
      collected 24h preoperatively and 24, 48, 72h, 5 and 7 days postoperatively.
      Besides the WBC, intracellular TH1/TH2 cytokines (IFN-gamma/IL-4) and the cell
      surface markers HLA-DR on monocytes and CD23 on B cells were measured by four
      colour flow cytometry. RESULTS: statistically significant higher values in the
      AAA-C group were demonstrated for neutrophiles. The TH1/TH2 immunobalance
      (expressed by forming the ratio of IFN-(gamma/IL-4 producing T cells as well as
      by the ratio of HLA-DR(pos) monocytes/CD23(pos) B-cells) showed a significant
      shift towards TH2 immunity in the AAA-C group whereas TPEG led to a significant
      lesser shift 24-72h after surgery (p < 0.05). CONCLUSIONS: TPEG leads to a minor
      distortion of the TH1/TH2 immunobalance. This implies that TPEG is a less
      stressing procedure, that is especially beneficial in patients whose conditions
      are considered less suitable for AAA-C due to age and serious comorbidity.

PMID- 12623339
TI  - Feasibility and reliability of on-line automated microemboli detection after
      carotid endarterectomy. A transcranial Doppler study.
AB  - OBJECTIVES: recently, a new algorithm for transcranial Doppler (TCD) ultrasound
      detection of microembolic signals (MES) was developed. In the present study, we
      investigated its on-line performance in TCD monitoring after carotid
      endarterectomy (CEA) and assessed off-line its accuracy in detecting MES.
      MATERIALS AND METHODS: first, the feasibility of MES detection in TCD monitoring
      after CEA in a routine clinical setting was evaluated in 50 patients. Second, to
      test the reliability of the software a 2-h digital audio study tape was made and
      analysed by the algorithm and five human experts. The "gold standard" was defined
      as the agreement between human experts: a MES was considered to be present if at
      least three human observers agreed. RESULTS: TCD monitoring for emboli detection
      after CEA was well tolerated by the patients and could be performed reliably. In
      the study tape, the human gold standard detected 107 MES, with 93 MES having an
      intensity of > or =7 dB. The software detected 81 and 77 MES, respectively. Using
      the 7 dB intensity threshold, the software had no false positives and 16 false
      negatives. The kappa value between the human gold standard and the software was
      0.91, the proportion of specific agreement was 0.83. CONCLUSIONS: the tested
      algorithm provides a reliable method for automated on-line microemboli detection
      after CEA. This makes monitoring of the effectiveness of antiplatelet agents in
      the prevention of stroke after CEA more practicable.

PMID- 12623340
TI  - Whole-leg duplex mapping for varicose veins: observations on patterns of reflux
      in recurrent and primary legs, with clinical correlation.
AB  - BACKGROUND: the variability of venous reflux patterns complicate the management
      of venous disease. Our study investigates specific variations in venous anatomy
      and patterns of reflux in varying clinical situations. METHODS: prospective
      analysis of 464 legs in 355 patients was performed by complete duplex venous
      mapping of both primary and recurrent varicose veins. Hand Held Doppler (HHD) and
      Duplex Ultrasonography (Duplex US) observations in the popliteal fossa were
      compared in a subgroup of 89 patients with primary varicose veins. Distribution
      of venous system disease was correlated with clinical severity in a subgroup of
      117 affected legs which was representative of the overall study group. RESULTS:
      sapheno-femoral junction (SFJ) incompetence predominated in both primary and
      recurrent varicose veins. Only 21% of primary legs and 25% of recurrent legs had
      sapheno-popliteal junction (SPJ) incompetence. SPJ incompetence was present in
      only 42% of cases where reflux in the popliteal region on HHD had been
      demonstrated. A proportion of both primary and recurrent varicose veins had
      evidence of deep venous incompetence (DVI). Sixty-four percent of primary leg
      ulcer patients had superficial incompetence alone. In patients with recurrent
      varicosities and ulceration, 57% had SPJ incompetence, 64% multiple sites and 50%
      DVI. CONCLUSION: the complex variations of varicose vein anatomy and functional
      pathology in the lower limb are currently best assessed by complete whole-leg
      venous duplex mapping.

PMID- 12623342
TI  - Repairing hernias at the same time as ruptured abdominal aortic aneurysms may
      increase the risk of abdominal compartment syndrome.

PMID- 12623341
TI  - Therapeutic angiogenesis by autologous bone-marrow transplantation in a general
      hospital setting.

PMID- 12623343
TI  - A second chance for prostate-cancer chemotherapy?

PMID- 12623349
TI  - New WHO Director General announced.

PMID- 12623350
TI  - Drug increases lean tissue mass in patients with cancer.

PMID- 12623351
TI  - Endonasal surgery for pituitary tumours replaces 40-year standard.

PMID- 12623353
TI  - New drug enters PDT clinical trials.

PMID- 12623354
TI  - New treatment regimen for thyroid cancer.

PMID- 12623358
TI  - Clinical-practice guidelines in Europe: time for European co-operation for cancer
      guidelines.

PMID- 12623359
TI  - Antivascular therapy of cancer: DMXAA.
AB  - The vascular endothelium of tumour tissue, which differs in several ways from
      that of normal tissues, is a potential target for selective anticancer therapy.
      By contrast with antiangiogenic agents, antivascular agents target the
      endothelial cells of existing tumour blood vessels, causing distortion or damage
      and consequently decreasing tumour blood flow. DMXAA (5,6-dimethylxanthenone-4
      acetic acid), a low-molecular-weight drug, has a striking antivascular and in
      some cases curative effect in experimental tumours. Its action on vascular
      endothelial cells seems to involve a cascade of events leading to induction of
      tumour haemorrhagic necrosis. These events include both direct and indirect
      effects, the latter involving the release of further vasoactive agents, such as
      serotonin, tumour necrosis factor, other cytokines, and nitric oxide from host
      cells. Phase I clinical trials of DMXAA have been completed and the next
      challenge to face is how the antivascular effect of this drug should be exploited
      for the treatment of human cancer.

PMID- 12623360
TI  - Management of terminal cancer in elderly patients.
AB  - Advances in health care and changing demographics worldwide have led to an ageing
      population whose care at the end of life has become increasingly complicated.
      Clinicians face a difficult challenge in the effective management of symptoms and
      suffering of elderly patients with terminal cancer, against a backdrop of
      complicated family and social structures. We describe the most pertinent features
      of management of key symptoms, focusing on pain, dyspnoea, constipation, and
      anorexia-cachexia syndromes. We present a rational approach to nutritional issues
      along with a description of the psychosocial issues that must be included in the
      overall management of these patients.

PMID- 12623361
TI  - Radiotherapy alone in the curative treatment of rectal carcinoma.
AB  - Surgery is the standard treatment for rectal adenocarcinoma. The tumour is
      resistant to radiation; doses above 80 Gy are necessary and have to be delivered
      by endocavitary irradiation. Contact radiotherapy is a basic method of delivering
      a high dose in a small volume. Brachytherapy can be used to deliver a boost of
      radiation into a residual lesion. External-beam radiotherapy can be used to
      supplement the dose to the deep part of the primary tumour and to the perirectal
      lymph nodes. T1N0 tumours have been treated by contact radiotherapy, and local
      control was achieved in 85-90% of patients with no severe toxic effects. Combined
      endocavitary irradiation and external-beam irradiation can achieve local control
      in 80% of patients with T2 tumours and 60% of patients with T3 tumours with only
      moderate toxic effects and a 60% 5-year overall survival. Radiotherapy alone is
      suitable for patients with T1N0 lesions (contact radiotherapy) or patients with
      T2-3 (combined endocavitary and external-beam radiotherapy) who cannot undergo
      surgery. For T2 or early T3 tumours of the lower rectum requiring surgery and a
      permanent colostomy, combined irradiation can be used as a first-line treatment
      in an attempt to avoid abdominoperineal amputation.

PMID- 12623362
TI  - Carcinoma of the gallbladder.
AB  - Carcinoma of the gallbladder is the most common malignant tumour of the biliary
      tract and a particularly high incidence is observed in Chile, Japan, and northern
      India. The aetiology of this tumour is complex, but there is a strong association
      with gallstones. Owing to its non-specific symptoms, gallbladder carcinoma is
      generally diagnosed late in the disease course, but if a patient with gallstones
      experiences a sudden change of symptoms, then a cancer diagnosis should be
      considered. Treatment with radical or extended cholecystectomy is potentially
      curative, although these procedures are only possible in 10-30% of patients.
      There is no role for cytoreductive surgery in this disease. If a gallbladder
      carcinoma is discovered via pathological examination of tissue samples, then the
      patient should be examined further and should have radical surgery if the tumour
      is found to be T1b or beyond. Additional port-site excision is necessary if the
      patient has already had their gallbladder removed during laparoscopy; however,
      patients with an intact gallbladder who are suspected to have gallbladder
      carcinoma should not undergo laparoscopic cholecystectomy. Patients with advanced
      inoperable disease should receive palliative treatment; however, the role of
      chemotherapy and radiation in these patients needs further evaluation.

PMID- 12623363
TI  - Study of suboptimum treatment response: lessons from breast cancer.
AB  - Drug resistance is the main cause of therapeutic failure and death in patients
      with cancer. However, there have been surprisingly few studies designed
      specifically to investigate the mechanisms underlying poor treatment response in
      vivo, compared with the number of phase II and III trials investigating treatment
      effects. We can now analyse the expression patterns of multiple genes by use of
      microarrays, rapid gene sequencing, and proteomics, and so need to reassess the
      way we design clinical trials to take full advantage of these new opportunities.
      I discuss the concept of clinical studies of chemoresistance in terms of the
      collection of tumour samples for biological studies, the use of appropriate
      clinical settings, and the importance of trial design. Ideally, such studies
      should investigate specific biological features in relation to measurable
      antitumour effects of single drugs.

PMID- 12623364
TI  - Extended hemipelvectomy--quality of life 20 years later.

PMID- 12623365
TI  - Conventional epidemiology and the link between SV40 and human cancers.
AB  - Simian virus 40 (SV40) is known to cause tumourigenesis. The main types of tumour
      induced by SV40 in laboratory animals mirror the human cancers that have been
      found to contain SV40 DNA or the viral oncoprotein. Increasing amounts of data
      support the notion that SV40 may be an aetiological factor in the development of
      human cancers. Retrospective birth cohort studies have been used in attempts to
      refute the alleged causal link between SV40 and human cancers. However, these
      observational studies are affected by several important confounding factors,
      which mean that firm conclusions cannot be drawn. In this essay, we consider the
      unique features of SV40 infection in humans and examine the limitations of
      conventional studies that seek to disprove the aetiological link with human
      cancer.

PMID- 12623380
TI  - Editorial.

PMID- 12623369
TI  - Cellular phrenology.

PMID- 12623381
TI  - Assessment of ambiguous coronary lesions by intravascular ultrasound.
AB  - Until recently, coronary angiography has been regarded as the 'gold standard' for
      visualizing and quantifying coronary artery disease. Coronary angiography,
      however, is a luminographic technique revealing only the inner lumen of the
      coronary artery. In contrast, intravascular ultrasound investigations yield a
      detailed morphological description of the vessel wall and plaque characteristics.
      Based on these analyses, new insights into the pathogenesis of atherosclerotic
      coronary disease have evolved, including the remodeling phenomena. Thus, nowadays
      intravascular ultrasound can be regarded as the new 'gold standard' for the
      morphological assessment of lesion severity during cardiac catheterizations.
      Likewise, intracoronary Doppler and intracoronary pressure measurements have
      demonstrated their superiority in the functional assessment of coronary stenoses.
      Intravascular ultrasound investigations can be performed with high success and
      low complication rates. The present manuscript concentrates on the value of IVUS
      for the assessment of ambiguous lesions. Several forms of ambiguous lesions based
      on the angiographic appearance, i.e. intermediate lesion with undetermined
      stenosis severity, aneurysmatic widening of the coronary segment, ostial lesions,
      branching vessels, vessel tortuosity, main stem lesions, focal spasm, sites of
      plaque rupture, dissections, unclear haziness and contrast density changes are
      discussed and illustrated by respective angiographic and IVUS examples. Both the
      advantages and the limitations of angiographic and intravascular ultrasound
      examination are discussed in detail. In conclusion, additional intravascular
      ultrasound examination helps to diagnose accurately the underlying
      atherosclerotic disease, to define lesion characteristics and to optimize
      individual patient care and cost with respect to diagnostic catheterizations and
      coronary interventions.

PMID- 12623382
TI  - Intravascular ultrasound observations of atherosclerotic lesion formation and
      restenosis in patients with diabetes mellitus.
AB  - Coronary artery disease is more aggressive in diabetic patients than in
      nondiabetics; they have more diffuse disease, higher mortality rates and worse
      clinical outcomes after coronary interventions. Intravascular ultrasound (IVUS)
      produces transmural tomographic images of the coronary arteries in vivo. Recent
      IVUS studies have provided new insights into the mechanisms of stenosis formation
      and restenosis in both nondiabetic and diabetic patients. Arterial remodeling is
      defined as a change in arterial area. During atherogenesis, an increase in
      arterial area usually accompanies plaque accumulation to delay lumen compromise.
      Stenosis formation is related to: (a) the rate of plaque accumulation versus the
      rate of positive remodeling; and (b) the limits and ultimate failure of positive
      remodeling. However, there is a marked variability in remodeling. IVUS studies
      have suggested that remodeling may be impaired in some diabetic patients during
      atherogenesis. Following non-stent catheter-based interventions, serial (post
      intervention and follow-up) IVUS studies have shown that the change in lumen area
      correlates better with the change in arterial area (remodeling) than with the
      change in plaque area (neointimal hyperplasia). In some patients, a positive
      remodeling response mitigates against the increase in plaque area to limit late
      lumen loss and restenosis. Neointimal hyperplasia is exaggerated in diabetic
      patients. Despite this, there is a reduced frequency of positive remodeling,
      potentially similar to the impaired positive remodeling in some diabetic patients
      during atherogenesis. Failed or inadequate arterial remodeling may contribute to
      the pathogenesis and natural history of atherosclerotic coronary artery disease
      in diabetic patients.

PMID- 12623383
TI  - Long period of balloon inflation and the implantation of stents potentiate smooth
      muscle cell death. Possible role of chronic vascular injury in restenosis.
AB  - BACKGROUND: It has been suggested that the severity of acute vascular injury
      immediately after percutaneous transluminal coronary angioplasty (PTCA) or stent
      implantation correlates with the extent of neointimal hyperplasia and restenosis.
      However, the influence of prolonged or chronic vessel injury on the pathogenesis
      of restenosis is unclear. METHODS: Rabbit iliac arteries were balloon dilated for
      a short (1 min) or prolonged (10 min) period of time, or were chronically dilated
      and received a Palmaz-Schatz stent (balloon inflation for 1 min). All arteries
      were overexpanded to a balloon:artery ratio of 1.2:1 as determined by
      angiography. The arteries were removed 30 min and 4 weeks after the angioplasty
      procedures. The sites of injury were evaluated by gross histology and
      transmission electron microscopy (TEM). Cell death of medial smooth muscle cells
      (SMCs) was specified by TEM images 30 min after the procedures. Computer-assisted
      quantification of the neointimal cross-sectional areas was performed after 4
      weeks using a light microscope connected to a digital image analyser. RESULTS:
      The results show that prolonged balloon dilatation and stent implantation
      increased necrotic SMC death compared with balloon dilatation for 1 min. After 30
      min, increased staining of SMC nuclei, enlarged intercellular spaces and changes
      in SMC shape in the media indicated cell death induced by prolonged balloon
      dilatation or chronic stent injury. Stent implantation markedly augmented vessel
      damage by persistent compression of the media, compared with a balloon dilatation
      for 1 or 10 min. Both prolonged balloon dilatation and stent implantation
      increased neointimal hyperplasia at 4 weeks compared with balloon dilatation for
      1 min (0.6 3 0.2 and 1.0 3 0.2 mm(2) versus 0.2 3 0.1 mm(2), P < 0.001 versus
      dilatation for 1 min). CONCLUSION: Prolonged or chronic vascular expansion due to
      long balloon-inflation periods or the implantation of stents increases medial SMC
      death, which subsequently stimulates neointimal growth in this restenosis model.
      Chronic vascular injury may be an important stimulus for restenosis after
      angioplasty procedures.

PMID- 12623384
TI  - Long-term clinical outcome after stent implantation in coronary arteries.
AB  - The long-term clinical outcome after planned and unplanned stent implantation was
      assessed in a single-center, observational study in 178 patients who underwent
      coronary stent implantation between November 1986 and July 1994. Main outcome
      measures were survival and event-free survival at 5 years (Kaplan-Meier method).
      Independent predictors for event-free survival were determined by using
      multivariate logistic regression analysis. Patients underwent planned (group 1, n
      3 101) or unplanned (group 2, n 3 77) stent implantation. During the in-hospital
      period, there were no deaths. The incidence of Q-wave and non-Q-wave acute
      myocardial infarction (AMI), coronary artery bypass graft (CABG) and repeat
      percutaneous transluminal coronary angioplasty (PTCA) was 5.0%, 2.0% and 4.0%,
      respectively, in group 1, versus 32.5%, 23.4% and 10.4%, respectively, in group
      2. During the follow-up period (median 4.0 years, range 0.29-9.8 years), the
      incidence of death, AMI, and repeat revascularization (CABG and PTCA) was 5.9%,
      8.9% and 40.6%, respectively, in group 1, versus 1.3%, 5.2% and 36.4%,
      respectively, in group 2. Survival and event-free survival at 5 years was 73 (7%)
      and 47 (7%), respectively, for patients who underwent planned stent implantation.
      It was 98 (0.1%) and 34 (6%), respectively, for patients who underwent unplanned
      stent implantation. At the end of follow-up, 31.9% of patients had angina
      pectoris class III or IV (Canadian Cardiovascular Society). The long-term
      clinical outcome after both planned and unplanned stent implantation was
      characterized by a high incidence of repeat revascularization. It is conceivable
      that changes in stent design and implantation techniques, in addition to novel
      therapeutic approaches addressing neointima formation and progression of
      atherosclerosis, may improve the long-term clinical outcome.

PMID- 12623385
TI  - Deferring angioplasty in intermediate coronary lesions based on coronary flow
      criteria is safe: comparison of a deferred group to an intervention group.
AB  - The decision for revascularization in patients with intermediate coronary lesions
      remains a challenging topic, particularly when objective data of reversible
      ischemia are lacking. In some of the patients, coronary revascularization is
      performed or deferred without definitive evidence on the clinical significance of
      the coronary stenosis. We investigated the usefulness of coronary flow reserve
      (CFR) measurements in 28 patients with intermediate coronary lesions. We compared
      20 patients who underwent angioplasty based on Doppler-wire-derived CFR with 8
      patients for whom angioplasty was deferred (diameter stenosis of 50.7 +/- 2.0%
      versus 46.5 +/- 3.1%, P < 0.0001 and CFR of 1.80 +/- 0.32 versus 2.65 +/- 0.11, P
      = 0.002, respectively). Angioplasty resulted in normalization of the CFR to 2.57
      +/- 0.53 (P < 0.0001, versus the baseline value). During a follow-up period of
      58.1 weeks (range 23-149 weeks), eight patients in the revascularization group
      were readmitted to the hospital, one of them with a myocardial infarction in the
      territory of the target vessel, compared with only one admission in the deferred
      group. Target-vessel revascularization was performed in three patients (a fourth
      patient declined it) in the former group, compared with only one in the latter.
      Symptomatic improvement or no change in clinical status was observed in the
      majority of patients in both groups (90% in the revascularization group and 87.5%
      in the deferred group). We conclude that in a selected group of patients with
      intermediate coronary lesions, measurement of CFR may be a useful tool in
      determining the need for revascularization based on its physiologic significance.
      Importantly, deferring PTCA in patients with intermediate lesions and normal CFR
      values seems to be safe.

PMID- 12623386
TI  - The ARTS (Arterial Revascularization Therapies Study): Background, goals and
      methods.
AB  - BACKGROUND: The rising costs of healthcare have forced policy makers to make
      choices, and new treatments are increasingly assessed in terms of the balance
      between additional costs and additional effects. The recent recognition that
      stenting has a major and long-lasting effect enhancing balloon PTCA procedure has
      made it imperative to compare in patients with multivessel disease the standard
      surgical procedure with multiple stenting in a large-scale multinational and
      multicenter approach (19 countries, 68 sites). METHODS: Selection and inclusion
      of patients is based on a consensus of the cardiac surgeon and interventional
      cardiologist on equal 'treatability' of patients by both techniques with analysis
      of clinical follow-up (event-free survival) on the short (30 days), medium (1
      year), and long term (3 and 5 years) with analysis of cost-effectiveness and
      quality of life (EuroQol and SF-36). Of the entire trial, the primary null
      hypothesis which needs to be rejected is that there will be no difference in
      event-free survival or effectiveness (E), at 1 year and also that the direct and
      indirect costs (C) per event-free year are not different between surgery or
      stenting. For this to become significant with a power of 90% requires 1200
      patients. Between April 97 and June 98, 1205 patients have been randomized with a
      monthly recruitment of 83 patients; the one year follow-up will thus be completed
      in June 1999. Expected costs, effects and cost-effectiveness ratio (CE ratio) for
      stents are: Stent: high-cost estimate, 2 vessel disease (C 3 $19,297, E 3 81%, CE
      ratio 3 $23,876); 3 vessel disease (C 3 $24,566, E 3 81%, CE ratio 3 $30,397) low
      cost estimate, 2 vessel disease (C 3 $16,638, E 3 81%, CE ratio 3 $20,586); 3
      vessel disease (C 3 $20,456, E 3 81%, CE ratio 3 $25,322) Compared with CABG (C 3
      $21,350, E 3 88%, CE ratio 3 $24,348) CONCLUSION: Clinically, stenting is not
      expected to be more effective than CABG, but should be cost-effective in both the
      2- and 3-vessel disease groups when using the lower-cost estimate and in the 2
      vessel group when using the higher-cost assumptions. (Int J Cardiovasc

PMID- 12623387
TI  - Acute coronary closure after stenting: a lesson from intravascular ultrasound.
AB  - Intravascular ultrasound (IVUS) is an imaging modality more sensitive for
      defining suboptimal stent deployment issues compared with conventional
      angiographic imaging. We report on a patient with unstable angina who underwent
      stent deployment using IVUS guidance. Despite an acceptable angiographic result,
      intrastent thrombus, incomplete expansion and an edge/marginal dissection were
      seen by IVUS examination. Both the incomplete expansion and the intrastent
      thrombus were successfully treated. The dissection, however, was not treated in
      the catheterization laboratory. This mechanical injury pattern at the stent edge
      led to vessel occlusion 4 h post-procedure.

PMID- 12623389
TI  - Correspondence: Stent implantation through a self-expanding stent: feasible, but.

PMID- 12623388
TI  - Late thrombotic occlusion of a malapposed stent 10 months after intracoronary
      brachytherapy.
AB  - We report a patient who received a stent following intracoronary 3-irradiation.
      Despite a good initial angiographic result, the stent appeared to be not fully
      expanded on intravascular ultrasound imaging at 6-month follow-up. Four months
      later, sudden thrombotic occlusion occurred shortly after aspirin cessation.

PMID- 12623390
TI  - Point - Counterpoint: The wide use of IIb/IIIa inhibitors in interventional
      cardiology - is it justified?

PMID- 12623391
TI  - View from the Cath Lab Topic: Multivessel stenting: staged vs non-staged
      approach.

PMID- 12623392
TI  - Images in Cardiology Imaging the coronary microcirculation: 3D micro-CT of
      coronary vasa vasorum.

PMID- 12623393
TI  - Hot topics ~ meeting report.

PMID- 12623394
TI  - Editorial.

PMID- 12623395
TI  - Radioisotope stents for the prevention of restenosis: what did we learn from pre
      clinical studies?
AB  - This article will discuss the lessons learned by using stents implanted with low
      activities of radioisotopes to prevent in-stent restenosis. A continuous low-dose
      rate radiation delivered by radioisotope stents has been shown to reduce the
      proliferative activity of smooth muscle cells and to inhibit neointimal growth.
      However, the radiation also delays endothelialization of the stents. Both the
      dose rate and the cumulative dose delivered by radioisotope stents appear to
      affect outcome. The neointima covering radioactive stents is characterized by a
      reduced cellularity, increased amounts of fibrin and extracellular matrix
      proteins. Aneurysm formation or excessive tissue destruction due to the radiation
      were not observed. Animals studies including up to 1 year follow-up periods
      suggest that beta-particle-radiation as well as gamma-radiation are effective in
      reducing neointimal hyperplasia. It is still unknown, however, which range of
      activities are needed and if a combination of radioisotopes, i.e. with short and
      long halflives, further reduce neotima formation over the long-term. An
      appropriate stent design for homogenous dose distribution around the stent may be
      important, i.e. articulations or large cell sizes may have disadvantages.
      Augmented neointima formation at the ends of radioactive stents, in particular
      when using beta-particle emitting stents, has been observed in animal models.
      Future studies will focus on the effects of increasing activity levels at the
      stent ends, optimal stent designs, alternative isotopes and different dosing
      strategies.

PMID- 12623396
TI  - Initial results and long-term clinical follow-up of an amorphous hydrogenated
      silicon-carbide-coated stent in daily practice.
AB  - The hemocompatibility and biocompatibility of a stent are determined by the
      physical and electrochemical properties of the stent surface. The aim of this
      study was to determine the feasibility, safety and efficacy of implantation of a
      stent coated with silicon carbide. Baseline characteristics were collected
      prospectively. The occurrence of cardiac adverse events and the angina score were
      assessed at clinical follow-up. A total of 193 Tensum stents were implanted in
      174 patients. In hospital, one patient experienced stent thrombosis and in 6% of
      the patients a creatinine kinase elevation to 240 U/l or more occurred. Long-term
      follow-up was performed in 172 patients, with a mean follow-up of 454 +/- 181
      days. Ninety-seven per cent were still alive, 15% had undergone target-vessel
      revascularization, and 2% had angiographic restenosis and were treated with
      medication only. Seventy-one per cent of the patients were free of anginal
      complaints, and 20% had anginal complaints in Canadian Cardiac Society class I or
      II. The Tensum coronary stent showed to be a safe and efficacious device in this
      study, with a high primary success rate and favorable long-term clinical
      followup.

PMID- 12623397
TI  - Periprocedural routines of coronary angioplasty--extreme diversity with
      unrevealed consequences.
AB  - Our objective was to evaluate the current trends of coronary angioplasty
      periprocedural care in the state of Israel. PTCA technology has undergone through
      some major developments and refinements, which have yielded new algorithms and
      routines. With this shift of paradigms, some of the periprocedural routines
      (these include medications and dosing before, during and after the procedure, as
      well as the handling of anti-coagulation, femoral sheath removal and the extent
      of patient monitoring post-PTCA) have been partially re-established. In order to
      assess trends in periprocedural care, we elected to analyze the current state of
      practice in the state of Israel. A questionnaire was sent to every cardiac
      catheterization laboratory in Israel that performs PTCA. An authorized senior
      cardiologist representing the laboratory submitted the information required for
      our survey. A nurse-to-nurse telephone questionnaire was conducted simultaneously
      to cross-examine the validity of the data. All centers submitted results. The
      average heparin dose for PTCA varied between 5000 and 15 000 units, ACT was
      monitored routinely by some and not at all by others, post-PTCA heparin
      administration was routinely administered by some institutions and not by others,
      and the mean femoral sheath dwell time ranged from 4 to 18 h. Post-PTCA cardiac
      monitoring varied from 6 to more than 24 h. Some institutions prescribed to all
      patients nitrates, calcium channel blockers and low-molecular-weight heparin,
      while others did not. We conclude that there is profound variability in the
      periprocedural routines that may translate into a significant cost increase,
      patient discomfort, a prolonged monitoring and hospital stay, and potential
      patient morbidity. We suggest that these routines should be critically evaluated,
      and that if they do not contribute to the procedural success and patient well
      being they should be abandoned.

PMID- 12623398
TI  - Plasma endothelin levels as a function of coronary artery manipulation during
      balloon angioplasty and high-speed rotational atherectomy.
AB  - This study was conducted to test the hypothesis that endothelin levels may be
      related to the coronary artery manipulation during balloon angioplasty (BA) or
      rotational atherectomy (RA). Blood endothelin levels were measured in 35 patients
      who underwent BA and in 11 patients who underwent RA followed by adjunctive
      balloon angioplasty. Arterial and venous levels were measured before, immediately
      after, and 24 h after the procedure. The levels were then related to the number
      of balloon inflations, the total inflation time and the maximal pressure in the
      balloon during inflation. There were no significant differences between groups or
      time periods. However, 24 h after BA the endothelin plasma levels in venous blood
      were directly related to the number of balloon inflations (r 3 0.49; P 3 0.03),
      to the total inflation time (r 3 0.67; P 3 0.005) and to the maximal inflation
      pressure (r 3 0.71; P 3 0.001). No such correlation was found in venous blood
      immediately after BA, either in arterial blood or in the RA group. It can be
      concluded that plasma endothelin levels do not change significantly after balloon
      angioplasty; however, venous endothelin levels 24 h after BA are related to
      procedural parameters, reflecting endothelial damage, which may determine the
      post-angioplasty late results.

PMID- 12623399
TI  - Initial single-center experience with a new intracoronary stent.
AB  - We investigated the safety and efficacy of the recently introduced intracoronary
      beStent(TM). High flexibility, zero shortening after expansion and delineating
      gold markers at either end of the stent are favorable features of this device.
      Between July 1996 and February 1997, 117 patients received a total of 126 stents,
      measuring 15, 25 and 35 mm in length. The majority of lesions were located in the
      LAD (n = 48; 38%), followed by lesions in the RCA (n = 41; 33%) and the
      circumflex artery (n = 28; 22%). Nine additional stents were delivered into vein
      grafts (7%). Successful stent deployment was achieved in 94% (n = 118), even in
      cases with complex lesion morphology and angulated segments. The markers proved
      to be helpful in placing the stent close to side-branches and whenever serial
      stents were used. Complications during hospitalization were as follows: one
      cardiac death unrelated to stenting, one subacute stent thrombosis after 30 min
      of effective anticoagulation and one Q-wave myocardial infarction due to
      peripheral thrombus embolization after stent placement in a vein graft. One
      patient was sent for elective CABG after an unsatisfactory procedural result.
      Stent loss occurred in four patients, and all stents could be retrieved
      successfully; in another four patients stent placement at the target site was
      impossible. We conclude that the investigated stent demonstrates several
      favorable stent characteristics which have proved to be useful in treating
      complex lesions by providing favorable acute results with a low complication
      rate.

PMID- 12623400
TI  - Imaging of left main trauma during diagnostic cardiac catheterization with
      intravascular ultrasound.
AB  - In this case report the occurrence of a catheter-induced coronary artery
      dissection is described. In our patient, angiography showed a mushroom-shaped
      exudate above the left main coronary artery. Intravascular ultrasound revealed a
      circular dissection with a huge false lumen connected to the true lumen by a
      small intimal tear. A brief review of the literature on catheter-induced coronary
      dissection is included. We believe that this case report provides a good
      illustration of the need for careful reviewing of indications for angiography.
      Although procedural risks are low, angiography remains an invasive diagnostic
      test with the potential to cause severe complications.

PMID- 12623402
TI  - Point - Counterpoint Coronary stent implantation in long diffuse or focal
      sequential lesions: Full coverage or Spot Stenting?

PMID- 12623401
TI  - 'Navius' kissing stents for coronary bifurcation stenosis, recreating a new
      metallic carina: an IVUS-assessed case report.
AB  - We report a case of implantation of a new design of stent which allows creation
      of a double-hemispheric lumen for the treatment of a bifurcational stenosis. The
      unfavourable outcome following the implantation of this stent is described.

PMID- 12623403
TI  - Images in Cardiology PTCA for in-stent restenosis: poor outcome explained.

PMID- 12623405
TI  - Hot topics ~ literature review January to July 1998.

PMID- 12623404
TI  - Hot topics ~ news from industry and research.

PMID- 12623406
TI  - Hot topics ~ conference report.

PMID- 12623407
TI  - Editorial.

PMID- 12623408
TI  - Direct myocardial revascularization in ischemic heart disease.

PMID- 12623409
TI  - Ultrasound angioplasty: an update review.
AB  - The use of therapeutic ultrasound to treat atherosclerosis and thrombosis has
      been appreciated for decades. However, it was only the explosive growth of
      angioplasty in the 1980s that brought real momentum to the development of
      therapeutic catheter ultrasound. The idea behind this technique was that
      ultrasound, by its bioselectivity, might provide a solution to some of the
      shortcomings of balloon angioplasty. In the late 1980s, two groups, headed by
      Rosenschein and Siegel, began serious work to address the technical challenge of
      developing a catheter that would provide efficient external ultrasound energy to
      the lesion. Current catheters from both groups consist of a solid metal probe
      which is connected to a piezoelectric transducer. In the distal segment, the wire
      is specially designed to increase energy delivery. Initial in vitro studies
      concentrated on understanding the mechanisms of ablation and the effects of
      mechanical vibration, thermal phenomena and cavitation. Clinical studies of
      ultrasound ablation were initially performed in peripheral vessels. Later, after
      safety had been assured, clinical studies involving the coronary arteries began
      to take place. In this article we aim to update the reader about the experimental
      and limited clinical experience in this novel technique for treating different
      kinds of arterial obstruction.

PMID- 12623410
TI  - Stent implantation in acute myocardial infarction using a heparin-coated stent: a
      pilot study as a preamble to a randomized trial comparing balloon angioplasty and
      stenting.
AB  - Preliminary experience with primary stenting in myocardial infarction has
      suggested a greater benefit in clinical outcome than has been obtained with
      direct balloon angioplasty. However, subacute thrombosis (SAT) remains a
      limitation for this new mode of therapy. In the BENESTENT II Pilot and main
      trials, the incidence of SAT with the heparin-coated Palmaz-Schatz stent was only
      0.15%. Therefore, as a preamble to a large randomized trial, the feasibility and
      safety of the use of the Heparin-Coated Palmaz-Schatz trade mark Stent in Acute
      Myocardial Infarction (AMI) was tested in 101 patients enrolled between April and
      September 1996 in 18 clinical centres. In 101 stent-eligible AMI patients, as
      dictated by protocol, a heparin-coated stent was implanted. The primary
      objectives were to determine the in-hospital incidence of major adverse cardiac
      events (MACE: death, MI, target lesion revascularization) and bleeding
      complications, while the secondary objectives were the procedural success rate
      and the MACE, the restenosis and reocclusion rates at 6.5 months. Stent
      implantation (n 3 129 stents) was successful in 97 patients of the 101 who were
      included in this trial. During their hospital stay, two patients died and no
      patient experienced re-infarction, ischaemia prompting re-PTCA or CABG. Four
      patients suffered a bleeding complication, three major and one minor, of whom
      three required surgical repair. At 210 days follow-up, 81% of the patients were
      event free. At 6.5 months restenosis was documented in 18% of the 88 patients who
      underwent follow-up angiography, including three total occlusions. The results,
      both with respect to QCA and the occurrence of MACE, compare favourably with
      studies using elective stenting in both stable and unstable angina patients. As a
      result of this pilot study, a large randomized trial comparing direct balloon
      angioplasty with direct stenting in 900 patients with AMI was initiated in
      December 1996.

PMID- 12623411
TI  - Coronary stent implantation throughout technical evolution: immediate and follow
      up results.
AB  - Coronary stenting (stent implantation) has evolved over the last 5 years with
      changes in stent design, stent material and the implantation technique. The use
      of high-pressure balloon inflation (HP), intravascular ultrasound (IVUS) and
      appropriate antiplatelet therapy have contributed to the abolishment of the need
      for subsequent anticoagulation, allowing extended stent applications. We compared
      results in three groups of patients having stent implantation throughout the
      period of evolution: group A: no IVUS, no HP, with subsequent anticoagulation
      treatment (n 3 434); group B: no IVUS, yes HP, without subsequent anticoagulation
      treatment (n 3 192); and group C: yes IVUS, yes HP, without subsequent
      anticoagulation treatment (n 3 588). The primary success rates were comparable in
      all groups. There was a clear change in indications for stenting in groups B and
      C compared with group A (elective stenting: group A 3 32%; group B 3 66%; group C
      3 69%; P < 0.0001), in reference vessel size (group A 3 3.22 3 0.37 mm; group B 3
      2.92 3 0.56 mm; group C 3 2.98 3 0.57 mm; P < 0.0001), and for presence of type
      B2 and C lesions (group A 3 57%; group B 3 72%; group C 3 74%; P < 0.001). The
      complication rate significantly decreased in group C (group A 3 3.6%; group B 3
      4.1%; group C 3 1.2%; P < 0.001) and the mean patient hospital stay decreased to
      2 days in groups B and C due to the abolition of the need for anticoagulant
      treatment. The angiographic restenosis rate increased in groups B and C (group A
      3 20%; group B 3 34%; group C 3 32%; P < 0.001). The need for a repeat procedure
      increased as stenting of more complex lesions and smaller vessels was attempted:
      target lesion revascularization (TLR) was performed in 16% of patients in group A
      (73/434), in 18% of group B (35/192) and in 22% of group C (129/588) (P 3 0.04
      for A versus C). Major cardiac events (MACE) occurred in 142 patients in group A
      (33%), 60 patients in group B (31%) and in 181 patients in group C (30%). The
      evolving technique of coronary stenting has expanded the spectrum of indications
      and range of coronary vessels attempted, and decreased the complication rates and
      hospital stay. However, in less-favorable subsets, additional improvements are
      needed to affect the long-term outcome.

PMID- 12623412
TI  - Low-energy X-radiation for prevention of restenosis results in localized
      inhibition of V79 fibroblast cell proliferation.
AB  - Local delivery of high-energy ionizing radiation by using 3 or 3 emitters to
      injured vessels demonstrated inhibition of cell proliferation (CP) and neointima
      formation. Low-energy ('soft') X-radiation (LEXR) offers logistic and safety
      advantages over the use of disposable radioisotopes. This study evaluated the
      efficacy of LEXR in penetration and inhibition of CP at doses similar to those
      prescribed for the use of radioisotopes for prevention of restenosis. Serial
      measurements in an ion chamber detected the attenuation of LEXR using potentials
      of 17 and 40 kV at a distance of 17 cm of air through 0-10 mm depths of serum
      containing tissue culture medium. The effect of inhibition on CP was determined
      by exposing V79 fibroblasts to a potential of 17 kV in order to deliver a
      prescribed dose of 13 Gy at a dose rate of 2.17 Gy/min to the surface of the
      cells. Complete inhibition of CP at a height of 0.00 mm occurred with 13 Gy;
      however, a 50% attenuation of the dose was measured at a medium depth of 1.22 mm
      and was associated with a reduction of 60% of the CP. LEXR demonstrated an
      ability to inhibit CP at doses equivalent to those used in techniques involving 3
      and 3 irradiation. Under such conditions, the dose gradient is too high,
      especially for large vessels. However, a catheter-based LEXR that could be
      inserted into the artery with the capability of varying effective energy would be
      ideal for intravascular applications.

PMID- 12623413
TI  - Stent implantation through a self-expanding stent.
AB  - Jailing of a side-branch is a known complication of stent implantation, and makes
      access to the side-branch difficult, especially if the stent is of the self
      expanding type. Although plain balloon angioplasty is feasible for the jailed
      side-branches, the use of newer devices (a stent, Rotablation or atherectomy) has
      not been described. We describe a novel way of treating a side-branch jailed by a
      self-expanding stent by using stent implantation through the strut of a self
      expanding stent.

PMID- 12623414
TI  - Renal artery stent implantation in a patient with bilateral renal artery stenoses
      presenting with flash pulmonary edema.
AB  - We describe a patient with a clinical presentation of moderate renal dysfunction,
      recurrent hospitalizations for congestive heart failure, and an episode of abrupt
      onset pulmonary edema (flash pulmonary edema). Diagnostic angiography revealed
      triple-vessel coronary artery disease (CAD) and bilateral severe renal artery
      stenosis. This patient underwent successful bilateral renal artery stent
      implantation with marked improvement in his functional class without further
      recurrence of pulmonary edema.

PMID- 12623415
TI  - Research letter.

PMID- 12623416
TI  - View from the Cath Lab: Topic: Intravascular ultrasound.

PMID- 12623417
TI  - Images in Cardiology.

PMID- 12623419
TI  - Hot topics ~ conference report.

PMID- 12623418
TI  - Hot topics ~ news from industry and research.

PMID- 12623420
TI  - T-cell prolymphocytic leukemia: update and focus on alemtuzumab (Campath-1H).
AB  - T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell
      lymphoproliferative disorder. While the etiology of T-PLL is unknown, recent
      progress in unraveling the molecular basis of leukemogenesis has been substantial
      and may yield novel therapeutic targets. T-PLL is a distinct disease entity and
      the diagnosis can be readily made based on characteristic clinical features and
      laboratory findings. Prior to the appearance of pentostatin and alemtuzumab in
      clinical protocols, outcome for T-PLL patients was exceedingly poor with median
      survival measured in months. While the use of alemtuzumab in particular has
      improved remissions, the disease remains incurable. Future collaborative efforts
      investigating novel treatment approaches will be crucial to improving survival
      for patients with this disease.

PMID- 12623422
TI  - "Pawn Ball Megakaryocytes": from the marvellous medici and dear Old Saint Nick to
      the unsanctified marrow of myelodysplasia.
AB  - The worlds of biology and medicine in general, and the discipline of hematology
      in particular, enjoy a rich lexicon full of fascinating etymologies. The term
      "Pawn Ball Megakaryocytes" has been used to describe a peculiar type of abnormal
      cell that can be found in bone marrow samples taken from some patients with the
      myelodysplastic syndrome (MDS). The three-ball pawnbroker's symbol that these
      megakaryocytes resemble is ancient and may have derived from the insignia of the
      Medici family or the symbol of Saint Nicholas of Myra. The murky history of the
      symbol and its significance for myelodysplasia are reviewed.

PMID- 12623421
TI  - Radiotherapy versus combined therapy in early stages with bulky disease
      aggressive malignant lymphoma.
AB  - The purpose of this study was to evaluate the use of radiotherapy compared with
      combined therapy (radiotherapy followed by chemotherapy) in early stages (I and
      II) in patients with diffuse large cell lymphoma and bulky disease. One hundred
      and thirty patients were randomly assigned to receive either radiotherapy
      involved field doses range from 40 to 48 Gy (median 44.5 Gy) or the same
      radiation therapy following chemotherapy (cyclophosphamide, doxorubicin,
      vincristine and prednisone, by six cycles. Complete response (CR) was achieved in
      58 out of 61 patients (95%) of the patients whose received radiotherapy, that was
      no different to 91% (63 out of 69 patients) in the combined therapy arm. However,
      at 10-years event-free survival (EFS) was 68% (95% confidence interval (CI): 61
      73%) in the radiotherapy arm that was statistical different to 90% (95% CI: 86
      94%) in the combined therapy group (p < 0.01). Overall survival (OS) showed
      statistical differences: 72% (95% CI 67-76%) in the radiotherapy group compared
      to 89% (95% CI: 84-93%) in the combined therapy arm (p < 0.01). Toxicity was mild
      in both groups, at this time, no second neoplasm or acute leukemia has been
      observed. We conclude that combined therapy appear to be superior in patients
      with early stages and bulky disease in patients with aggressive malignant
      lymphoma.

PMID- 12623423
TI  - Immune reconstitution and tolerance after allogeneic hematopoietic stem cell
      transplantation.
AB  - We have evaluated recovery of CD56 positive and other cell types following
      allogeneic stem cell transplantation and have found that the recovery of CD56
      positive cells was faster than other lymphoid cells after allogeneic stem cell
      transplantation, while the recovery of CD4 positive cells was markedly delayed.
      Chimerism analysis showed that mixed chimerism was often observed in younger (<30
      years old) patients. Mixed chimerism in older (> or =30 years old) patients was
      associated with rejection and relapse, while this was not found in younger
      patients. Among the chimerism of various cell populations, donor-derived CD56
      positive cells are important in early engraftment when determined in allogeneic
      nonmyeloablative stem cell transplantation (allo-NST), regardless of the
      proportion of donor-derived CD3-positive cells. Complementarity-determining
      region three (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies
      (Vbeta) showed that high level of diversity in TCR Vbeta repertoire is important
      for a late rejection and skewed TCR Vbeta repertoire is correlated with the
      occurrence of graft-versus-host disease (GVHD) especially chronic GVHD.
      Expression of inhibitory natural killer (NK) cell receptors such as CD158b and
      CD94/NKG2A on peripheral CD3-negative and -positive cells were increased in
      parallel with GVHD. Interestingly, these cells appeared to control GVHD, while
      preserving graft-versus-leukemia (GVL) effect. Analysis of cytokine gene
      expression in peripheral blood mononuclear cells showed that type 1 helper T
      cells (Th1)-derived cytokines increased in severe GVHD, while Th2-derived
      cytokines such as IL-4, IL-10 and IL-13 increased in mild GVHD. These results
      indicate that Th2 cells suppress GVHD, although Th1 cells augment GVHD. Taken
      together, evaluation of immune reconstitution and tolerance in patients receiving
      allogeneic stem cell transplantation from the various viewpoints is essential and
      useful to obtain better clinical outcome.

PMID- 12623424
TI  - Influence of one human leukocyte antigen mismatch on outcome of allogeneic bone
      marrow transplantation from related donors.
AB  - This study compares the clinical outcomes of 60 consecutive patients who received
      an allogeneic blood or marrow stem cell transplant (BMT) from one Human Leukocyte
      Antigen (HLA) mismatched related donors with those of 120 matched patients who
      had HLA identical sibling donors. The control patients were matched for
      diagnosis, disease status, conditioning regimen, and age at BMT. All patients
      received standard CYA and MTX for GVHD prophylaxis. The probability of overall
      survival (OS) at 5 years was 35% in the study group compared to 56% in the
      control group. The relapse rates and acute GVHD rates did not differ between the
      two groups. Graft failure was a significant problem in the study group compared
      to the control group (13 vs. 0%, p < 0.0001). All cases of graft failure occurred
      in patients with a mismatch in the host-versus-graft direction. BMT-related
      deaths were also increased in the study group. Forty percent of deaths were
      caused by infection in the study group vs. 19% in the control group (p < 0.01).
      In conclusion, the OS of patients receiving marrow/stem cells from one antigen
      mismatched related donors was inferior to that of controls with HLA-identical
      related donors. There was an increase in mortality related to infections
      occurring in the setting of an increased frequency of graft failure in these
      patients.

PMID- 12623425
TI  - Impaired phagocyte antibacterial effector functions in beta-thalassemia: a likely
      factor in the increased susceptibility to bacterial infections.
AB  - Bacterial diseases are serious complications of beta-thalassemia syndromes but
      the mechanisms underlying the increased susceptibility to these infections are
      not fully understood. Factors which are likely to be involved are anemia,
      splenectomy, iron-overload and alterations in innate/adaptive immune responses.
      There is substantial evidence that a defect in innate effector functions of
      phagocytes (neutrophils, monocytes/macrophages) plays an important role in the
      weakened resistance to pathogenic bacteria and is at least in part due to iron
      overload. There is substantial evidence of an iron-related defect in bacterial
      phagocytosis by neutrophils. Moreover, reduced chemotaxis by these phagocytes has
      been repeatedly demonstrated. Similarly, an impairment of monocyte bacterial
      phagocytosis and generation of anti-bacterial compounds have recently been
      delineated but any relation to iron overload needs to be established. Additional
      mechanisms of defective innate immune responses such as altered expression of
      pathogen recognising receptors and function seem possible and have to be
      explored. Further insight into innate phagocyte effector functions in beta
      thalassemia is essential for understanding the increased susceptibility to
      bacterial infections and their management.

PMID- 12623426
TI  - Detection of erythrocytes deficient in glycosylphosphatidyl-inositol anchored
      membrane proteins in patients with paroxysmal nocturnal hemoglobinuria by the
      toxin HEC secreted by Aeromonas hydrophila J-1.
AB  - OBJECTIVE: To study the feasibility of diagnosing paroxysmal nocturnal
      hemoglobinuria (PNH) with toxin HEC, the abbreviation of hemolytic,
      entreotoxigenicity and cytotoxity secreted by Aeromonas hydrophila J-1. METHODS:
      The crude toxin HEC was extracted from the culture medium of Aeromonas hydrophila
      J-1 by precipitating with saturated (NH(4))(2)SO(4) and then purified through
      DEAE52. Purified toxin HEC is different from Aerolysin in molecular weight and
      necessity of activation. Crude toxin is prepared possessed same effect as
      purified ones. This crude toxin was used to act on red blood cells (RBCs) from
      patients with PNH, non-PNH anemia, and normal persons. Absorbance at 630 nm was
      measured to quantitate the extent of hemolysis. Toxin HEC treated and untreated
      RBCs were both stained with anti-CD59 monoclonal antibody and FITC labeled goat
      anti-mouse IgG. The percentage of CD59(+) cells was detected by flow cytometry
      (FCM). RESULTS: After toxin HEC treatment, RBCs from PNH patients showed
      resistance to the toxin hemolysis, which was negatively related to the percentage
      of CD59(+) cells, while RBCs from normal persons and non-PNH anemic patient were
      nearly totally lysed. CONCLUSION: Detection of RBCs resistance to toxin HEC can
      be used for the diagnosis of PNH.

PMID- 12623427
TI  - Monitoring of low molecular weight heparin in pregnancy.

PMID- 12623428
TI  - Auto-immune haemolytic anaemia--a high-risk disorder for thromboembolism?
AB  - An audit of the effect of anticoagulant prophylaxis in acute exacerbations of
      severe autoimmune haemolysis was undertaken. All cases of this disorder
      presenting to one institution over a 16 year period were reviewed. There were 28
      patients who had a total of thirty six exacerbations of haemolysis. Anticoagulant
      prophylaxis had been introduced from 1992 following three cases with fatal
      pulmonary emboli. Venous thromboembolism occurred in 5 of 15 exacerbations
      without prophylaxis but in only one of 21 in which prophylaxis was given. It is
      suggested that auto-immune haemolysis increases the risk of thromboembolism but
      further studies are required to quantify the risks and to define optimal
      prophylactic regimens.

PMID- 12623431
TI  - Hematology morphology forum case 1. Granulocytic sarcoma.

PMID- 12623432
TI  - A biplanar reconstruction method based on 2D and 3D contours: application to the
      distal femur.
AB  - A three-dimensional (3D) reconstruction algorithm based on contours
      identification from biplanar radiographs is presented. It requires, as technical
      prerequisites, a method to calibrate the biplanar radiographic environment and a
      surface generic object (anatomic atlas model) representing the structure to be
      reconstructed. The reconstruction steps consist of: the definition of anatomical
      regions, the identification of 2D contours associated to these regions, the
      calculation of 3D contours and projection onto the radiographs, the associations
      between points of the X-rays contours and points of the projected 3D contours,
      the optimization of the initial solution and the optimized object deformation to
      minimize the distance between X-rays contours and projected 3D contours. The
      evaluation was performed on 8 distal femurs comparing the 3D models obtained to
      CT-scan reconstructions. Mean error for each distal femur was 1 mm.

PMID- 12623433
TI  - Finite element analysis of stresses developed in blood sacs of a pusherplate
      blood pump.
AB  - Mechanical circulatory support (MCS) devices are blood pumps that support or
      replace the function of the native heart. It is important to minimize the
      material stresses in the flexing blood sac or diaphragm in order to increase the
      duration of support these devices can provide. An axisymmetric finite element
      model of a pusherplate blood pump was constructed to evaluate the effect of
      various design parameters on the material stresses in a segmented poly(ether
      polyurethane urea) seamless blood sac. The design parameters of interest were the
      sac thickness, pump case wall taper, and radius of the sac between the
      pusherplate and pump case wall. The analysis involved a quasi-static analysis of
      the systolic ejection phase of the pump. The finite element solution suggested
      that the principal stresses and strains increased almost linearly with sac
      thickness. The pump case wall taper had the largest effect; decreasing the peak
      principal stresses by approximately 35% when the pump case was straight versus
      tapered. Lastly, the model demonstrated that the radius of the blood sac between
      the pusherplate and pump case wall had little or no effect on the magnitude of
      the blood sac stresses. Therefore, this study suggests that in order to minimize
      the stresses in a blood sac of a pusherplate blood pump, a straight pump case
      should be chosen with the thinnest sac.

PMID- 12623434
TI  - Assessment of the effect of mesh density on the material property discretisation
      within QCT based FE models: a practical example using the implanted proximal
      tibia.
AB  - A three-dimensional, quantitative computed tomography based finite element model
      of a proximal implanted tibia was analysed in order to assess the effect of mesh
      density on material property discretisation and the resulting influence on the
      predicted stress distribution. The mesh was refined on the contact surfaces
      (matched meshes) with element sizes of 3, 2, 1.4, 1 and 0.8 mm. The same loading
      conditions were used in all models (bi-condylar load: 60% medial, 40% lateral).
      Significant variations were observed in the modulus distributions between the
      coarsest and finest mesh densities. Poor discretisation of the material
      properties also resulted in poor correlations of the stresses and risk ratios
      between the coarsest and finest meshes. Little difference in Young's modulus, von
      Mises stress and risk ratio distributions were observed between the three finest
      models; hence, it was concluded that for this particular case an element size of
      1.4 mm on the contact surfaces was enough to properly describe the stiffness,
      stress and risk ratio distributions within the bone. Poor convergence of the
      material property distribution occurred when the element size was significantly
      larger than the pixel size of the source CT data. It was concluded that unless
      there is convergence in the Young's modulus distribution, convergence of the
      stress field or of other parameters of interest will not occur either.

PMID- 12623435
TI  - Biomechanical modeling of posterior instrumentation of the scoliotic spine.
AB  - Scoliosis is a three-dimensional deformation of the spine that can be treated by
      vertebral fusion using surgical instrumentation. However, the optimal
      configuration of instrumentation remains controversial. Simulating the surgical
      maneuvers with personalized biomechanical models may provide an analytical tool
      to determine instrumentation configuration during the pre-operative planning.
      Finite element models used in surgical simulations display convergence
      difficulties as a result of discontinuities and stiffness differences between
      elements. A kinetic model using flexible mechanisms has been developed to address
      this problem, and this study presents its use in the simulation of Cotrel
      Dubousset Horizon surgical maneuvers. The model of the spine is composed of rigid
      bodies corresponding to the thoracic and lumbar vertebrae, and flexible elements
      representing the intervertebral structures. The model was personalized to the
      geometry of three scoliotic patients (with a thoracic Cobb angle of 45 degrees,
      49 degrees and 39 degrees ). Binary joints and kinematic constraints were used to
      represent the rod-implant-vertebra joints. The correction procedure was simulated
      using three steps: (1) Translation of hooks and screws on the first rod; (2) 90
      degrees rod rotation; (3) Hooks and screws look-up on the rod. After the
      simulation, slight differences of 0-6 degrees were found for the thoracic spine
      scoliosis and the kyphosis, and of 1-8 degrees for the axial rotation of the
      apical vertebra and for the orientation of the plane of maximum deformity,
      compared to the real post-operative shape of the patient. Reaction loads at the
      vertebra-implant link were mostly below 1000 N, while reaction loads at the
      boundary conditions (representing the overall action of the surgeon) were in the
      range 7-470 N and maximum torque applied to the rod was 1.8 Nm. This kinetic
      modeling approach using flexible mechanisms provided a realistic representation
      of the surgical maneuvers. It may offer a tool to predict spinal geometry
      correction and assist in the pre-operative planning of surgical instrumentation
      of the scoliotic spine.

PMID- 12623437
TI  - Toward a generalised tensegrity model describing the mechanical behaviour of the
      cytoskeleton structure.
AB  - The control of many cell functions including growth, migration and
      mechanotransduction, depends crucially on stress-induced mechanical changes in
      cell shape and cytoskeleton (CSK) structure. Quantitative studies have been
      carried out on 6-bar tensegrity models to analyse several mechanical parameters
      involved in the mechanical responses of adherent cells (i.e. strain hardening,
      internal stress and scale effects). In the present study, we attempt to
      generalize some characteristic mechanical laws governing spherical tensegrity
      structures, with a view of evaluating the mechanical behaviour of the
      hierarchical multi-modular CSK-structure. The numerical results obtained by
      studying four different tensegrity models are presented in terms of power laws
      and point to the existence of unique and constant relationships between the
      overall structural stiffness and the local properties (length, number and
      internal stress) of the constitutive components.

PMID- 12623436
TI  - Dynamic finite element implementation of nonlinear, anisotropic hyperelastic
      biological membranes.
AB  - We present a novel method for the implementation of hyperelastic finite strain,
      non-linear strain-energy functions for biological membranes in an explicit finite
      element environment. The technique is implemented in LS-DYNA but may also be
      implemented in any suitable non-linear explicit code. The constitutive equations
      are implemented on the foundation of a co-rotational uniformly reduced Hughes-Liu
      shell. This shell is based on an updated-Lagrangian formulation suitable for
      relating Cauchy stress to the rate-of-deformation, i.e. hypo-elasticity. To
      accommodate finite deformation hyper-elastic formulations, a co-rotational
      deformation gradient is assembled over time, resulting in a formulation suitable
      for pseudo-hyperelastic constitutive equations that are standard assumptions in
      biomechanics. Our method was validated by comparison with (1) an analytic
      solution to a spherically-symmetric dynamic membrane inflation problem,
      incorporating a Mooney-Rivlin hyperelastic equation and (2) with previously
      published finite element solutions to a non-linear transversely isotropic
      inflation problem. Finally, we implemented a transversely isotropic strain-energy
      function for mitral valve tissue. The method is simple and accurate and is
      believed to be generally useful for anyone who wishes to model biologic membranes
      with an experimentally driven strain-energy function.

PMID- 12623438
TI  - A Geometro-mechanical model for pulsatile morphogenesis.
AB  - A model is proposed which imitates the morphogenesis of several species of the
      lower invertebrate animals, the hydroid polyps and permits the derivation of the
      geometry (surface curvature) of each developmental stage from that of the
      preceding stage. The model is based upon two experimentally verified assumptions.
      First, neighbouring cells are assumed to compress each other laterally in a
      regular and species-specific pulsatile manner. It is this pressure, and/or an
      active cell reaction to it, which changes the curvature of a cell layer.
      Secondly, cell layers are assumed to have quasi-elastic properties tending to
      smooth out their curvature. With our model, the different pulsatile patterns of
      cell-cell pressure are reproduced and the elasticity parameters are modulated. As
      a result, within a large zone of parameter values (a so-called "morphogenetic
      zone", MZ) realistic shapes of the rudiments are reproduced. The main principles
      of the model can also be used for interpreting the morphogenesis of other groups
      of animals. A suggested model emphasizes the self-organizing properties of a
      "stressed geometry" of embryonic rudiments.

PMID- 12623439
TI  - Abfraction and anisotropy--effects of prism orientation on stress distribution.
AB  - This work discusses the effect of enamel anisotropy in the stress concentration
      at the cement-enamel junction (CEJ), a probable cause of fracture in enamel
      leading to abfraction. Usual simplifications when developing computer models in
      dentistry are to consider enamel isotropic, or that the direction of the prisms
      is orthogonal to either the dentine-enamel interface or the tooth outer surface.
      In this paper, a more refined model for the material behavior is described, based
      on laboratory observation and on the work of Fernandes and Chevitarese. The
      material description is used in a two-dimensional (2D) finite element model of
      the first upper premolar, and the analysis is performed for two different
      situations: vertical loads, typical of normal mastication and horizontal loads,
      dominant in bruxism. The analyses were performed using a unit load, which under
      the hypothesis of linear response of the tooth, allows the combinations described
      in the text to simulate different functional and parafunctional loads. The
      results indicate that a realistic enamel description in terms of mechanical
      properties and spatial distribution of its prisms alters significantly the
      resulting stress distribution. For all cases included in this study, the detailed
      description of prism orientation and resulting anisotropy led to improved
      response in terms of stress distribution, even when loading was horizontal.

PMID- 12623440
TI  - Finite element analysis as a tool for parametric prosthetic foot design and
      evaluation. Technique development in the solid ankle cushioned heel (SACH) foot.
AB  - In this study, we developed an approach for prosthetic foot design incorporating
      motion analysis, mechanical testing and computer analysis. Using computer
      modeling and finite element analysis, a three-dimensional (3D), numerical foot
      model of the solid ankle cushioned heel (SACH) foot was constructed and analyzed
      based upon loading conditions obtained from the gait analysis of an amputee and
      validated experimentally using mechanical testing. The model was then used to
      address effects of viscoelastic heel performance numerically. This is just one
      example of the type of parametric analysis and design enabled by this approach.
      More importantly, by incorporating the unique gait characteristics of the
      amputee, these parametric analyses may lead to prosthetic feet more appropriately
      representing a particular user's needs, comfort and activity level.

PMID- 12623441
TI  - Supine rest reduces platelet activation and aggregation.
AB  - Platelet activation and aggregation are central processes in acute coronary
      syndromes and myocardial infarction, and are stimulated by physical and mental
      stress. However, it is not known if and to what extent the "ordinary" stress
      inherent in a person's daily routine contributes to platelet activation and
      aggregation. We measured platelet activation and aggregation in 12 healthy non
      smokers, before and after 45 min supine rest in a calm environment. This simple
      manouver resulted in a highly significant fall in platelet aggregation (7.9-4.4
      ohms, p<0.001) and in plasma epinephrine (35.6-22.5 ng/ml, p = 0.037),
      norepinephrine (392.8-202.7 ng/ml, p<0.001) and soluble P-selectin (51.9-44.7
      ng/ml, p<0.001). Von Willebrand factor (86.2-80.9 IU/ml) and beta-thromboglobulin
      (279.1-262.4 IU/ml) did not change significantly. Our findings show that a
      person's ordinary daily routine contributes to platelet activation and
      aggregation, and that these can be reduced by supine rest. This has
      methodological implications for studies involving measures of platelet activation
      and aggregation, and also suggests a mechanism by which bed rest in a calm
      environment may contribute, however slightly, to the management of acute coronary
      syndromes.

PMID- 12623442
TI  - Capacitative calcium influx and intracellular pH cross-talk in human platelets.
AB  - This study focuses on the potential interrelationships between changes in pH and
      capacitative calcium entry in stimulated platelets and on the participation of
      SOCs in the control of intracellular pH (pH(i)). Extracellular acidification
      reduces the Mn(2+) entry, measured by the slope of the quenching of FURA 2
      fluorescence at the isoemissive wavelength of 360 nm. In thrombin-stimulated
      platelets Mn(2+) entry is reduced by acidosis (pH(o) = 6.89) to 17 +/- 4% of
      control (pH(o) = 7.32). In platelets treated with thapsigargin (TG) to induce the
      opening of store-operated channels (SOCs) the rate of quenching was reduced by
      acidosis to 31 +/- 5 % of control. Calcium entry was measured as the peak of
      [Ca(2+)](i) response to extracellular calcium readmission after mobilization of
      calcium from intracellular stores. Changes in pH(o) of platelet suspension media
      markedly alters the calcium entry evoked by thrombin that reach a 16 +/- 6 % of
      control in acidosis (pH(o) = 6.89) and 150 +/- 15% of control in alkalosis (pH(o)
      = 7.62). The SERCA inhibitor TG was used to study the effect of pH(o) on Ca(2+)
      influx. Acidosis decreases and alkalosis increases the capacitative calcium entry
      to 22 +/- 4 % and 129 +/- 1% of control respectively. These changes in pH(o) also
      produced changes in pH(i). Treatment of platelets with titrated solutions of
      trimethylamine causes intracellular alkalinization without changes in pH(o)
      increasing the capacitative calcium entry to 120 +/- 5%. TG itself produces an
      intracellular alkalinization that is further increased by calcium entry. Blockage
      of the Na(+)/H(+) exchanger reverted TG effect on pH(i) without changes in
      capacitative calcium entry.

PMID- 12623443
TI  - Both the ADP receptors P2Y1 and P2Y12, play a role in controlling shape change in
      human platelets.
AB  - Two types of ADP receptors, P2Y(1) and P2Y(12) are involved in platelet
      aggregation. The P2X(1) receptor is also present but its role, in terms of
      platelet function, is not yet defined. The aim of this study was to establish if
      the ADP receptors, P2Y(1,) P2Y(12) and P2X(1) play a role in controlling platelet
      shape change (PSC) in human platelets. PSC is an early phase of platelet
      activation that precedes aggregation. Using a high-resolution channelyzer, PSC
      was assessed by measuring the median platelet volume (MPV). The P2Y(1) receptor
      antagonist MRS 2179 (1.06 - 10.25 micro mol/l) blocked ADP-induced PSC (by 100%).
      The median IC(50) was 3.16 micro mol/l. MRS 2179 also significantly (P = 0.01)
      inhibited PSC induced by the combination of ADP + serotonin (5HT). The P2Y(12)
      receptor antagonist AR-C69931MX significantly inhibited (at 10s, P = 0.009; 15 s,
      P = 0.001 and 30 s, P = 0.015) ADP-induced PSC. The P2X(1) receptor antagonist
      TNP-ATP had no significant effect on ADP- or ADP + 5HT-induced PSC. We conclude
      that the IC(50) of a P2Y(1)-blocker can be derived because of the high-resolution
      and reproducibility of the channelyzer technique. In addition to the P2Y(1)
      purinoceptor, the P2Y(12)receptor appears to be involved in ADP-induced PSC since
      this process was significantly inhibited by AR-C69931MX. The channelyzer
      technique may be more reliable than optical aggregometry to assess PSC.

PMID- 12623444
TI  - Molecular and biochemical evidence for the presence of type III adenylyl cyclase
      in human platelets.
AB  - The isoform(s) of adenylyl cyclase (AC) present in human platelets has not been
      identified, and evidence supporting a role for AC in platelet aggregation is
      equivocal. We recently characterized deaggregation as an active component of the
      platelet aggregation response that may be an important determinant of the extent
      and duration of aggregation. G(i)-coupled receptors are linked to the inhibition
      of AC and are targets of antiplatelet drugs. They also affect platelet
      aggregation by modulating deaggregation, suggesting a role for AC in modulating
      this response. The purpose of this study was to identify the AC isoform(s)
      present in human platelets and to identify its physiological modulators. RT-PCR
      screening of platelet, buffy coat layer cell and bone marrow megakaryocyte cDNA,
      and Western blot analysis with AC type III (AC-III) antibodies identified AC-III
      in platelets and in megakaryocytes. Human platelet AC-III was cloned and
      expressed in HEK293 cells and its characteristics compared to native platelet AC.
      Both platelet AC and cloned AC-III required Mg(2+) for activity, were insensitive
      to Ca(2+) and were G(s)- and G(i)-coupled. Zn(2+) and SQ22536 inhibited platelet
      AC activity. The affinity of SQ22536 was increased with Mg(2+)-related
      stimulation of AC, while that of Zn(2+) was unchanged, which is consistent with a
      non-competitive interaction between the two metal ions on AC. The Zn(2+) chelator
      TPEN reversed the inhibitory effects of Zn(2+). This study identified AC-III as
      the predominant AC isoform in human platelets, the activity of which may affect
      the extent and duration of the net aggregation response by modulating
      deaggregation.

PMID- 12623446
TI  - ATP diphosphohydrolase in human platelets from patients with coronary arteries
      heart disease.
AB  - ATP diphosphohydrolase is an enzyme described in platelets and may be related to
      the control of ADP-dependent platelet aggregation. Platelet aggregation in
      atherosclerotic coronary arteries, and the release of platelet-derived factors,
      play an important role in coronary artery disease syndromes. In this study, we
      determined the activity of ATP diphosphohydrolase in platelets from patients with
      chronic and acute coronary artery disease syndromes and healthy persons. The
      following groups were studied: healthy persons (group I), patients with chronic
      heart disease (group II) and acute heart disease (group III). Results did not
      demonstrate differences between the groups studied. The control group
      demonstrated a lower range of enzyme activity. The patients from groups II and
      III had ingested drugs with actions upon the cardiovascular system and the
      effect, in vitro, of these drugs upon the ATP diphosphohydrolase activity in
      human platelets was also investigated. The in vitro experiments demonstrated that
      2.0 mM acetylsalicylic acid inhibited ATP hydrolysis by human platelets by
      approximately 55%. Significant correlation was observed between ADP hydrolysis
      and glucose blood levels in the control group and between ATP hydrolysis and
      triglycerides in the group II. These results contribute to our understanding of a
      possible relationship between ATP diphosphohydrolase and thrombogenesis.

PMID- 12623445
TI  - Effect of infusing rat monoclonal antibodies to the murine GPIb-IX-V complex on
      platelet and megakaryocyte morphology in mice.
AB  - In the Bernard-Soulier syndrome, the absence of GPIb-IX-V leads to
      thrombocytopenia and giant platelets. In autoimmune thrombocytopenia in man, anti
      platelet antibodies are associated with changes in megakaryocyte (MK) morphology
      and platelet size heterogeneity. We have compared the ultrastructural changes in
      mature MK following the infusion of rat monoclonal antibodies (MoAbs) to
      different epitopes of the murine GPIb-IX-V complex in mice. Blood and marrow
      samples were examined during both the acute thrombocytopenic phase and during the
      recovery phase. A MoAb to GPV induced neither thrombocytopenia nor changes in
      platelet morphology. During the acute thrombocytopenic phase with anti-GPIbalpha
      MoAbs, the size of residual platelets was heterogeneous and included large forms
      and platelets with few granules. During recovery, platelet size heterogeneity
      continued, and some platelets showed signs of activation. But only rare platelets
      were giant forms with ultrastructural defects resembling BSS.
      Megakaryocytopoiesis during acute thrombocytopenia was already abnormal, with
      some mature cells often showing vacuoles and an irregular development of the
      demarcation membrane system which varied in extent. These changes continued into
      the recovery phase. The anti-GPV MoAb had no effect on MK. Thus, anti-platelet
      antibodies can induce a different medullary response even when binding to the
      same receptor.

PMID- 12623447
TI  - Giant electron-dense chains, clusters and granules in megakaryocytes and
      platelets with normal dense bodies: an inherited thrombocytopenic disorder I.
      Megakaryocytes.
AB  - A woman and her male child were referred because of life-long thrombocytopenia,
      moderately increased platelet size, and absence of laboratory findings suggesting
      immune thrombocytopenia or defective platelet function. Evaluation of their
      platelets in the electron microscope revealed the presence of organelles never
      seen before in human cells. The present study has focused on megakaryocyte
      pathology to be sure the aberrant platelet organelles originated in the parent
      cell. There were two different types of organelles developing in megakaryocytes
      from our patients unrelated to the formed organelles in the large cells. No
      relationship could be identified between the aberrant structures and alpha
      granules, lysosomes or dense bodies. One of the large organelles was intensely
      electron opaque and appeared to arise from small dense fragments forming in
      segments of endoplasmic reticulum. The second, target-like organelle also
      appeared to develop in the endoplasmic reticulum. Its smallest precursors were
      hexagonal fragments with a granular layer inside a more electron-dense outer
      layer. Fusion of these elements resulted in formation of typical target-like
      organelles. Ultimately the target-like organelles became electron opaque and
      difficult to distinguish from the large dense bodies. Other features of these
      unusual structures were identified in platelets from the two patients and will be
      discussed in a subsequent report.

PMID- 12623448
TI  - Leadership in education and the strategy of the dolphin.

PMID- 12623449
TI  - Writing effective consultation letters: 12 tips for teachers.
AB  - Written correspondence is the standard mode of communication between healthcare
      providers. Despite the importance of this skill and increased emphasis on
      ambulatory care, communication skills and professionalism in training programs,
      there has been very little written on the teaching and evaluation of consultation
      letter writing. Consultation letter writing is an essential skill that cannot be
      learned simply by reading others' letters and should be taught in a formal
      manner. This article describes the authors' experience in teaching the skill of
      writing effective consultation letters to residents and describes strategies for
      evaluating this skill.

PMID- 12623450
TI  - How we teach on a 'Return to General Practice' course.
AB  - This article describes a course, for doctors returning to general practice,
      modelled on Harden's 10 questions when planning a curriculum. The course has been
      running in the West Midlands region of the United Kingdom for the past four
      years.

PMID- 12623451
TI  - Developing the teaching instinct, 4: Needs assessment.

PMID- 12623452
TI  - Psychological myths in e-learning.
AB  - Traditional education and training has paid scant attention to the psychology of
      learning. Despite detailed research into motivation, distribution and
      reinforcement, most current methods of delivery still rely on a supply-led,
      lecture and classroom-based model that flies in the face of the theory. With e
      learning we have a chance to reflect on this gap between theory and practice. E
      learning, in the sense of web-based learning, is a new discipline but the
      psychology of learning has a much longer pedigree. This paper relates some common
      myths about e-learning back to some major themes in the psychology of learning.
      Is e-learning faster and more effective? Many people get the wrong learning at
      the wrong time. Can e-learning help with prerequisite knowledge? Should the
      learning be massed or distributed, i.e. all at once or little and often? There
      are also the issues of motivation and cognitive engagement. How can e-learning
      motivate learners or how can we motivate learners into using this new medium?
      What type of cognitive engagement is necessary for learning? Traditional 'sheep
      dip' methods of learning are poor on reinforcement. Can e-learning help reinforce
      learning?

PMID- 12623453
TI  - Computer-assisted instruction of carpal bone radiograph interpretation.
AB  - This paper describes the development of a computer-assisted self-directed
      learning module to teach carpal bone radiograph interpretation to clinical
      clerks, and the evaluation of its efficacy as a teaching tool. The module was
      developed using commercially available authoring software and in collaboration
      with radiologists. Following an eight-month period where the module was a
      mandatory component of the clerkship rotation in emergency medicine, a
      convenience sample of 36 volunteers from various levels of medical training were
      recruited, and their ability to interpret carpal radiographs was tested in an
      objective structured clinical examination (OSCE). The scores of the clinical
      clerks who had completed the module were shown to be similar to the scores of
      emergency medicine residents with specific experience and training in this skill
      (mean: 5 vs. 6), and different from the scores of trainees who had not completed
      the module and had no specific training in this skill (mean: 5 vs. 2). This study
      suggests that our module may be an effective tool in teaching this skill to
      clinical clerks.

PMID- 12623454
TI  - Alternative learning environments: what do they contribute to professional
      development of medical students?
AB  - Special study modules provide opportunities for students to develop lifelong
      learning skills and develop areas of interest. The GMC also recommends
      opportunities to study topics not included in the core medical curriculum. This
      paper reports the evaluation of modules based within alternative learning
      environments developed to provide students with experiences outside traditional
      medical, scientific or academic cultures. The attachment was highly rated as
      contributing to professional development, provided novel learning experiences,
      and was stimulating for both students and supervisors. All students achieved new
      skills that they felt were pertinent to their personal development. Assessment
      was by standardized pro forma, including generic transferable skills and module
      specific outcomes. Whilst overall assessment grades were comparable to similar
      course components, unease amongst both students and supervisors was expressed
      reflecting anxieties in the diversity of workloads and assessment. Attempts to
      standardize assessment across the diversity of modules did not reduce anxieties
      and potentially detracted from the learning experiences.

PMID- 12623455
TI  - The undergraduate curriculum of Faculty of Medicine and Health Sciences,
      Universiti Malaysia Sarawak in terms of Harden's 10 questions.
AB  - The curriculum of the Faculty of Medicine and Health Sciences (FMHS) is designed
      particularly to cater for the health needs of the State of Sarawak, Malaysia. The
      framework of the curriculum is built on four strands: biological knowledge,
      clinical skills, behavioural and population aspects. The training is community
      based and a graduate of FMHS is expected to possess the ability to deal with many
      ethnic groups with different cultures and beliefs; expertise in tropical
      infectious diseases; skills to deal with emergencies such as snakebite and near
      drowning; qualities of an administrator, problem-solver and community leader; and
      proficiency in information and communication technology. The content of the
      curriculum strives for commitment to lifelong learning and professional values.
      The FMHS has adopted a 'mixed economy' of education strategies and a 'mixed menu
      approach' to test a wide range of curriculum outcomes. The FMHS fosters
      intellectual and academic pursuits, encourages friendliness and a sense of social
      responsibility and businesslike efficiency.

PMID- 12623456
TI  - Professional socialization: students' expectations of being a physiotherapist.

PMID- 12623457
TI  - Evaluation of the impact of pharmacist-led therapeutic tutorials on third-year
      medical students' knowledge and understanding of drugs used in clinical practice.
AB  - Three cohorts of third-year medical students on clinical placements were compared
      (n = 48). One cohort (study group, n = 18) attended a series of therapeutic
      tutorials led by the pharmacist. The other two cohorts (control group A and
      control group B) did not. The tutorials focused on using problem-based cases to
      review the therapeutic management of common medical conditions. The performance
      of the three cohorts was assessed using a written therapeutics test consisting of
      multiple-choice questions and problem-based cases. The study group also completed
      a questionnaire, which sought to obtain their opinions on the tutorials. The
      study group performed significantly better than control group A and control group
      B in both the multiple-choice questions and problem-based cases (p < 0.05,
      Student's t-test). The responses to the questionnaires indicated that all
      students welcomed the opportunity for structured teaching of therapeutics during
      their clinical placements. The students identified the need for more teaching of
      therapeutics in the undergraduate medical curriculum. All the students agreed
      that the pharmacist was an appropriate person to lead the tutorials.

PMID- 12623458
TI  - Role of a medical students' association in improving the curriculum at a faculty
      of health sciences.
AB  - The Joyce and Irving Goldman School of Medicine, Faculty of Health Sciences at
      the Ben Gurion University of the Negev encourages students to take part in the
      development and evaluation of the teaching experience. These special relations
      between the school and the students contribute not only to changes in the
      curriculum but also to increased involvement of faculty and students in the
      community. This article reviews the special relationship between the Faculty of
      Health Sciences and its medical students through the Medical Students Association
      (ASRN). During the last decade, BGU medical students have initiated innovative
      programmes some of which have recently become integrated into the curriculum.
      These include: prevention of sexual violence among youth, decreasing white-coat
      fear in small children ('Teddy Bear hospital') and participation in home-hospice
      activities. By encouraging students to become equal partners in faculty
      development and rejecting the traditional paternalistic mode of teacher-student
      relationships, the faculty has created an improved learning experience, and
      increased student motivation and levels of communication between the teachers and
      the future clinicians.

PMID- 12623459
TI  - Who would become a successful Dean of Faculty of Medicine: academic or clinician
      or administrator?
AB  - It has been a long tradition that the medical school dean is an expert in a
      specialist field with a well-established reputation in research and clinical
      services. Medical education is no longer simply disease orientated; it is
      required to put an emphasis on prevention, the need for better management of the
      health care system, and the need for a better understanding of the sociopolitical
      aspects of medical care. The deans of medical schools must appreciate the social
      role of medical education, and the social contract with the community. Although
      doctors might have difficulties with leadership because they are trained to work
      as individuals and to value highly their independence and autonomy, good
      communication skills are an asset for clinicians in management roles. It does not
      matter whether the background of the dean is academic, clinical or
      administrative; the most important thing is to possess the managerial skills to
      tackle the three-way tension between management, academic leadership and
      professional leadership. The job should be open to people with a good knowledge
      of and background in health and fiscal expertise, and also a high degree of
      management, diplomatic and interpersonal skills. Those skills should also be
      emphasized in the medical curriculum.

PMID- 12623460
TI  - Chronically diseased patients and their doctors.
AB  - The doctor-patient relationship reflects the role of the physician in society and
      has thus experienced substantial changes over time. Medical authority can be
      dissected into three elements, all of which appear essential for any doctor
      patient relationship: sapiental authority, i.e. professional competence as called
      for e.g. by the system of evidence-based medicine; moral authority (paternalism);
      and charismatic-empathic authority (to treat any patient like a friend). These
      elements are mirrored by chronically diseased patients who want to be seen as
      either consumers, clients or patients. The healthcare system needs these three
      elements to be maintained and further developed and medical school education
      needs to focus more specifically on these basics of patient care.

PMID- 12623461
TI  - Guidelines for developing an online learning strategy for your subject.
AB  - In the academics' quest for curriculum implementation of flexible learning and
      flexible delivery methods, the tendency is simply to reformat subject materials
      and learning strategies to fit the technology and present them thus online.
      Attention is too often focused on the technology rather than the educational
      underpinnings, which eventually leads to compromising both the students and the
      subject. A multifaceted approach, integrating technological, disciplinary and
      pedagogical expertise, was found essential in solving this problem. Using this
      approach and the experience gained during the conversion of a subject taught face
      to-face through an online distance mode, this paper aims to focus on the
      processes that characterize the design and development of educationally sound
      online subjects. The guidelines include: identifying the target group,
      consideration of the five stages of developmental cycles, implementation of the
      subject, and evaluation. Favourable responses from participants, together with a
      10% increase in graded passes, suggest that the guidelines are sound.

PMID- 12623463
TI  - Teamshaping in medical teaching: changing groups to teams.
AB  - The ability to work in teams is stated increasingly often as a prerequisite in
      medical job descriptions. At the Institute of Medical Psychology, University of
      Vienna, a team development model (Teamshaping) that integrates self-reliance, the
      acquisition of knowledge and team sensitivity has been developed over the years.
      The model is recommended for teaching medical students because it not only
      expands the integrated approach to small-group learning but also includes
      competence for teamwork.

PMID- 12623462
TI  - Passive learning: a marker for the academically at risk.
AB  - The authors found that students who exhibited passive learning behavior (i.e.
      early and consistent signs of being disengaged during formal, curriculum-based
      interactive activities) were at greater risk of experiencing academic difficulty
      during the first two years of medical school.

PMID- 12623464
TI  - What do students say about the early clinical exposure at B.P. Koirala Institute
      of Health Sciences, Nepal?

PMID- 12623472
TI  - A multicentre evaluation of the two-layered repair of postpartum perineal trauma.
AB  - We set out to compare a policy of two-layered postpartum perineal repair leaving
      the skin unsutured with a policy of three-layered repair, which involved skin
      closure. Parturients who sustained a second-degree tear or an episiotomy in four
      Nigerian centers were randomised to have either a two-layered repair (417 women)
      or a three-layered repair (406 women). Fewer women in the two-layered group
      reported perineal pain at 48 hours (57% vs. 65%, relative risk [RR] 0.87, 95%
      confidence interval [CI] 0.78-0.97) and 14 days postpartum (22% vs. 28%, RR 0.77,
      CI 0.61-0.98). The two-layered repair was also associated with reduced risk of
      suture removal (6% vs. 10%, RR 0.62, CI 0.39-0.99), and less superficial
      dyspareunia at 3 months (6% vs. 12%, RR 0.52, CI 0.33-0.81). The rates of wound
      healing were similar between the two groups. Leaving the skin unsutured during
      postpartum perineal repair reduces perineal pain and dyspareunia.

PMID- 12623465
TI  - Doctors telling stories: the place of anecdote in GP registrar training.
AB  - Observational studies within a hospital setting confirm the widespread use of
      anecdotes in hospital-based medical education and hypothesize a number of reasons
      for this. Whilst anecdotes may be used effectively in teaching there can be
      dangers in their inappropriate use. There is no information on the level and
      nature of the use of anecdotes within medical education in the community. The
      authors undertook a questionnaire study that asked GP trainers about how they
      used anecdote in their GP registrar teaching. The results suggested that GP
      trainers use anecdotes frequently in their registrar teaching, recognize the use
      of anecdotes described in the literature and have little concern that anecdotes
      might mislead. The authors discuss how anecdotes may be used to help build
      registrars' illness scripts, and to develop ways of thinking and working
      congruent with the existing professional community.

PMID- 12623473
TI  - Active management of labour in a district hospital setting.
AB  - The aim of this randomised trial was to determine the effect of the policy of
      active management of labour in all its components on the rate of caesarean
      section in a Nigerian district hospital setting. Two hundred and twenty-one
      nulliparous women fulfilling selected inclusion criteria were randomised to
      receive active management of labour, and 227 control women received routine
      labour management. Labour was significantly shortened by over 2 hours with active
      management of labour, and caesarean section reduced (9% vs. 16%, RR 0.57, 95% CI
      0.34-0.95). There were no significant differences in maternal infectious
      morbidity, uterine hyperstimulation syndromes, ruptured uterus or neonatal Apgar
      scores between the two groups. We conclude that active management of labour
      shortens primigravid labour and reduces caesarean risk.

PMID- 12623474
TI  - A randomised controlled trial of misoprostol versus oxytocin in the active
      management of the third stage of labour.
AB  - Our objective was to compare oral misoprostol with intramuscular oxytocin in the
      prevention of postpartum haemorrhage. Four hundred and ninety-six women were
      randomised to receive either 600 microg misoprostol orally or 10 IU oxytocin
      intramuscularly after delivery. There were no significant differences between the
      misoprostol and oxytocin groups with regard to the incidence of postpartum
      haemorrhage (1% vs. 0% respectively, relative risk (RR) 3.02, 95% confidence
      interval (CI) 0.32-28.88) or drop in haemoglobin concentration (0.71 g/dl vs.
      0.68 g/dl, respectively, P = 0.699). The length of the third stage of labour and
      the percentage of women requiring manual removal of placenta, further oxytocics
      or blood transfusion were also similar. Shivering was significantly higher with
      misoprostol (57% vs. 14%; RR 4.06, CI 2.93-5.62), but there were no differences
      in other side effects. We conclude that oral misoprostol can replace
      intramuscular oxytocin in reducing postpartum haemorrhage in low-risk women, in
      developing countries, especially as it is administered orally and it is
      thermostable in tropical conditions.

PMID- 12623475
TI  - The significance of serum uric acid, creatinine and urinary microprotein levels
      in predicting pre-eclampsia.
AB  - The object of this study was to determine whether serum uric acid, serum
      creatinine and urinary microprotein levels could be used to identify women who
      might subsequently develop pre-eclampsia during pregnancy. This is a cross
      sectional descriptive study performed on women attending the University antenatal
      clinic in Colombo South Teaching Hospital, Sri Lanka. Serum uric acid, creatinine
      and microproteinuria levels were determined in 256 women attending the antenatal
      clinic at 28 weeks of pregnancy. Subsequently they were followed-up at 2-weekly
      intervals until 36 weeks and weekly thereafter until delivery. At each visit
      blood pressure was recorded and serum uric acid, creatinine and microprotein
      levels were determined. Fifty-nine women developed blood pressures of 140/90 mmHg
      or more during the study period. Serum uric acid and serum creatinine levels did
      not show any significant difference before the elevated blood pressures were
      recorded. Microprotenuria levels of more than 375 mg/l were recorded in 43 women
      before elevation of their blood pressure. Sixty-five women of 197 who remained
      normotensive had microproteinuria levels of more than 375 mg/l. The sensitivity
      and specificity of microproteinuria levels of more than 375 mg/l as a screening
      test for prediction of pre-eclampsia was 73% and 67%, respectively. Therefore,
      microproteinuria of more than 375 mg/l may be used as a cut-off value and as a
      screening test for the early detection of women at risk of developing pre
      eclampsia. Serum uric acid and creatinine had no predictive value as a screening
      test for pre-eclampsia.

PMID- 12623476
TI  - Lymphocyte subpopulations in pregnancy complicated by hypertension.
AB  - The immune responsiveness of women is altered during pregnancy in order to retain
      protective properties against disease and at the same time allow tolerance of the
      fetus. Diseases such as pre-eclampsia (PE) have been suggested to arise as a
      result of maladaptations in these immune alterations. Here we evaluate the effect
      of PE on the composition of peripheral blood lymphocyte subpopulations using
      lymphocyte surface antigen expression. Fifty-four women of various parities with
      pregnancy-induced hypertension (PIH) (39 non-proteinuric and 14 proteinuric) and
      matched controls (30 normotensive pregnant women (NTP) and 15 healthy non
      pregnant women (NP)) were investigated. Monoclonal antibodies specific for human
      T lymphocytes and subpopulations: CD2, CD3, CD4, CD8, CD19 and activation
      markers: CD25, CD45RA, CD45RO, CD54 AND HLA(-)DR were used and detected using a
      two-colour fluorescence analysis with an automated flow cytometer. The total
      number of T lymphocytes: CD2, CD3, CD4, CD8 and CD19 were significantly decreased
      in PIH particularly PE (P<0.05). T cells expressing NK surface markers
      (CD3/CD16(+)CD56) and CD4 cells expressing HLA(-)DR were higher in PE. CD8(+)HLA(
      )DR(+) cells and T-helper cells expressing adhesion molecules) CD4(+)CD54(+))
      were higher in NTP than in NP and PE (P<0.05, 0.05). PE is associated with
      elevated levels of CD4(+)HLA(-)DR(+), and CD3(+)NK cells but decreased total
      numbers of T lymphocytes, and the CD3(+)CD25(+) subpopulation. These findings
      indicate systemic alterations in maternal immunity associated with the PE state.
      This feature of the disease may contribute to abnormal adaptation to pregnancy
      resulting in PE and PIH, promoting adverse outcomes including pregnancy loss.

PMID- 12623477
TI  - A new predictor of cephalopelvic disproportion?
AB  - Cephalopelvic disproportion (CPD) is a recognised obstetric problem with
      potential risk to both mother and infant. Identification of those mothers at risk
      of CPD is difficult and has concentrated in the past on such measurements as
      maternal shoe size and height. Our objective in this study was to examine new
      anthropomorphic parameters as indicators of CPD. This was a case controlled study
      of sixty consecutive women, and their partners, who had caesarean section
      performed for CPD and 60 case matched controls. Measurements included maternal
      and paternal head circumference, height, shoe-size, body mass index (BMI), infant
      weight and head circumference. Parity, gestation at delivery, and mode of onset
      of labour were recorded. Data were analysed using Stata Release 6. Prognostic
      factors were tested for association with CPD using conditional logic regression.
      The most important anthropomorphic risk factors for CPD were maternal head
      circumference in relation of height (P < 0.001), and paternal head to height
      ratio (P = 0.017). Head to height ratio is taken as the head circumference in
      centimeters divided by the height in metres. Body mass index was higher in CPD
      cases (maternal case mean = 27.1, control mean = 25.5; paternal case mean = 27.2,
      control mean = 26.2). Infant head circumference was not a predictor. Primiparity
      was an important independent predictor (P<0.001), regardless of the mode of onset
      of labour. Maternal or paternal shoe-size, induction of labour and gestation at
      delivery were not predictors. The risk profile for CPD which emerges is one of a
      tall father where both mother and father have large head-to-height ratios.

PMID- 12623478
TI  - Fetal macrosomia at the University College Hospital, Ibadan: a 3-year review.
AB  - The study aimed to determine the maternal characteristics and contribution to
      obstetric morbidity of infants presenting with fetal macrosomia at the University
      College Hospital, Ibadan. This was a retrospective study. Obstetric data of the
      mothers were extracted from the casenotes and analysed. Fetal characteristics
      such as sex and weight, and perinatal complication were also analysed. The
      maternal characteristics that were significantly different in the study and
      control groups were parity, term weight >/= 90 kg, previous history of fetal
      macrosomia and mean duration of pregnancy. There was no significant difference in
      maternal age or height. The incidence of caesarean section was three times more
      common in the study group. There were three cases of shoulder dystocia in the
      study group but none in the control group. The mean birth weight of macrosomic
      babies delivered by section or macrosomic babies that died was higher than the
      mean birth weight of macrosomic babies delivered per vagina or that survived.
      Severe asphyxia at 1 minute was significantly higher in the study group.
      Perinatal mortality among macrosomic babies was 11.4/1,000. There was no
      mortality in the control group. It is suggested that clinical suspicion of
      macrosomic based on risk factors such as those identified in this study may be
      found useful in antenatal prediction.

PMID- 12623479
TI  - Changing patterns in the management and outcome of breech presentation over a 7
      year period. Review from a referral hospital in Saudi Arabia.
AB  - A retrospective study that was conducted on 755 singleton breech deliveries over
      a 7-year period between January 1994 and December 2000 at a referral hospital in
      Saudi Arabia showed that it represented 3.35% of all deliveries. There was a
      statistically significant trend in caesarean section (P = 0.001) accompanied by a
      modest linear trend in perinatal mortality (P = 0.049). There were no
      statistically significant differences in the mean age, parity and birth weight
      when the women delivered during each year were compared (P > 0.05), but there
      were statistically significant differences in the gestation at delivery (P <
      0.05). Furthermore, statistically significant differences were found in the
      trends of the preterm breech deliveries and booking status over the period of
      study (P > 0.05). However, there was no statistically significant linear trend in
      the birth trauma (P > 0.05). Nineteen cases of the fetal birth trauma (67.8%)
      were associated with vaginal breech delivery while nine cases (32.2%) were
      reported from caesarean section. This was statistically significant (P =
      0.00074). The role of selective external cephalic version as a way of reducing
      the caesarean section rate and also trauma during vaginal breech delivery at term
      in our community is discussed.

PMID- 12623480
TI  - Attitudes of patients to obstetric analgesia at the University College Hospital,
      Ibadan, Nigeria.
AB  - Pain relief, for different reasons, is controversial worldwide. We designed this
      study to assess the level of awareness of antenatal patients to analgesia in
      labour and to evaluate the effect of age, parity and educational status on the
      awareness and acceptability of pain relief in labour. A structured questionnaire
      was administered to 1,000 antenatal patients between 1 June 2000 and 31 May 2001.
      Spearman's correlation coefficient was applied to estimate the correlation
      between the ranked dependent variable (awareness and acceptability) and age,
      parity and educational status (independent variables). Awareness of pain relief
      methods was seen in only 27.1%. The most common method known was the use of
      systemic opioids (80%); only 10% were aware of epidural analgesia and about 14%
      knew of inhalational analgesia. Acceptance of methods was, however, 57.6%. The
      most common reason for non-acceptance was that 'The pain of labour is natural' in
      76.5%, 12% feared complications to the baby and 25% gave other reasons. Age,
      parity and educational status did not affect awareness. Educational status had
      positive correlation (rho = 0.13, P < 0.05) with acceptance while age had a
      negative correlation (rho = -0.124, P<0.05). Awareness of obstetric analgesia is
      still relatively low in this environment; however, a high proportion of patients
      would accept analgesia in labour if offered.

PMID- 12623481
TI  - Maternal neutrophil apoptosis in pre-eclampsia.

PMID- 12623482
TI  - Sex ratio imbalance and birth weight in newborns with isolated hypertrophic
      pyloric stenosis.

PMID- 12623483
TI  - Surgical management of early stages of cervical cancer: the value of internal
      iliac artery ligation.
AB  - Assessment and removal of pelvic lymph nodes is an essential component of radical
      surgery for gynaecological cancer. However, control of pelvic haemorrhage
      presents a challenge to the gynaecologist. This study was designed to determine
      the value of routine bilateral internal iliac artery ligation (BIIAL) in the
      management of patients with early states of cervical cancer treated at the
      University Teaching Hospital (Benin). The data sheets of 32 patients who had a
      radical hysterectomy for Stages 1-2a carcinoma of the cervix (cases) and 128
      patients (controls) who had had either total abdominal hysterectomy or other
      gynaecological pelvic surgery for benign conditions, between January 1992-2000,
      were analysed. Information extracted for analysis included socio-biological data,
      blood loss, complications at surgery and postoperative events. BIIAL was
      performed as a routine part of the procedure to control pelvic haemorrhage. The
      mean age of patients was 43.5 years +/- 9.4, with a range of 25-65. The mean
      parity was 6.64 +/- 2.11, range 2-11; 14/32(43.7%) and 11/32 (34.38%) of the
      patients had Stages IIA and Ib diseases. The mean pre- and postoperative PCV was
      32% and 31%, respectively (cases). There was no significant difference in the pre
      and postoperative PCV of the two groups. The estimated blood loss at surgery
      (cases) had a range of 300-850 mL, with a mean of 465 mL +/- 150.85. The mean
      blood loss of the controls (surgery without BIIAL) was 856 mL +/- 393.3, with a
      range of 300-2,500 mL. The difference was statistically significant P<0.0006,
      Student's two-tailed type 2, t-test). Eight patients (25.0%) had no blood
      transfusion, 19/32 and 5/32 patients (59.4% and 15.6%) had 2 and 3 units of blood
      transfused. No patient who had BIIAL required 4 units of blood transfusion. One
      patient (3.13%) had a laceration of the internal iliac vein; there was no
      operative mortality. The average hospital stay was 12 days. Ligature of the
      internal iliac artery seems to reduce operative blood loss when used as a
      prophylactic routine procedure at radical hysterectomy. This is of value to the
      surgeon in the developing world where there are inadequate blood transfusion and
      chemoradiation services. A randomized controlled trial is suggested.

PMID- 12623484
TI  - Increased vaginal bleeding: the reasons women give for consulting primary care.
AB  - A previous study identified interference with life as the main reason for
      consultation with increased vaginal bleeding. The purpose of this study was to
      determine the reasons why the heaviness of periods interferes with life and how
      this may be related to consultation. The design was a case-control study in which
      questionnaires were sent to women who consulted primary care with new episodes of
      increased vaginal bleeding and two groups of controls: consulting controls with
      another illness and non-consulting community controls. Of the 186 women who
      reported that heaviness of periods interfered with life the most common reason
      given was 'mood' (87%). There was no difference in the reporting of 'mood'
      interfering with life or general health questionnaire score between cases,
      consulting controls and non-consulting controls. Women who report heavy periods
      interfering with life complain most commonly of mood as one of the reasons. This
      does not distinguish consulters and non-consulters and is not reflected in
      objective measures of psychological distress. Clinicians should focus initially
      on treating the presenting physical symptoms.

PMID- 12623485
TI  - Endometrial ablation with the Cavaterm thermal balloon.
AB  - This prospective observational study evaluates the efficacy and safety of thermal
      Balloon endometrial ablation using the Cavaterm system for the treatment of
      dysfunctional uterine bleeding. Seventy-seven women with a mean age of 43 years
      who met the inclusion and exclusion criteria were treated under general
      anaesthesia. A 9-mm diameter catheter with a silicone balloon at its tip was
      inserted transcervically into the uterus and was inflated with sterile 1.5%
      glycine and connected to a control unit that maintained the temperature of the
      circulating heated fluid at 75 degrees C, monitored the pressure and terminated
      the treatment after 15 minutes. There were no intra-operative complications and
      patients tolerated the treatment well. Satisfaction rates were 90% at both 12 and
      24 months. At 24 months 10% of patients had heavy periods, 5% normal periods, 39%
      light periods and 46% amenorrhoea. Cavaterm balloon ablation seems a safe and
      effective option for women with menorrhagia. The procedure does not require
      additional training and expertise in operative hysteroscopy and compares
      favourably with established techniques.

PMID- 12623486
TI  - Plasma homocysteine levels correlated to interactions between folate status and
      methylene tetrahydrofolate reductase gene mutation in women with unexplained
      recurrent pregnancy loss.
AB  - Hyperhomocysteinaemia, a risk factor for recurrent pregnancy loss, is related
      either to a hereditary defect within the methionine-homocysteine pathway or it
      might be acquired as a result of deficiencies of vitamin B(12) and folate (B(9)).
      Because hyperhomocysteinaemia seems to be determined by both genetic and
      environmental factors, the current study was undertaken to find out the
      interactions between folate status and MTHFR mutation on the homocysteine
      concentration in 24 women experiencing unexplained three or more consecutive
      recurrent pregnancy losses. The median fasting total plasma homocysteine
      concentration in the study group was 10.23 micro mol/l compared to 8.95 micro
      mol/l; P = 0.096 in the controls. Elevated homocysteine levels > 18 micro mol/l,
      which was considered to be a risk factor for recurrent early pregnancy loss, was
      found in four women in the study group and none among the controls. Lower red
      cell folate levels (normal range >/= 160 ng/ml) were observed in nine (37.5%)
      women among the study group, compared to five (20.84%) women among controls. The
      mean +/- SD red cell folate levels in the study group was found to be 154.37 +/-
      37.07, while in the controls it was 159.0 +/- 28.97. In the present study six
      women in the study group and two among controls were found to be carriers for the
      C677T MTHFR mutation. None were homozygous for the mutant (TT) allele. The
      highest values of homocysteine concentration were found in women experiencing
      recurrent pregnancy loss with both the CT genotype and folate deficiency.
      Identification of hyperhomocysteinaemia in women with recurrent pregnancy loss
      may help in therapeutic normalisation and might permit a normal birth.

PMID- 12623487
TI  - Knowledge, attitude and practices related to prevention of cancer of the cervix
      among female health workers in Ibadan.
AB  - Cervical cancer, although largely preventable, remains a leading cause of cancer
      death in the developing world. The study was aimed at finding out the level of
      awareness of female health workers about cervical cancer and the level of
      utilisation of preventive measures. A 20-item questionnaire containing items on
      characteristics and knowledge of respondents on aetiology and prevention of
      cervical cancer was administered to a total of 205 female doctors, nurses and
      hospital maids in three hospitals within Ibadan metropolis. Knowledge about the
      condition was high among doctors, surprisingly inadequate among nurses and
      predictably poor among hospital maids (due possibly to lack of formal paramedical
      training). However, 93.2% of respondents have never had Pap smears performed. The
      poor utilisation of the test was independent of respondent's profession, marital
      status or hospital. Therefore, there is a need to intensify compaign towards
      prevention of cervical cancer even among health workers.

PMID- 12623488
TI  - Liberalisation of abortion laws in Nigeria: the undergraduates' perspective.
AB  - Nothing in the field of health care generates more controversy than does the
      issue of abortion. The views of 396 undergraduates of Obafemi Awolowo University,
      Ile-Ife, Nigeria concerning the liberalisation of abortion laws were investigated
      in May 2001. Ninety respondents (22.7%) supported the liberalisation of abortion
      laws in Nigeria because they believed that it would lead to reduction in
      associated morbidity and mortality, encourage more qualified personnel to perform
      it, encourage women to request abortion openly and encourage accurate statistics
      on abortion. However, the majority of the respondents (59.6%) opposed the
      liberalisation of abortion laws due to the fear that it would increase
      promiscuity, sexually transmitted diseases and abortion rates. Religious
      opposition and the belief that liberalisation would not reduce the level of
      poverty, ignorance and poor reproductive health facilities were the common
      factors leading to unwanted pregnancy and unsafe abortion in Nigeria. Support for
      the liberalisation of abortion laws shows significant relationship with
      increasing age (P = 0.001), male sex (P = 0.001) and a science-orientated faculty
      (P<0.05), but not religion. There is every indication that the issue of abortion
      is one that will continue to be unresolved for the forseeable future.

PMID- 12623489
TI  - Microbiological pattern of the contents of pelvic abscess at the University
      College Hospital, Ibadan, Nigeria.
AB  - A retrospective analysis of 49 cases of pelvic abscess over a 10-year study
      period spanning 1 January 1989 to 31 December 1998 was undertaken. Forty-one
      patients had laparotomy to drain the pelvic abscess, while eight had colpotomy.
      The volume of pus drained at surgery ranged between 10 ml and 3.5 l for
      laparotomy, with a median value of 500 ml and 100 ml to 1 l with a median of 200
      ml for colpotomy. There was no significant difference in these values. Swabs for
      bacteriological cultures were taken at surgery and results available in 18
      patients. In two patients (11%) the cultures were sterile. In the positive
      cultures, Escherichia coli was isolated in seven patients. Klebsiella species and
      Staphylococcus aureus were isolated in four patients each. It is important to
      know the causative organisms for this infection in our environment because pelvic
      abscess is the end stage in the progression of a treatable genital tract
      infection and is frequently an unnecessary complication that is very expensive to
      treat.

PMID- 12623490
TI  - A study of pre-referral evaluation of infertile couples.

PMID- 12623491
TI  - Surgical management of pelvic abscess: laparotomy versus colpotomy.

PMID- 12623492
TI  - Placental separation from a seat belt injury due to severe turbulence during
      aeroplane travel.

PMID- 12623493
TI  - Intracranial aneurysm in pregnancy presenting as hyperemesis gravidarum.

PMID- 12623495
TI  - Cognitive and affective sequelae in complicated and uncomplicated mild traumatic
      brain injury.
AB  - This study examined cognitive and affective disturbances in patients with
      complicated (presence of space occupying lesion) vs uncomplicated (absence of
      space occupying lesion) mild traumatic brain injury (TBI). It was predicted that
      the complicated group would perform worse in both domains compared to the
      uncomplicated group. Participants were 28 patients admitted to an inpatient
      neurorehabilitation unit with mild TBI and assessed within 40 days of their
      injury. The complicated group (n = 14) was matched to the uncomplicated group (n
      = 14) on Glasgow Coma Scale score and compared to 14 normal controls on the BNI
      Screen for Higher Cerebral Functions (BNIS). The complicated group showed greater
      cognitive disturbances than the uncomplicated and control groups, while both TBI
      groups performed worse on affective measures. These findings document the role of
      affective disturbances in mild TBI. They also highlight the importance of early
      intervention strategies for improving affective communication in patients with
      mild TBI.

PMID- 12623496
TI  - Presence of post-concussion syndrome symptoms in patients with chronic pain vs
      mild traumatic brain injury.
AB  - PRIMARY OBJECTIVE: Post-concussion syndrome (PCS) is a controversial diagnosis,
      in part because many symptoms may be present in other conditions, such as chronic
      pain (CP). However, direct comparisons between people with CP and mild traumatic
      brain injury (MTBI) are limited. The purpose of this study was to compare people
      with CP and MTBI on a measure of PCS symptoms. DESIGN: Group comparison between
      patients with CP and MTBI on the Rivermead Post-Concussion Questionnaire (RPCQ).
      METHODS: Sixty-three patients with CP and 32 with MTBI were evaluated at the
      authors' institutions. Patients completed the RPCQ as part of their initial
      evaluation. RESULTS: No group differences were found for total RPCQ scores. There
      were some differences in the proportion of patients endorsing specific symptoms.
      However, most people with CP endorsed symptoms consistent with PCS. CONCLUSIONS:
      PCS symptoms are not unique to MTBI, and may be seen in conditions such as CP.

PMID- 12623497
TI  - Blows to the head during development can predispose to violent criminal
      behaviour: rehabilitation of consequences of head injury is a measure for crime
      prevention.
AB  - Criminal behaviour and violence may be the consequence of head injuries acquired
      during childhood and youth (gang fights, domestic violence, small blows to the
      head while driving, falls and so forth). In this study, a comparison was made of
      the school and head injury histories of violent and non-violent prisoners. It was
      found that the delinquent subjects in both groups had a history of academic
      difficulties. However, what differentiated the violent from the non-violent group
      was a history of having suffered head injuries that were never treated. Problems
      at school are not enough themselves to predict violent behaviour. A history of
      discrete neurological damage as a consequence to blows received to the head must
      also be present. The results suggest to the authors that the treatment of the
      cognitive, behavioural and emotional consequences of brain injury could be a
      measure for crime prevention. Measures both for prevention and rehabilitation are
      discussed.

PMID- 12623498
TI  - Speech and language sequelae of severe malaria in Kenyan children.
AB  - PRIMARY OBJECTIVE: To conduct a preliminary investigation into the occurrence of
      speech and language impairments following severe malaria in Kenyan children.
      RESEARCH DESIGN: Cohort study comparing the prevalence of impairments in children
      exposed or unexposed to severe malaria. METHODS AND PROCEDURES: The study
      recruited 25 children who had previously been admitted to hospital with severe
      falciparum malaria and 27 unexposed to the disease. Assessments of comprehension,
      syntax, lexical semantics, higher level language abilities, pragmatics and
      phonology were administered to each child at 8-9 years of age, at least 2 years
      after admission to hospital in children exposed to severe malaria. MAIN OUTCOMES
      AND RESULTS: Exposed children were found to have lower scores on each assessment
      and significantly lower scores on four aspects of language ability: comprehension
      (p = 0.02); syntax (p = 0.02); content words (p = 0.02) and function words (p =
      0.004) components of lexical semantics. CONCLUSIONS: These data suggest that
      speech and language deficits may be an important and under-recognized sequela of
      severe falciparum malaria.

PMID- 12623499
TI  - A review of the scientific evidence on the treatment of traumatic brain injuries
      and strokes with hyperbaric oxygen.
AB  - OBJECTIVE: This review sought to determine the strength of the scientific
      evidence relating to the therapeutic use of hyperbaric oxygen for traumatic brain
      injury or stroke. In order to reduce the possibility of omitting relevant human
      clinical trials, parallel searches of the Medline, HealthStar and Embase
      databases were undertaken, and input was sought from local experts in hyperbaric
      medicine as well as from a widely noted proponent of this therapy. Papers
      retrieved were reviewed to ensure that they reported the results of comparative
      clinical trials and were then reviewed by a panel of scientists. Papers were
      scrutinized for methodological flaws, and the clinical significance of the
      results was examined. OUTCOME: The strongest papers indicated either no effect or
      harm from hyperbaric oxygen when used to treat traumatic brain injuries or
      strokes. CONCLUSION: The scientific literature up to August 2001 does not support
      the use of hyperbaric oxygen for traumatic brain injuries and strokes.

PMID- 12623500
TI  - Risperidone treatment of motor restlessness following anoxic brain injury.
AB  - PRIMARY OBJECTIVE: This paper examined the use of an atypical neuroleptic
      medication, risperidone, in reducing the excessive motor activity of an
      adolescent with an anoxic brain injury following cardiac arrest from a lightning
      strike. Lower extremity restlessness caused the patient to develop skin breakdown
      and interfered with healing of existing burns. RESEARCH DESIGN: Single-blind,
      placebo-controlled single-subject experimental design. EXPERIMENTAL INTERVENTION:
      Escalating doses of risperidone up to 1 mg and in combination with
      methylphenidate (10 mg) and amantidine (100 mg). MAIN OUTCOMES AND RESULTS: The
      patient demonstrated a reduction in restlessness in response to the use of
      risperidone, which permitted wound healing. The addition of methlphenidate to
      risperidone led to a slight increase in attention to task. CONCLUSIONS: The use
      of the atypical neuroleptic medication, risperidone, may be considered as part of
      the armamentarium available to physicians treating restlessness in severe brain
      injuries.

PMID- 12623501
TI  - A mysterious temporal penetrating head wound without fracture.
AB  - Unwitnessed head injuries are often diagnostic and management dilemmas. Low
      velocity penetrating head wounds are rare. This paper describes a case of an
      accidental low-velocity penetrating head wound through the soft tissue of the
      temporal region. This lesion resulted in a deep intra-cerebral haemorrhage, after
      the initial assessment revealed no evidence of skull fracture, missile or missile
      track. The diagnostic evaluation and medical course of this case are presented.
      This is the first case in the medical literature of a brain injury by an object
      that penetrated the calvarium at low velocity but which did not produce a
      fracture of the skull. The evolving diagnostic dilemma is outlined to its
      conclusion, through 3 years of follow-up observation.

PMID- 12623502
TI  - Antecedent analysis of therapeutic restraint in children and adolescents with
      acquired brain injury: a descriptive study of four cases.
AB  - Therapeutic restraint is sometimes required as a component of clinical
      intervention for persons who have serious behaviour disorders. However, there are
      few studies that describe empirically the conditions under which restraint is
      utilized. This project was a retrospective analysis of incident reports on the
      application of therapeutic restraint with four students (ages 10-16 years) who
      had acquired brain injury and attended a community-based programme of education
      and neurorehabilitation. Specifically, situations and interactions were examined
      that were in effect immediately prior to the implementation of restraint. This
      antecedent analysis identified several common influences, as well as effects that
      were unique to individual students. The role of antecedent events as
      "precipitants" to restraint and respective treatment implications are discussed.

PMID- 12623503
TI  - Parenteral estrogen versus combined androgen deprivation in the treatment of
      metastatic prostatic cancer -- Scandinavian Prostatic Cancer Group (SPCG) Study
      No. 5.
AB  - OBJECTIVE: In the mid-1980s, interest in parenteral estrogen therapy for prostate
      cancer was renewed when it was found that it influenced liver metabolism only
      marginally and had very few cardiovascular side-effects. In this study high-dose
      polyestradiol phosphate (PEP; Estradurin) was compared to combined androgen
      deprivation (CAD) for the treatment of patients with metastatic prostate cancer.
      The aim of the study was to compare anticancer efficacy and adverse events,
      especially cardiovascular side-effects. MATERIAL AND METHODS: A total of 917
      patients with T0-4, NX, M1, G1-3 prostate cancer and an Eastern Cooperative
      Oncology Group performance status of 0-2 were randomized to treatment with either
      PEP 240 mg i.m. twice a month for 2 months and thereafter once a month or
      flutamide (Eulexin) 250 mg t.i.d. per os in combination with either triptorelin
      (Decapeptyl) 3.75 mg per month i.m. or, on an optional basis, bilateral
      orchidectomy. A total of 556 patients had died at the time of this analysis.
      RESULTS: There was no difference between the treatment arms in terms of time to
      biochemical or clinical progression and overall or disease-specific survival.
      There was no increase in cardiovascular mortality in the PEP arm. The PEP group
      had a higher prevalence of cardiovascular disease prior to the study and a
      significantly higher incidence of non-fatal ischemic heart events and heart
      decompensation during the study. CONCLUSIONS: PEP has an equal anticancer
      efficacy to CAD and does not increase cardiovascular mortality. Final evaluation
      of cardiovascular morbidity is awaiting further analysis and follow-up. PEP is
      considerably cheaper than CAD.

PMID- 12623504
TI  - Renal cell carcinoma: gender difference in incidental detection and cancer
      specific survival.
AB  - OBJECTIVE: To look for an increase in the incidental detection of renal cell
      carcinoma (RCC) over the last two decades and to see if different patterns of
      healthcare use for men and women have implications for tumour detection and
      survival. MATERIAL AND METHODS: We present an historical series of 368
      consecutive patients treated with nephrectomy for RCC during the period 1978
      2000. The patients were classified according to detection mode (incidental or
      symptomatic disease), TNM stage and cancer-related death. RESULTS: The frequency
      of incidentally detected RCC (IRCC) increased from 21.1% to 34.7% between the
      first and second decades of the study. The IRCC group had significantly more low
      stage (I-II) tumours (p = 0.002), a smaller tumour size (p < 0.0001) at operation
      and significantly better cancer-specific survival (p = 0.0048) than the
      symptomatic renal cell carcinoma (SRCC) group. The frequency of women was
      significantly higher in the IRCC group than in the SRCC group (p = 0.02). Females
      had significantly more low-stage (I-II) tumours (p = 0.02) and better cancer
      specific survival (p = 0.05) than males. CONCLUSIONS: The number of incidentally
      discovered renal tumours is increasing. IRCC have lower TNM-stage and are smaller
      than SRCC. IRCC have better long term cancer specific survival than SRCC. The
      better survival rate found in females may be due to more extensive use of the
      healthcare system by females than males.

PMID- 12623505
TI  - Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer --
      Nordic cystectomy trial 2.
AB  - BACKGROUND: In the first Nordic cystectomy trial (1986-1989) a chemotherapy
      combination of cisplatin-doxorubicin and external radiation seemed to improve the
      long-term survival after cystectomy in patients with stage T3-T4a bladder
      carcinomas. The aim of this study was to investigate if solely neoadjuvant
      chemotherapy could influence survival in patients with advanced urothelial
      bladder cancer undergoing cystectomy. METHODS: The study (1991-1997) recruited
      317 patients with T2-T4aNXM0 urothelial bladder tumours. The patients were
      randomly allocated to three courses of cisplatin-methotrexate or no pretreatment
      before cystectomy, eight were subsequently excluded due to protocol violation.
      RESULTS: Chemotherapy according to protocol was administered to 74% (115/155) of
      the patients in the experimental arm. No chemotherapy related mortality was
      observed. Of remaining patients in the experimental arm, 14 did not receive any
      chemotherapy, nine discontinued after one course and 14 after two courses due to
      side effects. Median follow-up time among censored patients was 5.3 years.
      Estimated 5-year overall survival was 53% in the experimental arm and 46% in the
      control arm (n.s. log-rank test). The proportion of patients with pathological
      stage pT0 was 26.4% in the experimental arm and 11.5% in the control arm (p =
      0.001). Risk of locoregional relapse and distant metastases was similar in the
      study arms. CONCLUSIONS: The chemotherapy regimen was well tolerated. Despite
      substantial downstaging no statistically significant survival benefit with the
      neoadjuvant therapy could be seen after 5 years of follow-up.

PMID- 12623506
TI  - Modified anatrophic nephrolithotomy for complete staghorn calculus disease --
      does it still have a place?
AB  - OBJECTIVE: To report our experience with open surgery for the management of
      complete staghorn calculi using a modified anatrophic nephrolithotomy technique.
      MATERIAL AND METHODS: Between 1990 and 2001, 24 patients underwent anatrophic
      nephrolithotomy in our department. Bilateral complex stone disease was present in
      9 patients, so that a total of 33 procedures were carried out. Preoperative
      evaluation included excretory urography (intravenous pyelography) and routine
      laboratory study in all patients and in 9 patients renal function was assessed
      using (99m)Tc dimercaptosuccinic acid renal scans before and 6 months after
      surgery. Postoperative follow-up consisted of kidney-ureter-bladder (KUB),
      ultrasound (U/S), urinalysis and urine culture. RESULTS: The mean operative time
      was 180 min, mean blood loss was 500 ml and renal ischemia time ranged between 10
      and 35 min. Deep vein thrombosis occurred on the 5th postoperative day in an
      obese female patient. No other operative or postoperative complications were
      observed. Mean hospital stay was 8.2 days (range 7-12 days). The stone-free rate
      was 83.3%. Long-term follow up demonstrated stone fragments <4 mm in diameter in
      4 patients (16.6%). Renal function remained unchanged or slightly improved in 15
      patients; a slight worsening of renal function was noted in 9 patients (from an
      average of 39% before to 35% after the procedure). CONCLUSIONS: Anatrophic
      nephrolithotomy, although a major operative procedure, remains the most
      appropriate method for the one-stage management of a selected group of patients
      harboring large staghorn calculi with infundibular stenosis, and is associated
      with the highest stone-free rates.

PMID- 12623507
TI  - Reproducibility of non-invasive urodynamics, using the cuff-uroflow, for the
      diagnosis of bladder outlet obstruction in males.
AB  - OBJECTIVE: To determine the repeatability of the parameters obtained from non
      invasive urodynamics, using the cuff-uroflow, for the diagnosis of bladder outlet
      obstruction. MATERIAL AND METHODS: The study was carried out in a consecutive
      series of 34 males with functional urinary tract symptoms. The test-retest
      reproducibility of isometric pressure, flow in response to isovolumetric pressure
      and the energy transfer ratio obtained at two different times using the cuff
      uroflow method was determined. RESULTS: Very good agreement for the flow in
      response to isovolumetric pressure measurement (intraclass correlation
      coefficient 0.96) and good agreement for the isovolumetric pressure measurement
      (intraclass correlation coefficient 0.87) and the energy transfer ratio
      (intraclass correlation coefficient 0.84) were demonstrated. The patients were
      classified into three groups according to the value of the energy transfer ratio,
      and it was found that there was very good agreement between the groups into which
      patients were classified as a result of the first and second measurements (kappa
      index 0.81). CONCLUSIONS: The parameters obtained with the cuff-uroflow are
      reliable and the energy transfer ratio allows one to classify patients into
      reproducible groups.

PMID- 12623508
TI  - Effects of leukocytosis and macrophage activation on anti-Thy 1.1
      glomerulonephritis in the rat.
AB  - OBJECTIVE: In anti-Thy 1.1 proliferative glomerulonephritis (GN), glomerular
      infiltration of polymorphonuclear leukocytes (PMNs) reaches a peak level after 1
      h and that of macrophages does so 24 h after induction. However, the roles of
      PMNs and macrophages in the pathogenesis of anti-Thy 1.1 GN remain unclear. We
      examined the effects on this model of leukocytosis induced by granulocyte colony
      stimulating factor (G-CSF) and of macrophages stimulated by macrophage colony
      stimulating factor (M-CSF). MATERIAL AND METHODS: Anti-Thy 1.1 GN was induced in
      male Wistar rats by intravenous injection of OX-7, a monoclonal antibody to the
      Thy 1 antigen. G-CSF (10 microg/kg/day), M-CSF (20 microg/kg/day) or vehicle was
      administered intraperitoneally for 7 days starting 24 h before the injection of
      OX-7. Histological examination of renal biopsy specimens was performed on Days 1,
      5 and 14 after induction. RESULTS: Circulating and glomerular-infiltrating PMNs
      (RP-3-positive cells) were increased at Day 5 in G-CSF-treated rats compared with
      controls receiving vehicle, and glomerular mesangiolysis continued at Day 5. The
      number of proliferating cells positive for proliferating cell nuclear antigen at
      Day 5 and matrix scores at Day 14 were smaller in G-CSF-treated rats than in
      control rats. The mesangiolysis score was significantly higher in the G-CSF group
      than in the control group at Days 5 and 14, but not at Day 1. ED-1-positive cells
      were increased in number at Day 5 and matrix accumulation decreased at Day 14 in
      M-CSF-treated rats compared with controls. Serum creatinine level at Day 14 was
      lower in the M-CSF group, but not in the G-CSF group, compared with the control
      group. CONCLUSIONS: Activated macrophages may inhibit excess matrix accumulation
      and ameliorate the recovery of renal function, whereas leukocytosis inhibits the
      repair of mesangial cell injury in this model.

PMID- 12623509
TI  - Long-term effects of losartan on proteinuria and renal function in patients with
      renal amyloidosis.
AB  - OBJECTIVE: To investigate the effect of the angiotensin II receptor antagonist
      losartan on proteinuria in secondary amyloidosis cases. MATERIAL AND METHODS:
      Sixteen patients with renal biopsy-proven AA amyloidosis with proteinuria were
      included in the study. All the patients had received colchicine treatment for at
      least 18 months. The patients were divided into two groups with similar age and
      gender distributions. Eight patients were given losartan at a dose of 50 mg/day
      for 12 months and the other 8 patients served as controls. Mean arterial blood
      pressure, proteinuria, serum albumin level and renal function were determined at
      the initiation of the study and after 1 and 12 months. RESULTS: There were no
      significant differences in proteinuria, serum albumin level, renal function or
      mean arterial blood pressure at the initiation of the study. In the losartan
      group daily proteinuria decreased significantly from 5.2 +/- 0.7 g at the
      initiation of the study to 3.9 +/- 1.2 g at 1 month and 3.6 +/- 0.8 g at 12
      months, while in the control group it changed from 4.6 +/- 1.0 g to 4.7 +/- 1.0 g
      and 6.1 +/- 1.2 g, respectively. The increment at 12 months was significant.
      After 12 months of treatment with losartan, proteinuria was significantly lower
      in comparison to the degree of proteinuria in the control group. Serum albumin
      level increased significantly in the losartan group but was unchanged in the
      control group. In the control group, creatinine clearance showed a significant
      decrease. There was no significant difference in mean arterial blood pressure
      measurements, serum creatinine levels, total protein, albumin and creatinine
      clearance levels between the two groups. CONCLUSIONS: Losartan seemed to prevent
      an increase in proteinuria without altering the creatinine clearance level in
      patients with amyloidosis type AA during a 12-month period. This indicates that
      losartan may be used to decrease proteinuria in this patient group. However, our
      results are only preliminary and need to be confirmed by larger studies.

PMID- 12623510
TI  - Modified range of alanine aminotransferase is insufficient for screening of
      hepatitis C virus infection in hemodialysis patients.
AB  - OBJECTIVE: A moderate increase in serum alanine aminotransferase (ALT) has been
      reported to be a helpful, low-cost tool for predicting viremia in anti-hepatitis
      C virus (HCV)-positive hemodialysis (HD) patients. This study focused on
      evaluating the effectiveness of a lowered normal serum ALT value as a screening
      method for HCV infection in HD patients. MATERIAL AND METHODS: Serum ALT levels
      were compared with HCV virologic status in 125 patients on maintenance HD.
      RESULTS: The prevalence of HCV antibodies was 23%. A total of 3.7% of viremic HD
      patients did not have a detectable antibody response. Using the conventional
      upper limit of normal for ALT of 37 IU, there was no significant difference in
      the frequency of elevated ALT levels between HCV RNA-positive and-negative
      patients. However, if the upper limit of normal for ALT was lowered to 27 IU, the
      difference was significant. Nevertheless, 60% of viremic patients still fell
      within the normal range. CONCLUSION: Although inexpensive and widely available,
      the monitoring of serum ALT levels is not useful as a screening method for HCV
      infection in HD patients.

PMID- 12623511
TI  - Cytokines and other soluble factors in dialysate -- indicators of altered
      peritoneal function?
AB  - OBJECTIVE: The bioincompatibility of dialysis solutions and recurrent episodes of
      peritonitis may alter peritoneal function. Cytokines and growth factors may play
      a role in inflammatory and fibrotic processes. We therefore investigated whether
      there is a correlation between peritoneal function and excretion of cytokines and
      other soluble factors in dialysate. MATERIAL AND METHODS: A personal dialysis
      capacity test was performed in 40 stable peritoneal dialysis patients. Tumour
      necrosis factor-alpha, interleukin-6 (IL-6), hyaluronan, soluble intercellular
      cell adhesion molecule-1 and transforming growth factor-beta1 were analysed from
      overnight and 24-h dialysates during the test. RESULTS: We found little evidence
      for a direct correlation between cytokines and other soluble factors in dialysate
      and dialysis adequacy. There was, however, a strong correlation between the
      measured soluble factors and characteristics of the peritoneal membrane.
      Furthermore, IL-6 correlated with the number of previous episodes of peritonitis.
      CONCLUSIONS: Soluble factors in dialysate may indicate ongoing inflammatory
      processes in the peritoneal membrane, which may gradually lead to alterations in
      peritoneal function.

PMID- 12623512
TI  - Clinical and radiological renal characteristics of patients with terminal
      uraemia.
AB  - OBJECTIVE: To investigate, by means of ultrasonography and plain film
      radiography, the radiological appearance of the kidneys in patients with uraemia,
      and to study renal development during the time course preceding dialysis.
      Aetiology, clinical characteristics and long-term clinical outcome were also
      studied. MATERIAL AND METHODS: Ultrasonography and plain film radiography of the
      kidneys, physical examination, laboratory tests, review of hospital files and
      interviews regarding risk factors were performed in 67 patients (median age 65.0
      years) entering a dialysis programme. They were followed prospectively for 54-77
      months. In a retrospective part of the study, old radiographs of the kidneys were
      compared with radiographs obtained at the start of dialysis. RESULTS: Chronic
      glomerulonephritis (CGN) and diabetic nephropathy (DN) were the leading causes of
      uraemia. Forty-two patients (63%) died during follow-up, mostly due to
      cardiovascular disease. Normal kidney size and echogenicity were common among DN
      patients, while the kidneys of CGN patients were generally small and hyperechoic.
      Mean renal length reduction was 23.6 mm in CGN patients and 18.9 mm in DN
      patients, during median times of 7.7 years and 5.0 years preceding dialysis,
      respectively. The most rapid renal length reduction was 27 mm in 1.5 years.
      CONCLUSIONS: The study illustrates the changing aetiological spectrum and high
      mortality rate in patients with dialysis-treated uraemia. The ultrasonographic
      appearance of the kidneys in uraemia varies considerably, depending on the
      underlying disorder, but analysis of size and echogenicity are helpful in the
      evaluation of these patients. A rapid reduction in kidney size in renal failure
      patients is important to consider during radiological evaluation.

PMID- 12623513
TI  - Effect of light exercise on renal hemodynamics in patients with hypertension and
      chronic renal disease.
AB  - OBJECTIVE: Increased physical activity is followed by a stimulation of the
      sympathetic nervous system and this effect is probably more pronounced in
      patients with chronic renal failure and hypertension than in healthy controls.
      The role of sustained exercise in hypertensive patients with chronic renal
      failure, with and without antihypertensive therapy, is unclear, as is hormonal
      regulation of the renal hemodynamics. We hypothesized that prolonged low
      intensity bicycle exercise would have a greater effect in patients with chronic
      renal failure than in controls, and that antihypertensive treatment would
      ameliorate these effects. MATERIAL AND METHODS: Glomerular filtration rate (GFR),
      effective renal plasma flow (ERPF), mean arterial blood pressure (MAP),
      norepinephrine (NE) and atrial natriuretic peptide (ANP) were measured in the
      upright position before and during low-intensity exercise for 2 h in healthy
      controls (n = 8) and in hypertensive patients with moderately reduced renal
      function who were not taking antihypertensives (n = 7) or who were receiving
      treatment with captopril (n = 10), enalapril (n = 6) or verapamil (n = 9).
      RESULTS: GFR tended to decrease and ERPF decreased significantly in healthy
      individuals when exercise duration was prolonged from 1 to 2 h. An earlier
      decline in GFR and ERPF was seen in the renal failure patients compared with the
      controls. Filtration fraction (FF) increased during exercise in all groups except
      the group taking enalapril. MAP increased in the captopril group during exercise
      but was unchanged in the other groups. Treatment with captopril produced a more
      pronounced and earlier fall in exercise-induced GFR than in untreated controls,
      while verapamil treatment completely blunted the decline in GFR, with a
      concomitant increase in plasma ANP. No significant changes were seen in plasma NE
      levels, but urinary NE excretion increased in controls and captopril-treated
      patients during exercise. CONCLUSIONS: The results suggest that prolonged low
      intensity exercise has a substantially greater effect on renal hemodynamics in
      hypertensive renal failure patients than in healthy controls, with negligible
      changes in plasma NE levels. Verapamil treatment seems to ameliorate the renal
      effects of exercise on GFR in these patients, and this may in part be mediated
      via a stimulatory effect on ANP.

PMID- 12623514
TI  - Prevalence of transfusion transmitted virus infection and its effect on renal
      graft survival in renal transplant recipients.
AB  - OBJECTIVE: Little is known about the prevalence of transfusion transmitted virus
      (TTV) infection in renal transplant recipients (RTxs) and its effects on
      allograft survival. We investigated the prevalence of TTV and its effects on
      liver injury and graft survival in RTxs. MATERIAL AND METHODS: The study was
      performed in 33 consecutive RTxs (8 females, 25 males) and 100 blood donors (35
      females, 65 males). A nested polymerase chain reaction was used to detect TTV DNA
      in serum. Serum creatinine and alanine aminotransferase (ALT) levels and 24-h
      protein excretion were determined in both TTV-positive and-negative patients. The
      total number of blood transfusions, the duration of hemodialysis and the total
      duration after transplantation were recorded in RTxs. In addition, hepatitis B
      surface antigen (HbsAg), anti-hepatitis C virus (HCV) and hepatitis G virus DNA
      antibodies were determined in all patients. RESULTS: TTV DNA was detected in
      51.5% of RTxs and in 7% of the control group and this difference was
      statistically significant (p < 0.01). In the RTx group, 64.7% of TTV-positive and
      56.2% of TTV-negative patients had undergone a previous blood transfusion.
      However, the blood transfusion replacement rate, total duration of dialysis
      therapy and posttransplant period did not differ between these two groups. Five
      (15.1%) patients in the RTx group had abnormal liver function tests (ALT >40
      IU/l). Of these patients, 2 were anti-HCV-positive, 1 was HBsAg-positive and anti
      HCV- plus TTV DNA-positive and the serologic tests of the remaining 2 patients
      were all negative. Among the TTV-positive patients, 2 (11.7%) were anti-HCV
      positive, 1 (5.8%) was HBsAg-positive and 3 (17.6%) were HGV DNA-positive. The
      baseline serum creatinine levels did not differ significantly between the TTV
      positive and-negative patients, being 1.5 +/- 0.6 and 1.4 +/- 0.6 mg/dl,
      respectively ( p > 0.05). Two of the TTV-positive patients and 1 of the TTV
      negative patients had proteinuria. A 1-year follow-up of TTV-positive and
      negative patients demonstrated neither acute nor chronic graft rejection.
      CONCLUSION: In RTxs, TTV infection was more prevalent than in the normal
      population. In our patients the virus did not have an important effect on renal
      graft rejection and did not cause liver injury. However, the question of whether
      TTV infection may affect graft survival requires further long-term investigation
      in larger groups.

PMID- 12623515
TI  - Symmetrical peripheral gangrene after suprapubic prostatectomy.
AB  - Symmetrical peripheral gangrene is a rare condition with a multifactorial
      etiology and its treatment has not been clarified. The second case to have
      occurred in urologic patients is reported herein. This case highlights the need
      to be aware of this potential complication of urologic surgery.

PMID- 12623516
TI  - A case of amyloid of the urethra and review of this rare diagnosis, its natural
      history and management, with reference to the literature.
AB  - Primary localized genitourinary amyloid deposition is a rare disease that can be
      confused with cancer. Amyloid tumours of the urethra are exceptionally rare, with
      only 40 cases having been reported in the literature since 1909. A case is
      presented herein, with a full review of the presenting features, coexisting
      conditions and pathology and recommendations for treatment, based on the findings
      in previously reported cases.

PMID- 12623517
TI  - Welfare in Finland in the 1990s.

PMID- 12623518
TI  - Use of alcohol and illicit drugs among pregnant Danish women, 1998.
AB  - AIMS: In 1999 the Danish National Board of Health adjusted its recommendation
      concerning alcohol in pregnancy: "Avoid alcohol in pregnancy if possible; If you
      drink, drink no more than 1 drink per day; do not drink every day". In this paper
      frequency and pattern of alcohol consumption and the use of illicit drugs during
      early pregnancy among pregnant Danish women are described. METHODS: From October
      to December 1998, 432 Danish-speaking pregnant women referred to the Midwife
      Centre in Aarhus, Denmark, for routine antenatal care were interviewed at their
      first visit at 15-16 weeks of gestation. The women were interviewed about average
      alcohol intake before pregnancy, binge drinking (intake of > or =5 drinks on a
      single occasion), and the use of illicit drugs in pregnancy. They subsequently
      filled in a two week diary on current alcohol intake. RESULTS: Nearly 90% of the
      women reduced their alcohol intake when they became pregnant. A total of 92% of
      women reported a maximum intake of three drinks/week, and only 1% exceeded the
      recommendations of average alcohol intake of six drinks/week. Nevertheless, 25%
      exceeded the recommended maximum daily intake of one drink in the second
      trimester, and 40% of the women reported at least one binge episode since
      conception. Binge drinkers tended to be smokers and primiparous women.
      CONCLUSIONS: Consumption peaks were a major problem in the first and second
      trimester. Midwives and doctors should pay special attention to binge drinking
      when inquiring about alcohol consumption and providing information on alcohol to
      pregnant women.

PMID- 12623519
TI  - Predictive value and completeness of the registration of congenital abnormalities
      in three Danish population-based registries.
AB  - AIMS: The predictive value and completeness of data on congenital abnormalities
      (CAs) collected in three administrative health registries in the County of North
      Jutland, Denmark were compared. METHODS: The study included all singleton
      liveborn infants in the county during the period 1991-94 (n = 24,147). All
      infants recorded as having a CA in either the Medical Birth Registry (MBR), the
      Hospital Discharge Registry (HDR), or the National Registry of Congenital
      Abnormalities (NRCA) were identified, and the recordings in each registry were
      compared. Infants recorded in at least two registries were considered correctly
      diagnosed with a CA for the sake of the analyses. The predictive value was
      defined as the number of infants correctly diagnosed with a CA in the registry
      divided by the total number of infants recorded with a CA in the registry. In all
      cases with recording in one registry only, the predictive value of the
      registration with CA diagnosis was assessed through a review of a sample of
      medical records. The completeness was defined as the number of correctly
      diagnosed CAs in the registry divided by the total number of identified CAs.
      RESULTS: The predictive value and completeness were calculated as 89.1% (85.3
      92.8) and 32.3% (28.9-35.7) in the MBR; 88.2% (85.9-90.5) and 89.9% (87.7-92.1)
      in the HDR; and 99.6% (98.9-100.0) and 36.0% (32.5-39.5) in the NRCA.
      CONCLUSIONS: The HDR seems to have a predictive value and completeness that are
      acceptable for general surveillance and epidemiological research regarding CAs.
      The NRCA may be suitable for case-control studies owing to a high predictive
      value.

PMID- 12623520
TI  - Time trends in disability pensioning for rheumatoid arthritis, osteoarthritis and
      soft tissue rheumatism in Norway 1968-97.
AB  - AIMS: Disability pensioning with musculoskeletal diagnoses increased more than
      general disability pensioning in Norway during 1968-97. Incidences of disability
      pensioning for three main musculoskeletal diseases - rheumatoid arthritis,
      osteoarthritis and soft tissue rheumatism - during the period 1968-97 were
      assessed. Changes in incidence were related to changes in Norwegian society with
      respect to prevalence of these diseases, the number of individuals having high
      probability of disability pensioning for these diseases, the labour market and
      legal amendments that may have changed the probability of being granted a
      disability pension among these patients. METHODS: Data on all new disability
      pensioners aged 50-66 years registered by the National Insurance Administration
      during 1968-97 and the total population of Norway excluding disability pensioners
      were used to calculate annual incidence rates of disability pension for the
      selected musculoskeletal diagnoses. RESULTS: The incidence of disability pension
      for soft tissue rheumatism and osteoarthritis increased during the study period,
      and both increased more than the incidence of disability pension in general. The
      incidence of disability pension for rheumatoid arthritis decreased when compared
      with disability pensioning in general. The year an upward or downward trend
      started is similar for osteoarthritis and soft tissue rheumatism for men and
      women in the age groups studied. CONCLUSION: Changes in prevalence of a disease
      seem to be an important factor in explaining differences in time trends of
      disability pensioning with different diagnoses. Changes in unemployment, female
      employment, number of manual workers or the legal system do not appear to be
      related to the increases in incidence of disability pensioning with
      musculoskeletal diseases.

PMID- 12623521
TI  - Incidence and characteristics of falls leading to hospital treatment: a one-year
      population surveillance study of the Danish population aged 45 years and over.
AB  - AIMS: The aim was to quantify and characterize the incidence of fall injury
      events among middle-aged and older adults who require acute medical attention at
      Danish hospitals. METHODS: A one-year population surveillance study was carried
      out, based on the Danish National Hospital Register (DNHR), which covers all
      somatic hospital discharges and accident and emergency (A&E) services at
      hospitals in Denmark. RESULTS: During 1996 a total of 81,121 fall injury events
      were treated at A&E departments or resulted in admission to a somatic hospital
      department among Danes aged 45 years and over. Up to age 50 years the incidence
      rates of injurious fall events requiring medical attention were similar in men
      and women. At age 50 years, the incidence rates in women exceeded the rates in
      men and remained 1.2-1.8 times higher thereafter. After age 70 years, the rates
      increased exponentially in both sexes: from 27.4 and 49.3 per 1,000 person-years
      in men and women, respectively, to peaks of 112.8 and 170.8 per 1,000 person
      years, respectively, at age 85 years and over. The proportion of falls occurring
      indoors and in institutional settings increased with advancing age. Compared with
      men, women had higher rates of fall-related contusions, distortions and fractures
      at all ages. CONCLUSIONS: Fall-prevention programmes should be directed towards
      the population aged 70 years and over, in particular towards women and hazards in
      residential environments. Our finding of an increasing incidence of injurious
      fall events among women around the time of the menopause raises the hypothesis
      that loss of oestrogen production plays a role in the aetiology of falls in
      women.

PMID- 12623522
TI  - Long-term effects of widowhood after terminal cancer: a Swedish nationwide follow
      up.
AB  - AIMS: The authors investigated whether becoming a widow after the death of a
      husband from cancer results in long-term psychological or physical morbidity.
      METHOD: In April and May 1999, an attempt was made to contact all of the 506
      women who were living with men dying of prostate cancer in 1996 or of urinary
      bladder cancer in 1995 or 1996, as well as 287 population controls. RESULTS:
      Completed questionnaires were received from 379 of the widows and 220 of the
      controls. Widowhood was associated with a low or moderate subjective quality of
      life (relative risk [RR] = 1.4, 95% confidence interval 1.2-1.7), low or moderate
      psychological well-being (RR = 1.8, 1.4-2.3), anxiety (RR = 1.9, 1.3-2.7),
      depression (RR = 2.2, 1.6-2.9), sleep disturbances (RR = 1.9, 1.5-2.4), diabetes
      (RR = 3.5, 1.2-7.9), and economic dissatisfaction (RR = 1.6, 1.3-2.0).
      CONCLUSION: An excess risk of psychological morbidity, diabetes mellitus and
      dissatisfaction with the economic situation was found in the widowed population.

PMID- 12623523
TI  - Sociodemographic determinants of multiple unhealthy behaviours.
AB  - BACKGROUND: Although behaviours regarded as unhealthy are widespread, behaving in
      an unhealthy manner in several respects is relatively uncommon. However, people
      with multiple unhealthy behaviours exist and their number is larger than expected
      if the behaviours were not related to each other. The aim of this study was to
      examine sociodemographic determinants of multiple unhealthy behaviours, with
      special reference to independent and combined effects of the determinants.
      METHODS: Data on unhealthy behaviours were derived from nationwide surveys among
      Finnish adults. The mean number of unhealthy behaviours practised on a daily
      basis and the probability of reporting three or four of these behaviours was
      examined across sociodemographic groups. RESULTS: Age, educational level and
      marital status predicted reporting of three or four unhealthy behaviours.
      Interactions were observed between education and age in both genders as well as
      between marital status and age in men and educational level and living area in
      women. Mean numbers of unhealthy behaviours showed similar patterns to having
      three or four unhealthy behaviours but few differences between the means were
      statistically significant and there were no interactions. CONCLUSION: The
      influence of each sociodemographic determinant on multiple unhealthy behaviours
      was relatively independent from the other sociodemographic determinants. As the
      effect of these determinants tends to be cumulative, engaging in multiple
      unhealthy behaviours is common in population subgroups with several unfavourable
      characteristics. In health promotion initiatives special attention should be paid
      to such population groups and their social circumstances.

PMID- 12623524
TI  - "One-night stands" - risky trips between lust and trust: qualitative interviews
      with Chlamydia trachomatis infected youth in North Sweden.
AB  - AIM: The aim of the study was to get a deeper understanding of sexual risk
      taking, by interviewing young people diagnosed with Chlamydia trachomatis.
      METHOD: This qualitative study was conducted at a youth clinic in Umea, Sweden.
      Five young women and four men, aged 18-22, participated. In-depth interviews were
      performed. Open questions around certain themes were posed, such as thoughts
      about getting CT, sexual encounters, and attitudes towards condoms. Interviews
      were tape-recorded and transcribed verbatim. Data were analysed according to
      grounded theory. Norms, events, and emotions were explored. The goal was to
      develop credible and applicable concepts concerning sexual relationships, risk
      taking, and experiences of CT. RESULTS: Informants revealed that behind their
      sexual risk-taking was a drive to "go steady". Lust and trust were the guidelines
      if sex was going to take place. When discussing "one-night stands" gender
      stereotypes occurred. Females were expected to be less forward compared with
      males. We found an uneven distribution of responsibility concerning condoms.
      Males expected females to be "condom promoters". By catching CT, females
      experienced guilt, while males felt content through knowing "the source of
      contamination". CONCLUSION: An important public health issue is to implement how
      males should play an equal part in reproductive health. General CT screening of
      males is one suggestion.

PMID- 12623525
TI  - Violence against women and consequent health problems: a register-based study.
AB  - AIMS: This study set out to examine whether women victimized by domestic violence
      in a given year subsequently have more health problems measured by amount of
      hospital contacts due to disease than non-victimized women. METHODS: A case
      control study was carried out, based on data in the Danish National Patient
      Register, which covers all hospital contacts, identified by the unique citizen
      number. Three age groups were included: 15-19, 20-29, and 30-49 years. Cases were
      women with any hospital contact as a result of intentional injuries, defined as
      domestic violence, in 1995, and controls were women with all other reasons for
      hospital contact in 1995. The Nordic Classification of External Causes of
      Injuries classified reason for contact, place of occurrence, and mechanism of
      injury. Domestic violence was defined as intentional injury by blunt force and
      occurring in a residential area. The rate of subsequent hospital contacts because
      of any disease, induced abortions, gynaecological diseases, and mental illness
      among cases and controls in 1996-98 was compared. RESULTS: 1,815 women victimized
      by domestic violence and 388,366 controls were identified. In the entire period,
      the victims of violence presented significantly more health problems than the
      controls, as measured by hospital contacts due to any disease. The rate of
      contacts due to induced abortions, gynaecological diseases, and mental illness
      was significantly higher among the victims in all three age groups in the first
      year following the identified violence. In the entire period, victims of violence
      aged 20-49 presented a significantly higher rate of contacts due to mental
      illness, and victims aged 20-29 years a higher rate of induced abortions.
      CONCLUSIONS: Registration practice of all hospital contacts in Denmark
      facilitates nationally representative analyses of associations between violence
      and health problems. The observed differences among women victimized by domestic
      violence and controls point to violence against women as a major public health
      problem. Proper registration of hospital contacts due to intentional injury may
      both guarantee adequate follow-up of the individual victim, and serve as a useful
      tool in the monitoring of general violence prevention.

PMID- 12623526
TI  - Patterns of local migration and their consequences in a rural Ethiopian
      population.
AB  - AIMS: In the context of the Butajira Rural Health Programme (BRHP) in Ethiopia,
      which has maintained demographic surveillance in selected communities since 1987,
      this paper investigates patterns of migration and their consequences within that
      population over a ten year period 1987-1996. METHODS & RESULTS: Based on
      observations of over 336,000 person-years in nine rural villages and one small
      town, 48% of individuals migrated in or out of the study area at some stage, as
      recorded in monthly household visits. There was a net incidence of migration into
      the urban area, particularly among young adults. Mortality was higher among
      residents compared with in-migrants, with rates of 10.5 (95% CI 7.5 to 14.9) and
      8.2 (95% CI 5.8 to 11.7) per 1,000 person-years respectively after adjustment for
      age, sex and area of residence, a rate ratio of 1.3. Fertility among in-migrant
      and resident women was similar, at rates of 0.26 and 0.28 births per reproductive
      year respectively. CONCLUSIONS: The causes of the observed differences in
      mortality are not clear, though they may be partly due to self-selection effects
      among migrants, and may have important implications for future health policy and
      planning in Ethiopia and other similar settings.

PMID- 12623527
TI  - Duration of employment is not a predictor of disability of cleaners: a
      longitudinal study.
AB  - AIMS: Cleaning is a high-risk occupation for developing musculoskeletal
      disorders. Sickness absence is twice as high as in other occupations. Disability
      pensions for musculoskeletal disorders are twice as high in cleaners as in other
      employed women. However, a result from Norwegian and Danish studies shows that
      female cleaners do not report higher morbidity of musculoskeletal disorders than
      other women. The objective was to analyse whether female cleaners have a higher
      risk of obtaining a disability pension than women in other unskilled occupations
      and whether the length of employment influences the risk. METHODS: The material
      is from the National Census in 1980 and 1990 and supplemented with disability
      pensioning data from the National Insurance Administration and the Population
      registry. Women aged 20-49, working as cleaners, seamstresses, nursing, kitchen,
      or shop assistants in 1980 were followed until 1990 or until receiving disability
      pension. Female cleaners aged 30-59 years in 1990 were categorized into two
      cohorts by occupation in 1980. They were followed from 1991 to 1994, to the date
      they died, or received disability pension. Incidence rates and incidence rate
      ratio for disability pension and mortality was calculated by Poisson regression.
      Cox regression calculated the relative risk of obtaining disability pension.
      RESULTS: Disability pension rates were higher among cleaners than among other
      women in unskilled occupations (1.4 per 1,000 person years (CI 95% 1.35-1.46)),
      but the risk of obtaining disability pension did not increase with increasing
      exposure to cleaning (HR 0.8 (CI 95% 0.6-1.2)). CONCLUSIONS: The cleaning
      occupation has high disability rates compared with other unskilled occupations. A
      contribution factor to these high rates is a selection of women with poor health
      into the occupation.

PMID- 12623528
TI  - Adulthood mortality of infants isolated at birth due to tuberculosis in the
      family.
AB  - AIMS: In 1936 the Finnish Anti-Tuberculosis Association founded the first
      nursery, "Joulumerkkikoti", into which infants born into tuberculous families
      were admitted and given BCG vaccination to reduce the risk of tuberculosis. This
      prophylactic regimen was effective in reducing infant mortality and morbidity of
      tuberculosis. We investigated the mortality of these children later in childhood
      and adulthood. METHODS: The index cohort consisted of 3,020 subjects born between
      1945 and 1965 in Finland and isolated from their family immediately after birth.
      The average separation time was 218 days. The subjects alive on 1 January 1971
      were identified. For every index subject two reference subjects were chosen, the
      matching criteria being sex, year, and place of birth. Data on causes of deaths
      were obtained from the Finnish Cause of Death Registry by the end of 1998.
      RESULTS: The relative mortality rate (RR) was higher in the index cohort than in
      the reference cohort for all causes of death (RR 1.4; 95% CI 1.2-1.7), and
      particularly for unnatural deaths: RR 1.5 (1.1-1.9) for men and RR 1.9 (1.0-3.7)
      for women. CONCLUSIONS: The mortality in the index subjects later in childhood
      and adulthood was somewhat elevated. This may be explained by a variety of risks
      experienced during pregnancy, delivery, and childhood. The fall in the
      socioeconomic status of the family of origin due to tuberculosis may partially
      explain the result. Another interpretation is that the very early separation from
      the mother had unfavourable effects on later psychological developments in some
      children.

PMID- 12623529
TI  - Socioeconomic characteristics of fathers of children born to teenage mothers in
      Stockholm, Sweden.
AB  - AIMS: Teenage childbearing has been associated with adverse outcomes for the
      mother and the child. Despite this, no study in Sweden has focused on the fathers
      of those children. The aim of the present study was to describe and compare the
      socioeconomic situation of fathers of children born to teenage mothers with those
      of children born to average-aged mothers. METHODS: A descriptive comparative
      study was conducted, which comprised 132 fathers of children born to teenage
      mothers (Group A) and the same number of fathers of children born to older
      mothers (Group B). All fathers answered a structured questionnaire regarding
      socioeconomic and reproductive factors. RESULTS: On certain critical variables
      the Group A fathers were more likely to have had a more compromised and difficult
      socioeconomic background. Compared with the Group B fathers they were more likely
      to have tried illicit drugs and to be involved in criminality. In addition, the
      Group A fathers often came from single-parent households. CONCLUSION: Many
      fathers of children born to teenage mothers showed problem behaviours, which may
      negatively influence their ability to engage in successful parenting. Therefore
      increased attention should be paid to the fathers at an early stage of pregnancy,
      during the antenatal visits.

PMID- 12623533
TI  - Associative learning and representation. An EPS workshop for N. J. Mackintosh, 9
      July 2002.
AB  - The papers published in this Special Issue are based upon presentations at a
      workshop on Associative Learning and Representation, which was sponsored by the
      Experimental Psychology Society and hosted by Emmanuel College, Cambridge. The
      workshop celebrated the contribution of Professor Nicholas Mackintosh to animal
      learning and conditioning in particular and experimental psychology in general in
      the year of his retirement from the Chair of Psychology at the University of
      Cambridge after 21 years in post. The date of the workshop, 9 July 2002, was
      particularly auspicious as it was the day of Professor Mackintoshs birth 67 years
      ago. Moreover, it is particularly fitting that this tribute is published in the
      Comparative and Physiological Psychology Section (B) of Quarterly Journal of
      Experimental Psychology, which he founded in 1981 during his editorship of the
      Journal between 1977 and 1984.

PMID- 12623534
TI  - Context-sensitive elemental theory.
AB  - My theories of associative learning, like those of N. J. Mackintosh and almost
      all learning theorists, have employed elemental representations of the stimuli
      involved. We must take notice when two important contributors to elemental
      theory, J. M. Pearce and W. K. Estes, find sufficient problems with the theory
      type to cause them to defect from it. I will describe some of the essential
      problems, concerning the substantial influence of context on learning and
      retrieval, characterize the different responses of Pearce and Estes, and, then,
      propose a variation on a recently developed elemental model that was similarly
      inspired. The resulting elemental theory has a close quantitative relationship to
      the product-rule of Estes and D. L. Medin, and may help us to rationalize how the
      same formal experimental design can sometimes produce results that favour the
      configural interpretation of Pearce and at other times the elemental
      interpretation of R. A. Rescorla and A. R. Wagner, as these have often been
      pitted against each other.

PMID- 12623535
TI  - Representation and discrimination on an artificial dimension.
AB  - How we represent stimuli that are drawn from either natural (e.g., hue) or
      artificial (e.g., morphed face) dimensions is an issue of great significance for
      human learning. In this paper we outline a model of human dimensional
      representation in conjunction with some supporting empirical evidence for
      transfer along a continuum in humans (following Lawrence, 1952) and the first
      recorded case of transfer after outcome reversal with human subjects (following
      Mackintosh & Little, 1970). Our results support an elemental representation for
      dimensional stimuli in conjunction with algorithms that modulate both the
      salience and the associability of those representations.

PMID- 12623536
TI  - Learned changes in the sensitivity of stimulus representations: associative and
      nonassociative mechanisms.
AB  - Central to associative learning theory is the proposal that the concurrent
      activation of a pair of event representations will establish or strengthen a link
      between them. Associative theorists have devoted much energy to establishing what
      representations are involved in any given learning paradigm and the rules that
      determine the degree to which the link is strengthened. They have paid less
      attention to the question of what determines that a representation will be
      activated, assuming, for the case of classical conditioning, that presentation of
      an appropriately intense stimulus from an appropriate modality will be enough.
      But this assumption is unjustified. I present the results of experiments on the
      effects of stimulus exposure in rats that suggest that mere exposure to a
      stimulus can influence its perceptual effectiveness -- that the ability of a
      stimulus to activate its representation can be changed by experience. This
      conclusion is of interest for two reasons. First, it supplies a direct
      explanation for the phenomenon of perceptual learning -- the enhancement of
      stimulus discriminability produced by some forms of stimulus exposure. Second, it
      poses a theoretical challenge in that it seems to require the existence of a
      learning mechanism outside the scope of those envisaged by current formal
      theories of associative learning. I offer some speculations as to how this
      mechanism might be incorporated into such theories.

PMID- 12623537
TI  - Learning about cues in their absence: evidence from flavour preferences and
      aversions.
AB  - A simple behavioural task may involve the presentation of two or more stimuli.
      Any learning that takes place in such a situation may be analysed in terms of the
      formation of an association between the central representations of those stimuli.
      Presumably performance based on this learning can occur because presentation of
      one stimulus will then activate the representations of other stimuli that were
      previously presented with it. To examine the role that these representations play
      in learning in and of themselves requires that the stimuli themselves are absent.
      A review of a number of flavour preference and aversion studies indicates that an
      associatively activated stimulus representation can support learning that is both
      similar to and the opposite of that maintained by the presentation of the
      stimulus itself. Which occurs is dependent upon the nature of the reinforcer and
      the temporal relationships between the training events. Although this pattern of
      results appears suggestive of separate learning rules, a reanalysis raises the
      possibility of an explanation in terms of a single associative system.

PMID- 12623538
TI  - Learned associability and associative change in human causal learning.
AB  - The Mackintosh (1975) model of associative learning specifies that processing of
      both the cues presented on a trial and the outcome of that trial will interact to
      determine the amount of associative change undergone by a given cue. Experiments
      looking at the distribution of associative change among the elements of a
      reinforced compound in animal conditioning studies indicate that processing of
      the outcome of a trial does indeed influence associative change. The work
      reported here investigates the distribution of associative change among the
      elements of a reinforced compound in a human causal judgement paradigm, and it
      indicates that processing of the cues presented on a trial also plays a role in
      determining associative change (in terms of changes in the associability of cues
      as a result of experience). Taken in combination, these results provide good
      support for Mackintosh (1975) and the characterizations of both cue and outcome
      processing that it offers.

PMID- 12623539
TI  - Learned irrelevance: a contemporary overview.
AB  - This article reviews the recent literature on the topic of learned irrelevance.
      It asks whether the retardation of subsequent conditioning produced by
      uncorrelated preexposure is indeed the result of the animal learning that a
      conditioned stimulus (CS) and unconditioned stimulus (US) are unrelated, or
      whether it is better explained either as a result of the context specificity of
      latent inhibition, or as some other artefact of the uncorrelated schedule
      employed. The conclusion is that there is as yet no good evidence to support the
      existence of a genuine learned irrelevance effect.

PMID- 12623540
TI  - Learned irrelevance and retrospective correlation learning.
AB  - In 1973 Mackintosh reported an interference effect that he called learned
      irrelevance in which exposure to uncorrelated (CS/US) presentation of the
      unconditional stimulus (US) and the conditioned stimulus (CS) interfered with
      future Pavlovian conditioning. It has been argued that there is no specific
      interference effect in learned irrelevance; rather the interference is the sum of
      independent CS and US exposure effects (CS + US). We review previous research on
      this question and report two new experiments. We conclude that learned
      irrelevance is a consequence of a contingency learning and a specific learned
      irrelevance mechanism. Moreover even the independent exposure controls, used in
      previous experiments to support the CS and US exposure account, provide support
      for the correlation learning process.

PMID- 12623541
TI  - Acquisition of knowledge about spatial location: assessing the generality of the
      mechanism of learning.
AB  - A selection of studies in the last 20 years is reviewed. These studies show basic
      Pavlovian phenomena in the spatial domain (like blocking, overshadowing, latent
      inhibition, and perceptual learning) with nonhuman subjects, specifically with
      rats, both in the radial maze and in the circular pool. The generality of these
      phenomena with respect to other species and to other spatial preparations is also
      discussed. The conclusion is that the mechanism responsible for the acquisition
      of knowledge about spatial location seems to be associative in nature.

PMID- 12623542
TI  - Absence of overshadowing and blocking between landmarks and the geometric cues
      provided by the shape of a test arena.
AB  - In three experiments rats were required to escape from a pool of water by
      swimming to a submerged platform. The position of the platform was determined by
      the shape of the pool, which was either rectangular or triangular. A landmark
      that was located on the surface of the pool near the platform failed to
      overshadow (Experiment 1) or block (Experiment 2) learning about the position of
      the platform with reference to the shape of the pool. Experiment 3 revealed a
      similar outcome with cues outside the pool, which could be used, in addition to
      the shape of the pool, to identify the location of the platform. These findings
      imply that theories of learning that assume that stimuli must compete with each
      other for the control that they acquire may not apply to spatial learning based
      on the shape of the environment.

PMID- 12623543
TI  - The interaction between discriminative stimuli and outcomes during instrumental
      learning.
AB  - Rats were trained on a biconditional discrimination in which the delivery of a
      food pellet stimulus signalled that pressing on one of two levers would be
      reinforced, whereas the delivery of a sucrose solution stimulus signalled that
      the reward was contingent on pressing the other lever. The outcome was the same
      food type as the discriminative stimulus in the congruent group but the other
      food type in the incongruent group. Both responses were rewarded with the same
      outcome in the same group. All the three groups learned the discrimination at
      statistically indistinguishable rates. Prefeeding one of the outcomes selectively
      reduced the associated response thereby demonstrating that responding was
      mediated by a representation of the outcome. Moreover, the outcome of one trial
      controlled responding on the next trial in accord with the stimulus function of
      the food type. These results are discussed in relation to the associative
      structures mediating the discriminative control of instrumental performance.

PMID- 12623544
TI  - Palatability shifts in taste and flavour preference conditioning.
AB  - Changes in palatability of tastes and flavours as a result of flavour preference
      conditioning were examined. In Experiment 1, when tastes were paired with glucose
      in a reverse-order differential conditioning paradigm, rats acquired conditioned
      preferences for CS(+) and displayed more hedonic responses to CS(+) than to CS(-)
      in a postconditioning taste reactivity test. In Experiment 2, rats that received
      oral infusions of flavours as CSs during a reverse-order conditioning procedure
      expressed both palatability shifts and conditioned preferences for CS(+). Rats
      that received a forward conditioning procedure acquired a preference for CS(+),
      but the palatability of CS(+) was unchanged. In Experiment 3, hungry rats drank
      mixtures of a flavour CS and a calorific or sweet tasting reinforcer in a long
      exposure conditioning paradigm. When tested hungry, rats preferred CS(+) whether
      they had acquired flavour-calorie or flavour-taste associations. However, CS(+)
      became more palatable only for rats that acquired flavour-calorie associations.
      These results suggest that acquisition of flavour preferences, as measured by 2
      bottle tests, may not always be accompanied by enhanced palatability.

PMID- 12623552
TI  - Patient satisfaction study of unwanted facial and body hair: 5 years experience
      with intense pulsed light.
AB  - OBJECTIVE: This study was performed in order to evaluate patient satisfaction
      with epilation using an intense pulsed light source. METHODS: Between 1995 and
      2000, 416 patients consulted the authors' practice because of unwanted facial and
      body hair. A total of 309 patients received treatment with a non-coherent,
      filtered flashlamp intense pulsed light source. In February 2000, a questionnaire
      was mailed to each patient and 207 replies were obtained. RESULTS: Overall, 45
      (22%) of patients were very satisfied, 93 (45%) were satisfied and 69 (33%)
      remained unsatisfied with the outcome of light-assisted hair removal. The non
      coherent, filtered flashlamp intense pulsed light source satisfactorily removed
      unwanted dark hair. Hair-free periods from weeks to years could be observed.
      CONCLUSION: Hair removal by a non-coherent, filtered flashlamp intense pulsed
      light source is an effective and safe method for long-term epilation of unwanted
      hair. This technique offers a more reliable and practical solution than any other
      hair removal method, especially for patients with skin irritation and ingrown
      hair.

PMID- 12623553
TI  - Laser therapy of freckles and lentigines with quasi-continuous, frequency
      doubled, Nd:YAG (532 nm) laser in Fitzpatrick skin type IV: a 24-month follow-up.
AB  - BACKGROUND: Newly developed lasers produce excellent results with minimal
      complications compared with traditional treatments for freckles and lentigines.
      OBJECTIVES: To assess the efficacy and safety of the frequency-doubled Nd:YAG
      (532 nm) laser in the treatment of freckles and lentigines in type IV skin.
      PATIENTS AND METHODS: Twenty adult patients (14 with freckles and six with
      lentigines) were subjected to a variable number of treatments with a minimum 4
      week interval until no additional improvement occurred or > 75% improvement was
      obvious. Patients manifesting > 50% improvement were followed up once every 3
      months for 24 months. The rest were regarded as treatment failures and not
      followed up. RESULTS: Sixteen (80%) of 20. patients (freckles, n = 10;
      lentigines, n = 6) manifested more than 50% improvement. They were treat-
      irradiated between three and eight times with a 4-12-week interval. Complications
      included hypopigmentation (25%), mild textural changes (15%) and
      hyperpigmentation (10%). All these were mild and resolved within 2-6 months. Of
      10 patients with freckles followed up for 24 months, four (40%) patients showed
      partial recurrence. However, all the patients maintained > 50% improvement. None
      of the patients with lentigines showed recurrence. CONCLUSION: The quasi
      continuous, frequency-doubled Nd:Y AG (532 nm) laser safely and effectively
      treats freckles and lentigines in Fitzpatrick skin type IV.

PMID- 12623554
TI  - CO2 laser vaporization for disfiguring lupus pernio.
AB  - Presented in this paper are two cases of longstanding gross and disfiguring lupus
      pernio of the nose successfully treated by CO2 laser resurfacing Both patients
      were resistant to previous medical therapy and have had an excellent
      postoperative cosmetic result.

PMID- 12623555
TI  - Laser hair removal for recurrent pilonidal sinus disease.

PMID- 12623560
TI  - Biodegradable stents as a platform to drug loading.
AB  - Despite technical and mechanical improvement in coronary stents the incidence of
      restenosis caused by in-stent neointimal hyperplasia remains high. Oral
      administration of numerous pharmacological agents has failed to reduce restenosis
      after coronary stenting in humans, possibly owing to insufficient local drug
      concentration. Therefore, drug-eluting stents were developed as a vehicle for
      local drug administration. The authors developed a new drug-eluting polymer stent
      that is made of poly-l-lactic acid polymer mixed with tranilast, an anti-allergic
      drug that inhibits the migration and proliferation of vascular smooth muscle
      cells induced by platelet-derived growth factor and transforming growth factor
      >1. Polymer stents might be superior to polymer-coated metallic stents as local
      drug delivery stents in terms of biodegradation and the amount of loaded drug.
      Drug-mixed polymer stents can be loaded with a larger amount of drug than can
      drug-coated metallic stents because the polymer stent struts can contain the
      drug. Clinical application is required to assess the safety and efficacy of drug
      eluting polymer stents against stent restenosis.

PMID- 12623559
TI  - Impact of transport and drug properties on the local pharmacology of drug-eluting
      stents.
AB  - Drugs released from stents are driven by physiological transport forces,
      principally solvent-driven flow (convection) and random molecular agitation
      (diffusion). The relative strength of these two forces determines drug
      penetration and distribution in the arterial wall. Drug physicochemical factors
      can induce critical modulations to the primary distribution, both transiently and
      at steady state. Hydrophobic interactions and nonspecific binding, for example,
      can both result in tissue drug concentrations severalfold above administered
      concentration. Drug interaction with native proteins may also interfere with drug
      transfer at the stent-artery interface. These transport forces and tissue
      interactions can induce local drug concentrations even at steady state to vary by
      one or more orders of magnitude over the span of a few cells. To account for
      significant local variations in drug concentrations following stent-based
      delivery, rational design of vascular delivery systems requires consideration of
      drug distribution and tissue interactions on a local, continuum basis. Continuum
      analysis adapts traditional pharmacokinetics to the local environment by
      supplementing discrete global parameters of drug content with continuous local
      values of concentration, transport and binding. The interplay of these parameters
      with local flux conditions and drug and tissue properties defines the local drug
      distribution in space and over time. This type of analysis may well become
      increasingly relevant given the trend toward stent-based drug therapy in
      cardiovascular care.

PMID- 12623561
TI  - Direct stenting with the Bx VELOCITY balloon-expandable stent mounted on the
      Raptor rapid exchange delivery system versus predilatation in a European
      randomized Trial: the VELVET trial.
AB  - AIMS: This study examined the six-month angiographic results of direct coronary
      stenting, and compared the nine-month safety, efficacy and cost of this strategy
      versus stenting after balloon predilatation. METHODS: In phase I of VELVET, 122
      patients (mean age = 62.3 +/- 10.1 years, 77% male, 11% with diabetes) with
      angina pectoris or myocardial ischemia resulting from a single de novo 51% to 95%
      coronary stenosis underwent direct stenting. The endpoints of phase I included
      angiographic findings and rates of major adverse cardiac events up to six months
      of follow-up. In phase II, 401 patients (mean age = 61.3 +/- 10.8 years, 79%
      male, 16% with diabetes) with angina pectoris or documented myocardial ischemia
      resulting from single or multiple, de novo or restenotic, coronary lesions were
      randomized between direct stenting and stenting after predilatation. The
      immediate angiographic results, and clinical outcomes and costs associated with
      the two treatment strategies up to nine months of follow-up were compared.
      RESULTS: In phase I the mean diameter stenosis immediately before and after the
      procedure, and at six months was 61.7+/-9.4%, 13.5+/-6.3%, and 33.6+/-16.2%,
      respectively. The six-month binary restenosis rate was 11%. The overall rate of
      major adverse cardiac events, including two non-cardiac deaths, was 9.8%. In
      phase II, the success rates of the intended delivery strategies were 87.9% and
      97.9% for direct stenting and predilatation, respectively (p < 0.001), while the
      procedural success rates were similar (93.9% vs 96.5%). Over a follow-up period
      of nine months, major adverse cardiac events rates were 12.0% and 10.9% in
      patients randomized to direct stenting and predilatation, respectively (non
      significant). Analyses of the costs incurred up to nine months in each treatment
      group revealed a mean saving of e362 per patient in favor of the direct stenting
      strategy (non-significant). CONCLUSIONS: Compared with a strategy of stenting
      preceded by balloon dilatation, direct stenting was associated with an equivalent
      procedural success rate, equivalent clinical results up to nine months of follow
      up, and a reduction in procedural and in-hospital costs (p < 0.0001 and p <
      0.001, respectively), that was no longer significant after nine months.

PMID- 12623562
TI  - Therapeutic angiogenesis with vascular endothelial growth factor in peripheral
      and coronary artery disease: a review.
AB  - Therapeutic angiogenesis constitutes an alternative treatment for patients with
      extensive tissue ischaemia in whom primary vascular reconstruction procedures are
      not feasible or have previously failed. At present vascular endothelial growth
      factor (VEGF) has been the most widely used angiogenic factor in experimental and
      human clinical trials. Early clinical data provide evidence that gene transfer of
      the VEGF gene can achieve beneficial angiogenesis, with minimal side-effects.
      Ongoing phase III clinical studies will reveal definitive efficacy.

PMID- 12623563
TI  - Clinical introduction of the Tandemheart, a percutaneous left ventricular assist
      device, for circulatory support during high-risk percutaneous coronary
      intervention.
AB  - BACKGROUND: In patients with poor left ventricular function and high-risk
      coronary lesions, prolonged ischemia during percutaneous coronary intervention
      (PCI) may have major hemodynamic consequences. The Tandemheart is a percutaneous
      left ventricular assist device intended for short-term circulatory support.
      METHODS AND RESULTS: The Tandem-heart incorporates 9-17 F. arterial cannulae and
      a unique 21 F. transseptal cannula and centrifugal bloodpump. Operating at 7500
      rpm, the pump withdraws oxygenated blood from the left atrium and delivers up to
      4 liters/min to the arterial circulation. As of May 2001, the Tandem-heart was
      electively employed in three male patients (ages 52, 54 and 56) scheduled for
      high-risk PCI. The mean time to initial circulatory support was less than 30
      minutes. Systemic hemodynamics significantly improved prior to PCI in two
      patients. Pump flow after one hour ranged from 2.43 to 3.8 liters/min (mean 3.17
      liters/min) and duration of support from 23 to 49 hours (mean 33 hours).
      Procedural success was 100%, with no significant hemolysis or bleeding.
      Successful weaning was completed in all patients, who have remained free of major
      cardiac events up to seven months post-PCI. CONCLUSIONS: In this first clinical
      experience of elective use of Tandem-heart for circulatory support during high
      risk PCI, the device was easily inserted and preserved hemodynamic stability,
      regardless of the intrinsic cardiac function, creating optimism for more
      widespread use for this and other indications.

PMID- 12623564
TI  - Acquired coropulmonary and bronchopulmonary anastomoses occurring in association
      with pulmonary arterial occlusion and veno-occlusive disease generating potential
      coronary steal.
AB  - The development of collateral circulation is a general vascular response which is
      well characterised in the heart. The most common precipitant of this is ischaemia
      and the most common manifestation is intra coronary collateralisation. Collateral
      flow between the heart and other thoracic structures is also documented albeit
      rarely and can be congenital or acquired. In this case report we define a unique
      case of collateral flow between the coronary and pulmonary circulations in a
      complex case of mediastinal fibrosis.

PMID- 12623566
TI  - Meeting report: Transcatheter Cardiovascular Interventions: Washington, DC, USA,
      24-28 September, 2002.

PMID- 12623569
TI  - Editorial: Paving the way into the Third millennium.

PMID- 12623565
TI  - Recurrent stent thrombosis associated with lupus anticoagulant due to renal cell
      carcinoma.
AB  - A case is presented of recurrent stent thrombosis unexplained by angiographic
      appearance, which subsequently revealed a diagnosis of antiphospholipid syndrome
      secondary to renal cell carcinoma.

PMID- 12623570
TI  - The use of adjunctive GPIIb/IIIa inhibitors in patients with unstable angina/non
      Q-wave MI undergoing percutaneous coronary intervention.
AB  - Glycoprotein IIb/IIIa receptor inhibitors represent a relatively new therapeutic
      approach in the field of antiplatelet therapy. Following the development of
      abciximab a number of small molecule GPIIb/IIIa inhibitors have been introduced
      such as tirofiban and eptifibatide. In this fast-moving field the interventional
      cardiologist needs a framework to guide decision-making for the individual
      patient. This review covers the efficacy and safety data from the clinical trials
      of GPIIb/IIIa inhibitors in the context of patients undergoing percutaneous
      coronary intervention for unstable angina/non-Q-wave myocardial infarction. There
      is an increasing body of evidence to support the efficacy of GPIIb/IIIa
      inhibitors in reducing the risk of adverse ischemic events in high and low risk
      patients undergoing percutaneous coronary intervention. A number of unresolved
      efficacy and safety issues remain, including the duration of treatment before and
      after intervention; whether a reduction in the heparin dose would further
      decrease the risk of hemorrhage without affecting the periprocedural thrombotic
      rate in patients undergoing PTCA with adjunctive GPIIb/IIIa inhibitors; and the
      cost-effectiveness of this therapy. When a thorough analysis of cost
      effectiveness has been made, it will be easier to advocate the widespread use of
      these agents in all patients undergoing coronary intervention.

PMID- 12623571
TI  - Behaviour of implantable coronary stents during magnetic resonance imaging.
AB  - BACKGROUND: Magnetic resonance imaging (MRI) becomes more and more a routine
      diagnostic tool in clinical cardiology. In patients undergoing MRI, metallic
      implants may be harmful by motion or heating under certain circumstances. Many
      cardiac patients have implanted intracoronary stents. However, the safety of
      these metallic implants and especially their temperature behaviour during MRI has
      not been sufficiently tested. METHODS: This study investigated motion and
      temperature changes of 14 different stents for intracoronary application in two
      clinical scanners at field strengths of 1.0 and 1.5 T. At 1.5 T these studies
      were repeated after implantation of the stents into the coronary arteries of
      excised porcine hearts. Furthermore, the clinical status of 33 patients was
      assessed after a cardiac MR study and compared with a group of 33 patients
      matched for age, sex and risk factors for restenosis. RESULTS: No visible motion
      of the stents was observed. Furthermore, using a highly sensitive infrared camera
      any significant heating of the stents during MRI could be excluded. The rate of
      clinical events was not different in patients after MRI as compared with the
      control group. CONCLUSION: It is concluded that MRI is safe in patients with the
      currently available intracoronary stents.

PMID- 12623572
TI  - Safety and efficacy of treatment with platelet GPIIb/IIIa receptor blockade in
      unstable angina patients awaiting PTCA at a referring clinic.
AB  - BACKGROUND: Although balloon angioplasty has assumed an important role in the
      management of refractory unstable angina (UA), that is, UA that does not respond
      to conventional therapy, it is limited by complications related to thrombosis and
      acute coronary occlusion. The complication rate is higher in patients with UA
      than in those whose condition is stable. Preprocedural use of abciximab, a
      monoclonal platelet glycoprotein IIb/IIIa receptor blocker, has been used
      effectively in patients with UA, but its acceptance may be limited by safety
      concerns and economic constraints. The current trial investigated a protocol for
      abciximab pretreatment in patients with UA awaiting transfer from referring
      hospitals to a site of intervention (the 'drip and ship' protocol). AIMS: This
      observational study was conducted to evaluate whether a prophylactic,
      preprocedural regimen of abciximab can be safely and effectively administered to
      UA patients in referring hospitals while awaiting coronary angioplasty at the
      interventional clinic. METHODS: From April 1996 to December 1998, 168 consecutive
      patients with refractory UA (Braunwald class II or III) received abciximab
      prospectively at the referring clinic before undergoing PTCA or stent
      implantation at the interventional clinic. The following cost-conscious protocol
      was used: a 0.25 mg/kg bolus of abciximab followed by 10 micro g/min
      intravenously for 16 hours, in addition to intravenous nitrates, heparin and
      aspirin therapy. Patients were then transferred to a facility with PTCA
      capability via high-speed ambulance transport. No specific alterations of routine
      transfer protocol were needed. Platelet aggregation studies were conducted during
      abciximab infusion. All interventions were performed while abciximab was given.
      Procedural and clinical success and long-term outcomes also were assessed.
      RESULTS: The primary angiographic success rate (patients with post-PTCA diameter
      stenosis < 50%) was 98%, and the in-hospital clinical success rate (angiographic
      success without major complications) was 98%. No major bleeding complications
      occurred during the abciximab pretreatment period. Platelet aggregation findings
      in the study patients showed a stable inhibition of >80% at the time of
      angioplasty. At 30-day follow-up, all patients were alive and 91% were free of
      major adverse events. Outcomes of balloon angioplasty and stenting were equally
      favorable, indicating no device-specific effect. Event-free survival at six
      months was 89% with a target vessel revascularization rate of 10%. CONCLUSION:
      Abciximab was administered safely and effectively to angioplasty patients with
      refractory UA awaiting transfer from a noninterventional setting to the site of
      angioplasty. These results extend the current knowledge base that has been
      established in randomized trials performed in interventional centers. The study
      protocol potentially could make abciximab therapy more feasible economically, and
      therefore more widely available to patients who are most likely to benefit from
      prophylactic administration.

PMID- 12623573
TI  - Coronary stent implantation without balloon predilatation: a single-center
      experience.
AB  - OBJECTIVE: Assessment of safety and efficacy of coronary stent deployment,
      without balloon predilatation. BACKGROUND: With newer high-performance balloon
      premounted stents it has become more common to attempt coronary stent deployment
      without balloon pre- or postdilatation. METHODS: During 1998 524 coronary
      angioplasties were performed in the authors' institute, of which 279 resulted in
      coronary stenting. Of these 101 (36.2%) were stents without balloon predilatation
      (SWBP). PTCA was performed according to standard technique using mostly 7 F.
      guiding catheters, and 'rapid exchange' balloons and pre-mounted stents. RESULTS:
      Seventy-two patients had acute coronary syndromes (41 acute MI or post-MI angina,
      28 unstable angina, 10 rescue PTCA after failed thrombolysis). Mean age was 56.4
      3 11.1 years, 84.5% were males. Sixty per cent of the lesions were ACC-AHA type
      B2 or C. Target arteries were LAD 57.6%, LCX 21.2%, RCA 14.1% and SVG 7.1%.
      Procedure time was 18.2 3 17.3 minutes. Mean heparin dose was 3850 3 1570 units.
      Twenty-two patients received abciximab prior to stent deployment. Seven stents
      were not deployed without previous balloon dilatation and were retrieved safely
      via the guiding catheters and deployed after balloon dilatation. There was no
      stent embolization, ectopic suboptimal or partial stent deployment. Immediate
      angiographic success was obtained in 95 patients (94.1%). Minimal lumin diameter
      (MLD) increased from 0.27 3 0.15 to 3.23 3 2.1 mm. There were two in-hospital
      deaths (1.9%) due to cardiogenic shock. An intra-aortic balloon pump was required
      in eight patients. Two patients (1.9%) experienced subacute stent thrombosis.
      CONCLUSION: SWBP in selective groups of patients and lesions is feasible and
      safe. Larger randomized comparative trials are needed to assess the benefits and
      cost saving of this approach.

PMID- 12623574
TI  - Initial and long-term results with the CrossFlex stent--data from a national
      registry.
AB  - The Cordis CrossFlex trade mark stent is a balloon expandable helical coil made
      of stainless steel. OBJECTIVE: To assess the short- and long-term safety and
      efficacy of this stent by conducting a multi-center national registry. METHODS:
      One hundred and sixteen stents were implanted in 109 patients (mean age 59 3 10
      years, 95 males). The lesions were classified as type B2 or C in 56 patients
      (51%). Successful deployment was achieved in 103 patients (94.5%). Failure was
      due to damage to the stent (two patients) or inability to reach the lesion (four
      patients). High-pressure deployment (>14 atm) was used in 68% of cases. RESULTS:
      Edge dissections occurred in nine patients after high-pressure deployment and
      necessitated implantation of a second stent. One patient with a large acute
      myocardial infarction died during hospitalization. Side branch occlusion occurred
      in five patients (4.6%). Subacute thrombosis occurred in two patients (1.8%)
      during the first four weeks. During a six-month follow-up period, 18 patients
      (16.5%) were rehospitalized with recurrent angina. Fifteen patients had coronary
      angiography and 13 (12.1%) needed additional target lesion revascularization
      (TLR). Twelve patients required a second PTCA for in-stent restenosis, and one
      needed a coronary artery bypass graft operation. CONCLUSIONS: The CrossFlex
      coronary stent can successfully be used in complex coronary lesions, with few
      short-term complications and a low TLR rate. Operators should be aware of the
      possibility of edge dissection during high-pressure implantation.

PMID- 12623575
TI  - Treatment of coronary artery aneurysms by percutaneous sealing with bovine
      pericardium-covered stents.
AB  - The clinical significance of coronary artery aneurysms is briefly discussed.
      Until recently, surgical excision was the only treatment available. Single-case
      reports have documented aneurysm exclusion with vein-covered stents using 10 or
      11 F. guiding catheters. This paper reports four patients with coronary artery
      aneurysms which were successfully excluded with the use of a novel pericardium
      covered stent which is less invasive and shortens procedure time compared with
      the use of an autologous vein-grated stent and can be deployed using 8 F. or 9 F.
      guiding catheters. Short-term (five- to eight-month) clinical follow-up has been
      event-free in all patients, and in three patients six-month follow-up angiography
      has shown insignificant luminal loss.

PMID- 12623576
TI  - Palmaz-Schatz stent embolization: long-term clinical and angiographic follow-up.
AB  - A long-term clinical and angiographic follow-up of a case of peripheral coronary
      stent embolization is reported. No clinical sequelae occurred in the immediate
      and long-term (five years) followup. The five-year follow-up angiographic images
      provided visual documentation of absence of stent-associated stenosis. This case
      highlights the concept that fibro-intimal hyperplasia may not occur when plaque
      and balloon trauma are absent at the site of stent embolization.

PMID- 12623577
TI  - Bilateral coronary fistulae to pulmonic valve in presence of severe three-vessel
      coronary artery disease.
AB  - A 62-year-old man was admitted to the coronary care unit due to anginal pain and
      palpitations--coronary angiography revealed three-vessel coronary artery disease.
      The unexpected finding was the presence of coronary to pulmonary artery fistulae
      bilaterally, from both the proximal RCA and the proximal LAD. Right heart
      catheterization revealed normal right ventricular and pulmonary artery pressure
      and absence of hemodynamically significant left to right shunt. The patient
      underwent a triple coronary bypass including the closure of bilateral fistulae,
      which were draining into the left sinus of the pulmonary valve. One month after
      the operation he was in good health and had no complaints. Bilateral coronary
      artery fistulae is a rare anomaly diagnosed in 0.002-0.0013% of adult coronary
      angiograms. (Int J Cardiovasc Intervent 1999; 2: 249-251).

PMID- 12623578
TI  - Successful invasive management and surgical repair of subacute ventricular
      rupture complicating myocardial infarction.
AB  - We describe a patient following acute myocardial infarction with a protracted
      clinical course presenting transient episodes of hypotension, who eventually
      developed cardiac tamponade. Echocardiography demonstrated pericardial effusion
      and emergency pericardiocentesis revealed blood. The patient's condition was
      stabilized and she underwent emergency thoracotomy with successful repair of left
      ventricular rupture. We discuss the literature and suggest an approach for
      management of patients with suspected ventricular rupture after myocardial
      infarction.

PMID- 12623579
TI  - Images in Cardiovascular Interventions 'Ad hoc' PTCA to RIMA stenosis using a
      right brachial artery approach.

PMID- 12623581
TI  - Hot topics ~ conference report.

PMID- 12623582
TI  - Editorial.

PMID- 12623580
TI  - Images in Cardiovascular Interventions Dissection of the left internal mammary
      artery following diagnostic catheterization.

PMID- 12623583
TI  - Molecular biology and gene transfer in atherosclerosis in the stenting era.
AB  - Atherosclerosis is the major cause of death in the developed world. Understanding
      the pathogenesis of atherosclerosis has been a major challenge to cardiovascular
      research over the past several decades. During this period a number of advances
      in various scientific disciplines has increased our understanding of this
      disease. These include improved understanding of the structural and functional
      components of normal vessel wall and more recently the use of cell biology and
      molecular biology techniques to elucidate the pathogenesis of atherosclerosis.
      None of these advances has been more dramatic nor has potentially more far
      reaching consequences as the application of molecular biology and gene technology
      to the practice of cardiovascular medicine. These developments have already
      opened new and exciting areas of vascular research and may in the future provide
      for earlier identification of genetic predisposition to atherosclerosis,
      strategic planning of preventive therapy and more tailored pharmacologic
      approaches for established disease.

PMID- 12623584
TI  - Guidelines for indications for coronary revascularization in The Netherlands.
AB  - In 1996 the Minister of Public Health, Welfare and Sports in The Netherlands
      published a 'Planning Decree Special Interventions in the Heart'. She requested
      from the professional organizations guidelines for the indications for
      interventions in the heart. A working group was formed with representatives from
      the Dutch professional organizations for cardiology and thoracic surgery, to
      address this issue for patients with coronary artery disease. The working group
      confirmed the need to discuss all patients who are considered for either elective
      or emergency revascularization during a multidisciplinary consultation in (or
      with) one of the specialized Dutch hospitals. During this meeting of the 'heart
      team', at least one interventional cardiologist and one thoracic surgeon should
      be present. There are three possible outcomes of the heart team's consultations
      for each patient: drug therapy only ('conservative management'), coronary surgery
      or catheter intervention. For each case, the team should indicate the expected
      benefit, the risk of the intervention, the urgency and the estimated waiting
      time. The guidelines presented in this paper address these issues for three
      patient categories: stable angina pectoris, unstable angina pectoris and acute
      myocardial infarction.

PMID- 12623585
TI  - First clinical experience with the R Stent: a new highly flexible stainless steel
      tube intracoronary stent.
AB  - BACKGROUND: Coronary stents have been used with increasing frequency and in
      increasingly complex coronary disease. A new 316 LVM stainless steel coronary
      stent, the R Stent, has been designed to provide maximum flexibility for tracking
      and high radial strength post-deployment. PURPOSE: To assess the clinical
      feasibility of the R Stent in a tertiary referral population of patients with
      coronary heart disease. Specific objectives are to assess the R Stent's
      deployment success, angiographic and procedural success (<20% residual stenosis
      and >TIMI 2 flow), safety (absence of complications), and 30-day clinical success
      (angiographic/procedural success plus no major adverse coronary events). METHODS:
      Between April and November 1998, stent deployment was attempted in 27 patients
      with stable (46%) or unstable (54%) angina pectoris who qualified for
      percutaneous transluminal coronary angioplasty. Eighty per cent of patients had a
      pre-existing history of myocardial infarction, coronary bypass surgery or
      percutaneous transluminal coronary angioplasty, and several of the lesions were
      anatomically complex (totally occluded, n 32; thrombus present, n 32; heavily
      calcified, n 33; ostial, n 31; >20 mm long, n 39; angulation >45 degrees, n 37).
      Lesions in aortocoronary saphenous vein grafts were excluded. Adjunctive medical
      management included intraprocedural aspirin and heparin and post-procedural
      aspirin and ticlopidine. After deployment, patients were followed up in the
      hospital and at 30 days post procedure. RESULTS: Stent deployment was achieved in
      32 of 33 attempts (26 of 27 patients). There was one deployment failure in a
      long, calcified ostial and proximal left coronary lesion. In the 26 successful
      deployments, TIMI 3 flow was achieved. One other patient experienced a painless
      increase in creatine kinase to 375 (CK-MB of 59) at 12 h without ECG changes. At
      30 days, there were no deaths, no myocardial infarctions, no subacute thromboses,
      no repeat interventions, no bypass surgeries and no bleeding complications. Only
      the patient with post-procedural CK-MB elevation experience recurrence of CCS
      class 2 angina within the 30 days. CONCLUSION: The R Stent is a promising new
      device for the treatment of complex coronary heart disease. A larger, more
      broadly-based study is warranted.

PMID- 12623586
TI  - Clinical and quantitative angiographic outcomes following elective implantation
      of the self-expanding Wallstent for longer coronary artery lesions--final results
      of the Wellstent native study.
AB  - BACKGROUND: Implantation of short balloon-expandable stents provides superior
      clinical and angiographic outcome compared with balloon angioplasty in selected
      patients. The purpose of the Wellstent study was to evaluate the safety and
      efficacy of the self-expanding Wallstent combined with aspirin and ticlopidine in
      patients with stable or unstable angina related to a native coronary lesion up to
      45 mm in length. METHODS: 105 patients (111 lesions) with stable (57%) or
      unstable (43%) angina were included in this prospective multicentre evaluation.
      Angiography before and after Wallstent implantation and at 6-month follow-up was
      analysed at the core lab using the CAAS 2 system. The primary end-point was
      incidence of major adverse cardiac events (MACE) at 30 days. Secondary end-points
      were angiographic outcome at 6 months and MACE at 6 months and 1 year. RESULTS:
      Acute procedural success (successful stent implantation with residual stenosis
      <20%) was achieved in 99%. Mean reference diameter was 3.18 +/- 0.66 mm, minimal
      luminal diameter was 1.00 +/- 0.50 mm pre- and 2.84 +/- 0.47 mm poststent
      (diameter stenosis 16 +/- 6%). The mean hospital stay was 2.2 days. At 30 days,
      95% of patients were free of MACE. At 6 month and 1 year clinical follow-up, 75%
      and 71% of patients, respectively, remained free of MACE, the majority of which
      (19 of 30) were re-interventions at re-angiography. In 90% of eligible patients,
      MLD at follow-up was 1.65 +/- 0.75 mm (late loss 1.20 +/- 0.66 mm, loss index
      0.66), diameter stenosis 42 +/- 15%, with a restenosis rate of 32%. Longer stents
      were associated with greater luminal loss (P = 0.001) and less-favourable
      clinical outcome. CONCLUSIONS: Wallstent implantation, combined with aspirin and
      ticlopidine, achieved excellent acute and 30 day clinical results in a
      heterogenous high-risk patient group. Clinical outcome at 6 months and 1 year
      remained good, and most adverse events were re-PTCA during follow-up angiography.
      The loss index of 0.66 and restenosis rate of 32%, related in part to the use of
      longer stents, emphasizes the continuing need for effective anti-proliferative
      therapy.

PMID- 12623587
TI  - Cardioprotective effects of adenosine transport inhibition during reversible
      ischaemia in patients with coronary artery disease.
AB  - BACKGROUND: Adenosine plays a major role in protecting ischaemic myocardium and
      may potentiate ischaemic preconditioning. Nucleosine transport inhibition may
      enhance these favourable effects. DESIGN: Randomized, double blind, placebo
      controlled study, to investigate the haemodynamic and cardioprotective effects of
      nucleoside transport inhibition during ischaemia in patients with coronary artery
      disease. PATIENTS AND METHODS: Elective left anterior descending (LAD) coronary
      angioplasty was used to produce reversible ischaemia in 24 patients with stable
      angina and a single LAD lesion. They were randomized to receive either the
      nucleoside transport inhibitor draflazine or placebo. The study medication was
      infused between the 2nd and 3rd balloon inflation. The primary endpoint was
      ischaemia-induced wall motion abnormalities as measured by left septal echo
      amplitude, which was plotted against time to produce an area under the curve.
      RESULTS: No differences were observed in the systemic haemodynamics or the
      myocardial collateral circulation of the two groups. The ischaemia-induced
      regional wall motion abnormalities improved significantly after draflazine, while
      no difference was observed in the placebo group. This improvement was even more
      pronounced in patients with low caffeine levels compared with those with high
      caffeine levels. CONCLUSIONS: Draflazine, in the dose and route used, is
      associated with a significant improvement in regional myocardial function of the
      ischaemic area, without affecting systemic or collateral circulation, when
      compared with placebo. This implies that draflazine has a cardio-protective
      effect in ischaemic myocardium. High caffeine blood levels reduce these effects.

PMID- 12623588
TI  - The Cutting Balloon--a new technology?
AB  - The Cutting Balloon consists of a standard balloon dilatation catheter with four
      microtome-sharp blades that incise the plaque and minimize arterial wall trauma.
      It was used in 31 patients; nine had calcified arteries, ten had non-compliant
      lesions, three had in-stent restenosis and nine had aorto-ostial lesions.
      Seventeen lesions were predilated, 28 were post-dilated and 18 required stent
      implantation. The procedure was very effective in aorto-ostial lesions, non
      compliant lesions that were not responsive to high-pressure balloon dilatation,
      and was partially successful in calcified arteries. It has a very specific niche
      in selected lesions.

PMID- 12623589
TI  - Spontaneous coronary artery dissection: long stenting in a patient with
      polycythemia vera.
AB  - Spontaneous coronary artery dissection is a rare cause of myocardial ischemia or
      sudden cardiac death. We describe a patient with polycythemia vera and a chronic
      spontaneous coronary artery dissection who was treated with successful
      angioplasty and long stenting.

PMID- 12623590
TI  - Images in Cardiovascular Interventions Optimizing stent expansion and apposition
      using intravascular ultrasound.

PMID- 12623592
TI  - Hot topics ~ meeting report.

PMID- 12623593
TI  - Editorial.

PMID- 12623591
TI  - Hot topics ~ meeting report.

PMID- 12623594
TI  - Intravascular MR imaging and intravascular MR-guided interventions.
AB  - Intravascular MR technology, using an intravascularly placed MR receiver probe to
      acquire high-resolution angiographic MR images (i.e. intravascular MR imaging)
      and to guide cardiovascular interventional therapies (i.e. intravascular MR
      guided interventions), is a new, very attractive development in the field of MR
      imaging. The new technology offers unique advantages for cardiovascular imaging
      and interventions, including superior contrast capability and multiplanar imaging
      capabilities without the use of contrast agents and with no risk of ionizing
      radiation. Thecombination of intravascular MR techniques with other advanced MR
      imaging techniques, such as functional MR imaging, will open new avenues for the
      future comprehensive management of cardiovascular atherosclerotic disease.
      Further improvements in intravascular MR fluoroscopy with true real-time display,
      analogous to X-ray fluoroscopy, will dramatically establish the role of
      intravascular MR technology in modern medicine.

PMID- 12623595
TI  - The effects of L-arginine on atherosclerosis and heart disease.
AB  - L-arginine, a semi-essential amino acid, can enhance the synthesis of nitric
      oxide (NO) via the nitric oxide synthase pathway. Enhanced bioavailability of NO
      may prevent activation of pro-inflammatory endothelial genes by the inhibition of
      nuclear transcription factor NF 3B, thus preventing the expression of adhesion
      molecules on endothelial surfaces. Animal studies have demonstrated that the
      chronic administration of L-arginine reduces the extent of atherosclerosis and
      prevents xanthoma development in LDL receptor knockout mice. Human studies have
      demonstrated improvement in endothelium vasodilator function both in coronary
      arteries and forearm flow responses. In addition oral L-arginine reverses an
      increased monocyte-endothelial adhesion in men with coronary artery disease and
      normalizes platelet aggregation in hypercholesterolemic humans. L-arginine may be
      a promising drug in the therapy of atherosclerosis. (Int J Cardiovasc
      Interventions

PMID- 12623596
TI  - Intravascular ultrasound imaging of myocardial-infarction-related arteries after
      percutaneous transluminal coronary angioplasty reveals significant plaque burden
      and compensatory enlargement.
AB  - We studied patients with acute myocardial infarction (MI) by intravascular
      ultrasound (IVUS) to elucidate the controversy as to the amount and severity of
      the atherosclerotic disease at the culprit lesion site in acute MI, as
      discrepancies exist between angiographic and pathological reports. Twenty-five
      consecutive patients (age 56 3 10.5 years), with acute MI, underwent IVUS study
      of the MI-related artery immediately following successful PTCA to the culprit
      lesion. The IVUS images were analyzed quantitatively and qualitatively and were
      compared with the angiography of the same arteries. At the PTCA site, 64% of the
      lesions had an area stenosis of 50-70% and the plaque cross-sectional area (CSA)
      averaged 0.5 3 0.18 of the arterial CSA. IVUS-defined atherosclerosis was found
      also in 72% of the segments proximal and distal to the culprit lesion with a
      plaque/artery CSA ratio of 0.25 3 0.2. The angiogram revealed only 30% of these
      segments to be abnormal (P 3 0.001). Sixty-nine per cent of all the plaques were
      defined as 'soft' (low echo-genecity) versus 31% 'hard' (high echo-genecity). The
      hard plaques were larger than the soft plaques (0.5 3 1.6 versus 0.37 3 0.19 CSA
      index, respectively, P 3 0.01). With the increase in plaque area there was a
      significant increase in arterial cross-sectional area. This was demonstrated for
      all the diseased segments with a correlation coefficient of 0.49 (P 3 0.0001) and
      for the diseased reference sites a similar correlation coefficient of 0.49 (P 3
      0.003) was found. Contrary to coronary angiographic-based reports, this IVUS
      study revealed a significant atheromatous plaque burden at the culprit lesion of
      MI-related arteries as well as diffuse atherosclerosis in the reference segments
      proximal and distal to the lesion. The detection of compensatory enlargement may
      explain the discrepancies between the histopathological and the angiographic
      studies.

PMID- 12623597
TI  - Clinical trends in stent treatment of simple and complex coronary disease.
AB  - This is a retrospective analysis of a consecutive group of patients from a single
      medical center who underwent stent implantation. It describes 316 patients who
      constituted 53% of the angioplasty procedures carried out in a single year. The
      authors describe the complications and their 1-year follow-up. We aimed to study
      the short and long-term results of stenting in our centre in relation to multiple
      clinical and angiographic variables. During 1996, 316 consecutive patients were
      treated with stent implantation for a total of 381 coronary lesions. The
      pharmacological protocol methods of stent implantation and patient
      characteristics were used. Clinical variables were: age 59.1 3 10.7 years,
      diabetes mellitus 25.3%, hypertension 33.0% and angina pectoris 88.7% (unstable
      in 44.1%). Previous coronary surgery had been undergone by 9.2%. Multivessel
      disease was present in 56% of the patients. The indications for stenting were:
      primary 58.5%, suboptimal results 33.0% and threatened or acute occlusion 8.5%.
      Angiographic success was 98.9% and clinical success 96.8%. The major in-hospital
      complications were acute myocardial infarction (2.2%), acute revascularization
      (0.3%) and major bleeding (0.6%). All occurred within 24 h of revascularization.
      Repeated angiography was performed in 115 cases (30.2%) at 160.3 3 109.4 days
      after stent procedure for unstable angina (38.7%), stable angina (26.1%) and
      other causes (35.2%). The restenosis rate in those catheterized was 38.1%, with
      an overall clinical restenosis rate of 11.3% during the follow-up period.
      Restenosis was more prevalent among diabetic patients (17.9 vs 9.15%, P 3 0.02)
      and patients with prior balloon angioplasty (18.6 vs 9.75%, P 3 0.046). Clinical
      follow-up was available in 90.8% of the patients for 291 3 112 days. The
      actuarial survival at the end of the follow-up period was 93.8%. Death/myocardial
      infarction was associated with unstable angina pectoris (P 3 0.006), hypertension
      (P 3 0.001), smoking (P 3 0.046) and threatened or acute occlusion (P < 0.001).
      In the first year of extensive stent use, stenting is associated with high
      technical and clinical success rates. Long-term results after stent implantation
      are associated with the occurrence of acute or threatened occlusion, and the in
      hospital complications diabetes mellitus and hypertension.

PMID- 12623598
TI  - Treatment of a bifurcation lesion at the anastomosis of a vein graft by true 'Y'
      stenting.
AB  - We describe the treatment of a bifurcation lesion at the anastomosis of a vein
      graft by 'true Y' stenting which preserved both antegrade and retrograde flow
      away from the graft.

PMID- 12623599
TI  - A case of spontaneous coronary artery disease regression.
AB  - Coronary angiographic trials have demonstrated that lowering cholesterol can slow
      the progression of atherosclerosis, limit the formation of new lesions and
      enhance atherosclerotic regression together with reducing the incidence of
      clinical events (Waters D, 1996). Spontaneous regression of coronary
      atherosclerotic lesions is rare. We report the case of a patient with a severe
      within-stent restenotic lesion whose coronary disease spontaneously regressed 12
      months after initial diagnosis, allowing for medical treatment of symptoms rather
      than repeated intervention. (Int J Cardiovasc Interventions 1999; 2: 121-123)

PMID- 12623600
TI  - Detection of myocardial viability in the catheterization laboratory using the
      Biosense-guided electromechanical mapping system.
AB  - The current report demonstrates the feasibility and potential clinical
      application of a catheter-based approach for left-ventricular electromechanical
      mapping and on-line assessment of myocardial via bility in the catherization
      laboratory based on generated endocardial signals and three-dimensional left
      ventricular anatomical reconstruction.

PMID- 12623601
TI  - Images in Cardiovascular Interventions Endovascular treatment of two
      pseudoaneurysms of the superficial femoral artery with the Hemobahn graft-stent.

PMID- 12623602
TI  - Images in Cardiovascular Interventions Complications of balloon mitral
      valvuloplasty.

PMID- 12623606
TI  - Technological advances in renal care.
AB  - The first systems for treating kidney failure were developed in the 1940's, when
      it was found that blood could be successfully cleared of toxins and returned to
      the body using a relatively simple device based on artificial sausage skin
      wrapped around a wooden frame. This process was used to replace the function of
      the kidney, allowing patients to recover from conditions such as poisoning or
      crush injuries that temporarily stop the kidneys working. In the 1960's, advances
      in technology made long-term replacement of renal function using haemodialysis
      machines possible and allowed surgeons to carry out kidney transplants between
      people who were not identical twins. Long-term peritoneal dialysis became a
      viable treatment option two decades later. There are now over 1.1 million people
      world-wide receiving regular dialysis treatment and around 340,000 people living
      with a donated kidney. This paper reviews the pioneering work in the treatment of
      kidney failure and looks at some of the recent advances in equipment design,
      materials science, immunosuppression and information technology that aim to
      improve the quality of life and the life expectancy for patients living on renal
      replacement therapy.

PMID- 12623607
TI  - Automatic adjustment of chopping-modulated defibrillation pulses to patient
      transthoracic resistance.
AB  - Defibrillation of the heart requires a high amplitude short duration current
      pulse to be passed through large electrodes placed on the patient's chest. The
      current meets a virtually active resistance, which can vary in the approximate
      range of 25 to 180 Omega. As the delivered current or energy depends on the
      resistance, several methods have been developed to reduce or compensate its
      influence. For example, pre-shock resistance has been measured by a high
      frequency current and the current or energy set accordingly; measurements have
      been made from the initial tilt and the pulse durations adjusted; and pre-shock
      measurements have been made by a sub-shock pulse to generate an appropriately
      selected constant current. A method is proposed using high-frequency chopped
      biphasic pulses, with pulse-width and period modulation of the elementary pulses.
      Patient resistance is measured with the first elementary pulse and depending on
      its value a modulated waveform is generated, selected by a micro-controller from
      a preprogrammed set. Thus the selected energy is accurately delivered to the
      patient. In addition, this method allows the shaping of a desired mean patient
      current waveform, maintaining adequate charge balance between the two phases and
      securing an appropriate time course of the model-derived transmembrane potential.

PMID- 12623608
TI  - Reference value of young people's erythrocyte sedimentation rate and altitude.
AB  - The purpose of this paper is to provide a scientific basis for a unified standard
      of the reference value of young people's erythrocyte sedimentation rate (ESR) in
      China. The reference values of healthy young people's ESR were collected
      according to the Wintrobe method, and the relationship between the reference
      value of young people's ESR and altitude was tested in this paper. It was found
      that the reference value of young people's ESR decreases when the altitude
      gradually increases, and the relationship is significant. The method of
      mathematical univariate regression analysis was used to deduce two regression
      equations: Y(1) = 10.92-0.00183X +/-2.59 and Y(2) = 18.58-0.00319X +/-4.37. If
      the altitude value of a particular area of China is known, the reference value of
      young people's ESR can be calculated by means of the regression equations.
      Furthermore, depending on the altitude, China can be divided into three
      districts: Qingzang, Central and Eastern districts.

PMID- 12623609
TI  - Fluid-solid interaction: benchmarking of an external coupling of ANSYS with CFX
      for cardiovascular applications.
AB  - Fluid-solid interaction is a primary feature of cardiovascular flows. There is
      increasing interest in the numerical solution of these systems as the extensive
      computational resource required for such studies becomes available. One form of
      coupling is an external weak coupling of separate solid and fluid mechanics
      codes. Information about the stress tensor and displacement vector at the wetted
      boundary is passed between the codes, and an iterative scheme is employed to move
      towards convergence of these parameters at each time step. This approach has the
      attraction that separate codes with the most extensive functionality for each of
      the separate phases can be selected, which might be important in the context of
      the complex rheology and contact mechanics that often feature in cardiovascular
      systems. Penrose and Staples describe a weak coupling of CFX for computational
      fluid mechanics to ANSYS for solid mechanics, based on a simple Jacobi iteration
      scheme. It is important to validate the coupled numerical solutions. An extensive
      analytical study of flow in elastic-walled tubes was carried out by Womersley in
      the late 1950s. This paper describes the performance of the coupling software for
      the straight elastic-walled tube, and compares the results with Womersley's
      analytical solutions. It also presents preliminary results demonstrating the
      application of the coupled software in the context of a stented vessel.

PMID- 12623613
TI  - A head orientated wheelchair for people with disabilities.
AB  - PURPOSE: Most electric wheelchairs available on the market are joystick
      controlled making people with hand or arm disabilities unable to control the
      wheelchairs easily. This study proposes a new head-orientated wheelchair design
      for people with disabilities. METHOD: This study involves a tilt sensor module
      fitted onto the operator's headgear that will sense head movements used to
      control the wheelchair's direction and speed. This system includes: the tilt
      sensor module, the signal processing circuit and a main controller. RESULTS: The
      average times required for completing experiments by seven volunteers using
      joystick-controlled and the newly developed wheelchairs were recorded. It was
      revealed that the difference in average operating time for the two wheelchairs
      were statistically insignificant (p>0.05). CONCLUSIONS: The wheelchair developed
      in this study, although not absolutely superior to the joystick-controlled
      method, should still provide a better alternative for people with disabilities
      unsuited to traditional input devices.

PMID- 12623610
TI  - Equilibrium and non-equilibrium dynamics of the cranio-mandibular complex and
      cervical spine.
AB  - A dynamic model of the inverted pendulum characteristics of the head and cervical
      spine is presented. Using simple approximations and a single rotational-degree-of
      freedom approach, the model is shown to conform to the classical mathematical
      description of an inverted pendulum motion. It also exhibits the well-known point
      of unstable equilibrium which is a standard property of such systems. Specific
      predictions of this theoretical description are compared against other values for
      the tilt, angular velocity and acceleration of the head during acceleration-sled
      testing, and with the Kapitza relation for mechanical-dither stabilization of an
      inverted pendulum. Numerical evaluations of the dynamic variables, resonant
      frequencies and time constants important to the problem are provided, and
      suggestions are made about how further results might be derived from extended
      versions of the model. This approach can now be refined to serve as a testing
      ground for analysing the biomechanics of traumatic neck injuries and for
      interpreting the possible roles that mandibular dysfunctions and dental
      malocclusion may play in disorders of the cervical spine. (Some background needed
      for exploring the latter possibility is presented.)

PMID- 12623614
TI  - Transportable two-dimensional gait assessment: routine service experience for
      orthotic provision.
AB  - PURPOSE: The purpose of the pilot service was to establish the potential of the
      newly developed system to achieve, in a community setting, more effective
      orthotic outcomes for patients in whom alignment of ground reaction force is an
      important treatment objective. METHODS: Twelve visits were arranged to a
      paediatric community physiotherapy department. Up to six patients at each visit
      were selected for assessment of their lower limb orthotic prescription. The
      patient's gait was assessed using the video vector generator to determine
      alignment of ground reaction force. Where necessary, adjustments to the orthotic
      set-up were made to achieve more closely the stated objective. At the conclusion
      a specification of the orthosis was agreed. RESULTS: In only two of 61
      assessments that were conducted was it not possible to achieve a useful outcome.
      CONCLUSIONS: Improvements in biomechanical alignment were achieved in more than
      68% of assessments. The pilot service was sufficiently successful for it to be
      extended to a routine clinical service.

PMID- 12623615
TI  - Two year survival after malignant cerebral glioma: patient and relative reports
      of handicap, psychiatric symptoms and rehabilitation.
AB  - PURPOSE: To describe patient outcomes and contact with rehabilitation services
      two years after the diagnosis of malignant cerebral glioma. METHODS: A cross
      sectional interview study of patients treated two years previously between 1990
      1992 at six London hospitals. Twenty-two of 181 treated patients were found alive
      (12%). Fifteen were well enough to approach and 12 male patients (aged 28-60
      years) and ten relatives (9 female, 1 male) could be seen by 1994. Semi
      structured home interviews carried out separately with patients and relatives
      assessed return to previous work or activity, patient and relative reports of
      handicap, psychiatric symptoms, estimated percentage drop in verbal and non
      verbal performance and contact with rehabilitation services. RESULTS: Using
      accounts of return to work or normal activity two years after treatment, five
      patients were classed as broadly 'active' and seven as 'inactive'. The 'active'
      group appeared to have few physical or cognitive problems or were able to adapt
      their work around these. Disagreement between patients and relatives about
      handicap, patient and relative psychiatric symptoms and severe neuropsychological
      deficit appeared to cluster in the 'inactive group'. No patient had been formally
      referred for rehabilitation. CONCLUSIONS: Patient outcome, in terms of managing
      work and everyday activities, can be very good for some two-year survivors. For
      others, patient and relative accounts and neuropsychological testing may disclose
      a range of problems. Such inquiry might suggest referral for rehabilitation or
      other support.

PMID- 12623616
TI  - Reliability and validity of the Dutch version of QUEST 2.0 with users of various
      types of assistive devices.
AB  - PURPOSE: In this paper, the Dutch version of the Quebec User Evaluation of
      Satisfaction with assistive Technology (D-QUEST) is validated in users of a large
      variety of assistive devices (n=2002). METHOD: D-QUEST consists of a written
      questionnaire. The respondent rates his or her satisfaction with respect to 12
      aspects on a five-point scale. Users of 10 different types of assistive devices
      participated. Analyses were performed for each type of assistive device.
      Reliability is tested by analysing internal consistency. Content validity is
      tested by analysing applicability of the 12 aspects. The non-applicability option
      for answering questions is studied. Construct validity is tested by analysing
      correlations with problem solving and with general satisfaction. RESULTS:
      Reliability proves to be good for all types of assistive devices. Including the
      non-applicability option improves the feasibility of the instrument without
      affecting content validity. Correlations between D-QUEST scores on the one hand
      and problem solving and general satisfaction questions on the other are as
      expected, supporting validity. CONCLUSIONS: D-QUEST (and therefore also QUEST)
      proves itself to be a highly applicable, reliable and valid instrument to assess
      user-satisfaction of users of all kinds of assistive device provisions.

PMID- 12623617
TI  - Rehabilitation of a patient with critical illness polyneuropathy (CIP) following
      acute respiratory failure: a case report and review of literature.
AB  - Critical illness polyneuropathy (CIP), a neurologic complication that may occur
      secondary to cardio-respiratory distress, surgery, trauma and coma, is associated
      with sepsis or multiple organ failure. CIP is characterized by an axonal distal
      degeneration of sensory and motor fibres. The patients will often become
      neurologically conspicuous when weaning from mechanical ventilation is
      unexpectedly difficult. There are just a few cases reported with description of
      the functional outcome and rehabilitation issues of this condition. An additional
      CIP case of a 62-year old man complicated with anoxic brain damage during the
      respiratory distress is reported here. He was referred for rehabilitation, made a
      remarkable recovery (FIM gain 45!) and returned home after 79 days of treatment
      in the ward. A review of the pertinent literature is provided. Rehabilitation
      specialists and other professionals working within ICU's should be aware of this
      condition and be able to recognize and treat CIP at early possible stage.

PMID- 12623618
TI  - A new stroke activity scale-results of a reliability study.
AB  - PURPOSE: To investigate the internal consistency, inter-rater and intra-rater
      reliability of a disability stroke activity scale (SAS) for stroke patients. Its
      intended use is as a measure of motor function at the level of disability in
      stroke patients. METHOD: Twelve stroke in-patients were video-recorded performing
      the five activities from the SAS. Seven senior physiotherapists, experienced in
      stroke care, independently rated the recordings on two occasions, three weeks
      apart, using the SAS. Twelve hospital inpatients participated in the study. The
      subjects were aged between 48 and 86 and were between 6 and 87 days post stroke.
      RESULTS: Reliability for total scores was found to be excellent (generalizability
      correlation co-efficient (GCC) values> or =0.95) and reliability for individual
      item scores was good (kappa> or =0.7). Internal consistency reliability using
      Cronbach's alpha was also good (0.68 at time 1 and 0.68 at time 2). CONCLUSION:
      The stroke activity scale is a reliable instrument for hospital stroke patients.
      It can be administered in less than 10 minutes and requires minimal equipment and
      training. Further work on the validity and responsiveness of the SAS is in
      progress.

PMID- 12623619
TI  - Changes in the quality of life in severely disabled people following provision of
      powered indoor/outdoor chairs.
AB  - PURPOSE: To determine the benefits for patients who received an electric powered
      inoor/outdoor chair (EPIOC) and to quantify their perceived changes to their
      quality of life. METHOD: Community-based cohort study of all patients provided
      with an EPIOC over 4 months; and followed up about 3 months later in a community
      served by a regional wheelchair service in North West London (population about
      3.1 million) using the EuroQol EQ-5D with visual analogue scales for each of the
      five dimensions of the EQ-5D. RESULTS: Sixty-four wheelchair users were assessed
      initially and 51 completed follow up. Chair users showed no significant
      improvement in health state as measured by the EQ-5D after EPIOC provision. The
      visual analogue scales (VASs) indicated that, although perceived overall health
      state, independence and social life did not appear to improve, the dimensions of
      mobility, quality of life and pain/discomfort improved significantly on provision
      of an EPIOC. CONCLUSION: EPIOC users reported significant improvements in several
      important aspects of their lives; not just in mobility (as expected) but also in
      reduction of pain and discomfort. The use of VASs provided a more holistic set of
      outcome measures that demonstrate quality of life benefits beyond that of health
      state alone.

PMID- 12623620
TI  - Views of health professionals on discussing sexual issues with patients.
AB  - PURPOSE: This survey was carried out to study the views of multidisciplinary
      health professionals about discussing sexual issues with patients. METHODS: A
      questionnaire was sent to professionals (nurses, doctors, physiotherapists and
      occupational therapists) to return by post. A duplicate questionnaire was sent 4
      weeks later to a random sample of respondents. RESULTS: A total of 813 replies
      were analysed (61% response rate). Mean age+(SD) of respondents was 37+10. Most
      were female (85%). Test-retest reliability of the questions showed moderate to
      very good agreement. Most respondents (90%) agreed that addressing sexual issues
      ought to be part of the holistic care of patients. However, most staff (86%) were
      found to be poorly trained and most (94%) were unlikely to discuss sexual issues
      with their patients. The gender and age of respondents was not significantly
      related to their participation in such discussion. Therapists had less training,
      lower comfort level, and less willingness to discuss sexual issues than doctors
      and nurses while doctors discussed sexual issues significantly often more than
      others (p< or =0.001). Respondents from rehabilitation wards were equivalent to
      those from medical or surgical wards in their training and comfort. However, they
      participated in discussing sexuality with patients less often than those from
      medical wards. CONCLUSION: Health professionals agreed that patients' sexual
      issues needed to be addressed and discussed in health services. However, they
      were poorly trained, ill prepared and rarely participated in such discussion.
      This suggests that training in sexuality and sexual issues should be implemented
      as part of the training of health care professionals.

PMID- 12623621
TI  - Karaoke for quads: a new application of an old recreation with potential
      therapeutic benefits for people with disabilities.
AB  - PURPOSE: Karaoke is a recreational activity whereby individuals sing into a
      microphone along with the melodies and lyrics provided both visually and
      auditorily by a machine. METHODS: The potential therapeutic benefits of karaoke
      are explored in terms of increased respiratory strength, endurance, control, and
      capacity, as well as emotional and physical release for people with disabilities.
      RESULTS: Although many individuals with disabilities could benefit from this
      activity, it is likely to be particularly beneficial to people with compromised
      respiratory systems, such as persons with high-level quadriplegia (tetraplegia).
      CONCLUSION: This article examines theoretical considerations and proposes a
      research agenda. Empirical research would be valuable to confirm the potential
      benefits of karaoke for people with disabilities.

PMID- 12623622
TI  - Microswitch clusters to enhance non-spastic response schemes with students with
      multiple disabilities.
AB  - PURPOSE: The study explored whether the use of microswitch clusters could enhance
      the performance of correct (non-spastic) response schemes by two students with
      multiple disabilities. METHOD: The study started with baseline on the two
      responses selected for each student. Then, intervention was implemented on the
      first response. This was followed by new baseline and intervention on the second
      response. Subsequently, intervention sessions on the two responses were
      alternated. Post-intervention checks were carried out over periods of 4 and 2.5
      months. RESULTS AND CONCLUSIONS: Both students had an increase in correct
      response schemes and, conversely, a decline in spastic response schemes. The
      importance and practicality of microswitch clusters to enhance appropriate
      responding in students with multiple disabilities were discussed.

PMID- 12623624
TI  - Posteroanterior motion test of a lumbar vertebra: accuracy of perception.
AB  - PURPOSE: The aim of this study was to investigate the accuracy of perception of
      forces applied to and displacement produced in an electromechanical one vertebral
      spinal model, among inexperienced and experienced physical, therapists performing
      posteroanterior pressure on a lumbar vertebra, before and after a training
      session. METHODS: Ten relatively inexperienced physical therapists and ten
      experienced manual therapists participated. An electromechanical single level
      spinal model was used for applying oscillatory posteroanterior pressure and
      measuring the forces on and displacement of the vertebra. A digital oscilloscope
      was used to give direct feedback to the therapists while performing mobilization
      to discern the magnitude of these two variables. RESULTS: The inexperienced group
      estimated the displacement accurately but the experienced group was significantly
      inaccurate (p<0.02), and both groups were inaccurate in estimating the force
      (p<0.001), before training. Following training, the inexperienced group
      maintained their accuracy on displacement and the experienced group improved
      their accuracy significantly (p<0.001). Both groups approached significance in
      improving their accuracy of force estimation. CONCLUSION: An electromechanical
      spinal model can be used as training tool along with an oscilloscope. Longer
      training may be needed for the force than the displacement for accurate
      perception.

PMID- 12623625
TI  - Functional capacity evaluation of manual materials handlers: a review.
AB  - PURPOSE: To summarize currently existing research regarding the assessment of
      functional capacity in low back injured workers. METHOD: Literature review.
      RESULTS: Methods of functional capacity evaluation are described and critical
      components of an examination of functional capacity identified in relationship to
      federal occupational categorization and guidelines. CONCLUSIONS: Evaluation of
      the predictive validity of existing functional capacity evaluation templates is
      not possible given the absence of thorough descriptions in the published
      literature. While substantial research exists enabling comparison of the injured
      workers' manual materials handling ability to normative psychophysical data the
      validity of this approach remains uncertain.

PMID- 12623626
TI  - A 2-D model of wheelchair propulsion.
AB  - PURPOSE: To illustrate the potential benefits of kinetic and kinematic models in
      the exploration of biomechanical studies as illustrated using a simple 2-D static
      optimization model of wheelchair propulsion. METHOD: A four-bar linkage analysis
      was used to determine sagittal plane motion through the range of wheelchair
      propulsion. Using anthropometric measures of wheelchair users, this analysis
      determined the angles of shoulder and elbow flexion/extension at a given point in
      the propulsion cycle. Maximal strength inputs for the model were collected from
      isokinetic measurements of shoulder and elbow moments. The torque inputs were
      given as functions of sagittal plane joint angles. Through selection of
      appropriate model performance criteria, optimization techniques determined
      shoulder and elbow torque contributions throughout the propulsion cycle.
      Variations in the model parameters of anterior-posterior (AP) seat position and
      handrim size went used to show potential of model to evaluate wheelchair
      configuration using the performance criteria of propulsive moment (Mo) and
      efficiency as defined by fractional effective force (FEF). RESULTS: The model was
      able to predict the magnitude and direction of force applied to the handrim from
      shoulder and elbow moments. These joint moments may be examined along with the
      generated wheelchair axle propulsion moment. While the model showed no
      significant changes in either Mo or FEF for AP seat changes, an increase in
      handrim size was shown to increase FEF. CONCLUSIONS: This model was able to
      simulate wheelchair propulsion and allow for performance analyses. The open
      nature of the model allowed for tweaking of the kinematic inputs to examine the
      sensitivity of such factors as seat position and handrim size in wheelchair
      propulsion. Strength inputs to the model may also be altered to study the
      potential effects of strength training or muscle weakness.

PMID- 12623627
TI  - Maneuverability and usability analysis of three knee-extension propelled
      wheelchairs.
AB  - PURPOSE: The purpose of this study was to evaluate the maneuverability and
      usability of three knee-extension propelled wheelchairs. METHOD: The
      maneuverability of the knee-extension propelled wheelchairs was determined in a
      controlled test representing five standard wheelchair activities. The usability
      of the wheelchairs was evaluated in a field test with elderly residents of an
      extended care facility in Salt Lake City. RESULTS: The results indicate that the
      wheelchair designs using a swinging (four-bar linkage) or sliding belt mechanism
      are preferred to a sliding plate design. CONCLUSIONS: The use of knee-extension
      propelled wheelchairs is a feasible alternative to hand propelled wheelchairs.
      Further development and research is needed to address power requirements,
      maneuverability, and entrance/egress from the chairs.

PMID- 12623628
TI  - Wheelchair racing efficiency.
AB  - PURPOSE: For individuals with disabilities exercise, such as wheelchair racing,
      can be an important modality for community reintegration, as well as health
      promotion. The purpose of this study was to examine selected parameters during
      racing wheelchair propulsion among a sample of elite wheelchair racers. It was
      hypothesized that blood lactate accumulation and wheeling economy (i.e. oxygen
      consumed per minute) would increase with speed and that gross mechanical
      efficiency would reach an optimum for each athlete. METHOD: Twelve elite
      wheelchair racers with paraplegia participated in this study. Nine of the
      subjects were males and three were females. Each subject used his or her personal
      wheelchair during the experiments. A computer monitored wheelchair dynamometer
      was used during all testing. The method used was essentially a discontinuous
      economy protocol. Mixed model analysis of variance (ANOVA) was used to compare
      blood lactate concentration, economy (minute oxygen consumption), and gross
      mechanical efficiency across the stages. RESULTS: The results of this study show
      that both economy and blood lactate concentration increase linearly with speed if
      resistance is held constant. The subjects in this study had gross mechanical
      efficiencies (gme) of about 18%, with the range going from 15.222.7%. The results
      indicate that at the higher speeds of propulsion, for example near race speeds,
      analysis of respiratory gases may not give a complete energy profile. CONCLUSION:
      While there is a good understanding of training methods to improve cardiovascular
      fitness for wheelchair racers, little is known about improving efficiency (e.g.
      technique, equipment), therefore methods need to be developed to determine
      efficiency while training or in race situations.

PMID- 12623629
TI  - Effects of modular course training on mobility in older adults aged 79-90 years.
AB  - PURPOSE: To determine the effectiveness of an intervention programme utilizing
      modules specifically designed to challenge mobility in older adults. METHOD:
      Twelve older adults aged 79-90 years (84.3+/-3.2; mean+/-SD) living in a
      retirement community participated in a 10-week (3 sessions per week, 50 minutes
      per session) training programme. Performance on a modular course, comprised of
      nine stations representing common environmental conditions, provided information
      about dynamic balance and mobility before and after the intervention programme.
      Stations consisted of walking across carpet and foam pathways, walking up and
      down ramps and stairs, walking through a slalom course of eight plastic cones,
      and stepping over foam props. Performance on the mobility course was videotaped
      to determine the time to complete each station. The training intervention
      consisted of performing sections of the mobility course and standing on foam pads
      with the eyes open or closed. RESULTS: Using the Bonferroni-adjusted level of
      significance for multiple comparisons (p+/-0.005), paired sample t-tests
      indicated significant improvement for total time to complete the course
      (pre=100.9+/-40.5 s, post=79.6+/-40.3 s) and for all individual stations except
      stepping over props. CONCLUSIONS: These results indicate that an intervention
      programme utilizing functionally-oriented modules can improve mobility in older
      adults.

PMID- 12623630
TI  - Application of SEMG in computer mouse access for the disabilities.
AB  - PURPOSE: To improve the operating speed of the traditional row-column scanning
      computer keyboard-mouse composite panel controlled using a single key. METHOD:
      Using a single mouse input control window can avoid scanning unnecessary keyboard
      characters, thereby increasing the speed in performing mouse commands. In
      addition, the surface electromyographic (SEMG) sensing input can also be used to
      provide an input option for the disabled. RESULTS: Eleven volunteers operated the
      single mouse input control window using the SEMG input and the traditional
      computer keyboard-mouse composite panel controlled using a single key. The
      average operating times were 121.3+/-8.9 sec and 208.6+/-10.7 sec, respectively.
      The difference was statistically significant (p<0.05). CONCLUSIONS: The row
      column scanning method with the single mouse control window using SEMG input can
      effectively decrease the operating time. Through this system, the disabled can
      operate a computer and lead an independent life.

PMID- 12623631
TI  - The effect of automatic speech recognition systems on speaking workload and task
      efficiency.
AB  - PURPOSE: This investigation explored the speech-production behaviors associated
      with the use of automatic speech recognition (ASR) software for dictation of
      spontaneous and scripted material by individuals with and without spinal cord
      injury (SCI). The variables of interest in determining speaking workload and
      efficiency included syllables per breath group, frequency of breath groups,
      frequency of apnea, time needed for dictation and number of words spoken during a
      dictation task. METHOD: Twelve individuals participated, six with SCI and six
      able-bodied cohorts matched for age, sex and height. Subjects dictated with
      continuous-speech ASR, discrete-word ASR and no ASR in a spontaneous-speaking
      situation, as well as in a scripted speaking situation. RESULTS: For all
      variables, differences amongst dictation conditions were significant. No
      significant differences were found between speaker groups. Dictation with both
      discrete-word and continuous-speech ASR resulted in a decrease in the number of
      syllables produced per breath group, increases in the frequency of breath groups
      and apnea, with differences from normal being greater for dictation with discrete
      word ASR. In addition, when participants dictated with either type of ASR, the
      amount of time and number of words produced were significantly greater than that
      associated with production of the same message without ASR, requiring 'more work'
      on the part of the speaker and ultimately reducing the efficiency with which a
      message was produced. CONCLUSIONS: From a human factors perspective, these
      results suggest that ASR software, especially discrete-word ASR, has the
      potential to increase energy expenditure during dictation over a prolonged period
      of time, thereby increasing speech workloads and the potential for overuse of the
      laryngeal system.

PMID- 12623632
TI  - Validity and reliability of sincerity test for dynamic trunk motions.
AB  - PURPOSE: Marras et al. developed a technique to evaluate sincerity of effort
      during dynamic trunk motion performance. The validity and reliability of the
      technique have not been evaluated. Therefore, the objective of this study was to
      first determine whether or not a sincerity of effort measure correctly identified
      those giving a sincere effort in a blinded randomized control trial and second to
      quantify inter-rater and test-retest reliability. METHODS: This article reports
      the findings of a two phase study. In phase one, the blinded evaluation,
      participants were randomly assigned to either a sincere or insincere performance
      condition. An examiner tested participants without knowledge of the participant's
      group membership. In the second phase, two examiners evaluated each participant
      twice to quantify inter-rater and test-retest reliability. RESULTS: In the
      blinded phase the specificity was 100% and sensitivity was 90% for identifying
      sincere and insincere effort, respectively. Phase two results showed no
      significant difference in probability of sincere effort between raters or between
      testing sessions. CONCLUSION: A performance criterion that accurately identifies
      sincere vs insincere group membership during functional evaluations was
      identified. There were no significant differences between raters or between
      testing sessions. These findings indicate that this test is reliable and
      possesses good predictive validity in assessing sincerity of effort.

PMID- 12623633
TI  - Work load reduction through a new roll container traction device.
AB  - PURPOSE: For the distribution of dairy products, crates and roll containers are
      used. A roll container that is fully stacked with crates has a mass of 600 kg.
      The forces required to handle these roll containers, often aggravated by rough
      paving and inclined tailboards, are far in excess of ergonomic standards. This
      explains the high level of absenteeism among lorry drivers due to musculoskeletal
      complaints. The aim of this study was to reduce work load. METHOD: A new traction
      device for roll containers was developed, which couples easily and provides for
      easy manoeuvring. On a test circuit with obstacles, ten professional lorry
      drivers (aged 29-53 years) performed a user-test, both with and without the
      device. During the tests heart rate, blood pressure and time for completion of
      the track were measured. RESULTS: Heart rates were significantly lower with the
      traction device, the length of time needed to complete the track showed greater
      uniformity, and thanks to ease of use no prior lessons were necessary.
      CONCLUSION: The prototype was also tested by a lorry driver that was disabled by
      low back pain. With this device he was able to return to work.

PMID- 12623634
TI  - The effect of whole-body hyperthermia combined with 'metronomic' chemotherapy on
      rat mammary adenocarcinoma metastases.
AB  - Many women diagnosed with invasive breast cancer have undetected occult
      metastases at the time of their primary tumour diagnosis. The development and
      growth of these micro-metastases relies heavily on angiogenesis. Therefore,
      administering an angiogenesis-blocking treatment from the time of diagnosis could
      reduce the incidence of metastasis and, ultimately, increase patient survival. It
      is hypothesized that an antiangiogenesis strategy combining fever-range whole
      body hyperthermia (FR-WBH) and metronomic chemotherapy could inhibit the
      development of metastatic disease with minimal toxicity. To test this theory, a
      low, daily dose of the topoisomerase-I inhibitor irinotecan hydrochloride (CPT
      11) was administered over a prolonged period of time to rats bearing the highly
      metastatic MTLn3 mammary adenocarcinoma primary tumour surgically excised on day
      12 after implantation. The metronomic CPT-11 was combined with long-duration, low
      temperature, fever-range whole body hyperthermia (FR-WBH). This systemic
      hyperthermia enhances chemotherapy-induced cytotoxicity as well as immunological
      activity. Both the group treated with FR-WBH alone and the combined FR-WBH + CPT
      11 group had delayed onset and reduced incidence of axillary lymph node
      metastases compared to control (p < 0.05). Combination therapy of FR-WBH + CPT-11
      resulted in a significantly greater inhibition of axillary lymph node metastasis
      volume compared to both control and CPT-11 alone (p < 0.02) at day 16.
      Interestingly, none of the therapies significantly affected inguinal lymph node
      metastases. Lung metastases were decreased by 36% at the time of death in rats
      treated with FR-WBH + CPT-11, by 25% in the CPT-11 alone group and by 14% in the
      FR-WBH alone group. Rats treated with FR-WBH, + CPT-11 survived significantly
      longer (35%) than control animals (p < 0.04). Neither significant body weight
      loss nor gastrointestinal toxicity was observed in any group. These data suggest
      that, after excision of the primary tumour, FR-WBH and metronomic CPT-11 can be
      safely combined to reduce distant lymph node and lung metastases and, thus, to
      increase survival.

PMID- 12623635
TI  - Sequential pathological and immunologic analysis of percutaneous microwave
      coagulation therapy of hepatocellular carcinoma.
AB  - PURPOSE: To evaluate sequential pathologic and immunologic changes and their
      prognostic significance after percutaneous microwave coagulation therapy (PMCT)
      of hepatocellular carcinoma (HCC). METHODS: Eighty-nine nodules in 82 consecutive
      patients were studied. The 89 nodules were divided into two groups: a treatment
      group, with 82 primary nodules (average dimension was 3.4 +/- 1.2 cm) in 82
      patients, and a control group, of seven nodules (average dimension was 1.4 +/-
      0.6 cm) in seven patients. The criteria for a nodule's inclusion in the control
      group was that the nodule was one of two nodules in the same patient and that the
      two nodules were located in different liver lobes. This guarantees that while one
      nodule is treated by PMCT, the distant one will not be directly affected by the
      microwave thermal field. The control group nodules were treated after the study
      was completed. Specimens were taken with ultrasound-guided liver biopsy from the
      treated nodule and the control nodule, pre- and post-PMCT. Infiltration by T
      lymphocytes, B-lymphocytes, NK cells and macrophages in the tumour tissue were
      observed immunohistochemically using a panel of monoclonal antibodies against
      CD3, CD45RO, CD20, CD56 and CD68. The extent of immune cell infiltration was
      compared both before and after PMCT, as well as between the treated and control
      nodules. The relationship between the prognosis and the extent of immunocyte
      infiltration was analysed. RESULTS: The patients were followed for 2-26 months
      (mean 14.6 +/- 6.3) post-treatment. The recurrence rates at 1 and 2 years were
      20.4% and 28.1% within the liver in treatment group, respectively. The survival
      rates at 1 and 2 years were 92.5% and 75.3% for the treatment group. T-cells, NK
      cells and macrophages increased significantly in both treated and untreated
      nodules after PMCT, albeit less markedly within untreated nodules when compared
      to the treated ones. There is a statistically significant correlation between
      survival outcome and the extent of immunocyte infiltration. CONCLUSIONS: For
      inoperable HCC patients, PMCT is one of the treatment choices shown to be
      effective. Apart from its tissue coagulation effect, an increased systemic immune
      response directed against the tumour may also play an important role in improved
      survival.

PMID- 12623636
TI  - Accuracy of electrical field measurement using the flexible Schottky diode sheet
      at 433 MHz.
AB  - In this study, the accuracy of Schottky diode sensors mounted as a two
      dimensional array on a flexible 125 micro m thick polyester foil has been
      studied. The diodes are placed at a distance of 2.5 x 2.5 cm, resulting in a
      measuring area of 20 x 20 cm. The diodes are placed across the gap between both
      arms (3 x 5 mm) of a dipole, total length 12 mm. High resistance (1 M Omega/m)
      carbon transmission lines printed on the sheet are used to connect each
      electrical (E) field sensor to the read-out electronics and a data-acquisition
      system. It is demonstrated that the flexible Schottky diode sheet can
      quantitatively measure E-field distributions at 433 MHz with an overall accuracy
      of approximately 6% (1 SD). The largest contribution to the inaccuracy is related
      to the phantom heterogeneity. The absolute sensitivity of this electrical field
      sensor is 0.71 V/m per V/m of the applied external electromagnetic field. The DC
      voltage signal of the diodes shows a more or less square root relation to the RF
      power applied to the applicator over a 15-fold range. An important feature of the
      system is that it provides the ability to perform on-line monitoring of the E
      field, i.e. the SAR distribution of 433 MHz applicators. Further, it enables the
      introduction of fast and easy quality control protocols for superficial
      hyperthermia applicators.

PMID- 12623637
TI  - p53-dependent hyperthermic enhancement of tumour growth inhibition by X-ray or
      carbon-ion beam irradiation.
AB  - To elucidate p53-dependency on combined treatment with radiation and
      hyperthermia, growth inhibition and apoptosis were analysed using transplantable
      human tumour. Human head and neck squamous cell carcinoma (HNSCC) cells carrying
      different p53 genes were transplanted into the thigh of nude mice. When the mean
      diameter of tumour reached 5-6 mm, the tumours were exposed to X-rays (2 Gy) or
      Carbon-ion (C-) beams (1 Gy) followed by heating at 42 degrees C for 20 min.
      Tumour growth inhibition was evaluated by measuring the diameters of tumour. The
      induction of apoptosis and accumulation of apoptosis-related proteins were also
      analysed by immunohistochemical staining. Synergistic enhancement of tumour
      growth inhibition by hyperthermia was observed in wild-type p53 tumours treated
      with X-rays or C-beams but not in mutant p53 tumours. The incidence of apoptotic
      cells and activated-caspase-3-positive cells after combined treatment with them
      were significantly high in wild-type p53 tumours compared with that in mutant p53
      tumours. The hyperthermic enhancement of tumour growth inhibition by X-ray- or C
      beam-irradiation was p53-dependent, suggesting that it might be highly correlated
      with p53-dependent apoptosis.

PMID- 12623638
TI  - Effects of cell damage and glycosaminoglycan degradation on available
      extravascular space of different dextrans in a rat fibrosarcoma.
AB  - Drug delivery to solid tumors may be enhanced through increasing the available
      volume fraction (K(AV)) of drugs. Therefore, two approaches were investigated
      that may increase K(AV) of dextrans in a rat fibrosarcoma: (a) damaging cells in
      tumours via ex vivo incubation of tumour tissues, and (b) degrading tumour
      glycosaminoglycans (GAGs) with exogenous hyaluronidase. The molecular weights of
      dextrans used in this study were approximately 10,000 (D10), 70,000 (D70) and
      2,000,000 (D2000), respectively. It was found that GAG degradation had minimal
      effects on K(AV) of dextrans. Ex vivo incubation at 37 degrees C for up to 3 h
      caused only minor cell damage and had minimal effects on K(AV) of D10 and D70.
      However, the ex vivo incubation reduced K(AV) of D2000 (p < 0.05). When the
      incubation at 37 degrees C was maintained for 20 h, the amount of viable cells in
      tumours was reduced by 56% and K(AV) of all dextrans were significantly increased
      (p < 0.05). Ex vivo incubation at 41 degrees C for 3 h caused similar cell damage
      to that at 37 degrees C for 20 h, but only K(AV) of D10 and D70 were increased
      significantly (p < 0.05). There was no significant change in K(AV) of D2000,
      although it was higher than that in tumours incubated at 37 degrees C for 3 h (p
      < 0.05). These data suggest that cell damage is a more effective approach than
      GAG degradation for increasing K(AV) of macromolecules and that the amount of
      increase depends on the degree of cell damage and the size of molecules.

PMID- 12623640
TI  - Elevated levels of intracellular Ca2+ and apoptosis in human lung cancer cells
      given heat-shock.
AB  - The chronological changes in intracellular Ca(2+)concentrations ([Ca(2+)](i))
      were analysed during heat-induced apoptosis in human lung cancer cell lines LK-2
      (squamous cell carcinoma) and LU65A (large cell carcinoma). In LK-2 cells,
      increased [Ca(2+)](i) levels were maintained at levels between 250-350 nm 9 h
      after heat-shock. Treatment with BAPTA, an intracellular Ca(2+) chelator, prior
      to heat-shock, decreased the frequency of heat-induced apoptosis in LK-2, while
      thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, did not
      change the number of apoptotic cells, regardless of the presence or absence of
      Ca(2+)-supplemented medium. In LU65A cells, treatment with BAPTA or thapsigargin
      did not alter the apoptotic rates. Western blotting demonstrated that, although
      expression of Bax and Bcl-2 were not changed by heat-shock, p53 expression was
      elevated in LK-2, but not LU65A cells. Immunohistochemistry showed that p53 was
      localized predominantly in the cytoplasms of LK-2 cells, suggesting that p53
      protein is not functional in LK-2. Heat-shock also elevated activities of caspase
      3, -8 and -9 in both cell lines. It is concluded that a temporal increase in
      [Ca(2+)](i) is the important initiating factor in hyperthermia-induced apoptosis
      in LK-2 cells and that, in these two lung cancer cell lines, apoptosis may occur
      through 'cross-talk' between p53-independent mitochondrial and death receptor
      pathways.

PMID- 12623639
TI  - A lipophilic free radical initiator, 2,2'-azobis (2,4-dimethylvaleronitrile)
      (AMVN) enhances caspase-dependent apoptosis induced by hyperthermia.
AB  - PURPOSE: A free radical initiator, 2,2'-azobis (2-amidinopropane) dehydrochloride
      (AAPH), was previously found to enhance apoptosis by hyperthermia. Here, but more
      lipophilic free radical initiator, 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN)
      was investigated for its effects as a possible heat sensitizer. MATERIALS AND
      METHODS: Human myelogenous monocytic leukaemia U937 cells were treated with
      hyperthermia combined with a various concentration of AMVN for investigating its
      ability to induce apoptosis and various parameters to identify the pathway.
      RESULTS: Combined treatment of hyperthermia and AMVN induced DNA fragmentation
      markedly, while hyperthermia or AMVN alone induced marginal DNA fragmentation.
      Fractions of cells showed low mitochondrial membrane potential and increased
      superoxide production after the combined treatment. Experiments using various
      caspase inhibitors and a fluorogenic monitor of caspase 3 activities indicated
      that caspase acts both up- and down-stream of mitochondria. CONCLUSIONS: AMVN is
      suggested to be a potential heat sensitizer effective at a lower concentration
      than AAPH. The possible mechanism is discussed.

PMID- 12623641
TI  - The effect of various chemotherapeutic agents given with mild hyperthermia on
      different types of tumours.
AB  - It has been shown that hyperthermia can enhance the cytotoxicity of some
      chemotherapeutics. However, the most effective agent(s) at elevated temperatures
      have yet to be determined. A previous study suggests that the drug of choice at
      elevated temperatures may be different from that at the physiological
      temperature, and that the alkylating agents may be most effective at elevated
      temperatures. To further investigate these possibilities, the effect of
      chemotherapeutic agents were compared. These agents were cyclophosphamide,
      ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil,
      mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and
      squamous cell carcinoma) were used. They were transplanted into the feet of
      C3H/He mice. When tumours reached 65 mm(3), a test agent was injected
      intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min,
      and the tumour growth (TG) time was studied for each tumour. Using the TG times,
      the TG-50 (the time required for one-half of the total number of the treated
      tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated.
      Subsequently, the tumour growth delay time (GDT) and the thermal enhancement
      ratio (TER) were obtained. The GDT was the difference between the TG-50 of
      treated tumours and that of non-treated control tumours. The TER was the ratio of
      the GDT of a group treated with an agent at 41.5 degrees C to that of a group
      treated with the agent at room temperature. Results showed that the top three
      effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO
      and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of
      the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil,
      which was given for mammary carcinoma, and for mitomycin C, which was given for
      squamous cell carcinoma. It could be concluded that the alkylating agents at
      elevated temperatures might be the drugs of choice for many types of tumours. The
      possible mechanisms of thermal enhancement associated with these agents are
      discussed.

PMID- 12623642
TI  - Combination therapy of rat brain tumours using localized interstitial
      hyperthermia and intra-arterial chemotherapy.
AB  - Several investigators have reported that a high concentration of drugs in a
      tumour can be achieved using intra-arterial (IA) chemotherapy. This treatment was
      highly effective, especially in brain tumours, but the actual therapeutic
      advantage is still unknown. There are also indications that human malignant
      gliomas can effectively be treated using interstitial hyperthermia. Therefore, a
      combined treatment of IA chemotherapy and interstitial hyperthermia should be
      very promising and this has been studied in a tumour model. Wistar rats with
      isotransplanted C(6) gliomas in the brain were treated with adriamycin (ADR, 1.0
      mg/kg body weight) either infused via the carotid artery (i.a.) or via the tail
      vein (i.v.), with or without interstitial hyperthermia. Hyperthermia of the
      tumours was applied using a homemade radiofrequency antenna (RF-heating) and a
      heating device that maintained the tumour temperature above 40 degrees C.
      Concentration of adriamycin in tumours after treatment was measured using HPLC.
      The effectiveness of treatment was determined by the survival time of the animals
      and histopathological examinations. The highest uptake of adriamycin in the rat
      C(6) glioma was obtained when the animals were treated with hyperthermia and i.a.
      ADR infusion (p <0.01). These animals also showed significantly longer overall
      survival time (SF50 =46 days) in comparison to the other treatments (p < 0.05).
      The histological studies demonstrated a necroti c tumour; however, the
      surrounding normal brain tissue remained intact. Thus, a combination of IA
      chemotherapy with adriamycin and localized interstitial hyperthermia enhances
      considerably the efficacy of adriamycin and has a greater antitumour effect for
      malignant brain tumours. This method is suitable for clinical use, and may be a
      new strategy for treating gliomas not successfully treated today.

PMID- 12623643
TI  - Reproductive and neurobehavioural effects of piperonyl butoxide administered to
      mice in the diet.
AB  - Piperonyl butoxide was given in the diet to mice to provide levels of 0
      (control), 0.01, 0.03 and 0.09% from 5 weeks of age of the F(0) generation to 9
      weeks of age of the F(1) generation, and selected reproductive and
      neurobehavioural parameters were measured. There were no adverse effects of
      piperonyl butoxide on either litter size, litter weight or sex ratio at birth.
      The average body weight of male offspring was significantly increased in the
      middle-dose group at post-natal days 4 and 7 during lactation. That of female
      offspring was significantly increased in the middle-dose group at post-natal days
      7 and 14 during lactation. In behavioural developmental parameters, surface
      righting at post-natal day 7 was significantly delayed in the higher-dose groups
      in male offspring, and those effects were significantly dose related (p < 0.01).
      Olfactory orientation at post-natal day 14 was significantly depressed in the
      higher-dose groups in male offspring, and those effects were significantly dose
      related (p < 0.01). For movement activity of exploratory behaviour at 9 weeks of
      age of the F(1) generation, the total distance of males was significantly
      increased in the higher-dose groups, and those effects showed a dose-related
      manner (p < 0.01). Average distance and speed were significantly increased in the
      high-dose group, and those effects showed a dose-related manner (p < 0.01 in
      each). The dose levels of piperonyl butoxide in the present study produced some
      adverse effects in reproductive and neurobehavioural parameters in mice.

PMID- 12623644
TI  - Analysis of acrylamide by LC-MS/MS and GC-MS in processed Japanese foods.
AB  - Acrylamide concentrations in processed foods (63 samples covering 31 product
      types) from Japan were analysed by LC-MS/MS and GC-MS methods. The limit of
      detection and limit of quantification of acrylamide were 0.2 ng x ml(-1) (6 fmol)
      and 0.8 ng x ml(-1) (22 fmol), respectively, by LC-MS/MS, and those of 2,3
      dibromopropionamide derived from acrylamide were 12 ng x ml(-1) (52 fmol) and 40
      ng x ml(-1) (170 fmol), respectively, by GC-MS. Repeatability given as RSD was <5
      and <15% for the LC-MS/MS and GC-MS methods, respectively. High correlation (r(2)
      - 0.946) was observed between values obtained by the two methods. Most potato
      crisps and whole potato-based fried snacks showed acrylamide concentrations >1000
      microg x kg(-1). The concentrations in non-whole potato-based snacks, rice
      crackers processed by grilling or frying, and candied sweet potatoes were lower
      compared with those in the potato crisps and the whole potato-based fried snacks.
      One of the whole potato-based fried snacks, however, showed low acrylamide
      concentration (<50 microg x kg(-1)) suggesting the formation of acrylamide is
      strongly influenced by processing conditions. Acrylamide concentrations in
      instant precooked noodles and won-tons were <100 microg x kg(-1) with only one
      exception. Roasted barley grains for 'Mugi-cha' tea contained 200-600 microg x
      kg(-1) acrylamide.

PMID- 12623645
TI  - Antibodies to the quinolones and fluoroquinolones for the development of generic
      and specific immunoassays for detection of these residues in animal products.
AB  - Several quinolone and fluoroquinolone haptens have been used to raise polyclonal
      antibodies exhibiting both specific and generic properties for these classes of
      antimicrobial compounds. The antisera have been assessed in rapid enzyme
      immunoassays (ELISAs) designed to exploit the specificities obtained. A direct
      generic ELISA for both the quinolones and fluoroquinolones has been developed
      that uses the cross-reactivity of an antibody raised against norfloxacin (1-ethyl
      6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid) linked
      to ovalbumin via a secondary amine group on the piperazinyl moiety to detect nine
      different drugs in these classes. Specific ELISAs to ciprofloxacin (1-cyclopropyl
      6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid),
      enrofloxacin (1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo
      3-quinoline carboxylic acid), flumequin (9-fluoro-6,7-dihydro-5-methyl-1-oxo
      1H,5H-benzo(ij)quinolizine-2-carboxylic acid) and nalidixic acid (1-ethyl-1,4
      dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid) have also been
      developed with a high degree of specificity to the individual compounds. The
      assays measure drug residues in bovine milk and ovine kidney with an interassay
      relative standard deviation (s(r)) of 10.5% or less and intra-assay s(r) of 11.2%
      or less. Sensitivity is less than 4 microg x kg(-1) for both the generic and
      specific assays for all but one of the compounds tested. (Pipemidic acid (8-ethyl
      5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido(2,3-d)pyrimidine-6-carboxylic acid) is
      detectable at 6 microg x kg(-1) in kidney.)

PMID- 12623647
TI  - Selenium and mercury concentrations in sweet and dry bottled wines from the
      Canary Islands, Spain.
AB  - The concentrations of selenium and mercury were determined by atomic absorption
      spectrophotometry in sweet and dry bottled wines from the Canary Islands, Spain.
      The concentrations of mercury ranged from 2.6 to 4.9 microg x l(-1) for sweet
      wines, and from 1.5 to 2.6 microg x l(-1) for dry wines, differences (p < 0.05)
      being observed according to the island of production and type of wine, but not
      with respect to vintage. The concentration of selenium varied between 1.0 and 2.0
      microg x l(-1) for sweet wines, and between 0.6 and 1.6 microg x l(-1) for dry
      wines. Differences were found in the mean concentrations according to the type of
      wine. Dry wines produced in La Palma presented a higher (p < 0.05) mean content
      than those observed in the wines of El Hierro and Lanzarote.

PMID- 12623646
TI  - Disposition of 3-(4-cyano-2-oxobutylidene amino)-2-oxazolidone, a cyano
      metabolite of furazolidone, in furazolidone-treated grouper.
AB  - The cyano-metabolite of furazolidone (FZ), 3-(4-cyano-2-oxobutylidene amino)-2
      oxazolidone, was isolated from the mixture of FZ incubated with the post-9000 g
      hepatic supernatant of grouper. Its structure was confirmed by mass spectrometric
      and nuclear magnetic resonance spectroscopic studies. Thereafter, the disposition
      of the cyano-metabolite in the orange-spotted grouper (Epinephelus coioides)
      after oral and bath treatment with FZ was investigated. Qualitative and
      quantitative analyses of cyano-metabolite in the fish were performed by high
      performance liquid chromatography. Mean recoveries of the metabolite in serum,
      muscle, liver and kidney were 99.8 +/- 4.1, 98.6 +/- 3.5, 53.1 +/- 7.4 and 64.0
      11.4%, respectively. Cyano-metabolite was mainly distributed in the serum and
      muscle rather than in the liver and kidney. After oral treatment of FZ, the peak
      cyano-metabolite concentrations, 167.2 ng x ml(-1) in serum and 283.2 ng x g(-1)
      in muscle, were reached at 5.1 and 6.7 h, respectively. The elimination half-life
      of cyano-metabolite was 4 h. During 24-h bath treatment of FZ, the maximum
      concentrations of cyano-metabolite, 258 ng x ml(-1) in serum and 204 ng x g(-1)
      in muscle, were found at 0.25 and 6 h, respectively. The half-life of cyano
      metabolite was 0.5 h after transferring the fish to fresh seawater.

PMID- 12623648
TI  - Mercury, arsenic, lead and cadmium in fish and shellfish from the Adriatic Sea.
AB  - The aim was to measure concentrations of total mercury, total arsenic, lead and
      cadmium in common edible fresh fish and shellfish from various areas of the
      Adriatic Sea. Estimates of intake of these elements were made through seafood
      consumption by the general population. Samples were either wet digested for
      mercury and arsenic, or dry ashed for lead and cadmium analysis. Mercury was
      measured by cold vapour atomic absorption spectrometry (CV AAS) and arsenic, lead
      and cadmium by electrothermal atomic absorption spectrometry (ET AAS). Quality
      control procedures of analytical methods, which included analyses of dogfish
      muscle-certified reference material DORM-2, confirmed the acceptability of
      methods. The highest mercury and arsenic concentrations were found in hake
      (Merluccius merluccius) and the lowest in mackerel (Scomber scombrus). The
      respective values in hake were 0.373 +/- 0.075 and 23.3 +/- 3.6, and in mackerel
      0.153 +/- 0.028 and 1.06 +/- 0.29 mg x kg(-1) fresh weight (mean +/- SD). Lead
      and cadmium concentrations were about 10 times higher in shellfish than in
      analysed fish. The highest lead and cadmium concentrations were found in mussel
      (Mytilus galloprovincialis) and the lowest in hake. Respective lead and cadmium
      values in mussel were 0.150 +/- 0.009 and 0.142 +/- 0.017, and in hake were 0.007
      +/- 0.004 and 0.002 +/- 0.001 mg x kg(-1) fresh weight. The concentrations of
      analysed elements were below acceptable levels for human consumption set by the
      Croatian Ministry of Health, except for total arsenic. The estimated intake of
      those trace elements included in this study through seafood consumption by the
      general population did not exceed the provisional tolerable weekly intake
      recommended by the Joint FAO/WHO Expert Committee on Food Additives.

PMID- 12623649
TI  - Content and bioconcentration of mercury in mushrooms from northern Poland.
AB  - Mercury (Hg) was quantified using cold vapour-atomic absorption spectrometry (CV
      AAS) in the fruiting bodies of nine edible and five inedible mushrooms and in
      underlying soil substrate samples. In total, 404 samples comprising caps and
      stalks and 202 samples of soil substrate (0-10 cm layer) were collected in 1996
      from Trojmiejski Landscape Park, northern Poland. Mean Hg concentrations in the
      soil substrate for different species varied between 10 +/- 3 and 780 +/- 500 ng x
      g(-1) dry wt (range 2.3-1700). Among edible mushroom species, Horse Mushroom
      (Agaricus arvensis), Brown Birch Scaber Stalk (Leccinum scabrum), Parasol
      Mushroom (Macrolepiota procera), King Bolete (Boletus edulis) and Yellow-cracking
      Bolete (Xerocomus subtomentosus) contained elevated concentrations of Hg ranging
      from 1600 +/- 930 to 6800 +/- 4000 ng x g(-1) dry wt in the caps. Concentrations
      of Hg in the stalks were 2.6 +/- 1.1 to 1.7 +/- 1.0 times lower than those in the
      caps. Some mushroom species investigated had high Hg levels when compared with
      specimens collected from the background reference sites elsewhere (located far
      away from the big cities) in northern Poland. Bioconcentration factors of Hg in
      the caps of Horse Mushroom, Parasol Mushroom and Brown Birch Scaber Stalk were
      between 150 +/- 58 and 230 +/- 150 ng x g(-1) dry wt, respectively, and for
      inedible Pestle-shaged Puffball (Claviata excipulformis) was 960 +/- 300 ng x g(
      1) dry wt. Linear regression coefficients between Hg in caps and in stalks and Hg
      soil concentrations showed a positive relationship for A. arvensis and Horse
      mushroom (p < 0.05) and a negative correlation for the caps of Death Caps
      (Amanita phalloides) and Woolly Milk Cap (Lactarius torminosus) (p < 0.05), while
      for other species no clear trend was found.

PMID- 12623650
TI  - 2001 survey of organochlorine pesticides in retail milk from Beijing, P R China.
AB  - A monitoring study was conducted in 2001 to determine the organochlorine
      pesticides and their metabolite residues in milk taken from supermarkets in
      Beijing, P. R. China. The average concentrations of total HCH and DDT were 0.038
      and 0.046 mg x kg(-1), respectively, expressed on a fat basis. The aldrin residue
      was detected in nine milk samples, with a mean concentration of 0.035 mg x kg(
      1). Heptachlor and its epoxides were not found in any milk samples. Of 72 milk
      samples analysed, three from South China contained the higher levels of DDT and
      HCH residues that exceeded the FAO/WHO accepted tolerance level. Although
      organochlorine pesticides such as DDT and HCH have been banned in China since
      1983, the residues of such compounds still exist in the environment and cause
      food contamination, a fact likely attributed to the short prohibition period and
      illegal use for agricultural purposes at present.

PMID- 12623651
TI  - Organochlorine pesticide residues in cow's milk from a tropical region of Mexico.
AB  - A monitoring study was conducted to assess the magnitude of DDT [(1,1,1-trichloro
      2,2-bis(p-chlorophenyl)ethane)] and HCH (hexachlorocyclohexane) contamination of
      bovine milk from the central tropical region of Mexico as the chemicals are
      extensively used in livestock and public-health programmes. Among pesticide
      residues analysed, the milk samples collected from Tlalixcoyan showed a mean
      level of gamma-HCH (0.128 mg x kg(-1)), which was significantly higher than
      residues in milk samples from Medellin (0.049 mg x kg(-1)) and Paso San Juan
      (0.022 mg x kg(-1)). The mean level of pp'-DDE in Medellin samples (0.039 mg x
      kg(-1)) was significantly higher than in Paso San Juan (0.018 mg x kg(-1)) and
      Tlalixcoyan (0.024 mg x kg(-1)) milk samples. The pp'-DDT mean level from
      Medellin milk samples (0.089 mg x kg(-1)) was significantly higher than the
      levels detected in the other two areas. The highest mean Sigma-DDT level detected
      in Medellin samples (0.146 mg x kg(-1)) was three times the FAO/WHO tolerance
      level. The highest acceptable daily intakes calculated for Sigma-DDT were 0.017
      microg x kg(-1) bw day(-1) for adults and 0.530 microg x kg(-1) bw day(-1) for
      infants; for gamma-HCH residues, they were 0.021 microg x kg(-1) bw day(-1) for
      adults and 0.666 microg x kg(-1) bw day(-1) for infants, indicating that infants
      are more exposed to pesticide residues. Results indicate that cattle exposure to
      HCH and DDT results in high levels in dairy milk and a potential health risk for
      consumers.

PMID- 12623652
TI  - Persistent organochlorine pesticide levels in cow's milk samples from tropical
      regions of Mexico.
AB  - Organochlorine pesticides have been used in agriculture as a seed dresser, in
      sanitation, in malaria control programmes and in livestock to combat
      ectoparasites. Their residues accumulate in lipid-rich tissues due to their
      chemical stability and persistence. In the body they circulate throughout all
      compartments, deposit themselves in adipose fat and can be excreted during
      lactation. These pesticides are applied in tropical zones and drift to areas
      where cattle graze. Therefore, analyses of cow's milk samples can serve as an
      indicator of environmental and cows' exposure to them. One hundred and fifty milk
      samples were taken each year in 1998 and 2001 and analysed to determine
      concentrations of HCB, beta-HCH, pp"-DDE, op'-DDT and pp'-DDT. Results obtained
      indicate that beta-HCH is one of the main contaminants (0.106 and 0.087 mg x kg(
      1) on fat basis) followed by pp'-DDT (0.078 and 0.037 mg x kg(-1) on fat basis)
      and pp'-DDE (0.051 and 0.033 mg x kg(-1) on fat basis). The HCB and op'-DDT were
      detected in lower quantities respectively (0.008 and 0.006 mg x kg(-1), and 0.031
      and 0.010 mg x kg(-1) on fat basis). When comparing the results obtained with
      those from the previous study, it was noted that DDT levels decreased
      significantly in 2001 as a result of the substitution of the organochlorine
      insecticides with pyrethroids sprayed by the Mexican Ministry of Health to combat
      malaria since 1999.

PMID- 12623653
TI  - ELISA and HPLC determination of the occurrence of aflatoxin M(1) in raw cow's
      milk.
AB  - Raw cow's milk collected from dairy farms in the province of Leon, Spain, was
      examined for aflatoxin M(1) (AFM(1)). The samples were analysed with a commercial
      competitive enzyme-linked immunosorbent assay (ELISA) kit and high-performance
      liquid chromatography (HPLC). The concentrations of AFM(1) in the milk extracts
      were initially estimated by ELISA, with recovery rates of 74.6-109% for
      artificially contaminated milk at levels of 10-80 ng x l(1). Samples found to
      contain more than 10 ng x l(1) were further quantified with HPLC. The mean
      recovery for this method was 89.3%. The quantification limit was 10 ng x l(1) for
      both ELISA and HPLC. Although AFM(1) was confirmed in only 3.3% of the samples,
      the concentrations in all these cases were lower than the maximum limit
      applicable to these products pursuant to European Union legislation. Both methods
      were validated with reference material certified by the Community Bureau of
      Reference.

PMID- 12623654
TI  - Butter as an indicator of regional persistent organic pollutant contamination:
      further development of the approach using polychlorinated dioxins and furans
      (PCDD/Fs), and dioxin-like polychlorinated biphenyls (PCBs).
AB  - The potential for use of butter as a widely available, relatively uniform lipid
      rich matrix for the determination of spatial distributions of persistent organic
      pollutants has already been demonstrated. The present study determines the
      contributions to toxicity equivalence (TEQ) from polychlorinated dioxins and
      furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) using butter samples from
      24 countries world wide. Concentrations of PCDD/Fs and dioxin-like PCBs ranged
      from 0.07 to 5.69 pg SigmaWHO-TEQ g(-1) lipid. For most samples, PCDD/F TEQ fell
      within ranges reported for European dairy products over the last decade (0.3-2 pg
      x g(-1) lipid I-TEQ), though a single sample from Spain was a notable exception.
      Other than this sample, the highest values were recorded for samples from the
      Netherlands and Italy, with those from India, China and Tunisia also being
      relatively high. The contribution from non-ortho-PCBs was particularly
      significant in samples from Germany, Austria, Italy, the Czech Republic, Tunisia,
      India and Argentina. Although overall TEQs were generally highest in European and
      Mediterranean butters, elevated levels were also apparent in industrializing
      regions of Asia (India, China) and Latin America (Argentina). More detailed
      regional studies would be necessary to identify likely dioxin and PCB sources in
      each case. Nevertheless, this study supports the utility of butter as a
      monitoring matrix that may be especially applicable in regions for which
      monitoring programmes are currently lacking.

PMID- 12623655
TI  - Evaluating the migration of ingredients from active packaging and development of
      dedicated methods: a study of two iron-based oxygen absorbers.
AB  - The behaviour of two commercial oxygen-scavenging products with respect to
      migration of active ingredients into foodstuffs was investigated. Migrants were
      identified, and by using appropriate analytical methods, migration was determined
      in a variety of liquid, solid or gelled food simulants and foods. Simulants were
      chosen to cover a range of water activities and viscosities. Foods and the gelled
      food simulant agar were packed with and without vacuum, and with the oxygen
      scavenger in various locations relative to the packed food. The main migrants, as
      identified by X-ray fluorescence spectrometry, infrared spectroscopy and scanning
      electron microscopy with energy-dispersive spectrometry were Na(+) and Cl(-) in
      non-acidic aqueous simulants, and Na(+), Cl(-) and Fe(2+) in 3% acetic acid.
      Migration into aqueous simulants exceeded the current European Union limit for
      total migration from plastic materials (assumed to be currently applicable to
      these systems) and was probably excessive by any reasonable standard. However,
      neither oxygen scavenger appeared to release significant quantities of migrants
      into solid foods when the scavenger was properly located in the package and the
      packing process does not favour the contents becoming wet by water released from
      the food.

PMID- 12623656
TI  - Identification of extractable substances from rubber nettings used to package
      meat products.
AB  - Ten meat nettings were sampled from four different suppliers in the Netherlands.
      These meat nettings consisted both of natural rubber and of vegetable fibres.
      Nitrosamines were extractable up to 2 mg x kg(-1) netting, the nitrosamine being
      N-nitrosodibenzylamine. The nitrosatable substances found were precursors of N
      nitrosodimethylamine and N-nitrosodibenzylamine and were extracted up to 0.4 mg x
      kg(-1) nettings. Considering the ratio of meat netting and foodstuff, the
      extractable amount of nitrosamines and nitrosatable substances does not raise
      concern for public health. The meat nettings were also screened for other
      potential migrants. Extractable amounts of several alkanes, alkenes, acids,
      antioxidants, plasticizers and sterols were found. Several of these extracted
      substances are not allowed in the Netherlands, although some are authorized in
      other countries. Several substances, however, have not been evaluated for use in
      food-contact materials and therefore the possible risk to public health is
      unknown.

PMID- 12623657
TI  - HPLC method for determining ethylenediamine migration from epoxy-amine food
      packaging coatings into EU food simulants.
AB  - A simple, rapid, sensitive and inexpensive method has been developed for the
      determination of ethylenediamine (EDA) in European Union food simulants. The
      method involves precolumn derivatization with ortho-phthaldehyde (OPA) and 2
      mercaptoethanol (ME) to obtain a fluorescent derivative. Liquid chromatographic
      (HPLC) elution was achieved with methanol-ultrapure water (65:35) as mobile phase
      with a Waters Spherisorb 5 microm ODS 2 column. Fluorescence detection (FD) was
      performed at 330 nm (excitation wavelength) and 450 nm (emission). Total
      chromatographic analysis time was < 10 min. The proposed method was validated by
      checking linearity, detection and quantification limits, and precision. Relative
      recovery rates were of about 100% because samples and standard-spiked blanks were
      processed in the same way. Method precision (RSD < 6%) was satisfactory and the
      quantification limit (0.25 mg x (-1)) indicated that specific migration limit for
      EDA in EU food simulants (12 mg x kg(-1)) can be easily controlled. When the
      validated method was applied to epoxy-amine formulations used for can coatings
      under different curing conditions, EDA migration was < 1.4 mg x l(-1).

PMID- 12623658
TI  - Addendum to Food Additives and Contaminants 2002, 19, 492-501 migration of
      monomers from liquid crystalline poly(p-hydroxybenzoic acid-co-2-hydroxy-6
      naphthoic acid).
AB  - Liquid-crystalline co-polyesters (e.g. a random copolyester based on p
      hydroxybenzoic acid (HBA) and 2-hydroxy-6-naphthoic acid (HNA) known as Vectra
      A950) offer good barrier properties, but for food-contact use they require
      overall and specific migration testing. For Vectra A950 films, the highest
      overall migration level obtained was 2.3 mg x dm(-2) (13.8 mg x kg(-1)) in olive
      oil (10 days at 40 degrees C), well below the EC limit of 10 mg dm(-2) (60 mg x
      kg(-1)). The highest specific migration of HBA was 15.2 microg x dm(-2) (91.2
      microg x kg(-1)) in olive oil (2 h at 175 degrees C). In this case, the migration
      level was well below the EC limit of 10 mg dm(-2) (60 mg x kg(-1)). For HNA, the
      highest value obtained was 4.3 microg x dm(-2) (26 microg x kg(-1)) in 10%
      ethanol (4 h at 100 degrees C), well below the specific migration limit (SML = 50
      microg x kg(-1)). The results obtained shows that even at these severe
      conditions, the migration values comply with the new European Union Directive
      2002/72/EC, which regulates plastic materials and articles for food contact use.
      In addition, the polymer Vectra A950 complies with Food Contact Notification
      (FCN) No. 103 of the United States Food and Drug Administration (FDA). Vectra
      A950 is therefore permitted for food-contact use both in the European Union and
      the USA.

PMID- 12623659
TI  - Estimated intake of the artificial sweeteners acesulfame-K, aspartame, cyclamate
      and saccharin in a group of Swedish diabetics.
AB  - Few sweetener intake studies have been performed on the general population and
      only one study has been specifically designed to investigate diabetics and
      children. This report describes a Swedish study on the estimated intake of the
      artificial sweeteners acesulfame-K, aspartame, cyclamate and saccharin by
      children (0-15 years) and adult male and female diabetics (types I and II) of
      various ages (16-90 years). Altogether, 1120 participants were asked to complete
      a questionnaire about their sweetener intake. The response rate (71%, range 59
      78%) was comparable across age and gender groups. The most consumed 'light'
      foodstuffs were diet soda, cider, fruit syrup, table powder, table tablets, table
      drops, ice cream, chewing gum, throat lozenges, sweets, yoghurt and vitamin C.
      The major sources of sweetener intake were beverages and table powder. About 70%
      of the participants, equally distributed across all age groups, read the
      manufacturer's specifications of the food products' content. The estimated
      intakes showed that neither men nor women exceeded the ADI for acesulfame-K;
      however, using worst-case calculations, high intakes were found in young children
      (169% of ADI). In general, the aspartame intake was low. Children had the highest
      estimated (worst case) intake of cyclamate (317% of ADI). Children's estimated
      intake of saccharin only slightly exceeded the ADI at the 5% level for fruit
      syrup. Children had an unexpected high intake of tabletop sweeteners, which, in
      Sweden, is normally based on cyclamate. The study was performed during two winter
      months when it can be assumed that the intake of sweeteners was lower as compared
      with during warm, summer months. Thus, the present study probably underestimates
      the average intake on a yearly basis. However, our worst-case calculations based
      on maximum permitted levels were performed on each individual sweetener, although
      exposure is probably relatively evenly distributed among all sweeteners, except
      for cyclamate containing table sweeteners.

PMID- 12623661
TI  - Contamination of animal feedingstuffs with nicarbazin: investigations in a feed
      mill.
AB  - Some mechanisms of nicarbazin contamination were investigated in a feed mill.
      Three sequential 3-tonne batches of nicarbazin-free feed were produced directly
      after a batch of nicarbazin-containing feed (125 mg kg(-1)). Sampling of the
      nicarbazin-free feed took place at two points before pelleting and at one point
      post-pelleting. The study was repeated on two further occasions, i.e. three
      separate nicarbazin-containing feeds and 27 tonnes of 'flushing' feeds were
      manufactured and sampled in total. Pre-pelleting, the highest nicarbazin
      concentrations (3.4+/- 0.26 mg kg(-1)) were observed in the first tonne milled
      after the nicarbazin containing ration. Thereafter, concentrations steadily
      declined in successive batches. Post-pelleting samples contained much higher
      concentrations of the drug. After 8 tonnes had passed through, the concentrations
      (7.2+/- 1.29 mg kg(-1)) were between 10 and 20 times greater than the
      corresponding concentrations detected post-mixing. These concentrations are
      sufficient to cause violative residues in eggs and broiler liver. The practice of
      returning post-press sieved material to the pre-press bins was identified as the
      cause of the problem. Re-routing of sieved material along with better segregation
      of nicarbazin-containing and nicarbazin-free feedingstuffs markedly reduced the
      incidence of feed contamination with this compound.

PMID- 12623660
TI  - Assessment of estimated daily intakes of benzoates for average and high consumers
      in Korea.
AB  - A study was performed to evaluate the estimated daily intakes (EDI) of benzoates
      for the average and high (90th percentile) consumers by age and sex categories in
      Korea. The estimation of daily intakes of benzoates was based on individual
      dietary intake data from the National Health and Nutrition Survey in 1998 and on
      the determination of benzoates in eight food categories. The EDI of benzoates for
      average consumers of different age groups ranged from 0.009 to 0.025 mg kg(-1) bw
      day(-1). For high consumers, the range of EDI of benzoates was 0.195-1.878 mg kg(
      1) bw day(-1). The intakes represented 0.18-0.50% of the acceptable daily intake
      (ADI) of benzoates for average consumers and 3.9-37.6% of the ADI for high
      consumers. Foods that contributed most to the daily intakes of benzoates were
      mixed beverages and soy sauce in Korea.

PMID- 12623662
TI  - Analysis of arsenic, lead and cadmium in wines from the Canary Islands, Spain, by
      ICP/MS.
AB  - Because of their high toxicity, arsenic, lead and cadmium need to be quantified
      in food and beverages. For the first time, in this study the content of arsenic,
      lead and cadmium was investigated in 152 wine samples from the Canary Islands,
      Spain, belonging to eight Denominations of Origin (DO) and four islands by
      inductively coupled plasma mass spectrometry (ICP-MS). The ranges of
      concentration found were 0.58-8.45 microg l(-1) for arsenic, 0.20-1.73 microg l(
      1) for cadmium and 3.89-159.5 microg l(-1) for lead, and the mean content was
      3.13, 0.63 and 28.74 microg l(-1), respectively. None of the wines contained
      levels above the limits set by the International Office of Vine and Wine (OIV),
      and thus did not pose a health hazard. Significant differences in mean content of
      those elements between harvest, type of wine, islands and DO were observed.

PMID- 12623663
TI  - Analysis of lead in 55 brands of dietary calcium supplements by graphite furnace
      atomic absorption spectrometry after microwave digestion.
AB  - The lead (Pb) contents of calcium (Ca) supplements available in Korea were
      determined by graphite furnace atomic absorption spectrometry using Zeeman
      background correction and peak area mode. All samples were microwave-digested in
      concentrated HNO(3). Ammonium dihydrogen phosphate and magnesium nitrate were
      used as matrix modifiers. Fifty-five brands of Ca supplements were classified
      into seven categories based on the major composite: bone, milk, oyster/clam
      shell, egg shell, algae, shark cartilage and chelated. The mean Pb contents of Ca
      supplements were 1.1 microg g(-1) (coefficient of variation 5.7%), ranging from
      n.d. (not detected) to 6.7 microg g(-1). Ca supplements made of bone have the
      highest Pb contents (2.3 microg g(-1)) with a wide range (0.1-6.7 microg g(-1)).
      The results were similar to those reported in other countries. The mean daily
      intakes of Pb from the supplement could be about 5 microg (mean Pb concentration
      1.1 microg g(-1) x mean daily intake 4.5 g) taking 2% of provisional tolerable
      daily intake that the FAO/WHO Joint Food Additive and Contaminants Committee has
      set to evaluate its safety. However, measures to prevent potentials of Pb
      toxicity from overtaking some Ca supplements should be considered.

PMID- 12623664
TI  - Food safety implications of the distribution of azaspiracids in the tissue
      compartments of scallops (Pecten maximus).
AB  - Azaspiracids, a new class of shellfish toxins, have been implicated in several
      recent incidents of human intoxications following the consumption of mussels
      (Mytilus edulis). A study was undertaken to examine the distribution of
      azaspiracid poisoning (AZP) toxins in scallops (Pecten maximus) and individual
      shellfish were dissected into five tissue fractions for the determination of
      toxin composition. Separation of the predominant azaspiracids, AZA1-3, was
      achieved using reversed-phase liquid chromatography with detection by positive
      electrospray multiple tandem mass spectrometry. The AZP toxin composition was
      determined in the adductor muscle (meat), gonad (roe), hepatopancreas (digestive
      glands), mantle and gill of scallops. Substantial differences in the AZP toxin
      levels between tissue compartments were observed and toxins were concentrated
      predominantly, about 85%, in the hepatopancreas. There was also a significant
      variation in the total toxin levels between individual scallops from the same
      sample batch and the RSD was 60% (n = 9). Interestingly, although all three AZP
      toxins were present in phytoplankton and mussels, AZA3 was not detected in the
      scallop samples examined. It was concluded that to improve food safety, only the
      adductor muscle and gonad of scallops should be permitted for sale to the public.

PMID- 12623665
TI  - Hidden fumonisin in corn flakes.
AB  - Twenty-five samples of retail corn flakes (from 15 lots) were analysed for
      fumonisin B(1) (FB(1)) and fumonisin B(2) (FB(2)). They were detected in 22 and
      12 samples, respectively, at respective mean concentrations 68 and 8 ng g(-1).
      Samples were extracted with methanol-acetonitrile-water (25:25:50) and there was
      an excellent correlation for FB(1) between results obtained with C(18) clean-up
      and those obtained with the immunoaffinity column (IAC) clean-up. After
      extraction of the corn flakes' residue with 1% sodium dodecyl sulphate (SDS)
      solution and hydrolysis with 2 N potassium hydroxide, hidden (protein bound)
      fumonisin was determined as HFB(1), which was found in residues from all the corn
      flakes samples, even those containing no detectable FB(1); the average
      concentration of HFB(1) was 101 ng g(-1), equivalent to 180 ng FB(1) g(-1). Thus,
      our results showed an average of 2.6 times more FB(1) present in bound form as
      was determined by conventional analysis. We found a correlation coefficient of 
      0.5034 for a logarithmic relationship between the FB(1) (C(18) clean-up) and
      HFB(1) concentrations The highest concentration of HFB(1) formed was 288 ng g(-1)
      from a sample containing only 12-15 ng FB(1) g(-1), while the lowest
      concentration of HFB(1) was 26 ng g(-1) from a sample with 152-155 ng FB(1) g(
      1). This low degree of correlation should be taken into account by food safety
      authorities in estimates of human exposure to protein bound fumonisin.

PMID- 12623666
TI  - Modelling permeation through porous polymeric films for modified atmosphere
      packaging.
AB  - The use of perforated packaging films is increasing with the application of
      modified atmosphere packaging for fresh produce. These films provide high to very
      high mass exchange rates. However, irrespective of the chemistry of the material,
      mass transport through such films cannot be described using conventional
      permeability equations (Henry's plus Fick's laws). Other expressions such as
      Knudsen's law, gas diffusivities or Poiseuille's hydrodynamic flow can be
      applicable. The application of these laws is discussed and their corresponding
      range of validity is provided. These laws were also applied to model experimental
      permeation rates of oxygen and water and were further used to describe the
      headspace evolution of two fruit products in modified atmosphere packaging. In
      the light of these results, the contribution of different factors to the
      headspace evolution is discussed.

PMID- 12623667
TI  - Modelling the effect of oil/fat content in food systems on flavour absorption by
      LLDPE.
AB  - One of the phenomena in food-packaging interactions is flavour absorption.
      Absorption of flavour compounds from food products into food-packaging materials
      can result in loss of flavour compounds or an unbalance in the flavour profile
      changing a product's quality. The food matrix influences the amounts of absorbed
      flavour compounds; the presence of oil or fat especially determines the ability
      to absorb flavour compounds from the food to the package. On the other hand, the
      polarity of the flavour compound itself is a characteristic that also influences
      the level of absorption into synthetic polymers. A model based on the effect of
      the polarity (logP) of flavour compounds and on their partitioning coefficients
      between the food (matrix) and the packaging material is described. The model can
      be used for predicting absorption of flavour compounds from foods into LLDPE.
      However, an attempt to apply the proposed model on real foods shows serious
      limitations of the model for (very) low fat products. Predictive values deviate
      from the measured values, probably due to other interaction phenomena, e.g. with
      proteins. Predictive and measured values from a product with a substantial amount
      of fat match much better, suggesting that the model is valid for products having
      a substantial amount of (free) fat.

PMID- 12623668
TI  - Assessment of the risk of physical contamination of bread packaged in perforated
      oriented polypropylene films: measurements, procedures and results.
AB  - Perforated films used for wrapping factory-manufactured bread must permit a very
      rapid and intense moisture exchange because the packaging operation is carried
      out while the bread is still warm (about 80 degrees C) and releasing a high
      quantity of moisture. The open surface of the wrapping of those products sold in
      self-service retail outlets generates suspicion about possible contamination of
      bread not properly handled by the consumers and a better knowledge of the
      performance of these materials seems appropriate. Using two different approaches,
      the geometrical characteristics and perforation pattern of 13 different oriented
      polypropylene (OPP) films representative of the whole European market were
      assessed objectively. All the measured parameters (density of perforation, hole
      dimension, open surface, etc.) showed asymmetric distributions, i.e. with
      averages close to the lowest figures. Similar asymmetric distribution was shown
      from the 'risk of contamination' by artificial sweat and saliva: an empirical
      parameter which was measured by procedures developed to simulate the worst
      possible case of inappropriate manipulation of the packed bread. Good correlation
      was found between the 'risk of contamination' and both the 'hole surface' (mm(2))
      and the 'open surface' (percentage holes surface/film surface), leading to the
      conclusion that the proposed procedures could represent useful methodologies for
      assessment of such a particular case of possible food contamination.

PMID- 12623669
TI  - Development and application of an LC-MS method to determine possible migration of
      mercaptobenzothiazole, benzothiazole and related vulcanization residues from
      rubber used in contact with food and drink.
AB  - A method was developed for the analysis of food and drink for residues of
      specific vulcanization accelerators used to cross-link rubber. The method was
      applied to the analysis of 236 samples of selected retail foodstuffs that may
      have been in contact with rubber during their manufacture, transport and storage.
      The method of analysis involved extraction of the food using acidified solvent
      and analysis by liquid chromatography/atmospheric pressure chemical ionization
      mass spectrometry (LC-APcI-MS). The detection limit depended on the sample type
      and was in the range 0.005-0.043 mg kg(-1) for 2-mercaptobenzothiazole (MBT) and
      benzothiazole (BT). The average analytical recovery rate was 82% for MBT and 87%
      for BT. The analytical method was validated using a blind check sample exercise.
      For MBT and BT at seven different concentrations in the range 0.1-0.2 mg kg(-1),
      the laboratory found a mean of 91 and 90% of the expected concentrations,
      respectively. No trace of MBT or BT was found in any of the retail samples. It is
      also concluded that no sample contained significant 2-mercaptobenzothiazyl
      disulphide (MBTS) or N- cyclohexyl-2-benzothiazole sulphenamide (CBS). Both MBTS
      and CBS are important accelerators used to vulcanize rubber and they break down
      in foodstuffs to form MBT and BT. The absence of MBT and BT in the foodstuffs
      therefore also provides proof of the absence of MBTS and CBS.

PMID- 12623670
TI  - Irish National Food Ingredient Database: application for assessing patterns of
      additive usage in foods.
AB  - Patterns of food additive usage in the Irish food supply and changes in patterns
      of usage between 1995-97 and 1998-99 were assessed by means of an Irish National
      Food Ingredient Database (INFID). Of the 300 additives permitted for use
      according to the European Union food additives Directives, some 54% were recorded
      in foods in INFID. Colours, emulsifiers and acids were the most frequently used
      additive categories, representing 18, 13 and 12% of the total additives used,
      respectively. Colours were most commonly recorded in sauces (n = 182 brands, 26%
      of sauces), emulsifiers were most commonly recorded in biscuits (n = 181 brands,
      47% of biscuits) and acids were most commonly recorded in sauces (304 brands, 43%
      of sauces). Carotenes (E160a), Annatto (E160b), mono- and diglycerides of fatty
      acids (E471) and citric acid (E330) were the most commonly used colour,
      emulsifier and acid, respectively. All diet soft drinks (n = 37), low-fat spreads
      (n = 25) and liver pates (n = 10) recorded the use of at least one additive. When
      expressed in terms of the number of brands that contain additives, sauces (n =
      522, 73% of sauces), biscuits (n = 323, 84% of biscuits) and preserves (n = 321,
      85% of preserves) were ranked highest. For most categories of additive (n = 24),
      there appeared to be a minimal change in qualitative additive usage between 1995
      97 and 1998-99. However, there was a significant increase in the frequency of use
      of emulsifiers (p < 0.001), acids (p < 0.01), sweeteners (p < 0.05) and acidity
      regulators (p < 0.05), and a significant decrease in the frequency of use of
      antioxidants (p < 0.05) during the period 1998-99 compared with 1995-97. Despite
      changes in additive usage patterns, it appeared that changes in the types of
      brands on sale between both periods were more apparent than actual changes in
      qualitative ingredient formulations across brands, as some 17% of brands that
      were on sale in 1995-97 were no longer on sale in 1998-99.

PMID- 12623671
TI  - Verification of the findings of acrylamide in heated foods.
AB  - We report here the first confirmation of the recent Swedish findings of
      acrylamide in heated foods. The verification exercise used an LC-MS/MS method
      developed for the purpose as well as an established GCMS method for acrylamide
      analysis. LC-MS/MS was suitable for the direct determination of acrylamide in
      aqueous extracts of foods by isotope dilution mass spectrometry (IDMS) using
      triply deuterated acrylamide. Some food matrices were not suited to the new
      method and mixed-mode solid-phase extraction (SPE) was used to clean these
      extracts. The foods tested included UK versions of some of the key food groups
      analysed in Sweden. Also tested were some foods heated under home-cooking
      conditions. There was good agreement between the LC-MS/MS results and the GC-MS
      results and the levels of acrylamide found here were similar to those reported
      for the corresponding foods analysed in the Swedish study. The analyses confirmed
      that acrylamide is absent from the raw or boiled foods but present at significant
      levels in fried, grilled, baked and toasted foods. The highest result was 12000
      microg kg(-1) acrylamide in overcooked oil-fried chips.

PMID- 12623672
TI  - Nitrate and nitrite in vegetables from north China: content and intake.
AB  - The contents of nitrate and nitrite in potato, cabbage, Chinese cabbage, scallion
      (shallot), celery, cucumber, tomato, eggplant and wax gourd taken from the north
      China market from 1998 to 1999 were determined. These vegetables provide the
      major contribution to the nitrate intake from the diet. The highest content of
      nitrate was found in celery followed by Chinese cabbage, cabbage, scallion, wax
      gourd and eggplant. For all the products, a great variation in the content of
      nitrate was found. Generally, the nitrite content was low. The average intake of
      nitrate and nitrite from these vegetables was estimated as approximately 422.8
      and 0.68 mg day(-1), respectively.

PMID- 12623673
TI  - Development and validation of dry reagent time-resolved fluoroimmunoassays for
      zeranol and alpha-zearalenol to assist in distinguishing zeranol abuse from
      Fusarium spp. toxin contamination in bovine urine.
AB  - Zeranol, an oestrogenic growth promoter in food animals, is banned within the
      European Union (EU). However, commercially available immunoassay kits for zeranol
      cross-react with toxins formed by naturally occurring Fusarium spp. fungi,
      leading to false-positive screening results. This paper describes the validation
      of a specificity enhanced, rapid dry reagent time-resolved fluoroimmunoassay (TR
      FIA) for zeranol (recovery 99%, limit of detection 1.3 ng ml(-1)) demonstrating
      that up to 150 ng ml(-1) of Fusarium spp. toxins in urine do not lead to false
      positive results. This assay will assist EU Member States to implement Council
      Directive 96/23/EC, which requires states to monitor for potential abuses of
      zeranol. A similar TR-FIA for the Fusarium spp. toxin alpha-zearalenol, using the
      same sample extract, is also described (recovery 68%, limit of detection 5.6 ng
      ml(-1)). Only the addition of diluted sample extract is required to perform these
      dry-reagent TRFIAs, the results being available within 1h of extract application.
      The EU-funded project 'Natural Zeranol' (FAIR5-CT97-3443) will use these
      fluoroimmunoassays to screen bovine urine in four Member States to gather data on
      the seasonality of Fusarium spp. toxin contamination of urine and the incidence
      of zeranol screening test positives.

PMID- 12623674
TI  - A binary screening assay for pro-oestrogens in food: metabolic activation using
      hepatic microsomes and detection with oestrogen sensitive recombinant yeast
      cells.
AB  - An assay, employing microsomes prepared from rat liver and a recombinant cell
      bioassay (RCBA) expressing the human oestrogen receptor (alpha) linked to a
      reporter gene, was evaluated for the detection of pro-oestrogens in food using
      methoxychlor and mestranol as model compounds. Bio-activation of the hop
      phytoestrogen isoxanthohumol to the potent oestrogen 8-prenylnaringenin was also
      investigated. The oestrogenic potency values for reference standards determined
      with the RCBA (17beta-oestradiol = 100%) were: methoxychlor 0.0025%, mestranol
      1.3%, isoxanthohumol 0.001%, and for their potential respective metabolites were:
      bishydroxymethoxychlor 0.015%, 17alpha-ethynyl oestradiol 69% and 8
      prenylnaringenin 0.4%. Incubation of methoxychlor and mestranol (10 microM) with
      microsomes prepared from the liver of rats treated with Aroclor 1254
      significantly increased (p < 0.001) their oestrogenic potency from 0.0021 and
      2.4% to 0.015 and 8.3%, respectively. In contrast, the potency of the hop
      phytoestrogen isoxanthohumol was unchanged. Metabolites were identified by UV
      HPLC-MS/MS as monohydroxy methoxychlor and HPTE from methoxychlor, and the major
      metabolite of mestranol was 17alpha-ethynyl oestradiol. There was no evidence for
      the metabolism of isoxanthohumol. Mestranol was also activated by microsomes
      induced with saline (control), beta-napthoflavone, 3-methylcholantherene,
      isoniazid or pregnenolone-16alpha-carbonitrile, but not phenobarbitone. These
      studies demonstrate the principle for use of a binary assay system for the
      detection of pro-oestrogens and indicate the potential value for risk assessment
      of endocrine disrupting chemicals.

PMID- 12623675
TI  - Organochlorine pesticides and polychlorinated biphenyls in 12 edible marine
      organisms from the Adriatic Sea, Italy, Spring 1997.
AB  - Edible portions of 12 marine organisms from several areas of the Adriatic Sea,
      Italy, were collected during Spring 1997 and analysed for 32 organochlorine
      pesticides residues and 27 polychlorobiphenyl congeners. Only eight
      organochlorine pesticides - hexachlorobenzene (HCB), hexachlorocyclohexane (HCH)
      isomers, diphenyl-dichloro-trichloroethane (DDT) group, dieldrin - were
      determined at levels in the range <0.01-19.88 ng g(-1) wet weight, with 1,1'
      dichloro-2,2'-bis(4-chlorophenyl)ethylene (DDE) being the more relevant single
      organochlorine. The contamination by organochlorine pesticides was comparable in
      organisms from the North, Centre and South Adriatic. Polychlorinated biphenyls
      (PCBs) were determined at levels in the range <0.05-14.46 ng g(-1), with CB 101,
      118, 138, 153, 180 and 187 being more relevant (penta-, hexa- and hepta
      chlorinated congeners). The sum of PCBs congeners determined were in the range
      1.18-69.05 ng g(-1). The contamination by PCBs is more relevant in organisms from
      the North Adriatic Sea owing to the antropic discharge from major rivers such as
      Po and Adige that flow through highly industrialized and densely populated areas.

PMID- 12623676
TI  - Residues of cypermethrin in field-treated grapes and raisins produced after
      various treatments.
AB  - Residues of the synthetic pyrethroid insecticide cypermethrin in fresh grapes of
      cv. Thomson Seedless and in raisins were studied. The commercial formulation
      Cymbush10% EC was applied according to the label onto the typical seedless
      variety and on a seed-producing clone. Samples were collected at time zero and at
      15 or 21 days post-application. The raisins were produced either by submersion
      for 3 min in an aqueous solution of 3% potassium carbonate and 1% ethyl oleate,
      and dried for 15 days under direct sunlight or were dried without chemical
      processing. A gas chromatographic method was used for the analysis of residues.
      The residues in the grapes at the recommended preharvest interval (15 days)
      ranged from 0.23 to 0.41 mg kg(-1), whereas those in raisins ranged from 0.25 to
      0.46 mg kg(-1).

PMID- 12623677
TI  - Ochratoxin A in domestic and imported beers in Belgium: occurrence and exposure
      assessment.
AB  - Determination of ochratoxin A (OTA) concentration was performed in commercial
      beer in Belgium using immunoaffinity column (OchraTest) clean-up and liquid
      chromatography. The procedure was validated and fulfilled the European Committee
      for Standardization's criteria. It offered a detection limit of 3 ng l(-1) and a
      quantification limit of 10 ng l(-1). Recovery experiments carried out with the
      spiked samples in the range 50-200 ng OTA l(-1) showed an overall average
      recovery rate of 97% (RSD = 2.8%). The validated method was applied to the
      analysis of 62 Belgian beers and 20 commercial beers imported from Denmark,
      France, Germany, Ireland, Mexico, The Netherlands and Scotland. None of these
      beers exceeded the previously suggested EU limit of 200 ng l(-1). However, OTA
      was detected in 60 Belgian beers and in all imported beers. The average levels of
      contamination were 33 ng l(-1) (RSD = 112%) and 32 ng l(-1) (RSD = 81%),
      respectively. The highest level found was 185 ng l(-1). On the basis of the
      established tolerable daily intake (TDI) of 5 ng kg(-1) body weight, accepted by
      the scientific committee on food of the EU, this study indicates that beer
      consumption in Belgium is not likely to contribute to more than a few per cent of
      the TDI based on the average consumption. This study also shows variability of
      the OTA contamination in beer with time. Thus, there is a potential risk of
      having highly contaminated batches from time to time. We therefore recommend to
      control further the OTA contamination in brewery products and to take
      precautionary measures during harvest, transport and storage of the raw materials
      to maintain the OTA intake at the lowest achievable level.

PMID- 12623678
TI  - Occurrence of aflatoxins B1, B2, G1 and G2 in some Brazilian pet foods.
AB  - The presence of cereals and grains in the formulation of pet foods suggests the
      need to control aflatoxin contamination in these foods. The objective of the
      study was to analyse domestic pet food to determine the occurrence of aflatoxins
      as well as their risk to animal health. One hundred food samples (45 for dogs, 25
      for cats, 30 for birds) were collected at random from pet shops in Alfenas city,
      south-east Brazil. Thin-layer chromatography was used for separation,
      identification and quantification of the compounds after validation of the
      method. Aflatoxins were detected in 12.0% of the samples. Levels of aflatoxins
      (B(1) + B(2) + G(1) + G(2)) above the maximum limit established in Brazil (50
      microg kg(-1)) for animal food were detected in five of the 12 positive samples
      (41.7%). The concentration of total aflatoxins was 15-374 microg kg(-1) (mean 131
      microg kg(-1)). All samples containing peanuts were positive for aflatoxin B(1).
      Aflatoxins are carcinogenic and their consumption might be a risk for domestic
      animal health. The high prevalence of aflatoxin B(1) in foods prepared for birds,
      species highly susceptible to aflatoxins, shows the need for the re-evaluation of
      the use of peanuts (present in seven of the eight samples positives for
      aflatoxin) and/or the addition of fungicides to the food.

PMID- 12623679
TI  - Occurrence of ochratoxin A in Danish wheat and rye, 1992-99.
AB  - Ochratoxin A concentrations in rye and wheat in Denmark for 1992-99 are reported.
      The results show that the concentration of ochratoxin A is higher in rye than in
      wheat for both conventionally and organically grown rye and wheat. The levels in
      organically grown rye are higher than in conventionally grown based on multiyear
      mean contents. However, the difference between the two groups of cereals has
      decreased since the Danish food-monitoring system for ochratoxin A was started in
      1986; 2.0% of all samples exceeded the Danish maximum limit of 5 micro g kg(-1)
      introduced in 1995. For rye samples, 3.2% exceeded the maximum limit, and for
      wheat samples, 0.5% exceeded the maximum limit.

PMID- 12623680
TI  - Effect of ionizing radiation on the physicochemical and mechanical properties of
      commercial monolayer flexible plastics packaging materials.
AB  - The effect of gamma-radiation doses (5, 10, 30 kGy) on the mechanical properties,
      gas and water vapour permeability, infrared (IR) spectra, and overall migration
      into aqueous and alternative fatty food simulants of commercial monolayer
      flexible packaging films ethylene vinyl acetate (EVA), high-density polyethylene
      (HDPE), polystyrene (PS), bi-axially oriented polypropylene (BOPP), low-density
      polyethylene (LDPE) and Ionomer was studied. For comparison purposes, respective
      non-irradiated (control) films were also studied. The results showed that
      radiation doses of 5, 10 and 30 kGy did not induce any statistically significant
      changes in the permeability of all studied films to gases (oxygen and carbon
      dioxide) and water vapour. Likewise, IR spectra of all studied films showed no
      significant differences after all absorbed doses. The mechanical properties
      (tensile strength, percentage elongation at break and Young's modulus) of all
      studied films remained unaffected after absorbed doses of 5 and 10 kGy. In
      contrast, the tensile strength of HDPE, BOPP and Ionomer films irradiated at a
      dose of 30kGy decreased. In addition, the percentage elongation at break of LDPE
      and Ionomer films irradiated at a dose of 30 kGy decreased while Young's modulus
      of all samples remained unaffected. All mechanical properties of PS and EVA films
      remained unaffected after radiation at 30 kGy. Radiation (all absorbed doses)
      resulted in no statistically significant differences in overall migration values
      into distilled water for all studied films. For 3% aqueous acetic acid, absorbed
      doses of 5 and 10 kGy did not affect overall migration values of all investigated
      samples with the exception of the Ionomer film, for which the overall migration
      value decreased at 10 kGy. An absorbed dose of 30 kGy caused an increase in BOPP
      overall migration values and a decrease in Ionomer overall migration values. In
      contrast, a dose of 30 kGy induced no changes in overall migration values of EVA,
      HDPE, LDPE and PS films into the same simulant. There were no statistically
      significant differences in overall migration values of EVA, PS and LDPE films
      into iso-octane for all absorbed doses. In contrast, a dose of 30 kGy resulted in
      an increase in overall migration values of BOPP and a respective decrease in HDPE
      and Ionomer films.

PMID- 12623681
TI  - Migration of surrogate contaminants in paper and paperboard into water through
      polyethylene coating layer.
AB  - The migration of five surrogate contaminants, anthracene, benzophenone, dimethyl
      phthalate, methyl stearate and pentachlorophenol, from paper and paperboard into
      water through a polyethylene (PE) coating layer was investigated. Virgin paper
      and paperboard coated with PE films of 0.012 and 0.030 mm thickness were spiked
      evenly with standard 1-ml solutions containing 5mg of each surrogate. The spiked
      papers were placed in contact with the PE coating layer at 10 and 24 degrees C
      for 21 days. The resulting surrogate migration through the PE layer into 100ml
      water was measured by an analytical method developed here that used gas
      chromatography equipped with a flame ionization detector. Non-polar surrogates of
      anthracene and methyl stearate did not show any significant migration. In the
      case of the thin layer coating of 0.012 mm, polar water-soluble contaminants of
      benzophenone, dimethyl phthalate and pentachlorophenol showed an equilibrated or
      maximized migration after 1 day, even at a refrigerated temperature of 10 degrees
      C. A thick PE coating of 0.030 mm thickness delayed the progress of contaminant
      migration, which was also slower at lower temperature. Our results indicate that
      polyethylene coatings should not be seen as a complete barrier against possible
      contaminants in paper packaging materials under chilled or ambient conditions.
      Several variables such as coating thickness, temperature and suspected
      contaminants need to be considered to control the possible contamination risk
      from recycled or printed paper.

PMID- 12623684
TI  - Barriers to mental health care access in an African American population.
AB  - Emphasis has been placed on understanding the mental health disparities that
      exist within minority populations in the United States. Disparities are of
      particular importance when examining access to services. This paper reports
      findings from a NINR-funded qualitative study that examined the barriers to
      mental health care service use in an African American low-income population.
      Barriers were identified at three levels--Individual, Environmental, and
      Institutional. Fourteen barrier categories were identified within those levels
      with three categories common to the majority of participants. The identified
      categories provide insight into the process of seeking services within this
      population and provide direction for future investigation.

PMID- 12623685
TI  - Nursing in the Native American culture and historical trauma.
AB  - Historical trauma is a significant fact in the Native American community, a fact
      affecting both health status and social milieu. Mental health nurses and other
      persons working in the mental health professions will be confronted over and over
      with historical trauma when working with Native American peoples and communities.
      To heal historical trauma, culturally appropriate strategies derived from the
      ancient knowledge, philosophy, and world view of Native America are needed. One
      tool mental health care providers can use when encountering historical trauma is
      the Conceptual Framework of Nursing in the Native American Culture.

PMID- 12623686
TI  - Effects of in-home training for culturally diverse fathers of children with
      autism.
AB  - Recently there has been mounting interest in the role of fathers and the effect
      of their increasing involvement on child development. However, to date, little
      has been reported regarding the role of fathers with developmentally delayed
      children (e.g., autism, pervasive developmental delays) and cultural influences
      on father-child interactions. In this article we address this knowledge gap by
      reporting four cases representing the major ethnic groups. For each case, we (1)
      define the concept of fatherhood in its cultural context, (2) review and
      summarize related father-child research, and (3) present findings from our study
      evaluating the effects of an in-home intervention for autistic children. While
      variability is noted within and among the culturally diverse father-child dyads,
      there are also similarities across ethnic groups. Results of this study are
      promising, demonstrating the value of single subject experimental methods in
      characterizing and beginning to understand complex father-child interactions in
      autism and related child psychiatric disorders.

PMID- 12623687
TI  - Postpartum depression among African-American women.
AB  - The purpose of this qualitative study was to describe the nature of postpartum
      depression (PPD) among African-American women. Twelve women, who had experienced
      PPD within the last three years, were interviewed for approximately one hour at
      two intervals. Nudist-4 software and the constant comparative method were used to
      analyze the data. Five themes "Stressing Out," "Feeling Down," "Losing It,"
      "Seeking Help," and "Feeling Better" represented aspects of PPD as experienced by
      the participants. The last theme, "Dealing with It," represented the cultural
      ways in which African-American mothers managed their depression. These included
      Keeping the Faith, Trying to Be a Strong Black Woman, Living with Myths, and
      Keeping Secrets. Suggestions for future directions in nursing research are
      included.

PMID- 12623688
TI  - Ethnic identity development: implications for mental health in African-American
      and Hispanic adolescents.
AB  - One of the key tasks of adolescence is identity development. This includes ethnic
      identity, or the aspect of identity related to one's membership in an ethnic
      group. Ethnic identity development has implications for mental health. Those
      adolescents who achieve a secure sense of themselves as ethnic group members have
      higher self-esteem and tend to have better mental health overall. This paper
      reviews the pertinent literature that connects ethnic identity to mental health
      outcomes in African-American and Hispanic adolescents. The relevance to mental
      health nursing is also highlighted.

PMID- 12623690
TI  - Suicide among African Americans: reflections and a call to action.
AB  - Suicide among African Americans is increasing at an alarming rate, and it
      deserves attention from numerous sectors in the society. This paper discusses
      some of the historical issues related to mental health care and African
      Americans. It suggests that sociocultural contexts are significant developmental
      shapers in the lives of African Americans. Several theoretical perspectives on
      suicide are presented, and Durkheim's concept of fatalism is useful in helping to
      unravel the dynamics of suicide. Issues related to the mental health system as
      currently experienced by African Americans conclude the discussion, along with a
      brief list of helpful resources.

PMID- 12623689
TI  - Lifetime physical and sexual abuse, substance abuse, depression, and suicide
      attempts among Native American women.
AB  - Although there is preliminary evidence that violence against women and children
      may be particularly prevalent in some Native American communities, associations
      between abuse and substance abuse, mental health problems, and suicide attempts
      have rarely been studied in this population. This study examined lifetime and
      current physical and sexual abuse among 30 Native American women. Nearly half had
      experienced physical and/or sexual abuse as children, over half were sexually
      abused at some time in their lives, and over three-fourths were abused by a
      partner. All but four women (87%) had experience physical or sexual abuse in
      their lifetime. Significant relationships were found among childhood abuse,
      substance abuse, and adult revictimization, and among cumulative lifetime abuse
      events, substance abuse, and depression. Further research is needed to examine
      abuse and relationships between abuse and health sequelae in Native American
      populations. An accelerated public health and community response is needed to
      address abuse issues in this community.

PMID- 12623692
TI  - Changing the culture of patient safety and medical errors: a symposium
      introduction and overview.

PMID- 12623693
TI  - The end of the beginning: lessons learned from the patient safety movement.

PMID- 12623694
TI  - Benefiting from the "gift of failure": essentials for an event reporting system.

PMID- 12623695
TI  - A therapeutic jurisprudence perspective on legal responses to medical error.

PMID- 12623696
TI  - Resident safety and medical errors in nursing homes: reporting and disclosure in
      a culture of mutual distrust.

PMID- 12623697
TI  - Online pharmaceutical regulation: an avenue to a safer world.

PMID- 12623698
TI  - A proposal for a federal genetic privacy act.

PMID- 12623725
TI  - Cognitive and attentional changes with age: evidence from attentional blink
      deficits.
AB  - The attentional blink (AB) is a marked deficit in detecting a second target for
      up to 600 ms within a rapid serial visual presentation (RSVP). The phenomenon of
      the AB has typically been investigated using college students between 18 and 25
      years of age. However, the AB has not been closely studied within a senior
      population. Past studies have found age-related attentional deficits using cued
      location, visual conjunction search, and divided-attention tasks, all spatial
      measures of attention; however, the physiological basis of these deficits is not
      fully understood. The role of cognitive slowing and reduced attentional resources
      was examined using the AB paradigm--a temporal measure of attention. Experiment 1
      found an age-related deficit independent of lag for the single-task condition and
      a larger more prolonged deficit for dual-task conditions. Experiment 2, using
      similar methods to Experiment 1, incorporated a more rigorous cognitive screen. A
      similar deficit was found for the dual-task condition. However, single-task
      trials appeared to involuntarily capture attentional resources for the older
      population. Comparisons revealed a significant difference in the magnitude and
      the time course of the AB with age. Results are discussed in the context of
      cognitive slowing and reduced attentional resources.

PMID- 12623724
TI  - Divided attention in older but not younger adults is impaired by anxiety.
AB  - It has been hypothesized that the disruptive effects of negative emotional
      states, such as anxiety and depression, may contribute to poorer performance in
      older age. Some studies have reported that higher levels of anxiety are
      associated with poorer cognitive performance in older adults but not younger
      adults. The author examined if age and anxiety interact with performance by
      comparing the performance of normal healthy younger and older adults on cognitive
      and motor tests under conditions of selective and divided attention. Ninety-two
      older adults (mean age=70.1 years, SD=7.1 years) and 78 younger adults (mean
      age=18.8 years, SD=1.9 years), matched on education, vocabulary, and self
      reported health, performed a word-comparison and pursuit-rotor task under
      conditions of selective and divided attention. Anxiety was assessed using the
      Speilberger State-Trait anxiety scale. The hypothesis was supported: higher
      anxiety was associated with poorer divided attention performance in older, but
      not younger, adults. Anxiety was not associated with poorer motor performance in
      older adults. Implications of the results for cognitive-resource theories of
      aging cognition are discussed.

PMID- 12623726
TI  - Impact of stimulus integrity on age differences in letter matching.
AB  - Young and older adults were tested in both a letter-identification and a letter
      matching task in which the integrity of the letter stimuli was manipulated
      through contrast reduction and low-pass spatial frequency filtering. The use of
      the contrast and filtering manipulations was an attempt to increase encoding
      difficulty in an effort to examine whether stimulus integrity impacts more than
      just the initial encoding of the letter pairs in a letter-matching task, namely
      the comparison process as indexed by fast-same and false-different effects. Of
      interest in terms of aging is whether a decline in information-processing
      performance often reported in the aging literature is related to the known
      encoding deficits of older adults. In the letter-identification task, both
      contrast reduction and filtering slowed letter-identification speed for both
      groups, with the effect being larger for the older adults. In the letter-matching
      task, decreased processing efficiency produced by the contrast-reduction and low
      pass-filtering manipulations led to an overall increase in reaction time and
      errors, but it did not interact with the magnitude of the fast-same effect or
      false-different effects for either subject group. These findings suggest that the
      stimulus integrity manipulations only impact the encoding of the letter pairs in
      the matching task and not the comparison process. The results of the present
      study support a dual-process model of the matching task consisting of separate
      encoding and comparison processes. The finding of a larger fast-same effect for
      older adults suggests that the age effect is occurring at the comparison stage,
      but it is not impacted by the stimulus integrity manipulations. The findings are
      described within a generalized slowing framework.

PMID- 12623727
TI  - Aging and fear of crime: an experimental approach to an apparent paradox.
AB  - Many fear of crime studies have revealed an interesting paradox: Although older
      adults are less likely to be victims, they report a higher fear of crime than
      younger adults. In this study, we experimentally manipulated vicarious exposure
      to crime. Younger (ages 18-29) and older adults (ages 61-78) were randomly
      assigned to view either a vivid video reenactment of a violent crime or a crime
      report newscast. Subjects in the violent video condition demonstrated
      significantly higher fear than did control group participants, but this effect
      was reliable only for younger adults. The older adults appeared to be unfazed by
      the violent video, and reported significantly less fear than the younger group.
      This could not be explained away on the basis of age group differences in
      neighborhood crime rates, victimization experience, or media exposure. Thus, when
      greater fear of crime is found in older adults, "old age" per se is not the
      cause.

PMID- 12623728
TI  - Gambling among older adults: a comparative analysis.
AB  - With the spread of gambling in its many forms across the American landscape the
      question arises as to how senior citizens have been effected. This study examines
      data on gambling behavior and related attitudes gathered from a random sample of
      community residents in jurisdictions that had recently allowed casinos to open.
      Comparisons are made between senior and younger adults regarding their gambling
      behaviors. Though the results suggest that casino gambling is not a major threat
      to the elderly it is noted that more extensive research needs to be done to
      assess the individual and social costs and benefits, if any, associated with
      large numbers of the elderly regularly participating in gambling as a social
      activity.

PMID- 12623729
TI  - Balance, muscle strength, and fear of falling in older adults.
AB  - This study examined balance ability, lower-extremity muscle strength, fear of
      falling and their inter-relationships in 40 community-dwelling older adults (>65
      years). Subjects who self-identified either as being fearful of falling or not
      (no concern) were screened to exclude those with known risk factors for falling.
      Limits of stability, maximal isometric strength, gait speed, and fear of falling
      were contrasted between groups (27 control subjects, 13 fearful subjects). Those
      fearful of falling demonstrated smaller center of pressure (COP) excursions in
      anterior, left, and right directions (p<.0001) and used a smaller percentage of
      their base of support during maximal weight shifting in combined anterior
      posterior and right-left directions (p<.001) compared to the control group.
      Strength did not differ between groups, but was associated with the ability to
      shift the COP in the anterior-posterior direction (p<.05). Fear of falling also
      related to weight shifting ability (p<.017). Seniors fearful of falling
      demonstrated limitations in balance ability and balance confidence that could not
      be explained by muscle weakness.

PMID- 12623730
TI  - An examination of perceived stress in family caregivers of older adults with
      heart failure.
AB  - This investigation evaluates the moderating influence of social support on the
      negative effects of stress for family caregivers and validates the Perceived
      Stress Scale as a standard of measurement. Seventy-five family caregivers to
      older adults with heart failure were interviewed in their homes about perceived
      stress, depressive symptoms, and social support after hospital discharge. The
      Perceived Stress Scale demonstrated internal consistency. Social support did not
      moderate the effects of stress on depressive symptoms. Lack of a significant
      association between salivary cortisol and the Perceived Stress Scale did not
      support testing of construct validity. Stress levels, however, frequently vary
      due to caregiving demands and additional influencing factors.

PMID- 12623732
TI  - Chewing tobacco use: perceptions and knowledge in rural adolescent youths.
AB  - The purposes of this pilot study were to describe the incidence of chewing
      tobacco use among rural midwestern adolescents and to describe rural midwestern
      adolescents' perceptions and knowledge about chewing tobacco use. A Smokeless
      Tobacco Use Survey was administered to 34 adolescent subjects who attended 5th
      8th grades in two rural towns. None of the subjects reported trying chewing
      tobacco products. However, a group of male subjects who stated they may chew
      tobacco sometime in the future, performed less well on the test about chewing
      tobacco facts and perceptions of use, indicating some education needs are
      warranted. Risk factors and deterrent factors to using chewing tobacco are
      reported.

PMID- 12623731
TI  - Assessing teasing in school-age youth.
AB  - Teasing, a common childhood behavior and a frequent precursor to bullying, is
      known to affect children's developmental outcomes. Despite its ubiquity, no
      psychometrically valid instrument exists that directly assesses teasing in
      children. This study reports the development and validity of the Physical
      Appearance Related Teasing Scale-Revised (PARTS-R), a 14-item scale. The PARTS-R
      was evaluated using a sample (N = 89) of Arkansas students. Psychometric analysis
      involved item analysis, principal components analysis (PCA) with varimax
      rotation, and internal consistency reliability. Three factors--Forms of
      Harassment, Appearance-Related Teasing, and Physical-Related Teasing--were
      identified and accounted for 57% of the variance, confirming the conceptual
      intent of the instrument. Cronbach's alphas for the factors were.83,.74, and.70,
      respectively. Adequate stability also was demonstrated. Implications for further
      validation work are identified.

PMID- 12623733
TI  - Capturing parents' understanding about the health behaviors they practice with
      their preschool-aged children.
AB  - This qualitative, descriptive study first explored parents' concept of health and
      then examined the health practices they undertook for their preschool-aged
      children. The purposive sample of 11 parent couples and 3 single parents (14
      parent sets in total) with preschool-aged children attending long daycare and
      preschool/kindergarten centers was equally distributed between parents from two
      different socioeconomic groups in two suburbs of western Sydney, Australia.
      Consenting parents were interviewed and transcripts were analyzed concurrently in
      accordance with a grounded theory approach (Glaser Strauss, 1967). Results
      revealed the presence of three themes, and practice implications for community
      nurses stem from them. These themes were Educating About Family Health, The
      Dynamic, Multidimensional Nature of Teaching Child Health Behavior, and The
      Intergenerational Theme. There was only minimal support for health-related
      socioeconomic differences. The study also found that most families with preschool
      aged children were engaged in illness prevention rather than health promotion.
      Unlike those families focused on illness prevention, families focused on a health
      promotion mode were more sophisticated in their educational strategies and used
      more educational strategies associated with developing their child's health
      behaviors. This research validated the importance of the intergenerational
      transmission of values, particularly by mothers. The health behaviors that
      mothers considered important, and that they reinforced with their children, were
      transmitted equally to their daughters and sons.

PMID- 12623734
TI  - Marital and parenting satisfaction and infant care self-efficacy during the
      transition to parenthood: the effect of infant sex.
AB  - The purpose of this follow-up study was to examine the effect of infant sex on
      changes in and differences between parents' reports of infant care self-efficacy
      and parenting and marital satisfaction from 4 months to 12 months after the birth
      of their first child. A convenience sample of 32 couples was selected from 44
      couples who participated in a longitudinal study of the development of parenting
      satisfaction and infant care self-efficacy during the first 4 months after the
      birth of a first child (Brage Hudson, Elek, Fleck, 2001). Couples completed a
      demographic questionnaire, the Infant Care Survey (ICS, Froman Owen, 1989), the
      What Being the Parent of a New Baby is Like--Revised Questionnaire (WPBL-R,
      Pridham Chang, 1989), and the Dyadic Adjustment Scale (DAS, Spanier, 1976, 1989)
      4 and 12 months postpartum. Infant care self-efficacy, but not parenting
      satisfaction, increased from 4 to 12 months; mothers reported higher infant care
      self-efficacy and parenting satisfaction than fathers at both times. Fathers of
      boys reported greater parenting satisfaction and infant care self-efficacy at 12
      months than fathers of girls. Marital satisfaction decreased from 4 to 12 months
      for both mothers and fathers. Significant relationships existed among infant care
      self-efficacy, parenting satisfaction, and marital satisfaction at both 4 and 12
      months postpartum. Implications for families and for nursing interventions are
      discussed.

PMID- 12623735
TI  - Wise and trusted counselor.

PMID- 12623736
TI  - Stress and relapse to drug seeking: studies in laboratory animals shed light on
      mechanisms and sources of long-term vulnerability.
AB  - Relapse is a major characteristic of drug addiction disorders and remains the
      primary problem for treatment. Recently, there has been hope that these disorders
      may be amenable to pharmacological treatments that have successfully treated
      other psychopathological disorders. Pharmacological approaches to drug abuse have
      tended to be guided by the primary drug used by the individual, though
      substitution has been the guiding principle in some instances, as in the case of
      methadone maintenance in opioid addiction. Alternatively, blockade or antagonism
      of the effects of the primary drug being abused has been tried, as in the case of
      using naltrexone to treat opioid or alcohol addiction. Though reportedly
      successful in some populations, it is not clear that these approaches effectively
      control craving for 'highs' or euphoric experiences or a return to drug use as a
      response to stressful life experiences. Recent experimental studies of the
      factors that induce craving and relapse to drug use in both humans and laboratory
      animals, such as drug-related cues, re-exposure to the drug itself, or exposure
      to stressful events, have shown that the effects of these different events are
      mediated by dissociable neurochemical circuitry. Another finding that emerges
      from these studies is that the motivation underlying drug seeking induced by
      events that precipitate relapse is intensified by the duration and amount of pre
      exposure to a drug and the passage of time since withdrawal of the drug. One
      implication of such findings for the treatment of addiction is that whatever
      approach is taken, treatment will have to be multifaceted and maintained over an
      extended period of time after the initial termination of drug use.

PMID- 12623737
TI  - What general psychiatrists ask addiction psychiatrists: a review of 381 substance
      abuse consultations in a psychiatric hospital.
AB  - We reviewed the records of 381 consecutive substance abuse consultations
      completed by the Substance Abuse Consultation Service (SACS) of McLean Hospital
      to ascertain 1) the most frequent reasons why general psychiatrists consulted the
      SACS, and 2) the clinical characteristics of these patients. The most frequent
      reasons for consultation were to make aftercare recommendations (66.1%) or to
      make (19.7%) or clarify (6.3%) a substance use disorder (SUD) diagnosis. Mood
      disorders were the most prevalent co-occurring psychiatric disorder; alcohol use
      disorders were the most prevalent SUDs. The findings indicate the potential
      utility of a substance abuse consultation service in a psychiatric hospital.

PMID- 12623739
TI  - Acupuncture and substance abuse: a synopsis, with indications for further
      research.
AB  - Alcoholism and drug addiction are rampant in our society. Although current
      treatment works better than nothing, the search for more effective interventions
      continues. Incorporating acupuncture into existing programs offers a promising
      approach. Proponents say ear acupuncture alleviates acute opiate withdrawal,
      reduces craving for all substances, and helps retain patients in treatment. Over
      25 years of clinical experience has supported this claim, but scientific research
      has been sketchy, complicated by technical difficulties and often poorly
      designed. This article reviews the literature and offers a neurochemical model
      for future research.

PMID- 12623738
TI  - Coping styles and response to high versus low-structure individual counseling for
      substance abuse.
AB  - We compared outcomes during and after treatment for mixed substance dependent
      patients (N=143) randomly assigned to a high-structure, behaviorally-oriented
      (HSB) or a low-structure, facilitative (LSF) individual counseling style. We
      hypothesized that patients with different coping characteristics would respond
      differently to the two styles of counseling. Patients were treated in once-weekly
      individual HSB or LSF counseling for up to 12 weeks. Outcome measures included
      patient and counselor ratings of benefit, retention, symptom reduction, and
      negative urines; follow-up assessments included control of substance use and
      psychosocial adjustment. While no differences in outcomes during or after
      treatment were found for the HSB and LSF patients, both groups did improve
      equally. Contrary to our hypothesis, our coping measures did not predict
      different outcomes for patients treated in the LSF and HSB styles. Post-hoc
      analyses, however, revealed that outcomes could be predicted in each style from
      patterns of pretreatment characteristics, which included measures of coping
      strategies, psychological characteristics, and treatment readiness. Moreover, the
      patterns associated with positive outcomes were different for the HSB and LSF
      patients: high treatment readiness was most important for success in HSB
      counseling, while low psychiatric severity and positive coping styles were
      important for the LSF clients. The finding of no HSB-LSF outcome differences
      calls into question the exclusive emphasis on behavioral treatment approaches by
      the present-day managed care industry. Also, the traditional approach to matching
      studies, ie, employing one patient characteristic at a time to predict
      differential outcomes for particular treatments, may be simplistic. An
      alternative approach employing multivariate statistical procedures to predict
      outcomes from several patient characteristics may hold more promise.

PMID- 12623740
TI  - Changing trends in heroin-related deaths in Sydney, Australia-1995 to 1999.
AB  - This 1997-1999 study replicates an earlier one (1995-1997) in which coronial
      cases were reviewed at the Department of Forensic Medicine in Australia. Ten
      percent of the 2945 cases were considered accidental illicit drug deaths,
      compared to 4% in the previous study. Heroin was associated with 90% of the
      deaths, but in only 17% of these cases as a single drug. Concomitant drug use, in
      particular alcohol, benzodiazepines, and antidepressants, has increased
      considerably. The combined effects of these substances might play a role in the
      disturbingly large increase in heroin (morphine) related deaths during this
      period.

PMID- 12623741
TI  - Somatization, anxiety and depression in a drug-free residential therapeutic
      community.
AB  - This study aims to assess the nature and prevalence of somatization and related
      psychiatric symptoms among residents in Daytop Village, a drug-free residential
      therapeutic community (TC). Three hundred and twenty two residents at Daytop were
      surveyed, and when compared with a normal, non-patient reference group, residents
      at Daytop exhibited higher levels of somatization, depression, and anxiety as
      measured with the Brief Symptom Inventory. Multiple linear regression analysis
      showed that being widowed or divorced, having marijuana/hallucinogens as greatest
      drug problem, and the importance of a religious figure in entering Daytop were
      associated with higher levels of somatization. A length of stay of 3-6 months and
      acceptance of Daytop program philosophy was inversely correlated with
      somatization scores. These findings are discussed with particular attention
      focused on the role of somatization among TC residents.

PMID- 12623742
TI  - Relationship of tobacco use to depressive disorders and suicidality among
      patients treated for alcohol dependence.
AB  - This population-based, retrospective cohort study examined the association of
      tobacco use and diagnosis of a depressive disorder (DD) and suicide attempts (SA)
      before and after discharge from an inpatient addiction program (IAP). All 813
      Olmsted County, Minnesota residents (537 males, 276 females) admitted for the
      first time to the IAP for treatment of alcoholism during the period 1972-1983
      were studied. Tobacco use status at admission was classified as ever (current or
      former use) (85.5%), never (8.6%), or missing (5.9%). Subjects were followed
      through 1994. Current or former use of tobacco was markedly lower among those
      with a prior diagnosis of DD than those without this diagnosis (73.6% vs. 89.3%,
      p<0.001). Although females were more likely to have a diagnosis of DD and were
      less likely to have ever used tobacco than males, gender did not explain the
      relationship between tobacco use and DD. Tobacco use status was unrelated to a DD
      diagnosis after discharge from the IAP and was not associated with SA.

PMID- 12623743
TI  - Predictors of recovery following involuntary hospitalization of violent substance
      abuse patients.
AB  - The goal of this study was to evaluate the results and predictors of good
      recovery following involuntary hospitalization of violent substance abuse
      patients. Twenty patients (16 male, aged 13 to 53 years [mean+/-s.d.=32.9+/
      10.2]) were admitted in 1997 with a median hospital time of 73.5 days (20 to 455)
      for exhibiting violent behavior following drug abuse and a loss of self-control.
      They were treated with psychiatric medication, a 12-step program (Minnesota),
      psychotherapy and family therapy, and, following hospitalization, counselling,
      psychotherapy, and participation in self-help groups. Follow-up ranged from 3 to
      24 months (17.8+/-4.9). We studied the probability of maintenance of complete
      abstinence and social adaptation (professional-educational, family and legal
      parameters) using T and Fisher tests (significance level p< or =0.05). Of the
      twenty, thirteen patients (65%) achieved excellent social reintegration, and
      twelve maintained total abstinence. Two patients died (AIDS, hepatic cirrhosis).
      The chances of complete abstinence and social reintegration were increased by
      lower age at admission (p=0.02), some form of treatment following hospitalization
      (p=0.007), adherence to the entire period of treatment (p=0.05), and regular
      attendance at self-help groups (p=0.05). No significant differences were found in
      terms of other demographic parameters, drugs used (number or class), previous
      hospital admissions, length of hospitalization, or follow-up. Sixty percent of
      patients can expect an excellent outcome over a period of 18 months, according to
      strict clinical and social criteria. Early intervention and factors increasing
      adherence to prolonged treatment increase abstinence and social reintegration and
      thus should be further explored.

PMID- 12623745
TI  - Glutathione-related enzymes in cell cultures from different regions of human
      epididymis.
AB  - Protection of maturing sperm from potential endogenous or exogenous harmful
      substances during their transit throughout the epididymis is a critical event.
      The authors studied the activity of gamma-glutamyl transpeptidase (GGT) and
      glutathione S-transferase (GST), and glutathione (GSH) levels in epithelial cell
      cultures from human caput, corpus, and cauda epididymides. Tissue was obtained
      from patients undergoing therapeutic orchidectomy for prostatic cancer. Enzymatic
      activity was measured in conditioned media and cellular fractions. Androgen
      influence was also evaluated. Both enzymatic activities were found in cellular
      homogenates and conditioned media from cultures of all epididymal regions. GGT
      activity was highest in cultures from cauda epididymis, both in conditioned media
      and cell fractions, while GST activity did not show regional differences in
      conditioned media, but exhibited higher activity in cell homogenates from cauda
      cultures than those obtained from corpus and caput epididymis. GSH level showed
      no regional difference in cell homogenates and it could not be detected in
      conditioned media by the method used. Presence of different concentrations of
      dihydrotestosterone (DHT) had no influence neither on the enzymatic activities
      nor GSH concentration. The results indicate that GGT and GST are present along
      the human epididymis and a fraction or isoform of these enzymes might be secreted
      to the luminal fluid to play a detoxificative role in sperm maturation.

PMID- 12623744
TI  - Sperm oxidative stress and the effect of an oral vitamin E and selenium
      supplement on semen quality in infertile men.
AB  - Numerous studies have reported beneficial effects of antioxidant drugs on semen
      quality, but there is no well-defined therapeutical protocol in male infertility.
      This study aimed to test the effects of vitamin E and selenium supplementation on
      lipid peroxidation and on sperm parameters. The study included 54 voluntary and
      infertile men who produced semen samples for spermiogram and for
      spectrophotometric measurement of a lipid peroxidation marker, the
      malondialdehyde (MDA), and produced blood samples for high-performance liquid
      chromatography assessment of serum vitamin E level. The trial was randomized and
      open. Twenty-eight men were supplemented daily by vitamin E (400 mg) and selenium
      (225 microg), during 3 months. The remaining 26 patients received vitamin B (4,5
      g/day) for the same duration. Only 20 patients achieved their treatment and
      returned for control analysis. MDA concentrations in sperm were much less than in
      seminal plasma and motility and viability were inversely correlated with semen
      MDA levels. In contrast to vitamin B supplementation, vitamin E and selenium
      supplementation produced a significant decrease in MDA concentrations and an
      improvement of sperm motility. The results confirm the protective and beneficial
      effects of vitamin E and selenium on semen quality and advocate their use in male
      infertility treatment.

PMID- 12623747
TI  - Relation between immunosuppressive PGE(2) and IL-10 to pro-inflammatory IL-6 in
      seminal plasma of infertile and fertile men.
AB  - In vitro studies have reported that seminal plasma of fertile men has more
      inhibitory mitogenic effect and higher suppressive activity on antibody-dependent
      cellular cytotoxicity than seminal plasma from infertile males. Is it possible
      that variations in the seminal plasma composition could explain these results?
      The present study was conducted to investigate the relation between
      immunosuppressive PGE(2) and IL-10 to pro-inflammatory IL-6 in seminal plasma of
      infertile and fertile men. Utilizing specific ELISA commercial kit, semen samples
      from 45 infertile undiagnosed and 25 fertile men were examined for the presence
      of PGE(2), IL-10, and IL-6. The IL-6 concentration in seminal plasma of infertile
      men was significantly higher than that of fertile men (p<.0 4). However, levels
      of IL-10 were lower for the semen of infertile men than that of fertile men
      (p<.04). No differences were observed in PGE(2) concentrations between both
      groups. Increase in pro-inflammatory cytokines, such as IL-6, and decrease in
      immunosuppressive ones, such as IL-10, could alter the tolerance to sperm cell in
      male and female tracts and reduce the favorable conditions to reach the
      fecundation and implantation. It is necessary to conduct further studies that
      include other pro- and anti-inflammatory substances to evaluate the importance of
      the immune balance of semen in human fertility.

PMID- 12623746
TI  - Results and complications of laparoscopic Palomo varicocelecctomy.
AB  - The laparoscopic Palomo varicocelectomy were performed in 38 males with left
      sided varicocele. The mean operation time was 37 (25-56) min. There were no intra
      abdominal visceral or vascular complications during operation. Neither testicular
      atrophy nor recurrence was observed postoperatively. However, hydrocele formation
      was found in two (5.3%) patients. These findings suggest that laparoscopic Palomo
      varicocelectony is a safe and effective procedure for patients with varicocele.

PMID- 12623748
TI  - Isoprenoid pathway dysfunction in human male infertility.
AB  - The isoprenoid pathway produces 3 key metabolites: digoxin (membrane sodium
      potassium ATPase inhibitor and regulator of neurotransmitter transport), dolichol
      (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger).
      The pathway was assessed in patients with human male infertility (oligospermia
      and decreased motility). It was also studied for comparison in patients with
      right hemispheric, left hemispheric, and bihemispheric dominance. The results of
      the study showed that the isoprenoid pathway was upregulated with increased
      digoxin synthesis in all 3 groups of patients. There was also a reduction in
      membrane Na(+)-K(+) ATPase activity and serum magnesium levels. There was an
      increase in tryptophan catabolites and a reduction in tyrosine catabolites. The
      dolichol and glycoconjugate levels increased and lysosomal stability was reduced
      with increased serum lysosomal enzymes in all 3 groups. The ubiquinone levels
      were low and free radicals increased. The cholesterol:phospholipid ratio
      increased and glycoconjugate was reduced in the membrane of these patients. This
      pattern correlated with those in right hemispheric dominance. The significance of
      these factors in the pathogenesis of human male infertility is discussed.

PMID- 12623749
TI  - Change in International Prostate Symptom Score after transurethral prostatectomy
      in Taiwanese men with benign prostate hyperplasia: use of these changes to
      predict the outcome.
AB  - To investigate whether the pre- and postoperative International Prostate Symptom
      Score (IPSS) change predicts the outcome of transurethral prostatectomy in a
      Taiwanese population, 99 patients (transurethral prostatectomy candidates) were
      assessed with the IPSS before and 6-12 months after surgery. All symptoms
      improved significantly postoperatively. Patients with a greater preoperative IPSS
      benefited the most. Improvements in preoperative obstructive symptoms (incomplete
      emptying, intermittency, straining, and weak stream) were greater than those in
      irritable symptoms (urgency, frequency, and nocturia). A significant correlation
      was found between IPSS and quality of life (QOL) before and after transurethral
      prostatectomy. A change of 1 unit on the IPSS scale was found to decrease the QOL
      score 0.282 units. The positive predictive value of a >or=7-IPSS point decrease
      depended on the predictive IPSS criteria applied. When the preoperative IPSS was
      more than 17, the sensitivity was 83.5% and specificity was 30%. Postoperative
      improvement did not differ significantly between acute urinary retention (AUR)
      and non-AUR patients. Change in IPSS of more than 7 points predicted symptomatic
      improvement with high sensitivity. The predictive value depends on the definition
      of significant improvement (magnitude of IPSS change) and on the level of IPSS
      symptoms (sufficient to warrant transurethral prostatectomy).

PMID- 12623750
TI  - Changes in semen quality in Jerusalem between 1990 and 2000: a cross-sectional
      and longitudinal study.
AB  - The aim of the present study was to investigate whether sperm quality has changed
      during the years 1990-1999 among men residing in Jerusalem, Israel, who were
      involved in treatment by intrauterine insemination (IUI). Both cross-sectional
      and longitudinal analyses were performed. A total of 2638 male partners in
      couples that underwent treatment by IUI participated in the cross-sectional
      investigation. Of them, 417 men (16%) were included in the longitudinal study.
      Total sperm counts and percent motility were evaluated on an annual basis to
      assess changes over 10 years from 1990 through 1999. A significant downward trend
      in sperm count and motility was demonstrated in the cross-sectional study. Sperm
      count decreased by 5.2 x 10(6)+/-0.9 x 10(6) (p<.0001) each year and percent
      motility declined by 0.50+/-0.14% (p=.0003). Similar changes were found in the
      longitudinal evaluation, but they were not statistically significant. These data
      suggest that during the last decade in Jerusalem, sperm count and motility
      declined significantly among men involved in infertile relationships and treated
      by IUI.

PMID- 12623751
TI  - Effects of fertilization promoting peptide, adenosine, and pentoxifylline on
      thawed human sperm.
AB  - Fertilization promoting peptide (FPP) and adenosine were demonstrated to be
      potential modulators of sperm capacitation in mammals. Both FPP and adenosine, by
      modulating the adenylate cyclase (AC)/cAMP signaling pathway, elicit similar
      biphasic responses in mammalian sperm (i.e., stimulating capacitation and
      inhibiting spontaneous acrosome loss). Pentoxifylline, an artificial sperm
      stimulant, is clinically used to enhance motility of sperm from infertile men. By
      inhibiting phosphodiesterase, pentoxifylline increases the intracellular cAMP
      level of sperm, and thus contributes to capacitation, hyperactivation, and
      acrosome reaction in animal studies. The effects of FPP, adenosine, and
      pentoxifylline on thawed human sperm are stressed. Chlortetracycline (CTC)
      fluorescence assessment revealed that none of the 3 reagents improved
      fertilization ability of post-thawed sperm. Motility studies with computer-aided
      sperm analyzer (CASA) showed significantly smaller STR (straight-line velocity)
      and LIN (linearity) in the FPP-treated group at 4 h of incubation p<or=005,
      significantly larger VCL in the adenosine-treated group p<or=.05, and
      significantly larger VCL (curvilinear velocity) and smaller LIN in the
      pentoxifylline-treated group p<or=.05. Significant decreases in percentage
      motility were also noted in both FPP and adenosine-treated groups p<or=05. It
      would appear that FPP potentiates fertilizing ability and prevents spontaneous
      acrosome loss, via regulating membrane-bound Na(+)-K(+) ATPase, and/or Ca(2+)
      ATPase, by keeping the sperm intracellular Ca(2+) concentration within the
      physiological range optimal for fertilization.
      adenosinefertilizationFPPpentoxifyllinespermthawing

PMID- 12623752
TI  - Effect of transforming growth factors (TGFalpha and TGFbeta) on human sperm
      chemotactic migration in vitro.
AB  - The effect of transforming growth factors (TGFalpha and TGFbeta) on mouse sperm
      motion chemotactic behavior was examined. In an in vitro model, the number of
      mouse sperm cells migrating to medium containing TGFalpha in concentration 500
      ng/mL were significantly higher than the number migrating to control. This effect
      was observed after 3 and 5 h of incubation. The presence of 100 ng/mL of TGFalpha
      and TGFbeta in concentration 100 and 500 ng/mL in incubation fluid did not cause
      any statistically visible changes on the migration of sperm. Effect of
      combination of both cytokines was similar to influence purely TGFalpha. These
      effects were interpreted as chemotaxis but not chemokinesis of sperm induced by
      influence of this cytokine on membrane receptors. It is suggested that of TGFs
      contained in follicular fluid plays a direct and important role in the process of
      mammalian fertilization.

PMID- 12623753
TI  - Sperm toxicity evaluated by the overnight sperm survival test.
AB  - A subnormal sperm stress test has also been associated with implantation failure
      despite apparently normal fertilization; however, this test is cumbersome and
      time-consuming. The overnight sperm survival test has been considered to possibly
      demonstrate lipid peroxidation abnormalities similar to the sperm stress test.
      The present study evaluated whether lower overnight survival scores were
      associated with lower pregnancy and implantation rates following in vitro
      fertilization-embryo transfer. The results showed no adverse effect of poor
      overnight survival test scores. Possibly, the overnight survival test, though
      similar in some respects to the sperm stress test, is not similar for properties
      of predicting embryo implantation defects. Corroboration that subnormal stress
      tests predicts implantation disorders is needed.

PMID- 12623754
TI  - Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by
      H+/K+ -ATPase inhibitors and other xenobiotics.
AB  - 1. Xenobiotic-mediated regulation of mRNA expression of all members of the human
      cytochrome P450 (CYP) 1 family has been measured by RT-PCR in the hepatoma cell
      line, HepG2. Besides the positive control beta -naphthoflavone, the H(+)/K(+)
      ATPase inhibitors omeprazole, lansoprazole, pantoprazole and rabeprazole and the
      anti-malaria drug primaquine were included in this study. 2. beta-Naphthoflavone,
      primaquine, omeprazole and lansoprazole increased mRNA levels of CYP1A1, CYP1A2
      and CYP1B1. Induction by rabeprazole was significant only for CYP1A1 and CYP1A2,
      whereas none of the CYP1 mRNAs was induced by pantoprazole. This result was
      confirmed in primary human hepatocytes. 3. Transcriptional regulation was proved
      by inhibition of induction with actinomycin D. 4. Increase of CYP1 mRNA was
      significant after 1 h and maximal after 4 h. CYP1B1, but not CYP1A1 or CYP1A2,
      was dramatically down-regulated between 4 and 24 h. This decrease was prevented
      by treatment of cells with actinomycin D after induction, indicating an active
      transcription-dependent mechanism of CYP1B1 mRNA degradation. 5. In conclusion,
      xenobiotics inducing CYP1A1 mRNA expression have been shown also to induce CYP1A2
      and CYP1B1, differing only with regard to level and time course of induction.

PMID- 12623755
TI  - Induction of hepatic cytochrome P450s responsible for the metabolism of
      xenobiotics by nicardipine and other calcium channel antagonists in the male rat.
AB  - 1. The effects of nicardipine and three other calcium channel antagonists,
      nifedipine, diltiazem and verapamil, on hepatic gene expression of cytochrome
      P450s (P450), CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP3A1 and CYP3A2 in male rats were
      examined by an RT-PCR method. 2. Treatment of rats with nicardipine resulted in a
      significant increase in hepatic expression of all the P450 genes examined. Other
      calcium channel antagonists, nifedipine, diltiazem and verapamil, also enhanced
      the gene expression of CYP2B1, CYP2B2, CYP3A1 and CYP3A2, although these showed
      no capacity for activating CYP1A1 and CYP1A2 genes. 3. We have demonstrated for
      the first time that nicardipine activated not only the genes of CYP2B1, CYP2B2,
      CYP3A1 and CYP3A2, but also those of CYP1A1 and CYP1A2 in the rat liver and have
      further suggested that calcium channel antagonists may show a common capacity for
      activating the genes of CYP2B1, CYP2B2, CYP3A1 and CYP3A2. Furthermore, this
      increased expression of P450 genes was demonstrated to contribute to increase in
      the protein level of the corresponding P450s.

PMID- 12623756
TI  - Many P-glycoprotein substrates do not inhibit the transport process across cell
      membranes.
AB  - 1. The critical role of P-glycoprotein (P-gp) in the clinical exposure of many
      pharmaceuticals and toxins has become widely appreciated. The P-gp-mediated
      influence can often be more significant than that of other well-known xenobiotic
      defence enzymes in both breadth and impact. The inhibition of P-gp, therefore,
      has often been examined by testing a compound for its influence on the P-gp
      mediated transport of some marker substrate, often the compound is also evaluated
      for its active efflux mediated by P-gp. 2. Although a substrate for a xenobiotic
      defence enzyme is logically presumed to be an inhibitor of that enzyme toward an
      alternate substrate, that is not necessarily the case with a transmembrane active
      efflux transporter. A substrate that is ejected from the cytosolic side of the
      membrane bilayer that does not rapidly cross the membrane by passive diffusion
      back into the cell interior will not occlude the substrate binding site. Hence,
      some substrates may not significantly affect the overall P-gp function of causing
      a concentration gradient by efficient net transport. A wide variety of compounds
      that are documented as substrates of P-gp are characterized here as having no
      effect on the ability of P-gp to transport several conventional P-gp marker
      substrates. 3. Transbilayer passive diffusion apparently dictates the ability of
      a P-gp substrate to be an inhibitor, as described herein based on relative rates
      of transport (active efflux versus passive re-entry) and the interaction of
      amphipathic compounds with the cell membrane. 4. The portion of P-gp substrates
      whose disposition is dependent on P-gp function and which are not also inhibitors
      is striking. It is therefore important to characterize both the efflux rate
      parameters and those of inhibition. 5. This report affords a valuable list of
      known P-gp substrates that are non-inhibitors.

PMID- 12623757
TI  - CYP2D6-mediated catalysis of tamoxifen aromatic hydroxylation with an NIH shift:
      similar hydroxylation mechanism in chicken, rat and human liver microsomes.
AB  - 1. 4-Tritiated-tamoxifen (4-[(3)H]-tamoxifen) and 4-deuterated-tamoxifen (4
      [(2)H]-tamoxifen) were synthesized to examine tamoxifen metabolism by human P450
      (CYP) forms and also for the possibility of determining tamoxifen-4-hydroxylation
      in humans in vivo. 2. Liver microsomes from several species and cDNA-expressed
      human P450s were incubated with 4-[(3)H]-tamoxifen and the reaction monitored by
      assaying 4-hydroxytamoxifen (4-OH-tam) and (3)H(2)O formed. However, tamoxifen-4
      hydroxylation did not generate stoichiometric amounts of (3)H(2)O and the
      expected unlabelled 4-OH-tam but instead yielded radiolabelled 4-OH-tam,
      apparently from [(3)H]-migration to the ortho-position, referred to as the NIH
      shift. 3. CYP2D6 was the prime catalyst of tam-4-hydroxylation, whereas CYP2B6,
      2C9 and 2C19 yielded only low levels of 4-OH-tam; nevertheless, in all cases the
      4-OH-tam was radioactive, apparently resulting from reactions involving an NIH
      shift. 4. Chicken liver microsomal preparation, being catalytically the most
      active in tamoxifen-4-hydroxylation, was incubated with deuterated tamoxifen (4
      [(2)H]-tamoxifen) in order to determine whether an NIH shift occurs. Ion-trap
      mass-spectrometry of the HPLC-purified 4-OH-tam, from that incubation, indicated
      about 60% of [(2)H]-retention in 4-OH-tam, signifying an NIH shift. These
      findings indicate that the aromatic hydroxylation of tamoxifen does not entail
      hydroxyl insertion with an Sn2-displacement of hydrogen or a hydrogen isotope
      ((2)H or (3)H), but apparently involves epoxidation followed by migration of the
      (3)H, (2)H or (1)H to the ortho-position, and dissociation of the (1)H in
      preference to (3)H or (2)H, i.e. retention of the hydrogen isotope appears to be
      related to the bond strengths: C-(3)H>C-(2)H>C-(1)H.

PMID- 12623758
TI  - Identification of a furazolidone metabolite responsible for the inhibition of
      amino oxidases.
AB  - 1 Furazolidone, a drug widely used in human and veterinary medicine, exhibits
      inhibition of monoamine oxidase activity, as observed in the tissues of a number
      of different animal species, including man. The aim of the current study was to
      determine which of the two possible metabolites, 3-amino-2-oxazolidone (AOZ) or
      beta-hydroxyethylhydrazine (HEH), a well-known carcinogenic compound, is involved
      in the toxicological effects reported. 2 A new spectrometric method was set up to
      differentiate intracellular HEH from AOZ inside cells. This method works well at
      low pH where both AOZ and HEH are free in solution and available to react with
      the chemical chromophore (DAB). 3 The results confirm that furazolidone has to be
      metabolized in the intact cell in order to exhibit mitochondrial monoamine
      oxidase inhibition, whereas AOZ itself is able to exert a reversible monoamine
      oxidase inhibition. AOZ also inhibits bovine serum amino oxidase. On the
      contrary, HEH gives irreversible inhibition of both enzymes. However, the
      reversible nature of the AOZ inhibition with respect to HEH suggests that the two
      metabolites act by different mechanisms which do not require the
      biotransformation of AOZ to HEH. 4 Cell lysates, previously incubated with AOZ,
      were directly analysed and the formation of HEH from AOZ was not detected,
      supporting the conclusion that the amino oxidase inhibition observed on treatment
      with furazolidone was attributable to AOZ and not to HEH.

PMID- 12623759
TI  - Serotonin (5-hydroxytryptamine) glucuronidation in vitro: assay development,
      human liver microsome activities and species differences.
AB  - 1. The main purpose was to develop a high-performance liquid chromatography
      (HPLC)-based method to assay serotonin glucuronidation activity using liver
      microsomal fractions. Application of this method was then demonstrated by
      determining serotonin UDP-glucuronosyltransferase (UGT) enzyme kinetics using
      human liver microsomes and recombinant human UGT1A6. Interspecies differences
      were also evaluated using liver microsomes from 10 different mammalian species.
      2. Incubation of liver microsomes with serotonin, UDP-glucuronic acid and
      magnesium resulted in the formation of a single product peak using HPLC with
      fluorescence and ultraviolet absorbance detection. This peak was confirmed as
      serotonin glucuronide based on sensitivity to beta-glucuronidase and by obtaining
      the expected mass of 352 with positive-ion mass spectrometry. 3. Following a
      preparative HPLC isolation, the structure of this metabolite was established as
      serotonin-5-O-glucuronide by (1)H-NMR spectroscopy. 4. Enzyme kinetic studies
      showed apparent K(m) and V(max) of 8.8 +/- 0.3 mM and 43.4 +/- 0.4 nmoles min(-1)
      mg(-1) protein, respectively, for human liver microsomes, and 5.9 +/- 0.2 mM and
      15.8 +/- 0.2 nmoles min(-1) mg(-1), respectively, for recombinant UGT1A6. 5. The
      order of serotonin-UGT activities in animal liver microsomes was rat > mouse >
      human > cow > pig > horse > dog > rabbit > monkey > ferret. Cat livers showed no
      serotonin-UGT activity. Heterozygous and homozygous mutant Gunn rat livers had 40
      and 13%, respectively, of the activity of the normal Wistar rat, indicating a
      significant contribution by a rat UGT1A isoform to serotonin glucuronidation. 6.
      This assay provides a novel sensitive and specific technique for the measurement
      of serotonin-UGT activity in vitro.

PMID- 12623760
TI  - l-Deprenyl metabolism by the cytochrome P450 system in monkey (Cercopithecus
      aethiops) liver microsomes.
AB  - 1. The aim was to clarify the kinetic and cytochrome P450 (CYP) enzymes involved
      in l-deprenyl metabolism by liver microsomal preparations from African green
      monkeys, an animal model extensively used in the study of Parkinson's disease. 2.
      CYP levels and monoxygenase activities were similar to those observed in
      microsomes from other monkey strains. The enzyme kinetics of both l
      methamphetamine and l-nordeprenyl formation were characterized by a high- and low
      affinity component. For l-methamphetamine, the apparent K(m1) and K(m2) were 1.07
      +/- 0.01 and 350 +/- 2.7 micro M, and V(max1) and V(max2) were 4.70 +/- 0.01 and
      8.9 +/- 0.02 nmol min(-1) mg protein(-1), respectively. For l-nordeprenyl, K(m1)
      and K(m2) were 0.96 +/- 0.05 and 168 +/- 15 micro M, and V(max1) and V(max2) were
      3.34 +/- 0.02 and 3.91 +/- 0.02 nmol min(-1) mg protein(-1), respectively The
      ratio V(max)/K(m) for both metabolites was 2 orders of magnitude higher for the
      low K(m) component than for the high K(m), suggesting that the former component
      is the major determinant of l-deprenyl N-dealkylation. At 15 micro M l-deprenyl,
      both ketoconazole and 8-methoxypsoralen significantly inhibited l-methamphetamine
      and l-nordeprenyl formation, indicating that CYP3A and CYP2A enzymes were
      involved in both reactions. At 500 micro M l-deprenyl, however, inhibition
      studies suggest the involvement of CYP1A and 2D enzymes. 3. The metabolism of l
      deprenyl by monkey liver microsomes is very efficient, indicating that CYP
      dependent metabolism is relevant and could contribute to neuroprotection in
      primate models of Parkinson's disease.

PMID- 12623761
TI  - Pharmacokinetics and tissue distribution of the nonadecapeptide Moli1901 in rats
      and mice.
AB  - 1. Administration of aerosolized, radiolabelled Moli1901 (duramycin, 2622U90), a
      19 amino acid polycyclic peptide, to rats resulted in the deposition of high
      amounts of radiolabel in the respiratory tract, with deposited radiolabel
      persisting almost unchanged through 7 days after dosing. Little to no radiolabel
      was present in the bloodstream of these rats. 2. Rats absorbed little radiolabel
      after p.o. administration, with nearly all of the dose excreted in the faeces by
      2 days after dosing. 3. At 7 days following an intravenous dose, rats excreted
      54% of the radiolabel in faeces and 5.4% in the urine, with 44% remaining in the
      carcass, primarily in the liver (33%). 4. Following an intratracheal instillation
      dose to rats, radiolabel was eliminated from the pulmonary system with a half
      life of 64 days. Excretion was almost exclusively via faeces, with an elimination
      half-life of 52 days. Plasma and blood concentrations in these animals were
      uniformly <1 ng eq. ml(-1) at all sampling times. 5. Results in mice given
      intravenous and oral doses were consistent with those observed in rats. 6.
      Prolonged retention of Moli1901 in pulmonary tissue supports its use in the
      treatment of respiratory diseases.

PMID- 12623762
TI  - Inhibitory effect of troleandomycin on the metabolism of omeprazole is CYP2C19
      genotype-dependent.
AB  - 1. Eighteen healthy CYP2C19 genotyped male subjects were administered a 20-mg
      oral dose of omeprazole (OP) alone or received troleandomycin (TAO) 500 mg daily
      for 2 days before the dose of OP was administered. Blood samples were obtained
      and OP 5-hydroxyomeprazole (5-OH-OP) and OP sulfone in plasma were determined by
      reversed-phase HPLC. 2. The mean C(max), AUC and CL for OP in poor metabolizers
      (PMs) were greater with TAO than without TAO. The C(max) and AUC of 5-OH-OP in
      PMs were significantly (p < 0.05) less with TAO than without TAO. The differences
      in 5-OH-OP between heterozygous extensive metabolizers (EMs) with TAO versus
      without TAO were similar to those observed in PMs, except for the AUC. However,
      in homozygous EMs, there were no statistical differences for the effect of TAO.
      3. The effect of TAO on the metabolism of OP and its two principal metabolites
      differs in different genotype groups of CYP2C19. CYP3A4 not only plays a dominant
      role in the formation of OP sulfone, but also it contributes to the 5
      hydroxylation of OP. Both CYP2C19 and CYP3A contribute to the further elimination
      of 5-OH-OP and OP sulfone.

PMID- 12623763
TI  - Suggestions for improving intimacy in couples in which one partner has attention
      deficit/ hyperactivity disorder.
AB  - Attention-deficit/hyperactivity disorder (AD/HD) is a neurobiological disorder
      that is both hereditary and lifelong. Three types of AD/ HD have been determined:
      hyperactive-impulsive, inattentive, and combined. The hyperactive-impulsive type
      is marked by a lack of self-control; people with this type have a constant need
      for activity and are very impatient. The inattentive type has difficulty paying
      attention, especially to details. The combined type has characteristics of both.
      The goals of this article are to discuss the impact that AD/HD has on couples
      when one partner has the disorder and to offer some suggestions for improving
      intimacy.

PMID- 12623764
TI  - In the mood for sex: the value of androgens.
AB  - Androgen substitution is increasingly being employed to enhance sexual desire in
      women based on the assumption that low androgen levels cause low sexual desire.
      Sexual functioning in women is complex; therefore, decreased sexual interest can
      have various causes. An adequate female sexual biopsychosocial model that
      includes the role of androgens has not yet been developed. Moreover, a higher or
      lower degree of sexual desire does not form a measure for sexual satisfaction.
      One group of women at risk for androgen deficiency are women with
      pathophysiological problems that affect androgen production in the ovaries and/or
      adrenal glands. The available literature indicates that androgen substitution,
      despite leading to supraphysiological androgen levels, improves some aspects of
      sexual functioning, especially in women who have undergone oophorectomy. What
      this means in terms of satisfaction with sexual functioning in these women is not
      clear. We believe that, from an evidence-based point of view, testosterone
      substitution should only be administered as adjuvant treatment to sexological
      counseling in women with low libido in combination with low bioavailable androgen
      levels because of insufficiency of ovarian and/or adrenal function and normal
      estrogen levels. The routine administration of androgens to endocrinologically
      healthy women who have complaints of decreased sexual interest is not based on
      available evidence.

PMID- 12623766
TI  - Prevalence of sexual disorders in those young males who later become drug
      abusers.
AB  - The purpose of this study was to learn about the frequency of sexual disorders in
      young males who later become substance abusers. We interviewed 228 men treated in
      10 drug centers for substance abuse. The questionnaire that we used was designed
      to assess the onset of erectile dysfunction (ED) or of premature ejaculation
      (PE). Only those subjects who became substance users between the ages of 17 to 29
      were taken into consideration. Of the 228 subjects recruited, only 130 met the
      inclusion criteria (mean age 33). These male patients had a prevalence of ED of
      20.3% (cl 99% 12.3-31.2), whereas the prevalence of ED of age-matched males in
      the general population is 2.1% (cl 99% 0.36-5.46; p < 0.000001). The prevalence
      of PE in the sample prior to drug use was 37.5%. Sexual desire was in the normal
      range in nearly all subjects. The prevalence of ED in the men of our sample is
      higher than in age-matched individuals of the general population. These data
      suggest a new hypothesis: sexual disorders or the conviction that one has a
      sexual problem is a possible risk factor among men for drug abuse and addiction.

PMID- 12623765
TI  - Frequency of sexual dysfunction and other reproductive side-effects in patients
      with schizophrenia treated with risperidone, olanzapine, quetiapine, or
      haloperidol: the results of the EIRE study.
AB  - Atypical antipsychotics seem to differ mainly in their tolerability profile. The
      aim of this cross-sectional study, the Estudio de Investigaci n de Resultados en
      Esquizofrenia (Outcomes Research Study in Schizophrenia; EIRE study), was to
      assess in a clinical setting the frequency of several side-effects related to
      haloperidol, risperidone, olanzapine, and quetiapine. This article addresses
      sexual dysfunction and other reproductive side-effects (gynecomastia, menorrhage,
      amenorrhea, and galactorrhea). We recruited outpatients diagnosed with
      schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders
      (DSM-IV; American Psychiatric Association, 1994) criteria and who had received a
      single antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) for at
      least 4 weeks. During a single visit, we collected data, including demographic
      and clinical characteristics, current antipsychotic and concomitant treatment,
      and adverse effects listed in a modified version of the UKU Scale. We used a Chi
      squared test to determine pairs comparisons of the frequency of adverse reactions
      between treatments. To estimate risk of a given adverse reaction with a given
      treatment, we used a logistic regression method. We assessed 636 evaluable
      patients out of 669 recruited. Frequency of sexual dysfunction was high with
      haloperidol (38.1%) and also with olanzapine (35.3%), quetiapine (18.2%), and
      risperidone (43.2%). We found the frequency of other reproductive side-effects to
      be relatively low with all four drugs: haloperidol (6.9%), olanzapine (6.4%),
      quetiapine (2.7%), and risperidone (11.7%). Sexual dysfunction appeared to be
      dose-related with haloperidol, risperidone, and olanzapine. Risperidone and
      olanzapine showed a higher risk of sexual dysfunction and other reproductive
      sideeffects than haloperidol. Quetiapine showed a lower risk of sexual
      dysfunction during short-term treatment (< 12 weeks). However, data on longer
      term treatment (> 12 weeks) are lacking. Our results suggest that none of the
      atypical antipsychotics that we studied significantly improved sexual dysfunction
      and other reproductive side-effects of the conventional antipsychotic,
      haloperidol, in stabilized patients during long-term treatment. Quetiapine
      appears to improve this profile during short-term treatment; however, longterm
      data, with larger samples, are required with this latter drug.

PMID- 12623767
TI  - Factors associated with unwanted pregnancy.
AB  - The purpose of this study was to estimate the proportion of unwanted pregnancies
      (UWPs) and related factors among mothers delivering at all hospitals in Tehran.
      We investigated, in cross-sectional study 6,394 clients, parental age, education
      and occupation, interval of live children pregnancies, and rate of abortion. A
      Chi-square test and Hi-Log linear were used in this study. In this study, 2,443
      (38.2%) of all cases were UWPs, of which 4.6% (n = 297) resorted to abortion (p <
      0.0001). About 38% of all women had no prenatal care. Seventeen percent of the
      women under 20 and 66.2% of those above age 35 had had UWPs (p < 0.0001). Forty
      one percent (n = 2,640) of all cases were illiterate or had primary education and
      28% (n = 1,793) had a high school education or higher (p < 0.0001). Forty-seven
      percent (n = 18) of mothers were workers and 28.1% (n = 147) were employees (p <
      0.0001). Although such variables as age, occupation, level of education, prenatal
      care, family size, and pregnancy interval affect rates of unwanted pregnancy in
      developing countries, regardless of the cause unwanted pregnancy and its negative
      consequences can be prevented by access to health services.

PMID- 12623768
TI  - Modifying sensate focus for use with Haredi (Ultra-Orthodox) Jewish couples.

PMID- 12623769
TI  - The male marital satisfaction following treatment for lower urinary tract
      symptoms.

PMID- 12623772
TI  - Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an
      in situ rat preparation.
AB  - The perfused in situ juvenile rat preparation produces phrenic discharge patterns
      comparable to eupnea and gasping in vivo. These ventilatory patterns of eupnea
      and gasping differ in multiple aspects, including most prominently the rate of
      rise of inspiratory activity. Because gasping, but not eupnea, appeared similar
      after vagotomy in spontaneous breathing preparations, it has been assumed that
      gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In
      the present study, efferent activity of the phrenic nerve was recorded during
      eupnea and gasping in the in situ juvenile rat preparation. Gasping was induced
      in hypoxic-hypercapnia or ischemia. An increase in the pressure of tonic lung
      inflation from 1 to 10 cmH2O caused a prolongation of the duration between
      phrenic bursts in both eupnea or gasping. Bilateral vagotomy eliminated these
      changes. We conclude that the neural substrate mediating the Hering-Breuer reflex
      is retained in the in situ preparation and that the brain stem circuitry
      generating the respiratory patterns responds to tonic activation of pulmonary
      stretch receptors in a similar manner in eupnea and gasping. These findings
      support the homology of eupnea-like phrenic discharge patterns in the reduced in
      situ preparation and eupnea in vivo and disprove the common supposition that
      gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor
      mechanisms.

PMID- 12623773
TI  - Ca2+ uptake and cellular integrity in rat EDL muscle exposed to
      electrostimulation, electroporation, or A23187.
AB  - We tested the hypothesis that increased Ca2+ uptake in rat extensor digitorum
      longus (EDL) muscle elicits cell membrane damage as assessed from release of the
      intracellular enzyme lactate dehydrogenase (LDH). This was done by using 1)
      electrostimulation, 2) electroporation, and 3) the Ca2+ ionophore A23187.
      Stimulation at 1 Hz for 120-240 min caused an increase in 45Ca uptake that was
      closely correlated to LDH release. This LDH release increased markedly with
      temperature. After 120 min of stimulation at 1 Hz, resting 45Ca uptake was
      increased 5.6-fold compared with unstimulated muscles. This was associated with
      an eightfold increase in LDH release, and this effect was halved by lowering
      extracellular Ca2+ concentration ([Ca2+]o). The poststimulatory increase in
      resting 45Ca uptake persisted for at least 120 min. An acute increase in
      sarcolemma leakiness induced by electroporation markedly increased 45Ca uptake
      and LDH leakage. Both effects depended on [Ca2+]o. A23187 increased 45Ca uptake.
      Concomitantly, LDH leakage increased 18-fold within 30 min, and this effect was
      abolished by omitting Ca2+ from the buffer. We conclude that increased Ca2+
      influx may be an important cause of cell membrane damage that arises during and
      after exercise or electrical shocks. Because membrane damage allows further
      influx of Ca2+, this results in positive feedback that may further increase
      membrane degeneration.

PMID- 12623774
TI  - The spleen modulates the febrile response of guinea pigs to LPS.
AB  - The febrile responses of splenectomized (Splex) or sham-operated (Sham) guinea
      pigs challenged intravenously or intraperitoneally with lipopolysaccharide (LPS)
      7 and 30 days after surgery were evaluated. FITC-LPS uptake by Kupffer cells (KC)
      was additionally assessed 15, 30, and 60 min after injection. LPS at 0.05
      microg/kg iv did not evoke fever in Sham animals but caused a 1.2 degrees C core
      temperature (T(c)) rise in the Splex animals. LPS at 2 microg/kg iv induced a 1.8
      degrees C greater T(c) rise of the Splex animals than of their controls. LPS at 2
      and 8 microg/kg ip 7 days postsurgery induced 1.4 and 1.8 degrees C higher
      fevers, respectively, in the Splex than Sham animals. LPS at 2 and 8 microg/kg ip
      30 days postsurgery also increased the febrile responses of the asplenic animals
      by 1.6 and 1.8 degrees C, respectively. FITC-LPS at 7 days was detected in the
      controls within KC 15 min after its administration; the label density was reduced
      at 30 min and almost 0 at 60 min. In the Splex group, in contrast, the labeling
      was significantly denser and remained unchanged through all three time points;
      this effect was still present 30 days after surgery. Similar results were
      obtained at 60 min after FITC-LPS intraperitoneal injection. Gadolinium chloride
      pretreatment (-3 days) of the Splex group significantly reduced both their
      febrile responses to LPS (8 microg/kg ip) and their KC uptake of FITC-LPS 7 days
      postsurgery. Thus splenectomy increases the magnitude of the febrile response of
      guinea pigs and the uptake of systemically administered LPS.

PMID- 12623775
TI  - Intensity-dependent thermoregulatory responses at the onset of dynamic exercise
      in mildly heated humans.
AB  - To investigate quantitatively how sweating and cutaneous blood flow responses at
      the onset of dynamic exercise are affected by increasing exercise intensity in
      mildly heated humans, 18 healthy male subjects performed cycle exercise at 30,
      50, and 70% of maximal O2 uptake (VO2 max) for 60 s in a warm environment. The
      study was conducted in a climatic chamber with a regulated ambient temperature of
      35 degrees C and relative humidity of 50%. The subjects rested in the semisupine
      position in the chamber for 60 min, and then sweating rate (SR) and skin blood
      flow were measured during cycle exercise at three different intensities. Changes
      in the heart rate, rating of perceived exertion, and mean arterial blood pressure
      were proportional to increasing exercise intensity, whereas esophageal and mean
      skin temperatures were essentially constant throughout the experiment. The SR on
      the chest, forearm, and thigh, but not on the palm, increased significantly with
      increasing exercise intensity (P < 0.05). The mean SR of the chest, forearm, and
      thigh increased 0.05 mg.cm-2.min-1 with an increase in exercise intensity
      equivalent to 10% VO2 max. On the other hand, the cutaneous vascular conductance
      (CVC) on the chest, forearm, and palm decreased significantly with increasing
      exercise intensity (P < 0.05). The mean CVC of the chest and forearm decreased
      5.5% and the CVC on the palm decreased 8.0% with an increase in exercise
      intensity equivalent to 10% VO2 max. In addition, the reduction in CVC was
      greater on the palm than on the chest and forearm at all exercise intensities (P
      < 0.01). We conclude that nonthermal sweating and cutaneous blood flow responses
      are exercise intensity dependent but directionally opposite at the onset of
      dynamic exercise in mildly heated humans. Furthermore, cutaneous blood flow
      responses to increased exercise intensity are greater in glabrous (palm) than in
      nonglabrous (chest and forearm) skin.

PMID- 12623776
TI  - A cyclooxygenase-2 inhibitor attenuates spontaneous and TNF-alpha-induced non
      rapid eye movement sleep in rabbits.
AB  - Sleep is regulated in part by the brain cytokine network, including tumor
      necrosis factor-alpha (TNF-alpha). TNF-alpha activates the transcription factor
      nuclear factor-kappaB, which in turn promotes transcription of many genes,
      including cyclooxygenase-2 (COX-2). COX-2 is in the brain and is an enzyme
      responsible for production of prostaglandin D2. The hypothesis that central COX-2
      plays a role in the regulation of spontaneous and TNF-alpha-induced sleep was
      investigated. Three doses (0.5, 5, and 50 microg) of NS-398, a highly selective
      COX-2 inhibitor, were injected intracerebroventricularly. The highest dose
      decreased non-rapid eye movement sleep. The intermediate and highest doses
      decreased electroencephalographic slow-wave activity; the greatest reduction
      occurred after 50 microg of NS-398 during the first 3-h postinjection period.
      Rapid eye movement sleep and brain temperature were not altered by any dose of NS
      398. Pretreatment of rabbits with 5 or 50 microg of NS-398 blocked the TNF-alpha
      induced increases in non-rapid eye movement sleep, electroencephalographic slow
      wave activity, and brain temperature. These data suggest that COX-2 is involved
      in the regulation of spontaneous and TNF-alpha-induced sleep.

PMID- 12623778
TI  - Frequency characteristics of long-term heart rate variability during constant
      routine protocol.
AB  - The effects of such behavioral factors as physical activity, food intake, and
      circadian rhythm on long-term heart rate variability (HRV) in humans remain
      poorly understood. We therefore studied their effects on HRV using a constant
      routine protocol that included simultaneous core body temperature (CBT)
      correction. Seven healthy subjects completed the constant-routine and daily
      routine protocols, during which HRV and CBT were continuously monitored. During
      the constant routine, subjects were kept awake for 27 h in a semirecumbent
      posture with minimal physical activity; small isocaloric meals were provided
      every 2 h. During the daily routine, subjects carried on their lives normally.
      Data were analyzed using generic spectral analysis based on a fast Fourier
      transform; coarse-graining spectral analysis was also used to eliminate
      periodicity due to the regular meals for raw HRV and for the CBT-corrected HRV
      without circadian and/or low-frequency ultradian components. The results showed
      that 1) the power spectra of HRV in the constant routine and daily routine had
      similar power-law scalings at frequencies above approximately 10(-3.5) Hz, while
      2) below that crossover frequency, HRV was smaller in the constant routine than
      in the daily routine, with the difference becoming significant (P < 0.05) at <10(
      4) Hz, 3) coarse-graining spectral analysis eliminated diet-induced peaks in
      generic spectral analysis-based HRV spectra during the constant routine and
      emphasized the crossover at approximately 10(-3.5) Hz, and 4) CBT correction did
      not alter the results. Below a frequency of approximately 10(-3.5) Hz (a period
      >1 h), HRV is strongly influenced by behavioral factors; above that crossover
      frequency, HRV is behavior independent, possibly reflecting an intrinsic
      regulatory system.

PMID- 12623777
TI  - Elevated dietary salt suppresses renin secretion but not thirst evoked by
      arterial hypotension in rats.
AB  - Increased dietary salt intake was used as a nonpharmacological tool to blunt
      hypotension-induced increases in plasma renin activity (PRA) in order to evaluate
      the contribution of the renin-angiotensin system (RAS) to hypotension-induced
      thirst. Rats were maintained on 8% NaCl (high) or 1% NaCl (standard) diet for at
      least 2 wk, and then arterial hypotension was produced by administration of the
      arteriolar vasodilator diazoxide. Despite marked reductions in PRA, rats
      maintained on the high-salt diet drank similar amounts of water, displayed
      similar latencies to drink, and had similar degrees of hypotension compared with
      rats maintained on the standard diet. Furthermore, blockade of ANG II production
      by an intravenous infusion of the angiotensin-converting enzyme inhibitor
      captopril attenuated the hypotension-induced water intake similarly in rats fed
      standard and high-salt diet. Additional experiments showed that increases in
      dietary salt did not alter thirst stimulated by the acetylcholine agonist
      carbachol administered into the lateral ventricle; however, increases in dietary
      salt did enhance thirst evoked by central ANG II. Collectively, the present
      findings suggest that hypotension-evoked thirst in rats fed a high-salt diet is
      dependent on the peripheral RAS despite marked reductions in PRA.

PMID- 12623779
TI  - Effect of NO synthase inhibition on myocardial metabolism during moderate
      ischemia.
AB  - Nitric oxide (NO) is involved in the control of myocardial metabolism. In
      normoperfused myocardium, NO synthase inhibition shifts myocardial metabolism
      from free fatty acid (FFA) toward carbohydrate utilization. Ischemic myocardium
      is characterized by a similar shift toward preferential carbohydrate utilization,
      although NO synthesis is increased. The importance of NO for myocardial
      metabolism during ischemia has not been analyzed in detail. We therefore assessed
      the influence of NO synthase inhibition with N(G)-nitro-l-arginine (l-NNA) on
      myocardial metabolism during moderate ischemia in anesthetized pigs. In control
      animals, the increase in left ventricular pressure with l-NNA was mimicked by
      aortic constriction. Before ischemia, l-NNA decreased myocardial FFA consumption
      (MV(FFA); P < 0.05), while consumption of carbohydrate and O(2) (MVo(2)) remained
      constant. ATP equivalents [calculated with the assumption of complete oxidative
      substrate decomposition (ATP(eq))] decreased with l-NNA (P < 0.05), associated
      with a decrease of regional myocardial function (P < 0.05). In contrast, aortic
      constriction had no effect on MV(FFA), while MVo(2) increased (P < 0.05) and
      ATP(eq) and regional myocardial function remained constant. During ischemia,
      alterations in myocardial metabolism were similar in control and l-NNA-treated
      animals: MV(FFA) decreased (P < 0.05) and net lactate consumption was reversed to
      net lactate production (P < 0.05). Regional myocardial function was decreased (P
      < 0.05), although more markedly in animals receiving l-NNA (P < 0.05). We
      conclude that the efficiency of oxidative metabolism was impaired by l-NNA per
      se, paralleled by impaired regional myocardial function. During ischemia, l-NNA
      had no effect on myocardial substrate consumption, indicating that NO synthases
      were no longer effectively involved in the control of myocardial metabolism.

PMID- 12623780
TI  - PPAR-alpha effects on the heart and other vascular tissues.
AB  - Peroxisome proliferator-activated receptor (PPAR)-alpha is a member of a large
      nuclear receptor superfamily whose main role is to activate genes involved in
      fatty acid oxidation in the liver, heart, kidney, and skeletal muscle. While
      currently used mainly as hypolipidemic agents, the cardiac effects and anti
      inflammatory actions of PPAR-alpha agonists in arterial wall cells suggest other
      potential cardioprotective and antiatherosclerotic effects of these agents. This
      review summarizes current knowledge regarding the effects of PPAR-alpha agonists
      on lipid and lipoprotein metabolism, the heart, and the vessel wall and
      introduces some of the insights gained in these areas from studying PPAR-alpha
      deficient mice. The introduction of new and more potent PPAR-alpha agonists will
      provide important insights into the overall benefits of activating PPAR-alpha
      clinically for the treatment of dyslipidemia and prevention of vascular disease.

PMID- 12623781
TI  - Mechanism of glutamate stimulation of CO production in cerebral microvessels.
AB  - Dilation of piglet pial arterioles to glutamate involves carbon monoxide (CO)
      produced from heme by heme oxygenase-2 (HO-2). Piglet cerebral microvessels and
      endothelial and smooth muscle cells grown on microcarrier beads were used to
      address the hypothesis that glutamate increases endothelial CO production by
      increasing HO-2 catalytic activity. CO was measured by gas chromatography/mass
      spectrometry. Glutamate increased CO production from endogenous heme by cerebral
      microvessels, endothelial cells, and smooth muscle cells. Glutamate increased the
      conversion of exogenous heme to CO. Protein tyrosine kinase inhibition blocked
      glutamate stimulation of CO production. Inhibition of protein tyrosine
      phosphatases stimulated CO production. Conversely, neither phorbol myristate
      acetate nor H-7 changed glutamate stimulation of CO production. The mechanism of
      HO-2 stimulation by glutamate appears to be independent of cytosolic Ca, because
      stimulation of CO production by glutamate was the same in Careplete medium, Ca
      free medium with ionomycin, and Careplete medium with ionomycin. Therefore,
      glutamate appears to increase HO-2 catalytic activity in cerebral microvessels
      via a tyrosine kinase mediated pathway.

PMID- 12623782
TI  - Regional gap junction inhibition increases defibrillation thresholds.
AB  - It is clear that ischemia inhibits successful defibrillation by altering regional
      electro-physiology. However, the exact mechanisms are unclear. This study
      investigated whether regional gap junction inhibition increases biphasic shock
      defibrillation thresholds (DFT). Sixteen swine were instrumented with a mid-left
      anterior descending (LAD) perfusion catheter for regional infusion of 0.5 mM/h
      heptanol (n = 8) or saline (n = 8). DFT values and effective refractory periods
      (ERP) at five myocardial sites were determined. Regional conduction velocity (CV)
      was determined in an LAD drug-perfused and nondrug-perfused region in an
      additional seven swine. Regional heptanol infusion increased 50% DFT values by
      33% (P = 0.01) and slowed CV by 42-59% (P < 0.01) but did not affect ERP.
      Regional heptanol also increased CV dispersion by approximately 270% (P < 0.05)
      but did not change ERP dispersion. Regional placebo did not alter any of these
      parameters. Furthermore, regional heptanol infusion induced spontaneous
      ventricular fibrillation in eight of eight animals. Increasing spatial conduction
      velocity dispersion by impairing regional gap junction conductance increased DFT
      values. Dispersion in conduction velocity slowing during regional ischemia may be
      an important determinant of defibrillation efficacy.

PMID- 12623783
TI  - Diazoxide triggers cardioprotection against apoptosis induced by oxidative
      stress.
AB  - Although mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels have been
      reported to reduce the extent of apoptosis, the critical timing of mitoK(ATP)
      channel opening required to protect myocytes against apoptosis remains unclear.
      In the present study, we examined whether the mitoK(ATP) channel serves as a
      trigger of cardioprotection against apoptosis induced by oxidative stress.
      Apoptosis of cultured neonatal rat cardiomyocytes was determined by flow
      cytometry (light scatter and propidium iodide/annexin V-FITC fluorescence) and by
      nuclear staining with Hoechst 33342. Mitochondrial membrane potential (DeltaPsi)
      was measured by flow cytometry of cells stained with rhodamine-123 (Rh-123).
      Exposure to H(2)O(2) (500 microM) induced apoptosis, and the percentage of
      apoptotic cells increased progressively and peaked at 2 h. This H(2)O(2)-induced
      apoptosis was associated with the loss of DeltaPsi, and the time course of
      decrease in Rh-123 fluorescence paralleled that of apoptosis. Pretreatment of
      cardiomyocytes with diazoxide (100 microM), a putative mitoK(ATP) channel opener,
      for 30 min before exposure to H(2)O(2) elicited transient and mild depolarization
      of DeltaPsi and consequently suppressed both apoptosis and DeltaPsi loss after 2
      h exposure to H(2)O(2). These protective effects of diazoxide were abrogated by
      the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) but not by the
      sarcolemmal K(ATP) channel blocker HMR-1098 (30 microM). Our results suggest for
      the first time that diazoxide-induced opening of mitoK(ATP) channels triggers
      cardioprotection against apoptosis induced by oxidative stress in rat
      cardiomyocytes.

PMID- 12623784
TI  - Regulation of CO production in cerebral microvessels of newborn pigs.
AB  - Carbon monoxide (CO) is produced from heme by heme oxygenase-2 (HO-2) in cerebral
      blood vessels. Gas chromatography-mass spectrometry was used on piglet cerebral
      microvessels to address the hypothesis that CO production is regulated by heme
      delivery and HO-2 catalytic activity. CO production appears to be substrate
      limited because heme and its precursor aminolevulinate increase CO production.
      Ionomycin also increases CO production. However, CO production from exogenous
      heme was the same in Ca-replete medium, Ca-free medium with ionomycin, and Ca
      replete medium with ionomycin. Phorbol myristate acetate increases CO production
      but does not change the catalytic activity of HO-2. Also, the protein kinase C
      inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine has no effect on the HO
      2 catalytic activity. Protein tyrosine kinase inhibition reduces HO-2 catalytic
      activity. Inhibition of protein tyrosine phosphatases increased HO-2 catalytic
      activity. Therefore, regulation of CO production by cerebral microvessels can
      include changing heme availability and HO-2 catalytic activity. HO-2 catalytic
      activity is stimulated by tyrosine phosphorylation.

PMID- 12623785
TI  - Cytochrome p-450 epoxygenase products contribute to attenuated vasoconstriction
      after chronic hypoxia.
AB  - The systemic vasculature exhibits attenuated vasoconstriction following chronic
      hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle
      (VSM) cell hyperpolarization. We hypothesized that increased production of
      arachidonic acid metabolites such as the cyclooxygenase product prostacyclin or
      cytochrome p-450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs)
      contributes to VSM cell hyperpolarization following CH. VSM cell resting membrane
      potential (Em) was measured in superior mesenteric artery strips isolated from
      rats with control barometric pressure (Pb, congruent with 630 Torr) and CH (Pb,
      380 Torr for 48 h). VSM cell Em was normalized between groups following
      administration of the CYP inhibitors 17-octadecynoic acid and SKF-525A. VSM cell
      hyperpolarization after CH was not altered by cyclooxygenase inhibition, whereas
      the selective CYP2C9 inhibitor sulfaphenazole normalized VSM cell Em between
      groups. Iberiotoxin also normalized VSM cell Em, which suggests that large
      conductance, Ca2+-activated K+ (BKCa) channel activity is increased after CH.
      Sulfaphenazole administration restored phenylephrine-induced and myogenic
      vasoconstriction and Ca2+ responses of mesenteric resistance arteries isolated
      from CH rats to control levels. Western blot experiments demonstrated that CYP2C9
      protein levels were greater in mesenteric arteries from CH rats. In addition,
      11,12-EET levels were elevated in endothelial cells from CH rats compared with
      controls. We conclude that enhanced CYP2C9 expression and 11,12-EET production
      following CH contributes to BKCa channel-dependent VSM cell hyperpolarization and
      attenuated vasoreactivity.

PMID- 12623786
TI  - 15-deoxy-delta 12,14-prostaglandin J2 and laminar fluid shear stress stabilize c
      IAP1 in vascular endothelial cells.
AB  - Laminar shear stress strongly inhibits vascular endothelial cell apoptosis by
      unknown mechanisms. We reported that shear stress stimulates endothelial cells to
      produce 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) by elevating the
      expression level of lipocalin-type prostaglandin D synthase. To investigate the
      role of 15d-PGJ2 produced in the vascular wall, we examined the effect of 15d
      PGJ2 on endothelial cell apoptosis. We induced apoptosis in human umbilical vein
      endothelial cells (HUVECs) by growth factor deprivation. 15d-PGJ2 strongly
      inhibited DNA ladder formation, nuclear fragmentation, and caspase-3-like
      activity in HUVECs. To elucidate the mechanism by which 15d-PGJ2 inhibits
      endothelial cell apoptosis, we examined expression of the inhibitor of apoptosis
      proteins (IAP) cellular-IAP1 (c-IAP1), c-IAP2, x-linked IAP, and survivin in
      HUVECs. In parallel with the inhibition of apoptosis, 15d-PGJ2 elevated the
      expression level of c-IAP1 protein in a dose- and time-dependent manner without
      changing the mRNA level. Laminar shear stress also induced c-IAP1 expression.
      Chase experiments with the use of cycloheximide revealed that 15d-PGJ2 and shear
      stress both inhibited the proteolytic degradation of c-IAP1 protein. These
      results suggested that 15d-PGJ2 inhibits endothelial cell apoptosis through, at
      least in part, c-IAP1 protein stabilization. This mechanism might be involved in
      the antiapoptotic effect of laminar shear stress.

PMID- 12623787
TI  - Intramuscular gene transfer of FGF-2 attenuates endothelial dysfunction and
      inhibits intimal hyperplasia of vein grafts in poor-runoff limbs of rabbit.
AB  - We previously demonstrated that sustained disturbance of endothelium-dependent
      vasorelaxation and poor distal runoff in ischemic limbs were critical factors
      affecting the neointimal development of autologous vein grafts (VGs). Also, we
      recently showed the superior therapeutic potential of basic fibroblast growth
      factor (bFGF/FGF-2) boosted by the recombinant Sendai virus (SeV) for severe limb
      ischemia compared with that of vascular endothelial growth factor. Here, the
      effect of FGF-2 on neointimal hyperplasia of VGs was examined in a rabbit model
      of poor-runoff limbs. Two weeks after initial surgery for the induction of poor
      runoff, SeV-expressing human FGF-2 (SeV-hFGF2) or that encoding firefly
      luciferase (109 plaque-forming units/head) was injected into the thigh and calf
      muscle. At that time, the femoral vein was implanted in the femoral artery in an
      end-to-end manner in some groups. FGF-2 gene-transferred limbs demonstrated
      significantly increased blood flow assessed not only by laser Doppler flow image
      but also by ultrasonic transit-time flowmeter (USTF). USTF also showed a
      significant increase in the blood flow ratio of the deep femoral artery to
      external iliac artery, indicating that collateral flow was significantly restored
      in the thigh muscles (P < 0.01). Reduction of neointimal hyperplasia was also
      observed in the VGs treated by SeV-hFGF2; these grafts demonstrated significant
      restoration of endothelium-dependent vasorelaxation. These findings thus extend
      the indications of therapeutic angiogenesis using SeV-hFGF2 to include not only
      limb salvage but also prevention of late graft failure.

PMID- 12623788
TI  - Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2
      release, and enhances K+ transport.
AB  - Ischemic preconditioning, or the protective effect of short ischemic episodes on
      a longer, potentially injurious, ischemic period, is prevented by antagonists of
      mitochondrial ATP-sensitive K+ channels (mitoKATP) and involves changes in
      mitochondrial energy metabolism and reactive oxygen release after ischemia.
      However, the effects of ischemic preconditioning itself on mitochondria are still
      poorly understood. We determined the effects of ischemic preconditioning on
      isolated heart mitochondria and found that two brief (5 min) ischemic episodes
      are sufficient to induce a small but significant decrease ( approximately 25%) in
      mitochondrial NADH-supported respiration. Preconditioning also increased
      mitochondrial H2O2 release, an effect related to respiratory inhibition, because
      it is not observed in the presence of succinate plus rotenone and can be mimicked
      by chemically inhibiting complex I in the presence of NADH-linked substrates. In
      addition, preconditioned mitochondria presented more substantial ATP-sensitive K+
      transport, indicative of higher mitoKATP activity. Thus we directly demonstrate
      that preconditioning leads to mitochondrial respiratory inhibition in the
      presence of NADH-linked substrates, increased reactive oxygen release, and
      activation of mitoKATP.

PMID- 12623789
TI  - Functional reentry in cultured monolayers of neonatal rat cardiac cells.
AB  - Previous studies of reentrant arrhythmias in the heart have been performed in
      computer models and tissue experiments. We hypothesized that confluent monolayers
      of cardiac cells can provide a simple, controlled, and reproducible experimental
      model of reentry. Neonatal rat ventricular cells were cultured on 22-mm-diameter
      coverslips and stained with the voltage-sensitive dye RH-237. Recordings of
      transmembrane potentials were obtained from 61 sites with the use of a contact
      fluorescence imaging system. An electrical field stimulus, followed by a point
      stimulus, induced 39 episodes of sustained reentry and 21 episodes of
      nonsustained reentry. Sustained reentry consisted of single-loop (n = 18
      monolayers) or figure-of-eight (n = 4) patterns. The cycle length, action
      potential duration at 80% repolarization, and conduction velocity were (in means
      +/- SE) 358 +/- 33 ms, 118 +/- 12 ms, and 12.9 +/- 1.0 cm/s for single loop and
      311 +/- 78 ms, 137 +/- 18 ms, and 7.8 +/- 1.3 cm/s for figure-of-eight,
      respectively. Electrical termination by 6- to 13-V/cm field pulses or 15- to 20-V
      point stimuli was successful in 60% of the attempts. In summary, highly stable
      reentry can be induced, sustained for extensive periods of time, and electrically
      terminated in monolayers of cultured neonatal rat cardiac myocytes.

PMID- 12623791
TI  - Rheological properties of the blood influencing selectin-mediated adhesion of
      flowing leukocytes.
AB  - We studied how the rheological properties of blood influenced capture and rolling
      adhesion of leukocytes as well as their margination in the bloodstream. When
      citrated, fluorescently labeled blood was perfused through glass capillaries
      coated with P-selectin, leukocytes formed numerous rolling attachments. The
      number of attached leukocytes increased as the hematocrit was increased between
      10% and 30% and was essentially constant from 30% to 50%. In EDTA-treated blood,
      adhesion was absent, and the flux of marginated cells varied little with
      increasing hematocrit. However, the velocity of marginated leukocytes increased
      monotonically, whereas the volumetric flow rate was constant, implying that the
      flow velocity profile became blunted and wall shear rate increased. Thus
      increasing hematocrit promoted attachment for a given total flow rate, without
      increasing margination, even though wall shear rate and blood viscosity
      increased. Blood was diluted to 20% hematocrit with plasma, 40-kDa dextran (to
      reduce red blood cell aggregation), or 500-kDa dextran (to enhance aggregation).
      Increasing aggregation correlated with increasing leukocyte adhesion and with
      more slow-flowing leukocytes near the wall. Thus flowing erythrocytes promote
      leukocyte adhesion, either by causing margination of leukocytes or by initiating
      and stabilizing attachments that follow.

PMID- 12623790
TI  - Reduction of myocardial infarct size by fluvastatin.
AB  - Statins have a variety of cardioprotective properties following chronic
      treatment. In contrast, little is known about the acute effects. Reperfusion
      acutely injures the heart by activation of neutrophils as well as endothelial
      cells. Because statins are known to influence the processes pathogenetically
      involved, we hypothesized that acute application of statins attenuates the
      sequelae of cardiac reperfusion. In rats, myocardial infarction (MI) was induced
      by ligature of the left coronary artery followed by reperfusion. Myocardial blood
      flow (MBF) was determined by H2 clearance and regional myocardial function
      (fractional thickening, FT) by pulsed Doppler. MI size was measured by
      triphenyltetrazolium chloride (TTC) staining, neutrophil extravasation by
      determination of myeloperoxidase (MPO) activity, and nitric oxide generation via
      measurement of cGMP. Treatment with fluvastatin, administered intravenously 20
      min before the onset of ischemia, significantly attenuated the decline of FT and
      MBF at the end of the reperfusion period and significantly reduced MI size.
      Furthermore, fluvastatin induced a significant reduction of MPO activity and an
      increase of cGMP level compared with the control group. The effect of fluvastatin
      was completely abolished following pretreatment of NG-nitro-l-arginine methyl
      ester (l-NAME). These findings suggest that acute application of fluvastatin
      reduces MI size and attenuates reperfusion injury. We propose that the underlying
      mechanism is at least partially an inhibition of inflammation and endothelial
      dysfunction by preventing the activation and extravasation of neutrophils.

PMID- 12623792
TI  - Attenuation of activity-induced increases in cerebellar blood flow in mice
      lacking neuronal nitric oxide synthase.
AB  - We used mice deficient in neuronal nitric oxide (NO) synthase (nNOS) to
      specifically investigate the role of neuronal NO in the increase of cerebellar
      blood flow (BFcrb) produced by neural activation. Crus II, a region of the
      cerebellar cortex that receives trigeminal sensory afferents, was activated by
      low-intensity stimulation of the upper lip (5-25 V, 4-16 Hz) in anesthetized
      mice. BFcrb was recorded in Crus II by using a laser-Doppler flow probe. In wild
      type mice, upper lip stimulation increased BFcrb in the Crus II by 28 +/- 3% (25
      V, 10 Hz, n = 6). The rise in BFcrb was attenuated by 73 +/- 3% in nNOS-/- mice
      (P < 0.05, n = 6). The increases in BFcrb produced by superfusion of Crus II with
      glutamate or by systemic administration of harmaline were also attenuated in nNOS
      /- mice (P < 0.05). In contrast, the increases in BFcrb produced by topical
      superfusion of Crus II with acetylcholine or adenosine and the increase in BFcrb
      produced by hypercapnia were not affected (P > 0.05). The field potentials evoked
      in the Crus II by upper lip stimulation did not differ between wild-type and nNOS
      null mice. These data provide the first nonpharmacological evidence that nNOS
      derived NO is a critical link between glutamatergic synaptic activity and blood
      flow in the activated cerebellum.

PMID- 12623793
TI  - Kininase I-type carboxypeptidases enhance nitric oxide production in endothelial
      cells by generating bradykinin B1 receptor agonists.
AB  - Kininase I-type carboxypeptidases convert native kinin agonists for B(2)
      receptors into B(1) receptor agonists by specifically removing the COOH-terminal
      Arg residue. The membrane localization of carboxypeptidase M (CPM) and
      carboxypeptidase D (CPD) make them ideally situated to regulate kinin activity.
      Nitric oxide (NO) release from human lung microvascular endothelial cells
      (HLMVEC) was measured directly in real time with a porphyrinic microsensor.
      Bradykinin (1-100 nM) elicited a transient (5 min) peak of generation of NO that
      was blocked by the B(2) antagonist HOE 140, whereas B(1) agonist des-Arg(10)
      kallidin caused a small linear increase in NO over 20 min. Treatment of HLMVEC
      with 5 ng/ml interleukin-1beta and 200 U/ml interferon-gamma for 16 h upregulated
      B(1) receptors as shown by an approximately fourfold increase in prolonged (>20
      min) output of NO in response to des-Arg(10)-kallidin, which was blocked by the
      B(1) antagonist des-Arg(10)-Leu(9)-kallidin. B(2) receptor agonists bradykinin or
      kallidin also generated prolonged NO production in treated HLMVEC, which was
      significantly reduced by either a B(1) antagonist or carboxypeptidase inhibitor,
      and completely abolished with a combination of B(1) and B(2) receptor
      antagonists. Furthermore, CPM and CPD activities were increased about twofold in
      membrane fractions of HLMVEC treated with interleukin-1beta and interferon-gamma
      compared with control cells. Immunostaining localized CPD primarily in a
      perinuclear/Golgi region, whereas CPM was on the cell membrane. These data show
      that cellular kininase I-type carboxypeptidases can enhance kinin signaling and
      NO production by converting B(2) agonists to B(1) agonists, especially in
      inflammatory conditions.

PMID- 12623795
TI  - Orbital radiation therapy for Graves' ophthalmopathy.

PMID- 12623797
TI  - Orbital radiation therapy for Graves' ophthalmopathy.

PMID- 12623798
TI  - Orbital radiation therapy for Graves' ophthalmopathy.

PMID- 12623799
TI  - Orbital radiation therapy for Graves' ophthalmopathy.

PMID- 12623801
TI  - Orbital radiation therapy for Graves' ophthalmopathy.

PMID- 12623804
TI  - A reliable corneal tomography system is still needed.

PMID- 12623805
TI  - A phase III clinical trial of 0.5% levofloxacin ophthalmic solution versus 0.3%
      ofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis.
AB  - OBJECTIVE: To compare the efficacy and safety of 0.5% levofloxacin ophthalmic
      solution (QUIXIN) with 0.3% ofloxacin ophthalmic solution for the treatment of
      bacterial conjunctivitis. DESIGN: Prospective, randomized, active-controlled,
      double-masked, multicenter study. PARTICIPANTS: Four hundred twenty-three
      patients with a clinical diagnosis of bacterial conjunctivitis were enrolled.
      METHODS: Patients were randomly assigned to receive either 0.5% levofloxacin (n =
      211) or 0.3% ofloxacin (n = 212) for 5 days (every 2 hours on days 1 and 2 and
      every 4 hours on days 3-5). Conjunctival cultures were obtained, and ocular signs
      and symptoms were evaluated on day 1 (baseline), days 3 to 5 (interim), and days
      6 to 10 (final). End point was defined as the last evaluable observation. MAIN
      OUTCOME MEASURES: Primary microbial and clinical outcomes were based on culture
      results and resolution of cardinal signs, respectively. Secondary efficacy
      assessments included evaluations of ocular signs and symptoms. RESULTS: Two
      hundred eight patients (levofloxacin, n = 109; ofloxacin, n = 99) were evaluated
      for efficacy. Microbial eradication rates were significantly greater in the 0.5%
      levofloxacin treatment group compared with the 0.3% ofloxacin group at both the
      final visit (89% vs. 80%, P = 0.034) and at end point (90% vs. 81%; P = 0.038).
      Treatment with 0.5% levofloxacin was significantly more effective in resolving
      photophobia than was 0.3% ofloxacin treatment (94% vs. 73%, P = 0.006). Both
      study medications were well tolerated, with a low incidence of adverse events.
      CONCLUSIONS: Although clinical cure rates in the 0.5% levofloxacin and 0.3%
      ofloxacin treatment groups were similar, a 5-day treatment regimen with 0.5%
      levofloxacin achieved microbial eradication rates that were statistically
      superior to those attained with 0.3% ofloxacin. Despite the higher concentration
      of active drug in 0.5% levofloxacin versus 0.3% ofloxacin, there was no
      difference between treatment groups in the incidence of treatment-related adverse
      events.

PMID- 12623807
TI  - Role of amniotic membrane transplantation for conjunctival reconstruction in
      ocular-cicatricial pemphigoid.
AB  - PURPOSE: To evaluate the role and the effectiveness over time of amniotic
      membrane transplantation (AMT) as a first-step procedure to treat conjunctival
      reconstruction in late-stage ocular-cicatricial pemphigoid (OCP). DESIGN:
      Prospective interventional noncomparative case series. PARTICIPANTS: Nine eyes (9
      patients) with advanced OCP. METHODS: Preoperatively, the ocular surface
      conditions were evaluated by immunohistochemistry of conjunctival biopsy and
      impression cytology specimens. The amniotic membrane was obtained during cesarean
      section from women who were 39 weeks pregnant and seronegative for human
      immunodeficiency virus, hepatitis B and C, and syphilis; it was processed,
      histologically tested, and stored at -80 degrees C. After scar tissue was
      removed, the preserved amniotic membrane was placed over the cornea, the bulbar,
      and tarsal conjunctiva, and was secured with 8-0 Vicryl sutures to the
      conjunctival edges and the deep fornices with double-armed 6-0 silk sutures. In 2
      cases a double layer of amniotic membrane was transplanted. All patients received
      immunosuppressive systemic therapy and preservative-free tear substitutes and
      steroids topically for at least 6 months. During follow-up (average, 48 weeks;
      range, 28-96 weeks), a new standardized method was used to evaluate the fornix
      depth, and impression cytology testing was performed and conjunctival
      inflammation recorded and used as parameters for monitoring disease activity.
      MAIN OUTCOME MEASURES: Symblepharon, increased inferior fornix depth, presence of
      conjunctival goblet cells, and the degree of conjunctival inflammation. RESULTS:
      The conjunctival surface was free from symblepharon in all subjects for the first
      16 weeks. At the week 28 examination, a small area of symblepharon was present in
      four eyes (44.4%). The depth of the fornix was significantly (P < 0.0001,
      analysis of variance) improved at weeks 4, 16, and 28. The normal conjunctival
      epithelium with goblet cells was restored in 6 of 9 eyes (66.7%) at the week 4
      examination and in 4 eyes (44.4%) at the week 28 examination. Conjunctival
      inflammation was clinically but not statistically reduced. The visual acuity
      improved in 5 subjects. CONCLUSIONS: AMT can be a first-step procedure for ocular
      surface reconstruction in OCP, but its effectiveness deteriorates slightly over
      time.

PMID- 12623806
TI  - Amniotic membrane transplantation for partial and total limbal stem cell
      deficiency secondary to chemical burn.
AB  - PURPOSE: To evaluate the surgical outcome of preserved amniotic membrane
      transplantation (AMT) for ocular surface reconstruction in chemical burn with
      limbal stem cell deficiency. DESIGN: Prospective, noncomparative, interventional
      case series. PARTICIPANTS: Twenty eyes of 20 consecutive patients with limbal
      stem cell deficiency secondary to ocular chemical injury. INTERVENTION: AMT with
      or without adjunctive limbal transplantation using limbal tissue from either the
      healthy contralateral eye (CLAU) or a living related donor (lr-CLAL). MAIN
      OUTCOME MEASURES: Reconstruction of corneal epithelium (clear appearance without
      epithelial defect, normal fluorescein permeability and the absence of conjunctiva
      derived goblet cells on impression cytology), decrease in corneal vascularization
      and improvement in visual acuity. RESULTS: With a mean follow-up time of 19
      months (range, 8-27 months), satisfactory ocular surface reconstruction was
      obtained in 15 eyes (75%), with reduced inflammation and vascularization of the
      ocular surface and a mean epithelialization time of 3.3 weeks. Success was
      observed in all cases of partial limbal stem cell deficiency (PLD) and in 68.75%
      (11 eyes) of cases of total limbal stem cell deficiency (TLD). Surgical failure
      was observed in five severe cases (31.25%). A significant visual improvement was
      observed in all cases after surgery, except for 2 eyes that maintained
      preoperative visual acuity. CONCLUSIONS: AMT seems to be an efficient adjunct for
      ocular surface reconstruction in chemical burns with PLD. When performed in
      conjunction with limbal stem cell transplantation, it is also effective in most
      cases of TLD.

PMID- 12623808
TI  - Phenotypic study of a case receiving a keratolimbal allograft and amniotic
      membrane for total limbal stem cell deficiency.
AB  - PURPOSE: To report the expression pattern of key molecules by the reconstructed
      corneal epithelium after a keratolimbal allograft (KLAL) and amniotic membrane
      transplantation (AMT) for total limbal stem cell deficiency. DESIGN:
      Interventional case report. METHOD: A 50-year-old woman with severe chemical
      burns in both eyes received an AMT as a temporary patch at the acute stage, and a
      KLAL with AMT as a graft at the chronic stage for total limbal stem cell
      deficiency. The corneal button removed during subsequent corneal transplantation
      was submitted for immunofluorescence staining with monoclonal antibodies against
      keratin K3, MUC5AC, connexin 43, integrins alpha3beta1 and alpha6beta4, and
      laminin 5 for comparison with a normal cornea. RESULTS: Histologically, a normal
      stratified corneal epithelium has five to six cell layers that lay on the thick
      amniotic membrane basement membrane. The phenotype was of a corneal origin, based
      on expression of positive keratin K3, negative MUC5AC, and positive connexin 43.
      Furthermore, intact basement membrane complexes were present, evidenced by
      positive staining to integrins alpha3beta1 and alpha6beta4 and to laminin 5.
      CONCLUSIONS: A normal corneal epithelial phenotype with normal basement membrane
      complexes was restored after a KLAL and AMT in a case with total limbal stem cell
      deficiency.

PMID- 12623809
TI  - Tear and mucus eotaxin-1 and eotaxin-2 in allergic keratoconjunctivitis.
AB  - OBJECTIVE: Eotaxin-1 and eotaxin-2 are potent eosinophil chemotactic and
      activating peptides that may be implicated in the pathogenesis of the chronic
      allergic eye diseases vernal keratoconjunctivitis (VKC) and atopic
      keratoconjunctivitis (AKC). The purpose of this study was to measure these
      chemokines in tear and mucus samples of active-disease patients and in vitro
      cultured conjunctival epithelial cells and fibroblasts. DESIGN: Comparative,
      observational case series and in vitro study. PARTICIPANTS: Sixteen patients with
      clinically active and untreated VKC or AKC, six age-matched control patients, and
      five nonactive seasonal allergic conjunctivitis patients. METHODS: Tears were
      collected from the active VKC and AKC patients, and from the normal patients.
      Mucus was collected from six of these VKC patients. Tears were also collected
      from an additional five allergic patients after obtaining a positive reaction to
      conjunctival allergen challenge. Conjunctival epithelial cell and conjunctival
      fibroblast cultures were exposed to interleukin (IL)-4, IL-13, and tumor necrosis
      factor-alpha (TNF-alpha), or to combinations of these cytokines. MAIN OUTCOME
      MEASURES: Levels of eotaxin-1 and eotaxin-2 in tears, mucus, and culture medium.
      RESULTS: High levels of eotaxin-1 and eotaxin-2 were found in mucus of VKC
      patients, whereas only eotaxin-2 was found to have increased significantly in
      tears of VKC and AKC patients compared with those of normal patients. Mucus
      contained higher levels of chemokines than did tears. Both tear eotaxin-1 and
      eotaxin-2 were correlated significantly with the percent of eosinophils in tear
      fluid. Eotaxin-1 also was correlated significantly with the sum clinical score
      and corneal involvement in VKC patients. Conjunctival epithelial cells in culture
      did not produce eotaxin-1 or eotaxin-2, either at baseline or after cytokine
      exposure. Conjunctival fibroblasts produced eotaxin-1 only after exposure to IL
      4, TNF-alpha, and the combination of IL-4 plus TNF-alpha or IL-13 plus TNF-alpha.
      CONCLUSIONS: Eotaxin-1 and eotaxin-2 are implicated in eosinophil recruitment and
      in the pathogenesis of VKC and AKC. Cytokine-stimulated conjunctival fibroblasts
      may be one source of eotaxin-1 in severely allergic tissues.

PMID- 12623810
TI  - Bilateral herpetic keratoconjunctivitis.
AB  - PURPOSE: To review the clinical characteristics and visual outcomes of patients
      with bilateral herpetic keratitis. DESIGN: Retrospective, noncomparative,
      observational case series. PATIENTS AND METHODS: A retrospective review of
      medical records of 544 patients with herpes simplex virus (HSV) eye disease
      treated between January 1996 and September 2001 was performed at the Department
      of Ophthalmology, University of Minnesota. Seven patients (1.3%) with bilateral
      herpetic keratoconjunctivitis were identified. RESULTS: In these seven patients,
      the age at the initial onset of corneal disease ranged from 7 weeks to 46 years,
      with a median of 18 years and a mean of 19.3 years. Five patients had systemic
      atopy, and two patients had severe ocular rosacea. Systemic immune disorders were
      noted in two patients. Recurrent blepharoconjunctivitis was noted in 8 eyes
      (57%), epithelial keratitis in 12 eyes (85.7%), stromal keratitis in 9 eyes
      (64.3%), necrotizing stromal keratitis in 5 eyes (35.7%), and progressive
      endotheliitis in 2 eyes (14.2%). Corneal complications included opacification,
      neovascularization, and corneal thinning or perforation. Penetrating keratoplasty
      was performed in 1 eye, in which endophthalmitis subsequently developed and which
      required enucleation. Four patients with continued use of oral antiviral
      prophylaxis (acyclovir 400 mg twice daily) since September 1999 showed
      significant decreases in recurrence. The average remission in these four patients
      was 1.7 years. The visual acuity at the last follow-up was 20/40 or worse in 6
      eyes (42.8%). CONCLUSIONS: In contrast to unilateral HSV keratitis, our patients
      with bilateral herpetic corneal infections had underlying atopy or immune
      deviations and evinced more protracted clinical courses. Long-term prophylactic
      antiviral treatment has reduced the incidence of recurrence in this group of
      patients.

PMID- 12623811
TI  - Effect of myopic LASIK on human corneal sensitivity.
AB  - OBJECTIVE: To evaluate the changes in corneal sensitivity after LASIK for the
      correction of different degrees of myopia. DESIGN: Prospective, nonrandomized,
      comparative self-controlled trial. PARTICIPANTS: One hundred two myopic eyes of
      58 patients were included in this study. METHODS: The eyes were divided into four
      groups: group 1, from -0.75 to -3.75 diopters (D); group 2, from -4.00 to -7.75
      D; group 3, from -8.00 to -11.75 D; group 4, from -12.00 to -16.00 D. Corneal
      sensitivity was measured before and 1, 7, 30, 90, 180, 270, and 365 days after
      surgery or until full recovery. MAIN OUTCOME MEASURES: The recovery of corneal
      sensation after LASIK. RESULTS: Immediately after surgery, the lenticule was
      found to be completely anesthetic, and the full recovery varied according to the
      depth of the ablation. Normal levels of corneal sensitivity, but not full
      recovery, were found after 90 days in groups 1 and 2 and after 180 days in groups
      3 and 4. Full recovery of corneal sensitivity was found after 180 days in groups
      1 and 2 and after 270 days in groups 3 and 4. CONCLUSIONS: After LASIK, corneal
      sensitivity is decreased at the central and paracentral areas for as long as 9
      months. The depth of the ablation seems to be an important factor in the
      temporary decrease of corneal sensitivity and its recovery.

PMID- 12623812
TI  - Infectious keratitis after LASIK.
AB  - PURPOSE: To report the clinical course, management, and outcomes of culture
      proven infectious keratitis in 15 eyes of 13 subjects after LASIK. DESIGN:
      Retrospective, noncomparative, interventional case series. PARTICIPANTS: Fifteen
      eyes of 13 subjects who underwent LASIK and developed culture-positive keratitis.
      INTERVENTION: Infectious keratitis was encountered in the operative eyes between
      1 day and 450 days. Cultures were obtained, and topical antibiotic therapy was
      administered in all cases. Some cases required flap lifting, irrigation, and
      soaking of the bed with antibiotics, flap amputation, or further surgical
      intervention. MAIN OUTCOME MEASURES: Time periods from onset to diagnosis, from
      clinical diagnosis to clinical resolution, final acuities, microbiologic
      profiles, and medical and surgical interventions were reviewed. RESULTS: Onset of
      symptoms of infection varied, depending on the infectious organism. Bacterial
      organisms tended to present earlier, whereas mycobacterial and fungal organisms
      had a later mean onset of presentation. Furthermore, the atypical organisms such
      as mycobacteria, fungus, and acanthamoeba also had a more delayed diagnosis,
      resulting in a prolonged disease course. CONCLUSIONS: Infectious keratitis after
      LASIK is a potentially vision-threatening complication. Onset of symptoms varies
      depending on causative agents. Furthermore, atypical organisms in the interface
      or beneath the flap can pose both diagnostic and therapeutic dilemmas. Location
      in the interface can make it more difficult to culture the organisms and prevent
      adequate penetration of topical antibiotics.

PMID- 12623813
TI  - Reliability of pachymetric measurements using orbscan after excimer refractive
      surgery.
AB  - PURPOSE: To assess the accuracy of pachymetric measurements using Orbscan (Bausch
      & Lomb, Rochester, NY) after laser in situ keratomileusis (LASIK) and
      photorefractive keratectomy (PRK). DESIGN: Prospective instrument validation
      study. PARTICIPANTS: Seventy-nine nonoperated normal eyes, 84 eyes after LASIK,
      and 50 eyes after PRK. INTERVENTION: Laser in situ keratomileusis or PRK.
      METHODS: Central corneal thickness was measured using ultrasound and Orbscan II.
      The acoustic factor (AF) was adjusted, based on the results obtained in the
      normal eye group, to minimize the difference between ultrasound and Orbscan
      pachymetric values. MAIN OUTCOME MEASURES: Central corneal thickness as measured
      by Orbscan and ultrasound pachymeter. RESULTS: Using the adjusted AF, which was
      0.946, the mean difference between Orbscan and ultrasonic pachymetric
      measurements was 0 +/- 17, 16 +/- 28, and 68 +/- 39 microm in the normal, LASIK,
      and PRK groups, respectively. The difference between all groups was statistically
      significant (P < 0.0001). CONCLUSIONS: Orbscan pachymetric values may be
      underestimated and less accurate after LASIK and PRK.

PMID- 12623814
TI  - Correction of astigmatism with short arc-length intrastromal corneal ring
      segments: preliminary results.
AB  - OBJECTIVE: To evaluate the refractive effect of 130 degrees short arc length
      intrastromal corneal ring segments (ICRS) designed to correct myopia concurrent
      with astigmatism. DESIGN: Prospective, nonrandomized, comparative (self
      controlled) trial. PARTICIPANTS: Ten eyes of 6 patients from one surgical center
      with manifest refraction spherical equivalent between -1.00 and -6.00 diopters
      (D), manifest cylinder correction between 1.00 and 6.00 D, and best spectacle
      corrected visual acuity of 20/20 or better. INTERVENTION: The patients were
      assigned to receive 1 of 6 ICRS thicknesses, ranging from 0.25 to 0.50 mm by 0.05
      mm increments, with an arc length of 130 degrees. MAIN OUTCOME MEASURES: Vector
      analysis of astigmatic correction. Efficacy was assessed by uncorrected visual
      acuity and by deviation of postoperative spherical and cylindrical refractive
      error from predicted correction. Safety was assessed by maintenance or loss of
      preoperative best spectacle-corrected visual acuity. Measurements were made
      before surgery and after surgery at days 1 and 7 and months 1, 2, 3, and 6.
      RESULTS: At 6 months, uncorrected visual acuity was 20/20 or better in 80% of
      eyes (8/10) and 20/40 or better in all eyes. Eight of 10 eyes (80%) were within
      +/-0.25 D of plano spherical equivalent manifest refraction. There was no loss of
      best spectacle-corrected visual acuity, and 6 of 10 eyes (60%) gained a line.
      Reduction of keratometric cylinder by ICRS thickness was statistically
      significant (P = 0.039). CONCLUSIONS: Preliminary results of visual and
      refractive performance after correction of compound myopic astigmatism using
      short arc length ICRS are promising.

PMID- 12623815
TI  - Visual performance with night vision goggles after photorefractive keratectomy
      for myopia.
AB  - OBJECTIVE: To evaluate visual performance and resolution through night vision
      goggles (NVG) before and after photorefractive keratectomy (PRK). DESIGN:
      Nonrandomized, comparative (self-controlled) trial. PARTICIPANTS: Nineteen
      patients (38 eyes) of active-duty US Army Special Forces soldiers. INTERVENTION:
      PRK for myopia and astigmatism. MAIN OUTCOME MEASURES: Visual acuity with best
      optical correction was measured preoperatively and postoperatively (3 months)
      using acuity charts of various contrast (100%, 10%, 2.5%, 1.25%). Preoperative
      and postoperative (3 month) uncorrected and best-corrected visual resolutions
      through NVGs were assessed using a high contrast tribar chart presented at four
      light levels (3.44 x 10(-3), 1.08 x 10(-3), 1.04 x 10(-4), 1.09 x 10(-5) foot
      Lamberts) simulating a range of night sky conditions. Subjects were trained
      before testing. RESULTS: Uncorrected visual acuity at the 3-month postoperative
      assessment was greater than or equal to 20/20 in 33 of 38 (86.8%) eyes. No eyes
      lost 2 or more lines of best spectacle-corrected visual acuity. Preoperative and
      3-month postoperative best-corrected low-contrast acuity measurements showed no
      significant differences at all levels of resolution. Preoperative visual
      resolution through NVGs decreased systematically with decreasing night sky
      condition. Visual acuities before PRK were reduced without optical correction.
      Postoperative visual performance with NVGs (without optical correction) equaled
      or exceeded performance preoperatively with best correction. CONCLUSIONS: This
      prospective case series provides data on the safety and efficacy of PRK with
      respect to visual performance under night sky conditions using NVGs. There was no
      significant loss of visual acuity across a range of contrast levels 3 months
      postoperatively. There was no change in best-corrected NVG visual resolution
      postoperatively, whereas uncorrected visual resolution was significantly enhanced
      compared with preoperative levels. This improvement may translate into better
      function for soldiers who are unable to or choose not to use optical correction
      in operational environments.

PMID- 12623816
TI  - Multifocal intraocular lens implantation in patients with traumatic cataract.
AB  - OBJECTIVE: To evaluate the postoperative outcome and complication rate of
      cataract extraction with implantation of a zonal-progressive multifocal
      intraocular lens (IOL) for traumatic cataract. DESIGN: Prospective,
      nonrandomized, comparative trial. PARTICIPANTS: Fifty-one eyes of 51 subjects
      with traumatic cataract caused by nonpenetrating, penetrating, and perforating
      ocular trauma at two university institutions with more than 12 months follow-up.
      INTERVENTIONS: Temporal clear corneal phacoemulsification with foldable IOL
      implantation was performed in all eyes. In 29 subjects, a zonal-progressive optic
      multifocal IOL (Array SA40-N Allergan, Irvine, CA) was implanted, whereas 22
      subjects received a monofocal IOL and served as controls. RESULTS: Preoperative
      subjects demographics, mean postoperative spherical equivalent, astigmatism, and
      uncorrected and best-corrected distance visual acuity were similar in the two
      groups. Subjects with a multifocal IOL achieved a significantly better
      uncorrected near visual acuity than subjects with monofocal IOL (0.24 vs. 0.40; P
      = 0.0001). With distance correction only, mean near visual acuity was 0.21 vs.
      0.43 (P = 0.0001). Best-corrected near visual acuity was 0.17 for both groups (P
      = 0.91), with +1.24 diopters (D) for the multifocal group and +2.45 D for the
      monofocal group (P = 0.0001). Spectacle dependency differed significantly between
      the two groups, with 18 (81%) subjects of the monofocal group commonly requiring
      an additional plus add for near tasks compared with 5 (17%) subjects in the
      multifocal group (P = 0.001). Stereopsis was superior in the multifocal group (P
      < 0.001), with 20 (69%) and 16 (55%) patients with a multifocal IOL responding
      positively to the Lang and Titmus tests, respectively. In the monofocal group,
      only eight (36%) and five (22%) subjects gave correct answers. CONCLUSIONS:
      Multifocal IOL implantation is a viable alternative to monofocal pseudophakia in
      subjects with traumatic cataract.

PMID- 12623817
TI  - Recovery of visual function in patients with biopsy-proven giant cell arteritis.
AB  - OBJECTIVE: To assess the visual function of patients with giant cell arteritis
      (GCA) who had visual loss from either anterior ischemic optic neuropathy (AION)
      or central retinal artery occlusion and had a subsequent improvement in visual
      acuity after treatment with corticosteroids. DESIGN: Retrospective, observational
      case series. PARTICIPANTS: Thirty-two consecutive patients with biopsy-proven GCA
      treated at one institution between January 1992 and December 1997. INTERVENTION:
      Treatment with intravenous methylprednisolone 250 mg every 6 hours for 3 days,
      followed by oral prednisone 1 mg/kg daily for at least 4 weeks duration. MAIN
      OUTCOME MEASURES: The number of patients with an improvement in visual acuity
      after treatment with intravenous methylprednisolone; neuro-ophthalmic evaluation,
      including visual acuity, funduscopy, and visual field examination of these
      patients. RESULTS: Improvement in visual acuity occurred in 5 of 39 eyes (13%)
      with visual loss from biopsy-proven GCA, and all 5 patients had AION. Despite the
      improvement of visual acuity in these 5 patients, perimetry revealed marked
      constriction of the visual field in each affected eye. CONCLUSIONS: The prognosis
      for visual improvement in GCA is poor. Although an improvement in visual acuity
      occurred in 5 of our patients, marked constriction of the visual field was
      present in all of them.

PMID- 12623818
TI  - The role of unilateral temporal artery biopsy.
AB  - PURPOSE: To examine the role of unilateral temporal artery biopsy (TAB) in
      suspected giant cell arteritis (GCA). DESIGN: Retrospective interventional case
      series. PARTICIPANTS: We identified 181 subjects from pathology and diagnostic
      code databases at the University of Pennsylvania Medical Center who underwent TAB
      between January 1990 and January 2001. METHODS: The medical records for all
      subjects who underwent TAB were reviewed. Follow-up information was obtained by
      telephone or record review for those patients who had negative unilateral TAB.
      MAIN OUTCOME MEASURES: Follow-up information for patients with unilateral
      negative TAB was reviewed for potential adverse outcomes caused by missed or
      delayed diagnoses of GCA. Presenting signs and symptoms and laboratory values
      were recorded for all subjects. Comparisons of clinical profiles between subsets
      of subjects were performed using Fisher's exact test, significance level alpha =
      0.01. RESULTS: Follow-up information was available for 88 (86%) of 102 subjects
      who had unilateral negative biopsy samples. One (1%) subjects of 88 had a
      subsequent positive contralateral TAB; no adverse outcomes occurred for this
      subject or for any other subjects with unilateral negative TAB. Compared with
      subjects who had unilateral positive or who underwent bilateral TAB (n = 74),
      those who had unilateral negative TAB (n = 88) had a significantly lower
      prevalence of jaw claudication (P = 0.007). Compared with subjects diagnosed with
      GCA (n = 39), those with unilateral negative TAB (n = 88) had significantly lower
      frequencies of jaw claudication (P = 0.001), "chalky white" optic disc edema (P =
      0.002), and fever (P < 0.0001). Compared with subjects with positive TAB (n =
      33), subjects with negative TAB (n = 148) had significantly lower prevalence of
      jaw claudication (P < 0.0001), "chalky white" disc edema (P = 0.0002), pale disc
      edema (P = 0.006), or any systemic symptom other than headache (P = 0.0002).
      ("Chalky white" denotes notably extreme disc pallor). The most common indications
      for biopsy in subjects with unilateral negative TAB were elevated erythrocyte
      sedimentation rate (ESR) (74%), headache (69%), visual complaints (58%), and
      ophthalmic signs (52%). Although ESR was a significant predictor of positive TAB
      overall (unilateral and bilateral TAB) in logistic regression models accounting
      simultaneously for subject age (P = 0.04), ESR did not significantly predict
      unilateral negative status in our patients (P = 0.13). CONCLUSIONS: In this
      cohort of patients, unilateral TAB was associated with an extremely low frequency
      (1%) of subsequent positive contralateral TAB and was not associated with adverse
      visual or neurologic outcomes for any subject. We conclude that in the hands of
      experienced physicians, a unilateral TAB is sufficient to exclude a diagnosis of
      GCA in populations for which clinical suspicion is low. Jaw claudication, pale
      optic disc edema, particularly "chalky white" disc edema, fever, or any systemic
      symptom other than headache should raise suspicion for a diagnosis of GCA.

PMID- 12623820
TI  - Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis.
AB  - PURPOSE: To study the retinal degeneration in an 11 -year-old patient with Leber
      congenital amaurosis (LCA) caused by mutation in GUCY2D. STUDY DESIGN:
      Comparative human tissue study. PARTICIPANTS: Two subjects with LCA; postmortem
      eye from one LCA patient and three normal donors. METHODS: Clinical and visual
      function studies were performed between the ages of 6 and 10 years in the LCA eye
      donor and at age 6 in an affected sibling. Genomic DNA was screened for mutations
      in known LCA genes. The retina of the 11 -year-old subject with LCA was compared
      with normal retinas from donors age 3 days, 18 years, and 53 years. The tissues
      were processed for histopathologic studies and immunofluorescence with retinal
      cell-specific antibodies. RESULTS: Vision in both siblings at the ages examined
      was limited to severely impaired cone function. Mutation in the GUCY2D gene was
      identified in both siblings. Histopathologic study revealed rods and cones
      without outer segments in the macula and far periphery. The cones formed a
      monolayer of cell bodies, but the rods were clustered and had sprouted neurites
      in the periphery. Rods and cones were not identified in the midperipheral retina.
      The inner nuclear layer appeared normal in thickness throughout the retina, but
      ganglion cells were reduced in number. CONCLUSIONS: An 11-year-old subject with
      LCA caused by mutant GUCY2D had only light perception but retained substantial
      numbers of cones and rods in the macula and far periphery. The finding of
      numerous photoreceptors at this age may portend well for therapies designed to
      restore vision at the photoreceptor level.

PMID- 12623822
TI  - Intramuscular hemangiomas of extraocular muscles.
AB  - PURPOSE: To report two patients, 3 and 40 years of age, respectively, each of
      whom had an isolated intramuscular hemangioma of an extraocular muscle. DESIGN:
      Two retrospective, interventional case reports. INTERVENTION: Incisional biopsy
      and short-term oral corticosteroids. MAIN OUTCOME MEASURES: Clinical observation
      and pathologic examination of specimens and tumor status, visual acuity, and
      ocular motility at final follow-up. RESULTS: Orbital magnetic resonance imaging
      revealed that, compared with other extraocular muscles, the tumor was isointense
      on T1-weighted scans and hyperintense on T2-weighted images. Marked homogeneous
      enhancement was observed after contrast agent administration. Biopsy results
      showed a hemangioma of the lateral rectus muscle with predominantly capillary
      like small vessels in the child and a mixed small and large vessel type
      hemangioma of the medial rectus muscle in the adult. CONCLUSIONS: Intramuscular
      hemangiomas may cause painless, isolated extraocular muscle enlargement in
      children and in adults without disturbing the ocular motility. The tumors do not
      seem to be sensitive to systemic corticosteroid therapy.

PMID- 12623821
TI  - Use of methotrexate in sarcoid-associated optic neuropathy.
AB  - OBJECTIVE: To demonstrate the possible beneficial effects of methotrexate (MTX)
      therapy for patients with sarcoid-associated optic neuropathy (SAON). DESIGN:
      Retrospective, noncomparative, interventional case series. PARTICIPANTS: Three
      patients diagnosed with SAON who received MTX. Two patients had tissue biopsies
      consistent with sarcoidosis, and 1 patient had clinically diagnosed sarcoidosis
      based on laboratory and radiographic studies. All 3 patients developed side
      effects with corticosteroid treatment of their optic neuropathy. INTERVENTION:
      Patients were treated with weekly doses of oral MTX and monitored with neuro
      ophthalmic, medical, and laboratory examinations. MAIN OUTCOME MEASURES: Visual
      acuity, automated perimetry, and reduction of oral prednisone therapy. RESULTS:
      After initiation of MTX, all 3 patients showed an improvement or stabilization of
      visual acuity. All patients had a decrease in their corticosteroid requirements,
      and all had improved or stabilized visual field deficits. One of the 3 patients
      developed leukopenia that necessitated a reduction of the methotrexate dose.
      CONCLUSION: Methotrexate may be effective for SAON as an adjunct to
      corticosteroid therapy or as an alternative for corticosteroid-intolerant
      patients. Oral MTX reduced the corticosteroid requirements of 3 patients with
      SAON, and all 3 demonstrated stable or improved visual function.

PMID- 12623823
TI  - Bilateral cavernous sinus thromboses and intraorbital abscesses secondary to
      Streptococcus milleri.
AB  - PURPOSE: To report the first case of bilateral cavernous sinus thromboses and
      bilateral intraorbital abscesses secondary to Streptococcus milleri. STUDY
      DESIGN: Single interventional case report. INTERVENTION AND TESTING: The findings
      of the ophthalmic evaluation, radiographic imaging, medical and surgical
      intervention, specimen cultures, and clinical course were analyzed. RESULTS: A 17
      year-old female had bilateral proptosis, decreased vision in the left eye, and
      altered mental status at presentation. An orbital compartment syndrome developed
      in the left eye and purulent material was present after lateral canthotomy,
      suggestive of an intraorbital abscess. Magnetic resonance imaging (MRI) scans
      revealed bilateral cavernous sinus thromboses, and subsequent computed
      tomographic (CT) scans revealed bilateral intraorbital abscesses in the setting
      of acute ethmoid and sphenoid sinusitis. Antibiotic treatment and surgical
      drainage of the orbital abscess and sinuses was performed, and specimen cultures
      revealed S. milleri. After surgery, the patient experienced hearing loss and a
      right internal capsule infarct, in addition to complete vision loss in the left
      eye. A second intraorbital abscess developed in the right eye and was drained
      surgically. The vision remained 20/20. CONCLUSIONS: Streptococcus milleri is a
      virulent organism with a propensity to form abscesses in multiple areas of the
      body and should be considered as a possible etiologic agent in abscess formation
      of the orbit and cavernous sinus thrombosis.

PMID- 12623824
TI  - Attempted bilateral manual enucleation (gouging) during a physical assault.
AB  - OBJECTIVE: To report a rare, severe case of partial traumatic bilateral
      enucleation and its assessment and management. DESIGN: Case report and literature
      review. METHODS: A report of clinical and imaging findings, surgical procedure,
      medical treatment, and final outcome. RESULTS: Complete avulsion of the
      extraocular muscles and optic nerve resulted in total loss of vision in one eye.
      Partial visual recovery was achieved by operating on the fellow eye, which was
      partially avulsed. Both eyes underwent lateral canthotomy in the emergency room.
      This was followed by exploration, repair of all ruptured extraocular muscles, and
      anterior chamber tap under general anesthesia. The few previously reported cases
      of traumatic manual avulsion of the globe are reviewed and discussed in the
      context of the present case. CONCLUSIONS: Partial visual recovery can be achieved
      after severe orbital and optic nerve trauma. A multidisciplinary approach to the
      assessment and management of these patients is recommended.

PMID- 12623825
TI  - Serum lipids and age-related lens opacities: a longitudinal investigation: the
      Framingham Studies.
AB  - OBJECTIVE: To investigate whether serum lipid/lipoprotein levels are independent
      risk factors for nuclear, cortical, or posterior subcapsular (PSC) cataracts.
      DESIGN: Case-control study nested in a cohort study. PARTICIPANTS AND METHODS:
      Eye examinations were conducted on surviving members of the Framingham Offspring
      Heart Study cohort from 1989 to 1991 (Framingham Offspring Eye Study) to
      determine cataract case-control status. Data from the Framingham Offspring Heart
      Study, including fasting serum total cholesterol, high-density lipoprotein
      cholesterol, and triglyceride measurements collected first in 1971, again
      approximately 8 years later, and approximately every 4 years thereafter were used
      to examine associations between lipid levels (mean levels across examinations and
      slope of measurements over time) and the presence of specific cataract types. The
      multistage analyses included 1869 persons aged 45 years and older. MAIN OUTCOME
      MEASURES: A standardized grading system was used to grade cortical, nuclear, and
      PSC cataracts. RESULTS: The median age of participants was 55 years; 49% were
      males. In multivariable logistic regression models adjusted for potential
      confounders, fasting hypertriglyceridemia (>/=250 mg/dl) was associated with an
      increased risk of PSC cataract in men (P = 0.02). High-density lipoprotein
      cholesterol levels </=35 mg/dl were associated with PSC cataract in men at a
      borderline level of significance (P = 0.09). No associations were noted between
      serum lipid/lipoprotein variables and risk of cortical or nuclear cataract.
      CONCLUSIONS: These findings suggest that hypertriglyceridemia, a potentially
      modifiable factor, is associated with the development of PSC cataract in men.

PMID- 12623826
TI  - Incidence of blindness and low vision in a sample population: the Priverno Eye
      Study, Italy.
AB  - PURPOSE: To study the incidence of blindness and low vision over a 7-year period.
      DESIGN: Population-based cohort study. PARTICIPANTS: The survivors of the
      original cohort of 860 persons from Priverno, Italy, aged 45 to 69 years, were
      reexamined. Of the 760 eligible survivors, 619 (81.4%) had a 7-year follow-up
      visit. METHODS: Baseline and follow-up examinations included the collection of
      anamnestic and ophthalmologic data by the same observers using the same methods
      and classification criteria to minimize sources of variability. MAIN OUTCOME
      MEASURES: Best-corrected visual acuity (VA) measured at 4 m by standardized
      logarithmic chart was expressed as the logarithm of the minimum angle of
      resolution (logMAR). World Health Organization definitions of blindness and low
      vision were adopted (respectively, VA > 1.3 logMar and VA > 0.6 to 1.3 logMar in
      the better eye or in either eye). Participants at risk for visual impairment were
      those without blindness or low vision in one or both eyes at baseline;
      participants at risk for one-eye visual impairment were those without blindness
      or low vision in both eyes at baseline. RESULTS: A total of 33 participants were
      defined as incident cases of visual impairment. The overall incidence figures for
      blindness, low vision, one-eye blindness, and one-eye low vision were
      respectively 0.2% (95% confidence interval [CI], 0.0-0.9), 1.3% (95% CI, 0.7
      2.6), 1.2% (95% CI, 0.6-2.4), and 2.9% (95% CI, 1.8-4.6). CONCLUSIONS: This study
      provides population-based estimates of the incidence of visual impairment in an
      adult, free-living European population. With respect to the younger participants,
      older subjects at baseline were at higher risk for incident visual impairment,
      the main causes of which were cataract, myopia, and diabetic retinopathy. The
      incidence of visual impairment in the subgroup aged 55 to 64 years at baseline
      was significantly higher than that found in Beaver Dam 5-year study and similar
      to that found in Beaver Dam 10-year Study, when the same definitions were
      adopted. This difference may be partially explained by social and cultural habits
      of the female samples, but many other factors may play a role.

PMID- 12623827
TI  - Inverted pneumatic retinopexy: a method of treating retinal detachments
      associated with inferior retinal breaks.
AB  - PURPOSE: To introduce the new approach of inverted pneumatic retinopexy for the
      management of rhegmatogenous retinal detachments with inferior retinal breaks.
      DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Eleven patients
      presenting with rhegmatogenous retinal detachments with causative inferior
      retinal breaks. INTERVENTION: Sterile gas/air injection, cryopexy/laser
      retinopexy, with inverted positioning. MAIN OUTCOME MEASURES: Postoperative
      primary and final anatomical outcome, visual acuity, and complications. RESULTS:
      Patients were followed for a minimum of 3 months (mean, 5.1 months). Primary
      retinal reattachment was obtained in 10 of 11(91%) patients. One patient
      sustained a redetachment secondary to proliferative vitreoretinopathy, resulting
      in a single operation reattachment rate of 82%. Final reattachment was obtained
      in 11 of 11 (100%) patients. Mean visual acuity improved about 3 lines from 20/60
      to 20/30, with 11 of 11 patients experiencing improvement in their visual acuity.
      Two patients required an additional surgical procedure to achieve final anatomic
      success. No new breaks were identified in the postoperative period, and no
      complications resulted from the pneumatical procedure. CONCLUSIONS: Inverted
      pneumatic retinopexy can successfully repair retinal detachments with inferior
      retinal breaks under appropriate conditions.

PMID- 12623828
TI  - Vitreous aspiration needle tap in the diagnosis of intraocular inflammation.
AB  - PURPOSE: To determine the safety of vitreous aspiration needle tap as a clinical
      procedure and its usefulness in helping to distinguish between infective,
      inflammatory, and malignant causes of uveitis. DESIGN: Retrospective,
      noncomparative case series. PARTICIPANTS: Data were collected for 53 patients who
      had undergone vitreous aspiration needle tap as an outpatient in the clinic.
      METHODS: These patients underwent vitreous aspiration needle tap using a needle
      and syringe for the following indications: (1) when masquerade syndrome or
      infective retinitis was the primary diagnosis; and (2) to diagnose or exclude
      infective or malignant entities in patients not responding to treatment. The
      result of the analysis of the biopsy specimen and any complications that arose
      from the procedure were determined. RESULTS: In this series, vitreous aspiration
      needle tap generated an adequate sample for the relevant investigations in 92% of
      cases. The initial diagnosis of intraocular malignancy or infection was confirmed
      in 40% of patients. The remaining patients were treated with immunosuppressives
      for the ocular inflammation and showed clinical improvement over the follow-up
      period. Multiple procedures were required in two patients to make the diagnosis
      of B-cell intraocular lymphoma and in two patients with acute retinal necrosis
      who were treated for the presenting clinical features. CONCLUSIONS: Vitreous
      aspiration needle tap would seem to be a safe clinical procedure, which has a
      high success rate in differentiating between infectious, inflammatory, and
      malignant causes of uveitis. It is a quick procedure that can be carried out at
      the first outpatient visit.

PMID- 12623829
TI  - Heparin-induced antiheparin-platelet antibody associated with retinal venous
      thrombosis.
AB  - OBJECTIVE: To report a case of a 33-year-old white woman in whom retinal venous
      thromboses developed secondary to heparin-induced antiheparin-platelet
      antibodies. DESIGN: Interventional case report. METHODS: The patient underwent
      complete ophthalmic and medical examinations. Laser Doppler measurement of
      retinal blood circulation also was performed. INTERVENTION: Prolonged
      anticoagulation with thrombin inhibitors and warfarin. MAIN OUTCOME MEASURES:
      Visual symptoms, retinal appearance on clinical examination, and measurement of
      retinal blood flow by laser Doppler technique. RESULTS: The patient experienced a
      scotoma in the visual field of the left eye, left retinal venous thrombosis,
      decreased venous blood flow in the left eye, and heparin-induced antiheparin
      platelet antibodies in serum. After intervention, the visual symptoms and retinal
      appearance improved, and retinal blood flow normalized. CONCLUSIONS: Heparin
      induced antiheparin-platelet antibody can lead to thrombosis of the ocular
      circulation. This index case, which is the first one ever reported in association
      with antiheparin-platelet antibodies, further illustrates the potential side
      effects of heparin and widens the spectrum of complications of heparin-induced
      thrombocytopenia (HIT) and HIT thrombosis syndrome (HITTS).

PMID- 12623830
TI  - Persistence of fundus fluorescence after use of indocyanine green for macular
      surgery.
AB  - PURPOSE: To investigate the possible persistence and characteristics of infrared
      fluorescence of the fundus for several months after surgery with intraocular
      injection of indocyanine green (ICG). DESIGN: Interventional, noncomparative,
      prospective case series. PARTICIPANTS: Seventeen patients operated on in our
      department with ICG injection into the vitreous cavity, who gave prior informed
      consent. METHODS: After standard three-port pars plana vitrectomy and posterior
      vitreous detachment, 0.1 to 0.2 ml of an ICG solution at a concentration of 2.5
      mg/ml was injected through a 5- micro m sterile filter over the posterior pole
      and left in place for 3 minutes. The stained internal limiting membrane was then
      peeled off. Patients had postoperative infrared fundus photographs at each
      consultation in our department. Follow-up ranged from 1 to 7 months. Visual
      acuity and any unexpected event were also recorded. MAIN OUTCOME MEASURES:
      Postoperative infrared fluorescence of the fundus. RESULTS: The day after
      surgery, no green ICG staining of the fundus was visible on biomicroscopy.
      However, infrared photography showed diffuse fluorescence of the fundus. At 1 and
      3 postoperative months, infrared fundus photography showed an intensely
      fluorescent optic nerve disc. In patients with macular hole, the center of the
      macula also exhibited faint granular fluorescence. At 6 months postoperative or
      later, only the optic disc remained fluorescent, but the fluorescence was far
      less intense than at 3 months. Infrared photographs of the fellow eyes exhibited
      no fluorescence. Visual acuity improved or was unchanged compared with
      preoperative vision in 16 eyes and decreased by 1 line in 1 eye. CONCLUSIONS:
      After intraoperative use of ICG for macular surgery, fluorescence of the optic
      disc and of the macular center after macular hole surgery persisted for months in
      all cases. ICG may accumulate in the macular pigment epithelium and optic nerve,
      raising the problem of the as yet unknown pharmacokinetics of ICG after
      intravitreous administration and of its long-term safety.

PMID- 12623831
TI  - Effect of bimatoprost on patients with primary open-angle glaucoma or ocular
      hypertension who are nonresponders to latanoprost.
AB  - PURPOSE: To test the efficacy of bimatoprost 0.03% 2D for lowering intraocular
      pressure (IOP) in patients affected by primary open-angle glaucoma or ocular
      hypertension who did not respond to treatment with latanoprost 0.005% 2D. DESIGN:
      Prospective, randomized clinical trial with a cross over design (two 30-day
      treatment phases with a 30-day washout phase in between). PARTICIPANTS: Fifteen
      patients were enrolled. Random allocation to treatment to a single eye only of
      every subject. ELIGIBILITY CRITERIA: (1) IOP > 22 mmHg in both eyes on current
      treatment (on three separate readings > 24 hours apart), (2) angle wide open in
      both eyes, (3) no pseudoexfoliation and/or pigment dispersion in either eye, (4)
      documented medical history consistent with < 10% IOP decrease in both eyes on 2
      month treatment with latanoprost 0.005% every day. METHOD: The following
      variables were measured at each study visit: (1) IOP (Goldmann applanation
      tonometry, 5 readings, 8 AM, 12 noon, 4 PM, 8 PM, and 12 midnight); (2) visual
      acuity (Early Treatment of Diabetic Retinopathy Study chart, logarithm of the
      minimum angle of resolution); (3) estimate of conjunctival hyperemia based on 5
      standard photographs (graded as "none," "trace," "mild," "moderate," and
      "severe"). MAIN OUTCOME MEASURE: IOP. RESULTS: IOP data (mean and standard
      deviation) were the following: baseline = 24.7 +/- 0.9 mmHg, after washout = 24.8
      +/- 1.1 mmHg, after latanoprost phase = 24.1 +/- 0.9 mmHg, after bimatoprost
      phase = 18.1 +/- 1.7 mmHg. IOP on bimatoprost proved lower than both baseline (P
      < 0.0001) and latanoprost (P = 0.0001). Thirteen of 15 patients showed a > or
      =20% IOP decrease with bimatoprost treatment. None of the 15 patients showed a >
      or =20% decrease of IOP after 30 days of latanoprost treatment. No significant
      IOP changes were observed in the fellow untreated eye in each patient throughout
      the study. Trace-to-mild conjunctival hyperemia was recorded more often with
      bimatoprost phase (P = 0.035). CONCLUSIONS: Thirteen of 15 patients, who were
      nonresponders to latanoprost, 0.005%, 2D, were successfully treated with
      bimatoprost, 0.03%, 2D. Bimatoprost treatment was associated with a higher
      incidence of trace-to-mild conjunctival hyperemia than latanoprost.

PMID- 12623832
TI  - Dorzolamide/timolol combination versus concomitant administration of brimonidine
      and timolol: six-month comparison of efficacy and tolerability.
AB  - PURPOSE: To compare the efficacy and tolerability of the 2% dorzolamide/0.5%
      timolol combination ophthalmic solution twice daily to the concomitant
      administration of 0.2% brimonidine ophthalmic solution twice daily and 0.5%
      timolol ophthalmic solution twice daily. DESIGN: Randomized, multicenter,
      observer-masked, parallel-group study. PARTICIPANTS: Two hundred ninety-three
      patients with ocular hypertension or primary open-angle glaucoma participated.
      INTERVENTION: After an open-label 3-week 0.5% timolol run-in period, patients
      with an hour 2 intraocular pressure (IOP) of > or = 22 mmHg were randomly
      assigned to receive either the dorzolamide/timolol combination twice daily or the
      concomitant use of brimonidine twice daily and timolol twice daily (brimonidine +
      timolol) for 6 months. MAIN OUTCOME MEASURES: The IOP-lowering effects at hour 0
      and hour 2 were collected at 1, 3, and 6 months. We hypothesized that both
      treatment regimens would have comparable hour 2 IOP-lowering effects at month 3.
      The treatments were considered comparable if the two-sided 95% confidence
      interval of the treatment difference was within +/- 1.5 mmHg. Tolerability data
      were also collected at 1, 3, and 6 months. RESULTS: The primary efficacy analysis
      was based on the modified intent-to-treat population. At month 3, hour 2, the
      dorzolamide/timolol group had an adjusted mean (standard error) change in IOP of 
      5.04 (0.30) mmHg versus -5.41 (0.30) mmHg in the brimonidine + timolol group,
      with a treatment difference of 0.36 (0.40) mmHg (95% confidence interval [CI] of 
      0.42-1.14 mmHg). At month 3, hour 0, the dorzolamide/timolol group had a change
      in IOP of -3.66 (0.29) mmHg versus -4.15 (0.28) mmHg in the brimonidine + timolol
      group, with a treatment difference of 0.49 (0.39) mmHg (95% CI of -0.27-1.25
      mmHg). Likewise, at all other observed time points, the 95% confidence interval
      of the treatment difference was within +/- 1.5 mmHg. Ninety-three patients (64%)
      in the dorzolamide/timolol group and 88 patients (60%) in the brimonidine +
      timolol group had adverse experiences that were deemed drug related by the
      investigator, for which 7 patients (5%) in the dorzolamide/timolol group and 8
      patients (5%) in the brimonidine + timolol group were discontinued from the
      study. CONCLUSIONS: The efficacy of the dorzolamide/timolol combination and the
      concomitant administration of brimonidine and timolol were comparable. The
      incidence of drug-related adverse experiences and the incidence of
      discontinuations caused by drug-related adverse experiences were similar between
      groups.

PMID- 12623833
TI  - Cataract formation after initial trabeculectomy in young patients.
AB  - OBJECTIVE: To evaluate the risk of cataract formation in young patients after
      initial trabeculectomy. DESIGN: Retrospective, noncomparative case series.
      PARTICIPANTS: Thirty-four eyes from 27 patients undergoing initial trabeculectomy
      at the Glaucoma Consultation Service, Massachusetts Eye and Ear Infirmary (mean
      age, 43.7 years; range, 12-54 years). INTERVENTION: Follow-up averaged 42.6
      months (range, 11-90 months). METHODS: Lens status was observed before surgery
      and at 3 months; 6 months; and 1, 2, 3, 4, 5, and 6 years after initial
      trabeculectomy. MAIN OUTCOME MEASURE: The main outcome measure was defined as
      cataract extraction for visually significant lenticular opacifications that
      developed after trabeculectomy. RESULTS: The rate of cataract extraction after
      initial trabeculectomy was 24% (n = 8). The average time from trabeculectomy to
      cataract extraction was 26 months (range, 5-58 months). Progression of lenticular
      opacities occurred throughout the follow-up period. There was no increased rate
      of cataract formation in subjects with uveitic and steroid-induced glaucoma when
      compared with all other types of glaucoma. In the patients with both eyes in the
      study, the first eye was a predictor of cataract progression in the fellow eye.
      CONCLUSIONS: Cataract is a common complication after trabeculectomy in young
      patients. The 24% rate of cataract extraction after trabeculectomy reported in
      this study is a significant risk of which young patients contemplating surgery
      should be aware.

PMID- 12623834
TI  - A prospective ultrasound biomicroscopy evaluation of changes in anterior segment
      morphology after laser iridotomy in Asian eyes.
AB  - PURPOSE: To prospectively quantify changes in anterior segment morphology after
      laser iridotomy using gonioscopy and ultrasound biomicroscopy (UBM). DESIGN:
      Prospective comparative observational case series. PARTICIPANTS: Fifty-five
      fellow eyes of patients presenting with acute primary angle closure (APAC).
      METHODS: The fellow eyes of patients presenting with APAC were examined with UBM,
      A-scan ultrasonography, and optical pachymetry at presentation and 2 weeks after
      sequential argon/neodymium yttrium-aluminum-garnet laser peripheral iridotomy
      (LPI). UBM images were analyzed using UBM Pro 2000 software. Baseline
      measurements were made both under standard lighting conditions and in darkness to
      look for changes in anterior segment findings. MAIN OUTCOME MEASURES: The degree
      of angle opening was measured using the angle-opening distance (AOD) at 250 and
      500 microm from the scleral spur (AOD250 and AOD500, respectively) and angle
      recess area (ARA). RESULTS: Fifty-five Asian patients were examined; AOD250,
      AOD500, and ARA all significantly increased after sequential laser iridotomy (P <
      0.002). Gonioscopic grading of the angle opening significantly increased in all 4
      quadrants (P < 0.001). The Van Herick grade of limbal anterior chamber depth
      increased (P < 0.001), whereas the number of eyes classified as occludable
      decreased (73%-33%, P < 0.001). Anterior chamber depth did not change
      significantly (2.41 mm +/- 0.28 mm vs. 2.42 mm +/- 0.30 mm, P = 0.43) as measured
      with optical pachymetry. Increased illumination increased the angle-opening
      measures, but induced a different alteration in peripheral iris morphology.
      Illumination-induced changes were greater after iridotomy than before laser
      treatment. CONCLUSIONS: In Asian eyes at high risk of developing APAC, sequential
      LPI produced a significant widening of the anterior chamber angle without
      deepening the anterior chamber centrally. LPI produces changes in iris morphology
      that are different from those caused by an increase in illumination, indicating
      that different mechanisms account for angle opening under these 2 conditions.

PMID- 12623835
TI  - Severe telomere shortening in patients with paroxysmal nocturnal hemoglobinuria
      affects both GPI- and GPI+ hematopoiesis.
AB  - A most distinctive feature of paroxysmal nocturnal hemoglobinuria (PNH) is that
      in each patient glycosylphosphatidylinositol-negative (GPI-) and GPI+
      hematopoietic stem cells (HSCs) coexist, and both contribute to hematopoiesis.
      Telomere size correlates inversely with the cell division history of HSCs. In 10
      patients with hemolytic PNH the telomeres in sorted GPI- granulocytes were
      shorter than in sorted GPI+ granulocytes in 4 cases, comparable in 2 cases, and
      longer in the remaining 4 cases. Furthermore, the telomeres of both GPI- and GPI+
      hematopoietic cells were markedly shortened compared with age-matched controls.
      The short telomeres in the GPI- cells probably reflect the large number of cell
      divisions required for the progeny of a single cell to contribute a large
      proportion of hematopoiesis. The short telomeres of the GPI+ cells indicate that
      the residual hematopoiesis contributed by these cells is not normal. This
      epigenetic change is an additional feature shared by PNH and aplastic anemia.

PMID- 12623836
TI  - Anti-protein Z antibodies in women with pathologic pregnancies.
AB  - Protein Z deficiencies have recently been described in women with unexplained
      early fetal loss. Using a new, specifically elaborated, commercially available
      enzyme-linked immunosorbent assay (ELISA), we performed a case-control study on
      anti-protein Z immunoglobulin G (IgG) and IgM antibodies in 191 nonthrombotic,
      nonthrombophilic women with consecutive pathologic pregnancies. Levels of anti
      protein Z antibodies were categorized in 3 strata (percentiles 1 through 74, 75
      through 97, 98 through 100 among controls). The 2 upper levels of IgG and IgM
      anti-protein Z antibodies were associated with the risk of unexplained recurrent
      embryo loss or fetal death independently from habitual
      antiphospholipid/anticofactor antibodies, and a dose-effect relationship between
      antibody levels and the clinical risks was evidenced. In women, enhanced immune
      complex formation with protein Z may play a role in unexplained embryo losses
      and, from the 10th week of gestation, may favor hypercoagulability in the
      maternal placenta side.

PMID- 12623837
TI  - Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream
      of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases.
AB  - 17-allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone function of
      heat shock protein-90 (Hsp-90) and promotes the proteasomal degradation of its
      misfolded client proteins. Here, we demonstrate that treatment of the human acute
      myeloid leukemia HL-60 cells with 17-AAG attenuates the intracellular levels of a
      number of Hsp-90 client proteins, including Akt, c-Raf-1, and c-Src. Also, 17-AAG
      induced the mitochondrial release and cytosolic accumulation of cytochrome c (cyt
      c) and second mitochondria-derived activator of caspases (Smac)/DIABLO, resulting
      in the activation of caspase-9 and caspase-3 and apoptosis. Treatment with 17-AAG
      triggered the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) conformational
      change associated with apoptosis, while Bax-deficient cells were resistant to 17
      AAG-induced apoptosis. In addition, in HL-60/Bcl-2 and HL-60/Bcl-xL cells, which
      ectopically express Bcl-2 and Bcl-xL respectively, 17-AAG-induced Bax
      conformational change, cytosolic accumulation of cyt c and Smac/DIABLO, and
      apoptosis were markedly inhibited. Although the rate of 17-AAG-mediated decline
      in Akt, c-Raf-1, and c-Src levels was blunted, the total decline was not
      compromised in HL-60/Bcl-2 and HL-60/Bcl-xL cells. Cotreatment with HA14-1, a
      nonpeptidic ligand that can bind and inhibit the antiapoptotic activity of Bcl-2,
      significantly overcame the resistance to 17-AAG-induced apoptosis in HL-60/Bcl-2
      cells. Together, these findings indicate that although 17-AAG treatment causes
      the levels of a number of survival-signaling protein kinases to decline, the
      downstream engagement of the mitochondrial pathway of apoptosis is regulated by
      the activity of the Bcl-2 family of proteins. Also, neutralizing the
      antiapoptotic effect of Bcl-2 would further enhance the antileukemia activity of
      17-AAG.

PMID- 12623838
TI  - Gammadelta T cells for immune therapy of patients with lymphoid malignancies.
AB  - There is increasing evidence that gammadelta T cells have potent innate antitumor
      activity. We described previously that synthetic aminobisphosphonates are potent
      gammadelta T cell stimulatory compounds that induce cytokine secretion (ie,
      interferon gamma [IFN-gamma]) and cell-mediated cytotoxicity against lymphoma and
      myeloma cell lines in vitro. To evaluate the antitumor activity of gammadelta T
      cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in
      combination with pamidronate in 19 patients with relapsed/refractory low-grade
      non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial
      were to determine toxicity, the most effective dose for in vivo
      activation/proliferation of gammadelta T cells, and antilymphoma efficacy of the
      combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered
      the study received 90 mg pamidronate intravenously on day 1 followed by
      increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2
      (0.25 to 3 x 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level
      in vivo, gammadelta T-cell activation/proliferation and response to treatment
      were disappointing with only 1 patient achieving stable disease. Therefore, the
      next 9 patients were selected by positive in vitro proliferation of gammadelta T
      cells in response to pamidronate/IL-2 and received a modified treatment schedule
      (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B),
      significant in vivo activation/proliferation of gammadelta T cells was observed
      in 5 patients (55%), and objective responses (PR) were achieved in 3 patients
      (33%). Only patients with significant in vivo proliferation of gammadelta T cells
      responded to treatment, indicating that gammadelta T cells might contribute to
      this antilymphoma effect. Overall, administration of pamidronate and low-dose IL
      2 was well tolerated. In conclusion, this clinical trial demonstrates, for the
      first time, that gammadelta T-cell-mediated immunotherapy is feasible and can
      induce objective tumor responses.

PMID- 12623839
TI  - Map kinase signaling pathways and hematologic malignancies.
AB  - Mitogen-activated protein (Map) kinases are widely expressed serine-threonine
      kinases that mediate important regulatory signals in the cell. Three major groups
      of Map kinases exist: the p38 Map kinase family, the extracellular signal
      regulated kinase (Erk) family, and the c-Jun NH2-terminal kinase (JNK) family.
      The members of the different Map kinase groups participate in the generation of
      various cellular responses, including gene transcription, induction of cell death
      or maintenance of cell survival, malignant transformation, and regulation of cell
      cycle progression. Depending on the specific family isoform involved and the
      cellular context, Map kinase pathways can mediate signals that either promote or
      suppress the growth of malignant hematopoietic cells. Over the last few years,
      extensive work by several groups has established that Map kinase pathways play
      critical roles in the pathogenesis of various hematologic malignancies, providing
      new molecular targets for future therapeutic approaches. In this review, the
      involvement of various Map kinase pathways in the pathophysiology of hematologic
      malignances is summarized and the clinical implications of the recent advances in
      the field are discussed.

PMID- 12623840
TI  - Vitamin C inhibits FAS-induced apoptosis in monocytes and U937 cells.
AB  - The FAS receptor-FAS ligand system is a key apoptotic pathway for cells of the
      immune system. Ligation of the FAS-receptor (CD95) induces apoptosis by
      activation of pro-caspase-8 followed by downstream events, including an increase
      in reactive oxygen species (ROS) and the release of proapoptotic factors from the
      mitochondria, leading to caspase-3 activation. We investigated the role of
      vitamin C in FAS-mediated apoptosis and found that intracellular accumulation of
      pharmacologic concentrations of vitamin C inhibited FAS-induced apoptosis in the
      monocytic U937 cell line and in fresh human monocytes. Cells were loaded with
      vitamin C by exposure to dehydroascorbic acid (DHA), thereby circumventing in
      vitro artifacts associated with the poor transport and pro-oxidant effects of
      ascorbic acid (AA). Vitamin C inhibition of FAS-mediated apoptosis was associated
      with reduced activity of caspase-3, -8, and -10, as well as diminished levels of
      ROS and preservation of mitochondrial membrane integrity. Mechanistic studies
      indicated that the major effect of vitamin C was inhibition of the activation of
      caspase-8 with no effect on it enzymatic activity. An independent action of high
      intracellular concentrations of vitamin C on mitochondrial membrane stabilization
      was also detected. These studies illuminate the nature of redox-dependent
      signaling in FAS-induced apoptosis of human monocytes and suggest that vitamin C
      can modulate the immune system by inhibiting FAS-induced monocyte death.

PMID- 12623841
TI  - Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic
      motifs.
AB  - Receptor-mediated internalization appears to be the primary mean of regulating
      the plasma level of thrombopoietin (TPO). However, the processes that regulate
      Mpl internalization have not previously been described. Using the cytokine
      dependent cell line BaF3, we have identified 2 distinct motifs within the
      cytoplasmic domain of Mpl that underlie ligand-dependent internalization. Removal
      of the fourth cytoplasmic tyrosine residue by deletion or truncation results in a
      significant decrease in maximal internalization. The remaining receptor
      internalization is abrogated by deletion of cytoplasmic residues 54-69, which
      include the core box2 region (L54L55E56I57L58) and the only dileucine motifs
      (L54L55 and I57L58) within the cytoplasmic domain of Mpl. Receptor
      internalization mediated by this latter subdomain does not require Jak2
      activation. Furthermore, TPO-stimulated cellular proliferation appears to be
      directly correlated with receptor internalization, indicating that
      internalization of the TPO/Mpl complex may be essential for normal signal
      transduction. Finally, we have demonstrated that upon removal of TPO from the
      supernatant, Mpl promptly reappears on the cell surface, suggesting that a pool
      of intracellular Mpl can be rapidly recycled to the cell surface. These data help
      identify the receptor motifs involved in TPO-induced internalization of Mpl and
      suggest that Mpl translocation may be necessary for normal cellular
      proliferation.

PMID- 12623842
TI  - Gene expression profiling of multiple myeloma reveals molecular portraits in
      relation to the pathogenesis of the disease.
AB  - Although multiple myeloma (MM) is a unique entity, a marked heterogeneity is
      actually observed among the patients, which has been first related to
      immunoglobulin (Ig) types and light chain subtypes and more recently to
      chromosomal abnormalities. To further investigate this genetic heterogeneity, we
      analyzed gene expression profiles of 92 primary tumors according to their Ig
      types and light chain subtypes with DNA microarrays. Several clusters of genes
      involved in various biologic functions such as immune response, cell cycle
      control, signaling, apoptosis, cell adhesion, and structure significantly
      discriminated IgA- from IgG-MM. Genes associated with inhibition of
      differentiation and apoptosis induction were up-regulated while genes associated
      with immune response, cell cycle control, and apoptosis were down-regulated in
      IgA-MM. According to the expression of the 61 most discriminating genes, BJ-MM
      represented a separate subgroup that did not express either the genes
      characteristic of IgG-MM or those of IgA-MM at a high level. This suggests that
      transcriptional programs associated to the switch could be maintained up to
      plasma cell differentiation. Several genes whose products are known to stimulate
      bone remodeling discriminate between kappa- and lambda-MM. One of these genes,
      Mip-1alpha, was overexpressed in the kappa subgroup. In addition, we established
      a strong association (P =.0001) between kappa subgroup expressing high levels of
      Mip-1alpha and active myeloma bone disease. This study shows that DNA microarrays
      enable us to perform a molecular dissection of the bioclinical diversity of MM
      and provide new molecular tools to investigate the pathogenesis of malignant
      plasma cells.

PMID- 12623843
TI  - Clinical-cytogenetic associations in 306 patients with therapy-related
      myelodysplasia and myeloid leukemia: the University of Chicago series.
AB  - Therapy-related myelodysplasia and myeloid leukemia (t-MDS/t-AML) is a
      distinctive clinical syndrome occurring after exposure to chemotherapy (CT) or
      radiotherapy (RT). We report findings on 306 consecutive patients referred to our
      institution with morphologic review and cytogenetic analyses. Since 1972, 141
      males and 165 females with a median age of 51 years (range, 3-83 years) at
      primary diagnosis and 58 years (range, 6-86 years) at secondary diagnosis were
      analyzed. Patients had been administered various cytotoxic agents, including
      alkylating agents (240 patients, 78%) and topoisomerase 2 inhibitors (115
      patients, 39%). One hundred twenty-one (40%) had undergone CT alone, 43 (14%) had
      undergone RT alone, and 139 (45%) had undergone both modalities. At diagnosis of
      t-MDS/t-AML, 282 (92%) had clonal abnormalities involving chromosome 5 (n = 63),
      chromosome 7 (n = 85), chromosomes 5 and 7 (n = 66), recurring balanced
      rearrangements (n = 31), other clonal abnormalities (n = 39), or normal karyotype
      (n = 24). Abnormalities of chromosome 5, 7, or both accounted for 76% of all
      cases with an abnormal karyotype. Seventeen patients acquired t-MDS/t-AML after
      autologous stem cell transplantation, but no unique pattern of cytogenetic
      abnormalities was observed. Shorter latency was observed for patients with
      balanced rearrangements (median, 28 vs 67 months; P <.0001). Patients with acute
      leukemia were more likely to have balanced rearrangement than those with
      myelodysplasia (28% vs 4%; P <.0001). Median survival time after diagnosis of t
      MDS/t-AML was 8 months; survival at 5 years was less than 10%. These data confirm
      and extend previous associations between clinical, morphologic, and cytogenetic
      findings in t-MDS/t-AML.

PMID- 12623845
TI  - Rapid recruitment of inflammatory monocytes is independent of neutrophil
      migration.
AB  - Early neutrophil entry into an inflammatory site is thought to mediate a
      chemokine switch, inducing subsequent monocyte recruitment through the regulation
      of monocyte chemoattractant protein-1 (MCP-1) release. As the murine monocyte is
      poorly characterized and difficult to identify, there has been little examination
      of either its early recruitment in inflammatory models or of the factors that
      influence its early migration. The phenotyping of rapidly recruited inflammatory
      leukocytes with 7/4 and Gr-1 monoclonal antibodies (mAbs) identifies 2 distinct
      populations, which we characterize as murine monocytes and neutrophils. Monocytes
      migrate in the first 2 hours of inflammation making use of alpha4beta1 but not of
      Mac-1 or lymphocyte function-associated antigen-1 (LFA-1) integrins. Early
      migration is dependent on MCP-1, but neither MCP-1 release nor monocyte
      recruitment is affected by the reduced neutrophil migration seen in LFA-1-/-
      mice. Endogenous peritoneal macrophages and mesothelial cells lining the
      peritoneum contain MCP-1, which is released following thioglycollate stimulation.
      The murine monocyte therefore responds rapidly to chemokines produced in situ by
      tissue cells at the site of inflammation with no requirement for prior influx of
      neutrophils.

PMID- 12623844
TI  - Functional p85alpha gene is required for normal murine fetal erythropoiesis.
AB  - In vitro studies suggest that activation of class IA phosphatidylinositol 3 (PI
      3) kinase is necessary for normal erythroid cell development. However, when class
      IA PI-3 kinase-deficient mice were generated by a targeted deletion of the
      p85alpha regulatory subunit, fetal erythropoiesis was reportedly unaffected.
      Given the discrepancies between these studies, we performed a more detailed in
      vivo analysis of class IA PI-3 kinase-deficient embryos. Day-14.5 p85alpha-/-
      embryos are pale with a marked reduction of mature erythrocytes in their
      peripheral blood. Further, the absolute number and frequency of both early
      (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid
      colony-forming unit [CFU-E]) are reduced in p85alpha-/- fetal livers compared
      with wild-type controls, which is associated with reduced proliferation. Taken
      together, these data establish an important role for p85alpha and class IA PI-3
      kinase in regulating the development of both early and late erythroid progenitors
      in fetal liver.

PMID- 12623846
TI  - Myeloproliferative disease in transgenic mice expressing P230 Bcr/Abl: longer
      disease latency, thrombocytosis, and mild leukocytosis.
AB  - P230 Bcr/Abl has been associated with indolent myeloproliferative disease (MPD).
      We generated transgenic mice expressing P230Bcr/Abl driven by the promoter of the
      long terminal repeat of the murine stem cell virus of the MSCV neo P230 BCR/ABL
      vector. Two founder mice exhibited mild granulocytosis and marked thrombocytosis
      and developed MPD. The disease of one founder mouse, no. 13, progressed to
      extramedullary myeloblastic crisis in the liver at 12 months old. The other
      founder mouse, no. 22, was found to have chronic-phase MPD with large populations
      of megakaryocytes and granulocytes in an enlarged spleen. The transgenic progeny
      of no. 22 clearly exhibited MPD at 15 months old. These results showed that
      P230Bcr/Abl had leukemogenic properties and induced MPD. The phenotype of the MPD
      caused by P230Bcr/Abl was characterized by mild granulocytosis, a high platelet
      count, infiltration of megakaryocytes in some organs, and a longer disease
      latency compared with the MPD caused by P210Bcr/Abl.

PMID- 12623847
TI  - LFA-1 is required for retention of effector CD8 T cells in mouse lungs.
AB  - The adhesion molecules involved in the migration and retention of activated
      effector CD8 T cells in the lung microcirculation and their recruitment into lung
      tissue are largely unknown. Here, we have analyzed the role of lymphocyte
      function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) on adhesion
      of influenza hemagglutinin (HA)-specific CD8 T-cell clone D4 under shear
      conditions in an in vitro binding assay and in an in vivo homing assay to the
      lungs of naive or transgenic Balb/c mice expressing HA (HA-Tg) by a lung-specific
      promoter. Blocking LFA-1 or intercellular adhesion molecule 1 (ICAM-1)
      significantly inhibited adhesion of D4 cells to lung vascular endothelium and
      parenchyma of lung sections. However, blocking VLA-4 or vascular cell adhesion
      molecule 1 (VCAM-1) had no effect on cell adhesion. Blocking LFA-1 in vivo
      significantly delayed lethal injury following adoptive transfer of D4 cells into
      HA-Tg mice as assessed by weight loss and histology. Residence time of adoptively
      transferred Indium 111 (111In)-labeled D4 cells in lungs of normal and HA-Tg mice
      as analyzed by dual modality imaging revealed a significantly shorter transit
      time of 4 hours for the D4 cells upon in vivo blockade of LFA-1. These results
      demonstrate a crucial role for LFA-1 in retention of activated CD8 T cells in
      normal mouse lungs and in the progression of lethal injury in HA-Tg mice.

PMID- 12623848
TI  - Detection of BCR-ABL mutations in patients with CML treated with imatinib is
      virtually always accompanied by clinical resistance, and mutations in the ATP
      phosphate-binding loop (P-loop) are associated with a poor prognosis.
AB  - Imatinib-treated chronic myeloid leukemia (CML) patients with acquired resistance
      commonly have detectable BCR-ABL kinase domain mutations. It is unclear whether
      patients who remain sensitive to imatinib also have a significant incidence of
      mutations. We evaluated 144 patients treated with imatinib for BCR-ABL kinase
      domain mutations by direct sequencing of 40 accelerated phase (AP), 64 late
      chronic phase (> or = 12 months from diagnosis, late-CP), and 40 early-CP
      patients. Mutations were detected in 27 patients at 17 different residues, 13
      (33%) of 40 in AP, 14 (22%) of 64 in late-CP, and 0 of 40 in early-CP. Acquired
      resistance was evident in 24 (89%) of 27 patients with mutations. Twelve (92%) of
      13 patients with mutations in the adenosine triphosphate (ATP) binding loop (P
      loop) died (median survival of 4.5 months after the mutation was detected). In
      contrast, only 3 (21%) of 14 patients with mutations outside the P-loop died
      (median follow-up of 11 months). As the detection of mutations was strongly
      associated with imatinib resistance, we analyzed features that predicted for
      their detection. Patients who commenced imatinib more than 4 years from diagnosis
      had a significantly higher incidence of mutations (18 [41%] of 44) compared with
      those treated within 4 years (9 [9%] of 100), P <.0001. Lack of a major
      cytogenetic response (MCR) was also associated with a higher likelihood of
      detecting a mutation; 19 (38%) of 50 patients without a MCR had mutations
      compared with 8 (8.5%) of 94 with an MCR, P <.0001. In conclusion, the detection
      of kinase domain mutations using a direct sequencing technique was almost always
      associated with imatinib resistance, and patients with mutations in the P-loop
      had a particularly poor prognosis.

PMID- 12623849
TI  - Lack of NB1 GP (CD177/HNA-2a) gene transcription in NB1 GP- neutrophils from NB1
      GP-expressing individuals and association of low expression with NB1 gene
      polymorphisms.
AB  - The human neutrophil NB1 glycoprotein (NB1 GP, HNA-2a, CD177) has gained clinical
      importance for being involved in pulmonary transfusion reactions and immune
      neutropenias. The NB1 GP shows the unique feature of being expressed only on a
      neutrophil subpopulation. Recently, we identified splicing defects responsible
      for an NB1 GP deficiency. In this study, we have investigated the molecular basis
      of the heterogeneous expression of NB1 GP by separating the 2 neutrophil
      subpopulations using immunofluorescence followed by single-cell picking or by
      fluorescence-activated cell sorter. We found a lack of NB1 mRNA in the NB1 GP-
      cells that remained constant even after granulocyte colony-stimulating factor (G
      CSF) administration. Comparing the cDNA sequences of donors with a large (> 60%)
      and those with a small (< 40%) NB1 GP-expressing subpopulation, we found 6
      polymorphisms. Of the 6, 3 were significantly associated with a small NB1 GP
      expressing subpopulation, indicating a genetic basis for NB1 GP nonexpression.

PMID- 12623850
TI  - Differential STAT3, STAT5, and NF-kappaB activation in human hematopoietic
      progenitors by endogenous interleukin-15: implications in the expression of
      functional molecules.
AB  - Different forms of interleukin-15 (IL-15) have been identified and shown to
      elicit different transduction pathways whose impact on hematopoiesis is poorly
      understood. We demonstrated herein that hematopoietic CD34+ cells constitutively
      produced endogenous secreted IL-15 (ES-IL-15) that activated different
      transcription factors and controlled the expression of several functional
      proteins, depending on the progenitor source. Thus, nuclear factor-kappa B (NF
      kappa B) was activated in bone marrow (BM) and cord blood (CB) progenitors,
      whereas signal transducer and activator of transcription 3 (STAT3) and STAT5
      activation was restricted to peripheral granulocyte-colony-stimulating factor (G
      CSF)-mobilized and BM progenitors, respectively. ES-IL-15 acts through
      autocrine/paracrine loops controlled by high-affinity receptors involving IL-15
      receptor alpha (IL-15Ralpha). Furthermore, ES-IL-15 was found to differentially
      control the expression of several functional molecules important for
      hematopoietic differentiation. Indeed, in BM precursors, neutralizing anti-IL-15
      monoclonal antibody (mAb) inhibits the expression of the gamma c chain and of the
      chemokine stromal derived factor-1 (SDF-1) but had no effect on vascular cell
      adhesion molecule 1 (VCAM-1) and beta1 integrin adhesion molecule expression.
      Conversely, in CB progenitors, anti-IL-15 mAb inhibited VCAM-1 and beta1 integrin
      expression without affecting gammac chain expression and, most important, up
      regulated SDF-1 expression. In conclusion, unprimed human hematopoietic CD34+
      cells secrete cell-unbound IL-15, which activates through autocrine/paracrine
      loop distinct signaling pathways, depending on the progenitor source, thereby
      influencing the expression of several molecules important in the control of
      hematopoiesis.

PMID- 12623851
TI  - Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in
      allogeneic transplantations: relevance for early adoptive immunotherapy and
      infectious complications.
AB  - Persistence of alemtuzumab at lympholytic concentrations after reduced-intensity
      conditioning allogeneic stem cell transplantations (RITs) could impair immune
      reconstitution and reduce donor T-cell-mediated graft-versus-leukemia/lymphoma
      (GVL) effects, derived from the graft or subsequent adoptive immunotherapy. We
      have studied the pharmacokinetics of alemtuzumab in 2 different groups: RIT (100
      mg alemtuzumab in vivo over 5 days) and myeloablative allografts (20 mg
      alemtuzumab added in vitro to the stem cells prior to return). Alemtuzumab
      concentrations in RIT patients were in excess of that required to kill infused
      donor CD52+ cells at the time of transplantation and remained at potentially
      lympholytic levels (> 0.1 microg/mL) for approximately 56 days after
      transplantation, 26 days longer than for the myeloablative group. Total
      lymphocyte counts were significantly lower in the RIT group persisting beyond 6
      months after transplantation (P =.005), and median absolute CD4 counts higher
      than 200 x 106/L were delayed until 9 months after transplantation.

PMID- 12623852
TI  - Gene expression analysis of purified hematopoietic stem cells and committed
      progenitors.
AB  - Lifelong self-renewal is a unique property of somatic stem cells. Recently,
      several primitive multipotent yet committed (non-self-renewing) hematopoietic
      progenitor populations were identified in mouse bone marrow. We have
      characterized the expression of 1200 selected mouse genes using the Atlas cDNA
      array in highly purified hematopoietic stem cells (HSCs) and 6 closely related
      progenitor populations: common myeloid progenitors (CMPs), granulocyte-macrophage
      progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), common lymphoid
      progenitors (CLPs), and pro-T and pro-B cells. Cluster analysis revealed that
      nearly half of all differentially expressed transcripts are associated with HSCs,
      supporting the notion of an active transcriptional status of HSCs. Genes found
      enriched in the HSC cluster encompass many developmentally regulated genes, some
      previously associated with HSC self-renewal. In contrast, genes that are enriched
      in committed progenitors are mostly associated with hematopoietic
      differentiation, immune regulation, and metabolism. Thus, the transition from
      HSCs toward committed progenitors correlates with the down-regulation of a large
      number of HSC-associated genes and progressive up-regulation of a limited number
      of lineage-specific genes. These genetic analyses revealed both quantitative and
      qualitative differences between the transcripts associated with HSCs versus
      downstream progenitors and produced a list of the candidate genes, potentially
      involved in HSC self-renewal.

PMID- 12623853
TI  - Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate
      established MDR-1 multidrug-resistant T-cell leukemia.
AB  - Effective therapy of high-risk leukemia with established cytotoxic drugs may be
      limited by poor antitumor efficacy, systemic toxicity, and the induction of drug
      resistance. Here, we provide the first evidence that hydrolytically activated
      prodrugs may overcome these problems. For this purpose, VP16 was functionally
      blocked by hydrolytically cleavable carbonate linkers with unique characteristics
      to generate 2 novel prodrugs of VP16. First, we established a more than 3-log
      higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug
      resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced
      multidrug resistance-1 gene (MDR-1)-mediated multidrug resistance in vitro in a
      newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally
      blocking MDR-1-mediated efflux. Third, in vivo studies showed a maximum tolerated
      dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of
      VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft
      model of T-cell leukemia expressing MDR-1 indicated that only the mice treated
      with this prodrug revealed a complete and long-lasting regression of established,
      drug-resistant leukemia. In summary, the hydrolytically activated etoposide
      prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro
      and in vivo and provide proof of concept for a highly promising new strategy for
      the treatment of MDR-1 drug-resistant malignancies.

PMID- 12623854
TI  - Fluorescence measurements of the labile iron pool of sickle erythrocytes.
AB  - Sickle erythrocytes have increased ferritin and increased molecular iron on the
      inner membrane leaflet, and we postulated that cytosolic labile iron is also
      elevated. We used the fluorescent metallosensor, calcein, and a permeant Fe2+
      chelator to estimate labile cytoslic Fe2+, and calcein plus an Fe3+ chelator to
      estimate total cytosolic labile iron (Fe2+ + Fe3+). We measured membrane nonheme
      iron by its reactivity with ferrozine. As estimated by calcein and Fe2+ chelator,
      the mean +/- SD labile Fe2+ concentration was significantly lower in hemoglobin
      (Hb) SS (n = 29) than hemoglobin AA (n = 17) erythrocytes (0.56 +/- 0.35 microM
      versus 1.25 +/- 0.65 microM; P <.001). In contrast, as estimated by calcein and
      Fe3+ chelator, total erythrocyte labile iron was similar in hemoglobin SS (n =
      12) and hemoglobin AA (n = 10) participants (1.75 +/- 0.41 microM versus 2.14 +/-
      0.93 microM; P =.2). Mean membrane nonheme iron levels were higher in hemoglobin
      SS cells than hemoglobin AA cells (0.0016 x 10-4 versus 0.0004 x 10-4 fmol/cell;
      P =.01), but much lower than the mean amounts of total labile iron (1.6-1.8 x 10
      4 fmol/cell) or hemoglobin iron (18 000-19 000 x 10-4 fmol/cell). Both membrane
      iron and total labile iron were much less than the mean amount of iron
      potentially present in erythrocyte ferritin as calculated from results of other
      investigators (15 x 10-4 versus 34 x 10-4 fmol/cell in HbAA versus HbSS
      erythrocytes). We conclude that cytosolic labile iron is not elevated in
      hemoglobin SS erythrocytes and that elemental membrane iron is present in only
      trace amounts.

PMID- 12623855
TI  - Rifampin and pyrazinamide for treatment of latent tuberculosis infection: is it
      safe?

PMID- 12623856
TI  - Emergence of nontuberculous mycobacteria as pathogens in cystic fibrosis.

PMID- 12623857
TI  - Theophylline: new perspectives for an old drug.

PMID- 12623858
TI  - Aminoglycoside prescribing and surveillance in cystic fibrosis.

PMID- 12623859
TI  - Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates nitric
      oxide-induced activator protein-1 activation in human bronchial epithelial cells.
AB  - Exhaled nitric oxide (NO) is increased in individuals with bronchial asthma. NO
      may have antiinflammatory and proinflammatory effects; however, its role in
      bronchial asthma is unclear. In the present study, to clarify this issue we
      examined the effect of NO in inducing activator protein-1 (AP-1) activation in
      human bronchial epithelial cells (BEC) and a role of apoptosis signal-regulating
      kinase1 (ASK1), an upstream kinase kinase of c-Jun-NH2-terminal kinase (JNK) and
      p38 mitogen-activated protein kinase (MAPK) in NO-mediated AP-1 activation. The
      results showed that (1) the reactive nitrogen generating species NOR-1(+/--(E)
      methyl-2-[(E)-hydroxykmino]-5-nitro-6-methoxy-3-hexeneamide]) induced AP-1
      activation determined by AP-1-dependent luciferase gene activity, and an NO
      scavenger, carboxyl-PTIO, attenuated NOR-1-induced AP-1 activation; (2) NOR-1
      phosphorylated ASK1, JNK, and p38 MAPK; and (3) transient transfection of the
      dominant negative form of AKS1 attenuated NOR-1-induced AP-1 activation in BEC.
      To further characterize the role of ASK-1 cascade, the dominant negative form of
      ASK1-stable transfected porcine artery endothelial (PAE) cells were used. AP-1
      activity and JNK and p38 MAPK phosphorylation were depressed in the dominant
      negative form of ASK1-stable transfected PAE cells. These results indicate that
      NO is capable of inducing AP-1 activation, and that ASK1-p38 MAPK/JNK cascade
      regulates AP-1 activation in NO-stimulated BEC.

PMID- 12623860
TI  - Association between glycemic state and lung function: the Framingham Heart Study.
AB  - Diabetes mellitus has been inconsistently associated with a reduced level of
      pulmonary function. To elucidate this association further, we analyzed the
      relationship of diabetes and of fasting blood glucose to the level of pulmonary
      function assessed by spirometry in the 3,254 members of the Framingham Offspring
      Cohort. Diabetes was defined as a fasting blood glucose of 126 mg/dl or more or
      pharmacologic treatment. Subjects were classified as current, former, or never
      smokers based on questionnaire responses. Predicted pulmonary function was
      determined from the coefficients of a regression of pulmonary function on age,
      sex, and body habitus in the 1,110 never smokers. Both the diagnosis of diabetes
      and a higher level of fasting blood glucose were associated with lower than
      predicted levels of pulmonary function. The adverse effect of diabetes and
      glycemic level on pulmonary function was stronger among ever smokers than never
      smokers, suggesting an interaction between the level of fasting glycemia and
      tobacco smoking.

PMID- 12623861
TI  - Tidal volumes in ARDS and meta-analysis.

PMID- 12623862
TI  - GOLD stage 0.

PMID- 12623863
TI  - Pressure-induced activation of extracellular signal-regulated kinase 1/2 in small
      arteries.
AB  - Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling
      role in vascular remodeling. We investigated a possible combined role for the
      renin-angiotensin system and platelet-derived growth factor beta-receptor (PDGF
      beta-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small
      arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1
      hour plus a 5-minute intervention period. The intervention was either a rise in
      intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II,
      0.1 micromol/L) or PDGF-BB (30 microg/L). ERK1/2 activation was determined by
      Western blotting as formation of phosphorylated ERK1/2. All interventions caused
      ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response
      to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor
      type 1 (R-AT1) antagonist (candesartan), and tyrosine kinase inhibitors
      (genistein, herbimycin A). An R-AT2 antagonist (PD123319) had no significant
      effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a
      neutralizing PDGF-beta-R antibody (AF385) inhibited the activation of ERK1/2
      caused by PDGF-BB, Ang II, and pressure. That the latter interventions could
      indeed inhibit the PDGF-beta-R was supported by experiments with unmounted
      vessels in which PDGF-beta-R activation was measured by Western blot; both PDGF
      BB and Ang II-mediated PDGF-beta-R activation were inhibited by RPR101511A and
      AF385. Immunohistochemistry showed that ERK1/2 and PDGF-beta-R was located in the
      adventitia, tunica media, and intima. The results suggest that pressure in rat
      mesenteric small arteries causes acute activation of ERK1/2 through pathways
      involving Ang II and PDGF-beta-R.

PMID- 12623864
TI  - Akt is a major downstream target of PI3-kinase involved in angiotensin II-induced
      proliferation.
AB  - Different signal transduction cascades have been implicated in angiotensin II
      (Ang II)-mediated cell growth, such as the extracellular signal-regulated kinase
      1/2 (ERK1/2) and the phosphatidylinositol 3-kinase (PI3K) pathways. To identify
      the downstream targets of PI3K involved in Ang II-induced proliferation, we used
      both rat aortic smooth muscle (RASM) cells and a CHO cell line stably expressing
      the rat AT1A receptor. The ERK1/2 and PI3K pathways are independently activated
      and implicated in Ang II-mediated DNA synthesis and cell number increase in these
      2 cell lines. In addition, a specific inhibitor of Akt inhibited Ang II-induced
      Akt phosphorylation, DNA synthesis and proliferation in CHO-AT1A or RASM cells. A
      dominant-negative mutant of Akt was also found to selectively block Ang II
      induced proliferation of CHO-AT1A cells. To further elucidate the signaling
      events leading to Akt activation, we used an AT1 receptor mutant (AT1AD74E),
      deficient for Gq protein coupling, and the intracellular calcium chelator BAPTA
      AM. Although altered Akt and ERK1/2 activation was observed in the CHO-AT1AD74E
      cell line, blockade of intracellular calcium elevation did not affect
      phosphorylation of these kinases. These results provide the first evidence of a
      specific and necessary role of Akt in Ang II-induced proliferation through a Gq
      protein-dependent calcium-independent pathway.

PMID- 12623866
TI  - More hype than HOPE.

PMID- 12623867
TI  - Exercising restraint in measuring blood pressure in conscious mice.

PMID- 12623868
TI  - Plasma brain natriuretic peptide levels and blood pressure tracking in the
      Framingham Heart Study.
AB  - Increased brain natriuretic peptide (BNP) expression in the ventricles antedates
      elevated blood pressure (BP) in experimental studies. We hypothesized that higher
      plasma BNP levels in nonhypertensive individuals may be associated with a greater
      likelihood of future BP increase and/or hypertension. We evaluated the relations
      of plasma BNP to longitudinal BP tracking and incidence of hypertension in 1801
      nonhypertensive Framingham Heart Study participants (mean age, 56 years; 57%
      women) by using gender-specific multivariable logistic regression. Progression of
      BP stage was defined as an increment of one or more BP categories, as classified
      by the Joint National Committee on Prevention, Detection, Evaluation, and
      Treatment of High Blood Pressure (JNC VI). Hypertension was defined as a systolic
      BP > or =140 or diastolic BP > or =90 mm Hg or use of antihypertensive
      medications. On follow-up 4 years from baseline, progression of BP category was
      observed in 36.2% of men and 33.1% of women; hypertension developed in 16.4% of
      men and 15.5% of women. In multivariable models adjusting for known risk factors,
      elevated plasma BNP level was associated with increased risk of BP progression in
      men (odds ratio of 1.15 for trend across categories, P=0.046) but not in women
      (P=0.82). There were no significant trends of increasing incidence of
      hypertension across BNP categories in men or women. In our community-based
      sample, higher plasma BNP levels were associated with increased risk of BP
      progression in men but not women. Additional investigations are warranted to
      confirm these findings and elucidate the basis for these gender-related
      differences.

PMID- 12623869
TI  - The excitement and rewards of research with our discovery of some of the
      biological effects of nitric oxide.

PMID- 12623870
TI  - A magnificent time with the "magnificent seven" transmembrane spanning receptors.

PMID- 12623871
TI  - The cyclin-dependent kinase pathway moves forward.

PMID- 12623872
TI  - Vectorial sodium transport across the mammalian alveolar epithelium: it occurs
      but through which cells?

PMID- 12623873
TI  - Is depressed myocyte contractility centrally involved in heart failure?
AB  - This review examines the evidence for and against the hypothesis that
      abnormalities in cardiac contractility initiate the heart failure syndrome and
      drive its progression. There is substantial evidence that the contractility of
      failing human hearts is depressed and that abnormalities of basal Ca2+ regulation
      and adrenergic regulation of Ca2+ signaling are responsible. The cellular and
      molecular defects that cause depressed myocyte contractility are not well
      established but seem to culminate in abnormal sarcoplasmic reticulum uptake,
      storage, and release. There are also strong links between Ca2+ regulation, Ca2+
      signaling pathways, hypertrophy, and heart failure that need to be more clearly
      delineated. There is not substantial direct evidence for a causative role for
      depressed contractility in the initiation and progression of human heart failure,
      and some studies show that heart failure can occur without depressed myocyte
      contractility. Stronger support for a causal role for depressed contractility in
      the initiation of heart failure comes from animal studies where maintaining or
      improving contractility can prevent heart failure. Recent clinical studies in
      humans also support the idea that beneficial heart failure treatments, such as
      beta-adrenergic antagonists, involve improved contractility. Current or
      previously used heart failure treatments that increase contractility, primarily
      by increasing cAMP, have generally increased mortality. Novel heart failure
      therapies that increase or maintain contractility or adrenergic signaling by
      selectively modulating specific molecules have produced promising results in
      animal experiments. How to reliably implement these potentially beneficial
      inotropic therapies in humans without introducing negative side effects is the
      major unanswered question in this field.

PMID- 12623874
TI  - Spatial microstimuli in endothelial mechanosignaling.
AB  - Descriptive and quantitative analyses of microstimuli in living endothelial cells
      strongly support an integrated mechanism of mechanotransduction regulated by the
      spatial organization of multiple structural and signaling networks. Endothelial
      responses to blood flow are regulated at multiple levels of organization
      extending over scales from vascular beds to single cells, subcellular structures,
      and individual molecules. Microstimuli at the cellular and subcellular levels
      exhibit temporal and spatial complexities that are increasingly accessible to
      measurement. We address the cell and subcellular physical interface between flow
      related forces and biomechanical responses of the endothelial cell. Live cell
      imaging and computational analyses of structural dynamics, two important
      approaches to microstimulation at this scale, are briefly reviewed.

PMID- 12623875
TI  - Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction
      and calcium handling.
AB  - A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to
      the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a
      constitutive NOS in the proximity of an activating source of Ca2+ suggests that
      cardiac nNOS-derived NO may regulate contraction by exerting a highly specific
      and localized action on ion channels/transporters involved in Ca2+ cycling. To
      test this hypothesis, we have investigated myocardial Ca2+ handling and
      contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute
      nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO
      increased basal contraction both in left ventricular (LV) myocytes (steady-state
      cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in
      vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C;
      P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in
      nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of
      inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a
      greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus
      0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1)
      peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS
      /- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel
      mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate
      that nNOS is an important determinant of basal contractility in the mammalian
      myocardium. The full text of this article is available at
      http://www.circresaha.org.

PMID- 12623876
TI  - 12-lipoxygenase in opioid-induced delayed cardioprotection: gene array, mass
      spectrometric, and pharmacological analyses.
AB  - 12-lipoxygenase (12-LO) has been shown to be a factor in acute ischemic
      preconditioning (IPC) in the isolated rat heart; however, no studies have been
      reported in delayed PC. We characterized the role of 12-LO in an intact rat model
      of delayed PC induced by a delta-opioid agonist SNC-121 (SNC). Rats were
      pretreated with SNC and allowed to recover for 24 hours. They were then treated
      with either baicalein or phenidone, 2 selective 12-LO inhibitors. In addition,
      SNC-pretreated rats had plasma samples isolated at different times after ischemia
      reperfusion for liquid chromatographic-mass spectrometric analysis of the major
      metabolic product of 12-LO, 12-HETE. Similar studies were conducted with
      inhibitors. Gene array data showed a significant induction of 12-LO message
      (P<0.05) after opioid pretreatment. This induction in 12-LO mRNA was confirmed by
      real-time polymerase chain reaction, and 12-LO protein expression was enhanced by
      SNC pretreatment at 24 hours relative to vehicle treatment. Both baicalein and
      phenidone attenuated the protective effects of SNC pretreatment on infarct size
      (50+/-4% and 42+/-3% versus 29+/-2%, P<0.05, respectively). No significant
      differences were observed in 12-HETE concentrations between baseline control and
      SNC-treated rats. However, 12-HETE concentrations were increased significantly at
      both 15 minutes during ischemia and at 1 hour of reperfusion in the SNC-treated
      rats compared with controls. Baicalein and phenidone attenuated the increase in
      12-HETE at 1 hour of reperfusion. These data suggest that SNC-121 appears to
      enhance message and subsequently the activity and expression of 12-LO protein
      during times of stress, resulting in delayed cardioprotection.

PMID- 12623877
TI  - Protein kinase C signaling transduces endorphin-primed cardiogenesis in GTR1
      embryonic stem cells.
AB  - The prodynorphin gene and its product, dynorphin B, have been found to promote
      cardiogenesis in embryonic cells by inducing the expression of GATA-4 and Nkx
      2.5, two transcription factor-encoding genes essential for cardiogenesis. The
      molecular mechanism(s) underlying endorphin-induced cardiogenesis remain unknown.
      In the present study, we found that GTR1 embryonic stem (ES) cells expressed cell
      surface kappa opioid receptors, as well as protein kinase C (PKC)-alpha, -beta1, 
      beta2, -delta, -epsilon, and -zeta. Cardiac differentiation was associated with a
      marked increase in the Bmax value for a selective opioid receptor ligand and
      complex subcellular redistribution of selected PKC isozymes. PKC-alpha, -beta1, 
      beta2, -delta, and -epsilon all increased in the nucleus of ES-derived cardiac
      myocytes, compared with nuclei from undifferentiated cells. In both groups of
      cells, PKC-delta and -epsilon were mainly expressed at the nuclear level. The
      nuclear increase of PKC-alpha, -beta1, and -beta2 was due to a translocation from
      the cytosolic compartment. In contrast, the increase of both PKC-delta and PKC
      epsilon in the nucleus of ES-derived cardiomyocytes occurred independently of
      enzyme translocation, suggesting changes in isozyme turnover and/or gene
      expression during cardiogenesis. No change in PKC-zeta expression was observed
      during cardiac differentiation. Opioid receptor antagonists prevented the nuclear
      increase of PKC-alpha, PKC-beta1, and PKC-beta2 and reduced cardiomyocyte yield
      but failed to affect the nuclear increase in PKC-delta and -epsilon. PKC
      inhibitors prevented the expression of cardiogenic genes and dynorphin B in ES
      cells and abolished their development into beating cardiomyocytes.

PMID- 12623878
TI  - Dynorphin B is an agonist of nuclear opioid receptors coupling nuclear protein
      kinase C activation to the transcription of cardiogenic genes in GTR1 embryonic
      stem cells.
AB  - The cardiac differentiation of embryonic stem (ES) cells was found to involve
      prodynorphin gene and dynorphin B expression and was associated with the
      interaction of secreted dynorphin B with cell surface opioid receptors coupled
      with protein kinase C (PKC) signaling and complex subcellular redistribution
      patterning of selected PKC isozymes. Here, confocal microscopy revealed the
      presence of immunoreactive dynorphin B-like material in GTR1 ES cells, suggesting
      that dynorphin peptides may also act intracellularly. Opioid binding sites were
      identified in ES cell nuclei, with a single dissociation constant in the low
      nanomolar range. A significant increase in Bmax for a kappa opioid receptor
      ligand was observed in nuclei isolated from ES-derived cardiomyocytes compared
      with nuclei from undifferentiated cells. Direct exposure of nuclei isolated from
      undifferentiated ES cells to dynorphin B or U-50,488H, a synthetic kappa opioid
      receptor agonist, time- and dose-dependently activated the transcription of GATA
      4 and Nkx-2.5, 2 cardiac lineage-promoting genes. Nuclear exposure to dynorphin B
      also enhanced the rate of prodynorphin gene transcription. These responses were
      abolished in a stereospecific fashion by the incubation of isolated nuclei with
      selective opioid receptor antagonists. Nuclei isolated from undifferentiated
      cells were able to phosphorylate the acrylodan-labeled MARCKS peptide, a high
      affinity fluorescent PKC substrate. Exposure of isolated nuclei to dynorphin B
      induced a remarkable increase in nuclear PKC activity, which was suppressed by
      opioid receptor antagonists. Nuclear treatment with PKC inhibitors abolished the
      capability of dynorphin B to prime the transcription of cardiogenic genes.

PMID- 12623879
TI  - Reengineering inducible cardiac-specific transgenesis with an attenuated myosin
      heavy chain promoter.
AB  - Despite the advantages of reversibly altering cardiac transgene expression, the
      number of successful studies with inducible cardiac-specific transgene expression
      remains limited. The utility of the current system is hampered by the large
      number of lines needed before a nonleaky inducible line is isolated and by the
      use of a heterologous virus-based minimal promoter in the responder line. We
      developed an efficient, experimentally flexible system that enables us to
      reversibly affect both abundant and nonabundant cardiomyocyte proteins. The use
      of bacterial-codon-based transactivators led to aberrant splicing, whereas other
      more efficient transactivators, by themselves, caused disease when expressed in
      the heart. The redesign of the system focused on developing stable transactivator
      expressing lines in which expression was driven by the mouse alpha-myosin heavy
      chain promoter. A minimal responder locus was derived from the same promoter, in
      which the GATA sites and thyroid responsive elements responsible for robust
      cardiac specific expression were ablated, leading to an attenuated promoter that
      could be inducibly controlled. In all cases, whether activated or not, expression
      mimicked that of the parental promoter. By use of this system, an inducible
      expression of an abundant contractile protein, the atrial isoform of essential
      myosin light chain 1, and a powerful biological effector, glycogen synthase
      kinase-3beta (GSK-3beta), were obtained. Subsequently, we tested the hypothesis
      that GSK-3beta expression could reverse a preexisting hypertrophy. Inducible
      expression of GSK-3beta could both attenuate a hypertrophic response and
      partially reverse a pressure-overload-induced hypertrophy. The system appears to
      be robust and can be used to temporally control high levels of cardiac-specific
      transgene expression.

PMID- 12623880
TI  - Caspase-dependent cell death mediates the early phase of aortic hypertrophy
      regression in losartan-treated spontaneously hypertensive rats.
AB  - Blockade of angiotensin type 1 (AT1) receptors induces smooth muscle cell (SMC)
      death and regression of aortic hypertrophy in spontaneously hypertensive rats
      (SHR). We postulated that SMC death and vascular remodeling in this model may be
      attenuated by z-Val-Ala-Asp(OMe)-CH2F (z-VAD-fmk), a tripeptide inhibitor of
      caspase enzymes mediating apoptosis. To determine the time course of SMC death
      and aortic remodeling, SHR were treated with losartan (30 mg/kg per day) for up
      to 9.5 days. Transient SMC apoptosis occurred in the aortic media with a peak
      around day 5 of treatment, with increases in the Bax to Bcl-2 protein ratio (>3
      fold), in active caspase-3 (5.6-fold), in TUNEL-positive nuclei (19-fold),
      preceding by 24 hours the peak activation of capase-9 (3.8-fold), and significant
      reductions in SMC number (46%) and aortic cross-sectional area (8.5%) at 5.5
      days. The decrease in total aortic DNA reached significance at 6.5 days (29%).
      Blood pressure reduction with losartan was progressive and reached significance
      at day 7 of treatment. Next, we examined the causal link between vascular
      apoptosis and remodeling. SHR received placebo or losartan (30 mg/kg per day) for
      6 days. During the last 24 hours, a subgroup of losartan-treated rats received 3
      IV injections of z-VAD-fmk (cumulative dose: 4.4 mg x kg(-1)). All other rats
      received the vehicle, DMSO. The 24-hour cotreatment with z-VAD-fmk effectively
      prevented losartan-induced caspase-3 activation and internucleosomal DNA
      fragmentation, as well as SMC depletion and the reductions in aortic mass and DNA
      content. Together, these data suggest that caspase-dependent SMC death mediates
      the early phase of vascular remodeling in response to AT1 receptor blockade in
      this model of hypertension.

PMID- 12623881
TI  - A breaker of advanced glycation end products attenuates diabetes-induced
      myocardial structural changes.
AB  - The formation of advanced glycation end products (AGEs) on extracellular matrix
      components leads to accelerated increases in collagen cross linking that
      contributes to myocardial stiffness in diabetes. This study determined the effect
      of the crosslink breaker, ALT-711 on diabetes-induced cardiac disease.
      Streptozotocin diabetes was induced in Sprague-Dawley rats for 32 weeks.
      Treatment with ALT-711 (10 mg/kg) was initiated at week 16. Diabetic hearts were
      characterized by increased left ventricular (LV) mass and brain natriuretic
      peptide (BNP) expression, decreased LV collagen solubility, and increased
      collagen III gene and protein expression. Diabetic hearts had significant
      increases in AGEs and increased expression of the AGE receptors, RAGE and AGE-R3,
      in association with increases in gene and protein expression of connective tissue
      growth factor (CTGF). ALT-711 treatment restored LV collagen solubility and
      cardiac BNP in association with reduced cardiac AGE levels and abrogated the
      increase in RAGE, AGE-R3, CTGF, and collagen III expression. The present study
      suggests that AGEs play a central role in many of the alterations observed in the
      diabetic heart and that cleavage of preformed AGE crosslinks with ALT-711 leads
      to attenuation of diabetes-associated cardiac abnormalities in rats. This
      provides a potential new therapeutic approach for cardiovascular disease in human
      diabetes.

PMID- 12623882
TI  - Interstitial flow as a guide for lymphangiogenesis.
AB  - The lymphatic system is important in tissue fluid balance regulation, immune cell
      trafficking, edema, and cancer metastasis, yet very little is known about the
      sequence of events that initiate and coordinate lymphangiogenesis. Here, we
      characterize the process of lymphatic regeneration by uniquely correlating
      interstitial fluid flow and lymphatic endothelial cell migration with lymphatic
      function. A new model of skin regeneration using a collagen implant in a mouse
      tail has been developed, and it shows that (1) interstitial fluid channels form
      before lymphatic endothelial cell organization and (2) lymphatic cell migration,
      vascular endothelial growth factor-C expression, and lymphatic capillary network
      organization are initiated primarily in the direction of lymph flow. These data
      suggest that interstitial fluid channeling precedes and may even direct
      lymphangiogenesis (in contrast to blood angiogenesis, in which fluid flow
      proceeds only after the vessel develops); thus, a novel and robust model is
      introduced for correlating molecular events with functionality in
      lymphangiogenesis.

PMID- 12623883
TI  - Prognosis after heart transplantation: transplants alone cannot be the solution
      for end stage heart failure.

PMID- 12623884
TI  - The health of indigenous peoples.

PMID- 12623885
TI  - Neurocysticercosis: eradication of cysticercosis is an attainable goal.

PMID- 12623886
TI  - Moving beyond single and dual diagnosis in general practice: many patients have
      multiple morbidities, and their needs have to be addressed.

PMID- 12623888
TI  - WHO challenges food industry in report on diet and health.

PMID- 12623889
TI  - Asia grapples with obesity epidemics.

PMID- 12623890
TI  - BMA warns that too few people know response to a terrorist attack.

PMID- 12623891
TI  - Long term, low intensity warfarin helps against deep vein thrombosis.

PMID- 12623892
TI  - Three trusts deliberately misreported data, says Audit Commission.

PMID- 12623893
TI  - UK government advises tighter measures to reduce risk of CJD transmission during
      neurosurgery.

PMID- 12623895
TI  - US drug sales continue to rise.

PMID- 12623896
TI  - Biological father declared the legal father in IVF mix up.

PMID- 12623897
TI  - Strong anti-tobacco treaty rejected by two rich nations.

PMID- 12623898
TI  - Bayer is forced to release documents over withdrawal of cerivastatin.

PMID- 12623902
TI  - University is criticised for accepting tobacco money.

PMID- 12623903
TI  - Perinatal mortality in Iraq more than tripled since sanctions.

PMID- 12623904
TI  - Water purifying system could save lives in developing countries.

PMID- 12623905
TI  - India plans to expand private sector in healthcare review.

PMID- 12623908
TI  - Second coming for patient power.

PMID- 12623909
TI  - Modelling the cost effectiveness of interferon beta and glatiramer acetate in the
      management of multiple sclerosis. Commentary: evaluating disease modifying
      treatments in multiple sclerosis.
AB  - OBJECTIVE: To evaluate the cost effectiveness of four disease modifying
      treatments (interferon betas and glatiramer acetate) for relapsing remitting and
      secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling
      cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing
      remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN
      OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base
      case cost per quality adjusted life year gained by using any of the four
      treatments ranged from pound 42,000 (66,469 dollars; 61,630 euro) to pound 98,000
      based on efficacy information in the public domain. Uncertainty analysis suggests
      that the probability of any of these treatments having a cost effectiveness
      better than pound 20,000 at 20 years is below 20%. The key determinants of cost
      effectiveness were the time horizon, the progression of patients after stopping
      treatment, differential discount rates, and the price of the treatments.
      CONCLUSIONS: Cost effectiveness varied markedly between the interventions.
      Uncertainty around point estimates was substantial. This uncertainty could be
      reduced by conducting research on the true magnitude of the effect of these
      drugs, the progression of patients after stopping treatment, the costs of care,
      and the quality of life of the patients. Price was the key modifiable determinant
      of the cost effectiveness of these treatments.

PMID- 12623910
TI  - Disclosure of financial competing interests in randomised controlled trials:
      cross sectional review.

PMID- 12623911
TI  - Total and cause specific mortality among Swedish women with cosmetic breast
      implants: prospective study.

PMID- 12623912
TI  - Systematic review of lipid lowering for primary prevention of coronary heart
      disease in diabetes.

PMID- 12623913
TI  - Effect of NHS walk-in centre on local primary healthcare services: before and
      after observational study.
AB  - OBJECTIVE: To assess the effect of an NHS walk-in centre on local primary and
      emergency healthcare services. DESIGN: Before and after observational study.
      SETTING: Loughborough, which had an NHS walk-in centre, and Market Harborough,
      the control town. PARTICIPANTS: 12 general practices. MAIN OUTCOME MEASURES: Mean
      daily rate of emergency general practitioner consultations, mean number of half
      days to the sixth bookable routine appointment, and attendance rates at out of
      hours services, minor injuries units, and accident and emergency departments.
      RESULTS: The change between the before and after study periods was not
      significantly different in the two towns for daily rate of emergency general
      practice consultations (mean difference -0.02/1000 population, 95% confidence
      interval -0.75 to 0.71), the time to the sixth bookable routine appointment (
      0.24 half-days, -1.85 to 1.37), and daily rate of attendances at out of hours
      services (0.07/1000 population, -0.06 to 0.19). However, attendance at the local
      minor injuries unit was significantly higher in Loughborough than Market
      Harborough (rate ratio 1.22, 1.12 to 1.33). Non-ambulance attendances at accident
      and emergency departments fell less in Loughborough than Market Harborough (rate
      ratio 1.17, 1.03 to 1.33). CONCLUSIONS: The NHS walk-in centre did not greatly
      affect the workload of local general practitioners. However, the workload of the
      local minor injuries unit increased significantly, probably because it was in the
      same building as the walk-in centre.

PMID- 12623914
TI  - Impact of NHS walk-in centres on the workload of other local healthcare
      providers: time series analysis.
AB  - OBJECTIVES: To assess the impact of NHS walk-in centres on the workload of local
      accident and emergency departments, general practices, and out of hours services.
      DESIGN: Time series analysis in walk-in centre sites with no-treatment control
      series in matched sites. SETTING: Walk-in centres and matched control towns
      without walk-in centres in England. PARTICIPANTS: 20 accident and emergency
      departments, 40 general practices, and 14 out of hours services within 3 km of a
      walk-in centre or the centre of a control town. MAIN OUTCOME MEASURES: Mean
      number (accident and emergency departments) or rate (general practices and out of
      hours services) of consultations per month in the 12 month periods before and
      after an index date. RESULTS: A reduction in consultations at emergency
      departments (-175 (95% confidence interval -387 to 36) consultations per
      department per month) and general practices (-19.8 (-53.3 to 13.8) consultations
      per 1000 patients per month) close to walk-in centres became apparent, although
      these reductions were not statistically significant. Walk-in centres did not have
      any impact on consultations on out of hours services. CONCLUSION: It will be
      necessary to assess the impact of walk-in centres in a larger number of sites and
      over a prolonged period, to determine whether they reduce the demand on other
      local NHS providers.

PMID- 12623915
TI  - 10-minute consultation: chronic low back pain.

PMID- 12623916
TI  - Medical students' application of published evidence: randomised trial.
AB  - OBJECTIVES: To determine how medical students apply research evidence that varies
      in validity of methods and importance of results to a clinical decision. DESIGN:
      Students examined a standardised patient with a whiplash injury, decided whether
      to order a cervical spine radiograph, and rated their confidence in their
      decision. They then read one of four randomly assigned variants of a structured
      abstract from a study of a decision rule that argued against such a procedure in
      this patient. Variants factorially combined two levels of validity of methods
      (prospective cohort or chart review) with two levels of importance of results
      (high sensitivity or high specificity rule). After reading the abstract, students
      repeated their choice and rated their confidence. SETTING: Academic medical
      centre in the United States. PARTICIPANTS: 164 graduating medical students. MAIN
      OUTCOME MEASURES: Proportion of students in each group whose beliefs shifted or
      stayed the same. RESULTS: When abstracts were of low importance students were
      more likely to shift their beliefs in favour of radiography, which was not
      supported by the evidence (odds ratio 3.42, 95% confidence interval 1.10 to
      10.66). Neither methodological validity nor the interaction between validity and
      importance influenced decision shift. Few students acquired all necessary
      clinical data from the patient. CONCLUSIONS: Although the students could apply
      concepts of diagnostic testing, greater focus is needed on appraisal of validity
      and application of evidence to a particular patient.

PMID- 12623917
TI  - Diagnosis and management of scalp ringworm.

PMID- 12623918
TI  - Lesson of the week: interfering antibodies affecting immunoassays in woman with
      pet rabbits.

PMID- 12623919
TI  - ABC of learning and teaching in medicine: one to one teaching and feedback.

PMID- 12623920
TI  - Multisource feedback: a method of assessing surgical practice.

PMID- 12623921
TI  - Engaging patients with psychosis in consultations. Design of study has several
      problems.

PMID- 12623922
TI  - Some screening is necessary to identify excessive drinkers early in primary care.

PMID- 12623923
TI  - Current medical treatment for tuberculosis. Aspects of chemotherapy and
      management need clarifying.

PMID- 12623924
TI  - Meningoencephalitis due to primary HIV infection. HIV infection may also cause
      rash or glandular fever type illness.

PMID- 12623925
TI  - Care of dying patients. Education in palliative care for all.

PMID- 12623926
TI  - State can make drugs available cheaply to poor people.

PMID- 12623927
TI  - Inversion of emergency pyramid. Scheme does not address real problems.

PMID- 12623928
TI  - Working for a primary care trust.

PMID- 12623930
TI  - Putting them through their PACES. Practical Assessment of Clinical Examination
      Skills.

PMID- 12623931
TI  - Vasopeptidase inhibition: a double-edged sword?
AB  - The enormous benefits of inhibition of ACE demonstrate that manipulation of the
      metabolism of peptide hormones is a valuable therapeutic strategy for
      cardiovascular disease. Recent attempts to expand these benefits have combined
      ACE inhibition with inhibition of other peptidases such as neutral endopeptidase
      (NEP) in a single molecule, a strategy known as vasopeptidase inhibition. NEP
      metabolizes natriuretic peptides, and NEP inhibition offers the prospect of
      combining the benefits of increased natriuretic peptide levels with those of ACE
      inhibition. However, peptidases such as ACE and NEP have many different
      substrates, and there are complex interactions between ACE inhibition and NEP
      inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and
      kallidin, and NEP also converts angiotensin (Ang) I to Ang-(1-7) and metabolizes
      Ang II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates
      the ACE inhibitor-induced increase in kinin levels, increases Ang II levels,
      reduces Ang-(1-7) levels, and may increase endothelin levels. These additional
      consequences of combined ACE/NEP inhibition increase the risk of angioedema and
      may counteract any benefit of ACE inhibition that depends on reduced Ang II
      levels and increased Ang-(1-7) levels. Further considerations are that the ratio
      of ACE and NEP inhibition is fixed for vasopeptidase inhibitors, and there is
      uncertainty how these drugs should be compared with ACE inhibitors. Vasopeptidase
      inhibitors will therefore require careful evaluation before they are introduced
      to patient care.

PMID- 12623932
TI  - Commentary on Tikellis et al: There is more to discover about angiotensin
      converting enzyme.

PMID- 12623933
TI  - Characterization of renal angiotensin-converting enzyme 2 in diabetic
      nephropathy.
AB  - ACE2, initially cloned from a human heart, is a recently described homologue of
      angiotensin-converting enzyme (ACE) but contains only a single enzymatic site
      that catalyzes the cleavage of angiotensin I to angiotensin 1-9 [Ang(1-9)] and is
      not inhibited by classic ACE inhibitors. It also converts angiotensin II to Ang(1
      7). Although the role of ACE2 in the regulation of the renin-angiotensin system
      is not known, the renin-angiotensin system has been implicated in the
      pathogenesis of diabetic complications and in particular in diabetic nephropathy.
      Therefore, the aim of this study was to assess the possible involvement of this
      new enzyme in the kidney from diabetic Sprague-Dawley rats to compare and
      contrast it to ACE. ACE2 and ACE gene and protein expression were measured in the
      kidney after 24 weeks of streptozocin diabetes. ACE2 and ACE mRNA levels were
      decreased in diabetic renal tubules by approximately 50% and were not influenced
      by ACE inhibitor treatment with ramipril. By immunostaining, both ACE2 and ACE
      protein were localized predominantly to renal tubules. In the diabetic kidney,
      there was reduced ACE2 protein expression that was prevented by ACE inhibitor
      therapy. The identification of ACE2 in the kidney, its modulation in diabetes,
      and the recent description that this enzyme plays a biological role in the
      generation and degradation of various angiotensin peptides provides a rationale
      to further explore the role of this enzyme in various pathophysiological states
      including diabetic complications.

PMID- 12623934
TI  - ACE and alpha-adducin polymorphism as markers of individual response to diuretic
      therapy.
AB  - Renin-angiotensin system reactivity and the constitutive capacity of the renal
      tubule to reabsorb sodium play a role in the individual response to diuretic
      therapy; therefore we evaluated the blood pressure (BP) response to
      hydrochlorothiazide in 87 never-treated individuals with mild essential
      hypertension, according to ACE gene I/D and alpha-adducin Gly460Trp polymorphism.
      These genotypes where chosen because previous data showed their interaction in
      determining the BP response to salt probably was the result of their involvement
      in the activation of the renin-angiotensin system (ACE) and in the constitutive
      capacity of the kidney to reabsorb sodium (alpha-adducin) (treatment for 2
      months). BP was measured after 3 run-in visits and after the first and second
      months of treatment by means of a standardized procedure. Data were analyzed by
      ANOVA, t test, and multivariate ANOVA for repeated measures (covarying for
      gender, age, and body mass index). Although basal mean BP (MBP) was similar in
      the different ACE and alpha-adducin genotypes, patients carrying at least one I
      allele of ACE and one 460Trp allele of alpha-adducin had the largest MBP decrease
      with treatment (12.7+/-1.9 mm Hg), the effect of the combination of genotypes
      being additive but not epistatic. These patients had an odds ratio of 15.75 of
      being a responder to hydrochlorothiazide compared with patients with
      Gly460Gly+DD, with the least MBP decrease (3.4+/-1.7 mm Hg). Alpha-adducin and
      ACE I/D polymorphism may be useful to predict the interindividual degree of
      response to hydrochlorothiazide; the analysis of the combination of the 2
      genotypes increases the accuracy of the prediction of response to the drug.

PMID- 12623935
TI  - Association of coronary artery disease with glucocorticoid receptor N363S
      variant.
AB  - Overweight is associated with the N363S variant in the glucocorticoid receptor
      (encoded by nuclear receptor subfamily 3, group C, member 1 gene: NR3C1). The
      present study examined whether the N363S polymorphism might also be associated
      with coronary artery disease (CAD). This involved 556 patients with CAD, of which
      437 were analyzed, and 302 control subjects, all being of Anglo-Celtic descent
      residing in Sydney. An extensive range of phenotypic parameters was collected
      from the patients, and leukocyte DNA from all subjects was genotyped by
      polymerase chain reaction-restriction fragment length polymorphism analysis for
      the A1218G (N363S) variant. Frequency of the S363 allele was 0.04 in healthy
      normal-weight control subjects but was 0.15 in patients with CAD (P=2.0x10(-5))
      and was also elevated in subjects with CAD who were not overweight (0.14)
      (P=2.6x10(-5)), supporting a primary association with CAD. Frequency of S363
      allele carriers in subjects with CAD who had angina was particularly high:
      unstable angina (0.45), stable angina (0.29), and no angina (0.26) (P for
      trend=0.016). Elevated cholesterol (P=0.027), triglycerides (P=0.005), and total
      cholesterol/HDL ratio (P=0.011), after Bonferroni, tracked with the S363 allele,
      consistent with accentuation of mechanisms that predispose to atheroma formation
      in coronary vessels. The data suggest a role for glucocorticoid receptor
      variation in the underlying cause of CAD.

PMID- 12623936
TI  - Family history of hypertension and type 2 diabetes in relation to preeclampsia
      risk.
AB  - In a case-control study of 190 preeclamptic patients and 373 control subjects, we
      assessed maternal family history of chronic hypertension and type 2 diabetes in
      relation to preeclampsia risk. Participants provided information on first-degree
      family history of the 2 conditions and other covariates during postpartum
      interviews. Logistic regression was used to estimate odds ratios and 95%
      confidence intervals adjusted for confounding by age, race, and obesity. Compared
      with women with no parental history of hypertension, women with maternal only
      (odds ratio=1.9), paternal only (odds ratio=1.8), or both maternal and paternal
      history of hypertension (odds ratio=2.6) had a statistically significant
      increased risk of preeclampsia. The odds ratio for women with at least one
      hypertensive parent and a hypertensive sibling was 4.7 (95% confidence interval,
      1.9 to 11.6). Both maternal only (odds ratio=2.1; 95% confidence interval, 0.9 to
      4.6) and paternal only (odds ratio=1.9; 95% confidence interval, 1.0 to 3.2)
      history of diabetes was associated with an increased risk of preeclampsia. Women
      with a diabetic sibling had a 4.7-fold increased risk of preeclampsia (95%
      confidence interval, 1.1 to 19.8). For women with at least one hypertensive
      parent and at least one diabetic parent, relative to those with parents with
      neither diagnosis, the odds ratio for preeclampsia was 3.2 (95% confidence
      interval, 1.6 to 6.2). Our results are consistent with the thesis that family
      history of hypertension and diabetes reflects genetic and behavioral factors
      whereby women may be predisposed to an increased preeclampsia risk.

PMID- 12623937
TI  - Cardiac transcriptome analysis in obesity-related hypertension.
AB  - Obesity is associated with volumetric arterial hypertension and with early
      increase in heart rate and decreased heart rate variability. The consequences of
      obesity-related hypertension on heart gene regulation are poorly known and were
      investigated in a model of obesity-related hypertension induced by high fat diet
      in dogs. When compared with control animals (n=6), a 9-week high fat diet (n=6)
      provoked significant weight gain and increased blood pressure load and heart rate
      but failed to significantly change left ventricular mass assessed by
      echocardiography. Subtractive hybridization of dog heart cDNA libraries were used
      to generate sublibraries containing differentially expressed cDNAs that were in
      turn spotted onto membranes to create custom microarrays. Hybridizations of these
      microarrays with complex probes representing mRNAs expressed in right atria and
      left ventricles from obese hypertensive and control dogs were performed. Thirty
      eight differentially expressed genes were identified; altered expression was
      confirmed by Northern blot analysis in 15. In addition, real-time quantitative
      polymerase chain reaction confirmed differential expression for 80% of the
      randomly chosen tested genes. Once identified, transcripts were categorized into
      groups involved in metabolism, cell signaling, ionic regulation, cell
      proliferation, protein synthesis, and tissue remodeling. In addition, we found a
      set of 11 cDNAs encoding proteins with unknown functions. This study clearly
      shows that obesity-related hypertension, lasting for only 9 weeks, causes marked
      changes in gene expression in right atrium as well as the left ventricle that may
      contribute to early functional changes in heart function and to long-term
      structural changes such as left ventricular hypertrophy and remodeling.

PMID- 12623938
TI  - DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity.
AB  - Evidence suggests that obesity may raise blood pressure (BP) through oxidative
      stress-sensitive mechanisms and that the Dietary Approaches to Stop Hypertension
      combination diet (DASH-CD) may decrease BP by enhancing antioxidant capacity. To
      address this question, 12 obese patients with high-normal-to-stage 1 hypertension
      (hypertensives) and 12 lean normotensives were studied on their usual diets and
      after following the DASH-CD and a low-antioxidant diet in random sequence for 4
      weeks each. Acute oxidative stress was induced by a 4-hour infusion of intralipid
      and heparin. Ferric-reducing activity of plasma (FRAP) and plasma F2-isoprostanes
      were measured as biomarkers of antioxidant capacity and oxidative stress,
      respectively. BP was lower in obese hypertensives on the DASH-CD than on the
      usual and low-antioxidant diets (-8.1+/-1.5/-7.4+/-1.6 mm Hg, P<0.05). BP did not
      change significantly in lean normotensives after 4 weeks on the DASH-CD but
      tended to rise on the low-antioxidant diet. FRAP on usual diets was higher in
      lean subjects than in obese subjects. FRAP increased in obese but not lean
      volunteers on the DASH-CD compared with usual diet, and the group difference
      disappeared. F2-isoprostanes increased from baseline during intralipid and
      heparin in both groups on the low-antioxidant diet but not in obese hypertensives
      on the DASH-CD. Among free-living obese hypertensives, the DASH-CD raises
      antioxidant capacity, lowers BP, and reduces oxidative stress induced by acute
      hyperlipidemia. The findings are consistent with evidence that elevated BP in
      obese subjects may reflect an imbalance between antioxidant capacity and
      oxidative stress that is improved by the DASH-CD.

PMID- 12623939
TI  - Outcomes with nifedipine GITS or Co-amilozide in hypertensive diabetics and
      nondiabetics in Intervention as a Goal in Hypertension (INSIGHT).
AB  - To investigate the impact of treatment on cardiovascular mortality and morbidity,
      we assessed outcomes in patients with hypertension and diabetes who received co
      amilozide or nifedipine in the International Nifedipine GITS Study: Intervention
      as a Goal in Hypertension. Participants had to be 55 to 80 years of age, with
      hypertension (> or =150/95 or > or =160 mm Hg) and at least one additional
      cardiovascular risk factor. Patients received 30 mg nifedipine once daily or co
      amilozide (25 mg hydrochlorothiazide and 2.5 mg amiloride) daily. Doses were
      doubled if target blood pressures (<140/90 mm Hg) were not achieved. Primary
      (composite of cardiovascular death, myocardial infarction, heart failure, and
      stroke) and secondary outcomes (composite of primary outcomes, including all
      cause mortality and death from vascular and nonvascular causes) were assessed by
      means of intent-to-treat analyses. There was no significant difference in the
      incidence of primary outcomes between nifedipine-treated and co-amilozide-treated
      patients with diabetes at baseline (n=1302) (8.3% versus 8.4%; relative risk,
      0.99, 95% CI, 0.69 to 1.42; P=1.00). A significant benefit for nifedipine-treated
      patients was seen for the composite secondary outcome (14.2% versus 18.7%;
      relative risk, 0.76, 95% CI, 0.59 to 0.97; P=0.03). Among patients without
      diabetes at baseline (n=5019), there was a significant difference in the
      incidence of new diabetes (nifedipine 4.3% versus co-amilozide 5.6%, P=0.023).
      Nifedipine GITS once daily is as effective as diuretic therapy in reducing
      cardiovascular complications in hypertensive diabetics. Nifedipine-treated
      patients were also less likely to have diabetes or have secondary events (a
      composite of all-cause mortality, death from a vascular cause, and death from a
      nonvascular cause) than co-amilozide recipients. Our results suggest that
      nifedipine could be considered as first-line therapy for hypertensive diabetics.

PMID- 12623940
TI  - Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy.
AB  - A Working Group on Research in Hypertension in Pregnancy was recently convened by
      the National Heart, Lung, and Blood Institute to determine the state of knowledge
      in this area and suggest appropriate directions for research. Hypertensive
      disorders in pregnancy, especially preeclampsia, are a leading cause of maternal
      death worldwide and even in developed countries increase perinatal mortality
      rates 5-fold. Much has been learned about preeclampsia, but gaps in the knowledge
      necessary to direct therapeutic strategies remain. Oxidative stress is a
      biologically plausible contributor to the disorder that may be amenable to
      intervention. Hypertension that antedates pregnancy (chronic hypertension) bears
      many similarities to hypertension in nonpregnant women, but the special setting
      of pregnancy demands information to guide evidence-based therapy. The
      recommendations of the Working Group are to attempt a clinical trial of
      antioxidant therapy to prevent preeclampsia that is be complemented by
      mechanistic research to increase understanding of the genetics and pathogenesis
      of the disorder. For chronic hypertension, clinical trials are recommended to
      direct choice of drugs, evaluate degree of control, and assess implications to
      the mother and fetus. Recommendations to increase participation in this research
      are also presented.

PMID- 12623941
TI  - Self-perpetuating effects of birth size on blood pressure levels in elderly
      people.
AB  - It has been suggested that essential hypertension is determined by 2 separate
      mechanisms: a growth-promoting process in childhood and a self-perpetuating
      mechanism in adult life. We report a clinical study of 500 people taken from a
      cohort of 7086 men and women who were born in Helsinki from 1924 to 1933, and
      whose body size at birth was recorded. As expected, blood pressure levels were
      inversely related to birthweight and birth length. These associations, however,
      were confined to the 213 people who had previously been diagnosed as having
      hypertension. In them, a 1-kg increase in birthweight was associated with a 6.4
      mm Hg (95% confidence interval, 1.0 to 11.9) decrease in systolic blood pressure
      recorded at the clinic, and with a 9.3-mm Hg (95% confidence interval, 2.1 to
      16.5) decrease recorded by ambulatory measurement. We conclude that pathological
      processes initiated in utero become self-perpetuating in adult life and lead to
      hypertension. Among elderly people with established hypertension, these processes
      have a strong effect on blood pressure levels, because they are processes that do
      not respond well to treatment.

PMID- 12623942
TI  - Rapid child growth raises blood pressure in adolescent boys who were thin at
      birth.
AB  - Catch-up growth in previously growth-restricted children is a suggested risk
      factor for chronic disease risk. We use data from 2026 Filipino adolescents to
      identify periods of growth that matter more for risk of high blood pressure (BP).
      Subjects were drawn from the Cebu Longitudinal Health and Nutrition Survey, which
      enrolled pregnant women and followed up their offspring through age 14 to 16
      years. High BP was defined as the top 10% of residuals from gender-specific
      regressions of systolic and diastolic BP on age and height. After controlling for
      birth length, current body mass index, age, and height, the odds of high BP in
      males were significantly decreased with each kilogram increase in birth weight.
      The highest odds of elevated BP occurred among males who were relatively thin at
      birth but relatively heavy as adolescents. Larger weight increments from birth to
      2 years decreased the odds of high BP in boys, whereas larger increments from 8
      to 11 and 11 to 16 years increased the odds of high BP. Thinness at birth
      significantly interacted with growth rate after age 8, such that a high rate of
      weight gain increased risk only among boys who were in the lower two thirds of
      the body mass index distribution at birth. Results in girls indicated small or no
      effects of early growth. The synergistic effect on adolescent BP of rapid weight
      gain from late childhood into adolescence with thinness at birth is further
      evidence of fetal programming of BP in males and suggests long-term health risks
      associated with rapid growth, even in the absence of obesity.

PMID- 12623944
TI  - Blood lead level is associated with elevated blood pressure in blacks.
AB  - Chronic lead exposure has been associated with elevated blood pressure in
      epidemiological studies. It is not known whether the previously observed relation
      between blood lead and hypertension persists after significant reductions have
      been made in environmental lead contamination. We examined the relation between
      blood lead levels and blood pressure in a representative sample of 14 952 whites
      and blacks aged 18 years or older who participated in the Third National Health
      and Nutrition Examination Survey. Blood lead was measured by atomic absorption
      spectrophotometry and blood pressure by standard sphygmomanometry. Mean blood
      lead levels were significantly higher for black men and women (5.4 and 3.4
      microg/dL, respectively) compared with white men and women (4.4 and 3.0
      microg/dL, respectively). After multivariate adjustment for important
      covariables, each standard deviation higher blood lead (3.3 microg/dL) was
      associated with a 0.82 (95% confidence interval [CI], 0.19 to 1.44) mm Hg and a
      1.55 (95% CI, 0.47 to 2.64) mm Hg higher systolic blood pressure among black men
      and women, respectively. In contrast, blood lead level was not associated with
      blood pressure among white men or women. The multivariate-adjusted odds ratio
      (95% CI) of hypertension associated with a 1-SD higher level of blood lead was
      1.08 (95% CI, 0.99 to 1.19) for black men and 1.39 (95% CI, 1.21 to 1.61) for
      black women. These findings suggest that increased levels of blood lead remain an
      important environmental risk factor for elevated blood pressure in blacks.

PMID- 12623943
TI  - Placental insufficiency leads to development of hypertension in growth-restricted
      offspring.
AB  - Low birth weight is a suggested risk factor for the development of hypertension.
      The purpose of the present study was to determine whether a model of intrauterine
      growth restriction produced in response to placental insufficiency in the
      pregnant rat was associated with marked elevations in blood pressure. Reduced
      uterine perfusion initiated in late gestation resulted in low-birth-weight
      offspring (5.8+/-0.1 versus 6.6+/-0.2 g, P<0.05, growth-restricted versus
      control, respectively). Mean arterial pressure, as measured in conscious,
      chronically instrumented rats, was significantly elevated as early as 4 weeks of
      age (113+/-3 versus 98+/-2 mm Hg, P<0.05) and was associated with significant
      decreases in body weight (66+/-2 versus 81+/-3 g, P<0.05) in growth-restricted
      (n=15) versus control (n=15) rats. Marked elevations in arterial pressure at 8
      weeks of age (male: 133+/-3 versus 121+/-6 mm Hg, P<0.05; female: 137+/-4 versus
      112+/-6 mm Hg, P<0.01) were associated with sex-specific decreases in body weight
      (male: 251+/-6 versus 275+/-10 g, P<0.05; female: 163+/-6 versus 180+/-6 g) in
      male growth-restricted (n=12) versus male control (n=9) rats and in female growth
      restricted (n=8) versus female control (n=7) rats. At 12 weeks of age,
      hypertensive (144+/-4 versus 131+/-3 mm Hg, P<0.05) male growth-restricted
      offspring (n=10) had no alterations in glomerular filtration rate (2.3+/-0.3
      versus 2.2+/-0.2 mL/min) compared with control (n=10) offspring; even when
      adjusted for kidney weight (1.7+/-0.3 versus 1.5+/-0.3 mL x min(-1) x g(-1)
      kidney), despite marked decreases in body weight (305+/-9 versus 343+/-10 g,
      P<0.05). These data suggest that placental insufficiency induced by reduced
      uterine perfusion in the pregnant rat results in low-birth-weight offspring
      predisposed to development of hypertension.

PMID- 12623945
TI  - Left ventricular concentric geometry as a risk factor in gestational
      hypertension.
AB  - In the past, an adverse prognostic significance of an altered left ventricular
      geometry in essential hypertension has been demonstrated. There are no data on
      the prognostic significance of an altered cardiac structure during pregnancy. The
      present study was designed to evaluate the prognostic impact on the outcome of
      pregnancy of an altered geometry of the left ventricle in mild gestational
      hypertension. One hundred forty-eight consecutive, pregnant, mild gestational
      hypertensive women (systolic and diastolic blood pressure, 140 to 150 mm Hg and
      90 to 99 mm Hg, respectively) were included in the study. Patients were monitored
      until term to detect subsequent fetal and/or maternal adverse outcomes
      (preeclampsia, preterm delivery, abruptio placentae, other maternal medical
      problems, fetal distress, neonatal low birth weight, admittance to neonatal
      intensive care unit). One hundred one gestational hypertensive patients (68.2%)
      had an uneventful pregnancy; 47 patients (31.8%) showed a subsequent development
      of maternal and/or fetal complications. Concentric geometry was prevalent among
      patients with the subsequent development of complicated gestational hypertension
      (37 out of 47 patients) compared with the uneventful gestational hypertensive
      patients (31 out of 101 patients; 78.7% versus 30.1%; P=0.0001). The multivariate
      analysis showed concentric geometry as an independent predictor of adverse
      outcomes (odds ratio, 3.65; 95% confidence interval, 1.30 to 10.27; P=0.014). In
      patients with gestational hypertension, blood pressure values alone appear to be
      insufficient to identify the effective risk of adverse events. Ventricular
      geometry gives additional prognostic information, possibly improving our clinical
      ability to follow and eventually treat these patients.

PMID- 12623946
TI  - ST segment depression criteria and the prevalence of silent cardiac ischemia in
      hypertensives.
AB  - The reported prevalence of silent cardiac ischemia as assessed by ambulatory
      electrocardiographic recording varies widely. The influence of the stringency of
      the analysis criteria has never been reported. We performed 24-hour, 12-lead
      ambulatory electrocardiographic recording in patients with hypertension but
      without proven coronary artery disease. The recordings were analyzed according to
      strict ST segment depression criteria adapted from the American College of
      Cardiology/American Heart Association guidelines and according to basic ST
      segment depression criteria adapted from studies with only concise descriptions
      of ambulatory electrocardiographic recording analysis. Also, we performed 24-hour
      ambulatory blood pressure monitoring. More than 4400 hours of ambulatory
      electrocardiographic recording and ambulatory blood pressure monitoring in 194
      patients with hypertension were analyzed. Medication was withdrawn in 45% of the
      patients. The average systolic blood pressure during the day was 152+/-13 (mean+/
      SD); diastolic blood pressure was 94+/-17 mm Hg. According to the basic ST
      segment depression criteria, we found a prevalence of silent ischemia of 11.3%,
      and with the strict criteria the prevalence was 5.2%. The patients who were
      considered positive according to the basic criteria but not according to the
      strict criteria (false-positive) in the majority of cases (58%) had depression of
      an elevated baseline ST segment. We found a lower prevalence of silent cardiac
      ischemia as assessed by ambulatory electrocardiographic recording than generally
      reported. The stringency of applied analysis criteria appear to play an important
      role in this outcome.

PMID- 12623947
TI  - Myocardial uptake and biochemical and hemodynamic effects of ACE inhibitors in
      humans.
AB  - There is little information on the processes affecting selective tissue ACE
      inhibition and the implications in human subjects. We compared intravenously
      administered ACE inhibitors, perindoprilat and enalaprilat, for myocardial drug
      uptake and effects on angiotensin and bradykinin peptides versus hemodynamic
      effects in 25 patients with stable angina and well-preserved left ventricular
      systolic function. Myocardial uptake was rapid and more efficient for
      perindoprilat than for enalaprilat (peak content at 26+/-3 and 30+/-4 seconds,
      0.58+/-0.12% and 0.27+/-0.07% of the administered dose for perindoprilat and
      enalaprilat, respectively, P=0.04 for difference). Both drugs caused a decrease
      in angiotensin (Ang) II level, an increase in Ang I level, and reduction in Ang
      II/Ang I ratio in arterial and coronary sinus blood. Bradykinin (BK)-(1-9) and BK
      (1-8) levels increased in arterial blood and BK-(1-8) levels increased in
      coronary sinus blood after drug administration. Perindoprilat and enalaprilat
      caused a small decrease in mean arterial pressure (-3+/-1%, P<0.05; and -4+/-1%,
      P<0.01, respectively) and LV+dP/dt (-5.8+/-1.7%, P<0.01 and -4.2+/-2.8%, P<0.05,
      respectively), whereas systemic vascular resistance index was unchanged. Despite
      relatively cardioselective uptake of perindoprilat, both drugs had similar
      effects on the cardiac metabolism of angiotensin and bradykinin and on cardiac
      function. Under resting conditions, both drugs exerted small negative inotropic
      effects.

PMID- 12623948
TI  - Association between periodontal disease and left ventricle mass in essential
      hypertension.
AB  - Chronic periodontitis has been associated with an increased risk for
      cardiovascular disease. Left ventricular mass is an established independent
      predictor of cardiovascular disease. In the present cross-sectional study, we
      tested the association between periodontitis and left ventricular mass in
      subjects with essential hypertension. One hundred four untreated subjects with
      essential hypertension underwent clinical examinations, including
      echocardiographic study, laboratory tests, and assessment of periodontal status
      according to the community periodontal index of treatment needs (CPITN). With
      increasing severity of periodontitis, there was a progressive increase in left
      ventricle mass. Mean values (g/height2.7) were 39.0 (+/-2.7) in CPITN 0
      (periodontal health), 40.2 (+/-6.4) in CPITN 1 (gingival bleeding), 42.7 (+/-6.8)
      in CPITN 2 (calculus), 51.4 (+/-11.7) in CPITN 3 (pockets 4 to 5 mm), and 76.7
      (+/-11.3) in CPITN 4 (pockets > or =6 mm) (overall F 51.2; P<0.0001). Body
      surface area (P=0.04), systolic (P<0.0001) and diastolic (P<0.01) blood pressure,
      and left ventricular mass (P<0.0001) were determinants of a composite of CPITN 3
      and 4. In a multivariate logistic analysis, left ventricular mass was the sole
      determinant (P<0.0001) of CPITN stages 3 and 4. Our findings suggest a direct
      association between severity of periodontitis and left ventricular mass in
      subjects with essential hypertension. Periodontal evaluation might contribute to
      refine cardiovascular risk assessment in hypertensive subjects.

PMID- 12623949
TI  - Na/H exchange isoform 1 is involved in mineralocorticoid/salt-induced cardiac
      injury.
AB  - Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate
      (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid
      receptors (MRs). However, the underlying cellular mechanisms remain unclear. To
      determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular
      mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and
      an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and
      hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous
      injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups
      of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day
      SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated
      with only high salt after the operation. The DOCA/salt-induced perivascular
      collagen deposition was completely abolished by cariporide and spironolactone.
      DOCA/salt-induced interstitial collagen deposition was partially and completely
      suppressed by spironolactone and cariporide, respectively. The rats exposed to
      DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial
      regions, a finding that was completely inhibited by cariporide but not by
      spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly
      increased. This was partially and completely reversed by spironolactone and
      cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt
      induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide
      completely prevents the detrimental effects of DOCA/salt on the heart. We also
      demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs
      through NHE1 activation.

PMID- 12623950
TI  - Beta-adrenergic activation initiates chamber dilatation in concentric
      hypertrophy.
AB  - It is uncertain whether chronic beta-adrenoreceptor (beta-AR)-activation in
      hypertension could initiate the progression from compensated left ventricular
      (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is
      through adverse LV remodeling (chamber dilatation with wall thinning and pump
      dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the
      effect of 5 months of isoprenaline (0.02 mg x kg(-1) x d(-1)) on hemodynamics, LV
      wall thickness, cavity size, and interstitial characteristics in spontaneously
      hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of
      myocyte necrosis, changes in volume preload, pressure afterload, and heart rate
      or decreases in baseline systolic myocardial elastance (load independent measure
      of intrinsic myocardial contractility), ISO produced a right shift in LV
      diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV
      wall thickness despite a further increase in LV weight in SHR, LV pump
      dysfunction (right shift in LV systolic P-V relations), and deleterious
      interstitial remodeling (increments in total and noncrosslinked myocardial
      collagen concentrations). The isoprenaline-induced LV geometric, chamber
      performance, and interstitial changes were similar to alterations noted during
      decompensation in older SHR. In summary, in the absence of tissue necrosis and
      baseline intrinsic myocardial contractile dysfunction, chronic beta-AR activation
      induces interstitial and chamber remodeling and, hence, pump dysfunction. These
      data suggest that chronic sympathetic activation initiates the progression from
      compensated concentric LV hypertrophy in hypertension to cardiac dysfunction
      primarily through deleterious cardiac remodeling rather than intrinsic myocardial
      contractile dysfunction.

PMID- 12623951
TI  - Myocardial PKC beta2 and the sensitivity of Na/K-ATPase to marinobufagenin are
      reduced by cicletanine in Dahl hypertension.
AB  - Marinobufagenin (MBG), an endogenous ligand of alpha-1 Na/K-ATPase, becomes
      elevated and contributes to hypertension in NaCl-loaded Dahl-S rats (DS). Protein
      kinase C (PKC) phosphorylates alpha-1 Na/K-ATPase and increases its MBG
      sensitivity. Cicletanine, an antihypertensive compound with PKC-inhibitory
      activity, reverses MBG-induced Na/K-ATPase inhibition and vasoconstriction. We
      hypothesized that increased PKC levels in sodium-loaded hypertensive DS would
      sensitize alpha-1 Na/K-ATPase to MBG and that PKC inhibition by cicletanine would
      produce an opposite effect. We studied the effects of cicletanine on systolic
      blood pressure, left ventricular PKC isoforms, cardiac alpha-1 Na/K-ATPase
      levels, and sensitivity to MBG in hypertensive DS. Seven DS received 50 mg x kg(
      1) x d(-1) cicletanine, and 7 DS received vehicle during 4 weeks of an 8% NaCl
      diet. Vehicle-treated rats exhibited an increase in blood pressure, left
      ventricular mass, MBG excretion (74+/-11 vs 9+/-1 pmol/24 h, P<0.01), myocardial
      alpha-1 Na/K-ATPase protein, and PKC beta2 and delta. The sensitivity of Na/K
      ATPase to MBG was enhanced at the level of high-affinity binding sites (IC50, 0.8
      vs 4.4 nmol/L, P<0.01). Cicletanine-treated rats exhibited a 56-mm Hg reduction
      in blood pressure (P<0.01) and a 30% reduction in left ventricular weight,
      whereas cardiac alpha-1 Na/K-ATPase protein and MBG levels were unchanged. In
      cicletanine-treated rats, PKC beta2 was not increased, the sensitivity of Na/K
      ATPase to MBG was decreased (IC50=20 micromol/L), and phorbol diacetate-induced
      alpha-1 Na/K-ATPase phosphorylation was reduced versus vehicle-treated rats. In
      vitro cicletanine treatment of sarcolemma from vehicle-treated rats also
      desensitized Na/K-ATPase to MBG, indicating that this effect was not solely
      attributable to a reduction in blood pressure. Thus, PKC-induced phosphorylation
      of cardiac alpha-1 Na/K-ATPase is a likely target for cicletanine treatment.

PMID- 12623953
TI  - Echogenic carotid plaques are associated with aortic arterial stiffness in
      subjects with subclinical carotid atherosclerosis.
AB  - A better understanding of the interrelationships between the structure and
      function of the large arteries would lead to optimize cardiovascular disease
      prevention strategies. In this study, we investigated the relationships of aortic
      arterial stiffness assessed by carotid-femoral pulse-wave velocity (PWV), with
      carotid plaque echogenicity assessed by B-mode ultrasound. We analyzed 561
      subjects (without coronary heart disease or stroke) who were volunteers for free
      health examinations (age, 58.3+/-10.8 years; 32.6% women). Extracranial carotid
      plaque echogenicity was graded from 1 (plaque appearing black or almost black) to
      4 (plaque appearing white or almost white) according to the Gray-Weale
      classification. Plaques of grades 1 and 2 were defined as echolucent plaques, and
      plaques of grades 3 and 4 were defined as echogenic plaques. Fifty-one subjects
      (9.1%) had echolucent carotid plaques, 109 (19.4%) had echogenic plaques, and 401
      (71.5%) had no plaques. Subjects with echogenic plaques had higher PWV mean
      (12.9+/-2.8 m/s) compared with those without plaques (11.1+/-2.3 m/s, P<0.001)
      and compared with those with echolucent plaques (11.3+/-2.3 m/s, P<0.01). The PWV
      means in subjects without plaques and those with echolucent plaques were similar
      and not statistically different (P=0.55). When multivariate adjustment for major
      known cardiovascular risk factors was performed, these results were not markedly
      modified. Similar patterns of results were also observed in many subgroups
      according to age, gender, and hypertensive status. This study provides the first
      evidence that echogenic but not echolucent carotid plaques are associated with
      aortic arterial stiffness. This association applies to individuals with normal
      blood pressure and those with elevated blood pressure. Assessment of the joint
      and interaction effects of plaque morphology and arterial stiffness on the
      occurrence of cardiovascular events would permit a better identification of high
      risk subjects.

PMID- 12623952
TI  - Ventricular adrenomedullin system in the transition from LVH to heart failure in
      rats.
AB  - We investigated whether adrenomedullin (AM) participates in the pathophysiology
      during the transition from left ventricular hypertrophy (LVH) to heart failure
      (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic
      hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18
      weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH
      stage were significantly elevated compared with those in controls, and they were
      further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM
      total ratio was higher only in the HF group than in controls and LVH. The LV
      tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close
      relations with the LV weight/body weight (r=0.72, r=0.79, and r=0.70,
      respectively; all P<0.001). AM gene expression was significantly increased at the
      LVH stage and was further increased at the HF stage. Furthermore, gene expression
      of AM receptor system components such as calcitonin receptor-like receptor
      (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were
      significantly increased at the stage of LVH and HF. Regarding other neurohumoral
      factors, plasma renin and aldosterone levels were not increased at the LVH stage
      but were increased at the HF stage, whereas atrial natriuretic peptide was
      increased in both the plasma and myocardium at the LVH stage and was further
      increased at the HF stage. These results suggest that induction of the cardiac AM
      system, including the ligand, receptor, and amidating activity, may modulate
      pathophysiology during the transition from LVH to HF in this model.

PMID- 12623954
TI  - Low-density lipoprotein subfractions and cardiovascular risk in hypertension:
      relationship to endothelial dysfunction and effects of treatment.
AB  - Although hypertensive patients are at particular risk of vascular complications,
      the possible contribution of an atherogenic lipoprotein profile and endothelial
      dysfunction to this risk is unclear. We investigated this by measuring LDL
      subfractions and flow-mediated dilation (FMD) (reflecting endothelial
      dysfunction) in a cohort of high-risk hypertensive patients. We studied 84
      hypertensive patients (74 men; mean age, 64 years; SD 8). Chylomicron-free LDL
      subfractions were analyzed by disc polyacrylamide gel electrophoresis, producing
      an LDL score, with higher scores being equivalent to a greater proportion of the
      more atherogenic LDL subfractions. High-resolution ultrasound was used to assess
      endothelium-dependent brachial artery FMD after reactive hyperemia after vessel
      occlusion. Baseline levels were compared with 61 age- and gender-matched healthy
      normotensive control subjects. Mean LDL score was higher and FMD impaired in
      hypertensive subjects compared with control subjects. These indexes were
      significantly improved after 6 months of cardiovascular risk factor management.
      LDL score correlated significantly with the 10-year Framingham coronary heart
      disease risk score, with a negative correlation with FMD (both P<0.001). Abnormal
      atherogenesis and endothelial dysfunction are both present in hypertension and
      appear to be related to each other, potentially leading to vascular
      complications. The abnormal LDL scores also correlate with the 10-year
      cardiovascular risk and can be positively influenced by cardiovascular risk
      management.

PMID- 12623956
TI  - Contrasting regression of blood pressure and cardiovascular structure in
      declipped renovascular hypertensive rats.
AB  - We investigated the time relationship between changes in blood pressure and
      changes in the structure of the resistance vasculature. Blood pressure,
      heart/body weight ratio, and morphology and function of mesenteric resistance
      arteries from 1-kidney, 1-clip renovascular hypertensive rats were followed
      before and after declipping at age 14 weeks. The rats were divided into 5 groups,
      which were investigated 6 hours, 24 hours, 1 week, 4 weeks, and 8 weeks after
      declipping and compared with 2 normotensive and 2 renovascular hypertensive
      control groups at 14 weeks and 18 weeks. Systolic blood pressure was elevated 2
      weeks after application of the clip and stabilized after 6 weeks. Declipping
      induced a prompt fall in blood pressure within 6 hours, and blood pressure was
      normalized within 1 week. Heart/body weight ratio was increased in renovascular
      hypertensive rats, and declipping induced a gradual decrease in the ratio, which
      was normalized within 4 weeks. Media/lumen ratio and media area of mesenteric
      resistance arteries were increased in renovascular hypertensive rats, and
      declipping did not affect media/lumen ratio and media area within 8 weeks,
      although there was a tendency for some regression of media/lumen ratio. There
      were no differences in response to high potassium, noradrenaline, or
      acetylcholine. Thus, these findings show definitively that declipping causes
      rapid reversal of renovascular hypertension in rats accompanied by gradual
      reduction of the heart/body weight ratio but lack of normalization in the
      mesenteric resistance vessels. This provides clear evidence that neither vascular
      nor cardiac structural changes are capable of keeping rats hypertensive.

PMID- 12623955
TI  - Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H
      oxidase activities.
AB  - Antioxidant vitamins C and E have protective properties in genetic hypertension
      associated with enhanced oxidative stress. This study investigated whether
      vitamins C and/or E modulate vascular function by regulating enzymatic activities
      of endothelial nitric oxide synthase (eNOS) and NAD(P)H oxidase using thoracic
      aortas of 20- to 22-week-old male spontaneously hypertensive rats (SHR) and their
      matched normotensive counterparts, Wistar-Kyoto rats (WKY). SHR aortas had
      impaired relaxant responses to acetylcholine but not to sodium nitroprusside,
      despite an approximately 2-fold increase in eNOS activity and NO release. The
      levels of superoxide anion (O2-), a potent NO scavenger, and NAD(P)H oxidase
      activity were also 2-fold higher in SHR aortas. Mechanical but not
      pharmacological inactivation of endothelium (by rubbing and 100 micromol/L L
      NAME, respectively) significantly abrogated O2- in both strains. Treatments of
      SHR aortas with NAD(P)H oxidase inhibitors, namely diphenyleneiodinium and
      apocynin, significantly diminished O2- production. The incubation of SHR aortas
      with different concentrations of vitamin C (10 to 100 micromol/L) and
      specifically with high concentrations of vitamin E (100 micromol/L) improved
      endothelial function, reduced superoxide production as well as NAD(P)H oxidase
      activity, and increased eNOS activity and NO generation in SHR aortas to the
      levels observed in vitamin C- and E-treated WKY aortas. Our results reveal
      endothelial NAD(P)H oxidase as the major source of vascular O2- in SHR and also
      show that vitamins C and E are critical in normalizing genetic endothelial
      dysfunction through regulation of eNOS and NAD(P)H oxidase activities.

PMID- 12623957
TI  - ERK1/2-dependent contractile protein expression in vascular smooth muscle cells.
AB  - In vivo, vascular smooth muscle (VSM) cells change their contractile phenotype
      toward a more proliferative phenotype during the pathogenesis of vascular
      diseases. Because these dedifferentiated VSM cells may gradually regain
      contractile functions, we aimed to identify signaling pathways that result in an
      increased expression of contractile proteins in VSM cells. In vitro, serum and
      thrombin induced a reversible upregulation of smooth muscle myosin heavy-chain
      (SM-MHC) in cultured neonatal rat VSM cells. Cotransfection of a SM-MHC-promoter
      chloramphenicol acetyltransferase-construct with dominant-negative N17Ras or
      N17Raf or treatment with the mitogen-activated/ERK-activating kinase (MEK)
      inhibitor PD 98059 concentration dependently decreased the serum- or thrombin
      induced SM-MHC promoter activity. Consistently, the serum- or thrombin-induced
      phosphorylation of MEK and extracellular signal-regulated kinase 1/2 (ERK1/2)
      coincided with a MEK-dependent nuclear accumulation of phosphorylated ERK1/2 and
      subsequent nuclear phosphorylation of the transcription factors c-myc and Elk-1.
      A 5'-deletion analysis of cis-elements within the SM-MHC promoter demonstrated
      that a conserved region (nucleotide -1346 to -1102) was required for both cell
      type-specific expression and serum- or thrombin-induced upregulation of the SM
      MHC promoter in VSM cells. Within this region, 2 CArG-boxes, a GC-rich element,
      and a CTF/NF-1 site are critical positively acting cis-elements for the serum- or
      thrombin-induced upregulation of SM-MHC. We conclude that the serum- or thrombin
      induced differentiation requires an intact Ras/Raf/MEK/ERK signaling cascade,
      nuclear translocation of activated ERK1/2, phosphorylation of transcription
      factors, and several cis-elements within the SM-MHC promoter.

PMID- 12623958
TI  - Regional sympathetic effects of low-dose clonidine in heart failure.
AB  - This study examined the effects of low doses of intravenous clonidine on regional
      and global sympathetic nervous system activity in heart failure. In heart
      failure, adrenoceptor-blocking treatments have a limited sphere of activity.
      Centrally acting sympatholytic therapies should be further investigated, with a
      specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10
      patients with moderate-severe congestive heart failure, we examined the effect of
      intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on
      brain monoamine turnover using the norepinephrine spillover method. In addition,
      we assessed the effect of clonidine on cardiac release of the sympathetic
      cotransmitter neuropeptide Y. A dose of 1 microg/kg of clonidine resulted in a
      fall in cardiac (326+/-73 to 160+/-40 pmol/min, P<0.001), renal (2.5+/-0.6 to
      1.5+/-0.3 nmol/min, P=0.01), and global norepinephrine spillover (4.0+/-0.6 to
      3.1+/-0.5 nmol/min, P<0.01), with a significantly disproportionate reduction in
      cardiac versus total-body sympathetic activity (P<0.05). No significant changes
      in cardiac neuropeptide Y release or in central monoamine turnover were
      demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and
      renal sympathetic tone in heart failure. In addition to the beneficial effects of
      antiadrenergic therapy in the heart, the renal sympatholytic effect may counter
      the salt and water retention that is a hallmark of the condition.

PMID- 12623959
TI  - Short-versus long-term effects of different dihydropyridines on sympathetic and
      baroreflex function in hypertension.
AB  - Antihypertensive treatment with dihydropyridines may be accompanied by
      sympathetic activation. Data on whether this is common to all compounds and
      similar in the various phases of treatment are not univocal, however. In 28
      untreated essential hypertensives (age, 56.4+/-1.8 years; mean+/-SEM) finger
      blood pressure (BP, Finapres), heart rate (HR, ECG), plasma norepinephrine (NE,
      high-performance liquid chromatography), and muscle sympathetic nerve traffic
      (MSNA, microneurography) were measured at rest and during baroreceptor
      manipulation (vasoactive drugs) in the placebo run-in period and after
      randomization to double-blind acute and chronic (8 weeks) felodipine (10 mg/d,
      n=14) or lercanidipine (10 mg/d, n=14). Acute administration of both drugs
      induced pronounced BP reductions and marked increases in HR, NE, and MSNA. After
      8 weeks of treatment, BP reductions were similar to those observed after acute
      administration, whereas HR, NE, and MSNA responses were markedly attenuated (-7%,
      -32%, and -14%, respectively; P<0.05). There was a small residual increase in
      sympathetic activity in the felodipine group, whereas in the lercanidipine group,
      all adrenergic markers returned to baseline values. Baroreflex control of HR and
      MSNA was markedly impaired (-42% and -48%, respectively) after acute drug
      administration, with a recovery and complete resetting during chronic treatment.
      Thus, the sympathoexcitation induced by 2 different dihydropyridines is largely
      limited to the acute administration. The 2 drugs have, nevertheless, a different
      chronic sympathetic effect, indicating that dihydropyridines do not homogeneously
      affect this function. The acute sympathoexcitation, but not the small between
      drugs differential chronic adrenergic effect, is accounted for by baroreflex
      impairment.

PMID- 12623960
TI  - Downregulation of basal iNOS at the rostral ventrolateral medulla is innate in
      SHR.
AB  - We demonstrated recently that a significant reduction in both the molecular
      synthesis and functional expression of inducible nitric oxide synthase (iNOS) in
      the rostral ventrolateral medulla (RVLM), the medullary origin of sympathetic
      vasomotor outflow, underlies the augmented sympathetic vasomotor tone during
      hypertension. This study further evaluated the hypothesis that this
      downregulation of basal iNOS at the RVLM during hypertension is innate. In adult
      spontaneously hypertensive rats (SHR) treated for 4 weeks with the
      antihypertensive captopril to normalize elevated blood pressure or in young
      prehypertensive SHR, the significantly lower iNOS mRNA and protein levels at the
      ventrolateral medulla under basal conditions or on activation by microinjection
      bilaterally into the RVLM of lipopolysaccharide (10 ng) remained unaltered. The
      retarded efficacy of lipopolysaccharide (10 ng) to elicit cardiovascular
      depression (hypotension, bradycardia, and reduction in sympathetic vasomotor
      tone) also persevered in captopril-treated adult or young normotensive SHR. On
      the other hand, compared with Wistar-Kyoto normotensive rats, the magnitude of
      cardiovascular depression induced in adult SHR by local administration into the
      RVLM of the NO precursor l-arginine (40 nmol) was significantly smaller. In
      addition, microinjection bilaterally into the RVLM of a selective iNOS inhibitor,
      aminoguanidine (125 or 250 pmol), was discernibly less efficacious in unmasking
      hypertension, tachycardia, and the increase in sympathetic vasomotor tone in
      adult SHR. We conclude that a predisposed reduction in molecular synthesis and
      functional expression of basal iNOS in the RVLM is associated with the
      sympathetic vasomotor overactivity during hypertension.

PMID- 12623961
TI  - Alpha2A-adrenergic receptors mediate sympathoinhibitory responses to atrial
      natriuretic peptide in the mouse anterior hypothalamic nucleus.
AB  - In the rat, activation of alpha2-adrenergic receptors in the anterior
      hypothalamic nucleus inhibits sympathetic nervous system activity. Furthermore,
      local release of atrial natriuretic peptide inhibits norepinephrine release in
      this nucleus, blocking local activation of alpha2-adrenergic receptors, and
      thereby contributes to NaCl-sensitive hypertension in spontaneously hypertensive
      rats. To further test the specificity of this mechanism, either alpha2-adrenergic
      receptor agonists or atrial natriuretic peptide was microinjected into anterior
      hypothalamic nucleus of conscious C57BL/6 mice in which the alpha2-adrenergic
      receptor was functionally deleted by a single point mutation (n=10 per group). In
      control mice, microinjection of either clonidine or guanabenz (10-3 to 10-7
      mol/L) caused a rapid fall in mean arterial pressure that lasted for several
      minutes. In the knockout mice there was no response to the injection of either
      dose of either agonist. Microinjection of atrial natriuretic peptide (10-6 to 10
      7 mol/L) caused a rapid increase in mean arterial pressure (8.2+/-1.3 and 6.55+/
      1.2 mm Hg, respectively) in the control mice that was similar to the responses
      previously observed in Wistar-Kyoto rats. In contrast, the microinjections did
      not significantly alter mean arterial pressure in the knockout mice. These
      experiments demonstrate that in the anterior hypothalamic nucleus of the mouse
      (and probably in the rat) alpha2A-adrenergic receptors mediate both
      sympathoinhibitory responses to alpha2-adrenergic receptor agonists and the
      action of atrial natriuretic peptide.

PMID- 12623962
TI  - Role of the subfornical organ in the chronic hypotensive response to losartan in
      normal rats.
AB  - Angiotensin II is known to act at a unique set of brain regions known as the
      circumventricular organs. These structures lack the normal blood-brain barrier
      and are therefore thought to participate in the central nervous system processing
      of neuroendocrine signals. We have reported that chronic treatment with the
      angiotensin type 1 (AT1) receptor antagonist, losartan, decreases arterial
      pressure in normotensive rats. Furthermore, this hypotension is attenuated in
      area postrema-lesioned rats, suggesting a role of endogenous angiotensin II at
      this circumventricular organ. Another circumventricular organ, the subfornical
      organ (SFO), has also been shown to mediate actions of angiotensin II. The
      present study tested the hypothesis that the SFO is a central site of action of
      endogenous angiotensin II at AT1 receptors. Adult male Sprague-Dawley rats were
      anesthetized and placed in a stereotaxic apparatus, and the SFO was sham or
      electrolytically lesioned. One week later, rats were instrumented with venous
      catheters and radiotelemetry pressure transducers for continuous infusion and
      monitoring of mean arterial pressure, respectively. After 3 days of control,
      losartan was administered intravenously (10 mg x kg(-1) x d(-1)) for 10 days in
      both SFO-lesioned and sham rats. By day 4 of losartan administration, mean
      arterial pressure had decreased to 75+/-2 mm Hg in sham rats (n=9) but had only
      fallen to 83+/-2 mm Hg in lesioned rats (n=10). This attenuated hypotensive
      response in SFO-lesioned rats continued through day 10 of losartan treatment.
      These results support the hypothesis that the SFO mediates part of the
      hypotensive effects of chronic AT1 receptor blockade in the normotensive rat.

PMID- 12623963
TI  - Role of angiotensin II in the neural control of renal function.
AB  - The aim of the present study was to distinguish between the direct effects of the
      renal nerves on renal function and indirect effects via neurally mediated
      increased systemic angiotensin II. We applied low-level electrical stimulation (1
      Hz) to the left renal nerves in pentobarbitone-anesthetized rabbits for 180
      minutes and measured renal blood flow, sodium excretion, and urine flow rate from
      both the stimulated and the nonstimulated contralateral kidney in the presence
      and the absence of ACE inhibition (enalaprilat). Stimulation resulted in an
      angiotensin II-mediated rise in arterial pressure and decreases in renal blood
      flow, urine flow rate, and sodium excretion on the stimulated side. On the
      nonstimulated denervated side, we found no change in renal blood flow, but found
      a decrease in urine flow rate. With ACE inhibition, renal stimulation no longer
      caused an increase in arterial pressure, the antidiuretic responses of the
      stimulated kidney were attenuated, and, importantly, the decrease in urine flow
      rate on the nonstimulated kidney was completely abolished. We therefore propose
      that although a direct effect of the renal nerves on sodium excretion is clearly
      present, the antidiuresis and antinatriuresis observed during renal activation is
      further supported by a neurally mediated increase in systemic angiotensin II.

PMID- 12623964
TI  - Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high
      salt diet.
AB  - This study was performed to examine whether there is an inappropriate regulation
      of intrarenal angiotensinogen in Dahl-salt sensitive rats (DS) fed a high salt
      diet (HS). Dahl salt-resistant rats (DR) and DS were maintained on HS (8% NaCl)
      or low salt diet (LS, 0.3% NaCl) for 4 weeks. Systolic blood pressure (SBP),
      measured by tail-cuff plethysmography, was unaltered in DR (DR+HS, 127+/-3 mm Hg,
      n=5; DR+LS, 126+/-3, n=5); however, SBP was significantly increased in DS+HS
      (208+/-7, n=9) compared with DS+LS (134+/-2, n=5). HS suppressed plasma renin
      activity in both strains (0.7+/-0.2 ng of angiotensin I/mL per hour in DS+HS,
      3.1+/-0.5 in DS+LS, 0.8+/-0.2 in DR+HS, 5.1+/-0.7 in DR+LS). Plasma
      angiotensinogen levels, measured by Western blot analysis, were also suppressed
      by HS in both strains (36 919+/-2170 integrated densitometric unit in DS+HS, 53
      028+/-2752 in DS+LS, 44 722+/-1721 in DR+HS, 55782+/-3785 in DR+LS). However,
      kidney angiotensinogen levels were significantly increased in DS+HS (75 850+/
      4171, integrated densitometric unit) compared with DS+LS (47 232+/-3470), DR+HS
      (44 748+/-8236), and DR+LS (42 504+/-4052). Urinary excretion of angiotensinogen,
      measured by radioimmunoassay of angiotensin I after incubation with excess renin,
      had a similar profile. Urinary excretion of angiotensinogen was significantly
      increased in DS+HS (2958+/-531 pmol/d) compared with DS+LS (56+/-4), DR+HS (31+/
      12), and DR+LS (21+/-7). These data indicate that intrarenal angiotensinogen is
      enhanced in DS+HS, which is reflected by the increased urinary excretion of
      angiotensinogen. The results suggest that DS on HS have an inappropriate
      augmentation of intrarenal angiotensinogen, which may contribute to impaired
      sodium excretion during a high salt diet and the development of hypertension in
      this strain.

PMID- 12623965
TI  - Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone.
AB  - Thyroid hormone has a broad effect on cardiovascular system. 3,3',5-triiodo-l
      thyronine (T3), a biologically active form of thyroid hormone, increases cardiac
      contractility. T3 causes arterial relaxation and reduction of systemic vascular
      resistance, resulting in an increase in cardiac output. However, the molecular
      mechanisms of vascular relaxation by T3 are incompletely characterized. We
      studied the effect of T3 on the angiotensin (Ang) II type 1 receptor (AT1R)
      expression in vascular smooth muscle cells. T3 dose-dependently decreased
      expression levels of AT1R mRNA, with a peak at 6 hours of stimulation. Binding
      assay using [125I]Sar1-Ile8-Ang II revealed that AT1R number was decreased by
      stimulation with T3 without changing the affinity to Ang II. T3 reduced calcium
      response of vascular smooth muscle cells to Ang II by 26%. AT1R promoter activity
      measured by luciferase assay was reduced by 50% after 9 hours of T3
      administration. mRNA stability was also decreased by T3. Real-time quantitative
      reverse transcription-polymerase chain reaction and Western blot analysis
      revealed that AT1R mRNA and protein were downregulated in the aorta of T3-treated
      rats. These results suggest that T3 downregulates AT1R expression both at
      transcriptional and posttranscriptional levels, and attenuates biological
      function of Ang II. Our results suggest that downregulation of AT1R gene
      expression may play an important role for T3-induced vascular relaxation.

PMID- 12623966
TI  - Galpha12- and Galpha13-protein subunit linkage of D5 dopamine receptors in the
      nephron.
AB  - The roles of the G-protein alpha-subunits, Gs, Gi, and Gq/11, in the signal
      transduction of the D1-like dopamine receptors, D1 and D5, have been deciphered.
      Galpha12 and Galpha13, members of the 4th family of G protein subunits, are not
      linked with D1 receptors, and their linkage to D5 receptors is not known.
      Therefore, we studied the expression of Galpha12 and Galpha13 and interaction
      with D5 dopamine receptors in the kidney from normotensive Wistar-Kyoto (WKY)
      rats and D5 receptor-transfected HEK293 cells. Galpha12 and Galpha13 were found
      in the proximal tubule, distal convoluted tubule, and artery and vein in the WKY
      rat kidney. Whereas Galpha12 was expressed in the ascending limb of Henle,
      Galpha13 was expressed in the collecting duct and juxtaglomerular cells. In renal
      proximal tubules, Galpha12 and Galpha13, as with D5 receptors, were expressed in
      brush border membranes. Laser confocal microscopy revealed the colocalization of
      D5 receptors with Galpha12 and Galpha13 in rat renal brush border membranes,
      immortalized rat renal proximal tubule cells, and D5 receptor-transfected HEK293
      cells. In these cells, a D1-like agonist, fenoldopam, increased the association
      of Galpha12 and Galpha13 with D5 receptors, results that were corroborated by
      immunoprecipitation experiments. We conclude that although both D1 and D5
      receptors are linked to Galphas, they are differentially linked to Galpha12 and
      Galpha13. The consequences of the differential G-protein subunit linkage on D1-
      and D5-mediated sodium transport remains to be determined.

PMID- 12623967
TI  - Tissue kallikrein actions at the rabbit natural or recombinant kinin B2
      receptors.
AB  - We have examined whether exogenous human tissue kallikrein exerts pharmacological
      actions via the bradykinin B2 receptor; specifically, whether the protease can
      bind to, cleave, internalize, and/or activate a fusion protein composed of the
      rabbit B2 receptor conjugated to the green fluorescent protein (B2R-GFP). The
      enzyme partially digested the fusion protein at 1 micromol/L, but not 100 nmol/L,
      and promoted B2R-GFP endocytosis in HEK 293 cells (> or =50 nmol/L). Trypsin and
      endoproteinase Lys-C, but not plasma kallikrein, also cleaved B2R-GFP.
      Phospholipase A2 was activated by 50 nmol/L tissue kallikrein in HEK 293 cells
      expressing B2R-GFP, and this was mediated by the receptor, as shown by the effect
      of a B2 receptor antagonist and by the lack of response in untransfected cells.
      However, 500 nmol/L kallikrein elicited a strong receptor-independent activation
      of phospholipase A2. Tissue kallikrein competed for [3H]bradykinin binding to B2R
      GFP only at 1 micromol/L. A simulation involving kallikrein treatment of HEK 293
      cells, pretreated or not with human plasma, evidenced the formation of
      immunoreactive bradykinin. The enzyme (50 nmol/L) contracted the rabbit isolated
      jugular vein via its endogenous B2 receptors, but the effect was tachyphylactic,
      and there was no cross-desensitization with bradykinin effects. Aprotinin
      prevented all pharmacological responses to tissue kallikrein, indicating that the
      enzyme activity is required for its effect. The local generation of kinins is a
      plausible mechanism for the pharmacological effects of lower concentrations of
      tissue kallikrein (50 to 100 nmol/L); higher levels (0.5 to 1 micromol/L) can not
      only initiate the degradation of rabbit B2 receptors but also exert nonreceptor
      mediated effects.

PMID- 12623968
TI  - Does sildenafil indirectly inhibit phosphodiesterase 3 in vascular smooth muscle?

PMID- 12623969
TI  - Neural control of the kidney: past, present, and future.
AB  - This article provides a chronological perspective on the development of knowledge
      concerning the neural control of renal function and is divided into three parts:
      the past, the present, and the future.

PMID- 12623970
TI  - The kidney, hypertension, and obesity.
AB  - This paper provides a personal perspective of the role of abnormal renal-pressure
      natriuresis in the pathogenesis of hypertension. Direct support for a major role
      of renal-pressure natriuresis in long-term control of arterial pressure and
      sodium balance comes from studies demonstrating that (1) pressure natriuresis is
      impaired in all forms of chronic hypertension and (2) prevention of pressure
      natriuresis from operating, by servo-control of renal perfusion pressure, also
      prevents the maintenance of sodium balance hypertension. Although the precise
      mechanisms of impaired pressure natriuresis in essential hypertension have
      remained elusive, recent evidence suggests that obesity and overweight may play a
      major role. Obesity increases renal sodium reabsorption and impairs pressure
      natriuresis by activation of the renin-angiotensin and sympathetic nervous
      systems and by altered intrarenal physical forces. Chronic obesity also causes
      marked structural changes in the kidneys that eventually lead to a loss of
      nephron function, further increases in arterial pressure, and severe renal injury
      in some cases. Although there are many unanswered questions about the mechanisms
      of obesity hypertension and renal disease, this is one of the most promising
      areas for future research, especially in view of the growing, worldwide
      "epidemic" of obesity.

PMID- 12623971
TI  - Adult rabbit offspring of mothers with secondary hypertension have increased
      blood pressure.
AB  - Preexisting chronic hypertension complicates up to 5% of pregnancies and is
      associated with an increased risk of low-birth-weight babies. Studies suggest
      that an adverse intrauterine environment leading to low birth weight is linked to
      an increased risk of cardiovascular disease, including hypertension, in the
      adult. In this study, the blood pressure of offspring from mothers with
      hypertension were followed up into adulthood. Two-kidney, 1-wrapped hypertension
      was induced in 7 female rabbits; 5 other rabbits underwent sham surgery. Four
      weeks later, rabbits were mated, at which time mean arterial pressure was 118+/-3
      and 87+/-5 mm Hg in the hypertensive and sham groups, respectively (P<0.001). The
      blood pressure of 30-week-old females was 89+/-2 mm Hg in the offspring of
      hypertensive (n=14) and 79+/-1 mm Hg in the offspring of normotensive (n=13)
      mothers (P<0.005). Also, plasma renin activity was significantly lower in the
      female offspring of hypertensive mothers at 10 weeks of age (P<0.05), suggesting
      that development of the renin-angiotensin system was altered. In contrast, male
      offspring from hypertensive and normotensive mothers had similar mean arterial
      pressure and plasma renin activity. In conclusion, maternal secondary
      hypertension can "program" hypertension in female adult offspring. The results
      also suggest that there are gender-specific differences in sensitivity to altered
      in utero environmental influences.

PMID- 12623973
TI  - Birth weight impacts on wave reflections in children and adolescents.
AB  - The objective of the present study was to assess central aortic pressure and wave
      reflection in children and adolescents at different birth weights. Two hundred
      nineteen healthy children (126 girls), from 7 to 18 years of age (mean, 11.3
      years) and born at term after a normotensive pregnancy, were included. The
      subjects were divided according to birth weight: <2.5 kg, from 2.5 to 2.999 kg,
      from 3.0 to 3.5 kg, and >3.5 kg. Pressure waveforms were recorded from the radial
      artery of the wrist, and the waveform data were then processed by the SphygmoCor
      radial/aortic transform software module to produce the estimated aortic pressure
      waveform. Augmentation index, an estimate of the pulse wave reflection, was
      significantly higher in children with the lowest birth weights compared with the
      other birth weight groups. In a multiple regression analysis, short stature, low
      heart rate, female gender, and lower birth weight had independent significant
      inverse correlations to the augmentation index when adjusted for diastolic blood
      pressure (R2=0.21). In summary, the results showed a relatively aged phenotype of
      large-vessel function in the children with the lowest birth weights. These early
      alterations may be amplified throughout life and may contribute to the increased
      cardiovascular risk associated with low birth weight.

PMID- 12623972
TI  - Characterization of an animal model of postmenopausal hypertension in
      spontaneously hypertensive rats.
AB  - Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible
      are unknown. The present study was performed to characterize a model of
      postmenopausal hypertension in the rat and to determine the role that oxidative
      stress may play in mediating the postmenopausal hypertension. Spontaneously
      hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and
      were aged to 18 months. These animals were compared with young females (YF; 4 or
      8 months of age) and old males (18 months) for some measurements. Estradiol
      levels were decreased in PMR rats to levels not different from YF rats in
      proestrous or from old males. BP increased progressively with age in PMR rats but
      not in ovx or male rats, such that the gender difference in hypertension
      disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR
      rats than in YF rats. Renal plasma flow and renal vascular resistance were
      similar between YF and ovx rats, but lower and higher, respectively, in PMR rats.
      Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared
      with YF rats. Plasma renin activity also increased in PMR rats but not in ovx
      rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats
      with vitamins E and C, but not tempol, resulted in a significant reduction in BP
      and excretion of F2-isoprostanes. In contrast, tempol, but not vitamins E and C,
      reduced BP in old males. These data suggest that the PMR rats, but not ovx rats,
      may be a suitable model for the study of postmenopausal hypertension, and that
      oxidative stress plays a role in the increased BP.

PMID- 12623974
TI  - Administration time-dependent influence of aspirin on blood pressure in pregnant
      women.
AB  - This study prospectively investigates the potential influence of low-dose aspirin
      on blood pressure in pregnant women who were at a higher risk of developing
      preeclampsia than that of the general obstetric population and who received
      aspirin at different times of the day according to their rest-activity cycle. A
      double-blind, randomized, controlled trial was conducted in 341 pregnant women
      (181 primipara) randomly assigned to 1 of 6 possible groups according to
      treatment (either placebo or aspirin, 100 mg/day, starting at 12 to 16 weeks of
      gestation) and the time of treatment: on awakening (time 1), 8 hours after
      awakening (time 2), or before bedtime (time 3). Blood pressure was automatically
      monitored for 48 consecutive hours every 4 weeks from the day of recruitment
      until delivery, as well as at puerperium. There was no effect of aspirin on blood
      pressure at time 1 (compared with placebo). A blood pressure reduction was highly
      statistically significant when aspirin was given at time 2 and, to a greater
      extent, at time 3 (mean reductions of 9.7/6.5 mm Hg in 24-hour mean for
      systolic/diastolic blood pressure at the time of delivery as compared with
      placebo given at bedtime). Differences in blood pressure among women receiving
      aspirin at different circadian times disappeared at puerperium (P>0.096). Results
      indicate a highly significant effect of aspirin on blood pressure that is
      markedly dependent on the time of aspirin administration with respect to the rest
      activity cycle. Timed use of aspirin at low dose effectively contributes to blood
      pressure control in women at high risk for preeclampsia.

PMID- 12623975
TI  - Gender differences in ET and NOS systems in ETB receptor-deficient rats: effect
      of a high salt diet.
AB  - The purpose of this study was to determine if rats lacking the ETB receptor have
      altered renal endothelin (ET) production and NO synthase (NOS) activity in
      response to high salt and if female rats are better able to control blood
      pressure through higher NOS activity in rats heterozygous (sl/+) and homozygous
      (sl/sl) for ETB receptor deficiency. On normal salt (0.4% NaCl; NS), male sl/sl
      rats had higher systolic blood pressures compared with male sl/+ and female sl/+
      and sl/sl rats. On a high salt diet (10% NaCl; HS), blood pressure in male sl/+
      rats was significantly higher than female sl/+ rats. However, ETB receptor
      deficiency caused much larger increases in blood pressure in male and female
      rats. On NS, urinary ET excretion was not different between male and female of
      either genotype. HS significantly increased ET excretion in male and female sl/+
      rats, but the increase was significantly less in sl/sl compared with sl/+.
      Homogenates of inner medullary collecting duct tissue were separated into
      particulate and cytosolic fractions and total NOS activity measured by conversion
      of [3H]L-arginine to [3H]L-citrulline. Female rats had significantly greater
      cytosolic NOS activity compared with male rats on NS. On HS, cytosolic NOS
      activity was lower in all groups compared with NS rats, whereas particulate NOS
      activity was significantly greater in male and female sl/+ rats compared with
      male and female sl/sl rats. These data support our hypothesis that NOS protects
      against rises in blood pressure in female rats and ETB receptors prevent further
      increases in blood pressure due to increases in renal ET production and NOS
      activity.

PMID- 12623976
TI  - Vasopressin induces vascular superoxide via endothelin-1 in mineralocorticoid
      hypertension.
AB  - We have recently reported that endothelin-1 (ET-1), which is increased in the
      arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, stimulates
      superoxide production. However, the humoral mechanisms responsible for ET-1
      induced superoxide formation in low-renin models of hypertension, such as DOCA
      salt hypertension, remain undefined. Vasopressin is known to upregulate vascular
      preproET-1 gene expression in DOCA-salt rats, an effect that is absent in
      vasopressin-deficient Brattleboro rats treated with DOCA-salt. The present study
      tested the hypothesis that vasopressin contributes to ET-1-induced vascular
      superoxide production in DOCA-salt hypertensive rats. Carotid arterial segments
      of DOCA, sham (uninephrectomized), or normal (untreated) rats were used for the
      study. In vitro vasopressin treatment of carotid arteries from normal rats for 24
      hours, but not 4 hours, increased both ET-1 and superoxide levels. The increase
      of vasopressin-induced superoxide was reduced by pretreatment of the vessels with
      ABT627, a selective ETA receptor antagonist ABT627. Vasopressin, ET-1, and
      superoxide levels were significant elevated in carotid arteries of DOCA-salt rats
      compared with sham controls. The selective V1-vasopressin receptor antagonist
      (beta-Mercapto-beta, beta-cyclopentamethylenepropiony1, O-Me-Tyr2, Arg8
      vasopressin, ME-AVP), decreased superoxide both in vasopressin-treated vessels of
      normal rats and in vessels of DOCA-salt rats, with a concomitant reduction of ET
      1 content. These results suggest that vasopressin increases vascular superoxide
      levels by stimulating ET-1 formation in mineralocorticoid hypertension, and that
      V1-vasopressin receptors play an important role in this process.

PMID- 12623977
TI  - GTP cyclohydrolase 1 downregulation contributes to glucocorticoid hypertension in
      rats.
AB  - NO, a potent vasodilator, has been implicated in the pathogenesis of
      glucocorticoid hypertension. NO synthase requires the cofactor
      tetrahydrobiopterin for the production of NO. Guanosine-triphosphate (GTP)
      cyclohydrolase 1 is the rate-limiting enzyme for the production of
      tetrahydrobiopterin, and in the presence of low levels of tetrahydrobiopterin, NO
      production is decreased. We have previously shown that tetrahydrobiopterin
      dependent vasodilation is impaired in rats with glucocorticoid hypertension.
      However, the role GTP cyclohydrolase 1 plays in the pathogenesis of
      glucocorticoid hypertension has not been investigated. Therefore, we tested the
      hypothesis that downregulation of GTP cyclohydrolase 1 contributes to the
      development and maintenance of glucocorticoid hypertension in rats. Rats were
      implanted with dexamethasone (0.79 mg x kg(-1) x d(-1)) or sham-operated, and
      systolic blood pressures were measured at baseline and after 12 hours, 4 days, or
      15 days. Blood pressure increased significantly after dexamethasone treatment.
      Isometric force generation was measured in endothelium-intact aortic ring
      segments. Aortas from dexamethasone-treated rats exhibited a significant time
      dependent decrease in maximal relaxation to acetylcholine compared with control
      rats. Incubation with sepiapterin (10(-4) mol/L, 1 hour), which produces
      tetrahydrobiopterin via a salvage pathway, restored vasodilation to acetylcholine
      in aortas from 4- and 15-day dexamethasone-treated rats. GTP cyclohydrolase 1
      mRNA expression levels also significantly decreased in a time-dependent manner.
      These results support the hypothesis that downregulation of GTP cyclohydrolase 1
      contributes to increased blood pressure in glucocorticoid hypertensive rats.

PMID- 12623978
TI  - Endothelin inhibits NPR-A and stimulates eNOS gene expression in rat IMCD cells.
AB  - We have shown in previous studies that high extracellular tonicity is associated
      with increased expression of the type A natriuretic peptide receptor (NPR-A) and
      reduced expression of the endothelial NO synthase (eNOS) gene in cultured rat
      inner-medullary collecting duct cells. The vasoactive peptide endothelin has been
      shown to be avidly expressed in this nephron segment, and to be subject to
      osmotic regulation. We asked whether endothelin might play a role in the control
      of basal or osmotically regulated NPR-A or eNOS gene expression in these cells.
      Although exogenous endothelin had little or no effect on basal expression of eNOS
      mRNA or protein or NPR-A gene expression, both the type A (BQ610) and type B
      (IRL1038) endothelin receptor antagonists proved capable of reducing eNOS mRNA
      and protein expression, and increasing levels of the NPR-A mRNA. Increased
      extracellular tonicity reduced endothelin mRNA accumulation in these cells
      (approximately 15% of control levels); however, exogenous endothelin failed to
      normalize osmotically increased NPR-A activity or expression, or osmotically
      suppressed eNOS expression. Collectively, these data demonstrate the presence of
      a number of independent but highly interactive local regulatory networks
      governing fluid and electrolyte handling in this distal nephron segment.

PMID- 12623979
TI  - High-salt diet increases sensitivity to NO and eNOS expression but not NO
      production in THALs.
AB  - L-Arginine inhibits thick ascending limb (THAL) NaCl absorption by activating
      endothelial NO synthase (eNOS) and increasing NO production. Inhibition of renal
      NO production combined with a high-salt diet produces hypertension, and the THAL
      has been implicated in salt-sensitive hypertension. We hypothesized that a high
      salt diet enhances the inhibitory action of L-arginine on NaCl absorption by
      THALs because of increased eNOS expression and NO production. To test this, we
      used isolated THALs from rats on a normal-salt (NS) or high-salt diet (HS) for 7
      to 10 days. L-Arginine (1 mmol/L) decreased chloride absorption by 56+/-10% in
      THALs from rats on a HS diet, but only 29+/-3% in THALs from rats on a NS diet.
      eNOS expression in isolated THALs from rats on a HS diet was increased by 3.9
      fold compared with NS (P<0.03). However, L-arginine increased NO levels to the
      same extent in THALs from both groups, as measured with DAF-2 DA or a NO
      sensitive electrode. To determine whether a HS diet increases the sensitivity of
      the THAL to NO, we tested the effects of the NO donor spermine NONOate on
      chloride absorption. In THALs from rats on a HS diet, 1 and 5 micromol/L spermine
      NONOate reduced chloride absorption by 35+/-5% and 58+/-6%, respectively. In
      contrast, these same concentrations of spermine NONOate reduced chloride
      absorption by 4+/-4% (P<0.03 versus HS diet) and 43+/-9% in THALs from rats on a
      NS diet. We conclude that a HS diet enhances the effect of NO in the THAL. L
      Arginine-stimulated NO production was not enhanced by a HS diet, despite
      increased eNOS protein.

PMID- 12623980
TI  - Inhibition of apical Na+/H+ exchangers on the macula densa cells augments
      tubuloglomerular feedback.
AB  - NO produced by neuronal NO synthase (nNOS) in the macula densa blunts
      tubuloglomerular feedback (TGF). nNOS activity is strongly pH-dependent.
      Increasing luminal NaCl concentration increases nNOS activity, NO production, and
      apical Na+/H+ exchange. Na+/H+ exchange alkalinizes the macula densa. We
      hypothesized that inhibiting apical Na+/H+ exchange in macula densa cells would
      augment TGF by blunting nNOS activation caused by increasing luminal NaCl
      concentration. Rabbit afferent arterioles and attached macula densas were
      microperfused in vitro. TGF response was defined as the change in afferent
      arteriole diameter caused by increasing the NaCl concentration in the macula
      densa perfusate. 7-Nitroindazole (7-NI; 10 micromol/L) alone in the macula densa
      lumen increased the TGF response from 2.4+/-0.1 to 3.8+/-0.2 microm (P<0.01).
      When dimethyl amiloride (100 micromol/L), a Na+/H+ exchange inhibitor, was added
      to the macula densa lumen, it increased the TGF response from 2.5+/-0.3 to 3.7+/
      0.5 microm (P<0.01). In the presence of dimethyl amiloride, 7-NI had no effect on
      the TGF response (from 2.6+/-0.2 to 2.7+/-0.2 microm). Our data indicate that
      inhibiting apical Na+/H+ exchange in the macula densa mimics the effect of
      inhibiting NO production by nNOS in the macula densa on TGF. Thus, it is possible
      that increased apical Na+/H+ exchange caused by increasing the sodium
      concentration in the lumen of the macula densa activates macula densa nNOS. The
      link between nNOS and Na+/H+ exchange may be intracellular pH.

PMID- 12623981
TI  - Roles of oxidative stress and AT1 receptors in renal hemodynamics and oxygenation
      in the postclipped 2K,1C kidney.
AB  - The spontaneously hypertensive rat (SHR) exhibits angiotensin II (Ang II)
      dependent oxidative stress and reduced efficiency of renal oxygen usage (QO2) for
      tubular sodium transport (TNa). We tested the hypothesis that oxidative stress
      determines the reduced TNa:QO2 ratio in the clipped kidney of the early 2-kidney,
      1-clip (2K,1C) Ang II-dependent model. One week after sham operation (Sham) or
      clip placement, 2K,1C rats received for 2 weeks either a vehicle, the superoxide
      dismutase mimetic tempol (Temp), or candesartan (Cand). Oxidative stress was
      assessed from excretion of 8-isoprostaglandin F2alpha (PGF2alpha) and
      malondialdehyde (MDA) and renal oxygenation from pO2 in the renal cortex and from
      the ratio of calculated TNa and QO2 values. The mean arterial pressure (MAP) of
      Sham (113+/-6 mm Hg) was increased in 2K,1C vehicle-treated rats (148+/-4 mm Hg),
      but both Temp and Cand restored MAP to Sham levels. The excretions of 8-iso
      PGF2alpha and MDA were higher in 2K,1C vehicle-treated rats compared with Sham
      and were normalized by Temp. The pO2 of Sham (42+/-2 mm Hg) was lower in 2K,1C
      vehicle-treated animals (28+/-2 mm Hg). This was restored to Sham values by Temp
      (36+/-3 mm Hg) but not by Cand (28+/-2 mm Hg). The TNa:QO2 of Sham (12.9+/-1.6)
      was reduced in 2K,1C vehicle-treated rats (9.7+/-2.8) and was restored to Sham
      values by Temp (13.7+/-2.5) but not by Cand (7.5+/-1.6). We conclude that the
      correction of oxidative stress in the 2K,1C model partially corrects renal
      cortical hypoxia and inefficient utilization of O2 for Na+ transport, independent
      of the fall in blood pressure.

PMID- 12623982
TI  - Contributions of 20-HETE to the antihypertensive effects of Tempol in Dahl salt
      sensitive rats.
AB  - The present study evaluated whether reactive oxygen species-induced alterations
      in bioavailability of 20-HETE in the kidney contribute to the antihypertensive
      and renoprotective actions of antioxidant therapy with Tempol in the Dahl salt
      sensitive (DS) rat. Superoxide inhibited the synthesis of 20-HETE by renal
      cortical microsomes and enhanced breakdown of 20-HETE to a more polar product.
      Addition of Tempol (1 mmol/L) to the drinking water reduced mean arterial
      pressure from 187+/-9 to 160+/-3 mm Hg in DS rats fed an 8%-NaCl diet for 2
      weeks. 20-HETE excretion rose from 117+/-11 to 430+/-45 ng/day, and 8-isoprostane
      excretion fell from 14+/-1 to 8+/-1 ng/day. Tempol also increased creatinine
      clearance and reduced the severity of renal damage in DS rats fed a high-salt
      diet. Blockade of NO synthase with NG-nitro-L-arginine methyl ester (25 mg/kg per
      day) did not attenuate the antihypertensive or renoprotective actions of Tempol
      in DS rats. However, chronic blockade of the formation of 20-HETE with N-hydroxy
      N'-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) blunted the
      antihypertensive and renoprotective effects of Tempol. These findings indicate
      that the antihypertensive and renoprotective effects of reducing oxidative stress
      with Tempol depends in part on increasing the bioavailability of 20-HETE in the
      kidney.

PMID- 12623983
TI  - 20-HETE and furosemide-induced natriuresis in salt-sensitive essential
      hypertension.
AB  - Cyclooxygenase metabolites of arachidonic acid modulate the natriuretic effect of
      furosemide. It is not known whether 20-HETE, a monooxygenase metabolite of
      arachidonic acid that also inhibits sodium transport, participates in the action
      of furosemide. We measured urine sodium (UNaV) and 20-HETE during furosemide
      diuresis (40 mg three times over 12 hours) in 12 salt-sensitive (SS) and 11 salt
      resistant (SR), salt-replete hypertensive subjects (126+/-24 mmol/24 hours
      positive sodium balance produced by 160-mmol-sodium diet and 2 L saline
      infusion). Individual systolic blood pressure decreases from the salt-replete to
      the salt-depleted state were the index of salt-sensitivity. SS had low plasma
      renin with blunted responses to changes in salt balance, inappropriate plasma
      aldosterone, and an increased aldosterone/renin ratio. UNaV by furosemide was
      less in SS (263+/-25 mmol/12 hours) than in SR (351+/-25 mmol/12 hours, P<0.02)
      patients. 20-HETE was not different between SS and SR patients before (1.92+/
      0.38 versus 1.37+/-0.34 microg/h) or after furosemide (1.52+/-0.27 versus 2.01+/
      0.40 microg/h), but furosemide changed 20-HETE excretion in opposite direction in
      SR (0.63+/-0.26) versus SS (-0.40+/-0.17, P<0.005) patients. In all patients
      together, %Delta20-HETE by furosemide correlated with %DeltaUNaV (r=0.56, P<0.01)
      and negatively with salt-sensitivity of blood pressure (r=-0.55, P<0.01). In SS,
      Delta20-HETE by furosemide correlated with Deltaaldosterone/renin ratio (r=0.60,
      P<0.05), whereas 20-HETE during furosemide had a negative correlation with body
      mass index (r=-0.73, P<0.01). Our data suggest that 20-HETE modulates the
      natriuretic response to furosemide, and impaired natriuresis of SS involves a
      mechanism that alters the 20-HETE response to furosemide and is linked to salt
      sensitivity of blood pressure.

PMID- 12623985
TI  - Heme oxygenase attenuates angiotensin II-mediated increase in cyclooxygenase-2
      activity in human femoral endothelial cells.
AB  - Heme oxygenase (HO) regulates cellular heme levels and catalyzes the formation of
      bilirubin and carbon monoxide. We hypothesize that the status of the endothelial
      HO system influences the angiotensin (Ang) II-induced increase in the endothelial
      production of prostaglandin I2 (PGI2) (measured as 6-keto-PGF1alpha) and
      prostaglandin E2 (PGE2), eicosanoids that modulate the vascular actions of Ang
      II. In the present study, we determined the effect of interventions that suppress
      HO activity or induce HO-1 gene expression on Ang II-mediated increase in 6-keto
      PGF1alpha and PGE2 in cultures of human femoral artery endothelial cells.
      Incubation of endothelial cells with Ang II (100 ng/mL) for 24 hours increased
      the levels of both 6-keto-PGF1alpha and PGE2 in the culture media. This effect of
      Ang II on prostaglandin production by endothelial cells was attenuated in cells
      treated with SnCl2 (10 micromol/L), an inducer of HO-1, but was magnified in
      cells treated with the HO inhibitor ZnDPP or heme. Upregulation of HO-1 gene
      expression by retrovirus-mediated delivery of the human HO-1 gene also attenuated
      heme and Ang II-induced prostaglandin synthesis. Of note, prostaglandin synthesis
      by lysates of endothelial cells stimulated with heme or Ang II appear to involve
      COX-2, because it was blunted by NS-398, which is presumed to inhibit COX-2
      specifically. These results indicate that overexpression of the HO system exerts
      an inhibitory influence on Ang II-induced synthesis of prostaglandins by
      endothelial cells.

PMID- 12623984
TI  - Decreased renal cytochrome P450 2C enzymes and impaired vasodilation are
      associated with angiotensin salt-sensitive hypertension.
AB  - Excess dietary salt intake differentially modulates the activity of cytochrome
      (CYP) P450 enzymes in kidney cortex. Exactly how increased angiotensin (Ang) II
      levels and hypertension change the regulatory effect of high salt on CYP450
      enzymes remains unclear. The present study investigated the effects of combined
      administration of Ang II and a high-salt diet on P450 epoxygenase and hydroxylase
      protein levels in kidney, as well as afferent arteriolar responses to
      acetylcholine and sodium nitroprusside. High dietary salt administration for 14
      days resulted in increased renal cortical CYP2C11 protein levels, and a
      significant increase of CYP2C11 and CYP2C23 protein levels in renal microvessels.
      Administration of Ang II in combination with a high-salt diet prevented the
      upregulation of renal cortical CYP2C11 protein expression observed with high
      dietary salt alone, and significantly downregulated expression of CYP2C11,
      CYP2C23, and CYP2J protein in renal microvessels. A high-salt diet alone
      decreased CYP4A protein in kidney cortex, and renal cortical CYP4A protein level
      remained at a low level in Ang II-infused rats treated with a high-salt diet.
      Increases in blood pressure during Ang II infusion were greater in rats fed a
      high-salt diet. In addition, afferent arteriolar responsiveness to acetylcholine
      and sodium nitroprusside was significantly attenuated in Ang II-treated rats
      versus controls. This decrease was significantly enhanced in Ang II-treated rats
      given a high-salt diet. These results support the hypothesis that an inability to
      upregulate CYP2C and maintain CYP2J in the rat kidney and impaired afferent
      arteriolar vasodilation with chronic Ang II infusion contribute to salt-induced
      elevation of arterial pressure.

PMID- 12623986
TI  - Circulating endothelial cells are a novel marker of cyclosporine-induced
      endothelial damage.
AB  - Microvascular endothelial cells play a key role in transplant immunology. They
      are also important targets for calcineurin inhibitors. We recently demonstrated
      elevated numbers of circulating endothelial cells in renal transplant recipients
      with and without rejection in comparison with healthy controls. Because these
      patients received either cyclosporine or tacrolimus, we speculated that
      endothelial damage from calcineurin inhibitors might be responsible for these
      findings. In the present study, we tested the hypothesis that treatment with
      calcineurin inhibitors leads to an increase in circulating endothelial cells. We
      studied 57 renal transplant recipients: 19 on a calcineurin inhibitor-free
      immunosuppressive regimen and 38 patients on a standard immunosuppressive
      regimen, including cyclosporine, and matched them for age and serum creatinine.
      Endothelial cells were isolated from peripheral blood with anti-CD-146-coated
      immunomagnetic Dynabeads and were counted by fluorescence microscopy. Patients
      with cyclosporine therapy had elevated numbers of circulating endothelial cells
      (median 26, range 12 to 82 cells/mL) compared with healthy controls (median 6,
      range 0 to 82 cells/mL; P<0.001). Patients without calcineurin inhibitor
      treatment had significantly lower cell numbers (median 12, range 0 to 32
      cells/mL; P<0.003) and were not significantly different from normal, untreated
      controls. In conclusion, renal transplant recipients who do not receive
      calcineurin inhibitors have significantly lower numbers of circulating
      endothelial cells than their age- and creatinine-matched counterparts who receive
      these drugs. We suggest that elevated numbers of circulating endothelial cells
      indicate damage from calcineurin inhibitors in renal transplant recipients and
      that circulating endothelial cells are a novel marker of endothelial damage.

PMID- 12623987
TI  - Angiotensin II regulation of AT1 and D3 dopamine receptors in renal proximal
      tubule cells of SHR.
AB  - Dopamine and angiotensin II negatively interact to regulate sodium excretion and
      blood pressure. D3 dopamine receptors downregulate angiotensin type 1 (AT1)
      receptors in renal proximal tubule cells from normotensive Wistar-Kyoto rats. We
      determined whether AT1 receptors regulate D3 receptors and whether the regulation
      is different in cultured renal proximal tubule cells from normotensive and
      spontaneously hypertensive rats. Angiotensin II (10(-8)M/24 hours) decreased D3
      receptors in both normotensive (control, 36+/-3; angiotensin II, 24+/-3 U) and
      hypertensive (control, 30+/-3; angiotensin II, 11+/-3 U; n=9 per group) rats;
      effects that were blocked by the AT1 receptor antagonist, losartan (10(-8)M/24
      hours). However, the reduction in D3 expression was greater in hypertensive (60+/
      10%) than in normotensive rats (32+/-9%). In normotensive rats, angiotensin II
      (10(-8)M/24hr) also decreased AT1 receptors. In contrast, in cells from
      hypertensive rats, angiotensin II increased AT1 receptors. AT1 and D3 receptors
      co-immunoprecipitated in renal proximal tubule cells from both strains.
      Angiotensin II decreased D3/AT1 receptor co-immunoprecipitation similarly in both
      rat strains, but basal D3/AT1 co-immunoprecipitation was 6 times higher in
      normotensive than in hypertensive rats. Therefore, AT1 and D3 receptor
      interaction is qualitatively and quantitatively different between normotensive
      and hypertensive rats; angiotensin II decreases AT1 expression in normotensive
      but increases it in hypertensive rats. In addition, angiotensin II decreases D3
      expression to a greater extent in hypertensive than in normotensive rats.
      Aberrant interactions between D3 and AT1 receptors may play a role in the
      pathogenesis of hypertension.

PMID- 12623988
TI  - Angiotensin II-mediated negative regulation of Npr1 promoter activity and gene
      transcription.
AB  - Atrial natriuretic peptide receptor A (NPRA) plays important role(s) in the
      control of extracellular fluid volume and blood pressure homeostasis. We have
      determined and analyzed the functional promoter region of Npr1 gene (coding for
      NPRA) and studied the effect of angiotensin (Ang) II on its promoter activity and
      expression in cultured mouse mesangial cells. The promoter analysis of Npr1 gene
      revealed the presence of positive regulatory cis-elements in the regions -1982 to
      -1841 bp and -916 to -496 bp and of the repressor elements in the regions -1841
      to -916 bp and 56 to 382 bp relative to transcription start site. The Ang II
      pretreatment of cultured mouse mesangial cells transiently transfected with the
      promoter construct pNPRA-luc1 significantly inhibited the promoter activity in a
      time- and dose-dependent manner, with a maximum inhibition at 24 hours. The Ang
      II-dependent repression of Npr1 promoter activity was partially blocked by both
      angiotensin type 1 and type 2 antagonists candesartan and PD 123,319,
      respectively. The mRNA level of NPRA was also downregulated by Ang II treatment
      as determined by semiquantitative reverse transcriptase-polymerase chain reaction
      assay. The deletion analysis showed that the promoter region approximately 916 bp
      upstream of transcription start site contains the cis-elements involved in Ang II
      mediated repression of transcription of Npr1 gene. The present study thus reveals
      the presence of functional cis-regulatory elements in the promoter region of the
      murine Npr1 gene and its transcriptional downregulation by vasoactive peptide Ang
      II.

PMID- 12623989
TI  - Characterization of a new selective antagonist for angiotensin-(1-7), D-pro7
      angiotensin-(1-7).
AB  - Angiotensin-(1-7) [Ang-(1-7)] has biological actions that can often be
      distinguished from those of angiotensin II (Ang II). Recent studies indicate that
      the effects of Ang-(1-7) are mediated by specific receptor(s). We now report the
      partial characterization of a new antagonist selective for Ang-(1-7), D-Pro7-Ang
      (1-7). D-Pro7-Ang-(1-7) (50 pmol) inhibited the hypertensive effect induced by
      microinjection of Ang-(1-7) [4+/-1 vs 21+/-2 mm Hg, 25 pmol Ang-(1-7) alone] into
      the rostral ventrolateral medulla without changing the effect of Ang II (16+/-2.5
      vs 19+/-2.5 mm Hg after 25 pmol Ang II alone). At 10(-7) mol/L concentration, it
      completely blocked the endothelium-dependent vasorelaxation produced by Ang-(1-7)
      (10(-10) to 10(-6) mol/L) in the mouse aorta. The antidiuresis produced by Ang-(1
      7) (40 pmol/100 g body weight) in water-loaded rats was also blocked by its
      analog [1 microg/100 g body weight; 3.08+/-0.8 vs 1.27+/-0.33 mL in Ang-(1-7)
      treated rats]. D-Pro7-Ang-(1-7) at a molar ratio of 40:1 did not change the
      hypotensive effect of bradykinin. Moreover, D-Pro7-Ang-(1-7) did not affect the
      dipsogenic effect produced by intracerebroventricular administration of Ang II
      (11.4+/-1.15 vs 8.8+/-1.2 mL/h after Ang II) and did not show any demonstrable
      angiotensin-converting enzyme inhibitory activity in assays with the synthetic
      substrate Hip-His-Leu and rat plasma as a source of enzyme. Autoradiography
      studies with 125I-Ang-(1-7) in mouse kidney slices showed that D-Pro7-Ang-(1-7)
      competed for the binding of Ang-(1-7) to the cortical supramedullary region. In
      Chinese hamster ovary cells stably transfected with the AT1 receptor subtype, D
      Pro7-Ang-(1-7) did not compete for the specific binding of 125I-Ang-II in
      concentrations up to 10(-6) mol/L. There was also no significant displacement of
      Ang II binding to angiotensin type 2 receptors in membrane preparations of
      adrenal medulla. These data indicate that D-Pro7-Ang-(1-7) is a selective
      antagonist for Ang-(1-7), which can be useful to clarify the functional role of
      this heptapeptide.

PMID- 12623990
TI  - Ventrolateral medulla AT1 receptors support arterial pressure in Dahl salt
      sensitive rats.
AB  - The present study addresses the hypothesis that angiotensin type 1 receptors
      (AT1Rs) in the rostral ventrolateral medulla (RVLM) contribute to the elevation
      of mean arterial pressure (MAP) in Dahl salt-sensitive (DS) rats fed a diet with
      a high NaCl content. Groups of DS or Dahl salt-resistant (DR) rats were fed diets
      containing either 0.3% NaCl (LNa) or 8% NaCl (HNa) for 3 weeks. Rats were
      anesthetized with alpha-chloralose, and the effects of microinjecting the AT1R
      antagonist valsartan (Val) or angiotensin II (Ang II) into the RVLM on MAP were
      measured. Bilateral injection of 100 pmol Val into the RVLM reduced the elevated
      MAP in the DS-HNa rats by approximately 35 mm Hg. In contrast, Val had no effect
      on MAP in DS-LNa rats. DR rats were normotensive on either diet; Val injection
      into the RVLM had no significant effect on MAP in DR-HNa rats but did evoke a
      small decrease in MAP in DR-LNa rats. Injection of Ang II into the RVLM increased
      arterial pressure in all groups, but the response was substantially larger in DS
      HNa rats. Inhibition of neuronal function in the vicinity of the hypothalamic
      paraventricular nucleus, a possible source of innervation of the RVLM AT1R, by
      local injection with muscimol also produced a substantial decrease in MAP in DS
      HNa rats but not in DS-LNa rats or DR rats. Thus, RVLM AT1Rs appear to contribute
      to salt-dependent hypertension in DS rats, and the paraventricular nucleus may be
      a source of this tonic activation.

PMID- 12623991
TI  - Transduction of a functional domain of the AT1 receptor in neurons by HIV-Tat
      PTD.
AB  - Despite advances in transgenic and gene transfer technologies, in vivo structure
      function studies of the angiotensin II type I receptor (AT1R) have revealed
      limited information on the diverse actions of angiotensin II. Our objective in
      the present study was to determine if protein transduction technology with the
      use of the HIV-Tat protein transduction domain could fill this gap. Recombinant
      HIV-Tat protein transduction domain fused to EGFP and to the third intracellular
      loop of the AT1R was expressed. Incubation of hypothalamus and brainstem neurons
      with this peptide indicated an efficient transport of the protein to most of the
      cells. This transduction was accompanied by an increase in neuronal firing rate,
      an effect similar to that observed with angiotensin II stimulation of the
      neuronal AT1R. The characteristics of the chronotropic effects of recombinant
      third intracellular loop and its synthetic counterpart were similar and
      comparable to the effects of angiotensin II on these neurons. In addition, in the
      presence of the protein kinase C inhibitor calphostin C, the peptide failed to
      increase firing rate. These observations demonstrated that transduction of
      neurons with the third intracellular loop of the AT1R produces chronotropic
      effects similar to those induced by angiotensin II. The data suggests that
      protein transduction technology could be useful for in vivo AT1R domain
      transduction.

PMID- 12623992
TI  - Anandamide-induced depressor effect in spontaneously hypertensive rats: role of
      the vanilloid receptor.
AB  - To test the hypothesis that activation of the vanilloid receptor (VR1)
      contributes to the anandamide-induced depressor effect in spontaneously
      hypertensive rats (SHR), we used a selective VR1 antagonist capsazepine (CAPZ)
      and a selective cannabinoid type 1 receptor antagonist SR141716A in conjunction
      with a VR1 agonist capsaicin in both SHR and Wistar-Kyoto rats (WKY). Mean
      arterial pressure was increased in SHR compared with WKY (P<0.05). Intravenous
      administration of capsaicin caused a greater depressor response in SHR compared
      with WKY (P<0.05), which was blocked by approximately 60% by CAPZ (P<0.05) in SHR
      only. Methanandamide caused a similar greater depressor response (P<0.05), which
      was blocked by approximately 50% and 60% by CAPZ and SR141716A, respectively, in
      SHR (P<0.05) but not in WKY. Radioimmunoassay showed that methanandamide
      increased plasma calcitonin gene-related peptide (CGRP) levels from baseline in
      both SHR and WKY (P<0.05), with no difference between 2 strains. Western blot
      showed that protein expression for the calcitonin receptor-like receptor-but not
      receptor activity modifying protein 1, VR1, and cannabinoid type 1 receptors-was
      increased in mesenteric resistance arteries in SHR compared with WKY (P<0.05).
      These data indicate that in addition to activation of cannabinoid type 1,
      anandamide may serve as an endogenous compound to stimulate VR1, leading to a
      decrease in blood pressure via CGRP release from sensory nerve terminals.
      Increased mesenteric CGRP receptor expression in SHR may account for increased
      sensitivity of blood pressure to anandamide and may serve as a compensatory
      response to buffer the increase in blood pressure in SHR.

PMID- 12623993
TI  - Intracellular mechanisms involved in leptin regulation of sympathetic outflow.
AB  - Leptin acts in the hypothalamus to decrease appetite and increase sympathetic
      nerve activity. The leptin receptor is known to signal through the janus
      kinase/signal transducer and activator of transcription (JAK/STAT) pathway to
      modulate transcription of target genes. Alteration of the activity of
      phosphoinositol-3 kinase (PI3K) by leptin has also been reported, and inhibition
      of PI3K is known to block the leptin-induced suppression of feeding. We tested
      the hypothesis that leptin-induced renal sympathetic nerve activation is mediated
      by PI3K. We evaluated renal sympathetic nerve activity (RSNA) and feeding
      responses of C57BL/6J mice to intracerebroventricular (ICV) administration of
      leptin in the presence or absence of selective inhibitors of PI3K (LY294002 or
      wortmannin). As expected, ICV administration of leptin decreased food intake at 4
      hours and 24 hours and increased RSNA. Pretreatment with the PI3K inhibitor
      LY294002 markedly attenuated both the decrease in food intake and the increase in
      RSNA induced by leptin. Wortmannin also inhibited the RSNA response to leptin. In
      contrast, PI3K inhibitors did not affect the RSNA response to MTII (melanocortin
      3/4 receptor agonist). Our data demonstrate that PI3K appears to play an
      important role in the transduction of leptin-induced changes in renal sympathetic
      outflow.

PMID- 12623994
TI  - Hypothalamic melanocortin receptors and chronic regulation of arterial pressure
      and renal function.
AB  - This study examined control of cardiovascular and renal function during chronic
      melanocortin-3/4 receptor (MC3/4-R) activation or inhibition. Arterial and venous
      catheters were implanted in Sprague-Dawley rats for measurements of mean arterial
      pressure (MAP) and heart rate (HR) 24 h/d and for intravenous infusions, and the
      lateral ventricle was cannulated for chronic intracerebroventricular (ICV)
      infusions. In experiment 1, after a 5-day control period, rats were administered
      the MC3/4-R agonist MTII (n=7, 10 ng/h ICV) or 0.9% saline (n=6, ICV) for 14
      days, followed by a 5-day recovery period. In experiment 2, after a 5-day control
      period, rats were administered the MC3/4-R antagonist SHU-9119 (n=7, 1 nmol/h
      ICV) or 0.9% saline vehicle (n=7, ICV), or pair-fed during SHU-9119 infusion
      (n=5, 1 nmol/h ICV) for 12 days, followed by a 5-day recovery period. MC4-R
      activation transiently decreased food intake from 23+/-1 to 10+/-2 g/d. Despite
      the hypophagia, MC3/4-R activation increased MAP by 7+/-1 mm Hg. MC3/4-R
      inhibition for 12 days increased food intake from 21+/-1 to 35+/-4 g/d, decreased
      HR by 53+/-11 bpm, and caused no change in MAP despite the marked weight gain. In
      rats that were pair-fed to prevent increased food intake, MC3/4-R inhibition
      further decreased HR (-87+/-9 bpm), whereas MAP was unchanged. Thus, chronic
      hypothalamic MC3/4-R activation raises arterial pressure despite decreased food
      intake, whereas MC3/4-R inhibition causes marked weight gain without raising
      arterial pressure. These observations are consistent with the hypothesis that an
      intact hypothalamic MC3/4-R may be necessary for excess weight gain to raise
      arterial pressure.

PMID- 12623995
TI  - Insulin-induced Akt activation is inhibited by angiotensin II in the vasculature
      through protein kinase C-alpha.
AB  - Insulin resistance is an important risk factor in the development of
      cardiovascular diseases such as hypertension and atherosclerosis. However, the
      specific role of insulin resistance in the etiology of these diseases is poorly
      understood. Angiotensin (Ang) II is a potent vasculotrophic and vasoconstricting
      factor. We hypothesize that in vascular smooth muscle cells (VSMCs), Ang II
      interferes with insulin action by inhibiting Akt, a major signaling molecule
      implicated in the biological actions of insulin. By immunoblotting with a phospho
      specific antibody for Akt, we found that Ang II inhibits insulin-induced Akt
      phosphorylation in a time- and concentration-dependent manner. The inhibitory
      effect of Ang II was blocked by a Ang II type 1 receptor antagonist, RNH6270. A
      protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate, also inhibited
      insulin-induced Akt phosphorylation. PKC inhibitors, including Go6976 (specific
      for alpha- and beta-isoforms), blocked the Ang II- and PMA-induced inhibition of
      Akt phosphorylation by insulin. Moreover, overexpression of PKC-alpha but not PKC
      beta isoform by adenovirus inhibited insulin-induced Akt phosphorylation. By
      contrast, an epidermal growth factor receptor inhibitor (AG1478), a p42/44
      mitogen-activated protein kinase (MAPK) kinase inhibitor (PD 598,059), and a p38
      MAPK inhibitor (SB 203,580) did not block the Ang II-induced inhibition of Akt
      phosphorylation. From these data, we conclude that Ang II negatively regulates
      the insulin signal, Akt, in the vasculature specifically through PKC-alpha
      activation, providing an alternative molecular mechanism that may explain the
      association of hyperinsulinemia with cardiovascular diseases.

PMID- 12623996
TI  - Role of EGFR transactivation in angiotensin II signaling to extracellular
      regulated kinase in preglomerular smooth muscle cells.
AB  - Angiotensin (Ang) II promotes the phosphorylation of extracellular regulated
      kinase (ERK); however, the mechanisms leading to Ang II-induced ERK
      phosphorylation are debated. The currently accepted theory involves
      transactivation of epidermal growth factor receptor (EGFR). We have shown that
      generation of phosphatidic acid (PA) is required for the recruitment of Raf to
      membranes and the activation of ERK by multiple agonists, including Ang II. In
      the present report, we confirm that phospholipase D-dependent generation of PA is
      required for Ang II-mediated phosphorylation of ERK in Wistar-Kyoto and
      spontaneously hypertensive rat preglomerular smooth muscle cells (PGSMCs).
      However, EGF stimulation does not activate phospholipase D or generate PA. These
      observations indicate that EGF recruits Raf to membranes via a mechanism that
      does not involve PA, and thus, Ang II-mediated phosphorylation of ERK is
      partially independent of EGFR-mediated signaling cascades. We hypothesized that
      phosphoinositide-3-kinase (PI3K) can also act to recruit Raf to membranes;
      therefore, inhibition of PI3K should inhibit EGF signaling to ERK. Wortmannin, a
      PI3K inhibitor, inhibited EGF-mediated phosphorylation of ERK (IC50,
      approximately 14 nmol/L). To examine the role of the EGFR in Ang II-mediated
      phosphorylation of ERK we utilized 100 nmol/L wortmannin to inhibit EGFR
      signaling to ERK and T19N RhoA to block Ang II-mediated ERK phosphorylation.
      Wortmannin treatment inhibited EGF-mediated but not Ang II-mediated
      phosphorylation of ERK. Furthermore, T19N RhoA inhibited Ang II-mediated ERK
      phosphorylation, whereas T19N RhoA had significantly less effect on EGF-mediated
      ERK phosphorylation. We conclude that transactivation of the EGFR is not
      primarily responsible for Ang II-mediated activation of ERK in PGSMCs.

PMID- 12623997
TI  - Endothelin-induced increases in Ca2+ entry mechanisms of vascular contraction are
      enhanced during high-salt diet.
AB  - High-salt diet is often associated with increases in arterial pressure, and a
      role for endothelin (ET)-1 in salt-sensitive hypertension has been suggested;
      however, the vascular mechanisms involved are unclear. We investigated whether ET
      increases the sensitivity of the mechanisms of vascular contraction to changes in
      dietary salt intake. Active stress and 45Ca2+ influx were measured in endothelium
      denuded aortic strips of male Sprague-Dawley rats not treated or chronically
      infused intravenously with ET (5 pmol/kg per minute) and fed either normal-sodium
      diet (NS, 1%) or high-sodium diet (HS, 8%) for 9 days. Phenylephrine (Phe) caused
      increases in active stress that were similar in NS and HS, but were greater in
      NS/ET (maximum, 10.5+/-0.7) than in NS (maximum, 7.4+/-0.9) rats, and further
      enhanced in HS/ET (maximum, 14.4+/-1.1) compared with HS rats (maximum, 8.0+/-0.8
      x 10(4)N/m2). Phe was more potent in causing contraction in NS/ET than in NS rats
      and in HS/ET than in HS rats. In Ca2+-free (2 mmol/L EGTA) Krebs, stimulation of
      intracellular Ca2+ release by Phe (10(-5) mol/L) or caffeine (25 mmol/L) caused a
      transient contraction that was not significantly different in all groups of rats.
      In contrast, membrane depolarization by high-KCl solution, which stimulates Ca2+
      entry from the extracellular space, caused greater contraction in ET-infused
      rats, particularly those on HS diet. Phe (10(-5) mol/L) caused an increase in
      45Ca2+ influx that was greater in NS/ET (27.9+/-1.7) than in NS (20.1+/-1.8) rats
      and further enhanced in HS/ET (35.2+/-1.8) compared with HS rats (21.8+/-1.9
      micromol/kg/min). The Phe-induced 45Ca2+ influx-stress relation was not different
      between NS and HS rats, but was enhanced in ET-infused rats particularly those on
      HS. The enhancement of the 45Ca2+ influx-active stress relation in ET-infused
      rats was not observed in vascular strips treated with the protein kinase C
      inhibitor GF109203X or calphostin C (10(-6) mol/L). Thus, low-dose infusion of
      ET, particularly during HS, is associated with increased vascular reactivity that
      involves Ca2+ entry from the extracellular space, but not Ca2+ release from the
      intracellular stores. The ET-induced enhancement of the Ca2+ influx-stress
      relation particularly during HS suggests activation of other mechanisms in
      addition to Ca2+ entry, possibly involving protein kinase C. The results suggest
      that ET increases the sensitivity of the mechanisms of vascular smooth muscle
      contraction to high dietary salt intake and may, in part, explain the possible
      role of ET in salt-sensitive hypertension.

PMID- 12623998
TI  - PKC-zeta mediates norepinephrine-induced phospholipase D activation and cell
      proliferation in VSMC.
AB  - Norepinephrine (NE) stimulates phospholipase D (PLD) activity and cell
      proliferation in vascular smooth muscle cells (VSMCs). The objective of this
      study was to determine the contribution of PKC-zeta to NE-induced PLD activation
      and cell proliferation in VSMCs. PLD activity was measured by the formation of
      [3H]phosphatidylethanol in VSMCs labeled with [3H]oleic acid and exposed to
      ethanol. A high basal PLD activity was detected, and NE increased PLD activity
      over basal by 70%. This increase was abolished by the broad-range PKC inhibitor
      Ro 31-8220 (1 micromol/L, 30 minutes) and myristoylated PKC-zeta pseudosubstrate
      peptide inhibitor (25 micromol/L, 1 hour). Transfection of VSMCs with PKC-zeta
      antisense, but not sense, oligonucleotides, which reduced PKC-zeta protein level
      and basal PLD activity, caused a 92% decrease in NE-induced PLD activation. NE
      induced increase in PLD activity was also reduced by 61% in cells transfected
      with kinase-deficient FLAG-T410A-PKC-zeta plasmid but not in those transfected
      with wild-type PKC-zeta. NE increased immunoprecipitable PKC-zeta activity and
      phosphorylation, reaching a maximum at 2 and 5 minutes, respectively. NE-induced
      increase in PKC-zeta activity was inhibited by Ro 31-8220 and by the
      pseudosubstrate inhibitor. Treatment of VSMCs for 48 hours with PKC-zeta
      antisense, but not sense, oligonucleotides also inhibited basal and NE-stimulated
      cell proliferation by 54% and 57%, respectively, as measured by [3H]thymidine
      incorporation. The inhibitor of PLD activity n-butanol, but not its inactive
      analog tert-butanol, also reduced the basal and blocked NE-induced cell
      proliferation. These data suggest that PKC-zeta mediates PLD activation and cell
      proliferation elicited by NE in rabbit VSMCs.

PMID- 12623999
TI  - 20-HETE-induced contraction of small coronary arteries depends on the activation
      of Rho-kinase.
AB  - 20-HETE is a potent constrictor of small blood vessels and has been suggested to
      play a crucial role in the generation of myogenic tone and the development of
      hypertension. In the present study, we investigated the mechanisms by which
      exogenously applied 20-HETE modulates vascular tone in small porcine coronary
      arteries. In organ chamber experiments, 20-HETE elicited a concentration
      dependent contraction of small porcine coronary artery rings that was partially
      inhibited by the cyclooxygenase inhibitor diclofenac, the thromboxane and
      endoperoxide receptor antagonist SQ29548, and the thromboxane A2 synthase
      inhibitor furegrelate. Removal of endothelium attenuated the response to 20-HETE,
      whereas preconstriction of endothelium-denuded vessels to 25% of the maximum
      response with KCl markedly enhanced the response to 20-HETE. This 20-HETE-induced
      contraction was not associated with a significant increase in the intracellular
      concentration of Ca2+. 20-HETE-induced contraction was also observed in beta
      escin-permeabilized arteries precontracted with a submaximal concentration of
      Ca2+ and was abolished by the Rho-kinase inhibitor Y27632, but was insensitive to
      the PKC inhibitor RO 31-8220. 20-HETE elicited the phosphorylation of the myosin
      light chain (MLC20) in coronary artery rings, an effect that was sensitive to
      Y27632 and mimicked by the thromboxane analog U46619. These data suggest that in
      small porcine coronary arteries, 20-HETE can induce contraction by 2 mechanisms,
      one endothelium-dependent involving the cyclooxygenase-dependent generation of
      vasoconstrictor prostanoids, and the other endothelium-independent. The latter
      response is associated with the activation of Rho-kinase, phosphorylation of
      MLC20, and sensitization of the contractile apparatus to Ca2+.

PMID- 12624000
TI  - CYP450- and COMT-derived estradiol metabolites inhibit activity of human coronary
      artery SMCs.
AB  - The purpose of this study is to test the hypothesis that the inhibitory effects
      of estradiol in human coronary vascular smooth muscle cells are mediated via
      local conversion to methoxyestradiols via specific cytochrome P450s (CYP450s) and
      catechol-O-methyltransferase (COMT). The inhibitory effects of estradiol on serum
      induced cell activity (DNA synthesis, cell number, collagen synthesis, and cell
      migration) were enhanced by 3-methylcholantherene, phenobarbital (broad-spectrum
      CYP450 inducers), and beta-naphthoflavone (CYP1A1/1A2 inducer) and were blocked
      by 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor). Ellipticine, alpha
      naphthoflavone (selective CYP1A1 inhibitors), and pyrene (selective CYP1B1
      inhibitor), but not ketoconazole (selective CYP3A4 inhibitor) or furafylline
      (selective CYP1A2 inhibitor), abrogated the inhibitor effects of estradiol on
      cell activity, a profile consistent with a CYP1A1/CYP1B1-mediated mechanism. The
      inhibitory effects of estradiol were blocked by the COMT inhibitors OR486 and
      quercetin. The estrogen receptor antagonist ICI 182,780 blocked the inhibitory
      effects of estradiol, but only at concentrations that also blocked the metabolism
      of estradiol to hydroxyestradiols (precursors of methoxyestradiols). Western blot
      analysis revealed that coronary smooth muscle cells expressed CYP1A1 and CYP1B1.
      Moreover, these cells metabolized estradiol to hydroxyestradiols and
      methoxyestradiols, and the conversion of 2-hydroxyestradiol to 2-methoxyestradiol
      was blocked by OR486 and quercetin. These findings provide evidence that the
      inhibitory effects of estradiol on coronary smooth muscle cells are largely
      mediated via CYP1A1- and CYP1B1-derived hydroxyestradiols that are converted to
      methoxyestradiols by COMT.

PMID- 12624001
TI  - Cardioprotective role of AT2 receptor in postinfarction left ventricular
      remodeling.
AB  - The aim of this study was to determine the role of the AT2 receptor (AT2R) in
      left ventricular (LV) remodeling after myocardial infarction (MI). The left
      anterior descending arteries were ligated in AT2R gene knockout (Agtr2-) and wild
      type (Agtr2+) mice. The LV remodeling was evaluated by echocardiography and
      histology over a period of 2 weeks after MI. The infarct sizes in hearts excised
      from Agtr2+ and Agtr2- mice on day 1 were similar. The mortality rate of Agtr2-
      mice (62.9%) on day 14 after MI was significantly (P<0.05) higher than that of
      Agtr2+ mice (39.7%). Accordingly, LV/body weight ratios (3.7+/-0.2 versus 3.0+/
      0.1 on day 14) and LV end-diastolic (4.8+/-0.3 versus 3.9+/-0.4 mm on day 7) and
      end-systolic (4.4+/-0.3 versus 3.2+/-0.6 mm on day 7) dimensions evaluated by
      echocardiography were significantly greater in Agtr2- than in Agtr2+ mice. The
      rates of ventricular arrhythmia, rates of cardiac rupture, and blood pressures in
      the 2 strains were similar after MI. Myocyte cross-sectional areas were increased
      after MI, but the magnitudes were similar in Agtr2+ and Agtr2- mice, indicating
      the greater increases in LV dimensions and weight in Agtr2- mice are due to
      elongation of myocyte length and/or an increase in the interstitial weight
      (including vasculatures, infiltrated cells, and interstitial fluid). Interstitial
      fibrosis in remote myocardium was not evident in either strain. These results
      indicate AT2R plays a significant role in the protection against early
      development of LV dilation, thereby reducing the early mortality rate after MI.

PMID- 12624003
TI  - Antisense to epidermal growth factor receptor prevents the development of left
      ventricular hypertrophy.
AB  - We previously demonstrated that left ventricular hypertrophy (LVH) induced by
      angiotensin II infusion requires epidermal growth factor receptor (EGFR)
      activation to mediate the mitogen-activated protein kinase/extracellular signal
      regulated kinase (MAPK/ERK) pathway. To test whether the EGFR-mediated MAPK/ERK
      activation plays an important role in development and maintenance of LVH in
      spontaneously hypertensive rats (SHR), we investigated the effects of antisense
      oligodeoxynucleotide to EGFR (EGFR-AS) on LVH and blood pressure in young and
      adult SHR. EGFR-AS, sense oligonucleotide to EGFR (EGFR-S; 1.5 mg/kg), or vehicle
      control (5% dextrose) with liposome was injected once a week for 2 months in 5-
      or 13-week-old SHR. The effect of EGFR-AS on the expression of EGFR and
      phosphorylated ERK in the heart were examined by Western blots. After treatment,
      EGFR-AS significantly (P<0.05) decreased left ventricular weight/body weight and
      blood pressure in young SHR compared with EGFR-S or control-treated rats. In
      adult SHR, EGFR-AS did not affect left ventricular weight/body weight and blood
      pressure. EGFR and phosphorylated ERK significantly declined from 5 to 20 weeks
      (P<0.05). EGFR-AS, but not EGFR-S, significantly (P<0.05) decreased the
      expression of EGFR and phosphorylated ERK in young SHR, but had no significant
      effect in adult SHR. These results suggests that EGFR-mediated ERK activation is
      critically important for LVH in young SHR. This may be related to the high levels
      of EGFR and phosphorylated ERK in young SHR, suggesting a critical role of the
      EGFR-activated ERK pathway in cardiovascular development but not in the
      maintenance of established LVH in adult SHR.

PMID- 12624002
TI  - Roles of intercellular adhesion molecule-1 in hypertensive cardiac remodeling.
AB  - Recently, we have shown that in rats with a suprarenal abdominal aortic
      constriction (AC), pressure overload induces early perivascular fibro
      inflammatory changes (transforming growth factor [TGF]-beta induction and
      fibroblast proliferation) within the first week after AC and then causes the
      development of cardiac remodeling (myocyte hypertrophy and reactive myocardial
      fibrosis) associated with diastolic dysfunction. Intercellular adhesion molecule
      (ICAM)-1 is implicated in the recruitment of leukocytes, especially macrophages,
      in various inflammatory situations. Thus, we sought to investigate the causal
      relation of ICAM-1 to macrophage recruitment and cardiac remodeling in AC rats.
      In AC rats, immunoreactive ICAM-1 was observed transiently on endothelial cells
      of the intramyocardial coronary arterioles after day 1, with a peak at day 3,
      returning to baseline by day 7. Also, ED1+ macrophage accumulation was found in
      the area adjacent to the arteries expressing ICAM-1. Chronic treatment with an
      anti-ICAM-1 neutralizing antibody, but not with control IgG, remarkably reduced
      the accumulations of macrophages and proliferative fibroblasts and inhibited the
      upregulation of TGF-beta expression. Furthermore, the neutralizing antibody
      significantly prevented myocardial fibrosis without affecting arterial pressure
      and left ventricular and myocyte hypertrophy. In conclusion, ICAM-1 expression
      was induced by pressure overload in the intramyocardial arterioles, and triggered
      perivascular macrophage accumulation. In pressure-overloaded hearts, a crucial
      role in ICAM-1-mediated macrophage accumulation was suggested in the development
      of myocardial fibrosis, through TGF-beta induction and fibroblast activation.

PMID- 12624005
TI  - Molecular mechanisms mediating inflammation in vascular disease: special
      reference to monocyte chemoattractant protein-1.
AB  - There are several clinical challenges for the treatment of intractable
      cardiovascular diseases, including restenosis, atherosclerotic complications
      resulting from plaque rupture, severe tissue ischemia, and heart failure.
      Emerging evidence suggests that an inflammatory process is involved in the
      pathogenesis of such intractable diseases. In particular, inflammatory responses
      to arterial injury, which cause continuous recruitment and activation of
      monocytes mainly through activation of the monocyte chemoattractant protein-1
      (MCP-1) pathway, have a central role in restenosis and atherogenesis. We recently
      devised a new strategy for anti-MCP-1 therapy by transfecting an N-terminal
      deletion mutant of the MCP-1 gene into skeletal muscles. This mutant MCP-1 lacks
      the N-terminal amino acids 2 to 8, called 7ND, and works as a dominant-negative
      inhibitor of MCP-1. We demonstrated that 7ND gene transfer suppresses monocyte
      infiltration/activation after arterial injury and markedly inhibits experimental
      restenosis in animals after balloon injury or stent placement. Furthermore, 7ND
      gene transfer not only attenuated the development of early atherosclerotic
      lesions but also limited progression of preexisting atherosclerotic lesions and
      changed the lesion composition into a more stable phenotype in
      hypercholesterolemic mice. Vascular inflammation mediated by MCP-1 might create a
      positive feedback loop to enhance restenotic and atherosclerotic changes through
      activating lesional monocytes. Therefore, vascular inflammation mediated by MCP-1
      has a central role in the development of experimental restenosis,
      atherosclerosis, and plaque destabilization, leading to acute coronary syndrome.
      This strategy for gene therapy might be useful against human restenosis, thereby
      opening a new therapeutic window for antirestenosis and antiatherosclerosis
      paradigms.

PMID- 12624004
TI  - Abolition of end-organ damage by antiandrogen treatment in female hypertensive
      transgenic rats.
AB  - We aimed at studying the role of androgens in the development of cardiovascular
      pathology in hypertensive female rats. Female TGR(mREN2)27 rats harboring the
      mouse Ren-2 renin gene were treated with Flutamide (specific antagonist of the
      androgen receptor, 30 mg/kg per day) starting at 4 weeks of age. Flutamide
      treatment significantly attenuated the development of hypertension in female rats
      (systolic blood pressure: treated, 134.5+/-5.4 versus control, 165.4+/-3.8 mm
      Hg). Heart hypertrophy was significantly reduced by the treatment (treated,
      0.37+/-0.008 versus control, 0.45+/-0.01 g/100 g body wt). Urinary albumin
      excretion was blunted (treated, 0.4+/-0.1 versus control, 23.1+/-7.5 mg/24
      hours), collagen III mRNA was significantly decreased, and no histological
      characteristics of end-organ damage were observed in the kidney after treatment.
      Flutamide treatment significantly reduced plasma renin concentrations and rat
      renin mRNA in kidney but not plasma angiotensinogen levels. Plasma levels of
      estrogens, testosterone, and luteinizing hormone were not altered. These results
      demonstrate that the androgen receptor antagonist Flutamide protects against
      hypertension and end-organ damage not only in male but also in female
      TGR(mREN2)27 rats.

PMID- 12624006
TI  - Erythrocyte sodium-lithium countertransport and blood pressure: a genome-wide
      linkage study.
AB  - Increased activity of erythrocyte sodium-lithium countertransport is associated
      with essential hypertension. Sodium-lithium countertransport is highly heritable,
      but no single gene product mediating the exchange or explaining the association
      of increased sodium-lithium countertransport activity and hypertension has been
      identified. We performed a linkage study by using erythrocyte sodium-lithium
      countertransport as a quantitative phenotype and genome-wide markers at an
      average resolution of approximately 10 cM to identify quantitative trait loci
      explaining sodium-lithium countertransport activity. A peak LOD score of 2.83 was
      detected on chromosome 15q at D15S642, a marker previously shown to be linked to
      blood pressure. Several genes mapped to this region are possible candidates for
      factors affecting erythrocyte sodium-lithium countertransport and/or blood
      pressure. Further studies confirming the presence of a quantitative trait locus
      in this region and evaluating these candidate genes may help explain the
      association of elevated sodium-lithium countertransport and hypertension.

PMID- 12624007
TI  - Microarray analysis of rat chromosome 2 congenic strains.
AB  - Human essential hypertension is a complex polygenic trait with underlying genetic
      components that remain unknown. The stroke-prone spontaneously hypertensive rat
      (SHRSP) is a model of human essential hypertension, and a number of reproducible
      blood pressure regulation quantitative trait loci have been found to map to rat
      chromosome 2. The SP.WKYGla2c* congenic strain was produced by introgressing a
      region of rat chromosome 2 from the normotensive Wistar Kyoto (WKY) strain into
      the genetic background of the SHRSP. Systolic and diastolic blood pressures were
      significantly reduced in the SP.WKYGla2c* compared with the SHRSP parental strain
      (198/134+/-6.1/3.3 versus 172/120+/-3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013).
      Genome-wide microarray expression profiling was undertaken to identify
      differentially expressed genes among the parental SHRSP, WKY, and congenic
      strain. We identified a significant reduction in expression of glutathione S
      transferase mu-type 2, a gene involved in the defense against oxidative stress.
      Quantitative reverse transcription-polymerase chain reaction relative to a beta
      actin standard confirmed the microarray results with SHRSP mRNA at 8.56 x 10(-4)
      +/-1.6 x 10(-4) compared with SP.WKYGla2c* 3.67 x 10(-3)+/-2.8 x 10(-4) (95% CI 
      3.9 x 10(-3) to -1.8 x 10(-3); P=0.0034) and WKY 4.03 x 10(-3)+/-5.1 x 10(-4);
      (95% CI -5.4 x 10(-3) to -8.9 x 10(-4); P=0.027). We also identified regions of
      conserved synteny, each containing the Gstm2 gene, on mouse chromosome 3 and
      human chromosome 1.

PMID- 12624008
TI  - Two loci affect angiotensin I-converting enzyme activity in baboons.
AB  - Serum LDL cholesterol (LDLC) concentrations and ACE activities are risk factors
      for the development of cardiovascular disease (CVD). However, the relationship
      between ACE and CVD susceptibility, and possible mechanisms of action, is
      controversial. With data on 622 pedigreed baboons, we used statistical genetic
      methods to determine the mode of inheritance of ACE activities and its
      relationship to LDLC on different diets. ACE activity was moderately heritable,
      and quantitative trait linkage analyses detected a quantitative trait locus (QTL)
      for ACE activity on the baboon homolog of human chromosome 17 (near the ACE
      structural locus, maximum multipoint lod=7.5, genomic P=0.000003). Bivariate
      analyses revealed that ACE activity was genetically correlated (rhoG) with LDLC
      response (LDLCRC) to a high-cholesterol diet (rhoG=0.30+/-0.13, P=0.01) but not
      to LDLC on a basal diet (rhoG=0.08+/-0.13). Bivariate genetic analyses indicated
      that a previously detected QTL for LDLCRC had significant (P=0.025) pleiotropic
      effects on ACE activity levels and accounted for the genetic correlation.
      Therefore, we have detected 2 putative loci that affect ACE activity in baboons,
      one of which also affects LDLC dietary response. The existence of at least 2
      genes that affect ACE activity, one of which is diet-responsive, may help explain
      the lack of consistency among studies of the relationship between ACE and CVD.

PMID- 12624009
TI  - Clinical microbiology: past, present, and future.

PMID- 12624010
TI  - Diagnosis of Bartonella endocarditis by a real-time nested PCR assay using serum.
AB  - Bartonella endocarditis is a severe disease for which blood cultures frequently
      remain negative. We tested three PCR assays by using specimens of serum sampled
      early during the disease from 43 patients diagnosed in our laboratory as having
      Bartonella endocarditis on the basis of serological, culture, and/or valvular
      molecular detection. We tested a two-step nested PCR (TSN-PCR), a one-step nested
      PCR (OSN-PCR) with a regular thermal cycler, and a one-step nested PCR with the
      LightCycler (LCN-PCR). These assays were performed with primers derived from the
      riboflavin synthase-encoding gene ribC, never before amplified in our laboratory.
      Due to contamination of negative controls, the results of the TSN-PCR were not
      interpretable, and this technique was no longer considered. The LCN-PCR had a
      specificity of 100% and a sensitivity of 58.1%, higher than those of the OSN-PCR
      (18.6%; P < 0.01) and prolonged blood culturing (7.1%; P < 0.01). The LCN-PCR
      results correlated strictly with those of other direct diagnostic tests, when
      available, and identified the causative species for six patients previously
      diagnosed on the basis of serological analysis only. The efficacy of the LCN-PCR
      was not influenced by antibiotics (P = 0.96) but was altered by prolonged storage
      of serum specimens at -20 degrees C (P = 0.04). Overall, the LCN-PCR is specific
      and more sensitive than traditional methods (i.e., culturing and/or PCR with EDTA
      treated blood). It can easily be applied to the diagnosis of patients with
      suspected Bartonella endocarditis, especially when only serum is available.

PMID- 12624011
TI  - stx1c Is the most common Shiga toxin 1 subtype among Shiga toxin-producing
      Escherichia coli isolates from sheep but not among isolates from cattle.
AB  - Unlike Shiga toxin 2 (stx(2)) genes, most nucleotide sequences of Shiga toxin 1
      (stx(1)) genes from Shiga toxin-producing Escherichia coli (STEC), Shigella
      dysenteriae, and several bacteriophages (H19B, 933J, and H30) are highly
      conserved. Consequently, there has been little incentive to investigate variants
      of stx(1) among STEC isolates derived from human or animal sources. However
      stx(1OX3), originally identified in an OX3:H8 isolate from a healthy sheep in
      Germany, differs from other stx(1) subtypes by 43 nucleotides, resulting in
      changes to 12 amino acid residues, and has been renamed stx(1c). In this study we
      describe the development of a PCR-restriction fragment length polymorphism (RFLP)
      assay that distinguishes stx(1c) from other stx(1) subtypes. The PCR-RFLP assay
      was used to study 378 stx(1)-containing STEC isolates. Of these, 207 were
      isolated from sheep, 104 from cattle, 45 from humans, 11 from meat, 5 from swine,
      5 from unknown sources, and 1 from a cattle water trough. Three hundred fifty
      five of the 378 isolates (93.9%) also possessed at least one other associated
      virulence gene (ehxA, eaeA, and/or stx(2)); the combination stx(1), stx(2), and
      ehxA was the most common (175 of 355 [49.3%]), and 90 of 355 (25.4%) isolates
      possessed eaeA. One hundred thirty-six of 207 (65.7%) ovine isolates possessed
      stx(1c) alone and belonged to 41 serotypes. Seventy-one of 136 (52.2%) comprised
      the common ovine serotypes O5:H(-), O128:H2, and O123:H(-). Fifty-two of 207
      isolates (25.1%) possessed an stx(1) subtype; 27 (51.9%) of these belonged to
      serotype O91:H(-). Nineteen of 207 isolates (9.2%) contained both stx(1c) and
      stx(1) subtypes, and 14 belonged to serotype O75:H8. In marked contrast, 97 of
      104 (93.3%) bovine isolates comprising 44 serotypes possessed an stx(1) subtype,
      6 isolates possessed stx(1c), and the remaining isolate possessed both stx(1c)
      and stx(1) subtypes. Ten of 11 (91%) isolates cultured from meat in New Zealand
      possessed stx(1c) (serotypes O5:H(-), O75:H8/H40, O81:H26, O88:H25, O104:H(-)/H7,
      O123:H(-)/H10, and O128:H2); most of these serotypes are commonly recovered from
      the feces of healthy sheep. Serotypes containing stx(1) recovered from cattle
      rarely were the same as those isolated from sheep. Although an stx(1c) subtype
      was never associated with the typical enterohemorrhagic E. coli serogroups O26,
      O103, O111, O113, and O157, 13 human isolates possessed stx(1c). Of these, six
      isolates with serotype O128:H2 (from patients with diarrhea), four O5:H(-)
      isolates (from patients with hemolytic-uremic syndrome), and three isolates with
      serotypes O123:H(-) (diarrhea), OX3:H8 (hemolytic-uremic syndrome), and O81:H6
      (unknown health status) represent serotypes that are commonly isolated from
      sheep.

PMID- 12624012
TI  - Epidemiologic analysis of invasive and noninvasive group a streptococcal isolates
      in Hong Kong.
AB  - Since the mid-1980s, there has been a resurgence of severe forms of invasive
      group A streptococcal (GAS) disease in many Western countries. In Hong Kong, a
      similar increase has also been observed in recent years. One hundred seven GAS
      isolates collected from 1995 to 1998 from individuals with necrotizing fasciitis,
      toxic shock syndrome, meningitis, or other type of bacteremic sepsis (invasive
      group, n = 24) as well as from individuals with minor skin and throat infections
      (noninvasive group, n = 83) were characterized through serologic and/or emm
      sequence typing. Thirty-two M protein gene sequence types were identified. Types
      M1, M4, and M12 were the most prevalent in both the invasive group and the
      noninvasive group; together they accounted for 70.8 and 37.3% of the isolates,
      respectively. No clear pattern of skin and throat infection M types was observed.
      Type M1 was overrepresented in the invasive and pharyngeal isolates. The same
      pulsed-field gel electrophoresis pattern was shared by most invasive and all
      pharyngeal M1 isolates. Overall, resistance to erythromycin (32%) and
      tetracycline (53%) was high, but M1 isolates were significantly less likely to
      have resistance to either antimicrobial agent than non-M1 isolates. One novel emm
      sequence type, stHK, was identified in an isolate from a patient with necrotizing
      fasciitis. Minor emm gene sequence alterations were noted for 31 isolates, and
      for 13 of these isolates, deletion, insertion, or point mutations were seen in
      the hypervariable 50 N-terminal residues.

PMID- 12624013
TI  - Competitive enzyme-linked immunosorbent assay based on monoclonal antibody and
      recombinant hemagglutinin for serosurveillance of rinderpest virus.
AB  - A competitive enzyme-linked immunosorbent assay (C-ELISA) which detects
      antibodies unique to rinderpest virus (RPV) has been developed. This test can
      differentiate antibodies against RPV and those against peste des petits ruminants
      virus. The recombinant RPV hemagglutinin (H)-protein C-ELISA (recH C-ELISA) is
      based on the ability of a well-characterized monoclonal antibody (MAb) produced
      with the soluble, secreted form of the H protein (Sec H protein) of RPV made in a
      baculovirus expression system to compete with the binding of RPV antibodies in
      the serum of vaccinated or infected, recovered animals to the Sec H protein. The
      B-cell epitope recognized by the MAb corresponds to amino acids 575 to 583 on the
      H protein, which is not present on the antigenically closely related peste des
      petits ruminants virus hemagglutinin-neuraminidase protein. Initially, a positive
      negative threshold cutoff value for percent inhibition of 34 was established with
      500 known RPV-negative serum samples. The recH C-ELISA was developed with the
      enzyme immunoassay software of a commercial RPV C-ELISA kit. Comparative analysis
      of the test results for 700 serum samples obtained with the commercial kit gave a
      sensitivity of 112.4% and a specificity of 72.4%. Variations in percent
      inhibition values were observed for the two assay systems. These variations may
      have been due to the undefined amount of antigen present in the commercial kit as
      well as the use of a different MAb. The recH C-ELISA detected more positive serum
      samples compared to the number detected by the commercial kit, with the results
      confirmed by a virus neutralization test. Thus, recH C-ELISA is a sensitive tool
      for RPV serosurveillance in disease eradication programs.

PMID- 12624014
TI  - Cost-effectiveness analysis of the gen-probe amplified mycobacterium tuberculosis
      direct test as used routinely on smear-positive respiratory specimens.
AB  - A decision analysis was conducted to evaluate the cost-effectiveness of programs
      in which the Amplified Mycobacterium Tuberculosis Direct test (MTD) (Gen-Probe)
      is used to rapidly exclude Mycobacterium tuberculosis complex as a cause of
      disease in smear-positive respiratory specimens. MTD sensitivity, specificity,
      and probability of inhibition for smear-positive specimens were estimated from
      literature reports. Costs and laboratory performance characteristics were
      determined from review of records and practices at an urban hospital in the mid
      Atlantic United States. In the base case, 31.4% of smear-positive specimens were
      assumed to be culture positive for M. tuberculosis. Under these conditions, the
      marginal cost of the MTD testing program was estimated as $338 per smear-positive
      patient, or $494 per early exclusion of tuberculosis based on negative MTD
      results. By comparison, the cost of respiratory isolation ($27.77/day) and drugs
      ($5.66/day) averted by MTD testing was estimated at $201 per early tuberculosis
      exclusion. MTD testing was therefore not cost-effective in this scenario.
      Sensitivity analysis revealed that cost-effectiveness estimates are sensitive to
      the number of smear-positive specimens processed annually, the relative
      prevalence of M. tuberculosis in smear-positive specimens, and the marginal daily
      cost of respiratory isolation. A decision tool is therefore presented for
      assessing the cost-effectiveness of MTD under various combinations of those three
      variables. While routine MTD testing of smear-positive specimens is not expected
      to be cost-saving for most individual hospitals, centralized reference
      laboratories may be able to implement MTD in a cost-effective manner across a
      wide range of situations.

PMID- 12624015
TI  - Use of Fourier-transform infrared spectroscopy for typing of Candida albicans
      strains isolated in intensive care units.
AB  - Comparative studies of Candida albicans strains are essential for proving cross
      infections in epidemiological investigations. Typing of C. albicans strains is
      mainly based on genotypic methods. Fourier-transform infrared (FTIR) spectroscopy
      is described in this study as a novel phenotypic approach to the typing of C.
      albicans. The first step in the approach was the standardization of sample
      preparation (culture conditions and sampling parameters) and acquisition and
      classification parameters (spectral acquisition, spectral window selection,
      classification algorithm, and heterogeneity threshold). The second step consisted
      of validating the established parameters with a set of 79 strains of C. albicans
      isolated over 4 months from nine patients hospitalized in two intensive care
      units. Strains were isolated from multiple anatomical sites with repeated
      sampling. FTIR spectroscopy results were compared to randomly amplified
      polymorphic DNA (RAPD) results; this analysis showed that the amplification
      patterns of strains isolated from a given patient were identical and that
      different patients had different profiles. FTIR spectroscopy data were analyzed
      by hierarchical clustering performed with the second-derivative spectra. This
      classification revealed nine groups, one per patient. Only one spectrum out of 79
      was misclassified by the FTIR spectroscopy method. RAPD and FTIR spectroscopy
      results were in good agreement, showing that, when nosocomial candidiasis
      transmission is suspected and urgent information is needed, this technique may be
      useful as a quick identification tool to give solid clues before confirmation by
      a genotypic method.

PMID- 12624016
TI  - Interaction between porcine reproductive-respiratory syndrome virus and bacterial
      endotoxin in the lungs of pigs: potentiation of cytokine production and
      respiratory disease.
AB  - Porcine reproductive-respiratory syndrome virus (PRRSV) is a key agent in
      multifactorial respiratory disease of swine. Intratracheal administration of
      bacterial lipopolysaccharides (LPSs) to PRRSV-infected pigs results in markedly
      enhanced respiratory disease, whereas the inoculation of each component alone
      results in largely subclinical disease. This study examines whether PRRSV-LPS
      induced respiratory disease is associated with the excessive production of
      proinflammatory cytokines in the lungs. Gnotobiotic pigs were inoculated
      intratracheally with PRRSV and then with LPS at 3, 5, 7, 10, or 14 days of
      infection and euthanatized 6 h after LPS inoculation. Controls were inoculated
      with PRRSV or LPS only or with phosphate-buffered saline. Virus titers,
      (histo)pathological changes in the lungs, numbers of inflammatory cells, and
      bioactive tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6
      levels in bronchoalveolar lavage fluids were examined. All pigs inoculated with
      PRRSV-LPS developed severe respiratory disease, whereas the controls that were
      inoculated with PRRSV or LPS alone did not. PRRSV infection significantly
      enhanced cytokine production in response to LPS. Peak TNF-alpha, IL-1, and IL-6
      titers were 10 to 100 times higher in the PRRSV-LPS-inoculated pigs than in the
      pigs inoculated with PRRSV or LPS alone; and the titers correlated with the
      respiratory signs. The levels of neutrophil infiltration and the pathological
      changes detected in the lungs of PRRSV-LPS-inoculated pigs resembled those
      detected when the effects of PRRSV and LPS inoculated alone are combined, but
      with no synergistic effects between PRRSV and LPS. These data demonstrate a
      synergism between PRRSV and LPS in the induction of proinflammatory cytokines and
      an association between induction of these cytokines and disease.

PMID- 12624017
TI  - Blastocystis isolates from a pig and a horse are closely related to Blastocystis
      hominis.
AB  - Blastocystis has a widespread distribution in a variety of animals, which is a
      potential source of infection for humans. However, the contribution of zoonotic
      transmission remains unclear due to the absence of molecular proof of these
      organisms being identical to those found in humans. We report herein the similar
      subgroup of Blastocystis isolates from humans, pigs, and a horse using a
      restriction fragment length polymorphism (RFLP) analysis of partial small-subunit
      ribosomal DNA (ssu rDNA). Additionally, sequence and phylogenic analysis of
      partial ssu rDNA of Blastocystis from a human, a pig, and a horse sharing a
      common subgroup shows that Blastocystis isolates from a pig and a horse were
      monophyletic and closely related to B. hominis, with 92 to 94% identity. These
      results suggest the possibility of zoonotic potential of Blastocystis.

PMID- 12624018
TI  - Heterogeneity of cag genotypes in Helicobacter pylori isolates from human biopsy
      specimens.
AB  - The Helicobacter pylori chromosomal cluster of genes known as the cytotoxin
      associated gene (cag) island may have different compositions in infecting
      strains. In this study, we analyzed 150 single colonies obtained from gastric
      biopsy specimens from 10 patients infected with cagA-positive H. pylori strains
      and sweep isolates (isolates harvested with sweep in different points of the
      plate) from 6 patients infected with cagA-negative strains. Three loci in the cag
      island (cagA, cagE, and virB11) and the conserved gene glmM (ureC) were
      investigated by PCR. The levels of anti-H. pylori and anti-CagA antibodies in
      patient sera were also measured. For subjects infected with cagA-negative
      strains, all sweep isolates were also negative for cagE and virB11, suggesting
      the complete absence of the cag island. For subjects infected with cagA-positive
      strains, most of the isolates were positive for all three genes studied, whereas
      24.7% of the isolates had a partial or total deletion of the cag island. cagA,
      cagE, and virB11 were, respectively, present in 87.3, 77.3, and 90% of the
      colonies. The deletion of virB11 was always associated with the deletion of cagA
      and/or cagE. H. pylori colonies with different cag genotypes were isolated within
      a single gastric biopsy specimen from 3 of the 10 patients and were further
      characterized by random amplified polymorphic DNA (RAPD) analysis and by
      sequencing of an arbitrarily selected gene segment. Although the colonies had
      different cag genotypes, their RAPD profiles were highly similar within each
      patient, and the nucleotide sequences of the selected gene segment were
      identical. All of the patients had detectable antibodies against H. pylori, and 9
      of 10 had anti-CagA antibodies. In conclusion, we show that a single infecting H.
      pylori strain may include variable proportions of colony subtypes with different
      cag genotypes. The extension of our analysis to patients with well-characterized
      gastric diseases may provide significant information on the relationship between
      cag genotypes and clinical outcomes of H. pylori infections.

PMID- 12624020
TI  - Rapid detection of rpoB gene mutations in rifampin-resistant Mycobacterium
      tuberculosis isolates in shanghai by using the amplification refractory mutation
      system.
AB  - Rapid detection of drug resistance in Mycobacterium tuberculosis is essential for
      efficient treatment and control of this pathogen. The amplification refractory
      mutation system (ARMS) was used to detect mutations in the rifampin resistance
      determining region of the rpoB gene. A total of 39 rifampin-resistant M.
      tuberculosis isolates in Shanghai were analyzed by this assay, resulting in 92.3%
      sensitivity (36 of 39) and 87.2% concordance (34 of 39) relative to DNA
      sequencing, by which 41 mutations of 11 different types, including 9 point
      mutations and 2 deletions, were identified in the rpoB gene. The most frequent
      mutations were those associated with codon 531 (21 of 39 [53.8%]) and codon 526
      (9 of 39 [23.1%]). The results suggest that the ARMS assay is rapid and simple to
      implement and could be performed for detection of rifampin resistance in M.
      tuberculosis to complement conventional culture-based methods.

PMID- 12624021
TI  - Performance characteristics of human immunodeficiency virus type 1 (HIV-1)
      genotyping systems in sequence-based analysis of subtypes other than HIV-1
      subtype B.
AB  - Given the diversity of human immunodeficiency virus type 1 (HIV-1) subtypes and
      the emergence of subtypes other than HIV-1 subtype B in the United States,
      genotypic assays must be capable of delivering sequence data on diverse HIV-1
      subtypes. We evaluated the performance of Visible Genetics TRUGENE HIV-1
      genotyping kit and Applied Biosystems ViroSeq HIV-1 genotyping system on a panel
      of 34 well-characterized HIV-1 viral stocks (subtypes A through H). Both assays
      perform well on diverse HIV-1 subtypes despite being designed for HIV-1 subtype
      B. The TRUGENE assay produced sequence data for 31 isolates but not for one C and
      two G isolates. The TRUGENE assay using prototype 1.5 RT-PCR primers and the
      ViroSeq assay were both successful for all variants tested, although five
      isolates lacked double-strand sequence coverage in the ViroSeq assay. The
      availability of standardized HIV-1 genotyping kits that perform reliably with all
      HIV subtypes will facilitate broad implementation of HIV-1 resistance testing.

PMID- 12624019
TI  - Molecular epidemiological analysis of Cryptosporidium isolates from humans and
      animals by using a heteroduplex mobility assay and nucleic acid sequencing based
      on a small double-stranded RNA element.
AB  - Two extrachromosomal double-stranded RNA (dsRNA) elements occur in
      Cryptosporidium parvum. A heteroduplex mobility assay (HMA) was developed for the
      rapid characterization of sequence diversity in a 173-bp fragment of the small
      dsRNA element of Cryptosporidium with either a natural sequence from
      Cryptosporidium meleagridis or a synthetic sequence as reference DNA. The 173-bp
      fragment was generated from 265 samples of whole feces (242 from humans and 18
      from livestock with C. parvum genotype 1 or 2, 4 from humans with Cryptosporidium
      felis, and 1 from a human with C. meleagridis). The HMA method identified 21
      patterns in C. parvum (8 in genotype 1, 12 in genotype 2, and a type common to
      both genotypes), 4 patterns in C. felis, and 1 pattern in C. meleagridis. All
      patterns were confirmed as distinct by DNA sequencing. For genotype 1, a single
      HMA type was found in 89% of samples: 64 of 65 cases from three waterborne
      outbreaks, all 16 cases from eight intrafamilial outbreaks, and 17 of 28 sporadic
      cases. Among the remaining 11 sporadic cases due to genotype 1, seven other HMA
      types were detected. For genotype 2, a single HMA type was found in 72% of
      samples: 36 of 43 cases from three waterborne outbreaks, 11 of 15 cases from
      seven intrafamilial outbreaks, 44 of 75 sporadic cases, and all 18 samples from
      livestock. Within the intrafamilial outbreaks, two other HMA types were
      identified: the same HMA type was detected in samples from cases within the same
      outbreak. Among the sporadic cases due to genotype 2, 10 additional HMA types
      were detected.

PMID- 12624022
TI  - Invasive Streptococcus iniae infections outside North America.
AB  - Streptococcus iniae, a fish pathogen causing infections in aquaculture farms
      worldwide, has only been reported to cause human infections in North America. In
      this article, we report the first two cases of invasive S. iniae infections in
      two Chinese patients outside North America. While the first patient presented
      with bacteremic cellulitis, which is the most common presentation in previous
      cases, the second patient represents the first recognized case of S. iniae
      osteomyelitis. Both S. iniae strains isolated from the two patients were either
      misidentified or unidentified by three commercial systems and were only
      identified by 16S rRNA gene sequencing. Since no currently available commercial
      system for bacterial identification includes S. iniae in its database, 16S rRNA
      gene sequencing is the most practical and reliable method to identify the
      bacterium at the moment. In contrast to the distinct genetic profile described
      previously in clinical isolates from Canada, the present two isolates and a
      clinical isolate from a Canadian patient were found to be genetically unrelated,
      as demonstrated by pulsed-field gel electrophoresis. Morphologically, colonies of
      both isolates were also larger, more beta-hemolytic and mucoid, which differ from
      the usual morphotype described for S. iniae. Owing to their habit of cooking and
      eating fresh fish, the Asian population is strongly associated with S. iniae
      infections. As a result of the difficulty in making microbiological diagnosis in
      patients with cellulitis and the problem of identification in most clinical
      microbiology laboratories, the prevalence of S. iniae infections, especially in
      the Asian population, may have been under-estimated.

PMID- 12624023
TI  - Conventional methods versus 16S ribosomal DNA sequencing for identification of
      nontuberculous mycobacteria: cost analysis.
AB  - The clinical profile of nontuberculous mycobacteria (NTM) has been raised by the
      human immunodeficiency virus and AIDS pandemic. Different laboratory techniques,
      often molecular based, are available to facilitate the rapid and accurate
      identification of NTM. The expense of these advanced techniques has been
      questioned. At the National Reference Center for Mycobacteriology and the Health
      Sciences Center, University of Manitoba, in Winnipeg, Canada, we performed a
      direct cost analysis of laboratory techniques for commercial DNA probe-negative
      (Gen-Probe, Inc., San Diego, Calif.), difficult-to-identify NTM. We compared the
      costs associated with conventional phenotypic methodology (biochemical testing,
      pigment production, growth, and colony characteristics) and genotypic methodology
      (16S ribosomal DNA [rDNA] sequence-based identification). We revealed a higher
      cost per sample with conventional methods, and this cost varied with organism
      characteristics: $80.93 for slowly growing, biochemically active NTM; $173.23 for
      slowly growing, biochemically inert NTM; and $129.40 for rapidly growing NTM. The
      cost per sample using 16S rDNA sequencing was $47.91 irrespective of organism
      characteristics, less than one-third of the expense associated with phenotypic
      identification of biochemically inert, slow growers. Starting with a pure
      culture, the turnaround time to species identification is 1 to 2 days for 16S
      rDNA sequencing compared to 2 to 6 weeks for biochemical testing. The accuracy of
      results comparing both methodologies is briefly discussed. 16S rDNA sequencing
      provides a cost-effective alternative in the identification of clinically
      relevant forms of probe-negative NTM. This concept is not only useful in
      mycobacteriology but also is highly applicable in other areas of clinical
      microbiology.

PMID- 12624024
TI  - p24 Antigen detection assay modified with a booster step for diagnosis and
      monitoring of human immunodeficiency virus type 1 infection.
AB  - We modified a p24 antigen enzyme-linked immunosorbent assay as a method for
      diagnosis and monitoring of human immunodeficiency virus type 1 (HIV-1) subtype E
      infection. This modified assay is based on the use of preheated immune complex
      dissociation combined with a booster step using a regular Vironostika HIV-1 p24
      antigen assay (bioMerieux) to decrease the lower limit of p24 antigen detection
      from 10 pg/ml (lower limit achievable when using a regular p24 antigen assay) to
      0.5 pg/ml (100 virions/ml) by the new method. The correlation between the values
      obtained by the HIV-1 RNA (Amplicor HIV-1 Monitor) assay and the p24 antigen
      assay modified with a booster step antigen assay in 160 frozen plasma samples
      with known viral load and 80 blind fresh plasma samples by Spearman rank were
      0.671 (R(2) = 0.450; P < 0.01) and 0.782 (R(2) = 0.612; P < 0.01). During
      antiretroviral treatment, the change of p24 antigen level at >/=0.5 log
      correlated well with the level of HIV-1 in plasma. In order to improve the early
      diagnosis of HIV-1 infection in 121 infants born to HIV-1-infected mothers, a
      heat-denatured plasma p24 antigen assay modified with a booster step was compared
      with DNA-PCR and HIV RNA (nucleic acid sequence-based amplification) assays. The
      sensitivity of the antigen test modified with a booster step was similar to that
      of the HIV-1 RNA (NASBA QL) assay and better than that of the DNA-PCR assay (100
      versus 61.90%) for subjects 1 to 2 months old. The overall results from this
      study might renew interest in p24 antigen detection as an easily affordable
      alternative method for diagnosis of HIV-1 infection and monitoring of disease
      progression in developing countries.

PMID- 12624025
TI  - Epidemiology of tetracycline resistance determinants in Shigella spp. and
      enteroinvasive Escherichia coli: characterization and dissemination of tet(A)-1.
AB  - To make a comprehensive study of tetracycline resistance determinant distribution
      in the genus Shigella, a collection of 577 clinical isolates of Shigella spp. and
      enteroinvasive Escherichia coli (EIEC) from a variety of geographical locations
      was screened to identify tetracycline-resistant strains. The 459 tetracycline
      resistant isolates identified were then screened by PCR analysis to determine the
      distribution in these strains of tetracycline efflux resistance determinants
      belonging to classes A to E, G, and H that have been identified in gram-negative
      bacteria. Only classes A to D were represented in these strains. Although Tet B
      was the predominant determinant in all geographical locations, there were
      geographical and species differences in the distribution of resistance
      determinants. An allele of tet(A), designated tet(A)-1, was identified and
      sequenced, and the 8.6-kb plasmid containing determinant Tet A-1, designated
      pSSTA-1, was found to have homologies to portions of a Salmonella enterica
      cryptic plasmid and the broad-host-range resistance plasmid RSF1010. This allele
      and pSSTA-1 were used as epidemiological markers to monitor clonal and horizontal
      transmission of determinant Tet A-1. An analysis of serotype, distribution of
      tetracycline resistance determinants, and resistance profiles indicated that both
      clonal spread and horizontal transfer had contributed to the spread of specific
      tetracycline resistance determinants in these populations and demonstrated the
      use of these parameters as an epidemiological tool to follow the transmission of
      determinants and strains.

PMID- 12624026
TI  - Serology and genetics of the flagellar antigen of Escherichia coli O157:H7a,7c.
AB  - Among Escherichia coli strains of the O55:H7 serovar, which is considered the
      ancestor of Shiga toxin-producing E. coli (STEC) O157:H7, two subtypes, H7a,7b
      and H7a,7c (briefly, H7a,b and H7a,c, respectively), of the H7 flagellar antigen
      have been described previously [J. Wright and R. Villanueva, J. Hyg. (Camb.)
      51:39-48, 1953; Y. A. Ratiner and V. A. Sinelnikova, Zh. Microbiol. Epidemiol.
      Immunobiol. 3:111-116, 1969). We have now studied 13 STEC O157:H7 strains and 1
      O55:H7 strain that were epidemiologically unrelated, that originated from six
      countries on two continents, and that had different profiles when analyzed by
      multilocus enzyme electrophoresis, pulsed-field gel electrophoresis, and PCR for
      stx and eae. They were all found to possess the H7a,c flagellar antigen. Serum
      cross-absorption assays confirmed that their H antigens were indistinguishable
      from each other and from that of E. coli O55:H7a,c but differed from the standard
      H7a,b antigen of E. coli H test strain U5/41. It was shown by phage-mediated
      transduction that the flagellin genes for these two H-antigen subserotypes were
      alleles of the E. coli fliC locus. On the basis of the serological data obtained
      in this study and the molecular characteristics of E. coli fliC(H7) alleles
      recently published, it is inferred that H7a,c and H7a,b are the main serological
      subtypes of the group of E. coli H7 flagellins.

PMID- 12624027
TI  - Epitope-blocking enzyme-linked immunosorbent assays for the detection of serum
      antibodies to west nile virus in multiple avian species.
AB  - We report the development of epitope-blocking enzyme-linked immunosorbent assays
      (ELISAs) for the rapid detection of serum antibodies to West Nile virus (WNV) in
      taxonomically diverse North American avian species. A panel of flavivirus
      specific monoclonal antibodies (MAbs) was tested in blocking assays with serum
      samples from WNV-infected chickens and crows. Selected MAbs were further tested
      against serum samples from birds that represented 16 species and 10 families.
      Serum samples were collected from birds infected with WNV or Saint Louis
      encephalitis virus (SLEV) and from noninfected control birds. Serum samples from
      SLEV-infected birds were included in these experiments because WNV and SLEV are
      closely related antigenically, are maintained in similar transmission cycles, and
      have overlapping geographic distributions. The ELISA that utilized MAb 3.1112G
      potentially discriminated between WNV and SLEV infections, as all serum samples
      from WNV-infected birds and none from SLEV-infected birds were positive in this
      assay. Assays with MAbs 2B2 and 6B6C-1 readily detected serum antibodies in all
      birds infected with WNV and SLEV, respectively, and in most birds infected with
      the other virus. Two other MAbs partially discriminated between infections with
      these two viruses. Serum samples from most WNV-infected birds but no SLEV
      infected birds were positive with MAb 3.67G, while almost all serum samples from
      SLEV-infected birds but few from WNV-infected birds were positive with MAb 6B5A
      5. The blocking assays reported here provide a rapid, reliable, and inexpensive
      diagnostic and surveillance technique to monitor WNV activity in multiple avian
      species.

PMID- 12624028
TI  - Detection and characterization of the hemolysin genes in Aeromonas hydrophila and
      Aeromonas sobria by multiplex PCR.
AB  - A multiplex PCR assay was designed to amplify the Aeromonas hydrophila and A.
      veronii bv. sobria hemolysin and aerolysin genes. The assay was evaluated by
      using 121 clinical isolates and 7 reference strains of Aeromonas spp., and these
      were divided into five genotypes on the basis of the results of the multiplex
      PCR. The five genotypes were characterized as type 1 for those carrying the ahh1
      gene only (36% of isolates), type 2 for those carrying the asa1 gene only (8.5%
      of isolates), type 3 for those carrying both the ahh1 and the asa1 genes (4% of
      isolates), type 4 for those carrying the ahh1 gene and the A. hydrophila aerA
      (aerolysin) gene (37.5% of isolates), and type 5 for those in which no hemolysin
      genes were detected (14% of isolates). The most common single hemolysin gene
      carried among all the Aeromonas isolates examined was ahh1, with 99 of 128 (77%)
      of isolates testing positive for this gene either alone or in combination with
      other hemolysin genes. Phenotypic expression of toxins was evaluated in a Vero
      cell culture cytotoxicity assay. These results indicated that there is a
      statistically significant correlation between the cytotoxin titers and the
      hemolysin genotype. Isolates belonging to genotype 4 (carrying both the ahh1 gene
      and the aerolysin and hemolysin aerA genes) expressed higher cytotoxin titers
      than isolates of the other genotypes (P < 0.001). These isolates were more
      cytotoxic in cell culture and may have greater clinical significance.

PMID- 12624029
TI  - Use of listeriolysin O and internalin A in a seroepidemiological study of
      listeriosis in Swiss dairy cows.
AB  - Recombinant listeriolysin O and internalin A were used as antigens in an enzyme
      linked immunosorbent assay (ELISA) for the specific detection of anti-Listeria
      monocytogenes antibodies in cattle. The results showed sensitivities and
      specificities of 82 and 92%, respectively, for the listeriolysin O ELISA, and 100
      and 90%, respectively, for the internalin A ELISA, respectively. The test may be
      useful for the confirmation of listeria-related abortions and mastitis but does
      not seem to be indicated for use in the diagnosis of listeria-related
      encephalitis in cattle. A representative sample of 1,652 serum samples from the
      healthy dairy cattle population in Switzerland was tested by both ELISAs. The
      results showed that 11% of the healthy dairy cows in Switzerland simultaneously
      presented antibodies toward listeriolysin O and internalin A, and 48% of the
      farms had one or several animals simultaneously positive by assays with both
      antigens. Multivariable analysis at the farm level confirmed that feeding of
      silage represents a significant risk factor for a positive listeria serology.
      Detailed analysis identified corn silage but not grass silage as the major factor
      in this association. Cattle breed and hygiene on the farm were also identified as
      significant factors associated with the serological status of farms. In
      conclusion, the results of the study show that internalin A is a promising new
      antigen for use in listeria serology and that specific anti-L. monocytogenes
      antibodies are found in a significant proportion of healthy dairy cows in
      Switzerland.

PMID- 12624030
TI  - Comparison of broth microdilution, E Test, and agar dilution methods for
      antibiotic susceptibility testing of Campylobacter jejuni and Campylobacter coli.
AB  - A standardized broth microdilution method was compared to the E test and an agar
      dilution method for the antimicrobial susceptibility testing of Campylobacter
      jejuni and C. coli isolates. A group of 47 human clinical isolates, 37 isolates
      from retail poultry, and 29 isolates from living turkeys (total, 113 isolates)
      was included in the study. These encompassed 92 C. jejuni and 21 C. coli strains.
      The MICs of six antimicrobial agents were determined by the broth microdilution
      and E test methods, and the strains of human origin were additionally tested by
      the agar dilution method. In general, broth microdilution MICs agreed within 1
      log(2) MIC increment with 90.0% of E test results and 78.7% of agar dilution test
      results. The agar dilution method gave much lower gentamicin MICs than the broth
      microdilution method, but the data were significantly (P < 0.01) correlated and
      there was 100% agreement in the sensitivities and specificities in the comparison
      of the tests. The broth microdilution method had the highest sensitivity for
      analysis of the susceptibilities of Campylobacter to nalidixic acid and
      trimethoprim-sulfamethoxazole. The MICs of ciprofloxacin and erythromycin
      complied numerically by all three methods. The classification of the results and
      the correlation of the data demonstrated a high degree of agreement. All methods
      were equally suitable for the testing of the sensitivity of Campylobacter to
      tetracycline. Thus, the broth microdilution method appears to be an easy and
      reliable method for determination of the MICs of antibiotics for C. jejuni and C.
      coli, and it may offer an interesting alternative to MIC determination by the
      agar dilution technique or the E test.

PMID- 12624031
TI  - Detection and identification of Bartonella species pathogenic for humans by PCR
      amplification targeting the riboflavin synthase gene (ribC).
AB  - Several Bartonella species have now been implicated as human pathogens. The
      recovery of these fastidious organisms in the clinical microbiology laboratory
      remains difficult, and current methods are still relatively insensitive. Thus,
      the bartonellae are good candidates for detection by PCR. We have developed a PCR
      assay which uses a single primer pair targeting the riboflavin synthase gene
      (ribC) and detected six Bartonella species that have been implicated in human
      disease, B. henselae, B. quintana, B. bacilliformis, B. clarridgeiae, B.
      elizabethae, and B. vinsonii subsp. berkhoffii. Species identification is
      achieved simply by restriction enzyme digestion of the amplicon. This PCR assay
      appears to be specific for the Bartonella genus because it failed to amplify DNA
      from several other bacterial species.

PMID- 12624033
TI  - International proficiency study of a consensus L1 PCR assay for the detection and
      typing of human papillomavirus DNA: evaluation of accuracy and intralaboratory
      and interlaboratory agreement.
AB  - The PGMY L1 consensus primer pair combined with the line blot assay allows the
      detection of 27 genital human papillomavirus (HPV) genotypes. We conducted an
      intralaboratory and interlaboratory agreement study to assess the accuracy and
      reproducibility of PCR for HPV DNA detection and typing using the PGMY primers
      and typing amplicons with the line blot (PGMY-LB) assay. A test panel of 109
      samples consisting of 29 HPV-negative (10 buffer controls and 19 genital samples)
      and 80 HPV-positive samples (60 genital samples and 20 controls with small or
      large amounts of HPV DNA plasmids) were tested blindly in triplicate by three
      laboratories. Intralaboratory agreement ranged from 86 to 98% for HPV DNA
      detection. PGMY-LB assay results for samples with a low copy number of HPV DNA
      were less reproducible. The rate of intralaboratory agreement excluding negative
      results for HPV typing ranged from 78 to 96%. Interlaboratory reliability for HPV
      DNA positivity and HPV typing was very good, with levels of agreement of >95% and
      kappa values of >0.87. Again, low-copy-number samples were more prone to
      generating discrepant results. The accuracy varied from 91 to 100% for HPV DNA
      positivity and from 90 to 100% for HPV typing. HPV testing can thus be
      accomplished reliably with PCR by using a standardized written protocol and
      quality-controlled reagents. The use of validated HPV DNA detection and typing
      assays demonstrating excellent interlaboratory agreement will allow investigators
      to better compare results between epidemiological studies.

PMID- 12624032
TI  - Quantitative microbiologic models for preterm delivery.
AB  - Preterm delivery (PTD) is the leading cause of infant morbidity and mortality in
      the United States. An epidemiological association between PTD and various
      bacteria that are part of the vaginal microflora has been reported. No single
      bacterial species has been identified as being causally associated with PTD,
      suggesting a multifactorial etiology. Quantitative microbiologic cultures have
      been used previously to define normal vaginal microflora in a predictive model.
      These techniques have been applied to vaginal swab cultures from pregnant women
      in an effort to develop predictive microbiologic models for PTD. Logistic
      regression analysis with microbiologic information was performed for various risk
      groups, and the probability of a PTD was calculated for each subject. Four
      predictive models were generated by using the quantitative microbiologic data.
      The area under the curve (AUC) for the receiver operating curves ranged from 0.74
      to 0.94, with confidence intervals (CI) ranging from 0.62 to 1. The model for the
      previous PTD risk group with the highest percentage of PTDs had an AUC of 0.91
      (CI, 0.79 to 1). It may be possible to predict PTD by using microbiologic risk
      factors measured once the gestation period has reached the 20-week time point.

PMID- 12624034
TI  - Evaluation of Etest method for determining fluconazole and voriconazole MICs for
      279 clinical isolates of Candida species infrequently isolated from blood.
AB  - The performance of Etest in fluconazole and voriconazole testing of 279 isolates
      of uncommon Candida spp. was assessed in comparison with the National Committee
      for Clinical Laboratory Standards (NCCLS)-approved standard broth microdilution
      (BMD) method. The NCCLS method employed RPMI 1640 broth medium, and MICs were
      read after incubation for 48 h at 35 degrees C. Etest MICs were determined with
      RPMI agar containing 2% glucose and were read after incubation for 48 h at 35
      degrees C. The isolates include Candida krusei, C. lusitaniae, C. guilliermondii,
      C. kefyr, C. rugosa, C. lipolytica, C. pelliculosa, C. dubliniensis, C. famata,
      C. zeylanoides, C. inconspicua, and C. norvegensis. Overall agreement between
      Etest and BMD MICs was 96% for fluconazole and 95% for voriconazole. Where a
      discrepancy was observed between Etest and the reference method, the Etest tended
      to give lower values with both fluconazole and voriconazole. The Etest method
      using RPMI agar appears to be a useful method for determining fluconazole and
      voriconazole susceptibilities of uncommon species of Candida.

PMID- 12624035
TI  - Hepatitis C virus subtyping by a core-envelope 1-based reverse transcriptase PCR
      assay with sequencing and its use in determining subtype distribution among
      Danish patients.
AB  - A reverse transcriptase PCR (RT-PCR) assay using conserved primers deduced from
      the core-envelope 1 (C-E1) region of the hepatitis C virus (HCV) genome was
      developed for subtyping purposes. The sensitivity and specificity of this assay
      tested against two HCV reference panels containing genotype 1 through 5 subtypes
      were similar to those of an RT-PCR assay from the 5'-untranslated region (5'
      UTR). The sensitivity of the RT-PCR typing assay in the more variable C-E1 region
      was, however, lower than that of the RT-PCR in the highly conserved 5'-UTR when
      testing multiple clinical samples. Thus, 71 (88%) of 81 consecutive samples from
      hospitalized Danish patients positive for HCV antibodies and RNA (5'-UTR) were
      positive also in the C-E1 RT-PCR assay. Phylogenetic analysis of the E1 sequences
      obtained by direct sequencing of HCV from two reference panels and 71 Danish
      patients allowed us to readily distinguish the subtypes. In contrast,
      phylogenetic analysis of their corresponding 5'-UTR sequences was able to predict
      only major genotypes. Three different genotypes and four subtypes were identified
      among Danish samples: 1a (43%), 1b (11%), 2b (6%), and 3a (39%). An isolate from
      a Somalian refugee was identified as a new HCV type related to Somalian isolates
      described as subtype 3h. The most common genotype in Denmark is genotype 1 (53%),
      which is the most difficult to treat. However, Denmark had the highest prevalence
      in Europe of subtype 3a, which responds more favorably to treatment. The
      described C-E1 RT-PCR with sequencing is suggested as an easy routine assay for
      definitive genotyping and subtyping of HCV.

PMID- 12624038
TI  - Influence of culture conditions on the fatty acid profiles of laboratory-adapted
      and freshly isolated strains of Helicobacter pylori.
AB  - Cellular fatty acids of Helicobacter pylori have taxonomic, physiological, and
      pathogenic implications. However, little is known about the fatty acid
      composition under various culture conditions. H. pylori is usually grown on blood
      supplemented complex media, and the fatty acids in the blood may affect the fatty
      acids in the cells. In addition, frequently subcultivated laboratory-adapted
      strains may have properties different from those of fresh clinical isolates,
      which are culturable only for a limited number of passages. Therefore, the
      cellular fatty acid profiles of laboratory-adapted strains (LAS) and freshly
      isolated strains (FIS) were compared after growth on agar that was fatty acid
      free and growth on blood agar that contained fatty acids. LAS ATCC 43504, 51932,
      and 700392 and the FIS IMMi 88, 89, and 92, each with <10 subcultures, were
      cultured in parallel on a fatty acid-free agar (ISAF) and on 5% sheep blood agar
      (SBA), which contained oleic acid (18:1 9c), hexadecanoic acid (16:0), and
      octadecanoic acid (18:0). ISAF-grown cultures showed no 18:1 9c and no
      appreciable differences between the profiles of FIS and LAS. After culture on
      SBA, the strains showed 18:1 9c and increased 16:0 and 18:0 content combined with
      decreased tetradecanoic acid (14:0) content compared to ISAF-grown cells. The
      changes in the fatty acid profiles were much more pronounced in FIS than in LAS.
      LAS are obviously characterized by a lower uptake of the fatty acids from the
      growth medium than FIS. Furthermore, it could be shown that this LAS behavior is
      most likely a primary strain attribute that is favored under laboratory
      conditions. The pronounced uptake of fatty acids by strains with FIS behavior may
      be associated with the expression of virulence properties.

PMID- 12624036
TI  - Use of DNA extracts from Ziehl-Neelsen-stained slides for molecular detection of
      rifampin resistance and spoligotyping of Mycobacterium tuberculosis.
AB  - Multidrug resistance among new cases of tuberculosis (TB) is increasingly
      becoming a significant problem in countries with a high prevalence of TB and with
      inadequate therapies for TB. Rifampin resistance is widely used as a marker for
      multidrug-resistant (MDR) TB; therefore, a new approach to the retrospective
      measurement of rifampin resistance without the need of a viable culture has been
      introduced. In many developing countries culture is unavailable and diagnosis
      relies on clinical manifestations and the results of Ziehl-Neelsen staining of
      sputum smears. We determined rifampin resistance directly with DNA extracts from
      Ziehl-Neelsen-stained slides by identification of mutations in the rpoB gene
      using reverse line blot hybridization and DNA sequencing. Analysis of the rpoB
      gene revealed that samples containing rifampin-resistant Mycobacterium
      tuberculosis carried altered codons representing amino acid positions 516, 526,
      and 531 of the RNA polymerase. Although the sensitivities of both methods were
      equal (84%), sequencing of the rpoB gene was more accurate in identifying
      mutations in the core region of the rpoB gene. Sequence analysis of the rpoB gene
      in extracts from Ziehl-Neelsen-stained slides may be used to quantify more
      precisely the magnitude of MDR TB and, more importantly, provide information on
      trends in the development of resistance on a global scale. The nature of rifampin
      resistance and the genotype can be determined by analysis of Ziehl-Neelsen
      stained slides in a laboratory equipped for sequencing and spoligotyping without
      the need to ship biohazardous materials.

PMID- 12624037
TI  - Molecular characterization of gentamicin-resistant Enterococci in the United
      States: evidence of spread from animals to humans through food.
AB  - We evaluated the molecular mechanism for resistance of 360 enterococci for which
      the gentamicin MICs were >/=128 micro g/ml. The aac(6')-Ie-aph(2")-Ia, aph(2")
      Ic, and aph(2")-Id genes were identified by PCR in isolates from animals, food,
      and humans. The aph(2")-Ib gene was not identified in any of the isolates. Two
      Enterococcus faecalis isolates (MICs > 1,024 micro g/ml) from animals failed to
      generate a PCR product for any of the genes tested and likely contain a new
      unidentified aminoglycoside resistance gene. Pulsed-field gel electrophoresis
      (PFGE) analysis showed a diversity of strains. However, 1 human and 18 pork E.
      faecalis isolates from Michigan with the aac(6')-Ie-aph(2")-Ia gene had related
      PFGE patterns and 2 E. faecalis isolates from Oregon (1 human and 1 grocery store
      chicken isolate) had indistinguishable PFGE patterns. We found that when a
      gentamicin-resistant gene was present in resistant enterococci from animals, that
      gene was also present in enterococci isolated from food products of the same
      animal species. Although these data indicate much diversity among gentamicin
      resistant enterococci, the data also suggest similarities in gentamicin
      resistance among enterococci isolated from humans, retail food, and farm animals
      from geographically diverse areas and provide evidence of the spread of
      gentamicin-resistant enterococci from animals to humans through the food supply.

PMID- 12624039
TI  - New types of toxin A-negative, toxin B-positive strains among Clostridium
      difficile isolates from Asia.
AB  - A total of 56 C. difficile strains were selected from 310 isolates obtained from
      different hospitals in Japan and Korea and from healthy infants from Indonesia.
      Strains that had been previously typed by pulsed-field gel electrophoresis and
      PCR ribotyping, were characterized by toxinotyping and binary toxin gene
      detection. When toxinotyped, 35 strains were determined to be toxinotype 0,
      whereas 21 strains showed variations in toxin genes and could be grouped into 11
      variant toxinotypes. Six of the toxinotypes had been described before (I, III,
      IV, VIII, IX, and XII). In addition, five new toxinotypes were defined (XVI to
      XX). Three of the new toxinotypes (XVIII, XIX, and XX) vary only in repetitive
      regions of tcdA and produce both toxins. In two strains from toxinotypes XVI and
      XVII, the production of TcdA could not be detected with commercial immunological
      kits. Strain J9965 (toxinotype XVII) was in PaLoc similar but not identical to
      another known A(-)B(+) strain, C. difficile 8864. Strain SUC 36 (toxinotype XVI),
      on the other hand, was similar to well-defined group consisting of toxinotypes V,
      VI, and VII, which thus far includes only A(+)B(+) strains. Toxinotypes XVI and
      XVII represent two new groups of A(-)B(+) strains. Strains of the well-known A(
      )B(+) group from toxinotype VIII have a nonsense mutation at the beginning of
      tcdA gene, and the introduction of a stop codon at amino acid position 47 results
      in nonproduction of TcdA. The 5'-end sequence of tcdA in two newly described A(
      )B(+) strains does not contain an identical mutation. The prevalence of variant
      C. difficile strains varied greatly among nine hospitals. Only five strains from
      four different hospitals were positive in PCR for amplification of the binary
      toxin gene.

PMID- 12624040
TI  - In vitro susceptibility testing of Aspergillus spp.: comparison of Etest and
      reference microdilution methods for determining voriconazole and itraconazole
      MICs.
AB  - The performance of the Etest for voriconazole and for itraconazole susceptibility
      testing of 376 isolates of Aspergillus spp. was assessed in comparison with the
      National Committee for Clinical Laboratory Standards (NCCLS) proposed standard
      microdilution broth method. The NCCLS method employed RPMI 1640 broth medium, and
      MICs were read after incubation for 48 h at 35 degrees C. Etest MICs were
      determined with RPMI agar containing 2% glucose and were read after incubation
      for 48 h at 35 degrees C. The isolates included A. fumigatus, A. flavus, A.
      niger, A. terreus, A. versicolor, A. glaucus, A. nidulans, A. ustus, and A.
      sydowii. Overall agreement percentages between the Etest and microdilution MICs
      were 97.6% for voriconazole and 95.8% for itraconazole. Where a discrepancy was
      observed between Etest and the reference method, the Etest tended to give lower
      values with voriconazole and higher values with itraconazole. The Etest method
      using RPMI agar appears to be a useful method for determining the voriconazole
      and itraconazole susceptibilities of Aspergillus spp.

PMID- 12624041
TI  - Comparison of four chromogenic media and Hektoen agar for detection and
      presumptive identification of Salmonella strains in human stools.
AB  - Several chromogenic media have been developed to enhance the specificity of
      Salmonella detection. We compared the performance of four commercial chromogenic
      media-namely, ABC medium (Lab M. Ltd., Bury, United Kingdom), COMPASS Salmonella
      agar (Biokar Diagnostics, Beauvais, France), CHROMagar Salmonella agar (CHROMagar
      Company, Paris, France), and SM ID agar (bioMerieux, Marcy l'Etoile, France)-with
      conventional Hektoen medium. Nine hundred sixteen stool samples from inpatients
      at three hospitals were cultured, in parallel, on the five media, both by direct
      inoculation and after selective enrichment in selenite broth. Sixty-four
      Salmonella strains with 12 serotypes were isolated on at least one medium. After
      48 h of incubation, sensitivity before and after enrichment was 62.5 and 89.1%
      with ABC medium, 77.1 and 93.8% with COMPASS agar, 66.7 and 89.1% with CHROMagar,
      68.8 and 85.9% with SM ID agar, and 85.4 and 98.4% with Hektoen agar,
      respectively. Broth enrichment and prolonged incubation (48 versus 24 h)
      increased the sensitivity of all five media. Only one strain was not isolated on
      Hektoen agar. The number of false-positive isolates was higher with all five
      media after enrichment in selenite broth and after incubation for 48 h compared
      to 24 h. The specificity of the four chromogenic media was better than 91% after
      incubation for 24 h (77.7% with Hektoen agar) and better than 84% after
      incubation for 48 h (74.8% with Hektoen agar). This higher specificity reduces
      the need for confirmatory tests, thereby cutting technical time and reagent
      requirements. Both COMPASS agar and CHROMagar Salmonella, which after simple
      additional tests showed close efficiencies (96 and 97%, respectively), can be
      recommended as single-plate media of choice for the detection and presumptive
      identification of salmonellae in stools.

PMID- 12624042
TI  - Two-center collaborative evaluation of the performance of the BD Phoenix
      automated microbiology system for identification and antimicrobial susceptibility
      testing of Enterococcus spp. and Staphylococcus spp.
AB  - The performance of the BD Phoenix Automated Microbiology System (BD Diagnostic
      Systems, Sparks, Md.) was assessed for identification (ID) and antimicrobial
      susceptibility testing (AST) for the majority of clinically encountered bacterial
      isolates in a European collaborative two-center trial. A total of 469 bacterial
      isolates of the genera Staphylococcus (275 isolates), Enterococcus (179
      isolates), and Streptococcus (15 isolates, for ID only) were investigated; of
      these, 367 were single patient isolates, and 102 were challenge strains tested at
      one center. Sixty-four antimicrobial drugs were tested, including the following
      drug classes: aminoglycosides, beta-lactam antibiotics, beta-lactam-beta
      lactamase inhibitors, carbapenems, cephems, folate antagonists, quinolones,
      glycopeptides, macrolides-lincosamides-streptogramin B (MLS), and others. Phoenix
      ID results were compared to those of the laboratories' routine ID systems (API 32
      Staph, API 32 Strep, and VITEK 2 [bioMerieux, Marcy l'Etoile, France]); Phoenix
      AST results were compared to those of frozen standard broth microdilution (SBM)
      panels according to NCCLS guidelines (NCCLS document M 100-S 9, approved standard
      M 7-A 4). Discrepant results were repeated in duplicate. Concordant IDs of 97.1,
      98.9, and 100% were observed for staphylococci, enterococci, and streptococci,
      respectively. For AST results the overall essential agreement was 93.3%; the
      category agreement was 97.3%; and the very major error rate, major error rate,
      and minor error rate were 1.2, 1.9, and 1.3%, respectively. In conclusion, the
      Phoenix ID results showed high agreement with results of the systems to which
      they were being compared; the AST performance was highly equivalent to that of
      the SBM reference method.

PMID- 12624043
TI  - Proficiency testing program for clinical laboratories performing antifungal
      susceptibility testing of pathogenic yeast species.
AB  - Antifungal susceptibility testing is expected to facilitate the selection of
      adequate therapy for fungal infections. The general availability of antifungal
      susceptibility testing in clinical laboratories is low, even though a number of
      standard methods are now available. The objective of the present study was to
      develop and evaluate a proficiency testing program (PTP) for the antifungal
      susceptibility testing of pathogenic yeasts in laboratories licensed by the New
      York State Department of Health. A number of quality control standards, and
      methods for documenting laboratory performance, were developed in consultation
      with the laboratory directors. The participating laboratories were provided with
      five American Type Culture Collection strains of pathogenic yeasts for which the
      minimum inhibitory concentrations (MICs) of amphotericin B and fluconazole were
      well defined. A majority of laboratories (14 of 17) used broth microdilution, and
      these were evenly split between the NCCLS M-27A protocol and the Sensititre
      YeastOne method. The other three laboratories performed susceptibility testing
      with Etest. Overall, the levels of agreement between MIC reference ranges and the
      reported MICs were 85 and 74% for amphotericin B and for fluconazole,
      respectively. All laboratories except one successfully detected fluconazole
      resistance in a Candida krusei strain. However, amphotericin B resistance in a
      Candida lusitaniae strain was not detected by any of the participating labs. It
      is concluded that a suitably designed PTP could adequately monitor the competence
      of clinical laboratories performing antifungal susceptibility testing.

PMID- 12624044
TI  - High-level expression and purification of a truncated merozoite antigen-2 of
      Babesia equi in Escherichia coli and its potential for immunodiagnosis.
AB  - The gene encoding a truncated merozoite antigen-2 (EMA-2t) of Babesia equi was
      cloned and highly expressed in Escherichia coli as a glutathione S-transferase
      fusion protein (G-rEMA-2t). Both G-rEMA-2t and rEMA-2t (after the removal of
      glutathione S-transferase) had good antigenicity. Either Western blot analysis
      with rEMA-2t or enzyme-linked immunosorbent assay (ELISA) with G-rEMA-2t clearly
      discriminated the sera of horses experimentally infected with B. equi from sera
      of horses infected with Babesia caballi and healthy horses, although rEMA-2t was
      not suitable for ELISA, probably owing to its poor absorbability to the plates.
      The specific antibodies in B. equi-infected horses were detectable during both
      acute and latent infection (6 to 244 days postinfection). Horse sera from Jilin
      Province, China, were examined by the two tests. The seroprevalence of B. equi
      was 49.2% (31 of 63 sera) by Western blot analysis with rEMA-2t and 47.6% (30 of
      63 sera) by ELISA with G-rEMA-2t. The correspondence was 98.4% (62 of 63 sera)
      between the two tests. The results indicate that G-rEMA-2t and rEMA-2t proteins
      should be suitable antigens for the development of an effective immunodiagnostic
      assay due to their high sensitivity, specificity, and great yield.

PMID- 12624045
TI  - Differentiation of Candida albicans and Candida dubliniensis by using recombinant
      human antibody single-chain variable fragments specific for hyphae.
AB  - To identify antigens specific for the filamentous form of Candida albicans, a
      combinatorial phage display library expressing human immunoglobulin heavy and
      light chain variable regions was used to select phage clones capable of binding
      to the surfaces of viable C. albicans filaments. Eight distinct phage clones that
      bound specifically to filament surface antigens not expressed on blastoconidia
      were identified. Single-chain antibody variable fragments (scFv) derived from two
      of these phage clones (scFv5 and scFv12) were characterized in detail. Filament
      specific antigen expression was detected by an indirect immunofluorescence assay.
      ScFv5 reacted with C. dubliniensis filaments, while scFv12 did not. Neither scFv
      reacted with C. glabrata, C. parapsilosis, C. rugosa, C. tropicalis, or
      Saccharomyces cerevisiae grown under conditions that stimulated filament
      formation in C. albicans and C. dubliniensis. Epitope detection by the two scFv
      was sensitive to proteinase K treatment but not to periodate treatment,
      indicating that the cognate epitopes were composed of protein. The antigens
      reactive with scFv5 and scFv12 were extractable from the cell surface with
      Zymolyase, but not with sodium dodecyl sulfate (SDS) and 2-mercaptoethanol, and
      migrated as polydisperse, high-molecular-weight bands on SDS-polyacrylamide gel
      electrophoresis gels. The epitopes were detected on clinical specimens obtained
      from infants with thrush and urinary candidiasis without passage of the organisms
      on laboratory media, confirming epitope expression in human infection. The
      availability of a monoclonal immunologic reagent that recognizes filaments from
      both C. albicans and C. dubliniensis and another specific only to C. albicans
      adds to the repertoire of potential diagnostic reagents for differentiation
      between these closely related species.

PMID- 12624046
TI  - Patterns of resistance associated with integrons, the extended-spectrum beta
      lactamase SHV-5 gene, and a multidrug efflux pump of Klebsiella pneumoniae
      causing a nosocomial outbreak.
AB  - Multiresistant Klebsiella pneumoniae caused a nosocomial outbreak. Resistance
      patterns of the presumed outbreak isolates varied among and within patients. In
      order to control the outbreak, screening for extended-spectrum beta-lactamase
      (ESBL)-producing K. pneumoniae was commenced. A number of susceptible K.
      pneumoniae strains were stored to serve as controls in genetic strain typing.
      Typing by pulsed-field gel electrophoresis proved the clonality of the strains in
      the recognized outbreak patients. Typing of the control strains by pulsed-field
      gel electrophoresis showed that at least one patient had been missed by the ESBL
      screening procedure. Further genetic typing confirmed the presence of the SHV-5
      ESBL gene in all but one of the outbreak strains. Variable presence of integrons
      that carried the aminoglycoside resistance genes aadB and aadA2 was found. A gyrA
      mutation in codon 83 was present in all outbreak strains tested, despite
      considerable differences in ciprofloxacin MICs. The MICs of ciprofloxacin and the
      chemically unrelated drug cefoxitin were correlated (r = 0.86, P < 0.01) and were
      compatible with the overexpression of an efflux pump in a subset of the outbreak
      strains. We conclude that outbreak strains that express an ESBL gene only at a
      low level may pass unnoticed in a screening procedure, when the laboratory is
      unaware of variable ESBL expression. In this particular outbreak, screening for
      strains for which ciprofloxacin MICs were > or =0.25 micro g/ml would in
      retrospect have been the most sensitive method for detection of the K. pneumoniae
      outbreak strain.

PMID- 12624047
TI  - Identification of a mutation associated with erythromycin resistance in
      Bordetella pertussis: implications for surveillance of antimicrobial resistance.
AB  - Erythromycin treatment failures and in vitro resistance of Bordetella pertussis
      have been reported on several occasions in the past few years, but the mechanism
      of resistance has not been described. One potential mechanism, genetic
      modification of the erythromycin-binding site on the 23S rRNA of the 50S
      ribosomal subunit, has been observed in other bacteria. To explore this
      possibility, we amplified the portion of the 23S rRNA gene encoding the central
      loop of domain V. DNA sequencing and restriction fragment length polymorphism of
      the PCR products showed that each of the four erythromycin-resistant B. pertussis
      strains tested contained an A-to-G transition mutation at position 2058
      (Escherichia coli numbering) of the 23S rRNA gene. The mutation was not found in
      seven erythromycin-susceptible isolates tested. Two of the resistant isolates
      were heterozygous, containing at least one mutant copy and one wild-type copy of
      the 23S rRNA gene. These results indicate that erythromycin resistance in these
      strains is likely due to a mutation of the erythromycin-binding site in the 23S
      rRNA gene. Identification of the resistance mechanism will facilitate development
      of molecular susceptibility testing methods that can be used directly on clinical
      specimens in the absence of an isolate.

PMID- 12624048
TI  - Genotypes at the internal transcribed spacers of the nuclear rRNA operon of
      Pneumocystis jiroveci in nonimmunosuppressed infants without severe pneumonia.
AB  - The frequency of Pneumocystis jiroveci (human-derived Pneumocystis) in
      immunocompetent infants developing acute respiratory syndromes has recently been
      evaluated and has been shown to be close to 25%. Until now, there have been no
      data on the genomic characteristics of the fungus in these patients, while
      molecular typing of P. jiroveci organisms was mostly performed with samples from
      immunosuppressed patients with pneumocystosis (Pneumocystis carinii pneumonia
      [PCP]). The present report describes the genotypes of P. jiroveci organisms in 26
      nonimmunosuppressed infants developing a mild Pneumocystis infection
      contemporaneously with an episode of bronchioloalveolitis. The typing was based
      on sequence analysis of internal transcribed spacers (ITSs) 1 and 2 of the rRNA
      operon, followed by the use of two typing scores. By use of the first score, 11
      P. jiroveci ITS types were identified: 10 were previously reported in
      immunosuppressed patients with PCP, while 1 was newly described. By use of the
      second score, 13 types were identified, of which 2 were newly described. The most
      frequent type was identified as type B(1)a(3) (first score), which corresponds to
      type Eg (second score). Mixed infections were diagnosed in three infants. The
      occurrence of such diversity of P. jiroveci ITS types, an identical main type,
      and mixed infections has previously been reported in immunosuppressed patients
      with PCP. Thus, the P. jiroveci ITS genotypes detected in immunocompetent infants
      and immunosuppressed patients developing different forms of Pneumocystis
      infection share characteristics, suggesting that both groups of individuals make
      up a common human reservoir for the fungus. Finally, the frequency of P. jiroveci
      in nonimmunosuppressed infants with acute respiratory syndromes and the
      genotyping results provide evidence that this infant population is an important
      reservoir for the fungus.

PMID- 12624049
TI  - Longitudinal analysis of Prototheca zopfii-specific immune responses: correlation
      with disease progression and carriage in dairy cows.
AB  - In order to characterize the humoral and cellular immune responses to bovine
      mammary protothecosis, serum and whey samples obtained from 72 dairy cows
      assigned to four different clinical stages of infection were examined for
      specific antibodies by indirect enzyme-linked immunosorbent assay techniques.
      Milk samples were analyzed for the total numbers of excreted algal cells and
      somatic cells. After characterization of the course of immune induction in bovine
      protothecal mastitis, a long-term sentinel study was performed in an affected
      herd in order to investigate disease progression. A total of 61 dairy cows with
      protothecal mastitis were examined for shedding of algae cells and for local
      immune responses three times in 6-month intervals. During acute and chronic
      stages of protothecosis, significantly elevated specific antibody activities in
      sera were detected. A strong correlation of whey immunoglobulin A (IgA) and whey
      IgG1 antibody activity with the total counts of somatic cells in milk was
      observed, whereas only a weak correlation of whey IgA and whey IgG1
      concentrations to the number of algal cells excreted with the milk was seen. Our
      results from the sentinel long-term study of infected cows revealed that 70.5% of
      the persistently infected animals were continuously shedding the pathogen. About
      4.9% of the animals showed an intermittent shedding, whereas 18% of the cows were
      tested culturally negative throughout the study. It can be assumed that
      Prototheca zopfii mastitis in dairy cows is maintained on the herd level by
      subclinically infected alga-shedding cows.

PMID- 12624050
TI  - Detection by PCR and isolation assays of the anaerobic intestinal spirochete
      Brachyspira aalborgi from the feces of captive nonhuman primates.
AB  - The purpose of this study was to investigate the presence of the anaerobic
      intestinal spirochetes Brachyspira aalborgi and Brachyspira pilosicoli in the
      feces of captive nonhuman primates (n = 35) from 19 species housed at the
      Zoological Gardens, Perth, Western Australia. Both spirochete species are known
      to infect human beings. DNA was extracted from freshly collected feces with a
      commercially available QIAamp DNA stool minikit and subjected to PCR protocols
      amplifying portions of the 16S rRNA genes of the two spirochete species. The
      feces were also subjected to selective culture for the spirochetes. Subsequently,
      feces from 62 other captive animals or birds representing 39 species at the zoo
      were examined by PCR to determine whether they were reservoirs of infection. Six
      fecal samples from individuals from four primate species (two vervet monkeys, two
      Tonkean macaques, one Japanese macaque, and one hamadryas baboon) tested positive
      in the B. aalborgi PCR. B. aalborgi was not detected by PCR in any of the other
      animal or bird species tested, and B. pilosicoli was not detected in the primates
      or any of the other animals or birds. B. aalborgi was isolated from both PCR
      positive vervet monkeys. This is the first time that B. aalborgi has been
      isolated from nonhuman primates and the first time that it has been isolated from
      the feces of any species.

PMID- 12624052
TI  - Community-acquired poliovirus infection in children with primary
      immunodeficiencies in Tunisia.
AB  - The global polio eradication program recommends the use of massive vaccination
      campaigns with live vaccine through National Immunization Days (NIDs) to displace
      the wild virus from the community. Immunodeficient patients may be indirectly
      infected and become chronic excretors and potential reservoirs of polioviruses, a
      concern for the posteradication era. This prospective study aimed to assess the
      risk of community-acquired infection of immunodeficient patients following NIDs,
      the dynamics of viral excretion and the genetic variation of excreted viruses.
      Sixteen children with various primary immunodeficiencies, who did not receive the
      vaccine during the campaign, were investigated. Stool samples were collected
      weekly, shortly after the NIDs, during at least 3 months, and were processed for
      viral isolation. Isolates were characterized by three intratypic differentiation
      methods and partial sequencing of the VP1/2A region. Polioviruses were detected
      in 4 out of 16 patients (serotype 1 in 3 patients and serotype 3 in 1 patient).
      Sequencing revealed more than 99% homology with homotypic Sabin strains,
      suggesting recent infection. Duration of viral excretion ranged from 1 to 7
      weeks. Nine out of eleven isolates from the three poliovirus serotype 1-infected
      patients disclosed a non-Sabin-like phenotype by enzyme-linked immunosorbent
      assay and had recurrent mutations within or close to the neutralizing antigenic
      sites. In summary, the risk of secondary infection in immunodeficient patients is
      within the range previously reported for the general population. Although none of
      the four infected patients developed prolonged viral excretion, particular viral
      variants were selected and may be of epidemiological significance.

PMID- 12624051
TI  - Molecular epidemiology of Pseudomonas aeruginosa colonization in a burn unit:
      persistence of a multidrug-resistant clone and a silver sulfadiazine-resistant
      clone.
AB  - To study the epidemiology of Pseudomonas aeruginosa colonization in a 32-bed burn
      wound center (BWC), 321 clinical and 45 environmental P. aeruginosa isolates were
      collected by prospective surveillance culture over a 1-year period and analyzed
      by serotyping, drug susceptibility testing, and amplified fragment length
      polymorphism (AFLP) analysis. Among 441 patients treated at the center, 70 (16%)
      were colonized with P. aeruginosa, including 12 (17%) patients who were colonized
      on admission and 58 (83%) patients who acquired the organism during their stay.
      Of the 48 distinct AFLP genotypes found, 21 were found exclusively in the
      environment, 15 were isolated from individual patients only, and 12 were
      responsible for the colonization of 57 patients, of which 2 were also isolated
      from the environment, but secondary to patient carriage. Polyclonal P. aeruginosa
      colonization with strains of two to four genotypes, often with different
      antibiotic susceptibility patterns, was observed in 19 patients (27%). Two
      predominant genotypes were responsible for recurrent outbreaks and the
      colonization of 42 patients (60% of all colonized patients). The strain with one
      of those genotypes appeared to be endemic to the BWC and developed multidrug
      resistance (MDR) at the end of the study period, whereas the strain with the
      other genotype was antibiotic susceptible but resistant to silver sulfadiazine
      (SSD(r)). The MDR strain was found at a higher frequency in sputum samples than
      the SSD(r) strain, which showed a higher prevalence in burn wound samples,
      suggesting that anatomic habitat selection was associated with adaptive
      resistance to antimicrobial drugs. Repeated and thorough surveys of the hospital
      environment failed to detect a primary reservoir for any of those genotypes.
      Cross-acquisition, resulting from insufficient compliance with infection control
      measures, was the major route of colonization in our BWC. In addition to the AFLP
      pattern and serotype, analysis of the nucleotide sequences of three (lipo)protein
      genes (oprI, oprL, and oprD) and the pyoverdine type revealed that all
      predominant strains except the SSD(r) strain belonged to recently identified
      clonal complexes. These successful clones are widespread in nature and therefore
      predominate in the patient population, in whom variants accumulate drug
      resistance mechanisms that allow their transmission and persistence in the BWC.

PMID- 12624053
TI  - Bacillus anthracis virulence in Guinea pigs vaccinated with anthrax vaccine
      adsorbed is linked to plasmid quantities and clonality.
AB  - Bacillus anthracis is a bacterial pathogen of great importance, both historically
      and in the present. This study presents data collected from several
      investigations and indicates that B. anthracis virulence is associated with the
      clonality and virulence of plasmids pXO1 and pXO2. Guinea pigs vaccinated with
      Anthrax Vaccine Adsorbed were challenged with 20 B. anthracis isolates
      representative of worldwide genetic diversity. These same isolates were
      characterized with respect to plasmid copy number by using a novel method of
      quantitative PCR developed for rapid and efficient detection of B. anthracis from
      environmental samples. We found that the copy numbers for both pXO1 and pXO2
      differed from those in previously published reports. By combining the data on
      survival, plasmid copy numbers, and clonality, we developed a model predicting
      virulence. This model was validated by using a randomly chosen set of 12
      additional B. anthracis isolates. Results from this study will be helpful in
      future efforts to elucidate the basis for variation in the virulence of this
      important pathogen.

PMID- 12624054
TI  - Five-test simple scheme for species-level identification of clinically
      significant coagulase-negative staphylococci.
AB  - A working scheme developed in our laboratory for identification (by species group
      and species) of coagulase-negative staphylococci (CNS) was evaluated with 201
      consecutive isolates and then validated by using the reference method of Kloos
      and Schleifer (W. E. Kloos and K. H. Schleifer, J. Clin. Microbiol. 1:82-88,
      1975). This five-test simple scheme (referred to here as the simple scheme)
      combines the novobiocin susceptibility test with tests for urease, pyrrolidonyl
      arylamidase, ornithine decarboxylase, and aerobic acid from mannose. The addition
      of one or two tests within a particular species group could then positively
      identify the isolate. Two commercial systems, Staph-Zym (Rosco) and API-Staph
      (bioMerieux), along with results obtained by using Rosco diagnostic tablets
      (nongrowth tests), were also compared with the reference method. One isolate
      could not be identified even by the reference method. Of the remaining 200
      strains, 191 (95.5%) strains were correctly identified with Staph-Zym and 171
      strains (85.5%) were correctly identified with API-Staph. The most frequent
      clinical CNS species isolated were Staphylococcus epidermidis (50.5%), S.
      haemolyticus (18.5%), S. saprophyticus subsp. saprophyticus (16.0%), S.
      lugdunensis (6.0%), and S. warneri (2.5%). The simple scheme validated with the
      reference method has demonstrated an excellent correlation in the identification
      of the three most frequent species isolated: S. epidermidis, S. haemolyticus, and
      S. saprophyticus subsp. saprophyticus. With the simple scheme, identification of
      CNS was possible within 24 h after the enzymatic tests were used, whereas up to
      72 h is necessary for the growth tests. This methodology would be very useful in
      any clinical microbiology laboratory for the presumptive identification of CNS
      species groups and species.

PMID- 12624055
TI  - Characterization of monkey enteropathogenic Escherichia coli (EPEC) and human
      typical and atypical EPEC serotype isolates from neotropical nonhuman primates.
AB  - Enteropathogenic Escherichia coli (EPEC) has been associated with infantile
      diarrhea and mortality in humans in developing countries. While diarrhea is also
      a major problem among primates kept in captivity, the role of E. coli is unclear.
      This study was designed to characterize diarrheagenic E. coli recovered from the
      feces of 56 New World nonhuman primates, primarily marmosets (Callithrix spp.).
      Seventeen of the 56 primates had signs of diarrhea and/or enteritis. E. coli
      recovered from feces from these animals was tested by PCR for genes encoding
      virulence factors of diarrheagenic E. coli and for patterns of adherence to HeLa
      cells. In addition, isolates were characterized by the fluorescence actin
      staining test and by their ability to induce attaching and effacing lesions. PCR
      for the eae gene was positive in 10 of the 39 (27%) apparently healthy animals
      and in 8 of the 17 (47%) animals with diarrhea and/or enteritis. Colonies of
      eae(+) E. coli were serotyped and examined by PCR for genes encoding EPEC
      virulence markers. The eae(+) E. coli isolates recovered from both healthy and
      sick nonhuman primates demonstrated virulence-associated attributes similar to
      those of EPEC strains implicated in human disease and are designated monkey EPEC.
      The results presented here indicate that EPEC may be a significant pathogen for
      nonhuman primates, deserving further investigation. The similarities between the
      affected animals investigated in this study and human EPEC infections suggest
      that marmosets may represent an important model for EPEC in humans.

PMID- 12624056
TI  - Susceptibility testing with the manual mycobacteria growth indicator tube (MGIT)
      and the MGIT 960 system provides rapid and reliable verification of multidrug
      resistant tuberculosis.
AB  - The objective of the study was to compare the manual Mycobacteria Growth
      Indicator Tube (MGIT) method and the BACTEC MGIT 960 system to the BACTEC 460
      method for susceptibility testing of Mycobacterium tuberculosis. The evaluation
      was based on testing of 36 M. tuberculosis strains with various susceptibilities
      to isoniazid (INH), rifampin (RMP), ethambutol (EMB), and streptomycin (SM). In
      addition, five of the strains generating discrepant results in testing for EMB
      were analyzed for heteroresistance. For INH, the susceptibility test results
      obtained by the MGIT 960 and the manual MGIT systems agreed with the BACTEC 460
      results in 94 and 97% of the cases, respectively. The results of susceptibility
      to RMP were all in agreement. For SM, 78 and 72% of the results obtained by the
      MGIT 960 and the manual MGIT systems, respectively, agreed with the BACTEC 460
      results. In contrast, less than 80% of the results for susceptibility to EMB
      obtained by the two MGIT methods agreed with the BACTEC 460 results. All five
      strains analyzed for EMB heteroresistance were found to consist of resistant and
      susceptible subpopulations. The average turnaround times were 6.4 days for the
      MGIT 960 system, 6.5 for the manual MGIT system, and 8.7 days for the BACTEC 460
      method. Both MGIT methods can be regarded as accurate and rapid alternatives to
      the BACTEC 460 method for detection of strains resistant to INH and RMP. However,
      more studies are needed for solving the problems associated with susceptibility
      testing to EMB and SM.

PMID- 12624057
TI  - Clinical implications of Mycobacterium kansasii species heterogeneity: Swiss
      National Survey.
AB  - Several subtypes of Mycobacterium kansasii have been described, but their
      respective pathogenic roles are not clear. This study investigated the
      distribution of subtypes and the pathogenicity of M. kansasii strains (n = 191)
      isolated in Switzerland between 1991 and 1997. Demographic, clinical, and
      microbiological information was recorded from clinical files. Patients were
      classified as having an infection according to the criteria of the American
      Thoracic Society. Subtypes were defined by PCR-restriction enzyme analysis of the
      hsp65 gene. Subtype 1 comprised 67% of the isolates (n = 128), while subtypes 2
      and 3 comprised 21% (n = 40) and 8% (n = 15), respectively. Other subtypes
      (subtypes 4 and 6 and a new subtype, 7) were recovered from only 4% of patients
      (n = 8). M. kansasii subtype 1 was considered pathogenic in 81% of patients,
      while M. kansasii subtype 2 was considered pathogenic in 67% of patients and
      other subtypes were considered pathogenic in 6% of patients. The majority of
      patients with M. kansasii subtype 2 were immunocompromised due to the use of
      corticosteroids (21% of patients) or coinfection with HIV (62.5% of patients).
      Subtyping M. kansasii may improve clinical management by distinguishing
      pathogenic from nonpathogenic subtypes.

PMID- 12624058
TI  - Changes in the human immunodeficiency virus p7-p1-p6 gag gene in drug-naive and
      pretreated patients.
AB  - Resistance to antiretroviral agents often results from mutations within the human
      immunodeficiency virus (HIV) pol gene. Moreover, insertions within the p6 gag-pol
      region have recently been found to be involved with resistance to nucleoside
      analogs. Overall, we found that 21% of 156 specimens collected from HIV-infected
      individuals (17.6% from 74 drug-naive patients and 24.4% from 82 pretreated
      patients) harbored these insertions. Insertions around the KQE (Lys-Gln-Glu)
      motif were found in 12.2% of the pretreated patients but in none of the drug
      naive subjects (P = 0.002). In contrast, insertions around the PTAP (Prol-Thre
      Ala-Prol) motif were seen at similar rates ( approximately 15%) among drug-naive
      and pretreated patients, which supports the idea that they may be natural
      polymorphisms.

PMID- 12624059
TI  - Entirely automated quantification of human immunodeficiency virus type 1 (HIV-1)
      RNA in plasma by using the ultrasensitive COBAS AMPLICOR HIV-1 monitor test and
      RNA purification on the MagNA pure LC instrument.
AB  - The ultrasensitive COBAS AMPLICOR HIV-1 Monitor test was complemented with
      automated RNA purification on the MagNA Pure LC instrument. This enabled entirely
      automated ultrasensitive assessment of viral loads in human immunodeficiency
      virus type 1 (HIV-1)-infected individuals. The detection limit of the fully
      automated assay and the viral load measurements in 80 clinical samples were found
      to be in good agreement with those of the conventional ultrasensitive COBAS
      AMPLICOR HIV-1 Monitor test. The fully automated assay showed markedly reduced
      hands-on time and was found to be suitable for the routine assessment of HIV-1
      viral loads in a clinical diagnostic laboratory.

PMID- 12624060
TI  - Novel sample preparation method for safe and rapid detection of Bacillus
      anthracis spores in environmental powders and nasal swabs.
AB  - Bacillus anthracis spores have been used as a biological weapon in the United
      States. We wanted to develop a safe, rapid method of sample preparation that
      provided safe DNA for the detection of spores in environmental and clinical
      specimens. Our method reproducibly detects B. anthracis in samples containing <10
      spores.

PMID- 12624061
TI  - Detection and species-level identification of primate herpesviruses with a
      comprehensive PCR test for human herpesviruses.
AB  - A comprehensive assay for the identification of all eight human herpesviruses has
      been previously reported. This assay was extended to the detection and species
      level identification of herpes B virus (Cercopithecine herpesvirus 1) and African
      green monkey cytomegalovirus (Cercopithecine herpesvirus 5), two herpesviruses of
      relevance to the clinical virology laboratory.

PMID- 12624062
TI  - Casein agar: a useful medium for differentiating Candida dubliniensis from
      Candida albicans.
AB  - Production of chlamydospores on casein agar at 24 degrees C for 48 h provides a
      simple means for differentiating Candida dubliniensis from Candida albicans based
      on chlamydospore production. Of 109 C. dubliniensis isolates tested on this
      medium, 106 (97.2%) produced abundant chlamydospores and three produced few
      chlamydospores. In contrast, of the 120 C. albicans isolates tested, 111 (92.5%)
      failed to produce any chlamydospores, whereas the remaining nine isolates
      produced few chlamydospores. These findings indicate that abundant chlamydospore
      production on casein agar is a useful test for discriminating between C.
      dubliniensis and C. albicans.

PMID- 12624064
TI  - Conventional and molecular methods for verification of results obtained with
      BacT/Alert Nonvent blood culture bottles.
AB  - A strategy comparing molecular and conventional methods for verification of the
      BacT/Alert nonvent blood culture bottles (Organon Teknika, Durham, N.C.) was
      performed with seeded isolates. The bottles were evaluated with 12 common
      organisms from bloodstream infections. Overall, the bottles were equivalent as
      determined by conventional and molecular methods.

PMID- 12624063
TI  - Detection of Ehrlichia spp. in the blood of wild white-tailed deer in Missouri by
      PCR assay and serologic analysis.
AB  - Blood samples collected from wild deer in Missouri in November of 2000 and 2001
      were positive by PCR assays for Ehrlichia chaffeensis (50 of 217; 23%), Ehrlichia
      ewingii (44 of 217; 20%), and Anaplasma species (214 of 217; 99%). Nucleotide
      sequences of selected amplicons from the assay for anaplasma matched sequences of
      the white-tailed deer agent. Serologic analysis of 112 deer sampled in 2000
      showed a very high prevalence of antibodies to E. chaffeensis (97 of 112; 87%)
      and a low prevalence of antibodies reactive with Anaplasma phagocytophila (2 of
      112; 2%).

PMID- 12624065
TI  - Persistence of colonization of intestinal mucosa by a probiotic strain,
      Lactobacillus casei subsp. rhamnosus Lcr35, after oral consumption.
AB  - The colonization by the probiotic Lactobacillus casei subsp. rhamnosus Lcr35 of
      the gastrointestinal tracts of mice and humans was studied. The mice were orally
      given 10(9) CFU of Lcr35 either once or three times at 24-h intervals. A 16S
      ribosomal nucleic probe used in hybridization assays detected Lcr35 in the feces
      of mice for up to 3 days after the feeding, at a level of 10(8) to 10(9) CFU/g of
      feces. In the human assay, 12 healthy volunteers were enrolled in a randomized
      trial and ingested Lcr35 at a dosage of 10(8) or 10(10) or 10(12) CFU every day
      for 7 days. Then, after a 3-week posttreatment period, there was a second intake
      period similar to the first one. Analysis of fecal samples showed significant
      increases in the number of lactobacilli during the first intake period, whatever
      the dose given. The greatest increases were observed in subjects harboring the
      lowest indigenous population of Lcr35-like bacteria. During the 3-week
      posttreatment period, the number of CFU slightly decreased over time, and an
      increase, although not a statistically significant one, was observed during the
      second test period. These findings suggest that Lcr35 is able to survive within
      the gastrointestinal tract.

PMID- 12624066
TI  - Construction and evaluation of internal control DNA for PCR amplification of
      Chlamydia trachomatis DNA from urine samples.
AB  - An internal control DNA (ICD) with the same primer binding sequences as the
      target Chlamydia trachomatis DNA was constructed and evaluated in a PCR assay
      with immunoenzymatic detection. One hundred urine specimens were tested, and 23
      were found to contain inhibitors of the PCR, if not subjected to DNA extraction
      prior to amplification. Coamplification and detection of the ICD appeared to be a
      useful method for estimating the effects of inhibitors on C. trachomatis DNA
      amplification.

PMID- 12624067
TI  - Hepatitis B virus genotype C takes a more aggressive disease course than
      hepatitis B virus genotype B in hepatitis B e antigen-positive patients.
AB  - One hundred forty-six hepatitis B e antigen (HBeAg)-positive chronic hepatitis B
      patients were followed up for 32 +/- 13 months. All six patients with
      hepatocellular carcinoma had hepatitis B virus (HBV) genotype C. Disease activity
      was greater in patients infected by HBV genotype C than in those infected by HBV
      genotype B in the HBeAg-positive phase but not after HBeAg seroconversion.

PMID- 12624068
TI  - Molecular characterization of avian paramyxovirus 1 isolates collected from
      cormorants in Canada from 1995 to 2000.
AB  - Sequences encompassing cleavage sites of fusion protein genes were obtained for
      avian paramyxovirus 1 isolates from cormorants in Canada. All isolates have the
      virulent cleavage site SRGRRQKR*FVG. They form a distinct cluster within isolates
      obtained around the world and may represent a novel genotype closely related to
      genotype V.

PMID- 12624070
TI  - Paracoccus yeeii sp. nov. (formerly CDC group EO-2), a novel bacterial species
      associated with human infection.
AB  - CDC eugonic oxidizer group 2 (EO-2) is a group of unclassified gram-negative
      bacterial strains isolated from various human sources. As determined by
      biochemical tests and analyses of fatty acid compositions, these organisms form a
      homogeneous group that appears to be distinct from but related to other
      Paracoccus species. Molecular studies were performed on a set of 13 EO-2 strains
      from various clinical sources and geographic locations in the United States and
      Canada to determine their relationship to the Paracoccus genus. Control strains
      were Paracoccus denitrificans ATCC 17741(T), P. versutus ATCC 25364(T), P.
      aminophilus ATCC 49673(T), P. solventivorans ATCC 700252(T), and Psychrobacter
      immobilis ATCC 43116(T), which are phenotypically similar to EO-2. Nearly
      complete (1,500-base) 16S rRNA gene sequencing of eight EO-2 strains showed a
      high level of sequence similarity (>99.3%) within the group, and a BLAST search
      of GenBank placed the EO-2 cluster in close proximity to Paracoccus species (95
      to 97% similarity). DNA-DNA hybridization studies of 13 of the EO-2 strains
      showed all to be related at the species level, with >70% relatedness under
      stringent conditions and a divergence within the group of less than 2%. None of
      the Paracoccus control strains hybridized at >54% with any of the EO-2 strains.
      These results indicate that EO-2 represents a new Paracoccus species, the first
      isolated from human clinical specimens. A new species, Paracoccus yeeii, is
      proposed for the EO-2 strains. The type strain of P. yeeii is CDCG1212 (ATCC BAA
      599 and CCUG 46822), isolated in Pennsylvania from dialysate of a 77-year-old
      male with peritonitis.

PMID- 12624069
TI  - Genotypic and phenotypic characteristics of Corynebacterium diphtheriae strains
      isolated from patients in belarus during an epidemic period.
AB  - One hundred two Corynebacterium diphtheriae strains (93 of the gravis biotype and
      nine of the mitis biotype) isolated from clinical cases during the Belarus
      diphtheria epidemic were characterized by biotyping, toxigenicity testing by the
      Elek test and an indirect hemagglutination assay, phage typing, and ribotyping.
      The gravis biotype strains were characterized as high and medium toxin producers,
      and strains of biotype mitis were characterized as low and medium toxin
      producers. Most strains (82 of 102) were distributed among five phage types.
      Seventy-two strains (64 of the gravis biotype and 8 of the mitis biotype)
      belonged to phage type VI ls5,34add. Hybridization of genomic DNA digested with
      BstEII and PvuII revealed five ribotype patterns, namely, D1, D4, D6, D7, and
      D13. The majority of gravis biotype strains belonged to ribotypes D1 (49 of 93)
      and D4 (33 of 93) and included one clonal group of C. diphtheriae. This clone
      predominated in all regions in Belarus. There was a statistical association
      between ribotypes and phage types but not between ribotypes and levels of toxin
      production.

PMID- 12624071
TI  - Identification of Histoplasma capsulatum from culture extracts by real-time PCR.
AB  - We designed and tested a real-time LightCycler PCR assay for Histoplasma
      capsulatum that correctly identified the 34 H. capsulatum isolates in a battery
      of 107 fungal isolates tested and also detected H. capsulatum in clinical
      specimens from three patients that were culture positive for this organism.

PMID- 12624072
TI  - Significant improvement of the recombinant Borrelia-specific immunoglobulin G
      immunoblot test by addition of VlsE and a DbpA homologue derived from Borrelia
      garinii for diagnosis of early neuroborreliosis.
AB  - We investigated whether the recombinant Borrelia Western blot test previously
      described (B. Wilske, C. Habermann, V. Fingerle, B. Hillenbrand, S. Jauris
      Heipke, G. Lehnert, I. Pradel, D. Rossler, and U. Schulte-Spechtel, Med.
      Microbiol. Immunol. 188:139-144, 1999) can be improved by the addition of VlsE
      and additional DbpA and OspC homologues. By using a panel of sera from 36
      neuroborreliosis patients and 67 control patients, the diagnostic sensitivity of
      the recombinant immunoblot test was significantly increased (86.1% versus 52.7%)
      without loss of specificity and was higher (86.1% versus 63.8%) than that of the
      conventional whole-cell lysate immunoblot test (U. Hauser, G. Lehnert, R.
      Lobentanzer, and B. Wilske, J. Clin. Microbiol. 35:1433-1444, 1997). Improvement
      was mainly due to the presence of VlsE and DbpA.

PMID- 12624073
TI  - Isolation of sulfate-reducing bacteria from human thoracoabdominal pus.
AB  - To evaluate the prevalence of sulfate-reducing bacteria in septic processes, we
      searched for these bacteria by culture in 100 consecutive abdominal and pleural
      pus specimens. Twelve isolates were obtained from abdominal samples and were
      identified by a multiplex PCR as Desulfovibrio piger (formerly Desulfomonas
      pigra) (seven strains), Desulfovibrio fairfieldensis (four strains), and
      Desulfovibrio desulfuricans (one strain).

PMID- 12624074
TI  - emm Gene distribution among erythromycin-resistant and -susceptible Italian
      isolates of Streptococcus pyogenes.
AB  - The phenotypes and genetic determinants for macrolide resistance were determined
      for 167 erythromycin-resistant Streptococcus pyogenes strains. A cMLS phenotype
      was shown in 18% of the erythromycin-resistant strains, while inducible
      resistance was apparent in 31% and the M phenotype was apparent in 50%. The emm
      gene type of this set of resistant isolates and that of 48 erythromycin-sensitive
      isolates were determined. emm2 and emm48 were recorded only in the resistant
      strains of the M phenotype, while approximately all of the strains harboring the
      emm22 gene had the cMLS phenotype. More than 80% of the emm89-positive strains
      had the iMLS phenotype, and the same portion of emm4 strains presented the M
      phenotype. emm3 is recorded only among sensitive strains. The distribution of
      frequencies of the genetic determinant for the virulence factor M protein was
      significantly different both among organisms of different types of resistance and
      between resistant and sensitive populations of S. pyogenes under study.

PMID- 12624075
TI  - Identification of mycobacterial species by PCR sequencing of quinolone resistance
      determining regions of DNA gyrase genes.
AB  - The determination of the amino acid sequence of quinolone resistance-determining
      regions (QRDRs) in the A and B subunits of DNA gyrase is the molecular test for
      the detection of fluoroquinolone resistance in mycobacteria. We looked to see if
      the assignment of mycobacterial species could be obtained simultaneously by
      analysis of the corresponding nucleotide sequences. PCR sequencing of gyrA and
      gyrB QRDRs was performed for 133 reference and clinical strains of 21
      mycobacterial species commonly isolated in clinical laboratories. Nucleotide
      sequences of gyrA and gyrB QRDRs were species specific, regardless of
      fluoroquinolone susceptibility.

PMID- 12624076
TI  - Stability of allelic frequencies and distributions of Candida albicans
      microsatellite loci from U.S. population-based surveillance isolates.
AB  - Allelic distributions and frequencies of five Candida albicans microsatellite
      loci have been determined for strains isolated from the bloodstream and obtained
      through active population-based surveillance in two U.S. metropolitan areas
      between 1998 and 2000. These data were compared to data for isolates obtained
      from two other U.S. regions in 1992 to 1993. In a majority of pairwise
      combinations between sites, no evidence was seen for shifts in microsatellite
      allelic frequencies. One to three alleles were highly predominant and correlated
      with major genotypes. These data both support the concepts of allelic stability
      and genetic equilibria and suggest that, in the United States, strains of C.
      albicans isolated from the bloodstream may form a defined, genetically
      homogeneous population across geographical distance and time.

PMID- 12624077
TI  - Prospective clinical evaluation of the serologic tuberculous glycolipid test in
      combination with the nucleic acid amplification test.
AB  - We have conducted a prospective controlled multicenter study to evaluate
      differences in the levels of clinical utility of the tuberculous glycolipid
      (TBGL) serodiagnostic test and the nucleic acid amplification test in patients
      with smear-negative active pulmonary tuberculosis (TB). The TBGL test and the PCR
      test were individually not so useful for the rapid diagnosis of smear-negative
      active pulmonary TB. However, clinical utility was considerably improved by using
      the TBGL test and the PCR test in combination, especially in patients with smear
      negative and culture-negative active pulmonary TB and in patients with minimally
      advanced lesions.

PMID- 12624078
TI  - Age-specific Helicobacter pylori seropositivity rates of children in an
      impoverished urban area of northeast Brazil.
AB  - We determined age-specific Helicobacter pylori seropositivity rates of 166
      children and 39 mothers in an urban shantytown in northeast Brazil.
      Seropositivity rates increased from 23.1% at 0 to 11 months of age to only 39.3%
      by 96 to 131 months of age and were 82.1% at maturity. We observed no correlation
      between the seropositivity of the mothers and the seropositivity of their
      children.

PMID- 12624079
TI  - Horizontal in utero acquisition of cytomegalovirus infection in a twin pregnancy.
AB  - It is generally accepted that viral infections can be transmitted horizontally by
      direct or indirect contact with virus-excreting persons, and some viral
      infections can be transmitted vertically, either prenatally or perinatally, from
      mother to child. This report presents data strongly supporting a prenatal
      horizontal acquisition of human cytomegalovirus infection in a twin pregnancy.

PMID- 12624080
TI  - Two cases of subcutaneous infection due to Phaeoacremonium spp.
AB  - We describe two cases in Brazil of human subcutaneous infections due to
      Phaeoacremonium spp. The first case was caused by Phaeoacremonium aleophilum. The
      patient presented with a unique fistulized nodule on the left ankle. The fungus
      was detected by direct microscopic examination and was isolated repeatedly from
      material collected from the lesion. This is the first reported case of human
      infection caused by this fungus. The second case was caused by Phaeoacremonium
      rubrigenum. The patient presented with multiple nodules around the left ankle and
      foot. The fungus was detected by direct examination of pus and histological
      sections of the nodules. It was repeatedly isolated from the clinical specimens.
      This is the second reported case of human infection caused by this species.

PMID- 12624081
TI  - Bacteremia caused by Acinetobacter ursingii.
AB  - Acinetobacter ursingii has not been reported in infectious processes apart from
      its recent description as a new species. A bacteremia caused by A. ursingii in a
      patient with a pulmonary adenocarcinoma confirms that this microorganism is an
      opportunistic human pathogen. The isolate was susceptible to imipenem,
      aminoglycosides, rifampin, and fluoroquinolones.

PMID- 12624082
TI  - Septic shock caused by Ochrobactrum anthropi in an otherwise healthy host.
AB  - Reported is a case of life-threatening septic shock that occurred in an otherwise
      healthy host after administration of a peripheral venous infusion of a solution
      contaminated with Ochrobactrum anthropi, an unusual human pathogen. The rapid
      onset of shock may have been due to a large inoculum caused by nonsterile
      practices at the time of reconstitution.

PMID- 12624083
TI  - Identification of a genotype III swine hepatitis E virus that was isolated from a
      Japanese pig born in 1990 and that is most closely related to Japanese isolates
      of human hepatitis E virus.

PMID- 12624084
TI  - Recovery of Mycobacterium elephantis from sputum of a patient in Belgium.

PMID- 12624085
TI  - Is Mycobacterium africanum subtype II (Uganda I and Uganda II) a genetically well
      defined subspecies of the Mycobacterium tuberculosis complex?

PMID- 12624086
TI  - Molecular typing of Campylobacter jejuni and Campylobacter coli.

PMID- 12624087
TI  - Alternative splicing of the first intracellular loop of plasma membrane Ca2+
      ATPase isoform 2 alters its membrane targeting.
AB  - Plasma membrane Ca(2+)-ATPases (PMCAs) are involved in local Ca(2+) signaling and
      in the spatial control of Ca(2+) extrusion, but how different PMCA isoforms are
      targeted to specific membrane domains is unknown. In polarized MDCK epithelial
      cells, a green fluorescent protein-tagged PMCA4b construct was targeted to the
      basolateral membrane, whereas a green fluorescent protein-tagged PMCA2b construct
      was localized to both the apical and basolateral domain. The PDZ protein-binding
      COOH-terminal tail of PMCA2b was not responsible for its apical membrane
      localization, as a chimeric pump made of an NH(2)-terminal portion from PMCA4 and
      a COOH-terminal tail from PMCA2b was targeted to the basolateral domain. Deletion
      of the last six residues of the COOH terminus of either PMCA2b or PMCA4b did not
      alter their membrane targeting, suggesting that PDZ protein interactions are not
      essential for proper membrane localization of the pumps. Instead, we found that
      alternative splicing affecting the first cytosolic loop determined apical
      membrane targeting of PMCA2. Only the "w" form, which contains a 45-amino acid
      residue insertion, showed prominent apical membrane localization. By contrast,
      the x and z splice variants containing insertions of 14 and 0 residues,
      respectively, localized to the basolateral membrane. The w splice insert was the
      crucial determinant of apical PMCA2 localization, and this was independent of the
      splice configuration at the COOH-terminal end of the pump; both PMCA2w/b and
      PMCA2w/a showed prominent apical targeting, whereas PMCA2x/b, PMCA2z/b, and
      PMCA2z/a were confined to the basolateral membrane. These data report the first
      differential effect of alternative splicing within the first cytosolic loop of
      PMCA2 and help explain the selective enrichment of specific PMCA2 isoforms in
      specialized membrane compartments such as stereocilia of auditory hair cells.

PMID- 12624088
TI  - The 2.3-A crystal structure of the shikimate 5-dehydrogenase orthologue YdiB from
      Escherichia coli suggests a novel catalytic environment for an NAD-dependent
      dehydrogenase.
AB  - We present here the 2.3-A crystal structure of the Escherichia coli YdiB protein,
      an orthologue of shikimate 5-dehydrogenase. This enzyme catalyzes the reduction
      of 3-dehydroshikimate to shikimate as part of the shikimate pathway, which is
      absent in mammals but required for the de novo synthesis of aromatic amino acids,
      quinones, and folate in many other organisms. In this context, the shikimate
      pathway has been promoted as a target for the development of antimicrobial
      agents. The crystal structure of YdiB shows that the protomer contains two
      alpha/beta domains connected by two alpha-helices, with the N-terminal domain
      being novel and the C-terminal domain being a Rossmann fold. The NAD+ cofactor,
      which co-purified with the enzyme, is bound to the Rossmann domain in an
      elongated fashion with the nicotinamide ring in the pro-R conformation. Its
      binding site contains several unusual features, including a cysteine residue in
      close apposition to the nicotinamide ring and a clamp over the ribose of the
      adenosine moiety formed by phenylalanine and lysine residues. The structure
      explains the specificity for NAD versus NADP in different members of the
      shikimate dehydrogenase family on the basis of variations in the amino acid
      identity of several other residues in the vicinity of this ribose group. A cavity
      lined by residues that are 100% conserved among all shikimate dehydrogenases is
      found between the two domains of YdiB, in close proximity to the hydride acceptor
      site on the nicotinamide ring. Shikimate was modeled into this site in a geometry
      such that all of its heteroatoms form high quality hydrogen bonds with these
      invariant residues. Their strong conservation in all orthologues supports the
      possibility of developing broad spectrum inhibitors of this enzyme. The nature
      and disposition of the active site residues suggest a novel reaction mechanism in
      which an aspartate acts as the general acid/base catalyst during the hydride
      transfer reaction.

PMID- 12624089
TI  - In vitro refolding of human proinsulin. Kinetic intermediates, putative disulfide
      forming pathway folding initiation site, and potential role of C-peptide in
      folding process.
AB  - Human insulin is a double-chain peptide that is synthesized in vivo as a single
      chain human proinsulin (HPI). We have investigated the disulfide-forming pathway
      of a single-chain porcine insulin precursor (PIP). Here we further studied the
      folding pathway of HPI in vitro. While the oxidized refolding process of HPI was
      quenched, four obvious intermediates (namely P1, P2, P3, and P4, respectively)
      with three disulfide bridges were isolated and characterized. Contrary to the
      folding pathway of PIP, no intermediates with one- or two-disulfide bonds could
      be captured under different refolding conditions. CD analysis showed that P1, P2,
      and P3 retained partially structural conformations, whereas P4 contained little
      secondary structure. Based on the time-dependent distribution, disulfide pair
      analysis, and disulfide-reshuffling process of the intermediates, we have
      proposed that the folding pathway of HPI is significantly different from that of
      PIP. These differences reveal that the C-peptide not only facilitates the folding
      of HPI but also governs its kinetic folding pathway of HPI. Detailed analysis of
      the molecular folding process reveals that there are some similar folding
      mechanisms between PIP and HPI. These similarities imply that the initiation site
      for the folding of PIP/HPI may reside in the central alpha-helix of the B-chain.
      The formation of disulfide A20-B19 may guide the transfer of the folding
      information from the B-chain template to the unstructured A-chain. Furthermore,
      the implications of this in vitro refolding study on the in vivo folding process
      of HPI have been discussed.

PMID- 12624090
TI  - The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase
      (p110C) associates with p21-activated kinase 1 and inhibits its activity during
      anoikis.
AB  - The PITSLRE protein kinases are parts of the large family of p34cdc2-related
      kinases. During apoptosis induced by some stimuli, specific PITSLRE isoforms are
      cleaved by caspase to produce a protein that contains the C-terminal kinase
      domain of the PITSLRE proteins (p110C). The p110C induces apoptosis when it is
      ectopically expressed in Chinese hamster ovary cells. In our study, similar
      induction of this p110C was observed during anoikis in NIH3T3 cells. To
      investigate the molecular mechanism of apoptosis mediated by p110C, we used the
      yeast two-hybrid system to screen a human fetal liver cDNA library and identified
      p21-activated kinase 1 (PAK1) as an interacting partner of p110C. The association
      of p110C with PAK1 was further confirmed by in vitro binding assay, in vivo
      coimmunoprecipitation, and confocal microscope analysis. The interaction of p110C
      with PAK1 occurred within the residues 210-332 of PAK1. Neither association
      between p58PITSLRE or p110PITSLRE and PAK1 nor association between p110C and PAK2
      or PAK3 was observed. Anoikis was increased and PAK1 activity was inhibited when
      NIH3T3 cells were transfected with p110C. Furthermore, the binding of p110C with
      PAK1 and inhibition of PAK1 activity were also observed during anoikis. Taken
      together, these data suggested that PAK1 might participate in the apoptotic
      pathway mediated by p110C.

PMID- 12624091
TI  - Molecular characterization of an interleukin-4-inducing factor from Schistosoma
      mansoni eggs.
AB  - The eggs of the parasitic trematode Schistosoma mansoni are powerful inducers of
      a T helper type 2 (Th2) immune response and immunoglobulin E (IgE) production. S.
      mansoni egg extract (SmEA) stimulates human basophils to rapidly release large
      amounts of interleukin (IL)-4, the key promoter of a Th2 response. Here we show
      purification and sequence of the IL-4-inducing principle of S. mansoni eggs
      (IPSE). Stimulation studies with human basophils using SmEA fractions and natural
      and recombinant IPSE as well as neutralization and immunodepletion studies using
      antibodies to recombinant IPSE demonstrate that IPSE is the bioactive principle
      in SmEA leading to activation of basophils and to expression of IL-4 and IL-13.
      Regarding the mechanism of action, blot analysis showed that IPSE is an IgE
      binding factor, suggesting that it becomes effective via cross-linking receptor
      bound IgE on basophils. Immunohistology revealed that IPSE is enriched in and
      secreted from the subshell area of the schistosome egg. We conclude from these
      data that IPSE may be an important parasite-derived component for skewing the
      immune response toward Th2.

PMID- 12624092
TI  - Structure of the GTPase-binding domain of Sec5 and elucidation of its Ral binding
      site.
AB  - The exocyst complex is involved in the final stages of exocytosis, when vesicles
      are targeted to the plasma membrane and dock. The regulation of exocytosis is
      vital for a number of processes, for example, cell polarity, embryogenesis, and
      neuronal growth formation. Regulation of the exocyst complex in mammals was
      recently shown to be dependent upon binding of the small G protein, Ral, to Sec5,
      a central component of the exocyst. This interaction is thought to be necessary
      for anchoring the exocyst to secretory vesicles. We have determined the structure
      of the Ral-binding domain of Sec5 and shown that it adopts a fold that has not
      been observed in a G protein effector before. This fold belongs to the
      immunoglobulin superfamily in a subclass known as IPT domains. We have mapped the
      Ral binding site on this domain and found that it overlaps with protein-protein
      interaction sites on other IPT domains but that it is completely different from
      the G protein-geranyl-geranyl interaction face of the Ig-like domain of the Rho
      guanine nucleotide dissociation inhibitor. This mapping, along with available
      site-directed mutagenesis data, allows us to predict how Ral and Sec5 may
      interact.

PMID- 12624093
TI  - Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced
      activated protein kinase SAPK/JNK in embryonic stem cells.
AB  - Stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK), belonging
      to the mitogen-activated protein kinase family, plays an important role in stress
      signaling. SAPK/JNK activation requires the phosphorylation of both Thr and Tyr
      residues in its Thr-Pro-Tyr motif, and SEK1 and MKK7 have been identified as the
      dual specificity kinases. In this study, we generated mkk7(-/-) mouse embryonic
      stem (ES) cells in addition to sek1(-/-) cells and compared the two kinases in
      terms of the activation and phosphorylation of JNK. Although SAPK/JNK activation
      by various stress signals was markedly impaired in both sek1(-/-) and mkk7(-/-)
      ES cells, there were striking differences in the dual phosphorylation profile.
      The severe impairment observed in mkk7(-/-) cells was accompanied by a loss of
      the Thr phosphorylation of JNK without marked reduction in its Tyr-phosphorylated
      level. On the other hand, Thr phosphorylation of JNK in sek1(-/-) cells was also
      attenuated in addition to a decreased level of its Tyr phosphorylation. Analysis
      in human embryonic kidney 293T cells transfected with a kinase-dead SEK1 or a Thr
      Pro-Phe mutant of JNK1 revealed that SEK1-induced Tyr phosphorylation of JNK1 was
      followed by additional Thr phosphorylation by MKK7. Furthermore, SEK1 but not
      MKK7 was capable of binding to JNK1 in 293T cells. These results indicate that
      the Tyr and Thr residues of SAPK/JNK are sequentially phosphorylated by SEK1 and
      MKK7, respectively, in the stress-stimulated ES cells.

PMID- 12624094
TI  - Initiation factor 2B activity is regulated by protein phosphatase 1, which is
      activated by the mitogen-activated protein kinase-dependent pathway in insulin
      like growth factor 1-stimulated neuronal cells.
AB  - We have previously demonstrated that insulin-like growth factor 1 (IGF1) induces
      eukaryotic initiation factor 2B (eIF2B) activation in neuronal cells through the
      phosphatidylinositol 3 kinase/glycogen synthase kinase 3 pathway as well as by
      activation of the mitogen-activated protein kinase (MAPK)-activating kinase
      (MEK)/MAPK signaling pathway (Quevedo, C., Alcazar, A., and Salinas, M. (2000) J.
      Biol. Chem. 275, 19192-19197). This paper addresses the mechanism involved in
      IGF1-induced eIF2B activation via the MEK/MAPK cascade in cultured neurons
      treated with IGF1 and demonstrates that extracellular signal-regulated MAP kinase
      1 and 2 (ERK1 and -2) immunoprecipitates of IGF1-treated neuronal cells promote
      this activation. This effect did not directly result from eIF2B phosphorylation
      by ERK immunoprecipitates. In addition, recombinant ERK1 and -2 neither activate
      eIF2B nor phosphorylate it. Endogenous protein phosphatase 1 and 2A catalytic
      subunits (PP1C and PP2AC, respectively) were co-immunoprecipitated with ERK1 and 
      2, and the association of ERK with PP1C was stimulated by IGF1 treatment,
      resulting in increased PP1 activity. ERK immunoprecipitates incubated with PP1
      inhibitors did not activate eIF2B, indicating that PP1C activates eIF2B. In vitro
      experiments with phosphorylated eIF2B showed that recombinant PP1C (alpha
      isoform) dephosphorylates and activates eIF2B. Paralleling eIF2B activation, IGF1
      treatment induced PP1 activation in a MEK/MAPK-dependent fashion. Moreover, the
      treatment of neurons with the PP1 inhibitor tautomycin inhibited PP1 activation
      and prevented IGF1-induced eIF2B activation. These findings strongly suggest that
      IGF1-induced eIF2B activation in neurons is effected by PP1, the activation of
      which is mediated by the MEK/MAPK signaling pathway.

PMID- 12624095
TI  - A unique resting position of the ATP-synthase from chloroplasts.
AB  - The chloroplast ATP-synthase catalyzes ATP synthesis coupled to transmembrane
      proton transport. The enzyme consists of two parts, a membrane-embedded F(0) part
      and an extrinsic F(1) part, which are linked by two connectors. One of these
      rotates during catalysis and the other remains static. Although the atomic
      structures of various sub-complexes and individual subunits have been reported,
      only limited structural information on the complex, as a whole, is available. In
      particular, information on the static connector is lacking. We contribute a three
      dimensional map at about 20-A resolution, derived from electron cryomicroscopy of
      enzymes embedded in vitrified buffer followed by single particle image analysis.
      In the three-dimensional map both connectors, between the F(1) part and the F(0)
      part, are clearly visible. The static connector is tightly attached to an alpha
      subunit and faces the side of the neighboring beta subunit. The three-dimensional
      map provides a scaffold for fitting in the known atomic structures of various
      subunits and sub-complexes, and suggests that the oxidized, non-activated ATP
      synthase from chloroplasts adopts a unique resting position.

PMID- 12624096
TI  - The thanatophoric dysplasia type II mutation hampers complete maturation of
      fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer
      and activator of transcription 1 (STAT1) from the endoplasmic reticulum.
AB  - The K650E substitution in the fibroblast growth factor receptor 3 (FGFR3) causes
      constitutive tyrosine kinase activity of the receptor and is associated to the
      lethal skeletal disorder, thanatophoric dysplasia type II (TDII). The underlying
      mechanisms of how the activated FGFR3 causes TDII remains to be elucidated. FGFR3
      is a transmembrane glycoprotein, which is synthesized through three isoforms,
      with various degrees of N-glycosylation. We have studied whether immature FGFR3
      isoforms mediate the abnormal signaling in TDII. We show that synthesis of TDII
      FGFR3 presents two phosphorylated forms: the immature non-glycosylated 98-kDa
      peptides and the intermediate 120-kDa glycomers. The mature, fully glycosylated
      130-kDa forms, detected in wild type FGFR3, are not present in TDII.
      Endoglycosidase H cleaves the sugars on TDII intermediates thus indicating their
      intracellular localization in the endoplasmic reticulum. Accordingly, TDII-FGFR3
      GFP co-localizes with calreticulin in the endoplasmic reticulum. Furthermore,
      following TDII transfection, signal transducer and activator of transcription 1
      (STAT1) is phosphorylated in the absence of FGFR3 ligand and brefeldin A does not
      inhibit its activation. On the contrary, the cell membrane-anchored FRS2alpha
      protein is not activated in TDII cells. The opposite situation is observed in
      stable TDII cell clones where, despite the presence of phosphorylated mature
      receptor, STAT1 is not activated whereas FRS2alpha is phosphorylated. We
      speculate that the selection process favors cells defective in STAT1 activation
      through the 120-kDa TDII-FGFR3, thus allowing growth of the TDII cell clones.
      Accordingly, apoptosis is observed following TDII-FGFR3 transfection. These
      observations highlight the importance of the immature TDII-FGFR3 proteins as
      mediators of an abnormal signaling in TDII.

PMID- 12624097
TI  - Isochorismate synthase (PchA), the first and rate-limiting enzyme in salicylate
      biosynthesis of Pseudomonas aeruginosa.
AB  - In Pseudomonas aeruginosa the extracellular metabolite and siderophore pyochelin
      is synthesized from two major precursors, chorismate and l-cysteine via
      salicylate as an intermediate. The regulatory role of isochorismate synthase, the
      first enzyme in the pyochelin biosynthetic pathway, was studied. This enzyme is
      encoded by pchA, the last gene in the pchDCBA operon. The PchA protein was
      purified to apparent electrophoretic homogeneity from a PchA-overexpressing P.
      aeruginosa strain. The native enzyme was a 52-kDa monomer in solution, and its
      activity strictly depended on Mg(2+). At pH 7.0, the optimum, a K(m) = 4.5 microm
      and a k(cat) = 43.1 min(-1) were determined for chorismate. No feedback
      inhibitors or other allosteric effectors were found. The intracellular PchA
      concentration critically determined the rate of salicylate formation both in
      vitro and in vivo. In cultures grown in iron-limiting media to high cell
      densities, overexpression of the pchA gene resulted in overproduction of
      salicylate as well as in enhanced pyochelin formation. From this work and earlier
      studies, it is proposed that one important factor influencing the flux through
      the pyochelin biosynthetic pathway is the PchA concentration, which is determined
      at a transcriptional level, with pyochelin acting as a positive signal and iron
      as a negative signal.

PMID- 12624098
TI  - The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase
      functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling
      unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth
      factor.
AB  - The inhibitory gamma subunit of the retinal photoreceptor type 6 cGMP
      phosphodiesterase (PDEgamma) is phosphorylated by G-protein-coupled receptor
      kinase 2 on threonine 62 and regulates the epidermal growth factor- dependent
      stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney
      293 cells. We report here that PDEgamma is in a pre-formed complex with c-Src and
      that stimulation of cells with epidermal growth factor promotes the association
      of GRK2 with this complex. c-Src has a critical role in the stimulation of the
      p42/p44 mitogen-activated protein kinase cascade by epidermal growth factor,
      because c-Src inhibitors block the activation of this kinase by the growth
      factor. Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation
      resistant mutant that was less effective in associating with GRK2 in response to
      epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen
      activated protein kinase by this growth factor. The transcript for a short splice
      variant version of PDEgamma lacking the Thr-62 phosphorylation site is also
      expressed in certain mammalian cells and, in common with the Thr-62 mutant,
      failed to potentiate the stimulatory effect of epidermal growth factor on p42/p44
      mitogen-activated protein kinase. The mutation of Thr-22 (to Ala) in PDEgamma,
      which is a site for phosphorylation by p42/p44 mitogen-activated protein kinase,
      resulted in a prolonged activation of p42/p44 mitogen-activated protein kinase by
      epidermal growth factor, suggesting a role for this phosphorylation event in the
      negative feedback control of PDEgamma.

PMID- 12624099
TI  - Adipose-specific expression, phosphorylation of Ser794 in insulin receptor
      substrate-1, and activation in diabetic animals of salt-inducible kinase-2.
AB  - Salt-inducible kinase (SIK), first cloned from the adrenal glands of rats fed a
      high salt diet, is a serine/threonine protein kinase belonging to an AMP
      activated protein kinase family. Induced in Y1 cells at an early stage of ACTH
      stimulation, it regulated the initial steps of steroidogenesis. Here we report
      the identification of its isoform SIK2. When a green fluorescent protein-fused
      SIK2 was expressed in 3T3-L1 preadipocytes, it was mostly present in the
      cytoplasm. When coexpressed in cAMP-responsive element-reporter assay systems,
      SIK2 could repress the cAMP-responsive element-dependent transcription, although
      the degree of repression seemed weaker than that by SIK1. SIK2 was specifically
      expressed in adipose tissues. When 3T3-L1 cells were treated with the adipose
      differentiation mixture, SIK2 mRNA was induced within 1 h, the time of induction
      almost coinciding with that of c/EBPbeta mRNA. Coexpressed with human insulin
      receptor substrate-1 (IRS-1) in COS cells, SIK2 could phosphorylate Ser(794) of
      human IRS-1. Adenovirus-mediated overexpression of SIK2 in adipocytes elevated
      the level of phosphorylation at Ser(789), the mouse equivalent of human Ser(794).
      Moreover, the activity and content of SIK2 were elevated in white adipose tissues
      of db/db diabetic mice. These results suggest that highly expressed SIK2 in
      insulin-stimulated adipocytes phosphorylates Ser(794) of IRS-1 and, as a result,
      might modulate the efficiency of insulin signal transduction, eventually causing
      the insulin resistance in diabetic animals.

PMID- 12624100
TI  - Glutathione s-transferase omega 1-1 is a target of cytokine release inhibitory
      drugs and may be responsible for their effect on interleukin-1beta
      posttranslational processing.
AB  - Stimulus-induced posttranslational processing of human monocyte interleukin-1beta
      (IL-1beta) is accompanied by major changes to the intracellular ionic
      environment, activation of caspase-1, and cell death. Certain diarylsulfonylureas
      inhibit this response, and are designated cytokine release inhibitory drugs
      (CRIDs). CRIDs arrest activated monocytes so that caspase-1 remains inactive and
      plasma membrane latency is preserved. Affinity labeling with [(14)C]CRIDs and
      affinity chromatography on immobilized CRID were used in seeking potential
      protein targets of their action. Following treatment of intact human monocytes
      with an epoxide-bearing [(14)C]CRID, glutathione S-transferase (GST) Omega 1-1
      was identified as a preferred target. Moreover, labeling of this polypeptide
      correlated with irreversible inhibition of ATP-induced IL-1beta posttranslational
      processing. When extracts of human monocytic cells were chromatographed on a CRID
      affinity column, GST Omega 1-1 bound selectively to the affinity matrix and was
      eluted by soluble CRID. Recombinant GST Omega 1-1 readily incorporated
      [(14)C]CRID epoxides, but labeling was negated by co-incubation with S
      substituted glutathiones or by mutagenesis of the catalytic center Cys(32) to
      alanine. Peptide mapping by high performance liquid chromatography-mass
      spectrometry also demonstrated that Cys(32) was the site of modification.
      Although S-alkylglutathiones did not arrest ATP-induced IL-1beta
      posttranslational processing or inhibit [(14)C]CRID incorporation into cell
      associated GST Omega 1-1, a glutathione-CRID adduct effectively demonstrated
      these attributes. Therefore, the ability of CRIDs to arrest stimulus-induced IL
      1beta posttranslational processing may be attributable to their interaction with
      GST Omega 1-1.

PMID- 12624101
TI  - Inhibition of cell growth by conditional expression of kpm, a human homologue of
      Drosophila warts/lats tumor suppressor.
AB  - kpm is a human serine/threonine kinase that is homologous to Drosophila tumor
      suppressor warts/lats and its mammalian homologue LATS1. In order to define the
      biological function of kpm, we generated stable transfectants of wild-type kpm
      (kpm-wt), a kinase-dead mutant of kpm (kpm-kd), and luciferase in HeLa Tet-Off
      cells under the tetracycline-responsive promoter. Western blot analysis showed
      that high levels of expression of kpm-wt as well as kpm-kd with an apparent mass
      of 150 kDa were induced after the removal of doxycycline. Induction of kpm-wt
      expression resulted in a marked decline in viable cell number measured by both
      trypan blue dye exclusion and MTT assay, whereas that of kpm-kd or luciferase had
      no effect. We then analyzed the cell cycle progression and apoptosis upon
      induction of kpm expression. 2-3 days after removal of doxycycline, cells
      underwent G(2)/M arrest, demonstrated by flow cytometric analysis of propidium
      iodide incorporation and MPM-2 reactivity. In vitro kinase assay showed that
      induction of kpm-wt led to down-regulation of kinase activity of the Cdc2-cyclin
      B complex, which was accompanied by an increase in the hyperphosphorylated form
      of Cdc2 and a change of phosphorylation status of Cdc25C. Furthermore, both DAPI
      staining and TUNEL assay showed that the proportion of apoptotic cells increased
      as kpm expression was induced. Taken together, these results indicate that kpm
      negatively regulates cell growth by inducing G(2)/M arrest and apoptotic cell
      death through its kinase activity.

PMID- 12624102
TI  - Mutational analysis of stress-responsive peanut dual specificity protein kinase.
      Identification of tyrosine residues involved in regulation of protein kinase
      activity.
AB  - We recently reported that Arachis hypogaea serine/threonine/tyrosine (STY)
      protein kinase is developmentally regulated and is induced by abiotic stresses
      (Rudrabhatla, P., and Rajasekharan, R. (2002) Plant Physiol. 130, 380-390). Other
      than MAPKs, the site of tyrosine phosphorylation has not been documented for any
      plant kinases. To study the role of tyrosines in the phosphorylation of STY
      protein kinase, four conserved tyrosine residues were sequentially substituted
      with phenylalanine and expressed as histidine fusion proteins. Mass spectrometry
      experiments showed that STY protein kinase autophosphorylated within the
      predicted kinase ATP-binding motif, activation loop, and an additional site in
      the C terminus. The protein kinase activity was abolished by substitution of
      Tyr(297) with Phe in the activation loop between subdomains VII and VIII. In
      addition, replacing Tyr(148) in the ATP-binding motif and Tyr(317) in the C
      terminal domain with Phe not only obliterated the ability of the STY protein
      kinase protein to be phosphorylated, but also inhibited histone phosphorylation,
      suggesting that STY protein kinase is phosphorylated at multiple sites. Replacing
      Tyr(213) in the Thr-Glu-Tyr sequence motif with Phe resulted in a 4-fold increase
      in autophosphorylation and 2.8-fold increase in substrate phosphorylation
      activities. Mutants Y148F, Y297F, and Y317F displayed dramatically lower
      phosphorylation efficiency (k(cat)/K(m)) with ATP and histone, whereas mutant
      Y213F showed increased phosphorylation. Our results suggest that
      autophosphorylation of Tyr(148), Tyr(213), Tyr(297), and Tyr(317) is important
      for the regulation of STY protein kinase activity. Our study reveals the first
      example of Thr-Glu-Tyr domain-mediated autoinhibition of kinases.

PMID- 12624103
TI  - Domains of Gln3p interacting with karyopherins, Ure2p, and the target of
      rapamycin protein.
AB  - Gln3p is a GATA-type transcription factor responsive to the quality of nitrogen
      and carbon. In preferred nitrogen such as glutamine, Gln3p is phosphorylated and
      sequestered in the cytoplasm in a manner that is dependent on the target of
      rapamycin (TOR) protein and Ure2p. In nonpreferred nitrogen or nitrogen
      starvation, Gln3p is dephosphorylated and imported into the nucleus via
      karyopherin alpha/Srp1p. Upon reintroduction of preferred nitrogen, Gln3p is
      exported from the nucleus by Crm1p/Xpo1p. Although recent work has provided
      insights into Gln3p, a more detailed understanding is needed to elucidate the
      mechanism of its localization and function. In this study, we show that Gln3p
      contains canonical nuclear localization signal and nuclear export signal
      sequences necessary for its localization and interaction with its relevant
      karyopherins. In addition, we identify an N-terminal domain of Gln3p interacting
      with Ure2p and a C-terminal region for binding to TOR. Finally, we find a
      lysine/arginine-rich domain essential for the rapamycin-sensitive function, but
      dispensable for its localization. Our results reveal key domains of Gln3p
      important for its function and regulation.

PMID- 12624104
TI  - The exonuclease activity of human apurinic/apyrimidinic endonuclease (APE1).
      Biochemical properties and inhibition by the natural dinucleotide Gp4G.
AB  - Human DNA apurinic/apyrimidinic endonuclease (APE1) plays a key role in the DNA
      base excision repair process. In this study, we further characterized the
      exonuclease activity of APE1. The magnesium requirement and pH dependence of the
      exonuclease and endonuclease activities of APE1 are significantly different. APE1
      showed a similar K(m) value for matched, 3' mispaired, or nucleoside analog beta
      l-dioxolane-cytidine terminated nicked DNA as well as for DNA containing a
      tetrahydrofuran, an abasic site analog. The k(cat) for exonuclease activity on
      matched, 3' mispaired, and beta-l-dioxolane-cytidine nicked DNA are 2.3, 61.2,
      and 98.8 min(-1), respectively, and 787.5 min(-1) for APE1 endonuclease. Site
      directed APE1 mutant proteins (E96A, E96Q, D210E, D210N, and H309N), which target
      amino acid residues in the endonuclease active site, also showed significant
      decrease in exonuclease activity. Gp(4)G was the only potent inhibitor to compete
      against the substrates of endonuclease and exonuclease activities among all
      tested naturally occurring ribo-, deoxyribo-nucleoside/nucleotides, NAD(+),
      NADP(+), and Ap(4)A. The K(i) values of Gp(4)G for the endonuclease and
      exonuclease activities of APE1 are 10 +/- 0.6 and 1 +/- 0.2 microm, respectively.
      Given the relative concentrations of Gp(4)G, 3' mispaired, and abasic DNA, Gp(4)G
      may play an important role in regulating APE1 activity in cells. The data
      presented here suggest that the APE1 exonuclease and AP endonuclease are two
      distinct activities. APE1 may exist in two different conformations, and each
      conformation has a preference for a substrate. The different conformations can be
      affected by MgCl(2) or salt concentrations.

PMID- 12624106
TI  - A glutamine to proline exchange at amino acid residue 1098 in sucrase causes a
      temperature-sensitive arrest of sucrase-isomaltase in the endoplasmic reticulum
      and cis-Golgi.
AB  - A striking feature of phenotype II in congenital sucrase-isomaltase deficiency is
      the retention of the brush border protein sucrase-isomaltase (SI) in the cis
      Golgi. This transport block is the consequence of a glutamine to proline
      substitution at amino acid residue 1098 of the sucrase subunit. Here we provide
      unequivocal biochemical and confocal data to show that the SI(Q/P) mutant reveals
      characteristics of a temperature-sensitive mutant. Thus, correct folding,
      competent intracellular transport, and full enzymatic activity can be partially
      restored by expression of the mutant SI(Q/P) at the permissive temperature of 20
      degrees C instead of 37 degrees C. The acquisition of normal trafficking and
      function appears to utilize several cycles of anterograde and retrograde steps
      between the endoplasmic reticulum and the Golgi implicating the molecular
      chaperones calnexin and heavy chain-binding protein. The data presented in this
      communication are to our knowledge the first to implicate a temperature-sensitive
      mutation in an intestinal enzyme deficiency or an intestinal disorder.

PMID- 12624105
TI  - Differential and simultaneous adenosine di- and triphosphate binding by MutS.
AB  - The roles of ATP binding and hydrolysis in the function of MutS in mismatch
      repair are poorly understood. As one means of addressing this question, we have
      determined the affinities and number of adenosine di- and triphosphate binding
      sites within MutS. Nitrocellulose filter binding assay and equilibrium
      fluorescence anisotropy measurements have demonstrated that MutS has one high
      affinity binding site for ADP and one high affinity site for nonhydrolyzable ATP
      analogues per dimer equivalent. Low concentrations of 5'-adenylylimidodiphosphate
      (AMPPNP) promote ADP binding and a large excess of AMPPNP is required to displace
      ADP from the protein. Fluorescence energy transfer and filter binding assays
      indicate that ADP and nonhydrolyzable ATP analogues can bind simultaneously to
      adjacent subunits within the MutS oligomer with affinities in the low micromolar
      range. These findings suggest that the protein exists primarily as the
      ATP.MutS.ADP ternary complex in solution and that this may be the form of the
      protein that is involved in DNA encounters in vivo.

PMID- 12624107
TI  - Sp family of transcription factors is involved in valproic acid-induced
      expression of Galphai2.
AB  - Valproic acid-induced gene expression has been attributed to the DNA-binding
      activity of the transcription factor activator protein 1 (AP-1). Using K562
      cells, we have studied valproic acid-induced transcription from the human
      Galpha(i2) gene promoter, which lacks AP-1-binding motifs. We find that valproic
      acid-induced expression of Galpha(i2) is inhibited by mithramycin A, a compound
      that interferes with Sp1 binding to GC boxes in DNA. Three Sp1-binding sequences,
      located at +68/+75, -50/-36, and -92/-85 in the promoter, accounted for about 60%
      of this transcriptional effect, as judged by transient transfection assays.
      Electrophoretic mobility shift assays indicated that these sites bind members of
      the Sp family of transcription factors. Binding to DNA was inhibited by
      mithramycin A and was greater in nuclear extracts from cells treated with
      valproic acid than in control cells. Okadaic acid, calyculin A, and fostriecin,
      which are potent inhibitors of protein phosphatase, suppressed the
      transcriptional response to valproic acid. This inhibitory effect was not
      observed when promoter constructs containing mutations in the referenced Sp1
      binding sites were used for transfections. In nuclear extracts from cells
      cultured in the presence of these inhibitors, the binding of Sp1/Sp3 to DNA
      probes was much less than in control cells. Alkaline phosphatase treatment of
      nuclear extracts resulted in enhanced binding of Sp proteins to the DNA probes.
      These results are consistent with the idea that dephosphorylating conditions
      enhanced Sp binding to the DNA probes as well as Sp-mediated transcription
      induced by valproic acid. This study demonstrates that the gene expression
      inducing effect of valproic acid occurs, in part, through the Sp family of
      transcription factors.

PMID- 12624108
TI  - Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation,
      and Bax/Bak oligomerization suppressed.
AB  - Bcl-2 family proteins are important regulators of apoptosis. They can be pro
      apoptotic (e.g. Bid, Bax, and Bak) or anti-apoptotic (e.g. Bcl-2 and Bcl-x(L)).
      The current study examined Bid-induced apoptosis and its inhibition by Bcl-2.
      Transfection of Bid led to apoptosis in HeLa cells. In these cells, Bid was
      processed into active forms of truncated Bid or tBid. Following processing, tBid
      translocated to the membrane-bound organellar fraction. Bcl-2 co-transfection
      inhibited Bid-induced apoptosis but did not prevent Bid processing or tBid
      translocation. On the other hand, Bcl-2 blocked the release of mitochondrial
      cytochrome c in Bid-transfected cells, suggesting actions at the mitochondrial
      level. Alkaline treatment stripped off tBid from the membrane-bound organellar
      fraction of Bid plus Bcl-2-co-transfected cells, but not from cells transfected
      with only Bid, suggesting inhibition of tBid insertion into mitochondrial
      membranes by Bcl-2. Bcl-2 also prevented Bid-induced Bax translocation from
      cytosol to the membrane-bound organellar fraction. Finally, Bcl-2 diminished Bid
      induced oligomerization of Bax and Bak within the membrane-bound organellar
      fraction, shown by cross-linking experiments. In conclusion, Bcl-2 inhibited Bid
      induced apoptosis at the mitochondrial level by blocking cytochrome c release,
      without suppressing Bid processing or activation. Critical steps blocked by Bcl-2
      included tBid insertion, Bax translocation, and Bax/Bak oligomerization in the
      mitochondrial membranes.

PMID- 12624109
TI  - Distinct functional interactions of human Skn-1 isoforms with Ese-1 during
      keratinocyte terminal differentiation.
AB  - Among the three major POU proteins expressed in human skin, Oct-1, Tst-1/Oct-6,
      and Skn-1/Oct-11, only the latter induced SPRR2A, a marker of keratinocyte
      terminal differentiation. In this study, we have identified three Skn-1 isoforms,
      which encode proteins with various N termini, generated by alternative promoter
      usage. These isotypes showed distinct expression patterns in various skin
      samples, internal squamous epithelia, and cultured human keratinocytes. Skn-1a
      and Skn-1d1 bound the SPRR2A octamer site with comparable affinity and functioned
      as transcriptional activators. Skn-1d2 did not affect SPRR2A expression. Skn-1a,
      the largest protein, functionally cooperated with Ese-1/Elf-3, an epithelial
      specific transcription factor, previously implicated in SPRR2A induction. This
      cooperativity, which depended on an N-terminal pointed-like domain in Skn-1a, was
      not found for Skn-1d1. Actually, Skn-1d1 counteracted the cooperativity between
      Skn-1a and Ese-1. Apparently, the human Skn-1 locus encodes multifunctional
      protein isotypes, subjected to biochemical cross-talk, which are likely to play a
      major role in the fine-tuning of keratinocyte terminal differentiation.

PMID- 12624110
TI  - DEC1 negatively regulates the expression of DEC2 through binding to the E-box in
      the proximal promoter.
AB  - Human DEC (differentially expressed in chondrocytes), mouse STRA (stimulated with
      retinoic acid), and rat SHARP (split and hairy related protein) proteins
      constitute a new and structurally distinct class of the basic helix-loop-helix
      proteins. In each species, two members are identified with a sequence identity of
      >90% in the basic helix-loop-helix region and approximately 40% in the total
      proteins, respectively. Recently, we have reported that DEC1 is abundantly
      expressed in colon carcinomas but not in the adjacent normal tissues. The present
      study was undertaken to extend the expression study of DEC1 and to determine
      whether DEC1 and DEC2 had similar expression patterns among paired cancer-normal
      tissues from the colon, lung, and kidney. Without exceptions, DEC1 was markedly
      higher in the carcinomas, whereas the opposite was true with DEC2. In stable
      transfectants, tetracycline-induced expression of DEC1 caused proportional
      decreases in the expression of DEC2. Co-transfection with DEC1 repressed the
      activity of a DEC2 promoter reporter by as much as 90%. The repression was
      observed with wild type DEC1 but not its DNA binding-defective mutants. Studies
      with deletion and site-directed mutants located, in the proximal promoter, an E
      box motif that supported the DEC1-mediated repression. Disruption of this E-box
      markedly abolished the ability of the reporter to respond to DEC1. Our findings
      assign for DEC1 the first target gene that is regulated through direct DNA
      binding. DEC/STRA/SHARP proteins are highly identical in the DNA binding domain
      but much more diverse in other areas. DEC1-mediated repression on the expression
      of DEC2 provides an important mechanism that these transcription factors regulate
      the cellular function not only by modulating the expression of their target genes
      but also the expression of members within the same class.

PMID- 12624111
TI  - Small molecule modulators of histone acetyltransferase p300.
AB  - Histone acetyltransferases (HATs) are a group of enzymes that play a significant
      role in the regulation of gene expression. These enzymes covalently modify the N
      terminal lysine residues of histones by the addition of acetyl groups from acetyl
      CoA. Dysfunction of these enzymes is often associated with the manifestation of
      several diseases, predominantly cancer. Here we report that anacardic acid from
      cashew nut shell liquid is a potent inhibitor of p300 and p300/CBP-associated
      factor histone acetyltranferase activities. Although it does not affect DNA
      transcription, HAT-dependent transcription from a chromatin template was strongly
      inhibited by anacardic acid. Furthermore, we describe the design and synthesis of
      an amide derivative N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl
      benzamide (CTPB) using anacardic acid as a synthon, which remarkably activates
      p300 HAT activity but not that of p300/CBP-associated factor. Although CTPB does
      not affect DNA transcription, it enhances the p300 HAT-dependent transcriptional
      activation from in vitro assembled chromatin template. However, it has no effect
      on histone deacetylase activity. These compounds would be useful as biological
      switching molecules for probing into the role of p300 in transcriptional studies
      and may also be useful as new chemical entities for the development of anticancer
      drugs.

PMID- 12624112
TI  - A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting
      the catalytic activity of TAK1 MAPK kinase kinase.
AB  - TAK1, a member of the mitogen-activated kinase kinase kinase (MAPKKK) family,
      participates in proinflammatory cellular signaling pathways by activating JNK/p38
      MAPKs and NF-kappaB. To identify drugs that prevent inflammation, we screened
      inhibitors of TAK1 catalytic activity. We identified a natural resorcylic lactone
      of fungal origin, 5Z-7-oxozeaenol, as a highly potent inhibitor of TAK1. This
      compound did not effectively inhibit the catalytic activities of the MEKK1 or
      ASK1 MAPKKKs, suggesting that 5Z-7-oxozeaenol is a selective inhibitor of TAK1.
      In cell culture, 5Z-7-oxozeaenol blocked interleukin-1-induced activation of
      TAK1, JNK/p38 MAPK, IkappaB kinases, and NF-kappaB, resulting in inhibition of
      cyclooxgenase-2 production. Furthermore, in vivo 5Z-7-oxozeaenol was able to
      inhibit picryl chloride-induced ear swelling. Thus, 5Z-7-oxozeaenol blocks
      proinflammatory signaling by selectively inhibiting TAK1 MAPKKK.

PMID- 12624113
TI  - Roles of individual domains and conserved motifs of the AAA+ chaperone ClpB in
      oligomerization, ATP hydrolysis, and chaperone activity.
AB  - ClpB of Escherichia coli is an ATP-dependent ring-forming chaperone that mediates
      the resolubilization of aggregated proteins in cooperation with the DnaK
      chaperone system. ClpB belongs to the Hsp100/Clp subfamily of AAA+ proteins and
      is composed of an N-terminal domain and two AAA-domains that are separated by a
      "linker" region. Here we present a detailed structure-function analysis of ClpB,
      dissecting the individual roles of ClpB domains and conserved motifs in
      oligomerization, ATP hydrolysis, and chaperone activity. Our results show that
      ClpB oligomerization is strictly dependent on the presence of the C-terminal
      domain of the second AAA-domain, while ATP binding to the first AAA-domains
      stabilized the ClpB oligomer. Analysis of mutants of conserved residues in Walker
      A and B and sensor 2 motifs revealed that both AAA-domains contribute to the
      basal ATPase activity of ClpB and communicate in a complex manner. Chaperone
      activity strictly depends on ClpB oligomerization and the presence of a residual
      ATPase activity. The N-domain is dispensable for oligomerization and for the
      disaggregating activity in vitro and in vivo. In contrast the presence of the
      linker region, although not involved in oligomerization, is essential for ClpB
      chaperone activity.

PMID- 12624114
TI  - Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6
      paracrine/autocrine loop.
AB  - Mucus hypersecretion and persistent airway inflammation are common features of
      various airway diseases, such as asthma, chronic obstructive pulmonary disease,
      and cystic fibrosis. One key question is: does the associated airway inflammation
      in these diseases affect mucus production? If so, what is the underlying
      mechanism? It appears that increased mucus secretion results from increased mucin
      gene expression and is also frequently accompanied by an increased number of
      mucous cells (goblet cell hyperplasia/metaplasia) in the airway epithelium. Many
      studies on mucin gene expression have been directed toward Th2 cytokines such as
      interleukin (IL)-4, IL-9, and IL-13 because of their known pathophysiological
      role in allergic airway diseases such as asthma. However, the effect of these
      cytokines has not been definitely linked to their direct interaction with airway
      epithelial cells. In our study, we treated highly differentiated cultures of
      primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines
      (interleukin-1alpha, 1beta, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17,
      18, and tumor necrosis factor alpha). We found that IL-6 and IL-17 could
      stimulate the mucin genes, MUC5B and MUC5AC. The Th2 cytokines IL-4, IL-9, and IL
      13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of
      MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and
      mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL
      17's effect is at least partly mediated through IL-6 by a JAK2-dependent
      autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6
      and IL-17 mediate MUC5B expression through the ERK signaling pathway.

PMID- 12624115
TI  - A short form of the prolactin (PRL) receptor is able to rescue mammopoiesis in
      heterozygous PRL receptor mice.
AB  - The heterozygous prolactin (PRL) receptor (PRLR +/-) mouse fails to develop a
      fully functional mammary gland at the end of the first pregnancy and shows
      markedly impaired lobuloalveolar development and milk secretion in young females.
      The PRLR is expressed ubiquitously, with various proportions of long and short
      isoforms in different tissues. Conflicting data have appeared on the putative
      role of the receptor short forms, with both agonist and antagonistic actions
      proposed. To assess whether the mouse PR-1 short isoform of the PRLR is
      potentially able to transduce a signal, we overexpressed it in heterozygous mice
      and investigated its effect on the rescue of mammary development. PRLR+/- mice
      were not able to develop a functional mammary gland, but restoration of mammary
      alveolar development and an increase in the expressions of casein and whey acidic
      protein genes were observed in transgenic PRLR+/- mice expressing the short form
      of the PRLR, leading to a complete rescue of mammary gland development and
      function in young females. These results demonstrate that PR-1, the short form of
      the PRLR, can improve mammary development in PRLR+/- mice, which compensates for
      the haploinsufficiency of the receptor long form; this effect is probably caused
      by accelerated proliferation and an activation of the PRLR signaling cascade,
      resulting in activation of target genes involved in mammary development and milk
      synthesis.

PMID- 12624116
TI  - Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor
      (ER) Null mice reveals hypergonadism and endocrine sex reversal in females
      lacking ERalpha but not ERbeta.
AB  - To determine the role of each estrogen receptor (ER) form (ERalpha, ERbeta) in
      mediating the estrogen actions necessary to maintain proper function of the
      hypothalamic-pituitary-gonadal axis, we have characterized the hypothalamic
      pituitary-gonadal axis in female ER knockout (ERKO) mice. Evaluation of pituitary
      function included gene expression assays for Gnrhr, Cga, Lhb, Fshb, and Prl.
      Evaluation of ovarian steroidogenic capacity included gene expression assays for
      the components necessary for estradiol synthesis: i.e. Star, Cyp11a, Cyp17,
      Cyp19, Hsd3b1, and Hsd17b1. These data were corroborated by assessing plasma
      levels of the respective peptide and steroid hormones. alphaERKO and
      alphabetaERKO females exhibited increased pituitary Cga and Lhb expression and
      increased plasma LH levels, whereas both were normal in betaERKO. Pituitary Fshb
      expression and plasma FSH were normal in all three ERKOs. In the ovary, all three
      ERKOs exhibited normal expression of Star, Cyp11a, and Hsd3b1. In contrast, Cyp17
      and Cyp19 expression were elevated in alphaERKO but normal in betaERKO and
      alphabetaERKO. Plasma steroid levels in each ERKO mirrored the steroidogenic
      enzyme expression, with only the alphaERKO exhibiting elevated androstenedione
      and estradiol. Elevated plasma testosterone in alphaERKO and alphabetaERKO
      females was attributable to aberrant expression of Hsd17b3 in the ovary,
      representing a form of endocrine sex reversal, as this enzyme is unique to the
      testes. Enhanced steroidogenic capacity in alphaERKO ovaries was erased by
      treatment with a GnRH antagonist, indicating these phenotypes to be the indirect
      result of excess LH stimulation that follows the loss of ERalpha in the
      hypothalamic-pituitary axis. Overall, these findings indicate that ERalpha, but
      not ERbeta, is indispensable to the negative-feedback effects of estradiol that
      maintain proper LH secretion from the pituitary. The subsequent hypergonadism is
      illustrated as increased Cyp17, Cyp19, Hsd17b1, and ectopic Hsd17b3 expression in
      the ovary.

PMID- 12624120
TI  - Clinical 18F-FDG oncology patient preparation techniques.
AB  - OBJECTIVES: Clinical tumor imaging with (18)F-FDG in PET is growing in demand.
      This article will provide a review of current patient preparation and imaging
      techniques. The goal is to make the PET study as noninvasive as possible for the
      patient while obtaining quality images. Communication and coordination when
      scheduling these studies involves the patient and radiopharmacy, scanner, and
      support staff. A pertinent patient history (information about weight, pregnancy,
      breastfeeding, diabetes, etc.) is vital for appropriate patient instructions and
      patient sequencing. Patient preparation involves many variations on fluid intake,
      diet, medications, and other factors. Blood glucose levels must be </=150 mg/dL.
      If the patient has diabetes mellitus or is glucose intolerant, diet-exercise
      regime and glucose levels should be monitored. Accurate (18)F-FDG dose
      calculation to be used for region-of-interest analysis or standard uptake value
      determination is imperative. After (18)F-FDG injection, the patient must remain
      quiet and still to minimize muscle use. Before the scan, the patient may need
      relaxation medications, urinary catheterization, or other interventions. At the
      conclusion of this article, the reader should be able to list pertinent patient
      history issues that are useful for scheduling an (18)F-FDG tumor scan, discuss
      methods to ensure accurate (18)F-FDG patient dose calculations, and describe
      possible methods to help minimize urinary (18)F-FDG excretion.

PMID- 12624117
TI  - RFX1 and NF-1 associate with P sequences of the human growth hormone locus in
      pituitary chromatin.
AB  - The human GH family consists of five genes, including the placental chorionic
      somatomammotropins (CS), within a single locus on chromosome 17. Based on
      nuclease sensitivity, the entire GH/CS locus is accessible in pituitary
      chromatin, yet only GH-N is expressed. Previously, we reported a P sequence
      element (263P) capable of repressing placental CS promoter activity in
      transfected pituitary (GC) cells. Regions of protein binding within 263P include
      P sequence elements A and B (PSE-A and PSE-B), and we reported nuclear factor-1
      (NF-1) recognition of PSE-B. We now provide evidence for multiple interactions on
      PSE-A, including binding of the regulatory factor X (RFX) family. Disruption of
      the RFX site within 263P blunts repressor activity in transfected GC cells;
      however, repression is only abolished when both PSE-A/RFX and PSE-B/NF-1 sites
      are mutated. The capacity of RFX and NF-1 to participate in a novel common
      complex is further suggested by coimmunoprecipitation of RFX1 and epitope-tagged
      NF-1 family members. Finally, we confirm the association of NF-1 and RFX1 with P
      sequences in human pituitary tissue by chromatin immunoprecipitation. Taken
      together, our data suggest that an inverse relationship exists between 263P and
      CS promoter histone hyperacetylation and the association of these factors in
      vivo.

PMID- 12624121
TI  - Radiation hormesis, or, could all that radiation be good for us?
AB  - OBJECTIVE: Nuclear medicine technologists work under significant radiation
      protection constraints. These constraints are based on the linear no-threshold
      (LNT) radiation paradigm, which was developed in the 1960s and was based largely
      on the deleterious effects of radiation as they were understood at the time. More
      recently, the theory of radiation hormesis, or a beneficial effect of low-level
      exposure to radiation, has gained recognition. This article reviews the history
      of attitudes toward radiation, describes the radiation hormesis hypothesis,
      examines some of the evidence that supports it, and suggests ways that radiation
      protection regulations might change if the hypothesis were to become accepted.

PMID- 12624122
TI  - Factors affecting the hepatobiliary excretion of 99mTc-MAG3: its clinical
      significance in routine renography.
AB  - OBJECTIVE: Since the approval of mercaptoacetyltriglycine (MAG3) for routine
      clinical use, reports have appeared about hepatobiliary excretion deleteriously
      affecting available diagnostic and quantitative information. The purpose of this
      study was to evaluate gallbladder (GB) uptake of MAG3 in the clinical setting and
      its effect on the evaluation of relative renal function and imaging. METHODS:
      Sixty patients with varying degrees of renal impairment were studied. Routine
      renal function imaging was followed with anterior and right lateral 3-min
      abdominal images. Factors such as photolytic degradation, reconstitution steps,
      (99m)Tc O(4) solution, age, and concentration are discussed. In addition, patient
      fasting state and radiochemical purity are evaluated. The GB uptake was
      determined as a percentage of the injected dose. RESULTS: The MAG3 quality
      control ranged from 90.9% to 99.0%. The GB uptake ranged from 0.0% (not
      visualized) to 0.71%. The effective renal plasma flow ranged from 88 to 743
      mL/min. There was no correlation between the QC and the percentage of GB uptake
      (r = 0.12). The majority of patients in the nonfasting state showed minimal or
      reduced GB uptake when compared with the majority of patients in the fasting
      state. CONCLUSION: Our data suggest that GB uptake of MAG3 is minimal, with no
      adverse effects on the diagnostic and quantitative analysis of renal function.

PMID- 12624123
TI  - The day of contamination.
AB  - OBJECTIVE: We present 3 cases of suspected radioisotope urinary contamination
      that occurred on a single day. Because net clearance is via the kidneys, the
      injected dose is excreted in patients' urine. It is important to recognize the
      patterns of urinary contamination to avoid reporting false-positive
      abnormalities. MATERIALS AND METHODS: (99m)Tc-Medronate was administered
      intravenously and whole-body bone scans and spot views were obtained 2-3 h later.
      RESULTS: Two cases of urinary contamination were confirmed, and the third case
      was false-positive with a urinary collection leg bag seen in an orthogonal view.
      CONCLUSION: We believe that urinary contamination is probably the most common
      type of contamination. There are distinct urinary contamination patterns among
      male and female patients. It is unusual to find so many cases of contamination on
      a single day in our institution. Few statistics are widely available on the
      number or percentages of contamination for specific radiopharmaceuticals.

PMID- 12624124
TI  - Reduced hemithoracic uptake on 99mTc-MDP bone scintigraphy: an underrecognized
      sign of massive pleural effusion--a case report.
AB  - The uptake of (99m)Tc-methylene diphosphonate (MDP) in malignant pleural
      effusions and, rarely, in nonmalignant pleural effusions has been well documented
      in the literature. Although the exact mechanism of uptake in these conditions
      remains unclear, there have been attempts to use the bone scintigraphic features
      of pleural effusion to predict sensitivity and specificity for malignancy based
      on pleural fluid cytology. It has been suggested that activity in the chest
      increases with an increase in effusion volume. We report here, however, a case of
      malignant pleural effusion, that showed reduced hemithoracic activity in contrast
      to the expected increased activity. Our experience highlights the need for an
      open and inquisitive mind to avoid diagnostic pitfalls when confronted with a
      bone scintigram showing reduced uptake unilaterally or bilaterally in the chest.

PMID- 12624125
TI  - Determination of the efficiency of commercially available dose calibrators for
      beta-emitters.
AB  - OBJECTIVES: The goals of this investigation are to determine whether commercially
      available dose calibrators can be used to measure the activity of beta-emitting
      radionuclides used in pain palliation and to establish whether manufacturer
      supplied calibration factors are appropriate for this purpose. METHODS: Six types
      of commercially available dose calibrators were studied. Dose calibrator response
      was controlled for 5 gamma-emitters used for calibration or typically encountered
      in routine use. For the 4 most commonly used beta-emitters ((32)P, (90)Sr, (90)Y,
      and (169)Er) dose calibrator efficiency was determined in the syringe geometry
      used for clinical applications. Efficiency of the calibrators was also measured
      for (153)Sm and (186)Re, 2 beta-emitters with significant gamma-contributions.
      Source activities were traceable to national standards. RESULTS: All calibrators
      measured gamma-emitters with a precision of +/-10%, in compliance with Swiss
      regulatory requirements. For beta-emitters, dose calibrator intrinsic efficiency
      depends strongly on the maximal energy of the beta-spectrum and is notably low
      for (169)Er. Manufacturer-supplied calibration factors give accurate results for
      beta-emitters with maximal beta-energy in the middle-energy range (1 MeV) but are
      not appropriate for use with low-energy ((169)Er) or high-energy ((90)Y) beta
      emitters. beta-emitters with significant gamma-contributions behave like gamma
      emitters. CONCLUSION: Commercially available dose calibrators have an intrinsic
      efficiency that is sufficient for the measurement of beta-emitters, including
      beta-emitters with a low maximum beta-energy. Manufacturer-supplied calibration
      factors are reliable for gamma-emitters and beta-emitters in the middle-energy
      range. For low- and high-energy beta-emitters, the use of manufacturer-supplied
      calibration factors introduces significant measurement inaccuracy.

PMID- 12624126
TI  - Dextrose solutions yield radiochemical impurities: the "sweet" scans.
AB  - OBJECTIVE: If additional chemicals are inadvertently introduced in the
      preparation of radiopharmaceutical kits, radiochemical impurities may be formed.
      We report our experience with erroneously diluting (99m)Tc-pertechnetate eluate
      with 5% dextrose solution rather than normal saline during the preparation of
      (99m)Tc-tetrofosmin, (99m)Tc-methylene diphosphonate (MDP), (99m)Tc-stannous
      colloid, and (99m)Tc-mebrofenin. METHODS: Scintigrams for 3 of the 4
      radiochemicals unintentionally prepared with 5% dextrose were found to have an
      altered biodistribution. Therefore, radiopharmacy procedures for the day were
      reviewed, and instant thin-layer chromatography (ITLC) was performed. RESULTS:
      Scintigrams showed an altered biodistribution consistent with an impurity. Review
      of procedures that day uncovered the error of using 5% dextrose to dilute the
      (99m)Tc eluate. The altered biodistribution on (99m)Tc-stannous colloid, (99m)Tc
      MDP, and (99m)Tc-mebrofenin scintigrams consisted of cardiac blood-pool activity
      (possibly as a result of slow clearance of (99m)Tc-dextrose), soft-tissue
      background activity (possibly as a result of interstitial distribution of (99m)Tc
      dextrose), renal and bladder activity (possibly as a result of renal elimination
      of (99m)Tc-dextrose), and gallbladder activity (possibly as a result of
      hepatobiliary excretion of (99m)Tc-dextrose). Both scintigrams and ITLC showed no
      evidence of impurities for the (99m)Tc-tetrofosmin prepared using 5% dextrose.
      CONCLUSION: Unintended preparation of radiochemicals with 5% dextrose rather than
      normal saline often results in the production of impurities, possibly (99m)Tc
      dextrose. Because some but not all commercial radiochemical kits prepared with 5%
      dextrose will suffer this fate, nuclear medicine physicians reviewing the day's
      images will be confronted with a confusing combination of expected and grossly
      abnormal findings.

PMID- 12624127
TI  - A simple and effective technique to reduce staff exposure during the preparation
      of radiopharmaceuticals.
AB  - OBJECTIVE: In the preparation of radiopharmaceuticals, staff receive considerable
      radiation exposure to the hands during withdrawal of activity from the elution
      vial, from a combination of the syringe and elution vial activities. In an
      attempt to reduce the radiation burden to the hands, a simple technique was
      developed that utilizes a modified lead pot lid and a syringe bearing a long
      needle with a sterile needle guide. METHODS: An elution vial in a lead pot with
      an attached syringe was secured at an angle of 45 degrees, simulating the action
      of withdrawing (99m)Tc-pertechnetate from the elution vial. The (99m)Tc activity
      ratio of vial to syringe was 20:1. A gamma- camera detector without collimator
      was positioned at the syringe plunger and count profiles were obtained after 10
      min of data acquisition. The experiment was repeated using the same set-up with
      (a) the modified lid on the lead pot and (b) a cold syringe to determine the
      contribution of the radioactive syringe to the count profile. Each experiment was
      repeated at the vertical position, simulating the normal action of redispensing
      (99m)Tc activity into the elution vial. RESULTS: The modified lid reduced
      exposure from the elution vial, with a count reduction of >98% for both
      orientations. The contributions of vial radioactivity to the total count profile
      were 76% and 84% for vertical and 45 degrees orientations, respectively. The
      contributions of syringe activity were 24% and 16% for vertical and 45 degrees
      orientations, respectively. CONCLUSION: A reduction in the photon flux to the
      hands of up to 84% (with an associated reduction in hand dose) can be achieved by
      withdrawing activity through a modified lid on the lead pot housing the elution
      vial, without significantly altering normal work practices.

PMID- 12624130
TI  - An ICANL site visit: what can I expect?

PMID- 12624133
TI  - A common variant in the ABCA1 gene is associated with a lower risk for premature
      coronary heart disease in familial hypercholesterolaemia.
AB  - Familial hypercholesterolaemia (FH) is a common autosomal codominant hereditary
      disease caused by defects in the LDL receptor (LDLR) gene, and one of the most
      common characteristics of affected subjects is premature coronary heart disease
      (CHD). In heterozygous FH patients, the clinical expression of FH is highly
      variable in terms of the severity of hypercholesterolaemia and the age of onset
      and severity of CHD. Identification of mutations in the ATP binding cassette
      transporter 1 (ABCA1) gene in patients with Tangier disease, who exhibit reduced
      HDL cholesterol and apolipoprotein A1 concentrations and premature coronary
      atherosclerosis, has led us to hypothesise that ABCA1 could play a key role in
      the onset of premature CHD in FH. In order to know if the presence of the R219K
      variant in the ABCA1 gene could be a protective factor for premature CHD in FH,
      we have determined the presence of this genetic variant by amplification by PCR
      and restriction analysis in a group of 374 FH subjects, with and without
      premature CHD. The K allele of the R219K variant was significantly more frequent
      in FH subjects without premature CHD (0.32, 95% CI 0.27 to 0.37) than in FH
      subjects with premature CHD (0.25, 95% CI 0.21 to 0.29) (p<0.05), suggesting that
      the genetic variant R219K in ABCA1 could influence the development and
      progression of atherosclerosis in FH subjects. Moreover, the K allele of the
      R219K polymorphism seems to modify CHD risk without important modification of
      plasma HDL-C levels, and it appears to be more protective for smokers than non
      smokers.

PMID- 12624132
TI  - Nail patella syndrome: a review of the phenotype aided by developmental biology.
AB  - Nail patella syndrome (NPS) is an autosomal dominant condition affecting the
      nails, skeletal system, kidneys, and eyes. Skeletal features include absent or
      hypoplastic patellae, patella dislocations, elbow abnormalities, talipes, and
      iliac horns on x ray. Kidney involvement may lead to renal failure and there is
      also a risk of glaucoma. There is marked inter- and intrafamilial variability.
      The results of a British study involving 123 NPS patients are compared with
      previously published studies and it is suggested that neurological and vasomotor
      symptoms are also part of the NPS phenotype. In addition, the first data on the
      incidence of glaucoma and gastrointestinal (GI) symptoms in NPS are presented.
      NPS is caused by loss of function mutations in the transcription factor LMX1B at
      9q34. The expansion of the clinical phenotype is supported by the role of LMX1B
      during development.

PMID- 12624134
TI  - Identification of a 650 kb duplication at the X chromosome breakpoint in a
      patient with 46,X,t(X;8)(q28;q12) and non-syndromic mental retardation.
AB  - A female patient with non-syndromic mental retardation was shown by high
      resolution GTL banding to have inherited an apparently balanced translocation,
      46,X,t(X;8)(q28;q12)mat. Replication studies in the mother and daughter showed a
      skewed X inactivation pattern in lymphocytes, with the normal X chromosome
      preferentially inactivated. The mother also had significant intellectual
      disability. To investigate the possibility that a novel candidate gene for XLMR
      was disrupted at the X chromosome translocation breakpoint, we mapped the
      breakpoint using fluorescence in situ hybridisation (FISH). This showed that the
      four known genes involved in non-syndromic mental retardation in Xq28, FMR2,
      SLC6A8, MECP2, and GDI1, were not involved in the translocation. Intriguingly, we
      found that the X chromosome breakpoint in the daughter could not be defined by a
      single breakpoint spanning genomic clone and further analysis showed a 650 kb
      submicroscopic duplication between DXS7067 and DXS7060 on either side of the X
      chromosome translocation breakpoint. This duplicated region contains 11
      characterised genes, of which nine are expressed in brain. Duplication of one or
      several of the genes within the 650 kb interval is likely to be responsible for
      the mental retardation phenotype seen in our patient. Xq28 appears to be an
      unstable region of the human genome and genomic rearrangements are recognised as
      major causes of two single gene defects, haemophilia A and incontinentia
      pigmenti, which map within Xq28. This patient therefore provides further evidence
      for the instability of this genomic region.

PMID- 12624135
TI  - Clinical aspects, prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism.
AB  - INTRODUCTION: Analysis of data from cases of trisomy mosaicism can provide
      insight for genetic counselling after prenatal diagnosis and for the elucidation
      of the pathogenesis of trisomy during pregnancy. METHODS: Statistical analysis
      was carried out on data from 162 cases of pregnancies with prenatal diagnosis of
      trisomy 16 mosaicism. RESULTS: The majority of cases resulted in live birth (66%)
      with an average gestational age of 35.7 weeks and average birth weight of -1.93
      standard deviations from the population mean. Among the live births 45% had at
      least one malformation, the most common being VSD, ASD, and hypospadias. The
      level of trisomy on direct CVS (cytotrophoblast) was associated with more severe
      intrauterine growth restriction (IUGR) and higher risk of malformation, while the
      level of trisomy on cultured CVS (chorionic villous stroma) was associated only
      with more severe IUGR. Similarly, the presence of trisomy on amniocentesis
      (amniotic fluid) was associated with both IUGR and malformation, while the
      presence of trisomy in the amniotic mesenchyme was associated only with IUGR.
      Surprisingly, the degree of trisomy in placental tissues appeared to be
      independent of the degree of trisomy in amniotic fluid and amniotic mesenchyme.
      The sex of the fetus was not associated with any outcome variables, although
      there was an excess of females (sex ratio = 0.45) that may be explained by
      selection against male mosaic trisomy 16 embryos before the time of CVS
      (approximately 9-12 weeks). CONCLUSION: The levels of trisomy in different fetal
      placental tissues are significant predictors of some measures of outcome in
      mosaic trisomy 16 pregnancies.

PMID- 12624136
TI  - Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for
      the pathogenesis of disorders of interferon alpha metabolism.
AB  - Aicardi-Goutieres syndrome (AGS) is an early onset, progressive encephalopathy
      characterised by calcification of the basal ganglia, white matter abnormalities,
      and a chronic cerebrospinal fluid (CSF) lymphocytosis. Cree encephalitis shows
      phenotypic overlap with AGS although the conditions have been considered distinct
      because of immunological abnormalities observed in Cree encephalitis. We report
      that levels of interferon alpha (IFN-alpha), a marker of AGS, are raised in Cree
      encephalitis. Moreover, linkage analysis indicates that the disorders are allelic
      and refines the AGS1 locus to a 3.47 cM critical interval. Our data show that a
      CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest
      that AGS and pseudo-TORCH syndrome are the same disorder. Recognition of
      immunological dysfunction as part of the AGS phenotype provides further evidence
      of a primary pathogenic role for abnormal IFN-alpha production in AGS.

PMID- 12624138
TI  - Sanfilippo syndrome type D: identification of the first mutation in the N
      acetylglucosamine-6-sulphatase gene.
AB  - Mucopolysaccharidosis type IIID is the least common of the four subtypes of
      Sanfilippo syndrome. It is caused by a deficiency of N-acetylglucosamine-6
      sulphatase, which is one of the enzymes involved in the catabolism of heparan
      sulphate. We present the clinical, biochemical, and, for the first time, the
      molecular diagnosis of a patient with Sanfilippo D disease. The patient was found
      to be homozygous for a single base pair deletion (c1169delA), which will cause a
      frameshift and premature termination of the protein. Accurate carrier detection
      is now available for other members of this consanguineous family.

PMID- 12624137
TI  - The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is
      a frequent cause of Leigh-like syndrome with isolated complex I deficiency.
AB  - Leigh syndrome is a subacute necrotising encephalomyopathy frequently ascribed to
      mitochondrial respiratory chain deficiency. This condition is genetically
      heterogeneous, as mutations in both mitochondrial (mt) and nuclear genes have
      been reported. Here, we report the G13513A transition in the ND5 mtDNA gene in
      three unrelated children with complex I deficiency and a peculiar MRI aspect
      distinct from typical Leigh syndrome. Brain MRI consistently showed a specific
      involvement of the substantia nigra and medulla oblongata sparing the basal
      ganglia. Variable degrees of heteroplasmy were found in all tissues tested and a
      high percentage of mutant mtDNA was observed in muscle. The asymptomatic mothers
      presented low levels of mutant mtDNA in blood leucocytes. This mutation, which
      affects an evolutionary conserved amino acid (D393N), has been previously
      reported in adult patients with MELAS or LHON/MELAS syndromes, emphasising the
      clinical heterogeneity of mitochondrial DNA mutations. Since the G13513A mutation
      was found in 21% of our patients with Leigh syndrome and complex I deficiency
      (3/14), it appears that this mutation represents a frequent cause of Leigh-like
      syndrome, which should be systematically tested for molecular diagnosis in
      affected children and for genetic counselling in their maternal relatives.

PMID- 12624139
TI  - Clinical, radiological, and chondro-osseous findings in opsismodysplasia: survey
      of a series of 12 unreported cases.

PMID- 12624141
TI  - Cancer risk in 348 French MSH2 or MLH1 gene carriers.

PMID- 12624140
TI  - Acrocapitofemoral dysplasia: an autosomal recessive skeletal dysplasia with cone
      shaped epiphyses in the hands and hips.

PMID- 12624142
TI  - Haptoglobin and its association with the HELLP syndrome.

PMID- 12624143
TI  - Significant frequency deviation of the class I polymorphism HLA-A10 in
      schizophrenic patients.

PMID- 12624144
TI  - Identification of a mutation that perturbs NF1 agene splicing using genomic DNA
      samples and a minigene assay.

PMID- 12624146
TI  - From Aldrovandi's "Homuncio" (1592) to Buffon's girl (1749) and the "Wart Man" of
      Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis?

PMID- 12624145
TI  - Paternal uniparental disomy in monozygotic twins discordant for hemihypertrophy.

PMID- 12624147
TI  - Investigation of germline GFRA4 mutations and evaluation of the involvement of
      GFRA1, GFRA2, GFRA3, and GFRA4 sequence variants in Hirschsprung disease.

PMID- 12624148
TI  - No fumarate hydratase (FH) mutations in hereditary prostate cancer.

PMID- 12624149
TI  - Y chromosome haplotypes and testicular cancer in the English population.

PMID- 12624151
TI  - The RNASEL 471delAAAG allele and prostate cancer in Ashkenazi Jewish men.

PMID- 12624150
TI  - RNASEL mutations in hereditary prostate cancer.

PMID- 12624152
TI  - The BRCA2 variant 8204G>A is a splicing mutation and results in an in frame
      deletion of the gene.

PMID- 12624153
TI  - Neuronal migration defect in a BRCA1 gene carrier: possible focal nullisomy?

PMID- 12624154
TI  - Little value from including cousins in individual risk assessment of hereditary
      breast cancer: a simulation study.

PMID- 12624155
TI  - Comprehensive microsatellite marker analysis contradicts previous report of
      segmental maternal heterodisomy of chromosome 14.

PMID- 12624156
TI  - Analphoid de novo marker chromosome inv dup(3)(q28qter) with neocentromere in a
      dysmorphic and developmentally retarded girl.

PMID- 12624157
TI  - Partial hexasomy 15pter-->15q13 including SNRPN and D15S10: first molecular
      cytogenetically proven case report.

PMID- 12624159
TI  - Frequent genomic disorganisation of MLH1 in hereditary non-polyposis colorectal
      cancer (HNPCC) screened by RT-PCR on puromycin treated samples.

PMID- 12624158
TI  - Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome.

PMID- 12624160
TI  - High frequency of novel germline mutations in the VHL gene in the heterogeneous
      population of Brazil.

PMID- 12624161
TI  - A second heterozygous MDR3 nonsense mutation associated with intrahepatic
      cholestasis of pregnancy.

PMID- 12624162
TI  - Honeybee navigation: properties of the visually driven 'odometer'.
AB  - Recent work has revealed that honeybees determine distance flown by gauging the
      extent to which the image of the environment moves in the eye as they fly toward
      their destination. Here we examine the properties of this visually driven
      'odometer', by training bees to fly to a feeder in a tunnel lined with a range of
      different visual patterns, and analysing their dances when they return to the
      hive. We find that the odometric signal is relatively unaffected by variations in
      the contrast and spatial frequency content of the patterns. Furthermore, a strong
      signal is generated even when the walls or the floor of the tunnel provide only
      weak optic-flow cues. Thus, distance flown is measured by a visually driven
      odometer that is surprisingly robust to variations in the texture or sparseness
      of the visual environment through which the bee flies.

PMID- 12624163
TI  - Conservation of ecdysis-triggering hormone signalling in insects.
AB  - Pre-ecdysis- and ecdysis-triggering hormones (PETH and ETH) from endocrine Inka
      cells initiate ecdysis in moths and Drosophila through direct actions on the
      central nervous system (CNS). Using immunohistochemistry, we found Inka cells in
      representatives of all major insect orders. In most insects, Inka cells are
      numerous, small and scattered throughout the tracheal system. Only some higher
      holometabolous insects exhibit 8-9 pairs of large Inka cells attached to tracheae
      in each prothoracic and abdominal segment. The number and morphology of Inka
      cells can be very variable even in the same individuals or related insects, but
      all produce peptide hormones that are completely released at each ecdysis.
      Injection of tracheal extracts prepared from representatives of several insect
      orders induces pre-ecdysis and ecdysis behaviours in pharate larvae of Bombyx,
      indicating functional similarity of these peptides. We isolated several PETH
      immunoreactive peptides from tracheal extracts of the cockroach Nauphoeta cinerea
      and the bug Pyrrhocoris apterus and identified the gene encoding two putative
      ETHs in the mosquito Anopheles gambiae. Inka cells also are stained with antisera
      to myomodulin, FMRFamide and other peptides sharing RXamide carboxyl termini.
      However, our enzyme immunoassays show that these antisera cross-react with PETH
      and ETH. Our results suggest that Inka cells of different insects produce only
      peptide hormones closely related to PETH and ETH, which are essential endocrine
      factors required for activation of the ecdysis behavioural sequence.

PMID- 12624164
TI  - Minimal shortening in a high-frequency muscle.
AB  - Reducing the cost of high-frequency muscle contractions can be accomplished by
      minimizing cross-bridge cycling or by recycling elastic strain energy. Energy
      saving by contractile minimization has very different implications for muscle
      strain and activation patterns than by elastic recoil. Minimal cross-bridge
      cycling will be reflected in minimal contractile strains and highly reduced
      force, work and power output, whereas elastic energy storage requires a period of
      active lengthening that increases mechanical output. In this study, we used
      sonomicrometry and electromyography to test the relative contributions of energy
      reduction and energy recycling strategies in the tailshaker muscles of western
      diamondback rattlesnakes (Crotalus atrox). We found that tailshaker muscle
      contractions produce a mean strain of 3%, which is among the lowest strains ever
      recorded in vertebrate muscle during movement. The relative shortening velocities
      (V/V(max)) of 0.2-0.3 were in the optimal range for maximum power generation,
      indicating that the low power output reported previously for tailshaker muscle is
      due mainly to contractile minimization rather than to suboptimal V/V(max). In
      addition, the brief contractions (8-18 ms) had only limited periods of active
      lengthening (0.2-0.5 ms and 0.002-0.035%), indicating little potential for
      elastic energy storage and recoil. These features indicate that high-frequency
      muscles primarily reduce metabolic energy input rather than recycle mechanical
      energy output.

PMID- 12624165
TI  - Non-invasive imaging of blood cell concentration and blood distribution in
      zebrafish Danio rerio incubated in hypoxic conditions in vivo.
AB  - This is the first study to use a combination of digital imaging techniques and
      vital video microscopy to study hypoxia-induced changes in blood cell
      concentration, angiogenesis and blood redistribution in entire animals. Zebrafish
      Danio rerio, which are known to be independent of convective oxygen transport
      until about 2 weeks post-fertilization, were raised under chronic hypoxia
      (P(O(2))=8.7 kPa) starting at 1 day after fertilization (d.p.f.) until 15 d.p.f.
      In control animals, the concentration of red cells (i.e. the number of red cells
      per nl blood) remained constant until 7 d.p.f., and than decreased by
      approximately 70% until 15 d.p.f. In hypoxic animals, however, the concentration
      of red cells remained significantly elevated compared to control animals at 12
      and 15 d.p.f. Assuming that the hemoglobin content of the red cells is similar,
      hypoxic animals have a higher oxygen carrying capacity in their blood. Red cell
      distribution within the various parts of the circulatory system, taken as an
      indicator for blood distribution, revealed a significant modification in the
      number of blood cells perfusing the organs in hypoxic animals. At 12 d.p.f., gut
      perfusion was reduced by almost 50% in hypoxic animals, while perfusion of the
      segmental muscle tissue was increased to 350% of control values. No significant
      changes in brain perfusion were observed under these conditions. At 15 d.p.f.,
      the reduction in gut perfusion was abolished, although muscle perfusion was still
      significantly elevated. At this time, growth of hypoxic animals was less compared
      to control animals, revealing that hypoxia had become deleterious for further
      development. The vascular bed of various organs was not obviously different in
      hypoxic animals compared to normoxic animals.

PMID- 12624166
TI  - The role of the subelytral spiracles in respiration in the flightless dung beetle
      Circellium bacchus.
AB  - The role of the subelytral cavity in flightless beetle species as an adaptation
      to water saving in arid habitats is still in dispute. We found that relatively
      little CO(2) was released from the subelytral cavity of a large apterous beetle
      Circellium bacchus during simultaneous measurements of CO(2) emission from the
      anterior mesothoracic spiracles and posterior body, which included the subelytral
      spiracles. However, when we sampled air directly from inside the subelytral
      cavity, we discovered that this pattern was reversed. A discontinuous gas
      exchange cycle (DGC) was recorded from the posterior body half, revealing a
      flutter phase that had been absent from the anterior mesothoracic DGC. The
      anterior mesothoracic and posterior subelytral spiracles act in synchrony to
      maintain high CO(2) and water vapour levels inside the subelytral cavity. In
      addition, the O(2) concentration of the air within the subelytral cavity is lower
      than the air around the elytral case, irrespective of the time of sampling. These
      findings lead us to conclude that the subelytral spiracles work in a coordinated
      fashion with the anterior spiracles to create a DGC, which allows us to extend
      the hypothesis of the function of the subelytral cavity as a respiratory water
      saving device.

PMID- 12624167
TI  - Prolactin increases open-channel density of epithelial Na+ channel in adult frog
      skin.
AB  - The short-term effect of prolactin on the skin of the adult tree frog Hyla
      arborea japonica was investigated using current-fluctuation analysis. Basolateral
      application of ovine prolactin (10 microg ml(-1)) (1) increased the amiloride
      blockable short-circuit current (SCC) across the skin 2.6+/-0.4-fold and (2)
      increased the open-channel density (M) of the epithelial Na(+) channel 6.1+/-1.2
      fold but decreased the single-channel current i to 0.4+/-0.1 times the control
      value (N=9). The increase in SCC induced by prolactin was thus due to an increase
      in M, not i. Apparently, in amphibians prolactin has not only a counteracting
      effect on metamorphosis but also a stimulatory effect on the development of adult
      type features, such as this amiloride-blockable SCC.

PMID- 12624168
TI  - The effect of gait and digital flexor muscle activation on limb compliance in the
      forelimb of the horse Equus caballus.
AB  - A horse's legs are compressed during the stance phase, storing and then returning
      elastic strain energy in spring-like muscle-tendon units. The arrangement of the
      muscle-tendon units around the lever-like joints means that as the leg shortens
      the muscle-tendon units are stretched. The forelimb anatomy means that the leg
      can be conceptually divided into two springs: the proximal spring, from the
      scapula to the elbow, and the distal spring, from the elbow to the foot. In this
      paper we report the results of a series of experiments testing the hypothesis
      that there is minimal scope for muscle contraction in either spring to adjust
      limb compliance. Firstly, we demonstrate that the distal, passive leg spring
      changes length by 127 mm (range 106-128 mm) at gallop and the proximal spring by
      12 mm (9-15 mm). Secondly, we demonstrate that there is a linear relationship
      between limb force and metacarpo-phalangeal (MCP) joint angle that is minimally
      influenced by digital flexor muscle activation in vitro or as a function of gait
      in vivo. Finally, we determined the relationship between MCP joint angle and
      vertical ground-reaction force at trot and then predicted the forelimb peak
      vertical ground-reaction force during a 12 m s(-1) gallop on a treadmill. These
      were 12.79 N kg(-1) body mass (BM) (range 12.07-13.73 N kg(-1) BM) for the lead
      forelimb and 15.23 N kg(-1) BM (13.51-17.10 N kg(-1) BM) for the non-lead
      forelimb.

PMID- 12624169
TI  - Freshwater environment affects growth rate and muscle fibre recruitment in
      seawater stages of Atlantic salmon (Salmo salar L.).
AB  - The influence of freshwater environment on muscle growth in seawater was
      investigated in an inbred population of farmed Atlantic salmon (Salmo salar L.).
      The offspring from a minimum of 64 families per group were incubated at either
      ambient temperature (ambient treatment) or in heated water (heated treatment).
      Growth was investigated using a mixed-effect statistical model with repeated
      measures, which included terms for treatment effect and random fish effects for
      individual growth rate (alpha) and the instantaneous growth rate per unit change
      in temperature (gamma). Prior to seawater transfer, fish were heavier in the
      heated (61.6+/-1.0 g; N=298) than in the ambient (34.1+/-0.4 g; N=206)
      treatments, reflecting their greater growth opportunity: 4872 degree-days and
      4281 degree-days, respectively. However, the subsequent growth rate of the heated
      group was lower, such that treatments had a similar body mass (3.7-3.9 kg) after
      approximately 450 days in seawater. The total cross-sectional area of fast muscle
      and the number (FN) and size distribution of the fibres was determined in a
      subset of the fish. We tested the hypothesis that freshwater temperature regime
      affected the rate of recruitment and hypertrophy of muscle fibres. There were
      differences in FN between treatments and a significant age x treatment
      interaction but no significant cage effect (ANOVA). Cessation of fibre
      recruitment was identified by the absence of fibres of <10 micro m diameter. The
      maximum fibre number was 22.4% more in the ambient (9.3 x 10(5)+/-2.0 x 10(4)
      than in the heated (7.6 x 10(5)+/-1.5 x 10(4)) treatments (N=44 and 40 fish,
      respectively; P<0.001). For fish that had completed fibre recruitment, there was
      a significant correlation between FN and individual growth rate, explaining 35%
      of the total variation. The density of myogenic progenitor cells was quantified
      using an antibody to c-met and was approximately 2-fold higher in the ambient
      than in the heated group, equivalent to 2-3% of the total muscle nuclei. The
      number of myonuclei in isolated fibre segments showed a linear relationship with
      fibre diameter. On average, there were 20.6% more myonuclei in 200-microm
      diameter fibres isolated from the ambient (3734 myonuclei cm(-1)) than from the
      heated (3097 myonuclei cm(-1)) treatments. The maximum fibre diameter was greater
      in heated than in ambient groups, whereas the age x treatment interaction was not
      significantly different (ANCOVA). There were also no consistent differences in
      the rate of hypertrophy of muscle fibres between treatments. It was concluded
      that freshwater temperature regime affected fibre number and the nuclear content
      of fast muscle in seawater but not the rate of fibre hypertrophy. The mechanisms
      and life history consequences of developmental plasticity in fibre number are
      discussed.

PMID- 12624170
TI  - Serotonin modulates the electric waveform of the gymnotiform electric fish
      Brachyhypopomus pinnicaudatus.
AB  - The gymnotiform electric fish Brachyhypopomus pinnicaudatus communicates with a
      sexually dimorphic electric waveform, the electric organ discharge (EOD). Males
      display pronounced circadian rhythms in the amplitude and duration of their EODs.
      Changes in the social environment influence the magnitudes of these circadian
      rhythms and also produce more transient responses in the EOD waveforms. Here we
      show that injections of serotonin produce quick, transient, dose-dependent
      enhancements of the male EOD characters similar to those induced by encounters
      with another male. The response to serotonin administered peripherally begins 5
      10 min post injection and lasts approximately 3 h. The magnitude of the response
      to serotonin is tightly associated with the magnitude of the day-to-night swing
      of the circadian rhythm prior to injection. Taken together these findings suggest
      that the male's social environment influences his response to serotonin by
      altering the function of some part of the downstream chain between the serotonin
      receptors and the ion channels involved in control of the EOD waveform. Although
      chronic activation of serotonin circuitry is widely known to elicit subordinate
      behavior, we find that 5-HT initially increases a dominance signal in these fish.
      These findings are consistent with the emerging view that serotonin facilitates
      different adaptive responses to acute and chronic social challenge and stress.

PMID- 12624171
TI  - How cockatiels (Nymphicus hollandicus) modulate pectoralis power output across
      flight speeds.
AB  - The avian pectoralis muscle must produce a varying mechanical power output to
      achieve flight across a range of speeds (1-13 m s(-1)). We used the natural
      variation in the power requirements with flight speed to investigate the
      mechanisms employed by cockatiels (Nymphicus hollandicus) to modulate muscle
      power output. We found that pectoralis contractile function in cockatiels was
      generally conserved across speed and over a wide range of aerodynamic power
      requirements. Despite the 2-fold range of variation in muscle power output, many
      aspects of muscle performance varied little: duration of muscle shortening was
      invariant, and overall wingbeat frequency and muscle strain varied to a lesser
      degree (1.2-fold and 1.4-fold, respectively) than muscle power or work. Power
      output was primarily modulated by muscle force (accounting for 65% of the
      variation) rather than by muscle strain, cycle frequency or changes in the timing
      of force production relative to muscle strain. Strain rate and electromyogram
      (EMG) results suggest that the additional force was provided via increasing
      pectoralis recruitment. Due to their effect on the transformation of muscle work
      into useful aerodynamic work, changes in wing position and orientation during the
      downstroke probably also affect the magnitude of muscle force developed for a
      given level of motor recruitment. Analysis of the variation in muscle force and
      airflow over the wing suggests that the coefficients of lift and drag of the wing
      vary 4-fold over the speed range examined in this study.

PMID- 12624172
TI  - Whole-body mechanics and gaits in the gray short-tailed opossum Monodelphis
      domestica: integrating patterns of locomotion in a semi-erect mammal.
AB  - Gaits (footfall patterns) and external mechanical energy patterns of the center
      of mass were quantified in a generalized, semi-erect mammal in order to address
      three general questions. First, do semi-erect mammals exhibit the walk/run gait
      transitions that have been proposed as the primitive condition for tetrapods?
      Second, do small, semi-erect mammals employ the energy-saving pendular and spring
      based mechanics used by erect mammals? Third, how well do mechanical locomotor
      patterns of the center of mass correlate with gaits? Monodelphis domestica
      utilizes only fast walking and running trot gaits over a fivefold increase in
      speed, over which we could illicit constant velocity steps, although running
      trots were their preferred gait. In sustained level locomotion the opossums did
      not use other walking gaits presumed to be primitive for tetrapods. Across the
      full range of speeds their trotting gaits exhibited force patterns and in-phase
      mechanical energy fluctuations that are characteristic of spring-mass mechanics.
      Thus, opossums appear to prefer trotting gaits with bouncing mechanics for
      sustained locomotion. Integration of center-of-mass versus footfall perspectives
      reveals that spring-mass mechanics is associated with both walking trot and
      running trot gaits. Furthermore, the onset of an aerial phase was not clearly
      associated with either the walk/run gait transition (50% duty factor) or a change
      in center-of-mass mechanics. The assumption that energy-saving mechanisms are
      ubiquitous among mammals is tenuous because small non-cursorial mammals do not
      appear to use pendular-based mechanics for sustained locomotion and, although
      they prefer spring-based mechanics, they probably lack clear musculoskeletal
      spring elements that could store energy during running. Thus, it appears that
      simply paying for locomotion with muscular work may be the primitive condition
      for mammals.

PMID- 12624173
TI  - Water regulates oxygen binding in hagfish (Myxine glutinosa) hemoglobin.
AB  - Hagfish hemoglobin (Hb) is considered to represent a transition stage between
      invertebrate and vertebrate hemoglobins. The Hb system of Myxine glutinosa
      consists of three monomeric hemoglobins, which upon deoxygenation associate to
      form primarily heterodimers and heterotetramers. Myxine glutinosa is an
      osmoconformer, whose red blood cells show the exceptional ability to swell and
      remain swollen under hyposmotic conditions. In order to determine whether water
      activity regulates hemoglobin function, the effect of changes in osmolality on
      hemoglobin-O(2) affinity was investigated by applying the osmotic stress method
      to purified hemoglobins as well as intact red blood cells. Oxygen affinity
      decreases when water activity increases, indicating that water molecules
      stabilize the low-affinity, oligomeric state of the hemoglobin. This effect is
      opposite to that observed in tetrameric vertebrate hemoglobins, but resembles
      that seen in the dimeric hemoglobin of the marine clam Scapharca inaequivalvis.
      Our data show that water may act as an allosteric effector for hemoglobin within
      intact red cells and even in animals that do not experience large variations in
      blood osmolality.

PMID- 12624174
TI  - Comparative equilibrium mechanical properties of bovine and lamprey cartilaginous
      tissues.
AB  - In contrast to all other vertebrate cartilages, the major extracellular matrix
      protein of lamprey cartilages is not collagen. Instead, there exists a unique
      family of noncollagenous structural proteins, the significance of which is not
      completely understood. A custom-built uniaxial testing apparatus was used to
      quantify and compare equilibrium stress-relaxation behavior (equilibrium moduli,
      stress decay behavior, recovery times and relaxation times) of (1) lamprey
      pericardial cartilages with perichondria tested in tension (young adult and
      aged), (2) annular cartilages without perichondria tested in compression (young
      adult and aged) and (3) bovine auricular cartilage samples without perichondria
      tested in both tension and compression. Results of this study demonstrated that
      all cartilages were highly viscoelastic but with varying relaxation times;
      approximately 120 min for annular and pericardial cartilages and 30 min for
      bovine auricular cartilages. For mean equilibrium moduli, young adult lamprey
      annular cartilages (0.71 MPa) and pericardial cartilages (2.87 MPa) were found to
      be statistically different. The mean moduli of all bovine auricular cartilages
      were statistically identical to lamprey cartilages except in the case of aged
      adult pericardial cartilages, which were statistically larger than all other
      cartilages at 4.85 MPa. Taken together, the results of this study suggest that
      lamprey cartilages are able to exhibit mechanical properties largely similar to
      those of mammalian cartilages despite unique structural proteins and differences
      in extracellular matrix organization.

PMID- 12624175
TI  - Direct evidence for the role of pigment cells in the brain of ascidian larvae by
      laser ablation.
AB  - The anterior sensory vesicle of ascidian larvae contains a single large vesicle
      in which lie two distinct types of pigment cells, anterior and posterior. The
      ultrastructure of these pigment cells suggests that the anterior pigment cell is
      an otolith, presumably used for gravity detection, and the posterior pigment cell
      is an ocellus, used for photoreception. However, there is no direct experimental
      evidence for this assignment of function. Upward swimming behaviour occurring
      during the initial period of larval life was examined before and after laser
      ablation of the anterior pigment and posterior pigment cells. Posterior pigment
      cell-ablated larvae retained the upward swimming behaviour, but anterior pigment
      cell-ablated larvae lost it. These results suggest that the anterior pigment acts
      as a gravity sensor. The negatively phototactic swimming during the latter part
      of larval life was also examined before and after laser ablation of the anterior
      pigment or posterior pigment cells. Anterior pigment cell-ablated larvae retained
      the phototactic response, but posterior pigment cell-ablated larvae lost it.
      These results suggest that the posterior pigment of the sensory vesicle is
      involved in the negatively phototactic, downward swimming behavior. The effect of
      pressure on swimming behaviour was studied, and a putative pressure-detection
      organ was found not to be involved in the larval swimming behaviour. These are
      the first published experimental results that permit a functional role in
      ascidian larval behavior to be assigned to the sensory organs.

PMID- 12624176
TI  - Low turnover rates of carbon isotopes in tissues of two nectar-feeding bat
      species.
AB  - Stable isotopes of carbon are commonly used to characterize dietary preferences
      in animals. Because turnover rates of carbon isotopes are related to metabolic
      rate, we wanted to determine the rates at which carbon isotopes are exchanged in
      tissues of two species of nectar-feeding bats (Leptonycteris curasoae and
      Glossophaga soricina), both of which have relatively high mass-specific metabolic
      rates. To test the hypothesis that isotope turnover is higher in nectar-feeding
      bats, because of their high mass-specific metabolic rates, than in other
      eutherian mammals, we conducted diet-switching experiments and chose three target
      tissues (hair, wing membrane and blood) to evaluate the isotopic turnover rates.
      We made the following predictions: (1) isotopic composition should change towards
      higher delta(13)C-values due to the turnover of carbon isotopes of C(3) origin
      with those of C(4)/CAM origin; (2) the turnover rates of carbon isotopes would
      differ between the three types of tissues in the following order of decreasing
      turnover rates: blood>wing membrane>hair; and (3) turnover rates of nectar
      feeding bats should exceed those reported for other small mammals because of the
      high mass-specific metabolic rate of nectar-feeding bats. Compared to the initial
      diet, target tissues were enriched in heavy carbon isotopes by 2.8 per thousand
      in L. curasoae and by 2.6 per thousand in G. soricina. After changing the diet
      from C(3) to C(4)/CAM origin we found an increase in abundance of (13)C in blood
      and wing membrane in all experimental subjects. The estimated half life of carbon
      isotope turnover ranged from 100 to 134 days and did not differ significantly
      between blood and wing membrane, nor did it differ between the two species. The
      low turnover rate in wing membrane may reflect its specific composition and the
      relatively low temperature of this tissue, and long-lived erythrocytes in bat
      blood may be responsible for the low turnover rate of carbon isotopes in blood.
      The turnover rate of stable carbon isotopes in hair was low in L. curasoae and
      undetectable in G. soricina, which may be explained by the seasonal growth of the
      hair in these two species. Because both species are small (10 and 25 g,
      respectively) and nectar-feeding bats have higher mass-specific metabolic rates
      than bats in temperate regions or similar sized terrestrial mammals, our findings
      of low turnover rates were unexpected.

PMID- 12624177
TI  - Fluid core size of Mars from detection of the solar tide.
AB  - The solar tidal deformation of Mars, measured by its k2 potential Love number,
      has been obtained from an analysis of Mars Global Surveyor radio tracking. The
      observed k2 of 0.153 +/- 0.017 is large enough to rule out a solid iron core and
      so indicates that at least the outer part of the core is liquid. The inferred
      core radius is between 1520 and 1840 kilometers and is independent of many
      interior properties, although partial melt of the mantle is one factor that could
      reduce core size. Ice-cap mass changes can be deduced from the seasonal
      variations in air pressure and the odd gravity harmonic J3, given knowledge of
      cap mass distribution with latitude. The south cap seasonal mass change is about
      30 to 40% larger than that of the north cap.

PMID- 12624178
TI  - BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for
      apoptosis.
AB  - BAX and BAK are "multidomain" proapoptotic proteins that initiate mitochondrial
      dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic
      fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced
      resting concentration of calcium in the ER ([Ca2+]er) that results in decreased
      uptake of Ca2+ by mitochondria after Ca2+ release from the ER. Expression of
      SERCA (sarcoplasmic-endoplasmic reticulum Ca2+ adenosine triphosphatase)
      corrected [Ca2+]er and mitochondrial Ca2+ uptake in DKO cells, restoring
      apoptotic death in response to agents that release Ca2+ from intracellular stores
      (such as arachidonic acid, C2-ceramide, and oxidative stress). In contrast,
      targeting of BAX to mitochondria selectively restored apoptosis to "BH3-only"
      signals. A third set of stimuli, including many intrinsic signals, required both
      ER-released Ca2+ and the presence of mitochondrial BAX or BAK to fully restore
      apoptosis. Thus, BAX and BAK operate in both the ER and mitochondria as an
      essential gateway for selected apoptotic signals.

PMID- 12624179
TI  - Microstructural optimization of a zeolite membrane for organic vapor separation.
AB  - A seeded growth method for the fabrication of high-permeance, high-separation
      factor zeolite (siliceous ZSM-5, [Si96O192]-MFI) membranes is reported. The
      method consists of growing the crystals of an oriented seed layer to a well
      intergrown film by avoiding events that lead to a loss of preferred orientation,
      such as twin overgrowths and random nucleation. Organic polycations are used as
      zeolite crystal shape modifiers to enhance relative growth rates along the
      desirable out-of-plane direction. The polycrystalline films are thin
      (approximately 1 micrometer) with single grains extending along the film
      thickness and with large in-plane grain size (approximately 1 micrometer). The
      preferred orientation is such that straight channels with an open diameter of
      approximately 5.5 angstroms run down the membrane thickness. Comparison with
      previously reported membranes shows that these microstructurally optimized films
      have superior performance for the separation of organic mixtures with components
      that have small differences in size and shape, such as xylene isomers.

PMID- 12624180
TI  - Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty
      acid synthesis.
AB  - Insig-1 and -2 are closely related proteins of the endoplasmic reticulum (ER)
      that block proteolytic activation of sterol regulatory element-binding proteins
      (SREBPs), transcription factors that activate the synthesis of cholesterol and
      fatty acids in liver and other organs. When cellular cholesterol levels are high,
      Insig proteins bind and trap SREBP cleavage-activating protein (SCAP), retaining
      it in the ER and preventing it from escorting SREBPs from ER to the site of
      proteolytic activation in the Golgi complex. Here, we report the discovery of a
      liver-specific transcript of Insig-2, designated Insig-2a. This transcript and
      the ubiquitous transcript, designated Insig-2b, differ through the use of
      different promoters that produce different noncoding first exons that splice into
      a common second exon. Although the Insig-2a and -2b mRNAs encode identical
      proteins, they differ in patterns of regulation. Insig-2a is the predominant
      transcript in livers of fed animals, and it is selectively down-regulated by
      insulin. Insig-2a mRNA increases when mice are fasted, and it declines when they
      are refed. The transcript also increases in livers of rats whose insulin
      secreting pancreatic beta cells have been destroyed by streptozotocin, and it is
      reduced when insulin is injected. The insulin-mediated fall in Insig-2a may allow
      SREBP-1c to be processed, thereby allowing insulin to stimulate fatty acid
      synthesis, even under conditions in which hepatic cholesterol levels are
      elevated.

PMID- 12624181
TI  - Altered properties of quantal neurotransmitter release at endplates of mice
      lacking P/Q-type Ca2+ channels.
AB  - Transmission at the mouse neuromuscular junction normally relies on P/Q-type
      channels, but became jointly dependent on both N- and R-type Ca(2+) channels when
      the PQ-type channel alpha(1A) subunit was deleted. R-type channels lay close to
      Ca(2+) sensors for exocytosis and I(K(Ca)) channel activation, like the P/Q-type
      channels they replaced. In contrast, N-type channels were less well localized,
      but abundant enough to influence secretion strongly, particularly when action
      potentials were prolonged. Our data suggested that active zone structures may
      select among multiple Ca(2+) channels in the hierarchy P/Q >R >N. The alpha(1A)-/
      neuromuscular junction displayed several other differences from wild-type:
      lowered quantal content but greater ability to withstand reductions in the
      Ca(2+)/Mg(2+) ratio, and little or no paired-pulse facilitation, the latter
      findings possibly reflecting compensatory mechanisms at individual release sites.
      Changes in presynaptic function were also associated with a significant reduction
      in the size of postsynaptic acetylcholine receptor clusters.

PMID- 12624182
TI  - The spatial targeting and nuclear matrix binding domains of SRm160.
AB  - The Ser-Arg (SR)-related protein SRm160 is a coactivator of pre-mRNA splicing. It
      bridges splicing factors located at the 5' splice site, branch site, and 3'
      splice site. Recently, SRm160 has also been shown to be involved in mRNA export
      as part of an exon-junction complex. SRm160 is highly concentrated in splicing
      speckles but is also present in long branched intranuclear tracks connecting
      splicing speckles with sites at the nuclear lamina. In this study we identified
      domains of SRm160 important for spatial targeting within the nucleus and for
      binding to the nuclear matrix. Using a series of FLAG- and enhanced GFP
      conjugated deletion mutants we found two contiguous sequences that independently
      target SRm160 to nuclear matrix sites at splicing speckled domains: amino acids
      300-350 and 351-688. Constructs containing amino acids 300-350 were also targeted
      to sites peripheral to speckled domains where most mRNA originate subsequent to
      splicing. Sequences from the N-terminal domain localized proteins to the nuclear
      lamina near sites where mRNA leaves the nucleus.

PMID- 12624183
TI  - Large-scale delineation of secreted protein biomarkers overexpressed in cancer
      tissue and serum.
AB  - Genetic alterations in tumor cells often lead to the emergence of growth
      stimulatory autocrine and paracrine signals, involving overexpression of secreted
      peptide growth factors, cytokines, and hormones. Increased levels of these
      soluble proteins may be exploited for cancer diagnosis and management or as
      points of therapeutic intervention. Here, we combined the use of controlled
      vocabulary terms and sequence-based algorithms to predict genes encoding secreted
      proteins from among approximately 12,500 sequences represented on oligonucleotide
      microarrays. Expression of these genes was queried in 150 carcinomas from 10
      anatomic sites of origin and compared with 46 normal tissues derived from the
      corresponding sites of tumor origin and other body tissues and organs. Of 74
      different genes identified as overexpressed in cancer tissues, several encode
      proteins with demonstrated clinical diagnostic application, such as alpha
      fetoprotein in liver carcinoma, and kallikreins 6 and 10 in ovarian cancer, or
      therapeutic utility, such as gastrin-releasing peptide/bombesin in lung
      carcinomas. We show that several of the other candidate genes encode proteins
      with high levels of tumor-associated expression by immunohistochemistry on tissue
      microarrays and further demonstrate significantly elevated levels of another
      novel candidate protein, macrophage inhibitory cytokine 1, a distant member of
      the transforming growth factor-beta superfamily, in the serum of patients with
      metastatic prostate, breast, and colorectal carcinomas. Our results suggest that
      the combination of annotation/protein sequence analysis, transcript profiling,
      immunohistochemistry, and immunoassay is a powerful approach for delineating
      candidate biomarkers with potential clinical significance and may be broadly
      applicable to other human diseases.

PMID- 12624185
TI  - Long-term correction of globotriaosylceramide storage in Fabry mice by
      recombinant adeno-associated virus-mediated gene transfer.
AB  - Fabry disease is an X-linked recessive inborn metabolic disorder characterized by
      systemic and vascular accumulation of globotriaosylceramide (Gb(3)) caused by a
      deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). The
      condition is associated with an increased morbidity and mortality due to renal
      failure, cardiac disease, and early onset of stroke. Hemizygous males are
      primarily affected clinically with variable expression in heterozygous females.
      Gene-therapy trials have been initiated recently in alpha-gal A knockout mouse
      models of Fabry disease by using a variety of viral vectors. In the present
      investigation we administered single i.v. injections of 1 x 10(10) genomes of
      recombinant adeno-associated virus (rAAV) encoding the human alpha-gal A gene
      driven by a modified chicken beta-actin (CAG) promoter to alpha-gal A knockout
      (Fabry) mice. Transgenic mice were analyzed for expression of alpha-gal A
      activity and Gb(3) levels in liver, kidney, heart, spleen, small intestine, lung,
      and brain. Administration of the rAAV-CAG-hAGA vector resulted in stable
      expression of alpha-gal A in organs of the Fabry mice for >6 months. alpha-Gal A
      activity in the organs became equal to or higher than that of wild-type mice.
      Accumulated Gb(3) in the liver, heart, and spleen was reduced to that of wild
      type mice with lesser but significant reductions in kidney, lung, and small
      intestine. Injection of the rAAV-CAG-hAGA construct into skeletal muscle did not
      result in expression of alpha-gal A in it or in other tissues. This study
      provides a basis for a simple and efficient gene-therapy approach for patients
      with Fabry disease and is indicative of its potential for the treatment of other
      lysosomal storage disorders.

PMID- 12624184
TI  - Displacement of the tyrosyl radical cofactor in ribonucleotide reductase obtained
      by single-crystal high-field EPR and 1.4-A x-ray data.
AB  - The R2 protein of class I ribonucleotide reductase generates and stores a tyrosyl
      radical essential for ribonucleotide reduction and, thus, DNA synthesis. X-ray
      structures of the protein have enabled detailed mechanistic suggestions, but no
      structural information has been available for the active radical-containing state
      of the protein. Here we report on methods to generate the functional tyrosyl
      radical in single crystals of R2 from Escherichia coli (Y122(*)). We further
      report on subsequent high-field EPR experiments on the radical-containing
      crystals. A full rotational pattern of the spectra was collected and the
      orientation of the g-tensor axes were determined, which directly reflect the
      orientation of the radical in the crystal frame. The EPR data are discussed in
      comparison with a 1.42-A x-ray structure of the met (oxidized) form of the
      protein, also presented in this paper. Comparison of the orientation of the
      radical Y122(*) obtained from high-field EPR with that of the reduced tyrosine
      Y122-OH reveals a significant rotation of the tyrosyl side chain, away from the
      diiron center, in the active radical state. Implications for the radical transfer
      connecting the diiron site in R2 with the substrate-binding site in R1 are
      discussed. In addition, the present study demonstrates that structural and
      functional information about active radical states can be obtained by combined x
      ray and high-field EPR crystallography.

PMID- 12624186
TI  - The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease
      inhibitors.
AB  - CD8+ cells from healthy HIV-infected individuals can suppress HIV replication in
      infected CD4(+) cells without killing the cells. This CD8+ cell noncytotoxic
      antiviral response (CNAR), observed by coculture of CD8+ cells with infected CD4+
      cells, is associated with secretion of a CD8+ cell antiviral factor (CAF). In
      attempts to identify CAF, we discovered that certain protease inhibitors,
      particularly leupeptin, can block, by up to 95%, the anti-HIV activity in CD8+
      cell culture fluids as well as inhibit CNAR. The effect is dose-dependent and is
      observed in up to 70% of the CAF and CNAR assays by using fluids and cells from
      several different subjects. Pretreatment of CD8+ cells with leupeptin reduces
      CNAR, further supporting an inhibitory effect on a CD8+ cell product. This
      inhibitory activity of protease inhibitors does not affect cell growth,
      expression of activation antigens, or viability of either CD8+ cells or the
      infected CD4+ cells. The results suggest that a part of the CD8+ cell
      noncytotoxic response involves the activity of a protease or a protein that
      interacts with protease inhibitors. Proteolysis of a CD8+ cell product(s) may be
      involved. This observation offers a promising approach for identifying the
      mechanism of CNARCAF activity.

PMID- 12624187
TI  - A high-throughput gene expression analysis technique using competitive PCR and
      matrix-assisted laser desorption ionization time-of-flight MS.
AB  - We report here an approach for gene expression analysis by combining competitive
      PCR and matrix-assisted laser desorption ionization time-of-flight MS. A DNA
      standard is designed with an artificial single nucleotide polymorphism in the
      gene of interest. The standard is added to the reverse transcription product
      before PCR. Subsequently, a base extension reaction is carried out at the single
      nucleotide polymorphism position, and the products are quantified by matrix
      assisted laser desorption ionization time-of-flight MS. The approach is capable
      of relative and absolute quantification of gene expression; it is extremely
      sensitive (as few as five copies of DNA were quantified) and highly reproducible.
      It is also capable of simultaneous quantification of both alleles for
      heterozygotes and alternatively spliced genes. We have incorporated this
      technique with the homogeneous Mass Extension system (Sequenom) to create a high
      throughput, automated gene expression analysis platform where a few hundred genes
      from 20-500 different samples can be accurately quantified per day.

PMID- 12624188
TI  - Loss of p16INK4a results in increased glucocorticoid receptor activity during
      fibrosarcoma development.
AB  - Glucocorticoids inhibit proliferation of many cell types, but the relationship
      between the glucocorticoid receptor (GR) and the proteins regulating cell cycle
      progression is not fully understood. We previously found that during fibrosarcoma
      (FS) progression, GR displays only modest transcriptional activity in the
      preneoplastic stages, whereas it is highly active in FS cells. Now, we report
      that glucocorticoids reduce proliferation throughout FS development. The cyclin
      dependent kinase inhibitor p16(INK4a) is frequently absent in many cancers,
      including FSs. We observed that p16(INK4a) protein expression is lost at the
      tumor stage of FS progression. Treatment with the demethylating agent 5-aza-2'
      deoxycytidine restores p16(INK4a) expression and reverts the phenotype of FS
      cells to low GR transcriptional activity, similar to that of the p16(INK4a)
      expressing preneoplastic stages. Importantly, exogenous p16(INK4a) introduced by
      cotransfection is sufficient to reduce GR activity in FS cells, without affecting
      GR activity in p16-positive aggressive fibromatosis cells. Furthermore, GR
      transcriptional activity is elevated in mouse embryo fibroblasts derived from
      INK4a(-/-) mice compared with those derived from WT mice, implying that the
      difference in p16(INK4a) expression is sufficient to modulate GR activity. These
      results suggest a relationship between steroid hormone receptor activity and cell
      cycle inhibition, whereby absence of p16(INK4a) protein leads to higher GR
      transactivation activity and reduced cell sensitivity to dexamethasone. This
      observation might have important implications for current cancer therapies.

PMID- 12624189
TI  - Increasing vitamin C content of plants through enhanced ascorbate recycling.
AB  - Vitamin C (ascorbic acid) is essential to prevent disease associated with
      connective tissue (e.g., scurvy), improves cardiovascular and immune cell
      functions, and is used to regenerate alpha-tocopherol (vitamin E). In contrast to
      most animals, humans lack the ability to synthesize ascorbic acid as a result of
      a mutation in the last enzyme required for ascorbate biosynthesis. Vitamin C,
      therefore, must be obtained from dietary sources and, because it cannot be stored
      in the body, it must be obtained regularly. Once used, ascorbic acid can be
      regenerated from its oxidized form in a reaction catalyzed by dehydroascorbate
      reductase (DHAR). To examine whether overexpression of DHAR in plants would
      increase the level of ascorbic acid through improved ascorbate recycling, a DHAR
      cDNA from wheat was isolated and expressed in tobacco and maize, where DHAR
      expression was increased up to 32- and 100-fold, respectively. The increase in
      DHAR expression increased foliar and kernel ascorbic acid levels 2- to 4-fold and
      significantly increased the ascorbate redox state in both tobacco and maize. In
      addition, the level of glutathione, the reductant used by DHAR, also increased,
      as did its redox state. These results demonstrate that the vitamin C content of
      plants can be elevated by increasing expression of the enzyme responsible for
      recycling ascorbate.

PMID- 12624191
TI  - Are dental diseases examples of ecological catastrophes?
AB  - Dental diseases are among the most prevalent and costly diseases affecting
      industrialized societies, and yet are highly preventable. The microflora of
      dental plaque biofilms from diseased sites is distinct from that found in health,
      although the putative pathogens can often be detected in low numbers at normal
      sites. In dental caries, there is a shift towards community dominance by
      acidogenic and acid-tolerant Gram-positive bacteria (e.g. mutans streptococci and
      lactobacilli) at the expense of the acid-sensitive species associated with sound
      enamel. In contrast, the numbers and proportions of obligately anaerobic
      bacteria, including Gram-negative proteolytic species, increase in periodontal
      diseases. Modelling studies using defined consortia of oral bacteria grown in
      planktonic and biofilm systems have been undertaken to identify environmental
      factors responsible for driving these deleterious shifts in the plaque
      microflora. Repeated conditions of low pH (rather than sugar availability per se)
      selected for mutans streptococci and lactobacilli, while the introduction of
      novel host proteins and glycoproteins (as occurs during the inflammatory response
      to plaque), and the concomitant rise in local pH, enriched for Gram-negative
      anaerobic and asaccharolytic species. These studies emphasized (a). significant
      properties of dental plaque as both a biofilm and a microbial community, and (b).
      the dynamic relationship existing between the environment and the composition of
      the oral microflora. This research resulted in a novel hypothesis (the
      'ecological plaque hypothesis') to better describe the relationship between
      plaque bacteria and the host in health and disease. Implicit in this hypothesis
      is the concept that disease can be prevented not only by directly inhibiting the
      putative pathogens, but also by interfering with the environmental factors
      driving the selection and enrichment of these bacteria. Thus, a more holistic
      approach can be taken in disease control and management strategies.

PMID- 12624192
TI  - Prokaryotic motility structures.
AB  - Prokaryotes use a wide variety of structures to facilitate motility. The majority
      of research to date has focused on swimming motility and the molecular
      architecture of the bacterial flagellum. While intriguing questions remain,
      especially concerning the specialized export system involved in flagellum
      assembly, for the most part the structural components and their location within
      the flagellum and function are now known. The same cannot be said of the other
      apparati including archaeal flagella, type IV pili, the junctional pore, ratchet
      structure and the contractile cytoskeleton used by a variety of organisms for
      motility. In these cases, many of the structural components have yet to be
      identified and the mechanism of action that results in motility is often still
      poorly understood. Research on the bacterial flagellum has greatly aided our
      understanding of not only motility but also protein secretion and genetic
      regulation systems. Continued study and understanding of all prokaryotic motility
      structures will provide a wealth of knowledge that is sure to extend beyond the
      bounds of prokaryotic movement.

PMID- 12624193
TI  - Formation of the outer layer of the Dictyostelium spore coat depends on the inner
      layer protein SP85/PsB.
AB  - The Dictyostelium spore is surrounded by a 220 microm thick trilaminar coat that
      consists of inner and outer electron-dense layers surrounding a central region of
      cellulose microfibrils. In previous studies, a mutant strain (TL56) lacking three
      proteins associated with the outer layer exhibited increased permeability to
      macromolecular tracers, suggesting that this layer contributes to the coat
      permeability barrier. Electron microscopy now shows that the outer layer is
      incomplete in the coats of this mutant and consists of a residual regular array
      of punctate electron densities. The outer layer is also incomplete in a mutant
      lacking a cellulose-binding protein associated with the inner layer, and these
      coats are deficient in an outer-layer protein and another coat protein. To
      examine the mechanism by which this inner-layer protein, SP85, contributes to
      outer-layer formation, various domain fragments were overexpressed in forming
      spores. Most of these exert dominant negative effects similar to the deletion of
      outer-layer proteins, but one construct, consisting of a fusion of the N-terminal
      and Cys-rich C1 domain, induces a dense mat of novel filaments at the surface of
      the outer layer. Biochemical studies show that the C1 domain binds cellulose, and
      a combination of site-directed mutations that inhibits its cellulose-binding
      activity suppresses outer-layer filament induction. The results suggest that, in
      addition to a previously described early role in regulating cellulose synthesis,
      SP85 subsequently contributes a cross-bridging function between cellulose and
      other coat proteins to organize previously unrecognized structural elements in
      the outer layer of the coat.

PMID- 12624190
TI  - Non-heme iron protein: a potential target of nitric oxide in acute cardiac
      allograft rejection.
AB  - We examined iron nitrosylation of non-heme protein and enzymatic activity of the
      Fe-S cluster protein, aconitase, in acute cardiac allograft rejection.
      Heterotopic transplantation of donor hearts was performed in histocompatibility
      matched (isografts: Lewis --> Lewis) and mismatched (allografts: Wistar-Furth -->
      Lewis) rats. On postoperative days (POD) 4-6, Western blot analysis and
      immunohistochemistry revealed inducible nitric-oxide synthase (iNOS) protein in
      allografts but not isografts. EPR spectroscopy revealed background signals at g =
      2.003 (for semiquinone) and g = 2.02 and g = 1.94 (for Fe-S cluster protein) in
      isografts and normal hearts. In contrast, in allografts on POD4, a new axial
      signal at g = 2.04 and g = 2.02 appeared that was attributed to the dinitrosyl
      iron complex formed by nitrosylation of non-heme protein. Appearance of this
      signal occurred at or before significant nitrosylation of heme protein. Iron
      nitrosylation of non-heme protein was coincidental with decreases in the
      nonnitrosylated Fe-S cluster signal at g = 1.94. Aconitase enzyme activity was
      decreased to approximately 50% of that observed in isograft controls by POD4.
      Treatment with cyclosporine blocked the (i) elevation of plasma nitrate +
      nitrite, (ii) up-regulation of iNOS protein, (iii) decrease in Fe-S cluster EPR
      signal, (iv) formation of dinitrosyl-iron complexes, and (v) loss of aconitase
      enzyme activity. Formation of dinitrosyl-iron complexes and loss of aconitase
      activity within allografts also was inhibited by treatment of recipients with a
      selective iNOS inhibitor, l-N(6)-(1-iminoethyl)lysine. This report shows
      targeting of an important non-heme Fe-S cluster protein in acute solid organ
      transplant rejection.

PMID- 12624194
TI  - Cell line differences in bacterially translocated ExoS ADP-ribosyltransferase
      substrate specificity.
AB  - Exoenzyme S (ExoS) is an ADP-ribosyltransferase (ADPRT) directly translocated
      into eukaryotic cells by the type III secretory (TTS) process of Pseudomonas
      aeruginosa. Comparisons of the functional effects of ExoS on human epithelial and
      murine fibroblastic cells showed that human epithelial cells exhibited an overall
      increased sensitivity to the effects of bacterially translocated ExoS on cell
      proliferation, morphology and re-adherence. ExoS was also found to ADP-ribosylate
      a greater number of low-molecular-mass G (LMMG) proteins in human epithelial
      cells, as compared to murine fibroblasts. Examination of the cellular mechanism
      for differences in ExoS ADPRT substrate modification found that the more
      restricted pattern of substrate modification in murine fibroblasts was not linked
      to the efficiency of bacterial adherence nor to the efficiency of ExoS
      internalization by the TTS process. In exploring the cellular nature of patterns
      of substrate modification, more extensive substrate modification was detected in
      human and simian cell lines, while rodent cell lines, including rat, mouse and
      hamster lines, consistently exhibited the more limited pattern of LMMG protein
      ADP-ribosylation. Patterns of substrate modification were not altered by cellular
      transformation and occurred independently of cell type. These studies suggest
      that eukaryotic cell properties, as recognized through studies of cells of
      different animal origins, affect the substrate targeting of ExoS ADPRT activity,
      and that this in turn can influence the severity of effects of ExoS on host-cell
      function.

PMID- 12624196
TI  - Cell-type-dependent repression of yeast a-specific genes requires Itc1p, a
      subunit of the Isw2p-Itc1p chromatin remodelling complex.
AB  - In Saccharomyces cerevisiae MATa haploid cells, the a-specific genes are
      expressed, whereas in the MATalpha haploid and MATa/alpha diploid cell types
      their transcription is repressed. It is shown in this report that Itc1p, a
      component of the ATP-dependent Isw2p-Itc1p chromatin remodelling complex, is
      required for the repression of a-specific genes. It has previously been reported
      that disruption of the ITC1 gene leads, in MATalpha cells, to an aberrant cell
      morphology resembling the polarized mating projection of cells responding to
      pheromone. The activation of the pheromone signalling pathway in itc1 mutants of
      both mating types was examined and found to be constitutively active in MATalpha
      itc1 but not in MATa itc1 cells. Furthermore, unlike the wild-type, MATalpha itc1
      and MATa/alpha itc1/itc1 cells secrete a-factor and express significant levels of
      other a-specific genes. The results indicate that the inappropriate a-factor
      production in a MATalpha context, due to the derepression of the a-specific
      genes, produces an autocrine signalling loop that leads to the aberrant
      morphology displayed by MATalpha itc1 cells. It is suggested that the Isw2p-Itc1p
      complex contributes to maintain the repressive chromatin structure described for
      the asg operator present in the promoters of a-specific genes.

PMID- 12624195
TI  - Increased resistance in BALB/c mice to reinfection with Candida albicans is due
      to immunoneutralization of a virulence-associated immunomodulatory protein.
AB  - Here, it is shown that immunoneutralization of p43, a virulence-associated
      immunomodulatory protein secreted by Candida albicans, is responsible for
      immunoprotection against candidiasis after spontaneous healing of mice inoculated
      with 10(6) C. albicans blastoconidia. p43 is produced by the pathogenic Candida
      blastoconidia, and neither immunoprotection nor immunoneutralization can be
      elicited by priming the mice with attenuated or heat-killed C. albicans
      blastoconidia. The immunoprotection against systemic candidiasis was positively
      correlated with (i). serum levels of antibodies against p43 and (ii). a high
      ratio between antibodies against p43 and antibodies against C. albicans
      structural antigens. Immunoprotection against candidiasis can be induced in mice
      primed with heat-killed C. albicans, after treatment of the animals with anti-p43
      antibodies. The data described here provide a biological explanation for active
      immunoprotection achieved after spontaneous healing of infectious diseases,
      namely in candidiasis.

PMID- 12624198
TI  - Studies on distant regulation of bacterial growth and light emission.
AB  - Reciprocal interactions of two Escherichia coli MC1061 cultures separated by a
      glass window were investigated. The growth parameters and light emission from
      these cultures were analysed. A link between light emission and the growth
      parameters was observed.

PMID- 12624197
TI  - Quantitative variation of biofilms among strains in natural populations of
      Candida albicans.
AB  - This study examined the quantitative variation of biofilm formation and its
      relationship to multilocus genotypes in 115 strains of the human pathogenic
      fungus Candida albicans. These strains were isolated from three sources: 47 from
      oral cavities of healthy volunteers, 31 from the environment and 37 from the
      vaginas of patients with candidiasis. For each strain, biofilm formation was
      quantified as the ability to adhere to and grow on polystyrene plastic surfaces.
      Confocal laser scanning microscopy was used to visualize and confirm biofilm
      formation. Two methods were used to quantify biofilm formation abilities: (i).
      the XTT reduction assay, and (ii). absorbance following staining by crystal
      violet dye. Results obtained by the two methods were significantly correlated.
      Furthermore, biofilm formation ability was positively correlated with cell
      surface hydrophobicity. The analyses indicated that strains from each of the
      three sources varied widely in biofilm formation abilities. However, little
      correlation was observed between biofilm formation and multilocus genotypes as
      determined by PCR-RFLP at 16 polymorphic loci, regardless of source of strain.
      Strains with the same or similar multilocus genotypes often showed very different
      biofilm formation abilities. The results demonstrated that natural clones and
      clonal lineages of C. albicans exhibited extensive quantitative variation in
      biofilm formation.

PMID- 12624199
TI  - Effect of temperature, salinity and nutrient content on the survival responses of
      Vibrio splendidus biotype I.
AB  - The aim of this study was to evaluate the survival responses of two strains of
      Vibrio splendidus, both in natural and in defined media. For this purpose,
      freshwater and defined media containing different salinities (3.3-0.9 %) and
      nutrient concentrations (17-0.005 mg x l(-1)) were assayed. The incubation
      temperatures were established at 4, 10 and 22 degrees C. The acridine orange
      staining technique was used for total cell enumeration and the number of viable
      cells was determined using two direct assays, nalidixic acid and tetrazolium salt
      reduction and plate spreading. Resuscitation assays of viable but non-culturable
      (VBNC) cells were conducted. According to the counting procedures employed, at
      least four different subpopulations were found: (i). active (positive response in
      both nalidixic acid and tetrazolium assays) culturable cells; (ii). active non
      culturable cells; (iii). tetrazolium-salt-responsive non-culturable cells and
      (iv). non-active (responsive to none of the direct viable assays) non-culturable
      cells. Long-term survival was found at salinities and nutrient concentrations of
      seawater environments (3.3 % and 5 mg x l(-1) or 1 g l(-1)), whereas the strains
      entered a VBNC state in freshwater and in brackish (0.9 or 1.6 % salinities) or
      high nutrient content (17 g x l(-1)) defined medium. The recovery of VBNC cells
      was not achieved.

PMID- 12624200
TI  - Identification and in vivo characterization of PpaA, a regulator of photosystem
      formation in Rhodobacter sphaeroides.
AB  - A regulatory protein, PpaA, involved in photosystem formation in the anoxygenic
      phototrophic proteobacterium Rhodobacter sphaeroides has been identified and
      characterized in vivo. Based on the phenotypes of cells expressing the ppaA gene
      in extra copy and on the phenotype of the ppaA null mutant, it was concluded that
      PpaA activates photopigment production and puc operon expression under aerobic
      conditions. This is in contrast to the function of the PpaA homologue from
      Rhodobacter capsulatus, AerR, which acts as a repressor under aerobic conditions
      [Dong, C., Elsen, S., Swem, L. R. & Bauer, C. E. (2002). J Bacteriol 184, 2805
      2814]. The expression of the ppaA gene increases several-fold in response to a
      decrease in oxygen tension, suggesting that the PpaA protein is active under
      conditions of low or no oxygen. However, no discernible phenotype of a ppaA null
      mutant was observed under anaerobic conditions tested thus far. The photosystem
      gene repressor PpsR mediates repression of ppaA gene expression under aerobic
      conditions. Sequence analysis of PpaA homologues from several anoxygenic
      phototrophic bacteria revealed a putative corrinoid-binding domain. It is
      suggested that PpaA binds a corrinoid cofactor and the availability or structure
      of this cofactor affects PpaA activity.

PMID- 12624201
TI  - Oxidative-stress-inducible qorA encodes an NADPH-dependent quinone oxidoreductase
      catalysing a one-electron reduction in Staphylococcus aureus.
AB  - This work characterized the putative quinone oxidoreductase gene (qorA) from
      Staphylococcus aureus. The deduced amino acid sequence indicated that the 333 aa
      protein contains an NAD(P)H-binding motif. A Northern blot analysis revealed that
      2.6 kb and 1.4 kb signals were detected by using a qorA probe. Both the signals
      were enhanced under the presence of a redox-cycling agent, 9,10
      phenanthrenequinone (PQ). It was also revealed that the expression of three
      genes, SA1988, SA1989 (qorA) and SA1990, was enhanced at the transcriptional
      level by PQ exposure. The results suggested that the 2.6 kb signal detected by
      the qorA probe was in two co-transcripts, i.e. SA1990-qorA and qorA-SA1988 were
      transcribed. Besides, primer extension analyses confirmed the enhancement of qorA
      and SA1990 transcripts. The GST (glutathione S-transferase)-tagged QorA protein
      was expressed in Escherichia coli and purified using a glutathione affinity
      column. In purification steps, a 36 kDa band co-purified with the GST-QorA, and
      it was detected even in the thrombin-cleaved fraction. N-terminal amino acid
      sequences for the 36 kDa protein revealed that it was an intact QorA. They showed
      that QorA formed a multimer under physiological conditions. The purified
      recombinant GST-QorA catalysed NADPH consumption in the presence of PQ as a
      substrate, but not NADH. To characterize the catalytic activity of QorA,
      superoxide anion that was generated through one-electron reduction of PQ and
      hydroquinone that was produced by two-electron reduction of PQ were measured.
      During reduction of PQ by GST-QorA, superoxide anion was generated, whereas a
      small amount of 9,10-dihydroxyphenanthrene (hydroquinone of PQ) was produced.
      These results suggest that the activity of QorA is similar to zeta-Crystallin,
      catalysing an NADPH-dependent one-electron reduction of quinone.

PMID- 12624202
TI  - An amino acid change near the carboxyl terminus of the Streptococcus gordonii
      regulatory protein Rgg affects its abilities to bind DNA and influence expression
      of the glucosyltransferase gene gtfG.
AB  - The Streptococcus gordonii glucosyltransferase structural gene, gtfG, is located
      immediately downstream from its positive transcriptional regulatory determinant,
      rgg. Recent genetic studies have indicated that the 3' end of rgg is involved
      either directly as a binding site or indirectly, e.g. by playing a role in
      secondary structure, in the interaction of Rgg with the gtfG promoter. A
      previously identified spontaneous mutant with a point mutation near the 3' end of
      rgg had only approximately 25% of the parental level of glucosyltransferase
      activity. To determine if this decreased activity was due to a change in the DNA
      binding site of trans-acting Rgg, or due to a change in the Rgg protein itself,
      complementation analyses and DNA-binding studies were performed. In Rgg-deficient
      strains, the chromosomal rgg point mutation did not influence the ability of
      plasmid-borne rgg to increase glucosyltransferase expression. However, plasmids
      carrying parental rgg were able to increase glucosyltransferase activity and
      expression of a gtfG promoter fusion to a greater extent than plasmids carrying
      the mutant allele, indicating that the mutant Rgg protein had decreased activity.
      The ability of NH(2)-terminal (hexahistidine) tagged proteins to bind to a 107 bp
      dsDNA fragment corresponding to the region immediately upstream of gtfG was
      demonstrated by surface plasmon resonance. Despite their differences in activity,
      both mutant and parental recombinant Rgg proteins bound to this dsDNA, albeit
      with different strengths. These studies provide insights into functional domains
      of S. gordonii Rgg which influence glucosyltransferase expression, and may have
      implications for Rgg-like regulatory proteins in related bacteria.

PMID- 12624203
TI  - Role of the Streptococcus agalactiae ClpP serine protease in heat-induced stress
      defence and growth arrest.
AB  - The main causes of microbial death after heat exposure are not well understood.
      Here, it is shown that the heat-shock protein ClpP plays a major role in heat
      induced growth arrest in Streptococcus agalactiae. A mutant lacking the ClpP
      protease was more sensitive to the inhibitory effects of heat, salt and oxidative
      stress than the isogenic wild-type strain. During growth arrest, this mutant
      displayed important modifications of its total protein content, including a
      decreased level of essential metabolic enzymes such as the alcohol dehydrogenase.
      Analysis of protein carbonylation demonstrated that the ClpP protease plays a
      role in preventing accelerated protein oxidation. Higher levels of oxidized DnaK,
      a key modulator of the heat-shock regulon, were observed in the ClpP mutant and
      these were increased following heat shock. Accumulation of oxidized/inactivated
      DnaK might explain why the ClpP mutant was unable to properly synthesize DNA and
      proteins, and why it exhibited an aberrant cell morphology. Even though ClpP
      plays a minor role in the virulence of S. agalactiae in a murine infection model,
      the data presented here point to the importance of ClpP in oxidative stress
      defence in preventing heat-induced cell alterations.

PMID- 12624204
TI  - Thioredoxin 2 is involved in oxidative stress defence and redox-dependent
      expression of photosynthesis genes in Rhodobacter capsulatus.
AB  - Thioredoxins are small ubiquitous proteins that display different functions
      mainly via redox-mediated processes. The facultatively photosynthetic bacterium
      Rhodobacter capsulatus harbours at least two genes for thioredoxin 1 and 2, trxA
      and trxC. It is demonstrated that thioredoxin 2 of R. capsulatus can partially
      replace the thioredoxin 1 function as a hydrogen donor for methionine sulfoxide
      reductase but cannot replace thioredoxin 1 as a subunit of phage T7 DNA
      polymerase. By inactivating the trxC gene in R. capsulatus, it is shown that
      thioredoxin 2 is involved in resistance against oxidative stress. As thioredoxin
      1 of Rhodobacter sphaeroides, R. capsulatus thioredoxin 2 affects the oxygen
      dependent expression of photosynthesis genes, albeit in an opposite way. The trxC
      mutant of R. capsulatus shows a stronger increase in photosynthesis gene
      expression after a decrease in oxygen tension than the isogenic wild-type strain.
      The expression of the trxC gene is downregulated by oxygen.

PMID- 12624205
TI  - Genes involved in the synthesis of the exopolysaccharide methanolan by the
      obligate methylotroph Methylobacillus sp strain 12S.
AB  - Methylobacillus sp. strain 12S produces an exopolysaccharide (EPS), methanolan,
      composed of glucose, mannose and galactose. Twenty-four ORFs flanking a Tn5
      insertion site in an EPS-deficient mutant were identified, and 21 genes
      (epsCBAKLDEFGHIJMNOPQRSTU) were predicted to participate in methanolan synthesis
      on the basis of the features of the primary sequence. Gene disruption analyses
      revealed that epsABCEFGIJNOP and epsR are required for methanolan synthesis,
      whereas epsKD and epsH are not essential. EpsFG and EpsE showed homology with Wzc
      (chain length regulator) and Wza (export protein) of group 1 capsule-producing
      Escherichia coli, suggesting that methanolan was synthesized via a Wzy-like
      biosynthesis system. This possibility was supported by the fact that the putative
      hydropathy profiles of EpsH and EpsM were similar to those of Wzx and Wzy, which
      are also involved in the flipping of the repeating unit in the cytoplasmic
      membrane and the polymerization of the capsule in the Wzy-dependent system.
      EpsBJNOP and EpsR are probably glycosyltransferases involved in the synthesis of
      the repeating unit onto the lipid carrier. In particular, EpsB appeared to
      catalyse the initial transfer of the glucose moiety. On the basis of their
      predicted location in the cells, it is proposed that EpsI and EpsL are involved
      in methanolan export to the cell surface. E. coli strains expressing EpsQ, EpsS
      and EpsT showed enhanced activities of GDP-mannose pyrophosphorylase, UDP
      galactose 4-epimerase and UDP-glucose pyrophosphorylase, respectively, revealing
      that they were responsible for the production of the activated compositional
      sugars of methanolan. EpsU contains a conserved a lytic transglycosylase motif,
      indicating that it could participate in the degradation of polysaccharides. EpsA
      and EpsK, which have conserved DNA-binding and cAMP-binding motifs, respectively,
      were deduced to be transcriptional regulators. In particular, EpsA seems to
      positively regulate the transcription of methanolan synthesis genes, since the
      constitutive expression of epsA in strain 12S increased the EPS production.
      Interestingly, EpsD showed homology with peptidyl prolyl cis-trans isomerases
      that catalyse the folding of proteins following translocation across the
      cytoplasmic membrane.

PMID- 12624206
TI  - Catalytic properties of an endogenous beta-lactamase responsible for the
      resistance of Azospirillum lipoferum to beta-lactam antibiotics.
AB  - Azospirillum lipoferum RG20, a nitrogen-fixing bacterium found in all kind of
      soils, was found to be naturally resistant to penicillins and cephalosporins. 6
      beta-Bromopenicillanic acid, an irreversible inhibitor of serine-beta-lactamases,
      completely abolished this resistance. A beta-lactamase was purified 518-fold from
      a cell-free extract of A. lipoferum RG20. A single band on SDS-PAGE (apparent
      molecular mass 31000 Da) and on isoelectric focussing (pI9.35) was observed with
      the purified protein. The enzyme hydrolysed benzylpenicillin, ampicillin,
      cephalothin and cephaloridine with comparable k(cat) values and catalytic
      efficiencies. However, carbenicillin and cefotaxime were hydrolysed with
      significantly lower kinetic parameters and oxacillin was hydrolysed at a rate 100
      times slower. The purified beta-lactamase was inhibited by clavulanic acid and
      sulbactam but not by EDTA or aztreonam. Its substrate and inhibitor profiles are
      consistent with those of the broad-spectrum beta-lactamases inhibited by
      clavulanic acid (group 2b of the Bush-Jacoby-Medeiros scheme). The effect of pH
      on k(cat) and K(m) values for benzylpenicillin hydrolysis was studied. The
      dependence of k(cat) on pH suggests that the enzyme-substrate (ES) complex must
      be in at least three protonation states: two with k(cat) values equal to 2800 and
      1450 s(-1) and a third inactive one [pK(1(ES)) 4.7 and pK(2(ES)) 7.9]. Similarly,
      the dependence of k(cat)/K(m) on pH can be explained by postulating that the
      enzyme free form can be at least in three different protonation states: two of
      them with k(cat)/K(m) values equal to 2.7 x 10(6) and 3.7 x 10(8) M(-1) s(-1) and
      a third one unable to productively bind substrate. Interestingly, the dependence
      of k(cat)/K(m) on pH is consistent with positive cooperativity for proton binding
      to the enzyme free form [pK(1(E)) 8.5 and pK(2(E)) 7.2].

PMID- 12624207
TI  - Identification of the essential histidine residue for high-affinity binding of
      AlbA protein to albicidin antibiotics.
AB  - The albA gene from Klebsiella oxytoca encodes a protein that binds albicidin
      phytotoxins and antibiotics with high affinity. Previously, it has been shown
      that shifting pH from 6 to 4 reduces binding activity of AlbA by about 30%,
      indicating that histidine residues might be involved in substrate binding. In
      this study, molecular analysis of the albA coding region revealed sequence
      discrepancies with the albA sequence reported previously, which were probably due
      to sequencing errors. The albA gene was subsequently cloned from K. oxytoca ATCC
      13182(T) to establish the revised sequence. Biochemical and molecular approaches
      were used to determine the functional role of four histidine residues (His(78),
      His(125), His(141) and His(189)) in the corrected sequence for AlbA. Treatment of
      AlbA with diethyl pyrocarbonate (DEPC), a histidine-specific alkylating reagent,
      reduced binding activity by about 95 %. DEPC treatment increased absorbance at
      240-244 nm by an amount indicating conversion to N-carbethoxyhistidine of a
      single histidine residue per AlbA molecule. Pretreatment with albicidin protected
      AlbA against modification by DEPC, with a 1 : 1 molar ratio of albicidin to the
      protected histidine residues. Based on protein secondary structure and amino acid
      surface probability indices, it is predicted that His(125) might be the residue
      required for albicidin binding. Mutation of His(125) to either alanine or leucine
      resulted in about 32 % loss of binding activity, and deletion of His(125) totally
      abolished binding activity. Mutation of His(125) to arginine and tyrosine had no
      effect. These results indicate that His(125) plays a key role either in an
      electrostatic interaction between AlbA and albicidin or in the conformational
      dynamics of the albicidin-binding site.

PMID- 12624208
TI  - Kinetic and phylogenetic characterization of an anaerobic dechlorinating
      microbial community.
AB  - The reductive dechlorination (RD) of tetrachloroethene (PCE) to vinyl chloride
      (VC) and, to a lesser extent, to ethene (ETH) by an anaerobic microbial community
      has been investigated by studying the processes and kinetics of the main
      physiological components of the consortium. Molecular hydrogen, produced by
      methanol-utilizing acetogens, was the electron donor for the PCE RD to VC and ETH
      without forming any appreciable amount of other chlorinated intermediates and in
      the near absence of methanogenic activity. The microbial community structure of
      the consortium was investigated by preparing a 16S rDNA clone library and by
      fluorescence in situ hybridization (FISH). The PCR primers used in the clone
      library allowed the harvest of 16S rDNA from both bacterial and archaeal members
      in the community. A total of 616 clones were screened by RFLP analysis of the
      clone inserts followed by the sequencing of RFLP group representatives and
      phylogenetic analysis. The clone library contained sequences mostly from hitherto
      undescribed bacteria. No sequences similar to those of the known RD bacteria like
      'Dehalococcoides ethenogenes' or Dehalobacter restrictus were found in the clone
      library, and none of these bacteria was present in the RD consortium according to
      FISH. Almost all clones fell into six previously described phyla of the bacterial
      domain, with the majority (56.6 %) being deep-branching members of the
      Spirochaetes phylum. Other clones were in the Firmicutes phylum (18.5 %), the
      Chloroflexi phylum (16.4 %), the Bacteroidetes phylum (6.3 %), the Synergistes
      genus (1.1 %) and a lineage that could not be affiliated with existing phyla (1.1
      %). No archaeal clones were found in the clone library. Owing to the phylogenetic
      novelty of the microbial community with regard to previously cultured micro
      organisms, no specific microbial component(s) could be hypothetically affiliated
      with the RD phenotype. The predominance of Spirochaetes in the microbial
      consortium, the main group revealed by clone library analysis, was confirmed by
      FISH using a purposely developed probe.

PMID- 12624209
TI  - Quorum-sensing-directed protein expression in Serratia proteamaculans B5a.
AB  - N-Acyl-L-homoserine-lactone-producing Serratia species are frequently encountered
      in spoiling foods of vegetable and protein origin. The role of quorum sensing in
      the food spoiling properties of these bacteria is currently being investigated. A
      set of luxR luxI homologous genes encoding a putative quorum sensor was
      identified in the N-(3-oxo-hexanoyl)-L-homoserine lactone (3-oxo-C6-HSL)
      producing Serratia proteamaculans strain B5a. The 3-oxo-C6-HSL synthase SprI
      showed 79 % similarity with EsaI from Pantoea stewartii and the putative
      regulatory protein SprR was 86 % similar to the SpnR of Serratia marcescens.
      Proteome analysis suggested that the presence of at least 39 intracellular
      proteins was affected by the 3-oxo-C6-HSL-based quorum sensing system. The lipB
      encoded secretion system was identified as one target gene of the quorum sensing
      system. LipB was required for the production of extracellular lipolytic and
      proteolytic activities, thus rendering the production of food-deterioration
      relevant exoenzymes indirectly under the control of quorum sensing. Strain B5a
      caused quorum-sensing-controlled spoilage of milk. Furthermore, chitinolytic
      activity was controlled by quorum sensing. This control appeared to be direct and
      not mediated via LipB. The data presented here demonstrate that quorum-sensing
      controlled exoenzymic activities affect food quality.

PMID- 12624210
TI  - Mutation rates: estimating phase variation rates when fitness differences are
      present and their impact on population structure.
AB  - Phase variation is a mechanism of ON-OFF switching that is widely utilized by
      bacterial pathogens. There is currently no standardization to how the rate of
      phase variation is determined experimentally, and traditional methods of mutation
      rate estimation may not be appropriate to this process. Here, the history of
      mutation rate estimation is reviewed, describing the existing methods available.
      A new mathematical model that can be applied to this problem is also presented.
      This model specifically includes the confounding factors of back-mutation and the
      influence of fitness differences between the alternate phenotypes. These are
      central features of phase variation but are rarely addressed, with the result
      that some previously estimated phase variation rates may have been significantly
      overestimated. It is shown that, conversely, the model can also be used to
      investigate fitness differences if mutation rates are approximately known. In
      addition, stochastic simulations of the model are used to explore the impact of
      'jackpot cultures' on the mutation rate estimation. Using the model, the impact
      of realistic rates and selection on population structure is investigated. In the
      absence of fitness differences it is predicted that there will be phenotypic
      stability over many generations. The rate of phenotypic change within a
      population is likely, therefore, to be principally determined by selection. A
      greater insight into the population dynamics of mutation rate processes can be
      gained if populations are monitored over successive time points.

PMID- 12624211
TI  - Spontaneous sequence duplications within capsule genes cap8E and tts control
      phase variation in Streptococcus pneumoniae serotypes 8 and 37.
AB  - Capsule phase variants were isolated from serotype 8 and serotype 37 pneumococcal
      sorbarods. Sequence duplications within the essential capsule genes - cap8E (type
      8) and tts (type 37) - were found to introduce frameshifts and generate acapsular
      phenotypes. Capsular revertants possessed wild-type cap8E and tts genes,
      indicating the precise excision of these duplications. Reversion frequencies (OFF
      ON) fit a linear relationship between log(frequency of reversion) and log(length
      of duplication), previously found for serotype three pneumococci [Waite, R. D.,
      Struthers, J. K. & Dowson, C. G. (2001). Mol Microbiol 42, 1223-1232]. This study
      provides evidence that capsule phase variation can occur in pneumococcal
      serotypes with either simple (one to three genes) or complex capsule-encoding
      loci (12 genes). Given the key role of CapE (the first monosaccharide
      transferase) in other clinically important pneumococci, such as serotypes 14 and
      19F with complex capsular loci, the observed duplication within cap8E suggests
      that capsule phase variation could be controlled by tandem sequence duplication
      in capE homologues in other pneumococcal serotypes that construct their capsules
      through polymerization of lipid-linked intermediates.

PMID- 12624212
TI  - Streptomyces coelicolor A3(2) plasmid SCP2*: deductions from the complete
      sequence.
AB  - Plasmid SCP2* is a 31 kb, circular, low-copy-number plasmid originally identified
      in Streptomyces coelicolor A3(2) as a fertility factor. The plasmid was
      completely sequenced. The analysis of the 31 317 bp sequence revealed 34 ORFs
      encoding putative proteins from 31 to 710 aa long, most of them lacking
      similarity to known proteins. Three functional regions had been identified
      previously: the replication region, the transfer and spreading region, and the
      stability region. Three genes were identified in the stability region which
      contribute to the stability of SCP2 as shown by plasmid stability testing. The
      first gene, mrpA, encodes a new member of the lambda integrase family of site
      specific recombinases. The two genes downstream of mrpA were called parA and
      parB. The gene product, ParA, shows similarity to a family of ATPases involved in
      plasmid partition. An increase of plasmid stability could be seen only when both
      genes were present. By deletion analysis, the replication region could be
      narrowed down to a 1.6 kb region, consisting of a 650 bp non-coding region and
      two genes, repI and repII, encoding proteins of 161 and 131 aa. Only RepI
      exhibits similarities to DNA binding elements and contains a putative helix-turn
      helix motif. The traA gene that is essential for DNA transfer and pock formation
      was identified previously. Upstream of traA, 10 ORFs were found in the same
      orientation as traA which might be involved in conjugation and DNA spreading,
      together with one gene in the opposite orientation with similarities to
      transcriptional regulators of DNA transfer. Two transposable elements were found
      on SCP2*. IS1648 belongs to the IS3 family of insertion sequences. The second
      element, Tn5417, shows the highest similarity to the Tn4811 element located in
      the terminal inverted repeats of the Streptomyces lividans chromosome.

PMID- 12624213
TI  - Two new cellulosome components encoded downstream of celI in the genome of
      Clostridium thermocellum: the non-processive endoglucanase CelN and the possibly
      structural protein CseP.
AB  - Clostridium thermocellum produces a great number of extracellular cellulases
      which are free or cellulosome-bound. The nucleotide sequence of a gene cluster
      containing the genes celI, celN and cseP was determined from C. thermocellum
      strain F7. Gene products Cel9I and Cel9N are structurally related enzymes having
      a glycosyl hydrolase family 9 and a carbohydrate-binding module (CBM3c), but show
      characteristic differences: Cel9I is a non-cellulosomal protein with an
      additional CBM (CBM3b), whereas Cel9N contains a cellulosomal dockerin module and
      no additional CBM. Although Cel9I is a processive endoglucanase, Cel9N is non
      processive. Both enzymes hydrolyse phosphoric acid swollen cellulose, but the
      products of hydrolysis are different. The CseP protein encoded in the gene
      cluster is the first component attached to the cellulosomal scaffoldin for which
      no catalytic activity could be detected. It was shown to be present in the
      cellulosome. Its sequence is homologous to the spore-coat assembly protein CotH
      of Bacillus subtilis, suggesting a structural role of CseP in the cellulosome.

PMID- 12624214
TI  - CsgD, a regulator of curli and cellulose synthesis, also regulates serine
      hydroxymethyltransferase synthesis in Escherichia coli K-12.
AB  - The homologous CsgD and AgfD proteins are members of the FixJ/UhpA/LuxR family
      and are proposed to regulate curli (thin aggregative fibres) and cellulose
      production by Escherichia coli and Salmonella enterica serovar Typhimurium,
      respectively. A plasmid containing part of the csgD gene was isolated during a
      screen for multicopy suppressors of glycine auxotrophy caused by deleting the
      folA gene in E. coli. The sequence of the plasmid suggests it encodes a chimaeric
      protein. Plasmids containing the intact csgD or agfD gene also caused
      suppression. Cells transformed with the recombinant plasmids contained higher
      serine hydroxymethyltransferase (SHMT) activity than controls. The increase could
      also be monitored by assaying beta-galactosidase activity from a reporter strain
      with part of the SHMT gene, glyA, fused to lacZ. The increase in SHMT activity
      was sufficient to correct the glycine auxotrophy of strains lacking folA. The
      recombinant plasmids also enabled K-12 strains that are not curli-proficient to
      make curli. Curlin, the major component of curli, contains more glycine than
      normal E. coli proteins. It is proposed that CsgD upregulates glyA to facilitate
      synthesis of curli. It is suggested that recombinant plasmids produce enough CsgD
      or chimaeric protein to titrate out a ligand that switches CsgD into its inactive
      form. As a result, sufficient active CsgD is present to activate genes in its
      regulon. It is concluded that CsgD increases expression of the glyA gene either
      directly or indirectly.

PMID- 12624215
TI  - The mid genes of Rhizobium sp strain TAL1145 are required for degradation of
      mimosine into 3-hydroxy-4-pyridone and are inducible by mimosine.
AB  - Mimosine is a toxin present in the tree-legume leucaena (Leucaena leucocephala),
      including its root nodules and the root exudates. The leucaena-nodulating
      Rhizobium sp. strain TAL1145 degrades mimosine (Mid(+)) and utilizes it as a
      source of carbon and nitrogen. Twelve TAL1145 mutants defective in mimosine
      degradation (Mid(-)) were made through Tn3Hogus, TnphoA or kanamycin-resistance
      cassette insertions. A 5.0 kb PstI fragment of TAL1145, subcloned from a cosmid
      clone containing mid genes for mimosine degradation, complemented most of the
      Mid(-) mutants. Sequencing this fragment and the adjacent 0.9 kb PstI fragment
      identified five genes, midA, midB, midC, midD and midR, of which the first three
      genes encode ABC transporter proteins involved in mimosine uptake, while midD
      encodes an aminotransferase required for degrading mimosine into 3-hydroxy-4
      pyridone, and midR is a regulatory gene encoding a LysR-type transcriptional
      activator. The location of MidA in the periplasm was shown by making two midA : :
      phoA fusions, which made active alkaline phosphatase in the periplasm. The
      various mid : : gus and midA : : phoA fusions were inducible by mimosine, and a
      midD : : gus fusion mutant showed beta-glucuronidase activity in the leucaena
      nodules, indicating that midD is expressed in the nodules. Similarly, a midA : :
      phoA fusion expressed alkaline phosphatase activity in the leucaena nodules,
      indicating that mimosine induces midA transcription in the bacteroids. mid genes
      are specific for the Mid(+) strains of leucaena Rhizobium and are absent in
      strains of other Rhizobium, Sinorhizobium and Bradyrhizobium spp.

PMID- 12624217
TI  - Monitoring of cerebral vasodilatory capacity with transcranial Doppler carbon
      dioxide inhalation in patients with severe carotid artery disease.
AB  - BACKGROUND AND PURPOSE: Cerebral vasodilatory capacity (CVC) testing with
      transcranial Doppler has been shown to be useful in the assessment of stroke risk
      in patients with symptomatic and asymptomatic internal carotid artery (ICA)
      stenosis and occlusion, but whether hemodynamic status improves, deteriorates, or
      remains the same over time is uncertain. METHODS: Thirty-five patients with
      >or=80% carotid artery stenosis or complete occlusion underwent CVC testing at
      baseline and 6 months later. CVC was assessed by measuring the increase in
      ipsilateral middle cerebral artery mean flow velocity in response to 5% inhaled
      CO2. Continuous tracings of left and right middle cerebral artery flow velocity,
      heart rate, respiratory rate, and Pco2 were recorded and then analyzed offline.
      One-way analysis of variance was used to compare baseline CVC in symptomatic and
      asymptomatic patients with control subjects. A paired t test was used to compare
      CVC before and after revascularization. Also, chi2 analysis was used to compare
      rates of cerebrovascular events in patients with low compared with normal CVC
      over the 6-month period and in 14 patients whose ICAs were revascularized.
      RESULTS: Patients with high-grade stenosis or occlusion of the ICA who had ICA
      disease had an average CVC of 2.4+/-1.9%/mm Hg Pco2; control subjects averaged
      4.2+/-1.1%/mm Hg Pco2. (P=0.01). In the revascularization group, CVC increased
      from an average of 1.4+/-1.7%/mm Hg Pco2 at baseline to an average of 2.8+/
      1.0%/mm Hg Pco2 after revascularization, significantly different from the
      spontaneous change in the natural history group over 6 months (P=0.003). Over the
      6-month follow-up period, in the natural history group and in the treatment group
      after revascularization, 4 ischemic events occurred, all in patients with
      abnormal CVCs; abnormal CVC was associated with ischemic events (Fisher's exact
      test, P=0.03). CONCLUSIONS: In a timeframe pertinent to clinical decision making
      and clinical trial outcomes, cerebral hemodynamic status may not be constant. A
      higher ischemic risk may be present in patients with severe carotid artery
      disease whose CVC is poor at baseline, becomes poor over 6 months, or fails to
      normalize after revascularization.

PMID- 12624218
TI  - Cuyahoga County Operation Stroke speed of emergency department evaluation and
      compliance with National Institutes of Neurological Disorders and Stroke time
      targets.
AB  - BACKGROUND AND PURPOSE: Although the National Institutes of Neurological
      Disorders and Stroke (NINDS) has established time targets for the evaluation of
      acute stroke patients, little is known about how often these targets are met in
      the community. To track compliance with NINDS guidelines, Cuyahoga County
      Operation Stroke implemented a countywide data collection process that provides
      comparative reporting of hospital performance. METHODS: Data on the emergency
      department evaluation of stroke patients have been retrospectively collected
      since January 2000 by hospitals participating in Cuyahoga County Operation
      Stroke. All hospitals used a 1-page form that includes NINDS time target
      information. RESULTS: Median time to emergency department arrival for the 1003
      patients in this cohort was 115 minutes; 382 patients (38%) arrived in <3 hours;
      506 (50%) arrived in <6 hours. After arrival, median time to physician contact
      was 12 minutes, time to CT was 65 minutes, and time to imaging results was 105
      minutes. Earlier arrival intervals after symptom onset were independently
      associated with shorter evaluation times. All time targets were met in patients
      receiving intravenous tissue plasminogen activator. CONCLUSIONS: A countywide
      data collection system for acute stroke evaluation is feasible. In the Cleveland
      metropolitan area, time to physician contact is close to the recommended NINDS
      target. Time to CT and time to imaging results are substantially longer than
      recommended. However, there was wide variation between hospitals. The association
      between time to arrival, speed of evaluation, and administration of intravenous
      tissue plasminogen activator suggests that community physicians selectively
      accelerate the evaluation and management of potential thrombolysis candidates.

PMID- 12624219
TI  - Hyperhomocysteinemia is associated with the presence of left atrial thrombus in
      stroke patients with nonvalvular atrial fibrillation.
AB  - BACKGROUND AND PURPOSE: Blood stasis is the fundamental mechanism leading to
      thrombus formation in the venous system. Homocysteine also poses a significant
      risk for venous thrombosis through its endothelial toxic and prothrombotic
      properties. In the present study, we hypothesized that high homocysteine might be
      associated with thrombus formation in another stasis-related condition, atrial
      fibrillation. METHODS: Forty-two consecutive patients with ischemic stroke caused
      by nonvalvular atrial fibrillation and admitted within the first day of symptom
      onset were included. Total fasting plasma homocysteine, serum folic acid, and
      vitamin B12 levels were measured. All patients were evaluated by transesophageal
      echocardiography for the presence of a left atrial (LA) thrombus. Homocysteine
      and vitamin levels were compared between groups with or without LA thrombus.
      RESULTS: Transesophageal echocardiography revealed LA thrombus in 20 patients.
      Mean homocysteine levels were significantly higher in patients with LA thrombus
      (20.75 versus 13.34 micromol/L, P<0.001). Multivariate logistic regression
      analysis showed that the effect of high homocysteine was independent of other
      clinical or echocardiographic variables known to increase LA thrombus (P=0.017).
      There was no difference in vitamin B12 levels between groups (P=0.118), whereas
      the mean folic acid level was significantly lower in patients with LA thrombus
      (P=0.004). CONCLUSIONS: High plasma homocysteine conveys an independent risk for
      LA thrombus formation in patients with stroke caused by nonvalvular atrial
      fibrillation. This finding further supports the thrombogenic role of high
      homocysteine in conditions associated with blood stasis.

PMID- 12624220
TI  - Effects of race and poverty on the process and outcome of inpatient
      rehabilitation services among stroke patients.
AB  - BACKGROUND AND PURPOSE: The greater mortality and residual physical impairments
      among black stroke patients may be attributable to differential utilization of
      rehabilitation services. This report examines, within an equal-access healthcare
      system, racial differences in time to initiation of stroke rehabilitation
      services and in the trajectory of physical function recovery. METHODS: This study
      was a secondary analysis of data from an inception cohort of 1073 stroke patients
      hospitalized between April 1995 and March 1997 and followed up for up to 1 year.
      Inpatient data came from medical record reviews; follow-up data came from
      telephone interviews at 1, 6, and 12 months after stroke. The study included
      consecutive acute ischemic or intracerebral hemorrhagic stroke patients from 9 VA
      medical centers. The main outcome measures were time to initiation of inpatient
      rehabilitation services and ability to perform activities of daily living.
      RESULTS: There were no racial differences in receipt of inpatient rehabilitation
      services (blacks, 76%; whites, 70%) or in the proportion of patients referred
      within 3 days of admission (blacks, 43.5%; whites, 42.0%). Among patients who
      experienced delay in initiation of rehabilitation, only low-income blacks
      experienced worse functional recovery over 12 months. CONCLUSIONS: Low-income
      black stroke patients who experience delay in initiation of inpatient
      rehabilitation have a worse trajectory of functional recovery in the first year
      after stroke. Poverty-associated factors in the postdischarge setting may explain
      this phenomenon.

PMID- 12624235
TI  - A challenge to the world's scientists.

PMID- 12624236
TI  - Climate research. Right direction, but a long way to go for Bush's plan.

PMID- 12624238
TI  - Planetary science. Researchers watch solar eruption sideswipe bright comet.

PMID- 12624237
TI  - HIV/AIDS. Vaccine results lose significance under scrutiny.

PMID- 12624239
TI  - Former Soviet Union. Fears grow of nuclear brain drain to Iran.

PMID- 12624240
TI  - Cancer risk. Review rules out abortion-cancer link.

PMID- 12624241
TI  - Infectious disease. Shortage of meningitis vaccine forces triage in Burkina Faso.

PMID- 12624242
TI  - Environmental Protection Agency. Access to proposals triggers sharp debate.

PMID- 12624243
TI  - Infectious disease. Chasing the fickle swine flu.

PMID- 12624244
TI  - Infectious disease. An avian flu jumps to people.

PMID- 12624245
TI  - HIV. Escape artist par excellence.

PMID- 12624246
TI  - James Battey profile. NIH's man in the middle of the stem cell debate.

PMID- 12624247
TI  - Planning the genome institute's future.

PMID- 12624248
TI  - Consensus and ancestral state HIV vaccines.

PMID- 12624249
TI  - Perceptions in science. Is evolution a secular religion?

PMID- 12624250
TI  - Paleoanthropology. Whither the Neanderthals?

PMID- 12624252
TI  - Microbiology. Stomachs out of Africa.

PMID- 12624251
TI  - Biomedicine. A new angle on ocular development.

PMID- 12624253
TI  - Planetary science. Cassini imaging at Jupiter.

PMID- 12624255
TI  - Astrophysics. Precision cosmology? Not just yet...

PMID- 12624254
TI  - Botany. State transitions--a question of balance.

PMID- 12624256
TI  - Genesis of suicide terrorism.
AB  - Contemporary suicide terrorists from the Middle East are publicly deemed crazed
      cowards bent on senseless destruction who thrive in poverty and ignorance. Recent
      research indicates they have no appreciable psychopathology and are as educated
      and economically well-off as surrounding populations. A first line of defense is
      to get the communities from which suicide attackers stem to stop the attacks by
      learning how to minimize the receptivity of mostly ordinary people to recruiting
      organizations.

PMID- 12624257
TI  - Vertebrate microRNA genes.

PMID- 12624258
TI  - Cassini imaging of Jupiter's atmosphere, satellites, and rings.
AB  - The Cassini Imaging Science Subsystem acquired about 26,000 images of the Jupiter
      system as the spacecraft encountered the giant planet en route to Saturn. We
      report findings on Jupiter's zonal winds, convective storms, low-latitude upper
      troposphere, polar stratosphere, and northern aurora. We also describe previously
      unseen emissions arising from Io and Europa in eclipse, a giant volcanic plume
      over Io's north pole, disk-resolved images of the satellite Himalia,
      circumstantial evidence for a causal relation between the satellites Metis and
      Adrastea and the main jovian ring, and information on the nature of the ring
      particles.

PMID- 12624259
TI  - Mothers' transitions from welfare to work and the well-being of preschoolers and
      adolescents.
AB  - Results from a longitudinal study of 2402 low-income families during the recent
      unprecedented era of welfare reform suggest that mothers' transitions off welfare
      and into employment are not associated with negative outcomes for preschoolers
      (ages 2 to 4 years) or young adolescents (ages 10 to 14 years). Indeed, no
      significant associations with mothers' welfare and employment transitions were
      found for preschoolers, and the dominant pattern was also of few statistically
      significant associations for adolescents. The associations that did occur
      provided slight evidence that mothers' entry into the labor force was related to
      improvements in adolescents' mental health, whereas exits from employment were
      linked with teenagers' increased behavior problems.

PMID- 12624260
TI  - The cosmic production of helium.
AB  - We estimate the cosmic production rate of helium relative to metals
      (DeltaY/DeltaZ) using K dwarf stars in the Hipparcos catalog with accurate
      spectroscopic metallicities. The best fitting value is DeltaY/DeltaZ = 2.1 +/-
      0.4 at the 68% confidence level. Our derived value agrees with determinations
      from H II regions and with theoretical predictions from stellar yields with
      standard assumptions for the initial mass function. The amount of helium in stars
      determines how long they live and therefore how fast they will enrich the
      interstellar medium with fresh material.

PMID- 12624261
TI  - Dynamics-driven reaction pathway in an intramolecular rearrangement.
AB  - A critical role is traditionally assigned to transition states (TSs) and minimum
      energy pathways, or intrinsic reaction coordinates (IRCs), in interpreting
      organic reactivity. Such an interpretation, however, ignores vibrational and
      kinetic energy effects of finite temperature. Recently it has been shown that
      reactions do not necessarily follow the intermediates along the IRC. We report
      here molecular dynamics (MD) simulations that show that dynamics effects may
      alter chemical reactions even more. In the heterolysis rearrangement of
      protonated pinacolyl alcohol Me3C-CHMe-OH2+ (Me, methyl), the MD pathway involves
      a stepwise route with C-O bond cleavage followed by methyl group migration,
      whereas the IRC pathway suggests a concerted mechanism. Dynamics effects may lead
      to new interpretations of organic reactivity.

PMID- 12624263
TI  - Glacier surge after ice shelf collapse.
AB  - The possibility that the West Antarctic Ice Sheet will collapse as a consequence
      of ice shelf disintegration has been debated for many years. This matter is of
      concern because such an event would imply a sudden increase in sea level.
      Evidence is presented here showing drastic dynamic perturbations on former
      tributary glaciers that fed sections of the Larsen Ice Shelf on the Antarctic
      Peninsula before its collapse in 1995. Satellite images and airborne surveys
      allowed unambiguous identification of active surging phases of Boydell, Sjogren,
      Edgeworth, Bombardier, and Drygalski glaciers. This discovery calls for a
      reconsideration of former hypotheses about the stabilizing role of ice shelves.

PMID- 12624262
TI  - A supershear transition mechanism for cracks.
AB  - Seismic data indicate that fault ruptures follow complicated paths with variable
      velocity because of inhomogeneities in initial stress or fracture energy. We
      report a phenomenon unique to three-dimensional cracks: Locally stronger fault
      sections, rather than slowing ruptures, drive them forward at velocities
      exceeding the shear wave speed. This supershear mechanism differentiates barrier
      and asperity models of fault heterogeneity, which previously have been regarded
      as indistinguishable. High strength barriers concentrate energy, producing
      potentially destructive pulses of strong ground motion.

PMID- 12624264
TI  - Shock-induced localized amorphization in boron carbide.
AB  - High-resolution electron microscope observations of shock-loaded boron carbide
      have revealed the formation of nanoscale intragranular amorphous bands that occur
      parallel to specific crystallographic planes and contiguously with apparent
      cleaved fracture surfaces. This damage mechanism explains the measured, but not
      previously understood, decrease in the ballistic performance of boron carbide at
      high impact rates and pressures. The formation of these amorphous bands is also
      an example of how shock loading can result in the synthesis of novel structures
      and materials with substantially altered properties.

PMID- 12624265
TI  - Photolysis of sulfuric acid vapor by visible solar radiation.
AB  - Atmospheric field measurements and models of the stratospheric sulfate aerosol
      layer led to the suggestion that sulfuric acid (H2SO4) must photolyze at high
      altitudes. We propose that excitation of vibrational overtones of H2SO4 and its
      hydrate in the near-infrared and visible leads to photolysis, forming sulfur
      trioxide (SO3) and water. On the basis of absorption cross sections calculated
      with ab initio methods calibrated to experimental measurements, we estimated J
      values that are sufficient to explain stratospheric and mesospheric sulfur
      dioxide (SO2) concentrations and the observation of the sulfate layer.

PMID- 12624266
TI  - Role of chloroplast protein kinase Stt7 in LHCII phosphorylation and state
      transition in Chlamydomonas.
AB  - Photosynthetic organisms adapt to changes in light quality by redistributing
      light excitation energy between two photosystems through state transition. This
      reorganization of antenna systems leads to an enhanced photosynthetic yield.
      Using a genetic approach in Chlamydomonas reinhardtii to dissect the signal
      transduction pathway of state transition, we identified a chloroplast thylakoid
      associated serine-threonine protein kinase, Stt7, that has homologs in land
      plants. Stt7 is required for the phosphorylation of the major light-harvesting
      protein (LHCII) and for state transition.

PMID- 12624267
TI  - STAT1-dependent innate immunity to a Norwalk-like virus.
AB  - Norwalk-like caliciviruses (Noroviruses) cause over 90% of nonbacterial epidemic
      gastroenteritis worldwide, but the pathogenesis of norovirus infection is poorly
      understood because these viruses do not grow in cultured cells and there is no
      small animal model. Here, we report a previously unknown murine norovirus.
      Analysis of Murine Norovirus 1 infection revealed that signal transducer and
      activator of transcription 1-dependent innate immunity, but not T and B cell
      dependent adaptive immunity, is essential for norovirus resistance. The
      identification of host molecules essential for murine norovirus resistance may
      provide targets for prevention or control of an important human disease.

PMID- 12624268
TI  - Modification of ocular defects in mouse developmental glaucoma models by
      tyrosinase.
AB  - Mutations in the cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1)
      gene are a common cause of human primary congenital glaucoma (PCG). Here we show
      that Cyp1b1-/- mice have ocular drainage structure abnormalities resembling those
      reported in human PCG patients. Using Cyp1b1-/- mice, we identified the
      tyrosinase gene (Tyr) as a modifier of the drainage structure phenotype, with Tyr
      deficiency increasing the magnitude of dysgenesis. The severe dysgenesis in eyes
      lacking both CYP1B1 and TYR was alleviated by administration of the tyrosinase
      product dihydroxyphenylalanine (l-dopa). Tyr also modified the drainage structure
      dysgenesis in mice with a mutant Foxc1 gene, which is also involved in PCG. These
      experiments raise the possibility that a tyrosinase/l-dopa pathway modifies human
      PCG, which could open new therapeutic avenues.

PMID- 12624269
TI  - Traces of human migrations in Helicobacter pylori populations.
AB  - Helicobacter pylori, a chronic gastric pathogen of human beings, can be divided
      into seven populations and subpopulations with distinct geographical
      distributions. These modern populations derive their gene pools from ancestral
      populations that arose in Africa, Central Asia, and East Asia. Subsequent spread
      can be attributed to human migratory fluxes such as the prehistoric colonization
      of Polynesia and the Americas, the neolithic introduction of farming to Europe,
      the Bantu expansion within Africa, and the slave trade.

PMID- 12624270
TI  - Experience strengthening transmission by driving AMPA receptors into synapses.
AB  - The mechanisms underlying experience-dependent plasticity in the brain may depend
      on the AMPA subclass of glutamate receptors (AMPA-Rs). We examined the
      trafficking of AMPA-Rs into synapses in the developing rat barrel cortex. In vivo
      gene delivery was combined with in vitro recordings to show that experience
      drives recombinant GluR1, an AMPA-R subunit, into synapses formed between layer 4
      and layer 2/3 neurons. Moreover, expression of the GluR1 cytoplasmic tail, a
      construct that inhibits synaptic delivery of endogenous AMPA-Rs during long-term
      potentiation, blocked experience-driven synaptic potentiation. In general,
      synaptic incorporation of AMPA-Rs in vivo conforms to rules identified in vitro
      and contributes to plasticity driven by natural stimuli in the mammalian brain.

PMID- 12624271
TI  - Diurnal variance in stroke onset.

PMID- 12624272
TI  - Re: Stages and thresholds of hemodynamic failure.

PMID- 12624274
TI  - Anticoagulation uptake in emergency department patients with atrial fibrillation.

PMID- 12624273
TI  - Atrial fibrillation, stroke, and acute antithrombotic therapy.

PMID- 12624275
TI  - Potential pitfalls in applying carotid endarterectomy perioperative mortality and
      morbidity rates.

PMID- 12624276
TI  - Letter of apology.

PMID- 12624277
TI  - Pulse pressure and risk of Alzheimer disease in persons aged 75 years and older:
      a community-based, longitudinal study.
AB  - BACKGROUND AND PURPOSE: Elevated blood pressure has been found to increase the
      risk of dementia, including Alzheimer disease. We sought to investigate whether
      pulse pressure was predictive of Alzheimer disease and dementia. METHODS: A
      community-based, dementia-free cohort (n=1270) aged > or =75 years was clinically
      examined twice over 6 years to detect incident dementia with the use of the
      criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised
      Third Edition. Cox proportional hazards models were used to analyze pulse
      pressure in association with incident Alzheimer disease and dementia after
      adjustment for several potential confounders, including systolic pressure and
      diastolic pressure. RESULTS: During the 5464.6 person-years (median, 4.7 years)
      of follow-up, 339 subjects developed dementia, including 256 Alzheimer disease
      cases. Pulse pressure as a continuous variable was not statistically related to
      the risk of Alzheimer disease and dementia. In the categorical analysis, however,
      in comparison with median tertile of pulse pressure (70 to 84 mm Hg), subjects
      with higher pulse pressure had adjusted relative risks (95% CI) of 1.4 (1.0 to
      2.0; P=0.04) for Alzheimer disease and 1.3 (0.9 to 1.7) for dementia. The
      corresponding figures related to lower pulse pressure were 1.7 (1.2 to 2.3) for
      Alzheimer disease and 1.4 (1.0 to 1.9; P=0.03) for dementia. This association was
      particularly pronounced among women. CONCLUSIONS: Higher pulse pressure is
      associated with increased risk for Alzheimer disease and dementia in old adults,
      which is probably due to artery stiffness and severe atherosclerosis. Poor
      cerebral perfusion related to decreased pulse pressure may explain the
      association between lower pulse pressure and increased dementia risk.

PMID- 12624278
TI  - Promoter polymorphism in the endotoxin receptor (CD14) is associated with
      increased carotid atherosclerosis only in smokers: the Carotid Atherosclerosis
      Progression Study (CAPS).
AB  - BACKGROUND AND PURPOSE: The risk of atherosclerosis from endotoxemia is increased
      in smokers. Endotoxin is a potent mediator of inflammation, and smokers have
      elevated plasma levels of endotoxin. The endotoxin receptor CD14 can enhance the
      endotoxin-neutralization capacity of plasma. A functional polymorphism in the
      promoter region of the CD14 gene (CD14 -159C/T) was studied to determine its
      impact on common carotid artery (CCA) intima-media thickness (IMT) and any
      interactions with environmental inflammatory stimuli. METHODS: A community
      population (n=992; aged 50 to 65 years) underwent genotypic examination for the
      CD14 -159 polymorphism by restriction fragment length polymorphism analysis.
      RESULTS: The CC genotype was associated with increased CCA IMT. The age- and sex
      adjusted odds ratio for IMT above the 75th percentile was 1.63 (95% CI, 1.19 to
      2.24; P=0.002) and 1.70 (95% CI, 1.18 to 2.44; P=0.004) after additional
      adjustment for conventional risk factors. This gene effect was found only in
      current smokers and ex-smokers. Multivariate analysis in this group (n=503)
      increased the odds ratio to 2.02 (95% CI, 1.23 to 3.34; P=0.006). No significant
      interactions were found in nonsmokers or with alcohol consumption. CONCLUSIONS:
      The CD14 -159 polymorphism is associated with increased CCA IMT in smokers from a
      general population. CD14 may modulate the inflammatory effects of smoking in
      atherogenesis.

PMID- 12624279
TI  - Associations of a human G protein beta3 subunit dimorphism with insulin
      resistance and carotid atherosclerosis.
AB  - BACKGROUND AND PURPOSE: The C825T dimorphism of the gene encoding the human G
      protein beta3 subunit (GNB3) is associated with hypertension and obesity.
      Although these findings suggest an association with insulin resistance and
      atherosclerosis, this hypothesis has yet been tested only partially. METHODS: To
      investigate this hypothesis, the C825T dimorphism was determined in a population
      of 932 middle-aged white subjects of middle European (Austrian) origin. Insulin
      sensitivity was measured with the short insulin tolerance test; intima-media
      thickness of the carotid artery and morphological plaque burden were measured by
      ultrasound. RESULTS: Insulin sensitivity was found to be significantly lower in
      carriers of the T allele (3.55+/-1.27 versus 3.92+/-1.30%/min, P=0.012) in the
      group of male subjects with abdominal body fat distribution (waist-to-hip ratio
      >0.9). No effect was observed in women or men with a waist-to-hip ratio <0.9.
      Advanced carotid artery plaques were more frequent (odds ratio, 1.606; 95%
      confidence interval, 1.002 to 2.575; P=0.04) in carriers of the T allele
      regardless of sex. No effect was observed with regard to carotid artery intima
      media thickness. CONCLUSIONS: In summary, our results demonstrate that the GNB3
      825T allele is associated with reduced insulin sensitivity in men with abdominal
      fat distribution and with more advanced carotid atherosclerosis in middle-aged
      white men and women.

PMID- 12624280
TI  - Increased risk of atherosclerosis is confined to CagA-positive Helicobacter
      pylori strains: prospective results from the Bruneck study.
AB  - BACKGROUND AND PURPOSE: Accumulating evidence indicates that a variety of
      infections contribute to the pathogenesis of atherosclerosis, but there is
      controversy concerning the impact of Helicobacter pylori infections in
      atherosclerosis. METHODS: We evaluated seropositivity to H pylori and to its
      cytotoxin-associated gene A (CagA) product in a large, prospective, population
      based study (n=684). Intima-media thickness and atherosclerosis of carotid
      arteries were thoroughly assessed by high-resolution duplex scanning. RESULTS: In
      our study population, H pylori infections defined by seropositivity have no
      relationship with levels of classic cardiovascular risk factors or markers of
      systemic inflammation, except for elevated levels of immune reactions to
      mycobacterial heat shock protein 65. The latter showed a trend toward highest
      levels in those harboring virulent H pylori strains (P=0.08). Common carotid
      artery intima-media thickness-both absolute values and changes between 1995 and
      2000-were significantly enhanced in subjects seropositive to CagA but not in
      those infected with CagA-negative H pylori strains. There was a clear dose
      response relation between anti-CagA antibodies and both intima-media thickness
      and atherosclerosis risk. Notably, the risk of atherosclerosis associated with
      CagA seropositivity was amplified by elevated C-reactive protein levels.
      CONCLUSIONS: Infections with virulent CagA-bearing H pylori strains may
      contribute to the pathogenesis of early atherosclerosis by aggravating immune
      inflammatory reactions.

PMID- 12624281
TI  - Changes related to age and cerebrovascular symptoms in the extracellular matrix
      of human carotid plaques.
AB  - BACKGROUND AND PURPOSE: Many processes involved in the pathogenesis of
      atherosclerosis result in modifications of the extracellular matrix. These
      changes not only determine the mechanical stability of atherosclerotic lesions
      but can directly or indirectly influence further development of the lesions. The
      purpose of the present study was to compare the matrix composition of human
      carotid plaques from symptomatic patients with those obtained from patients
      without symptoms. Furthermore, matrix changes related to age were studied.
      METHODS: Thirty atherosclerotic carotid plaques were removed by endarterectomy
      from 27 patients and divided into 2 groups on the basis of the presence of
      ipsilateral symptoms. The plaques were homogenized, and the total levels of the
      major components of the extracellular matrix were determined. RESULTS: Plaques
      associated with symptoms were characterized by increased levels of elastin
      (1.58+/-0.46 versus 1.24+/-0.40 mg/g wet wt; P=0.03) and decreased levels of
      hydroxyapatite (45.1+/-46.3 versus 131.4+/-111.7 mg/g wet wt; P=0.02) compared
      with asymptomatic plaques. The increase in elastin in plaques from symptomatic
      patients was due to elevated levels of an intermediate-size fraction, as
      determined by liquid chromatography. Collagen and sulfated glycosaminoglycans
      were present in equal amounts in both groups. Elastin content in carotid plaques
      decreased with age. CONCLUSIONS: Carotid plaques from symptomatic patients have
      lower levels of hydroxyapatite than those from asymptomatic patients. The present
      study also raises the possibility that non-cross-linked forms of elastin,
      increased in plaques associated with symptoms, could be a marker of plaque
      vulnerability and/or directly induce harmful cellular activities or increase
      lipoprotein retention in the vascular wall.

PMID- 12624282
TI  - Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in
      Communities (ARIC) study.
AB  - BACKGROUND AND PURPOSE: The role of circulating lipids and lipoproteins in the
      pathogenesis of ischemic stroke remains uncertain despite 3 decades of research.
      We examined this issue in a large population-based cohort. METHODS: Between 1987
      and 1989, 14 175 middle-aged men and women, free of clinical cardiovascular
      disease, took part in the first examination of the Atherosclerosis Risk in
      Communities (ARIC) study cohort. Baseline measurements included plasma levels of
      LDL cholesterol, HDL cholesterol, apolipoprotein B, apolipoprotein A-1, and
      triglycerides and myriad risk factors for cardiovascular disease. The cohort was
      followed for cardiovascular disease end points. RESULTS: Over an average follow
      up of 10 years (142 704 person-years at risk), we documented clinical ischemic
      stroke in 305 participants (161 men and 144 women). After multivariable
      adjustment for stroke risk factors, categorical and spline regression analyses of
      the entire sample, as well as the sample of men alone, revealed weak and
      inconsistent associations between ischemic stroke and each of the 5 lipid
      factors. Among women, the most consistent findings were decreasing risk of
      ischemic stroke within the top half of the distribution of HDL cholesterol and
      increasing risk within the lower range of the triglyceride distribution.
      CONCLUSIONS: The relation of circulating cholesterol to ischemic stroke does not
      resemble its well-known relation to coronary heart disease. Either the
      pathogenesis of a substantial proportion of ischemic strokes does not involve
      classic atherosclerotic mechanisms, or the effect of plasma lipids on
      atherogenesis is substantially different in the intracranial vascular bed.

PMID- 12624283
TI  - Prospective study of serum homocysteine and risk of ischemic stroke among
      patients with preexisting coronary heart disease.
AB  - BACKGROUND AND PURPOSE: Substantial evidence is accumulating suggesting that
      hyperhomocysteinemia may be a risk factor for ischemic stroke. Results of
      prospective studies are, however, conflicting, and the role of
      hyperhomocysteinemia in patients with preexisting atherosclerotic vascular
      disease is not clear. Our aim was to assess prospectively the risk of incident
      ischemic stroke conferred by serum total homocysteine among patients with
      preexisting stable coronary heart disease (CHD). METHODS: We obtained baseline
      fasting serum samples from patients with chronic CHD enrolled in the Bezafibrate
      Infarction Prevention (n=3090) secondary prevention study cohort. With a nested
      case-control design, we measured baseline total homocysteine concentration by a
      high-performance liquid chromatography-based method in sera (n=160) of matched
      case-control pairs: patients who developed ischemic stroke during a mean follow
      up of 8.2 years (cases) and age- and sex-matched controls without subsequent
      cardiovascular events. RESULTS: An increase of 1 natural log unit in homocysteine
      concentration was associated with a >3-fold increase in relative odds of incident
      ischemic stroke (3.3; 95% CI, 1.2 to 10.2). Homocysteine concentrations at the
      highest quartile (>17.4 micromol/L) were associated with significantly higher
      odds of ischemic stroke compared with the lowest quartile in matched-pair
      analysis (3.1; 95% CI, 1.1 to 9.8) and after multivariable adjustments (4.6; 95%
      CI, 1.3 to 18.9). Adding fibrinogen or soluble intercellular adhesion molecule-1
      concentrations, markers of inflammation, to the model did not attenuate this
      association. The linear trends across the quartiles were significant for all
      models (P<0.05). CONCLUSIONS: Serum total homocysteine concentration is a strong
      predictor for incident ischemic stroke among patients at increased risk because
      of chronic CHD. The graded association observed is independent of traditional
      risk factors or inflammatory markers and indicates the importance of serum
      homocysteine levels in patients with preexisting vascular disease.

PMID- 12624284
TI  - Decreased cerebrospinal fluid apolipoprotein E after subarachnoid hemorrhage:
      correlation with injury severity and clinical outcome.
AB  - BACKGROUND AND PURPOSE: The apolipoprotein E (APOE) epsilon4 allele has been
      associated with unfavorable outcome after subarachnoid hemorrhage (SAH),
      suggesting that apoE plays an important role in the response of the brain to SAH.
      We determined the concentration of apoE in the cerebrospinal fluid (CSF) of
      patients with SAH and a control group to test the hypothesis that alterations in
      CSF apoE reflect the response of the brain to SAH and are correlated with the
      severity of injury and outcome. METHODS: ApoE and S100B (a marker of brain
      injury) were measured by ELISA in CSF from a non-brain-injured control group and
      patients with SAH. The severity of SAH was determined from the Glasgow Coma
      Scale, and the clinical outcome was determined from the Glasgow Outcome Scale.
      RESULTS: In contrast to increased CSF concentration of S100B, CSF apoE
      concentration was significantly lower in patients after SAH than in control
      subjects (Mann-Whitney test, P<0.0001). SAH patients with more severe injury and
      less favorable outcome had lower CSF apoE concentration than did patients with
      milder injury and better clinical outcome (Fisher exact test, P=0.02).
      CONCLUSIONS: The concentration of apoE in the CSF decreases after SAH, despite
      the likely leakage of plasma apoE into the CSF. We speculate that apoE is
      retained within the parenchyma of the central nervous system in response to
      injury, where, in view of previous data, it may have a protective role.

PMID- 12624285
TI  - L-arginine improves diminished cerebral CO2 reactivity in patients.
AB  - BACKGROUND AND PURPOSE: There is experimental evidence that L-arginine restores
      diminished CO2 reactivity after mild traumatic brain injury in rats. This effect
      is believed to be mediated by L-arginine-derived nitric oxide, which is a
      permissive substrate for CO2 reactivity. To clarify whether these findings can be
      transferred to the clinical situation and have beneficial effects in patients, we
      studied the effects of L-arginine on CO2 reactivity of the cerebral vessels in
      patients with impaired vasomotor reactivity (VMR) and compared them with patients
      with normal VMR. METHODS: Twenty-two patients with cardiovascular risk factors
      and VMR <50% with no extracranial or intracranial stenoses were examined by
      bilateral transcranial Doppler sonography of the right and left middle cerebral
      arteries and compared with 20 age- and risk-matched patients with normal VMR
      (>50%). VMR was tested by L-minute hyperventilation, followed by a 3-minute
      inhalation of 5% CO2. Examinations were performed before and after infusion of 30
      g L-arginine over 30 minutes. The 22 patients with reduced VMR (<50%) were
      compared with 20 patients with normal VMR (>50%). RESULTS: Initial mean VMR of
      the 42 patients was 50+/-12%. There was no difference between the right- and the
      left-side VMR. In the 22 patients with reduced VMR in the first examination (42+/
      8%), VMR increased significantly after infusion of L-arginine (52+/-14%,
      P=0.005). In contrast, values did not change after infusion of L-arginine in the
      20 patients with normal VMR (59+/-8% before versus 59+/-13% after L-arginine).
      There was a negative correlation of initial CO2 vasoreactivity and the percentage
      of VMR increase after infusion of L-arginine. CONCLUSIONS: Our data support the
      hypothesis that in humans L-arginine is able to improve impaired CO2 reactivity
      of the cerebral vessels. This effect can be found in patients at cardiovascular
      risk with impaired VMR and might have therapeutic implications in the future.

PMID- 12624286
TI  - Cerebral hemodynamics and metabolism in patients with symptomatic occlusion of
      the internal carotid artery.
AB  - BACKGROUND AND PURPOSE: The goals of this study were to investigate (1) whether
      the concentrations of choline, creatine, and N-acetyl aspartate (NAA) in cerebral
      white matter are changed in patients with symptomatic occlusion of the internal
      carotid artery (ICA) and (2) whether possible changes in metabolite concentration
      are related to regional cerebral perfusion or cerebral vasoreactivity. METHODS:
      In 19 patients (mean+/-SD age, 60+/-9 years), white matter metabolite
      concentrations were measured with proton MR spectroscopic imaging on average 4+/
      2 months after symptoms occurred. In selected voxels, corresponding cerebral
      blood flow and volume, mean transit time, and time-to-bolus peak were determined
      with dynamic susceptibility contrast MRI. Cerebral CO2 reactivity was determined
      with transcranial Doppler sonography. RESULTS: No significant changes in choline
      and creatine concentrations were observed. NAA concentration was significantly
      reduced in the hemisphere on the side of the symptomatic ICA (9.1+/-1.7 mmol/L)
      compared with the contralateral hemisphere (10.5+/-1.7 mmol/L, P<0.005) and
      control subjects (10.5+/-0.9 mmol/L, P<0.01). Although no significant
      interhemispheric difference in NAA concentration was found in patients who
      presented with retinal ischemia, patients with cerebral ischemia had a
      significantly lower NAA concentration in the symptomatic hemisphere (9.0+/-1.7
      mmol/L) compared with the asymptomatic hemisphere (10.4+/-1.6 mmol/L, P<0.05). In
      all patients, NAA concentration was not significantly correlated with
      quantitative cerebral perfusion parameters or CO2 reactivity. CONCLUSIONS:
      Patients with symptomatic ICA occlusion may show chronic neuronal damage in
      cerebral white matter as evidenced by reduced NAA concentration. This seems to be
      related to previous symptomatology rather than to the cerebral hemodynamic status
      in a chronic stage.

PMID- 12624287
TI  - Ischemic lacunar stroke in patients with and without potential mechanism other
      than small-artery disease.
AB  - BACKGROUND AND PURPOSE: Autopsy studies found that lacunar strokes differ in the
      size of the underlying brain infarct and that small lacunes are usually caused by
      hypertensive small-artery disease (SAD) and larger ones by atheromatous or
      embolic perforator occlusion. These findings suggest that larger lacunar infarcts
      might cause more severe neurological deficits and a higher detection rate on
      brain imaging compared with lacunar strokes caused by SAD. This prospective
      observational study was performed to investigate whether (1) neurological
      outcome, (2) prevalence of stroke risk factors, (3) prevalence of clinically
      asymptomatic occlusive cerebral artery disease, and (4) detection rate of
      underlying lacunar infarcts at brain imaging differ in ischemic lacunar strokes
      with (non-SAD) and without potential etiologies other than SAD. METHODS:
      Consecutive patients with lacunar stroke (n=244), defined by both clinical
      findings and brain imaging, were studied. Neurological deficit was quantified at
      presentation with the use of the National Institutes of Health Stroke Scale
      (NIHSS) and after 3 months with the NIHSS and the modified Rankin Scale (mRS).
      Cerebral arteries were investigated by ultrasound. RESULTS: Compared with
      patients with SAD lacunar strokes (n=155; 64%), patients with non-SAD lacunar
      strokes (n=89; 36%) had (1) higher NIHSS scores at presentation and higher NIHSS
      and mRS scores after 3 months (P<0.05); a higher prevalence of (2) hypertension
      (P<0.05), (3) coronary artery disease (P<0.0001), (4) previous transient ischemic
      attacks (P<0.01), and (5) asymptomatic stenoses of intracranial cerebral (P<0.01
      to P<0.0001) and extracranial carotid (30% to 50% narrowing; P<0.01) arteries;
      and (6) a higher detection rate of the underlying lesion at brain imaging
      (P<0.01). CONCLUSIONS: Our data suggest that patients with non-SAD lacunar
      strokes have a worse clinical outcome and a higher prevalence of large cerebral
      and coronary artery disease than patients with SAD lacunar strokes.

PMID- 12624288
TI  - Contrast-enhanced three-dimensional magnetic resonance angiography of
      atherosclerotic internal carotid stenosis as the noninvasive imaging modality in
      revascularization decision making.
AB  - BACKGROUND AND PURPOSE: In patients with severe internal carotid artery stenoses,
      thromboendarterectomy significantly reduces both ischemic stroke and the risk of
      more ischemic attacks. Digital subtraction angiography (DSA) is the accepted
      preoperative test to determine whether a high-grade stenosis is present and
      requires surgical therapy. However, DSA has a procedural risk of stroke between
      0.7% and 1%. An accurate, noninvasive imaging protocol with no risk of severe
      complications would significantly increase the benefit of surgical treatment. The
      aims of the study were (1) to evaluate the diagnostic accuracy of contrast
      enhanced magnetic resonance angiography (CEMRA) in detecting and grading internal
      carotid artery stenoses and (2) to assess the misclassification rate of vessels
      suitable for revascularization by CEMRA. METHODS: Ninety-two patients with
      sonographic evidence of neck vessel stenosis were enrolled in the study. All
      patients were submitted to CEMRA and DSA. CEMRA images were evaluated for the
      presence of mild, moderate, or severe stenosis and occlusion. RESULTS:
      Sensitivity, specificity, and diagnostic accuracy were 97%, 82%, and 92.5%,
      respectively. Agreement with DSA was optimal at kappa=0.87. The misclassification
      rate of CEMRA was 3.1% because of its tendency to overestimate the stenosis.
      CONCLUSIONS: The high diagnostic accuracy and limited misclassification rate
      suggest that CEMRA can be considered a powerful tool for the preoperative,
      noninvasive evaluation of atherosclerotic pathology of carotid arteries.

PMID- 12624289
TI  - Evidence for cortical functional changes in patients with migraine and white
      matter abnormalities on conventional and diffusion tensor magnetic resonance
      imaging.
AB  - BACKGROUND: In this study, we used functional MRI (fMRI) to investigate the
      pattern of cortical activations after a simple motor task in patients with
      migraine and white matter (WM) abnormalities on conventional MRI scans of the
      brain. We also investigated whether the extent of brain activations was
      correlated with WM structural pathology measured using diffusion tensor (DT) MRI.
      METHODS: From 15 right-handed patients with migraine and 15 sex- and age-matched,
      right-handed healthy volunteers, we obtained the following: (1) fMRI (repetitive
      flexion-extension of the last 4 fingers of the right hand), (2) dual-echo turbo
      spin echo scans, and (3) pulsed-gradient spin-echo echo-planar sequence to
      calculate DT-MRI maps. fMRI analysis was performed using SPM99 and cluster
      detection. We measured the volume, the average mean diffusivity (), and the
      average fractional anisotropy of all lesions seen on the dual-echo scans.
      histograms of the normal-appearing WM were also produced. RESULTS: Compared with
      healthy volunteers, migraine patients had a larger relative activation of the
      contralateral primary sensorimotor cortex (P=0.01) and a rostral displacement of
      the supplementary motor area (P=0.03). The shapes of the curves reflecting the
      time course for fMRI signal intensity changes were similar between migraine
      patients and controls for all of the cortical areas we studied. Compared with
      healthy subjects, migraine patients had significantly lower histogram peak height
      of the normal-appearing WM histogram (P=0.02), which was found to be correlated
      with the extent of displacement of the supplementary motor area (r=-0.80,
      P<0.001). CONCLUSIONS: This study suggests that functional cortical changes occur
      in patients with migraine and brain MRI abnormalities and that they might be
      secondary to the extent of subcortical structural damage.

PMID- 12624290
TI  - Levels of anti-inflammatory cytokines and neurological worsening in acute
      ischemic stroke.
AB  - BACKGROUND: Mechanisms involved in stroke progression are incompletely
      understood. Ischemic brain injury is characterized by acute local inflammatory
      response mediated by cytokines. Anti-inflammatory cytokines act in a feedback
      loop to inhibit continued proinflammatory cytokine production. We assessed the
      implication of interleukin (IL)-10 and IL-4 in deteriorating ischemic stroke.
      METHODS: Two hundred thirty-one patients with ischemic stroke within the first 24
      hours from onset were included. Neurological worsening was defined when the
      Canadian Stroke Scale score fell at least 1 point during the first 48 hours after
      admission. Anti-inflammatory cytokines were determined in plasma obtained on
      admission. RESULTS: Eighty-three patients (35.9%) worsened within the first 48
      hours after stroke onset. Significantly lower concentrations of IL-10 were found
      in patients with neurological worsening (P<0.05), but IL-4 levels were similar in
      patients with or without deterioration. Lower plasma concentrations of IL-10 (<6
      pg/mL) were associated with clinical worsening on multivariate analysis (odds
      ratio=3.1, 95% CI=1.1 to 8.9) independently of hyperthermia, hyperglycemia, or
      neurological condition on admission. Further analysis disclosed that early
      worsening was independently associated with lower IL-10 plasma levels in patients
      with subcortical infarcts or lacunar stroke but not in patients with cortical
      lesions. CONCLUSIONS: Anti-inflammatory cytokine IL-10 is associated with the
      early clinical course of patients with acute ischemic stroke, especially in
      patients with small vessel disease or subcortical infarctions.

PMID- 12624291
TI  - Occupational therapy for stroke patients: a systematic review.
AB  - BACKGROUND AND PURPOSE: Occupational therapy (OT) is an important aspect of
      stroke rehabilitation. The objective of this study was to determine from the
      available literature whether OT interventions improve outcome for stroke
      patients. METHODS: An extensive search in MEDLINE, CINAHL, EMBASE, AMED, and
      SCISEARCH was performed. Studies with controlled and uncontrolled designs were
      included. Seven intervention categories were distinguished and separately
      analyzed. If a quantitative approach (meta-analysis) of data analysis was not
      appropriate, a qualitative approach (best-evidence synthesis), based on the type
      of design, methodological quality, and significant findings of outcome and/or
      process measures, was performed. RESULTS: Thirty-two studies were included in
      this review, of which 18 were randomized controlled trials. Ten randomized
      controlled trials had a high methodological quality. For the comprehensive OT
      intervention, the pooled standardized mean difference for primary activities of
      daily living (ADL) (0.46; CI, 0.04 to 0.88), extended ADL (0.32; CI, 0.00 to
      0.64), and social participation (0.33; CI, 0.03 to 0.62) favored treatment. For
      the training of skills intervention, some evidence for improvement in primary ADL
      was found. Insufficient evidence was found to indicate that the provision of
      splints is effective in decreasing muscle tone. CONCLUSIONS: This review
      identified small but significant effect sizes for the efficacy of comprehensive
      OT on primary ADL, extended ADL, and social participation. These results
      correspond to the outcome of a systematic review of intensified rehabilitation
      for stroke patients. The amount of evidence with respect to specific
      interventions, however, is limited. More research is needed to enable evidence
      based OT for stroke patients.

PMID- 12624292
TI  - Association between diabetes and stroke subtype on survival and functional
      outcome 3 months after stroke: data from the European BIOMED Stroke Project.
AB  - BACKGROUND AND PURPOSE: Although diabetes is a strong risk factor for stroke, it
      is still unclear whether stroke subtype, severity, and prognosis are different in
      diabetic and nondiabetic patients. We sought to evaluate stroke features,
      prognosis, and functional outcome in patients with diabetes compared with
      patients without diabetes. METHODS: In a European Union Concerted Action
      involving 7 countries and 4537 patients hospitalized for a first-in-a-lifetime
      stroke, defined according to the Oxfordshire Community Stroke Project criteria,
      we collected data on demographics, risk factors, clinical presentation, and
      outcome. We used logistic regression to examine the relationship between diabetes
      and outcome at 3 months (disability, handicap, and death), controlling for risk
      factors, clinical presentation, and demographics. RESULTS: Overall, diabetes was
      present in 937 patients (21%). Diabetic patients, compared with those without
      diabetes, were more likely to have limb weakness (P<0.02), dysarthria (P<0.001),
      ischemic stroke (P<0.001), and lacunar cerebral infarction (P=0.03). At 3 months,
      the case fatality rates were not higher in the diabetic groups (P=0.33). Handicap
      (Rankin Scale) and disability (Barthel Index) were significantly higher in
      diabetic patients (P=0.005 and P=0.016, respectively). CONCLUSIONS: Stroke in
      diabetic patients has a specific clinical pattern and a poor prognosis in terms
      of motor function, which emphasizes the need for early diagnosis and treatment of
      every case of diabetes.

PMID- 12624293
TI  - Is the benefit of early recanalization sustained at 3 months? A prospective
      cohort study.
AB  - BACKGROUND AND PURPOSE: Early arterial recanalization can lead to dramatic
      recovery (DR) during intravenous tissue plasminogen activator (tPA) therapy.
      However, it remains unclear whether this clinical recovery is sustained 3 months
      after stroke. METHODS: We studied consecutive patients treated with intravenous
      tPA (0.9 mg/kg within 3 hours) who had M1 or proximal M2 middle cerebral artery
      occlusion on pretreatment transcranial Doppler according to previously validated
      criteria. Patients were continuously monitored for 2 hours after tPA bolus to
      determine complete, partial, or no early recanalization with the Thrombolysis in
      Brain Ischemia (TIBI) flow grading system. A neurologist obtained the National
      Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores
      independently of transcranial Doppler results. DR was defined as a total NIHSS
      score of 0 to 3 points, and early recovery (ER) was defined improvement by > or
      =10 points at 2 hours after tPA bolus. Good long-term outcome was defined as an
      NIHSS score of 0 to 2 or an mRS score of 0 to 1 at 3 months. RESULTS: Fifty-four
      patients with proximal middle cerebral artery occlusion had a median prebolus
      NIHSS score of 16 (range, 6 to 28; 90% with > or =10 points). The tPA bolus was
      given at 130+/-32 minutes (median, 120 minutes; 57% treated within the first 2
      hours). DR+ER was observed in 50% of patients with early complete recanalization
      (n=18), 17% with partial recanalization (n=18), and 0% with no early
      recanalization (n=18) (P=0.025). Overall, DR+ER was observed in 12 patients
      (22%), and 9 (75%) had good outcome at 3 months in terms of NIHSS (P=0.009) and
      mRS (P=0.006) scores compared with non-DR and non-ER patients. If early
      recanalization was complete, 50% of these patients had good outcome at 3 months,
      and 78% with DR+ER sustained early clinical benefit. If recanalization was
      partial, 44% had good long-term outcome, and 66% of patients with DR+ER sustained
      the benefit. If no early recanalization occurred, 22% had good long-term outcome
      despite the lack of DR within 2 hours of tPA bolus (P=0.046). Mortality was 11%,
      11%, and 39% in patients with complete, partial, and no early recanalization,
      respectively (P=0.025). Reasons for not sustaining DR in patients with early
      recanalization were subsequent symptomatic intracranial hemorrhage and recurrent
      ischemic stroke. CONCLUSIONS: DR or ER after recanalization within 2 hours after
      tPA bolus was sustained at 3 months in most patients (75%) in our study. Complete
      or partial early recanalization leads to better outcome at 3 months after stroke.
      Fewer patients achieve good long-term outcome without early recanalization.

PMID- 12624294
TI  - Long-term mortality in cerebrovascular disease.
AB  - BACKGROUND AND PURPOSE: Stroke is the third leading cause of death in the United
      States, yet data are limited about the temporal pattern of mortality among
      patients with cerebrovascular disease. The objectives of this study were to
      identify predictors of 6-month mortality and to evaluate 5-year mortality in
      patients with cerebrovascular disease. METHODS: Our population included fee-for
      service Medicare beneficiaries aged > or =65 years who were discharged with an
      acute ischemic stroke, transient ischemic attack (TIA), or carotid stenosis
      (International Classification of Diseases, Ninth Revision, Clinical Modification
      codes 433 to 436) from Connecticut acute care hospitals in 1995. This cohort was
      followed through 2000 by means of part A Medicare claims and Social Security
      Administration mortality data. RESULTS: Among 5123 patients, 4781 survived their
      hospitalization and were followed for an average of 3.4 years; 670 (14.0%) died
      within 6 months of discharge, and 2517 (52.6%) died within 5 years. Predictors of
      6-month mortality included older age, male sex, increasing comorbidity, discharge
      not to home, and prior admission within a year of the index hospitalization. The
      annual mortality rates for year 1 after discharge differed depending on the
      discharge diagnosis of the index hospitalization: carotid stenosis, 10.6%; TIA,
      14.8%; and acute ischemic stroke, 26.4%. The 5-year cumulative mortality rates
      were as follows: carotid stenosis, 38.3%; TIA, 49.6%; and acute ischemic stroke,
      60.0%. CONCLUSIONS: Mortality after acute ischemic stroke, TIA, and carotid
      stenosis is substantial. Rates and patterns of mortality differ according to
      patients' discharge diagnoses.

PMID- 12624295
TI  - Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic
      stroke.
AB  - BACKGROUND AND PURPOSE: The baroreceptor reflex arc is important in the short
      term regulation of the cardiovascular system, and small studies have reported
      impaired cardiac baroreceptor sensitivity (BRS) after acute stroke. However, the
      prognostic significance of impaired BRS is uncertain. METHODS: One hundred twenty
      four patients underwent simultaneous ECG and noninvasive beat-to-beat blood
      pressure (BP) monitoring within 72 hours of neuroradiologically confirmed acute
      ischemic stroke. Cardiac BRS was assessed from the combined alpha-index by means
      of power spectral analysis techniques. Baseline data for acute stroke patients
      were compared with those of a control group matched for age, sex, and casual BP.
      Patients were followed up for a median of 1508 days (range, 9 to 2656 days), and
      outcome was compared between patients with and without impaired BRS. RESULTS:
      Median BRS values were significantly lower in stroke patients than in controls (5
      [interquartile range, 3.5 to 7.4] versus 6.2 [interquartile range, 4.5 to 8.3]
      ms/mm Hg; P=0.04). Sixty-one (33 male) patients (mean age, 70.2 [SD 10.5] years)
      had impaired BRS (< or =5.0 ms/mm Hg) compared with 63 (35 male) patients (mean
      age, 70.6 [SD 11.7] years) without impaired BRS (>5.0 ms/mm Hg). Stroke patients
      with impaired BRS values had a significantly poorer prognosis (28% versus 8%
      mortality rate during the follow-up period) although there were no differences in
      age, stroke severity, stroke type, or casual or 24-hour BP parameters between the
      2 groups. CONCLUSIONS: Impaired cardiac BRS is associated with increased long
      term mortality after acute ischemic stroke, irrespective of age, sex, stroke
      type, and BP. This may reflect cardiac arrhythmias, but the mechanisms underlying
      this association are unknown, although therapies that improve cardiac BRS after
      stroke warrant further investigation.

PMID- 12624296
TI  - Relationship between process and outcome in stroke care.
AB  - BACKGROUND AND PURPOSE: Better processes in stroke care are assumed to lead to
      better stroke outcomes. We sought to test whether current measures of stroke
      process are related to measures of stroke outcome. METHODS: This was a
      prospective study of consecutive patients with acute stroke admitted to each of
      the 3 general hospitals in 1 region who were followed up for 12 months after
      hospital discharge. Process was measured by use of the Royal College of
      Physicians Stroke Audit Package, and outcomes were measured with a range of
      disability, health status, handicap, and independence measures, as well as
      mortality. RESULTS: One hundred eighty-one patients were recruited. There was
      evidence for a relationship between some process variables and outcomes at
      hospital discharge, but the relationships were generally weak. None of the
      process variables remained in regression models of functional outcomes at 12
      months. The hospital with the best process scores had the worst case mix-adjusted
      outcomes. CONCLUSIONS: The link between stroke process and outcome, through the
      use of currently available measures of process such as the Royal College of
      Physicians Stroke Audit Package, is not straightforward. Ongoing work may clarify
      some of these issues and provide guidance to stroke clinicians on how best to
      improve existing services.

PMID- 12624297
TI  - Hospital-based study of the care and cost of acute ischemic stroke in Japan.
AB  - BACKGROUND AND PURPOSE: To evaluate the current status of care and cost of acute
      ischemic stroke in Japan, we performed a hospital-based analysis at a tertiary
      emergency hospital with a 24-hour neurology-neurosurgery team and care unit.
      METHODS: During the 12-month period of October 2000 to September 2001, we
      collected data on 179 patients consecutively hospitalized with acute ischemic
      stroke within 7 days of onset. We examined demographic data, in-hospital care,
      length of hospital stay, outcome at discharge, and hospital costs. The medical
      cost data were collected from official hospital medical cost charts, which
      calculated direct medical costs for beds, staff, examinations, medications, and
      rehabilitation. RESULTS: The mean age was 70 years, and 69% were male. Hospital
      arrival was within 3 hours of onset in 30% of the patients. A history of stroke
      was present in 37%. The mean initial National Institutes of Health Stroke Scale
      score was 8.3 points (median, 6 points). Using the Trial of Org 10172 in Acute
      Stroke Treatment classification, 25% were lacunar, 27% were atherothrombotic, 33%
      were cardioembolic, and 15% were of unknown origin. All patients underwent
      neuroimaging studies during hospitalization; 96% and 92% underwent CT and MRI
      with MR angiography, respectively. Antithrombotic medications were given in 94%,
      none of whom received thrombolysis. A newly licensed neuroprotective agent,
      edaravone, was given in 16%. More than half of the patients (55%) were initially
      admitted to the neurological intensive care unit. Overall, 64% received in
      hospital rehabilitation. Mean length of stay was 33 days. In-hospital mortality
      rate was 3%. On the modified Rankin Scale (mRS), 63% were independent (mRS, 0 to
      2) and 34% were dependent (mRS, 3 to 5) at discharge. Two thirds of the patients
      (65%) went directly back home. The mean hospital cost per patient was $6887
      ($209/d), of which 69% was attributable to the costs for beds and staff, 12% for
      medications, 7% for rehabilitation, 6% for imaging studies, 5% for laboratory
      examinations, and 1% for other costs. CONCLUSIONS: Despite the single hospital
      based analysis, this study provided current, precise data on short-term inpatient
      care and costs of acute ischemic stroke in Japan. Because stroke often carries a
      permanent dependence, long-term cost-effective stroke care should be established.

PMID- 12624298
TI  - Telemedicine for acute stroke: triumphs and pitfalls.
AB  - BACKGROUND AND PURPOSE: Telemedicine is emerging as a potential timesaving,
      efficient means for evaluating patients experiencing acute stroke. In areas where
      local stroke care specialists are not available, telemedicine can link an
      emergency department physician with a specialist in a stroke treatment center.
      This consultation provides an opportunity for administration of thrombolytic
      drugs within the short therapeutic time window associated with ischemic stroke.
      Here, we describe our stroke treatment center experiences and report safe
      administration of recombinant tissue plasminogen activator (rtPA) during
      telemedicine consultation. METHODS: The University of Maryland Medical Center
      uses a triplexed integrated services digital network line providing a 30--frames
      per-second video link to St Mary's Hospital >100 miles away. The system uses a
      pan, tilt, and zoom camera with remote site control, allowing 2-way, real-time,
      audiovisual communication and CT image transfer. We retrospectively reviewed all
      acute stroke consultations provided to St Mary's Hospital between 1999 and 2001.
      RESULTS: We reviewed 50 consultations. Of the 50, 23 were attempted through
      telemedicine linkage, and 27 were by traditional telephone conversation, followed
      by transfer. Of the 23 telemedicine consultations, 2 were aborted because of
      technical difficulties. Of the patients evaluated by traditional means, 1 of 27
      (3.8%) received intravenous rtPA; 5 of 21 (23.8%) received rtPA after
      telemedicine consultation. No patients experienced complications. CONCLUSIONS:
      Telemedicine consultation provided treatment options not previously available at
      the remote hospital. Administration of rtPA during telemedicine consultation was
      feasible and safe, and the system was well received. Lack of reimbursement for
      telemedicine services will hinder widespread adaptation of this promising
      technology for remote acute stroke treatment.

PMID- 12624299
TI  - Use of a field-to-stroke center helicopter transport program to extend
      thrombolytic therapy to rural residents.
AB  - BACKGROUND AND PURPOSE: Giving stroke victims who reside outside communities with
      hospitals that can administer tissue plasminogen activator (rtPA) access to
      thrombolytic therapy is a challenge. Helicopter transport to a stroke center is a
      potential way to make rtPA available to these communities. We examined the
      experience of the Shands-Jacksonville Acute Stroke Transport Program, a field-to
      stroke center helicopter transport program that serves rural counties in the
      northeastern Florida/southeastern Georgia region. METHODS: Prospectively
      collected data of 111 consecutive helicopter transports to Shands-Jacksonville,
      from an 11-county region, over a 3-year period were reviewed. RESULTS: Eighty
      five patients (76%) had a cerebrovascular event. Forty-seven patients (42%) had
      an ischemic stroke, 19 (17%) had a transient ischemic attack, and 19 (17%) had a
      hemorrhagic stroke. Thrombolytic therapy was administered to 18 ischemic stroke
      patients (38%), with 15 being treated intravenously. Three patients who arrived
      beyond the 3-hour window were treated intra-arterially. Average field-to-hospital
      distance for all patients was 29.4 miles (range, 11 to 90 miles). Most patients
      (n=65) arrived within 135 minutes from symptom onset. CONCLUSIONS: A helicopter
      based transport system can link a rural region to a stroke center and promote
      access to thrombolytic therapy.

PMID- 12624300
TI  - Safety and efficacy of endovascular cooling and rewarming for induction and
      reversal of hypothermia in human-sized pigs.
AB  - BACKGROUND AND PURPOSE: Numerous studies indicate that mild hypothermia provides
      substantial neuroprotection. However, current systems transfer insufficient heat
      to rapidly vary core temperature. We thus evaluated the safety and efficacy of
      endovascular cooling and rewarming for the induction and reversal of hypothermia.
      METHODS: In 10 anesthetized pigs (weight, 66+/-2 kg), a heat-exchange balloon
      catheter was inserted into the inferior vena cava and used to cool to a core
      temperature of 32 degrees C and then rewarm to normothermia. Control animals had
      38 degrees C saline infused. Venous blood was sampled before, during, and after
      cooling. Three animals in each group were killed 1 week later, and the lungs and
      inferior vena cava were removed for gross and microscopic examination. In 5
      additional animals, cardiac output was measured during cooling to 32 degrees C.
      RESULTS: Body temperature in the hypothermic animals decreased at a rate of 4.5+/
      0.4 degrees C/h. Animals were subsequently rewarmed to 36.0+/-0.04 degrees C at
      2.5+/-0.2 degrees C/h. There was no difference in heart rate between hypothermic
      and control animals, whereas systolic pressure decreased during cooling. Cardiac
      output was well maintained during cooling. There were no thermal effects on blood
      elements or blood vessels. CONCLUSIONS: The endovascular heat-exchange system
      effectively cooled and rewarmed pigs with large thermal mass without producing
      any adverse effects on blood elements, blood vessel integrity, or cardiovascular
      function.

PMID- 12624301
TI  - Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout
      mice.
AB  - BACKGROUND AND PURPOSE: Cerebral hypoxic ischemia (HI) is an important cause of
      brain injury in the newborn infant. Adenosine is believed to protect against HI
      brain damage. However, the roles of the different adenosine receptors are
      unclear, particularly in young animals. We examined the role of adenosine A2A
      receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI.
      METHODS: HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30
      minutes after occlusion of the left common carotid artery. The resulting
      unilateral focal lesion was evaluated with the use of histopathological scoring
      and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after
      HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and
      beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood
      flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured
      during HI. RESULTS: Reduction in cortical cerebral blood flow during HI and
      rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout
      mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild
      type mice. The A2AR(-/-) mice subjected to HI displayed increased forward
      locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+)
      mice subjected to HI, whereas beam-walking performance was similarly defective in
      both groups. CONCLUSIONS: These results suggest that, in contrast to the
      situation in adult animals, A2AR play an important protective role in neonatal HI
      brain injury.

PMID- 12624302
TI  - Neuroprotective effect of granulocyte colony-stimulating factor after focal
      cerebral ischemia.
AB  - BACKGROUND AND PURPOSE: The potential neuroprotective effect of the granulocyte
      colony-stimulating factor (G-CSF) after glutamate-induced excitotoxicity in cell
      culture and after focal cerebral ischemia in rats was studied. We hypothesized
      the existence of the G-CSF receptor (G-CSFR) as a main G-CSF effector on neurons,
      and immunohistochemistry, immunoblotting, and polymerase chain reaction were
      performed. The G-CSFR-mediated action was studied by activation of signal
      transducer(s) and activator(s) of transcription-3 (STAT3) in the periphery of the
      infarction. METHODS: Neuroprotection of various G-CSF concentrations on glutamate
      induced excitotoxicity was studied in cell culture. In vivo, ischemia was induced
      by use of a suture occlusion model of the middle cerebral artery (90-minute
      occlusion) in the rat. Thirty minutes after the induction of ischemia, the
      animals (n=12 per group) received G-CSF at 60 microg/kg body wt IV for 90 minutes
      or vehicle (saline). Infarct volume was calculated on the basis of 2,3,5
      triphenyltetrazolium chloride staining 24 hours after ischemia. Expression of the
      G-CSFR was studied by immunohistochemistry and verified by reverse transcription
      polymerase chain reaction and immunoblotting. Expression of STAT3 was determined
      by immunohistochemistry. RESULTS: In cell culture, G-CSF exhibited a significant
      neuroprotective effect after glutamate-induced excitotoxicity (P<0.05). A G-CSF
      concentration of 10 ng/mL was maximally effective, resulting in a nearly complete
      protection. In vivo, G-CSF reduced infarct volume to 47% (132.0+/-112.7 mm3
      versus 278.9+/-91.6 mm3 [P<0.05] in the control group). Immunohistochemistry,
      Western blotting, and reverse transcription-polymerase chain reaction revealed
      the existence of G-CSFRs in neurons and glial cells. Animals treated with G-CSF
      significantly upregulated STAT3 in the periphery of the infarction compared with
      control animals (P<0.05). CONCLUSIONS: G-CSF achieved a significant
      neuroprotective effect in cell culture and after intravenous administration after
      stroke. Increased STAT3 expression in the penumbra of G-CSF-treated rats suggests
      mediation by G-CSFR.

PMID- 12624303
TI  - Aspirin inhibits p44/42 mitogen-activated protein kinase and is protective
      against hypoxia/reoxygenation neuronal damage.
AB  - BACKGROUND AND PURPOSE: Acetylsalicylic acid (ASA) is preventive against stroke
      and protects against focal brain ischemia in rats. We studied the mechanisms of
      the manner in which ASA provides neuroprotection against hypoxia/reoxygenation
      (H/R) injury. METHODS: Spinal cord cultures exposed to 20 hours of hypoxia
      followed by reoxygenation were treated with a vehicle, ASA or inhibitors of
      inducible nitric oxide synthase (iNOS), mitogen-activated protein kinases p38
      MAPK and ERK1/2, or an N-methyl-d-aspartic acid (NMDA) receptor antagonist. Cell
      viability was assessed by LDH release measurement and cell counts. Prostaglandin
      production was measured by enzyme immunoassay, MAPK signaling by immunoblotting,
      and DNA binding of nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP
      1) by electrophoretic mobility shift assay. RESULTS: One to 3 mmol/L ASA
      inhibited H/R-induced neuronal death when present during H/R but not when
      administered only for the reoxygenation period. Prostaglandin E2 production was
      very low and was not altered by ASA. The AP-1 and NF-kappaB DNA binding
      activities increased after H/R. ASA increased the H/R-induced AP-1 binding but
      had no effect on NF-kappaB binding. H/R induced a sustained ERK1/2 activation
      followed by neuronal death, whereas no changes in p38 or c-Jun N-terminal kinase
      were detected. ASA strongly inhibited this ERK1/2 activation. PD98059, an ERK1/2
      inhibitor, was also neuroprotective, prevented H/R-induced ERK1/2 activation, and
      had no effect on NF-kappaB binding activity. Inhibition of NMDA receptors, iNOS,
      or p38 MAPK did not provide neuroprotection. CONCLUSIONS: Inhibition of the
      sustained activation of ERK1/2 may partially contribute to neuroprotection
      achieved by ASA against H/R injury.

PMID- 12624304
TI  - Neuroprotective effect of SolCD39, a novel platelet aggregation inhibitor, on
      transient middle cerebral artery occlusion in rats.
AB  - BACKGROUND AND PURPOSE: SolCD39 is a soluble form of recombinant human ecto
      ATP/ADPase (NTPDase1) and represents a new class of antithrombotic agents.
      SolCD39 blocks and reverses platelet activation, preventing recruitment of
      additional platelets into a growing thrombus. The purpose of this study was to
      examine the effect of solCD39 on neurological deficit, infarct size, and extent
      of edema after transient middle cerebral artery occlusion (MCAO) in rats.
      METHODS: Physiologically controlled Sprague-Dawley rats underwent 2-hour MCAO by
      retrograde insertion of an intraluminal suture coated with poly-l-lysine. The
      agent (solCD39) was administered intravenously before MCAO or at 1-hour or 3-hour
      recirculation. Other groups received vehicle (Tris-buffered saline) or human
      albumin (as a "positive" neuroprotective control; 25%, 0.5% of body weight) at 1
      hour recirculation. Neurological status was evaluated during occlusion (at 60
      minutes) and daily for 3 days after MCAO. Brains were perfusion-fixed at 72
      hours, and infarct volumes and brain swelling were determined. RESULTS:
      Pretreatment with solCD39 significantly improved the neurological score at 72
      hours compared with the vehicle group (4.4+/-0.6 versus 7.6+/-0.6, respectively;
      P=0.008). Cortical infarct areas were significantly reduced at multiple levels by
      pretreatment with solCD39. Total striatal infarct area was also significantly
      reduced compared with vehicle by both solCD39 pretreatment (48% mean reduction)
      and solCD39 treatment at 3-hour recirculation (51% mean reduction). Treatment
      with SolCD39 significantly reduced total infarct volume (corrected for brain
      swelling) by an average of 71% to 72% when administered either before ischemia or
      at 3 hours of recirculation compared with vehicle. Treatment with albumin
      significantly reduced neurological score and total, cortical, and subcortical
      infarction at multiple levels, as expected. CONCLUSIONS: Treatment with SolCD39,
      administered either before or at 3 hours after MCAO, improves neurological score
      and reduces infarct size compared with vehicle. A pharmacological agent of this
      type appears to have potential for the treatment of focal ischemic stroke.

PMID- 12624305
TI  - Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein
      phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo
      studies.
AB  - BACKGROUND AND PURPOSE: Dipyridamole and in particular dipyridamole in
      combination with low-dose aspirin are very effective in preventing recurrent
      stroke. However, the mechanism(s) underlying this dipyridamole effect have not
      been elucidated. Since dipyridamole inhibits the cGMP-specific phosphodiesterase
      type V in vitro, we hypothesized and tested whether therapeutically relevant
      dipyridamole concentrations enhance NO/cGMP-mediated effects in intact human
      platelets studied ex vivo. METHODS: Phosphorylation of vasodilator-stimulated
      phosphoprotein (VASP), an established marker of NO/cGMP effects in human
      platelets, was quantified by phosphorylation-specific antibodies and Western
      blots. Serotonin secretion and thromboxane synthase activity were determined by
      fluorometric quantification of derivatized serotonin and synthase products,
      respectively. RESULTS: Endothelium-derived factors such as NO and prostaglandin
      I2 are known to elevate both cGMP and cAMP levels with concomitant platelet
      inhibition and VASP phosphorylation. In our in vitro experiments, therapeutically
      relevant concentrations (3.5 micromol/L) of dipyridamole amplified only cGMP
      mediated VASP phosphorylation due to the NO donor sodium nitroprusside, but not
      cAMP-mediated effects. Furthermore, thromboxane synthase activity and serotonin
      secretion, events important for initial platelet activation, were inhibited by
      sodium nitroprusside, an effect also enhanced by dipyridamole, demonstrating the
      functional relevance of these observations. Finally, the ex vivo enhancement of
      NO/cGMP effects was also observed with platelets obtained from healthy volunteers
      treated with extended-release dipyridamole. CONCLUSIONS: Under therapeutically
      relevant conditions, dipyridamole enhances platelet inhibition by amplifying the
      signaling of the NO donor sodium nitroprusside. These data support the concept
      that enhancement of endothelium-dependent NO/cGMP-mediated signaling may be an
      important in vivo component of dipyridamole action.

PMID- 12624306
TI  - Administration of melatonin after onset of ischemia reduces the volume of
      cerebral infarction in a rat middle cerebral artery occlusion stroke model.
AB  - BACKGROUND AND PURPOSE: In both permanent and transient 3-hour middle cerebral
      artery occlusion rat stroke models, a single intraperitoneal injection of
      melatonin at 5 or 15 mg/kg given before ischemia was shown to reduce infarct
      volume at 72 hours. The present study was conducted to examine the treatment time
      window when melatonin was commenced after onset of ischemia. METHODS: Adult male
      Sprague-Dawley rats were anesthetized to undergo right-sided middle cerebral
      artery occlusion for 3 hours. A single intraperitoneal injection of vehicle or
      melatonin at 5 mg/kg was given at 0, 1, or 3 hours after onset of ischemia. Other
      groups received multiple injections of vehicle or melatonin at 5 mg/kg with the
      first injection given at 1, 2, or 3 hours after onset of ischemia and the second
      and third injections at 24 and 48 hours, respectively. Multiple injections of
      melatonin at 15 mg/kg with the first injection given at 3 hours were also made.
      The infarct volume was determined at 72 hours. RESULTS: A single dose of
      melatonin at 5 mg/kg given at 0 or 1 but not 3 hours after onset of ischemia
      reduced the infarct volume. Multiple doses of melatonin at 5 mg/kg also reduced
      the infarct volume when the first dose was given at 1 or 2 but not 3 hours after
      onset. Significant hemodynamic effects were not observed. CONCLUSIONS: Our
      results indicate that melatonin at 5 mg/kg given as a single injection or
      multiple injections protects against focal cerebral ischemia when commenced
      within 2 hours of onset.

PMID- 12624307
TI  - Selective neuromicrovascular endothelial cell death by 8-Iso-prostaglandin
      F2alpha: possible role in ischemic brain injury.
AB  - BACKGROUND AND PURPOSE: Free radical-induced peroxidation is an important factor
      in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm
      infant. Isoprostanes are major peroxidation products. Since microvascular
      dysfunction seems to contribute to ischemic encephalopathies, we studied the
      cytotoxicity of 8-iso-prostaglandin F2alpha (PGF2alpha) on cerebral microvascular
      cells. METHODS: Microvascular endothelial, astroglial, and smooth muscle cells
      from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2alpha on these
      cells was determined by MTT assays and lactate dehydrogenase (LDH) release,
      propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl
      transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of
      intraventricular injections of 8-iso-PGF2alpha and possible involvement of
      thromboxane in 8-iso-PGF2alpha-induced cytotoxicity were determined. RESULTS: 8
      Iso-PGF2alpha induced time- and concentration-dependent endothelial cell death
      (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial
      cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide
      incorporation and LDH release). Cell death was associated with increased
      endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase
      inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused
      endothelial cell death. Intraventricular injection of 8-iso-PGF2alpha induced
      periventricular damage, which was attenuated by CGS12970 pretreatment.
      CONCLUSIONS: These data disclose a novel action of 8-iso-PGF2alpha involving TXA2
      in oxidant stress-induced cerebral microvascular injury and brain damage.

PMID- 12624308
TI  - Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic
      telangiectasia.
AB  - BACKGROUND AND PURPOSE: Hereditary hemorrhagic telangiectasia type 1 (HHT1) is an
      autosomal dominant vascular dysplasia caused by mutations in the endoglin gene
      and characterized by dilated vessels and arteriovenous malformations (AVMs). To
      understand the etiology of this disorder, we evaluated the cerebral vasculature
      of endoglin heterozygous (Eng+/-) mice, which represent the only animal model of
      HHT1. METHODS: The cerebral vasculature of Eng+/- and Eng+/+ mice from C57BL/6
      (B6) and 129/Ola (129) strains with a differential susceptibility to HHT1 was
      studied with corrosion casting. Casts were observed by scanning electron
      microscopy to detect malformations and evaluate arterial diameters and
      orientation of endothelial nuclei. Measurements were taken to assess relative
      constriction at arteriolar branching points and downstream relative dilatation.
      RESULTS: Three of 10 Eng+/- mice demonstrated abnormal vascular findings
      including AVMs, while none of 15 Eng+/+ mice did. The incidence of relative
      constriction at arteriolar branching points was significantly less in both Eng+/-
      groups than in their Eng+/+ counterparts. The occurrence of relative dilatation
      was significantly greater in B6-Eng+/- than in B6-Eng+/+ mice. Endothelial nuclei
      were significantly rounder and deviated more from the direction of blood flow in
      Eng+/- than in Eng+/+ mice. CONCLUSIONS: Eng+/- mice showed significant
      structural alterations in cerebral blood vessels, indicating that the level of
      endoglin on endothelium is critical for maintenance of normal vasculature. Since
      endoglin haploinsufficiency is associated with HHT1, such changes in arteriolar
      structures might occur in HHT1 patients and predispose them to AVMs and their
      sequelae.

PMID- 12624309
TI  - Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis.
AB  - BACKGROUND AND PURPOSE: Inflammation plays an important role in the development
      of atherosclerosis. The gene for the counterinflammatory cytokine interleukin-1
      receptor antagonist (IL-1ra) is polymorphic, and high frequencies of allele 2
      have been found to be associated with other inflammatory diseases. This study
      examined the association of allele and carrier frequencies of the IL-1ra gene
      with the presence of carotid atherosclerosis and plaque symptomaticity. METHODS:
      A total of 328 subjects identified as having carotid atherosclerosis or no
      atherosclerosis (controls) participated. Blood was obtained for DNA
      determination. RESULTS: Frequency of allele 2 was significantly greater in
      patients with atherosclerosis compared with nonatherosclerotic subjects. No
      difference was seen between symptomatic and asymptomatic atherosclerosis
      patients. Noncarriage of allele 2 was associated with reduced likelihood of
      atherosclerosis (odds ratio [OR], 0.44; 95% CI, 0.27 to 0.71). The homozygous
      carrier state for allele 2 was associated with greater likelihood of
      atherosclerosis (unadjusted OR, 7.30; 95% CI, 2.31 to 22.94; adjusted OR, 13.78;
      95% CI, 1.94 to 97.9). A gene-dose effect was detected. CONCLUSIONS: These data
      suggest that allele 2 of the IL-1ra gene represents a susceptibility factor in
      the development of carotid atherosclerosis. Further investigation appears
      warranted.

PMID- 12624310
TI  - Midazolam challenge reinduces neurological deficits after transient ischemic
      attack.
AB  - BACKGROUND AND PURPOSE: A transient ischemic attack (TIA) in the brain is
      classically considered a syndrome lasting <24 hours. Having previously shown that
      an experimental challenge with the GABAA agonist midazolam in recovered stroke
      patients can reinduce the acute clinical state, we determined whether TIA
      patients would demonstrate a similar effect. METHODS: Four right-handed patients
      participated: 3 with clinical TIA presumed to have affected the left hemisphere
      within the previous 24 to 72 hours and no evidence of a new lesion on diffusion
      weighted and fluid-attenuated inversion recovery imaging, and 1 patient with an
      asymptomatic temporal arteriovenous malformation. The TIA duration ranged from 30
      minutes to 3 hours. Each patient underwent baseline testing for motor function
      and aphasia, after which intravenous midazolam was delivered until mild
      drowsiness was detected. Patients were tested during the peak drug effect and
      again after 2 hours when sedation had dissipated. RESULTS: No patient showed
      weakness or aphasia at baseline. After administration of midazolam, all 3 TIA
      patients demonstrated re-emergence of features that characterized their recent
      transient neurological syndromes (right-sided weakness and/or aphasia) but no
      left-sided findings. The arteriovenous malformation patient who had never been
      symptomatic showed no drug effect. Two hours later, all TIA patients returned to
      their normal clinical state. CONCLUSIONS: Patients who had suffered recent
      transient cerebral ischemic episodes and were neurologically intact with negative
      diffusion-weighted imaging showed re-emergence of prior focal deficits after
      administration of a benzodiazepine in a dose that produces light sedation. These
      findings suggest that presumed TIA may produce neuronal dysfunction beyond the
      symptomatic period.

PMID- 12624311
TI  - Serial FLAIR imaging after Gd-DTPA contrast: pitfalls in stroke trial magnetic
      resonance imaging.
AB  - BACKGROUND: Most MRI protocols for stroke trials comprise 2 successive fluid
      attenuated inversion-recovery (FLAIR) imaging acquisitions in which the first
      scan is done pre-Gd-DTPA contrast while the second is within the contrast
      clearance window. SUMMARY OF REPORT: A 68-year-old male was diagnosed as having
      hyperacute right middle cerebral artery infarct and a subacute chronic small left
      occipital cortical infarct. The latter turned from hypointense to strikingly
      hyperintense on the second FLAIR image, resembling the picture of an acute-on
      chronic infarction or hemorrhage. However, the second DWI and CT refuted either
      of these. CONCLUSIONS: Image contrast using FLAIR in acute stroke trial imaging
      may also be affected by T1 effects of Gd-DTPA in chronic infarcts.

PMID- 12624312
TI  - Quality improvement and tissue-type plasminogen activator for acute ischemic
      stroke: a Cleveland update.
AB  - BACKGROUND AND PURPOSE: A systematic audit of intravenous tissue-type plasminogen
      activator (tPA) use and stroke outcomes in Cleveland, Ohio, during 1997-1998
      demonstrated higher rates of symptomatic intracranial hemorrhage (ICH) than
      reported in the National Institute of Neurological Disorders and Stroke (NINDS)
      trial. We now report updated results of intravenous tPA use in the Cleveland
      Clinic Health System (CCHS). METHODS: A stroke quality improvement program was
      initiated in the 9-hospital CCHS in 1999. A retrospective chart review for all
      stroke patients with primary International Classification of Diseases, Ninth
      Revision, Clinical Modification diagnosis codes 434 and 436 admitted to the 9
      hospitals from June 1999 to June 2000 was used to determine outcomes of patients
      treated with intravenous tPA. RESULTS: Intravenous tPA was given to 18.8% of
      patients arriving within 3 hours of symptom onset. Protocol deviations occurred
      in 19.1% of patients given intravenous tPA. The symptomatic ICH rate was 6.4%.
      CONCLUSIONS: Since 1997, intravenous tPA use has increased, while the rates of
      symptomatic ICH and protocol deviations have decreased in the CCHS. The CCHS
      symptomatic ICH rate is now similar to that reported in the NINDS trial. These
      improvements occurred after initiation of a stroke quality improvement program.

PMID- 12624313
TI  - Quality of life during and after inpatient stroke rehabilitation.
AB  - BACKGROUND AND PURPOSE: Very limited longitudinal data are available that assess
      the health-related quality of life (HRQOL) of stroke survivors after discharge
      from inpatient rehabilitation. The purpose of this research was to assess changes
      in HRQOL during inpatient rehabilitation and again 6 months after discharge.
      METHODS: This was a prospective study of all eligible patients admitted to an
      inpatient stroke rehabilitation hospital over a 3-year period. HRQOL was assessed
      by means of the Medical Outcomes Study 36-item Short Form (SF-36). Dependent t
      tests were used to compare the scores at admission and discharge and at discharge
      and 6 months. Changes in HRQOL were calculated for the period of admission to
      discharge and of discharge to the 6-month follow-up. RESULTS: Complete data were
      available for 85 patients. During rehabilitation, there were improvements in all
      8 domains of the SF-36, with 5 attaining statistical significance. After
      discharge, 3 domains continued to improve, with 1 attaining statistical
      significance. However, there were marked and statistically significant declines
      in the other 5 domains of the SF-36. Feedback was obtained from a subset of the
      patients as to the reasons for these declines. CONCLUSIONS: Substantial gains in
      HRQOL during inpatient stroke rehabilitation may be followed by equally
      substantial declines in the 6 months after discharge. There is a need for
      longitudinal research into the HRQOL of stroke survivors and their families, as
      well as a need to ensure that adequate community services and support are
      available.

PMID- 12624314
TI  - Is breakdown of the blood-brain barrier responsible for lacunar stroke,
      leukoaraiosis, and dementia?
AB  - BACKGROUND: The pathogenesis of and relationship between small deep (lacunar)
      infarcts, cerebral white matter disease (leukoaraiosis or white matter
      hyperintensities), and progressive cognitive impairment or dementia are much
      debated. SUMMARY OF COMMENT: We hypothesize that cerebral small-vessel
      endothelial (ie, blood-brain barrier) dysfunction, with leakage of plasma
      components into the vessel wall and surrounding brain tissue leading to neuronal
      damage, may contribute to the development of 3 overlapping and disabling
      cerebrovascular conditions: lacunar stroke, leukoaraiosis, and dementia. This
      hypothesis could explain the link between ischemic cerebral small-vessel disease
      and several apparently clinically distinct dementia syndromes. This hypothesis is
      supported by pathological, epidemiological, and experimental studies in lacunar
      stroke and leukoaraiosis and observations on the blood-brain barrier with MRI. We
      suspect that the potential significance of blood-brain barrier failure as a
      pathogenetic step linking vascular disease with common, disabling brain diseases
      of insidious onset has been overlooked. For example, lipohyalinosis, which has a
      pathological appearance of uncertain origin and is possibly responsible for some
      discrete lacunar infarcts, may be one end of a clinical spectrum of illness
      manifested by blood-brain barrier failure. CONCLUSIONS: Proof that blood-brain
      barrier failure is key to these conditions could provide a target for new
      treatments to reduce the effects of vascular disease on the brain and prevent
      cognitive decline and dementia.

PMID- 12624315
TI  - Early outcome of carotid angioplasty and stenting with and without cerebral
      protection devices: a systematic review of the literature.
AB  - BACKGROUND: Carotid angioplasty and stenting (CAS) is increasingly being used for
      treatment of symptomatic and asymptomatic carotid artery disease (CAD). To
      evaluate the efficacy of cerebral protection devices in preventing thromboembolic
      complications during CAS, we conducted a systematic review of studies reporting
      on the incidence of minor stroke, major stroke, or death within 30 days after
      CAS. SUMMARY OF REVIEW: We searched for studies published between January 1990
      and June 2002 by means of a PubMed search and a cumulative review of reference
      lists of all relevant publications. In 2357 patients a total of 2537 CAS
      procedures had been performed without protection devices, and in 839 patients 896
      CAS procedures had been performed with protection devices. Both groups were
      similar with respect to age, sex distribution, cerebrovascular risk factors, and
      indications for CAS. In many studies the periprocedural complication rates had
      not been presented separately for patients with symptomatic and asymptomatic CAD.
      The combined stroke and death rate within 30 days in both symptomatic and
      asymptomatic patients was 1.8% in patients treated with cerebral protection
      devices compared with 5.5% in patients treated without cerebral protection
      devices (chi2=19.7, P<0.001). This effect was mainly due to a decrease in the
      occurrence of minor strokes (3.7% without cerebral protection versus 0.5% with
      cerebral protection; chi2=22.4, P<0.001) and major strokes (1.1% without cerebral
      protection versus 0.3% with cerebral protection; chi2=4.3, P<0.05), whereas death
      rates were almost identical (approximately 0.8%; chi2=0.3, P=0.6). CONCLUSIONS:
      On the basis of this early analysis of single-center studies, the use of cerebral
      protection devices appears to reduce thromboembolic complications during CAS.
      These technical aspects should be taken into account before the initiation of
      further randomized trials comparing CAS with carotid endarterectomy.